PMID- 29105563 TI - Challenges related to migration and child attachment: A pilot study with South Asian immigrant mother-child dyads. AB - This pilot study examined psychological, social and cultural risk factors for child insecure attachment in a sample of South Asian immigrant families experiencing high migration stress in Montreal, Canada. Thirty-three participants were recruited through a local Health and Social Service organization. Maternal anxiety and depression, social support, and national and religious sense of belonging were assessed. Child attachment behaviors were coded from a 15 min free play period. Results indicated that maternal depressive symptoms were related to lower child attachment security scores. Lower support from friends was related to greater child ambivalent attachment behaviors. A higher sense of belonging to the country of origin was related to greater child disorganized attachment behaviors. These findings suggest that migration stresses, which include maternal depression, lack of social support and the sense of belonging, are associated with child attachment, and these variables should be considered in the design of appropriate interventions. PMID- 29105564 TI - Assessment of cognitive function in patients with stress-related exhaustion using the Cognitive Assessment Battery (CAB). AB - INTRODUCTION: The health care system is facing an increased number of patients seeking care for burnout/stress-related exhaustion. One of the core features of this condition is cognitive impairment-effective and easy tools are needed to assess cognition in this patient group. Our objective was to determine whether the Cognitive Assessment Battery (CAB) could be used for this purpose. METHOD: Ninety-three patients diagnosed with exhaustion disorder (ED) and 111 controls were included in the study and tested with CAB. CAB consists of six short tests covering the cognitive domains speed and attention, episodic memory, visuospatial, language, and executive functions. The patients also completed questionnaires on subjective memory problems, degree of burnout, anxiety, and depression. RESULTS: The patients performed worse than the controls on four tests of speed and attention, language, and executive function. Subjective memory problems, degree of burnout, and anxiety did not influence cognitive performance, only degree of depression influenced performance negatively on an executive test. CONCLUSION: CAB is a useful instrument for rapid, comprehensive screening of cognitive status in patients with stress-related exhaustion. Using it, we confirmed the most replicated findings regarding cognitive impairments in patients with stress-related exhaustion. PMID- 29105562 TI - Reduced Retinoblastoma Protein Expression Is Associated with Decreased Patient Survival in Medullary Thyroid Cancer. AB - BACKGROUND: The retinoblastoma (RB) transcriptional corepressor 1 protein functions to slow cell-cycle progression. Inactivation of RB by reduced expression and/or hyperphosphorylation allow for enhanced progression through the cell cycle. Murine models develop medullary thyroid carcinoma (MTC) after generalized loss of RB. However, RB expression in MTC has only been evaluated in a small number of tumors, with differing results. The objective of this study was to determine whether reduced expression of RB and/or overexpression of hyperphosphorylated RB predict MTC aggressive behavior. METHODS: Formalin-fixed, paraffin-embedded primary thyroid tumors and lymph node metastases from MTC patients were evaluated for calcitonin, RB, and phosphorylated RB (pRB) expression by immunohistochemistry. Two expert pathologists evaluated the slides in a blinded manner, and the immunohistochemistry results were compared to disease-specific survival as a primary endpoint. RESULTS: Seventy-four MTC samples from 56 patients were analyzed in this study, including 51 primary tumors and 23 lymph node metastases. The median follow-up time was 6.75 years after surgery (range 0.64-24.30 years), and the median primary tumor size was 30 mm (range 6-96 mm). Sixty-six percent of cases were classified as stage IV. RB nuclear expression was diffusely present in 88% of primary tumors and 78% of lymph node metastases. Nuclear pRB expression was present in 22% of primary tumors and 22% of lymph node metastases. On univariate analysis, reduced RB (<75% tumor cell staining) trended with lower MTC-specific survival for primary tumor and metastatic nodes (primary tumor hazard ratio = 3.54 [confidence interval 0.81 15.47], p = 0.08; and lymph node hazard ratio = 4.35 [confidence interval 0.87 21.83], p = 0.05). For primary tumors, multivariable analysis showed that low nuclear RB expression was independently associated with worse disease-specific (p = 0.01) and overall (p = 0.02) survival. pRB levels were not associated with survival for either primary tumor or lymph node metastases. CONCLUSIONS: Reduced RB expression is associated with decreased patient survival in univariate and multivariable analyses, independent from patient age at surgery or advanced TNM stage. Future studies involving larger MTC patient populations are warranted to determine if lower RB expression levels may serve as a biomarker for aggressive disease in patients with MTC. PMID- 29105565 TI - Validation of 2 point-of-care meters for measuring triglycerides in chickens using whole blood and plasma. AB - Disorders of the avian reproductive tract are common, yet monitoring their resolution presents a diagnostic dilemma. Reproductive hormones such as luteinizing hormone or estrogen are the best reflection of reproductive status, but the required sample volumes and lack of reference intervals limit their clinical utility. An alternative analyte is blood triglyceride, the concentration of which rises markedly during sustained estrogen release from the ovary. Portable meters for measuring human blood triglyceride concentration offer the advantage of using minimal sample volumes, but these have not been validated for use in birds. We assessed the precision and accuracy of 2 portable meters for measuring blood triglyceride concentration in pooled whole blood and plasma from chickens ( n = 42), and performed method comparison using a reference analyzer and determined total error. Within-run repeatability was fair-to-excellent using whole blood and plasma (range: 2.5-11.5%), and between-run repeatability using plasma was similar (3.1-12.2%). The meters performed well in recovery and dilution studies in which almost all readings fell within the preset requirement of 75-125%. Correlations between each meter, using whole blood and plasma, and the reference analyzer, using plasma only, were high to very high (0.86-0.98). Bias determined by Bland-Altman analysis was similar between whole blood and plasma for each meter, yet markedly different between the meters. The calculated total observed error was consequently within our pre-set total allowable error of 25% for one meter but not the other, indicating the requirement for a meter specific reference interval. PMID- 29105566 TI - Insights into the applicability of microbial fuel cells in wastewater treatment plants for a sustainable generation of electricity. AB - Microbial fuel cells (MFCs) are often discussed as a part of a sustainable generation of electricity for the coming 'energy revolution'. In particular, the application of MFCs in wastewater treatment plants (WWTPs) are often regarded as an attractive alternative to reduce costs while generating electricity. Field surveys are necessary to show the applicability of MFCs in WWTPs considering daily fluctuations and environmental effects such as rain events affecting the MFC performance remarkably. In this study, a MFC system was tested in four municipal WWTPs using different modes of operation. A correlation between current densities and sludge loading (SL) was identified. At low SLs, the activated sludge needs a large amount of the energy derived from the substrate for the maintenance metabolism resulting in quite low current densities of the MFC. At high SLs much more of the energy can be transferred from the activated sludge to the electrode, resulting in higher currents. Furthermore, the effect of environmental conditions on the current densities was evaluated. WWTPs have daily fluctuations depending on the wastewater composition, weather phenomena and population equivalents. Our data show that these daily fluctuations can only be observed in the MFC performance at WWTPs below 50,000 population equivalents. PMID- 29105567 TI - In Vivo Survival of Human Endometrial Mesenchymal Stem Cells Transplanted Under the Kidney Capsule of Immunocompromised Mice. AB - Human endometrial mesenchymal stem cells (eMSCs) are a well-characterized adult stem cell type with potential for use in regenerative medicine or cell therapy. As a proof of principle, we demonstrated that eMSCs promoted wound healing by reducing the inflammatory response through a paracrine action in a subcutaneous rat model of wound repair. However, an efficient protocol for culturing eMSCs in the undifferentiated state and a reliable method of labeling them for cell tracking were lacking. In this study, we investigated the use of a lentiviral vector containing the mCherry fluorescent reporter gene to transduce and label eMSCs following in vitro culturing in A83-01 containing medium, and different methods of tracing the labeled cells following transplantation under the kidney capsule of immunocompromised NSG mice. Perivascular SUSD2+ eMSCs were isolated from human endometrium. Passage 1 eMSCs were transduced by lentiviruses with mCherry fluorescent reporter gene; mCherry+ cells were isolated by fluorescence activated cell sorting and cultured until passage 6 in 5% O2 in serum-free medium with fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF). The cells were subsequently divided into two flasks and treated with either dimethyl sulfoxide (0.01%) or A83-01 (1 MUM) for 7 days. 5 * 105 control or A83-01 pretreated cells were encapsulated into a fibrin gel and transplanted under the subrenal capsules of NSG mice. Tissues were analyzed at 7, 14, and 30 days posttransplantation. Human eMSCs were efficiently transduced with mCherry gene. They proliferated and maintained high mCherry expression over five passages. Analyzing transplanted kidneys using polymerase chain reaction, flow cytometry, and immunofluorescence showed that both cell types survived at least 30 days. Efficient labeling of eMSCs using a lentiviral vector and culturing them in an environment maintaining them in an undifferentiated state enable reliable detection in preclinical animal models and highlight the need for generating a pure population of undifferentiated MSCs for long-term survival in vivo to prolong their treatment effect. PMID- 29105568 TI - The mechanical response of a polyetheretherketone femoral knee implant under a deep squatting loading condition. AB - The current study was designed to investigate the mechanical response of a polyetheretherketone-on-polyethylene total knee replacement device during a deep squat. Application of this high-demand loading condition can identify weaknesses of the polyetheretherketone relative to cobalt-chromium. This study investigated whether the implant is strong enough for this type of loading, whether cement stresses are considerably changed and whether a polyetheretherketone femoral component is likely to lead to reduced periprosthetic bone loss as compared to a cobalt-chromium component. A finite element model of a total knee arthroplasty subjected to a deep squat loading condition, which was previously published, was adapted with an alternative total knee arthroplasty design made of either polyetheretherketone or cobalt-chromium. The maximum tensile and compressive stresses within the implant and cement mantle were analysed against their yield and fatigue stress levels. The amount of stress shielding within the bone was compared between the polyetheretherketone and cobalt-chromium cases. Relative to its material strength, tensile peak stresses were higher in the cobalt-chromium implant; compressive peak stresses were higher in the polyetheretherketone implant. The stress patterns differed substantially between polyetheretherketone and cobalt-chromium. The tensile stresses in the cement mantle supporting the polyetheretherketone implant were up to 33% lower than with the cobalt-chromium component, but twice as high for compression. Stress shielding was reduced to a median of 1% for the polyetheretherketone implant versus 56% for the cobalt chromium implant. Both the polyetheretherketone implant and the underlying cement mantle should be able to cope with the stress levels present during a deep squat. Relative to the cobalt-chromium component, stress shielding of the periprosthetic femur was substantially less with a polyetheretherketone femoral component. PMID- 29105569 TI - Developing Equitable Primary Health Care in Conflict-Affected Settings: Expert Perspectives From the Frontlines. AB - Health systems are frequently among the casualties of conflict. Within these settings, increased knowledge is needed on how to rebuild and strengthen health infrastructure resilience, such as primary health care (PHC) systems, in context specific ways that promote health equity. Therefore, this study aimed to explore perspectives of experts with experience working on frontlines of social crises to contribute to understandings of pathways toward equitable PHC in conflict affected settings. Semistructured qualitative interviews with 18 expert participants were completed. Through engaging elements of grounded theory situational analysis, three themes emerged iteratively, including (a) Building Blocks, (b) Intermediating Factors, and (c) a Roadmap. These emergent themes contribute to conceptual frameworks explaining key contextually specific priorities, challenges, and facilitating factors for developing resilient health infrastructures under social crises. Findings inform policy and practical guidelines that address complexities of conflict conditions and underscore the importance of PHC development toward promoting health as a human right. PMID- 29105570 TI - Molecular survey of infectious agents associated with bovine respiratory disease in a beef cattle feedlot in southern Brazil. AB - We investigated the occurrence of infectious pathogens during an outbreak of bovine respiratory disease (BRD) in a beef cattle feedlot in southern Brazil that has a high risk of developing BRD. Nasopharyngeal swabs were randomly collected from steers ( n = 23) and assessed for the presence of infectious agents of BRD by PCR and/or RT-PCR assays. These included: Histophilus somni, Mannheimia haemolytica, Pasteurella multocida, Mycoplasma bovis, bovine respiratory syncytial virus (BRSV), bovine coronavirus (BCoV), bovine viral diarrhea virus (BVDV), bovine alphaherpesvirus 1 (BoHV-1), and bovine parainfluenza virus 3 (BPIV-3). Pulmonary sections of one steer that died with clinical BRD were submitted for pathology and molecular testing. The frequencies of the pathogens identified from the nasopharyngeal swabs were: H. somni 39% (9 of 23), BRSV 35% (8 of 23), BCoV 22% (5 of 23), and M. haemolytica 13% (3 of 23). PCR or RT-PCR assays did not identify P. multocida, M. bovis, BoHV-1, BVDV, or BPIV-3 from the nasopharyngeal swabs. Single and concomitant associations of infectious agents of BRD were identified. Fibrinous bronchopneumonia was diagnosed in one steer that died; samples were positive for H. somni and M. haemolytica by PCR. H. somni, BRSV, and BCoV are important disease pathogens of BRD in feedlot cattle in Brazil, but H. somni and BCoV are probably under-reported. PMID- 29105571 TI - Accuracy of PCR targeting different markers for Staphylococcus aureus identification: a comparative study using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as the gold standard. AB - Staphylococcus aureus is considered a major pathogen in veterinary and human medicine, and the emergence of multidrug-resistant strains, such as livestock associated methicillin-resistant S. aureus, means that reliable, inexpensive, and fast methods are required to identify S. aureus obtained from animal sources. We tested the accuracy of a PCR targeting the genes femA, nuc, and coa in identifying S. aureus from animals. A total of 157 Staphylococcus spp. isolates were examined by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry; 18 different Staphylococcus species were identified. Of 68 S. aureus isolates, the genes femA, nuc, and coa were found in 61, 53, and 32 isolates, respectively. Considering MALDI-TOF as the gold standard, the PCR assays targeting all 3 genes showed 100% specificity; the sensitivity values were 89.7, 77.9, and 47.0% for femA, nuc, and coa, respectively. Sensitivity was 100% when femA and nuc markers were targeted simultaneously. These results confirm PCR as an accurate method to identify S. aureus species from animal sources and strongly suggest the simultaneous use of primers targeting femA and nuc genes. PMID- 29105572 TI - Mild adverse childhood experiences increase neural efficacy during affective theory of mind. AB - Adverse childhood experiences (ACEs) affect the development of social cognition (and identify a risk factor for several physical and mental disorders). Theory of Mind (ToM) is a key predictor of social functioning, mental health, and quality of life. No previous study explored the effect of mild ACEs on the neural correlates of ToM in healthy humans. In 23 healthy participants, we used brain blood oxygen level-dependent fMRI to study the effect of ACEs on the neural responses to tasks targeting affective and cognitive ToM. Results pointed out an association between ACEs and a lower neural response in the vermis of the cerebellum (r = -.85), precentral gyrus, and inferior frontal operculum (putative Mirror Neural System, r = -.78) during affective ToM. A lower recruitment of these brain regions, paralleled by the same performance, could express an increased neural efficacy in inferring affective mental states driven by previous experience, in this case, ACEs. PMID- 29105573 TI - Comparison of CTA and DSA in the diagnosis of superior mesenteric artery dissecting aneurysm. AB - Objective To compare computed tomography arteriography (CTA) and digital subtraction arteriography (DSA) in the diagnosis of superior mesenteric artery dissecting aneurysm (SMADA). Methods All SMADA patients who underwent CTA and DSA at one of two medical centers between May, 2007 and April, 2017 were identified. The accuracy of CTA and DSA for the depiction of morphologic characteristics of SMADA was analyzed. Results Fourteen patients (12 men; mean age, 55.1 +/- 6.4 years) were included in this study. The mean diameter of the dissecting aneurysm was 3.78 +/- 1.53 mm on CTA and 3.81 +/- 1.54 mm on DSA ( p = 0.96). The luminal stenosis was 0.52 +/- 0.27 on CTA and 0.35 +/- 0.23 on DSA ( p = 0.09). The thrombosed false lumen was visualized on CTA in 79% (11/14) of patients but in no patients on DSA ( p < 0.001). The entry points of the dissection were visualized on CTA in 64.3% (9/14) of patients and on DSA in 100% (14/14) of patients ( p = 0.041); CTA and DSA did not visualize re-entry points in any patients. The intimal flap was visualized on CTA in 71.4% (10/14) of patients and on DSA in 78.6% (11/14) of patients ( p > 0.05). Branch vessel involvement was visualized in 7.1% (1/14) of patients on CTA but in no patients on DSA ( p > 0.05). Conclusions CTA can be used in place of DSA for the diagnosis of SMADA. Although CTA may exaggerate the degree of luminal stenosis and is weak in depicting the entry points of SMADA, this modality more accurately depicts the thrombosed false lumen and branch vessel involvement. PMID- 29105574 TI - Disagreement in Estimates of Kidney Function for Drug Dosing in Obese Inpatients. AB - BACKGROUND: The Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are used to estimate kidney function. However, utility has been questioned in the obese population. OBJECTIVE: To evaluate differences in estimates of kidney function in obese patients and implications for drug dosing. METHODS: This was a retrospective study of adult inpatients with a body mass index >=30 kg/m2 and stable kidney function. Patients were categorized based on creatinine clearance (CrCl): group 1-CrCl >= 60 mL/min and group 2-CrCl 15 to 59 mL/min. Mean estimates of kidney function and recommended doses of 8 renally eliminated medications were compared. RESULTS: For the 166 patients included, mean estimates using CG, MDRD, and CKD-EPI for group 1 were 87 (23) mL/min, 91 (21) mL/min, and 96 (23) mL/min, respectively. Group 2 estimates were 42 (13) mL/min, 51 (15) mL/min, and 51 (16) mL/min, respectively. MDRD and CKD-EPI estimates were significantly higher than CG in 125 (75%) and 140 (84%) patients, respectively. Dose discrepancies were most often due to higher dose recommendations using MDRD or CKD-EPI compared to CG. CONCLUSION: Careful consideration of the method used to estimate kidney function, the method used for developing dosing recommendations, and the risk-benefit profile is warranted when designing drug regimens in obese individuals. PMID- 29105575 TI - Pharmacy Students and Pharmacy Technicians in Medication Reconciliation: A Review of the Current Literature. AB - OBJECTIVE: A literature review was conducted to examine how pharmacy students and technicians have been utilized in medication reconciliation processes in an effort to evaluate expanded roles for pharmacy students and technicians. Data were summarized on accuracy of obtaining medication histories, time requirements, discrepancy identification, and cost savings. Limitations and areas for future research also were identified. DATA SOURCES: A search of PubMed, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and PsycINFO and a manual searching of bibliographies were performed. STUDY SELECTION: Articles were included in this literature review if they focused on medication reconciliation with pharmacy student or technician outcomes independent of pharmacist involvement, they are available in English from any country, and the outcomes were empirical. DATA SYNTHESIS: Of 2112 identified studies, 32 met the inclusion criteria. The literature review revealed pharmacy technicians or students were involved in several medication reconciliation activities. Trained pharmacy students and technicians were able to obtain thorough medication histories as well as identify medication history discrepancies and take appropriate action to correct these discrepancies. Through the use of pharmacy students and technicians in the medication reconciliation process, hospitals experienced cost savings and other health-care professionals had more time for other patient care activities as well as an increased trust in the accuracy of medication histories. CONCLUSION: These findings suggest that pharmacy students and technicians are accurate, time efficient, decrease costs, and provide support to other health-care professionals when they are included in the medication reconciliation process. PMID- 29105576 TI - Clinical signs of hypoxaemia in children aged 2 months to 5 years with acute respiratory distress in Switzerland and Senegal. AB - BACKGROUND: Hypoxaemia is a predictor of pneumonia-related mortality. WHO published recommendations for oxygen therapy based on clinical signs which state that, when oxygen is plentiful, it should be given to children with central cyanosis, inability to drink, severe chest indrawing, RR >70 breaths/min, grunting with every breath (in young infants) or those who display head nodding. These guidelines, however, are based on a few studies only. AIM: To assess the accuracy of combinations of clinical signs which predict hypoxaemia in pre-school children aged 2 months to 5 years with acute respiratory distress in hospitals in Switzerland and Senegal. METHODS: This observational study was conducted in four emergency units, two in Switzerland and two in Senegal. Patients aged 2 months to 5 years with acute respiratory distress were eligible for inclusion. Clinical signs were compared with transcutaneous blood saturation levels (SaO2). RESULTS: About 111 children were assessed, 67 in Switzerland and 44 in Senegal. The prevalence of hypoxaemia was 13%. Twelve models of combined symptoms were analysed. The WHO model, for when oxygen supply is ample, had the highest diagnostic performance with a sensitivity of 0.93 and a specificity of 0.60. CONCLUSIONS: Clinical signs alone are unreliable for the detection of hypoxaemia. The current WHO model, for ample oxygen supply proved to be the best clinical predictor, although a great number of non-hypoxaemic children were unnecessarily treated because of the low specificity of this model. PMID- 29105577 TI - Comparative assessment of patient outcomes with intraluminal or subintimal crossing of infrainguinal peripheral artery chronic total occlusions. AB - This study compares procedural complications and clinical outcomes between subintimal crossing versus intraluminal crossing during endovascular treatment of infrainguinal peripheral artery chronic total occlusions (CTO). We identified 1335 CTO interventions in 1001 patients from the multicenter Excellence in Peripheral Artery Disease (XLPAD) registry from January 2005 to October 2015. Outcomes included 30-day and 12-month all-cause death, non-fatal myocardial infarction or stroke, peripheral artery stent, or vessel, thrombosis (ST), need for any target limb endovascular or surgical revascularization, target limb major amputation and procedural complications. A subintimal crossing technique was necessary in 388 lesions (27% overall in 1335 lesions; 34% ( n=351) in 1023 femoropopliteal lesions, and 12% ( n=37) in 312 infrapopliteal lesions, p<0.01) with a lower procedural ( p<0.01) and technical ( p<0.01) success than the intraluminal in both femoropopliteal and infrapopliteal interventions. There were no significant differences in procedural complications, major adverse cardiac events, or clinically driven target limb revascularization at 1 year between the two groups, except a higher residual dissection rate in the subintimal crossing group than the intraluminal group in femoropopliteal target vessels ( p = 0.04). PMID- 29105579 TI - Bone and Joint Medical Devices: Methods, Models, and Regulations. AB - Repair of bone and joint tissue to restore normal function is a unique endeavor that requires recreating tissue structure and the integrated healing of both organic and inorganic tissue components. Session 5 (Structural approaches to bone and joint repair) at the 36th annual Society of Toxicologic Pathology Annual Symposium included 2 talks covering methods, models, and regulatory considerations used to evaluate novel approaches for repairing bones and joints. Lyn Wancket provided a general overview of medical devices, with an emphasis on preclinical and clinical evaluations of bone and joint devices. Karen Manhart outlined regulatory review of medical devices by the Food and Drug Administration. This summary includes highlights from both talks. PMID- 29105578 TI - Role of perforin secretion from CD8+ T-cells in neuronal cytotoxicity in multiple sclerosis. AB - OBJECTIVES: Multiple sclerosis (MS) is the most prevalent autoimmune disease of the central nervous system, and is characterized by inflammation and myelin damage. The immune system initiates the autoimmune response, although the mechanisms of neuronal damage have not been elucidated. The purpose of the present study was to investigate autoreactive CD4+ and CD8+ T lymphocytes, in conjunction with other inflammatory cells and cytokines in active MS lesions. METHODS: EAE animal models was established by plantar injections of MBP (200 MUg per rat). Purified CD4+ or CD8+ T-cells were isolated from heparinized peripheral blood (EAE animals and control animals) via negative selection. To examine effects of presence of autoreactive CD4+ and CD8+ T lymphocytes, we carried out ELISA, Western blot analysis and TUNEL. In addition, we examined the direct effects of various factors on neuronal cell death using MTT assay. RESULTS: The data revealed that CD8+ T-cells were more toxic to neurons compared to CD4+ T cells, in both the MBP and EAE conditions. Bax was greater increased when neurons were co-cultured with CD8+ T-cells in the MBP group. There is a significant increase in IL-17 secretion by CD4+ T-cells in both the MBP group and EAE group. Neuronal viability were affected by Perforin (1.5 MUg/mL). CONCLUSION: The present study extends previous research by demonstrating the role of CD8+ T-cells in MS and supports perforin secretion by CD8+ T-cells as a potential therapeutic factor. Furthermore, we determined that CD4+ T-cells can enhance CD8+ T-cell neuronal cytotoxicity via induction of intense inflammation. PMID- 29105580 TI - A Brief Overview of the STP 36th Annual Symposium: Musculoskeletal System. AB - The title of the 2017 Society of Toxicologic Pathology symposium was "Musculoskeletal System." A brief overview of the General Scientific Symposium is presented herein and describes the topics presented by each speaker. Symposium speakers addressed subjects pertinent to musculoskeletal system toxicologic pathology and drug development ranging from molecular biology of bone homeostasis to regulatory agency requirements and considerations for registration of bone therapeutics. This overview serves to summarize sessions and is intended as a guide to the individual submissions by speakers and symposium contributors. PMID- 29105581 TI - WNT-mediated Modulation of Bone Metabolism: Implications for WNT Targeting to Treat Extraskeletal Disorders. AB - The WNT-signaling pathway is involved in cellular and tissue functions that control such diverse processes as body axis patterning, cellular proliferation, differentiation, and life span. The long list of molecules that can participate or modify WNT signaling makes this pathway one of the most complex in cell biology. In bone tissues, WNT signaling is required for proper skeletal development, and human mutations in various components of the cascade revealed insights into pharmacologic targeting that can be harnessed to improve skeletal health. In particular, mutations in genes that code for the WNT-signaling inhibitor sclerostin or the WNT coreceptor lipoprotein receptor-related protein 5 have highlighted the potential therapeutic value of recapitulating those effects in patients with low bone mass. A constant challenge in this area is selectively modifying WNT components in the tissue of interest, as WNT has manifold effects in nearly every tissue. PMID- 29105582 TI - Rating of perceived exertion with Borg scale in stroke over two common activities of the daily living. AB - Background The Borg Scale for the rating of perceived exertion (RPE) is recommended to measure the intensity of physical exercise during stroke rehabilitation, but its reliability in activities of daily living is not explored. Objective To evaluate the correlation between the RPE using the Borg Scale (6-20) and the intensity of effort as measured by the Total Energy Expenditure per minute (TEE.min-1) in a post-stroke population for two tasks: walking at spontaneous comfortable speed and walking up and down stairs. Methods A cross-sectional study has been conducted. Any post-stroke subjects able to walk without being helped were recruited. Subjects were asked to walk at their spontaneous comfortable walking speed for 6 min and then to walk up and down stairs with a portable gas analyzer to measure the TEE.min-1. The RPE was evaluated by the Borg scale (6-20). The correlation between the RPE and the TEE.min-1 for each subject's walking task and stairs task was calculated with the Pearson coefficient. Results Twenty subjects were included. TEE.min-1 averaged at 5.6 (+/-1.2 kcal.min-1) for the walking task and 9.58 (+/-4.3 kcal.min-1) for the stairs task. The median RPE was 11 (min 6; max 15) for the walking task and 11 (min 6; max 16) for the stairs task. The correlation coefficient between the RPE and TEE.min-1 was r = 0.12 (p = 0.25). Conclusion Our work has not determined a correlation between the RPE and TEE.min-1 for two common activities of daily living in post-stroke subjects. PMID- 29105583 TI - The economic cost of stroke-associated pneumonia in a UK setting. AB - Introduction Stroke-associated pneumonia (SAP) is common, however, data on the economic impact of SAP are scarce. This study aimed to prospectively evaluate the impact of SAP on acute stroke care costs in a UK setting. Methods Prospective cohort study of 213 consecutive patients with stroke (196 ischemic, 17 hemorrhagic) was admitted to a UK hospital over 1 year. Socio demographic and clinical characteristics were recorded along with all treatments and rehabilitation activity. Patients were classified as having SAP if they fulfilled criteria for "probable" or "definite" respiratory tract infection according to the Centres for Disease Control and Prevention definition, within the first seven days following stroke. Resource use was calculated using a "bottom up" approach of cumulative unit costs. Univariate and multivariate regression analyses were used to establish independent predictors of direct costs. Results Probable or definite SAP occurred in 13.2% (28/213) of patients. Patients with SAP experienced greater inpatient stays (31 days vs. 9 days, p <= 0.001) and higher in-hospital mortality (29.2% vs. 10.2%, p = 0.007). Mean (SD) acute care costs per patient was L7035 (6767), but costs were significantly greater for patients with SAP than without [L14,371 (9484) versus L6,103 (5,735); p <= 0.001]. SAP was an independent predictor of costs along with increasing stroke severity (NIHSS) and age. Occurrence of SAP resulted in an adjusted incremental additional cost of L5817 (95% CI 4945-6689; p = 0.001) per patient. Conclusions SAP increased acute care costs for stroke by approximately 80%. This provides further impetus for research aimed at reducing SAP, and will inform cost-effectiveness analyses of potential therapeutic strategies. PMID- 29105584 TI - Is ulipristal acetate the new drug of choice for the medical management of uterine fibroids? Res ipsa loquitur? AB - Ulipristal acetate (Esmya(c)) has been hailed the new wonder drug with regard to the medical management of uterine fibroids, and many postulate that it will remove the need for surgical treatment in the future. While the results from the PEARL studies are certainly promising and its amenorrhoeic rates and reduction in fibroid size are unquestionable, there is still a paucity of data with regard to its long-term effects, the effects on its usage prior to surgery and its variable efficacy in different ethnic populations. To facilitate our knowledge further, independent studies with clear outcome measures evaluating the long-term effects of the drug in a wider, more representative, ethnic minority population as well as assessing its true cost-effectiveness compared to surgery are needed. The aim of this article is to review the historical aspects with regard to the management of uterine fibroids to gain an understanding of where we are now and to evaluate the wider use of ulipristal acetate, both its benefits and limitations and postulate where to go in the future in order to allow our women to make safe and informed choices regarding their treatment options. PMID- 29105585 TI - Fatal cases of Citrobacter freundii septicemia and encephalitis in sheep. AB - Citrobacter freundii is considered a ubiquitous organism and an opportunistic pathogen. Reports of C. freundii-associated disease in mammals have been very limited. We report an outbreak of C. freundii septicemia and encephalitis in sheep, with a high mortality rate; 13 adult sheep were found dead over a 6-d period on a farm in central China that housed ~1,370 sheep. Three animals were autopsied and showed septicemia, congestion of meningeal vessels, and pleural effusion. C. freundii was isolated in abundance in pure culture from 19 of 21 organs. All 3 C. freundii isolates had similar antimicrobial resistance phenotypes for 10 of the 11 agents tested, and were sensitive to 8 of the 11 agents. We reproduced C. freundii infection in sheep experimentally by oral or subcutaneous inoculation routes, and recovered the challenge organism from all of the experimentally infected sheep. Intramuscular injection of enrofloxacin protected sheep against an otherwise fatal challenge. Our results suggest that C. freundii played a major role in this disease outbreak. PMID- 29105586 TI - Radial styloidectomy for scaphoid nonunion advanced collapse - relevance of nonunion location. AB - : Radial styloidectomy along with scaphoid nonunion reconstructive surgery is considered an acceptable surgical treatment for stage 1 scaphoid nonunion advanced collapse. The extent of radioscaphoid joint wear that defines scaphoid nonunion advanced collapse stage 1 is unclear. An appropriate radial styloidectomy is limited to 6 mm styloid removal to prevent carpal instability. The aim of this study was to determine whether nonunion fracture location can be a guiding factor in determining whether the scaphoid bone can be retained with scaphoid nonunion reconstructive surgery and radial styloidectomy. We reviewed wrist radiographs and magnetic resonance imaging studies of 21 patients with a diagnosis of scaphoid nonunion advanced collapse stage 1, and quantified chondral wear as the length of a line (in mm) along the radioscaphoid joint traced from the tip of the radial styloid to the most ulnar position along the radioscaphoid joint. We concluded that scaphoid nonunion reconstructive surgery with radial styloidectomy is only appropriate for nonunions in the distal or middle third of the scaphoid. LEVEL OF EVIDENCE: III. PMID- 29105587 TI - Tenosynovial giant cell tumour of the hand in children under 10 years of age. PMID- 29105588 TI - Results of scaphocapitate arthrodesis with lunate excision in advanced Kienbock disease at 10.7-year mean follow-up. AB - : Scaphocapitate arthrodesis with lunate excision was performed for treatment of advanced Kienbock disease in 17 patients (18 wrists). Ten were women and seven men. Five were Lichtmann Stage IIIA, 12 Stage IIIB, and one Stage IV. Minimum follow-up period was 24 months; mean follow-up was 10.7 years (range 2.3 to 22 years, SD 7.1). At the latest follow-up, six patients were very satisfied, nine were satisfied and two were disappointed. Pain was significantly decreased in all cases. Wrist mobility was unchanged. Grip strength was significantly increased. Consolidation of the arthrodesis was confirmed in 17 wrists. We encountered a scaphocapitate nonunion at 12 years follow-up and two cases of styloscaphoid arthritis at 17 and 22 years. Scaphocapitate arthrodesis with lunate excision performed in an advanced stage of Kienbock disease significantly alleviates pain, while preserving functional mobility and satisfactory grip strength in the long term. LEVEL OF EVIDENCE: IV. PMID- 29105589 TI - The morphology of proximal pole scaphoid fractures: implications for optimal screw placement. AB - The purpose of this study was to measure the radiographic parameters of proximal pole scaphoid fractures, and calculate the ideal starting points and trajectories for antegrade screw insertion. Computed tomography scans of 19 consecutive patients with proximal pole fractures were studied using open source digital imaging and communications in medicine (DICOM) imaging measurement software. For scaphoid sagittal measurements, fracture inclination was measured with respect to the scaphoid axis. The ideal starting point for a screw in the proximal pole fragment was then identified on the scaphoid sagittal image that demonstrated the largest dimensions of the proximal pole, and hence the greatest screw thread purchase. Measurements were then taken for a standard screw trajectory in the axis of the scaphoid, and a trajectory that was perpendicular to the fracture line. The fracture inclination in the scaphoid sagittal plane was 25 (SD10) degrees , lying from proximal palmar to dorsal distal. The fracture inclination in the coronal plane was 9 (SD16) degrees , angling distal radial to proximal ulnar with reference to the coronal axis of the scaphoid. Using an ideal starting point that maximized the thread purchase in the proximal pole, we measured a maximum screw length of 20 (SD 2) mm when using a screw trajectory that was perpendicular to the fracture line. This was quite different from the same measurements taken in a trajectory in the axis of the scaphoid. We also identified a mean distance of approximately 10 mm from the dorsal fracture line to the ideal starting point. A precise understanding of this anatomy is critical when treating proximal pole scaphoid fractures surgically. PMID- 29105590 TI - Swan neck deformity due to chronic radial collateral ligament injury of the little finger proximal interphalangeal joint. AB - : We present seven cases of a relatively rare swan neck deformity resulting from chronic radial collateral ligament (RCL) injury of the proximal interphalangeal (PIP) joint in the little finger. All patients were middle-aged women (mean 51 years old, range 42-55), and the duration between the initial injury and surgery was 20 years (range 5-40). The chief complaint was painful snapping of the PIP joint. All patients had hyperextension and ulnar deviation of the PIP joint with mobile swan neck deformities that had not improved with conservative treatment. Radiographs revealed osteoarthritis and ulnar deviation of the PIP joints in all cases. We describe a method for reconstruction of both the palmar plate and the RCL of the affected PIP joint using a distally-based ulnar slip of flexor superficialis tendon. The prevention of PIP joint hyperextension was critical for successful resolution of symptoms; the aim of RCL augmentation was to prevent the recurrence of the deformity. LEVEL OF EVIDENCE: IV. PMID- 29105591 TI - Treatment of the scaphoid humpback deformity - is correction of the dorsal intercalated segment instability deformity critical? AB - Treatment of scaphoid fractures has been focused mainly on achieving union, with less attention to restoring normal scaphoid shape and orientation. Malalignment of one carpal bone will disrupt the kinetics of the entire wrist. The dorsal intercalated segment instability deformity associated with scaphoid waist nonunion is a nondissociative form of carpal instability. It has to be reduced in the treatment of scaphoid waist nonunions to avoid kinetic problems that will lead to arthritic changes. Computerized tomography scanning has become indispensable to visualize the humpback deformity clearly. Different techniques may be used to restore the normal anatomy of scaphoid, from non-vascularized graft to arthroscopic bone grafting, and also the option of vascularized bone grafting. PMID- 29105592 TI - Biologic Annulus Fibrosus Repair: A Review of Preclinical In Vivo Investigations. AB - Lower back pain, the leading cause of workplace absences and disability, is often attributed to intervertebral disc degeneration, in which nucleus pulposus (NP) herniates through lesions in the annulus fibrosus (AF) and impinges on the spinal cord and surrounding nerves. Surgeons remove extruded NP via discectomy when indicated by local/radicular pain supported by radiographic evidence; however, current interventions do not alter the underlying disease or seal the AF. The reported rates of recurrent herniation or pain following discectomy cases range from 5% to 25%, which has pushed spine research in recent years toward annular repair and closure strategies. Synthetic implants designed to mechanically seal the AF have been subject to large animal and clinical trials, with limited success in preventing recurrent herniation. Like gold standard interventions, purely mechanical devices fail to promote tissue integration, long-term healing, or restore native biomechanical function to the spine. Biological repair strategies utilizing principles of tissue engineering have demonstrated success in overcoming the inadequacies of current interventions and mechanical implants, yet, none has reached clinical or proof-of-concept trials in humans. In this review, we will discuss annular repair strategies promoting biological healing that have been implemented in small and large animal models in vivo, and ways to enhance the efficacy of these treatments. PMID- 29105593 TI - Manipulation of sensory input can improve stretching outcomes. AB - The primary purpose of our study was to assess the influence of modulating sensory input with either transcutaneous electrical nerve stimulation (TENS) or self-massage with therapy balls on the maximal range of motion (ROM) about the ankle joint when stretching the calf muscles. We also investigated the influence of these two conditions on the force capacity and force control of plantar flexor muscles. Twenty healthy adults (25 +/- 3 yr) performed three sessions of ankle plantar flexor stretching (three stretches of 30 s each): stretching alone (SS), stretching with concurrent TENS (TENS), and stretching after self-massage using therapy balls (SM). TENS was applied for 60 s prior to and during each stretch, and SM was performed for 60 s prior to each of the three stretches. Maximal voluntary contraction (MVC) torque and force steadiness at 20% MVC were recorded before and at 15 min after the final stretch. Ankle dorsiflexion ROM was assessed before, after, and at 5, 10, and 15 min after the last stretch. The increase in ROM was greater after SM (24%) than after SS (13%) and TENS (9%; p < .001). Maximal discomfort level (0-10 VAS) during stretching was similar for all conditions. MVC torque increased after SM only (p < .001, Cohen's D = 1.5): SM, 16%; SS, -1%; TENS, -3%. Force steadiness did not change. The sensory fibres that contribute to stretch tolerance were engaged by self-massage but not by TENS, resulting in greater increases in flexibility and MVC torque after self-massage. PMID- 29105595 TI - Host Defense Peptide Expression in Human Cervical Cells and Regulation by 1,25 Dihydroxyvitamin D3 in the Presence of Cytokines and Bacterial Endotoxin. AB - Host defense peptides (HDPs) in the pregnant female reproductive tract provide protection against infection. The relationship between HDPs and infection/inflammation is poorly understood. Therefore, we investigated the regulation of HDPs by 1alpha, 25-dihydroxyvitamin D3 (1,25-(OH)2) in the presence/absence of infectious/inflammatory agents. Endocervical epithelial cells (END1/E6E7, n = 6) were exposed to 1,25-(OH)2, calcipotriol, interleukin 1beta (IL-1beta), granulate-macrophage colony-stimulating factor (GM-GSF), and lipopolysaccharide (LPS). Elafin, human beta defensin (hBD2), cathelicidin, secretory leucocyte protease inhibitor, interleukin 8, 1,25-(OH)2 receptor, and toll-like receptor 4 (TLR4) expression was determined using quantitative polymerase chain reaction and/or enzyme-linked immunosorbent assay. Host defense peptide gene and protein expression was assessed in cervicovaginal cells/fluid, respectively, from first trimester pregnant women (n = 8-12). Interleukin 1beta induced elafin and hBD2. The 1,25-(OH)2 induced cathelicidin expression in the presence of IL-1beta and LPS. The 1,25-(OH)2 also attenuated IL-1beta-induced IL 8 expression and LPS enhancement of TLR4. Host defense peptides and TLR4 profiles in cervicovaginal cells and fluid samples from pregnant women were similar to END1/E6E7 cells. In conclusion, HDPs are differentially regulated in END1/E6E7 cells. The 1,25-(OH)2 induction of cathelicidin and suppression of IL-8 highlights a mechanism by which 1,25-(OH)2 supplementation could enhance the pregnant innate immune defenses. PMID- 29105596 TI - Ureteral Reconstruction in Goats Using Tissue-Engineered Templates and Subcutaneous Preimplantation. AB - Repair of long ureteral defects often requires long graft tissues and extensive surgery. This is associated with complications, including a lack of suitable tissue and graft site morbidity. Tissue engineering may provide an attractive alternative to the autologous graft tissues. In this study, ureteral repair using (preimplanted) tubular collagen-Vicryl templates was evaluated in a new goat model. Tubular templates were prepared from tubularized Vicryl meshes and 0.7% type-I collagen (length = 6 cm, inner diameter = 6 mm, wall thickness = 3 mm). In total, twelve goats were used and evaluated after 3 months. Eight goats were implanted with the collagen-Vicryl templates and in four goats the templates were first preimplanted in the subcutis and subsequently used as ureteral graft. Template implantation was successful in 92% of the goats(11/12). During follow up, 82% of the animals (9/11) survived without signs of discomfort. Two animals were sacrificed prematurely due to kidney perforation by the stent and urine leakage. Two other animals presented with stenosis of the neoureter due to stent migration. After preimplantation, the templates were remodeled mostly to autologous tissue with similar mechanical characteristics as the native ureter. Goats grafted with preimplanted templates presented with predominantly healthy kidneys, whereas the goats grafted with the collagen-Vicryl templates presented with fibrotic and inflamed regions in the kidneys. The use of preimplanted tissue templates showed favorable results compared with direct functional implantation of the templates. Partial remodeling toward autologous tissue and similar mechanical characteristics likely improved the integration in the ureteral tissue. Preimplantation of tissue-engineered templates should therefore be considered when two-stage procedures using a nephrostomy catheter are indicated or when planning allows for additional time to treatment. PMID- 29105598 TI - Parental reflective functioning and executive functioning in mothers with substance use disorder. AB - Having a substance use disorder (SUD) may adversely affect caregiving capacities. Reflective functioning (RF) and executive functioning (EF) are both important capacities for sensitive parenting, and are often impaired in a SUD. Only a few studies have explored the possible association between the two phenomena. In this study, we used a neuropsychological test battery to assess EF, and the Parent Development Interview to assess RF in a sample of mothers with a SUD (N = 43). Although parental RF (PRF) was associated with EF, when controlled for intelligence (IQ) and mental health, there was no significant association between EF and PRF. Mental health, however, showed a significant negative association with PRF. Splitting the group in two based on PRF level, mothers with a negative to low PRF exhibited more severe difficulties in SUD-related aspects, as well as in several EF components, compared to mothers with an adequate to high PRF, highlighting the association between EF and PRF. The results from this study contribute to enhance our understanding of the dynamics underlying vulnerability in PRF that mothers with small children may experience. We suggest EF to be a prerequisite for adequate PRF, and for interventions to be customized accordingly regarding parents with a SUD. PMID- 29105597 TI - Deoxynivalenol in wheat, maize, wheat flour and pasta: surveys in Hungary in 2008 2015. AB - Among Fusarium mycotoxins, deoxynivalenol (DON) is the most common contaminant in case of cereals and cereal-based foods in Hungary. In this study, Hungarian wheat (n = 305), maize (n = 108), wheat flour (n = 179) and pasta (n = 226) samples were analysed (N = 818). The samples were collected during 2008-2015 in Hungary. Applied methods of analysis were enzyme-linked immunosorbent assay and liquid chromatography coupled with a mass spectrometer. Results were compared and evaluated with Hungarian weather data. Among cereal samples, in 2011, wheat was contaminated with DON (overall average +/- standard deviation was 2159 +/- 2818 ug kg-1), which was above the maximum limit (ML). In case of wheat flour and pasta, no average values above ML were found during 2008-2015, but higher DON contamination could be observed in 2011 as well (wheat flour: 537 +/- 573 ug kg 1; pasta: 511 +/- 175 ug kg-1). PMID- 29105594 TI - Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, >=60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONS: Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .). PMID- 29105599 TI - Genotype-based epigenetic differences in monozygotic twins discordant for positive anti-thyroglobulin autoantibodies. AB - BACKGROUND: Epigenetic factors associated with the development of autoimmune diseases are unclear. Monozygotic twin pairs discordant for positive anti thyroglobulin autoantibodies (TgAb) are useful to examine the epigenetic factors because of their identical genetic background. PURPOSE: To clarify the discordant epigenetic differences affecting the development of TgAb. SUBJECTS: We selected subjects from 257 Japanese monozygotic twins, recruited from the registry established by the Center for Twin Research at Osaka University. TgAb positive concordant (PC) pairs were 5.7% (4 pairs) and 9.6% (18 pairs) of male and female pairs, respectively. TgAb discordant (DC) pairs were 11.4% (8 pairs) and 8.0% (15 pairs) of male and female pairs, respectively. TgAb negative concordant (NC) pairs were 78.6% (55 pairs) of male pairs and 74.3% (139 pairs) of female pairs. To perform stricter grouping, in this study, we set the cut-off value for positive TgAb to 50.0 IU/mL (TgAb Negative: <28.0IU/mL, TgAb Positive: >=50.0IU/mL. TgAb Borderline: =>28.0IU/mL and <50.0IU/mL). Nineteen discordant (6 male and 13 female pairs) and 185 concordant pairs (48 male and 137 female pairs) for TgAb positivity were finally examined. METHODS: We evaluated DNA methylation levels of genomic DNA using the Infinium HumanMethylation450 BeadChip Kit (Illumina). We also genotyped gene polymorphisms using the Omni5-4 BeadChip Kit (Illumina) to clarify genetic background specific for discordant twins. RESULTS: We did not find any CpG sites with significant within-pair differences of methylation levels in TgAb DC pairs after correction for multiple comparisons. However, 155 polymorphisms specific for TgAb DC pairs were significantly different in genotype frequencies from those of concordant pairs, and none of them was located on the HLA region of chromosome 6. In TgAb DC pairs with some specific genotypes of these polymorphisms, we observed four CpG sites exhibiting significant within-pair differences in each DC pair, even after correction for multiple comparisons. CONCLUSIONS: We found that the genetic background specific for TgAb DC twins who are susceptible to epigenetic changes are different from that specific for TgAb PC twins, and clarified the genotype-based epigenetic differences in TgAb-DC monozygotic twins. PMID- 29105600 TI - Microbiology in burns patients with blood stream infections: trends over time and during the course of hospitalization. AB - BACKGROUND: Bloodstream infections (BSI) are a major cause of mortality in burns patients. Knowledge of the microbiology is crucial to direct empirical therapy. We sought to determine the causative microorganisms and antibiotic resistance in burns patients with BSI. METHODS: All consecutive BSI episodes in a tertiary hospital burns unit from 2000 to 2014 were included. The following three subperiods were compared: 2000-2004, 2005-2009 and 2010-2014. Changes in BSI occurring during early and late hospitalization periods were evaluated. RESULTS: A total of 103 BSI episodes were included. The cumulative incidence was 2.4 episodes/1000 patient days. A positive trend in the frequency of Gram-negative BSI, especially in the upsurge of Pseudomonas aeruginosa and Klebsiella spp. BSI after 2004, was observed. The most common causative pathogens in early BSI were Gram-positive microorganisms. P. aeruginosa and Klebsiella spp. became the predominant aetiology in the fourth week of hospitalization and beyond. There was a progressive increase in imipenem-resistant P. aeruginosa over time (0%, 67%, 75% in 2000-2004, 2005-2009, 2010-2014, respectively) and during the hospital stay (50% vs. 85.7%, in <7 days-BSI vs. >30 days-BSI, respectively). A higher SOFA (Sepsis-related Organ Failure Assessment) score was associated with Gram negative BSI versus non-Gram-negative BSI (median: 2.5 vs. 0; p = 0.041). CONCLUSIONS: There is a changing trend in the types of pathogens causing BSI in burns patients over the 14-year period and during the course of hospitalization. The problematic increase in carbapenem-resistance highlights the need for new antimicrobial stewardship policies and antibiotic prescribing protocols. PMID- 29105601 TI - Pooling of interdigital swab samples for PCR detection of virulent Dichelobacter nodosus. AB - Virulent ovine foot rot is a contagious foot disease. Given the development and validation of a real-time PCR to detect Dichelobacter nodosus isolates that contain the virulence-associated protease genes aprV2 and aprB2, the diagnosis of foot rot has made considerable progress. We evaluated pooling methods to reduce the number of samples during a foot rot control program. Samples of individual feet were compared to a 4-feet sample of the same sheep. All further analyses based on 4-feet samples (pools-of-5 and pools-of-10 4-feet samples) were compared to samples of individual sheep, and a risk-based herd sampling was evaluated and compared to the whole flock. The sensitivity and specificity of the 4-feet samples for detection of aprV2-positive strains was 93.8% (CI: 87.6-97.5%) and 98.3% (CI: 96.5-99.3%), respectively. The sensitivity and specificity of the pools-of-10 was 86.7% (CI: 78.4-92.7%) and 100.0% (CI: 97.4-100%), respectively. Pools-of-5 were not significantly more sensitive than pools-of-10. The pooling of 4 individual foot samples into one 4-feet sample is an adequate method to reduce the number of samples of individual sheep. The sensitivity of pools-of-5 and pools-of-10 is too imprecise for a control program. Risk-based sampling allowed for a substantial reduction of samples to be tested, had a sensitivity of 95.8% (CI: 78.9-99.9%) and specificity of 100.0% (CI: 88.1-100.0%) when determining the foot rot flock status, and represents an adequate methodology to predict within flock freedom from infection. PMID- 29105602 TI - A new low-profile visualized intraluminal support (LVIS) device, LVIS Blue: laboratory comparison between old and new LVIS. AB - Objectives The Low-profile Visualized Intraluminal Support (LVIS) device is a flexible intracranial stent. The first generation of this system had significant challenges in consistently providing good wall apposition and aneurysm neck coverage. A new modified LVIS, LVIS Blue (Blue), has been developed to address these issues. The purpose of this study is to report a laboratory comparison of wall apposition and aneurysm neck coverage between the original LVIS and Blue. Methods In bench-top experiments, we noted the visual appearance of the devices and evaluated changes in stent cell angles, neck coverage surface area (%), and stent cell crossing profile for microcatheters using a fusiform aneurysm model. Our in vitro experiments included evaluation of wall apposition and aneurysm neck coverage of the devices under direct radiographic visualization. Results Blue showed three definite different zones (a mid-zone, a high-density zone, and a transitional zone) and higher metal coverage in the straight fusiform aneurysm model compared to LVIS. Two commercially available microcatheters easily crossed the stent cell at the greater curvature for both devices. In in vitro experiments, Blue showed better wall apposition in tortuous arteries and achieved higher neck coverage in the bifurcation aneurysm compared to LVIS. Discussion Blue achieved better wall apposition in tortuous arteries and higher aneurysm neck coverage (higher metal-to-artery ratio) in bifurcation aneurysms than LVIS. Our results may provide informative physical properties of LVIS and Blue to be expected when those are used for stent-assisted coil embolization of a large giant fusiform aneurysm or a bifurcation saccular aneurysm clinically. PMID- 29105603 TI - Influence of coping strategies on oral health-related quality of life in patients with myalgia. AB - Objective To identify coping strategies used by patients with myalgia and to assess the influence of pain characteristics and coping attitudes on their oral health-related quality of life (OHRQoL). Methods One hundred patients diagnosed with myalgia due to temporomandibular disorders were included in this study. They were administered a three-part questionnaire. For preselecting associated coping variables, correlation analysis was performed between coping strategies and OHRQoL domains. A block-wise hierarchical multiple regression analysis was carried out to evaluate whether coping strategies had any influence on OHRQoL. Results Notable trends were found between coping strategies and demographic variables and pain characteristics. OHRQoL appeared to worsen with pain severity and with coping strategies that reveal passive or avoidant attitudes of the patient. Discussion Individual coping strategies should be considered while managing myalgia. A multidisciplinary approach that aims to help these patients acquire suitable coping strategies may be useful in improving their OHRQoL. PMID- 29105604 TI - Effects of Surprisal and Entropy on Vowel Duration in Japanese. AB - Research on English and other languages has shown that syllables and words that contain more information tend to be produced with longer duration. This research is evolving into a general thesis that speakers articulate linguistic units with more information more robustly. While this hypothesis seems plausible from the perspective of communicative efficiency, previous support for it has come mainly from English and some other Indo-European languages. Moreover, most previous studies focus on global effects, such as the interaction of word duration and sentential/semantic predictability. The current study is focused at the level of phonotactics, exploring the effects of local predictability on vowel duration in Japanese, using the Corpus of Spontaneous Japanese. To examine gradient consonant vowel phonotactics within a consonant-vowel-mora, consonant-conditioned Surprisal and Shannon Entropy were calculated, and their effects on vowel duration were examined, together with other linguistic factors that are known from previous research to affect vowel duration. Results show significant effects of both Surprisal and Entropy, as well as notable interactions with vowel length and vowel quality. The effect of Entropy is stronger on peripheral vowels than on central vowels. Surprisal has a stronger positive effect on short vowels than on long vowels. We interpret the main patterns and the interactions by conceptualizing Surprisal as an index of motor fluency and Entropy as an index of competition in vowel selection. PMID- 29105609 TI - Task constraints and user-system interaction process under personnel decision support. AB - An experiment involving a simulated decision support system was carried out to examine the patterns of user-system interaction and decision information utilization under personnel decision support. A computer simulation program of personnel decision support was developed, using actual personnel management data from eight Chinese enterprises, and the process tracing techniques were adopted. Thirty-six subjects (users) participated in this experiment. A 2 * 2 design of task constraints was formulated including two forms of decision information representations (chunking vs. random) and two types of time pressure (3 minutes vs. 1 minute). The results showed that, in interacting with decision support systems, users' weights of decision information attributes were closely correlated with the types of information search patterns. Under high time pressure and chunking representation condition, more selective search strategies were adopted with a similar pattern of the sequential search as it was under low time-pressure. The user-system interaction revealed a linear additive process of information utilization. Implications of the results are discussed in relation to the design of effective decision support systems for complex decision situations. PMID- 29105607 TI - Driving errors, driving violations and accident involvement. AB - A survey of over 1600 drivers is reported, the results of which are consistent with those reported in an earlier study (Reason et al. 1990), which identified a three-fold typology of aberrant driving behaviours. The first type, lapses, are absent-minded behaviours with consequences mainly for the perpetrator, posing no threat to other road users. The second type, errors, are typically misjudgements and failures of observation that may be hazardous to others. The third type, violations, involve deliberate contraventions of safe driving practice. In the present study the survey instrument used, the Driver Behaviour Questionnaire, was also shown to be reliable over time. Each type of behaviour was found to have different demographic correlates. Most importantly, accident liability was predicted by self-reported tendency to commit violations, but not by tendency to make errors or to have lapses. The implications for road safety are discussed. PMID- 29105605 TI - The feasibility of an acute high-intensity exercise bout to promote locomotor learning after stroke. AB - BACKGROUND: People post-stroke can learn a novel locomotor task but require more practice to do so. Implementing an approach that can enhance locomotor learning may therefore improve post-stroke locomotor recovery. In healthy adults, an acute high-intensity exercise bout before or after a motor task may improve motor learning and has thus been suggested as a method that could be used to improve motor learning in neurorehabilitation. However, it is unclear whether an acute high-intensity exercise bout, which stroke survivors can feasibly complete in neurorehabilitation session, would generate comparable results. OBJECTIVE: To determine a feasible, high-intensity exercise protocol that could be incorporated into a post-stroke neurorehabilitation session and would result in significant exercise-induced responses. METHODS: Thirty-seven chronic stroke survivors participated. We allocated subjects to either a control (CON) or one of the exercise groups: treadmill walking (TMW), and total body exercise (TBE). The main exercise-induced measures were: average intensity (% max intensity) and time spent (absolute: seconds; normalized: % total time) at target exercise intensity, and magnitudes of change in serum lactate (mmol/l) and brain-derived neurotrophic factor (BDNF; ng/ml). RESULTS: Compared to CON, both exercise groups reached and exercised longer at their target intensities and had greater responses in lactate. However, the TBE group exercised longer at target intensity and with greater lactate response than the TMW group. There were no significant BDNF responses among groups. CONCLUSIONS: An acute high-intensity exercise bout that could be incorporated into a neurorehabilitation learning-specific session and results in substantial exercise-induced responses is feasible post-stroke. PMID- 29105611 TI - Data-entry keyboard geometry and keying movement times. AB - Experiments on fifteen simulated keyboards with different key sizes and inter-key spacings are reported. It was found that the movement time on these keyboards was well described by the model of Drury (Drury and Hoffmann 1992). Minimum movement times occurred when the inter-key spacing was approximately equal to the finger pad size. There was found to be an effect of the number of keys moved, which was not predicted by the model. This effect remained in a further experiment in which the target keys were marked. PMID- 29105613 TI - Effect of transported mass and constant force on times for ballistic and visually controlled movements. AB - A series of experiments are reported in which the effects of transferred mass and resistive/assistive forces were investigated for both ballistic and visually controlled movements. The first experiment involved the transfer of mass in the horizontal plane so that only inertia] forces were present. This was followed by experiments in which movements were made with a purely resistive or assistive force, without the presence of increased inertia. Finally the effects of transferring mass in the vertical direction were investigated, where resistive/assistive forces were present due to gravity, as well as increased inertia force due to the transferred mass. Both theoretical and empirical models are presented for each of these cases. It was found that, for both ballistic and visually-controlled movements, the data were well accounted for simply by a component of added time proportional to the transferred mass or the magnitude of the constant force. This result is in agreement with the procedure used in some predetermined motion time systems. PMID- 29105614 TI - A comparative study of three different kinds of school furniture. AB - Several studies indicate that the ISO standards for school furniture seem to be inappropriate, and there is increasing evidence that the inclination of the seat should be forward and that it should be possible to adjust the table-top to a certain non-horizontal angle. However, these studies have predominantly used objective measurement methods on adult subjects for short-term experiments in rather artificial surroundings. By means of structured interviews registering the school children's perception of ergonomic comfort, the present study has compared three types of school furniture-the original ISO-standard type, and two different new types characterized by forward slanting seats and tiltable desk-tops, the main difference between the two being approximately 15 cm in the height of the chair as well as the table. The study showed that the highest of the two tilting types was perceived to be significantly better than the two others in terms of table height, chair height, reading position, back-rest, and global assessment. Likewise, the feature of a tiltable table-top was considered overwhelmingly positive independently of the height of the furniture. It is recommended that school authorities, producers of school furniture, and relevant medical personnel consider these results for alternative designs of school furniture. It should be kept in mind, however, that school furniture is only one among many factors in the multifactorial field of the back health of school children. PMID- 29105617 TI - The handling of objects other than boxes: univariate analysis of handling techniques in a large transport company. AB - The purpose of this study, carried out on handlers in the distribution centre of a large transport company, was to identify the techniques used for handling objects other than boxes. Thirty-one workers, with experience varying from one month to 17 years, were each filmed during one shift. A grid with 36 variables allowed the successive operations to be described: the type of grip, the nature and the direction of the efforts by the upper limbs, the use of the back and the lower limbs, and the displacement of the object. Nine hundred and forty-four handlings carried out in 3217 distinct movements were analysed. These observations revealed the complexity of the handling techniques and the tendency to favour some of them. Seventy-nine per cent of the handlings observed included pre-transfer and/or post-placement phases in addition to the transfer itself. Essentially horizontal phases (pulling, pushing) are more frequent than essentially vertical ones (lifting, lowering); asymmetry is generalized, whether it involves the back position (torsion), the direction and the type of effort, the position of the hands on the object, etc. More than half of the efforts are used to move an object resting on a surface (sliding, pivoting, turning, rolling); resistive efforts downwards (e.g., lowering) are avoided in favour of 'throwing' or 'dropping'. PMID- 29105618 TI - Hemispatial neglect following right hemisphere stroke: clinical course and sensitivity of diagnostic tasks. AB - Background Stroke patients with severe symptoms of hemispatial neglect (HN) are known to experience a weaker recovery than those less affected from the outset. Correct identification of HN is therefore important throughout the course of rehabilitation. Objectives To explore: (i) the course of clinical symptoms in stroke patients with moderate/severe HN from acute setting to home, (ii) changes in sensitivity of diagnostic tasks over time, and (iii) agreement between the researcher's and patients' HN assessments. Methods Out of 79 consecutive patients, we included 23 patients with moderate/severe HN following right hemisphere stroke. The Catherine Bergego Scale was used as a benchmark for HN and to measure the congruence between the researcher's and patients' HN assessments. Diagnostic tasks included star cancellation, line crossing, line bisection, m fluff test, figure copying, and clock drawing. Data were collected at t1: sub acute stroke (days: M +/- SD = 10.3 +/- 5.25), t2: during rehabilitation (days: M +/- SD = 51 +/- 8), and t3: following discharge (days: M +/- SD = 141.5 +/- 47.3). Results (i) 20 out of 23 patients had HN at t3. Associated stroke challenges included paralysis, sensory loss, visual deficits, and extinction. (ii) Combining the star cancellation and figure copying yielded the highest sensitivity at all time points, even in patients with mild HN at t3. (iii) Patients' HN scores differed from the researcher's at t1. The difference was insignificant at t3. Conclusions Joint consideration of stroke severity, functional difficulties, and patients' insight into neglect provides new knowledge to increase clinicians' recognition of HN. More extensive studies are needed to validate bedside screening with star cancellation and figure copying. PMID- 29105619 TI - Methodological aspects of modeling household solid waste generation in Japan: Evidence from Okayama and Otsu cities. AB - This paper presents a quantitative methodology and two empirical case studies in Japan on modeling household solid waste (HSW) generation based on individual consumption expenditure (ICE) and local waste policy effects by using the coupled estimation model systems. Results indicate that ICE on food, miscellaneous commodities and services, as well as education, cultural, and recreation services are mainly associated with the changes of HSW generation and its components in Okayama and Otsu from 1980 to 2014. The effects of waste policy measures were also identified. HSW generation in Okayama will increase from 11.60 million tons (mt) in 1980 to 25.02 mt in 2025, and the corresponding figures are 6.82 mt (in 1980) and 14.00 mt (in 2025) in Otsu. To better manage local HSW, several possible and appropriate implications such as promoting a green lifestyle, extending producer responsibility, intensifying recycling and source separation, generalizing composting, and establishing flexible measures and sustainable policies should be adopted. Results of this study would facilitate consumer management of low waste generation and support an effective HSW policy design in the two case cities. Success could lead to emulation by other Japanese cities seeking to build and maintain a sustainable, eco-friendly society. Moreover, the methodologies of establishing coupled estimation model systems could be extended to China and other global cities. PMID- 29105620 TI - Loud Music Exposure and Cochlear Synaptopathy in Young Adults: Isolated Auditory Brainstem Response Effects but No Perceptual Consequences. AB - The purpose of this study was to test the hypothesis that listeners with frequent exposure to loud music exhibit deficits in suprathreshold auditory performance consistent with cochlear synaptopathy. Young adults with normal audiograms were recruited who either did ( n = 31) or did not ( n = 30) have a history of frequent attendance at loud music venues where the typical sound levels could be expected to result in temporary threshold shifts. A test battery was administered that comprised three sets of procedures: (a) electrophysiological tests including distortion product otoacoustic emissions, auditory brainstem responses, envelope following responses, and the acoustic change complex evoked by an interaural phase inversion; (b) psychoacoustic tests including temporal modulation detection, spectral modulation detection, and sensitivity to interaural phase; and (c) speech tests including filtered phoneme recognition and speech-in-noise recognition. The results demonstrated that a history of loud music exposure can lead to a profile of peripheral auditory function that is consistent with an interpretation of cochlear synaptopathy in humans, namely, modestly abnormal auditory brainstem response Wave I/Wave V ratios in the presence of normal distortion product otoacoustic emissions and normal audiometric thresholds. However, there were no other electrophysiological, psychophysical, or speech perception effects. The absence of any behavioral effects in suprathreshold sound processing indicated that, even if cochlear synaptopathy is a valid pathophysiological condition in humans, its perceptual sequelae are either too diffuse or too inconsequential to permit a simple differential diagnosis of hidden hearing loss. PMID- 29105621 TI - Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA(r), AbbVie, Maidenhead, UK), etanercept (Enbrel(r), Pfizer, New York, NY, USA) and ustekinumab (STELARA(r), Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. DATA SOURCES: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. REVIEW METHODS: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. RESULTS: Of the 2386 non duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks' follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE's usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. LIMITATIONS: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. CONCLUSIONS: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of L30,000 per quality adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016039494. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29105622 TI - The effects of T helper 17 and regulatory T cells on patients with carotid atherosclerosis. AB - This study was aimed to observe the level of T helper 17 (Th17) cells and CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) and their related factors in carotid atherosclerosis (AS) patients and AS model rats to explore the influence of Th17 on the pathological process of AS and its specific mechanism. 60 cases with AS in our hospital from July 2012 to July 2014 were recruited for this study as the observation group, and 40 healthy people who came to the hospital for a physical examination were the control group. Flow cytometry (FCM) was used to detect the Th17 and Treg cells in the peripheral blood of the two groups, ELISA was used to detect IL-17 and transforming growth factor-beta (TGF-beta), and RT-PCR was used to test the RORgammaT mRNA and Foxp3 mRNA expression levels. An AS model was created in rats using high-fat+ VD3 to explore the mechanism of Th17 on AS. The Th17 count, serum level of IL-17, and RORgammaT mRNA level of the observation group were significantly higher than those of the control group (P<0.001). The Tregs count, serum TGF-beta level, and Foxp3 mRNA level were significantly lower in the observation group than in the control group (P<0.001). In addition, the findings of the AS model in rats showed that the Th17 cell count and serum level of IL-17 in high-fat rats were significantly higher than in the normal rats (P<0.05). The Treg count and TGF-beta levels of the observation rats were significantly lower than in the normal rats (P<0.05). The IL-17 level, serum total cholesterol, and triglyceride in the high-fat-feed rats decreased after being injected with the IL-17 neutralizing antibody, but TGF-beta levels increased, and the difference was significant (P<0.05). Th17 cells and their related factors can be involved in promoting the pathological process of AS, while Tregs and its related factors can be involved in the inhibition of AS. Blocking IL-17 can be one potential method of treating AS. PMID- 29105623 TI - Bioactive compounds in Pinang Yaki (Areca vestiaria) fruit as potential source of antifertility agent. AB - Fruits of Pinang Yaki (Areca vestiaria) are used by the people around Bogani Nani Wartabone as contraseption for men. Extracts from the fruit contain tannin, triterpenoid, flavonoid and saponin which are potential as bioactive compounds. This research aimed at exploring the fractions or bioactive compounds contained in the fruit. The extract was prepared by fractionation using hexane. The fractions were separated and analysed by gas chromatography mass spectrometry (GC MS) technique. The fractions revealed the presence of five compounds. These compounds were identified by interpretation of mass spectra and comparing their retention time and covate indexes with those from literature. The five compounds are pentadecane, methyl-dodecanate, methyl-tetradecanoate, hexadecanoic acid and methyl-octadecanate. PMID- 29105624 TI - Effects of thyroid hormone replacement therapy on thyroid hormone levels and electrocardiogram changes in geriatric patients with hypothyroidism. AB - This paper aims to analyze the effects of thyroid hormone replacement therapy on thyroid hormone levels and electrocardiogram changes in elderly patients with hypothyroidism. 48 elderly patients with hypothyroidism admitted to our hospital from January 2014 to December 2014 were selected as subjects. All the patients were treated with thyroid hormone replacement therapy. The changes of thyroid hormone levels and ECG parameters were compared before and after treatment. After treatment, serum thyroid stimulating hormone (TSH) was significantly lower than that before treatment, and the free triiodothyronine (FT3) and free thyroxine (FT4) were significantly higher than those before treatment (t=15.587, 17.396, 19.593, P<0.05); R-R interval, QT interval, QTc interval were significantly lower than before treatment, and the Heart rate (HR), standard deviation of all normal R-R intervals (SDNN), standard deviation of 5 min average R-R intervals (SDANN) within 24h, high frequency power (HF) were significantly higher than before treatment (t=2.171, 2.354, 4.264, 3.100, 10.754, 11.467, 16.776, P<0.05). Thyroid hormone replacement therapy is helpful to improve the level of thyroid hormone and ventricular repolarization in patients with hypothyroidism, and to regulate the function of cardiac autonomic nervous system. PMID- 29105625 TI - Curative effect of Jin'gangteng capsule combined with Kangfuxiaoyan suppository in the treatment of chronic pelvic inflammatory disease. AB - This paper aims to analyze the curative effect of Jin'gangteng capsule combined with Kangfuxiaoyan suppository in the treatment of chronic pelvic inflammatory disease. 97 patients with chronic pelvic inflammatory disease admitted to our hospital from June 2015 to June 2016 were selected and randomly divided into observation group and control group. Patients in control group were treated with Kangfuxiaoyan suppository and patients in the observation group were treated with Jin'gangteng capsule combined with kangfuxiaoyan suppository treatment. The curative effect between the two groups was compared. The scores of symptoms and signs in the observation group after treatment were lower than those in the control group. The total effective rate of the observation group was higher than that of the control group, and there was significant difference between the two groups, P<0.05. Jin'gangteng capsule combined with Kangfuxiaoyan suppository in the treatment of chronic pelvic inflammatory disease can improve the treatment efficiency and promote the rapid and effective relief of clinical symptoms and signs. PMID- 29105626 TI - Anticancer activity of EA1 extracted from Equisetum arvense. AB - Plants and their byproducts have been used for the treatment of various diseases from the time immemorial. The current study was carried out to investigate the anticancer activity of ethanol extract of arial parts of Equisetum arvense (EA1). To check the anticancer potential of EA1, A549 lung carcinoma cells were treated with various concentrations of EA1 (100MUg/mL, and 150MUg/mL). The cell viability was checked using MTT assay, and apoptosis (programmed cell death) was assessed by acridine orange straining.. The results depicted that EA1 manifested cytotoxicity and decreased the cell viability of A549 cells in a concentration dependent manner. Moreover, EER induced apoptotic cell death as monitored using acridine orange staining. The results obtained suggest EA1 extracted from Equisetum arvense as a potential biological resource with pharmacological significance. PMID- 29105627 TI - Macrophage related cytokine expressions in depression mouse model induced by chronic unpredictable mild stress. AB - Depression is characterized by mental retardation, interest blank, hypoactivity, anxiety, appetite loss, sexual dysfunction, sleep disorders and other symptoms. The incidence of depressed patients has demonstrated an upward trend in recent years. Antidepressant drugs are commonly used in modern medicine, but they have the side effect of drug resistance. This study aims to explore the effect of acupuncture stimulation on expressions of macrophage-related cytokines in mice with depression induced by chronic unpredictable mild stress (CUMS), and to explore the underlying immunological mechanism. The CUMS model was successfully developed. The secretion of nuclear transcription factor-kB (NF-kB) and interleukin (IL)-8 increased significantly in the modeling group compared with the blank control group (P<0.05). However, no significant difference of tumor necrosis factor-alpha (TNF-alpha) concentration was found (P>0.05). After acupuncture treatment, the behavior indicator was improved and meanwhile, the levels of TNF-alpha, NF-kappaB, IL-8 decreased significantly compared with the sham group (P<0.05). Depression mice were given treatment of acupuncture, and the effect of behavior change was observed and the content of macrophage cytokine production was measured, respectively. These findings suggested that inflammatory cytokines secreted by peritoneal macrophages increased significantly in mild depression mice, which can be improved by stimulation with acupuncture. PMID- 29105628 TI - Enhanced physical endurance and improved memory performance following taurine administration in rats. AB - Energy drinks enhance physical endurance and cognitive ability. The ingredients present in these drinks are considered as ergogenic and have memory boosting effects. In the present study effects of taurine administration for one week was monitored on physical exercise and memory performance in rats. Animals were divided into two groups namely control and test. Taurine was injected intraperitoneally to the test group at the dose of 100mg/kg. After one week of treatment rats were subjected to physical exercise and memory task. Results of this study revealed that rats injected with taurine for one week exhibited improved muscular strength as well as enhanced memory performance in Morris water maze and elevated plus maze. Biomarker of lipid peroxidation was significantly reduced in brain and plasma of test animals. Taurine administration also resulted in higher levels of corticosterone in this study. The results highlight the significance of taurine ingestion in energy demanding and challenging situations in athletes and young subjects. PMID- 29105629 TI - Designing and molecular docking of cyclic peptides against HCV NS3 protease. AB - Hepatitis C Virus (HCV) infection is a worldwide serious health issue which contributes towards most of the hepatic morbidities. So far no prophylaxis is available to prevent this virus; therefore, development of antiviral compounds to fight HCV infection is the need of time. Chemically synthesized peptides that are potent immunogenic antigens are being pursued as candidate vaccines against HCV. The present study was planned to identify peptide inhibitors having potential to block the activity of NS3 protein of HCV that will ultimately arrest HCV multiplication. Docking of NS3 with peptides revealed that the majority of the peptides have strong binding affinity for active sites of NS3. Peptide 1, 2, 3 and 6 were found interactive with NS3 active residues while the active sites of NS3 had hydrophobic contact with the rest of peptides. Thus, these peptides bear therapeutic potential of a candidate drug for the prevention of HCV replication. Post docking analysis revealed important binding abilities of peptides with the active sites of NS3 protein, showing the efficiency of peptides as potential peptide inhibitors against HCV. The study revealed that HCV replication can be inhibited by these peptides. HCV replication inhibition potential of these peptides can contribute in reducing the burden of HCV infection and its associated complications worldwide. PMID- 29105630 TI - A hepatonephro-protective phenolic-rich extract from red onion (Allium cepa L.) peels. AB - Onion peel is a common bio-waste, occasionally used in traditional medicine in treatment of liver ailment and inflammation. However, a phytochemical and biological study is further required to provide the scientific evidence for this use. A phenolic-rich extract of red onion peels (coded as ACPE) was primarily prepared and then subjected to chromatographic separation. From the extract, six phenolic antioxidant compounds along with two phytosterols were isolated and identified by means of spectroscopic (NMR and MS) analyses. The in vivo protective activity of the ACPE against the oxidative stress induced by carbon tetrachloride (CCl4) free radicals, in liver and kidney, was assessed in rats. Relative to the CCl4-challenged animals, pre-treatment with ACPE could significantly ameliorate the hepatonephrolinked serum and tissue markers in a dose-dependent response. The flavonol- and phenolic acid-based nature of constituents, the high phenolic content (72.33+/-5.30 mg gallic acid equivalent per one gram) and the significant antioxidant capacity (>1/3 potency of rutin) of ACPE may be thus attributed strongly to the hepatonephro-protective and anti inflammatory effect of ACPE. The results suggest that red onion peels can serve as a convenient and cost-effective source of high-value antioxidant nutraceuticals for protection against oxidative stress-related disorders. PMID- 29105631 TI - Phytoformulation of Sassurea lappa plant extract: A Single blind, noninvasive and split face study of cream on various skin parameters. AB - Saussurea lappa (SL) has been reported for its antioxidant and anti-ageing properties. Due to this reason it can be incorporated in a stable phytoformulations for cosmetic use. The objective of the study was to evaluate the anti-aging potential of cosmetic o/w emulsion containing the botanical extract of SL. An emulsion (o/w) was prepared using TEGO(r) Care 450 (Polyglceryl 3-Methyl Glucose Distearate) emulsifier and final emulsion was loaded with 4 % extract of SL in aqueous phase. This emulsion evaluated for its antioxidant and anti-ageing properties on healthy human subjects using a non-invasive technique called surface evaluation of living skin (SELS). The formulation containing SL extract showed significant (p<0.05) changes in Skin roughness (SEr) as -3.13%, 6.26%, -9.39%; Skin Scaliness (SEsc) as - 4.19%, -8.39%, -12.58%; Skin wrinkles (SEw) as -0.5%, -1.08%, -1.63%; and Skin smoothness (SEsm) as 3.28%, 6.57%, 9.85%, respectively, after 30, 60 and 90 days of continous use. Topical application of the cosmetic cream containing SL extract exerts have a significant anti-aging effects, perhaps due to the presence of Kaempferol, gallic acid, Caffeic acid and other essential phenolics. PMID- 29105632 TI - Combinational effects of non n-Hexane Fractions of ant-plant (Myrmecodia tuberosa Jack) hypocotyl with doxorubicin against lymphocyte and cancer cells. AB - Doxorubicin is widely used as a chemotherapeutic drug despite having many side effects. It may cause the dysfunction of macrophage, decreasing proliferation of lymphocytes, decreasing CD4+/CD8+ ratio and inducing hepatotoxicity. Doxorubicin inhibits the growth of Vero, HeLa, and T47D cell lines, and also induces a resistance of MCF-7 cells. Previous studies showed that ethanolic extract and ethyl acetate fraction of ant-plant (Myrmecodia tuberose Jack) hipocotyl could increase macrophage phagocytosis activity and lymphocyte proliferation in vitro. Therefore, antplant is a potential immune stimulator. Combinational treatment of non n-hexane fraction (NHF) of ant-plant with doxorubicin did not affect the doxorubicin's potency. Nevertheless, increased lymphocyte viability induced by doxorubicin in varied dosages of NHF that lethal to HeLa, MCF-7 and T47D cells. Moreover, on Vero cells, doxorubicin became less toxic when induced together with NHF. Thus, NHF of ant-plant is potential to be proposed as doxorubicin co chemotherapeutic agent against cancer cells. PMID- 29105633 TI - Evaluation of antimicrobial, Cytotoxic and genotoxic activities of Ganoderma lucidum (Reishi mushroom). AB - Ganoderma lucidum (GL) is a mushroom used as a traditional remedy for the treatment of various infections since ancient times. This study, was aimed to investigate antimicrobial activity potential of GL against Staphylococcus aureus, Enterococcus faecalis, Listeria monocytogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, Candida glabrata, Candida krusei, and Candida parapsilopsis. Furthermore, it was also aimed to evaluate the toxicity potential of GL. Antimicrobial activities were screened by using microbroth dilution method. With regard to toxicity studies, cytotoxicity was evaluated by using XTT method against NIH3T3 cell lines, whereas genotoxicity study was conducted by Ames MPF 98/100 mutagenicity assay. Obtained data indicated that minimal inhibitory concentration values of the extract against the tested microorganisms ranged from 200 to 400MUg/ml. No cytotoxic activity was observed related to the Ganoderma lucidum administrations. However, results of the Ames test pointed out a genetic damage with metabolic activation against TA98. At the highest concentration (5mg/ml) the extract showed 2.71 fold increase over the baseline significantly. (p<0.05). In conclusion, in spite of significant antimicrobial effect potential, Ganoderma lucidum should be used carefully because of its genotoxicity potential. PMID- 29105634 TI - Essential oils showing in vitro anti MRSA and synergistic activity with penicillin group of antibiotics. AB - This study was planned in order to investigate effective essential oils to inhibit in-vitro growth of Methicillin resistant Staphylococcus aureus (MRSA). In this study using disc diffusion method anti MRSA activity of ten diverse essential oils extracted from traditional plants namely Thymus vulgaris L, Mentha pulegium, Ocimum sanctum, Mentha piperita, Cymbopogon citratus, Rosmarinus officinalis L., Cortex cinnamom, Citrus nobilis x Citrus deliciosa, Origanum vulgare and Mentha sp. was examined. All the essential oils inhibited growth of S. aureus to different extent, by exhibiting moderate to elevated zones of inhibitions. Essential oils of cinnamon (Cortex cinnamomi) and thyme (Thymus vulgaris L) were observed to be the most powerful against MRSA strains used in this study. At lowest concentration of 25MUl/ml essential oils comprehensible zone of inhibition was found 9+/-0.085mm and 8+/-0.051mm respectively, and at elevated concentrations there was a total decline in growth of MRSA and a very clear zone of inhibition was observed. A synergistic effect of essential oils in amalgamation with amoxicillin a Penicillin group of antibiotic was also examined. Interestingly a strong synergism was observed with oregano (Origanum vulgare) and pennyroyal mint (Mentha pulegium) essential oils, which were not so effective alone driven out to be important synergistic candidate. Our results demonstrated that essential oils of cinnamon and thyme can be used as potential antimicrobial agent against the Methicillin-resistant Staphylococcus aureus infections and Amoxicillin antibacterial activity can be enhanced using active constituents present in oregano and pennyroyal mint essential oils. PMID- 29105635 TI - Clinical efficacy of Unani medicine Renax for treatment of Urolithiasis. AB - Stone formation occurs most commonly in acute and chronic renal failure. A kidney stone is a solid lump made up of crystals that separate from the urine and build up on the inner surfaces of the kidney. The current study was conducted to investigate the clinical efficacy of Unani medicine Renax in comparison with allopathic medicine (Spironolactone + Furosemide) to treat urolithiasis. The study was conducted in District Dera Ghazi Khan, South Punjab region. This was case control, randomized, double blind clinical study. All patients were examined by the Physician and given either herbal or allopathic medicine for Urolithiasis. The patients were divided "into two groups" a control group and test groups. A Total of 24 patients were completely cured out of 50 by use of Renax while a total of 9 patients was cured out of 50 with allopathic medicine (Spironolactone + Furosemide). This study validated the claim of traditional healer for use of Unani medicine in the treatment of urolithiasis. PMID- 29105636 TI - Surveillance of variant mecA gene and analysis of efflux pump in mecA negative MRSA infections. AB - It has been known from the medical records of Kancheepuram district hospitals that there is a prevalence of Methicillin resistant Staphylococcus aureus strain. Now the recent epidemiology has shown the presence of Methicillin Resistant Staphylococcus aureus even in school going children community individuals. In view of the above situation, Methicillin resistant Staphylococcus aureus screening was undertaken in the above said region. Both samples from hospital sources and school going children were screened for Methicillin Resistant Staphylococcus aureus. The results have shown that the samples had multiantibiotic resistant property along with methicillin resistance. The genomic studies have revealed that there were of positive genomic sequence for mec A and 5 isolates for mecA negative gene sequence. This would assume that even negative mec A genome has the resistant expression. Out of the 5 isolates two isolates have shown the presence of both nor A and qac A/B genes. The above results are discussed with efflux of drugs and future proposal on proteomics. PMID- 29105637 TI - Detection of AD-BMP-2-IRES-HIF-1alpha MU on local promoting angiogenic and osteogenic capacity of necrosis area. AB - The induced EPCs were transfected by Ad-BMP-2-IRES-HIF-1alphamu, and then transplanted into femoral head necrotic zone, the effect on osteogenesis and agiogenesis of necrosis zone was detected. The Ad-BMP-2-IRES-HIF-1alpha was transfected into induced EPCs and then transplanted into avascular necrotic parts of the femoral head (ANFH).Afterwards, the promotion effect on angiogenic and osteogenic capabilities of the necrosis parts from Ad-BMP-2-IRES-HIF-1alpha was detected. Rabbit bone marrow MNCs were obtained by density gradient centrifugation method, and were induced into EPCs by M199 medium; EPCs were identified in accordance with the cell morphology, specific surface markers and uptake abilities. The Ad-BMP-2-IRES-HIF-1alpha was transfected to EPCs and then transplanted into parts of ANFH. The models were euthanized 2 and 4 weeks after operation and then the angiogenic and osteogenic indexes of necrotic parts were detected. The results showed that more blood vessels generated in group A than that in group B and C (P<0.05), and the statistical differences were found between group B and C (P<0.05). The detection of histology and BMP-2 immunohistochemistry showed that there were statistically significant differences between group A and B, group A and C (P<0.05). There was no significant difference between group B and C (P<0.05). To sum up, this experiment shows that the EPCs transfected by Ad-BMP-2-IRES-HIF-1alpha have stronger angiogenic and osteogenic capabilities. PMID- 29105638 TI - Development & validation of reversed phase HPLC method for quantification of water insoluble API. AB - In the present work a specific, accurate, precise, and reproducible UV-HPLC method was developed and validated for the analysis of Aceclofenac. This method involved elution of Aceclofenac in a mobile phase which is composed of buffer pH 6.8 (i.e. using 0.01N KH2PO4) and HPLC grade Acetonitrile (60:40). Separation of the analyte was achieved using HPLC isocratic pump attached to the UV-VIS detectorC18, guard column and C18 column. The injection volume was 20MUL, detected at 274 nm; flow rate: 1mL/min. Standard calibration curve was measured and found linear from 0.1 to 40MUg/ml. The validation parameters were measured according to FDA guidelines and successful results were obtained. The presented analytical method could be employed for pharmacokinetic studies. PMID- 29105639 TI - Evaluation of DNA vaccines encoding M. Tb gene Bfrb and Mpt32 in mice model. AB - Tuberculosis (TB) is a life threatening infectious disease which is prevalent throughout the world. Mycobacterium bovis based Bacille Calmette-Gue'rin (BCG) is the only vaccine available against TB however, this (single) vaccine is not enough to eradicate it. Furthermore, numbers of researches from different parts of the World have shown its efficacy as variable. Hence other (better) vaccines like DNA vaccines are needed in addition to BCG in order to achieve desired goal of TB eradication. The current study was aimed to develop subunit based DNA vaccines against TB and to check their efficacy. Two constructs Bfrb-pND14 and Mpt32-pND14 were made and used as DNA vaccines. Endotoxin free DNA preparations were made and used in immunization studies. Twenty Balb/c female mice of age eight weeks were used in trial. Two experimental groups each comprising eight animals were used to inoculate Mpt32-pND14 and Bfrb-pND14 vaccines respectively. A group of four animals was used as negative control. Animals were bled through tail periodically and finally through cardiac puncture before euthanization. Antibodies were confirmed through dot blot and Agar Gel Immuno Diffusion test (AGID). All the animals immunized with both vaccines were found positive as tested through dot blot and AGID. The results of this study have indicated that both the M. tb genes have produced strong immune response in mice model through pND14 vector and proved themselves as good subunit based DNA vaccines. PMID- 29105640 TI - Effect of aqueous extract of tops of date palm leaves on blood glucose of diabetic rats. AB - Present study was carried out to examine the effect of tops of date palm leaves extract on blood glucose of streptozotocin induced diabetic rats. Forty male Sprague Dawely rats (120-130g) were housed individually and randomly allocated to two main groups; diabetic group (n=30), and normal group (n=10) in the animal lab, Faculty of Agriculture and Veterinary Medicine, Qassim University, Saudi Arabia. An aqueous extracts were prepared from tops of date palm leaves (EDPL) and were orally administered to rats. Later, the determination of glucose, BUN, creatinine, uric acid, ALT, and AST was examined. Pancreas sample were taken for histopathological examination. It was clear that the higher the concentration of EDPL the lower the weight gain (P<0.001). Glucose concentration of normal group changed by - 0.79% and decreased by -20.4% among diabetic control group, while feeding 1% and 2% EDPL had no significant effects, and the higher the amount of EDPL the higher the concentration of blood glucose. The thought that tea made from date palm leaves decrease blood glucose level has been denied by the results of this study and this tea may worsen diabetes patient's status. PMID- 29105641 TI - Enhancement of memory function by antioxidant potential of Nigella sativa L. oil in restrained rats. AB - Stress is a vulnerable state to cellular homeostasis which leads to oxidative damage via free radical generation. The acute stress induces alteration in antioxidant enzyme activities to an extent which produce oxidative stress and causes certain pathological conditions. The use of Nigella sativa L. oil (NSO) in folk medicine has increased throughout the world for the prevention or treatment of various ailments because of potent antioxidant properties. In the present study, potential therapeutic effects of NSO on memory in both unrestrained and 2h restrained rats were observed. Shortterm memory (STM) and long-term memory (LTM) were assessed by elevated plus maze (EPM) and Morris water maze (MWM) respectively. The present study also demonstrated the effect of NSO on lipid peroxidation (LPO) and activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) along with the activity of acetyl cholinesterase (AChE). The results obtained from the present study showed that 2h restraint stress significantly enhanced both short-term memory (p<0.01) and long term memory (p<0.05) in rats. Pretreatment with NSO at a dose of 0.2ml/kg/day also significantly improved STM (p<0.05) in restrained rats and LTM (p<0.01) in unrestrained rats. This study also showed significantly decreased (p<0.01) LPO and significantly increased (p<0.01) endogenous antioxidant enzymes activity in NSO treated restrained rats. Similarly significant decreased (p<0.01) AChE activity was also observed in NSO treated unrestrained and 2h restrained rats. Therefore, current findings suggested that repeated administration of NSO may exert memory enhancing effects against restrained stress and it can be used for therapeutic purpose because of having fewer side effects. PMID- 29105642 TI - Tunable multimodal adhesion of 3D, nanocrystalline CoFe2O4 pollen replicas. AB - 3D replicas of sunflower pollen microparticles, comprised of a multicomponent magnetic spinel ferrite (CoFe2O4) with tailorable adhesive properties, have been synthesized for the first time via a conformal layer-by-layer (LbL) surface sol gel (SSG) deposition process followed by organic pyrolysis and oxide compound formation at a peak temperature of 600 degrees C-900 degrees C. These high fidelity ferrite pollen replicas exhibited multimodal (van der Waals, vdW, and magnetic) adhesion that could be tuned via control of the CoFe2O4 nanoparticle and crystal sizes. The CoFe2O4 pollen replicas exhibited a non-monotonic change in short-range (~10 nm) vdW adhesion with an increase in the peak firing temperature, which was consistent with the counteracting effects of particle coarsening on the size and number of nanoparticles present on the sharp tips of the echini (spines) on the pollen replica surfaces. The longer-range (up to ~1 mm) magnetic force of adhesion increased monotonically with an increase in firing temperature, which was consistent with the observed increases in the values of the saturation and remanent magnetization of CoFe2O4 with an increase in average nanocrystal size. By adjusting the nanocrystal/nanoparticle sizes of the CoFe2O4 pollen replicas, the total force of adhesion (vdW + magnetic) to a magnetic substrate could be increased by a factor of ~3 relative to native pollen grains. PMID- 29105643 TI - Special issue on domain walls and ferroelastics in honour of Prof Ekhard Salje's 70th birthday. PMID- 29105644 TI - Manifestation of intra-atomic 5d6s-4f exchange coupling in photoexcited gadolinium. AB - Intra-atomic exchange couplings (IECs) between 5d6s and 4f electrons are ubiquitous in rare-earth metals and play a critical role in spin dynamics. However, detecting them in real time domain has been difficult. Here we show the direct evidence of IEC between 5d6s and 4f electrons in gadolinium. Upon femtosecond laser excitation, 5d6s electrons are directly excited; their majority bands shift toward the Fermi level while their minority bands do the opposite. For the first time, our first-principles minority shift now agrees with the experiment quantitatively. Excited 5d6s electrons lower the exchange potential barrier for 4f electrons, so the 4f states are also shifted in energy, a prediction that can be tested experimentally. Although a significant number of 5d6s electrons, some several eV below the Fermi level, are excited out of the Fermi sea, there is no change in the 4f states, a clear manifestation of intra atomic exchange coupling. PMID- 29105645 TI - Understanding GaN/InGaN core-shell growth towards high quality factor whispering gallery modes from non-polar InGaN quantum wells on GaN rods. AB - GaN microrods are used as a basis for subsequent InGaN quantum well (QW) and quantum dot deposition by metal-organic vapor phase epitaxy. The coverage of the shell along the sidewall of rods is dependent on the rod growth time and a complete coverage is obtained for shorter rod growth times. Transmission electron microscopy measurements are performed to reveal the structural properties of the InGaN layer on the sidewall facet and on the top facet. The presence of layers in the microrod and on the microrod surface will be discussed with respect to GaN and InGaN growth. A detailed model will be presented explaining the formation of multiple SiN layers and the partial and full coverage of the shell around the core. Cathodoluminescence measurements are performed to analyze the InGaN emission properties along the microrod and to study the microresonator properties of such hexagonal core-shell structures. High quality factor whispering gallery modes with [Formula: see text] are reported for the first time in a GaN microrod/InGaN non-polar QW core-shell geometry. The GaN/InGaN core-shell microrods are expected to be promising building blocks for low-threshold laser diodes and ultra-sensitive optical sensors. PMID- 29105646 TI - Randomness in quantum mechanics: philosophy, physics and technology. AB - This progress report covers recent developments in the area of quantum randomness, which is an extraordinarily interdisciplinary area that belongs not only to physics, but also to philosophy, mathematics, computer science, and technology. For this reason the article contains three parts that will be essentially devoted to different aspects of quantum randomness, and even directed, although not restricted, to various audiences: a philosophical part, a physical part, and a technological part. For these reasons the article is written on an elementary level, combining simple and non-technical descriptions with a concise review of more advanced results. In this way readers of various provenances will be able to gain while reading the article. PMID- 29105647 TI - STM contrast of a CO dimer on a Cu(1 1 1) surface: a wave-function analysis. AB - We present a method used to intuitively interpret the scanning tunneling microscopy (STM) contrast by investigating individual wave functions originating from the substrate and tip side. We use localized basis orbital density functional theory, and propagate the wave functions into the vacuum region at a real-space grid, including averaging over the lateral reciprocal space. Optimization by means of the method of Lagrange multipliers is implemented to perform a unitary transformation of the wave functions in the middle of the vacuum region. The method enables (i) reduction of the number of contributing tip substrate wave function combinations used in the corresponding transmission matrix, and (ii) to bundle up wave functions with similar symmetry in the lateral plane, so that (iii) an intuitive understanding of the STM contrast can be achieved. The theory is applied to a CO dimer adsorbed on a Cu(1 1 1) surface scanned by a single-atom Cu tip, whose STM image is discussed in detail by the outlined method. PMID- 29105649 TI - Absence of single critical dose for the amorphization of quartz under ion irradiation. AB - In this work, we first simulated the amorphization of crystalline quartz under 50 keV [Formula: see text]Na ion irradiation with classical molecular dynamics (MD). We then used binary collision approximation algorithms to simulate the Rutherford backscattering spectrometry in channeling conditions (RBS-C) from these irradiated MD cells, and compared the RBS-C spectra with experiments. The simulated RBS-C results show an agreement with experiments in the evolution of amorphization as a function of dose, showing what appears to be (by this measure) full amorphization at about 2.2 eV?[Formula: see text]. We also applied other analysis methods, such as angular structure factor, Wigner-Seitz, coordination analysis and topological analysis, to analyze the structural evolution of the irradiated MD cells. The results show that the atomic-level structure of the sample keeps evolving after the RBS signal has saturated, until the dose of about 5 eV?[Formula: see text]. The continued evolution of the [Formula: see text] structure makes the definition of what is, on the atomic level, an amorphized quartz ambiguous. PMID- 29105648 TI - Effect of incorporating clustered silica nanoparticles on the performance and biocompatibility of catechol-containing PEG-based bioadhesive. AB - A composite adhesive capable of inducing cellular infiltration was prepared by incorporating control clustered silica microparticle (MP) derived from the aggregation of silica nanoparticle (NP) into a catechol-terminated poly(ethylene glycol) bioadhesive (PEG-DA). Incorporation of MP into PEG-DA significantly improved the mechanical and adhesive properties of the bioadhesive. There was no statistical difference between the measured values for NP- and MP-incorporated adhesives, indicating that MP was equally as effective in enhancing the material properties of PEG-DA as NP. Most importantly, MP was significantly less cytotoxic when compared to NP when these particles were directly exposed to L929 fibroblast. When the adhesives were implanted subcutaneously in rats, MP containing PEG-DA also exhibited reduced inflammatory responses, attracted elevated levels of regenerative M2 macrophage to its interface, and promoted cellular infiltration due to increased porosity within the adhesive network. Control clustered silica MP can be used to improve the performance and biocompatibility of PEG-based adhesive while minimizing undesirable cytotoxicity of silica NP. PMID- 29105650 TI - Quasiparticle conductance-voltage characteristics for break junctions involving d wave superconductors: charge-density-wave effects. AB - Quasiparticle tunnel conductance-voltage characteristics (CVCs), [Formula: see text], were calculated for break junctions (BJs) made up of layered d-wave superconductors partially gapped by charge-density waves (CDWs). The current is assumed to flow in the ab-plane of electrodes. The influence of CDWs is analyzed by comparing the resulting CVCs with CVCs calculated for BJs made up of pure d wave superconductors with relevant parameters. The main CDW-effects were found to be the appearance of new CVC peculiarities and the loss of CVC symmetry with respect to the V-sign. Tunnel directionality was shown to be one of the key factors in the formation of [Formula: see text] dependences. In particular, the orientation of electrodes with respect to the current channel becomes very important. As a result, [Formula: see text] can acquire a large variety of forms similar to those for tunnel junctions between superconductors with s-wave, d wave, and mixed symmetry of their order parameters. The diversity of peculiarities is especially striking at finite temperatures. In the case of BJs made up of pure d-wave superconductors, the resulting CVC can include a two-peak gap-driven structure. The results were compared with the experimental BJ data for a number of high-T c oxides. It was shown that the large variety of the observed current-voltage characteristics can be interpreted in the framework of our approach. Thus, quasiparticle tunnel currents in the ab-plane can be used as an additional mean to detect CDWs competing with superconductivity in cuprates or other layered superconductors. PMID- 29105651 TI - Suppressed Umklapp scattering of beta-FeSi2 thin film and single crystalline nanowires. AB - Thermal conductivity is an intriguing physical property in the nanometer or quantum regime. In this study, we report the growth and thermal conductivity of beta-FeSi2 thin film and single crystalline nanowires. The sample structures and chemical composition were identified by standard microscopy techniques. The temperature-dependent thermal conductivity of the thin film was measured by the 3omega method, whereas that of the nanowires was conducted by a suspended pattern technique. Temperature-dependent thermal conductivity was found to increase gradually from 300 to 500 K due to the effect of surface scattering. The experimental evidence presented herein is the suppression of Umklapp transport at the nanoscale near room temperature and the potential application of nanoengineered beta-FeSi2 for future design of thermoelectric materials. PMID- 29105652 TI - Spin reorientation and disordered rare earth magnetism in Ho2FeCoO6. AB - We report the experimental observation of spin reorientation in the double perovskite Ho2FeCoO6. The magnetic phase transitions in this compound are characterized and studied through magnetization and specific heat, and the magnetic structures are elucidated through neutron powder diffraction. Two magnetic phase transitions are observed in this compound-one at [Formula: see text] K, from paramagnetic to antiferromagnetic, and the other at [Formula: see text] K, from a phase with mixed magnetic structures to a single phase through a spin reorientation process. The magnetic structure in the temperature range 200 45 K is a mixed phase of the irreducible representations [Formula: see text] and [Formula: see text], both of which are antiferromagnetic. The phase with mixed magnetic structures that exists in Ho2FeCoO6 gives rise to a large thermal hysteresis in magnetization that extends from 200 K down to the spin reorientation temperature. At T N2, the magnetic structure transforms to [Formula: see text]. Though long-range magnetic order is established in the transition metal lattice, it is seen that only short-range magnetic order prevails in the Ho3+ lattice. Our results should motivate further detailed studies on single crystals in order to explore the spin reorientation process, spin switching and the possibility of anisotropic magnetic interactions giving rise to electric polarization in Ho2FeCoO6. PMID- 29105653 TI - Field enhancement of electronic conductance at ferroelectric domain walls. AB - Ferroelectric domain walls have continued to attract widespread attention due to both the novelty of the phenomena observed and the ability to reliably pattern them in nanoscale dimensions. However, the conductivity mechanisms remain in debate, particularly around nominally uncharged walls. Here, we posit a conduction mechanism relying on field-modification effect from polarization re orientation and the structure of the reverse-domain nucleus. Through conductive atomic force microscopy measurements on an ultra-thin (001) BiFeO3 thin film, in combination with phase-field simulations, we show that the field-induced twisted domain nucleus formed at domain walls results in local-field enhancement around the region of the atomic force microscope tip. In conjunction with slight barrier lowering, these two effects are sufficient to explain the observed emission current distribution. These results suggest that different electronic properties at domain walls are not necessary to observe localized enhancement in domain wall currents. PMID- 29105654 TI - Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells. AB - Interleukin-15 (IL-15) is essential for the development and maintenance of natural killer (NK) cells. IL-15 activates STAT5 proteins, which can form dimers or tetramers. We previously found that NK cell numbers are decreased in Stat5a Stat5b tetramer-deficient double knockin (DKI) mice, but the mechanism was not investigated. Here we show that STAT5 dimers are sufficient for NK cell development, whereas STAT5 tetramers mediate NK cell maturation and the expression of maturation-associated genes. Unlike the defective proliferation of Stat5 DKI CD8+ T cells, Stat5 DKI NK cells have normal proliferation to IL-15 but are susceptible to death upon cytokine withdrawal, with lower Bcl2 and increased active caspases. These findings underscore the importance of STAT5 tetramers in maintaining NK cell homoeostasis. Moreover, defective STAT5 tetramer formation could represent a cause of NK cell immunodeficiency, and interrupting STAT5 tetramer formation might serve to control NK leukaemia. PMID- 29105656 TI - Depth dependent stress revealed by aftershocks. AB - Characterising the state of stress in the brittle upper-crust is essential in mechanics of faulting, industrial production processes, and operational earthquake forecasting. Nevertheless, unresolved questions concern the variation of pore-fluid with depth and the absolute strength on tectonically active faults. Here we show that, along the San Andreas fault system, the time-delay before the onset of the power-law aftershock decay rate (the c-value) varies by three orders of magnitude in the first 20 km below the surface. Despite the influence of the lithostatic stress, there is no continuous change in c-value with depth. Instead, two decay phases are separated by an abrupt increase at an intermediate depth range of 2-5 km. This transitional regime is the only one observed in fluid injection-induced seismic areas. This provides strong evidence for the role of fluid and a porosity reduction mechanism at depth of few kilometres in active fault zones. Aftershock statistics can then be used to predict changes in differential shear stress with depth until the brittle-ductile transition is reached. PMID- 29105655 TI - Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. AB - Metastatic cancers produce exosomes that condition pre-metastatic niches in remote microenvironments to favor metastasis. In contrast, here we show that exosomes from poorly metastatic melanoma cells can potently inhibit metastasis to the lung. These "non-metastatic" exosomes stimulate an innate immune response through the expansion of Ly6Clow patrolling monocytes (PMo) in the bone marrow, which then cause cancer cell clearance at the pre-metastatic niche, via the recruitment of NK cells and TRAIL-dependent killing of melanoma cells by macrophages. These events require the induction of the Nr4a1 transcription factor and are dependent on pigment epithelium-derived factor (PEDF) on the outer surface of exosomes. Importantly, exosomes isolated from patients with non metastatic primary melanomas have a similar ability to suppress lung metastasis. This study thus demonstrates that pre-metastatic tumors produce exosomes, which elicit a broad range of PMo-reliant innate immune responses via trigger(s) of immune surveillance, causing cancer cell clearance at the pre-metastatic niche. PMID- 29105657 TI - Gait training after spinal cord injury: safety, feasibility and gait function following 8 weeks of training with the exoskeletons from Ekso Bionics. AB - STUDY DESIGN: Prospective quasi-experimental study, pre- and post-design. OBJECTIVES: Assess safety, feasibility, training characteristics and changes in gait function for persons with spinal cord injury (SCI) using the robotic exoskeletons from Ekso Bionics. SETTING: Nine European rehabilitation centres. METHODS: Robotic exoskeleton gait training, three times weekly over 8 weeks. Time upright, time walking and steps in the device (training characteristics) were recorded longitudinally. Gait and neurological function were measured by 10 Metre Walk Test (10 MWT), Timed Up and Go (TUG), Berg Balance Scale (BBS), Walking Index for Spinal Cord Injury (WISCI) II and Lower Extremity Motor Score (LEMS). RESULTS: Fifty-two participants completed the training protocol. Median age: 35.8 years (IQR 27.5-52.5), men/women: N = 36/16, neurological level of injury: C1-L2 and severity: AIS A-D (American Spinal Injury Association Impairment Scale). Time since injury (TSI) < 1 year, N = 25; > 1 year, N = 27. No serious adverse events occurred. Three participants dropped out following ankle swelling (overuse injury). Four participants sustained a Category II pressure ulcer at contact points with the device but completed the study and skin normalized. Training characteristics increased significantly for all subgroups. The number of participants with TSI < 1 year and gait function increased from 20 to 56% (P = 0.004) and 10MWT, TUG, BBS and LEMS results improved (P < 0.05). The number of participants with TSI > 1 year and gait function, increased from 41 to 44% and TUG and BBS results improved (P < 0.05). CONCLUSIONS: Exoskeleton training was generally safe and feasible in a heterogeneous sample of persons with SCI. Results indicate potential benefits on gait function and balance. PMID- 29105658 TI - Representativeness of the Spinal Cord Injury Model Systems National Database. AB - STUDY DESIGN: Secondary analysis of prospectively collected observational data. OBJECTIVES: To assess the representativeness of the Spinal Cord Injury Model Systems National Database (SCIMS-NDB) of all adults aged 18 years or older receiving inpatient rehabilitation in the United States (US) for new onset traumatic spinal cord injury (TSCI). SETTING: Inpatient rehabilitation centers in the US. METHODS: We compared demographic, functional status, and injury characteristics (nine categorical variables comprising of 46 categories and two continuous variables) between the SCIMS-NDB (N = 5969) and UDS-PRO/eRehabData (N = 99,142) cases discharged from inpatient rehabilitation in 2000-2010. RESULTS: There are negligible differences (<5%) between SCIMS-NDB patients and the population for 31 of the 48 comparisons. Minor differences (5-10%) exist for age categories, sex, race/ethnicity, marital status, FIM Motor score, and time from injury to rehabilitation admission. Important differences (>10%) exist in mean age and preinjury occupational status; the SCIMS-NDB sample was younger and included a higher percentage of individuals who were employed (62.7 vs. 41.7%) and fewer who were retired (10.2 vs. 36.1%). CONCLUSIONS: Adults in the SCIMS-NDB are largely representative of the population of adults receiving inpatient rehabilitation for new onset TSCI in the US. However, users of the SCIMS-NDB may need to adjust statistically for differences in age and preinjury occupational status to improve generalizability of findings. PMID- 29105659 TI - Marine oxygen production and open water supported an active nitrogen cycle during the Marinoan Snowball Earth. AB - The Neoproterozoic Earth was punctuated by two low-latitude Snowball Earth glaciations. Models permit oceans with either total ice cover or substantial areas of open water. Total ice cover would make an anoxic ocean likely, and would be a formidable barrier to biologic survival. However, there are no direct data constraining either the redox state of the ocean or marine biological productivity during the glacials. Here we present iron-speciation, redox sensitive trace element, and nitrogen isotope data from a Neoproterozoic (Marinoan) glacial episode. Iron-speciation indicates deeper waters were anoxic and Fe-rich, while trace element concentrations indicate surface waters were in contact with an oxygenated atmosphere. Furthermore, synglacial sedimentary nitrogen is isotopically heavier than the modern atmosphere, requiring a biologic cycle with nitrogen fixation, nitrification and denitrification. Our results indicate significant regions of open marine water and active biologic productivity throughout one of the harshest glaciations in Earth history. PMID- 29105660 TI - Erratum: A high-salt diet enhances leukocyte adhesion in association with kidney injury in young Dahl salt-sensitive rats. AB - This corrects the article DOI: 10.1038/hr.2017.31. PMID- 29105661 TI - Colour selective control of terahertz radiation using two-dimensional hybrid organic inorganic lead-trihalide perovskites. AB - Controlling and modulating terahertz signals is of fundamental importance to allow systems level applications. We demonstrate an innovative approach for controlling the propagation properties of terahertz (THz) radiation, through use of both the excitation optical wavelength (colour) and intensity. We accomplish this using two-dimensional (2D) layered hybrid trihalide perovskites that are deposited onto silicon substrates. The absorption properties of these materials in the visible range can be tuned by changing the number of inorganic atomic layers in between the organic cation layers. Optical absorption in 2D perovskites occurs over a broad spectral range above the bandgap, resulting in free carrier generation, as well as over a narrow spectral range near the bandedge due to exciton formation. We find that only the latter contribution gives rise to photo induced THz absorption. By patterning multiple 2D perovskites with different optical absorption properties onto a single device, we demonstrate both colour selective modulation and focusing of THz radiation. These findings open new directions for creating active THz devices. PMID- 29105662 TI - Neural Correlates of Impaired Reward-Effort Integration in Remitted Bulimia Nervosa. AB - The integration of reward magnitudes and effort costs is required for an effective behavioral guidance. This reward-effort integration was reported to be dependent on dopaminergic neurotransmission. As bulimia nervosa has been associated with a dysregulated dopamine system and catecholamine depletion led to reward-processing deficits in remitted bulimia nervosa, the purpose of this study was to identify the role of catecholamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa. To investigate the interaction between catecholamine functioning and behavioral, and neural responses directly, 17 remitted bulimic (rBN) and 21 healthy individuals (HC) received alpha-methyl-paratyrosine (AMPT) over 24 h to achieve catecholamine depletion in a randomized, crossover study design. We used functional magnetic resonance imaging (fMRI) and the monetary incentive delay (MID) task to assess reward-effort integration in relation to catecholaminergic neurotransmission at the behavioral and neural level. AMPT reduced the ability to integrate rewards and efforts effectively in HC participants. In contrast, in rBN participants, the reduced reward-effort integration was associated with illness duration in the sham condition and unrelated to catecholamine depletion. Regarding neural activation, AMPT decreased the reward anticipation-related neural activation in the anteroventral striatum. This decrease was associated with the AMPT-induced reduction of monetary earning in HC in contrast to rBN participants. Our findings contributed to the theory of a desensitized dopaminergic system in bulimia nervosa. A disrupted processing of reward magnitudes and effort costs might increase the probability of maintenance of bulimic symptoms. PMID- 29105663 TI - Exacerbated Craving in the Presence of Stress and Drug Cues in Drug-Dependent Patients. AB - In addiction, risk factors for craving and use include stress and drug-related cues. Stress and cues have additive or more-than-additive effects on drug seeking in laboratory animals, but, surprisingly, seem to compete with one another (ie, exert less-than-additive effects) in human laboratory studies of craving. We sought heretofore elusive evidence that human drug users could show additive (or more-than-additive) effects of stress and cues on craving, using ecological momentary assessment (EMA). Outpatients (N=182) maintained on daily buprenorphine or methadone provided self-reports of stress, craving, mood, and behavior on electronic diaries for up to 16 weeks. In three randomly prompted entries (RPs) per day, participants reported the severity of stress and craving and whether they had seen or been offered opioids, cocaine, cannabis, methamphetamine, alcohol, or tobacco. In random-effects models controlling for between-person differences, we tested effects of momentary drug-cue exposure and stress (and their interaction) on momentary ratings of cocaine and heroin craving. For cocaine craving, the Stress * Cue interaction term had a positive mean effect across participants (M=0.019; CL95 0.001-0.036), denoting a more-than-additive effect. For heroin, the mean was not significantly greater than 0, but the confidence interval was predominantly positive (M=0.019; CL95 -0.007-0.044), suggesting at least an additive effect. Heterogeneity was substantial; qualitatively, the Stress * Cue effect appeared additive for most participants, more than additive for a sizeable minority, and competitive in very few. In the field, unlike in human laboratory studies to date, craving for cocaine and heroin is greater with the combination of drug cues and stress than with either alone. For a substantial minority of users, the combined effect may be more than additive. PMID- 29105664 TI - Brain-Behavior Participant Similarity Networks Among Youth and Emerging Adults with Schizophrenia Spectrum, Autism Spectrum, or Bipolar Disorder and Matched Controls. AB - There is considerable heterogeneity in social cognitive and neurocognitive performance among people with schizophrenia spectrum disorders (SSD), autism spectrum disorders (ASD), bipolar disorder (BD), and healthy individuals. This study used Similarity Network Fusion (SNF), a novel data-driven approach, to identify participant similarity networks based on relationships among demographic, brain imaging, and behavioral data. T1-weighted and diffusion weighted magnetic resonance images were obtained for 174 adolescents and young adults (aged 16-35 years) with an SSD (n=51), an ASD without intellectual disability (n=38), euthymic BD (n=34), and healthy controls (n=51). A battery of social cognitive and neurocognitive tasks were administered. Data integration, cluster determination, and biological group formation were then obtained using SNF. We identified four new groups of individuals, each with distinct neural circuit-cognitive profiles. The most influential variables driving the formation of the new groups were robustly reliable across embedded resampling techniques. The data-driven groups showed considerably greater differentiation on key social and neurocognitive circuit nodes than groups generated by diagnostic analyses or dimensional social cognitive analyses. The data-driven groups were validated through functional outcome and brain network property measures not included in the SNF model. Cutting across diagnostic boundaries, our approach can effectively identify new groups of people based on a profile of neuroimaging and behavioral data. Our findings bring us closer to disease subtyping that can be leveraged toward the targeting of specific neural circuitry among participant subgroups to ameliorate social cognitive and neurocognitive deficits. PMID- 29105665 TI - S-Ketamine-Induced NMDA Receptor Blockade during Natural Speech Production and Its Implications for Formal Thought Disorder in Schizophrenia: A Pharmaco-fMRI Study. AB - Structural and functional changes in the lateral temporal language areas have been related to formal thought disorder (FTD) in schizophrenia. Continuous, natural speech production activates the right lateral temporal lobe in schizophrenia, as opposed to the left in healthy subjects. Positive and negative FTD can be elicited in healthy subjects by glutamatergic NMDA blockade with ketamine. It is unclear whether the glutamate system is related to the reversed hemispheric lateralization during speaking in patients. In a double-blind, crossover, placebo-controlled study, 15 healthy, male, right-handed volunteers overtly described 7 pictures for 3 min each while BOLD signal changes were acquired with fMRI. As a measure of linguistic demand, the number of words within 20 s epochs was correlated with BOLD responses. Participants developed S-ketamine induced psychotic symptoms, particularly positive FTD. Ketamine vs placebo was associated with enhanced neural responses in the right middle and inferior temporal gyri. Similar to a previous fMRI study in schizophrenia patients vs healthy controls applying the same design, S-ketamine reversed functional lateralization during speech production in healthy subjects. Results demonstrate an association between glutamatergic imbalance, dysactivations in lateral temporal brain areas, and FTD symptom formation. PMID- 29105667 TI - ? PMID- 29105666 TI - [Low or reduced? Semantics of the doses of new oral anticoagulants]. AB - The four new oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban and edoxaban are marketed in two doses each for the prevention of stroke and/or systemic thromboembolism in non-valvular atrial fibrillation (NVAF). The meaning and indications for use of the lower dose compared with the higher dose are, however, different between the thrombin-inhibitor dabigatran on the one hand and the activated factor X (Xa) inhibitors on the other. These differences stem from the different design of the registration studies where NOACs were compared with warfarin for the prevention of stroke and/or systemic thromboembolism in patients with NVAF. While in the RE-LY study, two different intensities of dabigatran treatment (150 and 110 mg bid) were evaluated in the same population, in the ROCKET AF, ARISTOTLE and ENGAGE AF-TIMI 48 studies two different populations were exposed to the same intensity of treatment, which was obtained however with the selective use of two doses of rivaroxaban (20/15 mg/die), apixaban (5/2.5 mg bid) and edoxaban (60/30 mg/die). With the two doses of dabigatran, efficacy and safety were proportional to treatment intensity. With the two doses of factor Xa inhibitors, the same effect on efficacy and safety was achieved (with the exception of edoxaban, which was further safer with dose reduction). The choice of the dose of dabigatran is therefore discretionary (except for patients aged >=80 years and/or treated with verapamil in whom only 110 mg bid can be prescribed), whereas that of factor Xa inhibitors is obligated. If dabigatran doses are properly defined as high and low and those of factor Xa inhibitors full and reduced, it is useful to memorize that in this context "low" should be semantically considered an adjective while "reduced" a participle. PMID- 29105668 TI - [Testosterone replacement therapy and cardiovascular risk]. AB - Late onset hypogonadism (LOH) is the most commonly used term to indicate the age dependent reduction of testosterone. Sexual dysfunction represents the most important determinant for medical consultation and the most specific symptoms associated with LOH. In particular, data from the European Male Ageing Study (EMAS), a population-based survey on more than 3400 subjects, recognized that a triad of sexual symptoms (low libido and reduced spontaneous and sex-related erections) is the only syndromic association with decreased testosterone levels. Accordingly, a meta-analysis of the available randomized controlled trials documented that testosterone therapy (TTh) is able to improve all aspects of sexual function when compared to placebo. Despite this evidence, however, the relative clinical significance and the potential benefit of TTh in LOH are still the subject of strong criticisms in the scientific community. The debate is further complicated by the recent position statement of the US Food and Drug Administration (FDA) emphasizing a possible increased cardiovascular risk of TTh. However, this position was not endorsed by the European Medicines Association (EMA), which reached an opposite position after a specific review of the available data. In this review, all the conflicting data supporting the different positions of the FDA and EMA will be discussed. In particular, data derived from either population-based studies or interventional trials will be analyzed in detail. Although some evidence suggests an increase in TTh-related cardiovascular risk, the data derived from controlled trials do not support this position especially when the incidence of major adverse cardiovascular events are considered. Symptomatic men with documented reduced testosterone levels can be safely treated with TTh. PMID- 29105669 TI - [Ten questions on Brugada syndrome]. AB - Brugada syndrome is a possible cause of sudden cardiac death in subjects with characteristic ECG pattern (type 1 Brugada ECG pattern). Brugada ECG pattern is not infrequent in the general population and the challenge is to identify within a large population those patients who are really at risk. Unfortunately, this is a partially unresolved problem and this uncertainty determines an inhomogeneous behavior among doctors. Some of them overestimate the risk extensively indicating cardioverter-defibrillator implantation, others apply restrictive indications of guidelines, many are not able to decide without doubts.In this paper we will try to clarify some doubts, to give some certain points, and to draw some perspectives for the future. PMID- 29105670 TI - [Application of a shared interdisciplinary and multiprofessional cardio-oncology in-hospital pathway]. AB - The burden of cardiac side effects in oncology patients will dramatically increase in the near future as a result of the widespread use of anticancer agents affecting the cardiovascular system, the general population aging, the heightened attention in the detection of cardiac toxicity and the absolute gain in terms of overall survival. The relationship between cardiologists and oncologists should therefore be closer leading to the definition of cardio oncology. The increased number of such patients requires the creation of a dedicated patient assistance program in order to guarantee every patient the possibility of an interdisciplinary and multiprofessional approach. A dedicated care pathway needs a reorganization of internal resources to ensure high standards of care. The proposed pathway is actually active at our institution and has been implemented taking into account available facilities and planned work amount. Our patient cardio-oncology program could be adapted with minimal changes to different hospitals. PMID- 29105671 TI - [Role of echocardiography in the assessment of cancer-related cardiac dysfunction]. AB - The use of echocardiography for the assessment of patients undergoing potentially cardiotoxic cancer treatments and for follow-up of treated patients is increasing and has become a significant public health problem due to the need for repeated examinations over time. Despite the technological advances of echocardiography, there are still uncertainties about how best to use this technique to identify and guide the management of cardiotoxicity. The purpose of this article is to discuss the role of echocardiography in the study of ventricular dysfunction due to cancer treatments, with the aim to clarify the main echocardiographic information to be provided, the methods to apply and the strategies to implement to streamline as much as possible the use of echocardiography in the field of cardioncology. PMID- 29105672 TI - [Sinus bradycardia and syncope: what pathophysiological mechanism and what management of the patient?] AB - Sick sinus syndrome (SSS) can be diagnosed only when there is a clear correlation between symptoms and sinus node dysfunction. In the absence of such correlation, the mechanism of undocumented intermittent symptoms such as syncopal spells in patients with permanent mild sinus bradycardia remains uncertain. Some clinical data suggest that a reflex mechanism is likely to be involved in many patients with syncope and sinus bradycardia: the course of syncopal recurrences is very variable from patient to patient and transient loss of consciousness does not recur in more than half of unpaced patients during an observation period of several years. The results of some studies seem to confirm a reflex mechanism as the cause of syncope in most cases: in patients with SSS and syncope the prevalence of positive response to tilt testing was high (~60%) and significantly higher than in patients with SSS without syncope and in other control groups. However, a depressed sinus node automaticity, roughly expressed by very prolonged sinus node recovery time, suggests a role of sinus node dysfunction in the origin of syncope. Patients with permanent mild sinus bradycardia and syncope as an isolated symptom should undergo tilt testing and electrophysiological study. In the presence of positive tilt test without very prolonged sinus node recovery time, the patient should be managed as the patients with neurally mediated syncope and normal sinus rate. PMID- 29105673 TI - [Sexual activity in women with cardiovascular disease: a literature review]. AB - Female sexual dysfunction (FSD) is a complex condition that involves both psychological and organic domains, including the cardiovascular system, and has an impact on quality of life in more than one third of women. However, only few papers are available in the medical literature regarding FSD and its relation with cardiac diseases. In this review, we discuss the physiology of sexual intercourse in women, the pathophysiology of FSD, the sexual counseling to provide, and the therapeutic choices to minimize the negative impact of cardiovascular diseases on female sexual activity. PMID- 29105674 TI - [Lack of association between LDL-cholesterol and carotid intima-media thickness in elderly women]. AB - BACKGROUND: It is known that the association between LDL-cholesterol (LDL-C) and cardiovascular morbidity and mortality in the elderly is controversial. The aim of this study was to investigate this issue using carotid intima-media thickness as a marker of cardiovascular disease. METHODS: Women aged 35-79 years were consecutively enrolled in the study. They underwent a questionnaire to assess cardiovascular disease, a clinical examination to assess blood pressure and anthropometric variables, a biochemical evaluation of lipid profile and glucose, and an ultrasound evaluation of carotid arteries. The study population was divided into two age groups (<=65 years and >65 years), and each group was then divided into two subgroups according to LDL-C level (normal and high). A Student's t-test was used to compare mean values between groups, and a chi square test was used to compare the prevalence of carotid atherosclerosis. RESULTS: A lack of association between LDL-C and carotid intima-media thickness was observed in subjects aged >65 years, with the intima-media thickness average being similar between those with and without high LDL-C. Conversely, a significant difference in carotid intima-media thickness was observed among adults with and without high LDL-C level. CONCLUSIONS: Our findings, similar to those obtained in other epidemiological studies, provide the rationale for revising the use of statins in elderly women without cardiovascular disease. PMID- 29105675 TI - [A case of pulmonary artery sarcoma and review of the literature]. AB - Pulmonary artery sarcoma (PAS) is a highly malignant tumor that originates in the pulmonary artery. This disease has a poor prognosis. Early diagnosis followed by radical surgical resection constitutes the only chance of survival for patients. However, owing to the rare and nonspecific clinical manifesta-tions and imaging findings, PAS is frequently misdiagnosed as various pulmonary thromboembolic diseases. We report the case of a 49-year-old woman who presented to our emergency department for dyspnea, hemoptysis, cough, and asthenia. A diagnosis of pulmonary thromboembolism was initially postulated. However, the rapid clinical progression of the disease, characterized by multiorgan involvement, together with the persistence of pulmonary filling defects despite appropriate anticoagulation therapy, induced to a late diagnosis of metastasized PAS. The peculiarity of our case consists of two main factors: the first is the atypical clinical presentation characterized by severe neurological impairment that finally led to patient's death; the second is the histopathological aspect of the lesion with a prevalent histiocytic cell component that is described in the literature as the less frequent pathological variant of this tumor. PMID- 29105676 TI - [Endovascular treatment of a celiac trunk aneurysm: a case report and review of the literature]. AB - Celiac trunk aneurysms are uncommon vascular lesions; treatment is usually an open surgical operation; in the medical literature, only few cases of celiac aneurysm treated with endovascular technique are reported; coil positioning or stent-graft placement are described using a femoral vascular access as first choice.Here we describe the case of a 57-year-old man with an asymptomatic large celiac trunk aneurysm involving the origin of the splenic, left gastric and hepatic arteries. The patient was treated in an elective clinical setting with a totally endovascular procedure performed through the left radial artery. First, two vascular plugs were put into splenic and gastric artery, respectively, to prevent type II endoleak, then the aneurysm was closed using a balloon expandable stent-graft into the celiac trunk-hepatic axis. The procedure was completed without any complication. The computed tomography angiography scan confirmed total occlusion of the aneurysm and normal blood flow in the visceral arteries.This case shows that endovascular technique is effective and safe also for the treatment of very complex vascular lesions, and radial access could be considered the preferred choice to minimize access-related vascular complications. PMID- 29105677 TI - [Saphenous vein graft aneurysm: percutaneous exclusion using detachable coils]. AB - We report the case of a 78-year-old man admitted to the emergency department for typical angina onset with evidence of a large aneurysm of the coronary artery venous bypass graft, successfully closed using a percutaneous approach. PMID- 29105678 TI - [Prof. Giorgio Antonio Feruglio]. PMID- 29105680 TI - ? PMID- 29105679 TI - [A practical tool for easier compilation of AIFA (Italian Medicines Agency) web based registry for PCSK9 inhibitor prescription]. PMID- 29105681 TI - [The RIVER-PCI study]. PMID- 29105682 TI - [The LEADERS FREE study]. PMID- 29105683 TI - [Palliative care in the intensive cardiac care unit: a new competence for the cardiac intensivist]. AB - Admissions to the intensive care unit at the end of life of patients with chronic non-malignant diseases are increasing. This involves the need for the development of palliative care culture and competence, also in the field of intensive cardiology. Palliative care should be implemented in the treatment of all patients with critical stages of disease, irrespective of prognosis, in order to improve the quality of care at the end of life.This review analyzes in detail the main clinical, ethical and communicational issues to move toward the introduction of basics of palliative care in cardiac intensive care units. It outlines the importance of shared decision-making with the patient and his family, with special attention to withholding/withdrawing of life-sustaining treatments, palliative sedation, main symptom control, patient and family psychological support. PMID- 29105684 TI - [Cardiogenic shock: from early diagnosis to multiparameter monitoring]. AB - Cardiogenic shock (CS) is a life-threatening condition that occurs in response to reduced cardiac output, in the presence of adequate intravascular volume, and results in tissue hypoxia. CS can occur as a result of several etiologies but the most common is acute myocardial infarction. Despite the introduction of emergency revascularization for CS complicating acute myocardial infarction, mortality still remains exceptionally high, particularly in patients with refractory CS. The diagnosis of CS is sometimes challenging and it is based on clinical, hemodynamic, and biochemical signs. A multidisciplinary technical platform as well as specialized and experienced medical teams are crucial to treat this group of patients.We briefly summarize the main aspects of diagnosis, etiology and pathophysiology with a particular focus on macro- and microhemodynamic parameters that are essential for the diagnosis and treatment of this patient population. PMID- 29105685 TI - [Cardiogenic shock: from pharmacological treatment to mechanical circulatory support]. AB - Cardiogenic shock (CS) is a state of critical end-organ hypoperfusion due to reduced cardiac output, despite adequate filling status. The development of multiorgan dysfunction is believed to be the major contributor to the high early mortality. Little evidence exists as to which vasopressor or inotrope should best be used for early treatment; however, customized pharmacological therapy, tailored on hemodynamic monitoring, is essential to achieve normal peripheral perfusion. Moreover, an increasing number of mechanical circulatory support devices are available for hemodynamic support in patients with CS but, at present, data derived from randomized clinical trials on the effectiveness, safety, differential indications for mechanical support devices, and optimal implant timing are limited.The aim of this review is to offer an overview of the pharmacological and device options, providing a practical approach to the treatment of patients with CS. PMID- 29105686 TI - [Cardiogenic shock is a rare disease: the dedicated network]. AB - Cardiogenic shock (CS) is a rare disease that needs a rapid and multiparameter diagnosis and a timely, aggressive and multidisciplinary goal-oriented treatment. Recently published epidemiological studies and registries underline how SC represents an infrequent clinical entity still burdened by high mortality rates, substantially unchanged over the years. Currently, only few patients with CS are treated with circulatory assistance in dedicated centers. Some consensus documents and expert recommendations emphasize the importance of early diagnosis of CS, immediate pharmacological support, and treatment of precipitating causes, and stress the need for hospitalization in high-volume intensive care centers. The aim of this review is to show the instructions for the creation of a SC network, emphasizing the necessary elements, in agreement with available resources and existing health regulations for giving the same care opportunities to all the patients. PMID- 29105687 TI - [Early and mid-term results of the transapical aortic valve Symetis Acurate TA: a viable solution in high-risk patients with severe vascular disease]. AB - BACKGROUND: Aortic valve stenosis is the most common valvular disease in the elderly. Transcatheter aortic valve implantation represents a viable alternative to conventional aortic valve replacement. In our Department, the transapical approach is the preferred method in patients with severe peripheral vascular disease. The aim of this study was to analyze the early and midterm results of Symetis Acurate TA implantation in our series. METHODS: From June 2013 to January 2017, 21 patients with severe peripheral vascular disease (11 male, mean age 78 +/- 2.8 years) underwent transapical implantation of the Symetis Acurate TA device. Mean logistic EuroSCORE I was 21.9 +/- 8.6, mean left ventricular ejection fraction was 51.9 +/- 12.2%, and mean aortic gradient was 46.7 +/- 12.3 mmHg. Valve implantation was performed through a left anterior minithoracotomy. Patients were followed up on a regular basis. Cardiac echocardiographic assessment was performed at 6 months post-implantation. RESULTS: Valve implantation was successful in all patients. Valve sizes were as follows: 7 size S, 6 size M, and 8 size L. Two patients died before hospital discharge (9.5%). Among survivors, 2 patients showed more than mild aortic regurgitation at discharge. Mean aortic gradient was 13.1 +/- 4.3 mmHg (p<0.01). Median follow-up was 11.3 months. Mean NYHA class at follow-up was 1.9 +/- 0.4 (p<0.05). Mean actuarial survival was 80%. CONCLUSIONS: Our series, even if small, demonstrates that transapical implantation of the Symetis Acurate TA device represents a viable solution in patients with severe peripheral vascular disease carrying a high operative risk. The relatively high operative mortality may be attributable to the learning curve of our team. PMID- 29105688 TI - [Valve-in-valve treatment of a degenerated supra-annular stentless bioprosthesis using a balloon-expandable transcatheter valve in a patient at high risk for coronary occlusion]. AB - Transcatheter valve-in-valve treatment of degenerated supra-annular stentless bioprostheses may be challenging and associated with a high risk of coronary occlusion. Preprocedural imaging evaluation is a key step to assess feasibility and to minimize or prevent coronary occlusion. We report the case of a degenerated Freedom Solo valve, treated with a balloon-expandable valve and a previously deflated stent positioned at the level of both coronary ostia. The procedure was successful but stent inflation at the right coronary ostium was required due to slow flow that occurred after valve implantation. PMID- 29105689 TI - [Feasibility and safety of right subclavian access for Edwards Sapien 3 balloon expandable transcatheter aortic valve implantation]. AB - Despite the technical advancements in transcatheter aortic valve implantation (TAVI), this procedure in patients with peripheral artery disease remains challenging and requires a patient-tailored management by the Heart Team. In depth assessment of the patient's vascular anatomy is of utmost importance for the management of TAVI procedures with the aim to use the less invasive approach according to the specific patient characteristics. The trans-subclavian approach should be the preferred option in patients with femoral arterial disease undergoing TAVI; however, self-expandable valves have potential limitations, as in case of ascending aorta dilation and high implantation. We present an elegant solution to overcome this challenging situation with good short- and mid-term outcome. A balloon-expandable Edwards Sapien 3 prosthesis was implanted by right subclavian surgical access using a multistep approach. The imaging controls showed good positioning with trivial paravalvular leak. The right subclavian approach for balloon-expandable TAVI implantation is feasible and safe when performed by skilled operators and can be a valid treatment strategy when no other options are available. PMID- 29105690 TI - [Quadricuspid aortic valve in a patient with previous patent arterial duct closure]. PMID- 29105693 TI - [Public health research in obstetrics coordinated by the Italian National Health Institute.] AB - The Italian National Institute of Health (ISS) has set up a population-based surveillance system for maternal mortality and severe morbidity that covers 75% of total births and promotes the prevention of avoidable outcomes through knowledge-based action. The surveillance system promotes the continuous training of health professionals by distance learning, provides recommendations for clinical practice under the auspices of the ISS - National Guidelines System and strengthens a "no blame" culture among health professionals. PMID- 29105694 TI - ["Handle with care": about the potential unintended consequences of oracular artificial intelligence systems in medicine.] AB - Decisional support systems based on machine learning (ML) in medicine are gaining a growing interest as some recent articles have highlighted the high diagnostic accuracy exhibited by these systems in specific medical contexts. However, it is implausible that any potential advantage can be obtained without some potential drawbacks. In light of the current gaps in medical research about the side effects of the application of these new AI systems in medical practice, in this article we summarize the main unexpected consequences that may result from the widespread application of "oracular" systems, that is highly accurate systems that cannot give reasonable explanations of their advice as those endowed with predictive models developed with ML techniques usually are. These consequences range from the intrinsic uncertainty in the data that are used to train and feed these systems, to the inadequate explainability of their output; through the risk of overreliance, deskilling and context desensitization of their end-users. Although some of these issues may be currently hard to evaluate due to the still scarce adoption of these decisional systems in medical practice, we advocate the study of these potential consequences also for a more informed policy of approval beyond hype and disenchantment. PMID- 29105695 TI - [GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction.] AB - Following the development of a unifying and transparent approach to grading the certainty of evidence and strength or recommendations, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group has refined its process of moving from Evidence to Decisions. The purpose of its new Evidence to Decision (EtD) frameworks is to help people use evidence in a structured and transparent way to inform decisions in the context of clinical recommendations, coverage decisions, and health system or public health recommendations and decisions. EtD frameworks inform users about the judgments that were made and the evidence supporting those judgments by making the basis for decisions transparent to target audiences. EtD frameworks also facilitate dissemination of recommendations and enable decision makers in other jurisdictions to adopt recommendations or decisions, or adapt them to their context. PMID- 29105696 TI - [Women and post-natal care: analysis of a rooming-in facility.] AB - INTRODUCTION: The practice of rooming-in (R-in) is widely but heterogeneously applied in Italian hospitals and consists in keeping babies in the same room with their mothers from the moment of birth through to the discharge. AIM: Explore the perception and use of R-in among Italian mothers who gave birth in a context where R-in is offered 24h. We aimed at comparing differences among women who consistently use the R-in practice to those who do not. METHOD: Sixty-five women in good health (average age=33.8 years old; sd=4.2) were assigned to two different groups: mothers who always kept their baby in the room (n=35) and mothers who referred their babies more than once to the nursery care (n=30). Women completed a questionnaire about their pregnancy, delivery, hospitalization, and R-in. Medical records were also collected. The two groups were compared with regard to medical/obstetrician/socio-demographic factors, as well as their perception of R-in. RESULTS: We observed no differences in terms of maternal age, education, and parity among the two groups. Women who had undergone Caesarean section were more likely to make use of the nursery care up to 72 hours after delivery (chi2=11,11, p<,001). A considerable proportion of the study population (42%) considered the level of information received about R-in unsatisfying; this percentage is higher (55%) among women who referred to the nursery. DISCUSSION: Women differ in the degree of R-in application use depending on the type of delivery and the subsequent maternal physical condition. It is important to support women by offering them a flexible service that accounts for their possible physical difficulties. Besides, it is crucial to provide an adequate level of information about R-in, so that mothers can feel in control of the situation, especially if they underwent Caesarean section. PMID- 29105697 TI - [Health education, what is the role for pharmacist? Results from a cross sectional study in Umbria, Italy.] AB - INTRODUCTION: Nowadays, the community pharmacist's role is undergoing profound transformations. As a healthcare provider of the National Health Service, pharmacists are expanding their expertise in Public Health through disease prevention and health promotion programme. In relation to health education and health promotion interventions, this research was aimed to evaluate the knowledge, attitudes and behaviours of a selected sample of private and public pharmacists, working in the Province of Perugia and Terni, Umbria region. METHODS: Cross-sectional study conducted using two detection tools: a 29-items self-administered, anonymous questionnaire and a 21-items environmental evaluation sheet, compiled by students of Pharmaceutical Sciences. RESULTS: 70% of umbrian pharmacists participated in the project, 68.9% of them consider health education interventions "very important", 57% support the gratuity of these interventions with a 14.5 hours/week dedicated to these activities. CONCLUSIONS: The survey shows a good pharmacist sensitivity to the issues of health education. Actually, the pharmacist can and should play an essential role in responsibly involving all citizens in promoting new health behaviours in collaboration with physicians. PMID- 29105699 TI - Focus on aggressive behaviour in mental illness. AB - Background: Aggression is a behaviour with evolutionary origins, but in today's society it is often both destructive and maladaptive. Increase of aggressive behaviour has been observed in a number of serious mental illnesses, and it represents a clinical challenge for mental healthcare provider. These phenomena can lead to harmful behaviours, including violence, thus representing a serious public health concern. Aggression is often a reason for psychiatric hospitalization, and it often leads to prolonged hospital stays, suffering by patients and their victims, and increased stigmatization. Moreover, it has an effect on healthcare use and costs in terms of longer length of stay, more readmissions and higher drug use. Materials and methods: In this review, based on a selective search of 2010-2016 pertinent literature on PubMed, we analyze and summarize information from original articles, reviews, and book chapters about aggression and psychiatric disorders, discussing neurobiological basis and therapy of aggressive behaviour. Results: A great challenge has been revealed regarding the neurobiology of aggression, and an integration of this body of knowledge will ultimately improve clinical diagnostics and therapeutic interventions. The great heterogeneity of aggressive behaviour still hampers our understanding of its causal mechanisms. Still, over the past years, the identification of specific subtypes of aggression has released possibilities for new and individualized treatment approaches. Conclusions: Neuroimaging studies may help to further elucidate the interrelationship between neurocognitive functioning, personality traits, and antisocial and violent behaviour. Recent studies point toward manipulable neurobehavioral targets and suggest that cognitive, pharmacological, neuromodulatory, and neurofeedback treatment approaches can be developed to ameliorate urgency and aggression in schizophrenia. These combined approaches could improve treatment efficacy. As current pharmacological and therapeutic interventions are effective but imperfect,new insights into the neurobiology of aggression will reveal novel avenues for treatment of this destructive and costly behaviour. PMID- 29105700 TI - [Seeking compulsory treatment as life-saving in the presence of eating disorders: a complex choice]. AB - Eating disorders (and especially anorexia nervosa) are associated with severe disability, poor quality of life and high mortality rate. Anorexia nervosa ranks among the main causes of death among young women. Despite physical and psycho social impairment, patients suffering from anorexia nervosa do not recognize low body weight and extreme calorie restriction as a clinical problem and are ambivalent towards treatment. Some patients with anorexia nervosa refuse treatments though presenting severe medical complications and having a high mortality risk. Hence the need to evaluate when it could be appropriate to prescribe a compulsory treatment in the more complex cases who refuse interventions, deemed necessary for them. To date, the compulsory treatment in anorexia nervosa is still under debate: some authors take into account the negative impact on the therapeutic relationship, other authors consider it as a compassionate treatment or as life-saving therapy. Indeed, compulsory treatment for eating disorders must always be weighed very carefully because it is considered by law as the highest form of restriction of personal freedom. Political Institutions must provide a clear framework for the society and for professionals, while the health care services must face the problem of the adequacy of available resources (not only in terms of hospital beds but also of skilled professionals) compared to patients' needs, considering the organization and the integration of clinical services dedicated to the treatment of eating disorders. PMID- 29105701 TI - [Engagement as motivational driver. Processes of change in an Italian department of mental health]. AB - The health care reforms of last years have deeply affected the National Health System, resulting in the need for a change in organizational processes and a more efficient and dynamic change management. An effective change management is not possible without a deep involvement (engagement) of professionals, which is itself a key requisite for motivation. This study aims to examine the main instruments of engagement management, as a tool of change according to a modern reorganization approach. We examine the results of this process in the Mental Health Department of the Local Health Company Naples 3 South in recent years, starting with the analysis of its main weaknesses. PMID- 29105702 TI - [Group-based rehabilitative interventions in the Department of Mental Health of Viterbo, Italy]. AB - : Standard treatment provided by mental health services, mainly based on drug therapy and individual sessions, does not help patients to enhance their capacity to prevent and manage crises. AIM: This paper aims at examining the effectiveness of four group-based rehabilitative interventions carried out in the Acute Psychiatric Inpatient Ward and in the Department of Mental Health of Viterbo, Italy. METHODS: The effectiveness of the four group-based interventions on patients and their relatives was evaluated in both inpatient and outpatient settings in terms of clinical efficacy, disease awareness, quality of life, and ability to cope with stress. A set of specific assessment tools was used for the purpose. RESULTS: Group-based interventions showed high level of effectiveness in improving patients' insight, clinical stability, quality of life and satisfaction in using the services, and in enhancing family members' ability to manage stress. CONCLUSIONS: Group-based rehabilitative interventions enable mental health services to provide users with additional treatment options complementary to drug therapy, improving the quality of life of patients and their families in a recovery-oriented perspective. PMID- 29105703 TI - [Disturbo dissociativo d'identita, auto-ipnosi e sintomi simil-psicotici: da un caso clinico a un problema di diagnosi differenziale]. AB - We report a case of a forty-nine-year-old patient suffering from his first psychiatric episode, who required hospitalization in a psychiatric unit. The presence of mood alterations with Schneiderian first-rank symptoms could have suggested an initial diagnosis of bipolar disorder (BD) with psychotic symptoms, directing the patient towards a definite therapeutic process. However, we hypothesized that the presence of a clear dissociative state similar to the hypnotic trance preceded by an uncontrolled self-hypnosis process, the presence of 'inner voices' and a high vulnerability to dissociation, were all elements that may reasonably lead to a diagnosis of Dissociative Identity Disorder (DID). Several authors have reported the presence of psychotic-like symptoms in patients with DID. However, in clinical practice there is a tendency not to acknowledge the possibility of dissociative disorders diagnoses, in favor of others more frequent psychiatric disorders. This paper aims to highlight some etiopathogenetic and psychopathological features that might help clinicians in identifying a DID. PMID- 29105704 TI - ? PMID- 29105705 TI - Guest control of a hydrogen bond-catalysed molecular rotor. AB - Herein, the control of a molecular rotor using hydrogen bonding guests is demonstrated. With a properly positioned phenol substituent, the N-arylimide rotors can form an intramolecular hydrogen bond that catalyses the rotational isomerization process. The addition of the guests disrupts the hydrogen bond and raises the rotational barrier, slowing the rotation by two orders of magnitude. PMID- 29105706 TI - Coincident velocity map image reconstruction illustrated by the single-photon valence photoionisation of CF3SF5. AB - Velocity map imaging offers high energy resolution and collection efficiency of the steady flux of photoelectrons and ions in continuous photoionisation experiments. In this proof-of-principle work, we show by the photoionisation of trifluoromethyl sulphur pentafluoride, CF3SF5, that the four-dimensional problem of reconstructing coincident velocity map images of electrons and ions of certain mass can be addressed by separating the energy distribution from the angular anisotropy. The energy spectrum is predominantly determined by the radial distribution of the image, whereas laboratory frame angular anisotropies are revealed based on the radial distribution of the image multiplied with a 2nd degree Legendre polynomial. The reconstruction yields the energy correlation between the photoion and the photoelectron characteristic of the photoelectron spectrum and the kinetic energy release. The angular anisotropy beta-parameter maps of the photoelectrons and photoions are also obtained as 2D functions of the electron and ion kinetic energies. For photoionisation of CF3SF5, the energy correlation reveals suprastatistical kinetic energy release (KER) in CF3+ production in the ground cationic X[combining tilde]+ state, but statistical KER in the excited A+ and B[combining tilde]+ state bands. Although the photoelectron distribution is isotropic, the photoion anisotropy in the energy range of the X[combining tilde]+ state speaks for prompt dissociation after preferential ionisation of CF3SF5 molecules aligned with the polarisation vector of the synchrotron radiation. The angular dependence of the photoionisation cross section is confirmed by ab initio calculations for vertical ionisation. PMID- 29105707 TI - Probing promoting effects of alkali cations on the reduction of CO at the aqueous electrolyte/copper interface. AB - The catalytic selectivity and reactivity of an electrocatalytic interface can profoundly depend on the identity of the supporting electrolyte's cation. In the case of CO2 reduction on copper electrodes, these cation effects have been utilized to suppress undesired hydrogen evolution and to promote the formation of C2 reduction products. However, to more effectively steer the catalytic selectivity of the electrolyte/copper interface by cations, it is crucial to reveal the various physical mechanisms by which cations impact the catalytic properties of this prototypical interface for CO2 reduction. Herein, we employ surface-sensitive infrared spectroscopy to probe how alkali cations (Li+, K+, and Cs+) control the coverage of CO, a key intermediate in CO2 reduction, on a polycrystalline copper electrode. We find that surface-adsorbed CO experiences an increasingly larger interfacial electric field with increasing cation size. The reduction of CO is further promoted by the two larger cations, leading to a significant drop of the CO coverage at high cathodic potential around -1 V vs. RHE. Our results demonstrate for the first time that the coverage of CO on the electrode is very sensitive to the identity of the cation. Since the relative coverage of CO and hydrogen on the copper surface affects the catalytic rates of CO2 reduction and hydrogen evolution, our results represent an essential step towards a better understanding of how cation effects control the product distribution. PMID- 29105708 TI - Role of free electrons in phosphorescence in n-type wide bandgap semiconductors. AB - Long persistent phosphorescence is generally known as a phenomenon involving carrier traps induced by defects or impurities in crystals. In this paper, phosphorescence sustained for tens of minutes was found in intentionally undoped ZnO and it was proposed to be a universal phenomenon in wide bandgap semiconductors upon satisfying several conditions. A new model was built to understand this attractive phenomenon within the framework of the traditional trapping-detrapping model but it was modified by considering the free electrons in the conduction band as a significant contributor to the long persistent phosphorescence besides the electrons trapped by shallow donors. This model, explicitly expressed as I(t) ? [1 + M(1 - Fe-gammat)-2]e-gammat, is not only capable of giving a quantitative description of the non-exponential decay of phosphorescence in a wide temperature range but also enables one to determine the depth of shallow donors in semiconductors. The participation of free electrons in phosphorescence was further confirmed by another carefully designed experiment. Thus, this study may represent significant progress in understanding phosphorescence. PMID- 29105709 TI - Solvent-free iodine-promoted synthesis of 3,2'-pyrrolinyl spirooxindoles from alkylidene oxindoles and enamino esters under ball-milling conditions. AB - A novel solvent-free iodine-promoted cyclization of alkylidene oxindoles with enamino esters via C-C/C-N bond formation has been demonstrated under ball milling conditions. This protocol provides efficient and green access to a variety of 3,2'-pyrrolinyl spirooxindoles with remarkable functional group tolerance, good yields and excellent diastereoselectivities. PMID- 29105710 TI - Pd(NHC)-catalyzed alkylsulfonylation of boronic acids: a general and efficient approach for sulfone synthesis. AB - Robust N-heterocyclic carbene palladium complexes are highly efficient catalysts for direct alkylsulfonylation of (hetero)aryl- or alkenyl-boronic acids with potassium metabisulfite and (hetero)alkyl-halides. Among them, acenaphthoimidazolylidene palladium(ii) complexes exhibited the highest activities, and up to quantitative yields were obtained for diverse structurally distinct sulfones under very mild reaction conditions. PMID- 29105711 TI - A novel bacteriochlorin-styrylnaphthalimide conjugate for simultaneous photodynamic therapy and fluorescence imaging. AB - Propargyl-152,173-dimethoxy-131-amide of bacteriochlorin e (BChl) and a 4-(4-N,N dimethylaminostyryl)-N-alkyl-1,8-naphthalimide bearing azide group in the N-alkyl fragment were conjugated by the copper(i)-catalyzed 1,3-dipolar cycloaddition to produce a novel dyad compound BChl-NI for anticancer photodynamic therapy (PDT) combining the modalities of a photosensitizer (PS) and a fluorescence imaging agent. A precise photophysical investigation of the conjugate in solution using steady-state and time-resolved optical spectroscopy revealed that the presence of the naphthalimide (NI) fragment does not decrease the photosensitizing ability of the bacteriochlorin (BChl) core as compared with BChl; however, the fluorescence of naphthalimide is completely quenched due to resonance energy transfer (RET) to BChl. It has been shown that the BChl-NI conjugate penetrates into human lung adenocarcinoma A549 cells, and accumulates in the cytoplasm where it has a mixed granular-diffuse distribution. Both NI and BChl fluorescence in vitro provides registration of bright images showing perfectly intracellular distribution of BChl-NI. The ability of NI to emit light upon excitation in imaging experiments has been found to be due to hampering of RET as a result of photodestruction of the energy acceptor BChl unit. Phototoxicity studies have shown that the BChl-NI conjugate is not toxic for A549 cells at tested concentrations (<8 MUM) without light-induced activation. At the same time, the concentration-dependent killing of cells is observed upon the excitation of the bacteriochlorin moiety with red light that occurs due to reactive oxygen species formation. The presented data demonstrate that the BChl-NI conjugate is a promissing dual function agent for cancer diagnostics and therapy. PMID- 29105712 TI - Oxygenated group and structural defect enriched carbon nanotubes for immobilizing gold nanoparticles. AB - Surface functionalized and defect enriched carbon nanotubes (oCNTs) by green ozone/H2O treatment can efficiently anchor gold nanoparticles. This Au/oCNT could be stabilized and well dispersed after thermal treatment and showed robust catalytic activity (20.6 mmol gcat-1 h-1) for the oxidative self-coupling of benzylamine to imine in solvent free conditions. PMID- 29105713 TI - Electrophilicity of oxalic acid monomer is enhanced in the dimer by intermolecular proton transfer. AB - We have analyzed the effect of excess electron attachment on the network of hydrogen bonds in the oxalic acid dimer (OA)2. The most stable anionic structures may be viewed as complexes of a neutral hydrogenated moiety HOA coordinated to an anionic deprotonated moiety (OA-H)-. HOA acts as a double proton donor and (OA-H) as a double proton acceptor. Thus the excess electron attachment drives intermolecular proton transfer. We have identified several cyclic hydrogen bonded structures of (OA)2-. Their stability has been analyzed in terms of the stability of the involved conformers, the energetic penalty for deformation of these conformers to the geometry of the dimer, and the two-body interaction energy between the deformed HOA and (OA-H)-. There are at least seven isomers of (OA)2- with stabilization energies in the range of 1.26-1.39 eV. These energies are dominated by attractive two-body interaction energies. The anions are vertically bound electronically by 3.0-3.4 eV and adiabatically bound by at least 1.6 eV. The computational predictions are consistent with the anion photoelectron spectrum of (OA)2-. The spectrum consists of a broad feature, with an onset of 2.5 eV and spanning to 4.3 eV. The electron vertical detachment energy (VDE) is assigned to be 3.3 eV. PMID- 29105714 TI - Oxygen induced enhancement of NIR emission in brookite TiO2 powders: comparison with rutile and anatase TiO2 powders. AB - Brookite TiO2 attracts considerable attention in photocatalysis owing to its superior performance in several photocatalytic reactions. In this work, we investigated the behavior of charge carriers in brookite, rutile, and anatase TiO2 by using photoluminescence (PL) and transient absorption (TA) spectroscopies. PL measurements revealed that brookite TiO2 exhibits a visible and a NIR emission at ~520 nm and ~860 nm, respectively. Addition of methanol vapor quenched both the visible and NIR emissions by the hole-consuming reaction of methanol. However, exposure to O2 shows curious behaviors: the visible emission was quenched but the NIR emission was enhanced. These results can be accounted for by the enhancement of upward band bending resulting in the effective separation of electrons and holes into the bulk and the surface, respectively. Furthermore, the shallowly trapped electrons, which are responsible for visible PL, are consumed by O2; hence, the visible emission is quenched. However, in the case of NIR emission, the deeply trapped electrons are responsible and they are mainly located at the surface defects. The O2 adsorption promotes the hole accumulation at the surface and then assists the recombination of these deeply trapped electrons, resulting in the enhancement of the NIR emission. We also found that the lifetime of NIR emission (tau1 = 43 +/- 0 ns and tau2 = 589 +/- 1 ns) was much longer than that of visible emission (tau1 = 15 +/- 0 ns and tau2 = 23 +/- 0 ns), since the mobility of these deeply trapped electrons to encounter with holes is lower than that of the shallowly trapped electrons. However, even for this slow NIR emission, the actual lifetime of the deeply trapped electrons estimated by TA (1.5 +/- 0.0 MUs and 17 +/- 0 MUs) was one or two orders of magnitude longer, confirming that non-radiative recombination is dominant and it is much slower than radiative recombination: TAS and PL provide detailed information on the radiative and non-radiative recombination processes. The PL of anatase and rutile TiO2 powders was also measured and the difference from brookite TiO2 was discussed. PMID- 29105715 TI - Vertically stacked nanocellulose tactile sensor. AB - Paper-based electronic devices are attracting considerable attention, because the paper platform has unique attributes such as flexibility and eco-friendliness. Here we report on what is claimed to be the firstly fully integrated vertically stacked nanocellulose-based tactile sensor, which is capable of simultaneously sensing temperature and pressure. The pressure and temperature sensors are operated using different principles and are stacked vertically, thereby minimizing the interference effect. For the pressure sensor, which utilizes the piezoresistance principle under pressure, the conducting electrode was inkjet printed on the TEMPO-oxidized-nanocellulose patterned with micro-sized pyramids, and the counter electrode was placed on the nanocellulose film. The pressure sensor has a high sensitivity over a wide range (500 Pa-3 kPa) and a high durability of 104 loading/unloading cycles. The temperature sensor combines various materials such as poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS), silver nanoparticles (AgNPs) and carbon nanotubes (CNTs) to form a thermocouple on the upper nanocellulose layer. The thermoelectric-based temperature sensors generate a thermoelectric voltage output of 1.7 mV for a temperature difference of 125 K. Our 5 * 5 tactile sensor arrays show a fast response, negligible interference, and durable sensing performance. PMID- 29105716 TI - Hydrogen bonds, and sigma-hole and pi-hole bonds - mechanisms protecting doublet and octet electron structures. AB - The hydrogen bond interaction and sigma-hole and pi-hole bonds are steered by the same mechanisms. There is electron charge transfer from the Lewis base to the Lewis acid unit, and further, for various interactions the same mechanisms try to protect the former electronic structure of the Lewis acid centre. The increase of the polarization of bonds to this centre seems to be the common effect. In the case of the A-HB hydrogen bond it is the increase of the polarization of the A-H bond connected with the outflow of the electron charge from the H-atom to the A centre. For other interactions the outflow of electron charge from the Lewis acid centre is also observed. These electron charge shifts try to protect the doublet/octet structure of the acidic centre. The extremely strong interaction is often equivalent to the formation of new covalent bonds or it may lead to chemical reactions. Numerous interactions may be treated as the preliminary stages of chemical reactions: hydrogen bond - proton transfer, dihydrogen bond - molecular hydrogen release, tetrel bond - SN2 reaction, etc. PMID- 29105717 TI - Active Brownian equation of state: metastability and phase coexistence. AB - As a result of the competition between self-propulsion and excluded volume interactions, purely repulsive self-propelled spherical particles undergo a motility-induced phase separation (MIPS). We carry out a systematic computational study, considering several interaction potentials, systems confined by hard walls or with periodic boundary conditions, and different initial conditions. This approach allows us to identify that, despite its non-equilibrium nature, the equations of state of Active Brownian Particles (ABP) across MIPS verify the characteristic properties of first-order liquid-gas phase transitions, meaning, equality of pressure of the coexisting phases once a nucleation barrier has been overcome and, in the opposite case, hysteresis around the transition as long as the system remains in the metastable region. Our results show that the equations of state of ABPs account for their phase behaviour, providing a firm basis to describe MIPS as an equilibrium-like phase transition. PMID- 29105718 TI - Capacitive pressure sensing with suspended graphene-polymer heterostructure membranes. AB - We describe the fabrication and characterisation of a capacitive pressure sensor formed by an ultra-thin graphene-polymer heterostructure membrane spanning a large array of micro-cavities each up to 30 MUm in diameter with 100% yield. Sensors covering an area of just 1 mm2 show reproducible pressure transduction under static and dynamic loading up to pressures of 250 kPa. The measured capacitance change in response to pressure is in good agreement with calculations. Further, we demonstrate high-sensitivity pressure sensors by applying a novel strained membrane transfer and optimising the sensor architecture. This method enables suspended structures with less than 50 nm of air dielectric gap, giving a pressure sensitivity of 123 aF Pa-1 mm-2 over a pressure range of 0 to 100 kPa. PMID- 29105719 TI - Fluorescent and colorimetric molecular recognition probe for hydrogen bond acceptors. AB - The association constants for formation of 1 : 1 complexes between a H-bond donor, 1-naphthol, and a diverse range of charged and neutral H-bond acceptors have been measured using UV/vis absorption and fluorescence emission titrations. The performance of 1-naphthol as a dual colorimetric and fluorescent molecular recognition probe for determining the H-bond acceptor (HBA) parameters of charged and neutral solutes has been investigated in three solvents. The data were employed to establish self-consistent H-bond acceptor parameters (beta) for benzoate, azide, chloride, thiocyanate anions, a series of phosphine oxides, phosphate ester, sulfoxide and a tertiary amide. The results demonstrate both the transferability of H-bond parameters between different solvents and the utility of the naphthol-based dual molecular recognition probe to exploit orthogonal spectroscopic techniques to determine the HBA properties of neutral and charged solutes. The benzoate anion is the strongest HBA studied with a beta parameter of 15.4, and the neutral tertiary amide is the weakest H-bond acceptor investigated with a beta parameter of 8.5. The H-bond acceptor strength of the azide anion is higher than that of chloride (12.8 and 12.2 respectively), and the thiocyanate anion has a beta value of 10.8 and thus is a significantly weaker H-bond acceptor than both the azide and chloride anions. PMID- 29105720 TI - Beam steering by liquid crystal elastomer fibres. AB - The problem of utilizing a laser beam as an information vehicle and dividing it into different channels is an open problem in the telecommunication field. The switching of a signal into different ports has been demonstrated, to date, by employing complex devices and mechanisms such as the electro optic effect, microelectromechanical system (MEMS) mirrors, or liquid crystal-based spatial light modulators (SLMs). We present here a simple device, namely a mirror held by a liquid crystal elastomer (LCE) fibre, as an optically and remotely driven beam steerer. In fact, a considered signal (laser beam) can be addressed in every in plane direction by controlling the fibre and mirror rotation, i.e., the deflected probe beam angle. Such movement is possible due to the preparation of LCE fibres able to rotate and contract under a selective light stimulus. By adjusting the irradiation stimulus power, elastic fibres are able to rotate with a specific angle, performing more than one complete revolution around their axis. The described movement is perfectly reversible as soon as the stimulus is removed. PMID- 29105721 TI - Nanostructured mesophase electrode materials: modulating charge-storage behavior by thermal treatment. AB - 3D nanostructured carbonaceous electrode materials with tunable capacitive phases were successfully developed using graphene/particulate polypyrrole (PPy) nanohybrid (GPNH) precursors without a separate process for incorporating heterogeneous species. The electrode material, namely carbonized GPNHs (CGPNHs) featured a mesophase capacitance consisting of both electric double-layer (EDL) capacitive and pseudocapacitive elements at the molecular level. The ratio of EDL capacitive element to pseudocapacitive element (E-to-P) in the mesophase electrode materials was controlled by varying the PPy-to-graphite weight (Pw/Gw) ratio and by heat treatment (TH), which was demonstrated by characterizing the CGPNHs with elemental analysis, cyclic voltammetry, and a charge/discharge test. The concept of the E-to-P ratio (EPR) index was first proposed to easily identify the capacitive characteristics of the mesophase electrode using a numerical algorithm, which was reasonably consistent with the experimental findings. Finally, the CGPNHs were integrated into symmetric two-electrode capacitor cells, which rendered excellent energy and power densities in both aqueous and ionic liquid electrolytes. It is anticipated that our approach could be widely extended to fabricating versatile hybrid electrode materials with estimation of their capacitive characteristics. PMID- 29105722 TI - Determination of the local density of polydisperse nanoparticle assemblies. AB - Quantitative characterization of the average structure of dense nanoparticle assemblies and aggregates is a common problem in nanoscience. Small-angle scattering is a suitable technique, but it is usually limited to not too big assemblies due to the limited experimental range, low concentrations to avoid interactions, and monodispersity to keep calculations tractable. In the present paper, a straightforward analysis of the generally available scattered intensity even for large assemblies, at high concentrations - is detailed, providing information on the local volume fraction of polydisperse particles with hard sphere interactions. It is based on the identical local structure of infinite homogeneous nanoparticle assemblies and their subsets forming finite-sized clusters. This approach is extended to polydispersity, using Monte-Carlo simulations of hard and moderately sticky hard spheres. As a result, a simple relationship between the observed structure factor minimum - termed the correlation hole - and the average local volume fraction kappa on the scale of neighboring particles is proposed and validated through independent aggregate simulations. This relationship shall be useful as an efficient tool for the structural analysis of arbitrarily aggregated colloidal systems. PMID- 29105723 TI - New horizons in microbiological food safety: Photodynamic Decontamination based on a curcumin derivative. AB - Outbreaks of foodborne diseases are regularly reported worldwide. In particular, uncooked plant food is considered risky in terms of microbiological safety. Food is also the most important transmission route for resistant microorganisms from animals to humans. Photodynamic Decontamination (PDc) of foodstuff was recently introduced as a novel approach for increasing microbiological food safety. We investigated the efficiency of PDc on plant food with different geometries (flat, spherical and complex) using a two-dimensional LED array as a light source (435 nm, 33.8 J cm-2) and the cationic curcumin derivative SACUR-3 as a photosensitiser. A photoantibacterial effect (>3 log10 CFU reduction) was achieved on all flat substrates (slices of cucumber, tomato and lettuce) with 10 MUM, 50 MUM or 100 MUM SACUR-3. The maximal photokilling with a relative inactivation of 5.6 log10 was measured on lettuce using 50 MUM of the photoactive compound. Phototreatment of non-germinated fenugreek seeds and mung beans was successful if the spherical objects were rotated while under illumination (antibacterial effect at 100 MUM SACUR-3). The decontamination of mung bean germlings with a more complex geometry using the PDc approach was ineffective with the two-dimensional light source. In conclusion, PDc based on the cationic curcumin derivative SACUR-3 is very effective at improving the microbiological safety of plant food with a flat or spherical geometry. More complex objects will require the development of novel illumination devices. PMID- 29105724 TI - Freezing of supercooled n-decane nanodroplets: from surface driven to frustrated crystallization. AB - Whether crystallization starts at the liquid-vapor interface or randomly throughout the bulk has been the subject of intense debate. In our earlier work, we investigated the freezing of supercooled nanodroplets of short chain (C8, C9) n-alkanes formed by homogeneous condensation in a supersonic nozzle. The rate at which the solid appeared suggested freezing starts at the droplet surface well before the rest of the droplet freezes. Experiments were, however, limited to a single condition for each compound and it was not clear whether freezing of n alkanes always occurs in this two step manner. Here, we expand our work to include freezing of a third n-alkane, n-decane, and, furthermore, we vary the temperatures at which droplets are formed and freeze. The phase transitions are again characterized using three experimental techniques - pressure trace measurements (PTM), Fourier Transform Infrared Spectroscopy (FTIR), and Small Angle X-ray Scattering (SAXS). We also use Wide Angle X-ray Scattering (WAXS) to confirm, for the first time, the crystalline nature of our frozen n-alkane nanodroplets. As the temperature at which the droplets form and freeze decreases, the kinetics of the phase transition changes. At higher temperatures, the phase transition occurs in two steps characterized by different rates, whereas at lower temperatures we observe only a single step. Finally, in the lowest temperature experiment, where droplets start to form and freeze ~50 K below the bulk melting temperature, we found that the particles develop a fractal structure and appear locked in a "frustrated" crystalline state. PMID- 29105725 TI - Visualization of Superficial Cerebral Lesions Using a Smartphone Application. AB - AIM: Accurate localizations of cerebral lesions ensure good surgical outcomes and minimize intraoperative complications. Currently, microscope-integrated neuronavigation systems compensate these requirements. Since these units are expensive and large, the need to create more practical and portable systems in this "smart" century has become apparent. MATERIAL AND METHODS: The See-Through Camera smartphone application (app) is a photography app that penetrates the existing background picture and merges this with a camera image on the smartphone display. This app was applied to neurosurgery for visualization of the projection of the tumors over head in 20 patients. App accuracy was tested according to neuronavigation system. RESULTS: Precision of the app was evaluated according to the superposition ratio of the tumor image drawn by the navigation system with the tumor picture on the smartphone display. This ratio was 40%-100% in 16 (80%) patients and below 40% as an unfavorable result in the rest of the patients. CONCLUSION: Basic rationality of this app can provide the basis of future pocket navigation systems in terms of its design and principles. PMID- 29105726 TI - Complications of 2-level dynamic stabilization. AB - AIM: A retrospective chart and a radiographic review. Evaluation of postoperative complications, clinical improvements and radiological parameters in patients who underwent surgery using a dynamic system for 2-level lumbar stabilization. We aimed to investigate the postoperative complications, such as screw loosening, screw breakage and ASD, in patients who underwent surgery with 2-level dynamic stabilization systems. MATERIALS AND METHODS: Dynamic lumbar systems enable the stabilization of unstable degenerative spines, while preventing fusion-related complications, such as adjacent segment disease(ASD) and pseudarthrosis. In our study a total of 103 patients with lumbar degenerative spinal instability underwent 2-level dynamic stabilization. Clinical findings were reviewed at a 2 year follow-up. Screw breakage and loosening were evaluated during this duration together with clinical findings. RESULTS: Visual analog scale(VAS) and Oswestry Disability Index(ODI) scores significantly decreased at the four-month evaluation, and they were also decreased at the 1-year follow up and at the 24th postoperative month. Adjacent segment disease was diagnosed in twelve (8 females, 4 males) of the 103 patients in the follow-up radiological and clinical controls. There were 9 screw breakages and 4 screw loosening. The complication rate of 2 level of dynamic stabilization was high in this study. CONCLUSIONS: Our results showed that complications (screw loosening or breakage and adjacent segment disease) are not rare after using the 2-level dynamic stabilization system, unlike the acceptable results with the single-level dynamic system. The most probable explanation is that the instrument system behaves more rigidly with every additional segment. PMID- 29105728 TI - Tests for detecting strabismus in children aged 1 to 6 years in the community. AB - BACKGROUND: Strabismus (misalignment of the eyes) is a risk factor for impaired visual development both of visual acuity and of stereopsis. Detection of strabismus in the community by non-expert examiners may be performed using a number of different index tests that include direct measures of misalignment (corneal or fundus reflex tests), or indirect measures such as stereopsis and visual acuity. The reference test to detect strabismus by trained professionals is the cover-uncover test. OBJECTIVES: To assess and compare the accuracy of tests, alone or in combination, for detection of strabismus in children aged 1 to 6 years, in a community setting by non-expert screeners or primary care professionals to inform healthcare commissioners setting up childhood screening programmes.Secondary objectives were to investigate sources of heterogeneity of diagnostic accuracy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library, the Health Technology Assessment Database (HTAD) in the Cochrane Library (2016, Issue 4), MEDLINE Ovid (1946 to 5 January 2017), Embase Ovid (1947 to 5 January 2017), CINAHL (January 1937 to 5 January 2017), Web of Science Conference Proceedings Citation Index-Science (CPCI S) (January 1990 to 5 January 2017), BIOSIS Previews (January 1969 to 5 January 2017), MEDION (to 18 August 2014), the Aggressive Research Intelligence Facility database (ARIF) (to 5 January 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 5 January 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 5 January 2017 and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 5 January 2017. We did not use any date or language restrictions in the electronic searches for trials. In addition, orthoptic journals and conference proceedings without electronic listings were searched. SELECTION CRITERIA: All prospective or retrospective population-based test accuracy studies of consecutive participants were included. Studies compared a single or combination of index tests with the reference test. Only those studies with sufficient data for analysis were included specifically to calculate sensitivity and specificity and determine diagnostic accuracy.Participants were aged 1 to 6 years. Studies reporting participants outside this range were included if subgroup data were available.Permitted settings included population based vision screening programmes or opportunistic screening programmes, such as those performed in schools. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. In brief, two review authors independently assessed titles and abstracts for eligibility and extracted the data, with a third senior author resolving any disagreement. We analysed data primarily for specificity and sensitivity. MAIN RESULTS: One study from a total of 1236 papers, abstracts and trials was eligible for inclusion with a total number of participants of 335 of which 271 completed both the screening test and the gold standard test. The screening test using an automated photoscreener had a sensitivity of 0.46 (95% confidence interval (CI) 0.19 to 0.75) and specificity of 0.97 (CI 0.94 to 0.99). The overall number affected by strabismus was low at 13 (4.8%). AUTHORS' CONCLUSIONS: There is very limited data in the literature to ascertain the accuracy of tests for detecting strabismus in the community as performed by non-expert screeners. A large prospective study to compare methods would be required to determine which tests have the greatest accuracy. PMID- 29105727 TI - Immune-pineal axis - acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes. AB - Melatonin is well known for its circadian production by the pineal gland, and there is a growing body of data showing that it is also produced by many other cells and organs, including immune cells. The chronobiotic role of pineal melatonin, as well as its protective effects in vitro and in vivo, have been extensively explored. However, the interaction between the chronobiotic and defence functions of endogenous melatonin has been little investigated. This review details the current knowledge regarding the coordinated shift in melatonin synthesis from the pineal gland (circadian and monitoring roles) to the regulation of acute immune responses via immune cell production and autocrine effects, producing systemic interactions termed the immune-pineal axis. An acute inflammatory response drives the transcription factor, NFkappaB, to switch melatonin synthesis from pinealocytes to macrophages/microglia and, upon acute inflammatory resolution, back to pinealocytes. The potential pathophysiological relevance of immune-pineal axis dysregulation is highlighted, with both research and clinical implications, across several medical conditions, including host/parasite interaction, neurodegenerative diseases and cancer. PMID- 29105729 TI - Rheumatic heart disease in pregnancy: How can health services adapt to the needs of Indigenous women? A qualitative study. AB - OBJECTIVES: To study rheumatic heart disease health literacy and its impact on pregnancy, and to identify how health services could more effectively meet the needs of pregnant women with rheumatic heart disease. MATERIALS AND METHODS: Researchers observed and interviewed a small number of Aboriginal women and their families during pregnancy, childbirth and postpartum as they interacted with the health system. An Aboriginal Yarning method of relationship building over time, participant observations and interviews with Aboriginal women were used in the study. The settings were urban, island and remote communities across the Northern Territory. Women were followed interstate if they were transferred during pregnancy. The participants were pregnant women and their families. We relied on participants' abilities to tell their own experiences so that researchers could interpret their understanding and perspective of rheumatic heart disease. RESULTS: Aboriginal women and their families rarely had rheumatic heart disease explained appropriately by health staff and therefore lacked understanding of the severity of their illness and its implications for childbearing. Health directives in written and spoken English with assumed biomedical knowledge were confusing and of limited use when delivered without interpreters or culturally appropriate health supports. CONCLUSIONS: Despite previous studies documenting poor communication and culturally inadequate care, health systems did not meet the needs of pregnant Aboriginal women with rheumatic heart disease. Language appropriate health education that promotes a shared understanding should be relevant to the gender, life-stage and social context of women with rheumatic heart disease. PMID- 29105730 TI - Surgical treatment is an excellent option for women with endometriosis and infertility. PMID- 29105731 TI - Expression of tabersonine 16-hydroxylase and 16-hydroxytabersonine-O methyltransferase in Catharanthus roseus hairy roots. AB - The monoterpene indole alkaloids vindoline and catharanthine, which are exclusively synthesized in the medicinal plant Catharanthus roseus, are the two important precursors for the production of pharmaceutically important anti-cancer medicines vinblastine and vincristine. Hairy root culture is an ideal platform for alkaloids production due to its industrial scalability, genetic and chemical stability, and availability of genetic engineering tools. However, C. roseus hairy roots do not produce vindoline due to the lack of expression of the seven step pathway from tabersonine to vindoline [Murata & De Luca (2015) Plant Journal, 44, 581-594]. The present study describes the genetic engineering of the first two genes tabersonine 16-hydroxylase (T16H) and 16-O-methyl transferase (16OMT) in the missing vindoline pathway under the control of a glucocorticoid inducible promoter to direct tabersonine toward vindoline biosynthesis in C. roseus hairy roots. In two transgenic hairy roots, the induced overexpression of T16H and 16OMT resulted in the accumulation of vindoline pathway metabolites 16 hydroxytabersonine and 16-methoxytabersonine. The levels of root-specific alkaloids, including lochnericine, 19-hydroxytabersonine and horhammericine, significantly decreased in the induced hairy roots in comparison to the uninduced control lines. This suggests tabersonine was successfully channeled to the vindoline pathway away from the roots competing pathway based on the overexpression. Interestingly, another two new metabolites were detected in the induced hairy roots and proposed to be the epoxidized-16-hydroxytabersonine and lochnerinine. Thus, the introduction of vindoline pathway genes in hairy roots can cause unexpected terpenoid indole alkaloids (TIA) profile alterations. Furthermore, we observed complex transcriptional changes in TIA genes and regulators detected by RT-qPCR which highlight the tight regulation of the TIA pathway in response to T16H and 16OMT engineering in C. roseus hairy roots. PMID- 29105732 TI - Metabolic profiles analysis of 1,3-propanediol production process by Clostridium butyricum through repeated batch fermentation coupled with activated carbon adsorption. AB - 1,3-propanediol production by Clostridium butyricum is a low productivity process due to the long time seed cultivation and thus hinders its industrial scale production. In the present study, repeated batch fermentation coupled with activated carbon adsorption strategy was first established which conduced not only to saving the time of seed cultivation and enhancing the productivity, but also to reducing the costs for the seed cultivation to achieve the purpose of 1,3 propanediol continuous production. The concentration of 1,3-propanediol from first to fourth cycle was 42.89, 45.78, 44.48, 42.39 (g/L), and the corresponding volumetric productivity was 2.14, 1.91, 1.85, 2.12 (g/L . h-1 ) respectively. More importantly, a relatively complete schematic diagram of the proposed metabolic pathways was firstly mapped out based on the intracellular metabolites analysis through GC-MS. At the same time, metabolic pathway and principal components analyses were carried out to give us deep insight into metabolic state. Many metabolites occurred to response to the stress in Cycle II. Even resting body formed and lipid accumulated owing to the worsening environment in the group without activated carbon in Cycle III. Thus, it demonstrated that activated carbon provided a favorable microenvironment for Clostridium butyricum in the repeated batch fermentation process to achieve the purpose of 1,3 propanediol continuous production. PMID- 29105733 TI - Engineering Escherichia coli for malate production by integrating modular pathway characterization with CRISPRi-guided multiplexed metabolic tuning. AB - The application of rational design in reallocating metabolic flux to overproduce desired chemicals is always restricted by the native regulatory network. Here, we demonstrated that in vitro modular pathway optimization combined with in vivo multiplexed combinatorial engineering enables effective characterization of the bottleneck of a complex biosynthetic cascade and improves the output of the engineered pathway. As a proof of concept, we systematically identified the rate limiting step of a five-gene malate biosynthetic pathway by combinatorially tuning the enzyme loads of a reconstituted biocatalytic reaction in a cell-free system. Using multiplexed CRISPR interference, we subsequently eliminated the metabolic constraints by rationally assigning an optimal gene expression pattern for each pathway module. The present engineered strain Escherichia coli B0013-47 exhibited a 2.3-fold increase in malate titer compared with that of the parental strain, with a yield of 0.85 mol/mol glucose in shake-flask culture and titer of 269 mM (36 g/L) in fed-batch cultivation. The strategy reported herein represents a powerful method for improving the efficiency of multi-gene pathways and advancing the success of metabolic engineering. PMID- 29105734 TI - Preferential capture of EpCAM-expressing extracellular vesicles on solid surfaces coated with an aptamer-conjugated zwitterionic polymer. AB - Extracellular vesicles (EVs) collectively represent small vesicles that are secreted from cells and carry biomolecules (e.g., miRNA, lncRNA, mRNA, proteins, lipids, metabolites, etc.) that originate in those cells. Body fluids, such as blood and saliva, include large numbers of EVs, making them potentially a rich source of diagnostic information. However, these EVs are mixtures of vesicles released from diseased tissues as well as from normal cells. This heterogeneous nature therefore blurs the clinical information obtainable from EV-based diagnosis. Here, we synthesized an EpCAM-affinity coating agent, which consists of a peptide aptamer for EpCAM and a zwitterionic MPC polymer, and have shown that this conjugate endowed the surfaces of inorganic materials with the preferential affinity to EpCAM-expressing EVs. This coating agent, designated as EpiVeta, could be useful as a coating for various diagnostic devices to allow concentration of cancer-related EVs from heterogeneous EV mixtures. PMID- 29105735 TI - Research Directions in Genetic Predispositions to Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis. AB - Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs. PMID- 29105736 TI - Stroke identification by criteria based dispatch - a register based study. AB - BACKGROUND: Rapid and precise dispatch of resources is a key element in pre hospital emergency medicine. Emergency medical communication centres (EMCCs) dispatch resources based on protocols and guidelines, balancing the acute need of the individual and the resource allocation of the pre-hospital emergency medical system. The aim of this study was to determine the validity of stroke identification by the Norwegian dispatch guidelines. METHOD AND MATERIAL: This was a register-based study where patients suspected for stroke were compared to those with the final diagnosis of stroke as an indicator group for the guideline validation. One EMCC and its three associated hospitals participated with 13 months of data. Four subcodes of the stroke dispatch code were defined as suspicious of stroke and further analysed. Factors associated with stroke identification were explored. RESULTS: The sensitivity for identifying a stroke patient at initial EMCC contact was 57.9% (51.5, 64.1), specificity was 99.1% (98.9, 99.2), positive predictive value was 45.7% (40.1, 51.4) and negative predictive value was 99.4% (99.3, 99.5). The emergency medical access telephone (113) was initial EMCC contact line in only 48% of the cases. Paralyses and admittance to a smaller hospital were associated with increased probability for stroke (OR 2.6, P = 0.001 and OR 2.7, P = 0.01), respectively. CONCLUSION: The sensitivity for identification of stroke patients by the dispatch guidelines is modest, while the specificity is high. The 113 telephone line was initial EMCC access point for less than half of the stroke patients. PMID- 29105737 TI - Enhanced tissue adhesiveness of injectable gelatin hydrogels through dual catalytic activity of horseradish peroxidase. AB - Development of bioadhesives with tunable mechanical strength, high adhesiveness, biocompatibility, and injectability is greatly desirable in all surgeries to replace or complement the sutures and staples. Herein, the dual catalytic activity of horseradish peroxidase is exploited to in situ form the hydroxyphenyl propionic acid-gelatin/thiolated gelatin (GH/GS) adhesive hydrogels including two alternative crosslinks (phenol-phenol and disulfide bonds) with fast gelation (few seconds - several minutes) and improved physicochemical properties. Their elastic moduli increase from 6.7 to 10.3 kPa by adding GS polymer that leads to the better stability of GH/GS hydrogels than GH ones. GH/GS adhesive strength is respectively 6.5-fold and 15.8-fold higher than GH-only and fibrin glue that is due to additional disulfide linkages between hydrogels and tissues. Moreover, in vitro cell study with human dermal fibroblast showed the cell-compatibility of GH/GS hydrogels. Taken together, GH/GS hydrogels can be considered as promising potential adhesive materials for various biomedical applications. PMID- 29105739 TI - Survival of human papillomavirus-associated cancers: Filling in the gaps. PMID- 29105738 TI - Five-year relative survival for human papillomavirus-associated cancer sites. AB - BACKGROUND: Human papillomavirus (HPV) vaccines can potentially prevent greater than 90% of cervical and anal cancers as well as a substantial proportion of vulvar, vaginal, penile, and oropharyngeal cancers caused by certain HPV types. Because more than 38,000 HPV-associated cancers are diagnosed annually in the United States, current studies are needed to understand how relative survival varies for each of these cancers by certain demographic characteristics, such as race and age. METHODS: The authors examined high-quality data from 27 population based cancer registries covering approximately 59% of the US population. The analyses were limited to invasive cancers that were diagnosed during 2001 through 2011 and followed through 2011 and met specified histologic criteria for HPV associated cancers. Five-year relative survival was calculated from diagnosis until death for these cancers by age, race, and sex. RESULTS: The 5-year age standardized relative survival rate was 64.2% for cervical carcinomas, 52.8% for vaginal squamous cell carcinomas (SCCs), 66% for vulvar SCCs, 47.4% for penile SCCs, 65.9% for anal SCCs, 56.2% for rectal SCCs, and 51.2% for oropharyngeal SCCs. Five-year relative survival was consistently higher among white patients compared with black patients for all HPV-associated cancers across all age groups; the greatest differences by race were observed for oropharyngeal SCCs among those aged <60 years and for penile SCCs among those ages 40 to 49 years compared with other age groups. CONCLUSIONS: There are large disparities in relative survival among patients with HPV-associated cancers by sex, race, and age. HPV vaccination and improved access to screening (of cancers for which screening tests are available) and treatment, especially among groups that experience higher incidence and lower survival, may reduce disparities in survival from HPV-associated cancers. Cancer 2018;124:203-211. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. PMID- 29105741 TI - Epidemiology of Huntington disease in Cyprus: A 20-year retrospective study. AB - Huntington disease (HD) is most prevalent among populations of western European descent and isolated populations where founder effects may operate. The aim of this study was to examine the epidemiology of HD in Cyprus, an island in southern Europe with extensive western European colonization in the past. All registered HD patients in the Cyprus, since 1994, were included. Detailed pedigrees and clinical information were recorded and maps, showing the geographic distribution of HD, were constructed. Requests for genetic testing were also examined. The project identified 58 clinically manifested cases of HD belonging to 19 families. The 16 families of Cypriot origin were concentrated in a confined geographical cluster in southeast Cyprus. In 2015, prevalence of symptomatic HD was 4.64/100 000 population, while incidence was 0.12/100 000 person-years. Prevalence displayed a marked increase during the past 20 years. Disease characteristics of HD patients were similar to those reported in western European populations. Lastly, the uptake of predictive and/or prenatal testing was limited. HD disease characteristics, incidence and prevalence in Cyprus were comparable to western European populations. Together with the geographical clustering observed, these results support the possibility for a relatively recent founder effect of HD in Cyprus, potentially of western European origin. PMID- 29105740 TI - Protease-activated receptor 1 inhibition protects mice against thrombin-dependent respiratory syncytial virus and human metapneumovirus infections. AB - BACKGROUND AND PURPOSE: Protease-activated receptor 1 (PAR1) has been demonstrated to be involved in the pathogenesis of viral diseases. However, its role remains controversial. The goal of our study was to investigate the contribution of PAR1 to respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections. EXPERIMENTAL APPROACH: Pharmacological approaches were used to investigate the role of PAR1 during RSV and hMPV infection, in vitro using epithelial A549 cells and in vivo using a mouse model of virus infection. KEY RESULTS: In vitro, the PAR1 antagonist RWJ-56110 reduced the replication of RSV and hMPV in A549 cells. In agreement with these results, RWJ-56110-treated mice were protected against RSV and hMPV infections, as indicated by less weight loss and mortality. This protective effect in mice correlated with decreased lung viral replication and inflammation. In contrast, hMPV-infected mice treated with the PAR1 agonist TFLLR-NH2 showed increased mortality, as compared to infected mice, which were left untreated. Thrombin generation was shown to occur downstream of PAR1 activation in infected mice via tissue factor exposure as part of the inflammatory response, and thrombin inhibition by argatroban reduced the pathogenicity of the infection with no additive effect to that induced by PAR1 inhibition. CONCLUSION AND IMPLICATIONS: These data show that PAR1 plays a detrimental role during RSV and hMPV infections in mice via, at least, a thrombin-dependent mechanism. Thus, the use of PAR1 antagonists and thrombin inhibitors may have potential as a novel approach for the treatment of RSV and hMPV infections. PMID- 29105742 TI - Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders. AB - We have developed an automated assay to enumerate and characterize circulating multiple myeloma cells (CMMC) from peripheral blood of patients with plasma cell disorders. CMMC show expression of genes characteristic of myeloma and fluorescence in situ hybridisation results on CMMC correlated well with bone marrow results. We enumerated CMMC from over 1000 patient samples including separate cohorts of newly diagnosed multiple myeloma and high/intermediate risk smouldering multiple myeloma (SMM) with clinical follow-up data. In newly diagnosed myeloma patient samples, CMMC counts correlated with other clinical measures of disease burden, including the percentage of bone marrow plasma cells, serum M protein, and International Staging System stage. CMMC counts decreased significantly from baseline when a remission was achieved due to treatment (P < 0.001). Patients with CMMC counts >=100 at remission showed reduced survival relative to patients with CMMC counts <100. Patients with undetectable CMMC in remission showed further overall survival benefits. In the SMM cohort, there was a trend toward higher CMMC in patients with higher-risk myeloma precursor states. Significantly higher CMMC counts were observed between intermediate/high risk SMM patients that progressed versus those without progression (P = 0.031). CMMC allow a non-invasive means of monitoring tumour biology and may have use as a prognostic test for patients with plasma cell disorders. PMID- 29105743 TI - Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer. AB - Sporadic synchronous colorectal cancer (CRC) refers to more than one primary tumor detected in a single patient at the time of the first diagnosis without predisposition of cancer development. Given the same genetic and microenvironment they raise, sporadic synchronous CRC is a unique model to study CRC tumorigenesis. We performed whole exome sequencing in 32 fresh frozen tumor lesions from 15 patients with sporadic synchronous CRC to compare their genetic alterations. This approach identified ubiquitously mutated genes in the range from 0.34% to 4.22% and from 0.8% to 7.0% in non-hypermutated tumors and hypermutated tumors, respectively, in a single patient. We show that both ubiquitously mutated genes and candidate cancer genes from different tumors in the same patient mutated at different sites. Consistently, obvious differences in somatic copy number variations (SCNV) were found in most patients with non hypermutated tumor lesions, which had ubiquitous copy number amplification rates ranging from 0% to 8.8% and ubiquitous copy number deletion rates ranging from 0% to 8.2%. Hypermutated lesions were nearly diploid with 0% to 18.8% common copy number aberrations. Accordingly, clonal structures, altered signaling pathways and druggable genes in a single patient with synchronous CRC varied significantly. Taken together, the disparate SCNVs and mutations in synchronous CRC supported the field effect theory of tumorigenesis. Moreover, the intertumor heterogeneity of synchronous CRCs implies that analysis of all tumor lesions from the same patient is necessary for appropriate clinical treatment decisions. PMID- 29105744 TI - Generational shift in melanoma incidence and mortality in Queensland, Australia, 1995-2014. AB - Public campaigns encouraging sun protection for skin cancer prevention began in Queensland, Australia, in the early 1980s. We examined recent trends to assess whether earlier evidence of stabilizing melanoma incidence in young people has persisted. Anonymized incidence and mortality data for in situ and invasive melanoma for the 20 years 1995-2014 were obtained from the Queensland Cancer Registry. Time trends were analyzed using JoinPoint regression. Birth cohort patterns were assessed using age-period-cohort models. Melanoma incidence in Queensland remains the highest recorded in the world (age-standardized incidence of invasive melanoma (2010-2014) = 72/100,000/annum). Over the 20-year period, incidence of in situ melanoma increased in all age groups. Incidence of both thin (<=1 mm) and thick (>1 mm) invasive melanoma was either stable or decreased in people under 60, while it increased in those aged 60 and above, particularly in men. Age-period-cohort analysis revealed decreasing age-specific incidence of invasive melanoma under 40 years of age, beginning with the birth cohort born around the mid-1960s, with steepest falls for those born around 1980 and later. Age-specific incidence was stable between 40 and 59 years of age from the 1945 birth cohort onwards. Melanoma mortality over the period was stable or decreased in all groups except in men aged 60 or over. These findings are evidence of real advances in the prevention and early detection of invasive melanoma in this very high-risk population. They make a compelling case for continued public health efforts to reduce the burden of melanoma in susceptible populations. PMID- 29105745 TI - The Emerging Role of Digital Technologies in Early Clinical Development. AB - Pharmaceutical development is witnessing an increase in the use of digital technologies in the delivery of pharmaceutical substances, data generation, and data interpretation. These digital technologies offer the valuable benefits of speed, enhanced integration with various other components, visualization of a continuum, and improving precision of delivery or measurement. The adoption of these opportunities in early clinical development has been slow and sparse. This commentary analyzes these benefits, including the socialization and adoption of such practices. PMID- 29105746 TI - Promoting Safe Early Clinical Research of Novel Drug Candidates: A European Union Regulatory Perspective. AB - The European Medicines Agency (EMA) revises its guideline on minimizing risk in first-in-human trials to reflect changing practice and in light of a recent tragic incident. PMID- 29105747 TI - Bedside to Bench: Integrating Quantitative Clinical Pharmacology and Reverse Translation to Optimize Drug Development. AB - With so much emphasis on reducing attrition and becoming more efficient in the delivery of healthcare, there are many opportunities to leverage existing clinical data in drug development and to foster the practice of reverse translation. The application of quantitative approaches to convert clinical trial and real-world data to knowledge will continue to drive innovation. Herein we discuss recent examples of reverse translation and consider future opportunities to capture critical clinical knowledge to inform decision-making in drug development. PMID- 29105748 TI - Digest: Gene duplication and social evolution-Using big, open data to answer big, open questions. PMID- 29105749 TI - Cerebral palsy after in vitro fertilization. PMID- 29105750 TI - What is the role of the General Movements Assessment in clinical practice? PMID- 29105751 TI - Real-Life Use of Neurohormonal Antagonists and Loop Diuretics in Chronic Heart Failure: Analysis of Serial Biomarker Measurements and Clinical Outcome. AB - We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d glucosaminidase and kidney-injury-molecule-1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03-1.22) per 40 mg higher doses. ACE-inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE-inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF. PMID- 29105753 TI - Digest: Unpacking fitness effects of spontaneous mutations. PMID- 29105752 TI - Buprenorphine in Neonatal Abstinence Syndrome. AB - Infants exposed in utero to opioids will demonstrate a withdrawal syndrome known as neonatal abstinence syndrome (NAS). Buprenorphine is a long-acting opioid with therapeutic use in medication-assisted treatment of opioid dependency in adults and adolescents. Emerging data from clinical trials and treatment cohorts demonstrate the efficacy and safety of sublingual buprenorphine for those infants with NAS who require pharmacologic treatment. Pharmacometric modeling will assist in defining the exposure-response relationships and facilitate dose optimization. PMID- 29105754 TI - Interaction between human angiogenin and the p53 TAD2 domain and its implication for inhibitor discovery. AB - Interaction between angiogenin and the p53 TAD2 domain in cancer cells can inhibit the function of the p53 tumor suppressor and promote cell survival. Based on a model structure using NMR and mutational analysis, positively charged 31 RRR33 and 50 KRSIK54 motifs of human angiogenin were identified as p53-binding sites that could interact with negatively charged D48/E51 and E56 residues of the p53 TAD2 domain, respectively. These results suggest that 31 RRR33 and 50 KRSIK54 motifs of human angiogenin might play a critical role in the regulation of p53 mediated apoptosis and angiogenesis in cancer cells. This study identifies potential target sites for screening angiogenin-specific inhibitors that could not only inhibit p53 binding but could also simultaneously inhibit cell binding, internalization, DNA binding, and nuclear translocation of human angiogenin. PMID- 29105755 TI - Identification of novel bone morphogenetic protein- responsive elements in a hepcidin promoter. AB - Hepcidin plays a central role in systemic iron metabolism. The bone morphogenetic protein (BMP) pathway regulates expression of hepcidin through transcriptional activation via BMP-responsive elements (REs) 1 and 2 on the promoter. Previous studies also revealed that the BMP pathway stimulates transcription of its target genes via GC-rich sequences on the promoter. A search for GC-rich sequences on the hepcidin promoter indicated 13 regions across the distal (A to F), middle (G to I), and proximal (J to M) areas; among them, mutations of the GC-rich element found in regions B to D exhibited decreased responsiveness to ALK3(QD) expression in the presence of BMP-RE1 mutations, indicating necessity of the elements for full expression of hepcidin by the BMP pathway. PMID- 29105756 TI - KIR downregulation by IL-12/15/18 unleashes human NK cells from KIR/HLA-I inhibition and enhances killing of tumor cells. AB - To exploit autologous NK cells for cancer immunotherapy, it is highly relevant to circumvent killer cell immunoglobulin-like receptor (KIR)-mediated self inhibition of human NK cells by HLA-I-expressing tumor cells. Here, we show that stimulation of NK cells with IL-12/15/18 for two days led to downregulation of surface expression of the inhibitory KIR2DL2/L3, KIR2DL1 and KIR3DL1 receptors on peripheral blood NK cells. Downregulation of KIR expression was attributed to decreased KIR mRNA levels which could be re-induced already 3 days after re culture in IL-2. Reduced KIR2DL2/L3 expression on IL-12/15/18-activated NK cells resulted in less inhibition upon antibody-mediated KIR engagement and increased CD16-dependent cytotoxicity in redirected lysis assays. Most importantly, downregulated KIR2DL2/L3 expression enabled enhanced cytotoxicity of IL-12/15/18 stimulated NK cells against tumor cells expressing cognate HLA-I molecules. NK cells pre-activated with IL-12/15/18 were previously shown to exert potent anti tumor activity and memory-like long-lived functionality, mediating remission in a subset of acute myeloid leukemia (AML) patients in a clinical trial. Our study reveals a novel mechanism of IL-12/15/18 in improving the cytotoxicity of NK cells by reducing their sensitivity to inhibition by self-HLA-I due to decreased KIR expression, highlighting the potency of IL-12/15/18-activated NK cells for anti-tumor immunotherapy protocols. PMID- 29105757 TI - Transforming the Activation of Clinical Trials. AB - The Institute of Medicine and US Food and Drug Administration (FDA) recognize that activating clinical trials in the United States is lengthy and inefficient. Downstream consequences include increased expense, suboptimal accrual, move of clinical trials overseas, and delayed availability of treatments for patients. An in-tandem processing initiative is here highlighted that transformed the activation of clinical trials (TACT), reduced the activation time by 70%, and offers a paradigm for enhanced translational readiness. PMID- 29105758 TI - Why are tropical mountain passes "low" for some species? Genetic and stable isotope tests for differentiation, migration and expansion in elevational generalist songbirds. AB - Most tropical bird species have narrow elevational ranges, likely reflecting climatic specialization. This is consistent with Janzen's Rule, the tendency for mountain passes to be effectively "higher" in the tropics. Hence, those few tropical species that occur across broad elevational gradients (elevational generalists) represent a contradiction to Janzen's Rule. Here, we aim to address the following questions. Are elevational generalists being sundered by diversifying selection along the gradient? Does elevational movement cause these species to resist diversification or specialization? Have they recently expanded, suggesting that elevational generalism is short-lived in geological time? To answer these questions, we tested for differentiation, movement and expansion in four elevational generalist songbird species on the Andean west slope. We used morphology and mtDNA to test for genetic differentiation between high- and low elevation populations. To test for elevational movements, we measured hydrogen isotope (delta2 H) values of metabolically inert feathers and metabolically active liver. Morphology differed for House Wren (Troglodytes aedon) and Hooded Siskin (Spinus magellanicus), but not for Cinereous Conebill (Conirostrum cinereum) and Rufous-collared Sparrow (Zonotrichia capensis) respectively. mtDNA was structured by elevation only in Z. capensis. delta2 H data indicated elevational movements by two tree- and shrub-foraging species with moderate-to high vagility (C. cinereum and S. magellanicus), and sedentary behaviour by two terrestrial-foraging species with low-to-moderate vagility (T. aedon and Z. capensis). In S. magellanicus, elevational movements and lack of mtDNA structure contrast with striking morphological divergence, suggesting strong diversifying selection on body proportions across the c. 50 km gradient. All species except C. cinereum exhibited mtDNA haplotype variation consistent with recent population expansion across the elevational gradient, potentially concurrent with Holocene anthropogenic habitat conversion for agriculture. In different ways, each species defies the tendency for tropical birds to have long-term stable distributions and sedentary habits. We conclude that tropical elevational generalism is rare due to evolutionary instability. PMID- 29105759 TI - Freshwater eutrophication drives sharp reductions in temporal beta diversity. AB - Eutrophication has become one of the most widespread anthropogenic forces impacting freshwater biological diversity. One potentially important mechanism driving biodiversity changes in response to eutrophication is the alteration of seasonal patterns of succession, particularly among species with short, synchronous, life cycles. We tested the hypothesis that eutrophication reduces seasonally driven variation in species assemblages by focusing on an understudied aspect of biodiversity: temporal beta diversity (betat ). We estimated the effect of eutrophication on betat by sampling benthic macroinvertebrate assemblages bimonthly for two years across 35 streams spanning a steep gradient of total phosphorus (P) and benthic algal biomass (as chlorophyll a [chl a]). Two widely used metrics of beta diversity both declined sharply in response to increasing P and chl a, regardless of covariates. The most parsimonious explanatory model for betat included an interaction between P and macroinvertebrate biomass, which revealed that betat was lower when macroinvertebrate biomass was relatively high. Macroinvertebrate biomass explained a greater amount of deviance in betat at lower to moderate concentrations of P, providing additional explanatory power where P concentration alone was unable to fully explain declines in betat . Chl a explained similar amounts of deviance in betat in comparison to the best P model, but only when temperature variability, which was positively related to betat , also was included in the model. Declines in betat suggest that nutrient enrichment decreases the competitive advantage that specialists gain by occupying particular temporal niches, which leads to assemblages dominated by generalists that exhibit little seasonal turnover. The collapse of seasonal variation in assemblage composition we observed in our study suggests that treating dynamic communities as static assemblages is a simplification that may fail to detect the full impact of anthropogenic stressors. Our results show that eutrophication leads to more temporally homogenous communities and therefore degrades a fundamental facet of biodiversity. PMID- 29105760 TI - Should the Gross Motor Function Classification System be used for children who do not have cerebral palsy? AB - : This literature review addressed four questions. (1) In which populations other than cerebral palsy (CP) has the Gross Motor Function Classification System (GMFCS) been applied? (2) In what types of study, and why was it used? (3) How was it modified to facilitate these applications? (4) What justifications and evidence of psychometric adequacy were used to support its application? A search of PubMed, MEDLINE, and Embase databases (January 1997 to April 2017) using the terms: 'GMFCS' OR 'Gross Motor Function Classification System' yielded 2499 articles. 118 met inclusion criteria and reported children/adults with 133 health conditions/clinical descriptions other than CP. Three broad GMFCS applications were observed: as a categorization tool, independent variable, or outcome measure. While the GMFCS is widely used for children with health conditions/clinical description other than CP, researchers rarely provided adequate justification for these uses. We offer recommendations for development/validation of other condition-specific classification systems and discuss the potential need for a generic gross motor function classification system. WHAT THIS PAPER ADDS: The Gross Motor Function Classification System should not be used outside cerebral palsy or as an outcome measure. The authors provide recommendations for development and validation of condition-specific or generic classification systems. PMID- 29105761 TI - The influence of tobacco retailers on adolescent smoking: prevention and policy implications. AB - BACKGROUND: Smoking rates are higher among adolescents in South Korea than among those in other Asian countries. Researchers have reported associations between the presence of licensed tobacco retailers and adolescent smoking rates. However, few researchers have examined the factors that influence adolescent smoking including those that are intrapersonal, interpersonal or related to the tobacco retailers' environment. AIM: The purpose of this study was to describe factors related to the students, the licensed tobacco retailers and the schools and how those factors are associated with adolescent smoking outcomes such as tobacco marketing receptivity, lifetime smoking and current smoking. METHODS: The survey data were gathered from 740 South Korean adolescents, and geographic data for 3488 licensed tobacco retailers were also used. Geographic Information Systems and multilevel modeling were used to describe the variables and determine the factors associated with smoking outcomes in the sample. RESULTS: The factors that influenced receptivity to tobacco marketing included the presence of peers who smoke and the frequencies of licensed tobacco retailers passed on the way to school. The factors that influenced lifetime smoking included gender, perceived economic status, weekly income, the presence of siblings or peers who smoke and frequencies of licensed tobacco retailers passed on the way to school. The factors that influenced current smoking included gender, weekly income, and the presence of siblings or peers who smoke. CONCLUSIONS: These factors will guide adolescent tobacco prevention programs and policies. IMPLICATIONS FOR NURSING PRACTICE AND HEALTH POLICY: The study's implications for nursing practice and health policy are that school nurses and public health nurses need to be encouraged to use retailer-related factors in adolescent smoking-prevention programs. There is also a need for zoning and licensing regulations to restrict licensed tobacco retailers in areas that adolescents frequent, including schools. PMID- 29105762 TI - Regulation of genome-wide DNA methylation by mobile small RNAs. AB - Contents Summary 540 I. Introduction 540 II. There are different types of sRNA mobility 541 III. Mechanisms of sRNA movement 541 IV. Long-distance, shoot-root, mobile siRNAs influence DNA methylation in recipient tissues 541 V. Classes of interactions between shoot-root mobile siRNAs and DNA methylation 542 VI. Loci targeted directly and indirectly by shoot-root mobile siRNAs are associated with different histone modifications 543 VII. Is mobile siRNA-regulated DNA methylation important in specific tissues or under specific conditions? 543 VIII. Mobile sRNAs can be used to modify plant traits 544 IX. Conclusions 544 Acknowledgements 544 References 544 SUMMARY: RNA-directed DNA methylation (RdDM) at cytosine residues regulates gene expression, silences transposable elements and influences genome stability. The mechanisms responsible for RdDM are guided to target loci by small RNAs (sRNAs) that can move within plants cell to cell and long distance. Here we discuss recent advances in the understanding of interactions between mobile sRNAs and DNA methylation. We describe the mechanisms of sRNA movement, the differences between known classes of mobile sRNA-DNA methylation interactions and the limits of current knowledge. Finally, we discuss potential applications of mobile sRNAs in modifying plant traits. PMID- 29105763 TI - Synthesis, Photophysical and Computational Study of Novel Coumarin-based Organic Dyes. AB - A series of novel coumarin pyrazoline moieties combined with tetrazoles, 3-(1 phenyl-4-(1H-tetrazol-5-yl)-1H-pyrazol-3-yl)-2H-chromen-2-one, 6-chloro-3-(1 phenyl-4-(1H-tetrazol-5-yl)-1H-pyrazol-3-yl)-2H-chromen-2-one, 6-bromo-3-(1 phenyl-4-(1H-tetrazol-5-yl)-1H-pyrazol-3-yl)-2H-chromen-2-one and 6-bromo-3-(1-(4 bromophenyl)-4-(1H-tetrazol-5-yl)-1H pyrazol-3-yl)-2H-chromen-2-one7(a-d), were designed and synthesized. Single crystal X-ray diffraction and their interactions were studied by Hirshfeld surface analysis. Thermal stabilities and electrochemical properties of these compounds were examined from differential scanning calorimetry (DSC), thermogravimetric (TGA) and cyclic voltammetric (CV) studies. Their spectroscopic properties were analyzed in various alcohols and general solvents by UV-Vis absorption, fluorescence and time-resolved spectroscopy. In addition, the ground and excited state electronic properties were investigated using density functional theory (DFT). The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and energy band gap (Eg ) values have revealed the effect of substitution of halogens. The substitution has equally affected the ground and excited states of 7(a-d) compounds. The solvatochromism on absorption, fluorescence spectra and fluorescence lifetimes of these compounds was investigated. All these results showed the chromen-2-one of pyrazoline tetrazole derivatives could play an important role in photonic and electronic devices. PMID- 29105765 TI - Ecosystem responses to elevated CO2 governed by plant-soil interactions and the cost of nitrogen acquisition. AB - Contents Summary 507 I. Introduction 507 II. The return on investment approach 508 III. CO2 response spectrum 510 IV. Discussion 516 Acknowledgements 518 References 518 SUMMARY: Land ecosystems sequester on average about a quarter of anthropogenic CO2 emissions. It has been proposed that nitrogen (N) availability will exert an increasingly limiting effect on plants' ability to store additional carbon (C) under rising CO2 , but these mechanisms are not well understood. Here, we review findings from elevated CO2 experiments using a plant economics framework, highlighting how ecosystem responses to elevated CO2 may depend on the costs and benefits of plant interactions with mycorrhizal fungi and symbiotic N fixing microbes. We found that N-acquisition efficiency is positively correlated with leaf-level photosynthetic capacity and plant growth, and negatively with soil C storage. Plants that associate with ectomycorrhizal fungi and N-fixers may acquire N at a lower cost than plants associated with arbuscular mycorrhizal fungi. However, the additional growth in ectomycorrhizal plants is partly offset by decreases in soil C pools via priming. Collectively, our results indicate that predictive models aimed at quantifying C cycle feedbacks to global change may be improved by treating N as a resource that can be acquired by plants in exchange for energy, with different costs depending on plant interactions with microbial symbionts. PMID- 29105764 TI - Genetic polymorphisms and periodontal disease in populations of African descent: A review. AB - Aggressive periodontitis is a rare but rapidly progressing form of periodontal disease that usually affects otherwise systemically healthy individuals, at a young age. It usually affects first molars and incisors, which are usually lost if treatment is not properly and early rendered. Although of low prevalence, it affects individuals of African descent at a higher prevalence, and usually multiple members within the same family. Several studies have been performed in the attempt to evaluate specific single nucleotide polymorphisms (SNPs) that could be associated with this disease. To the best of our knowledge, the present article provides the first review of the literature focusing on studies that evaluated SNPs in patients of African descent with aggressive periodontitis. Several SNPs have been evaluated in different genes according to their role in the pathogenesis of the disease, with positive and negative associations (such as IL1, FCGR3B, FPR1, LTF, CYBA, GLT6D1, TLR4) with both the localized and generalized forms of aggressive periodontitis. Given the complexity of periodontitis, the difficulty in gathering large cohorts diagnosed with this rare form of disease, and the fact that candidate gene studies may only determine part of the genetic risk of a disease, the search for specific SNPs associated with aggressive periodontitis seems to be a long one, most likely to result in the combination of multiple SNPs, in multiple genes. PMID- 29105766 TI - The cotton (Gossypium hirsutum) NAC transcription factor (FSN1) as a positive regulator participates in controlling secondary cell wall biosynthesis and modification of fibers. AB - Cotton (Gossypium hirsutum) fibers are the highly elongated and thickened single cell trichomes on the seed epidermis. However, little is known about the molecular base of fiber cell wall thickening in detail. In this study, a cotton NAC transcription factor (GhFSN1) that is specifically expressed in secondary cell wall (SCW) thickening fibers was functionally characterized. The GhFSN1 transgenic cotton plants were generated to study how FSN1 regulates fiber SCW formation. Up-regulation of GhFSN1 expression in cotton resulted in an increase in SCW thickness of fibers but a decrease in fiber length. Transcriptomic analysis revealed that GhFSN1 activates or represses numerous downstream genes. GhFSN1 has the ability to form homodimers, binds to its promoter to activate itself, and might be degraded by the ubiquitin-mediated proteasome pathway. The direct targets of GhFSN1 include the fiber SCW-related GhDUF231L1, GhKNL1, GhMYBL1, GhGUT1 and GhIRX12 genes. GhFSN1 binds directly to a consensus sequence (GhNBS), (C/T)(C/G/T)TN(A/T)(G/T)(A/C/G)(A/G)(A/T/G)(A/T/G)AAG, which exists in the promoters of these SCW-related genes. Our data demonstrate that GhFSN1 acts as a positive regulator in controlling SCW formation of cotton fibers by activating its downstream SCW-related genes. Thus, these findings give us novel insights into comprehensive understanding of GhFSN1 function in fiber development. PMID- 29105767 TI - The relationship between endolymphatic hydrops in the vestibule and low-frequency air-bone gaps. AB - OBJECTIVES/HYPOTHESIS: To investigate the relationship between endolymphatic hydrops and hearing level, focusing on significant vestibular endolymphatic hydrops adjacent to the stapes footplate and low-frequency air-bone gaps. STUDY DESIGN: Retrospective study. METHODS: The study included 1,548 ears from 775 patients who underwent magnetic resonance imaging examination in our university hospital to investigate possible endolymphatic hydrops between January 2012 and December 2015. Ears were evaluated by magnetic resonance imaging performed 4 hours after intravenous injection of a standard dose of gadodiamide hydrate and/or 24 hours after intratympanic injection of gadopentetate dimeglumine diluted eightfold. Comparison of hearing thresholds on pure-tone audiometry was performed between ears having endolymphatic hydrops adjacent to the stapes footplate and those having nonadjacent endolymphatic hydrops. RESULTS: Forty-one ears (22 men and 19 women, mean age 48.4 years) showed significant cochlear and vestibular endolymphatic hydrops adjacent to the stapes footplate, and 79 ears (30 men and 49 women, mean age 45.0 years) showed significant nonadjacent cochlear and vestibular endolymphatic hydrops. The average air-bone gap at 250 Hz was significantly higher in the group of ears with adjacent hydrops than in those with nonadjacent hydrops. CONCLUSIONS: The appearance of low-frequency air-bone gaps suggests deterioration of endolymphatic hydrops, particularly in ears with Meniere's disease, and could be a useful indicator for evaluating and treating patients with endolymphatic hydrops. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1658 1662, 2018. PMID- 29105768 TI - Comparative feeding ecology of the yellow ray Urobatis jamaicensis (Urotrygonidae) from The Bahamas. AB - Stomach contents were collected from 117 yellow rays Urobatis jamaicensis from three locations in south Eleuthera, The Bahamas and compared with ambient infauna via sediment surveys. Diets were relatively limited with a total of 535 prey items recovered, representing five taxonomic groups and dominated by polychaetes and decapod crustaceans (87% of total diet), while environmental sampling reported 5249 individual taxa represented by 62 taxonomic groups. Regardless of gravidity, sex or density of prey items among sites, no significant differences were detected. Foraging strategy plots suggested preferential prey is rare within the environment and the Manly-Chesson index validates polychaetes were consumed with high selectivity. This is the most comprehensive and updated assessment of comparative feeding in this species, particularly for The Bahamas, allowing insight into invertebrate community richness and diversity in ecologically sensitive coastal and nearshore habitats. PMID- 29105769 TI - Recovery and stability over time of phenolic fractions by an industrial filtration system of olive mill wastewaters: a three-year study. AB - BACKGROUND: The recovery of phenolic compounds from olive milling is recognized as strategic for producers. The aim of this work was to evaluate the quality and stability of retentates obtained from olive mill wastewaters treated with a membrane filtration system constituted by a micro-, ultra- and nanofiltration, followed by a final reverse osmosis, over three crop seasons. Efficiency was evaluated in terms of phenolic amount in the retentates and of organic load in the final discarded waters. Phenolic compounds were quantified using tyrosol as external standard. RESULTS: Our study highlighted a reproducibility of the process over years and a low organic load in permeates from reverse osmosis. Hydroxytyrosol was very stable in the liquid products at 18-28 degrees C over 24 months of storage. The retentates from reverse osmosis showed the highest phenolic content (78.6 mg g-1 dry matter in 2015), associated with a potassium content of 22 g kg-1 . CONCLUSIONS: The liquid concentrated retentates showed an unexpected stability over time of their bioactive phenolic compounds, particularly of hydroxytyrosol. These samples recovered from olive mill wastewaters can be good sources of natural antioxidants and potassium to guarantee the correct intake and to formulate new food ingredients or food products. (c) 2017 Society of Chemical Industry. PMID- 29105770 TI - Pediatric tinnitus: A clinical perspective. AB - OBJECTIVES/HYPOTHESIS: To define the clinical features and natural history of pediatric tinnitus from a practicing otolaryngologist's perspective and formulate hypotheses therein. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review of the electronic medical record was undertaken. Only relevant records with a prior otolaryngology clinic visit and audiologic testing were included. Patients seen during the last 2 years of the study period were contacted and completed a questionnaire to assess change in tinnitus and quantify potential alterations in quality of life, associated symptoms, and natural history. RESULTS: One hundred eighty subjects with mean/median age of 11.5/11.5 years were identified. Hearing loss was identified in 40 subjects (22.2%). Etiology of tinnitus was identified in 95 subjects (52.8 %). Tinnitus-specific and/or nonspecific therapies were given to 80 subjects (44.4%). Of the 54 available subjects, 28 (51.9%) participated in the telephone questionnaire. Tinnitus complaints shifted favorably to the improvement or resolution categories (P = .001) between the initial clinic visit and the telephone interview. Shorter duration of tinnitus was associated with a higher probability of having improved tinnitus (P = .046). CONCLUSIONS: This study distinguishes pediatric tinnitus from adult tinnitus in terms of lower association with underlying hearing loss, lower likelihood of reported anxiety, and higher likelihood of improvement and resolution. There are opportunities for tinnitus prevention in the areas of reducing head injury and noise-induced hearing loss. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:727-731, 2018. PMID- 29105771 TI - Preharvest treatments with salicylates enhance nutrient and antioxidant compounds in plum at harvest and after storage. AB - BACKGROUND: Previous reports have addressed the effectiveness of salicylic acid (SA), acetylsalicylic acid (ASA) and methylsalicylate (MeSA) postharvest treatments on maintaining quality properties during storage in several commodities. However, there is no literature regarding the effect of preharvest treatments with salicylates on plum quality attributes (at harvest or after long term cold storage), which was evaluated in this research. RESULTS: At harvest, weight, firmness, individual organic acids, sugars, phenolics, anthocyanins and total carotenoids were found at higher levels in plums from SA-, ASA- and MeSA treated trees than in those from controls. During storage, softening, colour changes and acidity losses were delayed in treated fruits as compared to controls. In addition, organic acids and antioxidant compounds were still found at higher levels in treated than in control plums after 40 days of storage. Results show a delay in the postharvest ripening process due to salicylate treatments, which could be attributed to their effect in delaying and decreasing ethylene production. CONCLUSION: Preharvest treatment with salicylates could be a safety, eco-friendly and new tool to improve (at harvest) and maintain (during storage) plum quality and especially its content of bioactive compounds with antioxidant properties, increasing the health effects of plum consumption. (c) 2017 Society of Chemical Industry. PMID- 29105772 TI - Vibratory function and healing outcomes after small intestinal submucosa biomaterial implantation for chronic vocal fold scar. AB - OBJECTIVES/HYPOTHESIS: Vocal fold scar is a major cause of dysphonia, and optimal treatments do not currently exist. Small intestinal submucosa (SIS) is a biomaterial developed for the treatment of a variety of pathologies. The purpose of this study was to investigate the effects of SIS implantation on tissue remodeling in scarred vocal folds using routine staining, immunohistochemistry, and high-speed videoendoscopy (HSV). STUDY DESIGN: Prospective, blinded group analysis. METHODS: Thirteen New Zealand White rabbits underwent a vocal fold scarring procedure followed by microflap elevation with or without SIS implantation. Seven months later, they underwent a phonation procedure with HSV and laryngeal harvest. Alcian blue and elastica van Gieson staining and immunohistochemistry for collagen types I and III were used to evaluate histological healing outcomes. Dynamic functional remodeling of the scarred vocal fold in the presence of SIS implants was evaluated using HSV imaging to capture restoration of vibratory amplitude, amplitude ratio, and left-right phase symmetry. RESULTS: Density of collagen I was significantly decreased in SIS versus microflap-treated vocal folds. No differences were found between groups for hyaluronic acid, elastin, or collagen type III. Organization of elastin in the subepithelial region appeared to affect amplitude of vibration and the shape of the vocal fold edge. CONCLUSIONS: SIS implantation into chronic scar reduced the density of collagen I deposits. There was no evidence of a negative impact or complication from SIS implantation. Regardless of treatment type, organization of elastin in the subepithelial region may be important to vibratory outcomes. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:901-908, 2018. PMID- 29105773 TI - Clinical trials in rhinosinusitis: Identifying areas for improvement. AB - OBJECTIVES/HYPOTHESIS: To characterize trends in rhinosinusitis clinical trials to provide recommendations for therapeutic directions, highlight possible redundancy, and provide a framework for prioritization of future clinical trials. STUDY DESIGN: Database analysis. METHODS: Data were collected from ClinicalTrials.gov including all clinical trials that focused on rhinosinusitis with the exclusion of trials withdrawn prior to enrollment. Variables recorded included study design, study population, pharmaceutical involvement, publication, and whether a trial was a medical or surgical intervention. Associated publications were identified using the PubMed, Embase, and Cochrane databases. RESULTS: There were 269 rhinosinusitis clinical trials, dating from 1993 to 2017, that met inclusion reauirements. Of the studies included in this analysis, 51.7% had at least one scientific publication, and of those with publications, 80.6% had positive results and 19.3% had negative results. Twenty-three clinical trials (8.5%) studied drugs already approved for rhinosinusitis, 113 (42.0%) trials studied drugs that were approved for other uses, 42 (15.6%) trials studied experimental drugs, and 102 (39.4%) studied surgical intervention. Of the trials studying drugs, the data showed many clinical trials that studied the same drug. The data demonstrate a steady decline in clinical trials with medical intervention and a rise in clinical trials with surgical intervention. CONCLUSIONS: This analysis is the first to characterize rhinosinusitis clinical trials, highlighting the over-representation of certain drugs and demonstrating an increased focus on clinical trials employing surgical intervention. We provide a framework to discuss prioritization of future studies to guide clinical and research practice. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1281-1286, 2018. PMID- 29105774 TI - Motor and sensory morbidity associated with the anterolateral thigh perforator free flap. AB - OBJECTIVE: To quantify changes in motor function, sensation, and lower extremity quality of life following anterior lateral thigh free flap (ALT) resection. METHODS: This mixed methods study contained both a prospective cohort arm (n = 20) and retrospective cross-sectional arm (n = 20). In both arms, patients underwent formal motor and sensation testing of the ipsilateral and contralateral thigh by sphygmomanometry and monofilament testing. In the prospective arm, data was collected preoperatively and at the 6-month and 1-year follow-up visits. In the retrospective arm, consecutive patients with a minimum of 6-month postoperative follow-up were enrolled. RESULTS: Postoperatively, 82% of participants endorsed some degree of numbness and tingling at the donor site. On monofilament testing, patients from the prospective arm showed decreased sensibility of the midthigh at both the 6- and 12-month assessment (P < 0.01). Two-point discrimination scores were moderately correlated with the cross sectional surface area of the flap. Donor thighs demonstrated a similar peak isometric quadriceps contraction (retrospective [retro]: 47 +/- 24 mmHg, prospective [pro]: 90 +/- 36 mmHg) to the unoperated thighs (retro: 43 mmHg +/- 22, pro: 69 +/- 35.3 mmHg, P = 0.49). When stratified by perforator anatomy, no significant differences were noted. Subjective donor site morbidity measured with the lower extremity function scale demonstrated no statistically significant difference between the preoperative and 12-month postoperative assessment. CONCLUSION: The ALT flap offers minimal donor site morbidity. Reduced sensibility of the ALT flap is a common complaint among patients. Quadriceps strength is not significantly affected by an ALT free flap harvest. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1057-1061, 2018. PMID- 29105775 TI - Is multidisciplinary team care for head and neck cancer worth it? PMID- 29105776 TI - Pediatric acute mastoiditis in the era of pneumococcal vaccination. AB - OBJECTIVES/HYPOTHESIS: The objective was to describe trends in the annual prevalence of hospitalization for pediatric acute mastoiditis since introduction of the 7-valent pneumococcal vaccine in 2000 and the 13-valent vaccine in 2010. STUDY DESIGN: Cross-sectional retrospective data analysis. METHODS: The Kids' Inpatient Database from years 2000 to 2012 was analyzed. To determine the annual prevalence of hospitalization for acute mastoiditis, nationally weighted frequencies of hospitalization for children <21 years with acute mastoiditis diagnoses were collected. Trend analysis of hospitalization rates from 2000 to 2012 was performed. RESULTS: From 2000 to 2012, there was no significant trend in hospitalization rates for acute mastoiditis overall (1.38 and 1.43 per 100,000 persons in 2000 and 2012, respectively; P = .86) or by age group. When comparing hospitalization rates at time points 2000 and 2012, children <1 year (4.65 and 3.27 per 100,000 persons, P = .0023) and 1 to 2 years of age (3.95 and 3.18 per 100,000 persons, respectively; P = .0107) demonstrated declines in hospitalization over time. Between 2009 and 2012, hospitalization rates also significantly declined for children aged <1 year (4.50 to 3.27 per 100,000 persons, P = .0056) and 1 to 2 years (4.30 to 3.18 per 100,000 persons, P = .0002) but increased for children 5 to 9 years (1.10 to 1.81 per 100,000 persons, P < .0001) and 10 to 20 years of age (0.41 to 0.72 per 100,000 persons, P < .0001). CONCLUSIONS: Despite introduction of two pneumococcal vaccines, rates of hospitalization for pediatric acute mastoiditis did not decline between 2000 and 2012. Between 2009 and 2012, however, children 0 to 2 years of age showed declining hospitalization rates, possibly reflecting the protective benefit of the 13-valent pneumococcal vaccine. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1480 1485, 2018. PMID- 29105777 TI - Temporal Trends in Rainwater Tank Suicides in Rijeka, Croatia-A 30-year Study. AB - Although drowning in rainwater tanks is a generally rare phenomenon, this method for suicide has been observed in parts of Croatia. Review of autopsy records at the University of Rijeka, Croatia, was undertaken from 1987 to 2016 to examine this phenomenon. Of 469 drowning deaths, there were 35 suicides in rainwater tanks (7.5%). Overall drowning deaths showed no temporal trends. In contrast, suicidal drownings in rain water tanks showed a marked decline over the years, with 15 cases in 1987-1991, seven in 1992-1996, six in 1997-2001, six in 2002 2006, one in 2007-2011, and none in 2012-2016. Thus, suicidal drowning cases as a percentage of overall drownings dropped from 18% to zero (p<0.001). This study reports a very unusual method of suicide that may have occurred because of the ready availability of large water reservoirs in homes. The recent fall in numbers may relate to less reliance on domestic reservoirs of water. PMID- 29105778 TI - Sonographically guided insertion of intrauterine device: Indications and results. AB - From 2011 to 2015, a total of 67 patients were referred for IUD insertion guided with transabdominal sonography (TAS). Fifty-six of the 67 patients had successful IUD insertion under TAS guidance. The clinical indications for referral included fibroids, uterine position, previous history of IUD expulsion, and limited tolerance of pelvic examination. Reasons for failed TAS-guided IUD insertion included patient discomfort, cervical stenosis, and inability to remove and replace an existing device. Ultrasound guidance could help broaden the patient population that may benefit from the therapeutic value of an IUD. PMID- 29105779 TI - Moderate- to long-term therapeutic outcomes of treated aggressive periodontitis patients without regular supportive care. AB - BACKGROUND AND OBJECTIVE: Risk for deterioration in treated aggressive periodontitis (AgP) individuals remained unclear. This retrospective cohort study investigated 7-26 years of periodontal outcomes and oral health-related quality of life (OHRQoL) of young adults with advanced periodontitis. MATERIAL AND METHODS: Eighty-nine previously treated patients with AgP were re-examined. Clinical and radiographic parameters before treatment discontinuation and at re examination were compared. OHRQoL at re-call was assessed with the short-form Oral Health Impact Profile (OHIP-14S). RESULTS: None of the subjects adhered to suggested periodontal therapy and maintenance after discharge. Mean percentage of sites with probing pocket depth (PPD) >=6 mm at re-examination was 4.5 +/- 5.9%. A total of 182 teeth had been lost over time. Tooth loss rate was 0.14/patient/year. From 68 subjects with documented favorable treatment outcomes, higher percentage of sites with PPD >=6 mm at re-examination and higher radiographic proximal bone loss was associated with current smoking status. Patients with AgP with <20 teeth at re-call had worse OHRQoL than those with >=20 teeth. Patients with higher full-mouth mean PPD also reported poorer OHRQoL. CONCLUSION: Treatment in patients with AgP who smoke and neglect proper supportive care, risk periodontal disease progression. Substantial tooth loss and higher full-mouth mean PPD led to poorer OHRQoL in this cohort. PMID- 29105780 TI - Structural, thermal, and morphological characteristics of cassava amylodextrins. AB - BACKGROUND: Amylodextrins from cassava starch were obtained by acid hydrolysis, and their structural, thermal and morphological characteristics were evaluated and compared to those from potato and corn amylodextrins. RESULTS: Cassava starch was the most susceptible to hydrolysis due to imperfections in its crystalline structure. The crystalline patterns of amylodextrins remained unchanged, and crystallinity and peak temperature increased with hydrolysis time, whereas thermal degradation temperature decreased, independent of treatment time and starch source. Cassava amylodextrins had similar structural and morphological characteristics to those from corn amylodextrins due to their A-type crystalline arrangements. A-amylodextrins were structurally and thermally more stable than potato amylodextrins (B-type). Starch nanocrystals (SNC) were observed by transmission electron microscopy from the third day of hydrolysis in cassava amylodextrins, whereas potato and corn amylodextrins displayed SNC only on the fifth day. A-SNC displayed platelet shapes, whereas B-SNC were rounded. The SNC shape was related to the packing form and geometry of unit cells of allomorphs A and B. CONCLUSION: Microstructures (agglomerated crystalline particles) and nanostructures (double helix organization) were observed for amylodextrins. Cassava starch was shown to be a promising material for SNC production, since it requires less hydrolysis time to obtaining more stable crystals. (c) 2017 Society of Chemical Industry. PMID- 29105781 TI - Prediction of mortality and morbidity in head and neck cancer patients 80 years of age and older undergoing surgery. AB - OBJECTIVES: To determine postoperative complications and mortality rates in octogenarian and older head and neck cancer patients undergoing ablative surgical resections and to identify factors associated with postoperative morbidity and mortality. METHODS: Retrospective cohort study investigating risk factors for 30 day serious complication risk and 90-day mortality risk for patients aged 80 years and older who underwent ablative head and neck oncologic surgical procedures at an academic tertiary care center between 2005 and 2015. RESULTS: Of the 219 patients who underwent 241 surgeries, 74 patients experienced serious complications within 30 days and 25 died within 90 days of surgery. American Society of Anesthesiologists (ASA) score of 4 or greater, and operating room (OR) time >=6 hours were independently associated with serious complications, whereas age >=90 years, overall severe comorbidity score, presence of preoperative dysphagia, and large extent of resection were associated with increased risk of death in 90 days. Models to predict risk of 30-day serious complications and 90 day mortality were then developed. CONCLUSION: Patient and surgical treatment factors predict risk of serious complications and mortality in patients aged 80 years and older undergoing ablative head and neck surgery. Predictive models may guide preoperative discussion with patients. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:871-877, 2018. PMID- 29105783 TI - Clinical implications of mast cell involvement in allergic conjunctivitis. AB - The conjunctiva is a common site for the allergic inflammatory response due to it being highly vascularized, having constant exposure to environmental pollutants and allergenic pollens and having a unique conjunctival associated lymphoid tissue. The primary morbidity of anterior surface conjunctival disorders that include allergic conjunctivitis and tear film disorders is associated with its high frequency of involvement rather than its severity, although the more chronic forms can involve the cornea and lead to sight-threatening conditions. Ocular allergy is associated with IgE-mediated mast cell activation in conjunctival tissue leading to the release of preformed mediators including histamine and proteases and subsequent de novo formation of lipid-derived mediators and cytokines that trigger a cascade of cellular and molecular events leading to extensive migration and infiltration of inflammatory cells to the ocular surface. The trafficking of neutrophils, eosinophils, and lymphocytes to the ocular surface is due to establishing various chemokine gradients (mainly CCL11, CCL24, CCL5, MCP-3, and MCP-4), cell surface expression of adhesion molecules (such as VCAM-1 the ligand for VLA-4), and leukocyte adhesion to vascular endothelium. The release of preformed mediators underlies the acute ocular surface response while the secondary influx of inflammatory cells leading to the recruitment and activation of eosinophils and the subsequent activation of Th2 and Th1 lymphocytes at the level of the conjunctiva reflects the late-phase reaction. PMID- 29105782 TI - Toxicity effects of AgZnO nanoparticles and rifampicin on Mycobacterium tuberculosis into the macrophage. AB - The World Health Organization acknowledges tuberculosis as a global threat. Tuberculosis infection is one of the top 10 causes of death worldwide. Nanotechnology and microbiology researchers are looking for new and safe nano drugs for eliminating Mycobacterium tuberculosis, the causative agent of tuberculosis. In this study, AgZnO nano-crystals (AgZnONCs) is synthesized via the decomposition of the precursor of oxalate method. Characterization of AgZnONCs were evaluated. Next, various concentrations of AgZnONCs, as well AgZnONCs+Rifampicin, were prepared. The MTT assay was employed to study the viability of human macrophage cell lines (THP-1) exposed to AgZnONCs. The bactericidal effects of AgZnONCs and AgZnONCs+Rifampicin were studied by Minimum Bactericidal Concentration (MBC) test. Subsequently, THP-1 were infected by H37 Rv strain of M. tuberculosis (H37 RvMtb). Also, bactericidal effects of AgZnONCs and AgZnONCs+Rifampicin were compared with ex-vivo conditions. The MBC of AgZnONCs and AgZnONCs+Rifampicin were ratios of 1:4 and 1:32 respectively (p value <0.05). Also, more than 50% and 80% of THP-1 were alive in ratios of 1:4 and 1:32 in the presence of AgZnONCs, respectively. All phagocytic H37 RvMtb were killed in the presence of AgZnONCs+Rifampicin (p-value <0.05), while AgZnONCs were not able to kill all the H37 RvMtb (p-value >0.05). This study showed that, AgZnONCs+Rifampicin has the most anti-tubercular behavior with respect to the macrophages. PMID- 29105784 TI - Early-life antibiotic exposure increases the risk of developing allergic symptoms later in life: A meta-analysis. AB - This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food allergy, positive skin prick testing (SPT), or elevated allergen-specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random-effects models. Early-life exposure to antibiotics appears to be related to an increased risk of allergic symptoms of hay fever, eczema, and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval (CI):1.13-1.34; I2 : 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI: 1.15-1.37; I2 : 74.2%, and the summary OR for food allergy (3 studies) was 1.42, 95% CI: 1.08-1.87; I2 : 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen-specific serum/plasma IgE levels. PMID- 29105785 TI - A color-code for glycosaminoglycans identification by means of polyacrylamide gel electrophoresis stained with the cationic carbocyanine dye Stains-all. AB - Cationic dyes such as toluidin blue are commonly employed to visualize glycosaminoglycans (GAGs) on electrophoresis gels; however, the carbocyanine based dye Stains-all have been increasingly used to stain the non-sulfated hyaluronic acid and other GAGs in submicrogram quantities. In this short communication, we demonstrate that Stains-all is able to stain the most common GAGs on polyacrylamide gels with distinct and contrasting colors in a reproducible manner. We also show that this staining method is useful to identify GAGs present both in mixtures and in submicrogram quantities. Therefore, Stains all has shown to be useful in identifying GAGs on polyacrylamide gels with basis on their specific colors, at least on screening level. PMID- 29105786 TI - Influenza burden, prevention, and treatment in asthma-A scoping review by the EAACI Influenza in asthma task force. AB - To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness, and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma-related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma. PMID- 29105787 TI - Kinematic behavior of a novel pedicle screw-rod fixation system for the canine lumbosacral joint. AB - OBJECTIVE: To determine the biomechanical behavior of a novel distraction stabilization system, consisting of an intervertebral distraction bolt, polyaxial screws, and connecting rods, in the canine lumbosacral spine. STUDY DESIGN: Biomechanical study. SAMPLE POPULATION: Cadaveric canine lumbosacral spines (L4 Cd3) (N = 8). METHODS: Cadaveric lumbosacral spines were harvested, stripped of musculature, mounted on a 4-point bending jig, and tested in extension, flexion, and lateral bending using nondestructive compressive axial loads (0-150 N). Angular displacement was recorded from reflective optical trackers rigidly secured to L6, L7, and S1. Data for primary and coupled motion were collected from intact spines, after destabilization at L7-S1, and following surgical stabilization with the new implant system. RESULTS: As compared with the intact spine, laminectomy resulted in a modest increase in angular displacement at L6-L7 and a marked increase at L7-S1. Instrumentation significantly reduced motion at the operated level (L7-S1) with a concomitant increase at the adjacent level (L6 L7). CONCLUSION: The combination of a polyaxial pedicle screw-rod system and intervertebral spacer provides a versatile solution of surgical stabilization of the lumbosacral joint following surgical decompression in the canine lumbosacral spine. The increase in motion at L6-L7 may suggest the potential for adjacent level effects and clinical trials should be designed to address this question. CLINICAL RELEVANCE: These results support the feasibility of using this new implant system for the management of degenerative lumbosacral disease in dogs. The increase in motion at L6-L7 may suggest the potential for adjacent level effects and clinical trials should be designed to address this question. PMID- 29105789 TI - Host-guest interactions between octa acid and cations/nucleobases. AB - The nature of host-guest interaction in between octa acid cavitand (OA) and some representative cationic guests (Li+ , Na+ , K+ , Be+2 , Mg+2 , Ca+2 , Li3 O+ , Na3 O+ , K3 O+ ) as well as heterocyclic moieties like [adenine (A), guanine (G), cytosine (C), thymine (T), uracil (U), and tetrathiafulvalene (TTF)] has been examined with the aid of density functional theory (DFT)-based computations. Thermochemical results indicate that all the guests bind with OA in a thermodynamically favorable fashion at 298.15 K temperature and one atmospheric pressure. OA exhibits high selectivity in binding the lighter cations/metal cluster cations as compared to the heavier congeners along each given series. Moreover, OA exhibits enhanced affinity as well as selectivity in binding A/G/TTF molecules as compared to C/T/U. Noncovalent interaction and energy decomposition analyses reveal that in addition to the van der Waals interaction, significant contribution from electrostatic as well as orbital interactions dictate the outcome in all the host-guest complexes. Time dependent DFT calculations have been carried out to assess the role of the guests in tuning the electronic properties as well as absorption spectrum of OA. (c) 2017 Wiley Periodicals, Inc. PMID- 29105788 TI - Economic evidence for nonpharmacological asthma management interventions: A systematic review. AB - Asthma management, education and environmental interventions have been reported as cost-effective in a previous review (Pharm Pract (Granada), 2014;12:493), but methods used to estimate costs and outcomes were not discussed in detail. This review updates the previous review by providing economic evidence on the cost effectiveness of studies identified after 2012, and a detailed assessment of the methods used in all identified studies. Twelve databases were searched from 1990 to January 2016, and studies included economic evaluations, asthma subjects and nonpharmacological interventions written in English. Sixty-four studies were included. Of these, 15 were found in addition to the earlier review; 53% were rated fair in quality and 47% high. Education and self-management interventions were the most cost-effective, in line with the earlier review. Self-reporting was the most common method used to gather resource-use data, accompanied by bottom-up approaches to estimate costs. Main outcome measures were asthma-related hospitalizations (69%), quality of life (41%) and utility (38%), with AQLQ and the EQ-5D being the most common questionnaires measured prospectively at fixed time points. More rigorous costing methods are needed with a more common quality of life tool to aid greater replicability and comparability amongst asthma studies. PMID- 29105790 TI - Use of direct near-infrared fluorescent lymphography for thoracoscopic thoracic duct identification in 15 dogs with chylothorax. AB - OBJECTIVE: To describe and assess techniques of intraoperative near-infrared fluorescence lymphography (NIRFL) using indocyanine green (ICG) for lymphatic duct identification during thoracoscopic thoracic duct (TD) ligation in dogs. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 15) with naturally occurring chylothorax that underwent TD ligation. METHODS: Medical records of dogs treated with thoracoscopic TD ligation in which NIRFL was utilized for intraoperative TD identification were reviewed. Data retrieved included CT lymphography (CTL) and surgical data, fluorophore dose and injection site, and timing and quality of operative TD identification. RESULTS: Preoperative CTL was successful in 13/15 dogs and operative NIRFL was successful in 15/15 dogs. Popliteal lymph node injection achieved successful NIRFL within <=10 minutes in 7/11 in which it was attempted. TDs identified by NIRFL imaging correlated with TDs identified by preoperative CTL in 12/13 cases in which CTL was achieved. In 1/13 cases, NIRFL identified small lymphatics not visible on CTL. In 5/9 cases in which methylene blue (MB) and ICG were combined for operative lymphography, no ducts or fewer ducts were recorded as identifiable by visible MB than by NIRFL or CTL. The median dose of ICG to achieve NIRFL imaging was 0.05 mg/kg. Thoracoscopic TD ligation was successfully achieved in all patients. CONCLUSION: NIRFL is a viable technique to aid in TD identification during thoracoscopy. High contrast NIRF illumination of the TD can be achieved with successful intraparenchymal injection of ICG into the popliteal lymph node. PMID- 29105791 TI - Implementation of dosimetry equipment and phantoms at the MedAustron light ion beam therapy facility. AB - PURPOSE: To describe the implementation of dosimetry equipment and phantoms into clinical practice of light ion beam therapy facilities. This work covers not only standard dosimetry equipment such as computerized water scanners, films, 2D array, thimble, and plane parallel ionization chambers, but also dosimetry equipment specifically devoted to the pencil beam scanning delivery technique such as water columns, scintillating screens or multilayer ionization chambers. METHOD: Advanced acceptance testing procedures developed at MedAustron and complementary to the standard acceptance procedures proposed by the manufacturer are presented. Detailed commissioning plans have been implemented for each piece of dosimetry equipment and include an estimate of the overall uncertainty budget for the range of clinical use of each device. Some standard dosimetry equipment used in many facilities was evaluated in detail: for instance, the recombination of a 2D-array or the potential use of a microdiamond detector to measure reference transverse dose profiles in water in the core of the primary pencil beams and in the low-dose nuclear halo (over four orders of magnitude in dose). RESULTS: The implementation of dosimetry equipment as described in this work allowed determining absolute spot sizes and spot positions with an uncertainty better than 0.3 mm. Absolute ranges are determined with an uncertainty comprised of 0.2-0.6 mm, depending on the measured range and were reproduced with a maximum difference of 0.3 mm over a period of 12 months using three different devices. CONCLUSION: The detailed evaluation procedures of dosimetry equipment and phantoms proposed in this work could serve as a guidance for other medical physicists in ion beam therapy facilities and also in conventional radiation therapy. PMID- 29105792 TI - Desiccation tolerance in Physcomitrella patens: Rate of dehydration and the involvement of endogenous abscisic acid (ABA). AB - The moss Physcomitrella patens, a model system for basal land plants, tolerates several abiotic stresses, including dehydration. We previously reported that Physcomitrella patens survives equilibrium dehydration to -13 MPa in a closed system at 91% RH. Tolerance of desiccation to water potentials below -100 MPa was only achieved by pretreatment with exogenous abscisic acid (ABA). We report here that gametophores, but not protonemata, can survive desiccation below -100 MPa after a gradual drying regime in an open system, without exogenous ABA. In contrast, faster equilibrium drying at 90% RH for 3-5 days did not induce desiccation tolerance in either tissue. Endogenous ABA accumulated in protonemata and gametophores under both drying regimes, so did not correlate directly with desiccation tolerance. Gametophores of a Ppabi3a/b/c triple knock out transgenic line also survived the gradual dehydration regime, despite impaired ABA signaling. Our results suggest that the initial drying rate, and not the amount of endogenous ABA, may be critical in the acquisition of desiccation tolerance. Results from this work will provide insight into ongoing studies to uncover the role of ABA in the dehydration response and the underlying mechanisms of desiccation tolerance in this bryophyte. PMID- 29105793 TI - What can we learn in drug allergy management from World Health Organization's international classifications? AB - Drug hypersensitivity reactions (DHRs) represent growing health problem worldwide, affecting more than 7% of the general population, and represent an important public health problem. However, knowledge in DHRs morbidity and mortality epidemiological data is still not optimal and international comparable standards remain poorly accessed. Institutional databases worldwide increasingly use the WHO International Classification of Diseases (ICD) system to classify diagnoses, health services utilization, and death data. The misclassification of disorders in the ICD system contributes to a lack of ascertainment and recognition of their importance for healthcare planning and resource allocation. It also hampers clinical practice and prevention actions. To further inform the allergy community and to ensure that the revision process is transparent as advised in the WHO ICD-11 revision agenda, we report the advances and use of the pioneering "Drug hypersensitivity" subsection of ICD-11 and implementation in the WHO International Classification of Health Interventions (ICHI). The new classification addressed to DHRs will enable the collection of more accurate epidemiological data to support quality management of patients with drug allergies and better facilitate healthcare planning and decision-making and public health measures to prevent and reduce the morbidity and mortality attributable to DHRs. PMID- 29105794 TI - In-line optical fiber metallic mirror reflector for monolithic common path optical coherence tomography probes. AB - BACKGROUND AND OBJECTIVES: Endoscopic optical coherence tomography probes suffer from various artifacts due to dispersion imbalance and polarization mismatch between reference and sample arm light. Such artifacts can be minimized using a common path approach. In this work, we demonstrate a miniaturized common path probe for optical coherence tomography using an inline fiber mirror. MATERIALS AND METHODS: A common path optical fiber probe suitable for performing high resolution endoscopic optical coherence tomography imaging was developed. To achieve common path functionality, an inline fiber mirror was fabricated using a thin gold layer. A commercially available swept source engine was used to test the designed probe in a cadaver human coronary artery ex vivo. RESULTS: We achieved a sensitivity of 104 dB for this probe using a swept source optical coherence tomography system. To test the probe, images of a cadaver human coronary artery were obtained, demonstrating the quality that is comparable to those obtained by OCT systems with separate reference arms. Additionally, we demonstrate recovery of ranging depth by use of a Michelson interferometer in the detection path. CONCLUSION: We developed a miniaturized monolithic inline fiber mirror-based common path probe for optical coherence tomography. Owing to its simplicity, our design will be helpful in endoscopic applications that require high-resolution probes in a compact form factor while reducing system complexity. Lasers Surg. Med. 50:230-235, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29105795 TI - FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer. AB - BACKGROUND: The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer. METHODS: Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmans test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area. RESULTS: In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart. CONCLUSIONS: Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti tumor immune response may be initiated even before the primary tumor is established. PMID- 29105796 TI - Penetration and pharmacokinetics of non-steroidal anti-inflammatory drugs in rat prostate tissue. AB - BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) involves inflammation of the prostate and affects the quality of life of men of all ages. It is well reported in clinical studies that the treatment for CP/CPPS using nonsteroidal anti-inflammatory drugs (NSAIDs) produced favorable outcomes. However, currently, there are no guidelines on choice of the NSAIDs for the treatment of CP/CPPS. Therefore, in the current research study, we evaluated the prostate tissue penetration of four NSAIDs in rats to provide guidance on choice of NSAIDs for the treatment of CP/CPPS. METHODS: Male Sprague-Dawley rats were administered orally with four NSAIDs viz. celecoxib, diclofenac, ibuprofen, and naproxen at 500 mg/kg dose. The animals were then sacrificed at various time points, and their prostate tissues were harvested. The NSAIDs were then extracted from the prostate tissues using liquid extraction technique, and their concentration in prostate tissue was quantified using high-performance liquid chromatography (HPLC). The prostate tissue penetration and related pharmacokinetic parameters were evaluated by non-compartmental analysis. RESULTS: The HPLC method for quantifying NSAIDs in prostate tissue resulted in single, sharp peaks without any interference and all validation parameters were within limits. Celecoxib showed the highest area under the curve (AUC) [146.50 +/- 2.75 MUg/mL*h] of all NSAID's. A two-factor analysis of variance (ANOVA) with replication indicated an overall statistically significant difference in the pharmacokinetic parameters for celecoxib, diclofenac, ibuprofen, and naproxen. CONCLUSIONS: This study for the first time reported the relative prostate tissue penetration of four NSAIDs. The pharmacokinetic data indicated that celecoxib has the highest penetration and retention in rat prostate tissues. Therefore, celecoxib may be considered as a better choice for the treatment CP/CPPS involving NSAIDs. PMID- 29105797 TI - 99m Tc-MIP-1404-SPECT/CT for the detection of PSMA-positive lesions in 225 patients with biochemical recurrence of prostate cancer. AB - BACKGROUND: 99m Tc-MIP-1404 (Progenics Pharmaceuticals, Inc., New York, NY) is a novel, SPECT-compatible 99m Tc-labeled PSMA inhibitor for the detection of prostate cancer. We present results of its clinical use in a cohort of 225 men with histologically confirmed prostate cancer referred for workup of biochemical relapse. METHODS: From April 2013 to April 2017, 99m Tc-MIP1404-scintigraphy was performed in 225 patients for workup of PSA biochemical relapse of prostate cancer. Whole-body planar and SPECT/CT images of the lower abdomen and thorax were obtained 3-4 h p.i. of 710 +/- 64 MBq 99m Tc-MIP-1404. Images were visually analyzed for presence and location of abnormal uptake. In addition, quantitative analysis of the SPECT/CT data was carried out on a subset of 125 patients. Follow up reports of subsequent therapeutic interventions were available for 59% (139) of all patients. RESULTS: Tracer-positive lesions were detected in 77% (174/225) of all patients. Detections occurred at the area of local recurrence in the prostate in 25% of patients (or a total of 56), with metastases in lymph nodes in 47% (105), bone in 27% (60), lung in 5% (12), and other locations in 2% (4) of patients. Detection rates were 90% at PSA levels >=2 ng/mL and 54% below that threshold. Lesional SUVmax values were, on average, 32.2 +/- 29.6 (0.8-142.2), and tumor-to-normal ratios 146.6 +/- 160.5 (1.9-1482.4). The PSA level correlated significantly with total uptake of MIP-1404 in tumors (P < 0.001). Furthermore, total tumor uptake was significantly higher in patients with Gleason scores >=8 compared to those with Gleason scores <=7 (P < 0.05). In patients with androgen deprivation therapy, the detection rate was significantly higher compared to patients without androgen deprivation therapy (86% vs 71%, P < 0.001). Based on 99m Tc-MIP-1404-imaging and other information, an interdisciplinary tumor board review recommended changes to treatment plans in 74% (104/139) of those patients for whom the necessary documentation was available. CONCLUSION: SPECT/CT with 99m Tc-labeled MIP-1404 has a high probability in detecting PSMA-positive lesions in patients with elevated PSA. Statistical analysis disclosed significant relationship between quantitative 99m Tc-MIP-1404 uptake, PSA level, and Gleason score. PMID- 29105798 TI - GLUT1 regulates cell glycolysis and proliferation in prostate cancer. AB - BACKGROUND: Glucose transporter 1 (GLUT1) plays a critical role in tumorigenesis and tumor progression in multiple cancer types. However, the specific function and clinical significance of GLUT1 in prostate cancer (PCa) are still unclear. Therefore, in this study, we investigated the role of GLUT1 in PCa. METHODS: GLUT1 protein levels in prostate cancer tissue and tumor-adjacent normal tissues were measured and compared. Furthermore, real-time PCR and Western blot analysis were both used to detect GLUT1 expression levels in different PCa cell lines. Flow cytometry and cell-based assays, such as a glucose uptake and lactate secretion assay, CCK-8 assay, and transwell migration and wound healing assay, were used to monitor cancer cell cycle distribution, glycolysis, proliferation, and motility, respectively. Moreover, a mouse tumor xenograft model was used to investigate the role of GLUT1 in tumor progression in vivo. RESULTS: GLUT1 expression levels are higher in PCa tissues than in tumor-adjacent normal tissues. The results from real-time PCR and Western blot analysis revealed a similar increase in the GLUT1 expression levels in PCa cell lines. Moreover, knockdown of GLUT1 inhibits cell glycolysis and proliferation and leads to cell cycle arrest at G2/M phase in the 22RV1 cell line but not in the PC3 cell line. In vivo experiments further confirmed that GLUT1 knockdown inhibits the growth of tumors derived from the 22RV1 cell line. In addition, we also showed that GLUT1 knockdown has no effect on cell migration in vitro. CONCLUSIONS: GLUT1 may play an important role in PCa progression via mediating glycolysis and proliferation. Our study also indicated a potential crosstalk between GLUT1-mediated glycolysis and androgen sensitivity in PCa. PMID- 29105799 TI - Microdialysis as a tool to determine the local tissue concentration of dicloxacillin in man. AB - AIMS: The most common pathogen to cause postoperative infections in Denmark is Staphylococcus aureus. Despite using prophylactic antibiotics, infections are still seen. Whether the tissue concentration is above the minimal inhibitory concentration (MIC) for the pathogen is unknown. Thus, the concentration of dicloxacillin in muscle and adipose tissue was measured after intravenous administration, in healthy men. METHODS: MIC for dicloxacillin against S. aureus was determined using the broth macrodilution method. A microdialysis (MD) catheter was placed in the subcutaneous tissue of the abdomen and in the lateral vastus muscle of the thigh of six healthy male volunteers. They were given 2 g dicloxacillin intravenously. Samples from blood and MD fluid were collected. The unbound dicloxacillin was isolated from plasma. Samples were analysed with high performance liquid chromatography (HPLC). RESULTS: The maximum concentration was reached in muscle tissue after 0.5 h and in adipose tissue after 0.8 h. AUC0-6h for the dicloxacillin concentration in adipose tissue was significantly lower when compared to the unbound dicloxacillin concentration in plasma. The dicloxacillin concentration was above the MIC for sensitive S. aureus for a minimum of 2.3 h and a median of 4.1 h in muscle tissue and a minimum of 1.8 h and a median of 3.2 h in adipose tissue. CONCLUSIONS: The unbound dicloxacillin concentration in adipose and muscle tissue remained above the MIC for sensitive S. aureus, for a period sufficient for many orthopaedic procedures. Whether this is true in patients with compromised circulation remains to be investigated. PMID- 29105800 TI - Biocontrol ability of killer yeasts (Saccharomyces cerevisiae) isolated from wine against Colletotrichum gloeosporioides on grape. AB - A total of 216 killer yeasts Saccharomyces cerevisiae, isolated from wine, were evaluated in controlling Colletotrichum gloeosporioides, a pre-harvest anthracnose agent of grape. Three of these yeast isolates were tested positive for antagonizing C. gloeosporioides and were further evaluated for their mechanisms as biological control agents (BCAs): production of antifungal compounds, production of hydrolytic enzymes, inhibition of C. gloeosporioides conidia germination, colonization on grape berry, and efficiency in controlling anthracnose of grape. The results showed that all three S. cerevisiae isolates produced antifungal compounds, inhibited C. gloeosporioides conidia germination and produced beta-1,3-glucanase and chitinase. All isolates colonized grape berry in large quantities and controlled C. gloeosporioides when artificially inoculated on grape berry. Among the three isolates, application of isolate GA8 resulted in 69.7% of disease reductions for C. gloeosporioides on grape berry. The antagonistic isolates of S. cerevisiae could represent important BCAs of anthracnose of grape caused by C. gloeosporioides that are responsible for economic losses in viticulture. PMID- 29105801 TI - Pharmacokinetics of pidotimod in broiler chickens by UHPLC-MS/MS after oral and intravenous administration. AB - Pidotimod is widely used in children as an immune promoter but it has not been fully evaluated in animals. The pharmacokinetics of pidotimod and its oral bioavailability have not been described in broiler chickens. We developed a simple and sensitive UHPLC-MS/MS assay for rapid determination of pidotimod levels in chicken blood. Recoveries were nearly 100% and the coefficients of accuracy and precision were minimal. Healthy broiler chickens were given 10 mg/kg pidotimod either orally or intravenously. The oral pidotimod was rapidly absorbed (time to reach maximum concentration, 1.25 h) and rapidly eliminated (the mean residence time was 3.2 h). A noncompartmental analysis of the intravenous route indicated a mean plasma clearance of 2.2 L (h kg)-1 with an estimated mean volume of distribution at steady state of 12.69 L/kg. The bioavailability of pidotimod after oral dosing was 27%. PMID- 29105803 TI - A Comparison of the Bow-Tie and STAMP Approaches to Reduce the Risk of Surgical Instrument Retention. AB - Although relatively rare, surgical instrument retention inside a patient following central venous catheterization still presents a significant risk. The research presented here compared two approaches to help reduce retention risk: Bow-Tie Analysis and Systems-Theoretic Accident Model and Processes. Each method was undertaken separately and then the results of the two approaches were compared and combined. Both approaches produced beneficial results that added to existing domain knowledge, and a combination of the two methods was found to be beneficial. For example, the Bow-Tie Analysis gave an overview of which activities keep controls working and who is responsible for each control, and the Systems-Theoretic Accident Model and Processes revealed the safety constraints that were not enforced by the supervisor of the controlled process. Such two-way feedback between both methods is potentially helpful for improving patient safety. Further methodology ideas to minimize surgical instrument retention risks are also described. PMID- 29105802 TI - Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone-sensitive prostate cancer. AB - BACKGROUND: Previous studies suggest circulating, blood-based microRNAs (miRNAs) may serve as minimally invasive prostate cancer biomarkers, however there is limited data from prospective clinical trials. Here, we explore the role of candidate plasma miRNAs as potential biomarkers in the SWOG 0925 randomized phase II study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer. METHODS: Correlative biospecimens, including circulating tumor cells (CTCs) and plasma for miRNA analysis, were collected at baseline and after 12 weeks on treatment from 50 patients enrolled on SWOG 0925. Circulating microRNAs were quantified using real-time RT-PCR microRNA array that allowed specific analysis of previously identified candidate miRNAs (miR-141, miR-200a, miR-200b, miR-210, and miR-375) as well as discovery analysis to identify new candidate miRNAs. MiRNA levels were correlated to previously reported CTC counts using CellSearch(r) (Veridex) and with the primary study outcome of 28-week PSA response (<=0.2, 0.2 to <=4.0, or >4.0 ng/mL), previously shown to correlate with overall survival. RESULTS: We observed a correlation between baseline circulating miR-141, miR-200a, and miR-375 levels with baseline CTCs. Baseline miR-375 levels were associated with 28-week PSA response (<=0.2, 0.2 to <=4.0, or >4.0 ng/mL, P = 0.007). Using ROC curve analysis, there was no significant difference between baseline miR-375 and baseline CTC in predicting 28-week PSA response (<=0.2 vs >0.2 ng/mL). To discover novel candidate miRNAs, we analyzed 365 miRNAs for association with the 28-week PSA response endpoint and identified new candidate miRNAs along with the existing candidates miR-375 and miR-200b (P = 0.0012, P = 0.0046, respectively. CONCLUSIONS: Baseline plasma miR-141, miR-200a, and miR-375 levels are associated with baseline CTC count. Baseline miR-375 was also associated with the trial endpoint of 28-week PSA response. Our results provide evidence that circulating miRNA biomarkers may have value as prognostic biomarkers and warrant further study in larger prospective clinical trials. PMID- 29105804 TI - Comparative Probabilistic Assessment of Occupational Pesticide Exposures Based on Regulatory Assessments. AB - Implementation of probabilistic analyses in exposure assessment can provide valuable insight into the risks of those at the extremes of population distributions, including more vulnerable or sensitive subgroups. Incorporation of these analyses into current regulatory methods for occupational pesticide exposure is enabled by the exposure data sets and associated data currently used in the risk assessment approach of the Environmental Protection Agency (EPA). Monte Carlo simulations were performed on exposure measurements from the Agricultural Handler Exposure Database and the Pesticide Handler Exposure Database along with data from the Exposure Factors Handbook and other sources to calculate exposure rates for three different neurotoxic compounds (azinphos methyl, acetamiprid, emamectin benzoate) across four pesticide-handling scenarios. Probabilistic estimates of doses were compared with the no observable effect levels used in the EPA occupational risk assessments. Some percentage of workers were predicted to exceed the level of concern for all three compounds: 54% for azinphos methyl, 5% for acetamiprid, and 20% for emamectin benzoate. This finding has implications for pesticide risk assessment and offers an alternative procedure that may be more protective of those at the extremes of exposure than the current approach. PMID- 29105805 TI - Should body image programs be inclusive? A focus group study of college students. AB - OBJECTIVE: Most evidence-based body image programs for college students (e.g., the Body Project) are designed for female-only audiences, although body dissatisfaction is not limited to female-identified individuals. Furthermore, programs do not explicitly discuss diversity, although individuals with marginalized gender, racial, and sexual identities may be particularly vulnerable to body image disturbances. Making programs more inclusive may increase their disseminability. METHOD: This qualitative study examined the feasibility of adapting the Body Project for universal and inclusive use with college students. Participants (N = 36; M age = 21.66 years; 73% female-identified; 20% sexual minority; 23% racial minority) attended one of five semi-structured focus groups to explore the inclusivity of appearance-based cultural norms using adapted Body Project activities and discuss the feasibility of universal and inclusive interventions. Inductive qualitative content analysis with three-rater consensus identified focus group themes. RESULTS: There was consensus that inclusive interventions could have a positive impact (broadening perspectives, normalizing body image concerns, increasing awareness) despite potential barriers (poor diversity representation, vulnerability). There was strong consensus regarding advice for facilitating inclusive interventions (e.g., skilled facilitation, education, increasing diversity). DISCUSSION: Results suggest that inclusive body image programs are desirable and provide a framework for creating the EVERYbody Project, a program for more universal audiences. PMID- 29105807 TI - The direct health care costs of eating disorders among hospitalized patients: A population-based study. AB - OBJECTIVE: To estimate the direct health care costs of eating disorders in Ontario, Canada, in 2012, using a prevalence-based cost-of-illness approach. METHOD: We selected a population-based sample of all patients eligible for public health care insurance over the age of 4 with a hospitalization for an eating disorder at any point since 1988. We estimated total and mean direct net costs per patient in 2012, from the third public payer perspective, by sex, age group, and health service type. RESULTS: In 2012, there were 6,326 patients ever hospitalized for an eating disorder. They had a mean age of 31 at hospitalization, were mostly female (93%), and generally from high-income, urban neighborhoods. Direct total costs were just under $63 million CAD; direct net costs were roughly $48 million CAD. Mean net costs per patient were higher for females than males ($7,743.40 and $6,340.50, respectively), and higher for patients under 20 and patients 65+ ($17,961.50 and $14,953.90, respectively). The main cost drivers were psychiatric hospitalizations and physician visits, although this varied by age group. For younger patients, net costs were mainly because of psychiatric hospitalizations, while for older patients net costs were mainly because of psychiatric and nonpsychiatric hospitalizations, and other care. DISCUSSION: The cost of eating disorders is substantial and varies by sex and age group. Our findings suggest that, from a health care utilization/cost perspective, the effect of eating disorders is likely to persist over the lifespan. PMID- 29105806 TI - The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress. AB - BACKGROUND: The targeted induction of reactive oxygen species (ROS) is a developing mechanism for cancer therapy. LQB-118 is a pterocarpanquinone and ROS inducing agent with proven antineoplastic activity. Here, LQB-118 efficacy and mechanism of activity, were examined in Prostate Cancer (PCa) cell and tumor models. METHODS: PC3, LNCaP, and LAPC4 PCa cells were applied. Dicoumarol treatment was used to inhibit quinone reductase activity. N-acetylcysteine (NAC) was applied as a ROS scavenger. ROS production was quantified by H2 DCFDA flow cytometry. LQB-118 treated cells were evaluated for changes in lipid peroxidation, viability, and apoptosis. Treatment-induced gene expression was measured by RT-qPCR and Western Blot. SOD1 knockdown was achieved with siRNA or miRNA mimic transfection. MicroRNA specificity was determined by 3'UTR reporter assay. Oral LQB-118 treatment (10 mg/kg/day) efficacy was determined in athymic male nude mice bearing subcutaneous PC3 xenograft tumors. RESULTS: LQB-118 treatment triggered PCa cell death and apoptosis. Therapeutic activity was at least partially dependent upon quinone reduction and ROS generation. LQB-118 treatment caused an increase in cellular ROS and lipid peroxidation. Treated cells exhibited elevated levels of NQO1, Nrf2, and SOD1. The miRNAs miR-206, miR 1, and miR-101 targeted and reduced SOD1 expression. The knockdown of SOD1, by siRNA or miRNA, enhanced LQB-118 cytotoxicity. Orally administered LQB-118 treatment significantly reduced the growth of established PCa xenograft tumors. CONCLUSION: LQB-118 is a developing and orally active pterocarpanquinone agent that effectively kills PCa cells through quinone reduction and ROS generation. The inhibition SOD1 expression enhances LQB-118 activity, presumably by impairing the cellular antioxidant response. PMID- 29105808 TI - Early childhood adversities and risk of eating disorders in women: A Danish register-based cohort study. AB - OBJECTIVE: Previous studies evaluating the association between early childhood adversities and eating disorders have yielded conflicting results. The aim of this study is to examine the association between a range of adversities and risk of anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS) in 495,244 women. METHOD: In this nationwide, register-based cohort study, nine types of early childhood adversity (family disruption, residential instability, placement in out-of-home care, familial death, parental somatic illness, parental psychiatric illness, parental disability, severe parental criminality, and parental substance use disorder) were defined and exposure during the first 6 years of life was determined. Hazard ratios for eating disorders were calculated using Cox regression. RESULTS: Few adversities were significantly associated with AN, and for each, the presence of the adversity was associated with lower risk for AN. BN, and EDNOS were positively associated with several types of adversities. AN rates were unchanged or reduced by up to 54% by adversities, whereas rates of BN and EDNOS were unchanged or increased by adversities by up to 49 and 89%, respectively. DISCUSSION: Our findings indicate that childhood adversities appear to be associated with an increased risk of BN and in particular EDNOS, whereas they seem to be either unassociated or associated with a decreased risk of AN. PMID- 29105809 TI - US Health Care Reform and Rural America: Results From the ACA's Medicaid Expansions. AB - PURPOSE: Medicaid expansions, prompted by the Affordable Care Act, generated generally positive effects on coverage and alleviated much of the financial burden associated with seeking health care. We do not know if these shifts also extend to the nation's rural populations. METHODS: Using 2011-2015 Behavioral Risk Factor Surveillance System data, this study compares trend changes for coverage, access to care, and health care utilization in response to Medicaid expansion among urban and rural residents using a difference-in-differences regression approach. FINDINGS: Following Medicaid expansion, low-income rural and urban residents both experienced reductions in uninsurance; however, the coverage uptake in rural settings (8.5 percentage points [pp], P < .01) was much larger than the uptake in coverage in more urban settings (4.1 pp, P > .10). In spite of larger uptakes in coverage among rural residents, reductions in cost-related barriers to medical care were slightly larger among urban residents, and access to a regular source of medical care (5.2 pp, P < .05) and doctor visitation (4.5 pp, P < .01) were only statistically significant among urban residents. CONCLUSIONS: The ACA Medicaid expansions produced larger gains in coverage for rural residents than urban residents; however, it appears there remain opportunities to improve access to care among potentially vulnerable rural residents. PMID- 29105810 TI - Levodopa-carbidopa intestinal gel therapy after deep brain stimulation. PMID- 29105811 TI - Business recovery: an assessment framework. AB - This paper presents a Business Recovery Assessment Framework (BRAF) to help researchers and practitioners design robust, repeatable, and comparable studies of business recovery in various post-disruption contexts. Studies assessing business recovery without adequately considering the research aims, recovery definitions, and indicators can produce misleading findings. The BRAF is composed of a series of steps that guide the decisions that researchers need to make to ensure: (i) that recovery is indeed being measured; (ii) that the indicators of recovery that are selected align with the objectives of the study and the definition of recovery; and, where necessary, (iii) that appropriate comparative control variables are in place. The paper draws on a large dataset of business surveys collected following the earthquakes in Canterbury, New Zealand, on 4 September 2010 and 22 February 2011 to demonstrate the varied conclusions that different recovery indicators can produce and to justify the need for a systematic approach to business recovery assessments. PMID- 29105812 TI - Response of the mayfly (Cloeon dipterum) to chronic exposure to thiamethoxam in outdoor mesocosms. AB - Thiamethoxam is a widely used neonicotinoid insecticide that has been detected in surface water monitoring programs in North America and Europe. This has led to questions about its toxicity to nontarget insects, specifically those with an aquatic life stage. To address the uncertainty associated with possible impacts from environmental exposures, a chronic (35-d) outdoor mesocosm study with a formulated product containing thiamethoxam was conducted. The specific focus of the study was the response of mayflies (Ephemeroptera), which have been reported to be particularly sensitive in laboratory studies. A range of concentrations (nominally 0.1, 0.3, 1.0, 3.0, and 10.0 ug/L thiamethoxam), plus untreated controls were tested, and the abundance and emergence of mayflies (Cloeon dipterum) were assessed weekly for 35 d. Mean measured time-weighted average exposures were within 6% of nominal over the duration of the study, with the mean half-life of thiamethoxam in each treatment ranging from 7 to 13 d. Statistically significant reductions in both larval abundance and adult emergence were observed at 10.0, 3.0, and 1.0 MUg/L following 1, 2, and 3 wk of exposure, respectively. Exposure to 0.1 and 0.3 ug/L thiamethoxam had no statistically significant effect on larval mayfly abundance or adult emergence at any point in the study. These findings support a 35-d no-observed-effect concentration (NOEC) of 0.3 ug thiamethoxam/L for mayflies (C. dipterum) under chronic conditions. Furthermore, because the 95th percentile of environmental concentrations has been reported to be 0.054 ug/L, these results indicate that populations of C. dipterum and similarly sensitive aquatic insects are unlikely to be significantly impacted by thiamethoxam exposure in natural systems represented by the conditions in our study. Environ Toxicol Chem 2018;37:1040-1050. (c) 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 29105813 TI - How can systems engineering inform the methods of programme evaluation in health professions education? AB - CONTEXT: We evaluate programmes in health professions education (HPE) to determine their effectiveness and value. Programme evaluation has evolved from use of reductionist frameworks to those addressing the complex interactions between programme factors. Researchers in HPE have recently suggested a 'holistic programme evaluation' aiming to better describe and understand the implications of 'emergent processes and outcomes'. FRAMEWORK: We propose a programme evaluation framework informed by principles and tools from systems engineering. Systems engineers conceptualise complexity and emergent elements in unique ways that may complement and extend contemporary programme evaluations in HPE. We demonstrate how the abstract decomposition space (ADS), an engineering knowledge elicitation tool, provides the foundation for a systems engineering informed programme evaluation designed to capture both planned and emergent programme elements. METHODS: We translate the ADS tool to use education-oriented language, and describe how evaluators can use it to create a programme-specific ADS through iterative refinement. We provide a conceptualisation of emergent elements and an equation that evaluators can use to identify the emergent elements in their programme. Using our framework, evaluators can analyse programmes not as isolated units with planned processes and planned outcomes, but as unfolding, complex interactive systems that will exhibit emergent processes and emergent outcomes. Subsequent analysis of these emergent elements will inform the evaluator as they seek to optimise and improve the programme. CONCLUSION: Our proposed systems engineering informed programme evaluation framework provides principles and tools for analysing the implications of planned and emergent elements, as well as their potential interactions. We acknowledge that our framework is preliminary and will require application and constant refinement. We suggest that our framework will also advance our understanding of the construct of 'emergence' in HPE research. PMID- 29105814 TI - Late-onset type I endoleak characterized by contrast enhanced ultrasound after endovascular repair of aortic aneurysm. AB - We report in the case of a patient with an intra-abdominal aortic aneurysm treated with endovascular aneurysm repair (EVAR) who developed renal impairment during the period of follow up. The repair was complicated with an early-onset type II endoleak which later evolved into a late-onset type I endoleak. It was treated with proximal extension of stent graft, with treatment success and follow up documented on contrast enhanced ultrasound (CEUS). This case illustrates the usefulness of CEUS in post-EVAR surveillance and emphasizes the need for life long monitoring as late-onset complications are not uncommon. PMID- 29105815 TI - Mate choice screening in captive solitary carnivores: The role of male behavior and cues on mate preference and paternity in females of a model species, American mink (Neovison vison). AB - Mate choice studies suggest that choosy females benefit from increased fecundity, litter size, and offspring survival. Thus, providing females with the opportunity to choose among potential mates, deemed genetically suitable based on studbook data, might improve breeding management in production and zoo animals and thereby the sustainability of captive populations. Investigating mate preference via odor from potential mates before animal transfer is a proposed strategy for incorporating mate choice into breeding management. In this study, we test whether olfactory cues and signals from males can be used to assess and measure female mate preference in American mink. Eighteen females were subjected to a 4 day stimulus test in which females showed a preference for one of two males' urine and feces. Subsequently, each female was subjected to a 10-day mate preference test involving the same two males of the first test. Paternity tests revealed that 13 females had offspring, which could be assigned to only one male, suggesting that these females performed a mate choice. In nine of these females preference during the stimulus test was directed toward the male that fathered their offspring. Our results suggest that even though there was a preference difference in scent stimulus trials from potential mates this preference was not predictive of eventual mate preference or paternity. Other factors such as aspects of male behavior seem to play a role, when the mates are introduced. Our study supports that mate preference and mate choice are complex matters influenced by multiple cues and signals. PMID- 29105816 TI - Comparison of laboratory-derived biomagnification factors for hexachlorobenzene in common carp conducted under 9 test conditions. AB - Nine dietary exposure bioaccumulation fish tests with hexachlorobenzene (HCB) were conducted with common carp to explore how differences in test conditions (different test foods and feeding rates) influenced the lipid-corrected, growth corrected kinetic biomagnification factor (BMFkgL ) value (BMFkgL = BMFkg * lipid content of test food/lipid content of test fish). The BMFkgL values for HCB differed by approximately a factor of 5 among the tests. The average, median, 95% confidence interval, and coefficient of variation of the BMFkgL values were 0.925, 0.998, 0.578 to 1.27, and 49%, respectively. The BMFkgL value differed markedly between tests conducted using test food with lipid contents of approximately 5 and 15%. Different feeding rates (2 or 3% of body weight/d) had comparatively little effect on the BMFkgL of HCB. The present study revealed that the lipid content of test fish was correlated with the growth-corrected kinetic BMF (BMFkg ) value of HCB but the lipid content of test food was poorly correlated with BMFkg . This lack of correlation might explain the large variations of the BMFkgL values observed. The value of the BMFkg normalized to a fish with a 5% lipid content (defined as the 5% lipid-normalized BMFkg in the present study) did not differ markedly between tests conducted using test food with different lipid contents (5-15%). It is therefore useful to report the 5% lipid-normalized BMFkg as well as the BMFkgL when dietary exposure tests are conducted. Environ Toxicol Chem 2018;37:1032-1039. (c) 2017 SETAC. PMID- 29105818 TI - Simplified profunda artery perforator (PAP) flap design using power Doppler ultrasonography (PDU): A prospective study. AB - INTRODUCTION: Optimal design of PAP flaps requires precise perforator mapping. In a systematic review, Doppler ultrasonography demonstrated the highest sensitivity and positive predictive value (PPV). We present a prospective study of PAP flap design comparing PDU, handheld Doppler (HHD), and clinical findings. METHODS: From May to July 2016, 12 head and neck cancer patients receiving PAP flaps were examined with PDU and HHD. We used PDU to evaluate number, course, emergence point, peak systolic velocity (PSV), and arterial diameter of perforators. PDU skin markings were measured in relation to the groin and gracilis. Distances to the adjacent HHD marking were determined. Diagnostic results were compared with intraoperative findings. RESULTS: All perforators identified with PDU were confirmed intraoperatively. No sizable perforators found surgically were missed by PDU. Detecting perforators with diameters of ?0.5 mm, false-negative rate of PDU was zero percent, sensitivity was 100%. Musculocutaneous courses were identified in all perforators and sensitivity of PDU was 96.7%. Arterial diameter was overestimated by PDU (1.49 +/- 0.39 vs. 0.75 +/- 0.31 mm, P > .05). PSV at the emergence point was 24.5 +/- 11.9 cm/s. Average distance from the emergence point to the PDU marking was 2.45 +/- 1.90 mm (0-6 mm). The PPV of PDU was calculated at 93.10%. Mean distance from the HHD to the PDU markings was 20.76 +/ 16.5 mm (1-70 mm). Assuming PDU findings demonstrated the true anatomy, sensitivity of HHD was calculated with 89.7%, and PPV was 66.7%. All PAP flaps were successful, only minor revisions were needed. CONCLUSIONS: PDU facilitated PAP flap design in all cases and offers a precise, non-invasive diagnostic tool for flap planning. PMID- 29105817 TI - Loss of Spry1 attenuates vascular smooth muscle proliferation by impairing mitogen-mediated changes in cell cycle regulatory circuits. AB - Signals from growth factors or mechanical stimuli converge to promote vascular smooth muscle cell (VSMC) migration and proliferation, key events in the pathogenesis of intimal hyperplasia upon vascular injury. Spry1, a regulator of receptor tyrosine kinases (RTK), plays a role in maintaining the contractile phenotype of VSMC. The aim of the current study was to determine the role of Spry1 in VSMC proliferation in vitro and injury induced neointimal hyperplasia in vivo. VSMC proliferation and neointima formation were evaluated in cultured human aortic SMC (hAoSMC) and ligation-induced injury of mouse carotid arteries from Spry1 gene targeted mice, and their corresponding wild type littermates. Human Spry1 or non-targeting control lentiviral shRNAs were used to knock down Spry1 in hAoSMC. Time course cell cycle analysis showed a reduced fraction of S-phase cells at 12 and 24 h after growth medium stimulation in Spry1 shRNA transduced hAoSMC. Consistent with reduced S-phase entry, the induction of cyclinD1 and the levels of pRbS807/S811, pH3Ser10, and pCdc2 were also reduced, while the cell cycle inhibitor p27Kip1 was maintained in Spry1 knockdown hAoSMC. In vivo, loss of Spry1 attenuated carotid artery ligation-induced neointima formation in mice, and this effect was accompanied by a decrease in cell proliferation similar to the in vitro results. Our findings demonstrate that loss of Spry1 attenuates mitogen-induced VSMC proliferation, and thus injury-induced neointimal hyperplasia likely via insufficient activation of Akt signaling causing decreased cyclinD1 and increased p27Kip1 and a subsequent decrease in Rb and cdc2 phosphorylation. PMID- 29105820 TI - The radial forearm free flap as a "vascular bridge" for secondary microsurgical head and neck reconstruction in a vessel-depleted neck. AB - BACKGROUND: In a vessel-depleted neck, distant recipient sites may be the only option for secondary free flap reconstruction. While interposition vein grafts and arteriovenous loops can bridge the gap between the recipient and donor pedicle, they are not without risks. In these scenarios, we examinate the reliablity of a radial forearm free flap (RFFF) as an alternative vascular conduit. PATIENTS AND METHODS: A retrospective review of cases between March 2005 and May 2016 was performed. Demographic data, prior surgical history, intraoperative details and outcomes were recorded. A total of ten patients, eight male and two female, with a mean age of 54.2 years (range, 39-74) were identified. The RFFF was initially anastomosed to either the thoracoacromial (n = 6) or internal mammary vessels (n = 4) and subsequently served as the recipient pedicle for the second "main" flap, an anterolateral thigh (n = 4), jejunum (n = 3) or fibula flap (n = 3). RESULTS: The average RFFF dimensions were 13.8 cm by 5.8 cm. All twenty flaps, ten RFFF and ten "main' flaps survived completely with only one case of minimal epidermal loss. One patient with esophageal reconstruction with jejunum developed a fistula that required closure with a local falp. At a mean follow-up of 18.4 months (range 8-29), the reconstructive goals had been achieved in all cases. CONCLUSIONS: The RFFF serves as a reliable "vascular bridge" that extends the reach of distant recipient sites to free flaps in secondary head and neck reconstruction. PMID- 29105819 TI - Neuroprotective effect of licochalcone A against oxygen-glucose deprivation/reperfusion in rat primary cortical neurons by attenuating oxidative stress injury and inflammatory response via the SIRT1/Nrf2 pathway. AB - Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal death and neurological disability. Oxidative stress and neuroinflammation are typical pathogenic factors of HIE. Licochalcone A (LCA) exerts various biological properties, including anti-inflammatory and antioxidant activities. However, no data have been reported to elucidate the role of LCA in the development of HIE. In the present study, primary cultured rat cortical neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro to simulate the in vivo situation of neonatal HIE. Interestingly, LCA significantly antagonized cell injury under OGD/R by increasing cell survival, inhibiting lactate dehydrogenase (LDH) release and cell apoptosis. Furthermore, treatment with LCA suppressed oxidative stress by decreasing reactive oxygen species (ROS) production and malondialdehyde (MDA) content, and increasing superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in primary rat cortical neurons after OGD/R. LCA stimulation also restrained OGD/R-triggered increase in pro inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production. Importantly, LCA treatment effectively counteracts OGD/R mediated downregulation of silent information regulator 1 (SIRT1), nuclear factor erythroid2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1), and upregulation of nuclear factor kappa B p65 (NF-kappaB p65). Moreover, administration with SIRT1 inhibitor EX527 partly abolished LCA-induced neuroprotective effects on rat cortical neurons exposed to OGD/R. In conclusion, our study indicates that LCA exerts a neuroprotective effect against OGD/R-induced neuronal injury in rat primary cortical neurons, suggesting that LCA might act as a candidate therapeutic target drug used for HIE and related diseases. PMID- 29105821 TI - Accurate prediction of acute fish toxicity of fragrance chemicals with the RTgill W1 cell assay. AB - Testing for acute fish toxicity is an integral part of the environmental safety assessment of chemicals. A true replacement of primary fish tissue was recently proposed using cell viability in a fish gill cell line (RTgill-W1) as a means of predicting acute toxicity, showing good predictivity on 35 chemicals. To promote regulatory acceptance, the predictivity and applicability domain of novel tests need to be carefully evaluated on chemicals with existing high-quality in vivo data. We applied the RTgill-W1 cell assay to 38 fragrance chemicals with a wide range of both physicochemical properties and median lethal concentration (LC50) values and representing a diverse range of chemistries. A strong correlation (R2 = 0.90-0.94) between the logarithmic in vivo LC50 values, based on fish mortality, and the logarithmic in vitro median effect concentration (EC50) values based on cell viability was observed. A leave-one-out analysis illustrates a median under-/overprediction from in vitro EC50 values to in vivo LC50 values by a factor of 1.5. This assay offers a simple, accurate, and reliable alternative to in vivo acute fish toxicity testing for chemicals, presumably acting mainly by a narcotic mode of action. Furthermore, the present study provides validation of the predictivity of the RTgill-W1 assay on a completely independent set of chemicals that had not been previously tested and indicates that fragrance chemicals are clearly within the applicability domain. Environ Toxicol Chem 2018;37:931-941. (c) 2017 SETAC. PMID- 29105822 TI - Why do women request an elective cesarean delivery for non-medical reasons? A systematic review of the qualitative literature. AB - BACKGROUND: Cesarean rates have increased significantly over the past decade. The reasons for this are both complex and context specific, and have significant consequences for health resources. The aim of this systematic review was to assess published, peer-reviewed, and gray qualitative literature on the reasons behind cesarean delivery on maternal request (CDMR). METHODS: A systematic search of MEDLINE, EMBASE, CINAHL, LILACS, and PsycINFO databases was performed for all relevant articles published between January 2006 and June 2016. Reference lists of all included studies were also searched in addition to select web-based sources. Studies were included if they qualitatively evaluated women's preferences for CDMR, with no geographic restriction. Findings from the studies were narratively and thematically synthesized. RESULTS: Sixteen studies were included in this review. Three themes were identified as to why women choose CDMR, which were: social norms, emotional experiences, and personal experiences. A woman's decision was often shaped by various influences including family, friends, and the media. In addition, previous experience of childbirth and interactions with health care professionals contributed to a strong preference for CDMR. CDMR provided women with a sense of control over the birth and diminished feelings of fear. CONCLUSIONS: The reasons behind CDMR are multifactorial and complex. Situation-specific cultural factors, fear of pain during childbirth, previous experience, and interactions with health care professionals are likely to have led to the increase in CDMR. Multifaceted, context-specific approaches are required if there is to be a reduction in CDMR rates. PMID- 29105823 TI - Pyridoxine-sensitive X-linked 'sideroblastic' anaemia in the absence of ring sideroblasts - molecular diagnosis. PMID- 29105824 TI - Wound culture isolated antibiograms and caregiver-reported skin care practices in children with epidermolysis bullosa. AB - BACKGROUND/OBJECTIVES: Many patients with epidermolysis bullosa (EB) require intensive daily wound care and individualized treatment plans. Understanding patient's home skin care routines and emerging antibiotic resistance patterns in EB wounds is necessary to optimize treatment recommendations. The objective was to identify patterns of antimicrobial resistance in EB wounds and characterize patient's home practices of skin care and bathing. METHODS: This was an observational study of 23 children with EB at an outpatient pediatric dermatology practice in New York City from 2012 to 2014. Information on individual bathing and skin care practices and wound cultures was collected as part of routine examinations and an institutional review board-approved antibiogram protocol. RESULTS: Sixty wound cultures were collected from 23 patients. Eleven organisms were isolated, most commonly methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, Streptococcus species, and Pseudomonas aeruginosa. Six patients (26%) were colonized with methicillin-resistant S. aureus. Over the course of the study, 13 patients (56%) were found to have mupirocin-resistant S. aureus. More than half of participants reported mupirocin or bacitracin use. Fewer than half indicated that they regularly used dilute bleach or dilute vinegar as part of their bathing routine. CONCLUSION: Numerous organisms, including resistant bacteria, are known to colonize the wounds of individuals with EB. Mupirocin resistance was prevalent and more than half of the participants reported its use. Testing for mupirocin resistance may be considered for certain patients. These observations may help guide questions for future longitudinal multicenter studies with the goal of optimizing EB wound care recommendations. PMID- 29105825 TI - Improved capture of stable flies (Diptera: Muscidae) by placement of knight stick sticky fly traps protected by electric fence inside animal exhibit yards at the Smithsonian's National Zoological Park. AB - Stable flies are noxious blood-feeding pests of exotic animals at zoological parks, inflicting painful bites, and causing discomfort to animals. Stable fly management is difficult because of the flies' tendency to remain on the host animals only when feeding. Non-toxic traps can be efficient but traps placed around exhibit perimeters captured fewer-than-expected numbers of flies. By surrounding traps with square electric fence enclosures, traps could be placed in the exhibits with the host animals and compared with an equal number of traps placed along perimeter fences. During a 21-week study, traps inside exhibits captured 5* more stable flies than traps placed along exhibit perimeters. Traps inside exhibits tended to show more fluctuations in fly populations than traps along perimeters. The increased numbers of flies captured using this technique should provide relief from this pestiferous fly and greatly improve animal health and welfare. We believe this to be the first study where traps were used to capture stable flies in exhibit yards at a zoological park. PMID- 29105827 TI - Cryptantigens: time to uncover the real significance of T-activation. PMID- 29105828 TI - Detection of three blood donors with multiple myeloma by routine viral individual donor nucleic acid testing screening. PMID- 29105829 TI - Significantly enhanced testing sensitivities of automated ORTHO VISION analyzers detect weak D phenotypes. PMID- 29105830 TI - Paternity probabilities when a child is a congenital chimera. PMID- 29105831 TI - The importance of clinical judgment for the diagnosis of thrombotic thrombocytopenic purpura. PMID- 29105832 TI - Facilitation of the clinical diagnosis of Mycoplasma pneumoniae by the blood bank. PMID- 29105833 TI - The 100th anniversary of the first blood bank. PMID- 29105834 TI - Characterization of a robust serine protease from Bacillus subtilis K-1. AB - Process apt microbial proteases due to their wide range industrial applications have become the focus of intense scientific research during recent years. Considering the hostile process milieu, the proteases intended for application must be robust enough to withstand the extremes of temperature and pH, and presence of organic solvents and other potential enzyme inhibitors. Current study presents the characterization of a robust protease from a previously isolated bacterium Bacillus subtilis K-1 (BSK-1). Purification of BSK-1 protease (5.21 fold) was achieved to homogeneity by salt (ammonium sulfate) precipitation, and ion-exchange (diethyl-aminoethyl-sephadex) and size exclusion chromatography (Sephadex G-100). Molecular weight of BSK-1 protease was determined by SDS-PAGE analysis (42 kDa). Though the optimum temperature and pH for BSK-1 protease activity was 50 degrees C and 10, respectively, but, the protease exhibited remarkable activity and stability over elevated temperatures (60-80 degrees C) and a broad pH range (pH 7-11). Protease showed resistance towards several organic solvents/other potential enzyme inhibitors. Drastic activity loss in presence of phenylmethylsulfonyl fluoride indicated that the enzyme is a serine protease. Kinetic parameters (Km and Vmax ) for BSK-1 protease were found to be 0.14 mg ml-1 and 1176 mg min-1 , respectively. Putative amino acid sequence of BSK-1 protease (derived from nucleotide sequence of protease gene) suggested that the enzyme belonged to peptidases S8/S53 super family with multidomain of S8. BSK 1 protease being stable under harsh conditions may serve a model system for understanding the molecular basis of stability, and may help designing novel proteases that are suitable for industrial applications. PMID- 29105835 TI - Translating animal research from the laboratory to the neonatal clinical arena requires great caution. PMID- 29105836 TI - Pediatric severity of alopecia tool. AB - The Severity of Alopecia Tool serves as a tool for alopecia research and a clinical guideline for following progression of disease. The original Severity of Alopecia Tool score does not take into account pediatric age groups. As new clinical trials for alopecia areata include more children, a more accurate tool should be available for this population. By collecting images from patients 2-21 years of age and aligning the hair-bearing regions of the scalp, we created an adaptation of the Severity of Alopecia Tool for scoring hair loss percentage of the top, parietal, and occipital scalp in individuals 2-5, 6-11, and 12-21 years of age. PMID- 29105837 TI - Environmental doses of perfluorooctanoic acid change the expression of genes in target tissues of common carp. AB - We aimed to evaluate the effects of environmental doses of perfluorooctanoic acid (PFOA) on bioconcentration and gene expression in common carp (Cyprinus carpio). Adult male and female carp were exposed to environmental (200 ng/L) and experimental (2 mg/L) doses of PFOA for 56 d. Carp exposed to 200 ng/L had levels of PFOA below the level of detection in all tissue samples analyzed, whereas variable concentrations were measurable in various tissues from carp exposed to 2 mg/L. The expression level of the glutathione S-transferase (GST) gene, coding for a detoxifying enzyme, increased in a PFOA dose-dependent manner in liver tissues from 200 ng/L to 2 mg/L exposure (p < 0.05). The expression levels of CYP19A gene, coding for the enzyme that converts testosterone into estrogen, were altered in gonadal tissues from male and female carp exposed to either 200 ng/L or 2 mg/L; expression increased in male gonads and decreased in female gonads. Unexpectedly, the expression levels of CYP19A in male and female gonads from carp exposed to 200 ng/L or 2 mg/L were similar (p > 0.05). Therefore, even though environmental doses of PFOA did not accumulate in tissues of the common carp, they did affect the gene expression levels of GST in the liver and CYP19A in the gonads. These observations raise concerns that exposure to environmental doses of PFOA may affect gene expression in animals and possibly in humans, with important health consequences. Environ Toxicol Chem 2018;37:942-948. (c) 2017 SETAC. PMID- 29105838 TI - A Parkinson's disease gene, DJ-1, repairs brain injury through Sox9 stabilization and astrogliosis. AB - Defects in repair of damaged brain accumulate injury and contribute to slow developing neurodegeneration. Here, we report that a deficiency of DJ-1, a Parkinson's disease (PD) gene, delays repair of brain injury due to destabilization of Sox9, a positive regulator of astrogliosis. Stereotaxic injection of ATP into the brain striatum produces similar size of acute injury in wild-type and DJ-1-knockout (KO) mice. However, recovery of the injury is delayed in KO mice, which is confirmed by 9.4T magnetic resonance imaging and tyrosine hydroxylase immunostaining. DJ-1 regulates neurite outgrowth from damaged neurons in a non-cell autonomous manner. In DJ-1 KO brains and astrocytes, Sox9 protein levels are decreased due to enhanced ubiquitination, resulting in defects in astrogliosis and glial cell-derived neurotrophic factor/ brain-derived neurotrophic factor expression in injured brain and astrocytes. These results indicate that DJ-1 deficiency causes defects in astrocyte-mediated repair of brain damage, which may contribute to the development of PD. PMID- 29105839 TI - Hemodialysis in neonates and infants: A systematic review. AB - Hemodialysis (HD) in neonates and infants poses unique challenges due to high risks of mortality attributable to obligatory small blood flow volumes. Although HD is often necessary in neonates, its effectiveness and feasibility are poorly understood. The aim of this review is to describe in detail the few studies reporting on HD in neonates and infants (<12 months old) and then dissertate more broadly on the subject with an emphasis on recent innovations with potential to overcome traditional barriers for effective HD in this population. We detail the clinical characteristics, outcomes, technical considerations, maintenance and complications associated with HD, and provide guidance for addressing challenges associated with HD in this population. PMID- 29105840 TI - Stereochemical analysis of beta-keto sulfoxides by circular dichroism. AB - Three beta-keto sulfoxides (1-3) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2, the X-ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all beta-keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations. PMID- 29105841 TI - Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. AB - Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received >=2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study >=7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with >=1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). (c) 2017 American Society for Bone and Mineral Research. PMID- 29105842 TI - VUV/Vis Photoluminescence, Site Occupancy, and Thermal-Resistance Properties of K4 SrSi3 O9 :Ce3. AB - A series of Ce3+ -activated K4 SrSi3 O9 materials emitting bright blue light under near-UV excitation was obtained by a facile solid-state reaction. The luminescence of Ce3+ -doped K4 SrSi3 O9 shows excellent thermal stability in a large temperature range. The detailed temperature/concentration-dependent luminescent properties of Ce3+ confirm that there are two different Ce3+ sites in K4 SrSi3 O9 :Ce3+ , and energy transfer from the high-energy Ce(1)3+ sites to the low-energy Ce(2)3+ sites was demonstrated to occur by electric dipole-dipole interaction. The maximum photoluminescence quantum yield of Ce3+ -doped K4 SrSi3 O9 can reach 56 %, and a UV-excited white LED device with low correlated color temperature (CCT=4617 K) and high color-rendering index (Ra =80) was fabricated with K4 SrSi3 O9 :Ce3+ . PMID- 29105843 TI - The liver recipient with acute renal dysfunction: A single institution evaluation of the simultaneous liver-kidney transplant candidate. AB - The Organ Procurement Transplant Network (OPTN) listing criteria for simultaneous liver-kidney transplant (SLK) are not well defined. Concerns remain about rising numbers of SLKs, which divert quality kidneys from candidates awaiting kidney transplants (KT). We performed a retrospective review of liver transplants (LTs) at our center from 2004 to 2014; 127 recipients (liver transplant alone; 102 LTA, 25 SLK) were identified with short-term preoperative kidney dysfunction (creatinine >4 mg/dL or preoperative hemodialysis [HD] for <6 weeks). Both cohorts had comparable baseline demographic characteristics with the exception of higher model for end-stage liver disease (MELD) score in the LTA group (41.4 vs 32.9, P < .0001) and higher incidence of pre-LT diabetes in the SLK cohort (52% vs 26.5%, P = .0176). Duration of pre-LT HD was higher in SLK recipients, but the difference was not statistically significant (P = .39). Renal nonrecovery (RNR) rate in LTA cohort was low (<5%). No significant difference was noted in 1-year mortality, liver graft rejection/failure, or length of stay (LOS) between the cohorts. Thus, it appears that liver recipients with short-term (<6 weeks) HD or AKI without HD have comparable outcomes between LTA and SLK. With provisions for a KT safety net, as proposed by OPTN, LTA may be the most adequate option for these patients. PMID- 29105846 TI - Role of two-step endoscopic ultrasonography-guided antegrade treatment as an option for bile duct stones in patients with surgically altered anatomy. PMID- 29105845 TI - Milk and other dairy foods in relation to prostate cancer recurrence: Data from the cancer of the prostate strategic urologic research endeavor (CaPSURETM). AB - BACKGROUND: High-fat dairy, particularly whole milk, in healthy men may increase risk of aggressive prostate cancer. However, data are limited regarding dairy after prostate cancer diagnosis. METHOD: We conducted a prospective study among 1334 men with non-metastatic prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavor. Men answered a food frequency questionnaire in 2004-2005 (median 2 years after diagnosis) and were followed until 2016 for recurrence, defined as: prostate cancer death, bone metastases, biochemical recurrence, or secondary treatment. Multivariate Cox proportional hazards regression was used to calculate hazards ratios (HR) and 95% confidence intervals (CI) for associations between whole and low-fat milk; total, high-fat, and low fat dairy; and other dairy items and risk of recurrence. RESULTS: During a median follow-up of 8 years, we observed 137 events. Men who consumed >4 servings/week versus 0-3 servings/month of whole milk had an 73% increased risk of recurrence (HR: 1.73; 95%CI: 1.00, 2.98; P-value = 0.04). Body mass index (BMI) modified the association (P-interaction = 0.01). Among men with a BMI >=27 kg/m2 , >4 servings/week versus 0-3 servings/month of whole milk was associated with a 3 fold higher risk of recurrence (HR: 2.96; 95%CI: 1.58, 5.54; P-value < 0.001). No association was seen in men with BMI <27 kg/m2 . Low-fat milk and other dairy foods were not associated with recurrence. CONCLUSION: In conclusion, whole milk consumption after prostate cancer diagnosis was associated with increased risk of recurrence, particularly among very overweight or obese men. Men with prostate cancer who choose to drink milk should select non-fat or low-fat options. PMID- 29105848 TI - Anion-Regulated Selective Generation of Cobalt Sites in Carbon: Toward Superior Bifunctional Electrocatalysis. AB - The introduction of active transition metal sites (TMSs) in carbon enables the synthesis of noble-metal-free electrocatalysts for clean energy conversion applications; however, there are often multiple existing forms of TMSs, which are of different natures and catalytic models. Regulating the evolution of distinctive TMSs is highly desirable but remains challenging to date. Anions, as essential elements involved in the synthesis, have been totally neglected previously in the construction of TMSs. Herein, the effects of anions on the creation of different types of TMSs are investigated for the first time. It is found that the active cobalt-nitrogen sites tend to be selectively constructed on the surface of N-doped carbon by using chloride, while metallic cobalt nanoparticles encased in protective graphite layers are the dominant forms of cobalt species with nitrate ions. The obtained catalysts demonstrate cobalt-sites dependent activity for oxygen reduction reaction and hydrogen evolution reaction in acidic media. The remarkably enhanced catalytic activities approaching that of benchmark Pt/C in an acidic medium have been obtained on the catalyst dominated with cobalt-nitrogen sites, confirmed by the advanced spectroscopic characterization. This finding demonstrates a general paradigm of anion-regulated evolution of distinctive TMSs, providing a new pathway for enhancing performances of various targeted reactions related with TMSs. PMID- 29105847 TI - Characterization of Leptospira species isolated from soil collected in Japan. AB - Leptospira were isolated from soil obtained from Hokkaido, the northernmost island, to Okinawa, the southernmost island, of Japan using sulfamethoxazole, trimethoprim, amphotericin B, fosfomycin, and 5- fluorouracil. Fifty of 132 soil samples (37.9%) were culture-positive. On the basis of 16S-rDNA sequences, 12 of the isolated Leptospira were classified into a pathogenic species clade that is closely associated with L. alstonii and L. kmetyi. Nine isolates were classified as intermediate species and were found to be similar to L. licerasiae. Twenty seven isolates were classified as non-pathogenic species, of which 23 were found to be related to L. wolbachii. Non-pathogenic Leptospira are commonly distributed in environmental soil. PMID- 29105849 TI - Effect of bovine seminal plasma on bovine endometrial epithelial cells in culture. AB - The purpose of this study was to investigate the effect of seminal plasma (SP) from bulls of known fertility on bovine endometrial epithelial cells (bEEC) in culture. The bEEC from passage 5, approximately 5.0-13 * 105 cells per flask, were challenged with SP from bulls of high or low fertility (n = 3 and 2, respectively) or PBS (control), at 1% (75 MUl) or 4% (300 MUl) and were incubated for 72 hr (n = 13 per challenge). Total cell number and viability of bEEC after challenge with 1% SP from either high- or low-fertility bulls (75H or 75L, respectively) did not differ from controls. In contrast, challenge with 4% of SP from high- or low-fertility bulls (300H or 300L) negatively affected bEEC cell number and viability. Challenge with 300 L had a greater adverse effect than 300H. These results suggest that the negative effect of bovine SP on bEEC is both dose-dependent and fertility-dependent. PMID- 29105850 TI - Cost-effectiveness analysis of interventions for prevention of invasive aspergillosis among leukemia patients during hospital construction activities. AB - OBJECTIVES: Invasive Aspergillosis (IA) is a serious problem among hematological patients and it is associated with high mortality. This situation can worsen at times of hospital construction, however there are several preventive measures available. This work aims to define the cost-effectiveness of some of these interventions. PATIENTS AND METHODS: A decision tree model was used, it was divided into four arms according to each 1 of the interventions performed. A cost effectiveness incremental analysis comparing environmental control measures, high efficiency particulate absorption (HEPA) filter installation and prophylaxis with posaconazole was done. Probabilistic and deterministic sensitivity analyses were also carried out. RESULTS: Among 86 patients with 175 hospitalization episodes, the incidence of IA with environmental protection measures, antifungal prophylaxis and hospitalization in rooms with HEPA filters was 14.4%, 6.3% and 0%, respectively. An Incremental Cost Effectiveness Ratio analysis was performed and it was found that HEPA filtered rooms and environmental protection measures are cost saving interventions when compared with posaconazole prophylaxis (-$2665 vs -$4073 vs $42 531 US dollars, respectively) for IA episode prevented. CONCLUSION: The isolation of inpatients with acute leukemia during hospital construction periods in HEPA filtered rooms could reduce the incidence of IA and might be a cost-effective prevention strategy. PMID- 29105851 TI - Perovskite Solar Cells with ZnO Electron-Transporting Materials. AB - Perovskite solar cells (PSCs) have developed rapidly over the past few years, and the power conversion efficiency of PSCs has exceeded 20%. Such high performance can be attributed to the unique properties of perovskite materials, such as high absorption over the visible range and long diffusion length. Due to the different diffusion lengths of holes and electrons, electron transporting materials (ETMs) used in PSCs play a critical role in PSCs performance. As an alternative to TiO2 ETM, ZnO materials have similar physical properties to TiO2 but with much higher electron mobility. In addition, there are many simple and facile methods to fabricate ZnO nanomaterials with low cost and energy consumption. This review focuses on recent developments in the use of ZnO ETM for PSCs. The fabrication methods of ZnO materials are briefly introduced. The influence of different ZnO ETMs on performance of PSCs is then reviewed. The limitations of ZnO ETM-based PSCs and some solutions to these challenges are also discussed. The review provides a systematic and comprehensive understanding of the influence of different ZnO ETMs on PSCs performance and potentially motivates further development of PSCs by extending the knowledge of ZnO-based PSCs to TiO2 -based PSCs. PMID- 29105852 TI - Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review. AB - The clinical features in cases that have mutations in the microtubule-associated protein tau gene but lack prominent behavioral changes remain unclear. Here, we describe detailed clinical and pathological features of a case carrying the P301L tau mutation that showed only apathy until the middle stage of the course. The mother of this case was suspected to have mild cognitive decline at age 46. However, before she was fully examined, she had a subarachnoid hemorrhage at age 49 and died at age 53. An autopsy was not done. The proband of this pedigree, a 60-year-old right-handed Japanese man at the time of death, began to make mistakes at work at the age of 51 years. Until age 54, he showed only mild apathy with bradykinesia. Insight was well spared. Parkinsonism and echolalia developed at age 55, and pyramidal signs and oral tendency at age 57. Personality change, disinhibition, stereotypy, or semantic memory impairment was not found throughout the course. The final neurological diagnosis was unspecified dementia. Pathological examination demonstrated numerous round four-repeat tau-positive three-repeat tau-negative or perinuclear ring-like neuronal cytoplasmic inclusions with many ballooned neurons in the frontal and temporal cortices and hippocampus. Genetic analysis using frozen brain tissue demonstrated a P301L tau mutation. Among 31 previously reported cases bearing the P301L tau mutation for which the data regarding initial symptoms are available, one clinical case showed only apathy with depression in the early stage. Given these findings, clinicians should be aware that a clinical course characterized only by apathy for several years, which can be misdiagnosed as a psychiatric disorder, is one of the clinical presentations associated with P301L tau mutation. PMID- 29105854 TI - Simultaneous determination and tissue distribution studies of four phenolic acids in rat tissue by UFLC-MS/MS after intravenous administration of salvianolic acid for injection. AB - A rapid, simple and sensitive ultra-fast liquid chromatography tandem mass spectrometric method was developed and validated for simultaneous determination and tissue distribution studies of rosmarinic acid, salvianolic acid D, lithospermic acid and salvianolic acid B in rats after intravenous administration of salvianolic acid for injection. The tissue homogenate samples were pretreated by protein precipitation with pre-cooled acetonitrile. Chromatographic separation was achieved on a Waters Cortecs UPLC C18 column (1.6 MUm, 2.1 * 100 mm) with a mobile phase composed of 0.1% formic acid-water and 0.1% formic acid acetonitrile. Analytes were detected by electrospray ionization mass spectrometry and quantitated using multiple reaction monitoring. The method was fully validated. The calibration curves for the four phenolic acids were linear in the given concentration ranges. The precisions (relative standard deviation) in the measurement of quality control samples were <10% and the accuracies (relative error) were in the range of 0.28-11.22%. The reliable method was successfully applied to the tissue distribution studies of the four phenolic acids. The results showed that rosmarinic acid, salvianolic acid D, lithospermic acid and salvianolic acid B were rapidly distributed in tissues with the major amount found in kidney, and little crossed the blood-brain barrier. The developed method and the results provide a basis for further studies. PMID- 29105853 TI - Measuring the impact of medicines regulatory interventions - Systematic review and methodological considerations. AB - AIMS: Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research. METHODS: We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non-European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted. RESULTS: From 1246 screened articles, 229 were eligible for full-text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill-over effects were rarely evaluated. Two-thirds used before-after time series and 15.7% before-after cross sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%). CONCLUSION: Whilst impact evaluation of pharmacovigilance and product-specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs. PMID- 29105855 TI - Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro. AB - AIM: The aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin. METHODS: We performed an open-label, randomized, two-phase, five-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1 g dicloxacillin three times daily for 10 days. Plasma and urine were collected over 24 h and the concentration of all five drugs and their primary metabolites was determined using a liquid chromatography coupled to triple quadrupole mass spectrometry method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48 h and changes in gene expression and the activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 were investigated. The activation of nuclear receptors by dicloxacillin was assessed using luciferase assays. RESULTS: A total of 10 days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0 to 24 h for omeprazole (CYP2C19) {geometric mean ratio [GMR] [95% confidence interval (CI)]: 0.33 [0.24, 0.45]}, tolbutamide (CYP2C9) [GMR (95% CI): 0.73 (0.65, 0.81)] and midazolam (CYP3A4) [GMR (95% CI): 0.54 (0.41, 0.72)]. Additionally, other relevant pharmacokinetic parameters were affected, indicating the induction of CYP2C- and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed a statistically significant dose-dependent increase in CYP expression and activity by dicloxacillin, caused by activation of the pregnane X receptor. CONCLUSIONS: Dicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism, and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window. PMID- 29105857 TI - Catalytic Asymmetric Synthesis of Fluoroalkyl-Containing Compounds by Three Component Photoredox Chemistry. AB - Multicomponent reactions allow the construction of molecular complexity in an economical fashion, fluorinated compounds play an important role in pharmaceuticals and agrochemicals, whereas visible light is an abundant and sustainable source of energy for activating chemical transformations. Here we report a visible-light-induced asymmetric three-component fluoroalkylation reaction scheme catalyzed by a chiral-at-rhodium Lewis acid. The photoredox process is mediated by the inexpensive, commercially available organic photoredox mediator 4,4'-difluorobenzil, which upon activation by visible light induces the generation of perfluoroalkyl radicals from their sulfinates via single electron transfer oxidation. The fluorinated radicals are trapped by electron-rich C-C double bonds to deliver alpha-oxy carbon-centered radicals, followed by a subsequent stereocontrolled reaction with acceptor-substituted alkenes. This three-component fluoroalkylation scheme provides a range of complex fluoroalkyl containing chiral compounds under dual C-C bond formation with high enantioselectivities (up to 98 % ee) and modest diastereoselectivities (up to 6:1 dr). Excellent diastereoselectivities (up to >38:1:1 dr) for natural chiral compound derivatives are observed. Broad substrate scope (25 examples), excellent functional group tolerance, scalability of the reaction, along with the option to recover the chiral catalyst and photoredox mediator reveal the practicability of this methodology in organic synthesis for the rapid synthesis of fluorinated chiral molecules. PMID- 29105856 TI - Rapid Iododeboronation with and without Gold Catalysis: Application to Radiolabelling of Arenes. AB - Radiopharmaceuticals that incorporate radioactive iodine in combination with single-photon emission computed tomography imaging play a key role in nuclear medicine, with applications in drug development and disease diagnosis. Despite this importance, there are relatively few general methods for the incorporation of radioiodine into small molecules. This work reports a rapid air- and moisture stable ipso-iododeboronation procedure that uses NIS in the non-toxic, green solvent dimethyl carbonate. The fast reaction and mild conditions of the gold catalysed method led to the development of a highly efficient process for the radiolabelling of arenes, which constitutes the first example of an application of homogenous gold catalysis to selective radiosynthesis. This was exemplified by the efficient synthesis of radiolabelled meta-[125 I]iodobenzylguanidine, a radiopharmaceutical that is used for the imaging and therapy of human norepinephrine transporter-expressing tumours. PMID- 29105858 TI - Investigation of metabolic profile of pimavanserin in rats by ultrahigh performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry. AB - RATIONALE: Pimavanserin, a selective serotonin 2A receptor inverse agonist, is a promising candidate for treating Parkinson's disease psychosis. Our previous study revealed that there might be the presence of extensive metabolites of pimavanserin in rats. However, the metabolic fate of pimavanserin in vivo remains unknown. Thus, it is essential to develop an efficient method to investigate the metabolic profile of pimavanserin in rats. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) to date has the highest mass measurement accuracy and resolution of any mass spectrometry platform. METHODS: After a single intragastric administration of pimavanserin at a dose of 50 mg kg-1 , plasma, bile, urine and feces were collected from rats. A novel and efficient strategy was developed to analyze the metabolic profile of pimavanserin in vivo based on ultrahigh-performance liquid chromatography (UHPLC) coupled with FT-ICR MS. RESULTS: A total of 23 metabolites were detected and tentatively identified through comparing their mass spectrometry profiles with those of pimavanserin. These metabolites were found in feces (22), bile (21), rat urine (16) and plasma (15). Results demonstrated that metabolic pathways of pimavanserin in rats included dehydrogenation, demethylation, deethylation, depropylation, debutylation, hydroxylation, dihydroxylation and trihydroxylation. CONCLUSIONS: A total of 22 phase I metabolites of pimavanserin were detected and tentatively identified. This report presents the first study of screening and identification of the metabolites of pimavanserin. The UHPLC/FT-ICR-MS method is a powerful tool for exploring and identifying metabolites in complex biological samples. PMID- 29105859 TI - Novel Viologen Derivative Based Uranyl Coordination Polymers Featuring Photochromic Behaviors. AB - A series of novel uranyl coordination polymers have been synthesized by hydrothermal reactions. Both complexes 1 and 2 prosess two ipbp- ligands (H2 ipbpCl=1-(3,5-dicarboxyphenyl)-4,4'-bipyridinium chloride), one uranyl cation, and two coordination water molecules, which can further extend to 2D networks through hydrogen bonding. In complex 1, two sets of equivalent nets are entangled together, resulting in a 2D + 2D -> 3D polycatenated framework. In complex 2, the neighbouring equivalent nets interpenetrate each other, forming a twofold interpenetrated network. Complexes 3 and 4 are isomers, and both of them are constructed from (UO2 )2 (OH)2 dinuclear units, which are connected with four ipbp- ligands. The 3D structures of complexes 3 and 4 are similar along the b axis. Similar to other viologen-based coordination polymers, complexes 3 and 4 exhibit photochromic and thermochromic properties, which are rarely observed in actinide coordination polymers. Unlike the monotonous coordination mode in complexes 1-4, the ipbp- ligands feature a MU3 -bridge through two kinds of coordination modes in complex 5. Notably, complex 5 presents a unique example in which terminal pyridine nitrogen atom is involved in the coordination. PMID- 29105860 TI - A stereodynamic fluorescent probe for amino acids. Circular dichroism and circularly polarized luminescence analysis. AB - The use of stereodynamic probes is becoming one of the leading strategies for the fast and effective determination of enantiomeric excess. Recently, we reported a series of novel molecular architectures based on a modified tris(2 pyridylmethyl)amine complex (TPMA), which are able to amplify the electronic CD, in the case of Zn(II) assemblies and vibrational CD, in the case of Co(II) assemblies. Herein, we report a structural modification of the ligand with the purpose to obtain a fluorescent chiral probe. The study deals with the synthesis of the novel ligand, the formation of the self-assembly system with amino acids, and the study of the electronic CD and circularly polarized luminescence. PMID- 29105861 TI - Using paradox theory to understand responses to tensions between service and training in general surgery. AB - CONTEXT: The tension between service and training in pressured health care environments can have a detrimental impact on training quality and job satisfaction. Yet the management literature proposes that competing demands are inherent in organisational settings: it is not the demands as such that lead to negative outcomes but how people and organisations react to opposing tensions. We explored how key stakeholders responded to competing service-training demands in a surgical setting that had recently gone through a highly-publicised organisational crisis. METHODS: This was an explanatory case study of a general surgery unit. Public documents informed the research questions and the data were triangulated with semi-structured interviews (n = 14) with key stakeholders. Data coding and analysis were initially inductive but, after the themes emerged, we used a paradox lens to group themes into four contextual dimensions: performing, organising, belonging and learning. RESULTS: Tensions were apparent in the data, with managers, surgeons and trainees or residents in conflict with each other because of different goals or priorities and divergent perspectives on the same issue of balancing service and training (performing). This adversely impacted on relationships across and within groups (belonging, learning) and led to individuals prioritising their own goals rather than working for the 'greater good' (performing, belonging). Yet although relationships and communication improved, the approach to getting a better balance maintained the 'compartmentalisation' of training (organising) rather than acknowledging that training and service cannot be separated. DISCUSSION: Stakeholder responses to the tensions provided temporary relief but were unlikely to lead to real change if the tension between service and training was considered to be an interdependent and persistent paradox. Reframing the service-training paradox in this way may encourage adjusting responses to create effective working partnerships. Our findings add to the body of knowledge on this topic, and will resonate with all those engaged in surgical and other postgraduate training. PMID- 29105862 TI - Co-Cluster-Based Metal-Organic Frameworks as Selective Catalysts for Benzene Tandem Acylation-Nazarov Cyclization to Benzocyclopentanone. AB - One-step selective benzene acylation-Nazarov cyclization is an attractive, yet challenging method for the synthesis of the benzocyclopentanone skeleton, which is key intermediate of many natural products. Herein, two metal-cluster-based metal-organic frameworks (MCOFs) {(H3 O)2 [Co4 (pbcd)2 (MU3 -OH)2 ]?CH3 CH2 OH?4 H2 O}n (1; pbcd=9,9'-(propan-1,3-diyl)bis(9H-carbazole-3,6-dicarboxylic acid) and {[Co5.25 (mcd)2 (HCO2 )(MU2 -O)0.5 (MU3 -OH)0.5 (H2 O)4 ]?6 H2 O?5 DMF}n (2; mcd=9,9'-methylenebis(9H-carbazole-3,6-dicarboxylic acid) were developed to catalyze a tandem Nazarov cyclization reaction of 1,3-dimethoxybenzene with alpha,beta-unsaturated carboxylic acids for the synthesis of cyclopentenone[b]benzenes. MCOFs 1 and 2, which were constructed from tetranuclear CoII cluster [Co4 (MU3 -OH)2 ] and hexanuclear CoII cluster [Co6 (HCO2 )(MU2 -O)(MU3 -OH)], respectively, exhibit high catalytic activity arising not only from their suitable channel size and accessible catalytic sites, but also because of their high density of Lewis acidic sites within the frameworks and the synergic activity among CoII ions. In contrast, {[Co2 (pbcd)(bpe)]?2 H2 O?2 DMF}n (3; bpe=1,2-bis(pyridin-4-yl)ethane) containing binuclear CoII and having large pore windows is a highly selective catalyst for obtaining exclusively the acylation products. Easy product separation, simple reaction procedures, and catalyst recycling make the catalyst system attractive. This work highlights the synergistic effect among ions of MCOFs in interacting with substrates in a sequential or cooperative manner to achieve tandem catalysis. PMID- 29105863 TI - Intensive cutaneous myiasis due to Musca domestica in a patient with Alzheimer disease: a rare larval infestation in a temperate zone. PMID- 29105865 TI - Oral medication prescription practices of tertiary-based specialists for dystonia in children with cerebral palsy. AB - AIM: To examine current clinical practice for prescribing medications for children with dystonic cerebral palsy (CP) by medical doctors working at a tertiary care centre. METHODS: Rehabilitation and developmental paediatric specialists completed: (i) a custom-designed online cross-sectional survey capturing their usual prescribing patterns; and (ii) one-page questionnaires detailing medication prescription for each child with CP who they started on a new medication for dystonia over a 12-month period. RESULTS: Eleven participating doctors ranged in experience in managing children with CP from less than 5 years to more than 20 years. The cross-sectional survey showed that most doctors used more than one medication, with six making choices taking into account four or more different medications. Oral baclofen was used by all doctors and was the first choice of 10 of 11. Prospective surveys from 57 children showed that medication was prescribed mainly for children aged 3-10 years (n = 35/57), classified within Gross Motor Function Classification System levels IV and V (n = 40/57) and with a mixed movement disorder (n = 38/57). Gabapentin and baclofen were the most frequently prescribed (n = 21/57 and 19/57, respectively), with other drugs used less frequently. Dosage regimens varied between and within doctors, particularly for the use of gabapentin and diazepam. CONCLUSIONS: Oral medication prescribing practices varied among doctors managing children with dystonic CP at a tertiary care hospital, particularly with respect to dosing. There is a need for clinical guidelines for medication prescription to be developed based on best evidence and consensus by clinical experts. PMID- 29105864 TI - Study of bone metabolism and angiogenesis in patients undergoing high-dose chemotherapy/autologous hematopoietic stem cell transplantation. AB - OBJECTIVES: As the interaction between hematopoietic stem cells (HSCs) and endosteal and endothelial niches in HSCs homing is essential, we aimed to study bone turnover and angiogenesis in 29 patients with lymphoma/multiple myeloma undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Serum samples were collected before high-dose chemotherapy (HDT), at the end of HDT, after HSC infusion, at the nadir of myelotoxicity, and at engraftment. Bone metabolism (CTX, TRACP-5b, bALP, OC, DKK1, RANKL, OPG), and angiogenesis (Ang1, Ang2) markers were measured. These markers were also measured in 21 control patients before and after conventional chemotherapy. RESULTS AND CONCLUSIONS: Bone resorption declined during HSCT (decrease in TRACP-5b [P < .001] and CTX [P = .006]). Bone formation declined as well (decrease in bALP and OC [P < .001 for both]). RANKL/OPG ratio, an indicator of osteoclastic activation, did not change significantly (P = .5). Ang1/Ang2 ratio, a vessel equilibrium marker, decreased significantly (P < .001) suggesting endothelial destabilization. The changes observed in the control group were similar except of bALP and RANKL/OPG ratio. Moreover, Ang1/Ang2 ratio on the day after HSC infusion strongly correlated with time to neutrophil and platelet engraftment (P < .001 for both). Conclusively, bone turnover and vessel destabilization represent important events during HSCT probably reflecting the effect of chemotherapy. PMID- 29105866 TI - Current practices for voice rest recommendations after phonomicrosurgery. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to understand current protocols for voice rest implemented by laryngologists immediately after phonomicrosurgery for benign vocal fold lesions. STUDY DESIGN: Cross-sectional survey. METHODS: A 24-item survey was sent via electronic mail to laryngologists across the country to gather data on their recommendations of type and dosage of voice rest, factors involved in this decision, and recommendations for other behavioral modifications. RESULTS: A majority of the laryngologists implement 7 days of complete voice rest for nodules, cysts, polyps, and Reinke's edema, 1 to 4 days for leukoplakia and papilloma, and over 8 days of relative voice rest for most lesions. A majority of the laryngologists also employ a combination of complete and relative voice rest. CONCLUSIONS: The more common recommendation for complete voice rest is 7 days for nodules, cysts, polyps, and Reinke's edema, and 1 to 4 days for leukoplakia and papilloma. Relative voice rest when recommended is typically recommended for over 8 days. Voice rest recommendations were not affected by surgery type alone, but were determined by either lesion type alone or lesion type combined with surgery type. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1170-1175, 2018. PMID- 29105867 TI - Structural destabilization of tropomyosin induced by the cardiomyopathy-linked mutation R21H. AB - The missense mutation R21H in striated muscle tropomyosin is associated with hypertrophic cardiomyopathy, a genetic cardiac disease and a leading cause of sudden cardiac death in young people. Tropomyosin adopts conformation of a coiled coil which is critical for regulation of muscle contraction. In this study, we investigated the effects of the R21H mutation on the coiled-coil structure of tropomyosin and its interactions with its binding partners, tropomodulin and leiomodin. Using circular dichroism and isothermal titration calorimetry, we found that the mutation profoundly destabilized the structural integrity of alphaTM1a1-28 Zip, a chimeric peptide containing the first 28 residues of tropomyosin. The mutated alphaTM1a1-28 Zip was still able to interact with tropomodulin and leiomodin. However, the mutation resulted in a ~30-fold decrease of alphaTM1a1-28 Zip's binding affinity to leiomodin. We used a crystal structure of alphaTM1a1-28 Zip that we solved at 1.5 A resolution to study the mutation's effect in silico by means of molecular dynamics simulation. The simulation data indicated that while the mutation disrupted alphaTM1a1-28 Zip's coiled-coil structure, most notably from residue Ala18 to residue His31, it may not affect the N-terminal end of tropomyosin. The drastic decrease of alphaTM1a1-28 Zip's affinity to leiomodin caused by the mutation may lead to changes in the dynamics at the pointed end of thin filaments. Therefore, the R21H mutation is likely interfering with the regulation of the normal thin filament length essential for proper muscle contraction. PMID- 29105868 TI - Successful Treatment of Disseminated Nocardiosis Caused by Nocardia veterana in a Dog. AB - A 5-year-old male castrated Lhasa Apso cross was evaluated for a 1-month history of inappetence, lethargy, gagging, and progressive right thoracic limb lameness. Synovial fluid analysis revealed nonseptic suppurative inflammation, and a diagnosis of immune-mediated polyarthritis (IMPA) was made. After 3 months of treatment with prednisone and later cyclosporine, the dog developed multiple firm cutaneous and subcutaneous masses and a focal mass within the jejunum. Cultures of blood, urine, skin lesions, and the jejunal mass identified Nocardia veterana by matrix-absorption laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and allowed for earlier identification of the organism compared to more traditional secA1 gene sequencing. Immunosuppressive drug treatment was discontinued, and the dog was treated for 3 months by administration of trimethoprim-sulfamethoxazole (TMS). No recurrence of clinical signs was reported 1 year later. This case report highlights the clinical utility of MALDI-TOF MS, particularly for the rapid identification of slow-growing, fastidious organisms. PMID- 29105869 TI - Downregulation of spinal astrocytic connexin43 leads to upregulation of interleukin-6 and cyclooxygenase-2 and mechanical hypersensitivity in mice. AB - Connexin43 (Cx43), involved in intercellular signaling, is expressed in spinal dorsal horn astrocytes and crucial in the maintenance of neuropathic pain. Downregulation of spinal astrocytic Cx43 in mice enhances glutamatergic neurotransmission by decreasing glutamate transporter GLT-1 expression, resulting in cutaneous hypersensitivity. Decreased expression of astrocytic Cx43 could lead to altered expression of other nociceptive molecules. Transfection of Cx43 targeting siRNA in cultured spinal astrocytes increased expression of the pronociceptive cytokine interleukin-6 (IL-6) and the prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2). Increased expression of IL-6 and COX-2 was due to decreased Cx43 expression rather than due to diminished Cx43 channel function. In mice, downregulation of spinal Cx43 expression by intrathecal treatment with Cx43-targeting siRNA increased IL-6 and COX-2 expression and induced hind paw mechanical hypersensitivity. Cx43 siRNA-induced mechanical hypersensitivity was attenuated by intrathecal treatment with anti-IL-6 neutralizing antibody and intraperitoneal treatment of selective COX-2 inhibitor celecoxib, demonstrating that these molecules play a role in nociceptive processing following Cx43 downregulation. Restoring spinal Cx43 by intrathecal injection of an adenovirus vector expressing Cx43 in mice with a partial sciatic nerve ligation reduced spinal IL-6 and COX-2 expression. Suppression of glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase, prevented upregulation of IL-6 and COX-2 expression induced by Cx43 downregulation in both cultured astrocytes and in mouse spinal dorsal horn. Inhibition of spinal GSK-3beta also ameliorated Cx43 siRNA-induced mechanical hypersensitivity. The current findings indicate that downregulation of spinal astrocytic Cx43 leads to changes in spinal expression of pronociceptive molecules underlying the maintenance of pain following nerve injury. PMID- 29105870 TI - Service-learning partnerships: Features that promote transformational and sustainable rural and remote health partnerships and services. AB - OBJECTIVE: To describe features that promote transformational and sustainable community engaged health partnerships and services in rural and remote Australian locations. DESIGN: A pragmatic qualitative study using focus groups and individual semi-structured interviews. Data were analysed using four stages of data comparison. SETTING: Far west New South Wales, Australia. The health partnership, initiated by primary school principals in 2008, aimed to address allied health service inequities experienced by regional children. A service learning program was developed, aligning allied health student placements to student-led services. The program has been operational since 2009. PARTICIPANTS: Community participants included school principals (n = 7) and senior managers (n = 2) from local facilitating agencies. Campus participants included allied health students (n = 10) and academics (n = 2), one rurally located with student supervision responsibility and one metropolitan located with a strategic partnership role. MEASURES: All data were collected by an independent researcher. Four stages of data comparison were undertaken. A thematic analysis was conducted and six key features identified through Stage Four comparison, a comparison across the findings from discrete community and campus groups, reflecting transformational community engagement were identified. RESULTS: These six features are: (i) identifying and responding to community need, (ii) providing services of value, (iii) community leadership and innovation, (iv) reputation and trust, (v) consistency, and (vi) knowledge sharing and program adaptation. CONCLUSION: We propose that these features contributed to the transformational engagement of community and university participants. These features can inform health sector approaches to community engagement, enhancing rural and remote service accessibility, acceptability, and sustainability outcomes. PMID- 29105871 TI - Cost-effectiveness of personal tailored risk information and taster sessions to increase the uptake of the NHS stop smoking services: the Start2quit randomized controlled trial. AB - AIMS: To assess the cost-effectiveness of a two-component intervention designed to increase attendance at the NHS Stop Smoking Services (SSSs) in England. DESIGN: Cost-effectiveness analysis alongside a randomized controlled trial (Start2quit). SETTING: NHS SSS and general practices in England. PARTICIPANTS: The study comprised 4384 smokers aged 16 years or more identified from medical records in 99 participating practices, who were motivated to quit and had not attended the SSS in the previous 12 months. INTERVENTION AND COMPARATOR: Intervention was a personalized and tailored letter sent from the general practitioner (GP) and a personal invitation and appointment to attend a taster session providing information about SSS. Control was a standard generic letter from the GP advertising SSS and asking smokers to contact the service to make an appointment. MEASUREMENTS: Costs measured from an NHS/personal social services perspective, estimated health gains in quality-adjusted life-years (QALYs) measured with EQ-5D and incremental cost per QALY gained during both 6 months and a life-time horizon. FINDINGS: During the trial period, the adjusted mean difference in costs was L92 [95% confidence interval (CI) = -L32 to -L216) and the adjusted mean difference in QALY gains was 0.002 (95% CI = -0.001 to 0.004). This generates an incremental cost per QALY gained of L59 401. The probability that the tailored letter and taster session is more cost-effective than the generic letter at 6 months is never above 50%. In contrast, the discounted life time health-care cost was lower in the intervention group, while the life-time QALY gains were significantly higher. The probability that the intervention is more cost-effective is more than 83% using a L20 000-30 000 per QALY-gained decision-making threshold. CONCLUSIONS: An intervention designed to increase attendance at the NHS Stop Smoking Services (tailored letter and taster session in the services) appears less likely to be cost-effective than a generic letter in the short term, but is likely to become more cost-effective than the generic letter during the long term. PMID- 29105872 TI - Dendritic and Core-Shell-Corona Mesoporous Sister Nanospheres from Polymer Surfactant-Silica Self-Entanglement. AB - Mesoporous nanospheres are highly regarded for their applications in nanomedicine, optical devices, batteries, nanofiltration, and heterogeneous catalysis. In the last field, the dendritic morphology, which favors molecular diffusion, is a very important morphology known for silica, but not yet for carbon. A one-pot, easy, and scalable co-sol-gel route by using the triphasic resol-surfactant-silica system is shown to yield the topologies of dendritic and core-shell-corona mesoporous sister nanospheres by inner radial phase speciation control on a mass-transfer-limited process, depending on the relative polycondensation rates of the resol polymer and silica phases. The trick was the use of polyolamines with different catalytic activities on each hard phase polycondensation. The self-entanglement of phases is produced at the {O- , S+ , I } organic-surfactant-inorganic interface. Mono- and biphasic mesoporous sister nanospheres of carbon and/or silica are derivatized from each mother nanospheres and called "syntaxic" because of similar sizes and mirrored morphologies. Comparing these "false twins", or yin and yang mesoporous nanospheres, functionalized by sulfonic groups provides evidence of the superiority of the dendritic topologies and the absence of a shell on the diffusion-controlled catalytic alkylation of m-cresol. PMID- 29105873 TI - Morphometric study of the porcine placental vascularization. AB - The early development in mammals is characterized by the contribution of nutrients from the maternal tissues through the placenta, which is in apposition with foetal membranes and the endometrium, allowing the physiological interchange between the embryos/foetuses and the mother. The aim of this work was to study the number of placental blood vessels and their vascular area through morphometric analyses and the haemotrophic diffusion distance in porcine placental tissues from early gestations, intermediates gestations, advanced gestations and term gestations. For those purposes, morphometric measurements, blood vessel quantification, high-resolution light microscopy and transmission electron microscopy were performed. The implementation of the high-resolution light microscopy allowed studying the placental vascular and tissue histoarchitecture with higher definition and resolution than using a conventional light microscopy. We highlight the close location of the subepithelial capillaries to the maternal/foetal interface as pregnancy progresses. We found statistically significant evidence to state that the area of blood vessels is dependent on the gestation period. In advanced gestations, the presence of numerous small blood vessels and its near location to foetal/maternal interface agree with the great remodelling reported in our previous studies. In conclusion, in gilts, given the type of non-invasive epithelial placentation, the new blood vessels generation and of haemotrophic diffusion distance reduction, determined in this report, assure the maternal/foetal haemotrophic exchange efficiency during gestation. PMID- 29105874 TI - Nocturnal nasal obstruction is frequent and reduces sleep quality in patients with obstructive sleep apnea. AB - The prevalence and consequences of nasal obstruction in untreated obstructive sleep apnea patients are not known. The study objectives were to investigate the frequency of subjective and objective nasal obstruction in untreated sleep apnea patients and the associations with sleep and quality of life. Patients in the Icelandic Sleep Apnea Cohort were subjected to a type 3 sleep study, answered questionnaires and had their nasal dimensions measured by acoustic rhinometry. In total, 810 patients participated (including 153 females), aged 54.5 +/- 10.6 years [mean +/- standard deviation (SD)] with an apnea/hypopnea index 44.7 +/- 20.7 h-1 . Nocturnal nasal obstruction (greater than or equal to three times per week) was reported by 35% of the patients. These patients had smaller nasal dimensions measured by the minimum cross-sectional area within the smaller nasal valve (0.42 +/- 0.17 versus 0.45 +/- 0.16 cm2 , P = 0.013), reported more daytime sleepiness (Epworth Sleepiness Scale score 12.5 +/- 4.9 versus 10.8 +/- 5.0; P < 0.001) and slightly lower mental quality of life than patients without nocturnal nasal obstruction. Nocturnal nasal obstruction is reported in one-third of the sleep apnea patients and they are more likely to suffer from daytime sleepiness and slightly reduced quality of life than other sleep apnea patients. PMID- 29105876 TI - Pheromones do regulate sexual development in Dictyostelium discoideum. AB - Based on negative data, Douglas et al refuted earlier work by the O'Day laboratory on the role of pheromones in the sexual development of Dictyostelium discoideum. This letter addresses some of the issues with their study. PMID- 29105875 TI - Questionnaire-based Analysis of Owner-reported Scratching and Pain Signs in Cavalier King Charles Spaniels Screened for Chiari-like Malformation and Syringomyelia. AB - BACKGROUND: Chiari-like malformation (CM) and syringomyelia (SM) cause a pain syndrome in Cavalier King Charles spaniels (CKCS). Clinical signs are not consistently apparent on neurologic examination, and owner reporting of signs provides vital clinical history. However, owner questionnaires for this disease are not well developed. OBJECTIVES: To develop a tool to capture owner-reported clinical signs for use in clinical trials and to compare owner-reported signs with the presence of pain on neurologic examination and SM on magnetic resonance imaging (MRI). ANIMALS: Fifty client-owned CKCS. METHODS: Owners completed a questionnaire and pain/scratch map. Each dog underwent a neurologic examination and craniocervical magnetic resonance imaging (MRI). Questionnaire responses were developed into scores, area of shading for pain/scratch maps was measured, and consistency of responses between these tools was assessed. Owner-reported findings were compared with neurologic examination findings and presence and severity of SM on MRI. RESULTS: Thirty-three dogs were symptomatic and 17 asymptomatic; 30 had SM. The most common sign of pain was crying out when lifted (n = 11). Extent of shaded areas on maps positively correlated with questionnaire scores for pain (r2 = 0.213, P = 0.006) and scratch (r2 = 0.104, P = 0.089). Owner-reported findings were not significantly associated with presence or severity of SM or neurologic examination findings. Owner-reported lateralization of signs was significantly associated with SM lateralization (P < 0.0001). CONCLUSIONS: The questionnaire and maps may be useful for clinical trials. Lack of association of owner-reported signs with SM highlights our lack of understanding of the pathophysiology of pain in this disease. PMID- 29105877 TI - Cognitive functioning in the general population: Factor structure and association with mental disorders-The neuropsychological test battery of the mental health module of the German Health Interview and Examination Survey for Adults (DEGS1 MH). AB - The objective of this study is to obtain population level data about cognitive functions and their association with mental disorders. We here report factor analytic and psychometric findings of a neuropsychological test battery and examine the association of current and past mental disorders with cognitive function in a large nationwide population-based sample of 18- to 79-year-old adults in Germany (n = 3,667) participating in the mental health module of the German Health Interview and Examination Survey for Adults 2008-2011. Confirmatory factor analysis confirmed verbal memory and executive function factors. Older age was strongly associated with lower verbal memory and executive function and with higher vocabulary scores. After adjustment for age, sex, and education, rather modest decrements were found for verbal memory (beta = -.118, p = .002) and executive functions (beta = -.191, p < .001) in participants with any current mental disorder (n = 442) compared to those without (n = 3,201). Small decrements in memory (beta = -.064, p = .031) and executive function (beta = -.111, p < .001) were found in participants with any mental disorder in the last 12 months but not in those with past (fully or partially remitted) mental disorders, compared to participants without a history of mental disorder. More fine-grained analyses of these data will investigate the complex interplay between cognition, health behaviors, and specific mental and somatic diseases. PMID- 29105878 TI - Introgression between divergent corn borer species in a region of sympatry: Implications on the evolution and adaptation of pest arthropods. AB - The Asian corn borer, Ostrinia furnacalis, and European corn borer, O. nubilalis (Lepidoptera: Crambidae), cause damage to cultivated maize in spatially distinct geographies and have evolved divergent hydrocarbons as the basis of sexual communication. The Yili area of Xinjiang Uyghur Autonomous Region in China represents the only known region where O. furnacalis has invaded a native O. nubilalis range, and these two corn borer species have made secondary contact. Genetic differentiation was estimated between Ostrinia larvae collected from maize plants at 11 locations in Xinjiang and genotyped using high-throughput SNP and microsatellite markers. Maternal lineages were assessed by direct sequencing of mitochondrial cytochrome c oxidase subunit I and II haplotypes, and a high degree of genotypic diversity was demonstrated between lineages based on SNP genotypes. Furthermore, historical introgression was predicted among SNP genotypes only at sympatric locations in the Yili area, whereas in Xinjiang populations only O. furnacalis haplotypes were detected and no analogous introgressed genotypes were predicted. Our detection of putative hybrids and historical evidence of introgression defines Yili area as a hybrid zone between the species in normal ecological interactions and furthermore, might indicate that adaptive traits could spread even between seemingly divergent species through horizontal transmission. Results of this study indicate there may be a continuum in the degree of reproductive isolation between Ostrinia species and that the elegance of distinct and complete speciation based on modifications to the pheromone communication might need to be reconsidered. PMID- 29105879 TI - Efficacy of a web-based intervention with and without guidance for employees with risky drinking: results of a three-arm randomized controlled trial. AB - AIMS: To test the efficacy of a web-based alcohol intervention with and without guidance. DESIGN: Three parallel groups with primary end-point after 6 weeks. SETTING: Open recruitment in the German working population. PARTICIPANTS: Adults (178 males/256 females, mean age 47 years) consuming at least 21/14 weekly standard units of alcohol (SUA) and scoring >= 8/6 on the Alcohol Use Disorders Identification Test. INTERVENTION: Five web-based modules including personalized normative feedback, motivational interviewing, goal setting, problem-solving and emotion regulation during 5 weeks. One intervention group received an unguided self-help version (n=146) and the second received additional adherence-focused guidance by eCoaches (n=144). Controls were on a waiting list with full access to usual care (n=144). MEASUREMENTS: Primary outcome was weekly consumed SUA after 6 weeks. SUA after 6 months was examined as secondary outcome, next to numbers of participants drinking within the low-risk range, and general and work-specific mental health measures. FINDINGS: All groups showed reductions of mean weekly SUA after 6 weeks (unguided: -8.0; guided: -8.5; control: -3.2). There was no significant difference between the unguided and guided intervention (P=0.324). Participants in the combined intervention group reported significantly fewer SUA than controls [B=-4.85, 95% confidence interval (CI)=-7.02 to -2.68, P < 0.001]. The intervention groups also showed significant reductions in SUA consumption after 6 months (B=-5.72, 95% CI=-7.71 to -3.73, P < 0.001) and improvements regarding general and work-related mental health outcomes after 6 weeks and 6 months. CONCLUSIONS: A web-based alcohol intervention, administered with or without personal guidance, significantly reduced mean weekly alcohol consumption and improved mental health and work-related outcomes in the German working population. PMID- 29105880 TI - Cooperative Folding of Linear Poly(dimethyl siloxane)s via Supramolecular Interactions. AB - The synthesis and characterization of graft copolymers are reported based on linear poly(dimethyl siloxane) (PDMS) and chiral, pendant benzene-1,3,5 tricarboxamides (BTAs). The copolymers differ in degree of polymerization (DP) and BTA graft density. Characterization of the bulk materials at room temperature reveals that the BTAs aggregate in a helical fashion via threefold hydrogen-bond formation within the PDMS matrix. A significant degree of hydrogen bonding persists up to 180 degrees C, regardless of DP and BTA content. Analysis of the solution behavior by 1 H NMR spectroscopy indicates that BTA aggregation occurs in CDCl3 , a solvent normally suppressing aggregation. Circular dichroism (CD) spectroscopy in 1,2-dichloroethane shows strong CD effects and reveals that increasing the DP and decreasing the BTA graft density results in an increase in the cooperativity of the BTA aggregation. Dynamic light scattering indicates the formation of particles with sizes of 400 nm. This is the first time that polymers with pendant BTAs show a sharp transition between a nonaggregated and aggregated state, a behavior similar to the one observed for "free" BTAs. The cooperative aggregation is attributed to the strong phase-segregation between the PDMS backbone and the BTAs, in combination with a high propensity of these polymers to form multichain aggregates. PMID- 29105881 TI - MRI-guided preoperative 125 I seed localizations: Case report. AB - Preoperative nonwire localizations with 125 I seeds are performed using mammographic or ultrasonographic guidance. Current MRI-guided interventions in the breast are primarily limited to biopsies and wire localizations. Occasionally, nonwire localization with 125 I seeds is preferred, but the target is only well seen on MRI. This case report describes how MRI-guided preoperative two 125 I seed bracket localization was performed. PMID- 29105882 TI - Iron-Catalyzed Hydroborylative Cyclization of 1,6-Enynes. AB - We report first Fe-catalyzed hydroborylative cyclization reaction. The process provides one C-C and one C-B bond in a single operation and shows a wide scope, allowing the formation of carbo- and heterocycles containing a homoallylic boryl unit that can be further functionalized. The reaction takes place in smooth conditions, with inexpensive catalytic system and full atom economy since HBpin is the borylation agent, in contrast to our previously reported Pd-catalyzed reaction. Both aryl and alkyl substituted alkynes are reactive, revealing a wide reaction scope. Mechanistic studies suggest the intermediacy of FeII -hydride active catalyst capable to react with the alkyne group prior to alkene insertion, and computational studies suggest the occurrence of barrierless sigma-bond metathesis involving HBpin and Fe-C bonds along the catalytic cycle. PMID- 29105883 TI - Physical contact is essential for macrocyst formation in wild Dictyostelium discoideum: a response to O'Day. PMID- 29105884 TI - Inhibition of IAP (inhibitor of apoptosis) proteins represses inflammatory status via nuclear factor-kappa B pathway in murine endometriosis lesions. AB - PROBLEM: How is the role of inhibitor of apoptosis proteins (IAPs) in the development of murine endometriosis lesions? METHOD OF STUDY: BALB/c female mice (n = 36) were used for the murine endometriosis model. Endometriotic lesions were surgically induced in mice by transplanting mouse uterine tissue. After 4 weeks of IAP antagonist (BV6) treatment, the expression of inflammatory factors in the implants was evaluated using real-time RT-PCR. Inflammatory state, angiogenic activity, and nuclear factor-kappa B (NF-kappaB) activation were assessed by immunohistochemical staining. RESULTS: The number, size, and level of inflammatory cytokines (Vegf, Il-6, Ccl-2, Lif) gene expression in the murine endometriosis-like lesions were reduced by BV6 treatment. BV6 repressed the intensity and rate of positive cells of CD3, F4/80, and PECAM immunostaining; in addition, the expression of NF-kappaB p65 and phospho-NF-kappaB p65 was also attenuated. CONCLUSION: Inhibitor of apoptosis proteins antagonist represses the inflammation status of murine endometriosis-like lesions viaNF-kappaB pathway. IAPs may be a novel therapeutic target for endometriosis. PMID- 29105885 TI - EMP-induced BBB-disruption enhances drug delivery to glioma and increases treatment efficacy in rats. AB - Chemotherapy on gliomas is not satisfactorily efficient because the presence of blood-brain barriers (BBB) leads to inadequate exposure of tumor cells to administered drugs. In order to facilitate chemotherapeutics to penetrate BBB and increase the treatment efficacy of gliomas, electromagnetic pulse (EMP) was applied and the 1-(2-Chlorethyl)-cyclohexyl-nitrosourea (CCNU) lomustine concentration in tumor tissue, tumor size, tumor apoptosis, and side effects were measured in glioma-bearing rat model. The results showed that EMP exposure could enhance the delivery of CCNU to tumor tissue, facilitate tumor apoptosis, and inhibit tumor growth without obvious side effects. The data indicated that EMP induced BBB disruption could enhance delivery of CCNU to glioblastoma multiforme and increase treatment efficacy in glioma-bearing rats. Bioelectromagnetics. 39:60-67, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29105886 TI - Altered structure and functional connection in patients with classical trigeminal neuralgia. AB - Classical trigeminal neuralgia (TN) is a specific type of neuropathic orofacial pain of which the plasticity of brain structure and connectivity have remained largely unknown. A total of 62 TN patients were included and referred to MRI scans. Voxel-based morphometry was used to analyze the change of gray matter volume. Resting-state functional imaging was used to analyze the connectivity between brain regions. The results showed gray matter volume reduction in components of the prefrontal cortex, precentral gyrus, cerebellar tonsil, thalamus, hypothalamus, and nucleus accumbens among right TN patient and in the inferior frontal gyrus, precentral gyrus, cerebellum, thalamus, ventral striatum, and putamen among left TN patients. The connections between the right superior frontal gyrus and right middle frontal gyrus were lower in right TN patients. The connection between the left precentral gyrus and the left superior frontal gyrus was lower while the connection between bilateral thalamus was higher in left TN patients. The changes of volume in bilateral thalamus of right TN patients and left ventral striatum of left TN patients, and the connectivity between bilateral thalamus of left TN patients were moderately correlated with pain duration. These findings suggest that brain regions such as the thalamus may not only be involved in processing of pain stimuli but also be important for the development of TN. The left hemisphere may be dominant in processing and modulation of TN pain signal. Chronification of TN induces volume changes in brain regions which are associated with emotional or cognitive modulation of pain. Hum Brain Mapp 39:609 621, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29105887 TI - Furans Accessed through Visible-Light-Mediated Oxidative [3+2] Cycloaddition of Enols and Alkynes. AB - Visible-light-mediated formation of furans though direct oxidative [3+2] cycloaddition of 1,3-diones and alkynes is described. This protocol provides a simple and mild route to poly-substituted furans in moderate-to-good yields. Preliminary mechanistic studies suggest that this reaction likely follows a radical addition/cyclization pathway. PMID- 29105888 TI - Simulation of the simultaneous dual-frequency resonance excitation of ions in a linear ion trap. AB - The process of ion resonance dipolar excitation in a linear ion trap by 2 ejection waveforms with close frequencies is studied. The physical mechanism of increasing the resolving power using the ion excitation is a nonlinearity of the electric radio frequency fields caused by space charge. Using 2 resonance forces with 2 close frequencies leads to the completion of 2 excitation processes. In the case of the perfect quadrupole electric field, the ion motion equations are linear, and as a result, the respondent ion ensemble is also a linear and valid superposition principle. Nevertheless, the resolution increases (20%) in the case of lack of a space charge in an operating mode with a dual-frequency. The numerical simulations show that the mass shift is removed, and the mass resolution is increased via dual-frequency resonance excitation when the frequency difference (approximately 2.5 kHz) is relatively small and the phase difference of 2 harmonic signals is 0-pi3 even at a high linear ion density of up to 50 000 ions per radius field r0 . PMID- 29105889 TI - Obstructive sleep apnoea in a paediatric patient with laryngeal Crohn's disease. PMID- 29105890 TI - Auto-Tandem Catalysis: PdII -Catalysed Dehydrogenation/Oxidative Heck Reaction of Cyclopentane-1,3-diones. AB - A PdII catalyst system has been used to successfully catalyse two mechanistically distinct reactions in a one-pot procedure: dehydrogenation of 2,2-disubstituted cyclopentane-1,3-diones and the subsequent oxidative Heck coupling. This auto tandem catalytic reaction is applicable to both batch and continuous flow processes, with the latter being the first example of a tandem aerobic dehydrogenation/oxidative Heck in flow. In addition, a telescoped reaction involving enantioselective desymmetrisation of the all-C quaternary centre was successfully achieved. PMID- 29105891 TI - Aortopulmonary collateral flow quantification by MR at rest and during continuous submaximal exercise in patients with total cavopulmonary connection. AB - BACKGROUND: Aortopulmonary collateral flow is considered to have significant impact on the outcome of patients with single ventricle circulation and total cavopulmonary connection (TCPC). There is little information on collateral flow during exercise. PURPOSE: To quantify aortopulmonary collateral flow at rest and during continuous submaximal exercise in clinical patients doing well with TCPC. STUDY TYPE: Prospective, case controlled. POPULATION: Thirteen patients with TCPC (17 (11-37) years) and 13 age and sex-matched healthy controls (18 (11-38) years). FIELD STRENGTH: 1.5T; free breathing; phase sensitive gradient echo sequence. ASSESSMENT: Blood flow in the ascending and descending aorta and superior vena cava were measured at rest and during continuous submaximal physical exercise in patients and controls. Systemic blood flow (Qs ) was assumed to be represented by the sum of flow in the superior caval vein (Qsvc ) and the descending aorta (QAoD ) at the diaphragm level. Aortopulmonary collateral flow (Qcoll ) was calculated by subtracting Qs from flow in the ascending aorta (QAoA ). STATISTICS: Mann-Whitney U-test and Wilcoxon test for comparison between groups and between rest and exercise. RESULTS: Absolute collateral flow in TCPC patients at rest was 0.4 l/min/m2 (-0.1-1.2), corresponding to 14% (-2-42) of Qs . Collateral flow did not change during exercise (difference -0.01 (-0.7-1.0) l/min/m2 , P = 0.97). TCPC patients had significantly lower Qs at rest (2.5 (1.6 4.1) vs. 3.5 (2.6-4.8) l/min/m2 , P = 0.001) and during submaximal exercise (3.2 (2.0-6.0) vs. 4.8 (3.3-6.9) l/min/m2 , P = 0.001), compared to healthy controls. The increase in Qs with exercise was also significantly lower in patients than in healthy controls (median 0.6 vs. 1.2 l/min/m2 , P < 0.02). DATA CONCLUSION: Clinical patients doing well with TCPC have significant aortopulmonary collateral flow at rest (14% of Qs ) compared to healthy controls, which does not change during submaximal exercise. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1509-1516. PMID- 29105892 TI - Patient preferences for breast biopsy result notification. PMID- 29105893 TI - Effects of meal palatability on postprandial sensations. AB - BACKGROUND: Food palatability has been shown to influence satiation and meal consumption; our aim was to determine its effects on postprandial satisfaction, ie digestive well-being (primary outcome), and homeostatic sensations (satiety, fullness). METHODS: Randomized, cross-over trial comparing the postprandial responses to conventional (potato-cheese cream followed by vanilla cream) vs unconventional test meals (mixture of both creams) with identical composition and physical characteristics (color, texture, consistency, temperature) but distinctively different palatability. In 22 non-obese healthy men sensations were measured on 10 cm scales before and during the 60-min postprandial period (-5 to +5 score scales for palatability, satiety, well-being, and mood, and 0-10 score scales for fullness and discomfort). Comparisons between meals were performed with a 2-way repeated measures ANCOVA with premeal data as co-variate. KEY RESULTS: As compared to the palatable conventional meal, the unconventional meal was rated unpalatable (-1.8 +/- 0.4 score vs 2.8 +/- 0.1 score potato cream and 2.9 +/- 0.2 vanilla cream; P < .001 for both), induced significantly more fullness sensation [meal effect F (1, 19) = 7.389; P = .014] but had less effect on digestive well-being [meal effect F (1, 19) = 47.016; P < .001] and mood [meal effect F (1, 19) = 6.609; P = .019]. The difference in satiety was not significantly different. CONCLUSION & INFERENCES: Meal palatability influences the postprandial experience: it bears a direct relation to the hedonic response (well-being/mood) but an inverse relation to homeostatic sensations (fullness). These relations could be applicable to influence eating behavior, because at equal conditions, more palatable meals induce less fullness but more satisfaction, and vice-versa. PMID- 29105894 TI - Estimating the opportunity costs of bed-days. AB - Opportunity costs of bed-days are fundamental to understanding the value of healthcare systems. They greatly influence burden of disease estimations and economic evaluations involving stays in healthcare facilities. However, different estimation techniques employ assumptions that differ crucially in whether to consider the value of the second-best alternative use forgone, of any available alternative use, or the value of the actually chosen alternative. Informed by economic theory, this paper provides a taxonomic framework of methodologies for estimating the opportunity costs of resources. This taxonomy is then applied to bed-days by classifying existing approaches accordingly. We highlight differences in valuation between approaches and the perspective adopted, and we use our framework to appraise the assumptions and biases underlying the standard approaches that have been widely adopted mostly unquestioned in the past, such as the conventional use of reference costs and administrative accounting data. Drawing on these findings, we present a novel approach for estimating the opportunity costs of bed-days in terms of health forgone for the second-best patient, but expressed monetarily. This alternative approach effectively re connects to the concept of choice and explicitly considers net benefits. It is broadly applicable across settings and for other resources besides bed-days. PMID- 29105895 TI - A dimensional approach to determine common and specific neurofunctional markers for depression and social anxiety during emotional face processing. AB - Major depression disorder (MDD) and anxiety disorder are both prevalent and debilitating. High rates of comorbidity between MDD and social anxiety disorder (SAD) suggest common pathological pathways, including aberrant neural processing of interpersonal signals. In patient populations, the determination of common and distinct neurofunctional markers of MDD and SAD is often hampered by confounding factors, such as generally elevated anxiety levels and disorder-specific brain structural alterations. This study employed a dimensional disorder approach to map neurofunctional markers associated with levels of depression and social anxiety symptoms in a cohort of 91 healthy subjects using an emotional face processing paradigm. Examining linear associations between levels of depression and social anxiety, while controlling for trait anxiety revealed that both were associated with exaggerated dorsal striatal reactivity to fearful and sad expression faces respectively. Exploratory analysis revealed that depression scores were positively correlated with dorsal striatal functional connectivity during processing of fearful faces, whereas those of social anxiety showed a negative association during processing of sad faces. No linear relationships between levels of depression and social anxiety were observed during a facial identity matching task or with brain structure. Together, the present findings indicate that dorsal striatal neurofunctional alterations might underlie aberrant interpersonal processing associated with both increased levels of depression and social anxiety. PMID- 29105896 TI - Organocatalytic Atroposelective Arylation of 2-Naphthylamines as a Practical Approach to Axially Chiral Biaryl Amino Alcohols. AB - The first phosphoric acid catalyzed direct arylation of 2-naphthylamines with iminoquinones for the atroposelective synthesis of axially chiral biaryl amino alcohols has been developed. This reaction constitutes a highly functional-group tolerant route for the rapid construction of enantioenriched axially chiral biaryl amino alcohols, and is a rare example of 2-naphthylamines acting as nucleophiles in an organocatalytic enantioselective transformation. Furthermore, the products, which feature various halogen atoms, provide access to structurally diverse axially chiral amino alcohols through further transformations. PMID- 29105897 TI - Chronic intensive care-related pain: Exploratory analysis on predictors and influence on health-related quality of life. AB - BACKGROUND: There is growing evidence for the development of chronic pain after intensive care. Nonetheless, there is only limited knowledge about factors leading to chronic intensive care-related pain (CIRP). Thus, the primary objective was the identification of predictors of CIRP. Moreover, we aimed to assess the impact of CIRP on patients' health-related quality of Life (HRQOL). METHODS: Comprehensive information on patients' pain before ICU admission and present pain was collected longitudinally by means of the German Pain Questionnaire 6 and 12 months after ICU discharge (ICUDC ). In addition, a subsample of patients underwent Quantitative Sensory Testing (QST). We used Generalized Estimating Equations to identify predictors of CIRP with logistic regression models. RESULTS: In total, 204 patients (197/159 at 6/12 months after ICUDC ) were available for the analyses. In the multivariate models, moderate to severe average pain in the 4 weeks after ICUDC , lower age, female sex, increased inflammation and chronic pain conditions and increased levels of anxiety before ICU admission were predictive for CIRP. In addition, small fibre deficits and lower disease severity were associated with CIRP in the QST subsample (81 patients, 77/55 at 6/12 months after ICUDC ). Patients with CIRP reported significantly lower HRQOL than patients without CIRP. CONCLUSIONS: Chronic intensive care-related pain is associated with specific decrements in HRQOL. Knowledge about the identified predictors is of clinical and scientific importance and might help to reduce the incidence of CIRP. SIGNIFICANCE: Chronic intensive care-related pain is associated with specific decrements in health related quality of life. While most of the identified predictors for CIRP can only be considered as risk factors, especially adequate (post-) acute pain management should be studied as preventive strategy. PMID- 29105898 TI - Early pneumopericardium after heart transplantation. AB - A 60-year-old woman with a history of dilated cardiomyopathy underwent heart transplantation. One month post discharge, she presented to clinic with low-grade fever and productive cough. Her chest radiograph showed air-fluid levels in the pericardial silhouette. Transthoracic echocardiogram showed a large complex pericardial collection with no evidence of cardiac tamponade. The patient was urgently taken to the operating room for exploration. A large "egg-shaped" mass in the pericardium measuring 10 * 12 cm with gaseous material was aspirated. As the posterior wall of the mass was firmly adhered to the right atrium, the capsule was incompletely excised. We present the case of a potentially life threatening complication post transplantation that required surgical debridement and life-long antibiotic suppressive therapy. To our knowledge, this is the first report of purulent pericardial collection caused by Enterobacter cancerogenous. Further research is required to better understand the biology of this microorganism and the role it may play as a pathogen in immunocompromised patients following solid organ transplantation. PMID- 29105899 TI - Left ventricular geometry as a major determinant of left ventricular ejection fraction: physiological considerations and clinical implications. AB - The limited myocardial fibre thickening and shortening alone cannot explain the marked left ventricular (LV) volume reduction during LV ejection. This can only be achieved with LV helical (spiral) orientation of myocardial fibres, which is determined by the non-contractile LV myocardial components (intrasarcomeric and extrasarcomeric cytoskeleton, extracellular matrix). Preservation of LV ejection fraction (LVEF) in heart failure (HF) is due to the presence of normal ellipsoid LV configuration and spiral myocardial fibre orientation. Conversely, reduction of LVEF in HF results from spherical LV configuration associated with impaired myocardial fibre orientation. These mechanisms are supported by the fact that biomarkers of inflammation and fibrosis are strong predictors of LV reverse remodelling in HF with reduced LVEF (HFrEF) and therapeutic interventions in HFrEF that retard or inhibit extracellular matrix remodelling are effective, whereas those that increase myocardial contractility are ineffective. Thus, current classification of HF, based on LVEF, should be revised, and future therapy in HF should focus on interventions affecting the non-contractile LV myocardial components rather than on LV myocardial contractility. PMID- 29105900 TI - Performance characteristics of digital vs film screen mammography in community practice. AB - We compared the performance characteristics of 297 629 full field digital (FFDM) and 416 791 screen film mammograms (SFM). Sensitivity increased with age, decreased with breast density, and was lower for more aggressive and lobular tumors. While sensitivity did not differ significantly by modality, specificity was generally 1%-2% points higher for FFDM than for SFM across age and breast density categories. The lower recall rate for FFDM vs SFM in our study may partially explain performance differences by modality. In this large health care organization, modest gains in performance were achieved with the introduction of FFDM as a replacement for SFM. PMID- 29105901 TI - A comparative study of synthetic and semisynthetic approaches for ligating the epidermal growth factor to a bivalent scaffold. AB - A prominent target of monoclonal antibodies as targeted therapies for cancer is the epidermal growth factor receptor, which is overexpressed on the surface of various cancer cell types. Its natural binder, the epidermal growth factor (EGF), is a 53 amino acid polypeptide. Anticancer synthetic targeted immune system engagers (ISErs) comprising two 'binder' peptides, which are attached to a scaffold conveying immune stimulating 'effector' properties, via monodisperse polyethylene glycol chains. So far, preparation of ISErs has been limited to the use of small peptides (8-20 amino acids) as binding functionalities, and they have been entirely synthesized by solid phase peptide synthesis. Here, we describe a synthetic and a semisynthetic approach for the preparation of an ISEr bearing two murine EGF molecules as binding entities (ISEr-EGF2 ). EGF was either synthesized in segments by solid phase peptide synthesis or expressed recombinantly and ligated to the scaffold by native chemical ligation. We report the successful generation of synthetic and semisynthetic ISEr-EGF2 as well as several challenges encountered during the synthesis and ligations. We demonstrate the application of native chemical ligation for the design of larger ISEr constructs, facilitating new objectives for the coupling of small binder peptides and larger proteins to multivalent ISEr scaffolds. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 29105902 TI - Commentary on Karsdorp et al. PMID- 29105904 TI - Predictors of symptomatic intracranial haemorrhage in off-label thrombolysis: an analysis of the Safe Implementation of Treatments in Stroke registry. AB - BACKGROUND AND PURPOSE: Intravenous thrombolysis (IVT) is the only approved pharmacological treatment for acute ischemic stroke. Off-label IVT for ischemic stroke is common. We aimed to analyse its safety in a large database. METHODS: This was a retrospective analysis of the safe implementation of treatments in stroke (SITS) thrombolysis registry with regard to 11 off-label criteria according to the European licence for alteplase. Symptomatic intracranial haemorrhage (SICH) according to SITS was defined as primary safety endpoint and SICH according to the European Cooperative Acute Stroke Study (ECASS II) definition and the National Institute of Neurological Disorders and Stroke definition as secondary safety endpoints. Multivariable logistic regression analyses after replacing missing values using multiple imputations were performed. RESULTS: Patients from 793 centres in 44 countries were included, mainly (95%) in Europe. A total of 56 258 patients who were treated with intravenous alteplase were included. Median age was 71 (IQR 61-78) years and median National Institutes of Health Stroke Scale score was 12 (IQR 7-17). A total of 16 740 (30%) patients received off-label IVT and 1037 (1.8%) patients suffered from SICH according to the SITS definition (SICH SITS). Median percentage of missing values per variable was 0.4%. The only two off-label criteria constituting independent positive and negative predictors for SICH SITS were high blood pressure (odds ratio, 1.39; 95% confidence interval, 1.08-1.80; P = 0.012) and minor stroke (odds ratio, 0.51; 95% confidence interval, 0.33-0.78; P = 0.002). Very severe stroke, previous stroke and diabetes, age and high glucose levels were additional independent predictors of SICH according to the ECASS II and National Institute of Neurological Disorders and Stroke definitions. CONCLUSIONS: Thrombolysis appears to be safe with regard to SICH for most of the off-label criteria, especially for minor stroke, but is risky in patients with high blood pressure. Individual risk-benefit evaluation should be performed. PMID- 29105905 TI - The post-mastectomy pain syndrome-A systematic review of the treatment modalities. PMID- 29105906 TI - Donor-sigma-Acceptor Motifs: Thermally Activated Delayed Fluorescence Emitters with Dual Upconversion. AB - A family of organic emitters with a donor-sigma-acceptor (D-sigma-A) motif is presented. Owing to the weakly coupled D-sigma-A intramolecular charge-transfer state, a transition from the localized excited triplet state (3 LE) and charge transfer triplet state (3 CT) to the charge-transfer singlet state (1 CT) occurred with a small activation energy and high photoluminescence quantum efficiency. Two thermally activated delayed fluorescence (TADF) components were identified, one of which has a very short lifetime of 200-400 ns and the other a longer TADF lifetime of the order of microseconds. In particular, the two D-sigma A materials presented strong blue emission with TADF properties in toluene. These results will shed light on the molecular design of new TADF emitters with short delayed lifetimes. PMID- 29105907 TI - Polyphthalaldehyde: Synthesis, Derivatives, and Applications. AB - o-Phthalaldehyde is, to this day, the only aromatic aldehyde that can be homopolymerized through chain-growth polymerization. The product, polyphthalaldehyde (PPA), is a brittle white solid, and, having a polyacetal main chain, presents the ability to depolymerize quite rapidly in the presence of an acid. This review highlights the unique polymerization chemistry of o phthalaldehyde since its discovery over half a century ago, describing the different methods for the preparation of PPA and its derivatives, how the polymerization chemistry affects the structure and thermomechanical properties of the obtained PPA, and summarizes recent developments in PPA chemistry as a responsive material. Modern material applications such as the use of PPA as photoresists or in thermal-scanning probe lithography, as well as exploration of judiciously end-capped PPA for its use as self-immolative materials are summarized. In addition, the use of PPA blocks in copolymers is described, leading to the development of films with well-defined nanochannels or nanopores that can serve as a template for the preparation of the microorganization of nanomaterials. PMID- 29105909 TI - Endobronchial valve placement in emphysema: When is it lung volume reduction? PMID- 29105908 TI - The research gap in chronic paediatric pain: A systematic review of randomised controlled trials. AB - BACKGROUND AND OBJECTIVE: Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain. METHODS: We performed a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. We included RCTs that involved children and adolescents (3 months-18 years) and evaluated the use of pharmacological or non pharmacological intervention(s) in the context of pain persisting or re-occurring for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias (ROB) Tool. RESULTS: A total of 58 RCTs were identified and numbers steadily increased over time. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 47.5 participants (Q1,Q3: 32, 70). Forty-five percent of RCTs included both adults and children and the median of the mean ages at inclusion was 12.9 years (Q1,Q3: 11, 15). Testing of non-pharmacological interventions was predominant and only 5 RCTs evaluated analgesics or co-analgesics. Abdominal pain, headache/migraine and musculoskeletal pain were the most common types of chronic pain among participants. Methodological quality was poor with 90% of RCTs presenting a high or unclear ROB. CONCLUSIONS: Evaluation of analgesics targeting chronic pain relief in children and adolescents through RCTs is marginal. Infants and children with long-lasting painful conditions are insufficiently represented in RCTs. We discuss possible research constraints and challenges as well as methodologies to circumvent them. SIGNIFICANCE: There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non-pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long-lasting diseases. PMID- 29105910 TI - Mindfulness for palliative care patients. Systematic review. AB - BACKGROUND: Nineteen million adults worldwide are in need of palliative care. Of those who have access to it, 80% fail to receive an efficient management of symptoms. OBJECTIVES: To assess the effectiveness and safety of mindfulness meditation for palliative care patients. METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, PEDro, CINAHL, PsycINFO, Opengrey, ClinicalTrials.gov and WHO ICTRP. No restriction of language, status or date of publication was applied. We considered randomised clinical trials (RCTs) comparing any mindfulness meditation scheme vs any comparator for palliative care. Cochrane Risk of Bias (Rob) Table was used for assessing methodological quality of RCTs. Screening, data extraction and methodological assessments were performed by two reviewers. Mean differences (MD) (confidence intervals of 95% (CI 95%)) were considered for estimating effect size. Quality of evidence was appraised by GRADE. RESULTS: Four RCTs, 234 participants, were included. All studies presented high risk of bias in at least one RoB table criteria. We assessed 4 comparisons, but only 2 studies showed statistically significant difference for at least one outcome. 1. Mindfulness meditation (eight weeks, one session/week, daily individual practice) vs control: statistically significant difference in favour of control for quality of life - physical aspects. 2. Mindfulness meditation (single 5-minute session) vs control: benefit in favour of mindfulness for stress outcome in both time-points. None of the included studies analysed safety and harms outcomes. CONCLUSIONS: Although two studies have showed statistically significant difference, only one showed effectiveness of mindfulness meditation in improving perceived stress. This study focused on one single session of mindfulness of 5 minutes for adult cancer patients in palliative care, but it was considered as possessing high risk of bias. Other schemes of mindfulness meditation did not show benefit in any outcome evaluated (low and very low quality evidence). PMID- 29105911 TI - Glass Microsphere-Supported Giant Vesicles for the Observation of Self Reproduction of Lipid Boundaries. AB - Growth and division experiments on phospholipid boundaries were carried out using glass microsphere-supported phospholipid (DOPC) giant vesicles (GVs) fed with a fatty acid solution (oleic acid) at two distinct feeding rates. Both fast and slow feeding methods produced daughter GVs. Under slow feeding conditions the membrane growth process (evagination, buds, filaments) was observed in detail by fluorescence microscopy. The density difference between supported mother vesicles and newly formed daughter vesicles allowed their easy separation. Mass spectrometric analysis of the resulting mother and daughter GVs showed that the composition of both vesicle types was a mixture of original supported phospholipids and added fatty acids reflecting the total composition of amphiphiles after the feeding process. Thus, self-reproduction of phospholipid vesicles can take place under preservation of the lipid composition but different aggregate size. PMID- 29105912 TI - How much do direct livestock emissions actually contribute to global warming? AB - Agriculture directly contributes about 10%-12% of current global anthropogenic greenhouse gas emissions, mostly from livestock. However, such percentage estimates are based on global warming potentials (GWPs), which do not measure the actual warming caused by emissions and ignore the fact that methane does not accumulate in the atmosphere in the same way as CO2 . Here, we employ a simple carbon cycle-climate model, historical estimates and future projections of livestock emissions to infer the fraction of actual warming that is attributable to direct livestock non-CO2 emissions now and in future, and to CO2 from pasture conversions, without relying on GWPs. We find that direct livestock non-CO2 emissions caused about 19% of the total modelled warming of 0.81 degrees C from all anthropogenic sources in 2010. CO2 from pasture conversions contributed at least another 0.03 degrees C, bringing the warming directly attributable to livestock to 23% of the total warming in 2010. The significance of direct livestock emissions to future warming depends strongly on global actions to reduce emissions from other sectors. Direct non-CO2 livestock emissions would contribute only about 5% of the warming in 2100 if emissions from other sectors increase unabated, but could constitute as much as 18% (0.27 degrees C) of the warming in 2100 if global CO2 emissions from other sectors are reduced to near or below zero by 2100, consistent with the goal of limiting warming to well below 2 degrees C. These estimates constitute a lower bound since indirect emissions linked to livestock feed production and supply chains were not included. Our estimates demonstrate that expanding the mitigation potential and realizing substantial reductions of direct livestock non-CO2 emissions through demand and supply side measures can make an important contribution to achieve the stringent mitigation goals set out in the Paris Agreement, including by increasing the carbon budget consistent with the 1.5 degrees C goal. PMID- 29105914 TI - Introducing Addiction's New Assistant Editors. PMID- 29105915 TI - Response to Commentaries: new data sources for understanding cannabis markets. PMID- 29105913 TI - A step-wise approach to developing indicators to compare the performance of maternity units using hospital administrative data. AB - : Hospital administrative data are attractive for comparing performance of maternity units because of their often large sample sizes, lack of selection bias and the relatively low costs of accessing these data compared with conducting primary data collection. However, using administrative data to develop indicators can also present challenges including varying data quality, the limited detail on clinical risk factors and a lack of structural and user experience measures. This review illustrates how to develop performance indicators for maternity units using hospital administrative data, including methods to address the challenges that administrative data pose. TWEETABLE ABSTRACT: How to develop maternity indicators from administrative data. PMID- 29105916 TI - Commentary on van der Maas et al. (2017): Going where the action is. PMID- 29105917 TI - The need for better marijuana sales data. PMID- 29105918 TI - Corrigendum. PMID- 29105919 TI - Why methamphetamine-related deaths need more attention. PMID- 29105921 TI - Potency increase, product development and marijuana marketing in times of legalization. PMID- 29105922 TI - Commentary on Witkiewitz et al. (2017): Abstinence or moderation-a choice for whom and why? PMID- 29105923 TI - Methamphetamine-related death is an under-addressed public health problem. PMID- 29105924 TI - Erratum. PMID- 29105925 TI - Precision medicine in addiction research: where has the time gone? PMID- 29105926 TI - What is the real distribution of methamphetamine-related causes of death? PMID- 29105927 TI - Resveratrol Interferes with an Early Step in the Fibrillization Pathway of Human Lysozyme and Modulates it towards Less-Toxic, Off-Pathway Aggregates. AB - The effect of resveratrol, a polyphenol in red wine, on the amyloid fibril formation of human lysozyme (HuL) was investigated, towards elucidating the mechanism of resveratrol action and probing its role as a possible modulator of lysozyme aggregation and toxicity. By using a number of biophysical tools, resveratrol was observed to alter the fibrillization kinetics of HuL and inhibit its fibrillization by binding with weak to moderate affinity to the conformations populated at the early stages of the pathway with concomitant stabilization of these initial conformations. The marginal decrease in the lifetime of HuL in the presence of resveratrol by time-resolved fluorescence measurements indicated the involvement of a static quenching mechanism in the interaction between HuL and resveratrol. Docking studies predicted the binding of resveratrol to aggregation prone regions in HuL, and structure and activity analyses demonstrated the retention of much of the alpha-helical structure and activity of HuL in the presence of resveratrol. Resveratrol modulated the fibrillization pathway towards less-hydrophobic, less-toxic, off-pathway aggregates. These results demonstrate that binding of resveratrol to HuL could protect against the formation of pathogenic, cytotoxic aggregates formed in amyloidogenic disorders, such as systemic amyloidosis; thus suggesting its potential as a plausible therapeutic agent against lysozyme amyloidosis. PMID- 29105929 TI - Computational Chemistry: The Fate of Current Methods and Future Challenges. AB - "Where do we go from here?" is the underlying question regarding the future (perhaps foreseeable) developments in computational chemistry. Although this young discipline has already permeated practically all of chemistry, it is likely to become even more powerful with the rapid development of computational hard- and software. PMID- 29105928 TI - Lego bricks and the octet rule: Molecular models for biochemical pathways with plastic, interlocking toy bricks. AB - The 8 studs on a 2 * 4 Lego brick conveniently represent the outer shell of electrons for carbon, nitrogen, and oxygen atoms. We used Lego bricks to model these atoms, which are then joined together to form molecules by following the Lewis octet rule. A variety of small biological molecules can be modeled in this way, such as most amino acids, fatty acids, glucose, and various intermediate metabolites. Model building with these familiar toys can be a helpful, hands-on exercise for learning-or re-learning-biochemical pathways. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):54-57, 2018. PMID- 29105930 TI - Temperature-Mediated Template Release: Facile Growth of Copper(I) Mixed Ethynediide/Isopropylethynide Nanoclusters. AB - In the comproportionation reaction of CuII X2 and Cu0 with isopropylacetylene (iPr-C=C-H), the ethynediide species C22- is generated via concomitant C-H/C-C bond cleavage of the iPr-C=C-H precursor under moderate temperature to direct the formation of CuI mixed ethynediide/isopropylethynide nanoclusters (potentially explosive). The active ethynediide dianion C22- exhibits chameleon-like templating behavior to form C2 @Cum (m=6 (3, 4), 7 (2, 4), 8 (1)) central structural units for successive formation of {C22- ?Cu24 } (1, 2), {6 C22- ?Cu48 } (3), and {18 C22- ?Cu92 } (4) complexes. Bearing the highest C22- content, complex 4 features an unprecedented nanoscale Cu2 C2 kernel. Furthermore, 1-3 exhibit structure-controlled photoluminescence in the solid state. PMID- 29105932 TI - Bioactive treatments in bone grafts for implant-based rehabilitation: Systematic review and meta-analysis. AB - BACKGROUND: The use of bioactive proteins, such as rhBMP-2, may improve bone regeneration in oral and maxillofacial surgery. PURPOSE: Analyze the effect of using bioactive proteins for bone regeneration in implant-based rehabilitation. MATERIALS AND METHODS: Seven databases were screened. Only clinical trials that evaluated the use of heterologous sources of bioactive proteins for bone formation prior to implant-based rehabilitation were included. Statistical analyses were carried out using a random-effects model by comparing the standardized mean difference between groups for bone formation, and risk ratio for implant survival (P <= .05). RESULTS: Seventeen studies were included in the qualitative analysis, and 16 in the meta-analysis. For sinus floor augmentation, bone grafts showed higher amounts of residual bone graft particles than bioactive treatments (P <= .05). While for alveolar ridge augmentation bioactive treatments showed a higher level of bone formation than control groups (P <= .05). At 3 years of follow-up, no statistically significant differences were observed for implant survival (P > .05). CONCLUSIONS: Bioactive proteins may improve bone formation in alveolar ridge augmentation, and reduce residual bone grafts in sinus floor augmentation. Further studies are needed to evaluate the long-term effect of using bioactive treatments for implant-based rehabilitation. PMID- 29105931 TI - Medroxyprogesterone acetate-treated human, primary endometrial epithelial cells reveal unique gene expression signature linked to innate immunity and HIV-1 susceptibility. AB - PROBLEM: Medroxyprogesterone acetate (MPA), a progestin-based hormonal contraceptive designed to mimic progesterone, has been linked to increased human immunodeficiency virus (HIV-1) susceptibility. Genital epithelial cells (GECs) form the mucosal lining of the female genital tract (FGT) and provide the first line of protection against HIV-1. The impact of endogenous sex hormones or MPA on the gene expression profile of GECs has not been comprehensively documented. METHOD OF STUDY: Using microarray analysis, we characterized the transcriptional profile of primary endometrial epithelial cells grown in physiological levels of E2, P4, and MPA. RESULTS: Each hormone treatment altered the gene expression profile of GECs in a unique manner. Interestingly, although MPA is a progestogen, the gene expression profile induced by it was distinct from P4. MPA increased gene expression of genes related to inflammation and cholesterol synthesis linked to innate immunity and HIV-1 susceptibility. CONCLUSION: The analysis of gene expression profiles provides insights into the effects of sex hormones and MPA on GECs and allows us to posit possible mechanisms of the MPA-mediated increase in HIV-1 acquisition. PMID- 29105933 TI - Sarcosine influences apoptosis and growth of prostate cells via cell-type specific regulation of distinct sets of genes. AB - BACKGROUND: Sarcosine is a widely discussed oncometabolite of prostate cells. Although several reports described connections between sarcosine and various phenotypic changes of prostate cancer (PCa) cells, there is still a lack of insights on the complex phenomena of its effects on gene expression patterns, particularly in non-malignant and non-metastatic cells. METHODS: To shed more light on this phenomenon, we performed parallel microarray profiling of RNA isolated from non-malignant (PNT1A), malignant (22Rv1), and metastatic (PC-3) prostate cell lines treated with sarcosine. Microarray results were experimentally verified using semi-quantitative-RT-PCR, clonogenic assay, through testing of the susceptibility of cells pre-incubated with sarcosine to anticancer agents with different modes of actions (inhibitors of topoisomerase II, DNA cross linking agent, antimicrotubule agent and inhibitor of histone deacetylases) and by evaluation of activation of executioner caspases 3/7. RESULTS: We identified that irrespective of the cell type, sarcosine stimulates up-regulation of distinct sets of genes involved in cell cycle and mitosis, while down-regulates expression of genes driving apoptosis. Moreover, it was found that in all cell types, sarcosine had pronounced stimulatory effects on clonogenicity. Except of an inhibitor of histone deacetylase valproic acid, efficiency of all agents was significantly (P < 0.05) decreased in sarcosine pre-incubated cells. CONCLUSIONS: Our comparative study brings evidence that sarcosine affects not only metastatic PCa cells, but also their malignant and non-malignant counterparts and induces very similar changes in cells behavior, but via distinct cell-type specific targets. PMID- 29105934 TI - Toward a Novel Drug To Target the EGF-EGFR Interaction: Design of Metabolically Stable Bicyclic Peptides. AB - In cancer, proliferation of malignant cells is driven by overactivation of growth signalling mechanisms, such as the epidermal growth factor receptor (EGFR) pathway. Despite its therapeutic relevance, the EGF-EGFR interaction has remained elusive to inhibition by synthetic molecules, mostly as a result of its large size and lack of binding pockets and cavities. Designed peptides, featuring cyclic motifs and other structural constraints, have the potential to modulate such challenging protein-protein interactions (PPIs). Herein, we present the structure-based design of a series of bicyclic constrained peptides that mimic an interface domain of EGFR and inhibit the EGF-EGFR interaction by targeting the smaller partner (i.e., EGF). This design process was guided by the integrated use of in silico methods and biophysical techniques, such as NMR spectroscopy and surface acoustic wave. The best analogues were able to reduce selectively the viability of EGFR+ human cancer cells. In addition to their efficacy, these bicyclic peptides are endowed with exceptional stability and metabolic resistance two features that make them suitable candidates for in vivo applications. PMID- 29105935 TI - Silique valves as sails in anemochory of Lunaria (Brassicaceae). AB - The generally held opinion that seeds of Lunaria remain at the replum after detachment of the two valves and then wind causes a shaking or rattling of the replum with its diaphragm, thus launching the seeds, is challenged. In a sparse forest in the Swabian Alb, the first author noticed flying valves of Lunaria rediviva to which the narrow-winged flat seeds are attached. Investigations with SEM and histology have shown that the valves secrete a glue only at those sites where the seeds rest on the valves before valve tissues die. Further analysis has shown (using the periodic acid-Schiff reaction) that the glue consists of polysaccharides. After detachment and dispersal of the valves, the adhesive strength continuously decreases. This is the first report for a sticky valve exudate in the Brassicaceae. Because of the adhesion of Lunaria seeds to their valves for some time, the 1st order diaspore is a mericarp, in a broad sense, and can be interpreted as an adaptation to long-distance dispersal by stronger winds. In this context, the 'flying carpets' of Lunaria are more effective and transport more than one seed. Molecular studies assigned Lunaria to the tribe Biscutelleae, which now contains the angustiseptate genera Biscutella and Megadenia as well as the latiseptate genera Lunaria and Ricotia. The valves in Ricotia can easily be detached (studied in herbarium material and a living plant), but, in contrast to Lunaria, the ripe seeds remain at the replum and its diaphragm, respectively. PMID- 29105936 TI - Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality. AB - BACKGROUND & AIMS: CXCR% ligands play an important role in hepatic injury, inflammation and fibrosis. While CXCL9 and CXCL11 are associated with survival in patients receiving transjugular intrahepatic portosystemic shunt (TIPS), the role of CXCL10 in severe portal hypertension remains unknown. METHODS: A total of 89 cirrhotic patients were analysed. CXCL10 protein levels were measured in portal and hepatic blood at TIPS insertion and 2 weeks later in 24 patients. CXCL10 and IL8 levels were assessed in portal, hepatic, cubital vein and right atrium blood in a further 25 patients at TIPS insertion. Furthermore, real-time PCR determined hepatic CXCL10-mRNA in 40 cirrhotic patients. RESULTS: Hepatic CXCL10 showed no association with decompensation. By contrast, circulating CXCL10-levels were higher in portal than in hepatic vein blood, suggesting an extrahepatic source of CXCL10 in cirrhosis. However, CXCL10 protein in blood samples from portal, hepatic, cubital veins and right atrium correlated excellently with each other and with IL-8 levels. Higher CXCL10 circulating levels were associated with presence of ascites and higher Child scores. Higher CXCL10 circulating protein levels were associated with acute decompensation, acute-on-chronic liver failure (ACLF) and independently with mortality. Moreover, a decrease in CXCL10 protein levels after TIPS insertion was associated with better survival in each cohort and analysed together. DISCUSSION: Circulating CXCL10 possibly reflects systemic inflammation and it is correlated with acute decompensation, ACLF and complications in patients with severe portal hypertension receiving TIPS. CXCL10 predicts survival in these patients and a decrease in CXCL10 after TIPS may be considered a good prognostic factor. PMID- 29105937 TI - Point-of-care testing facilitates screening and treatment for anaemia in women and children in rural Pakistan. AB - OBJECTIVE: To use point-of-care testing to screen and facilitate treatment for anaemia and to establish an estimate of the prevalence of anaemia in the local population. DESIGN: An uncontrolled before and after study design was used to evaluate the effectiveness of the intervention on the anaemia status of participants. SETTING: This study took place in a rural mountain community (population approximately 1000) in the Haripur district in northern Pakistan. PARTICIPANTS: Women of child-bearing age (15-49 years) and children (12-14 years) were included in this study. INTERVENTIONS: The intervention included point-of care testing for haemoglobin, treatment with mebendazole and oral iron supplementation, and an education campaign about anaemia delivered by community health workers and medical students. MAIN OUTCOME MEASURES: The main outcome measure was an increase in blood haemoglobin over the study period. A secondary outcome measure was a positive change in anaemia status or classification post intervention. RESULTS: Anaemia was initially detected in 64 (53%) women and 15 (47%) children. The mean haemoglobin concentration increased significantly (P < 0.001) from 118 to 130 g L-1 (women) and 120 to 130 g L-1 (children) post intervention. Overall prevalence of anaemia in women (P < 0.001) and children (P < 0.001) decreased significantly (by 30% and 34%, respectively) post intervention. CONCLUSIONS: Point-of-care testing used for the detection of anaemia in this rural community helped to identify the burden of disease and to reduce this significantly by way of rapid diagnosis, education and immediate medical intervention. PMID- 29105938 TI - Efficient Encapsulation of Fluorinated Drugs in the Confined Space of Water Dispersible Fluorous Supraparticles. AB - Fluorophobic-driven assemblies of gold nanomaterials were stabilized into water dispersible fluorous supraparticles by the film-forming protein hydrophobin II. The strategy makes use of fluorous nanomaterials of different dimensions to engineer size and inner functionalization of the resulting confined space. The inner fluorous compartments allow efficient encapsulation and transport of high loadings of partially fluorinated drug molecules in water. PMID- 29105939 TI - Are patients with concussion getting optimal discharge advice at a regional emergency department? PMID- 29105940 TI - The late-stage "ferruginization" of the Ediacara Member (Rawnsley Quartzite, South Australia): Insights from uranium isotopes. AB - The paleoenvironmental setting in which the Ediacara Biota lived, died, and was preserved in the eponymous Ediacara Member of the Rawnsley Quartzite of South Australia is an issue of long-standing interest and recent debate. Over the past few decades, interpretations have ranged from deep marine to shallow marine to terrestrial. One of the key features invoked by adherents of the terrestrial paleoenvironment hypothesis is the presence of iron oxide coatings, inferred to represent the upper horizons of paleosols, along fossiliferous sandstone beds of the Ediacara Member. We find that these surficial oxides are characterized by (234 U/238 U) values which are not in secular equilibrium, indicating extensive fluid-rich alteration of these surfaces within the past approximately 2 million years. Specifically, the oxide coatings are characterized by (234 U/238 U) values >1, indicating interaction with high-(234 U/238 U) fluids derived from alpha recoil discharge. These oxides are also characterized by light "stable" delta238/235 U values, consistent with a groundwater U source. These U isotope data thus corroborate sedimentological observations that ferric oxides along fossiliferous surfaces of the Ediacara Member consist of surficial, non-bedform parallel staining, and sharply irregular patches, strongly reflecting post depositional, late-stage processes. Therefore, both sedimentological and geochemical evidence indicate that Ediacara iron oxides do not reflect synsedimentary ferruginization and that the presence of iron oxides cannot be used to either invoke a terrestrial paleoenvironmental setting for or reconstruct the taphonomic pathways responsible for preservation of the Ediacara Biota. These findings demonstrate that careful assessment of paleoenvironmental parameters is essential to the reconstruction of the habitat of the Ediacara Biota and the factors that led to the fossilization of these early complex ecosystems. PMID- 29105941 TI - Assessment and manifestation of central sensitisation across different chronic pain conditions. AB - : Different neuroplastic processes can occur along the nociceptive pathways and may be important in the transition from acute to chronic pain and for diagnosis and development of optimal management strategies. The neuroplastic processes may result in gain (sensitisation) or loss (desensitisation) of function in relation to the incoming nociceptive signals. Such processes play important roles in chronic pain, and although the clinical manifestations differ across condition processes, they share some common mechanistic features. The fundamental understanding and quantitative assessment of particularly some of the central sensitisation mechanisms can be translated from preclinical studies into the clinic. The clinical perspectives are implementation of such novel information into diagnostics, mechanistic phenotyping, prevention, personalised treatment, and drug development. The aims of this paper are to introduce and discuss (1) some common fundamental central pain mechanisms, (2) how they may translate into the clinical signs and symptoms across different chronic pain conditions, (3) how to evaluate gain and loss of function using quantitative pain assessment tools, and (4) the implications for optimising prevention and management of pain. The chronic pain conditions selected for the paper are neuropathic pain in general, musculoskeletal pain (chronic low back pain and osteoarthritic pain in particular), and visceral pain (irritable bowel syndrome in particular). The translational mechanisms addressed are local and widespread sensitisation, central summation, and descending pain modulation. SIGNIFICANCE: Central sensitisation is an important manifestation involved in many different chronic pain conditions. Central sensitisation can be different to assess and evaluate as the manifestations vary from pain condition to pain condition. Understanding central sensitisation may promote better profiling and diagnosis of pain patients and development of new regimes for mechanism based therapy. Some of the mechanisms underlying central sensitisation can be translated from animals to humans providing new options in development of therapies and profiling drugs under development. PMID- 29105942 TI - The prevalence, incidence, and gender and age-specific incidence of problem gambling: results of the Swedish longitudinal gambling study (Swelogs). AB - AIMS: To estimate the prevalence, incidence and gender and age-specific incidence of problem gambling in the Swedish adult population. DESIGN: Longitudinal cohort study with linkage to register data. SETTING: Sweden. PARTICIPANTS: Stratified random sample aged 16-84 years at baseline (n = 8165) re-assessed a year later (n = 6021). MEASUREMENTS: Problem gambling (life-time and past 12 months) was measured by the South Oaks Gambling Screen-Revised (SOGS-R). Past 12-month (current) problem gambling was also measured by the Problem Gambling Severity Index (PGSI). FINDINGS: The SOGS-R combined current pathological and problem gambling prevalence rate (PR) was 2.1 [95% confidence interval (CI) = 1.8-2.4] at baseline and 1.7 (1.4-2.0) at follow-up, approximately half the corresponding life-time estimates.[Correction added on 22 Dec 2017, after first online publication: In the preceding sentence, the SOGS-R combined current pathological and problem gambling prevalence rate (PR) was incorrectly reported as being double the corresponding life-time rate. It has been corrected in this version.] PGSI combined current problem and moderate-risk gambling PRs were 2.2 (1.9-2.5) at baseline and 1.9 (1.6-2.2) at follow-up. Combined incidence rates (IRs) were 1.0 (0.8-1.3) (SOGS-R) and 1.4 (1.1-1.7) (PGSI), with more than three-quarters being new cases. While first-time IRs did not vary by gender, males had a higher relapse IR and proportionately more females were new cases. The young adult IR was more than double the older adult IR; similar proportions were new cases. CONCLUSIONS: The actual incidence of problem gambling relapse in Sweden is likely to be higher than estimated. The profile of problem gambling in Sweden is likely to change over time, with increased proportions of women and older adults. PMID- 29105943 TI - Characterization of printed PLA scaffolds for bone tissue engineering. AB - Autografts remain the gold standard for orthopedic transplantations. However, to overcome its limitations, bone tissue engineering proposes new strategies. This includes the development of new biomaterials such as synthetic polymers, to serve as scaffold for tissue production. The objective of this present study was to produce poly(lactic) acid (PLA) scaffolds of different pore size using fused deposition modeling (FDM) technique and to evaluate their physicochemical and biological properties. Structural, chemical, mechanical, and biological characterizations were performed. We successfully fabricated scaffolds of three different pore sizes. However, the pore dimensions were slightly smaller than expected. We found that the 3D printing process induced decreases in both, PLA molecular weight and degradation temperatures, but did not change the semicrystalline structure of the polymer. We did not observe any effect of pore size on the mechanical properties of produced scaffolds. After the sterilization by gamma irradiation, scaffolds did not exhibit any cytotoxicity towards human bone marrow stromal cells (HBMSC). Finally, after three and seven days of culture, HBMSC showed high viability and homogenous distribution irrespective of pore size. Thus, these results suggest that FDM technology is a fast and reproducible technique that can be used to fabricate tridimensional custom-made scaffolds for tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 887-894, 2018. PMID- 29105944 TI - Design of a Hypersensitive pH-Sensory System Created by a Combination of Charge Neutralization and Aggregation-Induced Emission (AIE). AB - In our bodies, a slight pH change causes remarkable activation or serious damage in the biological processes and continuously keeps biological homeostasis. Detection of such a slight pH change has been a constant demand in searching for unusual biological events. In this paper, we demonstrate a novel pH sensory system that has been achieved through a combination of charge neutralization by a slight pH change with aggregation-induced emission (AIE). We selected a cyano functionalized oligo(phenylene-vinylene) (cyanoOPV) backbone for AIE and introduced ammonium-tethered boronic acid groups as a pH-dependent function. The self-assembling of these dyes (OPV-Cn) was readily achieved by pH-dependent charge neutralization at the neutral pH region. This sensory system showed unusually sensitive pH responsiveness in a narrow pH range. Moreover, this pH change was observed in a biologically important neutral pH region. We therefore believe that this system is broadly applicable to detect the slight pH change occurring in the biological events. PMID- 29105945 TI - Role of BMI and age in predicting pathologic vertebral fractures in newly diagnosed multiple myeloma patients: A retrospective cohort study. AB - Vertebral fractures affect approximately 30% of myeloma patients and lead to a poor impact on survival and life quality. In general, age and body mass index (BMI) are reported to have an important role in vertebral fractures. However, the triangle relationship among age, BMI, and vertebral fractures is still unclear in newly diagnosed multiple myeloma (NDMM) patients. This study recruited consecutive 394 patients with NDMM at Taipei Veterans General Hospital between January 1, 2005 and December 31, 2015. Risk factors for vertebral fractures in NDMM patients were collected and analyzed. The survival curves were demonstrated using Kaplan-Meier estimate. In total, 301 (76.4%) NDMM patients were enrolled in the cohort. In the median follow-up period of 18.0 months, the median survival duration in those with vertebral fractures >= 2 was shorter than those with vertebral fracture < 2 (59.3 vs 28.6 months; P = 0.017). In multivariate Poisson regression, BMI < 18.5 kg/m2 declared increased vertebral fractures compared with BMI >= 24.0 kg/m2 (adjusted RR, 2.79; 95% CI, 1.44-5.43). In multivariable logistic regression, BMI < 18.5 kg/m2 was an independent risk factor for vertebral fractures >= 2 compared with BMI >= 24.0 kg/m2 (adjusted OR, 6.05; 95% CI, 2.43-15.08). Among age stratifications, patients with both old age and low BMI were at a greater risk suffering from increased vertebral fractures, especially in patients > 75 years and BMI < 18.5 kg/m2 (adjusted RR, 12.22; 95% CI, 3.02-49.40). This is the first study that demonstrated that age had a significant impact on vertebral fractures in NDMM patients with low BMI. Elder patients with low BMI should consider to routinely receive spinal radiographic examinations and regular follow-up. PMID- 29105946 TI - Impact of in-hospital blood pressure variability on cardiovascular outcomes in patients with acute coronary syndrome. AB - To evaluate the impact of blood pressure variability (BPV) on cardiovascular outcomes in patients with acute coronary syndrome, short-term BPV was estimated by using weighted standard deviation of 24-hour ambulatory blood pressure monitoring readings. The primary outcome was in-hospital major adverse cardiac events (MACE). Overall, 200 patients (mean age, 58.6 years; 27.5% women; 38% with diabetes mellitus; and 47% smokers) were divided into low and high BPV groups based on the median value (9.45). Patients in the high BPV group were more likely to have in-hospital MACE compared with patients with low BPV (47% vs 27%, P = .003). Multivariate binary logistic regression analysis of incidence of MACE showed that BPV (odds ratio, 2.4; confidence interval, 1.2-4.5 [P = .008]) and presence of type II diabetes mellitus (odds ratio, 2.6; confidence interval, 1.2 5.3 [P = .008]) were the only independent predictors of in-hospital MACE derived mainly by hypertensive emergencies. BPV could be an important risk factor for in hospital MACE in patients with acute coronary syndrome. PMID- 29105947 TI - Inversion of Bicyclic Decanes: Rotational Spectra of the Trans and Double Cis Conformations of 2-Decalone. AB - The conformational landscape of the bicyclic molecule 2-decalone has been studied in a jet-cooled expansion by using rotational spectroscopy. The investigation covered the frequency region 7-19 GHz using broadband fast-passage IMPACT Fourier transform microwave techniques. The introduction of the asymmetric carbonyl substituent in the double-chair decalin skeleton originates two distinct inverting conformers with cis ring junction, which were independently identified and characterized in the gas phase. Additionally, a single trans conformer was detected, as expected for the non-inverting equatorial ring junction. Accurate rotational parameters and quartic centrifugal distortion constants have been determined for the three observed species. A population estimation is given for the observed conformations based on relative intensities. Supporting ab initio calculations up to MP2/cc-pVTZ complement the experimental work. PMID- 29105948 TI - The importance of the TOR kinase growth regulator for seed development. PMID- 29105949 TI - A model for predicting the dose to the parotid glands based on their relative overlapping with planning target volumes during helical radiotherapy. AB - The sparing of the parotid glands in the treatment of head and neck cancers is of clinical relevance as high doses to the salivary glands may result in xerostomia. Xerostomia is a major cause of decreased quality of life for head and neck patients. This paper explores the relationship between the overlap of the target volumes and their expansions with the parotid glands for helical delivery plans and their ability to be spared. Various overlapping volumes were examined, and an overlap with a high statistical relevance was found. A model that predicts exceeding tolerance parotid mean dose based on its fractional overlapping volume with PTVs was developed. A fractional overlapping volume of 0.083 between the parotid gland and the high dose PTV plus 5 mm expansion - was determined to be the threshold value to predict parotid Dmean > 26 Gy for parotids that overlap with the high dose PTV plus 5 mm expansion. If the parotid gland only overlaps with the intermediate dose target (and/or low dose target) and the overlapping volume of the parotid gland and the intermediate dose target is less than 25%, the parotid mean dose is likely less than 26 Gy. If the parotid overlaps with the low dose target only then the mean dose to the parotid is likely to be less than 26 Gy. This finding will prove as a very useful guide for the physicians and planners involved in the planning process to know prior whether the parotid glands will be able to be spared with the current set of target volumes or if revisions are necessary. This work will serve as a helpful guide in the planning process of head and neck target cases. PMID- 29105950 TI - A probabilistic risk assessment for the Kirtland's warbler potentially exposed to chlorpyrifos and malathion during the breeding season and migration. AB - Two organophosphate pesticides, chlorpyrifos and malathion, are currently undergoing reregistration in the United States and were recently used by the US Environmental Protection Agency (USEPA) as case studies to develop a national procedure for evaluating risks to endangered species. One of the endangered bird species considered by the USEPA was the Kirtland's warbler (Setophaga kirtlandii). The Kirtland's warbler is an endangered migratory species that nests exclusively in young jack pine stands in Michigan and Wisconsin, and winters in the Bahamas. We developed probabilistic models to assess the risks of chlorpyrifos and malathion to Kirtland's warblers during the breeding season and the spring and fall migrations. The breeding area model simulates acute and chronic exposure and risk to each of 10 000 birds over a 60-d period following initial pesticide application. The model is highly species specific with regard to the foraging behavior of Kirtland's warblers during the breeding season. We simulated the maximum application rate and number of applications allowed on the labels for representative use patterns that could be found within 3 km of the breeding areas of Kirtland's warbler. The migration model simulates 10 000 birds during the course of their 12- to 23-d migration between their breeding area and the Bahamas. The model takes advantage of more than a century of observations of when, where, and for how long Kirtland's warblers forage in different habitats during the course of their migration. The data indicate that warblers only infrequently stop over in habitats that could be treated with chlorpyrifos and malathion. The breeding area and migration models resulted in predictions of very low acute and chronic risk for both pesticides to Kirtland's warblers. These results were expected, given that field observations indicate that the Kirtland's warbler has dramatically increased in abundance in recent decades. Integr Environ Assess Manag 2018;14:252-269. (c) 2017 SETAC. PMID- 29105951 TI - Intra-operative radiotherapy management for breast cancer treatment in patients with pseudoxanthoma elasticum: A case report. AB - Pseudoxanthoma elasticum is a systemic metabolic disease presenting calcifications and progressive fragmentation of elastic fibers. Actually, no targeted therapies are available for the treatment; only prevention of complications is possible. Classically, pseudoxanthoma elasticum is a "benign" disease, without cancer association. Herein, we reported a singular association of pseudoxanthoma elasticum with breast carcinoma, describing the clinical management, in particular intra-operative treatment, focusing on intra-operative radiotherapy since no specific guidelines are available in literature. PMID- 29105952 TI - Congenital factor V deficiency and decreased VWF in a Chinese male patient with hematuria. PMID- 29105953 TI - Comparison of self-expanding and balloon-expandable transcatheter aortic valves morphology and association with paravalvular regurgitation: Evaluation using multidetector computed tomography. AB - OBJECTIVES: Compare final morphology of self-expanding and balloon-expandable prosthesis and association with paravalvular regurgitation (PVR). BACKGROUND: PVR after transcatheter aortic valve replacement (TAVR) remains a frequent complication. A better understanding of the prosthesis geometry may be important to improve selection of the best device for each case and possibly reduce the rates of PVR. METHODS: Retrospective study including patients consecutively submitted to transcatheter aortic valve replacement: August/2007-October/2016. Three months after the procedure a multidetector computed tomography (MDCT) was performed to assess prosthesis geometry: dimensions, eccentricity, and expansion. RESULTS: A total of 147 individuals were included (mean age of 78.8 +/- 6.7 and 50.3% males), 57% treated with a self-expanding prosthesis. On the postprocedure MDCT, the self-expanding group had higher eccentricity index (15.0 vs. 7.1%, p < .001) and lower expansion (68.3 vs. 82.8%, p < .001). In that group, the volume of calcium of landing zone had a significant correlation with eccentricity index and under-expansion. Patients with >=mild PVR presented higher eccentricity (12.6 vs. 7.9%, p < .001) and lower expansion (68 vs. 75%, p = .012). Eccentricity index and landing zone calcium volume were independent predictors of PVR. CONCLUSIONS: Self-expanding prosthesis have greater eccentricity and under expansion. Calcium burden exerts more influence in the final morphology of that type of valve. Calcification and eccentricity are associated with the development of PVR. These factors should be considered in the selection of the most appropriate type of prosthesis for each scenario. PMID- 29105954 TI - Comparison of different cryopreservation methods for horse and donkey embryos. AB - BACKGROUND: Few studies have been published about cryopreservation and embryo assessment in horses and donkeys. OBJECTIVES: To evaluate the viability of embryos collected from mares and jennies that were cryopreserved by slow freezing or by vitrification. STUDY DESIGN: Randomised controlled experiment. METHODS: Horse (n=19) and donkey (n=16) embryos (<=300 MUm) were recovered on days 6.5-7.5 post-ovulation and assigned to control or cryopreservation protocols of slow freezing or vitrification. For slow freezing, 1.5 mol/L ethylene glycol (EG) was used. For vitrification, horse embryos were exposed to 1.4 mol/L glycerol, 1.4 mol/L glycerol + 3.6 mol/L EG and 3.4 mol/L glycerol + 4.6 mol/L EG, using Fibreplug or a 0.25 mL straw; donkey embryos were vitrified using Fibreplug with similar EG-glycerol solutions to above or 7.0 mol/L EG. Dead cells, apoptotic and fragmented nuclei, and cytoskeleton quality were assessed on thawed/warmed embryos. RESULTS: A significant decrease in embryo quality was observed after cryopreservation (P<0.05). Although the percentage of dead cells was lower (P<0.05) in control than in cryopreserved embryos, no differences were observed between freezing protocols used for horse or donkey embryos. While no differences were detected in the number of apoptotic cells in warmed horse embryos, in donkey embryos a higher incidence of apoptosis was measured after vitrification with EG glycerol in Fibreplug (P<0.05). Vitrified horse embryos had a significantly (P<0.05) higher percentage of nonviable cells than donkey embryo. Actin cytoskeleton quality did not differ between treatments. MAIN LIMITATIONS: Difficulties in obtaining a large number of embryos meant that the number of embryos per group was low. CONCLUSIONS: Vitrified horse and donkey embryos did not show higher susceptibility to cell damage than those preserved by slow freezing, whether using straws or Fibreplug. However, Fibreplug with EG 7 mol/L resulted in fewer nonviable and apoptotic cells in donkey embryos. Donkey embryos showed lower susceptibility to vitrification than horse embryos. THE SUMMARY IS AVAILABLE IN SPANISH - SEE SUPPORTING INFORMATION. PMID- 29105955 TI - Right ventricular systolic function and mechanical dispersion identify patients with arrhythmogenic right ventricular cardiomyopathy. AB - PURPOSE: To assess right ventricular (RV) regional and global systolic function using feature tracking (FT) in patients with a definite diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) and to investigate if changes in strain amplitude and mechanical dispersion indicate a propensity for arrhythmia. MATERIALS AND METHODS: Twenty-seven patients fulfilling Task Force Criteria for ARVC and 24 healthy volunteers underwent MR at 1.5 Tesla. Steady state free precession cine of long-axis slices and a short-axis stack of the RV was acquired. Segmental longitudinal systolic strain amplitude and time-to-peak (TTP) strain were measured in the four- and two-chamber views of the RV. RESULTS: Compared to controls, patients with ARVC had lower RV ejection fraction (RVEF), (53% vs 57%, P = 0.012) and lower longitudinal strain amplitude in the RV free wall (-20.6 vs -26.3%, P = 0.014) and in the basal part of the RV (-22.8 vs 31.7%, P<0.001). Mechanical dispersion, defined as the standard deviation (SD) of TTP of RV segments, was larger in patients with ARVC (48 ms [21-74] vs 35 ms [13 66 ms], P = 0.02). Patients with ventricular tachycardia (VT) or non-sustained VT had lower RVEF (46% vs 55%, P = 0.008), but did not have significantly lower RV strain amplitude (-19.5% vs 21.0%, P = 0.073) and no signs of mechanical dispersion (49 ms vs 48 ms, P = 0.861) compared to patients without arrhythmia. CONCLUSION: ARVC patients had lower longitudinal absolute strain amplitude in basal RV segments and increased mechanical dispersion compared to healthy volunteers, but the presence of mechanical dispersion was not predictive of ventricular arrhythmia. PMID- 29105956 TI - Response to Letter to the Editor The Contribution of the Emergency Department to Opioid Pain Reliever Misuse and Diversion: A Critical Review. PMID- 29105957 TI - Supplementary choline attenuates olive oil lipid emulsion-induced enterocyte apoptosis through suppression of CELF1/AIF pathway. AB - Enterocyte apoptosis induced by lipid emulsions is a key cause of intestinal atrophy under total parenteral nutrition (TPN) support, and our previous work demonstrated that olive oil lipid emulsion (OOLE) could induce enterocyte apoptosis via CUGBP, Elav-like family member 1 (CELF1)/ apoptosis-inducing factor (AIF) pathway. As TPN-associated complications are partially related to choline deficiency, we aimed to address whether choline supplementation could attenuate OOLE-induced enterocyte apoptosis. Herein we present evidence that supplementary choline exhibits protective effect against OOLE-induced enterocyte apoptosis both in vivo and in vitro. In a rat model of TPN, substantial reduction in apoptotic rate along with decreased expression of CELF1 was observed when supplementary choline was added to OOLE. In cultured Caco-2 cells, supplementary choline attenuated OOLE-induced apoptosis and mitochondria dysfunction by suppressing CELF1/AIF pathway. Compared to OOLE alone, the expression of CELF1 and AIF was significantly decreased by supplementary choline, whereas the expression of Bcl-2 was evidently increased. No obvious alterations were observed in Bax expression and caspase-3 activation. Mechanistically, supplementary choline repressed the expression of CELF1 by increasing the recruitment of CELF1 mRNA to processing bodies, thus resulting in suppression of its protein translation. Taken together, our data suggest that supplementary choline exhibits effective protection against OOLE-induced enterocyte apoptosis, and thus, it has the potential to be used for the prevention and treatment of TPN-induced intestinal atrophy. PMID- 29105958 TI - Additivity of nebivolol/valsartan single-pill combinations versus other single pill combinations for hypertension. AB - The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory beta1 -selective antagonist/beta3 -agonist, and valsartan (80 mg), a renin angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved beta-blocker/renin-angiotensin-aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration-approved non-beta-blocker/renin angiotensin-aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo-adjusted SPC blood pressure (BP) reduction to the placebo-adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735-0.866; systolic BP range: 0.717-0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non-beta-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable. PMID- 29105959 TI - Design of a software for calculating isoelectric point of a polypeptide according to their net charge using the graphical programming language LabVIEW. AB - A software to calculate the net charge and to predict the isoelectric point (pI) of a polypeptide is developed in this work using the graphical programming language LabVIEW. Through this instrument the net charges of the ionizable residues of the polypeptide chains of the proteins are calculated at different pH values, tabulated, pI is predicted and an Excel (-xls) type file is generated. In this work, the experimental values of the pIs (pI) of different proteins are compared with the values of the pIs (pI) calculated graphically, achieving a correlation coefficient (R) of 0.934746 which represents a good reliability for a p < 0.01. In this way the generated program can constitute an instrument applicable in the laboratory, facilitating the calculation to graduate students and junior researchers. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):39-46, 2018. PMID- 29105960 TI - Record High-Nuclearity Polyoxoniobates: Discrete Nanoclusters {Nb114 }, {Nb81 }, and {Nb52 }, and Extended Frameworks Based on {Cu3 Nb78 } and {Cu4 Nb78 }. AB - A series containing the highest nuclearity polyoxoniobate (PONb) nanoclusters, ranging from dimers to tetramers, has been obtained. They include one 114-nuclear {Li8 ?Nb114 O316 }, one 81-nuclear {Li3 K?Nb81 O225 }, and one 52-nuclear {H4 Nb52 O150 }. The Nb nuclearity of these PONbs is remarkably larger than those of all known high-nuclearity PONbs (<=32). Furthermore, the introduction of 3d Cu2+ ions can lead to the generation of extended inorganic-organic hybrid frameworks built from novel, high-nuclearity, nanoscale heterometallic PONb building blocks {H3 Cu3 Nb78 O222 } or {H3 Cu4 (en)Nb78 O222 }. These building blocks also contain the largest number of Nb centers of any heterometallic PONbs reported to date. The synthesis of new-type PONbs has long been a challenging subject in PONb chemistry. PMID- 29105961 TI - Ultrasound and hematological changes during early luteal phase in women at high risk for developing ovarian hyperstimulation syndrome. AB - OBJECTIVE: To assess ultrasound and hematological changes during the early luteal phase following triggering of final oocyte maturation with human chorionic gonadotropin (hCG) in women at high risk for developing ovarian hyperstimulation syndrome (OHSS). METHODS: This was a retrospective cohort study of 319 women undergoing in-vitro fertilization who were at high risk for OHSS following administration of hCG for the triggering of final oocyte maturation. Patients were treated with a gonadotropin-releasing hormone agonist or antagonist protocol and were monitored for 5 days post-oocyte retrieval (early luteal phase). Severe OHSS was diagnosed in the presence of at least moderate ascites and two or more of the following: maximum ovarian diameter (MOD) > 100 mm, hematocrit (Ht) > 45%, white blood cell count (WBC) > 15 000/mm3 , hydrothorax, dyspnea and oliguria. Outcome measures included change in Ht, ascites grade, WBC and MOD, as well as the association between these changes during the early luteal phase. RESULTS: Ascites grade, Ht and WBC increased significantly (P <= 0.001) during the early luteal phase, both in patients who developed and in those who did not develop severe early OHSS. MOD increased significantly (P = 0.001) only in patients who developed severe early OHSS. On multivariable analysis, both time following oocyte retrieval and whether severe early OHSS developed were significantly associated with ascites grade, Ht, WBC and MOD; furthermore, there was also a significant interaction between time and development of severe early OHSS for all four variables (P <= 0.001). CONCLUSIONS: In women at high risk of OHSS, ascites grade, Ht and WBC significantly increased with time over the 5-day observation period, in line with the pathophysiology of the syndrome. Our data support the use of MOD in the diagnosis of severe early OHSS, and provide novel evidence for the role of change in Ht as a patient-specific hemoconcentration marker during development of OHSS. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29105962 TI - Identification of Salvia species using high-performance liquid chromatography combined with chemical pattern recognition analysis. AB - Salvia miltiorrhiza, also known as Danshen, is a widely used traditional Chinese medicine for the treatment of cardiovascular diseases and hematological abnormalities. The root and rhizome of Salvia przewalskii and Salvia yunnanensis have been found as substitutes for Salvia miltiorrhiza in the market. In this study, the chemical information of 14 major compounds in Salvia miltiorrhiza and its substitutes were determined using a high-performance liquid chromatography method. Stepwise discriminant analysis was adopted to select the characteristic variables. Partial least squares discriminant and hierarchical cluster analysis were performed to classify Salvia miltiorrhiza and its substitutes. The results showed that all of the samples were correctly classified both in partial least squares discriminant analysis and hierarchical cluster analysis based on the four compounds (caffeic acid, rosmarinic acid, salvianolic acid B, and salvianolic acid A). This method can not only distinguish Salvia miltiorrhiza and its substitutes, but also classify Salvia przewalskii and Salvia yunnanensis. The method can be applied for the quality assessment of Salvia miltiorrhiza and identification of unknown samples. PMID- 29105963 TI - Does the use of pretreatment MRI change the management of patients with newly diagnosed breast cancer? AB - Breast MRI plays a critical role in the diagnosis and management of breast cancer. The purpose of this study is to evaluate the effect of preoperative breast MRI on the management of a large cohort of breast cancer patients at our institution. This study is a retrospective chart review of all newly diagnosed breast cancer patients who underwent preoperative breast MRI at our institution between January 1, 2004 and December 31, 2009. 1352 patients comprised the study population. 241 (17.8%) patients underwent a change in surgical management as a result of preoperative MRI. Patients with tumors in the lower inner quadrant and the central breast and those with pathology of invasive lobular carcinoma were significantly more likely to have their management changed by preoperative MRI. There was also a significant trend for larger tumors to be associated with a change in surgical management. No statistically significant association was found between breast density and change in management. This study supports the recommendation for the use of preoperative breast MRI in the majority of newly diagnosed breast cancer patients, especially those with larger tumors, pathology of invasive lobular carcinoma, and tumors in the lower inner quadrant. Preoperative breast MRI is a useful tool for the evaluation of additional disease that led to a change in the surgical management of 17.8% of patients. PMID- 29105964 TI - Simultaneous transcatheter transfemoral aortic and transeptal mitral valve replacement using Edward SAPIEN S3. AB - Patients with concomitant severe aortic stenosis (AS) and severe mitral stenosis (MS) with mitral annular calcification (MAC) constitute an elderly high-risk population with multiple baseline comorbidities that coexist even before they develop severe valvular dysfunction. Transcatheter mitral valve replacements (TMVR) offer an alternative option for high-risk patient with severe MS with MAC. A simultaneous transfemoral Transcatheter aortic valve replacement (TAVR) and transseptal TMVR is feasible and offers the least invasive approach of management. We are reporting a case of an 83-year-old man with very symptomatic severe AS and severe native MS with associated severe MAC and moderate mitral regurgitation with high STS score who underwent a simultaneous transfemoral TAVR and transseptal TMVR with good results and great improvement in symptoms that was maintained on 10 months follow-up. PMID- 29105965 TI - A Thermophilic Tetramolecular G-Quadruplex/Hemin DNAzyme. AB - The quadruplex-based DNAzyme system is one of the most useful artificial enzymes or catalysts; their unique properties make them reliable alternatives to proteins for performing catalytic transformation. The first prototype of a thermally stable DNAzyme system is presented. This thermophilic DNAzyme is capable of oxidizing substrates at high temperatures (up to 95 degrees C) and long reaction times (up to 18 h at 75 degrees C). The catalytic activity of the DNAzymes were investigated with the standard peroxidase-mimicking oxidation of 2,2'-azino-bis(3 ethylbenzothiozoline-6-sulfonic acid) (ABTS) by H2 O2 . The step-by-step design of this unique heat-activated G-quadruplex/hemin catalyst, including the modification of adenines at both ends of G-tracts, the choice of cation, and its concentration for DNAzyme stabilization, is described. This work investigates thoroughly the molecular basis of these catalytic properties and provides an example of an industrially relevant application. PMID- 29105967 TI - National study shows that abusive head trauma mortality in Sweden was at least 10 times lower than in other Western countries. AB - AIM: The validity of the diagnostic criteria for abusive head trauma (AHT) and its attributes has been widely debated. This national study investigated the possibility of false-positive and false-negative cases of fatal AHT in Sweden. METHOD: This was a retrospective evaluation of the records of 733 deceased infants up to the age of 365 days who were examined during 1994-2013 at the six forensic medicine departments. All the records were scrutinised for possible cases of AHT. RESULTS: We included 12 cases, of which eight had been diagnosed as AHT. Of these 12 infants, eight had a concomitant disease or perinatal illness, five were born prematurely and three were twins. Figures from other Western countries would suggest 6-7 deaths per 100,000 per year in Sweden, but in reality, there was a maximum possible incidence of 0.6 per 100,000 infants per year. CONCLUSION: The risk of unreported fatal AHT in Sweden was low, and there may have been cases misdiagnosed as AHT. The at least 10 times lower incidence than has been reported from other Western countries, raises the question if previously reported higher incidences of fatal AHT have been exaggerated. PMID- 29105966 TI - The effectiveness of interventions using relaxation therapy to improve breastfeeding outcomes: A systematic review. AB - Maternal psychological state is recognised to influence lactation success, largely by affecting milk ejection. Thus, increased psychological distress can disrupt milk flow and in the long-term, affect milk synthesis. Conversely, it is possible that milk ejection could be improved by using relaxation therapy during breastfeeding. We performed a systematic review to evaluate the effectiveness of interventions using relaxation therapy to improve breastfeeding outcomes and to assess the consequent impact(s) on infant growth and behaviour. A literature search was performed using the PRISMA guidelines where we included intervention studies (including nonrandomised controlled studies) using relaxation therapy in breastfeeding mothers during the post-natal period. Out of 147 identified records at the initial search, 5 studies were eligible, of which 3 were randomised controlled trials and 2 were nonrandomised or quasi-experimental studies. These studies were conducted in Europe, America, and India and included 311 mother infant pairs, of which 64 infants were full-term and 247 were premature infants. Relaxation therapy was shown to increase milk yield in mothers of preterm infants in 2 randomised trials, however, the milk sampling protocol for these studies could be questioned. None of the studies investigated the consequent effects on infant outcomes. Overall, limited evidence was found on the effectiveness of relaxation therapy on breast milk composition and infant outcomes. Experimental studies with better standardisation of protocol and robust methodological design are needed to investigate the effectiveness of relaxation therapy on both breastfeeding and infant growth and behavioural outcomes. PMID- 29105968 TI - Reports of adverse health effects related to synthetic cannabinoid use in New York State. AB - BACKGROUND/OBJECTIVES: We assessed synthetic cannabinoid (SC) outbreaks from 2011 2012 and 2015. METHODS: The National Poison Data System was utilized to collect reports of SC adverse effects in New York State from 2011-2012 and 2015 (N = 713). RESULTS: Cases from 2015 were more likely to be admitted to intensive care units and had different symptoms than those in 2011-2012. We identified two new SC structural classes from 2015 samples. DISCUSSION/CONCLUSIONS: The 2015 outbreak was associated with more severe SC-related illnesses than in 2011-2012. SCIENTIFIC SIGNIFICANCE: New SC compounds may pose a different or more severe risk than those previously identified. (Am J Addict 2017;26:772-775). PMID- 29105969 TI - Physiological and ultrastructural characterisation of a desiccation-tolerant filmy fern, Hymenophyllum caudiculatum: Influence of translational regulation and ABA on recovery. AB - The filmy fern Hymenophyllum caudiculatum can lose 60% of its relative water content, remain dry for some time and recover 88% of photochemical efficiency after 30 min of rehydration. Little is known about the protective strategies and regulation of the cellular rehydration process in this filmy fern species. The aim of this study was to characterise the filmy fern ultrastructure during a desiccation-rehydration cycle, and measure the physiological effects of transcription/translation inhibitors and ABA during desiccation recovery. Confocal and transmission electron microscopy were used to compare changes in structure during fast or slow desiccation. Transcription (actinomycin D) and translation (cycloheximide) inhibitors and ABA were used to compare photochemical efficiency during desiccation recovery. Cell structure was conserved during slow desiccation and rehydration, constitutive properties of the cell wall, allowing invagination and folding of the membranes and an important change in chloroplast size. The use of a translational inhibitor impeded recovery of photochemical efficiency during the first 80 min of rehydration, but the transcriptional inhibitor had no effect. Exogenous ABA delayed photochemical inactivation, and endogenous ABA levels decreased during desiccation and rehydration. Frond curling and chloroplast movements are possible strategies to avoid photodamage. Constitutive membrane plasticity and rapid cellular repair can be adaptations evolved to tolerate a rapid recovery during rehydration. Further research is required to explore the importance of existing mRNAs during the first minutes of recovery, and ABA function during desiccation of H. caudiculatum. PMID- 29105970 TI - Effects of platelet-rich plasma on biological activity and bone regeneration of brushite-based calcium phosphate cement. AB - In this study, we focused on identifying the effects of platelet-rich plasma (PRP) on bioactivity and bone ingrowths incorporated into brushite cement. We introduced PRP as a series of substitutions with an aqueous citrate-ion solution, and the optimized cement with PRP showed no disintegration of the paste consistency. Incorporating PRP showed that the setting time decreased with the increasing of PRP ratios, although the compressive strength was not significantly changed. We evaluated in vitro degradation and bioactivity with the simulated body fluid test, and the result showed that adding PRP accelerated the carbonated apatite nucleation and markedly improved the surface reactivity of the cement. The in vitro studies demonstrated that incorporating PRP into the brushite cement improved cell adhesion and proliferation. The in vivo effects of PRP were faster degradation, improved tissue response in the early stage, and bone ingrowths. We demonstrated based on our results of this study, incorporation of PRP into brushite cement could be helpful for improving biological activity of the cement as well as bone regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2316-2326, 2018. PMID- 29105971 TI - Home-Based Tactile Discrimination Training Reduces Phantom Limb Pain. AB - BACKGROUND: Phantom limb pain (PLP) affects a high percentage of amputees. Since treatment options are limited, low quality of life and addiction to pain medication frequently occur. New treatments, such as mirror therapy or electrical sensory discrimination training, make use of the brain's plasticity to alleviate this centrally derived pain. AIM: This pilot study assessed the question of whether home-based tactile discrimination training (TDT) leads to a stronger decrease in PLP levels compared to standard massage treatment. DESIGN: Controlled study. SETTING: Outpatient. POPULATION: Amputees (upper/lower extremity) with a PLP score of 4 or higher out of a possible 10 points on the visual analog scale. METHODS: Eight patients participated in the study. The treatment phase comprised 2 weeks (15 minutes daily). Subjects were examined at baseline, after treatment, 2 weeks after completing treatment, and 4 weeks after completing treatment. Pain was assessed using the West Haven-Yale Multidimensional Pain Inventory. RESULTS: There was a significantly stronger reduction in PLP in the treatment group receiving TDT. PLP intensity ratings were significantly reduced at the end of therapy, and at 2 and 4 weeks after completing treatment compared to pretreatment. CONCLUSIONS: TDT seems to be an easy, cheap, time-effective, and safe method to achieve sustained alleviation of PLP and also brings about a positive change in body image. REHABILITATION IMPACT: Home-based TDT could achieve a sustained reduction in PLP and should be considered as a possible alternative to established treatment methods. PMID- 29105972 TI - Sterilization effects on ultrathin film polymer coatings for silicon-based implantable medical devices. AB - Novel biomaterials for medical device applications must be stable throughout all stages of preparation for surgery, including sterilization. There is a paucity of information on the effects of sterilization on sub-10 nm-thick polymeric surface coatings suitable for silicon-based bioartificial organs. This study explores the effect of five standard sterilization methods on three surface coatings applied to silicon: polyethylene glycol (PEG), poly(sulfobetaine methacrylate) (pSBMA), and poly (2-methacryloyloxyethyl phosphorylcholine) (pMPC). Autoclave, dry heat, hydrogen peroxide (H2 O2 ) plasma, ethylene oxide gas (EtO), and electron beam (E beam) treated coatings were analyzed to determine possible polymer degradation with sterilization. Poststerilization, there were significant alterations in contact angle, maximum change resulting from H2 O2 (Delta - 14 degrees ), autoclave (Delta + 15 degrees ), and dry heat (Delta + 23 degrees ) treatments for PEG, pSBMA, and pMPC, respectively. Less than 5% coating thickness change was found with autoclave and EtO on PEG-silicon, E-beam on pSBMA-silicon and EtO treatment on pMPC-silicon. H2 O2 treatment resulted in at least 30% decrease in thickness for all coatings. Enzyme-linked immunosorbent assays showed significant protein adsorption increase for pMPC-silicon following all sterilization methods. E-beam on PEG-silicon and dry-heat treatment on pSBMA-silicon exhibited maximum protein adsorption in each coating subset. Overall, the data suggest autoclave and EtO treatments are well-suited for PEG-silicon, while E-beam is best suited for pSBMA-silicon. pMPC-silicon was least impacted by EtO treatment. H2 O2 treatment had a negative effect on all three coatings. These results can be used to determine which surface modifications and sterilization processes to utilize for devices in vivo. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2327-2336, 2018. PMID- 29105973 TI - Ligand-controlled Regiodivergent C-H Alkenylation of Pyrazoles and its Application to the Synthesis of Indazoles. AB - Regioselective C4-, C5-, and di-alkenylations of pyrazoles were achieved. An electrophilic Pd catalyst generated by trifluoroacetic acid (TFA) and 4,5 diazafluoren-9-one (DAF) leads to C4-alkenylation, whereas KOAc and mono protected amino acid (MPAA) ligand Ac-Val-OH give C5-alkenylation. A combination of palladium acetate, silver carbonate, and pivalic acid affords dialkenylation products. Annulation through sequential alkenylation, thermal 6pi electrocyclization, and oxidation gives functionalized indazoles. This comprehensive strategy greatly expands the range of readily accessible pyrazole and indazole derivatives, enabling useful regiodivergent C-H functionalization of pyrazoles and other heteroaromatic systems. PMID- 29105974 TI - Update on vaccine-derived polioviruses worldwide, January 2016-June 2017. PMID- 29105975 TI - Pigment retinopathy in warmblood horses with equine degenerative myeloencephalopathy and equine motor neuron disease. PMID- 29105976 TI - Therapeutic effect of lyophilized, Kefir-fermented milk on constipation among persons with mental and physical disabilities. AB - AIM: Constipation is a serious problem for persons with mental and physical disabilities in Japan. However, prophylaxis is extremely difficult because the major causes of constipation in these individuals are related to their mental and physical disabilities. Constipation can be successfully treated with glycerol enemas (GEs) and other aperients. As constipation is a lifetime issue for these persons, dietary regimens to prevent constipation can be important. METHODS: This study evaluated the probiotic effects of kefir-fermented milk for preventing constipation in 42 persons with mental and physical disabilities. The participants were administered 2 g of lyophilized kefir with each meal for 12 weeks and their bowel movements, the administration of GE and other aperients, and stool shape were recorded. RESULTS: The intake of kefir significantly reduced constipation, compared with the baseline status. Some individuals showed complete relief of constipation, whereas others showed no effect. CONCLUSION: Despite individual variations, consuming kefir daily could prevent constipation. PMID- 29105978 TI - What the FLOQ? A quality improvement project to reduce unnecessary paediatric respiratory viral swabs in a peripheral metropolitan hospital. AB - AIM: To reduce the number of paediatric respiratory viral swabs (locally referred to as a FLOQ) performed across the authors clinical centre from a baseline of over 800 ($38 000) per year by 25% over 4 months from 6 February 2017 to 31 May 2017. METHODS: A quality improvement project 'What the FLOQ?' (WTF) was instigated from 6 February 2017 to complement the Emergency Department (ED) 'Sensible Test Ordering Process' project from 1 April 2017. Stakeholder engagement across ED and general paediatric staff was sought. Alterations in practice included education of staff, targeted feedback to groups frequently ordering a FLOQ and rationalising patients appropriate for testing. Monthly requests were tallied on a run chart for FLOQs ordered in ED and the paediatric ward. A monthly audit of FLOQs performed on ED-discharged patients was conducted with feedback. RESULTS: Total FLOQ swabs decreased by 55% from 336 (February to May 2016) to 151 (February to May 2017). ED performed 66% less FLOQs from 237 (February to May 2016) to 82 (February to May 2017). There was no increase in the number of FLOQs performed on the paediatric ward February to May 2017. Monthly auditing of ED discharged patients under 2 years with a FLOQ went from 40 to 3%. CONCLUSION: Rationalising patient groups appropriate for testing with targeted feedback and broad stakeholder engagement successfully reduced FLOQs performed by 55%. This has projected savings of over $21 000 by 12 months. WTF has reduced the number of invasive patient procedures performed, benefitting staff and patients. Sustaining this change will be achieved through ongoing staff education on rationalisation criteria and consultant only requests outside of these parameters. PMID- 29105979 TI - Biocompatibility and immunogenicity of elastin-like recombinamer biomaterials in mouse models. AB - Novel thermo-sensitive elastin-like recombinamers (ELRs) containing bioactive molecules were created for use as a biomimetic biomaterial for tissue regeneration. For effective use for in vivo applications, it is essential to ensure that they do not induce adverse inflammatory, immune, or allergic responses that inhibit tissue repair. Therefore, we sought to establish a pre clinical approach to evaluate biocompatibility in experimental mice using ELRs as a prototype biomaterial. First, we measured in vitro proliferation and cytokine production from BALB/c and C57BL/6 mouse splenocytes incubated with ELRs. Second, we used a rapid, high throughput in vivo approach in which inflammatory cells and cytokines were measured following an intraperitoneal implantation. Lastly, a subchronic in vivo approach was used in which ELRs or positive controls were subcutaneously implanted and the implantation sites were assessed for inflammation and gene expression. We found that ELRs induced mild inflammation and minimal fibrosis compared to the intense response to Vitoss. Additionally, implantation increased antigen-specific antibody titers for both groups and gene expression profiling of the implantation sites revealed the upregulation of inflammation, fibrosis, and wound healing-related genes in ELR and positive control-implanted mice compared to sham controls. These data demonstrate that ELRs appear safe for use in tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 924-934, 2018. PMID- 29105977 TI - Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease. AB - Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD). 18 F-flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between 18 F flortaucipir and cognition in 14 mildly-impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic-variant primary progressive aphasia (lvPPA, n = 4). Amnestic AD patients had deficits in memory; lvPPA in language; and both amnestic AD and PCA patients in visuospatial function. Associations with cognition were tested using sparse regression and compared to associations in anatomical regions-of-interest (ROIs). 18 F-flortaucipir uptake was expected to show regionally-specific correlations with each domain. In multivariate analyses, uptake was elevated in neocortical areas specifically associated with amnestic and non-amnestic syndromes. Uptake in left anterior superior temporal gyrus accounted for 67% of the variance in language performance. Uptake in right lingual gyrus predicted 85% of the variance in visuospatial performance. Memory was predicted by uptake in right fusiform gyrus and cuneus as well as a cluster comprising right anterior hippocampus and amygdala; this eigenvector explained 57% of the variance in patients' scores. These results provide converging evidence for associations between 18 F-flortaucipir uptake, tau pathology, and patients' cognitive symptoms. PMID- 29105980 TI - Extracellular Vesicles in the Adaptive Process of Prostate Cancer during Inhibition of Androgen Receptor Signaling by Enzalutamide. AB - Current treatments for advanced prostate cancer focus on inhibition of the androgen receptor (AR) by androgen deprivation therapy (ADT). However, complex interactions mediated by tumor suppressors, oncogenes, aberrations of AR expression, or de novo androgen production have been shown to induce the adaptive response of prostate cancer, leading to the development of castration resistant prostate cancer. In this study, we report the effects of AR antagonist, enzalutamide on the protein contents of extracellular vesicles (EVs). EVs mediate cell-to-cell communication and increasing evidence shows the role of EVs in promoting cancer survival and metastasis. We found that treatment with enzalutamide alters the secretion of EVs, one of which is a plasma membrane calcium pump, ATP2B1/PMCA ATPase, as an AR-regulated EV protein. We highlight the networks of interactions between AR, Ca2+ , and ATP2B1, where the extracellular proteins thrombospondin-1, gelsolin, and integrinbeta1 were previously reported as regulators for cancer progression and metastasis, indicating the potential role of EV-derived proteins in mediating calcium homoeostasis under AR inhibition by enzalutamide. Our data further highlight the cross-talk between AR signaling and EV pathways in mediating resistance toward ADT. PMID- 29105981 TI - The function of the floral corona in the pollination of a Mediterranean style dimorphic daffodil. AB - Narcissus papyraceus is a style dimorphic species with two floral forms, with anthers at similar height and stigmas above (long-styled L) and below (short styled S) the anther level. The species is self-incompatible, but intra- and inter-morph compatible. Populations are either dimorphic (including both morphs) in the region of the Strait of Gibraltar, or L-monomorphic (with only L plants) in the inland of the Iberian Peninsula. This variation correlates with the most common floral visitors, being primarily long-tongued and short-tongued pollinators, respectively, a rare condition in Mediterranean plants. The maintenance of S-flowers relies on long-tongued insects, as only those deliver pollen to short-styled stigmas. Narcissus flowers present a long and narrow tube, at the bottom of which nectar accumulates, and a floral corona, which has been proposed as an important trait for the attraction of pollinators. Here we tested the importance of the corona on pollination of L and S flowers. We described UV reflectance patterns of the corona and tepals, and characterised VOCs in intact flowers and flowers with trimmed coronas. We also conducted a field experiment in the dimorphic and monomorphic region to estimate the importance of corona removal on seed production in stands with solitary plants and in groups to control for compatible pollen limitation. Reflectance was higher in the tepals than the corona, although both traits presented a reflectance peak around 450 nm wavelength. L- and S-flowers produced similar volatiles, regardless of the manipulation of the corona. Across dimorphic and monomorphic regions, S-flowers with the corona removed suffered a reduction in seed production of ca. 50%, while seed production remained similar in L flowers both with the corona intact and removed. Plants in solitary stands suffered a strong reduction in seed production, which was more pronounced in the monomorphic region. Our results suggest that the corona in Narcissus is more important for the pollination of S flowers, which generally have lower seed production compared to L-flowers. Taken together, these results suggest that the floral corona indirectly plays an important role for maintenance of the polymorphism. PMID- 29105982 TI - Trends in the diffusion of robotic surgery: A retrospective observational study. AB - BACKGROUND: Recent studies have suggested that the use of robotic surgery for prostatectomy has been increasing, but characterization of the diffusion of robotic surgery in other procedures has not been available. METHODS: Data were analysed for the years 2006-2014 using hospital episode statistics (HES), a database of all admissions to National Health Service (NHS) hospitals in England. OPCS codes were used to determine the annual number of prostatectomy, partial nephrectomy, and total abdominal hysterectomy procedures. Concurrent OPCS codes were then used to identify whether these procedures were robotic, conventional laparoscopic or open surgery. RESULTS: The proportion of robotic cases varied depending on the surgical procedure. Diffusion of robotic surgery was relatively rapid in prostatectomy, moderate in partial nephrectomy, and slow in total abdominal hysterectomy. CONCLUSIONS: Although high institutional cost might explain the earliest delays in diffusion, this barrier does not fully account for the different rates of diffusion among surgical procedures. PMID- 29105983 TI - Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to Design Functional Polyesters. AB - Free-radical copolymerization of cyclic ketene acetals (CKAs) and vinyl ethers (VEs) was investigated as an efficient yet simple approach for the preparation of functional aliphatic polyesters. The copolymerization of CKA and VE was first predicted to be quasi-ideal by DFT calculations. The theoretical prediction was experimentally confirmed by the copolymerization of 2-methylene-1,3-dioxepane (MDO) and butyl vinyl ether (BVE), leading to rMDO =0.73 and rBVE =1.61. We then illustrated the versatility of this approach by preparing different functional polyesters: 1) copolymers functionalized by fluorescent probes; 2) amphiphilic copolymers grafted with poly(ethylene glycol) (PEG) side chains able to self assemble into PEGylated nanoparticles; 3) antibacterial films active against Gram positive and Gram-negative bacteria (including a multiresistant strain); and 4) cross-linked bioelastomers with suitable properties for tissue engineering applications. PMID- 29105984 TI - Hemodynamic classification of paravalvular leakage after transcatheter aortic valve implantation compared with angiographic or echocardiographic classification for prediction of 1-year mortality. AB - OBJECTIVES: We sought to assess angiographic, echocardiographic and hemodynamic grading of paravalvular leakage (PVL) after transcatheter aortic valve implantation (TAVI) with respect to prediction of 1-year mortality. BACKGROUND: Meaningful criteria for the severity of PVL are needed to allow intraprocedural guidance and patient management after TAVI. METHODS: We pooled the prospective TAVI databases of 2 German centers. During TAVI, PVL was assessed angiographically and by the aortic regurgitation index (ARI). ARI was calculated as ratio of the gradient between diastolic blood pressure and left ventricular end-diastolic pressure to systolic blood pressure times hundred. In addition, we performed transthoracic echocardiography before discharge. RESULTS: A total of 723 patients undergoing TAVI with self-expandable (20.9%) or balloon-expandable (79.1%) valves were included. Grades of PVL as assessed during the procedure by angiography or ARI (below the previously defined cut-off of 25) did not show a significant association with 1-year mortality (P = 0.312 and 0.776, respectively). One-year mortality was 15.7% (39/249) in patienths with an ARI < 25 and 16.5% (71/430) in patients with an ARI >= 25. Echocardiographic classes of PVL at discharge showed a significant (P = 0.029) association with 1-year mortality, which was 11.5% (37/322) in patients with no/trace PVL, 18.0% (62/345) in patients with mild PVL and 23.1% (6/26) in patients with more than mild PVL. These findings prevailed after multivariable adjustment. CONCLUSIONS: ARI did not help identify PVLs that are relevant to 1-year survival. Angiographic assessment during the procedure was less predictive than echocardiographic assessment before discharge. PMID- 29105985 TI - Do body build and composition influence striae distensae occurrence and visibility in women? AB - BACKGROUND: Striae have been reported to be one of the most common skin changes and a commonly encountered esthetic problem. OBJECTIVES: To analyze risk factors of striae not associated with pregnancy and verify if body build and composition influence striae distensae (SD) occurrence and visibility. METHODS: Eighty female students (40 with striae (the mean age 23.9 years, SD 2.05 years) and 40 without these lesions (24.7 years, SD 6.2 years)) were included in the study. The subjects were asked to fill out a questionnaire including questions concerning risk factors of SD. Body build and composition were examined using Tanita SC-331S Body Composition Analyzer. RESULTS: Women without striae more often reported a history of intended weight loss (P < .0001), less frequently had a history of contraceptives intake (P < .001) and more often their family history of striae was negative or unknown (P = .01). Multivariate analysis including body build and composition parameters indicated BMI as risk factor of SD (P = .021; OR =1.155, 95% CI 1.006; 1.325). CONCLUSIONS: History of contraceptives intake and a family history of striae are risk factors of SD occurrence, while weight loss can reduce the risk of these lesions. BMI appeared to be the risk factor of striae visibility, especially in abdomen, but not on the buttocks. Further clinical researches are needed to examine the pathophysiology of this condition and to inform patients about the possibility to reduce the risk of striae occurrence. PMID- 29105986 TI - Charge Transport in 2D DNA Tunnel Junction Diodes. AB - Recently, deoxyribonucleic acid (DNA) is studied for electronics due to its intrinsic benefits such as its natural plenitude, biodegradability, biofunctionality, and low-cost. However, its applications are limited to passive components because of inherent insulating properties. In this report, a metal insulator-metal tunnel diode with Au/DNA/NiOx junctions is presented. Through the self-aligning process of DNA molecules, a 2D DNA nanosheet is synthesized and used as a tunneling barrier, and semitransparent conducting oxide (NiOx ) is applied as a top electrode for resolving metal penetration issues. This molecular device successfully operates as a nonresonant tunneling diode, and temperature variable current-voltage analysis proves that Fowler-Nordheim tunneling is a dominant conduction mechanism at the junctions. DNA-based tunneling devices appear to be promising prototypes for nanoelectronics using biomolecules. PMID- 29105987 TI - A Ketone Ester Drink Lowers Human Ghrelin and Appetite. AB - OBJECTIVE: The ketones d-beta-hydroxybutyrate (BHB) and acetoacetate are elevated during prolonged fasting or during a "ketogenic" diet. Although weight loss on a ketogenic diet may be associated with decreased appetite and altered gut hormone levels, it is unknown whether such changes are caused by elevated blood ketones. This study investigated the effects of an exogenous ketone ester (KE) on appetite. METHODS: Following an overnight fast, subjects with normal weight (n = 15) consumed 1.9 kcal/kg of KE, or isocaloric dextrose (DEXT), in drinks matched for volume, taste, tonicity, and color. Blood samples were analyzed for BHB, glucose, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY), and a three-measure visual analogue scale was used to measure hunger, fullness, and desire to eat. RESULTS: KE consumption increased blood BHB levels from 0.2 to 3.3 mM after 60 minutes. DEXT consumption increased plasma glucose levels between 30 and 60 minutes. Postprandial plasma insulin, ghrelin, GLP-1, and PYY levels were significantly lower 2 to 4 hours after KE consumption, compared with DEXT consumption. Temporally related to the observed suppression of ghrelin, reported hunger and desire to eat were also significantly suppressed 1.5 hours after consumption of KE, compared with consumption of DEXT. CONCLUSIONS: Increased blood ketone levels may directly suppress appetite, as KE drinks lowered plasma ghrelin levels, perceived hunger, and desire to eat. PMID- 29105988 TI - Strategies for Efficient Charge Separation and Transfer in Artificial Photosynthesis of Solar Fuels. AB - Converting sunlight to solar fuels by artificial photosynthesis is an innovative science and technology for renewable energy. Light harvesting, photogenerated charge separation and transfer (CST), and catalytic reactions are the three primary steps in the processes involved in the conversion of solar energy to chemical energy (SE-CE). Among the processes, CST is the key "energy pump and delivery" step in determining the overall solar-energy conversion efficiency. Efficient CST is always high priority in designing and assembling artificial photosynthesis systems for solar-fuel production. This Review not only introduces the fundamental strategies for CST but also the combinatory application of these strategies to five types of the most-investigated semiconductor-based artificial photosynthesis systems: particulate, Z-scheme, hybrid, photoelectrochemical, and photovoltaics-assisted systems. We show that artificial photosynthesis systems with high SE-CE efficiency can be rationally designed and constructed through combinatory application of these strategies, setting a promising blueprint for the future of solar fuels. PMID- 29105989 TI - Patient-reported experience of the impact and burden of neuroendocrine tumors: Oceania patient results from a large global survey. AB - AIM: Despite the considerable impact of neuroendocrine tumors (NETs) on patients' lives, the patient journey is not well documented. The aim of this survey was to identify the impact and burden of NETs from the patient perspective. METHODS: This was a self-reported global survey regarding NET knowledge/awareness, disease impact/management, interaction with medical teams, and desired improvements. One hundred thirty-eight patients (7% of the global study) in the Oceania region answered closed-ended questions using graded descriptors on their experience of living with NETs. RESULTS: The personal lives of patients were negatively impacted by NETs, including overall energy levels (72%, 99/138), emotional health (66%, 91/138), and finances (56%, 77/138). Eighty-one percent (22/27) of patients not currently working stated that their NET was the reason they were not employed. Of those still working, taking days off work (64%, 39/61), working reduced hours (44%, 27/61) and stopping work for a period of time (31%, 19/61) were the most frequently reported outcomes of having a NET. Although most patients felt supported by their medical team (53% [73/138] reported being extremely or very supported by healthcare professionals in general), patients also identified areas for improvement in patient care. Better access to NET specific treatments (58%, 80/138), more awareness about NETs (58%, 80/138) and materials to help patients better explain their condition (52%, 72/138) were indicated by patients as ways to help them live better with their disease. CONCLUSION: The survey demonstrated a considerable burden of NETs on patients' lives and identified areas for improvements in long-term management. PMID- 29105990 TI - Improving negative liquid chromatography/electrospray ionization mass spectrometry lipidomic analysis of human plasma using acetic acid as a mobile phase additive. AB - RATIONALE: Mobile-phase additives in liquid chromatography/mass spectrometry (LC/MS) are used to improve peak shape, analyte ionization efficiency and method coverage. Both basic and acidic mobile phases have been used successfully for negative electrospray ionization (ESI), but very few systematic investigations exist to date to justify the choice of mobile phase. Acetic acid was previously shown to improve ionization in untargeted metabolomics of urine, but has not been investigated in lipidomics. The goal of this study was to systematically compare the performance of acetic acid to that of other commonly employed additives in negative LC/ESI-MS lipidomics. METHODS: The performance of acetic acid was compared to that of commonly used mobile-phase additives in lipidomics, namely ammonium acetate, ammonium acetate with acetic acid and ammonium hydroxide, using lipid standard solutions containing representatives of major mammalian lipid subclasses and isopropanol-precipitated human plasma. This design allowed comparison of the influence of additive and additive concentration on lipid signal intensity, lipid peak shape and lipid coverage in both simple and complex biological matrices using both Orbitrap and quadrupole time-of-flight MS platforms with different ESI source designs. RESULTS: Ammonium hydroxide caused 2 to 1000-fold signal suppression of all lipid classes in comparison to acetic acid. In comparison to ammonium acetate, acetic acid increased lipid signal intensity from 2- to 19-fold for 11 lipid subclasses, and decreased ionization efficiency only for ceramide and phosphatidylcholine lipid classes which can be effectively ionized in positive ESI mode. The improved ionization efficiency using acetic acid also increased lipid coverage by 21-50% versus ammonium acetate additive. CONCLUSIONS: Acetic acid at a concentration of 0.02% (v/v) is the suggested choice as a mobile-phase additive for lipidomics and targeted lipid profiling with negative LC/ESI-MS based on signal enhancement and improved lipid coverage compared to ammonium acetate, ammonium acetate with acetic acid and ammonium hydroxide mobile phases. PMID- 29105991 TI - Hypertension and frailty in older adults. AB - The association between hypertension and frailty syndrome in older adults remains unclear. There is scarce information about the prevalence of hypertension among frail elderly patients or on its relationship with frailty. Up to one quarter of frail elderly patients present without comorbidity or disability, yet frailty is a leading cause of death. The knowledge and better control of frailty risk factors could influence prognosis. The present study evaluated: (1) the prevalence of hypertension in robust, prefrail, and frail elderly; and (2) factors that might be associated with frailty including hypertension. A cross sectional study was conducted in 619 older adults at a university-based outpatient center. Study protocol included sociodemographic data, measures of blood pressure and body mass index, frailty screening according to the internationally validated FRAIL (fatigue, resistance, ambulation, illnesses, and loss of weight) scale, number of comorbidities, drug use assessment, physical activity, cognitive status, and activities of daily living. Ordinal logistic regression was used to evaluate factors associated with frailty. Prevalence of hypertension and frailty was 67.3% and 14.8%, respectively, in the total sample. Hypertension was more prevalent in the prefrail (72.5%) and frail (83%) groups than among controls (51.7%). Hypertension, physical activity, number of prescribed drugs, and cognitive performance were significantly associated with frailty status. Hypertension presented an odds ratio of 1.77 towards frailty (95% confidence interval, 1.21-2.60; P = .002). Hypertension was more prevalent in frail elderly patients and was significantly associated with frailty. Intensive control of hypertension could influence the trajectory of frailty, and this hypothesis should be explored in future prospective clinical trials. PMID- 29105992 TI - Cystectomy for cT4 prostate cancer: the most radical treatment. PMID- 29105993 TI - Central pathology review of radical prostatectomy specimens does make a difference not only with grade. PMID- 29105994 TI - Selection-free method reveals phenotypic diversity among prostate cancer circulating tumour cells. PMID- 29105995 TI - Educational intervention in prostate cancer. PMID- 29105996 TI - Bone health in cancer patients - An important clinical issue. PMID- 29105997 TI - Doxorubicin induces ZAKalpha overexpression with a subsequent enhancement of apoptosis and attenuation of survivability in human osteosarcoma cells. AB - Human osteosarcoma (OS) is a malignant cancer of the bone. It exhibits a characteristic malignant osteoblastic transformation and produces a diseased osteoid. A previous study demonstrated that doxorubicin (DOX) chemotherapy decreases human OS cell proliferation and might enhance the relative RNA expression of ZAK. However, the impact of ZAKalpha overexpression on the OS cell proliferation that is inhibited by DOX and the molecular mechanism underlying this effect are not yet known. ZAK is a protein kinase of the MAPKKK family and functions to promote apoptosis. In our study, we found that ZAKalpha overexpression induced an apoptotic effect in human OS cells. Treatment of human OS cells with DOX enhanced ZAKalpha expression and decreased cancer cell viability while increasing apoptosis of human OS cells. In the meantime, suppression of ZAKalpha expression using shRNA and inhibitor D1771 both suppressed the DOX therapeutic effect. These findings reveal a novel molecular mechanism underlying the DOX effect on human OS cells. Taken together, our findings demonstrate that ZAKalpha enhances the apoptotic effect and decreases cell viability in DOX-treated human OS cells. PMID- 29105998 TI - Possible role of hyposensitivity of C-fiber afferents at the proximal urethra in the development of urge urinary incontinence in patients with detrusor overactivity. AB - OBJECTIVE: The aim of the present study was to investigate associations between urethral sensation and urge urinary incontinence (UUI) in patients with and without detrusor overactivity (DO). METHODS: The medical records of 80 consecutive patients who underwent filling cystometry and urethral current perception threshold (CPT) tests were examined retrospectively. Following the exclusion of 4 patients not eligible for analysis, patients were classified into neurogenic DO, idiopathic DO, or DO-negative groups based on neurological and cystometric findings (n = 30, 12, and 34, respectively). Eleven DO-negative patients were defined as normal controls on cystometrograms (CMG) using the following exclusion criteria: bladder compliance <12.5 mL/cmH2 O, volume >275 mL at first filling sensation, and comorbidities possibly affecting lower urinary tract function. Thus, 53 patients were finally included in the study. Proximal urethral CPT was evaluated with intraurethral square-wave stimulation at 3 Hz to activate C-fiber afferents. RESULTS: Median CPT was higher in neurogenic and idiopathic DO than in the normal CMG group (11.3 and 9.0 vs. 2.8 mA, respectively; P < .05), as well as in patients with UUI (n = 19) compared with non-UUI patients (n = 34; 12.5 vs. 5.4 mA, respectively; P < .05). The proportion of UUI patients was significantly greater in the DO-positive groups than in the normal CMG group (P < .05). CPTs were not associated with bladder capacity at the first filling sensation (r = 0.11). CONCLUSION: Hyposensitive C-fibers of the proximal urethra may contribute to the development of urodynamic DO as well as UUI in patients complaining of lower urinary tract symptoms. PMID- 29105999 TI - Fabrication of interconnected porous beta-tricalcium phosphate (beta-TCP) based on a setting reaction of beta-TCP granules with HNO3 followed by heat treatment. AB - beta-Tricalcium phosphate [beta-TCP] is the typical bone substitute due to its excellent osteoconductivity and bioresorbability. One of the keys to improve its potential as bone substitute is to introduce porous structure and its regulation. In this study, interconnected porous beta-TCP blocks were fabricated through a setting reaction of beta-TCP granules and subsequent heat treatment. First, beta TCP granules were mixed with HNO3 . Upon mixing, beta-TCP granules were bridged with dicalcium phosphate dihydrate [DCPD: CaHPO4 .2H2 O] containing Ca(NO3 )2 . Then, the DCPD-bridged beta-TCP was heated at 1100 degrees C. During the heating process, DCPD containing Ca(NO3 )2 transformed into beta-TCP and bonded with beta TCP granules. As a result, an interconnected porous beta-TCP block formed. The diametral tensile strength and porosity of the interconnected porous beta-TCP block fabricated from 200-300-MUm beta-TCP granules and 5 N HNO3 and then heated at 1,100 degrees C were 1.4 +/- 0.2 MPa and 57% +/- 2%, respectively. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 797-804, 2018. PMID- 29106000 TI - Delayed-type hypersensitivity to oral and parenteral drugs. AB - Adverse drug reactions of the delayed type rank among the most common dermatoses and are predominantly characterized by exanthematous macular or maculopapular eruptions. However, approximately 2 % of affected individuals develop severe or even life-threatening systemic immune reactions associated with organ involvement, requiring immediate diagnosis and treatment. Numerous drugs are capable of eliciting delayed-type hypersensitivity reactions, with antibiotics, anticonvulsant drugs, and the xanthine oxidase inhibitor allopurinol being the most common. Apart from genetic susceptibility, predisposing factors for the development of drug hypersensitivity reactions include high drug doses, polypharmacy, long treatment duration, female gender, as well as acute or chronic infections. PMID- 29106002 TI - Kongresskalender 2017. PMID- 29106001 TI - 75 Jahre Dissertation Erich Wagner: "Ein Beitrag zur Tatowierungsfrage" - Wissenschaftliches Fehlverhalten im Nationalsozialismus. PMID- 29106003 TI - Nachruf auf Helmut Tritsch 1923-2017. PMID- 29106004 TI - Genitales Ulkus am Penis eines 58-jahrigen HIV-positiven Patienten nach lokaler Injektion von Methamphetamin (Crystal Meth). PMID- 29106006 TI - Flachige Hyperpigmentierungen im Gesicht einer philippinischen Patientin. PMID- 29106005 TI - Sweet-Syndrom: Revision der diagnostischen Kriterien. PMID- 29106007 TI - Spattypreaktionen durch oral und parenteral applizierte Arzneimittel. PMID- 29106008 TI - Off-Label-Use und Entscheidungen uber Antrage auf Kostenubernahme in Deutschland eine retrospektive Analyse. PMID- 29106009 TI - Beurteilung der Lebensqualitat bei Patienten mit nicht-melanozytarem Hautkrebs - psychometrische Validierung des EORTC QLQ-C30-Fragebogens. PMID- 29106012 TI - Leserbrief zu Ebrahimi-Fakhari D et al. Dermatologische Manifestationen der tuberosen Sklerose (TSC). J Dtsch Dermatol Ges 2017; 15(7): 695-701. PMID- 29106011 TI - Prolidasemangel bei zwei Schwestern mit wiederkehrenden Ulzerationen an den unteren Extremitaten. PMID- 29106010 TI - Erythema anulare centrifugum: Remissionen wahrend zweier Schwangerschaften und Exazerbation dazwischen. PMID- 29106013 TI - Penile ulcer in a 58-year-old HIV-positive patient after local injection of methamphetamine (crystal meth). PMID- 29106014 TI - Virusreaktivierung tauscht Rezidiv des Pemphigus vulgaris bei einer immunsupprimierten Patientin vor. PMID- 29106015 TI - 75 years after Erich Wagner's doctoral dissertation: "A Contribution to the Issue of Tattooing" - scientific misconduct in Nazi Germany. PMID- 29106017 TI - Dr. Kurt und Eva Herrmann-Stipendium in Hohe von 10.000 Euro fur junge Dermatologinnen/Dermatologen. PMID- 29106016 TI - Ist eine komplette Lymphknotendissektion beim malignen Melanom mit positivem Sentinel notwendig? PMID- 29106018 TI - Quality of life assessment in patients with nonmelanoma skin cancer - psychometric validation of the EORTC QLQ-C30 questionnaire. AB - BACKGROUND: Nonmelanoma skin cancer (NMSC) is a chronic and sometimes difficult to-treat condition affecting the quality of life (QL). The present study was conducted to investigate whether the European Organization for Research and Treatment of Cancer (EORTC) core QL Questionnaire - Cancer (QLQ-C30) is a suitable tool for the assessment of QL in patients with NMSC. PATIENTS AND METHODS: In order to define the psychometric properties of the questionnaire, the QLQ-C30 and the Dermatology Life Quality Index (DLQI) were handed out to 172 patients of the Department of Dermatology at the University Hospital Regensburg, Germany. RESULTS: Internal consistencies of all multi-item scales (except one) were acceptable, with Cronbach's alpha ranging from 0.71 to 0.93. The hypothesized scale structure was supported by item/scale and interscale correlations within the QLQ-C30. Related scales of the QLQ-C30 and the DLQI correlated significantly, thus establishing construct validity. At the same time, the proportion of substantial correlations (6 % >= 0.40) indicated that the two questionnaires assessed distinct components of QL. The QLQ-C30 significantly differentiated between clinically distinct patient groups, indicating that severe clinical conditions were associated with greater impairment in physical, role, and cognitive functioning (p <= 0.030). CONCLUSIONS: These results confirm the QLQ-C30 to be a suitable tool for the assessment of QL in patients with NMSC. PMID- 29106019 TI - Rasche Entwicklung bilateraler Nekrosen der oberen Extremitat. PMID- 29106020 TI - Schwimmflossen-Vakuumversiegelung zur Behandlung plantarer Exzisionsdefekte. PMID- 29106021 TI - Beurteilung des Aussparphanomens im Nabelbereich bei grobetaen kongenitalen melanozytaren Navi anhand einer umfangreichen Fallserie. PMID- 29106022 TI - Dr. Christian Posch - Preistrager des Osterreichischen Wissenschaftspreis der OGDV. PMID- 29106023 TI - Wege zum Verstandnis neutrophiler Dermatosen. PMID- 29106025 TI - Kopfhautnekrose an Stirn und Schlafe. PMID- 29106026 TI - Anti-Desmoglein 1 IgG/IgA-Pemphigus in Verbindung mit einem Thymom. PMID- 29106027 TI - Hierarchical Core-Shell Nickel Cobaltite Chestnut-like Structures as Bifunctional Electrocatalyst for Rechargeable Metal-Air Batteries. AB - Nano-engineered hierarchical core-shell nickel cobaltite chestnut-like structures were successfully synthesized as a bifunctionally active electrocatalyst for rechargeable metal-air battery applications. Both the morphology and composition of the catalyst were optimized by a facile hydrothermal reaction, resulting in a 10 h reacted sample demonstrating significantly enhanced activity toward both the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) in 0.1 m KOH. Specifically, the catalyst demonstrated -0.28 and 0.60 V versus SCE (saturated calomel electrode) at the ORR half-wave potential and an OER current density of 10 mA cm-2 , respectively. The resulting ORR/OER potential difference of 0.90 V was the smallest compared to the catalysts synthesized using 2, 6, and 12 h of hydrothermal reaction time. The excellent bifunctional activity of the catalyst is attributed to the nanoscale porous morphology and the spinel nickel cobaltite composition, which improved the active site exposure and transport of reactants and charges during the oxygen reactions. PMID- 29106028 TI - Association of High Anti-Cyclic Citrullinated Peptide Seropositivity and Lean Mass Index With Low Bone Mineral Density in Rheumatoid Arthritis. AB - OBJECTIVE: Osteoporotic fractures are associated with high morbidity and mortality. Persons with rheumatoid arthritis (RA) have twice the risk of osteoporosis-related fracture than age-matched controls, the causes for which remain unknown. We investigated contributions of RA characteristics, medication use, and body composition to low bone mineral density (BMD) in patients with RA. METHODS: Data were from the Arthritis, Body Composition, and Disability Study (n = 138; 82 women, 56 men). Demographic, clinical, laboratory, and functional variables were collected at study visits. Body composition (fat, lean muscle, and BMD) was measured by dual x-ray absorptiometry. Linear regression analyses evaluated the association between predictors and femoral neck BMD. RESULTS: Average disease duration was 19 years, 70% of patients were rheumatoid factor positive, and 55% were high-positive anti-cyclic citrullinated peptide (anti CCP). Age and high anti-CCP positivity were negatively associated with BMD after controlling for other variables (beta = -0.003 and -0.055, respectively, P < 0.05). Appendicular lean mass index (ALMI) was positively associated with BMD (beta = 0.053, P < 0.0001). In high anti-CCP positivity participants, increasing anti-CCP levels were associated with a negative linear trend in BMD (beta = 0.011, P = 0.026). CONCLUSION: High anti-CCP positivity and ALMI were strongly associated with BMD in patients with RA. The linear relationship of anti-CCP levels with lower BMD supports the hypothesis that processes specific to RA negatively impact BMD. In contrast, ALMI was positively associated with BMD, emphasizing the importance of this potentially modifiable risk factor. Our findings highlight the complicated interplay of RA disease-specific and functional factors and their impact on bone mass. PMID- 29106029 TI - Development, content validity, and cross-cultural adaptation of a patient reported outcome measure for real-time symptom assessment in irritable bowel syndrome. AB - BACKGROUND: End-of-day questionnaires, which are considered the gold standard for assessing abdominal pain and other gastrointestinal (GI) symptoms in irritable bowel syndrome (IBS), are influenced by recall and ecological bias. The experience sampling method (ESM) is characterized by random and repeated assessments in the natural state and environment of a subject, and herewith overcomes these limitations. This report describes the development of a patient reported outcome measure (PROM) based on the ESM principle, taking into account content validity and cross-cultural adaptation. METHODS: Focus group interviews with IBS patients and expert meetings with international experts in the fields of neurogastroenterology & motility and pain were performed in order to select the items for the PROM. Forward-and-back translation and cognitive interviews were performed to adapt the instrument for the use in different countries and to assure on patients' understanding with the final items. KEY RESULTS: Focus group interviews revealed 42 items, categorized into five domains: physical status, defecation, mood and psychological factors, context and environment, and nutrition and drug use. Experts reduced the number of items to 32 and cognitive interviewing after translation resulted in a few slight adjustments regarding linguistic issues, but not regarding content of the items. CONCLUSIONS AND INFERENCES: An ESM-based PROM, suitable for momentary assessment of IBS symptom patterns was developed, taking into account content validity and cross-cultural adaptation. This PROM will be implemented in a specifically designed smartphone application and further validation in a multicenter setting will follow. PMID- 29106030 TI - High Lithium Insertion Voltage Single-Crystal H2 Ti12 O25 Nanorods as a High Capacity and High-Rate Lithium-Ion Battery Anode Material. AB - H2 Ti12 O25 holds great promise as a high-voltage anode material for advanced lithium-ion battery applications. To enhance its electrochemical performance, control of the crystal orientation and morphology is an effective way to cope with slow Li+ -ion diffusion inside H2 Ti12 O25 with severe anisotropy. In this report, Na2 Ti6 O13 nanorods, prepared from Na2 CO3 and anatase TiO2 in molten NaCl medium, were used as a precursor in the synthesis of long single-crystal H2 Ti12 O25 nanorods with reactive facets. The as-prepared H2 Ti12 O25 nanorods with a diameter of 100-200 nm showed higher charge (extraction) specific capacity and better rate performance than previously reported systems. The reversible capacity of H2 Ti12 O25 was 219.8 mAh g-1 at 1C after 100 cycles, 172.1 mAh g-1 at 10C, and 144.4 mAh g-1 at 20C after 200 cycles; these values are higher than those of H2 Ti12 O25 prepared by the conventional soft-chemical method. Moreover, the as prepared H2 Ti12 O25 nanorods exhibited superior cycle stability with more than 94 % retention of capacity with nearly 100 % coulombic efficiency after 100 cycles at 1C. On the basis of the above results, long single-crystal H2 Ti12 O25 nanorods synthesized in molten NaCl with outstanding electrochemical characteristics hold a significant amount of promise for hybrid electric vehicles and energy-storage systems. PMID- 29106031 TI - Comparison of morning vs bedtime administration of the combination of valsartan/amlodipine on nocturnal brachial and central blood pressure in patients with hypertension. AB - The aim of this study was to compare the effect of morning and bedtime administration of valsartan/amlodipine combination therapy (80/5 mg) on nocturnal brachial and central blood pressure (BP) measured by ambulatory BP monitoring in patients with hypertension. This was a 16-week prospective, multicenter, randomized, open-label, crossover, noninferiority clinical trial. Patients underwent 24-hour ambulatory BP monitoring at randomization, at switching, and at the end of the study. Twenty-three patients (mean age, 68.0 years) were studied. The difference in nocturnal brachial systolic BP between the morning and bedtime administrations of combination valsartan/amlodipine was -3.2 mm Hg, and the two sided 95% confidence interval ranged from -6.8 to 0.4 mm Hg. The difference in nocturnal central systolic BP was -4.0 mm Hg (95% confidence interval, -7.6 to 0.4 mm Hg). The upper limit of the 95% confidence interval was below the margin of 3.0 mm Hg in both nocturnal brachial and central systolic BP, confirming the noninferiority of morning administration to the bedtime administration of valsartan/amlodipine combination therapy. PMID- 29106032 TI - The effects of conditioned media generated by polarized macrophages on the cellular behaviours of bone marrow mesenchymal stem cells. AB - Macrophages (Mphis) are involved in a variety of physiological and pathological events including wound healing and tissue regeneration, in which they play both positive and negative roles depending on their polarization state. In this study, we investigated the cellular behaviours of bone marrow mesenchymal stem cells (BMMSCs) after incubation in different conditioned media (CMs) generated by unpolarized Mphis (M0) or polarized Mphis (M1 and M2). Mphi polarization was induced by stimulation with various cytokines, and CMs were obtained from in vitro Mphi cultures termed CM0, CM1 and CM2 based on each Mphi phenotype. We found that CM1 supported the proliferation and adipogenic differentiation of BMMSCs, whereas CM0 had a remarkable effect on cell osteogenic differentiation. To a certain degree, CM2 also facilitated BMMSC osteogenesis; in particular, cells incubated with CM2 exhibited an enhanced capacity to form robust stem cell sheets. Although incubation with CM1 also increased production of extracellular matrix components, such as fibronectin, COL-1 and integrin beta1during sheet induction, the sheets generated by CM2-incubated cells were thicker than those generated by CM1-incubated cells (P < 0.001). Our data suggest that each Mphi phenotype has a unique effect on BMMSCs. Fine-tuning Mphi polarization following transplantation may serve as an effective method to modulate the therapeutic potential of BMMSCs. PMID- 29106033 TI - Brain 5-lipoxygenase over-expression worsens memory, synaptic integrity, and tau pathology in the P301S mice. AB - Progressive accumulation of highly phosphorylated tau protein isoforms is the main feature of a group of neurodegenerative diseases collectively called tauopathies. Data from human and animal models of these diseases have shown that neuroinflammation often accompanies their pathogenesis. The 5-lipoxygenase (5LO) is an enzyme widely expressed in the brain and a source of potent pro inflammatory mediators, while its pharmacological inhibition modulates the phenotype of a tau transgenic mouse model, the htau mice. By employing an adeno associated viral vector system to over-express 5LO in the brain, we examined its contribution to the behavioral deficits and neuropathology in a different transgenic mouse model of tauopathy, the P301S mouse line. Compared with controls, 5LO-targeted gene brain over-expression in these mice resulted in a worsening of behavioral and motor deficits. Over-expression of 5LO resulted in microglia and astrocyte activation and significant synaptic pathology, which was associated with a significant elevation of tau phosphorylation at specific epitopes, tau insoluble fraction, and activation of the cdk5 kinase. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes via the cdk5 kinase pathway. These data demonstrate that 5LO plays a direct role in tau phosphorylation and is an active player in the development of the entire tau phenotype. They provide further support to the hypothesis that 5LO is a viable therapeutic target for the treatment and/or prevention of human tauopathy. PMID- 29106034 TI - Evaluation of central venous catheters coated with a noble metal alloy-A randomized clinical pilot study of coating durability, performance and tolerability. AB - : The use of Central Venous Catheters (CVCs) commonly results in complications. Coatings with silver or metal alloys can reduce the risk associated with the use of CVC. We have evaluated the durability of a noble metal coated CVC (the Bactiguard Infectious Protection, BIP CVC) and compared with an uncoated CVC for clinical tolerability (Adverse Events, AEs) and performance, in order to create a baseline for a large future study. Patients undergoing major surgery, randomised at a 2:1 ratio to BIP CVC (n = 22) or standard CVC (n = 12), were catheterized 9 12 days, respectively. Adverse events, microbial colonization and metal release were measured. FINDINGS: There were no AEs in the BIP CVC-group, but 5 AEs occurred in 4 patients (1 patient had 2 AEs) in the standard CVC-group, p = 0.011 (whereof 3 were catheter related). The BIP CVC showed an initial release of coating metals in blood (gold, silver and palladium), which rapidly decreased and were far below Permitted Paily Exposure (PDE) for chronical use. The levels of silver concentration were far below those needed to develop microbial resistance. The performance was equal, and there was no difference concerning microbial colonization, for the two CVCs. CONCLUSION: In this pilot study the BIP CVC had significantly lower AEs and showed a comparable performance to the standard CVC. The coating was durable throughout the study length (up to 16 days) and toxicological evaluation showed good safety margins. Larger studies are needed. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2337-2344, 2018. PMID- 29106035 TI - Genetic association of HLA-DRB1 multiple polymorphisms with dermatomyositis in Chinese population. AB - Genetic variation in HLA plays an important role in the pathogenesis of dermatomyositis (DM). The aim of this study was to investigate the association of HLA class II with DM in China. Two hundred and twenty-four DM patients and 300 healthy controls were randomly enrolled at China-Japan Friendship Hospital. High resolution typing of HLA-DRB1 alleles was performed by sequencing based typing. The HLA-DQA1 and HLA-DQB1 alleles were determined by polymerase chain reaction sequence-specific primers. The frequencies of HLA-DRB1*09:01 (28.6% vs 11.3%, P < .0001, odds ratio, OR = 3.14, 95% confidence interval, CI = 2.47-3.99) and HLA DRB1*12:01 (29.0% vs 11.0%, P < .0001, OR = 3.30, 95% CI = 2.59-4.20) in DM patients were significantly higher than that in healthy controls. No significant difference was found in HLA-DQA1 or DQB1 alleles between DM patients and healthy controls. Furthermore, DM patients with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5) had a significantly higher frequency of HLA DRB1*12:01 compared to that for patients without anti-MDA5 (P < .0001, OR = 4.77, 95% CI: 2.29-9.93). Multivariate binary logistic regression analysis was performed to identify the risk factors for interstitial lung disease. The HLA DRB1*09:01 allele was a poor prognostic factor (P = .01, OR = 9.21, 95% CI: 1.47 57.50) for DM patients with anti-MDA5 autoantibody. In summary, our findings indicate that HLA-DRB1*09:01 and HLA-DRB1*12:01 alleles may contribute to susceptibility of adult DM in Han Chinese population. In addition, the DRB1*12:01 genotype is significantly associated with the presence of anti-MDA5 antibody in DM patients. PMID- 29106036 TI - Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation. AB - Accumulating evidences showed metformin and berberine, well-known glucose lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes. Glucose output was measured in primary hepatocytes. Compound C and adenoviruses expressing dominant negative AMP-activated protein kinase (AMPK) alpha1/2 were exploited to inactivate AMPK pathway. Cellular NAD+ /NADH ratio was assayed to evaluate energy transforming and redox state. Rotenone ameliorated hyperglycaemia and insulin resistance in db/db mice. It induced glucose consumption and glycolysis and reduced hepatic glucose output. Rotenone also activated AMPK. Furthermore, it remained effective with AMPK inactivation. The enhanced glycolysis and repressed gluconeogenesis correlated with a reduction in cellular NAD+ /NADH ratio, which resulted from complex I suppression. Amobarbital, another representative complex I inhibitor, stimulated glucose consumption and decreased hepatic glucose output in vitro, too. Similar changes were observed while expression of NDUFA13, a subunit of complex I, was knocked down with gene silencing. These findings reveal mitochondrial complex I emerges as a key drug target for diabetes treatment. Inhibition of complex I improves glucose homoeostasis via non-AMPK pathway, which may relate to the suppression of the cellular NAD+ /NADH ratio. PMID- 29106037 TI - Mesenchymal stem cells seeded on a human amniotic membrane improve liver regeneration and mouse survival after extended hepatectomy. AB - Liver failure remains the leading cause of post-operative mortality after hepatectomy. This study investigated the effect of treatment with allogenic mesenchymal stem cells (MSCs) on survival and liver regeneration 48 hr and 7 days after 80% hepatectomy in C57Bl/6 mice. To optimize their biodistribution, MSCs were grown on acellular human amniotic membranes (HAM) and applied as a patch on the remnant liver. This approach was compared with MSC infusion and HAM patch alone. Hepatectomized mice without any treatment were used as control group. Survival rate was calculated and biological and histopathological parameters were analysed to monitor liver function and regeneration. MSCs grown on HAM retained their ability to proliferate, to differentiate into osteoblasts and adipocytes and to respond to pro-inflammatory stimuli. Extended hepatectomy (80%) led to liver failure that resulted in death within 72 hr in 76% of mice. MSC infusion showed an early but transitory positive effect on survival. MSC/HAM patches stimulated regeneration and significantly improved survival rate (54% vs. 24% in the control group at 7 days). They also decreased the severity of hepatectomy induced steatosis, suggesting a modulation of lipid metabolism in hepatocytes. MSCs were still present on HAM at Days 2 and 7 posthepatectomy. In conclusion, engineered tissue constructs that combine MSCs and HAM improve survival and liver regeneration after 80% hepatectomy in mice. These encouraging results pave the way to potential clinical application. PMID- 29106038 TI - The physical approximation of APP and BACE-1: A key event in alzheimer's disease pathogenesis. AB - Alzheimer's disease (AD) is characterized by the accumulation of insoluble deposits of Amyloid beta (Abeta) in brains. Abeta is derived by sequential cleavage of the amyloid precursor protein (APP) by beta-site secretase enzyme (BACE-1) and gamma-secretase. Proteolytic processing of APP by BACE-1 is the rate limiting step in Abeta production, and this pathway is a prime target for AD drug development. Both APP and BACE-1 are membrane-spanning proteins, transported via secretory and endocytic pathways; and the physical interaction of APP and BACE-1 during trafficking is a key cell biological event initiating the amyloidogenic pathway. Here, we highlight recent research on intracellular trafficking/sorting of APP and BACE-1, and discuss how dysregulation of these pathways might lead to enhanced convergence of APP and BACE-1, and subsequent beta-cleavage of APP. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 340-347, 2018. PMID- 29106039 TI - A European, multicentre, retrospective, non-interventional study (EU-TREAT) of the effectiveness of insulin degludec after switching basal insulin in a population with type 1 or type 2 diabetes. AB - AIMS: To evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin-treated patients with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM) under conditions of routine clinical care. MATERIALS AND METHODS: This was a multicentre, retrospective, chart review study. In all patients, basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are presented as mean [95%CI]. RESULTS: T1DM (n = 1717): HbA1c decreased by -2.2 [-2.6; -2.0] mmol/mol (-0.20 [ 0.24; -0.17]%) at 6 months vs baseline (P < .001). Rate ratio of overall (0.79 [0.69; 0.89]), non-severe nocturnal (0.54 [0.42; 0.69]) and severe (0.15 [0.09; 0.24]) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period (P < .001 for all). Total daily insulin dose decreased by 4.88 [-5.52; -4.24] U (-11%) at 6 months vs baseline (P < .001). T2DM (n = 833): HbA1c decreased by -5.6 [-6.3; -4.7] mmol/mol (-0.51 [-0.58; -0.43] %) at 6 months vs baseline (P < .001). Rate ratio of overall (0.39 [0.27; 0.58], P < .001), non-severe nocturnal (0.10 [0.06; 0.16], P < .001) and severe (0.075 [0.01; 0.43], P = .004) hypoglycaemia was significantly lower in the 6-month post switch period vs the pre-switch period. Total daily insulin dose decreased by 2.48 [-4.24; -0.71] U (-3%) at 6 months vs baseline (P = .006). Clinical outcomes for T1DM and T2DM at 12 months were consistent with results at 6 months. CONCLUSIONS: This study demonstrates that switching patients to IDeg from other basal insulins improves glycaemic control and significantly reduces the risk of hypoglycaemia in routine clinical practice. PMID- 29106040 TI - The effect of temporal manipulation of transforming growth factor beta 3 and fibroblast growth factor 2 on the derivation of proliferative chondrocytes from mensenchymal stem cells-A study monitored by quantitative reverse transcription polymerase chain reaction and molecular beacon based nanosensors. AB - Proliferative chondrocytes are critical to realize regeneration of damaged epiphyseal growth plate. However, acquiring autologous replacement cells involves highly invasive procedures and often results in limited cell quantity. Mesenchymal stem cells (MSCs) are a potential source of chondrogenic cells for the treatment of cartilage disorders and injuries. The temporal effect of transforming growth factor beta 3 (TGFbeta3) and fibroblast growth factor 2 (FGF2) on the derivation of proliferative chondrocytes from MSCs in three dimensional agarose was investigated by manipulating the duration of TGFbeta3 and FGF2 treatment. The differentiation process was monitored by quantitative reverse transcription polymerase chain reaction (qRT-PCR) as well as nanosensors containing two molecular beacons that target critical biomarkers for proliferative chondrocytes (i.e., collagen type-II messenger ribonucleic acid [mRNA] and Ki67 mRNA). The molecular beacon-based nanosensors were found to be comparable to qRT-PCR in measuring mRNA expression and thus providing a noninvasive mean to screen and monitor culture samples. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 895-904, 2018. PMID- 29106041 TI - Three-Dimensional Anionic Cyclodextrin-Based Covalent Organic Frameworks. AB - Three-dimensional covalent organic frameworks (3D COFs) are promising crystalline materials with well-defined structures, high porosity, and low density; however, the limited choice of building blocks and synthetic difficulties have hampered their development. Herein, we used a flexible and aliphatic macrocycle, namely gamma-cyclodextrin (gamma-CD), as the soft struts for the construction of a polymeric and periodic 3D extended network, with the units joined via tetrakis(spiroborate) tetrahedra with various counterions. The inclusion of pliable moieties in the robust open framework endows these CD-COFs with dynamic features, leading to a prominent Li ion conductivity of up to 2.7 mS cm-1 at 30 degrees C and excellent long-term Li ion stripping/plating stability. Exchanging the counterions within the pores can effectively modulate the interactions between the CD-COF and CO2 molecules. PMID- 29106042 TI - Searching for evidence or approval? A commentary on database search in systematic reviews and alternative information retrieval methodologies. AB - Despite recognition that database search alone is inadequate even within the health sciences, it appears that reviewers in fields that have adopted systematic review are choosing to rely primarily, or only, on database search for information retrieval. This commentary reminds readers of factors that call into question the appropriateness of default reliance on database searches particularly as systematic review is adapted for use in new and lower consensus fields. It then discusses alternative methods for information retrieval that require development, formalisation, and evaluation. Our goals are to encourage reviewers to reflect critically and transparently on their choice of information retrieval methods and to encourage investment in research on alternatives. PMID- 29106043 TI - Synthesis and application of a novel solid-phase extraction adsorbent for multiresidue analysis of insecticides in water. AB - A new solid-phase adsorbent was synthesized for the simultaneous enrichment of multiple classes of trace insecticides (neonicotinoids, organophosphates, fiproles, and organochlorines) in water. The adsorbent was spherical with a diameter, surface area, average pore volume, and pore size of approximately 5 MUm, 341 m2 /g, 0.092 m3 /g, and 2.22 nm, respectively. Extraction conditions were optimized, including water pH and the type and volume of the rinsing and eluting solvents. After extraction, target insecticides were analyzed by gas chromatography with mass spectrometry and high-performance liquid chromatography with tandem mass spectrometry. The recovery of neonicotinoids ranged from 63.0 to 124%, except for clothianidin (40.1-52.9%). Recoveries of organophosphates, fiproles, and organochlorines were in the ranges of 37.0-102, 64.0-101, and 42.0 69.3%, respectively. Relative standard deviations were <20% except for profenofos (5.1-30%) and method detection limits were 1.8-12.7 ng/L, suggesting that the precision and accuracy of the developed method were viable. At environmentally relevant concentrations, the new adsorbent achieved comparable recoveries of target insecticides to hydrophilic-lipophilic balance adsorbent while providing an additional advantage by further reducing matrix effects. Field water samples from the Pearl River in Guangzhou, China were analyzed, and the frequent detection of neonicotinoids raises concerns about their aquatic risk. PMID- 29106044 TI - An Improved Binary Differential Evolution Algorithm for Feature Selection in Molecular Signatures. AB - The discovery of biomarkers from high-dimensional data is a very challenging task in cancer diagnoses. On the one hand, biomarker discovery is the so-called high dimensional small-sample problem. On the other hand, these data are redundant and noisy. In recent years, biomarker discovery from high-throughput biological data has become an increasingly important emerging topic in the field of bioinformatics. In this study, we propose a binary differential evolution algorithm for feature selection. Firstly, we suggest using a two-stage approach, where three filter methods including the Fisher score, T-statistics, and Information gain are used to generate the feature pool for input to differential evolution (DE). Secondly, in order to improve the performance of differential evolution algorithm for feature selection, a new variant of binary DE called BDE is proposed. Three optimization strategies are incorporated into the BDE. The first strategy is the heuristic method in initial stage, the second one is the self-adaptive parameter control, and the third one is the minimum change value to improve the exploration behaviour thus enhance the diversity. Finally, Support vector machine (SVM) is used as the classifier in 10 fold cross-validation method. The experimental results of our proposed algorithm on some benchmark datasets demonstrate the effectiveness of our algorithm. In addition, the BDE forged in this study will be of great potential in feature selection problems. PMID- 29106045 TI - Hyaluronic acid in the tail and limb of amphibians and lizards recreates permissive embryonic conditions for regeneration due to its hygroscopic and immunosuppressive properties. AB - The present review focuses on the role of hyaluronate (hyaluronic acid; HA) during limb and tail regeneration in amphibians and lizards mainly in relation to cells of the immune system. This non-sulfated glycosaminoglycan (GAG) increases in early stages of wound healing and blastema formation, like during limb or tail embryogenesis, when the immune system is still immature. The formation of a regenerating blastema occurs by the accumulation of mesenchymal cells displaying embryonic-like antigens and HA. This GAG adsorbs large amount of water and generates a soft tissue over 80% hydrated where mesenchymal and epithelial cells can move and interact, an obligatory passage for organ regeneration. GAGs and HA in particular rise to a high amount and coat plasma membranes of blastema cells forming a shield that likely impedes to the circulating immune cells to elicit an immune reaction against the embryonic-like antigens present on blastema cells. The evolution of limb-tail regeneration in amphibians dates back to the Devonian Carboniferous, while tail regeneration in lizards is a more recent evolution process, possibly occurred since the Jurassic, which is unique among amniotes. Both processes are associated with the reactivation of proliferating embryonic programs that involve the upregulation of genes for Wnt, non-coding RNAs, and HA synthesis in an immune-suppress organ, the regenerative blastema. Failure of maintaining a lasting HA synthesis for the formation of a highly hydrated blastema leads to scarring, the common healing process of amniotes equipped with an efficient immune system. The study of amphibian and lizard regeneration indicates that attempts to stimulate organ regeneration in other vertebrates require the induction of a highly hydrated and immune-depressed, HA-rich environment, similar to the extracellular environment present during development. PMID- 29106047 TI - Difference in CD5 and CD10 expression according to anatomic site. PMID- 29106046 TI - Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining beta-cell function and the achievement of the glycated hemoglobin target 1 year after initiation. AB - AIMS/INTRODUCTION: The glucose-lowering effects of the glucagon-like peptide-1 receptor agonist, liraglutide, have been shown to rely on remaining beta-cell function. However, the possible associations of remaining beta-cell function with the glucose-lowering effects of liraglutide in combination with basal insulin remain unknown and warrant investigation. MATERIALS AND METHODS: This was a single-center, retrospective, observational study carried out in a private hospital in Osaka, Japan. Type 2 diabetes patients who received a prescription change from insulin therapy, both multiple-dose insulin and basal insulin supported oral therapy, to liraglutide and basal insulin combination and continued the therapy for 54 weeks without additional oral antidiabetic drugs or bolus insulin were retrospectively analyzed. RESULTS: Among the 72 participants who received a prescription change from multiple-dose insulin and basal insulin supported oral therapy to liraglutide and basal insulin combination, 57 continued the therapy for 54 weeks. Of those who continued the therapy without receiving additional oral antidiabetic drugs or bolus insulin, seven participants achieved glycated hemoglobin < 7.0% at 54 weeks, but 30 participants did not. The participants who achieved glycated hemoglobin < 7.0% at 54 weeks had a significantly higher C-peptide immunoreactivity index, a beta-cell function related index frequently used in Japanese clinical settings. The receiver operating curve analysis showed that the C-peptide immunoreactivity index cut-off value for the achievement of glycated hemoglobin <7.0% at 54 weeks is 1.103. CONCLUSIONS: The current findings show that the glucose-lowering effects of liraglutide rely on remaining beta-cell function, even when used with basal insulin; and suggest that liraglutide and basal insulin combination might require additional bolus insulin to fully compensate insulin insufficiency in individuals with reduced beta-cell function. PMID- 29106048 TI - Changes in floral biology and inbreeding depression in native and invaded regions of Datura stramonium. AB - Plant populations invading new environments might compromise their fitness contribution to the next generation, because of the lack of native specialist pollinators and/or potential mates. Thus, changes in plant mating system and traits linked to it are expected in populations colonising new environments where selection would favour selfing and floral traits that maximise reproductive output. To test this, we studied native (Mexico) and non-native (Spain) populations of the obligate sexual reproducing annual weed Datura stramonium. Flower size, herkogamy, total number of seeds per plant, number of visits by and type of pollinators, and inbreeding depression were assessed in native and non native populations. Finally, we measured phenotypic selection on corolla size and herkogamy in each population. Flower size and herkogamy showed wide and similar variation in both ranges. However, the largest average flower size was found in one non-native population whereas the highest average positive herkogamy was detected in one native population. On average, flowers in the native range received more visits by pollinators. Hawkmoths were the main visitors in the native populations while only bees were observed visiting flowers in Spain's populations. Only in the native range was inbreeding depression detected. Selection to reduce herkogamy was found only in one native population. Absence of both inbreeding depression and selection on floral traits suggest a change in mating system of D. stramonium in a new range where generalist pollinators may be promoting high reproductive success. Selection against deleterious alleles might explain the reduction of inbreeding depression, promoting the evolution of selfing. PMID- 29106049 TI - A newborn infant with respiratory distress: More than meets the eye. PMID- 29106050 TI - Radiological-pathological correlation of malignant teratoma with liposarcomatous transformation: Proven by repeated transthoracic needle biopsy. AB - A mediastinal germ cell tumor with a sarcomatous component is extremely rare and is accompanied by a poor prognosis. Clinical and radiologic diagnosis is very difficult. Herein, we report a rare case of anterior mediastinal malignant teratoma containing a growing liposarcomatous component and detail the diagnostic process. The case was diagnosed by repeated transthoracic needle biopsy and correlated with changes in follow-up chest computed tomography and serum tumor markers. We also provide a review of the literature. PMID- 29106051 TI - Treatment of Chronic Refractory Neuropathic Pelvic Pain with High-Frequency 10 kilohertz Spinal Cord Stimulation. AB - Chronic neuropathic pelvic pain remains a recalcitrant problem in the field of pain management. Case series on application of 10 kHz spinal cord stimulation is presented. High frequency stimulation can improve chronic neuropathic pain states that are known to be mediated at the conus medullaris and offers another avenue for the treatment of these patients. PMID- 29106052 TI - Regional differences in right versus left congenital heart disease diagnoses in neonates in the United States. AB - BACKGROUND: Differences in the prevalence of left and right congenital heart defects (CHD) across the United States are unclear. This study evaluated the overall prevalence and the distribution of right versus left CHD across US regions and divisions in neonates. METHODS: Newborns born from 2000 to 2014 diagnosed with CHD were identified using the National Inpatient Sample. Heart defects were stratified into right, left, and "neither" subtypes. The risk of right and left heart diagnoses between US Census regions and divisions was compared using multivariable binomial regression, adjusting for infant, and hospital characteristics. RESULTS: Two hundred forty thousand four hundred fifty five newborns were included and 38,185 (15.9%) were classifiable as having either right or left subtypes. Between 2000 and 2014, the prevalence of right defects increased from 1.65 to 2.88 cases/1,000 live born infants (p < .0001), left defects increased from 0.47 to 0.75 cases/1,000 live born infants (p < .0001), and "neither" defects increased from 10.82 to 20.09 cases/1,000 live born infants (p < .0001). Newborns in the Northeast (RDadj .03, 95% CI .02, .03), Midwest (RDadj .02, 95% CI .02, .03), and South (RDadj .02, 95% CI .02, .02) were significantly more likely to have a right heart defect diagnosis compared to the West. When stratified by division, New England states had a significantly higher prevalence of right defects compared to the Pacific (RDadj .09, 95% CI .06, 0.11). No differences in the prevalence of left defects were seen. CONCLUSIONS: The prevalence of CHD diagnoses at birth in the US has increased, and regional differences in the prevalence of right defects appear to exist. PMID- 29106053 TI - Population Pharmacokinetics of Fosdagrocorat (PF-04171327), a Dissociated Glucocorticoid Receptor Agonist, in Patients With Rheumatoid Arthritis. AB - Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639). A simultaneous fit of a two-compartment model for Metabolite-1 and a one-compartment model for Metabolite-2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite-1 (~26%) and Metabolite-2 (~33%) compared with males. Age influenced clearance of Metabolite-1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration-time curve of Metabolite-1 at the extremes. PMID- 29106054 TI - A New Pentiptycene-Based Dianhydride and Its High-Free-Volume Polymer for Carbon Dioxide Removal. AB - In addition to possessing excellent chemical, mechanical, and thermal stability, polyimides and polyetherimides have excellent solubility in many solvents, which renders them suitable for membrane preparation. Two new monomers [a pentiptycene based dianhydride (PPDAn) and a pentiptycene imide-containing diamine (PPImDA)] and a pentiptycene-based polyimide [PPImDA-4,4'-hexafluoroisopropylidene diphthalic anhydride (PPImDA-6FDA)] have been synthesized and characterized by FTIR and 1 H NMR spectroscopy, gel-permeation chromatography, mass spectrometry, X-ray photoelectron spectroscopy, thermogravimetric analysis, differential scanning calorimetry, BET surface area, and X-ray diffraction. High-molecular weight PPImDA-6FDA has remarkable thermal stability and excellent solubility in common organic solvents. It also has an extraordinarily high fractional free volume (0.233) owing to the presence of -C(CF3 )2 - units, the rigid diamine, and the pentiptycene moiety in the polymer structure. It has high CO2 permeability (812 Barrer) owing to poor chain packing, which is caused by the fact that its rigid groups veil the influence of the ethereal oxygen groups in its backbone. It has the highest CO2 permeability among all reported pentiptycene-containing polymers (about six times higher than that of the most permeable one) without sacrificing selectivity. The high free volume, good microporosity, high solubility in many solvents, and remarkable thermal stability of PPImDA-6FDA point to the great potential of this polymer for CO2 removal. PMID- 29106055 TI - Lnc-NTF3-5 promotes osteogenic differentiation of maxillary sinus membrane stem cells via sponging miR-93-3p. AB - BACKGROUND: The function and the mechanism of long non-coding RNAs (lncRNAs) on the osteogenic differentiation of maxillary sinus membrane stem cells (MSMSCs) remain largely unknown. MATERIALS AND METHODS: The expression of lnc-NTF3-5 and Runt-related transcription factor 2 (RUNX2), Osterix (OSX), and Alkaline Phosphatase (ALP) was examined by quantitative real-time PCR (qRT-PCR) in MSMSCs during the process osteogenic differentiation. Then the function of lnc-NTF3-5 was evaluated by loss- and gain-of-function techniques, as well as qRT-PCR, western blot, and Alizarin Red staining. In addition, the microRNAs (miRNAs) sponge potential of lnc-NTF3-5 was assessed through RNA immunoprecipitation, dual luciferase reporter assay, and in vivo ectopic bone formation. RESULTS: Lnc-NTF3 5, RUNX2, OSX, and ALP increased alone with the differentiation. Inhibition of lnc-NTF3-5 decreased the expression of RUNX2, OSX, and ALP both at mRNA and protein levels. Alizarin red staining showed similar trend. In contrast, overexpression of lnc-NTF3-5 presented totally opposite effects. Besides, overexpression of lnc-NTF3-5 could decrease the expression of microRNA-93-3p (miR 93-3p). Enhance miR-93-3p could also inhibit the expression level of lnc-NTF3-5. RNA immunoprecipitation demonstrated that lnc-NTF3-5 is directly bound to miR-93 3p and dual luciferase reporter assay proved that miR-93-3p targets 3' UTR of RUNX2 to regulate its expression. Ultimately, in vivo bone formation study showed that lnc-NTF3-5 and miR-93-3p inhibitor co-transfection group displayed the strongest bone formation. CONCLUSIONS: The novel pathway lnc-NTF3-5/miR-93 3p/RUNX2 could regulate osteogenic differentiation of MSMSCs and might serve as a therapeutic target for bone regeneration in the posterior maxilla. PMID- 29106056 TI - Microenvironmental Stiffness of 3D Polymeric Structures to Study Invasive Rates of Cancer Cells. AB - Cells are highly dynamic elements, continuously interacting with the extracellular environment. Mechanical forces sensed and applied by cells are responsible for cellular adhesion, motility, and deformation, and are heavily involved in determining cancer spreading and metastasis formation. Cell/extracellular matrix interactions are commonly analyzed with the use of hydrogels and 3D microfabricated scaffolds. However, currently available techniques have a limited control over the stiffness of microscaffolds and do not allow for separating environmental properties from biological processes in driving cell mechanical behavior, including nuclear deformability and cell invasiveness. Herein, a new approach is presented to study tumor cell invasiveness by exploiting an innovative class of polymeric scaffolds based on two-photon lithography to control the stiffness of deterministic microenvironments in 3D. This is obtained by fine-tuning of the laser power during the lithography, thus locally modifying both structural and mechanical properties in the same fabrication process. Cage-like structures and cylindric stent-like microscaffolds are fabricated with different Young's modulus and stiffness gradients, allowing obtaining new insights on the mechanical interplay between tumor cells and the surrounding environments. In particular, cell invasion is mostly driven by softer architectures, and the introduction of 3D stiffness "weak spots" is shown to boost the rate at which cancer cells invade the scaffolds. The possibility to modulate structural compliance also allowed estimating the force distribution exerted by a single cell on the scaffold, revealing that both pushing and pulling forces are involved in the cell-structure interaction. Overall, exploiting this method to obtain a wide range of 3D architectures with locally engineered stiffness can pave the way for unique applications to study tumor cell dynamics. PMID- 29106057 TI - Higher arterial stiffness is associated with lower cognitive performance in patients with hypertension. AB - Cognitive impairment and elevated arterial stiffness have been described in patients with arterial hypertension, but their association has not been well studied. We evaluated the correlation of arterial stiffness and different cognitive domains in patients with hypertension compared with those with normotension. We evaluated 211 patients (69 with normotension and 142 with hypertension). Patients were age matched and distributed according to their blood pressure: normotension, hypertension stage 1, and hypertension stage 2. Cognitive function was assessed using the Mini-Mental State Examination, Montreal Cognitive Assessment, and a battery of neuropsychological evaluations that assessed six main cognitive domains. Pulse wave velocity was measured using a Complior device, and carotid properties were assessed by radiofrequency ultrasound. Central arterial pressure and augmentation index were obtained using applanation tonometry. The hypertension stage 2 group had higher arterial stiffness and worse performance either by Mini-Mental State Examination (26.8+/-2.1 vs 27.3+/-2.1 vs 28.0+/-2.0, P=.003) or the Montreal Cognitive Assessment test (23.4+/-3.5 vs 24.9+/-2.9 vs 25.6+/-3.0, P<.001). On multivariable regression analysis, augmentation index, intima-media thickness, and pulse wave velocity were the variables mainly associated with lower cognitive performance at different cognitive domains. Cognitive impairment in different domains was associated with higher arterial stiffness. PMID- 29106058 TI - Looking beyond the forest: Using harvest plots, gap analysis, and expert consultations to assess effectiveness, engage stakeholders, and inform policy. AB - We describe a combination of methods for assessing the effectiveness of complex interventions, especially where substantial heterogeneity with regard to the population, intervention, comparison, outcomes, and study design of interest is expected. We applied these methods in a recent systematic review of the effectiveness of reinforced home-based palliative care (rHBPC) interventions, which included home-based care with an additional and explicit component of lay caregiver support. We first summarized the identified evidence, deemed inappropriate for statistical pooling, graphically by creating harvest plots. Although very useful as a tool for summary and presentation of overall effectiveness, such graphical summary approaches may obscure relevant differences between studies. Thus, we then used a gap analysis and conducted expert consultations to look beyond the aggregate level at how the identified evidence of effectiveness may be explained. The goal of these supplemental methods was to step outside of the conventional systematic review and explore this heterogeneity from a broader perspective, based on the experience of palliative care researchers and practitioners. The gap analysis and expert consultations provided valuable input into possible underlying explanations in the evidence, which could be helpful in the further adaptation and testing of existing rHBPC interventions or the development and evaluation of new ones. We feel that such a combination of methods could prove accessible, understandable, and useful in informing decisions and could thus help increase the relevance of systematic reviews to the decision making process. PMID- 29106059 TI - Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis. AB - AIMS: Neutrophil extracellular traps (NETs) comprise a unique form of non apoptotic cell death exhibited by neutrophils, which occurs in a stepwise process termed NETosis. It has been postulated that NETosis plays an important role in the pathogenesis of autoimmune disorders. The aim of this study was to evaluate serum levels of NET remnants in patients with rheumatoid arthritis (RA), as well as potential associations between NET remnants and indicators of RA. METHODS: Serum levels of myeloperoxidase (MPO)-DNA complexes (NET remnants) were examined in 74 RA patients and 50 healthy controls using a modified enzyme-linked immunosorbent assay. Associations between the levels of these complexes and indicators of RA were then statistically evaluated. RESULTS: RA patients exhibited significantly higher levels of MPO-DNA complexes than the healthy controls, and these levels were associated with increased neutrophil counts and positivity for rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA). Among the 63 ACPA-positive RA patients examined, those with ACPA titers > 1600 U/mL showed significantly increased MPO-DNA levels. Receiver operating characteristic analysis determined that the area under the curve for all 74 RA patients was 0.798, with a sensitivity of 91.9% and a specificity of 56.0%, while that for the ACPA-negative patients was 0.891, with a sensitivity and specificity of 81.8% and 84.0%, respectively. CONCLUSIONS: The results of this study suggest that the disease status of RA is associated with increased NETosis. In particular, evaluation of serum MPO-DNA levels may comprise a useful complementary tool for discriminating RA patients from healthy individuals. PMID- 29106060 TI - Attitudes of patients with metastatic cancer towards research biopsies. AB - AIM: To evaluate the attitudes of patients with different cancers towards research biopsies outside a clinical trial. METHODS: Patients with metastatic cancer completed a questionnaire that assessed patients' willingness to consider research biopsies. Research biopsies were divided into two groups: biopsies performed as stand-alone procedures (research purposes only biopsy, RPOB) or performed during a clinically indicated biopsy (additional pass biopsy, APB). Factors analyzed included biopsy timing, biopsy site, sociodemographic information and information about prior trial participation. Univariate and multivariable analyses were conducted using random-effects logistic regression. RESULTS: One hundred and sixty-five patients with cancer (40 melanoma, 37 colorectal, 32 breast, 30 lung, 26 prostate) completed the questionnaire. Patients with melanoma demonstrated the greatest willingness to consider a research biopsy compared to patients with other cancer types (P < 0.05). Patients' ethnicity, time since previous biopsies, time since metastatic diagnosis, and previous trial enrolment were all statistically significant for willingness to consider a research biopsy on univariate analysis. When adjusting for statistically significant variables on univariate analysis, the odds of patients considering APBs were 14.6 times greater than RPOBs (P < 0.0001). Patients were also more willing to consider having blood or skin taken for research purposes (P < 0.0001) compared to liver and bone biopsies. CONCLUSIONS: Patients with cancer show a greater willingness to consider APBs compared to RPOBs, and biopsies performed at less invasive body sites. There are differences in the attitudes of patients with different cancers towards research biopsies. Further research addressing motivations and barriers to research biopsies should be considered to increase the availability of this important resource. PMID- 29106062 TI - Co-delivery of hypoxia inducible factor-1alpha small interfering RNA and 5 fluorouracil to overcome drug resistance in gastric cancer SGC-7901 cells. AB - BACKGROUND: Drug resistance cancer cells have become a major problem in chemotherapy. To solve this problem, the co-delivery of small interefering RNA (siRNA) and 5-fluorouracil chitosan nanoparticles was employed, aiming to reverse the multidrug resistance of gastric cancer SGC-7901 cells in vitro. METHODS: Chitosan nanoparticles were prepared using an ionic gel method. siRNA nanoparticles were characterized by gel retardation assays. Particle size and zeta potential were measured to confirm nanoparticle formation. The transfection efficiency of siRNA was determined by flow cytometry and high-content screening. Western blotting and a quantitative real-time-polymerase chain reaction were used to assess the silencing efficiency of siRNA. Accumulation and efflux experiments for rhodamine-123, cell migration experiments, cell sensitivity analyses and cell apoptosis assays were used to determine whether siRNA could reverse multidrug resistance. A systemic toxicity assay was used to evaluate the safety of nanoparticles. RESULTS: Compared to naked siRNA, the co-delivery system demonstrated a higher transfection efficiency and gene silencing efficiency by inhibiting the efflux of P-glycoprotein and cell migration. Moreover, the combination treatment with siRNA and 5-fluorouracil co-delivered by chitosan nanoparticles can increase the sensitivity of drug resistance cells and cell apoptosis. Finally, the safety of nanoparticles was evaluated in vivo and the results obtained suggested that nanoparticles did not have any obvious toxicity. CONCLUSIONS: Co-delivery of siRNA and 5-fluorouracil chitosan nanoparticles is an attractive strategy for overcoming multidrug resistance. PMID- 29106063 TI - Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy. AB - AIMS: To determine the specific role of podocyte-expressed cannabinoid-1 receptor (CB1 R) in the development of diabetic nephropathy (DN), relative to CB1 R in other renal cell types. MATERIAL AND METHODS: We developed a mouse model with a podocyte-specific deletion of CB1 R (pCB1Rko) and challenged this model with streptozotocin (STZ)-induced type-1 DN. We also assessed the podocyte response to high glucose in vitro and its effects on CB1 R activation. RESULTS: High glucose exposure for 48 hours led to an increase in CB1 R gene expression (CNR1) and endocannabinoid production in cultured human podocytes. This was associated with podocyte injury, reflected by decreased podocin and nephrin expression. These changes could be prevented by Cnr1-silencing, thus identifying CB1R as a key player in podocyte injury. After 12 weeks of chronic hyperglycaemia, STZ-treated pCB1Rko mice showed elevated blood glucose similar to that of their wild-type littermates. However, they displayed less albuminuria and less podocyte loss than STZ-treated wild-type mice. Unexpectedly, pCB1Rko mice also have milder tubular dysfunction, fibrosis and reduction of cortical microcirculation compared to wild type controls, which is mediated, in part, by podocyte-derived endocannabinoids acting via CB1 R on proximal tubular cells. CONCLUSIONS: Activation of CB1 R in podocytes contributes to both glomerular and tubular dysfunction in type-1 DN, which highlights the therapeutic potential of peripheral CB1 R blockade. PMID- 29106061 TI - 2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups. AB - OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of >=90%, corresponding to a score of >=7.5 (>=8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of >=50-<55% as "possible IIM." CONCLUSION: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria. PMID- 29106064 TI - Chemical profiling and quantification of ShenKang injection, a systematic quality control strategy using ultra high performance liquid chromatography with Q Exactive hybrid quadrupole orbitrap high-resolution accurate mass spectrometry. AB - ShenKang injection is traditional Chinese medicine used to treat chronic renal failure in China. It is a compound preparation that consists of four herbs: Rhubarb, Salvia miltiorrhiza, Safflower and Radix Astragali. We developed an ultra high pressure liquid chromatography coupled with Q Exactive hybrid quadrupole-orbitrap high resolution accurate mass spectrometry tandem mass spectrometry method to analyze its chemical compositions, and a total of 90 compounds were identified from ShenKang injection. Among them, 19 major compounds were unambiguously detected by comparing with reference standards. Meanwhile, 13 representative compounds selected as quality control markers were simultaneously quantified in ShenKang injection samples. Chromatographic separation was accomplished on a Waters ACQUITY HPLC(r) HSS C18 column using gradient elution. The method was validated with respect to linearity, sensitivity, accuracy and precision, reproducibility and stability. And the validated method was successfully applied for simultaneous determination of 13 bioactive compounds in ShenKang injection from ten batches of samples by liquid chromatography with mass spectrometry. The results were analyzed by principal components analysis method, and three compounds had a significant relationship with the quality control of ShenKang injection. This research established a rapid and reliable method for the integrating quality control, including qualitation and quantification of ShenKang injection. PMID- 29106065 TI - Fast Setting Silk Fibroin Bioink for Bioprinting of Patient-Specific Memory-Shape Implants. AB - The pursuit for the "perfect" biomimetic and personalized implant for musculoskeletal tissue regeneration remains a big challenge. 3D printing technology that makes use of a novel and promising biomaterials can be part of the solution. In this study, a fast setting enzymatic-crosslinked silk fibroin (SF) bioink for 3D bioprinting is developed. Their properties are fine-tuned and different structures with good resolution, reproducibility, and reliability can be fabricated. Many potential applications exist for the SF bioinks including 3D bioprinted scaffolds and patient-specific implants exhibiting unique characteristics such as good mechanical properties, memory-shape feature, suitable degradation, and tunable pore architecture and morphology. PMID- 29106066 TI - Pharmacotherapy of nonalcoholic steatohepatitis: Reflections on the existing evidence. AB - Pharmacotherapy for nonalcoholic fatty liver disease (NAFLD) has not yet been approved by the US Food and Drug Administration. Over the past decade, a large number of clinical studies have explored the safety and efficacy of different drugs in treating nonalcoholic steatohepatitis (NASH), including diet pills, antioxidants, insulin sensitizers, lipid-lowering agents, anti-inflammatory cytokines, cytoprotective agents and intestinal probiotics. Based on the evidence from randomized controlled trials a number of academic groups have developed guidelines for the diagnosis and management of NAFLD and NASH. In this article, we discussed the current situation of NASH pharmacotherapy. PMID- 29106067 TI - Beyond disease susceptibility-Leveraging genome-wide association studies for new insights into complex disease biology. AB - Genetic studies in complex diseases have been highly successful, but have also been largely one-dimensional: predominantly focusing on the genetic contribution to disease susceptibility. While this is undoubtedly important-indeed it is a pre requisite for understanding the mechanisms underlying disease development-there are many other important aspects of disease biology that have received comparatively little attention. In this review, I will discuss how existing genetic data can be leveraged to provide new insights into other aspects of disease biology, why such insights could change the way we think about complex disease, and how this could provide opportunities for better therapies and/or facilitate personalised medicine. To do this, I will use the example of Crohn's disease-a chronic form of inflammatory bowel disease that has been one of the main success stories in complex disease genetics. Indeed, thanks to genetic studies, we now have a much more detailed understanding of the processes involved in Crohn's disease development, but still know relatively little about what determines the subsequent disease course (prognosis) and why this differs so considerably between individuals. I will discuss how we came to realise that genetic variation plays an important role in determining disease prognosis and how this has changed the way we think about Crohn's disease genetics. This will illustrate how phenotypic data can be used to leverage new insights from genetic data and will provide a broadly applicable framework that could yield new insights into the biology of multiple diseases. PMID- 29106068 TI - Global Proteome Analysis Links Lysine Acetylation to Diverse Functions in Oryza Sativa. AB - Lysine acetylation (Kac) is an important protein post-translational modification in both eukaryotes and prokaryotes. Herein, we report the results of a global proteome analysis of Kac and its diverse functions in rice (Oryza sativa). We identified 1353 Kac sites in 866 proteins in rice seedlings. A total of 11 Kac motifs are conserved, and 45% of the identified proteins are localized to the chloroplast. Among all acetylated proteins, 38 Kac sites are combined in core histones. Bioinformatics analysis revealed that Kac occurs on a diverse range of proteins involved in a wide variety of biological processes, especially photosynthesis. Protein-protein interaction networks of the identified proteins provided further evidence that Kac contributes to a wide range of regulatory functions. Furthermore, we demonstrated that the acetylation level of histone H3 (lysine 27 and 36) is increased in response to cold stress. In summary, our approach comprehensively profiles the regulatory roles of Kac in the growth and development of rice. PMID- 29106069 TI - L3 C3 P3 : Tricarbontriphosphide Tricyclic Radicals and Cations Stabilized by Cyclic (alkyl)(amino)carbenes. AB - Alkynes usually oligomerize to give rings with a conjugated pi-electron system. In contrast, phosphaalkynes, R-C=P, frequently give compounds with polycyclic structures, which are thermodynamically more stable than the corresponding pi conjugated isomers. The syntheses of the first C3 P3 tricyclic compounds are reported with either radical or cationic ground states stabilized by cyclic (alkyl)(amino)carbenes (CAACs). These compounds may be considered as examples of tricarbontriphosphide coordinated by carbenes and are likely formed via trimerization of the corresponding mono-radicals CAAC-CP. . The mechanism for the formation of these tricarbontriphosphide radicals has been rationalized by a combination of experiments and DFT calculations. PMID- 29106070 TI - Transverse partial stent ablation with rotational atherectomy for suboptimal culotte technique in left main stem bifurcation. AB - Longitudinal rotational atherectomy of metal struts is well described as bail-out strategy to treat undilatable instent restenosis. Ablation of metal stent struts jailing the ostium of a major side branch in a coronary bifurcation is not described. In the current report, we describe a case of "transverse" rotational atherectomy to treat a failure of culotte stenting in a left main stem bifurcation. We document for the first time in vivo and in man the effect of this strategy using optical coherence tomography. PMID- 29106071 TI - Multiple centre evaluation study of ADAMTS13 activity and inhibitor assays. AB - INTRODUCTION: Accurate evaluation of ADAMTS13 activity is required for the diagnosis and clinical management of thrombotic microangiopathies, and commercial kits are available for routine laboratory use. METHODS: Our study compares the results from Technoclone (Technoclone GmbH, Austria) activity and Inhibitor kits with specialist laboratory reference methods (FRETS and ELISA IgG) and the impact of transporting frozen samples and comparison of results. RESULTS: This multicentre study identified differences in Technoclone activity results compared to specialist testing, which could potentially impact diagnosis. A change in the commercial kit during the study period appears to have rectified the detection levels. Frozen samples provided comparable results between sites. CONCLUSION: With close attention to normal ranges, commercial kits are suitable for use in the clinical diagnosis of thrombotic microangiopathies and frozen transportation of samples between sites is a suitable approach. However, a robust external quality control system is essential to provide an independent evaluation of changes in kit production. PMID- 29106072 TI - Regulation of continuous but complex expression pattern of Six1 during early sensory development. AB - BACKGROUND: In vertebrates, cranial sensory placodes give rise to neurosensory and endocrine structures, such as the olfactory epithelium, inner ear, and anterior pituitary. We report here the establishment of a transgenic mouse line that expresses Cre recombinase under the control of Six1-21, a major placodal enhancer of the homeobox gene Six1. RESULTS: In the new Cre-expressing line, mSix1-21-NLSCre, the earliest Cre-mediated recombination was induced at embryonic day 8.5 in the region overlapping with the otic-epibranchial progenitor domain (OEPD), a transient, common precursor domain for the otic and epibranchial placodes. Recombination was later observed in the OEPD-derived structures (the entire inner ear and the VIIth-Xth cranial sensory ganglia), olfactory epithelium, anterior pituitary, pharyngeal ectoderm and pouches. Other Six1 positive structures, such as salivary/lacrimal glands and limb buds, were also positive for recombination. Moreover, comparison with another mouse line expressing Cre under the control of the sensory neuron enhancer, Six1-8, indicated that the continuous and complex expression pattern of Six1 during sensory organ formation is pieced together by separate enhancers. CONCLUSIONS: mSix1-21-NLSCre has several unique characteristics to make it suitable for analysis of cell lineage and gene function in sensory placodes as well as nonplacodal Six1-positive structures. Developmental Dynamics 247:250-261, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29106073 TI - 2D Lead Dihalides for High-Performance Ultraviolet Photodetectors and their Detection Mechanism Investigation. AB - 2D halide semiconductors, a new family of 2D materials in addition to transition metal dichalcogenides, present ultralow dark current and high light conversion yield, which hold great potential in photoconductive detectors. Herein, a facile aqueous solution method is developed for the preparation of large-scale 2D lead dihalide nanosheets (PbF2-x Ix ). High-performance UV photodetectors are successfully implemented based on 2D PbF2-x Ix nanosheets. By modulating the components of halogens, the bandgap of PbF2-x Ix nanosheets can be tuned to meet varied detection spectra. The photoresponse dependence on incident power density, wavelength, detection environment, and temperature are systematically studied to investigate their detection mechanism. For PbI2 photodetectors, they are dominantly driven by a photoconduction mechanism and show a fast response speed and a low noise current density. A high normalized detectivity of 1.5 * 1012 Jones and an ION /IOFF ratio up to 103 are reached. On the other hand, PbFI photodetectors demonstrate a photogating mechanism mediated by trap states showing high responsivity. The novel 2D halide materials with wide bandgaps, superior detection performance, and facile synthesis process can enrich the Van der Waals solids family and hold great potential for a wide variety of applications in advanced optoelectronics. PMID- 29106074 TI - Cross-Classified Multilevel Modelling of the Effectiveness of Similarity-Based Virtual Screening. AB - The screening effectiveness of a chemical similarity search depends on a range of factors, including the bioactivity of interest, the types of similarity coefficient and fingerprint that comprise the similarity measure, and the nature of the reference structure that is being searched against a database. This study introduces the use of cross-classified multilevel modelling as a way to investigate the relative importance of these four factors when carrying out similarity searches on the ChEMBL database. Two principal conclusions can be drawn from the analyses: that the fingerprint plays a more important role than the similarity coefficient in determining the effectiveness of a similarity search, and that comparative studies of similarity measures should involve many more reference structures than has been the case in much previous work. PMID- 29106075 TI - Decomposing multiple dimensions of stability in global change experiments. AB - Ecological stability is the central framework to understand an ecosystem's ability to absorb or recover from environmental change. Recent modelling and conceptual work suggests that stability is a multidimensional construct comprising different response aspects. Using two freshwater mesocosm experiments as case studies, we show how the response to single perturbations can be decomposed in different stability aspects (resistance, resilience, recovery, temporal stability) for both ecosystem functions and community composition. We find that extended community recovery is tightly connected to a nearly complete recovery of the function (biomass production), whereas systems with incomplete recovery of the species composition ranged widely in their biomass compared to controls. Moreover, recovery was most complete when either resistance or resilience was high, the latter associated with low temporal stability around the recovery trend. In summary, no single aspect of stability was sufficient to reflect the overall stability of the system. PMID- 29106076 TI - Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers. AB - : Essentials Specific reversal agents for managing severe factor Xa inhibitor associated bleeding are lacking. We assessed 4-factor-prothrombin complex concentrate (4F-PCC) and tranexamic acid (TXA). 4F-PCC, but not TXA, reduced the prothrombin time and increased endogenous thrombin potential. These agents may be viable options for reversal of therapeutic doses of rivaroxaban. SUMMARY: Background Oral activated factor X inhibitors such as rivaroxaban are widely used, but specific reversal agents are lacking. Although four-factor prothrombin complex concentrate (4F-PCC) and tranexamic acid (TXA) are sometimes used to manage serious bleeding, their efficacy is unknown. Prior studies in healthy subjects taking rivaroxaban revealed that 4F-PCC partially reverses the prolonged prothrombin time (PT), and fully restores the endogenous thrombin potential (ETP). The effect of TXA has not been evaluated. Methods In this double-blind, parallel-group study, 147 healthy volunteers given rivaroxaban 20 mg twice daily for 3 days were randomized after their morning dose on day 4 to receive intravenous 4F-PCC (50 IU kg-1 ), TXA (1.0 g), or saline. Standardized punch biopsies were performed at baseline and after 4F-PCC, TXA or saline administration. Reversal was assessed by measuring bleeding duration and bleeding volume at biopsy sites, and by determining the PT and ETP. Results As compared with saline, 4F-PCC partially reversed the PT and completely reversed the ETP, whereas TXA had no effect. Neither 4F-PCC nor TXA reduced bleeding duration or volume. All treatments were well tolerated, with no recorded adverse events. Conclusions Although 4F-PCC reduced the PT and increased the ETP in volunteers given supratherapeutic doses of rivaroxaban, neither 4F-PCC nor TXA influenced punch biopsy bleeding. PMID- 29106077 TI - In Silico Studies of Mammalian delta-ALAD Interactions with Selenides and Selenoxides. AB - Previous studies have shown that the mammalian delta-aminolevulinic acid dehydratase (delta-ALAD) is inhibited by selenides and selenoxides, which can involve thiol oxidation. However, the precise molecular interaction of selenides and selenoxides with the active center of the enzyme is unknown. Here, we try to explain the interaction of selenides and the respective selenoxides with human delta-ALAD by in silico molecular docking. The in silico data indicated that Se atoms of selenoxides have higher electrophilic character than their respective selenides. Further, the presence of oxygen increased the interaction of selenoxides with the delta-ALAD active site by O...Zn coordination. The interaction of S atom from Cys124 with the Se atom indicated the importance of the nucleophilic attack of the enzyme thiolate to the organoselenium molecules. These observations help us to understand the interaction of target proteins with organoselenium compounds. PMID- 29106078 TI - [Acute exacerbations of chronic obstrucive pulmonary disease in the emergency department: beyond white blood cells, C-reactive protein and chest X-ray]. PMID- 29106079 TI - [When and for how long do patients with acute heat failure have to be admitted?] PMID- 29106080 TI - [Factors associated with short stays for patients admitted with acute heart failure]. AB - OBJECTIVES: To identify factors associated with short hospital stays for patients admitted with acute heart failure (AHF) admitted to hospitals with short-stay units (SSU). MATERIAL AND METHODS: Multicenter nonintervention study in a multipurpose cohort of patients with AHF to 10 Spanish hospitals with short-stay units; patients were followed prospectively. We recorded demographic data, medical histories, baseline cardiorespiratory and function variables on arrival in the emergency department, on admission, and at 30 days. The outcome variable was a short hospital stay (<= 4 days). We built receiver operating characteristic curves of simple and mixed predictive models for short stays and calculated the area under the curves. RESULTS: A total of 1359 patients with a mean (SD) age of 78.7 (9.9) years (53.9% women) were included; 568 (41.8%) had short stays. Five hundred ninety patients (43.4%) were admitted to SSU and 769 (56.6%) were admitted to conventional wards. The variables associated with a short-stay according to the mixed regression model were hypertensive crisis (odds ratio [OR], 1.79; 95% CI, 1.17-2.73; P=.007) and admission to a SSU (OR, 16.6; 95% CI, 10.0-33.3; P<.001). Hypotensive AHF (OR, 0.49; 95% CI, 0.26-0.91; P=.025), hypoxemia (OR, 0.68; 95% CI, 0.53-0.88; P=.004); and admission on a Wednesday, Thursday, or Friday (OR, 0.62; 95% CI, 0.49-0.77; P<.001) were associated with a long stay. The area under the receiver operating characteristic curve was 0.827 (95% CI, 0.80-0.85; P<.001). Thirty-day mortality and readmission rates did not differ between patients with short vs long stays (mortality, 0.5% in both cases, P=.959; and readmission, 22.9% vs 27.7%, respectively; P=.059). CONCLUSION: Both clinical and administrative factors are independently related to whether patients with AHF have short stays in the hospitals studied, and among therapy, it is remaslcasle the existence of a SSU. PMID- 29106081 TI - [Impact of a quality of care improvement team on the use of sedatives during wound repair in young children]. AB - OBJECTIVES: To analyze the impact of actions organized by a quality of care improvement team on the use of sedatives when treating wounds in children under the age of 5 years. MATERIAL AND METHODS: Quasiexperimental pre/post study enrolling children under the age of 5 years brought to a pediatric emergency department with wounds requiring surgical repair with suturing. A team to promote the use of sedation in such minor procedures in these children was established. The team organized the following interventions: training workshops, development and circulation of a sedation protocol, and establishment of a computerized alert. The first analysis of results was done at 2 months and the second at 9 months. The quality of care indicators, the use of sedatives while wounds were treated in children, was analized in 2 age groups: (under the age of 2 years and between 2 and 5 years) and results were compared with the preintervention phase. RESULTS: A total of 22 958 emergencies were registered in children under 5 years old; 548 (2.4%) involved uncomplicated wounds. Of the 548 patients, 350 (63.8%) required surgical repair, 75 of them (21.4%) in children under the age of 2 years. Ten percent of these children had received a sedative in the period before the team's intervention; 22% had been sedated at the 2-month analysis and 31.4% at 9 months (P<.01). For children between 2 and 5 years old, the percentages were 4.4% (pre-intervention), 10% (2 months), and 25% (9 months) (P<.01). Eighty-two percent of the families and 69% of the physicians thought that anxiety was adequately controlled. CONCLUSION: Actions designed by a multidisciplinary quality of care team are effective for increasing the use of sedatives while wounds are treated in children under the age of 5 years. PMID- 29106082 TI - [Hospital emergency health service care as a risk factor for methicillin resistant Staphylococcus aureus in residents of long-term care facilities]. AB - OBJECTIVES: Residents of long-term care facilities (LTCFs) are at risk for methicillin-resistant Staphylococcus aureus(MRSA) colonization because of age related illnesses and high rates of hospital use, in particular, of visits to the emergency department (ED). We aimed to determine the prevalence of and risk factors for MRSA colonization in LTCF residents. MATERIAL AND METHODS: A descriptive cross-sectional study was carried out in 2014 (April-June). LTCF residents in the northern partof the island of Tenerife were eligible for enrollment. We collected clinical and epidemiologic data and took nasalswabs for culture (chromID MRSA agar) to screen for MRSA colonization. Molecular typing was established by pulsedfield gel electrophoresis. MRSA colonization was the dependent variable in logistic regression analysis. RESULTS: A total of 624 residents were enrolled. MRSA was detected in 25.8%. Sixty-four of the residents had receivedcare in a hospital ED in the 3 months prior to enrollment. Multivariant regression analysis detected 2 risk factors for MRSA colonization: hospital ED care in the last 3 months (odds ratio [OR], 2.05; 95% CI, 1.29-3.26; P=.002) and the presence of skin lesions (OR, 1.65; 95% CI, 1.11-2.44); P=.013). The health-care-associated, ST5 MRSA-IVa, was the most prevalent (75.8%). CONCLUSION: LTCF residents in our area are a significant reservoir of MRSA colonization. Hospital ED care was a predictorof MRSA colonization. We believe that stronger measures to prevent cross-contamination of multidrug resistantmicroorganisms must be implemented, along with active vigilance systems to detect MRSA in hospitals. PMID- 29106083 TI - [Quality of life in exacerbated chronic obstructive pulmonary disease emergencies: influence on the decision to admit patients and relation to poor outcome at 2 months]. AB - OBJECTIVES: To study the influence of quality of life on the decision to admit patients attended for exacerbated chronic obstructive pulmonary disease (COPD) in a hospital emergency department (ED) and to explore the association with poor outcome at 2 months. MATERIAL AND METHODS: Prospective study of a cohort of patients with exacerbated COPD attended in an ED between November 2011 and September 2012. We collected sociodemographic and clinical data as well as scores on the COPD Assessment Test (CAT), the modified scale of the Medical Research Council, and the Borg scale for Perceived Dyspnea at the following times: baseline (clinically stable) (t0), on exacerbation (emergency) (t1), 15 days later or on discharge (t2), and 2 months after the emergency (t3). The outcome measures were hospital admission, revisits to the ED, and readmission within 2 months of the exacerbation. RESULTS: A total of 191 patients treated for exacerbated COPD were included. The mean (SD) age was 74.9 (10.2) years; 173 (90.6%) were men. The exacerbations were mild in 97 cases (56.4%). The median (interquartile range) CAT scores were 14.5 (9-21), 20 (15-28), 16 (10-22), and 14.5 (10-21) at t0, t1, t2 and t3, respectively. One hundred twenty-three patients (64.4%) were admitted, 68 (35.6%) revisited the ED, and 39 (20.4%) were readmitted within 2 months. A high level of disease impact on quality of life at t1 (vs low impact) was independently associated with hospital admission (adjusted odds ratio [OR], 3.7; 95% CI, 1.0-13.2; P=.043). Impact on t2 was associated with a revisit within 2 months (adjusted OR, 3.6; 95% CI, 1.1-11.7; P=.031). Minimal change between the t1 and t2 CAT scores was independently associated with an ED revisit within 2 months (adjusted OR, 2.9; 95% CI, 1.2-7.4; P=.023). When the data for patients discharged from the ED were analyzed separately from those for admitted patients, the differences were statistically significant only for those who had been hospitalized. CONCLUSION: The CAT score could be useful for predicting hospital admissions and revisiting within 2 months, especially in patients admitted for exacerbated COPD. PMID- 29106084 TI - [Ultrasonography and the Alvarado score in the diagnosis of acute appendicitis: impact on the negative appendectomy rate]. AB - OBJECTIVES: To establish the negative appendectomy rate (NAR) after patients with acute abdomen were evaluated with the Alvarado score and compare it to the NAR in patients evaluated with abdominal ultrasound. MATERIAL AND METHODS: Cross sectional, retrospective, descriptive study in patients who underwent emergency surgery for suspected acute appendicitis in a tertiary-care hospital over a period of 1 year. RESULTS: A total of 225 patients were included. The NAR was 7.11% for the series. An Alvarado score of 5 or more had an odds ratio (OR) of 7.46 (P=.0002) for acute appendicitis; sensitivity was 94.2%. Ultrasound findings consistent with acute appendicitis had an OR of 3.58 (P=.0125) for the diagnosis; the NAR was 5%. CONCLUSION: The high sensitivity of an Alvarado score of 5 or more supports using this tool to evaluate all patients who come to the emergency department with pain in the right iliac fossa. With scores of 7 or more the NAR falls to 3%. Abdominal ultrasound is a rapid, inexpensive diagnostic procedure associated with a low NAR. PMID- 29106085 TI - [Recommendations for the management of emergencies in patients with diabetes, acute metabolic complications of diabetes, and steroid-related hyperglycemia]. AB - EN: Persons with diabetes make up a large percentage of patients attended in the emergency department. Most will be discharged, but patients who remain under observation in wards managed by the emergency department or who wait are waiting to be admitted to a conventional ward must receive appropriate, protocol-guided treatment for their diabetes. Situations of hyper- or hypoglycemia must be avoided because both worsen prognosis. Emergency physicians must correctly and efficiently prevent, diagnose, and manage acute metabolic complications of diabetes such as simple hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state. They must also be ready to prescribe and properly administer intravenous insulin to critically ill patients. Hyperglycemia induced by treatment with steroids deserves special mention. If this complication develops, the hyperglycemia is intense, influenced by increased insulin resistance and gluconeogenesis in the liver. Thus, it usually appears after meals and is dependent on steroid dose, duration of treatment, and individual predisposition. The recommendations in this paper elaborated by consensus of the Spanish Society of Emergency Medicine (SEMES) experts, are the first to be written specifically for use in emergency departments in Spain. They give a detailed, in-depth overview of emergencies related to diabetes and diabetic complications. PMID- 29106087 TI - [Giant abdominal cyst]. PMID- 29106086 TI - [Morphine for acute pulmonary edema?] PMID- 29106088 TI - [Advisability of not using a literal translation of "milking phenomenon"]. PMID- 29106089 TI - [Authors' reply]. PMID- 29106090 TI - [A linguist's response]. PMID- 29106092 TI - [Author's response]. PMID- 29106091 TI - [Management of severe sepsis and septic shock in a tertiary care urban hospital emergency department: opportunities for improvement]. PMID- 29106093 TI - [Emergency department staff, the limitation of life-sustaining treatment, and the feasibility of organ donation]. PMID- 29106094 TI - [Suspicion of chemical submission in a hospital emergency department: procedures followed and toxicological analyses in a case series]. PMID- 29106095 TI - [May-Thurner syndrome]. PMID- 29106096 TI - [Discharged from the emergency department with elevated troponin levels?] PMID- 29106097 TI - [Detection of human immunodeficiency virus infection in Spanish emergency departments: reality or to utopian dream?] PMID- 29106098 TI - [The European Curriculum of Geriatric Emergency Medicine: A collaboration between the European Society for Emergency Medicine (EuSEM) and the European Union of Geriatric Medicine Society (EUGMS)]. PMID- 29106099 TI - [Elevated troponin I level in patients discharged home directly from the emergency department: prognostic value for 1-year mortality]. AB - OBJECTIVES: To study the prognostic role of elevated troponin I levels in patients discharged home directly from a hospitalemergency department. MATERIAL AND METHODS: Observational study of a retrospective cohort of all patients attended for any emergency for whom troponin I tests were ordered and who were discharged home directly from our hospital emergency department between January and December 2012. We collected demographic information, medical histories, symptoms related to the acute coronary event, and diagnosis on discharge. The main outcome was all-cause mortality in the year following discharge. RESULTS: A total of 1381 patients discharged home directly from the emergency department were studied; 1192 (86.3%) had normal troponin I results and 189 (13.7%) had elevated levels. On multivariate analysis, troponin I elevation emerged as an independent risk factor for death within a year of discharge (hazard ratio, 2.41; 95% CI, 1.40-4.22; P<.01). CONCLUSION: A raised troponin I level is an independent predictor of 1-year mortality in patients for whom this test is ordered at least once and who are discharged home directly from a hospital emergency service. PMID- 29106100 TI - [Multicenter, triple-blind randomized placebo controlled trial of adjuvant nitrous oxide 50% in oxygen 50%: efficacy for reducing pain and increasing satisfaction in patients treated for renal colic in the emergency department]. AB - OBJECTIVES: To assess the efficacy of a nitrous oxide and oxygen mixture (N2O/O2 50/50) for reducing pain and increasing satisfaction in patients with an initial clinical diagnosis of renal colic in the emergency department. MATERIAL AND METHODS: Multicenter, triple-blind randomized placebo-controlled trial. We randomized 147 patients with a clinical diagnosis of renal colic to an experimental group to receive the N2O/O2 50/50 mixture (n = 70) or a control group to receive 50% oxygen in air (n = 77). Both groups also received conventional analgesia with dexketoprofen plus metamizol and opiates administered sequentially until pain was brought under control; rescue doses of opioids were also available. The endpoints were the reduction in pain intensity expressed on a visual analog scale (VAS) 5 minutes after the start of treatment and the patient's level of satisfaction with treatment on discharge. RESULTS: The mean (SD) reduction in pain 5 minutes after starting analgesic treatment was 1.84 (2.05) VAS points in the intervention group and 1.67 (1.91) in the placebo group. The difference was not significant (P = .603). Neither were between-group differences significant at other pain evaluation times (10, 15, 30, and 60 minutes). Treatment was considered satisfactory (?? 9 on a VAS) by 53 of the 70 intervention-group patients (75.7%) and 56 of the 77 (72.7%) placebo-group patients (P = .412). Adverse effects appeared in 33 of the 70 patients (48.5%) who received the N2O/O2 mixture and in 19 patients (24.7%) who received the placebo (P = .003). CONCLUSION: The addition of N2O/O2 50/50 to standard analgesic therapy does not enhance the efficacy of pain control or the satisfaction of patients treated for renal colic in the emergency department. PMID- 29106101 TI - [Prevalence of undiagnosed human immunodeficiency virus infection in an emergency department and the characteristics of newly diagnosed patients]. AB - OBJECTIVES: To estimate the prevalence of undiagnosed human immunodeficiency virus (HIV) infection detected by routine testing of patients seeking care in an emergency department and to describe the characteristics associated with new HIV infection diagnosis. MATERIAL AND METHODS: Walk-in patients between the ages of 15 and 75 years who required a blood test were included. Routine fourth generation enzyme-linked immunoassays were performed to detect HIV infection in all samples extracted. Patients with positive results were referred to the infectious diseases department for monitoring and treatment. RESULTS: Blood samples for 1722 patients were analyzed. Twenty-one patients (1.2%) refused to allow their samples to be tested; 19 more samples (1.1%) could not be tested. The prevalence of undiagnosed HIV infection among the remaining 1682 remaining patients was 0.6% (95% CI, 0.23%-0.96%). The prevalence tended to be nonsignificantly higher among patients born outside Spain (0.97% [95% CI, 0.3% 2.20%]) and in 36-50-year-olds (1.46% [95% CI, 0.4%-2.5%]). Characteristics associated with undiagnosed HIV infection were male sex (odds ratio [OR], 5.78 [95% CI, 1.0-31.4]), presenting with a chief complaint that suggested infection (OR, 8.14 [95% CI, 1.6-41.4]), and a history of hepatitis (OR, 5.53 [95% CI, 1.1 27.7]). CONCLUSION: The prevalence of undiagnosed HIV infection in our emergency department was high at 0.6%. The rate of patient acceptance of routine HIV testing was high. Strategies that target improving the detection of undiagnosed HIV infection are advisable. PMID- 29106102 TI - [Comparison of dressings and devices to secure peripheral venous catheters in the emergency department: suitability according to patient profile]. AB - OBJECTIVES: To identify the most suitably designed dressings and devices to secure peripheral venous catheters (PVCs) in different types of patients. To evaluate the traction force the dressings could withstand and times they are able to keep the PVC in place in the emergency department. MATERIAL AND METHODS: Quasi experimental descriptive observational study with inferential statistics to compare variables. We studied the designs of devices and dressings for securing PVCs in the emergency department (Omnifix, Tegaderm, Oper Dres, Steri-strip, and stopcocks) and special adaptations devised by the authors: A (Tegaderm), A1 (Tegaderm + Steristrip), A2 (Tegaderm + Oper Dres), B (Omnifix), C (Omnifix doubled). RESULTS: Participants carried out 520 tests on models of human patients to simulate standard, hairy, and hairy-sweaty skin. Costs were as follows: A, ? 0.15; A1, ? 0.35; A2, ? 0.18; B, ? 0.005; C, ? 0.01. The times in seconds required to apply the dressings were as follows: (A, 15; A1, 25; A2, 20; B, 20; C, 35). The dressings withstood the following traction forces in grams: lengthwise, A, 760; B, 1694; C, 1530); perpendicular (A, 785; B, 1450; C, 3290), and transversal (A, 760; A1, 1220; A2, 1510; B, 1720; C, 2255). CONCLUSION: Design C was able to withstand greater forces in the traction tests. Extra surgical tape significantly improved resistance to traction when a stopcock was used. Using a Steri-strip with the Tegaderm device increased resistance to traction, although the improvement was less than that obtained with the Omnifix. The Tegaderm plus Omnifix design was significantly more resistant to traction than the Tegaderm by itself at only a slightly higher cost; the combination design, therefore, may be more recommendable. However, our results for resistance, cost, and application time showed that the Omnifix (desing B) is the best choice for securing a PVC. PMID- 29106103 TI - [Circadian variation in the effectiveness of reperfusion therapy in ST-segment elevation myocardial infarction treated with primary angioplasty and circadian associations with prognosis]. AB - OBJECTIVES: To explore circadian variation in the effectiveness of percutaneous transluminal coronary angioplasty (PTCA) to treat ST-elevation myocardial infarction (STEMI) To explore the effects of circardian variation on infarct extension and in-hospital complications. MATERIAL AND METHODS: Observational retrospective cohort study including patients with PTCA-treated STEMI in a tertiary care university hospital between March 2003 and August 2009. The independent variable of interest was the time of onset of STEMI symptoms, grouped in 6-hour time frames. The main outcome variable was PTCA effectiveness. Secondary outcome variables were infarct extension and the presence of in hospital complications. RESULTS: A total of 522 patients records were studied. The mean (SD) age was 62.3 (13.6) years and 404 (77.4%) were men. The largest proportion of PTCA-treated STEMI cases first experienced symptoms between 6 AM and 12 PM (201 cases, 38.5%) (P<.001). PTCA was ineffective in 122 (23.4%). The 6 AM to 12 PM time frame was an independent predictor of PTCA ineffectiveness (odds ratio, 1.79; 95% CI, 1.09-2.94; P=.012). Onset in this interval was also associated with infarct extension but not with in-hospital complications. CONCLUSION: A time of onset of STEMI between 6 AM and 12 PM predicts the ineffectiveness of PTCA and greater infarct extension but not in-hospital complications. PMID- 29106105 TI - [Factors related to lack of autonomous mobility during out-of-hospital emergency care]. AB - OBJECTIVES: To explore the frequency of lack of autonomous mobility and factors related to it in patients requiring prehospital emergency services. MATERIAL AND METHODS: Cross-sectional, observational, retrospective analysis. We identified a stratified random sample of patients attended by the public health emergency service of Andalusia in 2011. RESULTS: The sample included 280 patients with a mean age of 56 years; 63.9% were men. The majority were attended in homes and streets or other public spaces. Most were transported to a hospital in a mobile intensive care unit. The reasons for calling the service were most often related to chest pain or injuries. Loss of autonomous mobility was seen more often in men, when care was required in a public area, when there were injuries or altered vital signs, and when the patient required transport in a mobile intensive care unit. Dependence on others was significantly associated with the presence of a prior condition before the patient required transport (odds ratio [OR], 3.27; 95% CI, 1.60-6.33), the use of immobilization strategies (OR, 7.71; 95% CI, 1.7 34.96], and the use of ambulance transport (OR, 4.35; 95% CI, 1.63-11.60]. The following 2 variables were at the limit of significance: pain during the care process (OR, 1.13; 95% CI, 0.99-1.29) and age (OR, 0.46; 95% CI, 0.97-1.01). CONCLUSION: The profile we identified for patients and situations in which patients cannot move autonomously during prehospital emergency care can be used to plan preventive strategies to ensure patient safety. PMID- 29106104 TI - [Process indicators: tools for monitoring the management of severe trauma cases in Catalonia]. AB - OBJECTIVES: Process indicators have been widely used to monitor the way trauma care is provided. We aimed to analyze whether data from a hospital's severe trauma register could facilitate the evaluation of aspects of the initial management of severe injuries. MATERIAL AND METHODS: Observational, retrospective population-based study. A working group of experts selected a set of trauma care process indicators relevant to some aspects of initial care, diagnosis, and treatment of severely injured patients. Four of the indicators referred to prehospital care and 5 to hospital care. We calculated the observed and expected compliance rates for all the indicators. RESULTS: A total of 1526 cases (44.4%) were analyzed for 2013; 1908 (55.6%) were analyzed for 2014. We were able to evaluate 3 of the 4 prehospital process indicators: endotracheal intubation in patients with a score of ?? 8 on the Glasgow coma scale (GCS) (84% compliance), venous access established before hospital arrival (83.4%), and placement of a neck collar to immobilize the cervical spine (72.7%). Compliance for the hospital phase indicators were as follows: performance of a computed tomography scan of the head within 60 minutes in cases with a GCS of ?? 13 (5.3% compliance, craniotomy in candidate patients within 2 hours of diagnosis (65%), diagnostic examination for abdominal injuries within 60 minutes in patients with systolic blood pressure ?? 90 mm Hg (89.3%), and therapeutic laparotomy or angiography within 4 hours of abdominal injury in candidate patients with systolic blood pressure ?? 90 mm Hg (51.7%). Compliance was 69.9% for the last process indicator: surgical treatment of open fractures within 8 hours of an accident. CONCLUSION: Our findings show that a hospital trauma register provides data about care process indicators that can allow us to monitor the quality of care of severely injured patients. PMID- 29106106 TI - [Relation between ultrasound-measured diaphragm movement and partial pressure of carbon dioxide in blood from patients with acute hypercapnic respiratory failure after the start of noninvasive ventilation in an emergency department]. AB - OBJECTIVES: To evaluate the correlation between variations in ultrasound-measured diaphragm movement and changes in the arterial partial pressure of carbon dioxide (PCO2) after the start of noninvasive ventilation (NIV). MATERIAL AND METHODS: RDescriptive study of a prospective case series comprised of nonconsecutive patients aged 18 years or older with hypercapnic respiratory failure who were placed on NIV in an emergency department. We recorded clinical data, blood gas measurements, and ultrasound measurements of diaphragm movement. RESULTS: Twenty one patients with a mean (SD) age of 83 (13) years were studied; 11 (52.4%) were women. The mean (SD) range of diaphragm movement and PCO2 values at 4 moments were as follows: 1) at baseline: diaphragm movement, 13.90 (7.7) mm and PCO2, 71.75 (11.4) mm Hg; 2) after 15 minutes on NIV: diaphragm movement, 17.10 (9.1) mm; 3) at 1 hour: diaphragm movement, 22.40 (10.4) mm and PCO2, 63.45 (16.0) mm Hg; and 4) at 3 hours: diaphragm movement, 26.60 (19.5) mm and PCO2, 61.85 (13.0) mm Hg. We detected a statistically significant correlation between the difference in range of diaphragm movement at baseline and at 15 minutes and the decrease in PCO2 after 1 hour of NIV (r=-0.489, P=.035). CONCLUSION: In patients with hypercapnic respiratory failure, the increase in range of diaphragm movement 15 minutes after starting NIV is associated with a decrease in PCO2 after 1 hour. PMID- 29106107 TI - [Injuries from pepper spray used for self defense: analysis of 15 cases managed in an emergency chemical decontamination area]. AB - EN: We analyzed epidemiologic and clinical characteristics, treatment received, and clinical course in cases of pepper spray injury treated in the chemical decontamination area of an emergency department over a 5-year period. A total of 15 patients with a mean (SD) age of 25 (8.3) years were included. Thirteen were men and 53% were foreign-born. All uses of pepper spray occurred during muggings that to place mainly in the early hours of the morning (66.7% between 4:30 and 6:30 AM). Two or more attackers were injured in 60% of the events. Seventy-three percent of the attacks took place on the street and the median delay in reaching the emergency department was 30 minutes. The face and eyes were usually injured, and symptoms included itching, irritation, burning, and pain. On arrival, the patients were treated immediately (mean delay, 3 minutes) with hypertonic saline, an amphoteric surfactant, and a chelating agent in 80% of the cases, in which improvement was substantial as mean pain scale scores changed from 7.2 on admission to 3 on discharge (P=.009). Patients spent an average of 40 minutes in the treatment area. Eleven patients required further care from an ophthalmologist and topical medication for symptoms. Outcomes were good and there were no complications in any of the cases. We conclude that pepper sprays are being used as an aid to self defense in muggings in our community. Decontamination measures have priority as they alleviate symptoms and prevent long-lasting effects. PMID- 29106108 TI - [Aortic-vena cava fistula]. PMID- 29106109 TI - [Cardiopulmonary resuscitation and "The Unknown Woman of the Seine"]. PMID- 29106110 TI - [Treatment for ingested foreign bodies]. PMID- 29106111 TI - [Work-related stress and emotional intelligence in a 112 emergency response service staff]. PMID- 29106112 TI - [Ultrasound diagnosis of a pelvic mass in the emergency department]. PMID- 29106113 TI - Progress with the implementation of rotavirus surveillance and vaccines in countries of the WHO African Region, 2007-2016. PMID- 29106114 TI - An Account of Two Cases of Polydipsia, or Excessive Thirft. PMID- 29106115 TI - An Account of the Spontaneous Cure of an Aneurism. PMID- 29106116 TI - Case of a Compound Fracture of the Leg; with Remarks. PMID- 29106117 TI - Case of a Boy Whose Left Leg and Thigh, Together with Part of the Scrotum, Were Torn off by a Slitting Mill. PMID- 29106118 TI - Some Remarks on the Angustura Bark: Communicated in a Letter to Dr. Simmons. PMID- 29106119 TI - Case of a Fungous Enlargement of the Extremity of the Female Urethra; with Remarks. PMID- 29106120 TI - Case of Emphysema, Brought on by Severe Labour Pains: Communicated in a Letter to Dr. Simmons. PMID- 29106121 TI - An Account of the Good Effects of Electricity in a Case of Paralytic Affection; Serving to Prove That, in Such Cases, the Electric Sparks Should Be Taken from the Muscles Which Are Antagonists to Those That Are Contracted: Communicated in a Letter to Dr. Simmons. PMID- 29106122 TI - Experiments and Observations on the Matter of Cancer, and on the Aerial Fluids Extricated from Animal Substances by Distillation and Putrefaction; Together with Some Remarks on Sulphureous Hepatic Air: From the Philosophical Transactions. PMID- 29106123 TI - Observations on Some Epidemical Effects. PMID- 29106125 TI - An Account of the Cure of a Preternatural Anus; with Remarks on the History and Treatment of Cases of This Kind: From the Journal de Chirurgie. PMID- 29106124 TI - Account of a Method of Curing Burns and Scalds: Communicated in Three Letters to John Hunter, Esq. F.R.S. Surgeon Extraordinary to the King, Surgeon General to the Army, &c., and by Him to Dr. Simmons. PMID- 29106126 TI - Case of a Boy Whose Head Was Pressed between Certain Parts of an Engine Employed for Draining a Coal Mine. PMID- 29106128 TI - Case of an Imperforate Rectum. PMID- 29106127 TI - A Case of Spontaneous Evolution of the Foetus: Communicated in a Letter to Dr. Simmons, F.R.S. PMID- 29106129 TI - An Account of the Preparation, Mode of Application, and Effects, of a Liniment Recommended by Roncalli in the Treatment of Scrophulous Tumours: From the Transactions of the Academy. PMID- 29106130 TI - Account of the Nardus Indica, or Spikenard: From the Same Work. PMID- 29106131 TI - An Account of an Uncommon Inflammation of the Epiglottis: Communicated in a Letter to Everard Home, Esq. F.R.S., and by Him to Dr. Simmons. PMID- 29106132 TI - Cases of the Extraction of the Cataract; with Practical Remarks: Communicated in a Letter to William Lister, M.D. Physician to Saint Thomas's Hospital in London, and by Him to Dr. Simmons. PMID- 29106133 TI - Case of a Gun-Shot Wound in the Mouth; in Which, on Account of Impeded Deglutition, a Flexible Catheter Was Introduced through the Nose into the Oesophagus, and Suffered to Remain There during the Space of a Month: From the Journal De Chirurgie. PMID- 29106134 TI - Case of a Catheter, Left in the Bladder, in Drawing off the Urine, for a Retroversion of the Uterus. PMID- 29106135 TI - A Case of Hydrophobia; with the Appearances on Dissection: Communicated in a Letter to Samuel Foart Simmons, M.D. F.R.S. PMID- 29106136 TI - Practical Observations on the Treatment and Causes of the Dropsy of the Brain. PMID- 29106138 TI - An Account of a Child with a Double Head: From the Same Work. PMID- 29106137 TI - An Account of the Tabasheer: From the Philosophical Transactions. PMID- 29106139 TI - Account of a Fact Relative to Menstruation, Not Hitherto Described: Communicated in a Letter to Dr. Simmons. PMID- 29106140 TI - Account of an Extraordinary Change, Not Hitherto Described, Which, under Certain Circumstances, Takes Place in the Human Body after Death: 'Rapport sur les 'Exhumations du Cimetiere et de l'Eglise 'des Saints Innocens.' PMID- 29106141 TI - Facts Relative to Pemphigus: Communicated in a Letter to Dr. Simmons. PMID- 29106142 TI - Instance of a Disease, to Which Sauvages Has Given the Name of Meteorismus Ventriculi; with Remarks. PMID- 29106144 TI - Some Observations on the Prevention and Treatment of Hydrophobia: Communicated in a Letter to Dr. Simmons. PMID- 29106143 TI - A Case of Petechioe Sine Febre: Communicated in a Letter to Dr. Simmons. PMID- 29106145 TI - Account of an Extra Uterine Conception: Communicated in a Letter to Dr. Simmons. PMID- 29106147 TI - A Return of the Sick of the Ship's Company, and of the Military, on Board the Ships in the Service of the Honourable the United East-India Company, for the Years 1792 and 1793. PMID- 29106146 TI - An Account of a New Species of Swietenia (Mahogany); and of Experiments and Observations on Its Bark, Made with a View to Ascertain Its Powers, and to Compare Them with Those of Peruvian Bark, for Which It Is Proposed as a Substitute: Being an Abstract of a Paper on This Subject, Addressed to the Honourable Court of Directors of the United East-India Company. PMID- 29106148 TI - An Account of a Singular Case of Ischuria, in a Young Woman, Which Continued for More Than Three Years; during Which Time, If Her Urine Was Not Drawn off with the Catheter, She Frequently Voided It by Vomiting; and, for the Last Twenty Months, Passed Much Gravel by the Catheter, as Well as by Vomiting, When the Use of That Instrument Was Omitted, or Unsuccessfully Applied. To Which Are Added Some Remarks and Physiological Observations: Vide Transactions of the College of Physicians, of Philadelphia. PMID- 29106149 TI - A Case of Aneurism of the Crural Artery: Communicated in a Letter to Dr. Simmons. PMID- 29106150 TI - An Account of Some Extraordinary Symptoms Which Were Apparently Connected with Certain Morbid Alterations about the Veins and Nerves: Communicated in a Letter to Dr. Simmons. PMID- 29106151 TI - An Account of the Extraction of an Extraneous Substance from the Rectum. PMID- 29106152 TI - Observations on the Use of Arsenic in the Intermittent Fevers of a Tropical Climate; to Which Is Prefixed an Account of the Weather, at Sierra Leone, during the Season in Which Such Fevers Are Most Prevalent. PMID- 29106153 TI - An Account of the Good Effects of a Solution of Sal Ammoniac, in Vinegar, Employed, as a Topical Application, in Cases of Lacerated Wounds. PMID- 29106154 TI - Account of Some Discoveries Made by Mr. Galvani, of Bologna; with Experiments and Observations on Them. In Two Letters from Mr. Alexander Volta, F.R.S. Professor of Natural Philosophy in the University of Pavia, to Mr. Tiberius Cavallo, F.R.S.: From the Philosophical Transactions of the Royal Society of London. PMID- 29106155 TI - An Account of the Effects of Mahogany Wood in Cases of Diarrhoea: Communicated in a Letter to Mr. John Pearson, Surgeon of the Lock Hospital, and by Him to Dr. Simmons. PMID- 29106156 TI - An Account of a Key Instrument of a New Construction; with Observations on the Principles on Which It Acts, in the Extraction of Teeth, and on the Mode of Applying It: Communicated in a Letter to Mr. Anthony Carlisle, Surgeon of the Westminster Hospital, and Reader of Anatomy in London; and by Him to Dr. Simmons. PMID- 29106157 TI - Case of a Diseased Kidney. PMID- 29106158 TI - Case of a Gun-Shot Wound of the Head. PMID- 29106159 TI - An Account of the Remarkable Effects of a Shipwreck on the Mariners; with Experiments and Observations on the Influence of Immersion in Fresh and Salt Water, Hot and Cold, on the Powers of the Living Body: From the Same Work. PMID- 29106161 TI - An Account of the Poisonous Effects of the Seeds of the Datura Stramonium Linn. PMID- 29106160 TI - Cases of the Urticaria or Nettle Rash, with Observations: Communicated in a Letter to Robert Willan, M. D. Physician in London, and by Him to Dr. Simmons. PMID- 29106162 TI - A Case of Hydrophobia. PMID- 29106164 TI - Case of a Compound Dislocation of the Tibia and Fibula, Accompanied with a Fracture and Loss of a Considerable Portion of the Astragalus, and Likewise with a Fracture of the Thigh Bone; with Remarks. PMID- 29106163 TI - An Account of the Effects of Vitriolic AEther in a Case of Spasmodic Affection of the Stomach; and in Two Cases of Intermittent Fever. PMID- 29106165 TI - An Attempt to Determine with Precision Such Injuries of the Head as Necessarily Require the Operation of the Trephine: From the Same Work. PMID- 29106167 TI - Erratum. AB - [This corrects the article on p. 118 in vol. 4.]. PMID- 29106166 TI - An Account of the Quassia Polygama, or Bitter-Wood of Jamaica; and of the Cinchona Brachycarpa, a New Species of Jesuit's Bark Found in the Same Island: From the Transactions of the Royal Society of Edinburgh. PMID- 29106168 TI - Some Observations on the Diseases That Occurred on Board the Ship Europa, in the Service of the Hon. East India Company, during a Voyage from England to and from Madrass and Bengal: Communicated to Dr. Simmons, by John Lorimer, M. D. Fellow of the Royal College of Physicians of Edinburgh, Physician to the Army, and to the Hon. East India Company. PMID- 29106169 TI - Description of Kilburn Wells, and Analysis of Their Water: From the Philosophical Transactions of the Royal Society of London. PMID- 29106171 TI - Extract of a Letter from the Reverend Charles Perceval to Robert Perceval, M. D. and M. R. I. A.: From the Transactions of the Royal Irish Academy. PMID- 29106170 TI - Account of a Fistulous Opening in the Stomach: From the Same Work. PMID- 29106172 TI - An Account of the Good Effects of Opium in the Case of a Person Poisoned by Digitalis: Communicated in a Letter to Dr. Simmons. PMID- 29106173 TI - An Account of Two Cases of Popliteal Aneurism: Communicated in a Letter to Samuel Foart Simmons, M.D. F.R.S. PMID- 29106174 TI - A Case of Violent Distortion of the Foot, Occasioned by a Rotation of the Astragalus, in Consequence of a Fall, and Accompanied with a Laceration of the Integuments at the Outer Ancle, and Exposure of a Portion of the Fibula: Communicated in a Letter to Dr. Simmons. PMID- 29106175 TI - Case of Apoplexy in a Pregnant Woman; with Observations: Communicated in a Letter to John Clarke, M.D. Teacher of Midwifery in London; and by Him to Dr. Simmons. PMID- 29106176 TI - An Account of a Child Born without Organs of Generation. PMID- 29106177 TI - An Account of a Child Who Drinks a Great Quantity of Water: From a Work entitled La Medecine Eclairee par les Sciences physiques, ou Journal des Decouvertes relatives aux differentes Parties de l'Art de Guerir. PMID- 29106178 TI - Two Cases of Fracture; One of the Upper, the Other of the Lower Jaw. PMID- 29106179 TI - Account of a Case of Double Hare Lip, Accompanied with a Fissure of the Palate; with Remarks: From the Journal de Chirurgie. PMID- 29106180 TI - Facts Relative to the Prevention of Hydrophobia: Communicated in a Letter to Dr. Simmons. PMID- 29106182 TI - Experiments on Human Calculi. In a Letter from Mr. Timothy Lane, F. R. S. to William Pitcairn, M.D. F.R.S.: From the Same Work. PMID- 29106181 TI - Cases of Ischuria Renalis in Children. PMID- 29106183 TI - Case of a Cyst Containing Hydatids, Extracted from the Right Anterior Ventricle of the Brain of a Cow: Communicated in a Letter to Dr. Simmons. PMID- 29106185 TI - An Account of the Experiments and Discoveries of Lewis Galvani, Professor of Anatomy at Bologna, Relative to the Powers of Electricity in Muscular Motion: Vide Aloysii Galvani de Viribus Electricitatis in Motu Musculari Commentarium. 4to. Bologna, 1791. PMID- 29106184 TI - Experiments and Observations to Investigate the Composition of James's Powder: From the Same Work. PMID- 29106186 TI - Case of a Singular Cutaneous Affection; with Some Remarks Relative to the Poison of Copper: Communicated in a Letter to Dr. Seguin Henry Jackson, Physician in London, and by Him to Dr. Simmons. PMID- 29106187 TI - Case of Injury of the Brain, without a Fracture, Relieved by Application of the Trephine. PMID- 29106188 TI - Two Letters on Animal Electricity: From the Journal de Physique. PMID- 29106189 TI - An Account of the Good Effects of Electricity in a Case of Violent Spasmodic Affection. PMID- 29106191 TI - Observations on Certain Horny Excrescences of the Human Body: From the Philosophical Transactions of the Royal Society of London. PMID- 29106190 TI - A Case of Double Uterus : Translated from the German. PMID- 29106192 TI - A Case of Pemphigus. PMID- 29106193 TI - Two Cases of Pulmonary Haemorrhage, Speedily and Successfully Cured by Abstinence from Liquids. PMID- 29106194 TI - Case of an Enlarged Nympha. PMID- 29106195 TI - Additional Observations on Animal Electricity: Communicated in a Letter to Samuel Foart Simmons, M. D. F. R. S. PMID- 29106196 TI - An Account of a Disease Which, until Lately, Proved Fatal to a Great Number of Infants in the Lying-In Hospital of Dublin; with Observations on Its Causes and Prevention: From the Transactions of the Royal Irish Academy. PMID- 29106197 TI - An Account of the Good Effects of a Mercurial Snuff in a Case of Gutta Serena. PMID- 29106198 TI - Observations on the Pathology and Mode of Treatment of Calculi in General, but More Particularly of Intestinal Calculi; with a Description and Chemical Analysis of the Intestinal Calculi of Horses: Communicated in a Letter to Mr. William Babington, Apothecary to Guy's Hospital, and by Him to Dr. Simmons. PMID- 29106199 TI - A Case of Imperforated Anus. PMID- 29106200 TI - An Account of the Good Effects of Opium Administered in Clysters, in Cases of Menorrhagia. PMID- 29106202 TI - Case of Phlegmonic Inflammation, with Reflections on Certain Effects of Heat and Cold on the Living System. PMID- 29106201 TI - On the Spikenard of the Ancients: From the Same Work. PMID- 29106203 TI - An Account of the Successful Treatment of a Case in Which the Brachial Artery Was Divided: Communicated in a Letter to Everard Home, Esq. F. R. S. and by Him to Dr. Simmons. PMID- 29106205 TI - A Case of Pulmonary Haemorrhage, with Remarks. PMID- 29106204 TI - A Case of Varicose Aneurism. PMID- 29106206 TI - On the Cure of the Elephantiasis: From the Asiatick Researches: Or, Transactions of the Society Instituted in Bengal, for Inquiring into the History and Antiquities, the Arts, Sciences, and Literature of Asia. PMID- 29106207 TI - An Account of Some Chemical Experiments on Tabasheer: From the Philosophical Transactions of the Royal Society of London. PMID- 29106208 TI - An Account of the Effects of Oil of Turpentine in a Case of Internal Haemorrhage. PMID- 29106209 TI - Observations on the Fevers and Dysentery of Hot Climates; and on the Use of Mercury in Those Diseases: Communicated in a Letter to William Saunders, M. D. Fellow of the College of Physicians, London, and Physician to Guy's Hospital; and by Him to Dr. Simmons. PMID- 29106210 TI - An Account of the Good Effects of Opium in a Case of Retention of Urine: Communicated in a Letter to Mr. John Pearson, Surgeon of the Lock Hospital and Public Dispensary, in London; and by Him to Dr. Simmons. PMID- 29106211 TI - Observations on the Good Effects of Caustics in Cases of White Swellings of the Joints. PMID- 29106212 TI - A Case of Monstrous Birth. PMID- 29106213 TI - A Case of Psoas Abscess Successfully Treated: Communicated in a Letter to Edward Whitaker Gray, M. D. F. R. S.; and by Him to Dr. Simmons. PMID- 29106214 TI - Description of an Instrument for Performing the Operation of Trepanning the Skull, with More Ease, Safety, and Expedition Than with Those Now in General Use: From the Transactions of the Royal Irish Academy. PMID- 29106215 TI - An Account of a Remarkable Affection of the Testes: Communicated in a Letter to William Babington, M. D. Physician in London; and by Him to Dr. Simmons. PMID- 29106216 TI - An Account of Some Experiments Made with a View to Ascertain the Comparative Quantities of Amylaceous Matter, Yielded by the Different Vegetables Most Commonly in Use in the West India Islands: Communicated in a Letter to Dr. Simmons. PMID- 29106217 TI - An Account of the Poisonous Quality of the Juice of the Root of Jatropha Manihot, or Bitter Cassada; and of the Use of Cayenne Pepper in Counteracting the Effects of This and Some Other Poisonous Substances; with Remarks on the Efficacy of the Spigelia Anthelmia in Worm Cases: Communicated in a Letter to Dr. Simmons. PMID- 29106218 TI - An Account of an Uncommon Case of Emphysema; and of an External Abscess, the Contents of Which Were Discharged by Coughing: From the Same Work. PMID- 29106219 TI - Cases and Remarks on the External Application of Charcoal. PMID- 29106220 TI - Some Observations Relative to the Angustura Bark: Communicated in a Letter to Dr. Simmons. PMID- 29106222 TI - An Account of the Effects of Negative Electricity, in Cases of Burns: From the Same Work. PMID- 29106221 TI - Practical Observations on the Treatment of Acute Diseases; Particularly Those of the West Indies: Communicated in a Letter to Maxwell Garthshore, M.D. F.R.S. Physician in London; and by Him to Dr. Simmons. PMID- 29106223 TI - An Estimate of the Excess of the Heat and Cold of the American Atmosphere beyond the European, in the Same Parallel of Latitude: To Which Are Added, Some Thoughts on the Causes of This Excess: From the Memoirs of the American Academy of Arts and Sciences. PMID- 29106224 TI - Account of Two Instances of Uncommon Formation in the Viscera of the Human Body: From the Philosophical Transactions of the Royal Society of London. PMID- 29106225 TI - Some Account of the Effects of the Vapour of Vitriolic AEther in Cases of Phthisis Pulmonalis: Communicated in a Letter to Dr. Simmons, F.R.S. PMID- 29106226 TI - Facts Relative to the Origin of Intermittent Fevers: Communicated in a Letter to Dr. Simmons. PMID- 29106228 TI - Description of an Extraordinary Production of Human Generation; with Observations: From the Same Work. PMID- 29106227 TI - Account of a Case in Which a Stone, Formed in One of the Kidneys, Was Extracted through an Abscess in the Back: From the Transactions of the Royal Academy of Sciences at Stockholm. PMID- 29106229 TI - Cases of Pins Extracted from the Breast of a Woman, after Remaining There Sixty Years: Communicated in a Letter to Dr. Simmons, by John Clarke, M. D. Physician in London. PMID- 29106230 TI - Description of a Case of Hydrocephalus: From the Memoirs of the Royal Academy of Sciences at Turin. PMID- 29106231 TI - Case of a Man Who Castrated Himself: Communicated in a Letter to Mr. Thompson Forster, Surgeon of Guy's Hospital, in London; and by Him to Dr. Simmons. PMID- 29106232 TI - On the Conversion of Animal Muscle into a Substance Much Resembling Spermaceti: From the Same Work. PMID- 29106233 TI - A Fatal Instance of the Poisonous Effects of the Oenanthe Crocata Linn. or Hemlock Dropwort: Communicated in a Letter to Dr. Simmons. PMID- 29106235 TI - Description of a New Key Instrument for the Extraction of Teeth: Communicated in a Letter to Dr. Simmons. PMID- 29106234 TI - Case of an Enlarged Spleen: From the Same Work. PMID- 29106237 TI - Account of a Locked Jaw: From the Same Work. PMID- 29106236 TI - An Experimental Inquiry Concerning the Reproduction of Nerves: From the Same Work. PMID- 29106238 TI - Experiments on the Nerves, Particularly on Their Reproduction; and on the Spinal Marrow of Living Animals: From the Same Work. PMID- 29106239 TI - Observations on the Nature of Corns, and the Means of Removing Them: Communicated in a Letter to Dr. Simmons, F.R.S. PMID- 29106240 TI - Description of a Human Male Monster, with Remarks: From the Transactions of the Royal Society of Edinburgh. PMID- 29106241 TI - Two Cases of Hernia Congenita: Communicated in a Letter to John Clarke, M.D. Physician in London; and by Him to Dr. Simmons. PMID- 29106243 TI - Case of Imperforate Hymen. PMID- 29106242 TI - Errata in Vol. VII. AB - [This corrects the article on p. 155 in vol. 7.]. PMID- 29106244 TI - A Case of Lithotomy, Attended with Some Remarkable Circumstances: Communicated in a Letter to John Latham, M.D. F.R.S. Physician at Romsey, in Hampshire; and by Him to Dr. Simmons. PMID- 29106245 TI - A Description of an Improved Screw Tourniquet. PMID- 29106246 TI - Case of Gangrenous Stomach, with Dysphagia, from Lightning: Communicated in a Letter to Dr. Simmons. PMID- 29106247 TI - An Account of a Ruptured Uterus. PMID- 29106249 TI - An Account of a Mode of Practice Which Has Been Successfully Adopted, in Cases of Distortion of the Pelvis, in Pregnant Women: Communicated in a Letter to Mr. W. Simmons, Surgeon, at Manchester; and by Him to Dr. Simmons. PMID- 29106248 TI - Case of Prolapsus Ani; Cured Partly by an Excision of a Portion of the Inner Coat of the Intestine, and Partly by the Introduction of a Wax Candle within the Cavity of the Rectum. PMID- 29106250 TI - A Case of Ruptured Uterus, with the Appearances on Dissection: Communicated in a Letter to John Clarke, M. D. Physician in London; and by Him to Dr. Simmons. PMID- 29106251 TI - Some Particulars in the Anatomy of the Whale: From the Same Work. PMID- 29106252 TI - Case of Fungus from a Wound in the Ear. PMID- 29106253 TI - Errata in Vol. VII. AB - [This corrects the article on p. 26 in vol. 7.]. PMID- 29106254 TI - History of a Case in Which Very Uncommon Worms Were Discharged from the Stomach; with Observations Thereon: From the Same Work. PMID- 29106255 TI - Remarks on the Causes and Cure of Some Diseases of Infancy: From the Transactions of the Royal Irish Academy. PMID- 29106257 TI - Case of a Wound Penetrating the Cavity of the Abdomen. PMID- 29106256 TI - A Case of Monstrosity in a Child; with Physiological Remarks. PMID- 29106258 TI - Observations on the Structure of Hydatids: From the Philosophical Transactions of the Royal Society of London. PMID- 29106259 TI - Some Observations Relative to the Climate and Diseases of Sierra Leone: Communicated in a Letter to Robert Willan, M.D. Physician in London; and by Him to Dr. Simmons. PMID- 29106261 TI - Of the Influence of Cold upon the Health of the Inhabitants of London: From the Same Work. PMID- 29106260 TI - An Account of the Good Effects of a Decoction of Peach Leaves, in Some Affections of the Urinary Passages: Communicated in a Letter to Samuel Foart Simmons, M.D. F.R.S. PMID- 29106262 TI - A Case of Hairy Concretions Found in the Human Stomach: Communicated in a Letter to Samuel Foart Simmons, M.D. F.R.S. PMID- 29106263 TI - Two Cases of the Successful Termination of Wounds That Have Been Hitherto Deemed Mortal; with Observations. PMID- 29106264 TI - Account of the Successful Treatment of a Large Swelling of the Lower Jaw, with an Abscess in the Neck, Occasioned by Supernumerary Teeth. PMID- 29106265 TI - Case of Retroversion of the Uterus Terminating in Abortion and Death: Communicated in a Letter to Dr. Simmons. PMID- 29106266 TI - Reports of maternal socialization goals, emotion socialization behaviors, and child functioning in China and India. AB - A body of literature connects parental emotion socialization behaviors to child outcomes, though little research attention has been devoted to parents' culturally embedded socialization goals that influence their socialization behaviors in diverse samples. In the present study, we examined interrelations among maternal socialization goals, emotion socialization behaviors, and child functioning in families from 2 major Asian countries, China and India. A total of 305 6th and 7th grade children and their mothers across both countries participated. Mothers completed measures of their socialization goals, their responses to children's emotions, child behavior problems, and children completed a measure of emotion regulation (ER) at a single point in time. Factor analysis of the measure of parental responses to children's emotions yielded 2 factors (supportive and nonsupportive responses), with some items from the commonly used parent-report measure Coping with Children's Negative Emotions Scale (Fabes, Eisenberg, & Bernzweig, 1990), while others reflected culturally salient socialization approaches in Asia (i.e., child training, explanation). Using these data-driven supportive and nonsupportive response composites, mediation models were tested for the full sample. Reports of mothers' supportive responses and child ER sequentially mediated the relation between maternal relational socialization goals and child internalizing problems. Reports of child emotion dysregulation mediated the relation between maternal nonsupportive responses and child externalizing problems. Findings of this study highlight the relevance of culturally salient parental socialization goals and socialization behaviors in understanding child functioning in diverse cultural groups. (PsycINFO Database Record PMID- 29106268 TI - Strategy selection as rational metareasoning. AB - Many contemporary accounts of human reasoning assume that the mind is equipped with multiple heuristics that could be deployed to perform a given task. This raises the question of how the mind determines when to use which heuristic. To answer this question, we developed a rational model of strategy selection, based on the theory of rational metareasoning developed in the artificial intelligence literature. According to our model people learn to efficiently choose the strategy with the best cost-benefit tradeoff by learning a predictive model of each strategy's performance. We found that our model can provide a unifying explanation for classic findings from domains ranging from decision-making to arithmetic by capturing the variability of people's strategy choices, their dependence on task and context, and their development over time. Systematic model comparisons supported our theory, and 4 new experiments confirmed its distinctive predictions. Our findings suggest that people gradually learn to make increasingly more rational use of fallible heuristics. This perspective reconciles the 2 poles of the debate about human rationality by integrating heuristics and biases with learning and rationality. (PsycINFO Database Record PMID- 29106269 TI - A dynamic approach to recognition memory. AB - We present a dynamic model of memory that integrates the processes of perception, retrieval from knowledge, retrieval of events, and decision making as these evolve from 1 moment to the next. The core of the model is that recognition depends on tracking changes in familiarity over time from an initial baseline generally determined by context, with these changes depending on the availability of different kinds of information at different times. A mathematical implementation of this model leads to precise, accurate predictions of accuracy, response time, and speed-accuracy trade-off in episodic recognition at the levels of both groups and individuals across a variety of paradigms. Our approach leads to novel insights regarding word frequency, speeded responding, context reinstatement, short-term priming, similarity, source memory, and associative recognition, revealing how the same set of core dynamic principles can help unify otherwise disparate phenomena in the study of memory. (PsycINFO Database Record PMID- 29106270 TI - The dark personality and psychopathology: Toward a brighter future. AB - The young field of research on dark personality traits (i.e., socially aversive traits such as psychopathy, narcissism, and Machiavellianism) is gaining momentum. This Special Section examines the nature, origins, development, and sequelae of dark traits, underscoring their largely unappreciated relevance to abnormal psychology. The articles in this section adopt diverse perspectives (e.g., clinical, developmental, organizational, social personality), use diverse methods (e.g., longitudinal, experience sampling), and sample diverse populations (e.g., offenders, psychiatric outpatients, schoolchildren). As an introduction to the Special Section, this article identifies key conceptual and methodological challenges to the field of dark personality research. Its aim is to spur novel approaches to how dark personality traits are implicated in psychopathology and abnormal behavior more broadly. (PsycINFO Database Record PMID- 29106271 TI - Developmental pathways of childhood dark traits. AB - The dark triad of personality has traditionally been defined by 3 interrelated constructs, defined as Narcissism, Machiavellianism, and Psychopathy. Although the content of each of these constructs is clearly represented in childhood maladaptive trait measures, no studies have jointly addressed the prospective developmental course of this core set of maladaptive characteristics throughout childhood and adolescence. The current study uses latent growth modeling to explore how early dark traits develop over time, relying on a selected set of 6 childhood maladaptive traits that conceptually cover the adult dark triad. Across a 5-wave multi-informant design spanning 10 years of childhood, adolescence, and emerging adulthood (Nwave 1 = 717, 54.4% girls, age range T1 = 8-14.7 years, mean age = 10.73), results indicate that childhood dark traits show to some extent shared growth across time, although notable unique growth variance was also observed. Early dark traits further demonstrate significant association patterns with an adult dark triad measure across informants and are increasingly able to discriminate among more and less prototypical profiles of adult dark triad scores. Findings are discussed from a developmental psychopathology framework, underscoring that the proposed set of childhood dark traits represents a meaningful developmental precursor of the adult dark triad. (PsycINFO Database Record PMID- 29106267 TI - A novel ecological account of prefrontal cortex functional development. AB - In this paper, we argue that prefrontal cortex ontogenetic functional development is best understood through an ecological lens. We first begin by reviewing evidence supporting the existing consensus that PFC structural and functional development is protracted based on maturational constraints. We then examine recent findings from neuroimaging studies in infants, early life stress research, and connectomics that support the novel hypothesis that PFC functional development is driven by reciprocal processes of neural adaptation and niche construction. We discuss implications and predictions of this model for redefining the construct of executive functions and for informing typical and atypical child development. This ecological account of PFC functional development moves beyond descriptions of development that are characteristic of existing frameworks, and provides novel insights into the mechanisms of developmental change, including its catalysts and influences. (PsycINFO Database Record PMID- 29106273 TI - Dark personality traits and impulsivity among adolescents: Differential links to problem behaviors and family relations. AB - Research on how dark personality traits develop and relate to risky behaviors and family relations during adolescence is scarce. This study used a person-oriented approach to examine (a) whether distinct groups of adolescents could be identified based on their developmental profiles of callous-unemotional (CU), grandiose manipulative (GM), and dysfunctional impulsivity (DI) traits and (b) whether these groups differ in their problem behaviors and parent-adolescent relationship quality. Latent class growth analyses on 4-wave data of 1,131 Dutch adolescents revealed 3 personality profiles: (1) a dark impulsive group (13.9%), with high scores on all 3 traits (CU, GM, and DI) that were stable over time; (2) an impulsive group (26.1%), with high and increasing levels of impulsivity and relatively low scores on CU and GM; and (3) and a low risk group (60.0%), with relatively low levels on all 3 personality characteristics, with impulsivity decreasing over time. Compared with adolescents in the low risk group, adolescents in the dark impulsive and impulsive groups reported higher initial levels of substance use, sexual risk behaviors, permissive sexual attitudes, parent-adolescent conflict, and lower parent-adolescent satisfaction, as well as greater increases in sexual risk behavior over time. Compared with adolescents in the impulsive group, those in the dark impulsive group showed the highest levels of risk behaviors. Hence, dark personality traits coupled with impulsivity may be indicative of an earlier and more severe trajectory of problem behaviors that may differ from the trajectory of youth who are only impulsive. (PsycINFO Database Record PMID- 29106272 TI - Concurrent and developmental correlates of psychopathic traits using a triarchic psychopathy model approach. AB - Psychopathy refers to a heterogeneous set of harmful dark traits and behaviors, including superficial charm, callousness, irresponsibility, and antisocial behavior. The triarchic psychopathy model (TriPM) posits that psychopathy is the combination of 3 traits: boldness, disinhibition, and meanness. However, little research has examined the concurrent and developmental correlates of these traits. We developed TriPM scales from the NEO Personality Inventory-Revised using an empirical-derived approach in a high-risk sample of 561 young adults (ages 17-25; 70.2% male). Concurrent correlates and developmental precursors of each scale were examined longitudinally using cross-informant reports from 3 critical developmental periods (ages 3-5; 9-11; 15-17). Using this approach, we identified consistent developmental precursors and concurrent correlates of boldness, including lower reactive control, fewer internalizing traits, and greater resiliency. Additionally, starting in adolescence we found that disinhibition was related to lower reactive control, more externalizing problems, substance use, and internalizing traits. Finally, although meanness demonstrated some expected concurrent relationships with criterion variables in early adulthood (e.g., lower adaptive functioning), we identified few consistent developmental precursors of meanness. Thus, a NEO-based approach to measuring the TriPM was successful in delineating boldness, disinhibition, and, to a lesser extent, meanness cross-sectionally during early adulthood. However, only boldness showed relative stability from developmental precursors in early childhood to our TriPM scale in early adulthood. (PsycINFO Database Record PMID- 29106274 TI - Antagonism trait facets and comprehensive psychosocial disability: Comparing information across self, informant, and interviewer reports. AB - It is widely known that personality traits collectively discussed as the Dark Triad are antagonistic and associated with poor interpersonal relationships, but few studies have examined how specific facets of antagonism are associated with psychosocial adjustment or how antagonism relates to psychosocial adjustment other than interpersonal functioning. The purpose of this study was to examine how 6 antagonism facets-manipulativeness, grandiosity, attention-seeking, hostility, callousness, and deceitfulness-relate to comprehensive psychosocial functional domains (i.e., well-being, interpersonal relationships, basic daily functioning) using information about both antagonism and functioning from 3 sources-self, informant, and interviewer. Data were from 318 primary participants and informants. We present 3 main findings: (1) When psychosocial functioning and antagonism traits were both rated by informants, all psychosocial disability domains were consistently positively associated with antagonism traits. (2) We next created a single psychosocial-disability factor score via principal factors analysis of all raters' psychosocial-functioning scores. When all 3 raters' reports of domain-level antagonism were used as independent variables in a simultaneous regression analysis to predict this overall functioning score, informant-reported antagonism most strongly predicted psychosocial functioning, followed by interviewer-rated antagonism. (3) We then created 6 facet scores by summing the 3 raters' scores on each. When we used these scores to predict psychosocial functioning, hostility was the main trait significantly predicting psychosocial functioning. The study provides further insight into associations of psychosocial disability with antagonism facets from different raters' perspectives. The findings thus further our understanding of psychosocial outcomes associated with antagonism, the core of the dark traits. (PsycINFO Database Record PMID- 29106276 TI - Leader dark traits, workplace bullying, and employee depression: Exploring mediation and the role of the dark core. AB - A growing body of empirical evidence now supports a negative association between dark traits in leaders and the psychological health of employees. To date, such investigations have mostly focused on psychopathy, nonspecific measures of psychological wellbeing, and have not considered the mechanisms through which these relationships might operate. In the current study (N = 508), we utilized other-ratings of personality (employees rated leaders' personality), psychometrically robust measures, and sophisticated modeling techniques, to examine whether the effects of leaders' levels of narcissism and psychopathy on employee depression are mediated by workplace bullying. Structural equation models provided clear evidence to suggest that employee perceptions of both leader narcissism and psychopathy are associated with increased workplace bullying (25.8% and 41.0% variance explained, respectively) and that workplace bullying fully mediates the effect of leader narcissism and psychopathy on employee depression (21.5% and 20.8% variance explained, respectively). However, when psychopathy and narcissism were modeled concurrently, narcissism did not explain any variance in bullying, suggesting that it is the overlap between psychopathy and narcissism, namely, the "dark core," which primarily accounts for the observed effects. We examined this assertion empirically and explored the unique effects of the subfactors of psychopathy. (PsycINFO Database Record PMID- 29106275 TI - The effect of pathological narcissism on interpersonal and affective processes in social interactions. AB - Narcissism has significant interpersonal costs, yet little research has examined behavioral and affective patterns characteristic of narcissism in naturalistic settings. Here we studied the effect of narcissistic features on the dynamic processes of interpersonal behavior and affect in daily life. We used interpersonal theory to generate transactional models of social interaction (i.e., linkages among perceptions of others' behavior, affect, and one's own behavior) predicted to be characteristic of narcissism. Psychiatric outpatients (N = 102) completed clinical interviews and a 21-day ecological momentary assessment protocol using smartphones. After social interactions (N = 5,781), participants reported on perceptions of their interaction partner's behavior (scored along the dimensions of dominant-submissive and affiliative-quarrelsome), their own affect, and their own behavior. Multilevel structural equation modeling was used to examine dynamic links among behavior and affect across interactions, and the role of narcissism in moderating these links. Results showed that perceptions of others' dominance did not predict dominant behavior, but did predict quarrelsome behavior, and this link was potentiated by narcissism. Furthermore, the link between others' dominance and one's own quarrelsome behavior was mediated by negative affect. Moderated mediation was also found: Narcissism amplified the link between ratings of others' dominance and one's own quarrelsomeness and negative affect. Narcissism did not moderate the link between other dominance and own dominance, nor the link between other affiliation and own affiliation. These results suggest that narcissism is associated with specific interpersonal and affective processes, such that sensitivity to others' dominance triggers antagonistic behavior in daily life. (PsycINFO Database Record PMID- 29106277 TI - Dark and vulnerable personality trait correlates of dimensions of criminal behavior among adult offenders. AB - Given the high-level impact of crime, empirical work is needed to identify personality traits, or overarching factors of personality pathology, that may leave individuals more prone to engage in criminal behaviors. This study empirically tested the distinction between the dark personality and vulnerable dark personality spectra (Miller et al., 2010) in a large offender sample and aimed to test how these personality factors relate to criminal dimensions and individual types of crime. Self-report and public record data verified criminal behaviors for 493 (34.7% women) adult offenders, and features of the 2 personality spectra were assessed using the Psychopathy Checklist: Screening Version, Narcissistic Personality Inventory-16, Hypersensitive Narcissism Scale, and Personality Assessment Inventory: Borderline Scale. Factor analyses supported the distinction between dark and vulnerable dark personality spectra and 3 dimensions of crime (i.e., crimes against property and persons, and drug-related crimes). Findings broadly pointed to trait vulnerabilities within the dark spectra (e.g., callousness) as relevant for criminal versatility and violent crimes against persons (e.g., assault, murder), and impulsive/reactive tendencies within the dark spectra (vulnerable dark) appeared to be particularly important for impulsive property crimes (e.g., theft, robbery) and drug offenses. Results may lend themselves well to refining offender intervention techniques and warrant further examination of the extent to which dark personality spectra coalesce as expected or similarly predict high-impact behaviors. (PsycINFO Database Record PMID- 29106278 TI - Dark traits and suicide: Associations between psychopathy, narcissism, and components of the interpersonal-psychological theory of suicide. AB - Studies have identified independent relationships between psychopathy, narcissism, and suicidality. The current study expands upon the extant literature by exploring psychopathic and narcissistic personality traits and components of the interpersonal-psychological theory of suicide, utilizing a 3-factor model of psychopathy and 2-factor model of pathological narcissism in community, undergraduate, and military individuals. We hypothesized that the impulsive antisocial facets of psychopathy would be related to suicidal desire, whereas all facets of psychopathy would relate to the capability for suicide. We anticipated an association between pathological narcissism, thwarted belongingness, and capability for suicide, but not perceived burdensomeness. We further hypothesized a relationship between physical pain tolerance and persistence and the affective (i.e., callousness) facet of psychopathy. Results partially supported these hypotheses and underscore the need for further examination of these associations utilizing contemporary models of psychopathy and narcissism. (PsycINFO Database Record PMID- 29106279 TI - Perils of partialing redux: The case of the Dark Triad. AB - The Dark Triad (DT) is a collection of overlapping aversive personality profiles constituting psychopathy, narcissism, and Machiavellianism. Debates remain regarding the optimal way to examine the unique outcomes associated with each construct, with several scholars advocating partialing these profiles in multiple regression analyses (i.e., removing their shared variance). The present paper details the pitfalls inherent in this approach by comparing the convergence and divergence of relations derived from raw and residualized DT composite scores. In Sample 1 (N = 393), DT scores were examined to determine the extent to which their raw and residualized components manifested similar relationships with the Five-Factor Model and the DSM-5 Section III personality disorder traits. In Sample 2 (N = 542), the same approach was taken in relation to an array of associated behaviors (e.g., antisocial behavior, promiscuity). Findings from Samples 1 and 2 demonstrate that the use of residualized (vs. raw) coefficients presents important interpretative challenges for both narcissism and Machiavellianism. This study illustrates the substantial interpretive difficulties that can arise when using findings from residualized analyses (e.g., multiple regression) to build nomological networks around Dark Triad constructs. We argue that bivariate relations be given preferential treatment, given their more direct ties to the assessments, and that if multivariate approaches are to be used, they must be accompanied by strong theory about the components of DT constructs. (PsycINFO Database Record PMID- 29106280 TI - The nature and correlates of the dark triad: The answers depend on the questions. AB - The past several decades have witnessed a proliferation of research on the dark triad (DT), a set of traits comprising Machiavellianism, narcissism, and psychopathy. The bulk of DT research has been marked by several core assumptions, most notably that each DT construct is a monolithic entity that is clearly separable from its counterpart DT constructs. To examine the tenability of these assumptions, we pooled data from 2 samples of North American community members (ns = 312 and 351) to explore (a) the external validity and profile similarities of DT indicators and (b) the factor structure of the DT. Using general personality dimensions as external criteria, we demonstrated that each DT measure is multidimensional and that subdimensions within DT measures often display sharply different and at times even opposing relations with personality domains; these opposing relations were largely obscured at the total score level adopted in most of the DT literature. In both samples, confirmatory factor analyses and exploratory structural equation models provided no clear support for the traditional tripartite DT structure delineated in the literature. Instead, various aspects of the DT constructs fractionated across a number of factors that represented more basic personality elements (e.g., emotional stability, grandiosity). Taken together, our findings raise serious questions regarding the standard model of DT research and suggest that the questions posed regarding the correlates of DT constructs hinge crucially on the specific DT measure and subdimension examined. (PsycINFO Database Record PMID- 29106281 TI - Evidence that psychopathology symptom networks have limited replicability. AB - Network analysis is quickly gaining popularity in psychopathology research as a method that aims to reveal causal relationships among individual symptoms. To date, 4 main types of psychopathology networks have been proposed: (a) association networks, (b) regularized concentration networks, (c) relative importance networks, and (d) directed acyclic graphs. The authors examined the replicability of these analyses based on symptoms of major depression and generalized anxiety between and within 2 highly similar epidemiological samples (i.e., the National Comorbidity Survey-Replication [n = 9282] and the National Survey of Mental Health and Wellbeing [n = 8841]). Although association networks were stable, the 3 other types of network analysis (i.e., the conditional independence networks) had poor replicability between and within methods and samples. The detailed aspects of the models-such as the estimation of specific edges and the centrality of individual nodes-were particularly unstable. For example, 44% of the symptoms were estimated as the "most influential" on at least 1 centrality index across the 6 conditional independence networks in the full samples, and only 13-21% of the edges were consistently estimated across these networks. One of the likely reasons for the instability of the networks is the predominance of measurement error in the assessment of individual symptoms. The authors discuss the implications of these findings for the growing field of psychopathology network research, and conclude that novel results originating from psychopathology networks should be held to higher standards of evidence before they are ready for dissemination or implementation in the field. (PsycINFO Database Record PMID- 29106282 TI - False alarm? A comprehensive reanalysis of "Evidence that psychopathology symptom networks have limited replicability" by Forbes, Wright, Markon, and Krueger (2017). AB - Forbes, Wright, Markon, and Krueger (2017) stated that "psychopathology networks have limited replicability" (p. 1011) and that "popular network analysis methods produce unreliable results" (p. 1011). These conclusions are based on an assessment of the replicability of four different network models for symptoms of major depression and generalized anxiety across two samples; in addition, Forbes et al. analyzed the stability of the network models within the samples using split-halves. Our reanalysis of the same data with the same methods led to results directly opposed to theirs: All network models replicated very well across the two data sets and across the split-halves. We trace the differences between Forbes et al.'s results and our own to the fact that they did not appear to accurately implement all network models and used debatable metrics to assess replicability. In particular, they deviated from existing estimation routines for relative importance networks, did not acknowledge the fact that the skip structure used in the interviews strongly distorted correlations between symptoms, and incorrectly assumed that network structures and metrics should be the same not only across the different samples but also across the different network models used. In addition to a comprehensive reanalysis of the data, we end with a discussion of best practices concerning future research into the replicability of psychometric networks. (PsycINFO Database Record PMID- 29106283 TI - A method for making inferences in network analysis: Comment on Forbes, Wright, Markon, and Krueger (2017). AB - Forbes, Wright, Markon, and Krueger (2017) make a compelling case for proceeding cautiously with respect to the overinterpretation and dissemination of results using the increasingly popular approach of creating "networks" from co occurrences of psychopathology symptoms. We commend the authors on their initial investigation and their utilization of cross-validation techniques in an effort to capture the stability of a variety of network estimation methods. Such techniques get at the heart of establishing "reproducibility," an increasing focus of concern in both psychology (e.g., Pashler & Wagenmakers, 2012) and science more generally (e.g., Baker, 2016). However, as we will show, the problem is likely worse (or at least more complicated) than they initially indicated. Specifically, for multivariate binary data, the marginal distributions enforce a large degree of structure on the data. We show that some expected measurements such as commonly used centrality statistics-can have substantially higher values than what would usually be expected. As such, we propose a nonparametric approach to generate confidence intervals through Monte Carlo simulation. We apply the proposed methodology to the National Comorbidity Survey - Replication, provided by Forbes et al., finding that the many of the results are indistinguishable from what would be expected by chance. Further, we discuss the problem of multiple testing and potential issues of applying methods developed for 1-mode networks (e.g., ties within a single set of observations) to 2-mode networks (e.g., ties between 2 distinct sets of entities). When taken together, these issues indicate that the psychometric network models should be employed with extreme caution and interpreted guardedly. (PsycINFO Database Record PMID- 29106284 TI - Further evidence that psychopathology networks have limited replicability and utility: Response to Borsboom et al. (2017) and Steinley et al. (2017). AB - In our target article, we tested the replicability of 4 popular psychopathology network estimation methods that aim to reveal causal relationships among symptoms of mental illness. We started with the focal data set from the 2 foundational psychopathology network papers (i.e., the National Comorbidity Survey Replication) and identified the National Survey of Mental Health and Wellbeing as a close methodological match for comparison. We compared the psychopathology networks estimated in each data set-as well as in 10 sets of random split-halves within each data set-with the goal of quantifying the replicability of the network parameters as they are interpreted in the extant psychopathology network literature. We concluded that current psychopathology network methods have limited replicability both within and between samples and thus have limited utility. Here we respond to the 2 commentaries on our target article, concluding that the findings of Steinley, Hoffman, Brusco, and Sher (2017)-along with other recent developments in the literature-provide further conclusive evidence that psychopathology networks have poor replicability and utility. (PsycINFO Database Record PMID- 29106285 TI - Liver-kidney simultaneous transplantation in adult patients with primary hyperoxaluria. Experience at Hospital Universitario 12 de Octubre. AB - Primary hyperoxaluria (PH) is a metabolic liver disease with an autosomal recessive inheritance that results in oxalate overproduction that cannot be metabolized by the liver. Urinary excretion of oxalate results in lithiasis and nephrocalcinosis leading to a progressive loss of renal function that often requires renal replacement therapy despite medical treatment. Type 1 PH is the most common form and is due to a deficiency in the alanine-glycolate aminotransferase enzyme found in hepatic peroxisomes. Therefore, a liver-kidney simultaneous transplant (LKST) is the definitive treatment for end-stage renal disease (ESRD) patients. However, some studies suggest that the morbidity and mortality rates are greater when this procedure is performed instead of only a kidney transplant (IKT). Herein, we report five patients with PH and a mean glomerular filtration rate of 20.2 +/- 1.3 ml/min/1.73 m2 who received a LKST between 1999 and 2015 at the Hospital Universitario 12 de Octubre. Recurrence and liver or kidney graft loss was not observed during the postoperative period and only one case of late acute rejection without graft loss was diagnosed. The recipient survival rate was 100% with a median follow up of 84 months. As LKST is a curative and safe procedure with a low mortality and high survival rate, it must be considered as the treatment of choice in adults with HP and ESRD. PMID- 29106287 TI - Endoscopic tattooing of colorectal neoplasms removed by laparoscopy: a proposal for selective marking. AB - BACKGROUND AND AIM: Preoperative endoscopic tattooing is an effective procedure to identify small intraoperative neoplasms. However, there are no defined criteria with regard to the indications for endoscopic tattooing of these lesions at the time of diagnosis. The aim of this study was to establish endoscopic criteria that allow the selection of patients who will need a tattoo during the diagnostic colonoscopy. METHODS: An ambispective study of patients undergoing laparoscopy due to a colorectal neoplasia who underwent endoscopic tattooing during the period from 2007-2013 and 2016-2017. According to the endoscopic description of the neoplasms, the classification was polypoid lesions, neoplasms occupying < 50% or >= 50% of the intestinal lumen and stenosing neoplasias. RESULTS: Tattooing of the lesion was performed in 120 patients and the same lesions were identified during surgery in 114 (95%) cases. Most of the neoplasias described as polypoids and neoplasias that occupied < 50% of the intestinal lumen were not visualized during surgery and therefore required a tattoo (33 of 42 and 18 of 26 respectively, p = 0.0001, X2). On the other hand, stenosing lesions or neoplasias occupying >= 50% of the intestinal lumen were mostly identified during surgery (15 of 15 and 36 of 37 respectively, p = 0.0001, X2) without the need for a tattoo. Overall, the identification of neoplasms according to established criteria was 98%. CONCLUSION: These results suggest that it is possible to establish endoscopic criteria that allow a successful selective tattooing during diagnostic endoscopy. PMID- 29106286 TI - Duodenal lengthening in an adult with ultra-short bowel syndrome. A case report. AB - BACKGROUND: We have recently demonstrated the feasibility of lengthening the duodenum in children with short bowel syndrome and a dilated duodenum. This procedure gains additional intestinal length in a challenging area of autologous gut reconstruction. Herein, we report the successful application of this technique in an adult with ultra-short bowel syndrome. CASE REPORT: A 25-year-old man with a history of mid-gut volvulus was referred to our center for intestinal transplant evaluation. Only a megaduodenum stump that reached as far as the third portion (30 cm of length) and the colon up to the hepatic flexure in the form of a mucous fistula was retained. A gastrostomy tube drained gastric and bilio pancreatic secretions (output range: 2.5-4 liters/day). The time spent on parenteral nutrition (3 liters/day; 1500 calories/day) and I.V. fluid (1.5-2 liters/day) administration was 24 hours per day. The patient underwent duodenal lengthening and tapering with 7 sequential transverse applications (5 of 45 mm and 2 of 60 mm) of an endoscopic stapler on the anterior and posterior walls of the duodenum, respecting the pancreatic parenchyma and end-to-side duodeno colonic anastomosis. The final duodenal length was 83 cm. The pre-lengthening citrulline level increased from 13.6 micromol/L to 21.6 micromol/L one year post lengthening. After 24 month of follow-up, the time on a parenteral pump was shortened to 9 hours during the night. The volume and calorie requirements were also reduced by half. DISCUSSION: Duodenal lengthening may be effective as part of the autologous intestinal reconstruction armamentarium in adults with short bowel syndrome. PMID- 29106288 TI - Localized gastrointestinal amyloidosis presenting with protein-losing enteropathy and massive hemorrhage. AB - Amyloidosis of the gastrointestinal tract is usually a systemic disease. Localized gastrointestinal amyloidosis without evidence of extraintestinal involvement or an associated plasma cell dyscrasia is uncommon and does not usually cause death. We report a case of a patient with localized gastrointestinal amyloidosis who presented with protein-losing enteropathy and a fatal upper gastrointestinal bleed. PMID- 29106290 TI - Normalization of FEV1/FVC Ratio to Greater Than 0.7 Does Not Equal Resolution of Disease. PMID- 29106289 TI - Insertion of fully covered self-expanding metal stents in benign biliary diseases. AB - INTRODUCTION: Benign biliary diseases are traditionally treated using plastic stents. However, fully covered self-expanding metal stents are currently gaining acceptance for the treatment of these pathologies. OBJECTIVE: To assess the effectiveness and complications associated with the placement of temporary endoscopic fully covered self-expanding metal stents for the treatment of benign biliary diseases. MATERIALS AND METHODS: This was a retrospective and observational study using a prospective database from a tertiary care center from March 2012 to May 2016. Some patients that had a fully covered metal stent due to a benign biliary disease were also included. The indications, resolution, technical success rates and adverse events were documented. RESULTS: 31 patients were included with a total of 34 stents inserted. The indications were as follows: 8 (25%) post cholecystectomy biliary stenoses, 11 (31%) large or multiple choledocholithiasis, 3 (8.3%) biliary fistulas, 2 (6%) post-liver transplant stenoses, 2 (8.3%) papillary stenoses, 2 (6%) perforations and 2 (6%) bleeds. The global resolution success rate of the stents for all pathologies was 88%, this included 87.5% (7/8) in post cholecystectomy stenoses, 73% (8/11) in large choledocholithiasis and 100% for the remaining indications. Thirty-three of 34 stents were removed after an average of 133 days (ranging from 10 to 180 days). No complications were registered. CONCLUSION: Fully covered self-expanding metal stents are an effective and reliable alternative for the resolution of benign biliary diseases. PMID- 29106291 TI - Spirometry Variability Must Be Critically Interpreted before Negating a Clinical Diagnosis of Chronic Obstructive Pulmonary Disease. PMID- 29106292 TI - Preanalytic Factors Associated With Hemolysis in Emergency Department Blood Samples. AB - CONTEXT: - Hemolysis of emergency department blood samples is a common occurrence and has a negative impact on health care delivery. OBJECTIVES: - To determine the effect of preanalytic factors (straight stick, intravenous [IV] line, needle gauge, location of blood draw, syringe versus vacuum tube use, tourniquet time) on hemolysis in emergency department blood samples. DESIGN: - A single 65 000 visit emergency department's electronic health record was queried for emergency department potassium results and blood draw technique for all samples obtained in calendar year 2014, resulting in 54 531 potassium results. Hemolyzed potassium was measured by hemolysis index. Comparisons of hemolysis by sampling technique were conducted by chi2 tests. RESULTS: - Overall hemolysis was 10.0% (5439 of 54 531). Hemolysis among samples obtained from straight stick was significantly less than among those obtained with IV line (5.4% [33 of 615] versus 10.2% [4821 of 47 266], P < .001). For IV-placed blood draws, antecubital location had a statistically significant lower overall hemolysis compared with other locations: 7.4% (2117 of 28 786) versus 14.6% (2622 of 17 960) ( P < .001). For blood drawn with a syringe compared with vacuum, hemolysis was 13.0% (92 of 705) and 11.0% (1820 of 16 590), respectively ( P = .09, not significant). For large-gauge IV blood draws versus smaller-gauge IV lines, a lower hemolysis was also observed (9.3% [3882 of 41 571] versus 16.7% [939 of 5633]) ( P < .001). For IV-drawn blood with tourniquet time less than 60 seconds, hemolysis was 10.3% (1362 of 13 162) versus 13.9% for more than 60 seconds (532 of 3832), P < .001. CONCLUSIONS: This study confirmed previous findings that straight stick and antecubital location are significantly associated with reduced hemolysis and indicated that shorter tourniquet time and larger gauge for IV draws were significantly associated with lower hemolysis. PMID- 29106293 TI - Worldwide Frequency of Commonly Detected EGFR Mutations. AB - CONTEXT: - Recurrent epidermal growth factor receptor ( EGFR) mutations are seen in a subset of pulmonary adenocarcinomas. These mutations are targeted by EGFR inhibitors and are a biomarker for response to EGFR inhibitor therapies. Initial data have indicated an increased frequency of activating EGFR mutations in nonsmoking Asian females. However, there are very few studies of global scope that address the question of mutation distribution across the population of lung cancer. OBJECTIVE: - To determine the frequency of EGFR mutations in exons 18 through 21 detected in clinical laboratories participating in the College of American Pathologists proficiency testing program for EGFR in calendar year 2013. DESIGN: - We reviewed the surveys from 170 clinical laboratories from 20 countries that participated in the College of American Pathologists EGFR proficiency testing program. The proficiency testing includes questions regarding the total numbers of tests performed at each common mutation site, including both activating and resistance mutations, and their frequency. Countries were grouped into regional groups in order to assess frequency of mutation by type, and to indirectly assess ethnic differences in mutation frequencies. RESULTS: - Among the treatment-sensitive activating mutations, the most common are exon 19 mutations (n = 10 802 of 136 533 cases; 7.9% of total cases tested) and the exon 21 L858R mutation (n = 10 351 of 136 533 cases; 7.6% of total cases tested) and the least common are exon 20 mutations (n = 466 of 136 533 cases; 0.3% of total cases tested). The T790M mutation in exon 20 is the more common resistance mutation (n = 1010 of 136 533 cases; 0.7% of all cases tested). The highest activating mutation frequency is seen in southern Asia (n = 4260 of 9337 cases; 46%) and the lowest activating mutation frequencies are in South and North America (n = 113 of 1439 cases and 7926 of 86 654 cases; 8% and 9%, respectively). CONCLUSIONS: - Our data confirm that activating EGFR mutations are more common in southern Asia and that the distribution of activating EGFR mutations varies significantly across the regions. Similarly, the frequency and distribution of resistance mutations also show significant variation when comparing southern Asia with other regions. PMID- 29106294 TI - Reply to Vazquez Guillamet et al. and to Magnussen et al.: "Normalization of FEV1/FVC Ratio to Greater Than 0.7 Does Not Equal Resolution of Disease" and "Spirometry Variability Must Be Critically Interpreted before Negating a Clinical Diagnosis of Chronic Obstructive Pulmonary Disease". PMID- 29106295 TI - Naive pluripotent stem cells as a model for studying human developmental epigenomics: opportunities and limitations. PMID- 29106296 TI - What is Recklessness in Scientific Research? The Frank Sauer Case. AB - On May 22, 2017, administrative law Judge Leslie Rogall of the Department of Health and Human Services' Departmental Appeals Board, Civil Remedies Division, ruled in favor of the Office of Research Integrity (ORI) concerning its decision to charge former University of California at Riverside biochemistry professor Frank Sauer with research misconduct for fabricating or falsifying digital image data included in three papers and seven grant applications submitted to the National Institutes of Health. More specifically, Sauer was deemed responsible for manipulating, reusing, and falsely labeling images of autoradiograms and gels in his research in epigenetics. One month after this decision, ORI announced its final ruling concerning Sauer, which barred him from serving in any advisory capacity to the Public Health Services and required him to retract affected papers. The case raises some interesting and important questions concerning research integrity because it focused on the legal issue of what constitutes recklessness in scientific research. PMID- 29106297 TI - Developments in Micro- and Nanotechnology for Foodborne Pathogen Detection. AB - In response to the potential hazards associated with the globalization of the food industry, research has been focused on the development of new sensing techniques to provide the means of contamination detection at any stage in the food supply chain. The demand for on-site detection is growing as pre-emptive sensing of pathogens could eliminate foodborne-related outbreaks and associated healthcare costs. Reduction in food waste is also a driver for point-of-use (POU) sensing, from both an economic and environmental standpoint. The following review discusses the latest advancements in platforms that have the greatest potential for inexpensive, real-time detection, and identification of foodborne pathogens. Specific focus has been placed on the development techniques, which utilize micro and nanoscale technology. Sample preparation-free techniques are also discussed, as the growing demand to enable POU sensing at any stage in the food supply chain will be a major driver toward the advancements of these nondestructive methods. PMID- 29106298 TI - Phenotypic and Molecular Characterization of Salmonella Enteritidis SE86 Isolated from Poultry and Salmonellosis Outbreaks. AB - Salmonella Enteritidis remains a standout among the leading causes of foodborne diseases worldwide. Previous studies have demonstrated that a unique clonal group of Salmonella Enteritidis, named SE86, is involved in foodborne outbreaks in southern Brazil and is frequently identified among strains isolated from poultry. The aim of this study was to determine the influence of the isolation source (food products involved in salmonellosis outbreaks and poultry sources) on the phenotypic and molecular characteristics of Salmonella Enteritidis SE86. A biofilm formation assay, antimicrobial susceptibility test, polymerase chain reaction identification of virulence-associated genes, and phage type 4 (PT4) assessment were performed to characterize Salmonella Enteritidis SE86. The human strains presented less antimicrobial resistance than the poultry strains. Resistance to some substances was related to the isolation source of the strain. Strains of the same clonal group presented different biofilm production abilities. Biofilm formation was independent of the isolation source at all temperatures. Temperature influenced biofilm formation only by the poultry strains. Most of the investigated genes presented a high frequency and a regular distribution, regardless of the isolation source. The spvB, spiA, pagC, sipB, prgH, spaN, sitC, and lpfC genes were associated with the avian strains, whereas iroN was associated with the strains isolated from food products involved in salmonellosis outbreaks. Most strains belonged to PT4. No relationship was found between biofilm production and antimicrobial resistance or between the virulence profile and biofilm production or antimicrobial resistance. PMID- 29106299 TI - Comparison of two early treatment protocols for anterior dental crossbite in the mixed dentition: A randomized trial. AB - OBJECTIVE: To evaluate and compare two treatment protocols to correct anterior dental crossbite in the mixed dentition. MATERIALS AND METHODS: Thirty children, 8-10 years of age, participated. Individuals were divided into two groups. Group 1 consisted of 15 children treated with an upper removable appliance with finger springs; group 2, 15 children treated by bonding resin-reinforced glass ionomer cement bite pads on the lower first molars. The 30 participants were evaluated before treatment (T1) and 12 months after treatment began (T2). The variables evaluated included overjet, perimeter of the maxillary arch, intercanine distances in the maxilla and mandible, SNA, SNB, ANB, and U1.NA. Data analysis included descriptive statistics, paired t-test and Student's t-test. Effect sizes and confidence intervals were also calculated. RESULTS: Group 1 showed a significant increase in overjet ( P < .001), intercanine distance in the maxilla ( P = .006), intercanine distance in the mandible ( P = .031), and U1.NA ( P = .002). Group 2 showed a significant increase in overjet ( P = .008), intercanine distance in the mandible ( P = .005), and U1.NA ( P < .001). For all the evaluated variables, no statistically significant differences were observed between the two groups. CONCLUSIONS: No significant differences were observed between the two protocols: use of a removable maxillary biteplate with finger springs and bonding of resin-reinforced glass ionomer cement bite pads on the lower first molars, for the correction of anterior crossbite in the mixed dentition. PMID- 29106300 TI - Increased correlation between methylation sites in epigenome-wide replication studies: impact on analysis and results. AB - AIM: To show that an increased correlation between CpGs after selection through an epigenome-wide association studies (EWAS) might translate into biased replication results. METHODS: Pairwise correlation coefficients between CpGs selected in two published EWAS, the top hits replication, Bonferroni p-values, Benjamini-Hochberg (BH) false discovery rate (FDR) and directional FDR r-values were calculated in the NINFEA cohort data. Exposures' random permutations were performed to show the empirical p-value distributions. RESULTS: The average pairwise correlation coefficients between CpGs were enhanced after selection for the replication (e.g., from 0.12 at genome-wide level to 0.26 among the selected CpGs), affecting the empirical p-value distributions and the usual multiple testing control. CONCLUSION: Bonferroni and Benjamini-Hochberg FDR are inappropriate for the EWAS replication phase, and methods that account for the underlying correlation need to be used. PMID- 29106301 TI - miRNA processing gene polymorphisms, blood DNA methylation age and long-term ambient PM2.5 exposure in elderly men. AB - AIM: We tested whether genetic variation in miRNA processing genes modified the association of PM2.5 with DNA methylation (DNAm) age. PATIENTS & METHODS: We conducted a repeated measures study based on 552 participants from the Normative Aging Study with multiple visits between 2000 and 2011 (n = 940 visits). Address level 1-year PM2.5 exposures were estimated using the GEOS-chem model. DNAm-age and a panel of 14 SNPs in miRNA processing genes were measured from participant blood samples. RESULTS & CONCLUSION: In fully adjusted linear mixed-effects models, having at least one copy of the minor rs4961280 [AGO2] allele was associated with a lower DNAm-age (beta = -1.13; 95% CI: -2.26 to -0.002). However, the association of PM2.5 with DNAm-age was significantly (Pinteraction = 0.01) weaker in homozygous carriers of the major rs4961280 [AGO2] allele (beta = 0.38; 95% CI: -0.20 to 0.96) when compared with all other participants (beta = 1.58; 95% CI: 0.76 to 2.39). Our results suggest that miRNA processing impacts DNAm-age relationships. Graphical abstract: miRNA processing AGO2 polymorphism (rs4961280) modifies the association of long-term ambient fine particle exposure with blood DNA methylation age [Formula: see text] The graph depicts lines from a fully adjusted linear regression model with fine particle exposure levels ranging from the tenth to the ninetieth percentile, all other continuous variables held constant at their means, and all other categorical variables held at their most frequent level. PMID- 29106303 TI - Dynamics of core body temperature cycles in long-term measurements under real life conditions in women. AB - Studies under real life conditions become more and more relevant in chronobiological and chronomedical research. The present study aims to analyze one of the most prominent biological rhythms: the core body temperature (CBT) rhythm in the real world outside the laboratory. CBT was recorded continuously in 37 healthy women (age between 21 and 44 years, median 29 years) with a newly developed intravaginal temperature sensor for up to 102 days. Sleep logs were available from 23 participants. To quantify the daily dynamics of each individual CBT-curve, novel measurement parameters are introduced which permit the quantification of the phase and shape of the CBT rhythms as well as their relation to the sleep-wake cycle. In addition to the classical phase markers (i.e. nadir and peak), the daily curves were segmented into quartiles by introducing the t25/t50/t75-values which can be used as phase and shape markers. At variance to previous studies, a conspicuous day-to-day variation was shown not only for the time point of the peak, but also for the time point of the nadir. However, the t-values, particularly the t75-value were relatively closely locked to external time and thus represent more reliable phase markers than the nadir. The (variable) time point of the nadir determined the period length, phase and shape of the subsequent CBT cycle. If a nadir occurred close to the wake-up time, the following cycle was considerably shorter than 24 hours, while a nadir distant from the wake-up time was followed by a longer cycle. Thus, the period lengths of the daily CBT cycles of each individual were characterized by an "expand/contract" rhythm. The analyses of the novel phase markers (t25/t50/t75) of the CBT curves allowed to identify "early" and "late" participants who may differ in their phase-response curves with regard to the entraining effect of light. In addition, the novel phase markers mirrored the different social entrainment conditions on weekends and workdays. PMID- 29106302 TI - Comparative study on the effects of apple peel polyphenols and apple flesh polyphenols on cardiovascular risk factors in mice. AB - Apple consumption has been demonstrated to be associated with reduced risk of cardiovascular disease, and the beneficial effect is probably due to the polyphenols in apple. Here, we for the first time evaluated and compared the in vivo effects of the polyphenolic extracts of apple peels (PAP) and apple fleshes (PAF) on blood pressure, vascular endothelial function, lipid metabolism and insulin resistance. A high-fat and high-fructose (HFHF) diet was used to cause cardiovascular disorders in mice, with blood pressure, serum ET-1, TC, TG, LDL-C, glucose and insulin levels increased, and serum NO and HDL-C levels decreased. Mice administered with 250 mg/kg of PAP and PAF for 28 days showed lower blood pressure, improved endothelial function, ameliorated lipid homeostasis and decreased insulin resistance compared with HFHF-fed mice. Furthermore, PAP exhibited much more potent cardioprotective effects than PAF in mice. Quantification and phenolic profile analysis showed that PAP contained remarkably higher amount of total phenolics and total flavonoids than PAF, and this may be the reason for the relatively stronger efficacy of PAP. This study demonstrates that apple polyphenols possess potential cardioprotective effects, and suggests that apple, especially apple peel, may be excellent source for exploration of preventive agents against cardiovascular disorders. PMID- 29106304 TI - Role of MAIT cells in the immunopathogenesis of inflammatory diseases: New players in old game. AB - Current advances in immunology have led to the identification of a population of novel innate immune T cells, called mucosa-associated invariant T (MAIT) cells. The cells in humans express an invariant TCRalpha chain (Valpha7.2-Jalpha33) paired with a limited subset of TCRbeta chains (Vbeta2, 13 and 22), are restricted by the MHC class I (MH1)-related (MR)-1, and recognize molecules that are produced in the bacterial riboflavin (vitamin B2) biosynthetic pathway. They are present in the circulation, liver and at various mucosal sites (i.e. intestine, lungs and female reproductive tract, etc.). They kill host cells infected with bacteria and yeast, and secrete soluble mediators such as TNF alpha, IFN-gamma, IL-17, etc. The cells regulate immune responses and inflammation associated with a wide spectrum of acute and chronic diseases in humans. Since their discovery in 1993, significant advances have been made in understanding biology of MAIT cells and the potential role of these cells in the pathogenesis of autoimmune, inflammatory and infectious diseases as well as cancer in humans. The purpose of this review is to provide a current state of our knowledge about MAIT cell biology and delineate their role in autoimmune and inflammatory diseases (sterile or caused by infectious agents) and cancer in humans. A better understanding of the role of MAIT cells in human diseases may lead to novel ways of immunotherapies. PMID- 29106305 TI - Prediction of age at menopause in women with polycystic ovary syndrome. AB - OBJECTIVE: Considering the role of anti-Mullerian hormone (AMH) in female fertility and its high levels in women with polycystic ovary syndrome (PCOS), the longer reproductive span of these women is in doubt. In the present study, we aimed to improve earlier predictions using a non-linear model to substantiate the question as to whether PCOS women reach menopause later. METHODS: In total, 1162 women aged 20-50 years, comprising 378 PCOS cases and 784 eumenorrheic non hirsute women, met the eligibility criteria. A scatterplot matrix was drawn to detect the association between age and AMH; this association was explored using a fractional polynomial regression model. Model assumptions were checked by examining the distribution of the residuals and plotting the standardized residuals against the functional form of AMH. RESULTS: The serum concentration of AMH among PCOS participants was significantly higher than in the controls (5.4 ng/ml (IQR 2.8-9.1 ng/ml) vs. 1.4 ng/ml (IQR 0.6-2.7 ng/ml), p < 0.001). The estimated mean age at menopause was 51.4 (95% CI 45-59) years and 49.7 (95% CI 45 55) years in PCOS cases and healthy controls, respectively. CONCLUSIONS: These findings provide the insight that, as reflected through significantly higher average levels of AMH in PCOS women, their predicted reproductive lifespan could be 2 years longer than their normo-ovulatory counterparts. PMID- 29106306 TI - Assessing the value of the Meaningful Use Clinical Summary for patients and families with pediatric asthma. AB - Electronic clinical summaries are innovations supported by the Electronic Health Record Incentive Program, known as "Meaningful Use" (MU). The MU clinical summary documents the shared understanding of the plan of care for patients and assists families in managing asthma-related health care. The purpose of this analysis was to identify the communicative value of the summaries to patients and families. Readability measurements, content analysis, and descriptive statistics were employed in a review of twenty clinical summaries and compared with provider encounter notes. The average age of the patients from whom we collected clinical summaries was six years old. The average reading level of the summaries was ninth grade. Neither summaries or health education contained visual images. There was a total of nine different asthma diagnoses. A full list of diagnoses was present in 45% of summaries. The average medications per patient was 5.75, and there were multiple medication changes noted (dosage adjustment, add, discontinued, and add). Allergies, vital signs, and smoking status were reliably reported (99 100%). Provider orders present included medication, follow up, and return to the clinic instructions. The plan of care was replicated on 45% of summaries. There was variable reporting of various asthma guidelines. Opportunities to improve the clinical summary include using plain language to promote readability, action, understanding, and health literacy, training providers to standardize their documentation and include asthma action plans, and configuring EHR settings to ensure diagnoses and plan of care is carried over from provider notes to the summary. PMID- 29106307 TI - Menopause, lung function and obstructive lung disease outcomes: a systematic review. AB - BACKGROUND: The menopausal transition may have significant consequences for respiratory health, risk of chronic respiratory disease and management strategies. OBJECTIVE: To systematically summarize the literature regarding the impact of menopause status on respiratory health outcomes. METHODS: PubMed was searched systematically to identify population-based studies investigating the associations between menopause status and respiratory outcomes including asthma, chronic obstructive pulmonary disease (COPD), respiratory symptoms and lung function. RESULTS: Ten publications were identified for full review. Evidence on menopause and asthma was conflicting, while studies on COPD were scarce. The findings generally support an association between menopause and clinically significant reductions in lung function in a non-obstructive pattern. However, the effects of menopause are clouded by aging, menopausal hormone therapy use, and increased risk of metabolic syndrome during this period. CONCLUSIONS: As the global burden associated with respiratory conditions continues to rise, the need to understand the associations between menopause and respiratory health is essential to identify potentially modifiable risk factors for respiratory disease in adult women. More studies are needed to clarify the impact of menopause on obstructive lung disease. PMID- 29106308 TI - Sleep quality and methylation status of core circadian rhythm genes among nurses and midwives. AB - ABSTARCT Poor sleep quality or sleep restriction is associated with sleepiness and concentration problems. Moreover, chronic sleep restriction may affect metabolism, hormone secretion patterns and inflammatory responses. Limited recent reports suggest a potential link between sleep deprivation and epigenetic effects such as changes in DNA methylation profiles. The aim of the present study was to assess the potential association between poor sleep quality or sleep duration and the levels of 5-methylcytosine in the promoter regions of PER1, PER2, PER3, BMAL1, CLOCK, CRY1 CRY2 and NPAS2 genes, taking into account rotating night work and chronotype as potential confounders or modifiers. A cross-sectional study was conducted on 710 nurses and midwives (347 working on rotating nights and 363 working only during the day) aged 40-60 years. Data from in-person interviews about sleep quality, chronotype and potential confounders were used. Sleep quality and chronotype were assessed using Pittsburgh Sleep Quality Questionnaire (PSQI) and Morningness-Eveningness Questionnaire (MEQ), respectively. Morning blood samples were collected. The methylation status of the circadian rhythm genes was determined via quantitative methylation-specific real-time PCR assays (qMSP) reactions using DNA samples derived from leucocytes. The proportional odds regression model was fitted to quantify the relationship between methylation index (MI) as the dependent variable and sleep quality or sleep duration as the explanatory variable. Analyses were carried out for the total population as well as for subgroups of women stratified by the current system of work (rotating night shift/day work) and chronotype (morning type/intermediate type/evening type). A potential modifying effect of the system of work or the chronotype was examined using the likelihood ratio test. No significant findings were observed in the total study population. Subgroup analyses revealed two statistically significant associations between a shorter sleep duration and 1) methylation level in PER2 among day workers, especially those with the morning chronotype (OR = 2.31, 95%CI:1.24-4.33), and 2) methylation level in CRY2 among subjects with the intermediate chronotype, particularly among day workers (OR = 0.52, 95%CI:0.28-0.96). The study results demonstrated a positive association between average sleep duration of less than 6 hours and the methylation level of PER2 among morning chronotype subjects, and an inverse association for CRY2 among intermediate chronotype subjects, but only among day workers. Both the system of work and the chronotype turned out to be important confounders and modifiers in a number of analyses, making it necessary to consider them as potential covariates in future research on sleep deficiency outcomes. Further studies are warranted to explore this under-investigated topic. PMID- 29106309 TI - Maternal gestational weight gain and DNA methylation in young women: application of life course mediation methods. AB - AIM: To investigate the role of maternal gestational weight gain (GWG) and prepregnancy BMI on programming offspring DNA methylation. METHODS: Among 589 adult (age = 32) women participants of the Jerusalem Perinatal Study, we quantified DNA methylation in five candidate genes. We used inverse probability weighting and parametric g-formula to estimate direct effects of maternal prepregnancy BMI and GWG on methylation. RESULTS: Higher maternal GWG, but not prepregnancy BMI, was inversely related to offspring ABCA1 methylation (beta = 1.1% per quartile; 95% CI: -2.0, -0.3) after accounting for ancestry, parental and offspring exposures. Total and controlled direct effects were nearly identical suggesting included offspring exposures did not mediate this relationship. Results were robust to sensitivity analyses for missing data and model specification. CONCLUSION: We find some support for epigenetic programming and highlight strengths and limitations of these methods relative to other prevailing approaches. PMID- 29106310 TI - Comparison of microtomography and optical coherence tomography on apical endodontic filling analysis. AB - OBJECTIVES: To compare in vitro differences in the apical filling regarding working length (WL) change and presence of voids and to validate optical coherence tomography (OCT) in comparison with computerized microtomography (uCT) for the detection of failures in the apical filling. METHODS: Forty-five uniradicular teeth with round canals, divided into groups (n = 15) following the obturation protocols: LC (lateral condensation), TMC (thermomechanical compaction) and SC (single cone). Samples were scanned using uCT (parameters: 80 kV, 222 uA, and resolution of 11 um), OCT (parameters: SSOCT, 1300 nm and axial resolution of 12 um), and periapical digital radiography. The images were analyzsed by two blind and calibrated observers using ImageJ software to measure the boundary of the obturation WL and voids presence. Categorical and metric data were submitted to inferential analysis, and the validity of the OCT as a diagnostic test was assessed with performance and reliability tests. RESULTS: The WL average remained constant for all obturation techniques and image methods. OCT showed adequate sensitivity and specificity to detect voids in the WL of apical obturations in vitro in comparison with uCT. Both image methods found a higher number of voids for LC technique (uCT p = 0.011/OCT p = 0.002). CONCLUSIONS: OCT can be used in apical obturation voids assessment and the LC technique revealed more voids with larger dimensions. PMID- 29106311 TI - Impact of an Automated Bihormonal Delivery System on Psychosocial Outcomes in Adults with Type 1 Diabetes. AB - OBJECTIVES: The study assessed the psychosocial impact of the bihormonal bionic pancreas (BP) on adults in a real-world outpatient setting. RESEARCH DESIGN AND METHODS: Thirty-nine adults with type 1 diabetes at four study centers across the U.S. participated in a two-arm, random-order, crossover design study: 11 days with the BP and 11 days with their usual care (UC). Psychosocial questionnaires were administered before the first study arm, at the end of the first study arm, and at the end of the second study arm. RESULTS: The mean age of participants was 33 years; mean diabetes duration was 17 years; and 84% were non-Hispanic Caucasian. Significantly greater improvements in psychosocial outcomes were found following the use of BP versus UC; these included reductions in diabetes-related distress (P < 0.001) with the greatest drops in distress related to hypoglycemia and to eating constraints, and greater treatment satisfaction (P < 0.05). The majority of BP users described their experience as positive with a reduction in worrying about low (72%) and high (69%) blood sugars. The majority reported trusting the device (69%) and feeling less burdened by the BP than their usual method of diabetes care (64%). Concerns about the burden of the BP were also expressed, with >75% of users highlighting the burden of carrying around the equipment and the need to change glucagon daily, and more than half of the participants reporting concerns about wearability, discomfort, the time it took to correct out-of-range numbers, and "glitches" in the system. CONCLUSIONS: Overall, participants report substantial psychosocial benefits accruing from the BP relative to their usual method of diabetes care. However, participants also reported a number of burdens associated with the system. Future versions of the BP device should be designed with the goal of addressing these concerns, and studies with larger, more diverse samples, and with more technology-naive participants are needed. PMID- 29106312 TI - Nitrogen Concentrations and Isotopic Compositions of Seafloor-Altered Terrestrial Basaltic Glass: Implications for Astrobiology. AB - Observed enrichments of N (and the delta15N of this N) in volcanic glasses altered on Earth's modern and ancient seafloor are relevant in considerations of modern global N subduction fluxes and ancient life on Earth, and similarly altered glasses on Mars and other extraterrestrial bodies could serve as valuable tracers of biogeochemical processes. Palagonitized glasses and whole-rock samples of volcanic rocks on the modern seafloor (ODP Site 1256D) contain 3-18 ppm N with delta15Nair values of up to +4.50/00. Variably altered glasses from Mesozoic ophiolites (Troodos, Cyprus; Stonyford volcanics, USA) contain 2-53 ppm N with delta15N of -6.3 to +70/00. All of the more altered glasses have N concentrations higher than those of fresh volcanic glass (for MORB, <2 ppm N), reflecting significant N enrichment, and most of the altered glasses have delta15N considerably higher than that of their unaltered glass equivalents (for MORB, -5 +/- 20/00). Circulation of hydrothermal fluids, in part induced by nearby spreading-center magmatism, could have leached NH4+ from sediments then fixed this NH4+ in altering volcanic glasses. Glasses from each site contain possible textural evidence for microbial activity in the form of microtubules, but any role of microbes in producing the N enrichments and elevated delta15N remains uncertain. Petrographic analysis, and imaging and chemical analyses by scanning electron microscopy and scanning transmission electron microscopy, indicate the presence of phyllosilicates (smectite, illite) in both the palagonitized cracks and the microtubules. These phyllosilicates (particularly illite), and possibly also zeolites, are the likely hosts for N in these glasses. Key Words: Nitrogen Nitrogen isotope-Palagonite-Volcanic glass-Mars. Astrobiology 18, 330-342. PMID- 29106313 TI - Prevalence and risk factors associated with hypertension in the Chinese Qiang population. AB - Our aim is to investigate the prevalence and risk factors associated with hypertension among the Chinese Qiang population. From September 2012 to March 2013, a cross-sectional study was conducted in urban and rural communities of the Qiang population using multistage cluster sampling. A total of 2676 people aged above 20 years were enrolled in the analysis. Standardized mercury sphygmomanometer was used to measure the blood pressure twice after a 10-minute seated rest, and the average blood pressure was obtained. The hypertension prevalence among the population aged above 20 years was 13.9%, and age standardized prevalence was 12.3%. Male and female prevalence of hypertension, as well as the prevalence in urban and rural areas, all increased with age. There were no significant differences between males and females and between urban and rural residents. Among hypertensive patients, 44.2% were aware of their hypertension, 38.0% were undergoing antihypertensive treatment, but only 10.5% achieved blood pressure control. Multivariate logistic regression analysis showed that the risk factors of hypertension included age, low income, overweight and obesity, family history of hypertension. The prevalence of hypertension in Chinese Qiang adults is significantly lower than the national level. Awareness, treatment, and control rates of hypertension were low in the Qiang population. Thus, hypertension-related health knowledge should be more aggressively delivered to improve public awareness and the capacity of community health services should be strengthened. PMID- 29106314 TI - Protein biomarkers in renal transplantation. AB - INTRODUCTION: The standard of care for monitoring renal transplant patients include transplant biopsy and serum creatinine measurements. These are invasive procedures and are late and nonspecific markers of injury. Proteomics and proteins can provide biomarkers for monitoring pathology and become a useful tool in detection and treatment of conditions that occur after transplant. Areas covered: A survey of 273 studies in the biomarker detection field which included proteomics relating to renal pathology and normal controls was done. Analysis of this data showed pathways and biomarkers specific to different pathologies such as: AR, CR, IRI, TI, VR, DGF, AABMR, ACMR, immunosuppressant toxicity, and infection. It also revealed biomarkers proposed for better detection of these pathologies and the strength (sensitivity and specificity) of such biomarkers. Finally, the field of proteomics in renal transplant in terms of its methodologies, current challenges in clinical translation, and possible solutions are also discussed. Expert commentary: An analysis of biomarkers of acute and chronic rejection revealed acute rejection may be a more inflammatory process. A comparison of proteomic and protein based (n = 183), transcriptomic (n = 1), and genomic (n = 4) studies revealed that proteomic and protein based approaches may offer a clearer picture of inflammation in acute rejection. PMID- 29106315 TI - The Paradox of End-of-Life Hospital Treatment Intensity among Black Patients: A Retrospective Cohort Study. AB - OBJECTIVE: Black patients are more likely than white patients to die in the hospital with intensive care and life-sustaining treatments and less likely to use hospice. Regional concentration of high end-of-life (EOL) treatment intensity practice patterns may disproportionately affect black patients. We calculated and compared race-specific hospital-level EOL treatment intensity in Pennsylvania. METHODS: We conducted a retrospective cohort analysis of Pennsylvania acute care hospital admissions, 2001-2007, among black and white admissions >=21 years old at high probability of dying (HPD) (>=15% predicted probability of dying at admission). We calculated hospitals' race-specific observed, expected, and Bayes' shrunken observed-to-expected ratios of intensive care unit (ICU) admission, ICU length of stay (LOS), intubation/mechanical ventilation, hemodialysis, tracheostomy, and gastrostomy among HPD admissions; and an empirically weighted EOL treatment intensity index summing these ratios. RESULTS: There were 35,609 black HPD admissions (27,576 unique patients) and 311,896 white HPD admissions (252,662 unique patients) to 182 hospitals. Among 95 hospitals with >=30 black HPD admissions, 80% of black admissions were concentrated in 29 hospitals, where black-specific observed and expected EOL measures were usually higher than white specific measures (p < 0.001 for all but 5/24 measures). Hospitals' black specific and white-specific observed-to-expected ratios of ICU and life sustaining treatment (LST) (rho 0.52-0.90) and EOL index (rho = 0.92) were highly correlated. However, black-specific observed-to-expected ratios and overall EOL intensity index were consistently lower than white-specific ratios (p < 0.001 for all except hemodialysis). CONCLUSIONS: In Pennsylvania, black-serving hospitals have higher standardized EOL treatment intensity than nonblack-serving hospitals, contributing to black patients' relatively higher use of intensive treatment. However, conditional on being admitted to the same high-intensity hospital and after risk adjustment, blacks are less intensively treated than whites. PMID- 29106316 TI - Applying Social Network Analysis to Identify the Social Support Needs of Adolescent and Young Adult Cancer Patients and Survivors. AB - PURPOSE: This article examines how theoretical and clinical applications of social network analysis (SNA) can inform opportunities for innovation and advancement of social support programming for adolescent and young adult (AYA) cancer patients and survivors. APPLICATIONS: SNA can help address potential barriers and challenges to initiating and sustaining AYA peer support by helping to identify the diverse psychosocial needs among individuals in the AYA age range; find strategic ways to support and connect AYAs at different phases of the cancer trajectory with resources and services; and increase awareness of psychosocial resources and referrals from healthcare providers. Network perspectives on homophily, proximity, and evolution provide a foundational basis to explore the utility of SNA in AYA clinical care and research initiatives. The uniqueness of the AYA oncology community can also provide insight into extending and developing current SNA theories. IMPLICATIONS: Using SNA in AYA psychosocial cancer research has the potential to create new ideas and pathways for supporting AYAs across the continuum of care, while also extending theories of SNA. SNA may also prove to be a useful tool for examining social support resources for AYAs with various chronic health conditions and other like groups. PMID- 29106317 TI - Is hepatitis B vaccination performed at infant and adolescent age able to provide long-term immunological memory? An observational study on healthcare students and workers in Florence, Italy. AB - Universal vaccination programmes against Hepatitis B Virus (HBV) have significantly reduced the burden of the disease; nevertheless, HBV infection remains a relevant issue for high-risk subjects, such as healthcare workers (HCWs), who may potentially be exposed to blood or body fluids. Our study evaluates the long-term duration of the immunological memory of HBV vaccination 11-23 years after primary immunization by examining the response to booster doses in HCWs and students of health disciplines at Careggi Teaching Hospital in Florence (Italy). All participants (n = 2,203) had received a complete HBV immunization course in infancy or adolescence. Blood samples were collected to measure antibody levels against the HBV surface antigen (anti-HBs); an anti-HBs titre <10 mIU/mL was considered as negative. The administration of the vaccination course during infancy induced lower long-term anti-HBs titres compared to those in case of vaccination performed during adolescence (titre <10 mIU/mL: 51.1% and 12.2% respectively; p < 0.001), also considering that an equal number of years has elapsed since vaccination. A booster dose administered to subjects vaccinated in infancy is able to induce anamnestic immunological response in a higher percentage of vaccinated people (p < 0.001). Few subjects (n. = 4) accepted a fifth dose of vaccine in the case of persistent anti-HBs negative titres; this aspect requires further investigation. The total absence of acute hepatitis B among vaccinated subjects suggests that the long incubation period of the disease allows the activation of immunologic memory mechanisms, which is also true in case of low anti-HBs level. In conclusion HCWs still represent a high-risk category; it is therefore, necessary to increase efforts to protect and vaccinate these subjects. PMID- 29106318 TI - Single Versus Multi-Incisional Video-Assisted Thoracic Surgery: A Systematic Review and Meta-analysis. AB - BACKGROUND: Video-Assisted Thoracic Surgery (VATS) is conventionally performed through multiple small incisions (C-VATS). Recent studies have reported encouraging results with the single-incision VATS (S-VATS) over the conventional technique. However, these studies were either small in size, unfocused, nonuniform, retrospective, lacking follow-up information, or focused on pain. We aim to validate previously reported results in a single large meta-analysis, including only the best evidence studies available. METHODS: Systematic review of the PubMed archive was conducted to include only full English articles with Newcastle Ottawa Scale score >=7. The primary outcome was the complications rate while secondary outcomes were operative time, resected lymph nodes (LNs), chest tube duration, estimated blood loss, length of postoperative stay (LOS), and postoperative pain on day 1 after surgery. Odds ratio and standard mean difference were used as effect estimates. Random model and leave-one-out analysis were used. RESULTS: A total of 39 studies were included with 4635 patients (1686 S-VATS versus 2949 C-VATS). S-VATS has resulted in significantly less postoperative pain (P < .001), blood loss (P = .006), LOS (P < .001), and chest tube duration (P < .001). In lung cancer patients, the number of retrieved LNs was similar to that of C-VATS (P > .05). Subgroup comparison of the rate of complications between lung resections versus other intrathoracic procedures, lung cancer versus pneumothorax, and lung cancer versus other lung-only lesions did not show any significant differences between the groups. CONCLUSION: Performing S VATS technique has shown superior postoperative outcomes over the C-VATS technique in the treatment of thoracic disorders. Substantial benefit was confirmed in terms of less postoperative pain, blood loss, drainage time, and postoperative hospital stay. PMID- 29106319 TI - Lesion location matters: The relationships between white matter hyperintensities on cognition in the healthy elderly. AB - White matter hyperintensities (WMH) are associated with cognitive decline. We aimed to identify the spatial specificity of WMH impact on cognition in non demented, healthy elderly. We quantified WMH volume among healthy participants of a community dwelling cohort ( n = 702, age range 60 - 82 years, mean age = 69.5 years, 46% female) and investigated the effects of WMH on cognition and behavior, specifically for executive function, memory, and motor speed performance. Lesion location influenced their effect on cognition and behavior: Frontal WMH in the proximity of the frontal ventricles mainly affected executive function and parieto-temporal WMH in the proximity of the posterior horns deteriorated memory, while WMH in the upper deep white matter-including the corticospinal tract compromised motor speed performance. This study exposes the subtle and subclinical yet detrimental effects of WMH on cognition in healthy elderly, and strongly suggests a causal influence of WMH on cognition by demonstrating the spatial specificity of these effects. PMID- 29106320 TI - Near-Infrared Fluorescence Imaging for Real-Time Intraoperative Guidance in Anastomotic Colorectal Surgery: A Systematic Review of Literature. AB - PURPOSE: The aims of this review are to determine the feasibility of near infrared fluorescence (NIRF) angiography in anastomotic colorectal surgery and to determine the effectiveness of the technique in improving imaging and quantification of vascularization, thereby aiding in decision making as to where to establish the anastomosis. METHODS: A systematic literature search of PubMed and EMBASE was conducted. Searching through the reference lists of selected articles identified additional studies. All English language articles presenting original patient data regarding intraoperative NIRF angiography were included without restriction of type of study, except for case reports, technical notes, and video vignettes. The intervention consisted of intraoperative NIRF angiography during anastomotic colorectal surgery to assess perfusion of the colon, sigmoid, and/or rectum. Primary outcome parameters included ease of use, added surgical time, complications related to the technique, and costs. Other relevant outcomes were whether this technique changed intraoperative decision making, whether effort was taken by the authors to quantify the signal and the incidence of postoperative complications. RESULTS: Ten studies were included. Eight of these studies make a statement about the ease of use. In none of the studies complications due to the use of the technique occurred. The technique changed the resection margin in 10.8% of all NIRF cases. The anastomotic leak rate was 3.5% in the NIRF group and 7.4% in the group with conventional imaging. Two of the included studies used an objective quantification of the fluorescence signal and perfusion, using ROIs (Hamamatsu Photonics) and IC-Calc(r) respectively. CONCLUSIONS: Although the feasibility of the technique seems to be agreed on by all current research, large clinical trials are mandatory to further evaluate the added value of the technique. PMID- 29106321 TI - A global function for transcription factors in assisting RNA polymerase II termination. AB - The role of transcription factors (TFs) on nucleosome positioning, RNA polymerase recruitment, and transcription initiation has been extensively characterized. Here, we propose that a subset of TFs such as Reb1, Abf1, Rap1, and TFIIIB also serve a major function in partitioning transcription units by assisting the Nrd1p Nab3p-Sen1p Pol II termination pathway. PMID- 29106322 TI - Neurovascular unit crosstalk: Pericytes and astrocytes modify cytokine secretion patterns of brain endothelial cells. AB - Crosstalk among brain endothelial cells (BECs), pericytes, and astrocytes occurs by way of soluble factors, including cytokines. Here, we studied cytokine secretion from both mouse BEC monocultures and tri-cultured with pericytes and astrocytes. Four cytokines were constitutively secreted by BEC monolayers, 12 by LPS-stimulated BECs, 10 by tri-cultures, and 14 by LPS-stimulated tri-cultures. Cytokine levels were generally higher with either LPS stimulation or tri-culture when compared to monocultures and highest in tri-cultures stimulated by LPS. LPS stimulated secretions fell into eight patterns as categorized by the polarization of cytokine secretions. To determine the cellular origin of cytokine increases in tri-cultures, we cultured mouse BECs with human pericytes and astrocytes and measured cytokines in species-specific assays. Thus, cytokines detected in the human immunoassay were from pericytes/astrocytes and those detected in the mouse immunoassay were from BECs. Several unique patterns were thus found. For example, TNF-alpha was only of pericyte/astrocyte origin; granulocyte colony-stimulating factor was only of BEC origin; IL-6, MCP-1, and GM-CSF of astrocyte/pericyte origin were found in both the luminal and abluminal chambers, suggesting the presence of brain-to-blood transporters. We conclude that crosstalk influences cytokine secretion under constitutive and stimulated conditions from both BECs and pericytes/astrocytes. PMID- 29106324 TI - Safety of specific immunotherapy using an ultra-rush induction regimen in bee and wasp allergy. AB - BACKGROUND: Specific allergen immunotherapy to Hymenoptera venom (VIT) is a basic treatment for patients allergic to Hymenoptera venom. The aim of the study was to evaluate the safety of an ultra-rush regimen compared with the rush and conventional protocols. MATERIALS AND METHODS: In 31 patients with an allergy to bee venom and 82 with an allergy to wasp venom, the allergic adverse reactions during VIT were monitored. Patients were selected based on the criteria established by EAACI (European Academy of Allergy and Clinical Immunology) recommendations. Adverse reactions during the ultra-rush immunotherapy were measured, documented and classified according to the criteria of Mueller. Ultra rush, rush or conventional protocols of the initial phase VIT using the Venomenhal vaccine (Hal Allergy, Leiden, Netherlands) were conducted. RESULTS: Six (13.7%) patients on the ultra-rush regimen, 5 (14.3%) patients on the rush regimen and 9 (26.5%) on conventional VIT experienced an allergic reaction. There were no associations between the adverse allergic reactions and the following factors: gender, total IgE and allergen-specific IgE to wasp or bee venom before the VIT and cardiological drugs that were used. CONCLUSION: We found that the ultra-rush protocol (similar to the rush protocol) using the Venomenhal vaccine is safer than the conventional protocol. PMID- 29106323 TI - SAM-VI RNAs selectively bind S-adenosylmethionine and exhibit similarities to SAM III riboswitches. AB - Five distinct riboswitch classes that regulate gene expression in response to the cofactor S-adenosylmethionine (SAM) or its metabolic breakdown product S adenosylhomocysteine (SAH) have been reported previously. Collectively, these SAM or SAH-sensing RNAs constitute the most abundant collection of riboswitches, and are found in nearly every major bacterial lineage. Here, we report a potential sixth member of this pervasive riboswitch family, called SAM-VI, which is predominantly found in Bifidobacterium species. SAM-VI aptamers selectively bind the cofactor SAM and strongly discriminate against SAH. The consensus sequence and structural model for SAM-VI share some features with the consensus model for the SAM-III riboswitch class, whose members are mainly found in lactic acid bacteria. However, there are sufficient differences between the two classes such that current bioinformatics methods separately cluster representatives of the two motifs. These findings highlight the abundance of RNA structures that can form to selectively recognize SAM, and showcase the ability of RNA to utilize diverse strategies to perform similar biological functions. PMID- 29106325 TI - Diarrheagenic Escherichia coli and Shigella with High Rate of Extended-Spectrum Beta-Lactamase Production: Two Predominant Etiological Agents of Acute Diarrhea in Shiraz, Iran. AB - This study was conducted to find the etiology of acute diarrhea in Iranian children and determine the antimicrobial resistance patterns. The pathogenic bacteria were recovered from 110/269 (40.9%) diarrheal fecal samples with the following profiles: the most predominant pathogen was diarrheagenic Escherichia coli (DEC) (43.6%), comprising enteroaggregative E. coli (23.6%), enteropathogenic E. coli (10.9%), enteroinvasive E. coli (5.5%), and enterotoxigenic E. coli (3.6%); Shigella spp. (37.3%), Salmonella spp. (12.7%) and Campylobacter jejuni (6.4%) were ranked second and fourth in terms of prevalence, respectively. The rates of extended-spectrum beta-lactamase (ESBL) production were 66.7% and 53.7% in DEC and Shigella, respectively. Resistance to ampicillin (AMP) (95.1%), trimethoprim/sulfamethoxazole (SXT) (73.2%), azithromycin (ATH) (21.9%), and ciprofloxacin (CIP) (14.6%) was observed among Shigella isolates. Multidrug resistance phenotype was observed in 24.4% (10/41) of Shigella isolates, with the most common pattern of resistance to cefotaxime, ceftriaxone, ceftazidime, AMP, SXT, and ATH. This study indicates an alarming increase in the ESBL production of DEC and Shigella spp. and identifies them as the two most prevalent diarrhea-causing enteropathogens in the region. The results show that CIP could be an alternative to third-generation cephalosporins against these two pathogens. Therefore, it is proposed that further investigation be done in the pursuit of alternative antibiotics that are effective against the resistant cases. For instance, one study could look into the comparative clinical effectiveness of third-generation cephalosporins versus CIP, the latter not being presently the drug of choice for the treatment of acute diarrhea in children in Iran. PMID- 29106326 TI - Purification, biochemical, and thermal properties of fibrinolytic enzyme secreted by Bacillus cereus SRM-001. AB - The discovery of microbial fibrinolytic enzymes is essential to treat cardiovascular diseases. This study reports the discovery of a fibrinolytic enzyme secreted by Bacillus cereus SRM-001, a microorganism isolated from the soil of a chicken waste-dump yard. The B. cereus SRM-001 was cultured and the secreted fibrinolytic enzyme purified to show that it is a ~28 kDa protein. The purified enzyme was characterized for its kinetics, biochemical and thermal properties to show that it possesses properties similar to plasmin. A HPLC-MS/MS analysis of trypsin digested protein indicated that the fibrinolytic enzyme shared close sequence homology with serine proteases reported for other Bacillus sp. The results show that the B. cereus SRM-001 secreted enzyme is a ~28 kDa serine protease that possesses fibrinolytic potential. PMID- 29106327 TI - Asymptomatic spinal cord lesions do not predict the time to disability in patients with early multiple sclerosis. AB - BACKGROUND: The presence of asymptomatic spinal cord (SC) lesions in patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) predicts conversion to clinically definite multiple sclerosis (CDMS). The relation between asymptomatic SC abnormalities and disability progression warrants further investigation. OBJECTIVE: To determine the prognostic value of asymptomatic SC lesions in CIS and early RRMS with respect to the time to disability development. METHODS: Clinical and demographic data, brain and SC magnetic resonance imaging (MRI) were collected of CIS or early RRMS patients. Two main analyses were performed. For the first analysis, patients were divided into two groups: (1) patients with asymptomatic SC lesions and (2) patients without SC lesions and patients with symptomatic SC lesions. The second analysis excluded patients with symptomatic SC lesions. Incidence curves were used to analyse differences between these groups in time to the development of disability and time to a second relapse. RESULTS: A total of 178 patients were included, and 42 patients (23.6%) had asymptomatic SC lesions. No significant differences were found on the time to disability development or the time to a second event. CONCLUSION: Asymptomatic SC lesions early in the disease course do not predict the time to disability development in patients diagnosed with CIS or early RRMS. PMID- 29106328 TI - Asia-Pacific Alliance for the Control of Influenza (APACI). PMID- 29106329 TI - The NAIMS cooperative pilot project: Design, implementation and future directions. AB - The North American Imaging in Multiple Sclerosis (NAIMS) Cooperative represents a network of 27 academic centers focused on accelerating the pace of magnetic resonance imaging (MRI) research in multiple sclerosis (MS) through idea exchange and collaboration. Recently, NAIMS completed its first project evaluating the feasibility of implementation and reproducibility of quantitative MRI measures derived from scanning a single MS patient using a high-resolution 3T protocol at seven sites. The results showed the feasibility of utilizing advanced quantitative MRI measures in multicenter studies and demonstrated the importance of careful standardization of scanning protocols, central image processing, and strategies to account for inter-site variability. PMID- 29106330 TI - Exploration of ligand-induced protein conformational alteration, aggregate formation, and its inhibition: A biophysical insight. AB - The association of protein aggregates with plentiful human diseases has fascinated studies regarding the biophysical characterization of protein misfolding and ultimately their aggregate formation mechanism. Protein-ligand interaction, their mechanism, conformational changes by ligands, and protein aggregate formation have been studied upon exploiting experimental techniques and computational methodologies. Such studies for the exploration of ligand-induced conformational changes in protein, misfolding and aggregation, has confirmed drastic progresses in the study of aggregate formation pathways. This review comprises of an inclusive description of contemporary experimental techniques as well as theoretical improvements in the interpretation of the conformational properties of protein. We have also discussed various factors responsible for the microenvironment change around protein that sequentially causes amyloidoses. Biophysical techniques and cell-based assays to gain comprehensive understandings of protein-ligand interaction, protein folding, and aggregation pathways have also been described. The promising therapeutic methods used to inhibit the protein fibrillogenesis have also been discussed. PMID- 29106332 TI - Conserved RxLR Effectors From Oomycetes Hyaloperonospora arabidopsidis and Phytophthora sojae Suppress PAMP- and Effector-Triggered Immunity in Diverse Plants. AB - Effector proteins are exported to the interior of host cells by diverse plant pathogens. Many oomycete pathogens maintain large families of candidate effector genes, encoding proteins with a secretory leader followed by an RxLR motif. Although most of these genes are very divergent between oomycete species, several genes are conserved between Phytophthora species and Hyaloperonospora arabidopsidis, suggesting that they play important roles in pathogenicity. We describe a pair of conserved effector candidates, HaRxL23 and PsAvh73, from H. arabidopsidis and P. sojae respectively. We show that HaRxL23 is expressed early during infection of Arabidopsis. HaRxL23 triggers an ecotype-specific defense response in Arabidopsis, suggesting that it is recognized by a host surveillance protein. HaRxL23 and PsAvh73 can suppress pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) in Nicotiana benthamiana and effector-triggered immunity (ETI) in soybean. Transgenic Arabidopsis constitutively expressing HaRxL23 or PsAvh73 exhibit suppression of PTI and enhancement of bacterial and oomycete virulence. Together, our experiments demonstrate that these conserved oomycete RxLR effectors suppress PTI and ETI across diverse plant species. PMID- 29106331 TI - Highly motif- and organism-dependent effects of naturally occurring hammerhead ribozyme sequences on gene expression. AB - Recent bioinformatics studies have demonstrated a wide-spread occurrence of the hammerhead ribozyme (HHR) and similar small endonucleolytic RNA motifs in all domains of life. It is becoming increasingly evident that such ribozyme motifs participate in important genetic processes in diverse organisms. Although the HHR motif has been studied for more than three decades, only little is known about the consequences of ribozyme activity on gene expression. In the present study we analysed eight different naturally occurring HHR sequences in diverse genetic and organismal contexts. We investigated the influence of active ribozymes incorporated into mRNAs in mammalian, yeast and bacterial expression systems. The experiments show an unexpectedly high degree of organism-specific variability of ribozyme-mediated effects on gene expression. The presented findings demonstrate that ribozyme cleavage profoundly affect gene expression. However, the extent of this effect varies and depends strongly on the respective genetic context. The fast-cleaving type 3 HHRs [CChMVd(-) and sLTSV(-)] generally tended to cause the strongest effects on intracellular gene expression. The presented results are important in order to address potential functions of naturally occurring ribozymes in RNA processing and post-transcriptional regulation of gene expression. Additionally, our results are of interest for biotechnology and synthetic biology approaches that aim at the utilisation of self-cleaving ribozymes as widely applicable tools for controlling genetic processes. PMID- 29106333 TI - Monomethyl fumarate treatment impairs maturation of human myeloid dendritic cells and their ability to activate T cells. AB - BACKGROUND: Dimethyl fumarate (DMF) and its active metabolite monomethyl fumarate (MMF) effectively lead to reduction in disease relapses and active magnetic resonance imaging (MRI) lesions. DMF and MMF are known to be effective in modulating T- and B-cell responses; however, their effect on the phenotype and function of human myeloid dendritic cells (mDCs) is not fully understood. OBJECTIVE: To investigate the role of MMF on human mDCs maturation and function. METHODS: mDCs from healthy controls were isolated and cultured in vitro with MMF. The effect of MMF on mDC gene expression was determined by polymerase chain reaction (PCR) array after in vitro MMF treatment. The ability of mDCs to activate T cells was assessed by in vitro co-culture system. mDCs from DMF treated multiple sclerosis (MS) patients were analyzed by flow cytometry and PCR. RESULTS: MMF treatment induced a less mature phenotype of mDCs with reduced expression of major histocompatibility complex class II (MHC-II), co-stimulatory molecules CD86, CD40, CD83, and expression of nuclear factor kappaB (NF-kappaB) subunits RELA and RELB. mDCs from DMF-treated MS patients also showed the same immature phenotype. T cells co-cultured with MMF-treated mDCs showed reduced proliferation with decreased production of interferon gamma (IFN-gamma), interleukin-17 (IL-17), and granulocyte-macrophage colony-stimulating factor (GM CSF) compared to untreated cells. CONCLUSION: We report that MMF can modulate immune response by affecting human mDC function. PMID- 29106334 TI - Effects of chronic alcohol consumption on DNA damage and immune regulation induced by the environmental pollutant dibenzo[a,l]pyrene in oral tissues of mice. AB - Previously, we showed that oral application of the environmental pollutant dibenzo[a,l]pyrene (DB[a,l]P) induces oral tumors in mice. Thus, in the present investigation we examined the effect of alcohol on DB[a,l]P-induced DNA damage and immune regulation; we showed that alcohol (6.4% v/v in the diet, 35% of Calories) significantly enhanced the levels of (-)-anti-trans-DB[a,l]P-dA while decreased the levels of GSH in the mouse oral tissues. Analysis of RNA expression revealed that DB[a,l]P alone upregulates inflammatory genes while alcohol suppresses several markers of immune surveillance. Collectively, these results suggest that alcohol may enhance oral carcinogenesis induced by DB[a,l]P. PMID- 29106335 TI - Psychosocial development through Masters sport: What can be gained from youth sport models? AB - Although sport participation is encouraged throughout the lifespan, little research has been conducted on the role of sport in development later in life. This qualitative study explored adults' experiences of development within the context of Masters sport. We interviewed 14 adults (nine men and five women) aged 46-61 years involved in Masters sport. Data was interpreted drawing upon frameworks from youth sport (i.e., Personal Assets Framework for Sport; Cote, J., Bruner, M., Strachan, L., Erickson, K., & Fraser-Thomas, J. (2010). Athletes' development and coaching. In J. Lyle & C. Cushion (Eds.), Sport coaching: Professionalism and practice (pp. 63-83). Oxford, UK: Elsevier, Cote, J., Turnnidge, J., & Evans, M. B. (2014). The dynamic process of development through sport. Kinesiologia Slovenica, 20(3), 14-26, Cote, J., Turnnidge, J., & Vieerima, M. (2016). A personal assets approach to youth sport. In K. Green & A. Smith (Eds.), Routledge handbook of youth sport (pp. 243-255). New York, NY: Routledge; 4/5Cs of positive youth development; Lerner, R. M., Fisher, C. B., & Weinberg, R. A. (2000). Toward a science for and of the people: Promoting civil society through the application of developmental science. Child Development, 71(1), 11 20. doi:10.1111/1467-8624.00113; Vierimaa, M., Erickson, K., Cote, J., & Gilbert, W. (2012). Positive youth development: A measurement framework for sport. International Journal of Sports Science & Coaching, 7(3), 601-614. doi:10.1260/1747-9541.7.3.601), combined with past research on mid-life and older athletes. Six key themes emerged as contributing to adults' personal development through sport: competence and confidence, character, commitment, connection, cognition, and challenge. Masters sport contexts appeared to facilitate changes in assets (i.e., 6Cs) similar to those within youth sport, but assets often held different meanings within the context of later life. Applying frameworks from youth sport and developmental psychology to Masters sport contexts appears useful. The current findings support the modification of existing models and highlight their potential in identifying lifelong developmental outcomes of sport participation. PMID- 29106337 TI - Open Access Acta going electronic-only for members of the Nordic Orthopaedic Federation. PMID- 29106336 TI - Will intelligent machine learning revolutionize orthopedic imaging? PMID- 29106339 TI - Goodbye, Eating Disorders. AB - In 1977, I fell in love at first sight, and since then eating disorders have been a central part of my life. As I step down after 25 years as editor of Eating Disorders: The Journal of Treatment and Prevention, I am also saying goodbye to the eating disorders field and moving on to retirement and other areas of interest. In this Last Word article, I will write about my history with the journal and the field and use this forum to thank a few of the people I've known along the way. PMID- 29106340 TI - On synchronicity, passing the torch, and the task of prevention. AB - The 15-year follow-up study (Bar, Chassin & Dionne, 2017) suggests of the Dance School Ecological Prevention Program (Piran, 1999) that it may have had long-term effects on the prevention of bulimia. This pattern of findings is in line with the results of the older cohort in the original outcome evaluation study. If the results of the follow up study hold when the 15-year outcome evaluation study is compared to a control group from a similarly competitive ballet school, this would reinforce the cause of prevention in the field of sports and dance, if not beyond. It will further support the implementation of systemic changes in the social and educational environments of children towards the prevention of eating disorders. PMID- 29106341 TI - The long-term impact of an eating disorder prevention program for professional ballet school students: A 15-year follow-up study. AB - Eating disorder prevention programs have been assessed up to 3 years post implementation; however, their impact on long-term resilience is unclear. The current study assessed disordered eating and body dissatisfaction in 116 dancers from a professional ballet school 15 or more years following their participation in an effective selective prevention program. Dancers who attended the ballet school during and following the program endorsed fewer thoughts and behaviours associated with bulimia, had lower lifetime prevalence of laxative use, and showed a trend toward lower lifetime rates of vomiting to control weight than those who attended the ballet school prior to the intervention. PMID- 29106343 TI - Eating disorders: A 25-year perspective. AB - I founded Eating Disorders: The Journal of Treatment & Prevention 25 years ago, and its character, reputation, and success are highly attributable to Arnold Andersen, John Foreyt, and Margo Maine, the three original senior editors, whose perspectives follow in this article. Having made the decision to retire from the journal, I asked the senior editors to transition to the emeritus board along with me, which I explain further in my own Last Word, "Goodbye, Eating Disorders," in this volume (Cohn, 2017). Over our 25 years of collaboration, the senior editors have acquired unique insights into the evolution of the eating disorders field; so, I asked them to contribute retrospective essays in which they also look forward within their primary areas of expertise-presented here in alphabetical order. - Leigh Cohn, Editor-in-Chief. PMID- 29106346 TI - Characterization of the Serralysin-Like Gene of 'Candidatus Liberibacter solanacearum' Associated with Potato Zebra Chip Disease. AB - The nonculturable bacterium 'Candidatus Liberibacter solanacearum' is the causative agent of zebra chip disease in potato. Computational analysis of the 'Ca. L. solanacearum' genome revealed a serralysin-like gene based on conserved domains characteristic of genes encoding metalloprotease enzymes similar to serralysin. Serralysin and other serralysin family metalloprotease are typically characterized as virulence factors and are secreted by the type I secretion system (T1SS). The 'Ca. L. solanacearum' serralysin-like gene is located next to and divergently transcribed from genes encoding a T1SS. Based on its relationship to the T1SS and the role of other serralysin family proteases in circumventing host antimicrobial defenses, it was speculated that a functional 'Ca. L. solanacearum' serralysin-like protease could be a potent virulence factor. Gene expression analysis showed that, from weeks 2 to 6, the expression of the 'Ca. L. solanacearum' serralysin-like gene was at least twofold higher than week 1, indicating that gene expression stays high as the disease progresses. A previously constructed serralysin-deficient mutant of Serratia liquefaciens FK01, an endophyte associated with insects, as well as an Escherichia coli lacking serralysin production were used as surrogates for expression analysis of the 'Ca. L. solanacearum' serralysin-like gene. The LsoA and LsoB proteins were expressed as both intact proteins and chimeric S. liquefaciens-'Ca. L. solanacearum' serralysin-like proteins to facilitate secretion in the S. liquefaciens surrogate and as intact proteins or as a truncated LsoB protein containing just the putative catalytic domains in the E. coli surrogate. None of the 'Ca. L. solanacearum' protein constructs expressed in either surrogate demonstrated proteolytic activity in skim milk or zymogram assays, or in colorimetric assays using purified protein, suggesting that the 'Ca. L. solanacearum' serralysin-like gene does not encode a functional protease, or at least not in our surrogate systems. PMID- 29106347 TI - Epidemiology and molecular characterization of influenza viruses, human parechoviruses and enteroviruses in children up to 5 years with influenza-like illness in Northern Italy during seven consecutive winter seasons (2010-2017). AB - Besides the influenza virus (IV), several other viruses are responsible for influenza-like illness (ILI). Although human parechoviruses (HPeVs) and enteroviruses (EVs) may impact on ILI, limited data on their epidemiological characteristics are available. During seven consecutive winter seasons (from 2010 2011 to 2016-2017), within the framework of an influenza surveillance system (InfluNet), 593 respiratory swabs were collected from children <=5 years of age with ILIs. Molecular detection showed that 58.3 % of swabs were positive for at least one of the viruses under study: 46 % for IV, 13 % for EV and 5.4 % for HPeV. A single virus was identified in 51.3 % of samples while more than one virus was detected in 7 % of the samples. The risk of contracting IV was higher than the risk associated with EV, which in turn was higher than the risk of contracting HPeV. The risk of developing an IV infection was twofold greater in children >3 years than in those <=3 years, who had higher risk of EV/HPeV infection. The frequency of EV/HPeV-positive swabs increased significantly during the 2016-2017 winter season compared to the previous six seasons. Sixteen EV genotypes were identified belonging to species A and B. HPeV-1 was the most frequently detected genotype, followed by -6 and -3. In this study, IV was mainly responsible for ILI, however EV and HPeV were also involved and particularly affected children <=3 years of age. Influenza surveillance samples could provide us with valuable insight into the epidemiological features of viruses involved in ILI. PMID- 29106349 TI - Corrigendum: Isolates of Lactobacillus plantarum and L. reuteri display greater antiproliferative and antipathogenic activity than other Lactobacillus isolates. PMID- 29106348 TI - Bats host diverse parvoviruses as possible origin of mammalian dependoparvoviruses and source for bat-swine interspecies transmission. AB - Compared to the enormous species diversity of bats, relatively few parvoviruses have been reported. We detected diverse and potentially novel parvoviruses from bats in Hong Kong and mainland China. Parvoviruses belonging to Amdoparvovirus, Bocaparvovirus and Dependoparvovirus were detected in alimentary, liver and spleen samples from 16 different chiropteran species of five families by PCR. Phylogenetic analysis of partial helicase sequences showed that they potentially belonged to 25 bocaparvovirus, three dependoparvovirus and one amdoparvovirus species. Nearly complete genome sequencing confirmed the existence of at least four novel bat bocaparvovirus species (Rp-BtBoV1 and Rp-BtBoV2 from Rhinolophus pusillus, Rs-BtBoV2 from Rhinolophus sinicus and Rol-BtBoV1 from Rousettus leschenaultii) and two novel bat dependoparvovirus species (Rp-BtAAV1 from Rhinolophus pusillus and Rs-BtAAV1 from Rhinolophus sinicus). Rs-BtBoV2 was closely related to Ungulate bocaparvovirus 5 with 93, 72.1 and 78.7 % amino acid identities in the NS1, NP1 and VP1/VP2 genes, respectively. The detection of bat bocaparvoviruses, including Rs-BtBoV2, closely related to porcine bocaparvoviruses, suggests recent interspecies transmission of bocaparvoviruses between bats and swine. Moreover, Rp-BtAAV1 and Rs-BtAAV1 were most closely related to human AAV1 with 48.7 and 57.5 % amino acid identities in the rep gene. The phylogenetic relationship between BtAAVs and other mammalian AAVs suggests bats as the ancestral origin of mammalian AAVs. Furthermore, parvoviruses of the same species were detected from multiple bat species or families, supporting the ability of bat parvoviruses to cross species barriers. The results extend our knowledge on the diversity of bat parvoviruses and the role of bats in parvovirus evolution and emergence in humans and animals. PMID- 29106350 TI - Acinetobacter dijkshoorniae is a later heterotypic synonym of Acinetobacter lactucae. AB - Acinetobacter lactucae and Acinetobacter dijkshoorniae were recently described as novel species, and both were reported to be closely related to Acinetobacter pittii. Because they were reviewed and published almost concurrently, their descriptions did not include a specific comparison between these two novel species. Genomic data were provided in both initial descriptions, which simplifies the comparisons. Genome comparisons based on in silico DNA-DNA hybridizations, average nucleotide identity and core genome phylogeny of the type strain genomes establish that these strains are conspecific. Based on the rules of priority, A. dijkshoorniae should be reclassified as a later heterotypic synonym of A. lactucae. PMID- 29106351 TI - Erratum: ICTV Virus Taxonomy Profile: Potyviridae. PMID- 29106352 TI - The Oral Health of Preschool Children of Refugee and Immigrant Families in Manitoba. AB - INTRODUCTION: Children of newcomers to Canada have been identified as at moderately high risk for developing early childhood caries (ECC). The purpose of this study was to investigate the oral health of preschool children of refugee and immigrant families in Winnipeg. METHODS: Children < 72 months of age and their parent or primary caregiver were recruited through several newcomer settlement agencies, dental clinics and community programs. Parents and caregivers completed a short questionnaire with the assistance of a research team member. Children underwent a dental examination. Results of the questionnaire were combined with those of the clinical examination and subjected to statistical analysis. RESULTS: We recruited 211 children. Their mean age was 40.2 +/- 15.4 months, and 54.0% were boys. Overall, 45.5% of the children had ECC and 31.8% had severe ECC (S-ECC). The mean decayed, missing and filled teeth (dmft) score was 2.2 +/- 3.8 (range 0-19), while the mean decayed, missing, filled surfaces (dmfs) score was 4.8 +/- 11.0 (range 0-63). Infant dental enucleation was observed in 6 children. Logistic regression analyses showed that increasing age, the presence of debris on teeth, parents believing their child has dental problems and the presence of enamel hypoplasia were significantly and independently associated with ECC and S-ECC (p <= 0.05). CONCLUSIONS: ECC is prevalent in children of newcomer families in Manitoba. These data will inform advocacy efforts to improve access to dental care and tailor early childhood oral health promotion and ECC prevention activities for refugees and recent immigrants. PMID- 29106353 TI - Testing direct oral anticoagulants: embedding in structured long-term care. PMID- 29106354 TI - Characteristics of thawed pooled cryoprecipitate stored at refrigerated temperature for 24 hours. AB - BACKGROUND: The need for thawed cryoprecipitate is growing. However, according to current guidelines, the shelf-life of pooled thawed cryoprecipitate at room temperature is limited because of possible bacterial contamination and loss of clotting factor activity. Here we assessed microbial growth and retention of clotting activity in cryoprecipitate stored at 4 degrees C after thawing to see whether its shelf life could be safely extended. MATERIALS AND METHODS: Pooled thawed cryoprecipitate units (n=10) were maintained at room temperature for 6 hours and then placed at 1-6 degrees C for 18 hours after thawing. We examined the cryoprecipitate pools for fibrinogen, factor VIII, and von Willebrand factor activity at the following time points: 0 hours (immediately after thawing), after 6 hours at room temperature, and after 24 hours at 1-6 degrees C. A 5-mL aliquot from each pool was collected for aerobic and anaerobic bacterial cultures at the 24-hour time point. RESULTS: Mean fibrinogen concentration and von Willebrand factor activity were similar at each time point, but factor VIII activity decreased significantly over the storage period. Bacterial growth was not detected in any cultured pooled sample. DISCUSSION: Extended storing of thawed cryoprecipitate at 1-6 degrees C does not appear to increase the risk of bacterial contamination or affect coagulation factor activity. PMID- 29106355 TI - Reply to "High-titre inhibitors in previously untreated patients with severe haemophilia A receiving recombinant or plasma-derived factor VIII: a budget impact analysis" by Messori et al. PMID- 29106356 TI - Cell salvage for postpartum haemorrhage during vaginal delivery: a case series. AB - BACKGROUND: The safety and effectiveness of cell salvage for vaginal delivery is unknown. This case series aimed to assess the utility and adverse events related to the use of cell salvage for maternal haemorrhage during vaginal delivery. MATERIALS AND METHODS: A cohort study design was chosen, focused on postpartum haemorrhages that occurred after vaginal delivery for which cell salvage equipment was requested to be set up in the labour and delivery room outside of a sterile operating room environment. Variables recorded included duration of stay in hospital, occurrence of wound infections, sepsis, thromboembolic events, and amniotic fluid embolism. RESULTS: Of 28 cases of postpartum haemorrhage during vaginal deliveries involving the setup or use of cell salvage equipment, ten were associated with successful re-infusion of salvaged shed blood. These ten cases were compared to the 18 cases in which cell salvage equipment was set up, but insufficient shed blood was salvaged for re-infusion. There were no instances of postpartum sepsis, wound infection, or thromboembolism associated with the use of cell salvage for vaginal delivery. Although one case of suspected amniotic fluid embolism occurred, severe symptoms began prior to the infusion of salvaged blood. DISCUSSION: Infusion of salvaged shed blood collected from a vaginal delivery field is feasible. The outcomes of these cases do not exclude an unacceptably high risk of infection or embolic events. Trials evaluating the safety and effectiveness associated with the use of cell salvage in vaginal deliveries are justified. PMID- 29106357 TI - Position Paper on laboratory testing for patients on direct oral anticoagulants. A Consensus Document from the SISET, FCSA, SIBioC and SIPMeL. AB - Although direct oral anticoagulants (DOAC) do not require dose-adjustment on the basis of laboratory test results, the measurement of their anticoagulant effect is useful in special situations. This position paper issued by the Italian Scientific Societies that are mainly involved in the management of patients on DOAC is aimed at providing guidance to care-givers on which tests should be used and the situations in which testing is useful. The guidance is based on the data from the literature so far available and/or on consensus among experts. PMID- 29106358 TI - Prostate-specific antigen testing for prostate cancer screening: A national survey of Canadian primary care physicians' opinions and practices. AB - INTRODUCTION: In 2014, the Canadian Task Force on Preventive Health Care (CTFPHC) recommended against routine prostate cancer screening with the prostate-specific antigen (PSA) blood test. We surveyed Canadian primary care physicians (PCPs) to understand their opinions and attitudes towards prostate cancer screening in 2016. METHODS: Twenty PCPs piloted the survey to assess its accessibility. We distributed a flyer to 19 633 PCPs as an insert in a large mailed package inviting them to attend a national meeting, and later promoted the survey at the meeting. Multinomial logistic regression models examined factors associated with agreement of key guideline statements and the overall benefit of PSA screening. RESULTS: A total of 1254 PCPs responded (rate of 6.4%); 54.7% of physicians aware of the CTFPHC recommendations report screening less often as a result. Overall, 55.6% of PCPs feel that the risks of PSA screening outweigh the benefits. On multivariable analysis, physicians who did not read the guidelines, did not have an academic appointment, or were in practice for over 20 years were significantly more likely to disagree with the statement that men 55-69 years old should not be screened for prostate cancer with PSA. CONCLUSIONS: Our national survey found that the prostate cancer screening practices of Canadian PCPs varies widely across physician demographic groups, with almost equal numbers for or against. This has significant ethical, medical, and legal implications. The poor response rate to highly incentivized survey request may suggest a reluctance or general apathy towards this subject because of the Task Force recommendations. Future efforts should provide physicians with objective guidance around PSA screening, incorporating input from all stakeholders, including PCPs, urologists, and patients. PMID- 29106359 TI - The emerging role of patient-reported outcomes in urology. PMID- 29106360 TI - Complications in the 90-day postoperative period following kidney transplant and the relationship of the Charlson Comorbidity Index. AB - INTRODUCTION: Renal transplant experiences widespread success, but little is published regarding the postoperative complications. The Charlson Comorbidity Index (CCI) is a system of mortality risk assessment. Our purpose is to assess the 90-day postoperative complications after renal transplantation. The secondary objective is to clarify whether CCI predicts complications. We hypothesized increased CCI corresponds to worse complication on the Clavien scale. METHODS: This is a retrospective analysis of renal recipients at our institution (2011 2013) who were >=18 years old and received complete follow up. CCI, age, gender, body mass index (BMI), and graft type were extracted from the electronic medical records. Complications were scored using the Clavien scale. Descriptive statistics and logistic regression were used to analyze 198 patients. RESULTS: The mean age was 53 (standard deviation [SD] 14), mean BMI 27.4 (SD 14), median CCI 1. Grade 2 or higher (significant) complications occurred in 60% of patients and Grade 3b or higher (severe) in 15% of patients in the 90-day postoperative period. Sixty-eight different complications were identified, the most common being blood transfusion (19%). Logistic regression suggests a predictive value of CCI (odds ratio [OR] 1.70; 95% confidence interval [CI] 1.3-2.3) for severe complications, with diabetes mellitus and peripheral vascular disease conferring increased risk. CONCLUSIONS: Renal transplant carries significant risk. This data can be used to improve patient counselling on the likely postoperative course. Study limitations include the retrospective design, predisposing to potential bias in data capture. PMID- 29106361 TI - Dr. Barry Caplan. PMID- 29106363 TI - Renal transplant complications: Moving toward comparison of relevant parameters and further improvement in outcomes. PMID- 29106362 TI - Preoperative nutritional factors and outcomes after radical cystectomy: A narrative review. AB - Only a few nutritional factors have been identified to predict the risk of developing complications after radical cystectomy (RC). This narrative review delineates the current known effects of preoperative nutritional status factors in this context. The report highlights the heterogeneity between study methods and results. We determined that low albuminemia values increase mortality risk and overall complications. In addition, obesity tends to increase the risk of developing venous thromboembolism and adverse events. Additional prospective studies, using standardized methods to both define and report complications, should be conducted to strengthen the connections between preoperative nutritional status factors and post-RC complications. Furthermore, intervention studies testing the impact of strategies to improve nutritional status on the risk of complications after RC are also needed. PMID- 29106364 TI - The kidney cancer research priority-setting partnership: Identifying the top 10 research priorities as defined by patients, caregivers, and expert clinicians. AB - It is critically important to define disease-specific research priorities to better allocate limited resources. There is growing recognition of the value of involving patients and caregivers, as well as expert clinicians in this process. To our knowledge, this has not been done this way for kidney cancer. Using the transparent and inclusive process established by the James Lind Alliance, the Kidney Cancer Research Network of Canada (KCRNC) sponsored a collaborative consensus-based priority-setting partnership (PSP) to identify research priorities in the management of kidney cancer. The final result was identification of 10 research priorities for kidney cancer, which are discussed in the context of current initiatives and gaps in knowledge. This process provided a systematic and effective way to collaboratively establish research priorities with patients, caregivers, and clinicians, and provides a valuable resource for researchers and funding agencies. PMID- 29106366 TI - Dr. John Vallely. PMID- 29106365 TI - Validation of the French-Canadian version of the Expanded Prostate Cancer Index Composite (EPIC) in a French-Canadian population. AB - INTRODUCTION: This study aims to empirically validate the French-Canadian version of the Expanded Prostate Cancer Index Composite (EPIC), a measure of health related quality of life for prostate cancer patients. METHODS: Two hundred fifty one participants completed a battery of self-report scales, including the French Canadian version of the EPIC, after having received radiation therapy or radical prostatectomy for prostate cancer. RESULTS: The internal consistency for the urinary incontinence, bowel, and sexual domains of the EPIC-26 was high (Cronbach's alpha coefficients from 0.80-0.92), while coefficients for the urinary irritation/obstruction (0.59) and hormonal (0.67) domains were lower. Item-total correlations (rs=0.15-0.85), and temporal stability (rs=0.72-0.93) generally supported the reliability of the instrument. The five-factor structure of the EPIC-26 was confirmed for the most part. The construct validity of the instrument was also supported by high correlations obtained between each domain and measures assessing similar constructs (rs=-0.56-0.83). The EPIC also showed an excellent sensitivity to change with significant differences obtained on EPIC scores (all p<0.05) between pre- and post-prostate cancer treatment. CONCLUSIONS: The psychometric qualities of the French-Canadian version of the EPIC are well supported, thus providing a valid tool to assess health-related quality of life in prostate cancer patients. PMID- 29106367 TI - Telephone consultations in urology: Who, when, where, and why? AB - INTRODUCTION: Telephone consultations are part of a strategy to allow access to medical expertise. Telephone consultations have been fee-for-services benefits in the province of Quebec since 2012. Recent studies have shown that adequate communication is one of the most common means to prevent disability and death. We sought to determine the characteristics of phone consultations made to a tertiary centre's urologists and to characterize their experience. METHODS: We performed a prospective study using all billing receipts filed by 15 academic urologists for phone consultations received during a 10-month period. A descriptive analysis was done to collect the principal characteristics of all phone calls received. Moreover, an online survey was distributed to those urologists. The survey was composed of 10 multiple-choice questions to review their personal experience. RESULTS: A total of 678 billing receipts were analyzed. The most common reasons for calls were lithiasis (11.5%), hematuria (10.5%), and urinary retention (8.4%). Most phone calls (57.7%) were made by emergency physicians and family doctors. The majority (88.7%) of calls were placed between 8:00 am and 5:00 pm. Most of the calls came from the immediate region covered by the group. Our survey demonstrated that urologists pay more attention to document telephone consultations since the introduction of the new remuneration plan. Most urologists found the phone consultations to be relevant. CONCLUSIONS: Lithiasis and hematuria are the primary reasons for telephone consultations. Continuing medical education on these subjects could be worthwhile. The RAMQ remuneration plan has improved documentation of phone consultations by urologists. PMID- 29106368 TI - Pop psychology and predatory journals. PMID- 29106369 TI - Partial cystectomy for urothelial carcinoma of the bladder: Practice patterns and outcomes in the general population. AB - INTRODUCTION: Partial cystectomy (PC) for urothelial carcinoma (UC) in selected patients may avoid the morbidity of radical cystectomy (RC). We describe use and outcomes of PC for UC in routine clinical practice. METHODS: All patients with urothelial carcinoma of the bladder (UCB) undergoing PC or RC in Ontario from 1994-2008 were identified using the Ontario Cancer Registry and linked electronic records. Pathology reports were reviewed. Variables associated with PC use were identified using logistic regression. Cox proportional hazards model identified factors affecting cancer-specific (CSS) and overall survival (OS). RESULTS: A total of 3320 patients underwent PC (n=181; 5%) or RC (n=3139; 95%) from 1994 2008. PC patients were older (36% 80+ years vs. 19%; p<0.001) and more likely to have organ-confined (10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin beta7 molecules. The MMG49 epitope, in the N-terminal region of the beta7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin beta7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin beta7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target. PMID- 29106401 TI - IRF3 and type I interferons fuel a fatal response to myocardial infarction. AB - Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutieres syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3 dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection. PMID- 29106402 TI - Selective neuronal lapses precede human cognitive lapses following sleep deprivation. AB - Sleep deprivation is a major source of morbidity with widespread health effects, including increased risk of hypertension, diabetes, obesity, heart attack, and stroke. Moreover, sleep deprivation brings about vehicle accidents and medical errors and is therefore an urgent topic of investigation. During sleep deprivation, homeostatic and circadian processes interact to build up sleep pressure, which results in slow behavioral performance (cognitive lapses) typically attributed to attentional thalamic and frontoparietal circuits, but the underlying mechanisms remain unclear. Recently, through study of electroencephalograms (EEGs) in humans and local field potentials (LFPs) in nonhuman primates and rodents it was found that, during sleep deprivation, regional 'sleep-like' slow and theta (slow/theta) waves co-occur with impaired behavioral performance during wakefulness. Here we used intracranial electrodes to record single-neuron activities and LFPs in human neurosurgical patients performing a face/nonface categorization psychomotor vigilance task (PVT) over multiple experimental sessions, including a session after full-night sleep deprivation. We find that, just before cognitive lapses, the selective spiking responses of individual neurons in the medial temporal lobe (MTL) are attenuated, delayed, and lengthened. These 'neuronal lapses' are evident on a trial-by-trial basis when comparing the slowest behavioral PVT reaction times to the fastest. Furthermore, during cognitive lapses, LFPs exhibit a relative local increase in slow/theta activity that is correlated with degraded single-neuron responses and with baseline theta activity. Our results show that cognitive lapses involve local state-dependent changes in neuronal activity already present in the MTL. PMID- 29106403 TI - Adipose tissue: a new target for electroporation-enhanced DNA vaccines. AB - DNA vaccines delivered using electroporation (EP) have had clinical success, but these EP methods generally utilize invasive needle electrodes. Here, we demonstrate the delivery and immunogenicity of a DNA vaccine into subcutaneous adipose tissue cells using noninvasive EP. Using finite element analysis, we predicted that plate electrodes, when oriented properly, could effectively concentrate the electric field within adipose tissue. In practice, these electrodes generated widespread gene expression persisting for at least 60 days in vivo within interscapular subcutaneous fat pads of guinea pigs. We then applied this adipose-EP protocol to deliver a DNA vaccine coding for an influenza antigen into guinea pigs. The resulting host immune responses elicited were of a similar magnitude to those achieved by skin delivery with EP. The onset of the humoral immune response was more rapid when the DNA dose was spread over multiple injection sites, and increasing the voltage of the EP device increased the magnitude of the immune response. This study supports further development of EP protocols delivering gene-based therapies to subcutaneous fat. PMID- 29106404 TI - Strategy to detect pre-existing immunity to AAV gene therapy. AB - Gene therapy may offer a new treatment option, particularly for patients with severe hemophilia, based on recent research. However, individuals with pre existing immunity to adeno-associated viruses (AAVs) may be less likely to benefit from AAV vector-based therapies. To study pre-existing AAV5 immunity in humans, we validated two complementary, sensitive, and scalable in vitro assays to detect AAV5 total antibodies and transduction inhibition (TI). Using these two assays, we found that 53% of samples from 100 healthy male individuals were negative in both assays, 18% were positive in both assays, 5% were positive for total antibodies but negative for TI and, of interest, 24% were negative for total antibodies but positive for TI activity, suggesting the presence of non antibody-based neutralizing factors in human plasma. Similar findings were obtained with 24 samples from individuals with hemophilia A. On the basis of these results, we describe the development of a dual-assay strategy to identify individuals without total AAV5 antibodies or neutralizing factors who may be more likely to respond to AAV5-directed gene therapy. These assays offer a universal, transferrable platform across laboratories to assess the global prevalence of AAV5 antibodies and neutralizing factors in large patient populations to help inform clinical development strategies. PMID- 29106406 TI - Tuning up T-cell receptors. PMID- 29106405 TI - Isolation and 3D expansion of multipotent Sox9+ mouse lung progenitors. AB - Multiple adult tissues are maintained by stem cells of restricted developmental potential which can only form a subset of lineages within the tissue. For instance, the two adult lung epithelial compartments (airways and alveoli) are separately maintained by distinct lineage-restricted stem cells. A challenge has been to obtain multipotent stem cells and/or progenitors that can generate all epithelial cell types of a given tissue. Here we show that mouse Sox9+ multipotent embryonic lung progenitors can be isolated and expanded long term in 3D culture. Cultured Sox9+ progenitors transcriptionally resemble their in vivo counterparts and generate both airway and alveolar cell types in vitro. Sox9+ progenitors that were transplanted into injured adult mouse lungs differentiated into all major airway and alveolar lineages in vivo in a region-appropriate fashion. We propose that a single expandable embryonic lung progenitor population with broader developmental competence may eventually be used as an alternative for region-restricted adult tissue stem cells in regenerative medicine. PMID- 29106407 TI - Highly accurate fluorogenic DNA sequencing with information theory-based error correction. AB - Eliminating errors in next-generation DNA sequencing has proved challenging. Here we present error-correction code (ECC) sequencing, a method to greatly improve sequencing accuracy by combining fluorogenic sequencing-by-synthesis (SBS) with an information theory-based error-correction algorithm. ECC embeds redundancy in sequencing reads by creating three orthogonal degenerate sequences, generated by alternate dual-base reactions. This is similar to encoding and decoding strategies that have proved effective in detecting and correcting errors in information communication and storage. We show that, when combined with a fluorogenic SBS chemistry with raw accuracy of 98.1%, ECC sequencing provides single-end, error-free sequences up to 200 bp. ECC approaches should enable accurate identification of extremely rare genomic variations in various applications in biology and medicine. PMID- 29106409 TI - DNA sequencing at ultra-high fidelity. PMID- 29106408 TI - Cell-type-specific metabolic labeling of nascent proteomes in vivo. AB - Although advances in protein labeling methods have made it possible to measure the proteome of mixed cell populations, it has not been possible to isolate cell type-specific proteomes in vivo. This is because the existing methods for metabolic protein labeling in vivo access all cell types. We report the development of a transgenic mouse line where Cre-recombinase-induced expression of a mutant methionyl-tRNA synthetase (L274G) enables the cell-type-specific labeling of nascent proteins with a non-canonical amino-acid and click chemistry. Using immunoblotting, imaging and mass spectrometry, we use our transgenic mouse to label and analyze proteins in excitatory principal neurons and Purkinje neurons in vitro (brain slices) and in vivo. We discover more than 200 proteins that are differentially regulated in hippocampal excitatory neurons by exposing mice to an environment with enriched sensory cues. Our approach can be used to isolate, analyze and quantitate cell-type-specific proteomes and their dynamics in healthy and diseased tissues. PMID- 29106410 TI - Generation of higher affinity T cell receptors by antigen-driven differentiation of progenitor T cells in vitro. AB - Many promising targets for T-cell-based cancer immunotherapies are self-antigens. During thymic selection, T cells bearing T cell receptors (TCRs) with high affinity for self-antigen are eliminated. The affinity of the remaining low avidity TCRs can be improved to increase their antitumor efficacy, but conventional saturation mutagenesis approaches are labor intensive, and the resulting TCRs may be cross-reactive. Here we describe the in vitro maturation and selection of mouse and human T cells on antigen-expressing feeder cells to develop higher-affinity TCRs. The approach takes advantage of natural Tcrb gene rearrangement to generate diversity in the length and composition of CDR3beta. In vitro differentiation of progenitors transduced with a known Tcra gene in the presence of antigen drives differentiation of cells with a distinct agonist selected phenotype. We purified these cells to generate TCRbeta chain libraries pre-enriched for target antigen specificity. Several TCRbeta chains paired with a transgenic TCRalpha chain to produce a TCR with higher affinity than the parental TCR for target antigen, without evidence of cross-reactivity. PMID- 29106411 TI - Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway. AB - Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNbeta production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells. Notably, the ALT suppressors histone H3.3 and the ATRX-Daxx histone chaperone complex were also required to activate the DNA-sensing pathway. Collectively, our data suggest that the loss of the cGAS-STING pathway may be required to evade ECTR-induced anti proliferation effects and permit ALT development, and this requirement may be exploited for treatments specific to cancers utilizing the ALT pathway. PMID- 29106412 TI - Short poly(A) tails are a conserved feature of highly expressed genes. AB - Poly(A) tails are important elements in mRNA translation and stability, although recent genome-wide studies have concluded that poly(A) tail length is generally not associated with translational efficiency in nonembryonic cells. To investigate whether poly(A) tail size might be coupled to gene expression in an intact organism, we used an adapted TAIL-seq protocol to measure poly(A) tails in Caenorhabditis elegans. Surprisingly, we found that well-expressed transcripts contain relatively short, well-defined tails. This attribute appears to be dependent on translational efficiency, as transcripts enriched for optimal codons and ribosome association had the shortest tail sizes, whereas noncoding RNAs retained long tails. Across eukaryotes, short tails were a feature of abundant and well-translated mRNAs. This seems to contradict the dogma that deadenylation induces translational inhibition and mRNA decay and suggests that well-expressed mRNAs accumulate with pruned tails that accommodate a minimal number of poly(A) binding proteins, which may be ideal for protective and translational functions. PMID- 29106413 TI - TFIIH generates a six-base-pair open complex during RNAP II transcription initiation and start-site scanning. AB - Eukaryotic mRNA transcription initiation is directed by the formation of the megadalton-sized preinitiation complex (PIC). After PIC formation, double stranded DNA (dsDNA) is unwound to form a single-stranded DNA bubble, and the template strand is loaded into the polymerase active site. DNA opening is catalyzed by Ssl2 (XPB), the dsDNA translocase subunit of the basal transcription factor TFIIH. In yeast, transcription initiation proceeds through a scanning phase during which downstream DNA is searched for optimal start sites. Here, to test models for initial DNA opening and start-site scanning, we measure the DNA bubble sizes generated by Saccharomyces cerevisiae PICs in real time using single molecule magnetic tweezers. We show that ATP hydrolysis by Ssl2 opens a 6-base pair (bp) bubble that grows to 13 bp in the presence of NTPs. These observations support a two-step model wherein ATP-dependent Ssl2 translocation leads to a 6-bp open complex that RNA polymerase II expands via NTP-dependent RNA transcription. PMID- 29106414 TI - Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. AB - TRPML3 channels are mainly localized to endolysosomes and play a critical role in the endocytic pathway. Their dysfunction causes deafness and pigmentation defects in mice. TRPML3 activity is inhibited by low endolysosomal pH. Here we present cryo-electron microscopy (cryo-EM) structures of human TRPML3 in the closed, agonist-activated, and low-pH-inhibited states, with resolutions of 4.06, 3.62, and 4.65 A, respectively. The agonist ML-SA1 lodges between S5 and S6 and opens an S6 gate. A polycystin-mucolipin domain (PMD) forms a luminal cap. S1 extends into this cap, forming a 'gating rod' that connects directly to a luminal pore loop, which undergoes dramatic conformational changes in response to low pH. S2 extends intracellularly and interacts with several intracellular regions to form a 'gating knob'. These unique structural features, combined with the results of electrophysiological studies, indicate a new mechanism by which luminal pH and other physiological modulators such as PIP2 regulate TRPML3 by changing S1 and S2 conformations. PMID- 29106416 TI - Bayesian inference of negative and positive selection in human cancers. AB - Cancer genomics efforts have identified genes and regulatory elements driving cancer development and neoplastic progression. From a microevolution standpoint, these are subject to positive selection. Although elusive in current studies, genes whose wild-type coding sequences are needed for tumor growth are also of key interest. They are expected to experience negative selection and stay intact under pressure of incessant mutation. The detection of significantly mutated (or undermutated) genes is completely confounded by the genomic heterogeneity of cancer mutation. Here we present a hierarchical framework that allows modeling of coding point mutations. Application of the model to sequencing data from 17 cancer types demonstrates an increased power to detect known cancer driver genes and identifies new significantly mutated genes with highly plausible biological functions. The signal of negative selection is very subtle, but is detectable in several cancer types and in a pan-cancer data set. It is enriched in cell essential genes identified in a CRISPR screen, as well as in genes with reported roles in cancer. PMID- 29106415 TI - Evolution and clinical impact of co-occurring genetic alterations in advanced stage EGFR-mutant lung cancers. AB - A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR inhibitor response, including WNT/beta-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer. PMID- 29106417 TI - High-throughput annotation of full-length long noncoding RNAs with capture long read sequencing. AB - Accurate annotation of genes and their transcripts is a foundation of genomics, but currently no annotation technique combines throughput and accuracy. As a result, reference gene collections remain incomplete-many gene models are fragmentary, and thousands more remain uncataloged, particularly for long noncoding RNAs (lncRNAs). To accelerate lncRNA annotation, the GENCODE consortium has developed RNA Capture Long Seq (CLS), which combines targeted RNA capture with third-generation long-read sequencing. Here we present an experimental reannotation of the GENCODE intergenic lncRNA populations in matched human and mouse tissues that resulted in novel transcript models for 3,574 and 561 gene loci, respectively. CLS approximately doubled the annotated complexity of targeted loci, outperforming existing short-read techniques. Full-length transcript models produced by CLS enabled us to definitively characterize the genomic features of lncRNAs, including promoter and gene structure, and protein coding potential. Thus, CLS removes a long-standing bottleneck in transcriptome annotation and generates manual-quality full-length transcript models at high throughput scales. PMID- 29106418 TI - Reduced mutation rate in exons due to differential mismatch repair. AB - While recent studies have identified higher than anticipated heterogeneity of mutation rate across genomic regions, mutations in exons and introns are assumed to be generated at the same rate. Here we find fewer somatic mutations in exons than expected from their sequence content and demonstrate that this is not due to purifying selection. Instead, we show that it is caused by higher mismatch-repair activity in exonic than in intronic regions. Our findings have important implications for understanding of mutational and DNA repair processes and knowledge of the evolution of eukaryotic genes, and they have practical ramifications for the study of evolution of both tumors and species. PMID- 29106420 TI - A small graphene oxide sheet/polyvinylidene fluoride bilayer actuator with large and rapid responses to multiple stimuli. AB - A high-performance actuator should be able to deliver large-shape deformations, fast actuations and sensitive responses to multiple stimuli. Here, we report such an actuator constructed from one layer of polyvinylidene fluoride (PVDF) with a high coefficient of thermal expansion (CTE), and another layer of small sheets of graphene oxide (SGO) with a negative CTE. The opposite deformations of both actuation layers make the SGO/PVDF bilayer actuator highly sensitive to the temperature stimulus with a large bending sensitivity of 1.5 cm-1 degrees C-1. Upon irradiation with 60 mW cm-2 infrared light, this SGO/PVDF bilayer actuator displayed an extremely rapid tip displacement rate of 140 mm s-1. Furthermore, this actuator can also sensitively respond to moisture because of its SGO layer, showing a curvature change from -22 to 13 cm-1 upon changing the relative humidity (RH) from 11% to 86%. This actuator can generate a contractile or relaxed stress 18 times that of mammalian skeletal muscle, under light irradiation or moisture with a response time as short as 1 s, being capable of lifting an object with a weight 80 times that of itself. Furthermore, it also showed excellent stability and repeatability. PMID- 29106419 TI - XtalFluor-E(r) mediated proto-functionalization of N-vinyl amides: access to N acetyl N,O-acetals. AB - XtalFluor-E(r) has been extensively used in a broad range of reactions in the past few years. Here we report its use with protic nucleophiles in a catalytic manner for the in situ generation of protons that lead to the proto functionalization of activated olefins. Utilizing the latter protocol, proto etherification of enamides gives rise to N,O-acetals in nearly quantitative yields. PMID- 29106421 TI - Insight into the structural and electronic nature of chemically exfoliated molybdenum disulfide nanosheets in aqueous dispersions. AB - Chemical exfoliation of molybdenum disulfide (2H-MoS2) for preparing high-yield single-layer sheets has attracted considerable attention in recent years. However, the stability and nature of the resulting nanosheets are poorly understood. Storing the dispersion in ambient air brings about the reoxidation of the nanosheets, releasing their residual negative charges into the environment. The reoxidation facilitates lateral fractures and destabilizes the dispersion. In plane X-ray diffraction of the nanosheets indicates that they have a 1T structure with a 2D ?3 * 1 rectangular cell as the intrinsic structure for chemically exfoliated MoS2. We found that the 1T structure was preserved after reoxidation upon aging the dispersions in air, suggesting the formation of metastable neutral MoS2. The changes in the chemical nature of the nanosheets can be monitored by X ray diffraction of the restacked nanosheets. The restacked nanosheets, obtained by drying the freshly prepared dispersion, exhibited an expanded bilayer hydrate structure, accommodating Li ions. On the other hand, dried samples from the aged dispersions were substantially composed of a deintercalated phase and the bilayer hydrate. Upon prolonged aging, the former phase became predominant with total disappearance of the latter. This evolution suggests that the reoxidation occurred sheet by sheet with a direct restoration of the original oxidation states of the nanosheets, whereas the oxidation states of the nanosheets can be discrete at 4+ and (4 - delta)+. PMID- 29106422 TI - Location and orientation of lone pairs in apatite-type materials: a computational study. AB - Electron localisation function (ELF) calculations have been used to provide the first computational location of the cation lone pairs in apatite materials. We show that the orientation of the lone pairs varies depending on the identity and positions of the channel anions. The results represent a new platform for interpreting experimentally observed structure-property relationships in functional apatites. In particular, they have significant implications for ionic conductivity and suggest that structure-property relationships in lone-pair containing apatite-type solid electrolytes are more complex than previously thought. PMID- 29106423 TI - Amplification of a metallacyclic receptor out of a dynamic combinatorial library. AB - We present herein the Pt(ii)-directed self-assembly in water of a new conformationally flexible N-monoalkyl-4,4-bipyridinium-based ditopic ligand into a library of six different metallacyclic structures. This constitutionally dynamic library can be pushed to increase the production of one of the supramolecules in aqueous media, either by controlling the concentration of the building blocks or upon addition of an appropriate aromatic substrate. PMID- 29106424 TI - A dry molten globule-like intermediate during the base-induced unfolding of a multidomain protein. AB - The nature of the initial structural events during the base-induced unfolding of the native (N) state of proteins is poorly understood. Combining site-specific fluorescence resonance energy transfer, size exclusion chromatography, dynamic fluorescence quenching, red-edge excitation shift and circular dichroism spectroscopy, we show here that an early intermediate during the base-induced unfolding of a multidomain protein, i.e., the B form, has features of a dry molten globule. We show that the N ? B transition involves protein expansion and loosening of packing of inter-domain helices near domains I and II without the disruption of intra-domain packing or any change in hydration of the inter-domain region which resembles a molten hydrocarbon. Surprisingly, the disruption of inter-domain packing accounts for 40-45% of the total change in free energy of complete unfolding. Our results show that the disruption of van der Waals packing can be decoupled in different regions of a protein and could occur prior to hydrophobic solvation during base-induced unfolding, challenging the existing notion. PMID- 29106425 TI - Siloxane-based linkers in the construction of hydrogen bonded assemblies and porous 3D MOFs. AB - A siloxane-based hexacarboxylic acid (L1-H6) has been prepared and applied in MOF construction. L1-H6 itself crystallizes as an unusual interpenetrated 3D hydrogen bonded framework. Reaction of L1-H6 with Zn(ii) gave IMP-18 - a 3D MOF incorporating Si-O-Si functionality. Cleavage of L1-H6 gives a silanol-based triacid which is shown to give a coordination polymer (IMP-19) with Zn(ii). PMID- 29106426 TI - Effect of a novel potential probiotic Lactobacillus paracasei Jlus66 isolated from fermented milk on nonalcoholic fatty liver in rats. AB - Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease worldwide. Previous evidence indicates that probiotics can be applied as a therapeutic agent for NAFLD. In this study, the potential probiotic strain Lactobacillus paracasei Jlus66 was isolated from natural fermented milk by a culture-dependent method, and its probiotic potentials were tested by established in vitro tests. In addition, the protective effect of Lactobacillus paracasei Jlus66 against NAFLD was evaluated in rat models. Compared with the high-fat-diet (HFD) group, the rats administered with 4 * 1010 cfu Jlus66 had significantly lower body weight gain, serum triglyceride (TG), low-density lipoprotein (LDL) as well as aminotransferase (ALT). Histopathological analysis showed Jlus66 also reduced the level of hepatic triglycerides and steatosis. From the above we conclude that L. paracasei Jlus66 has great potential as a probiotic in protecting from NAFLD. PMID- 29106427 TI - Micro/nanoelectrochemical probe and chip devices for evaluation of three dimensional cultured cells. AB - Herein, we present an overview of recent research progress in the development of micro/nanoelectrochemical probe and chip devices for the evaluation of three dimensional (3D) cultured cells. First, we discuss probe devices: a general outline, evaluation of O2 consumption, enzyme-modified electrodes, evaluation of endogenous enzyme activity, and the collection of cell components from cell aggregates are discussed. The next section is focused on integrated chip devices: a general outline, electrode array devices, smart electrode array devices, droplet detection of 3D cultured cells, cell manipulation using dielectrophoresis (DEP), and electrodeposited hydrogels used for fabrication of 3D cultured cells on chip devices are discussed. Finally, we provide a summary and discussion of future directions of research in this field. PMID- 29106428 TI - Modified acellular nerve-delivering PMSCs improve functional recovery in rats after complete spinal cord transection. AB - Due to the poor regeneration capacity of neurons and the inhibitory microenvironment, spontaneous regeneration in spinal cord injury (SCI) remains challenging. Tissue engineering is considered a promising approach for enhancing the regeneration of SCI by reconstructing the inherent structure and improving the microenvironment. In this study, the possibility of engineering a nerve complex, which is constructed by acellular nerve delivering placenta mesenchymal stem cells (PMSCs), was assessed for the recovery of a transected spinal cord. Modified acellular nerve grafts were developed, and PMSCs labeled with green fluorescent protein (GFP) were seeded on the graft to construct the engineered nerve complex. Then, the engineered nerve complex was implanted into a 2 mm length transected gap of the spinal cord. Four weeks after the transplantation, numerous surviving PMSCs were observed in the lesion cavity by immunofluorescence staining. Moreover, co-localization between GFP and neurofilament-200 (NF200) and Neuronal Class III beta-Tubulin (Tuj1) was observed at the bridge interface. The PMSCs-graft group exhibited significant function improvement as evaluated by the Basso, Beattie and Bresnahan (BBB) locomotion score and footprint analysis. Eight weeks after surgery, the evoked response was restored in the PMSCs-graft group and numerous thick myelin sheathes were observed compared to that in the control groups. Collectively, our findings suggest that the nerve complex prepared by acellular nerve delivering PMSCs enhanced the structure and function regeneration of the spinal cord after SCI. PMID- 29106429 TI - Different dominant transitions in holmium and ytterbium codoped oxyfluoride glass and glass ceramics originating from varying phonon energy environments. AB - Transparent oxyfluoride glass and glass ceramics doped with 0.5% Ho3+ and 1.0% Yb3+ ions have been prepared. X-ray diffraction and transmission electron microscopy demonstrated the formation of NaYF4 nanocrystals during the heat treatment process. Raman spectra indicated the variation of glass structure brought about by the formation of NaYF4 nanocrystals. XRD curves and Judd-Ofelt intensity parameters confirmed the incorporation of Ho3+ into NaYF4 nanocrystals. Significantly enhanced visible upconversion and 2.85 MUm emissions were achieved in glass ceramic under 980 nm laser diode pumping. A broadband spectrum with a full-width at half-maximum close to 132 nm was obtained in the glass ceramic. Besides, the calculated peak emission cross section was 0.6 * 10-20 cm2, suggesting that the glass ceramic is a promising gain material that can be applied to broadband amplifiers in the mid-infrared region. Furthermore, energy transfer mechanisms in glass and glass ceramics were proposed based on visible to mid-infrared emission spectra. It was found that the change in the photon energy environment around rare earth ions induced different dominant transitions in glass and glass ceramic. Finally, the influence of phonon energy on the transition processes was further quantitatively investigated, which may provide useful guidance for obtaining highly efficient 2.85 MUm emission of holmium. PMID- 29106430 TI - The growing importance of crystalline molecular flasks and the crystalline sponge method. AB - This article showcases recent advancements made using crystalline molecular flasks and the widening list of prospective applications for the crystalline sponge method. This expansion has coincided with an increasing number of materials termed crystalline sponges, and a report of a predictive means of identifying candidates from crystallographic databases. The crystalline sponge method's primary application has been determination of absolute configuration, and this has evolved from the analysis of carefully chosen planar aromatic guests to more diverse identification of natural products, biological metabolites, and analysis of volatile chemical components. However with time-resolved X-ray crystallography providing arguably the most informative atomic scale insights of dynamic chemical processes, this application of the crystalline sponge method may soon eclipse structural determination in terms of importance. PMID- 29106431 TI - Effects of oxidation on the plasmonic properties of aluminum nanoclusters. AB - The scouting of alternative plasmonic materials able to enhance and extend the optical properties of noble metal nanostructures is on the rise. Aluminum is endowed with a set of interesting properties which turn it into an attractive plasmonic material. Here we present the optical and electronic features of different aluminum nanostructures stemming from a multilevel computational study. Molecular Dynamics (MD) simulations using a reactive force field (ReaxFF), carefully validated with Density Functional Theory (DFT), were employed to mimic the oxidation of icosahedral aluminum nanoclusters. Resulting structures with different oxidation degrees were then studied through the Time-Dependent Density Functional Tight Binding (TD-DFTB) method. A similar approach was used in aluminum nanoclusters with a disordered structure to study how the loss of crystallinity affects the optical properties. To the best of our knowledge, this is the first report that addresses this issue from the fully atomistic time dependent approach by means of two different and powerful simulation tools able to describe quantum and physicochemical properties associated with nanostructured particles. PMID- 29106432 TI - Ultra-sensitive near-infrared graphene photodetectors with nanopillar antennas. AB - Graphene has been demonstrated as a candidate for optoelectronic devices due to its broad absorption spectrum and ultra-high carrier mobility. However, graphene is essentially transparent in visible and near-infrared regimes with an absorptivity of 2.3%, which largely limits its application in photodetection. Here, we show that metallic nanopillar antennas could improve light absorption in graphene detectors. The coupled antennas help to concentrate a free space electromagnetic wave around the nanopillars by localized surface plasmon resonance, strongly impacted by geometrical design. It is found that spectral selectivity can be realized by tuning key geometrical parameters such as period, radius, and height of the metallic nanopillar, leading to wavelength-tunable photodetectors within a broad range from 0.6 MUm to 1.2 MUm. With the optimized design, the detector exhibits an excellent photoresponsivity of 7 A W-1 at a wavelength of 0.82 MUm. PMID- 29106433 TI - Codelivery of sorafenib and GPC3 siRNA with PEI-modified liposomes for hepatoma therapy. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies imposing a serious threat to human health worldwide. To date, the effect of HCC chemotherapy has been limited due to drug resistance. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy that may improve anticancer effects by synergistic actions. The current study was aimed at achieving better HCC treatment via combination therapy, in which PEI-modified liposomes prepared by a thin-film hydration method were used to codeliver sorafenib (SF) and siRNA targeting GPC3 gene (siGPC3). Under optimized experimental conditions, SF and siGPC3 were effectively loaded into liposomes (SF-PL/siGPC3). SF-PL/siGPC3 with selected sizes and zeta potentials effectively accumulated at tumor sites and entered HCC cells. The two codelivered therapeutic agents exerted good anticancer effects by jointly suppressing the expression of the anti-apoptotic GPC3 gene and the proliferative cyclin D1 gene in HCC. Consequently, the intravenous injection of SF-PL/siGPC3 into nude mice bearing subcutaneous human HepG2 xenografts effectively inhibited tumor growth and also increased the survival rates of animals. These results revealed the great potential of the PEI-modified liposomal nanomedicine carrying SF and siGPC3 to improve HCC treatment. PMID- 29106434 TI - Nanoprodrug of retinoic acid-modified paclitaxel. AB - All-trans-retinoic acid (RA) is a non-toxic physiological metabolite of vitamin A. A paclitaxel (PTX) prodrug (RA-PTX) with high PTX content of 75% was synthesized via an easy condensation reaction. RA-PTX nanoparticles (RA-PTX NPs) were prepared through a nanoprecipitation method which increased the water solubility of PTX. RA-PTX NPs were spherical in shape and exhibited favorable structural stability in both water and the physiological environment. RA-PTX NPs possessed effective cellular uptake as revealed by confocal laser scanning microscopy and exerted potent cytotoxicity. These results highlight the potential of nanomedicines from PTX prodrugs for increasing the drug loading and water solubility of PTX. PMID- 29106435 TI - A self-assembly toolbox for thiophene-based conjugated polyelectrolytes: surfactants, solvent and copolymerisation. AB - Targeted control of the aggregation, morphology and optical properties of conjugated polymers is critical for the development of high performance optoelectronic devices. Here, self-assembly approaches are used to strategically manipulate the order, conformation and spatial distribution of conjugated polymers in solution and subsequently prepared thin films. The supramolecular complex organisation of phosphonium-functionalised homo- (P3HTPMe3) and diblock (P3HT-b-P3HTPMe3) ionic conjugated polythiophenes upon solvent-mediation and co assembly with oppositely charged surfactants is investigated. UV/Vis absorption and photoluminescence spectroscopies, small-angle neutron scattering (SANS), cryo transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM) are used to probe the organisation and photophysical response of the aggregates formed. Subtle differences in the surfactant mole fraction and structure, as well as the solvent polarity, yield differences in the nature of the resultant homopolyelectrolyte-surfactant complexes. In contrast, only moderate structural transformations are observed for the amphiphilic diblock copolyelectrolyte, emphasising the structure "anchoring" effect of a neutral polymer block when amphiphilic copolymers are dissolved in polar solvents. These results highlight the versatility of self-assembly to access a range of nanomorphologies, which could be crucial for the design of the next generation of organic optoelectronic devices. PMID- 29106436 TI - Copper(i)-catalyzed carbocyclization of acrylamide-tethered alkylidenecyclopropanes with diaryliodonium salts. AB - A novel copper-catalyzed carbocyclization of acrylamide-tethered alkylidenecyclopropanes with diaryliodonium salts to construct tetracyclic benzazepine derivatives under mild and convenient conditions has been disclosed. The chemoselective addition of in situ generated arylcopper(iii) intermediates onto the activated alkenes triggers the reaction followed by a ring-opening process of alkylidenecyclopropanes, leading to the formation of tetracyclic benzazepine derivatives in moderate to good yields, with excellent functional group tolerance. PMID- 29106437 TI - Does Increasing the Dose of Abobotulinumtoxina Impact the Duration of Effectiveness for the Treatment of Moderate to Severe Glabellar Lines? AB - OBJECTIVE: To evaluate the duration of effect of a single dose of 120 units of abobotulinumtoxinA for the treatment of moderate to severe glabellar lines. DESIGN: Investigator-initiated, prospective, multi-center, open-label study. MATERIAL AND METHODS: This open-label trial of thirty subjects with moderate to severe glabellar lines at maximum frown was per- formed at 2 private plastic surgery clinics. 120 units of abobotulinumtoxinA was injected in 5 equal aliquots (24 units each) into each of 5 injection sites in the glabellar complex. Investigator and subject assessments of wrinkle severity at maximum frown and repose using 4-point scales and adverse events were conducted. Follow-up was monthly for up to 11 months. RESULTS: The median duration of response for all subjects, as assessed by the investigator, was 150 days (95% CI: 120, 180). The median duration of response was 165 days (95% CI: 90, 180) for subjects with Grade 2 (Moderate) wrinkles at baseline and 75 days (95% CI: 30, 120) for subjects with Grade 3 (Severe) wrinkles at baseline. Overall, 76.7% of subjects had a duration of >= 120 days. At the end of study (day 300) 9/16 (53%) of subjects who were Grade 3 at baseline still rated themselves as not returning to Grade 3, demonstrating ongoing improvement. Adverse events were mild and transient. There were no events of lid or brow ptosis. CONCLUSIONS: The 120 units of abobotulinumtoxinA were significantly effective in reducing glabellar lines in subjects with Grade 2 (Moderate) wrinkles at baseline for a longer duration than the reported 85 days in the FDA Phase III randomized, placebo-controlled clinical studies using a standard 50 unit dose. Subject satisfaction was high. There was no increase in the incidence of adverse events with this higher dose. J Drugs Dermatol. 2016;15(12):1544-1549. PMID- 29106438 TI - The Neurocognitive Profile of Attention-Deficit/Hyperactivity Disorder: A Review of Meta-Analyses. AB - Objective: Numerous meta-analyses have summarized studies comparing the neurocognitive performance of individuals with attention-deficit/hyperactivity disorder (ADHD) to that of healthy controls. Method: The present study is a systematic review and quantitative summary of those meta-analyses that aimed to determine the extent to which individuals with ADHD differ cognitively from typically developing controls. Results: Of 253 standardized mean differences (SMDs) drawn from 34 meta-analyses, 244 (96%) were positive, indicating better neurocognitive performance in the control group than the ADHD group. The mean effect size was .45 (SD = .27). Unweighted means of SMDs for neurocognitive domains ranged from .35 (set shifting) to .54 (working memory). When weighted by the number of studies aggregated, they ranged from .35 (set shifting) to .66 (reaction time variability). Neurocognitive domains with mean effects over .50 included working memory (.54), reaction time variability (.53), response inhibition (.52), intelligence/achievement (.51), and planning/organization (.51). When weighted by number of aggregated studies, the domains with mean effects over .50 were reaction time variability (.66), intelligence/achievement (.60), vigilance (.56), working memory (.54), and response inhibition (.52). Age moderated the relationship between ADHD diagnosis and neurocognitive functioning, with greater between-groups differences among children and adults than among adolescents. Funding also moderated this relationship: meta-analyses that received drug funding found larger effect sizes than those without drug funding. Conclusions: The evidence suggests that ADHD is associated with substantial deficits across a variety of neurocognitive domains. This is the most in-depth review of the neurocognitive functioning of people with ADHD to date. PMID- 29106439 TI - Increased diastolic blood pressure is associated with MRI biomarkers of dementia related brain pathology in normative ageing. AB - Background: hypertension is a risk for brain ageing, but the mechanisms underlying this effect remain unclear. Magnetic resonance imaging (MRI) detected biomarkers of brain ageing include white matter hyperintensities (WMHs), a marker of cerebrovascular disease, and hippocampal volume, a marker of Alzheimer's disease pathology. Objective: to examine relationships between blood pressure (BP) components and brain pathology in older adults. Subjects: two hundred and twenty-seven members of the Aberdeen 1936 Birth Cohort between ages 64 and 68 years. Methods: BP was assessed biennially between 64 and 68 years and brain MRI performed at 68 years. The risk factors of interest were diastolic and systolic BP and their visit-to-visit variability. Outcomes were WMH abundance and hippocampal volume. Regression models, controlling for confounding factors, examined their relationships. Results: higher diastolic BP predicted increased WMH (beta = 0.13, P = 0.044) and smaller hippocampi (beta = -0.25, P = 0.006). In contrast, increased systolic BP predicted larger hippocampi (beta = 0.22, P = 0.013). Variability of diastolic BP predicted lower hippocampal volume (beta = 0.15, P = 0.033). These relationships were independent of confounding life-course risk factors. Anti-hypertensive medication did not modify these relationships, but was independently associated with increased WMH (beta = 0.17, P = 0.011). Conclusion: increased diastolic BP is associated with biomarkers of both cerebrovascular and Alzheimer's diseases, whereas the role of systolic BP is less clear, with evidence for a protective effect on hippocampal volume. These differing relationships emphasise the importance of considering individual BP components with regard to brain ageing and pathology. Interventions targeting diastolic hypertension and its chronic variability may provide new strategies able to slow the accumulation of these harmful pathologies. PMID- 29106441 TI - Orchid: a novel management, annotation and machine learning framework for analyzing cancer mutations. AB - Motivation: As whole-genome tumor sequence and biological annotation datasets grow in size, number and content, there is an increasing basic science and clinical need for efficient and accurate data management and analysis software. With the emergence of increasingly sophisticated data stores, execution environments and machine learning algorithms, there is also a need for the integration of functionality across frameworks. Results: We present orchid, a python based software package for the management, annotation and machine learning of cancer mutations. Building on technologies of parallel workflow execution, in memory database storage and machine learning analytics, orchid efficiently handles millions of mutations and hundreds of features in an easy-to-use manner. We describe the implementation of orchid and demonstrate its ability to distinguish tissue of origin in 12 tumor types based on 339 features using a random forest classifier. Availability and implementation: Orchid and our annotated tumor mutation database are freely available at https://github.com/wittelab/orchid. Software is implemented in python 2.7, and makes use of MySQL or MemSQL databases. Groovy 2.4.5 is optionally required for parallel workflow execution. Contact: JWitte@ucsf.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29106442 TI - Bioinformatics on a national scale: an example from Switzerland. AB - Switzerland has been a pioneer in the field of bioinformatics since the early 1980s. As time passed, the need for one entity to gather and represent bioinformatics on a national scale was felt and, in 1998, the SIB Swiss Institute of Bioinformatics was created. Hence, 2018 marks the Institute's 20th anniversary. Today, the Institute federates 65 research and service groups across the country-whose activity domains range from genomics, proteomics, medicine and health to structural biology, systems biology, phylogeny and evolution-and a group whose sole task is dedicated to training. The Institute hosts 12 competence centres that provide bioinformatics and biocuration expertise to life scientists across the country. SIB sensed early on that the wealth of data produced by modern technologies in medicine and the growing self-awareness of patients was about to revolutionize the way medical data are considered. In 2012, it created a Clinical Bioinformatics group to address the issue of personalized health, thus working towards a more global approach to patient management, and more targeted and effective therapies. In this respect, SIB has a major role in the Swiss Personalized Health Network to make patient-related data available to research throughout the country. The uniqueness of the Institute's governance structure has also inspired the structure of other European life science organizations, notably ELIXIR. PMID- 29106443 TI - Estimation of QTL heritability based on pooled sequencing data. AB - Motivation: Bulked segregant analysis combined with next generation sequencing has proven to be a simple and efficient approach for fast mapping of quantitative trait loci (QTLs). However, how to estimate the proportion of phenotypic variance explained by a QTL (or termed QTL heritability) in such pooled QTL mapping is an unsolved problem. Results: In this paper, we propose a method called PQHE to estimate QTL heritability using pooled sequencing data obtained under different experimental designs. Simulation studies indicated that our method is correct and feasible. Four practical examples from rice and yeast are demonstrated, each representing a different situation. Availability and implementation: The R scripts of our method are open source under GPLv3 license at http://genetics.fafu.edu.cn/PQHE or https://github.com/biotangweiqi/PQHE. The R scripts require the R package rootSolve. Contact: wuwr@fafu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29106444 TI - Automatic module selection from several microarray gene expression studies. AB - Independence of genes is commonly but incorrectly assumed in microarray data analysis; rather, genes are activated in co-regulated sets referred to as modules. In this article, we develop an automatic method to define modules common to multiple independent studies. We use an empirical Bayes procedure to estimate a sparse correlation matrix for all studies, identify modules by clustering, and develop an extreme-value-based method to detect so-called scattered genes, which do not belong to any module. The resulting algorithm is very fast and produces accurate modules in simulation studies. Application to real data identifies modules with significant enrichment and results in a huge dimension reduction, which can alleviate the computational burden of further analyses. PMID- 29106440 TI - Identification of PMN-released mutagenic factors in a co-culture model for colitis-associated cancer. AB - Microsatellite instability (MSI) is present in ulcerative colitis (UC) and colitis-associated colorectal cancers (CAC). Certain factors released by polymorphonuclear cells (PMNs) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116 + chr3 and human colonic epithelial cells (HCEC)-1CT MSI-reporter cell lines harboring mono , di- or tetranucleotide DNA repeats linked to enhanced green fluorescent protein (EGFP) to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry. Activated PMNs released superoxide and hydrogen peroxide (H2O2), as measured by lucigenin-amplified chemiluminescence and fluorometry, respectively. Catalase, which scavenges H2O2, reduced such PMN induced MSI. The NADPH-oxidase inhibitor apocynin, which blocks the oxidative burst in PMNs, similarly inhibited PMN-induced MSI. A bead-based multiplex assay revealed that PMNs release a wide range of cytokines such as interleukin (IL)-8, IL-6 and tumor necrosis factor-alpha (TNF-alpha). In vitro, these cytokines increased MSI in colon epithelial cells, and the Janus kinase (JAK) inhibitor tofacitinib abolished IL-6-induced or PMN-induced MSI. Intracellular reactive oxygen species (ROS) formation, as measured by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, was induced upon cytokine treatment. DNA oxidation upon IL-6 was present, as detected by formamidopyrimidine glycosylase (FPG)-modified comet assay. In conclusion, activated PMNs induce frameshift mutations in colon epithelial cells resulting in MSI. Both oxidative burst with release of ROS and PMN-secreted cytokines, such as IL-8, IL-6 or TNF-alpha, contribute to MSI. ROS scavengers and/or specific inhibitors of cytokine signaling may delay or prevent cancer development in the setting of colitis. PMID- 29106445 TI - A potent hydroxamic acid-based, small-molecule inhibitor A452 preferentially inhibits HDAC6 activity and induces cytotoxicity toward cancer cells irrespective of p53 status. AB - HDAC6-selective inhibitors are novel epigenetic anticancer agents. However, their precise mechanisms of action are incompletely understood. We investigated the anticancer mechanisms of the novel potent and selective HDAC6 inhibitor A452 compared with current clinically tested HDAC6 inhibitor ACY-1215. We demonstrate that A452 effectively inhibits the cell growth and viability of various cancer cell types, irrespective of p53 status. A452-induced apoptosis as evidenced by activated caspase 3 and PARP, increased Bak and Bax and decreased Bcl-xL. Moreover, A452 shifted cells away from antiapoptotic (AKT and ERK) pathways and toward proapoptotic (p38) pathways. A452 triggered DNA damage via increased gammaH2AX and activation of the checkpoint kinase Chk2. A452 induced the suppression of cell migration and invasion. Interestingly, A452 upregulated the expression of PD-L1, which regulates the PD-1 inhibitory pathway in T cells. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215. Therefore, therapeutically targeting HDAC6 may represent a novel strategy for cancer treatment irrespective of the p53 mutation status. PMID- 29106446 TI - FunImageJ: a Lisp framework for scientific image processing. AB - Summary: FunImageJ is a Lisp framework for scientific image processing built upon the ImageJ software ecosystem. The framework provides a natural functional-style for programming, while accounting for the performance requirements necessary in big data processing commonly encountered in biological image analysis. Availability and implementation: Freely available plugin to Fiji (http://fiji.sc/#download). Installation and use instructions available at http://imagej.net/FunImageJ. Contact: kharrington@uidaho.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29106447 TI - An evaluation of noncoding genome annotation tools through enrichment analysis of 15 genome-wide association studies. AB - Functionally annotating genetic variations is an essential yet challenging topic in human genetics research. As large consortia including ENCODE and Roadmap Epigenomics Project continue to generate high-throughput transcriptomic and epigenomic data, many computational frameworks have been developed to integrate these experimental data to predict functionality of genetic variations in both protein-coding and noncoding regions. Here, we compare a number of recently developed annotation frameworks for noncoding regions through enrichment analysis on genome-wide association studies (GWASs). We also compare several different strategies to quantify enrichment using GWAS summary statistics. Our analyses highlight the importance of jointly modeling context-specific annotations with genome-wide data in providing statistically powerful and biologically interpretable enrichment for complex disease associations. Our findings provide insights into when and how computational genome annotations may benefit future complex disease studies on the genome-wide scale. PMID- 29106448 TI - Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial. AB - Background: Coagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients. Patients and methods: We carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), incidence of VTE and hemorrhagic events. Results: In RASTEN, 390 patients were randomized over an 8-year period (2008-2016), of whom 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin [hazard ratio (HR), 1.11; 95% confidence interval (CI) 0.89-1.38; P = 0.36 and HR, 1.18; 95% CI 0.95-1.46; P = 0.14, respectively]. Subgroup analysis of patients with limited and extensive disease did not show reduced mortality by enoxaparin. The incidence of VTE was significantly reduced in the LMWH arm (HR, 0.31; 95% CI 0.11-0.84; P = 0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms. Conclusion: LMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Addition of LMWH cannot be generally recommended in the management of SCLC patients, and predictive biomarkers of VTE and LMWH-associated bleeding in cancer patients are warranted. PMID- 29106449 TI - AlloSigMA: allosteric signaling and mutation analysis server. AB - Motivation: Allostery is an omnipresent mechanism of the function modulation in proteins via either effector binding or mutations in the exosites. Despite the growing number of online servers and databases devoted to prediction/classification of allosteric sites and their characteristics, there is a lack of resources for an efficient and quick estimation of the causality and energetics of allosteric communication. Results: The AlloSigMA server implements a unique approach on the basis of the recently introduced structure-based statistical mechanical models of allosteric signaling. It provides an interactive framework for estimating the allosteric free energy as a result of the ligand(s) binding, mutation(s) and their combinations. Latent regulatory exosites and allosteric effect of mutations can be detected and explored, facilitating the research efforts in protein engineering and allosteric drug design. Availability and implementation: The AlloSigMA server is freely available at http://allosigma.bii.a-star.edu.sg/home/. Contact: igorb@bii.a-star.edu.sg. PMID- 29106451 TI - pLoc-mHum: predict subcellular localization of multi-location human proteins via general PseAAC to winnow out the crucial GO information. AB - Motivation: For in-depth understanding the functions of proteins in a cell, the knowledge of their subcellular localization is indispensable. The current study is focused on human protein subcellular location prediction based on the sequence information alone. Although considerable efforts have been made in this regard, the problem is far from being solved yet. Most existing methods can be used to deal with single-location proteins only. Actually, proteins with multi-locations may have some special biological functions that are particularly important for both basic research and drug design. Results: Using the multi-label theory, we present a new predictor called 'pLoc-mHum' by extracting the crucial GO (Gene Ontology) information into the general PseAAC (Pseudo Amino Acid Composition). Rigorous cross-validations on a same stringent benchmark dataset have indicated that the proposed pLoc-mHum predictor is remarkably superior to iLoc-Hum, the state-of-the-art method in predicting the human protein subcellular localization. Availability and implementation: To maximize the convenience of most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc-mHum/, by which users can easily get their desired results without the need to go through the complicated mathematics involved. Contact: xcheng@gordonlifescience.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29106450 TI - A novel experimental model for human mixed acinar-ductal pancreatic cancer. AB - Pancreatic cancer has remained refractory to treatment. In large part, this results from the lack of an animal model that mimics pancreatic cancer in man. We describe a novel experimental model of pancreatic cancer that shares the genetic background, histologic features and natural history of human mixed acinar-ductal carcinoma. Adult wild-type mice received an injection into the pancreatic duct of lentivirus coding two molecules, KrasG12D mutation and shRNA p53, which recapitulate the mechanisms of pancreatic cancer in humans. The lentivirus constructs also co-expressed the luciferase gene for in vivo imaging by bioluminescence using the Xenogen IVIS imaging system. Weeks post-injection wild type mice develop pancreatic cancer with the same histologic characteristics and metastases observed with human pancreatic mixed acinar-ductal carcinoma. This novel approach represents the first pancreatic cancer model that does not involve alterations of embryonic development, which is inherent with transgenic mice or knockout mice models. This novel experimental human pancreatic cancer model can be used to more effectively test new anti-cancer drug to inhibit tumor progression in situ and to retard metastases. Furthermore, our method of injecting lentivirus containing oncogenes and molecules implicated in the development of pancreatic can be employed in diabetic and obese mice, two common metabolic conditions characterized by an increased incidence of pancreatic cancer. PMID- 29106452 TI - Acute aortic syndromes: diagnosis and management, an update. AB - Acute aortic syndromes (AAS) encompass a constellation of life-threatening medical conditions including classic acute aortic dissection (AAD), intramural haematoma, and penetrating atherosclerotic aortic ulcer. Given the non-specific symptoms and physical signs, a high clinical index of suspicion is necessary to detect the disease before irreversible lethal complications occur. In order to reduce the diagnostic time delay, a comprehensive flowchart for decision-making based on pre-test sensitivity of AAS has been designed by the European Society of Cardiology guidelines on aortic diseases and should be thus applied in the emergency scenario. When the definitive diagnosis is made, prompt and appropriate therapeutic interventions should be undertaken if indicated by a highly specialized aortic team. Urgent surgery for AAD involving the ascending aorta (Type A) and medical therapy alone for AAD not involving the ascending aorta (Type B) are typically recommended. In complicated Type B AAD, thoracic endovascular aortic repair (TEVAR) is generally indicated. On the other hand, in uncomplicated Type B AAD, pre-emptive TEVAR rather than medical therapy alone to prevent late complications, while intuitive, requires further study in randomized cohorts. Finally, it should be highlighted that there is an urgent need to increase awareness of AAS worldwide, including dedicated education/prevention programmes, and to improve diagnostic and therapeutic strategies, outcomes, and lifelong surveillance. PMID- 29106453 TI - Medical oncologists' perception of antiestrogen therapy benefit in premenopausal women with hormone receptor-positive early-stage breast cancer. PMID- 29106455 TI - ViraPipe: scalable parallel pipeline for viral metagenome analysis from next generation sequencing reads. AB - Motivation: Next Generation Sequencing (NGS) technology enables identification of microbial genomes from massive amount of human microbiomes more rapidly and cheaper than ever before. However, the traditional sequential genome analysis algorithms, tools, and platforms are inefficient for performing large-scale metagenomic studies on ever-growing sample data volumes. Currently, there is an urgent need for scalable analysis pipelines that enable harnessing all the power of parallel computation in computing clusters and in cloud computing environments. We propose ViraPipe, a scalable metagenome analysis pipeline that is able to analyze thousands of human microbiomes in parallel in tolerable time. The pipeline is tuned for analyzing viral metagenomes and the software is applicable for other metagenomic analyses as well. ViraPipe integrates parallel BWA-MEM read aligner, MegaHit De novo assembler, and BLAST and HMMER3 sequence search tools. We show the scalability of ViraPipe by running experiments on mining virus related genomes from NGS datasets in a distributed Spark computing cluster. Results: ViraPipe analyses 768 human samples in 210 minutes on a Spark computing cluster comprising 23 nodes and 1288 cores in total. The speedup of ViraPipe executed on 23 nodes was 11x compared to the sequential analysis pipeline executed on a single node. The whole process includes parallel decompression, read interleaving, BWA-MEM read alignment, filtering and normalizing of non-human reads, De novo contigs assembling, and searching of sequences with BLAST and HMMER3 tools. Contact: ilari.maarala@aalto.fi. Availability and implementation: https://github.com/NGSeq/ViraPipe. PMID- 29106454 TI - Cell wall changes during the formation of aerenchyma in sugarcane roots. AB - Background and Aims: Aerenchyma develops in different plant organs and leads to the formation of intercellular spaces that can be used by the plant to transport volatile substances. Little is known about the role of cell walls in this process, although the mechanism of aerenchyma formation is known to involve programmed cell death and some cell wall modifications. We assessed the role that cell wall-related mechanisms might play in the formation of aerenchyma in sugarcane roots. Methods: Sections of roots (5 cm) were subjected to microtomography analysis. These roots were divided into 1-cm segments and subjected to cell wall fractionation. We performed analyses of monosaccharides, oligosaccharides and lignin and glycome profiling. Sections were visualized by immunofluorescence and immunogold labelling using selected monoclonal antibodies against polysaccharide epitopes according to the glycome profiles. Key Results: During aerenchyma formation, gas spaces occupied up to 40 % of the cortex cross section within the first 5 cm of the root. As some of the cortex cells underwent dissolution of the middle lamellae, leading to cell separation, cell expansion took place along with cell death. Mixed-linkage beta-glucan was degraded along with some homogalacturonan and galactan, culminating in the formation of cell wall composites made of xyloglucan, arabinoxylans, cellulose and possibly lignin. Conclusion: The composites formed seem to play a role in the physical-chemical properties of the gas chambers, providing mechanical resistance to forces acting upon the root and at the same time decreasing permeability to gases. PMID- 29106456 TI - CircView: a visualization and exploration tool for circular RNAs. AB - Circular RNAs (circRNAs) are novel rising stars of noncoding RNAs, which are highly abundant and evolutionarily conserved across species. Number of publications related to circRNAs increased sharply in recent years, representing emerging focuses in the field. Therefore, tools, pipelines and databases have been developed to identify and store circRNAs. However, there is no existing tool to visualize and explore circRNAs. Therefore, we introduce CircView, a user friendly visualization tool for circRNAs detected from existing tools. CircView enables users to visualize circRNAs and to quantify number of samples with detected circRNAs. CircView allows users to explore circRNAs detected by unique or multiple tools. Furthermore, CircView allows users to view the regulatory elements, such as microRNA response elements and RNA-binding protein binding sites. CircView is a unique tool to visualize and explore circRNAs, which helps users to better understand potential functions of circRNAs and design the functional experiments. PMID- 29106458 TI - Is Standard Histology Sufficient to Detect Cytomegalovirus Reactivation in Inflammatory Bowel Disease? PMID- 29106459 TI - Epitope Preservation Methods for Tissue Microarrays: Longitudinal Prospective Study. AB - Objectives: We sought to test recent guidelines for preserving immunoreactivity of precut slides, to quantify loss of immunoreactivity, and to determine potential for preservation by altering storage conditions. Methods: Precut slides from tissue microarrays were stored under one of several conditions: exposed to ambient air at room temperature, 4 degrees C, or -20 degrees C or in a vacuum sealed container at room temperature, -20 degrees C, -80 degrees C, or with paraffin coating. At multiple intervals over 1 year, slides were stained with antibodies against p53, isocitrate dehydrogenase 1, Ki-67, synaptophysin, and androgen receptor and evaluated. Results: Compared with time 0, the overall median percentage immunoreactivity was 66% at 6 months and 51% at 1 year. During the experiment, this was as low as 55% for precut slides stored in paraffin coating and up to 87% for those stored at -20 degrees C. Vacuum sealing was an effective preservative for some antibody targets and detrimental for others. Storage at -80 degrees C did not have added value. Conclusions: For precut slides, there is a time, storage condition, and antibody-dependent loss of immunoreactivity that could compromise analysis of prognostic, predictive, and diagnostic markers. Our findings support previous recommendations and suggest that the best storage conditions are at -20 degrees C, without paraffin coating or vacuum sealing. PMID- 29106457 TI - Rapid Loss of RNA Detection by In Situ Hybridization in Stored Tissue Blocks and Preservation by Cold Storage of Unstained Slides. AB - Objectives: Recent commercialization of methods for in situ hybridization using Z pair probe/branched DNA amplification has led to increasing adoption of this technology for interrogating RNA expression in formalin-fixed, paraffin-embedded (FFPE) tissues. Current practice for FFPE block storage is to maintain them at room temperature, often for many years. Methods: To examine the effects of block storage time on FFPE tissues using a number of RNA in situ probes with the Advanced Cellular Diagnostic's RNAscope assay. Results: We report marked reductions in signals after 5 years and significant reductions often after 1 year. Furthermore, storing unstained slides cut from recent cases (<1 year old) at -20 degrees C can preserve hybridization signals significantly better than storing the blocks at room temperature and cutting the slides fresh when needed. Conclusions: We submit that the standard practice of storing FFPE tissue blocks at room temperature should be reevaluated to better preserve RNA for in situ hybridization. PMID- 29106461 TI - Erratum. PMID- 29106460 TI - Correspondence. PMID- 29106462 TI - Erratum. PMID- 29106463 TI - Correspondence. PMID- 29106465 TI - A strategy for multimodal data integration: application to biomarkers identification in spinocerebellar ataxia. AB - The growing number of modalities (e.g. multi-omics, imaging and clinical data) characterizing a given disease provides physicians and statisticians with complementary facets reflecting the disease process but emphasizes the need for novel statistical methods of data analysis able to unify these views. Such data sets are indeed intrinsically structured in blocks, where each block represents a set of variables observed on a group of individuals. Therefore, classical statistical tools cannot be applied without altering their organization, with the risk of information loss. Regularized generalized canonical correlation analysis (RGCCA) and its sparse generalized canonical correlation analysis (SGCCA) counterpart are component-based methods for exploratory analyses of data sets structured in blocks of variables. Rather than operating sequentially on parts of the measurements, the RGCCA/SGCCA-based integrative analysis method aims at summarizing the relevant information between and within the blocks. It processes a priori information defining which blocks are supposed to be linked to one another, thus reflecting hypotheses about the biology underlying the data blocks. It also requires the setting of extra parameters that need to be carefully adjusted.Here, we provide practical guidelines for the use of RGCCA/SGCCA. We also illustrate the flexibility and usefulness of RGCCA/SGCCA on a unique cohort of patients with four genetic subtypes of spinocerebellar ataxia, in which we obtained multiple data sets from brain volumetry and magnetic resonance spectroscopy, and metabolomic and lipidomic analyses. As a first step toward the extraction of multimodal biomarkers, and through the reduction to a few meaningful components and the visualization of relevant variables, we identified possible markers of disease progression. PMID- 29106466 TI - Nivolumab in HIV-related non-small-cell lung cancer. PMID- 29106464 TI - Application of single-cell sequencing in human cancer. AB - Precision medicine is emerging as a cornerstone of future cancer care with the objective of providing targeted therapies based on the molecular phenotype of each individual patient. Traditional bulk-level molecular phenotyping of tumours leads to significant information loss, as the molecular profile represents an average phenotype over large numbers of cells, while cancer is a disease with inherent intra-tumour heterogeneity at the cellular level caused by several factors, including clonal evolution, tissue hierarchies, rare cells and dynamic cell states. Single-cell sequencing provides means to characterize heterogeneity in a large population of cells and opens up opportunity to determine key molecular properties that influence clinical outcomes, including prognosis and probability of treatment response. Single-cell sequencing methods are now reliable enough to be used in many research laboratories, and we are starting to see applications of these technologies for characterization of human primary cancer cells. In this review, we provide an overview of studies that have applied single-cell sequencing to characterize human cancers at the single-cell level, and we discuss some of the current challenges in the field. PMID- 29106467 TI - Marginal quantile regression for dependent data with a working odds-ratio matrix. AB - Dependent data arise frequently in applied research and several approaches to adjusting for the dependence among observations have been proposed in quantile regression. Cluster bootstrap is generally inefficient and computationally demanding, especially when the number of clusters is large. When the primary interest is on marginal quantiles, estimating equations have been proposed that estimate a working correlation matrix from the regression residuals' sign. However, the Pearson's correlation coefficient is an inadequate measure of dependence between binary variables because its range depends on their marginal probabilities. Instead, we propose to model the working correlation matrix through odds ratios. Different working structures can be easily estimated by suitable logistic regression models. These structures can be parametrized to depend on covariates and clusters. Simulations show that the proposed estimator has similar behavior to that of generalized estimating equations applied to regression for the mean. We study marginal quantiles of cognitive behavior with data from a randomized trial for treatment of obsessive compulsive disorder. PMID- 29106468 TI - Endometrial organoids: in vitro models for endometrial research and personalized medicine. PMID- 29106469 TI - DFAST: a flexible prokaryotic genome annotation pipeline for faster genome publication. AB - Summary: We developed a prokaryotic genome annotation pipeline, DFAST, that also supports genome submission to public sequence databases. DFAST was originally started as an on-line annotation server, and to date, over 7000 jobs have been processed since its first launch in 2016. Here, we present a newly implemented background annotation engine for DFAST, which is also available as a standalone command-line program. The new engine can annotate a typical-sized bacterial genome within 10 min, with rich information such as pseudogenes, translation exceptions and orthologous gene assignment between given reference genomes. In addition, the modular framework of DFAST allows users to customize the annotation workflow easily and will also facilitate extensions for new functions and incorporation of new tools in the future. Availability and implementation: The software is implemented in Python 3 and runs in both Python 2.7 and 3.4-on Macintosh and Linux systems. It is freely available at https://github.com/nigyta/dfast_core/under the GPLv3 license with external binaries bundled in the software distribution. An on-line version is also available at https://dfast.nig.ac.jp/. Contact: yn@nig.ac.jp. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29106470 TI - Phenology of the Pine Bark Adelgid, Pineus strobi (Hemiptera: Adelgidae), in White Pine Forests of Southwestern Virginia. AB - The pine bark adelgid, Pineus strobi Hartig (Hemiptera: Adelgidae), is a native herbivore of eastern white pine, Pinus strobus L. (Pinales: Pinaceae), in eastern North America. P. strobi does not appear to have any dominant overwintering lifestage in southwest Virginia, as it does in its northern range. Eggs can be found consistently from late March through early December and may be produced sporadically later throughout the winter during warm periods. Two distinct generations were observed in the spring, after which life stage frequencies overlapped. Adult body size varied seasonally and was greatest in the spring. The present study constitutes the first recording of phenological details of the P. strobi in its southern range, informing biological control efforts aimed at closely related invasive pests. The phenological plasticity observed between northern and southern P. strobi populations provides insight into the potential effects of climate on the population dymanics of this and related species. PMID- 29106471 TI - Kidney function modifies the selection of treatment strategies and long-term survival in stable ischaemic heart disease: insights from the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry. AB - Aims: Patients with chronic kidney disease (CKD) have been under-represented in stable ischaemic heart disease (SIHD) trials despite their heightened risk of cardiovascular mortality. We examine associations between kidney disease, treatment selection, and long-term survival in patients with SIHD. Methods and results: SIHD patients with angiographically significant stenosis (>=70%) were categorized by renal function [dialysis-dependent, severe CKD [estimated glomerular filtration rate (eGFR) < 30], mild-moderate CKD (eGFR 30-59), and no CKD (eGFR >= 60)] and by treatment groups [revascularization <=3 months of angiogram (percutaneous coronary intervention or coronary artery bypass surgery) vs. medical therapy]. The association between renal function category and treatment on long-term survival was examined and adjusted for differences in age, sex, co-morbidities, and coronary anatomy. Of the 17 910 SIHD patients, 0.7% (n = 118) were dialysis-dependent, 1.2% (n = 215) severe CKD, 12.0% (n = 2157) mild moderate CKD, and 86.1% (n = 15420) no CKD. The presence of CKD was associated with significantly lower adjusted odds of receiving revascularization [reference no CKD: dialysis-dependent: odds ratio (OR) 0.52 (0.35, 0.79), severe (non dialysis) CKD: OR 0.54 (0.40, 0.73), and mild-moderate CKD: OR 0.80 (0.71, 0.89)]. Over a median follow-up of 8.0 (interquartile range 3.2) years, patients with progressive CKD had higher long-term mortality (dialysis-dependent, 53.4%; severe CKD, 30.2%; mild-moderate CKD, 22.2%; no CKD, 11.9%, Ptrend < 0.0001). Revascularization was associated with improved long-term survival [adjusted hazard ratio (HR): dialysis-dependent: HR 0.29 (0.15, 0.55), severe CKD: HR 0.63 (0.36, 1.08), mild-moderate CKD: HR 0.49 (0.40, 0.60), and no CKD: HR 0.47 (0.42, 0.52)] (Pinteraction < 0.001). Conclusion: In SIHD, the presence of CKD was accompanied by lower revascularization rates and a higher risk of mortality. However, revascularization in CKD was associated with improved long-term survival. PMID- 29106472 TI - Commentary on: Current Trends in Breast Augmentation: An International Analysis. PMID- 29106474 TI - Open versus closed surgical exposure for permanent impacted canines: a systematic review and meta-analyses. AB - Background: Permanent canines are amongst the teeth most affected by impaction and ectopic eruption. Although impacted canines are often subjected to surgical exposure and alignment with either the open or the closed technique for many decades, their treatment effects have not yet been systematically asssessed. Objectives: The aim of this systematic review was to critically assess whether significant differences exist in the outcomes of the open or closed surgical exposure of impacted canines. Search methods: An unrestricted electronic search of nine databases from inception to December 2016 was performed. Selection criteria methods: Included were randomized or prospective non-randomized studies comparing open versus closed exposure of impacted canines in human patients. Data collection and analysis: After duplicate study selection, data extraction, and risk of bias assessment according to the Cochrane guidelines, random-effects meta analyses of mean differences (MDs) and odds ratios (ORs), including their 95 per cent confidence intervals (CIs) were performed, followed by subgroup and sensitivity analyses. Results: A total of eight unique studies and a total of 433 (30.1% male/59.9% female) patients were included, with an average age of 15.2 years and a total of 453 impacted canines (48.6% and 51.4% in the open and closed exposure, respectively). Open exposure of impacted canines was associated with reduced duration of canine alignment (two studies; MD = -2.14 months; 95% CI = 4.23 to -0.05 months; P < 0.05; moderate heterogeneity and moderate quality) and lower odds of tooth ankylosis (one study; OR = 0.15; 95% CI = 0.03-0.83; P < 0.05; low quality) compared to closed exposure; both findings being independent of canine localization. However, initial alignment of palatally impacted canines took overall significantly longer than labially impacted canines (8.87 versus 4.17 months). Conclusions: Based on existing evidence, open surgical exposure seems to be superior in treatment duration and ankylosis risk over the closed technique. Due to the limited number of small included trials, further research is needed for robust clinical recommendations. Registration: PROSPERO (CRD42016051916). PMID- 29106473 TI - Trends in acute pericarditis hospitalizations and outcomes among the elderly in the USA, 1999-2012. AB - Aims: The elderly are at risk of pericarditis from conditions such as malignancy, renal disease, and after cardiac surgery. However, the burden of pericarditis and, especially, the long-term outcomes associated with pericarditis have not been described before among the elderly. Methods and results: We examined hospitalization rates; in-hospital, 30-day, and 1-year all-cause mortality rates; all-cause 30-day readmission rates; length of stay and health care expenditure for Medicare beneficiaries aged 65 years or older with a principal discharge diagnosis of pericarditis from 1999 to 2012. A total of 45 504 hospitalizations were identified. The hospitalization rate for pericarditis remained stable at 26 per 100 000 person-years across the study period and was consistently higher among men and the oldest old. The adjusted all-cause 30-day mortality rates decreased from 7.6% [95% confidence interval (CI) 6.9-8.2] in 1999 to 5.7% (95% CI 4.5-7.1) in 2012 and all-cause 1-year mortality rates decreased from 19.7% (95% CI 18.8-20.8) in 1999 to 17.3% (95% CI 15.3-20) in 2011 respectively. The 30 day all-cause readmission rate remained unchanged at 18% across the study period. The length of stay ranged from a mean of 5.8 days in 1999 to 5.5 days in 2012. The consumer price index adjusted cost per hospitalization increased from $8404 in 1999 to $9982 in 2012. Conclusion: The hospitalization rate for acute pericarditis has remained unchanged among older adults. Although mortality rates associated with pericarditis have improved, hospitalization for pericarditis continues to signal a high risk of dying within a year. PMID- 29106477 TI - A Note From the Editors. PMID- 29106475 TI - Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Large-Scale Epidemiology: A Primer on -Omic Technologies. AB - Detailed metabolic profiling in large-scale epidemiologic studies has uncovered novel biomarkers for cardiometabolic diseases and clarified the molecular associations of established risk factors. A quantitative metabolomics platform based on nuclear magnetic resonance spectroscopy has found widespread use, already profiling over 400,000 blood samples. Over 200 metabolic measures are quantified per sample; in addition to many biomarkers routinely used in epidemiology, the method simultaneously provides fine-grained lipoprotein subclass profiling and quantification of circulating fatty acids, amino acids, gluconeogenesis-related metabolites, and many other molecules from multiple metabolic pathways. Here we focus on applications of magnetic resonance metabolomics for quantifying circulating biomarkers in large-scale epidemiology. We highlight the molecular characterization of risk factors, use of Mendelian randomization, and the key issues of study design and analyses of metabolic profiling for epidemiology. We also detail how integration of metabolic profiling data with genetics can enhance drug development. We discuss why quantitative metabolic profiling is becoming widespread in epidemiology and biobanking. Although large-scale applications of metabolic profiling are still novel, it seems likely that comprehensive biomarker data will contribute to etiologic understanding of various diseases and abilities to predict disease risks, with the potential to translate into multiple clinical settings. PMID- 29106478 TI - The Relationship Between Physical Activity and Frailty Among U.S. Older Adults Based on Hourly Accelerometry Data. AB - Background/Objectives: Accelerometry measures older adult (in)activity with high resolution. Most studies summarize activity over the entire wear time. We extend prior work by analyzing hourly activity data to determine how frailty and other characteristics relate to activity among older adults. Methods: Using wrist accelerometry data collected from the National Social Life, Health and Aging Project (n = 651), a nationally-representative probability sample of older adults, we used mixed effects linear regression to model the logarithm of hourly counts per minute as a function of an adapted phenotypic frailty score, adjusting for demographic and health characteristics, season, day of week and time of day. Results: Higher frailty scores were associated with modestly lower activity; each frailty point (0-4) corresponded to a 7% lower mean hourly counts per minute. Older age, more comorbidities, male gender, and higher BMI were also associated with lower activity, though the latter was not evident among frail respondents. After adjusting for differences associated with frailty and other covariates, a substantial amount of between-individual variability in activity remained, as well as within-individual variability across days. Conclusion: Our findings indicate that frail elders, men, those who are older, overweight or have multiple comorbidities are most likely to have low activity. However, residual differences between individuals remain larger than the differences associated with frailty and other covariates. We suggest defining individual-specific activity goals and further research to identify the sources of between-individual variability to better understand how activity reflects health status and to permit the development of more effective interventions. PMID- 29106479 TI - Establishing a distributed national research infrastructure providing bioinformatics support to life science researchers in Australia. AB - EMBL Australia Bioinformatics Resource (EMBL-ABR) is a developing national research infrastructure, providing bioinformatics resources and support to life science and biomedical researchers in Australia. EMBL-ABR comprises 10 geographically distributed national nodes with one coordinating hub, with current funding provided through Bioplatforms Australia and the University of Melbourne for its initial 2-year development phase. The EMBL-ABR mission is to: (1) increase Australia's capacity in bioinformatics and data sciences; (2) contribute to the development of training in bioinformatics skills; (3) showcase Australian data sets at an international level and (4) enable engagement in international programs. The activities of EMBL-ABR are focussed in six key areas, aligning with comparable international initiatives such as ELIXIR, CyVerse and NIH Commons. These key areas-Tools, Data, Standards, Platforms, Compute and Training-are described in this article. PMID- 29106476 TI - Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies. AB - Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroscedasticity-robust standard errors for these estimates. We compared several different forms of the standard error for linear and logistic TSRI estimates in simulations and in real-data examples. Among others, we consider standard errors modified from the approach of Newey (1987), Terza (2016), and bootstrapping. In our simulations Newey, Terza, bootstrap, and corrected 2-stage least squares (in the linear case) standard errors gave the best results in terms of coverage and type I error. In the real-data examples, the Newey standard errors were 0.5% and 2% larger than the unadjusted standard errors for the linear and logistic TSRI estimators, respectively. We show that TSRI estimators with modified standard errors have correct type I error under the null. Researchers should report TSRI estimates with modified standard errors instead of reporting unadjusted or heteroscedasticity-robust standard errors. PMID- 29106480 TI - An innovative technique of perventricular device closure of a coronary artery fistula through a left parasternal approach. PMID- 29106481 TI - Blood Concentrations of Persistent Organic Pollutants and Unhealthy Metabolic Phenotypes in Normal-Weight, Overweight, and Obese Individuals. AB - Factors underlying metabolic phenotypes, such as the metabolically healthy but obese phenotype, remain unclear. Differences in metabolic phenotypes particularly, among individuals with a similar body mass index-could be related to concentrations of persistent organic pollutants (POPs). To our knowledge, no studies have analyzed POPs and metabolic phenotypes in normal-weight persons. We investigated the relationships between serum concentrations of POPs and metabolic phenotypes in 860 normal-weight, overweight, and obese participants in the 2002 Catalan Health Interview Survey (Spain). POP concentrations were significantly higher in metabolically unhealthy than in metabolically healthy individuals. In models adjusting for body mass index and other confounders, hexachlorobenzene, beta-hexachlorocyclohexane, and polychlorinated biphenyls were associated with the unhealthy metabolic phenotype and metabolic syndrome. Among normal-weight individuals, the adjusted prevalence ratio of having an unhealthy phenotype for the upper category of the sum of orders of the 6 mentioned POPs (all individually associated with metabolic phenotypes) was 4.1 (95% confidence interval: 1.7, 10.0). Among overweight and obese individuals, the corresponding prevalence ratio for the sum of polychlorinated biphenyls was 1.4 (95% confidence interval: 1.0, 1.8). Our results supported the hypothesis that POP concentrations are associated with unhealthy metabolic phenotypes, not only in obese and overweight individuals but also (and probably more strongly) in normal-weight individuals. PMID- 29106482 TI - Do Not Fear an Implant's Shape: A Single Surgeon's Experience of Over 1200 Round and Shaped Textured Implants in Primary Breast Augmentation. AB - Background: Breast implants can be characterized by their fill material, surface texture, or shape. Whereas long-term good quality studies have provided evidence for the fill material and texture, there is still little consensus for choosing the shape of an implant. Surveys indicate that many surgeons choose only one implant shape, for reasons that may not always agree with outcomes from long-term studies. Objectives: We reviewed the first author's experience over the last six years with both round and anatomical implants, compared the rate of complications with either implant shape, and discussed the importance of keeping an open mind about using both implant shapes for primary breast augmentation. Methods: A review of all consecutive primary breast augmentation patients by the first author over a six-year time period who had a minimum follow up of 6 months after surgery. Results: Six-hundred and forty-eight female patients had 1296 silicone breast implants inserted over the six-year period. Mean age at surgery was 30.5 years and mean BMI was 20.6 kg/m2. All implants were textured, 134 (in 67 patients, 10.3%) were round in shape with mean volume of 338 cc (range, 220-560 cc), while 1162 implants (in 581 patients, 89.7%) were anatomical shaped with a mean volume of 309 cc (range, 140-615 cc). Among these patients, 11.9% (n = 8) with round implants and 9.0% (n = 52) of those with anatomical implants developed complications postoperatively. Conclusions: A single, ideal implant that is suitable for every primary breast augmentation does not exist. The optimum choice of implant shape in any given situation should take into account the patient's physical characteristics, available implant types, patient's desires, and the surgeon's experience. Together with round implants, anatomical devices ought to be considered as one of the tools in the surgeon's toolbox. By choosing to ignore them a priori means that the surgeon will only have access to half of his armamentarium and will therefore be able to offer a limited set of options to his patients. Level of Evidence 4: PMID- 29106483 TI - Corrigendum. PMID- 29106485 TI - Retinal glymphatic system: an explanation for transient retinal layer volume changes? PMID- 29106486 TI - Why the left posterior inferior temporal lobe is needed for word finding. PMID- 29106487 TI - Guillain-Barre syndrome in the 100 years since its description by Guillain, Barre and Strohl. PMID- 29106488 TI - Concordance between interictal MEG and stereo-EEG predicts seizure freedom after epilepsy surgery. PMID- 29106489 TI - Defining retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. PMID- 29106490 TI - Editorial. PMID- 29106492 TI - Centenarians Differ in Their Comorbidity Trends During The 6 Years Before Death Compared to Individuals Who Died in Their 80s or 90s. AB - Background: While compression of morbidity has now been studied in multiple cohorts, we hypothesize that centenarians might also have fewer chronic conditions as well. We assume that individuals who die as centenarians have less comorbidities and have a less steep rise of the number of comorbidities over the final years before death compared to those who died as nonagenarians (90-99 years) or octogenarians (80-89 years of age). Methods: This German cohort study used health insurance data. The data contain complete information on diagnoses and health care transactions for the 6 years prior to death. The sample (N = 1,398; 34,735-person calendar quarters) is comprised of three groups of individuals; those who died as centenarians were compared with random samples of individuals who died as nonagenarians or as octogenarians. Community-dwelling and institutionalized individuals were included. Results: One quarter prior to death, individuals who died as centenarians had, on average, 3.3 comorbidities. Octogenarians had 4.6 comorbidities one quarter prior to death. Further, there was a significant time-to-death by age-at-death interaction (B = -.03, p < .001), where centenarians showed a less steep increase in the number of comorbidities than the comparison groups in their last 6 years prior to death. Conclusions: The lower prevalence of comorbidities in individuals who died as centenarians compared with those who died at a younger age reinforces the notion of centenarians as a selective group. Avoiding the confounding and potentially synergistic effects of having multiple chronic illnesses is likely vital to being able to survive to extreme ages. PMID- 29106491 TI - Short-term outcomes of single- versus multi-port video-assisted thoracic surgery in mediastinal diseases. AB - OBJECTIVES: Although there is growing interest in single-port video-assisted thoracic surgery for a number of thoracic operations, there is still not enough known about its use for mediastinal pathologies. The present study was aimed at assessing the safety and efficacy of single-port video-assisted thoracic surgery in comparison with the multi-port variants in terms of short-term perioperative outcomes. METHODS: From July 2013 to December 2015, 285 consecutive non myasthenic adult patients undergoing single- or multi-port video-assisted thoracic surgery for mediastinal diseases including thymoma were retrospectively reviewed. Patients were stratified depending on whether the pathology was thymoma. A propensity score matching pertaining to the approach used was performed within each stratified category. Perioperative outcomes were compared between matched cohorts. RESULTS: During the study period, 141 (49.5%) patients were treated with single-port thoracoscopic surgery. Preoperative variables were comparable between both pairs of cohorts after matching. No morbidity or mortality occurred, except 1 case of empyema in a 2-port case. Single-port technique exhibited shorter operation time (thymoma: 78.8 vs 120.0 min, P = 0.011; non-thymoma: 78.4 vs 107.9 min, P < 0.001), less intraoperative blood loss (thymoma: 42.0 vs 78.4 ml, P = 0.002; non-thymoma: 46.0 vs 62.2 ml, P = 0.001) and a lower postoperative 10-point visual analogue scale pain score (thymoma: 2.6 vs 3.3, P = 0.026; non-thymoma: 2.4 vs 3.2, P < 0.001) than multi-port techniques in both patient categories. CONCLUSIONS: Single-port video-assisted thoracic surgery is a safe approach for patients with loco-regional mediastinal disease, with potential advantages of shorter operative time, less intraoperative bleeding and less postoperative pain when compared with multi-port techniques. PMID- 29106493 TI - Programmed death-1 inhibition and atherosclerosis: can nivolumab vanish complicated atheromatous plaques? PMID- 29106494 TI - Impact of pulmonary hypertension on long-term outcome in patients with severe aortic stenosis. AB - Aims: Pulmonary hypertension (PH) is common in severe symptomatic left-sided valvular disease, particularly in aging populations. Inconsistent results have been reported concerning the association between PH and adverse outcomes after aortic valve replacement for aortic stenosis (AS). We therefore retrospectively investigated the prognostic significance of PH using peak tricuspid regurgitation velocity (TRV), as defined by the current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines, in a large cohort of patients with severe AS. Methods and results: One thousand and nineteen patients (541 men; mean age 74 +/- 11 years) with severe AS (aortic valve area (AVA) <1 cm2 and/or indexed AVA <0.6 cm2/m2 of body surface area) and LV ejection fraction >=50% were included. Patients were divided into three groups according to the level of their peak TRV at the time of enrolment: Group 1 (n = 695, 68%) when TRV was <=2.8 m/s; Group 2 (n = 212, 21%) when TRV was between 2.9 m/s and 3.4 m/s and Group 3 (n = 112, 11%) when TRV was > 3.4 m/s. Median overall follow-up was 31 [6-182] months. On univariate analysis, overall mortality during follow-up was globally different between groups (P < 0.001). On multivariate analysis, Group 3 (TRV >3.4 m/s) exhibited significant excess mortality after adjustment for covariates of prognostic importance (P = 0.032) and after further adjustment for surgery (P = 0.012), using Group 1 as the reference group. Dividing the whole population into two groups with a 3.4 m/s TRV threshold, overall mortality during follow-up was higher in the PH group [hazard ratio (HR) 1.87; 95% confidence interval [1.37-2.56]; P < 0.001)]. On multivariate analysis, after covariate adjustment, including surgery, Group 3 exhibited major excess mortality (adjusted HR 1.46 [1.10-1.95], P = 0.009). Conclusion: This study demonstrates the negative impact of pulmonary pressure, as assessed by current ESC/ERS guidelines, on long term outcome of patients with severe AS, irrespective of functional status, chronic obstructive pulmonary disease, AS severity and surgery. Baseline TRV should therefore be taken into account in the management of severe AS. PMID- 29106495 TI - The impact of spontaneous ventilation on non-operative lung injury in thoracic surgery: a randomized controlled rabbit model study. AB - OBJECTIVES: One-lung ventilation (OLV) with general anaesthesia may increase adverse effects after thoracic surgery, specifically ventilator-induced lung injury. Spontaneous ventilation (SV) has no mechanical ventilation process, thus, we established a rabbit model to assess non-operative lung injury between OLV and SV. METHODS: Thirty-six rabbits were randomly divided into 6 groups: OLV and SV (0, 2 and 4 h). Blood gas analysis was performed after thoracic surgery. Lung tissue and bronchoalveolar lavage fluid were obtained from the non-operative lung. Pathological injury score in lung tissue and tumour necrosis factor alpha (TNF-alpha) level in bronchoalveolar lavage fluid using enzyme-linked immunosorbent assay were determined. Moreover, messenger RNA and protein of TNF alpha in lung tissue were also determined by quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: Compared with the OLV group, significantly higher partial pressure of carbon dioxide (47.78 +/- 3.57 vs 38.95 +/- 3.88 mmHg, P < 0.01) and partial pressure of oxygen (101.08 +/- 13.1 vs 85.6 +/- 11.07 mmHg, P < 0.01), as well as a significantly lower pathological injury score (6.83 +/- 1.17 vs 8.83 +/- 1.72, P < 0.05), TNF-alpha level in bronchoalveolar lavage fluid (290.32 +/- 29.38 vs 368.43 +/- 31.26 pg/ml, P < 0.01), TNF-alpha messenger RNA (6.31 +/- 1.13 vs 8.6 +/- 1.34, P < 0.01), immunostaining intensity in lung tissue were found at 4 h in the SV group. However, there are no significant differences between OLV and SV groups at 2 h (P > 0.05), except in TNF-alpha messenger RNA. CONCLUSIONS: Based on this rabbit model, SV for thoracic surgery is not inferior to OLV in terms of lung injury. Considering our results, when performing time-consuming thoracic procedures under OLV, surgeons should more closely examine patients for non-operative lung injury postoperatively. PMID- 29106496 TI - Transplantation of brown adipose tissue inhibits atherosclerosis in apoE-/- mice: contribution of the activated FGF-21-adiponectin axis. AB - Aims: Brown adipose tissue (BAT) has been identified as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Methods and results: Interscapular BAT was dissected from 12 week-old wild-type mice and transplanted into the visceral cavity of 12-week-old apoE-/- mice. Oil-red O staining of whole aortas after 3 months of a high cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 20% compared with the sham control mice. A significant increase in oxygen consumption and energy expenditure, concomitant improvement of glucose tolerance, and lower triglyceride levels were observed in BAT transplanted mice; however, serum cholesterol levels showed no difference between the two groups. Homologous transplantation of BAT from apoE-/- mice also showed a significant decrease in atherosclerotic lesion area by 28% compared with the sham control apoE-/- mice without affecting lipid levels, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. In the combination of wild-type donor and apoE-/- recipient mice, both mRNA and protein levels of fibroblast growth factor 21 (FGF-21) were increased significantly in endogenous BAT in BAT-transplanted mice (180 and 38%, respectively, P < 0.05), accompanied by a higher concentration of circulating FGF-21 and noradrenaline (47 and 45%, respectively, P < 0.05). Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice (35%, P < 0.05), and showed an inverse correlation with atherosclerotic lesion area (r = 0.44, P < 0.05). Treatment with the nonselective beta3-adrenergic receptor (AR) blocker completely abolished the anti-atherogenic effect of BAT transplantation and reduced concentrations of circulating FGF-21 and adiponectin to levels comparable with that of vehicle-treated BAT transplanted mice. Conclusions: Our findings demonstrate for the first time that anti-atherogenic action of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21 adiponectin axis. PMID- 29106497 TI - Effect of candesartan and metoprolol on myocardial tissue composition during anthracycline treatment: the PRADA trial. AB - Aims: Anthracycline treatment may cause myocyte loss and expansion of the myocardial extracellular volume (ECV) fraction by oedema and fibrosis. We tested the hypotheses that adjuvant treatment for early breast cancer with the anthracycline epirubicin is dose dependently associated with increased ECV fraction and total ECV, as well as reduced total myocardial cellular volume, and that these changes could be prevented by concomitant angiotensin or beta adrenergic blockade. Methods and results: PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) was a 2 * 2 factorial, placebo controlled, double-blinded trial of candesartan and metoprolol. Sixty-nine women had valid ECV measurements. ECV fraction, total ECV, and total cellular volume were measured by cardiovascular magnetic resonance before and at the completion of anthracycline therapy. ECV fraction increased from 27.5 +/- 2.7% to 28.6 +/- 2.9% (P = 0.002). A cumulative doxorubicin equivalent dose of 268 mg/m2 was associated with greater increase in ECV fraction than doses <268 mg/m2 (mean change 3.4% [95% confidence interval (CI) 1.2, 5.5] vs. 0.7% [95% CI 0.0, 1.5], P = 0.006), as well as greater increase in total ECV (1.9 mL [95% CI 0.4, 3.5] vs. 0.1 mL [95% CI -0.6, 0.8], P = 0.04). In patients receiving candesartan, total cellular volume decreased (-3.5 mL [95% CI - 4.7, -2.2], P < 0.001) while in patients not receiving candesartan, it remained unchanged (P = 0.45; between group difference P = 0.003). Conclusions: Anthracycline therapy is associated with dose-dependent increase in ECV fraction and total ECV. Concomitant treatment with candesartan reduces left ventricular total cellular volume. PMID- 29106498 TI - Introducing occupational health management in the German Armed Forces. AB - Holistic approaches to workplace health promotion (WHP) within the military setting are challenging. In 2015, the German Ministry of Defense initiated a 6 month pilot study of WHP in the Federal Armed Forces. The pilot study was to identify organizational challenges that should be addressed before the Ministry implemented a comprehensive occupational health management policy in all departments. Eleven diverse departments were selected to participate in a WHP program that addressed physical activity, diet, stress management and addiction prevention. As part of the evaluation concept, we interviewed coordinators, and department heads focusing on transfer factors from the perspective of the implementers. All coordinators and their department heads or deputies participated in semi-structured face-to-face on-site interviews. The data were analyzed based on qualitative content analysis. The coordinators (officers with sports science degree) seemed fully prepared and capable to master the new task. They experienced difficulties in adapting WHP activities to local structures and needs, and complications in administering modular activities. Department heads described conflict regarding human resources between the military mission and the implementation of WHP. Commitment to WHP was a strong facilitator. The interviews identified various barriers related to support by middle management (supervisors) and specific work conditions (e.g. shift work). If occupational health management is to be successfully implemented on a large scale, conceptional and practically collaboration is necessary between WHP and occupational safety and health, and organization and leadership, respectively. Supervisors will benefit from open communication about compensation for the release time of their subordinates to attend WHP. PMID- 29106499 TI - Autism Related Neuroligin-4 Knockout Impairs Intracortical Processing but not Sensory Inputs in Mouse Barrel Cortex. AB - Neuroligin-4 (Nlgn4) is a cell adhesion protein that regulates synapse organization and function. Mutations in human NLGN4 are among the causes of autism spectrum disorders. In mouse, Nlgn4 knockout (KO) perturbs GABAergic synaptic transmission and oscillatory activity in hippocampus, and causes social interaction deficits. The complex profile of cellular and circuit changes that are caused by Nlgn4-KO is still only partly understood. Using Nlgn4-KO mice, we found that Nlgn4-KO increases the power in the alpha frequency band of spontaneous network activity in the barrel cortex under urethane anesthesia in vivo. Nlgn4-KO did not affect single-whisker-induced local field potentials, but suppressed the late evoked multiunit activity in vivo. Although Nlgn4-KO did not affect evoked EPSCs in layer 4 (L4) spiny stellate cells in acute thalamocortical slices elicited by electrical stimulation of thalamocortical inputs, it caused a lower frequency of both miniature (m) IPSCs and mEPSCs, and a decrease in the number of readily releasable vesicles at GABAergic and glutamatergic connections, weakening both excitatory and inhibitory transmission. However, Nlgn4 deficit strongly suppresses glutamatergic activity, shifting the excitation-inhibition balance to inhibition. We conclude that Nlgn4-KO does not influence the incoming whisker-mediated sensory information to the barrel cortex, but modifies intracortical information processing. PMID- 29106501 TI - Corrigendum to: Changes in oral anticoagulation for elective cardioversion: results from a European cardioversion registry. PMID- 29106500 TI - Familial co-occurrence of congenital heart defects follows distinct patterns. AB - Aims: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis. Methods and results: We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes. Conclusion: Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes. PMID- 29106502 TI - Isolation of highly thermostable beta-xylosidases from a hot spring soil microbial community using a metagenomic approach. AB - The DNA extracted from a high-temperature environment in which micro-organisms are living will be a good source for the isolation of thermostable enzymes. Using a metagenomic approach, we aimed to isolate thermostable beta-xylosidases that will be exploited for biofuel production from lignocellulosic biomass. DNA samples obtained from the soil near a spout of a hot spring (70 degrees C, pH7.2) were subjected to sequencing, which generated a total of 84.2 Gbp with 967,925 contigs of >500 bp in length. Similarity search for beta-xylosidase in the contigs revealed the presence of 168 candidate sequences, each of which may have arisen from more than one gene. Individual genes were amplified by PCR using sequence-specific primers. The resultant DNA fragments were cloned and introduced into Escherichia coli BL21 Star(DE3). Consequently, 269 proteins were successfully expressed in the E. coli cells and then examined for beta-xylosidase activity. A total of 82 proteins exhibited beta-xylosidase activity at 50 degrees C, six of which retained the activity even at 90 degrees C. Out of the six, three proteins were originated from a single candidate sequence, AR19M-311. An amino acid sequence comparison suggested the amino acid residues that appeared to be crucial for thermal stability of the enzymes. PMID- 29106503 TI - Induction of non-apoptotic programmed cell death by oncogenic RAS in human epithelial cells and its suppression by MYC overexpression. AB - Oncogenic mutations of RAS genes, found in about 30% of human cancers, are considered to play important roles in cancer development. However, oncogenic RAS can also induce senescence in mouse and human normal fibroblasts. In some cell lines, oncogenic RAS has been reported to induce non-apoptotic programed cell death (PCD). Here, we investigated effects of oncogenic RAS expression in several types of normal human epithelial cells. Oncogenic RAS but not wild-type RAS stimulated macropinocytosis with accumulation of large-phase lucent vacuoles in the cytoplasm, subsequently leading to cell death which was indistinguishable from a recently proposed new type of PCD, methuosis. A RAC1 inhibitor suppressed accumulation of macropinosomes and overexpression of MYC attenuated oncogenic RAS induced such accumulation, cell cycle arrest and cell death. MYC suppression or rapamycin treatment in some cancer cell lines harbouring oncogenic mutations in RAS genes induced cell death with accumulation of macropinosomes. These results suggest that this type of non-apoptotic PCD is a tumour-suppressing mechanism acting against oncogenic RAS mutations in normal human epithelial cells, which can be overcome by MYC overexpression, raising the possibility that its induction might be a novel approach to treatment of RAS-mutated human cancers. PMID- 29106505 TI - Successful Treatment With Vedolizumab in a Patient With Chronic Refractory Pouchitis and Primary Sclerosing Cholangitis. PMID- 29106504 TI - Parvalbumin-Positive Interneurons Regulate Neuronal Ensembles in Visual Cortex. AB - For efficient cortical processing, neural circuit dynamics must be spatially and temporally regulated with great precision. Although parvalbumin-positive (PV) interneurons can control network synchrony, it remains unclear how they contribute to spatio-temporal patterning of activity. We investigated this by optogenetic inactivation of PV cells with simultaneous two-photon Ca2+ imaging from populations of neurons in mouse visual cortex in vivo. For both spontaneous and visually evoked activity, PV interneuron inactivation decreased network synchrony. But, interestingly, the response reliability and spatial extent of coactive neuronal ensembles during visual stimulation were also disrupted by PV cell suppression, which reduced the functional repertoire of ensembles. Thus, PV interneurons can control the spatio-temporal dynamics of multineuronal activity by functionally sculpting neuronal ensembles and making them more different from each other. In doing so, inhibitory circuits could help to orthogonalize multicellular patterns of activity, enabling neural circuits to more efficiently occupy a higher dimensional space of potential dynamics. PMID- 29106506 TI - The age-adjusted Charlson comorbidity index is a better predictor of survival in operated lung cancer patients than the Charlson and Elixhauser comorbidity indices. AB - OBJECTIVES: To compare the prognostic performance between different comorbidity assessments of survival in patients with operated lung cancer. METHODS: A total of 4508 lung cancer patients treated by surgery between 2003 and 2012 were identified through Taiwan's National Health Insurance Research Database. Information on pre-existing comorbidities prior to the cancer diagnosis was obtained and adapted to the Charlson comorbidity index, age-adjusted Charlson comorbidity index (ACCI) and Elixhauser comorbidity index scores. The influence on survival was analysed using a Cox proportional hazard model. The discriminatory ability of the comorbidity indices were evaluated using Akaike information criterion and Harrell's C-statistic. RESULTS: The mean age of the study cohort was 64.95 +/- 11.15 years, and 56.28% of the patients were male. The median follow-up time was 2.59 years, and the 3-year overall survival was 73.94%. Among these patients, 2134 (47.3%) patients received adjuvant therapy. The Charlson comorbidity index and ACCI scores correlated well with survival and higher scores were associated with an increased 3-year mortality risk (hazard ratio = 1.21, 95% confidence interval = 1.03-1.42 and hazard ratio = 1.43, 95% confidence interval = 1.08-1.90, respectively) in multivariate analysis. The ACCI scores provided better discriminatory ability with a smaller Akaike information criterion and greater Harrell's C-statistic for 3-year overall survival compared to the Charlson comorbidity index or Elixhauser comorbidity index scores. CONCLUSIONS: The operated lung cancer patients with severe comorbidities were associated with worse survival. The ACCI appears to be a more appropriate prognostic indicator and should be considered for use in clinical practice. PMID- 29106507 TI - Pedicled and free flaps for intrathoracic fistula management. AB - OBJECTIVES: Intrathoracic fistulae are among the potential sequelae of radiation therapy, empyema and abscess clearance and surgical tumour resections. Interdisciplinary plastic-reconstructive flap surgery is a helpful tool for the successful treatment of intrathoracic fistulae. METHODS: From February 2006 to April 2016, 13 patients (3 females and 10 males) underwent flap surgery for bronchial (n = 5), tracheal (n = 2), oesophageal (n = 2), post-pneumonectomy bronchopleural fistula (n = 2), tracheo-oesophageal (n = 1), gastrobronchial (n = 1) and oesophagobronchial (n = 1) fistulae. Patient characteristics, identified pathogenic micro-organisms, treatment and decision criteria, long-term outcome and postoperative complications were evaluated by analysing patient charts and surgical reports. RESULTS: The mean age of the 13 patients who underwent reconstructive surgery was 55.5 years (range: 42-66 years). The median follow-up time was 31.4 months (range: 2-96 months). American Society of Anaesthesiologists classification was II for 1 patient, III for 8 patients and IV for 4 patients. In total, 18 flaps were performed (7 latissimus dorsi pedicled flaps, 7 pectoralis major pedicled flaps, 2 rectus abdominis myocutaneous flaps, 1 free temporo parietal fascia flap and 1 intercostal muscle flap). A second flap was indicated in 5 cases (38.5%) due to fistula recurrence; of these, 1 patient developed a bronchial fistula after successful reconstruction of a gastrobronchial fistula. Eight of the 13 patients (61.5%) were evaluated postoperatively at regular intervals for at least 1 year and showed no signs of fistula recurrence. CONCLUSIONS: Our study showed that plastic-reconstructive flap surgery, although associated with significant morbidity and mortality, can be a life-saving tool for intrathoracic fistula reconstruction. Clinical Trial Registration: DRKS00010447. PMID- 29106508 TI - Gut region influences the diversity and interactions of bacterial communities in pikas (Ochotona curzoniae and Ochotona daurica). AB - The mammalian microbial communities in the gastrointestinal tract (GIT) play important roles in host nutrition and health. However, we still lack an understanding of how these communities are organized across GIT in natural environments. Here, using 16S rRNA gene sequencing, we analyzed the bacterial community diversity, network interactions and ecosystem stability across five gut regions (mouth, stomach, small intestine, cecum and colon) emanating from two common pika species in China, including Plateau pikas (Ochotona curzoniae) inhabiting high-altitude regions, as well as Daurian pikas (O. daurica) occupying low-altitude areas. The relative abundances of dominant Bacteroidetes and Firmicutes exhibited an increasing trend from mouth to colon. Cecum and colon harbored higher bacterial diversity compared with other anatomical regions. Gut region significantly influenced the structure of bacterial communities in the GIT. Network analysis indicated that topological features showed marked variations among gut regions. Interestingly, the ecosystem stability of bacterial communities increased gradually from mouth to colon. Our results suggest that gut region influences the diversity, structure and network interactions of bacterial communities in pikas. For hindgut-fermenting herbivorous mammals, relatively higher bacterial diversity and ecosystem stability in the cecum may provide a favorable condition for the fermentation of indigestible plant polysaccharides. PMID- 29106509 TI - fMRI-based Neuronal Response to New Odorants in the Newborn Brain. AB - The sense of smell is one of the oldest and the most primitive senses mammals possess, it helps to evaluate the surrounding environment. From birth, smell is an important sensory modality, highly relevant for neonatal behavioral adaptation. Even though human newborns seem to be able to perceive and react to olfactory stimuli, there is still a lack of knowledge about the ontogeny of smell and the underlying central processing involved in odor perception in newborns. Brain networks involved in chemosensory perception of odorants are well described in adults, however in newborns there is no evidence that central olfaction is functional given the largely unmyelinated neonatal central nervous system. To examine this question, we used functional magnetic resonance imaging (fMRI) in the newborn to characterize cortical response to olfactory and trigeminal odorants. Here we show that brain response to odors can be measured and localized using functional MRI in newborns. Furthermore, we found that the developing brain, only few days after birth, processes new artificial odorants in similar cortical areas than adults, including piriform cortex, orbitofrontal cortex and insula. Our work provides evidence that human olfaction at birth relies on brain functions that involve all levels of the cortical olfactory system. PMID- 29106510 TI - Yarrowia lipolytica: a model yeast for citric acid production. AB - Every year more than 2 million tons of citric acid (CA) are produced around the world for industrial uses. Although initially extracted from citrus, the low profitability of the process and the increasing demand soon stimulated the search for more efficient methods to produce CA. Currently, most world CA demand (99%) is satisfied by fermentations with microorganisms, especially filamentous fungi and yeasts. CA production with yeasts has certain advantages over molds (e.g. higher productivity and easier cultivation), which in the last two decades have triggered a clear increase in publications and patents devoted to the use of yeasts in this field. Yarrowia lipolytica has become a model yeast that proved to be successful in different production systems. Considering the current interest evidenced in the literature, the most significant information on CA production using Y. lipolytica is summarized. The relevance on CA yields of key factors such as strains, media formulation, environmental conditions and production regimes is thoroughly discussed, with particular focus on increasing CA productivity. Besides, the possibility of tuning the mentioned variables to reduce concomitant isocitric acid production-the biggest disadvantage of using yeasts-is analyzed. Available methods for CA purification/quantification are also discussed. PMID- 29106511 TI - Enhanced sodium acetate tolerance in Saccharomyces cerevisiae by the Thr255Ala mutation of the ubiquitin ligase Rsp5. AB - Sodium and acetate inhibit cell growth and ethanol fermentation by different mechanisms in Saccharomyces cerevisiae. We identified the substitution of a conserved Thr255 to Ala (T255A) in the essential Nedd4-family ubiquitin ligase Rsp5, which enhances cellular sodium acetate tolerance. The T255A mutation selectively increased the resistance of cells against sodium acetate, suggesting that S. cerevisiae cells possess an Rsp5-mediated mechanism to cope with the composite stress of sodium and acetate. The sodium acetate tolerance was dependent on the extrusion of intracellular sodium ions by the plasma membrane localized sodium pumps Ena1, Ena2, and Ena5 (Ena1/2/5) and two known upstream regulators: the Rim101 pH signaling pathway and the Hog1 mitogen-activated protein kinase. However, the T255A mutation affected neither the ubiquitination level of the Rsp5 adaptor protein Rim8 nor the phosphorylation level of Hog1. These data raised the possibility that Rsp5 enhances the function of Ena1/2/5 specifically in response to sodium acetate through an unknown mechanism other than ubiquitination of Rim8 and activation of Hog1-mediated signaling. Also, an industrial yeast strain that expresses the T255A variant exhibited increased initial fermentation rates in the presence of sodium acetate. Hence, this mutation has potential for the improvement of bioethanol production from lignocellulosic biomass. PMID- 29106513 TI - Effect of orthodontic treatment on periodontal clinical attachment: a systematic review and meta-analysis. AB - Background: Insertion of orthodontic fixed appliances has been known to induce a mostly transient qualitative and quantitative alteration of the intraoral microbiota. However, the extent to which treatment with fixed appliances might have a lasting adverse effect on the periodontal attachment of the teeth has not yet been investigated in an evidence-based manner. Objectives: Aim of this systematic review was to assess the effect of comprehensive treatment with fixed orthodontic appliances on clinical attachment levels of adolescent and adult periodontally healthy patients. Search methods: Seven databases were searched from inception to February 2017. Selection criteria: Prospective non-randomized longitudinal clinical studies. Data collection and analysis: After duplicate study selection, data extraction, and risk of bias assessment according to the Cochrane guidelines, Paule-Mandel random-effects meta-analyses of the clinical attachment loss and its 95 per cent confidence intervals (CIs) were calculated. Results: A total of 9 trials were identified that included 335 treated patients (at least 34 per cent male / 66 per cent female) with an average age of 22.6 years. The average pooled clinical attachment loss was 0.11 mm (9 studies; 335 patients; 95 per cent CI = 0.12 mm gain to 0.34 mm loss; P = 0.338) with high heterogeneity. Furthermore, one study hinted that a small amount of clinical attachment might be gained by intrusion of upper incisors. Additional analyses indicated that the results were robust to addition of untreated patient groups, while patient age and timing of outcome measurement might play an important role. Conclusions: According to existing evidence from longitudinal clinical studies orthodontic treatment with fixed appliances has little to no clinically relevant effect on periodontal clinical attachment levels. Registration: PROSPERO (CRD42017057042). Funding: None. PMID- 29106514 TI - Functional role of PLCE1 intronic insertion variant associated with susceptibility to esophageal squamous cell carcinoma. AB - Genome-wide association studies (GWAS) have consistently identified PLCE1 as esophageal squamous cell carcinoma (ESCC) susceptibility gene; however, the functional role of PLCE1 variants remains to be verified. In this study, we performed fine mapping of the PLCE1 region using our previous ESCC GWAS data and identified 33 additional risk variants in this susceptibility locus. Here, we report the functional characterization of a four-nucleotide insertion/deletion variation (rs71031566 C----/CATTT) in PLCE1 that was associated with risk of developing ESCC. We demonstrate for the first time that rs71031566[CATTT] insertion creates a silencer element, repressing PLCE1 transcription via long range interaction with PLCE1 promoter mediated by OCT-2 binding. PLCE1 is down regulated in majority of clinical ESCC samples and overexpression of PLCE1 in ESCC cells suppresses cell growth in vitro and in vivo, suggesting a tumor suppressor role of this gene. Therefore, repression of PLCE1 transcription may be the underlying mechanism for the rs71031566[CATTT] variant to be susceptible to ESCC. PMID- 29106515 TI - Communities driving change: evaluation of an Aboriginal driver licensing programme in Australia. AB - The Driving Change programme was developed to facilitate access to licensing in Aboriginal communities in Australia. This process evaluation aimed to explore whether Driving Change was implemented as intended and was addressing the needs of the communities. A mixed methods approach was used, with triangulation of client data (n = 984), semi-structured interviews (n = 18) and client discussion groups (n = 21). Descriptive and regression analyses of quantitative and thematic analysis of qualitative data were drawn together to develop an integrated understanding of implementation barriers and facilitators. The programme reached 984 clients, with the majority from the target age group 16-24 years (56-89%). In multivariate analysis, clients who had supervised driving practice were 2.4 times more likely to attain a licence (95% CI: 1.9-3.1) and clients who received a high level of case management were 1.8 times more likely to progress to attain a licence than those who received low levels of case management (95% CI: 1.3-2.6). Implementation was facilitated by community partnerships and this was attributed to local delivery, Aboriginal leadership, connections with community networks and community ownership of solutions. Driving Change is engaging communities and reaching clients with a high level of need for licensing support. The programme is working with communities, benefiting from the input of cultural values and sharing ownership of local solutions. Community partnerships were critical to successfully supporting clients to overcome challenging barriers to participation. The learnings from this programme are relevant to complex community programme implementation and evaluation, particularly with diverse or hard to reach populations. PMID- 29106512 TI - Interventions and approaches to integrating HIV and mental health services: a systematic review. AB - Background: The frequency in which HIV and AIDS and mental health problems co exist, and the complex bi-directional relationship between them, highlights the need for effective care models combining services for HIV and mental health. Here, we present a systematic review that synthesizes the literature on interventions and approaches integrating these services. Methods: This review was part of a larger systematic review on integration of services for HIV and non communicable diseases. Eligible studies included those that described or evaluated an intervention or approach aimed at integrating HIV and mental health care. We searched multiple databases from inception until October 2015, independently screened articles identified for inclusion, conducted data extraction, and assessed evaluative papers for risk of bias. Results: Forty-five articles were eligible for this review. We identified three models of integration at the meso and micro levels: single-facility integration, multi-facility integration, and integrated care coordinated by a non-physician case manager. Single-site integration enhances multidisciplinary coordination and reduces access barriers for patients. However, the practicality and cost-effectiveness of providing a full continuum of specialized care on-site for patients with complex needs is arguable. Integration based on a collaborative network of specialized agencies may serve those with multiple co-morbidities but fragmented and poorly coordinated care can pose barriers. Integrated care coordinated by a single case manager can enable continuity of care for patients but requires appropriate training and support for case managers. Involving patients as key actors in facilitating integration within their own treatment plan is a promising approach. Conclusion: This review identified much diversity in integration models combining HIV and mental health services, which are shown to have potential in yielding positive patient and service delivery outcomes when implemented within appropriate contexts. Our review revealed a lack of research in low- and middle- income countries, and was limited to most studies being descriptive. Overall, studies that seek to evaluate and compare integration models in terms of long term outcomes and cost-effectiveness are needed, particularly at the health system level and in regions with high HIV and AIDS burden. PMID- 29106516 TI - Cost-effectiveness of Bezlotoxumab Compared With Placebo for the Prevention of Recurrent Clostridium difficile Infection. AB - Background: Clostridium difficile infection (CDI) is the most commonly recognized cause of recurrent diarrhea. Bezlotoxumab, administered concurrently with antibiotics directed against C. difficile (standard of care [SoC]), has been shown to reduce the recurrence of CDI, compared with SoC alone. This study aimed to assess the cost-effectiveness of bezlotoxumab administered concurrently with SoC, compared with SoC alone, in subgroups of patients at risk of recurrence of CDI. Methods: A computer-based Markov health state transition model was designed to track the natural history of patients infected with CDI. A cohort of patients entered the model with either a mild/moderate or severe CDI episode, and were treated with SoC antibiotics together with either bezlotoxumab or placebo. The cohort was followed over a lifetime horizon, and costs and utilities for the various health states were used to estimate incremental cost-effectiveness ratios (ICERs). Both deterministic and probabilistic sensitivity analyses were used to test the robustness of the results. Results: The cost-effectiveness model showed that, compared with placebo, bezlotoxumab was associated with 0.12 quality adjusted life-years (QALYs) gained and was cost-effective in preventing CDI recurrences in the entire trial population, with an ICER of $19824/QALY gained. Compared with placebo, bezlotoxumab was also cost-effective in the subgroups of patients aged >=65 years (ICER of $15298/QALY), immunocompromised patients (ICER of $12597/QALY), and patients with severe CDI (ICER of $21430/QALY). Conclusions: Model-based results demonstrated that bezlotoxumab was cost-effective in the prevention of recurrent CDI compared with placebo, among patients receiving SoC antibiotics for treatment of CDI. PMID- 29106517 TI - TPD52L2 impacts proliferation, invasiveness and apoptosis of glioblastoma cells via modulation of wnt/beta-catenin/snail signaling. AB - Intratumoral heterogeneity greatly hinders efficiency of target therapy in glioblastoma (GBM). To decipher the underlying mechanisms of heterogeneity, patient-derived adult GBM cells were separately isolated from margins of T1 gadolinium enhancing tumor lesions (PNCs) and T1 gadolinium enhancing core lesions (ECs). Single clone culture was conducted in ECs and U87MG cell line to screen clones with distinct biological phenotypes. Single cell clones with diverse phenotypes were simultaneously separated from ECs and U87 cell line. PNCs, GCs(H) and U87(H) exhibited longer cellular protrusion than ECs, GCs(L) and U87(L), respectively. Cell strains with longer protrusion exhibited higher invasive ability and lower sensitivity to temozolomide (TMZ) and radiation. Subsequently, TPD52L2 was verified as the functional protein to regulate the cellular heterogeneity by the proteomics analysis. Downregulation of TPD52L2 enhanced cell invasion whereas inhibited cell proliferation rate and sensitivity to chemotherapy in vivo and in vitro, this condition was reversed when TPD52L2 was overexpressed. The invasiveness was facilitated by up-regulating CTNNB1/beta catenin and SNAI1/Snail mediated EMT process. In addition, the clinical data of 88 GBM cases in our neurosurgery center was analyzed to reveal the influence of TPD52L2 in the prognosis of GBM. Low expression of TPD52L2 exacerbated prognosis of GBM patients received standard radiotherapy plus concomitant and adjuvant TMZ (Stupp strategy). Taken together, TPD52L2 is an important biomarker influencing GBM prognosis. PMID- 29106519 TI - Desmocollin 1 is abundantly expressed in atherosclerosis and impairs high-density lipoprotein biogenesis. AB - Aims: The biogenesis of high-density lipoprotein (HDL) particles by cholesterol laden foam cells in atherosclerotic lesions is crucial for the removal of excess cholesterol from the lesions. Impairment in the HDL biogenic process contributes to the progression of atherosclerosis. The aim of this study is to identify novel cellular factors regulating HDL biogenesis. Methods and results: HDL biogenesis is a process of apolipoprotein (apo)-mediated solubilization of specific plasma membrane (PM) microdomains generated in cholesterol-accumulated cells. We established a new method to isolate PM microdomains interacting with the major HDL protein constituent, apoA-I. Lipidomic and proteomic analyses of an isolated PM microdomain revealed that apoA-I binds to cholesterol-rich and desmocollin 1 (DSC1)-containing microdomains. In this novel apoA-I binding microdomain, DSC1 binds and prevents apoA-I from interacting with another PM microdomain created by adenosine triphosphate-binding cassette transporter A1 (ABCA1) for the formation of HDL. Inhibition of apoA-I-DSC1 binding by silencing DSC1 expression or using DSC1 blocking antibodies increases apoA-I accessibility to ABCA1-created microdomains and thus enhances HDL biogenesis. Importantly, DSC1 is abundantly expressed in macrophages and human atherosclerotic lesions, suggesting that DSC1 may contribute to cholesterol accumulation in atherosclerotic lesions by sequestering apoA-I and impairing HDL biogenesis. Conclusions: The binding of apoA-I to two functionally opposing PM microdomains, ABCA1 and DSC1 domains, suggests that HDL biogenesis and PM cholesterol levels may be regulated by the relative abundance of the two domains and that novel HDL biogenic therapies may be developed by targeting DSC1. PMID- 29106518 TI - Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD. AB - Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrbeta and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health. PMID- 29106520 TI - Increased expression of Qnr is sufficient to confer clinical resistance to ciprofloxacin in Escherichia coli. AB - Background: Ciprofloxacin, a fluoroquinolone, targets two essential bacterial enzymes, DNA gyrase and topoisomerase IV. Plasmid-borne qnr genes, encoding proteins that protect DNA gyrase and topoisomerase IV from inhibition by fluoroquinolones, contribute to resistance development. However, the presence of a plasmid-borne qnr gene alone is insufficient to confer clinical resistance. Objectives: We asked whether the level of expression of qnr was a limiting factor in its ability to confer clinical resistance and whether expression could be increased without reducing fitness or viability. Methods: qnrB and qnrS were recombineered onto the chromosome of Escherichia coli under the control of constitutive promoters of various strengths. Expression was measured by qPCR, MIC and relative fitness as a function of expression level were determined. Results: For both qnr genes there was a positive relationship between the level of qnr mRNA and the MIC of ciprofloxacin. The highest MICs achieved with qnrB or qnrS as the sole resistance determinant were 0.375 and 1 mg/L, respectively, and were reached at expression levels that did not affect growth rate or viability. The qnrS-mediated MIC is above the EUCAST clinical breakpoint for resistance to ciprofloxacin. In the absence of Lon protease activity, overexpression of qnr genes was associated with high fitness cost, possibly explaining observations of toxicity in other genetic backgrounds. Conclusions: The ability to generate a high MIC without incurring a fitness cost shows that, in an appropriate genetic context, qnrS has the potential to generate clinical resistance to ciprofloxacin in one step. PMID- 29106521 TI - Solving the puzzle of yeast survival in ephemeral nectar systems: exponential growth is not enough. AB - Flower nectar is a sugar-rich ephemeral habitat for microorganisms. Nectar-borne yeasts are part of the microbial community and can affect pollination by changing nectar chemistry, attractiveness to pollinators or flower temperature if yeast population densities are high. Pollinators act as dispersal agents in this system; however, pollination events lead potentially to shrinking nectar yeast populations. We here examine how sufficiently high cell densities of nectar yeast can develop in a flower. In laboratory experiments, we determined the remaining fraction of nectar yeast cells after nectar removal, and used honeybees to determine the number of transmitted yeast cells from one flower to the next. The results of these experiments directly fed into a simulation model providing an insight into movement and colonization ecology of nectar yeasts. We found that cell densities only reached an ecologically relevant size for an intermediate pollination probability. Too few pollination events reduce yeast inoculation rate and too many reduce yeast population size strongly. In addition, nectar yeasts need a trait combination of at least an intermediate growth rate and an intermediate remaining fraction to compensate for highly frequent decimations. Our results can be used to predict nectar yeast dispersal, growth and consequently their ecological effects. PMID- 29106522 TI - Spontaneous isolated dissection of the right mediastinal bronchial artery with posterior mediastinal haematoma. PMID- 29106523 TI - Combining Watchman left atrial appendage closure and catheter ablation for atrial fibrillation: multicentre registry results of feasibility and safety during implant and 30 days follow-up. AB - Aims: Long-term results from catheter ablation therapy for atrial fibrillation (AF) remain uncertain and clinical practice guidelines recommend continuation of long-term oral anticoagulation in patients with a high stroke risk. Left atrial appendage closure (LAAC) with Watchman has emerged as an alternative to long-term anticoagulation for patients accepting of the procedural risks. We report on the initial results of combining catheter ablation procedures for AF and LAAC in a multicentre registry. Methods and results: Data were pooled from two prospective, real-world Watchman LAAC registries running in parallel in Europe/Middle East/Russia (EWOLUTION) and Asia/Australia (WASP) between 2013 and 2015. Of the 1140 patients, 139 subjects at 10 centres underwent a concomitant AF ablation and LAAC procedure. The mean CHA2DS2-VASc score was 3.4 +/- 1.4 and HAS-BLED score 1.5 +/- 0.9. Successful Watchman implantation was achieved in 100% of patients. The overall 30-day serious adverse event (SAE) rate was 8.7%, with the device and/or procedure-related SAE rate of 1.4%. One pericardial effusion required percutaneous drainage, but there were no strokes, device embolization, or deaths at 30 days. The 30-day bleeding SAE rate was 2.9% with 55% of patients prescribed NOAC and 38% taking warfarin post-procedure. Conclusion: The outcomes from these international, multicentre registries support the feasibility and safety of performing combined procedures of ablation and Watchman LAAC for patients with non-valvular AF and high stroke risk. Further data are needed on long-term outcomes for the hybrid technique on all-cause stroke and mortality. PMID- 29106524 TI - Cardiac myocyte beta3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signaling. AB - Aims: Human and mouse cardiac beta3-adrenergic receptors (beta3AR) exert antipathetic effects to those of beta1-2AR stimulation. We examined their role in modulating myocardial remodelling, particularly fibrosis in response to haemodynamic stress. Methods and results: Mice with cardiac myocyte-specific expression of beta3AR (ADRB3-tg) or tamoxifen-inducible homozygous deletion (c Adrb3-ko, with loxP-targeted Adrb3) were submitted to transaortic constriction. A superfusion assay was used for proteomic analysis of paracrine mediators between beta3AR-expressing cardiac myocytes and cardiac fibroblasts cultured separately. We show that cardiac beta3AR attenuate myocardial fibrosis in response to haemodynamic stress. Interstitial fibrosis and collagen content were reduced in ADRB3-tg, but augmented in c-Adrb3-ko. ADRB3 and collagen (COL1A1) expression were also inversely related in ventricular biopsies of patients with valve disease. Incubation of cardiac fibroblasts with media conditioned by hypertrophic myocytes induced fibroblast proliferation, myo-differentiation, and collagen production. These effects were abrogated upon ADRB3 expression in myocytes. Comparative shotgun proteomic analysis of the myocyte secretomes revealed a number of factors differentially regulated by beta3AR, among which connective tissue growth factor [CTGF (CCN2)] was prominently reduced. CTGF was similarly reduced in stressed hearts from ADRB3-tg, but increased in hearts from c-Adrb3-ko mice. CTGF expression was mediated by reactive oxygen species production which was reduced by ADRB3 expression in vitro and in vivo. This antioxidant and anti fibrotic effect involved beta3AR coupling to the neuronal isoform of nitric oxide synthase (nNOS) in cardiac myocytes, as both were abrogated upon nNOS inhibition or Nos1 homozygous deletion. Conclusion: Cardiac beta3AR protect from fibrosis in response to haemodynamic stress by modulating nitric oxide and oxidant stress dependent paracrine signaling to fibroblasts. Specific agonism at beta3AR may offer a new therapeutic modality to prevent cardiac fibrosis. PMID- 29106526 TI - Barriers to implement screening for alcohol consumption in Spanish hypertensive patients. AB - Background: Alcohol intake and hypertension (HT) are interrelated public health problems with cost-effective interventions at the primary care level that, to date, are poorly implemented. Objective: This study aims to explore the barriers to implementing alcohol interventions for people with HT in primary care. Methods: As part of the project BASIS (Baseline Alcohol Screening and Intervention Survey), an internet survey from five European countries was developed to determine the role of alcohol in the management of HT in primary care practice. The survey contained 28 core items and 7 country-specific items. We present answers from Spanish general practitioners (GPs), who were reached through the main professional and scientific societies via e-mail and asked to take the online survey. Results: In total, 867 GPs answered the survey (65.1% women, 70.4% > 30 years old). As indicated by the Alcohol Use Disorders Identification Test-C scores, 12.4% of GPs who responded were risky drinkers (21.3% of men versus 7.1% of women). GPs reported considering alcohol relatively unimportant in HT treatment, as well as a difficult condition to deal with. The three main barriers to implement screening for alcohol consumption in HT patients were the lack of time (50.0%), considering alcohol unimportant for HT (28.4%) and stigma (16.5%). Conclusions: GPs did not consider alcohol consumption a relevant factor for HT and, additionally, found it difficult to deal with alcohol problems. Some of the barriers for alcohol screening could be overcome through structural changes in the health system, such as empowering GPs to treat alcohol use disorders (rather than a single focus on implementing preventive strategies) by enhancing training in alcohol diagnosis and treatment. PMID- 29106525 TI - Loss of Drosophila FMRP leads to alterations in energy metabolism and mitochondrial function. AB - Fragile X Syndrome (FXS), the most prevalent form of inherited intellectual disability and the foremost monogenetic cause of autism, is caused by loss of expression of the FMR1 gene . Here, we show that dfmr1 modulates the global metabolome in Drosophila. Despite our previous discovery of increased brain insulin signaling, our results indicate that dfmr1 mutants have reduced carbohydrate and lipid stores and are hypersensitive to starvation stress. The observed metabolic deficits cannot be explained by feeding behavior, as we report that dfmr1 mutants are hyperphagic. Rather, our data identify dfmr1 as a regulator of mitochondrial function. We demonstrate that under supersaturating conditions, dfmr1 mutant mitochondria have significantly increased maximum electron transport system (ETS) capacity. Moreover, electron micrographs of indirect flight muscle reveal striking morphological changes in the dfmr1 mutant mitochondria. Taken together, our results illustrate the importance of dfmr1 for proper maintenance of nutrient homeostasis and mitochondrial function. PMID- 29106527 TI - Bedside autonomic risk stratification after myocardial infarction by means of short-term deceleration capacity of heart rate. AB - Aims: Twenty-four-hour deceleration capacity (DC24h) of heart rate is a strong predictor of mortality after myocardial infarction (MI). Assessment of DC from short-term recordings (DCst) would be of practical use in everyday clinical practice but its predictive value is unknown. Here, we test the usefulness of DCst for autonomic bedside risk stratification after MI. Methods and results: We included 908 patients after acute MI enrolled in Munich and 478 patients with acute (n = 232) and chronic MI (n = 246) enrolled in Tuebingen, both in Germany. We assessed DCst from high-resolution resting electrocardiogram (ECG) recordings (<30 min) performed under standardized conditions in supine position. In the Munich cohort, we also assessed DC24h from 24-h Holter recordings. Deceleration capacity was dichotomized at the established cut-off value of <= 2.5 ms. Primary endpoint was 3-year mortality. Secondary endpoint was 3-year cardiovascular mortality. In addition to DC, multivariable analyses included the Global Registry of Acute Coronary Events score >140 and left ventricular ejection fraction <= 35%. During follow-up, 48 (5.3%) and 48 (10.0%) patients died in the Munich and Tuebingen cohorts, respectively. On multivariable analyses, DCst <= 2.5 ms was the strongest predictor of mortality, yielding hazard ratios of 5.04 (2.68-9.49; P < 0.001) and 3.19 (1.70-6.02; P < 0.001) in the Munich and Tuebingen cohorts, respectively. Deceleration capacity assessed from short-term recordings <= 2.5 ms was also an independent predictor of cardiovascular mortality in both cohorts. Implementation of DCst <= 2.5 ms into the multivariable models led to a significant increase of C-statistics and integrated discrimination improvement score. Conclusion: Deceleration capacity assessed from short-term recordings is a strong and independent predictor of mortality and cardiovascular mortality after MI, which is complementary to existing risk stratification strategies. PMID- 29106529 TI - Transseptal puncture and catheter ablation of atrial fibrillation in patients with atrial septal occluder: initial experience of a single centre. AB - Aims: Catheter ablation is underutilized in atrial septal defect (ASD) patients who have undergone implantation of an atrial septal occluder (ASO). This study evaluates the feasibility and safety of catheter ablation of atrial fibrillation (AF) in this subset of patients. Methods and results: Sixteen patients (age 56 +/ 12 years, 10 men) with drug-refractory AF (10 paroxysmal and 6 persistent) and previously implanted ASO were enrolled. Balloon dilatation of the closure device was performed if the native septum passage could not be achieved. For paroxysmal AF, the ablation strategy was circumferential pulmonary vein isolation (CPVI), and for persistent AF, additional linear ablation was performed. Transseptal access was achieved through the native septum in 11 patients (Group A) and through the ASO using balloon dilatation in 5 patients (Group B). Circumferential pulmonary vein isolation was achieved in all 16 patients, and linear block was achieved in all persistent patients except for 1 patient who did not achieve mitral isthmus block. The transseptal, total fluoroscopy, and procedural durations were 5 +/- 3 vs. 38 +/- 8 min, 31 +/- 11 vs. 54 +/- 15 min, and 165 +/- 35 vs. 224 +/- 36 min, respectively, in Group A vs. Group B, respectively (all P < 0.05). No shunt at atrial level was detected by transthoracic echocardiography at 3-month follow-up. During a follow-up of 16 +/- 6 months, sinus rhythm was maintained in 12 of 16 patients. No severe complications were observed. Conclusion: In ASD patients with ASO, catheter ablation of AF is feasible, safe, and effective. The balloon dilatation technique can facilitate transseptal access through the ASO. PMID- 29106528 TI - The First Mitochondrial Genomics and Evolution SMBE-Satellite Meeting: A New Scientific Symbiosis. AB - The central role of the mitochondrion for cellular and organismal metabolism is well known, yet its functional role in evolution has rarely been featured in leading international conferences. Moreover, the contribution of mitochondrial genetics to complex disease phenotypes is particularly important, and although major advances have been made in the field of genomics, mitochondrial genomic data have in many cases been overlooked. Accumulating data and new knowledge support a major contribution of this maternally inherited genome, and its interactions with the nucleus, to both major evolutionary processes and diverse disease phenotypes. These advances encouraged us to assemble the first Mitochondrial Genomics and Evolution (MGE) meeting-an SMBE satellite and Israeli Science foundation international conference (Israel, September 2017). Here, we report the content and outcome of the MGE meeting (https://www.mge2017.com/; last accessed November 5, 2017). PMID- 29106530 TI - Multimorbidity and immigrant status: associations with area of origin and length of residence in host country. AB - Aim: Multimorbidity is a growing phenomenon in primary care, and knowledge of the influence of social determinants on its evolution is vital. The aim of this study was to understand the relationship between multimorbidity and immigration, taking into account length of residence in the host country and area of origin of the immigrant population. Methods: Cross-sectional retrospective study of all adult patients registered within the public health service of Aragon, Spain (N = 1092279; 144238 were foreign-born), based on data from the EpiChron Cohort. Age standardized prevalence rates of multimorbidity were calculated. Different models of binary logistic regressions were conducted to study the association between multimorbidity, immigrant status and length of residence in the host country. Results: The risk of multimorbidity in foreign-borns was lower than that of native-borns [odds ratio (OR): 0.54, 95% confidence interval (CI): 0.53-0.55]. The probability of experiencing multimorbidity was lowest for Asians (OR: 0.34, 95% CI: 0.31-0.37) and Eastern Europeans (OR: 0.42, 95% CI: 0.40-0.43), and highest for Latin Americans (OR: 0.70, 95% CI: 0.68-0.72). Foreign-born immigrants residing in Aragon for >=5 years had a higher multimorbidity risk than those residing for <5 years (OR: 2.3, 95% CI: 2.2-2.4). Conclusion: Prevalence of multimorbidity is lower among foreign-borns as compared with native-borns, but increases rapidly with length of residence in the host country. However, the progressive development of multimorbidity among immigrants varies widely depending on area of origin. These findings provide important insight into the health care needs of specific population groups and may help minimize the negative impact of multimorbidity among the most vulnerable groups. PMID- 29106531 TI - Medicaid Savings From The New York University Caregiver Intervention for Families with Dementia. AB - Purpose of the study: The economic burden of dementia is substantially borne by state Medicaid programs. We estimated savings, from the state payer perspective, from offering the New York University Caregiver Intervention (NYUCI), a well studied caregiver support and counseling program, to eligible Minnesota Medicaid enrollees. Design and Methods: A population-based microsimulation Markov model predicted and compared costs over 15 years with and without implementation of the NYUCI for family caregivers of community-based Medicaid eligibles with dementia. The model was informed by primary analysis of Minnesota Department of Human Services (MN DHS) data, and literature on the epidemiology, natural history, costs, and evidence-based management of the disease. Primary outcomes were predicted cumulative total direct costs, including medical, facility, and waiver program payments for eligibles, and estimated costs of providing the NYUCI. Results: Approximately 5-6% more eligibles with dementia would remain in the community annually from year 3 (2014) on, so that over 15 years 17% fewer would die in nursing homes (NH) if their caregivers received the NYUCI. After 15 years, MN DHS could realize savings of $40.4 million (2011 dollars, discounted at 3%) if all eligibles/caregivers enrolled. Savings were expected 5 years after implementation. Multiple sensitivity analyses, including best-and worst-case scenarios, estimated results ranging from 15-year cumulative savings of $178.9 million to a cumulative loss of $7.3 million, respectively, driven largely by assumed program effectiveness. Implications: State payers can use enhanced caregiver support to moderate the growing tax burden of dementia, even without a breakthrough in the pharmacologic treatment of the disease. PMID- 29106532 TI - Using genetics to explore whether the cholesterol-lowering drug ezetimibe may cause an increased risk of cancer. AB - Background: Results from randomized controlled trials (RCTs) have raised concern that the cholesterol-lowering drug ezetimibe might increase the risk of cancer. We tested the hypothesis that genetic variation in NPC1L1, mimicking treatment with ezetimibe, was associated with an increased risk of cancer. Methods: We included 67 257 individuals from the general population. Of these, 8333 developed cancer and 2057 died of cancer from 1968 to 2011. To mimic the effect of ezetimibe, we calculated weighted allele scores based on the low-density lipoprotein (LDL) cholesterol-lowering(= NPC1L1-inhibitory) effect of each variant. We tested the associations of the NPC1L1 allele scores with LDL cholesterol and with risk of any cancer, death from any cancer and 27 site specific cancers. As a positive control, we tested the association of the NPC1L1 allele scores with risk of ischaemic vascular disease (IVD). Results: The NPC1L1 allele scores did not associate with risk of any cancer, death from any cancer or with any of 27 site-specific cancers. Hazard ratios (HRs) for a 1-unit increase in internally weighted allele scores were 1.00 (95% confidence interval: 0.98 1.02) for any cancer, and 1.02 (0.98-1.06) for cancer death. The corresponding HR for IVD was 0.97 (0.94-0.99). Results were similar for an externally weighted allele score and for a simple allele count. Finally, the null association with cancer was robust in sensitivity analyses. Conclusions: Lifelong, genetic inhibition of NPC1L1, mimicking treatment with ezetimibe, does not associate with risk of cancer. These results suggest that long-term treatment with ezetimibe is unlikely to increase the risk of cancer, in agreement with the overall evidence from ezetimibe RCTs. PMID- 29106533 TI - YWHAE is a novel interaction partner of Helicobacter pylori CagA. AB - CagA, an important virulence factor of Helicobacter pylori, targets and interacts with a series of host proteins to activate signaling factors involved in many functions, such as development, cytoskeleton rearrangement and inflammatory molecule release. Despite extensive efforts, the relationship between CagA and gastric cancer is far from completely understood. Here, the GAL4 yeast two-hybrid system was used to screen cellular proteins for binding to CagA, and five cellular proteins, including tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon (YWHAE), were identified. The CagA-YWHAE interaction was further verified not only in vitro by a glutathione S-transferase pull-down assay, but also in vivo by immunolocalization and co-immunoprecipitation assays. In SGC7901 and AGS cells, overexpression of the YWHAE protein promoted the activation of NF-kappaB by CagA; conversely, knockdown of the YWHAE protein inhibited the activation of NF-kappaB by CagA. These results indicate that CagA enhances the YWHAE-mediated transactivation of NF-kappaB, providing a new clue to the molecular mechanisms of H. pylori-associated tumorigenesis mediated by CagA. PMID- 29106534 TI - Effective presentation skills. AB - Most PhD's will have a presentation component during the interview process, as well as presenting their work at conferences. This article will provide guidance on how to develop relevant content and effectively deliver it to your audience. PMID- 29106535 TI - Developmental Changes in the Integration of Affective and Cognitive Corticostriatal Pathways are Associated with Reward-Driven Behavior. AB - The relative influence of affective and cognitive processes on behavior is increasingly understood to transform through development, from adolescence into adulthood, but the neuroanatomical mechanisms underlying this change are not well understood. We analyzed diffusion magnetic resonance imaging in 115 10- to 28 year-old participants to identify convergent corticostriatal projections from cortical systems involved in affect and cognitive control and determined the age related differences in their relative structural integrity. Results indicate that the relative integrity of affective projections, in relation to projections from cognitive control systems, decreases with age and is positively associated with reward-driven task performance. Together, these findings provide new evidence that developmental differences in the integration of corticostriatal networks involved in affect and cognitive control underlie known developmental decreases in the propensity for reward-driven behavior into adulthood. PMID- 29106536 TI - The Intersection of Intellectual Disability and Dementia: Report of The International Summit on Intellectual Disability and Dementia. AB - An International Summit on Intellectual Disability and Dementia, held in Glasgow, Scotland (October 13-14, 2016), drew individuals and representatives of numerous international and national organizations and universities with a stake in issues affecting adults with intellectual disability (ID) affected by dementia. A discussion-based consensus process was used to examine and produce a series of topical reports examining three main conceptual areas: (a) human rights and personal resources (applications of the Convention for Rights of People with Disabilities and human rights to societal inclusion, and perspectives of persons with ID), (b) individualized services and clinical supports (advancing and advanced dementia, post-diagnostic supports, community supports and services, dementia-capable care practice, and end-of-life care practices), and (c) advocacy, public impact, family caregiver issues (nomenclature/terminology, inclusion of persons with ID in national plans, and family caregiver issues). Outcomes included recommendations incorporated into a series of publications and topical summary bulletins designed to be international resources, practice guidelines, and the impetus for planning and advocacy with, and on behalf of, people with ID affected by dementia, as well as their families. The general themes of the conceptual areas are discussed and the main recommendations are associated with three primary concerns. PMID- 29106537 TI - Symptomatic atrial fibrillation and risk of cardiovascular events: data from the Euro Heart Survey. AB - Aims: Atrial fibrillation (AF) is associated with a wide range of clinical presentations. Whether and how AF symptoms can affect prognosis is still unclear. Aims of the present analysis were to investigate potential predictors of symptomatic AF and to determine if symptoms are associated with higher incidence of cardiovascular (CV) events at 1-year follow-up. Methods and results: The Euro Heart Survey on Atrial Fibrillation included 3607 consecutive patients with documented AF and available follow-up regarding symptoms status. Patients found symptomatic at baseline were classified into still symptomatic (SS group; n = 896) and asymptomatic (SA; n = 1556) at 1 year. Similarly, asymptomatic patients at baseline were classified into still asymptomatic (AA group; n = 903) and symptomatic (AS group; n = 252) at 1 year. Demographics, as well as clinical variables and medical treatments, were tested as potential predictors of symptoms persistence/development at 1-year. We also compared CV events between SS and SA groups, and AS and AA groups at 1-year follow-up. Both persistence and development of AF symptoms were associated with an increased risk of CV hospitalization, stroke, heart failure worsening, and thrombo-embolism. AF type, hypothyroidism, chronic heart failure, and chronic obstructive pulmonary disease (COPD), were independently associated with an increased risk of symptomatic status at 1-year follow-up between SS and SA groups. Conclusion: Persistence or development of symptoms after medical treatment are associated with an increased risk of CV events during a 1-year follow-up. Type of AF, along with hypothyroidism, COPD and chronic heart failure are significantly associated with symptoms persistence despite medical treatment. PMID- 29106538 TI - Origin of the plasmid-mediated fosfomycin resistance gene fosA3. AB - Background: fosA3 is the most commonly reported plasmid-mediated fosfomycin resistance gene among Enterobacteriaceae. Objectives: To identify the origin of fosA3. Methods: The chromosome of Kluyvera georgiana clinical strain YDC799 was fully sequenced with single-molecule real-time sequencing. Comparative genetic analysis was performed for K. georgiana YDC799, K. georgiana type strain ATCC 51603 and representative fosA3-carrying plasmids. fosA genes were cloned in Escherichia coli to confirm function. Results: K. georgiana YDC799 harboured fosA (designated fosAKG) and blaCTX-M-8 on the chromosome. The genetic environments surrounding fosA3 and bounded by IS26 were nearly identical with the corresponding regions of K. georgiana YDC799 and ATCC 51603. The amino acid sequence of FosAKG from YDC799 and K. georgiana ATCC 51603 shared 99% and 94% identity with FosA3, respectively. Cloned FosAKG conferred fosfomycin resistance with an MIC of >1024 mg/L for E. coli. Conclusions: The plasmid-mediated fosA3 gene was likely mobilized from the chromosome of K. georgiana by an IS26-mediated event. PMID- 29106539 TI - Spontaneous chondroma formation in CD2-Cre-driven Erk-deficient mice. AB - Lineage-specific Cre Tg mice are widely used to delineate the functions of genes in a tissue-specific manner. Several T-cell-specific promoter cassettes have been developed; however, the activities of those promoters in non-T cells have not been investigated extensively. Here, we report that CD2-Cre-mediated deletion of Erk proteins by generating CD2-Cre * Erk1-/-Erk2flox/flox (Erk?CD2-Cre) mice results in abnormal cartilage hyperplasia. Histological analysis revealed that this abnormality is caused by aberrant hyperplasia of chondrocytes. The presence of Erk-deficient T cells is not required for this chondroma formation, as it was similarly observed in the absence of T cells in a CD3epsilon-deficient background. In addition, adoptive transfer of bone marrow cells from Erk?CD2-Cre mice to wild-type recipients did not cause chondroma formation, suggesting that Erk-deficient non-immune cells are responsible for this abnormality. By tracing Cre-expressed tissues using a ROSA26-STOP-RFP allele, we found that the chondroma emitted RFP fluorescence, indicating that functional Cre is expressed in hyperplastic chondrocytes in Erk?CD2-Cre mice. Furthermore, RFP+ chondrocytes were also found in an Erk-sufficient background, albeit without aberrant growth. These results suggest that unexpected expression of CD2-driven Cre in chondrocytes generates Erk-deficient chondrocytes, resulting in hyperplastic cartilage formation. Recently, two independent reports showed that CD4-Cre mediated Ras-Erk signaling ablation led to similar abnormal cartilage formation (Guittard, G., Gallardo, D. L., Li, W. et al. 2017. Unexpected cartilage phenotype in CD4-Cre-conditional SOS-deficient mice. Front. Immunol. 8:343; Wehenkel, M., Corr, M., Guy, C. S. et al. 2017. Extracellular signal-regulated kinase signaling in CD4-expressing cells inhibits osteochondromas. Front. Immunol. 8:482). Together with these reports, our study suggests that an unexpected link exists between T-like cell and chondrocyte lineages during ontogeny. PMID- 29106541 TI - Ultra-high density sequential mapping of a focal source of atrial fibrillation. PMID- 29106540 TI - A Journey across Genomes Uncovers the Origin of Ubiquinone in Cyanobacteria. AB - Ubiquinone (Q) is an isoprenoid quinone that functions as membrane electron carrier in mitochondria and bacterial organisms belonging to the alpha, beta, and gamma class of proteobacteria. The biosynthesis of Q follows various biochemical steps catalyzed by diverse proteins that are, in general, homologous in mitochondria and bacteria. Nonorthologous proteins can also contribute to some biochemical steps as originally uncovered in Escherichia coli, which is the best studied organism for Q biosynthesis in prokaryotes. However, the origin of the biosynthetic pathway of Q has remained obscure. Here, I show by genome analysis that Q biosynthesis originated in cyanobacteria and then diversified in anaerobic alpha proteobacteria which have extant relatives in members of the Rhodospirillaceae family. Two distinct biochemical pathways diverged when ambient oxygen reached current levels on earth, one leading to the well-known series of Ubi genes found in E. coli, and the other containing CoQ proteins originally found in eukaryotes. Extant alpha proteobacteria show Q biosynthesis pathways that are more similar to that present in mitochondria than to that of E. coli. Hence, this work clarifies not only the origin but also the evolution of Q biosynthesis from bacteria to mitochondria. PMID- 29106543 TI - Survival in homozygous familial hypercholesterolaemia is determined by the on treatment level of serum cholesterol. AB - Aims: Homozygous familial hypercholesterolaemia (FH) is a rare inherited disorder characterized by extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and premature death. Many forms of lipid-lowering therapies have been used in the past, but definitive evidence of benefit has been lacking. We therefore undertook a retrospective survey of lipid levels and clinical outcomes of FH homozygotes treated with a combination of lipid-lowering measures between 1990 and 2014 in South Africa and the UK. Methods and results: We divided 133 previously statin-naive homozygotes into quartiles according to their on treatment levels of serum cholesterol and compared the occurrence of any death, cardiovascular death, and major adverse cardiovascular events (MACE) between the quartiles during 25 years of follow-up, using Cox and competing risks regression analysis. Patients in Quartile 4, with an on-treatment serum cholesterol >15.1 mmol/L, had a hazard ratio of 11.5 for any death compared with those in Quartile 1, with an on-treatment cholesterol of < 8.1 mmol/L. Those in Quartiles 2 and 3 combined, with on-treatment cholesterol of 8.1-15.1 mmol/L had a hazard ratio of 3.6 compared with Quartile 1. These differences were statistically significant (P < 0.001) and remained so after adjustments for confounding factors (P = 0.04). Significant differences between quartiles were also evident for cardiovascular deaths and MACE. Conclusion: These findings provide unequivocal evidence that the extent of reduction of serum cholesterol achieved by a combination of therapeutic measures, including statins, ezetimibe, lipoprotein apheresis, and evolocumab, is a major determinant of survival in homozygous FH. PMID- 29106544 TI - Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile. AB - Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids. PMID- 29106542 TI - Dopamine System Dysregulation in Major Depressive Disorders. AB - Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this disorder. Dopaminergic activity is complex and under the regulation of multiple brain structures, including the ventral subiculum of the hippocampus and the basolateral amygdala. Whereas basic and clinical studies demonstrate deficits of the dopaminergic system in depression, the origin of these deficits likely lies in dysregulation of its regulatory afferent circuits. This review explores the current information regarding the afferent modulation of the dopaminergic system and its relevance to major depressive disorder, as well as some of the system level effects of novel antidepressants such as agomelatine and ketamine. PMID- 29106546 TI - Clinical validation of automatic local activation time annotation during focal premature ventricular complex ablation procedures. AB - Aims: Current navigation systems incorporate algorithms for automatic identification of local activation time (LAT). However, data about their utility and accuracy in premature ventricular complex (PVC) ablation procedures are scarce. This study analyses the accuracy of an algorithmic method based on automatic annotation of the maximal negative slope of the unipolar electrogram within the window demarcated by the bipolar electrogram compared with conventional manual annotation during PVC ablation procedures. Methods and results: Forty patients with successful ablation of focal PVC in three centres were included. Electroanatomical activation maps obtained with the automatic system (WF-map) were compared with manual annotation maps (M-map). Correlation and concordance of LAT obtained with both methods were assessed at 3536 points. The distance between the earliest activation site (EAS) and the effective radiofrequency application point (e-RFp) were determined in M-map and WF-map. The distance between WF-EAS and M-EAS was assessed. Successful ablation sites included left ventricular outflow tract (LVOT; 55%), right ventricular outflow tract (40%), and tricuspid annulus (5%). Good correlation was observed between the two annotation approaches (r = 0.655; P < 0.0001). Bland-Altman analysis revealed a systematic delayed detection of LAT by WF-map (bias 33.8 +/- 30.9 ms), being higher in LVOT than in the right ventricle (42.6 +/- 29.2 vs. 27.2 +/- 30.5 ms, respectively; P < 0.0001). No difference in EAS-eRFp distance was observed between M-map and WF-map (1.8 +/- 2.8 vs. 1.8 +/- 3.4 mm, respectively; P = 0.986). The median (interquartile range) distance between WF-EAS and M-EAS was 2.2(0-6) mm. Conclusion: Good correlation was found between M-map and WF-map. Local activation time detection was systematically delayed in WF-map, especially in LVOT. Accurate identification of e-RFp was achieved with both annotation approaches. PMID- 29106547 TI - Perceptions of Zika virus risk in Germany in 2016. AB - Background: Risks associated with Zika virus (ZIKV) transmission in the Americas have been discussed widely in the media as several European athletes declined to participate in the 2016 Summer Olympic Games. Since risk perceptions of individuals in unaffected areas are unknown, we assessed the risk perceptions of ZIKV and related behaviour in Lower Saxony, Germany, with a specific focus on pregnant women and their partners. Methods: In May 2016, we surveyed 1,037 participants aged 15-69 years of an online panel (addressing hygiene and preventive behaviour regarding infections) in Lower Saxony with respect to their risk perceptions related to ZIKV. We additionally included 26 expectant parents who were recruited at antenatal preparation courses in Braunschweig and Hannover between May and July 2016. Results: Six hundred fifty-five (69.1%) of the panel participants had ever heard about ZIKV. About 8% of the study participants reported to be concerned about ZIKV. Pregnant women had the highest odds of reporting concern about ZIKV (OR: 6.24; 95% CI: 2.94-13.26, reference: non pregnant women). The vast majority of participants (79%) would travel to the Olympics if they won a free trip; this proportion was lower in currently pregnant women (46%). Risk perceptions towards ZIKV were considerably lower than those towards Ebola during the 2014 epidemic. Conclusion: This study showed that fear of contracting ZIKV is not a major deterrent for travelling to high-risk areas. Pregnant women are appropriately concerned about the risk of ZIKV. Studies modelling the further spread of ZIKV need to account for these results. PMID- 29106548 TI - Comprehensive geriatric assessment for identifying older people at risk of hip fracture: cross-sectional study with comparative group. AB - Background: Hip fracture (HF) is by far the most common serious fragility fracture. Its care is a major challenge to all healthcare systems. Aim: To determine whether there are characteristics of older people identified via comprehensive geriatric assessment (CGA) that help identify those with an increased risk of HF. Methods: The demographic, functional, cognitive and nutritional data of a cohort of patients admitted for acute HF were compared with those of a population cohort representing community-dwelling older people in the same urban district without HF. Bivariate analysis was performed on the variables in both the complete samples and in a subsample of age and sex paired subjects, followed by logistic regression analysis. Results: A total of 509 HF patients and 1315 community-dwelling older people were included. The HF patients were older and more frequently women and had more frequent disability and cognitive impairment, lower handgrip strength, lower body mass index (BMI) and a higher frequency of vitamin D deficiency compared with the community controls (P < 0.001). The variables most strongly associated with the presence of HF in the multivariate analysis, aside from age and female sex, were BMI<22 kg/m2 [odds ratio (OR) = 5.11], disability (OR = 4.32), muscle weakness (OR = 3.01), and vitamin D deficiency (OR = 2.13). Conclusions: There are easily obtained CGA determinants that are strongly associated with fragility HF. The detection of low weight, disability, malnutrition, muscle weakness, and vitamin D deficiency can help identify at-risk older people to implement prevention strategies. PMID- 29106545 TI - Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. AB - Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit. PMID- 29106549 TI - The in Vitro Actions of Loxapine on Dopaminergic and Serotonergic Receptors. Time to Consider Atypical Classification of This Antipsychotic Drug? AB - Background: The denomination of typical antipsychotic for loxapine has poor relation to current knowledge of the molecule's relevant modes of action. Materials and Methods: Competition binding experiments were performed on expressed human recombinant receptors in CHO cells and HEK-293 cells for D1 to D5, 5-HT1A, 5-HT2A, 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro autoradiographies using [11C]-Raclopride [18F]-Altanserin [18F]-MPPF [11C]-SB207145, and [18F] 2FNQ1P were measured in brain tissue of a male primate followed by addition of increasing doses of loxapine succinate. Results: In cell cultures, the measured Kb confirmed high affinity of loxapine for the D2; intermediate affinity for the D1, D4, D5, 5-HT2C receptorsl and a lack of affinity toward D3, 5-HT1A, 5-HT4, 5 HT6, and 5-HT7 receptors. In brain tissue, PET autoradiographies showed a radiopharmaceutical displacement at low concentrations of loxapine on D2 and 5 HT2A receptors. Conclusion: This preclinical study reveals that loxapine receptorial spectrum is close to an "atypical" profile (D2/5HT2A ratio, 1.14). Loxapine is rightly classified as a DS-RAn agent in the Neuroscience Based Nomenclature classification. PMID- 29106550 TI - The OMA orthology database in 2018: retrieving evolutionary relationships among all domains of life through richer web and programmatic interfaces. AB - The Orthologous Matrix (OMA) is a leading resource to relate genes across many species from all of life. In this update paper, we review the recent algorithmic improvements in the OMA pipeline, describe increases in species coverage (particularly in plants and early-branching eukaryotes) and introduce several new features in the OMA web browser. Notable improvements include: (i) a scalable, interactive viewer for hierarchical orthologous groups; (ii) protein domain annotations and domain-based links between orthologous groups; (iii) functionality to retrieve phylogenetic marker genes for a subset of species of interest; (iv) a new synteny dot plot viewer; and (v) an overhaul of the programmatic access (REST API and semantic web), which will facilitate incorporation of OMA analyses in computational pipelines and integration with other bioinformatic resources. OMA can be freely accessed at https://omabrowser.org. PMID- 29106551 TI - Cohort Profile: 2001 Cohort of the Longitudinal Survey of Newborns in the 21st Century. PMID- 29106552 TI - Interrogating the Contested Spaces of Rural Aging: Implications for Research, Policy, and Practice. AB - Informed by a critical turn underway in rural gerontology, this article explores how the intersection of global and local trends relating to population aging and rural change create contested spaces of rural aging. The aim is to build our understanding of rural as a dynamic context within which the processes, outcomes, and experiences of aging are created, confronted, and contested by older adults and their communities. A review of key developments within gerontology and rural studies reveals how competing policies, discourses, and practices relating to healthy aging and aging in place, rural citizenship and governmentality, and social inclusion and inequality combine in particular ways to empower or disempower a diverse range of older rural adults aging in a diverse range of rural communities. The article provides a contextually sensitive perspective on potential sources of conflict and exclusion for older adults in dynamic rural spaces and further enhances our understanding of how rural physical and social environments are constructed and experienced in older age. A framework for interrogating emergent questions about aging in rural contexts is developed and implications for advancing research, policy, and practice are discussed. PMID- 29106554 TI - Active and Healthy Lifestyle - Nationwide Programs in Israeli Schools. AB - The World Health Organization (WHO) announced the 'Global School Health Initiative' in 1995 following recommendations formulated in the Ottawa Charter for Health Promotion. Hence, the aims of the present study were to describe the various programs for nurturing an active and healthy lifestyle implemented during 2011-12 in schools in Israel, and to identify variables that may explain the success versus lack of success in implementing these programs. Participants were a nationwide representative sample of 126 school principals from six supervisory districts of the Ministry of Education, including six sectors, from the elementary, junior-high and senior-high school levels. Semi-structured telephone interviews were recorded and processed using the ATLAS.ti software for qualitative analysis. Physical education teachers, sciences teachers and social coordinators led the programs' implementation. The programs included four main activities domains: health, physical education, nutrition and sustainability. Three types of program implementation were observed: leading principles, teaching methods, and external programs. Parents were involved mostly in elementary schools. Evidence of program integration into school life was presented by changes in children's behaviors, whereas difficulties stemmed from lack of budget and teaching hours. Science and physical education lessons constituted the anchor for the programs. The schools needed a committed leader to help conduct and maintain the program. Thus, the role of the school principal was to initiate the idea of developing a program, encourage its implementation, select a leader for the program, and then, most importantly, to reinforce the teachers' enthusiasm. PMID- 29106553 TI - Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis. AB - Background: Intermittent explosive disorder is defined as a recurrent, problematic, and impulsive aggression that affects 3% to 4% of the US population. While behavioral genetic studies report a substantial degree of genetic influence on aggression and impulsivity, epigenetic mechanisms underlying aggression and intermittent explosive disorder are not well known. Methods: The sample included 44 subjects (22 with a DSM-5 diagnosis of intermittent explosive disorder and 22 comparable subjects without intermittent explosive disorder). Peripheral blood DNA methylome was profiled using the Illumina Infinium HumanMethylation450 Beadchip. Intermittent explosive disorder-associated genome-wide DNA methylation changes were analyzed using the CpGassoc R package, with covariates age, sex, and race being adjusted. A gene-based functional enrichment analysis was performed to identify pathways that were overrepresented by genes harboring highly differentially methylated CpG sites. Results: A total of 27 CpG sites were differentially methylated in IED participants (P<5.0*10-5), but none reached genome-wide significant threshold. Functional enrichment analysis revealed that genes mapped by these CpG sites are involved in the inflammatory/immune system, the endocrine system, and neuronal differentiation. Conclusions: Consistent with our previous studies showing an association of inflammatory response with aggressive behavior in intermittent explosive disorder subjects, our gene-based pathway analysis using differentially methylated CpG sites supports inflammatory response as an important mechanism involved in intermittent explosive disorder and reveals other novel biological processes possibly associated with intermittent explosive disorder. PMID- 29106555 TI - Falling short: how state laws can address health information exchange barriers and enablers. AB - Objective: Research on the implementation of health information exchange (HIE) organizations has identified both positive and negative effects of laws relating to governance, incentives, mandates, sustainability, stakeholder participation, patient engagement, privacy, confidentiality, and security. We fill a substantial research gap by describing whether comprehensive state and territorial HIE legal frameworks address identified legal facilitators and barriers. Materials and Methods: We used the Westlaw database to identify state and territorial laws relating to HIEs in effect on June 7, 2016 (53 jurisdictions). We blind-coded all laws and addressed coding discrepancies in peer-review meetings. We recorded a consensus code for each law in a master database. We compared 20 HIE legal attributes with identified barriers to and enablers of HIE activity in the literature. Results: Forty-two states, the District of Columbia, and 2 territories have laws relating to HIEs. On average, jurisdictions address 8.32 of the 20 criteria selected in statutes and regulations. Twenty jurisdictions unambiguously address <=5 criteria in statutes and regulations. None of the significant legal criteria are unambiguously addressed in >60% of the 53 jurisdictions. Discussion: Laws can be barriers to or enablers of HIEs. However, jurisdictions are not addressing many significant issues identified by researchers. Consequently, there is a substantial risk that existing legal frameworks are not adequately supporting HIEs. Conclusion: The current evidence base is insufficient for comparative assessments or impact rankings of the various factors. However, the detailed Centers for Disease Control and Prevention dataset of HIE laws could enable investigations into the types of laws that promote or impede HIEs. PMID- 29106556 TI - Location matters: distinct DNA methylation patterns in GABAergic interneuronal populations from separate microcircuits within the human hippocampus. AB - Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain. PMID- 29106557 TI - Surgical results of mitral valve repair for congenital mitral valve stenosis in paediatric patients. AB - OBJECTIVES: Mitral valve (MV) repairs have been performed in paediatric patients with congenital MV stenosis. However, congenital MV stenosis lesions are a heterogeneous group of lesions, and their repair remains challenging. METHODS: From March 1999 to September 2014, MV repair was performed in 22 patients with congenital MV stenosis. The median age was 10.3 months (ranging from 22 days to 9.1 years), and the mean body weight was 7.9 +/- 4.0 kg at the time of the operation. Multiple-level left-side heart obstructions were present in 9 (45%) patients. RESULTS: The main aetiology of the mitral stenosis was a supravalvular mitral ring in 8 patients, valvular stenosis in 4 patients, a parachute deformity of the papillary muscles in 4 patients and other abnormal papillary muscles in 6 patients. The mean MV pressure gradient improved from 10.4 +/- 3.9 mmHg to 3.4 +/ 1.7 mmHg after MV repair (n = 18, P < 0.0001). The mean follow-up duration was 6.7 +/- 5.4 years. One patient died postoperatively due to septic shock. Four patients required a second operation (2 patients for mitral stenosis, 1 patient for left ventricular outflow tract obstruction and mitral stenosis and 1 patient for mitral regurgitation). Among them, 2 patients died: 1 patient died due to cardiopulmonary bypass weaning failure and another patient died due to multiple cerebral infarcts. At the last follow-up, the mean MV pressure gradient was 4.5 +/- 3.1 mmHg for all patients who did not have reoperation, and moderate or greater mitral insufficiency was detected in 3 patients. At 10 years, the survival rate was 85.9 +/- 7.6%, and the freedom from reoperation rate was 77.5 +/- 10.1%. In the log-rank test, MV repair in the neonate was associated with mortality (P = 0.010), and presentation of mitral insufficiency was associated with reoperation (P = 0.003). CONCLUSIONS: MV repair in paediatric patients with congenital mitral stenosis showed acceptable results. The follow-up echocardiogram also revealed satisfactory results. Close follow-up is necessary to detect the development of postoperative mitral stenosis or regurgitation. PMID- 29106558 TI - Anthropometric and cardiometabolic risk factors in parents and child obesity in Segamat, Malaysia. AB - Background: There is little evidence regarding risk factors for child obesity in Asian populations, including the role of parental anthropometric and cardiometabolic risk factors. We examined the relation between parental risk factors and child obesity in a Malaysian population. Methods: We used data from health and demographic surveillance conducted by the South East Asia Community Observatory in Segamat, Malaysia. Analyses included 9207 individuals (4806 children, 2570 mothers and 1831 fathers). Child obesity was defined based on the World Health Organization 2007 reference. We assessed the relation between parental anthropometric (overweight, obesity and central obesity) and cardiometabolic (systolic hypertension, diastolic hypertension and hyperglycaemia) risk factors and child obesity, using mixed effects Poisson regression models with robust standard errors. Results: We found a high burden of overweight and obesity among children in this population (30% overweight or obese). Children of one or more obese parents had a 2-fold greater risk of being obese compared with children of non-obese parents. Sequential adjustment for parental and child characteristics did not materially affect estimates (fully adjusted relative risk for obesity in both parents: 2.39, 95% confidence interval: 1.82, 3.10, P < 0.001; P for trend < 0.001). These associations were not modified by parental or child sex. We found no consistent evidence for associations between parental cardiometabolic risk factors and child obesity. Conclusions: Parental obesity was strongly associated with child obesity in this population. Further exploration of the behavioural and environmental drivers of these associations may help inform strategies addressing child obesity in Asia. PMID- 29106559 TI - Outcome of heart transplantation after bridge-to-transplant strategy using various mechanical circulatory support devices. AB - OBJECTIVES: Orthotopic heart transplantation (OHT) is limited by a chronic shortage of donors. With the evolution of technology, more patients have been bridged to transplant (BTT) through various pathways using various types of mechanical circulatory support. We compared short- and long-term outcomes among these various strategies of BTT. METHODS: We retrospectively reviewed 410 patients who had OHT between January 2009 and April 2015. Patients were divided into 4 groups according to BTT status: primary OHT without bridging (Group A, n = 246); bridge with implantable continuous-flow left ventricular assist device (CF LVAD) (Group B, n = 130); bridge with short-term mechanical circulatory support (Group C, n = 16) and bridge with multiple mechanical circulatory supports, including short-term mechanical circulatory support and CF-LVAD (Group D, n = 18). Early and late outcomes after OHT were compared among the groups. RESULTS: The total duration of device support was 110.4 patient-years, 1.8 patient-years and 21.0 patient-years in Groups B, C and D, respectively. Patients who were bridged with CF-LVAD (Groups B and D) were more likely to have larger body size, blood type O, idiopathic dilated cardiomyopathy and ischaemic cardiomyopathy as an aetiology, lower total bilirubin level and longer waiting time on the United Network for Organ Sharing Status 1A. There was no statistical difference between the 4 groups in serum panel reactive antigen levels before OHT. Hospital mortality was 4% in Group A, 8% in Group B, 13% in Group C and 6% in Group D (P = 0.307). Post-transplant survival at 3 years was 80% in Group A, 82% in Group B, 75% in Group C and 88% in Group D (P = 0.752). CONCLUSIONS: BTT strategies using various mechanical circulatory support devices can provide comparable clinical outcomes to primary OHT. Flexibility in the use of both short-term mechanical circulatory support and CF-LVAD is necessary depending on the patient's background. PMID- 29106560 TI - Preeclampsia mediates the association between shorter height and increased risk of preterm delivery. AB - Background: Maternal short stature has been observed to increase the risk of preterm birth; however, the aetiology behind this phenomenon is unknown. We investigated whether preeclampsia, an obstetric complication that often leads to preterm delivery and is reported to have an inverse association with women's height, mediates this association. Methods: We studied 218 412 women with no underlying diseases before pregnancy, who delivered singletons from 2005 to 2011 and were included in the Japan Society of Obstetrics and Gynecology perinatal database, which is a national multi-centre-based delivery database among tertiary hospitals. We assessed the risk of preterm delivery in relation to height using multivariate analysis, and how the association was mediated by risk of preeclampsia using mediation analysis. Results: Each 5-cm decrement in height was associated with significantly higher risk of preterm delivery [relative risk 1.20; 95% confidence interval (CI): 1.13, 1.27] and shorter gestational age ( 0.30; 95% CI: -0.44, -0.16 weeks). Mediation analysis showed that the effect of shorter height on increased risk of preterm delivery, due to an indirect effect mediated through increased risk of preeclampsia, was substantial for shorter gestational age (48%), as well as risk of preterm delivery (28%). When examining the three subtypes of preterm delivery separately, mediated effect was largest for provider-initiated preterm delivery without premature rupture of membranes (PROM) (34%), compared with spontaneous preterm delivery without PROM (17%) or preterm delivery with PROM (0%). Conclusions: Preeclampsia partially mediates the association between maternal short stature and preterm delivery. PMID- 29106562 TI - Incomplete fissures are associated with increased alveolar ventilation via spiracles in severe emphysema. AB - OBJECTIVES: In emphysema, air can flow preferentially via collateral pathways, which can connect an entire lung when incomplete fissures are present. Spiracles are openings through the chest wall into the lung parenchyma. We previously observed increased alveolar ventilation (VA) in subjects with severe emphysema, when spiracles occurred during lung transplant operations. In this study, we set out to identify a computed tomography (CT) imaging phenotype associated with improved VA via spiracles in severe emphysema. METHODS: We retrospectively reviewed 4 patients with severe emphysema who exhaled >=75% of the inhaled tidal volume via transpleural spiracles during a lung transplant operation. We used quantitative image analysis via VIDA VISION CT software to describe emphysema severity and distribution and fissure integrity from pretransplant CT scans of the chest. We analysed partial pressure of carbon dioxide and calculated estimates of VA at baseline and during spiracle ventilation. RESULTS: All 4 subjects demonstrated severe hyperinflation (total lung capacity 148 +/- 24%predicted, residual volume 296 +/- 79% predicted). On CT imaging, severe emphysema was present, with an average 38.7 +/- 9% (range 28-50%) of lung parenchyma showing low-attenuation areas of - 950 Hounsfield units or less. Lung fissure integrity analysis demonstrated evidence of incomplete fissures (average detectable fissure integrity 67 +/- 19%, range 40 +/- 11-90 +/- 10%). During spiracle ventilation on unchanged ventilator settings, there was a significant reduction in partial pressure of carbon dioxide (61 +/- 4-35 +/- 4 mmHg, P < 0.001) and increase in estimated VA (2.1 +/- 0.5-3.8 +/- 0.8 l/min, P < 0.001). CONCLUSIONS: Incomplete lung fissures on quantitative CT analysis seem to be a key image phenotype associated with substantial improvements in VA during transpleural ventilation via spiracles in severe emphysema. PMID- 29106563 TI - Tailoring device settings in cardiac resynchronization therapy using electrograms from pacing electrodes. AB - Aims: Left ventricular (LV) fusion pacing appears to be at least as beneficial as biventricular pacing in cardiac resynchronization therapy (CRT). Optimal LV fusion pacing critically requires adjusting the atrioventricular (AV)-delay to the delay between atrial pacing and intrinsic right ventricular (RV) activation (Ap-RV). We explored the use of electrogram (EGM)-based vectorloop (EGMV) derived from EGMs of implanted pacing leads to achieve optimal LV fusion pacing and to compare it with conventional approaches. Methods and results: During CRT-device implantation, 28 patients were prospectively studied. During atrial-LV pacing (Ap LVp) at various AV-delays, LV dP/dtmax, 12-lead electrocardiogram (ECG), and unipolar EGMs were recorded. Electrocardiogram and electrogram were used to reconstruct a vectorcardiogram (VCG) and EGMV, respectively, from which the maximum QRS amplitude (QRSampl), was extracted. Ap-RV was determined: (i) conventionally as the longest AV-delay at which QRS morphology was visually unaltered during RV pacing at increasing AV-delays(Ap-RVvis; reference-method); (ii) 70% of delay between atrial pacing and RV sensing (Ap-RVaCRT); and (iii) the delay between atrial pacing and onset of QRS (Ap-QRSonset). In both the EGMV and VCG, the longest AV-delay showing an unaltered QRSampl as compared with Ap-LVp with a short AV-delay, corresponded to Ap-RVvis. In contrast, Ap-QRSonset and Ap RVaCRT were larger. The Ap-LVp induced increase in LV dP/dtmax was larger at Ap RVvis, Ap-RVEGMV, and Ap-RVVCG than at Ap-QRSonset (all P < 0.05) and Ap-RVaCRT (P = 0.02, P = 0.13, and P = 0.03, respectively). Conclusion: In this acute study, it is shown that the EGMV QRSampl can be used to determine optimal and individual CRT-device settings for LV fusion pacing, possibly improving long-term CRT response. PMID- 29106561 TI - Toward an Ecological Framework for Assessing Reservoirs of Vector-Borne Pathogens: Wildlife Reservoirs of Trypanosoma cruzi across the Southern United States. AB - Wildlife species are critical for both feeding vectors and serving as reservoirs of zoonotic vector-borne pathogens. Transmission pathways leading to disease in humans or other target taxa might be better understood and managed given a complete understanding of the relative importance of different reservoir species in nature. Using the conceptual framework of "reservoir potential," which considers elements of both reservoir competence and vector-host contact, we review the wildlife reservoirs of Trypanosoma cruzi in the southern United States, where many species of triatomine vectors occur and wildlife maintain enzootic cycles that create a risk of spillover to humans, domestic dogs, and captive nonhuman primates that may develop Chagas disease. We reviewed 77 published reports of T. cruzi infection in at least 26 wildlife species across 15 southern states. Among the most well-studied and highly infected reservoirs are raccoon (Procyon lotor), woodrat (Neotoma spp.), and opossum (Didelphis virginiana), with aggregate overall infection prevalences of 36.4, 34.7, and 22.9%, respectively. Just over 60% of studies utilized methods from which an infectiousness index could be generated and show that raccoons and striped skunk (Mephitis mephitis) are among the most infectious wildlife hosts. Triatomine-host contact has sparsely been quantified in the southern United States, but 18 of the 24 host species previously identified to have been fed upon by triatomines are wildlife. Future studies to parameterize the reservoir potential model, especially to quantify wildlife infectiousness, vector-host contact, and the epidemiological importance of parasite strains maintained by wildlife, could open new doors for managing enzootic cycles and reducing T. cruzi spillover risk. PMID- 29106564 TI - Modelling recurrence and second cancer risks induced by proton therapy. AB - In the past few years, proton therapy has taken the centre stage in treating various tumour types. The primary contribution of this study is to investigate the tumour control probability (TCP), relapse time and the corresponding secondary cancer risks induced by proton beam radiation therapy. We incorporate tumour relapse kinetics into the TCP framework and calculate the associated second cancer risks. To calculate proton therapy-induced secondary cancer induction, we used the well-known biologically motivated mathematical model, initiation-inactivation-proliferation formalism. We used the available in vitro data for the linear energy transfer (LET) dependence of cell killing and mutation induction parameters. We evaluated the TCP and radiation-induced second cancer risks for protons in the clinical range of LETs, i.e. approximately 8 $?mathrm{keV/?mu m}$ for the tumour volume and 1-3 $?mathrm{keV/?mu m}$ for the organs at risk. This study may serve as a framework for further work in this field and elucidates proton-induced TCP and the associated secondary cancer risks, not previously reported in the literature. Although studies with a greater number of cell lines would reduce uncertainties within the model parameters, we argue that the theoretical framework presented within is a sufficient rationale to assess proton radiation TCP, relapse and carcinogenic effects in various treatment plans. We show that compared with photon therapy, proton therapy markedly reduces the risk of secondary malignancies and for equivalent dosing regimens achieves better tumour control as well as a reduced primary recurrence outcome, especially within a hypo-fractionated regimen. PMID- 29106565 TI - Optimum position of transthoracic intracardiac line following cardiac surgery. AB - OBJECTIVES: The transthoracic intracardiac line placed in the right atrium provides a convenient access to the central venous system following cardiac surgery. However, it is associated with risks such as migration and bleeding. We conducted a retrospective study to determine whether position of transthoracic line with respect to site of exit from the chest makes a difference in the rate of complications. METHODS: All infants receiving a transthoracic intracardiac line in the right atrium following cardiac surgery between June 2012 and December 2015 were part of the study. A 3.5-Fr double-lumen umbilical venous catheter was placed directly into the right atrium. The lines exited the thorax either above in the suprasternal notch (upper transthoracic line) or below the diaphragm across the abdominal wall (lower transthoracic line). Patients were analysed for complications such as catheter migration, bleeding upon removal, atrial thrombus, line occlusion, premature removal and failed removal. RESULTS: A total of 131 patients received a transthoracic intracardiac line during the study period. Of the total patients, 88 patients received the upper transthoracic line and 43 patients received the lower transthoracic line. The upper transthoracic line was associated with significantly lower incidence of catheter migration (1% vs 14%) and this held by multivariable logistic regression, adjusting for age and duration of the line (P = 0.003). There was no difference in the rate of other complications including bleeding. CONCLUSIONS: The upper transthoracic line is associated with significantly lower incidence of catheter migration and offers a more optimum position for central access following cardiac surgery. PMID- 29106566 TI - Numerical optimal control for HIV prevention with dynamic budget allocation. AB - This article is about numerical control of HIV propagation. The contribution of the article is threefold: first, a novel model of HIV propagation is proposed; second, the methods from numerical optimal control are successfully applied to the developed model to compute optimal control profiles; finally, the computed results are applied to the real problem yielding important and practically relevant results. PMID- 29106567 TI - Cohort Profile: Longitudinal study of preterm infants in the Pays de la Loire region of France (LIFT cohort). PMID- 29106568 TI - Spillover effects in epidemiology: parameters, study designs and methodological considerations. AB - Many public health interventions provide benefits that extend beyond their direct recipients and impact people in close physical or social proximity who did not directly receive the intervention themselves. A classic example of this phenomenon is the herd protection provided by many vaccines. If these 'spillover effects' (i.e. 'herd effects') are present in the same direction as the effects on the intended recipients, studies that only estimate direct effects on recipients will likely underestimate the full public health benefits of the intervention. Causal inference assumptions for spillover parameters have been articulated in the vaccine literature, but many studies measuring spillovers of other types of public health interventions have not drawn upon that literature. In conjunction with a systematic review we conducted of spillovers of public health interventions delivered in low- and middle-income countries, we classified the most widely used spillover parameters reported in the empirical literature into a standard notation. General classes of spillover parameters include: cluster-level spillovers; spillovers conditional on treatment or outcome density, distance or the number of treated social network links; and vaccine efficacy parameters related to spillovers. We draw on high quality empirical examples to illustrate each of these parameters. We describe study designs to estimate spillovers and assumptions required to make causal inferences about spillovers. We aim to advance and encourage methods for spillover estimation and reporting by standardizing spillover parameter nomenclature and articulating the causal inference assumptions required to estimate spillovers. PMID- 29106569 TI - Mechanism and Catalytic Site Atlas (M-CSA): a database of enzyme reaction mechanisms and active sites. AB - M-CSA (Mechanism and Catalytic Site Atlas) is a database of enzyme active sites and reaction mechanisms that can be accessed at www.ebi.ac.uk/thornton-srv/m-csa. Our objectives with M-CSA are to provide an open data resource for the community to browse known enzyme reaction mechanisms and catalytic sites, and to use the dataset to understand enzyme function and evolution. M-CSA results from the merging of two existing databases, MACiE (Mechanism, Annotation and Classification in Enzymes), a database of enzyme mechanisms, and CSA (Catalytic Site Atlas), a database of catalytic sites of enzymes. We are releasing M-CSA as a new website and underlying database architecture. At the moment, M-CSA contains 961 entries, 423 of these with detailed mechanism information, and 538 with information on the catalytic site residues only. In total, these cover 81% (195/241) of third level EC numbers with a PDB structure, and 30% (840/2793) of fourth level EC numbers with a PDB structure, out of 6028 in total. By searching for close homologues, we are able to extend M-CSA coverage of PDB and UniProtKB to 51 993 structures and to over five million sequences, respectively, of which about 40% and 30% have a conserved active site. PMID- 29106570 TI - The UCSC Genome Browser database: 2018 update. AB - The UCSC Genome Browser (https://genome.ucsc.edu) provides a web interface for exploring annotated genome assemblies. The assemblies and annotation tracks are updated on an ongoing basis-12 assemblies and more than 28 tracks were added in the past year. Two recent additions are a display of CRISPR/Cas9 guide sequences and an interactive navigator for gene interactions. Other upgrades from the past year include a command-line version of the Variant Annotation Integrator, support for Human Genome Variation Society variant nomenclature input and output, and a revised highlighting tool that now supports multiple simultaneous regions and colors. PMID- 29106572 TI - Do hospital admission rates increase in colder winters? A decadal analysis from an eastern county in England. AB - Background: The aim of the study was to measure the effect of colder winters compared to warmer winters on hospital admission rates in Suffolk County. Methods: The setting of this study was Suffolk County in eastern England. The period of the study was financial years 2003/04-2012/13. The study was an analytic ecological study. Analysis involved calculation of rate ratios of hospital admission rates in colder winters compared to warmer winters, in all persons and the elderly. Results: The main finding of the study was that all rate ratios for hospital admission rates in colder winters compared to warmer winters were significantly raised with effects of 2-5%. Rate ratios for all admissions in persons of all ages and persons aged 65 years and over were, respectively, 1.02 (99% confidence interval (CI): 1.01, 1.03; P < 0.001) and 1.02 (99% CI: 1.01, 1.04; P < 0.001). Rate ratios for emergency admissions in persons of all ages and persons aged 65 years and over were, respectively, 1.05 (99% CI: 1.03, 1.06; P < 0.001) and 1.04 (99% CI: 1.01, 1.06; P < 0.001). Conclusion: In Suffolk County, hospital admission rates are significantly raised in colder winters compared to warmer winters. This evidence may be useful in planning hospital services. PMID- 29106571 TI - Retrieval-Induced Upregulation of Tet3 in Pyramidal Neurons of the Dorsal Hippocampus Mediates Cocaine-Associated Memory Reconsolidation. AB - Background: Memory retrieval refers to reexposure to information previously encoded and stored in the brain. Following retrieval, a once-consolidated memory destabilizes and undergoes reconsolidation, during which gene expression changes to restabilize memory. Investigating epigenetic regulation during reconsolidation could provide insights into normal memory formation and pathological memory associated with psychiatric disorders. Methods: We used cocaine-induced conditioned place preference to assess the cocaine-associated memory of mice and used chemogenetic methods to manipulate the activity of the pyramidal neurons in the dorsal hippocampus. We isolated the ribosome-associated transcripts from the excitatory neurons in the dorsal hippocampus by RiboTag purification to identify the potential epigenetic regulators, and we specifically knocked down gene expression in pyramidal neurons with a Cre-dependent lentivirus. Results: Chemogenetically silencing the activity of the pyramidal neurons in the dorsal hippocampus immediately after memory retrieval markedly impaired memory reconsolidation, and the ribosome-associated mRNA level of the ten-eleven translocation (Tet) family methylcytosine dioxygenase Tet3, but not Tet1 or Tet2, was dramatically upregulated 10 minutes after memory retrieval. The protein level of Tet3 in the dorsal hippocampus but not in the anterior cingulate cortex was dramatically increased 1 hour after memory retrieval. Specifically, knockdown of Tet3 in pyramidal neurons in the dorsal hippocampus decreased the activation of pyramidal neurons and impaired the reconsolidation of cocaine-associated memory. Conclusions: Our findings highlight the new function of the DNA demethylation regulator Tet3 in pyramidal neurons of the dorsal hippocampus in regulating the reconsolidation of cocaine-associated memory. PMID- 29106573 TI - Endobronchial brachytherapy with curative intent: the impact of reference points setting according to the bronchial diameter. AB - Endobronchial brachytherapy (EBB) is an effective treatment for endobronchial tumors. However, bronchial toxicity caused by over-irradiation remains problematic. To decrease bronchial toxicity, we developed a source-centralizing applicator for EBB. The purpose of the present study was to assess the efficacy and safety of EBB with varying reference dose points according to the bronchial diameter, using a source-centralizing applicator. We reviewed 15 patients with endobronchial carcinoma who were treated with curative intent using a combination of external beam radiotherapy (EBRT) and high-dose-rate EBB between 2005 and 2014. During each EBB session, we used a source-centralizing applicator that maintained the source-delivering catheter in the center of the bronchial lumen. Reference dose points were 5-7 mm from the source axis, depending on the bronchial diameter. The median radiation doses of EBRT and EBB were 40 Gy in 20 fractions and 18 Gy in 3 fractions, respectively. The median observation period was 36 months. The 3-year overall survival, progression-free survival and local control rates were 79%, 77% and 100%, respectively. Grade 2 radiation pneumonitis was observed in two cases. Bronchial toxicities, such as hemoptysis or the symptoms of chronic bronchitis, were not observed. EBB with varying reference dose points according to bronchial diameter, using a source-centralizing applicator, is a promising procedure that may be effective for tumor elimination and reducing toxicity to the bronchial wall. PMID- 29106575 TI - Is the stroke volume during post-ectopic beat associated with ventricular premature complex-related symptoms? AB - Aims: This study aimed to investigate if increased stroke volume (SV) after a ventricular premature complex (VPC) was related to VPC-related symptoms. Methods and results: We selected patients having an isolated VPC during echocardiography from a prospective registry that included patients with a structurally normal heart and 24-h VPC >1%. Patients were divided into two groups according to the presence or absence of VPC-related symptoms (skipped beat or palpitation) when VPC occurred. Left ventricular (LV) volumes and time-velocity integral (TVI) at the LV outflow tract were measured during the preceding sinus beat, VPC, and post ectopic sinus beat. Percent LV SV of the VPC and post-ectopic sinus beat were calculated by dividing each SV by the SV of the preceding sinus beat. A total of 47 patients were eligible. Most patients had VPC with left bundle branch block morphology and inferior axis. Patients in the symptom (+) group had a significantly lower SV, %LV SV, and TVI during post-ectopic sinus beat than those in the symptom (-) group. The sum of SVs during VPC and post-ectopic beat was significantly lower in symptomatic patients than non-symptomatic patients (103.4 mL vs. 125.1 mL, P = 0.02), while the sum of %LV SVs during VPC and post-ectopic beat tended to be lower in patients with symptoms than those without symptoms (P = 0.08). The sum of %LV SVs during VPC and post-VPC was positively correlated with coupling interval (CI) and CI ratio. Conclusion: Ventricular premature complex-related symptoms may not be associated with the amount of post-VPC SV. PMID- 29106574 TI - A conceptual framework for investigating the impacts of international trade and investment agreements on noncommunicable disease risk factors. AB - We developed a conceptual framework exploring pathways between trade and investment and noncommunicable disease (NCD) outcomes. Despite increased knowledge of the relevance of social and structural determinants of health, the discourse on NCD prevention has been dominated by individualizing paradigms targeted at lifestyle interventions. We situate individual risk factors, alongside key social determinants of health, as being conditioned and constrained by trade and investment policy, with the aim of creating a more comprehensive approach to investigations of the health impacts of trade and investment agreements, and to encourage upstream approaches to combating rising rates of NCDs. To develop the framework we employed causal chain analysis, a technique which sequences the immediate causes, underlying causes, and root causes of an outcome; and realist review, a type of literature review focussed on explaining the underlying mechanisms connecting two events. The results explore how facilitating trade in goods can increase flows of affordable unhealthy imports; while potentially altering revenues for public service provision and reshaping domestic economies and labour markets-both of which distribute and redistribute resources for healthy lifestyles. The facilitation of cross-border trade in services and investment can drive foreign investment in unhealthy commodities, which in turn, influences consumption of these products; while altering accessibility to pharmaceuticals that may mediate NCDs outcomes that result from increased consumption. Furthermore, trade and investment provisions that influence the policy-making process, set international standards, and restrict policy-space, may alter a state's propensity for regulating unhealthy commodities and the efficacy of those regulations. It is the hope that the development of this conceptual framework will encourage capacity and inclination among a greater number of researchers to investigate a more comprehensive range of potential health impacts of trade and investment agreements to generate an extensive and robust evidence-base to guide future policy actions in this area. PMID- 29106576 TI - The stromal cell-derived factor 1/C-X-C chemokine receptor type 4 axis is important in neutrophil migration caused by cardiopulmonary bypass in children. AB - OBJECTIVES: Acute lung injury caused by cardiopulmonary bypass (CPB) is characterized by massive neutrophil migration to the lungs. Neutrophil migration may be closely related to stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor Type 4 (CXCR4) axis activation, which plays an essential role in modulating the trafficking of neutrophils. We investigated the changes in the expression of SDF-1/CXCR4 axis components before and after CPB as well as the role of the axis in driving the migration of neutrophils in patients with congenital heart disease. METHODS: Fifteen children undergoing elective open heart surgery under CPB (CPB group) and 15 children undergoing minimally invasive ultrasound-guided closure of a ventricular septal defect (control group) were enrolled in this non-randomized clinical trial. Neutrophil CXCR4 expression was evaluated using quantitative reverse transcription polymerase chain reaction and flow cytometry. An enzyme-linked immunosorbent assay was used to measure plasma SDF-1 levels. The migration characteristics of neutrophils under 8 different combinations designated A-H were assayed with and without a specific CXCR4 antagonist, AMD3100, to evaluate the functional significance of the SDF-1/CXCR4 axis. RESULTS: Both CXCR4 gene and protein expressions were elevated in the CPB group compared with the control group after CPB (0.81 +/- 0.55 vs 1.76 +/- 1.32; P < 0.05, 1.96 +/- 0.86 vs 2.65 +/- 0.79; P < 0.05), and plasma SDF-1 levels were also increased in the former compared with the latter (197.84 +/- 19.96 pg/ml vs 539.13 +/- 99.83 pg/ml; P < 0.05). The in vitro experiments showed that plasma isolated post-CPB exhibited the strongest chemotactic effect on neutrophils. The CPB group showed a higher chemotaxis index, which serves as a marker for the effects of plasma on neutrophils, than that for the control group after CPB (37.38 +/- 9.39 vs 13.61 +/- 2.59; P < 0.05). In addition, the CXCR4 antagonist AMD3100 significantly abrogated the increase in neutrophil migration in the CPB group. CONCLUSIONS: Exposure to CPB, which activates the SDF-1/CXCR4 axis, using an antagonist to prevent neutrophil trafficking, may be a beneficial therapy for the related complications. PMID- 29106577 TI - Pacing for hypertrophic obstructive cardiomyopathy: an update and future directions. AB - In hypertrophic cardiomyopathy (HCM) patients with symptoms caused by left ventricular outflow tract obstruction (LVOTO), treatment options include negative inotropic drugs, myectomy, septal alcohol ablation and AV sequential pacing with or without an implantable cardioverter defibrillator (ICD). Pacing is rarely used in spite of its relative simplicity and promising results. In this review the current evidence of AV sequential pacing from observational, randomised studies and long and very long-term follow-up studies is given and put in the context of present guidelines recommendations. These studies indicate that AV sequential pacing improves symptoms and quality of life through decreases in LVOTO, systolic anterior movement and mitral regurgitation. Effects on morbidity and mortality are lacking. We describe the mechanisms of action, the prerequisites for successful pacing and provide practical advice on how to optimise therapy. Moreover, the role of the ICD for primary and secondary prevention is discussed with reference to the ESC HCM guidelines. In summary, AV sequential pacing for HOCM is underused in clinical practise despite evidence from two randomised controlled studies. This concept is currently the focus of two randomised studies: a planned randomised controlled study that will compare AV sequential pacing to TASH and an ongoing study that compares CRT to AAI pacing in HOCM patients. In this review we highlight the current evidence and the new interest for this therapy. PMID- 29106578 TI - Cancer risk in children born after donor ART. AB - STUDY QUESTION: Do children born after donor ART have an increased risk of developing childhood cancer in comparison to the general population? SUMMARY ANSWER: This study showed no overall increased risk of childhood cancer in individuals born after donor ART. WHAT IS KNOWN ALREADY: Most large population based studies have shown no increase in overall childhood cancer incidence after non-donor ART; however, other studies have suggested small increased risks in specific cancer types, including haematological cancers. Cancer risk specifically in children born after donor ART has not been investigated to date. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study utilized record linkage to determine the outcome status of all children born in Great Britain (1992-2008) after donor ART. The cohort included 12 137 members who contributed 95 389 person years of follow-up (average follow-up 7.86 years). PARTICIPANTS/MATERIALS, SETTING, METHODS: Records of all children born in Great Britain (England, Wales, Scotland) after all forms of donor ART (1992-2008) were linked to the UK National Registry of Childhood Tumours (NRCT) to determine the number who subsequently developed cancer by 15 years of age, by the end of 2008. Rates of overall and type specific cancer (selected a priori) were compared with age, sex and calendar year standardized population-based rates, stratifying for potential mediating/moderating factors including sex, age at diagnosis, birth weight, multiple births, maternal previous live births, assisted conception type and fresh/ cryopreserved cycles. MAIN RESULTS AND THE ROLE OF CHANCE: In our cohort of 12 137 children born after donor ART (52% male, 55% singleton births), no overall increased risk of cancer was identified. There were 12 cancers detected compared to 14.4 expected (standardized incidence ratio (SIR) 0.83; 95% CI 0.43 1.45; P = 0.50). A small, significant increased risk of hepatoblastoma was found, but the numbers and absolute risks were small (<5 cases observed; SIR 10.28; 95% CI 1.25-37.14; P < 0.05). This increased hepatoblastoma risk was associated with low birthweight. LIMITATIONS REASONS FOR CAUTION: Although this study includes a large number of children born after donor ART, the rarity of specific diagnostic subgroups of childhood cancer results in few cases and therefore wide CIs for such outcomes. As this is an observational study, it is not possible to adjust for all potential confounders; we have instead used stratification to explore potential moderating and mediating factors, where data were available. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to investigate cancer risk in children born after donor ART. Although based on small numbers, results are reassuring for families and clinicians. The small but significant increased risk of hepatoblastoma detected was associated with low birthweight, a known risk factor for this tumour type. It should be emphasized that the absolute risks are very small. However, on-going investigation with a longer follow-up is needed. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by Cancer Research UK (C36038/A12535) and the National Institute for Health Research (405526) and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The work of the Childhood Cancer Research Group (CCRG) was supported by the charity CHILDREN with CANCER UK, the National Cancer Intelligence Network, the Scottish Government and the Department of Health for England and Wales. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 29106579 TI - A small amount of precisely measured high-intensity habitual physical activity predicts bone health in pre- and post-menopausal women in UK Biobank. AB - Background: Physical inactivity is a highly modifiable risk factor for the development of osteoporosis but, due to a lack of research that has precisely and objectively meaured physical activity (PA) relevant to bone, the specific contribution that PA can make to bone health is poorly understood. This study examined whether a more precise measure of PA relelvant to bone was associated with meaures of bone health in pre- and post-menopausal women in UK Biobank. Methods: Time spent at intensities specific to bone health [>=750 milli gravitational units (mg) and >=1000 mg] were analysed from raw tri-axial acceleration data averaged over 1-second epochs from 7-day monitoring of habitual PA using accelerometry-based activity monitors (100 Hz; AX3, Axivity, UK) of 1218 pre- and 1316 post-menopausal healthy women. In a cross-sectional analysis, associations between categories of time (<1, 1-2 and >=2 minutes) spent above the intensity thresholds and calcaneal quantitative ultrasound measures of bone health (bone mineral density T-score, BMDT-score; speed of sound, SOS; and broadband ultrasound attenuation, BUA) were examined. Results: Compared with <1 minute, spending 1-2 or >=2 minutes/day at intensities >=1000 mg in pre menopausal and >=750 mg in post-menopausal women was positively associated with BMDT-score, SOS and BUA. Conclusion: Brief bursts of high-intensity PA relevant to bone health can be captured by applying bone-specific thresholds of intensity to raw tri-axial accelerations averaged over 1-second epochs. Accumulating 1-2 minutes/day of high-intensity PA, equivalent to running in pre-menopausal women and slow jogging in post-menopausal women, is associated with better bone health. PMID- 29106580 TI - Physical activity phenotyping with activity bigrams, and their association with BMI. AB - Background: Analysis of physical activity usually focuses on a small number of summary statistics derived from accelerometer recordings: average counts per minute and the proportion of time spent in moderate-vigorous physical activity or in sedentary behaviour. We show how bigrams, a concept from the field of text mining, can be used to describe how a person's activity levels change across (brief) time points. These variables can, for instance, differentiate between two people spending the same time in moderate activity, where one person often stays in moderate activity from one moment to the next and the other does not. Methods: We use data on 4810 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). We generate a profile of bigram frequencies for each participant and test the association of each frequency with body mass index (BMI), as an exemplar. Results: We found several associations between changes in bigram frequencies and BMI. For instance, a one standard deviation decrease in the number of adjacent minutes in sedentary then moderate activity (or vice versa), with a corresponding increase in the number of adjacent minutes in moderate then vigorous activity (or vice versa), was associated with a 2.36 kg/m2 lower BMI [95% confidence interval (CI): -3.47, -1.26], after accounting for the time spent in sedentary, low, moderate and vigorous activity. Conclusions: Activity bigrams are novel variables that capture how a person's activity changes from one moment to the next. These variables can be used to investigate how sequential activity patterns associate with other traits. PMID- 29106582 TI - Effectiveness of community pharmacies in improving seasonal influenza uptake-an evaluation using the Donabedian framework. AB - Background: Community pharmacies are now commissioned nationally in England to provide a seasonal influenza vaccination service. However, there is little evidence about the effectiveness of a pharmacy-based immunization service in improving uptake. Methods: The Donabedian framework was used to evaluate a community pharmacy service in the West Midlands from a commissioning perspective. A mixed methods approach was adopted, including provider and patient surveys, data from the national influenza vaccination returns and an electronic pharmacy data recording system. Results: Patient satisfaction with the service was high. There was no increase in uptake rates. Impact on reaching new patients was limited. The service had an appropriate information system to record activity. Promotion and signposting for the service was weak. Poor engagement with stakeholders led to dissatisfaction and General Practitioner complaints. Commissioners responded to emerging issues to ensure the pharmacies' set up was compliant with the Service Level Agreement. Conclusions: Improvements in convenience and choice for patients did not result in an increase in uptake rates. With a national pharmacy influenza programme, local arrangements to optimize the service may be limited. Clear arrangements for activity transfer and recording, partnership working and a good communications strategy are crucial in achieving a positive outcome. PMID- 29106581 TI - The CD44 standard isoform contributes to radioresistance of pancreatic cancer cells. AB - Resistance to chemoradiotherapy is one reason for the increased recurrence rate of pancreatic cancer after these therapies. These cells change the expression levels of several proteins, such as epithelial-mesenchymal transition (EMT), while acquiring the chemo- or radio-resistance. In this study, we focused on CD44, a pancreatic cancer stem cell marker. CD44 has isoforms with different functions: standard isoform (CD44s) and several variant isoforms (CD44v). However, little is known about the roles of these isoforms after ionizing irradiation. The purpose of this study was to investigate the role of CD44 isoforms in radioresistance of pancreatic cancer cells. AsPC-1 (a human pancreatic cancer cell line) was irradiated with 4 MV X-rays. The mRNA and protein levels of CD44s were strongly upregulated, dose dependently, compared with CD44v after irradiation. Thus, we further investigated CD44s at the point of cell proliferation. We evaluated cell proliferation and survival, using CD44s knockdown cells. CD44s knockdown did not change the proliferation rate for up to 72 h after the irradiation, but decreased cell viability in the colony formation assay. As one of the reasons for these effects, we found downregulation of phosphorylated extracellular signal-regulated kinase (Erk; which is involved with cell proliferation) by CD44s knockdown, time dependently. Moreover, radiation induced EMT-like expression changes were detected and suppressed by CD44s knockdown. In conclusion, our work demonstrated that CD44 standard isoform was especially upregulated after high-dose X-ray irradiation in several isoforms of CD44 and contributed to longer-term cell survival after the irradiation through the maintenance of Erk phosphorylation and radiation-induced EMT. PMID- 29106583 TI - Pathogen transfer through environment-host contact: an agent-based queueing theoretic framework. AB - Queueing theory studies the properties of waiting queues and has been applied to investigate direct host-to-host transmitted disease dynamics, but its potential in modelling environmentally transmitted pathogens has not been fully explored. In this study, we provide a flexible and customizable queueing theory modelling framework with three major subroutines to study the in-hospital contact processes between environments and hosts and potential nosocomial pathogen transfer, where environments are servers and hosts are customers. Two types of servers with different parameters but the same utilization are investigated. We consider various forms of transfer functions that map contact duration to the amount of pathogen transfer based on existing literature. We propose a case study of simulated in-hospital contact processes and apply stochastic queues to analyse the amount of pathogen transfer under different transfer functions, and assume that pathogen amount decreases during the inter-arrival time. Different host behaviour (feedback and non-feedback) as well as initial pathogen distribution (whether in environment and/or in hosts) are also considered and simulated. We assess pathogen transfer and circulation under these various conditions and highlight the importance of the nonlinear interactions among contact processes, transfer functions and pathogen demography during the contact process. Our modelling framework can be readily extended to more complicated queueing networks to simulate more realistic situations by adjusting parameters such as the number and type of servers and customers, and adding extra subroutines. PMID- 29106585 TI - Development of the PHAST model: generating standard public health services data and evidence for decision-making. AB - Objective: Standardized data regarding the distribution, quality, reach, and variation in public health services provided at the community level and in wide use across states and communities do not exist. This leaves a major gap in our nation's understanding of the value of prevention activities and, in particular, the contributions of our government public health agencies charged with assuring community health promotion and protection. Public health and community leaders, therefore, are eager for accessible and comparable data regarding preventive services that can inform policy decisions about where to invest resources. Methods: We used literature review and a practice-based approach, employing an iterative process to identify factors that facilitate data provision among public health practitioners. Results: This paper describes the model, systematically developed by our research team and with input from practice partners, that guides our process toward maximizing the uptake and integration of these standardized measures into state and local data collection systems. Discussion: The model we developed, using a dissemination and implementation science framework, is intended to foster greater interest in and accountability for data collection around local health department services and to facilitate spatial exploration and statistical analysis of local health department service distribution, change, and performance. Conclusion: Our model is the first of its kind to thoroughly develop a means to guide research and practice in realizing the National Academy of Medicine's recommendation for developing systems to measure and track state and local public health system contributions to population health. PMID- 29106584 TI - Plasma trough concentrations of antiretrovirals in HIV-infected persons treated with direct-acting antiviral agents for hepatitis C in the real world. AB - Background: Possible drug-drug interactions (DDIs) between antiretrovirals (ARVs) and direct-acting antiviral agents (DAAs) are of some concern. Objectives: To investigate ARV plasma trough concentrations (Ctrough) before and during DAAs in patients treated in the real world. Methods: Single-centre, prospective, observational study including HIV/HCV coinfected persons undergoing DAA treatment. Self-reported adherence was assessed and ARVs Ctrough measured by HPLC UV. Blood samples were collected before and after 2 months of DAA treatment. Results: One-hundred and thirty-seven patients were included: 21.2% treated with ombitasvir/paritaprevir/ritonavir +/- dasabuvir (2D/3D) and 78.8% with sofosbuvir based regimens. Suboptimal Ctrough before and during DAA was found, respectively, in 3 (10.3%) and 3 (10.3%) cases treated with 2D/3D, and 16 (14.8%) and 11 (10.2%) with sofosbuvir-based regimens, even if self-reported ARV adherence was always >=93%. In 2D/3D-treated patients, median darunavir Ctrough during DAAs was significantly lower than observed before DAAs [1125 ng/mL (IQR, 810-1616) versus 1903 ng/mL (IQR 1387-3983), respectively] (n = 5; P = 0.009), with a 40.9% decrease. In the same group, no differences in atazanavir or raltegravir concentrations were found. In patients treated with sofosbuvir-based regimens, Ctrough of all ARVs were similar before and during DAAs. Conclusions: In the real world of HIV/HCV coinfected patients, ARV plasma concentrations during DAAs were generally not different from those found before anti-HCV treatment. Although assessed in a small number of patients, darunavir concentrations during 2D/3D showed a significant reduction when compared with those found before DAAs. ARV plasma concentrations measurement during anti-HCV treatment may give useful information for managing HIV/HCV coinfected persons receiving treatment for both infections. PMID- 29106587 TI - Tracking and responding to an outbreak of tuberculosis using MIRU-VNTR genotyping and whole genome sequencing as epidemiological tools. AB - Background: We describe an outbreak that contributed to a near doubling of the incidence of tuberculosis in Southampton, UK. We examine the importance of 24 locus mycobacterial interspersed repetitive unit variable number tandem repeat (MIRU-VNTR) genotyping in its identification and management and the role of whole genome sequencing (WGS) in tracing the spread of the strain. Methods: Outbreak cases were defined as those diagnosed between January and December 2011 with indistinguishable 24 locus-MIRU-VNTR genotypes or, cases linked epidemiologically. A cluster questionnaire was administered by TB nurses to identify contacts and social settings. Results: Overall, 25 patients fulfilled the case definition. No cases with this MIRU-VNTR genotype had been detected in the UK previously. Connections were found between all cases through household contacts or social venues including a football club, Internet cafe and barber's shop. Public health actions included extended contact tracing, venue screening and TB awareness-raising. The outbreak resulted in a high rate of transmission and high incidence of clinical disease among contacts. Conclusions: This outbreak illustrates the value of combining active case-finding with prospective MIRU-VNTR genotyping to identify settings to undertake public health action. In addition WGS revealed that the VNTR-defined cluster was a single outbreak and that active TB transmission not reactivation was responsible for this outbreak in non-UK born individuals. PMID- 29106586 TI - Vaccination With a Latch Peptide Provides Serotype-Independent Protection Against Group B Streptococcus Infection in Mice. AB - Streptococcus agalactiae (group B streptococcus [GBS]) is a leading cause of invasive diseases in neonates and severe infections in elderly individuals. GBS serine-rich repeat glycoprotein 1 (Srr1) acts as a critical virulence factor by facilitating GBS invasion into the central nervous system through interaction with the fibrinogen Aalpha chain. This study revealed that srr1 is highly conserved, with 86.7% of GBS clinical isolates expressing the protein. Vaccination of mice with different Srr1 truncated peptides revealed that only Srr1 truncates containing the latch domain protected against GBS meningitis. Furthermore, the latch peptide alone was immunogenic and elicited protective antibodies, which efficiently enhanced antibody-mediated opsonophagocytic killing of GBS by HL60 cells and provided heterogeneous protection against 4 different GBS serogroups. Taken together, these findings indicated that the latch domain of Srr1 may constitute an effective peptide vaccine candidate for GBS. PMID- 29106588 TI - NLSdb-major update for database of nuclear localization signals and nuclear export signals. AB - NLSdb is a database collecting nuclear export signals (NES) and nuclear localization signals (NLS) along with experimentally annotated nuclear and non nuclear proteins. NES and NLS are short sequence motifs related to protein transport out of and into the nucleus. The updated NLSdb now contains 2253 NLS and introduces 398 NES. The potential sets of novel NES and NLS have been generated by a simple 'in silico mutagenesis' protocol. We started with motifs annotated by experiments. In step 1, we increased specificity such that no known non-nuclear protein matched the refined motif. In step 2, we increased the sensitivity trying to match several different families with a motif. We then iterated over steps 1 and 2. The final set of 2253 NLS motifs matched 35% of 8421 experimentally verified nuclear proteins (up from 21% for the previous version) and none of 18 278 non-nuclear proteins. We updated the web interface providing multiple options to search protein sequences for NES and NLS motifs, and to evaluate your own signal sequences. NLSdb can be accessed via Rostlab services at: https://rostlab.org/services/nlsdb/. PMID- 29106589 TI - A Multicenter Consortium to Define the Epidemiology and Outcomes of Inpatient Respiratory Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients. AB - Background: Respiratory virus infections (RVIs) pose a threat to children undergoing hematopoietic stem cell transplantation (HSCT). In this era of sensitive molecular diagnostics, the incidence and outcome of HSCT recipients who are hospitalized with RVI (H-RVI) are not well described. Methods: A retrospective observational cohort of pediatric HSCT recipients (between January 2010 and June 2013) was assembled from 9 US pediatric transplant centers. Their medical charts were reviewed for H-RVI events within 1 year after their transplant. An H-RVI diagnosis required respiratory signs or symptoms plus viral detection (human rhinovirus/enterovirus, human metapneumovirus, influenza, parainfluenza, coronaviruses, and/or respiratory syncytial virus). The incidence of H-RVI was calculated, and the association of baseline HSCT factors with subsequent pulmonary complications and death was assessed. Results: Among 1560 HSCT recipients, 259 (16.6%) acquired at least 1 H-RVI within 1 year after their transplant. The median age of the patients with an H-RVI was lower than that of patients without an H-RVI (4.8 vs 7.1 years; P < .001). Among the patients with a first H-RVI, 48% required some respiratory support, and 14% suffered significant pulmonary sequelae. The all-cause and attributable case-fatality rates within 3 months of H-RVI onset were 11% and 5.4%, respectively. Multivariate logistic regression revealed that H-RVI onset within 60 days of HSCT, steroid use in the 7 days before H-RVI onset, and the need for respiratory support at H-RVI onset were associated with subsequent morbidity or death. Conclusion: Results of this multicenter cohort study suggest that H-RVIs are relatively common in pediatric HSCT recipients and contribute to significant morbidity and death. These data should help inform interventional studies specific to each viral pathogen. PMID- 29106590 TI - Antibody-Dependent Cellular Cytotoxicity Responses to Seasonal Influenza Vaccination in Older Adults. AB - Background: Older adults are at high risk of influenza disease, but generally respond poorly to vaccination. Antibody-dependent cellular cytotoxicity (ADCC) may be an important component of protection against influenza infection. An improved understanding of the ADCC response to influenza vaccination in older adults is required. Methods: We studied sera samples from 3 groups of subjects aged >=65 years (n = 16-17/group) receiving the 2008/2009 seasonal trivalent influenza vaccine (TIV). Subjects had minimal pre-existing hemagglutination inhibiting (HAI) antibodies and TIV induced either no, low, or high HAI responses. Serum ADCC activity was analyzed using Fc receptor cross-linking, NK cell activation, and influenza-infected cell killing. Results: Most subjects from TIV nonresponder, low responder, and high responder groups had detectable ADCC antibodies prevaccination, but baseline ADCC was not predictive of HAI vaccine responsiveness. Interestingly, ADCC and HAI responses tracked closely across all groups, against all 3 TIV hemagglutinins, and in all ADCC assays tested. Conclusions: Older adults commonly have pre-existing ADCC antibodies in the absence of high HAI titers to circulating influenza strains. In older vaccinees, ADCC response mirrored HAI antibodies and was readily detectable despite high postvaccination HAI titers. Alternate measures of vaccine responsiveness and improved vaccinations in this at-risk group are needed. PMID- 29106592 TI - Intrahost Genetic Diversity of Bacterial Symbionts Exhibits Evidence of Mixed Infections and Recombinant Haplotypes. AB - Even the simplest microbial-eukaryotic mutualisms are comprised of entire populations of symbionts at the level of the host individual. Early work suggested that these intrahost populations maintain low genetic diversity as a result of transmission bottlenecks or to avoid competition between symbiont genotypes. However, the amount of genetic diversity among symbionts within a single host remains largely unexplored. To address this, we investigated the chemosynthetic symbiosis between the bivalve Solemya velum and its intracellular bacterial symbionts, which exhibits evidence of both vertical and horizontal transmission. Intrahost symbiont populations were sequenced to high coverage (200 1,000*). Analyses of nucleotide diversity revealed that the symbiont genome sequences were largely homogeneous within individual host specimens, consistent with vertical transmission, except for particular regions that were polymorphic in ~20% of host specimens. These variant sites were also found segregating in other host individuals from the same population, colocalized to several regions of the genome, and consistently co-occurred on the same short read pairs (derived from the same chromosome). These results strongly suggest that these variant haplotypes originated through recombination events, potentially during prior mixed infections or in the external environment, rather than as novel mutations within symbiont populations. This abundant genetic diversity could have a profound influence on symbiont evolution as it provides the opportunity for selection to limit the extent of reductive genome evolution commonly seen in obligate intracellular bacteria and to enable the evolution of adaptive genotypes. PMID- 29106591 TI - Comprehensive Characterization of Alternative Polyadenylation in Human Cancer. AB - Background: Alternative polyadenylation (APA) is emerging as a major post transcriptional mechanism for gene regulation, and dysregulation of APA contributes to several human diseases. However, the functional consequences of APA in human cancer are not fully understood. Particularly, there is no large scale analysis in cancer cell lines. Methods: We characterized the global APA profiles of 6398 patient samples across 17 cancer types from The Cancer Genome Atlas and 739 cancer cell lines from the Cancer Cell Line Encyclopedia. We built a linear regression model to explore the correlation between APA factors and APA events across different cancer types. We used Spearman correlation to assess the effects of APA events on drug sensitivity and the Wilcoxon rank-sum test or Cox proportional hazards model to identify clinically relevant APA events. Results: We revealed a striking global 3'UTR shortening in cancer cell lines compared with tumor samples. Our analysis further suggested PABPN1 as the master regulator in regulating APA profile across different cancer types. Furthermore, we showed that APA events could affect drug sensitivity, especially of drugs targeting chromatin modifiers. Finally, we identified 1971 clinically relevant APA events, as well as alterations of APA in clinically actionable genes, suggesting that analysis of the complexity of APA profiles could have clinical utility. Conclusions: Our study highlights important roles for APA in human cancer, including reshaping cellular pathways and regulating specific gene expression, exemplifying the complex interplay between APA and other biological processes and yielding new insights into the action mechanism of cancer drugs. PMID- 29106593 TI - Long-term outcome in 145 patients with assumed benign immunoglobulin A nephropathy. AB - Background: Patients with immunoglobulin A nephropathy (IgAN) who present with mild to moderate proteinuria and normal renal function are assumed to have excellent short-term renal prognosis, but the long-term prognosis is uncertain. Methods: Patients were selected from the Norwegian Kidney Biopsy Registry based on the following criteria: diagnostic renal biopsy performed in the period 1988 99, with estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m2 and proteinuria <1 g/24 h at the time of biopsy. Patients were invited for a nephrological examination with a review of medical history and investigation of blood pressure, urinary findings and eGFR. Results: A total of 145 patients attended the examination, performed by the first author, after a median of 22 (interquartile range 19-25) years after diagnosis. At the examination, 27 patients (18.6%) had a >=50% decrease in GFR, of whom 4 (2.8%) had developed end stage renal disease (ESRD). The mean duration from renal biopsy to >= 50% decrease in GFR was 17.3 +/- 5.1 years in our cohort. Clinical remission was observed in 42 (29.0%) patients. Renal biopsies were re-examined utilizing the Oxford classification criteria. Mesangial hypercellularity was found in 12.3%, endocapillary proliferation was detected in 10.7% and segmental glomerulosclerosis was observed in 23.8%. All biopsies were scored as T0 (tubular atrophy in < 25% of the cortical area). None of the clinical or histopathological variables recorded at the time of biopsy could identify patients with progressive disease. Cumulative risks of >=50% decrease in eGFR were 2.1% after 10 years, 4.1% after 15 years, 13.9% after 20 years and 24.7% after 25 years. Conclusions: We have shown that 18.6% of patients with assumed benign IgAN had progressive disease after a median duration of 22 years and that these patients could not be predicted at the time of biopsy. Our study demonstrates that an extended follow up period is needed when assessing prognosis in this group of patients. PMID- 29106594 TI - Estradiol Therapy After Menopause Mitigates Effects of Stress on Cortisol and Working Memory. AB - Context: Postmenopausal estradiol therapy (ET) can reduce the stress response. However, it remains unclear whether such reductions can mitigate effects of stress on cognition. Objective: Investigate effects of ET on cortisol response to a physical stressor, cold pressor test (CPT), and whether ET attenuates stress effects on working memory. Design: Women completed the CPT or control condition across two sessions and subsequently completed a sentence span task. Setting: General community: Participants were recruited from the Early vs Late Intervention Trial with Estradiol (ELITE). Participants: ELITE participants (mean age = 66, standard deviation age = 6.8) in this study did not suffer from any major chronic illness or use medications known to affect the stress response or cognition. Interventions: Participants had received a median of randomized 4.7 years of estradiol (n = 21) or placebo (n = 21) treatment at time of participation in this study. Main Outcome Measures: Salivary cortisol and sentence span task performance. Results: Women assigned to estradiol exhibited blunted cortisol responses to CPT compared with placebo (P = 0.017) and lesser negative effects of stress on working memory (P = 0.048). Conclusions: We present evidence suggesting ET may protect certain types of cognition in the presence of stress. Such estrogenic protection against stress hormone exposure may prove beneficial to both cognition and the neural circuitry that maintains and propagates cognitive faculties. PMID- 29106595 TI - Prognostic implication of aquaporin 1 overexpression in resected lung adenocarcinoma. AB - OBJECTIVES: Aquaporins (AQPs) are a group of transmembrane water-selective channel proteins thought to play a role in the regulation of water permeability for plasma membranes. Indeed, high AQP levels have been suggested to promote the progression, invasion and metastasis of tumours. Specifically, AQP1 and AQP5 overexpression in lung adenocarcinoma (AC) have been suggested to be involved in molecular mechanisms in lung cancer. The aim of this retrospective cohort single centre study was to assess both the levels of expression and therein the prognostic significance, regarding outcome of AQP1 and AQP5 in resected AC patients. METHODS: Patients with histological diagnoses of lung AC submitted to pulmonary resection were included in this cohort study. Tissue microarrays containing cores from 185 ACs were prepared. AQP1 and AQP5 expressions were assessed by immunohistochemistry. Results were scored as either low (Score 0-2) or high (Score 3-9). Clinical data, pathological tumour-node-metastasis staging and follow-up were recorded. Multivariate Cox survival analysis and Fisher's t test were performed. RESULTS: AQP1 overexpression was detected in 85 (46%) patients, while AQP5 overexpression was observed in 45 (24%) patients. AQP1 did not result being significantly correlated with clinical and pathological parameters, while AQP5 resulted more expressed in AC with mucinous and papillary predominant patterns. Patients with AQP1 overexpression had shorter disease-free survival (P = 0.001) compared with patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter disease-free survival (P = 0.001). CONCLUSIONS: Our results evidenced that AQP1 overexpression resulted in a shorter disease-free survival in lung AC patients. Being so, AQP1 overexpression might be an important prognostic marker in lung AC. PMID- 29106597 TI - Thermophilic Adaptation in Prokaryotes Is Constrained by Metabolic Costs of Proteostasis. AB - Prokaryotes evolved to thrive in an extremely diverse set of habitats, and their proteomes bear signatures of environmental conditions. Although correlations between amino acid usage and environmental temperature are well-documented, understanding of the mechanisms of thermal adaptation remains incomplete. Here, we couple the energetic costs of protein folding and protein homeostasis to build a microscopic model explaining both the overall amino acid composition and its temperature trends. Low biosynthesis costs lead to low diversity of physical interactions between amino acid residues, which in turn makes proteins less stable and drives up chaperone activity to maintain appropriate levels of folded, functional proteins. Assuming that the cost of chaperone activity is proportional to the fraction of unfolded client proteins, we simulated thermal adaptation of model proteins subject to minimization of the total cost of amino acid synthesis and chaperone activity. For the first time, we predicted both the proteome average amino acid abundances and their temperature trends simultaneously, and found strong correlations between model predictions and 402 genomes of bacteria and archaea. The energetic constraint on protein evolution is more apparent in highly expressed proteins, selected by codon adaptation index. We found that in bacteria, highly expressed proteins are similar in composition to thermophilic ones, whereas in archaea no correlation between predicted expression level and thermostability was observed. At the same time, thermal adaptations of highly expressed proteins in bacteria and archaea are nearly identical, suggesting that universal energetic constraints prevail over the phylogenetic differences between these domains of life. PMID- 29106596 TI - Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model. AB - All DNA polymerases misincorporate ribonucleotides despite their preference for deoxyribonucleotides, and analysis of cultured cells indicates that mammalian mitochondrial DNA (mtDNA) tolerates such replication errors. However, it is not clear to what extent misincorporation occurs in tissues, or whether this plays a role in human disease. Here, we show that mtDNA of solid tissues contains many more embedded ribonucleotides than that of cultured cells, consistent with the high ratio of ribonucleotide to deoxynucleotide triphosphates in tissues, and that riboadenosines account for three-quarters of them. The pattern of embedded ribonucleotides changes in a mouse model of Mpv17 deficiency, which displays a marked increase in rGMPs in mtDNA. However, while the mitochondrial dGTP is low in the Mpv17-/- liver, the brain shows no change in the overall dGTP pool, leading us to suggest that Mpv17 determines the local concentration or quality of dGTP. Embedded rGMPs are expected to distort the mtDNA and impede its replication, and elevated rGMP incorporation is associated with early-onset mtDNA depletion in liver and late-onset multiple deletions in brain of Mpv17-/- mice. These findings suggest aberrant ribonucleotide incorporation is a primary mtDNA abnormality that can result in pathology. PMID- 29106598 TI - Safety and effectiveness of restrictive eculizumab treatment in atypical haemolytic uremic syndrome. AB - Background: Atypical haemolytic uremic syndrome (aHUS) is a rare but severe form of thrombotic microangiopathy as a consequence of complement dysregulation. aHUS has a poor outcome with high mortality and >50% of patients developing end-stage renal disease. Since the end of 2012, these outcomes have greatly improved with the introduction of eculizumab. Currently the duration of treatment is debated. Most guidelines advise lifelong treatment. However, there is no hard evidence to support this advice. Historically, a substantial number of aHUS patients were weaned of plasma therapy, often without disease recurrence. Moreover, the long term consequences of eculizumab treatment are unknown. In this retrospective study we describe 20 patients who received a restrictive treatment regimen. Methods: All aHUS patients who presented in the Radboud University Medical Center, Nijmegen, The Netherlands, between 2012 and 2016 and who received eculizumab are described. Clinical, diagnostic and follow-up data were gathered and reviewed. Results: Twenty patients (14 adults, 6 children) with aHUS have received eculizumab. Eculizumab was tapered in all and stopped in 17 patients. aHUS recurrence occurred in five patients. Due to close monitoring, recurrence was detected early and eculizumab was restarted. No clinical sequela such as proteinuria or progressive kidney dysfunction was detected subsequently. In total, eculizumab has been discontinued in 13 patients without aHUS recurrence, of which 5 are event free for >1 year. With this strategy ~?11.4 million have been saved. Conclusions: A restrictive eculizumab regimen in aHUS appears safe and effective. Prospective studies should further evaluate the most optimal treatment strategy. PMID- 29106599 TI - ASpedia: a comprehensive encyclopedia of human alternative splicing. AB - Alternative splicing confers the human genome complexity by increasing the diversity of expressed mRNAs. Hundreds or thousands of splicing regions have been identified through differential alternative splicing analysis of high-throughput datasets. However, it is hard to explain the functional impact of each splicing event. Protein domain formation and nonsense-mediated decay are considered the main functional features of splicing. However, other functional features such as miRNA target sites, phosphorylation sites and single-nucleotide variations are directly affected by alternative splicing and affect downstream function. Hence, we established ASpedia: a comprehensive database for human alternative splicing annotation, which encompasses a range of functions, from genomic annotation to isoform-specific function (ASpedia, http://combio.snu.ac.kr/aspedia). The database provides three features: (i) genomic annotation extracted from DNA, RNA and proteins; (ii) transcription and regulation elements analyzed from next generation sequencing datasets; and (iii) isoform-specific functions collected from known and published datasets. The ASpedia web application includes three components: an annotation database, a retrieval system and a browser specialized in the identification of human alternative splicing events. The retrieval system supports multiple AS event searches resulting from high-throughput analysis and the AS browser comprises genome tracks. Thus, ASpedia facilitates the systemic annotation of the functional impacts of multiple AS events. PMID- 29106601 TI - Flexible fate commitment of E2-2high common DC progenitors implies tuning in tissue microenvironments. AB - The basic helix-loop-helix transcription factor E2-2 is essential for the development of plasmacytoid dendritic cells (pDCs) but not conventional DCs (cDCs). Here, we generated E2-2 reporter mice and demonstrated that an E2-2high fraction among common DC progenitors, which are a major source of pDCs and cDCs in the steady state, strictly gave rise to pDCs in the presence of Flt3 (Fms-like tyrosine kinase receptor-3) ligand ex vivo or in the secondary lymphoid organs when transferred in vivo. However, in the small intestine, some of these E2-2high progenitors differentiated into cDCs that produced retinoic acid. This transdifferentiation was driven by signaling via the common beta receptor, a receptor for the cytokines IL-3, IL-5 and GM-CSF, which are abundant in the gut. In the presence of GM-CSF and Flt3 ligand, E2-2high-progenitor-derived cDCs consistently induced Foxp3+ Treg cells ex vivo. Our findings reveal the commitment and flexibility of E2-2high progenitor differentiation and imply that pertinent tuning machinery is present in the gut microenvironment. PMID- 29106600 TI - Chronic irradiation with low-dose-rate 137Cs-gamma rays inhibits NGF-induced neurite extension of PC12 cells via Ca2+/calmodulin-dependent kinase II activation. AB - Chronic irradiation with low-dose-rate 137Cs-gamma rays inhibits the differentiation of human neural progenitor cells and influences the expression of proteins associated with several cellular functions. We aimed to determine whether such chronic irradiation influences the expression of proteins associated with PC12 cells. Chronic irradiation at 0.027 mGy/min resulted in inhibition of NGF-induced neurite extension. Furthermore, irradiation enhanced the nerve growth factor (NGF)-induced increase in the phosphorylation of extracellular signal regulated kinase (ERK), but did not affect the phosphorylation of NGF receptors, suggesting that irradiation influences pathways unassociated with the activation of ERK. We then examined whether irradiation influenced the Akt-Rac1 pathway, which is unaffected by ERK activation. Chronic irradiation also enhanced the NGF induced increase in Akt phosphorylation, but markedly inhibited the NGF-induced increase in Rac1 activity that is associated with neurite extension. These results suggest that the inhibitory effect of irradiation on neurite extension influences pathways unassociated with Akt activation. As Ca2+/calmodulin dependent kinase II (CaMKII) is known to inhibit the NGF-induced neurite extension in PC12 cells, independent of ERK and Akt activation, we next examined the effects of irradiation on CaMKII activation. Chronic irradiation induced CaMKII activation, while application of KN-62 (a specific inhibitor of CaMKII), attenuated increases in CaMKII activation and recovered neurite extension and NGF induced increases in Rac1 activity that was inhibited by irradiation. Our results suggest that chronic irradiation with low-dose-rate gamma-rays inhibits Rac1 activity via CaMKII activation, thereby inhibiting NGF-induced neurite extension. PMID- 29106603 TI - Erratum: Disparities in cigarette smoking and use of other tobacco products in Minnesota, 2003-14. PMID- 29106602 TI - PRMT5 as a druggable target for glioblastoma therapy. AB - Background: In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM. Methods: Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. Results: In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state. Conclusion: In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation. PMID- 29106604 TI - The effect of differing kidney disease treatment modalities and organ donation and transplantation practices on health expenditure and patient outcomes. AB - The Effect of Differing Kidney Disease Treatment Modalities and Organ Donation and Transplantation Practices on Health Expenditure and Patient Outcomes (EDITH) aims to obtain information on long-term kidney transplant outcomes, long-term health outcomes of living kidney donors and detailed outcomes and costs related to the different treatment modalities of end-stage kidney disease. Nine partners from seven European Union countries will participate in this project. PMID- 29106605 TI - Surgical treatment of a pericardio-oesophageal fistula using a right lower lobe pulmonary tissue patch. AB - A 58-year-old man presented with fever and chest pain 11 days after atrial fibrillation catheter ablation. The diagnosis of pericardio-oesophageal fistula was made. Aggressive surgical management was decided. The patient was managed using extracorporeal life support, aortic valve replacement and a pulmonary patch, as well as an oesophageal stent. The patient was discharged from hospital approximately 2 months later. The use of a pulmonary patch is a rare but a highly effective technique that can be used in this indication. PMID- 29106607 TI - RNomics of Thermus themophilus HB8 by DNA microarray and next-generation sequencing. AB - By using the data obtained by the DNA microarray analysis for the intergenic regions applied to RNA samples extracted from Thermus thermophilus HB8, seven small non-coding RNAs, TtR-1 to TtR-7, were found to be expressed in the cells growing in rich and/or minimal media. By analysing the time course of the expression for the cell growth in combination with the sequence comparison to the known RNAs, two RNAs, TtR-1 and TtR-2, are suggested to be riboswitches. The existence of the seven RNAs and the exact sequence and length, ranging 77-284 nt, were confirmed by the next-generation sequencing. By the combination of these two high-throughput techniques, our understanding of RNAs in the cell will be increased significantly. PMID- 29106608 TI - 'Caput medusae': tension reduction on a dehiscent native annulus in valve implantation in an endocarditis case. AB - Interrupted pledget-armed braided sutures are widely used for valve implantation. In a 74-year-old woman with aortic valve endocarditis and shallow annular abscess, annulus dehiscence resulted after resection. As resistance was too high for sufficient primary approximation, a snug fit of the valve by means of circumferential application of curbed tourniquets resembling Medusa's head after suture placement was achieved. Closest possible approximation of the upper and lower part of the annulus with the prosthesis prior to final fixation was thus possible, so that application of too much tension on a single suture could be avoided. PMID- 29106606 TI - Increased Affinity for RNA Targets Evolved Early in Animal and Plant Dicer Lineages through Different Structural Mechanisms. AB - Understanding the structural basis for evolutionary changes in protein function is central to molecular evolutionary biology and can help determine the extent to which functional convergence occurs through similar or different structural mechanisms. Here, we combine ancestral sequence reconstruction with functional characterization and structural modeling to directly examine the evolution of sequence-structure-function across the early differentiation of animal and plant Dicer/DCL proteins, which perform the first molecular step in RNA interference by identifying target RNAs and processing them into short interfering products. We found that ancestral Dicer/DCL proteins evolved similar increases in RNA target affinities as they diverged independently in animal and plant lineages. In both cases, increases in RNA target affinities were associated with sequence changes that anchored the RNA's 5'phosphate, but the structural bases for 5'phosphate recognition were different in animal versus plant lineages. These results highlight how molecular-functional evolutionary convergence can derive from the evolution of unique protein structures implementing similar biochemical mechanisms. PMID- 29106609 TI - First Chimeric Antigen Receptor T-Cell Therapy Approved. PMID- 29106610 TI - Updates to the National Cancer Institute's PDQ Information from Recently Published Oncology Research. PMID- 29106611 TI - mVOC 2.0: a database of microbial volatiles. AB - Metabolic capabilities of microorganisms include the production of secondary metabolites (e.g. antibiotics). The analysis of microbial volatile organic compounds (mVOCs) is an emerging research field with huge impact on medical, agricultural and biotechnical applied and basic science. The mVOC database (v1) has grown with microbiome research and integrated species information with data on emitted volatiles. Here, we present the mVOC 2.0 database with about 2000 compounds from almost 1000 species and new features to work with the database. The extended collection of compounds was augmented with data regarding mVOC mediated effects on plants, fungi, bacteria and (in-)vertebrates. The mVOC database 2.0 now features a mass spectrum finder, which allows a quick mass spectrum comparison for compound identification and the generation of species specific VOC signatures. Automatic updates, useful links and search for mVOC literature are also included. The mVOC database aggregates and refines available information regarding microbial volatiles, with the ultimate aim to provide a comprehensive and informative platform for scientists working in this research field. To address this need, we maintain a publicly available mVOC database at: http://bioinformatics.charite.de/mvoc. PMID- 29106612 TI - Mediterranean diet as the diet of choice for patients with chronic kidney disease. AB - Traditional dietary management of chronic kidney disease (CKD) focuses on the quantity within the diet of energy and protein, and the restriction of single micronutrients, with little mention of dietary quality. Dietary patterns that are more plant-based, lower in meat (including processed meat), sodium and refined sugar, and have a higher content of grains and fibres are now included in multiple clinical guidelines for chronic disease prevention. The Mediterranean diet (MD) has been associated with reduced cardiovascular disease incidence in both observational and interventional studies. A wealth of evidence links MD with other beneficial effects on chronic diseases such as diabetes, obesity or cognitive health. This review examines each constituent of the classical MD and evaluates their suitability for the management of patients with CKD. We also evaluate the potential hyperkalaemia risk of increasing fruit and vegetable intake. Overall, a decrease in net endogenous acid production and increase in fibre may lead to a better control of metabolic acidosis. This, together with other putative favourable effects of MD on endothelial function, inflammation, lipid profile and blood pressure, provide mechanistic pathways to explain the observed reduced renal function decline and improved survival in CKD patients adhering to an MD. PMID- 29106613 TI - 3DIV: A 3D-genome Interaction Viewer and database. AB - Three-dimensional (3D) chromatin structure is an emerging paradigm for understanding gene regulation mechanisms. Hi-C (high-throughput chromatin conformation capture), a method to detect long-range chromatin interactions, allows extensive genome-wide investigation of 3D chromatin structure. However, broad application of Hi-C data have been hindered by the level of complexity in processing Hi-C data and the large size of raw sequencing data. In order to overcome these limitations, we constructed a database named 3DIV (a 3D-genome Interaction Viewer and database) that provides a list of long-range chromatin interaction partners for the queried locus with genomic and epigenomic annotations. 3DIV is the first of its kind to collect all publicly available human Hi-C data to provide 66 billion uniformly processed raw Hi-C read pairs obtained from 80 different human cell/tissue types. In contrast to other databases, 3DIV uniquely provides normalized chromatin interaction frequencies against genomic distance dependent background signals and a dynamic browsing visualization tool for the listed interactions, which could greatly advance the interpretation of chromatin interactions. '3DIV' is available at http://kobic.kr/3div. PMID- 29106614 TI - BioModels: expanding horizons to include more modelling approaches and formats. AB - BioModels serves as a central repository of mathematical models representing biological processes. It offers a platform to make mathematical models easily shareable across the systems modelling community, thereby supporting model reuse. To facilitate hosting a broader range of model formats derived from diverse modelling approaches and tools, a new infrastructure for BioModels has been developed that is available at http://www.ebi.ac.uk/biomodels. This new system allows submitting and sharing of a wide range of models with improved support for formats other than SBML. It also offers a version-control backed environment in which authors and curators can work collaboratively to curate models. This article summarises the features available in the current system and discusses the potential benefit they offer to the users over the previous system. In summary, the new portal broadens the scope of models accepted in BioModels and supports collaborative model curation which is crucial for model reproducibility and sharing. PMID- 29106615 TI - Measuring Self-Efficacy in the Context of Pediatric Diabetes Management: Psychometric Properties of the Self-Efficacy for Diabetes Scale. AB - Objective: The Self-Efficacy for Diabetes Scale (SED) is a widely used measure of diabetes-specific self-efficacy with three subscales: diabetes-specific self efficacy (SED-D), medical self-efficacy (SED-M), and general self-efficacy (SED G). The present study examined the factor structure and construct validity of the SED in 116 youth, aged 10-16 years (13.60 +/- 1.87), with type 1 diabetes mellitus. Methods: Confirmatory factor analysis (CFA) was used to examine the factor structure of the SED. Correlational and regression analyses examined relations between subscales and select outcomes. Results: CFA of the original three-factor structure provided a poor fit to the data. Factor models using rescaled items were tested. Results provided preliminary evidence for the SED-D as an independent one-factor model, and for a reduced one-factor model. Significant associations were found between the SED subscales, responsibility for diabetes management, and glycated hemoglobin. Conclusions: Results provide limited support for the SED-D as a reliable and valid measure of diabetes specific self-efficacy. PMID- 29106616 TI - MODOMICS: a database of RNA modification pathways. 2017 update. AB - MODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. In the current database version, we included the following new features and data: extended mass spectrometry and liquid chromatography data for modified nucleosides; links between human tRNA sequences and MINTbase - a framework for the interactive exploration of mitochondrial and nuclear tRNA fragments; new, machine-friendly system of unified abbreviations for modified nucleoside names; sets of modified tRNA sequences for two bacterial species, updated collection of mammalian tRNA modifications, 19 newly identified modified ribonucleosides and 66 functionally characterized proteins involved in RNA modification. Data from MODOMICS have been linked to the RNAcentral database of RNA sequences. MODOMICS is available at http://modomics.genesilico.pl. PMID- 29106617 TI - FnCpf1: a novel and efficient genome editing tool for Saccharomyces cerevisiae. AB - Cpf1 is a new class II family of CRISPR-Cas RNA-programmable endonucleases with unique features that make it a very attractive alternative or complement to Cas9 for genome engineering. Using constitutively expressed Cpf1 from Francisella novicida, the present study demonstrates that FnCpf1 can mediate RNA-guided DNA cleavage at targeted genomic loci in the popular model and industrial yeast Saccharomyces cerevisiae. FnCpf1 very efficiently and precisely promoted repair DNA recombination with efficiencies up to 100%. Furthermore, FnCpf1 was shown to introduce point mutations with high fidelity. While editing multiple loci with Cas9 is hampered by the need for multiple or complex expression constructs, processing itself a customized CRISPR array FnCpf1 was able to edit four genes simultaneously in yeast with a 100% efficiency. A remarkable observation was the unexpected, strong preference of FnCpf1 to cleave DNA at target sites harbouring 5'-TTTV-3' PAM sequences, a motif reported to be favoured by Cpf1 homologs of Acidaminococcus and Lachnospiraceae. The present study supplies several experimentally tested guidelines for crRNA design, as well as plasmids for FnCpf1 expression and easy construction of crRNA expression cassettes in S. cerevisiae. FnCpf1 proves to be a powerful addition to S. cerevisiae CRISPR toolbox. PMID- 29106618 TI - eRAM: encyclopedia of rare disease annotations for precision medicine. AB - Rare diseases affect over a hundred million people worldwide, most of these patients are not accurately diagnosed and effectively treated. The limited knowledge of rare diseases forms the biggest obstacle for improving their treatment. Detailed clinical phenotyping is considered as a keystone of deciphering genes and realizing the precision medicine for rare diseases. Here, we preset a standardized system for various types of rare diseases, called encyclopedia of Rare disease Annotations for Precision Medicine (eRAM). eRAM was built by text-mining nearly 10 million scientific publications and electronic medical records, and integrating various data in existing recognized databases (such as Unified Medical Language System (UMLS), Human Phenotype Ontology, Orphanet, OMIM, GWAS). eRAM systematically incorporates currently available data on clinical manifestations and molecular mechanisms of rare diseases and uncovers many novel associations among diseases. eRAM provides enriched annotations for 15 942 rare diseases, yielding 6147 human disease related phenotype terms, 31 661 mammalians phenotype terms, 10,202 symptoms from UMLS, 18 815 genes and 92 580 genotypes. eRAM can not only provide information about rare disease mechanism but also facilitate clinicians to make accurate diagnostic and therapeutic decisions towards rare diseases. eRAM can be freely accessed at http://www.unimd.org/eram/. PMID- 29106619 TI - NPASS: natural product activity and species source database for natural product research, discovery and tool development. AB - There has been renewed interests in the exploration of natural products (NPs) for drug discovery, and continuous investigations of the therapeutic claims and mechanisms of traditional and herbal medicines. In-silico methods have been employed for facilitating these studies. These studies and the optimization of in silico algorithms for NP applications can be facilitated by the quantitative activity and species source data of the NPs. A number of databases collectively provide the structural and other information of ~470 000 NPs, including qualitative activity information for many NPs, but only ~4000 NPs are with the experimental activity values. There is a need for the activity and species source data of more NPs. We therefore developed a new database, NPASS (Natural Product Activity and Species Source) to complement other databases by providing the experimental activity values and species sources of 35 032 NPs from 25 041 species targeting 5863 targets (2946 proteins, 1352 microbial species and 1227 cell-lines). NPASS contains 446 552 quantitative activity records (e.g. IC50, Ki, EC50, GI50 or MIC mainly in units of nM) of 222 092 NP-target pairs and 288 002 NP-species pairs. NPASS, http://bidd2.nus.edu.sg/NPASS/, is freely accessible with its contents searchable by keywords, physicochemical property range, structural similarity, species and target search facilities. PMID- 29106620 TI - Corrigendum: Enzymatic study on AtCCD4 and AtCCD7 and their potential to form acyclic regulatory metabolites. PMID- 29106621 TI - High day- and night-time temperatures affect grain growth dynamics in contrasting rice genotypes. AB - Rice grain yield and quality are predicted to be highly vulnerable to global warming. Five genotypes including heat-tolerant and susceptible checks, a heat tolerant near-isogenic line and two hybrids were exposed to control (31 degrees C/23 degrees C, day/night), high night-time temperature (HNT; 31 degrees C/30 degrees C), high day-time temperature (HDT; 38 degrees C/23 degrees C) and high day- and night-time temperature (HNDT; 38 degrees C/30 degrees C) treatments for 20 consecutive days during the grain-filling stage. Grain-filling dynamics, starch metabolism enzymes, temporal starch accumulation patterns and the process of chalk formation were quantified. Compensation between the rate and duration of grain filling minimized the impact of HNT, but irreversible impacts on seed-set, grain filling and ultimately grain weight were recorded with HDT and HNDT. Scanning electron microscopy demonstrated irregular and smaller starch granule formation affecting amyloplast build-up with HDT and HNDT, while a quicker but normal amylopast build-up was recorded with HNT. Our findings revealed temporal variation in the starch metabolism enzymes in all three stress treatments. Changes in the enzymatic activity did not derail starch accumulation under HNT when assimilates were sufficiently available, while both sucrose supply and the conversion of sucrose into starch were affected by HDT and HNDT. The findings indicate differential mechanisms leading to high day and high night temperature stress-induced loss in yield and quality. Additional genetic improvement is needed to sustain rice productivity and quality under future climates. PMID- 29106622 TI - A light-sensitive mutation in Arabidopsis LEW3 reveals the important role of N glycosylation in root growth and development. AB - Plant roots have the potential capacity to grow almost indefinitely if meristematic and lateral branching is sustained. In a genetic screen we identified an Arabidopsis mutant showing limited root growth (lrg1) due to defects in cell division and elongation in the root meristem. Positional cloning determined that lrg1 affects an alpha-1,2-mannosyltransferase gene, LEW3, involved in protein N-glycosylation. The lrg1 mutation causes a synonymous substitution that alters the correct splicing of the fourth intron in LEW3, causing a mix of wild-type and truncated protein. LRG1 RNA missplicing in roots and short root phenotypes in lrg1 are light-intensity dependent. This mutation disrupts a GC-base pair in a three-base-pair stem with a four-nucleotide loop, which seems to be necessary for correct LEW3 RNA splicing. We found that the lrg1 short root phenotype correlates with high levels of reactive oxygen species and low pH in the apoplast. Proteomic analyses of N-glycosylated proteins identified GLU23/PYK10 and PRX34 as N-glycosylation targets of LRG1 activity. The lrg1 mutation reduces the positive interaction between Arabidopsis and Serendipita indica. A prx34 mutant showed a significant reduction in root growth, which is additive to lrg1. Taken together our work highlights the important role of N glycosylation in root growth and development. PMID- 29106623 TI - Setting sub-organellar sights: accurate targeting of multi-transmembrane-domain proteins to specific chloroplast membranes. PMID- 29106624 TI - Regulation of flowering time: a splicy business. PMID- 29106625 TI - Association of the frequency of pre-end-stage renal disease medical care with post-end-stage renal disease mortality and hospitalization. AB - Background: Previous studies have demonstrated that early pre-end-stage renal disease (ESRD) nephrology care could improve postdialysis prognosis. However, less is known about the specific types of interventions responsible for the improved outcomes. We hypothesized that more frequent predialysis laboratory testing is associated with better postdialysis outcomes in incident ESRD patients. Methods: In all, 23 089 patients with available outpatient laboratory tests performed during the 2-year predialysis (i.e. prelude) period were identified from a total of 52 172 American veterans with chronic kidney disease (CKD) transitioning to dialysis between October 2007 and September 2011. The associations between the frequency of combined laboratory tests, including serum creatinine, serum potassium and hemoglobin (test trio), with postdialysis mortality and hospitalization were examined in multivariable adjusted Cox and logistic regression models. Results: When entering the 2-year prelude period, the mean age (Standard Deviation) of the patients was 66.2 (SD 11.3) years and the mean estimated glomerular filtration rate was 46.8 (SD 23.9) mL/min/1.73 m2. In all, 14% of patients had the test trio performed less than twice in 24 months and 8.9% had the trio measured more often than every other month. Over a 2.5-year median postdialysis follow-up period, 15 303 (66.3%) patients died (mortality rate 260/1000 patient-years). The adjusted hazard ratio of all-cause mortality and adjusted odds ratio of the composite of hospitalization or death associated with lab testing done >12/24 months compared with 2-<=4/24 months were 0.68 [95% confidence interval (CI) 0.65-0.73] and 0.70 (95% CI 0.62-0.79), respectively. Conclusions: More frequent laboratory testing in patients with advanced CKD is associated with better clinical outcomes after dialysis. Further examination in clinical trials is needed before the implementation of more frequent laboratory testing in clinical practice. PMID- 29106626 TI - PAMDB: a comprehensive Pseudomonas aeruginosa metabolome database. AB - The Pseudomonas aeruginosaMetabolome Database (PAMDB, http://pseudomonas.umaryland.edu) is a searchable, richly annotated metabolite database specific to P. aeruginosa. P. aeruginosa is a soil organism and significant opportunistic pathogen that adapts to its environment through a versatile energy metabolism network. Furthermore, P. aeruginosa is a model organism for the study of biofilm formation, quorum sensing, and bioremediation processes, each of which are dependent on unique pathways and metabolites. The PAMDB is modelled on the Escherichia coli (ECMDB), yeast (YMDB) and human (HMDB) metabolome databases and contains >4370 metabolites and 938 pathways with links to over 1260 genes and proteins. The database information was compiled from electronic databases, journal articles and mass spectrometry (MS) metabolomic data obtained in our laboratories. For each metabolite entered, we provide detailed compound descriptions, names and synonyms, structural and physiochemical information, nuclear magnetic resonance (NMR) and MS spectra, enzymes and pathway information, as well as gene and protein sequences. The database allows extensive searching via chemical names, structure and molecular weight, together with gene, protein and pathway relationships. The PAMBD and its future iterations will provide a valuable resource to biologists, natural product chemists and clinicians in identifying active compounds, potential biomarkers and clinical diagnostics. PMID- 29106627 TI - Bi-nucleation of podocytes is uniformly accompanied by foot processes widening in renal disease. AB - Background: Podocytes are terminally differentiated glomerular cells expressing a highly complex architecture and lacking the ability to proliferate. However, during renal injury or stress these cells can re-enter into the cell cycle but fail to divide. As a consequence, bi- and multi-nucleated podocytes can be identified in renal biopsies from patients with various kidney diseases. It is still unclear whether the occurrence of such cells is dependent on or correlates with renal damage and if bi- or multi-nucleation results in ultrastructural alterations such as e.g. foot process effacement. Therefore, we investigated the frequency, correlation with clinical parameters and morphological consequences of podocyte bi- or multi-nucleation in a cohort of 377 patients suffering from different renal diseases. Methods: Renal biopsies from patients with minimal change disease (MCD; n = 93), IgA-glomerulonephritis (IgA-GN, n = 95), lupus nephritis (LN; n = 90) and diabetic nephropathy (DN; n = 99) were investigated for the occurrence of bi-nucleated or multi-nucleated podocytes using semi-thin sections and light-microscopy at 1000* magnification. The frequency of bi nucleation and multi-nucleation in podocytes was correlated with clinical parameters and markers of renal injury. In addition, ultrastructural morphological features associated with podocyte bi- or multi-nucleation were analysed by scanning transmission electron microscopy at various magnifications. Results: Ultrastructural analysis of podocyte nuclear morphology revealed a broad spectrum of nuclear appearances. Therefore, podocytes were classified in cells with mono-nucleated, lobulated, potential bi-nucleated, symmetrically bi nucleated, asymmetrically bi-nucleated and multi-nucleated nuclear morphology. In 65-80% of all investigated glomeruli only mono-nuclear podocytes were identified. The highest frequency of bi-nucleated podocytes was found in patients with IgA-GN (18.6%) and the lowest in patients with DN (5.6%). The proportion of bi-nucleated podocytes with asymmetric nuclear morphology was about 50% of all bi-nucleated podocytes and independent of the underlying renal disease. In addition, ultrastructural analysis by electron microscopy showed significant widening of foot processes in bi-nucleated compared with mono-nucleated podocytes. Interestingly, foot process width of podocytes with lobulated nuclei was also significantly increased compared with podocytes with normal mono-nuclear morphology. Furthermore, podocyte density per glomerular area was significantly lower in glomeruli with bi-nucleated podocytes. Due to the relatively low frequency of bi- and multi-nucleated podocytes, correlations with clinical parameters were weak and dependent on renal disease. Conclusions: The frequency of bi-nucleated podocytes was highest in IgA-GN but can also be observed in all investigated renal diseases. In podocytes with altered nuclear morphology particularly in bi- and multi-nucleated podocytes ultrastructural analysis of podocytes revealed significant widening of foot processes as a potential maladaptive structural consequence. PMID- 29106628 TI - Magnetic resonance imaging versus ultrasonography for the diagnosis of synovitis in rheumatoid arthritis. PMID- 29106629 TI - Microsurgical Decompression in Trigeminal Neuralgia With or Without Vascular Compression: Illustrative Cases With 3-Dimensional Operative Video. PMID- 29106630 TI - TranslatomeDB: a comprehensive database and cloud-based analysis platform for translatome sequencing data. AB - Translation is a key regulatory step, linking transcriptome and proteome. Two major methods of translatome investigations are RNC-seq (sequencing of translating mRNA) and Ribo-seq (ribosome profiling). To facilitate the investigation of translation, we built a comprehensive database TranslatomeDB (http://www.translatomedb.net/) which provides collection and integrated analysis of published and user-generated translatome sequencing data. The current version includes 2453 Ribo-seq, 10 RNC-seq and their 1394 corresponding mRNA-seq datasets in 13 species. The database emphasizes the analysis functions in addition to the dataset collections. Differential gene expression (DGE) analysis can be performed between any two datasets of same species and type, both on transcriptome and translatome levels. The translation indices translation ratios, elongation velocity index and translational efficiency can be calculated to quantitatively evaluate translational initiation efficiency and elongation velocity, respectively. All datasets were analyzed using a unified, robust, accurate and experimentally-verifiable pipeline based on the FANSe3 mapping algorithm and edgeR for DGE analyzes. TranslatomeDB also allows users to upload their own datasets and utilize the identical unified pipeline to analyze their data. We believe that our TranslatomeDB is a comprehensive platform and knowledgebase on translatome and proteome research, releasing the biologists from complex searching, analyzing and comparing huge sequencing data without needing local computational power. PMID- 29106632 TI - Cost-effectiveness of screening type 2 diabetes patients for chronic kidney disease progression with the CKD273 urinary peptide classifier as compared to urinary albumin excretion. AB - Background: In type 2 diabetes mellitus (T2DM) patients, chronic kidney disease (CKD) progression may occur without detectable changes in urinary albumin excretion (UAE) rate. A new urinary peptide classifier (CKD273) has exhibited greater ability to detect CKD progression, however, its cost-effectiveness remains unknown. This study evaluated the cost-effectiveness of screening for CKD progression with the CKD273 classifier, as compared to UAE, in diabetic patients. Methods: A decision-analytic Markov model was developed to estimate costs and health outcomes [including overall survival and quality-adjusted life years (QALYs)] from a health system perspective for adopting a new annual screening strategy based on the CKD273 classifier as compared to annual UAE-based screening in a hypothetical cohort of T2DM patients. High-risk patients were defined as T2DM patients with at least one concomitant risk factor (i.e. patients with background genetic risk for developing the disease, obesity, hypertension and/or smoking history) for developing diabetic nephropathy secondary to cardiovascular disease (CVD)-related complications. Low-risk T2DM patients, were defined as those not having any of the aforementioned concomitant risk factors. Results: Over the projected course of a patient's lifetime, in all T2DM patients annual screening with the CKD273 classifier was more costly, but also more effective, than annual screening with UAE. The incremental costs incurred with screening based on the CKD273 classifier were ?3,053 per patient, while patients gained 0.13 QALYs. Hence, in all patients, annual screening with the CKD273 classifier was cost effective [incremental cost-effectiveness ratio (ICER) ?23,903/QALY gained], notably below current government thresholds for funding such health care interventions. For patients at high risk of developing diabetic nephropathy secondary to CVD-related complications, screening based on the CKD273 classifier was cost-saving (i.e. dominant, being both more effective and less expensive than UAE-based screening). Finally, in low-risk patients, CKD273 classifier-based screening was not cost effective (ICER ?73,140/QALY) given current government willingness-to-pay thresholds. Conclusions: In diabetic patients, annual CKD273 classifier-based screening is more costly but also more effective in QALYs gained as compared to UAE. From a health provider perspective, the observed benefits are greatest when such screening is implemented in patients at high risk for diabetes associated renal or cardiovascular diseases (CVDs). PMID- 29106631 TI - Effect of renin-angiotensin-aldosterone system blockade in adults with diabetes mellitus and advanced chronic kidney disease not on dialysis: a systematic review and meta-analysis. AB - The presumed superiority of renin-angiotensin-aldosterone system (RAAS)-blocking agents over other antihypertensive agents in patients with diabetes to delay development of end-stage kidney disease (ESKD) has recently been challenged. In addition, there is ongoing uncertainty whether RAAS-blocking agents reduce mortality and/or delay ESKD in patients with diabetes and chronic kidney disease (CKD) stages 3-5. In this subgroup, there might be an expedited need for renal replacement therapy (RRT) when RAAS-blocking agents are used. We conducted a meta analysis of randomized controlled trials (RCTs) of at least 6-months duration in adult patients with diabetes who also have non-dialysis CKD stages 3-5. RCTs comparing single RAAS-blocking agents to placebo or alternative antihypertensive agents were included. Outcomes of interest were all-cause mortality, cardiovascular morbidity, progression of renal function, ESKD and adverse events. A total of nine trials (n = 9797 participants with CKD stages 3-5) fit our inclusion criteria. There was no difference between the RAAS group and control group regarding all-cause mortality {relative risk [RR] = 0.97 [95% confidence interval (CI) 0.85-1.10]}, cardiovascular mortality [RR = 1.03 (95% CI 0.75 1.41)] and adverse events [RR = 1.05 (95% CI 0.89-1.25)]. There was a trend for a favourable effect for non-fatal cardiovascular events [RR = 0.90 (95% CI 0.81 1.00)] and a lower risk of the composite endpoint need for RRT/doubling of serum creatinine [RR = 0.81 (95% CI 0.70-0.92)] in the RAAS-blocking agents group versus the control group. We found evidence that in patients with diabetes mellitus and CKD stages 3-5, treatment with RAAS-blocking agents did not result in a clear survival advantage. The effect on renal outcomes did depend on the selected outcome measure. However, we did not find evidence that the use of RAAS blocking agents expedited the need for RRT in patients with CKD stages 3-5. PMID- 29106633 TI - Anabolic steroid abuse: what shall it profit a man to gain muscle and suffer the loss of his brain? PMID- 29106634 TI - TCMID 2.0: a comprehensive resource for TCM. AB - As a traditional medical intervention in Asia and a complementary and alternative medicine in western countries, Traditional Chinese Medicine (TCM) is capturing worldwide attention in life science field. Traditional Chinese Medicine Integrated Database (TCMID), which was originally launched in 2013, was a comprehensive database aiming at TCM's modernization and standardization. It has been highly recognized among pharmacologists and scholars in TCM researches. The latest release, TCMID 2.0 (http://www.megabionet.org/tcmid/), replenished the preceding database with 18 203 herbal ingredients, 15 prescriptions, 82 related targets, 1356 drugs, 842 diseases and numerous new connections between them. Considering that chemical changes might take place in decocting process of prescriptions, which may result in new ingredients, new data containing the prescription ingredients was collected in current version. In addition, 778 herbal mass spectrometry (MS) spectra related to 170 herbs were appended to show the variation of herbal quality in different origin and distinguish genuine medicinal materials from common ones while 3895 MS spectra of 729 ingredients were added as the supplementary materials of component identification. With the significant increase of data, TCMID 2.0 will further facilitate TCM's modernization and enhance the exploration of underlying biological processes that are response to the diverse pharmacologic actions of TCM. PMID- 29106635 TI - The multisystemic nature and natural history of joint hypermobility syndrome and Ehlers-Danlos syndrome in children: New research data conflict with widely held views. PMID- 29106636 TI - Endovascular Coil Retrieval Using Dual Synchronous Solitaire Revascularization Devices. AB - BACKGROUND AND IMPORTANCE: Coil migration is a potential complication of endovascular aneurysm treatment. Dislodged coils into the parent artery require retrieval to prevent thromboembolic complications. A variety of techniques for coil retrieval have been described, including the use of single stentrievers and aspiration catheters. CLINICAL PRESENTATION: The use of 2 stentrievers, as opposed to a single device, was thought to be advantageous in coil removal by the additional point of friction due to the extensive length of coil stretching and earlier failure of a single device. CONCLUSION: In this report, 2 synchronous Solitaire FR Revascularization Devices (Covidien/Medtronic, Dublin, Ireland) were deployed, 1 distal and 1 proximal, to retrieve an inadvertently deployed coil. PMID- 29106637 TI - Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. AB - Background: Large-scale studies comparing glomerular disease frequencies across continents are lacking. Methods: We surveyed 29 nephropathology laboratories in four continents using a standardized data collection form. We obtained recent consecutive kidney biopsy diagnosis frequencies at each center and summary demographics for each diagnosis. This report focuses on glomerular disease frequencies by region and race/ethnicity. Results: Among 42 603 glomerular disease diagnoses reported (median age 47 years, 52% male, 57% white), from a total of 60 340 diagnoses, glomerular disease subtype frequencies differed considerably by continent. Diabetic glomerulosclerosis (GS; 19.1%) and focal segmental glomerulosclerosis (FSGS; 19.1%) predominated in North America; lupus nephritis (38.1%) and FSGS (15.8%) predominated in Latin America; IgA nephropathy (IgAN; 22.1%) and FSGS (14.9%) predominated in Europe; and IgAN (39.5%) and lupus nephritis (16.8%) predominated in Asia. After stratifying by race, diabetic GS (17.4% versus 4.3%, P < 0.001) and FSGS (17.3% versus 11.8%, P < 0.001) were more, and lupus nephritis less (15.8% versus 45.6%, P < 0.001), frequent among Latinos in North versus Latin America; FSGS was more (13.1% versus 7.1%, P < 0.001), and IgAN less (27.4% versus 40.5%, P < 0.001), frequent among Asians in North America versus Asia; and FSGS (18.9% versus 13.5%, P < 0.001) and diabetic GS (18.7% versus 6.5%, P < 0.001) were more, and IgAN less (14.4% versus 25.4%, P < 0.001), frequent among whites in North America versus Europe. Conclusions: We determined that glomerular disease frequencies differed by continent, even among patients of similar race/ethnicity. Regional environmental and lifestyle factors, and local biopsy policies, might influence glomerular disease epidemiology independently of race/ethnicity. PMID- 29106638 TI - Linking Individual Natural History to Population Outcomes in Tuberculosis. AB - Background: Substantial individual heterogeneity exists in the clinical manifestations and duration of active tuberculosis. We sought to link the individual-level characteristics of tuberculosis disease to observed population level outcomes. Methods: We developed an individual-based, stochastic model of tuberculosis disease in a hypothetical cohort of patients with smear-positive tuberculosis. We conceptualized the disease process as consisting of 2 states progression and recovery-including transitions between the 2. We then used a Bayesian process to calibrate the model to clinical data from the prechemotherapy era, thus identifying the rates of progression and recovery (and probabilities of transition) consistent with observed population-level clinical outcomes. Results: Observed outcomes are consistent with slow rates of disease progression (median doubling time: 84 days, 95% uncertainty range 62-104) and a low, but nonzero, probability of transition from disease progression to recovery (median 16% per year, 95% uncertainty range 11%-21%). Other individual-level dynamics were less influential in determining observed outcomes. Conclusions: This simplified model identifies individual-level dynamics-including a long doubling time and low probability of immune recovery-that recapitulate population-level clinical outcomes of untreated tuberculosis patients. This framework may facilitate better understanding of the population-level impact of interventions acting at the individual host level. PMID- 29106639 TI - MNDR v2.0: an updated resource of ncRNA-disease associations in mammals. AB - Accumulating evidence suggests that diverse non-coding RNAs (ncRNAs) are involved in the progression of a wide variety of diseases. In recent years, abundant ncRNA disease associations have been found and predicted according to experiments and prediction algorithms. Diverse ncRNA-disease associations are scattered over many resources and mammals, whereas a global view of diverse ncRNA-disease associations is not available for any mammals. Hence, we have updated the MNDR v2.0 database (www.rna-society.org/mndr/) by integrating experimental and prediction associations from manual literature curation and other resources under one common framework. The new developments in MNDR v2.0 include (i) an over 220 fold increase in ncRNA-disease associations enhancement compared with the previous version (including lncRNA, miRNA, piRNA, snoRNA and more than 1400 diseases); (ii) integrating experimental and prediction evidence from 14 resources and prediction algorithms for each ncRNA-disease association; (iii) mapping disease names to the Disease Ontology and Medical Subject Headings (MeSH); (iv) providing a confidence score for each ncRNA-disease association and (v) an increase of species coverage to six mammals. Finally, MNDR v2.0 intends to provide the scientific community with a resource for efficient browsing and extraction of the associations between diverse ncRNAs and diseases, including >260 000 ncRNA-disease associations. PMID- 29106640 TI - Triatoma costalimai (Hemiptera: Reduviidae) in and Around Houses of Tocantins State, Brazil, 2005-2014. AB - Triatoma costalimai Verano & Galvao, a little-known vector of Trypanosoma cruzi Chagas, occupies rocky environments in the Brazilian Cerrado and occasionally infests man-made habitats. Entomological surveillance records show that T. costalimai occurs fairly often inside and around houses in south-eastern Tocantins, Brazil, with 859 specimens reported in 2005-2014. Most adults were caught indoors, and breeding colonies were found inside and around houses. Trypanosoma cruzi was detected in 13.7% of 839 bugs. These data suggest that T. costalimai can contribute to T. cruzi transmission in human environments, underscoring the need for long-term entomological-epidemiological surveillance wherever native Chagas disease vectors occur. PMID- 29106641 TI - The MAR databases: development and implementation of databases specific for marine metagenomics. AB - We introduce the marine databases; MarRef, MarDB and MarCat (https://mmp.sfb.uit.no/databases/), which are publicly available resources that promote marine research and innovation. These data resources, which have been implemented in the Marine Metagenomics Portal (MMP) (https://mmp.sfb.uit.no/), are collections of richly annotated and manually curated contextual (metadata) and sequence databases representing three tiers of accuracy. While MarRef is a database for completely sequenced marine prokaryotic genomes, which represent a marine prokaryote reference genome database, MarDB includes all incomplete sequenced prokaryotic genomes regardless level of completeness. The last database, MarCat, represents a gene (protein) catalog of uncultivable (and cultivable) marine genes and proteins derived from marine metagenomics samples. The first versions of MarRef and MarDB contain 612 and 3726 records, respectively. Each record is built up of 106 metadata fields including attributes for sampling, sequencing, assembly and annotation in addition to the organism and taxonomic information. Currently, MarCat contains 1227 records with 55 metadata fields. Ontologies and controlled vocabularies are used in the contextual databases to enhance consistency. The user-friendly web interface lets the visitors browse, filter and search in the contextual databases and perform BLAST searches against the corresponding sequence databases. All contextual and sequence databases are freely accessible and downloadable from https://s1.sfb.uit.no/public/mar/. PMID- 29106642 TI - MSDD: a manually curated database of experimentally supported associations among miRNAs, SNPs and human diseases. AB - The MiRNA SNP Disease Database (MSDD, http://www.bio-bigdata.com/msdd/) is a manually curated database that provides comprehensive experimentally supported associations among microRNAs (miRNAs), single nucleotide polymorphisms (SNPs) and human diseases. SNPs in miRNA-related functional regions such as mature miRNAs, promoter regions, pri-miRNAs, pre-miRNAs and target gene 3'-UTRs, collectively called 'miRSNPs', represent a novel category of functional molecules. miRSNPs can lead to miRNA and its target gene dysregulation, and resulting in susceptibility to or onset of human diseases. A curated collection and summary of miRSNP associated diseases is essential for a thorough understanding of the mechanisms and functions of miRSNPs. Here, we describe MSDD, which currently documents 525 associations among 182 human miRNAs, 197 SNPs, 153 genes and 164 human diseases through a review of more than 2000 published papers. Each association incorporates information on the miRNAs, SNPs, miRNA target genes and disease names, SNP locations and alleles, the miRNA dysfunctional pattern, experimental techniques, a brief functional description, the original reference and additional annotation. MSDD provides a user-friendly interface to conveniently browse, retrieve, download and submit novel data. MSDD will significantly improve our understanding of miRNA dysfunction in disease, and thus, MSDD has the potential to serve as a timely and valuable resource. PMID- 29106643 TI - Zika Virus Replicates in Proliferating Cells in Explants From First-Trimester Human Placentas, Potential Sites for Dissemination of Infection. AB - Background: Maternal Zika virus (ZIKV) infection with prolonged viremia leads to fetal infection and congenital Zika syndrome. Previously, we reported that ZIKV infects primary cells from human placentas and fetal membranes. Here, we studied viral replication in numerous explants of anchoring villi and basal decidua from first-trimester human placentas and midgestation amniotic epithelial cells (AmEpCs). Methods: Explants and AmEpCs were infected with American and African ZIKV strains at low multiplicities, and ZIKV proteins were visualized by immunofluorescence. Titers of infectious progeny, cell proliferation, and invasiveness were quantified. Results: In anchoring villus, ZIKV replicated reproducibly in proliferating cytotrophoblasts in proximal cell columns, dividing Hofbauer cells in villus cores, and invasive cytotrophoblasts, but frequencies differed. Cytotrophoblasts in explants infected by Nicaraguan strains were invasive, whereas those infected by prototype MR766 largely remained in cell columns, and titers varied by donor and strain. In basal decidua, ZIKV replicated in glandular epithelium, decidual cells, and immune cells. ZIKV-infected AmEpCs frequently occurred in pairs and expressed Ki67 and phosphohistone H3, indicating replication in dividing cells. Conclusions: ZIKV infection in early pregnancy could target proliferating cell column cytotrophoblasts and Hofbauer cells, amplifying infection in basal decidua and chorionic villi and enabling transplacental transmission. PMID- 29106644 TI - iUUCD 2.0: an update with rich annotations for ubiquitin and ubiquitin-like conjugations. AB - Here, we described the updated database iUUCD 2.0 (http://iuucd.biocuckoo.org/) for ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin-protein ligases (E3s), deubiquitinating enzymes (DUBs), ubiquitin/ubiquitin-like binding domains (UBDs) and ubiquitin-like domains (ULDs), which act as key regulators in modulating ubiquitin and ubiquitin-like (UB/UBL) conjugations. In total, iUUCD 2.0 contained 136 512 UB/UBL regulators, including 1230 E1s, 5636 E2s, 93 343 E3s, 9548 DUBs, 30 173 UBDs and 11 099 ULDs in 148 eukaryotic species. In particular, we provided rich annotations for regulators of eight model organisms, especially in humans, by compiling and integrating the knowledge from nearly 70 widely used public databases that cover cancer mutations, single nucleotide polymorphisms (SNPs), mRNA expression, DNA and RNA elements, protein-protein interactions, protein 3D structures, disease associated information, drug-target relations, post-translational modifications, DNA methylation and protein expression/proteomics. Compared with our previously developed UUCD 1.0 (~0.41 GB), iUUCD 2.0 has a size of ~32.1 GB of data with a >75-fold increase in data volume. We anticipate that iUUCD 2.0 can be a more useful resource for further study of UB/UBL conjugations. PMID- 29106646 TI - Coiling of a Carotidocavernous Fistula via the Foramen Ovale: 2-Dimensional Operative Video. PMID- 29106645 TI - Targeting different domains of gap junction protein to control malignant glioma. AB - A rational treatment strategy for glioma, the most common primary central nervous system tumor, should focus on early invasive growth and resistance to current therapeutics. Connexin 43 (Cx43), a gap junction protein, plays important roles not only in the development of the central nervous system and but also in the progression of glioma. The different structural domains of Cx43, including extracellular loops, transmembrane domains, and an intracellular carboxyl terminal, have distinct functions in the invasion and proliferation of gliomas. Targeting these domains of Cx43, which is expressed in distinct patterns in the heterogeneous glioma cell population, can inhibit tumor cell invasion and new tumor formation. Thus, this review summarizes the structural characteristics of Cx43, the effects of regulating different Cx43 domains on the biological characteristics of glioma cells, intervention strategies targeting different domains of Cx43, and future research directions. PMID- 29106647 TI - Contrast Time-Density Time on Digital Subtraction Angiography Correlates With Cerebral Arteriovenous Malformation Flow Measured by Quantitative Magnetic Resonance Angiography, Angioarchitecture, and Hemorrhage. AB - BACKGROUND: Digital subtraction angiography (DSA) currently provides angioarchitectural features of cerebral arteriovenous malformations (AVMs) but its role in the hemodynamic evaluation of AVMs is poorly understood. OBJECTIVE: To assess contrast time-density time (TT) on DSA relative to AVM flow measured using quantitative magnetic resonance angiography (QMRA). METHODS: Patients seen at our institution between 2007 and 2014 with a supratentorial AVM and DSA and QMRA obtained prior to any treatment were retrospectively reviewed. Regions of interest were selected on the draining veins at the point closest to the nidus. TT on DSA was defined as time needed for contrast to change image intensity from 10% to 100%, 100% to 10%, and 25% to 25%. TT was correlated to AVM total flow, angioarchitectural features, and hemorrhage. RESULTS: Twenty-eight patients (mean age 35.6 yr) were included. Six patients presented with hemorrhage. Mean AVM volume was 11.42 mL (range 0.3-57.7 mL). Higher total AVM flow significantly correlated with shorter TT100%-10% and TT25%-25% (P = .02, .02, respectively). Presence of venous stenosis correlated significantly with shorter TT100%-10% (P = .04) and TT25%-25% (P = .04). AVMs with a single draining vein exhibited longer TT25%-25% compared to those with multiple draining veins (P = .04). Ruptured AVMs had significantly shorter TT10%-100% compared to unruptured AVMs (P = .05). CONCLUSION: TT on DSA correlates with cerebral AVM flow measured using QMRA and with AVM angioarchitecture and hemorrhagic presentation. Thus, TT may be used to indirectly estimate AVM flow during angiography in real-time and may also be an indicator of important AVM characteristics associated with outflow resistance and increased rupture risk, such as venous stenosis. PMID- 29106648 TI - Validation of echocardiographic criteria for the clinical diagnosis of heart failure in chronic kidney disease. AB - Background: The Acute Dialysis Quality Initiative (ADQI) XI Workgroup has suggested defining heart failure (HF) in patients with end-stage renal disease by the presence of at least one out of eight predefined echocardiographic criteria. Given the high prevalence of echocardiographic alterations in chronic kidney disease (CKD) patients, we hypothesized that application of echocardiographic ADQI criteria will result in overdiagnosis of HF, without providing substantial prognostic information. Methods: Among 472 CKD stage G2-G4 patients recruited in the CARE FOR HOMe study, we assessed the presence of left-ventricular (LV) hypertrophy, valvular dysfunction, high left-atrial volume index (LAVI), systolic and diastolic LV dysfunction, enlarged LV diameter, and altered regional LV wall contractility. According to the ADQI proposal, presence of one or more of these alterations defined HF. We followed all patients for the occurrence of cardiac decompensation, defined as hospital admission for decompensated HF. Results: A total of 313 (66%) out of 472 patients fulfilled at least one ADQI echocardiographic criterion for HF. Echocardiographic alterations were more common in advanced (G3b/G4: 80%) than in milder (G2/G3a: 56%) CKD. Within subcategories of echocardiographic criteria, an increased LAVI (50%) and diastolic dysfunction (30%) were the most frequent findings. During follow-up of 4.3 +/- 2.0 years, the majority (87%) of all 313 patients who fulfilled ADQI echocardiographic criteria were not hospitalized for cardiac decompensation. Conclusions: Echocardiographic criteria proposed by ADQI as a precondition for the clinical staging of HF are virtually omnipresent among CKD patients. By labelling a majority of CKD patients as having HF, application of ADQI criteria fails to specifically identify patients at high risk for future cardiac events. PMID- 29106649 TI - Pain Management for Primary Care Providers: A Narrative Review of High-Impact Studies, 2014-2016. AB - Objective: This manuscript reviews high-impact, peer-reviewed studies published from January 2014 to March 2016 that are relevant to pain management in primary care. Given the recent release of the US Centers for Disease Control and Prevention's "Guideline for Prescribing Opioids for Chronic Pain" emphasizing the primacy of nonopioid treatment, we focused our review on nonopioid pain management. Design: Narrative review of peer-reviewed literature. Methods: We searched three article summary services and queried expert contacts for high impact, English-language studies related to the management of pain in adults in primary care. All authors reviewed 142 study titles to arrive at group consensus on article content domains. Within article domains, individual authors selected studies approved by the larger group according to their impact on primary care clinical practice, policy, and research, as well as quality of the study methods. Through iterative discussion, 12 articles were selected for detailed review, discussion, and presentation in this narrative review. Results: We present key articles addressing each of six domains of pain management: pharmacotherapy for acute pain; interventional treatments; medical cannabis; complementary and integrative medicine; care management in chronic pain; and prevention. Within each section, we conclude with implications for pain management in primary care. Conclusions: There is growing evidence for multiple nonopioid treatment modalities available to clinicians for the management of pain in primary care. The dissemination and implementation of these studies, including innovative care management interventions, warrant additional study and support from clinicians, educators, and policy-makers. PMID- 29106650 TI - Selective Cervical Denervation for Cervical Dystonia: Modification of the Bertrand Procedure. AB - BACKGROUND: Cervical dystonia, commonly referred to as spasmodic torticollis, is a neurological disorder characterized by aberrant, involuntary contraction of the muscles of the neck and shoulders. One surgical option that can be considered is selective cervical denervation. OBJECTIVE: To report our modification of the Bertrand procedure for selective cervical denervation. METHODS: Our modification of the Bertrand procedure for selective cervical denervation is reported with intraoperative photographs and schematic depictions of the operative steps. RESULTS: We report our modification of the Bertrand procedure for selective cervical denervation, which consists of a combination of C2-6 denervation, myectomy of the splenius capitis and/or semispinalis capitis, myotomy of the levator scapulae when indicated, and myotomy and selection denervation of the sternocleidomastoid. The combination of techniques utilized depends on the subtype and severity of cervical dystonia. CONCLUSION: Our modification of the original Bertrand procedure for selective cervical denervation represents an alternative surgical strategy for the treatment of cervical dystonia, with the potential advantages and disadvantages discussed. PMID- 29106652 TI - Albumin handling in different hemodialysis modalities. AB - Hypoalbuminemia is a major risk factor for morbidity and mortality in dialysis patients. With increasing interest in highly permeable membranes and convective therapies to improve removal of middle molecules, transmembrane albumin loss increases accordingly. Currently, the acceptable upper limit of albumin loss for extracorporeal renal replacement therapies is unknown. In theory, any additional albumin loss should be minimized because it may contribute to hypoalbuminemia and adversely affect the patient's prognosis. However, hypoalbuminemia-associated mortality may be a consequence of inflammation and malnutrition, rather than low albumin levels per se. The purpose of this review is to give an overview of albumin handling with different extracorporeal renal replacement strategies. We conclude that the acceptable upper limit of dialysis-related albumin loss remains unknown. Whether enhanced middle molecule removal outweighs the potential adverse effects of increased albumin loss with novel highly permeable membranes and convective therapies is yet to be determined. PMID- 29106651 TI - Target-Pathogen: a structural bioinformatic approach to prioritize drug targets in pathogens. AB - Available genomic data for pathogens has created new opportunities for drug discovery and development to fight them, including new resistant and multiresistant strains. In particular structural data must be integrated with both, gene information and experimental results. In this sense, there is a lack of an online resource that allows genome wide-based data consolidation from diverse sources together with thorough bioinformatic analysis that allows easy filtering and scoring for fast target selection for drug discovery. Here, we present Target-Pathogen database (http://target.sbg.qb.fcen.uba.ar/patho), designed and developed as an online resource that allows the integration and weighting of protein information such as: function, metabolic role, off targeting, structural properties including druggability, essentiality and omic experiments, to facilitate the identification and prioritization of candidate drug targets in pathogens. We include in the database 10 genomes of some of the most relevant microorganisms for human health (Mycobacterium tuberculosis, Mycobacterium leprae, Klebsiella pneumoniae, Plasmodium vivax, Toxoplasma gondii, Leishmania major, Wolbachia bancrofti, Trypanosoma brucei, Shigella dysenteriae and Schistosoma Smanosoni) and show its applicability. New genomes can be uploaded upon request. PMID- 29106653 TI - The Berlin International Consensus Meeting on Concussion in Sport. AB - The Fifth International Conference on Concussion in Sport was held in Berlin in October 2016. A series of 12 questions and subquestions was developed and the expert panel members were required to perform a systematic review to answer each question. Following presentation at the Berlin meeting of the systematic review, poster abstracts and audience discussion, the summary Consensus Statement was produced. Further, a series of tools for the management of sport-related concussion was developed, including the Sport Concussion Assessment Tool Fifth edition (SCAT5), the Child SCAT5, and the Concussion Recognition Tool Fifth edition. This paper elaborates on this process, the outcomes, and explores the implications for neurosurgeons in the management of sport-related concussion. PMID- 29106654 TI - The population-level costs of immunosuppression medications for the treatment of glomerulonephritis are increasing over time due to changing patterns of practice. AB - Background: Immunosuppression (IS) is the main treatment for most types of glomerulonephritis (GN). Quantifying the cost of IS is necessary to ensure equitable access to therapies and optimal health outcomes, but the real-world cost of IS treatment for GN is largely unknown. We examined temporal changes in the population-level IS medication costs for GN over a 14-year period in a large Canadian province. Methods: We linked a provincial pathology database (containing all GN cases from 2000 to 2012) with renal and medication administrative databases to capture clinical characteristics and IS medications, with follow-up until 2013. The primary outcome (mean IS medication cost per treated patient each year) was evaluated for trends over time. Results: The cohort included 2983 GN patients followed for a mean of 5.7 years. The yearly per-patient medication cost increased 6.8-fold from $205 to $1394 (P < 0.001), with significant increases of 3.5-11.7-fold in anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, focal segmental glomerulosclerosis, lupus nephritis, minimal change disease and membranous nephropathy (P <= 0.004), but no change in immunoglobulin A (IgA) nephropathy. The cost of mycophenolate mofetil, calcineurin inhibitors and rituximab increased significantly (P < 0.001) such that in 2000 they accounted for 17.6% of medication costs and were used by 2.2% of patients, which increased to 94.5% and 44.6%, respectively, in 2013. The costs of azathioprine, cyclophosphamide and prednisone increased only slightly or decreased. Patterns of drug use and contribution to cost varied by type of GN. Conclusions: These are the first population-level estimates of the IS treatment costs for GN, and demonstrate a striking increase due to changing practice patterns from older, cheaper medications to newer, more expensive therapies. These results provide important information to guide future health policy strategies and cost effectiveness research in glomerular diseases. PMID- 29106655 TI - Pathological Movements of the Pelvis and Trunk During Gait in Children With Cerebral Palsy: A Cross-Sectional Study With 3-Dimensional Kinematics and Lower Lumbar Spinal Loading. AB - Background: Increased loading at the lumbar spine, particularly in the coronal plane, has been reported in children with cerebral palsy (CP). As pelvic and trunk movements associated with Trendelenburg and Duchenne type gait are most significant in the coronal plane, the potential exists for lower lumbar spinal loading to be negatively affected in children with CP and these types of movement patterns. Objective: The objective of this study was to assess trunk and pelvic kinematics and lower lumbar spinal loading patterns in children with CP and Trendelenburg and Duchenne type gait. Design: This was a cross-sectional study. Methods: Three-dimensional kinematic (lower limb and thorax) and L5-S1 kinetic data were recorded. Children were divided according to clinical presentation of Trendelenburg or Duchenne type gait. Several discrete kinematic and kinetic parameters were assessed between groups. Results: Three distinct pelvic and trunk movement patterns were identified for children with CP: Trendelenburg, Duchenne, and complex Trendelenburg-Duchenne. Peak L5-S1 lateral bending moments were increased by 62% in children with CP and Duchenne type gait. Children with CP and complex Trendelenburg-Duchenne gait demonstrated the largest deviations from normal, with increased peak ipsilateral and contralateral directed moments of 69% and 54%, respectively, compared with children with typical development. Limitations: A test-retest reliability analysis or measure of minimal detectable change was not conducted as part of this study. Results suggest that measures of minimal detectable change may be high for some of the reported variables. In addition, the inverse dynamic approach determines only the net intersegmental reactive forces that reflect the effect of external loads. Previous studies have shown that spinal loads may be larger than the net intersegmental force. Conclusions: Trendelenburg and Duchenne type movements were not always distinct, and a third type of movement, a combination of the two, was the most common in this study. Clinicians should be aware that children with CP and the Duchenne type or the complex Trendelenburg-Duchenne type of gait pattern experience abnormal loading that may have significant implications for the lower spine in the long term. PMID- 29106656 TI - Discrimination, Serious Psychological Distress, and Church-Based Emotional Support Among African American Men Across the Life Span. AB - Objective: This study tested whether church-based social support buffers the negative effects of discrimination on serious psychological distress (SPD) among three age groups-early, middle, and late adulthood-of African American men. Methods: Negative binominal regression analyses for discrimination and SPD were performed using data from 1,271 African American men from the National Survey of American Life. Results: Discrimination was positively associated with SPD for all age groups. An interaction between church-based support and discrimination indicated that under conditions of high levels of support from congregants, discrimination, and SPD were positively correlated. However, discrimination and SPD were unrelated for low levels of church-based support. Further, the interaction was significant for men aged 18-34 and 55 or older but not significant for men aged 35-54. Discussion: This is the first study to document relationships among discrimination, SPD, and church-based support in a nationally representative sample of African American men. Overall, rather than revealing a stress-buffering function, findings were consistent with the resource mobilization perspective of social support, indicating that higher levels of assistance from church networks are provided when individuals experience high levels of both discrimination and SPD. PMID- 29106657 TI - Posterior Upper Rib Excision for Neurogenic Thoracic Outlet Syndrome-- Feasibility and Early Outcomes. AB - BACKGROUND: There are several surgical treatment options for neurogenic thoracic outlet syndrome (n-TOS). However, the first rib has been shown to be the common denominator of all TOS forms and the degree of its resection has been shown to correlate with the long-term success. OBJECTIVE: To demonstrate the feasibility of posterior upper rib excision (PURE) and report early outcomes. METHODS: Nine patients presented with signs and symptoms of n-TOS. Preoperative evaluation involved physical and neurological examination, arm visual analog score (VAS), cervical X-ray, magnetic resonance imaging (MRI) of the cervical spine, and brachial plexus MRI. All patients were operated at a single institution by a single surgeon. Postoperatively, clinical and radiological data were collected. RESULTS: There were 2 men and 7 women in the study with 10 procedures performed. The age range was 18 to 45 with mean of 36.6 yr. Mean preoperative arm visual analog scale score was 7.8. The patients underwent posterior upper rib excision (PURE) by a single surgeon. One patient had bilateral surgery. The causes of TOS were fibrous bands, enlarged C7 transverse processes, narrow scalene triangle, and accessory ribs. All patients improved after surgery in terms of arm pain and quality of life. Postoperative mean visual analog scale score was 1.1 at 6 mo. In addition, neurological examination was normal at 6 mo postoperatively and all patients returned to their previous full-time jobs. CONCLUSION: Posterior upper rib excision is a feasible surgical option for n-TOS. PMID- 29106658 TI - Investigating the Generalizability of the MultiFlow (r) DNA Damage Assay and Several Companion Machine Learning Models With a Set of 103 Diverse Test Chemicals. AB - The in vitro MultiFlow DNA Damage assay multiplexes p53, gammaH2AX, phospho histone H3, and polyploidization biomarkers into 1 flow cytometric analysis (Bryce, S. M., Bernacki, D. T., Bemis, J. C., and Dertinger, S. D. (2016). Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach. Environ. Mol. Mutagen. 57, 171-189). The work reported herein evaluated the generalizability of the method, as well as several data analytics strategies, to a range of chemical classes not studied previously. TK6 cells were exposed to each of 103 diverse chemicals, 86 of which were supplied by the National Toxicology Program (NTP) and selected based upon responses in genetic damage assays conducted under the Tox21 program. Exposures occurred for 24 h over a range of concentrations, and cell aliquots were removed at 4 and 24 h for analysis. Multiplexed response data were evaluated using 3 machine learning models designed to predict genotoxic mode of action based on data from a training set of 85 previously studied chemicals. Of 54 chemicals with sufficient information to make an a priori call on genotoxic potential, the prediction models' accuracies were 79.6% (random forest), 88.9% (logistic regression), and 90.7% (artificial neural network). A majority vote ensemble of the 3 models provided 92.6% accuracy. Forty-nine NTP chemicals were not adequately tested (maximum concentration did not approach assay's cytotoxicity limit) and/or had insufficient conventional genotoxicity data to allow their genotoxic potential to be defined. For these chemicals MultiFlow data will be useful in future research and hypothesis testing. Collectively, the results suggest the MultiFlow assay and associated data analysis strategies are broadly generalizable, demonstrating high predictability when applied to new chemicals and classes of compounds. PMID- 29106660 TI - Simultaneous Clipping of a Basilar Apex Aneurysm and Right Middle Cerebral Artery Aneurysm: 3-Dimensional Operative Video. PMID- 29106659 TI - Biological and Psychological Factors Associated With Smoking Abstinence Six Years Post-Stroke. AB - Introduction: Tobacco use is a public health problem causing high morbidity and mortality, including stroke. This study evaluates predictive factors of smoking cessation in the long term after stroke. Methods: We followed a cohort of 110 consecutive smokers with stroke for up to 6 years. Sociodemographic variables, stroke severity, insular involvement, stage of change in smoking habit before stroke and disruption of addiction variable (smoking cessation, absence of relapses, having stopped smoking without difficulties and not having had urge) were evaluated. Results: Twenty patients died during follow-up and two patients were lost leaving a final cohort of 88 patients. The prevalence of smoking cessation in the remaining population was 65.9% post-stroke, 54.9% at 3-6 months, 40.9% at 1 year and 37.5% at 6 years. Prevalence was significantly higher in patients with insular involvement during the first year of follow-up, but not at 6 years. Disruption immediately after stroke (OR = 10.1; 95% CI = 2.5 to 40.1) and intention to change before having the stroke (OR = 4.8; 95% CI = 1.0 to 23.0) were predictors of abstinence at 6 years after adjusting for age, sex and stroke severity at baseline. When tobacco abstinence at the 1 year follow-up was included in the model, this factor was the best predictor of tobacco abstinence at 1 year (OR = 10.5; 95% CI = 2.2 to 49.4). Conclusions: Intention of change, having the disruption criteria, and abstinence 1 year after stroke were predictors of abstinence at 6 years. An insular lesion in the acute phase of stroke does not determine the tobacco use status at 6 years. Implications: This study is the first prospective investigation with a cohort of stroke patients to examine the long-term influence of biological and psychological factors on smoking cessation. Tobacco abstinence 1 year after stroke was the strongest predictor of abstinence at 6 years of follow-up. The effect of the insular cortex lesion on tobacco cessation, which had been relevant during the first year, no longer had an influence over the longer period studied here. PMID- 29106661 TI - Direct and Indirect Pathways From Social Support to Health? AB - Objectives: We aimed to investigate potential direct and indirect pathways linking social support and health, while considering mental health and chronic inflammation as inter-related outcomes. The study also contributes to the literature through testing potential bidirectional relationships between social support, mental health, and chronic inflammation. Methods: This study uses Structural Equation Modeling and two waves of the National Social Life, Health, and Aging Project (NSHAP), including 1,124 community-living older adults aged 57 85 years at Wave 1 (2005). Results: Analyses show that social support influenced mental health indirectly through better self-esteem. Moreover, social support was associated with lower levels of chronic inflammation but chronic inflammation did not influence social support. Discussion: The growing number of older adults with an aging population urgently calls for a greater understanding of factors influencing their physical and mental health. The results of this study demonstrate the importance of social support in older adults' health, while specifically focusing on understudied indirect pathways from social support to health. PMID- 29106662 TI - Preoperative Nomograms Predict Patient-Specific Cervical Spine Surgery Clinical and Quality of Life Outcomes. AB - BACKGROUND: Clinical and quality of life (QOL) outcomes vary depending on the patient's demographics, comorbidities, presenting symptoms, pathology, and surgical treatment used. While there have been individual predictors identified, no comprehensive method incorporates a patient's complex clinical presentation to predict a specific individual postoperative outcome. OBJECTIVE: To create tool that predicts patient-specific outcomes among those undergoing cervical spine surgery. METHODS: A total of 952 patients at a single tertiary care institution who underwent anterior or posterior cervical decompression/fusion between 2007 and 2013 were retrospectively reviewed. Outcomes included postoperative emergency department visit or readmission within 30 d, reoperation within 90 d for infection, and changes in QOL outcomes. Nomograms were modeled based on patient demographics and surgical variables. Bootstrap was used for internal validation. RESULTS: Bias-corrected c-index for emergency department visits, readmission, and reoperation were 0.63, 0.78, and 0.91, respectively. For the QOL metrics, the bias-corrected adjusted R-squared was EQ-5D (EuroQOL): 0.43, for PHQ-9 (Patient Health Questionnaire-9): 0.35, and for PDQ (Pain/Disability Questionnaire): 0.47. Variables predicting the clinical outcomes varied, but included race and median income, body mass index, comorbidities, presenting symptoms, indication for surgery, surgery type, and levels. For the QOL nomograms, the predictors included similar variables, but were significantly more affected by the preoperative QOL of the patient. CONCLUSION: These prediction models enable referring physicians and spine surgeons to provide patients with personalized expectations regarding postoperative clinical and QOL outcomes following a cervical spine surgery. After appropriate validation, use of patient-specific prediction tools, such as nomograms, has the potential to lead to superior spine surgery outcomes and more cost effective care. PMID- 29106663 TI - Stress Is Associated with Poor Outcome of Acute Treatment for Chronic Migraine: A Multicenter Study. AB - Background: Chronic migraine (CM) is associated with severe psychological symptoms and disabilities. Information on the relationship between stress and the outcomes of acute CM treatment is limited. Methods: We evaluated the clinical presentation and stress levels of patients with CM who visited the neurology departments of 14 hospitals between September and December 2015. The patients were divided into stress and reference groups on the basis of the Korean version of the Brief Encounter Psychosocial Instrument (BEPSI-K). Quality of life was evaluated using EuroQol Five Dimension Questionnaire Three-Level. The Migraine Assessment of Current Therapy questionnaire was used to assess the outcomes of acute treatment. Results: This study included 186 CM patients. On the basis of the BEPSI-K score, 79 and 107 patients were assigned to the stress and reference groups, respectively. The stress group had more patients with poor outcomes of acute treatment than the reference group (67.1% vs 40.2%, P < 0.001). In a multivariate analysis, female gender (odds ratio [OR] = 3.266, 95% confidence interval [CI] = 1.172-9.103, P = 0.024), the number of headache-free days per month (OR = 0.932, 95% CI = 0.883-0.985, P = 0.012), and BEPSI-K score (OR = 1.667, 95% CI = 1.051-2.643, P = 0.030) predicted poor outcomes of acute treatment. Conclusions: High levels of stress were reported by 42.5% of patients with CM. The association between stress and the outcomes of acute treatment suggests that stress is an important clinical variable for improving the management of CM. PMID- 29106664 TI - ProteomicsDB. AB - ProteomicsDB (https://www.ProteomicsDB.org) is a protein-centric in-memory database for the exploration of large collections of quantitative mass spectrometry-based proteomics data. ProteomicsDB was first released in 2014 to enable the interactive exploration of the first draft of the human proteome. To date, it contains quantitative data from 78 projects totalling over 19k LC-MS/MS experiments. A standardized analysis pipeline enables comparisons between multiple datasets to facilitate the exploration of protein expression across hundreds of tissues, body fluids and cell lines. We recently extended the data model to enable the storage and integrated visualization of other quantitative omics data. This includes transcriptomics data from e.g. NCBI GEO, protein protein interaction information from STRING, functional annotations from KEGG, drug-sensitivity/selectivity data from several public sources and reference mass spectra from the ProteomeTools project. The extended functionality transforms ProteomicsDB into a multi-purpose resource connecting quantification and meta data for each protein. The rich user interface helps researchers to navigate all data sources in either a protein-centric or multi-protein-centric manner. Several options are available to download data manually, while our application programming interface enables accessing quantitative data systematically. PMID- 29106665 TI - Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. AB - Background: Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab +/- ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported. Methods: Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm. Results: Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for >=12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression >=1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients. Conclusions: Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma. PMID- 29106666 TI - TADB 2.0: an updated database of bacterial type II toxin-antitoxin loci. AB - TADB2.0 (http://bioinfo-mml.sjtu.edu.cn/TADB2/) is an updated database that provides comprehensive information about bacterial type II toxin-antitoxin (TA) loci. Compared with the previous version, the database refined and the new data schema is employed. With the aid of text mining and manual curation, it recorded 6193 type II TA loci in 870 replicons of bacteria and archaea, including 105 experimentally validated TA loci. In addition, the newly developed tool TAfinder combines the homolog searches and the operon structure detection, allowing the prediction for type II TA pairs in bacterial genome sequences. It also helps to investigate the genomic context of predicted TA loci for putative virulence factors, antimicrobial resistance determinants and mobile genetic elements via alignments to the specific public databases. Additionally, the module TAfinder Compare allows comparing the presence of the given TA loci across the close relative genomes. With the recent updates, TADB2.0 might provide better support for understanding the important roles of type II TA systems in the prokaryotic life activities. PMID- 29106667 TI - MicrobiomeDB: a systems biology platform for integrating, mining and analyzing microbiome experiments. AB - MicrobiomeDB (http://microbiomeDB.org) is a data discovery and analysis platform that empowers researchers to fully leverage experimental variables to interrogate microbiome datasets. MicrobiomeDB was developed in collaboration with the Eukaryotic Pathogens Bioinformatics Resource Center (http://EuPathDB.org) and leverages the infrastructure and user interface of EuPathDB, which allows users to construct in silico experiments using an intuitive graphical 'strategy' approach. The current release of the database integrates microbial census data with sample details for nearly 14 000 samples originating from human, animal and environmental sources, including over 9000 samples from healthy human subjects in the Human Microbiome Project (http://portal.ihmpdcc.org/). Query results can be statistically analyzed and graphically visualized via interactive web applications launched directly in the browser, providing insight into microbial community diversity and allowing users to identify taxa associated with any experimental covariate. PMID- 29106668 TI - USim: A New Device and App for Case-Specific, Intraoperative Ultrasound Simulation and Rehearsal in Neurosurgery. A Preliminary Study. AB - BACKGROUND: Intraoperative ultrasound (iUS) is an excellent aid for neurosurgeons to perform better and safer operations thanks to real time, continuous, and high quality intraoperative visualization. OBJECTIVE: To develop an innovative training method to teach how to perform iUS in neurosurgery. METHODS: Patients undergoing surgery for different brain or spine lesions were iUS scanned (before opening the dura) in order to arrange a collection of 3-dimensional, US images; this set of data was matched and paired to preoperatively acquired magnetic resonance images in order to create a library of neurosurgical cases to be studied offline for training and rehearsal purposes. This new iUS training approach was preliminarily tested on 14 European neurosurgery residents, who participated at the 2016 European Association of Neurosurgical Societies Training Course (Sofia, Bulgaria). RESULTS: USim was developed by Camelot and the Besta NeuroSim Center as a dedicated app that transforms any smartphone into a "virtual US probe," in order to simulate iUS applied to neurosurgery on a series of anonymized, patient-specific cases of different central nervous system tumors (eg, gliomas, metastases, meningiomas) for education, simulation, and rehearsal purposes. USim proved to be easy to use and allowed residents to quickly learn to handle a US probe and interpret iUS semiotics. CONCLUSION: USim could help neurosurgeons learn neurosurgical iUS safely. Furthermore, neurosurgeons could simulate many cases, of different brain/spinal cord tumors, that resemble the specific cases they have to operate on. Finally, the library of cases would be continuously updated, upgraded, and made available to neurosurgeons. PMID- 29106669 TI - A Randomized Trial of the Effect of Youth Appealing E-Cigarette Advertising on Susceptibility to Use E-Cigarettes Among Youth. AB - Introduction: Very little is known about how e-cigarette marketing is being perceived by youth, and the potential effect it will have on youth vaping and smoking behaviors. This limits the ability to identify youth-focused marketing efforts and to design effective policies for the regulation of e-cigarette marketing content and placement. Methods: A sample of 417 nonsmoking youth (mean age = 15, SD = 1.3) were randomly assigned to either view four e-cigarette ads with low youth appeal, four e-cigarette ads with high youth appeal or four control ads. After exposure, participants completed covert and overt measurements of e-cigarette and tobacco cigarette attitudes and susceptibility to use. Results: Youth in an e-cigarette ad condition were more likely to select an e cigarette item in a product choice task compared to control, and had more positive e-cigarette beliefs. Contrary to hypotheses, youth in the low youth appeal condition reported greater susceptibility to trying e-cigarettes and tobacco cigarettes compared to control. Conclusions: Exposure to any e-cigarette advertising may play a role in teens' decision to initiate e-cigarette and tobacco cigarette use. As the Food and Drug Administration now has regulatory authority over the marketing of e-cigarettes, regulations on e-cigarette advertising are suggested. Implications: Teens are increasingly being exposed to e-cigarette advertising, and many places are considering e-cigarette regulations, yet we know very little about how e-cigarette advertisements might influence youth tobacco use. This study utilized a novel dataset of e-cigarette ads coded for youth appeal and presented them to a sample of 417 nonsmoking teens in a randomized controlled design to test the effect of features on youth susceptibility to initiating e-cigarette and tobacco cigarette use. The findings inform evidence-based recommendations for regulating the marketing of e cigarettes. PMID- 29106670 TI - Initial Experience Using a High-Definition 3-Dimensional Exoscope System for Microneurosurgery. AB - BACKGROUND: The operative microscope and endoscope have significantly advanced modern neurosurgery. These devices are nonetheless limited by high costs and suboptimal optics, ergonomics, and maneuverability. A recently developed extracorporeal telescope ("exoscope") operative system combines characteristics from both the operative microscope and endoscope and provides an affordable, portable, high-definition operative experience. Widespread use of exoscopes in neurosurgery has previously been limited by a lack of stereopsis with 2 dimensional(2-D) monitors. OBJECTIVE: To assess the surgical potential of a novel, 3-D, high-definition (4K-HD) exoscope system. METHODS: Assess dissection time and visualization of critical structures in a series of human cadaveric cranial neurosurgical approaches with the 3-D 4K-HD exoscope as compared to a standard operating microscope. RESULTS: Dissection times and visualization of critical structures was comparable with the 3-D 4K-HD exoscope and a standard operating microscope. The low-profile exoscope nonetheless allowed for larger operative corridors, enhanced instrument maneuverability, and less obstruction in passing instrumentation. The large monitor also resulted in an immersive surgical experience, and gave multiple team members the same high-quality view as the primary operator. Finally, the exoscope possessed a more ergonomically favorable setup as compared to the traditional microscope, allowing the surgeon to be in a neutral position despite the operative angle. CONCLUSION: The novel 3-D 4K-HD exoscope system possesses favorable optics, ergonomics, and maneuverability as compared to the traditional operating microscope, with the exoscope's shared surgical view possessing obvious educational and workflow advantages. Further clinical trials are justified to validate this initial cadaveric experience. PMID- 29106671 TI - Palivizumab for Infants < 29 Weeks in Hong Kong without a Clear-Cut Season for Respiratory Syncytial Virus Infection-A Cost-Effectiveness Analysis. AB - Aim: To evaluate the cost-effectiveness of palivizumab prophylaxis for premature infants born <29 weeks in Hong Kong. Method: We evaluated the hospitalization rate for respiratory syncytial virus (RSV) infection within the first 12 months of discharge of a cohort of preterm infants born between 2010 and 2014 at two local hospitals. Results: In total, 40 of 135 infants were given palivizumab. The hospitalization rate for premature infants <29 weeks was reduced from 15.8 to 5% (p = 0.096) and that for infants <27 weeks was reduced from 33.3 to 8.7% (p = 0.046). In the former group, the incremental cost-effectiveness ratio per hospital admission prevented (ICER/HAP) was US dollar (USD) 24 365. In the latter subgroup, the ICER/HAP was USD 3108. Conclusion: The cost-effectiveness as measured for infants <27 weeks is more favorable than that for infants <29 weeks. PMID- 29106672 TI - ERRATUM: Fetal radiation dose in computed tomography. PMID- 29106674 TI - Allopurinol and the risk of incident peripheral arterial disease in the elderly: a US Medicare claims data study. AB - Objective: The aim was to examine whether allopurinol use is independently associated with a reduction in the risk of incident peripheral arterial disease (PAD) in the US elderly. Methods: We used the 5% random Medicare sample from 2006 to 2012 to examine the association of allopurinol use and duration of use with the risk or hazard of incident PAD in a retrospective cohort study using a new user design. Multivariable Cox regression models adjusted for demographics, co morbidity, cardiac medications and cardiac conditions. Hazard ratios (HRs) and 95% CIs were calculated. Results: We identified 26 985 episodes of incident allopurinol use in 25 282 beneficiaries; 3167 allopurinol use episodes (12%) ended in incident PAD. In multivariable-adjusted analyses, allopurinol use was associated with an HR of 0.88 (95% CI: 0.81, 0.95) for incident PAD, as was female gender, HR 0.84 (95% CI: 0.78, 0.90). In a separate multivariable-adjusted model, compared with no allopurinol use, longer durations of allopurinol use were associated with lower HR of PAD: 181 days to 2 years, 0.88 (95% CI: 0.79, 0.97); and >2 years, 0.75 (95% CI: 0.63, 0.89). Other factors significantly associated with a higher HR of PAD were age 75 to < 85 and ?85 years, higher Charlson index score and black race. Sensitivity analyses that adjusted for cardiac conditions and medications confirmed these findings, with minimal to no attenuation of HRs. Conclusion: New allopurinol use was independently associated with a lower risk of PAD in the elderly. Longer allopurinol use durations seemed more protective. Mechanisms of the protective effect need to be investigated in future studies. PMID- 29106673 TI - Nonionic Ethoxylated Surfactants Induce Adipogenesis in 3T3-L1 Cells. AB - Recent studies have demonstrated that a number of environmental contaminants can act as metabolic disruptors and modulate metabolic function both in vitro and in vivo. 3T3-L1 mouse preadipocytes are commonly utilized to assess perturbations to adipogenesis, providing insight into environmental contaminants that may impact in vivo metabolic health. This study sought to assess whether various alkylphenol ethoxylates and alcohol ethoxylates (APEOs and AEOs, respectively), ubiquitous contaminants used in common household products, could disrupt metabolic health. 3T3-L1 cells were exposed to increasing concentrations of individual ethoxylated surfactants and base hydrophobes, and assessed for triglyceride accumulation (relative to a rosiglitazone-induced maximum response) and preadipocyte proliferation (relative to a differentiated vehicle control). We report herein that nonionic APEOs and AEOs promoted triglyceride accumulation and/or preadipocyte proliferation in 3T3-L1 cells at concentrations from 0.1 to 10 MUM. Activity appeared to be an effect of the polyethoxylate chain length, as the alkylphenol/alcohol hydrophobes exhibited minimal or no adipogenic activity. In addition, nonylphenol ethoxylates (NPEO) of various ethoxylate chain lengths exhibited biphasic adipogenic activity, with increasing triglyceride accumulation and preadipocyte proliferation from NPEO (0, average ethoxylate number) through NPEO (4), and then decreasing activities from NPEO (4) through NPEO (20). Our results suggest potential metabolic impacts of these compounds at environmentally relevant concentrations, demonstrating a need to further assess molecular mechanisms and better characterize environmental concentrations of the specific AEOs and APEOs that are inducing the greatest degree of adipogenic activity herein. PMID- 29106675 TI - The Efficacy of Consensus Tree Methods for Summarizing Phylogenetic Relationships from a Posterior Sample of Trees Estimated from Morphological Data. AB - Consensus trees are required to summarize trees obtained through MCMC sampling of a posterior distribution, providing an overview of the distribution of estimated parameters such as topology, branch lengths, and divergence times. Numerous consensus tree construction methods are available, each presenting a different interpretation of the tree sample. The rise of morphological clock and sampled ancestor methods of divergence time estimation, in which times and topology are coestimated, has increased the popularity of the maximum clade credibility (MCC) consensus tree method. The MCC method assumes that the sampled, fully resolved topology with the highest clade credibility is an adequate summary of the most probable clades, with parameter estimates from compatible sampled trees used to obtain the marginal distributions of parameters such as clade ages and branch lengths. Using both simulated and empirical data, we demonstrate that MCC trees, and trees constructed using the similar maximum a posteriori (MAP) method, often include poorly supported and incorrect clades when summarizing diffuse posterior samples of trees. We demonstrate that the paucity of information in morphological data sets contributes to the inability of MCC and MAP trees to accurately summarise of the posterior distribution. Conversely, majority-rule consensus (MRC) trees represent a lower proportion of incorrect nodes when summarizing the same posterior samples of trees. Thus, we advocate the use of MRC trees, in place of MCC or MAP trees, in attempts to summarize the results of Bayesian phylogenetic analyses of morphological data. PMID- 29106676 TI - Safety and efficacy of taurolidine/urokinase versus taurolidine/heparin as a tunneled catheter lock solution in hemodialysis patients: a prospective, randomized, controlled study. AB - Background: Taurolidine citrate with heparin (Taurolock/Hep) is a promising central venous catheter lock solution. Despite its universal use among our hemodialysis patients, the prevalence of catheter malfunction was high. We aimed to compare Taurolock/Hep and taurolidine citrate with urokinase (Taurolock/U) as a catheter lock solution in order to identify whether either solution could reduce catheter-related dysfunction. Methods: In this prospective, randomized, controlled trial, patients were randomized to receive either Taurolock/Hep or Taurolock/U and were followed for 6 months. Episodes of acute catheter thrombosis, requirement of recombinant tissue plasminogen activator (rt-PA) and incidence of catheter-related blood stream infection (CRBSI) were recorded, along with dialysis adequacy ( Kt / V ), blood flow rates (BFRs) and adverse events. Results: There were 93 inclusions (85 patients) in the Taurolock/Hep group and 84 inclusions in the Taurolock/U group (79 patients). Three catheters were removed in the Taurolock/Hep group because of acute thrombosis, while no catheter was removed for the same reason in the Taurolock/U group. The total number of all causes catheter exchange (acute thrombosis and CRBSI) was significantly lower in Taurolock/U group (P = 0.028). rt-PA was used significantly less often in the Taurolock/U group than in the Taurolock/Hep group (P = 0.006). Moreover, higher BFR and Kt / V were noted in the Taurolock/U group than in the Taurolock/Hep group, although the differences were not uniformly significant. Conclusion: Taurolock/U is a safe and effective tunneled dialysis catheter lock solution, with a low rate of catheter exchange. PMID- 29106677 TI - Ra-223 DICHLORIDE: Hp(0.07) RATE ASSESSMENT FROM UNSHIELDED SYRINGES. PMID- 29106678 TI - Intradural Anterior Clinoidectomy for Ophthalmic Artery Aneurysm Clipping: 3 Dimensional Operative Video. PMID- 29106679 TI - Toward a Common Language for Measuring Patient Mobility in the Hospital: Reliability and Construct Validity of Interprofessional Mobility Measures. AB - Background: The lack of common language among interprofessional inpatient clinical teams is an important barrier to achieving inpatient mobilization. In The Johns Hopkins Hospital, the Activity Measure for Post-Acute Care (AM-PAC) Inpatient Mobility Short Form (IMSF), also called "6-Clicks," and the Johns Hopkins Highest Level of Mobility (JH-HLM) are part of routine clinical practice. The measurement characteristics of these tools when used by both nurses and physical therapists for interprofessional communication or assessment are unknown. Objective: The purposes of this study were to evaluate the reliability and minimal detectable change of AM-PAC IMSF and JH-HLM when completed by nurses and physical therapists and to evaluate the construct validity of both measures when used by nurses. Design: A prospective evaluation of a convenience sample was used. Methods: The test-retest reliability and the interrater reliability of AM PAC IMSF and JH-HLM for inpatients in the neuroscience department (n = 118) of an academic medical center were evaluated. Each participant was independently scored twice by a team of 2 nurses and 1 physical therapist; a total of 4 physical therapists and 8 nurses participated in reliability testing. In a separate inpatient study protocol (n = 69), construct validity was evaluated via an assessment of convergent validity with other measures of function (grip strength, Katz Activities of Daily Living Scale, 2-minute walk test, 5-times sit-to-stand test) used by 5 nurses. Results: The test-retest reliability values (intraclass correlation coefficients) for physical therapists and nurses were 0.91 and 0.97, respectively, for AM-PAC IMSF and 0.94 and 0.95, respectively, for JH-HLM. The interrater reliability values (intraclass correlation coefficients) between physical therapists and nurses were 0.96 for AM-PAC IMSF and 0.99 for JH-HLM. Construct validity (Spearman correlations) ranged from 0.25 between JH-HLM and right-hand grip strength to 0.80 between AM-PAC IMSF and the Katz Activities of Daily Living Scale. Limitations: The results were obtained from inpatients in the neuroscience department of a single hospital. Conclusions: The AM-PAC IMSF and JH HLM had excellent interrater reliability and test-retest reliability for both physical therapists and nurses. The evaluation of convergent validity suggested that AM-PAC IMSF and JH-HLM measured constructs of patient mobility and physical functioning. PMID- 29106680 TI - ESTIMATION OF ORGAN DOSES AMONG DIAGNOSTIC MEDICAL RADIATION WORKERS IN SOUTH KOREA. AB - This study aimed to estimate the radiation organ doses from occupational exposure in 94 396 Korean medical radiation workers. Data on badge doses (i.e. personal dose equivalent at 10 mm) between 1996 and 2011 obtained from a national dosimetry registry, survey data from 2012 to 2013, and organ dose conversion coefficients provided by the International Commission on Radiological Protection (ICRP) were used for the estimation. The highest mean cumulative badge doses (26.87 mSv) were observed in radiologists, followed by radiologic technologists (15.96 mSv). Male workers exhibited higher mean cumulative badge doses, across occupational groups. The estimated organ doses showed similar trends with those of badge doses. Organs located outside the apron's coverage such as the thyroid showed higher mean organ doses than those protected by the apron. Our findings could contribute to future radiation epidemiologic studies to investigate health effects from occupational radiation exposure in Korea. PMID- 29106681 TI - Common Missense Variant of SCN9A Gene Is Associated with Pain Intensity in Patients with Chronic Pain from Disc Herniation. AB - Objective: Lumbar intervertebral disk herniation (LDH) is considered one of the major risk factors for lower back pain, mainly caused by irritation of a spinal nerve or its root. One of the genes related to pain perception is SCN9A, which encodes the voltage gated sodium channel NaV1.7, a key molecule involved in peripheral pain processing. It had been presented before that a common polymorphism within SCN9A (rs6746030: G > A, R1150W) might influence nociception in the general population. Hence, the present study was aimed at investigating the association between SCN9A polymorphism and pain sensitivity. Methods: Pain intensity was measured by means of the visual analog pain scale (VAS) in 176 Caucasian patients with a history of leg and back pain who had been diagnosed with LDH and underwent lumbar discectomy. SCN9A polymorphism was determined by means of TaqMan assay. Results: A significantly higher preoperative back pain intensity was observed among rs6746030 A minor allele carriers, compared with GG homozygotes (VAS = 7.5 +/- 2.4 vs 6.5 +/- 2.7, P = 0.012). Similarly, A allele carriers were characterized by higher values of leg pain prior to surgery (VAS = 7.8 +/- 2.3 vs 6.8 +/- 2.6, P = 0.013). However, postoperative improvement in pain reduction was similar in both groups. Conclusions: Our results suggest that the SCN9A rs6746030 polymorphism may be associated with pain intensity in patients suffering from symptomatic disc herniation. PMID- 29106682 TI - Insights Into a Possible Influence on Gut Microbiota and Intestinal Barrier Function During Chronic Exposure of Mice to Imazalil. AB - The fungicide imazalil (IMZ) is widely used to prevent and treat fungal diseases in plants and animals. Here, male adult C57BL/6 mice were exposed to 0.1, 0.5, and 2.5 mg/kg body weight IMZ for 2, 5, or 15 weeks. The microbiota in cecal contents and feces changed during chronic IMZ exposure at phylum and genus levels. Sequencing of the V3-V4 region of the bacterial 16S rRNA gene revealed a significant change in the richness of microbiota in cecal contents and feces after exposure to 2.5 mg/kg IMZ for 15 weeks. Operational taxonomic unit (OTU) analysis indicated that 31.1% of cecal OTUs and 14.0% of fecal OTUs changed after IMZ exposure. In addition, chronic IMZ exposure also disturbed the intestinal barrier function of the mice, reducing mucus secretion, decreasing the expression of cystic fibrosis transmembrane conductance regulator (CFTR)-related genes in both the ileum and colon. Molecular docking analysis revealed that key hydrogen bonds were formed by nitrogen atoms of the imidazole bond with Val440 of CFTR and Ala697 of the SLC26 family. Our data suggested that gut microbiota and intestinal barrier were potential toxicological targets of IMZ. PMID- 29106683 TI - Neural Responses to Smoking Cues in Schizophrenia. AB - The high prevalence of nicotine dependence contributes to excess mortality in schizophrenia. Cue reactivity, or the encounter of drug-related cues or contexts, triggers craving, drug-seeking, and relapse. Prior functional magnetic resonance imaging (fMRI) research indicates that individuals with schizophrenia have blunted neural responses to rewarding stimuli in association with more severe negative symptoms. The objectives of this study are to determine if smokers with schizophrenia have altered neural reactivity to smoking cues compared with non psychiatrically ill smokers and to evaluate the influence of negative symptoms on cue reactivity. Twenty smokers with schizophrenia and 19 control smokers underwent fMRI while viewing smoking-related and neutral cues. The primary analysis was group comparison of Smoking-Neutral contrast using whole-brain analysis (Pcorrected < .05). Smokers with schizophrenia had significantly greater baseline carbon monoxide levels and longer duration of smoking, suggesting more nicotine use. While both groups had greater brain reactivity to smoking vs neutral cues, smokers with schizophrenia had significantly decreased cue reactivity (Smoking-Neutral) compared to controls in bilateral frontal midline regions. There were significant negative correlations between negative symptoms and frontal midline reactivity. Despite greater nicotine use, smokers with schizophrenia exhibited decreased smoking cue-induced neural reactivity in frontal midline regions, suggesting that increased smoking and low cessation rates in schizophrenia are not primarily driven by responses to smoking-related cues. The finding of negative correlations between cue reactivity and negative symptoms is consistent with previous research demonstrating decreased neural responses to rewarding cues, particularly in patients with negative symptoms. PMID- 29106684 TI - Frontal Lobe Epilepsy Surgery in Childhood and Adolescence: Predictors of Long Term Seizure Freedom, Overall Cognitive and Adaptive Functioning. AB - BACKGROUND: Although frontal lobe resections account for one-third of intralobar resections in pediatric epilepsy surgery, there is a dearth of information regarding long-term seizure freedom, overall cognitive and adaptive functioning. OBJECTIVE: To identify outcome predictors and define the appropriate timing for surgery. METHODS: We retrospectively analyzed the data of 75 consecutive patients aged 10.0 +/- 4.9 yr at surgery that had an 8.1 yr mean follow-up. RESULTS: Etiology comprised focal cortical dysplasia (FCD) in 71% and benign tumors in 16% cases. All patients but one had a magnetic resonance imaging-visible lesion. At last follow-up, 63% patients remained seizure-free and 37% had discontinued antiepileptic drugs. Presurgical predictors of seizure freedom were a shorter epilepsy duration, strictly regional epileptic discharges in electroencephalography (EEG), and an epileptogenic zone and/or lesion distant from eloquent cortex. Postsurgical predictors were the completeness of resection and the lack of early postoperative seizures or epileptic discharges in EEG. Higher presurgical overall cognitive and adaptive functioning was related to later epilepsy onset and to a sublobar epileptogenic zone and/or lesion. Following surgery, scores remained stable in the majority of patients. Postsurgical gains were determined by higher presurgical performance and tumors vs FCD. CONCLUSION: Our findings highlight the favorable long-term outcomes following frontal lobe epilepsy surgery in childhood and adolescence and underline the importance of early surgical intervention in selected candidates. Early postsurgical relapses and epileptic discharges in EEG constitute key markers of treatment failure and should prompt timely reevaluation. Postsurgical overall cognitive and adaptive functioning is stable in most patients, whereas those with benign tumors have higher chances of improvement. PMID- 29106685 TI - A Retrospective Propensity Score-Matched Early Thromboembolic Event Analysis of Prothrombin Complex Concentrate vs Fresh Frozen Plasma for Warfarin Reversal Prior to Emergency Neurosurgical Procedures. AB - BACKGROUND: Reversal of therapeutic anticoagulation prior to emergency neurosurgical procedures is required in the setting of intracranial hemorrhage. Multifactor prothrombin complex concentrate (PCC) promises rapid efficacy but may increase the probability of thrombotic complications compared to fresh frozen plasma (FFP). OBJECTIVE: To compare the rate of thrombotic complications in patients treated with PCC or FFP to reverse therapeutic anticoagulation prior to emergency neurosurgical procedures in the setting of intracranial hemorrhage at a level I trauma center. METHODS: Sixty-three consecutive patients on warfarin therapy presenting with intracranial hemorrhage who received anticoagulation reversal prior to emergency neurosurgical procedures were retrospectively identified between 2007 and 2016. They were divided into 2 cohorts based on reversal agent, either PCC (n = 28) or FFP (n = 35). The thrombotic complications rates within 72 h of reversal were compared using the chi2 test. A multivariate propensity score matching analysis was used to limit the threat to interval validity from selection bias arising from differences in demographics, laboratory values, history, and clinical status. RESULTS: Thrombotic complications were uncommon in this neurosurgical population, occurring in 1.59% (1/63) of treated patients. There was no significant difference in the thrombotic complication rate between groups, 3.57% (1/28; PCC group) vs 0% (0/35; FFP group). Propensity score matching analysis validated this finding after controlling for any selection bias. CONCLUSION: In this limited sample, thrombotic complication rates were similar between use of PCC and FFP for anticoagulation reversal in the management of intracranial hemorrhage prior to emergency neurosurgical procedures. PMID- 29106686 TI - The Identification of Pivotal Transcriptional Factors Mediating Cell Responses to Drugs With Drug-Induced Liver Injury Liabilities. AB - Drug-induced liver injury (DILI) is a leading cause of drug attrition during drug development and a common reason for drug withdrawal from the market. The poor predictability of conventional animal-based approaches necessitates the development of alternative testing approaches. A body of evidence associates DILI with the induction of stress-response genes in liver cells. Here, we set out to identify signal transduction pathways predominantly involved in the regulation of gene transcription by DILI drugs. To this end, we employed ATTAGENE's cell-based multiplexed reporter assay, the FACTORIAL transcription factor (TF), that enables quantitative assessment of the activity of multiple stress-responsive TFs in a single well of cells. Homogeneous reporter system enables quantitative functional assessment of multiple transcription factors. Nat. Methods 5, 253-260). Using this assay, we assessed TF responses of the human hepatoma cell line HepG2 to a panel of 64 drug candidates, including 23 preclinical DILI and 11 clinical DILI compounds and 30 nonhepatotoxic compounds from a diverse physicochemical property space. We have identified 16 TF families that specifically responded to DILI drugs, including nuclear factor (erythroid-derived 2)-like 2 antioxidant response element, octamer, hypoxia inducible factor 1 alpha, farnesoid-X receptor, TCF/beta-catenin, aryl hydrocarbon receptor, activator protein-1, E2F, early growth response-1, metal-response transcription factor 1, sterol regulatory element-binding protein, paired box protein, peroxisome proliferator-activated receptor, liver X receptor, interferone regulating factor, and P53, and 2 promoters that responded to multiple TFs (cytomegalovirus and direct repeat 3/vitamin D receptor). Some of TFs identified here also have previously defined role in pathogenesis of liver diseases. These data demonstrate the utility of cost-effective, animal-free, TF profiling assay for detecting DILI potential of drug candidates at early stages of drug development. PMID- 29106687 TI - ASPECTS, Large Vessel Occlusion, and Time of Symptom Onset: Estimation of Eligibility for Endovascular Therapy. AB - BACKGROUND: Understanding how many patients are eligible for endovascular therapy can help develop more effective stroke systems of care. OBJECTIVE: To determine the proportion of patients eligible for endovascular therapy. METHODS: In this single center retrospective cohort study, we identified patients with acute ischemic stroke from large vessel occlusion (LVO) from January 2014 to December 2015. Selection criteria including LVO location, Alberta stroke program early computed tomography score (ASPECTS) range, hospital arrival time, and the use of intravenous thrombolysis were applied to calculate proportions of patients eligible for endovascular therapy. RESULTS: Of 989 patients with acute ischemic stroke, LVO was identified in 224 (23%) cases. Eighty-four percent of patients admitted within 6 h, 75% of patients admitted within 6 to 12 h, and 77% of patients with M1 and internal carotid artery occlusions admitted within 12 to 24 h had favorable ASPECTS for thrombectomy, defined as ASPECTS >= 6. Severity of NIHSS (National Institutes of Health Stroke Scale) was predictive of favorable ASPECTS (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.04-0.74; P = .014 for NIHSS > 10 and OR 0.30, 95% CI 0.12-0.80; P = .014 for NIHSS > 20), whereas time of hospital arrival was not (OR 1.73, 95% CI 0.76-4.03; P = .26). Using all class I, Level of Evidence A American Heart Association guidelines criteria, 4% of patients with acute ischemic stroke were eligible for endovascular therapy. Up to 20% of patients were eligible for endovascular therapy with less restrictive criteria (Class IIb; Level of Evidence C). CONCLUSION: Depending on the sets of selection criteria, between 4% (the most restrictive criteria) and 20% (the least restrictive criteria) of patients with LVO are potentially eligible for endovascular therapy. PMID- 29106688 TI - DOSES AND RISKS FROM URANIUM ARE NOT INCREASED SIGNIFICANTLY BY INTERACTIONS WITH NATURAL BACKGROUND PHOTON RADIATION. PMID- 29106689 TI - Effects of Systematic Variation in Size and Surface Coating of Silver Nanoparticles on Their In Vitro Toxicity to Macrophage RAW 264.7 Cells. AB - In literature, varying and sometimes conflicting effects of physicochemical properties of nanoparticles (NPs) are reported on their uptake and effects in organisms. To address this, small- and medium-sized (20 and 50 nm) silver nanoparticles (AgNPs) with specified different surface coating/charges were synthesized and used to systematically assess effects of NP-properties on their uptake and effects in vitro. Silver nanoparticles were fully characterized for charge and size distribution in both water and test media. Macrophage cells (RAW 264.7) were exposed to these AgNPs at different concentrations (0-200 ug/ml). Uptake dynamics, cell viability, induction of tumor necrosis factor (TNF)-alpha, ATP production, and reactive oxygen species (ROS) generation were assessed. Microscopic imaging of living exposed cells showed rapid uptake and subcellular cytoplasmic accumulation of AgNPs. Exposure to the tested AgNPs resulted in reduced overall viability. Influence of both size and surface coating (charge) was demonstrated, with the 20-nm-sized AgNPs and bovine serum albumin (BSA) coated (negatively charged) AgNPs being slightly more toxic. On specific mechanisms of toxicity (TNF-alpha and ROS production) however, the AgNPs differed to a larger extent. The highest induction of TNF-alpha was found in cells exposed to the negatively charged AgNP_BSA, both sizes (80* higher than control). Reactive oxygen species induction was only significant with the 20 nm positively charged AgNP_Chit. PMID- 29106690 TI - Metabolic Syndrome and Associated Diseases: From the Bench to the Clinic. AB - Metabolic Syndrome and Associated Diseases: From the Bench to the Clinic, a Society of Toxicology Contemporary Concepts in Toxicology (CCT) workshop was held on March 11, 2017. The meeting was convened to raise awareness of metabolic syndrome and its associated diseases and serve as a melting pot with scientists of multiple disciplines (eg, toxicologists, clinicians, regulators) so as to spur research and understanding of this condition. The criteria for metabolic syndrome include obesity, dyslipidemia (low high-density lipoprotein and/or elevated triglycerides), elevated blood pressure, and alterations in glucose metabolism. It can lead to a greater potential of type 2 diabetes, lipid disorders, cardiovascular disease, hepatic steatosis, and other circulatory disorders. Although there are no approved drugs specifically for this syndrome, many drugs target diseases associated with this syndrome thus potentially increasing the likelihood of drug-drug interactions. There is currently significant research focusing on understanding the key pathways that control metabolism, which would be likely targets of risk factors (eg, exposure to xenobiotics, genetics) and lifestyle factors (eg, microbiome, nutrition, and exercise) that contribute to metabolic syndrome. Understanding these pathways could also lead to the development of pharmaceutical interventions. As individuals with metabolic syndrome have signs similar to that of toxic responses (eg, oxidative stress and inflammation) and organ dysfunction, these alterations should be taken into account in drug development. With the increasing frequency of metabolic syndrome in the general population, the idea of a "normal" individual may need to be redefined. This paper reports on the substance and outcomes of this workshop. PMID- 29106691 TI - Developmental Effects of Cannabidiol and Delta9-Tetrahydrocannabinol in Zebrafish. AB - Cannabidiol (CBD) has gained much attention in the past several years for its therapeutic potential in the treatment of drug-resistant epilepsy, such as Dravet syndrome. Although CBD has shown anecdotal efficacy in reducing seizure frequency, little is known regarding the potential adverse side effects of CBD on physiology, development, organogenesis, or behavior. The goal of this project was to compare the relative morphological, behavioral, and gene expression phenotypes resulting after a developmental exposure to Delta9-tetrahydrocannabinol (THC) or CBD. Zebrafish were exposed from blastula through larval stage (96 h postfertilization [hpf]) to 0.3, 0.6, 1.25, 2.5, 5 mg/l (1, 2, 4, 8, 16 uM) THC or 0.07, 0.1, 0.3, 0.6, 1.25 mg/l CBD (0.25, 0.5, 1, 2, 4 uM). Despite the similarity in THC and CBD dysmorphologies, ie, edemas, curved axis, eye/snout/jaw/trunk/fin deformities, swim bladder distention, and behavioral abnormalities, the LC50 for CBD (0.53 mg/l) was nearly 7 times lower than THC (3.65 mg/l). At 96 hpf, c-fos, dazl, and vasa were differentially expressed following THC exposure, but only c-fos expression was significantly increased by CBD. Cannabidiol was more bioconcentrated compared with THC despite higher THC water concentrations. This work supports the potential for persistent developmental impacts of cannabinoid exposure, but more studies are needed to assess latent effects and their molecular mechanisms of toxicity. PMID- 29106692 TI - Confirmation bias, conflicts of interest and cholesterol guidance: can we trust expert opinions? PMID- 29106693 TI - Embracing Psychosis: A Cognitive Insight Intervention Improves Personal Narratives and Meaning-Making in Patients With Schizophrenia. AB - Schizophrenia is a complex psychiatric disorder with unknown and presumably heterogeneous etiology. While the disorder can have various outcomes, research is predominantly "deficit-oriented" emphasizing the hardship that the disorder inflicts on sufferers as well as their families and society. Beyond symptom reduction, imparting patients with hope and meaning in life is increasingly considered an important treatment target, which may raise self-esteem, and reduce self-stigma and suicidal ideation. The present study compared a psychotherapeutic treatment aimed at improving cognitive insight, individualized metacognitive intervention (MCT+), with an active control in order to elucidate if personal meaning-making and hope can be improved in patients with psychosis across time. A total of 92 patients were randomized to either individualized metacognitive therapy (MCT+) or CogPack (neuropsychological training) and followed up for up to 6 months. The "Subjective Sense in Psychosis Questionnaire" (SUSE) was administered which covers different salutogenetic vs pathogenetic views of the disorder, valence of symptom experiences and the consequences of psychosis. Patients in the MCT+ group showed a significant positive shift in attitudes towards the consequences of their illness over time relative to patients in the active control condition. There was some evidence that MCT+ also enhanced meaning making. The perceived negative consequences of psychosis were highly correlated with depression and low self-esteem, as well as suicidality. The study shows that a cognitive insight training can improve meaning-making in patients and help them come to terms with their diagnosis. PMID- 29106694 TI - Episodic Memory for Dynamic Social Interaction Across Phase of Illness in Schizophrenia. AB - Although a number of studies examined recollection and familiarity memory in schizophrenia, most of studies have focused on nonsocial episodic memory. Little is known about how schizophrenia patients remember social information in everyday life and whether social episodic memory changes over the course of illness. This study aims to examine episodic memory for dynamic social interaction with multimodal social stimuli in schizophrenia across phase of illness. Within each phase of illness, probands and demographically matched controls participated: 51 probands at clinical high risk (CHR) for psychosis and 36 controls, 80 first episode schizophrenia patients and 49 controls, and 50 chronic schizophrenia patients and 39 controls. The participants completed the Social Remember-Know Paradigm that assessed overall social episodic memory, social recollection and familiarity memory, and social context memory, in addition to social cognitive measures and measures on community functioning. Probands showed impairment for recollection but not in familiarity memory and this pattern was similar across phase of illness. In contrast, impaired social context memory was observed in the first-episode and chronic schizophrenia samples, but not in CHR samples. Social context memory was associated with community functioning only in the chronic sample. These findings suggest that an impaired recollection could be a vulnerability marker for schizophrenia whereas impaired social context memory could be a disease-related marker. Further, a pattern of impaired recollection with intact familiarity memory for social stimuli suggests that schizophrenia patients may have a different pattern of impaired episodic memory for social vs nonsocial stimuli. PMID- 29106695 TI - Scaling-Up Ionic Liquid-Based Technologies: How Much Do We Care About Their Toxicity? Prima Facie Information on 1-Ethyl-3-Methylimidazolium Acetate. AB - The potential of the ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) to dissolve a variety of biopolymers such as cellulose and chitin, makes it an attractive candidate for scaled-up industrial utilization. In fact, the first steps towards its use at industrial scale have been taken. This increases the urgency to fill the knowledge gaps in its toxicity and environmental impact in order to predict and control its environmental fate. In this mini-review, we discuss the available literature surrounding this key IL. The literature (through the analysis of toxicity of the anion and the cation separately) suggests that [C2mim][OAc] is a relatively safe choice for industrial applications. However, because the IL should be considered as a compound, with unique properties arising from the interactions between the ions, comprehensive toxicity information for this particular IL is still required. To decide, prima facie, if this IL is toxic or not, evaluation of its influence on human health and ecotoxicity is needed prior to its large scale utilization. We chose in this mini-review to focus on toxicity surrounding this IL and evaluate what is known and what is not. Here with all the information in hand, we hope that the urgent need for [C2mim][OAc] toxicological assessment before it can be used in numerous technologies is highlighted. In the near future, we expect that the assessment of toxicity and environmental fate and impact can be integrated directly into any research into the industrial utilization of this IL and any others contemplated for industrial application. PMID- 29106697 TI - Navigational efficiency in a biased and correlated random walk model of individual animal movement. AB - Understanding how an individual animal is able to navigate through its environment is a key question in movement ecology that can give insight into observed movement patterns and the mechanisms behind them. Efficiency of navigation is important for behavioral processes at a range of different spatio temporal scales, including foraging and migration. Random walk models provide a standard framework for modeling individual animal movement and navigation. Here we consider a vector-weighted biased and correlated random walk (BCRW) model for directed movement (taxis), where external navigation cues are balanced with forward persistence. We derive a mathematical approximation of the expected navigational efficiency for any BCRW of this form and confirm the model predictions using simulations. We demonstrate how the navigational efficiency is related to the weighting given to forward persistence and external navigation cues, and highlight the counter-intuitive result that for low (but realistic) levels of error on forward persistence, a higher navigational efficiency is achieved by giving more weighting to this indirect navigation cue rather than direct navigational cues. We discuss and interpret the relevance of these results for understanding animal movement and navigation strategies. PMID- 29106696 TI - The mechanisms shaping the repertoire of CD4+ Foxp3+ regulatory T cells. AB - Regulatory T (Treg) cells expressing Foxp3 transcription factor control homeostasis of the immune system, antigenic responses to commensal and pathogenic microbiota, and immune responses to self and tumour antigens. The Treg cells differentiate in the thymus, along with conventional CD4+ T cells, in processes of positive and negative selection. Another class of Treg cells is generated in peripheral tissues by inducing Foxp3 expression in conventional CD4+ T cells in response to antigenic stimulation. Both thymic and peripheral generation of Treg cells depends on recognition of peptide/MHC ligands by the T-cell receptors (TCR) expressed on thymic Treg precursors or peripheral conventional CD4+ T cells. This review surveys reports describing how thymus Treg cell generation depends on the selecting peptide/MHC ligands and how this process impacts the TCR repertoire expressed by Treg cells. We also describe how Treg cells depend on sustained signalling through the TCR and how they are further regulated by Foxp3 enhancer sequences. Finally, we review the impact of microbiota-derived antigens on the maintenance and functionality of the peripheral pool of Treg cells. PMID- 29106698 TI - Preoperative screening and intervention for mild anemia with low iron stores in elective hip and knee arthroplasty. AB - BACKGROUND: Preoperative anemia in patients undergoing elective hip and knee arthroplasty is associated with increased postoperative morbidity and mortality, red blood cell (RBC) transfusion, and length of stay (LOS). The aim of this study was to assess the effect of optimizing hemoglobin (Hb) levels before elective primary hip and knee arthroplasty. STUDY DESIGN AND METHODS: This is a prospective comparative cohort study of patients who underwent elective hip and knee arthroplasty before (control) and after (intervention) the launch of a Hb optimization program. Patients with anemia followed an agreed upon algorithm dependent on their medical history and blood variables taken on listing for surgery. The primary outcome for this study was the requirement for allogenic RBC transfusion. Secondary outcomes included hospital LOS, admission to critical care, readmission, medical complications, incidence of thromboembolic events, mortality, and costs. RESULTS: A total of 1814 control patients operated between February 2012 and February 2013 were compared to 1622 intervention patients operated between February 2013 and May 2014. In the intervention group transfusion was significantly reduced (108 [6%] vs. 63 [4.1%], p = 0.005) as well as readmission (81 [4.5%] vs. 48 [2.3%], p= 0.020) and critical care admission (23 [1.3%] vs. 9 [0.5%], p = 0.030). LOS was significantly reduced from 3.9 days to 3.6 days (p = 0.017). The saving for the cohort was L263,000 ($342,000). CONCLUSIONS: Algorithm-led preoperative anemia screening and management in elective arthroplasty was associated with reduced RBC transfusion, readmission, critical care admission, LOS, and costs. PMID- 29106699 TI - Immunohistochemical expression of vitamin D receptor in melanocytic naevi and cutaneous melanoma: a case-control study. AB - BACKGROUND: Vitamin D deficiency is associated with higher risk of cancer, possibly due to its antiproliferative, antiangiogenic, proapoptotic, cell differentiating and anti-invasive effects. The anticarcinogenic role of vitamin D in melanoma is still a matter of debate. Loss of nuclear and cytoplasmic vitamin D receptor (VDR) expression in melanoma cells has been reported. OBJECTIVES: To analyse VDR immunohistochemical expression in benign dermal naevi (DN) and malignant melanoma (MM). METHODS: A case-control study evaluated nuclear and cytoplasmic VDR immunohistochemical staining in 54 DN and 55 MM tissue samples. RESULTS: There was significantly higher cytoplasmic VDR positivity in DN compared with MM (59% vs. 16%, P < 0.001). The mean VDR cytoplasmic expression was also higher in DN vs. MM (P < 0.001). No differences in nuclear VDR positivity were observed between groups, but mean nuclear VDR expression was significantly lower in DN vs. MM (P = 0.02). The loss of cytoplasmic VDR in MM was associated with Clark level, tumour staging and American Joint Committee on Cancer pTNM staging (P=0.004, 0.009 and 0.02, respectively). CONCLUSIONS: Alterations in VDR expression and localization are found in MM compared with DN. Loss of cytoplasmic VDR was associated with melanoma tumour size, suggesting that loss of cytoplasmic VDR may be a prognostic factor. PMID- 29106700 TI - Resource availability underlies the plant-fungal diversity relationship in a grassland ecosystem. AB - It is commonly assumed that microbial communities are structured by "bottom-up" ecological forces, although few experimental manipulations have rigorously tested the mechanisms by which resources structure soil communities. We investigated how plant substrate availability might structure fungal communities and belowground processes along an experimental plant richness gradient in a grassland ecosystem. We hypothesized that variation in total plant-derived substrate inputs, plant functional group diversity, as well as the relative abundance of C4 grasses and legumes would modulate fungal alpha- and beta-diversity and their rates of soil carbon (C) and nitrogen (N) cycling. To test these predictions, we molecularly characterized fungal communities, as well as potential extracellular enzyme activity, net N mineralization, and soil organic matter respiration. We found higher fungal richness was associated with increasing aboveground plant biomass; whereas, fungal beta-diversity was explained by contributions from C4 grass and legume relative dominance, plant functional group diversity, as well as plant biomass. Furthermore, aboveground plant biomass consistently shaped the richness and composition of individual fungal trophic modes (i.e., saprotrophs, symbiotrophs, pathotrophs). Finally, variation in extracellular enzyme activity, net N mineralization rates, and soil organic matter respiration was significantly explained by fungal beta-diversity when fungi were functionally classified. Via changes in the supply and composition of organic substrates entering soil, our study demonstrates that changes in the plant species richness and functional composition collectively influence fungal communities and rates of soil C and N cycling. PMID- 29106701 TI - Use of salivary cortisol and cortisone in the high- and low-dose synacthen test. AB - CONTEXT: Salivary cortisone reflects serum cortisol levels, is more sensitive than salivary cortisol at lower values of serum cortisol and is noninvasive. OBJECTIVE: To investigate the relationship between serum cortisol and salivary cortisol and cortisone following low- and high-dose synacthen. DESIGN AND SETTING: Prospective pharmacodynamic studies in clinical research facilities. PARTICIPANTS AND INTERVENTION: Thirty-five dexamethasone-suppressed, healthy adult males underwent an intravenous synacthen test: N = 23 low-dose (1 mcg), N = 12 high-dose (250 mcg). Paired serum and salivary samples were taken at 15 sampling points over 120 minutes. MAIN OUTCOME MEASURE: Serum cortisol and salivary cortisol and cortisone were analysed for correlations and by a mixed effects model. RESULTS: At baseline, the correlation between serum cortisol and salivary cortisol was weak with many samples undetectable (r = .45, NS), but there was a strong correlation with salivary cortisone (r = .94, P < .001). Up to 50 minutes following synacthen, the correlation coefficient between serum cortisol and salivary cortisol and cortisone was <0.8, but both had a stronger correlation at 60 minutes (salivary cortisol r = .89, P < .001, salivary cortisone r = .85, P < .001). The relationship was examined excluding samples in the dynamic phase (baseline to 60 minutes). Salivary cortisol and cortisone showed a close relationship to serum cortisol. Salivary cortisone showed the stronger correlation: salivary cortisol r = .82, P < .001, salivary cortisone r = .96, P < .001. CONCLUSION: Following synacthen, both salivary cortisol and cortisone reflect serum cortisol levels, but there is a lag in their rise up to 60 minutes. The results support further research for possible future use of a 60 minute salivary cortisone measurement during the synacthen test. PMID- 29106703 TI - Prevalence and incidence of chronic spontaneous urticaria in the entire Korean adult population. PMID- 29106702 TI - Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. AB - BACKGROUND: Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. OBJECTIVES: To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. SELECTION CRITERIA: All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. MAIN RESULTS: We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks.Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency. AUTHORS' CONCLUSIONS: We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d.Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose. PMID- 29106704 TI - Positive Kappa-Deleting Recombination Excision Circles (KREC) Newborn Screening in a Neonate With Intrauterine Exposure to Rituximab. PMID- 29106705 TI - The role of mitochondrial ROS in the aging brain. AB - The brain is the most complex human organ, consuming more energy than any other tissue in proportion to its size. It relies heavily on mitochondria to produce energy and is made up of mitotic and postmitotic cells that need to closely coordinate their metabolism to maintain essential bodily functions. During aging, damaged mitochondria that produce less ATP and more reactive oxygen species (ROS) accumulate. The current consensus is that ROS cause oxidative stress, damaging mitochondria and resulting in an energetic crisis that triggers neurodegenerative diseases and accelerates aging. However, in model organisms, increasing mitochondrial ROS (mtROS) in the brain extends lifespan, suggesting that ROS may participate in signaling that protects the brain. Here, we summarize the mechanisms by which mtROS are produced at the molecular level, how different brain cells and regions produce different amounts of mtROS, and how mtROS levels change during aging. Finally, we critically discuss the possible roles of ROS in aging as signaling molecules and damaging agents, addressing whether age associated increases in mtROS are a cause or a consequence of aging. PMID- 29106706 TI - The Role of Agent and Social Context in Judgments of Freedom of Speech and Religion. AB - This study examined children's, adolescents', and college students' judgments of the rights of child and adult agents to freedom of speech and religion in 3 social contexts: the general level of society, the school, and the family. Two hundred forty participants, evenly divided into 5 grade levels (mean ages 6,6, 8,5,10,6,12,4, and 22,7) made judgments of the legitimacy of authority prohibition, rule evaluation, generalizability, and rule violation for all freedom/social context/agent combinations. Concepts of freedom of speech and religion were found to emerge in the early elementary school years, and endorsements of freedoms were increasingly affected by social context and agent with age. College students were less likely than any other age group to affirm children's freedom of religion in the family context. Considerations of the mental competence and maturity of agents and the potential for harm to ensue from acting on freedoms played an important part in the decisions of older, but not younger, participants. PMID- 29106707 TI - c.518T > C missense mutation in the B glycosyltransferase gene responsible for a weak B variant. PMID- 29106708 TI - Surface applicator of a miniature X-ray tube for superficial electronic brachytherapy of skin cancer. AB - PURPOSE: We designed and fabricated a surface applicator of a novel carbon nanotube (CNT)-based miniature X-ray tube for the use in superficial electronic brachytherapy of skin cancer. To investigate the effectiveness of the surface applicator, the performance of the applicator was numerically and experimentally analyzed. METHODS: The surface applicator consists of a graphite flattening filter and an X-ray shield. A Monte Carlo radiation transport code, MCNP6, was used to optimize the geometries of both the flattening filter and the shield so that X-rays are generated uniformly over the desired region. The performance of the graphite filter was compared with that of conventional aluminum (Al) filters of different geometries using the numerical simulations. After fabricating a surface applicator, the X-ray spatial distribution was measured to evaluate the performance of the applicator. RESULTS: The graphite filter shows better spatial dose uniformity and less dose distortion than Al filters. Moreover, graphite allows easy fabrication of the flattening filter due to its low X-ray attenuation property, which is particularly important for low-energy electronic brachytherapy. The applicator also shows that no further X-ray shielding is required for the application because unwanted X-rays are completely protected. As a result, highly uniform X-ray dose distribution was achieved from the miniature X-ray tube mounted with the surface applicators. The measured values of both flatness and symmetry were less than 5% and the measured penumbra values were less than 1 mm. All these values satisfy the currently accepted tolerance criteria for radiation therapy. CONCLUSIONS: The surface applicator exhibits sufficient performance capability for their application in electronic brachytherapy of skin cancers. PMID- 29106709 TI - A new genetic background for the Jr(a-) blood group phenotype caused by the ABCG2*439T allele encoding a p.Arg147Trp change. PMID- 29106711 TI - Interventions for treating central venous haemodialysis catheter malfunction. AB - BACKGROUND: Adequate haemodialysis (HD) in people with end-stage kidney disease (ESKD) is reliant upon establishment of vascular access, which may consist of arteriovenous fistula, arteriovenous graft, or central venous catheters (CVC). Although discouraged due to high rates of infectious and thrombotic complications as well as technical issues that limit their life span, CVC have the significant advantage of being immediately usable and are the only means of vascular access in a significant number of patients. Previous studies have established the role of thrombolytic agents (TLA) in the prevention of catheter malfunction. Systematic review of different thrombolytic agents has also identified their utility in restoration of catheter patency following catheter malfunction. To date the use and efficacy of fibrin sheath stripping and catheter exchange have not been evaluated against thrombolytic agents. OBJECTIVES: This review aimed to evaluate the benefits and harms of TLA, preparations, doses and administration as well as fibrin-sheath stripping, over-the-wire catheter exchange or any other intervention proposed for management of tunnelled CVC malfunction in patients with ESKD on HD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 17 August 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included all studies conducted in people with ESKD who rely on tunnelled CVC for either initiation or maintenance of HD access and who require restoration of catheter patency following late-onset catheter malfunction and evaluated the role of TLA, fibrin sheath stripping or over-the-wire catheter exchange to restore catheter function. The primary outcome was be restoration of line patency defined as >= 300 mL/min or adequate to complete a HD session or as defined by the study authors. Secondary outcomes included dialysis adequacy and adverse outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently assessed retrieved studies to determine which studies satisfy the inclusion criteria and carried out data extraction. Included studies were assessed for risk of bias. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using GRADE. MAIN RESULTS: Our search strategy identified 8 studies (580 participants) as eligible for inclusion in this review. Interventions included: thrombolytic therapy versus placebo (1 study); low versus high dose thrombolytic therapy (1); alteplase versus urokinase (1); short versus long thrombolytic dwell (1); thrombolytic therapy versus percutaneous fibrin sheath stripping (1); fibrin sheath stripping versus over-the-wire catheter exchange (1); and over-the-wire catheter exchange versus exchange with and without angioplasty sheath disruption (1). No two studies compared the same interventions. Most studies had a high risk of bias due to poor study design, broad inclusion criteria, low patient numbers and industry involvement.Based on low certainty evidence, thrombolytic therapy may restore catheter function when compared to placebo (149 participants: RR 4.05, 95% CI 1.42 to 11.56) but there is no data available to suggest an optimal dose or administration method. The certainty of this evidence is reduced due to the fact that it is based on only a single study with wide confidence limits, high risk of bias and imprecision in the estimates of adverse events (149 participants: RR 2.03, 95% CI 0.38 to 10.73).Based on the available evidence, physical disruption of a fibrin sheath using interventional radiology techniques appears to be equally efficacious as the use of a pharmaceutical thrombolytic agent for the immediate management of dysfunctional catheters (57 participants: RR 0.92, 95% CI 0.80 to 1.07).Catheter patency is poor following use of thrombolytic agents with studies reporting median catheter survival rates of 14 to 42 days and was reported to improve significantly by fibrin sheath stripping or catheter exchange (37 participants: MD -27.70 days, 95% CI -51.00 to -4.40). Catheter exchange was reported to be superior to sheath disruption with respect to catheter survival (30 participants: MD 213.00 days, 95% CI 205.70 to 220.30).There is insufficient evidence to suggest any specific intervention is superior in terms of ensuring either dialysis adequacy or reduced risk of adverse events. AUTHORS' CONCLUSIONS: Thrombolysis, fibrin sheath disruption and over-the-wire catheter exchange are effective and appropriate therapies for immediately restoring catheter patency in dysfunctional cuffed and tunnelled HD catheters. On current data there is no evidence to support physical intervention over the use of pharmaceutical agents in the acute setting. Pharmacological interventions appear to have a bridging role and long-term catheter survival may be improved by fibrin sheath disruption and is probably superior following catheter exchange. There is no evidence favouring any of these approaches with respect to dialysis adequacy or risk of adverse events.The current review is limited by the small number of available studies with limited numbers of patients enrolled. Most of the studies included in this review were judged to have a high risk of bias and were potentially influenced by pharmaceutical industry involvement.Further research is required to adequately address the question of the most efficacious and clinically appropriate technique for HD catheter dysfunction. PMID- 29106712 TI - Investigation of pH effect on cationic solute binding to keratin and partition to hair. AB - OBJECTIVE: In the process of hair treatment, various cationic actives contained in hair care products can be absorbed into hair fibre to modulate the physicochemical properties of hair such as colour, strength, style and volume. There have been very limited studies on the binding and partition properties of hair care actives to hair. This study aimed to investigate the pH effects on cationic solute absorption into hair and binding to keratin. METHODS: The keratin binding and hair partition properties of three cationic solutes (theophylline, nortriptyline and amitriptyline) have been measured at different pH using fluorescence spectroscopy and equilibrium absorption experiment. The binding constants, thermodynamic parameters and hair-water partition coefficients determined at different pH were compared and analysed. RESULTS: Increasing the pH from 2.0 to 6.0 resulted in the net charge of hair keratin changed from positive to negative. As a consequence, the binding constants of the three cationic solutes with keratin increased with the increasing pH. This correlated with the variation of the electrostatic interaction between cationic solutes and keratin from repulsion to attraction. The positive DeltaH and DeltaS values indicated that hydrophobic interaction also played a major role in the binding of the three cationic solutes to keratin. There was a good correlation between solutes binding to keratin and hair-water partition of solutes. CONCLUSION: It appears that solute binding to hair keratin is driven first by hydrophobic interaction and then by electrostatic interaction. The fitted thermodynamic parameters suggested that hydrophobic interaction dominates for the binding of the three cationic solutes to keratin. That binding of cationic solutes to keratin correlates with the partition of the solutes to hair could provide theoretical guidance for further developing mathematical models of hair partition and penetration properties. PMID- 29106713 TI - A systematic review of diagnostic criteria for psoriasis in adults and children: evidence from studies with a primary aim to develop or validate diagnostic criteria. AB - BACKGROUND: The diagnosis of psoriasis in adults and children is made clinically, for both patient management and the selection of participants in research. Diagnostic criteria provide a structure for clinical assessment, which in turn helps standardize patient recruitment into clinical trials and case definitions in observational studies. OBJECTIVES: The aim of this systematic review was to identify and critically appraise the published studies to date that had a primary research aim to develop or validate diagnostic criteria for psoriasis. METHODS: A search of Ovid MEDLINE and Ovid Embase was conducted in October 2016. The primary objective was to record the sensitivity and specificity of diagnostic criteria for psoriasis. Secondary objectives included diagnostic recommendations, applicability to children and study characteristics. Diagnostic accuracy studies were critically appraised for risk of bias using the QUADAS-2 tool. RESULTS: Twenty-three studies met the inclusion criteria. None detailed clinical examination-based diagnostic criteria. The included criteria varied from genetic and molecular diagnostic models to skin imaging, histopathology, and questionnaire-based, computer-aided and traditional Chinese medicine criteria. High sensitivity and specificity (> 90%) were reported in many studies. However, the study authors often did not specify how the criteria would be used clinically or in research. This review identified studies with varying risk of bias, and due to each study developing separate criteria meta-analysis was not possible. CONCLUSIONS: Clinical examination-based diagnostic criteria are currently lacking for psoriasis. Future research could follow an international collaborative approach and employ study designs allowing high-quality diagnostic accuracy testing. Existing and newly developed criteria require validation. PMID- 29106710 TI - Investigating metabolic regulation using targeted neuromodulation. AB - The central nervous system (CNS) plays a vital role in regulating energy balance and metabolism. Over the last 50 years, studies in animal models have allowed us to identify critical CNS regions involved in these processes and even crucial cell populations. Now, techniques for genetically and anatomically targeted manipulation of specific neural populations using light (optogenetic), ligands (chemogenetic), or magnetic fields (radiogenetic/magnetogenetic) allow detailed investigation of circuits involved in metabolic regulation. In this review, we provide a brief overview of recent studies using light- and magnetic field regulated neural activity to investigate the neural circuits contributing to metabolic control. PMID- 29106714 TI - Pharmacokinetics, Immunogenicity, and Efficacy of Etanercept in Pediatric Patients With Moderate to Severe Plaque Psoriasis. AB - Etanercept has been recently approved in the United States for the treatment of moderate to severe plaque psoriasis in patients aged 4-17 years. The objective of this study was to characterize etanercept pharmacokinetics, immunogenicity, and efficacy in pediatric patients. Data from a phase 3 study and open-label extension study were analyzed. Etanercept serum concentrations in pediatric patients receiving etanercept 0.8 mg/kg (maximum, 50 mg) weekly were compared with adult psoriasis patients and pediatric patients with juvenile idiopathic arthritis (JIA) who received etanercept 0.4 mg/kg twice weekly. The developments of antietanercept antibodies and efficacy based on the Psoriasis Area and Severity Index were evaluated. Steady-state trough etanercept concentrations were similar across visits from weeks 12-48, between patients aged 4-11 and 12-17 years, between pediatric and adult psoriasis patients, and between pediatric patients with psoriasis or JIA. Etanercept serum concentrations and safety profiles were similar in patients with (15.9%) and without antietanercept antibodies. Dosing used in the study provided similar exposures and efficacy across ranges of weight and body mass index. Pharmacokinetic, immunogenicity, and efficacy data support 0.8 mg/kg (maximum, 50 mg) weekly dosing of etanercept in patients aged 4-17 years. PMID- 29106715 TI - Intergroup Attitudes among Ethnic Minority Adolescents: A Causal Model. AB - To examine the influence of ethnic idenilty and intergroup contact on adolescents' attitudes toward other ethnic groups, we studied eighth and eleventh graders from 2 predominantly non-white school districts. Surveys completed by 547 adolescents from 3 ethnic groups (133 African Americans, 219 Latinos, and 195 Asian Americans) assessed in-group and out-group attitudes, out-group interaction, out-group contact, and ethnic identity. A causal model suggested 2 pathways leading to positive out-group attitudes. In one pathway, ethnic identity increased with age and predicted positive in-group attitudes; these attitudes contributed to positive out-group attitudes. In a separate pathway, ethnic diversity outside of schcool led to more out-group interaction in school, which in turn predicted positive out-group attitudes. The results support developmental and multiculturalism views of intergroup relations. PMID- 29106717 TI - Cognitive Set and Coping Strategy Affect Mothers' Sensitivity to Infant Cries: A Signal Detection Approach. AB - We used Signal Detection methodology to examine how cognitiveset affects mothers' response to an infant cry. We asked whether a cry from a "difficult" versus an "easy" infant would elicit a change in sensitivity or response bias in mother processing of these cries. Thirty-eight mothers of 4- to 6-month-old infants participated in a Signal Detection task in which they were asked whether they could detect differences between a standard cry and 1 to 4 cry variants. Cry variants differed from the standard cry in small, systematic changes in fundamental frequency. The task was conducted in 2 parts; each part constituted a condition wherein mother received a cognitive set manipulation that labeled the identical cry as coming from either a''difficult''or an "easy" infant. An increase in mothers' sensitivity was associated with the "difficult" infant cognitive set. We examined as well how a coping strategy(illusion of control) affected cry signal processing. Mothers who Exhibited high illusory control were least -sensitive in detecting differences between cries. Two information prcessing, measures response time and heart rate, were also collected and showed that greater sensitivity was associated with more efficient processing of the cry signal. PMID- 29106716 TI - Supportive parenting, Ecological Context, and Children's Adjustment: A seven-Year Longitudianl Study. AB - Two major questions regarding the possible impact of early supportive parenting (SP) on children's school adjustment were addressed:(1) Does SP assessed prekindergarten predict grade 6 adjustment after controlling for early barsh parenting (HP)? (2) Does SP moderate (buffer) the impact of early family adversity on grade 6 adjustment? Parenting and family adversity data were drawn from home-visit interviews with 585 mothers conducted prekindergarten. Four SP measure were derived: mother-to-child warmth, proactive teaching, inductive discipline, and positive involvement. HP was indexed as the use of harsh, physical disciple. Family adversity indicators were socioeconomic disadvantage, family stress, and single parenthood. Children 's adjustment (behavior problems, social skills, and academic performance) in kindergarten and grade 6 was assessedvia teacher ratings and school records. SP predicted adjustment in grade 6, even after controlling for kindergarten adjustment and HP. High levels of SP mitigated the effects of family adversity on later behavior problems. These findings implicate both direct (main effect)and indirect (moderator of adversity) processes in the linkage between positive and supportive aspects of parenting and children's school adjustment. PMID- 29106718 TI - Peer Status in Boys With and Without Attention-Deficit Hyperactivity Disorder: Predictions from Overt and Covert Antisocial Behavior, Social Isolation, and Authoritative Parenting Beliefs. AB - Because of the centrality of peer relationship difficulties for children with attentiondeficit hyperactivity disorder (ADHD), we investigated behavioral (overt and covert antisocial activity), internalizing (self-reports and observed social isolation), and familial (authoritative, authoritarian, and permissive parenting beliefs) predictors of peer sociometric nominations among previously unfamiliar, ethnically diverse ADHD (N=73) and comparison (N=60) boys, aged 6-12 years. Authoritative maternal parenting beliefs and negatively weighted social isolation explained significant variance in positive peer regard; aggression, covert behavior, and authoritative parenting beliefs were the independent predictors of both negative peer status and peer social preference. We extended such predictions with statistical control of (1) child cognitive variables, (2) maternal psychopathology, and (3) ADHD boys, but authoritative parenting beliefs were stronger predictors in ADHD than in comparison youth. We discuss family-peer linkages regarding peer competence. PMID- 29106719 TI - Chinese and Canadian Children's Evaluations of Lying and Truth Telling: Similarities and Dfferences in the Context of pro-and Antisocial Behaviors. AB - The present study compared Chinese and Canadian children's moral evaluations of lie and truth telling in situations involving pro- and antisocial behaviors. Seven-, 9-, and 11-year-old Chinese and canadian children were presented 4 brief stories. Two stories involved a child who intentionally carried out a good deed, and the other2 stories involved a child who intentionally carried out a bad deed. When story characters were questioned by a teacher as to who had committed the deed, they either lied or told the truth. Children were asked to evaluate the story characters' deeds and their verbal statements. Overall, Chinese children rated truth telling less positively and lie telling more positively in prosocial settings than Canadian children, indicating that the emphasis on self-effacement and modesty in Chinese culture overrides Chinese children's evaluations of lying in some situations. Both Chinese and canadian children rated trugh telling positively and lie telling negatively in antisocial situations, reflecting the emphasis in both cultures on the distinction between misdeed and truth/lie telling. The findings of the present study suggest that, in the realm of lying and truth telling, a close relation between sociocultural practices and moral judgment exists. Specific social and cultural norms have an impact on children's developing moral judgments, which in turn, are modified by age and experience in a particular culture. PMID- 29106720 TI - Early Intervention and Mediating Processes in Cognitive Performance of Children of Low-Income African American Families. AB - This longitudinal study of 161 African American children from low-income families examined multiple influences, including early childhood interventions and characteristics of the child and family, on longitudinal patterns of children's cognitive performance measured between 6 months and 8 years of age. Results indicate that more optimal patterns of cognitive development were associated with intensive early educational child care, responsive stimulating care at home, and higher maternal IQ. In accordance with a general systems model, analyses also suggested that child care experiences were related to better cognitive performance in part through enhancing the infant's responsiveness to his or her environment. Maternal IQ had both a direct effect on cognitive performance during early childhood and, also, an indirect effect through its influence on the family environment. PMID- 29106721 TI - The Linguistic Mass/Count Distinction as an Indicator of Referent Categorization in Monolingual and Bilingual Children. AB - This study examines the acquisition of the linguistic mass/count distinction in English by bilingual (Spanish-English) children. The goal of the study is to explore whether bilingual children, like their monolingual peers, can draw information from the linguistic context in which a new noun id presented to determine whether the new word refers to an object or a substance. Results indicate that at 7 years of age, even bilinguals who are strong in English do not yet draw such inferences. By 9 years of age, however, bilinguals who are strong in English have response patterns similar to those of their monolingual peers but bilinguals who have lower English abilities still lag behind their monolingual peers in drawing such inferences. PMID- 29106722 TI - Categorization and Its Developmental Relation to Early Language. AB - Three studies examine the developmental relation between early linguistic and cognitive achievements. Studies 1 and 2 attempt to replicate previous findings of a strong temporal link between the ages at there is a sharp rise in new nominal productions and the appearance of 2-category grouping using a longitudinal design. Studies 1 and 2 differ principally in whether the same stimuli were employed each time the children's categorization was tested or whether different stimuli were employed. Study 3 compares the categorization performance of children identified as late talkers to age-matched and language-matched controls cross-sectionally. Our findings consistently show that children's ability to classify objects in a spatial of temporal order is independent of advances in productive vocabulary growth. These results suggest that although children's developing knowledge of object categories may underlie developments in categorization and naming such developments depend on other abilities as well Studyin the past experiences of the child and the particular context in which the behavior is exhibited may be a more meaningful approach to understanding changes in categorization and ultimately its relation to language. PMID- 29106723 TI - Stylistic Variation at the "Single-Word" Stage: Relations between Maternal Speech Characteristics and Children's Vocabulary Composition and Usage. AB - In this study we test a number of different claims about the nature of stylistic variation at the "single-word" stage by examining the relation between variation in early vocabulary composition, variation in early language use, and variation in the structural and functional propreties of mothers' child-directed speech. Maternal-report and observational data were collected for 26 children at 10, 50, and 100 words, These were then correlated with a variety of different measures of maternal speech at 10 words, The results show substantial variation in the percentage of common nouns and unanalyzed phrases in children's vocabularies, and singficant relations between this variation and the way in which language is used by the child. They also reveal singficant relations between the way in whch mothers use language at 10 words and the way in chich their children use language at 50 words and between certain formal properties of mothers speech at 10 words and the percentage of common nouns and unanalyzed phrases in children's early vocabularies, However, most of these relations desappear when an attempt is made to control for ossible effects of the child on the mother at Time 1. The exception is a singficant negative correlation between mothers tendency to produce speech that illustrates word boundaries and the percentage of unanalyzed phrases at 50 and 100 words. This suggests that mothers whose sprech provides the child with information about where new words begin and end tend to have children with few unanalyzed. phrases in their early vocabularies. PMID- 29106724 TI - Cognitive Brain Event-Related Potentials and Emotion Processing in Maltreated Children. AB - Cognitive event-related potentials (ERPs) were recorded from 23 maltreated and 21 nonmaltreated children. Children were presented with slides of Ekman photographs of asingle model posing an angry (25%), a happy (25%), or a neutral (50%) facial expression. In 1 of 2 counterbalanced target conditions, children were asked to press a button in response to the angry face; in the other target condition, they responded to the happy face. Both samples, as expected, exhibited the largest amplitude of the P300 component of the ERP to target stimuli and the smallest amplitude to nontargets. For nonmaltreated children, the average amplitude of P300 across slides was comparable for the 2 target conditions. In contrast, maltreated children displaed larger P300 ampltude to stimuli when they were directed to attend to angry, as opposd children displayed larger p300 amplitude to stimuli whe they were directed to attend to angry, as opposed to happy, targets. These reaults suggest different cognitive processing for positive versus negative affective expressions by children with histories of atypical emotiaonal exotional experiences. PMID- 29106725 TI - Developmental Growth Curves of Preschool Children with Vision Impairments. AB - In this study, we used growth curve analysis based on 566 assessments with the Battelle Developmental Inventory (BDI) to describe the development of 186 children (ages 12-73 months) with vision impairments. Developmental patterns varied markedly among the children, with part of that variability related to co occurring disabilities and amount of functional vision. Children with co occurring disabilities-in this case, mental retardation or developmental delay (MR/DD)- had lower developmental age scores overall and slower rates of growth. Visual function of 20/800 or worse was associated with significantly lower developmental ages across time on all domains measured by the BDI (personal social, adaptive, motor, cognition, and communication) and with slower rates of growth in the personal-social and motor domains. Amount of functional vision and MR/DD did not interact, indicating that these 2 factors had additive, not multiplicative, effects on development during early childhood. PMID- 29106726 TI - Child Development and Neuroscience. AB - Although developmental psychology and developmental neuroscience share interests in common problems (e.g., the nature of thought, emotion, consciousness), there has been little cross-fertilization between these disciplines. To facilitate such communication, we discuss 2 major advances in the developmental brain sciences that have potentially profound implications for under standing behavioral development. The first concerns neuroimaging, and the second concerns the molecular and cellular events that give rise to the developing brain and the myriad ways in which the brain is modified by both positive and negative life experiences. Recurring themes are that (1) critical, new knowledge of behavioral development can be achieved by considering the neurobiological mechanisms that guide and influence child development, and (2) these neurobiological mechanisms are in turn influenced by behavior. PMID- 29106727 TI - Ser Helps Speakers Identify "Real" Properties. AB - We examined the effects of language on developing knowledge of the distinction between "real" and "apparent" properties of bjects by comparing the perfomance of English- and Spanish-spiaking monolingual and bilingual children on an appearance reality task in 3 experiments. In Experiment 1, monolingul - s nf Spanish speaking preschoolers participated in an a peprance-reality task in which Spanish speakers heard forms of the Spanish verb ser in place of the English verb "is" in the reality questions and forms of the Spanish verb estar in palce of "is" in the appearance questions. Spanish speakers performed reliably better than English speakers on the question about the real properties of less familiar objecrd. In Experiment 2, English-Spanish bilingual children participated in the same tadk used in Experiment 1. They answered half of the questions in English and half in Spanish. Bilinguals identified the real properties of objects reliably better in Spanish than in English, indicating that language can affect the ability to identify real properties. In Experiment 3, we examined the role of language in the ability of monolingual English-speaking 3-year-olds to identify real and apparent properties. These children answerd different type of appearance and reality questions, using the same objects from Experiments 1 and Half of the children answered standard appearance-reality questions; the other children answered elaborated versions of the English questions. Children in both conditions performed equivalently, suggesting that English-speaking children are not easily influenced by language in these tasks. Apparently, the advantage that the Spanish copual, ser, gives speakers of Spanish is important and unique because it cannot easily be instantiated in English. PMID- 29106728 TI - The Effects of Infant Child Care on Infant-Mother Attachment Security: Results of the NICHD Study of Early Child Care NICHD Early Child Care Research Network. AB - The aims of this investigation were to determine whether Strange Situation attachment classifications were equally valid for infants with and without extensive child-care experience in the first year of life and whether early Child Care experience, alone or in combination with mother/child factors, was associated with attachment security, and specifically with insecure-avoidant attachment. Participants were 1,153 infants and their mothers at the 10 sites of the NICHD Study of Early Child Care. Mother were interviewed, given questionnairies, and observed in play and in the home when their infants were from 1 to 15 months of age; infants were observed in child care at 6 and 15 months and in the Strange Situation at 15 months. Infants with extensive Child Care experience did not differ from infants without child-care in the distress they exhibited during separations from mother in the Strange situation or in the confidence with which trained coders assigned them attachment classifications. There were no significant main effects of Child Care experience (quality, amount, age of entry, stability, or type of care) on attachment security or avoidance. There were, however, significant man effects of maternal sensitivity and responsiveness. Significant interaction effects revealed that infants were less likely to be secure when low maternal sensitivity/responsiveness was combined with poor quality child care, more than minimal amounts of child care, or more than one care arrangement. In addition, boys experiencing many hours in care and girls in minimal amounts of care were somewhat less likely to be securely attachment. PMID- 29106729 TI - Head Start Parents' Beliefs about Their Children's Abilities, Task Values, and Performances on Different Activities. AB - As part of larger intervention study designed to facilitate the transition of Head Start children into kindergarten and the early elementary grades, we assessed parents beliefs about former Head start children's abilities and values in several activity domains-academics, sports, and social skills-during the children's kindergarten ten year. Parents' expectations for their children's future also were examined. One hundred and twenty-four parents and 155 children participated; all children had attended Head Start, and the sample is ethnically and racially diverse. One group of children and parents received the additional services, and a second group did not. Parents, were quit optimistic about their children's prospects for the future. There were ethnic differences in parents were quit optimistic about their children's prospects for the future. There were ethnic differences in parents' beliefs about children's abilities and future prospects in different areas. Parents beliefs related both to children's attitudes toward school and to their performance on mathematical and reading achievement tests. PMID- 29106730 TI - Moderate Alcohol Consumption and Psychological Stress during Pregnancy Induce Attention and Neuromotor Impairments in Primate Infants. AB - This study examined the effect of moderate alcohol and/or psychological stress during prenancy on off-spring growth and behavior in 33 rhesus monkey infants (Macaca mulatta). Infants were derived from 1 of 3 groups of female: (1) alcohol consuming,0.6g/Kg, Daily throughou gestation (equivalet, to 1-2 drinks), beginning 5 day prior to breeding;(2) alcohol-consuming (as above) and exposed to mild psychological stress(removal from home cage and exposed to 3 random noise bursts); (3) sucrose-consuming, equivolemic, and equicaloric to the alcohol solution.Beginning on day 4 postpartum, intantrs underwent brief weekly separations from their mother for assessment of growth, behavior, and facial dimensions. Results indicated that moderate alcohol consumption throughout pregnancy was sufficient to affect attention and neuromotor functioning, even though the infants were normol in birthweight, gestational length, and facial dimensions, Moreover, alcohol-induced neuromotor impairments were exacerbated by maternal exposure to psychological stress, and males from the alcohol/stress condition had reduced birthweights. Finally, although all females consuming alcohol produced viable offspring, alcohol accompanie by stress during gestation resulted in 23% fetal losses (abortion and stillbirths). PMID- 29106731 TI - Up-regulation of IL-23 expression in human dental pulp fibroblasts by IL-17 via activation of the NF-kappaB and MAPK pathways. AB - AIM: To investigate the effects of the pro-inflammatory and Th17-polarizing mediator IL-17 on HDPFs-mediated IL-23 production and the molecular mechanism involved. METHODOLOGY: Interleukin (IL)-17R expression was determined by semi quantitative reverse transcriptase-polymerase chain reaction and Western blot in cultured human dental pulp fibroblasts (HDPFs). Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay were used to determine IL-23 mRNA and protein levels in IL-17-stimulated HDPFs, respectively. The nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) signalling pathways that mediate the IL-17-stimulated production of IL-23 was investigated using Western blot and specific signalling inhibitor analyses. Statistical analyses were performed using Kruskal-Wallis tests followed by the Mann-Whitney U-test. Statistical significance was considered when the P value < 0.05. RESULTS: Primary HDPFs steadily expressed IL-17R mRNA and surface-bound protein. IL-17 stimulated the expression of IL-23 mRNA and protein in cultured human dental pulp fibroblasts, which was attenuated by IL-17 or IL-17R neutralizing antibodies. In accordance with the enhanced expression of IL-23, IL 17 stimulation resulted in rapid activation of p38 MAPK, extracellular signal regulated kinase (ERK) 1/2, c-Jun-N-terminal kinase (JNK) and NF-kappaB in HDPFs. Inhibitors of p38 MAPK, ERK 1/2 or NF-kappaB significantly suppressed, whereas blocking JNK substantially augmented IL-23 production from IL-17-stimulated HDPFs. CONCLUSION: HDPFs expressed IL-17R and responded to IL-17 to produce IL-23 via the activation of the NF-kappaB and MAPK signalling pathways. The findings provide insights into the cellular mechanisms of the participation of IL-17 in the activation of HDPFs in inflamed pulp tissue. PMID- 29106732 TI - A systematic review of incentives in blood donation. AB - BACKGROUND: Incentives are often used to enhance the effectiveness of recruitment and retention campaigns targeting blood donors. However, the degree to which incentives succeed in attracting and facilitating repeat donation is unclear. A systematic literature review, following PRISMA guidelines, investigated the existing empirical evidence regarding the use of monetary and nonmonetary incentives within blood donation. STUDY DESIGN AND METHODS: A comprehensive search of relevant databases identified a total of 71 papers for inclusion in the review for defining and operationalizing incentives (Objective 1), of which nine papers empirically investigated attitudes toward incentives (Objective 2), 31 papers investigated the impact on blood donation behavior (Objective 3), and eight papers investigated the impact on blood safety (Objective 4). RESULTS: Overall, research into the use of incentives in blood donation is limited, characterized by comparatively few studies, predominantly focused on whole blood donors, that are confounded by current operating context (paid or voluntary). No incentive has been identified that all segments of the nondonor and donor panel report positive attitudes toward, that has a positive impact on behavior, and that has no negative impact on blood safety. Certain incentives (i.e., discounts, tickets, gifts, and paid time off work) have the strongest evidence base for potential inclusion within voluntary nonremunerated (VNR) donation systems. CONCLUSION: Due to the limited nature of the existing literature (particularly for apheresis donors) and inconsistencies observed within the results, additional research investigating the likely impact of introducing (or removing) monetary or nonmonetary incentives in VNR donor recruitment or retention is essential. PMID- 29106733 TI - Initiating a Dialogue. AB - The diversity of interpretations and themes raised by the commentators testifies to the richness of the issues addressed in this article, and to the need for continued research and debate on this topic. In my reply, I respond to some of the specific criticisms of the commentators by focus most of my efforts on highlighting and exploring what I consider to be the major themes running through the commentaries. PMID- 29106734 TI - Separating Judicial from Legislative Reasoning in Moral Dilemma Interviews. AB - Unlike previous studies of the development of reasoning about moral dilemmas, the 2 studies reported separated judicial reasoning (the application of rules) from legislative reasoning (the justification of rules), as well as attending to other aspects of context, using a modification of the weakly interpretive scoring method of Langford and D'Cruz. This assigns justifications to relatively simple conceptually defined categories. Findings were in accord with substantially modified versions of the views of Piaget and Kohlberg, according to which legislative reasoning can be divided into 3 main types of stages in the period 7 21 years: heteronomy (Piaget) or egocentrism (Kohlberg); local groups (attention to group interests, harmony, and reciprocity in local groups), wider groups (attention to these thing in wider groups). Findings contradicted Gibbs's theory. PMID- 29106735 TI - Human periodontal ligament fibroblasts synthesize C-reactive protein and Th related cytokines in response to interleukin (IL)-6 trans-signalling. AB - AIM: To characterize the potential of human periodontal ligament fibroblasts (HPLF) to synthesize CRP and Th-related cytokines in response to IL-6 in periodontal health and apical inflammation. METHODOLOGY: Primary HPLF stimulated with IL-6, soluble(s) IL-6 receptor (R) and controls were assayed for CRP, Th1, Th2, Th17 and Treg-related cytokines by quantitative real-time PCR and ELISA, respectively. IL-6R mRNA expression and its soluble protein levels were screened in HPLF cultures, and ex vivo samples of healthy periodontal ligaments (n = 5) and apical lesions (n = 13). Data were analysed with ANOVA or unpaired t-test. RESULTS: 0.5 ng mL-1 IL-6 plus 1 ng mL-1 of its soluble receptor (sIL-6R) for 24 h was effective in inducing CRP production. IL-6 alone had a mild dose-dependent effect; co-stimulation with sIL-6R significantly enhanced this effect, whereas it was completely abolished by the addition of IL-6R blocking antibody (P < 0.05). Similarly, higher mRNA expression and protein levels of Th1, Th17 and partially Treg-related cytokines were found for IL-6 combined with its soluble receptor versus the nonstimulated group and IL-6R antibody (P < 0.05). IL-6R mRNA expression was slightly induced by IL-6 compared to THP-1 cells, but sILR-6 protein could not be detected in HPLF. High sIL-6R levels were detected in apical lesions and were immunolocalized to mononuclear inflammatory cells and proliferating epithelium. CONCLUSION: IL-6 trans-signalling induced Th1 and Th17 related cytokines and represents an extra-hepatic mechanism for PCR synthesis in human periodontal ligament fibroblasts, contributing to explain the bone destructive phenotype of apical lesions and eventually its systemic complications. PMID- 29106737 TI - The efficacy of supplementary sonic irrigation using the EndoActivator(r) system determined by removal of a collagen film from an ex vivo model. AB - AIM: To evaluate the efficacy of sonic irrigation (EndoActivator(r) ) using various polymer tips and power settings in a stained collagen ex vivo model. METHODOLOGY: The root canals of fifty human, straight single-rooted extracted teeth were prepared to size 40, .08 taper. The roots were split longitudinally; stained collagen applied to the canal surfaces, photographed and re-assembled. The canals were subjected to syringe without supplementary (group 1, n = 10) or with supplementary sonic (groups 2-5, n = 10) irrigation. EndoActivator(r) tip sizes (size 15, .02 taper for groups 2 and 3; size 35, .04 taper for groups 4 and 5) and power settings (low for groups 2 and 4; high for groups 3 and 5) were tested. After irrigation, the canals were re-photographed and the area of residual stained collagen was quantified using the UTHSCA Image Tool program (Version 3.0). The data were analysed using Wilcoxon signed rank test and general linear mixed models. RESULTS: Supplementary sonic irrigation using EndoActivator(r) resulted in significantly (P < 0.0001) less residual collagen compared with syringe irrigation only. Agitation of irrigant using the large EndoActivator(r) tip with high power resulted in significantly less (22.4% - 29.5%) residual collagen compared to other combinations (large tip/low power P = 0.001; small tip/low power P = 0.01; small tip/high power P = 0.04). There was no significant difference amongst the latter three groups (P > 0.5). CONCLUSIONS: Supplementary sonic irrigation using the EndoActivator(r) system was significantly more effective in removing stained collagen from the canal surface than syringe irrigation alone. EndoActivator(r) used with large tip (size 35, .04 taper) and high power setting in size 40, .08 taper canals was more effective than other combinations. PMID- 29106736 TI - Extended beta distributions open the access to fast gating in bilayer experiments assigning the voltage-dependent gating to the selectivity filter. AB - Lipid bilayers provide many benefits for ion channel recordings, such as control of membrane composition and transport molecules. However, they suffer from high membrane capacitance limiting the bandwidth and impeding analysis of fast gating. This can be overcome by fitting the deviations of the open-channel noise from the baseline noise by extended beta distributions. We demonstrate this analysis step by-step by applying it to the example of viral K+ channels (Kcv), from the choice of the gating model through the fitting process, validation of the results, and what kinds of results can be obtained. These voltage sensor-less channels show profoundly voltage-dependent gating with dwell times in the closed state of about 50 MUs. Mutations assign it to the selectivity filter. PMID- 29106738 TI - Experimental miniature piglet model for the infection of human norovirus GII. AB - Ten Yucatan miniature piglets were challenged with the human norovirus (NoV) GII.12/GII.3 CAU140599 strain and five piglets were used as negative controls. Stool, serum, and organs were collected and processed from two NoV-infected piglets and one negative piglet at 1, 2, 3, 5, and 7 days post-inoculation (dpi). NoV was detected in stool and serum samples by real-time RT-PCR. Mild diarrhea was observed at 1-3 dpi. Fecal shedding and viremia were detected intermittently at 1, 3, and 7 dpi. While interferon-alpha was significantly elevated at 2-3 dpi, interferon-gamma was not changed. Immunohistochemistry demonstrated that the NoV capsid antigen was present in macrophages, lymphocytes, and dendritic cells of the stomach, intestines, lymph nodes, spleen, and tonsils. Intestinal epithelium did not exhibit a positive signal for NoV. In addition, negative-sense viral RNA was confirmed in immune cells by fluorescence in situ hybridization. Therefore, NoV might be associated with macrophages and lymphocytes in gastrointestinal tract and immune organs of experimentally infected miniature piglets. PMID- 29106739 TI - Evaluation of TomoTherapy dose calculations with intrafractional motion and motion compensation. AB - PURPOSE: Anatomical motion, both cyclical and aperiodic, can impact the dose delivered during external beam radiation. In this work, we evaluate the use of a research version of the clinical TomoTherapy(r) dose calculator to calculate dose with intrafraction rigid motion. We also evaluate the feasibility of a method of motion compensation for helical tomotherapy using the jaws and MLC. METHODS: Treatment plans were created using the TomoTherapy treatment planning system. Dose was recalculated for several simple rigid motion traces including a 4 mm step motion applied either longitudinally or transversely, and a sinusoidal motion. The calculated dose volumes were compared to dose measurements that were performed by translating the phantom with the same motion traces used in the calculations. Measurements were made using film and ion chambers. Finally, the delivery plans were modified to compensate for the motion by sweeping the jaws for longitudinal motion and shifting the MLC leaves for transverse motion, and the calculations and measurements were repeated. RESULTS: A transverse step motion shifted the dose that was delivered after the step occurred, but otherwise did not impact the dose distribution. Film measurements agreed with dose calculations to within 2%/2 mm for 99% of dose points within the 50% isodose line. A shift in the MLC leaf delivery pattern successfully compensated for the step motion to within the 3 mm accuracy allowed by the finite leaf widths. A longitudinal step motion impacted the dose in the interior of the target volume to a degree that was dependent on the planning field width and step size. Film measurements agreed with dose calculations to within 2%/2 mm for 98% of dose points within the 50% isodose line. Shifts in the jaw position successfully compensated for the longitudinal step motion. Sinusoidal (breathing-like) motion was also studied, with similar results. CONCLUSIONS: A research version of the clinical TomoTherapy dose calculator has been shown to accurately calculate the dose from treatment plans delivered in the presence of arbitrary rigid motion. Modifications to the delivery plan using jaw and MLC leaf shifts that follow the motion can successfully compensate for the target motion. PMID- 29106740 TI - Pharmacokinetics of Nintedanib in Subjects With Hepatic Impairment. AB - Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open-label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100-mg dose. Subjects with hepatic impairment classified as Child-Pugh A (mild hepatic impairment) or Child Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were Cmax and AUC0-infinity of nintedanib. Thirty-three subjects received nintedanib (8 in each of the Child Pugh A and Child-Pugh B groups and 17 controls). The shape of the plasma concentration-time curve for nintedanib was similar between Child-Pugh A or B and healthy subjects. Nintedanib exposure was ~2-fold higher in Child-Pugh A subjects and ~8-fold higher in Child-Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child-Pugh B subjects (37.5%), no Child-Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child-Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment. PMID- 29106741 TI - Development and characterization of a handheld hyperspectral Raman imaging probe system for molecular characterization of tissue on mesoscopic scales. AB - PURPOSE: Raman spectroscopy is a promising cancer detection technique for surgical guidance applications. It can provide quantitative information relating to global tissue properties associated with structural, metabolic, immunological, and genetic biochemical phenomena in terms of molecular species including amino acids, lipids, proteins, and nucleic acid (DNA). To date in vivo Raman spectroscopy systems mostly included probes and biopsy needles typically limited to single-point tissue interrogation over a scale between 100 and 500 microns. The development of wider field handheld systems could improve tumor localization for a range of open surgery applications including brain, ovarian, and skin cancers. METHODS: Here we present a novel Raman spectroscopy implementation using a coherent imaging bundle of fibers to create a probe capable of reconstructing molecular images over mesoscopic fields of view. Detection is performed using linear scanning with a rotation mirror and an imaging spectrometer. Different slits widths were tested at the entrance of the spectrometer to optimize spatial and spectral resolution while preserving sufficient signal-to-noise ratios to detect the principal Raman tissue features. The nonbiological samples, calcite and polytetrafluoroethylene (PTFE), were used to characterize the performance of the system. The new wide-field probe was tested on ex vivo samples of calf brain and swine tissue. Raman spectral content of both tissue types were validated with data from the literature and compared with data acquired with a single-point Raman spectroscopy probe. The single-point probe was used as the gold standard against which the new instrument was benchmarked as it has already been thoroughly validated for biological tissue characterization. RESULT: We have developed and characterized a practical noncontact handheld Raman imager providing tissue information at a spatial resolution of 115 microns over a field of view >14 mm2 and a spectral resolution of 6 cm-1 over the whole fingerprint region. Typical integration time to acquire an entire Raman image over swine tissue was set to approximately 100 s. Spectra acquired with both probes (single point and wide-field) showed good agreement, with a Pearson correlation factor >0.85 over different tissue categories. Protein and lipid content of imaged tissue were manifested into the measured spectra which correlated well with previous findings in the literature. An example of quantitative molecular map is presented for swine tissue and calf brain based on the ratio of protein-to-lipid content showing clear delineations between white and gray matter as well as between adipose and muscle tissue. CONCLUSION: We presented the development of a Raman imaging probe with a field of view of a few millimeters and a spatial resolution consistent with standard surgical imaging methods using an imaging bundle. Spectra acquired with the newly developed system on swine tissue and calf brain correlated well with an establish single-point probe and observed spectral features agreed with previous finding in the literature. The imaging probe has demonstrated its ability to reconstruct molecular images of soft tissues. The approach presented here has a lot of potential for the development of surgical Raman imaging probe to guide the surgeon during cancer surgery. PMID- 29106743 TI - Quantifying meniscal kinematics in dogs. AB - The dog has been used extensively as an experimental model to study meniscal treatments such as meniscectomy, meniscal repair, transplantation, and regeneration. However, there is very little information on meniscal kinematics in the dog. This study used MR imaging to quantify in vitro meniscal kinematics in loaded dog knees in four distinct poses: extension, flexion, internal, and external rotation. A new method was used to track the meniscal poses along the convex and posteriorly tilted tibial plateau. Meniscal displacements were large, displacing 13.5 and 13.7 mm posteriorly on average for the lateral and medial menisci during flexion (p = 0.90). The medial anterior horn and lateral posterior horns were the most mobile structures, showing average translations of 15.9 and 15.1 mm, respectively. Canine menisci are highly mobile and exhibit movements that correlate closely with the relative tibiofemoral positions. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1710-1716, 2018. PMID- 29106742 TI - Density-weighted concentric circle trajectories for high resolution brain magnetic resonance spectroscopic imaging at 7T. AB - PURPOSE: Full-slice magnetic resonance spectroscopic imaging at >=7 T is especially vulnerable to lipid contaminations arising from regions close to the skull. This contamination can be mitigated by improving the point spread function via higher spatial resolution sampling and k-space filtering, but this prolongs scan times and reduces the signal-to-noise ratio (SNR) efficiency. Currently applied parallel imaging methods accelerate magnetic resonance spectroscopic imaging scans at 7T, but increase lipid artifacts and lower SNR-efficiency further. In this study, we propose an SNR-efficient spatial-spectral sampling scheme using concentric circle echo planar trajectories (CONCEPT), which was adapted to intrinsically acquire a Hamming-weighted k-space, thus termed density weighted-CONCEPT. This minimizes voxel bleeding, while preserving an optimal SNR. THEORY AND METHODS: Trajectories were theoretically derived and verified in phantoms as well as in the human brain via measurements of five volunteers (single-slice, field-of-view 220 * 220 mm2 , matrix 64 * 64, scan time 6 min) with free induction decay magnetic resonance spectroscopic imaging. Density weighted-CONCEPT was compared to (a) the originally proposed CONCEPT with equidistant circles (here termed e-CONCEPT), (b) elliptical phase-encoding, and (c) 5-fold Controlled Aliasing In Parallel Imaging Results IN Higher Acceleration accelerated elliptical phase-encoding. RESULTS: By intrinsically sampling a Hamming-weighted k-space, density-weighted-CONCEPT removed Gibbs-ringing artifacts and had in vivo +9.5%, +24.4%, and +39.7% higher SNR than e-CONCEPT, elliptical phase-encoding, and the Controlled Aliasing In Parallel Imaging Results IN Higher Acceleration accelerated elliptical phase-encoding (all P < 0.05), respectively, which lead to improved metabolic maps. CONCLUSION: Density weighted-CONCEPT provides clinically attractive full-slice high-resolution magnetic resonance spectroscopic imaging with optimal SNR at 7T. Magn Reson Med 79:2874-2885, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 29106745 TI - Demonstration of velocity selective myocardial arterial spin labeling perfusion imaging in humans. AB - PURPOSE: Transit delay is a potential source of error in cardiac arterial spin labeled (ASL) in heart failure or with collateral circulation. This study demonstrates the feasibility of using transit delay insensitive velocity selective ASL and compares its performance with flow-sensitive alternating inversion recovery (FAIR) ASL. METHODS: Velocity selective labeling was achieved using an adiabatic BIR8 preparation. FAIR and velocity-selective ASL (VSASL) with various velocity cutoffs (VC = 10-40 cm/s) and labeling directions (anterior posterior X, lateral-septal Y, and apical-basal Z) were carried out in 10 healthy volunteers (1F/9M age 23-30 y). Myocardial blood flow (MBF) and temporal signal to-noise (TSNR) were measured. RESULTS: VSASL sensitivity to perfusion decreased with increasing VC . At low VC (<5 cm/s), spurious labeling of myocardium occurs and overestimates MBF. MBF measured with FAIR (1.12 +/- 0.26 ml/g/min) and VASL (1.26 +/- 0.27 ml/g/min) at VC of 10 cm/s in Z were comparable (TOST with difference of 0.30 ml/g/min, P = 0.049). TSNR was 2.8 times larger using FAIR (13.62 +/- 5.25) than in VSASL (4.87 +/- 1.58). VSASL was insensitive to perfusion in the Y direction. X and Z performed similarly with TSNR of 4.17 +/- 2.32 and 3.97 +/- 0.56, respectively. CONCLUSION: VSASL is a promising alternative to FAIR ASL in the heart and is well suited for scenarios when transit delays are long. Magn Reson Med 80:272-278, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29106746 TI - Low-dose lithium regimen enhances endochondral fracture healing in osteoporotic rodent bone. AB - Osteoporotic bone fractures are highly prevalent and involve lengthy recovery. Lithium, commonly used in psychiatric medicine, inhibits glycogen synthase kinase 3beta in the Wnt/beta-catenin pathway, leading to up-regulation of osteogenesis. Our recent preclinical work demonstrated that a 20 mg/kg lithium dose administered beginning 7 days post-fracture for 14 days optimally improved femoral fracture healing in healthy rats at 4 weeks post fracture (46% higher torsional strength). In this study, lithium treatment was evaluated for healing of osteoporotic bone fractures. Six-month-old ovariectomized rats were subjected to closed, load-drop induced femoral diaphyseal fracture. Two regimens involving treatment initiation on day 7 and day 10, respectively, 20 mg/kg/day oral dose and 14 days duration were evaluated. Femurs of lithium- vs. saline- treated rats were analyzed at 4 weeks (for day 7 onset regimen) or 6 weeks (for day 10 onset regimen) post-fracture by stereology and torsional mechanical testing. Initiation on day 10 led to a significant 50% higher maximum yield torque (primary outcome measure) at 6 weeks (309 vs. 206 N-mm, p = 0.005; n = 7, 7). Initiation on day 7 suggested a trend toward a more modest improvement in maximum yield torque (13%) evaluated at 4 weeks post-fracture (234 vs. 206 N-mm, p = 0.10; n = 10, 13). Qualitatively, lithium-treated femurs demonstrated better periosteal and mineralized callus bridging in the day 10 initiation group. Lithium is a widely available, orally administered, low-cost drug, which represents a feasible pharmacological intervention for both healthy and osteoporotic fracture healing. This study provides important guidelines for future clinical evaluation of lithium in osteoporotic fracture patients. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1783-1789, 2018. PMID- 29106744 TI - Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells. AB - AIMS: To report a series of 11 ovarian and one endometrial neoplasm in elderly patients with mixed clear cell tumour and germ cell tumour (GCT) components, to compare their immunohistochemical profiles and demonstrate a putative stem cell population. METHODS AND RESULTS: The clear cell tumours included 11 clear cell carcinomas (CCC) and one borderline clear cell tumour, while the GCT always included glandular yolk sac tumour (YST). In four cases, there were also foci of teratoma with immature neuroepithelial and endodermal tissues and undifferentiated areas showing true embryoids. To distinguish between the clear cell and YST components, the following antibodies were used: HNF1-beta, napsin-A, cytokeratin 7 (CK7), PAX8, EMA, AFP, SALL4, villin, glypican-3 (GPC-3), GATA3, HepPar-1, OCT4, CDX2, CD30 and SOX2. HNF1-beta, CK7, EMA and GPC-3 were often expressed in both components. Other markers had higher specificity for each cellular lineage; napsin-A and PAX8 were expressed only in CCC, while SALL4, villin, AFP and HepPar-1 were positive in the glandular YST component but negative in the clear cell component. OCT4 expression occurred in six of 10 cases and consistently in teratoma (four of four). CONCLUSIONS: There is considerable immunophenotypical overlap between the two components in these mixed neoplasms, and a panel of markers should be used to facilitate the distinction. We propose that OCT4-expressing somatic cancer cells differentiate into GCT and represent spontaneously induced pluripotent stem cells, possibly conditioned by age-related epigenetic factors. These neoplasms have features of prepubertal type GCT showing lack of 12p gain, preponderance of YST and coexistence with immature neuroectoderm. However, there may also be undifferentiated stem cell areas with embryoid bodies, of the type seen in postpubertal testicular GCT, but lacking a complete embryonal carcinoma immunophenotype. PMID- 29106747 TI - The prevalence of lower urinary tract symptoms (LUTS) in Brazil: Results from the epidemiology of LUTS (Brazil LUTS) study. AB - AIMS: We performed the first large population-based study to evaluate lower urinary tract symptoms (LUTS) in Brazil. The study objective was to assess the prevalence and bother of LUTS in the population aged >=40 years in five major cities of Brazil. METHODS: This study was conducted as a telephone survey with assessment of LUTS using a standardized protocol, which included the International Prostate Symptom Score (IPSS) and, for overactive bladder (OAB), the OAB-V8 questionnaire. Participants were asked to rate how often they experienced individual LUTS and the degree of associated bother. RESULTS: Of the 5184 participants, 53% were women, and the age group with most participants (34%) was 50-59 years. The prevalence of LUTS (symptoms occurring less than half the time or more) was 75%: 69% in men and 82% in women. There was a statistically significant association between the frequency and bother intensity of each symptom (P < 0.001). The prevalence of OAB was similar in men and women (25% and 24%, respectively). According to the IPSS questionnaire, moderate-to-severe symptoms were present in 21% of men and 24% of women. LUTS detrimentally affected quality of life in many individuals: 39% would be "mostly dissatisfied," "unhappy," or consider it "terrible" to spend the rest of their life with their urinary condition as it is currently. CONCLUSIONS: This was the first nationwide, population-based epidemiological study of LUTS to be performed in Brazil. LUTS are highly prevalent and often bothersome among men and women aged >=40 years. PMID- 29106748 TI - Solitary fibrous tumour of the female genital tract: a clinicopathological analysis of 25 cases. AB - AIMS: Solitary fibrous tumour (SFT) is an uncommon spindle cell neoplasm of fibroblastic origin, first described as a tumour of the pleura and now well established at extrapleural sites. However, SFT in the female genital tract is rare and therefore not fully characterised. Here, we describe a series of 25 SFTs arising throughout the gynaecological tract, including the vulva (14 cases), vagina (one), cervix (one), uterus (six), ovary (two), and fallopian tube (one). METHODS AND RESULTS: The tumours showed classic histology as well as known variant morphological features, including a fatty component, diffuse stromal hyalinisation, myxoid stroma, and giant-cell angiofibroma-like features. Eleven (11/25, 44%) were considered to be histologically malignant on the basis of mitotic counts of >=4 per 10 high-power fields. Follow-up data were available for nine (3-56 months; mean 25 months). Six patients are alive with no evidence of disease, and three are alive with disease. Both SFT and other spindle cell lesions of the gynaecological tract were stained for STAT6. Ninety per cent of SFTs showed nuclear expression of STAT6. The majority of other tumour types were negative for STAT6, except for a subset of inflammatory myofibroblastic tumours (1/3; 33%), fibroma/thecoma (3/56; 5%), and sclerosing stromal tumour (1/3; 33%), which showed weak/focal staining. CONCLUSION: Gynaecological SFT can be diagnosed reliably with careful morphological evaluation and judicious use of immunohistochemical stains, and should be considered in the diagnostic workup of spindle cell tumours of unclear lineage in the female genital tract. PMID- 29106749 TI - Orthodontic treatment simultaneous to or after periodontal cause-related treatment in periodontitis susceptible patients. Part I: Clinical outcome. A randomized clinical trial. AB - AIM: To compare two treatment strategies regarding the effect of orthodontic treatment on periodontal status in patients with plaque-induced periodontitis. SUBJECTS AND METHODS: This was a randomized clinical trial. Fifty periodontal patients were randomly assigned to the test or control groups according to periodontal treatment timing. All patients received supra- and subgingival debridement following baseline examination. Control group patients received cause related periodontal treatment before the start of orthodontic treatment and which was performed simultaneous to orthodontic treatment for the test group patients. RESULTS: No difference between the test and control groups was found regarding change of clinical attachment level (CAL) after periodontal-orthodontic treatment. Fewer sites with initial pocket depth (PD) of 4-6 mm healed after periodontal-orthodontic treatment in the test group (20.5%, IQR = 11.9%) in comparison with controls (30.4%, IQR = 27.1%) (p = .03). Anterior teeth [OR 2.5] and teeth in male patients [OR 1.6] had a greater chance for PD improvement >=2 mm. Total periodontal-orthodontic treatment duration was significantly longer for the control group (p < .01). CONCLUSIONS: Both groups showed a gain of CAL and a reduction in sites with PD >= 4 mm. Orthodontic treatment, simultaneously to the periodontal treatment, could be used in the routine treatment of patients with plaque-induced periodontitis. PMID- 29106750 TI - Cardiac apical swinging detected by computed tomography. AB - In cases with significant pericardial effusion, cardiac apical swinging is a characteristic finding, usually detected by echocardiography and electrocardiography. We present a case showing typical cardiac apical swinging, initially detected by routine computed tomography as a cardiac swinging artifact. The present case highlights the importance of multidisciplinary interpretation of cardiac images, specifically focusing on the difference between static images obtained by computed tomography and dynamic images visualized by echocardiography. PMID- 29106751 TI - Fast, Na+ /K+ pump driven, steady-state transcytolemmal water exchange in neuronal tissue: A study of rat brain cortical cultures. AB - PURPOSE: Water homeostasis and transport play important roles in brain function (e.g., ion homeostasis, neuronal excitability, cell volume regulation, etc.). However, specific mechanisms of water transport across cell membranes in neuronal tissue have not been completely elaborated. METHODS: The kinetics of transcytolemmal water exchange were measured in neuronal tissue using simultaneous, real-time fluorescence and nuclear magnetic resonance (NMR) measurements of perfused, active brain organotypic cortical cultures. Perfusion with a paramagnetic MRI contrast agent, gadoteridol, allows NMR determination of the unidirectional rate constant for steady-state cellular water efflux (kio ), and the mole fraction of intracellular water ( pi), related to the average cell volume (V). Changes in intracellular calcium concentration [Cai2+] were used as a proxy for neuronal activity and were monitored by fluorescence imaging. RESULTS: The kio value, averaged over all cultures (N = 99) at baseline, was 2.02 (+/ 1.72) s-1 , indicating that on average, the equivalent of the entire intracellular water volume turns over twice each second. To probe possible molecular pathways, the specific Na+ -K+ -ATPase (NKA) inhibitor, ouabain (1 mM), was transiently introduced into the perfusate. This caused significant transient changes (N = 8): [Cai2+] rose ~250%, V rose ~89%, and kio fell ~45%, with a metabolically active kio contribution probably eliminated by ouabain saturation. CONCLUSIONS: These results suggest that transcytolemmal water exchange in neuronal tissue involves mechanisms affected by NKA activity as well as passive pathways. The active pathway may account for half of the basal homeostatic water flux. Magn Reson Med 79:3207-3217, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29106753 TI - Salvage endoscopic resection (ER) after chemoradiotherapy for esophageal squamous cell carcinoma: What are the risk factors for recurrence after salvage ER? AB - BACKGROUND AND AIM: Salvage endoscopic resection (ER) is among the curative treatments for superficial local failure after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC). The present study aimed to clarify risk factors for recurrence after salvage ER. METHODS: This study enrolled consecutive ESCC patients treated with salvage ER for local failure after CRT between 1998 and 2013. Recurrences after salvage ER included locoregional recurrences and distant metastases. Multivariate analysis was carried out on clinicopathological parameters to identify risk factors for post-salvage ER recurrence. RESULTS: Of the 72 patients enrolled in this study, 37/8/23/4 patients had been staged before CRT as cT1/T2/T3/T4 and 44/28 patients as cN0/N1, respectively, and local failures detected before salvage ER were residual lesions after CRT in 19 and local recurrences in 53 patients. Resected specimens were classified as pT1a (M) in 45 and pT1b (SM) in 27 patients. During the median 45 month follow up (range, 3-175 months) after salvage ER, 27 (38%) patients developed recurrence with a 3-year recurrence-free survival rate of 48.9% (95% confidence interval [CI], 36.5-60.3). Multivariate analysis showed that residual lesions after CRT (HR, 2.55; 95% CI, 1.32-4.94) and lesions with a submucosal tumor (SMT)-like appearance before salvage ER (HR, 2.08; 95% CI, 1.04-4.18) were significantly associated with post-salvage ER recurrence. CONCLUSIONS: Clinical findings (e.g. residual tumors found immediately after CRT and macroscopic SMT like appearance before salvage ER) were shown to be significant risk factors for post-salvage ER recurrence. PMID- 29106752 TI - Subclinical anthracycline-induced cardiotoxicity in long-term follow-up of asymptomatic childhood cancer survivors: Assessment by speckle tracking echocardiography. AB - OBJECTIVE: Survivors of childhood cancer treated with anthracyclines carry the risk for developing late-onset cardiotoxicity. The purpose of this study was to evaluate left ventricular (LV) function in this patient group and compare it with healthy controls by means of conventional and speckle tracking echocardiography (STE) after exposure to chemotherapy. MATERIAL AND METHODS: Conventional and STE were performed in 45 childhood cancer survivors (mean age 11 +/- 4.6; 26 male) treated with anthracyclines (median cumulative dosage 240 mg/m2 ; range, 100-460) and compared with age, gender and body surface area matched healthy controls. Follow-up period after chemotherapy was 21.9 +/- 17.8 months. Blood samples were taken from survivors and controls to determine brain natriuretic peptide (BNP). RESULTS: Following anthracycline exposure, pediatric cancer survivors had lower longitudinal, radial anteroseptal, and radial anterior strain values compared to controls (P < .05). The calculated global longitudinal and global radial strain values were lower compared to the control group (P < .05). Both groups had normal ejection fraction (EF) and fractional shortening (FS). Brain natriuretic peptide (BNP) levels of both groups were in the normal range. CONCLUSION: Despite normal EF and FS, children exposed to anthracycline therapy may have late-onset subtle changes of LV strain values measured by STE. Whether these changes of strain can predict future risk of developing heart failure needs to be explored in further studies. PMID- 29106754 TI - Right heart function in impaired left ventricular diastolic function: 2D speckle tracking echocardiography-based and Doppler tissue imaging-based analysis of right atrial and ventricular function. AB - AIM: The aim of our study was to describe right atrial (RA) and right ventricular (RV) function, assessed by Doppler tissue imaging and 2D speckle tracking echocardiography (2DSTE), in women with signs of early impaired left ventricular diastolic function (DD). METHODS AND RESULTS: In a cross-sectional trial, standard parameters of diastolic and right heart function were investigated in 438 women of the Berlin Female Risk Evaluation (BEFRI) study. In a subset of women, average peak systolic RA strain (RAS), as well as the average peak systolic RV strain of the free wall (RVS free wall) and of all RV segments (average RV strain; RVS Avg), was analyzed using 2DSTE. Compared to women with normal diastolic function (DD0), RAS, RVS free wall and RVS Avg were significantly reduced in DD (43.1% +/- 11.9%, -26.7% +/- 5.6%, and -23.3% +/- 3.5% in DD0; vs 35.1% +/- 10.4%, -23.9% +/- 5.5%, and -20.6% +/- 3.8% in DD; P < .01). Peak RV myocardial velocity (RV-IVV) and acceleration during isovolumetric contraction (RV-IVA) were markedly higher in DD (15.0 +/- 3.9 cm/s and 3.1 +/- 1.0 m/s2 in DD vs 11.9 +/- 3.2 cm/s and 2.8 +/- 0.8 m/s2 in DD0; P < .05). RAS and RV-IVV were significantly associated with DD after adjustment to age, BMI, and left atrial strain in multivariate regression analysis. CONCLUSION: Systolic right heart function is significantly altered in DD. DTI as well as 2DSTE constitute sensitive echocardiographic tools that enable the diagnosis of impaired right heart mechanics in early-staged DD. PMID- 29106755 TI - Canine GM2-Gangliosidosis Sandhoff Disease Associated with a 3-Base Pair Deletion in the HEXB Gene. AB - BACKGROUND: GM2-gangliosidosis is a fatal neurodegenerative lysosomal storage disease (LSD) caused by deficiency of either beta-hexosaminidase A (Hex-A) and beta-hexosaminidase B (Hex-B) together, or the GM2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency. OBJECTIVES: To characterize the phenotype and genotype of GM2 gangliosidosis disease in an affected dog. ANIMALS: One affected Shiba Inu and a clinically healthy dog. METHODS: Clinical and neurologic evaluation, brain magnetic resonance imaging (MRI), assays of lysosomal enzyme activities, and sequencing of all coding regions of HEXA, HEXB, and GM2A genes. RESULTS: A 14 month-old, female Shiba Inu presented with clinical signs resembling GM2 gangliosidosis in humans and GM1-gangliosidosis in the Shiba Inu. Magnetic resonance imaging (MRI) of the dog's brain indicated neurodegenerative disease, and evaluation of cerebrospinal fluid (CSF) identified storage granules in leukocytes. Lysosomal enzyme assays of plasma and leukocytes showed deficiencies of Hex-A and Hex-B activities in both tissues. Genetic analysis identified a homozygous, 3-base pair deletion in the HEXB gene (c.618-620delCCT). CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical, biochemical, and molecular features are characterized in a Shiba Inu with GM2-gangliosidosis. The deletion of 3 adjacent base pairs in HEXB predicts the loss of a leucine residue at amino acid position 207 (p.Leu207del) supporting the hypothesis that GM2-gangliosidosis seen in this dog is the Sandhoff type. Because GM1-gangliosidosis also exists in this breed with almost identical clinical signs, genetic testing for both GM1- and GM2 gangliosidosis should be considered to make a definitive diagnosis. PMID- 29106756 TI - Biomechanical investigation of four different fixation techniques in sacrum Denis type II fracture with low bone mineral density. AB - With increasing life expectancy, fragility fractures of the pelvic ring are seen more frequently. Although their osteosynthesis can be very challenging, specific biomechanical studies for investigation of the fixation stability are still lacking. The aim of this study was to biomechanically evaluate four different fixation methods for sacrum Denis type II fractures in osteoporotic bone. Unstable Denis type II vertical sacrum fractures were created in 16 human pelves. Their osteosynthesis was performed with one sacro-iliac screw, posterior sacral plating, triangular fixation, or spino-pelvic fixation. For that purpose, each pelvis was randomly assigned to two paired groups for treatment with either SI screw/posterior sacral plating or triangular fixation/spino-pelvic fixation. Each hemi-pelvis was cyclically tested under progressively increasing axial compression. Relative interfragmentary movements were investigated via optical motion tracking analysis. Axial stiffness of triangular fixation was significantly higher versus posterior sacral plating and spino-pelvic fixation (p <= 0.022), but not significantly different in comparison to SI-screw fixation (p = 0.337). Cycles to 2, 3, 5, and 8 mm fracture displacement, as well as to 3 degrees , 5 degrees , and 8 degrees gap angle at the fracture site were significantly higher for triangular fixation compared to all other groups (p <= 0.041). Main failure mode for all osteosynthesis techniques was screw cutting through the bone, leading loss of fixation stability. From a biomechanical point of view, triangular fixation in sacrum Denis type II fractures demonstrated less interfragmentary movements and should be considered in unstable fragility fractures of the sacrum. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1624-1629, 2018. PMID- 29106757 TI - Echocardiographic predictors of coil vs device closure in patients undergoing percutaneous patent ductus arteriosus closure. AB - AIM: To determine anatomic and hemodynamic echocardiographic predictors for patent ductus arteriosus (PDA) device vs coil closure. METHODS: Seventy-six patients who were referred for elective transcatheter PDA closure were enrolled in the study. All patients underwent full echocardiogram including measurement of the PDA pulmonary end diameter, color flow width and extent, peak and end diastolic Doppler gradients across the duct, diastolic flow reversal, left atrial dimensions and volume, left ventricular sphericity index, and volumes. RESULTS: The study group was subdivided into 2 subgroups based on the mode of PDA closure whether by coil (n = 42) or device (n = 34). Using univariate analysis there was a highly significant difference between the 2 groups as regard the pulmonary end diameter measured in both the suprasternal and parasternal short-axis views as well as the color flow width and color flow extent (P < .0001). The device closure group had statistically significant higher end-systolic and end-diastolic volumes indexed, left atrial volume, and diastolic flow reversal. Receiver operating characteristic curve analysis showed a pulmonary end diameter cutoff point from the suprasternal view > 2.5 mm and from parasternal short-axis view > 2.61 mm to have the highest balanced sensitivity and specificity to predict the likelihood for device closure (AUC 0.971 and 0.979 respectively). The pulmonary end diameter measured from the suprasternal view was the most independent predictor of device closure. CONCLUSION: The selection between PDA coil or device closure can be done on the basis of multiple anatomic and hemodynamic echocardiographic variables. PMID- 29106758 TI - Transcriptomic analysis of synovial extracellular RNA following knee trauma: A pilot study. AB - Traumatic knee injuries often result in damage to articular cartilage and other joint structures. Such trauma is a strong risk factor for the future development and progression of osteoarthritis (OA). The molecular mechanisms and signaling pathways modulating response to knee joint trauma remain unclear. Moreover, investigations of biomarkers influencing responses have been targeted rather than broad, unbiased discovery studies. Herein, we characterize the complete complement of extracellular RNA (exRNA) in the synovial fluid of 14 subjects following knee injury. Fluid was collected during surgery from the injured knees, and from the contralateral knee in a subset, undergoing surgical repair of the ACL and/or meniscal repair/debridement. Arthroscopic grading of chondral damage in four knee compartments was performed using the Outerbridge classification. exRNA was extracted and subjected to massively parallel total RNA sequencing. Differential abundance of RNA was calculated between the subject cohorts of injured and non-injured knee, average Outerbridge score >=0.5 and less, and chronic and acute injury duration defined as <=4 months till surgery or longer. Overall, expression of several thousand genes was identified in the synovial fluid. Furthermore, differential expression analysis suggests a role of exRNA fragments of matrix metalloproteinases and skeletal muscle fiber genes in the response to traumatic injury. Together, these data suggest that high-throughput approaches can indicate exRNA molecular signatures following knee trauma. Future studies are required to more fully characterize the biological roles of these exRNA and the cadence of their respective release that may lead to translational treatment options for post-traumatic OA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1659-1665, 2018. PMID- 29106759 TI - Imidazole improves cognition and balances Alzheimer's-like intracellular calcium homeostasis in transgenic Drosophila model. AB - AIMS: The characteristic of Alzheimer's disease (AD) is the accumulation and aggregation of amyloid-beta (Abeta). So far, we already know that the dysregulation of intracellular calcium homeostasis is considered to be associated with Abeta neurotoxicity. Meantime, we also found that the channels formed by Abeta are electronegative as calcium channels. Base on this hypothesis, the formation of Abeta channels will provide us with a new therapeutic direction for AD. Abeta channel hypothesis is proposed that the axis of Abeta channel's pore was encompasses by the His13 -His14 diad. Imidazole especially the imidazole ring was supposed binding to the side chains of Abeta peptides. METHODS: In our study, we adopted Gal4/UAS system to establish transgenic drosophila model which lay a good foundation to explore the imidazole's function and mechanism of action. RESULTS: The results suggested that Imidazole could not only improve the cognition of Abeta42-expressing flies, but also decreases p-JNK activation in whole brain of Abeta42-expressing flies. CONCLUSIONS: Furthermore, freshly prepared oligomeric Abeta42 peptide ascended primary pupal neuronal calcium concentration and this phenomenon was alleviated by Imidazole and Zn2+ . PMID- 29106760 TI - Impaired beta-adrenoceptor mediated venodilation in patients with diabetes mellitus. AB - Aims We investigated whether venoconstriction by alpha-adrenoceptor stimulation, and venodilation by beta-adrenoceptor stimulation and nitroglycerin are altered in patients with diabetes mellitus (DM). Methods Eight male patients with non insulin-dependent DM and eight age-matched control subjects were included. The patients had neither hypertension nor hyperlipidaemia. Noradrenaline (1 to 512 ng min-1 ), isoprenaline (1 to 256 ng min-1 ) and nitroglycerin (0.5 to 128 ng min 1 ) were infused into a dorsal hand vein and its diameter was measured using a linear variable differential transformer. Results The venoconstricting response to noradrenaline and the venodilating response to nitroglycerin in DM patients were similar to those in control subjects, while the venodilation by isoprenaline was significantly (P<0.05) smaller in DM patients than in control subjects at the dose of 32 ng min-1 or more [32 ng min-1 : 11.5%vs 29.8% (DM vs control subjects), 64 ng min-1 : 19.0%vs 40.1%, 128 ng min-1 : 25.2%vs 49.0%, 256 ng min 1 : 34.3%vs 56.7%]. Conclusions These data suggested that venoconstriction by alpha-adrenoceptor stimulation and venodilation by nitroglycerin are not altered, whereas venodilation by beta-adrenoceptor stimulation might be impaired in patients with DM. PMID- 29106761 TI - Case of diminutive duodenal deep submucosal invasive adenocarcinoma resected by endoscopic mucosal resection. PMID- 29106762 TI - Addressing the Nature of Phosphinidene Sulfides via the Synthesis of P-S Heterocycles. AB - The phosphorus-sulfur heterocycles 1,2-thiaphosphetenes and phosphirene sulfides have been prepared, and represent the first structurally characterized derivatives for either class of compound. These strained P-S ring systems are formed by the reaction of a phosphinidene sulfide and alkyne. Using an internal alkyne, only the 3-membered PV , phosphirene sulfide was produced, whereas a terminal alkyne yielded a mixture of phosphirene sulfide and 1,2-thiaphosphetene (PIII ). Detailed computational analysis revealed that for numerous derivatives of alkynes, the corresponding 4-membered rings are always more stable than the 3 membered isomers. The electronic nature of "free" phosphinidene sulfides (R-P=S) is discussed based on computational results. PMID- 29106763 TI - Higher prevalence and increased severity of sleep-disordered breathing in male patients with chronic tinnitus: Our experience with 173 cases. PMID- 29106764 TI - An ENT smartphone handbook: Adopting new practice for induction. PMID- 29106765 TI - Relative identifiability of anisotropic properties from magnetic resonance elastography. AB - Although magnetic resonance elastography (MRE) has been used to estimate isotropic stiffness in the heart, myocardium is known to have anisotropic properties. This study investigated the determinability of global transversely isotropic material parameters using MRE and finite-element modeling (FEM). A FEM based material parameter identification method, using a displacement-matching objective function, was evaluated in a gel phantom and simulations of a left ventricular (LV) geometry with a histology-derived fiber field. Material parameter estimation was performed in the presence of Gaussian noise. Parameter sweeps were analyzed and characteristics of the Hessian matrix at the optimal solution were used to evaluate the determinability of each constitutive parameter. Four out of five material stiffness parameters (Young's modulii E1 and E3 , shear modulus G13 and damping coefficient s), which describe a transversely isotropic linear elastic material, were well determined from the MRE displacement field using an iterative FEM inversion method. However, the remaining parameter, Poisson's ratio, was less identifiable. In conclusion, Young's modulii, shear modulii and damping can theoretically be well determined from MRE data, but Poisson's ratio is not as well determined and could be set to a reasonable value for biological tissue (close to 0.5). PMID- 29106766 TI - Antioxidant responses and deregulation of epigenetic writers and erasers link oxidative stress and DNA methylation in bovine blastocysts. AB - Early mammalian embryos derived from in vitro fertilization are exposed to conditions distinct from the native oviduct-uterine environment, including atmospheric oxygen that promotes cellular oxidative stress and alters gene expression. High oxygen partial pressure during embryo development is associated with low pregnancy rates and increased embryonic apoptosis. We investigated how bovine embryos responded to high (20%) or low (5%) oxygen partial pressure during in vitro culture, evaluating levels of reactive oxygen species (ROS) as well as changes in the expression of oxidative stress- and epigenetic-related transcripts and miRNAs in blastocysts. Additionally, we determined the global DNA methylation levels in the resulting embryos. Our data indicated that bovine blastocysts produced in vitro under high oxygen partial pressure possessed elevated ROS abundance and exhibited increased expression of CAT, GLRX2, KEAP1, NFR2, PRDX1, PRDX3, SOD1, TXN, and TXNRD1, versus reduced levels of the oxidative stress related bta-miR-210. These stressed embryos also presented altered expression of the epigenetic-associated transcripts DNMT3A, H2AFZ, H3F3B, HDAC2, MORF4L2, REST, and PAF1. In addition, we demonstrated that embryos cultured under high oxygen partial pressure have increased global DNA methylation, suggesting that DNA hypermethylation is mediated by the deregulation of epigenetic-related enzymes due to oxidative stress. PMID- 29106767 TI - Phagocyte-extracellular matrix crosstalk empowers tumor development and dissemination. AB - Phagocytes, such as tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), are abundant in the stroma of experimental and human tumors and are locally educated to mediate important biological functions that profoundly affect tumor initiation, growth, and dissemination. Of considerable importance is the noncellular component of the tumor microenvironment, namely-the extracellular matrix (ECM). This milieu is often overlooked due to its complexity and vast heterogeneity. Biophysical and biomechanical cues provided by the dynamically evolving tumorigenic ECM fundamentally modulate every behavioral facet of the cancer cells and of associated stromal cells. In this review, we discuss the intricate interplay between phagocytes and ECM that are lined up to support tumor progression. TAMs and TANs shape the tumorigenic ECM by providing key matrix-remodeling enzymes and structural proteins and in turn, the altered tumor ECM modulates their migration and function. A better mechanistic comprehension of this reciprocal dependence has exciting implications for the development of new therapeutic options for cancer. PMID- 29106768 TI - Cyclic Triimidazole Derivatives: Intriguing Examples of Multiple Emissions and Ultralong Phosphorescence at Room Temperature. AB - The performance of solid luminogens depends on both their inherent electronic properties and their packing status. Intermolecular interactions have been exploited to achieve persistent room-temperature phosphorescence (RTP) from organic molecules. However, the design of organic materials with bright RTP and the rationalization of the role of interchromophoric electronic coupling remain challenging tasks. Cyclic triimidazole has been shown to be a promising scaffold for such purposes owing to its crystallization-induced room-temperature ultralong phosphorescence (RTUP), which has been associated with H-aggregation. Herein, we report three triimidazole derivatives as significant examples of multifaceted emission. In particular, dual fluorescence, RTUP, and phosphorescence from the molecular and supramolecular units were observed. H-aggregation is responsible for the red RTUP, and Br substituents favor yellow molecular phosphorescence while halogen-bonded Br???Br tetrameric units are involved in the blue-green phosphorescence. PMID- 29106769 TI - Resting Cysts of the Pigmented Ciliate Blepharisma sinuosum Sawaya, 1940 (Ciliophora: Heterotrichea). AB - The morphology of Blepharisma sinuosum resting cysts and the dynamics of pigmentation at different stages of encystment are presented for the first time. Cyst morphometrics are similar to other Blepharisma species, with three-wall layers, bacteria surrounding the ectocyst, a conical plug, and wrinkly surface toward the plug in mature stages. The vegetative moniliform macronucleus changes to a horseshoe shape, and at early stages, the cystic cytoplasm is homogeneously pigmented, comprising a contractile vacuole; later, pigments polarize toward the plug, decorate the cortical layer, and become brownish. This work reinforces the potential role of pigment dynamics on cyst biology. PMID- 29106770 TI - Probing the cardiac malate-aspartate shuttle non-invasively using hyperpolarized [1,2-13 C2 ]pyruvate. AB - Previous studies have demonstrated that using hyperpolarized [2-13 C]pyruvate as a contrast agent can reveal 13 C signals from metabolites associated with the tricarboxylic acid (TCA) cycle. However, the metabolites detectable from TCA cycle-mediated oxidation of [2-13 C]pyruvate are the result of several metabolic steps. In the instance of the [5-13 C]glutamate signal, the amplitude can be modulated by changes to the rates of pyruvate dehydrogenase (PDH) flux, TCA cycle flux and metabolite pool size. Also key is the malate-aspartate shuttle, which facilitates the transport of cytosolic reducing equivalents into the mitochondria for oxidation via the malate-alpha-ketoglutarate transporter, a process coupled to the exchange of cytosolic malate for mitochondrial alpha-ketoglutarate. In this study, we investigated the mechanism driving the observed changes to hyperpolarized [2-13 C]pyruvate metabolism. Using hyperpolarized [1,2-13 C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13 C-glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non-invasively. Via the [1-13 C]pyruvate label, we observed more than a five-fold increase in the cytosolic conversion of pyruvate to [1-13 C]lactate and [1-13 C]alanine with higher workload. 13 C-Bicarbonate production by PDH was increased by a factor of 2.2. Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. Via the [2-13 C]pyruvate label, we observed that 13 C-acetylcarnitine production increased 2.5 fold in proportion to the 13 C-bicarbonate signal, whereas the 13 C-glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13 C glutamate signal relative to the amount of 13 C-labeled acetyl-coenzyme A (acetyl CoA) entering the TCA cycle was decreased by 40%. The data strongly suggest that NADH (reduced form of nicotinamide adenine dinucleotide) shuttling from the cytosol to the mitochondria via the malate-aspartate shuttle is limited on adrenergic activation. Changes in [5-13 C]glutamate production from [2-13 C]pyruvate may play an important future role in non-invasive myocardial assessment in patients with cardiovascular diseases, but careful interpretation of the results is required. PMID- 29106771 TI - Tip-Enhanced Raman Spectroscopy: A Tool for Nanoscale Chemical and Structural Characterization of Biomolecules. AB - Due to its high molecular sensitivity and spatial optical resolution down to sub nanometer values, tip-enhanced Raman spectroscopy (TERS) has emerged as a powerful microscopy technique for nanoscale characterization. Progress in TERS instrumentation and in the manufacturing of efficient TERS tips allow for chemical and structural analysis under various experimental conditions (different wavelengths, substrates, and surrounding media). Many biological species have been examined by using this technique. Nucleic acids (individual nucleobases, DNA, and RNA) can show specific TERS features that reveal their composition, conformation, and defects. TERS studies on peptides and proteins (such as amyloid fibrils) provide relevant information on their morphology and structure, leading to valuable insight to their functions and behavior. Finally, lipid layers and membranes, viruses, bacteria, and cells can also be finely characterized. Generalizing TERS measurements in liq- uid medium to study biological systems is the main future challenge. PMID- 29106772 TI - Effects of aerobic interval training on arterial stiffness and microvascular function in patients with metabolic syndrome. AB - The authors determined the effect of high-intensity aerobic interval training on arterial stiffness and microvascular dysfunction in patients with metabolic syndrome with hypertension. Applanation tonometry was used to measure arterial stiffness and laser Doppler flowmetry to assess microvascular dysfunction before and after 6 months of stationary cycling (training group; n = 23) in comparison to a group that remained sedentary (control group; n = 23). While no variable improved in controls, hypertension fell from 79% (59%-91%) to 41% (24%-61%) in the training group, resulting in lower systolic and diastolic pressures than controls (-12 +/- 3 and -6 +/- 2 mm Hg, P < .008). Arterial stiffness declined ( 17% augmentation index, P = .048) and reactive hyperemia increased (20%, P = .028) posttreatment in the training group vs controls. Blood constituents associated with arterial stiffness and a prothrombotic state (high-sensitivity C reactive protein, fibrinogen, platelets, and erythrocytes) remained unchanged in the training and control groups. In summary, 6 months of an intense aerobic exercise program reduced both arterial stiffness and microvascular dysfunction in patients with metabolic syndrome despite unchanged blood-borne cardiovascular risk factors. Training lowers blood flow resistance in central and peripheral vascular beds in a coordinated fashion, resulting in clinically relevant reductions in hypertension. PMID- 29106773 TI - An integrative insight on dormancy alleviation in diaspores of Urochloa humidicola (Rendle) Morrone & Zuloaga, a tropical grass with great economic and ecological impact. AB - Even though exhaustively studied, dormancy alleviation in diaspores of Urochloa humidicola (Rendle) Morrone & Zuloaga remains a mystery. To clarify this, we asked the following question: could dormancy alleviation in diaspores of this species be associated with ageing, GA/ABA balance and remaining structures of the panicoid spikelet? We answer this question using diaspores of U. humidicola cv. BRS Tupi as a biological model, a cultivar with a wide edaphoclimatic range in Neotropical areas and whose diaspores possess 'deep dormancy' when dispersed. We analysed both germination and early plant development using a split-plot model. Our findings demonstrate that dormancy alleviation in diaspores of U. humidicola is a synergic phenomenon driven by crosstalk between age, GA/ABA balance and remaining structures of the panicoid spikelet covering caryopses, since this interaction acts on the dynamics of germination and early plant development. We demonstrate that: (i) spreading germination time is a maternal survival mechanism of this species, which has repercussions for occupational aggressiveness of the species; (ii) remaining structures of the panicoid spikelet covering caryopses are the main modulator of embryo development. These structures control the after ripening process, which is modulated by some molecular factor. We also highlight that it is necessary to review concepts about dormancy of dispersal units in this grass species. PMID- 29106774 TI - Do thiazide diuretics reduce central systolic blood pressure in hypertension? PMID- 29106775 TI - Oxygen delivery from the cerebral microvasculature to tissue is governed by a single time constant of approximately 6 seconds. AB - OBJECTIVE: The cerebral microvasculature plays a key role in the coupling between cerebral blood flow and metabolism. Although experimental imaging techniques now allow for finely detailed measurements of flow and oxygenation, within humans measurements remain confined to a voxel-level scale, of order 1 mm. Mathematical models are thus key in interpreting such data. However, these can be highly complicated, due to the large number of vessels and the nonlinearities in the governing equations. METHODS: We thus propose here a new model of the cerebral microvasculature and show how its behavior can be simplified based on the order of magnitude arguments. RESULTS: The resulting model shows a dependence upon just two time constants, termed "slow" and "metabolic" time constants; the tissue oxygenation response can be characterized by convolution of the difference between the fractional flow and metabolic responses with a single exponential, with time constant equal to half the ratio of tissue volume to blood flow multiplied by the ratio of effective oxygen solubility in tissue and blood. CONCLUSIONS: The overall response time for the whole network is approximately 6 seconds; this value indicates that the flow response to increases in metabolic activity cannot be driven solely by changes in tissue oxygenation. PMID- 29106776 TI - Imaging modalities for the detection of distant metastases in breast cancer patients diagnosed in the 1970s and 1990s: Does it make any sense? PMID- 29106777 TI - Quality of questionnaires for the assessment of otitis media with effusion in children. AB - OBJECTIVES: Audiometric tests provide information about hearing in otitis media with effusion (OME). Questionnaires can supplement this information by supporting clinical history-taking as well as potentially providing a standardized and comprehensive assessment of the impact of the disease on a child. There are many possible candidate questionnaires. This study aimed to assess the quality and usability of parent / child questionnaires in OME assessment. DESIGN AND MAIN OUTCOME MEASURES: Fifteen, published questionnaires, commonly used in audiological departments (Auditory Behaviour in Everyday Life (ABEL), Children's Auditory Performance Scale (CHAPS), Children's Home Inventory for Listening Difficulties (CHILD), Children's Outcome Worksheets (COW), Evaluation of Children's Listening and Processing Skills (ECLiPS), Early Listening Function (ELF), Fisher's Auditory Problem Checklist (FAPC), Hearing Loss 7 (HL-7), Listening Inventory for Education- Revised (LIFE-R Student), Listening Inventory for Education UK Individual Hearing Profile (LIFE-UK IHP), LittlEARS Auditory Questionnaire (LittlEARS), Listening Situations Questionnaire (LSQ), Otitis Media 6 (OM-6), Quality of Life in Children's Ear Problems (OMQ-14), Parents' Evaluation of Aural/Oral Performance of Children (PEACH) were assessed according to the following 8 criteria: conceptual clarity, respondent burden, reliability, validity, normative data, item bias, ceiling/ floor effects, and administrative burden. RESULTS: ECLiPS, LittlEARS and PEACH scored highest overall based on the assessment criteria established for this study. None of the questionnaires fully satisfied all 8 criteria. Although all questionnaires assessed issues considered to be of at least adequate relevance to OME, the majority had weaknesses with respect to the assessment of psychometric properties, such as item bias, floor/ceiling effects or measurement reliability and validity. Publications reporting on the evaluation of reliability, validity, normative data, item bias and ceiling/floor effects were not available for most of the questionnaires. CONCLUSIONS: This formal evaluation of questionnaires, currently available to clinicians, highlights three questionnaires as potentially offering a useful adjunct in the assessment of OME in clinical or research settings. These were the ECLiPS, which is suitable for children aged 6 years and older, and either the LittlEARS or the PEACH for younger children. The latter two are narrowly focused on hearing, whereas ECLiPS has a broader focus on listening, language and social difficulties. PMID- 29106779 TI - Reply to Imaging modalities for the detection of distant metastases in breast cancer patients diagnosed in the 1970s and 1990s: Does it make any sense? PMID- 29106778 TI - Evolution of soft palate surgery techniques for obstructive sleep apnea patients: A comparative study for single-level palatal surgeries. AB - OBJECTIVES: To compare the results of tissue preservation techniques of soft palate surgeries including expansion sphincter pharyngoplasty (ESP) and barbed reposition pharyngoplasty (BRP) for patients suffering from obstructive sleep apnoea (OSA) with the traditional uvulopalatopharyngoplasty (UPPP). DESIGN: Interventional comparative study. SETTING: Morgagni-Pierantoni Hospital. PARTICIPANTS: Seventy-five patients were included in the study, divided into three groups with 25 patients per group: UPPP, ESP or BRP. MAIN OUTCOMES MEASURES: Polysomnography was carried out for all patients pre- and postoperatively; the postoperative results were recorded at least 6 months after surgery. All patients were assessed preoperatively using drug-induced sleep endoscopy. Epworth Sleepiness Scale and body mass index (BMI) were registered for all patients before and after surgery. RESULTS: The mean of pre- and postoperative differences of apnoea-hypopnoea index values was higher in BRP group than ESP: 15.76 +/- 14.5 Vs 10.13 +/- 5.3; P < .05 and UPPP groups: 15.76 +/- 14.5 vs 6.08 +/- 5.5; P < .0005. The mean of differences of oxygen desaturation index values was higher in BRP group than UPPP group: 15.09 +/- 17.6 vs 7.13 +/- 6.8; P < .0005, but not significantly higher than ESP group: 15.09 +/ 17.6 vs 6.48 +/- 7.9; P > .05. The mean of differences of ESS values was higher in BRP group than ESP group: 5.52 +/- 4.1 vs 4.84 +/- 3.3; P < .005 and UPPP groups: 5.52 +/- 4.1 vs 1.36 +/- 1.9; P < .005. Finally, the pre- and postoperative means of differences of lowest oxygen saturation values were not statistically significant among the three groups (P > .05). CONCLUSION: Barbed reposition pharyngoplasty (BRP) can be considered an effective procedure on the basis of the postoperative outcomes. ESP still proves to be a good technique especially when performed by experienced surgeons. Both techniques proved to be superior to UPPP. PMID- 29106780 TI - Temperatures during flower bud development affect pollen germination, self incompatibility reaction and early fruit development of clementine (Citrus clementina Hort. ex Tan.). AB - One of the key environmental factors affecting plant reproductive systems is temperature. Characterising such effects is especially relevant for some commercially important genera such as Citrus. In this genus, failure of fertilisation results in parthenocarpic fruit development and seedlessness, which is a much-prized character. Here, we characterise the effects of temperature on flower and ovary development, and on pollen-pistil interactions in 'Comune' clementine (Citrus clementina Hort. ex Tan.). We examine flower bud development, in vitro pollen germination and pollen-pistil interaction at different temperatures (15, 20, 25 or 30 degrees C). These temperatures span the range from 'cold' to 'hot' weather during the flowering season in many citrus-growing regions. Temperature had a strong effect on flower and ovary development, pollen germination, and pollen tube growth kinetics. In particular, parthenocarpic fruit development (indicated by juice vesicle growth) was initiated early if flowers were exposed to warmer temperatures during anthesis. Exposure to different temperatures during flower bud development also alters expression of the self incompatibility reaction. This affects the point in the pistil at which pollen tube growth is arrested and confirms the role of sub- and supra-optimal temperatures in determining the numbers of pollen tubes reaching the ovary. PMID- 29106781 TI - A Critical Check for the Role of Resonance in Intramolecular Hydrogen Bonding. AB - Although resonance-assisted H-bonds (RAHBs) are well recognized, the role of pi resonance in RAHBs is controversial, as the seemingly enhanced H-bonds in unsaturated compounds may result from the constraints imposed by the sigma skeleton. Herein the block-localized wave function (BLW) method, which can derive optimal yet resonance-quenched structures with related physiochemical properties, was employed to examine the correlation between pi resonance and the strength of intramolecular RAHBs. Examination of a series of paradigmatic molecules with RAHBs and their saturated analogues showed that it is inappropriate to compare a conjugated system with its saturated counterpart, as they may have quite different sigma frameworks. Nevertheless, comparison between a conjugated system and its resonance-quenched (i.e., electron-localized) state, which have identical sigma skeletons, shows that in all studied cases, pi resonance unanimously reduces the bonding distance by 0.111-0.477 A, strengthens the bonding by 40-56 %, and redshifts the D-H vibrational frequency by 104-628 cm-1 . Furthermore, there is an excellent correlation between hydrogen-bonding strength and the classical Coulomb attraction between the hydrogen-bond donor and the acceptor, which suggests that the dominant role of the electrostatic interaction in H-bonds and RAHBs originates from the charge flow from H-bond donors to acceptors through pi conjugation. PMID- 29106782 TI - Expression and assembly of largest foreign protein in chloroplasts: oral delivery of human FVIII made in lettuce chloroplasts robustly suppresses inhibitor formation in haemophilia A mice. AB - Inhibitor formation is a serious complication of factor VIII (FVIII) replacement therapy for the X-linked bleeding disorder haemophilia A and occurs in 20%-30% of patients. No prophylactic tolerance protocol currently exists. Although we reported oral tolerance induction using FVIII domains expressed in tobacco chloroplasts, significant challenges in clinical advancement include expression of the full-length CTB-FVIII sequence to cover the entire patient population, regardless of individual CD4+ T-cell epitope responses. Codon optimization of FVIII heavy chain (HC) and light chain (LC) increased expression 15- to 42-fold higher than the native human genes. Homoplasmic lettuce lines expressed CTB fusion proteins of FVIII-HC (99.3 kDa), LC (91.8 kDa), C2 (31 kDa) or single chain (SC, 178.2 kDa) up to 3622, 263, 3321 and 852 MUg/g in lyophilized plant cells, when grown in a cGMP hydroponic facility (Fraunhofer). CTB-FVIII-SC is the largest foreign protein expressed in chloroplasts; despite a large pentamer size (891 kDa), assembly, folding and disulphide bonds were maintained upon lyophilization and long-term storage as revealed by GM1-ganglioside receptor binding assays. Repeated oral gavages (twice/week for 2 months) of CTB-FVIII HC/CTB-FVIII-LC reduced inhibitor titres ~10-fold (average 44 BU/mL to 4.7 BU/mL) in haemophilia A mice. Most importantly, increase in the frequency of circulating LAP-expressing CD4+ CD25+ FoxP3+ Treg in tolerized mice could be used as an important cellular biomarker in human clinical trials for plant-based oral tolerance induction. In conclusion, this study reports the first clinical candidate for oral tolerance induction that is urgently needed to protect haemophilia A patients receiving FVIII injections. PMID- 29106783 TI - Gestational diabetes - is diet and insulin the only solution? AB - Gestational diabetes (GDM) is a relatively common complication of pregnancy. Maternal hyperglycemia causes many serious side effects for mothers, fetuses and newborns. In 90% of women diagnosed with GDM, a dietary treatment results in satisfactory levels of blood glucose. The remaining 10% require insulin therapy to achieve the recommended glycemic levels. The majority of recent studies show the efficiency of metformin in gestational diabetes and prove that it is not a cause for any harmful side effects to the embryo and/or fetus. Metformin is an effective alternative to insulin in glycemic control in pregnant women. The implementation of metformin, as a routine procedure in gestational diabetes, requires further research, the results of which would unequivocally confirm its efficacy and safety for pregnant women and their offspring. PMID- 29106784 TI - Lucky gene 5-HTTLPR and postpartum depression: A systematic review. AB - BACKGROUND: Postpartum depression (PPD) should be given more attention for its increasing incidences, severe complications and complex pathogenesis. Previous studies of PPD have mainly been focused on the social contributions to its etiology such as age, marriage and economic status, whilst less attention has been given to inner biological factors. Currently, emerging researches have endeavored to explore 5-HTT related pathogenesis of PPD. OBJECTIVE: This report was aimed at proffering updates on some research advancements in the field of PPD through the reviewing published papers concerning postpartum depression, with prime focus on the role of 5-HTT. SEARCH STRATEGY: This review report dug into articles containing both PPD and 5-HTTLPR. Web of Science, Pubmed and CNKI (National Knowledge Infrastructure) were employed for searching relevant publications. SELECTION CRITERIA: There was a strong association between 5-HTTLPR polymorphism and the pathogenesis of PPD, with established evidence showing that L allele (Long allele) in 5-HTTLPR was associated with reduced susceptibility to PPD. LIMITATIONS: All things considered, sufficient clinical experiments are needed to ascertain the feasibility of our theoretical statements. In addition, relevant articles are comparatively scarce presently. PMID- 29106785 TI - N-terminal pro-B-type Natriuretic Peptide in three different mechanisms of dysnatremia onset after a child's craniopharyngioma surgery. AB - Craniopharyngioma, due to its sellar location, can be perioperatively complicated by different types of dysnatremia. We present a rare postoperative onset of a combination of three different mechanisms of dysnatremia with N-terminal pro-B type Natriuretic Peptide (NT-proBNP) and renal function parameters in a boy with a good outcome after craniopharyngioma surgery: 1/ Central diabetes insipidus (CDI) onset immediately after the operation, hypernatremia with peak serum sodium (SNa) 158 mmol/l) caused by free water polyuria (electrolyte-free water clearance, EWC 0.104 ml/s), NT-proBNP 350 pg/ml; 2/ cerebral salt wasting (CSW) onset on day 7, hyponatremia (SNa 128 mmol/l) with hypoosmolality (measured serum osmolality, SOsm 265 mmol/kg) caused by natriuresis (sodium - daily output 605 mmol/day, fractional excretion 0.035), NT-proBNP 191 pg/ml; 3/ Polydypsia onset on day 11 caused hyponatremia (SNa 132 mmol/l), EWC 0.015, NT-proBNP 68 pg/ml. PMID- 29106786 TI - Iatrogenic perforation of hypopharynx as a cause of severe descending necrotizing mediastinitis: A case report. AB - The authors present a case report of severe descending necrotizing mediastinitis (DNM) etiologically of unrecognized traumatic endotracheal intubation with hypopharynx-esophageal junction perforation. Patient was treated inadequately for seven days in local hospital what was the cause of sepsis progression into the septic shock with multiorgan dysfunction syndrome. Patient was transferred to specialized hospital and was immediately operated in general anaesthesia - combined transcervical approach and lateral thoracotomy was used for mediastinal drainage and debridement. Combination of appropriate conventional and surgical therapy led to reversing of the unfavorable situation. PMID- 29106787 TI - Familial Pallister-Hall in adulthood. AB - Pallister Hall syndrome is autosomal dominant disorder usually diagnosed in infants and children. Current diagnostic criteria include presence of hypothalamic hamartoma, post axial polydactyly and positive family history, but the disease has variable manifestations. Herein we report Pallister Hall syndrome diagnosed in a family where both patients were adults. A 59 year old man developed seizures 4 years prior to our evaluation of him, at which time imaging showed a hypothalamic hamartoma. The seizures were controlled medically. He did well until he had visual changes after a traumatic head injury. Repeat MRI showed slight expansion of the mass with formal visual field testing demonstrating bitemporal hemianopsia. There was no evidence of pituitary dysfunction except for large urine volume. He underwent surgery to debulk the hamartoma and the visual field defects improved. There was no hypopituitarism post-operatively, and the polydyspia resolved. His 29 year old daughter also had seizures and hypothalamic hamartoma. Both patients had had polydactyly with prior surgical correction in childhood. The daughter underwent genetic testing, which revealed a previously undescribed heterozygous single base pair deletion in exon 13 of the GLI3 gene causing a frameshift mutation. Further investigation into family history revealed multiple members in previous generations with polydactyly and/or seizures. Pallister-Hall syndrome is caused by an inherited autosomal dominant or de novo mutation in GLI3 gene. This rare syndrome has not had prevalence defined, however. Generally, diagnoses are made in the pediatric population. Our report adds to the few cases detected in adulthood. PMID- 29106788 TI - Early-onset inguinal hernia as risk factor for schizophrenia or related psychosis: a nationwide register-based cohort study. AB - OBJECTIVES: In an earlier interview study, we found that more men with familial schizophrenia had undergone inguinal hernia operation, than men with sporadic schizophrenia. However, there are no other studies published specifically on inguinal hernia and schizophrenia. Therefore, the aim of this study was to carry out a Swedish register-based cohort study on the association between inguinal hernia and schizophrenia or related psychosis. METHODS: Data from the Total Population- and Medical Birth-Registers were used to create a cohort of all individuals born in Sweden 1987-1999 (n=1 406 168). The cohort individuals were linked with the In- and Out-patient Registers and followed from birth to 2015 to identify onset of schizophrenia, schizoaffective disorder and inguinal hernia. Cox proportional hazards regression models were used to assess the association between inguinal hernia before age 13 and risk of developing schizophrenia or schizoaffective disorder during a follow-up from age 13. RESULTS: Inguinal hernia before age 13 was identified in 21 095 individuals, and during the follow-up in total 1314 individuals developed schizophrenia or schizoaffective disorder. The risk of schizophrenia or schizoaffective disorder was higher among individuals with inguinal hernia before age 13, than among individuals without such a diagnosis, especially among the men [adjusted hazard ratio (95% confidence interval); all: 1.44 (1.01-2.06), p=0.0452, men: 1.46 (1.01-2.12), p=0.0460, women: 0.56 (0.14-2.27), p=0.4173]. CONCLUSIONS: This study shows that early onset inguinal hernia is associated with increased risk of developing schizophrenia or schizoaffective disorder, especially in men. Such an association may point to a common biological basis for the development of inguinal hernia and schizophrenia or related psychosis. PMID- 29106789 TI - Depression and obstructive sleep apnea. AB - OBJECTIVE: Obstructive sleep apnea (OSA), is described as intermittent interruptions or reductions in airflow which are initiated by an incomplete or complete collapse of the upper airways despite respiratory effort. When left untreated, OSA is connected with comorbid conditions, such as cardiovascular and metabolic illnesses. METHOD: The PubMed database was used to examine papers published until April 2017 using the subsequent terms: "obstructive sleep apnea" or "obstructive sleep apnoea" and "depression" in successive combination with "CPAP (continuous positive airway pressure)", "therapy", "pharmacotherapy", "psychotherapy", "cognitive behavioral therapy" or "quality of life". RESULTS: After assessment for the suitability, 126 articles were chosen. The numerous evidence of a connection between OSA and depressive symptoms, as well as depressive disorder, were found. This connection may be directly or indirectly linked due to the participation of some OSA mediators consequences such as obesity, hypertension, and the decreased quality of life. Patients with the comorbid major depression and OSA reported more severe and longer episodes of depression. Nevertheless, the information on the effect of the treatment of OSA using CPAP on the depressive symptoms was limited. Still, the current state of the art suggests that this treatment decreases the severity of the comorbid depressive symptoms. CONCLUSIONS: It is important to evaluate the symptoms of depression in the patients with OSA. On the other side, a psychiatrist should not just treat the depression, as it is also important to screen individuals at high risk of OSA when assessing patients for depressive disorder, especially those with depression resistant to treatment. PMID- 29106790 TI - Phytoestrogen alpha-zearalanol attenuate endoplasmic reticulum stress to against cultured rat hippocampal neurons apoptotic death induced by amyloid beta25-35. AB - OBJECTIVE: Our previous studies demonstrated both phytoestrogen alpha-zearalanol (alpha-ZAL) and estrogen is effective decrease Alzheimer's disease (AD)-like apoptotic neuron death, but alpha-ZAL showed significantly less side-effect on breast and endometrial tissue compared to estrogen, it suggested that alpha-ZAL can be used as a potential substitute for estrogen. However, the molecular mechanism by which alpha-ZAL prevents neuron damage remains unclear. Growing evidence suggests that endoplasmic reticulum (ER) stress plays an important role in the process of cell apoptosis in AD; in addition, our published data indicated that alpha-ZAL possessed the potential ability to stabilize ER function. We therefore hypothesized that ER-stress mechanism maybe involved in the antiapoptotic effect of alpha-ZAL in this study. METHODS: Primary rat hippocampal neurons have been cultured and subsequently followed exposed to beta-peptide fragment 25-35(Abeta25-35) with or without alpha-ZAL pre-treatment, and then western blot and flow cytometry techniques has been used to evaluate the intracellular calcium balance, ER stress and apoptotic cell death. RESULTS: The results showed that Abeta25-35 treatment for 24h induced dramatic neuronal apoptosis, accompanied by an increase in calpain2 expression, a marker of intracellular calcium overload. On the other hand, ER stress sensitive hallmarks, glucose-regulated protein 78 (GRP78), double-stranded RNA-dependent protein kinase (PKR)-like ER-resident kinase (PERK) and C/EBP homologous protein-10 (CHOP10) expressions were up-regulated after Abeta25-35 administration. Importantly, alpha-ZAL pre-treatment effectively attenuated above changes. CONCLUSION: These results demonstrated that alpha-ZAL protects cells against AD like apoptosis and the effects at least partially by attenuating severely ER stress. PMID- 29106791 TI - Possibilities of objective identification of meniscoids in joint blocks of the axial system, by MRI and Transfer Vibration through the Spine. AB - OBJECTIVE: The aim of the study was to identify the meniscoids of the cervical spine using in-vivo MRI imaging and to determine their potential role in the development of functional joint blocks of the axial system (AS). Another objective was to find out how the articular blocks affect the rheological properties of the spine by the Transfer Vibration through the Spine (TVS) method. METHOD: In this study were used methods TVS and MRI. The study was conducted on a research file of 12 subjects and was conceived as a pilot one. RESULTS: It has been shown that the MRI method, in appropriate circumstances, enables the detection of changes in the size and shape of meniscoids in-vivo. On the basis of the investigations carried out, it can be assumed that several mechanisms are involved in the formation of functional joint blocks, and are not primarily caused by the incarceration of meniscoidal tissue. Using the TVS method, it has also been found that a functional articular blockade affects the rheological properties of the axial system, specifically reducing the damping capabilities of the particular spine segment. CONCLUSION: In the follow-up studies, it will be necessary to verify the theoretical interpretations on a larger statistical set. PMID- 29106792 TI - Novel insights in ultrasound evaluation of thyroid gland in children with papillary thyroid carcinoma. AB - BACKGROUND: The coincidence of autoimmune thyroiditis (AIT) in patients with papillary thyroid carcinoma (PTC) is ranging between 10 and 58% in the general population. MATERIAL AND METHODS: In the present study retrospective ultrasound, clinical and autoimmune assessment of 24 patients diagnosed with papillary thyroid carcinoma between 2000-2016 was performed. RESULTS: The coexistence of PTC and AIT was found in 50% of patients with PTC. Patients were divided into two groups. PTC AIT (+) group involved 12 children at the mean age 14.9 years (range 11-20 years, 9 girls) and PTC AIT (-) 12 children at the mean age 12.9 years (range 7-18 years, 5 girls). Papillary thyroid microcarcinoma (PTMC) was diagnosed in 6 patients (in 5 with AIT). US characteristics of PTC was heterogenous: hypoechogenic with/without increased vascularisation, normoechogenic with halo, with/without microcalcifications. In 70% PTC AIT (+) and in all PTC AIT (-) patients ultrasound analysis revealed that the thyroid tissue of the whole gland was normoechogenic. Local metastases in lymph nodes were found in 40% of PTMC AIT (+). CONCLUSION: Lack of increased vascularization and microcalcifications and presence of''halo'in the nodule does not exclude malignancy. Due to the presence of lymph node involvement in PTMC in all children with PTC total thyroidectomy should be performed with lymph nodes verification. PMID- 29106793 TI - Body mass index and plasma leptin in psychiatric suicide attempters. AB - OBJECTIVES: To evaluate body mass index (BMI) and its correlate plasma leptin levels that have been associated with psychiatric morbidity and suicidal behaviour, in relation to clinical features in psychiatric patients after a suicide attempt. METHODS: BMI and plasma leptin were assessed in 198 patients (66 males, age range of 21 to 80 years) who were admitted to the hospital after a suicide attempt, 98 with major depressive disorder, 28 with bipolar disorder, 30 with psychosis, and 42 with personality or adjustment disorder, compared to data of 134 healthy subjects, and evaluated in relation to gender, diagnosis, mode of attempt, and pharmacological treatment before attempt. The ratio leptin/BMI was used as a measure of adipocyte leptin secreting activity. RESULTS: Drugs taken for treatment before attempt, among them atypical neuroleptics, were not associated either to BMI or to plasma leptin. The positive correlation between BMI and leptin was significant in all groups. Compared to same gender controls, significant differences were found only for female patients, namely higher BMI for patients with psychosis and patients with bipolar disorder, while leptin/BMI ratio was higher only in females with bipolar disorder. CONCLUSION: BMI and plasma leptin in psychiatric suicide attempters are elevated in certain diagnostic groups in females, not related to previous pharmacologic treatment. The lack of a control group without a history of suicide attempts does not allow the attribution of enhanced leptin secreting activity found in female bipolar attempters specifically to suicidal behavior or to the disorder as a diagnostic entity. PMID- 29106799 TI - Abstracts of the 26th Semmelweis Symposium 2017 - New Challenges in Microbiology, 9-10 November, 2017 Budapest, Hungary. PMID- 29106794 TI - Sexual arousal by dominance and submission in relation to increased reproductive success in the general population. AB - OBJECTIVE: Sexual arousal by dominance and submissiveness was long considered a mental disorder. The origin of this sexual preference has not been clearly explained. This study scrutinizes the hypothesis that sexual arousal by hierarchical disparity is a manifestation of mating strategy by comparing number of offspring and self-reported attractiveness of the study participants. METHODS: Our data were obtained from the general population via e-mail questionnaire (n=673, age 25-34 years and 35-44 years). RESULTS: Sexually dominant men aged 35 44 years had more biological male children. Both the sexually dominant men aged 35-44 years and sexually submissive women aged 35-44 years perceived themselves as being more attractive. THE MAIN FINDINGS: Here we show that sexual arousal by dominance and submissiveness confers an increased capacity to pass on genes in the general population. CONCLUSION: We suggest that sexual arousal by dominance is likely to be the means by which the mating strategy is accomplished. Sexual arousal by dominance and submissiveness is a manifestation of mating strategy because such a behaviour results in an increased reproductive success and thus may lead to the preferential selection of individuals who prefer sexual arousal by hierarchical disparity. This fact explains why the high number of people is excited by sexual fantasies and activities connected to hierarchical disparity. This finding might open up novel insights into some reproductive medicine issues, as well as into such field as partnership therapy and partner violence. PMID- 29106802 TI - Abstracts of the Annual Meeting of the Hungarian Society for Microbiology, October 19-21, 2016, Keszthely, Hungary. PMID- 29106800 TI - The contribution of the glenoid labrum to glenohumeral stability under physiological joint loading using finite element analysis. AB - The labrum contributes to passive glenohumeral joint stability. Cadaveric studies have demonstrated that this has position and load dependency, which has not been quantified under physiological loads. This study aims to validate subject specific finite element (FE) models against in vitro measurements of joint stability and to utilise the FE models to predict joint stability under physiological loads. The predicted stability values were within +/- one standard deviation of experimental data and the FE models showed a reduction in stability of 10-15% with high, physiological, loads. The developed regression equations provide the first representation of passive glenohumeral stability and will aid surgical decision-making. PMID- 29106803 TI - Abstracts Of the 5th Central European Forum for Microbiology, October 18-20, 2017, Keszthely, Hungary. PMID- 29106801 TI - Contagious Anxiety: Anxious European Americans Can Transmit Their Physiological Reactivity to African Americans. AB - During interracial encounters, well-intentioned European Americans sometimes engage in subtle displays of anxiety, which can be interpreted as signs of racial bias by African American partners. In the present research, same-race and cross race stranger dyads ( N = 123) engaged in getting-acquainted tasks, during which measures of sympathetic nervous system responses (preejection period, PEP) and heart rate variability were continuously collected. PEP scores showed that African American partners had stronger physiological linkage to European American partners who evidenced greater anxiety-greater cortisol reactivity, behavioral tension, and self-reported discomfort-which suggests greater physiological responsiveness to momentary changes in partners' affective states when those partners were anxious. European Americans showed physiological linkage to African American and European American partners, but linkage did not vary as a function of their partner's anxiety. Using physiological linkage offers a novel approach to understanding how affective responses unfold during dynamic intergroup interactions. PMID- 29106804 TI - Targeting RAGE Signaling in Inflammatory Disease. AB - The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor implicated in diverse chronic inflammatory states. RAGE binds and mediates the cellular response to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA. RAGE can also act as an innate immune sensor of microbial pathogen-associated molecular pattern molecules (PAMPs) including bacterial endotoxin, respiratory viruses, and microbial DNA. RAGE is expressed at low levels under normal physiology, but it is highly upregulated under chronic inflammation because of the accumulation of various RAGE ligands. Blocking RAGE signaling in cell and animal models has revealed that targeting RAGE impairs inflammation and progression of diabetic vascular complications, cardiovascular disease (CVD), and cancer progression and metastasis. The clinical relevance of RAGE in inflammatory disease is being demonstrated in emerging clinical trials of novel small-molecule RAGE inhibitors. PMID- 29106805 TI - Innate Immunity and Neurodegeneration. AB - The innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection and is involved in tissue repair, wound healing, and clearance of apoptotic cells and cellular debris. Excessive or nonresolving innate immune activation can lead to systemic or local inflammatory complications and cause or contribute to the development of inflammatory diseases. In the brain, microglia represent the key innate immune cells, which are involved in brain development, brain maturation, and homeostasis. Impaired microglial function, either through aberrant activation or decreased functionality, can occur during aging and during neurodegeneration, and the resulting inflammation is thought to contribute to neurodegenerative diseases. This review highlights recent advances in our understanding of the influence of innate immunity on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. PMID- 29106806 TI - Strengthening Causal Estimates for Links Between Spanking and Children's Externalizing Behavior Problems. AB - Establishing causal links when experiments are not feasible is an important challenge for psychology researchers. The question of whether parents' spanking causes children's externalizing behavior problems poses such a challenge because randomized experiments of spanking are unethical, and correlational studies cannot rule out potential selection factors. This study used propensity score matching based on the lifetime prevalence and recent incidence of spanking in a large and nationally representative sample ( N = 12,112) as well as lagged dependent variables to get as close to causal estimates outside an experiment as possible. Whether children were spanked at the age of 5 years predicted increases in externalizing behavior problems by ages 6 and 8, even after the groups based on spanking prevalence or incidence were matched on a range of sociodemographic, family, and cultural characteristics and children's initial behavior problems. These statistically rigorous methods yield the conclusion that spanking predicts a deterioration of children's externalizing behavior over time. PMID- 29106807 TI - Computer aided design of architecture of degradable tissue engineering scaffolds. AB - One important factor affecting the process of tissue regeneration is scaffold stiffness loss, which should be properly balanced with the rate of tissue regeneration. The aim of the research reported here was to develop a computer tool for designing the architecture of biodegradable scaffolds fabricated by melt dissolution deposition systems (e.g. Fused Deposition Modeling) to provide the required scaffold stiffness at each stage of degradation/regeneration. The original idea presented in the paper is that the stiffness of a tissue engineering scaffold can be controlled during degradation by means of a proper selection of the diameter of the constituent fibers and the distances between them. This idea is based on the size-effect on degradation of aliphatic polyesters. The presented computer tool combines a genetic algorithm and a diffusion-reaction model of polymer hydrolytic degradation. In particular, we show how to design the architecture of scaffolds made of poly(DL-lactide-co glycolide) with the required Young's modulus change during hydrolytic degradation. PMID- 29106808 TI - A novel metadata management model to capture consent for record linkage in longitudinal research studies. AB - BACKGROUND: Informed consent is an important feature of longitudinal research studies as it enables the linking of the baseline participant information with administrative data. The lack of standardized models to capture consent elements can lead to substantial challenges. A structured approach to capturing consent related metadata can address these. OBJECTIVES: a) Explore the state-of-the-art for recording consent; b) Identify key elements of consent required for record linkage; and c) Create and evaluate a novel metadata management model to capture consent-related metadata. METHODS: The main methodological components of our work were: a) a systematic literature review and qualitative analysis of consent forms; b) the development and evaluation of a novel metadata model. DISCUSSION: We qualitatively analyzed 61 manuscripts and 30 consent forms. We extracted data elements related to obtaining consent for linkage. We created a novel metadata management model for consent and evaluated it by comparison with the existing standards and by iteratively applying it to case studies. CONCLUSION: The developed model can facilitate the standardized recording of consent for linkage in longitudinal research studies and enable the linkage of external participant data. Furthermore, it can provide a structured way of recording consent-related metadata and facilitate the harmonization and streamlining of processes. PMID- 29106809 TI - An Active Approach to Colloidal Self-Assembly. AB - In this review, we discuss recent advances in the self-assembly of self-propelled colloidal particles and highlight some of the most exciting results in this field, with a specific focus on dry active matter. We explore this phenomenology through the lens of the complexity of the colloidal building blocks. We begin by considering the behavior of isotropic spherical particles. We then discuss the case of amphiphilic and dipolar Janus particles. Finally, we show how the geometry of the colloids and/or the directionality of their interactions can be used to control the physical properties of the assembled active aggregates, and we suggest possible strategies for how to exploit activity as a tunable driving force for self-assembly. The unique properties of active colloids lend promise to the design of the next generation of functional, environment-sensing microstructures able to perform specific tasks in an autonomous and targeted manner. PMID- 29106810 TI - Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline. AB - Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence based guideline on treatment with stereotactic body radiotherapy (SBRT) for patients with early-stage non-small-cell lung cancer. ASCO has a policy and set of procedures for endorsing and/or adapting clinical practice guidelines that have been developed by other professional organizations. Methods The ASTRO Evidence-Based Guideline for Stereotactic Body Radiotherapy for Early-Stage Non Small-Cell Lung Cancer was reviewed for developmental rigor by methodologists. An ASCO Expert Panel updated the literature search and reviewed the guideline content and recommendations. Results The ASCO Expert Panel determined that the recommendations from the ASTRO guideline, published in 2017, are clear, thorough, and based on the most relevant scientific evidence. ASCO statements and minor modifications were added to enhance the applicability of the ASTRO guideline for the broader ASCO audience. Recommendations For standard operative risk patients with stage I NSCLC, SBRT is not recommended outside of a clinical trial. Lobectomy with systematic lymph node evaluation remains the recommended treatment, although a sublobar resection may be considered in select clinical scenarios. Recommendations are provided regarding the use of SBRT in high operative risk patients and for inoperative patients, including in challenging scenarios where tumors are: centrally located, > 5 cm in diameter, lacking tissue diagnosis, synchronous primary or multifocal, second primary after pneumonectomy, proximal to or involved with mediastinal structures, abutting the chest wall, or recurring after previous treatment. Qualifying statements are included to provide further guidance for implementation, and the importance of a discussion of treatment options among members of the multidisciplinary cancer care team is emphasized. Additional information is available at: www.asco.org/thoracic-cancer guidelines and www.asco.org/guidelineswiki . PMID- 29106811 TI - Epidemiology and Impact on Performance of Lower Extremity Stress Injuries in Professional Basketball Players. AB - BACKGROUND: Professional basketball players in the National Basketball Association (NBA) subject their lower extremities to significant repetitive loading during both regular-season and off-season training. Little is known about the incidence of lower extremity bony stress injuries and their impact on return to play and performance in these athletes. HYPOTHESIS: Stress injuries of the lower extremity will have significant impact on performance. STUDY DESIGN: Case series. LEVEL OF EVIDENCE: Level 4. METHODS: All bony stress injuries from 2005 to 2015 were identified from the NBA. Number of games missed due to injury and performance statistics were collected from 2 years prior to injury to 2 years after the injury. A linear regression analysis was performed to determine the impact of injury for players who returned to sport. RESULTS: A total of 76 lower extremity bony stress injuries involving 75 NBA players (mean age, 25.4 +/- 4.1 years) were identified. Fifty-five percent (42/76) involved the foot, and most injuries occurred during the regular season (82.9%, 63/76), with half occurring within the first 6 weeks. Among players who sustained a fifth metatarsal stress fracture, 42.9% were unable to return to professional play. Players who sustained stress injuries had reduced play performance, specifically related to number of games played ( P = 0.014) and number of steals per game ( P = 0.004). Players who had surgery had significantly better performance at 2 years than those who were managed nonoperatively, independent of the type of injury (beta = 4.561; 95% CI, 1.255-7.868). CONCLUSION: Lower extremity bony stress injuries may significantly affect both short- and long-term player performance and career length. Stress injuries result in decreased player performance, and surgical intervention results in improved performance metrics compared with those treated using conservative methods. CLINICAL RELEVANCE: Stress injuries result in decreased player performance, and surgical intervention results in improved performance metrics. PMID- 29106812 TI - Whey protein hydrolysate supplementation accelerates recovery from exercise induced muscle damage in females. AB - A number of different forms of protein and their analogues have been investigated for their efficacy in ameliorating exercise-induced muscle damage (EIMD) and recovery. Preliminary data regarding whey protein hydrolysate (WPH) supplementation are promising. However, its efficacy beyond acute eccentric/resistance exercise bouts or longer term training programmes are limited and all investigations have been conducted in male or mixed-sex groups. This study sought to elucidate whether the benefits of WPH previously reported can be demonstrated in females following repeated-sprint exercise. Twenty physically active females were assigned to consume 2 doses of 70 mL WPH or isoenergetic carbohydrate (CHO) for 4 days post-EIMD. Measures of muscle soreness, limb girth, flexibility, muscle function, and creatine kinase were collected before, immediately after, and 24, 48, and 72 h postexercise. Time effects were observed for all variables (p < 0.05) except limb girth, which is indicative of EIMD. Flexibility improved beyond baseline measures following WPH by 72 h, but had failed to recover in the CHO group (p = 0.011). Reactive strength index was higher throughout recovery in the WPH group compared with CHO (p = 0.016). Reductions in creatine kinase were greater following WPH compared with CHO at 48 h post-EIMD (p = 0.031). The findings suggest that 4-day supplementation of WPH is beneficial for reducing symptoms of EIMD and improving recovery of muscle function in physically active females. PMID- 29106814 TI - A multi-ingredient nutritional supplement enhances exercise training-related reductions in markers of systemic inflammation in healthy older men. AB - We evaluated whether twice-daily consumption of a multi-ingredient nutritional supplement (SUPP) would reduce systemic inflammatory markers following 6 weeks of supplementation alone (phase 1), and the subsequent addition of 12 weeks of exercise training (phase 2) in healthy older men, in comparison with a carbohydrate-based control (CON). Tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) concentrations were progressively reduced (P-time < 0.05) in the SUPP group. No change in TNF-alpha or IL-6 concentrations was observed in the CON group. PMID- 29106815 TI - HIGH-DOSE GLUCOCORTICOID TREATMENT DOES NOT INDUCE SEVERE HYPERGLYCEMIA IN YOUNG PATIENTS WITH AUTOIMMUNE DISEASES BY CGMS. AB - OBJECTIVE: High-dose glucocorticoids (HDG) are used in the treatment of autoimmune diseases. Glucocorticoids-induced hyperglycemia (GIH) is often described in elderly patients. In young patients with autoimmune diseases, however, the risk for GIH has not been well characterized. METHODS: We recruited 24 inpatients (median age, 32 years; interquartile range, 25-42) with exacerbations of autoimmune diseases, receiving 1 to 2 mg/kg/day prednisone or equivalent methylprednisone. Fourteen subjects were naive to glucocorticoids (group 1) and 10 subjects were on glucocorticoid maintenance (<=15 mg/day prednisone at least 3 months) (group 2) prior to HDG. All subjects were monitored by continuous glucose monitoring system (CGMS) for 3 days. RESULTS: GIH developed in 21 (91%) subjects, 11/13 in group 1 and 10/10 in group 2. The main peak of glucose excursion (128.7 +/- 6.4 mg/dL, group 1; 143.9 +/- 10.0 mg/dL, group 2) occurred at 2 to 3 pm. Another peak occurred before sleep. Two-hour mean postprandial glucose levels were normal in both groups: breakfast, 105.0 +/- 28.4 versus 125.6 +/- 24.4 mg/dL, P = .065; lunch, 115.7 +/- 21.1 versus 135.9 +/- 29.0 mg/dL, P = .082; dinner, 122.8 +/- 18.5 versus 137.8 +/- 26.4 mg/dL, P = .144 in groups 1 and 2, respectively. There was a positive association between pretreatment hemoglobin A1C and peak glucose levels ( P<.0001). Notably, 35% of our subjects experienced early morning hypoglycemia (65.2 +/- 2.8 mg/dL). CONCLUSION: In hospitalized young patients with auto-immune diseases, CGMS data revealed that short-term consistent HDG treatment induced mild hyperglycemia, peaking in the early afternoon and before sleep. Early morning hypoglycemia was found in 35%. ABBREVIATIONS: A1C = hemoglobin A1C; AUC = the area under the curve; BG = blood glucose; BMI = body mass index; CGMS = continuous glucose monitoring system; DM = diabetes mellitus; FBG = fasting blood glucose; GA = glycated albumin; GCs = glucocorticoids; GIH = glucocorticoids-induced hyperglycemia; HDG = high-dose glucocorticoids; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; IG = interstitial glucose; IQR = interquartile range; PUMCH = Peking Union Medical College Hospital; SLE = systemic lupus erythematosus. PMID- 29106816 TI - INSULIN GLARGINE 300 U/ML IS ASSOCIATED WITH LESS WEIGHT GAIN WHILE MAINTAINING GLYCEMIC CONTROL AND LOW RISK OF HYPOGLYCEMIA COMPARED WITH INSULIN GLARGINE 100 U/ML IN AN AGING POPULATION WITH TYPE 2 DIABETES. AB - OBJECTIVE: Assess efficacy, hypoglycemia, and weight gain in patients with type 2 diabetes (T2D) treated with insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla 100) across different age groups. METHODS: Pooled data were generated for patients randomized to Gla-300 or Gla-100 in the EDITION 2 (NCT01499095) and 3 (NCT01676220) studies. In 4 age groups (<55, >=55 to <60, >=60 to <65, >=65 years), glycated hemoglobin A1C (A1C), percentage of patients reaching A1C <7.5% (58 mmol/mol), weight change, confirmed hypoglycemia (blood glucose <=70 mg/dL), and/or severe hypoglycemia (events requiring third-party assistance) were analyzed with descriptive statistics and logistic, binomial, and analysis of covariance regression modeling. RESULTS: A1C reductions from baseline and proportions of patients at target were similar for Gla-300 and Gla-100 across all age groups at 6 and 12 months, but hypoglycemia incidence and event rate were lower with Gla-300 at 6 (both P<.001) and 12 months ( P<.001 and P = .005, respectively). Patients on Gla-300 gained less weight than those on Gla-100 at 6 ( P = .027) and 12 months ( P = .021). Changes in weight and daily weight adjusted insulin dose decreased with increasing age at 6 ( P<.001 and P = .017, respectively) and 12 months ( P<.001 and P = .011, respectively). CONCLUSION: Older patients with T2D may benefit from treatment with Gla-300, which is associated with a lower hypoglycemia rate and less weight gain with similar efficacy compared with Gla-100. ABBREVIATIONS: A1C = glycated hemoglobin A1C BMI = body mass index Gla-100 = insulin glargine 100 U/mL Gla-300 = insulin glargine 300 U/mL OAD = oral antidiabetes drug T2D = type 2 diabetes. PMID- 29106818 TI - VISUAL VIGNETTE. PMID- 29106817 TI - APPLICATION OF THE AACE/ACE ADVANCED FRAMEWORK FOR THE DIAGNOSIS OF OBESITY AND CARDIOMETABOLIC DISEASE STAGING IN A GENERAL POPULATION FROM 3 REGIONS OF VENEZUELA: THE VEMSOLS STUDY RESULTS. AB - OBJECTIVE: To determine the prevalence of obesity according to the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) framework based on a complications-centric model with further application of the Cardiometabolic Disease Staging (CMDS) system in a Venezuelan population. METHODS: A total of 1,320 adults were randomly selected from 3 regions. The AACE/ACE framework definitions were as follows: overweight, body mass index (BMI) 25 to 29.9 kg/m2 and no obesity-related complications (ORC); obesity stage 0, BMI >=30 and no ORC; stage 1, BMI >=25 and 1 or more mild-to moderate ORC; and stage 2, BMI >=25 and 1 or more severe ORC. CMDS definitions were as follows: stage 0, no metabolic syndrome (MS) components; stage 1, 1 to 2 MS components without impaired fasting glucose (IFG); stage 2, IFG or >=3 MS components but without IFG; stage 3, IFG and MS; and stage 4, type 2 diabetes (T2D) or cardiovascular disease. RESULTS: The mean age was 44.8 +/- 0.4 years, and 68.5% were female. The prevalence of obesity according to the AACE/ACE framework was 63.1%: overweight 3.0% (95% confidence interval [CI]: 2.1-3.9); obesity stage 0: 0.1% (0.07-0.27); obesity stage 1: 26.6% (24.2-29.0); and obesity stage 2: 36.4% (33.8-39.0). Most subjects with a BMI <25 were CMDS 0 or 1. In those with BMI >= 25, only 4.6% were CMDS 0. The prevalence of obesity according to the World Health Organization (WHO, BMI >=30) was 29.3% (24.7-33.7). CONCLUSION: In a general population study, applying the AACE/ACE framework for obesity and CMDS increased the detection of ORC and therefore higher risk subjects compared to classic anthropometric measurements. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; BMI = body mass index; CMDS = Cardiometabolic Disease Staging; DALY = disability-adjusted life years; LA = Latin America; MS = metabolic syndrome; ORC = obesity-related complications; WC = waist circumference; WHO = World Health Organization. PMID- 29106819 TI - Catfish Biology and Farming. AB - This article summarizes the biology and culture of ictalurid catfish, an important commercial, aquaculture, and sport fish family in the United States. The history of the propagation as well as spawning of common catfish species in this family is reviewed, with special emphasis on channel catfish and its hybridization with blue catfish. The importance of the channel catfish female*blue catfish male hybrid, including current and future methods of hybrid catfish production, and the potential role it plays in the recovery of the US catfish industry are discussed. Recent advances in catfish culture elements, including environment, management, nutrition, feeding, disease control, culture systems, genetic improvement programs, transgenics, and the application of genome based approaches in catfish production and welfare, are reviewed. The current status, needs, and future projections are discussed, as well as genetically modified organism developments that are changing the future. PMID- 29106820 TI - Development and Function of the Mucosal Immune System in the Upper Respiratory Tract of Neonatal Calves. AB - Respiratory infections remain the second most common cause of clinical disease and mortality in newborn calves, which has led to increased interest in using vaccines early in life to mitigate this risk. Intranasal vaccination of neonatal calves can be an effective strategy to circumvent vaccine interference by maternal antibody, but this raises questions regarding onset of immune competence in the upper respiratory tract (URT) following birth. Little is known, however, about the development and function of mucosa-associated lymphoid tissue (MALT) in the URT of newborn calves and what factors, including the commensal microbiome, contribute to this early development. We review the structure, development, and function of MALT in the bovine URT during the first six weeks of life and identify knowledge gaps regarding this early developmental time. This information is critical when designing vaccination programs for young calves, especially when targeting respiratory pathogens that may reside within the commensal microbiome. PMID- 29106821 TI - Detection Rates of Ductal Carcinoma in Situ with Biennial Digital Mammography Screening: Radiologic Findings Support Pathologic Model of Tumor Progression. AB - Purpose To compare detection rates of ductal carcinoma in situ (DCIS), classified according to nuclear grade, between the prevalence round (baseline screening) and two subsequent screening rounds of a population-based digital mammography screening program, to assess differences over time. Materials and Methods The cancer registry provided data for 1970 graded pure DCIS cases from 16 screening regions of the prevalence round (baseline screening, from 2005 to 2008), first subsequent round, and second subsequent round; the interval between all screening rounds was 22-30 months. Age-adjusted logistic regression analysis was performed to compare the grade-specific detection rates between the prevalence round (reference) and subsequent screening rounds. Results Over all screening rounds, cancer detection rates were lowest for low-grade DCIS (range, 0.11 [58 of 508 817 patients] to 0.25 [178 of 713 867 patients] per 1000 women screened) and highest for high-grade DCIS (range, 0.53[271 of 508 817 patients] to 0.59 [237 of 398 944 patients] per 1000 women screened). Detection rates for low-grade DCIS were significantly lower in the first (odds ratio [OR] = 0.45, P < .001) and second (OR = 0.57, P < .001) subsequent screening rounds compared with that in the prevalence round; the relative reduction of detection rates of intermediate-grade DCIS was less pronounced (OR = 0.79, P = .006 and OR = 0.76, P = .003, respectively). Conversely, the detection rate of high-grade DCIS remained at the high level found in the prevalence screening (OR = 0.89, P = .143 and OR = 0.97, P = .700, respectively). Conclusion The findings demonstrate persistently high detection rates of high-grade DCIS in two consecutive subsequent screening rounds compared with the prevalence round; conversely, rates of low-grade DCIS and, less markedly, intermediate-grade DCIS decreased in subsequent rounds. Grade-related changes of DCIS detection are suggestive of distinct dynamics of lesion progression. (c) RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on November 10, 2017. PMID- 29106823 TI - Low grade mucoepidermoid carcinoma of a minor salivary gland of the tongue in a paediatric patient. PMID- 29106824 TI - Inferring Relevant Cell Types for Complex Traits by Using Single-Cell Gene Expression. AB - Previous studies have prioritized trait-relevant cell types by looking for an enrichment of genome-wide association study (GWAS) signal within functional regions. However, these studies are limited in cell resolution by the lack of functional annotations from difficult-to-characterize or rare cell populations. Measurement of single-cell gene expression has become a popular method for characterizing novel cell types, and yet limited work has linked single-cell RNA sequencing (RNA-seq) to phenotypes of interest. To address this deficiency, we present RolyPoly, a regression-based polygenic model that can prioritize trait relevant cell types and genes from GWAS summary statistics and gene expression data. RolyPoly is designed to use expression data from either bulk tissue or single-cell RNA-seq. In this study, we demonstrated RolyPoly's accuracy through simulation and validated previously known tissue-trait associations. We discovered a significant association between microglia and late-onset Alzheimer disease and an association between schizophrenia and oligodendrocytes and replicating fetal cortical cells. Additionally, RolyPoly computes a trait relevance score for each gene to reflect the importance of expression specific to a cell type. We found that differentially expressed genes in the prefrontal cortex of individuals with Alzheimer disease were significantly enriched with genes ranked highly by RolyPoly gene scores. Overall, our method represents a powerful framework for understanding the effect of common variants on cell types contributing to complex traits. PMID- 29106826 TI - Operating at night does not increase the risk of intraoperative adverse events. AB - BACKGROUND: We sought to investigate the association between nighttime (NT) operating and the occurrence of intraoperative adverse events (iAEs). STUDY DESIGN: Our 2007-2012 institutional ACS-NSQIP and administrative databases were screened for iAEs using the ICD-9-CM-based Patient Safety Indicator "accidental puncture or laceration". Procedures were defined as AM (06.00-14.00 h), PM (14.00 22.00 h), or NT (22.00-06.00 h). Univariate and multivariable analyses were performed to investigate the association between PM and NT operating and the occurrence of iAEs. RESULTS: 9136 surgical procedures were included: 7445 AM, 1303 PM, 388 NT. iAEs occurred in 183 procedures. NT patients were younger and less comorbid, but sicker, and with less complex surgeries. There was no correlation between PM or NT operations and iAEs (multivariable analysis [reference: AM operations]: OR = 0.66 [95% CI = 0.40-1.12], P = 0.123; OR = 1.22 [95% CI = 0.51-2.93], P = 0.659, respectively). CONCLUSION: Operating at night does increase the risk of iAEs. PMID- 29106827 TI - High tech-low cost, the growing place of WII in rehabilitation. PMID- 29106825 TI - Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype. AB - The Rab GTPase family comprises ~70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization. PMID- 29106828 TI - Expanding the Scope of Single- and Double-Noncanonical Amino Acid Mutagenesis in Mammalian Cells Using Orthogonal Polyspecific Leucyl-tRNA Synthetases. AB - Engineered aminoacyl-tRNA synthetase/tRNA pairs that enable site-specific incorporation of noncanonical amino acids (ncAAs) into proteins in living cells have emerged as powerful tools in chemical biology. The Escherichia coli-derived leucyl-tRNA synthetase (EcLeuRS)/tRNA pair is a promising candidate for ncAA mutagenesis in mammalian cells, but it has been engineered to charge only a limited set of ncAAs so far. Here we show that two highly polyspecific EcLeuRS mutants can efficiently charge a large array of useful ncAAs into proteins expressed in mammalian cells, while discriminating against the 20 canonical amino acids. When combined with an opal-suppressing pyrrolysyl pair, these EcLeuRS variants further enabled site-specific incorporation of different combinations of two distinct ncAAs into proteins expressed in mammalian cells. PMID- 29106829 TI - [Sudden cardiac death and coronary thrombus]. AB - Out-of-hospital cardiac arrest is most often due to an acute coronary artery occlusion. The cause of coronary thrombosis in cardiac arrest is debated. Plaque erosion could be a trigger leading to immediate thrombus formation followed by ventricular fibrillation or rapid ventricular tachycardia. Coronary artery spasm is frequent: spasm provocation tests should be performed in survivors with normal coronary arteries. Use of drugs such as cocaine can lead to sudden death and blood sampling at arrival is recommended in survivors of out-of-hospital cardiac arrest. Delivery of immediate and effective basic life support remains the most important predictive factor for survival in out-of-hospital cardiac arrest. PMID- 29106830 TI - [Contribution of intracoronary imaging in acute coronary syndrome]. AB - Acute coronary syndrome (ACS) remains a major cause of mortality and morbidity in the world, although it has considerably decreased through technical and pharmacological advances. The physiopathological approach of the ACS has progressed considerably in recent years thanks to the anatomopathological work and the data of the endocoronary imaging, in particular of the endovascular ultrasound (IVUS). Plaque rupture is the most common cause of ACS, however OCT (optical coherence tomography) studies have shown that surface plaque erosion was more common than thought. The use of OCT in the ACS may prove to be a valuable diagnostic aid: study of the culpable lesion, spontaneous coronary dissection or intramural spontaneous hematoma, stent thrombosis; from a therapeutic point of view: reduction of the risk of stent malapposition, additional technique, delayed stenting, implantation of a bioresorbable stent, medical treatment of ACS without stenting. Endocoronary imaging, especially OCT, will of course never be systematic as treatment of ACS, but providing excellent value for both diagnosis and treatment, it must be an integral part of the therapeutic arsenal available in cathlab. PMID- 29106831 TI - [Transcatheter aortic valve thrombosis]. AB - GOALS: Transcatheter aortic valve or leaflets thrombosis are mainly misapprehended. It negatively impacts the long-term efficiency of such prosthesis. Moreover, its incidence is presumably higher than previously described. EPIDEMIOLOGY: Recently reported subclinical leaflet thrombosis, occurring between first to third months after implantation, is about 10to 15%. All prosthesis are concerned by potential thrombosis. DIAGNOSIS: Transcatheter aortic valve thrombosis is usually detected on the basis of increased transvalvular pressure gradients or symptoms at routine follow-up. Main causes of post-TAVI thrombosis are: elderly patients, incomplete TAVI expansion, incomplete TAVI apposition to the aortic wall, areas of diminished blood flow and stagnation around the prosthesis. Main risk-factors of thrombosis are: large valves, patients with ejection fraction lower than 35%, valve-in-valve implantation, males, patients with large sinus of Valsalva, patients without anticoagulants. TREATMENT: Post-TAVI anti thrombotic regimen remains empirical. It is based on aspirin alone or dual antiplatelet therapy for 1-6months, followed by aspirin for life. Symptomatic patients with thrombus-based valve dysfunction are to be treated by oral anticoagulation (i.e., VKA or new oral anticoagulants NOAC). This treatment allows the restoration of normal leaflet motion in patients with a median time of 14 days. PMID- 29106832 TI - [Diabetes Mellitus, a prothrombotic disease]. AB - In patients with acute atherothrombotic disease, diabetes or glucose intolerance is frequently found. Indeed, the number of people with diabetes in the world continues to increase and is expected to reach more than 500 million people by 2035. Diabetes is a pathology commonly associated with both microvascular and macrovascular complications. Although the mortality of coronary artery disease has decreased significantly over the past 20 years, mortality in patients with type 2 diabetes has changed little and atherothrombotic events remain the leading cause of death in diabetic patients. Although our understanding of vascular pathology has greatly evolved in recent years, the cellular and molecular mechanisms linking thrombogenicity and diabetes remain incompletely understood. Type 1 and type 2 diabetes are prothrombotic pathologies. This prothrombotic state is due to both hyperglycemia and chronic hyperinsulinism. Among the different agonists involved in the increased thrombogenicity of diabetic patients, abnormalities can be found in all phases of coagulation. Increased procoagulant factors and tissue factor associated with impaired fibrinolysis, platelet hyperreactivity, endothelial dysfunction, leukocyte activation, low grade inflammation, and microparticle involvement, they all play a role in the establishment of this prothrombotic condition. This review sought to provide an update on the prothrombotic nature of diabetes and its consequences in therapeutics. PMID- 29106833 TI - [Coronary ectasias and thrombosis]. AB - Ectasias and coronary aneurysms are uncommon coronary artery diseases, can coexist and are poorly known. Their principal etiology in adults is coronary atherosclerosis. It has been suggested that these abnormalities would have poor prognosis and that slow flow could lead to in situ thrombosis and distal embolisation. However, ectasias and aneurysms are most often associated with coronary stenosis. We report a series of 47 cases of ectasias and coronary aneurysms with evaluation of the clinical and angiographic characteristics, the therapeutic choices and we review the literature concerning these lesions. In situ thrombosis does not seem to be the usual pathophysiological mechanism. We retain that this is a particular form of coronary atherosclerosis in this population and present technical problems in case of revascularization with an predominant indication of medical treatment (57.4 % of the cases), but rarely the introduction of anticoagulants (4.25 % of the cases), except in acute coronary syndromes where revascularization is most common (70.6 % of cases) as is usually expected in the general population. The complex angiographic presentation of these lesions is probably an explanation for the low numbers of revascularizations performed. PMID- 29106834 TI - [Left atrial appendage closure and embolic events]. AB - Atrial fibrillation (AF) is frequent and responsible for embolic events. Currently, the gold standard to prevent such embolic events is anticoagulant therapy with vitamin K antagonist (VKA) or direct oral anticoagulant in nonvalvular AF. Recently, left atrial appendage closure was proposed as an alternative to anticoagulant inpatient with high embolic risk and contraindication to anticoagulant therapy. Data from randomized trials were consistent with a non-inferiority of left atrial appendage closure in comparison to VKA in terms of stroke and cardiovascular death. However, despite improvements in procedure results and complications reduction, this invasive strategy has to be performed with optimal security as this strategy is a preventive treatment in high-risk patients. These improvements may allow an extension of indications of left atrial appendage closure to lower profile risk patients as an alternative to anticoagulant. Indeed, anticoagulant is a risky therapy with hemorrhagic events and observance is a real issue in an asymptomatic population. Finally, there is a lack of data in recent literature comparing left atrial appendage closure to direct oral anticoagulant, widely used in daily practice, as well as cost effectiveness of this procedure in comparison to anticoagulant. PMID- 29106835 TI - Impact of Mitral Annular Calcium on Outcomes after Transcatheter Aortic Valve Implantation. AB - A high prevalence of mitral annular calcium (MAC) is expected in patients undergoing transcatheter aortic valve implantation (TAVI); however, data regarding the prevalence of MAC and impact on risk of cardiovascular events are lacking. To determine the prevalence of MAC and its association with clinical outcomes in patients undergoing TAVI, we retrospectively analyzed 424 patients who underwent transfemoral TAVI from 2007 to 2015 and whose preoperative computed tomography images were available for assessment of MAC. Severe circumferential MAC (SC-MAC) was defined as calcification involving at least the whole posterior annulus alone or with the attachment of the anterior leaflet. Clinical outcomes were examined according to Valve Academic Research Consortium-2 criteria up to 2 years. SC-MAC was found in 17.7% of patients. Patients with SC-MAC were more likely to be female, with a higher prevalence of atrial fibrillation and peripheral artery disease. There were no differences between the groups regarding age, functional class, prevalence of diabetes, kidney disease, and operative risk. Female gender and peripheral artery disease were independent predictors of SC-MAC. SC-MAC did not appear to be associated with periprocedural and 30-day outcomes. At 2 years' follow-up, patients with SC-MAC had significantly higher cardiovascular and all-cause mortality rates. SC-MAC was an independent predictor of cardiovascular mortality during follow-up. In conclusion, SC-MAC is a frequent finding in the TAVI population and appears to be an independent predictor of cardiovascular mortality at 2 years' follow-up. PMID- 29106836 TI - Impact of Transient or Persistent Contrast-induced Nephropathy on Long-term Mortality After Elective Percutaneous Coronary Intervention. AB - Contrast-induced nephropathy (CIN) is associated with increased long-term mortality. However, it is still controversial whether CIN is the cause of increased mortality or merely a marker of high-risk patients. The current study population included 5,516 patients who underwent their first elective percutaneous coronary intervention (PCI) in the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry cohort-2. CIN was defined as an elevation in the peak serum creatinine (SCr) of >=0.5 mg/dl from the baseline within 5 days after PCI. CIN, seen in 218 patients (4.0%), was independently associated with an increased long-term mortality risk (hazard ratio [HR] 1.43, 95% confidence interval [CI],1.11 to 1.83; p = 0.005). SCr data at 1 year (180 to 550 days) after PCI were available in 3,986 patients, who were subdivided into persistent CIN (follow-up SCr elevation >=0.5 mg/dl: n = 50 [1.3%]), transient CIN (follow-up SCr elevation <0.5 mg/dl: n = 90 [2.3%]), and non-CIN (n = 3,846 [96.5%]). In the landmark analysis at 1 year after PCI, 524 patients (13.1%) died during a median follow-up of 1,521 days. After adjustment for the 37 confounders, persistent CIN, but not transient CIN, was significantly correlated with a higher long-term mortality risk compared with non-CIN (HR 1.84, 95% CI 1.12 to 3.03; p = 0.02, and HR 1.11, 95% CI 0.71 to 1.76; p = 0.6, respectively). In conclusion, only persistent CIN was independently associated with increased long-term mortality. PMID- 29106838 TI - Our Experience With Strain Elastography in 2 Cases of Suspected Malignant Subcutaneous Lesions. PMID- 29106837 TI - Evaluation of Industrial Compensation to Cardiologists in 2015. AB - The categorization and characterization of pharmaceutical and device manufacturers or group purchasing organization payments to clinicians is an important step toward assessing conflicts of interest and the potential impact of these payments on practice patterns. Payments have not previously been compared among the subspecialties of cardiology. This is a retrospective analysis of the Open Payments database, including all installments and payments made to doctors in the calendar year 2015 by pharmaceutical and device manufacturers or group purchasing organization. Total payments to individual physicians were then aggregated based on specialty, geographic region, and payment type. The Gini Index was further employed to calculate within each specialty to measure income disparity. In 2015, a total of $166,089,335 was paid in 943,744 payments (average $175.00 per payment) to cardiologists, including 23,372 general cardiologists, 7,530 interventional cardiologists, and 2,293 cardiac electro-physiologists. Payments were mal-distributed across the 3 subspecialties of cardiology (p <0.01), with general cardiology receiving the largest number (73.5%) and total payments (62.6%) and cardiac electrophysiologists receiving significantly higher median payments ($1,662 vs $361 for all cardiologists; p <0.01). The Medtronic Company was the largest single payer for all 3 subspecialties. In conclusion, pharmaceutical and device manufacturers or group purchasing organizations continue to make substantial payments to cardiac practitioners with a significant variation in payments made to different cardiology subspecialists. The largest number and total payments are to general cardiologists, whereas the highest median payments are made to cardiac electrophysiologists. The impact of these payments on practice patterns remains to be examined. PMID- 29106839 TI - Proliferating Pilomatricoma Mimicking a Malignant Tumor. PMID- 29106840 TI - Cutaneous Metastasis in a Patient With Lung Cancer. PMID- 29106841 TI - Microvenular Hemangioma: Morphological Study of 3 Cases. PMID- 29106842 TI - Hats Off: A Study of Different Operating Room Headgear Assessed by Environmental Quality Indicators. AB - BACKGROUND: The effectiveness of operating room headgear in preventing airborne contamination has been called into question. We hypothesized that bouffant style hats would be as effective in preventing bacterial and particulate contamination in the operating room compared with disposable or cloth skull caps, and bouffant style hats would have similar permeability, particle penetration, and porosity compared with skull caps. STUDY DESIGN: Disposable bouffant and skull cap hats and newly laundered cloth skull caps were tested. A mock surgical procedure was used in a dynamic operating room environment. Airborne particulate and microbial contaminants were sampled. Hat fabric was tested for permeability, particle transmission, and pore sizes. RESULTS: No significant differences were observed between disposable bouffant and disposable skull caps with regard to particle or actively sampled microbial contamination. However, when compared with disposable skull caps, disposable bouffant hats did have significantly higher microbial shed at the sterile field, as measured by passive settle plate analysis (p < 0.05). When compared with cloth skull caps, disposable bouffants yielded higher levels of 0.5 MUm and 1.0 MUm particles and significantly higher microbial shed detected with passive analysis. Fabric assessment determined that disposable bouffant hats had larger average and maximum pore sizes compared with cloth skull caps, and were significantly more permeable than either disposable or cloth skull caps. CONCLUSIONS: Disposable bouffant hats had greater permeability, penetration, and greater microbial shed, as assessed by passive microbial analysis compared with disposable skull caps. When compared with cloth skull caps, disposable bouffants yielded greater permeability, greater particulate contamination, and greater passive microbial shed. Disposable style bouffant hats should not be considered superior to skull caps in preventing airborne contamination in the operating room. PMID- 29106843 TI - Intraductal Papillary Mucinous Neoplasms. PMID- 29106844 TI - Addressing Study Limitations: In Reply to Goh and Srinivasan. PMID- 29106845 TI - A Remodeled Gastric Stump Facilitates Digestive Reconstruction after Pancreaticoduodenectomy. PMID- 29106846 TI - November 2017 Featured Articles, Volume 225. PMID- 29106847 TI - Correction. PMID- 29106848 TI - Correction. PMID- 29106849 TI - The association of hypoalbuminemia with early perioperative outcomes - A comprehensive assessment across 16 major procedures. AB - BACKGROUND: Poor nutritional status is thought to influence peri- and postoperative outcomes. We assessed the association of hypoalbuminemia, a surrogate for poor nutritional status, with perioperative outcomes in patients undergoing one of 16 major surgical procedures. METHODS: Patients undergoing one of 16 major surgeries were identified using the ACS-NSQIP (2005-2011). Risk adjusted logistic regression models examined the association of hypoalbuminemia on perioperative outcomes. RESULTS: Overall, 204,819 complete cases were identified, of whom 25.4% underwent major cardiovascular, 19.0% orthopedic and 55.6% oncologic surgery. Patients with hypoalbuminemia had significantly higher rates of complications, reoperations, readmissions, prolonged length-of-stay and mortality (all p < 0.001). After adjustment, hypoalbuminemia was an independent predictor of overall complications in 12 of the procedures examined and 30-day mortality in 11 of the procedures. Individual perioperative complication profile varied widely among procedures. CONCLUSIONS: Hypoalbuminemia exerts significant impact on perioperative outcomes. Its effect is procedure-specific and thus warrants targeted management strategies to improve surgical outcomes. In the absence of clear recommendations, our findings invite surgeons to assess preoperative albumin levels and to manage nutritional status accordingly. PMID- 29106851 TI - Corrigendum. PMID- 29106850 TI - Corrigendum to "A sensitive, simple and robust LC-MS/MS method for the simultaneous quantification of seven androgen- and estrogen-related steroids in postmenopausal serum" [J. Steroid Biochem. Mol. Biol. 144 (2014) 523-534]. PMID- 29106852 TI - Postoperative objective detecting techniques for cochlear implant children with inner ear malformation. AB - OBJECTIVES: This study aims to investigate the changing characteristics and rules of electrically-evoked auditory brainstem response (EABR), electrically-evoked stapedius reflex threshold (ESRT) and neural response telemetry (NRT) after cochlear implant in children with inner ear malformation, and guide postoperative equipment debug. METHODS: A total of 88 children with either normal cochlea (control group) or inner ear malformation (test group) received Australian 24 multi-channel cochlear implants. The EABR, ESRT and NRT thresholds at different time points within one year postoperatively and behavioral responses (T-level and C-level) after one year were detected. Furthermore, the changing characteristics and rules of these thresholds were analyzed. RESULTS: The EABR, ESRT and NRT thresholds were all significantly higher at all time points in the test group than in the control group, but the general changing trends were similar. Particularly, these thresholds worsened at low frequencies and improved at high frequencies. Furthermore, EABR, ESRT and NRT thresholds gradually increased during the one year postoperative period. In addition, an extremely significant correlation was found between EABR and T-level and between ESRT and C-level, but a less significant correlation was found between NRT threshold and T-level in both groups. CONCLUSIONS: The postoperative changes in characteristics and rules of EABR, ESRT and NRT thresholds among cochlear implant children with inner ear malformation were all the same as those with normal cochlea. Thus, these thresholds can be used to guide the postoperative equipment debug for cochlear implants into patients with inner ear malformation. PMID- 29106853 TI - Sequential pediatric bilateral cochlear implantation: The effect of time interval between implants. AB - OBJECTIVE: To examine speech intelligibility in children subjected to sequential bilateral cochlear implants (CI) surgery and to assess the influence of the inter stage interval duration. INTRODUCTION: Binaural hearing recovery can have additional benefits, especially in speech and language development in patients with congenital profound sensorineural hearing loss; so recently there has been an increase in the number of children receiving bilateral CI. METHODS: Twenty seven children who underwent sequential bilateral cochlear implant (SBCI) with a short (1-3 yrs), medium (4-6 yrs) and long (7-12 yrs) range interval between both implantations, respectively, were evaluated. All patients underwent periodic speech perception test in quiet and noise after second implant activation in three conditions: with the first or second implant alone and with both implants. Results were examined according to the inter-stage interval. RESULTS: Speech intelligibility in noise was significantly better under bilateral conditions than either ear alone, in all three groups. Small improvements were seen in quiet, especially in the third group (6-12 yrs). CONCLUSION: Benefits of second implant in the early-implanted children and after a short inter-implant delay are more evident. However our study support that, even after a long period of deafness and despite a prolonged inter-stage interval, sequential bilateral cochlear implantation should be considered. LEVEL OF EVIDENCE: Level 4. PMID- 29106854 TI - Salivary cotinine levels in children with otolaryngological disorders. AB - OBJECTIVE: To determine if salivary cotinine, a biomarker for tobacco smoke exposure, is elevated more often or to a higher degree in children meeting criteria for tonsillectomy or tympanostomy tube insertion. METHODS: Saliva samples were obtained from 3 groups of children for salivary cotinine measurement. Group 1 served as healthy controls. Group 2 consisted of subjects meeting tympanostomy tube criteria. Group 3 consisted of patients meeting tonsillectomy criteria. Environmental tobacco smoke (ETS) exposure was defined as a salivary cotinine concentration >=1.0 ng/mL. Demographic data, smoke exposure history, and co-morbidities were also determined. RESULTS: 331 patients were included, with 112 in Group 1, 111 in Group 2, and 108 in Group 3. No differences were encountered for smoke exposure by history or smoker's identity, salivary cotinine level, or frequency of positive cotinine results. 42.6% of Group 1 had positive salivary cotinine compared to 51.8% of Group 2 and 47.7% of Group 3. Group 1 had a mean salivary cotinine level of 2.42 ng/mL compared to 2.54 ng/mL in Group 2 and 2.60 ng/mL in Group 3. The frequency of positive cotinine levels was higher than expected based on parental history. Among subjects with positive cotinine levels, 93 had no ETS exposure, and 64 had ETS exposure by history. CONCLUSION: Approximately 50% of children who undergo tonsillectomy and tympanostomy tube insertion have objective evidence of ETS exposure. Parental history underestimates passive smoke exposure, which can impact perioperative care. PMID- 29106855 TI - Practice patterns in the management of post-tonsillectomy hemorrhage: An American Society of Pediatric Otolaryngology survey. AB - OBJECTIVES: To evaluate practice patterns amongst pediatric otolaryngologists in the management of post-tonsillectomy hemorrhage. METHODS: A cross-sectional survey of the American Society of Pediatric Otolaryngology membership was administered electronically. The survey contained questions related to practice type, availability of resident and fellow call coverage, and management of different scenarios of post-tonsillectomy hemorrhage. Anonymous responses were collected and tabulated. RESULTS: The response rate was 157/443 (35%). For patients presenting with a convincing history of post-tonsillectomy hemorrhage but no clot or bleeding on exam, the most common management was overnight observation (55%) or discharge home with close follow-up (29%). In patients presenting with tonsillar clot but no active bleeding, the most common management was operating room for control (50%), followed by observation (25%) and bedside topical treatment (13%). In the same scenario with a cooperative teenager, bedside topical treatment was most common (45%), followed by operating room for control (27%) and observation (16%). In patients presenting with active tonsillar bleeding, operating room for control was most common (83%) while few (6%) attempted bedside treatment. If the patient was a cooperative teenager, 38% attempted bedside treatment while 52% would still go to the operating room. CONCLUSIONS: There is substantial variation in the management of post tonsillectomy hemorrhage amongst the pediatric otolaryngologists. Further studies to determine outcomes associated with differing treatment strategies would be useful in establishing practice recommendations. PMID- 29106856 TI - Genetic analysis of a Chinese family with members affected with Usher syndrome type II and Waardenburg syndrome type IV. AB - AIMS: The purpose of this study was to identify the genetic causes of a family presenting with multiple symptoms overlapping Usher syndrome type II (USH2) and Waardenburg syndrome type IV (WS4). METHODS: Targeted next-generation sequencing including the exon and flanking intron sequences of 79 deafness genes was performed on the proband. Co-segregation of the disease phenotype and the detected variants were confirmed in all family members by PCR amplification and Sanger sequencing. RESULTS: The affected members of this family had two different recessive disorders, USH2 and WS4. By targeted next-generation sequencing, we identified that USH2 was caused by a novel missense mutation, p.V4907D in GPR98; whereas WS4 due to p.V185M in EDNRB. This is the first report of homozygous p.V185M mutation in EDNRB in patient with WS4. CONCLUSION: This study reported a Chinese family with multiple independent and overlapping phenotypes. In condition, molecular level analysis was efficient to identify the causative variant p.V4907D in GPR98 and p.V185M in EDNRB, also was helpful to confirm the clinical diagnosis of USH2 and WS4. PMID- 29106857 TI - HLA-DRB1 and HLA-DQB1 alleles in Chinese Han patients with Juvenile-Onset recurrent respiratory papillomatosis. AB - Juvenile-Onset recurrent respiratory papillomatosis (JORRP) is a rare benign neoplasm of the respiratory mucosa caused by human papilloma virus. Previous studies on the possible associations between HLA alleles and JORRP have shown various results in different ethnic groups. The present study aims to investigate the association between JORRP and HLA class II DRB1and DQB1 alleles in Chinese Han children. We found that the frequencies of HLA-DRB1*03:01 (pc = 0.0378, OR = 4.8) and HLA-DQB1*02:01 (pc = 0.021, OR = 4.8) alleles were significantly higher in patients with JORRP than in controls. In addition, HLA-DRB1*03:01 allele significantly correlated with aggressive JORRP (r = 0.467, p = 0.009). This was the first study on the HLA alleles in Chinese Han patients with JORRP. Future studies are required to further elucidate the correlation of HLA class II alleles and susceptibility to JORRP. PMID- 29106858 TI - Congenital pharyngeal webs: Treatment of a rare clinical entity by endoscopic CO2 laser approach. AB - IMPORTANCE: Oesophageal inlet stenosis can promote dysphagia and aspiration. We report the cases of syndromic children with congenital pharyngeal webs successfully treated with endoscopic CO2 laser. OBSERVATIONS: Pharyngeal webs were excised with CO2 laser (Ultrapulse mode) and resurfaced using mucosal advancement flaps to avoid restenosis and/or formation of secondary synechia. This led to a significant enlargement of the oesophageal inlet, which was documented immediately postoperatively and the clinical improvement of dysphagia and decreased aspiration persisted at distant follow-up. CONCLUSION AND RELEVANCE: Pharyngeal webs are congenital anomalies that can be safely and effectively corrected with endoscopic treatment. PMID- 29106859 TI - Sleep disordered breathing in Bardet-Biedl Syndrome. AB - INTRODUCTION: Bardet-Biedl Syndrome (BBS) is an autosomal recessive ciliopathy, and obesity is among its defining characteristics. Consequently, the incidence of sleep disordered breathing (SDB) in this population is expected to be high. Due to its relative rarity, the nature of SDB in this population is poorly described. The objective of this study was to review a single institutional experience in the assessment and management of SDB in patients with BBS. METHODS: Retrospective chart review of tertiary care, academic pediatric hospital. RESULTS: 20 patients with BBS were evaluated over a 25-year period. Median age at initial consultation was 69 months; half of these patients were referred before the diagnosis of BBS was made. Eighteen of twenty patients had symptoms of sleep-disordered breathing. Median follow-up duration was 17.5 months. A wide range of polysomnographic outcomes was observed, including obstructive apnea-hypopnea indexes of 0-195 events/hour. Patients were managed with adenotonsillectomy and/or non-invasive positive pressure ventilation. CONCLUSIONS: SDB is commonly seen in BBS. These patients should be routinely screened for OSA and if present, a polysomnogram should be obtained. Based on patient characteristics, the failure rate of primary surgical intervention, namely adenotonsillectomy, is expected to be high. Further investigation into the role of ancillary diagnostic testing is still needed. PMID- 29106860 TI - Evaluating the sinus and Nasal Quality of Life Survey in the pediatric cystic fibrosis patient population. AB - INTRODUCTION: The Sinus and Nasal Quality of Life Survey (SN-5) is a validated quality of life (QOL) questionnaire for chronic rhinosinusitis in patients age 2 12. Its utility in the cystic fibrosis (CF) has been studied, but not yet validated. The purpose of this study is to determine the effectiveness of the SN 5 for evaluation of sinonasal symptoms in the pediatric CF population. METHODS: This retrospective study analyzed SN-5 surveys completed between 2012 and 2015 by pediatric CF patients and caregivers. Baseline and follow-up overall QOL scores and specific symptom scores were obtained from surveys completed in the three year span. Non-parametric statistics were conducted to identify differences in survey data. RESULTS: A total of 165 patients completed baseline and follow-up surveys. The overall QOL of the patient cohort did not change over the duration of the study (p = 0.660). Thirty-seven patients indicated higher overall QOL, with all five symptom scores showing significant improvement. Analysis by age group showed that QOL was significantly correlated with all five symptoms for children ages 0-4. In patients 5-12 years, overall QOL was only correlated with sinus infection (r = -0.3090, p = 0.01). QOL was significantly correlated with sinus infection (r = -0.2903, p = 0.04) and allergy symptoms (r = -0.5644, p < 0.01) in patients >12 years of age. CONCLUSION: There remains a need for a validated CRS QOL tool for children with CF. Though the SN-5 has previously been described as a potential instrument, our data suggest that it may be more valuable in children ages 0-4. PMID- 29106861 TI - Laryngotracheal reconstruction and swallowing: A review. AB - OBJECTIVES: Significant advances in laryngotracheal reconstruction over the last few decades have revolutionised the management of paediatric patients with complex congenital or acquired airway stenosis. The primary aim of laryngotracheal reconstruction has focused primarily on airway and surgery specific outcomes, often at the expense of voice, as well as swallowing function, which are all intricately related. There is currently a paucity of data on swallowing outcome. The goal of this paper is to review and discuss the existing research on the impact of laryngotracheal on swallowing. METHODS: Narrative review. RESULTS: Successful and safe oral feeding in children requires a highly complex and integrated sensorimotor system for proper timing and coordination, beginning with a well-coordinated suck-swallow-breathe sequence in infancy. Factors to consider include the normal laryngeal anatomy, nutrition as a stimulus and the development of feeding skills on swallowing, the underlying aetiology and other risk factors, LTR procedures and their adjuncts. All these impact on the children's growth. Swallow assessments and rehabilitation is therefore an important part of the post-operative care. CONCLUSIONS: As airway reconstructive surgeries have improved in airway and surgery specific outcomes, swallowing function is an important secondary outcome that impacts on the children's and their families' life. Management in a multi-disciplinary manner will optimise the outcome and improve their quality of life. PMID- 29106862 TI - An investigation of operative outcomes: Pediatric invasive fungal sinusitis. AB - OBJECTIVES/HYPOTHESIS: Invasive fungal sinusitis is an uncommon entity among children. Early recognition is crucial for facilitating successful treatment with minimal morbidity. The goal of this analysis was to identify patient characteristics associated with high-risk surgical disease through a population based examination into this rare and deadly disease process. METHODS: A retrospective chart review of the 2009 and 2012 Kids' Inpatient Database (KID) was conducted. A series of queries (Fungal infection->immunocompromised diagnosis >sinus procedure) identified 102 patients with likely invasive fungal sinusitis. Outcomes included: species, invasive extension, death, and other clinical characteristics. RESULTS: Patients with leukemia/lymphoma constituted 90.2% of individuals evaluated in this analysis. Nearly a quarter of pediatric patients receiving surgical treatment for invasive fungal sinusitis died during their hospital stay -24.9%. Aspergillus was the most commonly recorded mycotic species. Average hospital stay was 59.3 days, and associated hospital costs averaged $746,299 per stay. Patients 0-5 years old were more likely to have orbital involvement -56.3%. Brain extension was noted in 33.7% of this cohort as well. Mucormycosis was an independent predictor of death (p = 0.03), with an odds ratio of 3.835. CONCLUSION: To the best of our knowledge, this is the largest pediatric cohort with invasive fungal sinusitis in the literature. Patient demographics, cytology, and disease extension offer predictive information regarding patient outcomes for invasive fungal sinusitis. A high clinical suspicion and early treatment may decrease the lengthy and costly hospitalizations in this population. PMID- 29106863 TI - Clinical variables determining the success of adenotonsillectomy in children with Down syndrome. AB - OBJECTIVES: To evaluate the evolution of polysomnographic parameters of children with Down syndrome and obstructive sleep apnea syndrome submitted to adenotonsillectomy and the interaction of comorbidities on therapeutic outcome. METHODS: Ninety patients with Down syndrome and habitual snoring were identified between 2005 and 2015 in a Pediatric Otorhinolaryngology Clinic. Parent's complaints were evaluated by the test of equality of two proportions. Wilcoxon test was used to examine pre- and post-operative polysomnographic differences. Mann-Whitney test evaluated the influence of comorbidities. A p < 0.05 was considered significant. RESULTS: A total of 27 patients met the inclusion criteria (55.6% patients were males; mean (SD) age were 6.7 (3.6) years (range, 1.5-16 years). Significant improvement of parent's complaints (p < 0.001), arousal index (p = 0.045), and minimum oxygen saturation were observed post adenotonsillectomy (p = 0.034). Adenotonsillectomy was able to resolve obstructive sleep apnea syndrome in 29.6% of children with Down syndrome. Nineteen patients (70.4%) remained with obstructive sleep apnea syndrome and 44.4% showed a reduction of at least 50% of obstructive apnea-hypopnea index. Central apnea index post-adenotonsillectomy was worse in patients with heart disease (p = 0.022). Sleep efficiency (p = 0.031), N1 sleep stage (p = 0.001), apnea-hypopnea index (p = 0.023), and central apnea index (p = 0.008) were worse after surgery in patients with hypothyroidism. Patients with severe OSAS showed significant improvement in polysomnographic parameters after surgery. CONCLUSION: Although adenotonsillectomy improved symptoms and objective sleep data in children with Down syndrome, it was not able to resolve obstructive sleep apnea syndrome in most patients. Congenital heart diseases and hypothyroidism may affect the outcome. PMID- 29106864 TI - Six month-old infants with deformational plagiocephaly do not differ from unaffected infants with respect to vocal control. AB - OBJECTIVES: The recommendation of a supine sleeping position led to a significant reduction of SIDS, but increased positional skull deformities (DP). Here, a quantitative analysis of babbling aims to complement previous studies of language relevant competence based on items of the Bayley-scales that suggested the presence of developmental language delays in DP infants. Measures of fundamental frequency variability as proxies for vocal control are well suited for testing this assumption, since the laryngeal neuro-muscular system matures early and is coupled with brain function while working rapidly in coordinating the structures and mechanisms involved in infant sound production. METHODS: Sixty-six healthy, full-term infants with normal hearing and a monolingual background took part: (1) moderately asymmetrical DP group - N = 41; 21 male; (2) severely asymmetrical DP group - N = 10; 8 male; and (3) controls - N = 15; 5 male (group assignment based on stereophotogrammetric 360 degrees scans). Fundamental frequency (fo) measures were taken as proxies for vocal control skills during babbling. RESULTS: A MANOVA revealed no significant multivariate effect for the shape group, Wilks' lambda = 0.86, F(2, 63) = 1.21, p = 0.30, eta2 = 0.07 (medium effect-size). The results do not support previous findings based on Bayley scale evaluations that suggested a negative impact of DP on language development during infancy. CONCLUSIONS: A strong link between DP and brain dysfunction affecting vocal control, which would cause deviations in otherwise healthy DP infants, was not observed. Objective long-term studies of sound production are necessary to identify and/or understand the potential consequences of DP on early language development. PMID- 29106865 TI - Benign Rolandic epilepsy presenting like paradoxical vocal fold motion. AB - Paradoxical vocal fold motion (PVFM) is characterized by vocal fold adduction during respiration. Benign Rolandic epilepsy (BRE) is the most common childhood epilepsy and can cause oropharyngolaryngeal or facial manifestations. A 9-year old male presented with intermittent apnea lasting 30-60 seconds and presumed PVFM. The patient's physical and fiberoptic exam were normal. He was admitted and found to have episodes of oxygen desaturation, neck twitching, and tongue burning. An EEG revealed focal epilepsy. After starting anti-epileptic medications, he had resolution of symptoms. Our patient was eventually diagnosed with BRE, a focal onset epilepsy that can mimic primary otolaryngologic disease. PMID- 29106866 TI - Robotic epiglottopexy for severe epiglottic prolapse limiting decannulation. AB - Surgical management of supraglottic collapse at the level of the epiglottis limiting decannulation has historically consisted of placement of epiglottopexy sutures which are technically challenging and often unsuccessful. Herein we describe the use of robotic technology to assist with epiglottopexy for a case of a 9 year old child with severe epiglottic petiole prolapse limiting capping and decannulation. Postoperatively the patient is tolerating capping during waking hours. PMID- 29106867 TI - Audio-visual speech perception in prelingually deafened Japanese children following sequential bilateral cochlear implantation. AB - OBJECTIVES: An effect of audio-visual (AV) integration is observed when the auditory and visual stimuli are incongruent (the McGurk effect). In general, AV integration is helpful especially in subjects wearing hearing aids or cochlear implants (CIs). However, the influence of AV integration on spoken word recognition in individuals with bilateral CIs (Bi-CIs) has not been fully investigated so far. In this study, we investigated AV integration in children with Bi-CIs. METHODS: The study sample included thirty one prelingually deafened children who underwent sequential bilateral cochlear implantation. We assessed their responses to congruent and incongruent AV stimuli with three CI-listening modes: only the 1st CI, only the 2nd CI, and Bi-CIs. The responses were assessed in the whole group as well as in two sub-groups: a proficient group (syllable intelligibility >=80% with the 1st CI) and a non-proficient group (syllable intelligibility < 80% with the 1st CI). RESULTS: We found evidence of the McGurk effect in each of the three CI-listening modes. AV integration responses were observed in a subset of incongruent AV stimuli, and the patterns observed with the 1st CI and with Bi-CIs were similar. In the proficient group, the responses with the 2nd CI were not significantly different from those with the 1st CI whereas in the non-proficient group the responses with the 2nd CI were driven by visual stimuli more than those with the 1st CI. CONCLUSION: Our results suggested that prelingually deafened Japanese children who underwent sequential bilateral cochlear implantation exhibit AV integration abilities, both in monaural listening as well as in binaural listening. We also observed a higher influence of visual stimuli on speech perception with the 2nd CI in the non-proficient group, suggesting that Bi-CIs listeners with poorer speech recognition rely on visual information more compared to the proficient subjects to compensate for poorer auditory input. Nevertheless, poorer quality auditory input with the 2nd CI did not interfere with AV integration with binaural listening (with Bi-CIs). Overall, the findings of this study might be used to inform future research to identify the best strategies for speech training using AV integration effectively in prelingually deafened children. PMID- 29106868 TI - The use of CT-scan in foreign body aspiration in children: A 6 years' experience. AB - INTRODUCTION: A foreign body aspiration is a risky situation, common in pediatric emergency. The "gold standard" to rule out a foreign body or proceed to its extraction, is rigid bronchoscopy (RB) under general anesthesia. However, RB is an intrusive exam with possible complications. Depending on authors, RB in emergency is a procedure at risk of complications in 4-17% of cases. Advances in radiology allow CT-scanners of fast acquisition and high definition, which could be used as an alternative to RB. MATERIALS AND METHODS: This is a retrospective analysis of 6 years from May 2010 to May 2016, in a tertiary referral center. All children that presented a foreign body aspiration suspicion and had a cervical thoracic CT with multiplanar reconstruction were analyzed. RESULTS: 200 children were included. The average age was 30 months. 132 were considered normal and 68 pathological. Among the 68 RB performed for pathological scanner, a foreign body was found in 59 cases, and we had 9 cases of false positives. Among the 132 considered normal, 27 have had a RB despite this, due to persistent symptoms, all were negative; 105 were discharged home without endoscopy with monitoring instructions. 1 child was reviewed three months later for asthma, without second choking event reported. A new CT-scan found a foreign body that was removed by RB. Due to the nature of the foreign body it is very unlikely to link it to the first choking event, but retrospectively we cannot be certain. Considering this case as the only false negative, the negative predictive value (NPV) of CT was 99.2% and positive predictive value (PPV) of 83.8%. CONCLUSION: The use of CT scan with multiplanar reconstruction in suspected foreign body aspiration is a reliable alternative to endoscopy under general anesthesia, especially in asymptomatic patients, avoiding too many negative endoscopies. PMID- 29106869 TI - Check-list for the assessment of functional impairment in children with congenital aural atresia. AB - OBJECTIVES: Congenital Aural Atresia (CAA) is a deformity of the external ear and it is commonly associated with malformations of middle and inner ear and, in some cases, with other facial deformities. Very few assessment measures exist for evaluating the functional impairment in children with CAA. Purpose of this study is to introduce and describe an assessment Checklist, (nominated FOS Checklist) that covers feeding abilities (F), oralmotor skills (O), communication/language development (S) in children with CAA. FOS wants to offer a range of assessment providing a profile of the child in comparison to hearing peers and it aims to make clinicians able to identify additional problems and areas of difficulties as well as specific abilities and skills. Secondary, we want to investigate the presence of correlations between disorders and side of CAA. METHODS: a new Checklist (FOS Checklist) was administered to 68 children with CAA. RESULTS: Feeding abilities are age-adequate in 94,3% of all patients. 54,4% of all patients are in need for further assessment of their oral-motor skills; delays in language development were found in 44,1% of cases. Orofacial development delays have been observed in 57.2% of subjects among the bilateral CAA group, in 53.9% among the right CAA group and in 53.4% among the left CAA group. Patients referred for further language evaluation were 42,9% in the bilateral CAA group, 33.3% in the right CAA group and 33.3% in the left CAA group. According to the chi2 analysis, referral for further assessment is independent from side of aural atresia. CONCLUSIONS: Subjects with bilateral CAA are more likely to be referred for further assessment, both for oral motor aspects and for speech perception and language development. However, there is not a significant statistical difference between the performances of children with bilateral or unilateral CAA. FOS Checklist is simple, reliable and time effective and can be used in everyday clinical practice. FOS enable clinicians to identify additional problems and areas of difficulties as well as specific abilities and skills; moreover, FOS allows to determine appropriate referrals and intervention strategies. PMID- 29106870 TI - Pediatric tympanic membrane cholesteatoma: Systematic review and meta-analysis. AB - INTRODUCTION: Tympanic membrane cholesteatoma (TMC) is a rare anomaly found in pediatric patients with no significant otologic history. Its pathogenesis appears distinct from congenital mesotympanic cholesteatoma. This systematic review and meta-analysis evaluates the management of TMC. METHODS: Two authors independently conducted a systematic review using the PubMed-NCBI, Cochrane Library, and Web of Science databases. Studies describing cases of pediatric TMC were included. Patients with history of chronic otitis, otorrhea, trauma, or otologic surgery were excluded. RESULTS: Seventeen articles were included for a total of 45 patients. Mean age was 35.9 months with 56% female. Patients aged >=36 months had significantly larger cholesteatomas than younger patients (4.2 vs 1.9 mm, p = 0.004). Nine patients (20%) had middle ear extension but none had middle ear or ossicular disease. CT scans influenced management in 1 of 26 patients. All patients were managed surgically by transcanal approach (93%) or retroauricular approach (7%). Surgery involved enucleation without TM perforation (80%) or complete excision with TM grafting (20%). In 23 patients, the fibrous TM remained intact, and there were no recurrences in this group at a mean follow-up of 11 months. Overall, there was 1 recurrence (2%), eventually requiring reoperation. No patients experienced persistent tympanic membrane perforation, chronic otitis, or hearing loss. CONCLUSION: TMC occurs in pediatric patients without an otologic history. Associated middle ear involvement has not been reported. CT scanning may not be necessary for work up and management of this disorder. A transcanal approach with enucleation is often sufficient treatment. Risk of recurrence appears lower than with congenital mesotympanic cholesteatoma. PMID- 29106871 TI - Test-retest reliability of speech-evoked auditory brainstem response in healthy children at a low sensation level. AB - OBJECTIVE: Auditory brainstem responses evoked by complex stimuli such as speech syllables have been studied in normal subjects and subjects with compromised auditory functions. The stability of speech-evoked auditory brainstem response (speech-ABR) when tested over time has been reported but the literature is limited. The present study was carried out to determine the test-retest reliability of speech-ABR in healthy children at a low sensation level. METHODS: Seventeen healthy children (6 boys, 11 girls) aged from 5 to 9 years (mean = 6.8 +/- 3.3 years) were tested in two sessions separated by a 3-month period. The stimulus used was a 40-ms syllable /da/ presented at 30 dB sensation level. RESULTS: As revealed by pair t-test and intra-class correlation (ICC) analyses, peak latencies, peak amplitudes and composite onset measures of speech-ABR were found to be highly replicable. Compared to other parameters, higher ICC values were noted for peak latencies of speech-ABR. CONCLUSION: The present study was the first to report the test-retest reliability of speech-ABR recorded at low stimulation levels in healthy children. Due to its good stability, it can be used as an objective indicator for assessing the effectiveness of auditory rehabilitation in hearing-impaired children in future studies. PMID- 29106872 TI - Design and validation of key text messages (Tonsil-Text-To-Me) to improve parent and child perioperative tonsillectomy experience: A modified Delphi study. AB - OBJECTIVE: Parents can struggle while providing perioperative tonsillectomy care for their children at home. Short message service (SMS) technology is an accessible and direct modality to communicate timely, evidence-based recommendations to parents across the perioperative period. This study focused on validating a SMS protocol, Tonsil-Text-To-Me (TTTM), for parents of children undergoing tonsillectomy. METHODS: This study used a modified Delphi expert consensus method. Participants were an international sample of 27 clinicians/researchers. Participants rated level of agreement with recommendations across seven perioperative domains, derived systematically from scientific and lay literature. A priori consensus analysis was conducted using threshold criterion. A multidisciplinary team of local clinicians were also individually interviewed to consolidate text messages and implement recurrent suggestions. RESULTS: In the modified Delphi panel, 30 statements reached threshold agreement (>3.0 of 4.0); recommendations surrounding diet (3.87) and hygiene (3.83) had the highest level of consensus, while recommendations regarding activity (3.42) and non-pharmacologic pain management (3.55) had the lowest consensus. The 30 statements reconfigured into 12 concise text messages. After further interviews with local clinicians, 14 final text messages were included in the SMS protocol to be sent two weeks preoperatively to one week postoperatively. CONCLUSION: This study illustrates the development of TTTM which is designed to deliver key sequential text messages at the optimal time during the perioperative setting to parents caring for their children who are undergoing tonsillectomy. PMID- 29106873 TI - Evaluation of tracheobronchial branching abnormalities in patients with microtia using chest computed tomography. AB - BACKGROUND: The objective of this study was to identify the characteristics and incidence of Tracheobronchial branching abnormalities in patients with microtia and to evaluate the risk of anesthesia. METHODS: A total of 204 consecutive microtia patients and 465 nose cosmetic patients without microtia received a preoperative chest computed tomography. A retrospective study was performed with the clinical and imaging data from July 2016 to April 2017. RESULTS: With the chest computed tomography images, a total of 7 cases were documented with Tracheobronchial branching abnormalities, including 6 cases among the microtia patients and 1 case among the cosmetic patients without microtia. The incidence of Tracheobronchial branching abnormalities was higher in microtia patients than the cosmetic patients without microtia (2.94% versus 0.22%, P < 0.01). CONCLUSIONS: The incidence of Tracheobronchial branching abnormalities was high in patients with microtia. Preoperative diagnosis of tracheal bronchus can help anesthesiologists avoid complications. Microtia with Tracheobronchial branching abnormalities may involve a new syndrome previously undiscovered or just another extension with the very wide spectrum of microtia. PMID- 29106874 TI - Variations in electrode impedance during and after cochlear implantation: Round window versus extended round window insertions. AB - OBJECTIVES: To assess differences in intra- and postoperative electrode impedances following cochlear implantation between round window insertions (RWI) and extended round window insertions (ERWI). METHODS: Fifty patients with congenital hearing loss received unilateral hearing implants (Sonata Ti100, Med El GmbH, Innsbruck, Austria) with standard electrode arrays. The patients were divided into two groups according to the surgical technique used. Thirty-five procedures were performed with RWI (group A) and 15 with ERWI (group B). Electrode impedance was measured and analysed during the operation, and one week and one month postoperatively. RESULTS: There were no statistically significant differences (i.e., P > 0.05) in electrode impedance between groups A and B intraoperatively, or at one week or one month postoperatively. Electrode impedance at one month postoperatively was higher than the intraoperative and postoperative one week values in group A (P < 0.05), with similar results in group B. CONCLUSION: There was no significant difference between RWI and ERWI in operative duration or complications of cochlear implantation. Moreover, no significant differences in postoperative electrode impedance values were found between the two surgical routes. PMID- 29106875 TI - Regional differences of Turkey in risk factors of newborn hearing loss. AB - OBJECTIVE: The aim of this study was to discover Turkish regional differences in the risk factors of newborn hearing loss. METHOD: A multi-centered retrospective design was used. A total of 443 children, registered to the national newborn hearing screening programme, with bilateral hearing loss, from five different regions of Turkey, were evaluated in terms of the types of hearing loss, the degree of hearing loss, the types of risk factors, parental consanguinity, age at diagnosis and age of auditory intervention, respectively. RESULTS: There was no significant difference in the prevalence of hearing loss between regions (chi2 = 3.210, P = 0.523). Symmetric Sensorineural Hearing Loss (SSHL) was the most common type of HL in all regions (91.8%). Profound HL was the most common degree of HL in all regions (46.2%). There were statistically significant differences between regions in terms of types of HL (chi2 = 14.151, P = 0.000). As a total, 323 (72.9%) of subjects did not have any risk factors. There were statistically significant differences between regions in terms of the types of risk factors (pre, peri and post-natal) for SSNHL (chi2 = 16.095, P = 0.000). For all regions, the age of diagnosis was convenient with the JCIH criteria. However the age of hearing aid application was prolonged in some regions. There were statistically significant differences between regions in terms of the age of diagnosis (chi2 = 93.570, P = 0.000) and the age of auditory intervention (chi2 = 47.323, P = 0.000). The confounding effects of gender, age of diagnosis, age of hearing aids applications, HL in the family, types of risk factors for HL on SSNHL were detected. CONCLUSION: To reach the goal of a high quality newborn hearing screening, there is a need to develop an evidence-based standard for follow up guideline. In addition, risk factors should be re-evaluated according to regional differences and all regions should take their own precautions according to their evidence based data. PMID- 29106876 TI - Early signs and symptoms of intracranial complications of otitis media in pediatric and adult patients: A different presentation? AB - OBJECTIVES: The aim of this study was to review the clinical presentation and early signs and symptoms of otogenic intracranial complications (OIC) in children and adults. METHODS: retrospective chart review. The medical records of all children and adults admitted in our center with OIC during the period 2008-2017 were reviewed. Data concerning clinical presentation, treatment and outcomes were reviewed and analyzed. RESULTS: We included 47 patients with OIC: 21 children (range 1-13 years) and 26 adults (range 22-71 years). We included more patients with acute otitis media than with chronic otitis media (children 5% adults 19%, all with cholesteatoma). In children; the most common OIC was central cerebral venous thrombosis. In both children and adults; otogenic symptoms such as otalgia and otorrhea were present. Children presented more frequently with headache and nausea. Adults presented more frequently with decreased consciousness. Hearing loss was the most common long-term sequel. Three adults died. CONCLUSIONS: In our series, we found that OIC in children present as 'mimicking meningitis' (e.g. nausea and vomiting). Adults on the other hand have a clinical presentation 'mimicking stroke' (e.g. neurological deficits and decreased level of consciousness). In children, sinus thrombosis was observed more frequently than in adults. Despite the low mortality rate, death still occurs. Long -term sequelae most frequently include hearing loss in children as well as in adults. PMID- 29106877 TI - Role of imaging in the diagnosis of parotid infantile hemangiomas. AB - OBJECTIVES: To review the clinical presentation, imaging and follow-up of parotid infantile hemangiomas (IH). METHODS: Over a 15-year period, all patients with a clinical diagnosis of parotid IH were evaluated. Imaging was available in 35. The medical records, photographs, and radiology studies of these patients were reviewed. RESULTS: All patients presented at less than 4 months of age (M:F, 13:21). 19 (55)% of tumors were on the left and were bilateral in 2 patients. The majority (29 patients) presented due to localized swelling or palpable mass; the remainder had a cutaneous lesion, but no palpable mass at the time of presentation. The referring diagnosis was incomplete or incorrect in 9 patients (26%). The imaging studies all demonstrated a well-defined homogeneous mass, with no abnormality of the surrounding subcutaneous fat. Sonography showed a uniformly vascular lesion with pulsatile fast-flow seen on Doppler. On MRI, the lesion was hyperintense on T2-weighted images, isointense on T1, with intense enhancement post-contrast. Oral therapy (propranolol or corticosteroids) was prescribed in 15 (45%). Follow-up in 28 patients demonstrated stability of the lesion in 11, regression in size in 11 and complete involution in 6. After involution 2 patients underwent resection of residual tissue and/or excess skin. CONCLUSIONS: Typical clinical presentation alone may be adequate to establish a diagnosis of parotid infantile hemangioma. However, in patients with no overlying cutaneous lesion, imaging can play a critical role in confirming the diagnosis. The sonographic findings are sufficiently characteristic to allow for a definitive diagnosis, obviating the need for further investigations. If diagnostic uncertainty remains or the full extent of the lesion cannot be appreciated, then MRI should be preferred over CT to avoid ionizing radiation. PMID- 29106878 TI - The relationship between the GJB3 c.538C>T variant and hearing phenotype in the Chinese population. AB - BACKGROUND: Mutations in GJB3 were originally shown to underlie an autosomal dominant form of non-syndromic deafness in Chinese patients and the c.538C>T (p.R180*) variants caused high-frequency hearing loss. But after that, few reports have reported this mutation. This study investigated the relationship between the GJB3 c.538C>T variant and hearing phenotype in Chinese to assist with risk assessment and genetic counseling for hearing loss patients and their families. METHOD: The study enrolled 5700 patients with hearing loss and 4600 normal subjects. Deafness gene mutations were distinguished using a gene chip. The GJB3 c.538C>T variant rate was calculated from the results. RESULT: Of the 5700 patients, 23 (0.40%) carried a GJB3 c.538C>T heterozygous variant; of these, 11 patients had other gene (GJB2/SLC26A4) mutations simultaneously. Most patients had moderate to profound hearing loss. All 23 patients were sporadic cases and had no family history of deafness. Of the 4600 normal individuals, 11 (0.24%) had GJB3 c.538C>T heterozygous variant. There was no statistical difference in incidence between the two groups. CONCLUSIONS: Our results showed that the GJB3 c.538C>T variant has a very low incidence in the Chinese population, and there was no clear evidence to support a role of the GJB3 c.538C>T variant in the autosomal dominant form of non-syndromic deafness. Our findings suggested that GJB3 c.538C>T does not contribute to hearing loss, and this conclusion will assist with genetic counseling and risk prediction for deafness related to the GJB3 c.538C>T variant. PMID- 29106879 TI - Light-emitting diode aspiration: Distinct radiographic features and approach to management. AB - Foreign body aspiration is a potentially life threatening problem. The successful removal of airway foreign bodies is dependent on positively identifying the object and developing a solution to its extraction prior to attempts at retrieval. Thus, pre-operative radiographic evaluation is essential in the diagnosis and management of foreign body aspiration. The current case report describes the unique challenges in the evaluation and management of an unusual foreign body within the airway. The distinctive radiographic appearance of this foreign body allows it to be easily identified pre-operatively, and this may decrease the likelihood of operative complications and patient morbidity. PMID- 29106880 TI - Utility of screening questionnaire and polysomnography to predict postoperative outcomes in children. AB - INTRODUCTION: The prevalence of pediatric obstructive sleep apnea (OSA) has increased concurrently with the increasing prevalence of obesity. We have previously validated a short questionnaire predicting the occurrence of OSA on polysomnography (PSG). This follow-up study assessed the utility of the questionnaire in predicting postoperative outcomes. METHODS: Children undergoing surgery and completing a sleep study were prospectively screened for OSA using a short questionnaire. Procedures within 1 year of PSG were included in the analysis. Questionnaires were scored according to a cutoff previously deemed optimal for predicting OSA (apnea-hypopnea index >= 5) on the sleep study. Postoperative outcomes included prolonged (>60 min) length of stay (LOS) in the post-anesthesia care unit (PACU) and oxygen requirement in the PACU. RESULTS: The study cohort included 185 patients (100/85 male/female) age 8 +/- 4 years, undergoing adenotonsillectomy (n = 109), other ear, nose, and throat (ENT) procedures (n = 18), or non-ENT procedures (n = 58). There were 45 patients with OSA documented by PSG and 122 patients identified as likely to have OSA according to questionnaire responses (89% sensitivity, 41% specificity). PACU LOS was prolonged in 55/181 (30%) cases and supplemental oxygen was used in the PACU in 29/181 (16%) cases. In separate multivariable models, supplemental oxygen use in the PACU was more common if a patient scored >=2/6 points on the short questionnaire scale (OR = 5.0; 95% CI: 1.3, 19.9; p = 0.023) or if the patient was diagnosed with OSA on PSG (OR = 4.6; 95% CI: 1.6, 13.5; p = 0.005). Neither OSA on PSG nor questionnaire score >=2/6 were associated with prolonged PACU stay. CONCLUSION: Both OSA diagnosis based on the AHI and the questionnaire scale achieved comparable predictive value for the need for oxygen use in the PACU. The utility of the questionnaire in predicting rare adverse events (e.g., unplanned admission or rapid response team activation) remains to be determined. Our preliminary results support using a brief questionnaire scale for preoperative risk stratification among children with suspected OSA who have not had a formal sleep study. PMID- 29106881 TI - Utilization of a postoperative adenotonsillectomy teaching video: A pilot study. AB - BACKGROUND: Pediatric tonsillectomies are increasingly being performed as an outpatient procedure thereby increasing the parental role in post-operative pain management. However, it is unclear if parents receive adequate teaching regarding pain management. We introduced a video teaching tool and compared its efficacy alone and in combination with the standard verbal instruction. METHODS: A prospective study which randomized parents or caregivers of children undergoing tonsillectomy +/- adenoidectomy into three groups: 1) standard verbal post operative instructions; 2) watching the video teaching tool along with standard verbal instructions or 3) video teaching tool only. Parents completed pre and post-instruction assessments of their knowledge of post-operative pain management with responses scored from 0 to 8. Telephone assessments were conducted within 48 post-operative hours with a subjective rating of the helpfulness of the video teaching tool. RESULTS: The study cohort included 99 patients and their families. The median pre-instruction score was 5 of 8 points (Interquartile range [IQR]: 4, 6) and this remained at 5 following instruction. (IQR:4, 6; p = 0.702 difference from baseline). Baseline scores did not vary across the groups (p = 0.156) and there was no increase in the knowledge score from pre to post-test across the three groups. Groups B and C rated the helpfulness of the video teaching tool with a median score of 4 of 5. (IQR: 4, 5). CONCLUSIONS: A baseline deficit exists in parental understanding of post-operative pain management that did not statistically improve regardless of the form post-operative instruction used (verbal vs. video-based instruction). However, the high helpfulness scores in both video groups support the use of video instruction as an alternative to or to complement to verbal instruction. However, further identification of knowledge deficits is required for optimization of post-operative educational materials. PMID- 29106883 TI - Routine pathologic examination of tonsillectomy specimens: A 10-year experience at a tertiary care children's hospital. AB - OBJECTIVE: To review histopathologic diagnoses from tonsillectomy specimens and determine whether routine pathologic exam is necessary. METHODS: Pathology reports of patients undergoing tonsillectomy from 2005 to 2014 at our pediatric tertiary care hospital were reviewed. Histopathologic diagnoses were recorded with special attention to identification of malignancy. RESULTS: A total of 8807 paired tonsil specimens were sent to pathology over a 10-year course. Gross analysis was performed on all. Microscopic histopathologic analysis was performed on 612 (6.95%) specimens with all but one demonstrating strictly reactive lymphoid hyperplasia. The single specimen (0.16%) demonstrated follicular hyperplasia with focal necrotizing granulomatous lymphadenitis without organisms identified on special staining. The surgeon requested pathologic diagnosis to rule out lymphoma in 4 of 8087 (0.05%) of the specimens. No malignancies were identified. The approximate charges for gross examination of a paired tonsillectomy specimen and microscopic examination were $136.10 and $294.54, respectively. Over the 10 year period of the study, total charges were estimated at $1,115,340 (gross) and $180,258 (microscopic). DISCUSSION: Microscopic analysis of tonsil specimens is unlikely to identify abnormal pathology that changes patient management. This study suggests that neither gross nor microscopic pathologic examination of tonsillectomy specimens is necessary on a routine basis. Histologic analysis of tonsils should be requested only on a case by case basis when clinical suspicion for malignancy is high. Avoiding routine pathologic exam of tonsils may be cost effective and medically safe. PMID- 29106882 TI - GJB2 mutations: Genotypic and phenotypic correlation in a cohort of 690 hearing impaired patients, toward a new mutation? AB - OBJECTIVES: To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with GJB2 mutations. DESIGN: Case series. SETTING: Collaborative study in referral centers, institutional practice. PATIENTS: A total of 690 hearing-impaired patients were genotypically and phenotypically described. The mutations of GJB2 and GJB6 were studied. Heterozygous patients were searched for another mutation by microsatellite approach. MAIN OUTCOME MEASURES: Prevalence of GJB2 mutations, microsatellite approach, hearing-impairment. RESULTS: In 498 patients (72,17% of the cohort), no mutation was found. Homozygotous patients were 59 (8,55%), with 51 for c.35delG, 6 for p.M34T and 2 for GJB6. Compound heterozygous were 64 (9,28%) with 56 c.35delG-others mutations. Genotypes with biallelic non sense mutations had a high risk of severe to profound hearing impairment. It was frequently milder in compound heterozygotes than in c.35delG homozygotes. Heterozygous patients were 69 (10%) with 21 c.35delG, 20 p.M34T and 28 others mutations. We selected patients with a complete historical medical file (clinical and audiometric data). Then, we performed a microsatellite approach (multiplex PCR of short DNA fragments) to localize a new pathologic allele. Seventeen heterozygous patients were studied. Six patients (35%) showed the same haplotype. They were compound heterozygous bearing a new pathologic allele. CONCLUSION: Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness. A new haplotype for GJB2 is described but the exact mutation remains unknown. PMID- 29106884 TI - Impact of socioeconomic factors on paediatric cochlear implant outcomes. AB - OBJECTIVES: The study was aimed at evaluating the impact of certain socioeconomic factors such as family income, level of parents' education, distance between the child's home and auditory verbal therapy clinic, and age of the child at implantation on postoperative cochlear implant outcomes. METHODS: Children suffering from congenital bilateral profound sensorineural hearing loss and a chronologic age of 4 years or younger at the time of implantation were included in the study. Children who were able to complete a prescribed period of a 1-year follow-up were included in the study. These children underwent cochlear implantation surgery, and their postoperative outcomes were measured and documented using categories of auditory perception (CAP), meaningful auditory integration (MAIS), and speech intelligibility rating (SIR) scores. Children were divided into three groups based on the level of parental education, family income, and distance of their home from the rehabilitation-- auditory verbal therapy clinic. RESULTS: A total of 180 children were studied. The age at implantation had a significant impact on the postoperative outcomes, with an inverse correlation. The younger the child's age at the time of implantation, the better were the postoperative outcomes. However, there were no significant differences among the CAP, MAIS, and SIR scores and each of the three subgroups. Children from families with an annual income of less than $7,500, between $7,500 and $15,000, and more than $15,000 performed equally well, except for significantly higher SIR scores in children with family incomes more than $15,000. Children with of parents who had attended high school or possessed a bachelor's or Master's master's degree had similar scores, with no significant difference. Also, distance from the auditory verbal therapy clinic failed to have any significantimpact on a child's performance. DISCUSSION: These results have been variable, similar to those of previously published studies. A few of the earlier studies concurred with our results, but most of the studies had suggested that children in families of higher socioeconomic status had have better speech and language acquisition. CONCLUSIONS: Cochlear implantation significantly improves auditory perception and speech intelligibility of children suffering from profound sensorineural hearing loss. Younger The younger the age at implantation, the better are the results. Hence, early implantation should be promoted and encouraged. Our study suggests that children who followed the designated program of postoperative mapping and auditory verbal therapy for a minimum period of 1 year seemed to do equally well in terms of hearing perception and speech intelligibility, irrespective of the socioeconomic status of the family. Further studies are essential to assess the impact of these factors on long-term speech acquisition andlanguage development. PMID- 29106885 TI - Outpatient management of pediatric acute mastoiditis. AB - OBJECTIVE: Evaluate the Montreal Children's Hospital experience with outpatient management of uncomplicated acute mastoiditis with parenteral antibiotic therapy alone and determine if it is a safe alternative to inpatient management. SUBJECTS AND METHOD: A retrospective review of pediatric patients diagnosed with acute mastoiditis at a tertiary care pediatric hospital between 2013 and 2015 was performed. Patients with syndromes, immunodeficiency, cholesteatoma, chronic otitis media, cochlear implant in the affected ear, or incidental mastoid opacity were excluded. RESULTS: 56 children age 6 months to 15 years old were treated for acute mastoiditis, including 29 hospitalizations and 27 outpatients. Patients managed as outpatient with daily intravenous ceftriaxone had a 93% cure rate. Eighteen hospitalized and one outpatient had complications of acute mastoiditis. Children with complications were more likely to be febrile (p = 0.045). Two patients failed outpatient therapy and were admitted; one for myringotomy and piperacillin-tazobactam treatment and one required a mastoidectomy. 4/27 children treated as outpatient underwent myringotomy and tube insertion, 2 underwent myringotomy and tube along with admission and 21 did not require tube insertion. The average total duration of intravenous antibiotic therapy was respectively 4.9 and 18.9 days in the outpatient and hospitalized group. The average duration of admission was 5.9 days. CONCLUSION: Outpatient medical therapy of uncomplicated pediatric mastoiditis is safe, successful, and efficient. Benefits include efficient use of surgical beds, cost savings and patient and family convenience. Careful patient selection and close monitoring are keys for successful outcome. PMID- 29106886 TI - Surgical Treatment for Early Small Cell Lung Cancer: Variability in Practice and Impact on Survival. AB - BACKGROUND: Surgical resection with lobectomy is recommended for T1/T2 N0 small cell lung cancer (SCLC) patients after negative mediastinal staging. We sought to characterize variation in surgical therapy for early SCLC and determine the effect of a hospital's practice patterns on patient survival. METHODS: The National Cancer Database was examined from 2004 to 2013. Risk- and reliability adjusted hierarchical logistic regression was used to estimate the adjusted odds of resection by hospital. Hospitals were then grouped into quartiles by observed to-expected rates of surgical treatment. Patient, tumor, and hospital characteristics were compared across quartiles. Kaplan-Meier plots and Cox proportional hazard models were built to compare patient survival as a function of a hospital's tendency to use surgical intervention. RESULTS: We identified 5,079 patients with T1/T2 N0 SCLC in 317 hospitals, and 1,260 underwent resection. Analysis after adjusting for demographic, comorbidity, and tumor factors showed patients treated at hospitals in the highest quartile of surgical use were 17 times more likely to undergo surgical resection than those in the lowest quartile (44.8% vs 7.6%; odds ratio, 16.7l; 95% confidence interval, 12.59 to 22.18). Hospitals in the highest quartile were more likely to be academic centers (48% vs 21%), more likely to perform lobectomy (28.3% vs 5.0%), and treated more mixed-histology tumors (11.1% vs 4.5%). Survival was significantly longer for patients treated at hospitals most likely to use surgical therapy (median, 25.3 vs. 18.8 months; p < 0.0001). Hazard ratio differences in mortality persisted in multivariate Cox models (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.89; p < 0.0001). CONCLUSIONS: Large variation exists in the use of surgical therapy for early SCLC in the United States, which may represent a significant quality improvement opportunity for patients with early SCLC. PMID- 29106887 TI - Patterns of Treatment and Outcomes for Definitive Therapy of Early Stage Non Small Cell Lung Cancer. AB - BACKGROUND: Definitive surgical and radiation therapy (RT) treatments are evolving rapidly for stage I non-small cell lung cancer (NSCLC). We hypothesized that utilization of definitive therapies increased between 2000 and 2010 and that survival improved for stage I NSCLC patients over the same time period. Secondary objectives were determining trends in patterns of care and predictors of utilization. METHODS: Population-based, observational, comparative effectiveness study used Surveillance, Epidemiology, and End Results-18 data from 2000 to 2010. The main outcome measure was 2-year risk of death for stage I NSCLC. RESULTS: Between 2000 and 2010, 40,589 patients (62%) underwent surgery, 10,048 (15%) received RT, 2,130 (3%) received both surgery and RT, and 11,537 (18%) received neither surgery nor RT. Annually, the odds of receiving either definitive RT or undergoing surgery increased relative to the odds of receiving no treatment (odds ratio [OR] radiation 1.04, 95% confidence interval [CI]: 1.03 to 1.05; OR surgery 1.05, 95% CI: 1.04 to 1.05). Among surgical patients, the proportion of sublobar resections steadily increased from 12.9% to 17.9%. For all patients, the 2-year risk of death decreased by 3.5% each year (hazard ratio [HR] 0.965, 95% CI: 0.962 to 0.969), driven primarily by improved survival for surgical (annualized HR 0.959, 95% CI: 0.954 to 0.964) and RT (annualized HR 0.942, 95% CI: 0.935 to 0.949) patients. CONCLUSIONS: Between 2000 and 2010, stage I NSCLC patients were more likely to receive definitive treatment with either surgery or RT, leading to a decline in the number of untreated patients. Survival also improved substantially for stage I NSCLC patients, with the largest survival improvements observed in patients undergoing definitive RT. PMID- 29106888 TI - Acquired Vascular Tumors of the Head and Neck. AB - Vascular neoplasms of the head and neck present with a wide spectrum of signs and symptoms. Diagnosis requires a high index of suspicion and is usually made after tumors are large enough to be visually apparent or cause symptoms. This article discusses the most common acquired benign and malignant vascular tumors, with an emphasis on their evaluation and treatment. PMID- 29106890 TI - Special Contributions Celebrating the Anniversaries of the AAOMS and JOMS. PMID- 29106889 TI - Functional Anatomic Computer Engineered Surgery Protocol for the Management of Self-Inflicted Gunshot Wounds to the Maxillofacial Skeleton. AB - PURPOSE: Virtual surgical planning (VSP) is an indispensable aid in craniomaxillofacial reconstruction, yet no protocol is established in facial gunshot wounds. We review our experience with computer-aided reconstruction of self-inflicted facial gunshot wounds (SIGSW'S) and propose a protocol for the staged repair. METHODS: A retrospective case series enrolling patients with SIGSW's managed with the Functional Anatomic Computer Engineered Surgical protocol (FACES) was implemented. Subjects were evaluated at least one month postoperatively. Outcome variables were jaw position, facial projection, oro nasal communication, lip competence, feeding tube and tracheostomy dependence, descriptive statistics were computed. The FACES protocol implemented during the initial hospitalization is as follows 1) damage control; 2) selective debridement; 3) VSP reconstruction back converted into navigation software 4) navigation assisted midfacial skeletal reconstruction; 5) computer aided oro mandibular reconstruction with or without microvascular free flaps using custom cutting guides/hardware; 6) navigation assisted, computer aided palatomaxillary reconstruction with or without microvascular free flaps using cutting guides/hardware; 7) navigation assisted reconstruction of the internal orbit; 8) and confirmation of accurate reconstruction using intraoperative CT. RESULTS: The sample was composed of 10 patients, mean age of 43 years (range, 28 - 62 years, 70% M), 100% with SIGSW's to the submental/submandibular region. All had satisfactory facial projection (n=10), nine had satisfactory jaw position, were decannulated by one month's follow up and were feeding tube independent (90%). All traumatic oro-antral communications were closed (n=8, 7 surgical, 1 obturator), seven had adequate lip competence (70%). Complications included fibula malunion (n=1), plate exposure (n=2) infection (n=2), intracranial abscess (n=1) and microstomia (n=2). CONCLUSION: Computer-aided surgery is an indispensable tool in the reconstruction of SIGSW's. Successfully implemented, it proved to be a useful adjunct for: the restoration of orbital volume, facial projection and symmetry; the inset of composite tissue, and the facilitation of dental implant supported prosthetic rehabilitation. PMID- 29106891 TI - Unexpected Extracardiac Multifocal Adult Rhabdomyomas With 10 Lesions of the Head and Neck: Epidemiology, Diagnosis, and Therapy. AB - Adult rhabdomyomas (ARMs) are rare solitary benign neoplasms of the head and neck, and multifocal ARMs are even rarer. Owing to the low incidence and scanty knowledge of this peculiar entity, several patients have been reported to be misdiagnosed or overtreated. This report describes a patient with multifocal ARMs with as many as 10 synchronous lesions. In addition, all published cases of this entity in PubMed, Embase, and Web of Science databases were reviewed up to March 1, 2017. Overall, 10 of 29 reported cases had more than 2 lesions, with a maximum of 10 synchronous masses in the present report. Multifocal ARMs usually present as slow-growing lumps in the parapharyngeal region, with a predilection for older men. Treatments of multifocal ARMs should be tailored and close follow-up is recommended for tiny lesions located in vital structures. In addition, multifocal ARMs should be differentially diagnosed from other multifocal lesions in the head and neck region to avoid aggressive excision and produce a favorable outcome for patients. PMID- 29106892 TI - Fenestrated thoracic endovascular aortic repair for zone 2 lesions: Not just basic blocking and tackling. PMID- 29106893 TI - Infective endocarditis in patients with diabetes: More than meets the eye? PMID- 29106894 TI - Chylothorax: Abdominal approach. PMID- 29106895 TI - Improving the outcomes of failed Ross procedure. PMID- 29106896 TI - The rib cage reduces intervertebral disc pressures in cadaveric thoracic spines by sharing loading under applied dynamic moments. AB - The effects of the rib cage on thoracic spine loading are not well studied, but the rib cage may provide stability or share loads with the spine. Intervertebral disc pressure provides insight into spinal loading, but such measurements are lacking in the thoracic spine. Thus, our objective was to examine thoracic intradiscal pressures under applied pure moments, and to determine the effect of the rib cage on these pressures. Human cadaveric thoracic spine specimens were positioned upright in a testing machine, and Dynamic pure moments (0 to +/-5 N.m) with a compressive follower load of 400 N were applied in axial rotation, flexion - extension, and lateral bending. Disc pressures were measured at T4-T5 and T8-T9 using needle-mounted pressure transducers, first with the rib cage intact, and again after the rib cage was removed. Changes in pressure vs. moment slopes with rib cage removal were examined. Pressure generally increased with applied moments, and pressure-moment slope increased with rib cage removal at T4-T5 for axial rotation, extension, and lateral bending, and at T8-T9 for axial rotation. The results suggest the intact rib cage carried about 62% and 56% of axial rotation moments about T4-T5 and T8-T9, respectively, as well as 42% of extension moment and 36-43% of lateral bending moment about T4-T5 only. The rib cage likely plays a larger role in supporting moments than compressive loads, and may also play a larger role in the upper thorax than the lower thorax. PMID- 29106897 TI - Estimation and validation of spatio-temporal parameters for sprint running using a radio-based tracking system. AB - Spatio-temporal parameters like step length, step frequency and ground contact time are directly related to sprinting performance. There is still a lack of knowledge, however, on how these parameters interact. Recently, various algorithms for the automatic detection of step parameters during sprint running have been presented which have been based on data from motion capture systems, video cameras, opto-electronic systems or Inertial measurement units. However, all of these methods suffer from at least one of the following shortcomings: they are (a) not applicable for more than one sprinter simultaneously, (b) only capable of capturing a small volume or (c) do not provide accurate spatial parameters. To circumvent these issues, the radio-based local position measurement system RedFIR could be used to obtain spatio-temporal information during sprinting based on lightweight transmitters attached to the athletes. To assess and optimize the accuracy of these parameters 19 100 m sprints of twelve young elite athletes (age: 16.5 +/- 2.3 years) were recorded by a radio-based tracking system and a opto-electronic reference instrument. Optimal filter parameters for the step detection algorithm were obtained based on RMSE differences between estimates and reference values on an unseen test set. Attaching a transmitter above the ankle showed the best results. Bland-Altman analysis yielded 95% limits of agreement of [-14.65 cm, 15.05 cm] for step length [-0.016 s, 0.016 s] for step time and [-0.020 s, 0.028 s] for ground contact time, respectively. RMS errors smaller than 2% for step length and step time show the applicability of radio-based tracking systems to provide spatio-temporal parameters. This creates new opportunities for performance analysis that can be applied for any running discipline taking place within a stadium. Since analysis for multiple athletes is available in real-time this allows immediate feedback to coaches, athletes and media. PMID- 29106899 TI - Vinpocetine protects inner retinal neurons with functional NMDA glutamate receptors against retinal ischemia. AB - Retinal ischemia is involved in the pathogenesis of many major vision threatening diseases. Vinpocetine is a natural drug, which has a range of neuroprotective actions against retinal ischemia including modulating cation flow, improving metabolic activity and preventing apoptosis. The exact mechanism behind these actions remains unknown but may involve glutamate receptors, major components of the ischemic cascade. This study examined the effects of vinpocetine in association with specific ionotropic glutamate receptor agonists: N-methyl-D aspartate (NMDA) and kainate. Vinpocetine's actions to improve cation channel permeability and cell marker immunoreactivity following ischemia appeared to be limited to NMDA activation with no changes observed following kainate stimulation. Vinpocetine's actions were lost in the presence of an NMDA receptor inhibitor further suggesting they may be secondary to NMDA receptor activation. NMDA receptor function was also necessary for vinpocetine's actions on glucose availability during ischemia but not lactate dehydrogenase (LDH) activity in the ischemic retina suggesting not all of vinpocetine's actions are linked to NMDA receptor function. These results may explain vinpocetine's effectiveness as a neuroprotective agent as the NMDA receptor is implicated in the pathogenesis of ischemia in a range of tissues of the central nervous system. PMID- 29106898 TI - Dismantling Mindfulness-Based Cognitive Therapy: Creation and validation of 8 week focused attention and open monitoring interventions within a 3-armed randomized controlled trial. AB - BACKGROUND: While mindfulness-based interventions (MBIs) employ two distinct practices, focused attention (FA) and open monitoring (OM), the integrated delivery of these practices in MBIs precludes understanding of their practice specific effects or mechanisms of action. The purpose of this study is to isolate hypothesized active ingredients and practice-specific mechanistic target engagement by creating structurally equivalent interventions that differ only by the active ingredient (meditation practice) offered and to test whether the hypothesized components differentially engage the mechanistic targets that they are purported to engage. METHODS: Participants were intended to be representative of American meditators and had mild to severe affective disturbances. Measures of structural equivalence included participant-level (sample characteristics), treatment-level (program structure and duration, program materials, class size, attendance, homework compliance, etc.), and instructor-level variables (training, ratings and adherence/fidelity). Measures of differential validity included analysis of program materials and verification of differential mechanistic target engagement (cognitive and affective skills and beliefs about meditation acquired by participants after the 8-week training). RESULTS: The results indicate successful creation of structurally equivalent FA and OM programs that were matched on participant-level, treatment-level, and instructor-level variables. The interventions also differed as expected with respect to program materials as well as mechanistic targets engaged (skills and beliefs acquired). CONCLUSIONS: These validated 8-week FA and OM training programs can be applied in future research to assess practice-specific effects of meditation. PMID- 29106900 TI - Peripapillary distribution of Muller cells within the retinal nerve fiber layer in human eyes. AB - The purpose of this study was to describe the distribution of Muller cell within the peripapillary retinal nerve fiber layer (RNFL) in human eyes. Eleven unpaired normal postmortem eyes were recruited into this study. Each eye was sectioned using the "umbrella technique" to obtain a concentric peripapillary ring centered on the optic disc, with a diameter of 3.0 mm. Immunohistochemistry with anti- CRALBP stained Muller cell within each ring. The RNFL thickness measurements around the peripapillary ring were: 262.5, 339.4, 285.4 and 347.5 MUm for the temporal, superior, nasal and inferior quadrants, respectively. Muller cell were found to be unevenly distributed in the peripapillary RNFL of normal eyes. The relative Muller cell staining to the thickness of each measured segment (16.6%, 15.2%, 21.3%, and 17.9% for the temporal, superior, nasal and inferior quadrants, respectively) showed a significant increase in the nasal quadrant. The RNFL thickness measurements obtained using imaging techniques reflect the amount of axonal tissue present in this layer. In this study we highlight that around 20% of RNFL thickness is composed of non-axonal contents which do not represent neuronal tissue, nor are they necessarily lost in the glaucomatous process. More so, the ratio of the Muller cell component to the total RNFL thickness varies around the peripapillary RNFL ring, demonstrating the lowest relative content of Muller cell superiorly and the highest content nasally. Further studies should compare the amount and distribution of Muller cell in normal versus glaucomatous eyes. PMID- 29106901 TI - Robust Hinfinity cost guaranteed integral sliding mode control for the synchronization problem of nonlinear tele-operation system with variable time delay. AB - This paper is devoted to the synchronization problem of tele-operation systems with time-varying delay, disturbances, and uncertainty. Delay-dependent sufficient conditions for the existence of integral sliding surfaces are given in the form of Linear Matrix Inequalities (LMIs). This guarantees the global stability of the tele-operation system with known upper bounds of the time varying delays. Unlike previous work, in this paper, the controller gains are designed but not chosen, which increases the degree of freedom of the design. Moreover, Wirtinger based integral inequality and reciprocally convex combination techniques used in the constructed Lypunove-Krasoviskii Functional (LKF) are deemed to give less conservative stability condition for the system. Furthermore, to relax the analysis from any assumptions regarding the dynamics of the environment and human operator forces, Hinfinity design method is used to involve the dynamics of these forces and ensure the stability of the system against these admissible forces in the Hinfinity sense. This design scheme combines the strong robustness of the sliding mode control with the Hinfinity design method for tele operation systems which is coupled using state feedback controllers and inherit variable time-delays in their communication channels. Simulation examples are given to show the effectiveness of the proposed method. PMID- 29106902 TI - The Use of M-Mode Ultrasonography to Differentiate the Causes of B Lines. AB - BACKGROUND: The presence of B lines on lung ultrasonography is a characteristic feature of both cardiogenic pulmonary edema (CPE) and noncardiogenic alveolar interstitial syndrome (NCAIS), so their presence does not allow the clinician to differentiate between the two entities. Our study used M-mode ultrasonography of the pleura to differentiate CPE from NCAIS. METHODS: A total of 43 subjects were enrolled in the study, and based on history, physical examination, and chart review, the patients were divided into three groups: an NCAIS group, a CPE group, and a control group. Three distinct pleural line morphologic categories were identified: a continuous pleural line, a fragmented pleural line, and a sinusoidal pleural line. In addition, two separate subpleural patterns were independently identified by the investigators: a horizontal pattern and a vertical pattern. These pleural and subpleural patterns were correlated with subject diagnoses. RESULTS: A fragmented pleural line and a vertical subpleural pattern on M-mode ultrasonography is associated with patients who have NCAIS. Most patients with CPE have a continuous pleural line and a vertical subpleural pattern on M-mode ultrasonography. A sinusoidal pleural line on M-mode ultrasonography is suggestive of the presence of a pleural effusion. CONCLUSIONS: Our results indicate that M-mode ultrasonography is useful to distinguish CPE from NCAIS based on the pleural and the subpleural morphologic features. PMID- 29106903 TI - Crocin attenuates acute hypobaric hypoxia-induced cognitive deficits of rats. AB - This study investigated whether crocin exerted neuroprotective effects against acute hypobaric hypoxia at high altitude in vivo and determined the underlying mechanisms. Male Sprague-Dawley rats were randomly assigned to a normoxic group,a hypoxic group, and three crocin groups at three different doses. The rats were transferred from 50m to 4200m for 3 days after treatment with crocin for 3 days. The learning and memory of the rat were evaluated with the Morris water maze test. Transmission electron microscope (TEM) was used to analyze the changes in the ultrastructure of hippocampal neurons. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha) and sirtuin-1 (SIRT1) levels were determined using immunohistochemical staining and western blotting. The escape latency of the crocin group was shorter than that of the hypoxic group, while the frequency of the rats reaching the platform was significantly higher in the crocin group. The structures of nerve cells and mitochondria were destroyed in the hypoxic group, but were repaired in the crocin groups. The expressions of PGC 1alpha and SIRT1 were decreased in the hypoxic group, but were increased in the crocin group. All the effects improved by crocin were dose-dependent. Crocin attenuates acute hypobaric hypoxia-induced cognitive deficits in rats, accompanied by repairing the structures of hippocampal neurons and improving PGC 1alpha and SIRT1 levels. PMID- 29106904 TI - Prothymosin alpha interacts with SET, ANP32A and ANP32B and other cytoplasmic and mitochondrial proteins in proliferating cells. AB - Prothymosin alpha (ProTalpha) is an acidic protein with a nuclear role related to the chromatin activity through its interaction with histones in mammalian cells. ProTalpha acts as an anti-apoptotic factor involved in the control of the apoptosome activity in the cytoplasm, however the mechanisms underlying this function are still known. ProTalpha shares similar biological functions with acidic nuclear-cytoplasmic shuttling proteins included in SET and ANP32 family members. Using affinity chromatography, co-immunoprecipitation and chemical cross linking, we demonstrate that ProTalpha interacts with SET, ANP32A and ANP32B proteins. The study by mass spectrometry of the complexes stabilized by chemical cross-linking showed that associations of ProTalpha consist of six highly acidic ProTalpha-complexes, which corresponds to differentiated interactions of ProTalpha either with SET or ANP32 proteins. The presence in the ProTalpha complexes of cytoplasmic proteins involved in membrane remodeling and proteins implicated in the mitochondrial permeability, seems to indicate that they could be related to a cytoplasmic-mitochondrial activity. According to the cellular function of the characterized targets of ProTalpha, and the evolution in the composition of the diverse ProTalpha-complexes when proliferation activity was reduced or apoptosis induced, leads to hypothesized that ProTalpha interactions might be related to the proliferation activity and control of the cell survival. PMID- 29106905 TI - Characterisation of endogenous A2A and A2B receptor-mediated cyclic AMP responses in HEK 293 cells using the GloSensorTM biosensor: Evidence for an allosteric mechanism of action for the A2B-selective antagonist PSB 603. AB - Endogenous adenosine A2B receptors (A2BAR) mediate cAMP accumulation in HEK 293 cells. Here we have used a biosensor to investigate the mechanism of action of the A2BAR antagonist PSB 603 in HEK 293 cells. The A2A agonist CGS 21680 elicited a small response in these cells (circa 20% of that obtained with NECA), suggesting that they also contain a small population of A2A receptors. The responses to NECA and adenosine were antagonised by PSB 603, but not by the selective A2AAR antagonist SCH 58261. In contrast, CGS 21680 responses were not antagonised by high concentrations of PSB 603, but were sensitive to inhibition by SCH 58261. Analysis of the effect of increasing concentrations of PSB 603 on the response to NECA indicated a non-competitive mode of action yielding a marked reduction in the NECA EMAX with no significant effect on EC50 values. Kinetics analysis of the effect of PSB 603 on the A2BAR-mediated NECA responses confirmed a saturable effect that was consistent with an allosteric mode of antagonism. The possibility that PSB 603 acts as a negative allosteric modulator of A2BAR suggests new approaches to the development of therapeutic agents to treat conditions where adenosine levels are high. PMID- 29106906 TI - Transcriptional regulation of Nfix by NFIB drives astrocytic maturation within the developing spinal cord. AB - During mouse spinal cord development, ventricular zone progenitor cells transition from producing neurons to producing glia at approximately embryonic day 11.5, a process known as the gliogenic switch. The transcription factors Nuclear Factor I (NFI) A and B initiate this developmental transition, but the contribution of a third NFI member, NFIX, remains unknown. Here, we reveal that ventricular zone progenitor cells within the spinal cord express NFIX after the onset of NFIA and NFIB expression, and after the gliogenic switch has occurred. Mice lacking NFIX exhibit normal neurogenesis within the spinal cord, and, while early astrocytic differentiation proceeds normally, aspects of terminal astrocytic differentiation are impaired. Finally, we report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. This hierarchical organisation of NFI protein expression and function during spinal cord gliogenesis reveals a previously unrecognised auto-regulatory mechanism within this gene family. PMID- 29106907 TI - Quantification of sulphur amino acids by ultra-high performance liquid chromatography in aquatic invertebrates. AB - We examined the performance of an ultra-high performance liquid chromatography method to quantify protein-bound sulphur amino acids in zooplankton. Both cysteic acid and methionine sulfone were linear from 5 to 250 pmol (r2 = 0.99), with a method detection limit of 13 pmol and 9 pmol, respectively. Although there was no matrix effect on linearity, adjacent peaks and co-eluting noise from the invertebrate proteins increased the detection limits when compared to common standards. Overall, performance characteristics were reproducible and accurate, and provide a means for quantifying sulphur amino acids in aquatic invertebrates, an understudied group. PMID- 29106908 TI - Glycan profile of CHO derived IgM purified by highly efficient single step affinity chromatography. AB - Immunoglobulin M (IgM) antibodies are reckoned as promising tools for therapy and diagnostic approaches. Nevertheless, the commercial success of IgMs is hampered due to bottlenecks in recombinant production and downstream processing. IgMs are large, complex and highly glycosylated proteins that are only stable in a limited range of conditions. To investigate these sensitive IgM antibodies we optimized the elution conditions for a commercially available IgM affinity matrix (CaptureSelectTM). Applying a small-scale screening system, we optimized our single step purification strategy for high purity, high yield and retained antigen binding capacity. Here we show that IgMs are sensitive to aggregation at very acidic conditions (pH <= 3.0) despite often being used for affinity chromatography. We combined pH 3.5 with a high salt concentration to prevent aggregation during elution. The elution strategy presented in this paper will improve IgM processes for further applications. The herein used IgMs were produced in Chinese hamster ovary (CHO) cells. We present the first detailed glycan analysis of IgM produced in CHO cells with predominantly complex type structures at Asn171, Asn332 and Asn395 and oligomannosidic structures at Asn402 and Asn563 similar to human serum-IgM. PMID- 29106909 TI - A study of bio-hybrid silsesquioxane/yeast: Biosorption and neuronal toxicity of lead. AB - Lead is a heavy metal of high impact for the environment as well as for human health, being cause of several diseases. Considering the importance of obtaining an effective treatment for lead removal, a new hybrid material was developed for sorption of Pb2+ from aqueous solution. The effect of pH, temperature, liquid/solid ratio (g/cm3) and lead concentration on the sorption capacity of yeasts chemically modified with cubic silsesquioxane (YS) was analyzed. Additionally, the toxicity of lead on the neuronal activity was also investigated in order to assess whether the damage caused by the Pb2+ ion is reversible or not. The YS is highly promissory as sorbent of lead in high concentrations (100 and 500ppm), reaching high efficiency in short contact times (15min), and at the natural pH (4) of the Pb2+ solution and room temperature. The best sorption obtained was 82% removal and 248mg/g with 500cm3/g sorbent, pH 4, room temperature and contact time of 15min. Besides, such high efficiencies are obtained with low quantities of biosorbent, when compared with other similar materials. The impact of lead on neuronal function was studied by measuring autofluorescence signals, associated with changes in cellular metabolism, at the hippocampal CA3 area in brain slices. In this toxicity tests, the effect of low concentrations of lead (1 and 3MUM) on neuronal activity was evaluated. After removal of the lead, the irreversibility of the observed changes can be verified, which suggests the existence of neuronal damages. PMID- 29106910 TI - The role of mucus on drug transport and its potential to affect therapeutic outcomes. AB - A layer of mucus covers the surface of all wet epithelia throughout the human body. Mucus is a hydrogel mainly composed of water, mucins (glycoproteins), DNA, proteins, lipids, and cell debris. This complex composition yields a tenacious viscoelastic hydrogel that lubricates and protects the exposed epithelia from external threats and enzymatic degradation. The natural protective role of mucus is nowadays acknowledged as a major barrier to be overcome in non-invasive drug delivery. The heterogeneity of mucus components offers a wide range of potential chemical interaction sites for macromolecules, while the mesh-like architecture given to mucus by the intermolecular cross-linking of mucin molecules results in a dense network that physically, and in a size-dependent manner, hinders the diffusion of nanoparticles through mucus. Consequently, drug diffusion, epithelial absorption, drug bioavailability, and ultimately therapeutic outcomes of mucosal drug delivery can be attenuated. PMID- 29106911 TI - Stem cells, niches and scaffolds: Applications to burns and wound care. AB - The importance of skin to survival, and the devastating physical and psychological consequences of scarring following reparative healing of extensive or difficult to heal human wounds, cannot be disputed. We discuss the significant challenges faced by patients and healthcare providers alike in treating these wounds. New state of the art technologies have provided remarkable insights into the role of skin stem and progenitor cells and their niches in maintaining skin homeostasis and in reparative wound healing. Based on this knowledge, we examine different approaches to repair extensive burn injury and chronic wounds, including full and split thickness skin grafts, temporising matrices and scaffolds, and composite cultured skin products. Notable developments include next generation skin substitutes to replace split thickness skin autografts and next generation gene editing coupled with cell therapies to treat genodermatoses. Further refinements are predicted with the advent of bioprinting technologies, and newly defined biomaterials and autologous cell sources that can be engineered to more accurately replicate human skin architecture, function and cosmesis. These advances will undoubtedly improve quality of life for patients with extensive burns and difficult to heal wounds. PMID- 29106913 TI - Tractional Abnormalities of the Central Foveal Bouquet in Epiretinal Membranes: Clinical Spectrum and Pathophysiological Perspectives. AB - PURPOSE: To investigate the tractional alterations of the central bouquet (CB) in idiopathic epiretinal membranes (ERMs). DESIGN: Retrospective, consecutive, observational case series. METHODS: ERMs were classified according to a 4-stage grading system. The CB was defined as a circular area of approximately 100 MUm composed of densely packed cones (and Muller cells) in the central fovea. Tractional abnormalities of the CB were identified with spectral-domain optical coherence tomography. Ex vivo histopathologic analysis was performed. RESULTS: In this study 263 eyes with ERMs were included. Mean follow-up was 21.2 +/- 16.7 months. At baseline, tractional abnormalities of the CB were diagnosed in 58 out of 263 eyes (22%) and divided into 3 categories: cotton ball sign (defined as a fuzzy hyperreflective area between the ellipsoid zone and the interdigitation zone in the central fovea), foveolar detachment, and acquired vitelliform lesion. The presence of ectopic inner foveal layers was negatively correlated with the presence of CB tractional abnormalities (P = .002). Visual acuity was highest in association with the cotton ball sign and lowest in the acquired vitelliform lesion group. Sequential morphologic progression was identified in 7 eyes. Ex vivo histopathologic analysis illustrated characteristic staining patterns supporting a potential mechanism of traction by Muller cells in the CB. CONCLUSIONS: The cotton ball sign, foveolar detachment, and acquired vitelliform lesion may comprise a continuum in the same clinical spectrum and may represent subsequent stages of CB abnormalities. Foveal Muller cells may play an integral role in the transmission of mechanical forces to the central foveal cones. PMID- 29106914 TI - Geographic and Demographic Variation in Use of Ranibizumab Versus Bevacizumab for Neovascular Age-related Macular Degeneration in the United States. AB - PURPOSE: To examine demographic and geographic variation in the use of ranibizumab and bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) among Medicare beneficiaries. DESIGN: Retrospective cohort study. METHODS: Using a 100% sample of Medicare claims data, we evaluated Medicare beneficiaries (N = 195 812) with an index claim for neovascular AMD between July 1, 2006, and June 30, 2009, to determine whether beneficiaries first received ranibizumab or bevacizumab following initial diagnosis. RESULTS: The overall proportion of beneficiaries that first received ranibizumab for neovascular AMD was 35%, and varied significantly (0.9%-84.6%) across the 306 US hospital referral regions (median = 33%, interquartile range = 17%-49%). Based on hierarchical logistic regression models, the likelihood of receiving ranibizumab declined over time (adjusted odds ratio (aOR) comparing treatment in 2009 vs 2006 = 0.39, P < .001). After we controlled for year of treatment, black beneficiaries were 45% less likely to receive ranibizumab compared to non-blacks (P < .0001). Beneficiaries residing in urban areas (aOR vs isolated rural towns = 1.12, P < .001), in zip codes with higher median incomes, and in the New England and East South Central census regions (aOR vs Pacific census region = 5.57, P < .001; aOR = 3.58, P < .001, respectively) had increased odds of receiving ranibizumab. CONCLUSIONS: The odds of receiving bevacizumab vs ranibizumab as initial therapy for neovascular AMD among US Medicare beneficiaries varied substantially across geographic and demographic groups. Relatively fewer patients received ranibizumab for initial neovascular AMD treatment in 2009 vs 2006. Future research should study the drivers of variation in utilization of these interventions, the extent this variation indicates differential access to these agents, and whether treatment choice impacts patient outcomes. PMID- 29106912 TI - Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction. AB - Macrophages play critical roles in homeostatic maintenance of the myocardium under normal conditions and in tissue repair after injury. In the steady-state heart, resident cardiac macrophages remove senescent and dying cells and facilitate electrical conduction. In the aging heart, the shift in macrophage phenotype to a proinflammatory subtype leads to inflammaging. Following myocardial infarction (MI), macrophages recruited to the infarct produce both proinflammatory and anti-inflammatory mediators (cytokines, chemokines, matrix metalloproteinases, and growth factors), phagocytize dead cells, and promote angiogenesis and scar formation. These diverse properties are attributed to distinct macrophage subtypes and polarization status. Infarct macrophages exhibit a proinflammatory M1 phenotype early and become polarized toward an anti inflammatory M2 phenotype later post-MI. Although this classification system is oversimplified and needs to be refined to accommodate the multiple different macrophage subtypes that have been recently identified, general concepts on macrophage roles are independent of subtype classification. This review summarizes current knowledge about cardiac macrophage origins, roles, and phenotypes in the steady state, with aging, and after MI, as well as highlights outstanding areas of investigation. PMID- 29106916 TI - BK polyomavirus genotypes Ia and Ib1 exhibit different biological properties in renal transplant recipients. AB - BK polyomavirus (BKV) is an opportunist agent associated with nephropathy (BKVAN) in 1-10% of kidney transplant recipients. BKV is classified into genotypes or subgroups according to minor nucleotidic variations with unknown biological implications. Studies assessing the possible association between genotypes and the risk of BKVAN in kidney transplant patients have presented conflicting results. In these studies, genotype Ia, which is highly prevalent in Brazil, was less frequently found and, thus, comparative data on the biological properties of this genotype are lacking. In this study, BKV Ia and Ib1 genotypes were compared according to their viral load, genetic evolution (VP1 and NCCR) - in a cohort of renal transplant recipients. The patients infected with Ia (13/23; 56.5%) genotype exhibited higher viral loads in urine [>1.4 log over Ib1 (10/23; 43.5%); p=0.025]. In addition, genotype Ia was associated with diverse mutations at VP1 loops and sites under positive selection outside loops, which were totally absent in Ib1. Although the number of viremic patients was similar, the three patients who had BK nephropathy (BKVAN) were infected with Ia genotype. NCCR architecture (ww or rr) were not distinctive between Ia and Ib1 genotypes. Ia genotype, which is rare in other published BKV cohorts, presented some diverse biological properties in transplanted recipients in comparison to Ib1. PMID- 29106917 TI - Variation in prophylactic antibiotic use for laparoscopic cholecystectomy: need for better stewardship in pediatric surgery. AB - PURPOSE: The role of prophylactic antibiotics for elective laparoscopic cholecystectomy has been questioned over the last decade. Although gradually being discontinued in the adult population, the practice among pediatric surgeons remains unknown. Our aim was to investigate the use of perioperative antibiotics in children undergoing elective laparoscopic cholecystectomy (LC) for symptomatic cholelithiasis and biliary dyskinesia. METHODS: We retrospectively reviewed the Pediatric Health Information System (PHIS) database for 2015 and selected all patients 18years old or younger who underwent LC for cholelithiasis (without cholecystitis) or biliary dyskinesia. Demographic and hospital data were extracted as well as antibiotics administered and surgical complications. RESULTS: A total of 1112 patients from 44 hospitals were identified with a median age of 15years (IQR 13-16years). Eight out of every 10 hospitals routinely give prophylactic antibiotics in more than 50% of patients. In 37 hospitals that performed more than 5 LC per year, 19 to 100% of patients were given antibiotics. No surgical complications were identified in those who did not get antibiotics. CONCLUSION: There is significant inter-hospital variation in prophylactic antibiotic administration for elective LC in children. Perioperative antibiotic administration should be tracked as a quality metric in the current push for better stewardship. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective. PMID- 29106915 TI - Neighborhood price of healthier food relative to unhealthy food and its association with type 2 diabetes and insulin resistance: The multi-ethnic study of atherosclerosis. AB - This study examined the association between the price of healthier food relative to unhealthy food and type 2 diabetes prevalence, incidence and insulin resistance (IR). Data came from the Multi-Ethnic Study of Atherosclerosis exam 5 administered 2010-2012 (exam 4, five years prior, was used only for diabetes incidence) and supermarket food/beverage prices derived from Information Resources Inc. For each individual, average price of a selection of healthier foods, unhealthy foods and their ratio was computed for supermarkets within 3miles of the person's residential address. Diabetes status was confirmed at each exam and IR was assessed via the homeostasis model assessment index. Multivariable-adjusted logistic, modified Poisson and linear regression models were used to model diabetes prevalence, incidence and IR, respectively as a function of price and covariates; 2353 to 3408 participants were included in analyses (depending on the outcome). A higher ratio of healthy-to-unhealthy neighborhood food price was associated with greater IR (4.8% higher HOMA-IR score for each standard deviation higher price ratio [95% CI -0.2% to 10.1%]) after adjusting for region, age, gender, race/ethnicity, family history of diabetes, income/wealth index, education, smoking status, physical activity, and neighborhood socioeconomic status. No association with diabetes incidence (relative risk=1.11, 95% CI 0.85 to 1.44) or prevalence (odds ratio=0.95, 95% CI 0.81 to 1.11) was observed. Higher neighborhood prices of healthier food relative to unhealthy food were positively associated with IR, but not with either diabetes outcome. This study provides new insight into the relationship between food prices with IR and diabetes. PMID- 29106918 TI - Use of intraoperative nuclear imaging leads to decreased anesthesia time and real time confirmation of lesion removal. AB - BACKGROUND: Lymphatic mapping to guide sentinel lymph node biopsy (SLNB) typically requires lymphoscintigraphy prior to surgery. In young pediatric patients, this process often requires intubation in the nuclear medicine suite followed by transport to the operating room (OR). METHODS: We reviewed 14 pediatric cases in which a portable nuclear imaging camera was utilized to perform the entirety of the SLNB in the OR. RESULTS AND CONCLUSION: This method, utilizing intraoperative nuclear imaging, helped to confirm removal of the sentinel lymph node in real time, decreased anesthesia time, and avoided transport of a sedated or intubated child. LEVEL OF EVIDENCE: III. PMID- 29106919 TI - Using quality improvement methodology to improve ovarian salvage for benign ovarian masses. AB - PURPOSE: Most ovarian masses in children are benign and potentially amenable to ovarian salvage surgery (OSS). Despite the common use of OSS among pediatric and adolescent gynecologists (PAG) in recognition of reproductive and hormonal health advantages, this technique is not commonly performed by pediatric surgeons. The aim of this quality improvement (QI) initiative was to improve our institutional rate of OSS for benign ovarian masses. METHODS: Baseline data were obtained retrospectively from surgical procedures performed for benign ovarian masses between January 2012 and February 2016. Designed interventions to improve the rate of OSS included the development of an ovarian mass algorithm, standardization of radiologic templates, multidisciplinary analyses of ovarian procedures, and implementation of a training model for performing OSS. Procedures performed for benign ovarian masses from March 2016 to February 2017 comprised the process stage. RESULTS: Our institutional baseline OSS rate was 28.8%. After implementation of the institutional algorithm, a single oophorectomy was performed for a benign mass, increasing the OSS rate to 96%. There have been no missed ovarian malignancies. CONCLUSIONS: Utilizing preoperative risk assessment, QI methodology and multidisciplinary collaboration resulted in improved OSS rates for benign ovarian masses with no evidence of missed ovarian malignancies. LEVEL OF EVIDENCE: Level II. This is a prospective comparative study, with comparison to a retrospective cohort. This is a quality improvement initiative without randomization. PMID- 29106920 TI - Single visit surgery for pediatric ambulatory surgical procedures: a satisfaction and cost analysis. AB - BACKGROUND: Single visit surgery (SVS) consists of same-day pre-operative assessment and operation with telephone post-operative follow-up. This reduces family time commitment to 1 hospital trip rather than 2-3. We began SVS for ambulatory patients with clear surgical indications in 2013. We sought to determine family satisfaction, cost savings to families, and institutional financial feasibility of SVS. METHODS: SVS patients were compared to age/case matched conventional surgery (CS) patients. Satisfaction was assessed by post operative telephone survey. Family costs were calculated as the sum of lost revenue (based on median income) and transportation costs ($0.50/mile). RESULTS: Satisfaction was high in both groups (98% for SVS vs. 93% for CS; p=0.27). 40% of CS families indicated that they would have preferred SVS, whereas no SVS families indicated preference for the CS option (p<0.001). Distance from the hospital did not correlate with satisfaction. Estimated cost savings for an SVS family was $188. Reimbursement, hospital and physician charges, and day-of-surgery cancellation rates were similar. CONCLUSIONS: SVS provides substantial cost savings to families while maintaining patient satisfaction and equivalent institutional reimbursement. SVS is an effective approach to low-risk ambulatory surgical procedures that is less disruptive to families, facilitates access to pediatric surgical care, and reduces resource utilization. TYPE OF STUDY: Cost Effectiveness Study. LEVEL OF EVIDENCE: Level II. PMID- 29106921 TI - Furukawa Agar - A novel bacteriological agar designed to inhibit fungal contamination when sampling organic compost. AB - A novel bacteriological agar, named Furukawa Agar, has been specifically designed to inhibit the growth of filamentous fungi during microbiological examination of bacteria from organic compost, thereby allowing complete analysis of the resulting bacterial organisms, without the overgrowth with filamentous fungi. PMID- 29106922 TI - Measuring Anatomic Severity in Pediatric Appendicitis: Validation of the American Association for the Surgery of Trauma Appendicitis Severity Grade. AB - OBJECTIVE: To assess whether the American Association for the Surgery of Trauma (AAST) grading system accurately corresponds with appendicitis outcomes in a US pediatric population. STUDY DESIGN: This single-institution retrospective review included patients <18 years of age (n = 331) who underwent appendectomy for acute appendicitis from 2008 to 2012. Demographic, clinical, procedural, and follow-up data (primary outcome was measured as Clavien-Dindo grade of complication severity) were abstracted. AAST grades were generated based on intraoperative findings. Summary, univariate, and multivariable regression analyses were performed to compare AAST grade and outcomes. RESULTS: Overall, 331 patients (46% female) were identified with a median age of 12 (IQR, 8-15) years. Appendectomy was laparoscopic in 90% and open in 10%. AAST grades included: Normal (n = 13, 4%), I (n = 152, 46%), II (n = 90, 27%), III (n = 43, 13%), IV (n = 24 7.3%), and V (n = 9 2.7%). Increased AAST grade was associated with increased Clavien-Dindo severity, P =.001. The overall complication rate was 13.6% and was comprised by superficial surgical site infection (n = 13, 3.9%), organ space infection (n = 15, 4.5%), and readmission (n = 17, 5.1%). Median duration of stay increased with AAST grade (P < .0001). Nominal logistic regression identified the following as predictors of any complication (P < .05): AAST grade and febrile temperature at admission. CONCLUSIONS: The AAST appendicitis grading system is valid in a single institution pediatric population. Increasing AAST grade incrementally corresponds with patient outcomes including increased risk of complications and severity of complications. Determination of the generalizability of this grading system is required. PMID- 29106923 TI - Impact of Objective Echocardiographic Criteria for Timing of Congenital Diaphragmatic Hernia Repair. AB - OBJECTIVE: To assess the impact of specific echocardiographic criteria for timing of congenital diaphragmatic hernia repair on the incidence of acute postoperative clinical decompensation from pulmonary hypertensive crisis and/or acute respiratory decompensation, with secondary outcomes including survival to discharge, duration of ventilator support, and length of hospitalization. STUDY DESIGN: The multidisciplinary congenital diaphragmatic hernia management team instituted a protocol in 2012 requiring the specific criterion of echocardiogram estimated pulmonary artery pressure <=80% systemic blood pressure before repairing congenital diaphragmatic hernias. A retrospective review of 77 neonatal patients with Bochdalek hernias repaired between 2008 and 2015 were reviewed: group 1 included patients repaired before protocol implementation (n = 25) and group 2 included patients repaired after implementation (n = 52). RESULTS: The groups had similar baseline characteristics. Postoperative decompensation occurred less often in group 2 compared with group 1 (17% vs 48%, P = .01). Adjusted analysis accounting for repair type, liver herniation, and prematurity yielded similar results (15% vs 37%, P = .04). Group 2 displayed a trend toward improved survival to 30 days postoperatively, though this did not reach statistical significance (94% vs 80%, P = .06). Patient survival to discharge, duration of ventilator support, and length of hospitalization were not different between groups. CONCLUSIONS: The implementation of a protocol requiring echocardiogram-estimated pulmonary arterial pressure <=80% of systemic pressure before congenital diaphragmatic hernia repair may reduce the incidence of acute postoperative decompensation, although there was no difference in longer-term secondary outcomes, including survival to discharge. PMID- 29106924 TI - A Randomized Trial of Conditioned or Unconditioned Gases for Stabilizing Preterm Infants at Birth. AB - OBJECTIVE: To determine whether the use of heated-humidified gases for respiratory support during the stabilization of infants <30 weeks of gestational age (GA) in the delivery room reduces rates of hypothermia on admission to the neonatal intensive care unit (NICU). STUDY DESIGN: A multicenter, unblinded, randomized trial was conducted in Melbourne, Australia, between February 2013 and June 2015. Infants <30 weeks of GA were randomly assigned to receive either heated-humidified gases or unconditioned gases during stabilization in the delivery room and during transport to NICU. Infants born to mothers with pyrexia >38 degrees C were excluded. Primary outcome was rate of hypothermia on NICU admission (rectal temperature <36.5 degrees C). RESULTS: A total of 273 infants were enrolled. Fewer infants in the heated-humidified group were hypothermic on admission to NICU (36/132 [27%]) compared with controls (61/141 [43%], P < .01). There was no difference in rates of hyperthermia (>37.5 degrees C); 20% (27/132) in the heated-humidified group compared with 16% (22/141) in the controls (P = .30). There were no differences in mortality or respiratory outcomes. CONCLUSIONS: The use of heated-humidified gases in the delivery room significantly reduces hypothermia on admission to NICU in preterm infants, without increased risk of hyperthermia. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (www.anzctr.org.au) ACTRN12613000093785. PMID- 29106925 TI - Nosocomial Transmission and Genetic Diversity of Rhinovirus in a Neonatal Intensive Care Unit. AB - Rhinoviruses were detected as sole pathogens in 6 preterm infants who developed severe respiratory infections while hospitalized in a neonatal intensive care unit. We confirmed 2 nosocomial rhinovirus transmission episodes and describe the genetic diversity of rhinovirus strains that circulated simultaneously during a winter season. PMID- 29106926 TI - Increasing Prevalence of Hepatitis C among Hospitalized Children Is Associated with an Increase in Substance Abuse. AB - OBJECTIVE: To evaluate the impact of substance abuse on pediatric hepatitis C virus (HCV) prevalence, we examined geographic and demographic data on inpatient hospitalizations in children with HCV. STUDY DESIGN: We examined hospitalizations in children using the Kids' Inpatient Database, a part of the Healthcare Cost and Utilization Project. We identified cases using the International Classification of Diseases, 9th edition, codes for HCV infection during 2006, 2009, and 2012. Nonparametric tests for trend were used to calculate trend statistics. RESULTS: From 2006 to 2012 nationally, the number of hospitalizations of children with HCV increased 37% (2.69 to 3.69 per 10 000 admissions; P < .001). The mean age of children hospitalized was 17.6 years (95% CI, 17.4-17.8). HCV cases among those 19-20 years of age represented 68% of the total HCV diagnoses, with a 54% increase over the years sampled (P < .001 for trend). The burden of HCV in children was highest in whites, those in the lowest income quartile, and in the Northeast and Southern regions of the US (all P < .0001). The prevalence of substance use among children with HCV increased from 25% in 2006 to 41% in 2012 (P < .001). CONCLUSION: The increases of HCV in hospitalized children are largely in teenagers, highly associated with substance abuse, and concentrated in Northeast and Southern states. These results strongly suggest that public health efforts to prevent and treat HCV will also need to include adolescents. PMID- 29106927 TI - Desquamating Rash in a Patient with Undiagnosed Netherton Syndrome. PMID- 29106928 TI - Epithelial-to-Mesenchymal Stem Cell Transition in a Human Organ: Lessons from Lichen Planopilaris. AB - Epithelial-to-mesenchymal transition (EMT) is critical for embryonic development and wound healing, and occurs in fibrotic disease and carcinoma. Here, we show that EMT also occurs within the bulge, the epithelial stem cell (eSC) niche of human scalp hair follicles, during the inflammatory permanent alopecia, lichen planopilaris. We show that a molecular EMT signature can be experimentally induced in healthy human eSCs in situ by antagonizing E-cadherin, combined with transforming growth factor-beta1, epidermal growth factor, and IFN-gamma administration, which to our knowledge has not been reported previously. Moreover, induction of EMT within primary human eSCs can be prevented and even partially reversed ex vivo by peroxisome proliferator-activated receptor-gamma agonists, likely through suppression of the transforming growth factor-beta signaling pathway. Furthermore, we show that peroxisome proliferator-activated receptor-gamma agonists also attenuates the EMT signature even in lesional lichen planopilaris hair follicles ex vivo. We introduce lichen planopilaris as a model disease for pathological EMT in human adult eSCs, report a preclinical assay for therapeutically manipulating eSC EMT within a healthy human (mini-)organ, and show that peroxisome proliferator-activated receptor-gamma agonists are promising agents for suppressing and partially reversing EMT in human hair follicles eSCs ex vivo, including in lichen planopilaris. PMID- 29106929 TI - Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts. AB - Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical nonsense-suppression (readthrough) therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full length SERPINB7 protein synthesis in NPPK keratinocytes. We next conducted an investigator-blinded, randomized, bilaterally controlled compassionate use study of topical gentamicin in which five NPPK patients with c.796C>T were enrolled. Patients' self-reported improvement of hyperkeratosis was significantly greater on the gentamicin side than the control side (P = 0.0349). In two patients, hyperkeratosis was improved on the gentamicin side, as determined by a blinded investigator assessment. These results indicate the therapeutic potential of topical gentamicin for NPPK. Unexpectedly, we also found that mutant SERPINB7 mRNAs harboring r.796c>u were degraded by nonsense-mediated mRNA decay. Furthermore, the truncated SERPINB7 protein was degraded via a proteasome mediated pathway. These findings provide important insights into the mRNA/protein quality-control system in humans, which could be a potential therapeutic target for genetic diseases. PMID- 29106930 TI - Topical Inhibition of the Electron Transport Chain Can Stimulate the Hair Cycle. PMID- 29106931 TI - Interplay between Keratinocytes and Myeloid Cells Drives Dengue Virus Spread in Human Skin. AB - The skin is the site of dengue virus (DENV) transmission following the bite of an infected mosquito, but the contribution of individual cell types within skin to infection is unknown. We studied the dynamics of DENV infection in human skin explants using quantitative in situ imaging. DENV replicated primarily in the epidermis and induced a transient IFN-alpha response. DENV infected a wide range of cells, including Langerhans cells, macrophages, dermal dendritic cells, mast cells, fibroblasts, and lymphatic endothelium, but keratinocytes were the earliest targets of infection and made up 60% of infected cells over time. Virus inoculation led to recruitment and infection of Langerhans cells, macrophages, and dermal dendritic cells, and these cells emigrated from skin in increased numbers as a result of infection. DENV induced expression of proinflammatory cytokines and chemokines by infected keratinocytes. Blocking keratinocyte-derived IL-1beta alone reduced infection of Langerhans cells, macrophages, and dermal dendritic cells by 75-90% and reduced the overall number of infected cells in dermis by 65%. These data show that the innate response of infected keratinocytes attracts virus-permissive myeloid cells that inadvertently spread DENV infection. Our findings highlight a role for keratinocytes and their interplay with myeloid cells in dengue. PMID- 29106932 TI - Evaluating STZ-Induced Impaired Wound Healing in Rats. PMID- 29106933 TI - Prediction of Host-Pathogen Interactions for Helicobacter pylori by Interface Mimicry and Implications to Gastric Cancer. AB - There is a strong correlation between some pathogens and certain cancer types. One example is Helicobacter pylori and gastric cancer. Exactly how they contribute to host tumorigenesis is, however, a mystery. Pathogens often interact with the host through proteins. To subvert defense, they may mimic host proteins at the sequence, structure, motif, or interface levels. Interface similarity permits pathogen proteins to compete with those of the host for a target protein and thereby alter the host signaling. Detection of host-pathogen interactions (HPIs) and mapping the re-wired superorganism HPI network-with structural details can provide unprecedented clues to the underlying mechanisms and help therapeutics. Here, we describe the first computational approach exploiting solely interface mimicry to model potential HPIs. Interface mimicry can identify more HPIs than sequence or complete structural similarity since it appears more common than the other mimicry types. We illustrate the usefulness of this concept by modeling HPIs of H. pylori to understand how they modulate host immunity, persist lifelong, and contribute to tumorigenesis. H. pylori proteins interfere with multiple host pathways as they target several host hub proteins. Our results help illuminate the structural basis of resistance to apoptosis, immune evasion, and loss of cell junctions seen in H. pylori-infected host cells. PMID- 29106934 TI - Mechanistic Insights into Dimethylsulfoniopropionate Lyase DddY, a New Member of the Cupin Superfamily. AB - The marine osmolyte dimethylsulfoniopropionate (DMSP) is one of Earth's most abundant organosulfur molecules. Bacterial DMSP lyases cleave DMSP, producing acrylate and dimethyl sulfide (DMS), a climate-active gas with roles in global sulfur cycling and atmospheric chemistry. DddY is the only known periplasmic DMSP lyase and is present in beta-, gamma-, delta- and epsilon-proteobacteria. Unlike other known DMSP lyases, DddY has not been classified into a protein superfamily, and its structure and catalytic mechanism are unknown. Here, we determined the crystal structure of DddY from the gamma-proteobacterium Acinetobacter bereziniae originally isolated from human clinical specimens. This structure revealed that DddY contains a cap domain and a catalytic domain with a Zn2+ bound at its active site. We also observed that the DddY catalytic domain adopts a typical beta barrel fold and contains two conserved cupin motifs. Therefore, we concluded that DddY should belong to the cupin superfamily. Using structural and mutational analyses, we identified key residues involved in Zn2+ coordination, DMSP binding and the catalysis of DMSP cleavage, enabling elucidation of the catalytic mechanism, in which the residue Tyr271 of DddY acts as a general base to attack DMSP. Moreover, sequence analysis suggested that this proposed mechanism is common to DddY proteins from beta-, gamma-, delta- and epsilon-proteobacteria. The DddY structure and proposed catalytic mechanism provide a better understanding of how DMSP is catabolized to generate the important climate-active gas DMS. PMID- 29106935 TI - Completing fishing monitoring with spaceborne Vessel Detection System (VDS) and Automatic Identification System (AIS) to assess illegal fishing in Indonesia. AB - The Indonesian fisheries management system is now equipped with the state-of-the art technologies to deter and combat Illegal, Unreported and Unregulated (IUU) fishing. Since October 2014, non-cooperative fishing vessels can be detected from spaceborne Vessel Detection System (VDS) based on high resolution radar imagery, which directly benefits to coordinated patrol vessels in operation context. This study attempts to monitor the amount of illegal fishing in the Arafura Sea based on this new source of information. It is analyzed together with Vessel Monitoring System (VMS) and satellite-based Automatic Identification System (Sat-AIS) data, taking into account their own particularities. From October 2014 to March 2015, i.e. just after the establishment of a new moratorium by the Indonesian authorities, the estimated share of fishing vessels not carrying VMS, thus being illegal, ranges from 42 to 47%. One year later in January 2016, this proportion decreases and ranges from 32 to 42%. PMID- 29106937 TI - Factors influencing the microplastic contamination of bivalves from the French Atlantic coast: Location, season and/or mode of life? AB - Monitoring the presence of microplastics (MP) in marine organisms is currently of high importance. This paper presents the qualitative and quantitative MP contamination of two bivalves from the French Atlantic coasts: the blue mussel (Mytilus edulis) and the Pacific oyster (Crassostrea gigas). Three factors potentially influencing the contamination were investigated by collecting at different sampling sites and different seasons, organisms both wild and cultivated. Inter- and intra-species comparisons were also achieved. MP quantity in organisms was evaluated at 0.61+/-0.56 and 2.1+/-1.7MP per individual respectively for mussels and oysters. Eight different polymers were identified. Most of the MPs were fragments; about a half of MPs were grey colored and a half with a size ranging from 50 to 100MUm for both studied species. Some inter specific differences were found but no evidence for sampling site, season or mode of life effect was highlighted. PMID- 29106936 TI - Can pesticides, copper and seasonal water temperature explain the seagrass Zostera noltei decline in the Arcachon bay? AB - Dwarf eelgrasses (Zostera noltei) populations have decreased since 2005 in Arcachon Bay (southwest France). Various stressors have been pointed out, however the role of xenobiotics like pesticides or copper (Cu) and of parameters like water temperature warming have not yet been explored. To determine their impact, Z. noltei individuals were collected in a pollution-free site and transferred to the laboratory in seawater microcosms. This dwarf eelgrass was exposed to a pesticide cocktail and copper, alone or simultaneously, at temperatures (10 degrees C, 20 degrees C, 28 degrees C) representative of different seasons. After a two-week contamination, leaf growth, leaf bioaccumulation of Cu, and differential expression of target genes were studied. Eelgrasses bioaccumulated Cu regardless of the temperature, with reduced efficiency in the presence of the Cu and pesticide cocktail at the two higher temperatures. High temperature also exacerbated the effect of contaminants, leading to growth inhibition and differential gene expression. Mitochondrial activity was strongly impacted and higher mortality rates occurred. Experimental results have been confirmed during field survey. This is the first report on the impacts on Z. noltei of pesticides and Cu associate to temperature. PMID- 29106938 TI - Bioaccumulation and biomagnification of potentially toxic elements in the octopus Octopus hubbsorum from the Gulf of California. AB - The concentrations of 21 potentially toxic elements (PTEs) were determined in the tissues of Octopus hubbsorum from three locations along the Gulf of California coast: two near Santa Rosalia (SR), a site with historical metal contamination, and one in La Paz Bay, a reference site. Concentrations of Cd, Co, Cr, Mn, Ni, Pb, and Zn in octopus from the two SR sites were higher than those from the reference site, reflecting the higher sediment concentrations at the mining impacted locations. The highest bioaccumulation and biomagnification of elements was found in digestive gland and branchial hearts, while the lowest was observed in the mantle, where the mean concentration of PTEs did not exceed international standards for human consumption of octopus. This study found elevated PTEs in octopus from sites with high metal contamination, and presents the first data on these elements in octopus from the Gulf of California. PMID- 29106939 TI - Microplastic and tar pollution on three Canary Islands beaches: An annual study. AB - Marine debris accumulation was analyzed from three exposed beaches of the Canary Islands (Lambra, Famara and Las Canteras). Large microplastics (1-5mm), mesoplastics (5-25mm) and tar pollution were assessed twice a month for a year. There was great spatial and temporal variability in the Canary Island coastal pollution. Seasonal patterns differed at each location, marine debris concentration depended mainly of local-scale wind and wave conditions. The most polluted beach was Lambra, a remote beach infrequently visited. The types of debris found were mainly preproduction resin pellets, plastic fragments and tar, evidencing that pollution was not of local origin, but it cames from the open sea. The levels of pollution were similar to those of highly industrialized and contaminated regions. This study corroborates that the Canary Islands are an area of accumulation of microplastics and tar rafted from the North Atlantic Ocean by the southward flowing Canary Current. PMID- 29106940 TI - Sediment-associated polycyclic aromatic hydrocarbons and potential eco-hazards in Chabahar Bay, Iran. AB - The surface sediments (0-4cm, n=6) from Chabahar Bay were analyzed to assess the concentrations, composition, and potential eco-hazards of associated PAHs. The range of ?16 PAHs' concentration was 25.75-312.38ngg-1 dw, with mean and median levels of 126.7 and 55.12ngg-1 dw, respectively. The bay was classified as a region with low to moderate PAH pollution. The sources of PAHs varied, and 2-3 ring compounds were dominant (37-90%). There was no significant correlation between TOC/grain size and levels of PAHs. Total carcinogenic PAHs ranged from 0.21 to 79.68ngg-1 dw, and benzo(a)pyrene was the main constituent of calculated toxic equivalencies. The bay sediments were rarely hazardous and could not address narcotic hazards for the benthic community. Biota-sediment accumulation was not predicted for the examined coral Acropora valida. In equilibrium conditions, release of ?16PAHs from the bay sediments was estimated to be 0.536MUgL-1 at its maximum. PMID- 29106941 TI - Anthropogenic microlitter in the Baltic Sea water column. AB - Microlitter (0.5-5mm) concentrations in water column (depth range from 0 to 217.5m) of the main Baltic Proper basins are reported. In total, 95 water samples collected in 6 research cruises in 2015-2016 in the Bornholm, Gdansk, and Gotland basins were analysed. Water from 10- and 30-litre Niskin bathometers was filtered through the 174MUm filters, and the filtrate was examined under optical microscope (40*). The bulk mean concentration was 0.40+/-0.58 items per litre, with fibres making 77% of them. Other types of particles are the paint flakes (19%) and fragments (4%); no microbeads or pellets. The highest concentrations are found in the near-bottom samples from the coastal zone (2.2-2.7 items per litre max) and from near-surface waters (0.5m) in the Bornholm basin (5 samples, 1.6-2.5 items per litre). Distribution of particles over depths, types, and geographical regions is presented. PMID- 29106942 TI - Temporal evolution of cadmium, copper and lead concentration in the Venice Lagoon water in relation with the speciation and dissolved/particulate partition. AB - In order to study the role of sediment re-suspension and deposition versus the role of organic complexation, we investigated the speciation of cadmium (Cd), copper (Cu) and lead (Pb) in samples collected in the Venice Lagoon during several campaigns from 1992 to 2006. The increment in Cd and Pb concentration in the dissolved phases, observed in the central and northern basins, can be linked to important alterations inside the lagoon caused by industrial and urban factors. The study focuses on metal partition between dissolved and particulate phases. The analyses carried out in different sites illustrate the complex role of organic matter in the sedimentation process. While Cd concentration in sediments can be correlated with organic matter, no such correlation can be established in the case of Pb, whose particulate concentration is related only to the dissolved concentration. In the case of Cu, the role of organic complexation remains unclear. PMID- 29106943 TI - Heavy metal fractionation and ecological risk implications in the intertidal surface sediments of Zhelin Bay, South China. AB - Intertidal surface sediments collected from Zhelin Bay, the largest mariculture base of eastern Guangdong Province of China, were analyzed for total metal concentrations and chemical speciation. Average total metal concentrations (mg/kg) were 0.063 (Cd), 35.69 (Pb), 23.07 (Cr), 7.50 (Ni), 7.95 (Cu), 74.95 (Zn), and 751.32 (Mn). Concentrations of Cd, Cu, Zn, and Mn were significantly higher than the corresponding background values of Zhelin Bay. All studied metals were dominated by residual fractions, whereas the second relatively higher average portions of Cd (24.10%) and Mn (15.17%) were strongly associated with the acid-soluble fraction. Overall, the intertidal surface sediments of Zhelin Bay were only slightly polluted based on the pollution load index (PLI), with a 21% probability of toxicity based on the mean effects range-median quotient. The metals Cd and Mn posed medium to high risk levels based on the method of risk assessment code (RAC). PMID- 29106944 TI - Proteases and glycosidases on the surface of exosomes: Newly discovered mechanisms for extracellular remodeling. AB - Emergence of the field of exosome biology has opened an exciting door to better understand communication between cells. These tiny nanovesicles act as potent regulators of biological function by delivering proteins, lipids and nucleic acids from the cell of origin to target cells. Recently, several enzymes including membrane-type 1 matrix metalloproteinase (MT1-MMP), insulin-degrading enzyme (IDE), sialidase and heparanase, among others, were localized on the surface of exosomes secreted by various cell types. These exosomal surface enzymes retain their activity and can degrade their natural substrates present within extracellular spaces. To date, enzymes on exosome surfaces have been associated with the mobilization of growth factors, degradation of extracellular matrix macromolecules and destruction of amyloid beta plaques. This review focuses on the emerging role of exosomal surface enzymes and how this mechanism of remodeling within the extracellular space may regulate disease progression as related to cancer, inflammation and Alzheimer's disease. PMID- 29106945 TI - Activation of the STING-IRF3 pathway promotes hepatocyte inflammation, apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common result of obesity and metabolic syndrome. Hepatocyte injury and metabolic disorders are hallmarks of NAFLD. Stimulator of interferon genes (STING) and its downstream factor interferon regulatory factor 3 (IRF3) trigger inflammatory reaction in response to the presence of cytosolic DNA. STING has recently been shown to play an important role in early alcoholic liver disease. However, little is known about the role of STING-IRF3 pathway in hepatocyte injury. Here, we aimed to examine the effect of STING-IRF3 pathway on hepatocyte metabolism, inflammation and apoptosis. METHODS: We examined the activation of the STING-IRF3 pathway, a high-fat diet (HFD)-induced obese mouse model, and determined the role of this pathway in a free fatty acid (FFA)-induced hepatocyte inflammatory response, injury, and dysfunction in L-O2 human liver cells. RESULTS: STING and IRF3 were upregulated in livers of HFD-fed mice and in FFA-induced L-O2 cells. Knocking down either STING or IRF3 led to a significant reduction in FFA-induced hepatic inflammation and apoptosis, as evidenced by modulation of the nuclear factor kappaB (NF-kappaB) signaling pathway, inflammatory cytokines, and apoptotic signaling. Additionally, STING/IRF3 knockdown enhanced glycogen storage and alleviated lipid accumulation, which were found to be associated with increased expression of hepatic enzymes in glycolysis and lipid catabolism, and attenuated expression of hepatic enzymes in gluconeogenesis and lipid synthesis. CONCLUSIONS: Our results suggest that the STING-IRF3 pathway promotes hepatocyte injury and dysfunction by inducing inflammation and apoptosis and by disturbing glucose and lipid metabolism. This pathway may be a novel therapeutic target for preventing NAFLD development and progression. PMID- 29106946 TI - Orodispersible tablets containing taste-masked solid lipid pellets with metformin hydrochloride: Influence of process parameters on tablet properties. AB - Compaction of multiparticulates into tablets, particularly into orodispersible tablets (ODTs), is challenging. The compression of pellets, made by solid lipid extrusion/spheronization processes, presents peculiar difficulties since solid lipids usually soften or melt at relatively low temperature ranges and due to applied mechanical forces. Until now, there are no reports in literature about the development of ODTs based on solid lipid pellets. To investigate the feasibility of producing such tablets, a design of experiment (DoE) approach was performed to elucidate the influence of compression force and amount of two co processed excipients (Ludiflash(r) and Parteck(r) ODT) on properties of the tablets (friability, tensile strength, and disintegration time). ODTs (15 mm, flat-faced) with solid lipid pellets (250-1000 um in diameter) containing 500 mg of metformin HCl, presenting immediate drug release profile and taste-masked properties, were targeted. During compression, a strong lamination of the tablets containing Parteck(r) ODT was observed. This phenomenon was prominently observed when high compression forces (>=5 kN) and high excipient amounts (>=40%; w/w) were used. On the other hand, the DoE focused on tablets with Ludiflash(r) showed better results regarding the production of ODTs. A positive influence of the compression force on the tensile strength and disintegration time of the tablets, regarding specifications of the Ph. Eur., was observed. The increase in the amount of this excipient resulted in fast disintegrating tablets, however, a negative influence on the tensile strength was noticed. After optimization of the parameters and formulation, based on the DoE results and considering the Ph. Eur. specifications for tablets, ODTs based on lipid pellets containing metformin HCl presenting immediate release profile (85% drug release in less than 30 min) and taste-masked properties (determined by an electronic tongue) were successfully obtained. PMID- 29106947 TI - Glial cell line-derived neurotrophic factor (GDNF) counteracts hypoxic damage to hippocampal neural network function in vitro. AB - Glial cell line-derived neurotrophic factor (GDNF) is regarded as a potent neuroprotector and a corrector of neural network activity in stress conditions. This work aimed to investigate the effect of GDNF on primary hippocampal cultures during acute normobaric hypoxia. Hypoxia induction was performed using day 14 in vitro cultures derived from mouse embryos (E18) with the preventive addition of GDNF (1 ng/ml) to the culture medium 10 min before oxygen deprivation. An analysis of spontaneous bioelectrical activity that included defining the internal neural network structure, morphological studies, and viability tests was performed during the post-hypoxic period. This study revealed that GDNF does not influence spontaneous network activity during normoxia but protects cultures from cell death and maintains the network activity during hypoxia. GDNF created unique conditions that supported the viability of cells even in cases of cellular mitochondrial damage. GDNF partially negated the consequences of hypoxia by influencing synaptic plasticity. Intravital mRNA detection identified fewer GluR2 mRNA-positive cells, whereas GDNF preserved the number of these cells in the post hypoxic period. Activation of the synthesis of GluR2 subunits of AMPA-receptors is one possible mechanism of the neuroprotective action of GDNF. PMID- 29106948 TI - Good functional outcome but not regained health related quality of life in the majority of 20-69 years old patients with femoral neck fracture treated with internal fixation: A prospective 2-year follow-up study of 182 patients. AB - BACKGROUND AND PURPOSE: Prospective studies on patient related outcome in patients <70years with a femoral neck fracture (FNF) are few. We aimed to investigate functional outcome and health-related quality of life (HRQoL) in 20 69years old patients with a FNF treated with internal fixation. PATIENTS AND METHODS: 182 patients, 20-69years with a FNF treated with internal fixation were prospectively included in a multicenter study. Follow up included radiographic and clinical examination at 4, 12 and 24 months. Collected data were hip function using Harris Hip Score (HHS), HRQoL (EQ-5D and SF-36), fracture healing and re operations. RESULTS: At 24 months, HHS was good or excellent in 73% of the patients with a displaced fracture and 85% of the patients with a non-displaced fracture (p=0.15). Of the patients with displaced fracture (n=120), 23% had a non union (NU) and 15% had an avascular necrosis (AVN) with a 28% re-operation rate. None of the patients with non-displaced fracture (n=50) had an NU, 12% had a radiographic AVN and 8% needed a re-operation. The mean EQ-5Dindex in patients with displaced fracture decreased from 0.81 to 0.59 at 4 months, 0.63 at 12 months and 0.65 at 24 months (p<0.001). The corresponding values for patients with non-displaced fracture were 0.88, 0.69, 0.75 and 0.74 respectively (p<0.001). The mean SF-total score in patients with displaced fracture decreased from 76 to 55 at 4 months, 63 at 12 months and 65 at 24 months (p<0.001). The corresponding values for patients with non-displaced fracture were 80, 67, 74 and 76 respectively (p<0.001). INTERPRETATION: Two thirds of the patients with displaced femoral neck fracture healed after one operation and three quarters reported good or excellent functional outcome at 24 months. However, they did not regain their pre-fracture level of HRQoL. PMID- 29106949 TI - Identifying key factors of the seawater intrusion model of Dagu river basin, Jiaozhou Bay. AB - Seawater intrusion is a complex groundwater - seawater interaction process, and it is influenced by many factors from ground surface to underground, from groundwater to seawater. Generally, for seawater intrusion model, some model parameters and boundary conditions are always specified by model users' personal experiences or literature's reference value. The defective model would damage the groundwater management for controlling and preventing seawater intrusion when making decisions are based on this model. In order to improve the reliability of seawater intrusion model, the influences of model inputs on output should be identified prior at optimizing model inputs. Dagu river basin, Jiaozhou Bay is one of the most serious areas of seawater intrusion in China, and it is chosen as the study area in this study. The seawater intrusion model of Dagu river basin is built based on a general program SEAWAT4. The key influence factors of model output are analyzed by two sensitivity analysis methods, i.e., stepwise regression and mutual entropy. The results demonstrated that the most important influence factors which have largest sensitivities to groundwater Cl- concentration are the precipitation rate and groundwater pumping in agriculture area. In addition, the hydraulic conductivity of zone 1 has a non-negligible influence on seawater intrusion process. Stepwise regression analysis is capable of identifying most important influence factor, and it can't handle complicated nonlinear input-output relationship. Mutual entropy analysis is reliable for identifying the influence factors for complex seawater intrusion model. PMID- 29106950 TI - Prenatal exposure to perfluoralkyl substances (PFASs) associated with respiratory tract infections but not allergy- and asthma-related health outcomes in childhood. AB - BACKGROUND: Prenatal exposure to perfluoralkyl substances (PFASs) has been reported to be associated with immunosuppression in early childhood, but with contradictory findings related to atopic and lung diseases. AIM: We aimed to determine if prenatal exposure to PFASs is associated with asthma or other allergic diseases or respiratory tract infections in childhood. METHODS: Nineteen PFASs were measured in cord blood available from 641 infants in the Environment and Childhood Asthma (ECA) prospective birth cohort study. The six most abundant PFASs were perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonamide (PFOSA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUnDA). Health outcomes were assessed at two and ten years of age, and included reported obstructive airways disease (wheeze by 10 years; asthma by 2 and 10 years; reduced lung function at birth; allergic rhinitis by 10 years), atopic dermatitis (AD) by 2 and 10 years, allergic sensitization by 10 years, and episodes of common respiratory tract infections (common cold by 2 years, lower respiratory tract infections (LRTI) by 10 years). The associations between exposure and health outcomes were examined using logistic and Poisson regression. RESULTS: The number of reported airways infections were significantly associated with cord blood concentrations of PFAS; common colds by two years with PFUnDA (beta = 0.11 (0.08-0.14)) and LRTIs from 0 to 10 years of age with PFOS (beta = 0.50 (0.42 0.57)), PFOA (beta = 0.28 (0.22-0.35)), PFOSA (beta = 0.10 (0.06-0.14)), PFNA (beta = 0.09 (0.03-0.14)) and PFUnDA (beta = 0.18 (0.13-0.23)) concentrations. Neither reduced lung function at birth, asthma, allergic rhinitis, AD nor allergic sensitization were significantly associated with any of the PFASs. CONCLUSION: Although prenatal exposure to PFASs was not associated with atopic or lung manifestations by 10 years of age, several PFASs were associated with an increased number of respiratory tract infections in the first 10 years of life, suggesting immunosuppressive effects of PFASs. PMID- 29106951 TI - Localized real-time information on outdoor air quality at kindergartens in Oslo, Norway using low-cost sensor nodes. AB - In Norway, children in kindergartens spend significant time outdoors under all weather conditions, and there is thus a natural concern about the quality of outdoor air. It is well known that air pollution is associated with a wide variety of adverse health impacts for children, with greater impact on children with asthma. Especially during winter and spring, kindergartens in Oslo that are situated close to streets with busy traffic, or in areas where wood burning is used for house heating, can experience many days with bad air quality. During these periods, updated information on air quality levels can help the kindergarten teachers to plan appropriate outdoor activities and thus protect children's health. We have installed 17 low-cost air quality nodes in kindergartens in Oslo. These nodes are smaller, cheaper and less complex to use than traditional equipment. Performance evaluation shows that while they are less accurate and suffer from higher uncertainty than reference equipment, they still can provide reliable coarse information about local pollution. The main challenge when using this technology is that calibration parameters might change with time depending on the atmospheric conditions. Thus, even if the sensors are calibrated a priori, once deployed, and especially if they are deployed for a long time, it is not possible to determine if a node is over- or under-estimating the concentration levels. To enhance the data from the sensors, we employed a data fusion technique that allows generating a detailed air quality map merging the data from the sensors and the data from an urban model, thus being able to offer air quality information to any location within Oslo. We arranged a focus group with the participation of local administration, kindergarten staff and parents to understand their opinion and needs related to the air quality information that was provided to the participant kindergartens. They expressed concern about the data quality but agree that having updated information on the air quality in the surroundings of kindergartens can help them to reduce children's exposure to air pollution. PMID- 29106952 TI - Green space definition affects associations of green space with overweight and physical activity. AB - INTRODUCTION: In epidemiological studies, exposure to green space is inconsistently associated with being overweight and physical activity, possibly because studies differ widely in their definition of green space exposure, inclusion of important confounders, study population and data analysis. OBJECTIVES: We evaluated whether the association of green space with being overweight and physical activity depended upon definition of greenspace. METHODS: We conducted a cross-sectional study using data from a Dutch national health survey of 387,195 adults. Distance to the nearest park entrance and surrounding green space, based on the Normalized Difference Vegetation Index (NDVI) or a detailed Dutch land-use database (TOP10NL), was calculated for each residential address. We used logistic regression analyses to study the association of green space exposure with being overweight and being moderately or vigorously physically active outdoors at least 150min/week (self-reported). To study the shape of the association, we specified natural splines and quintiles. RESULTS: The distance to the nearest park entrance was not associated with being overweight or outdoor physical activity. Associations of surrounding green space with being overweight or outdoor physical activity were highly non-linear. For NDVI surrounding greenness, we observed significantly decreased odds of being overweight [300m buffer, odds ratio (OR) = 0.88; 95% CI: 0.86, 0.91] and increased odds for outdoor physical activity [300m buffer, OR = 1.14; 95% CI: 1.10, 1.17] in the highest quintile compared to the lowest quintile. For TOP10NL surrounding green space, associations were mostly non-significant. Associations were generally stronger for subjects living in less urban areas and for the smaller buffers. CONCLUSION: Associations of green space with being overweight and outdoor physical activity differed considerably between different green space definitions. Associations were strongest for NDVI surrounding greenness. PMID- 29106953 TI - The association between p,p'-DDE levels and left ventricular mass is mainly mediated by obesity. AB - BACKGROUND AND OBJECTIVES: The pesticide metabolite p,p'-DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p' DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p'-DDE with LV mass. METHODS: p,p'-DDE was measured in plasma from 70-year-old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70 , 75- and 80- years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques. RESULTS: We found that p,p'-DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p'-DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%). CONCLUSION: The obesogenic effect of p,p' DDE is a major determinant responsible for the association of p,p'-DDE with LV mass. PMID- 29106954 TI - The ascorbate peroxidase APX1 is a direct target of a zinc finger transcription factor ZFP36 and a late embryogenesis abundant protein OsLEA5 interacts with ZFP36 to co-regulate OsAPX1 in seed germination in rice. AB - Seed germination is a vital developmental process. Abscisic acid (ABA) is an essential repressor of seed germination, while ROS (reactive oxygen species) also plays a vital role in regulating seed germination. ABA could inhibit the production of ROS in seed germination, but the mechanism of ABA reduced ROS production in seed germination was hitherto unknown. Here, by ChIP (chromatin immunoprecipitation)-seq, we found that ZFP36, a rice zinc finger transcription factor, could directly bind to the promoter of OsAPX1, coding an ascorbate peroxidase (APX) which has the most affinity for H2O2 (substrate; a type of ROS), and act as a transcriptional activator of OsAPX1 promoter. Moreover, ZFP36 could interact with a late embryogenesis abundant protein OsLEA5 to co-regulate the promoter activity of OsAPX1. The seed germination is highly inhibited in ZFP36 overexpression plants under ABA treatment, while an RNA interference (RNAi) mutant of OsLEA5 rice seeds were less sensitive to ABA, and exogenous ASC (ascorbate acid) could alleviate the inhibition induced by ABA. Thus, our conclusion is that OsAPX1 is a direct target of ZFP36 and OsLEA5 could interact with ZFP36 to co-regulate ABA-inhibited seed germination by controlling the expression of OsAPX1. PMID- 29106955 TI - Molecular characterization of Pod1 during sex development in Chinese tongue sole (Cynoglossus semilaevis). AB - Pod1 encodes a Class II bHLH transcription factor involved in the development of a number of tissues such as gonad, spleen, lungs and heart. However, to date, little is known about its function in teleosts. In this study, we cloned and characterized Pod1 gene from Cynoglossus semilaevis. This gene contains three exons and two introns, with the full-length cDNA of 918 nucleotides that encodes a 183 amino acid protein with a conserved bHLH domain. Realtime quantitative PCR revealed that Pod1 was predominantly expressed in the testes of C. semilaevis. In different stages of testes development, Pod1 expression was undetectable up to 120 days after hatching (dah), and then increased at 210 dah and 1 year after hatching (yah). Furthermore, in situ hybridization (ISH) analysis revealed that Pod1 was mainly localized in the germ cells of testes, but was not detected in ovarian cells; which suggested its possible functions in spermatogenesis of C. semilaevis. The methylation profile analysis of Pod1 genomic sequence in the gonads showed that the differences in their putative promoter regions of Pod1 among ovary, male and pseudo-male testes were not obvious. Thus, further research might be needed to evaluate whether Pod1 expression is regulated by epigenetic level. PMID- 29106956 TI - Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice. AB - Although pancreatic enzyme replacement therapy (PERT) is effective in the alleviation of pancreatic exocrine insufficiency (PEI)-related symptoms in patients with chronic pancreatitis, its mechanism of action is poorly understood. Recent studies suggest that the intestinal microbiota is associated with the pathogenesis of chronic pancreatitis. Therefore, we hypothesized that PERT exerts its effect by modifying the intestinal microbiota in addition to its presumed role in promoting fat and protein absorption. To explore the mechanism of action of PERT, we analyzed the intestinal microbiotas of two groups of mice treated with either pancrelipase or tap water by using 16S rRNA amplicon sequencing. The results revealed that the bacterial compositions of the pancrelipase-treated mice were significantly different from those of the control samples. Akkermansia muciniphila, a key beneficial bacterium in the intestinal tract, showed a higher relative abundance in the pancrelipase-treated samples than in the control samples. Lactobacillus reuteri, a widely used probiotic bacterium known to relieve intestinal inflammation, also showed a higher relative abundance in the pancrelipase-treated samples. These results suggested that PERT induces the colonization of beneficial bacteria, thereby contributing to the attenuation of PEI-associated symptoms in addition to improvement of the nutritional state. PMID- 29106957 TI - Overexpression of DBC1, correlated with poor prognosis, is a potential therapeutic target for hepatocellular carcinoma. AB - Deleted in Breast Cancer 1 (DBC1) is a regulatory protein involved in cell metabolism and cancer progression. Nevertheless, the expression and prognostic values of DBC1 in hepatocellular carcinoma (HCC) are still not well understood. The following study investigated the clinical significance and biological function of DBC1 in HCC. Briefly, overexpression of DBC1 at transcriptional and translational levels in human HCC tissues compared to adjacent normal tissues was observed using quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB) and immunohistochemistry (IHC) approach. Furthermore, upregulated DBC1 was significantly correlated with tumor size (p = 0.005), N stage (p = 0.016), M stage (p = 0.011), tumor differentiation (p < 0.001), and American Joint Committee on Cancer (AJCC) stage (p = 0.001). Moreover, Kaplan Meier survival analysis revealed that DBC1 was an independent prognosis predictor for disease-free survival (DFS) (p < 0.001) and overall survival (OS) (p < 0.001). In addition, by using Cell Counting Kit-8 (CCK8) assays and colony formation assays, we found that the knockdown of DBC1 significantly suppressed the proliferation of HCC cells in vitro. To conclude, these findings demonstrated that DBC1 was essential in tumorigenesis and proliferation. Moreover, it was identified as a potential therapeutic target for HCC. PMID- 29106958 TI - Variation in the activity of distinct cytochalasins as autophagy inhibitiors in human lung A549 cells. AB - Autophagy is a cell survival process that represents a therapeutic target in cancer treatment. Many types of cytochalasins have been identified and some of them have been reported to interfere with the formation of the autophagosome, although only limited data are available to assess their potential effects. Therefore, in this study, we examined the effects of cytochalasins and structurally related compounds on cell survival and the regulation of autophagy in human lung A549 adenocarcinoma cells. Cytochalasin D (CD) and cytochalasin E (CE) prominently inhibited the growth of A549 cells in a dose-dependent manner. Following treatment with CE, F-actin filaments were disrupted, and the proportion of binucleated cells increased, whereas no such effects were observed with the seven other cytochalasins tested. We found that cytochalasin H (CH), CD, and especially CE could induce the up-regulation of autophagy-related protein (LC3 II) and SQSTM1/p62. Using bafilomycin A1, we demonstrated that CD, CE, and CH inhibited autophagosome turnover, resulting in a dysfunctional autophagic process. The results of this study reveal that CE is the most potent cytochalasin in terms of its ability to induce cell death and inhibit autophagy. CE may therefore be an effective therapeutic agent against lung cancer. PMID- 29106959 TI - Two intermediate states of the conformational switch in dual specificity phosphatase 13a. AB - Dual specificity phosphatases (DUSPs) include MAP kinase phosphatases and atypical dual specificity phosphatases and mediate cell growth and differentiation, brain function, and immune responses. They serve as targets for drug development against cancers, diabetes and depression. Several DUSPs have non canonical conformation of the central beta-sheet and active site loops, suggesting that they may have conformational switch that is related to the regulation of enzyme activity. Here, we determined the crystal structure of DUSP13a, and identified two different structures that represent intermediates of the postulated conformational switch. Amino acid sequence of DUSP13a is not significantly homologous to DUSPs with conformational switch, indicating that the conformational switch is not sequence-dependent, but rather determined by ligand interaction. The sequence-independency suggests that other DUSPs with canonical conformation may have the conformational switch during specific cellular regulation. The conformational switch leads to significant changes in the protein surface, including a hydrophobic surface and pockets, which can be exploited for development of allosteric modulators of drug target DUSPs. PMID- 29106960 TI - Carnosol-mediated Sirtuin 1 activation inhibits Enhancer of Zeste Homolog 2 to attenuate liver fibrosis. AB - Quiescent hepatic stellate cell (HSC) activation and subsequent conversion into myofibroblasts is the central event in hepatic fibrosis pathogenesis. Epithelial mesenchymal transition (EMT), another vital participant in liver fibrosis, has the potential to initiate HSC activation, which promotes abundant myofibroblast production. Previous studies suggest that Enhancer of Zeste Homolog 2 (EZH2) plays a significant role in myofibroblast transdifferentiation; however, the underlying mechanisms remain largely unaddressed. Carnosol (CS), a compound extracted from rosemary, displays multiple pharmacological activities. This study aimed to investigate the signaling mechanisms underlying EZH2 inhibition and the anti-fibrotic effect of CS in liver fibrosis. We found that CS significantly inhibited CCl4- and TGFbeta1-induced liver fibrosis and reduced both HSC activation and EMT. EZH2 knockdown also prevented these processes induced by TGFbeta1 in HSCs and AML-12 cells. Interestingly, the protective effect of CS was positively associated with Sirtuin 1 (SIRT1) activation and accompanied by EZH2 inhibition. SIRT1 knockdown attenuated the EZH2 inhibition induced by CS and increased EZH2 acetylation, which enhanced its stability. Conversely, upon TGFbeta1 exposure, SIRT1 activation significantly reduced the level of EZH2 acetylation; however, EZH2 overexpression prevented the SIRT1 activation that primed myofibroblast inhibition, indicating that EZH2 is a target of SIRT1. Thus, SIRT1/EZH2 regulation could be used as a new therapeutic strategy for fibrogenesis. Together, this study provides evidence of activation of the SIRT1/EZH2 pathway by CS that inhibits myofibroblast generation, and thus, CS may represent an attractive candidate for anti-fibrotic clinical therapy. PMID- 29106961 TI - Immunological analysis of food proteins using high-performance thin-layer chromatography-immunostaining. AB - The chromatographic analysis of intact proteins is still challenging, especially when biological functions as antigenicity of proteins or peptides are in the focus. Traditional immunoassays provide information about the entirety of antigenic proteins/peptides, e.g., in ELISA assays. On the other hand, when focusing on the investigation of (cross) reactivity of antibodies, Western blot following gel-electrophoresis represents the method of choice. However, gel electrophoresis is limited by the molecular weight and therefore, not suitable for peptides <=3kDa or proteins >=250kDa. Furthermore, for gaining detailed information about the protein sequence (e.g., via mass spectrometric analysis), a so called in-gel digest needs to be performed following electrophoretic separation and is therefore elaborate and accompanied by a significant loss of structural, and even more severe, conformational information. Here, protein analysis using HPTLC seems to be a promising alternative due to the high level of variability regarding the chromatographic system (multiple mobile and stationary phases, even mixed) and manifold detection as well as hyphenation possibilities. This study exemplarily focused on the immunological investigation of proteins in milk following thin-layer chromatographic separation. The detection of these antigens is mandatory, as they might trigger allergenic reactions in sensitized people. Besides the proof of its applicability on different stationary phase materials, the newly developed immunoassay can be used as an approach for semi quantitative estimation of antigenic proteins. In addition to the analysis of intact food allergens, also analyzing peptides thereof is worth considering which can be realized using HPTLC-immunostaining as well. PMID- 29106962 TI - A modified quick, easy, cheap, effective, rugged, and safe cleanup method followed by liquid chromatography-tandem mass spectrometry for the rapid analysis of perchlorate, bromate and hypophosphite in flour. AB - A selective, sensitive and useful method, based on modified QuEChERS cleanup combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the negative-ion electrospray ionization (ESI-) mode, was developed and validated for the simultaneous determination of three inorganic anions including perchlorate (ClO4-), bromate (BrO3-) and hypophosphite (H2PO2-) in flour. The extraction parameters and LC-MS/MS conditions were optimized by single-factor experiment and sorbent combination in modified QuEChERS clean-up was optimized through response surface analysis. Three target analytes were separated on a normal-phase Phenomenex Luna Silica (2) column (150mm*2.0mm, 5MUm, 100A) with the mobile phase of a mixture of 5mmol/L ammonium acetate water solution and acetonitrile, detected by MS/MS under multiple reaction monitoring and quantified by external standard method. The developed method was validated in terms of the sensitivity, linearity, accuracy and precision, and matrix effect. The method showed a good linearity (R2>0.999) for all analytes in their respective concentration ranges. The ILOQs and MLOQs for perchlorate, bromate and hypophosphite were 0.1, 0.5, 5.0MUg/L and 2.0, 6.0, 60.0MUg/L, respectively. The average recoveries of three target analytes from the negative samples spiked at three different concentrations were in a range from 84.6% to 104.9%. The intra-day precision (n=6) and inter-day precision (n=5) of the target analytes were in the ranges of 2.9%-6.9% and 6.4%-8.2%. The matrix effect of this method was observed between 0.83 and 1.17 and was acceptable. The validated method was successfully applied to determine the concentrations of these inorganic anions in flour. Results found that perchlorate and hypophosphite were detected in 33 out of 50 and 7 out of 50 flour samples. PMID- 29106963 TI - Optimizing loop-type cryogenic modulation in comprehensive two-dimensional gas chromatography using time-variable combination of the dual-stage jets for analysis of crude oil. AB - The enhanced chromatographic capability of the comprehensive two-dimensional gas chromatography (GC*GC) has already found several applications in analytical chemistry comprising complex samples. However, setting the appropriate chromatographic conditions that maximize sensitivity and separation efficiency in GC*GC may be more difficult than in conventional one-dimension gas chromatography, mainly due to the additional parameters strictly related to the modulation. Loop-type cryogenic modulators have been currently used for crude oil analysis using GC*GC, requiring sometimes a laborious try-and-error procedure to properly tune the dual-jets elapsed times on modulation. In this work, the advantages of choosing a time-variable combination of cold and hot jets pulses in a loop-type cryogenic modulator is presented when performing the fingerprinting analysis of crude oils using GC*GC-QMS, contrary to the conventional procedure based on a single combination for the dual-stage jets. A design of experiments approach is proposed to most effectively optimize the time-variable combination of the dual-jets elapsed times while modulating the wide hydrocarbons range along the GC*GC analysis. The most abundant classes of hydrocarbons contained in the maltenes fraction of a crude oil sample, such as paraffins, aromatics, steranes and hopanes were successfully resolved. PMID- 29106964 TI - Simulated molecular-scale interaction of supercritical fluid mobile and stationary phases. AB - In supercritical fluid chromatography, molecules from the mobile phase adsorb on the stationary phase. Stationary-phase alkylsilane-terminated silica surfaces might adsorb molecules at the silica, among the silanes, on a silane layer, or in pore space between surfaces. Mobile phases of carbon dioxide, pure and modified with methanol, and stationary phases were simulated at the molecular scale. Classical atomistic force fields were used in Gibbs-ensemble hybrid Monte Carlo calculations. Excess adsorption of pure carbon dioxide mobile phase peaked at fluid densities of 0.002-0.003A-3. Mobile phase adsorption from 7% methanol in carbon dioxide peaked at lower fluid density. Methanol was preferentially adsorbed from the mixed fluid. Surface silanes prevented direct interaction of fluid-phase molecules with silica. Some adsorbed molecules mixed with tails of bonded silanes; some formed layers above the silanes. Much adsorption occurred by filling the space between surfaces in the stationary-phase model. The distribution in the stationary phase of methanol molecules from a modified fluid phase varied with pressure. PMID- 29106965 TI - Unravelling the effects of multiple experimental factors in metabolomics, analysis of human neural cells with hydrophilic interaction liquid chromatography hyphenated to high resolution mass spectrometry. AB - This work introduces a strategy for decomposing variable contributions within the data obtained from structured metabolomic studies. This approach was applied in the context of an in vitro human neural model to investigate biochemical changes related to neuroinflammation. Neural cells were exposed to the neuroinflammatory toxicant trimethyltin at different doses and exposure times. In the frame of an untargeted approach, cell contents were analysed using HILIC hyphenated with HRMS. Detected features were annotated at level 1 by comparison against a library of standards, and the 126 identified metabolites were analysed using a recently proposed chemometric tool dedicated to multifactorial Omics datasets, namely, ANOVA multiblock OPLS (AMOPLS). First, the total observed variability was decomposed to highlight the contribution of each effect related to the experimental factors. Both the dose of trimethyltin and the exposure time were found to have a statistically significant impact on the observed metabolic alterations. Cells that were exposed for a longer time exhibited a more mature and differentiated metabolome, whereas the dose of trimethyltin was linked to altered lipid pathways, which are known to participate in neurodegeneration. Then, these specific metabolic patterns were further characterised by analysing the individual variable contributions to each effect. AMOPLS was highlighted as a useful tool for analysing complex metabolomic data. The proposed strategy allowed the separation, quantitation and characterisation of the specific contribution of the different factors and the relative importance of every metabolite to each effect with respect to the total observed variability of the system. PMID- 29106966 TI - Single-step preparation of selected biological fluids for the high performance liquid chromatographic analysis of fat-soluble vitamins and antioxidants. AB - Fat-soluble vitamins and antioxidants are of relevance in health and disease. Current methods to extract these compounds from biological fluids mainly need use of multi-steps and multi organic solvents. They are time-consuming and difficult to apply to treat simultaneously large sample number. We here describe a single step, one solvent extraction of fat-soluble vitamins and antioxidants from biological fluids, and the chromatographic separation of all-trans-retinoic acid, 25-hydroxycholecalciferol, all-trans-retinol, astaxanthin, lutein, zeaxanthin, trans-beta-apo-8'-carotenal, gamma-tocopherol, beta-cryptoxanthin, alpha tocopherol, phylloquinone, lycopene, alpha-carotene, beta-carotene and coenzyme Q10. Extraction is obtained by adding one volume of biological fluid to two acetonitrile volumes, vortexing for 60s and incubating for 60min at 37 degrees C under agitation. HPLC separation occurs in 30min using Hypersil C18, 100*4.6mm, 5MUm particle size column, gradient from 70% methanol+30% H2O to 100% acetonitrile, flow rate of 1.0ml/min and 37 degrees C column temperature. Compounds are revealed using highly sensitive UV-VIS diode array detector. The HPLC method suitability was assessed in terms of sensitivity, reproducibility and recovery. Using the present extraction and chromatographic conditions we obtained values of the fat-soluble vitamins and antioxidants in serum from 50 healthy controls similar to those found in literature. Additionally, the profile of these compounds was also measured in seminal plasma from 20 healthy fertile donors. Results indicate that this simple, rapid and low cost sample processing is suitable to extract fat-soluble vitamins and antioxidants from biological fluids and can be applied in clinical and nutritional studies. PMID- 29106967 TI - Asymmetric high-contrast masking in S cone increment and decrement pathways. AB - Physiological, anatomical, and psychophysical evidence points to important differences between visual processing of short-wave cone increments and decrement (S+ and S-) stimuli. The present study uses the pedestal discrimination paradigm to investigate potential differences, using S+ and S- tests presented on (L)ong wave, (M)edium-wave, S, L+M, L-M, and achromatic pedestals, of both contrast polarities. Results show that high contrast 'purplish' (S+ or -(L+M)) pedestals produce substantially more masking of both S+ and S- tests than 'yellowish' (S- or +(L+M)) pedestals do. The other pedestals produce no masking. These findings suggest greater nonlinearity - either a static nonlinearity or contrast gain control - in the mechanisms responsible for the 'purplish' polarity, likely the S ON pathway. PMID- 29106968 TI - Effects of El Nino and La Nina Southern Oscillation events on the adrenocortical responses to stress in birds of the Galapagos Islands. AB - El Nino Southern Oscillation events (ENSO) and the subsequent opposite weather patterns in the following months and years (La Nina) have major climatic impacts, especially on oceanic habitats, affecting breeding success of both land and sea birds. We assessed corticosterone concentrations from blood samples during standardized protocols of capture, handling and restraint to simulate acute stress from 12 species of Galapagos Island birds during the ENSO year of 1998 and a La Nina year of 1999. Plasma levels of corticosterone were measured in samples collected at capture (to represent non-stressed baseline) and subsequently up to 1 h post-capture to give maximum corticosterone following acute stress, and total amount of corticosterone that the individual was exposed to during the test period (integrated corticosterone). Seabird species that feed largely offshore conformed to the brood value hypothesis whereas inshore feeding species showed less significant changes. Land birds mostly revealed no differences in the adrenocortical responses to acute stress from year to year with the exception of two small species (<18 g) that had an increase in baseline and stress responses in the ENSO year - contrary to predictions. We suggest that a number of additional variables, including body size and breeding stage may have to be considered as explanations for why patterns in some species deviated from our predictions. Nevertheless, comparative studies like ours are important for improving our understanding of the hormonal and reproductive responses of vertebrates to large scale weather patterns and global climate change in general. PMID- 29106969 TI - Electrotransfer of single-chain LH gene into skeletal muscle induces early ovarian development of orange-spotted grouper (Epinephelus coioides). AB - Luteinizing hormone (LH) plays important roles in regulating steroidogenesis and reproductive development of vertebrates. In the present paper, we study function of LH on early ovarian development of orange-spotted grouper by electrotransfer of single-chain LH gene into skeletal muscle for the first time. Short-term and long-term injection experiments were performed in this work, respectively. For short-term injection experiments, fish received one electrotransfer with the plasmid in skeletal muscle, then blood and muscle around the injected area were sampled 1, 3, 5 and 7 days after the injection, mRNA expression levels of LH gene relative to 18S were determined by quantitative real-time PCR (RT-PCR) assays and serum 17beta-estradiol (E2) levels were quantified by ELISA method. The results showed that levels of mRNA of LH gene in muscle and serum E2 level increased from 1 day to 7 days after the injection. For long-term injection experiments, fish received electrotransfer with the plasmid 4 times at weekly intervals in skeletal muscle. 48 h after the last injection, blood, gonad and hypothalamus samples were collected. Transcripts of cyp19a1a, cyp19a1b and gnrh1 genes and levels of serum E2 were separately analyzed by RT-PCR assays and ELISA method, and ovarian tissues were made of paraffin sections and stained by hematoxylin-eosin by method and observed by optical microscopy. The results suggested that long-term injection of LH gene into muscle upregulated transcripts of cyp19a1a and cyp19a1b and downregulated that of gnrh1, and stimulated E2 production and early-stage oogenesis. Moreover, statistical data showed that 9 of 10 ovaries of injected fish with LH gene began to develop after the long-term experiments. These data suggest that single-chain LH gene introduced into skeletal muscle via electrotransfer can be expressed and induce the early ovarian development of juvenile orange-spotted grouper. This work contributes to solve reproductive dysfunctions associated with low hormone levels of teleosts, further it may represent the demonstration at regulation of LH on early ovarian development of orange-spotted grouper to a certain extent. PMID- 29106970 TI - Functional studies reveal the similarities and differences between AM2 and BM2 proton channels from influenza viruses. AB - AM2 and BM2 proton channels are attractive antiviral drug targets due to their essential roles during influenza virus replication. Although both AM2 and BM2 are proton-selective ion channels, they share little sequence similarity except for the HXXXW sequence, which suggests that their proton conductance properties might differ. To test this hypothesis, we applied two-electrode voltage clamp electrophysiological assays to study the specific conductance, leakage current, channel activation, and inhibition of AM2 and BM2 proton channels. It was found that BM2 channel has a higher specific conductance than AM2 channel at pH5.5. Unlike AM2 channel, whose proton conductance is asymmetric (from viral exterior to interior), BM2 channel is capable of conducting proton in both directions. Moreover, BM2 requires a more acidic pH for channel activation than AM2, as revealed by its lower pKa values. Finally, both AM2 and BM2 can be inhibited by Cu(II) and Cu(I). Overall, the results from this side-by-side comparison of AM2 and BM2 channels reveal the structure-function relationships of these two viroporins, and such information might be important for the designing of novel ion channels. PMID- 29106972 TI - Real-time analysis of protein and protein mixture interaction with lipid bilayers. AB - Artificial lipid bilayers in the form of planar supported or vesicular bilayers are commonly used as models for studying interaction of biological membranes with different substances such as proteins and small molecule pharmaceutical compounds. Lipid membranes are typically regarded as inert and passive scaffolds for membrane proteins, but both non-specific and specific interactions between biomolecules and lipid membranes are indeed ubiquitous; dynamic exchange of proteins from the environment at the membrane interface can strongly influence the function of biological membranes. Such exchanges would either be of a superficial (peripheral) or integrative (penetrating) nature. In the context of viral membranes (termed envelopes), this could contribute to the emergence of zoonotic infections as well as change the virulence and/or pathogenicity of viral diseases. In this study, we analyze adsorption/desorption patterns upon challenging tethered liposomes and enveloped virus particles with proteins - or protein mixtures - such as bovine serum albumin, glycosylphosphatidylinositol anchored proteins and serum, chosen for their different lipid-interaction capabilities. We employed quartz crystal microbalance and dual polarization interferometry measurements to measure protein/membrane interaction in real time. We identified differences in mass uptake between the challenges, as well as differences between variants of lipid bilayers. Tethered viral particles showed a similar adsorption/desorption behavior to liposomes, underlining their value as model system. We believe that this methodology may be developed into a new approach in virology and membrane research by enabling the combination of biophysical and biochemical information. PMID- 29106971 TI - Interaction of a quercetin derivative - lensoside Abeta with liposomal membranes. AB - Lensoside Abeta, representing the flavonol glycosides, is a compound isolated from the aerial parts of edible lentil (Lens culinaris) cultivar Tina. This substance arouses interest because so far there is very little data about secondary metabolites isolated from the leaves and stems of this plant. Additionally, bioactive potential of flavonoids is directly coupled with the membranes as a primary target of their physiological and pharmacological activity. The aim of this study was to investigate the effect of lensoside Abeta on lipid membranes. Interaction of examined compound with liposomes formed with dipalmitoylphosphatidylcholine (DPPC) was investigated with application of FTIR spectroscopy and 1H NMR technique. Molecular localization and orientation of lensoside Abeta in a single lipid bilayer system represented by giant unilamellar vesicles, was also investigated with application of confocal fluorescence lifetime imaging microscopy (FLIM). FTIR analysis revealed that the tested compound incorporates into DPPC membranes via hydrogen bonding to lipid polar head groups in the PO2 group region and the COPOC segment. Furthermore 1H NMR analysis showed ordering effect in both the hydrophobic alkyl chains region and the polar heads of phospholipids. FLIM investigation has revealed roughly parallel orientation of its molecules in the membranes. This suggests that one of the possible physiological functions of this flavonol could be screening a cell against short-wavelength radiation. PMID- 29106973 TI - Reconstitution of SNARE proteins into solid-supported lipid bilayer stacks and X ray structure analysis. AB - SNAREs are known as an important family of proteins mediating vesicle fusion. For various biophysical studies, they have been reconstituted into supported single bilayers via proteoliposome adsorption and rupture. In this study we extended this method to the reconstitution of SNAREs into supported multilamellar lipid membranes, i.e. oriented multibilayer stacks, as an ideal model system for X-ray structure analysis (X-ray reflectivity and diffraction). The reconstitution was implemented through a pathway of proteomicelle, proteoliposome and multibilayer. To monitor the structural evolution in each step, we used small-angle X-ray scattering for the proteomicelles and proteoliposomes, followed by X-ray reflectivity and grazing-incidence small-angle scattering for the multibilayers. Results show that SNAREs can be successfully reconstituted into supported multibilayers, with high enough orientational alignment for the application of surface sensitive X-ray characterizations. Based on this protocol, we then investigated the effect of SNAREs on the structure and phase diagram of the lipid membranes. Beyond this application, this reconstitution protocol could also be useful for X-ray analysis of many further membrane proteins. PMID- 29106974 TI - Direct visualization of the lateral structure of giant vesicles composed of pseudo-binary mixtures of sulfatide, asialo-GM1 and GM1 with POPC. AB - We compared the lateral structure of giant unilamellar vesicles (GUVs) composed of three pseudo binary mixtures of different glycosphingolipid (GSL), i.e. sulfatide, asialo-GM1 or GM1, with POPC. These sphingolipids possess similar hydrophobic residues but differ in the size and charge of their polar head group. Fluorescence microscopy experiments using LAURDAN and DiIC18 show coexistence of micron sized domains in a molar fraction range that depends on the nature of the GSLs. In all cases, experiments with LAURDAN show that the membrane lateral structure resembles the coexistence of solid ordered and liquid disordered phases. Notably, the overall extent of hydration measured by LAURDAN between the solid ordered and liquid disordered membrane regions show marked similarities and are independent of the size of the GSL polar head group. In addition, the maximum amount of GSL incorporated in the POPC bilayer exhibits a strong dependence on the size of the GSL polar head group following the order sulfatide>asialo GM1>GM1. This observation is in full harmony with previous experiments and theoretical predictions for mixtures of these GSL with glycerophospholipids. Finally, compared with previous results reported in GUVs composed of mixtures of POPC with the sphingolipids cerebroside and ceramide, we observed distinctive curvature effects at particular molar fraction regimes in the different mixtures. This suggests a pronounced effect of these GSL on the spontaneous curvature of the bilayer. This observation may be relevant in a biological context, particularly in connection with the highly curved structures found in neural cells. PMID- 29106976 TI - Early Worsening of Renal Function After Treatment with Antihyperglycemic Drugs: A Consistent Finding in Large-Scale Trials. PMID- 29106975 TI - Ib-AMP4 insertion causes surface rearrangement in the phospholipid bilayer of biomembranes: Implications from quartz-crystal microbalance with dissipation. AB - Most antimicrobial peptides exert their rapid bactericidal activity through a unique mechanism of bacterial membrane disruption. However, the molecular events that underlie this mechanism remain partly unresolved. In this study, the frequency shift (DeltaF) obtained through quartz-crystal microbalance with dissipation (QCM-D) indicated that the initial binding of Ib-AMP4 within the lipid membrane started at a critical Ib-AMP4 concentration that exceeded 100MUg/ml. Circular dichroism measurements provided evidence that Ib-AMP4 occurs in a beta-sheet configuration which is adapted for insertion into the lipid membrane. Monolayer experiments and the value of dissipation alteration (DeltaD) obtained through QCM-D showed that the pressure increased within the phospholipid bilayer upon peptide insertion, and the increase in pressure subsequently forced the bilayer to wrinkle and form pores. However, D continued to increase, indicating that the membrane surface underwent a dramatic morphological transition: the membrane surface likely became porous and uneven as Ib-AMP4 projected from the external surface of the lipid bilayer. Intensive peptide insertion, however, soon plateaued 1min after the addition of Ib-AMP4. This behaviour corresponded with the results of bactericidal kinetics and liposome leakage assays. A sudden decrease in D accompanied by a negligible decrease in F occurred after replacing the Ib-AMP4 solution with HEPES buffer. This result implied that the bilayer surface rearranged and that poration and wrinkling decreased without further peptide insertion. Transmission electron microscopy results indicated that pore formation occurred during Ib-AMP4 insertion but eventually subsided. Therefore, the mode of action of AMP in bacterial membranes could be elucidated through QCM-D. PMID- 29106978 TI - Coaching Patients Saves Lives and Money. AB - BACKGROUND: The Coaching On Achieving Cardiovascular Health (COACH) Program has been proven to improve biomedical and lifestyle cardiovascular disease (CVD) risk factors. The objective of this study was to evaluate the long-term impact of The COACH Program on overall survival, hospital utilization, and costs from the perspective of a private health insurer (payor), in patients with CVD. METHODS: A prospective parallel-group case-control study design with controls randomly matched to patients based on propensity score. There were 512 participants with CVD engaged in a structured disease management program of 6 months duration (The COACH Program) who were matched to 512 patients with CVD who were allocated to the control group. The independent variables that estimated the propensity score were preprogram hospital admissions, age, and sex. The primary outcome was overall survival with secondary outcomes, including hospital utilization and cost incurred by the private health insurer. Mean follow-up was 6.35 years. Difference in overall survival between the 2 groups was estimated using a Cox proportional hazard ratio (HR) with difference in total cost estimated using a generalized linear model. RESULTS: The COACH Program achieved a significant reduction in overall mortality (HR 0.70; 95% confidence interval [CI], 0.53-0.93; P = .014). There was an apparent dose-response effect: those who received up to 3 coaching sessions had no decrease in mortality (HR 1.02; 95% CI, 0.69-1.49; P = .926); those who received 4 or more coaching sessions had a substantial decrease in mortality (HR 0.58; 95% CI, 0.42-0.81; P = .001). Total cost to the health insurer was substantially lower in the intervention group ($12,707 per person lower; P = .078). The reduction in total cost was significantly greater in those who received 4 or more sessions ($19,418 per person; P = .006) and in males ($18,947 per person; P = .029). CONCLUSIONS: Those enrolled in The COACH program achieved a statistically significant decrease in overall mortality compared with usual care at 6.35 years. A substantive reduction in hospital costs was also observed among those who received The COACH program compared with those who did not, particularly in those who received 4 or more sessions and in males. PMID- 29106977 TI - Causes of Troponin Elevation and Associated Mortality in Young Patients. AB - BACKGROUND: While increased serum troponin levels are often due to myocardial infarction, increased levels may also be found in a variety of other clinical scenarios. Although these causes of troponin elevation have been characterized in several studies in older adults, they have not been well characterized in younger individuals. METHODS: We conducted a retrospective review of patients 50 years of age or younger who presented with elevated serum troponin levels to 2 large tertiary care centers between January 2000 and April 2016. Patients with prior known coronary artery disease were excluded. The cause of troponin elevation was adjudicated via review of electronic medical records. All-cause death was determined using the Social Security Administration's death master file. RESULTS: Of the 6081 cases meeting inclusion criteria, 3574 (58.8%) patients had a myocardial infarction, while 2507 (41.2%) had another cause of troponin elevation. Over a median follow-up of 8.7 years, all-cause mortality was higher in patients with nonmyocardial infarction causes of troponin elevation compared with those with myocardial infarction (adjusted hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.15-1.46; P < .001). Specifically, mortality was higher in those with central nervous system pathologies (adjusted HR 2.21; 95% CI, 1.85-2.63; P < .001), nonischemic cardiomyopathies (adjusted HR 1.66; 95% CI, 1.37-2.02; P < .001), and end-stage renal disease (adjusted HR 1.36; 95% CI, 1.07 1.73; P = .013). However, mortality was lower in patients with myocarditis compared with those with an acute myocardial infarction (adjusted HR 0.43; 95% CI:, 0.31-0.59; P < .001). CONCLUSION: There is a broad differential for troponin elevation in young patients, which differs based on demographic features. Most nonmyocardial infarction causes of troponin elevation are associated with higher all-cause mortality compared with acute myocardial infarction. PMID- 29106979 TI - Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat. AB - BACKGROUND: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. METHODS: Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61MUmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. RESULTS: In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO <10%), sub pharmacological dose (RO 10%-30%) and pharmacological dose (RO >30%). CONCLUSION: For the first time a predictive model that could describe the quantitative in vivo relationship between dose, PK and D2 RO of raclopride in non-anesthetized rat was established. The PK-RO model could facilitate the selection of optimal dose and dosing time when raclopride is used as tracer or as pharmacological blocker in various rat studies. The LC-MS based approach, which doses and quantifies a non-radiolabeled tracer, could be useful in evaluating the systemic disposition and brain kinetics of tracers. PMID- 29106980 TI - Pericyte implantation in the brain enhances cerebral blood flow and reduces amyloid-beta pathology in amyloid model mice. AB - Pericytes are a major component of cerebrovasculature playing a key role in maintaining cerebrovascular homeostasis. These cells have also been suggested to regulate brain metabolism of amyloid-beta (Abeta), disturbances of which are believed to contribute to the pathogenesis of Alzheimer's disease (AD). To examine the effects of pericytes on brain Abeta metabolism, C3H/10T1/2 mouse mesenchymal stem cells were differentiated into pericytes and stereotaxically injected into the brains of amyloid AD model APP/PS1 mice at the age of 18 to 20months. Consistent with a role of pericytes in modulating cerebrovascular function, brain microcirculation in the pericyte-injected hemisphere of the mice was increased 3weeks after implantation compared to the contralateral hemisphere when measured by laser speckle contrast analysis technology. Importantly, enzyme linked immunosorbent assay revealed that the levels of insoluble Abeta40 and Abeta42 were significantly lower in the hippocampus of the pericyte-injected hemisphere of the APP/PS1 mice than that of the contralateral side. Consistently, immunohistochemical analysis demonstrated that the pericyte implantation reduced Abeta deposition in the hippocampus. When brain slices from the APP/PS1 mice were incubated with C3H/10T1/2 cell-derived pericytes, Abeta42 levels were significantly reduced in a manner that depends on the expression of a major Abeta endocytic receptor, the low-density lipoprotein receptor-related protein 1 (LRP1). While LRP1 mediated the cellular uptake of Abeta in the pericytes, the amounts of major Abeta-degrading enzymes were not affected by LRP1 knockdown. Together, our findings indicate that mesenchymal stem cell-derived pericytes have the capacity to reduce brain Abeta and related pathology, and suggest that cell based therapy through transplantation of pericytes may be a promising approach to prevent and/or treat AD. PMID- 29106981 TI - Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury. AB - The inability of axons to regenerate over long-distances in the central nervous system (CNS) limits the recovery of sensory, motor, and cognitive functions after various CNS injuries and diseases. Although pre-clinical studies have identified a number of manipulations that stimulate some degree of axon growth after CNS damage, the extent of recovery remains quite limited, emphasizing the need for improved therapies. Here, we used traumatic injury to the mouse optic nerve as a model system to test the effects of combining several treatments that have recently been found to promote axon regeneration without the risks associated with manipulating known tumor suppressors or oncogenes. The treatments tested here include TPEN, a chelator of mobile (free) zinc (Zn2+); shRNA against the axon growth-suppressing transcription factor Klf9; and the atypical growth factor oncomodulin combined with a cAMP analog. Whereas some combinatorial treatments produced only marginally stronger effects than the individual treatments alone, co-treatment with TPEN and Klf9 knockdown had a substantially stronger effect on axon regeneration than either one alone. This combination also promoted a high level of cell survival at longer time points. Thus, Zn2+ chelation in combination with Klf9 suppression holds therapeutic potential for promoting axon regeneration after optic nerve injury, and may also be effective for treating other CNS injuries and diseases. PMID- 29106982 TI - Distinct TrkA and Ret modulated negative and positive neuropathic behaviors in a mouse model of resiniferatoxin-induced small fiber neuropathy. AB - Neurotrophic factors and their corresponding receptors play key roles in the maintenance of different phenotypic dorsal root ganglion (DRG) neurons, the axons of which degenerate in small fiber neuropathy, leading to various neuropathic manifestations. Mechanisms underlying positive and negative symptoms of small fiber neuropathy have not been systematically explored. This study investigated the molecular basis of these seemingly paradoxical neuropathic behaviors according to the profiles of TrkA and Ret with immunohistochemical and pharmacological interventions in a mouse model of resiniferatoxin (RTX)-induced small fiber neuropathy. Mice with RTX neuropathy exhibited thermal hypoalgesia and mechanical allodynia, reduced skin innervation, and altered DRG expression profiles with decreased TrkA(+) neurons and increased Ret(+) neurons. RTX neuropathy induced the expression of activating transcription factor 3 (ATF3), and ATF3(+) neurons were colocalized with Ret but not with TrkA (P<0.001). As a neuroprotectant, 4-Methylcatechol (4MC) promoted skin reinnervation partially with correlated reversal of the neuropathic behaviors and altered neurochemical expression. Gambogic amide, a selective TrkA agonist, normalized thermal hypoalgesia, and GW441756, a TrkA kinase inhibitor, induced thermal hypoalgesia, which was already reversed by 4MC. Mechanical allodynia was reversed by a Ret kinase inhibitor, AST487, which induced thermal hyperalgesia in naive mice. The activation of Ret signaling by XIB4035 induced mechanical allodynia and thermal hypoalgesia in RTX neuropathy mice in which the neuropathic behaviors were previously normalized by 4MC. Distinct neurotrophic factor receptors, TrkA and Ret, accounted for negative and positive neuropathic behaviors in RTX-induced small fiber neuropathy, respectively: TrkA for thermal hypoalgesia and Ret for mechanical allodynia and thermal hypoalgesia. PMID- 29106983 TI - GABAB receptor subtypes differentially regulate thalamic spindle oscillations. AB - Following the discovery of GABAB receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABAB receptors assemble multi subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABAB1a, GABAB1b and GABAB2 form two heterodimeric GABAB(1a,2) and GABAB(1b,2) receptors that can associate with tetramers of auxiliary KCTD (K+ channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABAB(1b,2) receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABAB(1a,2) receptors function as heteroreceptors and inhibit glutamate release. Both GABAB(1a,2) and GABAB(1b,2) receptors can serve as autoreceptors and inhibit GABA release. Auxiliary KCTD subunits regulate the duration of sIPSCs and scaffold effector channels at the receptor. GABAB receptors are well known to contribute to thalamic spindle oscillations. Spindles are generated through alternating burst-firing in reciprocally connected glutamatergic thalamocortical relay (TCR) and GABAergic thalamic reticular nucleus (TRN) neurons. The available data implicate postsynaptic GABAB receptors in TCR cells in the regulation of spindle frequency. We now used electrical or optogenetic activation of thalamic spindles and pharmacological experiments in acute slices of knock-out mice to study the impact of GABAB(1a,2) and GABAB(1b,2) receptors on spindle oscillations. We found that selectively GABAB(1a,2) heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABAB(1b,2) receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABAB(1a,2) and GABAB(1b,2) receptors. This article is part of the "Special Issue Dedicated to Norman G. Bowery". PMID- 29106984 TI - Evaluation of profile and functionality of memory T cells in pulmonary tuberculosis. AB - The cells T CD4+ T and CD8+ can be subdivided into phenotypes naive, T of central memory, T of effector memory and effector, according to the expression of surface molecules CD45RO and CD27. The T lymphocytes are cells of long life with capacity of rapid expansion and function, after a new antigenic exposure. In tuberculosis, it was found that specific memory T cells are present, however, gaps remain about the role of such cells in the disease immunology. In this study, the phenotypic profile was analyzed and characterized the functionality of CD4+ T lymphocytes and CD8+ T cells of memory and effector, in response to specific stimuli in vitro, in patients with active pulmonary TB, compared to individuals with latent infection with Mycobacterium tuberculosis the ones treated with pulmonary TB. It was observed that the group of patients with active pulmonary tuberculosis was the one which presented the highest proportion of cells T CD4+ of central memory IFN-gamma+ e TNF-alpha+, suggesting that in TB, these T of central memory cells would have a profile of protective response, being an important target of study for the development of more effective vaccines; this group also developed lower proportion of CD8+ T effector lymphocytes than the others, a probable cause of specific and less effective response against the bacillus in these individuals; the ones treated for pulmonary tuberculosis were those who developed higher proportion of T CD4+ of memory central IL-17+ cells, indicating that the stimulation of long duration, with high antigenic load, followed by elimination of the pathogen, contribute to more significant generation of such cells; individuals with latent infection by M. tuberculosis and treated for pulmonary tuberculosis, showed greater response of CD8+ T effector lymphocytes IFN-gamma+ than the controls, suggesting that these cells, as well as CD4+ T lymphocytes, have crucial role of protection against M. tuberculosis. These findings have contributed to a better understanding of the immunologic changes in M. tuberculosis infection and the development of new strategies for diagnosis and prevention of tuberculosis. PMID- 29106985 TI - The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis. AB - Thymic dendritic cells (DC) play a role in central tolerance. Three thymic DC subtypes have been described: plasmacytoid DC (pDC) and two conventional DC (cDC), CD8alpha+ Sirpalpha- DC and Sirpalpha+ CD8alpha- cDC. Both pDC and Sirpalpha+ cDC can take up antigen in periphery and migrate into the thymus in response to chemokine signaling via CCR9 and CCR2 respectively. CCL2 is a major ligand for CCR2 and we previously showed that it was constitutively expressed in thymus, and that mice overexpressing CCL2 in thymus had reduced numbers of autoreactive T cells but elevated numbers of pDC. We have here investigated the role of CCL2-CCR2 axis in thymic pDC migration. We found that pDC expressed CCR2 at a high level and that their frequency was decreased in thymus, spleen and inguinal lymph nodes in mice lacking CCR2, but not in mice lacking CCL2. pDC migration towards the cortex or medulla within the thymus was not affected by CCL2 or CCR2 deficiency. Although some thymic progenitors expressed CCR2, this did not include those that give rise to pDC. Based on these results, we propose that CCR2 is involved in pDC homeostasis but its ligand CCL2 does not play a major role. PMID- 29106986 TI - Intraperitoneal administration of a novel chimeric immunogen (rOP) elicits IFN gamma and IL-12p70 protective immune response in BALB/c mice against virulent Brucella. AB - Recombinant engineering of immunologically active chimeric protein consisting of Omp19 and P39 domains of B. abortus (rOP), was purified under denaturing conditions upon expression in E. coli BL21 (DE3) and refolded to dynamic form. The immuno-protective efficacy of rOP was evaluated by challenging the BALB/c mice intraperitoneally (I.P) with the infective species of Brucella in the absence or presence of adjuvants, such as Aluminum hydroxide gel (Al), or Freund's Complete Adjuvant (FCA)/Incomplete Freund's Adjuvant (IFA). Surprisingly, after second boosting, mice received rOP per se were found to be immunogenic in terms of IgG response with the dominant expression of IgG2a and significant IFN-gamma by splenic T cells, suggesting that rOP is a strong inducer of anti-Brucella immunity. The resulted anti-rOP antibodies recognized native Omp19 and P39 among species of Brucella with distinct double bands and single band against chimera in immunoblotting. An enhanced and comparable antibody response with varied IgG isotype combinations were noticed in the mice primed and boosted with rOP in adjuvants. However, rOP+FCA/IFA formulation was found to be the most effective in lymphocyte recall assays at inducing significant (P<0.001) proliferation index (P.I.) as well as increased Th1-coupled cytokines (IFN-gamma, IL-2 and IL-12p70) than rOP+Al in response to rOP re-stimulation. Furthermore, in vitro defensive assay revealed that compared to anti-rOP antisera, the polyclonal anti-sera from rOP+adjuvants exhibited enhanced protection of RAW264.7 cells against virulent challenge by B. melitensis 16M and B. abortus 544. In addition, compared to sham group, enumeration of Brucella CFU after challenge with the above species showed a significant (P<0.01) reduction of bacteria (log CFU) in the macrophage cell lines and organs of vaccinated mice. On the whole, a relatively higher and faster reduction was noticed in the mice vaccinated with similar amount of purified antigen in Freund's adjuvant. Ability of inducing Th1 directed immune protection in the absence of adjuvant support, postulated rOP as a plausible entrant for developing a chimeric based subunit vaccine against Brucella. PMID- 29106987 TI - Targeting interferons as a strategy for systemic sclerosis treatment. AB - Systemic Sclerosis (SSc) is an autoimmune disease characterised by vasculopathy, uncontrolled inflammation and enhanced fibrosis which can subsequently lead to the loss of organ function or even premature death. Interferons (IFNs) are pleiotropic cytokines that are critical not only in mounting an effective immune response against viral and bacterial infections but also strongly contribute to the pathogenesis of SSc. Furthermore, elevated levels of IFNs are found in SSc patients and correlate with skin thickness and disease activity suggesting potential role of IFNs as biomarkers. In this review, we summarise existing knowledge regarding all types of IFNs and IFN-inducible genes in the pathogenesis of SSc. We then argue why IFN-blocking strategies are promising therapeutic targets in SSc and other autoimmune diseases. PMID- 29106988 TI - Trans-generational immune priming in the mealworm beetle protects eggs through pathogen-dependent mechanisms imposing no immediate fitness cost for the offspring. AB - Immune-challenged mothers can improve their offspring immunity through trans generational immune priming (TGIP). In insects, TGIP endows the offspring with lifetime immunity, including the eggs, which are likely exposed soon after maternal infection. Egg protection may rely on the transfer of maternal immune effectors to the egg or/and the induction of egg immune genes. These respective mechanisms are assumed to have early-life fitness costs of different magnitude for the offspring. We provide evidence in the mealworm beetle Tenebrio molitor that enhanced egg immunity following a maternal immune challenge is achieved by both of these mechanisms but in a pathogen-dependent manner. While previously found having late-life fitness costs for the offspring, TGIP here improved egg hatching success and early larval survival, in addition of improving offspring immunity. These results suggest that early-life of primed offspring is critical in the optimization of life history trajectory of this insect under trans generational pathogenic threats. PMID- 29106991 TI - Regulation of vascular function and blood pressure by circadian variation in redox signalling. AB - There is accumulating evidence that makes the link between the circadian variation in blood pressure and circadian variations in vascular contraction. The importance of vascular endothelium-derived redox-active and redox-derived species in the signalling pathways involved in controlling vascular smooth muscle contraction are well known, and when linked to the circadian variations in the processes involved in generating these species, suggests a cellular mechanism for the circadian variations in blood pressure that links directly to the peripheral circadian clock. Relaxation of vascular smooth muscle cells involves endothelial derived relaxing factor (EDRF) which is nitric oxide (NO) produced by endothelial NO synthase (eNOS), and endothelial-derived hyperpolarising factor (EDHF) which includes hydrogen peroxide (H2O2) produced by NADPH oxidase (Nox). Both of these enzymes appear to be under the direct control of the circadian clock mechanism in the endothelial cells, and disruption to the clock results in endothelial and vascular dysfunction. In this review, we focus on EDRF and EDHF and summarise the recent findings on the influence of the peripheral circadian clock mechanism on processes involved in generating the redox species involved and how this influences vascular contractility, which may account for some of the circadian variations in blood pressure and peripheral resistance. Moreover, the direct link between the peripheral circadian clock and redox-signalling pathways in the vasculature, has a bearing on vascular endothelial dysfunction in disease and aging, which are both known to lead to dysfunction of the circadian clock. PMID- 29106990 TI - White light emitting diode suppresses proliferation and induces apoptosis in hippocampal neuron cells through mitochondrial cytochrome c oxydase-mediated IGF 1 and TNF-alpha pathways. AB - Light emitting diode (LED) light has been tested to treat traumatic brain injury, neural degenerative diseases and psychiatric disorders. Previous studies indicate that blue LED light affects cell proliferation and apoptosis in photosensitive cells and cancer cells. In this study, we demonstrate that white LED light exposure impaired proliferation and induced apoptosis in HeLa and HT-22 hippocampal neural cells, but not C2C12 cells. Furthermore, the mechanisms underlying the effect of white LED light exposure on HT-22 cells were elucidated. In HeLa and HT-22 cells, white LED light activated mitochondrial cytochrome c oxidase (Cco), in association with enhanced ATP synthase activity and elevated intracellular ATP concentration. Also, reactive oxygen species (ROS) and nitric oxide (NO) production were increased, accompanied by higher calcium concentration and lower mitochondrial membrane potential. HT-22 cells exposed to white LED light for 24h showed reduced viability, with higher apoptotic rate and a cell cycle arrest at G0/G1 phase. Concurrently, the mRNA expression and the concentration of IGF-1 were decreased, while that of TNF-alpha were increased, in light-exposed cells, which was supported by the luciferase activity of both gene promoters. The down-stream mitogen-activated protein kinase (MAPK), AKT/mTOR pathways were inhibited, in association with an activation of apoptotic caspase 3. N-Acetylcysteine, a ROS scavenger, protected the cells from LED light-induced cellular damage, with rescued cell viability and restored mRNA expression of IGF 1 and TNF-alpha. Our data demonstrate that white LED light suppresses proliferation and induces apoptosis in hippocampal neuron cells through mitochondrial Cco/ROS-mediated IGF-1 and TNF-alpha pathways. PMID- 29106989 TI - Gonadal hormones affect alcohol drinking, but not cue+yohimbine-induced alcohol seeking, in male and female rats. AB - Alcohol use disorder (AUD) is a chronic, relapsing disease characterized by maladaptive patterns of alcohol drinking and seeking. Though sex differences exist in the etiology of AUD, much remains to be elucidated concerning the mechanisms underlying sex-related vulnerability to developing excessive alcohol motivated behavior. While a large body of evidence points to an important role of circulating gonadal hormones in mediating cocaine reinforcement, findings are less consistent with respect to ethanol. Critically, the effects of gonadal hormones on the reinstatement of ethanol seeking, a model of "craving"-like behavior that reveals pronounced sex differences, has not yet been examined. Thus, the goal of the present experiment was to directly compare manipulations of gonadal hormones in male and female rats on ethanol-motivated behavior. Rats received sham or gonadectomy surgery with or without hormone replacement prior to and throughout three weeks of operant ethanol self-administration to determine the effects of chronically high or low gonadal hormone levels on ethanol drinking. Hormone treatment ceased during extinction training, and the effects of an acute injection of either testosterone (in males) or estradiol (in females) on cue+yohimbine-induced reinstatement of ethanol seeking was determined. Separate groups of gonadally-intact female rats went through similar training, but the effects of either the antiestrogen, fulvestrant, the selective estrogen receptor modulator, clomiphene, or the estrogen receptor beta antagonist, PHTPP, on the reinstatement of ethanol seeking were determined. Chronic estradiol replacement produced significant increases in ethanol drinking in female rats, while chronic testosterone significantly decreased ethanol drinking in male rats. Gonadectomy alone only produced modest shifts in drinking towards the opposite-sex pattern, and did not eliminate the robust sex differences that persisted regardless of hormone manipulations. Neither prior chronic nor acute hormone manipulations altered cue+yohimbine-induced reinstatement of ethanol seeking, though blockade of estrogen receptors tended to reduce reinstatement in gonadally-intact females. Overall, our findings indicate that gonadal hormones at least partially mediate, but do not totally account for the sex differences evident in ethanol self administration, and circulating gonadal hormones have little effect on the reinstatement of ethanol seeking. These results provide a foundation for future studies examining the neuronal mechanisms underlying sex differences in ethanol drinking and seeking. PMID- 29106992 TI - Biological novelty in the anthropocene. AB - It is well known that humans are creating new variants of organisms, ecosystems and landscapes. Here I argue that the degree of biological novelty generated by humans goes deeper than that. We use property rules to create exclusivity in cooperation among humans, and between humans and other biological entities, thus overcoming social dilemmas and breaking barriers to cooperation. This is leading to novel forms of cooperation. One of them is the human control, modification and replication of whole ecosystems. For the first time, there exist ecosystems with functional design, division of labor and unlimited heredity. We use mental representation and language as new mechanisms of inheritance and modification that apply to an increasing variety of biological and non-biological entities. As a result, the speed, depth and scale of biological innovation are unprecedented in the history of life. PMID- 29106993 TI - The role of cellular senescence in aging through the prism of Koch-like criteria. AB - Since Hayflick's discovery of cellular senescence (CS), a great volume of knowledge in the field has been accumulated and intensively discussed. Here, we attempted to organize the evidence "for" and "against" the hypothesized causal role of CS in aging. For that purpose, we utilized robust Koch-like logical criteria, based on the assumption that some quantitative relationships between the accumulation of senescent cells and aging rate should exist. If so, it could be expected that (i) the "CS load" would be greater in the premature aging phenotype and lesser in longevity phenotype; (ii) CS would promote age-related diseases, and (iii) the interventions that modulate the levels of senescent cells should also modulate health/lifespan. The analysis shows that CS can be considered a causal factor of aging and an important player in various age related diseases, though its contribution may greatly vary across species. While the relative impact of senescent cells to aging could overall be rather limited and their elimination is hardly expected to be the "fountain of youth", the potential benefits of the senolytic strategy seems a promising option in combating age-related diseases and extending healthspan. PMID- 29106994 TI - Induction of new metabolites from the endophytic fungus Bionectria sp. through bacterial co-culture. AB - A new alkaloid, 1,2-dihydrophenopyrrozin (1), along with five known compounds (2 6) was isolated from an axenic culture of the endophytic fungus, Bionectria sp., obtained from seeds of the tropical plant Raphia taedigera. Co-cultivation of this fungus either with Bacillus subtilis or with Streptomyces lividans resulted in the production of two new o-aminobenzoic acid derivatives, bionectriamines A and B (7 and 8) as well as of two additional known compounds (9 and 10). None of the latter compounds (7-10) were detected in axenic cultures of the fungus or of the bacteria indicating activation of silent biogenetic gene clusters through co cultivation with bacteria. The structures of the new compounds were unambiguously determined based on detailed NMR and MS spectroscopic analysis and by comparison with the literature. The crystal structure of agathic acid (6) is reported here for the first time. Penicolinate A (4) exhibited potent cytotoxic activity against the human ovarian cancer cell line A2780 with an IC50 value of 4.1MUM. PMID- 29106995 TI - Azacoccones A-E, five new aza-epicoccone derivatives from Aspergillus flavipes. AB - Azacoccones A-E (1-5), five new aza-epicoccone derivatives, were isolated from the culture of Aspergillus flavipes. Their structures were determined by extensive NMR spectroscopic analyses and the absolute configuration of 5 was determined by electronic circular dichroism (ECD) calculation. Compounds 1-5 are proposed to be generated via a Pictet-Spengler reaction-based biosynthetic route starting from the precursor flavipin. Pictet-Spengler reaction is rarely found in the fungal kingdom, which indicated the distinctive nature of 1-5. Compounds 3 and 5 exhibit significant free radical scavenging activities with IC50 values of 4.0 and 2.4MUg/mL, respectively, which are better than the positive control trolox (4.55MUg/mL). PMID- 29106996 TI - Chronic rhinosinusitis: Endotypes, biomarkers, and treatment response. AB - It is increasingly recognized that chronic rhinosinusitis (CRS) comprises a spectrum of different diseases with distinct clinical presentations and pathogenic mechanisms. Defining the distinct phenotypes and endotypes of CRS affects prognosis and, most importantly, is necessary as the basis for making therapeutic decisions. The need for individualized definitions of pathogenic mechanisms before initiating therapy extends to virtually all therapeutic considerations. This is clearly crucial with antibiotics, where, barring an influence from their off-target anti-inflammatory pharmacologic effects, an understanding of the role of the individual biome predicts likelihood of therapeutic benefit. However, this need for identifying individual phenotypes and endotypes also extends to the agent that is currently considered the mainstay of treatment of CRS, specifically glucocorticoids. As with asthma, it is recognized that a large minority of patients with CRS have a steroid-resistant phenotype, identification of which will preclude use of these agents with their potential side effects. Identification of endotypes is also becoming increasingly imperative because targeted biotherapeutic agents, such as anti-IgE and anti cytokine antibodies, are becoming available. These agents are likely to benefit patients in whom the targeted mediator is not only expressed but demonstrably driving a central mechanism in that patient. In summary, the treatment of CRS is at an exciting crossroad. On the positive side, numerous therapeutics are in development that seem likely to have a positive effect in our patients with this condition. The challenge is that these therapies will require targeted individualized treatments based on identifying subjects with the relevant endotype. PMID- 29106997 TI - Interferon response to respiratory syncytial virus by bronchial epithelium from children with asthma is inversely correlated with pulmonary function. AB - BACKGROUND: Respiratory viral infection in early childhood, including that from respiratory syncytial virus (RSV), has been previously associated with the development of asthma. OBJECTIVE: We aimed to determine whether ex vivo RSV infection of bronchial epithelial cells (BECs) from children with asthma would induce specific gene expression patterns and whether such patterns were associated with lung function among BEC donors. METHODS: Primary BECs from carefully characterized children with asthma (n = 18) and matched healthy children without asthma (n = 8) were differentiated at an air-liquid interface for 21 days. Air-liquid interface cultures were infected with RSV for 96 hours and RNA was subsequently isolated from BECs. In each case, we analyzed gene expression using RNA sequencing and assessed differences between conditions by linear modeling of the data. BEC donors completed spirometry to measure lung function. RESULTS: RSV infection of BECs from subjects with asthma, compared with uninfected BECs from subjects with asthma, led to a significant increase in expression of 6199 genes. There was significantly greater expression of 195 genes in BECs from children with asthma and airway obstruction (FEV1/forced vital capacity < 0.85 and FEV1 < 100% predicted) than in BECs from children with asthma without obstruction, or in BECs from healthy children. These specific genes were found to be highly enriched for viral response genes induced in parallel with types I and III interferons. CONCLUSIONS: BECs from children with asthma and with obstructive physiology exhibit greater expression of types I and III interferons and interferon-stimulated genes than do cells from children with normal lung function, and expression of interferon-associated genes correlates with the degree of airway obstruction. These findings suggest that an exaggerated interferon response to viral infection by airway epithelial cells may be a mechanism leading to lung function decline in a subset of children with asthma. PMID- 29106999 TI - Functional connectivity in the dorsal stream and between bilateral auditory related cortical areas differentially contribute to speech decoding depending on spectro-temporal signal integrity and performance. AB - Speech processing relies on the interdependence between auditory perception, sensorimotor integration, and verbal memory functions. Functional and structural connectivity between bilateral auditory-related cortical areas (ARCAs) facilitates spectro-temporal analyses, whereas the dynamic interplay between ARCAs and Broca's area (i.e., dorsal pathway) contributes to verbal memory functions, articulation, and sound-to-motor mapping. However, it remains unclear whether these two neural circuits are preferentially driven by spectral or temporal acoustic information, and whether their recruitment is predictive of speech perception performance and learning. Therefore, we evaluated EEG-based intracranial (eLORETA) functional connectivity (lagged coherence) in both pathways (i.e., between bilateral ARCAs and in the dorsal stream) while good- (GPs, N = 12) and poor performers (PPs, N = 13) learned to decode natural pseudowords (CLEAN) or comparable items (speech-noise chimeras) manipulated in the envelope (ENV) or in the fine-structure (FS). Learning to decode degraded speech was generally associated with increased functional connectivity in the theta, alpha, and beta frequency range in both circuits. Furthermore, GPs exhibited increased connectivity in the left dorsal stream compared to PPs, but only during the FS condition and in the theta frequency band. These results suggest that both pathways contribute to the decoding of spectro-temporal degraded speech by increasing the communication between brain regions involved in perceptual analyses and verbal memory functions. Otherwise, the left-hemispheric recruitment of the dorsal stream in GPs during the FS condition points to a contribution of this pathway to articulatory-based memory processes that are dependent on the temporal integrity of the speech signal. These results enable to better comprehend the neural circuits underlying word-learning as a function of temporal and spectral signal integrity and performance. PMID- 29106998 TI - Antiapoptotic serine protease inhibitors contribute to survival of allergenic TH2 cells. AB - BACKGROUND: The mechanisms that regulate maintenance of persistent TH2 cells and potentiate allergic inflammation are not well understood. OBJECTIVE: The function of serine protease inhibitor 2A (Spi2A) was studied in mouse TH2 cells, and the serine protease inhibitor B3 (SERPINB3) and SERPINB4 genes were studied in TH2 cells from patients with grass pollen allergy. METHODS: Spi2A-deficient TH2 cells were studied in in vitro culture or in vivo after challenge of Spi2A knockout mice with ovalbumin in alum. Expression of SERPINB3 and SERPINB4 mRNA was measured in in vitro-cultured TH2 cells and in ex vivo CD27-CD4+ cells and innate lymphoid cell (ILC) 2 from patients with grass pollen allergy by using quantitative PCR. SERPINB3 and SERPINB4 mRNA levels were knocked down in cultured CD27-CD4+ cells with small hairpin RNA. RESULTS: There were lower levels of in vitro-polarized TH2 cells from Spi2A knockout mice (P < .005) and in vivo after ovalbumin challenge (P < .05), higher levels of apoptosis (Annexin V positivity, P < .005), and less lung allergic inflammation (number of lung eosinophils, P < .005). In vitro-polarized TH2 cells from patients with grass pollen allergy expressed higher levels of both SERPINB3 and SERPINB4 mRNA (both P < .05) compared with unpolarized CD4 T cells. CD27-CD4+ from patients with grass pollen allergy expressed higher levels of both SERPINB3 and SERPINB4 mRNA (both P < .0005) compared with CD27+CD4+ cells. ILC2 expressed higher levels of both SERPINB3 and SERPINB4 mRNA (both P < .0005) compared with ILC1. Knockdown of either SERPINB3 or SERPINB4 mRNA (both P < .005) levels resulted in decreased viability of CD27-CD4+ compared with control transduced cells. CONCLUSION: The Serpins Spi2A in mice and SERPINB3 and SERPINB4 in allergic patients control the viability of TH2 cells. This provides proof of principle for a therapeutic approach for allergic disease through ablation of allergic memory TH2 cells through SERPINB3 and SERPINB4 mRNA downregulation. PMID- 29107000 TI - The ERP correlates of self-knowledge: Are assessments of one's past, present, and future traits closer to semantic or episodic memory? AB - Self-knowledge concerns one's own preferences and personality. It pertains to the self (similar to episodic memory), yet does not concern events. It is factual (like semantic memory), but also idiosyncratic. For these reasons, it is unclear where self-knowledge might fall on a continuum in relation to semantic and episodic memory. In this study, we aimed to compare the event-related potential (ERP) correlates of self-knowledge to those of semantic and episodic memory, using N400 and Late Positive Component (LPC) as proxies for semantic and episodic processing, respectively. We considered an additional factor: time perspective. Temporally distant selves have been suggested to be more semantic compared to the present self, but thinking about one's past and future selves may also engage episodic memory. Twenty-eight adults answered whether traits (e.g., persistent) were true of most people holding an occupation (e.g., soldiers; semantic memory condition), or true of themselves 5 years ago, in the present, or 5 years from now (past, present, and future self-knowledge conditions). The study ended with an episodic recognition memory task for previously seen traits. Present self knowledge produced mean LPC amplitudes at posterior parietal sites that fell between semantic and episodic memory. Mean LPC amplitudes for past and future self-knowledge were greater than for semantic memory, and not significantly different from episodic memory. Mean N400 amplitudes for the self-knowledge conditions were smaller than for semantic memory at sagittal sites. However, this N400 effect was not separable from a preceding P200 effect at these same electrode sites. This P200 effect can be interpreted as reflecting the greater emotional salience of self as compared to general knowledge, which may have facilitated semantic processing. Overall, our findings are consistent with a distinction between knowledge of others and self-knowledge, but the closeness of self-knowledge's neural correlates to either semantic or episodic memory appears to depend to some extent on time perspective. PMID- 29107001 TI - Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlowTM in immunotoxicology. AB - Determining changes in gene expression by measuring mRNA levels is an important capability in biological research. Real-Time Quantitative PCR (RT-qPCR) is the most ubiquitous technique for measuring changes in mRNA transcript levels, but heterogeneity of cell populations and low cell number are serious technical limitations. Recent advances in flow cytometric analytical techniques have enabled the quantification of mRNA levels in individual cells. Here, we present examples demonstrating the strength and challenges of concurrently measuring mRNA using PrimeFlowTM with other endpoints in immunotoxicological studies. Specifically, we demonstrate how measuring gene specific mRNA levels on a per cell basis was used to study: 1) markers of activation and differentiation; 2) cell signaling by measuring intracellular proteins in mature and developing cell types; and 3) a cell type that constitutes a minor population in peripheral blood. We also discuss cell type-specific modifications to the parent technique, which facilitated optimal performance in these cells. While the examples provided are focused on immunotoxicological questions and endpoints, this new strategy can be applied to a wide variety of toxicological research problems. PMID- 29107002 TI - Chronic treatment with caffeine and its withdrawal modify the antidepressant-like activity of selective serotonin reuptake inhibitors in the forced swim and tail suspension tests in mice. Effects on Comt, Slc6a15 and Adora1 gene expression. AB - Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5mg/kg, twice daily for 14days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5mg/kg) and escitalopram (2mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14-day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant-like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems. PMID- 29107004 TI - Extending existing structural identifiability analysis methods to mixed-effects models. AB - The concept of structural identifiability for state-space models is expanded to cover mixed-effects state-space models. Two methods applicable for the analytical study of the structural identifiability of mixed-effects models are presented. The two methods are based on previously established techniques for non-mixed effects models; namely the Taylor series expansion and the input-output form approach. By generating an exhaustive summary, and by assuming an infinite number of subjects, functions of random variables can be derived which in turn determine the distribution of the system's observation function(s). By considering the uniqueness of the analytical statistical moments of the derived functions of the random variables, the structural identifiability of the corresponding mixed effects model can be determined. The two methods are applied to a set of examples of mixed-effects models to illustrate how they work in practice. PMID- 29107003 TI - Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation. AB - BACKGROUND: Hypertension (HTN) has long been associated with abdominal aortic aneurysm (AAA) development, and these cardiovascular pathologies are biochemically characterized by elevated plasma levels of angiotensin II (AngII) as well as interleukin-6 (IL-6). A biologic relationship between HTN and AAA has not been established, however. Accordingly, the objective of this study was to evaluate whether elevated tension may initiate IL-6 production to accumulate monocyte/macrophages and promote dilation of the abdominal aorta (AA). METHODS: An IL-6 infusion model (4.36 MUg/kg/day) was created utilizing an osmotic infusion pump, and after 4 weeks, AA diameter was measured by digital microscopy. The AA was then excised for CD68 immunostaining and flow cytometric analysis with CD11b and F4/80 to identify macrophages. Aortic segments from wild-type mice were suspended on parallel wires in an ex vivo tissue myograph at experimentally derived optimal tension (1.2 g) and in the presence of elevated tension (ET, 1.7 g) for 3 hr, and expression of IL-6 and monocyte chemoattractant protein-1 (MCP 1) was evaluated by quantitative polymerase chain reaction (QPCR). Isolated aortic vascular smooth muscle cells (VSMCs) were subjected to 12% biaxial cyclic stretch or held static (control) for 3 hr (n = 7), and IL-6 and MCP-1 expressions were evaluated by QPCR. RESULTS: Four-week IL-6 infusion resulted in an AA outer diameter that was 72.5 +/- 5.6% (P < 0.05) greater than that of control mice, and aortic dilation was accompanied by an accumulation of macrophages in the AA medial layer as defined by an increase in CD68 + staining as well as an increase by flow cytometric quantification of CD11b+/F4/80+ cells. Wild-type AA segments did not respond to ex vivo application of ET but cyclic stretch of isolated VSMCs increased IL-6 (2.03 +/- 0.3 fold) and MCP-1 (1.51 +/- 0.11 fold) expression compared to static control (P < 0.05). Pretreatment with the selective STAT3 inhibitor WP1066 blunted the response in both cases. Interestingly, AngII did not stimulate expression of IL-6 and MCP-1 above that initiated by tension and again, the response was inhibited by WP1066, supporting an integral role of STAT3 in this pathway. CONCLUSIONS: An IL-6 infusion model can initiate macrophage accumulation as well as aortic dilation, and under conditions of elevated tension, this proinflammatory cytokine can be produced by aortic VSMCs. By activation of STAT3, MCP-1 is expressed to increase media macrophage abundance and create an environment susceptible to dilation. This biomechanical association between HTN and aortic dilation may allow for the identification of novel therapeutic strategies. PMID- 29107005 TI - A numerical framework for drug transport in a multi-layer system with discontinuous interlayer condition. AB - Discontinuous boundary conditions arise naturally when describing various physical phenomena and numerically modelling such conditions can prove difficult. In the field of pharmaceutical sciences, two such cases are the partitioning of a compound between different materials and a flux rate membrane controlling mass transfer between materials which both result in a discontinuous jump in concentration across adjacent materials. In this study, we introduce a general one-dimensional finite element drug delivery framework, which along with diffusion, reversible binding and dissolution within material layers, incorporates the partitioning and mass transfer conditions between layers of material. We apply the framework to construct models of experiments, which along with experimental data, allow us to infer pharmacokinetic properties of potential material for drug delivery. Understanding such material properties is the key to optimising the therepeutic effect of a targeted drug delivery system. PMID- 29107007 TI - Promoter hypermethylation of SLIT2 is a risk factor and potential diagnostic biomarker for nasopharyngeal carcinoma. AB - SLIT2 is a candidate tumor suppressor gene and recent studies have shown that SLIT2 expression is suppressed or reduced by hypermethylation in the promoter region in various cancers. The aim of this study was to investigate the association between SLIT2 promoter methylation and nasopharyngeal carcinoma (NPC) and its relative diagnostic ability for NPC. Bisulfite pyrosequencing technology was performed to measure methylation levels of the SLIT2 promoter in tissue and plasma samples from 61 NPC patients and 38 normal volunteers. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic ability of SLIT2 methylation for diagnosing NPC. Our results showed that methylation levels of the SLIT2 promoter were significantly higher in NPC patients compared with individuals, both in tissue samples (P=2.57E 10) and plasma samples (plasma: P=3.86E-13). In addition, the frequency of SLIT2 promoter methylation markedly increased in the advanced stage (tissue: P=3.50E 05; plasma: P=1.14E-04) and advanced T classified (tissue: P=9.00E-06; plasma: P=3.80E-05), as well as in lymph node metastasis patients (tissue: P=1.82E-03; plasma: P=2.22E-03). In addition, the AUCs according to tissue and plasma samples were 0.846 and 0.866, respectively. When these two sample-types were combined, the AUC increased slightly to 0.874. Our study revealed that elevated SLIT2 promoter methylation contributed to the risk of NPC, as well as being involved in its progression and metastasis. Therefore, the methylated SLIT2 promoter could serve as a potential biomarker for diagnosing NPC. PMID- 29107006 TI - Conformational preferences and structural analysis of hypermodified nucleoside, peroxywybutosine (o2yW) found at 37th position in anticodon loop of tRNAPhe and its role in modulating UUC codon-anticodon interactions. AB - Hypermodified bases present at 3'-adjacent (37th) position in anticodon loop of tRNAPhe are well known for their contribution in modulating codon-anticodon interactions. Peroxywybutosine (o2yW), a wyosine family member, is one of such tricyclic modified bases observed at the 37th position in tRNAPhe. Conformational preferences and three-dimensional structural analysis of peroxywybutosine have not been investigated in detail at atomic level. Hence, in the present study quantum chemical semi-empirical RM1 and multiple molecular dynamics (MD) simulations have been used to study structural significance of peroxywybutosine in tRNAPhe. Full geometry optimizations over the peroxywybutosine base have also been performed using ab-initio HF-SCF (6-31G**), DFT (B3LYP/6-31G**) and semi empirical PM6 method to compare the salient properties. RM1 predicted most stable structure shows that the amino-carboxy-propyl side chain of o2yW remains 'distal' to the five membered imidazole ring of tricyclic guanosine. MD simulation trajectory of the isolated peroxy base showed restricted periodical fluctuations of peroxywybutosine side chain which might be helpful to maintain proper anticodon loop structure and mRNA reading frame during protein biosynthesis process. Another comparative MD simulation study of the anticodon stem loop with codon UUC showed various properties, which justify the functional implications of peroxywybutosine at 37th position along with other modified bases present in ASL of tRNAPhe. Thus, this study presents an atomic view into the structural properties of peroxywybutosine, which can be useful to determine its role in the anticodon stem loop in context of codon-anticodon interactions and frame shift mutations. PMID- 29107008 TI - Acute and a 28-day repeated-dose toxicity study of total flavonoids from Clinopodium chinense (Benth.) O. Ktze in mice and rats. AB - Clinopodium chinense (Benth.) O. Ktze (Labiatae), known as 'Duanxueliu' in the Chinese Pharmacopoeia, has been widely used as a traditional Chinese medicine for the treatment of hemorrhagic disease. Total flavonoids from Clinopodium chinense (Benth.) O. Ktze (TFCC), the most active ingredient, possess a variety of properties, such as antioxygenation. Until now, evidence-based toxicity data on TFCC has been limited. This study evaluated the acute (in mice and rat) and the 28-day repeated-dose (in rat) toxicity study of TFCC, respectively. In acute study, oral administration of TFCC to rats and mice did not induce toxicity or mortality up to the maximum doses of 4000 and 5000 mg/kg, respectively. In subacute toxicity study, we administered TFCC at daily doses of 70, 210, and 630 mg/kg for 4 consecutive weeks to rats via gavage. We observed no changes in food consumption, water intake, body weight, chemistry and hematological parameters, organ weight, gross pathology or histopathology. No animals from any group died. These findings indicate that TFCC is relatively nontoxic, and provide practical guidance for selecting a safe dose for further investigation of TFCC in animal studies or clinical trials. PMID- 29107009 TI - Integration of a plasma protein binding factor to the Chemical-Specific Adjustment Factor (CSAF) for facilitating the estimation of uncertainties in interspecies extrapolations when deriving health-based exposure limits for active pharmaceutical ingredients: Investigation of recent drug datasets. AB - The objective was to challenge cross-species extrapolation factors with which to scale animal doses to human by any route for non-carcinogenic endpoints. The conventional hypothesis of the toxicokinetics (TK)-toxicodynamics (TD) relationship was equal toxicity at equal plasma level of the total drug moiety in each species, but this should also follow the free drug assumption, which states that only the unbound drug moiety in plasma may elicit a TD effect in tissue. Therefore, a protein binding factor (PBF) was combined with the Chemical-Specific Adjustment Factor (CSAF) (i.e., CSAF x PBF). The value of PBF of each drug was set equal to the ratio between human and animals of the unbound fraction in plasma (fup). Recent drug datasets were investigated. Our results indicate that any CSAF value would be increased or decreased while PBF deviates to the unity, and this required more attention. Accordingly, further testing indicated that the CSAF values set equal to basic allometric uncertainty factors according to the conventional hypothesis (dog~2, monkey~3.1, rat~7, mouse~12) would increase by including PBF for 30% of the drugs tested that showed a superior fup value in human compared to animals. However, default uncertainty factors in the range of 10-100 were less frequently exceeded. Overall, PBF could be combined with any other uncertainty factor to get reliable estimate of CSAF for each bound drug in deriving health-based exposure limits. PMID- 29107010 TI - Combining high-sensitivity cardiac troponin and B-type natriuretic peptide in the detection of inducible myocardial ischemia. AB - BACKGROUND: Single biomarker approaches provide only moderate accuracy in the non invasive detection of exercise-induced myocardial ischemia. We therefore assessed the combination of the two most promising single biomarkers: high-sensitivity cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP). METHODS: Consecutive patients with suspected myocardial ischemia referred to stress myocardial perfusion single-photon emission tomography imaging (MPI) were enrolled. Clinical judgment (CJ) of the treating cardiologist regarding myocardial ischemia, quantified using a visual analogue scale, and blood concentrations of hs-cTnI and BNP were determined before and after stress. The presence of myocardial ischemia was adjudicated by independent cardiologists using MPI, blinded to biomarker measurements. Death and acute myocardial infarction (AMI) during follow-up were the prognostic endpoints. RESULTS: Among 1142 consecutive patients inducible myocardial ischemia was found in 456 (40%) of all patients. For the detection of inducible myocardial ischemia, CJ before exercise stress testing (CJb) showed an area under the receiver-operating characteristics curve (AUC) of 0.66 (95%CI 0.63-0.69), hs-cTnI 0.70 (95%CI 0.67 0.73, p=0.07 vs CJb), and BNP 0.66 (95%CI 0.62-0.69, p=0.98). The use of a dual biomarker strategy combining hs-cTnI and BNP with CJb did not provide a significant advantage over the combination of hs-cTnI alone and CJb (AUC 0.74, 95%CI 0.72-0.77 vs AUC 0.74, 95%CI 0.71-0.77, p=0.16). Hs-cTnI showed good prognostic value for AMI (HR 1.6, 95%CI 1.3-1.9), and BNP for death (HR 1.6, 95%CI 1.3-2.1). CONCLUSION: A dual-biomarker strategy combing BNP and hs-cTnI does not further increase diagnostic accuracy on top of clinical judgment and hs cTnI alone. SUMMARY AND HIGHLIGHTS: We included 1142 consecutive patients with suspected inducible ischemia, and evaluated the added value of the biomarkers high-sensitivity cardiac troponin (hs-cTn) and B-type natriuretic peptide (BNP), alone and in combination, on top of clinical judgment. CLINICAL TRIAL REGISTRATION: Biochemical and Electrocardiographic Signatures in the Detection of Exercise-induced Myocardial Ischemia (BASEL VIII), NCT01838148, https://clinicaltrials.gov/ct2/show/NCT01838148. PMID- 29107011 TI - Moving standard deviation and moving sum of outliers as quality tools for monitoring analytical precision. AB - INTRODUCTION: An increase in analytical imprecision (expressed as CVa) can introduce additional variability (i.e. noise) to the patient results, which poses a challenge to the optimal management of patients. Relatively little work has been done to address the need for continuous monitoring of analytical imprecision. METHODS: Through numerical simulations, we describe the use of moving standard deviation (movSD) and a recently described moving sum of outlier (movSO) patient results as means for detecting increased analytical imprecision, and compare their performances against internal quality control (QC) and the average of normal (AoN) approaches. RESULTS: The power of detecting an increase in CVa is suboptimal under routine internal QC procedures. The AoN technique almost always had the highest average number of patient results affected before error detection (ANPed), indicating that it had generally the worst capability for detecting an increased CVa. On the other hand, the movSD and movSO approaches were able to detect an increased CVa at significantly lower ANPed, particularly for measurands that displayed a relatively small ratio of biological variation to CVa. CONCLUSION: The movSD and movSO approaches are effective in detecting an increase in CVa for high-risk measurands with small biological variation. Their performance is relatively poor when the biological variation is large. However, the clinical risks of an increase in analytical imprecision is attenuated for these measurands as an increased analytical imprecision will only add marginally to the total variation and less likely to impact on the clinical care. PMID- 29107012 TI - Woronin body-based sealing of septal pores. AB - In ascomycete fungi, hyphal cells are separated by perforate septa, which allow cell-to-cell communication. To protect against extensive wound-induced damage, septal pores are sealed by peroxisome-derived Woronin bodies (WBs). The mechanism underpinning WB movement is unknown, but cytoplasmic bulk flow may "flush" WBs into the pore. However, some studies suggest a controlled and active mechanism of WB movement. Indeed, in the wheat pathogen Zymoseptoria tritici cellular ATP prevents WBs from pore sealing in unwounded cells. Thus, cells appear to exert active control over WB closure. Here, we summarize our current understanding of WB-based pore sealing in ascomycete fungi. PMID- 29107013 TI - Changes in fenugreek transcriptome induced by methyl jasmonate and steroid precursors revealed by RNA-Seq. AB - Changes in fenugreek transcriptome related to enhanced production of steroids were induced by methyl jasmonate, cholesterol and squalene, and recorded using RNA-seq. A total of 112,850 unigenes were obtained after de novo assembling of next generation sequencing data, and used for functional annotations. In steroidal saponins pathway, transcripts involved in mevalonate, terpenoid backbone and plant sterol synthesis were annotated. Overexpression of several transcripts from phytosterol biosynthesis pathway was confirmed by quantitative RT-PCR. In diosgenin biosynthesis pathway, fatty acid omega-hydroxylase (CYP86A2) and steroid 22-alpha-hydroxylase (CYP90B1) genes were annotated in all induced transcriptomes. Moreover, direct sequencing confirmed increased levels of CYP90B1, unspecific monooxygenase and 26-hydroxylase genes in plants with elevated level of diosgenin. New unigenes corresponding to enzymes involved in biosynthesis of diosgenin from cycloartenol via cholesterol were obtained and the role of CYP72A family in steroidal saponin biosynthesis was proposed. Additional support for biosynthetic pathway from cycloartenol to diosgenin was provided. PMID- 29107014 TI - Circular RNA profiling reveals chi_circ_0008219 function as microRNA sponges in pre-ovulatory ovarian follicles of goats (Capra hircus). AB - Circular RNAs (circRNAs) are a new class of non-coding RNAs in animals and are a novel target of non-coding RNA (ncRNA) regulation. The mechanism and function of circRNAs have been reported in some species and tissues. However, there is little available information on the functions of circRNAs in the goat reproductive system. In the present study, we deeply sequenced and analyzed circRNAs through bioinformatics to reveal the expression profiles, and predicted 13,950 circRNAs in the pre-ovulatory ovarian follicles of goats for the first time. Thirty-seven circRNAs were differentially expressed in the Boer goat compared with the Macheng black goat. The chi_circ_0008219 was involved in a vast circRNA-miRNA-mRNA co expression network. Via a luciferase activity assay, chi_circ_0008219 is observed to sponge to 3 ovarian follicle-related miRNAs. These findings demonstrate that circRNAs have potential effects in the ovarian follicles of ewes and may represent a promising new research field in ovarian follicular development. PMID- 29107015 TI - iKcr-PseEns: Identify lysine crotonylation sites in histone proteins with pseudo components and ensemble classifier. AB - Lysine crotonylation (Kcr) is an evolution-conserved histone posttranslational modification (PTM), occurring in both human somatic and mouse male germ cell genomes. It is important for male germ cell differentiation. Information of Kcr sites in proteins is very useful for both basic research and drug development. But it is time-consuming and expensive to determine them by experiments alone. Here, we report a novel predictor called iKcr-PseEns that is established by incorporating five tiers of amino acid pairwise couplings into the general pseudo amino acid composition. It has been observed via rigorous cross-validations that the new predictor's sensitivity (Sn), specificity (Sp), accuracy (Acc), and stability (MCC) are 90.53%, 95.27%, 94.49%, and 0.826, respectively. For the convenience of most experimental scientists, a user-friendly web-server for iKcr PseEns has been established at http://www.jci-bioinfo.cn/iKcr-PseEns, by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved. PMID- 29107017 TI - Biochemical and structural characterization of Marinomonas mediterranead-mannose isomerase Marme_2490 phylogenetically distant from known enzymes. AB - d-Mannose isomerase (MI) reversibly isomerizes d-mannose to d-fructose, and is attractive for producing d-mannose from inexpensive d-fructose. It belongs to the N-acylglucosamine 2-epimerase (AGE) superfamily along with AGE, cellobiose 2 epimerase (CE), and aldose-ketose isomerase (AKI). In this study, Marinomonas mediterranea Marme_2490, showing low sequence identity with any known enzymes, was found to isomerize d-mannose as its primary substrate. Marme_2490 also isomerized d-lyxose and 4-OH d-mannose derivatives (d-talose and 4-O monosaccharyl-d-mannose). Its activity for d-lyxose is known in other d-mannose isomerizing enzymes, such as MI and AKI, but we identified, for the first time, its activity for 4-OH d-mannose derivatives. Marme_2490 did not isomerize d glucose, as known MIs do not, while AKI isomerizes both d-mannose and d-glucose. Thus, Marme_2490 was concluded to be an MI. The initial and equilibrium reaction products were analyzed by NMR to illuminate mechanistic information regarding the Marme_2490 reaction. The analysis of the initial reaction product revealed that beta-d-mannose was formed. In the analysis of the equilibrated reaction products in D2O, signals of 2-H of d-mannose and 1-H of d-fructose were clearly detected. This indicates that these protons are not substituted with deuterium from D2O and Marme_2490 catalyzes the intramolecular proton transfer between 1-C and 2-C. The crystal structure of Marme_2490 in a ligand-free form was determined and found that Marme_2490 is formed by an (alpha/alpha)6-barrel, which is commonly observed in AGE superfamily enzymes. Despite diverse reaction specificities, the orientations of residues involved in catalysis and substrate binding by Marme_2490 were similar to those in both AKI (Salmonella enterica AKI) and epimerase (Rhodothermus marinus CE). The Marme_2490 structure suggested that the alpha7->alpha8 and alpha11->alpha12 loops of the catalytic domain participated in the formation of an open substrate-binding site to provide sufficient space to bind 4-OH d-mannose derivatives. PMID- 29107016 TI - Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies. AB - Chimeric antigen receptor (CAR) T cells are patient T cells that are transduced with genetically engineered synthetic receptors to target a cancer cell surface antigen. The remarkable clinical response rates achieved by adoptive transfer of T cells that target CD19 in patients with leukemia and lymphoma have led to a growing number of clinical trials exploring CAR T-cell therapy for solid tumors. Herein, we review the evolution of adoptive T-cell therapy; highlight advances in CAR T-cell therapy for thoracic malignancies; and summarize the targets being investigated in clinical trials for patients with lung cancer, malignant pleural mesothelioma, and esophageal cancer. We further discuss the barriers to successfully translating CAR T-cell therapy for solid tumors and present strategies that have been investigated to overcome these hurdles. PMID- 29107018 TI - Flubendazole induces mitotic catastrophe and apoptosis in melanoma cells. AB - Flubendazole (FLU) is a widely used anthelmintic drug belonging to benzimidazole group. Recently, several studies have been published demonstrating its potential to inhibit growth of various tumor cells including those derived from colorectal cancer, breast cancer or leukemia via several mechanisms. In the present study we have investigated cytotoxic effects of FLU on malignant melanoma using A-375, BOWES and RPMI-7951 cell lines representing diverse melanoma molecular types. In all three cell lines, FLU inhibited cell growth and proliferation and disrupted microtubule structure and function which was accompanied by dramatic changes in cellular morphology. In addition, FLU-treated cells accumulated at the G2/M phase of cell cycle and displayed the features of mitotic catastrophe characterized by formation of giant cells with multiple nuclei, abnormal spindles and subsequent apoptotic demise. Although this endpoint was observed in all treated melanoma lines, our analyses showed different activated biochemical signaling in particular cells, thus suggesting a promising treatment potential of FLU in malignant melanoma warranting its further testing. PMID- 29107019 TI - Distinct effects of two separately applied stressors on behavior in the red flour beetle. AB - Stress is ubiquitous in nature and organisms have evolved mechanisms to cope with it. Stress responses nevertheless vary based on the type of stress, its duration, magnitude, and the organism's physiological status. We studied here the effect of two separately applied stress types, differing also in their duration, on various behavioral responses of the red flour beetle (Tribolium castaneum). The two stress types applied were short-term cold stress and long-term low protein stress. The behavioral response variables were movement activity, preference to move along the test arena edges, latency to emerge from shelter, and preference for dark microhabitat, measured at two stages of the beetles' lives, as young adults after eclosion and one month later. Behavioral responses were stress specific. Cold-stressed beetles moved over the longest distances but were also the most reluctant to leave an accessible shelter. We interpret this to mean that cold-stressed beetles were the most active under unfavorable conditions and least bold under more favorable, protected conditions. As beetles aged, their movement activity decreased and latency to emerge from shelter increased. Non-stressed beetles were the most consistent in their behavior across all behavioral tests. This finding is similar to those in previous studies and suggests that moderate stress reduces behavioral consistency. While all beetles gained mass during the study period, the two stress types led to different patterns of body mass increase, which was more moderate for cold-stressed than for protein-stressed beetles. PMID- 29107020 TI - AAA IBD 2017: Methodologies to Collect and Analyze Clinical Data to Support Quality Improvement Initiatives Designed to Optimize the Care of Patients With IBD. PMID- 29107021 TI - Historical Perspectives and Advances in Mesenchymal Stem Cell Research for the Treatment of Liver Diseases. AB - Liver transplantation is the only effective therapy for patients with decompensated cirrhosis and fulminant liver failure. However, due to a shortage of donor livers and complications associated with immune suppression, there is an urgent need for new therapeutic strategies for patients with end-stage liver diseases. Given their unique function in self-renewal and differentiation potential, stem cells might be used to regenerate damaged liver tissue. Recent studies have shown that stem cell-based therapies can improve liver function in a mouse model of hepatic failure. Moreover, acellular liver scaffolds seeded with hepatocytes produced functional bioengineered livers for organ transplantation in preclinical studies. The therapeutic potential of stem cells or their differentiated progenies will depend on their capacity to differentiate into mature and functional cell types after transplantation. It will also be important to devise methods to overcome their genomic instability, immune reactivity, and tumorigenic potential. We review directions and advances in the use of mesenchymal stem cells and their derived hepatocytes for liver regeneration. We also discuss the potential applications of hepatocytes derived from human pluripotent stem cells and challenges to using these cells in treating end-stage liver disease. PMID- 29107022 TI - Error blindness and motivational significance: Shifts in networks centering on anterior insula co-vary with error awareness and pupil dilation. AB - This investigation aims to further our understanding of the brain mechanisms underlying the awareness of one's erroneous actions. While all errors are registered as such in the rostral cingulate zone, errors enter awareness only when the anterior insula cortex is activated. Aware but not unaware errors elicit autonomic nervous system reactivity. Our aim is to investigate the hypothesis that activation in the insula during error awareness is related to autonomic arousal and to inter-regional interactions with other areas of the brain. To examine the role of the anterior insula in error awareness, we assessed its functional connectivity to other brain regions along with autonomic nervous system reactivity in young healthy participants who underwent simultaneous pupil diameter and functional magnetic resonance imaging measurements while performing a complex and error-prone task. Error blindness was associated with failures to engage sufficient autonomic reactivity. During aware errors increased pupil diameter along with increased task-related activation within, and increased connectivity between anterior insula and task-related networks suggested an increased capacity for action-control information transfer. Increased pupil diameter during aware errors was furthermore associated with decreased activation of the default-mode network along with decreased insular connectivity with regions of the default mode system, possibly reflecting decreased task-irrelevant information processing. This shifting mechanism may be relevant to a better understanding of how the brain and the autonomic nervous system interact to enable efficient adaptive behavior during cognitive challenge. PMID- 29107023 TI - Intermittent hypoxia alters dose dependent caffeine effects on renal prostanoids and receptors in neonatal rats. AB - Caffeine, one of the most commonly prescribed drugs in preterm neonates, is given in standard or suprapharmacologic doses. Although known as a diuretic, its effects in the neonatal kidneys are not well studied. We tested the hypothesis that neonatal intermittent hypoxia (IH) and high caffeine doses (HCD) alter renal regulators of vasomotor tone and water balance. Newborn rats were randomized to room air, hyperoxia, or IH and treated with standard or high caffeine doses; or placebo saline. Renal prostanoids; histopathology; and cyclooxygenase (COX), prostanoid receptor, and aquaporin (AQP) immunoreactivity were determined. HCD in IH caused severe pathological changes in the glomeruli and proximal tubules, consistent with acute kidney injury. This was associated with reductions in anthropometric growth, PGI2, and IP, DP, and AQP-4 immunoreactivity, well as a robust increase in COX-2, suggesting that the use of HCD should be avoided in preterm infants who experience frequent IH episodes. PMID- 29107024 TI - Relaxant effect of the prostacyclin analogue iloprost on isolated human radial artery: An approach for the reversal of graft spasm. AB - Radial artery graft spasm in the perioperative or postoperative period of coronary bypass surgery necessitates urgent treatment due to risk of graft failure and mortality. Herein, we evaluated the effect of iloprost, a prostacyclin (PGI2) analogue, against the contractions produced by noradrenaline and potassium chloride on isolated human radial artery. Following the determination of endothelial and vascular relaxing capacities of the arteries, iloprost (10-9M-10-6M) was cumulatively applied on rings precontracted submaximally with the spasmogens. In some rings, the response to iloprost was assessed following pretreatment with nitric oxide (NO) synthase inhibitor, l-NAME (3*10-4M,30min). Iloprost produced complete relaxations on radial artery rings precontracted with noradrenaline whereas, only moderate relaxations against the contractions induced by potassium chloride. Notably, the relaxation to iloprost was remarkably blunted in radial arteries with impaired endothelial function. Moreover, the relaxation to iloprost was unchanged in rings pretreated with l NAME. Our results demonstrated that iloprost could be a potent relaxant agent in reversing radial artery spasm, particularly initiated by noradrenaline, possibly acting via an endothelium-mediated mechanism unrelated to NO. PMID- 29107025 TI - Association of changes in ER stress-mediated signaling pathway with lead-induced insulin resistance and apoptosis in rats and their prevention by A-type dimeric epigallocatechin-3-gallate. AB - A-type dimeric epigallocatechin-3-gallate (A-type-EGCG-dimer, AEd), a new proanthocyanidins dimer from persimmon fruits, has been shown to have health benefit effects. However, A-type-EGCG-dimer affects gluose metabolism in the liver and the underlying mechanism is not clarified. The present study aims to examine the protective effects of A-type-EGCG-dimer on Pb-induced hepatic insulin resistance, endoplasmic reticulum (ER) stress and apoptosis in rats. Male wistar rats exposed to 0.05% w/v Pb acetate in the drinking water with or without A-type EGCG-dimer coadministration (200 mg/kg body weight/day, intragastrically) for three months. We found that A-type-EGCG-dimer and pioglitazone supplementation significantly deceased glucose and insulin levels in plasma as compared with the Pb group. A-type-EGCG-dimer markedly prevents Pb-induced oxidative stress, ER stress and apoptosis in livers. A-type-EGCG-dimer and pioglitazone reduced the expression levels of the GRP78, PEPCK, G6Pase, p-PERK, p-IRE1, p-JNK, ATF4, CHOP and increased p-AKT in livers of the Pb group. Moreover, A-type-EGCG-dimer reduced ROS production and restored the activities of SOD and GPx in livers. A type-EGCG-dimer decreased Bax, cytosolic cytochrome c and cleaved caspase-3 and increased Bcl-2 in livers of Pb-exposed rats. Our results suggest that A-type EGCG-dimer might be a potential natural candidate for the prevention of hepatic insulin resistance and apoptosis induced by Pb. PMID- 29107026 TI - Protective role of quercetin against copper(II)-induced oxidative stress: A spectroscopic, theoretical and DNA damage study. AB - The radical scavenging and metal chelating properties of flavonoids indicate that they may play a protective role in diseases with perturbed metal homeostasis such as Alzheimer's disease. In this work we investigated the effect of the coordination of quercetin to copper(II) in view of the formation of ROS in Cu catalyzed Fenton reaction. ABTS and DPPH assays confirmed that the copper(II) quercetin complex exhibits a stronger radical scavenging activity than does quercetin alone. EPR spin trapping experiments have shown that chelation of quercetin to copper significantly suppressed the formation of hydroxyl radicals in the Cu(II)-Fenton reaction. DNA damage experiments revealed a protective effect for quercetin, but only at higher stoichiometric ratios of quercetin relative to copper. DNA protective effect of quercetin against ROS attack was described by two mechanisms. The first mechanism lies in suppressed formation of ROS due to the decreased catalytic action of copper in the Fenton reaction, as a consequence of its chelation and direct scavenging of ROS by free quercetin. Since the Cu-quercetin complex intercalates into DNA, the second mechanism was attributed to a suppressed intercalating ability of the Cu-quercetin complex due to the mildly intercalating free quercetin into DNA, thus creating a protective wall against stronger intercalators. PMID- 29107027 TI - In vitro immunomodulation of splenocytes from DO11.10 mice by the food colouring agent amaranth. AB - The chemical amaranth (AM) is permitted as a colouring agent in a variety of foods. Safety was established based on chronic rodent studies. AM and its metabolite naphthionic acid (NA) can be absorbed through the intestine, exposing circulating immune cells including splenocytes. An AM feeding study in rats demonstrated an increase in blood lymphocytes. Yet, in contrast, AM inhibited the delayed-type hypersensitivity reaction to antigen. DO11.10 mice express a T Cell Receptor specific for ovalbumin323-339 peptide (OVAp) presented by I-Ad MHCII. DO11.10 splenocytes were cultured to evaluate mechanisms by which AM and NA modulate immune cell function in vitro. Exposure to OVAp alone for 72 h induced cell proliferation, and combination with 2 or 20 MUg/mL AM increased IFN-gamma. Cytotoxicity was evident at higher concentrations of AM (200 and 2000 MUg/mL) and NA (2000 MUg/mL) in combination with OVAp, as both cell number and cytokine secretion decreased. At 200 MUg/mL AM with OVAp, immunotoxicity gene expression was modified and OVAp-specific KJ1-26+ CD28+ cells became enriched. The equivalent dose of NA did not modify those parameters. Using an antigen-specific model in vitro, lower concentrations of AM potentiated pro-inflammatory cytokine production, and higher concentrations of AM and NA demonstrated cytotoxicity. PMID- 29107028 TI - Toxic equivalency factors (TEFs) after acute oral exposure of azaspiracid 1, -2 and -3 in mice. AB - Azaspiracids (AZAs) are marine algal toxins that can be accumulated by edible shellfish to cause a foodborne gastrointestinal poisoning in humans. In the European Union, only AZA1, -2 and -3 are currently regulated and their concentration in shellfish is determined through their toxic equivalency factors (TEFs) derived from the intraperitoneal lethal potency in mice. Nevertheless, considering the potential human exposure by oral route, AZAs TEFs should be calculated by comparative oral toxicity data. Thus, the acute oral toxicity of AZA1, -2 and -3 was investigated in female CD-1 mice treated with different doses (AZA1: 135-1100MUg/kg; AZA2 and AZA3: 300-1100MUg/kg) and sacrificed after 24h or 14days. TEFs derived from the median lethal doses (LD50) were 1.0, 0.7 and 0.5, respectively for AZA1, -2 and -3. In fact, after 24h from gavage administration, LD50s were 443MUg/kg (AZA1; 95% CL: 350-561MUg/kg), 626MUg/kg (AZA2; 95% CL: 430 911MUg/kg) and 875MUg/kg (AZA3; 95% CL: 757-1010MUg/kg). Mice dead more than 5h after the treatment or those sacrificed after 24h (doses: >=175MUg AZA1/kg, >=500MUg AZA2/kg and >=600MUg AZA3/kg) showed enlarged pale liver, while increased serum markers of liver alteration were recorded even at the lowest doses. Blood chemistry revealed significantly increased serum levels of K+ ions (>=500mg/kg), whereas light microscopy showed tissue changes in the gastrointestinal tract, liver and spleen. No lethality, macroscopic, tissue or haematological changes were recorded two weeks post exposure, indicating reversible toxic effects. LC-MS/MS analysis of the main organs showed a dose dependency in gastrointestinal absorption of these toxins: at 24h, the highest levels were detected in the stomach and, in descending order, in the intestinal content, liver, small intestine, kidneys, lungs, large intestine, heart as well as detectable traces in the brain. After 14days, AZA1 and AZA2 were still detectable in almost all the organs and intestinal content. PMID- 29107029 TI - Transcriptional inhibition of TCDD-mediated induction of cytochrome P450 1A1 and alteration of protein expression in a zebrafish hepatic cell line following the administration of TCDD and Cd2. AB - We studied the effects of Cd2+ on TCDD-mediated induction of the cytochrome P450 1A1 (cyp1a1) gene using a zebrafish liver cell line (ZFL). Our results showed that Cd2+ inhibited the TCDD-mediated induction of the cyp1a1 protein, enzyme activity, and mRNA expression level. Cd2+ also down-regulated levels of the aryl hydrocarbon receptor (ahr2) and the aryl hydrocarbon receptor nuclear translocator 2b (arnt2b) mRNAs. Compared with TCDD (3nM) treatment alone, co treatment with Cd2+ (0-30MUM) and TCDD (3nM) significantly inhibited the activity of the luciferase reporter gene constructs harboring the distal promoter region (P-2626/-2009) of CYP1A1 and the synthetic 3XRE gene promoter. This indicates that Cd2+ decreased the level of TCDD-induced cyp1a1 through transcriptional inhibition. Proteomic analysis was also used to evaluate the effect of Cd2+ on TCDD-altered protein expression in ZFL cells. The identified proteins are mainly enzymes of the glycolysis pathway and proteasomes, and have anti-oxidative and anti-stress effects. PMID- 29107030 TI - Cessation of Ureteral Colic Does Not Necessarily Mean that a Ureteral Stone Has Been Expelled. AB - PURPOSE: We evaluated whether cessation of renal colic is consistent with an expelled ureteral stone or whether imaging may be indicated even in the absence of symptoms. MATERIALS AND METHODS: We performed a retrospective study of patients who presented to our institution with acute renal colic and ureteral stone, and were subsequently evaluated at a followup visit where they reported complete cessation of pain for at least 72 hours. RESULTS: Study inclusion criteria were met by 52 patients, who reported no pain for at least 72 hours at the time of the followup visit. A persistent ureteral stone was demonstrated in 14 of the 52 patients (26%) although they denied any associated symptoms. Multivariate logistic regression did not show an association between stone size or location and the likelihood of passage in this cohort. CONCLUSIONS: Cessation of pain was associated with ureteral stone passage in almost 75% of this study cohort but 26% of patients still had persistent ureteral stones. We recommend routine followup imaging in all patients with ureteral stones to document stone passage and avoid the risks of silent ureteral obstruction. PMID- 29107031 TI - Prospective Multicenter Phase II Study on Focal Therapy (Hemiablation) of the Prostate with High Intensity Focused Ultrasound. AB - PURPOSE: We evaluated focal therapy with high intensity focused ultrasound hemiablation in a prospective trial. MATERIALS AND METHODS: We performed a prospective, multicenter, single arm study in patients with unilateral low/intermediate risk prostate cancer who were treated from April 2013 through March 2016 in Germany in AUO (Arbeitsgemeinschaft Urologische Onkologie) Study Protocol AP 68/11. Unilateral prostate cancer was assessed by transrectal ultrasound guided biopsy and multiparametric magnetic resonance imaging. Hemiablation was done using the Ablatherm(r) or the Focal One(r) device. The oncologic outcome was assessed by the salvage treatment rate, multiparametric magnetic resonance imaging and rebiopsy at 12 months. Functional outcome, quality of life, anxiety and depression were measured by validated questionnaires at baseline and every 3 months. RESULTS: Of the 54 recruited patients 51 completed 12-month or greater visits. Mean +/- SD followup was 17.4 +/- 4.5 months. Mean prostate specific antigen decreased from 6.2 +/- 2.0 to 2.9 +/- 1.9 ng/ml at 12 months (p <0.001). Biopsy at 12 months was positive for any prostate cancer and for clinically significant prostate cancer in 13 (26.5%) and 4 (8.2%) of the 49 patients, respectively. Posttreatment multiparametric magnetic resonance imaging had limited 25% sensitivity for clinically significant prostate cancer. Ten patients (19.6%) underwent salvage treatment. Potency was maintained in 21 of the 30 men who were potent preoperatively. There was no increase in incontinence. Quality of life, anxiety and depression did not change postoperatively. The study was limited by a short followup and the lack of a control arm. CONCLUSIONS: Focal therapy hemiablation is safe with little alteration of functional outcome. The oncologic outcome is acceptable on short-term followup. Followup multiparametric magnetic resonance imaging performed poorly and should not replace repeat biopsy. Focal therapy has no impact on posttreatment anxiety and depression. PMID- 29107032 TI - The Effect of Continued Low Dose Aspirin Therapy in Patients Undergoing Percutaneous Nephrolithotomy. AB - PURPOSE: Aspirin is often stopped prior to percutaneous nephrolithotomy due to concern about the surgical bleeding risk. There is evidence that discontinuing aspirin perioperatively increases thromboembolic events and continuing it may be safe. We assessed the effect of continuing low dose aspirin through percutaneous nephrolithotomy and its effect on surgical and safety outcomes. MATERIALS AND METHODS: We retrospectively reviewed the records of 285 consecutive percutaneous nephrolithotomies performed between 2012 and 2015 at our institution. We compared outcomes and complications in patients who continued 81 mg aspirin daily to those in patients not receiving aspirin. RESULTS: A total of 67 patients (24.5%) were maintained on low dose aspirin and 207 (75.5%) were not on aspirin. The aspirin group was older (66 vs 52 years), included more tobacco users (58.2% vs 31.4%) and had a higher ASA(r) (American Society of Anesthesiologists(r)) score (2.9 vs 2.5, all p <0.001). There was no difference in mean S.T.O.N.E. (size, topography [stone location], obstruction, number of stones and evaluation of HU) score (7.6 vs 7.7, p = 0.71) or blood loss (44 vs 54 ml, p = 0.151). There was no difference in residual stone fragment size, including 0 to 2 mm in 65.3% vs 61.4% of aspirin vs no aspirin cases, 3 to 4 mm in 19.4% vs 16.2% and greater than 4 mm in 15.3% vs 22.4% (p = 0.407). Length of stay and the change in hemoglobin, hematocrit and creatinine were similar. There was no difference in the readmission rate (14.9% vs 12.6%, p = 0.618) or the total complication rate (34.4% vs 26.6%, p = 0.221). There was also no difference in the number of major complications (10.4% vs 5.8%, p = 0.193), bleeding complications (3.0% vs 2.9%, p = 0.971) and the transfusion rate (1.5% vs 1.0%, p = 0.57). CONCLUSIONS: Percutaneous nephrolithotomy appears effective and safe in patients who continue low dose aspirin perioperatively. PMID- 29107033 TI - Producing Designer Oils in Industrial Microalgae by Rational Modulation of Co evolving Type-2 Diacylglycerol Acyltransferases. AB - Microalgal oils, depending on their degree of unsaturation, can be utilized as either nutritional supplements or fuels; thus, a feedstock with genetically designed and tunable degree of unsaturation is desirable to maximize process efficiency and product versatility. Systematic profiling of ex vivo (in yeast), in vitro, and in vivo activities of type-2 diacylglycerol acyltransferases in Nannochloropsis oceanica (NoDGAT2s or NoDGTTs), via reverse genetics, revealed that NoDGAT2A prefers saturated fatty acids (SFAs), NoDGAT2D prefers monounsaturated fatty acids (MUFAs), and NoDGAT2C exhibits the strongest activity toward polyunsaturated fatty acids (PUFAs). As NoDGAT2A, 2C, and 2D originated from the green alga, red alga, and eukaryotic host ancestral participants of secondary endosymbiosis, respectively, a mechanistic model of oleaginousness was unveiled, in which the indigenous and adopted NoDGAT2s formulated functional complementarity and specific transcript abundance ratio that underlie a rigid SFA:MUFA:PUFA hierarchy in triacylglycerol (TAG). By rationally modulating the ratio of NoDGAT2A:2C:2D transcripts, a bank of N. oceanica strains optimized for nutritional supplement or fuel production with a wide range of degree of unsaturation were created, in which proportion of SFAs, MUFAs, and PUFAs in TAG varied by 1.3-, 3.7-, and 11.2-fold, respectively. This established a novel strategy to simultaneously improve productivity and quality of oils from industrial microalgae. PMID- 29107034 TI - Histone Deacetylase AtSRT1 Links Metabolic Flux and Stress Response in Arabidopsis. AB - How plant metabolic flux alters gene expression to optimize plant growth and response to stress remains largely unclear. Here, we report that Arabidopsis thaliana NAD+-dependent histone deacetylase AtSRT1 negatively regulates plant tolerance to stress and glycolysis but stimulates mitochondrial respiration. We found that AtSRT1 interacts with Arabidopsis cMyc-Binding Protein 1 (AtMBP-1), a transcriptional repressor produced by alternative translation of the cytosolic glycolytic enolase gene LOS2/ENO2. We demonstrated that AtSRT1 could associate with the chromatin of AtMBP-1 targets LOS2/ENO2 and STZ/ZAT10, both of which encode key stress regulators, and reduce the H3K9ac levels at these genes to repress their transcription. Overexpression of both AtSRT1 and AtMBP-1 had synergistic effects on the expression of glycolytic genes, glycolytic enzymatic activities, and mitochondrial respiration. Furthermore, we found that AtMBP-1 is lysine-acetylated and vulnerable to proteasomal protein degradation, while AtSRT1 could remove its lysine acetylation and significantly enhance its stability in vivo. Taken together, these results indicate that AtSRT1 regulates primary metabolism and stress response by both epigenetic regulation and modulation of AtMBP-1 transcriptional activity in Arabidopsis. PMID- 29107035 TI - Sequence-Independent Identification of Active LTR Retrotransposons in Arabidopsis. PMID- 29107036 TI - Evaluation of an integrated treatment for active duty service members with comorbid posttraumatic stress disorder and major depressive disorder: Study protocol for a randomized controlled trial. AB - Posttraumatic stress disorder (PTSD) commonly co-occurs with major depressive disorder (MDD) in both civilian and military/veteran populations. Existing, evidence-based PTSD treatments, such as cognitive processing therapy (CPT), often reduce symptoms of both PTSD and depression; however, findings related to the influence of comorbid MDD on PTSD treatment outcomes are mixed, and few studies use samples of individuals with both conditions. Behavioral activation (BA), an approach that relies on behavioral principles, is an effective treatment for depression. We have integrated BA into CPT (BA+CPT), a more cognitive approach, to address depressive symptoms among active duty service members with both PTSD and comorbid MDD. We describe an ongoing randomized controlled trial investigating the efficacy of our innovative, integrated BA+CPT intervention, compared with standard CPT, for active duty service members with PTSD and comorbid MDD. We detail the development of this integrated treatment, as well as the design and implementation of the randomized controlled trial, to evaluate its effect on symptoms. PMID- 29107037 TI - Transcriptional correlates of proximal-distal identify and regeneration timing in axolotl limbs. AB - Cells within salamander limbs retain memories that inform the correct replacement of amputated tissues at different positions along the length of the arm, with proximal and distal amputations completing regeneration at similar times. We investigated the possibility that positional memory is associated with variation in transcript abundances along the proximal-distal limb axis. Transcripts were deeply sampled from Ambystoma mexicanum limbs at the time they were administered fore arm vs upper arm amputations, and at 19 post-amputation time points. After amputation and prior to regenerative outgrowth, genes typically expressed by differentiated muscle cells declined more rapidly in upper arms while cell cycle transcripts were expressed more highly. These and other expression patterns suggest upper arms undergo more robust tissue remodeling and cell proliferation responses after amputation, and thus provide an explanation for why the overall time to complete regeneration is similar for proximal and distal amputations. Additionally, we identified candidate positional memory genes that were expressed differently between fore and upper arms that encode a surprising number of epithelial proteins and a variety of cell surface, cell adhesion, and extracellular matrix molecules. Also, genes were discovered that exhibited different, bivariate patterns of gene expression between fore and upper arms, implicating dynamic transcriptional regulation for the first time in limb regeneration. Finally, 43 genes expressed differently between fore and upper arm samples showed similar transcriptional patterns during retinoic acid-induced reprogramming of fore arm blastema cells into upper arm cells. Our study provides new insights about the basis of positional information in regenerating axolotl limbs. PMID- 29107038 TI - Routine Urine Testing at the Spinal Cord Injury Annual Evaluation Leads to Unnecessary Antibiotic Use: A Pilot Study and Future Directions. AB - OBJECTIVES: To measure the prevalence of asymptomatic bacteriuria (ASB) in persons with spinal cord injury (SCI) at the time of their annual examination and to examine the effect on urine testing during the annual examination on subsequent antibiotic use. DESIGN: Retrospective cohort study. SETTING: A major SCI center. PARTICIPANTS: Veterans (N=393) with SCI seen for an outpatient annual evaluation in 2012 or 2013. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Antibiotic use for bacteriuria within 7 days of the annual evaluation encounter. RESULTS: There were 327 clinic visits that met inclusion criteria; of these 327 veterans, 249 had a urine culture performed. A total of 171 urine cultures (69%) were positive for bacteria, of which 22 (13%) represented urinary tract infection (UTI) cases and 149 (87%) were ASB cases. More than a third of the ASB cases (n=53 [36%]) were treated with antibiotics. None of the 78 visits with negative urine cultures received antibiotics to treat the UTI; thus, a positive urine culture alone was associated with antibiotic use (P<.01). Factors predicting antibiotic use were higher age, nitrite presence on urinalysis, and urease producing organism on culture media. When comparing bladder management strategies, indwelling catheterization was found to be associated with higher levels of pyuria and hematuria than did spontaneous voiding or intermittent catheterization (P<.01). CONCLUSIONS: Two-thirds of the urine cultures of persons with SCI presenting for their annual examination were positive. Most of the positive cultures represented ASB cases, and more than a third of these were treated with antibiotics. A better understanding of the mandate for urine testing at the annual examination and the outcomes of this practice is an important first step in developing antibiotic stewardship for UTI in persons with SCI. PMID- 29107039 TI - Perceived Participation and Its Correlates Among First-Stroke Survivors at Six Months After Discharge From a Tertiary Hospital in China. AB - OBJECTIVES: To describe perceived participation of first-stroke survivors in mainland China, and to determine variables that may correlate with perceived participation 6 months after discharge. DESIGN: Cross-sectional survey. SETTING: Neurology department of a tertiary hospital, with subsequent follow-up of patients in their homes. PARTICIPANTS: First-stroke survivors (N=236) who had been treated in the neurology department and discharged 6 months before their participation in our study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participation was assessed using the Chinese version of the self-report Impact on Participation and Autonomy Questionnaire. Performance on activities of daily living was measured using the Barthel Index, and physical function was measured with the Chinese Stroke Scale. The Hospital Anxiety and Depression Scale and the Social Support Rating Scale were also used. RESULTS: The mean score of perceived participation was 40.39+/-15.29, and 52.1%, 38.1%, 33.1%, and 5.5% of the participants reported insufficient participation in the domains of autonomy outdoors, family role, social relations, and autonomy indoors, respectively. Physical function served as the strongest correlate for the domains of family role and autonomy outdoors (standardized coefficients =.426 and .336, respectively), while depression was the strongest correlate for the domain of social relations (standardized coefficient =.315). CONCLUSIONS: Physical function and activities of daily living were significantly associated with perceived participation in almost all domains. Depression was an important correlater of participation in the social relations domain. Perceived participation may be influenced by multiple factors, and tailored strategies should be implemented early in the rehabilitation phase poststroke to promote participation in all domains of daily living. PMID- 29107040 TI - Longitudinal Recovery and Reduced Costs After 120 Sessions of Locomotor Training for Motor Incomplete Spinal Cord Injury. AB - OBJECTIVE: To determine the impact of long-term, body weight-supported locomotor training after chronic, incomplete spinal cord injury (SCI), and to estimate the health care costs related to lost recovery potential and preventable secondary complications that may have occurred because of visit limits imposed by insurers. DESIGN: Prospective observational cohort with longitudinal follow-up. SETTING: Eight outpatient rehabilitation centers that participate in the Christopher & Dana Reeve Foundation NeuroRecovery Network (NRN). PARTICIPANTS: Individuals with motor incomplete chronic SCI (American Spinal Injury Association Impairment Scale C or D; N=69; 0.1-45y after SCI) who completed at least 120 NRN physical therapy sessions. INTERVENTIONS: Manually assisted locomotor training (LT) in a body weight-supported treadmill environment, overground standing and stepping activities, and community integration tasks. MAIN OUTCOME MEASURES: International Standards for Neurological Classification of Spinal Cord Injury motor and sensory scores, orthostatic hypotension, bowel/bladder/sexual function, Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI), Berg Balance Scale, Modified Functional Reach, 10-m walk test, and 6-minute walk test. Longitudinal outcome measure collection occurred every 20 treatments and at 6- to 12-month follow-up after discharge from therapy. RESULTS: Significant improvement occurred for upper and lower motor strength, functional activities, psychological arousal, sensation of bowel movement, and SCI-FAI community ambulation. Extended training enabled minimal detectable changes at 60, 80, 100, and 120 sessions. After detectable change occurred, it was sustained through 120 sessions and continued 6 to 12 months after treatment. CONCLUSIONS: Delivering at least 120 sessions of LT improves recovery from incomplete chronic SCI. Because walking reduces rehospitalization, LT delivered beyond the average 20-session insurance limit can reduce rehospitalizations and long-term health costs. PMID- 29107041 TI - Lateral Corticospinal Tract Damage Correlates With Motor Output in Incomplete Spinal Cord Injury. AB - OBJECTIVE: To investigate the relationship between spinal cord damage and specific motor function in participants with incomplete spinal cord injury (iSCI). DESIGN: Single-blinded, cross-sectional study design. SETTING: University setting research laboratory. PARTICIPANTS: Individuals with chronic cervical iSCI (N=14; 1 woman, 13 men; average age +/- SD, 43+/-12y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Axial T2-weighted magnetic resonance imaging (MRI) of spinal cord damage was performed in 14 participants with iSCI. Each participant's damage was processed for total damage quantification, lateral corticospinal tract (LCST) and gracile fasciculus (GF) analysis. Plantarflexion and knee extension were quantified using an isokinetic dynamometer. Walking ability was assessed using a 6-minute walk test. RESULTS: Total damage was correlated with plantarflexion, knee extension, and distance walked in 6 minutes. Right LCST damage was correlated with right plantarflexion and right knee extension, while left LCST damage was correlated with left-sided measures. Right and left GF damage was not correlated with the motor output measures. CONCLUSIONS: MRI measures of spinal cord damage were correlated to motor function, and this measure appears to have spatial specificity to descending tracts, which may offer prognostic value after SCI. PMID- 29107042 TI - Measuring Participation After Stroke in Africa: Development of the Participation Measurement Scale. AB - OBJECTIVE: To develop a valid stroke-specific tool, named the Participation Measurement Scale (PM-Scale), for the measurement of participation after stroke. DESIGN: Observational study and questionnaire development. SETTING: Outpatient rehabilitation centers. PARTICIPANTS: Patients with stroke (N=276; mean age, 58.5+/-11.1y; 57% men). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants completed a 100-item experimental questionnaire of the PM-Scale. Items were scored as "not at all," "weakly," or "strongly." The Hospital Anxiety and Depression Scale was used to evaluate depression, and the modified Rankin Scale was used to categorize the severity of disability on the basis of observation. RESULTS: After successive Rasch analyses using unrestricted partial credit parameterization, a valid, unidimensional, and linear 22-item scale for the measurement of participation was constructed. All 22 items fulfilled the measurement requirements of overall and individual item and person fits, category discrimination, invariance, and local response independence. The PM-Scale showed good internal consistency (person separation index, .93). The test-retest reliability of item difficulty hierarchy (r=.96; P<.001) and patient location (r=.99; P<.001) were excellent. This patient-based scale covers all 9 International Classification of Functioning, Disability and Health domains of participation. CONCLUSIONS: The PM-Scale has good psychometric qualities and provides accurate measures of participation in patients with stroke in Africa. PMID- 29107043 TI - Proof of Principle for Local Delivery of a c-Met Inhibitor. AB - The reported proof of principle study demonstrated the feasibility of local delivery of a c-Met inhibitor (VXc-140) in a subcutaneous xenograft tumor model. VXc-140 was formulated in a wafer delivery system for direct implantation into the tumor. Systemic and local tumor exposure of VXc-140 was analyzed. High tumor exposures coupled with fast release of compound were associated with significant tumor regression and reduction in tumor levels of phosphorylated c-Met. High VXc 140 tumor-to-plasma ratios (~42 at the tumor periphery) were achieved. The tumor response achieved (7/11 partial response) with VXc-140 with the local delivery in the wafer (4 mg over 15 days) was comparable to the regression observed (11/15 partial response) for VXc-140 in the oral delivery (~8 mg total administered once a day for 2 weeks). Notably, the plasma levels in animals implanted with VXc-140 wafers ranged from 2 to 4 MUM, which, although higher than trough levels achieved with oral administration, were well below oral Cmax levels (~42 MUM) suggesting that toxicities associated with Cmax exposure may be reduced or eliminated by local delivery. The high tumor to plasma exposure of VXc-140 and the efficacy observed with local wafer delivery warrants further exploration into the utility of local delivery. PMID- 29107044 TI - Rapid, Room Temperature Nanoparticle Drying and Low-Energy Reconstitution via Electrospinning. AB - Nanoparticle formulations offer advantages over free drugs; however, stability of the nanoparticle dispersions is a significant obstacle, and drying is often required for long-term size stability. The main limitation of current drying methods is particle aggregation upon reconstitution which can be overcome with sonication (impractical in a clinical setting) or large amounts of cryoprotectants (result in hypertonic dispersions). Therefore, new approaches to nanoparticle drying are necessary. We demonstrate conversion of nanoparticle dispersions to a dry, thermostable form via electrospinning. As a proof-of concept, polyethylene glycol stabilized nanoparticles and polyvinyl alcohol were blended and electrospun into ~300 nm fibers. Following electrospinning, nanoparticles were stored for at least 7 months and redispersed with low osmolarity to their original size without sonication. The nanoparticles redisperse to their original size when the fiber diameter and nanoparticle diameter are comparable (nanoparticle:nanofiber ratio ~1). Nanoparticles with liquid cores and larger particles better maintained their size when compared to nanoparticles with solid cores and smaller particles, respectively. Storing the nanoparticles within nanofibers appears to prevent Ostwald ripening improving thermostability. Overall, this novel approach enables rapid, continuous drying of nanoparticles at room temperature to facilitate long-term nanoparticle storage. Improved nanoparticle drying techniques will enhance clinical translation of nanomedicines. PMID- 29107045 TI - Evaluation of a Biologic Formulation Using Customized Design of Experiment and Novel Multidimensional Robustness Diagrams. AB - Formulation development includes selection of appropriate excipients to stabilize the active pharmaceutical ingredient throughout its recommended shelf life, against potential excursions in its life cycle and sometimes to aid in the delivery of therapeutics into the patient. Identity and quantity of every ingredient in a therapeutic formulation are critical to achieve their intended purpose. Deviations from a target composition can result in manufacturing, safety, and efficacy challenges. It is mandatory to establish robustness of a formulation for the expected changes in its composition arising from the qualified "process variability" of the impacting process steps during manufacture. The approach for carrying out a robustness study evolved through improved understanding of a therapeutic stability and exploration of new tools, including the quality by design elements strongly recommended by regulatory agencies. An approach is presented here to study formulation robustness in multidimensional space using a customized experimental design and novel multidimensional diagrams, which present a unique way of identifying robustness limits. The concept is universally applicable to any multivariate analysis and such diagrams would be useful to comprehend the outcome on all variables at a glance. Interpretation of these diagrams is discussed, some of which are applicable in general to any statistical design of experiment. PMID- 29107046 TI - Pharmacological Efficacy/Toxicity of Drugs: A Comprehensive Update About the Dynamic Interplay of Microbes. AB - Oral ingestion is a common, easy to access, route for therapeutic drugs to be delivered. The conception of the gastrointestinal tract as a passive physiological compartment has evolved toward a dynamic perspective of the same. Thus, microbiota plays an important role in contributing with additional metabolic capacities to its host as well as to its phenotypic heterogeneity. These adaptations in turn influence the efficacy and toxicity of a broad range of drugs. Notwithstanding, xenobiotics and therapeutic drugs affecting the microbiome's activity also significantly impact metabolism affecting different organs and tissues, and thereby drugs' toxicity/efficacy effects. Other physiological interfaces (i.e., gut, lungs, and skin) also represent complex media with features about microbiota's composition. In addition, there have been described key regulatory effects of microbes on immunotherapy, because of its potential harnessing the host immune system, mental disorders by modulating neuroendocrine systems and cancer. These alterations are responsible of physiological variations in the response(s) between individuals and populations. However, the study of population-based differences in intestinal microbial related drug metabolism has been largely inferential. This review outlines major reciprocal implications between drugs and microbes regulatory capacities in pharmacotherapy. PMID- 29107047 TI - Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance. AB - Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS 817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (<=75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance. PMID- 29107048 TI - Beyond Q1/Q2: The Impact of Manufacturing Conditions and Test Methods on Drug Release From PLGA-Based Microparticle Depot Formulations. AB - Drug-loaded polymeric microparticles have been used as long-acting injectable (LAI) depot formulations. To obtain U.S. Food and Drug Administration approval, a generic LAI depot product needs to be qualitatively (Q1) and quantitatively (Q2) the same in terms of inactive ingredients as its reference-listed drug. However, Q1/Q2 sameness as the reference-listed drug does not guarantee the same in vitro drug release profile and in vivo performance, especially when the manufacturing methods are different. There is little consensus on how the in vitro testing needs to be done to examine the release profiles of LAI depot formulations. This study examined the manufacturing differences in making risperidone-loaded poly(lactide-co-glycolide) microparticles and their impact on the release kinetics. It also examined the impacts of in vitro testing methods on the drug release profiles. Two in-house manufactured risperidone poly(lactide-co glycolide) microparticles and Risperdal Consta(r) were used in the study. Of the in vitro release methods tested, the orbital agitation method provided the most reproducible release profiles. The results indicate that the in vitro release kinetics depend not only on manufacturing procedures but also on the in vitro testing conditions, such as the agitation speed, vessel-dimensions, solid beads, media exchange volume, and other parameters both under real-time and accelerated testing conditions. In the current case, the in vitro experimental condition seemed to affect the drug release kinetics more than the manufacturing differences. The developed orbital agitation release testing method is simple, robust, and reproducible, which allows the comparison of in vitro release profiles of formulations that are prepared with manufacturing differences. PMID- 29107049 TI - Environmentally Responsive Dual-Targeting Nanoparticles: Improving Drug Accumulation in Cancer Cells as a Way of Preventing Anticancer Drug Efflux. AB - Drug targeting and stimuli-responsive drug release are 2 active areas of cancer research and hold tremendous potential in the management of cancer drug resistance. In this study, I addressed this issue and focused on the synthesis and characterization of pH-responsive Fe3O4@SiO2(FITC)-BTN/folic acid/DOX multifunctional nanoparticles aiming to increase drug accumulation in malignancies with both dual active targeting and endosomal drug release properties. Dye-doped silica magnetic-fluorescent composite was constructed by a simple coprecipitation of Fe+2/Fe+3 salts followed by sol-gel formation and dual targeting function was obtained by conjugating folate and biotin moieties on the silica surface of nanoparticles via an esterification reaction. Doxorubicin was then successfully attached on the amine-functionalized nanoparticles using a pH sensitive Schiff-base formation. The physicochemical characterization of the structure was performed by dynamic light scattering, zeta potential measurement, X-ray diffraction, Fourier transform infrared spectroscopy, electron microscopy techniques, and an in vitro pH-dependent release study. Cellular uptake and cytotoxicity experiments demonstrated an enhanced intracellular delivery and reduction of cancer cell viability in the cervical carcinoma HeLa cell line. Furthermore, proapoptotic studies showed that the nanoparticles increased the apoptotic rates within the same cancer cells. The preliminary cell tests confirm the potential of these multifunctional nanoparticles against the development of drug resistance in cancer cells. PMID- 29107050 TI - MicroRNA-21 and long non-coding RNA MALAT1 are overexpressed markers in medullary thyroid carcinoma. AB - BACKGROUND: Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are well-recognized post-transcriptional regulators of gene expression. This study examines the expression of microRNA-21 (miR-21) and lncRNA MALAT1 in medullary thyroid carcinomas (MTCs) and their effects on tumor behavior. METHODS: Tissue microarrays (TMAs) were constructed using normal thyroid (n=39), primary tumors (N=39) and metastatic MTCs (N=18) from a total of 42 MTC cases diagnosed between 1987 and 2016. In situ hybridization with probes for miR-21 and MALAT1 was performed. PCR quantification of expression was performed in a subset of normal thyroid (N=10) and primary MTCs (N=32). An MTC derived cell line (MZ-CRC-1) was transfected with small interfering RNAs (siRNAs) targeting miR-21 and MALAT1 to determine the effects on cell proliferation and invasion. RESULTS: In situ hybridization (ISH) showed strong (2+ to 3+) expression of miR-21 in 17 (44%) primary MTCs and strong MALAT1 expression in 37 (95%) primary MTCs. Real-time PCR expression of miR-21 (P<0.001) and MALAT1 (P=0.038) in primary MTCs were significantly higher than in normal thyroid, supporting the ISH findings. Experiments with siRNAs showed inhibition of miR-21 and MALAT1 expression in the MTC-derived cell line, leading to significant decreases in cell proliferation (P<0.05) and invasion (P<0.05). CONCLUSION: There is increased expression of miR-21 and MALAT1 in MTCs. This study also showed an in vitro pro-oncogenic effect of MALAT1 and miR-21 in MTCs. The results suggest that overexpression of miR-21 and MALAT1 may regulate MTC progression. PMID- 29107052 TI - Weekly observations of online survey metadata obtained through home computer use allow for detection of changes in everyday cognition before transition to mild cognitive impairment. AB - INTRODUCTION: Subtle changes in instrumental activities of daily living often accompany the onset of mild cognitive impairment (MCI) but are difficult to measure using conventional tests. METHODS: Weekly online survey metadata metrics, annual neuropsychological tests, and an instrumental activity of daily living questionnaire were examined in 110 healthy older adults with intact cognition (mean age = 85 years) followed up for up to 3.6 years; 29 transitioned to MCI during study follow-up. RESULTS: In the baseline period, incident MCI participants completed their weekly surveys 1.4 hours later in the day than stable cognitively intact participants, P = .03, d = 0.47. Significant associations were found between earlier survey start time of day and higher memory (r = -0.34; P < .001) and visuospatial test scores (r = -0.37; P < .0001). Longitudinally, incident MCI participants showed an increase in survey completion time by 3 seconds per month for more than the year before diagnosis compared with stable cognitively intact participants (beta = 0.12, SE = 0.04, t = 2.8; P = .006). DISCUSSION: Weekly online survey metadata allowed for detection of changes in everyday cognition before transition to MCI. PMID- 29107053 TI - Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases. AB - INTRODUCTION: Comparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways. METHODS: We analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects. RESULTS: We identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in both AD and PSP, when compared with control TCX samples. DISCUSSION: Downregulation of myelination networks may underlie both PSP and AD pathophysiology, but may be more pronounced in PSP. These data also highlight conservation of transcriptional networks across brain regions and the influence of cell type changes on these networks. PMID- 29107054 TI - Selecting the correct cellular model for assessing of the biological response of collagen-based biomaterials. AB - : Accurate evaluation of the biological performance of biomaterials requires the correct assessment of their native-like cell ligation properties. However, cell attachment studies often overlook the details of the substrate-cell binding mechanisms, be they integrin-mediated or non-specific, and ignore the class- and species-specificities of the cell adhesion receptor involved. In this work we have used different collagen (Col) substrates (fibrillar collagens I, II and III and network-forming Col IV), containing different affinity cell-recognition motifs, to establish the influence of the receptor identity and species specificity on collagen-cell interactive properties. Receptor expression was varied by using cells of different origin, or transfecting collagen-binding integrins into integrin-null cells. These include mouse C2C12 myoblasts transfected with human alpha1, alpha2, alpha10 or alpha11; human fibrosarcoma HT1080 cells which constitutively express only human alpha2beta1, and rat glioma Rugli cells, with only rat alpha1beta1. Using these lines, the nature of integrin binding sites was studied in order to delineate the bioactivity of different collagen substrates. Integrin ligation was studied on collagen coatings alongside synthetic (GFOGER/GLOGEN) and Toolkit (Col II-28/Col III-7) triple-helical peptides to evaluate (1) their affinity towards different integrins and (2) to confirm the activity of the inserted integrin in the transfected cells. Thin films of dermal and tendon Col I were used to evaluate the influence of the carbodiimide (EDC)-based treatment on the cellular response on Col of different origin. The results showed that the binding properties of transfected C2C12 cells to collagens depend on the identity of inserted integrin. Similar ligation characteristics were observed using alpha1+ and alpha10+ cells, but these were distinct from the similar binding features of alpha2+ and alpha11+ cells. Recombinant human and rat-alpha1 I domain binding to collagens and peptides correlated with the cell adhesion results, showing receptor class- and species specificities. The understanding of the physiologically relevant cell anchorage characteristics of bio-constructs may assist in the selection of (1) the optimum collagen source for cellular supports and (2) the correct cellular model for their biological assessment. This, in turn, may allow reliable prediction of the biological performance of bio-scaffolds in vivo for specific TE applications. STATEMENT OF SIGNIFICANCE: Integrins play a vital role in cellular responses to environmental cues during early-stage cell-substrate interaction. We describe physiologically relevant cell anchorage to collagen substrates that present different affinity cell-recognition motifs, to provide experimental tools to assist in understanding integrin binding. Using different cell types and recombinant integrin alpha1-I-domains, we found that cellular response was highly dependent on collagen type, origin and EDC-crosslinking status, as well as on the integrin class and species of origin. This comprehensive study establishes selectivity amongst the four collagen-binding integrins and species-specific properties that together may influence choice of cell type and receptor in different experimental settings. This work offers key guidance in selecting of the correct cellular model for the biological testing of collagen-based biomaterials. PMID- 29107055 TI - Native and synthetic scaffolds for limbal epithelial stem cell transplantation. AB - : Limbal stem cell deficiency (LSCD) is a complex blinding disease of the cornea, which cannot be treated with conventional corneal transplants. Instead, a stem cell (SC) graft is required to replenish the limbal epithelial stem cell (LESC) reservoir, which is ultimately responsible for regenerating the corneal epithelium. Current therapies utilize limbal tissue biopsies that harbor LESCs as well as tissue culture expanded cells. Typically, this tissue is placed on a scaffold that supports the formation of corneal epithelial cell sheets, which are then transferred to diseased eyes. A wide range of biological and synthetic materials have been identified as carrier substrates for LESC, some of which have been used in the clinic, including amniotic membrane, fibrin, and silicon hydrogel contact lenses, each with their own advantages and limitations. This review will provide a brief background of LSCD, focusing on bio-scaffolds that have been utilized in limbal stem cell transplantation (LSCT) and materials that are being developed as potentially novel therapeutics for patients with this disease. STATEMENT OF SIGNIFICANCE: The outcome of patients with corneal blindness that receive stem cell grafts to restore eye health and correct vision varies considerably and may be due to the different biological and synthetic scaffolds used to deliver these cells to the ocular surface. This review will highlight the positive attributes and limitations of the myriad of carriers developed for clinical use as well as those that are being trialled in pre clinical models. The overall focus is on developing a standardized therapy for patients, however due to the multiple causes of corneal blindness, a personal regenerative medicine approach may be the best option. PMID- 29107051 TI - Added value of 18F-florbetaben amyloid PET in the diagnostic workup of most complex patients with dementia in France: A naturalistic study. AB - INTRODUCTION: Although some studies have previously addressed the clinical impact of amyloid positron emission tomography (PET), none has specifically addressed its selective and hierarchical implementation in relation to cerebrospinal fluid analysis in a naturalistic setting. METHODS: This multicenter study was performed at French tertiary memory clinics in patients presenting with most complex clinical situations (i.e., early-onset, atypical clinical profiles, suspected mixed etiological conditions, unexpected rate of progression), for whom cerebrospinal fluid analysis was indicated but either not feasible or considered as noncontributory (ClinicalTrials.gov: NCT02681172). RESULTS: Two hundred five patients were enrolled with evaluable florbetaben PET scans; 64.4% of scans were amyloid positive. PET results led to changed diagnosis and improved confidence in 66.8% and 81.5% of patients, respectively, and altered management in 80.0% of cases. DISCUSSION: High-level improvement of diagnostic certainty and management is provided by selective and hierarchical implementation of florbetaben PET into current standard practices for the most complex dementia cases. PMID- 29107056 TI - Strontium-modified premixed calcium phosphate cements for the therapy of osteoporotic bone defects. AB - : In this study a premixed strontium-containing calcium phosphate bone cement for the application in osteoporotic bone defects has been developed and characterised regarding its material and in vitro properties as well as minimally invasive applicability in balloon kyphoplasty. Strontium was introduced into the cement by substitution of one precursor component, CaCO3, with its strontium analogue, SrCO3. Using a biocompatible oil phase as carrier liquid, a cement paste that only set upon contact with aqueous environment was obtained. Strontium modification resulted in an increased strength of set cements and radiographic contrast; and the cements released biologically relevant doses of Sr2+-ions that were shown to enhance osteoprogenitor cell proliferation and osteogenic differentiation. Finally, applicability of strontium-containing cement pastes in balloon kyphoplasty was demonstrated in a human cadaver spine procedure. The cement developed in this study may therefore be well suited for minimally invasive, osteoporosis-related bone defect treatment. STATEMENT OF SIGNIFICANCE: Strontium-releasing calcium phosphate bone cements are promising materials for the clinical regeneration of osteoporosis-related bone defects since they have been shown to stimulate bone formation and at the same time limit osteoclastic bone resorption. Today clinical practice favours minimally invasive surgical techniques, e.g. for vertebral fracture treatment, posing special demands on such cements. We have therefore developed a premixed, strontium-releasing bone cement with enhanced mechanical properties and high radiographic visibility that releases biologically relevant strontium concentrations and thus stimulates cells of the osteogenic lineage. In a pilot experiment we also exemplify its excellent suitability for minimally invasive balloon kyphoplasty procedures. PMID- 29107057 TI - Rapid fabrication of microneedles using magnetorheological drawing lithography. AB - : Microneedles are micron-sized needles that are widely applied in biomedical fields owing to their painless, minimally invasive, and convenient operation. However, most microneedle fabrication approaches are costly, time consuming, involve multiple steps, and require expensive equipment. In this study, we present a novel magnetorheological drawing lithography (MRDL) method to efficiently fabricate microneedle, bio-inspired microneedle, and molding-free microneedle array. With the assistance of an external magnetic field, the 3D structure of a microneedle can be directly drawn from a droplet of curable magnetorheological fluid. The formation process of a microneedle consists of two key stages, elasto-capillary self-thinning and magneto-capillary self-shrinking, which greatly affect the microneedle height and tip radius. Penetration and fracture tests demonstrated that the microneedle had sufficient strength and toughness for skin penetration. Microneedle arrays and a bio-inspired microneedle were also fabricated, which further demonstrated the versatility and flexibility of the MRDL method. STATEMENT OF SIGNIFICANCE: Microneedles have been widely applied in biomedical fields owing to their painless, minimally invasive, and convenient operation. However, most microneedle fabrication approaches are costly, time consuming, involve multiple steps, and require expensive equipment. Furthermore, most researchers have focused on the biomedical applications of microneedles but have given little attention to the optimization of the fabrication process. This research presents a novel magnetorheological drawing lithography (MRDL) method to fabricate microneedle, bio-inspired microneedle, and molding-free microneedle array. In this proposed technique, a droplet of curable magnetorheological fluid (CMRF) is drawn directly from almost any substrate to produce a 3D microneedle under an external magnetic field. This method not only inherits the advantages of thermal drawing approach without the need for a mask and light irradiation but also eliminates the requirement for drawing temperature adjustment. The MRDL method is extremely simple and can even produce the complex and multiscale structure of bio-inspired microneedle. PMID- 29107058 TI - Immunogenicity and efficacy of replication-competent recombinant influenza virus carrying multimeric M2 extracellular domains in a chimeric hemagglutinin conjugate. AB - Current influenza vaccines provide hemagglutinin (HA) strain-specific protection. To improve cross protection, we engineered replication-competent influenza A virus to express tandem repeats of heterologous M2 extracellular (M2e) domains in a chimeric HA. M2e epitopes conjugated to HA glycoproteins (M2e4x-HA) were found to be expressed on the surfaces of a replicable influenza virus as examined by electron microscopy. The recombinant influenza virus containing M2e4x-HA was moderately attenuated but superior to the parental virus in inducing M2e specific antibodies without compromising HA immunogenicity. Recombinant influenza virus immune mice showed better cross protection than parental virus immune mice. Immune sera from the mice with inoculation of live recombinant influenza virus expressing M2e4x-HA were effective in conferring protection against H1, H3, and H5 subtype influenza viruses. This study indicates that recombinant influenza virus expressing conserved protective epitopes in an HA chimeric form can provide a new approach for improving the efficacy of influenza vaccines. PMID- 29107059 TI - One year effectiveness of neuromuscular exercise compared with instruction in analgesic use on knee function in patients with early knee osteoarthritis: the EXERPHARMA randomized trial. AB - OBJECTIVE: To test long-term effectiveness of neuromuscular exercise (NEMEX) with instructions in optimized pharmacological treatment (PHARMA) on activities of daily living (ADL) in patients with early knee osteoarthritis. DESIGN: 12-months follow-up from a randomized controlled trial. Participants with mild-to-moderate medial tibiofemoral knee osteoarthritis were randomly allocated to 8 weeks NEMEX or PHARMA. The primary outcome measure was the ADL-subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS). Secondary outcome measures included the other four KOOS-subscales, the University of California Activity Score (UCLA) and the European Quality of Life-5 Dimensions. RESULTS: Ninety-three patients (57% women, 58 +/- 8 years, body mass index 27 +/- 4 kg/m2) were randomized to NEMEX (n = 47) or PHARMA group (n = 46) with data from 85% being available at 12-months follow-up. Good compliance was achieved for 49% of the participants in NEMEX (>=12 sessions) and 7% in PHARMA (half the daily dose of acetaminophen/NSAIDs >= 28 days). Within-group improvements in NEMEX were considered to be clinically relevant (>=10 points) for all KOOS-subscales, except Sport/Rec whereas, no between-groups difference in the primary outcome KOOS ADL (3.6 [-2.1 to 9.2]; P = 0.216) was observed. For KOOS Symptoms, a statistically significant difference of 7.6 points (2.6-12.7; P = 0.004) was observed in favor of NEMEX with 47% improving >=10 points. CONCLUSIONS: No difference in improvement in difficulty with ADL was observed. NEMEX improved knee symptoms to a greater extent with half of patients reporting clinically relevant improvements. CLINICALTRIALS. GOV IDENTIFIER: NCT01638962 (July 3, 2012). ETHICAL COMMITTEE: S-20110153. PMID- 29107060 TI - Osteoarthritis biomarkers: year in review. AB - OBJECTIVE: To summarise important findings from biomarker studies relevant to osteoarthritis (OA), published between April 2016 and March 2017; to consider these findings in the context of new discoveries and technologies, and clinical and scientific need in OA. DESIGN: Studies were selected by PubMed search, conducted between 01/04/2016 and 01/03/2017. MeSH terms [biomarker] AND [OA] were used; the search was restricted to Human, English language and Full Text Available publications, which yielded 50 eligible publications. Any biomarker was considered, including non-proteins and other clinical measurements. RESULTS: Three main areas are overviewed: 1) Studies examining highly validated biomarkers, in the FNIH OA Biomarkers Consortium and elsewhere, particularly their ongoing application and validation. Control reference intervals, work on predictive validity and other longitudinal studies examining prognostic value of biomarkers in large cohorts are reviewed. 2) Novel studies relating to biomarkers of inflammation are discussed, including complement, the performance of markers of so-called 'cold inflammation' and results from clinical trials including biomarkers. 3) Discovery studies, including whole blood RNA, proteomics and metabolomics are reviewed, with an emphasis on new technologies. CONCLUSIONS: Discovery, characterisation and qualification of various biomarkers is ongoing; several novel protein and non-protein candidate biomarkers have been reported this year. Biomarkers provide us with an opportunity to better diagnose and stratify the disease, via established panels or new discovery approaches. Improving quality of sampling and testing, and measuring large numbers of markers simultaneously in large cohorts would seem likely to identify new clinically applicable biomarkers, which are still much needed in this disease. PMID- 29107061 TI - Physical activity and physical fitness of nursing home residents with cognitive impairment: A pilot study. AB - Physical activity and physical fitness are important for health, functional mobility and performance of everyday activities. To date, little attention has been given to physical activity and physical fitness among nursing home residents with cognitive impairment. Therefore, the main aim of this study was to examine physical activity behavior and physical fitness of institutionalized older adults with cognitive impairment and to investigate their interrelations. Forty-eight older adults with cognitive impairment (83.9+/-7.7years; 72.9% women) and 22 without cognitive impairment (82.2+/-8.8years; 54.5% women) participated. Physical activity was objectively assessed with accelerometers and physical fitness components (muscular strength, flexibility, balance, body composition and reaction time) were evaluated with physical fitness field tests. Nursing home residents with cognitive impairment spent only ~1min per day in moderate physical activity and ~89min in light physical activity. In average they accumulated 863 (+/-599) steps per day and spent 87.2% of the accelerometer wear time in sedentary behavior. Participants' physical fitness components were markedly low and according to the cut-offs used for interpreting the results a great number of nursing home residents had an increased risk of associated health problems, functional impairment and of falling. The performance in some physical fitness tests was positively associated with physical activity. Participants without cognitive impairment had higher levels of physical activity and physical fitness than their counterparts with cognitive impairment. These results indicate that nursing home residents, especially those with cognitive impairment, have low levels of physical activity, spent a high proportion of daytime in sedentary behavior and have low physical fitness. Nursing homes should implement health promotion strategies targeting physical activity and physical fitness of their residents. PMID- 29107062 TI - The anti-aging protein klotho alleviates injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine rat model of Parkinson's disease: Involvement of PKA/CaMKII/CREB signaling. AB - Parkinson's disease (PD) is a prevalent movement disorder in the elderly. PD is hallmarked with progressive deterioration of mesencephalic dopaminergic neurons and development of debilitating motor and non-motor clinical symptoms. Klotho protein is the product of an aging-suppressor gene that its overexpression could protect neurons against oxidative injury. This study was undertaken to explore whether exogenous klotho could alleviate injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA lesioned rats were pretreated with klotho at a dose of 10MUg/rat. Results showed that klotho mitigates apomorphine-induced rotational behavior and reduces the latency to initiate and the total time in the narrow beam test. In addition, beneficial effect of klotho was attenuated following i.c.v. microinjection of protein kinase A (PKA) inhibitor H-89 and Ca(2+)/calmodulin-dependent protein kinase II (CamKII) inhibitor KN-62. Additionally, klotho significantly lowered striatal levels of malondialdehyde (MDA), reactive oxygen species (ROS), glial fibrillary acid protein (GFAP), alpha synuclein, phospho-cAMP-response element binding protein (pCREB), and DNA fragmentation. Furthermore, klotho was capable to prevent degeneration of tyrosine hydroxylase (TH)-positive neurons within substantia nigra pars compacta (SNC). Collectively, these findings denote neuroprotective potential of exogenous klotho in 6-OHDA rat model of PD through alleviation of astrogliosis, apoptosis, and oxidative stress. It was also obtained that part of its protective effect is dependent on PKA/CaMKII/CREB signaling cascade. PMID- 29107064 TI - CCD and RSM optimization approach for antioxidative activity and immune regulation in head kidney of yellow catfish (Pelteobagrus fulvidraco) based on different lipid levels and temperatures. AB - Yellow catfish (Pelteobagrus fulvidraco) is an important economic cultured fish in China. Here we report antioxidative activity and immune regulation in head kidney using a central composite design based on water temperature (20-34 degrees C) and dietary lipid (2-17%). Response values were optimized using response surface methodology to maximize the immune response and relieve oxidative stress. The experiment was conducted under laboratory conditions and lasted for seven weeks. The results showed that the linear effects of lipid level on superoxide dismutase (SOD, and lysozyme (LYZ) activity, and malondialdehyde (MDA) content in head kidney, respiratory burst activity (RBA) of head kidney macrophages, and cumulative mortality of fish infected by Streptococcus iniae (S. iniae) were significant (P < 0.05). Similarly, the linear effects of water temperature on SOD activity, MDA content, and cumulative mortality were significant (P < 0.05). In addition, the quadratic effects of water temperature and lipid level on all experimental response values were significant (P < 0.05), and no interactive effect was found between water temperature and lipid level (P > 0.05). High water temperature and high lipid diet significantly reduced the antioxidative activity and immune response in head kidney, and increased MDA content, which caused increased mortality of the S. iniae-infected fish. The adjusted R2 values for SOD activity, MDA content, LYZ activity, RBA, phagocytic activity, and cumulative mortality regression models were 0.76, 0.85, 0.87, 0.79, 0.64, and 0.87, respectively. The optimal combination of water temperature and lipid level was 26.9 degrees C and 7.7%, at which good antioxidative activity and immune regulation were achieved, with reliability of 0.878. This combination was close to the optimal combination of water temperature and lipid level for growth performance (27.5 degrees C and 9.2%) reported previously. Thus, the optimal combination may not only promote growth, but also enhance antioxidant and immune levels. PMID- 29107065 TI - Efficacy of algal Ecklonia cava extract against viral hemorrhagic septicemia virus (VHSV). AB - The inhibition efficacy of an extract from Ecklonia cava (E. cava) was studied to determine whether the extract and compounds exhibited inhibitory activity against VHSV in the fathead minnow (FHM) cell line and following oral administration to the olive flounder. Based on its low toxicity and effective concentration, the E. cava extract (Ext) and compounds (eckol and phlorofucofuroeckol A) were selected for further analysis. In the plaque reduction assay, simultaneous co-exposure of VHSV to Ext, eckol and phlorofucofuroeckol A showed a higher level of inhibition than the pre- and post-exposure groups. The antiviral activity in the FHM cell line was time-dependent and increased with the exposure time with the virus and Ext or the compounds. In the in vivo experiments, different Ext concentrations were orally administered to the olive flounder. In trial I, the relative percent survival (RPS) following oral administration of 500 and 50 MUg/g/day of Ext was 31.25% and 12.50%, respectively. In trial II, the RPS for 1000, 500 and 50 MUg/g/day of Ext was 31.57%, 0% and 0%, respectively. In trial III, the RPS after 1 and 2 weeks (1000 MUg/g/day) of exposure to Ext was 26.31% and 31.57%, respectively. Oral administration of Ext (1000 MUg/g/day) significantly induced inflammatory cytokine responses (IL-1beta, IL-6 and IFN-gamma) at 1 and 2 days post-oral administration (dpa). Additionally, IFN-alpha/beta (7-12 dpa), ISG15 (2, 7 and 10 dpa) and Mx (7-12 dpa) were significantly activated in the olive flounder. In conclusion, we demonstrated an inhibitory ability of the E. cava extract and compounds against VHSV in the FHM cell line. Moreover, oral administration of the E. cava extract to the olive flounder enhanced antiviral immune responses and the efficacy of protection against VHSV, resulting in an anti-viral status in the olive flounder. PMID- 29107063 TI - Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses. AB - Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection. PMID- 29107066 TI - Glomerular filtration drug injury: In vitro evaluation of functional and morphological podocyte perturbations. AB - The kidney is an organ that plays a major role in the excretion of numerous compounds such as drugs and chemicals. However, a great number of pharmacological molecules are nephrotoxic, affecting the efficiency of the treatment and increasing morbidity or mortality. Focusing on glomerular filtration, we propose in this study a simple and reproducible in vitro human model that is able to bring to light a functional podocyte injury, correlated with morphologic/phenotypic changes after drug exposure. This model was used for the evaluation of paracellular permeability of FITC-dextran molecules as well as FITC BSA after different treatments. Puromycin aminonucleoside and adriamycin, compounds known to induce proteinuria in vivo and that serve here as positive nephrotoxic drug controls, were able to induce an important increase in fluorescent probe passage through the cell monolayer. Different molecules were then evaluated for their potential effect on podocyte filtration. Our results demonstrated that a drug effect could be time dependent, stable or scalable and relatively specific. Immunofluorescence studies indicated that these functional perturbations were due to cytoskeletal perturbations, monolayer disassembly or could be correlated with a decrease in nephrin expression and/or ZO-1 relocation. Taken together, our results demonstrated that this in vitro human model represents an interesting tool for the screening of the renal toxicity of drugs. PMID- 29107067 TI - Functional analysis of the cfdp1 gene in zebrafish provides evidence for its crucial role in craniofacial development and osteogenesis. AB - The CFDP1 proteins have been linked to craniofacial development and osteogenesis in vertebrates, though specific human syndromes have not yet been identified. Alterations of craniofacial development represent the main cause of infant disability and mortality in humans. For this reason, it is crucial to understand the cellular functions and mechanism of action of the CFDP1 protein in model vertebrate organisms. Using a combination of genomic, molecular and cell biology approaches, we have performed a functional analysis of the cfdp1 gene and its encoded protein, zCFDP1, in the zebrafish model system. We found that zCFDP1 is present in the zygote, is rapidly produced after MTZ transition and is highly abundant in the head structures. Depletion of zCFDP1, induced by an ATG-blocking morpholino, produces considerable defects in craniofacial structures and bone mineralization. Together, our results show that zCFDP1 is an essential protein required for proper development and provide the first experimental evidence showing that in vertebrates it actively participates to the morphogenesis of craniofacial territories. PMID- 29107068 TI - Targeting tumor cells based on Phosphodiesterase 3A expression. AB - We and others have previously reported a correlation between high phosphodiesterase 3A (PDE3A) expression and selective sensitivity to phosphodiesterase (PDE) inhibitors. This indicates that PDE3A could serve both as a drug target and a biomarker of sensitivity to PDE3 inhibition. In this report, we explored publicly available mRNA gene expression data to identify cell lines with different PDE3A expression. Cell lines with high PDE3A expression showed marked in vitro sensitivity to PDE inhibitors zardaverine and quazinone, when compared with those having low PDE3A expression. Immunofluorescence and immunohistochemical stainings were in agreement with PDE3A mRNA expression, providing suitable alternatives for biomarker analysis of clinical tissue specimens. Moreover, we here demonstrate that tumor cells from patients with ovarian carcinoma show great variability in PDE3A protein expression and that level of PDE3A expression is correlated with sensitivity to PDE inhibition. Finally, we demonstrate that PDE3A is highly expressed in subsets of patient tumor cell samples from different solid cancer diagnoses and expressed at exceptional levels in gastrointestinal stromal tumor (GIST) specimens. Importantly, vulnerability to PDE3 inhibitors has recently been associated with co-expression of PDE3A and Schlafen family member 12 (SLFN12). We here demonstrate that high expression of PDE3A in clinical specimens, at least on the mRNA level, seems to be frequently associated with high SLFN12 expression. In conclusion, PDE3A seems to be both a promising biomarker and drug target for individualized drug treatment of various cancers. PMID- 29107069 TI - The species origin of the cellular microenvironment influences markers of beta cell fate and function in EndoC-betaH1 cells. AB - Interaction between islet cell subtypes and the extracellular matrix influences beta-cell function in mammals. The tissue architecture of rodent islets is very different to that of human islets; cell-to-cell communication and interaction with the extracellular matrix may vary between species. In this work, we have compared the responses of the human EndoC-betaH1 cell line to non-human and human derived growth matrices in terms of growth morphology, gene expression and glucose-stimulated insulin secretion (GSIS). EndoC-betaH1 cells demonstrated a greater tendency to form cell clusters when cultured in a human microenvironment and exhibited reduced alpha cell markers at the mRNA level; mean expression difference - 0.23 and - 0.51; p = 0.009 and 0.002 for the Aristaless-related homeobox (ARX) and Glucagon (GCG) genes respectively. No differences were noted in the protein expression of mature beta cell markers such as Pdx1 and NeuroD1 were noted in EndoC-betaH1 cells grown in a human microenvironment but cells were however more sensitive to glucose (4.3-fold increase in insulin secretion following glucose challenge compared with a 1.9-fold increase in cells grown in a non-human microenvironment; p = 0.0003). Our data suggests that the tissue origin of the cellular microenvironment has effects on the function of EndoC-betaH1 cells in vitro, and the use of a more human-like culture microenvironment may bring benefits in terms of increased physiological relevance. PMID- 29107070 TI - Inflammation-driven colon neoplasmatogenesis in uPA-deficient mice is associated with an increased expression of Runx transcriptional regulators. AB - Deregulation of the bone morphogenetic protein (BMP) pathway has been documented in colorectal cancer (CRC). Previously, we investigated possible associations between urokinase-type plasminogen activator (uPA) deficiency and expression of extracellular constituents of BMP signaling in a newly developed mouse model of inflammation-driven intestinal neoplasmatogenesis, in which chronic colitis and CRC are induced using dextran sodium sulfate (DSS). In this report, we explored the contribution of intracellular components of Smad-mediated BMP signal transduction using the same model. Interestingly, upon DSS treatment, we noticed an overexpression of Runx1/2/3 transcription factors in both wild-type and uPA deficient mice. Moreover, Runx1 and Runx2 expression levels exhibited an even higher increase in DSS-treated/uPA-deficient mice as compared to DSS-treated/wild type animals. In all experimental conditions, in situ investigation of Runx expressing cell types, revealed detection of all three Runx in the immune cells, yet in the DSS-treated/uPA-deficient mice Runx1 and Runx2 were also identified in the preneoplastic epithelium of advanced high-grade dysplasia and carcinoma in situ colonic lesions. Finally, the uPA-deficient pro-tumorigenic colitic microenvironment exhibited increased levels of the Runx-induced target genes Snai2, Bim and Claudin1, known to have a role in tumor development and progression. These findings suggest that the absence of uPA correlates with increased levels of Runx transcriptional regulators in a way that promotes inflammation-associated carcinogenesis. PMID- 29107071 TI - Role of TLR4 in olfactory-based spatial learning activity of neonatal mice after developmental exposure to diesel exhaust origin secondary organic aerosol. AB - Exposure to ambient air pollutants has been reported to have various adverse health impacts. Ambient particulate matter comprises primary particles released directly via engine exhaust and secondary organic aerosols (SOAs) formed from oxidative reactions of the ultrafine particle fraction of diesel exhaust (DE). Toll-like receptor 4 (TLR4) is well known to initiate the inflammatory cascade in the central nervous system. However, whether and how DE and DE-SOA exposure influences TLR4 signaling in the immature brain remains unclear. We attempted to evaluate the roles of TLR-4, inflammatory mediators and microglial markers in the impaired spatial learning ability of neonatal mice exposed to DE and DE-SOAs. Pregnant C3H/HeN (TLR4-intact) and C3H/HeJ (TLR4- mutated) mice were exposed to clean air, DE or DE-SOA from gestational day 14 to postnatal day (PND) 10 (5h/day for 5days) in exposure chambers. PND11 neonatal mice were examined for their performance in the olfactory-based spatial learning test. After the spatial learning test, the hippocampi of the mice were removed and real-time RT-PCR analysis was performed to examine the neurological and immunological markers. Both male and female C3H/HeN and C3H/HeJ neonatal mice exposed to DE and DE-SOAs showed poor performance in the test phase of spatial learning as compared to the mice exposed to clean air. However, this spatial learning deficit was prominent in C3H/HeJ neonatal mice. In the neonatal C3H/HeN male mice exposed to DE and DE SOAs, the mRNA expression levels of the NMDA receptor subunits (NR1, NR2B), proinflammatory cytokines, tumor necrosis factor-alpha and cyclooxygenase-2, oxidative stress marker, heme oxygenase-1, and microglial marker, Iba1, in the hippocampus were significantly increased, but these changes were not observed in female mice. Our findings indicate that activation of the neuroimmune system and TLR4 signaling may possibly be involved in environmental pollutant-induced spatial learning impairment in neonatal mice. PMID- 29107073 TI - Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma. AB - Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. The interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) were assessed and changes in reactive oxygen species were evaluated as a mechanism of treatment response in tumor spheroid/immunocyte co-cultures. Pretreatment tumor biopsies were immunohistochemically characterized in 73 HNSCC patients treated by definitive chemoradiotherapy and correlated with survival. The prognostic significance of CD8A, GLUT1, and COX5B gene expression was analyzed within The Cancer Genome Atlas database. HNSCC spheroids were co cultured in vitro with peripheral blood mononuclear cells (PBMCs) in the presence of the glycolysis inhibitor 2-deoxyglucose and radiation treatment followed by PBMC chemotaxis determination via fluorescence microscopy. In the chemoradiotherapy-treated HNSCC cohort, mitochondrial-rich (COX5B) metabolism correlated with increased and glucose-dependent (GLUT1) metabolism with decreased intratumoral CD8/CD4 ratios. High CD8/CD4, together with mitochondrial-rich or glucose-independent metabolism, was associated with improved short-term survival. The Cancer Genome Atlas analysis confirmed that patients with a favorable immune and metabolic gene signature (high CD8A, high COX5B, low GLUT1) had improved short- and long-term survival. In vitro, 2-deoxyglucose and radiation synergistically up-regulated reactive oxygen species-dependent PBMC chemotaxis to HNSCC spheroids. These results suggest that glucose-independent tumor metabolism is associated with CD8-dominant antitumor immune infiltrate, and together, these contribute to improved chemoradiotherapy response in HNSCC. PMID- 29107072 TI - Ectopic Phosphorylated Creb Marks Dedifferentiated Proximal Tubules in Cystic Kidney Disease. AB - Ectopic cAMP signaling is pathologic in polycystic kidney disease; however, its spatiotemporal actions are unclear. We characterized the expression of phosphorylated Creb (p-Creb), a target and mediator of cAMP signaling, in developing and cystic kidney models. We also examined tubule-specific effects of cAMP analogs in cystogenesis in embryonic kidney explants. In wild-type mice, p Creb marked nephron progenitors (NP), early epithelial NP derivatives, ureteric bud, and cortical stroma; p-Creb was present in differentiated thick ascending limb of Henle, collecting duct, and stroma; however, it disappeared in mature NP derived proximal tubules. In Six2cre;Frs2alphaFl/Fl mice, a renal cystic model, ectopic p-Creb stained proximal tubule-derived cystic segments that lost the differentiation marker lotus tetragonolobus lectin. Furthermore, lotus tetragonolobus lectin-negative/p-Creb-positive cyst segments (re)-expressed Ncam1, Pax2, and Sox9 markers of immature nephron structures and dedifferentiated proximal tubules after acute kidney injury. These dedifferentiation markers were co-expressed with p-Creb in renal cysts in Itf88 knockout mice subjected to ischemia and Six2cre;Pkd1Fl/Fl mice, other renal cystogenesis models. 8-Br-cAMP addition to wild-type embryonic kidney explants induced proximal tubular cystogenesis and p-Creb expression; these effects were blocked by co-addition of protein kinase A inhibitor. Thus p-Creb/cAMP signaling is appropriate in NP and early nephron derivatives, but disappears in mature proximal tubules. Moreover, ectopic p-Creb expression/cAMP signaling marks dedifferentiated proximal tubular cystic segments. Furthermore, proximal tubules are predisposed to become cystic after cAMP stimulation. PMID- 29107074 TI - Loss of beta Epithelial Sodium Channel Function in Meibomian Glands Produces Pseudohypoaldosteronism 1-Like Ocular Disease in Mice. AB - Human subjects with pseudohypoaldosteronism-1 because of loss-of-function mutations in epithelial sodium channel (ENaC) subunits exhibit meibomian gland (MG) dysfunction. A conditional betaENaC MG knockout (KO) mouse model was generated to elucidate the pathogenesis of absent ENaC function in the MG and associated ocular surface disease. betaENaC MG KO mice exhibited a striking age dependent, female-predominant MG dysfunction phenotype, with white toothpaste like secretions observed obstructing MG orifices at 7 weeks of age. There were compensatory increases in tear production but higher tear sodium and indexes of mucin concentration in betaENaC MG KO mice. Histologically, MG acinar atrophy was observed with ductal enlargement and ductal epithelial hyperstratification. Inflammatory cell infiltration was observed in both MG and conjunctiva of betaENaC MG KO mice. In older betaENaC MG KO mice (5 to 11 months), significant ocular surface pathologies were noted, including corneal opacification, ulceration, neovascularization, and ectasia. Inflammation in MG and conjunctiva was confirmed by increased cytokine gene and protein expression and positive Ly 6B.2 immunostaining. Cell proliferation assays revealed lower proliferation rates of MG cells derived from betaENaC MG KO than control mice, suggesting that betaENaC plays a role in cell renewal of mouse MG. Loss of betaENaC function resulted in MG disease and severe ocular surface damage that phenocopied aspects of human pseudohypoaldosteronism-1 MG disease and was sex dependent. PMID- 29107076 TI - Hypomorphic RAG1 defect in a child presented with pulmonary hemorrhage and digital necrosis. PMID- 29107075 TI - The Role of Extracellular Histones in Influenza Virus Pathogenesis. AB - Although exaggerated host immune responses have been implicated in influenza induced lung pathogenesis, the etiologic factors that contribute to these events are not completely understood. We previously demonstrated that neutrophil extracellular traps exacerbate pulmonary injury during influenza pneumonia. Histones are the major protein components of neutrophil extracellular traps and are known to have cytotoxic effects. Here, we examined the role of extracellular histones in lung pathogenesis during influenza. Mice infected with influenza virus displayed high accumulation of extracellular histones, with widespread pulmonary microvascular thrombosis. Occluded pulmonary blood vessels with vascular thrombi often exhibited endothelial necrosis surrounded by hemorrhagic effusions and pulmonary edema. Histones released during influenza induced cytotoxicity and showed strong binding to platelets within thrombi in infected mouse lungs. Nasal wash samples from influenza-infected patients also showed increased accumulation of extracellular histones, suggesting a possible clinical relevance of elevated histones in pulmonary injury. Although histones inhibited influenza growth in vitro, in vivo treatment with histones did not yield antiviral effects and instead exacerbated lung pathology. Blocking with antihistone antibodies caused a marked decrease in lung pathology in lethal influenza-challenged mice and improved protection when administered in combination with the antiviral agent oseltamivir. These findings support the pathogenic effects of extracellular histones in that pulmonary injury during influenza was exacerbated. Targeting histones provides a novel therapeutic approach to influenza pneumonia. PMID- 29107077 TI - Occurrence of Pseudomonas aeruginosa in taps: implications for patients with cystic fibrosis. PMID- 29107078 TI - Randomized controlled trial of honey versus mupirocin to decolonize patients with nasal colonization of meticillin-resistant Staphylococcus aureus. AB - BACKGROUND: Mupirocin is used specifically for the eradication of nasal meticillin-resistant Staphylococcus aureus (MRSA), but increasing mupirocin resistance restricts its repeated use. The antibacterial effects of manuka honey have been established in vitro; antibacterial activity of other honeys has also been reported. AIM: To describe the learning experience from a randomized controlled trial (RCT) comparing the efficacy of medical-grade honey (MGH) with mupirocin 2% for the eradication of nasal MRSA. METHODS: Patients colonized in the nose with MRSA and age >=18 years were recruited. Participants received either one or two courses of MGH or mupirocin 2%, three times per day for five consecutive days. FINDINGS: The proportion of patients who were decolonized after one or two courses of treatment was not significantly different between MGH [18/42; 42.8%; 95% confidence interval (CI): 27.7-59.0] and mupirocin 2% (25/44; 56.8%; 95% CI: 41.0-71.7). Non-nasal MRSA colonization was significantly associated with persistent nasal colonization (odds ratio: 5.186; 95% CI: 1.736 5.489; P = 0.003). The rate of new acquisition of mupirocin resistance was 9.75%. CONCLUSION: Although not significant, a decolonization rate of 42.8% for MGH was impressive. Our findings suggest that this strategy, which has the potential to combat antimicrobial resistance, should be assessed in similar but larger studies. PMID- 29107079 TI - Clonal spread of carbapenem-resistant Acinetobacter baumannii in a neonatal intensive care unit. AB - Acinetobacter baumannii has often been associated with colonization and/or infection in neonatal intensive care units (NICU). This study describes a clonal spread of carbapenem-resistant A. baumannii (CRAB) isolates in an NICU. In total, 21 CRAB isolates were collected from premature newborns. Only polymyxin B was active against such isolates. Nineteen CRAB isolates were clonally related (Cluster C, which belonged to worldwide-disseminated ST1). All newborns had peripheral access and had received beta-lactam therapy previously. The implementation of strict infection control measures was of fundamental importance to eradicate the clonal type in the study hospital. PMID- 29107080 TI - Genotoxicity evaluation induced by Tityus serrulatus scorpion venom in mice. AB - Tityus serrulatus is the scorpion associated with the most severe cases of scorpion envenoming in Brazil. However, there are no studies reporting the genotoxic effects of this venom in natural or experimental envenomations. It is well known that DNA-damage responses are providing opportunities for improving disease detection and management. In this study was evaluating the genotoxicity of the T. serrulatus venom in different organs (hippocampus, cortex, striatum, blood, heart, lung, liver and kidney) and periods in mice experimentally envenomed. ELISA and the Comet assays were used to quantification of venoms antigens and DNA damage, respectively. Forty-eight Swiss mice were divided into five groups and 0.5 DL50 of T. serrulatus venom (0.90 mg/kg) was administered intraperitoneally in each animal. Euthanasia was performed by cervical dislocation in the period of 0h (control group) 1h, 2h, 6h and 12h, where it the tissues were removed. The results showed high DNA damage in all structures analyzed, suggesting that T. serrulatus venom presented genotoxic activity or some secondary effect generated by venom injection. In the ELISA test, toxic circulant antigens were verified in practically all organs at the time intervals analyzed. Therefore, the distribution of the venom changes from organ to organ. We conclude that scorpion envenoming affects DNA in all organs analyzed even when the venom concentration is lower or no detectable, DNA damage persists. PMID- 29107081 TI - Nodularin from benthic freshwater periphyton and implications for trophic transfer. AB - In 2013 and 2015, the Pennsylvania Department of Environmental Protection conducted a survey of lotic habitats within the Susquehanna, Delaware, and Ohio River basins in Pennsylvania, USA, to screen for microcystins/nodularins (MCs/NODs) in algae communities and smallmouth bass (Micropterus dolomieu). Periphyton (68 from 41 sites), juvenile whole fish (153 from 19 sites) and adult fish liver (115 from 16 sites) samples were collected and screened using an Adda enzyme-linked immunosorbent assay (ELISA). Samples that were positive for MCs/NODs were further analyzed using LC-MS/MS, including 14 variants of microcystin and NOD-R and the MMPB technique. The ELISA was positive for 47% of the periphyton collections, with NOD-R confirmed (0.7-82.2 ng g-1 d.w.) in 20 samples. NOD-R was confirmed in 10 of 15 positive juvenile whole fish samples (0.8-16.7 ng g-1 w.w.) and in 2 of 8 liver samples (1.7 & 2.8 ng g-1 w.w.). The MMPB method resulted in total MCs/NODs measured in periphyton (2.2-1269 ng g-1 d.w.), juvenile whole fish (5.0-210 ng g-1 d.w.) and adult livers (8.5-29.5 ng g 1 d.w.). This work illustrates that NOD-R is present in freshwater benthic algae in the USA, which has broader implications for monitoring and trophic transfer. PMID- 29107082 TI - Purification and characterization of an anti-hemorrhagic protein from Naja naja (Indian cobra) venom. AB - Snake venom Kunitz-type proteins are well known to inhibit serine proteases but a few studies have also shown matrix metalloproteases (MMPs) inhibition. In view of the fact that MMPs and snake venom metalloproteases (SVMPs) have similar catalytic site, inhibition of SVMP activity by Kunitz-type proteins remains to be studied. Recent proteomic studies of Naja naja (N. naja) venom revealed the abundance of Kunitz-type proteins. In this regard, present study aimed at purification of a protease inhibitor from N. naja venom that inhibits the toxicity of SVMPs rich Echis carinatus (E. carinatus) venom. N. naja venom effectively inhibited E. carinatus venom-induced hemorrhage. Purification of the active principle responsible for anti-hemorrhagic effect was achieved by fractionation of N. naja venom in three successive chromatographic steps. SDS PAGE revealed that purified anti-hemorrhagic protein (NNAh) has an apparent molecular mass of ~44 kDa and single peak in RP-HPLC demonstrated its homogeneity. NNAh also inhibited myonecrosis induced by E. carinatus venom and reduced activity of creatine kinase in NNAh treated animal sera substantiated the anti-myonecrotic effect. Hemorrhage and myonecrosis inhibitory effects of NNAh were further supported by inhibition of E. carinatus venom-mediated gelatinolysis and collagenolysis. NNAh falls into the category of Kunitz-type serine protease inhibitor as determined by peptide mass fingerprinting and shown to be a strong inhibitor of chymotrypsin. Collectively our data signify that NNAh is a Kunitz type chymotrypsin inhibitor which also inhibited metalloprotease activities of E. carinatus venom. In future, complete sequence of NNAh and peptide region(s) responsible for inhibition will assist to deduce the mechanism of action. PMID- 29107083 TI - p63 and p73 repress CXCR5 chemokine receptor gene expression in p53-deficient MCF 7 breast cancer cells during genotoxic stress. AB - Many types of chemotherapeutic agents induce of DNA-damage that is accompanied by activation of p53 tumor suppressor, a key regulator of tumor development and progression. In our previous study we demonstrated that p53 could repress CXCR5 chemokine receptor gene in MCF-7 breast cancer cells via attenuation of NFkB activity. In this work we aimed to determine individual roles of p53 family members in the regulation of CXCR5 gene expression under genotoxic stress. DNA alkylating agent methyl methanesulfonate caused a reduction in CXCR5 expression not only in parental MCF-7 cells but also in MCF-7-p53off cells with CRISPR/Cas9 mediated inactivation of the p53 gene. Since p53 knockout was associated with elevated expression of its p63 and p73 homologues, we knocked out p63 using CRISPR/Cas9 system and knocked down p73 using specific siRNA. The CXCR5 promoter activity, CXCR5 expression and CXCL13-directed migration in MCF-7 cells with inactivation of all three p53 family genes were completely insensitive to genotoxic stress, while pairwise p53+p63 or p53+p73 inactivation resulted in partial effects. Using deletion analysis and site-directed mutagenesis, we demonstrated that effects of NFkB on the CXCR5 promoter inversely correlated with p63 and p73 levels. Thus, all three p53 family members mediate the effects of genotoxic stress on the CXCR5 promoter using the same mechanism associated with attenuation of NFkB activity. Understanding of this mechanism could facilitate prognosis of tumor responses to chemotherapy. PMID- 29107084 TI - Evidence for M2 macrophages in granulomas from pulmonary sarcoidosis: A new aspect of macrophage heterogeneity. AB - BACKGROUND: Sarcoidosis is a granulomatous disease of unknown etiology. Macrophages play a key role in granuloma formation with the T cells, having a significant impact on macrophage polarization (M1 and M2) and the cellular composition of the granuloma. This study evaluates macrophage polarization in granulomas in pulmonary sarcoidosis. MATERIALS AND METHODS: Tissue specimens from the Department of Pathology biobank at the Masih Daneshvari Hospital were obtained. Paraffin sections from 10 sarcoidosis patients were compared with those from 12 cases of tuberculosis using immunohistochemical staining. These sections consisted of mediastinal lymph nodes and transbronchial lung biopsy (TBLB) for sarcoidosis patients versus pleural tissue, neck, axillary lymph nodes and TBLB for tuberculosis patients. The sections were stained for T-cells (CD4+, CD8+) and mature B lymphocytes (CD22+). CD14+ and CD68+ staining was used as a marker of M1 macrophages and CD163+ as a marker for M2 macrophages. RESULTS: Immunohistochemical staining revealed a 4/1 ratio of CD4+/CD8+ T-cells in sarcoidosis granuloma sections and a 3/1 ratio in tuberculosis sections. There was no significance difference in single CD4+, CD8+, CD22+, CD14+ and CD68+ staining between sarcoidosis and tuberculosis sections. CD163 expression was significantly increased in sarcoidosis sections compared with those from tuberculosis subjects. CONCLUSION: Enhanced CD163+ staining indicates a shift towards M2 macrophage subsets in granulomas from sarcoidosis patients. Further research is required to determine the functional role of M2 macrophages in the immunopathogenesis of sarcoidosis. PMID- 29107085 TI - Hsp70 participates in PINK1-mediated mitophagy by regulating the stability of PINK1. AB - INTRODUCTION: Loss-of function mutations in PTEN-induced putative kinase 1 (PINK1) is one of the most common causes of autosomal recessive Parkinson's disease (PD). PINK1-mediated mitophagy is critical to mitochondrial quality control and plays an important role in PD pathogenesis. Therefore, identifying the regulatory mechanisms of PINK1 expression may provide novel opportunities for PD therapy. Heat-shock protein 70kDa (Hsp70) is involved in neuroprotection as a molecular chaperone in neurodegenerative disorders such as PD. Thus far, the interaction between Hsp70 and PINK1 remains unclear. OBJECTIVES: This study aimed to verify the interaction between Hsp70 and PINK1, as well as the role of Hsp70 in PINK1 stability, cell autophagy, and PINK1-mediated mitophagy. METHODS: The interaction and subcellular location of Hsp70 and PINK1 were verified by coimmunoprecipitation and immunofluorescence colocalization. Western blot analysis was used to determine the role of Hsp70 in PINK1 stability. Immunofluorescence and Western blot analyses were performed to determine the role of Hsp70 in PINK1-mediated mitophagy. RESULTS: We identified the interaction between Hsp70 and PINK1 and revealed that Hsp70 stabilized PINK1 by decreasing PINK1 degradation. Our data demonstrated that Hsp70 participated in PINK1 mediated mitophagy. CONCLUSIONS: Hsp70participated in PINK1-mediated mitophagy by stabilizing PINK1. PMID- 29107086 TI - Age-dependent elevations of oligomeric and phosphorylated alpha-synuclein synchronously occurs in the brain and gastrointestinal tract of cynomolgus monkeys. AB - Fibrillary alpha-synuclein (alpha-syn), which constitutes the major component of Lewy pathology characterized for Parkinson's disease (PD), is found also in the aged enteric nervous system (ENS) and central nervous system (CNS). However, what happens to oligomeric alpha-syn (o-alpha-syn) in the aged ENS and CNS remains poorly understood. Here, by using ELISA methods specific for o-alpha-syn and phosphorylated alpha-syn (p-alpha-syn), we measured the levels of o-alpha-syn and p-alpha-syn in the gastrointestinal (GI) tract and brain of aging cynomolgus monkeys. We detected a synchronously occurred age-dependent elevation of o-alpha syn in the GI tract and brain, which was accompanied by an age-dependent increase of alpha-syn phosphorylated at serine 129, a modification that promotes alpha-syn aggregation. Correlation analysis revealed that alterations in p-alpha-syn and o alpha-syn in the colon were positively correlated to those in some brain regions such as the striatum, hippocampus, thalamus and temporal lobe. The results obtained suggest that age-dependent elevations of p-alpha-syn and o-alpha-syn occur synchronously in various regions of the ENS and CNS. PMID- 29107087 TI - Labelled animal toxins as selective molecular markers of ion channels: Applications in neurobiology and beyond. AB - Animal toxins are traditional and indispensible molecular tools that find application in different fields of biochemistry, neurobiology and pharmacology. These compounds possess several outstanding properties such as high affinity and selectivity with respect to particular molecular targets, most importantly ion channels and neuroreceptors, and stability. In addition to using toxins per se, a wide variety of labelled modifications have been obtained including radioactive and fluorescent derivatives. Here, we discuss the major types of labelled toxins, methods of their production and principal possibilities of application ranging from receptor localization and visualization to development of screening systems and diagnostic tools, and drug discovery. PMID- 29107088 TI - Intrinsic frequency specific brain networks for identification of MCI individuals using resting-state fMRI. AB - Numerous brain oscillations are well organized into several brain rhythms to support complex brain activities within distinct frequency bands. These rhythms temporally coexist in the same or different brain areas and may interact with each other with specific properties and physiological functions. However, the identification and evaluation of these various brain rhythms derived from BOLD fMRI signals are obscure. To address this issue, we introduced a data-driven method named Complementary Ensemble Empirical Mode Decomposition (CEEMD) to automatically decompose the BOLD oscillations into several brain rhythms within distinct frequency bands. Thereafter, in order to evaluate the performance of CEEMD in the detection of subtle BOLD signals, a novel CEEMD-based high dimensional pattern classification framework was proposed to accurately identify mild cognitive impairment individuals from the healthy controls. Our results showed CEEMD is a stable frequency decomposition method. Furthermore, CEEMD-based frequency specific topological profiles provided a classification accuracy of 93.33%, which was saliently higher than that of the conventional frequency separation based scheme. Importantly, our findings demonstrated that CEEMD could provide an effective means for brain oscillation separation, by which a more meaningful frequency bins could be used to detect the subtle changes embedded in the BOLD signals. PMID- 29107089 TI - Orexins/hypocretins and sex. PMID- 29107090 TI - Inhibition of angiotensin II and calpain attenuates pleural fibrosis. AB - Pleural fibrosis is associated with various inflammatory processes such as tuberculous pleurisy and bacterial empyema. There is currently no ideal therapeutic to attenuate pleural fibrosis. Some pro-fibrogenic mediators induce fibrosis through inflammatory processes, suggesting that blockage of these mediators might prevent pleural fibrosis. The MeT-5A human pleural mesothelial cell line (PMC) was used in this study as an in vitro model of fibrosis; and intra-pleural injection of bleomycin with carbon particles was used as an in vivo mouse model of pleural fibrosis. Calpain knockout mice, calpain inhibitor (calpeptin), and angiotensin (Ang) II type 1 receptor (AT1R) antagonist (losartan) were evaluated in prevention of experimental pleural fibrosis. We found that bleomycin and carbon particles induced calpain activation in cultured PMCs. This in vitro response was associated with increased collagen-I synthesis, and was blocked by calpain inhibitor or AT1R antagonist. Calpain genetic or treatment with calpeptin or losartan prevented pleural fibrosis in a mouse model induced by bleomycin and carbon particles. Our findings indicate that Ang II signaling and calpain activation induce collagen-I synthesis and contribute to fibrotic alterations in pleural fibrosis. Inhibition of Ang II and calpain might therefore be a novel strategy in treatment of pleural fibrosis. PMID- 29107091 TI - The hypothalamus as the primary brain region of metabolic abnormalities in APP/PS1 transgenic mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is an amyloid-related neurodegenerative disorder and is also considered to be a metabolic disease. Thus, investigation of metabolic mechanisms of amyloid pathology progression is of substantial importance for the diagnosis, prevention and treatment of AD. In the present study, cognitive function and brain metabolism were explored in the transgenic APP/PS1 mouse model of amyloid pathology at different ages. Using an NMR-based metabolomic approach, we examined metabolic changes in six different brain regions of wild-type and APP/PS1 mice at 1, 5 and 10months of age. Learning and memory performance in mice was evaluated using the Morris water maze test. Furthermore, a generalized linear mixed model was employed to analyze the interaction effect between the mouse-type and brain region (or age) on metabolic alterations. Brain region-specific changes in energy metabolism occurred prior to a very early-stage of amyloid pathology (1month of age) in APP/PS1 mice. A hypermetabolic state was identified in the brains of APP/PS1 mice at 5months of age, and the hypothalamus was identified as the main brain region that underwent significant metabolic alterations. The cognitive function of APP/PS1 mice was impaired at 10months of age; moreover, the hypermetabolic state identified in various brain regions at 5months of age was also significantly decreased. In conclusion, our results suggest that a hypothalamic metabolism abnormality may comprise a potential indicator for the early-diagnosis and monitoring of amyloid pathology progression. PMID- 29107092 TI - The Galphaq/11-provoked induction of Akr1c18 in murine luteal cells is mediated by phospholipase C. AB - Towards the end of gestation prostaglandin F2alpha (PGF2alpha) stimulates the expression of Akr1c18 in the murine corpus luteum. Akr1c18 codes for 20alpha hydroxysteroid dehydrogenase, an enzyme that precipitates parturition by catabolizing progesterone. Previous results from our laboratory have shown that this effect of PGF2alpha is mediated by the activation of Galphaq/11, but the downstream effector(s) of Galphaq/11 that elicit the increase in Akr1c18 expression have not been identified. The physiological effects of Galphaq/11 are mediated by its ability to interact with phospholipase Cbeta, p63RhoGEF, and PKCzeta. In the experiments described herein we used biochemical and pharmacological approaches, as well as adenoviral-mediated expression of a constitutively active form of Galphaq and mutants thereof, to examine the role of each of these effectors as potential mediators of the increased expression of luteal Akr1c18. By measuring the effects of PGF2alpha on the activation of RhoA (activated by p63RhoGEF) and the effects of activators and inhibitors of RhoA on the PGF2alpha-induced expression of luteal Akr1c18, we determined that RhoA is neither activated by PGF2alpha or involved in the PGF2alpha-induced expression of luteal Akr1c18. The potential involvement of PKCzeta was ruled out by the inability of a mutant of a constitutively active Galphaq that prevents PKCzeta binding to block the increased expression of Akr1c18. Furthermore, PGF2alpha does not increase the phosphorylation of ERK-5, the only known downstream target of PKCzeta. On the other hand, three different mutants of a constitutively active Galphaq that prevent phospholipase C activation blocked the induction of luteal Akr1c18. We conclude that the induction of luteal Akr1c18 by Galphaq/11 is mediated by the activation of phospholipase C. PMID- 29107093 TI - Resveratrol enhancement staphylococcus aureus survival under levofloxacin and photodynamic treatments. AB - Reactive oxygen species (ROS) are an efficient tool to eradicate micro-organisms owing to the capacity of these species to damage almost all types of biomolecules and to kill cells. The increase in mechanisms of antimicrobial resistance has led to the exploration of new strategies to eliminate micro-organisms that involve the production of ROS such as superoxide anion (O2*-) and hydrogen peroxide (H2O2). ROS are produced during several antimicrobial treatments, including antibiotic and photodynamic therapies. Among the natural antioxidants, resveratrol (RSV) is efficient at preventing damage from ROS, and every day more people incorporate it as a dietary or cosmetic supplement. However, the consequences of the administration of RSV during antimicrobial treatment are unknown. To investigate possible antagonistic or synergistic effects of RSV during antibiotic therapy (levofloxacin) or photodynamic therapy (visible radiation and methylene blue), killing of planktonic Staphylococcus aureus bacteria was evaluated in the presence of RSV. The results showed that the antimicrobial capacity of these therapies is significantly diminished when levofloxacin or methylene blue are co-administered with RSV, indicating that consumption of RSV during antimicrobial treatment must be, at least, cautioned. Moreover, considering the ROS antimicrobial activity of antibacterial agents, the topical addition of RSV may also affect the control of pathogens of the human body. The results presented in this article highlight the importance of the evaluation of possible antagonistic effects when an antimicrobial agent with ROS mediated action is co-administrated with RSV. PMID- 29107094 TI - Hyperspectral imaging for monitoring of perfusion failure upon microvascular anastomosis in the rat hind limb. AB - BACKGROUND/PURPOSE: Objective, reliable and easy monitoring of microvascular tissue perfusion is a goal that was achieved for many years with limited success. Therefore, a new non-invasive hyperspectral camera system (TIVITATM) was tested for this purpose in an in vivo animal model. METHODS: Evaluation of tissue oxygenation during ischemia and upon reperfusion was performed in left hind limb in a rat model (n=20). Ischemia was induced by clamping and dissection of the superficial femoral artery. Reperfusion of the limb was achieved by microsurgical anastomosis of the dissected artery. Oxygenation parameters of the hind limb were assessed via TIVITATM before and immediately after clamping and dissection of the artery, 3 and 30min after reperfusion as well as on postoperative days 1 and 2. Thereby, the non-operated hind limb served as control. As clinical parameters, the refill of the anastomosis as well as the progress of the affected leg were assessed. RESULTS: In 12 from 20 cases, TIVITATM recorded a sufficient reperfusion with oxygenation parameters comparable to baseline or control condition. However, in 8 from 20 cases oxygenation was found impaired after reperfusion causing a re-assessment of the microvascular anastomosis. Thereby, technical problems like stenosis or local thrombosis were found in all cases and were surgically treated leading to an increased tissue oxygenation. CONCLUSIONS: The TIVITATM camera system is a valid non-invasive tool to assess tissue perfusion after microvascular anastomosis. As it safely shows problems in oxygenation, it allows the clinician a determined revision of the site in time in order to prevent prolonged ischemia. PMID- 29107095 TI - Anticancer activity of seaweeds. AB - Cancer is a major health problem worldwide and still lacks fully effective treatments. Therefore, alternative therapies, using natural products, have been proposed. Marine algae are an important component of the marine environment, with high biodiversity, and contain a huge number of functional compounds, including terpenes, polyphenols, phlorotannins, and polysaccharides, among others. These compounds have complex structures that have shown several biological activities, including anticancer activity, using in vitro and in vivo models. Moreover, seaweed-derived compounds target important molecules that regulate cancer processes. Here, we review our current understanding of the anticancer activity of seaweeds. PMID- 29107096 TI - Chitosan-film associated with mesenchymal stem cells enhanced regeneration of peripheral nerves: A rat sciatic nerve model. AB - OBJECTIVE: Peripheral nerve injuries comprise significant portion of the nervous system injuries. Although peripheral nerves show some capacity of regeneration after injury, but the extent of regeneration is not remarkable. Regeneration might be through the activity of the mesenchymal stem cells (MSCs) which can release growth factors or extracellular matrix components or by the therapeutic effect of some material with the MSCs. The present study aimed to evaluate the regeneration of transected sciatic nerve by a therapeutic value of mesenchymal stem cells (MSCs) associated with chitosan-film (Cs) in rat. MATERIALS & METHODS: Male Wistar rats (n=42, 180-200g) were randomly divided into intact; control; sham; Cs; MSCs; MSCs + Cs groups. Functional recovery was evaluated at 2, 4, 6 and 8 weeks after surgery using sciatic functional index (SFI), hot water paw immersion test, electrophysiological, histological analyses. RESULTS: The rats in the MSCs+Cs group showed significant decrease in SFI and hot water paw immersion test during the 2nd to 8th weeks after surgery. Electrophysiological findings showed a significant decrease in latency time in the MSCs +Cs group. Amplitude of the nerve impulses also increased. Number of nerve fibers with more than 6 MUm diameters increased significantly in MSCs+Cs. The number of nerve fibers with less than 4 MUm diameters also increased significantly in MSCs+Cs group. CONCLUSION: Taken together, mesenchymal stem cells associated with Cs could improve functional and histomorphological properties of the sciatic nerve after injury which may have some clinical outcomes as well. PMID- 29107097 TI - Low-Grade Astrocytoma within a Mature Cystic Teratoma in an Adolescent Patient. AB - BACKGROUND: Mature cystic teratomas are the most common ovarian neoplasm in adolescents. They are typically benign, however, malignant transformation rarely occurs. We report a low-grade astrocytoma arising from a mature cystic teratoma in an adolescent patient. CASE: The patient was a 12-year-old girl with an asymptomatic ovarian cyst and subsequent cystectomy. Final pathology identified a solid tumor with glial tissue within the cyst, reported as low-grade astrocytoma arising in a mature cystic teratoma. SUMMARY AND CONCLUSION: There are few data on astrocytomas in the gynecologic tract. Risk factors for malignant transformation in a mature cystic teratoma include increased age, postmenopausal status, elevated carcinoma antigen 125, and large tumor size. Interestingly, this patient had a history of partial trisomy 20, which has been associated with teratoma formation in a mouse model. PMID- 29107099 TI - Expression and characterization of a novel chitinase with antifungal activity from a rare actinomycete, Saccharothrix yanglingensis Hhs.015. AB - Saccharothrix yanglingensis Hhs.015, a new type of rare actinomycete, was isolated from the roots of cucumber. A novel chitinase gene was cloned from S. yanglingensis Hhs.015 and overexpressed as a soluble protein Chi6769 (77.9 kDa) in Escherichia coli. Chi6769 was purified by HisTrap HP affinity chromatography with optimal pH of 7.0. The enzymatic hydrolysis assay revealed that Chi6769 was capable of hydrolyzing chitin to (GlcNAc)3, (GlcNAc)2 and GlcNAc. (GlcNAc)2 was the main hydrolyzate. The antifungal activity result showed that Chi6769 exhibited strong antifungal activity toward Valsa mali 03-8. Overall, Chi6769 was potential to be a novel biofunctional chitinase that could be used as a biological agent in the control of plant diseases. PMID- 29107098 TI - Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase. AB - Stressor exposure induces neuronal remodeling in specific brain regions. Given the persistence of stress-related illnesses, key next steps in determining the contributions of neural structure to mental health are to identify cell types that fail to recover from stressor exposure and to identify "trigger points" and molecular underpinnings of stress-related neural degeneration. We evaluated dendrite arbor structure on hippocampal CA1 pyramidal neurons before, during, and following prolonged exposure to one key mediator of the stress response - corticosterone (cortisol in humans). Basal dendrite arbors progressively simplified during a 3-week exposure period, and failed to recover when corticosterone was withdrawn. Corticosterone exposure decreased levels of the dendrite stabilization factor Abl2/Arg nonreceptor tyrosine kinase and phosphorylation of its substrates p190RhoGAP and cortactin within 11days, suggesting that disruption of Arg-mediated signaling may trigger dendrite arbor atrophy and, potentially, behavioral abnormalities resulting from corticosterone exposure. To test this, we administered the novel, bioactive Arg kinase activator, 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin, 5-[3-(4-fluorophenyl)-1 phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione (DPH), in conjunction with corticosterone. We found that repeated treatment corrected CA1 arbor structure, otherwise simplified by corticosterone. DPH also corrected corticosterone-induced errors in a hippocampal-dependent reversal learning task and anhedonic-like behavior. Thus, pharmacological compounds that target cytoskeletal regulators, rather than classical neurotransmitter systems, may interfere with stress associated cognitive decline and mental health concerns. PMID- 29107100 TI - Expression, purification, and characterization of the TRIM49 protein. AB - Autophagy is the process of degradation of intracellular proteins through the lysosome. Members of the tripartite motif (TRIM) proteins have shown to directly recognize autophagic cargo and also to act as a hub for the phagophore nucleation complex. The TRIM proteins are classically characterized by the presence of an amino-terminal RING domain and a B-box domain followed by a coiled coil domain. Although regarded as ubiquitin E3 ligases, this activity has been shown only for a minor set of the 79 human TRIM proteins. Additionally, the role of each domain in the E3 ligase activity is unknown. We investigated the role of the SPRY and RING domains of the human TRIM49 protein in its E3 ubiquitin ligase activity. Wild-type and mutant constructs of tagged TRIM49 were expressed in E. coli or mammalian cells, and the autoubiquitination activity of the purified protein was assessed. The purified TRIM49 showed no ubiquitin E3 ligase activity in vitro. However, cells transfected with the wild-type or mutant protein showed increased levels of lower mass polyubiquitinated proteins and both proteins copurified with polyubiquitinated proteins. Taken together, these results indicate that the TRIM49 protein plays a role in autophagic protein degradation independently of an ubiquitin E3 ligase activity. PMID- 29107101 TI - Single pixel quantitative phase imaging with spatial frequency projections. AB - We introduce a new single pixel imaging technique that automatically co-registers quantitative phase and incoherent image modalities through the simultaneous acquisition of identical object spatial frequency information. The technique consists of using a time varying groove density diffraction grating to produce a reference and scan beam. The interference between the beams produce time varying spatial frequencies in the sample. The collected light on a single pixel detector produces a time trace that allows easy recovery of coherent and incoherent contrast mechanisms. We derive theory for the quantitative phase and show excellent agreement with experimental data and numeric model. Additionally, we derive a general theory of single pixel quantitative phase theory that can be applied broadly to general methods that use a sequence of modulated light patterns for single pixel phase imaging. PMID- 29107102 TI - miR-342-3p suppresses cell proliferation and migration by targeting AGR2 in non small cell lung cancer. AB - AGR2 is a well-studied secreted protein that is involved in multiple biological processes including cell proliferation and migration. The mechanism by which AGR2 increases the growth and migration of non-small cell lung cancer cells (NSCLC) is still unknown. In this study, we report that AGR2 is directly targeted by miR-342 3p. Functional studies suggest that overexpression of miR-342-3p inhibits the proliferation and migration of non-small cell lung cancer cells. Overexpression of AGR2 counteracts the phenotypes induced by miR-342-3p. Moreover, AGR2 expression is up-regulated and negatively correlated with miR-342-3p levels in NSCLC cells and tissues. A meta-analysis of survival data indicates that NSCLC patients with high levels of AGR2 in their tumors have a worse prognosis. Collectively, the identification of miR-342-3p and AGR2 might facilitate the development of biomarkers and therapeutic targets for this devastating disease. PMID- 29107103 TI - Long noncoding RNA LINC00675 enhances phosphorylation of vimentin on Ser83 to suppress gastric cancer progression. AB - Long noncoding RNAs (lncRNAs) play a crucial role in cancer development, but few lncRNAs have been functionally characterized in gastric cancer (GC). Here, we reported an lncRNA LINC00675 whose expression was significantly decreased in GC tissues compared with the adjacent non-tumor tissues, and its low expression was associated with the poor survival of GC patients. Gain-and loss-of-function studies indicated that LINC00675 was a tumor suppressor because it repressed the proliferation, migration and invasion of GC cells in vitro and also inhibited the distal pulmonary and hepatic metastases of GC cells in vivo. Mechanistic investigations revealed that LINC00675 interacted with vimentin, a protein involved in cell metastasis, and enhanced its phosphorylation level on Ser83 to result in the collapse of vimentin filament in GC cells, thereby reducing cell metastasis. Taken together, our findings indicate that LINC00675 expression signature may serve as a novel biomarker for the diagnosis and prognosis of GC, and also highlight that LINC00675/vimentin complex may be a potentially therapeutic target of GC. PMID- 29107104 TI - Novel recurrence risk stratification of resected pancreatic neuroendocrine tumor. AB - Radical surgical resection represents the only hope of cure for pancreatic neuroendocrine tumor (PanNET). Adjuvant therapy is rarely used because there is no evidence to distinguish patients with high recurrence risk. Here we investigated the recurrence feature of resected PanNET and established a novel risk stratification to predict its recurrence. We analyzed 505 PanNET patients who underwent R0 resection at our institute from January 2004 through May 2015. The median follow-up was 71months (range: 12months-143months), 129 patients (25.5%) experienced recurrence with median disease-free survival (mDFS) of 19months. Restricted cubic spline (RCS) functions revealed a positive, linear relationship between Ki-67 index and recurrence. Multivariate analysis showed T stage, N stage, insulinoma and Ki-67 index were independent predictors of recurrence (P < 0.05). Based on scores of these independent factors, we generated a recurrent-risk stage system with HCI of 0.806, superior to TNM stage (HCI 0.704) and grading system (HCI 0.706). Resected PanNET were classified into low risk (65.3%, mDFS not reached), intermediate risk (16.6%, mDFS 48months, 95%CI 26.5-73.4), high risk (13.3%, mDFS 24months, 95%CI 19.4-50.5) and very high risk (4.8%, mDFS 10months, 95%CI 6.9-13.0) (Hazard ratio: 2.650, 95%CI: 2.233-3.145, P < 0.001). This novel risk stratification thus identified PanNET patients of different recurrent-risk. Patients with very high recurrence risk may be suitable for post-operative clinical trials investigating adjuvant treatment. PMID- 29107105 TI - Kruppel-like factor 9 down-regulates matrix metalloproteinase 9 transcription and suppresses human breast cancer invasion. AB - Kruppel-like factor 9 (KLF9) plays critical roles in several types of tumor. However, the biological functions and the underlying mechanisms of KLF9 in breast cancer metastasis are still unknown. Here, we found the expression of KLF9 was significantly down-regulated in breast cancer and was inversely correlated with the expression of matrix metalloproteinase 9 (MMP9) in breast cancer patients. Functionally, KLF9 transcriptionally down-regulated MMP9 expression and inhibited the metastasis of breast cancer cells. Mechanistically, KLF9 repressed human MMP9 promoter activity by binding to the CACCC motif and interacting with NF-kappaB p50/p65, which interacted with the NF-kappaB response element of the MMP9 promoter, leading to decreased expression of MMP9. In the context of breast cancer, KLF9 promoted the accumulation of HDAC1, thereby decreasing the acetylation of the KLF9-binding site on the MMP9 promoter, and this might be the molecular basis of KLF9-mediated inhibition of MMP9 transcription. In addition to MMP9, KLF9 also down-regulated several other NF-kappaB targets, such as TNF alpha, VEGFA and uPA in breast cancer cells. Taken together, these results uncovered a new mechanism by which KLF9 could down-regulate MMP9 expression to inhibit breast cancer metastasis. PMID- 29107107 TI - Roles of tRNA-derived fragments in human cancers. AB - Transfer RNAs (tRNAs) were traditionally considered to participate in protein translation. Recent studies have identified a novel class of small non-coding RNAs (sncRNAs), produced by the specific cleavage of pre- and mature tRNAs, which have been named tRNA-derived fragments. tRNA-derived fragments are classified into diverse subtypes based on the different cleavage positions of the pre- and mature tRNAs. Recently, accumulated evidence has shown that these tRNA-derived fragments are frequently dysregulated in several cancers. Several tRNA-derived fragments were found to participate in cell proliferation, apoptosis, and invasive metastasis in several malignant human tumors. These dysregulated fragments are able to bind both Argonaute proteins and Piwi proteins to regulate gene expression. Some of the newly identified tRNA-derived fragments have been considered as the new biomarkers and therapeutic targets for the treatment of cancer. This review summarizes the biogenesis and biological functions of different subtypes of tRNA-derived fragments and discusses their molecular mechanisms in cancer progression. PMID- 29107108 TI - Long non-coding RNA HAND2-AS1 inhibits invasion and metastasis in endometrioid endometrial carcinoma through inactivating neuromedin U. AB - Endometrioid endometrial carcinoma (EEC) is one of the common causes of cancer related mortality in women. Mounting evidences suggest that long noncoding RNAs (lncRNAs) function in multiple cancers. In this study, we discovered that HAND2 AS1, a lncRNA transcribed antisense adjacent to Heart and Neural Crest Derivatives Expressed 2 (HAND2) in chromosome 4q33-34, is significantly down regulated in EEC. HAND2-AS1 and HAND2 were frequently down-regulated in EEC tissues, especially in poor differentiated tumor tissues. Down-regulation of HAND2-AS1 and HAND2 was correlated with tumor grade, lymph node metastasis and recurrence of EEC patients. HAND2-AS1 and HAND2 were co-downregulated by promoter DNA hypermethylation in EEC. Overexpression of HAND2-AS1 in EEC cells demonstrated that HAND2-AS1 suppressed migration and invasion of EEC cells. Similarly, overexpression of HAND2 also inhibited migration and invasion EEC cells indicating that HAND2-AS1 and HAND2 had a concordant role in the progression of EEC. However, HAND2 was not regulated by HAND2-AS1 in EEC. Furthermore, the anti-tumorigenic effect of HAND2-AS1 was mediated by down regulating NMU, which has an oncogenic role in EEC. Our findings therefore provide the first evidence that HAND2-AS1 is a critical tumor suppressor in EEC. PMID- 29107106 TI - The role of nitric oxide in metabolic regulation of Dendritic cell immune function. AB - Dendritic cells (DCs) are canonical antigen presenting cells of the immune system and serve as a bridge between innate and adaptive immune responses. When DCs are activated by a stimulus through toll-like receptors (TLRs), DCs undergo a process of maturation defined by cytokine & chemokine secretion, co-stimulatory molecule expression, antigen processing and presentation, and the ability to activate T cells. DC maturation is coupled with an increase in biosynthetic demand, which is fulfilled by a TLR-driven upregulation in glycolytic metabolism. Up-regulation of glycolysis in activated DCs provides these cells with molecular building blocks and cellular energy required for DC activation, and inhibition of glycolysis during initial activation impairs both the survival and effector function of activated DCs. Evidence shows that DC glycolytic upregulation is controlled by two distinct pathways, an early burst of glycolysis that is nitric oxide (NO) independent, and a sustained commitment to glycolysis in NO-producing DC subsets. This review will address the complex role of NO in regulating DC metabolism and effector function. PMID- 29107109 TI - LOX-1 activation by oxLDL triggers an epithelial mesenchymal transition and promotes tumorigenic potential in prostate cancer cells. AB - Obesity is related to an increased risk of developing prostate cancer with high malignancy stages or metastasis. Recent results demonstrated that LOX-1, a receptor associated with obesity and atherosclerosis, is overexpressed in advanced and metastatic prostate cancer. Furthermore, high levels of oxLDL, the main ligand for LOX-1, have been found in patients with advanced prostate cancer. However, the role of LOX-1 in prostate cancer has not been unraveled completely yet. Here, we show that LOX-1 is overexpressed in prostate cancer cells and its activation by oxLDL promotes an epithelial to mesenchymal transition, through of lowered expression of epithelial markers (E-cadherin and plakoglobin) and an increased expression of mesenchymal markers (vimentin, N-cadherin, snail, slug, MMP-2 and MMP-9). Consequently, LOX-1 activation by oxLDL promotes actin cytoskeleton restructuration and MMP-2 and MMP-9 activity inducing prostate cancer cell invasion and migration. Additionally, LOX-1 increased the tumorigenic potential of prostate cancer cells and its expression was necessary for tumor growth in nude mice. In conclusion, our results suggest that oxLDL/LOX-1 could be ones of mechanisms that explain why obese patients with prostate cancer have an accelerated tumor progression and a greater probability of developing metastasis. PMID- 29107111 TI - Entinostat reverses cisplatin resistance in esophageal squamous cell carcinoma via down-regulation of multidrug resistance gene 1. AB - Cisplatin resistance frequently occurs in esophageal squamous cell carcinoma (ESCC). The underlying mechanism for cisplatin resistance in ESCC remains largely obscure. Here we report that entinostat reversed cisplatin resistance in ESCC both in vitro and in vivo by induction of apoptosis and inhibition of cell proliferation, accompanied by a decrease of multidrug resistance gene 1 (MDR1), P Src, Mcl-1, Cyclin D1 and an increase of cleaved PARP. MDR1 expression was associated with worsen survival of ESCC patients with cisplatin-based chemotherapy. Dasatinib potentiated entinostat to overcome cisplatin resistance. By inhibiting Src, dasatinib reduced the expression of MDR1 and Mcl-1. Furthermore, Obatoclax, an inhibitor of Mcl-1, obviously decreased the expression of MDR1, suggesting that entinostat might surmount cisplatin resistance in ESCC via a Src-Mcl-1-MDR1 pathway. Interestingly, cisplatin also enhanced the effect of entinostat both in vitro and in vivo. Our data disclose a molecular basis that entinostat reverses cisplatin resistance, and provide a promising strategy with combinatorial drugs to treat cisplatin resistant ESCC patients. PMID- 29107110 TI - Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive disease and current treatment regimens fail to effectively cure PDAC. Development of resistance to current therapy is one of the key reasons for this outcome. Nimbolide (NL), a triterpenoid obtained from Azadirachta indica, exhibits anticancer properties in various cancer including PDAC cells. However, the underlying mechanism of this anticancer agent in PDAC cells remains undefined. We show that NL exerts a higher level of apoptotic cell death compared to the first-line agent gemcitabine for PDAC, as well as other anticancer agents including sorafenib and curcumin. The anticancer efficacy of NL was further evidenced by a reduction in the CD44+ as well as cancer stem-like cell (CSC) population, as it causes decreased sphere formation. Mechanistically, the anticancer efficacy of NL associates with reduced mutant p53 as well as increased mitochondrial activity in the form of increased mitochondrial reactive oxygen species and mitochondrial mass. Together, this study highlights the therapeutic potential of NL in mutant p53 expressing pancreatic cancer. PMID- 29107112 TI - The emerging role of exosome-derived non-coding RNAs in cancer biology. AB - Exosomes are a new means of intercellular information exchange that have aroused great research interest. Long neglected in research, exosomes were deemed nonfunctional cellular components to be discarded. However, it has been gradually revealed that exosomes are an important tool for the exchange of intercellular information and material. Exosomes contain specific repertoires of non-coding RNAs (ncRNAs, including microRNA and lncRNA), indicating that a specific RNA sorting mechanism may exist. Correspondingly, intracellular multivesicular bodies (MVBs) are produced after fusion with the cell membrane to release exosomes rather than inducing autophagy, which reveals that there may be a specific regulatory mechanism for MVB secretion. Cells can trigger cancer-related disorders after the recognition and uptake of circulating exosomal ncRNAs, providing indications for early tumor biopsy and treatment. The use of exosomes as a biological carrier in targeted therapy has been demonstrated. However, there may be a specific, unknown switch for loading drugs. This review focuses on the mechanisms of exosome biogenesis, release, and uptake. We also review the promotion of tumor development by exosomal ncRNAs including chemotherapy resistance, metastasis and the prospective use of exosomes in cancer diagnosis and treatment. PMID- 29107113 TI - miR-346 functions as a pro-survival factor under ER stress by activating mitophagy. AB - Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), which attempts to restore normal function of the ER. Both autophagy and miRNAs have been reported to participate in the process of ER stress, but the relationship between these two factors is still obscure. In this study, we demonstrated that miR-346, which was induced under ER stress, modulated autophagic flux in HeLa cells. By regulating the process of autophagy, miR-346 reduced the ROS level in the cells, thus protecting them from death following ER stress. Furthermore, we demonstrated that GSK3B was the target of miR-346 and participated in ER stress-related autophagy. miR-346 activated autophagy by interrupting the association between BCL2 and BECN1 in a GSK3B-dependent manner. Our findings shed new light on the role of miRNAs during ER stress and suggest a new mechanism for the induction of autophagy under ER stress. PMID- 29107115 TI - Heme and hemolysis in innate immunity: adding insult to injury. AB - Heme is a vital, iron-containing prosthetic molecule present in a variety of proteins, of which hemoglobin is the most abundant. While the reactivity afforded by its central iron ion is essential for many cellular processes, it renders heme a potentially damaging molecule upon its release from hemeproteins, as it can catalyze the generation of reactive oxygen species. Severe intravascular hemolysis results in the leakage of vast amounts of hemoglobin, and subsequently, heme into the plasma. As such, heme is increasingly recognized as a major driving force for hemolysis-associated pathology including an increased risk for bacterial infections, due to its pro-oxidant, cytotoxic and immunomodulatory effects. Here, we provide a succinct review of recent, significant developments on how heme can influence innate immune functions, ranging from the maintenance of iron homeostasis by macrophages, the modulation of inflammatory responses, to its role in altering resistance mechanisms against bacterial infections. PMID- 29107114 TI - Cancer chemoprevention via activation of proteostatic modules. AB - Proteins carry out the majority of cellular functions and maintain cellular homeodynamics mostly by participating in multimeric assemblies that operate as protein machines. Proteome quality control is thus critical for cellular functionality, and it is carried out through the curating activity of the proteostasis network (PN). Key components of the PN are the protein synthesis and trafficking modules, the endoplasmic reticulum unfolded protein response, molecular chaperones, and the two main degradation machineries, namely the ubiquitin proteasome and autophagy lysosome pathways. Part of the PN are also several stress responsive pathways, including nuclear factor erythroid 2-related factor 2 (Nrf2), which mobilises genomic responses against oxidative and/or xenobiotic damage. Nevertheless, the gradual accumulation of stressors during ageing or earlier due to lifestyle results in an increasingly damaged and unstable proteome. This outcome may then increase genomic instability due to reduced DNA replication fidelity or repair, leading to various age-related diseases such as cancer. Considering that the activation of proteostatic modules exerts anti-ageing effects in model organisms, we present herein a synopsis of studies showing that proteostatic modules activation (e.g. by natural products) represents a promising tumour-chemopreventive approach. PMID- 29107116 TI - Mitophagy and the release of inflammatory cytokines. AB - Mitophagy is a selective form of autophagy in which damaged or dysfunctional mitochondria are specifically targeted by autophagosomes for lysosomal degradation. Studies have demonstrated that loss of autophagy/mitophagy can lead to a build-up of cytosolic reactive oxygen species and mitochondrial DNA, which can, in turn, activate immune signalling pathways that ultimately lead to the releases of inflammatory cytokines, including IL-1alpha, IL-1beta, IL-18, type I IFN and macrophage migration inhibitory factor (MIF). Moreover, release of these cytokines can subsequently promote the release of others, including IL-23 and IL 17. Thus, as well as being essential for normal cell homeostasis and mitochondrial health, mitophagy may represent an important regulatory mechanism controlling inflammatory responses in immune cells. This review discusses our current understanding of the mechanisms through which mitophagy regulates inflammatory cytokine release. PMID- 29107117 TI - Burnout and Stress Among US Surgery Residents: Psychological Distress and Resilience. AB - BACKGROUND: Burnout among physicians affects mental health, performance, and patient outcomes. Surgery residency is a high-risk time for burnout. We examined burnout and the psychological characteristics that can contribute to burnout vulnerability and resilience in a group of surgical trainees. STUDY DESIGN: An online survey was distributed in September 2016 to all ACGME-accredited general surgery programs. Burnout was assessed with an abbreviated Maslach Burnout Inventory. Stress, anxiety, depression, resilience, mindfulness, and alcohol use were assessed and analyzed for prevalence. Odds ratios (ORs) were used to determine the magnitude of presumed risk and resilience factors. RESULTS: Among 566 surgical residents who participated in the survey, prevalence of burnout was 69%, equally driven by emotional exhaustion and depersonalization. Perceived stress and distress symptoms (depression, suicidal ideation, and anxiety) were notably high across training levels, but improved during lab years. Higher burnout was associated with high stress (OR 7.8; p < 0.0001), depression (OR 4.8; p < 0.0001), and suicidal ideation (OR 5.7; p < 0.0001). In contrast, dispositional mindfulness was associated with lower risk of burnout (OR 0.24; p < 0.0001), stress (OR 0.15; p < 0.0001), anxiety (OR 0.21; p < 0.0001), suicidal ideation (OR 0.25; p < 0.0001), and depression (OR 0.26; p = 0.0003). CONCLUSIONS: High levels of burnout, severe stress, and distress symptoms are experienced throughout general surgery training, with some improvement during lab years. In this cross-sectional study, trainees with burnout and high stress were at increased risk for depression and suicidal ideation. Higher dispositional mindfulness was associated with lower risk of burnout, severe stress, and distress symptoms, supporting the potential of mindfulness training to promote resilience during surgery residency. PMID- 29107118 TI - Transvaginal Single-Port Laparoscopy Sacrocolpopexy. AB - STUDY OBJECTIVE: More and more patients are pursuing minimally invasive surgery, which is becoming the trend for gynecologic surgery today. Pelvic organ prolapse (POP) is no exception. With the application of natural orifice transluminal endoscopic surgery, minimally invasive transvaginal sacrocolpopexy surgery assisted by single-port laparoendoscopy for POP becomes feasible. Here we describe our technique of transvaginal sacrocolpopexy using single-port laparoscopy for middle compartment POP. DESIGN: Step-by-step explanation of the procedure using video. SETTING: University hospital. PATIENT: A 59-year-old woman from China. INTERVENTIONS: Transvaginal single-port laparoscopy sacrocolpopexy. MEASUREMENTS AND MAIN RESULTS: We performed transvaginal single-port laparoscopy sacrocolpopexy on a 59-year-old woman from China who was diagnosed with POP-Q stage II anterior compartment, stage III middle compartment, stage II posterior compartment. This patient complained of a vaginal mass that had been prolapsed for 3 months. Institutional Review Board/Ethics Committee approval was obtained. Vaginal hysterectomy was performed first. Preventative bilateral salpingo oophorectomy was done after a single-port platform was established. Right pelvic peritoneum was incised, from the promontory to the vault. Then, we exposed the rectovaginal and vesicovaginal spaces after injection of a water cushion (normal saline, 0.9% Nacl). A Y-shaped mesh (ARTISYN; Johnson & Johnson international, c/o European Logistics Centre, Diegem, Belgium) was fixed to the posterior vaginal wall and then to the sacral promontory (S1). After closing the pelvic peritoneum the anterior mesh was sutured. Before finishing the surgery we closed the vaginal cuff. The operation last for about 2 hours, with a blood loss of 50 mL. The patient was discharged with complete recovery. A 5-month follow-up showed no prolapse, mesh erosion, or other complications. CONCLUSION: Transvaginal single-port laparoscopic sacrocolpopexy is a considerable choice for middle compartment POP. However, more cases should be enrolled, and additional studies are required. PMID- 29107119 TI - The Impact of Carbon Dioxide Pneumoperitoneum on Ovarian Ischemia-Reperfusion Injury during Laparoscopic Surgery: A Preliminary Study. AB - STUDY OBJECTIVE: To investigate whether carbon dioxide pneumoperitoneum causes ischemia-reperfusion injury to the ovaries during laparoscopic surgery. DESIGN: A prospective controlled clinical study (Canadian Task Force classification II-1). SETTING: A tertiary academic center. PATIENTS: Premenopausal women who underwent hysterectomy with bilateral salpingo-oophorectomy (HSO) via open abdominal and laparoscopic approaches between 2014 and 2015. INTERVENTIONS: In both surgical approaches, unilateral oophorectomy was performed immediately after abdominal entry, and the remaining contralateral ovary was excised at the end of the hysterectomy in order to compare the effect of these surgical procedures on ovarian tissue. Additionally, plasma samples were collected at the following time points: (1) before abdominal entry, (2) at the end of hysterectomy, and (3) before contralateral oophorectomy. Plasma samples were assessed for biochemical oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8 OHdG). Ovarian tissue samples were assessed for MDA and further evaluated for ischemia-reperfusion injury using a histologic scoring method. MEASUREMENTS AND MAIN RESULTS: Twenty premenopausal women undergoing HSO via open abdominal surgery (n = 10) and laparoscopy (n = 10) were included. Baseline characteristics (age, body mass index, parity, and gravida) and operative data (operative time, estimated blood loss, and intraoperative complication) were similar between groups. Perioperative plasma MDA levels, histologic scores, and tissue oxidative stress markers did not show a significant difference in either group or between groups. However, plasma 8-OHdG levels were significantly different when the second sample in the abdominal HSO group was compared with the first sample in the abdominal HSO group and the third sample in the laparoscopic HSO group (p = .012 and .001, respectively). CONCLUSION: Carbon dioxide pneumoperitoneum does not cause ischemia-reperfusion injury in the human ovaries at clinically safe levels of intra-abdominal pressure. PMID- 29107120 TI - Inter-individual differences in trait anxiety shape the functional connectivity between the bed nucleus of the stria terminalis and the amygdala during brief threat processing. AB - An influential framework suggests that the central nucleus of the amygdala (CeA) is involved in phasic responses to threat, while the bed nucleus of the stria terminalis (BNST) mediates sustained anxiety. However, this model has been questioned, proposing that the role of the BNST is not limited to sustained threat contexts. Rather, amygdala and BNST also seem to work in concert in the processing of discrete and briefly presented threat-related stimuli, likely dependent on inter-individual differences in anxiety. A direct test of this assumption with sufficient experimental power is missing in human research and the degree to which individual differences in trait anxiety moderate phasic responses and functional connectivity of amygdala and BNST during threat processing remains unclear. The current event-related functional magnetic resonance imaging (fMRI) study investigated activation and connectivity of amygdala and BNST, as well as modulating effects of trait anxiety, during processing of briefly presented threat-related relative to neutral standardized pictures in 93 psychiatrically healthy individuals. Both amygdala and BNST activation was increased during presentation of threat-related relative to neutral pictures. Furthermore, functional connectivity between BNST and amygdala in response to threat was positively associated with trait anxiety. These findings suggest that amygdala and BNST form a functional unit during phasic threat processing whereby their connectivity is shaped by inter-individual differences in trait anxiety. PMID- 29107121 TI - Longitudinally and inter-site consistent multi-atlas based parcellation of brain anatomy using harmonized atlases. AB - As longitudinal and multi-site studies become increasingly frequent in neuroimaging, maintaining longitudinal and inter-scanner consistency of brain parcellation has become a major challenge due to variation in scanner models and/or image acquisition protocols across scanners and sites. We present a new automated segmentation method specifically designed to achieve a consistent parcellation of anatomical brain structures in such heterogeneous datasets. Our method combines a site-specific atlas creation strategy with a state-of-the-art multi-atlas anatomical label fusion framework. Site-specific atlases are computed such that they preserve image intensity characteristics of each site's scanner and acquisition protocol, while atlas pairs share anatomical labels in a way consistent with inter-scanner acquisition variations. This harmonization of atlases improves inter-study and longitudinal consistency of segmentations in the subsequent consensus labeling step. We tested this approach on a large sample of older adults from the Baltimore Longitudinal Study of Aging (BLSA) who had longitudinal scans acquired using two scanners that vary with respect to vendor and image acquisition protocol. We compared the proposed method to standard multi atlas segmentation for both cross-sectional and longitudinal analyses. The harmonization significantly reduced scanner-related differences in the age trends of ROI volumes, improved longitudinal consistency of segmentations, and resulted in higher across-scanner intra-class correlations, particularly in the white matter. PMID- 29107122 TI - EBOLA Ag K-SeT rapid test: field evaluation in Sierra Leone. AB - OBJECTIVES: Efficient interruption of Ebola virus disease (EVD) transmission chains critically depends on reliable and fast laboratory diagnosis. We evaluated the performance of the EBOLA Virus Antigen Detection K-SeT (EBOLA Ag K-SeT), a new rapid diagnostic antigen test in field settings. METHODS: The study was conducted in a field laboratory located in Freetown (Sierra Leone) by the Italian National Institute for Infectious Diseases 'L. Spallanzani' and the EMERGENCY Onlus NGO. The EBOLA Ag K-SeT was tested on 210 residual plasma samples (EVD prevalence 50%) from patients hospitalized at the EMERGENCY Ebola treatment center in Goderich (Freetown), comparing the results with quantitative real-time PCR. RESULTS: Overall, the sensitivity of EBOLA Ag K-SeT was 88.6% (95% confidence interval (CI), 82.5-94.7), and the corresponding specificity was 98.1% (95% CI, 95.5-100.7). The positive and negative predictive values were 97.9% (95% CI, 95.0-100.8) and 89.6% (95% CI, 84-95.2), respectively. The sensitivity strongly increased up to 98.7% (95% CI, 96.1-101.2) for those samples with high virus load (>=6.2 log RNA copies/mL). CONCLUSIONS: Our results suggest that EBOLA Ag K-SeT could represent a new effective diagnostic tool for EVD, meeting a need for resource-poor settings and rapid diagnosis for individuals with suspected EVD. PMID- 29107123 TI - Use of buccal fat pads to prevent vestibular gingival recession of zygomatic implants. AB - Zygomatic implants can be used for dental rehabilitation in atrophic maxillae. This allows for maxillary grafts to be avoided while also permitting immediate functional use. Initially, the implants had a palatal emergence. The surgical technique has undergone continuous development and the implants are now sometimes extra-maxillary in order to better match with the prosthetic space. The main risk is vestibular exposure of the implant as a gingival recession caused by mucositis or peri-implantitis. When the first patients exhibited this problem, the authors sought a solution in order to prevent this complication from occurring. The authors here describe a technique for covering the implants with the buccal fat pad. The dissection and the suture of the fat pad around the implants provide a thick gingiva and mucosa on the vestibular side. The authors have used this technique for the past four years. Twenty-five patients had coverage of the implants. Nineteen had Hybrid Zygoma and six had Quad Zygoma All-on-Four implants. Not a single patient had a gingival recession upon follow-up examination. This technique allows a considerable amount of thick gingiva around the implants to be retained. It also prevents long-term exposure of the implants on the vestibular side. PMID- 29107125 TI - Degradation of extracellular matrix regulates osteoblast migration: A microfluidic-based study. AB - Bone regeneration is strongly dependent on the capacity of cells to move in a 3D microenvironment, where a large cascade of signals is activated. To improve the understanding of this complex process and to advance in the knowledge of the role of each specific signal, it is fundamental to analyze the impact of each factor independently. Microfluidic-based cell culture is an appropriate technology to achieve this objective, because it allows recreating realistic 3D local microenvironments by taking into account the extracellular matrix, cells and chemical gradients in an independent or combined scenario. The main aim of this work is to analyze the impact of extracellular matrix properties and growth factor gradients on 3D osteoblast movement, as well as the role of cell matrix degradation. For that, we used collagen-based hydrogels, with and without crosslinkers, under different chemical gradients, and eventually inhibiting metalloproteinases to tweak matrix degradation. We found that osteoblast's 3D migratory patterns were affected by the hydrogel properties and the PDGF-BB gradient, although the strongest regulatory factor was determined by the ability of cells to remodel the matrix. PMID- 29107126 TI - The International Anaerobe Quality Assurance Scheme (IAQAS). PMID- 29107124 TI - Genetic inhibition of PPARgamma S112 phosphorylation reduces bone formation and stimulates marrow adipogenesis. AB - A common feature of many skeletal diseases is the accumulation of marrow fat. A reciprocal relationship exists between osteogenesis and adipogenesis in bone marrow that is mediated by the relative activity of PPARgamma and RUNX2 transcription factors. The ERK/MAPK pathway is an important inducer of MSC differentiation to osteoblasts and an inhibitor of adipogenesis that functions by phosphorylating RUNX2 and PPARgamma. To begin to assess the importance of this regulation in vivo, we examined the consequences of blocking one arm of this pathway, PPARgamma S112 phosphorylation, by evaluating the bone phenotype of PPARgamma S112A mutant mice. This mutation prevents MAPK phosphorylation and inhibition of PPARgamma transcriptional activity. Both male and female PPARgamma S112A mice had decreased tibial and vertebral BV/TV and decreased trabecular bone relative to wild type littermates. These results were explained by a decrease in bone formation and osteoblast activity in the absence of changes in resorption. In contrast, marrow adipose tissue, adipocyte markers and serum adiponectin were all dramatically increased. Bone marrow stromal cells isolated from PPARgamma S112A mice had elevated PPARgamma and preferentially differentiated to adipocytes while total and phosphorylated RUNX2 and osteoblastogenesis were inhibited, indicating that the PPARgamma S112A mutation affects bone in a cell autonomous manner. Changes in osteoblast/adipocyte lineage allocation in MSC cultures were also seen where CFU-OBs were reduced with a parallel increase in CFU-AD. This study emphasizes the importance of PPARgamma phosphorylation in controlling bone mass and marrow adiposity and demonstrates how a regulatory mutation in PPARgamma previously associated with peripheral fat metabolism can have broader effects on bone homeostasis that may in turn affect whole body energy metabolism. PMID- 29107127 TI - Cyclodextrins as versatile building blocks for regenerative medicine. AB - Cyclodextrins (CDs) are one of the most versatile substances produced by nature, and it is in the aqueous biological environment where the multifaceted potential of CDs can be completely unveiled. CDs form inclusion complexes with a variety of guest molecules, including polymers, producing very diverse biocompatible supramolecular structures. Additionally, CDs themselves can trigger cell differentiation to distinct lineages depending on the substituent groups and also promote salt nucleation. These features together with the affinity-driven regulated release of therapeutic molecules, growth factors and gene vectors explain the rising interest for CDs as building blocks in regenerative medicine. Supramolecular poly(pseudo)rotaxane structures and zipper-like assemblies exhibit outstanding viscoelastic properties, performing as syringeable implants. The sharp shear-responsiveness of the supramolecular assemblies is opening new avenues for the design of bioinks for 3D printing and also of electrospun fibers. CDs can also be transformed into polymerizable monomers to prepare alternative nanostructured materials. The aim of this review is to analyze the role that CDs may play in regenerative medicine through the analysis of the last decade research. Most applications of CD-based scaffolds are focussed on non-healing bone fractures, cartilage reparation and skin recovery, but also on even more challenging demands such as neural grafts. For the sake of clarity, main sections of this review are organized according to the architecture of the CD-based scaffolds, mainly syringeable supramolecular hydrogels, 3D printed scaffolds, electrospun fibers, and composites, since the same scaffold type may find application in different tissues. PMID- 29107128 TI - Targeted cancer therapy through antibody fragments-decorated nanomedicines. AB - Active targeting in cancer nanomedicine, for improved delivery of agents and diagnose, has been reviewed as a successful way for facilitating active uptake of theranostic agents by the tumor cells. The application of a targeting moiety in the targeted carrier complexes can play an important role in differentiating between tumor and healthy tissues. The pharmaceutical carriers, as main part of complexes, can be polymeric nanoparticles, micelles, liposomes, nanogels and carbon nanotubes. The antibodies are among the natural ligands with highest affinity and specificity to target pharmaceutical nanoparticle conjugates. However, the limitations, such as size and long circulating half-lives, hinder reproducible manufacture in clinical studies. Therefore, novel approaches have moved towards minimizing and engineering conventional antibodies as fragments like scFv, Fab, nanobody, bispecific antibody, bifunctional antibody, diabody and minibody preserving their functional potential. Different formats of antibody fragments have been reviewed in this literature update, in terms of structure and function, as smart ligands in cancer diagnosis and therapy of tumor cells. PMID- 29107129 TI - Herbal Supplements for Prostate Enlargement: Current State of the Evidence. AB - OBJECTIVE: To provide a comprehensive review of the current state of herbal supplement market for lower urinary tract symptoms (LUTS) and correlate the ingredients of each product with available scientific evidence. MATERIALS AND METHODS: Twenty-seven products from Amazon.com that were advertised as herbal supplements for LUTS and had listed their active ingredients were selected. Active ingredients were reviewed on Google Scholar. Product price, warranty, and consumer review information were also collected. RESULTS: A total of 58 unique active ingredients were identified. The mean number of ingredients was 8.26 (standard deviation 5.25). Whereas 17 (63%) products had an ingredient with a systematic review to support their use, 20 (74%) had an ingredient with conflicting evidence based on systematic reviews. Out of the supplements that contained ingredients supported by literature, all (100%) products simultaneously had other ingredients with no, conflicting, or refuting evidence. There was no (0%) product that contained only scientifically proven ingredients. There is no scientific study to evaluate these supplements as a whole. CONCLUSION: Despite the widespread use of herbal supplements for LUTS, there is scant scientific evidence to support their safety and efficacy. Lack of adequate regulation and government support for research and development are some of the factors that disincentivize researchers to study safety and efficacy of these products. We encourage physicians to warn their patients on the lack of adequate evidence to support the safety and efficacy of many of these supplements. PMID- 29107130 TI - Robotic Left-sided Level II Caval Thrombectomy and Nephrectomy Using a Novel Supine, Single-dock Approach: Primary Description. AB - OBJECTIVE: To demonstrate a novel supine, single-dock approach for robotic nephrectomy and inferior vena cava (IVC) thrombectomy for a left-sided renal cell carcinoma with level II IVC thrombus. METHODS: We perform robotic nephrectomy and IVC thrombectomy in a 79-year-old man with a 6-cm left renal mass and level II IVC thrombus. For this approach, the patient is placed in steep Trendelenburg, and a 6-port transperitoneal technique is used, with the robot docked such that the arms are oriented in a cephalad direction. We describe key steps, including (1) exposure of the retroperitoneum, (2) IVC exposure and control, (3) left renal hilar control, (4) cavotomy, thrombectomy, and reconstruction, (5) nephrectomy and lymph node dissection. Perioperative outcomes are reported. RESULTS: Robotic left nephrectomy and level II IVC thrombectomy were successfully completed using this novel, single-dock approach. Total operative time was 7 hours with IVC clamp time of 27 minutes. Estimated blood loss was 500 cc without perioperative transfusion. There were no intraoperative or major perioperative complications. The patient was discharged on postoperative day 5. This approach allows rapid caval control, bilateral renal hilar access, and obviates the need for preoperative renal artery embolization or intraoperative redocking or repositioning steps, as has been previously described for other approaches. CONCLUSION: We demonstrate the first description of robotic left-sided level II IVC thrombectomy and radical nephrectomy using a supine, single-dock approach. This novel, versatile approach adds to the armamentarium for minimally invasive surgical management of renal cell carcinoma with IVC thrombus. PMID- 29107131 TI - The Impact of Stress Urinary Incontinence on Individual Components of Quality of Life in Malaysian Women. AB - OBJECTIVE: To assess the impact of stress urinary incontinence (SUI) on individual components of quality of life (QoL) using both condition-specific and generic questionnaires, and to compare the results of the 2 instruments with a control group. METHODS: Women with or without SUI aged >=21 years old were recruited. Subjects completed the International Consultation of Incontinence Urinary Incontinence Short Form (ICIQ-UI-SF), International Consultation of Incontinence-Lower Urinary Tract Symptoms Quality of Life (ICIQ-LUTSqol), and EQ 5D questionnaires. RESULTS: A total of 120 women with SUI and 145 controls participated. The ICIQ-LUTSqol total score (mean +/- standard deviation) was significantly higher in the SUI group (38.96 +/- 10.28) compared with the control group (20.78 +/- 2.73) (P <.001). When adjusted for significant confounders, the SUI group continued to have significantly poorer QoL compared with the control group (P <.001). The negative effect of SUI on "physical activities" and "jobs" were the 2 most frequently reported and burdensome components of the ICIQ LUTSqol, with approximately 50% of women with SUI affected "moderately" or "a lot." When measured using the EQ-5D questionnaire, there were significantly higher percentages of patients with SUI who had problems with usual activities, pain or discomfort, and anxiety or depression (P <.05). CONCLUSION: Women suffering from SUI have significantly poorer QoL compared with continent women when measured using both condition-specific and generic QoL measures. Clinicians should pay closer attention to the impact of SUI on individual components of QoL, particularly limitations on physical activities and jobs, which were the 2 most impairing and frequently reported components of QoL. PMID- 29107132 TI - Staged Urethroplasty for Penile Urethral Strictures From Lichen Sclerosus and Failed Hypospadias Repair. AB - OBJECTIVE: To present our technique for staged urethroplasty with buccal mucosa graft. METHODS: The patient presented is a 42-year-old man with a history of congenital hypospadias repaired as a child. He developed a penile urethral stricture at age 30 and was managed with self-intermittent dilation. Recently, dilation became more difficult, and he was referred for reconstruction. Workup revealed a high-grade stricture extending from the meatus to the site of the previous anastomosis at the penoscrotal junction. To contextualize the presented case, we performed a retrospective review of all staged penile urethroplasties performed at our institution from 2013 to 2016 (n = 20). RESULTS: At 18 months' follow-up, the patient voids with an unobstructed, directable stream and has not required any urethral instrumentation. In our series, stricture etiology was lichen sclerosus in 9 (45%), failed hypospadias repair in 8 (40%), trauma in 2 (10%), and penile calciphylaxis in 1 (5%). At median follow-up of 520 days, 60% underwent second-stage urethroplasty at a median of 277 days after first-stage urethroplasty (range 213-738). No patients required grafting after first-stage surgery. Complications of second-stage surgery included wound dehiscence in 2 (17%), fistula in 1 (8%), and meatal stenosis in 1 (8%). CONCLUSION: Staged penile urethroplasty is a safe and effective treatment option for patients with complex urethral strictures resulting from lichen sclerosus and failed hypospadias repair. PMID- 29107133 TI - Physeal fractures of the lower leg in children and adolescents: Therapeutic results, pitfalls and suggested management protocol - based on the experience of the authors and contemporary literature. AB - PURPOSE: Physeal fractures in children frequently give rise to concerns about the condition of the growth plate. Our observations have proven that the dysfunction of the growth plate is less frequent complication in those cases than misdiagnosed interposition of the periosteum. The aim of this paper is to familiarize the readers with the issue of treatment of physeal fractures of the distal tibia and fibula in the growing skeleton. MATERIALS AND METHODS: We analyzed the group of 75 patients - children and adolescents - with surgically treated physeal fractures of the lower leg. The analysis included age, sex, circumstances of trauma infliction, type of sustained damage, employed therapeutic technique, timing of surgical procedure, duration of hospitalization, complications, duration of follow-up, radiological and functional results according to the AOFAS scale. RESULTS: The group consisted of 23 girls and 52 boys. The mean age was 13.6 years. The most frequent cause of trauma was same level fall, usually during sports activities (35 cases). The most common type of damage was Salter-Harris type II fracture (35 cases). Among the employed surgical techniques, open reduction and stabilization with K-wires was the most often used (52 cases). A group of four patients attracted our attention, in whom after a closed reduction, signs of periosteum interposition were noted. These patients required a second procedure. In one patient, the growth plate arrest occurred; it was directly caused by local osteomyelitis. CONCLUSIONS: With adequately conducted treatment of distal tibia and distal fibula physeal fractures, the results are good. Misdiagnosed periosteum interposition poses a more serious clinical problem as opposed to the commonly anxiety-provoking post-traumatic growth plate dysfunction. PMID- 29107134 TI - Restoration of severely damaged endodontically treated premolars: The influence of the endo-core length on marginal integrity and fatigue resistance of lithium disilicate CAD-CAM ceramic endocrowns. AB - OBJECTIVES: To explore fatigue limits of ceramic endocrowns for premolars. METHODS: Forty-eight devitalized premolars were cut at the CEJ. They were restored with standardized CAD-CAM lithium disilicate reinforced ceramic restorations (IPS e.max CAD, Ivoclar-Vivadent) and divided into four Groups (n=12): overlays (Group A, no endo-core, negative control), endocrowns with an endo-core of 2mm (Group B), 4mm (GroupC) and crowns with post and core (Group D, positive control). All specimens were first submitted to thermo-mechanical cyclic loading (TCML)(1.7Hz, 49N, 600000 cycles, 1500 thermo-cycles). Margins were analysed before and after the loading. Survived specimens were then submitted to cyclic isometric stepwise loading (5Hz, 200N to 1200N) until completion of 105000 cycles or failure. In case of fracture, fragments were analysed using SEM and failure mode was determined. Results of stepwise loading were statistically analysed by Kaplan-Meier life survival analysis and log rank test (p=0.05). RESULTS: All the specimens survived the TCML test except four specimens of Group A (early restorations' debonding). No difference in percentages of closed margins was found between endocrowns (Groups B, C) and crowns (Group D). After the stepwise test, differences in survival within the groups were not statistically significant. Most of restorations experienced non-reparable fracture. CONCLUSIONS: Endocrowns with both 2-mm and 4-mm long endo-cores displayed outcomes after fatigue equivalent to classical crowns. Results of this study discourage the use of flat overlays with only adhesive retention. CLINICAL SIGNIFICANCE: When restoring extremely destroyed devitalized premolars, adhesive strategies should be coupled to a macro-mechanical retention in the root. PMID- 29107135 TI - Influence of the addition of microsphere load amoxicillin in the physical, chemical and biological properties of an experimental endodontic sealer. AB - AIM: To develop an endodontic sealer with amoxicillin-loaded microsphere and to evaluate its properties. METHODS: Experimental sealer was obtained by mixing 70wt% UDMA, 15wt% GDMA and 15wt% BISEMA. In addition, CQ, DHEPT and PB were incorporated at 1 mol% and 0.01wt% BHT and 10wt% YbF3. Microspheres were produced by drying in spray dryer. Two experimental groups (10 and 15wt% of microspheres) and one control group (without microspheres) were formulated. The sealers were evaluated for the degree of conversion (n=3), degradation in solvent (n=3), drug release profile (n=3), antimicrobial activity (n=3), flow (n=3), film thickness (n=3) and cytotoxicity (n=3). Data were analyzed by ANOVA and Tukey with significance level of 5%. RESULTS: Microespheres presented a mean size of 2.664MUm. Immediate degree of conversion ranged from 51.73% to 55.13% and the 24h degree of conversion ranged from 60.79% to 73.80%. Upon solvent degradation 54.44% and 56.21% reduction in hardness were observed for 10% and 15% concentrations respectivelly. The drug release profile showed an average release of 73.76% of the drug in 96h. Significant reduction in antimicrobial activity was observed for 10% concentration after 24h, 48h and 96h compared to control. The flow and film thickness showed values in accordance to the ISO 6876. Cytotoxicity showed high cellular viability. CONCLUSION: The addition of up to 10% of microspheres containing amoxicillin presented antimicrobial activity and did not alter the properties of the experimental endodontic cement. CLINICAL SIGNIFICANCE: Amoxicillin microspheres with its antimicrobial activity in root canal sealers could reduce reintervations in endodontics when persistent bacteria or reinfection takes place in root canal system. PMID- 29107136 TI - Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation. AB - In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE-/- mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P?.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7alphaHC, 7betaHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid lowering option during hypercholesterolemic pregnancies for which there are currently limited options. PMID- 29107137 TI - A novel iron supplements preparation from Grifola frondosa polysaccharide and assessment of antioxidant, lymphocyte proliferation and complement fixing activities. AB - Grifola frondosa polysaccharide-iron (III) complex (GFP-iron) was synthesized and characterized. Based on single factor and orthogonal optimization experiments of GFP-iron (III) complex synthesis, the optimum conditions were the reaction temperature 80 degrees C, pH 8, reaction time 90min and ratio of catalyst to GFP 1:1.0gg-1. The iron content of GFP-iron (III) complex reached 24.15% under the optimums and characterized by fourier transform infrared (FTIR), scanning electron microscopy (SEM), X-Ray Diffraction (XRD), thermogravimetry (TG) and iron release in vitro assay. By 5-axe cobweb charts, the antioxidant activity of GFP-iron (III) complex was comprehensively evaluated. The results showed GFP-iron (III) complex retained a certain antioxidant activity. The lymphocytes proliferation of GFP-iron (III) complex was increased by 61.68% comparing with that of GFP at the sample concentration of 62.5MUg/mL. At giving 50% haemolysis, the concentration of GFP-iron (III) complex was 0.261mg/mL. Therefore, GFP-iron (III) complex would be expected to exploit into a new-type comprehensive iron supplements. PMID- 29107138 TI - Portable bioactive paper based genosensor incorporated with Zn-Ag nanoblooms for herpes detection at the point-of-care. AB - The present work describes the fabrication of an electrochemical paper-based analytical device (EPAD) integrated with Zn-Ag nanoblooms for detection of herpes in human, caused by Herpes virus 5(HHV-5) DNA, at the point of care. The cyclic voltammetry(CV) was used for electrochemical detection of the HHV-5 DNA in infected patient samples. The EPAD exihibited optimum current response within 5s at pH7.0 and 35 degrees C with two dynamic linear/working ranges, 113-103 and 3*105-106copies/mL and detection limit of 97copies/mL. The device showed high selectivity, repeatability, and sensitivity. The device had many advantageous features such as portable, facile approach, economical and potential for commercialization. The proposed sensing scheme is highly feasible for future clinical detection of Herpes virus. PMID- 29107139 TI - Spatial attributes of the four-helix bundle group of bacteriocins - The high resolution structure of BacSp222 in solution. AB - BacSp222 is a multifunctional bacteriocin produced by Staphylococcus pseudintermedius strain 222, an opportunistic pathogen of domestic animals. At micromolar concentrations, BacSp222 kills Gram-positive bacteria and is cytotoxic toward mammalian cells, while at nanomolar doses, it acts as an immunomodulatory factor, enhancing nitric oxide release in macrophage-like cell lines. The bacteriocin is a cationic, N-terminally formylated, 50-amino-acid-long linear peptide that is rich in tryptophan residues. In this study, the solution structure of BacSp222 was determined and compared to the currently known structures of similar bacteriocins. BacSp222 was isolated from a liquid culture medium in a uniformly 13C- and 15N-labeled form, and NMR data were collected. The structure was calculated based on NMR-derived constraints and consists of a rigid and tightly packed globular bundle of four alpha-helices separated by three short turns. Although the amino acid sequence of BacSp222 has no significant similarity to any known peptide or protein, a 3D structure similarity search indicates a close relation to other four-helix bundle-motif bacteriocins, such as aureocin A53, lacticin Q and enterocins 7A/7B. Assuming similar functions, biology, structure and physicochemical properties, we propose to distinguish the four helix bundle bacteriocins as a new Type A in subclass IId of bacteriocins, containing linear, non-pediocin-like peptides. PMID- 29107140 TI - Characterization of a new endo-type alginate lyase from Vibrio sp. NJU-03. AB - A gene, encoding a new alginate lyase AlgNJU-03, was cloned from marine bacteria Vibrio sp. NJU-03. The recombinant alginate lyase was characterized followed by being purified by NTA-Ni Sepharose. It exhibited the highest activity (6468.99U/mg) at pH 7.0 and 30 degrees C. Interestingly, AlgNJU-03 possessed broader substrate specificity and high activity toward both polyM (poly beta-d mannuronate) and polyG (poly alpha-l-guluronate), indicating that it is a bifunctional alginate lyase. Furthermore, Km of AlgNJU-03toward polyG (4.00mM) is lower than those toward alginate (8.50mM) and polyM (10.94mM), demonstrating that the enzyme has a higher affinity to polyG. Meanwhile, the catalytic efficiency (Kcat/Km) toward polyG (11.47s-1/mM) is much higher than those toward sodium alginate (3.60s-1/mM) and polyM (0.50s-1/mM). ESI-MS analysis suggested that AlgNJU-03 mainly released disaccharides, trisaccharides and tetrasaccharides from the three kinds of substrates in an endolytic manner. Therefore, it may be a potential tool to produce alginate oligosaccharides with low DP. PMID- 29107141 TI - Immunoadjuvant activity in mice of polysaccharides isolated from the leaves of Panax ginseng C.A. Meyer. AB - Our previous study showed polysaccharide (GS-P) isolated from the leaves of Panax ginseng C.A. Meyer possessed anti-tumor metastatic activity in mouse model. In this study, we evaluated the immunoadjuvant effect of GS-P on the induction of humoral and cellular immune responses against ovalbumin (OVA) in mice. When mice were immunized subcutaneously with OVA admixed with or without GS-P, the OVA+GS-P group showed significantly higher antibody production than the group immunized with OVA alone. This suggests that GS-P has the ability to enhance the adaptive immune response. In addition, the OVA+GS-P+FIA (Freund's incomplete adjuvant) group induced higher levels of antigen-specific IgG1 and IgG2b antibodies than the OVA+FIA group. The culture supernatant obtained from the splenocytes of mice immunized with OVA+GS-P+FIA showed higher levels of OVA-specific Th1-type (IL-2, IFN-gamma, GM-CSF) and Th2-type (IL-10) cytokines. Following in vitro analysis of T cell proliferation, the splenocytes of mice treated with OVA+GS-P+FIA showed significantly more proliferation than those treated with OVA+FIA. Further, the production of IgE antibody was dramatically reduced when OVA+GS-P+FIA was used to immunize mice rather than OVA+FIA or OVA+FCA (Freund's complete adjuvant). Collectively, these results suggest that GS-P may possess adjuvant activity that potentially enhances humoral as well as cellular immune responses. PMID- 29107142 TI - Antibacterial activity and cytotoxicity of Pterocarpus erinaceus Poir extracts, fractions and isolated compounds. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pterocarpus erinaceus has been chosen based on ethnobotanical surveys carried out in the Tchamba district of the Republic of Togo. AIM OF THE STUDY: Investigation of the antibacterial as well as cytotoxic activities of whole extracts, fractions and compounds isolated from the leaves, trunk bark and roots of Pterocarpus erinaceus. MATERIALS AND METHODS: Bio-guided fractionation of the raw extracts of plant parts and subsequent isolation of compounds from active fractions using normal phase open column chromatography. The broth microdilution method was used to evaluate the antibacterial activity, based on the determination of Minimal Inhibitory Concentrations (MICs) against several bacterial species representative of the most commonly encountered infectious diseases worldwide. The cytotoxicity of the raw extract and the most active fractions on a human non-cancerous cell (namely MRC-5) was estimated with a MTT assay. The chemical structure of the compounds isolated was elucidated using a combination of advanced Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). RESULTS: All extracts and fractions tested have shown good activities against Gram-positive bacteria (including Methicillin-Resistant Staphylococcus aureus, MRSA) and against Pseudomonas aeruginosa with MIC values ranging from 32ug/mL to 256ug/mL. In contrast, extracts were not toxic to MRC-5 cells. Four compounds have been isolated: Compound 1 (friedeline); Compound 2 (2,3 dihydroxypropyloctacosanoate); Compound 3 (a mixture of beta-sitosterol, stigmasterol and campesterol); Compound 4 (beta-sitosteryl-beta-D glucopyranoside) and shown to be active against some of the bacteria tested. They were active with MIC equal to 4ug/mL against strains of S. aureus (including MRSA). To the best of our knowledge, all of them except friedeline have never been reported in this plant species. CONCLUSION: P. erinaceus is confirmed as a plant harboring promising antibacterial activity with activities against serious human pathogens at very low concentrations. Some of the compounds isolated are also active at concentrations as low as 4ug/mL and therefore, may provide new leads for the development of antibacterial agents. PMID- 29107143 TI - A thirteen-week oral toxicity study of So-ochim-tang-gami-bang, a traditional Korean medicine, in Sprague-Dawley rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: So-ochim-tang-gamibang (SOCG) is a traditional Korean medicine formulated to control internal energy flow (Qi) and has been prescribed to improve stress-induced depressive disorders. AIM OF THE STUDY: SOCG has been used in clinical practice for the last two decades and its efficacy against stress-induced thoracic pain has been suggested. Although SOCG has been used as an herbal formula in Korean medicine, its toxicity has not yet been evaluated. In this study, we evaluated the safety of SOCG through a 13-week general toxicity study in rats. MATERIAL AND METHODS: SOCG was administered by oral gavage to rats at doses of 0 (control), 800, 2000, and 5000mg/kg/day over a 13-week period. Toxicity testing was conducted by evaluating mortality, clinical signs, body weight, food consumption, urinalysis, hematology, serum biochemistry, organ weight, necropsy, and histopathology compared with the concurrent control. RESULTS: SOCG-related changes were noted in clinical signs and urinalysis. The observed clinical signs were compound-colored stool and salivation. Urinalysis results revealed brown or amber colored urine and elevated levels of protein. However, these changes were not considered to be adverse. CONCLUSIONS: The no observed-adverse-effect-level of SOCG was determined to be above 5000mg/kg in both male and female rats. The result of this study can lay the foundation for the application of SOCG in humans and prove useful for detailed investigations on the toxicity or pharmacological effects of SOCG. PMID- 29107144 TI - Osteon Myospalacem Baileyi attenuates osteoclast differentiation through RANKL induced NFAT pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Osteon Myospalacem Baileyi, known as Sai long gu (Tibetan language, means "blind rat bone"), is the whole skeleton of Tibet plateau rodentia animal Myospalacem Baileyi. Osteon Myospalacem Baileyi had been widely used in the Tibet region as an anti-osteoporosis drug and since 1991 Osteon Myospalacem Baileyi has been listed in the Pharmacopoeia of People's Republic of China as the first-class animal new medical material. However, the mechanism of its anti-osteoporosis activities is still unclear. It is very desirable to solve this problem for further study. MATERIALS AND METHODS: in this study, preparative chromatography was employed to produce the active fraction ET4 from Osteon Myospalacem Baileyi crude. Flow cytometry and MTT assay were used to evaluate the toxicities of ET4. BMM cells were separated from mouse bone marrow to test the inhibition effects of ET4 on osteoclastogenesis. Western blot was used to find out the pathways, through which ET4 could act on osteoclastogenesis. Q-PCR was used to test the osteoclastogenesis marker genes. At last, immunofluorescence confocal microscopy was used to test the osteoclastogenesis master protein NFATc1 nuclei translocation. RESULTS: In this study we report that ET4, at the dose of 60MUg/mL, significantly inhibited the formation of osteoclasts. Notably, ET4 did not affect the BMM viability at that dose. In addition, Osteon Myospalacem Baileyi could inhibit the expression of osteoclast marker genes, including cathepsin K (CTSK), nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAP, Acp5) dendrite cell-specific transmembrane protein (DC-STAMP), calcitonin receptor (CTR), osteoclast associated and immunoglobulin-like receptor (OSCAR). Mechanistically, ET4 dose- and time-dependently blocked the RANKL-induced activation of ERK and c Fos as well as the induction of NFATc1 which is essential for OC formation. CONCLUSIONS: These data suggest that ET4 might be a useful alternative therapy in preventing or treating osteolytic diseases. PMID- 29107145 TI - Overlapping CD8+ and CD4+ T-cell epitopes identification for the progression of epitope-based peptide vaccine from nucleocapsid and glycoprotein of emerging Rift Valley fever virus using immunoinformatics approach. AB - Rift Valley fever virus (RVFV) is an emergent arthropod-borne zoonotic infectious viral pathogen which causes fatal diseases in the humans and ruminants. Currently, no effective and licensed vaccine is available for the prevention of RVFV infection in endemic as well as in non-endemic regions. So, an immunoinformatics-driven genome-wide screening approach was performed for the identification of overlapping CD8+ and CD4+ T-cell epitopes and also linear B cell epitopes from the conserved sequences of the nucleocapsid (N) and glycoprotein (G) of RVFV. We identified overlapping 99.39% conserved 1 CD8+ T cell epitope (MMHPSFAGM) from N protein and 100% conserved 7 epitopes (AVFALAPVV, LAVFALAPV, FALAPVVFA, VFALAPVVF, IAMTVLPAL, FFDWFSGLM, and FLLIYLGRT) from G protein and also identified IL-4 and IFN-gamma induced (99.39% conserved) 1 N protein CD4+ T-cell epitope (HMMHPSFAGMVDPSL) and 100% conserved 5 G protein CD4+ T-cell epitopes (LPALAVFALAPVVFA, PALAVFALAPVVFAE, GIAMTVLPALAVFAL, GSWNFFDWFSGLMSW, and FFLLIYLGRTGLSKM). The overlapping CD8+ and CD4+ T-cell epitopes were bound with most conserved HLA-C*12:03 and HLA-DRB1*01:01, respectively with the high binding affinity (kcal/mol). The combined population coverage analysis revealed that the allele frequencies of these epitopes are high in endemic and non-endemic regions. Besides, we found 100% conserved and non allergenic 2 decamer B-cell epitopes, GVCEVGVQAL and RVFNCIDWVH of G protein had the sequence similarity with the nonamer CD8+ T-cell epitopes, VCEVGVQAL and RVFNCIDWV, respectively. Consequently, these epitopes may be used for the development of epitope-based peptide vaccine against emerging RVFV. However, in vivo and in vitro experiments are required for their efficient use as a vaccine. PMID- 29107146 TI - NABi, a novel beta-sheet breaker, inhibits Abeta aggregation and neuronal toxicity: Therapeutic implications for Alzheimer's disease. AB - Amyloid beta (Abeta) aggregates are an important therapeutic target for Alzheimer's disease (AD), a fatal neurodegenerative disease. To date, AD still remains a big challenge due to no effective treatments. Based on the property that Abeta aggregates have the cross-beta-structure, a common structural feature in amyloids, we systemically designed the Abeta-aggregation inhibitor that maintains Abeta-interacting ability but removes toxic part from SOD1 (superoxide dismutase 1)-G93A. We identified NABi (Natural Abeta Binder and Abeta-aggregation inhibitor) composed of beta2-3 strands, a novel breaker of Abeta aggregation, which does not self-aggregate and has no cytotoxicity at all. The NABi blocks Abeta-fibril formation in vitro and in vivo and prevents neuronal cell death, a hallmark of AD pathogenesis. Such anti-amyloidogenic properties can provide novel strategies for treating AD. Furthermore, our study provides molecular insights into the design of amyloidogenic inhibitors to cure various neurodegenerative and amyloid-associated diseases, as NABi would regulate aggregation of other toxic beta-sheet proteins other than Abeta. PMID- 29107147 TI - Solution scattering approaches to dynamical ordering in biomolecular systems. AB - Clarification of solution structure and its modulation in proteins and protein complexes is crucially important to understand dynamical ordering in macromolecular systems. Small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS) are among the most powerful techniques to derive structural information. Recent progress in sample preparation, instruments and software analysis is opening up a new era for small-angle scattering. In this review, recent progress and trends of SAXS and SANS are introduced from the point of view of instrumentation and analysis, touching on general features and standard methods of small-angle scattering. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato. PMID- 29107148 TI - Amino acid misincorporation in recombinant proteins. AB - Proteins provide the molecular basis for cellular structure, catalytic activity, signal transduction, and molecular transport in biological systems. Recombinant protein expression is widely used to prepare and manufacture novel proteins that serve as the foundation of many biopharmaceutical products. However, protein translation bioprocesses are inherently prone to low-level errors. These sequence variants caused by amino acid misincorporation have been observed in both native and recombinant proteins. Protein sequence variants impact product quality, and their presence can be exacerbated through cellular stress, overexpression, and nutrient starvation. Therefore, the cell line selection process, which is used in the biopharmaceutical industry, is not only directed towards maximizing productivity, but also focuses on selecting clones which yield low sequence variant levels, thereby proactively avoiding potentially inauspicious patient safety and efficacy outcomes. Here, we summarize a number of hallmark studies aimed at understanding the mechanisms of amino acid misincorporation, as well as exacerbating factors, and mitigation strategies. We also describe key advances in analytical technologies in the identification and quantification of sequence variants, and some practical considerations when using LC-MS/MS for detecting sequence variants. PMID- 29107149 TI - Metabolic engineering frontiers emerging with advanced tools and methodologies. PMID- 29107150 TI - Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study. AB - BACKGROUND & AIMS: Statins are widely used to treat hypercholesterolemia. Statins may prevent hepatocellular carcinoma (HCC), but have not yet been fully studied, particularly in patients at high risk. Therefore, we investigated the risk of HCC after statin use in the whole general population and evaluated the effects of preexisting diabetes mellitus (DM) and liver cirrhosis (LC) on that risk. METHODS: A nationwide, nested case-control study was conducted with data from the National Health Insurance Service Physical Health Examination Cohort 2002-2013 in the Republic of Korea. Individuals diagnosed with HCC were matched to controls based on the time of the follow-up, sex, and age at index date. Odds ratios (ORs) and 95% confidence intervals (CIs) for HCC associated with statin use were analyzed by multivariable conditional logistic regression analyses. In total, 1,642 HCC cases were matched to 8,210 control individuals from 514,866 participants. RESULTS: Statin use was associated with reduced risk of HCC development (adjusted OR [AOR] 0.44; 95% CI 0.33-0.58) compared with nonusers. The reduction in risk was significant in the presence (AOR 0.28; 95% CI 0.17 0.46) and absence of DM (AOR 0.53; 95% CI 0.39-0.73) and in the presence (AOR 0.39; 95% CI 0.26-0.60) and absence of LC (AOR 0.42; 95% CI 0.32-0.57). Statin use also significantly reduced the risk of HCC among patients with DM, without chronic complications (AOR 0.19; 95% CI 0.08-0.46) or with chronic complications (AOR 0.34; 95% CI 0.19-0.64), compared to nonusers. CONCLUSIONS: Statin use may have a beneficial inhibitory effect on HCC development, particularly in patients with DM or LC, at high risk of HCC. LAY SUMMARY: In this longitudinal nationwide population-based nested case-control study, the association between statin use and the risk of HCC was investigated in Asian populations. Herein, we noted a beneficial effect of statin use on the development of HCC in the general population and individuals at high risk of HCC (i.e. those with diabetes or liver cirrhosis). PMID- 29107152 TI - The contribution of alcohol use disorder to decompensated cirrhosis among people with hepatitis C: An international study. AB - BACKGROUND & AIMS: The advent of direct-acting antivirals (DAAs) has led to ambitious targets for hepatitis C virus (HCV) elimination. However, in the context of alcohol use disorder the ability of DAAs to achieve these targets may be compromised. The aim of this study was to evaluate the contribution of alcohol use disorder to HCV-related decompensated cirrhosis in three settings. METHODS: HCV notifications from British Columbia, Canada; New South Wales, Australia, and Scotland (1995-2011/2012/2013, respectively) were linked to hospital admissions (2001-2012/2013/2014, respectively). Alcohol use disorder was defined as non liver-related hospitalisation due to alcohol use. Age-standardised decompensated cirrhosis incidence rates were plotted, associated factors were assessed using Cox regression, and alcohol use disorder-associated population attributable fractions (PAFs) were computed. RESULTS: Among 58,487, 84,529, and 31,924 people with HCV in British Columbia, New South Wales, and Scotland, 2,689 (4.6%), 3,169 (3.7%), and 1,375 (4.3%) had a decompensated cirrhosis diagnosis, and 28%, 32%, and 50% of those with decompensated cirrhosis had an alcohol use disorder, respectively. Age-standardised decompensated cirrhosis incidence rates were considerably higher in people with alcohol use disorder in New South Wales and Scotland. Decompensated cirrhosis was independently associated with alcohol use disorder in British Columbia (aHR 1.92; 95% CI 1.76-2.10), New South Wales (aHR 3.68; 95% CI 3.38-4.00) and Scotland (aHR 3.88; 95% CI 3.42-4.40). The PAFs of decompensated cirrhosis-related to alcohol use disorder were 13%, 25%, and 40% in British Columbia, New South Wales and Scotland, respectively. CONCLUSIONS: Alcohol use disorder was a major contributor to HCV liver disease burden in all settings, more distinctly in Scotland. The extent to which alcohol use would compromise the individual and population-level benefits of DAA therapy needs to be closely monitored. Countries, where appropriate, must develop strategies combining promotion of DAA treatment uptake with management of alcohol use disorders, if World Health Organization 2030 HCV mortality reduction targets are going to be achieved. LAY SUMMARY: The burden of liver disease has been rising among people with hepatitis C globally. The recent introduction of highly effective medicines against hepatitis C (called direct-acting antivirals or DAAs) has brought renewed optimism to the sector. DAA scale-up could eliminate hepatitis C as a public health threat in the coming decades. However, our findings show heavy alcohol use is a major risk factor for liver disease among people with hepatitis C. If continued, heavy alcohol use could compromise the benefits of new antiviral treatments at the individual- and population-level. To tackle hepatitis C as a public health threat, where needed, DAA therapy should be combined with management of heavy alcohol use. PMID- 29107153 TI - Fatty liver and renal function impairment - Time for awareness? PMID- 29107151 TI - Hedgehog signalling in liver pathophysiology. AB - Liver disease remains a leading cause of mortality worldwide despite recent successes in the field of viral hepatitis, because increases in alcohol consumption and obesity are fuelling an epidemic of chronic fatty liver disease for which there are currently no effective medical therapies. About 20% of individuals with chronic liver injury ultimately develop end-stage liver disease due to cirrhosis. Hence, treatments to prevent and reverse cirrhosis in individuals with ongoing liver injury are desperately needed. The development of successful treatments requires an improved understanding of the mechanisms controlling liver disease progression. The liver responds to diverse insults with a conserved wound healing response, suggesting that it might be generally beneficial to optimise pathways that are crucial for effective liver repair. The Hedgehog pathway has emerged as a potential target based on compelling preclinical and clinical data, which demonstrate that it critically regulates the liver's response to injury. Herein, we will summarise evidence of the Hedgehog pathway's role in liver disease and discuss how modulating pathway activity might be applied to improve liver disease outcomes. PMID- 29107154 TI - Species and hybrids in the genus Diaphanosoma Fischer, 1850 (Crustacea: Branchiopoda: Cladocera). AB - Cladocerans are well-studied planktonic crustaceans, especially those of the genus Daphnia in which interesting evolutionary questions have been addressed on speciation processes. The aim of the present study is to demonstrate that other genera of cladocerans show similar levels of cryptic diversity, intraspecific gene flow, and thus become useful model systems for comparison. In order to do so, we chose the genus Diaphanosoma, widespread in tropical and temperate areas. We started with a survey of species diversity in the genus Diaphanosoma in Asia using a morphological approach, then obtained sequences from a mitochondrial and a nuclear marker from multiple individuals of different species, performed tests on DNA taxonomy and molecular phylogenies, and assessed the role of hybridization in explaining the cases of mitonuclear discordance. The results are that cryptic diversity occurs in Diaphanosoma, and mitonuclear discordance was found in about 6% of the sequenced animals. Past hybridization is supported as the most likely explanation for the discordance: no evidence was found of first generation hybrids with heterozygous sequences. Our analysis on patterns of genetic diversity in Diaphanosoma supports similarities and differences with what is known in Daphnia. PMID- 29107155 TI - The blood-brain interface: a culture change. AB - The blood-brain interface (BBI) is the subject of a new named series at Brain, Behavior, and Immunity. It is timely to reflect on a number of advances in the field within the last ten years, which may lead to an increased understanding of human behaviour and a wide range of psychiatric and neurological conditions. We cover discoveries made in solute and cell trafficking, endothelial cell and pericyte biology, extracellular matrix and emerging tools, especially those which will enable study of the human BBI. We now recognize the central role of the BBI in a number of immunopsychiatric syndromes, including sickness behaviour, delirium, septic encephalopathy, cognitive side effects of cytokine-based therapies and the frank psychosis observed in neuronal surface antibody syndromes. In addition, we find ourselves interrogating and modulating the brain across the BBI, during diagnostic investigation and treatment of brain disease. The past ten years of BBI research have been exciting but there is more to come. PMID- 29107156 TI - Advantages of Staged Angioplasty in a Patient with Internal Carotid Artery Pseudo Occlusion Besides Prevention of Cerebral Hyperperfusion Syndrome. AB - BACKGROUND: Staged angioplasty for carotid artery stenosis has been reported to be effective in preventing postoperative cerebral hyperperfusion syndrome (CHS) in patients with severe carotid stenosis; thus, it is also recommended for patients with internal carotid artery (ICA) pseudo-occlusion, the treatment strategy for which is controversial. CASE DESCRIPTION: This study reports the case of an Asian man in his 50s who had motor aphasia and right-side weakness caused by pseudo-occlusion of the left ICA. After medical treatment, he underwent a staged angioplasty. After the first stage of percutaneous transluminal angioplasty, anterograde blood flow to the left ICA increased but the distal ICA remained partially collapsed. Initially, the second stage of carotid artery stenting (CAS) was planned for 2 weeks after the first stage; however, hemorrhagic infarction was observed the day before the CAS, and it was postponed by 2 weeks, after adjustment of antiplatelet therapy. At the time of the CAS, the diameter of the initially collapsed left distal ICA was remodeled and it was fully dilated; thus, we used a balloon-type embolic protection device and conducted CAS successfully without apparent embolic complications. The postoperative course was uneventful. The patient did not develop CHS. CONCLUSIONS: Besides preventing CHS, staged angioplasty has advantages when used for treating patients with ICA pseudo-occlusions in that the extent of dilation of the distal ICA after percutaneous transluminal angioplasty can be confirmed and the development of a possible hemorrhagic infarction can be assessed before stent placement. PMID- 29107157 TI - Efficacy, Reliability, and Safety of Completely Autologous Fibrin Glue in Neurosurgical Procedures: Single-Center Retrospective Large-Number Case Study. AB - OBJECTIVE: Commercially available fibrin glue (Com-FG), which is used commonly worldwide, is produced with pooled human plasma from multiple donors. However, it has added bovine aprotinin, which involves the risk of infection, allogenic immunity, and allergic reactions. We evaluate the efficacy, reliability, and safety of completely autologous fibrin glue (CAFG). METHODS: From August 2014 to February 2016, prospective data were collected and analyzed from 153 patients. CAFG was prepared with the CryoSeal System using autologous blood and was applied during neurosurgical procedures. Using CAFG-soaked oxidized regenerated cellulose and/or polyglycolic acid sheets, we performed a pinpoint hemostasis, transposed the offending vessels in a microvascular decompression, and covered the dural incision to prevent cerebrospinal fluid leakage. RESULTS: The CryoSeal System had generated up to a mean of 4.51 mL (range, 3.0-8.4 mL) of CAFG from 400 mL autologous blood. Com-FG products were not used in our procedures. Only 6 patients required an additional allogeneic blood transfusion. The hemostatic effective rate was 96.1% (147 of 153 patients). Only 1 patient who received transsphenoidal surgery for a pituitary adenoma presented with the complication of delayed postoperative cerebrospinal fluid leakage (0.65%). No patient developed allergic reactions or systemic complications associated with the use of CAFG. CONCLUSIONS: CAFG effectively provides hemostatic, adhesive, and safety performance. The timing and three-dimensional shape of CAFG-soaked oxidized regenerated cellulose and/or polyglycolic acid sheets solidification can be controlled with slow fibrin formation. The cost to prepare CAFG is similar compared with Com-FG products, and it can therefore be easily used at most institutions. PMID- 29107158 TI - The Relationship Between Intracranial Pressure and Age-Chasing Age-Related Reference Values. AB - BACKGROUND: No true reference values for intracranial pressure (ICP) in humans exist; current values are estimated from measurements in adults who undergo treatment in order to correct ICP. We report ICP values in a "pseudonormal" group of children and adults to examine if age affects ICP. METHODS: We analyzed data from all nonshunted patients undergoing a 24-hour ICP monitoring as part of a diagnostic work-up and included patients with no subsequent suspicion of increased ICP and no need for pressure-relieving treatment with a minimum follow up period of 3 years. RESULTS: From February 2008 to November 2014, a 24-hour ICP monitoring was performed in 221 patients. Of these patients, 35 (14 children, 21 adults) met the inclusion criteria. Follow-up time to confirm absence of ICP related disease was 3-9 years. Daytime ICP was 2.8 mmHg +/- 2.2 in children and 1.9 mmHg +/- 4.2 in adults (P = 0.39). Of 35 patients, 32 had higher nighttime ICP. The difference between daytime and nighttime ICP was similar in children (DeltaICP = 5.8 mmHg +/- 4.0, P < 0.0001) and adults (DeltaICP = 6.1 mm Hg +/- 3.3, P < 0.0001). ICP could be described as a decreasing function of age, with an ICP decrement of 0.69 mmHg per decade (P = 0.015). CONCLUSIONS: We found similar differences in daytime and nighttime ICP between children and adults with no ICP related disease. ICP seems to decrease with age across all ages. This has implications for therapeutic interventions (e.g., shunt valve selection or resistance in external ventricular drainage). PMID- 29107159 TI - Assessment of a Novel Adult Cervical Deformity Frailty Index as a Component of Preoperative Risk Stratification. AB - OBJECTIVE: To determine the value of a novel adult cervical deformity frailty index (CD-FI) in preoperative risk stratification. METHODS: We reviewed a prospective, multicenter database of adults with cervical spine deformity. We selected 40 variables to construct the CD-FI using a validated method. Patients were categorized as not frail (NF) (<0.2), frail (0.2-0.4), or severely frail (SF) (>0.4) according to CD-FI score. We performed multivariate logistic regression to determine the relationships between CD-FI score and incidence of complications, length of hospital stay, and discharge disposition. RESULTS: Of 61 patients enrolled from 2009 to 2015 with at least 1 year of follow-up, the mean CD-FI score was 0.26 (range 0.25-0.59). Seventeen patients were categorized as NF, 34 as frail, and 10 as SF. The incidence of major complications increased with greater frailty, with a gamma correlation coefficient of 0.25 (asymptotic standard error, 0.22). The odds of having a major complication were greater for frail patients (odds ratio 4.4; 95% confidence interval 0.6-32) and SF patients (odds ratio 43; 95% confidence interval 2.7-684) compared with NF patients. Greater frailty was associated with a greater incidence of medical complications and had a gamma correlation coefficient of 0.30 (asymptotic standard error, 0.26). Surgical complications, discharge disposition, and length of hospital stay did not correlate significantly with frailty. CONCLUSIONS: Greater frailty was associated with greater risk of major complications for patients undergoing cervical spine deformity surgery. The CD-FI may be used to improve the accuracy of preoperative risk stratification and allow for adequate patient counseling. PMID- 29107160 TI - Resumption of Antithrombotic Agents in Chronic Subdural Hematoma: A Systematic Review and Meta-analysis. AB - BACKGROUND: The clinical decision whether and when to resume antithrombotics in patients with chronic subdural hematomas (CSDH) postoperatively is limited by a lack of quality evidence exploring this topic. Our study aims to assess the available evidence of patient complication outcomes, specifically hemorrhagic and thromboembolic events, following the resumption or non-resumption of antithrombotic agents postoperatively in CSDH patients already on these agents before CSDH. METHODS: We followed recommended PRISMA guidelines for systematic reviews. Electronic database searches were performed to identify included studies. Data were extracted and analyzed using meta-analysis. RESULTS: Eight studies were included for analysis. The most common indication for antithrombotic treatment before onset of CSDH was atrial fibrillation (29.6%), followed by prosthetic heart valve (16.6%), recent myocardial infarction (14.1%), prior stroke or transient ischemic attack (11.6%), and finally venous thromboembolism (8.3%). The overall hemorrhagic complication rate was 14.8% in the resumption group versus 18.6% in the no resumption group (P = 0.591). This did not differ between early (<2 weeks) versus late (>1 month) resumption (15% vs. 18.6%, P = 0.97). The rate of thromboembolism however was statistically lower in those who resumed antithrombotics (2.9% vs. 6.8%, P<0.001). There was a non-significant trend towards higher thromboembolic rates with early resumption (5.3% vs. 2.1%, P = 0.23). CONCLUSIONS: The decision to resume antithrombotics postoperatively in the clinical management of CSDH patients is a complex one and should therefore be a highly individualized process. Our meta-analysis demonstrates that in selected cases, it is feasible to resume early antithrombotic treatment without additional hemorrhagic or thromboembolic risk. PMID- 29107161 TI - Evaluation of Problem- and Simulator-Based Learning in Lumbar Puncture in Adult Neurology Residency Training. AB - BACKGROUND: Lumbar puncture (LP) is an essential part of adult neurology residency training. Technologic as well as nontechnologic training is needed. However, current assessment tools mostly focus on the technologic aspects of LP. We propose a training method-problem- and simulator-based learning (PSBL)-in LP residency training to develop overall skills of neurology residents. METHODS: We enrolled 60 neurology postgraduate-year-1 residents from our standardized residents training center and randomly divided them into 2 groups: traditional teaching group and PSBL group. After training, we assessed the extent that the residents were ready to perform LP and tracked successful LPs performed by the residents. We then asked residents to complete questionnaires about the training models. Performance scores and the results of questionnaires were compared between the 2 groups. RESULTS: Students and faculty concluded that PSBL provided a more effective learning experience than the traditional teaching model. Although no statistical difference was found in the pretest, posttest, and improvement rate scores between the 2 groups, based on questionnaire scores and number of successful LPs after training, the PSBL group showed a statistically significant improvement compared with the traditional group. Findings indicated that nontechnical elements, such as planning before the procedure and controlling uncertainties during the procedure, are more crucial than technical elements. CONCLUSIONS: Compared with traditional teaching model, PSBL for LP training can develop overall surgical skills, including technical and nontechnical elements, improving performance. Residents in the PSBL group were more confident and effective in performing LP. PMID- 29107162 TI - Artificial Stroke Clots: How Wide is the Gap to the Real World? AB - OBJECTIVE: Especially since the establishment of mechanical thrombectomy as part of standard stroke therapy, artificial thrombi have become important in the training of interventionalists as well as for the development and testing of devices. So far, these in vitro clots have lacked direct comparisons with ex vivo thrombi. We therefore compared the histologic appearance of dynamically produced clots with that of stroke thrombi acquired during mechanical recanalization. METHODS: Thrombi of 145 consecutive patients with stroke with large-vessel occlusions were histologically compared with 10 artificial clots, dynamically created from human blood and pig's blood using a Chandler loop system. Quantified FP/RBC ratios (fibrin/platelets divided by red blood cell fraction) and white blood cell (WBC) fractions were identified and compared between artificial (human and pig) and ex vivo thrombi obtained from patients with various stroke causes. RESULTS: There were no significant differences in the analysis of FP/RBC ratios between artificial thrombi and ex vivo thrombi (P = 0.42) or in the more precise analyses considering etiologic subgroups. Distinct differences were observed for the WBC fraction, with lower values in artificial thrombi (median, 1.34%) than in ex vivo thrombi (median, 5%) (P < 0.001). CONCLUSIONS: The main clot components, FP and RBC, are presumably the most influential factors for clot stability and mechanical resistance. Similarities between artificially generated and ex vivo stroke clots (and when considering different stroke subgroups) support the usefulness of these artificial thrombi in the pre-evaluation of thrombus extraction devices and as appropriate training material. PMID- 29107163 TI - Exome Sequencing Identifies LOXL2 Mutation as a Cause of Familial Intracranial Aneurysm. AB - BACKGROUND: Genetic risk factors can contribute to the etiology of intracranial aneurysms (IAs), and the genetic predisposition of IAs is largely unknown. Our study aimed to explore the role of rare variations in IA susceptibility. METHODS: Whole-exome sequencing (WES) was performed in a representative family with a history of multiple cases of IAs. WES variants were prioritized by various filtering strategies, including frequency, predicted pathogenicity, and functional prediction. Sanger sequencing also was performed in an additional 2 families and sporadic IA cases. RESULTS: After WES and filtering, 15 single nucleotide variants and 3 insertion/deletions (indels) were prioritized in the family. Among them, we selected 5 candidate variants (located in DHRS3, OR2G3, LOXL2, FGL1, and KLC3) by considering known disease genes or ontology association with cardiovascular morphogenesis or other known diseases. Genotyping results revealed that only c.C133T/p.H45Y in exon 2 of LOXL2 gene was segregated fully with definite IA phenotypes in the family. Moreover, LOXL2 has been reported as a susceptibility gene for IAs. CONCLUSIONS: LOXL2 c.C133T is a pathogenic mutation that is responsible for a fraction of familial IAs. PMID- 29107164 TI - Subarachnoid Hemorrhage and Readmissions: National Rates, Causes, Risk Factors, and Outcomes in 16,001 Hospitalized Patients. AB - INTRODUCTION: The acute complications of aneurysmal subarachnoid hemorrhage (aSAH) often lead to readmissions, which are linked to hospital reimbursement. The national rates, causes, risk factors, and outcomes associated with 30-day and 90-day readmission after aSAH have not previously been reported. METHODS: The Nationwide Readmissions Database was queried from January to September 2013 for all patients (age >=18 years) with a diagnosis of aSAH. Data points included demographics, comorbidities, complications, and discharge outcomes. Causes and risk factors for 30-day and 90-day readmission were identified in univariate and multivariable analysis. RESULTS: In 12,777 patients discharged alive after hospitalization for aSAH, 962 (7.5%) were readmitted within 30 days and 2153 (16.7%) within 90 days. Common causes of readmission included stroke, hydrocephalus, septicemia, and headache. At 30-day and 90-day readmission, 39.7% and 51.2% of patients with diagnosis of hydrocephalus underwent ventriculoperitoneal shunt placement, respectively. In multivariable analysis, cannabis use and diabetes were predictors of both 30-day and 90-day readmission and older patients were uniquely susceptible to 30-day readmissions. Risk factors for 90-day readmission included Medicare insurance, hypothyroidism, initial discharge to skilled nursing facility, and several index complications including bowel obstruction, gastrostomy, acute lung injury, and cerebral edema. Average cost and length of stay were calculated at 30-day ($16.647, 7.1 days) and 90-day readmission ($17,926, 6.7 days). Mortality was 2.8% within 30 days and 3.8% within 90 days. CONCLUSIONS: Many readmissions occur outside the 30-day follow-up period in patients subarachnoid hemorrhage and possess unique risk factors, which may help identify high-risk patients. PMID- 29107165 TI - Transarterial Onyx Embolization of Bilateral Transverse-Sigmoid Dural Arteriovenous Malformation with Transvenous Balloon Assist-Initial U.S. Experience with Copernic RC Venous Remodeling Balloon. AB - BACKGROUND: Currently, the mainstay treatment of dural arteriovenous fistula (DAVF) involves endovascular approaches, especially for high-grade lesions. Transarterial embolization with preservation of venous sinuses has become the preferred approach due to the development of newer liquid embolic agents. For further precision during embolization, the use of temporary balloon occlusion to protect the patency of dural sinuses from the embolic agent's migration has been described. METHODS: A 64-year-old man presented with bilateral pulsatile tinnitus and visual decline. A diagnostic cerebral angiogram demonstrated a complex bilateral Borden type II and Cognard type IIB DAVF. Treatment was carried out endovascularly under general anesthesia in a staged fashion. In the first stage, the balloon was inflated during embolization to protect the right transverse sigmoid venous sinus system and torcula. In the second stage, the balloon was again inflated to protect the left transverse sigmoid venous sinus system and torcula during embolization. Complete obliteration of the left DAVF was achieved, and patency of the left transverse and sigmoid sinuses was preserved. Patency of the right transverse and sigmoid sinus was also conserved post procedure. RESULTS: The patient was treated successfully with transarterial Onyx embolization with transvenous balloon protection of the sinus. CONCLUSIONS: This case is the first reported use of the Copernic RC balloon in the United States under the compassionate use guidelines of the U.S. Food and Drug Administration. The use of this balloon is becoming a useful treatment alternative in selected cases of DAVFs as it improves the safety and efficacy of transarterial embolization as evidenced in this case. PMID- 29107166 TI - A Critical Analysis of the Utility of Intraoperative Angiography. AB - OBJECTIVE: Intraoperative digital subtraction angiography (ioDSA) is touted as the gold standard imaging evaluation for aneurysm clip constructs. Candid evaluations of its limitations are sparse. METHODS: A prospectively collected hospital billing database was queried to identify craniotomies for aneurysm clipping from January 2010 to December 2013. We evaluated the rate of occult residual and parent vessel stenosis determined on follow-up angiography for patients undergoing ioDSA and those not undergoing ioDSA. Comparisons were performed via Fisher exact test, with P < 0.05 considered statistically significant. RESULTS: From our database search, we found 187 patients who underwent ioDSA after aneurysm clipping and an additional 91 patients who did not. Results from ioDSA influenced operative management in 17% of cases. Sixty four patients with 70 treated aneurysms undergoing ioDSA had postoperative angiography; 7 occult residuals were discovered, yielding a 10% false-negative rate, with 10% of aneurysms showing residual. Occult residuals at the middle cerebral artery bifurcation represented most discovered residuals (6/7). Thirty two patients with 37 treated aneurysms did not undergo ioDSA and had angiographic follow-up; 24% of patients were found to have residual aneurysms (P = 0.08 compared with patients undergoing ioDSA). Residuals at the anterior communicating artery (ACoA) represented 56% of all residuals, whereas the ACoA represented only 18% of aneurysms clipped. The rate of residuals was significantly higher than that for patients with clipped ACoA aneurysms undergoing ioDSA (P = 0.008). CONCLUSIONS: ioDSA influenced management in nearly one fifth of cases. It can be particularly beneficial in detecting residuals for ACoA aneurysms; its benefit was less apparent for middle cerebral artery aneurysms. PMID- 29107167 TI - Does Temperature Increase by Sympathetic Neurolysis Improve Pain in Complex Regional Pain Syndrome? A Retrospective Cohort Study. AB - BACKGROUND: Lumbar sympathetic neurolysis (LSN) is a treatment option for complex regional pain syndrome (CRPS). We examined whether LSN-related temperature changes are associated with clinical outcome and investigated relationships between the outcome of LSN and clinical variables in patients with CRPS-I. METHODS: We included 95 patients with CRPS-I affecting a single lower extremity, by the Budapest criteria, and who underwent LSN after successful lumbar sympathetic blocks, in this retrospective study. Fluoroscopy-guided LSN was conducted with 1.5 mL of 99% alcohol at L2 and L3 vertebral levels. Positive outcome was defined as a reduction of >=50% on a numeric rating scale pain score at 6 months after LSN. The relationship between successful outcome and clinical variables was analyzed. RESULTS: Positive LSN outcome occurred in 49.5% of patients, and it was suggested that Sympathetically maintained pain may accompany CRPS-I in 28% of patients. The overall temperature in the affected limb was increased after LSN, without contralateral limb temperature changes, but did not differ significantly between the positive and negative outcome groups (P = 0.590). Temperature after LSN in warm-type CRPS was reduced in the affected limb, without contralateral limb temperature changes. The absolute temperature change was significantly greater in cold-type than in warm-type CRPS (P = 0.026). In multivariate analysis, a short duration of pain and concurrent cold intolerance were significant factors predicting a positive outcome after LSN. CONCLUSIONS: LSN may be effective in some patients with CRPS, irrespective of temperature changes and temperature asymmetry pattern. A short duration of pain and concurrent cold intolerance significantly predict successful LSN. PMID- 29107168 TI - Risk of Recurrence in Operated Parasagittal Meningiomas: A Logistic Binary Regression Model. AB - BACKGROUND: Parasagittal meningiomas arise from the arachnoid cells of the angle formed between the superior sagittal sinus (SSS) and the brain convexity. In this retrospective study, we focused on factors that predict early recurrence and recurrence times. METHODS: We reviewed 125 patients with parasagittal meningiomas operated from 1985 to 2014. We studied the following variables: age, sex, location, laterality, histology, surgeons, invasion of the SSS, Simpson removal grade, follow-up time, angiography, embolization, radiotherapy, recurrence and recurrence time, reoperation, neurologic deficit, degree of dependency, and patient status at the end of follow-up. RESULTS: Patients ranged in age from 26 to 81 years (mean 57.86 years; median 60 years). There were 44 men (35.2%) and 81 women (64.8%). There were 57 patients with neurologic deficits (45.2%). The most common presenting symptom was motor deficit. World Health Organization grade I tumors were identified in 104 patients (84.6%), and the majority were the meningothelial type. Recurrence was detected in 34 cases. Time of recurrence was 9 to 336 months (mean: 84.4 months; median: 79.5 months). Male sex was identified as an independent risk for recurrence with relative risk 2.7 (95% confidence interval 1.21-6.15), P = 0.014. Kaplan-Meier curves for recurrence had statistically significant differences depending on sex, age, histologic type, and World Health Organization histologic grade. A binary logistic regression was made with the Hosmer-Lemeshow test with P > 0.05; sex, tumor size, and histologic type were used in this model. CONCLUSIONS: Male sex is an independent risk factor for recurrence that, associated with other factors such tumor size and histologic type, explains 74.5% of all cases in a binary regression model. PMID- 29107169 TI - The complement system is dysfunctional in metabolic disease: Evidences in plasma and adipose tissue from obese and insulin resistant subjects. AB - The relationship between chronic low-grade inflammation, insulin resistance and other obesity-associated metabolic disturbances is increasingly recognized. The possible mechanisms that trigger these immunologic alterations remain to be fully understood. The complement system is a crucial element of immune defense system, being important in the activation of innate and adaptative immune response, promoting the clearance of apoptotic and damaged endogenous cells and participating in processes of tissue development, degeneration, and regeneration. Circulating components of the complement system appear to be dysregulated in obesity-associated metabolic disturbances. The activation of the complement system is also evident in adipose tissue from obese subjects, in association with subclinical inflammation and alterations in glucose metabolism. The possible contribution of some components of the complement system in the development of insulin resistance and obesity-associated metabolic disturbances, and the possible role of complement system in adipose tissue physiology is reviewed here. The modulation of the complement system could constitute a potential target in the pathophysiology and therapy of obesity and associated metabolic disease. PMID- 29107171 TI - Progression from isolated growth hormone deficiency to combined pituitary hormone deficiency. AB - Growth hormone deficiency (GHD) can present at any time of life from the neonatal period to adulthood, as a result of congenital or acquired insults. It can present as an isolated problem (IGHD) or in combination with other pituitary hormone deficiencies (CPHD). Pituitary deficits can evolve at any time from GHD diagnosis. The number, severity and timing of occurrence of additional endocrinopathies are highly variable. The risk of progression from IGHD to CPHD in children varies depending on the etiology (idiopathic vs organic). The highest risk is displayed by children with abnormalities in the Hypothalamo-Pituitary (H P) region. Heterogeneous data have been reported on the type and timing of onset of additional pituitary hormone deficits, with TSH deficiency being most frequent and Diabetes Insipidus the least frequent additional deficit in the majority, but not all, of the studies. ACTH deficiency may gradually evolve at any time during follow-up in children or adults with childhood onset IGHD, particularly (but not only) in presence of H-P abnormalities and/or TSH deficiency. Hence there is a need in these patients for lifelong monitoring for ACTH deficiency. GH treatment unmasks central hypothyroidism mainly in patients with organic GHD, but all patients starting GH should have their thyroid function monitored closely. Main risk factors for development of CPHD include organic etiology, H-P abnormalities (in particular pituitary stalk abnormalities, empty sella and ectopic posterior pituitary), midline brain (corpus callosum) and optic nerves abnormalities, genetic defects and longer duration of follow-up. The current available evidence supports longstanding recommendations for the need, in all patients diagnosed with IGHD, of a careful and indefinite follow-up for additional pituitary hormone deficiencies. PMID- 29107170 TI - Cellular and molecular mechanisms underlying planar cell polarity pathway contributions to cancer malignancy. AB - While the mutational activation of oncogenes drives tumor initiation and growth by promoting cellular transformation and proliferation, increasing evidence suggests that the subsequent re-engagement of largely dormant developmental pathways contributes to cellular phenotypes associated with the malignancy of solid tumors. Genetic studies from a variety of model organisms have defined many of the components that maintain epithelial planar cell polarity (PCP), or cellular polarity in the axis orthogonal to the apical-basal axis. These same components comprise an arm of non-canonical Wnt signaling that mediates cell motility events such as convergent extension movements essential to proper development. In this review, we summarize the increasing evidence that the Wnt/PCP signaling pathway plays active roles in promoting the proliferative and migratory properties of tumor cells, emphasizing the importance of subcellular localization of PCP components and protein-protein interactions in regulating cellullar properties associated with malignancy. Specifically, we discuss the increased expression of Wnt/PCP pathway components in cancer and the functional consequences of aberrant pathway activation, focusing on Wnt ligands, Frizzled (Fzd) receptors, the tetraspanin-like proteins Vangl1 and Vangl2, and the Prickle1 (Pk1) scaffold protein. In addition, we discuss negative regulation of the Wnt/PCP pathway, with particular emphasis on the Nrdp1 E3 ubiquitin ligase. We hypothesize that engagement of the Wnt/PCP pathway after tumor initiation drives malignancy by promoting cellular proliferation and invasiveness, and that the ability of Wnt/PCP signaling to supplant oncogene addiction may contribute to tumor resistance to oncogenic pathway-directed therapeutic agents. PMID- 29107172 TI - Pyroelectricity as a possible mechanism for cell membrane permeabilization. AB - The effects of pyroelectricity on cell membrane permeability had never been explored. Pyroelectricity consists in the generation of an electric field in the surface of some materials when a change in temperature is produced. In the present study, tourmaline microparticles, which are known to display pyroelectrical properties, were subjected to different changes in temperature upon exposure to cells in order to induce an electric field at their surface. Then, the changes in the permeability of the cell membrane to a cytotoxic agent (bleomycin) were assessed by a cloning efficacy test. An increase in the permeability of the cell membrane was only detected when tourmaline was subjected to a change in temperature. This suggests that the apparition of an induced pyroelectrical electric field on the material could actually be involved in the observed enhancement of the cell membrane permeability as a result of cell electropermeabilization. PMID- 29107173 TI - Deaths and parasuicides associated with mefloquine chemoprophylaxis: A systematic review. AB - BACKGROUND: Mefloquine is recommended in international health guidelines for preventing malaria in travellers. Reports of psychosis and suicide are often alluded to but are not clearly established. METHODS: We carried out a systematic review of the literature to identify and critically appraise any reported death or parasuicide associated with mefloquine prophylaxis. We developed a comprehensive search that included publications up to 11 July 2017. We included case studies but excluded newspaper reports. Two authors independently appraised each death or parasuicide against a standardised causality assessment tool. The protocol was registered on PROSPERO (CRD42016041988). RESULTS: We identified 527 articles that required full-text retrieval; of these 17 were unique publications that reported deaths or parasuicide. Eight unique publications had sufficient detail to be included in causality assessment. We identified 2 deaths with a probable association that appeared to be idiosyncratic drug reactions; we categorised the remaining 8 deaths as "unlikely" to be related to mefloquine, or "unclassifiable". There was one parasuicide with a possible causal association. There were 9 additional publications that searched spontaneous drug reporting databases; none provided sufficient detail to perform a causality assessment. CONCLUSIONS: Overall, the number of deaths that we could reliably attribute to the prophylactic use of mefloquine is very low. PMID- 29107174 TI - Influenza risk at Muslim pilgrimages in Iraq and Saudi Arabia. PMID- 29107175 TI - Entrapment of focal atrial tachycardia using cryoballoon ablation; Sinus rhythm in the left atrium and ongoing atrial tachycardia in the left atrial appendage. AB - Left atrial appendage (LAA) is a well-known source of focal atrial tachycardias (AT). Although radio-frequency (RF) energy is the most commonly used technique in such cases, there was an option other than epicardial approach when RF technique fails. Cryoballoon technology is primarily developed to be used for pulmonary vein isolation (PVI). Also, there was no report regarding the isolation of LAA by using cryo-balloon in patients with focal AT. In this case, for the first time in the literature, we successfully isolated the LAA because of failed attempts of RF ablation for focal AT in whom the surface electrogram showed a sinus rhythm while arrhythmia continues inside the LAA. PMID- 29107176 TI - The effects of multi-component weight management interventions on weight loss in adults with intellectual disabilities and obesity: A systematic review and meta analysis of randomised controlled trials. AB - BACKGROUND: Adults with intellectual disabilities have been shown to experience higher rates of obesity in comparison to the general population. AIM: To examine the effectiveness of randomised controlled trials of multi-component weight management interventions for adults with intellectual disabilities and overweight/obesity. METHODS AND PROCEDURES: A systematic search of six electronic databases was conducted from database inception to January 2016. Risk of bias was assessed by the Cochrane Collaboration tool. Behavioural change techniques were defined by coding against the Coventry Aberdeen LOndon REfined (CALO-RE) taxonomy. Meta-analyses were conducted as Weighted Mean Difference (WMD) between intervention and control/comparator intervention. OUTCOMES AND RESULTS: Six randomised controlled trials were included. The interventions did not adhere to clinical recommendations [the inclusion of an energy deficit diet (EDD), physical activity, and behaviour change techniques]. Meta-analysis revealed that current multi-component weight management interventions are not more effective than no treatment (WMD: -0.38kg; 95% CI -1.34kg to 0.58kg; p=0.44). CONCLUSION AND IMPLICATIONS: There is a paucity of randomised controlled trials of multi component weight management interventions for adults with intellectual disabilities and overweight/obesity. Current interventions, based on a health education approach are ineffective. Future long-term interventions that include an EDD and adhere to clinical recommendations on the management of obesity are warranted. PMID- 29107177 TI - Efficiency of the sulfate pathway in comparison to the Delta4- and Delta5-pathway of steroidogenesis in the porcine testis. AB - Sulfonated steroids are increasingly recognized as a circulating reservoir of precursors for the local production of active steroids in certain target tissues. As an alternative to sulfonation of unconjugated steroids by cytosolic sulfotransferases, their direct formation from sulfonated precursors has been described. However, productivity and physiological relevance of this sulfate pathway of steroidogenesis are still widely unclear. Applying the porcine testis as a model, conversion of pregnenolone sulfate (P5S, sulfate pathway) by CYP17A1 was assessed in comparison to the parallel conversions of pregnenolone (P5, Delta5-pathway) and progesterone (P4, Delta4-pathway). To characterize conversions in the virtual absence of competing enzyme activities, in a first series of experiments porcine recombinant CYP17A1 was incubated with the respective substrate in the presence of bovine recombinant cytochrome P450 oxidoreductase (CPR) and cytochrome b5 (b5). Moreover, porcine testicular microsomal fractions were used as a source of homologous CYP17A1, CPR and b5. Invariably 17alpha-hydroxylation of P5S was, if at all, only minimal and no formation of dehydroepiandrosterone sulfate from P5S was detectable. Consistent with earlier studies porcine CYP17A1 efficiently metabolized P4 and P5 in both assay systems. Metabolism of P4 and P5 by testicular microsomal protein varied substantially between the five animals tested. In conclusion, a physiologically relevant sulfate pathway for the production of C19-steroids from P5S via CYP17A1 is very unlikely in the porcine testis. PMID- 29107178 TI - 1,25-Dihydroxycholecalciferol (calcitriol) modifies uptake and release of 25 hydroxycholecalciferol in skeletal muscle cells in culture. AB - The major circulating metabolite of vitamin D3, 25-hydroxycholecalciferol [25(OH)D], has a remarkably long half-life in blood for a (seco)steroid. Data from our studies and others are consistent with the hypothesis that there is a role for skeletal muscle in the maintenance of vitamin D status. Muscle cells internalise vitamin D-binding protein (DBP) from the circulation by means of a megalin/cubilin plasma membrane transport mechanism. The internalised DBP molecules then bind to actin and thus provide an intracellular array of high affinity binding sites for its specific ligand, 25(OH)D. There is evidence that the residence time for DBP in muscle cells is short and that it undergoes proteolytic degradation, releasing bound 25(OH)D. The processes of internalisation of DBP and its intracellular residence time, bound to actin, appear to be regulated. To explore whether 1,25-dihydroxycholecalciferol (calcitriol) has any effect on this process, cell cultures of myotubes and primary skeletal muscle fibers were incubated in a medium containing 10-10M calcitriol but with no added DBP. After 3h pre-incubation with calcitriol, the net uptake of 25(OH)D by these calcitriol-treated cells over a further 4h was significantly greater than that in vehicle-treated control cells. This was accompanied by a significant increase in intracellular DBP protein. However, after 16h of pre-incubation with calcitriol, the muscle cells showed a significantly depressed ability to accumulate 25(OH)D compared to control cells over a further 4 or 16hours. These effects of pre-incubation with calcitriol were abolished in fibers from VDR-knockout mice. The effect was also abolished by the addition of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), which inhibits chloride channel opening. Incubation of C2 myotubes with calcitriol also significantly reduced retention of previously accumulated 25(OH)D after 4 or 8h. It is concluded from these in vitro studies that calcitriol can modify the DBP dependent uptake and release of 25(OH)D by skeletal muscle cells in a manner that suggests some inducible change in the function of these cells. PMID- 29107179 TI - Uptake and metabolism of water-borne progesterone by the mussel, Mytilus spp. (Mollusca). AB - Previous studies have shown that mussels can pick up 17beta-estradiol [E2] and testosterone [T] from water, metabolize them and conjugate them to fatty acids (esterification), leading to their accumulation in tissue. A key requirement for the esterification process is that a steroid must have a 'reactive' hydroxyl group to conjugate to a fatty acid (which in T, and probably E2, is the beta hydroxyl group on carbon 17). Progesterone (P) lacks any hydroxyl groups and theoretically cannot be esterified and hence should not accumulate in mussels in the same way as E2 or T. However, it is already known that mussels have an enzyme that can achieve 5alpha-reduction of the A ring of T and P and that there is also another reductase that can transform the 3-oxo group of the 5alpha-reduced A ring of T into a hydroxyl group. We hypothesized that, although intact P cannot be directly esterified, it might nevertheless be transformed into metabolites that can. To test this hypothesis, we investigated the rate and capacity of uptake, metabolism and potential depuration of tritiated P by the common mussel, Mytilus spp. We found that tritiated P was taken up from water at a similar rate to E2 and T (mean clearance rate 49mL-1 animal-1h-1) and that, as found with the other steroids, the rate of uptake could not be saturated by the addition of non radioactive steroid (even at 7.6MUgL-1). We found that up to 66% of the radioactivity that was taken up was present in the ester fraction, suggesting that hydroxylation of the P must indeed have occurred. We then definitively identified two metabolites in the ester fraction: 5alpha-pregnane-3beta,20beta diol and 3beta-hydroxy-5alpha-pregnan-20-one. These same two steroids were also present in the free steroid fraction. Intact P was not detected in either of the fractions. When undergoing depuration (under semi-static conditions), the radioactivity in the ester fractions remained at the same concentration in the animals for at least 10 days. Our findings suggest that the lack of reactive hydroxyl groups on P does not preclude it from being taken up, metabolized and subsequently stored. Many questions remain, not least of which is why, when P seems to be so rapidly metabolized, two previous studies on mussels have reported concentrations of up to 30ngg-1 wet weight of P in their flesh. PMID- 29107180 TI - Molecular pathways involved in the transport of nuclear receptors from the nucleus to cytoplasm. AB - Nuclear receptors (NRs) are transcription regulators that direct the expression of many genes linked to cellular processes, such as proliferation, differentiation, and apoptosis. Additionally, some cellular events are also modulated by signaling pathways induced by NRs outside of the nucleus. Hence, the subcellular transport of NRs is dynamic and is modulated by several signals, protein-protein interactions, and posttranslational modifications. Particularly, the exit of NRs from the nucleus to cytoplasm and/or other compartments is transcendental, as it is this export event, which determines their abundance in the cells' compartments, the activation or attenuation of nuclear or extranuclear pathways, and the magnitude and duration of their effects inside or outside of the nucleus. Consequently, an adequate control of the distribution of NRs is critical for homeostasis, because a deregulation in the nucleo-cytoplasmic transport of NRs could be involved in diseases including cancer as well as metabolic and vascular alterations. In this review, we investigated the pathways and molecular and biological aspects that have been described for the nuclear export of NRs so far and their functional relevance in some diseases. This information suggests that the transport of NRs out of the nucleus is a key mechanism for the identification of new therapeutic targets for alterations associated with the deregulation of the function of NRs. PMID- 29107181 TI - Antimony trichloride induces a loss of cell viability via reactive oxygen species dependent autophagy in A549 cells. AB - Antimony (Sb) is one of the most prevalent heavy metals and frequently leads to biological toxicity. Although autophagy is believed to be involved in metal associated cytotoxicity, there is no evidence of its involvement following exposure. Moreover, the underlying mechanism of autophagy remains unclear. In this study, treatment with antimony trichloride caused autophagy in a dose- and time-dependent manner in A549 cells but did not affect the level of Atg5 or Atg7 mRNA expression. Furthermore, Sb enhanced autophagic flux while upregulating p62 gene and protein levels. The classic mechanistic target of rapamycin (mTOR) pathway is not involved in Sb-induced autophagy. However, Sb-induced autophagy and the upregulation of p62 were inhibited by treatment with the antioxidant N acetylcysteine (NAC). Subsequent analyses demonstrated that the inhibition of autophagy protected A549 cells from a loss of cell viability, while the activation of autophagy by rapamycin had the opposite effect. These data suggest that reactive oxygen species-dependent autophagy mediates Sb-stimulated cell viability loss in A549 cells. PMID- 29107182 TI - Identification of the internal ribosome entry sites (IRES) of prion protein gene. AB - Many studies demonstrated that there are several type bands of prion protein in cells. However, the formation of different prion protein bands is elusive. After several low molecular weight bands of prion protein appeared in SMB-S15 cells infected with scrapie agent Chandler, we think that IRES-dependent translation mechanism induced by prion is involved in the formation of prion protein bands. Then we designed a series of pPrP-GFP fusing plasmids and bicistronic plasmids to identify the IRES sites of prion protein gene and found 3 IRES sites inside of PrP mRNA. We also demonstrated that cap-independent translation of PrP was associated with the ER stress through Tunicamycin treatment. We still found that only IRE1 and PERK pathway regulated the IRES-dependent translation of PrP in this study. Our results indicated, we found that PrP gene had an IRES-dependent translation initiation mechanism and we successfully identified the IRESs inside of the prion protein gene. PMID- 29107184 TI - Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by progressive cognitive decline and the presence of aggregates of amyloid beta (plaques) and hyperphosphorylated tau (tangles). Early diagnosis through neuropsychological testing is difficult due to comorbidity of symptoms between AD and other types of dementia. As a result, there is a need to identify the range of behavioral phenotypes expressed in AD. In the present study, we utilized a transgenic rat (TgF344-AD) model that bears the mutated amyloid precursor protein as well as presenilin-1 genes, resulting in progressive plaque and tangle pathogenesis throughout the cortex. We tested young adult male and female TgF344-AD rats in a spatial memory task in the Morris water maze and for anxiety-like behavior in the elevated plus-maze. Results indicated that regardless of sex, TgF344-AD rats exhibited increased anxiety-like behavior in the elevated plus-maze, which occurred without significant deficits in the spatial memory. Together, these results indicate that enhanced anxiety-like behavior represents an early-stage behavioral marker in the TgF344-AD rat model. PMID- 29107185 TI - Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. AB - This study was designed to test our hypothesis that an ultra-low dose of delta-9 tetrahydrocannabinol (THC) reverses age-dependent cognitive impairments in old mice and to examine the possible biological mechanisms that underlie this behavioral effect. Old female mice aged 24 months that had been injected once with 0.002 mg/kg THC (3-4 orders of magnitudes lower than doses that induce the conventional cannabinoid effects in mice) performed significantly better than vehicle-treated old mice and performed similarly to naive young mice aged 2 months, in 6 different behavioral assays that measured various aspects of memory and learning. The beneficial effect of THC lasted for at least 7 weeks. The single injection of THC increased the level of Sirtuin1, an enzyme that has been previously shown to be involved in neuroprotection and neuroplasticity, in the hippocampus and in the frontal cortex of old mice, for at least 7 weeks. Magnetic resonance imaging demonstrated a larger volume and higher tissue density in various regions of the brain of THC-treated old mice. These findings suggest that extremely low doses of THC that are devoid of any psychotropic effect and do not induce desensitization may provide a safe and effective treatment for cognitive decline in aging humans. PMID- 29107183 TI - Therapeutic targeting of PP2A. AB - Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A. Additional insight into the structural, molecular, and biological framework driving the efficacy of these therapeutic strategies will provide a foundation for the refinement and development of novel and clinically tractable PP2A targeted therapies. PMID- 29107186 TI - A bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of Alzheimer's disease. AB - Functioning at the interface between the nervous and immune systems, in the amyloid-depositing brain, astrocytes become hypertrophic and accumulate around senile plaques. Moreover, hippocampal astrocytes upregulate their gamma aminobutyric acid (GABA) content and enhance tonic inhibition, likely causing local circuit imbalance. It remains, however, unclear whether this effect is hippocampus specific and how it is regulated during disease progression. Here, we studied changes in astrocytic morphology and GABA content in the frontal cortex and dentate gyrus of control and amyloid-depositing mice. Healthy aging was accompanied by a transient increase in astrocytic GABA content at middle age and region-specific alterations of soma size. In contrast, amyloid deposition caused a gradual cortex-accentuated increase in soma size. Importantly, our data uncovered a bell-shaped relationship between the mouse age and astrocytic GABA content in both brain regions. Moreover, in mice carrying an Alzheimer's disease related mutation in presenilin 1, astrocytes accumulated GABA even in the absence of amyloidosis. These data question the proposed inhibition of astrocytic GABA synthesis as a universal strategy for treating network dysfunction in Alzheimer's disease. PMID- 29107187 TI - Generation of recombinant affinity reagents against a two-phosphosite epitope of ATF2. AB - Activating Transcription Factor 2 (ATF2) plays an important role in mammalian cell proliferation, apoptosis and DNA repair. Its activation is dependent on the sequential phosphorylation of residue threonine 71 (T71) followed by threonine 69 (T69) in its transactivation domain. While these modifications can be directed by a variety of kinases, the time to reach full phosphorylation is dependent on which signaling pathway has been activated, which is thought to be important for proper temporal regulation. To explore this phenomenon further, there have been ongoing efforts to generate affinity reagents for monitoring phosphorylation events in cellular assays. While phospho-specific antibodies have been valuable tools for monitoring cell signaling events, those raised against a peptide containing two or more adjacent phosphosites tend to cross-react with that peptide's various phospho-states, rendering such reagents unusable for studying sequential phosphorylation. As an alternative, we have employed the N-terminal Forkhead-associated 1 (FHA1) domain of yeast Rad53p as a scaffold to generate recombinant affinity reagents via phage display and were successful in generating a set of reagents that can distinguish between the dual-phosphorylated epitope, 63-IVADQpTPpTPTRFLK-77, and the mono-phosphorylated epitope, 63-IVADQpTPTPTRFLK 77, in the human ATF2 transactivation domain. PMID- 29107188 TI - The number of positive lymph node is a better predictor of survival than the lymph node metastasis status for pancreatic neuroendocrine neoplasms: A retrospective cohort study. AB - BACKGROUND: The recently released AJCC TNM staging system of pancreatic adenocarcinoma has endorsed the number of positive lymph node(NPLN) as the criterion of N staging. However, the prognostic role of NPLN is still unclear for pancreatic neuroendocrine neoplasms (pNENs). METHODS: Patients underwent resection and at least one lymph node examined were identified from the Surveillance, Epidemiology, and End Results database. The overall survival (OS) and disease specific survival (DSS) were estimated using Kaplan-Meier analysis and compared by log-rank test. The prognostic factors were determined by cox proportional regression model. RESULTS: Totally, 1,269 pNENs were included in the present study. The increasing NPLN (NPLN > 3) was corresponding significantly (P < 0.05) shorter OS and DSS in both entire cohort (OS: NPLN <= 3 vs. NPLN > 3, 93.624 +/- 1.765 months vs. 75.075 +/- 4.005 months; DSS: NPLN <= 3 vs. NPLN > 3, 104.829 +/- 1.455 months vs. 85.443 +/- 3.938 months, respectively) and cohort with the number of examined lymph node more than 11 (OS: NPLN <= 3 vs. NPLN > 3, 88.759 +/- 2.756 months vs. 73.664 +/- 4.700 months; DSS: NPLN <= 3 vs. NPLN > 3, 99.021 +/- 2.212 months vs. 85.139 +/- 4.686 months, respectively). Furthermore, the multivariate analysis showed the NPLN > 3 rather than lymph node status was the independent prognostic factors for OS and DSS in these two cohorts. CONCLUSIONS: The NPLN seems more meaningful than the lymph node metastasis status as prognostic factor for survival. Taking into account the prognostic value of NPLN for pNENs might improve the current TNM staging systems. However, prospective study is needed to demonstrate our findings. PMID- 29107189 TI - Localized reentrant atrial tachycardia with a very small circuit in very low voltage areas. PMID- 29107190 TI - Pulmonary vein isolation cryoablation for patients with persistent and long standing persistent atrial fibrillation: Clinical outcomes from the real-world multicenter observational project. AB - BACKGROUND: Pulmonary vein isolation (PVI) is a cornerstone ablation strategy in the management of patients with atrial fibrillation (AF). Consensus guidelines and statements recommend PVI during the index catheter ablation procedure in patients with paroxysmal and persistent AF. OBJECTIVE: The objective of this analysis was to evaluate patients with persistent and long-standing persistent AF who were treated with the cryoballoon ablation catheter by PVI technique. METHODS: Consecutive patients with drug-refractory symptomatic persistent and long-standing persistent AF who underwent cryoballoon catheter ablation by a PVI only procedure were prospectively included in this single-arm multicenter evaluation. Data on procedural characteristics, safety, and long-term freedom from AF recurrence were analyzed. RESULTS: Four hundred eighty-six subjects (mean age 60.8 +/- 9.3 years; 389 (80%) men; 434 (89.3%) with persistent AF; 52 (10.7%) with long-standing persistent AF; left atrial diameter 44.6 +/- 6.2 mm) underwent cryoballoon ablation in 35 Italian centers. The mean procedure time (skin-to skin) was 109.9 +/- 52.9 minutes, and the mean fluoroscopy time was 29.6 +/- 14.5 minutes. Periprocedural complications were observed in 21 subjects (4.3%), and the acute PVI success rate was 97.6% across all patients. Using a 90-day blanking period, the single procedure Kaplan-Meier estimates of AF event-free survival were 63.9% at 12 months and 51.5% at 18 months. CONCLUSION: In this multicenter evaluation of cryoballoon ablation, the PVI procedure was safe, effective, and efficient with regard to the treatment of patients with persistent and long standing persistent AF. The reasonable mid-term success rates agree with current clinical studies that establish PVI as a cornerstone index ablation strategy. PMID- 29107191 TI - Noninducibility of atrial fibrillation after catheter ablation: A nonissue? PMID- 29107192 TI - Renal function and risk of stroke and bleeding in patients undergoing catheter ablation for atrial fibrillation: Comparison between uninterrupted direct oral anticoagulants and warfarin administration. AB - BACKGROUND: The effect of uninterrupted oral anticoagulant use in patients with chronic kidney disease (CKD) during catheter ablation for atrial fibrillation (AF) is not fully understood. OBJECTIVE: The present study aimed to evaluate the safety and efficacy of periprocedural uninterrupted direct oral anticoagulant (DOAC) use compared with those of uninterrupted warfarin use in patients undergoing catheter ablation for AF stratified by various renal function groups. METHODS: A total of 2091 patients were retrospectively included in this study. The study population was divided into 4 groups: creatinine clearance level >=80 mL/min (n = 1086), 50-79 mL/min (n = 774), 15-49 mL/min (n = 209), and <15 mL/min (n = 22). We investigated periprocedural complications and compared them between uninterrupted DOAC and warfarin groups. RESULTS: There was no significant difference in thromboembolic events among the 4 groups (0.6%, 0.6%, 1.0%, and 0%, respectively; P = .792). However, major bleeding events (0.9%, 1.4%, 4.8%, and 4.5%; P < .001) and minor bleeding events (4.1%, 6.1%, 11.5%, and 13.6%; P < .001) primarily occurred in patients with CKD. The rate of periprocedural complications in the DOAC group was similar to that in the warfarin group for each renal function category. Adverse events did not differ after adjustment using propensity score-matched analysis. Multivariate analysis showed that lower body weight, antiplatelet drug use, initial ablation session, and CKD were independent predictors of adverse events. CONCLUSION: The periprocedural bleeding risk was increased in patients with CKD. Uninterrupted DOAC and warfarin administration during catheter ablation for AF in patients with CKD is feasible and effective. PMID- 29107193 TI - High load of hepatitis E viral RNA in pork livers but absence in pork muscle at French slaughterhouses. AB - Pork ham muscle can be contaminated with HEV via blood vessels during viremia and represents a possible source of human contamination via the consumption of dried ham. This study evaluated the prevalence of HEV RNA in pork ham muscles and pork livers at slaughterhouses. Serology was determined on the corresponding serum samples. The apparent individual seroprevalence rate in the 49 pig farms studied was 59% [55.5%-61.4%]. None of the 1134 ham muscles tested was positive for the presence of HEV. HEV prevalence in paired liver samples was 2.8% with a level of contamination of up to 1.46 108copies/g. Sequences of viral strains isolated from positive livers belonged to genotype 3 and subtypes 3c, 3e, 3f and 3j. Our results confirmed that raw pork liver food products are a source of risk for humans but they also showed that there is a limited risk of human infection by HEV through the consumption of ham muscle. PMID- 29107194 TI - Anti-aflatoxigenic effect of organic acids produced by Lactobacillus plantarum. AB - Lactic acid bacteria (LAB), which are commonly used in the production of fermented foods, have been gaining attention for their antifungal and antimycotoxin properties. In this work, the strain Lactobacillus plantarum UM55 was selected among other LAB for inhibiting the growth of Aspergillus flavus. Further, it is shown that cell-free supernatant (CFS) of this strain inhibits the production of aflatoxins (AFLs) by 91%. This inhibition was dependent on CFS pH, increased with increasing concentrations of CFS, and was independent of fungal growth, which was inhibited only by 32%. CFS was also effective in inhibiting the growth and AFLs production in A. parasiticus, A. arachidicola, A. nomius and A. minisclerotigenes. Further, L. plantarum UM55 CFS was analysed for the presence of organic acids and the main differences compared to controls were found in the levels of lactic acid, phenyllactic acid (PLA), hydroxyphenyllactic acid (OH PLA), and indole lactic acid (ILA). These compounds were individually tested against A. flavus, with all of the compounds showing an inhibiting effect on fungal growth and AFLs production. PLA showed the stronger effects, and the obtained IC90 for the inhibition of growth and AFLs was of 11.9 and 0.87mg/mL, respectively. AFLs IC90 for ILA, OH-PLA and lactic acid were of 1.47, 1.80, and 3.92mg/mL, respectively. The antiaflatoxigenic properties of LAB depend on strain's capability to produce lactic acid, PLA, OH-PLA and ILA. PMID- 29107195 TI - Application of whole genome sequence data in analyzing the molecular epidemiology of Shiga toxin-producing Escherichia coli O157:H7/H. AB - Seventeen clusters of Shiga toxin-producing Escherichia coli O157:H7/- (O157) strains, determined by cluster analysis of pulsed-field gel electrophoresis patterns, were analyzed using whole genome sequence (WGS) data to investigate this pathogen's molecular epidemiology. The 17 clusters included 136 strains containing strains from nine outbreaks, with each outbreak caused by a single source contaminated with the organism, as shown by epidemiological contact surveys. WGS data of these strains were used to identify single nucleotide polymorphisms (SNPs) by two methods: short read data were directly mapped to a reference genome (mapping derived SNPs) and common SNPs between the mapping derived SNPs and SNPs in assembled data of short read data (common SNPs). Among both SNPs, those that were detected in genes with a gap were excluded to remove ambiguous SNPs from further analysis. The effectiveness of both SNPs was investigated among all the concatenated SNPs that were detected (whole SNP set); SNPs were divided into three categories based on the genes in which they were located (i.e., backbone SNP set, O-island SNP set, and mobile element SNP set); and SNPs in non-coding regions (intergenic region SNP set). When SNPs from strains isolated from the nine single source derived outbreaks were analyzed using an unweighted pair group method with arithmetic mean tree (UPGMA) and a minimum spanning tree (MST), the maximum pair-wise distances of the backbone SNP set of the mapping derived SNPs were significantly smaller than those of the whole and intergenic region SNP set on both UPGMAs and MSTs. This significant difference was also observed when the backbone SNP set of the common SNPs were examined (Steel-Dwass test, P<=0.01). When the maximum pair-wise distances were compared between the mapping derived and common SNPs, significant differences were observed in those of the whole, mobile element, and intergenic region SNP set (Wilcoxon signed rank test, P<=0.01). When all the strains included in one complex on an MST or one cluster on a UPGMA were designated as the same genotype, the values of the Hunter-Gaston Discriminatory Power Index for the backbone SNP set of the mapping derived and common SNPs were higher than those of other SNP sets. In contrast, the mobile element SNP set could not robustly subdivide lineage I strains of tested O157 strains using both the mapping derived and common SNPs. These results suggested that the backbone SNP set were the most effective for analysis of WGS data for O157 in enabling an appropriation of its molecular epidemiology. PMID- 29107196 TI - High prevalence of the IGF2 rs680 GG polymorphism among top-level sprinters and jumpers. AB - : Previous studies have shown that the IGF1 polymorphism is associated with greater muscle mass and improved power athletic ability, but very little is known about the IGF2 polymorphism and athletic performance. PURPOSE: The aim of the present study was to assess the frequency distribution of the IGF2 rs680 polymorphism among Israeli athletes. METHODS: 185 short- (n=72) and long-distance (n=113) runners, 94 short- (n=44) and long-distance (n=50) swimmers, 54 weight lifters and 111 controls participated in the study. Genomic DNA was extracted from peripheral EDTA treated anti-coagulated blood using a standard protocol. Genotyping of the IGF2 A/G polymorphism (rs680) was performed using allelic discrimination assay. RESULTS: The frequency of IGF2 (rs680) G allele carriers was significantly greater among top compared to national-level track and field sprinters and jumpers (p<0.05). The IGF2 (rs680) GG genotype frequency was significantly greater among track and field sprinters and jumpers compared to weight lifters p<0.02), and among top-level sprinters and jumpers compared to top level weight lifters p<0.01). There were no statistically significant differences in the IGF2 (rs680) GG genotype frequency among endurance athletes and between the swimmers and the other sports disciplines and the controls. CONCLUSIONS: While a single polymorphism cannot determine athletic success or failure, the findings of the present study suggest a potential importance of the IGF2 polymorphism, mainly regarding speed sport performance. PMID- 29107197 TI - The adaptation and translation of the PEACHTM RCT intervention: the process and outcomes of the PEACHTM in the community trial. AB - OBJECTIVE: To describe the process and report selected outcomes of translating an effective child weight management initiative (PEACHTM) from a randomised controlled trial intervention to a community health programme. STUDY DESIGN AND METHODS: Pre-post study design utilising the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) evaluation framework. Adaptation of PEACHTM required significant promotional activity and consideration of legal, ethical and financial issues. PEACHTM components were revised and an evaluation design based on the RE-AIM framework was developed. Facilitator training workshops were made available to South Australian health or education professionals initially, then opened up to new graduates, interstate dietitians and others interested in professional development. Facilitators completed pretraining and post-training questionnaires and a third questionnaire following programme delivery. Data were collected from families by facilitators and returned to university staff for assessment of change (baseline to programme end) in body mass index (BMI) and waist circumference (WC) z-scores. RESULTS: Changes to organisational and political environments prevented maximum programme reach and adoption. Nonetheless, data indicated that PEACHTM was effective at improving facilitators' confidence (P < 0.05) and children's (n = 37) BMI z-score (-0.17, 95% confidence interval [CI]: 0.03:0.30, P = 0.016), WC z-score (-0.14, 95% CI: 0.02:0.30, P = 0.09) and lifestyle behaviours. Collection of maintenance data was prevented due to time and financial constraints. CONCLUSIONS: Translational research needs to develop ways to effectively and efficiently bridge the gap between behavioural research and practice to improve the adoption of evidence based approaches to child weight management. Nutrition educators and researchers can drive these nutrition-focussed translational research efforts forward. Funding bodies and health service organisations are encouraged to provide financial and structural support for such activity. PMID- 29107198 TI - The effect of e-cigarette indoor vaping restrictions on adult prenatal smoking and birth outcomes. AB - We estimate the effect of county-level e-cigarette indoor vaping restrictions on adult prenatal smoking and birth outcomes using United States birth record data for 7 million pregnant women living in places already comprehensively banning the indoor use of traditional cigarettes. We use both cross-sectional and panel data to estimate our difference-in-difference models. Our panel model results suggest that adoption of a comprehensive indoor vaping restriction increased prenatal smoking by 2.0 percentage points, which is double the estimate obtained from a cross-sectional model. We also document heterogeneity in effect sizes along lines of age, education, and type of insurance. PMID- 29107199 TI - Kindling epileptogenesis and panic-like behavior: Their bidirectional connection and contribution to epilepsy-associated depression. AB - Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA+DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA+DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and the precipitation of depressive-like state by the epilepsy-PLB comorbidity. PMID- 29107200 TI - The association of psychosocial variables with adherence to antiepileptic drugs in patients with temporal lobe epilepsy. AB - OBJECTIVE: The aim of this study was to explore the association between psychosocial factors and adherence to antiepileptic drugs (AEDs) in patients with temporal lobe epilepsy (TLE). METHODS: This cross-sectional study was conducted with 123 individuals with TLE, admitted to our epilepsy center from December 2015 to May 2017. The participants completed standardized self-report questionnaires measuring medication adherence, anxiety, depression, and family and social support. Adherence was measured by the 8-item Morisky Medication Adherence Scale (MMAS), and logistic regression was used to examine statistically significant associations of different variables with adherence. RESULTS: We found a 33.3% rate of poor AED adherence. Moderate-to-severe anxiety (odds ratio (OR)=2.851, 95% confidence interval (CI)=1.138-7.144, P=0.025) and the presence of hippocampal sclerosis (OR=3.098, 95% CI=1.259-7.620, P=0.014) were positively associated with poor adherence to antiepileptic drugs. Social support (OR=0.925, 95% CI=0.863-0.990, P=0.025) was negatively associated with poor adherence. Neither depression nor family support was associated with adherence. CONCLUSION: One-third of patients with TLE were prone to poor AED adherence, especially individuals with hippocampal sclerosis. Intervention approaches designed to improve AED adherence in patients with TLE should focus on psychosocial factors. PMID- 29107201 TI - Alexithymia and problematic alcohol use: A critical update. AB - There has been a substantial growth in empirical research aimed at examining the co-occurrence of alexithymia and problematic alcohol use and alcohol use disorder (AUD) since Thorberg, Young, Sullivan, and Lyvers (2009) original review article. The objective of the present paper is therefore to provide a critical update review of research on alexithymia and problematic alcohol use published since 2009. A systematic search was conducted through PsychINFO, Medline, and ProQuest databases to obtain relevant literature published between 2009 and 2016. Studies that involved measures of alexithymia and problematic alcohol use among clinical and non-clinical samples were included. Prevalence rates of alexithymia among Alcohol Dependent (AD) samples were identified between 30 and 49%, and were therefore much lower than originally reported. The findings of this update review highlight an indirect relationship between alexithymia and alcohol problem severity that is mediated by a number of psychological drinking constructs (e.g., alcohol expectancy, drinking motives, craving and alcohol related intrusive thoughts) and psychological risk factors for the development of alcohol related problems (e.g., mood and emotion dysregulation, attachment, trauma, and cognitive function). In addition, this review provides reasonable evidence to support alexithymia as an independent risk factor for alcohol related problems among clinical samples only. In conclusion, alexithymia is a multifaceted construct that has a complex relationship with various risk factors and psychological drinking constructs. The growing body of research highlights the demand for understanding the interrelationships between alexithymia, psychosocial risk factors, and problematic alcohol use in order to tailor and target therapeutic interventions. PMID- 29107202 TI - Defining the phenotype of young adults with family histories of alcohol and other substance use disorders: Studies from the family health patterns project. AB - Individuals with a family history of alcohol and other drug use disorders (FH+) are at increased risk for developing substance use disorders themselves relative to those with no such histories (FH-). Here we sought to identify key characteristics associated with FH+ status and alcohol and other drug use disorder status in a large cohort of FH+ and FH- young adults. We conducted principal component analyses on demographic, temperament, and cognitive measures differentiating 506 FH+ and 528 FH- young adults. Three principal components were identified, and these component scores were then used to predict the odds of being FH+ and the odds of having an alcohol or other drug use disorder. Component 1 consisted of measures indexing internalizing traits, with higher component scores indicating greater depressive, anxious, and emotional instability tendencies. Component 2 consisted of measures of externalizing traits as well as exposure to early life adversity (ELA), with higher scores indicating less impulse control, more antisocial behavior, and greater ELA exposure. Component 3 consisted of estimated intelligence, delay discounting, and demographic characteristics, with higher scores indicating lower estimated intelligence, greater discounting of delayed rewards, less education, and lower childhood socioeconomic status. For each 1-point increase in the Component 1, 2, and 3 scores, the odds of being classified FH+ increased by 2%, 8%, and 4%, respectively. Similar findings were observed when individuals with alcohol or other drug use disorders were removed from the analyses. Finally, greater Component 2 scores were also associated with increased odds of having an alcohol or other drug use disorder. Collectively, these findings provide a more comprehensive understanding of the FH+ phenotype in young adults and help form a basis for further studies on biological mechanisms underlying risk for substance use disorders. The present findings also provide further support for a prominent role of ELA in promoting risk for problem alcohol and other drug use. PMID- 29107203 TI - The impact of the legalization of recreational marijuana on college students. AB - In January of 2014 the Regulate Marijuana like Alcohol Act or, Amendment 64, went into effect in Colorado. Even though it was the first state to enact recreational legalization, attitudes towards marijuana use have been changing for decades. Prompted by medical marijuana legalization, studies have found mixed results in regards to the impact that legalization has on frequency of use and abuse. With college students having the highest rates of use in the United States (U.S.), whether legal or not, it was important to explore the impact that legalization has on this population. In the current study, rates of marijuana and alcohol use in college students before and after recreational legalization were explored. Data was collected in four waves from October 2013 to March 2015, to be able to determine the trends in marijuana and alcohol use, and relationship between the substances. In addition, grade point average was measured as a possible consequence of marijuana use. We found the frequency of marijuana use in Colorado college students is much higher than the national average t(94445)=24.424, p<0.001, especially the percentage of daily or almost daily users, t(2191)=10.373, p<0.001. There were significant differences between the marijuana non-users and the once a week or more often but not daily marijuana users in grade point average, F(6, 227)=2.935, p<0.001. In addition, it seems that the relationship between alcohol and marijuana use in general is decreasing since the passing of Amendment 64, but not among the binge drinkers. PMID- 29107204 TI - Laser photobiomodulation of pro-inflammatory mediators on Walker Tumor 256 induced rats. AB - : Laser photobiomodulation or low-level laser therapy (LLLT) is recognized worldwide for its expansive use in medicine. LLLT has been reported to increase enzymatic activity, increasing the mitochondrial transmembrane potential, leading to an increased energy availability and signal transduction. Nevertheless, an inhibitory effect is also observed by the production of excessive ROS which can result the shutdown of mitochondrial energy production, and finally to apoptosis. However, the mechanism of apoptosis induced by LLLT is still not well understood. The main objective of the present study was to investigate the hypothesis that LLLT induces oxidative stress and stimulates the generation of pro-inflammatory markers interfering in tumor progression. METHODS: Seventy-two female Walker Tumor induced Wistar rats (eight weeks of age, 200g body weight) were used for this study. TW-256 cells were suspended in phosphate buffered saline and then subcutaneously inoculated at 1*107viabletumorcells/ml per rat into the right flank (tumor-bearing rats). After a period of 14days in order to assess the development of the solid tumor mass, the animals were randomized and distributed in four groups (n=8 animals/group): (1) Control or irradiated by LLLT (2) Laser 1J - 35,7J/cm2, (3) Laser 3J - 107,14J/cm2 and (4) Laser 6J - 214,28J/cm2; (Thera Laser - 660nm, 100mW DMC(r), Sao Carlos, Brazil) at four equidistant points according to their respective treatment groups, conducted three times on alternate days. The regulation and expression of inflammatory mediators IL-1beta, IL-6, IL-10, TNF-alpha was assessed by ELISA and gene expression of COX-1, COX-2, iNOS, eNOS was analyzed by RT-PCR. RESULTS: We found that the 1Joule (J) treated group promoted a significant increase in the levels of different inflammatory markers IL-1beta, the gene expression of COX-2, iNOS, which was statistically different (p<0.05) when compared among different treatment and control groups. With Respect IL-6, IL-10, TNF-alpha levels statistically significant reduce was observed in 1Joule treated group when comparing to different energies groups and control group. CONCLUSION: Our results suggest the evidence 1J-35,7J/cm2 treatment was able to produce cytotoxic effects by generation of ROS causing acute inflammation and thus may be employed as the best energy dose associated with Photodynamic Therapy. PMID- 29107205 TI - Photodynamic damage predominates on different targets depending on cell growth phase of Candida albicans. AB - Photodynamic inactivation (PDI) has been reported to be effective to eradicate a wide variety of pathogens, including antimicrobial-resistant microorganisms. The aim of this study was to identify the potential molecular targets of PDI depending on growth phase of Candida albicans. Fungal cells in lag (6h) and stationary (48h) phases were submitted to PDI mediated by methylene blue (MB) combined with a (662+/-21) nm-LED, at 360mW of optical power. Pre-irradiation time was 10min and exposure times were 12min, 15min and 18min delivering radiant exposures of 129.6J/cm2, 162J/cm2 and 194.4J/cm2, respectively, on a 24-well plate of about 2cm2 at an irradiance of 180mW/cm2. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force spectroscopy (AFS) and Fourier transform infrared spectroscopy (FT-IR) were employed to evaluate the photodynamic effect in young and old fungal cells following 15min of irradiation. Morphological analysis revealed wrinkled and shrunk fungal cell membrane for both growth phases while extracellular polymeric substance (EPS) removal was only observed for old fungal cells. Damaged intracellular structures were more pronounced in young fungal cells. The surface nanostiffness of young fungal cells decreased after PDI but increased for old fungal cells. Cellular adhesion force was reduced for both growth phases. Fungal cells in lag phase predominantly showed degradation of nucleic acids and proteins, while fungal cells in stationary phase showed more pronounced degradation of polysaccharides and lipids. Taken together, our results indicate different molecular targets for fungal cells in lag and stationary growth phase following PDI. PMID- 29107206 TI - Efficient antibacterial nanosponges based on ZnO nanoparticles and doxycycline. AB - Bacterial soft rot is responsible for the loss of about 25% of worldwide production in vegetables and fruits. Efforts have been made to develop an effective nanosponge with the capacity to load and release antibacterial drugs to protect plants. Based on the potential of the ZnO nanoparticles (ZnO-NPs) to achieve this goal, this study synthesized NP via the sol-gel and hydrothermal methods by controlling native defects, such as oxygen vacancies, using thermal treatments and reduced atmospheres. To characterize the ZnO NPs, X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscopy (TEM), optical spectroscopy, electron paramagnetic resonance (EPR), Zeta Potential measurements and surface area with the Brunauer-Emmett-Teller (BET) method were used. The photophysical and photochemical properties via spin trapping method aligned with EPR using UVA light showed a greater formation of electron-hole pairs and hydroxyl radicals for the reduced ZnO NPs when compared with the oxidized ones. Additionally, we found that reduced ZnO-NPs have high effectively against Escherichia coli, Erwinia carotovora and Pantoea sp. bacteria using the photocatalytic effect in the UV range. Moreover, ZnO-NPs loaded with DOX release profile enables the release of DOX within 46days, where 25% was released during the first 10h followed by a second delivery phase with an interesting short-term efficacy (<1day) against E. carotovora and Pantoea sp. Bacteria. For the first time, it was demonstrated that ZnO-NPs and ZnO-NPs loaded with DOX have efficient UV photocatalytic activities against bacterial soft rot infections. PMID- 29107207 TI - Association of serum gamma-glutamyltransferase and C-reactive proteins with neuromyelitis optica and multiple sclerosis. AB - BACKGROUND: Many studies have demonstrated that serum gamma glutamyltransferase (GGT) within normal range might be an early marker of oxidative stress. However the role of GGT in neuromyelitis optica (NMO) and multiple sclerosis (MS) is unknown. METHODS: We assessed the correlations among GGT and C-reactive protein (CRP) levels, as well as clinical characteristics of NMO and MS. Serum GGT and CRP levels were measured in 106 NMO patients, 87 MS patients, 79 patients with non-inflammatory neurological diseases (Parkinson disease) and 80 healthy controls (HC). Clinical parameters, blood-brain barrier (BBB) index and Delpech index of MS and NMO were also investigated. RESULTS: We found that NMO patients had higher serum GGT and CRP levels within their normal ranges compared to MS, PD, healthy controls. NMO patients exhibited significantly higher EDSS scores than MS patients. The BBB index in NMO patients was significantly higher than that in MS patients. Significant correlations existed between serum GGT and CRP levels and EDSS scores, BBB index in NMO and MS patients. CONCLUSION: Elevated GGT and CRP levels within their normal ranges in NMO and MS may be associated with inflammatory response, oxidative stress and BBB disturbance in the diseases. Further study into the underlying pathophysiology of this relationship is warranted. PMID- 29107208 TI - Enzyme function and its evolution. AB - With rapid increases over recent years in the determination of protein sequence and structure, alongside knowledge of thousands of enzyme functions and hundreds of chemical mechanisms, it is now possible to combine breadth and depth in our understanding of enzyme evolution. Phylogenetics continues to move forward, though determining correct evolutionary family trees is not trivial. Protein function prediction has spawned a variety of promising methods that offer the prospect of identifying enzymes across the whole range of chemical functions and over numerous species. This knowledge is essential to understand antibiotic resistance, as well as in protein re-engineering and de novo enzyme design. PMID- 29107209 TI - PhKv a toxin isolated from the spider venom induces antinociception by inhibition of cholinesterase activating cholinergic system. AB - BACKGROUND AND AIMS: Cholinergic agents cause antinociception by mimicking the release of acetylcholine (ACh) from spinal cholinergic nerves. PhKv is a peptide isolated from the venom of the armed spider Phoneutria nigriventer. It has an antiarrythmogenic activity that involves the enhanced release of acetylcholine. The aim of this study was to investigate whether PhKv had an antinociceptive action in mice. METHODS: Male albino Swiss mice (25-35g) were used in this study. The PhKv toxin was purified from a PhTx3 fraction of the Phoneutria nigriventer spider's venom. Because of its peptide nature, PhKv is not orally available and it was delivered directly into the central nervous system by an intrathecal (i.t.) route. PhKV on the thermal and mechanical sensitivity was evaluated using plantar test apparatus and the up-and-down method. The analgesic effects of PhKv were studied in neuropathic pain (CCI) and in the peripheral capsicin test. In order to test whether PhKv interfered with the cholinergic system, the mice were pre-treated with atropine (5mg/kg, i.p.) or mecamylamine (0.001mg/kg, i.p.) and the PhKv toxin (30pmol/site i.t.) or neostigmine (100pmol/site) were applied 15min before the intraplantar capsaicin (1nmol/paw) administrations. To investigate PhKv action on the AChE activities, was performed in vitro and ex vivo assay for AChE. For the in vitro experiments, mice spinal cord supernatants of tissue homogenates (1mg/ml) were used as source of AChE activity. The AChE assay was monitored at 37 degrees C for 10min in a FlexStation 3 Multi-Mode Microplate Reader (Molecular Devices) at 405nm. RESULTS: PhKv (30 and 100pmol/site, i.t.) had no effect on the thermal or mechanical sensitivity thresholds. However, in a chronic constriction injury model of pain, PhKv (10pmol/site, i.t.) caused a robust reduction in mechanical withdrawal with an antinociceptive effect that lasted 4h. A pretreatment in mice with PhKv (30pmol/site, i.t.) or neostigmine (100pmol/site, i.t.) 15min before an intraplantar injection of capsaicin (1nmol/paw) caused a maximal antinociceptive effect of 69.5+/-4.9% and 85+/-2.5%, respectively. A pretreatment in mice with atropine; 5mg/kg, i.p. or mecamylamine 0.001mg/kg, i.p. inhibited a neostigimine and PhKv-induced antinociception, suggesting a cholinergic mechanism. Spinal acetylcholinesterase was inhibited by PhKv with ED50 of 7.6 (4.6-12.6pmol/site, i.t.). PhKv also inhibited the in vitro AChE activity of spinal cord homogenates with an EC50 of 20.8 (11.6-37.3nM), shifting the Km value from 0.06mM to 18.5mM, characterizing a competitive inhibition of AChE activity by PhKv. CONCLUSIONS: Our findings provide, to our knowledge, the first evidence that PhKv caused inhibition of AChE, it increased the ACh content at the neuronal synapses, leading to an activation of the cholinergic system and an antinociceptive response. IMPLICATIONS: Studies regarding the nociceptive mechanisms and the identification of potential targets for the treatment of pain have become top priorities. PhKv, by its action of stimulating the cholinergic receptors muscarinic and nicotinic system, reduces pain it may be an alternative for controlling the pain processes. PMID- 29107210 TI - Biological and cognitive correlates of cortical curvature in schizophrenia. AB - Mean cortical curvature may relate to cortico-cortical connections integrity. We explored the association between prefrontal (PFC) cortical curvature and fractional anisotropy (FA) values for tracts connecting PFC and relevant cortical regions. In schizophrenia Anatomical and diffusion magnetic resonance images were obtained from 34 patients (16 of them first-episodes) and 32 healthy controls. We calculated curvature at rostral lateral prefrontal (RLPF) and superior medial prefrontal (SMPF) areas and mean FA for the tracts respectively connecting RLPF and SMPF areas with anterior caudal cingulate (ACC), superior temporal gyrus (STG) and superior parietal SP regions. Cognitive and clinical data were collected, including baseline symptoms, Clinical Global Impression change scores from baseline to follow-up, illness duration and treatment dosage. Patients showed significantly lower FA values in the tracts linking right RLPF-ACC, right SMPF-SPG and bilaterally PFC-STG. FA values in short-range cortico-cortical connections (linking PFC and ACC) were inversely associated with PFC curvature. In patients, cognitive performance was negatively associated with PFC curvature. Larger curvature values were associated to lack of clinical improvement at follow up. We conclude that cortical curvature is influenced by integrity in short-range cortico-cortical connections and relates to cognition and clinical outcome in schizophrenia patients. PMID- 29107211 TI - Cyclothymic temperament and glucose metabolism in the right superior parietal lobule. AB - Cyclothymic temperament possesses a central dimension that includes rapid fluctuations in mood and emotional instability, and it is regarded as a prodromal state of bipolar disorder. The aim of the present study is to explore the neural correlates of cyclothymic temperament. We used the data of 55 healthy participants in our previous study and analyzed the association between cyclothymic temperament scores rated by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A) and the uptake of [18F]-FDG measured by positron emission tomography (PET). A whole brain analysis revealed a cluster of [18F]-FDG uptake significantly and positively associated with cyclothymic temperament scores, located in the right superior parietal lobule (SPL). Even after adjustment for relevant factors, there remained a significant cluster of [18F]-FDG uptake with cyclothymic temperament scores in the right SPL. In ROI analyses, there were similar significant peaks in the right SPL in association with cyclothymic temperament scores. These findings suggest that the right superior parietal lobule may be one of the neural correlates of cyclothymic temperament. PMID- 29107212 TI - Distance-dependent alterations in local functional connectivity in drug-naive major depressive disorder. AB - Previous studies using resting-state functional magnetic resonance imaging (fMRI) have found abnormal functional connectivity in patients with major depressive disorder (MDD). Yet, effect of distance thresholds on local functional connectivity changes in MDD is largely unknown. Here, we used resting-state fMRI data and functional connectivity strength (FCS) method to test local functional connectivity differences at different distance thresholds between 47 drug-naive patients with MDD and 47 healthy controls. For the distribution of functional brain hubs with high local FCS, the overall changing trend from distance thresholds of 10mm to 100mm was from lateral to medial. Compared to controls, MDD patients exhibited decreased local FCS independent of distance threshold in the sensorimotor system (postcentral gyrus, paracentral lobule, and supplementary motor area). MDD Patients exhibited increased local FCS in the inferior temporal gyrus at two lower distance thresholds (20mm and 30mm) and a higher distance threshold (100mm). In addition, MDD patients showed increased local FCS in the putamen at higher distance thresholds (80-100mm). These findings suggest that local functional connectivity abnormalities in MDD are dependent on distance thresholds and that future studies should take the distance thresholds into account when measuring local functional connectivity in MDD. PMID- 29107213 TI - Current and future treatment options for pemphigus: Is it time to move towards more effective treatments? AB - Systemic administration of corticosteroid (CS) remains the standard gold treatment for pemphigus. However, because of several long-term adverse effects, steroid-sparing agents are usually prescribed in combination with CSs. Despite the high number of available studies, the choice of best drugs to treat pemphigus remains controversial. Therapeutic approaches for pemphigus can be divided into traditional treatment and emerging ones. Personalized medicine, which aims to increase the efficacy as well as reduce adverse effects of treatments, could be considered as the future option. Here, the most common agents, including azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclophosphamide (CP), rituximab (RTX) and intravenous immunoglobulin (IVIg) have been discussed in detail and compared. Besides, the efficacy and safety profiles of the less frequently used agents such as cyclosporine, dapsone, mizoribine, chlorambucil, plasmapheresis, immunoadsorption and hematopoietic stem cell transplantation have been evaluated. Moreover, some emerging therapeutic options for pemphigus patients, such as B cell activating factor (BAFF), proliferation inducing ligand (APRIL) inhibitors, anti-cytokine therapy, co-stimulatory and co inhibitors manipulators and inhibitors of pathogenic signaling pathways (e.g., p38MAPK, c-Myc and EGFR) have been described. In addition to the conventional approaches, some clues to moving towards personalized medicine for the treatment of pemphigus have been proposed. According to the last evidence, seven available first-line combination therapies, including RTX+IVIg, CS+RTX, CS+MMF, CS+AZA, CS+MTX, CS+CP and CS+IVIg were suggested and compared. Subsequently, the most optimum drugs for three different conditions, including patients with no pregnancy or infection, those at high risk of development/reactivation of infection or pregnant women were suggested. PMID- 29107214 TI - Tim-3 enhances brain inflammation by promoting M1 macrophage polarization following intracerebral hemorrhage in mice. AB - Macrophage polarization contributes to brain inflammation following spontaneous intracerebral hemorrhage (ICH). T cell immunoglobulin and mucin domain-3 (Tim-3) has been identified to induce macrophage mediated inflammation following ICH. However, the regulation of Tim-3 on macrophage polarization following ICH has not been fully studied. In current experiment, we explored Tim-3 expression, macrophage polarization, brain water content and neurological function in WT and Tim-3-/- ICH mice. In addition, downstream transcriptional factor TRIF and IRF3 were also analyzed. We found that ICH promoted Tim-3 expression and M1 polarization in the perihematomal region of WT mice, leading to increased brain water content and neurological impairment. However, deletion of Tim-3 expression attenuated M1 polarization, decreased rain water content and improved neurological function of ICH mice. Furthermore, Tim-3 signal promoted transcriptional factors TRIF and IRF3 levels, regulating macrophage polarization. The data suggested that Tim-3 played a crucial role in the macrophage polarization and brain inflammation following ICH, and might represent a promising way in ICH therapy. PMID- 29107215 TI - Oxymatrine protects against DSS-induced colitis via inhibiting the PI3K/AKT signaling pathway. AB - Oxymatrine (OMT), an alkaloid derived from the root of the Sophora flavescens, has been reported to possess a significant effect on relieving UC owing to its anti-inflammatory property. But the other therapeutic mechanism of OMT remains unclear. Recent studies have found, PI3K/AKT signaling pathway is involved in the pathogenesis of UC by pro-inflammatory effects and activating T cells. Moreover, PI3K/AKT pathway is one of the most important pathways for regulating cell apoptosis. Thus, we aim to explore whether OMT protects against UC by targeting PI3K/AKT pathway. We established the UC mice models, using LY294002 (a specific inhibitor of PI3K/AKT) as a positive control, to observe the effect of low, medium and high dose of OMT on UC and its influence on PI3K/AKT signaling pathway. Our data indicated that OMT can significantly ameliorate UC through anti inflammatory, pro-apoptotic, down-regulating the differentiation of Th1 and Th17 cells via PI3K/AKT pathway. This study reveals that PI3K/AKT signaling pathway is a potential mechanism of OMT-induced UC remission and suggests that OMT is a promising therapeutic agent for the treatment of UC. PMID- 29107216 TI - Pharmacological effects and potential therapeutic targets of DT-13. AB - DT-13 is an isolated compound from Dwarf lillytruf tuber and currently among active research drugs by National Natural Science foundation of China for its several potential effects. The drug has been reported for its multiple pharmacological actions however no thorough review studies are available on it. Our present study is highlighting the pros and cons of DT-13 focusing on its potential pharmacological actions, therapeutic utilization and further exploration for novel targets. The drug possesses very low toxicity profile, quick onset and long duration of action with slow elimination that combinely makes it favorable for the clinical studies. In vivo and in vitro studies show that the drug regulates multiple cellular functions for its several pharmacological effects including, anti-adhesive effects via regulation of tissue factor and transforming growth factor; anti-migratory effects through indirect regulation of NM-IIA in the tumor microenvironment, Tissue factor, down regulation of CCR5-CCL5 axis and MMP-2/9 inhibition; anti-metastatic effects via regulation of MMPs and tissue factor; pro-apoptotic effects by modulation of endocytosis of EGF receptor; anti-angiogenic effects via regulation of HIF 1alpha,ERK, Akt signalling and autophagy inducing characteristics by regulating PI3K/Akt/mTOR signalling pathway. In addition to anti-tumor activities, DT-13 has significant anti-inflammatory, cardioprotective, hepatoprotective and immunomodulating effects. Pharmaceutical dosage form and targeted drug delivery system for DT-13 has not been established yet. Moreover, DT-13, has not been studied for its action on brain, colorectal, hepatic, pancreatic, prostate and blood cancers. Similarly the effects of drug on carbohydrate and glucose metabolism is another niche yet to be explored. In some traditional therapies, crude drug from the plant is used against diabetic and neurological disorders that are not reported in scientific literature, however due to profound effects of DT-13 on blood and cerebral ischemic disorders, it is reasonable to hypothesize that there could be an association of DT-13 that require further exploration. PMID- 29107217 TI - Ultrasensitive MRI detection of spontaneous pancreatic tumors with nanocage-based targeted contrast agent. AB - Contrast agents with greater specificity and sensitivity are required for the diagnosis of pancreatic cancers by magnetic resonance imaging (MRI). In this study, small heat shock protein 16.5 (Hsp16.5)-based nanocages conjugated to gadolinium(III)-chelated contrast agents and iRGD peptides (which target neuropilin-1 expressed on pancreatic cancer cells) were developed. To investigate whether template size influences relaxivity, nanocages with one to four hydrophobic domains were designed. MRI data showed that larger nanocages had higher T1 relaxivity than smaller nanocages, which resulted from a reduction in molecular tumbling rates caused by an increase in nanocage size, and a robust cage structure resulting from the introduction of hydrophobic domains. For in vivo MRI studies, the engineered nanocages were evaluated using the KrasG12D; Trp53R172H; Pdx-1Cre (KPC) transgenic mouse models, which develop clinically relevant pancreatic tumor under normal processes of angiogenesis, immune function and inflammation. Molecular MRI with protein nanocages was enabled to detect neuropilin-1-positive cells and to produce strong signal enhancement of spontaneous pancreatic tumors in KPC genetically engineered mouse models. Novel iRGD-modified nanocages displayed potential as a specific and sensitive MRI contrast agent for the diagnosis of pancreatic tumors for clinical translation. PMID- 29107218 TI - Dual-targeting Wnt and uPA receptors using peptide conjugated ultra-small nanoparticle drug carriers inhibited cancer stem-cell phenotype in chemo resistant breast cancer. AB - Heterogeneous tumor cells, high incidence of tumor recurrence, and decrease in overall survival are the major challenges for the treatment of chemo-resistant breast cancer. Results of our study showed differential chemotherapeutic responses among breast cancer patient derived xenograft (PDX) tumors established from the same patients. All doxorubicin (Dox)-resistant tumors expressed higher levels of cancer stem-like cell biomarkers, including CD44, Wnt and its receptor LRP5/6, relative to Dox-sensitive tumors. To effectively treat resistant tumors, we developed an ultra-small magnetic iron oxide nanoparticle (IONP) drug carrier conjugated with peptides that are dually targeted to Wnt/LRP5/6 and urokinase plasminogen activator receptor (uPAR). Our results showed that simultaneous binding to LRP5/6 and uPAR by the dual receptor targeted IONPs was required to inhibit breast cancer cell invasion. Molecular analysis revealed that the dual receptor targeted IONPs significantly inhibited Wnt/beta-catenin signaling and cancer stem-like phenotype of tumor cells, with marked reduction of Wnt ligand, CD44 and uPAR. Systemic administration of the dual targeted IONPs led to nanoparticle-drug delivery into PDX tumors, resulting in stronger tumor growth inhibition compared to non-targeted or single-targeted IONP-Dox in a human breast cancer PDX model. Therefore, co-targeting Wnt/LRP and uPAR using IONP drug carriers is a promising therapeutic approach for effective drug delivery to chemo resistant breast cancer. PMID- 29107219 TI - Adult fly age estimations using cuticular hydrocarbons and Artificial Neural Networks in forensically important Calliphoridae species. AB - Blowflies (Diptera: Calliphoridae) are forensically important as they are known to be one of the first to colonise human remains. The larval stage is typically used to assist a forensic entomologists with adult flies rarely used as they are difficult to age because they remain morphologically similar once they have gone through the initial transformation upon hatching. However, being able to age them is of interest and importance within the field. This study examined the cuticular hydrocarbons (CHC) of Diptera: Calliphoridae species Lucilia sericata, Calliphora vicina and Calliphora vomitoria. The CHCs were extracted from the cuticles of adult flies and analysed using Gas Chromatography-Mass Spectrometry (GC-MS). The chemical profiles were examined for the two Calliphora species at intervals of day 1, 5, 10, 20 and 30 and up to day 10 for L. sericata. The results show significant chemical changes occurring between the immature and mature adult flies over the extraction period examined in this study. With the aid of a Principal Component Analysis (PCA) and Artificial Neural Networks (ANN), samples were seen to cluster, allowing for the age to be established within the aforementioned time frames. The use of ANNs allowed for the automatic classification of novel samples with very good performance. This was a proof of concept study, which developed a method allowing to age post-emergence adults by using their chemical profiles. PMID- 29107220 TI - Do longus capitis and colli really stabilise the cervical spine? A study of their fascicular anatomy and peak force capabilities. AB - BACKGROUND: Longus capitis and colli are proposed to play a role in stabilising the cervical spine, targeted in clinical and research practice with cranio cervical flexion. However, it is not clear if these muscles are anatomically or biomechanically suited to a stabilising role. OBJECTIVES: To describe the fascicular morphology of the longus capitis and colli, and estimate their peak force generating capabilities across the individual cervical motion segments. STUDY DESIGN: Biomechanical force modelling based on anatomical data. METHODS: Three-part design including cadaveric dissection (n = 7), in vivo MRI muscle volume calculation from serial slices in young healthy volunteers (n = 6), and biomechanical modelling of the peak force generating capacities based on computed tomography scans of the head and neck. RESULTS: Longus capitis and colli are small muscles spanning multiple cervical motion segments. Bilateral peak flexion torque estimates were higher in the upper cervical spine (0.5 Nm), and unlikely to affect motion below the level of C5 (<0.2 Nm). Peak shear estimates were negligible (<20 N), while peak compression estimates were small (<80 N). CONCLUSIONS: These data highlight the complex anatomy and small force capacity of longus capitis and colli, and have implications for their function. In particular, the small peak compression forces indicate that these muscles have a limited capacity to contribute to cervical stability via traditional mechanisms. This implies that the mechanism(s) by which cranio-cervical flexion exercises produce clinical benefits is worth exploring further. PMID- 29107221 TI - Factors promoting polyploid persistence and diversification and limiting diploid speciation during the K-Pg interlude. AB - The large wave of polyploidization following the Cretaceous-Paleogene (K-Pg) mass extinction has been explained by enhanced polyploid persistence arising from adaptive properties of the polyploids themselves, as well as an increase in unreduced gamete production and diploid hybridization. We propose that the demise of diploids afforded opportunities for polyploid establishment and expansion into novel habitats. Augmented polyploid gene pools from diploid and polyploid relatives, in association with their multiple and independent origins (of both autopolyploids and allopolyploids), facilitated their subsequent diversification. Their ability to recruit genetic variation from their diploid relatives or from products of recurrent origins sharing their genome(s) ostensibly contributed to polyploid persistence. Concomitantly, we propose that the number of congeneric diploid species dramatically contracted disproportionally to polyploids during the K-Pg interval (i.e. a diploid trough), resulting in a reduction in the rate of diploid speciation. Accordingly, the preponderance of neopolyploids was likely autopolyploids. PMID- 29107222 TI - Comprehensive characterization of the in vitro and in vivo metabolites of limonin in human samples using LC-Q-TOF/MS. AB - Limonin is a bitter triterpenoid dilactone in the genus Citrus with potential medicinal value. In this study, the metabolism of limonin in human was characterized by high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS). A total of 7 metabolites were identified from human samples. Among them, 3 metabolites of M1, M2 and M4 were detected in urine and feces, and the others were found in intestinal bacteria sample. Notably, M1 and M3 were chemically synthesized, of which the structures were further confirmed by NMR spectra data. The metabolism of limonin involved three major pathways, namely, reduction, hydrolysis and methylation. The reduction and hydrolysis were commonly observed in ring D of limonin. The metabolites showed decomposition in ring A. This study provides data for the metabolism of limonin in humans, and will contribute to explain its biological activity. PMID- 29107223 TI - Rapid gas chromatography with flame photometric detection of multiple organophosphorus pesticides in Salvia miltiorrhizae after ultrasonication assisted one-step extraction. AB - A simple and rapid gas chromatography-flame photometric detection (GC-FPD) method was developed for the determination of 12 organophosphorus pesticides (OPPs) in Salvia miltiorrhizae by using ultrasonication assisted one-step extraction (USAE) without any clean-up steps. Some crucial parameters such as type of extraction solvent were optimized to improve the method performance for trace analysis. Any clean-up steps were negligent as no interferences were detected in the GC-FPD chromatograms for sensitive detection. Under the optimized conditions, limits of detection (LODs) and quantitation (LOQs) for all pesticides were in the range of 0.001-0.002mg/kg and 0.002-0.01mg/kg and 0.002-0.01mg/kg, respectively, which were all below the regulatory maximum residue limits suggested. RSDs for method precision (intra- and inter-day variations) were lower than 6.8% in approval with international regulations. Average recovery rates for all pesticides at three fortification levels (0.5, 1.0 and 5.0mg/kg) were in the range of 71.2-101.0% with relative standard deviations (RSDs) <13%. The developed method was evaluated for its feasibility in the simultaneous pre-concentration and determination of 12 OPPs in 32 batches of real S. miltiorrhizae samples. Only one pesticide (dimethoate) out of the 12 targets was simultaneously detected in four samples at concentrations of 0.016-0.02mg/kg. Dichlorvos and omethoate were found in the same sample from Sichuan province at 0.004 and 0.027mg/kg, respectively. Malathion and monocrotophos were determined in the other two samples at 0.014 and 0.028mg/kg, respectively. All the positive samples were confirmed by LC-MS/MS. The simple, reliable and rapid USAE-GC-FPD method with many advantages over traditional techniques would be preferred for trace analysis of multiple pesticides in more complex matrices. PMID- 29107224 TI - Spatial analysis of concentrations of multiple air pollutants using NASA DISCOVER AQ aircraft measurements: Implications for exposure assessment. AB - In recent years, multipollutant approaches have been employed to investigate the association with health outcomes to better represent real-world conditions than more traditional analysis that considers a single pollutant. With regard to the exposure assessment of a mixture of air pollutants, it is critical to understand the spatial variability in multipollutant relations in order to assess their potential health implications. In this study, we investigated the spatial relations of multiple pollutant concentrations (i.e., NOx, NOy, black carbon, carbon monoxide, acetaldehyde, formaldehyde, toluene, xylenes/ethylbenzene, ozone, water-soluble organic carbon, and aerosol extinction) observed from the P 3B aircraft in the 2011 NASA field campaign in Baltimore/Washington D.C. areas during July 2011. The between-pollutant Pearson correlations and Z-scores (calculated from log-transformed concentrations) between near-highways and non highways and between near-urban centers and non-urban centers varied by pollutant pair and space. We found generally lower correlations between NOx and other pollutants for near-highways (average r = 0.36) than for non-highways (average r = 0.41) and also for non-urban centers (average r = 0.37) than for near-urban centers (average r = 0.41). This indicated that the temporal associations between NOx and health outcomes might be less affected by other pollutants, which were also related to same health outcomes, for near-highways and non-urban centers. The analysis of between-pollutant Z-scores showed varying spatial relations for popular traffic-related pollutants with the Z-score differences of 0.43 (NOx carbon monoxide), 0.29 (NOx-black carbon), and 0.17 (black carbon-carbon monoxide) between near-highways and non-highways. This result exhibited heterogeneous traffic-related pollutant mixtures with the proximity to highways, potentially leading to the diverse extent of health associations. Furthermore, a mixed effects model presented pollutant-specific associations between the concentrations and the proximity to highways and urban centers, showing larger declines for NOx, xylenes/ethylbenzene, toluene, and NOy than those for the pollutants related to secondary pollutant formation. The model also demonstrated the different sensitivity of each pollutant to meteorological parameters, which may modify the spatial and temporal variability in the relations between the pollutants. Our findings provide insights for exposure assessment studies to better understand the cumulative health consequences associated with multiple air pollutants simultaneously. PMID- 29107225 TI - Removal of polycyclic aromatic hydrocarbons (PAHs) from textile dyeing sludge by ultrasound combined zero-valent iron/EDTA/Air system. AB - This paper proposes a combined ultrasound (US) and zero-valent iron/EDTA/Air (ZEA) system to remove polycyclic aromatic hydrocarbons (PAHs) from textile dyeing sludge. The removal efficiencies of 16 PAHs using ZEA, US/Air (air injected into the US process), and US/ZEA treatments were investigated, together with the effects of various operating parameters. The enhanced mechanisms of US and the role of reactive oxygen species (ROS) in removing PAHs in the US/ZEA system were explored. Results showed that only 42.5% and 32.9% of ?16 PAHs were removed by ZEA and US/Air treatments respectively, whereas 70.1% were removed by US/ZEA treatment, (with favorable operating conditions of 2.0 mM EDTA, 15 g/L ZVI, and 1.08 w/cm3 ultrasonic density). The US/ZEA system could be used with a wide pH range. US led to synergistic improvement of PAHs removal in the ZEA system by enhancing sludge disintegration to release PAHs and promoting ZVI corrosion and oxygen activation. In the US/ZEA system, PAHs could be degraded by ROS (namely OH, O2-/HO2, and Fe(IV)) and adsorbed by ZVI, during which the ROS made the predominant contribution. This study provides important insights into the application of a US/ZEA system to remove PAHs from sludge. PMID- 29107226 TI - The fingerprint nature of PCDD in iron ore sinter strand emissions, the effect of suppressants and alternative fuels, and the potential for comparison with the isomer profile of PCDF. AB - It has been previously shown that the isomer profile of PCDF emissions from iron ore sinter plant only varies within limits even when suppressants or alternative fuels are added, to the extent that it can be said to have a 'fingerprint'. The isomer profiles of PCDD from tetra- to hexacholrodibenzo-p-dioxin from the same samples examined for PCDF emissions have been obtained, and show the same tendency for a 'fingerprint ' isomer distribution to occur. Occasional exceptionally high isomer abundances are observed, but these are uncommon. The potential for comparison of the abundances of PCDF and PCDD isomers with similar chlorination patterns to determine whether the same formation process is involved has been examined. It is found that co-elutions prevent extensive comparisons irrespective of whether the SP2331 or DB5ms column is used in the analyses for separation of isomers to provide the results used for comparisons, although they allow limited results to be obtained. It is suggested that analyses using the two chromatography columns to analyse the same sample in parallel could provide more resolution of the isomer profiles for use in comparisons. A pilot study using samples analysed using each column is limited because of detailed differences in the emissions profiles, but demonstrates that greater resolution is possible if the two columns are used to analyse one sample. PMID- 29107227 TI - Response of ammonia oxidizing archaea and bacteria to decabromodiphenyl ether and copper contamination in river sediments. AB - Ammonia oxidation plays a fundamental role in river nitrogen cycling ecosystems, which is normally governed by both ammonia oxidizing archaea (AOA) and ammonia oxidizing bacteria (AOB). Co-contamination of typical emerging pollutant Polybrominated diphenyl ethers (PBDEs) and heavy metal on AOA and AOB communities in river sediments remains unknown. In this study, multiple analytical tools, including high-throughput pyrosequencing and real-time quantitative PCR (qPCR), were used to reveal the ammonia monooxygenase (AMO) activity, subunit alpha (amoA) gene abundance, and community structures of AOA and AOB in river sediments. It was found that the inhibition of AMO activities was increased with the increase of decabromodiphenyl ether (BDE 209, 1-100 mg kg-1) and copper (Cu, 50-500 mg kg-1) concentrations. Moreover, the synergic effects of BDE 209 and Cu resulted in a higher AMO activity reduction than the individual pollutant BDE 209. The AOA amoA copy number declined by 75.9% and 83.2% and AOB amoA gene abundance declined 82.8% and 90.0% at 20 and 100 mg kg-1 BDE 209 with a 100 mg kg 1 Cu co-contamination, respectively. The pyrosequencing results showed that both AOB and AOA community structures were altered, with a higher change of AOB than that of AOA. The results demonstrated that the AOB microbial community may be better adapted to BDE 209 and Cu pollution, while AOA might possess a greater capacity for stress resistance. Our study provides a better understanding of the ecotoxicological effects of heavy metal and micropollutant combined exposure on AOA and AOB in river sediments. PMID- 29107228 TI - Comparison of in vitro and in vivo bioassays to measure thyroid hormone disrupting activity in water extracts. AB - Environmental chemicals can induce thyroid disruption through a number of mechanisms including altered thyroid hormone biosynthesis and transport, as well as activation and inhibition of the thyroid receptor. In the current study six in vitro bioassays indicative of different mechanisms of thyroid disruption and one whole animal in vivo assay were applied to 9 model compounds and 4 different water samples (treated wastewater, surface water, drinking water and ultra-pure lab water; both unspiked and spiked with model compounds) to determine their ability to detect thyroid active compounds. Most assays correctly identified and quantified the model compounds as agonists or antagonists, with the reporter gene assays being the most sensitive. However, the reporter gene assays did not detect significant thyroid activity in any of the water samples, suggesting that activation or inhibition of the thyroid hormone receptor is not a relevant mode of action for thyroid endocrine disruptors in water. The thyroperoxidase (TPO) inhibition assay and transthyretin (TTR) displacement assay (FITC) detected activity in the surface water and treated wastewater samples, but more work is required to assess if this activity is a true measure of thyroid activity or matrix interference. The whole animal Xenopus Embryonic Thyroid Assay (XETA) detected some activity in the unspiked surface water and treated wastewater extracts, but not in unspiked drinking water, and appears to be a suitable assay to detect thyroid activity in environmental waters. PMID- 29107229 TI - Seasonal implications on toxicity biomarkers of Loricariichthys anus (Valenciennes, 1835) from a subtropical reservoir. AB - Cropping systems based on intensive land use and continuous application of agricultural chemicals inflict a threat to aquatic organisms since these substances will inevitably be carried in to water bodies where they can accumulate, particularly in lentic sites. Pesticides exposure in aquatic animals can cause changes that can be quantified through biomarkers. Thus, this study aimed to investigate the effects of season on oxidative stress and neurotoxicity biomarkers in Loricariichthys anus from a subtropical reservoir surrounded by agricultural areas in southern Brazil. Ten armored catfish were collected from six sites in February and August 2016. Pesticides present in the water, sediment and muscle were identified and quantified. No pesticides were detected either in sediment nor in muscle. During the winter, the water contained atrazine, imidacloprid, simazine, azoxystrobin, and propoxur; however, in summer, only atrazine was present in the water. In the winter, there was an increase in the hepatic GST activity and in GPx that kept lipid peroxidation (TBARS) constant and, in the summer, there was an increase in metallothioneins levels. In the gills, variables related to summer were possibly responsible for the elevation of GST, GPx and TBARS; during the winter, there was greater carbonylation of proteins. In the winter, the increased AChE activity in brain and muscle tissue was related to carbonylation of proteins in brain. Although the amount of pesticides detected in the water was low, chronic exposure in addition to environmental variations can cause direct and indirect effects on L. anus population. PMID- 29107230 TI - Assessing PCB pollution in the Baltic Sea - An equilibrium partitioning based study. AB - Sediment cores and bottom water samples from across the Baltic Sea region were analyzed for freely dissolved concentrations (Cfree), total sediment concentrations (CT) and the dissolved aqueous fraction in water of seven indicator PCBs. Ex-situ equilibrium sampling of sediment samples was conducted with polydimethylsiloxane (PDMS) coated glass fibers that were analyzed by automated thermal desorption GC-MS, which yielded PCB concentrations in the fiber coating (CPDMS). Measurements of CPDMS and CT were then applied to determine (i) spatially resolved freely dissolved PCB concentrations; (ii) baseline toxicity potential based on chemical activities (a); (iii) site specific mixture compositions; (iv) diffusion gradients at the sediment water interface and within the sediment cores; and (vi) site specific distribution ratios (KD). The contamination levels were low in the Gulf of Finland and moderate to elevated in the Baltic Proper, with the highest levels observed in the western Baltic Sea. The SPME method has been demonstrated to be an appropriate and sensitive tool for area surveys presenting new opportunities to study the in-situ distribution and thermodynamics of hydrophobic organic chemicals at trace levels in marine environments. PMID- 29107231 TI - Influence of the RDL A301S mutation in the brown planthopper Nilaparvata lugens on the activity of phenylpyrazole insecticides. AB - We discovered the A301S mutation in the RDL GABA-gated chloride channel of fiprole resistant rice brown planthopper, Nilaparvata lugens populations by DNA sequencing and SNP calling via RNASeq. Ethiprole selection of two field N. lugens populations resulted in strong resistance to both ethiprole and fipronil and resulted in fixation of the A301S mutation, as well as the emergence of another mutation, Q359E in one of the selected strains. To analyse the roles of these mutations in resistance to phenylpyrazoles, three Rdl constructs: wild type, A301S and A301S+Q359E were expressed in Xenopus laevis oocytes and assessed for their sensitivity to ethiprole and fipronil using two-electrode voltage-clamp electrophysiology. Neither of the mutant Rdl subtypes significantly reduced the antagonistic action of fipronil, however there was a significant reduction in response to ethiprole in the two mutated subtypes compared with the wild type. Bioassays with a Drosophila melanogaster strain carrying the A301S mutation showed strong resistance to ethiprole but not fipronil compared to a strain without this mutation, thus further supporting a causal role for the A301S mutation in resistance to ethiprole. Homology modelling of the N. lugens RDL channel did not suggest implications of Q359E for fiprole binding in contrast to A301S located in transmembrane domain M2 forming the channel pore. Synergist bioassays provided no evidence of a role for cytochrome P450s in N. lugens resistance to fipronil and the molecular basis of resistance to this compound remains unknown. In summary this study provides strong evidence that target-site resistance underlies widespread ethiprole resistance in N. lugens populations. PMID- 29107232 TI - Characterization of heat shock protein 70 transcript from Nilaparvata lugens (Stal): Its response to temperature and insecticide stresses. AB - The brown planthopper, Nilaparvata lugens, possesses a strong adaptability to extreme temperature and insecticide stresses. Heat shock proteins (Hsps) are highly conserved molecular chaperones and play a pivotal role in response to various environmental stresses in insects. However, little is known about the response of Hsps to stresses in N. lugens. In the present study, an inducible Hsp70 (NlHsp70) was isolated from this insect and transcriptional expression patterns of NlHsp70 under temperature and insecticide stresses were analyzed. The full-length of NlHsp70 was 2805bp with an open reading frame (ORF) of 1896bp, showing high homology to its counterparts in other species. Expression of NlHsp70 was not altered by heat shock for 1h, nor following recovery from thermal stress. Conversely, decreased expression of NlHsp70 was observed in response to cold shock. In addition, the expression of NlHsp70 increased after imidacloprid exposure. RNA interference experiment combined with insecticide injury assay also demonstrated that NlHsp70 was essential for resistance against insecticide exposure. These observations indicated that NlHsp70 was an important gene involved in the resistance or tolerance to environmental stresses in N. lugens. Interestingly, weak changes in mRNA expression levels of two thermal-inducible Hsp genes, NlHsp90 and NlHsc70 were observed in imidacloprid-exposed N. lugens adults, suggesting that different Hsps may respond differential to the extreme temperature and insecticide stresses. PMID- 29107233 TI - Comparison of ALS functionality and plant growth in ALS-inhibitor susceptible and resistant Myosoton aquaticum L. AB - Herbicide target-site resistance mutations may cause pleiotropic effects on plant ecology and physiology. The effect of several known (Pro197Ser, Pro197Leu Pro197Ala, and Pro197Glu) target-site resistance mutations of the ALS gene on both ALS functionality and plant vegetative growth of weed Myosoton aquaticum L. (water chickweed) have been investigated here. The enzyme kinetics of ALS from four purified water chickweed populations that each homozygous for the specific target-site resistance-endowing mutations were characterized and the effect of these mutations on plant growth was assessed via relative growth rate (RGR) analysis. Plants homozygous for Pro197Ser and Pro197Leu exhibited higher extractable ALS activity than susceptible (S) plants, while all ALS mutations with no negative change in ALS kinetics. The Pro197Leu mutation increased ALS sensitivity to isoleucine and valine, and Pro197Glu mutation slightly increased ALS sensitivity to isoleucine. RGR results indicated that none of these ALS resistance mutations impose negative pleiotropic effects on relative growth rate. However, resistant (R) seeds had a lowed germination rate than S seeds. This study provides baseline information on ALS functionality and plant growth characteristics associated with ALS inhibitor resistance-endowing mutations in water chickweed. PMID- 29107234 TI - Changes in antioxidants potential, secondary metabolites and plant hormones induced by different fungicides treatment in cotton plants. AB - The use of fungicides for an effective control of plant diseases has become crucial in the last decades in the agriculture system. Seeds of cotton plants were treated with systemic and contact fungicides to study the efficiency of seed dressing fungicides in controlling damping off caused by Rhizoctonia solani under greenhouse conditions and its effect on plant growth and metabolism. The results showed that Mon-cut showed the highest efficiency (67.99%) while each of Tondro and Hemixet showed the lowest efficiency (31.99%) in controlling damping off. Rhizolex T, Mon-cut and Tondro fungicides caused significant decrease in plant height, dry weight of plant, phytohormones, photosynthetic pigments, soluble sugars, soluble proteins, total free amino acids but caused significant increases in total phenols, flavonoids, antioxidant enzymes, ascorbic acid, reduced glutathione, MDA and hydrogen peroxide as compared with untreated plants. On the other hand, the other fungicides (Maxim, Hemixet and Flosan) increased all the above recorded parameters as compared with untreated plants. Our results indicated that the fungicides application could be a potential tool to increase plant growth, the antioxidative defense mechanisms and decreased infection with plant diseases. PMID- 29107235 TI - Larvicidal activity and insecticidal mechanism of Chelidonium majus on Lymantria dispar. AB - Based on the broad spectrum of its biological activities, Chelidonium majus has been studied extensively in the medical field. However, few studies have focused on the insecticidal activity of C. majus, and the precise mechanism of its insecticidal activity. In the present study, larvicidal activity and insecticidal mechanism of C. majus on Lymantria dispar were investigated using bioassays, in vitro and in vivo enzyme activity assays, determination of the nutritional index, and gene transcription analysis. The results showed that alkaloids are the main insecticidal ingredients in C. majus. Among the five isoquinoline alkaloids, coptisine was present at the highest concentration (1624.23mg/L), while tetrahydrocoptisine showed the lowest concentration (0.47mg/L). Both the crude extract of C. majus (CECm) and the total alkaloids of C. majus (TACm) possessed a potent insecticidal activity toward L. dispar larvae. TACm had significant effects on the relative consumption rate, efficiency of conversion of digested food into growth, approximate digestibility, and approximate digestibility of L. dispar larvae. Enzyme activity assays suggested that both CECm and TACm displayed their strongest inhibitory activity to in vitro glutathione S-transferase (GST) and acetylcholinesterase (AChE), and showed the weakest inhibition of in vitro carboxylesterase (CarE). Moreover, CECm and TACm affected the in vivo activities of five enzymes. The in vivo activities of AChE and CarE in L. dispar larvae were inhibited significantly by CECm and TACm. Additionally, qRT-PCR analysis revealed that the transcription of the five enzymes was also affected by TACm. In conclusion, alkaloids in C. majus showed a prominent toxicity to L. dispar by reducing food intake, influencing nutritional indices, and affecting the activity and mRNA transcription of detoxifying and protective enzymes. This study provides novel insights into the insecticidal mechanism of C. majus. PMID- 29107236 TI - Long term biochemical changes in offspring of rats fed diet containing alpha cypermethrin. AB - To investigate the possible developmental programming, we analyzed the effects of maternal and postnatal low dose alpha-cypermethrin exposure on metabolic and redox parameters in the offspring. Postnatal changes in plasma biochemical parameters and plasma and tissue oxidative stress markers were determined in offspring of dams fed standard chow or diet containing alpha cypermethrin at 1.50mg/kg/day during gestation and lactation, weaned on to standard chow or on treated diet until adulthood (5months). Our results showed that exposure to alpha cypermethrin induced a significant reduction in body weight, food intake and metabolic alterations such as an increase in plasma glucose, triglyceride, urea, creatinine and AST levels in both postnatal and prenatal/postnatal treated female and male rats. This increase was more pronounced in prenatal/postnatal exposed rats. Alpha-cypermethrin exposure resulted in an imbalance of oxidant/antioxidant status, marked by high levels of carbonyl proteins and MDA, and low levels of antioxidants in erythrocytes, liver and kidney of both male and female offspring. Offspring of exposed dams have pre-existing oxidative stress that was accentuated with postnatal pesticide exposure. In conclusion, maternal alpha-cypermethrin exposure affected metabolism leading to permanent changes in biochemical parameters, enzyme activities and redox markers in the offspring. These abnormalities in offspring were worsened under postnatal pesticide exposure from weaning to adulthood. PMID- 29107237 TI - Purification and properties of the chymotrypsin inhibitor from wild emmer wheat (Triticum dicoccoides) of Israel and its toxic effect on beet armyworm, Spodoptera exigua. AB - A novel chymotrypsin inhibitor, which detected in the seed of wild emmer wheat (Triticum dicoccoides), was purified by ion-exchange chromatography, affinity chromatography and Ultracentrifugation. On the basis of its specificity, this inhibitor was named WeCI (wild emmer chymotrypsin inhibitor). SDS-PAGE analysis displayed that the purified WeCI is a single chain polypeptide with a molecular weight of approximately 13kDa. The inhibition constants (Ki) for amylase and bovine pancreatic chymotrypsin were 1.12*10-9M and 2.41*10-9M, respectively. Automated sequencing and mass spectrometry analyses revealed that WeCI is a neutral monomeric protein consisting of 119 residues. In vitro, WeCI strongly suppressed bovine pancreatic chymotrypsin as well as chymotrypsin-like activities separated from the midgut of the beet armyworm Spodoptera exigua. No inhibitory activities were found against bovine pancreatic trypsin, bacterial subtilisin, or porcine pancreatic elastase. The primary structure of WeCI was markedly similar (46-95%) to those of several proteins belonging to the wheat crop chymotrypsin/alpha-amylase inhibitor superfamily and displayed the typical sequence motif of the alpha-amylase inhibitor-seed storage protein group. WeCI significantly inhibited the growth and development of Spodoptera exigua, dependent on inhibitor concentration. WeCI significantly increased the mortality rate of Spodoptera exigua and caused a significant decrease in its fertility. PMID- 29107238 TI - In vitro and in vivo activities of eugenol against tobacco black shank caused by Phytophthora nicotianae. AB - Phytophthora nicotianae causes serious black shank disease in tobacco. Syringa oblata essential oil and its main components were evaluated to develop an effective and environmentally friendly biocontrol agent. Eugenol, which exhibited the strongest activity, was intensively investigated in vitro and in vivo. The mycelial growth of P. nicotianae was inhibited by eugenol at a minimum inhibitory concentration of 200MUgmL-1, and inhibition occurred in a dose-dependent manner. Extracellular pH and extracellular conductivity results indicated that eugenol increased membrane permeability. Flow cytometry and fluorescent staining results further showed that eugenol disrupted mycelial membranes but did not affect spore membrane integrity. The in vivo results confirmed that treatment of tobacco with various concentrations of eugenol formulations reduced disease incidence and better controlled against the disease. Our results suggested that the ability of eugenol to control tobacco black shank depended on its ability to damage mycelial membranes and that eugenol formulations have potential as an eco-friendly antifungal agent for controlling tobacco blank shank. PMID- 29107239 TI - Mini review: Gustatory reception of chemicals affecting host feeding in aedine mosquitoes. AB - Mosquitoes vector dangerous human diseases during blood feeding. Gustatory (taste) receptor neurons in the mosquito provide important chemical information including the nature and suitability of a potential host. Here we discuss the behavior, neurophysiology and molecular mechanisms associated with feeding in aedine mosquitoes, important vectors of emerging diseases including Zika fever, chikungunya and dengue fever. We describe how interactions between feeding stimulation and deterrency at the peripheral neural receptor level provide input to higher order neural processing centers affecting decisions to feed. A better understanding of gustatory mechanisms involved in the female's decision to bite will provide the framework for novel strategies aimed at preventing the spread of vector-borne disease. PMID- 29107240 TI - Synthesis and biological activity of benzoylcyclohexanedione herbicide SYP-9121. AB - Benzoylcyclohexanedione herbicides work by inhibiting 4-hydroxyphenylpyruvate dioxygenase which was the last new target site introduced for herbicides. In an attempt to find new 4-hydroxyphenylpyruvate dioxygenase inhibitors with high efficacy and selectivity, a novel benzoylcyclohexanedione compound SYP-9121 was synthesized and studied in greenhouse and field. In the greenhouse, SYP-9121 showed broad spectrum herbicidal activity and good safety to maize. Its control of barnyard grass, crabgrass, redroot pigweed, purslane, dayflower and night shade was equivalent to that of the commercial herbicide mesotrione. Three field trials in summer maize showed that SYP-9121 could efficiently control both grass and broadleaf weeds with good selectivity. Herbicidal activity of SYP-9121 was comparable to that of mesotrione. PMID- 29107241 TI - TEMPORARY REMOVAL: Effects of oxathiapiprolin on photosynthetic activity of Chlorella pyrenoidosa probed by chlorophyll fluorescence and thermoluminescence assays. PMID- 29107242 TI - Silence of inositol 1,4,5-trisphosphate receptor expression decreases cyantraniliprole susceptibility in Bemisia tabaci. AB - Cyantraniliprole is the second active ingredient of anthranilic diamide insecticide, and the first to control a cross-spectrum of chewing and sucking pests such as sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). The inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) are two families of Ca2+ release channels to raise the cytoplasmic free calcium concentration when it is activated by various extracellular stimuli. Previous study proved the over-expression of ryanodine receptor (RyR) was associated with the resistance to diamide insecticides, while the roles of IP3R in diamide resistance remain unknown. In this study, a full-length cDNA sequence of IP3R was cloned from B. tabaci through RT-PCR and rapid amplification of cDNA ends (RACE). The gene (named BtIP3R) is 9922bps long, with an open reading frame (ORF) of 8202bps, encoding a predicted IP3R of 2733 amino acids. The BtIP3R shares 47-78% identity with other insect IP3Rs. Quantitative real-time PCR (qRT PCR) analysis showed that the BtIP3R was highly expressed in larva, pseudopupa, and female adult, while lowly expressed in egg and male adult. RNA interference (RNAi) by dietary introduction of double-stranded RNA (dsRNA) of BtIP3R significantly reduced the mRNA levels of the target gene in the adult, and dramatically decreased the susceptibility of adult B. tabaci to cyantraniliprole. The results shed light on further understanding of cyantraniliprole resistance mechanisms in B. tabaci as well as in other insects. PMID- 29107243 TI - New evidence for primordial action site of Fluazifop-P-butyl on Acanthospermum hispidum seedlings: From the effects on chlorophyll fluorescence characteristics and histological observation. AB - Acanthospermum hispidum DC, an Asteraceae weed species, was very susceptible to fluazifop-P-butyl, but tolerant to other aryloxyphenoxypropionate herbicides, such as haloxyfop-P-methyl. However, other Asteraceae weeds including Bidens pilosa were all tolerant to fluazifop-P-butyl. Membrane lipid peroxidation by increasing the levels of reactive oxygen species (ROS) was proposed as an action mechanism of fluazifop-P-butyl in A. hispidum. To further clarify the primordial action site of fluazifop-P-butyl in this species, the effects on chlorophyll fluorescence characteristics and cytohistology of apical meristems were studied. Chlorophyll fluorescence characteristics (CFC) in sensitive A. hispidum seedlings were markedly affected by 10MUM fluazifop-P-butyl, with the dark fluorescence yield (Fo), maximal fluorescence yield (Fm), maximal PS II quantum yield (Fv/Fm), effective photosystem II (PS II) quantum yield [Y(II)], and quantum yield of regulated energy dissipation [Y(NPQ)] declining, quantum yield of nonregulated energy dissipation [Y(NO)] rising, but these measures were not affected in Bidens pilosa. The effects of fluazifop-P-butyl on chlorophyll fluorescence properties were observed on the growing point before the mature leaves by about 4-6h. Haloxyfop-P-methyl, a control herbicide, had no effects on CFC of either A. hispidum or B. pilosa. In addition, damage to apical meristem cells of A. hispidum was observed at 6 HAT prior to changes in chlorophyll fluorescence parameters suggesting that the primary action site of fluazifop-P-butyl in this species is in the apical meristem and the effects on CFC may be the results of secondary action. PMID- 29107244 TI - Phytoremediation of azoxystrobin and its degradation products in soil by P. major L. under cold and salinity stress. AB - Azoxystrobin is a broad-spectrum, systemic and soil-applied fungicide used for crop protection against the four major classes of pathogenic fungi. The use of azoxystrobin use has induced water pollution and ecotoxicological effects upon aquatic organisms, long half-life in soils, as well as heath issues. Such issues may be solved by phytoremediation. Here, we tested the uptake and translocation of azoxystrobin and its degradation products by Plantago major, under cold stress and salt stress. The result demonstrated that azoxystrobin significantly accumulated in P. major roots under salinity conditions more than that in the P. major roots under cold conditions and natural condition within two days of experimental period. In P. major roots and leaves, the chromatograms of HPLC for azoxystrobin and metabolites under natural condition (control) and stressed samples (cold stress and salt stress) show different patterns of metabolism pathways reflecting changes in the degradation products. Azoxystrobin carboxylic acid (AZ-acid) formed by methyl ester hydrolysis was an important route in the roots and the leaves. AZ-pyOH and AZ-benzoic were detected in P. major roots under cold and salt stress, while did not detected in P. major roots under natural condition. In the leaves, AZ-pyOH and AZ-benzoic were detected in all treatments between 4 and 12days of exposure. Shoots of the stressed plants had greater H2O2 and proline contents than was observed in the control plants. The level of 100mM NaCl treatment induced significantly higher peroxidase (POD) activity than the non-treated control group. Leaf Chlorophyll contents in the plants at 80 and 100mM NaCl were significantly reduced than was observed in the control plants. I concluded that P. major had a high potential to contribute to remediation of saline-soil contaminated with azoxystrobin. PMID- 29107245 TI - Biochemical interactions between Glycine max L. silicon dioxide (SiO2) and plant growth-promoting bacteria (PGPR) for improving phytoremediation of soil contaminated with fenamiphos and its degradation products. AB - Fenamiphos is a systematic nematicide-insecticide used extensively for the control of soil nematodes. Fenamiphos and oxidation products have been known to induce water pollution, soil pollution and ecotoxicological effects on aquatic organisms, as well as heath issues. This contaminant can be removed by phytoremediation. Herein, we tested several strategies to improve the effectiveness of this technology. A combination of G. max plus Pseudomonas fluorescens was more efficient than G. max plus Serratia marcescens or G. max alone in degrading fenamiphos to other metabolites. Three major metabolites, namely fenamiphos sulfoxide (FSO), fenamiphos sulfone (FSO2) and fenamiphos phenol (F-phenol), were detected in roots and leaves in which G. max amended with P. fluorescens or amended with S. marcescens produced a significant accumulation of FSO and FSO2 with higher amounts than for G. max alone. Leaf concentrations of FSO were always higher than in the roots, while FSO2 accumulated significantly more in G. max roots than in G. max leaves. In soil treated with fenamiphos, G. max roots and leaves alone, and in combined effects of plant and microorganisms, resulted in the disappearance of fenamiphos and the appearance of F-SO, F-SO2 and F-phenol, which in turn caused toxic stress in G. max and the resulting production of reactive oxygen species such as H2O2 with higher content and an increase in antioxidant GPX activity. Although a batch equilibrium technique showed that use of SiO2 resulted in the efficient removal of fenamiphos when compared with other treatments for removing adsorbed fenamiphos from soil, a fewer amount of fenamiphos was removed by G. max L. with SiO2. H2O2 content and GPX activity increased in G. max under fenamiphos treatment and its degradation products, while amended G. max with SiO2 or Argal led to a decrease in GPX activity and H2O2 content. PMID- 29107246 TI - The inhibition of myometrial contractions by chlorinated herbicides (atrazine and linuron), and their disruptive effect on the secretory functions of uterine and ovarian cells in cow, in vitro. AB - The effect of atrazine and linuron, the popular and widely used chlorinated herbicides, on both myometrial contractions and secretory functions of bovine uterus and ovaries in vitro, was investigated. The pesticides inhibited (P<0.05) the basal and oxytocin (OT)-stimulated myometrial strips contractions, as well as the effect of OT on secretion of prostaglandins (PGs: PGF2alpha and PGE2) from endometrium. But only linuron inhibits the effect of OT on myometrial contractions. Neither of herbicides affected PGs secretion from myometrium and PGF2alpha from endometrium. Only the lowest dose of both tested compounds decreased PGE2 secretion from endometrium. The pesticides increased (P<0.05) the OT secretion from granulosa. However, only linuron stimulated (P<0.05) the OT secretion from the luteal cells, and it increased (P<0.05) the expression of mRNA for the OT precursor. Both compounds stimulated (P<0.05) the secretion of testosterone and atrazine increased (P<0.05) also the secretion of estradiol from the granulosa cells. While atrazine and linuron reduced (P<0.05) the progesterone secretion from the luteal cells. The data show that atrazine and linuron altered the secretory functions of ovarian cells and inhibited the myometrial contractions in vitro. PMID- 29107247 TI - Agroinfiltration-based expression of hairpin RNA in soybean plants for RNA interference against Tetranychus urticae. AB - The coatomer subunit alpha (COPA) and aquaporin 9 (AQ9) genes from the two spotted spider mite, Tetranychus urticae, were previously determined to exhibit RNA interference (RNAi)-based lethality when their double-stranded RNAs were systemically delivered via multi-unit chambers (Kwon et al., 2016 [8]). In current study, the hairpin RNAs of the COPA and AQ9 were transiently expressed in soybean plants by agroinfiltration. When T. urticae was fed with the soybean plants agroinfiltrated with the COPA and AQ9 hairpin RNA cassettes, the cumulative mortality increased significantly at 6days post-infestation. Quantitative PCR analysis revealed that the transcript level of both COPA and AQ9 was significantly reduced in T. urticae after 2days post-infestation, thereby confirming that the significant increases in mortality resulted from the knockdown of COPA and AQ9 transcripts. Our findings demonstrate the utility of COPA and AQ9 as potential genes for plant host-mediated RNAi control of T. urticae. In addition, we proved the usefulness of agroinfiltration as a rapid validation tool for confirming the RNAi-based lethality of target genes against arthropod pests before producing transgenic plants as agroinfiltration requires less time and skill to validate transgene function. Furthermore, these findings prove the concept that hairpin RNA expressed in plant hosts can also induce RNAi and eventually kill T. urticae, a sap-sucking pest. PMID- 29107248 TI - Molecular cloning, mRNA expression and alternative splicing of a ryanodine receptor gene from the citrus whitefly, Dialeurodes citri (Ashmead). AB - Insect ryanodine receptors are the main targets of diamide insecticides that have highly selective insecticidal activity but are less toxic to mammals. Therefore, these insecticides are ideal for pest control. Ryanodine receptors (RyRs) play a critical role in Ca2+ signaling in muscle and non-muscle cells. In this study, we cloned the complete cDNA (DcRyR) of the RyR from the citrus whitefly, Dialeurodes citri, a serious pest of citrus orchards in China. The open reading frame of RyR is 15,378bp long and encodes a protein with 5126 amino acids with a computed molecular weight of 579.523kDa. DcRyR shows a high amino acid sequence identity to RyRs from other insects (76%-95%) and low identity to those from nematodes and mammals (44%-52%). DcRyR shares many features of insect and vertebrate RyRs, including a MIR domain, two RIH domains, three SPRY domains, four copies of RyR repeat domain, RIH-associated domain at the N-terminus, two consensus calcium binding EF-hands and six transmembrane domains at the C-terminus. The expression of DcRyR mRNA was the highest in the nymphs and lowest in eggs; DcRyR mRNA was 1.85-fold higher in the nymphs than in the eggs. Among the tissues, DcRyR mRNA expression was 4.18- and 4.02-fold higher in the adult head and thorax than in the abdomen. DcRyR had three alternative splice sites and the splice variants showed body part-specific expression and were developmentally regulated. These results may help investigate target-based resistance to diamide insecticides in D. citri. PMID- 29107249 TI - A chitin-binding lectin from Moringa oleifera seeds (WSMoL) impairs the digestive physiology of the Mediterranean flour larvae, Anagasta kuehniella. AB - Biotechnological techniques allow the investigation of alternatives to outdated chemical insecticides for crop protection; some investigations have focused on the identification of molecules tailored from nature for this purpose. We, herein, describe the negative effects of water-soluble lectin from Moringa oleifera seeds (WSMoL) on Anagasta kuehniella development. The chitin-binding lectin, WSMoL, impaired the larval weight gain by 50% and affected the activity of the pest's major digestive enzymes. The commitment of the digestive process became evident after controlled digestion studies, where the capacity of protein digestion was compromised by >90%. Upon acute exposure, the lectin was not resistant to digestion; however, chronic ingestion of WSMoL was able to reverse this feature. Thus, we show that resistance to digestion may not be a prerequisite for a lectin's ability to exert negative effects on larval physiology. The mechanism of action of WSMoL involves binding to chitin with possible disruption to the peritrophic membrane, causing disorder between the endo- and ectoperitrophic spaces. Additionally, results suggest that WSMoL may trigger apoptosis in gut cells, leading to the lower enzymatic activity observed in WSMoL-fed larvae. Although assays employing an artificial diet did not demonstrate effects of WSMoL on A. kuehniella mortality, this lectin may hold potential for exerting insecticide effects on other pest insects, as well for use in other experimental approaches, such as WSMoL-expressing plants. Moreover, the use of WSMoL with other biotechnological tools, such as 'pyramid' crops, may represent a strategy for delaying the evolution of pest resistance to transgenic crops, since its multiple site targets could act in synergism with other insecticide compounds. PMID- 29107250 TI - Cypermethrin resistance conferred by increased target insensitivity and metabolic detoxification in Culex pipiens pallens Coq. AB - In order to elucidate the molecular mechanisms of cypermethrin resistance in Culex pipiens pallens Coq, the susceptible strain (SS strain) and cypermethrin resistant strain (CR strain) of Cx. p. pallens were investigated in this paper. The cypermethrin resistance ratio of CR strain to SS strain was measured by biological assays method, the cDNA sequence of sodium channel was cloned and analyzed. Real-time quantitative RT-PCR was used to detect the expression levels of the detoxification-related genes across between CR strain and SS strain of Cx. p. pallens. Bioassays indicated that CR strain was 283.06 and 80.68-fold resistance to cypermethrin and permethrin as compared to the susceptible strain, respectively. The sequence variability analysis of sodium channel gene between SS strain and CR strain shows that 4 point mutations (R954Q, L1023F, S1775G and A1989E) appear on the amino acid sequence of sodium channel of CR strain. The transcriptional levels of CYP6Z10, CYP9M10, CPGSTd1 and CPGSTd2 in the resistant strain are significantly higher than it is in the susceptible. The transcripts of CYP4H34 and E4 esterase have no significant difference between the CR strain and SS strain. The results indicated that sodium channel mutations, combined with elevated levels of P450s and GSTs, are associated with cypermethrin resistance in CR strain. PMID- 29107251 TI - Progressive metabolic impairment underlies the novel nematicidal action of fluensulfone on the potato cyst nematode Globodera pallida. AB - BACKGROUND: Fluensulfone is a new nematicide with an excellent profile of selective toxicity against plant parasitic nematodes. Here, its effects on the physiology and biochemistry of the potato cyst nematode Globodera pallida have been investigated and comparisons made with its effect on the life-span of the free-living nematode Caenorhabditis elegans to provide insight into its mode of action and its selective toxicity. RESULTS: Fluensulfone exerts acute effects (<=1h; >=100MUM) on stylet thrusting and motility of hatched second stage G. pallida juveniles (J2s). Chronic exposure to lower concentrations of fluensulfone (>=3days; <=30MUM), reveals a slowly developing metabolic insult in which G. pallida J2s sequentially exhibit a reduction in motility, loss of a metabolic marker for cell viability, high lipid content and tissue degeneration prior to death. These effects are absent in adults and dauers of the model genetic nematode Caenorhabditis elegans. CONCLUSION: The nematicidal action of fluensulfone follows a time-course which progresses from an early impact on motility through to an accumulating metabolic impairment, an inability to access lipid stores and death. PMID- 29107252 TI - Trp574 substitution in the acetolactate synthase of Sinapis arvensis confers cross-resistance to tribenuron and imazamox. AB - Rate-response experiments with nine putative resistant wild mustard (Sinapis arvensis) populations from Greece showed cross-resistance to tribenuron and imazamox. The calculated GR50 values [herbicide rate (gaiha-1) required for 50% reduction of fresh weight] of the nine resistant (R) populations ranged from 51.8 to 555.6gaitribenuronha-1 and from 66.3 to 900.4gaiimazamoxha-1. Regarding the susceptible population, GR50 value was not estimated for tribenuron as its lower treatment reduced fresh weight by >95%, whereas the respective value for imazamox was 0.5gaiha-1. Gene sequencing of als revealed that a point mutation at Trp574 position, leading to amino acid substitution by Leu in the ALS enzyme was present and the likely cause of resistance. The in vitro activity of the ALS enzyme indicated I50 values (herbicide concentration required for 50% reduction of the ALS activity) ranging from 19.11 to 217.45MUM for tribenuron, whereas the respective value for the S population was 1.17MUM. All populations were susceptible to MCPA at the recommended rate. These results strongly support that cross-resistance of 9 S. arvensis populations was due a point mutation of the als gene, which resulted in a less sensitive ALS enzyme. PMID- 29107253 TI - Attribution of Bax and mitochondrial permeability transition pore on cantharidin induced apoptosis of Sf9 cells. AB - To investigate the insecticidal mechanism of cantharidin, a promising biological pesticide substance from blister beetle, on Sf9 cells, a cultured cell line derived from fall armyworm, Spodoptera frugiperda, we preliminary studied the attribution of Bax channel and mitochondrial permeability transition pore on cantharidin-induced mitochondrial apoptosis signal pathway. Changes in cell morphology, activity of mitochondrial dehydrogenases, release of cytochrome C and mitochondrial transmembrane potential were detected when the two channels were blocked by specific inhibitors, Bax channel blocker and cyclosporin A. Results showed that cantharidin-induced apoptotic features, including changes in the cell morphology, release of cytochrome C and decrease in mitochondrial transmembrane potential could be significantly inhibited by Bax channel blocker, while cyclosporin A accelerated the downward trend of mitochondrial dehydrogenases activity and caused a decrease of Ca2+ in mitochondria. In summary, Bax might be necessary but not exclusively for the apoptosis induced by cantharidin and the attribution of these channels seems to be more complexity. PMID- 29107254 TI - Embrace Action: Celebrate Perioperative Nurse Week and Thanksgiving. PMID- 29107255 TI - The Future of Certification: Beyond Contact Hours. PMID- 29107256 TI - Local Anesthetic Systemic Toxicity. AB - Local anesthetics are commonly used in the perioperative environment to facilitate surgical procedures or to provide postoperative pain management for patients. The use of local anesthetics, however, introduces the risk of complications resulting from local anesthetic systemic toxicity and the risks of increased morbidity and mortality for the surgical patient. Systemic toxicity from the injection or overdose of local anesthetics is a rare but potentially fatal complication that occurs in less than 1 in 1,000 patients. This article provides the perioperative nurse with information about local anesthetics, the signs and symptoms of local anesthetic systemic toxicity, and the information needed to manage a patient experiencing this complication. PMID- 29107257 TI - Translating Evidence Into Practice: How Advanced Practice RNs Can Guide Nurses in Challenging Established Practice to Arrive at Best Practice. AB - Nursing is an information-intensive profession, requiring nurses to have high information literacy and the skills to find, understand, evaluate, and use information from a multitude of sources. The advanced practice RN (APRN) is a valuable resource to support and guide nurses in this effort. The APRN's skills encompass understanding and implementing evidence-based practice, evaluating the organizational structure (eg, units, facilities, multisystem organizations) across the continuum of care, and facilitating collaboration between perioperative nurses and other interprofessional team members to sustain practice changes in the clinical setting. Perioperative APRNs play an important role as evidence-based practice experts to assist with translating research and evidence into clinical practice for safe, quality care in the perioperative setting. PMID- 29107258 TI - Epilepsy: Clinical Review and Surgical Options. AB - Epilepsy is the fourth leading neurologic disorder in the United States and affects the quality of life of approximately 2.9 million Americans. Despite modern progress in medicine and technology, the disease may prove to be drug resistant, a condition that serves as a primary indication to consider invasive treatment modalities. Current evidence supports the efficacy of early surgical intervention for patients with drug-resistant epilepsy, although this approach continues to be underused. The positive outcomes of epilepsy surgery are a result of multidisciplinary efforts, and perioperative nurses play a vital role in the continuum of care for this patient population. In the effort to optimize nursing care for patients with epilepsy, this article provides a clinical review of epilepsy as a neurologic disorder and specifically focuses on surgical interventions and perioperative nursing considerations. PMID- 29107259 TI - Temporary Perioperative Tobacco Cessation: A Literature Review. AB - Perioperative tobacco cessation decreases rates of surgical complications associated with the use of tobacco. The link between patient outcomes and reimbursement to health care providers and systems is another important motivating factor supporting temporary pre- and postoperative tobacco cessation to improve surgical patient outcomes. The optimal time frame for tobacco cessation to improve surgical outcomes has not been definitively established. We examined the literature from June 1989 to July 2017 regarding various tobacco cessation time frames for perioperative patients, searching MEDLINE, the Cumulative Index to Nursing and Allied Health (CINAHL), the Cochrane Collaboration, and various online-only journals accessed through Google Scholar. We reviewed evidence from 15 studies that report wide variability in recommended time frames (eg, four to six months) for perioperative tobacco cessation. PMID- 29107260 TI - Back to Basics: Environmental Cleaning Hazards. AB - Perioperative personnel must clean and disinfect the perioperative environment numerous times throughout the day to help prevent the risk of exposing patients to pathogenic microorganisms. However, this practice exposes perioperative team members to chemicals that could be harmful to their health. Exposure to cleaning and disinfecting products has been associated with potential health problems such as skin irritation, burns, rashes, and difficulty breathing. This Back to Basics article offers strategies for perioperative team members to implement to decrease their risk of harmful exposure to these products. PMID- 29107261 TI - Situational Awareness and Patient Safety. PMID- 29107262 TI - Enhancing Pediatric Perioperative Patient Safety. PMID- 29107263 TI - Clinical Issues-November 2017. AB - Heating, ventilation, and air-conditioning (HVAC) systems in the OR Key words: airborne contaminants, HVAC system, air pressure, air quality, temperature and humidity. Air changes and positive pressure Key words: air changes, positive pressure airflow, unidirectional airflow, outdoor air, recirculated air. Product selection Key word: product evaluation, product selection, selection committee. Entry into practice Key words: associate degree in nursing, bachelor of science in nursing, entry-level position, advanced education, BSN-prepared RNs. Mentoring in perioperative nursing Key words: mentor, novice, practice improvement, nursing workforce. PMID- 29107265 TI - Guideline at a Glance: Positioning. PMID- 29107264 TI - Evidence appraisal of Yuwen P, Chen W, Lv H, et al. Albumin and surgical site infection risk in orthopaedics: a meta-analysis.: BMC Surg. 2017;17(1):7. doi:10.1186/s12893-016-0186-6. PMID- 29107267 TI - Empowering the Patient While Developing an Osteoporosis Management Strategy. PMID- 29107266 TI - Editorial overview: Viruses and cancer: How tumor viruses affect the cellular genome. PMID- 29107269 TI - How to Biopsy: Transperineal Versus Transrectal, Saturation Versus Targeted, What's the Evidence? AB - Until recently, prostate biopsy for the detection of prostate cancer has been performed transrectally and in an untargeted sampling fashion. Consequently, the procedure has suffered a small but significant risk of severe morbidity through infection, and low diagnostic accuracy, with undergrading and missed diagnosis being common. MRI is revolutionizing prostate cancer diagnosis by improving detection accuracy via targeted biopsy. Transperineal biopsy is eradicating sepsis as a risk of prostate biopsy, while avoiding the need for broad-spectrum or combination prophylactic antibiotics. This article analyzes the data on the various current methods of performing prostate biopsy and recommends an optimal technique. PMID- 29107268 TI - Whom to Biopsy: Prediagnostic Risk Stratification with Biomarkers, Nomograms, and Risk Calculators. AB - This article describes markers used for prostate biopsy decisions, including prostrate-specific antigen (PSA), free PSA, the prostate health index, 4Kscore, PCA3, and ConfirmMDx. It also summarizes the use of nomograms combining multiple variables for prostate cancer detection. PMID- 29107270 TI - Prediagnostic Risk Assessment with Prostate MRI and MRI-Targeted Biopsy. AB - Prostate MRI is commonly used in the detection of prostate cancer to reduce the detection of clinically insignificant disease; maximize the detection of clinically significant cancer; and better assess disease size, grade, and location. The clinical utility of MRI seems to apply to men with no prior biopsy, who have had a previous negative biopsy, and men who are candidate for active surveillance. In conjunction with traditional clinical parameters and secondary biomarkers, MRI may allow more accurate risk stratification and assessment of need for prostate biopsy. PMID- 29107271 TI - Whom to Treat: Postdiagnostic Risk Assessment with Gleason Score, Risk Models, and Genomic Classifier. AB - Management of prostate cancer presents unique challenges because of the disease's variable natural history. Accurate risk stratification at the time of diagnosis in clinically localized disease is crucial in providing optimal counseling about management options. To accurately distinguish pathologically indolent tumors from aggressive disease, risk groups are no longer sufficient. Rather, multivariable prognostic models reflecting the complete information known at time of diagnosis offer improved accuracy and interpretability. After diagnosis, further testing with genomic assays or other biomarkers improves risk classification. These postdiagnostic risk assessment tools should not supplant shared decision making, but rather facilitate risk classification and enable more individualized care. PMID- 29107272 TI - 68Gallium-Prostate-Specific Membrane Antigen PET/Computed Tomography for Primary and Secondary Staging in Prostate Cancer. AB - Prostate-specific membrane antigen (PSMA) PET has been recently introduced for the diagnosis of patients with metastatic prostate cancer (PCa). Until today, staging of patients with PCa relied mostly on morphologic features, such as size or shape, resulting in low detection rates in disease recurrence. PSMA PET imaging provides molecular information and, in combination with conventional imaging, offers improved sensitivity and specificity. This review discusses the benefits and limitations of PSMA imaging in the setting of primary staging and detection of recurrent disease in comparison with standard-of-care imaging techniques. PMID- 29107273 TI - Contemporary Active Surveillance: Candidate Selection, Follow-up Tools, and Expected Outcomes. AB - This article is a summary of the rationale for conservative management, the molecular biology of low-grade cancer, the principles of management, the expected outcome of surveillance, unanswered questions, and research opportunities. PMID- 29107274 TI - Focal Ablation of Early-Stage Prostate Cancer: Candidate Selection, Treatment Guidance, and Assessment of Outcome. AB - Prostate cancer lesions smaller than 0.5 m3, or Gleason pattern 3, are likely clinically insignificant. Clinically significant disease is often limited to a single index lesion. Focal ablation targets this index lesion, maintains oncological control, and minimizes complications by preserving healthy prostate tissue. Template mapping biopsy or multiparametric MRI-targeted biopsies are used to identify appropriate index lesions. Multiple energy modalities have been tested, including high-intensity frequency ultrasound, cryoablation, laser ablation, photodynamic therapy, focal brachytherapy, radiofrequency ablation, irreversible electroporation. Outcome is assessed by biopsy of the target area, triggered by prostate-specific antigen measurements or MRI imaging, or performed per protocol at 12 months. PMID- 29107275 TI - Extent of Lymphadenectomy at Time of Prostatectomy: An Evidence-Based Approach. AB - Pelvic lymph node dissection (PLND) at the time of radical prostatectomy is the most accurate method of lymph node staging in prostate cancer. Although there are varied practices in anatomic extent of PLND, evidence favors an extended PLND (ePLND) including external iliac, obdurator, and internal iliac nodes. Removing presacral and/or common iliac nodes to the ureteric crossing can improve staging. The oncologic benefits of extended dissection are unclear based on methodologic limitations and bias in the available evidence. Diverse nomograms may clarify which patients warrant ePLND. Higher level evidence is needed to clarify the therapeutic effects of ePLND and who benefits most. PMID- 29107276 TI - Managing Cancer Relapse After Radical Prostatectomy: Adjuvant Versus Salvage Radiation Therapy. AB - An increasing proportion of men are undergoing radical prostatectomy for locally advanced prostate cancer. More than half of men with adverse pathologic features are expected to experience disease recurrence within 10 years. This article discusses the use of postoperative radiation therapy to decrease this risk. Evidence from 3 randomized trials and multiple retrospective studies indicates that either adjuvant or salvage radiation improve biochemical progression-free survival and may improve overall survival. Novel imaging and genomic analysis can improve patient selection for either modality, however current tests are unable to identify all patients who may benefit from additional local therapy. PMID- 29107277 TI - Newly Diagnosed Metastatic Prostate Cancer: Has the Paradigm Changed? AB - Androgen deprivation therapy (ADT) has been conventional treatment of newly diagnosed metastatic prostate cancer for more than 70 years. However, all patients eventually become castration-resistant and a significant proportion of life span is spent in the castration-resistant state. Prospective randomized control trials have incorporated early chemotherapy along with ADT based on the hypothesis that a significant level of resistance to ADT already exists in newly diagnosed metastatic prostate cancer and ADT exhibits synergistic antitumor activity with taxanes. We discuss the changing landscape of management of patients with newly diagnosed metastatic prostate cancer based on recently published landmark randomized trials. PMID- 29107278 TI - The Role of Local Therapy for Oligometastatic Prostate Cancer: Should We Expect a Cure? AB - The role of local treatment in oligometastatic prostate cancer remains contentious. Treatment of the prostate in metastatic disease may confer benefit, but prospective data are lacking. With improvements in treatments, aggressive strategies directed at metastases have increasingly become of clinical interest. Current evidence suggests good local control can be achieved; however, further data are required to determine overall cancer outcomes. This article evaluates the evidence available and consider whether local treatment of oligometastatic disease is a feasible, safe, and a positive strategy in this disease cohort. Cure should not be expected, although prolonged disease and treatment-free survival may be observed. PMID- 29107279 TI - Approach to the Patient with High-Risk Prostate Cancer. AB - Men classified as having high-risk prostate cancer warrant treatment because durable outcomes can be achieved. Judicious use of imaging and considerations of risk factors are essential when caring for men with high-risk disease. Radical prostatectomy, radiation therapy, and androgen deprivation therapy all play pivotal roles in the management of men with high-risk disease, and potentially in men with metastatic disease. The optimal combinations of therapeutic regimens are an evolving area of study and future work looking into therapies for men with high-risk disease will remain critical. PMID- 29107280 TI - Castration-Resistant Prostate Cancer: An Algorithmic Approach. AB - Since 2010, 5 new agents have been approved for advanced prostate cancer treatment. The American Urologic Association (AUA) published guidelines for the management of castration-resistant prostate cancer in 2013. These guidelines identify 6 index patients to consider when selecting the most appropriate treatment. No comparative trials have provided an approach to optimize the sequencing of these drugs. For the urologist, incorporating the guidelines into clinical practice typically requires a multidisciplinary team. This article provides an algorithmic approach based on indication and mechanism of action that complements the AUA guidelines to ensure patients receive the most optimal care. PMID- 29107281 TI - Prostate Cancer. PMID- 29107282 TI - The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice. AB - OBJECTIVES: Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice. METHODS: The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1rCM-/-). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo. RESULTS: Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1rCM-/- mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1rCM-/- mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart. CONCLUSIONS: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart autonomous manner. PMID- 29107283 TI - Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity. AB - OBJECTIVE: Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. METHODS: We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp. RESULTS: We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neuronsNTS enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly. CONCLUSIONS: We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity. PMID- 29107284 TI - Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice. AB - OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. METHODS: OCA and IP118 alone and in combination were sub chronically administered to Lepob/Lepob mice with diet-induced NASH or diet induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lepob/Lepob mice was graded using a customized integrated scoring system. RESULTS: OCA reduced liver weight and lipid in NASH mice (both by -17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (-21%), liver lipid (-15%), ALT (-29%), and AST (-27%). The combination of OCA + IP118 further reduced liver weight (-29%), liver lipid ( 22%), ALT (-39%), and AST (-36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (-4.3% and -3.5% respectively) and improved glycemic control in OCA + IP118 treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight ( 25.3%) to a greater degree than IP118 alone (-12.5%) and further improved glucose tolerance and reduced hepatic lipid. CONCLUSION: Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH. PMID- 29107285 TI - Host-microbiota interaction induces bi-phasic inflammation and glucose intolerance in mice. AB - OBJECTIVE: Gut microbiota modulates adiposity and glucose metabolism in humans and mice. Here we investigated how colonization of germ-free (GF) mice affects kinetics of adiposity and glucose metabolism. METHODS: Adiposity and glucose metabolism were evaluated at different time points in ex-GF and antibiotic treated mice after colonization with gut microbiota from a conventionally raised (CONV-R) mouse. Mouse physiology, microbiome configuration, serum cytokine levels, and gene expression for inflammatory markers were performed in different tissues. RESULTS: Colonization resulted in a bi-phasic glucose impairment: the first phase occurring within 3 days of colonization (early phase) and the second 14-28 days after colonization (delayed phase). The early phase co-occurred with an inflammatory response and was independent of adiposity, while the delayed phase was mostly ascribed to adipose tissue expansion and inflammation. Importantly, re-colonization of antibiotic treated mice displays only the delayed phase of glucose impairment and adiposity, suggesting that the early phase may be unique to colonization of the immature GF mice gut. CONCLUSIONS: Our results provide new insights on host-microbiota interaction during colonization of GF mice and the resulting effects on adiposity and glucose metabolism in a time resolved fashion. PMID- 29107286 TI - Deletion of hepatic carbohydrate response element binding protein (ChREBP) impairs glucose homeostasis and hepatic insulin sensitivity in mice. AB - OBJECTIVE: Carbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have linked adipose ChREBP to insulin sensitivity in mice. However, while ChREBP is most highly expressed in the liver, the effect of hepatic ChREBP on insulin sensitivity remains unknown. To clarify the importance of hepatic ChREBP on glucose homeostasis, we have generated a knockout mouse model that lacks this protein specifically in the liver (Liver-ChREBP KO). METHODS: Using Liver-ChREBP KO mice, we investigated whether hepatic ChREBP deletion influences insulin sensitivity, glucose homeostasis and the development of hepatic steatosis utilizing various dietary stressors. Furthermore, we determined gene expression changes in response to fasted and fed states in liver, white, and brown adipose tissues. RESULTS: Liver ChREBP KO mice had impaired insulin sensitivity as indicated by reduced glucose infusion to maintain euglycemia during hyperinsulinemic-euglycemic clamps on both chow (25% lower) and high-fat diet (33% lower) (p < 0.05). This corresponded with attenuated suppression of hepatic glucose production. Although Liver-ChREBP KO mice were protected against carbohydrate-induced hepatic steatosis, they displayed worsened glucose tolerance. Liver-ChREBP KO mice did not show the expected gene expression changes in liver in response to fasted and fed states. Interestingly, hepatic ChREBP deletion also resulted in gene expression changes in white and brown adipose tissues, suggesting inter-tissue communication. This included an almost complete abolition of BAT ChREBPbeta induction in the fed state (0.15-fold) (p = 0.015) along with reduced lipogenic genes. In contrast, WAT showed inappropriate increases in lipogenic genes in the fasted state along with increased PEPCK1 in both fasted (3.4-fold) and fed (5.1-fold) states (p < 0.0001). CONCLUSIONS: Overall, hepatic ChREBP is protective in regards to hepatic insulin sensitivity and whole body glucose homeostasis. Hepatic ChREBP action can influence other peripheral tissues and is likely essential in coordinating the body's response to different feeding states. PMID- 29107287 TI - Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury. AB - OBJECTIVE: Excess ethanol consumption has serious pathologic consequences. In humans, repeated episodes of binge drinking can lead to liver damage and have adverse effects on other organs such as pancreas and brain. Long term chronic consumption of ethanol can also result in progressive alcoholic liver disease and cirrhosis. Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple physiologic functions. FGF21 is a novel biomarker for non-alcoholic fatty liver disease (NAFLD) in humans and limits hepatotoxicity in mice. Therefore, we explored the possibility that FGF21 plays a role in response to ethanol consumption in both humans and mice. METHODS: We used a binge drinking paradigm in humans to examine the effect of acute ethanol consumption on circulating FGF21. We adapted this paradigm to evaluate the acute response to ethanol in mice. We then examined the role of FGF21 on liver pathology in two models of chronic ethanol consumption in both wild type (WT) mice and mice lacking FGF21 (FGF21-KO). RESULTS: Acute ethanol consumption resulted in a robust induction of serum FGF21 after 6 h in both humans and mice. Serum ethanol peaked at 1 h in both species and was cleared by 6 h. Ethanol clearance was the same in WT and FGF21-KO mice, indicating that FGF21 does not play a major role in ethanol metabolism in a binge paradigm. When FGF21-KO mice were fed the Lieber-DeCarli diet, a high fat diet supplemented with ethanol, a higher mortality was observed compared to WT mice after 16 days on the diet. When FGF21-KO mice consumed 30% ethanol in drinking water, along with a normal chow diet, there was no mortality observed even after 16 weeks, but the FGF21-KO mice had significant liver pathology compared to WT mice. CONCLUSIONS: Acute or binge ethanol consumption significantly increases circulating FGF21 levels in both humans and mice. However, FGF21 does not play a role in acute ethanol clearance. In contrast, chronic ethanol consumption in the absence of FGF21 is associated with significant liver pathology alone or in combination with excess mortality, depending on the type of diet consumed with ethanol. This suggests that FGF21 protects against long term ethanol induced hepatic damage and may attenuate progression of alcoholic liver disease. Further study is required to assess the therapeutic potential of FGF21 in the treatment of alcoholic liver disease. PMID- 29107288 TI - Identification of islet-enriched long non-coding RNAs contributing to beta-cell failure in type 2 diabetes. AB - OBJECTIVE: Non-coding RNAs constitute a major fraction of the beta-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of beta-cell functions and in diabetes development remains poorly understood. The aim of this study was to identify novel islet lncRNAs differently expressed in type 2 diabetes models and to investigate their role in beta-cell failure and in the development of the disease. METHODS: Novel transcripts dysregulated in the islets of diet-induced obese mice were identified by high throughput RNA-sequencing coupled with de novo annotation. Changes in the level of the lncRNAs were assessed by real-time PCR. The functional role of the selected lncRNAs was determined by modifying their expression in MIN6 cells and primary islet cells. RESULTS: We identified about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in beta-cells, betalinc2, and betalinc3, correlated to body weight gain and glycemia levels in obese mice and was also modified in diabetic db/db mice. The expression of both lncRNAs was also modulated in vitro in isolated islet cells by glucolipotoxic conditions. Moreover, the expression of the human orthologue of betalinc3 was altered in the islets of type 2 diabetic patients and was associated to the BMI of the donors. Modulation of the level of betalinc2 and betalinc3 by overexpression or downregulation in MIN6 and mouse islet cells did not affect insulin secretion but increased beta-cell apoptosis. CONCLUSIONS: Taken together, the data show that lncRNAs are modulated in a model of obesity associated type 2 diabetes and that variations in the expression of some of them may contribute to beta-cell failure during the development of the disease. PMID- 29107289 TI - Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety. AB - OBJECTIVE: Genetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis. METHODS: In this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. We characterized the metabolic and behavioral phenotype of obese mutant mice and examined changes in hypothalamic gene expression. In humans, we examined genetic data from people with severe early onset obesity. RESULTS: We identified an obese mouse heterozygous for a missense mutation (pR108W) in orthopedia homeobox (Otp), a homeodomain containing transcription factor required for the development of neuroendocrine cell lineages in the hypothalamus, a region of the brain important in the regulation of energy homeostasis. OtpR108W/+ mice exhibit increased food intake, weight gain, and anxiety when in novel environments or singly housed, phenotypes that may be partially explained by reduced hypothalamic expression of oxytocin and arginine vasopressin. R108W affects the highly conserved homeodomain, impairs DNA binding, and alters transcriptional activity in cells. We sequenced OTP in 2548 people with severe early-onset obesity and found a rare heterozygous loss of function variant in the homeodomain (Q153R) in a patient who also had features of attention deficit disorder. CONCLUSIONS: OTP is involved in mammalian energy homeostasis and behavior and appears to be necessary for the development of hypothalamic neural circuits. Further studies will be needed to investigate the contribution of rare variants in OTP to human energy homeostasis. PMID- 29107290 TI - An unbiased silencing screen in muscle cells identifies miR-320a, miR-150, miR 196b, and miR-34c as regulators of skeletal muscle mitochondrial metabolism. AB - OBJECTIVE: Strategies improving skeletal muscle mitochondrial capacity are commonly paralleled by improvements in (metabolic) health. We and others previously identified microRNAs regulating mitochondrial oxidative capacity, but data in skeletal muscle are limited. Therefore, the present study aimed to identify novel microRNAs regulating skeletal muscle mitochondrial metabolism. METHODS AND RESULTS: We conducted an unbiased, hypothesis-free microRNA silencing screen in C2C12 myoblasts, using >700 specific microRNA inhibitors, and investigated a broad panel of mitochondrial markers. After subsequent validation in differentiated C2C12 myotubes, and exclusion of microRNAs without a human homologue or with an adverse effect on mitochondrial metabolism, 19 candidate microRNAs remained. Human clinical relevance of these microRNAs was investigated by measuring their expression in human skeletal muscle of subject groups displaying large variation in skeletal muscle mitochondrial capacity. CONCLUSION: The results show that that microRNA-320a, microRNA-196b-3p, microRNA-150-5p, and microRNA-34c-3p are tightly related to in vivo skeletal muscle mitochondrial function in humans and identify these microRNAs as targets for improving mitochondrial metabolism. PMID- 29107291 TI - Absence of the kinase S6k1 mimics the effect of chronic endurance exercise on glucose tolerance and muscle oxidative stress. AB - OBJECTIVE: Ribosomal protein S6 Kinase-1 (S6K1) has been linked to resistance exercise-mediated improvements in glycemia. We hypothesized that S6K1 may also play a role in regulating glycemic control in response to endurance exercise training. METHODS: S6k1-knockout (S6K1KO) and WT mice on a 60 cal% high-fat diet were trained for 4 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. RESULTS: WT mice showed improved glucose tolerance after training. In contrast, S6K1KO mice displayed equally high glucose tolerance already in the sedentary state with no further improvement after training. Similarly, training decreased mitochondrial ROS production in skeletal muscle of WT mice, whereas ROS levels were already low in the sedentary S6K1KO mice with no further decrease after training. Nevertheless, trained S6K1KO mice displayed an increased running capacity compared to trained WT mice, as well as substantially reduced triglyceride contents in liver and skeletal muscle. The improvements in glucose handling and running endurance in S6K1KO mice were associated with markedly increased ketogenesis and a higher respiratory exchange ratio. CONCLUSIONS: In high-fat fed mice, loss of S6K1 mimics endurance exercise training by reducing mitochondrial ROS production and upregulating oxidative utilization of ketone bodies. Pharmacological targeting of S6K1 may improve the outcome of exercise-based interventions in obesity and diabetes. PMID- 29107292 TI - FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/betaKlotho complex in non-adipocytes. AB - OBJECTIVE: Fibroblast Growth Factor 21 (FGF21) is a potent stimulator of brown fat thermogenesis that improves insulin sensitivity, ameliorates hepatosteatosis, and induces weight loss by engaging the receptor complex comprised of Fibroblast Growth Factor Receptor 1 (FGFR1) and the requisite coreceptor betaKlotho. Previously, recombinant antibody proteins that activate the FGFR1/betaKlotho complex were proposed to act as an FGF21-mimetic; however, in vivo action of these engineered proteins has not been well studied. METHODS: We investigated the mechanism by which anti-FGFR1/betaKlotho bispecific antibody (bFKB1) stimulates thermogenesis in UCP1-expressing brown adipocytes using genetically engineered mice. Anti-FGFR1 agonist antibody was also used to achieve brown adipose tissue restricted activation in transgenic mice. RESULTS: Studies with global Ucp1 deficient mice and adipose-specific Fgfr1 deficient mice demonstrated that bFKB1 acts on targets distal to adipocytes and indirectly stimulates brown adipose thermogenesis in a UCP1-independent manner. Using a newly developed transgenic system, we also show that brown adipose tissue restricted activation of a transgenic FGFR1 expressed under the control of Ucp1 promoter does not stimulate energy expenditure. Finally, consistent with its action as a FGF21 mimetic, bFBK1 suppresses intake of saccharin-containing food and alcohol containing water in mice. CONCLUSIONS: Collectively, we propose that FGFR1/betaKlotho targeted therapy indeed mimics the action of FGF21 in vivo and stimulates UCP1-independent brown fat thermogenesis through receptors outside of adipocytes and likely in the nervous system. PMID- 29107293 TI - The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity. AB - OBJECTIVE: Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. METHOD: We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD induced obesity. RESULTS: Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. CONCLUSIONS: By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D. PMID- 29107294 TI - Amino acid sensing in hypothalamic tanycytes via umami taste receptors. AB - OBJECTIVE: Hypothalamic tanycytes are glial cells that line the wall of the third ventricle and contact the cerebrospinal fluid (CSF). While they are known to detect glucose in the CSF we now show that tanycytes also detect amino acids, important nutrients that signal satiety. METHODS: Ca2+ imaging and ATP biosensing were used to detect tanycyte responses to l-amino acids. The downstream pathway of the responses was determined using ATP receptor antagonists and channel blockers. The receptors were characterized using mice lacking the Tas1r1 gene, as well as an mGluR4 receptor antagonist. RESULTS: Amino acids such as Arg, Lys, and Ala evoke Ca2+ signals in tanycytes and evoke the release of ATP via pannexin 1 and CalHM1, which amplifies the signal via a P2 receptor dependent mechanism. Tanycytes from mice lacking the Tas1r1 gene had diminished responses to lysine and arginine but not alanine. Antagonists of mGluR4 greatly reduced the responses to alanine and lysine. CONCLUSION: Two receptors previously implicated in taste cells, the Tas1r1/Tas1r3 heterodimer and mGluR4, contribute to the detection of a range of amino acids by tanycytes in CSF. PMID- 29107295 TI - The FGF21 response to fructose predicts metabolic health and persists after bariatric surgery in obese humans. AB - OBJECTIVE: Fructose consumption has been implicated in the development of obesity and insulin resistance. Emerging evidence shows that fibroblast growth factor 21 (FGF21) has beneficial effects on glucose, lipid, and energy metabolism and may also mediate an adaptive response to fructose ingestion. Fructose acutely stimulates circulating FGF21 consistent with a hormonal response. We aimed to evaluate whether fructose-induced FGF21 secretion is linked to metabolic outcomes in obese humans before and after bariatric surgery-induced weight loss. METHODS: We recruited 40 Roux-en-Y gastric bypass patients and assessed the serum FGF21 response to fructose (75-g fructose tolerance test) and basal and insulin mediated glucose and lipid fluxes during a 2-step hyperinsulinemic-euglycemic clamp with infusion of [6,6-2H2] glucose and [1,1,2,3,3-2H5] glycerol. Liver biopsies were obtained during bariatric surgery. Nineteen subjects underwent the same assessments at 1-year follow-up. RESULTS: Serum FGF21 increased 3-fold at 120 min after fructose ingestion and returned to basal levels at 300 min. Neither basal FGF21 nor the fructose-FGF21 response correlated with liver fat content or liver histopathology, but increased levels were associated with elevated endogenous glucose production, increased lipolysis, and peripheral/muscle insulin resistance. At 1-year follow-up, subjects had lost 28 +/- 6% of body weight and improved in all metabolic outcomes, but fructose-stimulated FGF21 dynamics did not markedly differ from the pre-surgical state. The association between increased basal and stimulated FGF21 levels with poor metabolic health was no longer present after weight loss. CONCLUSIONS: Fructose ingestion in obese humans stimulates FGF21 secretion, and this response is related to systemic metabolism. Further studies are needed to establish if FGF21 signaling is (patho)physiologically involved in fructose metabolism and metabolic health. PMID- 29107296 TI - Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants. AB - OBJECTIVE: Infants born to mothers with obesity have greater adiposity, ectopic fat storage, and are at increased risk for childhood obesity and metabolic disease compared with infants of normal weight mothers, though the cellular mechanisms mediating these effects are unclear. METHODS: We tested the hypothesis that human, umbilical cord-derived mesenchymal stem cells (MSCs) from infants born to obese (Ob-MSC) versus normal weight (NW-MSC) mothers demonstrate altered fatty acid metabolism consistent with adult obesity. In infant MSCs undergoing myogenesis in vitro, we measured cellular lipid metabolism and AMPK activity, AMPK activation in response to cellular nutrient stress, and MSC DNA methylation and mRNA content of genes related to oxidative metabolism. RESULTS: We found that Ob-MSCs exhibit greater lipid accumulation, lower fatty acid oxidation (FAO), and dysregulation of AMPK activity when undergoing myogenesis in vitro. Further experiments revealed a clear phenotype distinction within the Ob-MSC group where more severe MSC metabolic perturbation corresponded to greater neonatal adiposity and umbilical cord blood insulin levels. Targeted analysis of DNA methylation array revealed Ob-MSC hypermethylation in genes regulating FAO (PRKAG2, ACC2, CPT1A, SDHC) and corresponding lower mRNA content of these genes. Moreover, MSC methylation was positively correlated with infant adiposity. CONCLUSIONS: These data suggest that greater infant adiposity is associated with suppressed AMPK activity and reduced lipid oxidation in MSCs from infants born to mothers with obesity and may be an important, early marker of underlying obesity risk. PMID- 29107297 TI - Decreasing CB1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice. AB - OBJECTIVE: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance. METHODS: We used intravenously administered beta-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs. RESULTS: We demonstrate that a robust knock down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin induced Akt phosphorylation. CONCLUSION: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro-inflammatory mechanism. PMID- 29107298 TI - KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes. AB - OBJECTIVE: Increasing plasma levels and activity of dipeptidyl peptidase-4 (DPP4 or CD26) are associated with rapid progression of metabolic syndrome to overt type 2 diabetes mellitus (T2DM). While DPP4 inhibitors are increasingly used as anti-hyperglycemic agents, the reason for the increase in plasma DPP4 activity in T2DM patients remains elusive. METHODS: We looked into the source of plasma DPP4 activity in a cohort of 135 treatment naive nonobese (BMI < 30) T2DM patients. A wide array of ex vivo, in vitro, and in silico methods were employed to study enzyme activity, gene expression, subcellular localization, protease identification, surface expression, and protein-protein interactions. RESULTS: We show that circulating immune cells, particularly CD4+ T cells, served as an important source for the increase in plasma DPP4 activity in T2DM. Moreover, we found kallikrein-related peptidase 5 (KLK5) as the enzyme responsible for cleaving DPP4 from the cell surface by directly interacting with the extracellular loop. Expression and secretion of KLK5 is induced in CD4+ T cells of T2DM patients. In addition, KLK5 shed DPP4 from circulating CD4+ T helper (Th)17 cells and shed it into the plasma of T2DM patients. Similar cleavage and shedding activities were not seen in controls. CONCLUSIONS: Our study provides mechanistic insights into the molecular interaction between KLK5 and DPP4 as well as CD4+ T cell derived KLK5 mediated enzymatic cleavage of DPP4 from cell surface. Thus, our study uncovers a hitherto unknown cellular source and mechanism behind enhanced plasma DPP4 activity in T2DM. PMID- 29107299 TI - Bombesin-like receptor 3 (Brs3) expression in glutamatergic, but not GABAergic, neurons is required for regulation of energy metabolism. AB - OBJECTIVE: Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor. Brs3 null mice have reduced resting metabolic rate and body temperature, increased food intake, and obesity. Here we study the role of Brs3 in different neuron types. METHODS: Mice able to undergo Cre recombinase dependent inactivation or re-expression of Brs3 were generated, respectively Brs3fl/y and Brs3loxTB/y. We then studied four groups of mice with Brs3 selectively inactivated or re-expressed in cells expressing Vglut2-Cre or Vgat Cre. RESULTS: Deletion of Brs3 in glutamatergic neurons expressing Vglut2 reproduced the global null phenotype for regulation of food intake, metabolic rate, body temperature, adiposity, and insulin resistance. These mice also no longer responded to a BRS-3 agonist, MK-5046. In contrast, deletion of Brs3 in GABAergic neurons produced no detectable phenotype. Conversely, the wild type phenotype was restored by selective re-expression of Brs3 in glutamatergic neurons, with no normalization achieved by re-expressing Brs3 in GABAergic neurons. CONCLUSIONS: Brs3 expression in glutamatergic neurons is both necessary and sufficient for full Brs3 function in energy metabolism. In these experiments, no function was identified for Brs3 in GABAergic neurons. The data suggest that the anti-obesity pharmacologic actions of BRS-3 agonists occur via agonism of receptors on glutamatergic neurons. PMID- 29107301 TI - Corrigendum to "Insulin controls food intake and energy balance via NPY neurons" [Mol Metabol 6 (2017) 574-584]. PMID- 29107302 TI - Building bridges between disciplines for sustainable management of plant virus diseases. PMID- 29107300 TI - Adult neural stem cell fate is determined by thyroid hormone activation of mitochondrial metabolism. AB - OBJECTIVE: In the adult brain, neural stem cells (NSCs) located in the subventricular zone (SVZ) produce both neuronal and glial cells. Thyroid hormones (THs) regulate adult NSC differentiation towards a neuronal phenotype, but also have major roles in mitochondrial metabolism. As NSC metabolism relies mainly on glycolysis, whereas mature cells preferentially use oxidative phosphorylation, we studied how THs and mitochondrial metabolism interact on NSC fate determination. METHODS: We used a mitochondrial membrane potential marker in vivo to analyze mitochondrial activity in the different cell types in the SVZ of euthyroid and hypothyroid mice. Using primary adult NSC cultures, we analyzed ROS production, SIRT1 expression, and phosphorylation of DRP1 (a mitochondrial fission mediator) as a function of TH availability. RESULTS: We observed significantly higher mitochondrial activity in cells adopting a neuronal phenotype in vivo in euthyroid mice. However, prolonged hypothyroidism reduced not only neuroblast numbers but also their mitochondrial activity. In vitro studies showed that TH availability favored a neuronal phenotype and that blocking mitochondrial respiration abrogated TH-induced neuronal fate determination. DRP1 phosphorylation was preferentially activated in cells within the neuronal lineage and was stimulated by TH availability. CONCLUSIONS: These results indicate that THs favor NSC fate choice towards a neuronal phenotype in the adult mouse SVZ through effects on mitochondrial metabolism. PMID- 29107303 TI - Physiology of Pain. AB - Acutely ill patients are challenging to frontline nurses because they frequently also have multiple chronic conditions. This article empowers all nurses to develop a foundational understanding of the physiology of acute and chronic pain. The skills, knowledge, and attitude to care for patients experiencing pain are a legal and ethical responsibility of all nurses. This article discusses the physiology of pain to include the neuronal receptors that respond to various painful stimuli, substances that stimulate nociceptors, the nerve pathways, modulation of the perception of pain, and acute verses chronic physiologic changes. PMID- 29107305 TI - Postoperative Visual Analog Pain Scores and Overall Anesthesia Patient Satisfaction. AB - Patient satisfaction is evolving into an important measure of high-quality health care and anesthesia care is no exception. Pain management is an integral part of anesthesia care and must be assessed to determine patient satisfaction; therefore, it is a measure for quality of care. One issue is how patients reflect individual experiences into their overall anesthesia experience. There is a need to identify how postoperative pain scores correlate with anesthesia patient satisfaction survey results. Postoperative pain is not a dominant measure in determining anesthesia patient satisfaction. PMID- 29107304 TI - The Role of Pain Classification Systems in Pain Management. AB - Pain is a multidimensional experience that can significantly impair an individual's quality of life. This article describes the pain classification systems, including anatomic, etiologic, intensity, duration, pathophysiological, and conditions that are not easily classified. A holistic approach is taken by addressing key components to assist with effective pain management, including the psychological and spiritual aspects of care. A case study scenario demonstrates the implementation of pain classifications in pain management. Also discussed are current controversies, potential genetic impacts, and the barriers chronic pain sufferers face, including addiction, diversion, and socioeconomic factors. PMID- 29107306 TI - Pharmacologic Interventions for Pain Management. AB - Serious life-threatening respiratory depression may occur with pharmacologic pain intervention. The nurse has an ethical and legal duty to provide safe, quality, and accountable pain management. The nurse must acquire self-efficacy for the administration of pain medications for critically ill patients to prevent serious side effects and adverse reactions. This article presents a clinical toolkit for acute pain pharmacologic management by presenting professional guidelines, evidence-based pain assessment tools, common pain medication therapy, and focused monitoring specific to the drug. Medical adjustments owing to special populations is also discussed. Case reports demonstrate application of clinical reasoning skills needed for pain management. PMID- 29107307 TI - Pain and Complementary Therapies. AB - Treatment of both acute and chronic pain typically involves a combination of pharmacologic and provider-based interventions, which is effective for some patients but not for others. Use of pain medications, especially repeated and frequent usage, involves the risk of adverse reactions, overuse, and dependency. Complementary and alternative therapies (CAT) offer an alternative or adjunctive method to decrease the pain experience and enhance function and quality of life. Various evidence-based CAT methods have been proved to be effective in the management of both acute and chronic pain. Nurses are well placed to implement various CAT modalities. PMID- 29107308 TI - Dyspnea. AB - Dyspnea is a subjective experience of breathing discomfort that can only be known through a patient's report. Numeric rating or visual analog scales allow assessment of intensity when the patient can self-report. The Respiratory Distress Observation Scale is a valid, reliable tool for estimating distress when self-report cannot be elicited. Treating dyspnea begins with managing the underlying condition. Other dyspnea-specific evidence-based interventions include morphine and fentanyl, upright positioning, oxygen, invasive and noninvasive ventilation, and balancing rest with activity. Effectiveness has not been established for benzodiazepines, nebulized furosemide, oxygen in the face of normoxemia, other opioids, and nebulized fentanyl. PMID- 29107309 TI - Pain Management in Obstetrics. AB - Critical care clinicians may be called on to care for a laboring woman. Comprehension of the anatomic changes associated with pregnancy, and labor and birth, is essential. A working knowledge of the current options for pain management in labor, both pharmacologic and nonpharmacologic, is necessary to facilitate patient-centered care. Pharmacologic options include intravenous or intramuscular agents, inhalational agents, and neuraxial anesthesia. Each modality has contraindications, risks, and benefits that must be considered when choosing the most appropriate method. PMID- 29107310 TI - Management of Chronic Stable Angina. AB - Chronic stable angina (CSA) is a symptomatic problem that is precipitated by ischemic heart disease. CSA is diagnosed when symptoms are present for at least 2 months without changes in severity, character, or triggering circumstances. This article is a summary of current treatment strategies aimed to prevent progression of atherosclerosis, and medication therapies to control angina symptoms and improve quality of life for the individual. PMID- 29107311 TI - The Use of Remifentanil as the Primary Agent for Analgesia in Parturients. AB - Pain control in parturients can be particularly challenging for the hospital staff. To achieve optimal outcomes in anesthesia patients, it is important to consider multiple options for pain control, especially when traditional options pose a problem or are not options. In particular, there are parturient clients for whom the use of neuraxial anesthesia (epidural and spinal blockade) is not an option. One option that warrants consideration for patient centered anesthesia practice is the use of remifentanil. PMID- 29107313 TI - Pain Today. PMID- 29107312 TI - Using Complementary and Alternative Medicine to Treat Pain and Agitation in Dementia: A Review of Randomized Controlled Trials from Long-Term Care with Potential Use in Critical Care. AB - The risk of pain in adults with dementia worsens with advancing age. Painful comorbidities may be underassessed and inadequately treated. Receiving treatment in critical care settings may indicate greater occurrences of pain and complications. Pain may exacerbate behavioral and psychological symptoms of dementia (BPSD), such as agitation. Complementary and alternative medicine (CAM) therapies may alleviate pain and BPSD, and continuity of therapy may bolster these therapeutic effects. This review did not reveal an apparent benefit of aromatherapy; however, improvements in BPSD have been shown previously. Massage and human interaction did demonstrate efficacy in reducing BPSD and pain. PMID- 29107314 TI - [The 2017 Nobel prize in physiology and medicine for the circardian clock]. PMID- 29107316 TI - Editor's Perspectives - November 2017. PMID- 29107315 TI - Biochemistry of Synthetic Biology - Recent Developments. PMID- 29107317 TI - Retraction notice to "Fast track for elderly patients: Is it feasible for colorectal surgery?" [International Journal of Surgery 12 (2014) S20 - S22]. PMID- 29107318 TI - A Quality Improvement Project to Improve Education Provided by Nurses to ED Patients Prescribed Opioid Analgesics at Discharge. AB - BACKGROUND: The opioid crisis continues to take an unprecedented number of lives and is the top cause of injury death in the United States. The emergency department is a setting where patients with pain seek care and may be prescribed an opioid, yet many patients do not receive evidence-based education about taking their opioid safely. Like many communities across the country, Allegheny County, Pennsylvania, has experienced an increased rate of opioid overdoses; from 2015 2016, the number of opioid-related overdose deaths in the county increased by 44%. METHODS: This quality improvement project is the implementation of a nurse delivered, evidence-based education initiative for patients prescribed an opioid in an emergency department. Nurses were briefly trained on opioid safety and patient education, then over 12 weeks, delivered the dual-modal (verbal and written) education with a patient teach-back to verify comprehension. RESULTS: Nurses who completed the project training on opioid safety and patient education had a statistically significant improvement in their knowledge. Patient satisfaction surveys showed 100% of patients reported clear understanding of how to take their pain medication, and out of the patients receiving the opioid pain education for the first time, 88.2% learned something new about how to safely take, store, or dispose of their pain medication. IMPLICATIONS FOR PRACTICE: Improving the delivery of opioid prescription education at emergency department discharge will enhance patient knowledge and promote safety, which may help mitigate the opioid crisis by reducing the rate of opioid use disorder and accidental overdoses. PMID- 29107319 TI - Thermodynamic Activity-Based Progress Curve Analysis in Enzyme Kinetics. AB - Macrokinetic Michaelis-Menten models based on thermodynamic activity provide insights into enzyme kinetics because they separate substrate-enzyme from substrate-solvent interactions. Kinetic parameters are estimated from experimental progress curves of enzyme-catalyzed reactions. Three pitfalls are discussed: deviations between thermodynamic and concentration-based models, product effects on the substrate activity coefficient, and product inhibition. PMID- 29107320 TI - Walking my way? Walker gender and display format Confounds the perception of specific emotions. AB - Previous evidence has shown that males and females display different gait kinematics which may influence the perception of emotions displayed through the same walking gait. We therefore investigated the influence of walker gender on the perception of happiness, sadness, anger and fear displayed through walking movements. Full-light (FL), point-light (PL) and synthetically modelled point light walkers (SW) of both genders were shown to perceivers over three experiments. Additionally, gender ambiguous synthetic walkers were shown to control for the influence of form, gender stereotypes and idiosyncratic gait movements on emotional gait perception. Each emotion was identified above chance level for both walker genders and in all display conditions though significantly less in PL and SW than in FL. The gender of the walker did not influence the pattern of identifications in FL walkers (Fear > Sad > Happy > Anger > Neutral), but did influence the identification patterns in PL (Female: [Happy = Sad = Fear = Anger] > Neutral; Male: Fear = Sad = [Happy > Anger] > Neutral) and SWs (Female: Happy = Sad = Anger = Fear = Neutral; Male: [Happy = Sad = Anger] > [Fear = Neutral]; Ambiguous: [[Happy = Sad = Anger] > Fear] = Neutral). The gender of the walker and format in which they are displayed influenced the perception of different basic emotions. The constructed SW stimuli also displayed happiness, sadness and anger with equivalent intensity in female, male and gender ambiguous walkers thus untangling the perception-expression entanglement that has plagued previous emotion perception research. PMID- 29107321 TI - Multiscale coordination between athletes: Complexity matching in ergometer rowing. AB - Complex systems applications in human movement sciences have increased our understanding of emergent coordination patterns between athletes. In the current study, we take a novel step and propose that movement coordination between athletes is a multiscale phenomenon. Specifically, we investigated so-called "complexity matching" of performance measured in the context of rowing. Sixteen rowers participated in two sessions on rowing ergometers: One individual session of 550 strokes and one dyadic session of 550 strokes side-by-side with a team member. We used evenly-spaced detrended fluctuation analysis (DFA) to calculate the complexity indices (DFA exponents) of the force-peak interval series for each rower in each session. The DFA exponents between team members were uncorrelated in the individual sessions (r = 0.06), but were strongly and significantly correlated when team members rowed together (r = 0.87). Furthermore, we found that complexity matching could not be attributed to the rowers mimicking or locally adapting to each other. These findings contribute to the current theoretical understanding of coordination dynamics in sports. PMID- 29107322 TI - An Interview with Harald H. Sitte. PMID- 29107323 TI - Circadian rhythm and ischaemia-reperfusion injury. PMID- 29107325 TI - Stemness distinctions between the ectomesenchymal stem cells from neonatal and adult mice. AB - Ectomesenchymal stem cells (EMSCs), a type of adult stem cells derived from cranial neural crest, can be non-invasively harvested from respiratory mucosa and play vital roles in therapies based on their stemness. However, whether donor age has any impact on the stemness of EMSCs remains elusive and is essential for EMSCs-based therapies. To address this, we first cultivated EMSCs from neonatal mice aged 1 week and adult mice aged 3 months or 6 months, and then compared their morphology, proliferative capacity, and pluripotency through various induced differentiation assays. The results showed that neonatal EMSCs were fibroblast-like, more regular compared to adult EMSCs; the proliferative capacity of neonatal EMSCs was higher than that of adult EMSCs. More importantly, after neural, adipogenic, chondrogenic, and osteogenic differentiation, neonatal EMSCs differentiated into respective cell types significantly better than adult EMSCs. Notably, EMSCs from mice aged 3 months differentiated into mesodermal lineages better than those from 6 months old mice after induction. Collectively, these results suggest donor ages have significant impact on the EMSCs from respiratory mucosa. PMID- 29107324 TI - Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbalpha antagonism: a single-centre propensity-matched cohort study and a randomised study. AB - BACKGROUND: On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia-reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. METHODS: We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia-reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. FINDINGS: In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0.50 (95% CI 0.32 0.77; p=0.0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0.79 [95% CI 0.68-0.93; p=0.0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning-afternoon variation in hypoxia-reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbalpha being highest in the morning. In a mouse Langendorff model of hypoxia-reoxygenation myocardial injury, Rev-Erbalpha gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia-reperfusion injury modulator CDKN1a/p21. INTERPRETATION: Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbalpha antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. FUNDING: Fondation de France, Federation Francaise de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX 46, and CPER-Centre Transdisciplinaire de Recherche sur la Longevite. PMID- 29107326 TI - Adult hippocampal neurogenesis in neuropathic pain and alkyl glycerol ethers treatment. AB - Neuropathic pain manifested by a number of sensory symptoms is often accompanied by disorders of higher nervous activity, such as memory impairment, depression, anxiety, anhedonia, etc. This emphasizes the involvement of supraspinal structures including the hippocampus in neuropathic pain pathogenesis. In the present study, we focused on the impact of chronic neuropathic pain on hippocampal neurogenesis and microglial state. In addition, we test the effect of alkyl glycerol ethers on hippocampal neuronal and microglial plasticity as well as behavioral parameters. Neuropathic pain was induced using the model of sciatic nerve chronic constriction injury. We found an impairment of working memory and locomotor activity in animals with neuropathic pain, which was prevented by alkyl glycerol ethers treatment. Sciatic nerve ligation in mice contributed to the decrease in hippocampal neurogenesis intensity. Alkyl glycerol ethers administration significantly reduced this effect. Neuropathic pain-associated neurogenesis reduction was accompanied by an increased percentage of Iba1-labeled area in the CA1 hippocampal region on the 14th and 28th days after surgery. In addition, we observed a decrease in hippocampal pro-inflammatory microglia marker CD86 immunostaining on day 28 after surgery in alkyl glycerol ethers-treated mice with sciatic nerve ligation. These results are consistent with data on pro- and anti-inflammatory cytokines expression in the hippocampus. Alkyl glycerol ethers administration increased IL-10 and decreased IL-1beta hippocampal expression in animals with neuropathic pain. Taken together, these data suggest that neuropathic pain-behavior in rodents is accompanied by changes in microglia polarization, thereby contributing to neurogenesis impairment and cognitive disturbances. Alkyl glycerol ethers prevented M1 microglial activation, contributing to the maintenance of normal neurogenesis levels within the hippocampus and normalizing working memory. PMID- 29107327 TI - Microglia are continuously activated in the circumventricular organs of mouse brain. AB - Microglia are the primary resident immune cells of the brain parenchyma and transform into the amoeboid form in the "activated state" under pathological conditions from the ramified form in the "resting state" under physiologically healthy conditions. In the present study, we found that microglia in the circumventricular organs (CVOs) of adult mice displayed the amoeboid form with fewer branched cellular processes even under normal conditions; however, those in other brain regions showed the ramified form, which is characterized by well branched and dendritic cellular processes. Moreover, microglia in the CVOs showed the strong protein expression of the M1 markers CD16/32 and CD86 and M2 markers CD206 and Ym1 without any pathological stimulation. Thus, the present results indicate that microglia in the CVOs of adult mice are morphologically and functionally activated under normal conditions, possibly due to the specialized features of the CVOs, namely, the entry of blood-derived molecules into parenchyma through fenestrated capillaries and the presence of neural stem cells. PMID- 29107328 TI - Effect of cerebrolysin on the cerebellum of diabetic rats: An imunohistochemical study. AB - BACKGROUND: Diabetes mellitus represents one of the disorders in the metabolism that affects all body systems including CNS. Cerebrolysin contains many neurotrophic factors, and many studies reported that it can be used treatment of many neurological disorders. AIM OF THE WORK: The aim of the current study was to study the potential neuroprotective effect of cerebrolysin on the cerebellum of diabetic rat. MATERIALS AND METHODS: Sprague Dawley male rats were divided randomly into four groups: control, cerebrolysin (Cbl), diabetes and diabetes treated with Cbl groups. Induction of diabetes was performed by intraperitoneal injection of 60mg/kg streptozotocin once. Eight weeks later, the rats were anaesthetized, sacrificed and the cerebellum was removed. Cerebellum oxidative stress markers were analysis. Cerebellar tissue was subjected to histolopathological examination and immune-histological assessment of GFAP and Synaptophysin. RESULTS: As compared to the control group, diabetes caused degenerative changes in the cerebellum with significant elevation of MDA and decrease of SOD levels and gliosis confirmed by increase the GFAP expression area fraction. Diabetes increased significantly the optical density of synaptophysin expression with increase in its area fraction in the granular layer. Although Cbl treatment succeeded in minimizing the changes in the oxidative stress markers, it had no effect on pathological changes of the diabetic cerebellum. Cerebrolysin treatment of diabetic rats decreased the area fraction of GFAP positive immunoreactivity and had no effect on synaptophysin expression. CONCLUSION: Cerebrolysin can potentially protect against diabetes induced changes in the cerebellum through minimizing the oxidative stress and improving the gliosis. PMID- 29107329 TI - Cytosolic Protein Vms1 Links Ribosome Quality Control to Mitochondrial and Cellular Homeostasis. AB - Eukaryotic cells have evolved extensive protein quality-control mechanisms to remove faulty translation products. Here, we show that yeast cells continually produce faulty mitochondrial polypeptides that stall on the ribosome during translation but are imported into the mitochondria. The cytosolic protein Vms1, together with the E3 ligase Ltn1, protects against the mitochondrial toxicity of these proteins and maintains cell viability under respiratory conditions. In the absence of these factors, stalled polypeptides aggregate after import and sequester critical mitochondrial chaperone and translation machinery. Aggregation depends on C-terminal alanyl/threonyl sequences (CAT-tails) that are attached to stalled polypeptides on 60S ribosomes by Rqc2. Vms1 binds to 60S ribosomes at the mitochondrial surface and antagonizes Rqc2, thereby facilitating import, impeding aggregation, and directing aberrant polypeptides to intra-mitochondrial quality control. Vms1 is a key component of a rescue pathway for ribosome-stalled mitochondrial polypeptides that are inaccessible to ubiquitylation due to coupling of translation and translocation. PMID- 29107331 TI - Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores. AB - YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation. PMID- 29107332 TI - Neuronal Representation of Social Information in the Medial Amygdala of Awake Behaving Mice. AB - The medial amygdala (MeA) plays a critical role in processing species- and sex specific signals that trigger social and defensive behaviors. However, the principles by which this deep brain structure encodes social information is poorly understood. We used a miniature microscope to image the Ca2+ dynamics of large neural ensembles in awake behaving mice and tracked the responses of MeA neurons over several months. These recordings revealed spatially intermingled subsets of MeA neurons with distinct temporal dynamics. The encoding of social information in the MeA differed between males and females and relied on information from both individual cells and neuronal populations. By performing long-term Ca2+ imaging across different social contexts, we found that sexual experience triggers lasting and sex-specific changes in MeA activity, which, in males, involve signaling by oxytocin. These findings reveal basic principles underlying the brain's representation of social information and its modulation by intrinsic and extrinsic factors. PMID- 29107333 TI - Granzyme B Disrupts Central Metabolism and Protein Synthesis in Bacteria to Promote an Immune Cell Death Program. AB - Human cytotoxic lymphocytes kill intracellular microbes. The cytotoxic granule granzyme proteases released by cytotoxic lymphocytes trigger oxidative bacterial death by disrupting electron transport, generating superoxide anion and inactivating bacterial oxidative defenses. However, they also cause non-oxidative cell death because anaerobic bacteria are also killed. Here, we use differential proteomics to identify granzyme B substrates in three unrelated bacteria: Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis. Granzyme B cleaves a highly conserved set of proteins in all three bacteria, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding, and degradation are also substrates, including multiple aminoacyl tRNA synthetases, ribosomal proteins, protein chaperones, and the Clp system. Because killer cells use a multipronged strategy to target vital pathways, bacteria may not easily become resistant to killer cell attack. PMID- 29107334 TI - MHC-I Genotype Restricts the Oncogenic Mutational Landscape. AB - MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. To validate this hypothesis, we developed and applied a residue-centric patient presentation score to 9,176 cancer patients across 1,018 recurrent oncogenic mutations. We found that patient MHC-I genotype-based scores could predict which mutations were more likely to emerge in their tumor. Accordingly, poor presentation of a mutation across patients was correlated with higher frequency among tumors. These results support that MHC-I genotype-restricted immunoediting during tumor formation shapes the landscape of oncogenic mutations observed in clinically diagnosed tumors and paves the way for predicting personal cancer susceptibilities from knowledge of MHC-I genotype. PMID- 29107335 TI - Analysis of Chromatin Opening in Heterochromatic Non-Small Cell Lung Cancer Tumor Initiating Cells in Relation to DNA-Damaging Antitumor Treatment. AB - PURPOSE: We previously reported that sphere-forming non-small cell lung cancer (NSCLC) tumor-initiating cells (TICs) have an altered activation of DNA damage response- and repair proteins and are refractory to DNA-damaging treatments. We analyzed whether chromatin organization plays a role in the observed refractoriness. METHODS AND MATERIALS: Bulk cells and TICs from the NSCLC H23 and H1299 cell lines were examined using cell viability, clonogenic survival, Western blot, short interfering RNA analysis, and micronucleus assay. RESULTS: NSCLC TICs displayed elevated heterochromatin markers trimethylated lysine 9 of histone H3 and heterochromatin protein 1gamma relative to bulk cells and reduced cell viability upon histone deacetylase inhibition (HDACi). Vorinostat and trichostatin A increased the euchromatin markers acetylated lysine 9/14 of histone H3 and lysine 8 of histone H4, and HDACi pretreatment increased the phosphorylation of the DNA damage response proteins ataxia telangiectasia mutated and DNA-dependent protein kinase, catalytic subunit, upon irradiation in TICs. HDACi sensitized TICs to cisplatin and to some extent to ionizing irradiation. The protectiveness of a dense chromatin structure was indicated by an enhanced frequency of micronuclei in TICs following irradiation, after knockdown of heterochromatin protein 1gamma. CONCLUSIONS: Although confirmatory studies in additional NSCLC model systems and with respect to analyses of other DNA damage response proteins are needed, our data point toward a heterochromatic structure of NSCLC TICs, such that HDACi can sensitize TICs to DNA damage. PMID- 29107336 TI - Citrulline in health and disease. Review on human studies. AB - The amino acid L-citrulline (CIT) is safely used from the neonatal period onwards in those with urea cycle defects and carbamyl phosphate synthetase or ornithine transcarbamylase deficiencies, but several lines of enquiry indicate that it might have a much wider therapeutic role. When protein intake is low and there is a catabolic state, endogenous arginine (ARG) synthesis cannot fully be met and its supplementation can prove challenging, particularly in patients with critical and multisystem illness. Supplementary CIT could constitute a safer but still focused means of delivering ARG to endothelial and immune cells as CIT is efficiently recycled into these cells and as kidneys can convert CIT into ARG. Unlike ARG, CIT is efficiently transported into enterocytes and bypasses liver uptake. It also appears to prevent excessive and uncontrolled nitric oxide (NO) production. Animal studies and early human data indicate positive effects of CIT on protein synthesis, in which its contribution is thought mediated through the mTOR pathway. It appears that CIT is an anabolic pharmaconutrient that can be safely administered even in critically ill patients. Promising results in cardiovascular diseases and in disease-related malnutrition can now be considered sufficient to justify formal clinical exploration in these areas and in sarcopenia in general. PMID- 29107337 TI - CD169+ macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair. AB - Osteal macrophages (osteomacs) contribute to bone homeostasis and regeneration. To further distinguish their functions from osteoclasts, which share many markers and growth factor requirements, we developed a rapid, enzyme-free osteomac enrichment protocol that permitted characterization of minimally manipulated osteomacs by flow cytometry. Osteomacs differ from osteoclasts in expression of Siglec1 (CD169). This distinction was confirmed using the CD169-diphtheria toxin (DT) receptor (DTR) knock-in model. DT treatment of naive CD169-DTR mice resulted in selective and striking loss of osteomacs, whilst osteoclasts and trabecular bone area were unaffected. Consistent with a previously-reported trophic interaction, osteomac loss was accompanied by a concomitant and proportionately striking reduction in osteoblasts. The impact of CD169+ macrophage depletion was assessed in two models of bone injury that heal via either intramembranous (tibial injury) or endochondral (internally-plated femoral fracture model) ossification. In both models, CD169+ macrophage, including osteomac depletion compromised bone repair. Importantly, DT treatment in CD169-DTR mice did not affect osteoclast frequency in either model. In the femoral fracture model, the magnitude of callus formation correlated with the number of F4/80+ macrophages that persisted within the callus. Overall these observations provide compelling support that CD169+ osteomacs, independent of osteoclasts, provide vital pro anabolic support to osteoblasts during both bone homeostasis and repair. PMID- 29107330 TI - Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. AB - Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT. PMID- 29107338 TI - Prevalence and clinicopathologic characteristics of multiple myeloma with cutaneous involvement: A case series from Korea. AB - BACKGROUND: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of a clonal proliferation of tumor cells. Cutaneous involvement of MM is very rare and remains poorly understood. OBJECTIVE: The aim of this study was to examine the clinical and histopathologic characteristics of cutaneous involvement in MM and identify factors associated with overall survival of MM with cutaneous involvement. METHODS: The medical records of 1228 patients with MM were retrieved and analyzed. Of those patients, 14 with cutaneous involvement of MM (1.14%) were further evaluated for their clinical and histopathologic findings. RESULTS: Patients with cutaneous involvement showed significantly reduced overall survival compared with those without cutaneous involvement (median, 28 vs. 57 months; hazard ratio, 1.929; 95% confidence interval, 1.030-3.613). In subgroup analyses of patients with MM with cutaneous involvement, erythematous nodules (P = .004), multiple cutaneous lesions (P = .002), and absence of a grenz zone (P = .004) were clinicopathologic features associated with reduced overall survival after Bonferroni correction. LIMITATIONS: The retrospective design and the small sample size are the limitations. CONCLUSION: Cutaneous involvement accounted for about 1.14% of patients with MM and was associated with reduced overall survival. PMID- 29107339 TI - Comorbidities in rosacea: A systematic review and update. AB - BACKGROUND: Rosacea is linked to abnormalities of cutaneous vasculature and dysregulation of the inflammatory response. Recent reports on rosacea have shown a significant association with cardiovascular, gastrointestinal, and psychiatric diseases, all of which may affect morbidity and mortality among these patients. OBJECTIVE: To review available data regarding comorbidities associated with rosacea, discuss their pathogenesis, and highlight the evaluation of affected patients. METHODS: We performed a complete and systematic literature review in PubMed/Medline, Embase, and the Cochrane Collaboration databases, searching for all articles on possible associated diseases that have been reported with rosacea, with no limits on publication date, participant age, sex, or nationality. RESULTS: A total of 29 studies were included in this systematic review, including 14 case-control, 8 cross-sectional, and 7 cohort studies. Statistically significant association with rosacea has been mostly demonstrated with depression (n = 117,848 patients), hypertension (n = 18,176), cardiovascular diseases (n = 9739), anxiety disorder (n = 9079), dyslipidemia (n = 7004), diabetes mellitus (n = 6306), migraine (n = 6136), rheumatoid arthritis (n = 4192), Helicobacter pylori infection (n = 1722), ulcerative colitis (n = 1424), and dementia (n = 1194). LIMITATIONS: Limitations included the accuracy of the published data, potential patient selection, and possible confounding factors. The true nature of the drawn correlations is uncertain, and causality cannot be established. CONCLUSIONS: Rosacea is associated with a number of systemic disorders. Recognition of these conditions is critical to providing appropriate screening and management of affected patients. PMID- 29107340 TI - Langerhans cell histiocytosis: A neoplastic disorder driven by Ras-ERK pathway mutations. AB - Langerhans cell histiocytosis (LCH) is a disorder of myeloid neoplasia of dendritic cells that affects 1 in 200,000 children <15 years of age and even fewer adults. LCH presents with a spectrum of clinical manifestations. High-risk stratification is reserved for infiltration of blood, spleen, liver, and lungs. After decades of debate on the disease pathogenesis, a neoplastic mechanism is now favored on the basis of LCH cell clonality, rare cases of familial clustering, and recent evidence of mutations involving the Ras/Raf/MEK (mitogen activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathway in lesional biopsy specimens. Somatic mutations are most often found in BRAF (BRAFV600E in 47.1% of reported patients) and MAP2K1 (21.7%) and uncommonly found in MAP3K1 or ARAF. Increased levels of phospho-ERK in lesional tissue, activation of Ras/Raf/MEK/ERK signaling with these mutations in vitro, and the mutual exclusivity of these mutations in a given patient suggest a central role for activation of the Ras/Raf/MEK/ERK oncogenic pathway in LCH. Immunohistochemical assessment of lesional tissue using the VE1 BRAFV600E mutation-specific antibody can serve as a screening tool for BRAFV600E-positive LCH. Case reports suggest that BRAFV600E-positive LCH unresponsive to standard therapy might respond to B-Raf-MEK pathway inhibition, but rigorous randomized clinical trials have yet to be performed. PMID- 29107341 TI - Clinicopathologic features of 28 cases of nail matrix nevi (NMNs) in Asians: Comparison between children and adults. AB - BACKGROUND: Clinical distinction between nail matrix nevus (NMN) and subungual melanoma (SUM) can be challenging. More precise delineation of the clinicodermoscopic characteristics specific for NMNs is needed. OBJECTIVE: We sought to analyze the clinicopathologic features of childhood and adult NMNs and to propose clinicodermoscopic features that can aid in differentiating NMNs from SUM. METHODS: We retrospectively reviewed clinical, dermoscopic, and histologic findings of patients (20 children and 8 adults) in whom NMN was diagnosed between 2012 and 2015. RESULTS: Except for 2 cases of total melanonychia, the affected nails demonstrated longitudinal melanonychia sharply demarcated from the adjacent nail plate. Melanonychia was wider among children than among adults (P = .002). Nail dystrophy was more frequent in wider lesions (P = .028). Hutchinson's sign was observed in pediatric cases at the hyponychium and/or proximal nailfold cuticles. All hyponychial pigmentations demonstrated a longitudinal brush pigmentation pattern under dermoscopy. LIMITATIONS: This was a retrospective study of Asians in a single center. CONCLUSION: Our study is the largest case series to date of biopsy-confirmed NMNs. It highlighted important clinicodermoscopic differences between pediatric and adult NMNs. We propose that in pediatric cases of longitudinal melanonychia presenting as a sharply demarcated pigment band of even width, the presence of Hutchinson's sign with longitudinal brush pigmentation may favor a diagnosis of NMN over SUM. PMID- 29107343 TI - ? PMID- 29107342 TI - Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center. AB - BACKGROUND: Sweet syndrome is a neutrophilic dermatosis that may be categorized into classic, malignancy-associated, and drug-induced subtypes. Few studies have systematically analyzed this rare disorder. OBJECTIVE: To describe the clinicopathologic characteristics and treatment of Sweet syndrome and identify characteristics associated with concurrent malignancy. METHODS: We retrospectively reviewed patients with Sweet syndrome at the University of Pennsylvania from 2005 to 2015. RESULTS: We identified 83 patients (mean age, 57 years; 51% male) with Sweet syndrome: 30% with the classic form, 44% with the malignancy-associated form, 24% with the drug-induced form in the setting of malignancy, and 2% with the drug-induced form. Acute myeloid leukemia was the most common malignancy (in 24 of 83 patients [29%]). Filgrastim was the most common medication (used in 8 of 83 patients [10%]). Leukopenia (P < .001), anemia (P = .002), thrombocytopenia (P < .001), absence of arthralgia (P < .001), and histiocytoid or subcutaneous histopathology (P = .024) were associated with malignancy (chi2 test). LIMITATIONS: This was a retrospective study that represents patients from a single tertiary academic referral center, which may limit its generalizability to other settings. CONCLUSION: When caring for patients with Sweet syndrome, dermatologists should be aware of the potential association of leukopenia, anemia, thrombocytopenia, absence of arthralgia, and histiocytoid or subcutaneous histopathology with malignancy. PMID- 29107344 TI - Faithful Artificial Chromosome Propagation Using Spermatogonial Stem Cells. AB - Artificial chromosomes are useful in making functional vectors for very large genes, studying chromosome physiology, and modeling chromosomal disorders. Shinohara et al. have succeeded for the first time in creating transchromosomic mice by manipulating spermatogonial stem cells (SSCs), which exhibited superior chromosomal stability compared with embryonic stem cells (ESCs). PMID- 29107346 TI - Potential impact and cost-effectiveness of rotavirus vaccination in Afghanistan. AB - INTRODUCTION: Despite progress made in child survival in the past 20 years, 5.9 million children under five years died in 2015, with 9% of these deaths due to diarrhea. Rotavirus is responsible for more than a third of diarrhea deaths. In 2013, rotavirus was estimated to cause 215,000 deaths among children under five years, including 89,000 in Asia. As of April 2017, 92 countries worldwide have introduced rotavirus vaccination in their national immunization program. Afghanistan has applied for Gavi support to introduce rotavirus vaccination nationally. This study estimates the potential impact and cost-effectiveness of a national rotavirus immunization program in Afghanistan. METHODS: This study examined the use of Rotarix(r) (RV1) administered using a two-dose schedule at 6 and 10 weeks of age. We used the ProVac Initiative's UNIVAC model (version 1.2.09) to evaluate the impact and cost-effectiveness of a rotavirus vaccine program compared with no vaccine over ten birth cohorts from 2017 to 2026 with a 3% annual discount rate. All monetary units are adjusted to 2017 US$. RESULTS: Rotavirus vaccination in Afghanistan has the potential to avert more than one million cases; 660,000 outpatient visits; approximately 50,000 hospital admissions; 650,000 DALYs; and 12,000 deaths, over 10 years. Not accounting for any Gavi subsidy, rotavirus vaccination can avert DALYs at US$82/DALY from the government perspective and US$80/DALY from the societal perspective. With Gavi support, DALYs can be averted at US$29/DALY and US$31/DALY from the societal and government perspective, respectively. The average yearly cost of a rotavirus vaccination program would represent 2.8% of the total immunization budget expected in 2017 and 0.1% of total health expenditure. CONCLUSION: The introduction of rotavirus vaccination would be highly cost-effective in Afghanistan, and even more so with a Gavi subsidy. PMID- 29107347 TI - Sex-differential effects of diphtheria-tetanus-pertussis vaccine for the outcome of paediatric admissions? A hospital based observational study from Guinea Bissau. AB - BACKGROUND: In spite of protection against the targeted infections, a large volume of observational data indicates that diphtheria-tetanus-pertussis (DTP) vaccine may have a negative impact on overall childhood mortality in low-income countries, especially in girls. METHODS: In an observational study using data from Bandim Health Project's continuous registration of all admissions to the paediatric ward at the National Hospital Simao Mendes in Bissau, we investigated whether DTP was associated with higher female than male in-hospital mortality (female/male case fatality ratio (F/M CFR)) and whether the CFR comparing DTP vaccinated and DTP-unvaccinated children differed by sex. We included children aged 6 weeks to 8 months (274 days) admitted to the paediatric ward with a vaccination card seen during admission. RESULTS: From May 2001 to January 2008, 4230 children aged 6 weeks to 8 months were admitted and 3450 (82%; 1997 boys, 1453 girls) presented a vaccination card. The proportion presenting a vaccination card and DTP coverage did not differ by sex. During admission, 16% (200/1250) of the girls and 13% (220/1694) of the boys who had received DTP died. The F/M CFR among the 2944 DTP-vaccinated children was 1.23 (1.03-1.46); while it was 0.95 (0.66-1.38) among the 506 children who had not received DTP. DTP-vaccinated children were older and had better socioeconomic status. Adjusted for age, BCG vaccination, residence, and maternal education the CFR comparing DTP-vaccinated boys with DTP-unvaccinated boys was 0.84 (0.63-1.11), while the CFR comparing DTP vaccinated girls with DTP-unvaccinated girls was 1.28 (0.90-1.83) (p = .07 for same effect in boys and girls). CONCLUSION: Among DTP-vaccinated children, female in-hospital mortality was higher than male in-hospital mortality and DTP vaccination tended to be associated with higher mortality in girls. The data are consistent with DTP having negative effects on mortality for girls. Further studies are necessary to design the optimal vaccination programme for both sexes. PMID- 29107345 TI - Functional Genomics of Host-Microbiome Interactions in Humans. AB - The human microbiome has been linked to various host phenotypes and has been implicated in many complex human diseases. Recent genome-wide association studies (GWASs) have used microbiome variation as a complex trait and have uncovered human genetic variants that are associated with the microbiome. Here we summarize results from these studies and illustrate potential regulatory mechanisms by which host genetic variation can interact with microbiome composition. We argue that, similar to human GWASs, it is important to use functional genomics techniques to gain a mechanistic understanding of causal host-microbiome interactions and their role in human disease. We highlight experimental, functional, and computational genomics methodologies for the study of the genomic basis of host-microbiome interactions and describe how these approaches can be utilized to explain how human genetic variation can modulate the effects of the microbiome on the host. PMID- 29107348 TI - Validation of the modified Glasgow Prognostic Score (mGPS) in recurrent ovarian cancer (ROC) - Analysis of patients enrolled in the GCIG Symptom Benefit Study (SBS). AB - BACKGROUND: Modified Glasgow Prognostic Score (mGPS) is predictive of survival in many advanced cancers, but has not been evaluated in recurrent ovarian cancer (ROC). The aim was to determine validity of mGPS in ROC, investigate its associations with health related quality of life (HRQL) and ECOG performance status (PS). METHODS: mGPS is based on serum C reactive protein (CRP) and albumin, with scores ranging from 0 (least) to 2 (most). HRQL was measured with EORTC QLQ C-30 and OV-28. chi2 tests for trend were used to examine the relationship between HRQL, PS and mGPS. Cox proportional hazards regression was used to assess associations between mGPS, HRQL, clinicopathological factors, and overall survival (OS). RESULTS: Inflammatory markers were available in 516 of 948 patients in GCIG SBS. 200(39%) had potentially platinum sensitive ROC with >=3 lines of chemotherapy, 316(61%) had platinum resistant ROC. 282(55%), 123(24%), 111(22%) had mGPS of 0, 1, 2, respectively. Median OS (months) was 18.1, 9.6, and 6.6 for mGPS 0, 1, and 2 respectively. mGPS was an independent predictor of OS after adjusting for PS and platinum sensitivity (p<0.001). mGPS remained a predictor of OS after adjusting for physical function, role function, global health status, abdominal/GI symptoms, and multiple clinicopathologic factors (p=0.02). Worse PS and higher mGPS were associated with poorer HRQL (p<0.001). Higher mGPS was associated with worse HRQL, independent of PS. CONCLUSION: The mGPS is an independent predictor of OS in ROC after adjusting for HRQL and clinicopathological factors. Higher mGPS is associated with worse HRQL independent of PS. mGPS is simple, inexpensive and may be suitable for clinical practice, clinical trial patient selection and stratification. PMID- 29107349 TI - Prognostic significance of lymphadenectomyin malignant ovarian sex cord stromal tumor: A retrospective cohort study and meta-analysis. AB - OBJECTIVES: To evaluate the prognostic significance of lymphadenectomy in malignant ovarian sex cord stromal tumor (SCST). METHODS: The medical records of patients with malignant ovarian SCST who underwent primary surgery from April 2005 to December 2016 were retrospectively reviewed in the Department of Obstetrics and Gynecology of Qilu Hospital. A meta-analysis was performed by searching the PubMed and Embase database up to July 20, 2017. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by STATA statistical software version 19.0. RESULTS: Seventy-two patients with malignant SCST were identified in our institution. The mean age of the patients was 44.3years (range, 8-80years). Among the 72 patients, 69.4% had granulosa cell tumors (GCTs, n=50); 47.2% (n=34) underwent lymphadenectomy, and 52.8% (n=38) did not undergo the surgery. None of the lymph nodes had pathologically confirmed metastasis. No significant differences in overall survival of the patients with SCST or GCT were noted based on patient age, tumor size, surgery extent, or administration of cytotoxic chemotherapy, except tumor stage (P=0.010 in SCTs and 0.029 in GCTs, respectively). Lymphadenectomy showed no statistically significant difference in overall survival of patients with SCST or GCT (P=0.734 and 0.079, respectively). In our meta-analysis, a total of 179 studies were identified through a search strategy, and 13 studies were included eventually; 3223 cases were identified, including those from our institution. The random-effects model was used because of moderate heterogeneity (I2=43.8%, P=0.040). The estimated pooled OR was 0.87 (95% CI, 0.57-1.31), indicating that lymphadenectomy has no statistical significance in improving overall survival in SCSTs (Z=0.68, P=0.496). CONCLUSIONS: Tumor stage is the most important prognostic factor affecting SCST overall survival. There is no significant effect of lymphadenectomy in improving the overall survival of SCSTs. Lymphadenectomy is not recommended in initial staging surgery of SCST due to the extremely low lymph node metastasis rate. PMID- 29107350 TI - Dynamics of persistent organic pollutants in obese adolescents during weight loss. AB - We have investigated the dynamics of various persistent organic pollutants (POPs) in the serum of 94 obese adolescents (34 boys and 60 girls: age range 11-19years) before (0M) and after 5months (5M) of undergoing weight loss treatment. Six groups of POPs, such as polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs), chlordane compounds (CHLs), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB) and polybrominated diphenyl ethers (PBDEs), were detected in all samples in the decreasing order of median levels: DDTs>PCBs>HCB>HCHs>CHLs>PBDEs. Levels and patterns of POPs between boys and girls at two time-points were similar. DDTs (0M/5M; median: 31/42ng/g lw) and PCBs (0M/5M; median: 17/28ng/g lw) were the major POPs. PCB 153 (0M/5M; 33/34% of the sum PCBs) was the most dominant PCB congener, followed by PCB 138 (0M/5M; 31/31%) and PCB 180 (0M/5M; 13/12%), respectively. The most important PBDE congeners were BDE 47 and 153, although total PBDE levels were low and ranged between 0.63 and 0.88ng/g lw. In general, levels of POPs in the obese adolescents were lower than previously reported in Belgian adolescents and adults. Due to weight loss, serum levels (except PBDEs) increased significantly thereafter combined with a body weight decrease (from 4 to 42kg). Serum concentrations increased by 1-3.5% per kilogram weight loss and 1 2.5% per BMI z-score loss for most POPs. To our knowledge, this is the first report on the dynamics of POPs in obese adolescents during weight loss. Lipid soluble contaminants were released from adipose tissue into the blood leading to redistribution into the body. Whether the increase in the internal exposure to POPs may adversely influence health remains to be determined. PMID- 29107351 TI - Drinking water disinfection by-products during pregnancy and child neuropsychological development in the INMA Spanish cohort study. AB - BACKGROUND: Disinfection by-products (DBPs) constitute a complex mixture of prevalent chemicals in drinking water and there is evidence of neurotoxicity for some of them. OBJECTIVES: We evaluated the association between estimates of DBP exposure during pregnancy and child neuropsychological outcomes at 1 and 4-5years of age. METHODS: We conducted a population-based mother-child cohort study in Spain with recruitment at first trimester of gestation (INMA Project, 2003-2008). Neuropsychological development was measured at 1year of age using the Bayley Scales of Infant Development and at 4-5years with the McCarthy Scales of Children's Abilities. Modeled tap water concentrations of trihalomethanes (THM) were combined with personal ingestion, showering and bathing habits to estimate exposure as ingestion uptake, all route (showering, bathing, ingestion) uptake (MUg/day) and crude levels (MUg/l) in the residence. Chloroform, brominated THMs (bromodichloromethane, dibromochloromethane, bromoform) and total THMs (chloroform and brominated THMs) were analysed separately. Nine haloacetic acids levels were available in one of the areas. Linear regression was used to estimate associations in 1855 subjects adjusting for covariables. RESULTS: The median concentration of total THMs, chloroform, brominated THMs, total haloacetic acids, dichloroacetic acid, and trichloroacetic acid were, respectively 30.3MUg/L, 9.4MUg/L, 11.6MUg/L, 10.5MUg/L, 2.7MUg/L, and 3.1MUg/L. The associations between THM exposure and neuropsychological outcomes were null, except for total and brominated THM uptake though all routes and the general cognitive score at 4 5years, with a decrease in -0.54 points (95%CI -1.03, -0.05) and -0.64 (95%CI 1.16, -0.12), respectively, for doubling total and brominated THM uptake. A positive association found between dichloroacetic acid and the mental score at 1year did not persist at 4-5years. CONCLUSIONS: Minor associations observed between DBP exposure during gestation and child neuropsychological development at 1year disappeared at 4-5years. Although a suggestive association is identified for exposure to brominated THMs and the cognitive score at 4-5years, chance cannot be ruled out. PMID- 29107352 TI - Review of antibiotic resistance in China and its environment. AB - Antibiotic resistance is a global health crisis linked to increased, and often unrestricted, antibiotic use in humans and animals. As one of the world's largest producers and consumers of antibiotics, China is witness to some of the most acute symptoms of this crisis. Antibiotics and antibiotic resistance genes (ARGs) are widely distributed in surface water, sewage treatment plant effluent, soils and animal wastes. The emergence and increased prevalence of ARGs in the clinic/hospitals, especially carbapenem-resistant gram negative bacteria, has raised the concern of public health officials. It is important to understand the current state of antibiotic use in China and its relationship to ARG prevalence and diversity in the environment. Here we review these relationships and their relevance to antimicrobial resistance (AMR) trends witnessed in the clinical setting. This review highlights the issues of enrichment and dissemination of ARGs in the environment, and also future needs in mitigating the spread of antibiotic resistance in the environment, particularly under the 'planetary health' perspective, i.e., the systems that sustain or threaten human health. PMID- 29107354 TI - Effects of Extracorporeal Shock Wave-Mediated Transdermal Local Anesthetic Drug Delivery on Rat Caudal Nerves. AB - Cavitation plays a substantial role in the clinical effects of extracorporeal shock wave therapy (ESWT). It is also generally accepted as a major mechanism in sonophoresis. To identify the enhancing effect of extracorporeal shock wave mediated transdermal drug delivery, 24 Wistar rats were randomly assigned to four groups: (i) topical application of a eutectic mixture of local anesthetics (EMLA); (ii) 1-MHz ultrasound; (iii) ESWT pre-treatment combined with EMLA application; (iv) ESWT concurrent with EMLA application on rat tails. The degree of anesthesia was assessed using the amplitude and latency of sensory nerve action potentials within 5 min after a 60-min EMLA application. The results indicated that ESWT pre-treatment and concurrent ESWT accelerated the anesthetic effects of the EMLA cream on the tail nerve (p < 0.05). This finding might indicate that shock wave-mediated transdermal drug delivery is possible during the ESWT period. PMID- 29107355 TI - Spatial Compounding of 3-D Fetal Brain Ultrasound Using Probabilistic Maps. AB - A new method to address the problem of shadowing in fetal brain ultrasound volumes is presented. The proposed approach is based on the spatial composition of multiple 3-D fetal head projections using the weighted Euclidean norm as an operator. A support vector machine, which is trained with optimal textural features, was used to assign weighting according to the posterior probabilities of brain tissue and shadows. Both phantom and real fetal head ultrasound volumes were compounded using previously reported operators and compared with the proposed composition method to validate it. The quantitative evaluations revealed increases in signal-to-noise ratio <=35% and in contrast-to-noise ratio <=135% using real data. Qualitative comparisons made by obstetricians indicated that this novel method adequately recovers brain tissue and improves the visibility of the main cerebral structures. This may prove useful both for fetal monitoring and in the diagnosis of brain defects. Overall this new approach outperforms spatial composition methods previously reported. PMID- 29107356 TI - A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion. AB - Pericardial effusion is the abnormal accumulation of fluid in the pericardial space. The complications of pericardial effusion can either be acute (e.g., cardiac tamponade) or chronic (e.g., constrictive pericarditis). We have conducted a systematic review of the scientific literature to evaluate the efficacy and safety of intrapericardial fibrinolysis in preventing complications of pericardial effusion. We searched for both published and unpublished studies. 29 studies, with a total of 109 patients were included in this review; 17 case reports, 11 case series, and one randomised controlled trial (RCT). All included studies had a high risk of bias. The most common causes of pericardial effusion were Staphylococcus aureus (12 studies with 23 cases) and Mycobacterium tuberculosis (2 studies with 19 cases). The most common fibrinolytic agents used were streptokinase (15 studies) and urokinase (5 studies). Intrapericardial fibrinolysis prevented complications in 94 (86.2%) patients. Non-fatal procedure related complications were reported 21 (19.2%) patients. No patient died following intrapericardial fibrinolysis. There is very low certainty of the efficiency and safety of intrapericardial fibrinolysis in preventing the complications of pericardial effusion. High quality RCTs are required to address this question. PMID- 29107357 TI - Late gadolinium enhancement as a predictor of functional recovery, need for defibrillator implantation and prognosis in non-ischemic dilated cardiomyopathy. AB - BACKGROUND: Aim of the study was to investigate whether late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) predict reverse remodeling (RR) in non-ischemic dilated cardiomyopathy (NIDCM). METHODS: Seventy-one NIDCM patients (age 57+/-14years, 43 males, median left ventricular ejection fraction [LVEF] 35%, [interquartile range 27-41%]) with two CMR scans within 5years were included. RR was defined as >=10% reduction in left ventricular (LV) end diastolic volume and >=10% LVEF increase. The end-point was a composite of all cause death, cardiovascular hospitalization or appropriate defibrillator discharge. LGE was assessed both visually and as percentage of LV mass (LGE%). RESULTS: LGE was present in 42 patients (59%). During the interval between the 2 CMR scans (median 28 [15-44]months), 22 patients (31%) displayed RR. LGE absence predicted RR irrespectively of baseline LV volumes and LVEF. Over a median 42[15 73]-month follow-up, the endpoint occurred in 36 patients (51%). LGE absence was associated with better prognosis (P=0.043), with best quantitative LGE cut-point <7% at ROC analysis (P=0.017), but RR was the strongest prognostic predictor. Among 35 patients with baseline LVEF <35%, 25 (69%) crossed the 35% LVEF threshold. Both LGE absence and quantitative LGE <7% were associated with crossing of the 35% LVEF threshold for defibrillator implantation; patients with either LGE or quantitative LGE>=7% had a worse prognosis. CONCLUSIONS: In NIDCM, the absence of LGE at baseline CMR is associated with RR. When baseline LVEF is <35%, LGE absence is associated with more frequent crossing of the 35% LVEF threshold for defibrillator implantation. PMID- 29107353 TI - Ultrasound Imaging Technologies for Breast Cancer Detection and Management: A Review. AB - Ultrasound imaging is a commonly used modality for breast cancer detection and diagnosis. In this review, we summarize ultrasound imaging technologies and their clinical applications for the management of breast cancer patients. The technologies include ultrasound elastography, contrast-enhanced ultrasound, 3-D ultrasound, automatic breast ultrasound and computer-aided detection of breast ultrasound. We summarize the study results seen in the literature and discuss their future directions. We also provide a review of ultrasound-guided, breast biopsy and the fusion of ultrasound with other imaging modalities, especially magnetic resonance imaging (MRI). For comparison, we also discuss the diagnostic performance of mammography, MRI, positron emission tomography and computed tomography for breast cancer diagnosis at the end of this review. New ultrasound imaging techniques, ultrasound-guided biopsy and the fusion of ultrasound with other modalities provide important tools for the management of breast patients. PMID- 29107358 TI - Patient-reported outcomes in adults with congenital heart disease: Inter-country variation, standard of living and healthcare system factors. AB - AIMS: Geographical differences in patient-reported outcomes (PROs) of adults with congenital heart disease (ConHD) have been observed, but are poorly understood. We aimed to: (1) investigate inter-country variation in PROs in adults with ConHD; (2) identify patient-related predictors of PROs; and (3) explore standard of living and healthcare system characteristics as predictors of PROs. METHODS AND RESULTS: Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease - International Study (APPROACH-IS) was a cross sectional, observational study, in which 4028 patients from 15 countries in 5 continents were enrolled. Self-report questionnaires were administered: patient reported health (12-item Short Form Health Survey; EuroQOL-5D Visual Analog Scale); psychological functioning (Hospital Anxiety and Depression Scale); health behaviors (Health Behavior Scale-Congenital Heart Disease) and quality of life (Linear Analog Scale for quality of life; Satisfaction With Life Scale). A composite PRO score was calculated. Standard of living was expressed as Gross Domestic Product per capita and Human Development Index. Healthcare systems were operationalized as the total health expenditure per capita and the overall health system performance. Substantial inter-country variation in PROs was observed, with Switzerland having the highest composite PRO score (81.0) and India the lowest (71.3). Functional class, age, and unemployment status were patient related factors that independently and consistently predicted PROs. Standard of living and healthcare system characteristics predicted PROs above and beyond patient characteristics. CONCLUSIONS: This international collaboration allowed us to determine that PROs in ConHD vary as a function of patient-related factors as well as the countries in which patients live. PMID- 29107359 TI - Heart transplantation in arrhythmogenic right ventricular cardiomyopathy - Experience from the Nordic ARVC Registry. AB - OBJECTIVE: There is a paucity of data on heart transplantation (HTx) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and specific recommendations on indications for listing ARVC patients for HTx are lacking. In order to delineate features pertinent to HTx assessment, we explored the pre-HTx characteristics and clinical history in a cohort of ARVC patients who received heart transplants. METHODS: Data from 31 ARVC/HTx patients enrolled in the Nordic ARVC Registry, transplanted between 1988 and 2014 at a median age of 46years (14 65), were compared with data from 152 non-transplanted probands with Definite ARVC according to 2010 Task Force Criteria from the same registry. RESULTS: The HTx patients were younger at presentation, median 31 vs. 38years (p=0.001). There was no difference in arrhythmia-related events. The indication for HTx was heart failure in 28 patients (90%) and ventricular arrhythmias in 3 patients (10%). During median follow-up of 4.9years (0.04-28), there was one early death and two late deaths. Survival was 91% at 5years after HTx. Age at first symptoms under 35years independently predicted HTx in our cohort (OR=7.59, 95% CI 2.69-21.39, p<0.001). CONCLUSION: HTx in patients with ARVC is performed predominantly due to heart failure. This suggests that current 2016 International Society for Heart and Lung Transplantation heart transplant listing recommendations for other cardiomyopathies could be applicable in many cases when taking into account the haemodynamic consequences of right ventricular failure in conjunction with ventricular arrhythmia. PMID- 29107361 TI - Race but not Hepatitis C co-infection affects survival of HIV+ individuals on dialysis in contemporary practice. AB - Individuals with HIV infection are at elevated risk of developing end-stage renal disease. However, their outcomes after starting chronic dialysis in the contemporary era of widespread antiretroviral therapy are not well described. Using detailed data from a national dialysis provider, we determined HIV status by administrative codes and antiretroviral medication prescriptions, with hepatitis C virus (HCV) co-infection status provided by routinely measured serology. The survival on dialysis among 5348 individuals in the HIV+ group and 1863 HIV+/HCV+ individuals to a HIV-/HCV- reference cohort was compared. Race significantly modified the effect of HIV and HIV/HCV infection on mortality. In a multivariable model, HIV infection was not associated with an increased risk of death among Caucasians (hazard ratio 1.03, 95% confidence interval 0.91-1.16) but HIV/HCV co-infection (1.48, 1.18-1.87) was. In the same model for non-Caucasians, both HIV infection (1.44, 1.37-1.52) and HIV/HCV co-infection (1.71, 1.60-1.84) were significantly associated with higher mortality. A secondary analysis using propensity scores yielded similar results. Median follow-up for the reference group was 645 days (interquartile range 230-1323), 772 days (276-1623) for the HIV+ group and 777 days (334-1665) for the co-infected group. Thus, in the contemporary era of widespread antiretroviral use, HIV infection remains associated with a significant reduction in dialysis survival for non-Caucasians while HIV/HCV co-infection is associated with impaired survival regardless of race or ethnicity. Hence, interventions to improve the care for these vulnerable populations are needed. PMID- 29107362 TI - Minimising farm crop protection pressure supported by the multiple functionalities of the DISCUSS indicator set. AB - Sustainable crop protection (SCP) has many facets. Farmers may therefore perceive transition to SCP as very complex. The Dual Indicator Set for Crop Protection Sustainability (DISCUSS) can handle this complexity. To provide targeted support throughout the transition to SCP, complexity capture must be synchronised with the time course of on-farm decision-making. Tool use must be tuned to farmer awareness and appropriate level of data in consecutive stages. This paper thus explores the potential functionalities of DISCUSS in relation to both complexity and time. Results from apple and potato crop protection show three potential functions: DISCUSS can be used as (1) a simulation tool for communication and decision support, (2) an assessment and monitoring tool, and (3) a discussion support tool for farmer groups. Analysis of these functionalities using a framework for guiding on-farm sustainability assessment and strategic decision making shows how each functionality can support the consecutive steps of transition to SCP, i.e. using the right tool functionality at the right time. PMID- 29107360 TI - Yield of atrial fibrillation detection with Textile Wearable Holter from the acute phase of stroke: Pilot study of Crypto-AF registry. AB - BACKGROUND: We describe the feasibility of monitoring with a Textile Wearable Holter (TWH) in patients included in Crypto AF registry. METHODS: We monitored cryptogenic stroke patients from stroke onset (<3days) continuously during 28days. We employed a TWH composed by a garment and a recorder. We compared two garments (Lead and Vest) to assess rate of undiagnosed Atrial Fibrillation (AF) detection, monitoring compliance, comfortability (1 to 5 points), skin lesions, and time analyzed. We describe the timing of AF detection in three periods (0-3, 4-15 and 16-28days). RESULTS: The rate of undiagnosed AF detection with TWH was 21.9% (32 out of 146 patients who completed the monitoring). Global time compliance was 90% of the time expected (583/644h). The level of comfortability was 4 points (IQR 3-5). We detected reversible skin lesions in 5.47% (8/146). The comfortability was similar but time compliance (in hours) was longer in Vest group 591 (IQR [521-639]) vs. Lead 566 (IQR [397-620]) (p=0.025). Also, time analyzed was more prolonged in Vest group 497 (IQR [419-557]) vs. Lead (336h (IQR [140-520]) (p=0.001)). The incidence of AF increases from 5.6% (at 3days) to 17.5% (at 15th day) and up to 20.9% (at 28th day). The percentage of AF episodes detected only in each period was 12.5% (0-3days); 21.7% (4-15days) and 19% (16 28days). CONCLUSIONS: 28days Holter monitoring from the acute phase of the stroke was feasible with TWH. Following our protocol, only five patients were needed to screen to detected one case of AF. PMID- 29107363 TI - Effects of biochar addition on toxic element concentrations in plants: A meta analysis. AB - Consuming food contaminated by toxic elements (TEs) could pose a substantial risk to human health. Recently, biochar has been extensively studied as an effective soil ameliorant in situ because of its ability to suppress the phytoavailability of TEs. However, despite the research interest, the effects of biochar applications to soil on different TE concentrations in different plant parts remain unclear. Here, we synthesize 1813 individual observations data collected from 97 articles to evaluate the effects of biochar addition on TE concentrations in plant parts. We found that (1) the experiment type, biochar feedstock and pyrolysis temperature all significantly decreased the TE concentration in plant parts; (2) the responses of Cd and Pb concentrations in edible and indirectly edible plant parts were significantly more sensitive to the effect of biochar than the Zn, Ni, Mn, Cr, Co and Cu concentrations; and (3) the biochar dosage and surface area, significantly influenced certain TE concentrations in plant tissues as determined via correlation analysis. Moreover, the only exception in this study was found for metalloid element (i.e., As) concentrations in plants, which were not significantly influenced by biochar addition. Overall, the effects of biochar on TE concentrations in plant tissues were negative, at least on average, and the central trends suggest that biochar has a considerable ability to mitigate the transfer of TEs to food, thereby reducing the associated health risks. Our results provide an initial quantitative determination of the effects of biochar addition on multifarious TEs in different plant parts as well as an assessment of the ability of biochar to reduce TE concentrations in plants. PMID- 29107364 TI - Environmental and water sustainability of milk production in Northeast Spain. AB - This study focuses on the assessment of the environmental profile of a milk farm, representative of the dairy sector in Northeast Spain, from a cradle-to-gate perspective. The Life Cycle Assessment (LCA) principles established by ISO standards together with the carbon footprint guidelines proposed by International Dairy Federation (IDF) were followed. The environmental results showed two critical contributing factors: the production of the livestock feed (e.g., alfalfa) and the on-farm emissions from farming activities, with contributions higher than 50% in most impact categories. A comparison with other LCA studies was carried out, which confirmed the consistency of these results with the values reported in the literature for dairy systems from several countries. Additionally, the Water Footprint (WF) values were also estimated according to the Water Footprint Network (WFN) methodology to reveal that feed and fodder production also had a predominant influence on the global WF impacts, with contributions of 99%. Green WF was responsible for remarkable environmental burdens (around 88%) due to the impacts associated with the cultivation stage. Finally, the substitution of alfalfa by other alternative protein sources in animal diets were also proposed and analysed due to its relevance as one of the main contributors of livestock feed. PMID- 29107365 TI - Controlled burn and immediate mobilization of potentially toxic elements in soil, from a legacy mine site in Central Victoria, Australia. AB - Conducting controlled burns in fire prone areas is an efficient and economic method for forest management, and provides relief from the incidence of high severity wild fires and the consequent damage to human property and ecosystems. However, similar to wild fires, controlled burns also affect many of the physical and biogeochemical properties of the forest soil and may facilitate remobilization of potentially toxic elements (PTEs) sequestered in vegetation and soil organic matter. The objective of the current study is to investigate the mobilization of PTEs, in Central Victorian forest soils in Australia after a controlled burn. Surface soil samples were collected two days before and after the controlled burn to determine the concentration of PTEs and to examine the physicochemical properties. Results show that As, Cd, Mn, Ni and Zn concentrations increased 1.1, 1.6, 1.7, 1.1 and 1.9 times respectively in the post-burn environment, whereas the concentrations of Hg, Cr and Pb decreased to 0.7, 0.9 and 0.9 times respectively, highlighting considerable PTE mobility during and after a controlled burn. Whilst these results do not identify very strong correlations between physicochemical properties of soil and PTEs in the pre- and post-burn environments, PTEs themselves demonstrated very strong and significant correlations. The mobilization of As, Hg and other toxic elements raise potential health concerns as the number of controlled burns are projected to increase in response to climate change. Due to this increased level of PTE release and remobilization, the use of any kinds of controlled burn must be carefully considered before being used as a forest management strategy in mining affected landscapes which include areas with high PTE concentrations. PMID- 29107366 TI - Correlations between hair and tissue mercury concentrations in Icelandic arctic foxes (Vulpes lagopus). AB - Monitoring organic pollutants in wildlife is a common approach to evaluate environmental health, chemical exposure and to make hazard assessments. However, pollutant concentrations measured from different tissue types among studies impede direct comparisons of levels and toxicity benchmarks among species and regions. For example, mercury (Hg) is a metal of both natural and anthropogenic origin which poses health risks for marine and arctic biota in particular. Although hair is recognized as the least invasive sample type for Hg exposure measurement in wildlife, measurements in previous studies have used different tissues among individuals and species. This lack of tissue type consistency hinders cross study comparisons. Therefore to systematically evaluate the use of hair in ecotoxicological studies, total mercury (THg) concentrations measured from hair were compared to values obtained from liver and kidney in 35 Icelandic arctic foxes (Vulpes lagopus). THg concentrations varied considerably among tissues with hair and kidney levels generally lower than in liver. Nevertheless, significant correlations among tissue types were observed. THg values in hair were predictive for liver (R2=0.61) and kidney THg levels (R2=0.51) and liver values were a good predictor of THg in kidney (R2=0.77). We provide further evidence that non-invasively collected hair samples reflect the THg levels of internal tissues. We present equations derived from multiple linear regression models that can be used to relate THg levels among tissue types in order to extrapolate THg values from hair to soft tissues. Using these equations, we compare the results of previous studies monitoring THg levels in different tissues of arctic foxes from various regions of the Arctic. Our findings support that hair is a suitable sample matrix for ecotoxicological studies of arctic predators and may be applied in both wildlife welfare and conservation contexts for arctic vulpine species. PMID- 29107367 TI - Under which climate and soil conditions the plant productivity-precipitation relationship is linear or nonlinear? AB - Understanding under which climate and soil conditions the plant productivity precipitation relationship is linear or nonlinear is useful for accurately predicting the response of ecosystem function to global environmental change. Using long-term (2000-2016) net primary productivity (NPP)-precipitation datasets derived from satellite observations, we identify >5600pixels in the North Hemisphere landmass that fit either linear or nonlinear temporal NPP precipitation relationships. Differences in climate (precipitation, radiation, ratio of actual to potential evapotranspiration, temperature) and soil factors (nitrogen, phosphorous, organic carbon, field capacity) between the linear and nonlinear types are evaluated. Our analysis shows that both linear and nonlinear types exhibit similar interannual precipitation variabilities and occurrences of extreme precipitation. Permutational multivariate analysis of variance suggests that linear and nonlinear types differ significantly regarding to radiation, ratio of actual to potential evapotranspiration, and soil factors. The nonlinear type possesses lower radiation and/or less soil nutrients than the linear type, thereby suggesting that nonlinear type features higher degree of limitation from resources other than precipitation. This study suggests several factors limiting the responses of plant productivity to changes in precipitation, thus causing nonlinear NPP-precipitation pattern. Precipitation manipulation and modeling experiments should combine with changes in other climate and soil factors to better predict the response of plant productivity under future climate. PMID- 29107368 TI - Thinning but not understory removal increased heterotrophic respiration and total soil respiration in Pinus massoniana stands. AB - Quantifying soil respiration (Rs) and its components [autotrophic respiration (Ra) and heterotrophic respiration (Rh)] in relation to forest management is vital to accurately evaluate forest carbon balance. Thus, Rs, Ra, and Rh were continuously monitored from November 2013 to November 2016 in Pinus massoniana forests subjected to four different management practices in China. We hypothesized that understory removal and thinning decrease Ra and Rh and thus Rs, and these decreases will change with time following UR and thinning. Mean values of Rs, Ra, and Rh in light thinned plots (LT=15% of tree basal area thinned) and heavily thinned plots (HT=70% of tree basal area thinned) were significantly higher than in control (CK) and understory removal plots (UR). The annual Rh/Rs ratio ranged from 58% to 70% across all treatments, and this ratio was significantly higher in HT and LT than in UR and CK. Only HT significantly increased soil temperature. Soil temperature could better explain Rh (R2=0.69 0.96) than Ra (R2=0.51-0.86). HT and LT increased Q10 for both Ra and Rh, except for Rh in UR. Soil moisture content (W; %) was significantly higher in HT than in other treatments, but W had limited effects on soil respiration in that rain-rich subtropical China. This result suggests that global warming alone, or in combination with clear-cutting or canopy tree thinning will markedly increase soil heterotrophic respiration and thus the total soil CO2 emission. To get firewood for local people and to reduce soil CO2 emissions under global warming, canopy trees are needed to be protected and understory shrubs may be allowed to be used in the subtropical China. PMID- 29107369 TI - Modeling impacts of sea-level rise, oil price, and management strategy on the costs of sustaining Mississippi delta marshes with hydraulic dredging. AB - Over 25% of Mississippi River delta plain (MRDP) wetlands were lost over the past century. There is currently a major effort to restore the MRDP focused on a 50 year time horizon, a period during which the energy system and climate will change dramatically. We used a calibrated MRDP marsh elevation model to assess the costs of hydraulic dredging to sustain wetlands from 2016 to 2066 and 2016 to 2100 under a range of scenarios for sea level rise, energy price, and management regimes. We developed a subroutine to simulate dredging costs based on the price of crude oil and a project efficiency factor. Crude oil prices were projected using forecasts from global energy models. The costs to sustain marsh between 2016 and 2100 changed from $128,000/ha in the no change scenario to ~$1,010,000/ha in the worst-case scenario for sea level rise and energy price, an ~8-fold increase. Increasing suspended sediment concentrations, which is possible using managed river diversions, raised created marsh lifespan and decreased long term dredging costs. Created marsh lifespan changed nonlinearly with dredging fill elevation and suspended sediment level. Cost effectiveness of marsh creation and nourishment can be optimized by adjusting dredging fill elevation to the local sediment regime. Regardless of management scenario, sustaining the MRDP with hydraulic dredging suffered declining returns on investment due to the convergence of energy and climate trends. Marsh creation will likely become unaffordable in the mid to late 21st century, especially if river sediment diversions are not constructed before 2030. We recommend that environmental managers take into consideration coupled energy and climate scenarios for long term risk assessments and adjust restoration goals accordingly. PMID- 29107370 TI - LCA of greywater management within a water circular economy restorative thinking framework. AB - Greywater reuse is an attractive option for the sustainable management of water under water scarcity circumstances, within a water circular economy restorative thinking framework. Its successful deployment relies on the availability of low cost and environmentally friendly technologies. The life cycle assessment (LCA) approach provides the appropriate methodological tool for the evaluation of alternative treatments based on environmental decision criteria and, therefore, it is highly useful during the process conceptual design. This methodology should be employed in the early design phase to select those technologies with lower environmental impact. This work reports the comparative LCA of three scenarios for greywater reuse: photocatalysis, photovoltaic solar-driven photocatalysis and membrane biological reactor, in order to help the selection of the most environmentally friendly technology. The study has been focused on the removal of the surfactant sodium dodecylbenzenesulfonate, which is used in the formulation of detergents and personal care products and, thus, widely present in greywater. LCA was applied using the Environmental Sustainability Assessment methodology to obtain two main environmental indicators in order to simplify the decision making process: natural resources and environmental burdens. Energy consumption is the main contributor to both indicators owing to the high energy consumption of the light source for the photocatalytic greywater treatment. In order to reduce its environmental burdens, the most desirable scenario would be the use of solar light for the photocatalytic transformation. However, while the technological challenge of direct use of solar light is approached, the environmental suitability of the photovoltaic solar energy driven photocatalysis technology to greywater reuse has been demonstrated, as it involves the smallest environmental impact among the three studied alternatives. PMID- 29107371 TI - Understanding farmers' safety behaviour towards pesticide exposure and other occupational risks: The case of Zanjan, Iran. AB - Preventive interventions for reducing occupational risks and health problems among farmers require the identification of factors contributing to unsafe behaviour, but research on this topic is rather limited. A theoretical model for studying factors affecting farmers' use of occupational safety and health (OSH) practices in Iran was developed. The model was empirically tested using data collected from a survey of 301 tomato farmers of Zanjan Province of Iran. The examined OSH practices encompassed a wide range of behaviours, grouped in four categories, i.e., use of pesticides, use of machinery, use of personal protective equipment (PPE), and applying ergonomic principles (i.e., fitting the task to the individual, designing the workplace based on human factors, taking into account the interaction between the workplace and the workers, exercising during work or rest). Almost half of the farmers (49.5%) showed unsafe behaviour in the use of PPE. Moreover, significant proportions of the farmers showed potentially unsafe behaviour in the use of pesticides (42.2%), in applying ergonomic principles (40.2%) and in the use of machinery (35.9%). Attitude towards OSH practices, knowledge on OSH practices, and self-efficacy in safety had a direct positive effect on farmers' use of OSH practices, explaining 73% of the variance in farmers' safety behaviour. Overall, findings contribute to a better understanding of the use of OSH practices among farmers, providing empirical evidence in the cognitive processing of farmers' with respect to safety behaviour in farming and offering practical information that can be incorporated into OSH intervention programs in Iran and other developing countries. PMID- 29107372 TI - Hepatotoxicity of paraquat on common carp (Cyprinus carpio L.). AB - Paraquat (PQ) is a nonselective herbicide that is used worldwide and has been demonstrated to be a high risk to aquatic organisms. However, relatively little is known about the mechanisms on detoxification and hepatotoxicity of PQ in fish. In the present study, a sub-acute toxicity test of PQ exposure on common carp at 1.596 and 3.192mgL-1 for 7d was conducted under laboratory conditions. The results showed that the transcriptional levels of cytochrome P450s (CYPs), such as CYP1A, CYP2K, and CYP3A138, GSTalpha and GSTpi, and export pump gene MDR1, as well as the erythromycin-N-demethylase (ERND) activity were generally up regulated by PQ exposure for 7d, indicating that these genes or enzymes are potentially involved in the detoxification of PQ in the fish liver. Further research showed that PQ exposure significantly increased the levels of HSP70, HSP90, NOS, and MDA; promoted expression of pro-inflammatory cytokines, including IL-6 and IL-8; altered the levels of anti-inflammatory cytokines IL-10 and TGF beta, and generally reduced the levels of T-AOC, SOD, CAT, and GSH. In addition, we also found that caspase-3, caspase-8, and caspase-9 were significantly activated in the fish liver following PQ exposure. In brief, the present study showed that PQ exposure induced fish liver injury by destabilizing the metabolism of fish, inhibiting antioxidant enzyme activity, elevating lipid peroxidation, and promoting an immune inflammatory response and apoptosis. The present study further enriches and perfects the mechanism theory of PQ hepatotoxicity to fish, which may be valuable for the risk assessment of PQ and human health protection. PMID- 29107373 TI - Evaluation of mercury in a freshwater environment impacted by an organomercury fungicide using diffusive gradient in thin films. AB - The use of pesticides to manage pest problems for crop protection is common practice around the world, and their accumulation in soils and contamination of water bodies is a global environmental problem. In Australia, an organomercury (Hg)-based fungicide is the most popular for control of pineapple disease of sugarcane. However, the presence of Hg is of great concern because of potential adverse effects in the environment. The purpose of this work was to evaluate the residual levels of Hg in soils of sugarcane cultivation from a catchment in North Queensland (Australia). Mercury was surveyed in soils close to the Tully River at 3 different depths (100, 200 and 300mm). Additionally, total Hg (THg) and the labile fraction of Hg in water (measured by the diffusive gradient in thin film technique) were determined in the Tully River. A pristine site, the Tully Gorge National Park upstream of sugarcane fields, was selected for background Hg concentration estimation. In soils, Hg levels ranged from 18 to 264MUgkg-1, with one of the soil samples being almost 10 times higher than at other sites at the surface level (199MUgkg-1). Total and labile concentrations of Hg in water increased from the Hg-elevated soil sampling sites (0.085MUgL-1 and 0.061MUgL-1) to downstream sites (0.082MUgL-1 and 0.066MUgL-1), which is likely due to agricultural runoff. Indeed, except for the upstream control site, the THg concentration in water is over the limit permitted by the Australian freshwater quality guideline for protection of 99% species (0.06MUgL-1). These findings point to the need to perform further research to reveal the mechanisms for release of Hg from soil and whether this might be causing important adverse effects to the Great Barrier Reef located in front of this river catchment. PMID- 29107374 TI - Enhanced removal of aqueous acetaminophen by a laccase-catalyzed oxidative coupling reaction under a dual-pH optimization strategy. AB - Acetaminophen is one kind of pharmaceutical contaminant that has been detected in municipal water and is hard to digest. A laccase-catalyzed oxidative coupling reaction is a potential method of removing acetaminophen from water. In the present study, the kinetics of radical polymerization combined with precipitation was studied, and the dual-pH optimization strategy (the enzyme solution at pH7.4 being added to the substrate solution at pH4.2) was proposed to enhance the removal efficiency of acetaminophen. The reaction kinetics that consisted of the laccase-catalyzed oxidation, radical polymerization and precipitation were studied by UV in situ, LC-MS and DLS (dynamic light scattering) in situ. The results showed that the laccase-catalyzed oxidation is the rate-limiting step in the whole process. The higher rate of enzyme-catalyzed oxidation under a dual-pH optimization strategy led to much faster formation of the dimer, trimer and tetramer. Similarly, the formation of polymerized products that could precipitate naturally from water was faster. Under the dual-pH optimization strategy, the initial laccase activity was increased approximately 2.9-fold, and the activity remained higher for >250s, during which approximately 63.7% of the total acetaminophen was transformed into biologically inactive polymerized products, and part of these polymerized products precipitated from the water. Laccase belongs to the family of multi-copper oxidases, and the present study provides a universal method to improve the activity of multi-copper oxidases for the high performance removal of phenol and its derivatives. PMID- 29107375 TI - Tracing of particulate organic C sources across the terrestrial-aquatic continuum, a case study at the catchment scale (Carminowe Creek, southwest England). AB - Soils deliver crucial ecosystem services, such as climate regulation through carbon (C) storage and food security, both of which are threatened by climate and land use change. While soils are important stores of terrestrial C, anthropogenic impact on the lateral fluxes of C from land to water remains poorly quantified and not well represented in Earth system models. In this study, we tested a novel framework for tracing and quantifying lateral C fluxes from the terrestrial to the aquatic environment at a catchment scale. The combined use of conservative plant-derived geochemical biomarkers n-alkanes and bulk stable delta13C and delta15N isotopes of soils and sediments allowed us to distinguish between particulate organic C sources from different land uses (i.e. arable and temporary grassland vs. permanent grassland vs. riparian woodland vs. river bed sediments) (p<0.001), showing an enhanced ability to distinguish between land use sources as compared to using just n-alkanes alone. The terrestrial-aquatic proxy (TAR) ratio derived from n-alkane signatures indicated an increased input of terrestrial derived organic matter (OM) to lake sediments over the past 60years, with an increasing contribution of woody vegetation shown by the C27/C31 ratio. This may be related to agricultural intensification, leading to enhanced soil erosion, but also an increase in riparian woodland that may disconnect OM inputs from arable land uses in the upper parts of the study catchment. Spatial variability of geochemical proxies showed a close coupling between OM provenance and riparian land use, supporting the new conceptualization of river corridors (active river channel and riparian zone) as critical zones linking the terrestrial and aquatic C fluxes. Further testing of this novel tracing technique shows promise in terms of quantification of lateral C fluxes as well as targeting of effective land management measures to reduce soil erosion and promote OM conservation in river catchments. PMID- 29107376 TI - Relevance of transportation to correlations among criticality, physical means of propagation, and distribution of dengue fever cases in the state of Bahia. AB - Dengue infection is a public health problem with a complex distribution. The physical means of propagation and the dynamics of diffusion of the disease between municipalities need to be analysed to direct efficient public policies to prevent dengue infection. The present study presents correlations of occurrences of reported cases of dengue infection among municipalities, self-organized criticality (SOC), and transportation between areas, identifying the municipalities that play an important role in the diffusion of dengue across the state of Bahia, Brazil. The significant correlation found between the correlation network and the SOC demonstrates that the pattern of intramunicipal diffusion of dengue is coupled to the pattern of synchronisation between the municipalities. Transportation emerges as influential in the dynamics of diffusion of epidemics by acting on the aforementioned variables. PMID- 29107377 TI - Determination of annual and seasonal daytime and nighttime trends of MODIS LST over Greece - climate change implications. AB - Climate change is one of the most challenging research topics during the last few decades, as temperature rise has already posed a significant impact on the earth's functions thus affecting all life of the planet. Land Surface Temperature (LST) is identified as a key variable in environmental and climate studies. The present study investigates the distribution of daytime and nighttime LST trends over Greece, a country in the Mediterranean area which is identified as one of the main "hot-spots" of climate change projections. Remotely sensed LST data were obtained from MODerate Resolution Imaging Spectroradiometer (MODIS) sensor in the form of 8-day composites of day and night values at a resolution of 1km for a 17 year period, i.e. from 2000 to 2017. Spatial aggregates of 10km*10km were computed and the annual and seasonal temporal trends were determined for each one of those sub-areas. Results showed that annual trends of daily LST in the majority of areas demonstrated decrease ranging from -1*10-2 degrees C to -1.3*10 3 degrees C, with some sporadic parts showing a slight increase. A totally different outcome is observed in the fate of night LST, with all areas over Greece demonstrating increasing annual trends ranging from 4.6*10-5 degrees C to 3.1*10-3 degrees C, with highest values in the South-East parts of the country. Seasonal trends in day and night LST showed the same pattern, i.e., a general decrease in the day LST and a definite increase in night. An interesting finding is the increase in winter LST trends observed both for day and night LST, indicating that the absolute minimum annual LST observed during winter in Greece increases. Our results also indicate that the annual diurnal LST range is decreasing. PMID- 29107378 TI - The role of the indoor environment: Residential determinants of allergy, asthma and pulmonary function in children from a US-Mexico border community. AB - The El Paso Children's Health Study examined environmental risk factors for allergy and asthma among fourth and fifth grade schoolchildren living in a major United States-Mexico border city. Complete questionnaire information was available for 5210 children, while adequate pulmonary function data were available for a subset of 1874. Herein we studied indoor environmental health risk factors for allergy and asthma. Several indoor environmental risk factors were associated with allergy and asthma. In particular, we found that ant and spider pest problems, pet dogs, fireplace heat, central air conditioning, humidifier use, and cooking with gas stoves were positively associated with both allergy and asthma prevalence. With regards to asthma severity, our analysis indicated that exposure to pet dogs increased monotonically with increasing asthma severity while the lack of any heat source and gas stove use for cooking decreased monotonically with increasing asthma severity. Lung function also decreased among children who lived in homes with reported cockroach pest problem in the past year without concurrent use of pesticides. These effects on pulmonary function were present even after excluding children with a current physician's diagnosis of asthma. Clinicians and public health professionals may need to look closely at the contribution of these indoor risk factors on pulmonary health and quality of life among susceptible populations. PMID- 29107379 TI - Engineered/designer biochar for the removal of phosphate in water and wastewater. AB - During the past decade, biochar has attracted immense scientific interest for agricultural and environmental applications. A broad range of biochars with advantageous properties (e.g., high surface area, flexible architecture, and high porosity) has been developed for pollution abatement. Nevertheless, biochar suffers from certain drawbacks (e.g., limited sorption capacity for anions and poor mechanical properties) that limit their practical applicability. This review focuses on recent advancements in biochar technology, especially with respect to its technical aspects, the variables associated with removing phosphates from water, and the challenges for such abatement. The attention paid to the specific remediation of phosphate from water using biochar is limited (n=1114 - Scopus) compared to the application of biochar to other common water pollutants (n=3998 - Scopus). The subject warrants immediate rigorous research because of the undesirable effects of excess phosphate in water bodies. This review will thus facilitate the construction of a roadmap for further developments and the expansion of this challenging area of research. PMID- 29107380 TI - The fate of multilamellar bodies produced and secreted by Dictyostelium discoideum amoebae. AB - The amoeba Dictyostelium discoideum produces and secretes multilamellar bodies (MLBs) mainly composed of amoebal membranes upon digestion of bacteria. After their secretion, the fate of these MLBs remains unknown. The aim of this study was to determine if protozoa can internalize and digest secreted D. discoideum MLBs. Our results showed that MLBs were ingested by naive axenic D. discoideum cells (i. e. cells not exposed to bacteria and consequently not producing MLBs). Only a small fraction of the ingested MLBs were found in cells' post-lysosomes compared to undigestible beads suggesting that naive amoebae digest them. D. discoideum MLBs were also ingested by the ciliates Tetrahymena pyriformis and Tetrahymena thermophila. MLBs internalized by the ciliates were compacted into pellets and expelled in the extracellular medium without obvious signs of degradation. The results of this study provide new insights on the biological function of MLBs and, considering that MLBs are also involved in bacteria packaging, suggest additional layers of complexity in microbial interactions. PMID- 29107381 TI - Circumferential Adipofascial Graft for Prevention of Recurrence of Posttraumatic Radioulnar Synostosis. AB - Radioulnar synostosis can cause substantial loss of function, and surgical treatment can be challenging. Recurrence of the contracture related to scar or reformation of the synostosis is problematic. Several techniques have been described for prevention of recurrence. We present a technique utilizing a free wrap around adipofascial graft for interposition and circumferential coverage of the ulna after resection of the heterotopic bone. We believe this technique has the advantages of technical simplicity, secure interposition, and reliable outcomes. PMID- 29107382 TI - Human monoclonal antibodies neutralizing influenza virus A/H1N1pdm09 and seasonal A/H1N1 strains - Distinct Ig gene repertoires with a similar action mechanism. AB - Influenza virus causes acute respiratory infection in humans, and is a major public health concern globally. Antibodies play a central role in host protection against influenza virus. We isolated human monoclonal antibodies (hMAb) 206-2-4 and 201-6-8 by a human hybridoma protocol that neutralized various but distinct influenza virus (IFV) A/H1N1 strains, including 2009 pandemic strains. The half inhibitory concentration of 206-2-4 and 201-6-8 against A/H1N1pdm09 strains was 2 100ng/mL and 5-20MUg/mL, respectively. Prophylactic and therapeutic potencies of 206-2-4 were demonstrated in a mouse model of IFV infection at i.p. dosages of 0.25 and 2.5mg/kg, respectively, suggesting that 206-2-4 is one of the most potent hnMAbs against IFV reported thus far. The Ig genes of 206-2-4 and 201-6-8 were originated from distinct germ line repertoires, and accompanied by 63 and 23 somatic hypermutations, respectively. The hemagglutination inhibitory activity indicated that the mechanism of neutralization was to interfere the virus receptor interaction. The binding epitope of the two antibodies was mapped to hemagglutinin 1 (HA1) amino acid residues 111-120. Additional interaction between the antibody and the HA1 globular head was necessary for neutralization. Such hnMAbs bearing distinct binding epitope have been rarely reported. The potency is likely due to the coverage of a wide surface area of HA protein by these hnMABs. IFV is a highly variable. Our knowledge on the mechanisms by which these cross reactive hnMAbs function should help design a novel immunogen for the development of a vaccine effective against broader spectrum of IFV strains. PMID- 29107383 TI - Alteration in Ikaros expression promotes B-1 cell differentiation into phagocytes. AB - Ikaros is a broad transcription factor pointed as a critical regulator of lymphocyte development. Recent reports have emphasized that distinct isoforms of Ikaros control the dichotomy of the hematopoietic system into lymphoid and myeloid lineages. In addition, expression of dominant-negative isoforms of Ikaros is linked to abnormal hematopoiesis, which could culminate in hematological disorders due to loss of function of the protein. B-1 cells are an intriguing subtype of B-lymphocytes that preserves some myeloid characteristics. These cells are able to differentiate into phagocytes (B-1CDP - B-1 cell derived phagocytes) in vitro and in vivo. During such process, reprogramming of gene expression occurs: lymphoid genes are turned off, while expression of myeloid genes is increased. This study aims to investigate whether Ikaros could be related to the control of B-1 cell plasticity. Interestingly, Ikaros expression by B-1CDP cells was found to be relatively low, and the protein is abnormally localized in the cytoplasm. Moreover, the isoforms expressed by B-1 cells are different from those expressed by other lymphocytes, with expression of active isoforms being almost absent in B-1CDP. Based on these findings, Ikaros could be an important factor driving the differentiation and proliferation of B-1 cells. PMID- 29107384 TI - Binding of human complement C1 sterase inhibitor to Leptospira spp. AB - Leptospirosis is an important zoonosis of global importance caused by bacteria Leptospira spp. Pathogenic Leptospira is resistant to Complement System killing while non-pathogenic Leptospira is rapidly killed by exposure to normal human serum (NHS). Pathogenic Leptospira interact with Complement Regulators such as Factor H, C4b binding protein and Vitronectin avoiding Complement activation and killing by Alternative and Classical Pathways. One important regulator is C1 inhibitor (C1INH) that interacts with C1s or MASPs controlling the cleavage of C4 and C2 molecules, thereby inhibiting the activation of the Classical and Lectin Pathways. In this study, we demonstrate that attenuated, saprophytic and pathogenic Leptospira interact with C1INH that maintain its regulatory capacity of interaction with C1s preventing the activation of Complement system. Although the interaction with C1INH is not crucial for pathogenic Leptospira survival, it seems to be important for the survival of attenuated and saprophytic Leptospira in normal human serum. PMID- 29107385 TI - CCL2 conditionally determines CCL22-dependent Th2-accumulation during TGF-beta induced breast cancer progression. AB - We investigated expressions of -CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 breast cancer (BCa) patients and correlated with transforming growth factor-beta (TGF-beta) expression. We observed an inverse correlation of TGF-beta expression with CCL2, CCL5 expression in early stages of BCa. On contrary, in late stages, CCL2, not CCL5, expression was found to be directly proportional with TGF-beta expression. TGF-beta stimulated MDA-MB-231 cells to express CCL2, however, downregulated both CCL2 and CCL5 in MCF-7. Interestingly, a significant swing of Th1-Th2 ratio towards Th2 is seen within the primary tumors expressing moderate/high-CCL2-low/negative-CCL5. We observed that CCL2 CCR2 interaction induces monocytes/macrophages to secrete Th2-attracting chemokine CCL22 in vitro. Therefore, CCL2 secreted from the tumor microenvironment may attract and interact with monocytes/macrophages, and favor Th2 accumulation by inducing CCL22 secretion. Study in 4T1-BALB/c BCa mouse model demonstrated significant (p<0.05) decrease in CCL2, CCL5 and CCL22 levels and reduction in lung metastatic nodule numbers upon administering TGF-beta inhibitor. These findings collectively indicate that TGF-beta regulates CCL2 and CCL5 expression in a stage-dependent manner during BCa progression, which in turn, determines Th1-Th2 balance within the tumor microenvironment. PMID- 29107386 TI - Impact of holding and equilibration time on post-thaw quality of shipped boar semen. AB - Cryopreservation of boar semen is of growing interest for breeding companies. Overnight-shipping of pre-diluted ejaculates to specialized laboratories offers a practicable method, but requires fine-tuned protocols. In this study, the impact of holding post shipping at 17 degrees C for 2 or 24h (n=10 samples) and of equilibration in lactose-egg yolk extender without glycerol at 5 degrees C for 2, 4, 24 or 48h (n=11 samples) before freezing was investigated. Sperm-rich fractions of ejaculates from 21 mature Pietrain boars were collected at a single boar stud. After pre-dilution (1+1, v:v) with Beltsville thawing solution, samples were sent to the laboratory. Temperature profiles during transport and initial equilibration time were recorded. Semen quality post-thaw (PT) was evaluated using CASA and flow cytometry. Holding of 2h after shipping resulted in higher sperm motility (P=0.013) and beat cross frequency (BCF; P=0.047) compared to 24h. Differences between both groups vanished with prolonged incubation at 38 degrees C PT. Equilibration at 5 degrees C for 4h yielded the highest motility and BCF, whereas the equilibration for 48h impaired sperm motility. Membrane integrity, mitochondrial activity and DNA fragmentation index were not affected by any protocol modification. In conclusion, processing of pre-diluted boar semen shipped overnight within 2h after arrival at the laboratory is preferred to 24h of additional holding at 17 degrees C. Extending the equilibration period in lactose-egg yolk extender without glycerol at 5 degrees C from 2h to 4h before freezing is recommended. PMID- 29107387 TI - Dynamics of the vaginal wall dose in HDR interstitial brachytherapy for gynecological cancer: Systematic analysis of phantom vs patient case. AB - This study aimed to investigate the dynamics of the vaginal wall dose for interstitial brachytherapy (ISBT). A patient undergoing ISBT was selected as the patient case. The phantom case was generated to simulate the patient case in all regards with the exception of parallel needle positions. The vaginal wall was contoured as a 0.5-cm expansion around the vaginal surface of the obturator. The prescribed ISBT dose was 20 Gy in 4 fractions. Six treatment plans were generated by modifying relative dwell times and needle positions (DTNP). The volume of the vaginal wall receiving > 150% of prescription dose (V> 150%) and D2cc of the vaginal wall were compared among plans. The V> 150% was much larger in the patient case (49.3%) due to unparallel needles compared with the phantom case (14.3%) without modification (plan 1). Among the 6 plans, reduced dwell time (plan 3) and no dwell time (plans 5 and 6) on the vaginal surface needles had the lowest vaginal wall doses with the use of a central obturator needle in both cases. In comparison of patient case plans 1, 3, 5, and 6, V150% was 49.2%, 19.0%, 21.3%, and 28.7%, respectively, and D2cc was 41.15 Gy, 33.10 Gy, 36.51 Gy, and 34.37 Gy, respectively, which was limited around each loaded needle. Modification of DTNP is able to reduce the vaginal wall volume exceeding 150% of the prescription dose in the patient case. Understanding these dynamics of the vaginal wall dose will improve dose optimization of ISBT and may reduce vaginal morbidities. PMID- 29107388 TI - Synthesis of Au nanoparticle-decorated carbon nitride nanorods with plasmon enhanced photoabsorption and photocatalytic activity for removing various pollutants from water. AB - Herein we have developed Au nanoparticle-decorated carbon nitride (Au-CN) nanorods as novel and efficient photocatalysts. Au-CN with different Au/CN precursor molar ratios (0.5%, 1% and 2%) have been prepared by a solvothermal hydrothermal two-step method, where CN nanorods have diameters of 20-30nm and length of 0.5-1MUm while Au nanoparticle have diameter of ~13nm. Au-CN nanorods exhibit a broad photoabsorption from ultraviolet to near-infrared with edge at ~790nm, revealing an obvious red-shift compared with g-C3N4 bulk (~460nm), CN nanorods (~715nm). Under visible-light irradiation, 1%Au-CN nanorods exhibit the highest photocatalytic activity, and they can degrade 98.2% rhodamine B (RhB), 77.2% 4-chlorophenol (4-CP), 83.9% tetracycline (TC) and reduce 43.6% hexavalent chromium (Cr(VI)) in 120min, higher than those by pure CN nanorods (70.3% RhB, 36.6% 4-CP, 54.6% TC, 23.1% Cr(VI)) and g-C3N4 bulk (31.5% RhB, 17.2% 4-CP, 36.9% TC, 11.8% Cr(VI)). Compared with CN nanorods, the obvious improvement of photocatalytic activity of 1%Au-CN nanorods should be attributed to the plasmon enhanced photoabsorption and efficient separation of hole-electron pairs due to the introduction of Au nanoparticles. PMID- 29107389 TI - Open questions and misconceptions in the diagnosis and management of anemia in patients with gastrointestinal bleeding. AB - Despite high prevalence of iron deficiency anemia (IDA) in patients with acute or chronic gastrointestinal bleeding (GIB), IDA and iron deficiency (ID) are frequently untreated. Reasons may be misconceptions about the impact and diagnosis of IDA and the efficacy of new treatments. Addressing these misconceptions, this article summarizes current evidence for better understanding and management of GIB-associated IDA. Despite only few controlled studies evaluated the efficacy of iron treatment in patients with GIB, there is consistent evidence suggesting that: (a) IDA should be diligently investigated, (b) effective treatment of ID/IDA improves outcomes such as health-related quality of life and can avoid severe cardiovascular consequences, and (c) intravenous iron should be considered as well-tolerated treatment in this setting. Overall, the misconceptions and practices outlined in this article should be replaced with strategies that are more in line with current guidelines and best practice in GIB and other underlying conditions of ID/IDA. PMID- 29107390 TI - Eosinophilic ascites: A case report. PMID- 29107391 TI - The Application and Feasibility of Using Routine Data Sources for Long-term Cancer Clinical Trial Follow-up. PMID- 29107392 TI - Innovative Solutions for Clinical Trial Follow-up: Adding Value from Nationally Held UK Data. AB - Clinical trials provide the data that underpin evidence-based oncological practice. Over and above their primary outcome measures, collected and analysed by the clinical trials unit, trials provide an opportunity to generate a wide range of additional information over a prolonged period of time. Nationally held data have potential to facilitate longer term follow-up and explore associated toxicities and downstream consequences and in the UK include data from secondary care, including hospital episode statistics, national chemotherapy and radiotherapy datasets and primary care records. Specific to use in oncological practice, the National Cancer Data Repository contains linked data from a variety of sources for patients with a diagnosis of cancer, both cancer and non-cancer related. The challenge of using these data in clinical trials relates to the need to extract identifiable patient data, with the associated ethical and legal issues. The data access processes are time consuming and require evidence of information governance compliance. This overview article reviews the current data available, the current and potential uses both within and outside clinical trials and the challenges encountered in the process of acquiring data. We focus specifically on the use of nationally held data for non-cancer outcomes, including toxicity and associated conditions. PMID- 29107393 TI - Prognostic utility of the multiorgan failure scores and inotropic index in the postoperative of cardiac transplantation in children. PMID- 29107394 TI - Tuboovarian abscess due to Eikenella corrodens. PMID- 29107395 TI - Blood culture time to positivity in oncology pediatric patients. PMID- 29107396 TI - Parenchymal sparing surgery for colorectal liver metastases: The need for a common definition. AB - BACKGROUND: The definition of parenchymal sparing surgery (PSS) for colorectal liver metastases (CRLM) diverges requiring a clarification of the concept. METHOD: A consecutive series of patients were treated by PSS for their CRLMs, either by resection or intra-operative ablation (IOA), whenever possible a one stage surgery and minimal usage of portal vein embolization. Post-operative complications were the primary endpoint with a special focus on post-operative liver failure. RESULTS: Three hundred and eighty-seven patients underwent a PSS out of which 328 patients received a median of 9 pre-operative cycles of chemotherapy. One hundred and twenty-eight patients had a major resection, combined with IOA in 137 patients and IOA alone in 50 cases. The 5yr-overall survival was 50.3%. There was no difference in post-operative complications between minor and major resections, validating our PSS definition based on the Tumor burden/Healthy liver ratio and not just the retrieved volume. CONCLUSIONS: PSS is defined as a high ratio of tumoral burden per specimen retrieved while favoring one-stage surgery approach. Our series, using combined resections and IOAs, matches this definition well. Furthermore, complications were correlated neither to chemotherapy nor to liver-induced toxicities, contrary to extended hepatectomies. PMID- 29107397 TI - Traumatic Injury to the Portal Vein With Shock Bowel. AB - A portal vein aneurysm is the dilatation of the portal vein due to a defect in the vein wall. This rare disease manifestation is difficult to predict and has the potential for severe complications. We describe the case of a 68-year-old man involved in a motor vehicle collision who presented with abdominal hemorrhage found on ultrasound, hypotension, and vague abdominal pain. The patient underwent an exploratory laparotomy to control bleeding. Surgery and a subsequent abdominal computed tomography revealed the presence of a portal vein pseudoaneurysm and shock bowel. This case highlights the importance of radiologists to consider the prospect of portal vein aneurysm in the differential diagnosis of hypotension following abdominal trauma. PMID- 29107398 TI - The stress-reward-mentalizing model of depression: An integrative developmental cascade approach to child and adolescent depressive disorder based on the Research Domain Criteria (RDoC) approach. AB - The Research Domain Criteria (RDoC) propose a much-needed change in approach to the study of vulnerability factors implicated in mental disorders, shifting away from a categorical, disease-oriented model to a dimensional approach that focuses on underlying systems implicated in psychopathology. In this paper we illustrate this approach with a focus on the emergence of depression in childhood and adolescence. Based on evolutionary biological and developmental psychopathology considerations, we present an integrative developmental cascade model of depression that essentially suggests that depression emerges out of a three pronged series of interacting impairments in the domains of stress regulation, reward, and mentalizing. We discuss the relation of these impairments to the five domains proposed by RDoC. We also focus on how this model may explain in large part the marked comorbidity of depression with other psychiatric disorders, as well as with functional somatic and somatic disorders. Limitations of this theoretical approach are discussed, as well as implications for the development, evaluation, and dissemination of interventions aimed at preventing or treating depression. PMID- 29107399 TI - Airway diseases and health literacy (HL) measurement tools: A systematic review to inform respiratory research and practice. AB - OBJECTIVE: To identify and evaluate asthma/COPD measurement tools that assess any of the five health literacy (HL) domains: (1) access, (2) understand, (3) evaluate, (4) communicate, and (5) use, as well as numeracy. METHODS: MEDLINE/Embase (via Ovid) databases from 1974 to 2016 were searched and complimented by grey literature. Study selection and data extraction were conducted by two reviewers independently. RESULTS: We identified 65 tools including 40 asthma, 22 COPD, and 3 asthma/COPD focused tools. Thirty tools had been validated and two assessed all five domains. The 'understand' domain was captured in 49 tools, followed by 'access' in 29 tools, 'use' in 24 tools, 'evaluate' in 20 tools, and 'communicate' in 10 tools. Two tools assessed 'numeracy'. Tool content comprised disease physiology, triggers, symptoms, inhaler technique, self-management practices, and rehab programs. CONCLUSIONS: This review highlights paucity of HL tools that have been validated and/or assess the 'communicate' domain and makes a valuable contribution to filling an existing research gap in the field of HL by determining the deficiencies of such tools. PRACTICE IMPLICATIONS: Our review uncovers which HL domains are under-measured, justifying the need to develop an airways HL measurement tool which applies the 5 domain model for asthma/COPD management. PMID- 29107400 TI - Factors associated with professional healthcare advice seeking in women at risk for developing breast cancer-related lymphedema. AB - OBJECTIVES: Approximately 6-20% of breast cancer patients undergoing lymph node surgery will develop lymphedema. At-risk individuals are encouraged to seek professional healthcare advice if symptoms arise. This study aimed to identify cognitive and affective factors associated with professional healthcare advice (PHCA) seeking behavior in women with heightened lymphedema risk. METHODS: Women with increased lymphedema risk (N=462) completed an online survey measuring cognitive and affective responses to lymphedema risk, including the Illness Perception Questionnaire (Revised), and adherence to seeking PHCA. RESULTS: Overall, 62% of women reported seeking professional healthcare advice if symptoms arose. Logistic regression analysis indicated that adherence to seeking PHCA if lymphedema symptoms arise was associated with greater illness coherence, belief in the efficacy of seeking PHCA, and lymphedema risk-related emotional distress. CONCLUSION: Women were more likely to seek PHCA if symptoms arose if they held a coherent understanding of lymphedema and believed in the usefulness of seeking PHCA. For these women, psychological distress associated with lymphedema risk was associated with enhanced adherence to seeking PHCA. PRACTICE IMPLICATIONS: Health professionals should target lymphedema education to ensure at-risk women have a coherent understanding of lymphedema and that they believe in the effectiveness of seeking PHCA to help manage lymphedema symptoms. PMID- 29107401 TI - [Map of Alzheimer's disease and other dementias in Spain. MapEA Project]. AB - INTRODUCTION: In the current context of increased life expectancy and progressive aging of the population a very significant increase in the number of people with cognitive impairment and dementia is expected. Consequently, Spain will face an enormous social and health problem in the next decades. The Mapa de la enfermedad de Alzheimer y otras demencias en Espana project aims to analyse plans, prevention and early diagnosis activities, process of care and resources available across the 17 Spanish regions for the management of cognitive impairment and dementia in order to identify improvement areas, as well as to provide a list of recommendations. METHODS: The working group consisted of an Advisory Committee of 5 national experts and a Committee of Experts from each region made up of professionals in the field of Neurology, Geriatrics, Psychiatry, and Primary Care, as well as representatives of Family Associations of People with Alzheimer's and other dementias. The Expert Committee of each region held meetings in which the current situation of care was reviewed. RESULTS: Plans available in Spain for dementia management are mostly obsolete or have not been implemented. Prevention and early detection activities are generally not carried out. There is great variability of care process that patients must follow for the diagnosis, treatment, and follow-up of the disease, and not all diagnostic test are available in different regions. In general, resources are considered scarce and unknown. CONCLUSIONS: The Mapa de la enfermedad de Alzheimer y otras demencias en Espana study has been able to detect the main points that require changing n the management, organisation, and coordination of resources, such as information and training of the personnel involved. Furthermore, the study has revealed that, in Spain, the necessary conditions are in place in Spain, such as the availability and capacity of professionals involved, as well as there being the potential diagnostic and health care resources to address this room for improvement through the approval and development of a National Alzheimer's Plan, supported by a deep and truthful political commitment, which will be the ideal framework for the development of these possibilities. PMID- 29107402 TI - Malpractice Claims: It's a Crapshoot-Time to Stop the Self-Blame and Ask Different Questions. PMID- 29107403 TI - What Is the Diagnostic Accuracy of Magnetic Resonance Imaging for Acute Appendicitis? PMID- 29107404 TI - What Is the Utility of Noninvasive Ventilation in the Management of Acute Hypercapnic Respiratory Failure Associated With Chronic Obstructive Pulmonary Disease? PMID- 29107405 TI - How Effective Is a Regional Nerve Block for Treating Pain Associated With Hip Fractures? PMID- 29107406 TI - How Reliable Are Signs and Symptoms for Diagnosing Pneumonia in Pediatric Patients? PMID- 29107407 TI - Transesophageal Echocardiography: Guidelines for Point-of-Care Applications in Cardiac Arrest Resuscitation. AB - Cardiac arrest is one of the most challenging patient presentations managed by emergency care providers, and echocardiography can be instrumental in the diagnosis, prognosis, and treatment guidance in these critically ill patients. Transesophageal echocardiography has many advantages over transthoracic echocardiography in a cardiac arrest resuscitation. As transesophageal echocardiography is implemented more widely at the point of care during cardiac arrest resuscitations, guidelines are needed to assist emergency providers in acquiring the equipment and skills necessary to successfully incorporate it into the management of cardiac arrest victims. PMID- 29107408 TI - Change in Lactate Levels After Hemodialysis in Patients With End-Stage Renal Disease. AB - STUDY OBJECTIVE: Patients with end-stage renal disease commonly visit the emergency department (ED). The purpose of this investigation is to examine the prevalence of baseline abnormal lactate levels and to evaluate the effects of hemodialysis on serum lactate levels. METHODS: This was a prospective observational cohort study performed at an outpatient dialysis facility at an urban tertiary care hospital. The study consisted of 226 patients with end-stage renal disease who were receiving long-term hemodialysis and were enrolled during a 2-day period at the beginning of December 2015. Blood drawn for lactate levels was immediately analyzed before and after hemodialysis sessions. All patients completed their hemodialysis sessions. RESULTS: The prevalence of an abnormal lactate level (greater than 1.8 mmol/L) before hemodialysis was 17.7% (n=40). Overall, lactate levels decreased by 27% (SD 35%) after hemodialysis, with a decrease of 37% (SD 31%) for subgroups with a lactate level of 1.9 to 2.4 mmol/L, and 62% (SD 14%) with a lactate of 2.5 to 3.9 mmol/L. CONCLUSION: The data presented help providers understand the prevalence of abnormal lactate values in an outpatient end-stage renal disease population. After hemodialysis, lactate levels decreased significantly. This information may help medical providers interpret lactate values when patients with end-stage renal disease present to the ED. PMID- 29107409 TI - Validity and Reliability of the Verbal Numerical Rating Scale for Children Aged 4 to 17 Years With Acute Pain. AB - STUDY OBJECTIVE: The Verbal Numerical Rating Scale is the most commonly used self report measure of pain intensity. It is unclear how the validity and reliability of the scale scores vary across children's ages. We aimed to determine the validity and reliability of the scale for children presenting to the emergency department across a comprehensive spectrum of age. METHODS: This was a cross sectional study of children aged 4 to 17 years. Children self-reported their pain intensity, using the Verbal Numerical Rating Scale and Faces Pain Scale-Revised at 2 serial assessments. We evaluated convergent validity (strong validity defined as correlation coefficient >=0.60), agreement (difference between concurrent Verbal Numerical Rating Scale and Faces Pain Scale-Revised scores), known-groups validity (difference in score between children with painful versus nonpainful conditions), responsivity (decrease in score after analgesic administration), and reliability (test-retest at 2 serial assessments) in the total sample and subgroups based on age. RESULTS: We enrolled 760 children; 27 did not understand the Verbal Numerical Rating Scale and were removed. Of the remainder, Pearson correlations were strong to very strong (0.62 to 0.96) in all years of age except 4 and 5 years, and agreement was strong for children aged 8 and older. Known-groups validity and responsivity were strong in all years of age. Reliability was strong in all age subgroups, including each year of age from 4 to 7 years. CONCLUSION: Convergent validity, known-groups validity, responsivity, and reliability of the Verbal Numerical Rating Scale were strong for children aged 6 to 17 years. Convergent validity was not strong for children aged 4 and 5 years. Our findings support the use of the Verbal Numerical Rating Scale for most children aged 6 years and older, but not for those aged 4 and 5 years. PMID- 29107410 TI - Contralateral trigeminal neuralgia in a rapidly growing vestibular schwannoma: A case report. AB - We present a rare case of vestibular schwannoma (VS) with contralateral trigeminal neuralgia. A 59 year-old woman presented with right-sided trigeminal neuralgia and a small VS in the left cerebellopontine angle (CPA) that was found via magnetic resonance imaging. The patient was administered medication; however, her symptoms gradually aggravated, and the size of the tumor increased. Two years after the initial diagnosis, the patient underwent surgical resection. After surgical resection, the patient's facial pain was improved. The trigeminal neuralgia appeared to be related to brainstem displacement caused by the contralateral VS. For VS with contralateral trigeminal neuralgia, surgical resection of the tumor should be considered as a possible treatment strategy. PMID- 29107411 TI - Fracture of fusion mass following anterior cervical plate removal: Case report. AB - We present the case of a delayed pseudoarthrosis resulting from a fracture at the site of a radiographically confirmed anterior cervical fusion following plate removal. In this case, an anterior cervical plate was removed to allow for further surgery at a supra-adjacent level. A modicum of literature exists describing delayed fractures following hardware removal in thoracolumbar fusion constructs. The development of a fracture/pseudoarthrosis following hardware removal at the site of a radiographically confirmed anterior cervical fusion has not been previously reported. We describe the clinical presentation and operative management in the case of this rare and unexpected complication. PMID- 29107412 TI - Ketamine infusion for refractory status epilepticus: A case report of cardiac arrest. AB - BACKGROUND: Refractory status epilepticus (RSE) has a high mortality rate and is often difficult to treat. When traditional therapies fail ketamine may be considered. There are limited reports of adverse cardiac events with the use of ketamine for RSE and no reports of cardiac arrest in this context. OBJECTIVE: Evaluate the occurrence of cardiac arrhythmias associated with the use of ketamine for RSE. METHODS: Retrospective chart review of nine patients who underwent ketamine infusion for RSE. RESULTS: Etiology of refractory status epilepticus included autoimmune/infectious process (Zeiler et al., 2014), ischemic stroke (Bleck, 2005) and subarachnoid hemorrhage (Bleck, 2005). Of the nine patients who received ketamine, two had documented cardiac events; one remained clinically stable and the other developed multiple arrhythmias, including recurrent episodes of asystole. Once ketamine was discontinued the latter patient stabilized with the addition of anti arrhythmic therapy. CONCLUSION: Ketamine is utilized to treat refractory status epilepticus, but should be used with caution in patients with subarachnoid hemorrhage, as there may be an increased risk of life threatening arrhythmias and cardiac arrest. PMID- 29107413 TI - Modelling firing regularity in the ventral cochlear nucleus: Mechanisms, and effects of stimulus level and synaptopathy. AB - The auditory system processes temporal information at multiple scales, and disruptions to this temporal processing may lead to deficits in auditory tasks such as detecting and discriminating sounds in a noisy environment. Here, a modelling approach is used to study the temporal regularity of firing by chopper cells in the ventral cochlear nucleus, in both the normal and impaired auditory system. Chopper cells, which have a strikingly regular firing response, divide into two classes, sustained and transient, based on the time course of this regularity. Several hypotheses have been proposed to explain the behaviour of chopper cells, and the difference between sustained and transient cells in particular. However, there is no conclusive evidence so far. Here, a reduced mathematical model is developed and used to compare and test a wide range of hypotheses with a limited number of parameters. Simulation results show a continuum of cell types and behaviours: chopper-like behaviour arises for a wide range of parameters, suggesting that multiple mechanisms may underlie this behaviour. The model accounts for systematic trends in regularity as a function of stimulus level that have previously only been reported anecdotally. Finally, the model is used to predict the effects of a reduction in the number of auditory nerve fibres (deafferentation due to, for example, cochlear synaptopathy). An interactive version of this paper in which all the model parameters can be changed is available online. PMID- 29107414 TI - Kinetics of anti-ZIKV antibodies after Zika infection using two commercial enzyme linked immunoassays. AB - High performance assays are essential for the serological diagnosis of recent and past Zika virus (ZIKV) infections but few are presently available. We used two commercially available NS1 antigen-based enzyme-linked immunoassays to study the kinetics of anti-ZIKV IgM and IgG in 15 ZIKV-infected patients for up to 180days after clinical onset. The Diapro assay detected anti-ZIKV IgM reactivity more frequently (100%) and for longer (median 53days) than did the Euroimmun assay (60%; 13days, P<0.005). Both assays detected anti-ZIKV IgG reactivity 11days after clinical onset in all subjects. ZIKV IgG reactivity decreased in 3 subjects, suggesting long-term false-negative results with the Euroimmun assay. Existing anti-Dengue antibodies seem to modify the detection of ZIKV IgG but the specificity of the immunoassays was not assessed. These enzyme-linked immunoassays were user-friendly and provided results rapidly in our hands but they need further assessment before being widely used for diagnosis or public health surveys. PMID- 29107415 TI - Enhanced detection of carbapenemase-producing Enterobacteriaceae by an optimized phenol red assay. AB - Screening for the detection of carbapenemase-producing bacteria still encounters issues related to workflow, limit of detection, or qualitative interpretation. We developed a spectrophotometry-based version of the Carba NP phenol red assay (Nordmann et al., 2012) in a microtiter plate format, compatible with low bacterial cell counts. We were able to detect highly active carbapenemases such as KPC and IMP in 30min. A wider range of carbapenemases including OXA-48 were detected using higher inocula, still being competitive compared with currently available phenol red assays. Validation experiments of our test with a panel of 81 Enterobacteriaceae showed good performance with 93% of sensitivity and 92% of specificity. The compatibility of our routine-friendly protocol with automation offers great perspectives for high throughput screening in outbreak situations and/or in big laboratories. PMID- 29107416 TI - Evaluation of PyroMark Q24 pyrosequencing as a method for the identification of mycobacteria. AB - We evaluated PyroMark Q24 (QIAGEN) pyrosequencing as a method for the identification of mycobacteria, with potential application in clinical practice. Sequence data from the hypervariable region A of the 16S rRNA gene (43 and 35bp sequences) were obtained using PyroMark Q24, and a similarity search was performed automatically with PyroMark IdentiFire software. Of the 148 mycobacterial type strains tested, 138 (93.2%) were accurately identified to single or clade species level, including complex level. From the remaining 10 strains, 3 (Mycobacterium gilvum, Mycobacterium goodi, and Mycobacterium thermoresistible) showed poor sequencing quality of homopolymers. For 6 other strains (Mycobacterium cosmeticum, Mycobacterium flavescens, Mycobacterium pallens, Mycobacterium hodleri, Mycobacterium xenopi, and Mycobacterium crocinum), the sequences were unreadable from the middle, and Sanger sequencing indicated biallelic site. Finally, a 40bp sequence for Mycobacterium gordonae could not be obtained despite repeated attempts. PyroMark Q24 provided accurate identification of multiple mycobacterial strains isolated from common clinical settings, but additional gene sequencing is required to distinguish species identified as a group or complex. PMID- 29107417 TI - Osteoarticular and skin and soft-tissue infections caused by Streptococcus agalactiae in elderly patients are frequently associated with bacteremia. AB - Older persons (>=65 years) are at risk for invasive group B streptococcal (GBS) infections. The most frequent clinical syndromes in 174 infection episodes were osteoarticular (40%) and skin and soft-tissue infections (30%). In 36% of episodes, a companion microorganism was isolated, and in 45%, blood culture results were positive. Antibiotics were streamlined after species identification in 29% of monomicrobial infections. These findings have clinical and therapeutic implications for GBS infections in the elderly. PMID- 29107418 TI - Evaluation of microplastic release caused by textile washing processes of synthetic fabrics. AB - A new and more alarming source of marine contamination has been recently identified in micro and nanosized plastic fragments. Microplastics are difficult to see with the naked eye and to biodegrade in marine environment, representing a problem since they can be ingested by plankton or other marine organisms, potentially entering the food web. An important source of microplastics appears to be through sewage contaminated by synthetic fibres from washing clothes. Since this phenomenon still lacks of a comprehensive analysis, the objective of this contribution was to investigate the role of washing processes of synthetic textiles on microplastic release. In particular, an analytical protocol was set up, based on the filtration of the washing water of synthetic fabrics and on the analysis of the filters by scanning electron microscopy. The quantification of the microfibre shedding from three different synthetic fabric types, woven polyester, knitted polyester, and woven polypropylene, during washing trials simulating domestic conditions, was achieved and statistically analysed. The highest release of microplastics was recorded for the wash of woven polyester and this phenomenon was correlated to the fabric characteristics. Moreover, the extent of microfibre release from woven polyester fabrics due to different detergents, washing parameters and industrial washes was evaluated. The number of microfibres released from a typical 5 kg wash load of polyester fabrics was estimated to be over 6,000,000 depending on the type of detergent used. The usage of a softener during washes reduces the number of microfibres released of more than 35%. The amount and size of the released microfibres confirm that they could not be totally retained by wastewater treatments plants, and potentially affect the aquatic environment. PMID- 29107419 TI - An update of the Pb isotope inventory in post leaded-petrol Singapore environments. AB - Pb is a trace metal that tracks anthropogenic pollution in natural environments. Despite recent leaded petrol phase out around Southeast Asia, the region's growth has resulted in continued exposure of Pb from a variety of sources. In this study, sources of Pb into Singapore, a highly urbanised city-state situated in the central axis of Southeast Asia, are investigated using isotopic ratios and concentrations. We compiled data from our previous analyses of aerosols, incineration fly ash and sediments, with new data from analyses of soil from gas stations, water from runoff and round-island coastal seawater to obtain a spatio temporal overview of sources of Pb into the Singapore environment. Using 206Pb/207Pb ratio, we identified three main Pb source origins: natural Pb (1.215 +/- 0.001), historic/remnant leaded petrol (1.123 +/- 0.013), and present-day industrial and incinerated waste (1.148 +/- 0.005). Deep reservoir sediments bore larger traces of Pb from leaded petrol, but present-day runoff waters and coastal seawater were a mix of industrial and natural sources with somewhat variable concentrations. We found temporal variability in Pb isotopic ratio in aerosols indicating alternating transboundary Pb sources to Singapore that correspond to seasonal changes in monsoon winds. By contrast, seasonal monsoon circulation did not significantly influence isotopic ratios of coastal seawater Pb. Instead, seawater Pb was driven more by location differences, suggesting stronger local scale drivers of Pb such as point sources, water flushing, and isotope exchange. The combination of multiple historic and current sources of Pb shown in this study highlights the need for continued monitoring of Pb in Southeast Asia, especially in light of emerging industries and potential large sources of Pb such as coal combustion. PMID- 29107420 TI - African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase. AB - African trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead. PMID- 29107421 TI - Discovery of novel pyrrolo-pyridine/pyrimidine derivatives bearing pyridazinone moiety as c-Met kinase inhibitors. AB - In continue to our previous research, eight series of pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives bearing pyridazinone moiety were designed, synthesized, and the in vitro antitumor activity was evaluated against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). Some selected compounds (22f, 22g, 26c and 26e) were evaluated for the activity against c-Met kinase, and according to the results of kinase inhibitory activity, the compound 22g was further evaluated for other four tyrosine kinases (Flt-3, VEGFR-2, c-Kit and EGFR) to test the enzyme-based selectivity. The most promising compound 22g showed excellent activity than lead compound Foretinib against A549, HepG2, MCF-7 and PC-3 cell lines, with the IC50 values of 2.19 +/- 0.45 MUM, 1.32 +/- 0.26 MUM, 6.27 +/- 1.04 MUM and 4.63 +/- 0.83 MUM. The structure-activity relationships (SARs) and docking studies indicated that the pyrrolo[2,3 b]pyridine derivatives bearing 4-oxo-pyridazinone moiety was superior to the pyrrolo[2,3-d]pyrimidine derivatives bearing 6-oxo-pyridazinone moiety. What's more, the target compounds modified with X and Y (X = H, Y = H) were favorable to the activity. And electron drawing groups (EWGs) of 4-Cl-3CF3 on the aryl group show the best activity. PMID- 29107422 TI - Synthesis, antitumor evaluation and microarray study of some new pyrazolo[3,4 d][1,2,3]triazine derivatives. AB - Design and synthesis of new anticancer scaffolds; pyrazolo[3,4-d][1,2,3]triazine derivatives, is a promising solution to overcome drug resistance problem. A series of (E)-2-cyano-N-(aryl)-3-methylthio-3-(substituted-amino)acrylamides 3a-e was synthesized and transformed to the 3-aminopyrazole derivatives 4a-e which were then transformed to the target pyrazolotriazinones 6a-e. All compounds were evaluated for their anticancer activity against three different cancer cell lines namely Huh-7, Panc-1 and CCRF. Compounds 3a, 3c, 6a and 6c showed excellent anticancer activity against Huh-7 cell line (IC50: 4.93-8.84 MUM vs doxorubicin 5.43 MUM). Similarly, compounds 6a and 6d showed excellent activities against Panc-1 cells (IC50: 9.91 MUM and 4.93 MUM vs doxorubicin 6.90 MUM). Caspase-Glo 3/7 assay was done and the results revealed that the pro-apoptotic activity of the target compounds could be due to the stimulation of caspases 3/7. Microarray experiment for Huh-7 cells treated with 6c was performed to search for other molecular changes. SLC26A3, UGT1A1, UGT2B15, UGT2B7, DNASE1, MUCDH1 and UGT2B17 were among the up-regulated genes, while, GIP3, TAGL, THBS1, IFI27, FSCN1 and SOCS2 were among the most extensively down-regulated genes. These genes belong to apoptosis, metabolism, cell cycle, tumor growth and suppressor genes. Finally, pyrazolo[3,4-d][1,2,3]triazine derivatives could be potent anticancer drugs in the future. PMID- 29107423 TI - Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder known for the presence of amyloid beta plaques resulting from the sequential action of beta-secretase and gamma-secretase on amyloid precursor protein. We developed and synthesized, through click reactions, a new family of iminochromene carboxamides containing different aminomethylene triazole. The BACE1 inhibition, neuroprotective capacity and metal chelation of these derivatives make them ideal candidates against AD. Most of the synthesized compounds were shown to have potent BACE1 inhibitory activity in a FRET assay, with an IC50 value of 2.2 MUM for the most potent compound. Moreover, molecular modeling evaluation of these BACE1 inhibitors demonstrates the vital role of the amine and amide linkers through hydrogen bond interactions with key amino acids in the BACE1 active site. Our in vitro neuroprotective evaluations in PC12 neuronal cells of Abeta-induced neuroprotection demonstrated promising activity for most of the compounds as neuroprotective agents. Based on our findings, we propose that introduction of a phthalimide substitute on the triazole ring shown to be interesting multifunctional lead compound worthy of further study. PMID- 29107424 TI - Selective kappa opioid antagonists for treatment of addiction, are we there yet? AB - Kappa opioid receptor (KOP) is a G-protein coupled receptor mainly expressed in the cerebral cortex and hypothalamus. It is implicated in nociception, diuresis, emotion, cognition, and immune system functions. KOP agonists possess a strong analgesic effect accompanied by a feeling of dysphoria. On the other hand, antagonists of this receptor were found to block depression, anxiety, and drug seeking behaviors in animal models. Recently, great interest has been given to the development of selective KOP antagonists as an addiction treatment that does not cause dependence itself or show high relapse rates like the currently used agents. This review provides a comprehensive survey of the KOP antagonists developed for this purpose together with their in vivo studies and clinical trials. In addition, a future perspective and recommendations for the work needed to develop clinically relevant KOP antagonists are presented. PMID- 29107425 TI - Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders. AB - Tyrosine kinases including LCK and FMS are involved in inflammatory disorders as well as many types of cancer. Our team has designed and synthesized thirty novel pyrimidine based inhibitors targeting LCK, classified into four different series (amides, ureas, imines (Schiff base) and benzylamines). Twelve of them showed nanomolar IC50 values. Compound 7g showed excellent selectivity profile and was selectively potent over FMS kinase (IC50 value of 4.6 nM). Molecular docking study was performed to help us rationalize the obtained results and predict the possible binding mode for our compounds in both LCK and FMS. Based on the obtained biological assay data and modelling results, a detailed SAR study was discussed. As a further testing regarding the anti-inflammatory effect of the new compounds, in vitro cellular assay over RAW 264.7 macrophages was performed. Compound 7g exhibited excellent anti-inflammatory effect. Therefore, we report the design of novel phenoxypyrimidine derivatives as potent and selective LCK inhibitors and the discovery of 7g as potent and selective FMS/LCK dual inhibitor for the potential application in inflammatory disorders including rheumatoid arthritis (RA). PMID- 29107426 TI - Synthesis and biological evaluation of NH2-acyl oseltamivir analogues as potent neuraminidase inhibitors. AB - Neuraminidase inhibitors can deter nascent viruses from infecting intact cells by preventing their release from host cells. Herein, a neuraminidase inhibitor 11b absent of basic moieties was discovered in the process of searching for inhibitors targeting 150 cavity. It exhibited potent inhibitions against wild type neuraminidases from group 1 (H5N1 and H1N1) and group 2 (H7N9) subtypes with IC50 values similar to those of oseltamivir carboxylate. Moreover, 11b showed moderate inhibitions against mutant neuraminidases from H5N1-H274Y and H1N1-H274Y with IC50 values of 2075 nM and 1382 nM, which were inferior to those of oseltamivir carboxylate (6095 nM and 4071 nM). The results were not consistent with the recognized SARs that a basic moiety was an indispensable part of a potent inhibitor. PMID- 29107427 TI - Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors. AB - Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/beta-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the molecular interactions with the target, we discuss only those ones acting against Wnt cancer cell lines. In addition, comprehensive structure property relationships (SPR) emerging from the hit evolution processes and preclinical results are provided. We then review the most promising TNKSi hitherto reported in literature, acting in vivo models of Wnt-driven cancers. Some outlooks on current issues and future directions in this field are also discussed. PMID- 29107428 TI - PtII, PdII and AuIII complexes with a thiosemicarbazone derived from diacethylmonooxime: Structural analysis, trypanocidal activity, cytotoxicity and first insight into the antiparasitic mechanism of action. AB - New complexes of composition [MX(HL1)] (M = PtII, PdII, X = Cl- or I-) and [MX(L1)] (M = AuIII, X = Cl-; M = PtII, PdII, X = PPh3) have been synthesized using a potentially tridentate thiosemicarbazone (H2L1) containing an additional oxime binding site. Among other analytical methods, all the seven complexes have been structurally characterized by single crystal X-ray diffractometry. Interesting structural features such as the influence of the halide ligands on hydrogen bonds and the formation of supramolecular structures for the phosphine derivatives are discussed. The in vitro trypanocidal activity of the free ligand H2L1 and its derivatives against both extracellular trypomastigote and intracellular amastigote (IC50try/ama) forms of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity was assessed on LLC-MK2 cell line. The results showed that complexation of the thiosemicarbazone ligand H2L1 to PtII, PdII and AuIII metal centers enhances the in vitro trypanocidal activity and that the cytotoxicity is dependent on both the metal center and coligands. Within the studied series, the AuIII complex showed the greatest potential, being not the most active but the most selective compound with a similar selectivity index to that of the standard drug benznidazole. In order to get a preliminary insight into the mechanism of action of these compounds, in vitro experiments of fluorescence quenching and enzymatic activity were performed using the AuIII complex and Trypanosoma cruzi Old Yellow Enzyme (TcOYE) which indicated that the gold derivative was capable of abstracting the hydride from the prosthetic FMN group of the enzyme. Additionally, molecular docking studies followed by semiempirical simulations showed that the [AuCl(L1)] binds to the binary complex TcOYE/FMN, almost parallel to the FMN prosthetic group, in a close distance that an electron/proton transfer might occur among them. PMID- 29107429 TI - Discovery of 1-(3-aryl-4-chlorophenyl)-3-(p-aryl)urea derivatives against breast cancer by inhibiting PI3K/Akt/mTOR and Hedgehog signalings. AB - PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231. PMID- 29107430 TI - Utility of a Medical Alert Protection System compared to telephone follow-up only for home-alone elderly presenting to the ED - A randomized controlled trial. AB - OBJECTIVE: Medical Alert Protection Systems (MAPS) are a form of assistive technology designed to support independent living in the care of elderly patients in the community. We aimed to investigate the utility of using such a device (eAlert! System) in elderly patients presenting to an Emergency Department (ED). METHODS: Elderly patients presenting to an ED were randomized to receive MAPS or telephone follow-up only (control arm). All patients were followed up at one week, one-month and six-month post-intervention. A confidence scale (at 1week, 1month and 6months) and EQ-5D score (at 6months) were also administered. RESULTS: 106 and 91 participants enrolled in the MAPS and control arms respectively. Within both individual arms, there were significant reductions in the median number of ED visits and median number of admissions in the six month periods before, compared to after intervention (p<0.01 for both). However, the reductions were not significantly different between the two arms. Among participants who have had one or more admissions during the six months period post intervention, the MAPS arm had significantly lower median total length of stay (8days, Interquartile Range [IQR]=(4, 14)) compared to the control arm (15days, IQR=(3, 25), p=0.045). The median health state score for health state was significantly higher in the MAPS arm (70 IQR=(60,80) versus 60 IQR=(50,70), p=0.008). CONCLUSION: In this population of elderly ED patients, the use of a MAPS decreased length of stay for admissions and improved quality of life measures. PMID- 29107431 TI - Office stent placement under local anesthesia is a safe and efficient procedure for the management of multiple ureteral disorders. AB - OBJECTIVE: To assess the outcomes of ureteral stent placement under local anesthesia for the management of multiple ureteral disorders. METHODS: Retrospective study of 45 consecutive ureteral stents placed under local anesthesia from January 2015 to July 2016. Inclusion criteria were hemodynamically stable patients with urinary obstruction, urinary fistula or for prophylactic ureteral localization during surgery. Five minutes before the procedure, 10ml of lidocaine gel and 50ml of lidocaine solution were instilled in the bladder. A 4.8Fr ureteral stent was placed using a 15.5Fr flexible cystoscope under fluoroscopic control. Characteristics of procedures and outcomes were analysed. RESULTS: A total of 45 procedures (33 placement, 12 replacements) were attempted in 37 patients, of which 40 (89%) were successful. There were 10 male (27%) and 27 female patients (73%) with a mean age of 58.6 years (+/-17.5). Main indications for stent placement were stones (37.8%), extrinsic ureteral compression (28.9%) and surgery ureteral localization (22.2%). The reasons for failing to complete a procedure were the inability to pass the guidewire/stent in 4 cases (8.8%) or to identify the ureteral orifice in 1 (2.2%). Postoperative complications occurred in 8 patients (17.8%) (7 Clavien I, 1 Clavien IIIa). No procedure was prematurely terminated due to pain. Statistical analysis did not find significant successful predictors. The outpatient setting provided a fourfold cost decrease. CONCLUSIONS: Ureteral stent placement can be safely and effectively performed under local anesthesia in the office cystoscopy room. This procedure could free operating room time, reduce costs and minimize side effects of general anesthesia. PMID- 29107432 TI - [Reconstruction of abdo-perineal resection by Taylor flap: About 68 patients]. AB - PURPOSES: Healing after abdomino-perineal resection is often difficult, especially in patients who have undergone radiation therapy. Vaginal reconstruction is also an important issue for the women who undergo this surgery. We describe and analyze here our series of perineal reconstructions with modified Taylor flaps. Between 2010 and 2016, 68 patients (52 women, 16 men) with cancer of the anal canal (53), adenocarcinoma of the lower rectum (9), or other malignant neoplasms of the perineum underwent reconstruction with a rectus abdominis myocutaneous (RAM) flap with an inferior pedicle and an oblique skin paddle. RESULTS: This review of records showed that all patients healed, with a median of 30 days. The reoperation rate was 11.7% including 1 for eventration. The principal causes for delayed healing were scar dehiscence, abscess, and partial necrosis. No flap required removal, however. The mean duration of hospitalization was 23.7 days. CONCLUSION: Modified Taylor flaps substantially improved the reconstruction of defects resulting from abdomino-perineal resection. They enabled complete and rapid healing with low comorbidity. PMID- 29107433 TI - [Use of indocyanine green angiography in oncological and reconstructive breast surgery]. AB - The Indocyanine green (ICG) is a soluble dye that is eliminated by the liver and excreted in bile. When illuminated by an near-infrared light, the ICG emits fluorescence in the near-infrared spectrum, which can be captured by a near infrared camera-handled device. In case of intravenous injection, ICG may be used as a marker of skin perfusion. In case of interstitial injection, it may be useful for lymphatic network mapping. In oncological and reconstructive breast surgery, ICG is used for sentinel lymph node identification, to predict mastectomy skin flap necrosis, to assess the perfusion of free flaps in autologous reconstruction and for diagnosis and treatment of upper limb secondary lymphedema. Intraoperative indocyanine green fluorescence might also be used to guide the excision of nonpalpable breast cancer. PMID- 29107434 TI - Right Subclavian Venous Stent Fracture. PMID- 29107435 TI - Growing Cyst-Like White Matter Lesions in Children With Neurofibromatosis Type 1. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with prominent neurocutaneous manifestations. The most common intracranial imaging finding of NF1 on brain magnetic resonance imaging (MRI) is the high-signal intensity foci without a mass effect or growth in size. PATIENT DESCRIPTION: We describe two children with NF1 in whom brain MRI showed growing cystic lesions and adjacent white matter signal abnormalities, which were confirmed as non neoplastic cystic degeneration and reactive gliosis. CONCLUSION: Growing cyst like white matter lesions can be seen on serial brain MRI in children with NF1. Reactive gliosis with cystic degeneration could be a pathogenic basis of these cystic lesions. PMID- 29107436 TI - The Collateral Circulation in Moyamoya Disease: A Single-Center Experience in 140 Pediatric Patients. AB - BACKGROUND: The patterns and clinical significance of the presence of collaterals in moyamoya disease has not been elucidated thoroughly. We aimed to summarize the clinical features of collaterals in pediatric moyamoya disease. BASIC PROCEDURES: We reviewed consecutive pediatric patients with moyamoya vasculopathy who were admitted to our hospital from 2009 to 2015. Only pediatric moyamoya patients with digital subtraction angiography examinations were included in this study. We classified spontaneous collaterals into two groups by their origins, the internal carotid artery and vertebral artery (ICA-VA)-originated collaterals and the external carotid artery (ECA)-originated collaterals. MAIN FINDINGS: A total of 140 pediatric patients with moyamoya disease (mean age, 10.1 +/- 3.7 years) were included in this study. We identified collaterals originated from ICA-VA in 122 (87.1%) pediatric patients (222 hemispheres). Patients in the ICA-VA collaterals group had similar Suzuki stages with patients without collaterals originated from ICA-VA (mean, 3.86 vs 3.50; P = 0.157). We identified collaterals originated from ECAs in 70 (50.0%) pediatric patients (106 hemispheres) with moyamoya disease. The infarctions were more common in patients with ECA-originated collaterals than in patients without ECA-originated collaterals (25 versus 12; P = 0.021). PRINCIPAL CONCLUSIONS: Our results demonstrate that collaterals originating from ECAs are associated with advanced Suzuki stages and infarction presentations in children with moyamoya disease. PMID- 29107438 TI - Comments on "Predictors of hemodynamic derangement during intubation in the critically ill: A nested case-control study of hemodynamic management". PMID- 29107437 TI - Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation. AB - The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3 phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3 fluorophenoxy)phenoxyethyl selenocyanates and (+/-)-5-phenoxy-2 (selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED50 values of 0.084 uM, 0.11 uM, 0.083, uM, 0.085, and 0.075 uM, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1800 making these molecules promising candidates as antiparasitic agents. PMID- 29107439 TI - Effects of exercise improves muscle strength and fat mass in patients with high fracture risk: A randomized control trial. AB - BACKGROUND: The deterioration of the musculoskeletal system imposes significant impact on physical activity. Exercise is an important strategy which minimizes these changes. It is not clear which type of exercise provides better improvement on low physical performance, low muscle mass and low strength of sarcopenia. We aim to develop an integrated care (IC) model and compare its relative efficacy in limb fat free mass, muscle strength, and physical performance with low extremities exercise (LEE) in community dwelling older adults with high risk of fractures (Fracture Risk Assessment Tool (FRAX(r))) ?3% for hip fracture, ?20% for major osteoporotic fracture or 1-min osteoporosis risk test (?1 point) or fall (?2 falls in previous year). METHODS: Patients were assigned randomized to participate in either IC or LEE group (n = 55 each) for 3 months. All participants received education including home-based exercise. The IC group consisted of different modalities of exercise while the LEE group performed machine-based low extremities exercise. Fat free mass, muscle strength, and physical performance were measured at their baseline and 3-months follow-up. RESULTS: Mean age was 73.8 +/- 7 years with 69.1% women. Entire cohort demonstrated significant increment in fat free mass, muscle strength (4 indicators) and physical performance (3 indicators). However, between group differences were not significant. CONCLUSION: With regular supervise exercise; both groups are equally effective in decreasing fat mass and increasing physical performance, muscle mass and strength. However, the IC group required fewer resources and thus more financially feasible in a community setting. PMID- 29107440 TI - The technological basis for adaptive ion beam therapy at MedAustron: Status and outlook. AB - The ratio of patients who need a treatment adaptation due to anatomical variations at least once during the treatment course is significantly higher in light ion beam therapy (LIBT) than in photon therapy. The ballistic behaviour of ion beams makes them more sensitive to changes. Hence, the delivery of LIBT has always been supported by state of art image guidance. On the contrary CBCT technology was adapted for LIBT quite late. Adaptive concepts are being implemented more frequently in photon therapy and also efficient workflows are needed for LIBT. The MedAustron Ion Beam Therapy Centre was designed to allow the clinical implementation of adaptive image-guided concepts. The aim of this paper is to describe the current status and the potential future use of the technology installed at MedAustron. Specifically addressed is the beam delivery system, the patient alignment system, the treatment planning system as well as the Record & Verify system. Finally, an outlook is given on how high quality X-ray imaging, MR image guidance, fast and automated treatment planning as well as in vivo range verification methods could be integrated. PMID- 29107441 TI - Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent. AB - We conducted the first nation-wide cohort study of sickle cell disease (SCD) in Italy, a Southern European country exposed to intense recent flux migration from endemic areas for SCD. We evaluate the impact of hydroxyurea on a total of 652 pediatric and adult patients from 33 Reference Centers for SCD (mean age 24.5+/ 15years, 51.4% males). Hydroxyurea median treatment duration was 7years (range: <1year to 29years) at a mean therapeutic dose of 18+/-4.7mg/kg/day. Hydroxyurea was associated with a significant increase in mean total and fetal hemoglobin and a significant decrease in mean hemoglobin S, white blood and platelet counts, and lactate dehydrogenase levels. Hydroxyurea was associated with a significant reduction in the incidence of acute chest syndrome (-29.3%, p<0.001), vaso occlusive crisis (-34.1%, p<0.001), hospitalization (-53.2%, p<0.001), and bone necrosis (-6.9%, p<0.001). New silent cerebral infarction (SCI) occurred during treatment (+42.4%, p<0.001) but not stroke (+0.5%, p=0.572). These observations were generally consistent upon stratification for age, descent (Caucasian or African), genotype (betaS/betaS, betaS/beta0 or betaS/beta+) and duration of treatment (< or >=10years). There were no new safety concerns observed compared to those commonly reported in the literature. Our study, conducted on a large population of patients with different descent and compound state supports the benefits of hydroxyurea therapy as a treatment option. Registered at clinical trials.gov (NCT02709681). PMID- 29107442 TI - Erratum. PMID- 29107443 TI - Recurrent Strokes After Gore Septal Occluder Device Closure of Atrial Septal Defect. AB - We report a case of recurrent strokes in a healthy teenager after complete closure of atrial septal defect with Gore Septal Occluder (W.L. Gore and Associates, Newark, DE) device. The disk of the device produced a friction injury to the left atrial endocardium promoting thrombus formation with subsequent embolization to the brain requiring surgical intervention. PMID- 29107444 TI - Dopamine D2L receptor-interacting proteins regulate dopaminergic signaling. AB - Dopamine receptor family proteins include seven transmembrane and trimeric GTP binding protein-coupled receptors (GPCRs). Among them, the dopamine D2 receptor (D2R) is most extensively studied. All clinically used antipsychotic drugs serve as D2R antagonists in the mesolimbic dopamine system, and their ability to block D2R signaling is positively correlated with antipsychotic efficiency. Human genetic studies also show a significant association of DRD2 polymorphisms with disorders including schizophrenia and Parkinson's disease. D2R exists as two alternatively spliced isoforms, the long isoform (D2LR) and the short isoform (D2SR), which differ in a 29-amino acid (AA) insert in the third cytoplasmic loop. Importantly, previous reports demonstrate functional diversity between the two isoforms in humans. In this review, we focus on binding proteins that specifically interact with the D2LR 29AA insert. We discuss how D2R activities are mediated not only by heterotrimeric G proteins but by D2LR-interacting proteins, which in part regulate diverse D2R activities. PMID- 29107445 TI - "Apple Far from the Tree": comparative effectiveness of fiberoptic single operator cholangiopancreatoscopy (FSOCP) and digital SOCP (DSOCP). AB - BACKGROUND: While the fiberoptic single-operator cholangiopancreatoscopy (FSOCP) system has demonstrated efficacy in the diagnosis and management of pancreaticobiliary diseases, the digital SOCP (DSOCP) appears to provide higher resolution digital imaging, however a comparison of these devices has not been established. The aim of this work was to compare the efficacy of FSOCP and DSOCP in biliary stone disease and indeterminate biliary strictures. METHODS: A retrospective analysis of a prospective cohort was performed in patients undergoing FSOCP or DSOCP demographics included indication, diagnostic yield, procedure time, radiation dose, and complications. RESULTS: 324 patients underwent cholangioscopy. FSOCP and DSOCP were utilized in 198 and 126 patients respectively. Male/female ratio was similar and mean age was 66 +/- 13 years. Indications included stone disease, indeterminate stricture evaluation and "other" were 47%, 42% and 11% respectively. Mean procedure time for stone disease and the amount of radiation doses in DSOCP group were lower than the FSOCP group (P = 0.032 and P = 0.02, respectively). Diagnostic yield in indeterminate strictures was higher 78% with DSOCP system compared to 37% with FSOCP system (P = 0.004). Complication were low and similar between the groups. CONCLUSIONS: DSOCP system provides enhanced diagnostic yield, shorter procedure times and less radiation exposure compared to FSOCP system. PMID- 29107446 TI - Characterisation of the site-specific monoPEGylated rhG-CSF analogue pegteograstim. AB - We describe the characterisation of a novel monoPEGylated recombinant human granulocyte colony-stimulating factor analogue, pegteograstim (Neulapeg), prepared by site-specific 20 kDa maleimide-PEG conjugation. An additional cysteine was inserted between Gly136 and Ala137 of filgrastim (methionyl human granulocyte colony-stimulating factor) for site-specific PEGylation, and Cys18 of filgrastim was replaced with Ser18 to prevent unwanted PEGylation. Pegteograstim was produced by Escherichia coli and purified by cation exchange chromatography, and its structural, physicochemical, biological and immunological properties were investigated. Male Sprague-Dawley rats were administered pegteograstim (100 MUg/kg) and the pharmacokinetics and pharmacodynamics compared with those of filgrastim. The results of long-term stability testing of pegteograstim revealed no significant change in its quality attributes at 2-8 degrees C for 36 months. In addition, pegteograstim was stable under the accelerated conditions (25 +/- 2 degrees C, RH of 60 +/- 5%) for 6 months. The site-specific monoPEGylated pegteograstim is a highly pure, stable and novel drug for long-lasting treatment of chemotherapy-induced neutropenia. PMID- 29107447 TI - Smoking and subsequent human papillomavirus infection: a mediation analysis. AB - PURPOSE: Smoking is an established risk factor for a human papillomavirus (HPV) infection advancing to cervical precancer and cancer, but its role earlier in the natural history is less clear. Smoking is inversely associated with possessing HPV antibodies from a past infection suggesting that smoking may influence acquiring subsequent infections. METHODS: In a cohort of 1976 U.S. women, we evaluate whether reduced antibodies to HPV-16 is a mechanism for smoking's role on acquiring a subsequent HPV-16 infection, through the analytic technique of causal mediation analysis. We posit a causal model and estimate two counterfactually defined effects: a smoking impaired antibody-mediated indirect effect and a nonmediated direct effect representing all other potential mechanisms of smoking. RESULTS: Compared to never smokers, current smokers had increased odds of HPV-16 infection by the antibody-mediated indirect effect (odds ratio [OR] = 1.29; 95% confidence interval [CI]: 1.11, 1.73); the estimated direct effect was very imprecise (OR = 0.57; 95% CI, 0.26-1.13). We observed a stronger estimated indirect effect among women who smoked at least half a pack of cigarettes daily (OR = 1.61, 95% CI, 1.27-2.15) than among women who smoked less than that threshold (OR = 1.09; 95% CI, 0.94-1.44). CONCLUSIONS: This is the first study to directly test the mechanism underlying smoking as an HPV cofactor. The results support current smoking as a risk factor earlier in the natural history of HPV and are consistent with the hypothesis that smoking increases the risk of a subsequent infection by reducing immunity. PMID- 29107448 TI - Hope in Parents of Very-Low Birth Weight Infants and its Association with Parenting Stress and Quality of Life. AB - PURPOSE: Being a parent of a very-low-birth-weight (VLBW) infant can be stressful. We aimed to describe parental hope 42months after the birth of a VLBW infant and determine whether there is an association between hope and parenting stress with quality of life (QoL), respectively. DESIGN AND METHODS: Fifty-nine parents of VLBW infants completed questionnaires about hope, parenting stress and QoL. Pearson correlation coefficients (r) and linear regression models were used to examine the relationship between the selected variables. To compare groups, t test was used and Cohen's d for effect size was calculated. RESULTS: Parents of VLBW infants were more hopeful than the general population (p<0.001). Parenting stress and hope were both independently associated with QoL (p<0.001). The subgroup of parents of infants with birth weight <1000g had less hope (p=0.041) and higher parenting stress (p=0.041) than parents of infants with birth weight 1000-1500g. CONCLUSIONS: Hope and parenting stress were both independent determinants of QoL. Parents of the presumably sickest infants had less hope and higher parenting stress than parents of VLBW infants with a birth weight over 1000g. Hope should be further explored as a coping mechanism in parents of VLBW infants. PRACTICE IMPLICATIONS: The clinical implications of the strong association between hope, parenting stress and QoL remain to be determined, but reducing stress and strengthening hope seem to be important. This should be taken into account both at hospital discharge and at follow-up, especially for lower birth-weight infants. PMID- 29107449 TI - Risk of gastrointestinal Hypomotility in schizophrenia and schizoaffective disorder treated with antipsychotics: A retrospective cohort study. AB - OBJECTIVE: The risk of gastrointestinal hypomotility (GIHM) with the use of antipsychotic medications in patients with schizophrenia remains inadequately recognized. The aim of this study was to explore the incidence of GIHM and its risks in patients with schizophrenia treated with antipsychotics. METHODS: We conducted a retrospective cohort study using the National Health Insurance Research Database. We identified adult (>= 20years of age) patients with a first time diagnosis of schizophrenia or schizoaffective disorder in the Registry for Catastrophic Illness Patients during the period from 2001 to 2011. Each subject in the cohort was followed until their corresponding diagnosis of GIHM was made, until the time of death, or to December 31, 2012. The incidence rates of each outcome were calculated. Cox proportional hazards regression with time-dependent covariates for antipsychotics use was employed to evaluate the associations between different types of antipsychotics and the risk of GIHM. RESULTS: Our study found that the incidence densities of constipation, ileus, and ischemic bowel disease were 42.5, 4.4, and 0.1 per 1000 person-years. In terms of the risk of hypomotility with the use of antipsychotics, clozapine and quetiapine were significant in developing constipation, with a hazard ratio of 2.15 and 1.34, respectively. High-potency first-generation antipsychotics and clozapine were also significant in the occurrence of ileus, with a hazard ratio of 1.30 and 1.95, respectively. Similar associations were found in an anticholinergic agent subgroup analysis. CONCLUSION: Patients receiving antipsychotics such as high potency first-generation antipsychotics, clozapine, or quetiapine should undergo proper evaluation and intervention to minimize the disease burden and life threatening outcomes of treatment. PMID- 29107450 TI - Epilepsy as a Network Disorder (1): What can we learn from other network disorders such as autistic spectrum disorder and mood disorders? AB - Epilepsy is a neurologic condition which often occurs with other neurologic and psychiatric disorders. The relation between epilepsy and these conditions is complex. Some population-based studies have identified a bidirectional relation, whereby not only patients with epilepsy are at increased risk of suffering from some of these neurologic and psychiatric disorders (migraine, stroke, dementia, autism, depression, anxiety disorders, Attention deficit hyperactivity disorder (ADHD), and psychosis), but also patients with these conditions are at increased risk of suffering from epilepsy. The existence of common pathogenic mechanisms has been postulated as a potential explanation of this phenomenon. To reassess the relationships between neurological and psychiatric conditions in general, and specifically autism, depression, Alzheimer's disease, schizophrenia, and epilepsy, a recent meeting brought together basic researchers and clinician scientists entitled "Epilepsy as a Network Disorder." This was the fourth in a series of conferences, the "Fourth International Halifax Conference and Retreat". This manuscript summarizes the proceedings on potential relations between Epilepsy on the one hand and autism and depression on the other. A companion manuscript provides a summary of the proceedings about the relation between epilepsy and Alzheimer's disease and schizophrenia, closed by the role of translational research in clarifying these relationships. The review of the topics in these two manuscripts will provide a better understanding of the mechanisms operant in some of the common neurologic and psychiatric comorbidities of epilepsy. PMID- 29107451 TI - A protocol to prevent and deal with aggressive behavior against health workers. AB - Violence against health workers is a highly prevalent phenomenon with serious psychological and labour consequences among professionals. This paper aims, first, to find out the main studies undertaken to date to describe and analyse the phenomenon, as well as to present different initiatives and protocols of action carried out. The second objective is to offer a procedure of action both to prevent aggression and to intervene in the event of receiving an aggression at work. After a bibliographic search in PubMed, Scopus and SciELO databases, the impact of the aggressions suffered by health professionals, the contexts in which aggressions are more frequent, their main consequences and different strategies and protocols conducted in Spain are reviewed. Given that rigorous reviews supporting such procedures are lacking in scientific journals, different action guidelines for professionals to prevent and to deal with hostile behaviour based on available evidence are developed and proposed. Finally, an easily consultable and applicable action procedure for health workers attacked in the workplace is presented. PMID- 29107452 TI - Effectiveness of patient empowerment over stress related to knee arthroplasty surgery. AB - OBJECTIVE: This study aims to show evidence of the Empowerment Session's effectiveness through measurements of surgery related emotional stress before and after this session. METHOD: The study was performed on 41 patients with knee arthroplasty surgery prescription by measuring the evolution of their emotional stress generated by surgery expectative, during the empowerment session. Two sets of measurements per patient were performed, before and after the empowerment session. Each set consisted of recording an electrocardiogram for 10min while the patients were seated and then applying two standard psychometric tests: State Trait Anxiety Inventory test and Visual Analog Stress test. Differences in emotional stress were analyzed using psychometric tests and heart rate variability (HRV) analysis as stress biomarkers. RESULTS: Psychometric stress measurement shows a 17.8% reduction in stress according to the total stress scale value, and a 41.9% reduction in stress between test results before and after the session. Mean heart rate values increased by 7.4% with respect to the initial values, very low frequency power and total power also change in value suggesting more sympathetic and less parasympathetic activity. CONCLUSIONS: Both psychological and physiological measurements suggest the effectiveness of the empowerment session due to a significant increase in the wellness state of patients. Additionally, the correlation between psychometric tests and HRV indices demonstrates that both emotional stress indicators could be used as feedback on the empowerment sessions or as a reference to enhance surgical outcomes. PMID- 29107453 TI - Longitudinal trends and predictors of statin use among patients with diabetes. AB - AIM: Statins reduce morbidity and mortality among patients with diabetes, but their use remains suboptimal. Understanding trends in statin use may inform strategies for improvement. METHODS: We enrolled a national, retrospective cohort of 899,664 veterans aged>=40years with diabetes in 2003. We followed them through 2011, dividing the nine-year follow-up into 90-day periods. For each period, we determined statin use, defined as possession of >=30-day supply. We examine factors associated with statin uptake among baseline non-users with a multivariate model. RESULTS: Baseline prevalence of statin use was 43%, increased by 1.8% per period (p for trend<0.001), and reached a maximum of ~59%. Statin use among non-Hispanic racial/ethnic minorities lagged behind their white counterparts. Among baseline non-users, statin use was 9% after Year 1 and reached 36% by Year 9. Factors associated with statin uptake included use of hypoglycemic agents, HbA1c between 7 and 8.9% (53-74mmol/mol), hypertension, heart failure, peripheral vascular disease, and Hispanic ethnicity. CONCLUSION: Statin use is slowly increasing among patients with diabetes, and at varying rates within subgroups of this population. Policies that prioritize these subgroups for statin promotion may help guide future, intervention-based research to increase compliance with current guidelines. PMID- 29107454 TI - Prevalence of micro- and macrovascular diabetes complications at time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional baseline study of 6958 patients in the Danish DD2 cohort. AB - AIMS: To examine the prevalence of micro- and macrovascular complications and their associated clinical characteristics at time of type 2 diabetes (T2D) diagnosis. METHODS: We examined the prevalence of complications and associated clinical characteristics among 6958 newly diagnosed T2D patients enrolled in the prospective Danish Center for Strategic Research in T2D cohort during 2010-2016. We calculated age- and gender-adjusted prevalence ratios (aPRs) of complications using log-binomial and Poisson regression. RESULTS: In total, 35% (n=2456) T2D patients had diabetic complications around diagnosis; 12% (n=828) had microvascular complications, 17% (n=1186) macrovascular complications, and 6% (n=442) had both. HbA1c levels of >=7% were associated with microvascular complications [HbA1c 7%-8%; aPR: 1.35, 95% confidence interval (CI): 1.12-1.62] but not macrovascular complications [aPR: 0.91, 95% CI: 0.76-1.08]. High C peptide>=800pmol/L was associated with macrovascular [aPR 1.34, 95% CI: 1.00 1.80] but not microvascular [aPR 0.97, 95% CI: 0.71-1.33] complications. Macrovascular complications were associated with male sex, age>50years, obesity, hypertriglyceridemia, low HDL cholesterol, smoking, elevated CRP levels, and anti hypertensive therapy. Microvascular complications were associated with high blood pressure, hypertriglyceridemia, and absence of lipid-lowering therapy. CONCLUSIONS: One-third of patients with T2D had diabetes complications around time of diagnosis. Our findings suggest different pathophysiological mechanisms behind micro- and macrovascular complications. PMID- 29107455 TI - Type 2 diabetes mellitus and risk of open-angle glaucoma development in Koreans: An 11-year nationwide propensity-score-matched study. AB - PURPOSE: To evaluate the risk of primary open-angle glaucoma (POAG) development in type 2 diabetes mellitus (T2DM) patients. METHODS: In this 11-year longitudinal study based on the Korean National Health Insurance research database, the data collected comprised 1,025,340 (2.2%) participants who were randomly selected from 46,605,433 Korean residents in 2002. The database was analyzed to identify participants with an initial diagnosis of T2DM in 2003-2004. The control group was composed of participants without T2DM who were propensity score-matched, five controls per T2DM patient, according to age, gender, household income, residential area and underlying diseases, including hypertension, dyslipidaemia, coronary heart disease, cerebrovascular disease and thyroid disease. Cox proportional-hazards regression was used to calculate the overall hazard ratios (HRs) in participants with and without T2DM for development of POAG before and after adjusting for confounding factors. RESULTS: There were 12,657 participants with T2DM and 63,285 propensity-score-matched controls without T2DM. POAG developed in 413 (3.3%) and 1188 (1.9%) participants in the T2DM and control groups, respectively. T2DM was associated with an increased risk of POAG development [HR: 1.80; 95% confidence interval (CI): 1.58-2.04] after adjusting for age, gender, household income and other potential confounders. CONCLUSION: T2DM was significantly associated with the development of POAG after adjusting for potential confounders in the Korean population. PMID- 29107456 TI - Educational Implications of Health Insurance Changes. PMID- 29107457 TI - Increased Epicardial Fat Volume in Systemic Sclerosis: A New Cardiovascular Risk Marker? PMID- 29107458 TI - Imaging Facilities' Adherence to PI-RADS v2 Minimum Technical Standards for the Performance of Prostate MRI. AB - PURPOSE: This study aimed to assess variability in imaging facilities' adherence to the minimum technical standards for prostate magnetic resonance imaging acquisition established by Prostate Imaging-Reporting and Data System (PI-RADS) version 2 (v2). METHODS: A total of 107 prostate magnetic resonance imaging examinations performed at 107 unique imaging facilities after the release of PI RADS v2 and that were referred to a tertiary care center for secondary interpretation were included. Image sets, DICOM headers, and outside reports were reviewed to assess adherence to 21 selected PI-RADS v2 minimum technical standards. RESULTS: Hardware arrangements were 23.1%, 1.5T without endorectal coil; 7.7%, 1.5T with endorectal coil; 63.5%, 3T without endorectal coil; and 5.8%, 3T with endorectal coil. Adherence to minimum standards was lowest on T2 weighted imaging (T2WI) for frequency resolution <=0.4 mm (16.8%) and phase resolution <=0.7 mm (48.6%), lowest on diffusion-weighted imaging (DWI) for field of view (FOV) 120-220 mm (30.0%), and lowest on dynamic contrast-enhanced (DCE) imaging for slice thickness 3 mm (33.3%) and temporal resolution <10 s (31.5%). High b-value (>=1400 s/mm2) images were included in 58.0% (calculated in 25.9%). Adherence to T2WI phase resolution and DWI inter-slice gap were greater (P < .05) at 3T than at 1.5T. Adherence did not differ (P > .05) for any parameter between examinations performed with and without an endorectal coil. Adherence was greater for examinations performed at teaching facilities for T2WI slice thickness and DCE temporal resolution (P < .05). Adherence was not better for examinations performed in 2016 than in 2015 for any parameter (P > .05). CONCLUSION: Facilities' adherence to PI-RADS v2 minimum technical standards was variable, being particularly poor for T2WI frequency resolution and DCE temporal resolution. The standards warrant greater community education. Certain technical standards may be too stringent, and revisions should be considered. PMID- 29107459 TI - Depression and Functional Impairment: A Pernicious Pairing in Older Adults. PMID- 29107460 TI - Electroconvulsive Therapy for Agitation and Aggression in Dementia: A Systematic Review. AB - OBJECTIVES: Many patients with dementia develop agitation or aggression in the course of their disease. In some severe cases, behavioral, environmental, and pharmacological interventions are not sufficient to alleviate these potentially life-threatening symptoms. It has been suggested that in those cases, electroconvulsive therapy (ECT) could be an option. This review summarizes the scientific literature on ECT for agitation and aggression in dementia. METHODS: We performed a systematic review in accordance with PRISMA guidelines. A search was conducted in Ovid MEDLINE, EMBASE, and PsycINFO. Two reviewers extracted the following data from the retrieved articles: number of patients and their age, gender, diagnoses, types of problem behavior, treatments tried before ECT, specifications of the ECT treatment, use of rating scales, treatment results, follow-up data, and adverse effects. RESULTS: The initial search yielded 264 articles, 17 of which fulfilled the inclusion criteria. Of these studies, one was a prospective cohort study, one was a case-control study, and the others were retrospective chart reviews, case series, or case reports. Clinically significant improvement was observed in the majority (88%) of the 122 patients described, often early in the treatment course. Adverse effects were most commonly mild, transient, or not reported. CONCLUSIONS: The reviewed articles suggest that ECT could be an effective treatment for severe and treatment-refractory agitation and aggression in dementia, with few adverse consequences. Nevertheless, because of the substantial risk of selection bias, the designs of the studies reviewed, and their small number, further prospective studies are needed to substantiate these preliminary positive results. PMID- 29107461 TI - Vignettes and Viewpoints From a Professional Autobiography. AB - In this professional autobiography, the author describes factors contributing to important decisions in his academic geriatric psychiatry career. Major inflection points included embarking on clinical research and later deciding to focus more on leadership roles in education and in faculty affairs. The discussion then examines themes that have emerged in reviewing this career arc, including the value of: the variety and social connectedness inherent in the academic life; cultivation of interpersonal relationships and best efforts as much as possible; an open mind ready to (collegially) seize new opportunities; and family, friends, and avocational pursuits as complements to one's profession. The author hopes that this public life review is of help to others planning or reflecting on their own career paths. . PMID- 29107462 TI - Each meal matters in the exposome: Biological and community considerations in fast-food-socioeconomic associations. AB - Advances in omics and microbiome technology have transformed the ways in which the biological consequences of life in the 'ecological theatre' can be visualized. Exposome science examines the total accumulated environmental exposures (both detrimental and beneficial) as a means to understand the response of the 'total organism to the total environment' over time. The repetitive stimulation of compensatory physiological responses (immune, cardiovascular, neuroendocrine) in response to stress - including sources of stress highly relevant to socioeconomic disadvantage - may lead to metabolic dysregulation and cellular damage, ultimately influencing behavior and disease. The collective toll of physiological wear and tear, known as allostatic load, is not paid equally throughout developed societies. It is paid in excess by the disadvantaged. In the context of fast-food, human and experimental research demonstrates that the biological response to a single fast-food-style meal - especially as mediated by the microbiome- is a product of the person's total lived experience, including the ability to buffer the fast-food meal-induced promotion of inflammation and oxidative stress. Emerging research indicates that each meal and its nutritional context matters. As we discuss, equal weekly visits to major fast-food outlets by the affluent and deprived do not translate into biological equivalency. Hence, debate concerning reducing fast-food outlets through policy - especially in disadvantaged neighborhoods where they are prevalent - requires a biological context. The fast-food establishment and fast-food meal - as they represent matters of food justice and press upon non-communicable disease risk - are far more than physical structures and collections of carbohydrate, fat, sugar and sodium. PMID- 29107463 TI - Association of consistently suboptimal quality of life with consistently poor asthma control in children with asthma. PMID- 29107464 TI - Paternal gonadal mosaicism as cause of a puzzling inheritance pattern of activated PI3-kinase delta syndrome. PMID- 29107465 TI - Forced expiratory values in 1 second corresponding to Pediatric Respiratory Assessment Measure and Acute Asthma Intensity Research Score values during pediatric acute asthma exacerbations. PMID- 29107466 TI - Bee moth (Galleria mellonella) allergy: New insight from a case of monosensitization. PMID- 29107467 TI - [Adult deafness: Towards new paradigm]. AB - Screening and early treatment of deafness regardless of age is essential. Deafness leads to social isolation, depression, and decreased cognitive function. The diagnosis requires an otoscopy and a confirmation of the type and degree of deafness by audiometry. Sudden deafness and meningitis are neuro-sensorial emergencies. Deafness may be the mode of disclosure of an autoimmune disease or part of the evolutionary profile. Hearing complaints with a normal classical audiogram may be the manifestation of a so-called "hidden" hearing loss and must be explored more carefully. PMID- 29107468 TI - What more can we learn about sleep education programs in young people? PMID- 29107469 TI - Diseases of the retina and the optic nerve associated with obstructive sleep apnea. AB - Many associations between ocular disorders and obstructive sleep apnea (OSA) have been studied, such as nonarteritic anterior ischemic optic neuropathy, glaucoma, papilledema, retinal vein occlusion, eyelid hyperlaxity, lower-eyelid ectropion and recurrent corneal erosions. The objective of this review is to synthetize the possible vascular disorders of the retina and the optic nerve associated with sleep apnea patients and to discuss the underlying pathophysiological hypotheses. Main mechanisms involved in the ocular complications of OSA are related to intermittent hypoxia, sympathetic system activation, oxidant stress, and deleterious effects of endothelin 1. The main evidence-based medicine data suggest that OSA should be screened in patients with ischemic optic neuropathy and diabetic retinopathy. The effect of OSA treatment and emerging therapies are discussed. PMID- 29107470 TI - Is an off-task mind a freely-moving mind? Examining the relationship between different dimensions of thought. AB - Mind wandering is frequently defined as task-unrelated or perceptually decoupled thought. However, these definitions may not capture the dynamic features of a wandering mind, such as its tendency to 'move freely'. Here we test the relationship between three theoretically dissociable dimensions of thought: freedom of movement in thought, task-relatedness, and perceptual decoupling (i.e., lack of awareness of surroundings). Using everyday life experience sampling, thought probes were randomly delivered to participants' phones for ten days. Results revealed weak intra-individual correlations between freedom of movement in thought and task-unrelatedness, as well as perceptual decoupling. Within our dataset, over 40% of thoughts would have been misclassified under the assumption that off-task thought is inherently freely moving. Overall, freedom of movement appears to be an independent dimension of thought that is not captured by the two most common measures of mind wandering. Future work focusing on the dynamics of thought may be crucial for improving our understanding of the wandering mind. PMID- 29107472 TI - Depression and anxiety in caregivers of patients with celiac disease. PMID- 29107471 TI - Quality of care indicators in inflammatory bowel disease in a tertiary referral center with open access and objective assessment policies. AB - BACKGROUND: In the management of inflammatory bowel diseases, there is considerable variation in quality of care. AIMS: The aim of this study was to evaluate structural, access/process components and outcome quality indicators in our tertiary referral IBD center. METHODS: In the first phase, structural/process components were assessed, followed by the second phase of formal evaluation of access and management on a set of consecutive IBD patients with and without active disease (248CD/125UC patients, median age 35/39 years). RESULTS: Structural/process components of our IBD center met the international recommendations. At or around the time of diagnosis usual procedures were full colonoscopy in all patients, with ileocolonoscopy/gastroscopy/CT/MRI in 81.8/45.5/66.1/49.6% of CD patients. A total of 86.7% of CD patients had any follow-up imaging evaluation or endoscopy. The median waiting time for non emergency endoscopy/CT/MRI was 16/14/22 days. During the observational period patients with flares (CD/UC:50.6/54.6%) were seen by specialist at the IBD clinic within a median of 1day with same day laboratory assessment, abdominal US, CT scan/surgical consult and change in therapy if needed. Surgery and hospitalization rates were 20.1/1.4% and 17.3/3.2% of CD/UC patients. CONCLUSION: Our results highlight that structural components and processes applied in our center are in line with international recommendations, including an open clinic concept and fast track access to specialist consultation, endoscopy and imaging. PMID- 29107473 TI - Food Insecurity and Perceived Diet Quality Among Low-Income Older Americans with Functional Limitations. AB - OBJECTIVE: To evaluate how functional limitations are associated with food insecurity and perceived diet quality in low-income older Americans. DESIGN: Nationwide repeated cross-sectional surveys regarding health and nutritional status. SETTING: The National Health and Nutrition Examination Surveys, 2007 2008, 2009-2010, and 2011-2012. PARTICIPANTS: Individuals aged >=65 years with household incomes <=130% of the federal poverty level (n = 1,323). MAIN OUTCOME MEASURES: Dependent variables included dichotomous indicators of food insecurity and poor-quality diet, measured with the household food security survey module and respondents' own ratings, respectively. Independent variable was presence of limitations in physical functioning. ANALYSIS: Weighted logistic regressions with nested controls and interaction terms. RESULTS: Functional limitations in low income older adults were associated with 1.69 times higher odds of food insecurity (P < .01) and 1.65 times higher odds of poor-quality diet (P < .01) after accounting for individuals' health care needs and socioeconomic conditions. These associations were greatest among those living alone (odds ratio = 3.38 for food insecurity; 3.07 for poor-quality diet; P < .05) and smallest among those living with a partner. CONCLUSIONS AND IMPLICATIONS: Low-income older adults who live alone with functional limitations are exposed to significant nutritional risk. Resources should be directed to facilitating their physical access to healthful foods. PMID- 29107474 TI - Breakfast Quality Varies by Location among Low-Income Ethnically Diverse Children in Public Urban Schools. AB - OBJECTIVE: To evaluate breakfast location and children's food choices. METHODS: Cross-sectional analysis of 1,371 fourth- through sixth-grade students in 2013. Foods and beverages in 17 categories characterized breakfast choices: (1) >= 1 fruits or vegetables, (2) >= 1 foods high in saturated fats and added sugars (SFAS), and (3) meeting School Breakfast Program (SBP) requirements. RESULTS: Among breakfast eaters (n = 1,133; 82.6%), 46.0% ate at home, 13.1% ate at school, 41.0% ate at multiple locations; and 21.8% ate at a corner store. Those eating at school were more likely to consume >=1 fruit or vegetable (odds ratio [OR] = 1.90; 95% confidence interval [CI], 1.26-2.87), less likely to eat >=1 SFAS food (OR = 0.46; 95% CI, 0.22-0.94), and more likely to meet SBP requirements (OR = 2.47; 95% CI, 1.42-4.29). Those eating at corner stores (n = 247) were more likely to consume high-SFAS foods (63.9% vs 9.2%; P < .001). CONCLUSIONS AND IMPLICATIONS: Eating school breakfast increased the odds of consuming fruit, choosing lower SFAS, and meeting nutritional requirements of the SBP relative to other locations. PMID- 29107476 TI - The blueprint of the vertebrate forebrain - With special reference to the habenulae. AB - The medial and lateral habenulae are conserved throughout vertebrate evolution, and form an integrated part in the forebrain control of behavior together with the basal ganglia, the dopamine and serotonin systems and cortex. The lateral habenula plays a role in the control of dopamine activity in the context of aversive behavior and the converse, a reward situation. These circuits are important for a value-based evaluation of the success of prior actions. The medial habenula is involved in mediating escape and freezing behavior. These structures are reviewed with a focus on the lamprey, belonging to the oldest group of now living vertebrate, showing that most aspects of the habenular structure and function have been conserved throughout vertebrate phylogeny. PMID- 29107475 TI - Development and connectivity of the habenular nuclei. AB - Accumulating evidence has reinforced that the habenular region of the vertebrate dorsal forebrain is an essential integrating center, and a region strongly implicated in neurological disorders and addiction. Despite the important and diverse neuromodulatory roles the habenular nuclei play, their development has been understudied. The emphasis of this review is on the dorsal habenular nuclei of zebrafish, homologous to the medial nuclei of mammals, as recent work has revealed new information about the signaling pathways that regulate their formation. Additionally, the zebrafish dorsal habenulae have become a valuable model for probing how left-right differences are established in a vertebrate brain. Sonic hedgehog, fibroblast growth factors and Wingless-INT proteins are all involved in the generation of progenitor cells and ultimately, along with Notch signaling, influence habenular neurogenesis and left-right asymmetry. Intriguingly, a genetic network has emerged that leads to the differentiation of dorsal habenular neurons and, through localized chemokine signaling, directs the posterior outgrowth of their newly emerging axons towards their postsynaptic target, the midbrain interpeduncular nucleus. PMID- 29107477 TI - Contribution of Implanted, Genetically Modified Muscle Progenitor Cells Expressing BMP-2 to New Bone Formation in a Rat Osseous Defect. AB - Because muscle contains osteoprogenitor cells and has a propensity to form bone, we have explored its utility in healing large osseous defects. Healing is achieved by the insertion of muscle fragments transduced with adenovirus encoding BMP-2 (Ad.BMP-2). However, it is not known whether the genetically modified muscle contributes osteoprogenitor cells to healing defects or merely serves as a local source of BMP-2. This question is part of the larger debate on the fate of progenitor cells introduced into sites of tissue damage to promote regeneration. To address this issue, we harvested fragments of muscle from rats constitutively expressing GFP, transduced them with Ad.BMP-2, and implanted them into femoral defects in wild-type rats under various conditions. GFP+ cells persisted within defects for the entire 8 weeks of the experiments. In the absence of bone formation, these cells presented as fibroblasts. When bone was formed, GFP+ cells were present as osteoblasts and osteocytes and also among the lining cells of new blood vessels. The genetically modified muscle thus contributed progenitor cells as well as BMP-2 to the healing defect, a property of great significance in light of the extensive damage to soft tissue and consequent loss of endogenous progenitors in problematic fractures. PMID- 29107478 TI - Intrabiliary Rupture of Hepatic Hydatid Cyst Leading to Biliary Obstruction, Cholangitis, and Septicemia. PMID- 29107480 TI - A Case of Wooden Foreign-Body Ingestion. PMID- 29107479 TI - Clinical Factors and Outcomes of Dialysis-Dependent End-Stage Renal Disease Patients with Emergency Department Septic Shock. AB - BACKGROUND: Infection is the second leading cause of death in end-stage renal disease (ESRD) patients. Prior investigations of acute septic shock in this specific population are limited. OBJECTIVE: We aimed to evaluate the clinical presentation and factors associated with outcome among ESRD patients with acute septic shock. METHODS: We reviewed patients prospectively enrolled in an emergency department (ED) septic shock treatment pathway registry between January 2014 and May 2016. Clinical and treatment variables for ESRD patients were compared with non-ESRD patients. A second analysis focused on ESRD septic shock survivors and nonsurvivors. RESULTS: Among 4126 registry enrollees, 3564 (86.4%) met inclusion for the study. End-stage renal disease was present in 3.8% (n = 137) of ED septic shock patients. Hospital mortality was 20.4% and 17.1% for the ESRD and non-ESRD septic shock patient groups (p = 0.31). Septic shock patients with ESRD had a higher burden of chronic illness, but similar admission clinical profiles to non-ESRD patients. End-stage renal disease status was independently associated with lower fluid resuscitation dose, even when controlling for severity of illness. Age and admission lactate were independently associated with mortality in ESRD septic shock patients. CONCLUSION: ESRD patients comprise a small but important portion of patients with ED septic shock. Although presentation clinical profiles are similar to patients without ESRD, ESRD status is independently associated with lower fluid dose and compliance with the 30 mL/kg fluid goal. Hyperlactatemia is a marker of mortality in ESRD septic shock. PMID- 29107481 TI - Physical Examination is the Best Predictor of the Need for Abdominal Surgery in Children Following Motor Vehicle Collision. AB - BACKGROUND: Exploratory laparotomy in children after motor vehicle collision (MVC) is rare. In the absence of definitive hemorrhage or free abdominal air on radiographic imaging, predictors for operative exploration are conflicting. OBJECTIVE: The purpose of this study was to explore objective findings that may aid in determining which children require operative abdominal exploration after MVC. METHODS: Data from 2010-2014 at an American College of Surgeons-certified level 1 pediatric trauma center were retrospectively reviewed. Demographics, vital signs, laboratory data, radiologic studies, operative records, associated injuries, and outcomes were analyzed and p < 0.05 was considered statistically significant. RESULTS: Eight hundred sixty-two patients 0-18 years of age presented to the hospital after an MVC during the study period. Seventeen patients (2.0%) required abdominal exploration and all were found to have intraabdominal injuries. Respiratory rate was the only vital sign that was significantly altered (p = 0.04) in those who required abdominal surgery compared with those who did not. Physical examination findings, such as the seat belt sign, abdominal bruising, abdominal wound, and abdominal tenderness, were present significantly more frequently in those requiring abdominal surgery (p < 0.0001). Each finding had a negative predictive value for the need for operative exploration of at least 0.98. There were no significant differences in trauma laboratory values or radiographic findings between the 2 groups. CONCLUSION: Data from this study solidify the relationship between specific physical examination findings and the need for abdominal exploration after MVC in children. In addition, these data suggest that a lack of the seat belt sign, abdominal bruising, abdominal wounds, or abdominal tenderness are individually predictive of patients who will not require surgical intervention. PMID- 29107482 TI - Prevalence and Outcome of High-Risk QT Prolongation Recorded in the Emergency Department from an Institution-Wide QT Alert System. AB - BACKGROUND: QT prolongation is an independent risk factor for sudden death, stroke, and all-cause mortality. However, additional studies have shown that in certain settings, QT prolongation may be transient and a result of external factors. OBJECTIVE: In this study, we evaluated the clinical characteristics and outcomes of patients seen in the emergency department (ED) with QT prolongation. METHODS: Between November 2010 and June 2011, 7522 patients had an electrocardiogram (ECG) obtained during their evaluation in the ED. Clinical, laboratory, and therapeutic information was collected for all patients with QT prolongation (i.e., >= 500 ms and QRS < 120 ms). Potential QT-inciting factors (drugs, electrolyte disturbances, and comorbidities) were synthesized into a pro QT score. RESULTS: Among the 7522 patients with an ECG obtained in the ED, a QT alert was activated in 93 (1.2%; mean QTc 521 +/- 34 ms). The majority of ED patients (64%) had more than one underlying condition associated with QT prolongation, with electrolyte disturbances in 51%, a QT prolonging condition in 56%, and QT-prolonging drugs in 77%. Thirty-day mortality was 13% for patients with QT prolongation noted in the ED. CONCLUSIONS: One percent of patients evaluated with an ECG in the ED activated our prolonged QTc warning system, with most demonstrating > 1 QT-prolonging condition. Thirty-day mortality was significant, but it requires further investigation to determine whether the QTc simply provided a non-invasive indicator of increased risk or heralded the presence of a vulnerable host at risk of a QT-mediated sudden dysrhythmic death. PMID- 29107483 TI - Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin. AB - Sortilin is a neuronal receptor involved in transmembrane signaling, endocytosis, and intracellular sorting of proteins. It cycles through a number of cellular compartments where it encounters various acidic conditions. The crystal structure of the sortilin ectodomain has previously been determined at neutral pH. Here, we present the 3.5-A resolution crystal structure of sortilin at pH 5.5, which represents an environment similar to that of late endosomes, where ligands are released. The structure reveals an overall distortion of the 10-bladed beta propeller domain. This distortion and specific conformational changes, caused by protonation of a number of histidine residues, render the currently known binding sites unavailable for ligand binding. Access to the binding sites is furthermore blocked by a reversible and pH-dependent formation of tight sortilin dimers, also confirmed by electron microscopy, size-exclusion chromatography, and mutational studies. This study reveals how sortilin binding sites are disrupted and explains pH-dependent ligand affinity. PMID- 29107485 TI - The cryo-EM Structure of a Novel 40S Kinetoplastid-Specific Ribosomal Protein. AB - Kinetoplastids are potentially lethal protozoan pathogens affecting more than 20 million people worldwide. There is a critical need for more specific targets for the development of safer anti-kinetoplastid therapeutic molecules that can replace the scarce and highly cytotoxic current drugs. The kinetoplastid ribosome represents a potential therapeutic target due to its relative structural divergence when compared with its human counterpart. However, several kinetoplastid-specific ribosomal features remain uncharacterized. Here, we present the near-atomic cryoelectron microscopy structure of a novel bona fide kinetoplastid-specific ribosomal (r-) protein (KSRP) bound to the ribosome. KSRP is an essential protein located at the solvent face of the 40S subunit, where it binds and stabilizes kinetoplastid-specific domains of rRNA, suggesting its role in ribosome integrity. KSRP also interacts with the r-protein eS6 at a region that is only conserved in kinetoplastids. The kinetoplastid-specific ribosomal environment of KSRP provides a promising target for the design of safer anti kinetoplastidian drugs. PMID- 29107484 TI - Structural and Biophysical Analysis of the Soluble DHH/DHHA1-Type Phosphodiesterase TM1595 from Thermotoga maritima. AB - The concentration of messenger molecules in bacterial cells needs to be tightly regulated. This can be achieved by either controlling the synthesis rate, degradation, or export by specific transporters, respectively. The regulation of the essential second messenger c-di-AMP is achieved by modulation of the diadenylate cyclase activity as well as by specific phosphodiesterases that hydrolyze c-di-AMP in the cell. We provide here structural and biochemical data on the DHH-type phosphodiesterase TmPDE (TM1595) from Thermotoga maritima. Our analysis shows that TmPDE is preferentially degrading linear dinucleotides, such as 5'-pApA, 5'-pGpG, and 5'-pApG, compared with cyclic dinucleotide substrates. The high-resolution structural data provided here describe all steps of the PDE reaction: the ligand-free enzyme, two substrate-bound states, and three post reaction states. We can furthermore show that Pde2 from Streptococcus pneumoniae shares both structural features and substrate specificity based on small-angle X ray scattering data and biochemical assays. PMID- 29107486 TI - Insights into the Structure of Dimeric RNA Helicase CsdA and Indispensable Role of Its C-Terminal Regions. AB - CsdA has been proposed to be essential for the biogenesis of ribosome and gene regulation after cold shock. However, the structure of CsdA and the function of its long C-terminal regions are still unclear. Here, we solved all of the domain structures of CsdA and found two previously uncharacterized auxiliary domains: a dimerization domain (DD) and an RNA-binding domain (RBD). Small-angle X-ray scattering experiments helped to track the conformational flexibilities of the helicase core domains and C-terminal regions. Biochemical assays revealed that DD is indispensable for stabilizing the CsdA dimeric structure. We also demonstrate for the first time that CsdA functions as a stable dimer at low temperature. The C-terminal regions are critical for RNA binding and efficient enzymatic activities. CsdA_RBD could specifically bind to the regions with a preference for single-stranded G-rich RNA, which may help to bring the helicase core to unwind the adjacent duplex. PMID- 29107487 TI - Quantitatively Excessive Normal Tissue Toxicity and Poor Target Coverage in Postoperative Lung Cancer Radiotherapy Meta-analysis. AB - BACKGROUND: A previous meta-analysis (MA) found postoperative radiotherapy (PORT) in lung cancer patients to be detrimental in N0/N1 patients and equivocal in the N2 setting. We hypothesized that treatment plans generated using MA protocols had worse dosimetric outcomes compared to modern plans. PATIENTS AND METHODS: We retrieved plans for 13 patients who received PORT with modern planning. A plan was recreated for each patient using the 8 protocols included in MA. Dosimetric values were then compared between the modern and simulated MA plans. RESULTS: A total of 104 MA plans were generated. Median prescribed dose was 50.4 (range, 50 60) Gy in the modern plans and 53.2 (30-60) Gy in the MA protocols. Median planning volume coverage was 96% (93%-100%) in the modern plans, versus 58% (0% 100%) in the MA plans (P < .001). Internal target volume coverage was 100% (99% 100%) versus 65% (0%-100%), respectively (P < .001). Organs at risk received the following doses: spinal cord maximum dose, 36.8 (4.6-50.4) Gy versus 46.8 (2.9 74.0) Gy (P < .001); esophageal mean dose, 22.9 (5.5-35) Gy versus 30.5 (11.1 52.5) Gy (P = .003); heart V30 (percentage of volume of an organ receiving at least a dose of 30 Gy), 16% (0%-45%) versus 35% (0%-79%) (P = .047); mean lung dose, 12.4 (3.4-24.3) Gy versus 14.8 (4.1-27.4) Gy (P = .008); and lung V20, 18% (4%-34%) versus 25% (8%-67%) (P = .023). CONCLUSION: We quantitatively confirm the inferiority of the techniques used in the PORT MA. Our analysis showed a lower therapeutic ratio in the MA plans, which may explain the poor outcomes in the MA. The findings of the MA are not relevant in the era of modern treatment planning. PMID- 29107488 TI - Perioperative Complications of Total Knee Arthroplasty in Dialysis Patients. AB - BACKGROUND: Total hip arthroplasty in patients with end-stage renal disease (ESRD) may be associated with a high complication rate. However, the perioperative complication and mortality rates in these patients after total knee arthroplasty (TKA) have rarely been investigated. The purposes of this study were to measure the mortality and complication rates and to evaluate the 2- to 10-year clinical outcome of TKA in dialysis patients at our hospital during the past decade. METHODS: We retrospectively assessed 21 patients (26 knees) with ESRD who underwent primary TKA between 2007 and 2015. A preoperative medical evaluation was performed in all patients to assess the risk of surgery. All patients had complete clinical and radiographic evaluations, and the outcome was scored using American Knee Society Scores and the Western Ontario and McMaster Universities Arthritis Index. Perioperative complications and mortality were recorded. RESULTS: One patient died of stroke 1 year after surgery (4.8% mortality). The mean follow-up period of other 20 patients was 5.8 years (69.7 months, 24 to 119 months). Six patients (28.5%) had medical complications, including pneumonia (n = 3), stroke (n = 2), and cardiovascular events (n = 3), after discharge from hospital. At the latest follow-up, 19 patients (90.5%) had improved clinical outcomes of the knee after TKA according to the American Knee Society Scores (P < .01) and Western Ontario and McMaster Universities Arthritis Index scores (P < .01). CONCLUSION: Our study showed that TKA was a valid option for dialysis patients after careful preoperative evaluation. Most patients had an improved clinical outcome. There were no instances of prosthetic loosening or deep infection. However, dialysis patients under consideration for TKA need to be informed of the risk of possible medical complications due to the nature of ESRD. PMID- 29107489 TI - Contact Kinematics Correlates to Tibial Component Migration Following Single Radius Posterior Stabilized Knee Replacement. AB - BACKGROUND: Contact kinematics between total knee arthroplasty components is thought to affect implant migration; however, the interaction between kinematics and tibial component migration has not been thoroughly examined in a modern implant system. METHODS: A total of 24 knees from 23 patients undergoing total knee arthroplasty with a single radius, posterior stabilized implant were examined. Patients underwent radiostereometric analysis at 2 and 6 weeks, 3 and 6 months, and 1 and 2 years to measure migration of the tibial component in all planes. At 1 year, patients also had standing radiostereometric analysis examinations acquired in 0 degrees , 20 degrees , 40 degrees , and 60 degrees of flexion, and the location of contact and magnitude of any condylar liftoff was measured for each flexion angle. Regression analysis was performed between kinematic variables and migration at 1 year. RESULTS: The average magnitude of maximum total point motion across all patients was 0.671 +/- 0.270 mm at 1 year and 0.608 +/- 0.359 mm at 2 years (P = .327). Four implants demonstrated continuous migration of >0.2 mm between the first and second year of implantation. There were correlations between the location of contact and tibial component anterior-posterior tilt, varus-valgus tilt, and anterior-posterior translation. The patients with continuous migration demonstrated atypical kinematics and condylar liftoff in some instances. CONCLUSION: Kinematics can influence tibial component migration, likely through alterations of force transmission. Abnormal kinematics may play a role in long-term implant loosening. PMID- 29107490 TI - Cementless Tapered-Wedge Stem Length Affects the Risk of Periprosthetic Femoral Fractures in Direct Anterior Total Hip Arthroplasty. AB - BACKGROUND: Although the popularity of the direct anterior approach for total hip arthroplasty has increased, the femoral procedure in this approach is considered technically challenging, and one of the most frequent complications reported was periprosthetic femoral fractures. The present study aimed to identify factors for predicting the risk of periprosthetic femoral fractures after using stems with a cementless tapered-wedge design through the direct anterior approach. METHODS: We retrospectively assessed the medical records of 686 patients (851 hips) who underwent primary total hip arthroplasty using a single stem with a cementless tapered-wedge design having a short or standard length option. The direct anterior approach on a standard operating table was used for all hips. Multivariate logistic regression analysis was performed to identify the independent predictors of intraoperative and early postoperative periprosthetic fractures. RESULTS: Seventeen periprosthetic femoral fractures (2.0%) were observed, including 10 intraoperative (1.2%) and 7 postoperative (0.8%) fractures. The occurrence rate of fractures using short stems was significantly higher compared with that using standard stems. The multivariate logistic regression analysis revealed that only stem length was significantly associated with periprosthetic fractures. CONCLUSION: Our results indicate that the stem design affects the risk of periprosthetic femoral fractures. PMID- 29107491 TI - Readmission, Reoperation, and Complications: Total Hip vs Total Knee Arthroplasty. AB - BACKGROUND: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are currently grouped under the same Diagnosis-Related Group (DRG). With the introduction of bundled payments, providers are accountable for all the costs incurred during the episode of care, including the costs of readmissions and management of complications. However, it is unclear whether readmission rates and short-term complications are similar in primary THA and TKA. METHODS: The National Surgical Quality Improvement Project database was queried from 2011 to 2015 to identify 248,150 primary THA/TKA procedures using Current Procedural Terminology codes. After excluding 1602 hip fractures and 5062 bilateral procedures, 94,326 THAs and 147,160 TKAs were included in the study. Length of stay, discharge disposition, and 30-day readmission, reoperation and complication rates were compared between THA and TKA using multivariate regression models. RESULTS: After adjusting for baseline characteristics, length of stay (P = .055) and discharge disposition (P = .304) were similar between THA and TKA. But the 30 day rates of readmission (P < .001) and reoperation (P < .001) were higher in THA. Of the 18 complications evaluated in the study, 7 were higher in THA, 3 were higher in TKA, and 8 were similar between THA and TKA. CONCLUSION: THA patients had higher 30-day rates of readmission and reoperation. As both readmissions and reoperations can result in higher episode costs, a common target price for both THA and TKA may be inappropriate. Further studies are required to fully understand the extent of differences in the episode costs of THA and TKA. PMID- 29107492 TI - Is Rapid Recovery Hip and Knee Replacement Possible and Safe in the Octogenarian Patient? AB - BACKGROUND: Rapid recovery programs are now aimed to reduce costs of hip and knee arthroplasties by discharging patients directly home, shortening hospital length of stay (LOS), and reducing readmission rates. Although patients aged 80 years and older are included in the Medicare bundle, little work has been performed to determine if older patients can safely participate in rapid recovery programs. METHODS: We retrospectively reviewed 2482 patients undergoing primary and revision total hip and knee arthroplasties (THA and TKA) who all participated in a multifaceted rapid recovery program. The goals of this program were next day discharge to home without the use of home services or post-acute care admission. We examined the hospital LOS and the percentage of patients discharged home as well as 90-day readmission rates to determine efficacy and safety of this program in the patients aged 80 years and older. RESULTS: Octogenarians receiving primary THA and TKA were discharged home >90% of the time with LOSs <2 days and low readmission rates. Revision THA and TKA patients aged 80 years and older were discharged home about 70% of the time with significantly longer LOSs than patients aged more than 80 years. The revision THA patients aged more than 80 years had the highest readmission rates. CONCLUSION: Patients aged more than 80 years can successfully and safely participate in rapid recovery programs. PMID- 29107493 TI - Association Between Body Mass Index and Thirty-Day Complications After Total Knee Arthroplasty. AB - BACKGROUND: Although previous studies have evaluated the effect of obesity on the outcomes of total knee arthroplasty (TKA), most considered obesity as a binary variable. It is important to compare different weight categories and consider body mass index (BMI) as a continuous variable to understand the effects of obesity across the entire range of BMI. Therefore, the objective of this study is to analyze the effect of BMI on 30-day readmissions and complications after TKA, considering BMI as both a categorical and a continuous variable. METHODS: The National Surgical Quality Improvement Project database was queried from 2011 to 2015 to identify 150,934 primary TKAs. Thirty-day rates of readmissions, reoperations, and medical/surgical complications were compared between different weight categories (overweight: BMI >25 and <=30 kg/m2; obese: BMI >30 and <=40 kg/m2; morbidly obese: BMI >40 kg/m2) and the normal weight category (BMI >18.5 and <=25 kg/m2) using multivariate regression models. Spline regression models were created to study BMI as a continuous variable. RESULTS: Obese patients were at increased risk of pulmonary embolism (PE) (P < .001), while morbidly obese patients were at increased risk of readmission (P < .001), reoperation (P < .001), superficial infection (P < .001), periprosthetic joint infection (P < .001), wound dehiscence (P < .001), PE (P < .001), urinary tract infection (P = .003), reintubation (P = .004), and renal insufficiency (P < .001). Transfusion was lower in overweight (P < .001), obese (P < .001), and morbidly obese (P < .001) patients. BMI had a nonlinear relationship with readmission (P < .001), reoperation (P < .001), periprosthetic joint infection (P = .041), PE (P < .001), renal insufficiency (P = .046), and transfusion (P < .001). CONCLUSION: Obesity increased the risk of readmission and various complications after TKA, with the risk being dependent on the severity of obesity. Relationships between BMI and complications showed considerable variations with some outcomes like readmission and reoperation showing a U-shaped relationship. Based on our findings, a potential BMI goal in weight management for obese patients could be established around 29-30 kg/m2, in order to decrease the risk of most TKA postoperative complications. PMID- 29107494 TI - Letter to the Editor on "Risk Factors, Outcomes, and Timing of Manipulation Under Anesthesia After Total Knee Arthroplasty". PMID- 29107495 TI - Oral vs Intravenous vs Topical Tranexamic Acid in Primary Hip Arthroplasty: A Prospective, Randomized, Double-Blind, Controlled Study. AB - BACKGROUND: Tranexamic acid (TXA) has demonstrated efficacy in reducing blood loss, reduction in hemoglobin, and blood transfusion requirements in primary total hip arthroplasty (THA). The optimal mode of TXA administration for patients undergoing primary THA is unclear. The purpose of this randomized controlled trial is to determine whether oral administration of TXA was superior to intravenous or topical routes in these patients. METHODS: In this double-blinded, placebo-controlled trial, patients undergoing primary THA were randomized to oral (2 g TXA orally 2 hours preoperatively), intravenous (20 mg/kg intravenous TXA bolus 5 minutes before the incision), or topical (2 g TXA applied topically) TXA groups. The primary outcome was the reduction in hemoglobin. Secondary outcomes included blood loss, transfusion rate, cost of TXA (Chinese yuan (Y); in 2017, Y1 = $0.147), and adverse events. RESULTS: One hundred eighty patients were randomized into the 3 groups. Demographic characteristics were similar among the groups. The mean reduction in hemoglobin was similar among the oral, intravenous, and topical groups (3.48 +/- 1.32, 3.58 +/- 1.07, and 3.66 +/- 1.26 g/dL, respectively). Similarly, the mean total blood loss did not differ significantly among the 3 groups. The oral group incurred the lowest TXA cost (Y480) compared with that in the intravenous (Y3329.28) and topical (Y3540) groups (P = .01). None of the patients sustained a deep venous thrombosis, pulmonary embolism, or an infection. CONCLUSION: The blood-sparing efficacy of oral TXA is comparable to that of the intravenous and topical forms. Oral TXA is recommended because of its cost-benefit superiority and ease of administration. PMID- 29107496 TI - Fourteen Year Follow-Up of Randomized Clinical Trials of Active Robotic-Assisted Total Hip Arthroplasty. AB - BACKGROUND: Active robotic total hip arthroplasty (THA) has been used clinically for over 20 years, but long-term results have never been studied. The aims of this study are to determine whether active robotic THA improves clinical outcomes and results in fewer revisions over a long-term follow-up. METHODS: Patients from 2 US Food and Drug Administration clinical trials (1994-1998 and 2001-2006) who had undergone THA using either an active robotic system or a traditional manual technique were examined to determine if any differences existed in radiographic analysis and patient pain and function using the University of California, Los Angeles; visual analog scale; Health Status Questionnaire (HSQ) pain; HSQ role physical; HSQ physical functioning; Harris pain scores; and the total Western Ontario and McMaster Universities Osteoarthritis Index scores at a mean follow-up of 14 years. RESULTS: The ROBODOC group had statistically significant higher HSQ pain and Harris pain scores and lower Western Ontario and McMaster Universities Osteoarthritis Index scores. There was no statistically significant difference in probability of a revision for wear between the groups (chi2 = 1.80; P = .179), and no revisions for loosening in either group. CONCLUSION: Prior studies have demonstrated improved implant fit and alignment with the use of this active robot system. This long-term study now shows no failures for stem loosening at a mean follow-up of 14 years and small but potentially important improvements in clinical outcomes in the robot group. PMID- 29107498 TI - Letter to the Editor on "Transitioning to the Direct Anterior Approach in Total Hip Arthroplasty: Is It Safe in the Current Health Care Climate?" PMID- 29107497 TI - R3 Cup Does Not Have a High Failure Rate in Conventional Bearings: A Minimum of 5 Year Follow-Up. AB - BACKGROUND: The R3 cementless acetabular system was first marketed in Australia and Europe in 2007. Previous papers have shown high failure rates of the R3 cup with up to 24% with metal-on-metal bearing. There are currently no medium term clinical results on this cup. The aim of the study is to review our results of the R3 acetabular cup with conventional bearings with a minimum of 5-year follow up. METHODS: Patients who were implanted with the R3 acetabular cup were identified from our center's arthroplasty database. A total of 293 consecutive total hip arthroplasties were performed in 286 patients. The primary outcome was revision. The secondary outcomes were the Oxford Hip Scores (OHS) and radiographic evaluation. RESULTS: The mean age of the patients was 69.4 years. The mean preoperative OHS was 23 (range 10-34) and the mean OHS was 40 (range 33 48) at the final follow-up. Radiological evaluation showed an excellent ARA score in all patients at 5 years. None of the R3 cups showed osteolysis at the final follow-up. There were 3 revisions in our series, of which 2 R3 cups were revised. The risk of revision was 1.11% at 5 years. CONCLUSION: Our experience of using the R3 acetabular system with conventional bearings showed high survivorship and is consistent with the allocated Orthopaedic Data Evaluation Panel rating of 5A* as rated in 2015 in the United Kingdom. PMID- 29107499 TI - Clinical Outcome of Massive Endoprostheses Used for Managing Periprosthetic Joint Infections of the Hip and Knee. AB - BACKGROUND: Endoprosthetic replacement (EPR) is an option for management of massive bone loss resulting from infection around failed lower limb implants. The aim of this study is to determine the mid-term outcome of EPRs performed in the treatment of periprosthetic joint infection (PJI) and infected failed osteosyntheses around the hip and knee joint and identify factors that influence it. METHODS: We retrospectively reviewed all hip and knee EPRs performed between 2007 and 2014 for the management of chronic infection following complex arthroplasty or fracture fixation. Data recorded included indication for EPR, number of previous surgeries, comorbidities, and organism identified. Outcome measures included PJI eradication rate, complications, implant survival, mortality, and functional outcome (Oxford Hip or Knee Score). RESULTS: Sixty-nine EPRs (29 knees and 40 hips) were performed with a mean age of 68 years (43-92). Polymicrobial growth was detected in 36% of cases, followed by coagulase-negative staphylococci (28%) and Staphylococcus aureus (10%). Recurrence of infection occurred in 19 patients (28%): 5 were treated with irrigation and debridement, 5 with revision, 1 with above-knee amputation, and 8 remain on long-term antibiotics. PJI eradication was achieved in 50 patients (72%); the chance of PJI eradication was greater in hips (83%) than in knees (59%) (P = .038). The 5-year implant survivorship was 81% (95% confidence interval 74-88). The mean Oxford Hip Score and Oxford Knee Score were 22 (4-39) and 21 (6-43), respectively. CONCLUSION: This study supports the use of EPRs for eradication of PJI in complex, multiply revised cases. We describe PJI eradication rate of 72% with acceptable functional outcome. PMID- 29107501 TI - Corrections. PMID- 29107500 TI - Corrigendum to Outcome of 4 Surgical Treatments for Wear and Osteolysis of Cementless Acetabular Components [The Journal of Arthroplasty 32 (2017) 2799 2805]. PMID- 29107502 TI - Transcatheter Aortic Valve Replacement for All-comers With Severe Aortic Stenosis: Could It Become a Reality? PMID- 29107503 TI - Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence. AB - Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/Mfn2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/Mfn2/Drp1 cardiac triple-knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy. Over time, however, combined abrogation of fission and fusion provoked massive progressive mitochondrial accumulation that severely distorted cardiomyocyte sarcomeric architecture. Mitochondrial biogenesis was not responsible for mitochondrial superabundance, whereas mitophagy was suppressed despite impaired mitochondrial proteostasis. Similar but milder defects were observed in aged hearts. Thus, cardiomyopathies linked to dynamic imbalance between fission and fusion are temporarily mitigated by forced mitochondrial adynamism at the cost of compromising mitochondrial quantity control and accelerating mitochondrial senescence. PMID- 29107505 TI - System-wide Benefits of Intermeal Fasting by Autophagy. AB - Autophagy failure is associated with metabolic insufficiency. Although caloric restriction (CR) extends healthspan, its adherence in humans is poor. We established an isocaloric twice-a-day (ITAD) feeding model wherein ITAD-fed mice consume the same food amount as ad libitum controls but at two short windows early and late in the diurnal cycle. We hypothesized that ITAD feeding will provide two intervals of intermeal fasting per circadian period and induce autophagy. We show that ITAD feeding modifies circadian autophagy and glucose/lipid metabolism that correlate with feeding-driven changes in circulating insulin. ITAD feeding decreases adiposity and, unlike CR, enhances muscle mass. ITAD feeding drives energy expenditure, lowers lipid levels, suppresses gluconeogenesis, and prevents age/obesity-associated metabolic defects. Using liver-, adipose-, myogenic-, and proopiomelanocortin neuron specific autophagy-null mice, we mapped the contribution of tissue-specific autophagy to system-wide benefits of ITAD feeding. Our studies suggest that consuming two meals a day without CR could prevent the metabolic syndrome. PMID- 29107504 TI - Overlapping Brain Circuits for Homeostatic and Hedonic Feeding. AB - Central regulation of food intake is a key mechanism contributing to energy homeostasis. Many neural circuits that are thought to orchestrate feeding behavior overlap with the brain's reward circuitry both anatomically and functionally. Manipulation of numerous neural pathways can simultaneously influence food intake and reward. Two key systems underlying these processes those controlling homeostatic and hedonic feeding-are often treated as independent. Homeostatic feeding is necessary for basic metabolic processes and survival, while hedonic feeding is driven by sensory perception or pleasure. Despite this distinction, their functional and anatomical overlap implies considerable interaction that is often overlooked. Here, we argue that the neurocircuits controlling homeostatic feeding and hedonic feeding are not completely dissociable given the current data and urge researchers to assess behaviors extending beyond food intake in investigations of the neural control of feeding. PMID- 29107507 TI - Evaluation of ground calcite/water heavy media cyclone suspensions for production of residual plastic concentrates. AB - Viable recycled residual plastic (RP) product(s) must be of sufficient quality to be reusable as a plastic or source of hydrocarbons or fuel. The varied composition and large volumes of such wastes usually requires a low cost, high through-put recycling method(s) to eliminate contaminants. Cyclone separation of plastics by density is proposed as a potential method of achieving separations of specific types of plastics. Three ground calcite separation medias of different grain size distributions were tested in a cylindrical cyclone to evaluate density separations at 1.09, 1.18 and 1.27 g/cm3. The differences in separation recoveries obtained with these medias by density offsets produced due to displacement of separation media solid particles within the cyclone caused by centrifugal settling is evaluated. The separation density at which 50% of the material of that density is recovered was found to increase from 0.010 to 0.026 g/cm3 as the separation media density increased from 1.09 to 1.27 g/cm3. All separation medias were found to have significantly low Ep95values of 0.012-0.033 g/cm3. It is also demonstrated that the presence of an excess content of <10 um calcite media particles (>75%) resulted in reduced separation efficiencies. It is shown that the optimum separations were achieved when the media density offset was 0.03-0.04 g/cm3. It is shown that effective heavy media cyclone separations of RP denser than 1.0 g/cm3 can produce three sets of mixed plastics containing: PS and ABS/SAN at densities of >1.0-1.09 g/cm3; PC, PMMA at a density of 1.09 1.18 g/cm3; and PVC and PET at a density of >1.27 g/cm3. PMID- 29107506 TI - Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. AB - Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles, and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR mediated longevity. Strikingly, however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together, these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging. PMID- 29107508 TI - Waste picker livelihoods and inclusive neoliberal municipal solid waste management policies: The case of the La Chureca garbage dump site in Managua, Nicaragua. AB - The modernization (i.e. mechanization, formalization, and capital intensification) and enclosure of municipal solid waste management (MSWM) systems threaten waste picker livelihoods. From 2009 to 2013, a major development project, embodying traditional neoliberal policies with inclusive social policies, transformed the Managua, Nicaragua, municipal solid waste site from an open-air dump where as many as 2,000 informal waste pickers toiled to a sanitary landfill. To investigate waste pickers' social and economic condition, including labor characteristics, household income, and poverty incidence, after the project's completion, 146 semi-structured survey questionnaires were administered to four communities adjacent to the landfill and 45 semi-structured interviews were completed with key stakeholders. Findings indicate that hundreds of waste pickers were displaced by the project, employment benefits from the project were unevenly distributed by neighborhood, and informal waste picking endures due to persistent impoverishment, thereby contributing to continued social and economic marginalization and environmental degradation. The findings highlight the limitations of inclusive neoliberal development efforts to transform MSWM in a low-income country. PMID- 29107509 TI - Predictive model for the Dutch post-consumer plastic packaging recycling system and implications for the circular economy. AB - The Dutch post-consumer plastic packaging recycling network has been described in detail (both on the level of packaging types and of materials) from the household potential to the polymeric composition of the recycled milled goods. The compositional analyses of 173 different samples of post-consumer plastic packaging from different locations in the network were combined to indicatively describe the complete network with material flow analysis, data reconciliation techniques and process technological parameters. The derived potential of post consumer plastic packages in the Netherlands in 2014 amounted to 341 Gg net (or 20.2 kg net.cap-1.a-1). The complete recycling network produced 75.2 Gg milled goods, 28.1 Gg side products and 16.7 Gg process waste. Hence the net recycling chain yield for post-consumer plastic packages equalled 30%. The end-of-life fates for 35 different plastic packaging types were resolved. Additionally, the polymeric compositions of the milled goods and the recovered masses were derived with this model. These compositions were compared with experimentally determined polymeric compositions of recycled milled goods, which confirmed that the model predicts these compositions reasonably well. Also the modelled recovered masses corresponded reasonably well with those measured experimentally. The model clarified the origin of polymeric contaminants in recycled plastics, either sorting faults or packaging components, which gives directions for future improvement measures. PMID- 29107510 TI - Substance P Attenuates Hypoxia/Reoxygenation-Induced Apoptosis via the Akt Signalling Pathway and the NK1-Receptor in H9C2Cells. AB - BACKGROUND: Myocardial ischaemia/reperfusion (I/R) injury is a major cause of morbidity and mortality associated with coronary heart disease. During I/R injury, cardiomyocytes undergo cell death including apoptosis and necrosis with increased frequency, and this leads to compensatory cardiac hypertrophy, dysfunction, ventricular remodelling, and ultimately, heart failure. Accumulating evidence indicates that substance P is cardio-protective following I/R primarily due to its potent coronary vasodilator actions. However, its direct effect on cardiomyocytes in vitro remains controversial. METHODS: An hypoxia/reoxygenation (H/R)-induced cell death model was established to mimic I/R injury, in which the effect of substance P (SP) pretreatment on H9C2 cardiomyocytes and the mechanism of action were explored. RESULTS: Substance P was demonstrated to inhibit H/R induced apoptosis. Phosphorylated-Akt (p-Akt) was decreased in H/R groups and was increased by SP pretreatment. Inhibition of p-Akt reduced the beneficial effects of SP in reducing apoptosis, whereas activation of Akt failed to provide additional improvement in the presence of SP. This suggests a key role for Akt in the process of reduced apoptosis by SP following H/R injury. In addition, the NK1 receptor antagonist prohibited the anti-apoptotic effect of SP. CONCLUSIONS: This study indicates that SP pretreatment attenuates H/R-induced apoptosis via the Akt signalling pathway and the NK1-receptor. PMID- 29107511 TI - Red Blood Cells Distribution Width as a Potential Prognostic Biomarker in Patients With Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension. AB - BACKGROUND: Red blood cells distribution width (RDW) predicts survival in cardiovascular diseases. Little is known about the variability of RDW level over time among patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). To our knowledge, RDW has never been analysed as a marker of response to specific treatment. MATERIALS AND METHODS: We retrospectively analysed 77 patients for: i) RDW measured during the last hospitalisation before death or during the last follow-up (RDWlast); ii) mean RDW from all hospitalisations during the entire follow-up of the patient (RDWmean); iii) maximum RDW of all hospitalisations of each patient (RDWmax). In order to assess response to specific treatment and association with prognosis, we compared RDW levels (obtained from 56 patients) before and 3 to 6 months after introduction or intensification of treatment in both the alive and deceased group. RESULTS: Twenty-eight of 77 patients died, whereas in specific drugs treatment response analysis, 22 of 56 patients died during follow-up. The cut-off values derived from the ROC analysis and assessed using the log-rank test were significant for RDWlast (p<0.0001), RDWmean (p<0.001) and RDWmax (p=0.02). A decrease in RDW levels after introduction or intensification of specific treatment was significant (p=0.015) in survivors, whereas there was no significance (p=0.29) in decrease in RDW levels in non-survivors after change of therapy. CONCLUSIONS: Red blood cells distribution width might be a potential prognostic biomarker in patients with PAH and inoperable CTEPH. The decrease in RDW level after introduction or escalation of PAH-targeted and CTEPH-targeted drugs is associated with a good treatment response and better prognosis. PMID- 29107513 TI - Impurities in Tc-99m radiopharmaceutical solution obtained from Mo-100 in cyclotron. AB - The gamma emitting impurities in 99mTc solution obtained from enriched molybdenum 100Mo metallic target after its irradiation in a cyclotron were measured using a high-purity germanium (HPGe) detector. The radioactivity range of tested samples of 99mTc was rather low, in the range from 0.34 to 2.39 MBq, thus creating a challenge to investigate the standard measurement HPGe system for impurity detection and quantification. In the process of 99mTc separation from irradiated target the AnaLig(r) Tc-02 resin, Dionex H+ and Alumina A columns were used. Fractions of eluates from various steps of separation process were taken and measured for radionuclidic purity. The overall measurement sensitivity of gamma emitters in terms of minimum detectable activity (MDA) was found at the level of 14-70Bq with emission lines in range of 36 - 1836keV resulting in impurity content range of 6.7 * 10-4 to 3.4 * 10-3 % for 93Tc, 93mTc, 94Tc, 94mTc, 95Tc, 95mTc, 96Tc 96Nb, 97Nb, 99Mo contaminants and 9.4 * 10-3 % for 97mTc. The usefulness of the chosen measurement conditions and the method applied to testing the potential contaminators was proved by reaching satisfactory results of MDAs less than the criteria of impurity concentration of all nuclides specified in the European Pharmacopoeia. PMID- 29107512 TI - American Strain of Zika Virus Causes More Severe Microcephaly Than an Old Asian Strain in Neonatal Mice. AB - Zika virus (ZIKV) has evolved from an overlooked mosquito-borne flavivirus into a global health threat due to its astonishing causal link to microcephaly and other disorders. ZIKV has been shown to infect neuronal progenitor cells of the fetal mouse brain, which is comparable to the first-trimester human fetal brain, and result in microcephaly. However, whether there are different effects between the contemporary ZIKV strain and its ancestral strain in the neonatal mouse brain, which is comparable with the second-trimester human fetal brain, is unclear. Here we adopted a mouse model which enables us to study the postnatal effect of ZIKV infection. We show that even 100 pfu of ZIKV can replicate and infect neurons and oligodendrocytes in most parts of the brain. Compared with the ancestral strain from Cambodia (CAM/2010), infection of the ZIKV strain from Venezuela (VEN/2016) leads to much more severe microcephaly, accompanied by more neuronal cell death, abolishment of oligodendrocyte development, and a more dramatic immune response. The serious brain damage caused by VEN/2016 infection would be helpful to elucidate why the American strain resulted in severe neurovirulence in infants and will provide clinical guidance for the diagnosis and treatment of infection by different ZIKV strains. PMID- 29107514 TI - 134Cs activity standardization by 4pibeta(LS)-gamma(NaI-Tl) anticoincidence counting and submission to international reference system. AB - From a commercial supplier a solution containing 134Cs has been standardized at National Laboratory for Ionizing Radiation Metrology (LNMRI) for the first time using three Liquid scintillation based measurement. These measurement methods are 4pibeta-gamma live-timed anticoincidence counting, 4pibeta-gamma coincidence counting and 3H-standard efficiency tracing with the CNET methods. The results obtained by anticoincidence counting was adopted as reference value and its combined uncertainty was 0.38%. The agreement of this reference value with coincidence counting and CNET methods were 0.39% and 0.34% respectively and were in consistency with each uncertainty method. The weighted mean results coincidence counting and CNET methods are also in close agreement 0.03% with anticoincidence counting method and meets the requirement of primary and national standard. This standardization was made in order to reduce the uncertainty in 134Cs measurement in Brazil and also following a request made by Bureau International des Poids and Mesures for new submission to International Reference System. The LNMRI last submission was made in 1987. Therefore from a 134Cs master solution a NIST ampoules was prepared and LNMRI/IRD submitted it to the International Reference System, Bureau International of Poids and Measures (SIR/BIPM). In this paper will be analyzed the LNMRI measurement and performance each measurement methods and also take into account the reference value of KCDB, we determined also the 134Cs gamma emission probabilities of main energy. PMID- 29107515 TI - Standardization of 67Cu and calibration of the ionization chamber. Impurities and decay scheme problems. AB - This paper describes the standardization of 67Cu by the 4pibeta(PC)-gamma coincidence method, and the calibration of ionization chamber. The difficulties were. (i) One of the excited levels of 67Zn has a half life of 9.10MUs. (ii) A recent publication reconsiders the decay scheme parameters. (iii) The solution had a significant content of impurities. The conclusions were that the result of absolute standardization is less influenced by the decay scheme parameters and impurities than the measurements by ionization chamber. PMID- 29107516 TI - Study of the 243Am decay. AB - Gamma-ray emission probabilities for 243Am were published in 1996. Three new gamma transitions were then found: 46.84, 98.36 and 102.02keV. In the last evaluation by the Decay Data Evaluation Project, the emission probabilities of 46.84 and 102.02keV transitions were not included. Alpha-gamma coincidence measurements have been now used to check and revise the values for these two transitions and their emission probabilities. The emissions of the 31.13, 43.53, 74.66, 86.71 and 141.89keV transitions were also studied. PMID- 29107519 TI - Direct Dopaminergic Projections from the SNc Modulate Visuomotor Transformation in the Lamprey Tectum. AB - Dopamine neurons in the SNc play a pivotal role in modulating motor behavior via striatum. Here, we show that the same dopamine neuron that targets striatum also sends a direct branch to the optic tectum (superior colliculus). Whenever SNc neurons are activated, both targets will therefore be affected. Visual stimuli (looming or bars) activate the dopamine neurons coding saliency and also elicit distinct motor responses mediated via tectum (eye, orienting or evasive), which are modulated by the dopamine input. Whole-cell recordings from tectal projection neurons and interneurons show that dopamine, released by SNc stimulation, increases or decreases the excitability depending on whether they express the dopamine D1 or the D2 receptor. SNc thus exerts its effects on the visuomotor system through a combined effect directly on tectum and also via striatum. This direct SNc modulation will occur regardless of striatum and represents a novel mode of motor control. PMID- 29107518 TI - Transsynaptic Mapping of Second-Order Taste Neurons in Flies by trans-Tango. AB - Mapping neural circuits across defined synapses is essential for understanding brain function. Here we describe trans-Tango, a technique for anterograde transsynaptic circuit tracing and manipulation. At the core of trans-Tango is a synthetic signaling pathway that is introduced into all neurons in the animal. This pathway converts receptor activation at the cell surface into reporter expression through site-specific proteolysis. Specific labeling is achieved by presenting a tethered ligand at the synapses of genetically defined neurons, thereby activating the pathway in their postsynaptic partners and providing genetic access to these neurons. We first validated trans-Tango in the Drosophila olfactory system and then implemented it in the gustatory system, where projections beyond the first-order receptor neurons are not fully characterized. We identified putative second-order neurons within the sweet circuit that include projection neurons targeting known neuromodulation centers in the brain. These experiments establish trans-Tango as a flexible platform for transsynaptic circuit analysis. PMID- 29107517 TI - Entrainment of Arteriole Vasomotor Fluctuations by Neural Activity Is a Basis of Blood-Oxygenation-Level-Dependent "Resting-State" Connectivity. AB - Resting-state signals in blood-oxygenation-level-dependent (BOLD) imaging are used to parcellate brain regions and define "functional connections" between regions. Yet a physiological link between fluctuations in blood oxygenation with those in neuronal signaling pathways is missing. We present evidence from studies on mouse cortex that modulation of vasomotion, i.e., intrinsic ultra-slow (0.1 Hz) fluctuations in arteriole diameter, provides this link. First, ultra-slow fluctuations in neuronal signaling, which occur as an envelope over gamma-band activity, entrains vasomotion. Second, optogenetic manipulations confirm that entrainment is unidirectional. Third, co-fluctuations in the diameter of pairs of arterioles within the same hemisphere diminish to chance for separations >1.4 mm. Yet the diameters of arterioles in distant (>5 mm), mirrored transhemispheric sites strongly co-fluctuate; these correlations are diminished in acallosal mice. Fourth, fluctuations in arteriole diameter coherently drive fluctuations in blood oxygenation. Thus, entrainment of vasomotion links neuronal pathways to functional connections. PMID- 29107520 TI - Deprivation-Induced Homeostatic Spine Scaling In Vivo Is Localized to Dendritic Branches that Have Undergone Recent Spine Loss. AB - Synaptic scaling is a key homeostatic plasticity mechanism and is thought to be involved in the regulation of cortical activity levels. Here we investigated the spatial scale of homeostatic changes in spine size following sensory deprivation in a subset of inhibitory (layer 2/3 GAD65-positive) and excitatory (layer 5 Thy1 positive) neurons in mouse visual cortex. Using repeated in vivo two-photon imaging, we find that increases in spine size are tumor necrosis factor alpha (TNF-alpha) dependent and thus are likely associated with synaptic scaling. Rather than occurring at all spines, the observed increases in spine size are spatially localized to a subset of dendritic branches and are correlated with the degree of recent local spine loss within that branch. Using simulations, we show that such a compartmentalized form of synaptic scaling has computational benefits over cell-wide scaling for information processing within the cell. PMID- 29107521 TI - Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development. AB - In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development. PMID- 29107523 TI - A Large-Scale Semi-Chronic Microdrive Recording System for Non-Human Primates. AB - Multi-electrode recordings in the non-human primate provide a critical method for measuring the widely distributed activity patterns that underlie brain function. However, common techniques rely on small, often immovable arrays, or microdrives, that are only capable of manipulating a small number of closely spaced probes. These techniques restrict the number of cortical areas that can be simultaneously sampled and are typically not capable of reaching subcortical targets. To overcome these limitations, we developed a large-scale, semi-chronic microdrive recording system with up to 256 independently movable microelectrodes spanning an entire cerebral hemisphere. The microdrive system is hermetically sealed, free of internal connecting wires, and has been used to simultaneously record from up to 37 cortical and subcortical areas in awake behaving monkeys for up to 9 months. As a proof of principle, we demonstrate the capability of this technique to address network-level questions using a graph theoretic analysis of functional connectivity data. PMID- 29107522 TI - "Silent" NMDA Synapses Enhance Motion Sensitivity in a Mature Retinal Circuit. AB - Retinal direction-selective ganglion cells (DSGCs) have the remarkable ability to encode motion over a wide range of contrasts, relying on well-coordinated excitation and inhibition (E/I). E/I is orchestrated by a diverse set of glutamatergic bipolar cells that drive DSGCs directly, as well as indirectly through feedforward GABAergic/cholinergic signals mediated by starburst amacrine cells. Determining how direction-selective responses are generated across varied stimulus conditions requires understanding how glutamate, acetylcholine, and GABA signals are precisely coordinated. Here, we use a combination of paired patch clamp recordings, serial EM, and large-scale multi-electrode array recordings to show that a single high-sensitivity source of glutamate is processed differentially by starbursts via AMPA receptors and DSGCs via NMDA receptors. We further demonstrate how this novel synaptic arrangement enables DSGCs to encode direction robustly near threshold contrasts. Together, these results reveal a space-efficient synaptic circuit model for direction computations, in which "silent" NMDA receptors play critical roles. PMID- 29107525 TI - Mindful Communication: Being Present. AB - OBJECTIVES: To review how mindfulness can be elicited in and strategically managed through communication, with a goal toward enhancing the patient/family relationship in the experience of cancer care. DATA SOURCES: Published, peer reviewed literature, research reports, and Web-based resources. CONCLUSION: Mindful communication, an active process whereby the health care provider and patient /family unit are attentive to the timing, nature, and context of the dialogue exchange, helps direct care that is patient-centered, reflective, and relational. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses using a patient centered approach to communication will be more equipped to use mindfulness-based strategies that can potentially shift the way cancer care is delivered. PMID- 29107524 TI - A polyphenol-rich cranberry extract reverses insulin resistance and hepatic steatosis independently of body weight loss. AB - OBJECTIVE: Previous studies have reported that polyphenol-rich extracts from various sources can prevent obesity and associated gastro-hepatic and metabolic disorders in diet-induced obese (DIO) mice. However, whether such extracts can reverse obesity-linked metabolic alterations remains unknown. In the present study, we aimed to investigate the potential of a polyphenol-rich extract from cranberry (CE) to reverse obesity and associated metabolic disorders in DIO-mice. METHODS: Mice were pre-fed either a Chow or a High Fat-High Sucrose (HFHS) diet for 13 weeks to induce obesity and then treated either with CE (200 mg/kg, Chow + CE, HFHS + CE) or vehicle (Chow, HFHS) for 8 additional weeks. RESULTS: CE did not reverse weight gain or fat mass accretion in Chow- or HFHS-fed mice. However, HFHS + CE fully reversed hepatic steatosis and this was linked to upregulation of genes involved in lipid catabolism (e.g., PPARalpha) and downregulation of several pro-inflammatory genes (eg, COX2, TNFalpha) in the liver. These findings were associated with improved glucose tolerance and normalization of insulin sensitivity in HFHS + CE mice. The gut microbiota of HFHS + CE mice was characterized by lower Firmicutes to Bacteroidetes ratio and a drastic expansion of Akkermansia muciniphila and, to a lesser extent, of Barnesiella spp, as compared to HFHS controls. CONCLUSIONS: Taken together, our findings demonstrate that CE, without impacting body weight or adiposity, can fully reverse HFHS diet induced insulin resistance and hepatic steatosis while triggering A. muciniphila blooming in the gut microbiota, thus underscoring the gut-liver axis as a primary target of cranberry polyphenols. PMID- 29107526 TI - Nurse Handoff Communication. AB - OBJECTIVE: To describe the communication behaviors identified by nurses as key to a competent patient handoff at change of shift. DATA SOURCES: Qualitative analysis of nurse descriptions of best and worst handoffs from the incoming and outgoing nursing perspective. CONCLUSION: Competent, quality nursing handoffs include specific information exchange and socioemotional (relational) communication behaviors. IMPLICATIONS FOR NURSING PRACTICE: A communication-based perspective may be useful in establishing handoff routines that reduce communication-related patient care errors and foster a positive nursing environment. PMID- 29107527 TI - Communication Concerns When Transitioning to Cancer Survivorship Care. AB - OBJECTIVES: To discuss communication needs that relate to transitioning care for cancer survivors and strategies to facilitate patient-centered communication. DATA SOURCES: National Cancer Institute monograph and peer reviewed articles related to survivorship and communication. CONCLUSION: Key communication tasks in survivorship include managing uncertainty, exchanging information, and enabling self-management. These tasks inform assessment strategies and interventions in survivorship care planning. Communication training must target survivors and providers given the reciprocal and interactive nature of communication. IMPLICATIONS FOR NURSING PRACTICE: Implications for Nursing Practice: Nurses need to evaluate survivors' concerns and incorporate communication strategies in survivorship care planning to reduce distress and facilitate the exchange of information to improve referrals to supportive care resources. PMID- 29107528 TI - Understanding Family Caregiver Communication to Provide Family-Centered Cancer Care. AB - OBJECTIVES: To describe a family caregiver communication typology and demonstrate identifiable communication challenges among four caregiver types: Manager, Carrier, Partner, and Lone. DATA SOURCES: Case studies based on interviews with oncology family caregivers. CONCLUSION: Each caregiver type demonstrates unique communication challenges that can be identified. Recognition of a specific caregiver type will help nurses to adapt their own communication to provide tailored support. IMPLICATIONS FOR NURSING PRACTICE: Family-centered cancer care requires attention to the communication challenges faced by family caregivers. Understanding the challenges among four family caregiver communication types will enable nurses to better address caregiver burden and family conflict. PMID- 29107529 TI - Learning the Patient's Story. AB - OBJECTIVES: To provide a brief history on narrative medicine and highlight its importance in providing quality patient care. DATA SOURCES: Explains narrative medicine using published, peer-reviewed literature and highlights some of the literary, medical, sociological, and communication perspectives that contributed to the narrative medicine movement. CONCLUSION: A commitment to the patient provider relationship and knowing the patient's story is a critical aspect in providing quality cancer care. IMPLICATIONS FOR NURSING PRACTICE: Teaching oncology nurses skills that are grounded in narrative medicine will improve health care by increasing the nurses' knowledge of their patients and strengthening the nurse-patient relationship. PMID- 29107530 TI - Spiritual Care Communication in Cancer Patients. AB - OBJECTIVES: To provide a definition of spirituality, define the scope and nature of spiritual care communication, describe how to initiate communication about, and elicit, a spiritual history, and introduce the AMEN protocol to support patient/family hopes for a miracle. DATA SOURCES: Literature review. CONCLUSION: Spiritual communication is important throughout cancer care. Nurses can assess and integrate patient and family caregivers' spiritual needs in clinical care by practicing self-awareness and engaging in spiritual care communication strategies. IMPLICATIONS FOR NURSING PRACTICE: Spirituality is recognized as an essential component of quality care. Spiritual conversations can increase patients' satisfaction with care and improve well-being. PMID- 29107531 TI - The Family Meeting in Palliative Care: Role of the Oncology Nurse. AB - OBJECTIVES: To describe the family meeting in palliative and end-of-life care, highlighting the role of the oncology nurse. Specific strategies will be provided for pre-meeting preparation, communication, and follow-up activities. DATA SOURCES: A conceptual framework drawn from family and communication theory, and best practices from the clinical, research, nursing, and palliative care literature. CONCLUSION: Working with patients and families is complex, but the family meeting is a promising tool and a potential quality indicator in palliative care. IMPLICATIONS FOR NURSING PRACTICE: The nurse is well positioned to participate fully in every aspect of the family meeting. PMID- 29107532 TI - Palliative Care Communication in the ICU: Implications for an Oncology-Critical Care Nursing Partnership. AB - OBJECTIVES: To describe the development, launch, implementation, and outcomes of a unique multisite collaborative (ie, IMPACT-ICU [Integrating Multidisciplinary Palliative Care into the ICU]) to teach ICU nurses communication skills specific to palliative care. To identify options for collaboration between oncology and critical care nurses when integrating palliation into nursing care planning. DATA SOURCES: Published literature and collective experiences of the authors in the provision of onco-critical-palliative care. CONCLUSION: While critical care nurses were the initial focus of education, oncology, telemetry, step-down, and medical-surgical nurses within five university medical centers subsequently participated in this learning collaborative. Participants reported enhanced confidence in communicating with patients, families, and physicians, offering emotional support and involvement in family meetings. IMPLICATIONS FOR NURSING PRACTICE: Communication education is a vital yet missing element of undergraduate nursing education. Programs should be offered in the work setting to address this gap in needed nurse competency, particularly within the context of onco-critical palliative care. PMID- 29107535 TI - Genetically Encoded Tools for Optical Dissection of the Mammalian Cell Cycle. AB - Eukaryotic cells spend most of their life in interphase of the cell cycle. Understanding the rich diversity of metabolic and genomic regulation that occurs in interphase requires the demarcation of precise phase boundaries in situ. Here, we report the properties of two genetically encoded fluorescence sensors, Fucci(CA) and Fucci(SCA), which enable real-time monitoring of interphase and cell-cycle biology. We re-engineered the Cdt1-based sensor from the original Fucci system to respond to S phase-specific CUL4Ddb1-mediated ubiquitylation alone or in combination with SCFSkp2-mediated ubiquitylation. In cultured cells, Fucci(CA) produced a sharp triple color-distinct separation of G1, S, and G2, while Fucci(SCA) permitted a two-color readout of G1 and S/G2. Fucci(CA) applications included tracking the transient G1 phase of rapidly dividing mouse embryonic stem cells and identifying a window for UV-irradiation damage in S phase. These results show that Fucci(CA) is an essential tool for quantitative studies of interphase cell-cycle regulation. PMID- 29107533 TI - H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas. AB - Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies. PMID- 29107534 TI - m6A Facilitates eIF4F-Independent mRNA Translation. AB - In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m7G) cap found on the 5' end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The broad spectrum of eIF4F-resistant translatomes is incompatible with cap independent translation mediated by internal ribosome entry sites (IRESs). Here, we report that N6-methyladenosine (m6A) facilitates mRNA translation that is resistant to eIF4F inactivation. Depletion of the methyltransferase METTL3 selectively inhibits translation of mRNAs bearing 5' UTR methylation, but not mRNAs with 5' terminal oligopyrimidine (TOP) elements. We identify ABCF1 as a critical mediator of m6A-promoted translation under both stress and physiological conditions. Supporting the role of ABCF1 in m6A-facilitated mRNA translation, ABCF1-sensitive transcripts largely overlap with METTL3-dependent mRNA targets. By illustrating the scope and mechanism of eIF4F-independent mRNA translation, these findings reshape our current perceptions of cellular translational pathways. PMID- 29107536 TI - The Unfolded Protein Response and Cell Fate Control. AB - The secretory capacity of a cell is constantly challenged by physiological demands and pathological perturbations. To adjust and match the protein-folding capacity of the endoplasmic reticulum (ER) to changing secretory needs, cells employ a dynamic intracellular signaling pathway known as the unfolded protein response (UPR). Homeostatic activation of the UPR enforces adaptive programs that modulate and augment key aspects of the entire secretory pathway, whereas maladaptive UPR outputs trigger apoptosis. Here, we discuss recent advances into how the UPR integrates information about the intensity and duration of ER stress stimuli in order to control cell fate. These findings are timely and significant because they inform an evolving mechanistic understanding of a wide variety of human diseases, including diabetes mellitus, neurodegeneration, and cancer, thus opening up the potential for new therapeutic modalities to treat these diverse diseases. PMID- 29107537 TI - Base-Resolution Mapping Reveals Distinct m1A Methylome in Nuclear- and Mitochondrial-Encoded Transcripts. AB - Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N1-methyladenosine (m1A) is a recently identified mRNA modification; however, little is known about its precise location and biogenesis. Here, we develop a base-resolution m1A profiling method, based on m1A induced misincorporation during reverse transcription, and report distinct classes of m1A methylome in the human transcriptome. m1A in 5' UTR, particularly those at the mRNA cap, associate with increased translation efficiency. A different, small subset of m1A exhibit a GUUCRA tRNA-like motif, are evenly distributed in the transcriptome, and are dependent on the methyltransferase TRMT6/61A. Additionally, we show that m1A is prevalent in the mitochondrial encoded transcripts. Manipulation of m1A level via TRMT61B, a mitochondria localizing m1A methyltransferase, demonstrates that m1A in mitochondrial mRNA interferes with translation. Collectively, our approaches reveal distinct classes of m1A methylome and provide a resource for functional studies of m1A-mediated epitranscriptomic regulation. PMID- 29107539 TI - Is inertial flywheel resistance training superior to gravity-dependent resistance training in improving muscle strength? A systematic review with meta-analyses. AB - OBJECTIVE: The primary aim of this systematic review was to determine if inertial flywheel resistance training is superior to gravity-dependent resistance training in improving muscle strength. The secondary aim was to determine whether inertial flywheel resistance training is superior to gravity-dependent resistance training in improving other muscular adaptations. DESIGN: A systematic review with meta analyses of randomised and non-randomised controlled trials. METHODS: We searched MEDLINE, Scopus, SPORTDiscus, Web of Science and Cochrane Central Register of Controlled Trials with no publication date restrictions until November 2016. We performed meta-analyses on randomised and non-randomised controlled trials to determine the standardized mean difference between the effects of inertial flywheel and gravity-dependent resistance training on muscle strength. A total of 76 and 71 participants were included in the primary and secondary analyses, respectively. RESULTS: After systematic review, we included three randomised and four non-randomised controlled trials. In the primary analysis for the primary outcome muscle strength, the pooled results from randomised controlled trials showed no difference (SMD=-0.05; 95%CI -0.51 to 0.40; p=0.82; I2=0%). In the secondary analyses of the primary outcome, the pooled results from non-randomised controlled trials showed no difference (SMD=0.02; 95%CI -0.45 to 0.49; p=0.93; I2=0%; and SMD=0.03; 95%CI -0.43 to 0.50; p=0.88; I2=0%). Meta-analysis on secondary outcomes could not be performed. CONCLUSION: Based on the available data, inertial flywheel resistance training was not superior to gravity-dependent resistance training in enhancing muscle strength. Data for other strength variables and other muscular adaptations was insufficient to draw firm conclusions from. PMID- 29107538 TI - Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex. AB - The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. The crystal structure of the five-subunit human Ragulator at 1.4 A resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1. EM was used to reconstruct the assembly of the full-length RagAGTP:RagCGDP dimer bound to Ragulator at 16 A resolution, revealing that the G-domains of the Rags project away from the Ragulator core. The combined structural model shows how Ragulator functions as a platform for the presentation of active Rags for mTORC1 recruitment, and might suggest an unconventional mechanism for Rag GEF activity. PMID- 29107540 TI - Protective effect of Opuntia ficus-indica L. cladodes against UVA-induced oxidative stress in normal human keratinocytes. AB - Opuntia ficus-indica L. is known for its beneficial effects on human health, but still little is known on cladodes as a potent source of antioxidants. Here, a direct, economic and safe method was set up to obtain water extracts from Opuntia ficus-indica cladodes rich in antioxidant compounds. When human keratinocytes were pre-treated with the extract before being exposed to UVA radiations, a clear protective effect against UVA-induced stress was evidenced, as indicated by the inhibition of stress-induced processes, such as free radicals production, lipid peroxidation and GSH depletion. Moreover, a clear protective effect against apoptosis in pre-treated irradiated cells was evidenced. We found that eucomic and piscidic acids were responsible for the anti-oxidative stress action of cladode extract. In conclusion, a bioactive, safe, low-cost and high value-added extract from Opuntia cladodes was obtained to be used for skin health/protection. PMID- 29107541 TI - Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units. AB - Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability. PMID- 29107542 TI - Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors. AB - A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAFV600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2. PMID- 29107543 TI - Additive effect of heparin on the photoinactivation of Escherichia coli using tricationic P-porphyrins. AB - Polycationic porphyrins have received substantial attention in developing singlet oxygen-sensitizers for biological use such as in the photoinactivation of bacteria and photodynamic therapy (PDT) of tumor cells because they have strong binding affinities for DNA and proteins. However, these strong cellular interactions can retard elimination of the drug after PDT. Therefore, the studies on the interactions of porphyrins with other molecules present much interest, in order to modulate the sensitizers' activity or even remove them from the human body after PDT. Here, we studied the additive effect of heparin on the photoinactivation by polycationic porphyrins using Escherichia coli as a model cell. Tricationic P-porphyrin sensitizers substituted with an N-alkylpyridinium group (alkyl = pentyl (1a), hexyl (1b), and heptyl (1c)) or N-hexylammonium (1d) as the axial ligand were used. Additionally, dicationic Sb-porphyrin substituted with an N-hexylpyridinium group (1e) was prepared. We studied the additive effect of heparin on the photoinactivation of E. coli by 1a-1e. The bactericidal activities were evaluated using the half-life (T1/2 in min) of E. coli and the minimum effective concentrations ([P]) of the porphyrin sensitizers. In the absence of heparin, the [P] values were determined to be 0.4-0.5 MUM for 1a-1c and 2.0 MUM for 1d-1e. The bactericidal activity of 1a-1c was completely retarded by the addition of heparin (1.0 MUM). However, the addition of heparin (1.0 MUM) could not completely retard the bactericidal activity of 1d-1e whose [P] values were relatively large. It is suggested that tricationic 1a-1c adsorbed onto the anionic heparin through electrostatic interactions. The adsorption of 1 on heparin disturbs the uptake of 1 into E. coli cells. Thus, the addition of heparin was found to be a useful method for retarding photoinactivation. PMID- 29107544 TI - Prognostic relevance of right heart reverse remodeling in idiopathic pulmonary arterial hypertension. AB - BACKGROUND: Right ventricular (RV) failure is a major determinant of symptoms and shortened survival in pulmonary arterial hypertension (PAH). This study assessed the prognostic relevance of increased right heart (RH) dimensions determined by echocardiography and RH reverse remodeling (RHRR) with targeted therapies in idiopathic PAH (IPAH). METHODS: The study prospectively monitored 102 therapy naive IPAH patients for the presence of clinical worsening. Baseline evaluation included RH catheterization and echocardiography. RHRR at the 1-year follow-up was defined by a decrease in RV end-diastolic area, right atrial area, and the left ventricular systolic eccentricity index. RESULTS: At the 1-year follow-up, 18 of 102 patients (17.6%) presented with RHRR. A decrease in pulmonary vascular resistance was the only independent determinant of RHRR. The 94 surviving patients were monitored for 995 +/- 529 days. RHRR was an independent prognostic factor and significantly improved the power of the prognostic model based on traditional clinical and hemodynamic parameters. The respective event-free survival rates at 1, 3, and 5 years were 94%, 94%, and 94% in patients with RHRR and 75%, 55%, and 24% in those without RHRR (p = 0.0001). Interestingly, RHRR was able to further stratify patients' risk assessment through the Registry to Evaluate Early And Long-term PAH Disease Management risk score. CONCLUSIONS: RHRR after 1 year of treatment is an independent predictor of prognosis in IPAH. The likelihood of RHRR is proportional to decreased pulmonary vascular resistance. PMID- 29107545 TI - Infectious complications of ventricular assist device use in children in the United States: Data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs). AB - BACKGROUND: Infections are frequent in pediatric ventricular assist device (VAD) patients. In this study we aimed to describe infections in durable VAD patients reported to Pedimacs. METHODS: Durable VAD data from the Pedimacs registry (September 19, 2012 to December 31, 2015) were analyzed. Infections were described with standard descriptive statistics, Kaplan-Meier analysis and competing outcomes analysis. RESULTS: There were 248 implants in 222 patients, with a mean age and a median follow-up of 11 +/- 6.4 years and 2.4 patient-months (<1 day to 2.6 years), respectively. Device types were pulsatile flow (PF) in 91 (41%) patients and continuous flow (CF) in 131 (59%) patients. PF patients were younger (4 +/- 4 vs 14 +/- 4 years; p < 0.0001) and were more likely to have congenital heart disease (25% vs 12%; p = 0.03), prior surgery (53% vs 26%; p < 0.0001) and prior extracorporeal membrane oxygenation (24% vs 7%; p = 0.0003). Infection accounted for 17% (96 of 564) of the reported adverse events (AEs). A non-device infection was most common (51%), followed by sepsis (24%), external pump component infection (20%) and internal pump component infection (5%). Most infections were bacterial (73%) and required intravenous therapy only (77%). The risk of infection in the constant phase was higher in patients with a history of prior infection and in patients with a history of a non-infectious major AEs. Survival was lower after infection only in CF patients (p = 0.008). CONCLUSIONS: Infection was the most common AE after pediatric VAD implantation. Non-device infections were most common. The best predictor of a future infection was a past infection. CF patients have higher risk of death after an infection. PMID- 29107547 TI - CaMKIIalpha Expression Defines Two Functionally Distinct Populations of Granule Cells Involved in Different Types of Odor Behavior. AB - Granule cells (GCs) in the olfactory bulb (OB) play an important role in odor information processing. Although they have been classified into various neurochemical subtypes, the functional roles of these subtypes remain unknown. We used in vivo two-photon Ca2+ imaging combined with cell-type-specific identification of GCs in the mouse OB to examine whether functionally distinct GC subtypes exist in the bulbar network. We showed that half of GCs express Ca2+/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha+) and that these neurons are preferentially activated by olfactory stimulation. The higher activity of CaMKIIalpha+ neurons is due to the weaker inhibitory input that they receive compared to their CaMKIIalpha-immunonegative (CaMKIIalpha-) counterparts. In line with these functional data, immunohistochemical analyses showed that 75% 90% of GCs expressing the immediate early gene cFos are CaMKIIalpha+ in naive animals and in mice that have been exposed to a novel odor and go/no-go operant conditioning, or that have been subjected to long-term associative memory and spontaneous habituation/dishabituation odor discrimination tasks. On the other hand, a perceptual learning task resulted in increased activation of CaMKIIalpha- cells. Pharmacogenetic inhibition of CaMKIIalpha+ GCs revealed that this subtype is involved in habituation/dishabituation and go/no-go odor discrimination, but not in perceptual learning. In contrast, pharmacogenetic inhibition of GCs in a subtype-independent manner affected perceptual learning. Our results indicate that functionally distinct populations of GCs exist in the OB and that they play distinct roles during different odor tasks. PMID- 29107546 TI - Life-Long Neurogenic Activity of Individual Neural Stem Cells and Continuous Growth Establish an Outside-In Architecture in the Teleost Pallium. AB - Spatiotemporal variations of neurogenesis are thought to account for the evolution of brain shape. In the dorsal telencephalon (pallium) of vertebrates, it remains unresolved which ancestral neurogenesis mode prefigures the highly divergent cytoarchitectures that are seen in extant species. To gain insight into this question, we developed genetic tools to generate here the first 4 dimensional (3D + birthdating time) map of pallium construction in the adult teleost zebrafish. Using a Tet-On-based genetic birthdating strategy, we identify a "sequential stacking" construction mode where neurons derived from the zebrafish pallial germinal zone arrange in outside-in, age-related layers from a central core generated during embryogenesis. We obtained no evidence for overt radial or tangential neuronal migrations. Cre-lox-mediated tracing, which included following Brainbow clones, further demonstrates that this process is sustained by the persistent neurogenic activity of individual pallial neural stem cells (NSCs) from embryo to adult. Together, these data demonstrate that the spatiotemporal control of NSC activity is an important driver of the macroarchitecture of the zebrafish adult pallium. This simple mode of pallium construction shares distinct traits with pallial genesis in mammals and non mammalian amniotes such as birds or reptiles, suggesting that it may exemplify the basal layout from which vertebrate pallial architectures were elaborated. PMID- 29107548 TI - Countershading and Stripes in the Theropod Dinosaur Sinosauropteryx Reveal Heterogeneous Habitats in the Early Cretaceous Jehol Biota. AB - Countershading is common across a variety of lineages and ecological time [1-4]. A dark dorsum and lighter ventrum helps to mask the three-dimensional shape of the body by reducing self-shadowing and decreasing conspicuousness, thus helping to avoid detection by predators and prey [1, 2, 4, 5]. The optimal countershading pattern is dictated by the lighting environment, which is in turn dependent upon habitat [1, 3, 5, 6]. With the discovery of fossil melanin [7, 8], it is possible to infer original color patterns from fossils, including countershading [3, 9, 10]. Applying these principles, we describe the pattern of countershading in the diminutive theropod dinosaur Sinosauropteryx from the Early Cretaceous Jehol Biota of Liaoning, China. From reconstructions based on exceptional fossils, the color pattern is compared to predicted optimal countershading transitions based on 3D reconstructions of the animal's abdomen, imaged in different lighting environments. Reconstructed patterns match well with those predicted for animals living in open habitats. Jehol is presumed to have been a predominantly closed forested environment [3, 11, 12], but our results indicate a more heterogeneous range of habitats. Sinosauropteryx is also shown to exhibit a "bandit mask," a common pattern in many living vertebrates, particularly birds, that serves multiple functions including camouflage [13-18]. Sinosauropteryx therefore shows multiple color pattern features likely related to the habitat in which it lived. Our results show how reconstructing the color of extinct animals can inform on their ecologies beyond what may be obvious from skeletal remains alone. VIDEO ABSTRACT. PMID- 29107549 TI - Myosin 2-Induced Mitotic Rounding Enables Columnar Epithelial Cells to Interpret Cortical Spindle Positioning Cues. AB - During epithelial cell proliferation, planar alignment of the mitotic spindle allows the daughter cells to stay within the epithelium. Previous work has identified cortical cues that regulate spindle orientation and the division axis [1, 2]. One such cue is cortical Pins (LGN in vertebrates) [3-6], which recruits the conserved Mud/NuMA protein and the dynein/dynactin complex to the cortex. The dynein/dynactin motor complex pulls astral microtubules to orient the spindle. Cortical Pins can therefore dictate the division axis. In addition to cortical cues, cell shape can also serve as a division orientation cue [7-9]. Here, we investigated the interplay between cortical cues and cell shape in a proliferating tissue. We analyzed division orientation in the first mitotic divisions of the early Drosophila embryo, where groups of epithelial cells synchronously divide. Using chemical inhibitors, knockdowns, and mutants with known deficits in motor activity, we showed that the myosin 2 motor is required to orient cell division in the plane of a columnar epithelium. Disrupting myosin activity caused the division axis to orient perpendicular to the epithelial plane. This effect was independent of Pins cortical localization, which became uncoupled from spindle orientation. Instead, myosin motor activity was required for the formation of the actomyosin cortex and for cell rounding upon mitotic entry. We propose that mitotic cell rounding in columnar epithelia allows cells to properly interpret cortical cues that orient the spindle. In the absence of mitotic rounding, geometric cues imposed by tight cell packing prevail and cells divide along their long apical-basal axis. PMID- 29107550 TI - A Parallel Adder Coordinates Mycobacterial Cell-Cycle Progression and Cell-Size Homeostasis in the Context of Asymmetric Growth and Organization. AB - In model bacteria, such as E. coli and B. subtilis, regulation of cell-cycle progression and cellular organization achieves consistency in cell size, replication dynamics, and chromosome positioning [1-3]. Mycobacteria elongate and divide asymmetrically, giving rise to significant variation in cell size and elongation rate among closely related cells [4, 5]. Given the physical asymmetry of mycobacteria, the models that describe coordination of cellular organization and cell-cycle progression in model bacteria are not directly translatable [1, 2, 6-8]. Here, we used time-lapse microscopy and fluorescent reporters of DNA replication and chromosome positioning to examine the coordination of growth, division, and chromosome dynamics at a single-cell level in Mycobacterium smegmatis (M. smegmatis) and Mycobacterium bovis Bacillus Calmette-Guerin (BCG). By analyzing chromosome and replisome localization, we demonstrated that chromosome positioning is asymmetric and proportional to cell size. Furthermore, we found that cellular asymmetry is maintained throughout the cell cycle and is not established at division. Using measurements and stochastic modeling of mycobacterial cell size and cell-cycle timing in both slow and fast growth conditions, we found that well-studied models of cell-size control are insufficient to explain the mycobacterial cell cycle. Instead, we showed that mycobacterial cell-cycle progression is regulated by an unprecedented mechanism involving parallel adders (i.e., constant growth increments) that start at replication initiation. Together, these adders enable mycobacterial populations to regulate cell size, growth, and heterogeneity in the face of varying environments. PMID- 29107551 TI - Caudate Microstimulation Increases Value of Specific Choices. AB - Value-based decision-making involves an assessment of the value of items available and the actions required to obtain them. The basal ganglia are highly implicated in action selection and goal-directed behavior [1-4], and the striatum in particular plays a critical role in arbitrating between competing choices [5 9]. Previous work has demonstrated that neural activity in the caudate nucleus is modulated by task-relevant action values [6, 8]. Nonetheless, how value is represented and maintained in the striatum remains unclear since decision-making in these tasks relied on spatially lateralized responses, confounding the ability to generalize to a more abstract choice task [6, 8, 9]. Here, we investigate striatal value representations by applying caudate electrical stimulation in macaque monkeys (n = 3) to bias decision-making in a task that divorces the value of a stimulus from motor action. Electrical microstimulation is known to induce neural plasticity [10, 11], and caudate microstimulation in primates has been shown to accelerate associative learning [12, 13]. Our results indicate that stimulation paired with a particular stimulus increases selection of that stimulus, and this effect was stimulus dependent and action independent. The modulation of choice behavior using microstimulation was best modeled as resulting from changes in stimulus value. Caudate neural recordings (n = 1) show that changes in value-coding neuron activity are stimulus value dependent. We argue that caudate microstimulation can differentially increase stimulus values independent of action, and unilateral manipulations of value are sufficient to mediate choice behavior. These results support potential future applications of microstimulation to correct maladaptive plasticity underlying dysfunctional decision-making related to neuropsychiatric conditions. PMID- 29107552 TI - Feeding Ecology and Morphology Make a Bamboo Specialist Vulnerable to Climate Change. AB - Animals with dietary specializations can be used to link climate to specific ecological drivers of endangerment. Only two mammals, the giant panda (Ailuropoda melanoleuca) in Asia and the greater bamboo lemur (Prolemur simus) in Madagascar, consume the nutritionally poor and mechanically challenging culm or trunk of woody bamboos [1-3]. Even though the greater bamboo lemur is critically endangered, paleontological evidence shows that it was once broadly distributed [4, 5]. Here, integrating morphological, paleontological, and ecological evidence, we project the effects of climate change on greater bamboo lemurs. Both the giant panda and the greater bamboo lemur are shown to share diagnostic dental features indicative of a bamboo diet, thereby providing an ecometric indicator [6, 7] of diet preserved in the fossil record. Analyses of bamboo feeding in living populations show that bamboo culm is consumed only during the dry season and that the greater bamboo lemur is currently found in regions with the shortest dry season. In contrast, paleontological localities of the greater bamboo lemurs have the longest dry seasons. Future projections show that many present-day greater bamboo lemur populations will experience prolonged dry seasons similar to those of the localities where only fossils of the greater bamboo lemur are found. Whereas abundant foods such as bamboo allow feeding specialists to thrive, even a moderate change in seasonality may outstrip the capacity of greater bamboo lemurs to persist on their mechanically demanding food source. Coupling known changes in species distribution with high-resolution ecological and historical data helps to identify extinction risks. PMID- 29107553 TI - A Single Community Dominates Structure and Function of a Mixture of Multiple Methanogenic Communities. AB - The ecology of microbes frequently involves the mixing of entire communities (community coalescence), for example, flooding events, host excretion, and soil tillage [1, 2], yet the consequences of this process for community structure and function are poorly understood [3-7]. Recent theory suggests that a community, due to coevolution between constituent species, may act as a partially cohesive unit [8-11], resulting in one community dominating after community coalescence. This dominant community is predicted to be the one that uses resources most efficiently when grown in isolation [11]. We experimentally tested these predictions using methanogenic communities, for which efficient resource use, quantified by methane production, requires coevolved cross-feeding interactions between species [12]. After propagation in laboratory-scale anaerobic digesters, community composition (determined from 16S rRNA sequencing) and methane production of mixtures of communities closely resembled that of the single most productive community grown in isolation. Analysis of each community's contribution toward the final mixture suggests that certain combinations of taxa within a community might be co-selected as a result of coevolved interactions. As a corollary of these findings, we also show that methane production increased with the number of inoculated communities. These findings are relevant to the understanding of the ecological dynamics of natural microbial communities, as well as demonstrating a simple method of predictably enhancing microbial community function in biotechnology, health, and agriculture [13]. PMID- 29107554 TI - Genomic Analyses of Pre-European Conquest Human Remains from the Canary Islands Reveal Close Affinity to Modern North Africans. AB - The origins and genetic affinity of the aboriginal inhabitants of the Canary Islands, commonly known as Guanches, are poorly understood. Though radiocarbon dates on archaeological remains such as charcoal, seeds, and domestic animal bones suggest that people have inhabited the islands since the 5th century BCE [1 3], it remains unclear how many times, and by whom, the islands were first settled [4, 5]. Previously published ancient DNA analyses of uniparental genetic markers have shown that the Guanches carried common North African Y chromosome markers (E-M81, E-M78, and J-M267) and mitochondrial lineages such as U6b, in addition to common Eurasian haplogroups [6-8]. These results are in agreement with some linguistic, archaeological, and anthropological data indicating an origin from a North African Berber-like population [1, 4, 9]. However, to date there are no published Guanche autosomal genomes to help elucidate and directly test this hypothesis. To resolve this, we generated the first genome-wide sequence data and mitochondrial genomes from eleven archaeological Guanche individuals originating from Gran Canaria and Tenerife. Five of the individuals (directly radiocarbon dated to a time transect spanning the 7th-11th centuries CE) yielded sufficient autosomal genome coverage (0.21* to 3.93*) for population genomic analysis. Our results show that the Guanches were genetically similar over time and that they display the greatest genetic affinity to extant Northwest Africans, strongly supporting the hypothesis of a Berber-like origin. We also estimate that the Guanches have contributed 16%-31% autosomal ancestry to modern Canary Islanders, here represented by two individuals from Gran Canaria. PMID- 29107555 TI - Forearm diaphyseal fractures in children: intramedullary Kirschner's wire fixation treatment. AB - INTRODUCTION: Diaphyseal fractures of the forearm comprise 6%-10% of all fractures in children. The treatment depends on the age and type of displacement, and conservative and surgical management with fixation of intramedullary nails, among other techniques, is valid. The aim is to show the radiological and functional outcomes, and complications of intramedullary fixation with Kirschner nails in children. MATERIALS AND METHODS: A retrospective descriptive case series of patients treated with intramedullary fixation of forearm fractures. The radiological and functional results, and complications are correlated. RESULTS: Of the 117 patients operated, 59 met the inclusion criteria. The average age was 10 years. Eighty-four point seven percent were males and the left side was the most affected (62.7%). In 88.1% both bones were fractured and 11 cases had open fractures. An open reduction was performed in 72.8% of the cases, the main indications for this being instability, failed reduction and refracture. There were 52 excellent outcomes, 2 good, and 4 regular and 1 bad. There were 13.5% minor complications. DISCUSSION: This study shows that intramedullary fixation with Kirschner nails in radius and ulna diaphysis fractures in children is a safe, low-cost procedure and offers adequate short and medium term functional outcomes, with a low prevalence of serious complications with only 6 cases of non consolidation and refracture. Larger preoperative angulations in the anteroposterior and lateral planes, and lateral postoperative angulations, could be considered predictors of less satisfactory functional results. PMID- 29107556 TI - [Blood pressure and sleep apnoea hypopnoea syndrome in workers. STOP-Bang test versus Epworth test]. AB - INTRODUCTION: OSAHS is associated with an increased risk of cardiovascular disease and stroke. Arterial hypertension is a key risk factor to consider due to its impact on health. METHOD: Cross-sectional study carried out on Spanish public service workers. The nocturnal apnoea risk using the Epworth and STOP-Bang questionnaires and their influence on the mean values of blood pressure are assessed. RESULTS: The detection of OSAHS using the Epworth test and, particularly with the STOP-Bang shows a significant relationship with the mean values of blood pressure, with differences between both questionnaires. CONCLUSION: The Epworth and STOP-Bang questionnaires are useful for the initial detection of OSAHS and a higher prevalence of high blood pressure. Both can be used in screening procedures in occupational health. PMID- 29107557 TI - Boundary Formation through a Direct Threshold-Based Readout of Mobile Small RNA Gradients. AB - Small RNAs have emerged as a new class of mobile signals. Here, we investigate their mechanism of action and show that mobile small RNAs generate sharply defined domains of target gene expression through an intrinsic and direct threshold-based readout of their mobility gradients. This readout is highly sensitive to small RNA levels at the source, allowing plasticity in the positioning of a target gene expression boundary. Besides patterning their immediate targets, the readouts of opposing small RNA gradients enable specification of robust, uniformly positioned developmental boundaries. These patterning properties of small RNAs are reminiscent of those of animal morphogens. However, their mode of action and the intrinsic nature of their gradients distinguish mobile small RNAs from classical morphogens and present a unique direct mechanism through which to relay positional information. Mobile small RNAs and their targets thus emerge as highly portable, evolutionarily tractable regulatory modules through which to create pattern. PMID- 29107558 TI - ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development. AB - Alternative splicing contributes to gene expression dynamics in many tissues, yet its role in auditory development remains unclear. We performed whole-exome sequencing in individuals with sensorineural hearing loss (SNHL) and identified pathogenic mutations in Epithelial Splicing-Regulatory Protein 1 (ESRP1). Patient derived induced pluripotent stem cells showed alternative splicing defects that were restored upon repair of an ESRP1 mutant allele. To determine how ESRP1 mutations cause hearing loss, we evaluated Esrp1-/- mouse embryos and uncovered alterations in cochlear morphogenesis, auditory hair cell differentiation, and cell fate specification. Transcriptome analysis revealed impaired expression and splicing of genes with essential roles in cochlea development and auditory function. Aberrant splicing of Fgfr2 blocked stria vascularis formation due to erroneous ligand usage, which was corrected by reducing Fgf9 gene dosage. These findings implicate mutations in ESRP1 as a cause of SNHL and demonstrate the complex interplay between alternative splicing, inner ear development, and auditory function. PMID- 29107559 TI - Genetic Intersection of Tsix and Hedgehog Signaling during the Initiation of X Chromosome Inactivation. AB - X-chromosome inactivation (XCI) silences one X chromosome in the female mammal and is essential to peri-implantation development. XCI is thought to be cell autonomous, with all factors required being produced within each cell. Nevertheless, external cues may exist. Here, we search for such developmental signals by combining bioinformatic, biochemical, and genetic approaches. Using ex vivo and in vivo models, we identify the Hedgehog (HH) paracrine system as a candidate signaling cascade. HH signaling keeps XCI in check in pluripotent cells and is transduced by GLI transcription factors to binding sites in Tsix, the antisense repressor of XCI. GLI potentiates Tsix expression and impedes XCI. In vivo, mutating Indian Hedgehog results in a sex ratio bias against females, and the female lethality is rescued by a second-site mutation in Tsix. These data demonstrate a genetic and functional intersection between HH and XCI and support a role for intercellular signaling during XCI. PMID- 29107560 TI - Myosin II Controls Junction Fluctuations to Guide Epithelial Tissue Ordering. AB - Under conditions of homeostasis, dynamic changes in the length of individual adherens junctions (AJs) provide epithelia with the fluidity required to maintain tissue integrity in the face of intrinsic and extrinsic forces. While the contribution of AJ remodeling to developmental morphogenesis has been intensively studied, less is known about AJ dynamics in other circumstances. Here, we study AJ dynamics in an epithelium that undergoes a gradual increase in packing order, without concomitant large-scale changes in tissue size or shape. We find that neighbor exchange events are driven by stochastic fluctuations in junction length, regulated in part by junctional actomyosin. In this context, the developmental increase of isotropic junctional actomyosin reduces the rate of neighbor exchange, contributing to tissue order. We propose a model in which the local variance in tension between junctions determines whether actomyosin-based forces will inhibit or drive the topological transitions that either refine or deform a tissue. PMID- 29107561 TI - Association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with HIV: a systematic review and meta-analysis. AB - BACKGROUND: The interactions between antiretroviral therapy (ART) and high-risk human papillomavirus (HPV) and cervical lesions in women living with HIV are poorly understood. We reviewed the association of ART with these outcomes. METHODS: We did a systematic review and meta-analysis by searching MEDLINE and Embase databases for cross-sectional or cohort studies published in English between Jan 1, 1996, and May 6, 2017, which reported the association of ART with prevalence of high-risk HPV or prevalence, incidence, progression, or regression of histological or cytological cervical abnormalities, or incidence of invasive cervcal cancer. Studies were eligible if they reported the association of combination ART or highly active ART use with the following outcomes: high-risk HPV prevalence; squamous intraepithelial lesion (SIL) or cervical intraepithelial neoplasia (CIN) prevalence, incidence, progression, or regression; and invasive cervical cancer incidence among women living with HIV. We did random-effects meta analyses to estimate summary statistics. We examined heterogeneity with the I2 statistic. This review is registered on the PROSPERO database at the Centre of Reviews and Dissemination, University of York, York, UK (registration number CRD42016039546). FINDINGS: We identified 31 studies of the association of ART with prevalence of high-risk HPV (6537 women living with HIV) and high grade cervical lesions (HSIL-CIN2+; 9288 women living with HIV). Women living with HIV on ART had lower prevalence of high-risk HPV than did those not on ART (adjusted odds ratio [aOR] 0.83, 95% CI 0.70-0.99; I2=51%, adjusted for CD4 cell count and ART duration), and there was some evidence of association with HSIL-CIN2+ (0.65, 0.40-1.06; I2=30%). 17 studies reported the association of ART with longitudinal cervical lesion outcomes. ART was associated with a decreased risk of HSIL-CIN2+ incidence among 1830 women living with HIV (0.59, 0.40-0.87; I2=0%), SIL progression among 6212 women living with HIV (adjusted hazard ratio [aHR] 0.64, 95% CI 0.54-0.75; I2=18%), and increased likelihood of SIL or CIN regression among 5261 women living with HIV (1.54, 1.30-1.82; I2=0%). In three studies among 15 846 women living with HIV, ART was associated with a reduction in invasive cervical cancer incidence (crude HR 0.40, 95% CI 0.18-0.87, I2=33%). INTERPRETATION: Early ART initiation and sustained adherence is likely to reduce incidence and progression of SIL and CIN and ultimately incidence of invasive cervical cancer. Future cohort studies should aim to confirm this possible effect. FUNDING: UK Medical Research Council. PMID- 29107562 TI - Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial. AB - BACKGROUND: The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART. METHODS: We did this open label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged >=18 years) were on combination ART, had been virologically suppressed (HIV RNA <50 copies per mL) for at least 6 months, and had CD4 nadirs of 200 cells per MUL or higher, HIV RNA zeniths of 100 000 copies per mL or less, and no history of virological failure. Patients were randomly assigned (1:1), via a web-based block randomisation method (variable block sizes of 4 and 6), to switch to dolutegravir monotherapy (50 mg once a day) either immediately or after a delay of 24 weeks of continued combination ART. Randomisation was stratified by HIV RNA zenith (<50 000 copies per mL vs 50 000 99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828. FINDINGS: Between March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI -5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation. INTERPRETATION: Dolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy. FUNDING: Erasmus Trustfonds. PMID- 29107563 TI - Dolutegravir monotherapy as maintenance ART bites the dust. PMID- 29107564 TI - The effect of ART on cervical cancer precursor lesions. PMID- 29107565 TI - Rubber stamp templates for improving clinical documentation: A paper-based, m Health approach for quality improvement in low-resource settings. AB - BACKGROUND: The United Nations' Sustainable Development Goal #3.8 targets 'access to quality essential healthcare services'. Clinical practice guidelines are an important tool for ensuring quality of clinical care, but many challenges prevent their use in low-resource settings. Monitoring the use of guidelines relies on cumbersome clinical audits of paper records, and electronic systems face financial and other limitations. Here we describe a unique approach to generating digital data from paper using guideline-based templates, rubber stamps and mobile phones. INTERVENTION: The Guidelines Adherence in Slums Project targeted ten private sector primary healthcare clinics serving informal settlements in Nairobi, Kenya. Each clinic was provided with rubber stamp templates to support documentation and management of commonly encountered outpatient conditions. Participatory design methods were used to customize templates to the workflows and infrastructure of each clinic. Rubber stamps were used to print templates into paper charts, providing clinicians with checklists for use during consultations. Templates used bubble format data entry, which could be digitized from images taken on mobile phones. Besides rubber stamp templates, the intervention included booklets of guideline compilations, one Android phone for digitizing images of templates, and one data feedback/continuing medical education session per clinic each month. In this paper we focus on the effect of the intervention on documentation of three non-communicable diseases in one clinic. METHODS: Seventy charts of patients enrolled in the chronic disease program (hypertension/diabetes, n=867; chronic respiratory diseases, n=223) at one of the ten intervention clinics were sampled. Documentation of each individual patient encounter in the pre-intervention (January-March 2016) and post-intervention period (May-July) was scored for information in four dimensions - general data, patient assessment, testing, and management. Control criteria included information with no counterparts in templates (e.g. notes on presenting complaints, vital signs). Documentation scores for each patient were compared between both pre- and post-intervention periods and between encounters documented with and without templates (post-intervention only). RESULTS: The total number of patient encounters in the pre-intervention (282) and post-intervention periods (264) did not differ. Mean documentation scores increased significantly in the post-intervention period on average by 21%, 24% and 17% for hypertension, diabetes and chronic respiratory diseases, respectively. Differences were greater (47%, 43% and 27%, respectively) when documentation with and without templates was compared. Changes between pre- vs.post-intervention, and with vs.without template, varied between individual dimensions of documentation. Overall, documentation improved more for general data and patient assessment than in testing or management. CONCLUSION: The use of templates improves paper-based documentation of patient care, a first step towards improving the quality of care. Rubber stamps provide a simple and low-cost method to print templates on demand. In combination with ubiquitously available mobile phones, information entered on paper can be easily and rapidly digitized. This 'frugal innovation' in m-Health can empower small, private sector facilities, where large numbers of urban patients seek healthcare, to generate digital data on routine outpatient care. These data can form the basis for evidence-based quality improvement efforts at large scale, and help deliver on the SDG promise of quality essential healthcare services for all. PMID- 29107566 TI - Hypersexuality induced by Aripiprazole: Two case reports and review of the literature. PMID- 29107567 TI - Prevalence & correlates of areca use among rural south Indian schizophrenia patients: A comparative study with general population. AB - Aims of this study were to compare the prevalence of areca use among schizophrenia patients and general population of a south Indian rural community and to study the correlates of areca use among patients. A cohort of 300 schizophrenia patients, who are being followed up as a part of a community intervention program, formed the study group. The control group (n=382) was selected randomly from the general population of this region. Both were interviewed regarding the sociodemographic details, use of areca nut, alcohol and tobacco. Among patients, Positive and Negative Syndrome Scale (PANSS), Simpson's Angus Scale (SAS) and Indian Disability Evaluation and Assessment Scale (IDEAS) were applied. Use of antipsychotic and anticholinergic medications was also noted. These clinical correlates were compared between users and non-users. The prevalence of areca use among schizophrenia patients was significantly higher when compared to the general population (39.0% vs 14.4%, p<0.001). There was no significant difference in positive symptoms, negative symptoms, extrapyramidal symptoms, antipsychotic and anticholinergic drug dosage between areca chewers and non-chewers. Areca use is significantly higher among schizophrenia patients of this rural area when compared to that among the general population. Considering the health hazards that areca abuse may lead to, this issue needs attention. PMID- 29107569 TI - School Support as Structural HIV Prevention for Adolescent Orphans in Western Kenya. AB - PURPOSE: Using a clustered randomized controlled trial design, we evaluated whether support to keep Kenyan orphaned adolescents in school reduces the risk of HIV infection. METHODS: Participants included 835 orphaned boys and girls in grades 7 and 8 (mean age at the baseline = 15 years) in western Kenya. Primary schools (N = 26) were randomized to the study condition. Intervention participants received school uniforms, payment of tuition when they transitioned into high school, and nurse visits to monitor school absenteeism and provide assistance to stay in school. Annual surveys were conducted from 2011 through 2014, and HIV and herpes simplex virus 2 (HSV-2) biomarker data were collected at the baseline and the end line. Data were analyzed using survey logistic regression or generalized estimating equations controlling for age, gender, and socioeconomic status. RESULTS: Intervention and control groups were equivalent at the baseline and did not differ on new HIV or HSV-2 incidence at the end line. The school support intervention increased school retention but had few HIV related effects, except increased circumcision among male participants and reduced likelihood of transactional sex. CONCLUSIONS: Despite a strong study design, we found no relative reduction in HIV or HSV-2 infection after 3 years of intervention implementation. New incidence of HIV was lower than expected in this region among youth whose average age at end line was 18 years (range = 14-23). Although support for secondary school promises many benefits for vulnerable youth, our study adds to the growing body of research showing weak evidence for its effectiveness as an HIV prevention. PMID- 29107568 TI - ASK family in cardiovascular biology and medicine. AB - Cardiovascular disease is a major cause of death worldwide. Mitogen-activated protein kinase (MAPK) signal cascades signaling pathways play crucial roles in cardiovascular pathophysiology. Apoptosis signal-regulating kinase (ASK) family members ASK1, ASK2 and ASK3 are the key molecules in MAPK signal cascades and are activated by various stresses. ASK1 is the most extensively studied MAPKKK and is involved in regulation of the cellular functions such as cell survival, proliferation, inflammation and apoptosis. The current review focuses on the relationship between ASK1 and cardiovascular disease, while exploring the novel therapeutic strategies for cardiovascular disease involved in the ASK1 signal pathway. PMID- 29107570 TI - Triatoma infestans relies on salivary lysophosphatidylcholine to enhance Trypanosoma cruzi transmission. AB - Triatoma infestans is a mandatory haematophagous vector of Chagas disease in Brazil. Despite a large number of studies on the anti-haemostatic molecules present in its saliva, the role of its salivary components on parasite transmission is poorly understood. Here, we show that the bioactive lipid molecule, lysophosphatidylcholine (LPC), is present in the salivary gland of T. infestans. We characterized the lipid profiles of each unit of the T. infestans salivary gland. We noticed that LPC is present in the three units of the salivary gland and that the insect feeding state does not influence its proportion. T. infestans saliva and LPC can enhance T. cruzi transmission to mice by dramatically altering the profile of inflammatory cells at the site of inoculation on mouse skin, facilitating the transmission of T. cruzi to the vertebrate host. Consequently, the mortality curves of either saliva- or LPC injected mice display significant higher mortality rates than the control. Altogether, these results implicate LPC as one of key salivary molecule involved in Chagas disease transmission. PMID- 29107571 TI - A rapid high-resolution melting method for differentiation of Leishmania species targeting lack gene. AB - OBJECTIVES: The aim of this research is to verify that if lack gene can be used for differentiation of Leishmania under HRM assay. METHODS: Two specific primers were designed targeting polymorphic sites on the lack gene sequence. DNA from promastigotes of six species of Leishmania based on reference strains were tested following a HRM protocol. We also tested ten Chinese isolates in blind to validate our method. RESULTS: Combined with amplicon of the two primers, the six reference strains can be easily discriminated without the effect of initial concentration of DNA templates. Ten Chinese isolates detected by our HRM method resulted in full accord with the standard identification results in previous study. CONCLUSION: HRM is a rapid and reproducible method to discriminate different Leishmania species and lack gene is a potential novel biological characteristic for easy differentiation of Leishmania isolates in China. PMID- 29107573 TI - Abscess with osteomyelitis of the clivus after adenoidectomy: An uncommon complication of a common procedure. PMID- 29107572 TI - Trapeziometacarpal joint contact varies between men and women during three isometric functional tasks. AB - Trapeziometacarpal (TMC) joint osteoarthritis (OA) affects women two to six times more than men, and is influenced by stresses and strains in the cartilage. The purpose of this study was to characterise sex and age differences in contact area and peak stress location of the healthy TMC joint during three isometric tasks including pinch, grasp and jar twist. CT images of the hand from 50 healthy adult men and women were used to create a statistical shape model that was used to create finite element models for each subject and task. Force-driven simulations were performed to evaluate cartilage contact area and peak stress location. We tested for sex and age differences using Principal Component Analysis, linear regression, and Linear Discriminant Analysis. We observed sex differences in peak stress location during pinch (p = .0206), grasp (p = .0264), and jar twist (p = .0484). The greatest sex differences were observed during jar twist, where 94% of peak stresses in men were located in the centre compared with 50% in the central volar region in women. These findings show that peak stress locations are more variable in women during grasp and jar twist than men, and suggest that women may employ different strategies to perform these tasks. PMID- 29107574 TI - High prevalence of Salmonella spp. in wastewater reused for irrigation assessed by molecular methods. AB - Salmonella spp. is one of the most important causal agents of food-borne illness in developed countries and its presence in irrigation water poses a risk to public health. Its detection in environmental samples is not easy when culture methods are used, and molecular techniques such as PCR or ribosomal rRNA probe hybridization (Fluorescent in situ Hybridization, FISH) are outstanding alternatives. The aim of this work was to determine the environmental risk due to the presence of Salmonella spp. in wastewater by culture, PCR and FISH. A new specific rDNA probe for Salmonella was designed and its efficiency was compared with the rest of methods Serotype and antibiotic resistance of isolated strains were determined. Forty-five wastewater samples (collected from two secondary wastewater treatment plants) were analysed. Salmonella strains were isolated in 24 wastewater samples (53%), two of them after disinfection treatment. Twenty three Salmonella strains exhibited resistance to one or more antimicrobial agent. Analysis of wastewater samples yielded PCR positive results for Salmonella in 28 out of the 45 wastewater samples (62%). FISH analysis allowed for the detection of Salmonella in 27 (60%) samples. By using molecular methods, Salmonella was detected in four samples after disinfection treatment. These results show the prevalence of Salmonella in reclaimed wastewater even after U.V. disinfection, what is a matter of public health concern, the high rates of resistance to antibiotics and the adequacy of molecular methods for its rapid detection. FISH method, with SA23 probe developed and assayed in this work provides a tool for detecting Salmonella in water within few hours, with a high rate of effectiveness. PMID- 29107575 TI - Historic Physician Quality and Reporting System Reporting by Radiologists: A Wake up Call to Avoid Penalties Under the Medicare Access and CHIP Reauthorization Act (MACRA). AB - PURPOSE: The Medicare Access and CHIP Reauthorization Act (MACRA) Quality performance category is the successor to the Physician Quality and Reporting System (PQRS) program and now contributes to physicians' income adjustments based upon performance rates calculated for a minimum of six measures. We assess radiologists' frequency of reporting PQRS measures as a marker of preparedness for MACRA. METHODS: Medicare-participating radiologists were randomly searched through the Physician Compare website until identifying 1,000 radiologists who reported at least one PQRS measure. Associations were explored between the number of reported measures and radiologist characteristics. RESULTS: For PQRS-reporting radiologists, the number of reported PQRS measures was 1 (25.2%), 2 (27.3%), 3 (18.2%), 4 (19.3%), 5 (8.3%), and 6 (1.7%). The most commonly reported measures were "documenting radiation exposure time for procedures using fluoroscopy" (64.3%) and "accurate measurement of carotid artery narrowing" (56.8%). Reporting at least two measures was significantly (P < .001) more likely for nonacademic (77.3%) versus academic (44.9%) radiologists, generalists (82.7%) versus subspecialists (59.1%), and radiologists in smaller (<=9 members) (84.7%) versus larger (>=100 members) (39.7%) practices. Reporting six measures was significantly (P < .05) more likely for generalists (2.6%) versus subspecialists (0.4%). CONCLUSION: Most PQRS-reporting radiologists reported only one or two measures, well below MACRA's requirement of six. Radiologists continuing such reporting levels will likely be disadvantaged in terms of potential payment adjustments under MACRA. Lower reporting rates for academic and subspecialized radiologists, as well as those in larger practices, may relate to such radiologists' reliance on their hospitals or networks for PQRS reporting. Qualified clinical data registries should be embraced to facilitate more robust measure reporting. PMID- 29107576 TI - GRADE system, systematic and transparent evaluation. PMID- 29107577 TI - Edema and dermatomyositis. Migratory edema and edematous and vesiculobullous dermatomyositis overlap. PMID- 29107578 TI - Facile detection of microRNA based on phosphorescence resonance energy transfer and duplex-specific nuclease-assisted signal amplification. AB - MicroRNAs (miRNAs) play an important role in many biological processes, and its level in plasma and other biological fluids is closely related to many diseases. In this work, a selective room-temperature phosphorescence (RTP) detection method for miRNA was developed based on a duplex-specific nuclease (DSN) -assisted signal amplification strategy and phosphorescence resonance energy transfer (PRET) between poly-diallyldimethylammonium chloride-modified quantum dots (QDs@PDDA) and 6-carboxy-X-rhodamine-modified miRNA sequences complementary oligonucleotide (ROX-ssDNA). The positively charged QDs@PDDA could adsorb negatively charged ROX-ssDNA by electrostatic interaction, whereas the RTP signal of QDs@PDDA could be efficiently quenched by ROX-ssDNA via PRET. In the presence of microRNA-21 (miR-21) and DSN, miR-21 hybridized with ROX-ssDNA initially to form a DNA-RNA heteroduplex as the substrate of DSN, then ssDNA in DNA-RNA heteroduplex would be cleaved into small fragments by DSN and liberate miR-21 to hybridize with another ROX-ssDNA. Eventually, due to weak interaction between ROX ssDNA fragments and QDs@PDDA, PRET efficiency continually decreased whereas the RTP signal was significantly amplified. By employing the strategy above, quantitative detection of miR-21 in the range of 0.25-40 nM with a detection limit of 0.16 nM was realized, showing excellent performance with simplicity, good selectivity and the ability to be a promising method for miRNA detection. PMID- 29107579 TI - Detection of Pseudomonas aeruginosa biomarkers from thermally injured mice in situ using imaging mass spectrometry. AB - Monitoring patients with burn wounds for infection is standard practice because failure to rapidly and specifically identify a pathogen can result in poor clinical outcomes, including death. Therefore, a method that facilitates detection and identification of pathogens in situ within minutes of biopsy would be a significant benefit to clinicians. Mass spectrometry is rapidly becoming a standard tool in clinical settings, capable of identifying specific pathogens from complex samples. Imaging mass spectrometry (IMS) expands the information content by enabling spatial resolution of biomarkers in tissue samples as in histology, without the need for specific stains/antibodies. Herein, a murine model of thermal injury was used to study infection of burn tissue by Pseudomonas aeruginosa. This is the first use of IMS to detect P. aeruginosa infection in situ from thermally injured tissue. Multiple molecular features could be spatially resolved to infected or uninfected tissue. This demonstrates the potential use of IMS in a clinical setting to aid doctors in identifying both presence and species of pathogens in tissue. PMID- 29107580 TI - Awareness of blood group and blood donation among medical students. AB - BACKGROUND: Transfusion of blood-derived products is often used as a life-saving treatment, and being a blood donor should be common, especially among medical professionals. Thus, an awareness of one's own blood type in medical students should be common. Our aim was to assess if students of the Medical University of Warsaw know their blood type and how many of them are registered blood donors. MATERIAL AND METHODS: A survey was conducted in a group of 1121 students. The survey included questions addressing awareness of the students' blood type, the frequency of blood types in Poland, being a blood donor, and willingness to become a blood donor. RESULTS: Of all students, 86.8% knew their blood type and 13.2% did not. Approximately 30.2% of students in the survey declared that they are blood donors, 57.9% had only considered becoming a blood donor and 11.9% had not even considered becoming a blood donor. Of all non-donors, 48.2% had contraindications to becoming a blood donor, 11.5% were afraid of blood collection and 21.9% did not have time to register as a blood donor. Most students (81%) declared that they could become a blood donor if someone closely related needed a transfusion, and 5.2% declared that there is nothing that could force them to become a blood donor. CONCLUSION: Compared to Polish society medical students are significantly more aware of the necessity of blood donation. The majority know their blood type, but they do not know what is the most common blood type in Poland. PMID- 29107581 TI - Developmental estrogen exposures and disruptions to maternal behavior and brain: Effects of ethinyl estradiol, a common positive control. AB - Due of its structural similarity to the endogenous estrogen 17beta-estradiol (E2), the synthetic estrogen 17alpha-ethinyl estradiol (EE2) is widely used to study the effects of estrogenic substances on sensitive organs at multiple stages of development. Here, we investigated the effects of EE2 on maternal behavior and the maternal brain in females exposed during gestation and the perinatal period. We assessed several components of maternal behavior including nesting behavior and pup retrieval; characterized the expression of estrogen receptor (ER)alpha in the medial preoptic area (MPOA), a brain region critical for the display of maternal behavior; and measured expression of tyrosine hydroxylase, a marker for dopaminergic cells, in the ventral tegmental area (VTA), a brain region important in maternal motivation. We found that developmental exposure to EE2 induces subtle effects on several aspects of maternal behavior including time building the nest and time spent engaged in self-care. Developmental exposure to EE2 also altered ERalpha expression in the central MPOA during both early and late lactation and led to significantly reduced tyrosine hydroxylase immunoreactivity in the VTA. Our results demonstrate both dose- and postpartum stage-related effects of developmental exposure to EE2 on behavior and brain that manifest later in adulthood, during the maternal period. These findings provide further evidence for effects of exposure to exogenous estrogenic compounds during the critical periods of fetal and perinatal development. PMID- 29107582 TI - Perinatal exposure to endocrine disrupting compounds and the control of feeding behavior-An overview. AB - Endocrine disrupting compounds (EDC) are ubiquitous environmental contaminants that can interact with steroid and nuclear receptors or alter hormone production. Many studies have reported that perinatal exposure to EDC including bisphenol A, PCB, dioxins, and DDT disrupt energy balance, body weight, adiposity, or glucose homeostasis in rodent offspring. However, little information exists on the effects of perinatal EDC exposure on the control of feeding behaviors and meal pattern (size, frequency, duration), which may contribute to their obesogenic properties. Feeding behaviors are controlled centrally through communication between the hindbrain and hypothalamus with inputs from the emotion and reward centers of the brain and modulated by peripheral hormones like ghrelin and leptin. Discrete hypothalamic nuclei (arcuate nucleus, paraventricular nucleus, lateral and dorsomedial hypothalamus, and ventromedial nucleus) project numerous reciprocal neural connections between each other and to other brain regions including the hindbrain (nucleus tractus solitarius and parabrachial nucleus). Most studies on the effects of perinatal EDC exposure examine simple crude food intake over the course of the experiment or for a short period in adult models. In addition, these studies do not examine EDC's impacts on the feeding neurocircuitry of the hypothalamus-hindbrain, the response to peripheral hormones (leptin, ghrelin, cholecystokinin, etc.) after refeeding, or other feeding behavior paradigms. The purpose of this review is to discuss those few studies that report crude food or energy intake after perinatal EDC exposure and to explore the need for deeper investigations in the hypothalamic-hindbrain neurocircuitry and discrete feeding behaviors. PMID- 29107583 TI - Outcomes of Patients With Relapsed Core Binding Factor-Positive Acute Myeloid Leukemia. AB - PURPOSE: To determine the factors associated with outcomes in patients with core binding factor acute myeloid leukemia (CBF-AML) in first relapse. MATERIAL AND METHODS: We conducted a retrospective analysis of 92 patients with CBF-AML in first relapse who presented to our institution from 1990-2014. Clinical and demographic parameters were included in univariate and multivariate Cox proportional hazards regression model to predict overall survival. RESULTS: Among the 92 relapsed patients, 60 (65%) patients had inv (16) and 32 (35%) had t (8;21). The median survival for patients with inv(16) cytogenetic group was 15.6 months (range 10.32 to 20.88 months) while for the t(8;21) group was 9 months (range 3.68 to 14.32) (P = .004). Univariate Cox model analysis showed that increased age, high white blood cell count, t (8;21) cytogenetic group, and high bone marrow blast percentage were associated with poor overall outcome, while stem cell transplant intervention was associated with better survival. Additional cytogenetic aberrations at relapse were not associated with survival outcomes (P = .4). Multivariate Cox model analysis showed that t(8;21) cytogenetic group has more hazard of death after adjusting, age, marrow blast percentage, blood cell count, and stem cell transplant(hazard ratio 1.802; P = .02). CONCLUSION: Among patients with relapsed CBF-AML, median survival was less than a year and half and the outcome was worse in patients with t (8;21). Despite the relatively better outcomes, dedicated clinical trials are needed to improve the outcome in all patients with relapsed CBF-AML. PMID- 29107585 TI - Changing identity through sport: The Paralympic sport club experience among adolescents with mobility impairments. AB - BACKGROUND: Adolescents with mobility impairments have fewer opportunities to challenge identity as an athlete through sport participation. OBJECTIVE/HYPOTHESIS: This study examined athletic identity impact of adolescent athletes with mobility impairments who participate in Paralympic Sport Clubs. METHODS: This cross-sectional web-survey design examined demographics (gender, academic level, hours of time spent in sports participation, and preferred amount of time in sport participation) and athletic identity through the Athletic Identity Measurement Scale (AIMS). Forty-seven adolescents (male = 34, female = 13) between the ages of 13-18 with mobility impairments who were currently participating in a Paralympic Sport Club were recruited for the study. RESULTS: Two factorial ANOVA examined the differences of AIMS scores by gender and academic level, and gender and hours of time spent in sports participation per week. Hours of time spent in sports participation by adolescent athletes with physical disabilities showed significant difference on athletes' identity. AIMS score increased along with augmented time spent in sport participation. However, gender and academic level made no significant difference on athletic identity. A one-way ANOVA test was applied to compare the effect of preferred amount of time in sport participation per week on scores for AIMS and showed significant group difference on AIMS. Participants who indicated more preferred amount of time in sport participation also scored higher on AIMS. CONCLUSIONS: These findings support the notion that hours of time spent and preferred amount of time in sports participation influences athletic identity. Sport participation, when available can influence athletic identity with this population. PMID- 29107584 TI - First molecular typing of Mycobacterium avium subspecies paratuberculosis identified in animal and human drinking water from dairy goat farms in Brazil. AB - Mycobacterium avium subspecies paratuberculosis, the etiologic agent of Johne's disease or paratuberculosis, was identified by culture and/or polymerase chain reaction (PCR) in 50% and 30% of water samples for animal and human consumption, respectively, from ten dairy goat farms in Brazil. IS1311 restriction fragment length polymorphism analysis identified the isolates as cattle type C. PMID- 29107586 TI - Ru/Fe bimetallic complexes: Synthesis, characterization, cytotoxicity and study of their interactions with DNA/HSA and human topoisomerase IB. AB - Three ruthenium/iron-based compounds, 1: [Ru(MIm)(bipy)(dppf)]PF6 (MIm = 2 mercapto-1-methylimidazole anion), 2: [RuCl(Im)(bipy)(dppf)]PF6 (Im = imidazole), and 3: [Ru(tzdt)(bipy)(dppf)]PF6 (tzdt = 1,3-thiazolidine-2-thione anion) (dppf = 1,1'-bis(diphenylphosphine)ferrocene and bipy = 2,2'-bipyridine), were synthesized, and characterized by elemental analyses, conductivity, UV/Vis, IR, 1H, 13C and 31P{1H} NMR spectroscopies, and by electrochemical technique. The complex 3 was also characterized by single-crystal X-ray. The three ruthenium(II) complexes show cytotoxicity against DU-145 (prostate carcinoma cells) and A549 (lung carcinoma cells) tumor cells. The free ligands do not exhibit any cytotoxic activity, such as evident by the IC50 values higher than 200 MUM. UV/Vis and viscosity experiments showed that the complexes interact weakly with the DNA molecule, via electrostatic forces. The interaction of the complexes 1-3 with the HSA is moderate, with Kb values in range of 105-107 M-1, presenting a static mechanism of interaction stabilized by hydrophobic. Complexes 2 and 3 showed high affinity for the FA7 HSA site as evidenced by fluorescence spectroscopy and molecular docking. Complexes 1-3 were tested as potential human Topoisomerase IB inhibitors by analysing the different steps of the enzyme catalytic cycle. The results indicate that all compounds efficiently inhibit the DNA relaxation and the cleavage reaction, in which the effect increases upon pre-incubation. Complexes 1 and 2 are also able to slow down the religation reaction. PMID- 29107587 TI - Women's Perceptions of Usefulness and Ease of Use of Four Healthy Eating Blog Characteristics: A Qualitative Study of 33 French-Canadian Women. AB - BACKGROUND: Healthy eating blogs are knowledge translation tools used by nutrition and dietetics practitioners for helping people improve their health behaviors and food choices. OBJECTIVE: Our aim was to explore women's perceptions of the usefulness and ease of use of healthy eating blog (HEB) characteristics that might increase potential users' intention to use them as tools to improve their dietary habits. DESIGN: We conducted qualitative research using semi structured individual interviews. PARTICIPANTS: Thirty-three women (mean age of 44 years; range=27 to 61 years) living in the Quebec City, Canada, metropolitan area were studied. INTERVENTION: Four existing HEBs, written by French-Canadian registered dietitians (RDs) whose main objective was the promotion of a healthy diet, were explored by women during individual interviews. A standardized open ended interview questionnaire based on the Technology Acceptance Model was used to identify women's perceptions about characteristics of type of blog content delivery, RD blogger's delivery of information, blog layout, and blog design. MAIN OUTCOME MEASURES: Women's perceptions toward the contribution of HEB characteristics to the usefulness and ease of use of those tools to improve their dietary habits were measured. ANALYSES PERFORMED: Interviews were audiorecorded, transcribed verbatim, coded, and analyzed through an inductive content analysis using NVivo software. RESULTS: The most useful characteristics of type of blog content delivery identified by women were recipes, hyperlinks, and references. Among characteristics of RD blogger's delivery of information, most women reported that interaction between blog readers and the RD blogger created a sense of proximity and of connection that was helpful for improving their dietary behaviors. Women's perceptions toward various characteristics of blog layout and design were also discussed. CONCLUSIONS: Incorporating specific characteristics when designing HEBs should be considered by RDs and future research to promote the use of those tools to support dietary behavior change efforts of internet users. PMID- 29107588 TI - Review of the Society of Thoracic Surgeons Congenital Heart Surgery Database: 2017 Update on Outcomes and Quality Implications for the Anesthesiologist. PMID- 29107589 TI - Metamizole and Platelet Inhibition by Aspirin Following On-Pump Coronary Artery Bypass Grafting. AB - OBJECTIVE: The purpose of the study was to evaluate the impact of intravenous metamizole on platelet inhibition by aspirin in patients with coronary artery disease early after on-pump coronary artery bypass grafting (CABG). DESIGN: Prospective, single-blind, randomized trial. SETTING: Tertiary referal hospital. PARTICIPANTS: The study comprised 43 patients with multivessel coronary artery disease undergoing CABG. INTERVENTIONS: Patients were randomized to postoperative intravenous metamizole +/- opioids (study group; n = 23) or opioids alone (control group; n = 20). Aspirin was withheld at least 7 days before the surgery and reinitiated (300 mg) immediately after the procedure prior to metamizole use, and continued daily thereafter (150 mg). Platelet function was evaluated using multielectrode impedance aggregometry (acid-induced platelet activation [ASPI] and collagen-induced platelet activation [COL] test), P-selectin expression and urinary 11-dehydro-thromboxane B2 (11-DTXB2) level at baseline, postoperative day (POD) 0, POD 1, POD 2, and POD 6. Residual platelet reactivity (RPR) was defined as ASPI test >400 AU*min. MEASUREMENTS AND MAIN RESULTS: In all study participants, postoperative ASPI test value moderately decreased (1058.2 v 966.6 AU*min, p = 0.047), urinary 11-DTXB2 level increased (923.4 v 4367.3 pg/mg, p < 0.001), and P-selectin expression and COL test value remained stable postprocedure. The decreases of ASPI (p = 0.146) and COL test (p = 0.642), and P selectin expression (p = 0.318) did not differ between both groups. Patients in the control group had higher postoperative increase of urinary 11-DTXB2 level (p = 0.001). The prevalence of RPR was high and comparable between study and control groups (day 1, 95.6% v 100%, p = 0.535; day 6, 100% v 90%, p = 0.21). Multivariate analysis revealed that metamizole use did not predict the fluctuations of ASPI and COL test values and P-selectin expression, yet it independently predicted postoperative change of 11-DTXB2 level (b = -0.518, p = 0.001). CONCLUSIONS: Intravenous metamizole preceded by a loading dose of aspirin did not modify platelet response to aspirin in the postoperative period after CABG. PMID- 29107590 TI - Human Pluripotent Stem Cell-Derived Cardiac Tissue-like Constructs for Repairing the Infarcted Myocardium. AB - High-purity cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are promising for drug development and myocardial regeneration. However, most hiPSC-derived CMs morphologically and functionally resemble immature rather than adult CMs, which could hamper their application. Here, we obtained high-quality cardiac tissue-like constructs (CTLCs) by cultivating hiPSC CMs on low-thickness aligned nanofibers made of biodegradable poly(D,L-lactic-co glycolic acid) polymer. We show that multilayered and elongated CMs could be organized at high density along aligned nanofibers in a simple one-step seeding process, resulting in upregulated cardiac biomarkers and enhanced cardiac functions. When used for drug assessment, CTLCs were much more robust than the 2D conventional control. We also demonstrated the potential of CTLCs for modeling engraftments in vitro and treating myocardial infarction in vivo. Thus, we established a handy framework for cardiac tissue engineering, which holds high potential for pharmaceutical and clinical applications. PMID- 29107591 TI - Naked Mole Rat Induced Pluripotent Stem Cells and Their Contribution to Interspecific Chimera. AB - Naked mole rats (NMRs) are exceptionally long-lived, cancer-resistant rodents. Identifying the defining characteristics of these traits may shed light on aging and cancer mechanisms. Here, we report the generation of induced pluripotent stem cells (iPSCs) from NMR fibroblasts and their contribution to mouse-NMR chimeric embryos. Efficient reprogramming could be observed under N2B27+2i conditions. The iPSCs displayed a characteristic morphology, expressed pluripotent markers, formed embryoid bodies, and showed typical differentiation patterns. Interestingly, NMR embryonic fibroblasts and the derived iPSCs had propensity for a tetraploid karyotype and were resistant to forming teratomas, but within mouse blastocysts they contributed to both interspecific placenta and fetus. Gene expression patterns of NMR iPSCs were more similar to those of human than mouse iPSCs. Overall, we uncovered unique features of NMR iPSCs and report a mouse-NMR chimeric model. The iPSCs and associated cell culture systems can be used for a variety of biological and biomedical applications. PMID- 29107592 TI - Generation of a Motor Nerve Organoid with Human Stem Cell-Derived Neurons. AB - During development, axons spontaneously assemble into a fascicle to form nerves and tracts in the nervous system as they extend within a spatially constrained path. However, understanding of the axonal fascicle has been hampered by lack of an in vitro model system. Here, we report generation of a nerve organoid composed of a robust fascicle of axons extended from a spheroid of human stem cell-derived motor neurons within our custom-designed microdevice. The device is equipped with a narrow channel providing a microenvironment that facilitates the growing axons to spontaneously assemble into a unidirectional fascicle. The fascicle was specifically made with axons. We found that it was electrically active and elastic and could serve as a model to evaluate degeneration of axons in vitro. This nerve organoid model should facilitate future studies on the development of the axonal fascicle and drug screening for diseases affecting axon fascicles. PMID- 29107593 TI - Escape from Pluripotency via Inhibition of TGF-beta/BMP and Activation of Wnt Signaling Accelerates Differentiation and Aging in hPSC Progeny Cells. AB - Human pluripotent stem cells (hPSCs) represent a potentially valuable cell source for applications in cell replacement therapy, drug development, and disease modeling. For all these uses, it is necessary to develop reproducible and robust protocols for differentiation into desired cell types. However, differentiation protocols remain unstable and inefficient, which makes minimizing the differentiation variance among hPSC lines and obtaining purified terminally differentiated cells extremely time consuming. Here, we report a simple treatment with three small molecules-SB431542, dorsomorphine, and CHIR99021-that enhanced hPSC differentiation into three germ layers with a chemically transitional embryoid-body-like state (CTraS). Induction of CTraS reduced the innate differentiation propensities of hPSCs (even unfavorably differentiated hPSCs) and shifted their differentiation into terminally differentiated cells, particularly neurons. In addition, CTraS induction accelerated in vitro pathological expression concurrently with neural maturation. Thus, CTraS can promote the latent potential of hPSCs for differentiation and potentially expand the utility and applicability of hPSCs. PMID- 29107594 TI - Genes Associated with Pancreas Development and Function Maintain Open Chromatin in iPSCs Generated from Human Pancreatic Beta Cells. AB - Current in vitro islet differentiation protocols suffer from heterogeneity and low efficiency. Induced pluripotent stem cells (iPSCs) derived from pancreatic beta cells (BiPSCs) preferentially differentiate toward endocrine pancreas-like cells versus those from fibroblasts (FiPSCs). We interrogated genome-wide open chromatin in BiPSCs and FiPSCs via ATAC-seq and identified ~8.3k significant, differential open chromatin sites (DOCS) between the two iPSC subtypes (false discovery rate [FDR] < 0.05). DOCS where chromatin was more accessible in BiPSCs (Bi-DOCS) were significantly enriched for known regulators of endodermal development, including bivalent and weak enhancers, and FOXA2 binding sites (FDR < 0.05). Bi-DOCS were associated with genes related to pancreas development and beta-cell function, including transcription factors mutated in monogenic diabetes (PDX1, NKX2-2, HNF1A; FDR < 0.05). Moreover, Bi-DOCS correlated with enhanced gene expression in BiPSC-derived definitive endoderm and pancreatic progenitor cells. Bi-DOCS therefore highlight genes and pathways governing islet-lineage commitment, which can be exploited for differentiation protocol optimization, diabetes disease modeling, and therapeutic purposes. PMID- 29107595 TI - Activation of the Aryl Hydrocarbon Receptor Interferes with Early Embryonic Development. AB - The transcriptional program of early embryonic development is tightly regulated by a set of well-defined transcription factors that suppress premature expression of differentiation genes and sustain the pluripotent identity. It is generally accepted that this program can be perturbed by environmental factors such as chemical pollutants; however, the precise molecular mechanisms remain unknown. The aryl hydrocarbon receptor (AHR) is a widely expressed nuclear receptor that senses environmental stimuli and modulates target gene expression. Here, we have investigated the AHR interactome in embryonic stem cells by mass spectrometry and show that ectopic activation of AHR during early differentiation disrupts the differentiation program via the chromatin remodeling complex NuRD (nucleosome remodeling and deacetylation). The activated AHR/NuRD complex altered the expression of differentiation-specific genes that control the first two developmental decisions without affecting the pluripotency program. These findings identify a mechanism that allows environmental stimuli to disrupt embryonic development through AHR signaling. PMID- 29107596 TI - Default Patterning Produces Pan-cortical Glutamatergic and CGE/LGE-like GABAergic Neurons from Human Pluripotent Stem Cells. AB - Default differentiation of human pluripotent stem cells has been promoted as a model of cortical development. In this study, a developmental transcriptome analysis of default-differentiated hPSNs revealed a gene expression program resembling in vivo CGE/LGE subpallial domains and GABAergic signaling. A combination of bioinformatic, functional, and immunocytochemical analysis further revealed that hPSNs consist of both cortical glutamatergic and CGE-like GABAergic neurons. This study provides a comprehensive characterization of the heterogeneous group of neurons produced by default differentiation and insight into future directed differentiation strategies. PMID- 29107598 TI - Bone metabolism in anorexia nervosa and hypothalamic amenorrhea. AB - Anorexia nervosa (AN) and hypothalamic amenorrhea (HA) are states of chronic energy deprivation associated with severely compromised bone health. Poor bone accrual during adolescence followed by increased bone loss results in lifelong low bone density, degraded bone architecture, and higher risk of fractures, despite recovery from AN/HA. Amenorrhea is only one of several compensatory responses to the negative energy balance. Other hypothalamic-pituitary hormones are affected and contribute to bone deficits, including activation of hypothalamic-pituitary-adrenal axis and growth hormone resistance. Adipokines, particularly leptin, provide information on fat/energy stores, and gut hormones play a role in the regulation of appetite and food intake. Alterations in all these hormones influence bone metabolism. Restricted in scope, current pharmacologic approaches to improve bone health have had overall limited success. PMID- 29107597 TI - Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming. AB - Naked mole rat (NMR) is a valuable model for aging and cancer research due to its exceptional longevity and cancer resistance. We observed that the reprogramming efficiency of NMR fibroblasts in response to OSKM was drastically lower than that of mouse fibroblasts. Expression of SV40 LargeT antigen (LT) dramatically improved reprogramming of NMR fibroblasts. Inactivation of Rb alone, but not p53, was sufficient to improve reprogramming efficiency, suggesting that NMR chromatin may be refractory to reprogramming. Analysis of the global histone landscape revealed that NMR had higher levels of repressive H3K27 methylation marks and lower levels of activating H3K27 acetylation marks than mouse. ATAC-seq revealed that in NMR, promoters of reprogramming genes were more closed than mouse promoters, while expression of LT led to massive opening of the NMR promoters. These results suggest that NMR displays a more stable epigenome that resists de differentiation, contributing to the cancer resistance and longevity of this species. PMID- 29107599 TI - Faecal calprotectin concentrations in young children with cystic fibrosis. PMID- 29107600 TI - Inflammation and host-pathogen interaction: Cause and consequence in cystic fibrosis lung disease. AB - Cystic Fibrosis (CF) lung disease is associated with dysregulation of host defence systems, which ultimately disrupts the balance between inflammation and resolution and leaves the host susceptible to repeated infection. However, the mechanisms underlying these defects are complex and continue to garner significant interest among the CF research community. This review explores emerging data on novel aspects of innate host defence with promising biomarker and therapeutic potential for CF lung disease. Improved understanding of inflammation and host defence against pathogens in patients and animal models during the progression of CF lung disease is pivotal for the discovery of new therapeutics that can limit and/or prevent damage from birth. PMID- 29107601 TI - Expression of sf1 and dax-1 are regulated by thyroid hormones and androgens during Silurana tropicalis early development. AB - Thyroid hormones (THs) and androgens have been shown to be extensively involved in sexual development; however, relatively little is known with regard to TH related and androgenic actions in sex determination. We first established expression profiles of three sex-determining genes (sf1, dax-1, and sox9) during the embryonic development of Western clawed frogs (Silurana tropicalis). Transcripts of sf1 and sox9 were detected in embryos before the period in which embryonic transcription commences indicating maternal transfer, whereas dax-1 transcripts were not detected until later in development. To examine whether TH status affects sex-determining gene expression in embryonic S. tropicalis, embryos were exposed to co-treatments of iopanoic acid (IOP), thyroxine (T4), or triiodothyronine (T3) for 96 h. Expression profiles of TH receptors and deiodinases reflect inhibition of peripheral deiodinase activity by IOP and recovery by T3. Relevantly, elevated TH levels significantly increased the expression of sf1 and dax-1 in embryonic S. tropicalis. Further supporting TH mediated regulation, examination of the presence and frequency of transcription factor binding sites in the putative promoter regions of sex-determining genes in S. tropicalis and rodent and fish models using in silico analysis also identified TH motifs in the putative promoter regions of sf1 and dax-1. Together these findings advocate that TH actions as early as the period of embryogenesis may affect gonadal fate in frogs. Mechanisms of TH and androgenic crosstalk in relation to the regulation of steroid-related gene expression were also investigated. PMID- 29107602 TI - Maternal ophthalmic artery Doppler ultrasonography in preeclampsia and pregnancy outcomes. AB - OBJECTIVE: To examine the association of ophthalmic artery (OA) Doppler measure - the ratio of velocity peaks (PR) - to adverse pregnancy outcomes in preeclampsia. STUDY DESIGN AND MAIN OUTCOMES: Prospective cohort study of 56 women with preeclampsia that underwent Doppler measurements of OA flow, medial to optic nerve. PR results were classified as normal (PR < 0.78), abnormal (PR 0.78-0.98), or highly abnormal (PR >= 0.99). Attending clinicians were blinded to OA Doppler results. The primary endpoints were (1) a composite of adverse maternal outcomes central nervous system injury (eclampsia or posterior reversible encephalopathy syndrome), HELLP syndrome, hypertensive crisis, maternal admission to the intensive care unit, and maternal death-and (2) a composite of adverse perinatal outcomes-birth weight <10th percentile for gestational age, neonatal acidemia, 5 min Apgar score <7, admission of infants weighing >2500 g to the neonatal intensive care, preterm birth <32 weeks, fetal or neonatal death. RESULTS: Adverse maternal outcomes became more frequent as the PR values increased (p=.005). The occurrence of hypertensive crisis after hospital admission (secondary endpoint) was also positively associated with PR values (p=.001). Adverse perinatal outcomes were not associated with PR values (p=.551), but women in the highly abnormal PR group (PR >= 0.99) had the earliest deliveries (p=.001) and the smallest newborns (p=.004). All women in the highly abnormal PR group (n=16) had an adverse outcome. CONCLUSIONS: Maternal OA Doppler PR >= 0.99 in preeclampsia may identify women at increased risk of adverse maternal outcomes and pregnancies at the greatest risk of preterm birth. PMID- 29107603 TI - Have you tried spermine? A rapid and cost-effective method to eliminate dextran sodium sulfate inhibition of PCR and RT-PCR. AB - The Dextran Sulfate Sodium (DSS) induced colitis mouse model is commonly used to investigate human inflammatory bowel disease (IBD). Nucleic acid extracts originating from these animals are often contaminated with DSS, which is a strong inhibitor of many enzymatic based molecular biology reactions including PCR and reverse-transcription (RT). Methods for removing DSS from nucleic acids extracts exist for RNA, but no effective protocol for DNA or cDNA is currently available. However, spermine has previously been shown to be an effective agent for counteracting DSS inhibition of polynucleotide kinase, which led to the hypothesis, that spermine could be used to counteract DSS inhibition of PCR and RT. We investigated the means of adding spermine in an adequate concentration to PCR based protocols (including qPCR, two-step RT-qPCR, and amplicon sequencing library preparation) to remove DSS inhibition. Within the range up to 0.01g/L, spermine can be added to PCR/qPCR or RT prophylactically without a significant reduction of reaction efficiency. Addition of spermine at the concentration of 0.08g/L can be used to recover qualitative PCR signal inhibited by DSS in concentrations up to 0.32g/L. For optimal quantitative analysis, the concentration of spermine requires fine adjustment. Hence, we present here a simple fluorometric based method for adjusting the concentration of spermine ensuring an optimal efficiency of the reaction exposed to an unknown concentration of DSS. In conclusion, we demonstrate a cost effective and easy method to counteract DSS inhibition in PCR and two-step RT-qPCR. Fixed or fine tuned concentrations of spermine can be administered depending on the qualitative or quantitative character of the analysis. PMID- 29107604 TI - The effect of membrane softeners on rigidity of lipid vesicle bilayers: Derivation from vesicle size changes. AB - Deformability is not just a fundamentally interesting vesicle characteristic; it is also the key determinant of vesicle ability to cross the skin barrier; i.e. skin penetrability. Development of bilayer vesicles for drug and vaccine delivery across the skin should hence involve optimization of this property, which is controllable by the concentration of bilayer softeners in or near the vesicle bilayers. To this end, we propose a simple method for quantifying the effect of bilayer softeners on deformability of bilayer vesicles. The method derives the bending rigidity of vesicle bilayers from vesicle size dependence on softener concentration. To exemplify the method, we studied mixtures of soybean phosphatidylcholine with anionic sodium deoxycholate, non-ionic polyoxyethylene (20) sorbitan oleyl ester (polysorbate 80), or non-ionic polyoxyethylene (20) oleyl ether (C18:1EO20, Brij(r) 98). With each of the tested bilayer softeners, the bending rigidity of the resulting mixed-amphipat vesicle bilayers decreased quasi-exponentially as the concentration of the bilayer softener increased, as one would expect on theoretical ground. The bilayer bending rigidity reached low values, near the thermal stability limit, i.e. kBT, before vesicle transformation into non-vesicular aggregates began. For a soybean phosphatidylcholine concentration of 5.0mmolkg-1, the bilayer bending rigidity reached 1.5kBT at the total deoxycholate concentration of 4.1mmolkg-1 and 3.4kBT at the total polysorbate 80 concentration of 2.0mmolkg-1. In the case of C18:1EO20, the bilayer bending rigidity reached 1.5kBT at the bilayer surface occupancy alpha=0.1. The dependence of vesicle size on bilayer softener concentration thus reveals vesicle transformation into different aggregate structures (such as mixed micelles with poor skin penetrability) and practically valuable information on vesicle deformability. Our results compare favorably with results of literature measurements. We provide practical guidance on using the new analytical method to optimize deformable vesicle formulations. PMID- 29107605 TI - Human health risks related to the consumption of foodstuffs of animal origin contaminated by bisphenol A. AB - Bisphenol A (BPA) is used in a wide variety of products and objects for consumers use (digital media such as CD's and DVD's, sport equipment, food and beverage containers, medical equipment). For humans, the main route of exposure to BPA is food. Based on previous estimates, almost 20% of the dietary exposure to BPA in the French population would be from food of animal origin. However, due to the use of composite samples, the source of the contamination had not been identified. Therefore, 322 individual samples of non-canned foods of animal origin were collected with the objectives of first updating the estimation of the exposure of the French population and second identifying the source of contamination of these foodstuffs using a specific analytical method. Compared to previous estimates in France, a decline in the contamination of the samples was observed, in particular with regard to meat. The estimated mean dietary exposures ranged from 0.048 to 0.050 MUg (kg bw)-1 d-1 for 3-17 year children and adolescents, from 0.034 to 0.035 MUg (kg bw)-1 d-1 for adults and from 0.047 to 0.049 MUg (kg bw)-1 d-1 for pregnant women. The contribution of meat to total dietary exposure of pregnant women, adults and children was up to three times lower than the previous estimates. Despite this downward trend in contamination, the toxicological values were observed to have been exceeded for the population of pregnant women. With the aim of acquiring more knowledge about the origin the potential source(s) of contamination of non-canned foods of animal origin, a specific analytical method was developed to directly identify and quantify the presence of conjugated BPA (BPA-monoglucuronide, BPA-diglucuronide and sulphate forms) in 50 samples. No conjugated forms of BPAs were detected in the analysed samples, indicating clearly that BPA content in animal food was not due to metabolism but arise post mortem in food. This contamination may occur during food production. However, despite extensive sampling performed in several different shops (butcheries, supermarkets .... ) and in different conditions (fresh, prepared, frozen ...), the source(s) of the contamination could not be specifically identified. PMID- 29107606 TI - Anti-atherosclerotic effect of Fermentum Rubrum and Gynostemma pentaphyllum mixture in high-fat emulsion- and vitamin D3-induced atherosclerotic rats. AB - BACKGROUND: The mixture of Hongqu and gypenosides (HG) is composed of Fermentum Rubrum (Hongqu, in Chinese) and total saponins of Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan, in Chinese) in a 3.6:1 weight ratio. Both Hongqu and Jiaogulan are considered valuable traditional Chinese medicines (TCMs); they have been commonly used in China for the treatment of hyperlipidemia and related diseases for centuries. The aim of the current study was assess the anti atherosclerotic effect of HG. METHODS: Sixty-four Wistar rats were randomly divided into eight groups: normal, model, positive control (simvastatin, 1 mg/kg), Hongqu-treated (72 mg/kg), gypenoside (total saponin)-treated (20 mg/kg), and three doses HG-treated (50, 100, and 200 mg/kg). All of the rats were fed a basal diet. Additionally, the model group rats were intragastrically administered a high-fat emulsion and intraperitoneally injected with vitamin D3. The serum lipid profiles, oxidative stress, inflammatory cytokine, and hepatic antioxidant levels were then determined. Furthermore, the liver histopathology and arterial tissue were analyzed, and the expression of hyperlipidemia- and atherosclerosis (AS)-related genes was measured using reverse transcription-polymerase chain reaction. RESULTS: The AS rat model was established after 80 days. Compared to the model group, the HG-treated groups showed an obvious improvement in the serum lipid profiles, oxidative stress, and inflammatory cytokine levels, and showed markedly increased hepatic total antioxidant capacity. Moreover, the expression of genes related to lipid synthesis and inflammation reduced and that of the genes related to lipid oxidation increased in the liver and arterial tissue, which also reflected an improved health condition. CONCLUSION: the anti atherosclerotic effects of HG were superior to those of simvastatin, Hongqu, and the gypenosides. Therefore, HG may be a useful anti-atherosclerotic TCM preparation. PMID- 29107607 TI - Emergence and mechanism of carbapenem-resistant Escherichia coli in Henan, China, 2014. AB - The emergence and dissemination of carbapenem-resistant Escherichia coli (E. coli) strains is a main risk for global public health, but little is known of carbapenemase producing E. coli in Henan, China. The study was undertaken to investigate the prevalence and mechanism of carbapenem-resistant E. coli strains in a hospital in Xinxiang, Henan, China, 2014. A total of 5 carbapenemase producing E. coli strains were screened from 1014 isolates. We found that they were all resistant to meropenem and imipenem. Amikacin showed the best sensitivity, with gentamicin coming up next. The positive rate of blaNDM was 80% (4/5). The sequencing results showed that two isolates belonged to blaNDM-1 whereas other 2 isolates carried the blaNDM-5. Other carbapenemase genes including blaIMP,blaVIM, blaKPC and blaOXA-48 were not detected. The blaCTX-M 15,blaTEM-1,sul2, aad, and aac(6")-Ib-cr were also detected. MLST analysis showed that NDM-producing E. coli were sporadic. Conjugation test indicated blaNDM could be transferred. In conclusion, the blaNDM was the principal resistance mechanism of carbapenem-resistant E. coli in the hospital, Henan, China. PMID- 29107608 TI - A fatal case of rhinocerebral mucormycosis of the jaw after dental extractions and review of literature. AB - The purpose of presenting this case is to report a fatal case of rhinocerebral mucormycosis post-dental extraction in a patient with uncontrolled diabetes mellitus. Several cases of rhinocerebral mucormycosis have been reported, but mucocutaneous mucormycosis has not been commonly reported to be a part of polymicrobial wound infections at multifocal sites. To the best of author's knowledge, this is the second case of polymicrobial rhinocerebral infection involving mucormycosis. PMID- 29107610 TI - Altered resting-state functional connectivity in patients with obsessive compulsive disorder: A magnetoencephalography study. AB - Aberrant cortical-striatal-thalamic-cortical circuits have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the neurobiological basis of OCD remains unclear. We compared patterns of functional connectivity in patients with OCD and in healthy controls using resting-state magnetoencephalography (MEG). Participants comprised 24 patients with OCD (21 men, 3 women) and 22 age- and sex-matched healthy controls (19 men, 3 women). Resting-state measurements were obtained over a 6-min period using a 152-channel whole-head MEG system. We examined group differences in oscillatory activity and distribution of functional cortical hubs based on the nodal centrality of phase locking value (PLV) maps. Differences in resting-state functional connectivity were examined through PLV analysis in selected regions of interest based on these two findings. Patients with OCD demonstrated significantly lower delta band activity in the cortical regions of the limbic lobe, insula, orbitofrontal, and temporal regions, and theta band activity in the parietal lobe regions than healthy controls. Patients with OCD exhibited fewer functional hubs in the insula and orbitofrontal cortex and additional hubs in the cingulate and temporo parietal regions. The OCD group exhibited significantly lower phase synchronization among the insula, orbitofrontal cortex, and cortical regions of the limbic lobe in all band frequencies, except in the delta band. Altered functional networks in the resting state may be associated with the pathophysiology of OCD. These MEG findings indicate that OCD is associated with decreased functional connectivity in terms of phase synchrony, particularly in the insula, orbitofrontal cortex, and cortical regions of the limbic lobe. PMID- 29107611 TI - SSR analysis of genetic diversity and structure of the germplasm of faba bean (Vicia faba L.). AB - Assessing the diversity and genetic structure of faba bean (Vicia faba L.) germplasm is essential to improve the quality and yield of this economically important crop. In this study, simple sequence repeats (SSRs) were utilized to evaluate the diversity and structure of 35 faba bean genotypes originating from three different geographical regions (Northern Africa, Eastern Africa, and Near East). All 15 SSR loci generated a total of 100 alleles. The allele number per locus varied from 4 to 11, with a mean of 6.67. The expected heterozygosity (He) of SSR loci ranged between 0.51 and 0.81, with a mean of 0.63. The PIC value also varied from 0.44 to 0.78, with an average of 0.58. The expected heterozygosity of 22 faba bean genotypes was higher than the observed one. Interestingly, AMOVA analysis showed that much of variability resided within accessions (79.2%). A highly significant difference among regions was also evidenced, and represented 5.3% of the total variation. Moreover, cluster analysis divided the 35 faba bean genotypes into two main clusters. The first main cluster comprised all faba bean genotypes originating from the Near East region, whereas the second main cluster comprised all the genotypes originating from the Northern and Eastern Africa regions, indicating that the Northern and Eastern African faba bean genotypes were more closely related to each other than to the Near East genotypes. Structure analysis also revealed that the 35 faba bean genotypes might be assigned to two populations, in complete accordance with cluster analysis data. In conclusion, this study showed high levels of diversity in the analysed genotypes of faba bean, and could be utilized in future breeding programmes to develop new cultivars of high yield. PMID- 29107612 TI - The protective effect of 2-(2-benzonfu-ranyl)-2-imidazoline against oxygen glucose deprivation in cultured rat cortical astrocytes. AB - Astrocytes play a pivotal role in neuronal survival in the setting of post ischemic brain inflammation, but the astrocyte-derived mediators of ischemic brain injury remain to be defined. 2-(2-Benzofu-ranyl)-2-imidazoline (2-BFI) is a newly discovered ligand for high-affinity imidazoline I2 receptors (I2Rs) mainly located on the mitochondrial outer membrane in astrocytes. We previously reported that in a rat model of cerebral ischemia-reperfusion injury, 2-BFI limits infarct volume, reduces neurological impairment scores, and inhibits neuronal apoptosis in the ischemic penumbra. This study was performed to clarify the underlying mechanism in an astrocyte oxygen-glucose deprivation (OGD) model. The results show that 2-BFI reduces lipid peroxidation and inhibits mitochondria apoptotic pathways. PMID- 29107609 TI - The utility of twins in developmental cognitive neuroscience research: How twins strengthen the ABCD research design. AB - The ABCD twin study will elucidate the genetic and environmental contributions to a wide range of mental and physical health outcomes in children, including substance use, brain and behavioral development, and their interrelationship. Comparisons within and between monozygotic and dizygotic twin pairs, further powered by multiple assessments, provide information about genetic and environmental contributions to developmental associations, and enable stronger tests of causal hypotheses, than do comparisons involving unrelated children. Thus a sub-study of 800 pairs of same-sex twins was embedded within the overall Adolescent Brain and Cognitive Development (ABCD) design. The ABCD Twin Hub comprises four leading centers for twin research in Minnesota, Colorado, Virginia, and Missouri. Each site is enrolling 200 twin pairs, as well as singletons. The twins are recruited from registries of all twin births in each State during 2006-2008. Singletons at each site are recruited following the same school-based procedures as the rest of the ABCD study. This paper describes the background and rationale for the ABCD twin study, the ascertainment of twin pairs and implementation strategy at each site, and the details of the proposed analytic strategies to quantify genetic and environmental influences and test hypotheses critical to the aims of the ABCD study. PMID- 29107613 TI - Bet-hedging against male-caused reproductive failures may explain ubiquitous cuckoldry in female birds. AB - The origin and maintenance of polyandry is one of the key unresolved questions in evolutionary biology. In particular, extra-pair paternity (EPP) due to polyandry is observed in most (socially-) monogamous female birds and the frequency of EPP is surprisingly high (up to 72% in a clutch on average in some species). Many case-by-case hypotheses have been presented to explain this phenomenon but a ubiquitous explanation is still lacking. One possible general explanation is bet hedging, which is a strategy to avoid the risk associated to mating with a single unsuitable male and thus to minimize the chances of complete reproductive failure by the female. Here, we present a mathematical solution to demonstrate that bet hedging polyandry becomes highly effective if the risk of extinction of a female lineage attributable to male deficiencies is high in small subpopulation or under limited mate availability. Therefore, cuckoldry or polyandry may be a female strategy to spread the risk of extinction of her genotype over multiple males. The results agree well with the observed EPP frequencies in natural populations and the results of a meta-population simulation model. Our theory contributes new insights applicable not only to birds but also to a broad taxonomic range of animals. PMID- 29107615 TI - The natural bile acid surfactant sodium taurocholate (NaTC) as a coformer in coamorphous systems: Enhanced physical stability and dissolution behavior of coamorphous drug-NaTc systems. AB - The amorphization of 18 different drugs on milling with one mole equivalent sodium taurocholate (NaTC) was investigated. In all cases the X-ray powder pattern showed an amorphous halo after milling at room temperature or after cryomilling and 14 of the 18 coamorphous drug-NaTC systems were physically stable for between one to eleven months under ambient storage conditions. In three cases, namely carbamazepine-NaTC, indomethacin-NaTC and mefenamic acid-NaTC, significant dissolution advantages over the crystalline drugs were observed, both for the freshly prepared samples and after storage for seven months. To understand the increased physical stability, infrared-, near-infrared and Raman spectroscopic studies were carried out. The effectiveness of NaTC as a coformer in a diverse range of coamorphous systems is attributed to its awkward molecular shape that hampers recrystallization and phase separation and its propensity to form a range of similar, yet different drug-coformer hydrogen bonding arrangements. PMID- 29107614 TI - Solid lipid nanoparticles as carriers for oral delivery of hydroxysafflor yellow A. AB - Hydroxysafflor yellow A (HSYA) is the main bioactive flavonoid extracted from the flower of Carthamus tinctorius L., which is widely used in traditional Chinese medicine for the treatment of myocardial ischemia and cerebral ischemia. HSYA has high water solubility but poor intestinal membrane permeability, resulting in low oral bioavailability. Currently, only HSYA sodium chloride injection has been approved for clinical use and oral formulations are urgently needed. In this study, HSYA solid lipid nanoparticles (SLNs) with the structure of w/o/w were prepared by a warm microemulsion process using approved drug excipients for oral delivery to increase the oral absorption of HSYA. The optimized HSYA SLNs are spherical with an average size of 214nm and the encapsulation efficiency is 55%. HSYA SLNs exhibited little cytotoxicity in Caco-2 and Hela cells, but increased the oral absorption of HSYA about 3.97-fold in rats, compared to HSYA water solution. In addition, cycloheximide pretreatment significantly decreased the oral absorption of HSYA delivered by SLNs. Importantly, the pharmacodynamics evaluation demonstrated that SLNs further decreased the infarct areas in rats. In conclude, SLNs could be a promising delivery system to enhance the oral absorption and pharmacological activities of HSYA. PMID- 29107616 TI - Chronic pain disrupts ability to work by interfering with social function: A cross-sectional study. AB - BACKGROUND AND AIMS: Some 100 million adults in the United States suffer from chronic pain. While research to date has focused primarily on pain interference with physical and psychological function and its effects on employment, few studies have examined the impact of pain interference on social functioning and its effects on employment. The aims of our study were to (1) evaluate the association between pain interference with ability to work and actual employment status among working age adults with chronic pain; and (2) evaluate pain interference with four types of functioning - cognitive, physical, psychological, and social - as possible mediators of pain interference with the ability to work. METHODS: Data were collected via a self-selected sample of individuals visiting the American Chronic Pain Association (ACPA) website. The final dataset included 966 respondents. We examined the association between pain interference with the ability to work and employment in a population with chronic pain. We then analyzed pain interference with four types of functioning, physical, psychological, cognitive, and social, for their impact on the ability to work. RESULTS: Pain interference with ability to work was significantly inversely associated with employment status, i.e., the less that pain interfered with one's ability to work, the greater the likelihood of being employed. Moreover, pain interference with ability to work was a stronger predictor of employment status than an individual's rating of their pain intensity. Pain interference with social functioning partially mediated the effects of pain interference with cognitive and physical functioning and fully mediated the effects of pain intensity and pain interference with psychological functioning on pain interference with the ability to work. Results suggest that pain interference with social function may be a significant contributor to pain interference with ability to work in working age adults with chronic pain. CONCLUSIONS: In the development of effective solutions to address the economic and societal burden of chronic pain, this paper highlights the role of social function as an important, yet frequently overlooked, contributor to chronic pain's effect on the ability to work. Our findings underscore the importance of an integrated biopsychosocial approach to managing chronic pain, especially when addressing ability to work. From a clinical standpoint, assessing and managing pain intensity is necessary but not sufficient in addressing the far-reaching negative consequences of chronic pain. IMPLICATIONS: The development of interventions that improve social function may improve the ability to work in adults with chronic pain. Likewise, sick leave should be prescribed restrictively in the management of chronic pain since it may further interfere with social functioning. PERSPECTIVE: This study highlights the importance of the assessment of pain interference with social function as a part of a comprehensive biopsychosocial approach to the evaluation and management of patients with chronic pain. Interventions that improve social function may improve the ability to work in this population. In addition, sick leave should be prescribed restrictively in the management of chronic pain since it by itself interferes with social functioning. PMID- 29107617 TI - Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination. AB - The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR-gamma receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination of its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to the coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the in vivosafety of the combination. PMID- 29107618 TI - Impact of tree priors in species delimitation and phylogenetics of the genus Oligoryzomys (Rodentia: Cricetidae). AB - The use of genetic data and tree-based algorithms to delimit evolutionary lineages is becoming an important practice in taxonomic identification, especially in morphologically cryptic groups. The effects of different phylogenetic and/or coalescent models in the analyses of species delimitation, however, are not clear. In this paper, we assess the impact of different evolutionary priors in phylogenetic estimation, species delimitation, and molecular dating of the genus Oligoryzomys (Mammalia: Rodentia), a group with complex taxonomy and morphological cryptic species. Phylogenetic and coalescent analyses included 20 of the 24 recognized species of the genus, comprising of 416 Cytochrome b sequences, 26 Cytochrome c oxidase I sequences, and 27 Beta Fibrinogen Intron 7 sequences. For species delimitation, we employed the General Mixed Yule Coalescent (GMYC) and Bayesian Poisson tree processes (bPTP) analyses, and contrasted 4 genealogical and phylogenetic models: Pure-birth (Yule), Constant Population Size Coalescent, Multiple Species Coalescent, and a mixed Yule-Coalescent model. GMYC analyses of trees from different genealogical models resulted in similar species delimitation and phylogenetic relationships, with incongruence restricted to areas of poor nodal support. bPTP results, however, significantly differed from GMYC for 5 taxa. Oligoryzomys early diversification was estimated to have occurred in the Early Pleistocene, between 0.7 and 2.6 MYA. The mixed Yule-Coalescent model, however, recovered younger dating estimates for Oligoryzomys diversification, and for the threshold for the speciation-coalescent horizon in GMYC. Eight of the 20 included Oligoryzomys species were identified as having two or more independent evolutionary units, indicating that current taxonomy of Oligoryzomys is still unsettled. PMID- 29107619 TI - Molecular phylogeny of Candidula (Geomitridae) land snails inferred from mitochondrial and nuclear markers reveals the polyphyly of the genus. AB - The genus Candidula (Geomitridae), consisting of 28 species in Western Europe as currently described, has a disjunct distribution in the Iberian Peninsula, Italy, the Balkans, the Aegean Islands, and one species on the Canary Islands. Although the genus is seemingly well defined by characters of the reproductive system, the relationships within the genus are still unclear and some authors have indicated a possible subgeneric division based on the internal morphology of the dart sac. Despite substantial phylogenetic incongruence, we present a well-resolved molecular phylogeny of Candidula based on two mitochondrial genes (COI and 16S rRNA), the nuclear rDNA region (5.8S rNRA + ITS2 + 28S rRNA) and seven additional nuclear DNA regions developed specifically for this genus (60SL13, 60SL17, 60SL7, RPL14, 40SS6, 60SL9, 60SL13a), in total 5595 bp. Six reciprocally monophyletic entities including Candidula species were recovered, grouping into two major clades. The incorporation of additional geomitrid genera allowed us to unequivocally demonstrate the polyphyly of the genus Candidula. One major clade grouped species from southern France and Italy with the widely distributed species C. unifasciata. The second major clade grouped all the species from the Iberian Peninsula, including C. intersecta and C. gigaxii. Candidula ultima from the Canary Islands was recovered as separated lineage within the latter clade and related to African taxa. The six monophyla were defined as six new genera belonging to different tribes within the Helicellinae. Thus, we could show that similar structures of the stimulatory apparatus of the genital system in different taxa do not necessarily indicate a close phylogenetic relationship in the Geomitridae. More genera of the family are needed to clarify their evolutionary relationships, and to fully understand the evolution of the stimulatory apparatus of the genital system within the Geomitridae. PMID- 29107620 TI - Lacking quality in research: Is behavioral neuroscience affected more than other areas of biomedical science? AB - There are many reasons why novel therapeutics fail in clinical trials but these failures are often attributed to lacking quality of preclinical data. These problems are not limited to any specific therapeutic area, academic or industrial research and are due in large part to several generic factors influencing research quality (e.g., related to definition of pre-specified endpoints, principles of study design and analysis, biased reporting, and lack of proper training). Yet, neuroscience drug discovery is often said to be affected more than the other fields. Within neuroscience, behavioral studies are the most blamed for being poorly designed, underpowered and mis-reported and there are indeed several factors that may be rather unique for behavioral research, such as a multitude of environmental conditions that are difficult to control and that are often not reported, ethical concerns about in vivo research and the pressure to reduce animal numbers, contributing to under-powered studies, and the complexity of study design and analysis, creating too much room for post hoc data massaging and selective reporting. Also, the blood-brain barrier as a frequently neglected complicating factor has to be considered in CNS research. The importance of these factors is increasingly recognized and urgent efforts are needed to demonstrate that behavioral methods of preclinical neuroscience research deliver results that can be as robust as with the non-behavioral methods Until this goal is achieved, behavioral neuroscience and neuroscience in general may be losing young talent, CNS drug discovery may lack the needed investment and this field may indeed be amongst the most affected by the current preclinical data quality crisis. PMID- 29107621 TI - Effectiveness of single-dose azithromycin to treat latent yaws: a longitudinal comparative cohort study. AB - BACKGROUND: Treatment of latent yaws is a crucial component of the WHO yaws eradication strategy to prevent relapse and the resulting transmission to uninfected children. We assessed the effectiveness of single-dose azithromycin to treat patients with latent yaws. METHODS: This population-based cohort study included children (age <20 years) living on Lihir Island, Papua New Guinea, with high-titre (rapid plasma reagin titre >=1:8) latent or active yaws, between April, 2013, and May, 2015. Latent yaws was defined as lack of suspicious skin lesions or presence of ulcers negative for Treponema pallidum subsp pertenue on PCR, and active yaws was defined as ulcers positive for T pertenue on PCR. All children received one oral dose of 30 mg/kg azithromycin. The primary endpoint was serological cure, defined as a two-dilution decrease in rapid plasma reagin titre by 24 months after treatment. Treatment of latent yaws was taken to be non inferior to that of active yaws if the lower limit of the two-sided 95% CI for the difference in rates was higher than or equal to -10%. This study is registered with ClinicalTrials.gov, number NCT01955252. FINDINGS: Of 311 participants enrolled, 273 (88%; 165 with latent yaws and 108 with active yaws) completed follow-up. The primary endpoint was achieved in 151 (92%) participants with latent yaws and 101 (94%) with active yaws (risk difference -2.0%, 95% CI 8.3 to 4.3), meeting the prespecified criteria for non-inferiority. INTERPRETATION: On the basis of decline in serological titre, oral single-dose azithromycin was effective in participants with latent yaws. This finding supports the WHO strategy for the eradication of yaws based on mass administration of the entire endemic community irrespective of clinical status. FUNDING: Newcrest Mining Limited and ISDIN laboratories. PMID- 29107622 TI - Single-dose azithromycin to treat latent yaws. PMID- 29107623 TI - Early symptom improvement at 10 sessions as a predictor of rTMS treatment outcome in major depression. AB - BACKGROUND: Predicting rTMS nonresponse could be helpful in sparing patients from futile treatment, and in improving use of limited rTMS resources. While several predictive biomarkers have been proposed, few are accurate for individual-level prediction; none have entered routine use. An alternative approach in pharmacotherapy predicts outcome from early response; patients showing minimal (e.g., <=20%) improvement at 2 weeks can be predicted as nonresponders with negative predictive values (NPV) > 80-90%. This approach has recently been extended to ECT, but never before to rTMS. OBJECTIVE: To assess the accuracy of 2 week clinical response in predicting rTMS treatment outcome. METHODS: We reviewed clinical symptom scores for 101 patients who underwent 20 sessions of dorsomedial prefrontal rTMS for unipolar major depression in a naturalistic retrospective case series, defining nonresponders both at the conventional <50% improvement criterion and at a more stringent <35% criterion. RESULTS: Patients achieving <20% improvement at session 10 were correctly predicted as nonresponders with NPVs of 88.2% by the conventional and 80.4% by the stringent criterion. Achieving <10% improvement at session 10 predicted nonresponse with NPVs of 89.5% and 86.8% by conventional and stringent criteria, respectively. Using the least-depressed score of either session 5 or 10, <20% improvement predicted nonresponse with NPVs of 91.3% and 82.6%, and <10% improvement predicted nonresponse with NPVs of 93.5% and 93.5%, by conventional and stringent criteria. CONCLUSION: For DMPFC-rTMS, a '<20% improvement at 2 weeks' rule concurred with previous pharmacotherapy and ECT studies on predicting nonresponse, and could prove useful for treatment decision-making in clinical settings. PMID- 29107624 TI - A simple and cost effective method for preparing FL and LG solutions. AB - PURPOSE: The purpose of this study was to develop a clinically feasible method for obtaining dye concentrations of 2% fluorescein (FL) and 1% lissamine green (LG) by soaking commercially available dye impregnated strips in saline. METHODS: Calibration curves were established to related known concentrations of dye to prepared FL fluorescence and LG absorbance. To determine the optimum number of dye strips and soaking times (preliminary testing), 1, 2, 3 FL or LG strips were soaked in 200 MUl commercially available saline for 0.5, 1, 2, 3, 4 and 5 min, using calibration curves to determine FL and LG concentrations. The best combination of number of dye strips and soaking time was soaking 3FL and 3LG strips for 5 min and these were finally tested in 2 ml centrifuge tubes, selected for ease of use in a clinical setting. RESULTS: Preliminary testing indicated that soaking 3 FL or 3 LG strips for 5 min in saline yielded an average (+/ standard deviation) of 2.0 +/- 0.000% FL and 0.93 +/- 0.010% LG. Final testing of FL in centrifuge tubes (strips soaked for 3-15 min) yielded an average of 1.99 +/ 0.040% FL, with no significant difference among time periods or dye lots tested. However, LG showed more variable results with an average of 0.80 +/- 0.160% LG (5 15 min), with significant differences among dye lots and times (2-way ANOVA, p < 0.05). CONCLUSIONS: This simple, reliable and relatively inexpensive method involves soaking 3 FL or LG strips in saline solution, yielding concentrations close to the 2%FL and 1%LG recommended for clinical trials, although LG showed more variability. PMID- 29107625 TI - Activation of ERK/CREB pathway in noradrenergic neurons contributes to hypernociceptive phenotype in H4 receptor knockout mice after nerve injury. AB - G-protein coupled receptor H4 (H4R) is a histamine receptor subtype that is involved in a condition of pathological chronic pain, but its pathophysiological function is unknown. Here, we investigate the role of H4R in a model of traumatic nerve injury. H4R knockout (H4R-/-) mice exposed to spared nerve injury (SNI) developed a more prominent mechanical and thermal hypersensitivity than wild type mice. Western blotting and immunofluorescence were used to characterize the cellular mechanisms. Nerve injury increased phosphorylated pERK MAPK expression in the spinal cord that was further promoted in H4R-/- genotype. Additionally, the increase in the phosphorylated cAMP response element-binding protein (CREB) was significantly enhanced in neuropathic H4R-/- mice. In the same way, after SNI a remarkable increase of dopamine beta-hydroxylase (DbetaH) immunoreactive neurons was detected in spinal cord of H4R-/- mice. The number of injured DRG neurons after SNI of H4R-/- mice, identified by activating transcription factor 3 (ATF3) staining was comparable to that of wild type littermates. Similarly the density of intraepidermal nerve fibres in plantar skin after SNI was reduced with the same degree in H4R-/- mice and with wild type mice. We conclude that the phenotype of H4R-/- mice leads to increased neuropathic pain hypersensitivity promoting an overactivation of spinal ERK-CREB pathway in DbetaH expressing neurons without modifying the innervation of the hind paw skin and integrity of the primary sensory neurons. In summary, our results provide H4R as a potential new target for the clinical management of chronic neuropathic pain conditions. PMID- 29107627 TI - Optimal 13C-labeling of glycerol carbon source for precise flux estimation in Escherichia coli. AB - Glycerol is a promising carbon source for bio-production and is particularly attractive because it is produced in excess as a biodiesel byproduct. Elucidating the flux distribution of glycerol catabolism would greatly aid metabolic engineering, but 13C-labeling of glycerol has not yet been optimized for precise flux estimations. In this study, an Escherichia coli wild type strain was aerobically cultured using glycerol as the sole carbon source. [1,3-13C], [2 13C], and [U-13C] glycerols were independently mixed with an equal amount of naturally labeled glycerol; these mixtures were used as 13C-labeled substrates, and flux distributions during exponential growth were estimated based on 13C enrichment of proteinogenic amino acids. The glycerol catabolism pathway in E. coli has four branches: the oxidative pentose phosphate pathway (PP), Entner Doudoroff pathway (ED), and malic enzyme (ME) pathways, and the glyoxylate shunt (GX). The 95% confidence intervals of these fluxes were compared across the 13C labeling experiments. The [2-13C] and [U-13C] glycerols, but not [1,3-13C] glycerol allowed precise characterization of the PP, ED, and ME pathway fluxes. All three types of 13C-labeling aided in successfully determining the GX flux. Based on the above estimated flux distribution, various patterns of 13C-labeling of glycerol were computationally generated. These in silico experiments revealed that the sole use of [2-13C] glycerol or [1,3-13C] glycerol is optimal for precise flux estimation, where simultaneous using glycerols with different types of 13C-labeling failed to improve flux estimation as assessed by confidence intervals. PMID- 29107626 TI - MRI measurements of Blood-Brain Barrier function in dementia: A review of recent studies. AB - Blood-brain barrier (BBB) separates the systemic circulation and the brain, regulating transport of most molecules to protect the brain microenvironment. Multiple structural and functional components preserve the integrity of the BBB. Several imaging modalities are available to study disruption of the BBB. However, the subtle changes in BBB leakage that occurs in vascular cognitive impairment and Alzheimer's disease have been less well studied. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is the most widely adopted non-invasive imaging technique for evaluating BBB breakdown. It is used as a significant marker for a wide variety of diseases with large permeability leaks, such as brain tumors and multiple sclerosis, to more subtle disruption in chronic vascular disease and dementia. DCE-MRI analysis of BBB includes both model-free parameters and quantitative parameters using pharmacokinetic modelling. We review MRI studies of BBB breakdown in dementia. The challenges in measuring subtle BBB changes and the state of the art techniques are initially examined. Subsequently, a systematic review comparing methodologies from recent in-vivo MRI studies is presented. Various factors related to subtle BBB permeability measurement such as DCE-MRI acquisition parameters, arterial input assessment, T1 mapping and data analysis methods are reviewed with the focus on finding the optimal technique. Finally, the reported BBB permeability values in dementia are compared across different studies and across various brain regions. We conclude that reliable measurement of low-level BBB permeability across sites remains a difficult problem and a standardization of the methodology for both data acquisition and quantitative analysis is required. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 29107628 TI - Increase in hydrophobicity of Bacillus subtilis spores by heat, hydrostatic pressure, and pressurized carbon dioxide treatments. AB - The effects of heat treatment (HT), hydrostatic pressure treatment (HPT), and pressurized carbon dioxide treatment (CT) on surface hydrophobicity of B. subtilis 168 spores were investigated. The spore surface hydrophobicity was measured by determining the ratio of hydrophobic spores (RHS) that were partitioned into the n-hexadecane phase from the aqueous spore suspension. The RHS after HT generally increased in a temperature-dependent manner and reached approximately 10% at temperatures above 60 degrees C. The effects of pressurization by HPT and accompanying temperature on increased RHS were complex. The highest RHS after HPT was approximately 17%. Following CT, RHS reached approximately 80% at 5 MPa at 80 degrees C for 30 min. An increased treatment temperature enhanced RHS by CT. The increase in RHS by CT led to the formation of spore clumps and adhesion of spores to hydrophobic surfaces. Acidification of spore suspension to pH 3.2, expected pH during CT, by HCl also increased the adhesion of spores at the similar degree with CT. The spore surface zeta potential distribution was not changed by CT. Furthermore, spores with increased RHS after CT had germination-like phenomena including loss of their refractility and enhanced staining by 4',6-diamidino-2-phenylindole. Physiological germination that was induced by the addition of l-alanine also increased the RHS. From these results, it is clear that CT under heating considerably increases RHS. CT under heating considerably increases RHS. This increase in RHS may be due to acidification or germination-like phenomena during CT. PMID- 29107629 TI - Simultaneous carbon and nitrogen removal from anaerobic effluent of the cassava ethanol industry. AB - This study investigated the simultaneous carbon and nitrogen removal from anaerobic effluent of cassava stillage using a lab-scale integrated system consisting of an upflow anaerobic sludge blanket (UASB) reactor and an activated sludge (AS) process. Simultaneous denitrification and methanogenesis (SDM) was observed in the UASB with nitrate recirculation. Compared with the blank reactor without recirculation, the overall chemical oxygen demand (COD) removal efficiencies in the combined system with nitrate recirculation were similar (80 90%), while the TN removal efficiencies were significantly improved from 4.7% to 71.0%. Additionally, the anaerobic COD removal efficiencies increased from 21% to 40% as the recirculation ratio decreased from 3 to 1. Although the influent nitrate concentrations fluctuated (60-140 mg N/L), the nitrate removal efficiencies could be maintained at about 97% under different recirculation conditions. With the decreasing recirculation ratio from 3 to 1, the CH4 content in biogas improved from 2% to 40% while the N2 content reduced from 95.8% to 50.6%. The 16S rDNA sequencing results indicated that bacteria diversity in anaerobic SDM granular sludge was much higher than archaea. The effect of recirculation ratios on the bacterial and archaeal communities in SDM granular sludge could be further confirmed by the relative abundance of denitrifying bacteria. PMID- 29107630 TI - Surgical hand preparation with chlorhexidine soap or povidone iodine: new methods to increase immediate and residual effectiveness, and provide a safe alternative to alcohol solutions. AB - BACKGROUND: Surgical use of 4% chlorhexidine soap (CHX-4) and 10% povidone iodine (PVP-I-10) does not meet the standards defined by EN 12791. AIM: To investigate the possibility of increasing the immediate and residual effects of these antiseptics. METHODS: Over three consecutive weeks, n-propanol, standard CHX-4 and PVP-I-10 were tested in two experimental groups of volunteers. The new method for applying the antiseptic substances involved standard hand rub and rinse of CHX-4 or PVP-I-10, followed by application of an aqueous solution based on 5% chlorhexidine or PVP-I-10 with no further rinsing of the hands prior to donning gloves. Samples were taken to assess immediate and residual effects, analysing the logarithmic reduction of colony-forming units. FINDINGS: At t=0 h, n-propanol was superior in bactericidal effect to standard CHX-4 (P<0.05), but the new chlorhexidine protocol was superior to both standard CHX-4 (P<0.01) and n propanol (P<0.05); the same effect was observed at t=3 h (residual effect). At t=0 h, n-propanol was significantly superior to standard PVP-I-10, but the new PVP-I-10 protocol was superior, although not significantly, to n-propanol. There was no significant residual effect at t=3 h. CONCLUSION: The new protocol for chlorhexidine application permits surgical hand preparation with chlorhexidine, as a safe alternative to alcohol solutions, because it meets the standards defined by EN 12791. PMID- 29107631 TI - Cryopreservation of sperm from the coral Acropora humilis. AB - Corals are sensitive to minute changes in their environments, and their continued existence is substantially threatened by the increasing number of destructive anthropogenic activities and unprecedented rates of climate change. Although cryopreservation has been successfully to preserve mammalian gametes for decades, coral cryopreservation was attempted for the first time less than 15 years ago, and freezing protocols exist for only a handful of coral species. The present study developed a cryopreservation protocol for the sperm of the common Indo Pacific reef-builder Acropora humilis. Colonies of reefs of Sattahip Bay, Chonburi Province, Thailand were collected from 3 m depth with a mesh net during a spawning event. Immediately after collection, the sperm were isolated and subjected to a two-step freezing method featuring DMSO, polyethylene glycol, or methanol as the cryoprotectant. Viability and motility were assessed via a bioluminescence technique and a "computer-assisted semen analysis, and it was found that a 15-min equilibration with 2 M DMSO followed by cooling at 41.7 degrees C was the optimum cryopreservation protocol for A. humilis sperm. The post-thaw sperm achieved 45% fertilization success, and 35% of the fertilized eggs developed into blastopore larvae. The present optimized protocol can therefore facilitate the preservation of sperm for future propagation efforts of this species and provide an experimental platform for optimizing cryopreservation protocols for gametes of other scleractinian coral species. PMID- 29107632 TI - Keratin biomaterials augment anti-inflammatory macrophage phenotype in vitro. AB - : Tissue regeneration following injury is mediated by macrophage recruitment and differentiation in response to environmental signals. In general, macrophages adopt either a classically M1 (M[IFN-gamma, LPS]) or alternatively activated M2 (M[IL-4, IL-13] or M[IL-10]) phenotype. Recent studies have highlighted the importance of alternatively activated macrophages in tissue remodeling and repair as well as the contribution of an imbalance of classically and alternatively activated macrophages to tissue degeneration and disease progression. Keratin biomaterials have recently demonstrated their ability to promote alternatively activated macrophage polarization in an in vitro model using a monocytic cell line. In the present study, the ability of extracted human hair keratins to influence alternative activation of human primary monocytes in vitro is assessed by evaluating changes in surface receptor expression, inflammatory cytokine secretion, and phagocytic activity. The impact of keratin molecular weight fractionation on these outcomes was also investigated. High and low molecular weight fractions of the oxidized form of extractable human hair keratins - referred to as keratose (KOSH and KOSP, respectively) - were characterized by size exclusion chromatography, mass spectrometry, and Western blot. Primary macrophages underwent traditional differentiation to the M[IFN-gamma, LPS], M[IL 4, IL-13], or M[IL-10]) phenotypes or were plated on different molecular weight keratin coatings (KOSH and KOSP). Macrophages plated on keratin and analyzed via flow cytometry yielded the largest CD163+ cell populations and CD163 mean fluorescence intensities. Cells in the KOSP group were significantly more phagocytic than all other cell types at the 1.5 and 3 h time points and exhibited behavior and a cytokine production profile most similar to the M[IL-10] treated group. These findings may have important implications for understanding and evaluating the ability of keratin biomaterials to influence inflammation and tissue regeneration in disease and injury models. STATEMENT OF SIGNIFICANCE: Biomaterials made from human hair keratins have previously been shown to elicit anti-inflammatory responses from naive macrophages and polarize them toward an M2 phenotype. In this work we show for the first time that primary human cells respond similarly, that it is the M2c phenotype that predominates, that a sub fraction of hydrolyzed keratin peptides are most likely responsible for the response, and that immobilization of the keratin peptides to a surface is required. Keratin biomaterials have been used to regenerate several tissues such as skin, muscle, bone, nerve, and cornea, in vitro and in animal studies. Our current findings will help guide the development of keratin-based biomaterials that seek to direct responses toward regenerative outcomes by attenuating inflammation. PMID- 29107633 TI - Babesiosis - of joint Romanian and US ancestry. PMID- 29107634 TI - Unusual Intracranial Arterial Calcification and Vitamin D Deficiency. AB - Although intracranial arterial calcifications (IACs) are encountered in approximately 85% of patients with acute ischemic stroke (IS), the significance of IAC in plaque instability is still controversial. Because most tissues including brain tissue have vitamin D receptors, vitamin D deficiency might play multiple roles in variable sites. Here, we report a novel presentation of IS with IAC including anterior cerebral artery involvement due to vitamin D deficiency. In conclusion, although the role of IAC in cerebral infarction is still controversial, we suggest that insufficient vitamin D should be examined and treated appropriately in all patients with IS. We believe that this article provides important implications for the treatment of vitamin D deficiency in patients with IS. PMID- 29107635 TI - Predictors of Need for Critical Care Support, Adverse Events, and Outcome after Stroke Thrombolysis. AB - BACKGROUND: Results from trials and international registries exhibit heterogeneity regarding safety, efficacy, markers of prognosis, and markers of the need for critical care support after intravenous thrombolysis (IVT) for strokes. The purpose of our study was to indentify such markers after performance of comparisons among patients who received thrombolysis in our intensive care unit. MATERIALS AND METHODS: Our study included 124 patients who received IVT in accordance with international criteria. Outcome measures of univariate and regression analyses resulted from comparisons between groups of patients with or without the need for critical care support (advanced life support and neurocritical care interventions), groups of patients developing or not developing primary adverse events (symptomatic intracranial hemorrhage [SICH] and/or Death and/or Serious systemic bleeding and/or New stroke) and groups of patients with different main outcome variables (mortality, functional independence at 3 months). RESULTS: Our results suggested that higher severity scores (Simplified Acute Physiology Score II, National Institutes of Health Stroke Scale) correlated with the need for critical care support, primary adverse events, and main outcome variables, whereas older age was significantly associated with fewer adverse events. Hyperlipidemia, symptom-to-needle time, and vascular disease were associated with functional capacity at 3 months, whereas diabetes mellitus and vascular disease correlated with the need for critical care support. CONCLUSION: Patients' age, hyperlipidemia, presence of vascular disease, Simplified Acute Physiology Score II (a novel marker), and National Institutes of Health Stroke Scale at 2 hours and at 7 days are independent predictors of the need for critical care support, adverse events, and clinical outcomes after thrombolysis. PMID- 29107636 TI - Impact of Side Branches on the Computation of Fractional Flow in Intracranial Arterial Stenosis Using the Computational Fluid Dynamics Method. AB - BACKGROUND: Computational fluid dynamics (CFD) allows noninvasive fractional flow (FF) computation in intracranial arterial stenosis. Removal of small artery branches is necessary in CFD simulation. The consequent effects on FF value needs to be judged. METHODS: An idealized vascular model was built with 70% focal luminal stenosis. A branch with one third or one half of the radius of the parent vessel was added at a distance of 5, 10, 15 and 20 mm to the lesion. With pressure and flow rate applied as inlet and outlet boundary conditions, CFD simulations were performed. Flow distribution at bifurcations followed Murray's law. By including or removing side branches, five patient-specific intracranial artery models were simulated. Transient simulation was performed on a patient specific model, with a larger branch for validation. Branching effect was considered trivial if the FF difference between paired models (branches included or removed) was within 5%. RESULTS: Compared with the control model without a branch, in all idealized models the relative differences of FF was within 2%. In five pairs of cerebral arteries (branches included/removed), FFs were 0.876 and 0.877, 0.853 and 0.858, 0.874 and 0.869, 0.865 and 0.858, 0.952 and 0.948. The relative difference in each pair was less than 1%. In transient model, the relative difference of FF was 3.5%. CONCLUSION: The impact of removing side branches with radius less than 50% of the parent vessel on FF measurement accuracy is negligible in static CFD simulations, and minor in transient CFD simulation. PMID- 29107637 TI - Overlapped Stenting Is Associated with Postoperative Hypotension after Carotid Artery Stenting. AB - BACKGROUND: Hypotension (HT) is well recognized to frequently occur during and after carotid artery stenting (CAS), which sometimes causes postoperative complications such as stroke or myocardial infarction. This study aimed to examine the risk factors associated with HT after CAS based on the hypothesis that overlapped stenting may affect postoperative HT. METHODS: A total of 106 lesions in 95 patients with carotid artery stenosis who underwent CAS were reviewed. Bradycardia and HT were defined as a heart rate and a systolic blood pressure less than 60 beats/min and 100 mm Hg, respectively. The patients were categorized by the presence (group H) or the absence (group N) of postoperative HT, respectively, and demographic data, risk factors, conditions of carotid artery stenosis, procedures, and pre- and intraoperative hemodynamics were compared between these 2 groups. Multivariate analysis was performed to evaluate independent factors associated with postoperative HT. RESULTS: In total, postoperative HT was observed in 30 (28.3%) cases. The incidence of overlapped stenting, the use of an open-cell stent, and intraoperative HT were significantly higher in group H (P = .03, .01 and < .01, respectively). The distance from carotid bifurcation and the maximum stenotic lesion tended to be shorter in group H (P = .09). In the multivariate logistic regression analysis, using all these variables, the overlapped stenting and intraoperative HT were found to be independent predictors for postoperative HT. CONCLUSION: The overlapped stenting affected postoperative HT after CAS. Blood pressure should be strictly controlled in cases with overlapped stenting or intraoperative HT after CAS. PMID- 29107638 TI - Herniation despite Decompressive Hemicraniectomy in Large Hemispherical Ischemic Strokes. AB - BACKGROUND: Despite decompressive hemicraniectomy (DHC), progressive herniation resulting in death has been reported following middle cerebral artery (MCA) strokes. We aimed to determine the surgical parameters measured on brain computed tomography (CT) scan that are associated with progressive herniation despite DHC in large MCA strokes. METHODS: Retrospective chart review of medical records of patients with malignant hemispheric infarction who underwent DHC for cerebral edema was performed. Infarct volume was calculated on CT scans obtained within 24 hours of ictus. Radiological parameters of craniectomy bone flap size, brain volume protruding out of the skull, adequate centering of the craniectomy over the stroke bed, and the infarct volume outside the craniectomy bed (volume not centered [VNC]) were measured on the postoperative brain CT. RESULTS: Of 41 patients who underwent DHC, 7 had progressive herniation leading to death. Radiographic parameters significantly associated with progressive herniation included insufficient centering of craniectomy bed on the stroke bed (P = .03), VNC (P = .011), additional anterior cerebral artery infarction (P = .047), and smaller craniectomy length (P = .05). Multivariate logistic regression analysis for progressive herniation using craniectomy length and VNC as independent variables demonstrated that a higher VNC was significantly associated with progressive herniation despite surgery (P = .029). CONCLUSIONS: In large MCA strokes, identification of large infarct volume outside the craniectomy bed was associated with progressive herniation despite surgery. These results will need to be verified in larger prospective studies. PMID- 29107639 TI - cJun N-terminal kinase (JNK) mediates cortico-striatal signaling in a model of Parkinson's disease. AB - The cJun N-terminal kinase (JNK) signaling pathway has been extensively studied with regard to its involvement in neurodegenerative processes, but little is known about its functions in neurotransmission. In a mouse model of Parkinson's disease (PD), we show that the pharmacological activation of dopamine D1 receptors (D1R) produces a large increase in JNK phosphorylation. This effect is secondary to dopamine depletion, and is restricted to the striatal projection neurons that innervate directly the output structures of the basal ganglia (dSPN). Activation of JNK in dSPN relies on cAMP-induced phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32), but does not require N-methyl-d-aspartate (NMDA) receptor transmission. Electrophysiological experiments on acute brain slices from PD mice show that inhibition of JNK signaling in dSPN prevents the increase in synaptic strength caused by activation of D1Rs. Together, our findings show that dopamine depletion confers to JNK the ability to mediate dopamine transmission, informing the future development of therapies for PD. PMID- 29107640 TI - Analysis of network motifs in cellular regulation: Structural similarities, input output relations and signal integration. AB - Much of the complexity of regulatory networks derives from the necessity to integrate multiple signals and to avoid malfunction due to cross-talk or harmful perturbations. Hence, one may expect that the input-output behavior of larger networks is not necessarily more complex than that of smaller network motifs which suggests that both can, under certain conditions, be described by similar equations. In this review, we illustrate this approach by discussing the similarities that exist in the steady state descriptions of a simple bimolecular reaction, covalent modification cycles and bacterial two-component systems. Interestingly, in all three systems fundamental input-output characteristics such as thresholds, ultrasensitivity or concentration robustness are described by structurally similar equations. Depending on the system the meaning of the parameters can differ ranging from protein concentrations and affinity constants to complex parameter combinations which allows for a quantitative understanding of signal integration in these systems. We argue that this approach may also be extended to larger regulatory networks. PMID- 29107641 TI - Genetic coding algorithm for sense and antisense peptide interactions. AB - Sense and antisense peptides, i.e. peptides specified by complementary DNA and RNA sequences, interact with increased probability. Biro, Blalock, Mekler, Root Bernstein and Siemion investigated the recognition rules of peptide-peptide interaction based on the complementary coding of DNA and RNA sequences in 3'->5' and 5'->3' directions. After more than three decades of theoretical and experimental investigations, the efficiency of this approach to predict peptide peptide binding has been experimentally verified for more than 50 ligand-receptor systems, and represents a promising field of research. The natural genetic coding algorithm for sense and antisense peptide interactions combines following elements: of amino acid physico-chemical properties, stereochemical interaction, and bidirectional transcription. The interplay of these factors influences the specificity of sense-antisense peptide interactions, and affects the selection and evolution of peptide ligand-receptor systems. Complementary mRNA codon-tRNA anticodon complexes, and recently discovered Carter-Wolfenden tRNA acceptor-stem code, provide the basis for the rational modeling of peptide interactions based on their hydrophobic and lipophilic amino acid physico-chemical properties. It is shown that the interactions of complementary amino acid pairs according to the hydrophobic and lipophilic properties strongly depend on the central (second) purine base of the mRNA codon and its pyrimidine complement of the tRNA anticodon. This enables the development of new algorithms for the analysis of structure, function and evolution of protein and nucleotide sequences that take into account the residue's tendency to leave water and enter a nonpolar condensed phase considering its mass, size and accessible surface area. The practical applications of the sense-antisense peptide modeling are illustrated using different interaction assay types based on: microscale thermophoresis (MST), tryptophan fluorescence spectroscopy (TFS), nuclear magnetic resonance spectroscopy (NMR), and magnetic particles enzyme immunoassay (MPEIA). Various binding events and circumstances were considered, e.g., in situations with-short antisense peptide ligand (MST), L- and D-enantiomer acceptors (TFS), in low affinity conditions (NMR), and with more than one antisense peptide targeting hormone (MPEIA). PMID- 29107643 TI - Nuclear TRIM25 Specifically Targets Influenza Virus Ribonucleoproteins to Block the Onset of RNA Chain Elongation. AB - TRIM25 is an E3 ubiquitin ligase that activates RIG-I to promote the antiviral interferon response. The NS1 protein from all strains of influenza A virus binds TRIM25, although not all virus strains block the interferon response, suggesting alternative mechanisms for TRIM25 action. Here we present a nuclear role for TRIM25 in specifically restricting influenza A virus replication. TRIM25 inhibits viral RNA synthesis through a direct mechanism that is independent of its ubiquitin ligase activity and the interferon pathway. This activity can be inhibited by the viral NS1 protein. TRIM25 inhibition of viral RNA synthesis results from its binding to viral ribonucleoproteins (vRNPs), the structures containing individual viral RNA segments, the viral polymerase, and multiple viral nucleoproteins. TRIM25 binding does not inhibit initiation of capped-RNA primed viral mRNA synthesis by the viral polymerase. Rather, the onset of RNA chain elongation is inhibited because TRIM25 prohibits the movement of RNA into the polymerase complex. PMID- 29107642 TI - Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria. AB - Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRalpha1.7 domains. Furthermore, a recombinant CIDRalpha1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR binding CIDRalpha1 domains in brain swelling. PMID- 29107644 TI - The Glycolytic Pyruvate Kinase Is Recruited Directly into the Viral Replicase Complex to Generate ATP for RNA Synthesis. AB - Viruses accomplish their replication by exploiting many cellular resources, including metabolites and energy. Similarly to other (+)RNA viruses, tomato bushy stunt virus (TBSV) induces major changes in infected cells. However, the source of energy required to fuel TBSV replication is unknown. We find that TBSV co-opts the cellular glycolytic ATP-generating pyruvate kinase (PK) directly into the viral replicase complex to boost progeny RNA synthesis. The co-opted PK generates high levels of ATP within the viral replication compartment at the expense of a reduction in cytosolic ATP pools. The ATP generated by the co-opted PK is used to promote the helicase activity of recruited cellular DEAD-box helicases, which are involved in the production of excess viral (+)RNA progeny. Altogether, recruitment of PK and local production of ATP within the replication compartment allow the virus replication machinery an access to plentiful ATP, facilitating robust virus replication. PMID- 29107645 TI - Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy. AB - INTRODUCTION: The finding of mutations of the COQ2 gene and reduced coenzyme Q10 levels in the cerebellum in multiple system atrophy (MSA) suggest that coenzyme Q10 is relevant to MSA pathophysiology. Two recent studies have reported reduced coenzyme Q10 levels in plasma and serum (respectively) of MSA patients compared to Parkinson's disease and/or control subjects, but with largely overlapping values, limited comparison with other parkinsonisms, or dependence on cholesterol levels. We hypothesized that cerebrospinal fluid (CSF) is reliable to assess reductions in coenzyme Q10 as a candidate biomarker of MSA. METHODS: In this preliminary cross-sectional study we assessed CSF coenzyme Q10 levels in 20 patients with MSA from the multicenter Catalan MSA Registry and of 15 PD patients, 10 patients with progressive supranuclear palsy (PSP), and 15 control subjects from the Movement Disorders Unit Biosample Collection of Hospital Clinic de Barcelona. A specific ELISA kit was used to determine CSF coenzyme Q10 levels. CSF coenzyme Q10 levels were compared in MSA vs. the other groups globally, pair wise, and by binary logistic regression models adjusted for age, sex, disease severity, disease duration, and dopaminergic treatment. RESULTS: CSF coenzyme Q10 levels were significantly lower in MSA than in other groups in global and pair wise comparisons, as well as in multivariate regression models. Receiver operating characteristic curve analyses yielded significant areas under the curve for MSA vs. PD, PSP and controls. CONCLUSIONS: These findings support coenzyme Q10 relevance in MSA. Low CSF coenzyme Q10 levels deserve further consideration as a biomarker of MSA. PMID- 29107646 TI - Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability. AB - Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency. A four generation family from Japan, including 12 members, was investigated clinically and genetically. Seven affected members displayed pure spastic paraplegia. Impression of genetic anticipation was observed in the family, including tendency of earlier age-at-onset and increasing severity in subsequent generations. Genetic analysis revealed a heterozygous intronic variant, c.303+2T > A, in REEP1, which segregated with disease, and was also identified in one unaffected member. The variant causes exon 4 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products. Measurement of REEP1 transcripts in lymphocytes demonstrated a reduction through nonsense mediated mRNA decay (NMD). Our study demonstrated further evidence of allelic heterogeneity in SPG31, mutant REEP1 mRNA dosage effects through NMD and intra-familial phenotype variability. PMID- 29107647 TI - Muscle-protective effects of Schisandrae Fructus extracts in old mice after chronic forced exercise. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schisandrae Fructus (SF), the dried fruit of Schisandra chinensis (Turcz.) Baill., is a well-known traditional herb used in Asia for enhancing physical work capacity as well as providing anti-stress and anti-inflammatory effects. Extracts of SF (SFe) have also been reported to increase skeletal muscle mass and inhibit muscle atrophy. AIM OF THE STUDY: We examined whether SFe had muscle-protective effects in old mice after chronic forced exercises, and, if so, relevant mechanisms. MATERIALS AND METHODS: Ten month-old aged male mice were divided into six groups. One group received no forced swimming after oral administration of distilled water (Intact); the other groups received forced swimming after administration of distilled water (SW), oxymetholone (OXY), or SFe at 500, 250 and 125mg/kg (SFe500, SFe250, and SFe125, respectively). Forced swimming was conducted for 2min at 30min after oral administration; the treatment was repeated for 28 days. Muscle thickness, weight, lean proportion, and strength were examined. The sampled muscles were subjected to histopathological and biochemical analyses. Plasma was examined by biochemical analyses. RESULTS: The thicknesses of the calf muscle and the sampled gastrocnemius and soleus, protein proportion and muscle strength increased significantly in the SW group versus Intact, and they were further increased in the SFe and OXY groups versus SW. The forced swimming in the SW group upregulated mRNA expression related to protein synthesis (Akt1, PI3K) and muscle growth (A1R, TRPV4), while it downregulated mRNAs related to protein degradation (atrogin-1, MuRF1) and muscle growth inhibitor (myostatin, SIRT1). The detected upregulation and downregulation were enhanced in the SFe groups. In addition, the SFe administration inhibited lipid peroxidation and reactive oxygen species, and accelerated activities of endogenous anti-oxidants and anti-oxidant enzymes. Plasma biochemistry showed decreases in creatine, creatine kinase and LDH in the SFe groups versus SW, suggesting muscle-protective effects of SFe. In the SFe groups versus SW, histopathological analyses revealed an increase in myofibre diameter, and immunohistochemistry showed increases in myofibres immunoreactive for ATPase and decreases in myofibres for apoptosis markers (caspase-3, PARP) and oxidative stress markers (NT, 4HNE, iNOS). CONCLUSIONS: Oral administration of SFe, especially SFe500, enhanced exercise-induced adaptive muscle strengthening in aged mice after forced swimming through anti-apoptotic and anti-oxidant effects, mediated via modulation of gene expression related to muscle synthesis or degradation. These results suggest that SFe may be helpful in improvement various muscle disorders as an adjuvant therapy to exercise-based remedies. PMID- 29107649 TI - [Do laymen understand information about hospital quality? An empirical verification using risk-adjusted mortality rates as an example]. AB - INTRODUCTION: The effect of public reporting to improve quality in healthcare is reduced by the limited intelligibility of information about the quality of healthcare providers. This may result in worse health-related choices especially for older people and those with lower levels of education. There is, as yet, little information as to whether laymen understand the concepts behind quality comparisons and if this comprehension is correlated with hospital choices. METHODS: An instrument with 20 items was developed to analyze the intelligibility of five technical terms which were used in German hospital report cards to explain risk-adjusted death rates. Two online presentations of risk-adjusted death rates for five hospitals in the style of hospital report cards were developed. An online survey of 353 volunteers tested the comprehension of the risk-adjusted mortality rates and included an experimental hospital choice. RESULTS: The intelligibility of five technical terms was tested: risk-adjusted, actual and expected death rate, reference range and national average. The percentages of correct answers for the five technical terms were in the range of 75.0-60.2%. Between 23.8% and 5.1% of the respondents were not able to answer the question about the technical term itself. The least comprehensible technical terms were "risk-adjusted death rate" and "reference range". The intelligibility of the 20 items that were used to test the comprehension of the risk-adjusted mortality was between 89.5% and 14.2%. The two items that proved to be least comprehensible were related to the technical terms "risk-adjusted death rate" and "reference range". For all five technical terms it was found that a better comprehension correlated significantly with better hospital choices. DISCUSSION: We found a better than average intelligibility for the technical terms "actual and expected death rate" and for "national average". The least understandable were "risk-adjusted death rate" and "reference range". Since the self-explanatory technical terms "actual and expected death rate" and "national average" are easy to understand and the comprehension is correlated with hospitals choices, we recommend using them for the presentation of measures which contain risk-adjusted mortality. The technical terms "risk-adjusted death rate" and "reference range" should stay in the background, since comprehension problems can be expected and explanations would have to be provided. PMID- 29107651 TI - Is antibiotic prophylaxis to prevent infective endocarditis worthwhile? AB - Infective endocarditis (IE) is a rare condition which is associated with considerable morbidity and mortality. Almost 100 years ago, the links between endocarditis and procedures, particularly dental procedures, were postulated. Over 50 years ago the first guidelines recommending antibiotic prophylaxis (AP), with the aim of preventing IE developing after procedures, were proposed. However, there has only ever been circumstantial evidence in humans that AP prevents IE. The rarity of IE has made a randomised controlled clinical trial impractical to date. This article outlines the history of AP and reviews the evidence base for the use of AP to prevent IE. PMID- 29107652 TI - Association of the exoU genotype with a multidrug non-susceptible phenotype and mRNA expressions of resistance genes in Pseudomonas aeruginosa. AB - The increased prevalence of the virulence factor exoU + genotype among multidrug resistant Pseudomonas aeruginosa has been previously reported. However, the genes that are related to the multidrug resistance of the exoU + genotype strain have not been analyzed and remain to be elucidated. The objective of this study was to analyze the correlations between virulence factors and resistance genes. The exoU + genotype was frequently found in carbapenem and fluoroquinolone non-susceptible strains. The imp carbapenemase genotype, the quinolone-resistance-determining region mutation in GyrA and ParC and the defective mutation in OprD were not frequently found in the exoU + genotype and carbapenem and fluoroquinolone non susceptible strains. On the other hand, mexY and ampC mRNA overexpressing strains were more frequently found in the exoU + genotype and carbapenem and fluoroquinolone non-susceptible strains. Moreover, sequence type 235, a high risk clone of multidrug-resistant P. aeruginosa, was prevalent among the exoU + genotype and carbapenem and fluoroquinolone non-susceptible strains. ExoU is highly virulent protein, and the overexpression of efflux pumps and AmpC beta lactamase induce a multidrug-resistant phenotype. Therefore, the increased prevalence of P. aeruginosa strains with an exoU + genotype and the overexpression of efflux pumps and AmpC beta-lactamase are likely to make P. aeruginosa infections difficult to treat. An understanding of the prevalence of both the exoU + genotype and the mRNA overexpression of resistance genes may help to select empirical therapy for the treatment of nosocomial infections caused by P. aeruginosa. PMID- 29107648 TI - Corrigendum to "European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)" [Redox Biol. 13 (2017) 94-162]. PMID- 29107650 TI - Molecular characterization and antibiotic resistance of Streptococcus dysgalactiae subspecies equisimilis isolated from patients with streptococcal toxic shock syndrome. AB - Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock, multiorgan failure, and high mortality. Although STSS is mainly caused by Streptococcus pyogenes, group G streptococcus identified as S. dysgalactiae subsp. equisimilis (SDSE) causing STSS has also been reported; however, no study has analyzed >100 isolates of SDSE causing STSS. Therefore, we characterized the emm genotype of 173 SDSE isolates obtained from STSS patients in Japan during 2014-2016 and performed antimicrobial susceptibility testing using the broth microdilution method and emm gene typing. The predominant emm genotype was found to be stG6792, followed by stG485, stG245, stG10, stG6, and stG2078. These six genotypes constituted more than 75% of the STSS isolates. The proportion of each emm genotype in STSS isolates correlated with that in invasive isolates previously reported. We found that 16.2% of the isolates showed clindamycin resistance. The proportion of clindamycin-resistant SDSE isolates was significantly higher than that of S. pyogenes isolates. Thus, while treating STSS caused by SDSE, it is necessary to consider the possibility of clindamycin resistance and to ensure judicious use of the drug. PMID- 29107653 TI - Effect of controlled cortical impact on the passage of pituitary adenylate cyclase activating polypeptide (PACAP) across the blood-brain barrier. AB - Injuries to the central nervous system can affect the blood-brain barrier (BBB), including disruption and influencing peptide transport across the BBB. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a potent neurotrophic and neuroprotective peptide currently being investigated for its therapeutic role following injury to the central nervous system and can cross the BBB in a saturable manner. The goal of the current study was to investigate for the first time PACAP38 uptake by the brain following traumatic brain injury (TBI). Using radioactively labeled PACAP38, we measured the levels of PACAP38 present in the injured, ipsilateral cortex in Sham-treated mice compared to mice receiving a controlled cortical impact (CCI), a model of TBI. Experiments were conducted at 6 different time points (from 2h up to 4 weeks) following CCI to determine temporal changes in PACAP38 transport. PACAP38 uptake was increased at 2 and 72h post-CCI compared to Sham. We did not detect changes in PACAP38 uptake in the contralateral cortex and cerebellum between Sham and CCI-treatment. The rate of PACAP38 transport into the ipsilateral cortex following CCI was increased 3.6 fold 72h after compared to 2h post-CCI. In addition, the rate of transport into the cerebellum was greater than that of the cortices. The data presented here shows PACAP38 transport is temporally altered following CCI-treatment and PACAP38 uptake is greater in the cerebellum compared to the cortices. PMID- 29107654 TI - Effectiveness of varicella vaccine as post-exposure prophylaxis during a varicella outbreak in Shanghai, China. AB - OBJECTIVES: Varicella vaccine (VarV) is recommended as effective post-exposure prophylaxis (PEP) within 3-5days to control outbreaks. However, the effectiveness of PEP at >5days after exposure and the administration of a second dose to those with a history of one dose prior to exposure have not been fully examined. This study evaluated the vaccine effectiveness (VE) of PEP in preventing disease during a varicella outbreak in Shanghai, China in 2013. METHODS: Self administered questionnaires were used to obtain the students' varicella history, vaccination status, and willingness to receive PEP. One dose of VarV was provided free of charge to eligible students. The VE of PEP was calculated as [1-relative risk (RR)]*100%. Analyses were restricted to grade 8 students, as no students from the other grades or teachers developed varicella during the outbreak. RESULTS: Twenty-seven varicella cases were identified, 16 (59%) of which were infected after the PEP campaign. Sixty-five students received one dose of VarV on day 13 or 19 after the index case. Attack rates were 28% (9/32), 16% (15/94), 0% (0/10), and 6% (3/55) among unvaccinated, one-dose Pre-PEP, first dose as PEP, and second dose as PEP recipients, respectively. Cases among second dose as PEP recipients tended to have less fever compared with unvaccinated or one-dose Pre PEP recipients. Compared with unvaccinated students, the VE of first dose as PEP recipients was 100% and of the second dose as PEP recipients was 60% (95% confidence interval -72% to 91%). CONCLUSIONS: Post-exposure vaccination should be given as soon as possible after exposure. Nevertheless, vaccination is still recommended even at more than 5days post-exposure to control varicella outbreaks. PMID- 29107655 TI - Cytochromes bd-I and bo3 are essential for the bactericidal effect of microcin J25 on Escherichia coli cells. AB - Microcin J25 has two targets in sensitive bacteria, the RNA polymerase, and the respiratory chain through inhibition of cellular respiration. In this work, the effect of microcin J25 in E. coli mutants that lack the terminal oxidases cytochrome bd-I and cytochrome bo3 was analyzed. The mutant strains lacking cytochrome bo3 or cytochrome bd-I were less sensitive to the peptide. In membranes obtained from the strain that only expresses cytochrome bd-I a great ROS overproduction was observed in the presence of microcin J25. Nevertheless, the oxygen consumption was less inhibited in this strain, probably because the oxygen is partially reduced to superoxide. There was no overproduction of ROS in membranes isolated from the mutant strain that only express cytochrome bo3 and the inhibition of the cellular respiration was similar to the wild type. It is concluded that both cytochromes bd-I and bo3 are affected by the peptide. The results establish for the first time a relationship between the terminal oxygen reductases and the mechanism of action of microcin J25. PMID- 29107656 TI - Molecular prevalence of spotted fever group rickettsiae in ticks from Qinghai Province, northwestern China. AB - Tick-borne rickettsioses is one of the oldest known vector-borne diseases and has been viewed as emerging or re-emerging disease in China. The causative agents have been increasingly recognized and exhibited a high degree of genetic diversity and widespread distribution. This study was conducted to determine the prevalence of spotted fever group rickettsiae in ticks from Qinghai Province, northwestern China. In total, 860 questing adult ticks representing six species were collected. The SFG rickettsiae were detected in Haemaphysalis qinghaiensis (19.6%, 79/404), Dermacentor abaensis (73.7%, 157/213), Dermacentor silvarum (50.0%, 47/94), Dermacentor nuttalli (67.4%, 97/144), and Ixodes crenulatus (100%, 3/3), with an overall infection rate of 44.5%. The infection rates of SFG rickettsiae were significantly higher in Dermacentor spp. than in Haemaphysalis spp. (p<0.05). Sequence analyses of the gltA and ompA genes revealed that five SFG rickettsiae are present in ticks in Qinghai, including R. sibirica subspecies sibirica, R. raoultii, "Candidatus Rickettsia tibetani", and "Candidatus Rickettsia gannanii" Y27 and F107. Moreover, a potential novel Rickettsia species (Rickettsia sp. 10CYF) was identified in D. nuttalli and I. crenulatus. These findings extend our knowledge of the potential vector spectrum and distribution of rickettsiae, and provided valuable information for assessing the potential risk for public health. PMID- 29107657 TI - Alcohol-related deaths will go uncounted in new UK scheme. PMID- 29107658 TI - Physiological characterization and regulation of the contractile properties of the mosquito ventral diverticulum (crop). AB - In adult dipteran insects (flies), the crop is a diverticulum of the esophagus that serves as a food storage organ. The crop pumps stored contents into the alimentary canal for digestion and absorption. The pumping is mediated by peristaltic contractions of the crop musculature. In adult female mosquitoes, the crop (ventral diverticulum) selectively stores sugar solutions (e.g., nectar); proteinaceous blood meals by-pass the crop and are transferred directly to the midgut for digestion. The mechanisms that regulate crop contractions have never been investigated in mosquitoes. Here we provide the first physiological characterization of the contractile properties of the mosquito crop and explore the mechanisms that regulate crop contractions. Using an in vitro bioassay we found that the isolated crop spontaneously contracts in Ringer solution for at least 1 h and its contractions are dependent on extracellular Ca2+. Adding serotonin (5-hydroxytryptamine, 5-HT) or a membrane-permeable analog of cyclic adenosine monophosphate (cAMP) to the extracellular bath increased the frequency of crop contractions. On the other hand, adding benzethonium chloride (BzCl; a chemical that mimics the effects of myosuppressins), H-89 or Rp-cAMPS (inhibitors of protein kinase A, PKA), or carbenoxolone (an inhibitor of gap junctions) reduced the frequency of the unstimulated, spontaneous and/or 5-HT-stimulated crop contractions. Adding aedeskinin III did not detectably alter crop contraction rates. In addition to pharmacological evidence of gap junctions, we demonstrated that the crop expressed several mRNAs encoding gap junctional proteins (i.e. innexins). Furthermore, we localized immunoreactivity for innexin 2 and innexin 3 to muscle and epithelial cells of the crop, respectively. Our results 1) suggest that 5-HT and myosupressins oppositely regulate contractile activity of the mosquito crop, and 2) provide the first evidence for putative roles of cAMP, PKA, and gap junctions in modulating contractile activity of the dipteran crop. PMID- 29107659 TI - Is this blood? An ERP study on the visual identification of red fluids in patients with blood phobia. AB - Blood can be easily recognized in situations involving injury. However, very little is known about the ability of humans to identify blood without such context information. We investigated the blood detection capacity and associated electrocortical correlates (event-related potentials) in 20 women with blood phobia and 20 non-phobic females. The participants viewed images depicting droplets of pig blood, and water with pink or red food coloring. They were asked to decide, whether the pictures showed real blood or not. Blood provoked enhanced P100 amplitudes (90-140 ms) in blood phobics. Late positivity (P300: 340-500 ms) as well as classification accuracy did not differ between the groups. However, blood elicited a general P300 enhancement (relative to red and pink fluids) possibly reflecting elevated visual attention to blood as a general characteristic in humans. The P100 augmentation in blood phobics very likely reflects enhanced early selective attention. Patients with BII phobia showed prioritized visual processing of blood without having to rely on contextual information. PMID- 29107660 TI - Hemispheric differences in the number of parvalbumin-positive neurons in subdivisions of the rat basolateral amygdala complex. AB - The amygdala is a bilateral temporal lobe brain region which plays an important role in emotional processing. Past studies on the amygdala have shown hemispheric differences in amygdalar processes and responses associated with specific pain and fear behaviors. Despite the functional differences in the amygdala, few studies have been performed to characterize whether anatomical differences exist between the left and right amygdala. Parvalbumin (PV) is a phenotypic marker for an inhibitory interneuronal population in cortical brain structures such as the basolateral amygdala complex (BLC). This study examined the number of PV-positive neurons in the left and right BLC of adult, male Long-Evans rats using unbiased stereology. Coronal sections through the rostral-caudal extent of the BLC were immunohistochemically-stained for PV and the optical fractionator method was used to obtain an unbiased estimate of the number of PV-positive neurons in subdivisions through the BLC. The lateral and basolateral amygdala divisions of the BLC were analyzed, were subdivided into the dorsolateral, ventrolateral and ventromedial and the posterior, anterior and ventral subdivisions, respectively. The results indicate that there are significantly more PV-positive neurons in the left basolateral amygdala compared to the right, with a significant difference specifically in the posterior subdivision. This difference in PV neuronal number could help explain the distinct hemispheric roles of the BLC in the behavioral processing following exposure to painful and fearful stimuli. PMID- 29107661 TI - On understanding creative language: The late positive complex and novel metaphor comprehension. AB - Novel metaphoric sentences have repeatedly evoked larger N400 amplitudes than literal sentences, while investigations of the late positive complex (LPC) have brought inconsistent results, with reports of both increased and reduced amplitudes. In two experiments, we examined novel metaphor comprehension in Polish, using the same set of literal, novel metaphoric, and anomalous sentences. The first aim of the study was to test whether novel metaphors would evoke larger or smaller late positivity complex (LPC) amplitudes compared to literal and anomalous sentences. Some earlier studies have shown that whether increased LPC amplitudes are observed or not may be related to the task participants are asked to perform, with explicit acceptability judgments being more likely to evoke the LPC effect. The second aim of the study was, thus, to test whether the observed LPC pattern would be the same across two tasks, the semantic decision task (Experiment 1) and the reading task (Experiment 2). Our results replicated the N400 effect observed in earlier studies on metaphor in both experiments. Most importantly, a reduction in late positivity to novel metaphors relative to anomalous sentences was found in both experiments. Additionally, this difference was broadly distributed over parietal sites in Experiment 1, and clearly left lateralized in Experiment 2, which might imply differences in the involvement of recollection and semantic processes. Overall, these results seem to indicate that both conventionality and task demands modulate the LPC pattern. PMID- 29107663 TI - Bone sarcoidosis. PMID- 29107662 TI - Methylphenidate alters brain connectivity after enhanced physical performance. AB - Muscle fatigue is a disturbed homeostatic state characterized by a temporary inability to maintain force output and has lasting effects on the brain in the period immediately after exercise, such as decreased interhemispheric functional connectivity (FC). Stimulants that increase dopamine and norepinephrine neurotransmission can enhance performance during muscle fatiguing exercise (i.e. are ergogenic). We recently demonstrated that methylphenidate (MPH) increased force output and increased FC between the insular (IC) and hand motor cortex during a fatiguing handgrip task. However, whether resting FC is altered in the recovery period after enhanced force is unknown. The objective of these follow-up analyses was to examine the effects of performing a fatiguing handgrip task with MPH on subsequent resting state FC. In a double-blind counter-balanced design, participants ingested placebo or MPH and in a magnetic resonance imaging scanner performed: a six-minute pre-task resting scan, a fatiguing handgrip task during scanning, and then a six-minute post-task resting scan. We investigated task related force and resting state FC pre- and post-task between: (1) interhemispheric motor cortices (M1) and (2) the right IC and left hand motor area. We found 1) a post-task reduction in M1 interhemispheric FC and that the extent of reduciton was negatively correlated with enhanced mean trial force in MPH conditions. 2) MPH but not placebo increased post-task FC between the right IC and left hand motor area. This study demonstrates that using MPH during a muscle fatiguing task has lasting effects on the brain that are markedly different from drug naive conditions. PMID- 29107664 TI - Eruption of lymphocyte recovery with atypical lymphocytes mimicking a primary cutaneous T-cell lymphoma: a series of 12 patients. AB - Eruption of lymphocyte recovery (ELR) may occur during bone marrow aplasia after chemotherapies. We reviewed the clinical and pathologic features of 12 patients (male-female ratio, 7:5; median age, 61 years) with an atypical ELR histologically mimicking a primary cutaneous T-cell lymphoma such as Sezary syndrome or CD30+ T-cell lymphoproliferative disorder. All the patients displayed an erythematous maculopapular eruption on the trunk and the limbs associated with fever. All but one had received a polychemotherapy for an acute myeloid leukemia (n=10) or a urothelial carcinoma (n=1) before the occurrence of the skin eruption. One had an autoimmune lymphoproliferative syndrome causing chronic agranulocytosis requiring granulocyte colony-stimulating factor injection. In all patients, the skin eruption was associated with a slight increase of white blood cell count followed by bone marrow recovery within the next weeks. All skin biopsies showed a dermal perivascular lymphocytic infiltrate containing atypical medium- to large-sized CD3+, CD4+ and CD8+, CD25+, ICOS+, PD1- lymphocytes with a strong CD30 expression in most instances (n=10), suggesting the recruitment of strongly activated T cells in the skin. In 6 patients, a diagnosis of CD30+ lymphoproliferative disorder or Sezary syndrome was proposed or suspected histopathologically, and only the clinical context allowed the diagnosis of ELR with a peculiar presentation with atypical lymphocytes. We describe a series of patients with an unusual form of ELR characterized by the presence of atypical activated T cells in the skin. On a practical ground, pathologists should be aware of this distinctive and misleading presentation. PMID- 29107665 TI - Eps8 expression is significantly lower in p16+ head and neck squamous cell carcinomas (HNSCCs) compared with p16- HNSCCs. AB - In vitro head and neck cancer studies have demonstrated that epidermal growth factor receptor kinase substrate 8 (Eps8) overexpression contributes to squamous carcinogenesis. Oral squamous cell carcinoma studies have correlated Eps8 expression with metastatic disease and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) studies comparing its expression by anatomic site or in in vivo regional metastases have not been performed. In this study, we compared Eps8 expression in HNSCCs arising in the oral cavity (OCSCC) and oropharynx (OPSCC) along with their corresponding regional lymph node (LN) metastases. We then correlated our findings with clinicopathologic data including tumor-node metastasis stage, p16 status, age, sex, and smoking and alcohol history. Eps8 immunohistochemistry was performed on 69 archived OCSCCs and OPSCCs, and 24 paired and 4 unpaired LNs. Expression was scored from 0 to 3. Eps8 expression was detected in 49% of combined OCSCC and OPSCC cases. We found that expression correlated with advanced tumor stage (P = .022) and p16 status (P = .032) but not with anatomic site. Notably, p16+ HNSCCs had significantly lower Eps8 expression than p16- HNSCCs. No significant difference was observed between primary HNSCCs and their corresponding metastatic LNs. Neither p16 status nor anatomic site influenced Eps8 expression in regional LN metastases. In conclusion, our data offer in vivo support that, in HNSCCs, Eps8 is involved in tumor invasion but not necessarily the development of regional LN metastasis. The association between low Eps8 expression and p16+ HNSCCs suggests that alternative signaling pathways may be used for their tumorigenesis. PMID- 29107666 TI - JAK2-mutated Langerhans cell histiocytosis associated with primary myelofibrosis treated with ruxolitinib. AB - The pathogenesis and cellular origin of Langerhans cell histiocytosis (LCH) are debated. Recently, mutations on MAPK and PI3K pathways have been linked to disrupted cell proliferation in LCH. Janus Kinase 2 (JAK2) mutations play the same role in Philadelphia-negative chronic myeloproliferative neoplasms. We describe the case of a patient affected by JAK2-positive primary myelofibrosis (PMF) who developed a clonally related LCH while in treatment with ruxolitinib. JAK inhibitors are well known to affect function and differentiation of different hematological lineages, including mononuclear phagocytes precursors. Nevertheless, the literature describes cases of LCH clonally associated with non LCH hematological neoplasm, suggesting how multilinear myeloid neoplasms may arise from bone marrow. Hence, we briefly discuss the possible pathogenic roles of genetic mutations and JAK inhibition therapy in the pathogenesis of LCH and associated neoplasms. PMID- 29107667 TI - FGFR1 translocation with concurrent myeloproliferative neoplasm, systemic mastocytosis, and lymphoblastic lymphoma: a case report. AB - FGFR1 translocation may cause myeloid or lymphoid neoplasm but rarely systemic mastocytosis (SM). Conversely, SM is associated with myeloproliferative neoplasm (MPN) but rarely lymphoblastic lymphoma (LBL) or FGFR1 translocation. We report the first case of FGFR1 translocation in a patient with concurrent LBL, MPN, and SM. A 21-year-old male patient presented with diffuse lymphadenopathies and leukocytosis. TdT+/cytoCD3+/CD79aweakly+ LBL was identified in the lymph node. Bone marrow had MPN, SM, and TdT+/CD79a+/cytoCD3weakly+ LBL. The cytogenetic study, reverse-transcription polymerase chain reaction, and sequencing revealed t(8;13)(p11;q12) involving FGFR1 and ZMYM2. Under the hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen, complete remission of LBL was achieved despite persistent MPN and SM in the bone marrow. This rare case implies FGFR1 translocation in a precursor cell capable of differentiation into mast cells and lymphoblasts, strengthening the relationship between the 2 tumors in the World Health Organization classification: myeloid and lymphoid neoplasms with FGFR1 abnormalities, and SM with an associated hematologic neoplasm. PMID- 29107668 TI - Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome. AB - Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian, and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer (EC) hysterectomy specimens by mismatch repair immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression. Patients with tumors negative for MLH1 methylation and those with a loss of the heterodimer pair MSH2 and MSH6, or isolated loss of either PMS2 or MSH6 were referred to the Familial Cancer Program for genetic counseling and consideration of germline testing. Between May 2015 to Dec 2016, 233 EC patients were screened by IHC for LS with a median age of 63 years. Sixty tumors (27%) had abnormal IHC staining results. Fifty-one (22%) harbored heterodimeric loss of MLH1 and PMS2, 49 of which showed MLH1 promoter methylation (1 failure, 1 negative). One showed loss of MLH1/PMS2 and MSH6, 2 showed loss of MSH2/MSH6, and 6 had isolated loss of MSH6 only. Ten patients underwent genetic counseling, and germline testing was performed in 8; LS was confirmed in 5 patients (2.1%). In addition, 3 patients with negative germline testing and presumed Lynch-like syndrome were identified and offered additional somatic testing. Universal screening for LS in EC patients has yielded positive results for identification of patients at risk for this inherited syndrome. PMID- 29107669 TI - Impact of signal peptide and transmembrane segments on expression and biochemical properties of a lipase from Bacillus sphaericus 205y. AB - A total of 97 amino acids, considered as the signal peptide and transmembrane segments were removed from 205y lipase gene using polymerase chain reaction technique that abolished the low activity of this enzyme. The mature enzyme was expressed in Escherichia coli using pBAD expression vector, which gave up to a 13 fold increase in lipase activity. The mature 205y lipase (without signal peptide and transmembrane; -SP/TM) was purified to homogeneity using the isoelectric focusing technique with 53% recovery. Removing of the signal peptide and transmembrane segments had resulted in the shift of optimal pH, an increase in optimal temperature and tolerance towards more water-miscible organic solvents as compared to the characteristics of open reading frame (ORF) of 205y lipase. Also, in the presence of 1mM inhibitors, less decrease in the activity of mature 205y lipase was observed compared to the ORF of the enzyme. Protein structure modeling showed that 205y lipase consisted of an alpha/beta hydrolase fold without lid domain. However, the transmembrane segment could effect on the enzyme activity by covering the active site or aggregation the protein. PMID- 29107670 TI - New findings from the first transcriptome of the Bothrops moojeni snake venom gland. AB - Snakebites are a serious health problem in tropical countries. In Brazil, the genus Bothrops (Viperidae family) causes most of the ophidic accidents, characterized by proteolysis and haemorrhage. Snake venoms are rich sources of toxins with great therapeutic and biotechnological potential and omics approaches is a valuable tool for identification of new bioactive components in the venom. In this study, we described the first transcriptome of the venom gland of Bothrops moojeni snake, using the next-generation sequencing with the Illumina platform. We identified: (i) 20 venom components classes, among which metalloproteases were the most expressed ones, followed by serine proteases and phospholipases; and (ii) the 33 full-length amino acid sequences of toxins that have never been reported before in B. moojeni venom, such as one cysteine-rich secretory protein (Moojin), two hyaluronidases (BmooHyal-1 and BmooHyal-2), and one three-finger toxin (Bmoo-3FTx). Altogether, the transcripts identified herein represent a starting point for the analysis of structure-function relationships of toxins, which shall help develop novel biological tools and therapeutic drugs. PMID- 29107671 TI - Evaluation of the effects of a new series of SMTPs in the acetic acid-induced embolic cerebral infarct mouse model. AB - We reported previously that Stachybotrys microspora triprenyl phenol-7 (SMTP-7) showed potential thrombolytic, anti-inflammatory and anti-oxidant effects that account for its excellent pharmacological activity such as having a wider therapeutic time window than tissue plasminogen activator (t-PA) and a significant protection against hemorrhage. The aim of the present study was to evaluate and compare the effect of a new series of SMTPs in the acetic acid induced embolic cerebral infarct mouse model. Thrombotic occlusion was produced in mice by inducing the transfer of acetic acid-induced thrombi from the right common carotid artery into the brain. SMTPs were evaluated by their effect on reducing infarct area, neurological score and edema. Furthermore, plasmin formation, anti-inflammatory and anti-oxidant activities were assessed by fibrin zymography, measuring pro-inflammatory gene expression, and thiobarbituric acid reactive substances (TBARS) assay, respectively. Treatment with either SMTP-22 or SMTP-43 (10mg/kg), which have similar plasmin formation, anti-inflammatory and anti-oxidant activities to SMTP-7, resulted in reduced infarct area, neurological score and edema. Coexistence of all these three activities appears to be important for the treatment of embolic infarction because SMTP-6, SMTP-25, and SMTP-44D (10mg/kg), which are each missing at least one of the three functions, were not as effective. Therefore, these results indicate that SMTP-22 and SMTP-43 have potential as medicinal compounds for the treatment of embolic cerebral infarction. PMID- 29107672 TI - Lovastatin inhibits visceral allodynia and increased colonic permeability induced by lipopolysaccharide or repeated water avoidance stress in rats. AB - Statins have been reported to block inflammatory somatic pain and have an anti cytokine property. Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral hypersensitivity and increases gut permeability in rats, which are mediated through proinflammatory cytokine-dependent pathways. Since visceral hypersensitivity with increased gut permeability plays a crucial role in the pathophysiology of irritable bowel syndrome (IBS), these above animal models are considered to simulate IBS. We hypothesized that lovastatin improves symptoms in the patients with IBS by attenuating these visceral changes. The threshold of visceromotor response (VMR) induced by colonic balloon distention was measured for the assessment of visceral sensation in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15min using a spectrophotometer. Subcutaneously (s.c.) injected LPS (1mg/kg) reduced the threshold of VMR after 3h. Pretreatment with lovastatin (20mg/kg s.c. daily for 3 days) abolished this response by LPS. Repeated WAS (1h daily for 3 days) induced visceral allodynia, which was also blocked by repeated injection of lovastatin before each stress session. The antinociceptive effect of lovastatin on the LPS-induced allodynia was reversed by mevalonolactone, NG-nitro-L-arginine methyl ester or naloxone. Lovastatin also blocked the LPS- or repeated WAS induced increased gut permeability. These results indicate the possibility that lovastatin can be useful for treating IBS. PMID- 29107673 TI - Tranilast inhibits interleukin-33 production by macrophages. AB - Tranilast is an anti-allergy medication that inhibits the release of chemical mediators such as histamine. However, the mechanisms underlying its anti-allergy effects are not fully understood. Interleukin (IL)-33, a novel member of the IL-1 cytokine family, promotes T helper type 2 immune responses and plays a pathogenic role in allergic disorders. In the present study, we examined the effects of tranilast on IL-33 production by RAW264.7 macrophages. Lipopolysaccharide (LPS) increased both IL-33 mRNA expression and IL-33 protein synthesis. Tranilast significantly inhibited LPS-induced IL-33 protein production by RAW264.7 macrophages in a dose-dependent manner; these same effects were observed on IL-33 mRNA levels in RAW264.7 macrophages and a primary culture of macrophages. LPS markedly activated Akt in RAW264.7 macrophages, whereas tranilast suppressed LPS induced Akt activation. The effects of tranilast on Akt activation appeared to be responsible for the decrease in IL-33 production. Our present findings suggest that the inhibition of IL-33 production by tranilast might contribute to the anti allergy effects of this medication. PMID- 29107674 TI - Children saving lives: Training towards CPR excellence levels in chest compression based on age and physical characteristics. AB - BACKGROUND: The World Health Organization's endorsement of the "Kids save lives" statement fosters the implementation of cardiopulmonary resuscitation (CPR) training for school children worldwide. However, not every child achieves and maintains the recommended chest compression depth of 5-6cm. PURPOSE: To investigate the variability in compression depth for three age groups (grade 1: 12-14; grade 2: 14-16; grade 3: 16-18 years) as a function of physical characteristics and to define minimal compression excellence levels for training. METHODS: Compression depth of 265 subjects (111 girls, 154 boys) aged 12-18 years from one secondary school was individually assessed and reported in percentiles per age group. Pearson correlations between physical characteristics and CPR variables were calculated. Excellence level was defined as the percentage compressions with depth 5-6cm. RESULTS: In grade 1 (12-14 years), achieved excellence levels were 1% for girls and 23% for boys at the 75th percentile. In grade 2 (14-16 years), it increased to 24% for girls and 80% for boys. In grade 3 (16-18 years) finally, it was 59% for girls and 87% for boys. Significant positive correlations were found between CPR and physical variables (p<0.05), especially weight >50kg (p<0.01). CONCLUSION: A minimal excellence level of 25% is achievable by boys 12-14year and girls 14-16year and can be gradually improved to 60% and 90% according to age and gender. This might necessitate more exertion and training for some younger children, especially girls, and will probably be more easily achieved for children weighing >50kg. PMID- 29107675 TI - Point-of-care ultrasound during advanced cardiopulmonary resuscitation: Rule of art has to be respected! PMID- 29107676 TI - Perinatal exposure to low dose 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) alters sperm DNA methylation in adult rats. AB - Polybrominated diphenyl ethers (PBDEs) are a group of ubiquitous reproductive toxins. Given that spermatogenesis requires extensive epigenetic changes, we hypothesize that PBDEs impact sperm DNA methylation. Pregnant Wistar rats were exposed perinatally to 0.2mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and caudal epididymal sperm were collected from offspring on postnatal days (PNDs) 65 and 120. Libraries were prepared from sperm DNA and sequenced with an average of 18.0 million unique reads per sample. Differential methylated regions (DMRs) were identified via MethPipe package. BDE-47 exposure increased DNA methylation of epididymal sperm on PND 65 in genes, promoters and intergenic regions; however, on PND120 methylation decreased in these genomic elements. We identified 21 and 9 exposure-related DMRs in sperm collected on PND65 and PND120, respectively. Two DMRs overlapped between the two time-points. This is the first study to demonstrate that environmentally-relevant perinatal exposure to PBDE results in long-lasting changes in sperm DNA methylation. PMID- 29107677 TI - Ischaemia in liver resection predicts cancer-specific survival. PMID- 29107678 TI - Carcinogenicity of benzene. PMID- 29107680 TI - Grant, deny, or reassess the role of yttrium-90 in hepatocellular carcinoma? PMID- 29107682 TI - Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase. AB - Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids. Once extracted, ubiquitinated reductase becomes dislocated into the cytosol for degradation by 26S proteasomes. In this review, we will highlight several advances in the understanding of reductase ERAD, which includes the discovery for a role of the vitamin K2 synthetic enzyme UBIAD1 in the reaction and demonstration that sterol-accelerated ERAD significantly contributes to feedback regulation of reductase and cholesterol metabolism in livers of whole animals. PMID- 29107679 TI - Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. AB - BACKGROUND: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma. METHODS: SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. FINDINGS: Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27.9 months (IQR 21.9-33.6) in the SIRT group and 28.1 months (20.0-35.3) in the sorafenib group. Median overall survival was 8.0 months (95% CI 6.7-9.9) in the SIRT group versus 9.9 months (8.7-11.4) in the sorafenib group (hazard ratio 1.15 [95% CI 0.94-1.41] for SIRT vs sorafenib; p=0.18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. INTERPRETATION: In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. FUNDING: Sirtex Medical Inc. PMID- 29107683 TI - Hypoxia regulates the level of glutamic acid decarboxylase enzymes and interrupts inhibitory synapse stability in primary cultured neurons. AB - Gamma-aminobutyric acid (GABA) is the main neurotransmitter of inhibitory synaptic transmission, which is critical for oscillatory activity and synchronization of neurons in neural networks. GABA is synthesized by glutamic acid decarboxylase (GAD) enzymes in the inhibitory neuron and, thus, the deregulation of GAD enzymes and subsequent change of GABAergic activity are involved in various neurological and neuropsychiatric diseases. Under hypoxic conditions, neurons undergo neuropathological alterations which can be subtle or severe. Many studies have focused on the alteration of excitatory neurons by hypoxic injury, while inhibitory neuronal changes have not been well determined. Here, we demonstrated that hypoxic conditions decrease the expression of inhibitory neuron-related proteins, including GAD enzymes, through transcript downregulation and proteasomal degradation. Hif-1alpha induction and glutamate release under hypoxic conditions were implicated in the mechanism of GAD enzyme level reduction. Surprisingly, these conditions altered the density and size of inhibitory synapses, which was irreversible by reoxygenation, but was mediated by glutamate activity. Our findings suggest that potential implication of the compositional and structural alterations of inhibitory neuron in the pathogenesis of various hypoxic injuries. PMID- 29107684 TI - Ethylene glycol dimethacrylate and diethylene glycol dimethacrylate exhibits cytotoxic and genotoxic effect on human gingival fibroblasts via induction of reactive oxygen species. AB - Although methacrylic acid derivatives in their polymeric form are considered to be safe, insufficient polymerization and the release of monomers due to either mechanical or enzymatical factors can lead to their reaching millimolar concentrations in local tissue. The present study evaluates the effect of two methacrylate monomers - ethylene glycol dimethacrylate (EGDMA) and diethylene glycol dimethacrylate (DEGDMA) - on human gingival fibroblasts (HGFs). Both monomers were found to reduce cells viability in MTT assay, increase apoptosis and cause cell cycle arrest in G1/G0 phase. They also increased intracellular reactive oxygen species (ROS) production as measured by DCFH-DA and DHE probes and increased expression of GPx4 and SOD2. Both monomers increased DNA damage in comet assay. Moreover, HGFs were not able to repair those lesions within 120min of repair incubation. However, the monomers were not found to have any effect on the integrity of isolated plasmids. We postulate that EGDMA and DEGDMA exhibit their cytotoxic and genotoxic properties via increased production of ROS, which cause DNA damage, affect apoptosis, viability and cell cycle. Further studies are needed to better understand the properties of methacrylic acid monomers and to evaluate the risk that they cause for patients, dentists and dental technicians. PMID- 29107681 TI - Myogenic progenitor specification from pluripotent stem cells. AB - Pluripotent stem cells represent important tools for both basic and translational science as they enable to study mechanisms of development, model diseases in vitro and provide a potential source of tissue-specific progenitors for cell therapy. Concomitantly with the increasing knowledge of the molecular mechanisms behind activation of the skeletal myogenic program during embryonic development, novel findings in the stem cell field provided the opportunity to begin recapitulating in vitro the events occurring during specification of the myogenic lineage. In this review, we will provide a perspective of the molecular mechanisms responsible for skeletal myogenic commitment in the embryo and how this knowledge was instrumental for specifying this lineage from pluripotent stem cells. In addition, we will discuss the current limitations for properly recapitulating skeletal myogenesis in the petri dish, and we will provide insights about future applications of pluripotent stem cell-derived myogenic cells. PMID- 29107685 TI - Toxicity and structure-activity relationship (SAR) of alpha,beta-dehydroamino acids against human cancer cell lines. AB - A library of N-protected dehydroamino acids, namely dehydroalanine, dehydroaminobutyric acid and dehydrophenylalanine derivatives, was screened in three human cancer cell lines [(lung (A549), gastric (AGS) and neuroblastoma (SH SY5Y)] in order to characterize their toxicological profile and identify new molecules with potential anticancer activity. Results showed N-protected dehydrophenylalanine and dehydroaminobutyric acid derivatives have no or low toxicity for all tested cell lines. The N-protected dehydroalanines exhibit significant toxic effects and the AGS and SH-SY5Y cells were significantly more vulnerable than A549 cells. Four alpha,beta-dehydroalanine derivatives, with IC50<62.5MUM, were selected to investigate the pathways by which these compounds promote cell death. All compounds, at their IC50 concentrations, were able to induce apoptosis in both AGS and SH-SY5Y cell lines. In both cell lines, loss of mitochondrial membrane potential (DeltaPsim) was found and caspase activity was increased, namely endoplasmic reticulum-resident caspase-4 in AGS cells and caspase-3/7 in SH-SY5Y cells. When evaluated in a non-cancer cell line, the molecules displayed no to low toxicity, thus suggesting some degree of selectivity for cancer cells. The results indicate that alpha,beta-dehydroalanine derivatives can be considered a future resource of compounds able to work as anticancer drugs. PMID- 29107686 TI - A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance. AB - Letermovir is a human cytomegalovirus (CMV) terminase inhibitor that was clinically effective in a Phase III prevention trial. In vitro studies have shown that viral mutations conferring letermovir resistance map primarily to the UL56 component of the terminase complex and uncommonly to UL89. After serial culture of a baseline CMV laboratory strain under letermovir, mutation was observed in a third terminase component in 2 experiments, both resulting in amino acid substitution P91S in gene UL51 and adding to a pre-existing UL56 mutation. Recombinant phenotyping indicated that P91S alone conferred 2.1-fold increased letermovir resistance (EC50) over baseline, and when combined with UL56 mutation S229F or R369M, multiplied the level of resistance conferred by those mutations by 3.5-7.7-fold. Similarly a combination of UL56 mutations S229F, L254F and L257I selected in the same experiment conferred 54-fold increased letermovir EC50 over baseline, but 290-fold when combined with UL51 P91S. The P91S mutant was not perceptibly growth impaired. Although pUL51 is essential for normal function of the terminase complex, its biological significance is not well understood. Letermovir resistance mutations mapping to 3 separate genes, and their multiplier effect on the level of resistance, suggest that the terminase components interactively contribute to the structure of a letermovir antiviral target. The diagnostic importance of the UL51 P91S mutation arises from its potential to augment the letermovir resistance of some UL56 mutations at low fitness cost. PMID- 29107687 TI - MiR-150 deficiency ameliorated hepatosteatosis and insulin resistance in nonalcoholic fatty liver disease via targeting CASP8 and FADD-like apoptosis regulator. AB - The prevalence of Non-alcoholic fatty liver diseases (NAFLD) increased rapidly in the world. However, the pathogenesis of is still unclear. Hepatic steatosis and insulin resistance are considered to be central to the pathophysiology of NAFLD. MicroRNAs are short non-coding RNAs and has been reported to be involved in pathogenesis of NAFLD and related metabolic diseases. Here, we investigated the mechanisms by which miR-150 regulate hepatic steatosis and insulin resistance in high fat diet (HFD) induced NAFLD model. The expression of miR-150 was up regulated dramatically in both human NAFLD patients and HFD mice model, as well as in hepatocytes treated with oleic acid. miR-150 deficiency ameliorated the hepatic steatosis and insulin resistance significantly in NAFLD mice. miR-150 deficiency decreased the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis, while increased the expression of genes related to fatty acid beta-oxidation. Further, we identified that CFLAR is a direct downstream target of miR-150. Overexpression of miR-150 reduced both the mRNA and protein levels of CFLAR in vitro. And overexpression of miR-150 significantly inhibited the luciferase activity of CFLAR 3'-UTR, while the effect of miR-150 was blocked when the binding site of miR-150 within the CFLAR 3'-UTR was mutated. We also found that miR-150 deficiency decreased the expression of p-Jnk1 and p Ask1, while the effect of miR-150 on steatosis and insulin signaling was blocked by CFLAR overexpression. In conclusion, our data indicated that miR-150 potentially contributes to the hepatic steatosis and insulin resistance in NAFLD. miR-150/CFLAR pathway may be a new therapeutic strategy against NAFLD. PMID- 29107688 TI - Identification of antigenic peptides from novel renal cancer stem-like cell antigen, DNAJB8. AB - OBJECTIVES: To identify antigenic peptides of cancer stem-like cells (CSCs) antigen, DNAJB8, and establish a mouse CSCs-targeting immunotherapy model. MATERIALS AND METHODS: To induce DNAJB8-specific immune reaction, we stimulated human CD8+ lymphocytes with antigen-presenting cells pulsed with a cocktail of three candidate HLA-A*24:02 restricted peptides and assessed peptide specific human cytotoxic T lymphocytes (CTLs) induction. One of the antigenic peptides showed identical amino acid sequence as corresponding mouse DNAJB8. We evaluated CTL induction with the peptide immunization in mouse model. RESULTS: We confirmed peptide-specific interferon-gamma secretions and cytotoxic activities of induced human CTLs. In vivo immunization with the peptide to mice, peptide-specific CTL response could be observed in mouse CD8+ T cells. Furthermore, immunization with the peptide showed significant anti-tumor effects compared with negative controls. CONCLUSION: DNAJB8-derived peptide is a novel candidate for CSCs targeting immunotherapy, and mouse models can be used to evaluate CSCs-targeting immunotherapy. PMID- 29107689 TI - Semi-synthetic salinomycin analogs exert cytotoxic activity against human colorectal cancer stem cells. AB - Salinomycin, a polyether antibiotic, is a well-known inhibitor of human cancer stem cells. Chemical modification of the allylic C20 hydroxyl of salinomycin has enabled access to synthetic analogs that display increased cytotoxic activity compared to the native structure. The aim of this study was to investigate the activity of a cohort of C20-O-acyl analogs of salinomycin on human colorectal cancer cell lines in vitro. Two human colorectal cancer cell lines (SW480 and SW620) were exposed to three C20-O-acylated analogs and salinomycin. The impact of salinomycin and its analogs on tumor cell number, migration, cell death, and cancer stem cell specifity was analyzed. Exposure of human colorectal cancer cells to the C20-O-acylated analogs of salinomycin resulted in reduced tumor cell number and impaired tumor cell migration at lower concentrations than salinomycin. When used at higher (micromolar) concentrations, these effects were accompanied by induction of apoptotic cell death. Salinomycin analogs further expose improved activity against cancer stem cells compared to salinomycin. PMID- 29107690 TI - Effects of oral and subcutaneous administration of HSP60 on myeloid-derived suppressor cells and atherosclerosis in ApoE-/- mice. AB - HSP60 has been proved to be closely related to atherosclerosis due to its antigenicity. To determine this antigenicity effect, the ApoE-/- mice were fed with western-type diet and HSP60 was administrated orally or subcutaneously (SC) for potential vaccine against atherosclerosis. Here, we observed the ApoE-/- mice with oral HSP60 administration group showed a significant reduction in plaque size at the aortic root; accompanied by increased MSDCs (CD11b+Gr1+) in peripheral blood and spleen which was mostly composed of M-MDSCs (CD11b+LY6G LY6Chigh), and increased plasma IL-10 and splenic Foxp3, Arg1, iNOS mRNA as well as decreased plasma IFN-gamma and splenic T-bet mRNA compared to control group. Surprisingly, ApoE-/- mice with subcutaneous HSP60 administration group showed contrary results and their MDSCs were mostly composed of G-MDSCs (CD11b+LY6G+LY6Clow). As expected, both PBS-oral and PBS-SC groups showed no significant effects on both the immune response and atherosclerotic plaque formation. In contrast, subcutaneous administration of HSP60 causes the opposite response. Thus, we propose the proper method for administering HSP60 as a new immunologic agent for prevention and treatment of atherosclerosis. PMID- 29107691 TI - Antibiotic bedaquiline effectively targets growth, survival and tumor angiogenesis of lung cancer through suppressing energy metabolism. AB - Tumor angiogenesis plays essential roles during lung cancer progression and metastasis. Therapeutic agent that targets both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy. We demonstrate that bedaquiline, a FDA-approved antibiotic drug, effectively targets lung cancer cells and angiogenesis. Bedaquiline dose-dependently inhibits proliferation and induces apoptosis of a panel of lung cancer cell lines regardless of subtypes and molecular heterogeneity. Bedaquiline also inhibits capillary network formation of human lung tumor associated-endothelial cell (HLT-EC) on Matrigel and its multiple functions, such as spreading, proliferation and apoptosis, even in the presence of vascular endothelial growth factor (VEGF). We further demonstrate that bedaquiline acts on lung cancer cells and HLT-EC via inhibiting mitochondrial respiration and glycolysis, leading to ATP reduction and oxidative stress. Consistently, oxidative damage on DNA, protein and lipid were detected in cells exposed to bedaquiline. Importantly, the results obtained in in vitro cell culture are reproducible in in vivo xenograft lung cancer mouse model, confirming that bedaquiline suppresses lug tumor growth and angiogenesis, and increases oxidative stress. Our findings demonstrating that energy depletion is effectively against lung tumor cells and angiogenesis. Our work also provide pre-clinical evidence to repurpose antibiotic bedaquiline for lung cancer treatment. PMID- 29107692 TI - Autophagy in endometriosis: Friend or foe? AB - Endometriosis is a chronic, estrogen-dependent disease and characterized by the implantation of endometrial glands and stroma deep and haphazardly into the outside the uterine cavity. It affects an estimated 10% of the female population of reproductive age and results in obvious reduction in health-related quality of life. Unfortunately, there is no a consistent theory for the etiology of endometriosis. Furthermore, the endometriosis is hard to diagnose in early stage and the treatment methods are limited. Importantly, emerging evidence has investigated that there is a close relationship between endometriosis and autophagy. However, autophagy is a friend or foe in endometriosis is puzzling, the precise mechanism underlying autophagy in endometriosis has not been fully elucidated yet. Here, we provide an integrated view on the acquired findings of the connections between endometriosis and autophagy. We also discuss which may contribute to the abnormal level of autophagy in endometriosis. PMID- 29107693 TI - WDR74 participates in an early cleavage of the pre-rRNA processing pathway in cooperation with the nucleolar AAA-ATPase NVL2. AB - WD repeat-containing protein 74 (WDR74), a nucleolar-localized protein, is the mammalian ortholog of Nsa1, a 60S ribosome assembly factor in yeast. We previously showed that WDR74 associates with MTR4, the nuclear exosome-assisting RNA helicase, whose dissociation is prohibited by an ATPase-deficient mutant of the AAA-type chaperone NVL2. However, the functions and regulation of WDR74 during ribosome biogenesis in cooperation with NVL2 remains unknown. Here, we demonstrated that knockdown of WDR74 leads to significant defects in the pre-rRNA cleavage within the internal transcribed spacer 1 (ITS1), occurring in an early stage of the processing pathway. Interestingly, when the dissociation of WDR74 from the MTR4-containing exonuclease complex was impaired upon expression of the mutant NVL2, the same processing defect, with partial migration of WDR74 from the nucleolus towards the nucleoplasm, was observed. In the nucleoplasm, an increased interaction between WDR74 and MTR4 was detected by in situ proximity ligation assay. Therefore, the dissociation of WDR74 from MTR4 in a late stage of rRNA synthesis is thought to be required for appropriate maturation of the pre-60S particles. These results suggest that the spatiotemporal regulation of ribosome biogenesis in the nucleolus is mediated by the ATPase activity of NVL2. PMID- 29107694 TI - Chaetospirolactone reverses the apoptotic resistance towards TRAIL in pancreatic cancer. AB - The pancreatic cancer is one of the most aggressive tumors. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) can trigger apoptosis by interaction with death receptors. However, in TRAIL-resistant pancreatic cancer, responsiveness to TRAIL treatment is terribly poor. In current work, we have demonstrated that a natural product chaetospirolactone (CSL) isolated from an endophytic fungus Chaetomium sp. NF00754 can enhance the susceptibility of TRAIL resistant pancreatic cancer cells to apoptosis. CSL can induce apoptosis in TRAIL treated pancreatic cancer cells. Furthermore, combined CSL and TRAIL treatment significantly inhibits viability and migration of pancreatic cancer cells. Combinatorial TRAIL and CSL treatment repressed xenograft tumor growth without substantially toxic side effects. CSL can specifically upregulate expression of death receptor 4 (DR4). Further study revealed that CSL represses the activities of an epigenetic regulator enhancer of zeste homolog 2 (EZH2) and consistently reduces histone H3 lysine 27 trimethylation (H3K27me3) to allow DR4 transcription. Taken together, CSL treatment may reverse TRAIL resistance in pancreatic cancer cells via epigenetic regulation of DR4 implying that administration of CSL might represent a putative strategy for pancreatic cancer therapy. PMID- 29107695 TI - Contrast enhanced MUCT imaging of early articular changes in a pre-clinical model of osteoarthritis. AB - OBJECTIVE: The objective of this study was to characterize early osteoarthritis (OA) development in cartilage and bone tissues in the rat medial meniscus transection (MMT) model using non-destructive equilibrium partitioning of an ionic contrast agent micro-computed tomography (EPIC-MUCT) imaging. Cartilage fibrillation, one of the first physiological developments in OA, was quantified in the rat tibial plateau as three-dimensional (3D) cartilage surface roughness using a custom surface-rendering algorithm. METHODS: Male Lewis rats underwent MMT or sham-operation in the left leg. At 1- and 3-weeks post-surgery, the animals (n = 7-8 per group) were euthanized and the left legs were scanned using EPIC-MUCT imaging to quantify cartilage and bone parameters. In addition, a custom algorithm was developed to measure the roughness of 3D surfaces. This algorithm was validated and used to quantify cartilage surface roughness changes as a function of time post-surgery. RESULTS: MMT surgery resulted in significantly greater cartilage damage and subchondral bone sclerosis with the damage increasing in both severity and area from 1- to 3-weeks post-surgery. Analysis of rendered 3D surfaces could accurately distinguish early changes in joints developing OA, detecting significant increases of 45% and 124% in surface roughness at 1- and 3-weeks post-surgery respectively. CONCLUSION: Disease progression in the MMT model progresses sequentially through changes in the cartilage articular surface, extracellular matrix composition, and then osteophyte mineralization and subchondral bone sclerosis. Cartilage surface roughness is a quantitative, early indicator of degenerative joint disease in small animal OA models and can potentially be used to evaluate therapeutic strategies. PMID- 29107696 TI - The potential mechanism for Hydroxysafflor yellow A attenuating blood-brain barrier dysfunction via tight junction signaling pathways excavated by an integrated serial affinity chromatography and shotgun proteomics analysis approach. AB - Our previous studies elucidated that hydroxysafflor yellow A (HSYA) exerted anti inflammatory effects against ischemia stroke by inhibiting TLR4 pathway-mediated signaling transduction. However, only several targets were verified in that limited work. The integrated method of serial affinity chromatography (SAC) and shotgun proteomics analysis (SPA) might be an alternative approach for exploring a potential therapeutic role. SAC was induced to extract specific binding proteins in the brain tissue of 2 h of ischemia stroke mice via HSYA affinity matrices. SPA was conducted by nanoLC-MS/MS, while the identified proteins were mapped on to Gene Ontology and KEGG pathway components analysis. The protection of HSYA for blood-brain barrier in mice with ischemia stroke was assessed with the leakage of Evans Blue. The expression of tight junction proteins of blood brain barrier: occludin, claudin-5, and ZO-1 were detected with ischemia boundary positive areas staining. The regulation of nonmuscle myosin heavy chain IIA (NMMHC IIA), TLR4-mediated PI3K/AKT/JNK1/2/14-3-3epsilon/NF-kappaB p65 signaling pathway were evaluated using western blot analysis. A total of 35 proteins with molecular eights ranging from 27,841.22 to 234,122.79 KD were identified. Gene Ontology annotation and KEGG pathways analysis of the identified proteins were conducted with tight junction and PI3K/AKT signaling pathways. HSYA could significantly reduce the leakage of Evans Blue in mice with ischemia stroke, while attenuating the expression of occludin, claudin-5, and ZO-1. Western blot demonstrated that regulation of NMMHC IIA, TLR4-mediated PI3K/AKT/JNK1/2/14-3 3epsilon/NF-kappaB p65 signaling pathway played an essential role in the protective effect of HSYA. The integrated method of SAC and SPA provides the promising explanations for exploring the mechanism underlying blood-brain barrier dysfunction via the tight junction pathway. HSYA could attenuate blood-brain barrier dysfunction in anti-inflammatory patterns in ischemia stroke mice via the tight junction pathway. PMID- 29107697 TI - Permanent His bundle pacing: Recommendations from a Multicenter His Bundle Pacing Collaborative Working Group for standardization of definitions, implant measurements, and follow-up. AB - His bundle pacing (HBP) prevents ventricular dyssynchrony and its long-term consequences by preserving normal electrical activation of the ventricles. Since the original description of permanent HBP in 2000, the adoption of HBP has increased over the past several years. However, the reporting of procedural and clinical outcomes to date is not uniform. This article is a collaboration between several implanters with significant experience in HBP to establish a uniform set of definitions encompassing the different forms of HBP as well as define a standardized approach to gathering data end points to ensure consistency in reported outcomes. PMID- 29107698 TI - Should the force be with us? PMID- 29107699 TI - Synthetic Three-Component HIV-1 V3 Glycopeptide Immunogens Induce Glycan Dependent Antibody Responses. AB - Eliciting broadly neutralizing antibody (bNAb) responses against HIV-1 is a major goal for a prophylactic HIV-1 vaccine. One approach is to design immunogens based on known broadly neutralizing epitopes. Here we report the design and synthesis of an HIV-1 glycopeptide immunogen derived from the V3 domain. We performed glycopeptide epitope mapping to determine the minimal glycopeptide sequence as the epitope of V3-glycan-specific bNAbs PGT128 and 10-1074. We further constructed a self-adjuvant three-component immunogen that consists of a 33-mer V3 glycopeptide epitope, a universal T helper epitope P30, and a lipopeptide (Pam3CSK4) that serves as a ligand of Toll-like receptor 2. Rabbit immunization revealed that the synthetic self-adjuvant glycopeptide could elicit substantial glycan-dependent antibodies that exhibited broader recognition of HIV-1 gp120s than the non-glycosylated V3 peptide. These results suggest that the self adjuvant synthetic glycopeptides can serve as an important component to elicit glycan-specific antibodies in HIV vaccine design. PMID- 29107700 TI - General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases. AB - Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl alpha-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery. PMID- 29107701 TI - B. subtilis LytR-CpsA-Psr Enzymes Transfer Wall Teichoic Acids from Authentic Lipid-Linked Substrates to Mature Peptidoglycan In Vitro. AB - Gram-positive bacteria endow their peptidoglycan with glycopolymers that are crucial for viability and pathogenesis. However, the cellular machinery that executes this function is not well understood. While decades of genetic and phenotypic work have highlighted the LytR-CpsA-Psr (LCP) family of enzymes as cell-wall glycopolymer transferases, their in vitro characterization has been elusive, largely due to a paucity of tools for functional assays. In this report, we synthesized authentic undecaprenyl diphosphate-linked wall teichoic acid (WTA) intermediates and built an assay system capable of monitoring LCP-mediated glycopolymer transfer. We report that all Bacillus subtilis LCP enzymes anchor WTAs to peptidoglycan in vitro. Furthermore, we probed the catalytic requirements and substrate preferences for these LCP enzymes and elaborated in vitro conditions for facile tests of enzyme function. This work sheds light on the molecular features of glycopolymer transfer and aims to aid drug discovery and development programs exploiting this promising antibacterial target. PMID- 29107702 TI - Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene. AB - : The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS: The tgDISC1 group exhibited intact short term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model. PMID- 29107704 TI - Perceptual training enhances temporal acuity for multisensory speech. AB - The temporal relationship between auditory and visual cues is a fundamental feature in the determination of whether these signals will be integrated. The window of perceived simultaneity (TBW) is a construct that describes the epoch of time during which asynchronous auditory and visual stimuli are likely to be perceptually bound. Recently, a number of studies have demonstrated the capacity for perceptual training to enhance temporal acuity for audiovisual stimuli (i.e., narrow the TBW). These studies, however, have only examined multisensory perceptual learning that develops in response to feedback that is provided when making judgments on simple, low-level audiovisual stimuli (i.e., flashes and beeps). Here we sought to determine if perceptual training was capable of altering temporal acuity for audiovisual speech. Furthermore, we also explored whether perceptual training with simple or complex audiovisual stimuli generalized across levels of stimulus complexity. Using a simultaneity judgment (SJ) task, we measured individuals' temporal acuity (as estimated by the TBW) prior to, immediately following, and one week after four consecutive days of perceptual training. We report that temporal acuity for audiovisual speech stimuli is enhanced following perceptual training using speech stimuli. Additionally, we find that changes in temporal acuity following perceptual training do not generalize across the levels of stimulus complexity in this study. Overall, the results suggest that perceptual training is capable of enhancing temporal acuity for audiovisual speech in adults, and that the dynamics of the changes in temporal acuity following perceptual training differ between simple audiovisual stimuli and more complex audiovisual speech stimuli. PMID- 29107703 TI - Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin deficient mice. AB - Orexin A is produced in neurons of the lateral, perifornical and dorsomedial regions of the lateral hypothalamic area, which then project widely throughout the central nervous system to regulate arousal state, sleep-wake architecture, energy homeostasis and cognitive processes. Disruption of orexin signaling leads to sleep disturbances and increased body mass index, but recent studies also indicate that orexin neuron activation improves learning and memory. We hypothesized that hippocampal orexin receptor activation improves memory. To test this idea, we obtained orexin/ataxin-3 (O/A3) mice, which become deficient in orexin neurons by about 12 weeks of age. We first measured hippocampal orexin receptor 1 (OX1R) gene expression and protein levels, then tested acquisition and consolidation of two-way active avoidance (TWAA) memory, a hippocampal-dependent learning and memory task. Finally, we determined if exogenous intra-hippocampal OXA treatment could reverse cognitive impairment (as determined by TWAA) in OA/3 mice. We showed that OX1R mRNA expression and protein levels were significantly elevated in O/A3 mice, indicating the potential for preserved orexin responsiveness. The O/A3 mice were significantly impaired in TWAA memory vs. control mice, but OXA treatment (both acute and chronic) reversed these memory deficits. These results demonstrate that orexin plays an important role in hippocampal-dependent consolidation of two-way active avoidance memory, and orexin replacement can rescue the cognitive impairment. PMID- 29107705 TI - AMP-activated protein kinase (AMPK) is decreased in the mouse brain during experimental cerebral malaria. AB - Cerebral malaria (CM) is a severe form of malaria caused by Plasmodium falciparum and P.vivax. CM affects the brain leading to coma and is the leading cause of death in malaria patients. The enzyme, adenosine 5'-monophosphate-activated protein kinase (AMPK), is an important metabolic sensor that helps in maintaining energy homeostasis during normal physiological as well as pathological conditions. In the present study, we studied the status of AMPK in the mouse model of CM. The C57BL/6 mice infected by rodent-specific P.berghei ANKA were used for the study. We found a statistically significant reduction in the gene expressions of Prkaa1 (alpha1 subunit) and Prkaa2 (alpha2 subunit) in the brains of CM mice compared to uninfected control. Also, there was a statistically significant reduction in the ratio of phospho-AMPK/AMPK protein levels in CM compared to uninfected control. There was no statistically significant decrease in phospho-ACC/ACC ratio in the brain compared to control. As AMPK is downregulated in CM, there is a possible involvement in neuronal cell death during CM pathogenesis, and therefore we feel that novel AMPK activating drugs might be helpful as an adjunctive therapy for conferring neuroprotection. PMID- 29107706 TI - Effects of transcranial direct current stimulation over the supplementary motor area body weight-supported treadmill gait training in hemiparetic patients after stroke. AB - Transcranial direct current stimulation (tDCS) is used in a variety of disorders after stroke including upper limb motor dysfunctions, hemispatial neglect, aphasia, and apraxia, and its effectiveness has been demonstrated. Although gait ability is important for daily living, there were few reports of the use of tDCS to improve balance and gait ability. The supplementary motor area (SMA) was reported to play a potentially important role in balance recovery after stroke. We aimed to investigate the effect of combined therapy body weight-supported treadmill training (BWSTT) and tDCS on gait function recovery of stroke patients. Thirty stroke inpatients participated in this study. The two BWSTT periods of 1weeks each, with real tDCS (anode: front of Cz, cathode: inion, 1mA, 20min) on SMA and sham stimulation, were randomized in a double-blind crossover design. We measured the time required for the 10m Walk Test (10MWT) and Timed Up and Go (TUG) test before and after each period. We found that the real tDCS with BWSTT significantly improved gait speed (10MWT) and applicative walking ability (TUG), compared with BWSTT+sham stimulation periods (p<0.05). Our findings demonstrated the feasibility and efficacy of tDCS in gait training after stroke. The facilitative effects of tDCS on SMA possibly improved postural control during BWSTT. The results indicated the implications for the use of tDCS in balance and gait training rehabilitation after stroke. PMID- 29107707 TI - Time of day but not aging regulates 5-HT7 receptor binding sites in the hamster hippocampus. AB - Activation of 5-HT7 receptors influences memory as well as circadian rhythms and other processes. This study investigated the regulation of the 5-HT7 receptors in the hippocampus, a likely substrate for the effects of 5-HT7 receptor compounds on memory. Because endogenous serotonin release is higher during the active phase, and chronic treatment with a serotonin-selective reuptake inhibitor down regulates 5-HT7 receptors, we hypothesized that 5-HT7 receptors exhibit 24-h variations. We also hypothesized that aging decreases 5-HT7 receptors in the hippocampus, as it does in the dorsal raphe nucleus, a brain site for serotonergic resetting of circadian rhythms. Male hamsters (young, 3-5 mos; old, 17-21 mos) exposed to a light:dark cycle were euthanized at 4 times of day (zeitgeber times [ZT]1, 6, 13, & 19; ZT12=time of lights:off). 5-HT7 receptor autoradiography was conducted on hippocampal sections using [3H]8-OH-DPAT [2nM] as the radioligand and SB-269970 [1MUM] to define nonspecific binding. Slide mounted sections and radioactive standards were apposed to X-ray films; the resultant autoradiograms were assessed by computer-assisted microdensitometry. Specific 5-HT7 receptor binding was robustly expressed in the dentate gyrus (DG) and CA1 but not in the CA2 or CA3. In the CA1 and DG, specific 5-HT7 receptor binding exhibited 24-h rhythms with troughs at night (P<0.005; P<0.05, respectively). Aging did not significantly affect specific 5-HT7 receptor binding in these regions, nor were significant time and age interactions observed. These findings suggest that the therapeutic effectiveness of 5-HT7 drugs may vary with time of day of administration but not with the age of the recipient. PMID- 29107708 TI - Rab20, a novel Rab small GTPase that negatively regulates neurite outgrowth of PC12 cells. AB - The Rab family small GTPases are key players in the membrane traffic that underlies various cellular phenomena. Neurite outgrowth, which is a prerequisite for neuronal network formation, also requires membrane traffic from the cell body to the tips of neurites. Although several Rabs have been shown to promote neurite outgrowth, very little is known about Rab involvement in the negative regulation of neurite outgrowth. Here we used nerve growth factor-stimulated PC12 cells to perform siRNA-based comprehensive knockdown screenings for Rabs that negatively regulate neurite outgrowth and succeeded in identifying Rab20 as a novel negative regulator of neurite outgrowth. Our findings showed that knockdown of endogenous Rab20 in PC12 cells promoted neurite outgrowth, whereas overexpression of active Rab20 inhibited it. We also found that the presence of Gly-64 and Cys-70, both of which are conserved only in the switch II region, a putative effector binding domain, of Rab20 is required for the inhibitory effect of Rab20 on neurite outgrowth. These findings indicated that active Rab20 suppresses neurite outgrowth of PC12 cells, possibly through interaction with an unidentified effector molecule that specifically recognizes certain amino acids in the switch II region of Rab20. PMID- 29107709 TI - IFNL4 Genotype Is Associated With Virologic Relapse After 8-Week Treatment With Sofosbuvir, Velpatasvir, and Voxilaprevir. PMID- 29107710 TI - GREM1 Defect Unlikely to be Disease Causing and Hence Not Useful for Screening and Surveillance in Singapore Mixed Polyposis Families. PMID- 29107711 TI - Quality Indicators for Colonoscopy: Missing the Wood for the Trees? PMID- 29107712 TI - Multiple Serrated Polyps and Serrated Polyposis Syndrome: Equally Hazardous? PMID- 29107714 TI - Nonspatial sequence coding varies along the CA1 transverse axis. AB - The hippocampus plays a critical role in the memory for sequences of events, a defining feature of episodic memory. To shed light on the fundamental mechanisms supporting this capacity, we recently recorded neural activity in CA1 as rats performed a nonspatial odor sequence memory task. Our main finding was that, while the animals' location and behavior remained constant, a proportion of CA1 neurons fired differentially to odors depending on whether they were presented in or out of sequence (sequence cells). Here, we further examined if such sequence coding varied along the distal-to-proximal axis of the dorsal CA1 region (distal: toward subiculum; proximal: toward CA3). Differences in information processing along this axis have been suggested by recent anatomical and electrophysiological evidence that odor information may be more strongly represented in the distal segment, whereas spatial information may be more strongly represented in the proximal segment. Recorded neurons were grouped into four arbitrary sections of dorsal CA1, ranging from distal to proximal. We found that, although sequence cell coding was observed across the distal-to-proximal extent of CA1 from which we recorded, it was significantly higher in intermediate CA1, a region with more balanced anatomical input from lateral and medial entorhinal regions. More specifically, in that particular segment of CA1, we observed a significant increase in the magnitude of sequence coding of all cells, as well as in the sequential information content of sequence cells. Importantly, a different pattern was observed when examining the distribution of spatial coding from the same electrodes. Consistent with previous reports, our results suggest that spatial information was more strongly represented in the proximal section of CA1 (higher proportion of cells with place fields). These findings indicate that nonspatial sequence memory coding is not uniformly distributed along the transverse axis of CA1, and that this distribution does not simply follow the expected gradient based on the stimulus modality or the degree of spatial selectivity. Instead, the observed distribution suggests this form of sequence coding may be associated with convergent input from lateral and medial entorhinal regions, which is present throughout the proximodistal axis but greater in intermediate CA1. PMID- 29107713 TI - The enduring impact of neurulation stage alcohol exposure: A combined behavioral and structural neuroimaging study in adult male and female C57BL/6J mice. AB - Prenatal alcohol exposure (PAE) can cause behavioral and brain alterations over the lifespan. In animal models, these effects can occur following PAE confined to critical developmental periods, equivalent to the third and fourth weeks of human gestation, before pregnancy is usually recognized. The current study focuses on PAE during early neurulation and examines the behavioral and brain structural consequences that appear in adulthood. On gestational day 8 C57BL/6J dams received two alcohol (2.8g/kg, i.p), or vehicle, administrations, four hours apart. Male and female offspring were reared to adulthood and examined for performance on the elevated plus maze, rotarod, open field, Morris water maze, acoustic startle, social preference (i.e. three-chambered social approach test), and the hot plate. A subset of these mice was later evaluated using magnetic resonance imaging to detect changes in regional brain volumes and shapes. In males, PAE increased exploratory behaviors on the elevated plus maze and in the open field; these changes were associated with increased fractional anisotropy in the anterior commissure. In females, PAE reduced social preference and the startle response, and decreased cerebral cortex and brain stem volumes. Vehicle treated females had larger pituitaries than did vehicle-treated males, but PAE attenuated this sex difference. In males, pituitary size correlated with open field activity, while in females, pituitary size correlated with social activity. These findings indicate that early neurulation PAE causes sex specific behavioral and brain changes in adulthood. Changes in the pituitary suggest that this structure is especially vulnerable to neurulation stage PAE. PMID- 29107715 TI - Differed surgery in patient with colorectal endometriosis and pregnancy intention: Is it reasonable? AB - The management of patients presenting deep infiltrating endometriosis involving the rectum (DIER) and pregnancy intention is controversial. Assisted Reproduction Techniques (ART) are often proposed first, but this may lead to complications and further difficulties managing DIER. A 29-years-old woman was diagnosed with pre occlusive DIER. However, she was offered in vitro fertilization (IVF) and underwent six unsuccessful cycles with serious complications: an ectopic pregnancy and a hemoperitoneum following arterial injury during oocyte retrieval, requiring two laparotomies in emergency. The patient's symptoms worsened over time and colorectal resection with diverting colostomy was performed. The patient's quality of life was then improved. In our opinion, prior ART in patients presenting DIER delays surgery and may have harmful complications. Therefore, primary surgery followed by ART may be a valuable option in some cases and should be discussed with the patients. PMID- 29107716 TI - Pacsin 2 is required for the maintenance of a normal cardiac function in the developing mouse heart. AB - The Pacsin proteins (Pacsin 1, 2 and 3) play an important role in intracellular trafficking and thereby signal transduction in many cells types. This study was designed to examine the role of Pacsin 2 in cardiac development and function. We investigated the development and electrophysiological properties of Pacsin 2 knockout (P2KO) hearts and single cardiomyocytes isolated from 11.5 and 15.5days old fetal mice. Immunofluorescence experiments confirmed the lack of Pacsin 2 protein expression in P2KO cardiac myocytes in comparison to wildtype (WT). Western blotting demonstrates low expression levels of connexin 43 and T-box 3 proteins in P2KO compared to wildtype (WT). Electrophysiology measurements including online Multi-Electrode Array (MEA) based field potential (FP) recordings on isolated whole heart of P2KO mice showed a prolonged AV-conduction time. Patch clamp measurements of P2KO cardiomyocytes revealed differences in action potential (AP) parameters and decreased pacemaker funny channel (If), as well as L-type Ca2+ channel (ICaL), and sodium channel (INa). These findings demonstrate that Pacsin 2 is necessary for cardiac development and function in mouse embryos, which will enhance our knowledge to better understand the genesis of cardiovascular diseases. PMID- 29107717 TI - Coccidioidomycosis for Neurosurgeons. PMID- 29107718 TI - Rapid Progression of Ossification of the Posterior Longitudinal Ligament After Anterior Cervical Discectomy and Fusion. AB - BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) has a reported incidence of 1.9%-4.3%. Disease progression is associated with surgery, with most studies focusing on OPLL progression after laminoplasty. The continued range of motion following surgery is believed to place strain on adjacent levels, driving calcification of the ligament. We present a case of marked progression of OPLL at levels adjacent to a previous anterior cervical discectomy and fusion. CASE REPORT: A 59-year-old man initially presented for progressive loss of balance and dexterity and underwent a C4-6 anterior cervical discectomy and fusion procedure. Computed tomography performed 1 year postoperatively showed fusion across C4-6 with no evidence of OPLL at any level. Two years following index surgery, the patient reported right-side arm pain. Computed tomography revealed new minimal OPLL opposite the C3-4 level that was not causing cord compression. A sparing midline bilateral C3-7 laminotomy was performed to correct stenosis seen on magnetic resonance imaging. At 7 years after the index procedure, the patient presented with myelopathic symptoms exceeding symptoms at his index presentation. Computed tomography revealed marked progression of OPLL. The patient underwent C2-T2 posterior fusion with laminectomy from C2-C7 and responded well with gradual improvements in balance and arm pain after surgery. CONCLUSIONS: Our report demonstrates that OPLL progression, which is largely reported following laminoplasty, may similarly occur following anterior cervical discectomy and fusion and supports the concept of motion-related OPLL progression. PMID- 29107719 TI - Cryopreservation of Autologous Cranial Bone Flaps for Cranioplasty: A Large Sample Retrospective Study. AB - OBJECTIVE: To clarify the clinical outcomes of cranioplasty with cryopreserved bone flaps and identify risk factors related to bone flap infection and resorption after cranioplasty with cryopreserved bone flaps. METHODS: A total of 946 patients (989 bone flaps) underwent decompressive craniectomy and delayed cranioplasty via the use of cryopreserved autogenous cranial bone flaps. Cranial bone flaps were removed during the initial craniectomy and reserved in liquid nitrogen (-196 degrees C) with dimethyl sulfoxide as a cryoprotectant. Cranioplasty subsequently was performed once the brain injury had healed. Data regarding complications and clinical outcomes were recorded and the potential risk factors were analyzed. RESULTS: Data from 960 flaps were available for analysis. The overall complication rate was 15.83% (152 of 960). Bone resorption occurred in 42 flaps in 37 patients (4.38%). The bone flaps resorption rate was greater in patients <=18 years than in patients >18 years (9.38% vs. 3.61%, P < 0.05). Cryopreservation for more than 365 days tended to result in a greater bone resorption rate (6.88% vs. 2.92%, P < 0.01). Skull bone grafts infection occurred in 39 flaps in 34 patients (4.06%). The bone graft infection rate was greater in emergency craniectomy cases (8.81% vs. 2.59%, P < 0.01) and in patients with diabetes (10.53% vs. 3.07%, P < 0.01). CONCLUSIONS: Cryopreservation of autologous cranial bone flaps is safe and effective for cranioplasty. Cranioplasty with cryopreserved autologous cranial bone flaps should be performed no more than 1 year after craniectomy. Emergency craniectomy and patients with diabetes require special attention. PMID- 29107720 TI - Sporadic Intradural Extramedullary Hemangioblastoma of the Cauda Equina: Case Report and Literature Review. AB - BACKGROUND: Spinal hemangioblastomas account for 1%-5% of all spinal cord tumors. Although spinal hemangioblastomas are rare, it is exceedingly rare to have a case of intradural extramedullary hemangioblastoma of the spine, especially in isolation without von Hippel-Lindau syndrome. The purpose of this report is to present a rare case of intradural extramedullary hemangioblastoma of the cauda equina and a literature review. CASE DESCRIPTION: An 82-year-old man presented with an intradural mass at the L4 spinal level on magnetic resonance imaging. Given the benign appearance on magnetic resonance imaging and lack of radiculopathy, the decision was made to observe the patient. Over the course of 4 years, the tumor enlarged and caused left lower extremity radicular pain. Posterior laminectomy and tumor excision was performed. Owing to intimate involvement with multiple nerve roots, subtotal resection was performed. Immunohistopathologic analysis revealed a highly vascular and cellular tumor, with findings consistent with intradural extramedullary hemangioblastoma. The patient ultimately underwent CyberKnife radiosurgery for residual tumor, with improvement in neurologic symptoms. Follow-up studies at 2 years failed to show any tumor growth. CONCLUSIONS: Literature review revealed cauda equina intradural extramedullary spinal hemangioblastoma to be a rare diagnosis. Furthermore, this was a sporadic case without associated von Hippel-Lindau syndrome. Only 20 previous cases have been reported. Immunohistopathologic analysis was required to make the diagnosis. Radiosurgery appears to be useful in cases of residual tumor after subtotal tumor resection. PMID- 29107721 TI - The Correlation Between Vertical Laminar Fractures and the Severity of Associated Burst Fractures. AB - BACKGROUND: Patients with laminar fractures have a higher chance of experiencing severe trauma and neurologic deficit. In previous studies, laminar fractures were divided into different types based on the axial plane of computed tomographic scans. No report described the morphology of vertical laminar fractures in the coronal plane. Furthermore, the correlation between a specific type of laminar fracture and the extent of severity of thoracolumbar (TL) burst fractures has rarely been mentioned. METHODS: A retrospective evaluation of 341 patients with TL burst fractures with or without laminar fractures were divided into 6 groups based on the morphology observed across reconstructed coronal and axial computed tomographic planes. The Thoracolumbar Injury Classification and Severity Score (TLICS), Load Sharing Classification (LSC), and American Spinal Injury Association (ASIA) impairment scale were evaluated for each patient. Intergroup comparisons were also performed for all metrics. RESULTS: The TLICS, LSC, and ASIA impairment scale were determined for each laminar fracture group. Statistical differences were found in most intergroup comparisons across all metrics. Significantly higher injury scores were observed in the groups with a more severe coronal and axial laminar fracture, and the injury severity in the coronal scan played a more decisive role. CONCLUSIONS: The morphology of vertical laminar fractures as observed across multiple image planes was more complex and accurate than an analysis based solely on the axial plane. Different morphologies indicated differences in the severity of associated TL burst fractures. The laminar fracture in the coronal plane was associated with the severity of spinal injury. PMID- 29107722 TI - Adolescent Idiopathic Scoliosis Surgery by a Neurosurgeon: Learning Curve for Neurosurgeons. AB - OBJECTIVE: To determine a neurosurgeon's learning curve of surgical treatment for adolescent idiopathic scoliosis (AIS) patients. METHODS: This study is a retrospective analysis. Forty-six patients were treated by a single neurosurgeon between 2011 and 2017 using posterior segmental instrumentation and fusion. According to the time period, the former and latter 23 patients were divided into group 1 and group 2, respectively. Patients' demographic data, curve magnitude, number of levels treated, amount of correction achieved, radiographic/clinical outcomes, and complications were compared between the groups. RESULTS: The majority were females (34 vs. 12) with average ages of 15.0 versus 15.6, respectively. The mean follow-up period was 24.6 months. The average number of fusion levels was similar with 10.3 and 11.5 vertebral bodies in groups 1 and 2, respectively. The average Cobb angle of major curvature was 59.8 degrees and 58.5 degrees in groups 1 and 2, respectively. There observed significant reductions of operative time (324.4 vs. 224.7 minutes, P = 0.007) and estimated blood loss (648.3 vs. 438.0 mL, P = 0.027) in group 2. The correction rate of the major structural curve was greater in group 2 (70.7% vs. 81.0%, P = 0.001). There was no case of neurologic deficit, infection, and revision for screw malposition. One patient of group 1 underwent fusion extension surgery for shoulder asymmetry. CONCLUSION: Radiographic and clinical outcomes of AIS patients treated by a neurosurgeon were acceptable. AIS surgery may be performed with an acceptable rate of complications after about 20 surgeries. With acquisition of surgical experiences, neurosurgeons could perform deformity surgery for AIS effectively and safely. PMID- 29107723 TI - Results of a Policy of Fast Tapering of Steroids After Resection Surgery in Glioblastoma. AB - BACKGROUND: Corticosteroids are routinely used to treat brain tumors. Although steroids have an immediate clinical benefit, their use can lead to a number of relevant complications, and a negative association with overall survival has been shown in glioblastoma (GBM) patients. There is no evidence in the literature regarding the ideal dose. We assessed the use of steroids in patients with GBM after resection surgery. METHODS: This is a cohort study of 131 newly diagnosed GBM patients that underwent tumor resection surgery. Dose of steroids was as low as possible, without a formal guideline. Fifteen patients were lost at baseline (retention rate, 88.5%). Our population for analysis included 114 patients that were still at risk of death at a landmark time point 2 months after surgery. RESULTS: Within 1 month of surgery, 93.9% of patients came off steroids, and 84.7% came off steroids before 2 weeks. One month after radiotherapy, 86 (75.4%) patients remained steroid-free and 28 (24.6%) were steroid-dependent. During 2235 person-months of follow-up, we documented 101 incident deaths. After adjusting for age, sex, Karnofsky Performance Scale score, MGMT promoter methylation, and extent of tumor resection, and time to surgery, the hazard ratio for the steroid free group of patients was 0.46 (95% confidence interval, 0.28-0.77) compared with steroid-dependent patients. CONCLUSIONS: This study provides evidence for an inverse association between the lack of steroid dependency and mortality risk in patients whose steroid dosage was rapidly tapered after surgery. After resection, most patients can stop steroids within 2 weeks and finish radiotherapy without steroids. PMID- 29107724 TI - Prosthetic Replacement of the Ocular Surface Ecosystem Treatment of Ocular Surface Disease After Skull Base Tumor Resection. AB - BACKGROUND: Prosthetic replacement of the ocular surface ecosystem (PROSE) treatment is an effective, nonsurgical therapeutic option for patients with ocular surface disease related to cranial nerve deficits secondary to skull base tumor resection. METHODS: This case series describes the impact of PROSE treatment in patients with symptomatic exposure keratopathy or neurotrophic keratitis after skull base tumor surgery. RESULTS: All patients improved symptomatically and functionally with PROSE treatment, and have had sustained improvement for as long as 3 years. CONCLUSIONS: In postneurosurgical cases in which neurologic function may recover, PROSE treatment offers a safe, nonsurgical treatment option to support the ocular surface during the period of observation awaiting neurologic recovery. PMID- 29107725 TI - Proximal Stenosis Is Associated with Rupture Status in Middle Cerebral Artery Aneurysms. AB - BACKGROUND: Hemodynamic factors impact cerebral aneurysm development and progression. Parent vessel architectural features, such as caliber, curvature, and angle, can affect downstream pressure and shear stress. OBJECTIVE: To investigate the association between proximal parent vessel stenosis and aneurysm rupture status at the middle cerebral artery (MCA) bifurcation. METHODS: Catheter 3-dimensional rotational angiographic datasets from 69 Japanese patients with MCA aneurysms (58 unruptured/11 ruptured) were analyzed. The narrowest cross sectional area of the M1 segment was evaluated through equidistant cross sectional plane cuts along the M1 length. The degree of stenosis relative to M1 size (StenosisIndex) and the distance from stenosis to the aneurysm neck (StenosisAnDist) were statistically evaluated. The effects of StenosisIndex and StenosisAnDist were determined in parametric aneurysm models with/without stenosis using computational fluid dynamic and fluid-structure interaction simulations. RESULTS: MCA harboring ruptured aneurysms had significantly greater StenosisIndex (0.31 +/- 0.21 vs. 0.17 +/- 0.14, P = 0.01), indicative of greater narrowing, and shorter StenosisAnDist (4.26 +/- 1.91 vs. 6.94 +/- 4.06 mm, P = 0.02) compared with unruptured aneurysms. Multivariate analysis combining StenosisIndex and StenosisAnDist resulted in P = 0.003, area under the curve = 0.81 (80% sensitivity, 74% specificity). Computational fluid dynamic and fluid structure interaction simulations identified a synergetic effect of high stenosis and short StenosisAnDist in inducing greater aneurysm inflow velocity and deeper jet penetration, greater dome pressure, and greater tensile stress in the aneurysm wall. CONCLUSIONS: Ruptured status in bifurcation MCA aneurysms was associated with severity of proximal M1 stenosis and its proximity to the aneurysm neck, a novel risk factor, which acts by increasing aneurysm dome wall tension, and should be considered in investigations of rupture risk stratification. PMID- 29107726 TI - Systematic Review of Woven EndoBridge for Wide-Necked Bifurcation Aneurysms: Complications, Adequate Occlusion Rate, Morbidity, and Mortality. AB - BACKGROUND: Although the Woven EndoBridge (WEB [Sequent Medical, Aliso Viejo, California, USA]) is a highly innovative technique for the endovascular treatment of wide-necked bifurcation aneurysms (WNBAs), there are no studies available comparing this technique with surgical results or other endovascular results of stent-assisted coiling or balloon-assisted coiling for WNBAs. The purpose of this study was to assess complications, complete occlusion rate, and morbidity and mortality of the WEB in WNBA treatment. METHODS: Published literature citing embolization results for WNBAs using the WEB was reviewed. A systematic review was performed to evaluate the complications, complete occlusion rate, and morbidity and mortality. RESULTS: We identified 19 studies, including 935 patients. The most frequent aneurysm locations were the bifurcation of the middle cerebral artery (MCA) (42.8%), the anterior communicating artery (23%), and the basilar bifurcation (20.8%). The technical success rate of the WEB was 97% (95% confidence interval [CI], 96%-98%). The thromboembolic complication rate was 8% (95% CI, 6%-11%). The thromboembolic complication rate was 10% (95% CI, 7%-13%) in cases before 2013, which was higher than in cases after 2013 (6%; 95% CI, 4% 9%; P = 0.045). MCA bifurcation aneurysm has a higher thromboembolic complication rate than posterior circulation aneurysm. The overall bleeding complication rate of the WEB was 2% (95% CI, 1%-3%). The adequate occlusion rate was 81% (95% CI, 76%-85%). Morbidity during follow-up was 3% (95% CI, 1%-4%) (I2 = 30.4%), and mortality was 2% (95% CI, 1%-3%). CONCLUSIONS: Adequate aneurysm occlusion was found in 81% of WEB cases with low morbidity and mortality. PMID- 29107727 TI - Severe Spinal Cord Compression by Pure Giant Intradural Schwannoma of Cervical Spine. AB - Giant intradural extramedullary schwannoma of the cervical spine usually causes severe spinal cord compression. This type of tumor has a low incidence. Patients present progressive loss of strength and other functions of the spinal cord. This article shows the clinical images of a 75-year-old male with the diagnosis of giant intradural extramedullary schwannoma and the cases reported in the literature. PMID- 29107729 TI - Quantitative determination of chromium picolinate in animal feeds by solid phase extraction and liquid chromatography-tandem mass spectrometry. AB - Chromium picolinate is one of the important Cr3+ resources and is widely used in animal production. A convenient, reliable and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative determination of chromium picolinate in animal feeds. Feed samples were extracted with acetonitrile and subsequently cleaned up by solid phase extraction cartridges SupelcleanTM LC-18. Chromium picolinate was efficiently separated with a Waters ACQUITY UPLC(r) BEH C18 column, ionized with electrospray ion source in positive mode (ESI+), and quantitatively determined by tandem mass spectrometry in multiple reaction monitoring mode. Standard calibration curve of chromium picolinate in the concentration range from 0.5 to 1000ng/mL was obtained with good linearity correlation coefficient (R2=0.9982). Average recoveries ranged from 95.37%~105.54%, as detected by spiking 0.02~640mg/kg of chromium picolinate in complete feed, concentrated feed and premix. Intra-day and inter day coefficient of variation were 0.59%~6.67% and 2.36%~6.97%, respectively. The limits of quantitation were 0.02mg/kg, 0.025mg/kg, and 2mg/kg for complete feed, concentrated feed, and premix, respectively. Actual sample analysis indicated that the developed method can be an effective tool to monitoring CrPic content in animal feed. PMID- 29107728 TI - Acute and long-term effects of Delta9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice. AB - Use of exogenous cannabinoids disrupts the fine-tuned endocannabinoid receptor system, possibly leading to alterations in cognition, memory, and emotional processes that endure long after cannabinoid use has stopped. Long-term adolescent use may uniquely disrupt these behaviors when compared to adult use. The current study explored the acute and long-term behavioral effects of six 10mg/kg Delta9-tetrahydrocannabinol (THC) injections across the adolescent or early adult period in male inbred C57Bl/6J and DBA/2J mice. The acute and prolonged effects of THC on object memory using the novel object recognition task, unconditioned anxiety in the elevated plus maze and open field, and sedative effects in the open field were examined. Acute THC treatment resulted in anxiogenic activity in both strains, but only caused sedation in B6 mice. Repeated THC treatment resulted in a protracted effect on object recognition, but not unconditioned anxiety, assessed 4weeks later. In both strains, an adolescent history of THC treatment disrupted later object recognition. Interestingly, in B6 mice an adult history of THC exposure appeared to rescue a deficit in object recognition observed in vehicle-treated adults. Repeated THC administration also produced a protracted effected on CB1R protein expression. Animals treated with THC in adolescence maintained increased levels of CB1R protein expression compared to their adult THC-treated counterparts at five weeks following the last injection. These results indicate that THC use may have long-lasting effects with adolescence being a unique period of susceptibility. PMID- 29107730 TI - Determination of the authenticity of plastron-derived functional foods based on amino acid profiles analysed by MEKC. AB - Plastron is a nutritive and superior functional food. Due to its limited supply yet enormous demands, some functional foods supposed to contain plastron may be forged with other substitutes. This paper reports a novel and simple method for determination of the authenticity of plastron-derived functional foods based on comparison of the amino acid (AA) profiles of plastron and its possible substitutes. By applying micellar electrokinetic chromatography (MEKC), 18 common AAs along with another 2 special AAs - hydroxyproline (Hyp) and hydroxylysine (Hyl) were detected in all plastron samples. Since chicken, egg, fish, milk, pork, nail and hair lacked of Hyp and Hyl, plastron could be easily distinguished. For those containing collagen, a statistical analysis technique - principal component analysis (PCA) was adopted and plastron was successfully distinguished. When applied the proposed method to authenticate turtle shell glue in the market, fake products were commonly found. PMID- 29107731 TI - Liquid chromatography-tandem mass spectrometric assay for determination of unstable arecoline in rat plasma and its application. AB - Arecoline, a predominant alkaloid in areca nut, shows several pharmacological and toxicological effects. In present study, a sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and fully validated for quantification of arecoline in rat plasma. Importantly, our group found that arecoline was highly unstable in rat plasma samples, which brought challenges to accurately quantify in vivo. The hydrolysis of ester moiety of arecoline by carboxylesterases was responsible for its instability, and arecoline was hydrolyzed to arecaidine. The degradation of arecoline was completely inhibited using 5% formic acid as a stabilizer, which was immediately added to freshly collected rat plasma samples. EDTA was adopted as the anticoagulant to also reduce the degradation during blood collection and plasma separation owing to its anti-esterase effect. The plasma sample was separated by a C18 analytical column with a mobile phase of 0.1% formic acid and methanol (95:5v/v) at an isocratic flow rate of 300MUL/min. The analyte was monitored on a tandem mass spectrometer using the multiple reaction monitoring scan in a positive electrospray ionization mode. The method exhibited high sensitivity and a good linearity rang of 1-1000ng/mL. The developed analytical method was employed in a pilot pharmacokinetic study of arecoline in rats. Arecoline was rapidly eliminated within 45min in rats after oral treatment of 150mg/kg arecoline. PMID- 29107732 TI - The rapid determination of bromadiolone in liver and blood plasma by in-injector pyrolysis gas chromatography - Ion trap tandem mass spectrometry. AB - The unintentional poisoning of off-target animals by bromadiolone, a second generation anticoagulant rodenticide, is an undesirable outcome requiring sensitive analytical methods. In this study, a rapid and sensitive method for the determination of bromadiolone in liver and blood plasma by means of gas chromatography coupled with tandem mass spectrometry without need for derivatization was developed. The method is based on the in-injector pyrolysis of bromadiolone and subsequent gas chromatography coupled with ion trap tandem mass spectrometry with electron ionization. Sample preparation includes extraction with methanol, evaporation under nitrogen stream, and dissolution in toluene. The pyrolysis of bromadiolone was carried out in an injector at 390 degrees C. Chromatographic separation of the pyrolytical fragment of bromadiolone was achieved using a VF-5ms column with helium as the mobile phase. Tandem in-time mass spectrometry of the separated pyrolytical fragment of bromadiolone was carried out using an ion trap mass spectrometer after electron ionization. Recovery ranged from 94 to 98%. The method showed good linearity up to 1000MUgkg 1 for liver and 1000MUgL-1 for plasma. The limit of detection was 0.38MUgkg-1 for liver and 0.26MUgL-1 for plasma. The developed method was used successfully in several animal poisoning cases. PMID- 29107733 TI - Determination of the R(-) and S(+)-enantiomers of vigabatrin in human plasma by ultra-high-performance liquid chromatography and tandem mass-spectrometry. AB - An analytical method was developed for the quantification in plasma of the R and S enantiomers of vigabatrin (VGB), a drug used for the treatment of some refractory pediatric epileptic syndromes. After adding 50MUL of the internal standard, which consisted of a 15mg/L solution of deuterated racemic VGB, and 100MUL of water to 100MUL of plasma samples, a protein precipitation was performed by adding 600MUL of methanol. The supernatant was evaporated to dryness under a stream of nitrogen and the dry residue was reconstituted with 500MUL of water. Then, 100MUL of 0.01M o-phthaldialdehyde and 0.01M N-acetyl-l-cysteine in borate buffer (0.1M, pH=9.5) were added for pre-column derivatization of the enantiomers as diastereomeric isoindoles. One microliter of the resulting mixture was injected in the chromatographic system. The chromatographic separation was performed in gradient elution mode at a flow rate of 400MUL/min using a phenomenex EVO C-18 column with a mobile phase composed of 5mM ammonium acetate and a methanol:acetonitrile (63:37v/v) mixture. Detection was performed by mass spectrometry in selected reaction monitoring mode using heated electrospray ionization in positive mode as the ion source. Intra- and inter-day precision and accuracy were lower than 15% over the calibration range (0.2-50mg/L for each enantiomer) and the method was successfully used to assess plasma concentrations of VGB in epileptic children. PMID- 29107734 TI - Involvement of SNARE protein Ykt6 in glycosome biogenesis in Trypanosoma brucei. AB - The kinetoplastid parasites Trypanosoma and Leishmania are etiologic agents of diseases like African sleeping sickness, Chagas and leishmaniasis that inflict many tropical and subtropical parts of the world. These parasites are distinctive in that they compartmentalize most of the usually cytosolic enzymes of the glycolytic pathway within a peroxisome-like organelle called the glycosome. Functional glycosomes are essential in both the procyclic and bloodstream forms of trypanosomatid parasites, and mislocalization of glycosomal enzymes to the cytosol is fatal for the parasite. The life cycle of these parasites is intimately linked to their efficient protein and vesicular trafficking machinery that helps them in immune evasion, host-pathogen interaction and organelle biogenesis and integrity. Soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins play important roles in vesicular trafficking and mediate a wide range of protein-protein interactions in eukaryotes. We show here that the SNARE protein Ykt6 is necessary for glycosome biogenesis and function in Trypanosoma brucei. RNAi-mediated depletion of Ykt6 in both the procyclic and bloodstream forms of T. brucei leads to mislocalization of glycosomal matrix proteins to the cytosol, pronounced reduction in glycosome number, and cell death. GFP-tagged Ykt6 appears as punctate structures in the T. brucei cell and colocalizes in part to glycosomes. Our results constitute the first demonstration of a role for SNARE proteins in the biogenesis of peroxisomal organelles. PMID- 29107735 TI - Impaired math achievement in patients with acute vestibular neuritis. AB - Broad cognitive difficulties have been reported in patients with peripheral vestibular deficit, especially in the domain of spatial cognition. Processing and manipulating numbers relies on the ability to use the inherent spatial features of numbers. It is thus conceivable that patients with acute peripheral vestibular deficit show impaired numerical cognition. Using the number Stroop task and a short math achievement test, we tested 20 patients with acute vestibular neuritis and 20 healthy, age-matched controls. On the one hand, patients showed normal congruency and distance effects in the number Stroop task, which is indicative of normal number magnitude processing. On the other hand, patients scored lower than healthy controls in the math achievement test. We provide evidence that the lower performance cannot be explained by either differences in prior math knowledge (i.e., education) or slower processing speed. Our results suggest that peripheral vestibular deficit negatively affects numerical cognition in terms of the efficient manipulation of numbers. We discuss the role of executive functions in math performance and argue that previously reported executive deficits in patients with peripheral vestibular deficit provide a plausible explanation for the lower math achievement scores. In light of the handicapping effects of impaired numerical cognition in daily living, it is crucial to further investigate the mechanisms that cause mathematical deficits in acute PVD and eventually develop adequate means for cognitive interventions. PMID- 29107736 TI - Absence of vitamin D receptor in mature osteoclasts results in altered osteoclastic activity and bone loss. AB - Mature osteoclasts express the vitamin D receptor (VDR) and are able to synthesise and respond to 1,25(OH)2D3 via CYP27B1 enzyme activity. Whether vitamin D signalling within osteoclasts is necessary for the regulation of osteoclastic bone resorption in an in vivo setting is unclear. To determine the requirement for the VDR- and CYP27B1-mediated activity in mature osteoclasts, conditional deletion mouse models were created whereby either Vdr or Cyp27b1 gene was inactivated by breeding either Vdrfl/fl or Cyp27b1fl/fl mice with Cathepsin K Cre transgenic mice (CstkCre) to generate CtskCre/Vdr-/- and CtskCre/Cyp27b1-/- mice respectively. To account for potential CtskCre-meaited off-target deletion of Vdr, Dmp1Cre were also used determine the effect of Vdr deletion in osteocytes. Furthermore, CtskCre/Vdr-/- mice were ovariectomised (OVX) to assess the role of VDR in osteoclasts under bone-loss conditions and bone marrow precursor cells were cultured under osteoclastogenic conditions to assess osteoclast formation. Six-week-old CtskCre/Vdr-/- female mice demonstrated a 15% decrease in femoral BV/TV (p<0.05). In contrast, BV/TV remained unchanged in CtskCre/Cyp27b1-/- mice as well as in Dmp1Cre/VDR-/- mice. When CtskCre/Vdr-/- mice were subjected to OVX, the bone loss that occurred in CtskCre/Vdr-/- was predominantly due to a diminished volume of thinner trabeculae when compared to control levels. These changes in bone volume in CtskCre/Vdr-/- mice occurred without an observable histological change in osteoclast numbers or size. However, while cultured bone marrow-derived osteoclasts from CtskCre/Vdr-/- mice were marginally increased when compared to VDRfl/fl mice, elevated expression of genes such as Cathepsin K, Nfatc1 and VATPase was observed. Collectively, these data indicate that the absence of VDR in mature osteoclasts causes exacerbated bone loss in young mice and during OVX which is associated with enhanced osteoclastic activity and without increased osteoclastogenesis. PMID- 29107738 TI - Extracellular vesicles released from mesenchymal stromal cells stimulate bone growth in osteogenesis imperfecta. AB - BACKGROUND: Systemic infusion of mesenchymal stromal cells (MSCs) has been shown to induce acute acceleration of growth velocity in children with osteogenesis imperfecta (OI) despite minimal engraftment of infused MSCs in bones. Using an animal model of OI we have previously shown that MSC infusion stimulates chondrocyte proliferation in the growth plate and that this enhanced proliferation is also observed with infusion of MSC conditioned medium in lieu of MSCs, suggesting that bone growth is due to trophic effects of MSCs. Here we sought to identify the trophic factor secreted by MSCs that mediates this therapeutic activity. METHODS: To examine whether extracellular vesicles (EVs) released from MSCs have therapeutic activity, EVs were isolated from MSC conditioned medium by ultracentrifugation. To further characterize the trophic factor, RNA or microRNA (miRNA) within EVs was depleted by either ribonuclease (RNase) treatment or suppressing miRNA biogenesis in MSCs. The functional activity of these modified EVs was evaluated using an in vitro chondrocyte proliferation assay. Finally, bone growth was evaluated in an animal model of OI treated with EVs. RESULTS: We found that infusion of MSC-derived EVs stimulated chondrocyte proliferation in the growth plate, resulting in improved bone growth in a mouse model of OI. However, infusion of neither RNase-treated EVs nor miRNA depleted EVs enhanced chondrocyte proliferation. CONCLUSION: MSCs exert therapeutic effects in OI by secreting EVs containing miRNA, and EV therapy has the potential to become a novel cell-free therapy for OI that will overcome some of the current limitations in MSC therapy. PMID- 29107737 TI - Respiratory functional and motor control deficits in children with spinal cord injury. AB - Children with spinal cord injury (SCI) are at high risk for developing complications due to respiratory motor control deficits. However, underlying mechanisms of these abnormalities with respect to age, development, and injury characteristics are unclear. To evaluate the effect of SCI and age on respiratory motor control in children with SCI, we compared pulmonary function and respiratory motor control outcome measures in healthy typically developing (TD) children to age-matched children with chronic SCI. We hypothesized that the deficits in respiratory functional performance in children with SCI are due to the abnormal and age-dependent respiratory muscle activation patterns. Fourteen TD (age 7+/-2 yrs., Mean+/-SD) and twelve children with SCI (age 6+/-1 yrs.) were evaluated by assessing Forced Vital Capacity (FVC); Forced Expiratory Volume in 1sec (FEV1); and respiratory electromyographic activity during maximum inspiratory and maximum expiratory airway pressure measurements (PImax and PEmax). The results indicate a significant reduction (p<.01) of FVC, FEV1 and PEmax values in children with SCI compared to TD controls. During PEmax assessment, children with SCI produced significantly decreased (p<.01) activation of respiratory muscles below the neurological level of injury (rectus abdominous and external oblique muscles). In addition, children with SCI had significantly increased (p<.05) compensatory muscle activation above the level of injury (upper trapezius muscle). In the TD group, age, height, and weight significantly (p<.05) contributed towards increase in FVC and FEV1. In children with SCI, only age was significantly (p<.05) correlated with FVC and FEV1 values. These findings indicate the degree of SCI-induced respiratory functional and motor control deficits in children are age-dependent. PMID- 29107739 TI - Comparative restoration of acute liver failure by menstrual blood stem cells compared with bone marrow stem cells in mice model. AB - BACKGROUND AIMS: The application of menstrual blood stem cells (MenSCs) in regenerative medicine is gaining increasing attention. The aim of this study was to investigate the therapeutic potential of MenSCs compared with bone marrow derived stem cells (BMSCs) in an animal model of CCl4-induced acute hepatic failure. METHODS: Injured Balb/C mice were divided into multiple groups and received MenSCs, BMSCs or hepatocyte progenitor-like (HPL) cells derived from these cells. RESULTS: Tracking of green fluorescent protein-labeled cells showed homing of cells in injured areas of the liver. In addition, the liver engraftment of MenSCs was shown by immunofluorescence staining using anti-human mitochondrial antibody. Microscopically examination, periodic acid-Schiff and Masson's trichrome staining of liver sections demonstrated the considerable liver regeneration post-cell therapy in all groups. Assessment of serum parameters including aspartate aminotransferase, alanine aminotransferase, total bilirubin, urea and cholesterol at day 7 exhibited significant reduction, such that this downward trend continued significantly until day 30. The restoration of liver biochemical markers, changes in mRNA levels of hepatic markers and the suppression of inflammatory markers were more significant in the MenSC-treated group compared with the BMSC-treated group. On the other hand, HPL cells in reference to undifferentiated cells had better effectiveness in the treatment of the acute liver injury. CONCLUSIONS: Our data show that MenSCs may be considered an appropriate alternative stem cell population to BMSCs for treatment of acute liver failure. PMID- 29107740 TI - Autonomic function testing: Compliance and consequences. AB - BACKGROUND: The deep breathing test (DB) and Valsalva maneuver (VM) are used to detect autonomic dysfunction. The VM induces sympathetically mediated changes in blood pressure (phase II late, phase IV, and recovery time) and both tests induce vagally mediated heart rate changes. There is limited information on effects of key variables, compliance with testing and the effects of non-compliance This study has twin goals of evaluating compliance with standard instructions and the effects of changes in key variables. We also evaluated the effect of position on the VM. MATERIAL AND METHODS: Forty healthy males performed DB at air exchange volumes of 50, 80, and 100% of vital lung capacity (VLC). The VM was performed at 40 and 30mmHg expiratory pressure for 15 and 10s in sitting and supine position, respectively. RESULTS: Participants performed DB at lower volumes than intended and were not able to maintain 100% VLC for the duration of the test. The DB heart rate response decreased 6.3beats/min per liter below VLC. During the VM, subjects blew at lower pressures than instructed. The VM responses were significantly larger with longer expiration durations, higher expiratory pressures and when performed sitting. Performing the VM at 40mmHg for 10s in supine position increased the odds ratio of experiencing flat-top responses. CONCLUSION: The ability of subjects to strictly comply with methodological guidelines significantly improves results. Recording of both test parameters and ensuing results is suggested. PMID- 29107741 TI - Constructing cell lineages from single-cell transcriptomes. AB - Advances in single-cell RNA-sequencing have helped reveal the previously underappreciated level of cellular heterogeneity present during cellular differentiation. A static snapshot of single-cell transcriptomes provides a good representation of the various stages of differentiation as differentiation is rarely synchronized between cells. Data from numerous single-cell analyses has suggested that cellular differentiation and development can be conceptualized as continuous processes. Consequently, computational algorithms have been developed to infer lineage relationships between cell types and construct developmental trajectories along which cells are re-ordered such that similarity between successive cell pairs is maximized. Here, we compare and contrast the existing computational methods, and illustrate how they may be applied to build mouse myeloid progenitor lineages from massively parallel RNA single-cell sequencing data. PMID- 29107742 TI - Polyvalent protective immunogens identified from outer membrane proteins of Vibrio parahaemolyticus and their induced innate immune response. AB - Vaccines are the most economic, efficient and environment-friendly agents in protecting host against bacterial infection. In aquaculture, polyvalent vaccines targeting more than one bacterial specie are highly demanded due to the presence of various types of bacterial pathogens in farming environment. Here eighteen genes encoding outer membrane proteins of Vibrio parahaemolyticus were cloned and expressed. The expressed recombinant proteins were used for antiserum preparation. Passive and active immune protection of the antiserum and recombinant proteins was investigated in the zebrafish model. Two recombinant proteins, VP1667 and VP2369, showed effective immune protection against at least two genera of bacteria, Vibrio (V. parahaemolyticus and V. alginolyticus), Pseudomonas (P. fluorescens) or/and Aeromonas (A. hydrophila), and thereby are potential polyvalent vaccine candidates to defend against bacterial infection in fish farming. Furthermore, the mechanisms for the two polyvalent vaccines in triggering immune response were explored. Antiserum to VP1667 or VP2369 was not cross-reacted with P. fluorescens and A. hydrophila, whereas both recombinant proteins induced significant innate immune response. Comparatively, VP1667 stimulates stronger lymphokine and monokine, and VP2369 induces stronger humoral immune response, while both produce similar NF-kappaB, COX-2, TLR-1 and TLR-3 expression. Our results identify two polyvalent vaccines and demonstrate characteristics features of their cross-protection at the content of the innate immune response. PMID- 29107743 TI - Allelic variation partially regulates galactose-dependent hydrogen peroxide release from circulating hemocytes of the snail Biomphalaria glabrata. AB - Freshwater snails are the intermediate hosts for numerous parasitic worms that are detrimental to human and agricultural health. Understanding the immune responses of these snails could be vital for finding ways to block transmission of those parasites. Allelic variation in a recently discovered genomic region in the snail, Biomphalaria glabrata, influences their susceptibility to schistosomes. Here we tested whether genes in that region, termed the Guadeloupe Resistance Complex (GRC), are involved in recognition of common pathogen associated molecules that have been shown to be stimulants of the hydrogen peroxide defense pathway. We show that hemocytes extracted from individuals with one of the three GRC genotypes released less hydrogen peroxide than the other two genotypes, after stimulation with galactose. This difference was not observed after stimulation with several other microbial-associated carbohydrates, despite those ligands sharing the same putative pathway for hydrogen peroxide release. Therefore, we conclude that allelic variation in the GRC region may influence the recognition of galactose, rather than the conserved downstream steps in the hydrogen peroxide pathway. These results thus are consistent with the hypothesis that proteins produced by this region are involved in pathogen recognition. PMID- 29107744 TI - Detection and inhibition of lipid-derived radicals in low-density lipoprotein. AB - Oxidized low density lipoprotein (Ox-LDL) is implicated in a variety of oxidative diseases. To clarify the mechanisms involved and facilitate the investigation of therapeutics, we previously developed a detection method for lipid-derived radicals using the fluorescent probe 2,2,6-trimethyl-6-pentyl-4-(4 nitrobenzo[1,2,5]oxadiazol-7-ylamino)piperidine-1-oxyl (NBD-Pen). In this study, NBD-Pen was used to detect lipid-derived radicals in Ox-LDL from in vitro and in vivo samples using an iron overloaded mouse model. By following the timeline of lipid radical generation using this method, the iron overloaded mice could be successfully treated with the antioxidant Trolox, resulting in successful lowering of the plasma lipid peroxidation, aspartate transaminase and alanine transaminase levels. Furthermore, using a combination therapy of the chelating agent deferoxamine (DFX) and Trolox, liver injury and oxidative stress markers were also reduced in iron overloaded mice. The NBD-Pen method is highly sensitive as well as selective and is suitable for targeting minimally modified LDL compared with other existing methods. PMID- 29107745 TI - Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway. AB - Respiratory syncytial virus (RSV) is the most important cause of viral acute respiratory tract infections and hospitalizations in children, for which no vaccine or specific treatments are available. RSV causes airway mucosa inflammation and cellular oxidative damage by triggering production of reactive oxygen species and by inhibiting at the same time expression of antioxidant enzymes, via degradation of the transcription factor NF-E2-related factor 2 (NRF2). RSV infection induces NRF2 deacetylation, ubiquitination, and degradation through a proteasome-dependent pathway. Although degradation via KEAP1 is the most common mechanism, silencing KEAP1 expression did not rescue NRF2 levels during RSV infection. We found that RSV-induced NRF2 degradation occurs in an SUMO-specific E3 ubiquitin ligase - RING finger protein 4 (RNF4)-dependent manner. NRF2 is progressively SUMOylated in RSV infection and either blocking SUMOylation or silencing RNF4 expression rescued both NRF2 nuclear levels and transcriptional activity. RNF4 associates with promyelocytic leukemia - nuclear bodies (PML-NBs). RSV infection induces the expression of PML and PML-NBs formation in an interferon (INF)-dependent manner and also induces NRF2 - PMN-NBs association. Inhibition of PML-NB formation by blocking IFN pathway or silencing PML expression resulted in a significant reduction of RSV-associated NRF2 degradation and increased antioxidant enzyme expression, identifying the RNF4-PML pathway as a key regulator of antioxidant defenses in the course of viral infection. PMID- 29107747 TI - Vanillin selectively modulates the action of antibiotics against resistant bacteria. AB - The treatment of infections caused by microorganisms that are resistant to antibiotics represent one of the main challenges of medicine today, especially due to the inefficacy of long-term drug therapy. In the search for new alternatives to treat these infections, many researchers have been looking for new substances derived from natural products to replace, or be used in combination with conventional antibiotics. Vanillin is a phenolic compound whose antimicrobial activity has been used in the elimination of pathogens present in fruits and vegetables. However, its antibacterial and modulating properties remain to be characterized. Therefore, this work aimed to evaluate the antibacterial activity and analyze the modulator activity of vanillin in association with conventional antibiotics. The antimicrobial activity of vanillin was evaluated using the microdilution method to determine the Minimum Inhibitory Concentration (MIC) Standard strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and multi-resistant strains of Escherichia coli 06, Staphylococcus aureus 10, Pseudomonas aeruginosa 24 were used in this study. The antibiotic modulating effect was analyzed by combining vanillin with Norfloxacin, Imipenem, Gentamicin, Erythromycin and Tetracycline against the following multiresistant bacteria strains: Escherichia coli 06, Staphylococcus aureus 10 and Pseudomonas aeruginosa 24. Data were analyzed using the ANOVA test of two tracks followed by the post hoc Bonferroni test. Vanillin presented CIMs >=1024MUg/mL against all tested strains demonstrating that it did not present significant antibacterial activity. However, modulated the activity of gentamicin and imipenem against S. aureus and E. coli, causing a synergistic effect, but did not affect the activity of norfloxacin, tetracycline and erythromycin against these same microorganisms. A synergistic effect was also obtained from the association of vanillin with norfloxacin against P. aeruginosa. On the other hand, against this strain the association of vanillin with tetracycline and erythromycin caused antagonism, although the activity of gentamicin and imipenem was not affected. In conclusion, vanillin selectively modulated the activity of antibiotics against multiresistant bacteria and as such, might be useful in the development of new therapies against resistant microorganism. PMID- 29107748 TI - Rheological characteristics and chain conformation of mannans obtained from Saccharomyces cerevisiae. AB - Mannans were extracted from S. cerevisiae, the rheological properties of mannan solutions were important in many industrial applications. In this paper, effects of mannans concentration, solution temperature, pH, salts and their concentrations on apparent viscosity were investigated. The conformational parameters of yeast mannans were determined by SEC-MALS-RI-DP. The Higiro's 1 and Higiro's 2 plots were obtained by capillary viscometry gave an intrinsic viscosity of 0.166 and 0.131dl/g. The yeast mannans solution showed Newtonian flow behavior at all the tested concentrations. The apparent viscosity of yeast mannans solution decreased continuously with the temperature increase (25 degrees C-85 degrees C) at a given shear rate. The viscosity did not change within the pH values of 4.0-10.0, however, it increased when the pH decreased from 4.0 to 2.0. The viscosity decreased with addition of CaCl2 up to 10mM and remained constant above this concentration. The conformational parameters (derived from [eta] vs Mw and Rg vs Mw) showed yeast mannans existed as a sphere-like shape with many shorter branches. The special flow behavior and conformation of yeast mannans may make it preferable polysaccharide in food industry. PMID- 29107746 TI - How many deficits in the same dyslexic brains? A behavioural and fMRI assessment of comorbidity in adult dyslexics. AB - Dyslexia can have different manifestations: this has motivated different theories on its nature, on its underlying brain bases and enduring controversies on how to best treat it. The relative weight of the different manifestations has never been evaluated using both behavioural and fMRI measures, a challenge taken here to assess the major systems called into play in dyslexia by different theories. We found that adult well-compensated dyslexics were systematically impaired only in reading and in visuo-phonological tasks, while deficits for other systems (e.g., motor/cerebellar, visual magnocellular/motion perception) were only very occasional. In line with these findings, fMRI showed a reliable hypoactivation only for the task of reading, in the left occipito-temporal cortex (l-OTC). The l OTC, normally a crossroad between the reading system and other systems, did not show the same level of intersection in dyslexics; yet, it was not totally silent because it responded, in segregated parts, during auditory phonological and visual motion perception tasks. This minimal behavioural and functional anatomical comorbidity demonstrates that a specific deficit of reading is the best description for developmental dyslexia, at least for adult well-compensated cases, with clear implications for rehabilitation strategies. The reduced intersection of multiple systems in the l-OTC suggests that dyslexics suffer from a coarser connectivity, leading to disconnection between the multiple domains that normally interact during reading. PMID- 29107749 TI - Antioxidant activity and controlled drug delivery potential of tragacanth gum-cl- poly (lactic acid-co-itaconic acid) hydrogel. AB - Tragacanth gum-cl-poly (lactic acid-co-itaconic acid) (TG-cl-p(LA-co-IA)) hydrogel is synthesized through graft copolymerization reaction using microwave assisted technique. The synthesized hydrogel was characterised using various analytical and characterization techniques such as FTIR, FESEM, XRD, TGA, TEM and SEM. It was observed that, the maximum percentage swelling (Ps) of the hydrogel was 311.61% after 6h at room temperature and 298.06% after 3h at 60 degrees C and TG-cl-p(LA-co-IA) exhibited highest Amoxicillin loading (73%) in double distilled waterafter 24h. From the controlled release studies, it was evident that maximum drug release of about 96% took place at pH 2.2=after 6h. The synthesized hydrogel also showed mild antioxidant properties and 43.85% of free radical scavenging was occurred at a concentration of 640MUg/mL and hence it can be effectively used to reduce the oxidative stresses. In addition to this, the antibacterial studies also showed that it is more effective against S. aureus. PMID- 29107750 TI - Molecular cloning, prokaryotic expression, purification, structural studies and functional implications of Heat Shock Protein 70 (Hsp70) from Rutilus frisii kutum. AB - A novel Hsp70 chaperone from Rutilus frisii kutum was identified, cloned, expressed, purified and its functional characteristics revealed. The 3D structure of Hsp70 from Rutilus kutum was constructed using the crystal structure of E. coli Hsp70 as the template, with 47% sequence identity. The in vitro ATPase activity assay after 60min, ATP hydrolysis of purified recombinant Hsp70 (8MUM) was improved by binding to denatured thermally luciferase (3MUM) about 2.5-fold compared with that of Hsp70 alone. Based on the results, it was found that the purified Hsp70 chaperone was able to considerably suppress heat-induced aggregation of luciferase by binding to DnaJ co-chaperone (5MUM) more than 70% after 10min at 42 degrees C. In addition, Hsp70 DnaJ complex improved the refolding of heat-shocked luciferase nearly 40% after 60min at 25 degrees C. It was concluded that Hsp70 protein from Rutilus frisii kutum has the critical role in preventing heat-induced aggregation of luciferase and refolding of heat denatured luciferase was strictly dependent on the activity of Hsp70, thus, this protein can potentially be used for improving the functional properties of luciferase in various applications. PMID- 29107752 TI - Staging and follow-up of a Ewing sarcoma patient using 18F-FDG PET/CT. PMID- 29107751 TI - 18F-FDG PET/contrast enhanced CT in the standard follow-up of patients with lymphoma. AB - AIM: To assess the diagnostic accuracy of 18F-FDG PET/contrast enhanced computed tomography (ceCT) in the detection of asymptomatic recurrences in patients with lymphoma. MATERIAL AND METHODS: Patients with lymphoma and clinical complete remission underwent 18F-FDG PET/ceCT for standard follow-up.18F-FDG PET and ceCT were evaluated blindly by two independent observers, and classified as positive or negative for recurrence. Additionally a combined evaluation of both techniques was performed. The final diagnosis was established by histopathological analysis or a clinical follow-up longer than 6 months. Statistical diagnostic parameters and concordance levels between both diagnostic techniques were calculated. RESULTS: A total of 114 explorations on 90 patients were analyzed. Only 4 patients were diagnosed as asymptomatic recurrence during the follow-up. 18F-FDG PET/ceCT, 18F-FDG PET and ceCT showed an association with the final diagnosis (p=0.002 and chi2=11.96; p<0.001 and chi2=15.60; p=0.001 and chi2=11.96, respectively). The concordance between 18F-FDG PET and ceCT was moderate/high and significant (kappa=0.672; p<0.001). A sensitivity and specificity of 50% and 88% was obtained for the 18F-FDG PET/ceCT civ, 50% and 93% for the 18F-FDG PET, and 50% and 91% for the ceCT. CONCLUSION: The combined use of 18F-FDG PET/ceCT did not offer any advantage compared to any isolated diagnostic technique in the detection of asymptomatic lymphoma recurrence. PMID- 29107753 TI - Bladder wall paraganglioma located using 123I-mIBG SPECT and CT imaging. PMID- 29107755 TI - Interaction between shock coils increased the incidence of inappropriate therapies and lead failure in implantable cardioverter defibrillator. AB - AIMS: Shock coil interaction in patients with multiple implantable cardioverter defibrillator (ICD) leads is occasionally observed. We aimed to evaluate the incidence of shock coil interaction and its clinical relevance. METHODS AND RESULTS: All ICD patients (646 patients) who came to follow up control in our ICD ambulance between January 1, 2011, and December 31, 2011 in the department of cardiology in Bad Berka hospital were retrospectively evaluated in this study. All baseline demographic, clinical, and procedural characteristics and postoperative chest x ray in postero-anterior and lateral view as well as clinical and ICD follow up data were evaluated. Among 646 patients 42 had multiple ICD leads (6.5%) of whom 36 patients (5.5% of total cohort patients and 85.7% of patients with multiple ICD leads) had shock coil interaction and presented the study group (Group I). The control group (Group II) consisted of 610 patients without coil-coil interaction including patients with single shock lead (604 patients) or patients with multiple leads but without interaction between shock coils (6 patients). Inappropriate anti-tachycardia therapies and RV lead revisions were more frequent in patients with interaction between shock coils (Group I vs Group II: 27.7% and 5.7%; p = 0.049 and 30.6% vs 6.4; p = 0.0001, respectively). CONCLUSIONS: Interaction between shock coils may be one of possible causes of lead failure and resulted in inappropriate therapies and subsequent lead revision. PMID- 29107754 TI - Long-term effects of prenatal drug exposure on the neural correlates of memory at encoding and retrieval. AB - The objective of the current study was to examine what stage of memory (encoding or retrieval) may be compromised in adolescents with a history of prenatal drug exposure (PDE) and how the effects of PDE on memory ability are substantiated at the neural level. To achieve this goal, we examined memory performance and associated brain activations in adolescents with and without a history of PDE via event-related fMRI during encoding and retrieval. Consistent with previous studies, we found that PDE subjects remembered fewer items than community comparison subjects. However, there were no differences in behavior after adjusting for correct rejections (i.e., d'). Novel extensions of previous work are findings that PDE is associated with changes in brain activation during memory encoding but not during retrieval. These results suggest that less optimal memory performance often observed in adolescents with a history of PDE may result from variations in encoding rather than retrieval processes. PMID- 29107756 TI - Mortality in elderly patients with a systematic ICU admission programme. PMID- 29107757 TI - Ten recommendations for assessing the comparative effectiveness of therapeutic medical devices: a targeted review and adaptation. AB - OBJECTIVES: The aim of this study was to review existing guidance on the methods for evaluation of the comparative effectiveness (CE) of therapeutic medical devices (TMDs) and develop recommendations for systematic reviews (SRs) of CE of TMDs as part of health technology assessments. STUDY DESIGN AND SETTING: We performed a targeted literature review of evaluation frameworks and recommendations for evaluation methods for TMDs and related technologies. An electronic database search was combined with systematic screening of tables of content of selected journals and scanning the reference lists of relevant papers. RESULTS: We identified a framework for SRs of complex interventions (FSRCIs) and three documents providing detailed methodology for TMD evaluation. We applied the FSRCIs to TMD evaluation taking into account the more complex composition of the intervention, its rapid, incremental development, as well as the dependency of treatment effects on contextual factors and user proficiency. In 10 recommendations, including a template for a logic model for TMD, we summarized relevant factors that should be systematically considered. CONCLUSION: The quality of SRs of CE assessments of TMDs can be improved by applying these recommendations. This also may require an increase of the quality of primary studies. PMID- 29107758 TI - Exploring correlates of diabetes-related stress among adults with Type 1 diabetes in the T1D exchange clinic registry. AB - AIMS: To explore relations between diabetes-related stress and multiple sociodemographic, diabetes health, other health, and treatment-related variables among a large sample of adults with Type 1 Diabetes (T1D). METHODS: The sample consisted of 10,821 adults (over 18 years old) enrolled in the T1D Exchange Clinic Registry. The T1D Exchange clinic network consists of 67 diabetes clinical centers throughout the United States selected to broadly represent pediatric and adult patients with T1D. Variables were assessed through participant self-report and extraction of clinic chart data. Univariate and multiple linear regression (with simultaneous entry of all predictors) analyses were conducted. RESULTS: Robustly associated with increased diabetes-related stress across analyses were multiple sociodemographic (female [vs. male], native Hawaiian/other Pacific islander [vs. white/Caucasian], decreased age and diabetes duration), diabetes health (higher HbA1c), other health (lower general health, presence of major life stress and depression, less physical activity), and treatment related variables (use of injections/pen or combination injection/pen/pump [vs. pump], use of CGM, increased frequency of missing insulin doses and BG checking, decreased frequency of BG checking prior to bolus, receipt of mental health treatment). CONCLUSIONS: We replicated and extended research demonstrating that diabetes-related stress among people with T1D occurs at higher levels among those with particular sociodemographic characteristics and is associated with a range poorer diabetes health and other health variables, and multiple treatment-related variables. The strong incremental prediction of diabetes-related stress by multiple variables in our study suggests that a multi-variable, personalized approach may increase the effectiveness of treatments for diabetes-related stress. PMID- 29107759 TI - The unique clinical spectrum of maturity onset diabetes of the young type 3. AB - Phenotypic variability in maturity-onset diabetes of the young (MODY) makes screening criteria for genomic analysis challenging. We describe the clinical spectrum in a large pedigree with HNF1A-MODY; as generations progressed, the course and outcome became poorer. Although uncommon, pancreatic autoantibodies and diabetes ketoacidosis should not exclude the diagnosis of MODY. PMID- 29107760 TI - Leukocyte telomere length correlates with glucose control in adults with recently diagnosed type 2 diabetes. AB - AIMS: We investigated leukocyte relative telomere length (TL) in patients with type 2 diabetes (T2D) diagnosed for no longer than five years and its association with clinical and biochemical variables. METHODS: Peripheral blood leukocyte relative TL was investigated in 108 patients with T2D (87 women, 21 men) and 125 (37 women, 88 men) age-matched control subjects with normal glucose tolerance, by quantitative polymerase chain reaction. Multiple linear regression analysis was used to examine the association between relative TL and demographic, anthropometric and biochemical indicators of metabolic control among patients with T2D. RESULTS: Patients with T2D had a median time since diagnosis of 1 year and most were on metformin monotherapy, with satisfactory glucose control determined by HbA1c levels. Median relative TL was not different between patients with T2D and control subjects. However, multiple linear regression analyses showed that relative TL was inversely associated with time since T2D diagnosis, fasting plasma glucose levels and HbA1c levels, but not with HbA1c levels assessed in the preceding 5-12 months, after adjustment for age, sex and body mass index. CONCLUSION: This study suggests that relative TL is not shorter in patients with recently diagnosed T2D, but is inversely correlated with glucose levels, even among patients with overall satisfactory glucose control. PMID- 29107761 TI - Improved limb salvage for patients with vascular disease and tissue loss associated with new model of provision targeted at the diabetic foot. AB - AIMS: The establishment of a vascular surgeon-led emergency diabetic foot service in 2006 has evolved to provide lower limb wound care for patients with and without diabetes. We aimed to determine whether the service was associated with sustained, improved limb salvage rates for the whole population, analyse key aspects of service provision and compare outcomes against published studies. METHODS: The vascular unit serves a largely rural population of approximately 240,000. Data was collected prospectively on lower limb amputations, arterial and minor surgical interventions from 2006 to 2015, and retrospectively retrieved for 2004-2005, prior to service commencement. Data was also collected on referral patterns, volume of patient admissions and attendances, and delays. Lower limb amputation rates were compared against published data and analysis of admission trends and delays employed non-parametric tests. RESULTS: Age/gender adjusted major lower limb amputations for the populations with and without diabetes were 412/100,000 in 2004 and 15/100,000 in 2005 respectively. Following service introduction, major amputations reduced and since 2012 have been sustained at between 15-44/100,000 and 1-3/100,000 for patients with and without diabetes respectively, comparing favourably with published data. Vascular interventions have remained static, but referrals of patients directly to the service and numbers of minor procedures have increased. CONCLUSIONS: The sustained decreases in all major lower limb amputations that have coincided with the development of a core team approach to providing rapid access and comprehensive care for patients with emergency diabetic foot problems may indicate that this service design benefits patients with and without diabetes. PMID- 29107762 TI - Major depression prevention effects for a cognitive-behavioral adolescent indicated prevention group intervention across four trials. AB - Major depressive disorder (MDD) in young people is a leading cause of disability but most depressed youth are not treated, emphasizing the need for effective prevention. Our goal is to synthesize MDD onset prevention effects for the Blues Program, a brief cognitive-behavioral (CB) indicated prevention group, by merging data from four trials (three of which included CB bibliotherapy) and conducting an individual patient data (IPD) meta-analysis. Data were available from 766 high school/college students (M age = 16.4, SD = 2.3; 60% female, 64% White). CB group resulted in significantly lower MDD incidence rates relative to brochure control that persisted to 6-month follow-up; CB group also was associated with a lower 2 year MDD incidence rate relative to bibliotherapy but heterogeneity across trials was detected. Contrasts between bibliotherapy and brochure control were nonsignificant. For significant contrasts, the number needed to treat (NNT) by CB group to prevent one MDD onset relative to brochure or bibliotherapy ranged from 10 to 21. A brief CB group depression prevention intervention for at-risk adolescent is achieving meaningful effects compared to both active and minimal controls but outcomes need to be improved, perhaps by better screening or augmentations to produce more persistent intervention effects. PMID- 29107763 TI - A brighter future: The effect of positive episodic simulation on future predictions in non-depressed, moderately dysphoric & highly dysphoric individuals. AB - Previous research suggests depressed individuals have difficulties with future directed cognitions. For instance, compared with non-depressed individuals, they predict positive events are less likely to occur. Recent work suggests that episodic simulation of positive futures may represent a useful strategy for improving prospective predictions. The current studies investigated positive future episodic simulation as a method of modifying predictions regarding the likelihood of occurrence, perceived control, and importance of positive and negative future events. Experiment 1 compared positive episodic simulation to a neutral visualization task in a non-clinical sample. Predictions regarding future events were rated more positively after the use of positive episodic simulation but not as a result of neutral visualization. Experiment 2 extended these findings to show that future episodic simulation can be used to modify predictions, for both positive and negative events, in individuals experiencing significant levels of dysphoric mood and depressive symptoms. Taken together, these findings suggest that training in positive episodic future simulation can improve future outlook and may represent a useful tool within cognitive therapeutic techniques. PMID- 29107764 TI - Current attempts to implement microRNA-based diagnostics and therapy in cardiovascular and metabolic disease: a promising future. AB - MicroRNAs (miRNAs) are small, noncoding RNAs regulating gene expression at the post-translational level. miRNA-based therapeutic agents are important because of the functionality of miRNAs in regulating lipid and glucose metabolism and their role in the pathogenesis of metabolic disorders such as diabetes and obesity, where dysregulation leads to disease; they are also important in angiogenesis. miRNAs additionally serve as biomarkers in the diagnosis, prognosis and risk assessment of disease and in monitoring the response to treatment. Here, we provide a brief overview of progress in miRNA-based therapeutics in the preclinical and clinical setting and highlight the novel outcomes and opportunities in the diagnosis and treatment of metabolic conditions. In addition, we present the role of miRNAs in stem cell therapy which could have great potential in regenerative medicine. PMID- 29107765 TI - NCp7: targeting a multitasking protein for next-generation anti-HIV drug development part 1: covalent inhibitors. AB - The major internal component of the HIV virion core is the nucleocapsid protein 7 (NCp7), a small, highly basic protein that is essential for multiple stages of the viral replicative cycle, and whose structure is preserved in all viral strains, including clinical isolates from therapy-experienced patients. This key protein is recognised as a potential target for an effective next-generation antiretroviral therapy, because it could offer the possibility to develop broad spectrum agents that are less prone to select for resistant strains. Here, we provide a comprehensive overview of the covalent NCp7 inhibitors that have emerged over the past 25 years of drug discovery campaigns, emphasising, where possible, their structure-activity relationships (SARs) and pharmacophoric features. PMID- 29107766 TI - Rotavirus detection in bulk stool and rectal swab specimens in children with acute gastroenteritis in Norway. AB - BACKGROUND: Bulk stool specimens are traditionally used for rotavirus detection but may be challenging to obtain from young children. Immediate and easy sampling may however be required in different situations, such as outbreak investigation. OBJECTIVES: We assessed the diagnostic performance of rectal swabs compared to bulk stools for the detection of rotavirus by Enzyme Immunoassay (EIA) and multiplex semi-nested reverse transcription PCR (semi-nested RT-PCR) in children recruited through active hospital-based surveillance of acute gastroenteritis in Norway. STUDY DESIGN: We obtained 265 paired bulk stool and rectal swab specimens from children under 5 years of age hospitalized with acute gastroenteritis (AGE). Both types of specimens were analyzed for rotavirus by EIA and semi-nested RT PCR. In addition, VP6-spesific real-time PCR was used to evaluate the detection performance in the two specimen types. RESULTS: Concordant results were obtained in 257 (97%) paired specimens by EIA and in 248 (94%) pairs by semi-nested RT PCR. Results of VP6-specific real-time PCR obtained from 100 pairs of specimens showed concordance in 91% of the pairs. Sensitivity and specificity for rectal swab specimens were 95% and 100% by EIA; 95% and 92% by semi-nested RT-PCR, respectively. CONCLUSION: Both EIA and semi-nested RT-PCR showed a high accuracy, and rectal swab specimens are appropriate for rotavirus diagnosis and may be used as an alternate specimen type when collection of bulk stool is not feasible. PMID- 29107767 TI - Prevalence of methicillin-resistant Staphylococcus aureus isolated from burn patients in Iran: A systematic review and meta-analysis. AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) is considered a major cause of infection and mortality in burn patients, especially when nosocomially acquired. However, limited information is available on the prevalence of MRSA among burn patients in Iran. METHODS: A systematic search was performed using different electronic databases including Medline (via PubMed), Embase, Web of Science and Iranian Database. A meta-analysis was performed using Comprehensive Meta-Analysis Software (BioStat v.2.2). Use of a fixed- or random effects model was used based on a heterogeneity test, and publication bias was assessed using Begg rank correlation and Egger weighted regression methods. RESULTS: Of 555 articles published from January 2000 to January 2016, 13 studies were included in this review. The meta-analyses showed that the prevalence of MRSA infection in burn patients was 77.9% (95% confidence interval 70.2-84.0%) among culture-positive cases. CONCLUSIONS: The results of this study indicate that the prevalence of MRSA among burn patients is very high in Iran. Thus, a comprehensive infection control strategy based on hand hygiene, education and training in antibiotic prescribing, environmental cleaning, contact precautions, good antibiotic stewardship and an active surveillance system on the basis of international criteria is urgently needed. PMID- 29107768 TI - Copycat snacks: Can students differentiate between school and store snacks? AB - In 2014, the national Smart Snacks in School nutrition standards placed regulations on all snack foods sold in schools. Many food companies reformulated common snack food products for sale in schools, called "copycat snacks", which look similar to nutritionally different foods sold in stores. It is possible that these snacks create consumer confusion among students. The purpose of this study was to determine if middle school students could differentiate, in taste and appearance, between school (copycat) and store versions of common snacks. Seventy six middle school students evaluated three different food products offered in schools: Froot Loops, Rice Krispy Treats, and Doritos. Students tasted snacks in a series of triangle tests for difference, one for each snack food, including school and store versions. Students were also presented with packages, school and store versions of the same products, and asked to determine the expected taste, purchase intentions, and perceived healthfulness. Students could determine taste differences between school and store Rice Krispy Treats yet could not differentiate between Froot Loop and Dorito varieties. Students rated store versions of all three snacks with greater expected taste, higher intention to purchase, and as less healthy. While it seems product confusion concerning copycat snacks may not be severe in this sample, snack food brands are still a prominent feature in schools. It is possible that these copycat snacks can confuse students' perceptions of healthy foods. Alternative packaging for school foods or reformation of store versions of snack foods may be viable solutions to this problem. PMID- 29107769 TI - The evaluative role of rostrolateral prefrontal cortex in rule-based category learning. AB - Category learning is a critical neurobiological function that allows organisms to simplify a complex world. Rostrolateral prefrontal cortex (rlPFC) is often active in neurobiological studies of category learning; however, the specific role this region serves in category learning remains uncertain. Previous category learning studies have hypothesized that the rlPFC is involved in switching between rules, whereas others have emphasized rule abstraction and evaluation. We aimed to clarify the role of rlPFC in category learning and dissociate switching and evaluation accounts using two common types of category learning tasks: matching and classification. The matching task involved matching a reference stimulus to one of four target stimuli. In the classification task, participants were shown a single stimulus and learned to classify it into one of two categories. Matching and classification are similar but place different demands on switching and evaluation. In matching, a rule can be known with certainty after a single correct answer. In classification, participants may need to evaluate evidence for a rule even after an initial correct response. This critical difference allows isolation of evaluative functions from switching functions. If the rlPFC is primarily involved in switching between representations, it should cease to be active once participants settle on a given rule in both tasks. If the rlPFC is involved in rule evaluation, its activation should persist in the classification task, but not matching. The results revealed that rlPFC activation persisted into correct trials in classification, but not matching, suggesting that it continues to be involved in the evaluations of evidence for a rule even after participants have arrived at the correct rule. PMID- 29107770 TI - Nocebo-induced modulation of cerebral itch processing - An fMRI study. AB - It has been shown repeatedly that perceiving itch-related pictures or listening to a lecture on itch can enhance itch sensation and scratching behaviour (Niemeier and Gieler, 2000; Holle et al., 2012; Lloyd et al., 2013), indicating that itch is strongly influenced by expectations. Using fMRI, we investigated the neural correlates of the itch-related nocebo effect in healthy male and female human subjects. Itch sensation on the left forearm was induced by cutaneous histamine application and thermally modulated, with cooling leading to higher itch. Nocebo-induced aggravation of histaminergic itch was achieved by ostensibly treating volunteers with "transcutaneous electrical nerve stimulation (TENS)" about which subjects were instructed that it would increase itch. During a conditioning phase subjects indeed experienced stronger itch due to slightly altered cooling and histamine concentrations, but attributed it to the alleged "TENS stimulation". Importantly, in the subsequent test phase where no "TENS" or electrical stimulation was applied, volunteers significantly reported stronger itch during the nocebo as compared to the control condition. Comparing BOLD responses during nocebo in contrast to control, we observed increased activity in contralateral (right) rolandic operculum. Opercular involvement was repeatedly reported in studies related to the expectation of stimulus intensification and might thus represent an early area integrating expectation information with somatosensory information. Finally, functional coupling between the insula and the periaqueductal gray (PAG) was enhanced specifically in the nocebo condition. This cortex-PAG interaction indicates that context-dependent top-down modulation during itch might represent a shared mechanism with other modalities such as pain. PMID- 29107771 TI - Overlapping frontoparietal networks for tactile and visual parametric working memory representations. AB - Previous working memory (WM) research based on non-human primate electrophysiology and human EEG has shown that frontal brain regions maintain frequencies of flutter stimulation across different sensory modalities by means of a supramodal parametric WM code. These findings imply that frontal regions encode the memorized frequencies in a sensory-unspecific, quantitative format. Here, we explored which brain regions maintain information about frequencies provided by different sensory modalities at the level of activity pattern across fMRI voxel populations. Moreover, we sought evidence for a supramodal multivariate WM representation. Participants maintained the same set of frequencies of tactile vibration and visual flicker for a 6 s WM delay in a frequency discrimination task. A support vector regression model for multivariate pattern analysis was applied. We observed that sensory cortices were only selective for memoranda of their corresponding modalities, while frontoparietal regions exhibited distinguishable activity patterns to memorized frequencies regardless of sensory modality. A common multivariate code was not evident in our data. Collectively, we show that mnemonic representations for stimulus frequencies are maintained throughout the cortical hierarchy, in line with the suggested transformation of information across different representational formats. Although evidence for a supramodal multivariate code is absent, our findings underpin the generalized role of the frontoparietal cortex for maintaining quantitative information across sensory modalities. PMID- 29107772 TI - Gastric-bypass surgery induced widespread neural plasticity of the obese human brain. AB - Bariatric surgery has become the gold standard for the treatment of morbid obesity (body mass index (BMI) >= 40 kg/m2), but only few studies investigated its plastic influences on the obese brain. In this longitudinal study, we combined structural and functional magnetic resonance brain imaging (MRI) in 27 patients (BMI 47.8 +/- 5.5 kg/m2) undergoing gastric-bypass surgery and 14 non obese matched controls (BMI 24.7 +/- 3.4 kg/m2). Over the first year after surgery, patients presented widespread changes in white matter density (WMD) as well as gray matter density (GMD) in the cerebral cortex of all lobes, subcortical structures, the brainstem as well as the cerebellum, but no changes in white matter water diffusivity throughout the brain. Voxel-by-voxel regression analyses revealed that all GMD and WMD changes were well associated with elevated regional homogeneity of spontaneous neural activity (ReHo) in blood-oxygenation level-dependent signals. Spatial-temporal integration of structural and functional MRI suggests that gastric-bypass surgery induces widespread plastic changes in brain structure that concurrently homogenizes the functional profile of the cortex, subcortical regions as well as white matter structures. PMID- 29107773 TI - Midfrontal theta and pupil dilation parametrically track subjective conflict (but also surprise) during intertemporal choice. AB - Many everyday choices are based on personal, subjective preferences. When choosing between two options, we often feel conflicted, especially when trading off costs and benefits occurring at different times (e.g., saving for later versus spending now). Although previous work has investigated the neurophysiological basis of conflict during inhibitory control tasks, less is known about subjective conflict resulting from competing subjective preferences. In this pre-registered study, we investigated subjective conflict during intertemporal choice, whereby participants chose between smaller immediate versus larger delayed rewards (e.g., $15 today vs. $22 in 30 days). We used economic modeling to parametrically vary eleven different levels of conflict, and recorded EEG data and pupil dilation. Midfrontal theta power, derived from EEG, correlated with pupil responses, and our results suggest that these signals track different gradations of subjective conflict. Unexpectedly, both signals were also maximally enhanced when decisions were surprisingly easy. Therefore, these signals may track events requiring increased attention and adaptive shifts in behavioral responses, with subjective conflict being only one type of such event. Our results suggest that the neural systems underlying midfrontal theta and pupil responses interact when weighing costs and benefits during intertemporal choice. Thus, understanding these interactions might elucidate how individuals resolve self-control conflicts. PMID- 29107774 TI - Analysis of the efficacy and cost-effectiveness of best management practices for controlling sediment yield: A case study of the Joumine watershed, Tunisia. AB - Soil erosion can be reduced through the strategic selection and placement of best management practices (BMPs) in critical source areas (CSAs). In the present study, the Soil Water Assessment Tool (SWAT) model was used to identify CSAs and investigate the effectiveness of different BMPs in reducing sediment yield in the Joumine watershed, an agricultural river catchment located in northern Tunisia. A cost-benefit analysis (CBA) was used to evaluate the cost-effectiveness of different BMP scenarios. The objective of the present study was to determine the most cost-effective management scenario for controlling sediment yield. The model performance for the simulation of streamflow and sediment yield at the outlet of the Joumine watershed was good and satisfactory, respectively. The model indicated that most of the sediment was originated from the cultivated upland area. About 34% of the catchment area consisted of CSAs that were affected by high to very high soil erosion risk (sediment yield >10t/ha/year). Contour ridges were found to be the most effective individual BMP in terms of sediment yield reduction. At the watershed level, implementing contour ridges in the CSAs reduced sediment yield by 59%. Combinations of BMP scenarios were more cost effective than the contour ridges alone. Combining buffer strips (5-m width) with other BMPs depending on land slope (> 20% slope: conversion to olive orchards; 10 20% slope: contour ridges; 5-10% slope: grass strip cropping) was the most effective approach in terms of sediment yield reduction and economic benefits. This approach reduced sediment yield by 61.84% with a benefit/cost ratio of 1.61. Compared with the cost of dredging, BMPs were more cost-effective for reducing sediment loads to the Joumine reservoir, located downstream of the catchment. Our findings may contribute to ensure the sustainability of future conservation programs in Tunisian regions. PMID- 29107776 TI - Long-term exposure to thiolated graphene oxide in the range of MUg/L induces toxicity in nematode Caenorhabditis elegans. AB - The in vivo toxicity and translocation of thiolated graphene oxide (GO-SH) are still largely unclear. We hypothesized that long-term exposure to GO-SH may cause the adverse effects on environmental organisms. We here employed in vivo assay system of Caenorhabditis elegans to investigate the possible toxicity and translocation of GO-SH after long-term exposure. In wild-type nematodes, we observed that prolonged exposure to GO-SH at concentrations>100MUg/L resulted in the toxicity on functions of both primary targeted organs such as the intestine and secondary targeted organs such as the neurons and the reproductive organs. The severe accumulation of GO-SH was further detected in the body of wild-type nematodes. The translocation of GO-SH into secondary targeted organs such as reproductive organs through intestinal barrier might be associated with the enhancement in intestinal permeability in GO-SH exposed wild-type nematodes. Prolonged exposure to GO-SH (100MUg/L) decreased the expression of gas-1 encoding a subunit of mitochondrial complex I, and mutation of gas-1 caused the formation of GO-SH toxicity at concentration>10MUg/L and more severe accumulation of GO-SH in the body of animals. Therefore, our results confirm the possibility for prolonged exposure to GO-SH in inducing adverse effects on nematodes. Our data highlight the potential adverse effects of GO-SH in the range of MUg/L on environmental organisms after long-term exposure. PMID- 29107775 TI - Bacterial, archaeal, and fungal community responses to acid mine drainage-laden pollution in a rice paddy soil ecosystem. AB - Lacking sufficient clean water, the paddy soils along the Hengshi River have suffered from long-term acid mine drainage (AMD) contamination. The impacted cropland is too heavily contaminated to grow food safely. The microbial communities inhabiting the environment play pivotal roles in the crop growth, health, and ecological services. In this study, the bacterial, archaeal, and fungal communities in the impacted paddy soil were examined using high-throughput Illumina MiSeq sequencing. The results showed that AMD irrigation considerably enriched the bacterial phylum Acidobacteria and the archaeal phylum Crenarchaeota, while the fungal community was more stable. The abundances of Acidobacteria and Crenarchaeota were significantly positively correlated with the AMD-related environmental factors of pH and heavy metals (Cu, Pb, and Zn). In the most contaminated samples, communities were dominated by the bacteria Candidatus Solibacter and Candidatus Koribacter from the Acidobacteria family. Functional gene profile analysis demonstrated that the energy metabolic processes of the microbial communities, especially C/N related pathways, have adjusted and are well-adapted to tolerating AMD contamination. The present study described the structural and functional differentiation of microbial communities in the rice paddy soil under AMD irrigation. The results are useful for the development of bioremediation strategies using native microbes in the cleanup and biorestoration of AMD-contaminated agriculture soil. PMID- 29107777 TI - Legacy and emerging organohalogenated contaminants in wild edible aquatic organisms: Implications for bioaccumulation and human exposure. AB - Highly industrialized and urbanized watersheds may receive various contaminants from anthropogenic activities. In this study, legacy and emerging organohalogenated contaminants (OHCs) were measured in edible wild aquatic organisms sampled from the Pearl River and Dongjiang River in a representative industrial and urban region in China. High concentrations of target contaminants were observed. The Pearl River exhibited higher concentrations of OHCs than the Dongjiang River due to high industrialization and urbanization. Agrochemical inputs remained an important source of OHCs in industrialized and urbanized watershed in China, but vigilance is needed for recent inputs of polychlorinated biphenyls (PCBs) originated from e-waste recycling activities. Bioaccumulation of dichlorodiphenyltrichloroethane and its metabolites (DDTs), hexachlorocyclohexanes (HCHs), PCBs, polybrominated diphenyl ethers (PBDEs), and Dechlorane Plus (DP) was biological species- and compound-specific, which can be largely attributed to metabolic capability for xenobiotics. No health risk was related to the daily intake of DDTs, HCHs, and PBDEs via consumption of wild edible species investigated for local residents. However, the current exposure to PCBs through consuming fish is of potential health concern. PMID- 29107778 TI - Potential export of soluble reactive phosphorus from a coastal wetland in a cold temperate lagoon system: Buffer capacities of macrophytes and impact on phytoplankton. AB - The main pathways for phosphorus flux from land to sea are particle-associated (erosion) and dissolved runoff (rivers, groundwater, and agricultural drainage systems). These pathways can act as diffused sources for aquatic systems and support primary production, therefore, counteracting the efforts aimed at reducing phosphorus input from point sources such as sewage treatment plants. Phosphorus supports primary production in the water column and can elevate phytoplankton and macrophyte growth. Coastal wetlands with emerged (Phragmites australis) and submerged (Stuckenia pectinata and Chara sp.) macrophytes can affect phosphorus fluxes in the land-water transitional zone. The macrophytes have the potential to act as a buffer for phosphorus run-off. The aim of this study was to determine the phosphorus stocks in the transitional land-sea zone of a cold temperate lagoon at the southern Baltic Sea. Phosphorus in macrophytes, water samples, and phytoplankton growth were analyzed along a gradient moving away from the wetland. The phosphorus stocks in the above ground biomass of the Phragmites plants were the highest at the end of August and with more than 8000mgPm-2 in the interior zone of the wetland, threefold the amount of P in Phragmites plant tissue at the wetland fringe. The submerged macrophytes stored only 300mgPm-2, close to the wetland. Concentrations of soluble reactive phosphorus in the water column were higher in the zones of emerged macrophytes than in the zones of submerged macrophytes and decreased along the land-sea transect. Phytoplankton could grow proximal to the wetland during all seasons, but not further away. This study indicates that macrophytes can act as phosphorus sinks. However, short-term releases of phosphate within the Phragmites wetland have the potential to lead to phytoplankton growth. Phytoplankton can use these nutrient pulses either immediately or later, and support high biomass and turbidity within the system. PMID- 29107779 TI - Wet-only deposition of atmospheric inorganic nitrogen and associated isotopic characteristics in a typical mountain area, southwestern China. AB - To quantify and compare atmospheric nitrogen (N) deposition and its N isotopic ratio are critical for constraining N sources and effective reduction of reactive N emissions. In this study, a total of 223 rainwater samples were collected by wet-only auto-samplers, and wet-only deposition and isotopic composition (delta15N) of reduced (NH4+-N) and oxidized (NO3--N) N were measured at three typical mountain sites, including an urban (Wanzhou, WZ), a town (Gaoyang, GY) and a rural (Dade, DD) site in Chongqing, southwestern China in 2016. The wet only inorganic N deposition (DIN, sum of NO3--N and NH4+-N) were 17.50, 8.63 and 12.16kgNha-1yr-1 at WZ, GY and DD site, respectively. Annual delta15N-NH4+ values of rainwaters were negative at the urban site (-3.12+/-3.210/00, WZ) and positive at both town and rural site (0.65+/-12.510/00, GY; 2.16+/-6.110/00, DD). Annual delta15N-NO3- values, on the contrary, were positive at the urban site (0.33+/ 7.870/00, WZ) and negative at both town and rural site (-5.59+/-2.200/00, GY; 0.39+/-8.890/00, DD). These results reveal the urban site was wet-only DIN hotspot and had a different N source compared with the town-rural site in the mountain area. Moreover, precipitation DIN had a potentially negative risk on both aquatic and forest ecosystems. PMID- 29107780 TI - Cd isotope fractionation during sulfide mineral weathering in the Fule Zn-Pb-Cd deposit, Yunnan Province, Southwest China. AB - Zinc (Zn)-Lead (Pb) deposits are generally rich in cadmium (Cd), and the weathering of sulfide minerals in such deposits results in large releases of Cd into the environment. From an environmental and public health standpoint, understanding Cd sources and cycling is critical to identifying potential hazards to humans. In this study, the Cd isotope compositions (expressed as delta114/110Cd) of secondary minerals such as anglesite (-0.57+/-0.030/00; 2S.D.), granular smithsonite (0.04+/-0.140/00; 2S.D.), layered smithsonite (0.15+/-0.400/00; 2S.D.), hydrozincite (0.26+/-0.010/00; 2S.D.) and clay minerals (-0.01+/-0.060/00; 2S.D.) from the Fule Zn-Pb-Cd deposit, Southwest China, are investigated to better understand the Cd sources and cycling in this area. Combined with our previous study (Zhu et al., 2017), the work herein elucidates the patterns of Cd isotopic fractionation during the formation processes of such secondary minerals and traces the weathering of these minerals into the ecosystem. The delta114/110Cd values of secondary minerals exhibit the following decreasing trend: hydrozincite>large granular smithsonite>small granular smithsonite>anglesite. Although different amounts of Cd were lost during the formation of equally sized samples, no or minor variations in Cd isotopic composition were observed. However, significant isotopic differences were observed between different size fractions. These results demonstrate that the particle size of secondary minerals and weathering products of sulfide significantly influence Cd isotope composition and fractionation during natural weathering. This systematic fractionation provides an initial foundation for the use of Cd isotopes as environmental tracers in ecosystems and in the global Cd isotope budget. PMID- 29107781 TI - Drought evolution, severity and trends in mainland China over 1961-2013. AB - Droughts have destructive impacts on crop yields and water supplies, and researching droughts is vital for societal stability and human life. This work aimed to assess the spatiotemporal evolution of droughts in mainland China over 1961-2013 using four drought indices. These indices were the percentage of precipitation anomaly (Pa), standard precipitation index (SPI), standard precipitation evapotranspiration index (SPEI) and evaporative demand drought index (EDDI) at multiple timescales ranging from 1-week to 24-month. The variations of the SPI, SPEI and EDDI were compared with historical severe or extreme droughts. The general increases of the Pa, SPI and SPEI, and general decrease of the EDDI, consistently implied an overall relief of drought conditions over 1961-2013. The different drought indices revealed historical drought conditions, including the national extreme droughts in 1961, 1965, 1972, 1978, 1986, 1988, 1992, 1994, 1997, 1999 and 2000, but various drought severity levels were classified for each drought event since the classification standards differed. Although the SPI and SPEI performed better than the EDDI and there were higher correlations between the SPI and the SPEI, all the indices were regional- or station-specific and have identified historical severe or extreme drought events. At shorter timescales, the EDDI revealed earlier onsets and ends of flash droughts, unlike those indicated by the SPI and SPEI. The comparison of the different indices based on the historical drought events confirmed the uses of the Pa, SPI and SPEI for determining continuous droughts and that of the EDDI for identifying flash droughts. PMID- 29107782 TI - Salmonella, including antibiotic-resistant Salmonella, from flies captured from cattle farms in Georgia, U.S.A. AB - Flies can be transmission vehicles of Salmonella from cattle to humans. This study determined the prevalence of Salmonella in/on flies captured from 33 cattle farms, including 5 beef and 28 dairy farms, in Georgia, USA, and characterized antibiotic resistance profiles of the isolated Salmonella. Twenty-six out of the 33 cattle farms (79%) and 185 out of the 1650 flies (11%) tested positive for Salmonella in the study. The incidence of Salmonella-positive flies varied from farm to farm, ranging from 0 to 78%. Among the 185 Salmonella isolated from flies, 29% were resistant to ampicillin, 28% to tetracycline, 21% to amoxicillin/clavulanic acid, 20% to cefoxitin, and 12% to streptomycin. Incidences of resistance against other tested antibiotics were low, ranging from 0 to 3%. Furthermore, 28% of the Salmonella isolates were multidrug resistant, demonstrating resistance to 3 or more antibiotics. The minimal inhibitory concentrations of ampicillin, cefoxitin, streptomycin, and tetracycline against the Salmonella isolates ranged from 32 to >2048, 64 to 2048, 128 to 1024, and 32 to 1024MUg/mL, respectively. These data suggest that flies could be effective vehicles of transmitting antibiotic resistant Salmonella and disseminating antibiotic resistance genes on cattle farms, posing risks to human and animal health. PMID- 29107783 TI - PBT assessment under REACH: Screening for low aquatic bioaccumulation with QSAR classifications based on physicochemical properties to replace BCF in vivo testing on fish. AB - Aquatic bioconcentration factors (BCFs) are critical in PBT (persistent, bioaccumulative, toxic) and risk assessment of chemicals. High costs and use of more than 100 fish per standard BCF study (OECD 305) call for alternative methods to replace as much in vivo testing as possible. The BCF waiving scheme is a screening tool combining QSAR classifications based on physicochemical properties related to the distribution (hydrophobicity, ionisation), persistence (biodegradability, hydrolysis), solubility and volatility (Henry's law constant) of substances in water bodies and aquatic biota to predict substances with low aquatic bioaccumulation (nonB, BCF<2000). The BCF waiving scheme was developed with a dataset of reliable BCFs for 998 compounds and externally validated with another 181 substances. It performs with 100% sensitivity (no false negatives), >50% efficacy (waiving potential), and complies with the OECD principles for valid QSARs. The chemical applicability domain of the BCF waiving scheme is given by the structures of the training set, with some compound classes explicitly excluded like organometallics, poly- and perfluorinated compounds, aromatic triphenylphosphates, surfactants. The prediction confidence of the BCF waiving scheme is based on applicability domain compliance, consensus modelling, and the structural similarity with known nonB and B/vB substances. Compounds classified as nonB by the BCF waiving scheme are candidates for waiving of BCF in vivo testing on fish due to low concern with regard to the B criterion. The BCF waiving scheme supports the 3Rs with a possible reduction of >50% of BCF in vivo testing on fish. If the target chemical is outside the applicability domain of the BCF waiving scheme or not classified as nonB, further assessments with in silico, in vitro or in vivo methods are necessary to either confirm or reject bioaccumulative behaviour. PMID- 29107784 TI - Incidence of postpartum anaemia and risk factors associated with vaginal birth. AB - BACKGROUND: Postpartum anaemia is a frequent and potentially preventable complication that has serious repercussions on health and maternal well-being. AIM: Determine the incidence and perinatal risk factors associated with postpartum anaemia in women who gave birth vaginally. METHODS: An observational and analytical retrospective cohort study conducted at the Mancha-Centro Hospital during the 2010-2014 period. Data were collected from 2990 women who gave birth vaginally. The main outcome variable was postpartum anaemia for two cut-off points (haemoglobin (Hb) <11g/dL and <9g/dL at 24-h postpartum). Women with prepartum anaemia (<11g/dL) were excluded. It included a multivariate analysis by multiple linear regression. FINDINGS: 45% (1341) of women had postpartum levels of Hb <11g/dL, and 7.1% (212) of women had Hb <9g/dL. The most strongly associated risk factors with more severe anaemia (Hb <9g/dL) were episiotomy (OR 3.19. 95%CI: 2.10-4.84), first stage of labour >9h (OR 2.50. 95%CI: 1.58-3.94), primiparity (OR 2.50. 95%CI: 1.61-3.87) and previous caesarean section (OR 2.43. 95%CI: 1.51-3.90). The other independent risk factors for both Hb cut-off points were prolonged second stage of labour, instrumental birth, tearing>first degree, non-practice of active management and heavier birth weight of newborns. CONCLUSION: Postpartum anaemia has a high incidence. The active management of third stage of labour, selective practice of episiotomies, and performing instrumental births only when strictly necessary are efficient measures to lower the incidence of postpartum anaemia. PMID- 29107785 TI - An information diffusion technique to assess integrated hazard risks. AB - An integrated risk is a scene in the future associated with some adverse incident caused by multiple hazards. An integrated probability risk is the expected value of disaster. Due to the difficulty of assessing an integrated probability risk with a small sample, weighting methods and copulas are employed to avoid this obstacle. To resolve the problem, in this paper, we develop the information diffusion technique to construct a joint probability distribution and a vulnerability surface. Then, an integrated risk can be directly assessed by using a small sample. A case of an integrated risk caused by flood and earthquake is given to show how the suggested technique is used to assess the integrated risk of annual property loss. PMID- 29107786 TI - Predictors of treatment utilization and barriers to treatment utilization among individuals with lifetime cannabis use disorder in the United States. AB - OBJECTIVE: To present information on predictors of treatment utilization and barriers to treatment utilization among individuals with lifetime DSM-5 cannabis use disorder (CUD). METHOD: Face-to-face survey of a representative sample of the adult US general population (n=36,309). RESULTS: Treatment rates for CUD were low in this general population survey (13.7%). Severity of CUD and comorbidity of other lifetime drug use disorders were significant predictors of lifetime treatment utilization for CUD. Preference for self-reliance, minimizing problems, fear of stigma, and financial and structural issues were among the most frequently endorsed reasons for respondents not seeking treatment when they perceived the need for treatment among individuals with lifetime CUD, regardless of whether they eventually utilized treatment at some time in their lives. CONCLUSIONS: Given the rising prevalence of CUD in the US over the past decade and currently low treatment rates for CUD, increased provision for services for CUD appears critically needed, especially those that screen for and treat, when present, other drug use disorders. Programs to reduce stigma and financial barriers are needed, as well as programs to increase awareness among the general public, health care professionals about the nature and seriousness of CUD, and the availability and effectiveness of treatment for this disorder. PMID- 29107787 TI - Marijuana use during pregnancy: A comparison of trends and correlates among married and unmarried pregnant women. AB - BACKGROUND/PURPOSE: While recent evidence indicates increases in marijuana use among adult women in the United States (US), important questions remain with respect to marijuana use during pregnancy. This study examines trends and correlates of prenatal marijuana use and the effects of marijuana-specific risk/protective factors on marijuana use trends using a nationally representative sample. METHOD: Data were derived from the National Survey on Drug Use and Health (2005-2014), a nationally representative survey that included 3640 married and 3987 unmarried pregnant women in the United States. The significance of marijuana use trends was tested using logistic regression analyses while adjusting for complex sampling design effects and controlling for sociodemographic and marijuana-specific factors. RESULTS: From 2005-2014, marijuana use prevalence among unmarried pregnant women increased by 85% from 5.4% to 10.0% while the prevalence among married pregnant women remained stable (mostly under 1.5%). The increasing trend among unmarried pregnant women was associated with their lower disapproval and risk perceptions of marijuana use. In addition, past-year anxiety (AOR=3.30, 95% CI=1.87-5.82) and depression (AOR=3.85, 95% CI=2.33-6.36) diagnoses were linked with marijuana use among unmarried, but not married, pregnant women. DISCUSSION: Increased attention should be paid to reducing prenatal marijuana use among unmarried women. Findings also suggest the need to attend to unmarried pregnant women's mental health problems as well as their physical health-risk behaviors. PMID- 29107788 TI - Corrigendum to "Prescribing of benzodiazepines and opioids to individuals with substance use disorders" [Drug Alcohol Depend. 178 (2017) 223-230]. PMID- 29107789 TI - Overcoming the Challenges of Low Drug Solubility in the Intravenous Formulation of Solithromycin. AB - Solithromycin is a fluoro-ketolide (a fourth-generation macrolide) antibiotic that has been undergoing clinical trials for the treatment of community-acquired bacterial pneumonia. In this study, development of the tri-amino acid-buffered solithromycin intravenous (IV) formulation was performed to minimize the occurrence of infusion-associated local adverse events (infusion-site pain or phlebitis) observed in patients who received the tartaric acid-buffered IV formulation with a lower buffered capacity during phase I clinical trials. Development of the tri-amino acids-buffered solithromycin IV formulation was achieved using a dynamic in vitro precipitation model. Computational modeling also supports the superiority of the amino acid-buffered formulation over the tartaric aid-buffered formulation. PMID- 29107790 TI - The Selection of a Pharmaceutical Salt-The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance. AB - A roadmap for the selection of a pharmaceutical salt form for a development candidate is presented. The free base of the candidate did not have sufficient chemical stability for development. The initially selected salt form turned out to be undevelopable because it was unstable during scale-up synthesis and storage. The rationale for the new solid form screening and the criteria for selection are discussed. Before the final selection, the pH solubility profiles of the 2 new salts, a benzoate and a besylate, were compared. Atypical solubility behavior was observed for the benzoate salt in hydrochloric acid with and without normal saline. A scheme is proposed illustrating how the pKas of the counterion and active pharmaceutical ingredient, the medium composition, and final pH affect the solubility and solution equilibria of the 2 selected salt forms. This scheme also includes the equilibria between solution and solid phases in different pH ranges. The pharmaceutical importance of this research is that it sheds light on how the acidity of the counterion can affect the solubility of the selected salt form in the gastric environment. With a well-designed formulation strategy, this property potentially can be translated to optimal biopharmaceutical performance of the drug product. PMID- 29107791 TI - Complexes of Felodipine Nanoparticles With Zein Prepared Using a Dual Shift Technique. AB - To improve the dissolution of felodipine, felodipine-zein complexes were prepared using a dual shift technique, with zein as both stabilizer and carrier. The complexes were characterized by particle size, zeta potential, morphology, crystalline properties, and release behavior. The complexes could be prepared in high yield and showed good redispersibility. The mean diameters of the felodipine particles in complexes were 150-300 nm, with negative zeta potentials of -30 to 25 mV after rehydration, and the particle sizes of the complexes were in the range 10-80 MUm. The size of the felodipine nanoparticles incorporated into zein increased gradually with increasing drug content. Powder X-ray diffraction and differential scanning calorimetry indicated that felodipine in the complexes was markedly less crystalline than the pure drug. Both the rate and extent of dissolution of the complexes were significantly greater than those of the active pharmaceutical ingredient or physical mixtures. Spectroscopic analyses indicated that intermolecular interactions, especially hydrophobic interactions, are the major driving forces for the formation of the felodipine nanoparticles and contribute to the stabilization effect. This study provides a promising strategy for enhancing the dissolution rate of drugs using simplified preparation processes and showcases the design of zein-based oral delivery systems for bioactive components. PMID- 29107792 TI - Caffeine and acetaminophen association: Effects on mitochondrial bioenergetics. AB - AIMS: Many studies have been demonstrating the role of mitochondrial function in acetaminophen (APAP) hepatotoxicity. Since APAP is commonly consumed with caffeine, this work evaluated the effects of the combination of APAP and caffeine on hepatic mitochondrial bioenergetic function in mice. MAIN METHODS: Mice were treated with caffeine (20mg/kg, intraperitoneal (i.p.)) or its vehicle and, after 30minutes, APAP (250mg/kg, i.p.) or its vehicle. Four hours later, livers were removed, and the parameters associated with mitochondrial function and oxidative stress were evaluated. Hepatic cellular oxygen consumption was evaluated by high resolution respirometry (HRR). KEY FINDINGS: APAP treatment decreased cellular oxygen consumption and mitochondrial complex activities in the livers of mice. Additionally, treatment with APAP increased swelling of isolated mitochondria from mice livers. On the other hand, caffeine administered with APAP was able to improve hepatic mitochondrial bioenergetic function. Treatment with APAP increased lipid peroxidation and reactive oxygen species (ROS) production and decreased glutathione levels in the livers of mice. Caffeine administered with APAP was able to prevent lipid peroxidation and the ROS production in mice livers, which may be associated with the improvement of mitochondrial function caused by caffeine treatment. SIGNIFICANCE: We suggest that the antioxidant effects of caffeine and/or its interactions with mitochondrial bioenergetics may be involved in its beneficial effects against APAP hepatotoxicity. PMID- 29107793 TI - Sustained beta-AR stimulation induces synthesis and secretion of growth factors in cardiac myocytes that affect on cardiac fibroblast activation. AB - Paracrine factors, including growth factors and cytokines, released from cardiac myocytes following beta-adrenergic receptor (beta-AR) stimulation regulate cardiac fibroblasts. Activated cardiac fibroblasts have the ability to increase collagen synthesis, cell proliferation and myofibroblast differentiation, leading to cardiac fibrosis. However, it is unknown which beta-AR subtypes and signaling pathways mediate the upregulation of paracrine factors in cardiac myocytes. In this study, we demonstrated that sustained stimulation of beta-ARs significantly induced synthesis and secretion of growth factors, including connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF), via the cAMP dependent and protein kinase A (PKA)-dependent pathways. In addition, isoproterenol (ISO)-mediated synthesis and secretion of CTGF and VEGF through the beta1-AR and beta2-AR subtypes. Paracrine factors released by cardiac myocytes following sustained beta-AR stimulation are necessary for the induction of cell proliferation and synthesis of collagen I, collagen III and alpha-smooth muscle actin (alpha-SMA) in cardiac fibroblasts, confirming that beta-AR overstimulation of cardiac myocytes induces cardiac fibrosis by releasing several paracrine factors. These effects can be antagonized by beta-blockers, including atenolol, metoprolol, and propranolol. Thus, the use of beta-blockers may have beneficial effects on the treatment of myocardial fibrosis in patients with heart failure. PMID- 29107794 TI - The clinical presentation of bradyopsia in children. AB - Diagnosing bradyopsia can be challenging in young children because structural ophthalmic examination is typically normal and visual acuity can improve with pinhole despite no significant refractive error. This case series highlights the clinical presentations and features of 5 affected children (3 Arab families) who harbored the same homozygous RGS9 frameshift mutation, which seems to represent a founder effect for the Arabian Peninsula. PMID- 29107795 TI - Gustatory lid retraction: an unusual congenital cranial dysinnervation disorder. AB - Congenital cranial dysinnervation disorders are developmental abnormalities of cranial nerves that often include abnormal synkinesis. Among the most common ophthalmic congenital cranial dysinnervation disorders are Duane retraction syndrome and the Marcus-Gunn jaw-winking phenomenon. This report documents gustatory lid retraction as an unusual congenital cranial dysinnervation. PMID- 29107796 TI - Periorbital lesions misdiagnosed as dermoid cysts. AB - Several periorbital lesions can be clinically misdiagnosed as dermoid cyst. We retrospectively reviewed the histopathological findings for 97 biopsied periorbital lesions with a clinical diagnosis of dermoid cyst from January 2006 to July 2016 at a single center and identified 5 cases that were eventually found to have been misdiagnosed. The main presenting symptom was a long-standing mobile painless mass with intact overlying skin below the medial aspect of the brow in 4 patients and below the center of the brow in 1 patient. The tissue diagnoses included vascular lesions (hemangiomas and cavernous venous malformation) in 4 patients and pilomatrixoma in 1 patient. The agreement between the clinical and pathological diagnosis of a periocular dermoid cyst in our series was 94.8%. PMID- 29107797 TI - Establishment of a de novo Reference Transcriptome of Histomonas meleagridis Reveals Basic Insights About Biological Functions and Potential Pathogenic Mechanisms of the Parasite. AB - The protozoan flagellate Histomonas meleagridis is the causative agent of histomonosis in poultry. In turkeys, high mortality might be noticed whereas in chickens the disease is less severe despite production losses. Discovered over a century ago, molecular data on this parasite are scarce and genetic studies are in its infancy. To expand genomic information, a de novo transcriptome sequencing of H. meleagridis was performed from a virulent and an attenuated strain, cultivated in vitro as monoxenic mono-eukaryotic culture. Normalized cDNA libraries were prepared and sequenced on Roche 454 GS FLX resulting in 1.17 million reads with an average read length of 458bp. Sequencing reads were assembled into two sets of >4500 contigs, which were further integrated to establish a reference transcriptome for H. meleagridis consisting of 3356 contigs. Following gene ontology analysis, data mining provided novel biological insights into proteostasis, cytoskeleton, metabolism, environmental adaptation and potential pathogenic mechanisms of H. meleagridis. Finally, the transcriptome data was used to perform an in silico drug screen to identify potential anti histomonal drugs. Altogether, data recruited from virulent and attenuated parasites facilitate a better understanding of the parasites' molecular biology aiding the development of novel diagnostics and future research. PMID- 29107798 TI - Parent emotion socialization and pre-adolescent's social and emotional adjustment: Moderating effects of autonomic nervous system reactivity. AB - This study examined whether measures of children's autonomic nervous system (ANS) reactivity to social stress moderated the effect of parent emotion socialization on children's social and emotional adjustment. Sixty-one children (9-13 years) completed a peer rejection task while their respiratory sinus arrhythmia reactivity (RSA-R) and skin conductance level reactivity (SCL-R) were assessed. Parents' report of supportive and non-supportive reactions to their child's negative emotions served as measures of emotion socialization. Measures of children's social and emotional adjustment included: teacher-rated peer rejection, aggression, and prosocial behavior and parent-rated aggressive/dysregulated behavior and emotion regulation skills. Measures of children's ANS reactivity moderated the effect of parent emotion socialization on children's adjustment. Supportive responses were more protective for children evidencing RSA augmentation whereas non-supportive responses were more detrimental for children evidencing low SCL-R. Thus children's ANS reactivity during social stress may represent a biological vulnerability that influences sensitivity to parent emotion socialization. PMID- 29107799 TI - Central theta amplitude as a negative correlate of performance proficiency in a dynamic visuospatial task. AB - Dynamic visuospatial tasks, requiring continuous engagement of attention over long time periods, have been little studied with the electroencephalogram. Specifically, the role of the theta band in these tasks is unclear, with task related theta enhancements improving performance in some studies, and hindering it in others. In this study, 30 participants performed the Pong videogame as a dynamic visuospatial task to analyze the influence of theta and alpha amplitude as well as alpha asymmetry on performance. The theta band increased significantly at central-parietal regions and correlated negatively with performance, especially at anterior regions. The alpha band showed a significant decrease, greater at right over left parietal regions, but neither the amplitude nor the asymmetry ratio correlated with performance. With theta being an indicator of top down cognitive control, it may be concluded that proficient performance in dynamic visuospatial tasks depends on a bottom-up guidance of attention with little top-down intervention. PMID- 29107800 TI - Exploring the relationship of peripheral total bilirubin, red blood cell, and hemoglobin with blood pressure during childhood and adolescence. AB - OBJECTIVE: Total bilirubin is beneficial for protecting cardiovascular diseases in adults. The authors aimed to investigate the association of total bilirubin, red blood cell, and hemoglobin levels with the prevalence of high blood pressure in children and adolescents. METHODS: A total of 3776 students (aged from 6 to 16 years old) were examined using cluster sampling. Pre-high blood pressure and high blood pressure were respectively defined as the point of 90th and 95th percentiles based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Both systolic and diastolic blood pressure were standardized into z-scores. RESULTS: Peripheral total bilirubin, red blood cell and hemoglobin levels were significantly correlated with age, and also varied with gender. Peripheral total bilirubin was negatively correlated with systolic blood pressure in 6- and 9-year-old boys, whilst positively correlated with diastolic blood pressure in the 12-year-old boys and 13- to 15-year-old girls (p<0.05). Higher levels of red blood cell and hemoglobin were observed in pre-high blood pressure and high blood pressure students when compared with their normotensive peers (p<0.01). The increases in red blood cell and hemoglobin were significantly associated with high blood pressure after adjusting for confounding factors. The ORs (95% CI) of each of the increases were 2.44 (1.52-3.92) and 1.04 (1.03-1.06), respectively. No statistical association between total bilirubin and high blood pressure was observed (p>0.05). CONCLUSION: Total bilirubin could be weakly correlated with both systolic and diastolic blood pressure, as correlations varied with age and gender in children and adolescents; in turn, the increased levels of red blood cell and hemoglobin are proposed to be positively associated with the prevalence of high blood pressure. PMID- 29107801 TI - Linear infrastructure impacts on landscape hydrology. AB - The extent of roads and other forms of linear infrastructure is burgeoning worldwide, but their impacts are inadequately understood and thus poorly mitigated. Previous studies have identified many potential impacts, including alterations to the hydrological functions and soil processes upon which ecosystems depend. However, these impacts have seldom been quantified at a regional level, particularly in arid and semi-arid systems where the gap in knowledge is the greatest, and impacts potentially the most severe. To explore the effects of extensive track, road, and rail networks on surface hydrology at a regional level we assessed over 1000 km of linear infrastructure, including approx. 300 locations where ephemeral streams crossed linear infrastructure, in the largely intact landscapes of Australia's Great Western Woodlands. We found a high level of association between linear infrastructure and altered surface hydrology, with erosion and pooling 5 and 6 times as likely to occur on-road than off-road on average (1.06 erosional and 0.69 pooling features km-1 on vehicle tracks, compared with 0.22 and 0.12 km-1, off-road, respectively). Erosion severity was greater in the presence of tracks, and 98% of crossings of ephemeral streamlines showed some evidence of impact on water movement (flow impedance (62%); diversion of flows (73%); flow concentration (76%); and/or channel initiation (31%)). Infrastructure type, pastoral land use, culvert presence, soil clay content and erodibility, mean annual rainfall, rainfall erosivity, topography and bare soil cover influenced the frequency and severity of these impacts. We conclude that linear infrastructure frequently affects ephemeral stream flows and intercepts natural overland and near-surface flows, artificially changing site-scale moisture regimes, with some parts of the landscape becoming abnormally wet and other parts becoming water-starved. In addition, linear infrastructure frequently triggers or exacerbates erosion, leading to soil loss and degradation. Where linear infrastructure densities are high, their impacts on ecological processes are likely to be considerable. Linear infrastructure is widespread across much of this relatively intact region, but there remain areas with very low infrastructure densities that need to be protected from further impacts. There is substantial scope for mitigating the impacts of existing and planned infrastructure developments. PMID- 29107802 TI - Value orientation and payment for ecosystem services: Perceived detrimental consequences lead to willingness-to-pay for ecosystem services. AB - This research analyzed whether the three distinct value orientations posited under the Value-Belief-Norm (VBN) model determine willingness-to-pay (WTP) for a payment for ecosystem services (PES) program. A survey instrument gathered U.S. residents' knowledge and attitudes toward ecosystem services and PES, and elicited WTP for the restoration of a hypothetical degraded forest watershed for improved ecosystem services. Data from over 1000 respondents nationwide were analyzed using exploratory factor analysis (EFA) and ordered logistic regression. Urban respondents were more familiar with the concepts of ecosystem service and PES than rural respondents but familiarity did not yield statistically different WTP estimates. Based on results from the EFA, we posit that latent value orientations might be distinguished as 'detrimental', 'biospheric' and 'beneficial (egoistic)' - as compared to 'altruistic', 'biospheric' and 'egoistic' as suggested in the VBN's general awareness of consequences scale. Awareness of biospheric and detrimental consequences along with ascriptions to personal norms had positive and significant effects on stated WTP. Beneficial (egoistic) value orientation was negatively associated with WTP and carried a negative average WTP per household per year (US$ -30.48) for the proposed PES restoration program as compared with biospheric (US$ 15.53) and detrimental (US$ 3.96) orientations. Besides personal norms, awareness of detrimental consequences to human wellbeing from environmental degradation seems the stronger driver of WTP for the restoration and protection of forest watershed ecosystem services under a PES program. PMID- 29107803 TI - Correlation between system performance and bacterial composition under varied mixing intensity in thermophilic anaerobic digestion of food waste. AB - This study examines the stability and efficiency of thermophilic anaerobic digesters treating food waste under various mixing velocities (50-160 rpm). The results showed that high velocities (120 and 160 rpm) were harmful to the digestion process with 18-30% reduction in methane generation and 1.8 to 3.8 times increase in volatile fatty acids (VFA) concentrations, compared to mild mixing (50 and 80 rpm). Also, the removal rate of soluble COD dropped from 75 to 85% (at 50-80 rpm) to 20-59% (at 120-160 rpm). Similarly, interrupted mixing caused adverse impacts and led to near-failure conditions with excessive VFA accumulation (15.6 g l-1), negative removal rate of soluble COD and low methane generation (132 ml gVS-1). The best efficiency and stability were achieved under mild mixing (50 and 80 rpm). In particular, the 50 rpm stirring speed resulted in the highest methane generation (573 ml gVS-1). High-throughput sequencing of 16S rRNA genes revealed that the digesters were dominated by one bacterial genus (Petrotoga; phylym Thermotogae) at all mixing velocities except at 0 rpm, where the community was dominated by one bacterial genus (Anaerobaculum; phylum Synergistetes). The Petrotoga genus seems to have played a major role in the degradation of organic matter. PMID- 29107804 TI - Sustainability assessment in forest management based on individual preferences. AB - This paper presents a methodology to elicit the preferences of any individual in the assessment of sustainable forest management at the stand level. The elicitation procedure was based on the comparison of the sustainability of pairs of forest locations. A sustainability map of the whole territory was obtained according to the individual's preferences. Three forest sustainability indicators were pre-calculated for each point in a study area in a Scots pine forest in the National Park of Sierra de Guadarrama in the Madrid Region in Spain to obtain the best management plan with the sustainability map. We followed a participatory process involving fifty people to assess the sustainability of the forest management and the methodology. The results highlighted the demand for conservative forest management, the usefulness of the methodology for managers, and the importance and necessity of incorporating stakeholders into forestry decision-making processes. PMID- 29107805 TI - Neuronal expression patterns of the PlexinA family during zebrafish development. AB - Plexins (Plxns) and Semaphorins (Semas) are key signaling molecules that regulate many aspects of development. Plxns are a family of transmembrane protein receptors that are activated upon extracellular binding by Semas. Activated Plxns trigger intracellular signaling cascades, which regulate a range of developmental processes, including axon guidance, neuronal positioning and vasculogenesis. Semas are a large family of both transmembrane and secreted signaling molecules, and show subtype specific binding to different Plxn family members. Each Plxn can play different roles in development, and so tightly regulated temporal and spatial expression of receptor subtypes is critical to ensure appropriate signaling. Here we elucidate the expression profiles of the plxnA family, plxnA1a, A1b, A2, A3 and A4 at 18, 24, 36, 48, 60 and 72 h post fertilization in the developing zebrafish. We show that PlxnA family members are expressed in neuronal tissues during zebrafish development, but exhibit key differences in expression within these tissues. We also highlight that plxnA1 has two genes in zebrafish, A1a and A1b, which show divergences in expression patterns during early development. PMID- 29107806 TI - Chronic hyperammonemia alters in opposite ways membrane expression of GluA1 and GluA2 AMPA receptor subunits in cerebellum. Molecular mechanisms involved. AB - Hyperammonemia contributes to altered neurotransmission and cognition in patients with hepatic encephalopathy. Hyperammonemia in rats affects differently high- and low-affinity AMPA receptors (AMPARs) in cerebellum. We hypothesized that hyperammonemia would alter differently membrane expression of AMPARs GluA1 and GluA2 subunits by altering its phosphorylation. This work aims were: 1) assess if hyperammonemia alters GluA1 and GluA2 subunits membrane expression in cerebellum and 2) analyze the underlying mechanisms. Hyperammonemia reduces membrane expression of GluA2 and enhances membrane expression of GluA1 in vivo. We show that changes in GluA2 and GluA1 membrane expression in hyperammonemia would be due to enhanced NMDA receptors activation which reduces cGMP levels and phosphodiesterase 2 (PDE2) activity, resulting in increased cAMP levels. This leads to increased protein kinase A (PKA) activity which activates phospholipase C (PLC) and protein kinase C (PKC) thus increasing phosphorylation of GluA2 in Ser880, which reduces GluA2 membrane expression, and phosphorylation of GluA1 in Ser831, which increases GluA1 membrane expression. Blocking NMDA receptors or inhibiting PKA, PLC or PKC normalizes GluA2 and GluA1 phosphorylation and membrane expression in hyperammonemic rats. Altered GluA2 and GluA1 membrane expression would alter signal transduction which may contribute to cognitive and motor alterations in hyperammonemia and hepatic encephalopathy. PMID- 29107808 TI - Genetic therapies for cystic fibrosis lung disease. AB - Gene therapy for cystic fibrosis (CF) has been the subject of intense research over the last twenty-five years or more, using both viral and liposomal delivery methods, but so far without the emergence of a clinical therapy. New approaches to CF gene therapy involving recent improvements to vector systems, both viral and non-viral, as well as new nucleic acid technologies have led to renewed interest in the field. The field of therapeutic gene editing is rapidly developing with the emergence of CRISPR/Cas9 as well as chemically modified mRNA therapeutics. These new types of nucleic acid therapies are also a good fit with delivery by non-viral delivery approaches which has led to a renewed interest in lipid-based and other nanoformulations. PMID- 29107807 TI - Increased intraocular pressure alters the cellular distribution of HuR protein in retinal ganglion cells - A possible sign of endogenous neuroprotection failure. AB - The RNA-binding protein, HuR, modulates mRNA processing and gene expression of several stress response proteins i.e. Hsp70 and p53 that have been postulated to be involved in the pathogenesis of glaucoma, a chronic optic neuropathy leading to irreversible blindness. We evaluated HuR protein expression in retinas and optic nerves of glaucomatous rats and human primary open angle glaucoma patients and its possible impact on stress response mechanisms. We found that the cytoplasmic content of HuR was reduced more extensively in glaucomatous retinas than in optic nerves and this was linked with a declined cytoplasmic Hsp70 level and p53 nuclear translocation. In the optic nerve, the p53 content was decreased as a feature of reactive gliosis. Based on our findings, we conclude that the alteration in the HuR content, observed both in rat glaucoma model and human glaucoma samples, affects post-transcriptionally the expression of genes crucial for maintaining cell homeostasis; therefore, we postulate that HuR may be involved in the pathogenesis of glaucoma. PMID- 29107809 TI - Sanguinarine is reduced by NADH through a covalent adduct. AB - Sanguinarine is a benzo[c]phenanthridine alkaloid with interesting cytotoxic properties, such as induction of oxidative DNA damage and very rapid apoptosis, which is not mediated by p53-dependent signaling. It has been previously documented that sanguinarine is reduced with NADH even in absence of any enzymes while being converted to its dihydro form. We found that the dark blue fluorescent species, observed during sanguinarine reduction with NADH and misinterpreted by Matkar et al. (Arch. Biochem. Biophys. 2008, 477, 43-52) as an anionic form of the alkaloid, is a covalent adduct formed by the interaction of NADH and sanguinarine. The covalent adduct is then converted slowly to the products, dihydrosanguinarine and NAD+, in the second step of reduction. The product of the reduction, dihydrosanguinarine, was continually re-oxidized by the atmospheric oxygen back to sanguinarine, resulting in further reacting with NADH and eventually depleting all NADH molecules. The ability of sanguinarine to diminish the pool of NADH and NADPH is further considered when explaining the sanguinarine-induced apoptosis in living cells. PMID- 29107810 TI - Seco-dammarane triterpenoids from the leaves of Cyclocarya paliurus. AB - The leaves of Cyclocarya paliurus with sweet taste are often used as herbal tea in People's Republic of China. In this study eight previously undescribed seco dammarane type triterpenoids, cyclocariols A-H along with seven known compounds were isolated and characterized from its leaves. A possible biogenetic pathway for seco-dammarane type triterpenoids formation has been discussed. Cyclocariols A-H were evaluated for their cytotoxicities against human liver (SMMC-7721) and breast cancer (BT-549) cell lines. Cyclocariols A, B, E, and H were also tested against human colon tumor (HCT-116) cell lines, where all four exhibited good activities with IC50 values of 6.53, 4.94, 8.24, and 6.48 MUM, respectively. PMID- 29107811 TI - Highly oxygenated and structurally diverse diterpenoids from Euphorbia helioscopia. AB - A phytochemical investigation on the aerial part of Euphorbia helioscopia (Euphorbiaceae) led to the isolation of 22 highly oxygenated diterpenoids with structural types of ent-abietane, ent-kaurane, lathyrane, ent-atisane and ingenane. 17 of them, named euphelionolides A - N, 16-epi-18-hydroxy-abbeokutone, as well as eupheliotriols A and B, were identified to be previously undescribed compounds by extensive analysis of spectroscopic data. The stereostructures of euphelionolides A - K were determined by single crystal X-ray diffraction combined with analysis of substituent effects and comparison of optical characteristics. Eupheliotriol B is the first example of natural occurring lathyrol with 12Z-ene, while ent-atisanes are the first reported from the title plant. Furthermore, euphelionolides F and L exhibited significant cytotoxicity against MCF-7 and PANC-1 cell lines. PMID- 29107812 TI - Proteolytic maturation of Drosophila Neuroligin 3 by tumor necrosis factor alpha converting enzyme in the nervous system. AB - BACKGROUND: The functions of autism-associated Neuroligins (Nlgs) are modulated by their post-translational modifications, such as proteolytic cleavage. A previous study has shown that there are different endogenous forms of DNlg3 in Drosophila, indicating it may undergo proteolytic processing. However, the molecular mechanism underlying DNlg3 proteolytic processing is unknown. Here, we report a novel proteolytic mechanism that is essential for DNlg3 maturation and function in the nervous system. METHODS: Molecular cloning, cell culture, immunohistochemistry, western blotting and genetic studies were employed to map the DNlg3 cleavage region, identify the protease and characterize the cleavage manner. Behavior analysis, immunohistochemistry and genetic manipulations were employed to study the functions of different DNlg3 forms in the nervous system and neuromuscular junction (NMJs). RESULTS: Tumor necrosis factor alpha converting enzyme (TACE) cleaved DNlg3 exclusively at its extracellular acetylcholinesterase-like domain to generate the N-terminal fragment and the short membrane-anchored fragment (sDNlg3). DNlg3 was constitutively processed in an activity-independent manner. Interestingly, DNlg3 was cleaved intracellularly in the Golgi apparatus before it arrived at the cell surface, a unique cleavage mechanism that is distinct from 'conventional' ectodomain shedding of membrane proteins, including rodent Nlg1. Genetic studies showed that sDNlg3 was essential for maintaining proper locomotor activity in Drosophila. CONCLUSIONS: Our results revealed a unique cleavage mechanism of DNlg3 and a neuron-specific role for DNlg3 maturation which is important in locomotor activity. GENERAL SIGNIFICANCE: Our study provides a new insight into a cleavage mechanism of Nlgs maturation in the nervous system. PMID- 29107813 TI - Curcumin stably interacts with DNA hairpin through minor groove binding and demonstrates enhanced cytotoxicity in combination with FdU nucleotides. AB - We report, based on biophysical studies and molecular mechanical calculations that curcumin binds DNA hairpin in the minor groove adjacent to the loop region forming a stable complex. UV-Vis and fluorescence spectroscopy indicated interaction of curcumin with DNA hairpin. In this novel binding motif, two gamma H of curcumin heptadiene chain are closely positioned to the A16-H8 and A17-H8, while G12-H8 is located in the close proximity of curcumin alpha H. Molecular dynamics (MD) simulations suggest, the complex is stabilized by noncovalent forces including; pi-pi stacking, H-bonding and hydrophobic interactions. Nuclear magnetic resonance (NMR) spectroscopy in combination with molecular dynamics simulations indicated curcumin is bound in the minor groove, while circular dichroism (CD) spectra suggested minute enhancement in base stacking and a little change in DNA helicity, without significant conformational change of DNA hairpin structure. The DNA:curcumin complex formed with FdU nucleotides rather than Thymidine, demonstrated enhanced cytotoxicity towards oral cancer cells relative to the only FdU substituted hairpin. Fluorescence co-localization demonstrated stability of the complex in biologically relevant conditions, including its cellular uptake. Acridine orange/EtBr staining further confirmed the enhanced cytotoxic effects of the complex, suggesting apoptosis as mode of cell death. Thus, curcumin can be noncovalently complexed to small DNA hairpin for cellular delivery and the complex showed increased cytotoxicity in combination with FdU nucleotides, demonstrating its potential for advanced cancer therapy. PMID- 29107814 TI - Synthesis of substrate analogues as potential inhibitors for Mycobacterium tuberculosis enzyme MshC. AB - Mycothiol cysteine ligase (MshC) is a key enzyme in the mycothiol (MSH) biosynthesis and a promising target for developing new anti-mycobacterial compounds. Herein, we report on the synthesis of substrate analogues, as potential inhibitors, for the MshC enzyme. The target molecules were synthesized employing a Schmidt glycosylation strategy using an enantiomerically pure inositol acceptor and 2-deoxy trichloroacetimidate glycosyl donors with glycosylation yields greater than 70% and overall yields >5%. The inositol acceptor was obtained via chiral resolution of (+/-)-myo-inositol. PMID- 29107815 TI - Synthesis of P1-(11-phenoxyundecyl)-P2-(2-acetamido-2-deoxy-3-O-alpha-D rhamnopyranosyl-alpha-D-glucopyranosyl) diphosphate and P1-(11-phenoxyundecyl)-P2 (2-acetamido-2-deoxy-3-O-beta-D-galactopyranosyl-alpha-D-galactopyranosyl) diphosphate for the investigation of biosynthesis of O-antigenic polysaccharides in Pseudomonas aeruginosa and Escherichia coli O104. AB - Two new phenoxyundecyl diphosphate sugars were synthesized for the first time: P1 (11-phenoxyundecyl)-P2- (2-acetamido-2-deoxy-3-O-alpha-D-rhamnopyranosyl-alpha-D glucopyranosyl) diphosphate and P1-(11-phenoxyundecyl)-P2-(2-acetamido-2-deoxy-3 O-beta-D-galactopyranosyl-alpha-D-galactopyranosyl) diphosphate to study the third step of biosynthesis of the repeating units of O-antigenic polysaccharides in Pseudomonas aeruginosa and E.coli O104 respectively. PMID- 29107816 TI - Long-term follow-up of the incidence of Helicobacter pylori. AB - OBJECTIVES: Helicobacter pylori causes peptic ulcer disease and gastric cancer. Understanding the incidence of H. pylori could help guide research on potential infection prevention strategies. Previous studies indicate infection occurs in young children, but the risk of infection in older children and adolescents is unclear. Our hypothesis was that H. pylori infection is rare in adolescence or adulthood. Our aim was to determine the incidence of H. pylori over a prolonged follow-up in a cohort of 626 noninfected individuals. METHODS: Participants, including index children, mothers, fathers and siblings, from a previous study (1997-2002) were traced, and 883 of 946 participated in this extended follow-up. We used the 13C urea breath test (13C-UBT) to determine the incidence of H. pylori among 626 family members not infected in 2002, including 75 younger siblings who were not born or too young for testing in 2002. RESULTS: Eight (3.8%) of 210 index participants (mean +/- standard deviation age 17.92 +/- 0.77 years) became infected during 11.07 +/- 0.56 years of follow-up (incidence, 3.42 per 1000 person-years; 95% confidence interval (CI), 1.48-6.74). Only one (0.6%) of 165 older siblings became infected (incidence, 0.57 per 1000 person-years; 95% CI, 0.007-3.16) and one of 176 parents became infected (incidence, 0.63 per 1000 person-years; 95% CI, 0.01-3.5). Of 75 younger siblings (age 10.9 +/- 2.85 years) who were too young for testing or not yet born in 2002, nine (12%) became infected (incidence, 11.32 per 1000 person-years; 95% CI, 5.27-21.49). The highest incidence of H. pylori infection was in those born after 2005. CONCLUSIONS: The incidence of H. pylori was extremely low in older children and adults in developed countries. Spontaneous clearance of infection was uncommon in our study population. PMID- 29107817 TI - Adjustment disorder: A diagnosis whose time has come. AB - BACKGROUND: Adjustment disorder is among the most frequently diagnosed mental disorders in clinical practice although it has received little academic attention and been the subject of substantial criticism over the past decades. While those suffering with adjustment disorders are often treated by mental health professionals, research interest in the origin of the disorder or the effectiveness of psychotherapeutic and medical interventions has only recently begun to emerge. This article summarizes the empirical literature published on adjustment disorder and points out current diagnostic developments in DSM-5 and ICD-11. METHODS: Literature for this review was identified through established online search tools, including publications in English, German, and Spanish. RESULTS: This paper reviews literature on the evolution of adjustment disorder, and highlights the current state of research with regard to genesis and treatment. Importantly, for the first time ICD-11 intends to define adjustment disorder by explicit symptom groups, unlike DSM-5. LIMITATIONS: Publications without an English abstract were not included. CONCLUSIONS: Key directions for future research include investigating the concordance of the ICD-11 and DSM-5 concepts and the effect that the diverging conceptualizations may have. Risk and protective factors specific to AD should be identified and the biological underpinnings of the disorder should be explored. Finally, given the high prevalence of AD in certain clinical settings effective disorder-specific interventions should be developed and evaluated. PMID- 29107819 TI - Functional disability and suicidal behavior in middle-aged and older adults: A systematic critical review. AB - BACKGROUND: Middle-aged and older adults have elevated rates of suicide around the globe, but there is a paucity of knowledge about risk factors for suicide in these age groups. One possible risk factor may be functional disability, which is more common at later ages. METHODS: The current systematic critical review examined findings regarding the associations between functional disability and suicidal behavior (suicidal ideation, suicide attempts, and death by suicide) in middle-aged and older adults (i.e. age 50 and older). RESULTS: Forty-five studies were found that examined these associations. The majority of studies supported a significant association between functional disability and suicidal ideation. In addition, findings to date strongly suggest that depression serves as a mediator of the association between functional disability and suicidal ideation, though most studies did not directly test for mediation. LIMITATIONS: Firm conclusions regarding suicide attempts and death by suicide, as well as mediation, cannot be drawn due to a relative lack of research in these areas. CONCLUSIONS: The association between functional disability and suicidal behavior suggests an important area for prevention and intervention among middle-aged and older adults, but additional research is necessary to clarify the specifics of these associations and examine appropriate intervention strategies. Important future directions for research in this area include the direct comparison of associations of risk factors with different types of suicidal behavior, greater use of longitudinal data with multiple time points, and further examination of potential mediators and moderators of the association between functional disability and suicidal behavior. PMID- 29107818 TI - Low comorbid obsessive-compulsive disorder in patients with major depressive disorder - Findings from a European multicenter study. AB - BACKGROUND: This cross-sectional European multicenter study examined the association between major depressive disorder (MDD) and comorbid obsessive compulsive disorder (OCD). METHODS: Socio-demographic, clinical, and treatment features of 1346 adult MDD patients were compared between MDD subjects with and without concurrent OCD using descriptive statistics, analyses of covariance (ANCOVA), and binary logistic regression analyses. RESULTS: We determined a point prevalence of comorbid OCD in MDD of 1.65%. In comparison to the MDD control group without concurrent OCD, a higher proportion of patients in the MDD + comorbid OCD group displayed concurrent panic disorder (31.81% vs 7.77%, p<.001), suicide risk (52.80% vs 44.81%, p=.04), polypsychopharmacy (95.45% vs 60.21%, p=.001), and augmentation treatment with antipsychotics (50.00% vs 25.46%, p=.01) and benzodiazepines (68.18% vs 33.31%, p=.001). Moreover, they were treated with higher mean doses of their antidepressant drugs (in fluoxetine equivalents: 48.99mg/day +/- 18.81 vs 39.68mg/day +/- 20.75, p=.04). In the logistic regression analyses, comorbid panic disorder (odds ratio (OR)=4.17, p=.01), suicide risk (OR=2.56, p=.04), simultaneous treatment with more psychiatric drugs (OR=1.51, p=<.05), polypsychopharmacy (OR=14.29, p=.01), higher antidepressant dosing (OR=1.01, p=<.05), and augmentation with antipsychotics (OR=2.94, p=.01) and benzodiazepines (OR=4.35, p=.002) were significantly associated with comorbid OCD. CONCLUSION: In summary, our findings suggest that concurrent OCD in MDD (1) has a low prevalence rate compared to the reverse prevalence rates of comorbid MDD in OCD, (2) provokes higher suicide risk, and (3) is associated with a characteristic prescription pattern reflected by a high amount of polypsychopharmaceutical treatment strategies comprising particularly augmentation with antipsychotics and benzodiazepines. PMID- 29107820 TI - Audiovisual integration increases the intentional step synchronization of side-by side walkers. AB - When people walk side-by-side, they often synchronize their steps. To achieve this, individuals might cross-modally match audiovisual signals from the movements of the partner and kinesthetic, cutaneous, visual and auditory signals from their own movements. Because signals from different sensory systems are processed with noise and asynchronously, the challenge of the CNS is to derive the best estimate based on this conflicting information. This is currently thought to be done by a mechanism operating as a Maximum Likelihood Estimator (MLE). The present work investigated whether audiovisual signals from the partner are integrated according to MLE in order to synchronize steps during walking. Three experiments were conducted in which the sensory cues from a walking partner were virtually simulated. In Experiment 1 seven participants were instructed to synchronize with human-sized Point Light Walkers and/or footstep sounds. Results revealed highest synchronization performance with auditory and audiovisual cues. This was quantified by the time to achieve synchronization and by synchronization variability. However, this auditory dominance effect might have been due to artifacts of the setup. Therefore, in Experiment 2 human-sized virtual mannequins were implemented. Also, audiovisual stimuli were rendered in real-time and thus were synchronous and co-localized. All four participants synchronized best with audiovisual cues. For three of the four participants results point toward their optimal integration consistent with the MLE model. Experiment 3 yielded performance decrements for all three participants when the cues were incongruent. Overall, these findings suggest that individuals might optimally integrate audiovisual cues to synchronize steps during side-by-side walking. PMID- 29107821 TI - Comparison of pre-contact joint kinematics and vertical impulse between vertical jump landings and step-off landings from equal heights. AB - Although impact phase differences between vertical jump landings (VJL) and step off landings (STL) may be related to task-specific pre-contact strategies, pre contact mechanics are rarely examined. Thus, pre-contact kinematics and vertical ground reaction force (vGRF) impulse were examined between VJL and STL. Ten health adults (20.9 +/- 1.6 yrs; 167.8 +/- 4.2 cm; 68.5 +/- 7.15 kg) performed 15 VJL and 15 STL from equal heights. Limb (lead; trail) by task (VJL; STL) ANOVAs (alpha = 0.05) compared hip, knee, and ankle joint angles 150 ms pre-contact, 100 ms pre-contact, 50 ms pre-contact, and at ground contact. Joint angular displacement was also evaluated between 150 ms pre-contact and ground contact. vGRF impulse was compared during the loading (ground contact to peak vGRF) and attenuation (peak vGRF to end of impact) phases. Greater hip flexion angles occurred during STL versus VJL at each event except 150 ms pre-contact (p <= .004). Trail limb knee flexion angles were greater at each event when compared to the lead limb during STL (p <= .019). Greater trail limb knee flexion angles occurred during STL versus VJL at all four events (p <= .018), while greater plantarflexion angles occurred at all four events during VJL versus STL (p <= .034). During STL, greater trail limb plantarflexion angles were detected at each event versus the lead limb (p < .001). Lesser hip, lead and trail limb knee displacement occurred during STL versus VJL (p < .05). Greater vGRF impulse was detected during the loading phase of VJL (<.001), while greater vGRF impulse occurred during the attenuation phase of STL (p = .025). These tasks are characterized by distinct pre-contact kinematic strategies and post-contact kinetics. The task utilized in practice should reflect the requirements of the population of interest. PMID- 29107822 TI - Molecular architectures and mechanisms of Class 2 CRISPR-associated nucleases. AB - Prokaryotic Class 2 CRISPR-Cas systems mediate adaptive immunity against invasive genetic elements by means of standalone effector proteins that function as RNA guided nucleases. The effectors Cas9 and Cas12 generate double-strand breaks in DNA substrates, which has been exploited for genome editing applications. In turn, Cas13 enzymes function as RNA-guided ribonucleases whose non-specific activity is triggered by target RNA binding. In this review, we highlight recent structural investigations of Cas9, Cas12 and Cas13 nucleases that have illuminated many aspects of their molecular mechanisms. In particular, these studies have highlighted the role of guide RNA seed sequences in facilitating target recognition and the importance of conformational transitions in controlling target binding and cleavage. PMID- 29107823 TI - Photodynamic Therapy for an iris metastasis from pulmonary adenocarcinoma. AB - Uveal metastasis is the most common intraocular malignancy. Lung cancer is one of the most common malignancies that metastasize to uvea. Iris involvement is rarely reported. Here we report a case of iris metastasis from pulmonary adenocarcinoma that was treated with photodynamic therapy (PDT). A 65-year-old Chinese man was referred to our hospital for iris white neoplasm and blurred vision for 2 weeks in his right eye. His accepted pulmonary lobectomy, radiotherapy and chemotherapy for pulmonary adenocarcinoma 1year ago and liver metastases were found 2 months earlier. At presentation, anterior segment examination of the right eye showed a hypopigmented, vascularized papillary 3.8 *3.19mm neoplasm located on the temporal iris expanding to 9-clock anterior chamber angle. The patient refused to accept MRI, biopsy and treatment. One week later the tumor grew up to 5.5*7.4mm with diffuse mixed conjunctiva congestion and elevated IOP. A modified PDT was applied. Intravenous verteporfin (3mg/m2) was infused with a 1min bolus. PDT with 3 partly overlapped 5mm laser spots, 689nm (50J/cm2) and 166s were performed 4 minuets later without contact lens. The neo-genesis vessels were occluded with small patch bleeding on the edema tumor that was separated from the anterior chamber angle in the 3days follow-up. PDT may be a safe, noninvasive and psychologically well-accepted treatment for iris metastasis. PMID- 29107824 TI - Antimicrobial photodynamic therapy (aPDT) and photobiomodulation (PBM - 660nm) in a dog with chronic gingivostomatitis. AB - Chronic gingivostomatitis in dogs is an inflammatory syndrome of the oral cavity, which treatment and control of concomitant periodontitis allow healing in most of the cases. In the presence of recurrent lesions, invasive methods are necessary to treat lesions and pain. As a conservative adjuvant method, photobiomodulation (PBM) with low power laser is able to promote reduction of tissue pain and tissue inflammation besides increasing vascularization and healing, restoring the normal function of the irradiated organ in a shorter time. In veterinary medicine, there is no standardization of technique for its use in oral tissue for treating gingivostomatitis in dogs. In the present case, a dog was submitted to aPDT (7.2J/point, 3min/point, 180J/cm2) and PBM (1.6J/point, 40s/point, 25J/cm2), using a semiconductor diode laser, with wavelength of 660nm, spot size of 0.04cm2 and output power of 40mW. The established protocol proved to be effective as coadjutant treatment for chronic gingivostomatitis, restoring the integrity of dog's affected mucosa and gingiva. PMID- 29107825 TI - Atrazine-induced environmental nephrosis was mitigated by lycopene via modulating nuclear xenobiotic receptors-mediated response. AB - The burden and morbidity of environmental nephrosis is increasing globally. Atrazine (ATR) and degradation products in the environment are considered key determinants of nephrosis. However, the lack of highly effective treatments for environmental nephrosis creates an urgent need to better understand the preventive strategies and mechanisms. This study aimed to highlight the mechanism of ATR-induced environmental nephrosis and the chemoprotective potential of lycopene (LYC) against the renal injury and nephrosis. Male mice were treated with LYC (5 mg/kg) and/or ATR (50 mg/kg or 200 mg/kg) by gavage administration for 21 days. Histopathological changes and biochemical function, cytochrome P450 enzymes system (CYP450s), nuclear xenobiotic receptors (NXRs) response and the transcription of CYP isoforms (CYPs) were detected. ATR exposure caused the changes of the histopathological and biochemical function, activated the NXR response and disturbed the CYP450s homeostasis. Supplementary LYC significantly prevented ATR-induced nephrotoxicity and alleviated the alternation of histopathological and biochemical function via modulating the CYP450s homeostasis and the NXR response. The results demonstrated AHR, CAR, PXR, PPAR (alpha, gamma), CYP1, CYP2, CYP3 and CYP4 superfamily play a vital role in LYC-ATR interaction. Our findings provide new evidence that ATR exposure can cause the environmental nephrosis via inducing the kidney injury. Supplementary LYC showed significant chemoprotective potential against ATR-induced renal injury and environmental nephrosis via regulating the NXR response and the CYP450s homeostasis. PMID- 29107826 TI - Inhibition of vascular smooth muscle cells premature senescence with rutin attenuates and stabilizes diabetic atherosclerosis. AB - Atherosclerosis is an age-associated disease; however, diabetic atherosclerosis has higher severity beyond age range for accumulative premature senescent cells in diabetes. Recent findings suggest that rutin, a flavonoid, has potential benefits for diabetic individuals. This study was designed to evaluate the effects of rutin on premature senescence and atherosclerosis. Apolipoprotein E knockout mice exhibiting insulin resistance after 6 weeks of high-fat diet were administered with a low dose of streptozotocin (STZ) to induce diabetes. After 8 weeks of STZ administration, rutin (40 mg/kg/d) was supplemented by gavage for the last 6 weeks. We evaluated the prosperity of the plaque and diabetes using serial echocardiography, histopathologic and metabolite analysis. Premature senescence induced by hydrogen peroxide in primary vascular smooth muscle cells (VSMCs) was used to analyze the underlying mechanism. Mice with diabetes showed more severe plaque burden on aortic arteries and less smooth muscle cells but larger senescent cell ratio in plaque compared with mice with control diets. Rutin significantly improves glucose and lipid metabolic disturbance in diabetes. Moreover, rutin decreased the atherosclerotic burden and senescent cell number and increased the VSMC ratio in aortic root plaque. In vitro, we demonstrated that rutin ameliorated premature senescence induced by oxidative stress, and the protective function may be mediated by inhibiting oxidative stress and protecting telomere. Rutin administration attenuates atherosclerosis burden and stabilizes plaque by improving metabolic disturbance and alleviating premature senescence of VSMCs. Inhibition of VSMCs premature senescence with rutin may be an effective therapy for diabetic atherosclerosis. PMID- 29107828 TI - Perturbation-evoked potentials: Significance and application in balance control research. AB - Historically, balance control was thought to be mediated solely by subcortical structures based on animal research. However, recent findings provide compelling evidence of cortical involvement during balance reactions evoked by whole-body postural perturbations. In humans, an external perturbation elicits an evoked potential, termed the perturbation-evoked potential (PEP). PEPs are widely distributed over fronto-centro-parietal areas with maximal amplitude at the FCz/Cz electrode. From our literature review it is evident that the PEPs are comprised of a small positive potential (P1) that peaks around 30-90ms after perturbation onset, a large negative potential (N1) that peaks around 90-160ms, followed by positive (P2) and negative (N2) potentials between 200 and 400ms. Converging results across multiple studies suggest that these different PEP components are influenced by perturbation characteristics, postural set, environmental, and psychological factors. This review summarizes and integrates seminal research on the PEP, with a special emphasis on the PEP N1. Implications for future studies in PEP research are discussed to encourage further empirical investigation of PEP characteristics in healthy and patient populations. PMID- 29107827 TI - Growth-mediated plant movements: hidden in plain sight. AB - While fast plant movements are spectacular but rare, almost all plants exhibit relatively slow, growth-mediated tropic movements that are key to their survival in the natural world. In this brief review, we discuss recent insights into the molecular mechanisms underlying phototropism, gravitropism, hydrotropism, and autostraightening. Careful molecular genetic and physiological studies have helped confirm the importance of lateral auxin gradients in gravitropic and phototropic responses. However, auxin signaling does not explain all tropisms: recent work has shown that abscisic acid signaling mediates root hydrotropism and has implicated mechanosensing in autostraightening, the organ straightening process recently modeled as a proprioceptive response. The interactions between distinct tropic signaling pathways and other internal and external sensory processes are also now being untangled. PMID- 29107829 TI - Evaluating rodent motor functions: Which tests to choose? AB - Damage to the motor cortex induced by stroke or traumatic brain injury (TBI) can result in chronic motor deficits. For the development and improvement of therapies, animal models which possess symptoms comparable to the clinical population are used. However, the use of experimental animals raises valid ethical and methodological concerns. To decrease discomfort by experimental procedures and to increase the quality of results, non-invasive and sensitive rodent motor tests are needed. A broad variety of rodent motor tests are available to determine deficits after stroke or TBI. The current review describes and evaluates motor tests that fall into three categories: Tests to evaluate fine motor skills and grip strength, tests for gait and inter-limb coordination and neurological deficit scores. In this review, we share our thoughts on standardized data presentation to increase data comparability between studies. We also critically evaluate current methods and provide recommendations for choosing the best behavioral test for a new research line. PMID- 29107830 TI - Magnetic resonance imaging of the human locus coeruleus: A systematic review. AB - The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, innervates extensive areas throughout the brain and is implicated in a variety of autonomic and cognitive functions. Alterations in the LC-noradrenergic system have been associated with healthy ageing and neuropsychiatric disorders including Parkinson's disease, Alzheimer's disease and depression. The last decade has seen advances in imaging the structure and function of the LC, and this paper systematically reviews the methodology and outcomes of sixty-nine structural and functional MRI studies of the LC in humans. Structural MRI studies consistently showed lower LC signal intensity and volume in clinical groups compared to healthy controls. Within functional studies, the LC was activated by a variety of tasks/stimuli and had functional connectivity to a range of brain regions. However, reported functional LC location coordinates were widely distributed compared to previously published neuroanatomical locations. Methodological and demographic factors potentially contributing to these differences are discussed, together with recommendations to optimize the reliability and validity of future LC imaging studies. PMID- 29107831 TI - Behavioral changes in models of chemoconvulsant-induced epilepsy: A review. AB - Epilepsy is one of the most common neurological disorders in the general population and affects over 50 million people worldwide. Epilepsy is characterized by the presence of spontaneous recurrent seizures as a result of sudden and abnormal electrical activity in specific areas of the cerebral cortex. However, this condition encompasses much more than simply the presence of seizures. Cognitive problems and behavioral impairments are also frequent actors, as well as mood disorders. These must be precisely described in order to develop more successful pharmacological, or even behavioral, treatments. We review some of the fundamental behavioral experimental rodent protocols that have recently been applied to the study of behavioral impairments in epilepsy, particularly in epilepsy modeled by different chemoconvulsants, such as pilocarpine or kainic acid. These experimental protocols are classified into two categories: Tests designed for studying emotional factors, and those designed for studying cognitive impairments and social behavior. Behavioral impairments and adaptations identified by the use of these procedures are described. PMID- 29107832 TI - Impaired action self-monitoring and cognitive confidence among ultra-high risk for psychosis and first-episode psychosis patients. AB - BACKGROUND: Self-monitoring biases and overconfidence in incorrect judgments have been suggested as playing a role in schizophrenia spectrum disorders. Little is known about whether self-monitoring biases may contribute to early risk factors for psychosis. In this study, action self-monitoring (i.e., discrimination between imagined and performed actions) was investigated, along with confidence in judgments among ultra-high risk (UHR) for psychosis individuals and first episode psychosis (FEP) patients. METHODS: Thirty-six UHR for psychosis individuals, 25 FEP patients and 33 healthy controls (CON) participated in the study. Participants were assessed with the Action memory task. Simple actions were presented to participants verbally or non-verbally. Some actions were required to be physically performed and others were imagined. Participants were asked whether the action was presented verbally or non-verbally (action presentation type discrimination), and whether the action was performed or imagined (self-monitoring). Confidence self-ratings related to self-monitoring responses were obtained. RESULTS: The analysis of self-monitoring revealed that both UHR and FEP groups misattributed imagined actions as being performed (i.e., self-monitoring errors) significantly more often than the CON group. There were no differences regarding performed actions as being imagined. UHR and FEP groups made their false responses with higher confidence in their judgments than the CON group. There were no group differences regarding discrimination between the types of actions presented (verbal vs non-verbal). CONCLUSIONS: A specific type of self monitoring bias (i.e., misattributing imagined actions with performed actions), accompanied by high confidence in this judgment, may be a risk factor for the subsequent development of a psychotic disorder. PMID- 29107833 TI - Vertical distributions and source identification of the radionuclides 239Pu and 240Pu in the sediments of the Liao River estuary, China. AB - Activity concentration of plutonium (Pu) and its isotopic compositions are extensively used for measuring transport processes of Pu and identifying its source. We investigated the spatial distribution characteristics of 239+240Pu activity concentrations and 240Pu/239Pu atom ratio in several sediment cores collected from the Liao River coastal zone. Additionally, we calculated the 239+240Pu inventories and based on the 240Pu/239Pu atom ratio to trace Pu source. The activity concentrations of 239+240Pu in surface sediments of the Liao River estuary ranged between 0.103 +/- 0.008 and 0.978 +/- 0.035 mBq/g, with an average of 0.294 +/- 0.024 mBq/g. The 240Pu/239Pu atom ratios, ranging from 0.173 +/- 0.047 to 0.215 +/- 0.061 (mean: 0.188 +/- 0.049 (1sigma)), were consistent with global fallout value, which indicates the global atmospheric fallout is the main source of Pu in sediment cores from the both sides of Liao River estuary. As for the tidal flat core LT-2, the mean 240Pu/239Pu atom ratio, slightly higher than that of the global fallout value, was 0.217 +/- 0.050. Such pattern of Pu isotopic compositions indicated that Pu on the tidal flat in the Liao River estuary is sourced from a combination of global fallout and close-in fallout from the PPG by ocean currents transporting. And by using a two end-member mixing model, the results indicate the relative contribution of the PPG close-in fallout to core LT-2 is round 27% and 73% can be attributed to global fallout and river input. Therefore, these results clearly indicate that the direct global fallout is the main source of Pu in the Liao River estuary. PMID- 29107834 TI - Offspring sex ratio: Coital rates and other potential causal mechanisms. AB - In recent years, scientists have begun to pay serious attention to the hypothesis that human parental coital rates around the time of conception causally influences the sexes of subsequent births. In this paper, the grounds of the argument are outlined. The point is important because, if the hypothesis were credible, it can potentially explain one of the best established (and otherwise unexplained) epidemiological features of sex ratio at birth - its rises during and just after World Wars 1 and 2 insofar as increased coital rates increase the ratio. Moreover, the greater the understanding of the variations of sex ratio at birth, the greater will be the understanding of the causes of those selected diseases associated with unusual sex ratios at birth (testicular cancer, hepatitis B, Toxoplasma gondii, and, perhaps, prostatic cancer). PMID- 29107835 TI - Co-delivery of sorafenib and siVEGF based on mesoporous silica nanoparticles for ASGPR mediated targeted HCC therapy. AB - Combination with chemotherapeutic drug and gene therapy has been proven highly effective in suppressing tumor progression. Hence, an asialoglycoprotein receptor (ASGPR)-targeting nanodrug delivery system based on mesoporous silica (MSN) nanocarrier for co-delivery of sorafenib (SO) and vascular endothelial growth factor (VEGF) targeted siRNA (siVEGF) to hepatocellular carcinoma (HCC) was successfully designed and synthesized. The structure of nanoparticles was characterized by IR, particle size, zeta potential and N2 adsorption-desorption. The nanoparticles were further evaluated for drug release, cellular uptake, transfection, cell cytotoxicity and cell cycle against HepG2 and Huh7 cells. In vitro testing demonstrated that MSN-LA delivery system could not only induce S cell cycle arrest, enhance the cytotoxicity and improve the tumor target of SO and siVEGF, but also enhance the siVEGF transfection efficiency in ASGPR overexpressing Huh7 cells. Overall, the MSN-LA delivery system can be a promising drug carrier which could further enhance the anti-cancer efficacy of SO and siVEGF via the active targeting property of LA. PMID- 29107836 TI - Using verbal instructions to influence lifting mechanics - Does the directive "lift with your legs, not your back" attenuate spinal flexion? AB - "Use your legs" is commonly perceived as sound advice to prevent lifting-related low-back pain and injuries, but there is limited evidence that this directive attenuates the concomitant biomechanical risk factors. Body segment kinematic data were collected from 12 men and 12 women who performed a laboratory lifting/lowering task after being provided with different verbal instructions. The main finding was that instructing participants to lift "without rounding your lower back" had a greater effect on the amount of spine flexion they exhibited when lifting/lowering than instructing them to lift "with your legs instead of your back" and "bend your knees and hips". It was concluded that if using verbal instructions to discourage spine flexion when lifting, the instructions should be spine- rather than leg-focused. PMID- 29107837 TI - Power frequency spectrum analysis of surface EMG signals of upper limb muscles during elbow flexion - A comparison between healthy subjects and stroke survivors. AB - After a stroke, motor units stop working properly and large, fast-twitch units are more frequently affected. Their impaired functions can be investigated during dynamic tasks using electromyographic (EMG) signal analysis. The aim of this paper is to investigate changes in the parameters of the power/frequency function during elbow flexion between affected, non-affected, and healthy muscles. Fifteen healthy subjects and ten stroke survivors participated in the experiments. Electromyographic data from 6 muscles of the upper limbs during elbow flexion were filtered and normalized to the amplitudes of EMG signals during maximal isometric tasks. The moments when motion started and when the flexion angle reached its maximal value were found. Equal intervals of 0.3407 s were defined between these two moments and one additional interval before the start of the flexion (first one) was supplemented. For each of these intervals the power/frequency function of EMG signals was calculated. The mean (MNF) and median frequencies (MDF), the maximal power (MPw) and the area under the power function (APw) were calculated. MNF was always higher than MDF. A significant decrease in these frequencies was found in only three post-stroke survivors. The frequencies in the first time interval were nearly always the highest among all intervals. The maximal power was nearly zero during first time interval and increased during the next ones. The largest values of MPw and APw were found for the flexor muscles and they increased for the muscles of the affected arm compared to the non-affected one of stroke survivors. PMID- 29107839 TI - Efficient one-pot enzymatic synthesis of dephospho coenzyme A. AB - Dephospho coenzyme A (depCoA) is the last intermediate for CoA biosynthesis, and it can be used as a transcription initiator to prepare CoA-linked RNA by in vitro transcription. However, commercially available depCoA is expensive. We hereby describe a simple and efficient enzymatic synthesis of depCoA in a single-step from commercially available and inexpensive oxidized pantethine (Ox-Pan) and ATP. A plasmid (pCoaDAa) was constructed to co-express and co-purify two enzymes pantothenate kinase (PanK/coaA) and phosphopantetheine adenylyltransferase (PPAT/coaD). Starting from Ox-Pan and ATP, two different synthetic routes of one pot reaction catalyzed by PanK and PPAT, followed by a simple column purification step, afforded depCoA and its oxidized dimer (Ox-depCoA) with high yields and purity. The simplicity and low cost of our method should make depCoA easily accessible to a broad scientific community, and promote research on CoA-related areas in biology and biomedicine. PMID- 29107838 TI - Genetic bottlenecks in intraspecies virus transmission. AB - Ultimately, viral evolution is a consequence of mutations that arise within and spread between infected hosts. The transmission bottleneck determines how much of the viral diversity generated in one host passes to another during transmission. It therefore plays a vital role in linking within-host processes to larger evolutionary trends. Although many studies suggest that transmission severely restricts the amount of genetic diversity that passes between individuals, there are important exceptions to this rule. In many cases, the factors that determine the size of the transmission bottleneck are only beginning to be understood. Here, we review how transmission bottlenecks are measured, how they arise, and their consequences for viral evolution. PMID- 29107840 TI - The Wnt/beta-catenin signaling in endometriosis, the expression of total and active forms of beta-catenin, total and inactive forms of glycogen synthase kinase-3beta, WNT7a and DICKKOPF-1. AB - OBJECTIVES: The cyclical changes in proliferation and differentiation of endometrial cells are regulated by estrogen and progesterone via modulating Wnt/beta-catenin signaling. Imbalance in the expression of estrogen and progesterone receptors causes progesterone resistance in endometriosis patients. The aim of this study was to investigate the expression of some main components of Wnt/beta-catenin signaling including WNT7a, DKK-1, beta-catenin, and GSK-3beta in eutopic endometrium and peritoneal endometriotic lesions of endometriosis patients compared to healthy endometrium in the mid-secretory phase of menstrual cycle. STUDY DESIGN: This prospective study was performed, during a 12 months period from December 2015 to November 2016, on healthy women as the control group (n=14) and endometriosis patients (n=34). We used real-time polymerase chain reaction and Western blot techniques. RESULTS: Protein and mRNA expression of DKK 1 were significantly down-regulated in both endometriotic lesions and eutopic endometrium of endometriosis group. We also demonstrated that the expression of non-phosphorylated beta-catenin (active form) and phosphorylated GSK-3beta (inactive form) were up-regulated in endometriosis patients. The mRNA levels of beta-catenin, GSK-3beta, and WNT7a, as well as the protein levels of total beta catenin, total GSK-3beta, and WNT7a in endometriosis group, were not significantly different with those in control group. The patterns of mRNA and protein expression of all interested factors in the lesions were similar to those in the eutopic endometrium of same patients. CONCLUSIONS: It seems that the aberrant activation of Wnt/beta-catenin signaling in the secretory phase of the menstrual cycle in endometriosis has two essential elements: excessive inactivation of GSK-3beta and suppression of the expression of Wnt signaling inhibitor DKK-1. Interventions in this signaling pathway may allow for the exploration of potential new targets for the control of development and progression of endometriosis. PMID- 29107842 TI - Volatile organic compounds from Wickerhamomyces anomalus, Metschnikowia pulcherrima and Saccharomyces cerevisiae inhibit growth of decay causing fungi and control postharvest diseases of strawberries. AB - The effectiveness of Wickerhamomyces anomalus, Metschnikowia pulcherrima and Saccharomyces cerevisiae as biocontrol agents on postharvest decay of strawberry (Fragaria x ananassa, cv. 'Alba') fruit, and their inhibitory activities on some decay-causing fungi were evaluated. Volatile organic compounds from these yeasts decreased mycelial growth of Botrytis cinerea by 69%, and by less for Monilinia fructicola, Alternaria alternata, Aspergillus carbonarius, Penicillium digitatum, Cladosporium spp., and Colletotrichum spp. Strawberry fruit exposed to 6-day-old liquid cultures of W. anomalus, M. pulcherrima and S. cerevisiae for 48h showed 89%, 40%, and 32% reductions, respectively, in gray mold McKinney Index. Vapours of ethyl acetate, the main volatile organic compound of these yeasts, completely inhibited B. cinerea growth at 8.97mg/cm3, and suppressed gray mold on strawberry fruit at 0.718mg/cm3. The biocontrol activities of these yeasts can be ascribed to ethyl acetate, which can be used for control of postharvest gray mold of strawberry fruit. PMID- 29107841 TI - A novel non-dairy beverage from durian pulp fermented with selected probiotics and yeast. AB - This study investigated the effects of sequential inoculation (Seq-I) of Bifidobacterium animalis subsp. lactis or Lactobacillus casei with yeast Williopsis saturnus on durian pulp fermentation. Seq-I of W. saturnus following B. animalis subsp. lactis did not bring about any significant differences compared to the B. animalis subsp. lactis monoculture due to the sharp early death of W. saturnus soon after inoculation. However, Seq-I of W. saturnus significantly enhanced the survival of L. casei and improved the utilization of fructose and glucose compared to L. casei monoculture. In addition, there were significant differences in the metabolism of organic acids especially for lactic acid and succinic acid. Furthermore, Seq-I produced significantly higher levels of volatile compounds including alcohols (ethanol and 2-phenylethyl alcohol) and acetate esters (2-phenylethyl acetate, isoamyl acetate and ethyl acetate), which would positively contribute to the flavour notes. Although the initial volatile sulphur compounds were reduced to trace levels after fermentation, but the durian odour still remained. This study suggests that the use of probiotics and W. saturnus to ferment durian pulp could act as a potential avenue to develop a novel non-dairy durian-based functional beverage to deliver probiotics. PMID- 29107843 TI - A comparison of bioinformatic approaches for 16S rRNA gene profiling of food bacterial microbiota. AB - The different pipelines that may be used in 16S rRNA gene profiling of bacterial communities are known to have a significant impact on alpha and beta diversity measures and this may prevent direct comparison of results obtained in studies using different bioinformatic approaches to analyse raw sequences. To evaluate the feasibility of meta-studies on food bacterial communities, we compared four analysis procedures, varying in OTU picking and taxonomy assignment strategies. A closed reference OTU picking resulted in the most divergent results in terms of both alpha and beta diversity, compared to open reference methods. Nevertheless, when OTUs were collapsed at the genus level, a high correlation was obtained among the estimated abundances of taxa for most studies. Aggregation of samples by their nature and occurrence of food spoilage or fermentation resulted in a very similar classification using two beta diversity analysis methods. We conclude that comparisons of data obtained from different studies are feasible at the genus level, when the same OTU picking strategy is used. Finally, we provide a new version of FoodMicrobionet (Parente et al., 2016), including data from 26 recent studies on food bacterial communities, together with R scripts allowing both the extraction of data in formats which can be used in several analysis tools (including the R package phyloseq and the Cytoscape app CoNet) and the statistical and graphical analysis using common alpha- and beta-diversity analysis methods. PMID- 29107844 TI - The mechanisms underlying olfactory deficits in apolipoprotein E-deficient mice: focus on olfactory epithelium and olfactory bulb. AB - Apolipoprotein E (ApoE) is highly expressed in the central nervous system including the olfactory epithelium (OE) and olfactory bulb (OB). ApoE induction is beneficial for Alzheimer's disease (AD) treatment, whereas ApoE deficiency results in impaired olfaction, but the timing and underlying molecular and cellular mechanisms of these effects remain unclear. Uncovering the mechanisms underlying olfactory dysfunction in ApoE-deficient mice might provide a potential avenue for the early diagnosis of AD. We used an ApoE knockout (ApoE-/-) mouse model and a cookie-finding test to reveal an olfactory deficit in 3- to 5-month old, but not 1- to 2-month-old, ApoE-/- mice. Electrophysiological experiments indicated a significant decline in the electroolfactogram (EOG) amplitude, which was associated with an increase in rise time in ApoE-/- mice. Knockout mice also exhibited compromised olfactory adaptation, as well as a reduced number of mature olfactory sensory neurons in the OE. Local field potential recording in the OB showed that gamma oscillation power was enhanced, which might be attributed to an increase in GABAergic inhibition mediated by parvalbumin-expressing (PV) interneurons. This study demonstrates the critical involvement of ApoE in olfactory information processing in the OE and OB. ApoE deficiency results in olfaction deficits in mice as young as 3 months old, which has implications for AD pathogenesis. PMID- 29107845 TI - Early Alzheimer-type lesions in cognitively normal subjects. AB - Amyloid deposits and tau-immunoreactive neurofibrillary tangles, together with neuronal and synaptic loss, are the neuropathological hallmarks of Alzheimer's disease (AD). Both proteins are present in the normal brain during aging. However, the temporal sequence of their involvement in the onset of AD pathology remains controversial. To define whether amyloid beta protein deposits or tau protein lesions appear first during normal brain aging, we performed an immunohistological study on serial sections from 105 autopsy brains (age range: 40-104 years) from patients free of clinical signs of cognitive decline, using anti-tau (AT8) and anti-amyloid (4G8) antibodies in the hippocampus, entorhinal cortex, inferior temporal cortex (Brodmann area 20), prefrontal cortex (Brodmann area 9), occipital cortex (Brodmann areas 17 and 18), and in the brainstem. All cases older than 48 years displayed at least a few neurofibrillary tangles, which appeared more frequently in the entorhinal than in the transentorhinal cortex. Tau pathology in these areas preceded tau inclusions in the brainstem. Furthermore, the first site of the apparition of tau pathology is inconsistent, being the entorhinal cortex in most cases, and in fewer cases, the transentorhinal region. There was no case presenting with amyloid deposition in the absence of neurofibrillary tangles, lending evidence to the fact that neurofibrillary tangles appear earlier than amyloid plaques during normal brain aging. However, the role of amyloid in promoting tau deposition cannot be excluded in some cases but may not represent the sole mechanism of disease induction and progression. PMID- 29107846 TI - Relevance of raised cerebrospinal fluid monocyte levels in patients with frontotemporal dementia. AB - Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder. The contribution of the immune system to its pathogenesis remains incompletely understood. In this study, we performed comprehensive immune cell profiling in the cerebrospinal fluid (CSF) and peripheral blood of patients with FTD. Thirty two patients with behavioral variant frontotemporal dementia and 25 patients with primary progressive aphasia were included and compared to 14 healthy elderly controls. All patients underwent neuropsychological examination, magnetic resonance imaging, voxel-based diffusion tensor imaging, and peripheral blood and CSF immune cell profiling by multiparameter flow cytometry. The percentage of CSF monocytes was significantly increased specifically in patients with primary progressive aphasia. The proportion of monocytes in the CSF of the total FTD patient group directly correlated with semantic language impairment and microstructural temporal lesions. Increased intrathecal numbers of monocytes suggest a specific response of the innate immune system in a subset of patients with FTD. The findings are of clinical relevance since monocyte levels in the CSF were correlated with typical neuropsychological deficits and microstructural patterns of temporal degeneration. PMID- 29107847 TI - The FBN rat model of aging: investigation of ABR waveforms and ribbon synapse changes. AB - Age-related hearing loss is experienced by one-third of individuals aged 65 years and older and can be socially debilitating. Historically, there has been poor correlation between age-related threshold changes, loss of speech understanding, and loss of cochlear hair cells. We examined changes in ribbon synapse number at four different ages in Fisher Brown Norway rats, an extensively studied rat model of aging. In contrast to previous work in mice/Wistar rats, we found minimal ribbon synapse loss before 20 months, with significant differences in 24- and 28 month-old rats at 4 kHz. Significant outer HC loss was observed at 24 and 28 months in low- to mid-frequency regions. Age-related reductions in auditory brainstem response wave I amplitude and increases in threshold were strongly correlated with ribbon synapse loss. Wave V/I ratios increased across age for click, 2, 4, and 24 kHz. Together, we find that ribbon synapses in the Fisher Brown Norway rat cochlea show resistance to aging until ~60% of their life span, suggesting species/strain differences may underpin decreased peripheral input into the aging central processor. PMID- 29107849 TI - Teratogenic bluetongue and related orbivirus infections in pregnant ruminant livestock: timing and pathogen genetics are critical. AB - Congenital infections of domestic animals with viruses in several families, including Bunyaviridae, Flaviridae, Parvoviridae, and Reoviridae, are the cause of naturally occurring teratogenic central nervous system and/or musculoskeletal defects (arthrogryposis) in domestic animals. Congenital infections of ruminant livestock with bluetongue virus (BTV) and some related members of the genus Orbivirus (family Reoviridae) have clearly shown the critical role of gestational age at infection in determining outcome. Specifically, fetuses infected prior to mid-gestation that survive congenital BTV infection are born with cavitating central nervous system defects that range from severe hydranencephaly to cerebral cysts (porencephaly). Generally, the younger the fetus (in terms of gestational age) at infection, the more severe the teratogenic lesion at birth. Age-dependent virus infection and destruction of neuronal and/or glial cell precursors that populate the developing central nervous system are responsible for these naturally occurring virus-induced congenital defects of animals, thus lesions are most severe when progenitor cells are infected prior to their normal migration during embryogenesis. Whereas congenital infection is characteristic of certain BTV strains, notably live-attenuated (modified-live) vaccine viruses that have been passaged in embryonating eggs, transplacental transmission is not characteristic of many field strains of the virus and much remains to be determined regarding the genetic determinants of transplacental transmission of individual virus strains. PMID- 29107850 TI - Inflammatory markers in dependence on the plasma concentration of 37 fatty acids after the coronary stent implantation. AB - Using the regression model building the relationships between the concentration of 37 fatty acids of blood plasma phospholipids of 41 patients with coronary artery disease after coronary stent implantation, the inflammatory response and oxidative stress markers were estimated. The dynamics of the inflammatory response and the oxidative stress was indicated by measuring plasma concentrations of highly sensitive C-reactive protein, interleukin-6, serum amyloid A and malondialdehyde before, 24h after stent implantation. The multiple linear regression analysis was preceded by an exploratory data analysis, principal component analysis, factor analysis and cluster analysis, which proved a hidden internal relation of 37 fatty acids. The concentration of cerotic acid (C26:0) has been positively associated with an increase of malondialdehyde concentration after stent implantation, while the concentrations of tetracosatetraenoic (C24:4 N6) and nonadecanoic (C19:0) acids were associated with decrease of lipoperoxidation. The increase of interleukin-6 during the 24h after implantation was associated with higher levels of pentadecanoic acid (C15:0) and lower levels of alpha-linolenic acid (C18:3 N3). Regression models found several significant fatty acids at which the strength of the parameter beta for each fatty acid on selected markers of C-reactive protein, malondialdehyde, interleukin-6 and serum amyloid A was estimated. Parameter beta testifies to the power of the positive or negative relationship of the fatty acid concentration on the concentration of selected markers. The influencing effect of the cerotic acid (C26:0) concentration in plasma phospholipids exhibiting parameter beta=140.4 is, for example, 3.5 times higher than this effect of n-3 tetracosapentaenoic acid (C24:5 N3) with beta=40.0. Composition of fatty acids in plasma phospholipids shows spectrum of fatty acids available for intercellular communication in systemic inflammatory response of organism and should affect clinical outcomes. PMID- 29107848 TI - Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. AB - Thyroid hormone disease is common among older adults and is associated with cognitive impairment. However, pathologic correlates are not well understood. We studied pathologic and clinical factors associated with hypothyroidism, the most common manifestation of thyroid disease, in research subjects seen annually for clinical evaluations at U.S. Alzheimer's Disease Centers. Thyroid disease and treatment status were assessed during clinician interviews. Among autopsied subjects, there were 555 participants with treated hypothyroidism and 2146 without known thyroid disease; hypothyroidism was associated with severe atherosclerosis (odds ratio: 1.35; 95% confidence interval: 1.02, 1.79) but not Alzheimer's disease pathologies (amyloid plaques or neurofibrillary tangles). Among participants who did not undergo autopsy (4598 with treated hypothyroidism and 20,945 without known thyroid hormone disease), hypercholesterolemia and cerebrovascular disease (stroke and/or transient ischemic attack) were associated with hypothyroidism, complementing findings in the smaller autopsy sample. This is the first large-scale evaluation of neuropathologic concomitants of hypothyroidism in aged individuals. Clinical hypothyroidism was prevalent (>20% of individuals studied) and was associated with cerebrovascular disease but not Alzheimer's disease-type neuropathology. PMID- 29107851 TI - Are WISC IQ scores in children with mathematical learning disabilities underestimated? The influence of a specialized intervention on test performance. AB - BACKGROUND: Intelligence measures play a pivotal role in the diagnosis of mathematical learning disabilities (MLD). Probably as a result of math-related material in IQ tests, children with MLD often display reduced IQ scores. However, it remains unclear whether the effects of math remediation extend to IQ scores. AIMS: The present study investigated the impact of a special remediation program compared to a control group receiving private tutoring (PT) on the WISC IQ scores of children with MLD. METHODS: We included N=45 MLD children (7-12 years) in a study with a pre- and post-test control group design. Children received remediation for two years on average. RESULTS: The analyses revealed significantly greater improvements in the experimental group on the Full-Scale IQ, and the Verbal Comprehension, Perceptual Reasoning, and Working Memory indices, but not Processing Speed, compared to the PT group. Children in the experimental group showed an average WISC IQ gain of more than ten points. CONCLUSION: Results indicate that the WISC IQ scores of MLD children might be underestimated and that an effective math intervention can improve WISC IQ test performance. Taking limitations into account, we discuss the use of IQ measures more generally for defining MLD in research and practice. PMID- 29107852 TI - Feasibility and validity of a tool for identification of people with intellectual disabilities in need of palliative care (PALLI). AB - BACKGROUND: There is a need for a specific tool that supports healthcare professionals in timely identifying people with intellectual disabilities (ID) in need of palliative care. Therefore, we developed PALLI: a tool for screening deteriorating health, indicative of a limited life expectancy. AIMS: We evaluated feasibility, construct validity and predictive validity of PALLI. METHODS: 190 people with ID likely to be in need of palliative care were included. Physicians and daily care professionals (DCPs) completed PALLI and provided information on health outcomes at baseline, after 5-6 months and after 10-12 months. Linear Mixed Models and Generalized Linear Mixed Models were used to test validity. RESULTS: Feasibility was adequate: physicians and DCPs were able to answer most items with 'yes' or 'no' and within a short amount of time. Construct validity was promising: a higher PALLI score at baseline was related to a higher level of decline in health, a higher symptom burden, a lower quality of life and more ADL dependency at baseline. Predictive validity: only a higher physician-reported PALLI score at baseline significantly increased risk of death within 12 months. CONCLUSIONS: PALLI shows promising feasibility and validity and has potential as a tool for timely identifying people with ID who may benefit from palliative care. PMID- 29107853 TI - The effect of tranexamic acid to reduce blood loss and transfusion on off-pump coronary artery bypass surgery: A systematic review and cumulative meta-analysis. AB - STUDY OBJECTIVE: To assess the safety and efficacy of tranexamic acid (TA) on off pump coronary artery bypass (OPCAB) surgery. DESIGN: Meta-analysis. SETTING: Operating room, OPCAB surgery, all surgeries were elective measurements. Searching the following data sources respectively: PubMed/MEDLINE, the Cochrane Library, EMBASE and reference lists of identified articles, we performed a meta analysis of postoperative 24h blood loss, postoperative allogeneic transfusion, re-operation for massive bleeding, postoperative mortality, and postoperative thrombotic complications. MAIN RESULTS: Using electronic databases, we selected 15 randomized control trials (RCTs), carried out between 2003 and 2016, with a total of 1250 patients for our review. TA significantly reduced the postoperative 24h blood loss (mean difference -213.32ml, 95% confidence intervals, -247.20ml to -179.43ml; P<0.0001). And, TA also significantly reduced the risk of packed red blood cell (PRBCs) transfusion (risk ratio 0.62; 95% confidence intervals 0.51 to 0.76; P<0.0001) and fresh frozen plasma (FFP) transfusion (0.65; 0.52 to 0.81; P<0.001). There were no statistical significance on platelet transfusion (risk difference -0.00, 95% confidence interval -0.02 to 0.02; P=0.73) and re-operation (0.00, -0.02 to 0.02; P=1.00). No association was found between TA and morbility (risk difference -0.00, 95% confidence interval -0.02 to 0.02; P=0.99) and thrombotic complications (-0.01, -0.01 to 0.02; P=0.70). CONCLUSIONS: TA reduced the probability of receiving a PRBCs and FFP transfusion during OPCAB surgery. And no association with postoperative death and thrombotic events was found. However, further trials with an appropriate sample size are required to confirm TA safety in OPCAB surgery. PMID- 29107854 TI - A combination of AirTraq and Truflex for intubation in morbidly obese patient. PMID- 29107855 TI - Is CPAP treatment not effective after supratentorial craniotomy? PMID- 29107856 TI - Distal adductor canal block for administering postoperative analgesia in lower limb surgery. PMID- 29107857 TI - Development of an automated wax-printed paper-based lateral flow device for alpha fetoprotein enzyme-linked immunosorbent assay. AB - In this study, a novel wax-printed paper-based lateral flow device has been developed as an alternative approach for an automated and one-step enzyme-linked immunosorbent assay (ELISA). The design pattern consisted of a non-delayed channel, a wax-delayed channel, a test zone and a control zone. This system was easily fabricated on a nitrocellulose membrane using a wax-printing method and then baked in an oven at 100 degrees C for 1min. The four barriers of the wax delayed channel could delay the flow time for 11s compared to the flow time of the non-delayed channel. To use the device under optimal conditions, alpha fetoprotein (AFP) was detected at a limit of detection of 1ngmL-1 and assessed with the naked eye within 10min. A colorimetric intensity was also measured using a smart phone and computer software at a linear range of 0.1-100ngmL-1 with a good correlation. Furthermore, the proposed device was successfully applied to detect AFP in human serum. Therefore, the wax-printing demonstrates a user friendly, easy and quick method for the fabrication of the device, which could be used as a one-step, portable, disposable, low-cost, simple, instrument-free and point-of-care device for the automated ELISA. PMID- 29107858 TI - Effects of a penalty point system on traffic violations. AB - We analysed data from the Norwegian driver's licence penalty point register over a three-year period, in order to investigate whether the number of incurred penalty points in a given time period can predict the probability of incurring additional points in the subsequent period. Data for all category B drivers without penalty points at the start of the study period were included in the analyses. Norway's penalty point system implies that speeding and various other traffic violations result in two or three penalty points for full-license drivers and four or six points for probationary-license drivers. Eight points within a three-year period results in a six-month disqualification. Two hypotheses were formulated: 1) A "driving style effect" implying that drivers with previous penalty points have a higher probability of incurring new points than drivers without previous points; and 2) a "deterrence effect" implying that drivers with more than four points have a reduced probability of incurring new points, due to impending risk of license revocation. Results showed an inverted U-shaped relationship between number of penalty points incurred during a one-year period and the number of additional penalty points incurred in the subsequent year, with the highest number for drivers with four previous points. Thus, both hypotheses were clearly supported, and it is concluded that the penalty point system has a significant deterring effect for drivers who are at high risk of losing their license at the next infraction. PMID- 29107859 TI - The effect of the Progesterone-Induced Blocking Factor (PIBF) on E-cadherin expression, cell motility and invasion of primary tumour cell lines. AB - In addition to being immunomodulatory, Progesterone-Induced Blocking Factor (PIBF) plays a role in cell cycle regulation and invasion. The full length protein is associated with the pericentriolar satellites and as such, it is crucial for maintaining the integrity of spindle poles during mitosis. Another suggestive evidence for the involvement of PIBF in tumour progression is the fact that the PIBF gene has been identified on chromosome 13 in the region associated with breast cancer susceptibility. Earlier we showed that PIBF differentially regulates the invasiveness of trophoblast and tumour cell lines. The aim of the present study was to further investigate the role of PIBF in tumour development, using primary ovarian- (OC) and primary lung carcinoma (LC) cell cultures, and JEG-3 choriocarcinoma cell line. In the cultured cells PIBF was knocked down by siRNA treatment, and the impact of PIBF deficiency on MMP-9 activity and E cadherin expression as well as on invasive and migratory capacity of the cells was tested. In conditioned media of PIBF-deficient JEG-3 cells, LC cells and OC cells MMP-9 activity was reduced to 36% 35%, and 65% respectively compared to controls. Though PIBF knock down did not affect migration, in JEG-3 cells, LC primary cells and OC primary cells PIBF deficiency resulted 20%, 50% and 50% decrease of invasion respectively. PIBF silencing resulted in increased E cadherin expression, suggesting that by down regulating E-cadherin expression, PIBF might interfere with the cell-cell adhesion mechanisms and by increasing MMP activity induced extracellular matrix degradation, facilitates the invasion of tumour cells. PMID- 29107860 TI - Site of childhood cancer care in the Netherlands. AB - BACKGROUND: Due to the complexity of diagnosis and treatment, care for children and young adolescents with cancer preferably occurs in specialised paediatric oncology centres with potentially better cure rates and minimal late effects. This study assessed where children with cancer in the Netherlands were treated since 2004. METHODS: All patients aged under 18 diagnosed with cancer between 2004 and 2013 were selected from the Netherlands Cancer Registry (NCR) and linked with the Dutch Childhood Oncology Group (DCOG) database. Associations between patient and tumour characteristics and site of care were tested statistically with logistic regression analyses. RESULTS: This population-based study of 6021 children diagnosed with cancer showed that 82% of them were treated in a paediatric oncology centre. Ninety-four percent of the patients under 10 years of age, 85% of the patients aged 10-14 and 48% of the patients aged 15-17 were treated in a paediatric oncology centre. All International Classification of Childhood Cancers (ICCC), 3rd edition, ICCC-3 categories, except embryonal tumours, were associated with a higher risk of treatment outside a paediatric oncology centre compared to leukaemia. Multivariable analyses by ICCC-3 category revealed that specific tumour types such as chronic myelogenous leukaemia (CML), embryonal carcinomas, bone tumours other type than osteosarcoma, non rhabdomyosarcomas, thyroid carcinomas, melanomas and skin carcinomas as well as lower-staged tumours were associated with treatment outside a paediatric oncology centre. CONCLUSION: The site of childhood cancer care in the Netherlands depends on the age of the cancer patient, type of tumour and stage at diagnosis. Collaboration between paediatric oncology centre(s), other academic units is needed to ensure most up-to-date paediatric cancer care for childhood cancer patients at the short and long term. PMID- 29107861 TI - Is post-mastectomy radiation therapy contributive in pN0-1mi breast cancer patients? Results of a French multi-centric cohort. AB - AIM: To assess the value of post-mastectomy radiation therapy (PMRT) to breast cancer (BC) patients with no or minimal lymph node (LN) involvement. MATERIALS AND METHODS: We retrospectively analysed a French multi-centric cohort of 4283 patients treated by mastectomy and axillary dissection, with or without PMRT, between 1980 and 2013. Practices were analysed for three treatment periods (1980 1999, 2000-2005 and 2006-2013). The impact of PMRT on loco-regional recurrence (LRR), disease-free survival (DFS), BC-specific survival and overall survival was assessed in pN0-1mi patients using multivariate analyses (logistic regression and Cox model). It was subsequently assessed based on the number of clinicopathological recurrence-risk factors, generating a prognostic index (French-PMRT index), to isolate a pN0-1mi patients subgroup that might derive a benefit from PMRT. We tested the accuracy of the Cambridge-PMRT (c-PMRT) index to discriminate between patients with significantly different outcomes and the value of PMRT in each c-PMRT prognostic group. RESULTS: More than half of the pN0-1mi patients of our cohort underwent PMRT, which almost significantly improved LRR free survival and DFS. Matching pN0-1mi patients based on the number of clinicopathologic recurrence-risk factors identified a higher risk subpopulation (>=3 recurrence-risk factors), but PMRT did not improve patient outcomes. Although the c-PMRT index had the potential to predict patient outcomes, its use did not help in making the decision of whether or not to use PMRT. CONCLUSION: We failed to isolate a subgroup of early BC patients without LN involvement suitable for PMRT, despite studying a large cohort. PMID- 29107862 TI - Gypsophila elegans isoorientin-2"-O-alpha-l-arabinopyranosyl ameliorates porcine serum-induced immune liver fibrosis by inhibiting NF-kappaB signaling pathway and suppressing HSC activation. AB - The present study was to investigate the inhibitory effect of Gypsophila elegans isoorientin-2"-O-alpha-l-arabinopyranosyl (GEI) on hepatic stellate cells (HSCs), to reveal the underlying mechanism of GEI against hepatic fibrosis. Our study showed that GEI significantly alleviated liver injury induced by porcine serum (PS) in rats; it notably alleviated collagen accumulation as evidenced by a significant decrease in the levels of collagen biomarkers including hyaluronic acid, laminin, hydroxyproline and procollagen III N-terminal peptide. Moreover, GEI treatment markedly decreased the secretion of inflammatory cytokines by inhibiting the NF-kappaB pathway and significantly inhibited the generation of excessive extracellular matrix (ECM) components by restoring the balance between matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases (TIMPs). Additionally, the cell experiments in vitro showed that GEI strongly inhibited HSC proliferation, migration and clonogenicity and markedly induced HSC apoptosis. Moreover, GEI caused cell cycle arrest at G2 phase. In conclusion, our study demonstrates that GEI significantly alleviates PS induced hepatic fibrosis by inhibiting the NF-kappaB pathway, restoring the balance between MMPs and TIMPs, and suppressing HSC activation. PMID- 29107863 TI - Elevated expression of miR-146, miR-139 and miR-340 involved in regulating Th1/Th2 balance with acute exposure of fine particulate matter in mice. AB - Airborne fine particulate matter (PM2.5) is detrimental to human health, and frequently leads to a variety of lung diseases. Recently, IARC conclude that particulate matter is carcinogenic to humans (level one). However, the pulmonary toxicological mechanism induced by PM2.5 remains obscure. Our previous studies confirmed that PM2.5 hurt the human immune system by means of causing the imbalance of Th1/Th2 lymphocytes. MicroRNAs (miRNAs) are post-transcriptional gene suppressors and potential mediators of environmental effects, which play an important role in the regulation of CD4+T lymphocyte differentiation. In order to further understand the roles of microRNAs in regulating the imbalance of Th1/Th2 differentiation triggered by PM2.5, mice were subjected to intratracheal instillation of 2.5, 10, or 20mg/kg PM2.5 in this study. Mice were euthanized on the 1st, 7th and 14th day to screen out differential miRNAs in lung tissue by employing the miRNA microarray. The expression levels of IL-4 and IFN-gamma in bronchoalveolar lavage fluid (BALF) were quantified by ELISA and their mRNA expressions in lung tissue were detected by qRT-PCR. The experiment demonstrated that 10 differential miRNAs (miR-146a, -146b, -139, -129, -340, -691, -181a, 155, -21-3p, and -21-5p) were up-regulated. IL-4 levels were found decreased, nevertheless, IFN-gamma levels were increased, and the IL-4/IFN-gamma ratio was inclined to Th1 shifting. Besides that, we also found that miRNA-691, -181a, 146a, -146b, -21a-3p, -21a-5p, and -340 had a positive linear correlation with BALF IFN-gamma, while a negative linear correlation between microRNAs (miR-146, 139, -340, -21, and -181a) and the IL-4/IFN-gamma level of BALF was observed. In conclusion, elevated microRNAs profiles correlated with T lymphocyte immune imbalance, driving a Th1-biased immune response after acute PM2.5 exposure. These findings improve our understanding of the toxicological pathways of PM2.5 exposure. PMID- 29107864 TI - TRPM2 dependence of ROS-induced NLRP3 activation in Alzheimer's disease. AB - Recent studies have shown that neuroinflammation plays an important role in Alzheimer's disease (AD). Microglial cells are responsible for the phagocytosis of Amyloid-beta (Abeta). However, it has been demonstrated that in AD patients the efficiency of phagocytosis decreases due to proinflammatory cytokines, such as Interleukin-1beta (IL-1beta), which is produced through the activation of NLRP3 inflammasome. In this study, we aimed at deciphering the mechanism underlying the NLRP3 activation. The results showed that Abeta induces an increase in the level of reactive oxygen species (ROS). According to this study, ROS produced from both mitochondria and NADPH oxidase was responsible for NLRP3 activation. In addition, it was observed that this high level of ROS activated the transient receptor potential melastatin 2 (TRPM2) channel, which causes an increase in the level of intracellular calcium. The results demonstrated that in the absence of intracellular calcium, caspase-1 cannot be activated and therefore the level of IL-1beta decreases. Altogether, our findings supported the role of TRPM2 channel in ROS-induced NLRP3 activation in microglial cells through the exposure to Abeta. PMID- 29107865 TI - Landmark-based deep multi-instance learning for brain disease diagnosis. AB - In conventional Magnetic Resonance (MR) image based methods, two stages are often involved to capture brain structural information for disease diagnosis, i.e., 1) manually partitioning each MR image into a number of regions-of-interest (ROIs), and 2) extracting pre-defined features from each ROI for diagnosis with a certain classifier. However, these pre-defined features often limit the performance of the diagnosis, due to challenges in 1) defining the ROIs and 2) extracting effective disease-related features. In this paper, we propose a landmark-based deep multi-instance learning (LDMIL) framework for brain disease diagnosis. Specifically, we first adopt a data-driven learning approach to discover disease related anatomical landmarks in the brain MR images, along with their nearby image patches. Then, our LDMIL framework learns an end-to-end MR image classifier for capturing both the local structural information conveyed by image patches located by landmarks and the global structural information derived from all detected landmarks. We have evaluated our proposed framework on 1526 subjects from three public datasets (i.e., ADNI-1, ADNI-2, and MIRIAD), and the experimental results show that our framework can achieve superior performance over state-of-the-art approaches. PMID- 29107866 TI - The gender background of texture attributes of pork loin. AB - The tenderness of pork loins from castrates, entire males and females was quantified with sensory analysis and measurement of instrumental texture during ageing. Furthermore, the effects of intramuscular fat (IMF), collagen content and solubility, hot carcass weights and meat percentages on tenderness were examined. Meat from castrates was significantly (p=0.043) more tender than meat from entire males and females as assessed by trained sensory panellists. Tenderness scores were positively affected by IMF content (p=0.008) and hot carcass weight (p<0.001), but no effect of collagen content and solubility was found. Meat from all three genders had the same tenderisation rate during ageing (two, five, seven and ten days). It is therefore suggested that meat from entire males and females should be aged for longer than meat from castrates to obtain the same level of tenderness. PMID- 29107867 TI - Application of high temperature (14 degrees C) aging of beef M. semimembranosus with low-dose electron beam and X-ray irradiation. AB - The effects of irradiation source (electron beam [EB] and X-ray [XR]), aging temperature (4 degrees C and 14 degrees C), and aging time (0, 3, 7, and 14days) were evaluated on microbial quality, physicochemical properties, and calpain-1 autolysis in beef M. semimembranosus. Regardless of irradiation source, irradiation prior to aging reduced the total number of aerobic bacteria in beef and this reduction was maintained during aging. Irradiation did not affect the pH, b* value, shear force, or myofibrillar fragmentation index of beef at day 0. Degradation of sarcoplasmic and myofibrillar proteins was greater in beef aged at 14 degrees C compared with beef aged at 4 degrees C. EB- or XR-irradiated samples showed slower autolysis of calpain-1; however, beef tenderness was not affected. Therefore, EB or XR irradiation can be applied to beef prior to aging to control microbial growth during high temperature (14 degrees C) aging, thus shortening the aging time without adversely affecting the physicochemical properties of beef. PMID- 29107868 TI - Growth performance, carcass quality, fresh belly characteristics, and commercial bacon slicing yields of growing-finishing pigs fed a subtherapeutic dose of an antibiotic, a natural antimicrobial, or not fed an antibiotic or antimicrobial. AB - The objective was to compare growth performance, belly characteristics, and bacon slicing yields of growing-finishing pigs fed a subtherapeutic dose of an antibiotic, a natural antimicrobial, or a diet containing no antibiotics or antimicrobials. Barrows and gilts (96 each, initial BW: 27.52+/-3.98kg) were housed in 48 pens (8 replications per treatment) in a 2*3 factorial randomized complete block design. Pens were assigned 1 of 3 diets: antibiotic free, oregano or tylosin phosphate. Pigs were slaughtered at an average BW of 127.31+/-10.18kg. There were no differences among dietary treatments for growth performance (P>=0.06), carcass cutability (P>=0.42), loin quality (P>=0.28), fresh belly dimensional characteristics (P>=0.11), IV (P>=0.87) or bacon processing characteristics (P>=0.07). Given the lack of differences in meat quality from pigs fed diets without antibiotics, the implementation of VFD in the United States should not result in changes in pork quality. PMID- 29107869 TI - Surfactant protein D regulates caspase-8-mediated cascade of the intrinsic pathway of apoptosis while promoting bleb formation. AB - Surfactant-associated protein D (SP-D) is a soluble innate immune collectin present on many mucosal surfaces. We recently showed that SP-D suppresses the extrinsic pathway of apoptosis by downregulating caspase-8 activation. However, the effects of SP-D on the intrinsic pathway of apoptosis are not clearly understood. In the intrinsic pathway, cytochrome c is released by mitochondria into the cytoplasm. Oxidation of cytochrome c by cytochrome c oxidase activates the apoptosome and caspase-9 cascade. Both caspase-8- and caspase-9-mediated branches are activated in the intrinsic pathway of apoptosis; however, little is known about the relevance of the caspase-8 pathway in this context. Here we studied the effects of SP-D on different branches of the intrinsic pathway of apoptosis using UV-irradiated Jurkat T-cells. We found that SP-D does not inhibit the caspase-9 branch of apoptosis and the relevance of the caspase-8-related branch became apparent when the caspase-9 pathway was inhibited by blocking cytochrome c oxidase. Under these conditions, SP-D reduces the activation of caspase-8, executioner caspase-3 and exposure of phosphatidylserine (PS) on the membranes of dying cells. By contrast, SP-D increases the formation of nuclear and membrane blebs. Inhibition of caspase-8 confirms the effect of SP-D is unique to the caspase-8 pathway. Overall, SP-D suppresses certain aspects of the intrinsic pathway of apoptosis via reduction of caspase-8 activation and PS flipping while at the same time increasing membrane and nuclear bleb formation. This novel regulatory aspect of SP-D could help to regulate intrinsic pathway of apoptosis to promote effective blebbing and breakdown of dying cells. PMID- 29107870 TI - Consent process for US-based family reference DNA samples. AB - DNA collection from family members of the missing is a tenet for missing persons' and mass fatality investigations. Procedures for consenting family members are disparate, depending on the context supporting the reason for sample collection. While guidelines and best practices have been developed for handling mass fatalities and for identification of the missing, these guidelines do not address standard consent practices for living family members of potential victims. We examined the relevant U.S. laws, international guidelines and best practices, sampled consent forms currently used for DNA collection of family members, and drafted model language for a consent form to communicate the required and recommended information. We modeled the consent form on biobank consenting practices and tested the consent language among students and the general population for constructive feedback and readability. We also asked respondents to consider the options for DNA collection and either hypothetically agree or disagree. The model language presented here highlights information important to relay in consent processes and can serve as a foundation for future consent practices in mass fatalities and missing persons' investigations. PMID- 29107871 TI - An appetite for life: brain regulation of hunger and satiety. AB - Obesity results from the consumption of food in excess of bodily energy requirements, with the excess energy stored as adipose tissue. Sequelae of obesity, such as heart disease and type 2 diabetes, consistently rank among the top causes of death worldwide. The global prevalence of obesity highlights the urgency of understanding the mechanisms regulating hunger and satiety. Appetite, defined as the motivational drive to obtain food, is regulated by a complex neurocircuitry which integrates a variety of interoceptive signals to gauge nutritional state and guide appropriate levels of food-seeking. Here we review key recent developments in the identification of cell groups, neural circuits, endogenous and exogenous substances, and intracellular signaling pathways which drive hunger and satiety. We also consider particularly promising pharmacological targets for appetite modulation. PMID- 29107872 TI - Inflammation and gut-brain axis link obesity to cognitive dysfunction: plausible pharmacological interventions. AB - Obesity prevalence is increasing steadily throughout the world's population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer's disease. The precise mechanisms that underlie the connections between obesity and the risk of cognitive impairment are still largely unknown but potential avenues of further research include insulin resistance, the gut-brain axis, and systemic mediators and central inflammation processes. A common feature of metabolic diseases is a chronic and low-grade activation of the inflammatory system. This inflammation may eventually spread from peripheral tissue to the brain, and recent reports suggest that neuroinflammation is an important causal mechanism in cognitive decline. This inflammatory status could be triggered by changes in the gut microbiota composition. Consumption of diets high in fat and sugar influences the microbiota composition, which may lead to an imbalanced microbial population in the gut. Thus, it has recently been hypothesized that the gut microbiota could be part of a mechanistic link between the consumption of high fat and other unbalanced diets and impaired cognition, termed 'gut-brain axis'. The present review will aim at providing an integrative analysis of the effects of obesity and unbalanced diets on cognitive performance and discusses some of the potential mechanisms involved, namely inflammation and changes in gut-brain axis. Moreover, the review aims to analyze anti-inflammatory drugs that have been tested for the treatment of cognition and obesity, recently approved anti-obesity drugs that could also have an impact on central nervous system, and bioactive food compounds that modulate gut microbiota and could have an impact through the gut-brain axis. In this era of precision nutrition medicine, it is imperative to identify the various metabolic-neurocognitive phenotypes in order to understand the processes that drive these diseases so that targeted therapeutic strategies to prevent and successfully manage these complex, multifactorial diseases could be designed and developed. PMID- 29107873 TI - Influence of surface roughness on the measurement of acoustic nonlinearity parameter of solids using contact piezoelectric transducers. AB - The current article reports on the experimental study of the influence of surface roughness on the measurement of the acoustic nonlinearity parameter. The nonlinearity parameter was measured using contact piezoelectric transducers, which were calibrated using the reciprocity based technique. Aluminum and steel samples were chosen to study the influence of hardness of the sample on the measurement of the nonlinearity parameter. While, lower Ra value (average asperity height) aluminum samples were more susceptible to surface deformation and scratches from coupling the transducer to the sample, the same could not be observed for steel samples. Results demonstrate a large variation in nonlinearity parameter for aluminum (~35%) compared to steel (~2%) between two consecutive experiments, suggesting flattening of asperities after the first experiment. Experiments were also performed with 3 different setup configurations; (1) receiver and transmitter on rough sides, (2) receiver on smooth and transmitter on rough side and (3) receiver on rough and transmitter on smooth side. Results show that least variation in the measured nonlinearity parameter was observed when the receiver was placed on the smooth side, and a 10% variation was observed between the three setup configurations. Finally, a comparison of relative nonlinearity parameter calculated using current or voltage ratio and absolute nonlinearity parameter showed large discrepancies. Conclusions were drawn from the experimental observations. PMID- 29107874 TI - Migration of two antibiotics during resuspension under simulated wind-wave disturbances in a water-sediment system. AB - In this study, the migration of antibiotics (norfloxacin, NOR; and sulfamethoxazole, SMX) under simulated resuspension conditions across the sediment-water interface were quantified for two locations in China: point A, located in Meiliang Bay of Lake Taihu, and point B, located in Dapukou of Lake Taihu. The concentrations of suspended solids (SS) in the overlying water amounted to 100, 500, and 1000 mg/L during background, moderate, and strong simulated wind-wave disturbances, respectively. At each SS level, the initial concentrations of the two antibiotics were set to 1, 5, and 10 mg/L. The results showed that both resuspended SS and the initial concentration of antibiotics could influence the migration of NOR in the water-sediment system. Specifically, both higher SS and initial antibiotic concentrations were associated with higher rates of migration and accumulation of NOR from water to sediment. In contrast, the migration of SMX in the water-sediment system was not impacted by SS or initial antibiotic concentration. The adsorption capacities of sediments for NOR and SMX were significantly different at both locations, possibly reflecting differences in cation exchange capacity (CEC) and organic material (OM) contents. In general, higher CEC and OM values were found in sediments with a higher adsorption capacity for the antibiotics. When CEC and OM values of sediments were higher, the adsorption capacity reached up to 51.73 mg/kg. Large differences in the migration from water to sediment were observed for the two antibiotics, with NOR migration rates higher than those of SMX. The accumulation of NOR in surface sediment during resuspension was about 14 times higher than that of SMX. The main reason for this is that the chemical adsorption of NOR is seldom reversible. Overall, this study demonstrates that resuspension of NOR and SMX attached to sediments under simulated wind-wave disturbances can promote the migration of the antibiotics from water to sediment; these results could be useful for assessing the migration and fate of commonly used antibiotics in water-sediment systems. PMID- 29107875 TI - The Henry's constant of monochloramine. AB - Monochloramine is a secondary disinfectant used in drinking water and is also formed in chlorinated wastewater. While known to hydrolyze over time and react with dissolved organic matter, its partitioning between the aqueous and gas phase has not been extensively studied. Preliminary experiments demonstrated that monochloramine concentrations in solutions open to the atmosphere or actively aerated decreased more rapidly than in sealed solutions, indicating significant losses to the atmosphere. For example, a monochloramine solution open to the atmosphere yielded a loss rate constant of 0.08 d-1, a value twice that for sealed samples without headspace (0.04 d-1) where loss occurs exclusively as a result of hydrolysis. A solution aerated at 10 mL s-1 had a loss rate constant nearly 10* greater than that for hydrolysis alone (0.35 d-1). To better understand partitioning of monochloramine to the gas phase and potential for volatilization, the dimensionless Henry's law constants of monochloramine (KH) were determined using an equilibrium headspace technique at five different temperatures (11, 16, 21, 27, and 32 degrees C). The resulting values ranged from 8 * 10-3 to 4 * 10-2, indicating a semi-volatile compound, and were found to be consistent with quantitative structure activity relationship predictions. At 20 degrees C, monochloramine exhibits a dimensionless Henry's constant of about 1.7 * 10-2 which is 35 times greater than ammonia but comparable to the Henry's constant of inorganic semi-volatile compounds such sulfur dioxide. The Henry's constant values for monochloramine suggests that volatilization could be a relevant loss process in open systems such as rivers receiving chlorinated wastewater effluent, swimming pools and cooling towers. PMID- 29107876 TI - Size-dependent emission characteristics of airborne parent and halogenated PAHs from municipal solid waste incinerators in Shenzhen, China. AB - Two waste incinerators were selected for investigation of size-dependent emission characteristics of airborne parent and halogenated PAHs (PAHs and HPAHs) and incidence of these pollutants from trash incineration. The concentrations of total PAHs (gas and particles with aerodynamic diameter 0.43-10 MUm) in ambient air of Shenzhen incinerators were at the lower end of the global range while those of HPAHs were higher than those of urban air in other studies. High-ring PAHs dominated in PM2.5 (66%-86%), while low-ring PAHs dominated in PM10 (83% 86%). As for PAHs in gaseous phase, low-ring PAHs were collectively account for 86%-97%. SigmaHPAH mainly enriched in coarse particles (>83%). The size distributions of SigmaPAH and SigmaHPAH were both characterized by bimodal peaks dominate in 9.0-10 MUm and subordinate in 4.7-5.8 MUm. PAHs and HPAHs enrichment in the coarse particles indicates that particle-bound PAHs and HPAHs from incinerators cannot travel great distances. Model simulation results showed the peak of airborne PAHs and HPAHs occurred in approximate 300 m from incinerator, then their concentrations reduced sharply. The extent of affected areas by municipal solid waste incinerators (MSWIs) seem very large, intensity of impacts can be neglected for the very low level of pollutants. Although waste incineration is perceived as most polluting way to manage waste, our study found the damage from incinerator to be far less than originally feared. PMID- 29107877 TI - A novel biodegradable arsenic adsorbent by immobilization of iron oxyhydroxide (FeOOH) on the root powder of long-root Eichhornia crassipes. AB - In this study, FeOOH was immobilized on the biodegradable root powder, abbreviated as RP, of long-root Eichhornia crassipes, a kind of waste biomass, to improve the adsorption performances for aqueous arsenic contaminants. The adsorption kinetics and thermodynamics experiments showed that the adsorption rates and capacities of the root powder for arsenate (As(V)) and arsenite (As(III)) were both enhanced markedly after modification with FeOOH. The adsorption of As(V) and As(III) by the modified root powder, abbreviated as MRP, could arrive at equilibrium in 50 min and the saturated adsorption capacities reached up to 8.67-9.43 mg/g for As(V) and 5.21-5.65 mg/g for As(V) at temperature of 10-50 degrees C, respectively. Besides, the effect of pH and ionic strength on adsorption was investigated and the results showed that the optimum pH for the arsenic adsorption using the MRP was 9.0 and the As(V) adsorption was more sensitive to ionic strength. Furthermore, the complexation of hydratable hydroxyls on FeOOH with arsenic contaminants was concluded as the adsorption force according FTIR and XPS analyses. The MRP used could be regenerated via 0.4 mol/L NaOH solution and no apparent adsorption capacity losses appeared after 6 cyclic utilizations. PMID- 29107878 TI - Breakthrough during air sampling with polyurethane foam: What do PUF 2/PUF 1 ratios mean? AB - Frontal chromatography theory is applied to describe movement of gaseous semivolatile organic compounds (SVOCs) through a column of polyurethane foam (PUF). Collected mass fractions (FC) are predicted for sample volume/breakthrough volume ratios (tau = VS/VB) up to 6.0 and PUF bed theoretical plate numbers (N) from 2 to 16. The predictions assume constant air concentrations and temperatures. Extension of the calculations is done to relate the collection efficiency of a 2-PUF train (FC1+2) to the PUF 2/PUF 1 ratio. FC1+2 exceeds 0.9 for PUF 2/PUF 1 <= 0.5 and lengths of PUF commonly used in air samplers. As the PUF 2/PUF 1 ratio approaches unity, confidence in these predictions is limited by the analytical ability to distinguish residues on the two PUFs. Field data should not be arbitrarily discarded because some analytes broke through to the backup PUF trap. The fractional collection efficiencies can be used to estimate air concentrations from quantities retained on the PUF trap when sampling is not quantitative. PMID- 29107879 TI - Comparative values of various wastewater streams as a soil nutrient source. AB - In order to assess whether wastewaters from different industries (winery, abattoir, dairy and municipal) could be used safely to irrigate agricultural crops, a pot experiment in glass house was conducted in a sandy clay loam soil (pH = 6.12) from South Australia. Different concentrations (0, 0.05, 5, 25, 50, 75 and 100%) of the wastewaters diluted in an ordinary tap water were applied to soils sown with sunflower and maize seeds, and the effect of these irrigation treatments were evaluated at the early crop growth stages by recording the biomass yields, plant mineral nutrient contents, and also the soil chemical properties. Results showed that the winery effluent reduced the early growth of maize and sunflower when applied without any dilution, but increased yields of both plants when applied at 25% dilution with tap water. At this dilution of the winery wastewater, 80% more dry shoot yield (DSY) of sunflower and 58% more DSY of maize were obtained in comparison to the application of 100% concentration of the wastewater. Abattoir wastewater showed the highest yields at 100% concentration. Furthermore, municipal effluent did not show any inhibitory effect on both the crops. It was observed that metal contents in both the crops were different due to the application of different wastewaters, but did not exceed any toxic level. This study demonstrated that abattoir wastewater as such, and winery and dairy wastewaters at appropriate dilutions could be used for irrigation in agricultural fields to enhance crop productivity. PMID- 29107880 TI - Fine particulate air pollution and hospital admissions and readmissions for acute myocardial infarction in 26 Chinese cities. AB - Monitoring data on fine particulate matter (PM2.5) level in China's major cities were available since 2013. We conducted a time-stratified case-crossover study to evaluate the association between short-term exposure to PM2.5 and hospital admissions for acute myocardial infarction (AMI), as well as subsequent cardiac and AMI readmissions among AMI survivors. Hospital admissions for ST-elevation myocardial infarction (STEMI) and non ST-elevation myocardial infarction (NSTEMI) from 1 January 2014 through 31 December 2015 were identified from electronic Hospitalization Summary Reports. Conditional logistic regression was used to explore the relation between PM2.5 and hospital admissions for AMI. Individuals discharged alive following STEMI in 2014 were followed up for subsequent readmissions through 31 December 2015. We used the Cox proportional hazards model to evaluate the effect of PM2.5 pollution on subsequent cardiac and STEMI readmissions. Hospital admissions for STEMI (n = 106,467) and NSTEMI (n = 12,719) were examined separately. Exposure to an interquartile range (IQR) increase in PM2.5 concentration (47.5 MUg/m3) at lags 2, 3, 4 and 0-5 days corresponded with 0.6% (95% CI, 0.1%-1.1%), 0.8 (95% CI, 0.3%-1.3%), 0.6% (95% CI, 0.1%-1.1%) and 0.9% (95% CI, 0-1.8%) increases in STEMI admissions, respectively. For NSTEMI, no significant association was observed with PM2.5. We also observed significant associations of PM2.5 concentration with both subsequent cardiac and STEMI readmissions among STEMI survivors. In conclusion, short-term elevations in PM2.5 concentration may increase the risk of STEMI but not NSTEMI, and the association appeared to be more evident among STEMI survivors. PMID- 29107881 TI - Increased estrogen level can be associated with depression in males. AB - BACKGROUND: Several studies have shown a positive association between depression and obesity; however the underlying mechanisms are not fully understood. It is not known if this association is driven by altered sex hormone levels in men due to increased BMI. PATIENTS AND METHODS: Data were obtained from the LIFE-Adult Study, a population-based cohort study. A total of 3925 men (2244<60years and 1681>60years) were included into analyses. Associations between BMI, sex hormones and depressive symptomatology according to CES-D score were evaluated. RESULTS: Obese men had compared to normal weight controls lower total testosterone (12.6+/ 4.7 vs 19.4+/-5.5 nmol/L, p<0.001 in <60years, and 13.8+/-6.9 vs 18.3+/-5.9 nmol/L, p<0.001 in >60years group) and free testosterone (249.0+/-73.9 vs 337.2+/ 82.0pmol/L, p<0.001, and 217.8+/-71.2 vs 263.4+/-72.2pmol/L, p<0.001), and increased estradiol in older group only (97.3+/-43.0 vs 82.3+/-34.2pmol/L, p<0.001 in obese). Men <60years old with depressive symptomatology had higher estradiol levels compared to those without depressive symptomatology (96.3+/-40.7 vs 84.4+/-36.6pmol/L, p<0.001), however no association with BMI was observed. CONCLUSIONS: Selected sex hormone parameters were significantly different in overweight and obese compared to normal weight males and certain differences could be seen between younger and older males. Depressive symptomatology was associated with increased estradiol levels in younger men, regardless of BMI. PMID- 29107882 TI - Improved screen-printed carbon electrode for multiplexed label-free amperometric immuniosensor: Addressing its conductivity and reproducibility challenges. AB - A new screen-printed carbon electrode (SPCE) with multiple working electrodes and one signal output channel without counter and reference electrodes was designed. The multiple working electrodes can be individually modified for each target of interest. The SPCE contained one signal output channel, making the immuniosensor be realized by common single-channel electrochemical workstation. The counter and reference electrodes were independent of disposable SPCE, reducing costs and eliminating precious metal pollution. Platinum network as counter electrode improved the reproducibility of the SPCE. Moreover, method of generating hydrogel on working electrode was used to enhance the conductivity of SPCE. Based on this, a multiplexed single channel label-free amperometric immuniosensor for four tumor markers, namely, squamous cell carcinoma antigen (SCCA), fragment antigen 21-1 (Cyfra21-1), carbohydrate antigen 125 (CA125), and neuron specific enolase (NSE) was developed, and the corresponding detection limits were 5.5pgmL-1, 4.8pgmL-1, 0.0054UmL-1 and 2.3pgmL-1, respectively. The sensitivity of this immunosensor was 0.83uA (lg(ngmL-1))-1 for SCCA, 1.92uA (lg(ngmL-1))-1 for Cyfra21-1, 4.75uA (lg(UmL-1))-1 for CA125 and 2.40uA (lg(ngmL-1))-1 for NSE. Among them, the sensitivities of CA125 and NSE were four-fold higher than those of the previous works. PMID- 29107884 TI - Editorial overview: Pharmaceutical biotechnology. PMID- 29107883 TI - Visuo-spatial abilities are key for young children's verbal number skills. AB - Children's development of verbal number skills (i.e., counting abilities and knowledge of the number names) presents a milestone in mathematical development. Different factors such as visuo-spatial and verbal abilities have been discussed as contributing to the development of these foundational skills. To understand the cognitive nature of verbal number skills in young children, the current study assessed the relation of preschoolers' verbal and visuo-spatial abilities to their verbal number skills. In total, 141 children aged 5 or 6 years participated in the current study. Verbal number skills were regressed on vocabulary, phonological awareness and visuo-spatial abilities, and verbal and visuo-spatial working memory in a structural equation model. Only visuo-spatial abilities emerged as a significant predictor of verbal number skills in the estimated model. Our results suggest that visuo-spatial abilities contribute to a larger extent to children's verbal number skills than verbal abilities. From a theoretical point of view, these results suggest a visuo-spatial, rather than a verbal, grounding of verbal number skills. These results are potentially informative for the conception of early mathematics assessments and interventions. PMID- 29107885 TI - Structure-based mechanistic insights into catalysis by small self-cleaving ribozymes. AB - Small self-cleaving ribozymes are widely distributed in nature and are essential for rolling-circle-based replication of satellite and pathogenic RNAs. Earlier structure-function studies on the hammerhead, hairpin, glmS, hepatitis delta virus and Varkud satellite ribozymes have provided insights into their overall architecture, their catalytic active site organization, and the role of nearby nucleobases and hydrated divalent cations in facilitating general acid-base and electrostatic-mediated catalysis. This review focuses on recent structure function research on active site alignments and catalytic mechanisms of the Rzb hammerhead ribozyme, as well as newly-identified pistol, twister and twister sister ribozymes. In contrast to an agreed upon mechanistic understanding of self cleavage by Rzb hammerhead and pistol ribozymes, there exists a divergence of views as to the cleavage site alignments and catalytic mechanisms adopted by twister and twister-sister ribozymes. One approach to resolving this conundrum would be to extend the structural studies from currently available pre-catalytic conformations to their transition state mimic vanadate counterparts for both ribozymes. PMID- 29107886 TI - Determination of rare earth elements concentration at different depth profile of Precambrian pegmatites using instrumental neutron activation analysis. AB - The Keffi area hosts abundant pegmatite bodies as a result of the surrounding granitic intrusions. Keffi is part of areas that are geologically classified as North Central Basement Complex. Data on the mineralogy and mineralogical zonation of the Keffi pegmatite are scanty. Hence the need to understand the geology and mineralogical zonation of Keffi pegmatites especially at different depth profiles is relevant as a study of the elemental composition of the pegmatite is essential for the estimation of its economic viability. Here, the relative standardization method of instrumental neutron activation analysis (INAA) has been used to investigate the vertical deviations of the elemental concentrations of rare earth elements (REEs) at different depth profile of Keffi pegmatite. This study adopted the following metrics in investigating the vertical variations of REEs concentrations. Namely, the total contents of rare earth elements (?REE); ratio of light to heavy rare earth elements (LREE/HREE), which defines the enrichment or depletion of REEs; europium anomaly (Eu/Sm); La/Lu ratio relative to chondritic meteorites. The study showed no significant variations in the total content of rare elements between the vertical depth profiles (100-250m). However, higher total concentrations of REEs (~ 92.65ppm) were recorded at the upper depth of the pegmatite and the europium anomaly was consistently negative at all the depth profiles suggesting that the Keffi pegmatite is enriched with light REEs. PMID- 29107888 TI - Expected but omitted stimuli affect crossmodal interaction. AB - One of the most important ability of our brain is to integrate input from different sensory modalities to create a coherent representation of the environment. Does expectation affect such multisensory integration? In this paper, we tackled this issue by taking advantage from the crossmodal congruency effect (CCE). Participants made elevation judgments to visual target while ignoring tactile distractors. We manipulated the expectation of the tactile distractor by pairing the tactile stimulus to the index finger with a high frequency tone and the tactile stimulus to the thumb with a low-frequency tone in 80% of the trials. In the remaining trials we delivered the tone and the visual target, but the tactile distractor was omitted (Study 1). Results fully replicated the basic crossmodal congruency effect. Strikingly, the CCE was observed, though at a lesser degree, also when the tactile distractor was not presented but merely expected. The contingencies between tones and tactile distractors were reversed in a follow-up study (Study 2), and the effect was further tested in two conceptual replications using different combinations of stimuli (Studies 5 and 6). Two control studies ruled out alternative explanations of the observed effect that would not involve a role for tactile distractors (Studies 3, 4). Two additional control studies unequivocally proved the dependency of the CCE on the spatial and temporal expectation of the distractors (Study 7, 8). An internal small-scale meta-analysis showed that the crossmodal congruency effect with predicted distractors is a robust medium size effect. Our findings reveal that multisensory integration, one of the most basic and ubiquitous mechanisms to encode external events, benefits from expectation of sensory input. PMID- 29107887 TI - The early social significance of shared ritual actions. AB - Many rituals are socially stipulated such that engaging in a group's rituals can fundamentally signal membership in that group. Here, we asked whether infants infer information about people's social affiliation based on whether those people perform the same ritualistic action versus different actions. We presented 16 month-old infants with two people who used the same object to achieve the same goal: turning on a light. In a first study, the actions that the actors used to turn on the light had key properties of ritual: they were not causally necessary to reach the overall goal, and there were no features of the situation that required doing the particular actions. We varied whether the two actors performed the same action or performed different actions to turn on the light. Infants expected people who used the same ritualistic action to be more likely to affiliate than people who used different actions. A second study indicated that these results were not due to perceptual similarity: when the differences in the actors' actions were not marked by properties of ritual, but were instead due to situational constraints, infants expected the actors to affiliate. Thus, infants understand the social significance of people engaging in common, potentially ritualistic actions, and expect these actions to provide information about third party social relationships. PMID- 29107889 TI - Full interpretation of minimal images. AB - The goal in this work is to model the process of 'full interpretation' of object images, which is the ability to identify and localize all semantic features and parts that are recognized by human observers. The task is approached by dividing the interpretation of the complete object to the interpretation of multiple reduced but interpretable local regions. In such reduced regions, interpretation is simpler, since the number of semantic components is small, and the variability of possible configurations is low. We model the interpretation process by identifying primitive components and relations that play a useful role in local interpretation by humans. To identify useful components and relations used in the interpretation process, we consider the interpretation of 'minimal configurations': these are reduced local regions, which are minimal in the sense that further reduction renders them unrecognizable and uninterpretable. We show that such minimal interpretable images have useful properties, which we use to identify informative features and relations used for full interpretation. We describe our interpretation model, and show results of detailed interpretations of minimal configurations, produced automatically by the model. Finally, we discuss possible extensions and implications of full interpretation to difficult visual tasks, such as recognizing social interactions, which are beyond the scope of current models of visual recognition. PMID- 29107890 TI - Potentially inappropriate prescribing according to STOPP-2 criteria among patients discharged from Internal Medicine: prevalence, involved drugs and economic cost. AB - AIM: This study aims to determine the prevalence of potentially inappropriate prescribing (PIP) among patients discharged from Internal Medicine, the drugs and factors associated and economic cost of PIP. METHODS: This retrospective cross sectional, single-center study included participants aged >=65 years consecutively discharged from the Internal Medicine Unit in a tertiary hospital of Southern Spain. PIP was defined by the Screening Tool for Older Persons Prescriptions (STOPP-2) criteria version 2 (2015 update). The association of PIP with chronic conditions was analyzed using multilevel logistic regression model. Data on economic cost associated to PIP were determined according to the computerized prescribing database of Andalusia ("Receta XXI"). RESULTS: Out of the 275 patients studied, a total of 249 PIPs were detected in 114 (41.5%) patients of whom 79 (28.7%) had one or two STOPP-2 criteria and 35 (12.7%) 3 or more criteria. The most involved drugs were benzodiazepines (45.5%); antithrombotics (14.5%), including anticoagulants or antiplatelets, and opioids (11.4%). The multivariate logistic regression analysis identified polypharmacy (OR=11.00; 95% CI 1.41-85.52) and extreme polypharmacy (OR=26.25; 95% CI 3.34 206.07) as independent risk factors for PIP. The mean cost of PIP was ?18.75+/ 4.24 per patient and month. Opioids accounted for the highest percentage expenditure of PIP (39.02%), followed by inhaled bronchodilator drugs (30.30%), antithrombotics (12.20%) and benzodiazepines (7.92%). CONCLUSIONS: PIP is frequent among patients discharged from Internal Medicine. The number of prescribed drugs was independently associated to PIP and benzodiazepines were the most involved drugs. PIP was associated to a significant economic cost. PMID- 29107891 TI - Elevated blood pressure and household solid fuel use in premenopausal women: Analysis of 12 Demographic and Health Surveys (DHS) from 10 countries. AB - BACKGROUND: Approximately three billion people are exposed to household air pollution (HAP) from solid fuel cookstoves. Studies from single settings have linked HAP with elevated blood pressure (BP), but no evidence exists from multi country analyses. OBJECTIVES: Using nationally representative and internationally comparable data, we examined the association between solid fuel use and BP in 77,605 largely premenopausal women (aged 15-49) from ten resource-poor countries. METHODS: We obtained data on systolic and diastolic BP, self-reported primary cooking fuel, health and socio-demographic characteristics from 12 Demographic and Health Surveys conducted in Albania, Armenia, Azerbaijan, Bangladesh, Benin, Ghana, Kyrgyzstan, Lesotho, Namibia, and Peru. We estimated associations between history of fuel use [solid fuel (coal or biomass) versus clean fuel (electricity or gas)] with systolic and diastolic BP and hypertension using a meta-analytical approach. RESULTS: Overall, the country-level mean systolic and diastolic BP were 117 (range: 111-127) and 74 (71-83) mmHg, respectively. The country-level mean age of the women was 30.8 years (range: 28.4-32.9). The prevalence of solid fuel use was 46.0% (range: 4.1-95.8). In adjusted, pooled analyses, primary use of solid fuel was associated with 0.58mmHg higher systolic BP (95% CI: 0.23, 0.93) as compared to primary use of clean fuel. The pooled estimates for diastolic BP and pulse pressure were also positive, but the confidence intervals contained zero. The pooled odds of hypertension was [OR = 1.07 (95% CI: 0.99, 1.16)], an effect that was driven by rural participants for whom solid fuel use was associated with a 16% greater odds of hypertension [OR = 1.16 (95% CI: 1.01, 1.35)]. CONCLUSIONS: Cooking with solid fuels was associated with small increases in BP and odds of hypertension. Use of cleaner fuels like gas or electricity may reduce cardiovascular risk in developing countries, particularly among rural residents. PMID- 29107892 TI - Implementation of deinstitutionalization of child care institutions in post soviet countries: The case of Azerbaijan. AB - Institutional care has proven to be detrimental for child development. This study examined the status of the State Program on Deinstitutionalization and Alternative Care (SPDAC), a public policy aimed at transforming 55 institutions covering 14,500 children during 2006-2016 in Azerbaijan. The success of this public policy was crucial for the country's entire child welfare system. The study used a crosssectional, descriptive, exploratory, and qualitative method. Data were collected through in-depth, semistructured interviews and archival resources. Twenty key informants were selected through a purposive sampling strategy. They led projects or were heads of departments related to implementing the SPDAC at government agencies, national or international nongovernmental organizations, UNICEF, or as social workers in newly established alternative services. Interviews were analyzed in TAMSAnalyzer. Themes supporting possible explanations such as lack of political will, weak child protection systems, weak civil society, illequipped human resources, absence of alternative services, and low levels of knowledge of children's rights emerged in the analysis. The findings could contribute to research on child welfare reform and reflect hidden factors behind policies to guide practice in former Soviet Union states and countries rich in natural resources such oil, gas, and minerals. The primary finding of a lack of political will raises the question of how to create political will and how to motivate government officials to invest in the welfare of children. PMID- 29107893 TI - Lung regeneration after toxic injury is improved in absence of dioxin receptor. AB - Recent experimental evidences from cellular systems and from mammalian and non mammalian animal models highlight novel functions for the aryl hydrocarbon/dioxin receptor (AhR) in maintaining cell differentiation and tissue homeostasis. Notably, AhR depletion stimulates an undifferentiated and pluripotent phenotype likely associated to a mesenchymal transition in epithelial cells and to increased primary tumorigenesis and metastasis in melanoma. In this work, we have used a lung model of epithelial regeneration to investigate whether AhR regulates proper tissue repair by adjusting the expansion of undifferentiated stem-like cells. AhR-null mice developed a faster and more efficient repair of the lung bronchiolar epithelium upon naphthalene injury that required increased cell proliferation and the earlier activation of stem-like Clara, Basal and neuroepithelial cells precursors. Increased basal content in multipotent Sca1+/CD31-/CD4- cells and in cells expressing pluripotency factors NANOG and OCT4 could also improve re-epithelialization in AhR-null lungs. The reduced response of AhR-deficient lungs to Sonic Hedgehog (Shh) repression shortly after injury may also help their improved bronchiolar epithelium repair. These results support a role for AhR in the regenerative response against toxins, and open the possibility of modulating its activation level to favor recovery from lesions caused by environmental contaminants. PMID- 29107894 TI - Web-based accurate measurements of carotid lumen diameter and stenosis severity: An ultrasound-based clinical tool for stroke risk assessment during multicenter clinical trials. AB - BACKGROUND: This pilot study presents a completely automated, novel, smart, cloud based, point-of-care system for (a) carotid lumen diameter (LD); (b) stenosis severity index (SSI) and (c) total lumen area (TLA) measurement using B-mode ultrasound. The proposed system was (i) validated against manual reading taken by the Neurologist and (ii) benchmarked against the commercially available system. METHOD: One hundred patients (73 M/27 F, mean age: 68 +/- 11 years), institutional review board approved, written informed consent, consisted of left/right common carotid artery (200 ultrasound scans) were acquired using a 7.5 MHz linear transducer. RESULTS: The measured mean LD for left and right carotids were (in mm): (i) for proposed system (6.49 +/- 1.77, 6.66 +/- 1.70); and (ii) for manual (6.29 +/- 1.79, 6.45 +/- 1.63), respectively and coefficient of correlation between cloud-based automated against manual were 0.98 (P < 0.0001) and 0.99 (P < 0.0001), respectively. The corresponding TLA error, Precision-of Merit, and Figure-of-Merit when measured against the manual were: 4.56 +/- 3.54%, 96.18 +/- 3.21%, and 96.85%, respectively. The AUC for the receiving operating characteristics for the cloud-based system was: 1.0. Four statistical tests such as: Two-tailed z-test, Mann-Whitney test, Kolmogorov-Smirnov (KS) and one-way ANOVA were performed to demonstrate consistency and reliability. CONCLUSIONS: The proposed system is reliable, accurate, fast, completely automated, anytime anywhere solution for multi-center clinical trials and routine vascular screening. PMID- 29107895 TI - Evaluating the protective effect of etazolate on memory impairment, anxiety- and depression-like behaviors induced by post traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that develops after an individual experiences severe life-threatening traumatic stress. Etazolate is a selective phosphodiesterase-4 inhibitor that is specific for cAMP. Etazolate showed anxiolytic and antidepressant activity, and could be useful in managing PTSD co-morbidities. The current study was done to evaluate the role of etazolate in preventing PTSD induced memory impairment, anxiety and depression-like symptoms. PTSD was induced in rats using single prolonged stress model. Etazolate was administered via oral gavage at a dose of 1mg/kg/day. The radial arm water maze was used to assess learning and memory. The elevated plus maze, open field, and tail suspension tests were conducted to test anxiety- and depression-like symptoms. The PTSD was associated with short- and long-term memory impairment, which was prevented by etazolate administration. Moreover, PTSD was associated with symptoms of anxiety and depression. Etazolate administration prevented these symptoms. In conclusion, our data suggests that memory impairment, anxiety, and depression symptoms that are induced by PTSD can be prevented using etazolate. PMID- 29107897 TI - Infection by bacteriophage lambda: an evolving paradigm for cellular individuality. AB - Since the earliest days of molecular biology, bacteriophage lambda has served to illuminate cellular function. Among its many roles, lambda infection is a paradigm for phenotypic heterogeneity among genetically identical cells. Early studies attributed this cellular individuality to random biochemical fluctuations, or 'noise'. More recently, however, attention has turned to the role played by deterministic hidden variables in driving single-cell behavior. Here, I briefly describe how studies in lambda are driving the shift in our understanding of cellular heterogeneity, allowing us to better appreciate the precision at which cells function. PMID- 29107898 TI - Negative effects of microplastic exposure on growth and development of Crepidula onyx. AB - Microplastics exposure could be detrimental to marine organisms especially under high concentrations. However, few studies have considered the multiphasic nature of marine invertebrates' life history and investigated the impact of experiencing microplastics during early development on post-metamorphic stages (legacy effect). Many planktonic larvae can feed selectively and it is unclear whether such selectivity could modulate the impact of algal food-sized microplastic. In this two-stage experiment, veligers of Crepidula onyx were first exposed to additions of algae-sized micro-polystyrene (micro-PS) beads at different concentrations, including ones that were comparable their algal diet. These additions were then either halted or continued after settlement. At environmentally relevant concentration (ten 2-MUm microplastic beads ml-1), larval and juvenile C. onyx was not affected. At higher concentrations, these micro-PS fed larvae consumed a similar amount of algae compared to those in control but grew relatively slower than those in the control suggesting that ingestion and/or removal of microplastic was/were energetically costly. These larvae also settled earlier at a smaller size compared to the control, which could negatively affect post-settlement success. Juvenile C. onyx receiving continuous micro-PS addition had slower growth rates. Individuals only exposed to micro-PS during their larval stage continued to have slower growth rates than those in the control even if micro-PS had been absent in their surroundings for 65 days highlighting a legacy effect of microplastic exposure. PMID- 29107896 TI - CryoEM-based hybrid modeling approaches for structure determination. AB - Recent advances in cryo-electron microscopy (cryoEM) have dramatically improved the resolutions at which vitrified biological specimens can be studied, revealing new structural and mechanistic insights over a broad range of spatial scales. Bolstered by these advances, much effort has been directed toward the development of hybrid modeling methodologies for the construction and refinement of high fidelity atomistic models from cryoEM data. In this brief review, we will survey the key elements of cryoEM-based hybrid modeling, providing an overview of available computational tools and strategies as well as several recent applications. PMID- 29107899 TI - Role of microRNAs in senescence and its contribution to peripheral neuropathy in the arsenic exposed population of West Bengal, India. AB - Arsenic induced senescence (AIS) has been identified in the population of West Bengal, India very recently. Also there is a high incidence of arsenic induced peripheral neuropathy (PN) throughout India. However, the epigenetic regulation of AIS and its contribution in arsenic induced PN remains unexplored. We recruited seventy two arsenic exposed and forty unexposed individuals from West Bengal to evaluate the role of senescence associated miRNAs (SA-miRs) in AIS and their involvement if any, in PN. The downstream molecules of the miRNA associated with the disease outcome, was also checked by immuoblotting. In vitro studies were conducted with HEK 293 cells and sodium arsenite exposure. Our results show that all the SA-miRs were upregulated in comparison to unexposed controls. miR 29a was the most significantly altered, highest expression being in the arsenic exposed group with PN, suggesting its association with the occurrence of PN. We looked for the expression of peripheral myelin protein 22 (PMP22), a specific target of miR-29a associated with myelination and found that both in vitro and in vivo results showed over-expression of the protein. Since this was quite contrary to miRNA regulation, we checked for intermediate players beta-catenin and GSK 3beta upon arsenic exposure which affects PMP22 expression. We found that beta catenin was upregulated in vitro and was also highest in the arsenic exposed group with PN while GSK-3beta followed the reverse pattern. Our findings suggest that arsenic exposure alters the expression of SA-miRs and the mir-29a/beta catenin/PMP22 axis might be responsible for arsenic induced PN. PMID- 29107900 TI - Hydroxylated and methoxylated polybrominated diphenyl ethers in a marine food web of Chinese Bohai Sea and their human dietary exposure. AB - Hydroxylated (OH-) and methoxylated (MeO-) polybrominated diphenyl ethers (PBDEs) have been identified ubiquitous in wildlife and environment. However, understanding on their trophic accumulation and human exposure was hitherto limited. In this study, the occurrences and trophic behaviors were demonstrated for OH- and MeO-PBDEs using the biota samples collected from Dalian, a coastal city near Chinese Bohai Sea. ?OH-PBDEs exhibited a wider concentration range (=20 degrees C, TOC removal increased from 10% to 17% (median). This review demonstrates biofiltration can be an efficient treatment technology to remove a portion of the BOM from the filter influent and should be optimized to achieve maximum removal. PMID- 29107909 TI - Human health tradeoffs in wellhead drinking water treatment: Comparing exposure reduction to embedded life cycle risks. AB - Treatment of drinking water decreases human health risks by reducing pollutants, but the required materials, chemicals, and energy emit pollutants and increase health risks. We explored human carcinogenic and non-carcinogenic disease tradeoffs of water treatment by comparing pollutant dose-response curves against life cycle burden using USEtox methodology. An illustrative wellhead sorbent groundwater treatment system removing hexavalent chromium or pentavalent arsenic serving 3200 people was studied. Reducing pollutant concentrations in drinking water from 20 MUg L-1 to 10 MUg L-1 avoided 37 potential cancer cases and 64 potential non-cancer disease cases. Human carcinogenicity embedded in treatment was 0.2-5.3 cases, and non-carcinogenic toxicity was 0.2-14.3 cases, depending on technology and degree of treatment. Embedded toxicity impacts from treating Cr(VI) using strong-base anion exchange were <10% of those from using weak base anion exchange. Acidification and neutralization contributed >90% of the toxicity impacts for treatment options requiring pH control. In scenarios where benefits exceeded burdens, tradeoffs still existed. Benefits are experienced by a local population but burdens are born externally where the materials and energy are produced, thus exporting the health risks. Even when burdens clearly exceeded benefits, cost considerations may still drive selecting a detrimental treatment level or technology. PMID- 29107910 TI - Polyhydroxyalkanoates (PHA) production from fermented crude glycerol: Study on the conversion of 1,3-propanediol to PHA in mixed microbial consortia. AB - Crude glycerol, a by-product from the biodiesel industry, can be converted by mixed microbial consortia into 1,3-propanediol (1,3-PDO) and volatile fatty acids. In this study, further conversion of these main products into polyhydroxyalkanoates (PHA) was investigated with the focus on 1,3-PDO. Two different approaches for the enrichment of PHA accumulating microbial consortia using an aerobic dynamic feeding strategy were applied. With the first approach, where nitrogen was present during the whole cycle, no net production of PHA from 1,3-PDO was observed in the fermented effluent, not even in a nitrogen-limited PHA accumulation assay. Nevertheless, experiments in synthetic substrates revealed that the conversion of 1,3-PDO to PHA was possible under nitrogen limiting conditions. Thus, a different enrichment strategy was formulated where nitrogen was limited during the feast phase to stimulate the storage response. Nitrogen was still supplied during the famine phase. With the latter strategy, a net production of PHA from 1,3-PDO was observed at a yield of 0.24 Cmol PHA/Cmol 1,3-PDO. The overall yield from the fermented effluent was 0.42 Cmol PHA/Cmol substrate. Overall, the PHA yield from 1,3-PDO seemed to be limited, similarly to when using glycerol as a substrate, by a decarboxylation step and accumulation of other storage polymers such as glycogen, and possibly, lipid inclusions. PMID- 29107911 TI - Dairy farm wastewater treatment and lipid accumulation by Arthrospira platensis. AB - Dairy cattle treated wastewaters are potential resources for production of microalgae biofuels. A study was conducted to evaluate the capability of Arthrospira platensis cultivated in dairy farm wastewater for biodiesel production. The biomass of Arthrospira platensis was found to be 4.98 g L-1 and produced 30.23 wt% lipids to dry biomass cultivated in wastewater which was found nitrogen stressed in photo bioreactor. The extracted lipid displayed a suitable fatty acid profile for biodiesel, although the content of linolenic acid was found a little higher than the standard EN14214. It was found that nitrogen stressed medium increase the total lipid content but temperature and intensities of light were the most important factors to control the quantity of linolenic acid and hence the quality of biodiesel, while the optimum CO2 helped to achieve maximum biomass and triacylglycerols. The Arthrospira platensis offer a good option for the treatment of wastewater before final discharge. PMID- 29107912 TI - Metagenomic characterization of biofilter microbial communities in a full-scale drinking water treatment plant. AB - Microorganisms inhabiting filtration media of a drinking water treatment plant can be beneficial, because they metabolize biodegradable organic matter from source waters and those formed during disinfection processes, leading to the production of biologically stable drinking water. However, which microbial consortia colonize filters and what metabolic capacity they possess remain to be investigated. To gain insights into these issues, we performed metagenome sequencing and analysis of microbial communities in three different filters of a full-scale drinking water treatment plant (DWTP). Filter communities were sampled from a rapid sand filter (RSF), granular activated carbon filter (GAC), and slow sand filter (SSF), and from the Schmutzdecke (SCM, a biologically active scum layer accumulated on top of SSF), respectively. Analysis of community phylogenetic structure revealed that the filter bacterial communities significantly differed from those in the source water and final effluent communities, respectively. Network analysis identified a filter-specific colonization pattern of bacterial groups. Bradyrhizobiaceae were abundant in GAC, whereas Nitrospira were enriched in the sand-associated filters (RSF, SCM, and SSF). The GAC community was enriched with functions associated with aromatics degradation, many of which were encoded by Rhizobiales (~30% of the total GAC community). Predicting minimum generation time (MGT) of prokaryotic communities suggested that the GAC community potentially select fast-growers (<15 h of MGT) among the four filter communities, consistent with the highest dissolved organic matter removal rate by GAC. Our findings provide new insights into the community phylogenetic structure, colonization pattern, and metabolic capacity that potentially contributes to organic matter removal achieved in the biofiltration stages of the full-scale DWTP. PMID- 29107913 TI - Direct potable reuse microbial risk assessment methodology: Sensitivity analysis and application to State log credit allocations. AB - Understanding pathogen risks is a critically important consideration in the design of water treatment, particularly for potable reuse projects. As an extension to our published microbial risk assessment methodology to estimate infection risks associated with Direct Potable Reuse (DPR) treatment train unit process combinations, herein, we (1) provide an updated compilation of pathogen density data in raw wastewater and dose-response models; (2) conduct a series of sensitivity analyses to consider potential risk implications using updated data; (3) evaluate the risks associated with log credit allocations in the United States; and (4) identify reference pathogen reductions needed to consistently meet currently applied benchmark risk levels. Sensitivity analyses illustrated changes in cumulative annual risks estimates, the significance of which depends on the pathogen group driving the risk for a given treatment train. For example, updates to norovirus (NoV) raw wastewater values and use of a NoV dose-response approach, capturing the full range of uncertainty, increased risks associated with one of the treatment trains evaluated, but not the other. Additionally, compared to traditional log-credit allocation approaches, our results indicate that the risk methodology provides more nuanced information about how consistently public health benchmarks are achieved. Our results indicate that viruses need to be reduced by 14 logs or more to consistently achieve currently applied benchmark levels of protection associated with DPR. The refined methodology, updated model inputs, and log credit allocation comparisons will be useful to regulators considering DPR projects and design engineers as they consider which unit treatment processes should be employed for particular projects. PMID- 29107914 TI - Fast anaerobic sludge granulation at elevated salinity. AB - It is commonly accepted that high salt concentrations negatively affect microbial activity in biological wastewater treatment reactors such as upflow anaerobic sludge blanket (UASB) reactors. Microbial aggregation in such reactors is equally important. It is well documented that anaerobic granules, when exposed to high salinity become weak and disintegrate, causing wash-out, operational problems and decreasing process performance. In this research, the possibility of microbial granule formation from dispersed biomass was investigated at salinity levels of 5 and 20 g Na+/L. High removal efficiencies of soluble influent organics were achieved at both salinity levels and this was accompanied by fast and robust formation of microbial granules. The process was found to be stable for the entire operational period of 217 days. As far as we know this is the first time it has been demonstrated that stable granule formation is possible at a salinity level as high as 20 g Na+/L. Methanosaeta was identified as the dominant methanogen at both salinity levels. Streptococcus spp. and bacteria belonging to the family Lachnospiraceae were identified as the dominant microbial population at 5 and 20 and g Na+/L, respectively. PMID- 29107915 TI - Predicting influent biochemical oxygen demand: Balancing energy demand and risk management. AB - Ready access to comprehensive influent information can help water reclamation plant (WRP) operators implement better real-time process controls, provide operational reliability and reduce energy consumption. The five-day biochemical oxygen demand (BOD5), a critical parameter for WRP process control, is expensive and difficult to measure using hard-sensors. An alternative approach based on a soft-sensor methodology shows promise, but can be problematic when used to predict high BOD5 values. Underestimating high BOD5 concentrations for process control could result in an insufficient amount of aeration, increasing the risk of an effluent violation. To address this issue, we tested a hierarchical hybrid soft-sensor approach involving multiple linear regression, artificial neural networks (ANN), and compromise programming. While this hybrid approach results in a slight decrease in overall prediction accuracy relative to the approach based on ANN only, the underestimation percentage is substantially lower (37% vs. 61%) for predictions of carbonaceous BOD5 (CBOD5) concentrations higher than the long term average value. The hybrid approach is also flexible and can be adjusted depending on the relative importance between energy savings and managing the risk of an effluent violation. PMID- 29107916 TI - Faradaic reactions in capacitive deionization (CDI) - problems and possibilities: A review. AB - Capacitive deionization (CDI) is considered to be one of the most promising technologies for the desalination of brackish water with low to medium salinity. In practical applications, Faradaic redox reactions occurring in CDI may have both negative and positive effects on CDI performance. In this review, we present an overview of the types and mechanisms of Faradaic reactions in CDI systems including anodic oxidation of carbon electrodes, cathodic reduction of oxygen and Faradaic ion storage and identify their apparent negative and positive effects on water desalination. A variety of strategies including development of novel electrode materials and use of alternative configurations and/or operational modes are proposed for the purpose of mitigation or elimination of the deterioration of electrodes and the formation of byproducts caused by undesired side Faradaic reactions. It is also recognized that Faradaic reactions facilitate a variety of exciting new applications including i) the incorporation of intercalation electrodes to enhance water desalination or to selectively separate certain ions through reversible Faradaic reactions and ii) the use of particular anodic oxidation and cathodic reduction reactions to realize functions such as water disinfection and contaminant removal. PMID- 29107917 TI - Differential effects of graphene oxide nanosheets on Candida albicans phagocytosis by murine peritoneal macrophages. AB - Macrophages, as effector cells involved in the innate and adaptive immunity, play a key role in the response to nanomaterials as graphene oxide (GO) and in their cellular uptake. The interactions at the interface of GO nanosheets, macrophages and microbial pathogens need to be assessed to determine the possible impairment of the immune system induced by biomedical treatments with this nanomaterial. Here, we have evaluated by flow cytometry and confocal microscopy the ability of murine peritoneal macrophages to phagocytose the fungal pathogen Candida albicans, alive or heat-killed, after treatment with poly(ethylene glycol-amine) derivatized GO nanosheets (PEG-GO). After GO treatment, differences in fungal phagocytosis were observed between macrophages that had taken up GO nanosheets (GO+ population) and those that had not (GO- population). GO treatment increased the ingested alive yeasts in GO- macrophages, whereas phagocytosis diminished in the GO+ population. Ingestion of heat-killed yeasts was slightly higher in both GO- and GO+ populations when comparing with control macrophages. For the first time, we show that GO uptake by macrophages modulates its phagocytic capability, affecting differentially the subsequent ingestion of either alive or heat-killed yeasts. Enhanced ingestion of heat-killed yeast by GO-treated macrophages suggests a beneficial role of this nanomaterial for the clearance of dead microorganisms during infection. PMID- 29107918 TI - Nanostructured superhydrophobic polysiloxane coating for high barrier and anticorrosion applications in marine environment. AB - The use of epoxy and polyurethane coatings as marine topcoats, have been influenced by their inherent high surface energy property which increases their affinity to water and microorganisms. Thus, their susceptibility to degradation is enhanced. Because of this defect, recently, nanostructured hydrophobic and superhydrophobic polysiloxane coatings are being preferred as topcoats. But the appropriate nanoparticle size and matrix:filler ratio which provide guide for the design of desired topcoats are scarcely available. In view of this, a series of hydrophobic and superhydrophobic coatings were prepared by sol-gel process based on perfluorodecyltrichlorosilane (FDTS), different nanoZnO particles and poly(dimethylsiloxane) (PDMS):nanoZnO ratios. The liquid repellency, surface morphology and roughness of the coatings were conducted by use of contact angle goniometer, field emission scanning electron microscopy and atomic force microscopy, respectively. Additionally, the electrochemical and salt spray corrosion tests were conducted. According to the results, modifications of the coatings showed that anticorrosion performance was considerably influenced by the surface properties which were dependent on nanoZnO size and PDMS:nanoZnO ratio. Remarkably, the optimum effect was observed on the superhydrophobic coating based on 30 nm ZnO and 1:1 ratio. This displayed highest anticorrosion performance, and is therefore recommended as a guide for the design of marine topcoats. PMID- 29107919 TI - Synthesis and characterization of alginate beads encapsulated zinc oxide nanoparticles for bacteria disinfection in water. AB - The use of polymer nanocomposites as novel materials for water remediation has emerged as a promising alternative for disinfection of bacteria contaminated water. Sodium alginate, a natural biopolymer has been investigated in this study by encapsulating antimicrobial zinc oxide nanoparticles supported bentonite. The confirmation of the alginate nanocomposites was done by use of TEM, SEM-EDS and XRD. The antimicrobial activity of the alginate nanocomposites was investigated by batch studies using surface water and synthetic bacteria contaminated water containing Staphylococcus aureus. The effect of nanocomposite amount and initial bacteria concentration has been studied. The inactivation results indicated that the nanocomposite effectively inactivated bacteria in both the synthetic and surface water. With an amount of 0.5 g of the nanocomposites, no bacteria was observed in the water after 70 min of contact time with initial bacteria concentration of 200 cfu/ml for synthetic water and within a min, no bacteria was observed in the water for surface water. It is worth noting that 200 cfu/ml is the bacteria concentration range in which environmental water is likely to contain. Therefore, the results of this study have indicated that the alginate nanocomposites can be deemed as a potential antimicrobial agent for water disinfection. PMID- 29107920 TI - Enhanced photocatalytic activity of graphitic carbon nitride/carbon nanotube/Bi2WO6 ternary Z-scheme heterojunction with carbon nanotube as efficient electron mediator. AB - All-solid-state Z-scheme heterojunction has attracted much attention in photocatalytic field because of its strong ability in charge separation and transfer. In the present study, all-solid-state ternary Z-scheme heterojunction constructed by graphitic carbon nitride (CN) nanosheet, carbon nanotube (CNT), and Bi2WO6 (BWO) nanosheet, in which CNT was employed as the electron mediator. The CN/CNT/BWO ternary Z-scheme heterojunction shows the enhanced photocatalytic activity towards the degradation of tetracycline hydrochloride (TC) as compared to the pristine g-C3N4, Bi2WO6, CNT/BWO, CNT/CN, and CN/BWO. The significantly improved photocatalytic activity can be mainly ascribed to the formed CNT mediated Z-scheme heterojunction, which facilitates the separation and transfer of photogenerated electron-hole pairs. Our work provides a rational design of all solid-state Z-scheme heterojunction with CNT as the electron mediator for highly efficient photocatalysis. PMID- 29107921 TI - Cu(I)/Cu(II) mixed-valence surface complexes of S-[(2-hydroxyamino)-2-oxoethyl] N,N-dibutyldithiocarbamate: Hydrophobic mechanism to malachite flotation. AB - HYPOTHESIS: Hydroxamate and sulfhydryl surfactants are effective collectors for flotation of copper minerals. The combination application of hydroxamate and sulfhydryl collectors has been proved to be an effective approach for improving the flotation recovery of non-sulfide copper minerals. A surfactant owing both hydroxamate and dithiocarbamate groups might exhibit strong affinity to non sulfide copper minerals through double sites adsorption, rendering an enhanced hydrophobization to non-sulfide copper minerals flotation. EXPERIMENTS: The flotation performance of S-[(2-hydroxyamino)-2-oxoethyl]- N,N dibutyldithiocarbamate (HABTC) to malachite, calcite and quartz were first evaluated through systematic micro-flotation experiments. HABTC's hydrophobic mechanism to malachite was further investigated and analyzed by zeta potential, Fourier transform infrared spectroscopy (FTIR), time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS). FINDINGS: The micro-flotation results demonstrated HABTC was an excellent collector for malachite flotation and exhibited favorable selectivity for flotation separation of malachite from quartz or calcite under pH 8.5-10.3. Zeta potential and FTIR implied that HABTC might bond with the surface copper atoms of malachite, with releasing the H+ ions of its hydroxamate group into pulp. ToF-SIMS provided clear evidences that the Cu-hydroxamate and Cu-dithiocarbamate groups were formed on malachite surfaces after HABTC adsorption. XPS revealed that Cu(I)/Cu(II) mixed valence surface complexes of HABTC anchored on malachite through formation of Cu(I)S and Cu(II)O bonds, accompanying with reduction of partial surface Cu(II) to Cu(I). The Cu(I)/Cu(II) mixed-valence double chelating character and "chair" shape N,N-dibutyldithiocarbamate hydrophobic group, resulting in an enhanced affinity and hydrophobization of HABTC to malachite flotation. PMID- 29107922 TI - Electrospun mulberry-like hierarchical carbon fiber web for high-performance supercapacitors. AB - In this work, we have fabricated a kind of N-doped hierarchal carbon fiber web by electrospinning hollow mesoporous carbon spheres (HMCSs) into fibrous structure. The as-synthesized carbon fiber web with novel mulberry-like morphology, thus denoted as MC-FW, possesses micro/meso/macroporous porosity, large surface area, high conductivity and multi-level structure, which are highly desired for supercapacitor electrode materials. The electrochemical measurements demonstrate that the designed MC-FW shows high capacitance (298.6 F g-1), favorable capacitance retention (71.0%) and long cycle life (97.3% capacitance retention after 5000 cycles). Notably, the capacitance of 298.6 F g-1 for MC-FW is higher than the capacitance reported so far for many hollow carbon spheres and carbon fibers, which may contribute to the synergistic effect between the merits of HMCSs (e.g. micro/meso/macroporous hierarchal structure, large surface area, high pore volume) and advantages of 1D carbon fiber (e.g. large aspect ratio and high conductivity). It is believed that this distinctive carbon fiber web may show promising prospects as advanced energy storage materials and catalyst. PMID- 29107923 TI - Multilayered films made from tannic acid and alkaline phosphatasewith enzymatic activity and electrochemical behavior. AB - Layer-by-layer-deposition of enzymes and polyphenols, like tannic acid may provide a reservoir of antioxidant and antibacterial molecules of controlled thickness and degradability with an additional activity due to the presence of the enzyme. The layer-by-layer deposition of films made from tannic acid and alkaline phosphatase is shown to yield an exponential growth with the number of deposited layer pairs. The films display the electrochemical behavior of tannic acid and the enzymatic activity of alkaline phosphatase. However, it is shown that only the enzyme close to the film-solution interface is active and follows the Michaelis-Menten mechanism. Similarly, only tannic acid close to the electrode-film interface can be oxidized. The enzymatic activity is almost completely lost when the multilayer film is treated with sodium periodate which oxidizes tannic acid even if the solubilized enzyme is not affected by the oxidant. This shows that the formation of covalent bonds between alkaline phosphatase and tannic acid is deleterious for its conformation and activity. PMID- 29107924 TI - Selective adsorption activities toward organic dyes and antibacterial performance of silver-based coordination polymers. AB - Two silver-based coordination polymers, [Ag2(bpy)2(cbda)] (BUC-51) and [Ag3(bpy)3(cpda)].(NO3).9H2O (BUC-52), have been successfully prepared by slow evaporation at room temperature. These coordination polymers exhibited good adsorptive performances toward series organic dyes with sulfonic groups, which could be ascribed to the AgcdotsO interaction between the silver(I) atoms in CPs and the oxygen atoms from sulfonic groups attached to organic dyes. Both BUC-51 and BUC-52 favoured slow release of Ag+ ions resulting into outstanding long-term antibacterial abilities toward Gram-negative bacteria, Escherichia coli (E. coli), which was tested by a minimal inhibition concentration (MIC) benchmark and an inhibition zone testing method. Both scanning electron microscope (SEM) and transmission electron microscope (TEM) images demonstrated that these two Ag based coordination polymers could destroy the bacterial membrane and further cause death. Additionally, the excellent stability in common solvents and good optical stability under UV-visible light facilitated their adsorptive and antibacterial applications. PMID- 29107925 TI - Enhanced nitrogen oxide sensing performance based on tin-doped tungsten oxide nanoplates by a hydrothermal method. AB - The great demand for gas sensors in practical applications has stimulated tremendous attention in this area due to its important significance in real life. A facile synthesis of WO3 nanoplates and their subsequent Sn doping strategy by using a hydrothermal method was investigated to enhance gas sensing performance for NO2 gas, one of the gases toxic to human beings and the environment. Various techniques were used to characterize all the products. The morphology characterizations demonstrated that all the samples exhibited a similar nanoplate structure with or without Sn doping. The gas sensing properties of the sensors based on different doping concentrations (0, 1, 2 and 5wt%) have been systematically investigated. The sensor based on the 2wt% Sn-doped WO3 nanoplates showed the maximum response to NO2 (55-100ppb NO2). Furthermore, the introduction of Sn ions into the sensing materials of WO3 resulted in shorter response and recovery times. This finding could be attributed to the increased number of oxygen vacancies on the surface of the sensing material and the resistance of the gas sensors. The results provide a new doping strategy to fabricate high performance NO2 gas sensors. PMID- 29107926 TI - Comparison in waterborne Cu, Ni and Pb bioaccumulation kinetics between different gammarid species and populations: Natural variability and influence of metal exposure history. AB - Kinetic parameters (uptake from solution and elimination rate constants) of Cu, Ni and Pb bioaccumulation were determined from two Gammarus pulex and three Gammarus fossrum wild populations collected from reference sites throughout France in order to assess the inter-species and the natural inter-population variability of metal bioaccumulation kinetics in that sentinel organism. For that, each population was independently exposed for seven days to either 2.5MUgL 1 Cu (39.3nM), 40MUgL-1 Ni (681nM) or 10MUgL-1 Pb (48.3nM) in laboratory controlled conditions, and then placed in unexposed microcosms for a 7-day depuration period. In the same way, the possible influence of metal exposure history on subsequent metal bioaccumulation kinetics was addressed by collecting wild gammarids from three populations inhabiting stations contaminated either by Cd, Pb or both Pb and Ni (named pre-exposed thereafter). In these pre-exposed organisms, assessment of any changes in metal bioaccumulation kinetics was achieved by comparison with the natural variability of kinetic parameters defined from reference populations. Results showed that in all studied populations (reference and pre-exposed) no significant Cu bioaccumulation was observed at the exposure concentration of 2.5MUgL-1. Concerning the reference populations, no significant differences in Ni and Pb bioaccumulation kinetics between the two species (G. pulex and G. fossarum) was observed allowing us to consider all the five reference populations to determine the inter-population natural variability, which was found to be relatively low (kinetic parameters determined for each population remained within a factor of 2 of the minimum and maximum values). Organisms from the population exhibiting a Pb exposure history presented reduced Ni uptake and elimination rate constants, whereas no influence on Ni kinetic parameters was observed in organisms from the population exhibiting an exposure history to both Ni and Pb. Furthermore Pb bioaccumulation kinetics were unaffected whatever the condition of pre-exposure in natural environment. Finally, these results highlight the complexity of confounding factors, such as metal exposure history, that influence metal bioaccumulation processes and showed that pre-exposure to one metal can cause changes in the bioaccumulation kinetics of other metals. These results also address the question of the underlying mechanisms developed by organisms to cope with metal contamination. PMID- 29107927 TI - Photochemoprotective effect of a fraction of a partially purified extract of Byrsonima crassifolia leaves against UVB-induced oxidative stress in fibroblasts and hairless mice. AB - Ultraviolet B (UVB) irradiation increases the risk of various skin disorders, leading to inflammation and oxidative stress and thereby increasing the risk of skin photoaging and carcinogenesis. The use of photochemoprotectors such as natural products with antioxidant and anti-inflammatory properties represents a strategy for preventing UVB-induced skin damage. We investigated the photochemoprotective effect of a fraction of a partially purified extract of Byrsonima crassifolia leaves (BCF) on fibroblasts and hairless mice exposed to UVB radiation. The mixture of phenolic compounds in BCF prevented the decrease in reduced glutathione (GSH) levels in fibroblast cultures induced by UVB radiation more than some of their individual standards ((+)-catechin (CAT), epigallocatechin gallate and quercetin 3-O-beta-d-glucopyranoside). Prepared gel formulations increased skin antioxidant activity, and BCF components and the CAT standard were retained in the HRS/J hairless mice epidermis 2h after application. Topical treatment with the BCF or CAT formulations (1%) significantly reduced the decrease in GSH levels and decreased myeloperoxidase activity and the secretion of pro-inflammatory cytokines IL-1beta and IL-6 induced by UVB radiation (P<0.05), indicating that both BCF and CAT had anti-inflammatory effects. BCF inhibited UVB-induced metalloproteinase (MMP)-9 secretion/activity, whereas CAT had no effect on MMP-9 activity in the skin of treated animals. These results therefore suggest that BCF can be used as a photochemoprotective agent and antioxidant in the prevention/treatment of inflammation and oxidative stress of the skin induced by UVB radiation. PMID- 29107928 TI - The influence of eye-movements on the development of a movement sequence representation during observational and physical practice. AB - An experiment was conducted to examine the development of a movement sequence representation and the role of eye-movements during observational and physical practice. The task was to reproduce a 1300ms spatial-temporal pattern of a sequence of elbow flexions and extensions. An inter-manual transfer design with a retention and two effector transfer tests (contralateral limb) was used. The mirror transfer test required the same pattern of homologous muscle activation and a sequence of joint angles as experienced during the acquisition phase, and the non-mirror transfer test required the same visual-spatial pattern as performed or observed during acquisition. Participants were randomly assigned to one of four groups differing in eye-movements (free to use their eyes vs. instruction to fixate) and the practice type (observational practice vs. physical practice). The results indicated that permitting to use eye-movements facilitates sequence learning. This advantage was found on both practice types. The results of the transfer tests indicated that participants of the physical practice group who were permitted to use their eyes demonstrated superior transfer performance in the mirror transfer test, while participants in the observational practice group demonstrated better performance on the non-mirror transfer test. These findings indicated that eye-movements enhanced the development of a visual spatial representation during observational practice as well as a motor representation during physical practice. PMID- 29107929 TI - Viral sequences in human cancer. AB - We have developed a virus detection and discovery computational pipeline, Pickaxe, and applied it to NGS databases provided by The Cancer Genome Atlas (TCGA). We analyzed a collection of whole genome (WGS), exome (WXS), and RNA (RNA Seq) sequencing libraries from 3052 participants across 22 different cancers. NGS data from nearly all tumor and normal tissues examined contained contaminating viral sequences. Intensive computational and manual efforts are required to remove these artifacts. We found that several different types of cancers harbored Herpesviruses including EBV, CMV, HHV1, HHV2, HHV6 and HHV7. In addition to the reported associations of Hepatitis B and C virus (HBV & HCV) with liver cancer, and Human papillomaviruses (HPV) with cervical cancer and a subset of head and neck cancers, we found additional cases of HPV integrated in a small number of bladder cancers. Gene expression and mutational profiles suggest that HPV drives tumorigenesis in these cases. PMID- 29107930 TI - Glycan analysis by ion mobility-mass spectrometry and gas-phase spectroscopy. AB - Due to the existence of numerous isomers, the in-depth analysis of glycans represents a major challenge. Currently, the majority of glycans are analysed using mass spectrometry (MS)-based techniques, which can provide information on regioisomers but usually fail to differentiate stereoisomers. A promising approach to overcome this limitation is to implement ion mobility spectrometry (IMS) as an additional gas-phase separation dimension. This review highlights recent developments in which IM-MS was used as a tool for comprehensive glycan analysis or as rapid screening method for glycan feature analysis. Furthermore, we summarize a series of very recent investigations in which gas-phase spectroscopy is applied to study glycans and discuss the potential of the hyphenation between IM-MS and infrared (IR) spectroscopy as a future tool for glycomics and glycoproteomics. PMID- 29107931 TI - The potential of ion mobility-mass spectrometry for non-targeted metabolomics. AB - Non-targeted analysis of metabolites in hypothesis-generating workflows has proven its potential to answer essential questions that arise when dealing with complex biological systems. Nevertheless, tracking changes in perturbed systems via accurate quantification and the identification process itself represent the most critical challenges in these workflows. Recent advances in ion mobility-mass spectrometry have enabled this technique to increase the confidence of metabolite annotation by introducing a complementary conditional molecular descriptor, that is collision cross section. PMID- 29107932 TI - Glycyrrhizin induces reactive oxygen species-dependent apoptosis and cell cycle arrest at G0/G1 in HPV18+ human cervical cancer HeLa cell line. AB - Cervical cancer is the fourth most common cancer among women worldwide and is a major cause of morbidity and mortality. High-risk Human Papilloma Virus (mostly type 16 & 18) infection is the primary risk factor for the development of cervical carcinoma. The quest for strong, safe and cost effective natural antiproliferative agents that could reduce cervical cancer have been focussed now a day. Recently, glycyrrhizin, a triterpene glycoside (saponin) from licorice (Glycyrrhiza glabra Linn.), has been shown to exhibit potent antiproliferative and anticancer properties in a few preliminary studies. However, potential of this compound in cervical cancer has not been elucidated yet. Therefore the objective of this study was to analyze the antiproliferative and apoptotic properties of glycyrrhizin in human cervical cancer HeLa cells. Our results showed that glycyrrhizin exposure significantly reduced the cell viability of HeLa cells with a concomitant increase in nuclear condensation and DNA fragmentation in a dose dependent manner. The intracellular ROS generation assay showed dose-related increment in ROS production induced by glycyrrhizin. Glycyrrhizin also induced apoptosis in cervical cancer cells by exerting mitochondrial depolarization. Cell cycle study showed that glycyrrhizin induced cell cycle arrest in G0/G1 phase of cell cycle in a dose dependent manner. Thus, this study confirms the efficacy of glycyrrhizin in cervical cancer cells which could be an adjunct in the better prevention and management of cervical cancer worldwide. PMID- 29107933 TI - Local administration of calcitonin inhibits alveolar bone loss in an experimental periodontitis in rats. AB - Calcitonin (CTN), a calcium regulatory hormone, promotes calcium diuresis from the kidney and suppresses bone resorption. The objective of this study was to evaluate whether the topical and intermittent application of CTN inhibits alveolar bone resorption using ligature-induced experimental periodontitis in rats. Experimental periodontitis was induced by placing a nylon ligature around maxillary molars of 8-week-old male Wistar rats for 20 days. Thirty-two rats were divided into four groups: basal sham control group, periodontitis group, periodontitis plus 0.2 U CTN (low dose), and periodontitis plus 1.0 U CTN (high dose) group. To investigate the effects of CTN on alveolar bone resorption, CTN was topically injected into the palatal gingivae every 2 days after ligature removal (day 0). Micro-computed tomography (CT) analysis was performed for linear parameter assessment of alveolar bone on day 5 and day 14. Periodontal tissues were examined histo-pathologically to assess the differences among the study groups. Micro-CT images showed that alveolar bone resorption was induced statistically around the molar of ligatured rats on day 5 and day 14. The amount of bone resorption was more severe on day 14 than that on day 5. On day 5, only high-dose CTN treatment significantly suppressed bone resorption. In addition, both doses of CTN significantly suppressed bone resorption on day 14. Histological examination clarified that there were fewer TRAP-positive cells in the CTN treatment groups than in the periodontitis group on day 5. Local administration of CTN decreased alveolar bone resorption by regulating osteoclast activation in rats with periodontitis. PMID- 29107934 TI - The clinical significance and biological function of interferon regulatory factor 1 in cholangiocarcinoma. AB - Interferon regulatory factor 1 (IRF1) has been suggested to act as a tumor suppressor in human cancers. However, the clinical significance and biological function of IRF1 in cholangiocarcinoma is poorly understood. In our results, IRF1 mRNA and protein expressions were decreased in cholangiocarcinoma tissues and cell lines compared with paired normal hepatic tissues and intrahepatic bile duct epithelial cell line. IRF1 protein low-expression was associated with tumor stage, tumor size, vascular invasion and metastasis and served as a poor independent prognostic parameter in cholangiocarcinoma patients. Up-regulation of IRF1 expression suppressed cholangiocarcinoma cells proliferation, migration and invasion, and blocked cell cycle progression, but has no effect on apoptosis. In conclusion, IRF1 is low-expressed in cholangiocarcinoma tissues and cell lines, and correlated with malignant status and prognosis in cholangiocarcinoma patients. IRF1 served as tumor suppressor in the regulation of cholangiocarcinoma cells proliferation, cell cycle, migration and invasion. PMID- 29107935 TI - Targeting Akt as strategy to kill cancer cells using 3-substituted 5 anilinobenzo[c]isoxazolequinones: A preliminary study. AB - Several new 3-substituted 5-anilinobenzo[c]isoxazolequinones were synthesized from 1,4-benzoquinone and alkyl- or arylcarbaldehydes by a three-step synthetic sequence. The new compounds (3a-h) were tested in vitro in normal human fibroblasts and two cancer cell lines for their cytotoxic activity. The range of IC50 values obtained for the compounds was from 3.4 to 74.2MUM. Five members of the series (3b, 3d, 3e, 3f, 3g) were further selected and evaluated as inhibitors of the Hsp90 chaperoning function taking Akt as example of Hsp90 client proteins. We also evaluated the changes of intracellular levels of GSH and ATP as markers of cellular metabolic status in response to these compounds in T24 cells. One of such isoxazolquinones (3b) decreased the expression of Akt, PARP and Hsp90. Compounds 3b and 3d decreased the amount of ATP but caused no effect on GSH levels. These compounds also activated caspase-3 but an apoptosis-like type of cell death was unlike since PARP protein was not cleaved and caspase activation was substantially lower than its activation induced by staurosporine, a known caspase-3 activator in T24 cells. Taken together, preliminary results led to the discovery of an original lead compound (3b) which can be used as model to obtain new Akt inhibitors. PMID- 29107936 TI - A harpin elicitor induces the expression of a coiled-coil nucleotide binding leucine rich repeat (CC-NB-LRR) defense signaling gene and others functioning during defense to parasitic nematodes. AB - The bacterial effector harpin induces the transcription of the Arabidopsis thaliana NON-RACE SPECIFIC DISEASE RESISTANCE 1/HARPIN INDUCED1 (NDR1/HIN1) coiled-coil nucleotide binding leucine rich repeat (CC-NB-LRR) defense signaling gene. In Glycine max, Gm-NDR1-1 transcripts have been detected within root cells undergoing a natural resistant reaction to parasitism by the syncytium-forming nematode Heterodera glycines, functioning in the defense response. Expressing Gm NDR1-1 in Gossypium hirsutum leads to resistance to Meloidogyne incognita parasitism. In experiments presented here, the heterologous expression of Gm-NDR1 1 in G. hirsutum impairs Rotylenchulus reniformis parasitism. These results are consistent with the hypothesis that Gm-NDR1-1 expression functions broadly in generating a defense response. To examine a possible relationship with harpin, G. max plants topically treated with harpin result in induction of the transcription of Gm-NDR1-1. The result indicates the topical treatment of plants with harpin, itself, may lead to impaired nematode parasitism. Topical harpin treatments are shown to impair G. max parasitism by H. glycines, M. incognita and R. reniformis and G. hirsutum parasitism by M. incognita and R. reniformis. How harpin could function in defense has been examined in experiments showing it also induces transcription of G. max homologs of the proven defense genes ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1), TGA2, galactinol synthase, reticuline oxidase, xyloglucan endotransglycosylase/hydrolase, alpha soluble N-ethylmaleimide-sensitive fusion protein (alpha-SNAP) and serine hydroxymethyltransferase (SHMT). In contrast, other defense genes are not directly transcriptionally activated by harpin. The results indicate harpin induces pathogen associated molecular pattern (PAMP) triggered immunity (PTI) and effector-triggered immunity (ETI) defense processes in the root, activating defense to parasitic nematodes. PMID- 29107937 TI - Avoidance in posttraumatic stress among refugee survivors of violent conflict and atrocities: Testing trans-cultural risk processes and candidate intervention targets. AB - BACKGROUND: A fast-growing population of refugees and survivors of violent conflict and atrocities are at risk for trauma-related mental health problems. Experimental clinical research key to the development of interventions tailored to this population is limited. AIMS: In an experimental psychopathology laboratory paradigm, we tested the expression and function of avoidance in posttraumatic stress (PTS) among a highly traumatized community sample of forcibly displaced refugees seeking asylum. METHOD: We measured behavioral avoidance and emotional reactivity to repeated exposure to threatening stimuli (trauma-, war-, and geographically-relevant natural threat) in 110 Sudanese male asylum seekers (M(SD)age = 32.7(6.5)) recruited from the community in Israel. RESULTS: First, we found evidence of sensitization - traumatized refugees expressed increasing levels of behavioral avoidance and emotional reactivity in response to repeated exposure to threatening stimuli. Second, as predicted, refugees suffering from more severe PTS were more likely to exhibit greater behavioral avoidance and emotional reactivity reflexively or immediately upon exposure to threat stimuli. Finally, as predicted, behavioral avoidance mediated the effect of PTS severity on emotional reactivity to threat exposure. CONCLUSIONS: Findings are consistent with theorizing that avoidance may function as a trans-cultural malleable risk process sub-serving PTS and thereby a promising intervention target among highly traumatized refugees from E. Africa. PMID- 29107938 TI - The mucormycete-host interface. AB - Mucormycosis is a fungal infection with fulminant angioinvasion leading to high morbidity and mortality in susceptible individuals. The major predisposing conditions are uncontrolled diabetes, neutropenia, malignancies, receipt of a transplant and traumatic injury [1]. Over the past decade, mucormycosis has become an emerging fungal infection due to the increase in patient groups presenting with these pre-disposing conditions and our medical advances in diagnosing the infection [2-4]. Yet, we currently lack clinical interventions to treat mucormycosis effectively. This in turn is due to a lack of understanding of mucormycosis pathogenesis. Here, we discuss our current understanding of selected aspects of interactions at the mucormycete-host interface. We will highlight open questions that might guide future research directions for investigations into the pathogenesis of mucormycosis and potential innovative therapeutic approaches. PMID- 29107939 TI - Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating Mapks/Nrf2 Signaling in Doxorubicin-Induced Cardiotoxicity. AB - BACKGROUND Anthracyclines-induced cardiotoxicity has become one of the major restrictions of their clinical applications. Klotho showed cardioprotective effects. This study aimed to investigate the effects and possible mechanisms of klotho on doxorubicin (DOX)-induced cardiotoxicity. MATERIAL AND METHODS Rats and isolated myocytes were exposed to DOX and treated with exogenous klotho. Specific inhibitors and siRNAs silencing MAPKs were also used to treat the animals and/or myocytes. An invasive hemodynamic method was used to determine cardiac functions. Intracellular ROS generation was evaluated by DHE staining. Western blotting was used to determine the phosphorylation levels of JNK, ERK, and p38 MAPKs in plasma extracts and Nrf2 in nuclear extracts. Nuclear translocation of Nrf2 in myocytes was evaluated by immunohistochemistry. Cell apoptosis was evaluated by TUNEL assay and flow cytometry. RESULTS Klotho treatment improved DOX-induced cardiac dysfunction in rats. The DOX-induced ROS accumulation and cardiac apoptosis were attenuated by klotho. Impaired phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also attenuated by klotho treatment. However, the anti-oxidant and anti-apoptotic effects of klotho on DOX-exposed myocardium and myocytes were impaired by both specific inhibitors and siRNAs against MAPKs. Moreover, the recovery effects of klotho on phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also impaired by specific inhibitors and siRNAs against MAPKs. CONCLUSIONS By recovering the activation of MAPKs signaling, klotho improved cardiac function loss which was triggered by DOX-induced ROS mediated cardiac apoptosis. PMID- 29107941 TI - Collective emission of matter-wave jets from driven Bose-Einstein condensates. AB - Scattering is used to probe matter and its interactions in all areas of physics. In ultracold atomic gases, control over pairwise interactions enables us to investigate scattering in quantum many-body systems. Previous experiments on colliding Bose-Einstein condensates have revealed matter-wave interference, haloes of scattered atoms, four-wave mixing and correlations between counter propagating pairs. However, a regime with strong stimulation of spontaneous collisions analogous to superradiance has proved elusive. In this regime, the collisions rapidly produce highly correlated states with macroscopic population. Here we find that runaway stimulated collisions in Bose-Einstein condensates with periodically modulated interaction strength cause the collective emission of matter-wave jets that resemble fireworks. Jets appear only above a threshold modulation amplitude and their correlations are invariant even when the number of ejected atoms grows exponentially. Hence, we show that the structures and atom occupancies of the jets stem from the quantum fluctuations of the condensate. Our findings demonstrate the conditions required for runaway stimulated collisions and reveal the quantum nature of matter-wave emission. PMID- 29107940 TI - Structure of the human MHC-I peptide-loading complex. AB - The peptide-loading complex (PLC) is a transient, multisubunit membrane complex in the endoplasmic reticulum that is essential for establishing a hierarchical immune response. The PLC coordinates peptide translocation into the endoplasmic reticulum with loading and editing of major histocompatibility complex class I (MHC-I) molecules. After final proofreading in the PLC, stable peptide-MHC-I complexes are released to the cell surface to evoke a T-cell response against infected or malignant cells. Sampling of different MHC-I allomorphs requires the precise coordination of seven different subunits in a single macromolecular assembly, including the transporter associated with antigen processing (TAP1 and TAP2, jointly referred to as TAP), the oxidoreductase ERp57, the MHC-I heterodimer, and the chaperones tapasin and calreticulin. The molecular organization of and mechanistic events that take place in the PLC are unknown owing to the heterogeneous composition and intrinsically dynamic nature of the complex. Here, we isolate human PLC from Burkitt's lymphoma cells using an engineered viral inhibitor as bait and determine the structure of native PLC by electron cryo-microscopy. Two endoplasmic reticulum-resident editing modules composed of tapasin, calreticulin, ERp57, and MHC-I are centred around TAP in a pseudo-symmetric orientation. A multivalent chaperone network within and across the editing modules establishes the proofreading function at two lateral binding platforms for MHC-I molecules. The lectin-like domain of calreticulin senses the MHC-I glycan, whereas the P domain reaches over the MHC-I peptide-binding pocket towards ERp57. This arrangement allows tapasin to facilitate peptide editing by clamping MHC-I. The translocation pathway of TAP opens out into a large endoplasmic reticulum lumenal cavity, confined by the membrane entry points of tapasin and MHC-I. Two lateral windows channel the antigenic peptides to MHC-I. Structures of PLC captured at distinct assembly states provide mechanistic insight into the recruitment and release of MHC-I. Our work defines the molecular symbiosis of an ABC transporter and an endoplasmic reticulum chaperone network in MHC-I assembly and provides insight into the onset of the adaptive immune response. PMID- 29107942 TI - Differential expression of microRNAs among cell populations in the regenerating adult mouse olfactory epithelium. AB - Despite a robust capacity for adult neurogenesis in the olfactory epithelium (OE), olfactory sensory losses are common. Identification of mechanisms regulating adult OE neurogenesis is, therefore, of interest. MicroRNAs (miRNAs) are broadly important in regulating vertebrate neurodevelopment, and are required in embryonic olfactory differentiation. We report here that a panel of miRNAs is differentially expressed by either progenitor or progeny cells in the regenerating mouse OE. Progenitor cells were purified from lesioned OE based on c Kit expression, and miRNA expression was assayed in c-Kit (+) and c-Kit (-) cell populations. 28 miRNAs were significantly downregulated by at least 4 fold in the c-Kit (+) fraction, which marks the globose basal progenitor cell population. In addition, 10 miRNAs were upregulated in these basal cells. MiR-486, the most strongly downregulated miRNA identified, was further characterized to verify results. MiR-486 expression was confirmed in the c-Kit (-) OE layers using in situ hybridization. As a functional assay, over-expression of miR-486 in purified c-Kit (+) basal cell cultures resulted in a reduction in neurogenesis, consistent with a possible negative feedback regulatory model. Our data provide new insights regarding miRNA expression and function during adult OE neurogenesis, and identify candidate miRNAs warranting further study. PMID- 29107943 TI - Comparison of diagnostic accuracy of magnetic resonance elastography and Fibroscan for detecting liver fibrosis in chronic hepatitis B patients: A systematic review and meta-analysis. AB - AIM: This systematic review and meta-analysis was carried out to compare the diagnostic accuracy of Magnetic resonance elastography (MRE) and Fibroscan for detecting liver fibrosis in Chronic Hepatitis B (CHB) patients. METHODS: The PubMed, the Cochrane Library, and the Web of science databases were searched for studies that evaluated the diagnostic value of MRE and Fibroscan for liver fibrosis in CHB patients until March 1st 2017. The quality of the included studies was assessed by the revised Quality Assessment for Studies of Diagnostic Accuracy tool (QUADAS-2). Meta-disc 4.1 was used to summary the area under receiver operating characteristics curve (AUROC), sensitivity, specificity, diagnostic odds ratios to assess the accuracy of staging liver fibrosis using MRE and Fibroscan. RESULTS: A total of nine MRE studies with 1470 patients and fifteen Fibroscan studies with 3641 patients were included in this systematic review. The summary AUROC values using MRE and Fibroscan for detecting significant fibrosis, advanced fibrosis and cirrhosis were 0.981 vs. 0.796(p<0.001), 0.972 vs. 0.893(p<0.001), and 0.972 vs. 0.905 (p<0.001). The pooled sensitivity and specificity using MRE for the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis were 92.8% and 93.7%, 89.6% and 93.2%, 89.5% and 92.0%, respectively. The pooled sensitivity and specificity using Fibroscan for the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis were 71.6% and 81.6%, 79.0% and 84.6%, 80.0% and 86.6%, respectively. CONCLUSION: MRE is more accurate than Fibroscan in diagnosing liver fibrosis in CHB patients, especially in diagnosing significant fibrosis and advanced fibrosis. PMID- 29107944 TI - Correction: Utility of abdominal skin plus subcutaneous fat and rectal mucosal biopsy in the diagnosis of AL amyloidosis with renal involvement. AB - [This corrects the article DOI: 10.1371/journal.pone.0185078.]. PMID- 29107945 TI - Neurogenesis in the olfactory bulb induced by paced mating in the female rat is opioid dependent. AB - The possibility to control the rate of sexual stimulation that the female rat receives during a mating encounter (pacing) increases the number of newborn neurons that reach the granular layer of the accessory olfactory bulb (AOB). If females mate repeatedly, the increase in the number of neurons is observed in other regions of the AOB and in the main olfactory bulb (MOB). It has also been shown that paced mating induces a reward state mediated by opioids. There is also evidence that opioids modulate neurogenesis. In the present study, we evaluated whether the opioid receptor antagonist naloxone (NX) could reduce the increase in neurogenesis in the AOB induced by paced mating. Ovariectomized female rats were randomly divided in 5 different groups: 1) Control (not mated) treated with saline, 2) control (not mated) treated with naloxone, 3) females that mated without controlling the sexual interaction (no-pacing), 4) females injected with saline before pacing the sexual interaction and 5) females injected with NX before a paced mating session. We found, as previously described, that paced mating induced a higher number of new cells in the granular layer of the AOB. The administration of NX before paced mating, blocked the increase in the number of newborn cells and prevented these cells from differentiating into neurons. These data suggest that opioid peptides play a fundamental role in the neurogenesis induced by paced mating in female rats. PMID- 29107947 TI - Contributing to the debate on categorising shared sanitation facilities as 'unimproved': An account based on field researchers' observations and householders' opinions in three regions, Tanzania. AB - BACKGROUND: Health risks associated with poor sanitation behaviours continue to be reported mostly from low-income countries (LICs). Reports show that various factors limit many people from accessing and using improved latrines, forcing some to opt for sharing latrines with neighbours, others practicing open defecation. Meanwhile, debate prevails on whether shared latrines should be categorised as unimproved according to WHO/UNICEF-JMP criteria. We contribute to this debate based on results from a study undertaken in three regions, Tanzania. MATERIALS AND METHODS: Data were collected through observations in 1,751 households with latrines, coupled with collection of opinions from heads of such households regarding the latrine-sharing practices. Bivariate and multivariate logistic regression analyses were performed to assess associations between the outcome and possible predictor variables. RESULTS: Of all 1,751 latrines, 14.6% were shared. Among the shared latrines, 74.2% were found being generally clean as compared to 69.2% of the non-shared ones. Comparing the shared and non-shared latrines, the non-shared latrines were significantly less likely to be found with floors built with permanent materials (OR = 0.73, 95% CI: 0.55, 0.98); washable floors (OR = 0.69; 95% CI: 0.51, 0.93); and lockable doors (OR = 0.73; 95% CI: 0.56, 0.95). Shared latrines were less likely to have floors with faecal matter, functional handwashing facilities (HWFs), HWFs with running water, and roofs; albeit the differences in all these scenarios were not statistically significant. Respondents expressed desire for improved latrines, but also did not find it wrong to share latrines if cleanliness was maintained. CONCLUSION: Having an 'improved' latrine remains important as JMP recommends, but based on our study findings, we argue that possessing a non-shared latrine neither guarantees safety to its users nor its categorisation as 'improved'. Instead, the state of the latrine, the construction technology used and the behaviours of the users may be more important. PMID- 29107946 TI - Yeast casein kinase 2 governs morphology, biofilm formation, cell wall integrity, and host cell damage of Candida albicans. AB - The regulatory networks governing morphogenesis of a pleomorphic fungus, Candida albicans are extremely complex and remain to be completely elucidated. This study investigated the function of C. albicans yeast casein kinase 2 (CaYck2p). The yck2Delta/yck2Delta strain displayed constitutive pseudohyphae in both yeast and hyphal growth conditions, and formed enhanced biofilm under non-biofilm inducing condition. This finding was further supported by gene expression analysis of the yck2Delta/yck2Delta strain which showed significant upregulation of UME6, a key transcriptional regulator of hyphal transition and biofilm formation, and cell wall protein genes ALS3, HWP1, and SUN41, all of which are associated with morphogenesis and biofilm architecture. The yck2Delta/yck2Delta strain was hypersensitive to cell wall damaging agents and had increased compensatory chitin deposition in the cell wall accompanied by an upregulation of the expression of the chitin synthase genes, CHS2, CHS3, and CHS8. Absence of CaYck2p also affected fungal-host interaction; the yck2Delta/yck2Delta strain had significantly reduced ability to damage host cells. However, the yck2Delta/yck2Delta strain had wild type susceptibility to cyclosporine and FK506, suggesting that CaYck2p functions independently from the Ca+/calcineurin pathway. Thus, in C. albicans, Yck2p is a multifunctional kinase that governs morphogenesis, biofilm formation, cell wall integrity, and host cell interactions. PMID- 29107948 TI - Assessment of pleural air leakage using digital chest drainage system after surgical pulmonary resection: Comparison of visible alveolar air leakage with the digital value measured by a digital chest drainage system. AB - BACKGROUND: The sensitivity of postoperative pleural air leakage (PAL) after pulmonary resection is evaluated by a simple subjective grading method in clinical practice. A new electronic digital chest drainage evaluation system (DCS) recently became clinically available. This study was designed to evaluate the clinical application of the DCS in monitoring the airflow volume and managing postoperative PAL. METHODS: We prospectively enrolled 25 patients who underwent pulmonary resection. Postoperative PAL was evaluated using both conventional PAL grading based on the physician's visual judgment (analog chest drainage evaluation system [ACS]: Level 0 = no leakage to 4 = continuous leakage) and the DCS. The DCS digital measurement was recorded as the flow volume (ml/min), which was taken once daily from postoperative day 1 to the day of chest drainage tube removal. RESULTS: In total, 45 measurements were performed on 25 patients during the evaluation period. Postoperative PAL was observed in five patients (20.0%) and judged as ACS Level >1. The mean DCS values corresponding to ACS Levels 0, 1, 2, and 3 were 2.42 (0.0-11.3), 48.6 (35.4-67.9), 95.6 (79.7-111.5), and 405.3 (150.3-715.6), respectively. The Spearman correlation test showed a significant positive correlation between the ACS PAL level and DCS flow volume (R = 0.8477, p < 0.001). CONCLUSIONS: A relationship between the visual PAL level by the ACS and the digital value by the DCS was identified in this study. The numeric volume obtained by the DCS has been successful in information-sharing with all staff. The digital PAL value evaluated by the DCS is appropriate, and the use of the DCS is promising in the treatment of postoperative PAL after pulmonary resection. PMID- 29107949 TI - User perception of endocervical sampling: A randomized comparison of endocervical evaluation with the curette vs cytobrush. AB - OBJECTIVES: To evaluate whether the endocervical brush (ECB) is better accepted by patients and health care providers for endocervical evaluation when compared to the endocervical curette (ECC), without a decrease in the quality of sampling. METHODS: Two hundred patients with cervical dysplasia were randomized at the colposcopy clinic of the University Hospital of Geneva into two groups according to technique. Patients and physicians' preference regarding the technique as well as the quality of samples were assessed. ECB samples were analyzed using both cytological (cell block) and histologic analysis, while ECC samples were analyzed using standard histologic analysis. RESULTS: Of the 200 patients, 89 were randomized to ECC, 101 to ECB and 10 were excluded due to incomplete information or cervical stenosis. Physicians preferred ECB against ECC, classifying it more frequently as an easy technique (94.1% vs.61.4%, p<0.001). Physicians more frequently evaluated the ECB as little or not uncomfortable for patients (28.7% vs.10.2%, p<0.001), though patients themselves didn't express a preference for either technique. From a quality standpoint, the brush allowed for a better quality of samples, with a lower rate of inadequate samples (2.0% vs 14.3%, p = 0.002) and greater amount of material. CONCLUSION: Endocervical sampling using ECB seems to be easier to perform and provides better quality samples. ECB can therefore be an acceptable alternative to ECC in standard practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT01435590. PMID- 29107950 TI - A new method to determine cortical bone thickness in CT images using a hybrid approach of parametric profile representation and local adaptive thresholds: Accuracy results. AB - MOTIVATION: Cortical bone is an important contributor to bone strength and is pivotal to understand the etiology of osteoporotic fractures and the specific mechanisms of antiosteoporotic treatment regimen. 3D computed tomography (CT) can be used to measure cortical thickness, density, and mass in the proximal femur, lumbar vertebrae, and distal forearm. However, the spatial resolution of clinical whole body CT scanners is limited by radiation exposure; partial volume artefacts severely impair the accurate assessment of cortical parameters, in particular in locations where the cortex is thin such as in the lumbar vertebral bodies or in the femoral neck. METHOD: Model-based deconvolution approaches recover the cortical thickness by numerically deconvolving the image along 1D profiles using an estimated scanner point spread function (PSF) and a hypothesized uniform cortical bone mineral density (reference density). In this work we provide a new essentially analytical unique solution to the model-based cortex recovery problem using few characteristics of the measured profile and thus eliminate the non linear optimization step for deconvolution. Also, the proposed approach allows to get rid of the PSF in the model and reduces sensitivity to errors in the reference density. Additionally, run-time and memory effective computation of cortical thickness was achieved with the help of a lookup table. RESULTS: The method accuracy and robustness was validated and compared to that of a deconvolution approach recently proposed for cortical bone and of the 50% relative threshold technique: in a simulated environment with noise and various error levels in the reference density and using CT acquisitions of the European Forearm Phantom (EFP II), a modification of a widely used anthropomorphic standard of cortical and trabecular bone compartments that was scanned with various scan protocols. CONCLUSION: Results of simulations and of phantom data analysis verified the following properties of the new method: 1) Robustness against errors in the reference density. 2) Excellent accuracy on ground truth data with various noise levels. 3) Very fast computation using a lookup table. PMID- 29107951 TI - The effect of tranexamic acid on blood loss and maternal outcome in the treatment of persistent postpartum hemorrhage: A nationwide retrospective cohort study. AB - BACKGROUND: Recent results show a protective effect of tranexamic acid on death due to bleeding in patients with postpartum hemorrhage in low- and middle resource countries. We quantify the association between early administration of tranexamic acid compared to late or no administration and severe acute maternal morbidity and blood loss among women suffering from persistent severe postpartum hemorrhage in a high-income country. METHODS AND FINDINGS: We performed a nationwide retrospective cohort study in 61 hospitals in the Netherlands. The study population consisted of 1260 women with persistent postpartum hemorrhage who had received at least four units of red cells, or fresh frozen plasma or platelets in addition to red cells. A review of medical records was performed and cross-referenced with blood bank data. The composite endpoint comprised maternal morbidity (hysterectomy, ligation of the uterine arteries, emergency B-Lynch suture, arterial embolization or admission into an intensive care unit) and mortality. RESULTS: 247 women received early tranexamic acid treatment. After adjustment for confounding, odds ratio for the composite endpoint for early tranexamic acid (n = 247) versus no/late tranexamic acid (n = 984) was 0.92 (95% confidence interval (CI) 0.66 to 1.27). Propensity matched analysis confirmed the absence of a difference between women with and without tranexamic acid. Blood loss after administration of first line therapy did not differ significantly between the two groups (adjusted difference -177 mL, CI -509.4 to +155.0). CONCLUSIONS: Our findings suggest that in a high-resource country the effect of tranexamic acid on both blood loss and the combined endpoint of maternal mortality and morbidity may be disappointing. PMID- 29107952 TI - Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction. AB - BACKGROUND: Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1 INH-HAE)are often triggered by stressful events/hormonal changes. OBJECTIVE: Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation. METHODS: Twenty-three HAE patients (6 males, mean age 47.5+/-11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3+/-10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10') and 75-degrees-head-up tilt (10'). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively. RESULTS: HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4+/-132.9 pg/ml vs 210.5+/-89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 +/- 7.5% after T vs 47.1 +/- 7.8% at R, p = 0.01). CONCLUSIONS: Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production. PMID- 29107953 TI - Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model. AB - BACKGROUND: Tumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer xenograft mouse tumor model to investigate the spread of malignant cells during different treatments modalities. METHODS: The biological data gained during these experiments were fed into our previously developed computer model "Cancer and Treatment Simulation Tool" (CaTSiT) to model the growth of the primary tumor, its metastatic deposit and also the influence on different therapies. Furthermore, we performed quantitative histology analyses to verify our predictions in xenograft mouse tumor model. RESULTS: According to the computer simulation the number of cells engrafting must vary considerably to explain the different weights of the primary tumor at the end of the experiment. Once a primary tumor is established, the fractal dimension of its vasculature correlates with the tumor size. Furthermore, the fractal dimension of the tumor vasculature changes during treatment, indicating that the therapy affects the blood vessels' geometry. We corroborated these findings with a quantitative histological analysis showing that the blood vessel density is depleted during radiotherapy and cisplatin chemotherapy. The CaTSiT computer model reveals that chemotherapy influences the tumor's therapeutic susceptibility and its metastatic spreading behavior. CONCLUSION: Using a system biological approach in combination with xenograft models and computer simulations revealed that the usage of chemotherapy and radiation therapy determines the spreading behavior by changing the blood vessel geometry of the primary tumor. PMID- 29107954 TI - Distribution and identification of sand flies naturally infected with Leishmania from the Southeastern Peruvian Amazon. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is an important health problem in the New World affecting civilian and military populations that are frequently exposed in endemic settings. The Peruvian region of Madre de Dios located near the border with Brazil is one of the most endemic CL regions in South America with more than 4,451 reported cases between 2010 and 2015 according to the Peruvian epidemiology directorate. However, little is known regarding the diversity and distribution of sand fly vectors in this region. In this study, we aimed to characterize the sand fly fauna in this endemic setting and identify sand fly species naturally infected with Leishmania possibly involved in pathogen transmission. METHODS: Sand fly collections were carried out during 2014 and 2015 in the communities of Flor de Acre, Villa Primavera, Mavila and Arca Pacahuara using CDC light traps and Shannon traps. Collected specimens were identified and non-blood-fed females were selected for Leishmania infection screening using kinetoplastid DNA-PCR (kDNA-PCR) and nested Real time PCR for species identification. RESULTS: A total of 10,897 phlebotomines belonging to the genus Lutzomyia (58 species) and Brumptomyia (2 species) were collected. Our study confirmed the widespread distribution and abundance of Lutzomyia (Trichophoromyia) spp. (24%), Lu. whitmani (19.4%) and Lu. yucumensis (15.8%) in the region. Analysis of Shannon diversity index indicates variability in sand fly composition across sites with Villa Primavera presenting the highest sand fly diversity and abundance. Leishmania screening by kDNA-PCR resulted in 45 positive pools collected from Flor de Acre (34 pools), Mavila (10 pools) and Arca Pacahuara (1 pool) and included 14 species: Lu. yucumensis, Lu. aragoi, Lu. sallesi, Lu. sherlocki, Lu. shawi, Lu. walkeri, Lu nevesi, Lu. migonei, Lu. davisi, Lu. carrerai, Lu. hirsuta, Lu. (Trichophoromyia) spp., Lu. llanosmartinsi and Lu. whitmani. Lutzomyia sherlocki, Lu. walkeri and Lu. llanosmartinsi had the highest infection rates (8%, 7% and 6%, respectively). We identified Leishmania guyanensis in two Lu. whitmani pools, and L. braziliensis in two Lu. llanosmartinsi pools and one Lu. davisi pool. CONCLUSIONS: Based on our collections there is high sand fly diversity in Madre de Dios, with differences in sand fly abundance and species composition across sites. We identified 14 sand fly species naturally infected with Leishmania spp., having detected natural infection with L. (V.) guyanensis and L. (V.) braziliensis in three sand fly species. These results suggest the presence of several potential vectors that vary in their spatial and geographical distribution, which could explain the high prevalence of CL cases in this region. PMID- 29107955 TI - The impact of financial incentives on the implementation of asthma or diabetes self-management: A systematic review. AB - INTRODUCTION: Financial incentives are utilised in healthcare systems in a number of countries to improve quality of care delivered to patients by rewarding practices or practitioners for achieving set targets. OBJECTIVES: To systematically review the evidence investigating the impact of financial incentives for implementation of supported self-management on quality of care including: organisational process outcomes, individual behavioural outcomes, and health outcomes for individuals with asthma or diabetes; both conditions with an extensive evidence base for self-management. METHODS: We followed Cochrane methodology, using a PICOS search strategy to search eight databases in November 2015 (updated May 2017) including a broad range of implementation methodologies. Studies were weighted by robustness of methodology, number of participants and the quality score. We used narrative synthesis due to heterogeneity of studies. RESULTS: We identified 2,541 articles; 12 met our inclusion criteria. The articles were from the US (n = 7), UK (n = 4) and Canada (n = 1). Measured outcomes were HbA1c tests undertaken and/or the level achieved (n = 10), written action plans for asthma (n = 1) and hospital/emergency department visits (n = 1). Three of the studies were part of a larger incentive scheme including many conditions; one focused on asthma; eight focussed on diabetes. In asthma, the proportion receiving 'perfect care' (including providing a written action plan) increased from 4% to 88% in one study, and there were fewer hospitalisations/emergency department visits in another study. Across the diabetes studies, quality-of-care/GP performance scores improved in three, were unchanged in six and deteriorated in one. CONCLUSIONS: Results for the impact of financial incentives for the implementation of self-management were mixed. The evidence in diabetes suggests no consistent impact on diabetic control. There was evidence from a single study of improved process and health outcomes in asthma. Further research is needed to confirm these findings and understand the process by which financial incentives may impact (or not) on care. TRIAL REGISTRATION: Protocol registration number: CRD42016027411. PMID- 29107957 TI - Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2 dependent manner. AB - Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce alpha-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS. PMID- 29107958 TI - Activation of plantar flexor muscles is constrained by multiple muscle synergies rather than joint torques. AB - Behavioral evidence has suggested that a small number of muscle synergies may be responsible for activating a variety of muscles. Nevertheless, such dimensionality reduction may also be explained using the perspective of alternative hypotheses, such as predictions based on linear combinations of joint torques multiplied by corresponding coefficients. To compare the explanatory capacity of these hypotheses for describing muscle activation, we enrolled 12 male volunteers who performed isometric plantar flexor contractions at 10-100% of maximum effort. During each plantar flexor contraction, the knee extensor muscles were isometrically contracted at 0%, 50%, or 100% of maximum effort. Electromyographic activity was recorded from the vastus lateralis, medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus muscles and quantified using the average rectified value (ARV). At lower plantar flexion torque, regression analysis identified a clear linear relationship between the MG and soleus ARVs and between the MG and LG ARVs, suggesting the presence of muscle synergy (r2 > 0.65). The contraction of the knee extensor muscles induced a significant change in the slope of this relationship for both pairs of muscles (MG * soleus, P = 0.002; MG * LG, P = 0.006). Similarly, the slope of the linear relationship between the plantar flexion torque and the ARV of the MG or soleus changed significantly with knee extensor contraction (P = 0.031 and P = 0.041, respectively). These results suggest that muscle synergies characterized by non mechanical constraints are selectively recruited according to whether contraction of the knee extensor muscles is performed simultaneously, which is relatively consistent with the muscle synergy hypothesis. PMID- 29107956 TI - Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol. AB - Gender differences in psychiatric disorders such as addiction may be modulated by the steroid hormone estrogen. For instance, 17beta-estradiol (E2), the predominant form of circulating estrogen in pre-menopausal females, increases ethanol consumption, suggesting that E2 may affect the rewarding properties of ethanol and thus the development of alcohol use disorder in females. The ventral tegmental area (VTA) is critically involved in the rewarding and reinforcing effects of ethanol. In order to determine the role of E2 in VTA physiology, gonadally intact female mice were sacrificed during diestrus II (high E2) or estrus (low E2) for electrophysiology recordings. We measured the excitation by ethanol and inhibition by dopamine (DA) of VTA DA neurons and found that both excitation by ethanol and inhibition by dopamine were greater in diestrus II compared with estrus. Treatment of VTA slices from mice in diestrus II with an estrogen receptor antagonist (ICI 182,780) reduced ethanol-stimulated neuronal firing, but had no effect on ethanol-stimulated firing of neurons in slices from mice in estrus. Surprisingly, ICI 182,780 did not affect the inhibition by DA, indicating different mechanisms of action of estrogen receptors in altering ethanol and DA responses. We also examined the responses of VTA DA neurons to ethanol and DA in ovariectomized mice treated with E2 and found that E2 treatment enhanced the responses to ethanol and DA in a manner similar to what we observed in mice in diestrus II. Our data indicate that E2 modulates VTA neuron physiology, which may contribute to both the enhanced reinforcing and rewarding effects of alcohol and the development of other psychiatric disorders in females that involve alterations in DA neurotransmission. PMID- 29107959 TI - Sleep quality and health-related quality of life among long-term survivors of (non-) Hodgkin lymphoma in Germany. AB - This study investigated sleep quality and health-related quality of life (HRQOL) among long-term survivors of Hodgkin (HL) and non-Hodgkin lymphoma (NHL). The aim was to explore the impact of personal and health-related factors on sleep quality as well as associations between sleep quality and HRQOL. For the postal survey, participants with a minimum age of 18 years initially treated between 1998 and 2008 were recruited via the population-based cancer registry in Schleswig Holstein, Northern Germany. Questionnaires included amongst others the Pittsburg Sleep Quality Index (PSQI) and the 36-Item Short Form Health Survey (SF-36v1). Descriptive and comparative statistics were performed. Additionally, a regression analysis was conducted to identify predictors of sleep quality. In total, we recruited 515 participants (398 NHL, 117 HL) with a mean age of 63.1 years. Approximately half of the survivors were classified as good sleepers. HRQOL scores differed between good and poor sleepers with lower scores in poor sleepers. In a prediction model, self-reported depression, exhaustion, higher age, inability to work, endocrinological disorders and female gender classified as predictors of sleep quality. This study highlights the impact of sleep quality on HRQOL in long-term survivors of NHL and HL. Thus, sleep quality should be routinely assessed during follow-up of cancer survivors with special attention to patients with potential risk factors. PMID- 29107960 TI - Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes. AB - Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer. PMID- 29107961 TI - National substance use patterns on Twitter. AB - PURPOSE: We examined openly shared substance-related tweets to estimate prevalent sentiment around substance use and identify popular substance use activities. Additionally, we investigated associations between substance-related tweets and business characteristics and demographics at the zip code level. METHODS: A total of 79,848,992 tweets were collected from 48 states in the continental United States from April 2015-March 2016 through the Twitter API, of which 688,757 were identified as being related to substance use. We implemented a machine learning algorithm (maximum entropy text classifier) to estimate sentiment score for each tweet. Zip code level summaries of substance use tweets were created and merged with the 2013 Zip Code Business Patterns and 2010 US Census Data. RESULTS: Quality control analyses with a random subset of tweets yielded excellent agreement rates between computer generated and manually generated labels: 97%, 88%, 86%, 75% for underage engagement in substance use, alcohol, drug, and smoking tweets, respectively. Overall, 34.1% of all substance-related tweets were classified as happy. Alcohol was the most frequently tweeted substance, followed by marijuana. Regression results suggested more convenience stores in a zip code were associated with higher percentages of tweets about alcohol. Larger zip code population size and higher percentages of African Americans and Hispanics were associated with fewer tweets about substance use and underage engagement. Zip code economic disadvantage was associated with fewer alcohol tweets but more drug tweets. CONCLUSIONS: The patterns in substance use mentions on Twitter differ by zip code economic and demographic characteristics. Online discussions have great potential to glorify and normalize risky behaviors. Health promotion and underage substance prevention efforts may include interactive social media campaigns to counter the social modeling of risky behaviors. PMID- 29107962 TI - Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: Implications for cardiorenal syndrome. AB - Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro hypertrophic (alpha-skeletal muscle actin and beta-MHC) and pro-fibrotic genes (TGF-beta1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-kappaB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy. PMID- 29107963 TI - Sensitivity analysis of the Aquacrop and SAFYE crop models for the assessment of water limited winter wheat yield in regional scale applications. AB - Process-based models can be usefully employed for the assessment of field and regional-scale impact of drought on crop yields. However, in many instances, especially when they are used at the regional scale, it is necessary to identify the parameters and input variables that most influence the outputs and to assess how their influence varies when climatic and environmental conditions change. In this work, two different crop models, able to represent yield response to water, Aquacrop and SAFYE, were compared, with the aim to quantify their complexity and plasticity through Global Sensitivity Analysis (GSA), using Morris and EFAST (Extended Fourier Amplitude Sensitivity Test) techniques, for moderate to strong water limited climate scenarios. Although the rankings of the sensitivity indices was influenced by the scenarios used, the correlation among the rankings, higher for SAFYE than for Aquacrop, assessed by the top-down correlation coefficient (TDCC), revealed clear patterns. Parameters and input variables related to phenology and to water stress physiological processes were found to be the most influential for Aquacrop. For SAFYE, it was found that the water stress could be inferred indirectly from the processes regulating leaf growth, described in the original SAFY model. SAFYE has a lower complexity and plasticity than Aquacrop, making it more suitable to less data demanding regional scale applications, in case the only objective is the assessment of crop yield and no detailed information is sought on the mechanisms of the stress factors affecting its limitations. PMID- 29107965 TI - Digital case-based learning system in school. AB - With the continuing growth of multi-media learning resources, it is important to offer methods helping learners to explore and acquire relevant learning information effectively. As services that organize multi-media learning materials together to support programming learning, the digital case-based learning system is needed. In order to create a case-oriented e-learning system, this paper concentrates on the digital case study of multi-media resources and learning processes with an integrated framework. An integration of multi-media resources, testing and learning strategies recommendation as the learning unit is proposed in the digital case-based learning framework. The learning mechanism of learning guidance, multi-media materials learning and testing feedback is supported in our project. An improved personalized genetic algorithm which incorporates preference information and usage degree into the crossover and mutation process is proposed to assemble the personalized test sheet for each learner. A learning strategies recommendation solution is proposed to recommend learning strategies for learners to help them to learn. The experiments are conducted to prove that the proposed approaches are capable of constructing personalized sheets and the effectiveness of the framework. PMID- 29107964 TI - Obesogenic diet-induced gut barrier dysfunction and pathobiont expansion aggravate experimental colitis. AB - Consumption of a typical Western diet is a risk factor for several disorders. Metabolic syndrome is the most common disease associated with intake of excess fat. However, the incidence of inflammatory bowel disease is also greater in subjects consuming a Western diet, although the mechanism of this phenomenon is not clearly understood. We examined the morphological and functional changes of the intestine, the first site contacting dietary fat, in mice fed a high-fat diet (HFD) inducing obesity. Paneth cell area and production of antimicrobial peptides by Paneth cells were decreased in HFD-fed mice. Goblet cell number and secretion of mucin by goblet cells were also decreased, while intestinal permeability was increased in HFD-fed mice. HFD-fed mice were more susceptible to experimental colitis, and exhibited severe colonic inflammation, accompanied by the expansion of selected pathobionts such as Atopobium sp. and Proteobacteria. Fecal microbiota transplantation transferred the susceptibility to DSS-colitis, and antibiotic treatment abrogated colitis progression. These data suggest that an experimental HFD-induced Paneth cell dysfunction and subsequent intestinal dysbiosis characterized by pathobiont expansion can be predisposing factors to the development of inflammatory bowel disease. PMID- 29107966 TI - Spinosaur taxonomy and evolution of craniodental features: Evidence from Brazil. AB - Fossil sites from Brazil have yielded specimens of spinosaurid theropods, among which the most informative include the cranial remains of Irritator, Angaturama, and Oxalaia. In this work some of their craniodental features are reinterpreted, providing new data for taxonomic and evolutionary issues concerning this particular clade of dinosaurs. The mesial-most tooth of the left maxilla of the holotype of Irritator is regarded as representing the third tooth position, which is also preserved in the holotype of Angaturama. Thus, both specimens cannot belong to the same individual, contrary to previous assumptions, although they could have been the same taxon. In addition, the position of the external nares of Irritator is more comparable to those of Baryonyx and Suchomimus instead of other spinosaurine spinosaurids. In fact, with regards to some craniodental features, Brazilian taxa represent intermediate conditions between Baryonychinae and Spinosaurinae. Such a scenario is corroborated by our cladistic results, which also leave open the possibility of the former subfamily being non monophyletic. Furthermore, the differences between spinosaurids regarding the position and size of the external nares might be related to distinct feeding habits and degrees of reliance on olfaction. Other issues concerning the evolution and taxonomy of Spinosauridae require descriptions of additional material for their clarification. PMID- 29107967 TI - Embedding graphs in Lorentzian spacetime. AB - Geometric approaches to network analysis combine simply defined models with great descriptive power. In this work we provide a method for embedding directed acyclic graphs (DAG) into Minkowski spacetime using Multidimensional scaling (MDS). First we generalise the classical MDS algorithm, defined only for metrics with a Riemannian signature, to manifolds of any metric signature. We then use this general method to develop an algorithm which exploits the causal structure of a DAG to assign space and time coordinates in a Minkowski spacetime to each vertex. As in the causal set approach to quantum gravity, causal connections in the discrete graph correspond to timelike separation in the continuous spacetime. The method is demonstrated by calculating embeddings for simple models of causal sets and random DAGs, as well as real citation networks. We find that the citation networks we test yield significantly more accurate embeddings that random DAGs of the same size. Finally we suggest a number of applications in citation analysis such as paper recommendation, identifying missing citations and fitting citation models to data using this geometric approach. PMID- 29107968 TI - The trophoblast survival capacity in preeclampsia. AB - BACKGROUND: Preeclampsia has become the world's major maternal health problem putting a huge burden on mothers, newborns and also on the health systems. The pathogenesis of preeclampsia seems to include events in very early pregnancy affecting differentiation of placental villous trophoblast. The arising changes of the cell death spectrum from apoptosis via increased autophagy and aponecrosis to necrosis in turn induce systemic inflammation of the mother. METHODS: Placental tissue samples and maternal serum samples from 40 pregnant women were collected from normal pregnancy, IUGR, early-onset and late-onset preeclampsia. Immunohistochemistry for LC3B and Beclin-1 was quantified using systematic random sampling techniques. Serum levels of LDH and other markers were assessed in serum. RESULTS: Expression of the autophagy markers LC3B and Beclin-1 was significantly different between groups as was the LC3B/Beclin-1 ratio. Early onset preeclampsia and IUGR had the highest autophagy protein expression levels, while normal pregnancy and late-onset preeclampsia had the highest LC3B/Beclin-1 ratio. Early-onset preeclampsia had the highest negative correlation with free LDH as cell defect marker. CONCLUSIONS: Autophagy plays a critical role in the cell death spectrum and cellular survival capacity of villous trophoblast. Alterations in autophagic protein expression are involved in pathological pregnancies such as preeclampsia. PMID- 29107969 TI - Assessing single-stranded oligonucleotide drug-induced effects in vitro reveals key risk factors for thrombocytopenia. AB - Single-stranded oligonucleotides (ON) comprise a promising therapeutic platform that enables selective modulation of currently undruggable targets. The development of novel ON drug candidates has demonstrated excellent efficacy, but in certain cases also some safety liabilities were reported. Among them are events of thrombocytopenia, which have recently been evident in late stage trials with ON drugs. The underlying mechanisms are poorly understood and the risk for ON candidates causing such events cannot be sufficiently assessed pre-clinically. We investigated potential thrombocytopenia risk factors of ONs and implemented a set of in vitro assays to assess these risks. Our findings support previous observations that phosphorothioate (PS)-ONs can bind to platelet proteins such as platelet collagen receptor glycoprotein VI (GPVI) and activate human platelets in vitro to various extents. We also show that these PS-ONs can bind to platelet factor 4 (PF4). Binding to platelet proteins and subsequent activation correlates with ON length and connected to this, the number of PS in the backbone of the molecule. Moreover, we demonstrate that locked nucleic acid (LNA) ribosyl modifications in the wings of the PS-ONs strongly suppress binding to GPVI and PF4, paralleled by markedly reduced platelet activation. In addition, we provide evidence that PS-ONs do not directly affect hematopoietic cell differentiation in culture but at higher concentrations show a pro-inflammatory potential, which might contribute to platelet activation. Overall, our data confirm that certain molecular attributes of ONs are associated with a higher risk for thrombocytopenia. We propose that applying the in vitro assays discussed here during the lead optimization phase may aid in deprioritizing ONs with a potential to induce thrombocytopenia. PMID- 29107970 TI - Motor expertise facilitates the accuracy of state extrapolation in perception. AB - Predicting the behavior of objects in the environment is an important requirement to overcome latencies in the sensorimotor system and realize precise actions in rapid situations. Internal forward models that were acquired during motor training might not only be used for efficiently controlling fast motor behavior but also to facilitate extrapolation performance in purely perceptual tasks. In this study, we investigated whether preceding virtual cart-pole balancing training facilitates the ability to extrapolate the virtual pole motion. Specifically, subjects had to report the expected pole orientation after an occlusion of the pole of 900ms duration. We compared a group of 10 subjects, proficient in performing the virtual cart-pole balancing task, to 10 naive subjects without motor experience in cart-pole balancing task. Our results demonstrate that preceding motor training increases the accuracy of pole movement extrapolation, although extrapolation is not trained explicitly. Additionally, we modelled subjects' behaviors and show that the difference in extrapolation performance can be explained by individual differences in the accuracy of internal forward models. When subjects are provided with feedback about the true orientation of the pole after the occlusion in a second phase of the experiment, both groups improve rapidly. The results indicate that the perceptual capability to extrapolate the state of the cart-pole system accurately is implicitly trained during motor learning. We discuss these results in the context of shared representations and action-perception transfer. PMID- 29107971 TI - Sex differences in the characteristics and short-term prognosis of patients presenting with acute symptomatic pulmonary embolism. AB - BACKGROUND: We sought to examine sex-related differences in the characteristics and outcome in patients presenting with acute symptomatic pulmonary embolism (PE). METHODS: We conducted a retrospective cohort study of 2,096 patients diagnosed with acute PE. The characteristics were recorded at presentation. Treatment was at the discretion of patients' physicians. The primary study outcome, all-cause mortality, and the secondary outcomes of PE-specific mortality, recurrent venous thromboembolism, and major bleeding were assessed during the first month of follow-up after PE diagnosis. RESULTS: Overall, the women were older than the men and had significantly higher rates of immobilization. They had significantly lower rates of chronic obstructive pulmonary disease and cancer. Women had a higher prevalence of syncope and elevated brain natriuretic peptide levels. Thirty-day all-cause mortality was similar between women and men (7.1% versus 6.2%; P = 0.38). Male gender was not independently significantly associated with PE-related death (adjusted odds ratio [OR] 1.02; 95% CI, 0.50 to 2.07; P = 0.96). Restricting the analyses to haemodynamically stable patients (n = 2,021), female gender was an independent predictor of all-cause (adjusted OR 1.56; 95% CI, 1.07 to 2.28; P = 0.02) and PE specific mortality (adjusted OR 1.85; 95% CI, 1.02 to 3.33; P = 0.04). Compared with men, women were 2.05 times more likely to experience a major bleed. CONCLUSIONS: Women and men with PE had different clinical characteristics, presentation, and outcomes. Women receiving anticoagulation have a significantly higher risk of major bleeding, suggesting the need for careful monitoring of anticoagulant intensity in women. PMID- 29107972 TI - RNA-Seq analysis reveals insight into enhanced rice Xa7-mediated bacterial blight resistance at high temperature. AB - Plant disease is a major challenge to agriculture worldwide, and it is exacerbated by abiotic environmental factors. During some plant-pathogen interactions, heat stress allows pathogens to overcome host resistance, a phenomenon which could severely impact crop productivity considering the global warming trends associated with climate change. Despite the importance of this phenomenon, little is known about the underlying molecular mechanisms. To better understand host plant responses during simultaneous heat and pathogen stress, we conducted a transcriptomics experiment for rice plants (cultivar IRBB61) containing Xa7, a bacterial blight disease resistance (R) gene, that were infected with Xanthomonas oryzae, the bacterial blight pathogen of rice, during high temperature stress. Xa7-mediated resistance is unusual relative to resistance mediated by other R genes in that it functions better at high temperatures. Using RNA-Seq technology, we identified 8,499 differentially expressed genes as temperature responsive in rice cultivar IRBB61 experiencing susceptible and resistant interactions across three time points. Notably, genes in the plant hormone abscisic acid biosynthesis and response pathways were up regulated by high temperature in both mock-treated plants and plants experiencing a susceptible interaction and were suppressed by high temperature in plants exhibiting Xa7-mediated resistance. Genes responsive to salicylic acid, an important plant hormone for disease resistance, were down-regulated by high temperature during both the susceptible and resistant interactions, suggesting that enhanced Xa7-mediated resistance at high temperature is not dependent on salicylic acid signaling. A DNA sequence motif similar to known abscisic acid responsive cis-regulatory elements was identified in the promoter region upstream of genes up-regulated in susceptible but down-regulated in resistant interactions. The results of our study suggest that the plant hormone abscisic acid is an important node for cross-talk between plant transcriptional response pathways to high temperature stress and pathogen attack. Genes in this pathway represent an important focus for future study to determine how plants evolved to deal with simultaneous abiotic and biotic stresses. PMID- 29107973 TI - Second thoughts on the final rule: An analysis of baseline participant characteristics reports on ClinicalTrials.gov. AB - BACKGROUND: ClinicalTrials.gov is valuable for aggregate-level analysis of trials. The recently published final rule aims to improve reporting of trial results. We aimed to assess variability in ClinicalTirals.gov records reporting participants' baseline measures. METHODS AND FINDINGS: The September 2015 edition of the database for Aggregate Analysis of ClinicalTrials.gov (AACT), was used in this study. To date, AACT contains 186,941 trials of which 16,660 trials reporting baseline (participant) measures were analyzed. We also analyzed a subset of 13,818 Highly Likely Applicable Clinical Trials (HLACT), for which reporting of results is likely mandatory and compared a random sample of 30 trial records to their journal articles. We report counts for each mandatory baseline measure and variability reporting in their formats. The AACT dataset contains 8,161 baseline measures with 1206 unique measurement units. However, of these 6,940 (85%) variables appear only once in the dataset. Age and Gender are reported using many different formats (178 and 49 respectively). "Age" as the variable name is reported in 60 different formats. HLACT subset reports measures using 3,931 variables. The most frequent Age format (i.e. mean (years) +/- sd) is found in only 45% of trials. Overall only 4 baseline measures (Region of Enrollment, Age, Number of Participants, and Gender) are reported by > 10% of trials. Discrepancies are found in both the types and formats of ClinicalTrials.gov records and their corresponding journal articles. On average, journal articles include twice the number of baseline measures (13.6+/-7.1 (sd) vs. 6.6+/-7.6) when compared to the ClinicalTrials.gov records that report any results. CONCLUSIONS: We found marked variability in baseline measures reporting. This is not addressed by the final rule. To support secondary use of ClinicalTrials.gov, a uniform format for baseline measures reporting is warranted. PMID- 29107974 TI - Significant relationships between a simple marker of redox balance and lifestyle behaviours; Relevance to the Framingham risk score. AB - Oxidative stress has been closely linked to the progressive cell damage associated with emerging non-communicable disease (NCDs). Early detection of these biochemical abnormalities before irreversible cell damage occurs may therefore be useful in identifying disease risk at an individual level. In order to test this hypothesis, this study assessed the relationship between a simple measure of redox status and lifestyle risk factors for NCDs, and the population based risk score of Framingham. In a cross-sectional study design, 100 apparently healthy middle-aged males (n = 48) and females (n = 52) were asked to complete a comprehensive lifestyle assessment questionnaire, followed by body fat percentage and blood pressure measurements, and blood collection. The ratio of plasma total antioxidant capacity to hydroperoxide (TAC/HPX) was used as an index of redox balance. One-way ANOVA and multiple linear regression analysis were performed to analyse the association between TAC/HPX, lifestyle components and other plasma biomarkers. The TAC/HPX ratio was higher in males compared to females (t96 = 2.34, P = 0.021). TAC/HPX was also lower in participants with poor sleep quality (t93 = 2.39, P = 0.019), with high sleep apnoea risk (t62.2 = 3.32, P = 0.002), with high caffeine (F(2, 93) = 3.97, P = 0.022) and red meat intake (F(2, 93) = 5.55, P = 0.005). These associations were independent of gender. Furthermore, the TAC/HPX ratio decreased with increasing body fat percentage (F(2, 95) = 4.74, P = 0.011) and depression score (t94 = 2.38, P = 0.019), though these associations were dependent on gender. Importantly, a negative association was observed between TAC/HPX levels and the Framingham risk score in both males (r(45) = 0.39, P = 0.008) and females (r(50) = -0.33, P = 0.019) that was independent of other Framingham risk score components. Findings from this study suggests that a relatively simple measure of redox balance such as the TAC/HPX ratio may be a sensitive indicator of redox stress, and may therefore serve as a useful biomarker for assessing an individual's specific NCD risk linked to unhealthy lifestyle practices. PMID- 29107976 TI - Piecing together the puzzle: Improving event content coverage for real-time sub event detection using adaptive microblog crawling. AB - In an age when people are predisposed to report real-world events through their social media accounts, many researchers value the benefits of mining user generated content from social media. Compared with the traditional news media, social media services, such as Twitter, can provide more complete and timely information about the real-world events. However events are often like a puzzle and in order to solve the puzzle/understand the event, we must identify all the sub-events or pieces. Existing Twitter event monitoring systems for sub-event detection and summarization currently typically analyse events based on partial data as conventional data collection methodologies are unable to collect comprehensive event data. This results in existing systems often being unable to report sub-events in real-time and often in completely missing sub-events or pieces in the broader event puzzle. This paper proposes a Sub-event detection by real-TIme Microblog monitoring (STRIM) framework that leverages the temporal feature of an expanded set of news-worthy event content. In order to more comprehensively and accurately identify sub-events this framework first proposes the use of adaptive microblog crawling. Our adaptive microblog crawler is capable of increasing the coverage of events while minimizing the amount of non-relevant content. We then propose a stream division methodology that can be accomplished in real time so that the temporal features of the expanded event streams can be analysed by a burst detection algorithm. In the final steps of the framework, the content features are extracted from each divided stream and recombined to provide a final summarization of the sub-events. The proposed framework is evaluated against traditional event detection using event recall and event precision metrics. Results show that improving the quality and coverage of event contents contribute to better event detection by identifying additional valid sub-events. The novel combination of our proposed adaptive crawler and our stream division/recombination technique provides significant gains in event recall (44.44%) and event precision (9.57%). The addition of these sub-events or pieces, allows us to get closer to solving the event puzzle. PMID- 29107975 TI - Trajectories of maternal ante- and postpartum depressive symptoms and their association with child- and mother-related characteristics in a West African birth cohort study. AB - BACKGROUND: The vast majority of research on mental health has been undertaken in high income countries. This study aimed at investigating the long-term course of maternal depressive symptoms and its association with various mother- and child related characteristics in two West African lower middle income countries with focus on the relationship with long-term anxiety symptoms. METHODS: In the Child Development Study, a prospective birth cohort study in Cote d'Ivoire and Ghana, the 9-item Patient Health Questionnaire (PHQ-9) was answered by N = 776 women 3 months antepartum, and 3, 12, and 24 months postpartum between April 2010 and March 2014. Growth mixture modeling was used to identify distinct trajectories of depressive symptoms. Several psychosocial, obstetric, and sociodemographic characteristics were assessed and multinomial regression analysis was performed to investigate the influence of these variables on the different depression trajectories. RESULTS: We found three distinct classes of depressive symptoms that were characterized by an asymptomatic trajectory (91.5%), by recurrent risk (4.3%) and by postnatal risk (4.3%). The longitudinal course of depressive symptoms was strongly associated with anxiety symptoms (chi2 = 258.54, df = 6, p < 0.001; phi = .577). Among other factors, higher levels of anxiety, new pregnancy 2 years after birth, economic stress, and family stress were associated with the risk classes. CONCLUSIONS: A substantial proportion of West African women in our sample developed unfavorable patterns of depressive symptoms during the vulnerable phase of pregnancy and early motherhood. Psychosocial factors, especially antepartum anxiety symptoms, played a decisive role in this process. Perceived economic hardship further exaggerated the mental health burden. PMID- 29107977 TI - Temperature and heat in informal settlements in Nairobi. AB - Nairobi, Kenya exhibits a wide variety of micro-climates and heterogeneous surfaces. Paved roads and high-rise buildings interspersed with low vegetation typify the central business district, while large neighborhoods of informal settlements or "slums" are characterized by dense, tin housing, little vegetation, and limited access to public utilities and services. To investigate how heat varies within Nairobi, we deployed a high density observation network in 2015/2016 to examine summertime temperature and humidity. We show how temperature, humidity and heat index differ in several informal settlements, including in Kibera, the largest slum neighborhood in Africa, and find that temperature and a thermal comfort index known colloquially as the heat index regularly exceed measurements at the Dagoretti observation station by several degrees Celsius. These temperatures are within the range of temperatures previously associated with mortality increases of several percent in youth and elderly populations in informal settlements. We relate these changes to surface properties such as satellite-derived albedo, vegetation indices, and elevation. PMID- 29107978 TI - Encapsulation of curcumin in polymeric nanoparticles for antimicrobial Photodynamic Therapy. AB - Curcumin (CUR) has been used as photosensitizer in antimicrobial Photodynamic Therapy (aPDT). However its poor water solubility, instability, and scarce bioavalibility hinder its in vivo application. The aim of this study was to synthesize curcumin in polymeric nanoparticles (NP) and to evaluate their antimicrobial photodynamic effect and cytoxicity. CUR in anionic and cationic NP was synthesized using polylactic acid and dextran sulfate by the nanoprecipitation method. For cationic NP, cetyltrimethylammonium bromide was added. CUR-NP were characterized by physicochemical properties, photodegradation, encapsulation efficiency and release of curcumin from nanoparticles. CUR-NP was compared with free CUR in 10% dimethyl sulfoxide (DMSO) as a photosensitizer for aPDT against planktonic and biofilms (mono-, dual- and triple-species) cultures of Streptococcus mutans, Candida albicans and Methicillin-Resistant Staphylococcus aureus. The cytotoxicity effect of formulations was evaluated on keratinocytes. Data were analysed by parametric (ANOVA) and non-parametric (Kruskal-Wallis) tests (alpha = 0.05). CUR-NP showed alteration in the physicochemical properties along time, photodegradation similar to free curcumin, encapsulation efficiency up to 67%, and 96% of release after 48h. After aPDT planktonic cultures showed reductions from 0.78 log10 to complete eradication, while biofilms showed no antimicrobial effect or reductions up to 4.44 log10. Anionic CUR-NP showed reduced photoinactivation of biofilms. Cationic CUR-NP showed microbicidal effect even in absence of light. Anionic formulations showed no cytotoxic effect compared with free CUR and cationic CUR-NP and NP. The synthesized formulations improved the water solubility of CUR, showed higher antimicrobial photodynamic effect for planktonic cultures than for biofilms, and the encapsulation of CUR in anionic NP reduced the cytotoxicity of 10% DMSO used for free CUR. PMID- 29107979 TI - Helicobacter pylori bab characterization in clinical isolates from Bhutan, Myanmar, Nepal and Bangladesh. AB - BACKGROUND: Helicobacter pylori BabA is an important outer membrane protein that involves in the attachment to the gastric mucosa and enhances the virulence property of the bacterium. This study was aimed to characterize the bab genotypes, to evaluate its association with cagA, vacA and clinical diseases as well as degree of gastric inflammation. METHODS: H. pylori isolates from four countries were subjected for the characterization of bab. The locus specific forward and bab specific reverse primers were used to get the specific products by PCR, which could distinguish the three locus (A, B and C). The histological activities were evaluated according to the Updated Sydney system. RESULT: In patients from high risk countries (Bhutan and Myanmar) relatively higher frequencies of strains with babA-positivity (91.8% and 90.7%, respectively), babA at locus A (98% and 91.2%, respectively) and with single babA (96.8% and 91.2%, respectively) were found. Strains with two loci occupied were the most prevalent in Bhutan (84.6%), Myanmar (74.7%), Nepal (58.3%) and Bangladesh (56.9%). The genotype babA at locus A/babB at locus B/bab-negative at locus C (babA/babB/-) was the most common genotype isolated from Bhutan (82.7%), Myanmar (58.7%), Nepal (32%) and Bangladesh (31.4%) among all genotypes assessed. This genotype was also associated with the peptic ulcer disease (P = 0.013) when compared to gastritis. babA-positive characteristics and the genotype babA/babB/- exhibited the enhanced histological activities. CONCLUSIONS: The higher prevalence of virulence associated babA-positive characteristics and enhanced histological activities in Bhutan than in Myanmar, Nepal and Bangladesh might partly explain why the peoples in Bhutan are at higher risk for developing severe gastric complications. PMID- 29107981 TI - Prevalence and risk factors of monochorionic diamniotic twinning after assisted reproduction: A six-year experience base on a large cohort of pregnancies. AB - OBJECTIVE: To characterize the incidence and risk factors for monochorionic diamniotic(MC-DA) twinning after assisted reproductive technologies (ART). DESIGN: Retrospective population-based study. SETTING: The study was conducted in China; Department of Reproductive Medicine Center at The First Affiliated Hospital of Anhui Medical University. POPULATION: A cohort of 8860 clinical pregnancies after embryo transfer (ET) carried out in our center between 2011 and 2016 were retrospectively analyzed for the incidence of MC-DA twinning. METHODS: Logistic regression was used to model the effect on the incidence of MC-DA twinning after ART. Different clinical data (maternal age) and laboratory procedures (type of ET (fresh versus frozen), insemination (IVF or ICSI)), embryo stage at time of ET (cleavage or blastocyst)) on the incidence of MC-DA twinning were evaluated. MAIN OUTCOME MEASURES: Monochorionic-diamniotic pregnancies were identified when more than one fetal poles was visualized in one gestational sac via trans-vaginal ultrasound at early first-trimester (7 to 8 weeks). RESULTS: The overall MC-DA twinning rate was 2.55% (226/8860). Eighty one MC-DA twinnings occurred in the fresh cycles and 145 in the frozen cycles (2.67% vs. 2.49%). MC DA twinning incidence showed no significant difference whether ICSI was performed or not (2.79% vs. 2.44%). The MZT that resulted from single embryo transfer (SET) cycles (1.99%) was slightly lower than multiple embryo transfer cycles (2.61%),but with non-significance. However, women <35 years displayed a significant higher rate (2.81%) than women >=35 years old (1.16%). Blastocyst transfer was associated with a significantly increase in MC-DA twinning incidence than cleavage-stage embryos transfer (2.79% VS 2.02%, P = 0.008). In the results of logistic regression analysis, blastocyst transfer is a major risk factor of MZT in the fresh cycles (P = 0.044), while maternal age plays a more important role in the frozen cycles (P = 0.004). CONCLUSIONS: There is an elevated prevalence of MC-DA twinning after ART. Both maternal age and blastocyst transfer are risk factors of monozygotic pregnancy independently. Blastocyst transfer is a major risk factor of MC-DA twinning in the fresh cycles, while maternal age plays a more important role in the frozen cycles. PMID- 29107980 TI - Base pair probability estimates improve the prediction accuracy of RNA non canonical base pairs. AB - Prediction of RNA tertiary structure from sequence is an important problem, but generating accurate structure models for even short sequences remains difficult. Predictions of RNA tertiary structure tend to be least accurate in loop regions, where non-canonical pairs are important for determining the details of structure. Non-canonical pairs can be predicted using a knowledge-based model of structure that scores nucleotide cyclic motifs, or NCMs. In this work, a partition function algorithm is introduced that allows the estimation of base pairing probabilities for both canonical and non-canonical interactions. Pairs that are predicted to be probable are more likely to be found in the true structure than pairs of lower probability. Pair probability estimates can be further improved by predicting the structure conserved across multiple homologous sequences using the TurboFold algorithm. These pairing probabilities, used in concert with prior knowledge of the canonical secondary structure, allow accurate inference of non-canonical pairs, an important step towards accurate prediction of the full tertiary structure. Software to predict non-canonical base pairs and pairing probabilities is now provided as part of the RNAstructure software package. PMID- 29107982 TI - Competitive tuning: Competition's role in setting the frequency-dependence of Ca2+-dependent proteins. AB - A number of neurological disorders arise from perturbations in biochemical signaling and protein complex formation within neurons. Normally, proteins form networks that when activated produce persistent changes in a synapse's molecular composition. In hippocampal neurons, calcium ion (Ca2+) flux through N-methyl-D aspartate (NMDA) receptors activates Ca2+/calmodulin signal transduction networks that either increase or decrease the strength of the neuronal synapse, phenomena known as long-term potentiation (LTP) or long-term depression (LTD), respectively. The calcium-sensor calmodulin (CaM) acts as a common activator of the networks responsible for both LTP and LTD. This is possible, in part, because CaM binding proteins are "tuned" to different Ca2+ flux signals by their unique binding and activation dynamics. Computational modeling is used to describe the binding and activation dynamics of Ca2+/CaM signal transduction and can be used to guide focused experimental studies. Although CaM binds over 100 proteins, practical limitations cause many models to include only one or two CaM-activated proteins. In this work, we view Ca2+/CaM as a limiting resource in the signal transduction pathway owing to its low abundance relative to its binding partners. With this view, we investigate the effect of competitive binding on the dynamics of CaM binding partner activation. Using an explicit model of Ca2+, CaM, and seven highly-expressed hippocampal CaM binding proteins, we find that competition for CaM binding serves as a tuning mechanism: the presence of competitors shifts and sharpens the Ca2+ frequency-dependence of CaM binding proteins. Notably, we find that simulated competition may be sufficient to recreate the in vivo frequency dependence of the CaM-dependent phosphatase calcineurin. Additionally, competition alone (without feedback mechanisms or spatial parameters) could replicate counter-intuitive experimental observations of decreased activation of Ca2+/CaM-dependent protein kinase II in knockout models of neurogranin. We conclude that competitive tuning could be an important dynamic process underlying synaptic plasticity. PMID- 29107983 TI - Synthetic host defense peptide IDR-1002 reduces inflammation in Pseudomonas aeruginosa lung infection. AB - Pseudomonas aeruginosa is a frequent cause of lung infections, particularly in chronic infections in cystic fibrosis patients. However, treatment is challenging due to P. aeruginosa evasion of the host immune system and the rise of antibiotic resistant strains. Host defense peptides (HDPs) and synthetic derivatives called innate defense regulators (IDRs) have shown promise in several infection models as an alternative to antibiotic treatment. Here we tested peptide IDR-1002 against P. aeruginosa in vitro and in vivo. Treatment of bronchial epithelial cells and macrophages with IDR-1002 or in combination with live P. aeruginosa or its LPS led to the reduction of agonist-induced cytokines and chemokines and limited cell killing by live P. aeruginosa. In an in vivo model using P. aeruginosa combined with alginate to mimic a chronic model, IDR-1002 did not reduce the bacterial burden in the lungs, but IDR-1002 mice showed a significant decrease in IL-6 in the lungs and in gross pathology of infection, while histology revealed that IDR-1002 treated mice had reduced alveolar macrophage infiltration around the site of infection and reduced inflammation. Overall, these results indicate that IDR-1002 has promise for combating P. aeruginosa lung infections and their resulting inflammation. PMID- 29107985 TI - Potential worldwide distribution of Fusarium dry root rot in common beans based on the optimal environment for disease occurrence. AB - Root rots are a constraint for staple food crops and a long-lasting food security problem worldwide. In common beans, yield losses originating from root damage are frequently attributed to dry root rot, a disease caused by the Fusarium solani species complex. The aim of this study was to model the current potential distribution of common bean dry root rot on a global scale and to project changes based on future expectations of climate change. Our approach used a spatial proxy of the field disease occurrence, instead of solely the pathogen distribution. We modeled the pathogen environmental requirements in locations where in-situ inoculum density seems ideal for disease manifestation. A dataset of 2,311 soil samples from commercial farms assessed from 2002 to 2015 allowed us to evaluate the environmental conditions associated with the pathogen's optimum inoculum density for disease occurrence, using a lower threshold as a spatial proxy. We encompassed not only the optimal conditions for disease occurrence but also the optimal pathogen's density required for host infection. An intermediate inoculum density of the pathogen was the best disease proxy, suggesting density-dependent mechanisms on host infection. We found a strong convergence on the environmental requirements of both the host and the disease development in tropical areas, mostly in Brazil, Central America, and African countries. Precipitation and temperature variables were important for explaining the disease occurrence (from 17.63% to 43.84%). Climate change will probably move the disease toward cooler regions, which in Brazil are more representative of small-scale farming, although an overall shrink in total area (from 48% to 49% in 2050 and 26% to 41% in 2070) was also predicted. Understanding pathogen distribution and disease risks in an evolutionary context will therefore support breeding for resistance programs and strategies for dry root rot management in common beans. PMID- 29107984 TI - Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3-mediated transport in a substrate-dependent manner. AB - OATP1B1 and OATP1B3 mediate hepatic uptake of many drugs (e.g., statins) and can mediate transporter-mediated drug-drug-interactions (DDIs). Bortezomib is the first-in-class proteasome inhibitor drug approved by the U. S. Food and Drug Administration for the treatment of multiple myeloma. The potential of bortezomib to cause OATP-mediated DDIs has not been assessed. The current study investigated the involvement of the ubiquitin-proteasome system (UPS) in OATP1B1 and OATP1B3 degradation and determined the effects of proteasome inhibitors on OATP1B1- and OATP1B3-mediated transport. Co-immunoprecipitation of FLAG-OATP1B1/1B3 and HA ubiquitin was observed in human embryonic kidney (HEK) 293 cells co-transfected with FLAG-tagged OATP1B1/OATP1B3 and hemagglutinin (HA)-tagged ubiquitin, suggesting that OATP1B1 and OATP1B3 can be ubiquitin-modified. Although blocking proteasome activity by bortezomib treatment (50 nM, 7 h) increased the endogenous ubiquitin-conjugated FLAG-OATP1B1 and FLAG-OATP1B3 in HEK293-FLAG-OATP1B1 and OATP1B3 cells, such treatment did not affect the total protein levels of OATP1B1 and OATP1B3, suggesting that the UPS plays a minor role in degradation of OATP1B1 and OATP1B3 under current constitutive conditions. Pretreatment with bortezomib (50-250 nM, 2-7 h) significantly decreased transport of [3H]CCK-8, a specific OATP1B3 substrate, in HEK293-OATP1B3 and human sandwich-cultured hepatocytes (SCH). However, bortezomib pretreatment had negligible effects on the transport of [3H]E217betaG and [3H]pitavastatin, dual substrates of OATP1B1 and OATP1B3, in HEK293-OATP1B1/1B3 cells and/or human SCH. Compared with vehicle control treatment, bortezomib pretreatment significantly decreased the maximal transport velocity (Vmax) of OATP1B3-mediated transport of CCK-8 (92.25 +/- 14.2 vs. 133.95 +/- 15.5 pmol/mg protein/min) without affecting the affinity constant (Km) values. Treatment with other proteasome inhibitors MG132, epoxomicin, and carfilzomib also significantly decreased OATP1B3-mediated [3H]CCK-8 transport. In summary, the current studies for the first time report ubiquitination of OATP1B1 and OATP1B3 and the apparent substrate-dependent inhibitory effect of bortezomib on OATP1B3-mediated transport. The data suggest that bortezomib has a low risk of causing OATP-mediated DDIs. PMID- 29107986 TI - Distributed rewiring model for complex networking: The effect of local rewiring rules on final structural properties. AB - The study of complex networks has become an important subject over the last decades. It has been shown that these structures have special features, such as their diameter, or their average path length, which in turn are the explanation of some functional properties in a system such as its fault tolerance, its fragility before attacks, or the ability to support routing procedures. In the present work, we study some of the forces that help a network to evolve to the point where structural properties are settled. Although our work is mainly focused on the possibility of applying our ideas to Information and Communication Technologies systems, we consider that our results may contribute to understanding different scenarios where complex networks have become an important modeling tool. Using a discrete event simulator, we get each node to discover the shortcuts that may connect it with regions away from its local environment. Based on this partial knowledge, each node can rewire some of its links, which allows modifying the topology of the entire underlying graph to achieve new structural properties. We proposed a distributed rewiring model that creates networks with features similar to those found in complex networks. Although each node acts in a distributed way and seeking to reduce only the trajectories of its packets, we observed a decrease of diameter and an increase in clustering coefficient in the global structure compared to the initial graph. Furthermore, we can find different final structures depending on slight changes in the local rewiring rules. PMID- 29107987 TI - Individual versus superensemble forecasts of seasonal influenza outbreaks in the United States. AB - Recent research has produced a number of methods for forecasting seasonal influenza outbreaks. However, differences among the predicted outcomes of competing forecast methods can limit their use in decision-making. Here, we present a method for reconciling these differences using Bayesian model averaging. We generated retrospective forecasts of peak timing, peak incidence, and total incidence for seasonal influenza outbreaks in 48 states and 95 cities using 21 distinct forecast methods, and combined these individual forecasts to create weighted-average superensemble forecasts. We compared the relative performance of these individual and superensemble forecast methods by geographic location, timing of forecast, and influenza season. We find that, overall, the superensemble forecasts are more accurate than any individual forecast method and less prone to producing a poor forecast. Furthermore, we find that these advantages increase when the superensemble weights are stratified according to the characteristics of the forecast or geographic location. These findings indicate that different competing influenza prediction systems can be combined into a single more accurate forecast product for operational delivery in real time. PMID- 29107988 TI - Basic emotions and adaptation. A computational and evolutionary model. AB - The core principles of the evolutionary theories of emotions declare that affective states represent crucial drives for action selection in the environment and regulated the behavior and adaptation of natural agents in ancestrally recurrent situations. While many different studies used autonomous artificial agents to simulate emotional responses and the way these patterns can affect decision-making, few are the approaches that tried to analyze the evolutionary emergence of affective behaviors directly from the specific adaptive problems posed by the ancestral environment. A model of the evolution of affective behaviors is presented using simulated artificial agents equipped with neural networks and physically inspired on the architecture of the iCub humanoid robot. We use genetic algorithms to train populations of virtual robots across generations, and investigate the spontaneous emergence of basic emotional behaviors in different experimental conditions. In particular, we focus on studying the emotion of fear, therefore the environment explored by the artificial agents can contain stimuli that are safe or dangerous to pick. The simulated task is based on classical conditioning and the agents are asked to learn a strategy to recognize whether the environment is safe or represents a threat to their lives and select the correct action to perform in absence of any visual cues. The simulated agents have special input units in their neural structure whose activation keep track of their actual "sensations" based on the outcome of past behavior. We train five different neural network architectures and then test the best ranked individuals comparing their performances and analyzing the unit activations in each individual's life cycle. We show that the agents, regardless of the presence of recurrent connections, spontaneously evolved the ability to cope with potentially dangerous environment by collecting information about the environment and then switching their behavior to a genetically selected pattern in order to maximize the possible reward. We also prove the determinant presence of an internal time perception unit for the robots to achieve the highest performance and survivability across all conditions. PMID- 29107989 TI - Insight into glucocorticoid receptor signalling through interactome model analysis. AB - Glucocorticoid hormones (GCs) are used to treat a variety of diseases because of their potent anti-inflammatory effect and their ability to induce apoptosis in lymphoid malignancies through the glucocorticoid receptor (GR). Despite ongoing research, high glucocorticoid efficacy and widespread usage in medicine, resistance, disease relapse and toxicity remain factors that need addressing. Understanding the mechanisms of glucocorticoid signalling and how resistance may arise is highly important towards improving therapy. To gain insight into this we undertook a systems biology approach, aiming to generate a Boolean model of the glucocorticoid receptor protein interaction network that encapsulates functional relationships between the GR, its target genes or genes that target GR, and the interactions between the genes that interact with the GR. This model named GEB052 consists of 52 nodes representing genes or proteins, the model input (GC) and model outputs (cell death and inflammation), connected by 241 logical interactions of activation or inhibition. 323 changes in the relationships between model constituents following in silico knockouts were uncovered, and steady-state analysis followed by cell-based microarray genome-wide model validation led to an average of 57% correct predictions, which was taken further by assessment of model predictions against patient microarray data. Lastly, semi quantitative model analysis via microarray data superimposed onto the model with a score flow algorithm has also been performed, which demonstrated significantly higher correct prediction ratios (average of 80%), and the model has been assessed as a predictive clinical tool using published patient microarray data. In summary we present an in silico simulation of the glucocorticoid receptor interaction network, linked to downstream biological processes that can be analysed to uncover relationships between GR and its interactants. Ultimately the model provides a platform for future development both by directing laboratory research and allowing for incorporation of further components, encapsulating more interactions/genes involved in glucocorticoid receptor signalling. PMID- 29107990 TI - Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor. AB - The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5alpha-dihydrotestosterone (5alpha-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis. PMID- 29107991 TI - Structure and function of a CE4 deacetylase isolated from a marine environment. AB - Chitin, a polymer of beta(1-4)-linked N-acetylglucosamine found in e.g. arthropods, is a valuable resource that may be used to produce chitosan and chitooligosaccharides, two compounds with considerable industrial and biomedical potential. Deacetylating enzymes may be used to tailor the properties of chitin and its derived products. Here, we describe a novel CE4 enzyme originating from a marine Arthrobacter species (ArCE4A). Crystal structures of this novel deacetylase were determined, with and without bound chitobiose [(GlcNAc)2], and refined to 2.1 A and 1.6 A, respectively. In-depth biochemical characterization showed that ArCE4A has broad substrate specificity, with higher activity against longer oligosaccharides. Mass spectrometry-based sequencing of reaction products generated from a fully acetylated pentamer showed that internal sugars are more prone to deacetylation than the ends. These enzyme properties are discussed in the light of the structure of the enzyme-ligand complex, which adds valuable information to our still rather limited knowledge on enzyme-substrate interactions in the CE4 family. PMID- 29107992 TI - Software-assisted dosimetry in peptide receptor radionuclide therapy with 177Lutetium-DOTATATE for various imaging scenarios. AB - In peptide receptor radionuclide therapy (PRRT) of patients with neuroendocrine neoplasias (NENs), intratherapeutic dosimetry is mandatory for organs at risk (e.g. kidneys) and tumours. We evaluated commercial dosimetry software (Dosimetry Toolkit) using varying imaging scenarios, based on planar and/or tomographic data, regarding the differences in calculated organ/tumour doses and the use for clinical routines. A total of 16 consecutive patients with NENs treated by PRRT with 177Lu-DOTATATE were retrospectively analysed. Single-photon emission computed tomography (SPECT)/low-dose computed tomography (CT) of the thorax and abdomen and whole body (WB) scintigraphy were acquired up to 7 days p.i. (at a maximum of five imaging time points). Different dosimetric scenarios were evaluated: (1) a multi-SPECT-CT scenario using SPECT/CT only; (2) a planar scenario using WB scintigraphy only; and (3) a hybrid scenario using WB scintigraphy in combination with a single SPECT/low-dose CT. Absorbed doses for the kidneys, liver, spleen, lungs, bladder wall and tumours were calculated and compared for the three different scenarios. The mean absorbed dose for the kidneys estimated by the multi-SPECT-CT, the planar and the hybrid scenario was 0.5 +/- 0.2 Sv GBq-1, 0.8 +/- 0.4 Sv GBq-1 and 0.6 +/- 0.3 Sv GBq-1, respectively. The absorbed dose for the residual organs was estimated higher by the planar scenario compared to the multi-SPECT-CT or hybrid scenario. The mean absorbed tumour doses were 2.6 +/- 1.5 Gy GBq-1 for the multi-SPECT-CT, 3.1 +/- 2.2 Gy GBq-1 for the hybrid scenario and 5.3 +/- 6.3 Gy GBq-1 for the planar scenario. SPECT-based dosimetry methods determined significantly lower kidney doses than the WB scintigraphy-based method. Dosimetry based completely on SPECT data is time-consuming and tedious. Approaches combining SPECT/CT and WB scintigraphy have the potential to ensure compromise between accuracy and user friendliness. PMID- 29107993 TI - Nanoencapsulated capsaicin changes migration behavior and morphology of madin darby canine kidney cell monolayers. AB - We have developed a drug delivery nanosystem based on chitosan and capsaicin. Both substances have a wide range of biological activities. We investigated the nanosystem's influence on migration and morphology of Madin Darby canine kidney (MDCK-C7) epithelial cells in comparison to the capsaicin-free nanoformulation, free capsaicin, and control cells. For minimally-invasive quantification of cell migration, we applied label-free digital holographic microscopy (DHM) and single cell tracking. Moreover, quantitative DHM phase images were used as novel stain free assay to quantify the temporal course of global cellular morphology changes in confluent cell layers. Cytoskeleton alterations and tight junction protein redistributions were complementary analyzed by fluorescence microscopy. Calcium influx measurements were conducted to characterize the influence of the nanoformulations and capsaicin on ion channel activities. We found that both, capsaicin-loaded and unloaded chitosan nanocapsules, and also free capsaicin, have a significant impact on directed cell migration and cellular motility. Increase of velocity and directionality of cell migration correlates with changes in the cell layer surface roughness, tight junction integrity and cytoskeleton alterations. Calcium influx into cells occurred only after nanoformulation treatment but not upon addition of free capsaicin. Our results pave the way for further studies on the biological significance of these findings and potential biomedical applications, e.g. as drug and gene carriers. PMID- 29107994 TI - Moderators of wellbeing interventions: Why do some people respond more positively than others? AB - Interventions rarely have a universal effect on all individuals. Reasons ranging from participant characteristics, context and fidelity of intervention completion could cause some people to respond more positively than others. Understanding these individual differences in intervention response may provide clues to the mechanisms behind the intervention, as well as inform future designs to make interventions maximally beneficial for all. Here we focus on an intervention designed to improve adolescent wellbeing, and explore potential moderators using a representative and well-powered sample. 16-year old participants (N = 932) in the Twins Wellbeing Intervention Study logged online once a week to complete control and wellbeing-enhancing activities consecutively. Throughout the study participants also provided information about a range of potential moderators of intervention response including demographics, seasonality, personality, baseline characteristics, activity fit, and effort. As expected, some individuals gained more from the intervention than others; we used multi-level modelling to test for moderation effects that could explain these individual differences. Of the 15 moderators tested, none significantly explained individual differences in intervention response in the intervention and follow-up phases. Self-reported effort and baseline positive affect had a notable effect in moderating response in the control phase, during which there was no overall improvement in wellbeing and mental health. Our results did not replicate the moderation effects that have been suggested by previous literature and future work needs to reconcile these differences. They also show that factors that have previously been shown to influence baseline wellbeing do not also influence an individual's ability to benefit from a wellbeing intervention. Although future research should continue to explore potential moderators of intervention efficacy, our results suggest that the beneficial effect of positive activities in adolescents were universal across such factors as sex and socioeconomic status, bolstering claims of the scalability of positive activities to increase adolescent wellbeing. PMID- 29107995 TI - The intratracheal administration of locked nucleic acid containing antisense oligonucleotides induced gene silencing and an immune-stimulatory effect in the murine lung. AB - Locked nucleic acid containing antisense oligonucleotides (LNA-ASOs) have the potential to modulate the disease-related gene expression by the RNaseH-dependent degradation of mRNAs. Pulmonary drug delivery has been widely used for the treatment of lung disease. Thus, the inhalation of LNA-ASOs is expected to be an efficient therapy that can be applied to several types of lung disease. Because the lung has a distinct immune system against pathogens, the immune-stimulatory effect of LNA-ASOs should be considered for the development of novel inhaled LNA ASOs therapies. However, there have been no reports on the relationship between knock-down (KD) and the immune-stimulatory effects of inhaled LNA-ASOs in the lung. In this report, LNA-ASOs targeting Scarb1 (Scarb1-ASOs) or negative control LNA-ASOs targeting ApoB (ApoB-ASOs) were intratracheally administered to mice to investigate the KD of the gene expression and the immune-stimulatory effects in the lung. We confirmed that the intratracheal administration of Scarb1-ASOs exerted a KD effect in the lung without a drug delivery system. On the other hand, both Scarb1-ASOs and ApoB-ASOs induced neutrophilic infiltration in the alveoli and increased the expression levels of G-CSF and CXCL1 in the lung. The dose required for KD was the same as the dose that induced the neutrophilic immune response. In addition, in our in vitro experiments, Scarb1-ASOs did not increase the G-CSF or CXCL1 expression in primary lung cells, even though Scarb1 ASOs exerted a strong KD effect. Hence, we hypothesize that inhaled LNA-ASOs have the potential to exert a KD effect in the lung, but that they may be associated with a risk of immune stimulation. Further studies about the mechanism underlying the immune-stimulatory effect of LNA-ASOs is necessary for the development of novel inhaled LNA-ASO therapies. PMID- 29107997 TI - Comparing pseudo-absences generation techniques in Boosted Regression Trees models for conservation purposes: A case study on amphibians in a protected area. AB - Boosted Regression Trees (BRT) is one of the modelling techniques most recently applied to biodiversity conservation and it can be implemented with presence-only data through the generation of artificial absences (pseudo-absences). In this paper, three pseudo-absences generation techniques are compared, namely the generation of pseudo-absences within target-group background (TGB), testing both the weighted (WTGB) and unweighted (UTGB) scheme, and the generation at random (RDM), evaluating their performance and applicability in distribution modelling and species conservation. The choice of the target group fell on amphibians, because of their rapid decline worldwide and the frequent lack of guidelines for conservation strategies and regional-scale planning, which instead could be provided through an appropriate implementation of SDMs. Bufo bufo, Salamandrina perspicillata and Triturus carnifex were considered as target species, in order to perform our analysis with species having different ecological and distributional characteristics. The study area is the "Gran Sasso-Monti della Laga" National Park, which hosts 15 Natura 2000 sites and represents one of the most important biodiversity hotspots in Europe. Our results show that the model calibration ameliorates when using the target-group based pseudo-absences compared to the random ones, especially when applying the WTGB. Contrarily, model discrimination did not significantly vary in a consistent way among the three approaches with respect to the tree target species. Both WTGB and RDM clearly isolate the highly contributing variables, supplying many relevant indications for species conservation actions. Moreover, the assessment of pairwise variable interactions and their three-dimensional visualization further increase the amount of useful information for protected areas' managers. Finally, we suggest the use of RDM as an admissible alternative when it is not possible to individuate a suitable set of species as a representative target-group from which the pseudo-absences can be generated. PMID- 29107996 TI - Epigenetic memory via concordant DNA methylation is inversely correlated to developmental potential of mammalian cells. AB - In storing and transmitting epigenetic information, organisms must balance the need to maintain information about past conditions with the capacity to respond to information in their current and future environments. Some of this information is encoded by DNA methylation, which can be transmitted with variable fidelity from parent to daughter strand. High fidelity confers strong pattern matching between the strands of individual DNA molecules and thus pattern stability over rounds of DNA replication; lower fidelity confers reduced pattern matching, and thus greater flexibility. Here, we present a new conceptual framework, Ratio of Concordance Preference (RCP), that uses double-stranded methylation data to quantify the flexibility and stability of the system that gave rise to a given set of patterns. We find that differentiated mammalian cells operate with high DNA methylation stability, consistent with earlier reports. Stem cells in culture and in embryos, in contrast, operate with reduced, albeit significant, methylation stability. We conclude that preference for concordant DNA methylation is a consistent mode of information transfer, and thus provides epigenetic stability across cell divisions, even in stem cells and those undergoing developmental transitions. Broader application of our RCP framework will permit comparison of epigenetic-information systems across cells, developmental stages, and organisms whose methylation machineries differ substantially or are not yet well understood. PMID- 29107998 TI - Impact of surgical parathyroidectomy on chronic kidney disease-mineral and bone disorder (CKD-MBD) - A systematic review and meta-analysis. AB - For more than 6 decades, many patients with advanced chronic kidney disease (CKD) have undergone surgical parathyroidectomy (sPTX) for severe secondary hyperparathyroidism (SHPT) mainly based historical clinical practice patterns, but not on evidence of outcome.We aimed in this meta-analysis to evaluate the benefits and harms of sPTX in patients with SHPT. We searched MEDLINE (inception to October 2016), EMBASE and Cochrane Library (through Issue 10 of 12, October 2016) and website clinicaltrials.gov (October 2016) without language restriction. Eligible studies evaluated patients reduced glomerular filtration rate (GFR), below 60 mL/min/1.73 m2 (CKD 3-5 stages) with hyperparathyroidism who underwent sPTX. Reviewers working independently and in duplicate extracted data and assessed the risk of bias. The final analysis included 15 cohort studies, comprising 24,048 participants. Compared with standard treatment, sPTX significantly decreased all-cause mortality (RR 0.74 [95% CI, 0.66 to 0.83]) in End Stage Kidney Disease (ESKD) patients with biochemical and / or clinical evidence of SHPT. sPTX was also associated with decreased cardiovascular mortality (RR 0.59 [95% CI, 0.46 to 0.76]) in 6 observational studies that included almost 10,000 patients. The available evidence, mostly observational, is at moderate risk of bias, and limited by indirect comparisons and inconsistency in reporting for some outcomes (eg. short term adverse events, including documented voice change or episodes of severe hypocalcaemia needing admission or long-term adverse events, including undetectable PTH levels, risk of fractures etc.). Taken together, the results of this meta-analysis would suggest a clinically significant beneficial effect of sPTX on all-cause and cardiovascular mortality in CKD patients with SHPT. However, given the observational nature of the included studies, the case for a properly conducted, independent randomised controlled trial comparing surgery with medical therapy and featuring many different outcomes from mortality to quality of life (QoL) is now very strong. PMID- 29107999 TI - Association between biomarkers and clinical characteristics in chronic subdural hematoma patients assessed with lasso regression. AB - Chronic subdural hematoma (CSDH) is characterized by an "old" encapsulated collection of blood and blood breakdown products between the brain and its outermost covering (the dura). Recognized risk factors for development of CSDH are head injury, old age and using anticoagulation medication, but its underlying pathophysiological processes are still unclear. It is assumed that a complex local process of interrelated mechanisms including inflammation, neomembrane formation, angiogenesis and fibrinolysis could be related to its development and propagation. However, the association between the biomarkers of inflammation and angiogenesis, and the clinical and radiological characteristics of CSDH patients, need further investigation. The high number of biomarkers compared to the number of observations, the correlation between biomarkers, missing data and skewed distributions may limit the usefulness of classical statistical methods. We therefore explored lasso regression to assess the association between 30 biomarkers of inflammation and angiogenesis at the site of lesions, and selected clinical and radiological characteristics in a cohort of 93 patients. Lasso regression performs both variable selection and regularization to improve the predictive accuracy and interpretability of the statistical model. The results from the lasso regression showed analysis exhibited lack of robust statistical association between the biomarkers in hematoma fluid with age, gender, brain infarct, neurological deficiencies and volume of hematoma. However, there were associations between several of the biomarkers with postoperative recurrence requiring reoperation. The statistical analysis with lasso regression supported previous findings that the immunological characteristics of CSDH are local. The relationship between biomarkers, the radiological appearance of lesions and recurrence requiring reoperation have been inclusive using classical statistical methods on these data, but lasso regression revealed an association with inflammatory and angiogenic biomarkers in hematoma fluid. We thus suggest that lasso regression should be a recommended statistical method in research on biological processes in CSDH patients. PMID- 29108001 TI - Retraction: Anti Japanese encephalitis virus IgM positivity among patients with acute encephalitic syndrome admitted to different hospitals from all over Nepal. PMID- 29108000 TI - Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1. AB - : Host genetic variation modifying HIV-1 acquisition risk can inform development of HIV-1 prevention strategies. However, associations between rare or intermediate-frequency variants and HIV-1 acquisition are not well studied. We tested for the association between variation in genic regions and extreme HIV-1 acquisition phenotypes in 100 sub-Saharan Africans with whole genome sequencing data. Missense variants in immunoglobulin-like regions of CD101 and, among women, one missense/5' UTR variant in UBE2V1, were associated with increased HIV-1 acquisition risk (p = 1.9x10-4 and p = 3.7x10-3, respectively, for replication). Both of these genes are known to impact host inflammatory pathways. Effect sizes increased with exposure to HIV-1 after adjusting for the independent effect of increasing exposure on acquisition risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT00194519; NCT00557245. PMID- 29108002 TI - Structural basis of antifreeze activity of a bacterial multi-domain antifreeze protein. AB - Antifreeze proteins (AFPs) enhance the survival of organisms inhabiting cold environments by affecting the formation and/or structure of ice. We report the crystal structure of the first multi-domain AFP that has been characterized. The two ice binding domains are structurally similar. Each consists of an irregular beta-helix with a triangular cross-section and a long alpha-helix that runs parallel on one side of the beta-helix. Both domains are stabilized by hydrophobic interactions. A flat plane on the same face of each domain's beta helix was identified as the ice binding site. Mutating any of the smaller residues on the ice binding site to bulkier ones decreased the antifreeze activity. The bulky side chain of Leu174 in domain A sterically hinders the binding of water molecules to the protein backbone, partially explaining why antifreeze activity by domain A is inferior to that of domain B. Our data provide a molecular basis for understanding differences in antifreeze activity between the two domains of this protein and general insight on how structural differences in the ice-binding sites affect the activity of AFPs. PMID- 29108003 TI - Schistosoma, other helminth infections, and associated risk factors in preschool aged children in urban Tanzania. AB - BACKGROUND: Despite the high prevalence of helminth infections among preschool aged children, control programs in sub-Saharan countries primarily focus on school-aged populations. We assessed the prevalence of helminth infections and determined risk factors for infection among preschool-aged children in the urban setting of Dar es Salaam, Tanzania. METHODOLOGY: Starting in October 2015, we conducted a 12-month prospective study among tuberculosis (TB)-exposed children under the age of 5 years and unexposed controls from neighboring households. At the time of recruitment, we collected medical histories, assessed development and cognitive functions, and performed medical examinations. We performed full blood cell counts and screened for HIV and malaria. Point-of-care circulating cathodic antigen (POC-CCA), urine filtration, Kato-Katz, FLOTAC, and Baermann tests were employed to detect helminth infections in urine and stool. Helminth infections were stratified for Schistosoma and other helminths to identify risk factors, using logistic regression. PRINCIPAL FINDINGS: We included 310 children with a median age of 26 months (inter quartile range 17-42 months) in the study. Among these, 189 were TB-exposed and 121 TB-unexposed. Two thirds of the children were anemic (hemoglobin level <11 g/dl) and the HIV prevalence was 1.3%. Schistosoma spp. was the predominant helminth species (15.8%; 95% confidence interval [CI] 12.1-20.3%). Other helminth infections were less frequent (9.0%, 95% CI 6.3 12.8%). Poor hygiene, use of household water sources, and TB-exposure were not associated with helminth infection. Development and cognitive scores did not significantly differ in helminth-infected and uninfected peers, but hemoglobin levels were significantly lower in helminth-infected children (10.1 g/dl vs. 10.4 g/dl, p = 0.027). CONCLUSIONS/SIGNIFICANCE: In Dar es Salaam, a city with more than 4 million inhabitants, the prevalence of Schistosoma spp. infection among preschool-aged children was unexpectedly high. Setting-specific interventions that target preschool-aged children and urban settlements should be considered to reduce the transmission of Schistosoma and other helminth infections and to improve children's health. PMID- 29108004 TI - Direct and indirect effects of different types of microplastics on freshwater prey (Corbicula fluminea) and their predator (Acipenser transmontanus). AB - We examined whether environmentally relevant concentrations of different types of microplastics, with or without PCBs, directly affect freshwater prey and indirectly affect their predators. Asian clams (Corbicula fluminea) were exposed to environmentally relevant concentrations of polyethylene terephthalate (PET), polyethylene, polyvinylchloride (PVC) or polystyrene with and without polychlorinated biphenyls (PCBs) for 28 days. Their predators, white sturgeon (Acipenser transmontanus), were exposed to clams from each treatment for 28 days. In both species, we examined bioaccumulation of PCBs and effects (i.e., immunohistochemistry, histology, behavior, condition, mortality) across several levels of biological organization. PCBs were not detected in prey or predator, and thus differences in bioaccumulation of PCBs among polymers and biomagnification in predators could not be measured. One of the main objectives of this study was to test the hypothesis that bioaccumulation of PCBs would differ among polymer types. Because we could not answer this question experimentally, a bioaccumulation model was run and predicted that concentrations of PCBs in clams exposed to polyethylene and polystyrene would be greater than PET and PVC. Observed effects, although subtle, seemed to be due to microplastics rather than PCBs alone. For example, histopathology showed tubular dilation in clams exposed to microplastics with PCBs, with only mild effects in clams exposed to PCBs alone. PMID- 29108005 TI - Identification of genes and critical control proteins associated with inflammatory breast cancer using network controllability. AB - One of the most aggressive forms of breast cancer is inflammatory breast cancer (IBC), whose lack of tumour mass also makes a prompt diagnosis difficult. Moreover, genomic differences between common breast cancers and IBC have not been completely assessed, thus substantially limiting the identification of biomarkers unique to IBC. Here, we developed a novel statistical analysis of gene expression profiles corresponding to microdissected IBC, non-IBC (nIBC) and normal samples that enabled us to identify a set of genes significantly associated with a specific disease state. Second, by using advanced methods based on controllability network theory, we identified a set of critical control proteins that uniquely and structurally control the entire proteome. By mapping high change variance genes in protein interaction networks, we found that a large statistically significant fraction of genes whose variance changed significantly between normal and IBC and nIBC disease states were among the set of critical control proteins. Moreover, this analysis identified the overlapping genes with the highest statistical significance; these genes may assist in developing future biomarkers and determining drug targets to disrupt the molecular pathways driving carcinogenesis in IBC. PMID- 29108006 TI - Incidence and outcomes of acute kidney injury in extremely-low-birth-weight infants. AB - BACKGROUND: Acute kidney injury (AKI) is a common event in the neonatal intensive care unit (NICU), especially in extremely-low-birth-weight (ELBW) infants. This cohort study investigated the incidence of and risk factors for AKI in ELBW infants and their overall survival at the postmenstrual age (PMA) of 36 weeks. METHODS: All ELBW infants admitted to our NICU between January 2010 and December 2013 were enrolled. Those who died prior to 72 hours of life, had congenital renal abnormality, or had only one datum of the serum creatinine (SCr) level after the first 24 hours of life were excluded. The criteria used for the diagnosis of AKI was set according to the modified neonatal KDIGO AKI definition. RESULTS: AKI occurred in 56% of 276 infants. Specifically, stage 1, stage 2, and stage 3 AKI occurred in 30%, 17%, and 9% of ELBW infants, respectively. High frequency ventilation support (adjusted odds ratio [OR]: 3.4, 95% confidence interval [CI]: 1.78-6.67, p< 0.001), the presence of patent ductus arteriosus (adjusted OR: 4.3, 95% CI: 2.25-8.07, p < 0.001), lower gestational age (adjusted OR for gestational age: 0.7, 95% CI: 0.58-0.83, < 0.001), and inotropic agent use (adjusted OR: 2.6, 95% CI: 1.31-5.21, p = 0.006) were independently associated with AKI. Maternal pre-eclampsia was a protective factor (adjusted OR: 0.4, 95% CI: 0.14-0.97, p = 0.044). Infants with AKI had higher mortality before the PMA of 36 weeks with an adjusted hazard ratio (HR) of 5.34 (95% CI: 1.21-23.53, p = 0.027). Additionally, infants with stage 3 AKI had a highest HR of 10.60, 95% CI: 2.09-53.67, p = 0.004). CONCLUSION: AKI was a very common event (56%) in ELBW infants and was associated with a lower GA, high-frequency ventilation support, the presence of PDA, and inotropic agent use. AKI reduced survival of ELBW infants before the PMA of 36 weeks. PMID- 29108007 TI - Drop-out from the tuberculosis contact investigation cascade in a routine public health setting in urban Uganda: A prospective, multi-center study. AB - SETTING: Seven public tuberculosis (TB) units in Kampala, Uganda, where Uganda's national TB program recently introduced household contact investigation, as recommended by 2012 guidelines from WHO. OBJECTIVE: To apply a cascade analysis to implementation of household contact investigation in a programmatic setting. DESIGN: Prospective, multi-center observational study. METHODS: We constructed a cascade for household contact investigation to describe the proportions of: 1) index patient households recruited; 2) index patient households visited; 3) contacts screened for TB; and 4) contacts completing evaluation for, and diagnosed with, active TB. RESULTS: 338 (33%) of 1022 consecutive index TB patients were eligible for contact investigation. Lay health workers scheduled home visits for 207 (61%) index patients and completed 104 (50%). Among 287 eligible contacts, they screened 256 (89%) for symptoms or risk factors for TB. 131 (51%) had an indication for further TB evaluation. These included 59 (45%) with symptoms alone, 58 (44%) children <5, and 14 (11%) with HIV. Among 131 contacts found to be symptomatic or at risk, 26 (20%) contacts completed evaluation, including five (19%) diagnosed with and treated for active TB, for an overall yield of 1.7%. The cumulative conditional probability of completing the entire cascade was 5%. CONCLUSION: Major opportunities exist for improving the effectiveness and yield of TB contact investigation by increasing the proportion of index households completing screening visits by lay health workers and the proportion of at-risk contacts completing TB evaluation. PMID- 29108008 TI - Insights into the molecular evolution of peptidase inhibitors in arthropods. AB - Peptidase inhibitors are key proteins involved in the control of peptidases. In arthropods, peptidase inhibitors modulate the activity of peptidases involved in endogenous physiological processes and peptidases of the organisms with which they interact. Exploring available arthropod genomic sequences is a powerful way to obtain the repertoire of peptidase inhibitors in every arthropod species and to understand the evolutionary mechanisms involved in the diversification of this kind of proteins. A genomic comparative analysis of peptidase inhibitors in species belonging to different arthropod taxonomic groups was performed. The results point out: i) species or clade-specific presence is shown for several families of peptidase inhibitors; ii) multidomain peptidase inhibitors are commonly found in many peptidase inhibitor families; iii) several families have a wide range of members in different arthropod species; iv) several peptidase inhibitor families show species-specific (or clade-specific) gene family expansions; v) functional divergence may be assumed for particular clades; vi) passive expansions may be used by natural selection to fix adaptations. In conclusion, conservation and divergence of duplicated genes and the potential recruitment as peptidase inhibitors of proteins from other families are the main mechanisms used by arthropods to fix diversity. This diversity would be associated to the control of target peptidases and, as consequence, to adapt to specific environments. PMID- 29108009 TI - Zika virus displacement by a chikungunya outbreak in Recife, Brazil. AB - BACKGROUND: Several arboviruses, including dengue virus (DENV), Zika virus (ZIKV) and chikungunya virus (CHIKV), transmitted by Aedes mosquitoes, circulate in northeast Brazil. Diseases caused by these viruses are of great public health relevance, however, their epidemiological features in areas where the three viruses co-circulate are scarce. Here, we present analyses of molecular and serological diagnostics in a prospective study of acute febrile patients recruited from May 2015 to May 2016 in Recife, Brazil. METHODS: Two hundred sixty three acute febrile patients with symptoms suggestive of an arboviral disease who attended an urgent heath care clinic in the Recife Metropolitan Region in northeast Brazil were enrolled. Acute and convalescent blood samples were collected and tested using molecular and serological assays for infection with DENV, ZIKV and CHIKV. RESULTS: Quantitative real-time reverse-transcriptase polymerase chain reactions (qRTPCR) performed on acute phase sera detected no patients positive for DENV, but 26 (9.9%) positive for ZIKV and 132 (50.2%) positive for CHIKV. There were a few suspected and only one confirmed dengue case. Specific serological assays for ZIKV and CHIKV confirmed the qRTPCR data. Analyses of DENV IgM and IgG ELISAs in the context of qRTPCR results suggested high levels of cross reactive antibodies in ZIKV-positive samples. Results from neutralization assays highly corroborated those from qRTPCR and ZIKV ELISA, indicating very few positive DENV cases. ZIKV infections were temporally clustered in the first months of the study and started to decrease concomitantly with an increase in CHIKV infections in August 2015. The proportion of CHIKV infections increased significantly in September 2015 and remained high until the end of the study period, with an average of 84.7% of recruited patients being diagnosed from August 2015 to May 2016. ZIKV infections exhibited a female bias and the cases were spread over the study site, while CHIKV cases had a male bias and were spatially clustered in each month. CONCLUSIONS: In 2015-2016 in the Recife Metropolitan Region, we detected the tail end of a Zika epidemic, which was displaced by a chikungunya epidemic. Few dengue cases were identified despite a high number of official dengue notifications in the area during this period. We show here important epidemiological features of these cases. PMID- 29108010 TI - Maternal immune activation in rats produces temporal perception impairments in adult offspring analogous to those observed in schizophrenia. AB - The neurophysiology underlying temporal perception significantly overlaps with areas of dysfunction identified in schizophrenia. Patients commonly exhibit distorted temporal perception, which likely contributes to functional impairments. Thus, study of temporal perception in animal models of the disease may help to understand both cognitive and neurobiological factors involved in functional impairments in patients. As maternal immune activation (MIA) has been shown to be a significant etiological risk factor in development of schizophrenia and other developmental psychiatric diseases, we tested interval timing in a rat model of MIA that has previously been shown to recapitulate several behavioural and neurophysiological impairments observed in the disease. Rats were tested on a temporal-bisection task, in which temporal duration stimuli were categorized as either "short" or "long" by responding to a corresponding lever. Data from this task were modeled to provide estimates of accuracy and sensitivity of temporal perception. Parameter estimates derived from the model fitting showed that MIA rats significantly overestimated the passage of time compared to controls. These results indicate that the MIA rat paradigm recapitulates timing distortions that are phenotypical of schizophrenia. These findings lend further support to the epidemiological validity of this MIA rat model, supporting its relevance for future research into the role of maternal immune activation in producing neurobiological and behavioural impairments in schizophrenia. PMID- 29108011 TI - Evidence of increased exposure to Toxoplasma gondii in individuals with recent onset psychosis but not with established schizophrenia. AB - A possible role for Toxoplasma gondii in the etiopathogenesis of schizophrenia is supported by epidemiological studies and animal models of infection. However, recent studies attempting to link Toxoplasma to schizophrenia have yielded mixed results. We performed a nested case-control study measured serological evidence of exposure to Toxoplasma gondii in a cohort of 2052 individuals. Within this cohort, a total of 1481 individuals had a psychiatric disorder and 571 of were controls without a psychiatric disorder. We found an increased odds of Toxoplasma exposure in individuals with a recent onset of psychosis (OR 2.44, 95% Confidence Interval 1.4-4.4, p < .003). On the other hand, an increased odds of Toxoplasma exposure was not found in individuals with schizophrenia or other psychiatric disorder who did not have a recent onset of psychosis. By identifying the timing of evaluation as a variable, these findings resolve discrepancies in previous studies and suggest a temporal relationship between Toxoplasma exposure and disease onset. PMID- 29108012 TI - Oral immunization of a non-recombinant Lactococcus lactis surface displaying influenza hemagglutinin 1 (HA1) induces mucosal immunity in mice. AB - Mucosal immunization of influenza vaccine is potentially an effective approach for the prevention and control of influenza. The objective of the present study was to evaluate the ability of oral immunization with a non-recombinant Lactococcus lactis displaying HA1/L/AcmA recombinant protein, LL-HA1/L/AcmA, to induce mucosal immune responses and to accord protection against influenza virus infection in mice. The LL-HA1/L/AcmA was orally administered into mice and the immune response was evaluated. Mice immunized with LL-HA1/L/AcmA developed detectable specific sIgA in faecal extract, small intestine wash, BAL fluid and nasal fluid. The results obtained demonstrated that oral immunization of mice with LL-HA1/L/AcmA elicited mucosal immunity in both the gastrointestinal tract and the respiratory tract. The protective efficacy of LL-HA1/L/AcmA in immunized mice against a lethal dose challenge with influenza virus was also assessed. Upon challenge, the non-immunized group of mice showed high susceptibility to influenza virus infection. In contrast, 7/8 of mice orally immunized with LL HA1/L/AcmA survived. In conclusion, oral administration of LL-HA1/L/AcmA in mice induced mucosal immunity and most importantly, provided protection against lethal influenza virus challenge. These results highlight the potential application of L. lactis as a platform for delivery of influenza virus vaccine. PMID- 29108013 TI - A computational approach for designing D-proteins with non-canonical amino acid optimised binding affinity. AB - Redesigning protein surface topology to improve target binding holds great promise in the search for highly selective therapeutics. While significant binding improvements can be achieved using natural amino acids, the introduction of non-canonical residues vastly increases sequence space and thus the chance to significantly out-compete native partners. The potency of protein inhibitors can be further enhanced by synthesising mirror image, D-amino versions. This renders them non-immunogenic and makes them highly resistant to proteolytic degradation. Current experimental design methods often preclude the use of D-amino acids and non-canonical amino acids for a variety of reasons. To address this, we build an in silico pipeline for D-protein designs featuring non-canonical amino acids. For a test scaffold we use an existing D-protein inhibitor of VEGF: D-RFX001. We benchmark the approach by recapitulating previous experimental optimisation with canonical amino acids. Subsequent incorporation of non-canonical amino acids allows designs that are predicted to improve binding affinity by up to -7.18 kcal/mol. PMID- 29108014 TI - Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil. AB - New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy related mutations. PMID- 29108015 TI - Mutations that impair Eyes absent tyrosine phosphatase activity in vitro reduce robustness of retinal determination gene network output in Drosophila. AB - A limited collection of signaling networks and transcriptional effectors directs the full spectrum of cellular behaviors that comprise development. One mechanism to diversify regulatory potential is to combine multiple biochemical activities into the same protein. Exemplifying this principle of modularity, Eyes absent (Eya), originally identified as a transcriptional co-activator within the retinal determination gene network (RDGN), also harbors tyrosine and threonine phosphatase activities. Although mounting evidence argues for the importance of Eya's phosphatase activities to mammalian biology, genetic rescue experiments in Drosophila have shown that the tyrosine phosphatase function is dispensable for normal development. In this study, we repeated these rescue experiments in genetically sensitized backgrounds in which the dose of one or more RDGN factor was reduced. Heterozygosity for sine oculis or dachshund, both core RDGN members, compromised the ability of phosphatase-dead eya, but not of the control wild type eya transgene, to rescue the retinal defects and reduced viability associated with eya loss. We speculate that Eya's tyrosine phosphatase activity, although non-essential, confers robustness to RDGN output. PMID- 29108016 TI - Behavioral and pathophysiological outcomes associated with caffeine consumption and repetitive mild traumatic brain injury (RmTBI) in adolescent rats. AB - Given that caffeine consumption is exponentially rising in adolescents and they are at increased risk for repetitive mild traumatic brain injury (RmTBI), we sought to examine the pathophysiological outcomes associated with early life caffeine consumption and RmTBI. Adolescent male and female Sprague Dawley rats received either caffeine in the drinking water or normal water and were then randomly assigned to 3 mild injuries using our lateral impact device or 3 sham procedures. Following injury induction, behavioral outcomes were measured with a test battery designed to examine symptoms consistent with clinical manifestation of PCS (balance and motor coordination, anxiety, short-term working memory, and depressive-like behaviours). In addition, pathophysiological outcomes were examined with histological measures of volume and cellular proliferation in the dentate gyrus, as well as microglia activation in the ventromedial hypothalamus. Finally, modifications to expression of 12 genes (Adora2a, App, Aqp4, Bdnf, Bmal1, Clock, Cry, Gfap, Orx1, Orx2, Per, Tau), in the prefrontal cortex, hippocampus, and/or the hypothalamus were assessed. We found that chronic caffeine consumption in adolescence altered normal developmental trajectories, as well as recovery from RmTBI. Of particular importance, many of the outcomes exhibited sex-dependent responses whereby the sex of the animal modified response to caffeine, RmTBI, and the combination of the two. These results suggest that caffeine consumption in adolescents at high risk for RmTBI should be monitored. PMID- 29108017 TI - Assessing risk of fibrosis progression and liver-related clinical outcomes among patients with both early stage and advanced chronic hepatitis C. AB - OBJECTIVE: Assessing risk of adverse outcomes among patients with chronic liver disease has been challenging due to non-linear disease progression. We previously developed accurate prediction models for fibrosis progression and clinical outcomes among patients with advanced chronic hepatitis C (CHC). The primary aim of this study was to validate fibrosis progression and clinical outcomes models among a heterogeneous patient cohort. DESIGN: Adults with CHC with >=3 years follow-up and without hepatic decompensation, hepatocellular carcinoma (HCC), liver transplant (LT), HBV or HIV co-infection at presentation were analyzed (N = 1007). Outcomes included: 1) fibrosis progression 2) hepatic decompensation 3) HCC and 4) LT-free survival. Predictors included longitudinal clinical and laboratory data. Machine learning methods were used to predict outcomes in 1 and 3 years. RESULTS: The external cohort had a median age of 49.4 years (IQR 44.3 54.3); 61% were male, 80% white, and 79% had genotype 1. At presentation, 73% were treatment naive and 31% had cirrhosis. Fibrosis progression occurred in 34% over a median of 4.9 years (IQR 3.2-7.6). Clinical outcomes occurred in 22% over a median of 4.4 years (IQR 3.2-7.6). Model performance for fibrosis progression was limited due to small sample size. The area under the receiver operating characteristic curve (AUROC) for 1 and 3-year risk of clinical outcomes was 0.78 (95% CI 0.73-0.83) and 0.76 (95% CI 0.69-0.81). CONCLUSION: Accurate assessments for risk of clinical outcomes can be obtained using routinely collected data across a heterogeneous cohort of patients with CHC. These methods can be applied to predict risk of progression in other chronic liver diseases. PMID- 29108018 TI - Swimming championship finalist positions on success in international swimming competitions. AB - The primary goal was to determine whether the achievement of finalist positions in the Junior Championship was associated with the achievement of success in the International Swimming Federation (FINA) World Championship (WC). Secondary goals included analyzing the effect of various factors (gender, age, country, etc) on swimmers' performances. Data were obtained from FINA information about the finalists from 2007 to 2015 WCs and finalists from 2006 to 2013 Junior-WCs (2400 entries). Final filtered database just included swimmers who participated in both junior and senior WCs (719 entries). A univariate general linear model (GLM) was used to examine the association between time; origin (swimmer who participated in Junior WC or not); maintenance years (number of years achieving finalist positions); country; and age, adjusting for year of competition. An ordinal logistic regression (OLR) model was used to identify predictors of achieving the top positions. The origin variable was not significant in either the GLM or the OLR. The only significant variables in the GLM were maintenance years (F4,706 = 7.689; p < .05) and year of competition (F4,706 = 23.239; p < .05). The OLR revealed a strong association (p < .001) between the position variable and maintenance years, getting better positions as you get more WCs (odds = 1.85). In conclusion, no evidence was obtained to conclude finalist position in Junior WC have influence in achieve success in FINA WC. Maintenance years in WCs have a positive impact to achieve better positions. PMID- 29108019 TI - Stochastic loss and gain of symmetric divisions in the C. elegans epidermis perturbs robustness of stem cell number. AB - Biological systems are subject to inherent stochasticity. Nevertheless, development is remarkably robust, ensuring the consistency of key phenotypic traits such as correct cell numbers in a certain tissue. It is currently unclear which genes modulate phenotypic variability, what their relationship is to core components of developmental gene networks, and what is the developmental basis of variable phenotypes. Here, we start addressing these questions using the robust number of Caenorhabditis elegans epidermal stem cells, known as seam cells, as a readout. We employ genetics, cell lineage tracing, and single molecule imaging to show that mutations in lin-22, a Hes-related basic helix-loop-helix (bHLH) transcription factor, increase seam cell number variability. We show that the increase in phenotypic variability is due to stochastic conversion of normally symmetric cell divisions to asymmetric and vice versa during development, which affect the terminal seam cell number in opposing directions. We demonstrate that LIN-22 acts within the epidermal gene network to antagonise the Wnt signalling pathway. However, lin-22 mutants exhibit cell-to-cell variability in Wnt pathway activation, which correlates with and may drive phenotypic variability. Our study demonstrates the feasibility to study phenotypic trait variance in tractable model organisms using unbiased mutagenesis screens. PMID- 29108020 TI - Post-conflict opponent affiliation reduces victim re-aggression in a family group of captive arctic wolves (Canis lupus arctos). AB - Post-conflict affiliative interactions have been widely investigated in primates but not extensively in other species. Using the Post Conflict-Matched Control (PC MC) comparison method, this study investigated the patterns of post-conflict opponent affiliation (POA) of a captive family group of 19 arctic wolves (Canis lupus arctos), investigating the correlation with various factors. We found that POAs occurred mainly in the non-feeding context and more often when the victim was dominant and the aggressor subordinate. Furthermore, POAs were more likely to have been initiated by the victim than the aggressor. Victims' stress related behaviours occurred more in PC than MC periods, and more after high vs. low intensity aggressions but they were not more likely to occur after conflicts between wolves with a stronger social bond and POAs did not reduce their rate of occurrence. Our results showed that re-aggression was twice less frequent when a friendly interaction occurred between the aggressor and the victim, and consistent with this, victims engaged in POAs more often than the aggressor. Overall, our results support the hypothesis that POAs in wolves may have been selected for as a mechanism to avoid conflict escalation, which could lead to social disruption and hence jeopardize cooperative activities. The high relatedness among individuals in the pack and the greater dependence of all members on cooperation in breeding and hunting may reduce the importance of 'relationship quality' as a mediating factor of POAs, although dominance relationships, which are directly linked to the risks of further conflicts, do play an important role. PMID- 29108023 TI - Health seeking behavior following snakebites in Sri Lanka: Results of an island wide community based survey. AB - INTRODUCTION: Sri Lanka has a population of 21 million and about 80,000 snakebites occur annually. However, there are limited data on health seeking behavior following bites. We investigated the effects of snakebite and envenoming on health seeking behavior in Sri Lanka. METHODS: In a community-based island wide survey conducted in Sri Lanka 44,136 households were sampled using a multistage cluster sampling method. An individual who reported experiencing a snakebite within the preceding 12 months was considered a case. An interviewer administered questionnaire was used to obtain details of the bite and health seeking behavior among cases. RESULTS: Among 165,665 individuals surveyed, there were 695 snakebite victims. 682 (98.1%) had sought health care after the bite; 381 (54.8%) sought allopathic treatment and 301 (43.3%) sought traditional treatment. 323 (46.5%) had evidence of probable envenoming, among them 227 (70.3%) sought allopathic treatment, 94 (29.1%) sought traditional treatment and 2 did not seek treatment. There was wide geographic variation in the proportion of seeking allopathic treatment from <20% in the Western province to > 90% in the Northern province. Multiple logistic regression analysis showed that seeking allopathic treatment was independently associated with being systemically envenomed (Odds Ratio = 1.99, 95% CI: 1.36-2.90, P < 0.001), distance to the healthcare facility (OR = 1.13 per kilometer, 95% CI: 1.09 to 1.17, P < 0.001), time duration from the bite (OR = 0.49 per day, 95% CI: 0.29-0.74, P = 0.002), and the local incidence of envenoming (OR = 1.31 for each 50 per 100,000, 95% CI: 1.19-1.46, P < 0.001) and snakebite (OR = 0.90 for each 50 per 100,000, 95% CI: 0.85-0.94, P < 0.001) in the relevant geographic area. CONCLUSIONS: In Sri Lanka, both allopathic and traditional treatments are sought following snakebite. The presence of probable envenoming was a major contribution to seeking allopathic treatment. PMID- 29108024 TI - Generation of polychromatic projection for dedicated breast computed tomography simulation using anthropomorphic numerical phantom. AB - Numerical simulations are fundamental to the development of medical imaging systems because they can save time and effort in research and development. In this study, we developed a method of creating the virtual projection images that are necessary to study dedicated breast computed tomography (BCT) systems. Anthropomorphic software breast phantoms of the conventional compression type were synthesized and redesigned to meet the requirements of dedicated BCT systems. The internal structure of the breast was randomly constructed to develop the proposed phantom, enabling the internal structure of a naturally distributed real breast to be simulated. When using the existing monochromatic photon incidence assumption for projection-image generation, it is not possible to simulate various artifacts caused by the X-ray spectrum, such as the beam hardening effect. Consequently, the system performance could be overestimated. Therefore, we considered the polychromatic spectrum in the projection image generation process and verified the results. The proposed method is expected to be useful for the development and optimization of BCT systems. PMID- 29108021 TI - Hippo, TGF-beta, and Src-MAPK pathways regulate transcription of the upd3 cytokine in Drosophila enterocytes upon bacterial infection. AB - Cytokine signaling is responsible for coordinating conserved epithelial regeneration and immune responses in the digestive tract. In the Drosophila midgut, Upd3 is a major cytokine, which is induced in enterocytes (EC) and enteroblasts (EB) upon oral infection, and initiates intestinal stem cell (ISC) dependent tissue repair. To date, the genetic network directing upd3 transcription remains largely uncharacterized. Here, we have identified the key infection-responsive enhancers of the upd3 gene and show that distinct enhancers respond to various stresses. Furthermore, through functional genetic screening, bioinformatic analyses and yeast one-hybrid screening, we determined that the transcription factors Scalloped (Sd), Mothers against dpp (Mad), and D-Fos are principal regulators of upd3 expression. Our study demonstrates that upd3 transcription in the gut is regulated by the activation of multiple pathways, including the Hippo, TGF-beta/Dpp, and Src, as well as p38-dependent MAPK pathways. Thus, these essential pathways, which are known to control ISC proliferation cell-autonomously, are also activated in ECs to promote tissue turnover the regulation of upd3 transcription. PMID- 29108022 TI - Risk factors for HIV infection among female sex workers in Bangui, Central African Republic. AB - OBJECTIVE: The aims of the study were i) to categorize female sex workers (FSW) according to socio-anthropologic criteria in Bangui; ii) to examine the association between a selection of demographic and risk variables with the different categories of female sex work as outcome, and iii) to investigate factors associated with HIV status. METHODS: A cross-sectional questionnaire survey was conducted to describe the spectrum of commercial sex work in Bangui among 345 sexually active women. After collection of social and behavioral characteristics, each woman received a physical examination and a blood sample was taken for biological analyses, including HIV testing. The relationships between sociodemographic characteristics, behavioral variables involved in high risk for HIV as well as biological results were investigated by bivariate analysis in relationship with FSW categories as main outcomes, and by bivariate analysis followed by multivariate logistic regression analysis in relationship with HIV as the main outcome. The strength of statistical associations was measured by crude and adjusted Odds ratios (OR) and their 95% confidence intervals. RESULTS: The typology of FSW comprised six different categories. Two groups were the "official" professional FSW primarily classified according to their locations of work [i) "kata"(18.55%) representing women working in poor neighborhoods of Bangui; ii) "pupulenge" (13.91%) working in hotels and night clubs to seek white men]. Four groups were "clandestine" nonprofessional FSW classified according to their reported main activity [i) "market and street vendors" (20.86%); ii) "schoolgirls or students" (19.13%) involved in occasional transactional sex (during holidays); iii) "housewives or unemployed women" (15.65%); iv) "civil servants" (11.88%) working as soldiers or in the public sector]. The overall prevalence of HIV-1 was 19.12% (66/345). HIV varied according to FSW categories. Thus, among professional FSW, the HIV prevalence was 6-fold higher in "kata" than "pupulenge" (39.13% versus 6.30%; P = 0.001). Among nonprofessional FSW, the "vendors" showed the highest HIV prevalence (31.91%), which was higher than in "students" (6.10%; P = 0.001), "civil servants" (9.83%; P = 0.005), and "housewives" (13.00%; P = 0.01). In bivariate analysis, the following variables showed statistically significant association with risk for HIV infection: nationality; age of first sexual intercourse; self-assessment of HIV risk; knowledge of HIV status; anal sex practice with last clients; irregular condom use in last week; consumption of alcohol; other psycho-active substances; past history of STIs; HBs Ag; HSV-2 and bacterial vaginosis. However, the variable "sex workers categories" dichotomized into professional versus nonprofessional FSW was no longer associated with HIV. In multivariate logistical regression analysis, HIV infection was strongly associated with nationality (15.65% versus 3.77%) [adjusted OR (aOR) 3.39: 95% CI:1.25-9.16, P<0.05]; age of first sexual intercourse (21.10% versus 14.00%) (aOR 2.13: 95% CI: 1.03-4.39, P<0.05); anal sex practice with last clients (43.40% versus 11.50%) (aOR 4.31: 95% CI:2.28-8.33, P<0.001); irregular condom use in past week (33.50% versus 3.00%) (aOR 5.49: 95% CI:1.89-15.98, P<0.001); alcohol consumption before sex (34.70% versus 7.80%) (aOR 2.69: 95% CI:1.22-4.96, P<0.05); past history of STIs (41.00% versus 10.80%) (aOR 2.46: 95% CI:1.22-4.97, P<0.05) and bacterial vaginosis (29.80% versus 4.29%) (aOR 6.36: 95% CI: 2.30-17.72, P<0.001). CONCLUSION: Our observations highlight the high level of vulnerability for HIV acquisition of both poor professional "kata" and nonprofessional "street vendor" FSW categories. These categories should be particularly taken into account when designing specific prevention programs for STIs/HIV control purposes. PMID- 29108025 TI - The risk factor of clinical relapse in ulcerative colitis patients with low dose 5-aminosalicylic acid as maintenance therapy: A report from the IBD registry. AB - BACKGROUND: 5-Aminosalicylic acids (5-ASA) are effective for ulcerative colitis (UC) as a maintenance therapy. It is not clear when and how to reduce a dose of 5 ASA after inducing remission. We aimed to investigate the clinical characteristics and evaluate the risk factors of relapse for UC patients receiving 5-ASA. METHODS: The medical records of prospectively registered UC patients who received oral 5-ASA as maintenance therapy between January and December 31, 2014, were investigated. The patients' clinical characteristics in a 2-year follow-up were compared between a relapse group and a remission group. RESULTS: Of 527 UC patients receiving only oral 5-ASA, 390 (74.0%) maintained remission and 137 (26.0%) relapsed during the follow-up period. Multivariable analysis indicated that a shorter duration of disease remission (p < 0.001, OR: 1.24, 95% CI: 1.12-1.38) was statistically significant for each comparison between the remission and relapse groups among all the patients. Risk factors for clinical relapse were a shorter duration of disease remission (p <0.001, OR: 1.17, 95% CI: 1.04-1.33) in the high-dose 5-ASA group and a shorter duration of disease remission (p = 0.003, OR: 1.45, 95% CI: 1.13-1.89) and a history of steroid use (p = 0.048, OR: 4.73, 95% CI: 1.01-22.2) in the low-dose group. CONCLUSIONS: A dose reduction of 5-ASA might be cautiously selected in UC patients with a history of steroid use and a shorter duration of disease remission. PMID- 29108026 TI - Status of soil-transmitted helminth infections in schoolchildren in Laguna Province, the Philippines: Determined by parasitological and molecular diagnostic techniques. AB - BACKGROUND: Soil-transmitted helminths (STH) are the most common parasitic infections in impoverished communities, particularly among children. Current STH control is through school-based mass drug administration (MDA), which in the Philippines is done twice annually. As expected, MDA has decreased the intensity and prevalence of STH over time. As a result, the common Kato Katz (KK) thick smear method of detecting STH is less effective because it lacks sensitivity in low intensity infections, making it difficult to measure the impact of deworming programs. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was carried out over a four-week period from October 27, 2014 until November 20, 2014 in Laguna province, the Philippines. Stool samples were collected from 263 schoolchildren, to determine the prevalence of STH and compare diagnostic accuracy of multiplex quantitative polymerase chain reaction (qPCR) with the KK. A large discrepancy in the prevalence between the two techniques was noted for the detection of at least one type of STH infection (33.8% by KK vs. 78.3% by qPCR), Ascaris lumbricoides (20.5% by KK vs. 60.8% by qPCR) and Trichuris trichiura (23.6% by KK vs. 38.8% by qPCR). Considering the combined results of both methods, the prevalence of at least one type of helminth infection, A. lumbricoides, and T. trichiura were 83.3%, 67.7%, and 53.6%, respectively. Sensitivity of the qPCR for detecting at least one type of STH infection, A. lumbricoides, and T. trichiura were 94.1%, 89.9%, and 72.3% respectively; whereas KK sensitivity was 40.6%, 30.3%, and 44.0%, respectively. The qPCR method also detected infections with Ancylostoma spp. (4.6%), Necator americanus (2.3%), and Strongyloides stercoralis (0.8%) that were missed by KK. CONCLUSION/SIGNIFICANCE: qPCR may provide new and important diagnostic information to improve assessment of the effectiveness and impact of integrated control strategies particularly in areas where large-scale STH control has led to low prevalence and/or intensity of infection. PMID- 29108027 TI - Local application of an ibandronate/collagen sponge improves femoral fracture healing in ovariectomized rats. AB - Non-union is a major clinical problem in the healing of fractures, especially in patients with osteoporosis. The systemic administration of drugs is time consuming and large doses are demanding and act slowly, whereas local release acts rapidly, increases the quality and quantity of the bone tissue. We hypothesize that local delivery demonstrates better therapeutic effects on an osteoporotic fracture. The aim of this paper is to investigate the effect of the local application of ibandronate loaded with a collagen sponge on regulating bone formation and remodeling in an osteoporotic rat model of fracture healing. We found that the local delivery of ibandronate exhibited excellent effects on improving the bone microarchitecture and suppressed effects on bone remodeling. At 4 weeks, more callus formation and improvement of mechanical character and microstructure were observed in a local delivery via MUCT, mechanical test, histological research and serum analysis. The suppression of bone remodeling was compared with a systemic treatment at 12 weeks, and the structural mechanical properties and microarchitecture were also improved with local delivery. This research identifies an earlier, safer and integrated approach for local delivery of ibandronate with collagen and provides a better strategy for the treatment of osteoporotic fracture in rats. PMID- 29108029 TI - Accelerometric estimates of physical activity vary unstably with data handling. AB - BACKGROUND: Because of unreliable self-report, accelerometry is increasingly used to objectively monitor physical activity (PA). However, results of accelerometric studies vary depending on the chosen cutpoints between activity intensities. Population-specific activity patterns likely affect the size of these differences. To establish their size and stability we apply three sets of cutpoints, including two calibrated to a single reference, to our accelerometric data and compare PA estimates. METHODS: 1402 German adolescents from the GINIplus and LISAplus cohorts wore triaxial accelerometers (Actigraph GT3x) for one week (mean 6.23 days, 14.7 hours per day) at the hip. After validation of wear, we applied three sets of cutpoints for youth, including the most common standard (Freedson, 2005) and two calibrated to a single reference, (Romanzini uni- and triaxial, from Romanzini, 2014) to these data, estimating daily sedentary, light, moderate, vigorous and moderate-to-vigorous PA (MPA, VPA, MVPA). Stability of differences was assessed by comparing Romanzini's two sets of cutpoints. RESULTS: Relative agreement between cutpoints was closer for activity of lower intensities (largest difference for sedentary behaviour 9%) but increased for higher intensities (largest difference for light activity 40%, MPA 102%, VPA 88%; all p<0.01). Romanzini's uniaxial and triaxial cutpoints agreed no more closely with each other than with Freedson's. CONCLUSIONS: Estimated PA differed significantly between different sets of cutpoints, even when those cutpoints agreed perfectly on another dataset (i.e. Romanzini's.) This suggests that the detected differences in estimated PA depend on population-specific activity patterns, which cannot be easily corrected for: converting activity estimates from one set of cutpoints to another may require access to raw data. This limits the utility of accelerometry for comparing populations in place and time. We suggest that accelerometric research adopt a standard for data processing, and apply and present the results of this standard in addition to those from any other method. PMID- 29108030 TI - Genetic parameters for semen quality and quantity traits in five pig lines. AB - We aimed to estimate genetic parameters for semen quality and quantity traits as well as for within-boar variation of these traits to evaluate their inclusion in breeding goals. Genetic parameters were estimated within line using a multiple trait (4 * 4) repeatability animal model fitted for 5 pig lines, considering 4 semen traits: sperm motility (MOT), sperm progressive motility (PROMOT), log transformed number of sperm cells per ejaculate (lnN), and total morphological abnormalities (ABN). The within-boar variation of these traits was analyzed based on a multiple-trait (2 * 2) approach for SD and average (AVG) and a single-trait analysis for CV. The average heritabilities across the 5 lines estimated by multiple-trait analysis were 0.18 +/- 0.07 (MOT), 0.22 +/- 0.08 (PROMOT), 0.16 +/ 0.04 (lnN), and 0.20 +/- 0.04 (ABN). The average genetic correlations were favorable between MOT and PROMOT (0.86 +/- 0.10), between MOT and ABN (-0.66 +/- 0.25), and between PROMOT and ABN (-0.65 +/- 0.25). As determined by within-boar variation analysis, AVG exhibited the greatest heritabilities followed by SD and CV, respectively, for the traits MOT and ABN. For PROMOT, average SD heritability was lower than CV heritability, whereas for lnN, they were the same. The average genetic correlations between AVG and SD were favorable for MOT (-0.60 +/- 0.13), PROMOT (-0.79 +/- 0.14), and ABN (0.78 +/- 0.17). The moderate heritabilities indicate the possibility of effective selection of boars based on semen traits. Average and SD are proposed as appropriate traits for selection regarding uniformity. PMID- 29108028 TI - Decreased plasma concentrations of BDNF and IGF-1 in abstinent patients with alcohol use disorders. AB - The identification of growth factors as potential biomarkers in alcohol addiction may help to understand underlying mechanisms associated with the pathogenesis of alcohol use disorders (AUDs). Previous studies have linked growth factors to neural plasticity in neurocognitive impairment and mental disorders. In order to further clarify the impact of chronic alcohol consumption on circulating growth factors, a cross-sectional study was performed in abstinent AUD patients (alcohol group, N = 91) and healthy control subjects (control group, N = 55) to examine plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and IGF-1 binding protein-3 (IGFBP-3). The association of these plasma peptides with relevant AUD-related variables and psychiatric comorbidity was explored. The alcohol group was diagnosed with severe AUD and showed an average of 13 years of problematic use and 10 months of abstinence at the moment of participating in the study. Regarding common medical conditions associated with AUD, we observed an elevated incidence of alcohol-induced liver and pancreas diseases (18.7%) and psychiatric comorbidity (76.9%). Thus, AUD patients displayed a high prevalence of dual diagnosis (39.3%) [mainly depression (19.9%)] and comorbid substance use disorders (40.7%). Plasma BDNF and IGF-1 concentrations were significantly lower in the alcohol group than in the control group (p<0.001). Remarkably, there was a negative association between IGF-1 concentrations and age in the control group (r = -0.52, p<0.001) that was not found in the alcohol group. Concerning AUD-related variables, AUD patients with liver and pancreas diseases showed even lower concentrations of BDNF (p<0.05). In contrast, the changes in plasma concentrations of these peptides were not associated with abstinence, problematic use, AUD severity or lifetime psychiatric comorbidity. These results suggest that further research is necessary to elucidate the role of BDNF in alcohol-induced toxicity and the biological significance of the lack of correlation between age and plasma IGF-1 levels in abstinent AUD patients. PMID- 29108031 TI - Beef steers with average dry matter intake and divergent average daily gain have altered gene expression in the jejunum. AB - The objective of this study was to determine the association of differentially expressed genes (DEG) in the jejunum of steers with average DMI and high or low ADG. Feed intake and growth were measured in a cohort of 144 commercial Angus steers consuming a finishing diet containing (on a DM basis) 67.8% dry-rolled corn, 20% wet distillers grains with solubles, 8% alfalfa hay, and 4.2% vitamin/mineral supplement. From the cohort, a subset of steers with DMI within +/-0.32 SD of the mean for DMI and the greatest (high) and least (low) ADG were chosen for slaughter and jejunum mucosa collection ( = 8 for each group). Dry matter intake (10.1 +/- 0.05 kg/d) was not different ( = 0.41) but ADG was greater in the high-gain group (2.17 and 1.72 +/- 0.02 kg/d for the high- and low ADG groups, respectively; < 0.01). A total of 13,747 genes were found to be expressed in the jejunum, of which 64 genes were differentially expressed between the 2 groups (corrected < 0.05). Ten of the DEG were upregulated in the low-ADG group and 54 were upregulated in the high-ADG group. Gene ontology analysis determined that 24 biological process terms were overrepresented ( < 0.05), including digestion, drug and xenobiotic metabolism, and carbohydrate metabolism. Additionally, 89 molecular function terms were enriched ( < 0.05), including metallopeptidase activity, transporter activity, steroid hydrolase activity, glutathione transferase activity, and chemokine receptor binding. Metabolic pathways (28 pathways) impacted by the DEG ( < 0.05) included drug and xenobiotic metabolism by cytochrome P450, carbohydrate digestion and absorption, vitamin digestion and absorption, galactose metabolism, and linoleic acid metabolism. Results from this experiment indicate that cattle with average DMI and greater ADG likely have a greater capacity to handle foreign substances (xenobiotics). It is also possible that cattle with a greater ADG have a greater potential to digest and absorb nutrients in the small intestine. PMID- 29108032 TI - A heuristic method to identify runs of homozygosity associated with reduced performance in livestock. AB - Although, for the most part, genome-wide metrics are currently used in managing livestock inbreeding, genomic data offer, in principle, the ability to identify functional inbreeding. Here, we present a heuristic method to identify haplotypes contained within a run of homozygosity (ROH) associated with reduced performance. Results are presented for simulated and swine data. The algorithm comprises 3 steps. Step 1 scans the genome based on marker windows of decreasing size and identifies ROH genotypes associated with an unfavorable phenotype. Within this stage, multiple aggregation steps reduce the haplotype to the smallest possible length. In step 2, the resulting regions are formally tested for significance with the use of a linear mixed model. Lastly, step 3 removes nested windows. The effect of the unfavorable haplotypes identified and their associated haplotype probabilities for a progeny of a given mating pair or an individual can be used to generate an inbreeding load matrix (ILM). Diagonals of ILM characterize the functional individual inbreeding load (IIL). We estimated the accuracy of predicting the phenotype based on IIL. We further compared the significance of the regression coefficient for IIL on phenotypes with genome-wide inbreeding metrics. We tested the algorithm using simulated scenarios (12 scenarios), combining different levels of linkage disequilibrium (LD) and number of loci impacting a quantitative trait. Additionally, we investigated 9 traits from 2 maternal purebred swine lines. In simulated data, as the LD in the population increased, the algorithm identified a greater proportion of the true unfavorable ROH effects. For example, the proportion of highly unfavorable true ROH effects identified rose from 32 to 41% for the low- to the high-LD scenario. In both simulated and real data, the haplotypes identified were contained within a much larger ROH (9.12-12.1 Mb). The IIL prediction accuracy was greater than 0 across all scenarios for simulated data (mean of 0.49 [95% confidence interval 0.47 0.52] for the high-LD scenario) and for nearly all swine traits (mean of 0.17 [SD 0.10]). On average, across simulated and swine data sets, the IIL regression coefficient was more closely related to progeny performance than any genome-wide inbreeding metric. A heuristic method was developed that identified ROH genotypes with reduced performance and characterized the combined effects of ROH genotypes within and across individuals. PMID- 29108033 TI - Responses of fresh cows to three feeding strategies that reduce starch levels by feeding beet pulp. AB - The study objective was to evaluate the effects of reducing dietary starch content in fresh cow diets while maintaining NDF levels by substituting barley grain (BG), corn silage (CS), or both with beet pulp (BP) on nutrient digestion, ruminal fermentation, DMI, lactation performance, meal patterns, chewing activity, and sorting behavior. Thirty-six multiparous cows were randomly assigned to 1 of 4 experimental diets from calving to 21 d in lactation. Experimental diets were a high-starch diet with ground BG (CO; 24.9% starch; 0% BP) and 3 low-starch diets: the CO with BP substituted for ground BG (BB; 19.6% starch; 7% BP), the CO with BP substituted for CS (BC; 20.6% starch; 12% BP), or the CO with BP substituted for CS and ground BG (BCB; 20.3% starch; 12% BP). The CO, BB, BC, and BCB contained 33.4, 34.4, 32.9, and 33.7% NDF, respectively, and 23.1, 22.0, 18.2, and 19.2% forage NDF, respectively. There was no effect of diet on total tract nutrient digestibility ( > 0.20), ruminal pH ( = 0.49), or total VFA ( = 0.39). However, diets affected molar proportions of propionate and acetate ( <= 0.01). Relative to CO cows, the molar propionate percentage was less in BB cows ( < 0.01) and tended to be greater in BC cows ( = 0.10), whereas the molar percentage of acetate was less in BC cows than in BB ( < 0.01) and CO cows ( = 0.02). Relative to CO cows (16.50 kg/d), DMI was greater for BC (17.70 kg/d; < 0.01) and BCB cows (17.50 kg/d; = 0.01), but it was less in BB cows (15.60 kg/d; = 0.02). Similar to DMI results, milk yields tended to be greater for BC (37.89 kg/d; = 0.08) and BCB cows (37.81 kg/d; = 0.09) compared with CO cows (35.41 kg/d), but BB cows (33.05 kg/d) tended to produce less milk than CO cows ( = 0.1). Milk fat content tended to be less in BC ( = 0.08) and BCB cows ( = 0.10) than in CO cows. There was no effect of diet on eating and rumination patterns ( >= 0.18), except shortened meal intervals for BC and BCB cows compared with CO cows ( = 0.02). Dietary treatments did not affect chewing activities per day or bout ( = 0.50), but BC and BCB cows spent less time on chewing activities per kilogram DM ( < 0.01) and NDF intake ( < 0.01) compared with CO cows. Cows fed the BC and BCB sorted for long particles (>19 mm; < 0.01) but against particles < 1.18 mm ( < 0.01). In the present study, propionate did not seem to play a central role in feed intake regulation of fresh cows, because BB cows had depressed DMI and the lowest molar proportion of propionate. However, reducing starch levels in fresh cow diets by replacing CS and both CS and BG with BP positively affected DMI and milk yield. PMID- 29108034 TI - Genetic evaluation for birth and conformation traits in dual-purpose Belgian Blue cattle using a mixed inheritance model. AB - The segregation of the causal mutation () in the muscular hypertrophy gene in dual-purpose Belgian Blue (dpBB) cattle is considered to result in greater calving difficulty (dystocia). Establishing adapted genetic evaluations might overcome this situation through efficient selection. However, the heterogeneity of dpBB populations at the locus implies separating the major gene and other polygenic effects in complex modeling. The use of mixed inheritance models may be an interesting option because they simultaneously assume both influences. A genetic evaluation in dpBB based on a mixed inheritance model was developed for birth and conformation traits: gestation length (GL), calving difficulty (CD), birth weight (BiW), and body conformation score (BC). A total of 27,362 animals having records were used for analyses. The total number of animals in the pedigree used to build the numerator relationship matrix was 62,617. Genotypes at the locus were available for 2,671 animals. Missing records at this locus were replaced with genotype probabilities. A total of 13,221 (48.3%) were registered as dpBB, 1,287 (4.7%) as beef Belgian Blue, and 12,854 (47.0%) were unknown. From those 13,221 dpBB animals, 650, 849, and 534 had double or single copies or no copy, respectively, of the causal mutation () in the muscular hypertrophy gene, whereas 11,188 had missing genotypes. This heterogeneity at the locus may be the reason for high variability in the studied traits, that is, high heritability estimates of 0.33, 0.30, 0.38, and 0.43 for GL, CD, BiW, and BC, respectively. In general, additive ( < 0.05) and dominance ( < 0.001) allele substitution for calves and dams had significant impact for all traits. The moderate coefficient of genetic variation (27.80%) and high direct heritability (0.28) for CD suggested genetic variability in dpBB and possible genetic improvement through selection. This variability has allowed dpBB breeders to successfully apply mass selection in the past. Genetic trend means from 1988 to 2016 showed that sire selection for CD within genotype was progressively applied by breeders. The selection intensity was more important for CD in double-muscled lines than in segregated lines. Our study illustrated the possible confusion caused by the use of major genes in selection and the importance of fitting appropriate models such as mixed inheritance models that combine polygenic and gene content information. PMID- 29108035 TI - Sex effects on macromineral requirements for growth in Saanen goats: A meta analysis. AB - The aim of this study was to investigate the effects of sex on the net requirements of growth for Ca (NCa), P (NP), Na (NNa), K (NK), and Mg (NMg) in Saanen goats from 5 to 45 kg BW, with or without consideration of the degree of maturity. A database containing 209 individual records for Saanen goats (69 castrated males, 71 intact males, and 69 females) was generated from 6 comparative slaughter studies. Total amounts of Ca, P, Na, K, and Mg in the body were fitted to logarithmized allometric equations using empty BW (EBW) or degree of maturity (EBW/mature EBW) as regressors. The equations were fitted using a mixed model, where sex was considered a fixed effect and study was considered a random effect. Net requirements were estimated by the first derivative of the logarithmized allometric equations. Then, a Monte Carlo simulation was used to assess the uncertainty of calculated net requirement values. Without considering the degree of maturity, sex did not affect NCa, NP, and NNa ( > 0.10). Conversely, considering the degree of maturity, NCa and NP of intact males were 5% and 2%, respectively, greater than those of castrated males and females ( < 0.01), and NNa of males (castrated and intact) was 6% greater than that of females ( < 0.01). Regardless of approach used, NCa and NP remained constant, whereas NNa decreased by 32% as BW ranged from 5 to 45 kg. Without considering the degree of maturity, NMg of castrated and intact males were 8% and 18% greater than that of female goats ( = 0.054), respectively. Hereof NMg of castrated and intact males increased by 8% and 15%, respectively, whereas that of females decreased by 8% as BW ranged from 5 to 45 kg. Considering the degree of maturity, NMg of castrated and intact males were 7% and 17% greater than that of female goats ( = 0.054), respectively. In this regard, NMg of castrated and intact males increased 8% and 16%, respectively, whereas that of females decreased by 7% from 5 to 45 kg BW. Both approaches showed that, regardless of sex ( > 0.10), NK decreased by 26% (i.e., without considering the maturity degree) or 27% (i.e., considering the degree of maturity) from 5 to 45 kg BW. Therefore, the consideration of maturity stage highlights differences across sexes in the net macromineral requirements for growth in goats. Elucidation of sex effects on macromineral requirements for growth may be useful for improving the accuracy of recommendations for mineral requirements for dairy goats. PMID- 29108036 TI - Effect of the inoculation of sugarcane silage with Lactobacillus hilgardii and Lactobacillus buchneri on feeding behavior and milk yield of dairy cows. AB - Despite its low NDF digestibility, sugarcane is an option for feeding dairy cattle in tropical regions. We evaluated the effect of sugarcane silages inoculated with CCMA 0170 (LH; an epiphytic bacteria isolated from sugarcane) or with NCIMB 40788 (LB; a commercial strain isolated from temperate grasses) on dairy cow performance and feeding behavior. The microbial inoculums were previously grown in the laboratory to obtain 5 log cfu/g of fresh forage. Nine tons of each inoculated silage and a noninoculated control silage (CON) were harvested from the same field and stored for at least 35 d in experimental 20 * 2.1 * 0.4 m bunker silos. Fifteen Holstein cows in late lactation (336 +/- 175 days in milk at the start of the experiment) received the treatments in five 3 * 3 Latin squares with 21-d periods. The diets contained 20% of DM of sugarcane silage and 41% of DM of corn silage. Milk yield was increased from 18.0 kg/d for CON to18.8 kg/d for LH, but LB did not elicit a detectable increase in milk yield (18.1 kg/d). The daily yields of fat, protein, lactose, and total solids were increased by LH. Daily DMI and total tract apparent digestibility of nutrients did not differ among treatments. Both inoculated silages reduced acetate and increased butyrate proportions in ruminal VFA, but only LH silage reduced the acetate to propionate ratio (3.0 vs 3.3). First meal duration was shorter for CON compared to LH and LB. The proportion of daily intake between 0700 and 1300 h tended to be increased, and the proportion between 1900 and 0700 h was reduced by LH. The inoculation of sugarcane silage with affected rumen fermentation profile and feeding behavior of late lactation dairy cows, increasing the yield of milk solids. PMID- 29108038 TI - Prepartum daylight exposure increases serum calcium concentrations in dairy cows at the onset of lactation. AB - In dairy cows, hypocalcemia is caused by the sudden calcium demand by the mammary gland at the onset of lactation. Calcitriol (1,25-dihydroxy vitamin D; 1,25-VitD) increases the intestinal calcium absorption and the renal calcium reabsorption. Daylight contributes to the formation of 1,25-VitD, as it transforms 7 dehydrocholesterol into cholecalciferol, a 1,25-VitD precursor. Calving pens are usually set in quiet places where cows can stay calm and relaxed before parturition. However, those pens often have poor lighting conditions and therefore cows may become vitamin D deficient because of inadequate daylight exposure. Therefore, we have tested the hypothesis that direct daylight exposure supports the synthesis of 1,25-VitD and consequently attenuates the decline of calcium concentrations at parturition. Twenty Holstein dairy cows were randomly assigned to 2 experimental groups (daylight group, DL; and control group). Beginning on d -10 before expected parturition, both groups were placed in a standard indoor calving pen from 1700 h to 800 h. From 800 h to 1700 h cows from the DL group were moved into a contiguous open pen with direct access to daylight whereas controls remained at the standard indoor calving pen. After parturition both groups were permanently placed in an indoor calving pen until the end of the experimental period (d 30 postpartum). Blood samples were collected daily from d 10 prior to expected parturition through d 7 postpartum with an additional sample on d 30 postpartum. Milk yield was recorded at each milking during the whole experimental period. In the DL group, 25-hydroxyvitamin D (25-VitD), 1,25-VitD and total calcium concentrations around parturition were higher than in the controls. Higher parathyroid hormone concentrations were observed in the control group compared to the DL group at parturition. Pyridinoline concentrations did not differ between groups on d 1, and therefore it is assumed that the intensity of calcium transfer from the bones to the bloodstream was not affected by the increased daylight exposure. The measured plasma metabolites (beta hydroxybutyrate, fatty acids and glucose) as well as milk yield were not affected by the increased daylight exposure. In conclusion, the increased daylight exposure before parturition increased 25-VitD and 1,25-VitD concentrations, preventing a considerable decline of total calcium concentrations around parturition. PMID- 29108039 TI - Effect of band and knife castration of beef calves on welfare indicators of pain at three relevant industry ages: II. Chronic pain. AB - Three experiments were conducted to evaluate the effects of band and knife castration on behavioral and physiological indicators of chronic pain in beef calves at 3 different ages (36 calves/age group): 1 wk of age (Exp. 1, 4 +/- 1.1 d of age, 43 +/- 1.1 kg BW), 2 mo of age (Exp. 2, 63 +/- 2.3 d of age, 92 +/- 1.7 kg BW), and 4 mo of age (Exp. 3, 125 +/- 4.6 d of age, 160 +/- 3.4 kg BW). In each experiment calves were randomly assigned to either sham (CT), band (BA) or knife (KN) castration. Experiments 1, 2, and 3 ended when the testicles of banded calves had sloughed off (68, 49, and 42 d, respectively). Animal BW and rectal temperature were recorded weekly over the experimental period. Salivary cortisol, substance P, haptoglobin, scrotal area temperature using infrared thermography, visual evaluation of swelling (5-point scale), and gait stride length were collected on d -1 and immediately before castration and weekly thereafter until the end of the study. Hair samples were collected 1 d prior to and 28 d after castration and at the end of the study for cortisol concentration. Standing and lying behaviors were recorded over a 28-d period immediately after castration. No differences ( > 0.10) were observed in salivary cortisol, substance P, haptoglobin, or hair cortisol among castration methods for any of the 3 ages. No changes in behavior were observed in calves castrated at 1 wk or 2 mo of age. In 4 mo-old-calves, BA spent less time lying ( < 0.01) than CT and KN calves. Also, the average duration of lying time for BA calves was greater ( < 0.05) than for CT calves. Both, 1-wk- and 2-mo-old calves had inflammation in the scrotal area lasting 7 d after KN castration, whereas inflammation was observed for up to 14 d in 4-mo-old calves. Swelling in BA calves lasted for 21 to 28 d in the 2 younger groups of calves, whereas in 4-mo-old calves swelling was observed until d 35 postcastration. Knife- and band-castrated calves did not exhibit indicators of chronic pain or distress when the procedures were performed in calves younger than 2 mo of age. Therefore, pain mitigation should be used when castrating to improve animal welfare, especially when castrations are performed in calves older than 2 mo of age independent of the method of castration. PMID- 29108040 TI - Replacing dietary nonessential amino acids with ammonia nitrogen does not alter amino acid profile of deposited protein in the carcass of growing pigs fed a diet deficient in nonessential amino acid nitrogen. AB - Amino acid usage for protein retention, and, consequently, the AA profile of retained protein, is the main factor for determining AA requirements in growing animals. The objective of the present study was to determine the effect of supplementing ammonia N on whole-body N retention and the AA profile of retained protein in growing pigs fed a diet deficient in nonessential AA (NEAA) N. In total, 48 barrows with a mean initial BW of 13.6 kg (SD 0.7) were used. At the beginning of the study, 8 pigs were euthanized for determination of initial protein mass. The remaining animals were individually housed and fed 1 of 5 dietary treatments. A common basal diet (95% of experimental diets) was formulated to meet the requirements for all essential AA (EAA) but to be deficient in NEAA N (CP = 8.01%). The basal diet was supplemented (5%) with cornstarch (negative control) or 2 N sources (ammonia or NEAA) at 2 levels each to supply 1.35 or 2.70% extra CP. The final standardized ileal digestible (SID) NEAA content in the high-NEAA-supplemented diet (positive control) was based on the NEAA profile of whole-body protein of 20-kg pigs, and it was expected to reduce the endogenous synthesis of NEAA. Pigs were fed at 3.0 times maintenance energy requirements for ME in 3 equal meals daily. At the end of a 3-wk period, pigs were euthanized and the carcass and visceral organs were weighed, frozen, and ground for determination of protein mass. From pigs in the initial, negative control, high-ammonia, and high-NEAA groups, AA contents in the carcass and pooled visceral organs were analyzed to determine the total and deposited protein AA profile, dietary EAA efficiencies, and minimal de novo synthesis of NEAA. Carcass weight and whole-body N retention linearly increased ( < 0.05) with N supplementation. The AA profile of protein and deposited protein in the carcass was not different ( > 0.10) between N sources, but Cys content increased ( < 0.05) with NEAA compared with ammonia in visceral organ protein and deposited protein. The dietary SID EAA efficiency for increasing EAA deposition in whole body protein increased ( < 0.05) with N supplementation, but it was not different ( > 0.10) between N sources. The de novo synthesis of NEAA increased ( < 0.05) for ammonia compared with NEAA supplementation. In conclusion, adding ammonia as a N source to diets deficient in NEAA N increases whole-body N retention without affecting the carcass AA profile. PMID- 29108041 TI - Effects of silage type and inclusion level on ruminal characteristics and feeding behavior of steers fed finishing diets. AB - Crossbred beef steers fitted with a ruminal cannula were used to study the effects of silage type (BH 8895 corn or AF7401 sorghum) and level of inclusion (10 or 20%) in beef cattle finishing diets on digestibility of nutrients, ruminal kinetics, in vitro methane production, and feeding behavior. A 4 * 6 unbalanced Latin square design was used (6 steers; 363 +/- 23 kg; 4 diets: corn silage [CS] or sorghum silage [SS], both at 10 or 20% inclusion, DM basis). Each period consisted of 14 d of adaptation and 7 d of collection. Steers were fed once daily at 1000 h. An additional study evaluated the ruminal degradability of intact ensiled sorghum grain ruminally incubated in 3 steers (547 +/- 56 kg BW), using the same hybrids from the main study from 10 laboratory experimental silos. The GLIMMIX procedures of SAS were used for statistical analyses. Steers fed SS had greater NDF intake ( < 0.01) compared with the ones fed CS. The magnitude of the NDF intake change depended on the level of inclusion ( < 0.01), which was 6 and 16% for 10 and 20% inclusion, respectively. Regardless the level of inclusion, CS diets promoted greater ( <= 0.01) apparent total tract digestibility of nutrients evaluated (DM, OM, NDF, ADF, hemicellulose, and starch) compared with SS diets. Steers fed SS diets tended to chew 1.1 h/d more ( = 0.07) than steers fed CS diets. The level of inclusion increased ( = 0.02) the chewing time per day by 1.3 h. No major differences were observed in any of the ruminal pH and in vitro gas production variables evaluated for silage type and inclusion level ( >= 0.09). The CS-fed steers had 12% greater total VFA concentration and an 18.5% lower ( < 0.01) acetate-to-propionate ratio compared with SS-fed steers. The acetate-to propionate ratio was 16% greater ( < 0.01) when steers were fed SS compared with when steers were fed CS. The CS samples were more extensively ruminally degraded ( < 0.01) than the SS samples. Greater ( < 0.01) NDF ruminal disappearance was observed in ruminal environments containing 20% silage compared with those containing 10% silage. After 96 h inside the rumen, intact ensiled sorghum grain degradability of DM reached only 51.7%. Replacing CS with SS in beef finishing diets (low roughage inclusion) requires adjustments to balance dietary energy. Sorghum material induced a desirable roughage effect in feeding behavior but also offered the potential for improved regarding fiber digestibility and intact grain ruminal degradability. PMID- 29108042 TI - Ground Juniperus pinchotii and urea in supplements fed to Rambouillet ewe lambs Part 2: Ewe lamb rumen microbial communities. AB - This study evaluated effects of ground redberry juniper () and urea in dried distillers grains with solubles-based supplements fed to Rambouillet ewe lambs ( = 48) on rumen physiological parameters and bacterial diversity. In a randomized study (40 d), individually-penned lambs were fed ground sorghum-sudangrass hay and of 1 of 8 supplements (6 lambs/treatment; 533 g/d; as-fed basis) in a 4 * 2 factorial design with 4 concentrations of ground juniper (15%, 30%, 45%, or 60% of DM) and 2 levels of urea (1% or 3% of DM). Increasing juniper resulted in minor changes in microbial beta-diversity (PERMANOVA, pseudo F = 1.33, = 0.04); however, concentrations of urea did not show detectable broad-scale differences at phylum, family, or genus levels according to ANOSIM ( > 0.05), AMOVA ( > 0.10), and PERMANOVA ( > 0.05). Linear discriminant analysis indicated some genera were specific to certain dietary treatments ( < 0.05), though none of these genera were present in high abundance; high concentrations of juniper were associated with and , low concentrations of urea were associated with , and high concentrations of urea were associated with and . were decreased by juniper and urea. , , and increased with juniper and were positively correlated (Spearman's, < 0.05) with each other but not to rumen factors, suggesting a symbiotic interaction. Overall, there was not a juniper * urea interaction for total VFA, VFA by concentration or percent total, pH, or ammonia ( 0.29). When considering only percent inclusion of juniper, ruminal pH and proportion of acetic acid linearly increased ( < 0.001) and percentage of butyric acid linearly decreased ( = 0.009). Lamb ADG and G:F were positively correlated with (Spearman's, < 0.05) and negatively correlated with Synergistaceae, the BS5 group, and Lentisphaerae. Firmicutes were negatively correlated with serum urea nitrogen, ammonia, total VFA, total acetate, and total propionate. Overall, modest differences in bacterial diversity among treatments occurred in the abundance or evenness of several OTUs, but there was not a significant difference in OTU richness. As diversity was largely unchanged, the reduction in ADG and lower-end BW was likely due t* reduced DMI rather than a reduction in microbial fermentative ability. PMID- 29108043 TI - Effects of clay on toxin binding capacity, ruminal fermentation, diet digestibility, and growth of steers fed high-concentrate diets. AB - Three experiments were conducted to determine the effect of increasing concentrations of a smectite clay on toxin binding capacity, ruminal fermentation, diet digestibility, and growth of feedlot cattle. In Exp. 1, 72 Angus * Simmental steers were blocked by BW (395 +/- 9.9 kg) and randomly allotted to 3 treatments (4 pens/treatment and 6 steers/pen) to determine the effects of increasing amounts of clay (0, 1, or 2%) on performance. The clay was top-dressed on an 80% concentrate diet at a rate of 0, 113, or 226 g/steer daily to achieve the 0, 1, and 2% treatments, respectively. Steers were slaughtered at a target BW of 606 kg. In Exp. 2, 6 steers (596 +/- 22.2 kg initial BW) were randomly allotted to the same 3 treatments in a replicated 3 * 3 Latin square design (21-d periods) to determine the effects of increasing amounts of clay on ruminal pH, VFA, and nutrient digestibility. In Exp. 3, 150 mg of clay was incubated in 10 mL of rumen fluid with 3 incremental concentrations (6 replicates per concentration) of aflatoxin B (AFB) or ergotamine tartate (ET) to determine binding capacity. During the first 33-d period, there was a quadratic effect of clay on ADG ( < 0.01) and G:F ( < 0.01), increasing from 0 to 1% clay and then decreasing from 1 to 2% clay. However, during the second 30-d period, clay linearly decreased ADG and G:F ( <= 0.03) and overall ADG, DMI, and G:F were not impacted ( >= 0.46). Clay linearly decreased marbling score ( = 0.05). Hepatic enzyme activity did not differ among treatments on d 0 or at slaughter ( >= 0.15). Clay linearly decreased ruminal lactate and propionate, linearly increased formate and the acetate:propionate ratio ( <= 0.04), and tended ( = 0.07) to linearly increase butyrate. Clay tended to linearly increase ( = 0.06) OM and CP apparent digestibility. Ruminal pH, urine pH, and other digestibility measures did not differ among treatments ( >= 0.15). Clay was able to effectively bind AFB and ET at concentrations above the normal physiological range (52 and 520 MUg/mL), but proportional adsorption was decreased to 35.5 and 91.1% at 5,200 MUg/mL ( < 0.01) for AFB and ET, respectively. In conclusion, clay effectively binds ruminal toxins, decreases ruminal lactate, and improves performance only during adaptation to a high-concentrate feedlot diet. PMID- 29108044 TI - Consequences of exposure of embryos produced in vitro in a serum-containing medium to dickkopf-related protein 1 and colony stimulating factor 2 on blastocyst yield, pregnancy rate, and birth weight. AB - Embryokines are molecules secreted by the mother that regulate embryonic development. Among these molecules in cattle are colony stimulating factor 2 (CSF2) and dickkopf-related protein 1 (DKK1). Here, we evaluated actions of CSF2 and DKK1 alone or in combination on characteristics of embryos produced in vitro in the presence of serum. A total of 70 beef cows from 4 farms were subjected to oocyte retrieval on 1 to 4 occasions. Within each farm, donors were randomly allocated to 1 of 4 treatment groups (vehicle, CSF2, DKK1, CSF2 + DKK1). Embryos from a given donor were always exposed to the same treatment. Treatments were added to the culture medium on d 5 after insemination, and blastocyst stage embryos were transferred to recipient females 2 d later. Treatment did not affect the percent of oocytes or cleaved embryos that developed to the blastocyst stage or the percent of recipients that became pregnant after embryo transfer. However, calves derived from embryos treated with DKK1 were smaller at birth, regardless of CSF2 treatment. Results indicate no effects of addition of CSF2 or DKK1 to culture of embryos produced in vitro with serum-containing medium on development to the blastocyst stage or competence to establish pregnancy after transfer to recipients. The fact that embryos cultured with DKK1 resulted in calves with reduced birth weight illustrates the potential ability of this embryokine to program postnatal phenotype. Results support the concept that properties of the offspring can be programmed as early as the preimplantation period. PMID- 29108045 TI - Effects of rotating antibiotic and ionophore feed additives on volatile fatty acid production, potential for methane production, and microbial populations of steers consuming a moderate-forage diet. AB - Ionophores and antibiotics have been shown to decrease ruminal methanogenesis both in vitro and in vivo but have shown little evidence toward a sustainable means of mitigation. Feed additive rotation was proposed and investigated for methane, VFA, and microbial population response. In the present study, cannulated steers ( = 12) were fed a moderate-forage basal diet in a Calan gate facility for 13 wk. In addition to the basal diet, steers were randomly assigned to 1 of 6 treatments: 1) control, no additive; 2) bambermycin, 20 mg bambermycin/d; 3) monensin, 200 mg monensin/d; 4) the basal diet + weekly rotation of bambermycin and monensin treatments (B7M); 5) the basal diet + rotation of bambermycin and monensin treatments every 14 d (B14M); and 6) the basal diet + rotation of bambermycin and monensin treatments every 21 d (B21M). Steers were blocked by weight in a randomized complete block design where the week was the repeated measure. Rumen fluid was collected weekly for analysis ( = 13), and results were normalized according to individual OM intake (OMI; kg/d). Potential activity of methane production was not significantly different among treatments ( > 0.05). However, treatment tended to affect the CH-to-propionate ratio ( = 0.0565), which was highest in the control and lowest in the monensin, B21M, and B14M treatments (0.42 vs. 0.36, 0.36, and 0.33, respectively). The CH:propionate ratio was lowest in wk 2 and 3 ( < 0.05) but the ratio in wk 4 to 12 was not different from the ratio in wk 0. Week also affected total VFA, with total VFA peaking at wk 3 and plummeting at wk 4 (4.02 vs. 2.86 m/kg OMI; < 0.05). A significant treatment * week interaction was observed for the acetate-to-propionate (A:P) ratio, where bambermycin- and rotationally fed steers did not have a reduced A:P ratio compared with monensin-fed steers throughout the feeding period ( < 0.0001). Microbial analysis revealed significant shifts, but several predominant classes showed adaptation between 4 and 6 wk after additive initiation. There was no significant evidence to suggest that rotations of monensin and bambermycin provided additional benefits to steers consuming a moderate-forage diet at the microbial/animal and environmental level versus those continuously fed. PMID- 29108046 TI - Stockpiled Tifton 85 bermudagrass for backgrounding stocker cattle. AB - A 2-yr grazing trial was conducted to evaluate the use of conserved forage type, stockpiled Tifton 85 bermudagrass ( L.; T85) or T85 hay, and supplement type for stocker cattle during the fall forage deficit in the southeastern United States. The study site consisted of six 0.75-ha paddocks of stockpiled T85 for grazing and six 0.20-ha drylot paddocks for feeding T85 hay. Steers ( = 5 per paddock; mean initial BW for both yr, 263 +/- 30 kg) were randomly assigned to paddocks on November 11, 2014 and October 28, 2015 in yr 1 and yr 2, respectively. Treatments included T85 hay or stockpile (control), T85 hay or stockpile plus 0.2 kg cottonseed meal and 0.7 kg soybean hulls?steer?d (SUPPL1), or 0.45 kg cottonseed meal and 0.45 kg soybean hulls?steer?d (SUPPL2). Polytape fencing was used for frontal grazing stockpiled T85 paddocks to allocate a 3- to 4-d allotment of forage DM for the animals based on available forage mass and steer DMI requirements. There were no differences among treatments ( > 0.10) in mean pregrazing forage mass across sampling dates (5,099 kg DM/ha and 7,998 kg DM/ha in yr 1 and yr 2, respectively), forage allowance (1.9 kg DM/kg steer BW and 3.0 kg DM/kg steer BW in yr 1 and yr 2, respectively) and forage utilization (84% and 88% in yr 1 and yr 2, respectively). No differences ( > 0.10) were detected for nutritive value parameters CP, ADF, NDF, and TDN among stockpiled T85 treatments in both yr. However, there were differences across sampling dates ( < 0.0001) for stockpiled T85 such that forage quality generally declined as the grazing season progressed in both yr. Steers fed T85 hay had greater final BW and ADG ( = 0.018) than those grazing stockpiled T85. Mean final BW and ADG of steers grazing T85 stockpile or fed hay with no supplementation was less ( = 0.020) than those receiving supplementation. Steers grazing stockpiled T85 had decreased ADG in the second half of the grazing season in both yr of the study, which is a result of declining forage nutritive value as the stockpiling season progressed. Results indicate that stockpiled T85 supplemented with CP and energy can support stocker cattle at a maintenance level, but to achieve a target gain of 0.9 kg/day would require a greater level of supplementation to overcome decreasing forage nutritive value dynamics. PMID- 29108047 TI - Imposed running exercise does not alter cell proliferation in the neurogenic niches of young lambs. AB - Neurogenesis, the process by which neurons are generated in the brain from progenitor cells, occurs in the subventricular zone (SVZ) and the subgranular zone (SGZ) in the adult human brain. Recently, rodent studies have demonstrated that exercise can increase neurogenesis in the SGZ; however, it is unclear if exercise also has this effect in more complex mammalian brains. The overarching aim of this study was to explore whether exercised-induced neurogenesis occurs in larger mammalian brains more representative of human brains and to explore the use of a model for exercising large animals such as sheep. For these studies, 6 male twin lambs had a structured exercise regime for 4 wk and 6 other twin male lambs were kept in an open field pen. All lambs were injected with bromodeoxyuridine (BrdU), a thymidine analog that is incorporated into the DNA of proliferating cells. Immunoperoxidase was used to visualize and quantify BrdU positive cells in the SVZ and SGZ. Overall, no significant change in the number or distribution of BrdU-positive cells was observed in the lamb SVZ and SGZ with exercise or colabeling of BrdU with mature neuronal or glial markers in the exercised and nonexercised lamb SVZ and SGZ. Overall, this study provides a novel methodology to investigate the effects of imposed exercise on large animals and exercise-induced neurogenesis in animals with gyrencephalic brains. PMID- 29108048 TI - Amino acid composition of fetus, placenta, and uterus in gilts throughout gestation. AB - An accurate understanding of the AA composition of the products of conception is needed to accurately model dietary AA needs of pregnant swine. To determine AA composition in fetal pigs, the placenta, and the uterus at various stages of gestation, samples from a total of 65 gilts slaughtered at assigned days of gestation (d 43, 58, 73, 91, 101, and 108) were used. The AA concentrations (g/kg each wet tissue) in the fetus, placenta, or uterus increased as gestation progressed, with major increases occurring from d 73 to 108 of gestation ( < 0.05). For fetus, AA content on a DM basis (%) and AA contribution to total fetal AA (g/100 g total AA of fetal tissue) generally decreased as gestation progressed ( < 0.05) except for Arg and Ala, which increased from d 73 of gestation, and for Gly and Pro, which increased progressively ( < 0.05) from d 43. Placental AA content on a DM basis increased up to d 91 or 101 of gestation ( < 0.05) and then slightly decreased on d 108 of gestation except for His, Cys, and Met + Cys. Amino acid contribution to total placental AA decreased for all AA as gestation progressed ( < 0.05), except for Arg, Ala, Gly, and Pro, which increased from d 58 of gestation. Essential AA content in the uterus on a DM basis had no major changes during gestation, whereas nonessential AA content decreased ( < 0.05) as gestation progressed, except for Asp. For AA contribution to total uterine AA, some essential AA (Ile, Leu, Lys, Met, Trp, and Val; < 0.06) and Asp ( < 0.01) contributions increased with increasing gestational ages, whereas Arg ( = 0.08), Cys, Gly, and Pro ( < 0.05) contributions decreased as gestation progressed. Differences in AA contribution to total AA within each tissue varied among the fetus, placenta, and uterus by type of AA. These results demonstrate that AA compositions of fetal pigs, placenta, and uterus are changed differentially as gestation progresses; in particular, Arg, Ala, Gly, and Pro compositions in fetus and placenta increased progressively. These compositional data for each reproductive tissue and fetus will help to model AA requirements in gestation. PMID- 29108049 TI - Body fat of stock-type horses predicted by rump fat thickness and deuterium oxide dilution and validated by near-infrared spectroscopy of dissected tissues. AB - Body condition score and percent body fat (BF; %) of horses are positively correlated with reproductive efficiency and are indicative of metabolic issues. However, BF in horses may be poorly predicted because current procedures are either subjective or dependent on one anatomical location. Therefore, the objectives of the current study were to compare 2 methods of predicting BF using rump fat thickness (RFT) and deuterium oxide (DO) dilution with actual tissue fat analysis by near-infrared spectroscopy (NIRS) in stock-type horses and to identify the relationship between BF and BCS. Twenty-four stock-type horses were selected to be humanely euthanized based on 3 primary criteria: geriatric, crippled, and/or unsafe. Approximately 20 h before slaughter, horses were weighed and BCS assessed to be 1 ( = 1; 433 kg), 2 ( = 1; 415 kg), 3 ( = 1; 376 kg), 4 ( = 7; 468 +/- 13 kg), 5 ( = 10; 455 +/- 11 kg), and 6 ( = 4; 493 +/- 12 kg) and RFT was measured using ultrasonography. Blood samples were collected immediately before and 4 h after DO infusion (0.12 g/kg BW). Deuterium oxide concentration of plasma was determined by gas isotope ratio mass spectrometry. Horses were housed in a dry lot overnight before being individually sedated (1.1 mg xylazine/kg BW) and anesthetized using a jugular venipuncture (2.2 mg ketamine/kg BW), and potassium chloride (KCl) solution was administered to cease cardiac function before exsanguination. After euthanasia, horse carcasses were processed and dissected and tissues were collected for NIRS analysis. Body fat predicted by DO dilution was correlated with BF measured by NIRS analysis on various weight bases ( = 0.76 to 0.81, < 0.001), whereas no correlation was observed for BF predicted by RFT. A paired -test indicated that both DO dilution and RFT overestimated BF by 2.48 to 3.26% ( < 0.001) and 5.81 to 6.59% ( < 0.001), respectively, compared with NIRS analysis. Body condition scores affected BF measured by NIRS analysis ( <= 0.038) and predicted by DO dilution ( < 0.001) and RFT ( = 0.042). The current study provided evidence that DO dilution was a better prediction method for BF than RFT and that BCS may serve as a BF predictor in stock-type horses. PMID- 29108050 TI - The effects of maternal nutrition on the messenger ribonucleic acid expression of neutral and acidic amino acid transporters in bovine uteroplacental tissues from day sixteen to fifty of gestation. AB - We hypothesized that both day of gestation and maternal nutrition would alter the relative mRNA expression of neutral and acid AA transporters , , , , and . Crossbred Angus heifers ( = 49) were synchronized, bred via AI, assigned to nutritional treatment (100% of NRC requirements for 0.45 kg/d gain [control heifers {CON}] and 60% of CON [restricted heifers {RES}]), and ovariohysterectomized on d 16, 34, or 50 of gestation ( = 6 to 9/d). Nonbred, nonpregnant (NB-NP) controls were ovariohysterectomized on d 16 of the estrous cycle ( = 6) after synchronization. The resulting arrangement was a 2 * 3 factorial + 1 (CON vs. RES * d 16, 34, or 50 + NB-NP controls). Tissues collected included caruncular endometrium (CAR), intercaruncular endometrium (ICAR), fetal membranes (FM; chorioallantois; d 16 and 34), cotyledonary placenta (COT; d 50 only), intercotyledonary placenta (ICOT; d 50 only), and amnion (AMN; d 50 only]). Relative expression of , , , , and was determined for each tissue using NB-NP CAR and NB-NP ICAR tissues for the baseline; for FM, endometrium from NB-NP controls served as the baseline. In CAR, no day * treatment interaction was observed ( > 0.05). However, day of gestation affected relative expression of , where expression on d 16 was greater ( < 0.01) than expression on d 34 and 50. Additionally, relative expression of and was greater ( <= 0.05) in pregnant heifers compared with NB-NP heifers. For ICAR, was influenced by a day * treatment interaction ( < 0.01), where expression in d 16 RES was greater ( <= 0.05) than that of any other day or nutritional treatment. Furthermore, expression in d 16 CON was greater ( <= 0.05) than that in d 50 RES, with those in d 34 CON and RES and d 50 CON being intermediate. In addition, was affected by day of gestation, where expression on d 16 was greater ( < 0.01) than that on d 34 and 50. A day * treatment interaction was not observed ( > 0.05) in FM; however, expression on d 34 was greater ( = 0.02) than on d 50, with that on d 16 being intermediate. Day of gestation also affected expression of , where expression on d 34 and 50 was greater ( < 0.01) than that on d 16. These data support our hypothesis in that both day of gestation and maternal nutrition affected the relative mRNA expression of AA transporter in ICAR, whereas day of gestation has a greater effect on the relative mRNA expression of other neutral and acidic AA transporters in the various tissues studied. PMID- 29108051 TI - Grazing management of mixed alfalfa bermudagrass pastures. AB - Rotational grazing management is commonly recommended to improve persistence of legumes interseeded into bermudagrass, but impacts on animal performance are poorly understood. Steers (n = 365, BW = 249 +/- 22.9 kg) grazed mixed alfalfa (Medicago sativa L.)/bermudagrass (Cynodon dactylon [L.] Pers.) pastures (n = 10; 1.6-ha) with either continuous grazing (CONT) or rotational grazing (ROT) management over 3 yr. Initial stocking rate was set at 6.25 steers/ha. When forage allowance of CONT became limiting in mid-July each year, 2 randomly selected steers were removed from all pastures to maintain equal stocking rates in CONT and ROT. Rotational grazing pastures were divided into 8 paddocks with 3 d grazing and 21-d rest between grazing events. Initial, final, and interim (28 d) BW were collected following a 16-h removal from feed and water. Data were analyzed as a repeated measures experiment with completely random design using the mixed procedure of SAS (SAS Inst. Inc., Cary, NC) using pasture within treatment by year in the random statement. Across years, steer BW did not differ (P >= 0.47) at the midpoint or end of the grazing season. Daily BW gains during the early summer period tended (P = 0.10) to be 0.11 kg greater for CONT than ROT in yr 1, but did not differ (P >= 0.24) in yr 2 and 3. In the late summer, ADG was 0.15 kg less (P < 0.01) for CONT than ROT in yr 1, were not different (P = 0.23) in yr 2, and were 0.29 kg less (P < 0.01) for CONT than ROT in yr 3. Over the entire experimental period, ADG did not differ (P >= 0.67) in yr 1 or 2, but tended (P = 0.09) to be 0.10 kg greater for ROT than CONT in yr 3. Forage mass of ROT was greater (P < 0.01) than CONT throughout the grazing season. Because stocking rates were maintained at the same level, ROT pastures provided greater (P < 0.01) forage allowance during the grazing season than CONT explaining differences in ADG between treatments. Alfalfa stand percentage did not differ (P = 0.79) at the beginning of the experiment, but was less (P <= 0.03) for CONT than ROT at all other sampling dates. These data indicate that at equal stocking rates, ROT can maintain greater alfalfa persistence, forage nutritive quality, and forage allowance compared with continuous grazing and provided increased animal performance during the late summer when the alfalfa stand was reduced in CONT pastures. PMID- 29108052 TI - Comparison of nitrogen utilization and urea kinetics between yaks (Bos grunniens) and indigenous cattle (Bos taurus). AB - Under traditional management on the Qinghai-Tibetan Plateau, yaks () graze only on natural pasture without supplements and are forced to cope with sparse forage of low N content, especially in winter. In contrast, indigenous Tibetan yellow cattle () require supplements during the cold season. We hypothesized that, in response to harsh conditions, yaks cope with low N intakes better than cattle. To test this hypothesis, a study of whole-body N retention and urea kinetics was conducted in 2 concurrent 4 * 4 Latin squares, with 1 square using yaks and 1 square using cattle. Four isocaloric forage-concentrate diets differing in N concentrations (10.3, 19.5, 28.5, and 37.6 g N/kg DM) were formulated, and by design, DMI were similar between species and across diets. Urea kinetics were determined with continuous intravenous infusion of NN urea for 104 h, and total urine and feces were concomitantly collected. Urea production, urea recycling to the gut, and ruminal microbial protein synthesis all linearly increased ( < 0.001) with increasing dietary N in both yaks and cattle. Urinary N excretion was less ( = 0.04) and N retention was greater ( = 0.01) in yaks than in cattle. Urea production was greater in yaks than in cattle at the 3 lowest N diets but greater in cattle than in yaks at the highest N diet (species * diet, < 0.02). Urea N recycled to the gut ( < 0.001), recycled urea N captured by ruminal bacteria ( < 0.001), and ruminal microbial protein production ( = 0.05) were greater in yaks than in cattle. No more than 12% of urea recycling was through saliva, with no difference between species ( = 0.61). Glomerular filtration rate was lower ( = 0.05) in yaks than in cattle. The higher urea recycling and greater capture of recycled urea by ruminal microbes in yaks than in cattle suggest that yaks use mechanisms to utilize dietary N more efficiently than cattle, which may partially explain the better survival of yaks than cattle when fed low-N diets. PMID- 29108053 TI - Effect of band and knife castration of beef calves on welfare indicators of pain at three relevant industry ages: I. Acute pain. AB - Three experiments evaluated the effect of band and knife castration on acute pain for the first 7 d after the procedure on 1-wk-, 2-mo-, and 4-mo-old calves. All calves were blocked by age and weight and randomly assigned to 1 of 3 treatments: sham castration (control, CT), band castration (BA), and knife castration (KN). Experiment 1 evaluated 1-wk-old Angus bull calves ( = 34; 43.0 +/- 6.61 kg BW), Exp. 2 evaluated 2-mo-old Angus bull calves ( = 34; 91.5 +/- 11.93 kg BW), and Exp. 3 evaluated 4-mo-old Angus bull calves ( = 35; 157.6 +/- 22.52 kg BW). For all experiments, physiological and behavioral parameters were collected before (d -1 and immediately before castration [T0]) and after (60 and 120 min and on d 7) castration to assess acute pain. Physiological measures included complete blood cell count, cortisol, substance P, and scrotal temperature. Behavioral measures consisted of a visual analog scale, stride length, and time and frequency budgets for walking, standing, lying, tail flicking, foot stamping, and head turning. Performance parameters included initial and final BW and ADG. In Exp. 1, tail flicking was greater ( = 0.02) in KN calves compared to BA calves 2 to 4 h after castration, although no differences were seen between BA and KN compared to CT calves. In Exp. 2, a treatment * time interaction ( = 0.02) was observed for cortisol, where KN calves had greater cortisol concentrations 120 min after castration compared to BA and CT calves; KN calves also lay down and ate less ( < 0.01; = 0.02) and stood and walked more ( < 0.01; = 0.05) compared to BA and CT calves 2 to 4 h after castration. In Exp. 3, a treatment * time interaction ( < 0.01) was observed for cortisol concentrations in which all treatments were different from one another at 60 and 120 min, with BA calves having the greatest concentrations, KN calves being intermediate, and CT having the lowest concentrations. Overall, KN and BA castrated calves presented physiological and behavioral changes associated with acute pain; however, 2-mo-old BA calves presented the fewest behavioral changes and no physiological changes associated with acute pain compared to CT calves. PMID- 29108054 TI - Phenotypic relationships among methane production traits assessed under ad libitum feeding of beef cattle. AB - Angus cattle from 2 beef cattle projects in which daily methane production (MPR) was measured were used in this study to examine the nature of the relationships among BW, DMI, and methane traits of beef cattle fed ad libitum on a roughage diet or a grain-based feedlot diet. In both projects methane was measured using the GreenFeed Emission Monitoring system, which provides multiple short-term breath measures of methane production. The data used for this study were from 119 Angus heifers over 15 d on a roughage diet and 326 Angus steers over 70 d on a feedlot diet. Mean (+/-SD) age, BW, and DMI were 372 +/- 28 d, 355 +/- 37 kg, and 8.1 +/- 1.3 kg/d for the heifers and 554 +/- 86 d, 577 +/- 69 kg, and 13.3 +/- 2.0 kg/d for the steers, respectively. The corresponding mean MPR was 212 g/d for heifers and 203 g/d for steers. Additional traits studied included methane yield (MY; MPR/DMI), methane intensity (MPR/BW), and 3 forms of residual methane production (RMP), which is a measure of actual minus predicted MPR. For RMP, RMP, and RMP predicted MPR were obtained by regression of MPR on BW, on DMI, and on both DMI and BW, respectively. The 2 data sets were analyzed separately using the same statistical procedures. For both feed types the relationships between MPR and DMI and between MPR and BW were both positive and linear. The correlation between MPR and DMI was similar to that between MPR and BW, although the correlations were stronger for the roughage diet ( = 0.75 for MPR vs. DMI; = 0.74 for MPR vs. BW) than the grain-based diet ( = 0.62 for MPR vs. DMI; = 0.66 for MPR vs. BW). The correlation between MY and DMI was negative and moderate for the roughage ( = -0.68) and grain-based ( = -0.59) diets, a finding that is different from the nonsignificant correlations reported in studies of cattle on a restricted roughage diet. The 3 RMP traits were strongly correlated ( values from 0.76 to 0.99) with each other for both the roughage and the grain-based diets, which indicates that using RMP to lower MPR could provide a result similar to using RMP in cattle. As feed intake (DMI) is more difficult to measure than BW, this result implies that under ad libitum feeding situations in which DMI cannot be measured, RMP can be used to identify higher- or lower-RMP animals with similar levels of effectiveness as RMP. PMID- 29108055 TI - Effects of in ovo feeding of l-arginine on hatchability, hatching time, early posthatch development, and carcass traits in domestic pigeons (Columba livia). AB - The objective of this research was to test the hypothesis that in ovo feeding of arginine (Arg) may improve hatchability and posthatch performance in domestic pigeons (). A completely randomized design ( = 3) with an Arg feeding treatment (Arg group, 1.14 mg Arg dissolved in 200 MUL of 0.75% NaCl buffered saline as 1% concentration compared to total Arg in the egg), a buffered saline feeding treatment (SC group, 7.5 g NaCl dissolved in 1 L sterile distilled water as the concentration of poultry physiological saline), and a nonfeeding treatment (NC group) was used. Six squabs from each treatment were randomly sampled on day of hatch (DOH), posthatch d 7 (D7), and posthatch d 14 (D14), respectively. Hatchability, hatch time, BW, organ development, and carcass traits were examined. Results showed that in ovo feeding of the Arg solution increased ( < 0.05) the hatchability and advanced ( < 0.05) the hatching time in comparison with those of the other groups. Body weight of pigeon squabs that received Arg in ovo feeding was heavier ( < 0.05) on DOH and D14 than that of the NC group, and a greater ( < 0.05) BW gain from DOH to D14 and D7 to D14 was observed. Three clusters of 12 organs were classified according to the changes of organ indices. Squabs provided the Arg in ovo feeding treatment gained a priority in organ development. The heart index and gizzard index on D7 and the proventriculus index on D14 of squabs receiving Arg in ovo feeding were increased ( < 0.05) compared to those of the other groups. The brain index on DOH, the small intestine index and pancreas index on D7, and the liver index, pancreas index, and spleen index on D14 of squabs fed Arg were higher ( < 0.05) than those of the NC group. The spleen index on D7 and the small intestine index on D14 of squabs provided the Arg feeding treatment were enhanced ( < 0.05) compared with those of the SC group. The semieviscerated carcass weight of squabs receiving Arg was higher ( < 0.05) on D14 than that of other groups. The absolute weight of breast meat yield on D7 and breast meat yield percentage on D7 and D14 were improved ( < 0.05) in the Arg group compared with the NC group. The leg meat percentage on D7 and the carcass weight, eviscerated carcass weight, and absolute weight of breast meat yield on D14 were increased ( < 0.05) in the Arg group compared with those of the SC group. The results of this study indicate that in ovo feeding of pigeon embryos with Arg may have beneficial effects on squab hatch performance and early posthatch performance. PMID- 29108056 TI - A deterministic, dynamic systems model of cow-calf production: The effects of breeding replacement heifers before mature cows over a 10-year horizon. AB - Some cattle production experts believe that cow-calf producers should breed replacement heifers (nulliparous cows) before cows (primiparous and multiparous cows), sometimes referred to as providing a heifer lead time (tHL). Our objective was to model the effects different durations of tHL may have on measures of herd productivity, including the percent of the herd cycling before the end of the first 21 d of the breeding season (%C21), the percent of the herd pregnant at pregnancy diagnosis (%PPD), the distribution of pregnancy by 21-d breeding intervals, the kilograms of calf weaned per cow exposed (KPC), and the replacement percentage (%RH), using a deterministic, dynamic systems model of cow calf production over a 10-yr horizon. We also wished to examine differences in the effect of tHL related to the primiparous duration of postpartum anestrus (dPPA). The study model examined 6 different dPPA for primiparous cows (60, 70, 80, 90, 100, or 110 d). The multiparous cow duration of postpartum anestrus was set to 60 d. The breeding season length for nulliparous cows was 63 d, as was the breeding season length for primiparous and multiparous cows. Nulliparous cows were modeled with a tHL of 0, 7, 14, 21, 28, 35, or 42 d. Results are reported for the final breeding season of the 10-yr horizon. Increasing tHL resulted in a greater %C21 for the herd and for primiparous cows. Length of tHL had minimal impact on the %PPD unless the dPPA was 80 d or greater. For a dPPA of 110 d, a 0 d tHL resulted in the herd having 88.1 %PPD. When tHL was 21 d, the %PPD increased to 93.0%. The KPC was 161.2 kg when the dPPA was 110 d and tHL was 0 d and improved to 183.2 kg when tHL was increased to 42 d. The %RH did not vary much unless the dPPA was 90 d or greater, but increasing tHL resulted in decreased %RH. Based on the model results, increasing tHL improves the production outcomes included in the analysis, but herds with dPPA of 90 d or greater had the greatest degree of improvement. For these herds, approximately two-thirds of the improvement in outcomes by increasing tHL from 0 d to 42 d was realized when tHL was 21 d. Costs are likely incurred when implementing tHL in a breeding management program, and an ideal tHL likely depends on the dPPA of the herd, the expected improvement in productivity, and the costs associated with increasing tHL. Determining the dPPA of a herd could help veterinarians and producers develop optimal herd management strategies. PMID- 29108057 TI - Endocannabinoid concentrations in plasma during the finishing period are associated with feed efficiency and carcass composition of beef cattle. AB - We previously have shown that plasma concentrations of endocannabinoids (EC) are positively correlated with feed efficiency and leaner carcasses in finishing steers. However, whether the animal growth during the finishing period affects the concentration of EC is unknown. The objective of this study was to quantify anandamide (AEA) and 2-arachidonyl glycerol (2-AG) in plasma during different stages of the finishing period and identify possible associations with production traits and carcass composition in beef calves. Individual DMI and BW gain were measured on 236 calves ( = 127 steers and = 109 heifers) for 84 d on a finishing ration. Blood samples were collected on d 0 (early), 42 (mid), and 83 (late) of days on study (DOS). Cattle were slaughtered 44 d after the feeding study. Plasma concentration of AEA at 0 DOS was indirectly associated with the G:F ( < 0.01) and directly associated with residual feed intake (RFI; < 0.05) in steers. In contrast, plasma concentration of AEA at 83 DOS was directly associated with the G:F and indirectly associated RFI in heifers and steers ( < 0.01). In addition, AEA concentration at 42 and 83 DOS was positively associated with ADG and DMI ( < 0.01) in heifers and steers. Furthermore, 2-AG concentration at 42 DOS was positively associated with ADG in steers ( < 0.01) and heifers ( < 0.10). Plasma concentration of AEA was positively associated ( < 0.05) with HCW, USDA calculated yield grade, and 12th-rib fat thickness in heifers, whereas no associations were found in steers. In contrast, 2-AG concentration was not associated with any carcass traits. These results provide evidence that circulating EC change during animal growth and that AEA concentration may be a useful predictor of growth and feed efficiency and, in females, of carcass attributes. PMID- 29108058 TI - Understanding the drivers of improved pig weaning weight by investigation of colostrum intake, sow lactation feed intake, or lactation diet specification. AB - Modern sows have low feed intake (FI) during lactation. The main aim of this study was to understand interactions between and separate effects of FI and nutrient density on litter weaning weight (WW). Key drivers of colostrum intake (CIn), piglet survival, WW, and colostrum yield (CY) were also investigated. Sows ( = 82) were offered a High (15.8 MJ/kg DE; 1.3% total lysine) or Normal (15.2 MJ/kg DE; 1.28% total lysine) specification lactation diet at either a High (feed allowance increased by 0.5 kg/d after farrowing until intake reached 10 kg/d) or Low (feed allowance was increased by 0.3 kg/d after farrowing until intake reached 7.5 kg/d) feeding level (2 * 2 factorial design). A subset of sows ( = 18) were observed during farrowing to collect data on factors affecting CIn. No interactions were found between diet specification and feeding level. Sows on the Low feeding level lost 10.6 kg more BW during lactation than those on the High feeding level ( < 0.001). Sows offered the High specification diet lost 6.4 kg more BW than those on the Normal specification diet ( = 0.018). Diet specification had no effect on ADFI. Between birth and weaning, litters of sows offered the High feeding level grew 326 g/d faster ( < 0.001) and were heavier at 28 d (114 kg; < 0.001) compared with those of sows offered the Low feeding level (104 kg). Although litters from sows offered the High specification diet had WW similar to that of litters from sows offered the Normal specification diets, their ADG was 190 g/d greater ( = 0.018) between birth and weaning. A regression analysis was completed using data from 192 sows and indicated that FI and lysine intake throughout lactation and DE and lysine intake from 14 to 28 d of lactation were the main drivers of litter WW. Lactation efficiency was 0.65 from 0 to 7 d and decreased to 0.42 from 21 to 28 d. Variation in CIn was mainly explained by 24-h weight, birth weight, and the duration of farrowing. Colostrum yield was significantly correlated ( = 0.004; pseudo = 54.5%) with litter birth weight. Piglet WW was positively correlated with 3-wk weight ( < 0.001) but negatively correlated with sow parity ( = 0.035), number born alive ( = 0.045), and being female ( < 0001). Out of 45 variables, preweaning piglet survival was positively correlated ( = 0.008) with only 24- to 48-h weight gain. In conclusion, lactation FI and DE and lysine intake in the second half of lactation were the main drivers of litter WW. PMID- 29108059 TI - Chromium, CLA, and ractopamine for finishing pigs. AB - This study aimed to evaluate the effects of dietary chromium, CLA, and ractopamine on performance, carcass traits, and pork quality of finishing pigs slaughtered at 115 kg BW. Ninety-six crossbred barrows (initial BW = 70.21 +/- 1.98 kg) were randomly assigned to 1 of 6 dietary treatments. There were 8 replicates per treatment (48 pens; 2 pigs/pen). A diet formulated according to the nutritional requirements was used as the control (CON). The other 5 diets were based on the CON and supplemented as follows: 0.4 mg/kg Cr yeast (CrY); 0.5% CLA; 0.4 mg/kg CrY and 0.5% CLA (CrY + CLA); 20 mg/kg ractopamine (RAC); 0.4 mg/kg CrY and 20 mg/kg RAC (CrY + RAC). Lysine levels on diets containing ractopamine were raised by 20% compared to CON to meet the greater requirements of pigs fed ractopamine. Pigs fed RAC and CrY + RAC were fed CON for the first 17 d, and then the respective diets for the last 28 d on trial. Data were analyzed in a model including the fixed effect of treatment (6 levels) and initial BW as a covariate for all characteristics, with the exception of carcass traits, in which final BW was used as a covariate. Least-squares means were separated using Tukey Kramer's method. Differences were considered when probability values were lower than 0.05. Pigs fed RAC and CrY + RAC had the greatest ( < 0.001) final BW and ADG. Pigs fed CrY + RAC had greater ( < 0.001) G:F than pigs within the other groups, except for those fed RAC. Pigs fed CrY + RAC and RAC had similar G:F, both greater ( < 0.001) than pigs fed CON. Average daily feed intake was similar ( = 0.83) for all diets. Pigs fed CrY + RAC had greater LM area ( = 0.01) and carcass yield ( < 0.02) than pigs fed CON, CrY, CLA, and CrY + CLA. Loin muscle area and carcass yield of pigs fed RAC were not different from pigs fed the others diets. Pigs fed CON diets had greater BF ( = 0.02) than pigs fed CLA diet. Additives did not affect ( > 0.05) pork quality, except for color. No differences ( > 0.05) were observed for carcasses pH and temperature. The values for pigs fed RAC were greater ( = 0.01) than pigs fed other diets. Pigs fed RAC had lower ( < 0.01) values compared to pigs fed other experimental diets. Serum urea nitrogen concentration (SUN) was lower ( = 0.02) in pigs fed CrY + RAC than in pigs fed CON and RAC and similar to pigs fed the other feeding additives. In summary, it was demonstrated that, when combined, CrY and RAC increase LM area and carcass yield, and reduce SUN, suggesting that chromium could improve nutrient utilization by muscle cells in RAC-fed pigs. Additionally, the additives have no major effects on pork quality. PMID- 29108060 TI - Effect of dried distiller's grains plus solubles in postpartum diets of beef cows on reproductive performance of dam and heifer progeny. AB - Forty-eight primiparous and multiparous cows were fed a silage-based total mixed ration (TMR; CON), a TMR with 2.5 kg/d DM dried distiller's grains plus solubles (DDGS; MID), or a TMR with 4.7 kg/d DM DDGS (HIGH) from 8.5 +/- 4 to 116 +/- 4 d postpartum (DPP). All diets were formulated to be isocaloric for a postpartum ADG targeted at 0.22 kg, whereas CP exceeded requirements in both diets containing DDGS. Blood samples were collected from dams at 7- and 21-d intervals for progesterone concentration (resumption of cyclicity) and plasma urea nitrogen, respectively. A weigh-suckle-weigh procedure was used to measure milk production, and samples were collected for milk composition and fatty acid profile. A 5-d Co Synch + controlled internal drug release (CIDR) protocol was used, and cows were bred (97 +/- 4 DPP) by timed AI (TAI). Ultrasonography was used for measurement of the largest antral follicle at TAI and pregnancy diagnosis. Nineteen days after TAI, cow and calf pairs were managed as a single group until weaning and exposed to natural mating for a total of a 60-d breeding season. Starting at weaning, blood samples were collected from heifer offspring at 7-d intervals for progesterone concentration used as an indicator of puberty. A 5-d Co-Synch + CIDR protocol was used, and heifers were bred by TAI. Transrectal ultrasonography was used for measurement of the largest antral follicle at TAI and antral follicle count (AFC) at CIDR device insertion as well as pregnancy diagnosis. There were no differences in dam ADG ( = 0.364); however, DMI decreased with increasing DDGS ( < 0.0001), resulting in an increased feed efficiency ( = 0.042). Milk fat and lactose tended to increase with the addition of DDGS in the diet ( <= 0.055), and milk urea nitrogen increased ( < 0.001). There were no differences in resumption of cyclicity ( = 1.00) or diameter of the largest antral follicle ( >= 0.372). Timed AI pregnancy rates were not different with the addition of DDGS in the diet ( >= 0.174). Heifer ADG was reduced with DDGS during late lactation ( = 0.031). Heifer AFC had a tendency to increase with increasing DDGS ( = 0.081), with no impacts on dominant follicle diameter at TAI ( = 0.161). Heifer TAI pregnancy rate also was not different among treatments ( = 0.508). Overall, feeding 4.7 kg/d DM of DDGS to dams during early lactation increases feed efficiency of the dam, with minor statistically significant effects on dam or heifer offspring reproduction. PMID- 29108061 TI - Genetic correlations between wool traits and meat quality traits in Merino sheep. AB - Genetic correlations between 29 wool production and quality traits and 25 meat quality and nutritional value traits were estimated for Merino sheep from an Information Nucleus (IN). Genetic correlations among the meat quality and nutritional value traits are also reported. The IN comprised 8 flocks linked genetically and managed across a range of sheep production environments in Australia. The wool traits included over 5,000 yearling and 3,700 adult records for fleece weight, fiber diameter, staple length, staple strength, fiber diameter variation, scoured wool color, and visual scores for breech and body wrinkle. The meat quality traits were measured on samples from the and included over 1,200 records from progeny of over 170 sires for intramuscular fat (IMF), shear force of meat aged for 5 d (SF5), 24 h postmortem pH (pHLL; also measured in the , pHST), fresh and retail meat color and meat nutritional value traits such as iron and zinc levels, and long-chain omega-3 and omega-6 polyunsaturated fatty acid levels. Estimated heritabilities for IMF, SF5, pHLL, pHST, retail meat color lightness (), myoglobin, iron, zinc and across the range of long-chain fatty acids were 0.58 +/- 0.11, 0.10 +/- 0.09, 0.15 +/- 0.07, 0.20 +/- 0.10, 0.59 +/- 0.15, 0.31 +/- 0.09, 0.20 +/- 0.09, 0.11 +/- 0.09, and range of 0.00 (eicosapentaenoic, docosapentaenoic, and arachidonic acids) to 0.14 +/- 0.07 (linoleic acid), respectively. The genetic correlations between the wool production and meat quality traits were low to negligible and indicate that wool breeding programs will have little or no effect on meat quality. There were moderately favorable genetic correlations between important yearling wool production traits and the omega-3 fatty acids that were reduced for corresponding adult wool production traits, but these correlations are unlikely to be important in wool/meat breeding programs because they have high SE, and the omega-3 traits have little or no genetic variance. Significant genetic correlations among the meat quality traits included IMF with SF5 (-0.76 +/- 0.24), fresh meat color * (0.50 +/- 0.18), and zinc (0.41 +/- 0.19). Selection to increase IMF will improve meat tenderness and color which may address some of the issues with Merino meat quality. These estimated parameters allow Merino breeders to combine wool and meat objectives without compromising meat quality. PMID- 29108062 TI - Detoxification, metabolism, and glutathione pathway activity of aflatoxin B1 by dietary lactic acid bacteria in broiler chickens. AB - Lactic acid bacteria (LAB) and the glutathione (GSH) pathway are protective against aflatoxin, but information on the effect of LAB on aflatoxin metabolism and GSH activity in farm animals is scarce. This study aimed to investigate the effects of LAB and aflatoxin B (AFB) on growth performance, aflatoxin metabolism, and GSH pathway activity using 480 male Arbor Acres broiler chickens from d 1 to 35 of age. Diets were arranged in a 2 * 2 factorial design, including AFB at 0 or 40 ug/kg of feed and LAB at 0 or 3 * 10 cfu/kg of feed, and the LAB was a mixture of equal amounts of , , and . The results showed that there were highly significant ( < 0.01) effects of AFB toxicity, LAB protection, and their interaction on ADFI, ADG, and G:F of broilers during d 1 to 35. Compared with the AFB diet, the LAB diet reduced ( < 0.05) the residues of AFB in the liver, kidney, serum, ileal digesta, and excreta on d 14 by 121.5, 80.6, 43.7, 47.0, and 26.5%, respectively, and on d 35 by 40.6, 60.2, 131.7, 37.9, and 32.9%, respectively, whereas the LAB diet increased ( < 0.05) the contents of aflatoxin M, a metabolite of AFB, in the liver, kidney, serum, and ileal digesta on d 14 by 98.2, 154.2, 168.6, 19.1, and 34.1%, respectively, and in the kidney and serum on d 35 by 32.6 and 142.2%, respectively. For the activity of the GSH pathway in the liver and duodenal mucosa, there were significant ( <= 0.01) effects of LAB and AFB on reduced GSH, glutathione S-transferases (GST), and glutathione reductase (GR) on d 14 and 35; compared with the control diet, the LAB diet increased ( < 0.05) GSH, GST, and GR by a range of 11.6 to 86.1%, and compared with the AFB diet, the LAB diet increased ( < 0.05) GSH, GST, and GR by a range of 24.1 to 146.9%. In the liver, there were interactions ( < 0.05) on GSH and GST on d 14 and on GSH on d 35; in the mucosa, interactions were significant ( <= 0.01) on GSH and GR on d 14 and on GST on d 35. It can be concluded that LAB is effective in the detoxification of AFB by modulating toxin metabolism and activating the GSH pathway in animals. PMID- 29108063 TI - Rapid Communication: Period2 gene silencing increases the synthesis of alphas casein protein in bovine mammary epithelial cells. AB - (), a core clock gene, encodes a circadian rhythm protein which has been shown to control mammary metabolism in rodents. Whether regulates milk component synthesis such as alpha-casein protein in bovine mammary cells is unknown. Thus, we used gene silencing technology to determine if silencing could affect alpha-casein synthesis and cell growth in cultured primary bovine mammary epithelial cells (BMEC). The BMEC were established by enzymatic digestion of mammary tissue from mid-lactation cows. A transient-transfection technique was used to insert a small interfering RNA (siRNA) oligonucleotide specific for to inhibit transcription. Control and siRNA-transfected cells were cultured for 48 h. qRT-PCR and ELISA analysis showed that silencing enhanced the synthesis of 2 kinds of alpha-casein ( < 0.05) through upregulating the mRNA level of and ( < 0.01). Furthermore, the 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) results demonstrated that cell proliferation was not affected ( > 0.05). These data led us to hypothesize that PER2 protein may potentially play an important role in the control of milk protein synthesis and, hence, represents a target that can be used to regulate protein synthesis rate during lactation. PMID- 29108064 TI - Placement. PMID- 29108065 TI - Estimation of the effects of selection on French Large White sow and piglet performance during the suckling period. AB - The effects of 21 yr of selection were estimated for sow and piglet performance during the suckling period in a French Large White (LW) pig population using frozen semen. Two experimental groups (EXP = L77 and L98) were produced by inseminating LW sows with either stored frozen semen from 17 LW boars born in 1977 (EXP = L77) or with fresh semen from 23 LW boars born in 1998 (EXP = L98). Seventy-four L77 and 89 L98 randomly chosen females were mated to 15 L77 and 15 L98, respectively, randomly chosen boars for 6 successive parities. They produced 2,796 L77 progeny (G77) and 3,529 L98 progeny (G98) piglets including stillbirths. To disentangle direct and maternal effects on piglet growth, a 2 * 2 factorial design was set by cross-fostering half-litters across genetic groups the day after farrowing, resulting in mixed G77/G98 litters nursed by either L77 or L98 sows. Piglet traits investigated included individual weight at birth (IWB), at 21 d of age (IW21d), and at weaning at 4 wk of age (IWW) and ADG from birth to 21 d of age (ADG21d) and from birth to weaning (ADGBW) as well as probability of stillbirth, probability of mortality on the first day after farrowing and from d 2 to weaning. Sow traits analyzed included weight before farrowing and at weaning, feed intake, milk production, colostrum, and milk composition. The variability of performance across genetic groups and litters was also investigated. The data were analyzed using generalized (piglet mortality) or linear mixed models (other traits). Results showed an increase in IWB (+240 +/- 72 g in 21 yr for IWB adjusted for total number born), and a negative maternal genetic trend was observed on piglet growth during the suckling period (e.g., +33 +/- 13 g/d in 21 yr for ADG21d, that is, 14% of the mean), whereas direct genetic effects remained unchanged. Piglets from L98 litters also had a 40% larger probability of being stillborn and a 28% larger probability of dying on d 1 and had a more heterogeneous IWB (358 vs. 336 g; < 0.001) and growth during the suckling period (60 vs. 56 g/d; < 0.001). Sows from L77 and L98 experimental groups did not differ in weight, feed intake, colostrum, and milk composition. These results give evidence of negative correlated effects of selection for piglet traits related to robustness. These adverse effects are at least partly of maternal origin. PMID- 29108066 TI - Estimates of genetic parameters, genetic trends, and inbreeding in a crossbred dairy sheep research flock in the United States. AB - For the past 2 decades, the Spooner Agriculture Research Station (ARS) of the University of Wisconsin-Madison operated the only dairy sheep research flock in North America. The objectives of the present study were to 1) obtain estimates of genetic parameters for lactation and reproductive traits in dairy ewes, 2) estimate the amount of genetic change in these traits over time, and 3) quantify the level of inbreeding in this flock over the last 20 yr. Multiple-trait repeatability models (MTRM) were used to analyze ewe traits through their first 6 parities. The first MTRM jointly analyzed milk (180-d-adjusted milk yield [180d MY]), fat (180-d-adjusted fat yield [180d FY]), and protein (180-d-adjusted protein yield [180d PY]) yields adjusted to 180 d of lactation; number of lambs born per ewe lambing (NLB); and lactation average test-day somatic cell score (LSCS). A second MTRM analyzed 180d MY, NLB, LSCS, and percentage milk fat (%F) and percentage milk protein (%P). The 3 yield traits were moderately heritable (0.26 to 0.32) and strongly genetically correlated (0.91 to 0.96). Percentage milk fat and %P were highly heritable (0.53 and 0.61, respectively) and moderately genetically correlated (0.61). Milk yield adjusted to 180 d was negatively genetically correlated with %F and %P (-0.31 and -0.34, respectively). Ewe prolificacy was not significantly ( > 0.67) genetically correlated with yield traits, %P, or LSCS but lowly negatively correlated with %F (-0.26). Lactation somatic cell score was unfavorably genetically correlated with yield traits (0.28 to 0.39) but not significantly ( > 0.09) correlated with %F, %P, and NLB. Within trait multiple-trait models through the first 4 parities revealed that 180d MY, 180d FY, 180d PY, %F, and %P were strongly genetically correlated across parity (0.67 to 1.00). However, the genetic correlations across parity for NLB and LSCS were somewhat lower (0.51 to 0.96). Regressing predicted breeding values for 180d MY, without and with the addition of breed effects, on ewe year of birth revealed a positive genetic gain of 2.30 and 6.24 kg/yr, respectively, over the past 20 yr in this flock. Inbreeding coefficients of ewes with an extended pedigree ranged from 0.0 to 0.29, with an average of 0.07. To optimize genetic gains and avoid excessive inbreeding, the development of a national genetic improvement program should be a top priority for the growing dairy sheep industry. PMID- 29108067 TI - Rapid Communication: The correlation between histone modifications and expression of key genes involved in accumulation of adipose tissue in the pig. AB - Histone modification is a well-known epigenetic mechanism involved in regulation of gene expression; however, it has been poorly studied in adipose tissues of the pig. Understanding the molecular background of adipose tissue development and function is essential for improving production efficiency and meat quality. The objective of this study was to identify the association between histone modification and the transcript level of genes important for lipid droplet formation and metabolism. Histone modifications at the promoter regions of 6 genes (, , , , , and ) were analyzed using a chromatin immunoprecipitation assay. Two modifications involved in activation of gene expression (acetylation of H3 histone at lysine 9 and methylation of H3 histone at lysine 4) as well as methylation of H3 histone at lysine 27, which is known to be related to gene repression, were examined. The level of histone modification was compared with transcript abundance determined using real-time PCR in tissue samples (subcutaneous fat, visceral fat, and longissimus dorsi muscle) derived from 3 pig breeds significantly differing in fatness traits (Polish Large White, Duroc, and Pietrain). Transcript levels were found to be correlated with histone modifications characteristic to active loci in 4 of 6 genes. A positive correlation between histone H3 lysine 9 acetylation modification and the transcript level of ( = 0.53, < 4.8 * 10), ( = 0.34, < 0.02), and ( = 0.43, < 1.0 * 10) genes was observed. The histone H3 lysine 4 trimethylation modification correlated with transcripts of ( = 0.64, < 4.6 * 10) and ( = 0.37, < 0.01) genes. No correlation was found between transcript level of all studied genes and histone H3 lysine 27 trimethylation level. This is the first study on histone modifications in porcine adipose tissues. We confirmed the relationship between histone modifications and expression of key genes for adipose tissue accumulation in the pig. Epigenetic modulation of the transcriptional profile of these genes (e.g., through nutritional factors) may improve porcine fatness traits in future. PMID- 29108068 TI - Rapid Communication: 16S ribosomal ribonucleic acid characterization of liver abscesses in feedlot cattle from three states in the United States. AB - Liver abscesses are a major economic burden to beef producers. Although a few causative organisms have been cultured from purulent material, the full polymicrobial diversity of liver abscesses has not been reported. The objective of this study was to characterize purulent material collected from liver abscess in beef cattle produced in different production systems in 3 cattle producing states in the United States using 16S rRNA gene sequencing. Differences between purulent material microbial communities among geographic region of feeding and application of a common antimicrobial were also investigated. Cattle included in the study were fed in California (dairy type) and Colorado and Texas (both beef type). Liver abscesses from a cross section of feedlots, geographic areas, and tylosin phosphate-administered groups were collected at harvest; DNA from 34 liver abscess samples was extracted; and the V4 region of the 16S rRNA gene was amplified and sequenced. Sequences were classified into 5 phyla, 13 classes, and 17 orders in the domain Bacteria. The phyla identified included Bacteroidetes (35.2% of reads), Proteobacteria (28.6%), Fusobacteria (18.2%), Firmicutes (12.4%), and Actinobacteria (5.5%). Sequences matching the genera and , which have previously been identified as causative agents in liver abscesses, were both present in the abscess bacterial communities at a relative abundance of 15.1 and 3.2%, respectively, of the overall relative abundance. Furthermore, 3 of the most common phyla were Gram-negative bacteria. An analysis-of-similarities test was conducted on Euclidean distances to assess differences between cattle treated and not treated with tylosin as well as to assess differences between geographic regions. Geographical region and treatment with tylosin did affect the microbiome ( = 0.002 and = 0.026 respectively); however, a more robust sample scheme is needed to explore these differences. To our knowledge, this is the first publication describing the complex community of liver purulent material using next generation sequencing in cattle. These data provide a framework for research on a more targeted approach to liver abscess prevention and treatment. PMID- 29108069 TI - Dietary sources of phosphorus affect postileal phosphorus digestion in growing pigs. AB - The present study was conducted to investigate the postileal P digestion response of growing pigs to dietary P concentrations and sources. Twenty-four pigs (57.3 +/- 1.9 kg initial BW) fitted with T-cannulas at the distal ileum were assigned to a duplicated 12 * 4 incomplete Latin square design with 12 diets and 4 periods. The 12 experimental diets consisted of 9 cornstarch-based diets using soybean meal (SBM), corn distiller's dried grains with solubles (DDGS), and canola meal (CM) as assay ingredients at 3 levels and 3 corn-SBM-based practical diets with 3 levels of dicalcium phosphate (DCP). Chromic oxide was included as an indigestible marker to calculate apparent ileal digestibility (AID), apparent total tract digestibility (ATTD), and apparent postileal digestibility (APID) of P. Each period consisted of 5 d of adaption period, 2 d of fecal samples collection, and 2 d of ileal digesta collection. The results showed that ileal P output, fecal P output, ileal digested P, total tract digested P, and the AID and ATTD of P were affected by the interaction of P concentrations and sources ( < 0.01). When pigs were fed the semipurified diets containing SBM and corn-SBM based practical diets, the AID and ATTD of P increased with increasing dietary P level (linear, < 0.01). However, there were no linear or quadratic responses in the AID and ATTD of P for pigs fed diets containing increasing levels of CM and corn DDGS. Postileal digested P, the proportion of ileal digested P to total tract digested P, the proportion of postileal digested P to total tract digested P, APID of P, and hindgut disappearance of P were affected by dietary sources of P ( < 0.01). When pigs were fed the semipurified diets containing SBM and CM, there were no differences between the AID and ATTD of P. In contrast, the ATTD of P were greater than the AID of P for pigs fed diets containing corn DDGS and corn SBM-based practical diets with DCP supplementation. In summary, postileal P digestion response of growing pigs was affected by dietary P sources. PMID- 29108070 TI - Estimation of genetic parameters for lesion scores and growth traits in group housed pigs. AB - Pigs housed in groups are remixed with unfamiliar individuals, which can trigger aggressive interactions, potentially compromising animal welfare. Skin lesions are a reliable indicator trait of aggression and are moderately heritable, suggesting that aggression may be reduced through selection. This study estimated genetic parameters of skin lesions of pigs at multiple life stages, explored genetic correlations of skin lesions between age groups and body location, and studied the relationship between skin lesions and production traits of commercial importance. A population of 1,079 Yorkshire pigs was strategically remixed into new groups of familiar and unfamiliar animals at 3 life stages (weaning, grow finish, and mature gilts). Skin lesions (fresh, bright red cuts) were counted immediately prior to mixing and 24 h and 3 wk after mixing across 3 body regions: anterior, central, and caudal. Weights were recorded prior to each mixing event. Prior to slaughter, backfat thickness and loin muscle area were determined using ultrasound. Univariate analyses were performed to obtain heritability estimates of lesion scores. Bivariate analyses were performed with response variables being skin lesions, weight gain per life stage, backfat thickness, or loin muscle area, depending on the relationship of interest, to obtain correlations. Lesion score heritabilities ranged from 0.10 to 0.40 and were significant ( < 0.05). Heritability was highest for lesions on the anterior region of the body for 24 h and 3 wk after mixing. Lesions to the central and caudal areas showed the highest genetic correlation at each stage of production, whereas those to the anterior and caudal regions had the lowest correlation. The highest genetic correlation was found between the mature gilt and grow-finish stages, whereas the weaning and mature gilt stages had the lowest correlations. Genetic correlations between lesions and production traits were not significantly different from 0 for weight gain and backfat thickness, but loin muscle area was negatively correlated with lesions ( = 1.17 * 10, = 2.30 * 10, and = 6.08 * 10 for anterior, central, and caudal lesions, respectively). These results are promising for the industry because they suggest that pigs selected for reduced lesions will show increased loin muscle area without negative effects on growth. Alternatively, selection for these production traits would not increase lesions. PMID- 29108071 TI - Milk yield and genomewide expression profiling in the mammary gland of beef primiparous cows in response to the dietary management during the pre- and postweaning periods. AB - Accelerated growth programs during prepubertal periods have been promoted to advance the first calving of beef heifers. The objectives of the present study were to evaluate nutrition-induced changes on first lactation milk yield and composition and on gene expression of the mammary gland in Parda de Montana primiparous cows. Female calves ( = 16) were involved in a 2 * 2 factorial experiment. In the preweaning period (PRE-W; 0-6 mo), female calves were either fed a creep feed supplement (Creep) or fed only their dam's milk (Control). In the postweaning period (POST-W; 6-15 mo), heifers received either a high-energy diet (91.7 MJ/d) or a moderate-energy diet (79.3 MJ/d). All the heifers were managed together from breeding (15 mo) to the end of their first lactation (32 mo). Animal performance; milk production and quantity during the first lactation; plasma glucose, IGF-I, and leptin concentrations; and RNA samples from the mammary gland at the end of the first lactation of the primiparous cows (32 mo) were analyzed. The BW and ADG of the primiparous cow during its first lactation were not different among treatments; however, creep feeding during PRE-W reduced milk production ( < 0.01), milk CP, crude fat, lactose, nonfat solids, and casein content throughout lactation and increased somatic cell count in the third ( < 0.05) and fourth month of lactation ( < 0.10). The energy level during the POST-W had no effect on milk production and quality. Gene expression in the mammary gland was affected by the diet in the PRE-W and POST-W, with the PRE-W diet having the greatest impact. During the PRE-W, creep feeding resulted in upregulation of genes related to immune response and chemokine activity, suggesting that these animals might be in a compromised immune status. Therefore, this strategy would not be recommendable; meanwhile, increasing the energy level in the diet during the POST-W would be recommendable, because it had no deleterious effects on milk yield and composition. PMID- 29108072 TI - Rapid Communication: Large exploitable genetic variability exists to shorten age at slaughter in cattle. AB - Apprehension among consumers is mounting on the efficiency by which cattle convert feedstuffs into human edible protein and energy as well as the consequential effects on the environment. Most (genetic) studies that attempt to address these issues have generally focused on efficiency metrics defined over a certain time period of an animal's life cycle, predominantly the period representing the linear phase of growth. The age at which an animal reaches the carcass specifications for slaughter, however, is also known to vary between breeds; less is known on the extent of the within-breed variability in age at slaughter. Therefore, the objective of the present study was to quantify the phenotypic and genetic variability in the age at which cattle reach a predefined carcass weight and subcutaneous fat cover. A novel trait, labeled here as the deviation in age at slaughter (DAGE), was represented by the unexplained variability from a statistical model, with age at slaughter as the dependent variable and with the fixed effects, among others, of carcass weight and fat score (scale 1 to 15 scored by video image analysis of the carcass at slaughter). Variance components for DAGE were estimated using either a 2-step approach (i.e., the DAGE phenotype derived first and then variance components estimated) or a 1 step approach (i.e., variance components for age at slaughter estimated directly in a mixed model that included the fixed effects of, among others, carcass weight and carcass fat score as well as a random direct additive genetic effect). The raw phenotypic SD in DAGE was 44.2 d. The genetic SD and heritability for DAGE estimated using the 1-step or 2-step models varied from 14.2 to 15.1 d and from 0.23 to 0.26 (SE 0.02), respectively. Assuming the (genetic) variability in the number of days from birth to reaching a desired carcass specifications can be exploited without any associated unfavorable repercussions, considerable potential exists to improve not only the (feed) efficiency of the animal and farm system but also the environmental footprint of the system. The beauty of the approach proposed, relative to strategies that select directly for the feed intake complex and enteric methane emissions, is that data on age at slaughter are generally readily available. Of course, faster gains may potentially be achieved if a dual objective of improving animal efficiency per day coupled with reduced days to slaughter was embarked on. PMID- 29108073 TI - LncRNA profiling of skeletal muscles in Large White pigs and Mashen pigs during development. AB - Long noncoding RNA (lncRNA) has been increasingly implicated in the regulation of muscle development. Large White pigs have a higher muscle growth rate than do Mashen pigs. In the present study, the lncRNA expression profiles in skeletal muscle of these 2 pig breeds were compared at 1, 90, and 180 d of age using RNA sequencing. We obtained 2,718 million clean reads and identified a total of 5,153 novel lncRNA. We found 1,407 differentially expressed lncRNA that showed consistent expression patterns between the 2 breeds at all the 3 sampling points. Ten lncRNA were randomly selected, and their expression was validated using Real time Quantitative PCR. In summary, this study identifies a number of lncRNA that correlate with muscle growth. The regulation and function of these lncRNA in muscle growth and development need to be further explored. PMID- 29108074 TI - Interactive effects of supplemental Zn sulfate and ractopamine hydrochloride on growth performance, carcass traits, and plasma urea nitrogen in feedlot heifers. AB - Interactive effects of supplemental Zn and ractopamine hydrochloride (RH) were evaluated using 156 crossbred heifers (initial BW = 527 kg +/- 6.61; gross BW * 0.96) to determine the impact on feedlot performance, plasma urea nitrogen (PUN), and carcass characteristics. The study was conducted as a randomized complete block design with a 2 * 2 factorial arrangement of treatments. Factors consisted of 1) 30 or 100 mg supplemental Zn/kg diet DM (30Zn or 100Zn) as Zn sulfate and 2) 0 or 200 mg RH/heifer daily. Heifers were blocked by BW and assigned randomly within block to treatments for a 43-d trial. Heifers were housed in partially covered feeding pens (3 heifers/pen; 13 pens/treatment) and provided ad libitum access to feed. Ractopamine hydrochloride was fed for 42 d and removed from the diet until cattle were harvested on d 43. Zinc treatments were fed until harvest. Plasma samples were collected on d 0 and 36 to assess changes in plasma Zn and PUN. On d 43, heifers were weighed, then transported to a commercial abattoir where HCW and incidence of liver abscesses were recorded. Carcass data were collected after 32 h of refrigeration. No Zn * RH interactions were observed for plasma Zn or PUN ( >= 0.58); however, there was a tendency for a RH * day interaction for PUN ( = 0.08). Supplementing 100Zn resulted in increased plasma Zn ( = 0.02) compared to 30Zn. No RH * Zn interactions were observed for feedlot performance ( >= 0.24). Final BW and ADG increased with RH supplementation ( <= 0.02), but DMI was not affected ( = 0.63); thus, feed efficiency improved ( < 0.01) when heifers were fed RH. Supplementing 100Zn tended to reduce ADG ( = 0.07) but did not affect other measures of feedlot performance ( >= 0.12). Zinc * RH interactions were observed for LM area and yield grade ( <= 0.01); LM area decreased and yield grade increased when heifers were supplemented 100Zn with no RH compared to other treatments. A tendency for a Zn * RH interaction was observed for dressed yield ( = 0.08), but no other interactions or effects of Zn were detected for carcass traits ( >= 0.11). Supplementing RH increased HCW ( = 0.03) but did not affect other carcass traits ( >= 0.13). In conclusion, supplemental Zn had little impact on feedlot performance or PUN concentration but may alter muscle and fat deposition when fed in conjunction with RH. PMID- 29108075 TI - Polyunsaturated fatty acids are less effective to reduce methanogenesis in rumen inoculum from calves exposed to a similar treatment early in life. AB - The aim of this study was to evaluate the dose response on in vitro methane (CH) production of PUFA to which the inoculum donor animals had been exposed early in life. Sixteen Holstein calves (160 +/- 3 and 365 +/- 2 kg BW) at 6 and 12 mo of age were used as inoculum donors. Half of the calves were given increasing amounts of extruded linseed from birth (22 g/d) until 4 mo of age (578 g/d) first mixed with milk and then included in their concentrate. Linseed oil (LSO) was supplemented in vitro at 5 different doses (0, 0.6, 1.2, 2.4, and 4.8 mg/mL). Supplementation of LSO in the rumen inocula at both ages linearly decreased ( < 0.05) the in vitro CH production. Total in vitro VFA production was not affected by LSO supplementation. Inhibition of CH was smaller when using the rumen inoculum from calves that had received a similar treatment early in life ( < 0.05). Differences in response to in vitro supplementation of a type of fatty acids similar to those applied during early life suggest some "changes" in the functioning of the rumen microbial community. PMID- 29108076 TI - Significance of Thoracic and Lung Ultrasound in Thoracic Surgery. PMID- 29108077 TI - Characterization of Focal Liver Lesions using CEUS and MRI with Liver-Specific Contrast Media: Experience of a Single Radiologic Center. AB - AIM: The purpose of this study was to compare contrast-enhanced ultrasound (CEUS), magnetic resonance imaging (MRI) using liver-specific contrast agent and a combination of both for the characterization of focal liver lesions (FLL). METHODS: 83 patients with both benign and malignant liver lesions were examined using CEUS and MRI after the intravenous administration of liver-specific contrast media. All patients had inconclusive results from prior imaging examinations. Histopathological specimens could be obtained in 53 patients. Ultrasound was performed using a multi-frequency curved probe (1 - 6 MHz) after the injection of 1 - 2.4 ml ultrasound contrast media. The sensitivity, specificity, positive predictive value and negative predictive value of CEUS, MRI and a combination of both (CEUS + MRI) were compared. RESULTS: The sensitivity, specificity, positive and negative predictive values regarding lesion classification were 90.9 %, 70.6 %, 92.3 % and 66.6 %, respectively, for CEUS; 90.9 %, 82.4 %, 95.2 % and 70.0 %, respectively, for MRI; and 96.9 %, 70.6 %, 92.7 % and 85.7 % respectively, for CEUS + MRI. There were no statistically significant differences. 6 malignant lesions were missed using CEUS or MRI alone (false negatives). The use of both modalities combined reduced the false-negative results to 2. CONCLUSION: CEUS and MRI with liver-specific contrast media are very reliable and of equal informative value in the characterization of focal liver lesions. The number of false-negative results can be decreased using a combination of the two methods. PMID- 29108078 TI - [Big Data and Public Health - Results of the Working Group 1 of the Forum Future Public Health, Berlin 2016]. AB - Big Data is a diffuse term, which can be described as an approach to linking gigantic and often unstructured data sets. Big Data is used in many corporate areas. For Public Health (PH), however, Big Data is not a well-developed topic. In this article, Big Data is explained according to the intention of use, information efficiency, prediction and clustering. Using the example of application in science, patient care, equal opportunities and smart cities, typical challenges and open questions of Big Data for PH are outlined. In addition to the inevitable use of Big Data, networking is necessary, especially with knowledge-carriers and decision-makers from politics and health care practice. PMID- 29108079 TI - Prevalence and Correlates of Emergency Contraceptive Use in Transitional Albania. AB - Objectives The two emergency contraceptive drugs ("morning-after pill") ulipristal acetate and levonorgestrel are available without prescription in many European countries. In Albania, ulipristal acetate is not marketed yet and levonorgestrel has still prescription-only status. The objective of this study was to assess the prevalence and socioeconomic correlates of emergency contraceptive (EMC) use, collect sales figures, and gain information on the women's way of purchasing EMCs in post-communist Albania. Methods For this cross sectional study, self-administered questionnaires were made accessible to women in Albania in March 2015 by hard copy or online via social networks. Women were asked about lifetime use and last year's use of EMCs, and if they purchased EMCs with or without a prescription. Additionally, pharmacies were contacted and asked about EMC sales figures. Results Of the 205 participating women, 80.5% knew about the availability and use of EMCs, and 15.1% reported EMC use during the previous 12 months. The lifetime prevalence of use was 46.8%. Although having prescription only status in Albania, 96% of the women bought EMCs without a physician's prescription. Knowledge was significantly lower among the lower educated women and among women residing in small cities. Use of EMCs was significantly higher in women with a weaker financial background and, compared with small cities, in those from large or mid-sized cities. The 54 participating pharmacies (3% of all Albanian pharmacies) reported selling 11 EMCs on average per month. The use of EMCs may be estimated at 0.22 defined daily doses per 1,000 inhabitants per day. Compared to January 2015, EMC sales increased by 17% in February 2016. Conclusions Compared to other European countries, the prevalence of EMC use seems to be higher in Albania. Use and knowledge of EMCs depend on socioeconomic characteristics. It is recommended to switch EMCs to non-prescription status in transitional Albania. PMID- 29108080 TI - [Utilization of Outpatient Emergency Care in Westphalia-Lippe: A Health Geographic Analysis]. AB - Identification of geographical variations in the utilization of outpatient emergency care facilities is the most effective tool to locate regions with the greatest potential for increasing quality and efficiency in emergency care. The aim of the study was to estimate utilization of emergency care facilities in a regression model, taking into account local dependencies and agglomeration effects. The basis of this ecological study was formed by all outpatient emergency patient contacts in 2013 (n=1,927,471), which were aggregated according to the place of residence to the 231 municipalities of the supply area of the Association of Statutory Health Insurance Physicians Westphalia-Lippe. With the help of geostatistical procedures, the proportion of outpatient emergency patient contacts in hospital ambulances was modeled by socio-economic, patient-focused and geographic variables. The use of hospital ambulances (O=56.2%) in Westphalia Lippe is heterogeneous (min=14.8%, max=83.9%). The patient autonomy and state of health, the spatial distance to emergency care facilities and the Ruhr region were identified as important influencing factors. In this study, the cross-border perspective plays an important role in the outpatient use of emergency care facilities and helps to identify potential intervention areas. PMID- 29108082 TI - [Old and New Public Health Structures in Germany - Plenary Lecture of the Forum Future Public Health, Berlin 2016]. AB - Basic structures serving public health in Germany in the second decade of the 21st century are described. They are related to the governmental public health grant programs of the late 20th century and the successful re-introduction of public health competencies and capacities at universities and colleges. Structures under direct governmental responsibility, public law self-government and in the non-governmental for-profit and not-for-profit sector are described. Future challenges are sketched and a networked, three-dimensional model of research and development, politics and practice is suggested. PMID- 29108081 TI - [Workplace Interventions to Reduce Sedentary Behavior: A Systematic Review]. AB - Background Sedentary behaviour is a health risk factor independent of physical activity. Interventions that aim to reduce sitting at the workplace are particularly important as office workers spend a large proportion of their working hours sitting. This systematic review examines whether these interventions (SB or PA interventions during work time) reduce sitting time among office workers and which variables moderate intervention effects. Methods A systematic literature search was conducted from April to May 2016 in the following databases: PubMed, PsycINFO and SPORTDiscus. In total, we identified 17 studies that assessed the time spent in sedentary behaviour at the office workplace. To summarize the study results, we applied a best-evidence synthesis. Additionally, we evaluated potential moderators, such as intervention strategies. Results Multi-component interventions and sit-stand workstations were most promising sedentary reduction interventions. The analysis of moderators highlighted that the proportion of positive intervention effects was higher in interventions based on the strategies "environmental restructuring", "adding objects to the environment" and "instructions on how to carry out the behaviour". Furthermore, interventions focusing on sedentary behaviour only and studies using objective measurement tools showed more often positive interventions effects. Conclusions There are many promising interventions to reduce sitting time at the office workplace. However, there is insufficient evidence if the effects of these interventions are sustainable in the long term. Moreover, the considerable heterogeneity of included studies limits the validity of our findings. Future intervention studies should build on a theoretical planning approach and use subjective as well as objective evaluation measures. PMID- 29108084 TI - [Participatory and Collaborative Strategies in Psychiatric Research]. PMID- 29108083 TI - [Pedicled Omentum Flaps in the Management of Deep Sternal Wound Infections]. AB - AIM: Coverage of a deep sternal wound infection with a greater omentum flap. Due to a persistent infection caused by an infected aortic prosthesis, the primarily performed reconstruction with a latissimus dorsi flap had to be revised, and an alternative solution had to be found. INDICATION: A deep sternal wound infection is a rare but devastating complication following median sternotomy. If the commonly used muscle flap is not sufficient and artificial material is still present in the wound, for instant drivelines or a vascular prosthesis, the greater omentum flap is a useful option due to its immunologic capacity. METHOD: After an exploration of the persisting infected deep sternal wound, a radical debridement is performed followed by a jet lavage. The soft tissue from the greater omentum is prepared via median laparotomy and transferred through a tunnel created in the diaphragm. Then it is pulled into the wound cavity and can be used for tension-free sheathing of the aortic prosthesis. The previously used muscle flap can additionally be used for superficial soft tissue coverage. CONCLUSION: Due to its immunologic competence, the greater omentum flap is a good treatment alternative to the commonly used muscle flaps in defects with infected artificial material. PMID- 29108085 TI - [Limitations of Routine Assessment and Presentation of Trends of Patient Assaults in Psychiatric Hospitals]. AB - Objective Contribution to the analysis of patient assault routine data from psychiatric wards over a period of 10 years. Methods A recently published time series of violent incidents reported an increase over 8 years. The entire series including subsequent 1.5 years is re-analyzed regarding influencing factors and trend lines. Results The number of incidents fluctuates at a low level. A non linear trend appears appropriate. Conclusions Assessment of routine data is important, should be standardized and consider influences and limitations. PMID- 29108086 TI - Anti-degenerative effect of Apigenin, Luteolin and Quercetin on human keratinocyte and chondrocyte cultures: SAR evaluation. AB - BACKGROUND: Inflammation is a dynamic process that occur on vascularized tissue in response to different stimuli causing cell injury and tissue degeneration. Reactive oxygen and nitrogen species (ROS and RNS) and advanced glycation end products (AGEs) have a key mediatory role in the development and progression of degenerative tissue process. The bioflavonoids possess a broad-spectrum of pharmacological activities. Their capability is related to their chemical structure. METHODS: In this study we evaluated and compare antioxidant, anti glycative and anti-degenerative actions of two flavones apigenin and luteolin and a flavonol quercetin, in function of their hydroxyl groups arrangement. Moreover we assay, on NCTC 2544 and chondrocytes cultures, the flavonoids capacity to modulate NO and glycosamminoglycans levels, index of antidegenerative capacity. RESULTS: All tested flavonoids act as free radicals scavengers (ROO* and NO*) and advanced glycation end products inhibitors, in agreement with their BDE, IP and molecular planarity. Quercetin showed a high ORAC value (2.70+/-0.12 ORAC Units), according to a low BDE (74.54 Kcal/mol) and IP (174.44 Kcal/mol) values. Luteolin is the most active compound in the NO (48.19+/-0.18%) and AGEs (60.06+/-0.52%) inhibition, in function of a low torsion angle (16.3 degrees ) between the 3-OH moiety and C'6 carbon atom. CONCLUSION: All tested flavonoids posses a protective role on degenerative tissue events. They acts in different manner depending on the functional groups, the biological substrate and the concentration used. In any case, it can be considered a suitable product preventing a degenerative processes. PMID- 29108087 TI - Bupivacaine Versus Liposomal Bupivacaine For Pain Control. AB - Local infiltrations and regional blocks have been some of the effective ways employed to manage and control post-operative pain. One of the limitations of administration of local anesthesia drugs in post-operative conditions is its inability to act for a longer period of time. Multi-vesicular liposomes made up of bupivacaine have been progressively used for their increased duration of action. Compared to bupivacaine HCL, local infiltration of liposomal bupivacaine have shown to have a significantly increase the duration and delay in peak plasma concentration. In this article, we attempt to compare liposomal bupivacaine and bupivacaine based on available clinical literatures. Liposomal bupivacaine has been demonstrated to have promising implications in post- operative pain control resulting in increased patient satisfaction; reduced hospital admission and opioid induced adverse events. Clinical studies have identified liposomal bupivacaine to be effective in delivering increased post-operative pain control. The purpose of this review is to give a comprehensive comparison between bupivacaine liposomal and conventional bupivacaine based on reported clinical trials. PMID- 29108088 TI - [Rare Perirenal Masses: What Radiologists Should Know about them]. PMID- 29108089 TI - Impacts of weatherization on indoor air quality: A field study of 514 homes. AB - Residential energy efficiency retrofits continue to be common in the United States, especially through governmental and utility programs. Because of the potential for reduced air exchange, there have been concerns raised regarding the potential for negative impacts on health and safety of residents when air sealing occurs. To address this concern, a study was undertaken in 2009-2010 to evaluate the indoor air quality impacts of weatherization performed through the U.S. Department of Energy's Weatherization Assistance Program. Testing was conducted on 514 homes throughout the United States. The results show that weatherization, as performed at the time of the study, could result in small but statistically significant increases in some indoor contaminants such as radon and humidity, while also reducing exposures to elevated carbon monoxide in some homes. PMID- 29108090 TI - Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort. AB - : Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of <= 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year. PMID- 29108091 TI - Effects of low-dose epinephrine on perioperative hemostasis and inflammatory reaction in major surgical operations: a randomized clinical trial. AB - : Essentials Blood loss and immune reaction are closely related to morbidity and recovery after surgery. We studied the effect of epinephrine plus tranexamic acid on blood loss and immune reaction. Epinephrine plus tranexamic acid reduced postoperative total blood loss and immune reaction. Epinephrine plus tranexamic acid did not increase the incidence of complications. SUMMARY: Background Hemostasis, thrombosis and surgical stress-induced immune reactions are important for perioperative morbidity and recovery after major surgical operations. Objectives To evaluate the effects of combined administration of low-dose epinephrine (LDEPI) and tranexamic acid (TXA) on perioperative blood loss, thromboembolic complications and inflammatory responses in patients undergoing total hip arthroplasty (THA). Patients/Methods Patients scheduled for THA (n = 195) were randomized into three interventions: intravenous LDEPI plus TXA (group IV); topical diluted epinephrine plus TXA (group TP); and TXA alone as control (group CT). The primary outcome was perioperative blood loss on postoperative day (POD) 1. Secondary outcomes included perioperative blood loss on POD 3, intraoperative blood loss, volume of drainage, transfusion values, coagulation and fibrinolysis parameters, inflammatory cytokine levels, cases of thrombosis, intravenous fluid on the operation day, and length of hospital stay. Results The mean calculated amounts of total blood loss in groups IV, TP and CT were 631.2 mL, 760.5 mL, and 825.6 mL, respectively, on POD 1; treatment effects (differences) were 194.4 mL (95% confidence interval [CI] 146.7-242.0) and 65.0 mL (95% CI 17.4-112.7). Groups IV and TP had lower levels of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin [IL]-1beta) and higher levels of the anti-inflammatory cytokine IL-10, and showed faster development of coagulation and fibrinolysis (without change in peak levels), than group CT early postoperation. No differences were observed in transfusion, thromboembolic and other outcomes among the groups. Conclusion The combined administration of LDEPI and TXA was more effective in reducing perioperative blood loss and alleviating the inflammatory response than TXA alone, without increasing the incidence of thromboembolic and other complications. PMID- 29108092 TI - 1,1-Hydroboration and a Borane Adduct of Diphenyldiazomethane: A Potential Prelude to FLP-N2 Chemistry. AB - Diphenyldiazomethane reacts with HB(C6 F5 )2 and B(C6 F5 )3 , resulting in 1,1 hydroboration and adduct formation, respectively. The hydroboration proceeds via a concerted reaction involving initial formation of the Lewis adduct Ph2 CN2 BH(C6 F5 )2 . The highly sensitive adduct Ph2 CN2 (B(C6 F5 )3 ) liberates N2 and generates Ph2 CB(C6 F5 )3 . DFT computations reveal that formation of Ph2 CN2 B(C6 F5 )3 from carbene, N2 , and borane is thermodynamically favourable, suggesting steric frustration could preclude carbene-borane adduct formation and affect FLP-N2 capture. PMID- 29108093 TI - The self-reported quality of life of Lithuanian children with asthma was comparable to Western populations. AB - AIM: Quality of life (QoL) has been widely researched among children with asthma in Western countries, but there is a lack of data from eastern Europe, where the prevalence is relatively low, but hospital admission rates are higher. We evaluated the overall level and major determinants of QoL in Lithuanian children aged 5-11 years with asthma. METHODS: This study was carried out in six asthma outpatient clinics in the two largest cities of Lithuania from January 2015 to July 2016. The children's QoL was measured using the Pediatric Quality of Life Inventory (PedsQL) asthma module, which was completed by the child and one parent. RESULTS: We collected questionnaires from 226 children (68% boys) with a mean age of eight (+/-2) years: 65% had mild asthma, 31% had moderate asthma and 4% had severe asthma. One in 10 had been hospitalised in the preceding 6 months. The mean self-reported QoL score was 74 and the parent-reported QoL score was 73. QoL was associated with asthma severity and control, shortness of breath and the child's general health, but not socioeconomic factors. CONCLUSION: The overall level and major determinants of QoL in children with asthma in Lithuania were comparable with Western populations. PMID- 29108094 TI - Dimethyl fumarate treatment alters NK cell function in multiple sclerosis. AB - Dimethyl fumarate (DMF) treatment in multiple sclerosis (MS) increased the proportion of immunoregulatory CD56bright NK cells and this change was proportional to reductions in CD8+ memory T cells. DMF and monomethyl fumarate (MMF) treatment in vitro had directs effects on NK cells and promoted degranulation and cytotoxicity. PMID- 29108095 TI - Solid-State Structure of Protonated Ketones and Aldehydes. AB - Protonated carbonyl compounds have been invoked as intermediates in many acid catalyzed organic reactions. To gain key structural and electronic data about such intermediates, oxonium salts derived from five representative examples of ketones and aldehydes are synthesized in the solid state, and characterized by X ray crystallography and Raman spectroscopy for the first time. DFT calculations were carried out on the cations in the gas phase. Whereas an equimolar reaction of the carbonyl compounds, acetone, cyclopentanone, adamantanone, and acetaldehyde, with SbF5 in anhydrous HF yielded mononuclear oxonium cations, the same stoichiometry in a reaction with benzaldehyde resulted in formation of a hemiprotonated, hydrogen-bridged dimeric cation. Hemiprotonated acetaldehyde was obtained when a 2:1 ratio of aldehyde and SbF5 was used. Experimental and NBO analyses quantify the significant increase in electrophilicity of the oxonium cations compared to that of the parent ketones/aldehydes. PMID- 29108096 TI - A Randomized Controlled Trial Assessing the Efficacy of Cognitive Behavioral Therapy for Substance-Dependent Domestic Violence Offenders: An Integrated Substance Abuse-Domestic Violence Treatment Approach (SADV). AB - The current study evaluates a therapy for substance-dependent perpetrators of partner violence. Sixty-three males arrested for partner violence within the past year were randomized to a cognitive behavioral substance abuse-domestic violence (SADV; n = 29) or a drug counseling (DC; n = 34) condition. Seventy percent of offenders completed eight core sessions with no differences between SADV and DC conditions in the amount of substance or aggression at pretreatment. SADV participants had fewer cocaine-positive toxicology screens and breathalyzer results during treatment, were less likely to engage in aggressive behavior proximal to a drinking episode, and reported fewer episodes of violence than DC participants at posttreatment follow-up. SADV shows promise in decreasing addiction and partner violence among substance-dependent male offenders. PMID- 29108097 TI - Routine haemostasis testing before transplanted kidney biopsy: a cohort study. AB - Kidney biopsy can result in bleeding complications. Prebiopsy testing using bleeding time (BT) is controversial. New whole blood haemostasis tests, such as platelet function analyser-100 (PFA-100) and multiple electrode aggregometry (MEA), might perform better. We postulated that PFA-100 would be suitable to replace BT prebiopsy. In 154 patients, transplanted kidney biopsies were performed after measurement of bleeding time, PFA-100, MEA and mean platelet volume (MPV). Bleeding outcome (haemoglobin (Hb) drop, haematuria (+/-bladder catheterization), ultrasound finding of a bleeding, need for (non)surgical intervention and/or transfusion) after the biopsy was correlated to each test. Male-female ratio was 2:1. 50% had a surveillance biopsy at either three or 12 months. Around 17% (had) used acetylsalicylic acid (ASA) prebiopsy. Of 17 bleeding events, one subject needed a transfusion. Most bleeding events were Hb reductions over 1 mmol/l and all resolved uneventful. BT, PFA-100, MEA and MPV did not predict a bleeding outcome; prior ASA use however could (odds ratio 3.19; 95%-CI 1.06 to 9.61). Diagnostic performance data and Bland-Altman analysis showed that BT could not be substituted by PFA-100. ASA use was the best determinant of bleeding after kidney biopsy. Routine haemostasis testing prebiopsy has no added value. PMID- 29108098 TI - A High-Resolution Crystal Structure that Reveals Molecular Details of Target Recognition by the Calcium-Dependent Lipopeptide Antibiotic Laspartomycin C. AB - The calcium-dependent antibiotics (CDAs) are an important emerging class of antibiotics. The crystal structure of the CDA laspartomycin C in complex with calcium and the ligand geranyl-phosphate at a resolution of 1.28 A is reported. This is the first crystal structure of a CDA bound to its bacterial target. The structure is also the first to be reported for an antibiotic that binds the essential bacterial phospholipid undecaprenyl phosphate (C55 -P). These structural insights are of great value in the design of antibiotics capable of exploiting this unique bacterial target. PMID- 29108099 TI - Aqueous Bismuth Titanium-Oxo Sulfate Cluster Speciation and Crystallization. AB - Inorganic aqueous metal-oxo clusters are both functional "molecular metal oxides" and intermediates to understand metal oxide growth from water. There has been a recent surge in discovery of aqueous Ti-oxo clusters but without extensive solution characterization. We use small-angle and total X-ray scattering, dynamic light scattering, transmission electron microscopy, and a single-crystal X-ray structure to show that heterometals such as bismuth stabilize labile Ti-oxo sulfate clusters in aqueous solution.[Ti22 Bi7 O41 (OH)(OH2 )30 (SO4 )12 ]2+ features edge-sharing between the Ti and Bi polyhedra, in contrast to the dominant corner-linking of Ti-oxo clusters. Bi stabilizes the Ti-polyhedra, which are synergistically stabilized by the bidentate sulfates. Gained stability and potential functionality from heterometals is an incentive to develop more broadly the landscape of heterometallic Ti-oxo clusters. PMID- 29108100 TI - Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions. AB - The increasing global prevalence of diabetes mellitus presents a significant challenge to healthcare systems today. Although diabetic retinopathy, nephropathy and neuropathy are well-established complications of diabetes, there is a paucity of research examining the impact of dysglycaemia on the olfactory system. Olfaction is an important sense, playing a role in the safety, nutrition and quality of life of an individual, but its importance is often overlooked when compared with the other senses. As a result, olfactory dysfunction is often underdiagnosed. The present review article aims to present and discuss the available evidence on the relationship between diabetes and olfaction. It also explores the associations between olfactory dysfunction and diabetes complications that could explain the underlying pathogenesis. Finally, it summarizes the putative pathological mechanisms underlying olfactory dysfunction in diabetes that require further investigation. PMID- 29108101 TI - Practice and safety of allergen-specific immunotherapy for allergic rhinitis in the UK national health service: A report of "real world" clinical practice. PMID- 29108102 TI - Examining Proximal Risk Factors for Suicide in a Sample of Mexican Adults in Rehabilitation Centers. AB - The cross-cultural generalizability of the interpersonal theory of suicide was examined in this study. One hundred ninety-nine adults in an inpatient setting in Mexico completed the Personal Resources Questionnaire, Beck Hopelessness Scale, Interpersonal Needs Questionnaire, Acquired Capability for Suicide Scale, and Suicide Behaviors Questionnaire-Revised. Analyses revealed the interaction between perceived burdensomeness and thwarted belongingness did not predict suicide ideation. The interactions between perceived burdensomeness and thwarted belongingness and between perceived burdensomeness and acquired capacity significantly predicted suicidal behaviors, whereas the hypothesized three-way interaction did not. These findings highlight the importance of perceived burdensomeness in the development of suicidal behaviors among Mexican-origin adults. PMID- 29108103 TI - ADAMTS-13 and von Willebrand factor: a dynamic duo. AB - von Willebrand factor (VWF) is a key player in hemostasis, acting as a carrier for factor VIII and capturing platelets at sites of vascular damage. To capture platelets, it must undergo conformational changes, both within its A1 domain and at the macromolecular level through A2 domain unfolding. Its size and this function are regulated by the metalloproteinase ADAMTS-13. Recently, it has been shown that ADAMTS-13 undergoes a conformational change upon interaction with VWF, and that this enhances its activity towards its substrate. This review summarizes recent work on these conformational transitions, describing how they are controlled. It points to their importance in hemostasis, bleeding disorders, and the developing field of therapeutic application of ADAMTS-13 as an antithrombotic agent in obstructive microvascular thrombosis and in cardiovascular disease. PMID- 29108104 TI - Renal function after intravitreal administration of vascular endothelial growth factor inhibitors in patients with diabetes and chronic kidney disease. AB - The present study aimed to determine whether intravitreal administration of vascular endothelial growth factor inhibitors is associated with deterioration of renal function, as seen with systemic administration, in patients with diabetes and chronic kidney disease. Estimated glomerular filtration rates before and after 160 intravitreal injections of vascular endothelial growth factor inhibitors (aflibercept, bevacizumab or ranibizumab) were compared in 69 patients with diabetes and with a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 . We also determined the incidence of acute kidney injury. The data showed no significant difference in the estimated glomerular filtration rate before and after vascular endothelial growth factor inhibitor administration in all patients and in patient subgroups based on each inhibitor. Furthermore, no episodes of acute kidney injury occurred. In conclusion, intravitreal administration of vascular endothelial growth factor inhibitors is unlikely to be associated with a deterioration of renal function in patients with diabetes and chronic kidney disease. PMID- 29108105 TI - T cells are involved in the induction of macrophage phenotypes in oral leukoplakia and squamous cell carcinoma-a preliminary report. AB - BACKGROUND: The prognosis of human malignancies has been shown to depend on immunological parameters, such as macrophage polarization (M1 and M2). In this study, we identify the phenotype of macrophages, and investigate an involvement of infiltrated T cells that participate in the polarization of macrophages, in oral leukoplakia (OLK), and oral squamous cell carcinoma (OSCC). METHODS: Immunohistochemical method was used to examine the number of CD68+ , CD163+ (M2), iNOS+ (M1) macrophages, and CD4+ , CD8+ , CCR4+ (Th2), CCR5+ (Th1) cells in 102 cases of OSCC: without metastases-OSCC M(-) (n = 54), and with metastases-OSCC M(+) (n = 48), 23 cases of OLK, and 18 control cases. RESULTS: The mean number of CD68+ , CD163+ , iNOS+ , CD4+ , CCR4+ , CCR5+ cells was significantly increased in OSCC M(+) group compared with OLK, OSCC M(-) and control group. We found positive correlations between the number of CD4+ T cells and CD163+ and iNOS+ macrophages as well as CCR4+ and CCR5+ cells in both OSCC groups. The mean number of CD8+ cells was significantly increased in OSCC M(-) and OLK compared with OSCC M(+) and control group. In OSCC M(+) and OSCC M(-) groups, a negative correlation between the number of CD8+ cells and CD163+ and iNOS+ macrophages was found. CONCLUSIONS: The number and co-localization of lymphocytes and macrophages in OLK and OSCC may indicate that infiltrating cells influence the early and subsequent stage of oral carcinogenesis. PMID- 29108106 TI - Measurement tools for assessment of older age bipolar disorder: A systematic review of the recent global literature. AB - OBJECTIVES: More than 50% of people with bipolar disorder will be age 60 years or older by 2030. There is a need for more data to guide assessment and treatment in older age bipolar disorder (OABD); however, interpretation of findings from small, single-site studies may not be generalizable and there are few large trials. As a step in the direction of coordinated large-scale OABD data collection, it is critical to identify which measurements are currently used and identify potential gaps in domains typically assessed. METHODS: An international group of OABD experts performed a systematic literature review to identify studies examining OABD in the past 6 years. Relevant articles were assessed to categorize the types of clinical, cognitive, biomarker, and neuroimaging OABD tools routinely used in OABD studies. RESULTS: A total of 53 papers were identified, with a broad range of assessments. Most studies evaluated demographic and clinical domains, with fewer studies assessing cognition. There are relatively few biomarker and neuroimaging data, and data collection methods were less comprehensively covered. CONCLUSION: Assessment tools used in the recent OABD literature may help to identify both a minimum and a comprehensive dataset that should be evaluated in OABD. Our review also highlights gaps where key clinical outcomes have not been routinely assessed. Biomarker and neuroimaging assessment could be further developed and standardized. Clinical data could be combined with neuroimaging, genetic, and other biomarkers in large-scale coordinated data collection to further improve our understanding of OABD phenomenology and biology, thereby contributing to research that advances care. PMID- 29108107 TI - Smart Combinations of Bioactive Compounds in Fruits and Vegetables May Guide New Strategies for Personalized Prevention of Chronic Diseases. AB - There is ample scientific evidence suggesting that the health benefits of eating the right amounts of a variety of vegetables and fruit are the consequence of the combined action of different phytochemicals. The present review provides an update of the scientific literature on additive and synergistic effects of mixtures of phytochemicals. Most research has been carried out in in vitro systems in which synergistic or additive effects have been established on the level of cell proliferation, apoptosis, antioxidant capacity, and tumor incidence, accompanied by changes in gene and protein expression in relevant pathways underlying molecular mechanisms of disease prevention. The number of human dietary intervention studies investigating complex mixtures of phytochemicals is relatively small, but showing promising results. These studies have demonstrated that combining transcriptomic data with phenotypic markers provide insight into the relevant cellular processes which contribute to the antioxidant response of complex mixtures of phytochemicals. Future studies should be designed as short-term studies testing different combinations of vegetables and fruit, in which markers for disease outcome as well as molecular ('omics) markers and genetic variability between subjects are included. This will create new opportunities for food innovation and the development of more personalized strategies for prevention of chronic diseases. PMID- 29108109 TI - Inserting Porphyrin Quantum Dots in Bottom-Up Synthesized Graphene Nanoribbons. AB - Diels-Alder copolymerization of tetraphenylcyclopentadienone, a precursor for cove graphene nanoribbons (cGNRs), with bifunctional porphyrins yields defined nanostructures comprised of a single cGNR-porphyrin-cGNR heterojunction within each ribbon. 13 C NMR labeling and high-resolution mass spectrometry of solubilized polymer intermediates indicates that every porphyrin is covalently linked to two extended segments of cGNRs. UV/Vis absorption and fluorescence emission spectroscopy reveal a strong electronic correlation between the porphyrin and the adjacent cGNR segments that can be attenuated through reversible metalation of the porphyrin core. This versatile bottom-up synthetic strategy provides access to structurally well-defined, functional GNR-quantum dot GNR heterostructures within a single graphene nanoribbon. PMID- 29108108 TI - Antibacterial aryl-crowned polyketide from Bacillus subtilis associated with seaweed Anthophycus longifolius. AB - AIMS: Microbiological, biotechnological and chemical characterization of a previously undescribed aryl-crowned polyketide from Bacillus subtilis MTCC 10403 isolated from brown seaweed Anthophycus longifolius with activity against opportunistic Gram-negative food-borne pathogenic bacterial strains. METHODS AND RESULTS: A culture-dependent method was used to isolate heterotrophic B. subtilis associated with A. longifolius and assessed for its antimicrobial properties. Minimum inhibitory concentration (MIC) of the title compound against the test pathogens was analysed by microtube dilution coupled with the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based colorimetric endpoint detection. Bacillus subtilis MTCC 10403 was found to be antagonistic against Gram negative food-borne pathogenic Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica serotype Typhi, Aeromonas hydrophila and Vibrio sp. (diameter of zone of growth inhibition 13-22 mm). Bacillus subtilis was assessed for the presence of secondary metabolite coding polyketide synthase (pks) gene (KC589397, 700-bp gene product) and carboxylate siderophore framework in the aryl-crowned polyketide designated as 7-O-6'-(2"-acetylphenyl) 5'-hydroxyhexanoate-macrolactin by exhaustive spectroscopic techniques. The MIC assay showed that the reference antibiotics tetracycline and ampicillin were active at 25 MUg ml-1 against the test pathogens, whereas the newly isolated polyketide displayed anti-infective properties against E. coli, A. hydrophilla, P. aeruginosa and Vibrio sp. at a lower concentration (MIC <13 MUg ml-1 ). The MIC of the aryl macrolactin against K. pneumoniae was comparable with that of the referral antibiotics (~25 MUg ml-1 ). The mode of antimicrobial action of acryl crowned macrolactin was found to be iron chelating similar to siderophores. Putative biosynthetic pathway of the pks gene product further validated its molecular attributions. CONCLUSIONS: This study recognized new variant of antimicrobial aryl-crowned polyketide bearing methyl 6'-(2"-acetylphenyl)-5' hydroxyhexanoate moiety at the C-7 position of the macrolactin system from A. longifolius-associated bacterium B. subtilis. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed seaweed-associated micro-organisms as promising biological strata to produce new-generation anti-infective agents. PMID- 29108110 TI - Design of a species-specific PCR method for the detection of the heat-resistant fungi Talaromyces macrosporus and Talaromyces trachyspermus. AB - : Heat-resistant fungi occur sporadically and are a continuing problem for the food and beverage industry. The genus Talaromyces, as a typical fungus, is capable of producing the heat-resistant ascospores responsible for the spoilage of processed food products. Isocitrate lyase, a signature enzyme of the glyoxylate cycle, is required for the metabolism of non-fermentable carbon compounds, like acetate and ethanol. Here, species-specific primer sets for detection and identification of DNA derived from Talaromyces macrosporus and Talaromyces trachyspermus were designed based on the nucleotide sequences of their isocitrate lyase genes. Polymerase chain reaction (PCR) using a species specific primer set amplified products specific to T. macrosporus and T. trachyspermus. Other fungal species, such as Byssochlamys fulva and Hamigera striata, which cause food spoilage, were not detected using the Talaromyces specific primer sets. The detection limit for each species-specific primer set was determined as being 50 pg of template DNA, without using a nested PCR method. The specificity of each species-specific primer set was maintained in the presence of 1,000-fold amounts of genomic DNA from other fungi. The method also detected fungal DNA extracted from blueberry inoculated with T. macrosporus. This PCR method provides a quick, simple, powerful and reliable way to detect T. macrosporus and T. trachyspermus. SIGNIFICANCE AND IMPACT OF THE STUDY: Polymerase chain reaction (PCR)-based detection is rapid, convenient and sensitive compared with traditional methods of detecting heat-resistant fungi. In this study, a PCR-based method was developed for the detection and identification of amplification products from Talaromyces macrosporus and Talaromyces trachyspermus using primer sets that target the isocitrate lyase gene. This method could be used for the on-site detection of T. macrosporus and T. trachyspermus in the near future, and will be helpful in the safety control of raw materials and in food and beverage production. PMID- 29108111 TI - Genetic Variants in ERAP1 and ERAP2 Associated With Immune-Mediated Diseases Influence Protein Expression and the Isoform Profile. AB - OBJECTIVE: Endoplasmic reticulum aminopeptidase 1 (ERAP-1) and ERAP-2, encoded on chromosome 5q15, trim endogenous peptides for HLA-mediated presentation to the immune system. Polymorphisms in ERAP1 and/or ERAP2 are strongly associated with several immune-mediated diseases with specific HLA backgrounds, implicating altered peptide handling and presentation as prerequisites for autoreactivity against an arthritogenic peptide. Given the thorough characterization of disease risk-associated polymorphisms that alter ERAP activity, this study aimed instead to interrogate the expression effect of chromosome 5q15 polymorphisms to determine their effect on ERAP isoform and protein expression. METHODS: RNA sequencing and genotyping across chromosome 5q15 were performed to detect genetic variants in ERAP1 and ERAP2 associated with altered total gene and isoform specific expression. The functional implication of a putative messenger RNA splice-altering variant on ERAP-1 protein levels was validated using mass spectrometry. RESULTS: Polymorphisms associated with ankylosing spondylitis (AS) significantly influenced the transcript and protein expression of ERAP-1 and ERAP 2. Disease risk-associated polymorphisms in and around both genes were also associated with increased gene expression. Furthermore, key risk-associated ERAP1 variants were associated with altered transcript splicing, leading to allele dependent alternate expression of 2 distinct isoforms and significant differences in the type of ERAP-1 protein produced. CONCLUSION: In accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the increased risk also attributed to increased expression of ERAP1 and ERAP2 supports the notion of using aminopeptidase inhibition to treat AS and other ERAP-associated conditions. PMID- 29108112 TI - Ethanol addition enhances acid treatment to eliminate Lactobacillus fermentum from the fermentation process for fuel ethanol production. AB - : Fermentation is one of the most critical steps of the fuel ethanol production and it is directly influenced by the fermentation system, selected yeast, and bacterial contamination, especially from the genus Lactobacillus. To control the contamination, the industry applies antibiotics and biocides; however, these substances can result in an increased cost and environmental problems. The use of the acid treatment of cells (water-diluted sulphuric acid, adjusted to pH 2.0 2.5) between the fermentation cycles is not always effective to combat the bacterial contamination. In this context, this study aimed to evaluate the effect of ethanol addition to the acid treatment to control the bacterial growth in a fed-batch system with cell recycling, using the industrial yeast strain Saccharomyces cerevisiae PE-2. When only the acid treatment was used, the population of Lactobacillus fermentum had a 3-log reduction at the end of the sixth fermentation cycle; however, when 5% of ethanol was added to the acid solution, the viability of the bacterium was completely lost even after the first round of cell treatment. The acid treatment +5% ethanol was able to kill L. fermentum cells without affecting the ethanol yield and with a low residual sugar concentration in the fermented must. SIGNIFICANCE AND IMPACT OF THE STUDY: In Brazilian ethanol-producing industry, water-diluted sulphuric acid is used to treat the cell mass at low pH (2.0) between the fermentative cycles. This procedure reduces the number of Lactobacillus fermentum from 107 to 104 CFU per ml. However, the addition of 5% ethanol to the acid treatment causes the complete loss of bacterial cell viability in fed-batch fermentation with six cell recycles. The ethanol yield and yeast cell viability are not affected. These data indicate the feasibility of adding ethanol to the acid solution replacing the antibiotic use, offering a low cost and a low amount of residue in the biomass. PMID- 29108113 TI - Anxiety Sensitivity Differentially Predicts Factors of Interpersonal Psychological Suicide Risk: A Consideration of Specificity. AB - Recent studies have identified anxiety sensitivity (AS) as a risk factor for suicidality; however, limited work has been performed to understand this risk within the context of the interpersonal-psychological theory of suicide (IPTS; Joiner, 2005). The current study examined the relationship between overall AS, each AS subfactor (cognitive, social, and physical), and the three IPTS domains (perceived burdensomeness, thwarted belongingness, and acquired capability). While each AS subfactor uniquely predicted one IPTS domain, greater overall AS only predicted greater acquired capability, suggesting that assessment of AS at the subfactor level may offer us more information about an individual's interpersonal suicide risk. PMID- 29108114 TI - Reply. PMID- 29108115 TI - MoNSTR-seq, a restriction site-associated DNA sequencing technique to characterize Agrobacterium-mediated transfer-DNA insertions in Phomopsis longicolla. AB - : Phomopsis longicolla (Hobbs) causes Phomopsis seed decay and stem lesions in soybean (Glycine max). In this study, a novel, high-throughput adaptation of RAD seq termed MoNSTR-seq (Mutation analysis via Next-generation DNA Sequencing of T DNA Regions) was developed to determine the genomic location of T-DNA insertions in P. longicolla mutants. Insertional mutants were created via Agrobacterium tumefaciens-mediated transformation, and one mutant, strain PL343, was further investigated due to impaired stem lesion formation. Mutation analysis via Next generation DNA Sequencing of T-DNA Regions, in which DNA libraries are created with two distinct restriction enzymes and customized adapters to simultaneously enrich both T-DNA insertion borders, was developed to characterize the genomic lesion in strain PL343. MoNSTR-seq successfully identified a T-DNA insertion in the predicted promoter region of a gene encoding a cellobiose dehydrogenase (CDH1), and the position of the T-DNA insertion in strain PL343 was confirmed by Sanger sequencing. Thus, MoNSTR-seq represents an effective tool for molecular genetics in P. longicolla, and is readily adaptable for use in diverse fungal species. SIGNIFICANCE AND IMPACT OF THE STUDY: This study describes MoNSTR-seq (Mutation analysis via Next-generation DNA Sequencing of T-DNA Regions), an adaptation of restriction site-associated DNA sequencing (RAD-seq) to identify the position of transfer-DNA (T-DNA) insertions in the genome of Phomopsis longicolla, an important pathogen of soybean. The technique enables high throughput characterization of mutants generated via Agrobacterium tumefaciens mediated transformation (ATMT), thus accelerating gene discovery via forward genetics. This technique represents a significant advancement over existing approaches to characterize T-DNA insertions in fungal genomes. With minor modifications, this technique could be easily adapted to taxonomically diverse fungal pathogens and additional mutagenesis cassettes. PMID- 29108116 TI - Arthritis in Melorheostosis-An Uncommon Feature in a Rare Disease. PMID- 29108117 TI - Don't forget the general practitioner. PMID- 29108118 TI - Should venous ammonia be used in decision-making acute liver failure patients? PMID- 29108119 TI - Duct-to-duct biliary reconstruction in pediatric split-liver transplantation. PMID- 29108120 TI - Reply. PMID- 29108121 TI - Hepatitis C and human immunodeficiency virus coinfection in the era of direct acting antiviral agents: No longer a difficult-to-treat population. AB - : The treatment of chronic hepatitis C (HCV) in human immunodeficiency virus 1 (HIV)-infected individuals has been historically marked by low sustained virologic response (SVR) rates in comparison to those without HIV infection, resulting in the Food and Drug Administration labeling those coinfected as a "special population with an unmet medical need." We systematically reviewed the treatment of chronic HCV infection in those infected with HIV. We propose that with the advent of direct-acting antiviral (DAA) agents, patients coinfected with HCV and HIV have similar SVR rates as HCV-monoinfected persons and that DAAs address an unmet medical need in this population. A review was performed using Medical Subject Heading terms within the PubMed, EMBASE, and Cochrane Library databases to search for studies dated between January 2004 and July 2017. Keywords used in the study included "hepatitis C," "HIV," "coinfection," and "direct-acting antiviral." SVR rates for those with HCV and HIV coinfection treated with interferon-based therapies were substantially lower that SVR rates of HCV-monoinfected individuals. The advent of DAA agents has resulted in similar SVR rates between monoinfected and coinfected individuals, with SVR >93%. These medications have been demonstrated to have improved safety, efficacy, and tolerability in comparison to interferon-based regimens. CONCLUSION: The designation of a "special population" for those with coinfection requires reconsideration; DAA therapies have resulted in similarly high rates of SVR for HCV infection in those with and without HIV infection; despite these improvements, however, clinicians must be cognizant of negative predictors of SVR and barriers to treatment that may be more common in the coinfected population. (Hepatology 2018;67:847-857). PMID- 29108122 TI - Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. AB - : Alcoholic hepatitis (AH) continues to be a disease with high mortality and no efficacious medical treatment. Although severe AH is presented as acute on chronic liver failure, what underlies this transition from chronic alcoholic steatohepatitis (ASH) to AH is largely unknown. To address this question, unbiased RNA sequencing and proteomic analyses were performed on livers of the recently developed AH mouse model, which exhibits the shift to AH from chronic ASH upon weekly alcohol binge, and these results are compared to gene expression profiling data from AH patients. This cross-analysis has identified Casp11 (CASP4 in humans) as a commonly up-regulated gene known to be involved in the noncanonical inflammasome pathway. Immunoblotting confirms CASP11/4 activation in AH mice and patients, but not in chronic ASH mice and healthy human livers. Gasdermin-D (GSDMD), which induces pyroptosis (lytic cell death caused by bacterial infection) downstream of CASP11/4 activation, is also activated in AH livers in mice and patients. CASP11 deficiency reduces GSDMD activation, bacterial load in the liver, and severity of AH in the mouse model. Conversely, the deficiency of interleukin-18, the key antimicrobial cytokine, aggravates hepatic bacterial load, GSDMD activation, and AH. Furthermore, hepatocyte specific expression of constitutively active GSDMD worsens hepatocellular lytic death and polymorphonuclear leukocyte inflammation. CONCLUSION: These results implicate pyroptosis induced by the CASP11/4-GSDMD pathway in the pathogenesis of AH. (Hepatology 2018;67:1737-1753). PMID- 29108124 TI - A Bayesian approach for analyzing zero-inflated clustered count data with dispersion. AB - In practice, count data may exhibit varying dispersion patterns and excessive zero values; additionally, they may appear in groups or clusters sharing a common source of variation. We present a novel Bayesian approach for analyzing such data. To model these features, we combine the Conway-Maxwell-Poisson distribution, which allows both overdispersion and underdispersion, with a hurdle component for the zeros and random effects for clustering. We propose an efficient Markov chain Monte Carlo sampling scheme to obtain posterior inference from our model. Through simulation studies, we compare our hurdle Conway-Maxwell Poisson model with a hurdle Poisson model to demonstrate the effectiveness of our Conway-Maxwell-Poisson approach. Furthermore, we apply our model to analyze an illustrative dataset containing information on the number and types of carious lesions on each tooth in a population of 9-year-olds from the Iowa Fluoride Study, which is an ongoing longitudinal study on a cohort of Iowa children that began in 1991. PMID- 29108123 TI - Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. AB - : The optimal threshold of controlled attenuation parameter (CAP) for the detection of hepatic steatosis using both M and XL probe is unknown in nonalcoholic fatty liver disease (NAFLD). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) is an accurate and precise method of detecting the presence of hepatic steatosis that is superior to CAP. Thus, the aim of this study was to evaluate the diagnostic accuracy and optimal threshold of CAP for the detection of hepatic steatosis as defined by MRI-PDFF >= 5%. This prospective cross-sectional study included 119 adults (59% women) with and without NAFLD who underwent MRI-PDFF and CAP using either M or XL probe when indicated within a 6 month period at the NAFLD Research Center, University of California, San Diego. The mean ( +/- standard deviation) age and body mass index were 52.4 (+/-15.2) years and 29.9 (+/-5.5) kg/m2 , respectively. The prevalence of NAFLD (MRI-PDFF >= 5%) and MRI-PDFF >= 10% was 70.6% and 47.1%, respectively. The area under the receiver operating characteristic (AUROC) of CAP for the detection of MRI-PDFF >= 5% was 0.80 (95% confidence interval [CI], 0.70-0.90) at the cut-point of 288 dB/m and of MRI-PDFF >= 10% was 0.87 (95% CI, 0.80-0.94) at the cut-point of 306 dB/m. When stratified by the interquartile range (IQR) of CAP, we observed that an IQR below the median (30 dB/m) had a robust AUROC compared with an IQR above the median (0.92 [95% CI, 0.85-1.00] versus 0.70 [95% CI, 0.56-0.85]; P = 0.0117), and these differences were statistically and clinically significant. CONCLUSION: The cut-point of CAP for presence of hepatic steatosis (MRI-PDFF >= 5%) was 288 dB/m. The diagnostic accuracy of CAP for the detection of hepatic steatosis is more reliable when the IQR of CAP is <30 dB/m. These data have implications for the clinical use of CAP in the assessment of NAFLD. (Hepatology 2018;67:1348-1359). PMID- 29108125 TI - Robust fit of Bayesian mixed effects regression models with application to colony forming unit count in tuberculosis research. AB - Early bactericidal activity of tuberculosis drugs is conventionally assessed using statistical regression modeling of colony forming unit (CFU) counts over time. Typically, most CFU counts deviate little from the regression curve, but gross outliers due to erroneous sputum sampling are occasionally present and can markedly influence estimates of the rate of change in CFU count, which is the parameter of interest. A recently introduced Bayesian nonlinear mixed effects regression model was adapted to offer a robust approach that accommodates both outliers and potential skewness in the data. At its most general, the proposed regression model fits the skew Student t distribution to residuals and random coefficients. Deviance information criterion statistics and compound Laplace Metropolis marginal likelihoods were used to discriminate between alternative Bayesian nonlinear mixed effects regression models. We present a relatively easy method to calculate the marginal likelihoods required to determine compound Laplace-Metropolis marginal likelihoods, by adapting methods available in currently available statistical software. The robust methodology proposed in this paper was applied to data from 6 clinical trials. The results provide strong evidence that the distribution of CFU count is often heavy tailed and negatively skewed (suggesting the presence of outliers). Therefore, we recommend that robust regression models, such as those proposed here, should be fitted to CFU count. PMID- 29108126 TI - High sensitivity of the HematoflowTM solution for chronic myelomonocytic leukemia screening. AB - BACKGROUND: Accumulation of classical monocytes CD14++ CD16- (also called MO1) >= 94% can accurately distinguish chronic myelomonocytic leukemia (CMML) from reactive monocytosis. The HematoFlowTM solution, able to quantify CD16 negative monocytes, could be a useful tool to manage monocytosis which remains a common issue in routine laboratories. METHODS: Classical monocytes were quantified from 153 whole blood samples collected on EDTA using both flow cytometry methods, either MO1 percentage determination by the multiparameter assay previously published and regarded here as the reference method, or CD16 negative monocyte percentage determination by the means of HematoFlowTM. RESULTS: Both methods of classical monocyte percentage determination were highly and significantly correlated (r = 0.87, P < 0.0001). The HematoFlowTM solution leant toward an overestimation of the genuine classical monocyte percentages obtained by the reference method. Percentages of CD16 negative monocytes provided by HematoFlow were higher than 94% for all the 73 patients displaying classical monocytes MO1 found >=94% by the reference method, indicating a sensitivity of 100%. Furthermore, the calculation of CD16 negative monocyte percentage can be easily computerized and integrated to the middleware. CONCLUSIONS: We propose a new application of the HematoflowTM solution that can be used as a flag system for monocytosis management and CMML detection. (c) 2017 International Clinical Cytometry Society. PMID- 29108127 TI - Multi-dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists. AB - PURPOSE: Multi-dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self-reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use. METHODS: We conducted a before-after study in non-adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non-adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison). RESULTS: Eighty-three non adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD-patients increased 10% (95%CI 2% to 19%) higher as compared with non-MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI -2% to 9%). CONCLUSIONS: Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months. PMID- 29108128 TI - Safety assessment of niacin in the US Food and Drug Administration's mini sentinel system. AB - PURPOSE: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial found higher incidence rates of adverse reactions, including bleeding, in patients receiving the combination of extended release niacin and laropiprant versus placebo. It is not known whether these adverse events are attributable to laropiprant, not approved in the USA, or to extended-release niacin. We compared rates of major gastrointestinal bleeding and intracranial hemorrhage among initiators of extended-release niacin and initiators of fenofibrate. METHODS: We used Mini-Sentinel (now Sentinel) to conduct an observational, new user cohort analysis. We included data from 5 Data Partners covering the period from January 1, 2007 to August 31, 2013. Individuals who initiated extended-release niacin were propensity score-matched to individuals who initiated fenofibrate. Within the matched cohorts, we used Cox proportional hazards models to compare rates of hospitalization for major gastrointestinal bleeding events and intracranial hemorrhage assessed using validated claims-based algorithms. RESULTS: A total of 234 242 eligible extended release niacin initiators were identified, of whom 210 389 (90%) were 1:1 propensity score-matched to eligible fenofibrate initiators. In propensity score matched analyses, no differences were observed between exposure groups in rates of major gastrointestinal bleeding (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.82 to 1.18) or intracranial hemorrhage (HR, 1.21; 95% CI, 0.66 to 2.22). Results were similar in pre-specified sensitivity and subgroup analyses. CONCLUSIONS: We did not observe evidence for an association between extended-release niacin versus fenofibrate and rates of major gastrointestinal bleeding or intracranial hemorrhage. PMID- 29108129 TI - Simultaneous quantitation of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma using solid-phase extraction and gas chromatography/mass spectrometry: Method validation and application to cardiovascular safety of therapeutic doses. PMID- 29108131 TI - Moving from place to place in the last year of life: A qualitative study identifying care setting transition issues and solutions in Ontario. AB - Moving from one care setting to another is common as death nears. Many concerns exist over these end-of-life (EOL) care setting transitions, including low quality moves as mistakes and other mishaps can occur. Delayed or denied moves are also problematic, such as a move out of hospital for dying inpatients who want to spend their last hours or days at home. The aim of the study was to identify current issues or problems with care setting transitions during the last year of life as well as potential or actual solutions for these problems. A grounded theory analysis approach was used based on interviews with 38 key informants who represent a wide range of healthcare providers, healthcare managers, government representatives, lawyers, healthcare recipients and their family/friends across Ontario in 2016. Three interrelated themes were revealed: (a) communication complexities, (b) care planning and coordination gaps and (c) health system reform needs. Six solutions were highlighted, with these designed to prevent care setting transition issues and monitor care setting transitions for continued improvements. PMID- 29108130 TI - Comparative risk of serious hypoglycemia with oral antidiabetic monotherapy: A retrospective cohort study. AB - PURPOSE: To examine and compare risks of serious hypoglycemia among antidiabetic monotherapy-treated adults receiving metformin, a sulfonylurea, a meglitinide, or a thiazolidinedione. METHODS: We performed a retrospective cohort study of apparently new users of monotherapy with metformin, glimepiride, glipizide, glyburide, pioglitazone, rosiglitazone, nateglinide, or repaglinide within a dataset of Medicaid beneficiaries from California, Florida, New York, Ohio, and Pennsylvania. We did not include users of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, or sodium-glucose co-transporter 2 inhibitors. We identified serious hypoglycemia outcomes within 180 days following new use using a validated, diagnosis-based algorithm. We calculated age- and sex standardized outcome occurrence rates for each drug and generated propensity score-adjusted hazard ratios vs metformin using Cox proportional hazards regression. RESULTS: The ranking of standardized occurrence rates of serious hypoglycemia was glyburide > glimepiride > glipizide > repaglinide > nateglinide > rosiglitazone > pioglitazone > metformin. Rates were increased for all study drugs at higher average daily doses. Adjusted hazard ratios (95% confidence intervals) vs metformin were 3.95 (3.66-4.26) for glyburide, 3.28 (2.98-3.62) for glimepiride, 2.57 (2.38-2.78) for glipizide, 2.03 (1.64-2.52) for repaglinide, 1.21 (0.89-1.66) for nateglinide, 0.90 (0.75-1.07) for rosiglitazone, and 0.80 (0.68-0.93) for pioglitazone. CONCLUSIONS: Sulfonylureas were associated with the highest rates of serious hypoglycemia. Among all study drugs, the highest rate was seen with glyburide. Pioglitazone was associated with a lower adjusted hazard for serious hypoglycemia vs metformin, while rosiglitazone and nateglinide had hazards similar to that of metformin. PMID- 29108132 TI - Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. AB - : Hepatitis B surface antigen (HBsAg) loss is a rare event during nucleos(t)ide analogue (Nuc) therapy. Limited data suggest that stopping Nuc therapy may increase HBsAg loss rate in hepatitis B e antigen-negative patients. A large study was conducted to investigate this issue in more detail. Of the 1,075 hepatitis B e antigen-negative patients treated with Nuc for a median of 156 (61 430) weeks, 5 showed HBsAg seroclearance during treatment at an estimated annual incidence of 0.15%. Of the patients who remained HBsAg-seropositive, 691 (52.3 years old, 86% male, 44.6% cirrhosis) had stopped Nuc therapy by the Asian Pacific Association for the Study of the Liver stopping rule and then were prospectively followed up. Baseline and on-treatment clinical and viral features, treatment duration, consolidation duration, time to undetectable hepatitis B virus DNA, time to normal alanine aminotransferase, end-of-treatment HBsAg, and HBsAg log reduction were compared between patients with and without HBsAg seroclearance after end of treatment. During a median off-therapy follow-up period of 155 (2-614) weeks, HBsAg seroclearance was confirmed in 42 patients. The 6-year cumulative incidence was 13% with an estimated annual incidence of 1.78%. Cox regression analysis showed that shorter time to undetectable hepatitis B virus DNA (<12 weeks), greater HBsAg reduction during therapy (>1 log10 ), lower end-of-treatment HBsAg level (<100 IU/mL), patients with sustained response, and relapsers not retreated were factors for off-therapy HBsAg seroclearance. CONCLUSION: The incidence of HBsAg seroclearance after stopping Nuc was much higher than that during therapy and highest in patients without virologic and clinical relapse; patients with clinical relapse who remained untreated had a 7.34 times higher incidence of HBsAg clearance than those who received retreatment, suggesting that transient untreated clinical relapse may drive sufficient immune control to functional cure. (Hepatology 2017). PMID- 29108133 TI - Targeted delivery of microRNA-199a-3p using self-assembled dipeptide nanoparticles efficiently reduces hepatocellular carcinoma in mice. AB - : Hepatocellular carcinoma (HCC) is an aggressive tumor with limited systemic and locoregional modalities of treatment. Although microRNA (miRNA) based therapies have significant potential, their targeted delivery remains a major challenge. miR-199a-3p functions as an important tumor suppressor in HCC, which regulates various cellular processes. Recently, peptide-based nanoparticles (NPs) have been developed to deliver oligonucleotides including miRNA. Here, we describe the synthesis and characterization of arginine alpha,beta-dehydrophenylalanine (RDeltaF) nanoparticles for the selective delivery of miR-199a-3p to restore dysregulated gene expression in HCC. Targeted delivery was achieved by conjugating lactobionic acid (LA) with RDeltaF NPs (RDeltaF-LA NPs), a ligand for the asialoglycoprotein receptor known to be overexpressed in HCC cell lines. RDeltaF-LA NPs condensed miR-199a-3p had an average size of ~60nm and a zeta potential of ~+2.54 mV. RDeltaF-LA/miR NPs were found to be stable in serum as well as against RNase attack. RDeltaF-LA/miR NPs showed an enhanced cellular uptake and an efficient delivery of miR-199a-3p leading to a significant increase in miR-199a-3p levels (over 500 fold). The increased miR-199a-3p levels remarkably suppressed cell proliferation and migration as well as induced cellular apoptosis and downregulation of the specific target gene (mTOR) in vitro. RDeltaF-LA/miR NPs showed high tumor/ low organ ratios after intravenous injection into HCC tumor bearing nude mice. RDeltaF-LA/miR NPs treated mice demonstrated>50% decline in tumor growth, which also corresponded well with suppression of mTOR protein expression, tumor cell proliferation and increased survival rate (P < 0.05). CONCLUSION: RDeltaF-LA/miR NPs showed significantly enhanced delivery of the miRNA which underscores their potential for further development as a therapeutic approach for HCC. (Hepatology 2018;67:1392-1407). PMID- 29108134 TI - Production of recombinant human tektin 1, 2, and 4 and in vitro assembly of human tektin 1. AB - Proteins predicted to be composed of large stretches of coiled-coil structure have often proven difficult to crystallize for structural determination. We have successfully applied EPR spectroscopic techniques to the study of the structure and assembly of full-length human vimentin assembled into native 11 nm filaments, in physiologic solution, circumventing the limitations of crystallizing shorter peptide sequences. Tektins are a small family of highly alpha helical filamentous proteins found in the doublet microtubules of cilia and related structures. Tektins exhibit several similarities to intermediate filaments (IFs): moderate molecular weight, highly alpha helical, hypothesized to be coiled-coil, and homo- and heteromeric assembly into long smooth filaments. In this report, we show the application of IF research methodologies to the study of tektin structure and assembly. To begin in vitro studies, expression constructs for human tektins 1, 2, and 4 were synthesized. Recombinant tektins were produced in E. coli and purified by chromatography. Preparations of tektin 1 successfully formed filaments. The recombinant human tektin 1 was used to produce antibodies which recognized an antigen in mouse testes, most likely present in sperm flagella. Finally, we report the creation of seven mutants to analyze predictions of coiled coil structure in the rod 1A domain of tektin 1. Although this region is predicted to be coiled-coil, our EPR analysis does not reflect the parallel, in register, coiled-coil structure as demonstrated in vimentin and kinesin. These results document that tektin can be successfully expressed and assembled in vitro, and that SDSL EPR techniques can be used for structural analysis. PMID- 29108135 TI - Regimens of ultrasound surveillance for twin pregnancies for improving outcomes. AB - BACKGROUND: Increased ultrasound surveillance of twin pregnancies has become accepted practice due to the higher risk of complications. There is no current consensus however as to the method and frequency of ultrasound monitoring that constitutes optimal care. OBJECTIVES: To systematically review the effects of different types and frequency of ultrasound surveillance for women with a twin pregnancy on neonatal, fetal and maternal outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (all searched 11 August 2017), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised trials (including those published in abstract form) comparing the effects of described antenatal ultrasound surveillance regimens in twin pregnancies. Trials using a cluster-randomised design would have been eligible for inclusion in this review but none were identified. Trials using a cross-over design are not eligible for inclusion in this review.Different types and frequencies of ultrasound testing (for fetal surveillance and detection of specific problems) compared with each other and also compared with no testing. For example, an intervention might comprise a specific approach to ultrasound examination with dedicated components to detect twin-specific pathology. Different interventions could also include a specific type of surveillance at different intervals or different combinations at the same intervals.In this review we only found one study looking at fetal growth (biometry) and Doppler ultrasounds at 25, 30 and 35 weeks' gestation versus fetal growth alone. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and quality, and extracted data. We checked data for accuracy. MAIN RESULTS: We included one trial of 526 women with a twin pregnancy of two viable twins, with no known morphological abnormality, in this review. The trial compared women receiving fetal growth and Doppler ultrasounds at 25, 30 and 35 weeks' gestation to fetal growth alone. We judged the included study to be at low risk of bias however the risk of performance and detection bias were unclear.The primary outcome was the perinatal mortality rate (after randomisation), for which there was no evidence of a clear difference between the fetal growth + Doppler and the fetal growth alone groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.32 to 2.41, low-quality evidence) with similar rates in both groups (seven events in the Dopper + fetal growth group and eight in the fetal growth alone group). No clear differences were seen between the two regimens for the other outcomes in this review: stillbirth (RR 0.67, 95% CI 0.11 to 3.99), neonatal death (RR 1.01, 95% CI 0.29 to 3.46, low-quality evidence), gestational age at birth (weeks) (mean difference 0.10, 95% CI -0.39 to 0.59, moderate-quality evidence), infant requiring ventilation (RR 0.86, 95% CI 0.59 to 1.25), admission to special care or intensive care units (RR 0.96, 95% CI 0.88 to 1.05), caesarean section (any) (RR 1.00, 95% CI 0.81 to 1.23, high-quality evidence), elective caesarean section (RR 1.06, 95% CI 0.77 to 1.47), emergency caesarean section (RR 0.93, 95% CI 0.66 to 1.32), induction of labour (RR 1.10, 95% CI 0.80 to 1.50, moderate-quality evidence) or antenatal hospital admission (RR 0.96, 95% CI 0.80 to 1.15, high-quality evidence). The number of preterm births before 28 weeks' gestation was not reported in the included study. For the mortality-related outcomes, event numbers were small.The included study did not report the majority of our maternal and infant secondary outcomes. Infant outcomes not reported included fetal acidosis, Apgar scores less than 7 at five minutes and preterm birth before 37 and 34 weeks' gestation. The maternal outcomes; length of antenatal hospital stay, timely diagnosis of significant complications, rate of preterm, prelabour rupture of membranes and women's level of satisfaction with their care were not reported. The study did not classify twin pregnancies according to their chorionicity. An awareness of the chorionicity may have improved applicability of this data set.We downgraded outcomes assessed using GRADE for imprecision of effect estimates. AUTHORS' CONCLUSIONS: This review is based on one small study which was underpowered for detection of rare outcomes such as perinatal mortality, stillbirth and neonatal death.There is insufficient evidence from randomised controlled trials to inform best practice for fetal ultrasound surveillance regimens when caring for women with a twin pregnancy. More studies are needed to evaluate the effects of currently used ultrasound surveillance regimens in twin pregnancies. Future research could report on the important maternal and infant outcomes as listed in this review. PMID- 29108136 TI - Application and optimisation of the Comparison on Extreme Laboratory Tests (CERT) algorithm for detection of adverse drug reactions: Transferability across national boundaries. AB - PURPOSE: The Singapore regulatory agency for health products (Health Sciences Authority), in performing active surveillance of medicines and their potential harms, is open to new methods to achieve this goal. Laboratory tests are a potential source of data for this purpose. We have examined the performance of the Comparison on Extreme Laboratory Tests (CERT) algorithm, developed by Ajou University, Korea, as a potential tool for adverse drug reaction detection based on the electronic medical records of the Singapore health care system. METHODS: We implemented the original CERT algorithm, comparing extreme laboratory results pre- and post-drug exposure, and 5 variations thereof using 4.5 years of National University Hospital (NUH) electronic medical record data (31 869 588 laboratory tests, 6 699 591 drug dispensings from 272 328 hospitalizations). We investigated 6 drugs from the original CERT paper and an additional 47 drugs. We benchmarked results against a reference standard that we created from UpToDate 2015. RESULTS: The original CERT algorithm applied to all 53 drugs and 44 laboratory abnormalities yielded a positive predictive value (PPV) and sensitivity of 50.3% and 54.1%, respectively. By raising the minimum number of cases for each drug laboratory abnormality pair from 2 to 400, the PPV and sensitivity increased to 53.9% and 67.2%, respectively. This post hoc variation, named CERT400, performed particularly well for drug-induced hepatic and renal toxicities. DISCUSSION: We have demonstrated that the CERT algorithm can be applied across national boundaries. One modification (CERT400) was able to identify adverse drug reaction signals from laboratory data with reasonable PPV and sensitivity, which indicates potential utility as a supplementary pharmacovigilance tool. PMID- 29108137 TI - Multi-arm trials with multiple primary endpoints and missing values. AB - We present an extension of multiple contrast tests for multiple endpoints to the case of missing values. The endpoints are assumed to be normally distributed and correlated and to have equal covariance matrices for the different treatments. Different multivariate t distributions will be applied, differing in endpoint specific degrees of freedom. In contrast to competing methods, the familywise error type I is maintained in the strong sense in an admissible range, and the problem of different marginal errors type I is avoided. The information of all observations is exploited, thereby enabling a gain in power compared with a complete case analysis. PMID- 29108138 TI - High-energy collision-induced dissociation of histidine ions [His + H]+ and [His H]- and histidine dimer [His2 + H]. AB - RATIONALE: Histidine (His) is an essential amino acid, whose side group consists of an aromatic imidazole moiety that can bind a proton or metal cation and act as a donor in intermolecular interactions in many biological processes. While the dissociation of His monomer ions is well known, information on the kinetic energy released in the dissociation is missing. METHODS: Using a new home-built electrospray ionization (ESI) source adapted to a double-focusing mass spectrometer of BE geometry, we investigated the fragmentation reactions of protonated and deprotonated His, [His + H]+ and [His - H]- , and the protonated His dimer [His2 + H]+ , accelerated to 6 keV in a high-energy collision with helium gas. We evaluated the kinetic energy release (KER) for the observed dissociation channels. RESULTS: ESI of His solution in positive mode led to the formation of His clusters [Hisn + H]+ , n = 1-6, with notably enhanced stability of the tetramer. [His + H]+ dissociates predominantly by loss of (H2 O + CO) with a KER of 278 meV, while the dominant dissociation channel of [His - H]- involves loss of NH3 with a high KER of 769 meV. Dissociation of [His2 + H]+ is dominated by loss of the monomer but smaller losses are also observed. CONCLUSIONS: The KER for HCOOH loss from both [His + H]+ and [His - H]- is similar at 278 and 249 meV, respectively, which suggests that the collision-induced dissociation takes place via a similar mechanism. The loss of COOH and C2 H5 NO2 from the dimer suggests that the dimer of His binds through a shared proton between the imidazole moieties. PMID- 29108139 TI - Psychometric testing of the Family-Carer Diabetes Management Self-Efficacy Scale. AB - The aim of this study was to develop and test the construct and content validity, internal consistency of the Family-Carer Diabetes Management Self-Efficacy Scale (F-DMSES). A sample of 70 Thai individuals who cared for those living with type 2 diabetes mellitus (T2DM) in a rural community in Thailand was included in the study. Data were collected by a questionnaire survey in January 2014. The F-DMSES was initially derived from the DMSES, with subsequent forward and backward translations from and to English and Thai languages. The psychometric properties (content, construct and internal consistency) of the Thai version were explored using the Content Validity Index approach, exploratory factor analysis and Cronbach's alpha test. The F-DMSES initially designed with 20 items was reduced to 14 items within four factors (general diet and blood glucose monitoring, medications and complications, diet in differing situations, and weight control and physical activities), and explained 72.2% of the total variance in overarching construct. Internal consistency was supported (alpha = 0.89). The F DMSES was also able to measure change over time following an intervention, with an effect size of 0.9. The F-DMSES is a valid and reliable self-administered instrument that measures the diabetes management self-efficacy of family-carers of individuals with T2DM. This instrument can be used in practice and clinical trials to assess the impact of family-carers on the health outcomes of individuals with T2DM. PMID- 29108140 TI - Clinical decision-making: the case against the new casuistry. AB - Albert Jonsen and Stephen Toulmin have argued that the best way to resolve the complex issues in medical settings is to focus on the actual details of cases and then determine what to do in the given cases. This approach to medical decision making, labeled "casuistry," has met with much criticism. In response, Carson Strong has attempted to save much of Jonsen and Toulmin's version of casuistry. This analysis reveals that Strong's recent salvage efforts fail to deflect the major criticisms. The upshot of this analysis is that Jonsen and Toulmin's version of casuistry is not an appropriate framework from which to resolve complex issues in clinical settings. PMID- 29108141 TI - Teaching OB/GYN residents bioethics within a Catholic healthcare context. AB - Residents entering training in the specialty of Obstetrics and Gynecology (OB/GYN) often have misconceptions as to what medical interventions Roman Catholic healthcare institutions prohibit, and why certain restrictions are placed on the provision of reproductive health options that are otherwise legally available to women. The Ethical and Religious Directives for Catholic Healthcare Services, produced by the United States Conference of Catholic Bishops seeks to provide a stable framework upon which reproductive health decisions can be based. However, Catholic healthcare ethics may conflict with secular bioethical assertions that place a premium on autonomous patient choice. Residents training in part or whole at a Catholic institution may feel frustration at what they perceive to be a conflict with current secular ethics paradigms-such as access to abortion, contraception, sterilization, and assisted reproductive technologies. The recent adoption of Clinical Competencies by the Accreditation Council for Graduate Medical Education (ACGME), directs that residents shall be trained to function within the framework of their larger healthcare system ("Systems-based Practice"). This article will first, clarify areas of conflict and convergence between Catholic and secular reproductive ethics, which are unique to OB/GYN training. Next, using the ACGME's new Clinical Competency in Systems-Based practice as a model, a rationale for incorporating Catholic Healthcare ethics into an ethics curriculum for OB/GYN residents will be discussed. Finally, guidelines for faculty tackling the problem of how to teach Catholic Healthcare ethics will be described. Incorporating the rich tradition of Catholic healthcare ethics into the educational curriculum of OB/GYN residency fulfills training requirements while exposing young physicians to a rational decision-making framework in bioethics. PMID- 29108142 TI - Euthanasia in Belgium: legal, historical and political review. AB - This article describes and evaluates the Belgian euthanasia experience by considering its practice and policy, both before and after the formal decriminalisation of euthanasia in 2002. The pre-legal practice of euthanasia, the evolution of euthanasia legislation, criticism of this legislation, the influence of politics, and later changes to the 2002 Act on Euthanasia are discussed, as well as the subject of euthanasia of minors and the matter of organ procurement. It is argued that the Belgian euthanasia experience is characterised by political expedition, and that the 2002 Act and its later amendments suffer from practical and conceptual flaws. Illegal euthanasia practices remain a live concern in Belgium, something which nations who are seeking to decriminalise euthanasia should consider. PMID- 29108143 TI - Medical malpractice web advertising: a qualitative, cross-sectional analysis of plaintiff medical malpractice firms in Suffolk County, Massachusetts. AB - Medical malpractice plaintiff firms play a central role in the prosecution of malpractice claims. There have been limited studies on the online advertising practices of plaintiff medical malpractice firms. The Martindale-Hubbell directory was used to identify all plaintiff medical malpractice firms in Suffolk County, Massachusetts. Each firm's website was individually mined for relevant data. Thirty-one unique medical malpractice law firms were identified. Seventy seven percent of law firms advertised awards with the Martindale-Hubbell AV rating, AVVO, and Super Lawyer being the three most common. The second most common method of advertising was accomplished through descriptions of successful verdicts and settlements (61%). A total of 408 verdicts, settlements, and arbitrations collectively representing $1.4 billion dollars were advertised by all law firms. Median awarded values for verdicts was advertised as $4.5 million, while the median awarded values for settlements was $1.25 million. Defendants most commonly practiced obstetrics (18%), followed by primary care (14%). Law firms report treatment and diagnosis delay as the most common successful claim (50%), followed much further by misdiagnosis (8%), and communication error (4%). Our sample correlates with larger claims-based studies surrounding the most commonly sued specialties, however, median reported settlement and verdict values were significantly higher in our cohort. Considerations should be made to provide advertising guidelines for medical malpractice plaintiff firms. PMID- 29108144 TI - Lives worth living. PMID- 29108145 TI - Framing the conversation for exploring innovative techniques in therapy: the example of bilateral renal agenesis. PMID- 29108146 TI - 3-parent embryos, gene edited babies and the human future. PMID- 29108147 TI - Surrogacy, the handmaid's tale, and reproductive ethics. PMID- 29108150 TI - The abortion agenda in Africa. PMID- 29108148 TI - Grief, bereavement, and traumatic stress as natural results of reproductive losses. PMID- 29108149 TI - Conscientious objection to referral for reproductive services. PMID- 29108151 TI - Upholding the sanctity of life in a culture of death. PMID- 29108152 TI - The menstrual cycle as a vital sign: the use of naprotechnology. PMID- 29108153 TI - Gender dysphoria in children. AB - Gender dysphoria (GD) of childhood describes a psychological condition in which children experience a marked incongruence between their experienced gender and the gender associated with their biological sex. When this occurs in the pre pubertal child, GD resolves in the vast majority of patients by late adolescence. Currently there is a vigorous, albeit suppressed, debate among physicians, therapists, and academics regarding what is fast becoming the new treatment standard for GD in children. This new paradigm is rooted in the assumption that GD is innate, and involves pubertal suppression with gonadotropin releasing hormone (GnRH) agonists followed by the use of cross-sex hormones-a combination that results in the sterility of minors. A review of the current literature suggests that this protocol is founded upon an unscientific gender ideology, lacks an evidence base, and violates the long-standing ethical principle of "First do no harm." PMID- 29108154 TI - How to have a pro-life private practice. PMID- 29108155 TI - Healthcare and Planned Parenthood: the significance for pro-life OB/GYNs. PMID- 29108156 TI - Abortion-breast cancer link: review of recent evidence from Asia. PMID- 29108157 TI - We're all blobs of tissue now: how modern biology has defined life itself out of existence. PMID- 29108158 TI - Overruling Roe v. Wade: the implications for the law. PMID- 29108159 TI - Reproductive loss: giving permission to grieve. PMID- 29108160 TI - Embryo Survival after Mifepristone: A Systematic Review of the Literature. PMID- 29108161 TI - Psychological Impact of Abortion due to Fetal Anomaly: A Review of Published Research. AB - Over the past several decades, prenatal testing for fetal anomalies has become standard across the developed world. Most women who learn of a severe anomaly during pregnancy elect to terminate. The authors reviewed ten studies which examined the psychological sequelae of pregnant women following prenatal diagnoses of severe life limiting conditions. Based on the available data, the authors found evidence that women who abort due to a poor prenatal diagnosis are at higher risk of post-traumatic stress and depression than women who continue with pregnancy. They also found that current practice is to make reactive recommendations for post-abortion care, suggesting a presumption in favor of abortion, leaving alternatives like perinatal hospice inadequately explored. This review critiques that approach, recommending that doctors and patients need to have the best possible information before a decision is made. PMID- 29108162 TI - Fetal Therapy for Down Syndrome: Report of Three Cases and a Review of the Literature. AB - BACKGROUND: Down syndrome (trisomy 21) is a well-known cause of mental retardation. It can be diagnosed in early pregnancy. Scientists have made great strides in outlining the pathophysiologic mechanisms of mental retardation in Down syndrome. Much less has been published on human therapy. To our knowledge, these are the first published cases of fetal therapy for Down syndrome. METHODOLOGY: Reports of three cases. In all cases, treatment was both biochemical (e.g. nutritional) and educational. In all cases, treatment was both before and after birth. RESULTS: All children lacked the characteristic faces usually seen in the children with Down syndrome. This suggests a treatment effect before birth. All children had better than expected development. DISCUSSION: Enhancement of development is proposed as a new therapeutic principle. Developing neurons exchange neurotrophic factors during development when they give or receive stimulation from other neurons. Neurons which receive neurotrophic stimulation survive, and those, which do not, are lost to apoptosis. The developmental therapeutic principle seeks to optimize brain development. Biochemical inputs (neurotransmitters, drugs, hormones, nutrients) and functional stimulation are integrated to optimize the growth and survival of neurons individually; other cells; subcellular organelles; and the brain as a whole. Treatment may be before and after birth, both biochemical and functional. These principles may be applied to Down syndrome, other conditions, and normal fetuses or children. PREVIOUSLY PUBLISHED: Baggot PJ and Baggot RM (2014). Fetal Therapy for Down Syndrome: Report of three cases and review of the literature. J Am Phys Surg 19(1):20-24. PMID- 29108163 TI - Abortion's Impact on Prematurity: Closing the Knowledge Gap. PMID- 29108164 TI - How to Provide a Legal Safe Harbor for Mothers of Unwanted Newborns. PMID- 29108165 TI - The Burden of Abortion and the Preterm Birth Crisis. PMID- 29108166 TI - Information for the Adolescent Woman and Her Parents: Abortion and the Risk of Breast Cancer. AB - Studies from many nations suggest that induced abortion (IA) may be a causal risk factor for the development of breast cancer. Researchers agree that IA contributes to the increased risk of breast cancer by delaying the timing of a full-term pregnancy which is a protective factor. Increasing numbers of studies now show that IA prior to 32 weeks in and of itself is a risk factor for breast cancer due to the physiology of breast development and the manner in which abortion interferes with the maturation of the breast cells. Although largely ignored by the mainstream medical community, this risk information deserves a prominent place in the education of all adolescent women who may, in the future, consider an IA. PMID- 29108167 TI - Testimony in Support of Indiana Senate Bill 334, A Bill to Prohibit Prenatal Discrimination by Prohibiting Abortion Based on Sex Selection or Genetic Abnormality. PMID- 29108168 TI - Declaration and Expert Report. PMID- 29108169 TI - Red River Women's Clinic v. Stenehjem: Eighth Circuit Court Opinion On a Challenge to the North Dakota Statute Banning Abortion After Detectable Heartbeats. PMID- 29108170 TI - Stuart v. Camnitz: Setting the Standard of Care for Abortion Providers In North Carolina. PMID- 29108171 TI - Dignum et justum est: Obamacare and Travail of the Little Sisters. AB - This essay traces the Affordable Care Act from initiation through the bureaucratic unfolding of required preventive health services for women and presents the ethically reasoned objections to provision of certain services and compliance with regulations for implementation by the Little Sisters of the Poor, an international order of consecrated nuns dedicated to care of the elderly poor. The author's intent is to understand and intelligently convey the fundamental issues raised by their challenge. PMID- 29108172 TI - Doubling the rate of neurologic development in Down syndrome: a pilot study. AB - BACKGROUND: Recently, Von Tetzchner and colleagues completed the first study in three decades of the method of Institutes for the Achievement of Human Potential (IAHP.) They found no benefit. Because Von Tetzchner's study had few patients (17 18), many diagnoses, and numerous (13) different outcome measures, these flaws may have obscured a treatment benefit with excessive variance. This study was designed to correct those flaws. One diagnosis (Down syndrome), a larger study (218), and a single outcome measure were used before and after (the IAHP developmental profile). Each child was compared to himself, before and after treatment. The goal was to minimize variance. METHODS: Study patients were encouraged to crawl early and engage in movement and balance exercises. Patterning was used to help children learn to crawl. The children were taught to read and count from a very young age. Nutrition and physiology was also addressed. RESULTS: Before IAHP treatment, children had neurologic age/chronologic age=0.55. This is consistent with standard median Down syndrome IQs of about 40. After treatment, from initial exam to first follow-up, children had delta NA/CA = 1.43. The rate of neurologic progress more than doubled. The p value was p < 10-15. DISCUSSION: The animal literature on environmental studies provides strong foundation for IAHP methods. Human adoption literature demonstrates substantial catch-up recovery is possible in humans. While surprising, these results are consistent with scientific literature. CONCLUSION: Conventional methods, according to von Tetzchner, have no proven benefit. The evidence presented here demonstrates a strong, clinically significant benefit, which is highly statistically significant. The IAHP method enhances development and cognitive performance, and is highly cost effective since 1) it works and 2) most of therapy is done by parents. This study is a verbatim reprint of Baggot PJ and Baggot RM (2016), Doubling the rate of neurologic progress in Down syndrome: a pilot study, Journal of American Physicians and Surgeons, 21 (2): 41-46. It is reprinted here to make it available to a wider audience of physicians and scientists, as the Journal of American Physicians and Surgeons is not indexed on Pubmed. For metanalyses, it should be counted once, not twice. PMID- 29108173 TI - From birth mothers to first mothers: toward a compassionate understanding of the life-long act of adoption placement. AB - OBJECTIVE: Women who place a child for adoption have historically been far less actively researched than the other individuals in the adoption triad (adoptees and adoptive parents). They often have unmet psychological needs related to the decision to place for adoption, the placement experience, and as they endeavor to move forward post-adoption. In this review an effort is made to provide a description and analysis of the professional literature on women's placement experiences, with attention to methodological challenges inherent in deriving valid results. Next an overview of the results of a mixed method pilot study on birth mothers' decision-making and adjustment is shared. Finally, the most pressing future research needs on the topic of adoption placement from the birth mother's perspective are outlined. Data sources and extraction: Employing the following search terms: adoption, open-adoption, closed adoption, birth-mother, biological mother, relinquishment, and adoption placement, an exhaustive search for empirical journal articles, reviews, and edited book chapters was conducted yielding over 80 publications. Sources spanning a 50 year period (1974-2014) were identified via MEDLINE, PUBMED, and PsycINFO. RESULTS: Based on an in-depth analysis of the best available evidence on the psychological lives of women who choose adoption, an argument is made for more focused research attention and enhanced sensitivity to the unmet needs of birth mothers in our communities. DISCUSSION: As the experiences of birth mothers are more fully understood, more substantive and compassionate counseling before, during, and after adoption will become more feasible. PMID- 29108174 TI - Hippocratic medicine and the myth of moral neutrality in medicine. PMID- 29108175 TI - The freedom of divided people. PMID- 29108176 TI - Becoming a healthy physician: the transformation. PMID- 29108177 TI - Safe sex belief and sexual risk behaviors among adolescents. PMID- 29108178 TI - Healthy management of very early adolescent pregnancy. AB - BACKGROUND: Very Early Pregnancy (< 15 years at delivery) is suggested as a risk factor for adverse pregnancy outcome including low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA) infants, stillbirth, and neonatal mortality. OBJECTIVE: To systematically review the risk of an infant being born LBW/ PTB/SGA/stillbirth or neonatal mortality among patients < 15 years of age. Search strategy: Medline, Embase, CINAHL, and bibliographies of identified articles were searched for English language studies. SELECTION CRITERIA: Selection criteria: Studies reporting birth outcomes to mothers < 15 years of age with an appropriate control group of older gravidas. Data collection and analysis: A single reviewer collected data and assessed the quality of the studies for biases in sample selection, correct age cohorts, confounder adjustment, analytical, outcome assessments, and attrition. Main results: Forty six studies were located with very early adolescent pregnancy. Of these, only 21 papers had the correct age group (< 15 years) with a comparison cohort. The studies found in the very early adolescent pregnancy: Increased risk of SGA; Increased risk of LBW < 2,500 gms; Increased risk of PTD < 37 weeks; Decreased risk of DM; Decreased risk of cesarean section; Decreased risk of use of pitocin/active phase length; Conflicting risks for Preeclampsia/VLBW/Episiotomy/instrumental delivery rates. SELECTION CRITERIA: Very early adolescent pregnancies (< 15 years) do not have universally grim outcomes as normally quoted. Very early adolescent pregnancies have decreased risk of cesarean delivery, DM, and of active phase disorders. Further, many of the adverse outcomes may be ameliorated with earlier, adolescent-focused, and improved antenatal care. PMID- 29108179 TI - Behavioral methods of family planning: A comparative study of efficacy and safety. PMID- 29108180 TI - Family structure and child well-being: dads make a difference. PMID- 29108181 TI - Endogenous tissue generation and restoration: Maximizing our human potential. PMID- 29108182 TI - Insertional mutagenesis and autoimmunity induced disease caused by human fetal and retroviral residual toxins in vaccines. PMID- 29108183 TI - Transgender medicine: "out of the frying pan"! PMID- 29108184 TI - Watt, Helen. The ethics of pregnancy, abortion and childbirth: Exploring moral choices in childbearing. PMID- 29108185 TI - [Immune status of liver failure patients and related immune regulation therapy]. AB - Liver failure refers to a series of clinical syndromes manifesting as coagulation disorders, jaundice, hepatic encephalopathy, ascites, and other decompensated abnormalities due to serious hepatic dysfunction or decompensation in terms of synthesis, detoxification, excretion, and biological transformation caused by a variety of factors. In recent years, with the development of the research on immunological pathogenesis of liver failure, the "three-hit" theory clarifies the pathogenesis of liver failure. Major therapeutic strategies for liver failure are to prevent hepatocyte necrosis, promote hepatocyte regeneration, create a good internal environment for hepatocyte regeneration, and actively prevent and treat complications. An understanding of the immune status of liver failure patients and early application of glucocorticoids at right timing may help to improve prognosis and reduce adverse reactions. Establishment of a quantitative or functional balance between different cell subsets and new thoughts on some key cytokines may provide new directions and targets for immune regulation of liver failure. PMID- 29108186 TI - [Changes and perspectives of non-biological artificial liver treatment]. AB - Liver failure is a common clinical syndrome of serious liver diseases with a high mortality rate. Artificial liver support system can significantly reduce the mortality rate of patients with liver failure and is widely used in clinical practice. Due to the shortage of blood resource, the increase in blood-borne diseases, increased demands for liver transplantation, and the change in treatment concepts, single non-biological artificial liver treatment is often unable to satisfy clinical needs, and it is urgent to develop new therapeutic paradigms of non-bioartificial liver. This article reviews the changes and perspectives of non-biological artificial liver in the treatment of liver failure. PMID- 29108187 TI - [Advances in liver transplantation for patients with liver failure]. AB - Liver transplantation is the most effective salvage treatment for advanced liver failure, but its clinical application is limited by a shortage of liver donor, strict technology admittance, and complex and diverse issues in liver damage control before transplantation. We need to better understand the indications for liver transplantation in liver failure patients, select surgical timing correctly, and develop proper surgical regimens, in order to improve the rescue and cure rate of such patients. In addition, great achievements have been made in living-donor liver transplantation, auxiliary liver transplantation, and ABO incompatible liver transplantation, which should be taken seriously in clinical practice. PMID- 29108188 TI - [Definition and diagnosis of acute-on-chronic liver failure: new knowledge and implication]. AB - Acute-on-chronic liver failure (ACLF) is a common critical and severe syndrome in patients with chronic liver diseases in China and other countries in the Asia Pacific region. In recent years, both the Eastern and Western experts have defined ACLF as a new type of liver disease manifesting as a high 28-day mortality rate (>30%) and extensive systematic inflammatory response. ACLF has become a hot topic in the field of liver diseases. This article reviews the research advances in the definition and etiological spectrum of ACLF and discusses the inspirations of such new knowledge for future research. PMID- 29108189 TI - [Guidelines on the management of ascites and complications in cirrhosis]. PMID- 29108190 TI - [Consensus on pegylated interferon alpha in treatment of chronic hepatitis B]. PMID- 29108191 TI - [An interpretation of the AASLD practice guideline on the diagnosis and management of nonalcoholic fatty liver disease in 2017]. AB - The American Association for the Study of Liver Diseases (AASLD) updated and published the Practice Guidance for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease (NAFLD) in July 2017, which provides recommendations for the accurate diagnosis, treatment, and effective prevention of NAFLD. Related metabolic diseases should be considered during the initial evaluation of patients suspected of NAFLD. Noninvasive diagnostic techniques including transient elastography, magnetic resonance elastography, and serum biochemical models should be used to evaluate the development and progression of liver fibrosis in patients with NAFLD. Clinical liver pathology report should clearly differentiate between nonalcoholic fatty liver (NAFL), NAFL with inflammation, and nonalcoholic steatohepatitis (NASH) and identify the presence or absence of liver fibrosis and its degree. Early medication for NAFLD can only be used in patients with pathologically confirmed NASH and liver fibrosis, and it is not recommended to use pioglitazone and vitamin E as the first-line drugs for patients with NASH which has not been proven by biopsy or non-diabetic NASH patients. Foregut bariatric surgery can be considered for obese patients with NAFLD/NASH who meet related indications. It is emphasized that the risk factors for cardiovascular disease should be eliminated for NAFLD patients. Statins can be used for the treatment of dyslipidemia in patients with NAFLD/NASH, but they cannot be used in patients with decompensated liver cirrhosis. Routine screening or hepatocellular carcinoma surveillance is not recommended for NASH patients without liver cirrhosis. Cardiovascular disease should be taken seriously during liver transplantation evaluation. There is still no adequate clinical evidence for the treatment of NAFLD in children and adolescents, and intensive lifestyle intervention is recommended as the first-line therapy for such patients. PMID- 29108192 TI - [Protective effect of the histone deacetylase inhibitor ACY1215 against brain edema in mice with acute liver failure]. AB - Objective: To investigate the protective effect of ACY1215 (Rocilinostat), a histone deacetylase inhibitor, against brain edema in mice with acute liver failure. Methods: Lipopolysaccharide combined with D-galactosamine was used to establish a mouse model of acute liver failure, and ACY1215 was used for intervention. The effect of ACY1215 on histopathological changes of the liver was observed after 24 hours, as well as the changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood ammonia, tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), brain water content, blood-brain barrier structure, NF-kappaB-p65, histone, acetylated histone, and TNF-alpha mRNA in brain tissue. Results: The mice with acute liver failure had marked pathological damage in liver tissue, as well as significant increases in the levels of ALT, AST, blood ammonia, TNF-alpha, and IFN-gamma (t>=5.367, all P < 0.05). ACY1215 significantly improved the pathological damage in liver tissue and reduced the serum levels of ALT, AST, blood ammonia, TNF-alpha, and IFN-gamma (t<=-3.515, all P < 0.05). ACY1215 also significantly reduced the expression of NF-kappaB-p65 (t = -5.871, P = 0.004) and the mRNA expression of TNF-alpha (t = 11.913, P < 0.01) in brain tissue and brain water content (t = -2.355, P < 0.01). According to the results of electron microscopy, the model group had an abnormal blood-brain barrier structure, and the ACY1215 group had slighter damage than the model group. Compared with the normal group, the model group had significant increases in the acetylation level of histone H3 and H4 in brain tissue (t>=3.009, both P < 0.05), while ACY1215 further upregulated the acetylation levels of histone H3 and H4 (t>=6.682, both P < 0.05). Conclusion: ACY1215 exerts a protective effect against brain edema in mice with acute liver failure, possibly by regulating histone acetylation and inhibiting inflammation. PMID- 29108193 TI - [Transforming growth factor-beta1 small interfering RNA regulates platelet derived growth factor and phosphorylated extracellular regulated protein kinase in rats with hepatic fibrosis: an experimental study]. AB - Objective: To investigate the impact of transforming growth factor-beta1 (TGF beta1) silencing by small interfering RNA (siRNA) on the expression of platelet derived growth factor-beta (PDGF-BB) and its receptor (PDGF-betaR) in rats with hepatic fibrosis. Methods: A total of 40 male Sprague-Dawley rats were randomly divided into normal control group, model group, TGF-beta1 siRNA treatment group, and negative control group. All rats except those in the normal control group were given subcutaneous injection of 40% carbon tetrachloride to establish a rat model of hepatic fibrosis. The rats in the negative control group and the TGF beta1 siRNA treatment group were given tail vein injection of negative control plasmid or TGF-beta1 siRNA plasmid twice a week at a dose of 0.25 mg/kg, and those in the normal control group and the model group were given the injection of sterile isotonic saline twice a week. The rats were sacrificed after 12 weeks and liver tissue samples were collected. Real-time PCR, immunohistochemistry, and Western blot were used to measure the expression of PDGF-BB, PDGF-betaR, and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) in liver tissue. A one-way analysis of variance, the q test, and the Kruskal-Wallis test were used for statistical analysis based on data type. Results: Compared with the model group and the negative control group, the TGF-beta1 siRNA treatment group had significantly inhibited mRNA and protein expression of PDGF-BB and PDGF-betaR (F = 24.785 and 22.92, P < 0.01), as well as significantly inhibited expression of p-ERK1/2 (P < 0.05). Conclusion: Targeted TGF-beta1 siRNA can effectively downregulate the expression of PDGF-BB, PDGF-betaR, and p-ERK1/2 in liver tissue and thus help to improve hepatic fibrosis. PMID- 29108194 TI - [MicroRNA-30a inhibits proliferation of hepatocellular carcinoma cells via targeted regulation of forkhead-box protein A1]. AB - Objective: To investigate the expression of microRNA-30a (miR-30a) in hepatocellular carcinoma (HCC) and related molecular mechanisms in regulating HCC cell proliferation. Methods: A total of 30 pairs of HCC and adjacent tissue samples were collected, and quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression of forkhead-box protein A1 (FOXA1). Methyl thiazolyl tetrazolium (MTT) assay was used to evaluate the proliferation of HCC cells, luciferase reporter gene assay was performed to verify the target relationship between miR-30a and FOXA1, and MTT assay and Western blot were used to measure the proliferation of HepG2 cells and the protein expression of FOXA1 after miR-30a transfection. The t-test was used for comparison of data between two groups, and a one-way analysis of variance was used for comparison of data between multiple groups. P < 0.05 was considered statistically significant. Results: HCC tissue had significantly lower relative expression of miR-30a than adjacent tissue (1.049 +/- 0.380 vs 1.982 +/- 1.013, t = 3.985, P < 0.001). At 72 hours after miR-30a overexpression, there was a significant difference in the proliferative capacity of HepG2 cells between the blank control group, the miR 30a-NC group, and the miR-30a group (0.821 +/- 0.006 vs 0.816 +/- 0.013 vs 0.546 +/- 0.020, F = 3.396, P < 0.05), suggesting that miR-30a overexpression significantly inhibited the proliferation of HepG2 cells. FOXA1 was a target gene of miR-30a and its protein expression was negatively regulated by miR-30a, and there was a significant difference in luciferase activity between wild-type and mutant FOXA1-3'UTR vectors (1.221 +/- 0.024 vs 2.658 +/- 0.031, F = 6.737, P < 0.05). In HepG2 cells, miR-30a overexpression significantly inhibited the protein expression of FOXA1, and there was a significant difference in the relative expression of FOXA1 between the blank control group, the miR-30a-NC group, and the miR-30a group (1.019 +/- 0.016 vs 1.022 +/- 0.017 vs 0.227 +/- 0.021, F = 45.43, P < 0.05). Upregulating the protein expression of FOXA1 reversed the inhibitory effect of miR-30a on the proliferation of HepG2 cells, and there was a significant difference in the proliferative capacity of HepG2 cells between the miR-30a group and the miR-30a+FOXA1 group (0.524 +/- 0.023 vs 0.843 +/- 0.019, t = 2.507, P < 0.05). Conclusion: MiR-30a exerts its inhibitory effect on the proliferation of HCC cells by negatively regulating the expression of FOXA1. PMID- 29108195 TI - [Mechanism of action of glucagon-like peptide-1 receptor agonist in promoting the apoptosis of hepatic stellate cells based on the extracellular signal-regulated kinase signaling pathway]. PMID- 29108196 TI - [A case of interstitial pneumonia induced by interferon therapy for chronic hepatitis C]. PMID- 29108197 TI - [Advances in clinical differentiation between immunological and drug-induced liver injury]. AB - The differentiation between autoimmune hepatitis (AIH) and drug-induced liver injury (DILI) is a difficult task in clinical practice. Some AIH patients had a medication history before disease onset, and some DILI patients may have positive serum antibody. In addition, these two groups of patients have similar clinical symptoms, serological examination results, and liver histopathology, which lead to the difficulties in differentiation. However, correct differential diagnosis is of great significance in making clinical treatment decisions and preventing liver cirrhosis. Therefore, it is necessary to investigate the association between immunological and drug-induced liver injury from the perspectives of pathogenesis, similarities and differences in clinical features, serological examination results, and histological changes, prospects of new biomarkers in differentiation, and the significance of hormone therapy and clinical follow-up in differential diagnosis and treatment, in order to provide a reference for clinical decision-making and research in future. PMID- 29108198 TI - [Clinical effect of entecavir versus tenofovir in treatment of HBeAg-positive chronic hepatitis B patients with a high viral load: a comparative analysis]. AB - Objective: To investigate the clinical effect and safety of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in the treatment of previously untreated HBeAg-positive chronic hepatitis B (CHB) patients with a high viral load. Methods: A retrospective analysis was performed for the clinical data of 152 HBeAg-positive CHB patients with a high viral load (HBV DNA>=10(6) IU/ml) who were firstly treated with ETV (ETV group) or TDF (TDF group), with 76 patients in each group. The serum levels of alanine aminotransferase (ALT), HBV DNA, HBeAg, anti-HBe, creatinine, and creatine kinase were measured at baseline, and the patients were followed up and evaluated at weeks 4, 12, 24, 36, 48, 60, 72, 84, and 96 of treatment. The Kaplan-Meier survival curves were used to analyze cumulative complete virologic response, HBeAg seroconversion, and ALT normalization rate. The Cox proportional hazards regression model was used to identify the influencing factors for virologic response. P < 0.05 was considered statistically significant. Results: There were no significant differences in ALT normalization rate between the ETV group and the TDF group at weeks 4, 12, 24, 48, 72, and 96 of treatment (18.1%/55.6%/83.3%/90.3%/93.1%/97.2% vs 16.0%/53.6%/75.4%/94.2%/100%/100%, P > 0.05). There were also no significant differences in virologic response rate between the ETV group and the TDF group at weeks 48 and 96 of treatment (89.5%/97.3% vs 93.4%/98.7%, P > 0.05). The multivariate analysis showed that the baseline parameters were not predictive factors for virologic response. At week 48 of treatment, the TDF group had a significantly higher HBeAg seroconversion rate than the ETV group (14.5% vs 3.9%, P = 0.048); at week 96 of treatment, there was no significant difference in HBeAg seroconversion rate between the two groups (15.8% vs 7.9%, P = 0.132). The Kaplan Meier survival analysis showed that there were no significant differences between the two groups in cumulative ALT normalization rate, cumulative HBV DNA undetectable rate, and cumulative seroconversion rate. Only one patient in the ETV group experienced virologic breakthrough from weeks 60 to 72 of treatment, and there were no serious adverse reactions. Conclusion: TDF and ETV had similar clinical effects, HBeAg seroconversion rate, and safety in previously untreated HBeAg-positive CHB patients with a high viral load. PMID- 29108199 TI - [Value of neutrophil-lymphocyte ratio in predicting hepatitis B-related liver failure]. AB - Objective: To investigate the value of neutrophil-lymphocyte ratio (NLR) in predicting hepatitis B-related liver failure. Methods: A total of 349 subjects were enrolled, among whom 60 were healthy persons who underwent physical examination (group A), 111 had severe chronic hepatitis B (group B), 92 had decompensated hepatitis B cirrhosis (group C), and 86 had acute-on-chronic liver failure (ACLF) (group D). Routine blood test results, liver function parameters, and coagulation parameters were collected, and NLR was calculated. According to disease progression, group B was further divided into groups B1 (with progression to ACLF) and B2 (without progression to ACLF). NLR was compared between groups, and its prognostic value was evaluated. Results: NLR was 2.22(1.76-3.05) in group A, 2.54(1.78-3.49) in group B, 3.07(1.95-5.04)in group C, and 3.41(2.01-5.15) in group D, and NLR gradually increased with the aggravation of disease condition. The univariate and multivariate regression analyses of groups B1 and B2 showed that NLR and prothrombin activity were prognostic factors for disease progression. There was a significant difference in baseline NLR between groups B1 and B2 (3.87 +/- 1.54 vs 2.71 +/- 1.54, P = 0.004). There was a significant increase in NLR when severe hepatitis B in 16 patients progressed to ACLF (P = 0.042). The receiver operating characteristic (ROC) curve analysis showed that the cut-off value of NLR for predicting the progression of severe hepatitis B to ACLF was 2.79, with an area under the ROC curve (AUC) of 0.739 (P = 0.002). NLR was also a reference index for judging end-stage liver disease with a cut-off value of 3.94 (AUC = 0.612, P = 0.001). Conclusion: Peripheral NLR can reflect disease progression and predict the development of liver failure. PMID- 29108200 TI - [Effect of transforming growth factor-beta1 on HBV replication and antigen synthesis in HepG2.2.15 cells with steatosis]. AB - Objective: To investigate the effect of transforming growth factor-beta1 (TGF beta1) on HBV replication and protein expression in HepG2.2.15 cells with steatosis, as well as the association of TGF-beta1 with suppressor of cytokine signaling-3 (SOCS-3) mRNA and sterol regulatory element-binding protein-1c (SREBP 1c) mRNA during the steatosis of HepG2.2.15 cells. Methods: The cells were divided into HepG2/HepG2.2.15 cell control groups (C1/C2 groups) and HepG2/HepG2.2.15 cell steatosis groups (F1/F2 groups). 5 ng/ml TGF-beta1 was added to the two cell systems for intervention to establish TGF-beta1 intervention groups (T1/T2 groups) and steatosis+TGF-beta1 intervention groups (TF1/TF2 groups). A time-resolved fluorescence analyzer was used to measure HBsAg and HBeAg, and quantitative real-time PCR was used to measure HBV DNA, SOCS-3 mRNA, and SREBP-1 mRNA. A one-way analysis of variance and a factorial analysis were used for the statistical analysis of data. Results: TGF-beta1 significantly reduced the level of HBeAg in C2 group (P = 0.034) and the levels of HBsAg (P < 0.001) and HBeAg (P = 0.004) in F2 group. There was an interaction between steatosis and TGF-beta1 in inhibiting HBsAg. In addition, TGF-beta1 significantly reduced the mRNA expression of SOCS-3 in C1, F1, C2, and F2 groups (P < 0.05) and significantly increased the mRNA expression of SREBP-1c in C1, F1, C2, and F2 groups (P < 0.05), suggesting that there was an interaction between steatosis and TGF-beta1 in downregulating the mRNA expression of SOCS-3 and upregulating the mRNA expression of SREBP-1c. Conclusion: TGF-beta1 does not affect HBV duplication in HepG2.2.15 cells and can inhibit the expression of HBsAg and HBeAg. TGF-beta1 can downregulate the mRNA expression of SOCS-3 and upregulate the mRNA expression of SREBP-1c. PMID- 29108201 TI - [Clinical features of imbalance between Th1 and Th22 cells and its association with disease progression in patients with liver cirrhosis]. AB - Objective: To investigate the clinical features of imbalance between Th1 and Th22 cells and its association with disease progression in patients with liver cirrhosis, and to explore immune therapeutic strategies for targeted therapy for liver cirrhosis. Methods: In vitro peripheral blood mononucleated cells (PBMCs) were collected by centrifugation. CD3-BV500 and CD8-PerCP-Cy5.5 staining was performed for these cells. IFNgamma-PE-Cy7, IL-17a-APC, IL-22-PE, or the corresponding isotype control was added, and then PBMCs were fixed with 1% polyoxymethylene after being washed once by permeabilization-wash buffer. Flowjo software was used for the analysis of T lymphocyte subsets and cytokines. Th1 (CD4+IFNgamma(+)), Th17 (CD4+IL-17a(+)), Th22 (CD4+IL-22(+)), Tc1 (CD8+IFNgamma(+)), Tc17 (CD8+IL-17a(+)), and Tc22 (CD8+IL-22(+)) subsets were defined and the secretions of interferon-gamma (IFN-gamma), interleukin-17a (IL 17a), and interleukin-22 (IL-22) were measured for all subsets. LX-2 cells were cultured in a serum-free medium and different concentrations of recombinant human IL-22 protein (25, 50, 100 ng/ml) were added; 24 hours later, the activation marker alpha-smooth muscle actin (alpha-SMA) was used to measure LX-2 activation. Fetal bovine serum with a volume fraction of 10% was used as a positive control. Enzyme-linked immunosorbent assay (chemiluminescence) was used to measure the concentrations of hyaluronic acid, type III precollagen, and type IV collagen in supernatant. A one-way analysis of variance, the non-parametric Mann-Whitney U test, and the non-parametric Kruskal-wallis H test were used for statistical analysis based on data type. Results: Compared with the health control group, the liver cirrhosis groups with various causes had significant increases in peripheral Tc1, Th17, and Th22 cells. The percentage of Th17 cells in the liver cirrhosis group was 1.64 times that in the control group (4.25%+/-2.45% vs 2.59%+/-1.36%, P < 0.05), and the mean percentage of Th22 cells in the liver cirrhosis group was 2.18 times that in the control group (4.17%+/-2.55% vs 1.31%+/-0.64%, P < 0.05). The percentages of Th17 (5.89%+/-3.44%) and Th22 cells (5.32%+/-3.67%) in the patients with alcoholic cirrhosis were 1.27 and 3.06 times those in the control group (P < 0.05). The patients with alcoholic cirrhosis had a significant increase in Th22 cells. The patients with different types of liver cirrhosis had a significant reduction in the ratio between anti-fibrotic and pro fibrotic factors (Th1/Th22), which was positively correlated with the severity of liver cirrhosis and was a common immunological feature of liver cirrhosis with different causes. In addition, IL-22 activated hepatic stellate cells and promoted the production of collagen. Conclusion: The imbalance between anti fibrotic and pro-fibrotic factors (Th1/Th22) is a common feature of the progression of liver fibrosis with various causes and may contribute to the progression of liver fibrosis. PMID- 29108202 TI - [Clinical effect of ultraselective transcatheter arterial chemoembolization in treatment of hepatocellular carcinoma originating from the caudate lobe: an analysis of 13 cases]. AB - Objective: To investigate the clinical effect of ultraselective transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC) originating from the caudate lobe. Methods: A retrospective analysis was performed for 13 patients with solitary HCC originating from the caudate lobe who were admitted to Department of Interventional Radiology in PLA General Hospital from March 2013 to December 2016. A 2.6-F microcatheter was used to perform ultraselective TACE, and the embolization material was ultra-liquefied iodinated oil. The number of tumor-feeding arteries, success rate and short-term efficacy of ultraselective technique, and long-term survival were evaluated after surgery. Results: Of all patients, 8 (61.5%) had a single tumor-feeding artery and 5 (38.5%) had multiple tumor-feeding arteries. The success rate of ultraselective technique was 84.6% (11/13). The complete remission rate at 1 month after ultraselective TACE was 63.6% (7/11). During the follow-up period after the expiration date, 10 out of 11 patients who underwent successful ultraselective TACE survived, and one out of two patients who underwent failed ultraselective TACE survived. Conclusion: Ultraselective TACE has good feasibility, clinical effect, and safety in the treatment of HCC originating from the caudate lobe, with an important clinical significance in the prognosis of such disease. PMID- 29108203 TI - [Association between miR-146a single nucleotide polymorphism and genetic susceptibility to hepatocellular carcinoma: a meta-analysis]. AB - Objective: To investigate the association between miR-146a single nucleotide polymorphism and genetic susceptibility to hepatocellular carcinoma (HCC). Methods: PubMed, Web of Science, Cochrane Library, Wanfang Data, and Google Scholar were searched for case-control studies on the association between miR 146a single nucleotide polymorphism and genetic susceptibility to HCC published up to October, 2016 in Chinese or English. The Q-statistics test was used to evaluate the heterogeneity of these articles. Results: A total of 18 articles with 5 610 cases and 7 531 controls were included for the meta-analysis. There was no significant association between miR-146a single nucleotide polymorphism and genetic susceptibility to HCC. The odds ratio (OR), 95% confidence interval (95% CI), and P values for the five genetic models were as follows: the allele model C/G (OR = 0.99, 95% CI 0.88-1.06, P = 0.440); the heterozygous model CG/GG (OR = 0.99, 95% CI 0.90-1.10, P = 0.898); the homozygous model CC/GG (OR = 0.91, 95% CI 0.75-1.10, P = 0.314); the dominant model CC+CG/GG (OR = 0.97, 95% CI 0.79 1.19, P = 0.759); the recessive model CG+GG/CC (OR = 1.05, 95% CI 0.94-1.18, P = 0.405). A subgroup analysis of race, source of control population, and Hardy Weinberg equilibrium were performed in these five genetic models, and miR-146a single nucleotide polymorphism increased the susceptibility to HCC only in the control population-based subgroups of the recessive model CG+GG/CC (OR = 1.20, 95% CI 1.02-1.40, P = 0.024). There was no association between miR-146a rs2910164 polymorphism and susceptibility to HCC in all the other subgroups. A stratified analysis of HBV infection revealed that miR-146a rs2910164 polymorphism increased the risk of HBV-positive HCC (OR = 1.26, 95% CI 1.10-1.49, P = 0.001). Conclusion: There is no significant association between miR-146a rs2910164 polymorphism and the risk of HCC, but miR-146a rs2910164 polymorphism may increase the risk of HBV-positive HCC. PMID- 29108204 TI - [Clinical features of autoimmune hepatitis patients with poor response to treatment]. AB - Objective: To investigate the clinical features of autoimmune hepatitis (AIH) patients with poor response to treatment. Methods: A total of 61 AIH patients were enrolled, among whom 49 (80.33%) achieved complete response (good response group) and 12 (19.67%) had incomplete response (poor response group). The two groups were compared in terms of clinical manifestations, laboratory markers, abdominal ultrasound findings, pathological features by liver biopsy, and response to treatment. Continuous data were expressed as mean +/- standard deviation (x+/-s), and the t-test was used for comparison between groups; categorical data were expressed as rates or percentages, and the chi-square test was used for comparison between groups; a binary logistic regression analysis was used to determine influencing factors. Results: Most patients were female in both groups, and there were no significant differences in sex ratio, mean age of onset, and general status including extrahepatic autoimmune disease between the two groups. Compared with the good response group, the poor response group had significantly higher levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), total bilirubin, immunoglobulin G, and immunoglobulin M (P < 0.05). Compared with the good response group, the poor response group had a significantly higher positive rate of autoimmune antibodies except anti-nuclear antibody (ANA), anti-smooth muscle antibody (SMA), antimitochondrial antibody (AMA), and AMA/M2 (75% vs 16.3%, P < 0.001), and there was a significant difference in the positive rate of gp210 antibody between the two groups (25% vs 0%, P < 0.01). There were significant differences between the poor response group and the good response group in the proportion of patients with liver cirrhosis (50.0 % vs 16.3%, P < 0.05) and splenomegaly (58.3% vs 22.4%, P < 0.05). The binary logistic regression analysis showed that a high serum level of ALP (odds ratio [OR] = 1.017, 95% confidence interval [CI] 1.001 1.033, P = 0.034), positive autoimmune antibodies except ANA, SMA, and AMA/M2 (OR = 70.842, 95% CI 2.132-2 354.371, P = 0.017), and liver cirrhosis (OR = 28.777, 95% CI 1.015-815.854, P = 0.049) were independent risk factors for initial treatment outcome. Conclusion: A high serum level of ALP, positive autoimmune antibodies except ANA, SMA, and AMA/M2, and liver cirrhosis are closely associated with poor response in AIH patients. PMID- 29108205 TI - [Investigation and analysis of the knowledge of nonalcoholic fatty liver disease among residents in Hebei Province, China]. AB - Objective: To investigate the knowledge of nonalcoholic fatty liver disease (NAFLD) among medical staff and general population in Hebei Province, China, understand the degree of awareness of NAFLD among residents, standardize the diagnosis and treatment of NAFLD, improve the correct awareness of NAFLD among general population, promote the establishment of a reasonable lifestyle, and scientifically and effectively control the incidence and mortality rates of NAFLD. Methods: The investigation was performed in 30 hospitals and neighboring schools and communities in Hebei Province, and a questionnaire survey on the knowledge of NAFLD was performed for 1 300 medical workers and 2 000 persons from the general population. EpiData3.1 software was used to input data, and SPSS21.0 was used for statistical analysis. The chi-square test was used for comparison of rates between groups. Results: Of all medical staff, 39.0% knew that liver biopsy was the gold standard for the diagnosis of NAFLD; 63.7% thought liver biopsy had the highest diagnostic value, followed by liver ultrasound (61.0%) and liver CT (48.1%); only 1.2% thought improvement of insulin resistance was the preferred treatment for NAFLD. Among 486 medical workers who had participated in the diagnosis and treatment of NAFLD, only 1.2% thought that the patients had good compliance. Of all persons from the general population, 15.2% thought NAFLD was infectious and 58.6% thought NAFLD might progress to liver cirrhosis or liver cancer. Of all respondents with body mass index >=28 kg/m(2), 17.8% did not know that he/she had obesity, and as high as 55.8% were obese or did not control body weight within the past 1 year. Of all NAFLD patients, 50.5% were complicated by hyperlipidemia, 18.5% were complicated by diabetes, and 29.5% were complicated by hypertension; 43.0% had not received standardized treatment, and among the other 57.0% respondents who received treatment, 79.0% were given non-drug treatment such as reasonable diet and physical exercise. In NAFLD patients who were not improved after treatment, the major cause of failure was that they were not able to stick to healthy living habits. Most NAFLD patients were willing to obtain the knowledge of disease through television, website, and newspaper. Conclusion: Medical staff do not have enough awareness of NAFLD, and some of them cannot perform standardized diagnosis and treatment of NAFLD with reference to clinical guidelines. Therefore, the education on NAFLD should be enhanced for medical staff to guide them to perform accurate screening, diagnosis, evaluation, and treatment of NAFLD. The general population has low awareness of NAFLD and NAFLD patients have poor treatment compliance, which are important causes of increased incidence rate of NAFLD and disease progression. The general population should be educated about NAFLD to help them establish a reasonable lifestyle. PMID- 29108206 TI - [Association between IL28B gene polymorphisms and therapeutic effect of individualized pegylated interferon alpha therapy in HBeAg-positive chronic hepatitis B patients]. PMID- 29108207 TI - [Epidemiological and clinical features of pregnant women with positive hepatitis C virus antibody]. PMID- 29108208 TI - [Feasibility and significance of transjugular liver biopsy in diagnosis and treatment of complicated and severe liver diseases: a single-center analysis of 5 cases]. PMID- 29108209 TI - [Analysis the clinical features of Pseudomonas pseudomallei liver abscesses]. PMID- 29108210 TI - [Expression of P16 and survivin in liver cancer and their clinical significance]. PMID- 29108211 TI - [A case of Caroli disease in Tibet, China]. PMID- 29108212 TI - [Tenofovir in treatment of postoperative recurrent hepatitis B in a patient with positive anti-HBs before kidney transplantation: a case report]. PMID- 29108213 TI - [Research advances in chronicity of hepatitis E virus infection]. AB - Hepatitis E virus (HEV) infection usually causes acute hepatitis and has a self limiting progression. The patients often recover within 6 months with good prognosis. Recent studies have found that HEV infection may become chronic in special situations, which manifests as persistent liver function abnormalities for at least 6 months after acute HEV infection and the presence of viral nucleic acid in serum, feces, and/or liver tissue. Chronicity of HEV infection mainly occurs in immunocompromised patients, and it is rare but very dangerous in clinical practice. An understanding of the pathogenesis, clinical manifestations, treatment methods, and preventive measures of chronicity of HEV infection helps clinical physicians develop an effective management regimen and improve patient prognosis. This article introduces related issues, in order to raise the awareness of this disease among clinical physicians. PMID- 29108214 TI - [Association between intestinal flora imbalance and nonalcoholic fatty liver disease]. AB - With the improvement of living standards in recent years, the incidence rate of nonalcoholic fatty liver disease (NAFLD) has kept increasing, with 15%-30% in general population and 50%-90% in obese population. The "second-hit" theory has been widely recognized as the pathogenesis of NAFLD. In-depth studies have found that intestinal flora imbalance may promote the progression of NAFLD by increasing energy absorption in the body, damaging intestinal mucosal barrier, and producing large amounts of toxic metabolites, which provides a new direction for exploring the pathogenesis of NAFLD and effective therapies. This article reviews the role of intestinal flora imbalance in the development and progression of NAFLD. PMID- 29108215 TI - [Research advances in the role of mesenchymal stem cells and their exosomes in treatment of liver diseases]. AB - At present, liver transplantation remains the most effective treatment for acute liver failure and advanced cirrhosis, but its use and promotion are limited by insufficient organ donors, financial consideration, and requirements for lifelong immunosuppression. In recent years, stem cell transplantation has been recommended as an effective substitutive therapy for liver disease. Mesenchymal stem cells, also known as pluripotent interstitial stromal cells, are self renewing cells that can be found in almost all postnatal organs and tissues, including the liver. Their potential to differentiate into hepatocytes and immunomodulatory properties provide new insights into the use of mesenchymal stem cells in the treatment of acute and chronic liver diseases. This article reviews the characteristics of mesenchymal stem cells, their mechanisms in the treatment of acute and chronic liver diseases, and related risks. PMID- 29108216 TI - [Research advances in the role of the Hippo signaling pathway in pathogenesis of liver cancer]. AB - The Hippo signaling pathway consists of four core components in mammals, i.e., Mst1/2, WW45, Mob1, and LATS1/2, which can inhibit the transcriptional coactivator YAP from entering the nucleus, maintain the balance between cell proliferation and apoptosis, control organ size, and maintain homeostasis. If the core components of the Hippo signaling pathway are inactivated due to gene mutation or epigenetic alterations, YAP is overexpressed and activated in the nucleus, which then induces excessive cell proliferation and inhibits cell apoptosis. It has been confirmed that this process is closely associated with the formation of various tumors including liver cancer. Research on the Hippo signaling pathway may provide new directions for exploring the pathogenesis of liver tumor and developing effective therapies. PMID- 29108217 TI - Advancing the management of double hit lymphoma. PMID- 29108218 TI - Advances in lung cancer. PMID- 29108219 TI - Getting a GRP on histone deacetylase inhibitor selectivity. PMID- 29108220 TI - Minimal residual disease in pediatric ALL. PMID- 29108221 TI - Salvage therapy for relapsed testicular cancer. PMID- 29108222 TI - Which second line treatments after ESA failure? PMID- 29108223 TI - Bcr-Abl: one kinase, two isoforms, two diseases. PMID- 29108224 TI - Hyperhaploid karyotypes in multiple myeloma. PMID- 29108225 TI - Second cancer risk following Hodgkin lymphoma. PMID- 29108226 TI - Endometriosis: benign, malignant, or something in between? PMID- 29108227 TI - Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma. AB - The most pressing unmet clinical need for patients with Ewing sarcoma (ES) is the prevention and treatment of metastasis. The Wnt signaling pathway regulates a number of cellular functions associated with metastasis, including proliferation, motility, and stem cell self-renewal. Functional interaction between Wnt ligands and their receptors requires palmitoylation by Porcupine (Porcn), making this an ideal therapeutic target. We studied the effect of WNT974, a potent, selective Porcn inhibitor, on ES metastasis. In vitro, WNT974 does not affect ES proliferation or sarcosphere formation, but suppresses multiple transcriptional regulators of metastasis and inhibits cell migration. In vivo, in an orthotopic implantation/amputation model of spontaneous distant metastasis, single agent WNT974 treatment leads to a significant delay in formation of lung metastasis and a substantial improvement in post-amputation survival without a major effect on primary tumor growth. The drug produces no survival benefit in a tail vein injection model, supporting the hypothesis that WNT974 inhibits early steps in the metastatic cascade, such as migration and invasion. Our findings strongly implicate Wnt signaling in the early steps of ES metastasis and demonstrate that WNT974 has the potential to significantly improve the survival of ES patients through the specific inhibition of metastasis. PMID- 29108228 TI - CBP501 induces immunogenic tumor cell death and CD8 T cell infiltration into tumors in combination with platinum, and increases the efficacy of immune checkpoint inhibitors against tumors in mice. AB - CBP501, a calmodulin-binding peptide, is an anti-cancer drug candidate and functions as an enhancer of platinum uptake into cancer cells. Here we show that CBP501 promotes immunogenic cell death (ICD) in combination with platinum agents. CBP501 enhanced a clinically relevant low dose of cisplatin (CDDP) in vitro as evidenced by upregulation of ICD markers, including cell surface calreticulin exposure and release of high-mobility group protein box-1. Synergistic induction of ICD by CDDP plus CBP501 as compared to CDDP alone was confirmed in the well established vaccination assay. Furthermore, cotreatment of CDDP plus CBP501 significantly reduced the tumor growth and upregulated the percentage of tumor infiltrating CD8+ T cell in vivo. Importantly, the antitumor effect of CDDP plus CBP501 was significantly reduced by anti-CD8 antibody treatment. Based on this novel effect of CBP501, we analyzed the combination treatment with immune checkpoint inhibitors in vivo. Mice treated with CBP501 in combination with CDDP and anti-PD-1 or anti-PD-L1 showed an additive antitumor effect. These results support the conclusion that CBP501 enhances CDDP-induced ICD in vitro and in vivo. The findings also support the further clinical development of the CBP501 for enhancing the antitumor activity of immune checkpoint inhibitors in combination with CDDP. PMID- 29108229 TI - MeCP2 mediated dysfunction in senescent EPCs. AB - Aging endothelial progenitor cells (EPCs) exhibit functional impairment in terms of proliferation, migration and survival. SIRT1 plays an important role in improving EPCs function. MeCP2, another important epigenetic regulator, is involved in regulating many life-related activities such as cell growth, death and senescence. Here we aim to explore the effect of MeCP2 on the functional activities of senescent EPCs and the underlying mechanisms. By using western blot and real-time PCR, we found that the expression levels of MeCP2 were up-regulated and SIRT1 were down-regulated with replicative senescence and H2O2-induced senescence. Through transduction with adenoviral vectors, EPCs overexpressing MeCP2 had significantly reduced EPCs function, and silencing MeCP2 improved EPCs function. In addition, the protein and mRNA levels of SIRT1 were decreased with MeCP2 overexpression and increased with MeCP2 knockdown. Through co-transfection of EPCs with MeCP2 and SIRT1, we observed that SIRT1 could reverse the effects of MeCP2 on EPCs. In summary, our work demonstrated that MeCP2 inhibited SIRT1 in senescent EPCs. PMID- 29108230 TI - Apigenin enhances skeletal muscle hypertrophy and myoblast differentiation by regulating Prmt7. AB - Apigenin, a natural flavone abundant in various plant-derived foods including parsley and celery, has been shown to prevent inflammation and inflammatory diseases. However, the effect of apigenin on skeletal muscle hypertrophy and myogenic differentiation has not previously been elucidated. Here, we investigated the effects of apigenin on quadricep muscle weight and running distance using C57BL/6 mice on an accelerating treadmill. Apigenin stimulated mRNA expression of MHC (myosin heavy chain) 1, MHC2A, and MHC2B in the quadricep muscles of these animals. GPR56 (G protein-coupled receptor 56) and its ligand collagen III were upregulated by apigenin supplementation, together with enhanced PGC-1alpha, PGC-1alpha1, PGC-1alpha4, IGF1, and IGF2 expression. Prmt7 protein expression increased in conjunction with Akt and mTORC1 activation. Apigenin treatment also upregulated FNDC5 (fibronectin type III domain containing 5) mRNA expression and serum irisin levels. Furthermore, apigenin stimulated C2C12 myogenic differentiation and upregulated total MHC, MHC2A, and MHC2B expression. These events were attributable to an increase in Prmt7-p38-myoD expression and Akt and S6K1 phosphorylation. We also observed that Prmt7 regulates both PGC 1alpha1 and PGC-1alpha4 expression, resulting in a subsequent increase in GPR56 expression and mTORC1 activation. Taken together, these findings suggest that apigenin supplementation can promote skeletal muscle hypertrophy and myogenic differentiation by regulating the Prmt7-PGC-1alpha-GPR56 pathway, as well as the Prmt7-p38-myoD pathway, which may contribute toward the prevention of skeletal muscle weakness. PMID- 29108231 TI - TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells. AB - Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pH e ) has been found to increase intracellular Ca2+ and matrix metalloproteinase-9 (MMP-9) expression by activating NF-kappaB in the mouse B16 melanoma model. The present study assessed whether TRPM5, an intracellular Ca2+-dependent monovalent cation channel, is associated with acidic pH e signaling and induction of MMP-9 expression in this mouse melanoma model. Treatment of B16 cells with Trpm5 siRNA reduced acidic pH e -induced MMP-9 expression. Enforced expression of Trpm5 increased the rate of acidic pH e -induced MMP-9 expression, as well as increasing experimental lung metastasis. This genetic manipulation did not alter the pH e critical for MMP-9 induction but simply amplified the percentage of inducible MMP-9 at each pH e . Treatment of tumor bearing mice with triphenylphosphine oxide (TPPO), an inhibitor of TRPM5, significantly reduced spontaneous lung metastasis. In silico analysis of clinical samples showed that high TRPM5 mRNA expression correlated with poor overall survival rate in patients with melanoma and gastric cancer but not in patients with cancers of the ovary, lung, breast, and rectum. These results showed that TRPM5 amplifies acidic pH e signaling and may be a promising target for preventing metastasis of some types of tumor. PMID- 29108232 TI - TAp63gamma and DeltaNp63gamma are regulated by RBM38 via mRNA stability and have an opposing function in growth suppression. AB - The p63 gene is expressed as TAp63 from the P1 promoter and as DeltaNp63 from the P2 promoter. Through alternative splicing, five TA and five DeltaN isoforms (alpha-epsilon) are expressed. Isoforms alpha-beta and delta share an identical 3' untranslated region (3'UTR) whereas isoform gamma has a unique 3'UTR. Recently, we found that RBM38 RNA-binding protein is a target of p63 and RBM38 in turn regulates p63alpha/beta expression via mRNA stability. However, it is uncertain whether p63gamma has a unique biological activity and whether p63gamma is regulated by RBM38. Here, we found that the levels of DeltaNp63gamma transcript and protein are induced upon overexpression of RBM38 but decreased by RBM38 knockdown. Conversely, we found that the levels of DeltaNp63beta transcript and protein are decreased by ectopic expression of RBM38 but increased by RBM38 knockdown, consistent with our previous report. Interestingly, RBM38 increases the half-life of p63gamma mRNA by binding to a GU-rich element in p63gamma 3'UTR. In contrast, our previous studies showed that RBM38 decreases the half-life of p63alpha/beta mRNAs by binding to AU-/U-rich elements in their 3'UTR. We also found that knockout of p63gamma in ME180 and HaCaT cells, in which DeltaNp63 isoforms are predominant, inhibits cell proliferation and migration, suggesting that DeltaNp63gamma has a pro-growth activity. In contrast, we found that knockout of TAp63gamma in MIA PaCa-2 cells, in which TAp63 isoforms are predominant, promotes cell proliferation, migration, and inhibits cellular senescence. Taken together, we conclude that DeltaNp63gamma has an oncogenic potential whereas TAp63gamma is a tumor suppressor. PMID- 29108233 TI - Mitoketoscins: Novel mitochondrial inhibitors for targeting ketone metabolism in cancer stem cells (CSCs). AB - Previous studies have now well-established that epithelial cancer cells can utilize ketone bodies (3-hydroxybutyrate and aceto-acetate) as mitochondrial fuels, to actively promote tumor growth and metastatic dissemination. The two critical metabolic enzymes implicated in this process are OXCT1 and ACAT1, which are both mitochondrial proteins. Importantly, over-expression of OXCT1 or ACAT1 in human breast cancer cells is sufficient to genetically drive tumorigenesis and/or lung metastasis, validating that they indeed behave as metabolic "tumor promoters". Here, we decided to target these two enzymes, which give cancer cells the ability to recycle ketone bodies into Acetyl-CoA and, therefore, to produce increased ATP. Briefly, we used computational chemistry (in silico drug design) to select a sub-set of potentially promising compounds that spatially fit within the active site of these enzymes, based on their known 3D crystal structures. These libraries of compounds were then phenotypically screened for their effects on total cellular ATP levels. Positive hits were further validated by metabolic flux analysis. Our results indicated that four of these compounds effectively inhibited mitochondrial oxygen consumption. Two of these compounds also induced a reactive glycolytic phenotype in cancer cells. Most importantly, using the mammosphere assay, we showed that these compounds can be used to functionally inhibit cancer stem cell (CSC) activity and propagation. Finally, our molecular modeling studies directly show how these novel compounds are predicted to bind to the active catalytic sites of OXCT1 and ACAT1, within their Coenzyme A binding site. As such, we speculate that these mitochondrial inhibitors are partially mimicking the structure of Coenzyme A. Thus, we conclude that OXCT1 and ACAT1 are important new therapeutic targets for further drug development and optimization. We propose that this new class of drugs should be termed "mitoketoscins", to reflect that they were designed to target ketone re-utilization and mitochondrial function. PMID- 29108234 TI - Metapristone (RU486 metabolite) suppresses NSCLC by targeting EGFR-mediated PI3K/AKT pathway. AB - Therapies targeting epidermal growth factor receptor (EGFR) can effectively treat with non-small cell lung cancer (NSCLC), but NSCLC's drug resistance makes it intractable. Herein, we showed that RU486 metabolite metapristone inhibited the proliferation of various NSCLC cell lines with either wild (A549, H1299, H520) or mutated EGFR (H1975, HCC827). The suppression was resulted from inhibition by metapristone of EGFR signaling pathways through down-regulating the EGFR, PTEN, as well as AKT and ERK proteins. In addition, metapristone inhibited anti apoptotic marker Bcl-2, and activated pro-apoptotic key signaling proteins caspase-3, and poly (ADP-ribose) polymerase. Metapristone induced A549 and H1975 cell cycle via arrest at the G0-G1 stage. What's more, metapristone inhibited the growth of NSCLC xenografts in BALB/c nude mice through decreasing the expression of tumor growth biomarkers PCNA and EGFR. Taken together, the present study demonstrated that metapristone suppressed NSCLC proliferation by promoting apoptosis via decrease the cellular EGFR-mediated PI3K/AKT pathways. The results suggest metapristone a new treatment for EGFR-overexpressed NSCLC. PMID- 29108235 TI - Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer by Helicobacter pylori oncoprotein CagA. AB - Injection of the Helicobacter pylori cytotoxin-associated gene A (CagA) is closely associated with the development of chronic gastritis and gastric cancer. Individuals infected with H. pylori possessing the CagA protein produce more reactive oxygen species (ROS) and show an increased risk of developing gastric cancer. Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and mitochondrial SIRT3 is known to be a tumor suppressor via its ability to suppress ROS and hypoxia inducible factor 1alpha (HIF-1alpha). However, it is unclear whether increased ROS production by H. pylori is regulated by SIRT3 followed by HIF-1alpha regulation and whether intracellular CagA acts as a regulator thereof. In this study, we investigated correlations among SIRT3, ROS, and HIF-1alpha in H. pylori-infected gastric epithelial cells. We observed that SIRT3-deficient AGS cells induce HIF-1alpha protein stabilization and augmented transcriptional activity under hypoxic conditions. In CagA +H. pylori infected cells, CagA protein localized to mitochondria where it subsequently suppressed SIRT3 proteins. CagA +H. pylori infection also increased HIF-1alpha activity through the ROS production induced by the downregulated SIRT3 activity, which is similar to the hypoxic condition in gastric epithelial cells. In contrast, overexpression of SIRT3 inhibited the HIF-1alpha protein stabilization and attenuated the increase in HIF-1alpha transcriptional activity under hypoxic conditions. Moreover, CagA +H. pylori attenuated HIF-1alpha stability and decreased transcriptional activity in SIRT3-overexpressing gastric epithelial cells. Taken together, these findings provide valuable insights into the potential role of SIRT3 in CagA +H. pylori-mediated gastric carcinogenesis and a possible target for cancer prevention via inhibition of HIF-1alpha. PMID- 29108236 TI - The autophagic inhibition oral squamous cell carcinoma cancer growth of 16 hydroxy-cleroda-3,14-dine-15,16-olide. AB - 16-hydroxycleroda-3, 13-dine-15, 16-olide (HCD) isolated from Polyalthia longifolia possesses numerous biological activities. Previous studies have reported that HCD can block phosphorylation activity of cancer cells to inhibit tumor cell growth, but the anti-tumor activity in oral squamous cell carcinoma is unrevealed. This study investigates the inhibiting effect of HCD on human OSCC cell growth; thereby, developing a new oral cancer drug. In in vitro cultured human OSCC cells (OECM1 and SAS) were employed to test the inhibitory growth of HCD via cell cytotoxic effect using 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay, Western blotting, and further determining of the inhibitory efficacy of tumor growth by a xenograft tumor on BALB/c male nude mice (in vivo test). Under various concentrations of HCD and time course treatments were shown to effectively cause cell death and cell-cycle arrest in OECM1 and SAS cells, which was confirmed via a clinical drug (cisplatin) as a positive control. In addition, HCD induced the autophagic cell death in OECM1 and SAS cells by LC3-mediated LC3-I/LC3-II/p62 pathway at the in vitro level. An in vivo assay indicated that HCD could treat oral cancer by deferring tumor growth. These findings provide a favorable assessment for further elucidating the role of HCD that targets autophagic cell death pathways as a potential agent for cancer therapy. PMID- 29108237 TI - The circRNA interactome-innovative hallmarks of the intra- and extracellular radiation response. AB - Generated by Quaking (QKI), circular RNAs (circRNAs) are newly recognised non coding RNA (ncRNA) members characterised by tissue specificity, increased stability and enrichment within exosomes. Studies have shown that ionizing radiation (IR) can influence ncRNA transcription. However, it is unknown whether circRNAs or indeed QKI are regulated by IR. Microarray circRNA profiling and next generation sequencing revealed that circRNA expression was altered by low and medium dose exposure sourced predominantly from genes influencing the p53 pathway. CircRNAs KIRKOS-71 and KIRKOS-73 transcribed from the WWOX (WW Domain Containing Oxidoreductase) tumor suppressor (a p53 regulator) responded within hours to IR. KIRKOS-71 and KIRKOS-73 were present in exosomes yet exhibited differential transcript clearance between irradiated cell lines. Dual-quasar labelled probes and in-situ hybridization demonstrated the intercellular distribution of KIRKOS-71 and KIRKOS-73 predominantly within the perinucleus. QKI knockdown removed nuclear expression of these circRNAs with no significant effect on cytosolic KIRKOS-71 and KIRKOS-73. Distinct QKI transcription between cell lines and its augmented interaction with KIRKOS-71 and KIRKOS-73 was noted post IR. This foremost study provides evidence that QKI and circRNAs partake in the cellular irradiation response. KIRKOS-71 and KIRKOS-73 as stable secreted circRNAs may afford vital characteristics worth syphoning as promising diagnostic radiotherapy biomarkers. PMID- 29108238 TI - Sites of extranodal involvement are prognostic in patients with stage 1 follicular lymphoma. AB - Objectives: Follicular lymphoma (FL) is the most common indolent B cell lymphoma in the United States and a quarter of patients present with stage I disease. The objective of this study was to examine if primary site of disease influences survival in early stage lymphoma. Results: The most common extranodal primary sites were the integumentary system (8%), followed by the GI tract (6.4%) and head & neck (5.6%). We stratified patients into a pre-rituximab era (1983-1998) and the rituximab era (1999-2011). In multivariable analysis, integumentary disease was associated with better overall survival (Hazard Ratio [HR], 0.77; Confidence Interval [CI], 0.66-0.9) while primary site FL of the nervous system (HR, 2.40; CI, 1.72-3.38) and the musculoskeletal system (HR, 2.14; CI, 1.44 3.18) were associated with worse overall survival when compared to primary nodal FL. Treatment in the pre-rituximab era, male gender and older age at diagnosis were associated with worse survival. Methods: We queried the SEER database from 1983 to 2011. We included all adult patients (>18 years) with histologically confirmed stage I FL, active follow-up, and a single primary tumor. A total of 9,865 patients met eligibility criteria, with 2520 (25%) having an extranodal primary site. We classified the primary sites by organ or anatomic location into 11 sites. Conclusion: Primary site of disease is a prognostic factor for patients with early stage FL and may help identify subsets of patients that could benefit from early, aggressive treatment. PMID- 29108239 TI - Interactions between vitamin D receptor (VDR) gene and Interleukin-6 gene and environment factors on coronary heart disease risk in a Chinese Han population. AB - Aims: To investigate the association of several single nucleotide polymorphisms (SNPs) within Interleukin-6 (IL- 6) and vitamin D receptor (VDR) gene, and additional gene- gene and gene- smoking interaction with coronary heart disease (CHD) risk in a Chinese population. Methods: Hardy-Weinberg equilibrium (HWE) examination was used by SNPstats (http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Stratified analysis for gene smoking interaction was investigated by logistic regression. Results: CHD risk was significantly higher in carriers with the C allele of rs1800796 within IL-6 gene than those with GG genotype (GC+ CC versus GG), adjusted OR (95%CI) =1.62 (1.19-2.23); CHD risk was also higher in carriers with the T allele of rs2228570 within VDR gene than those with CC genotype (CT+ TT versus CC), adjusted OR (95%CI) = 1.68 (1.26-2.17). However, we did not find any direct associations of the others SNPs in IL- 6 and VDR gene with CHD risk. We also found a significant interaction between rs1800796 and smoking, the cross-validation consistency of this two- locus model was 10/ 10, and the testing accuracy was 60.11%. Current smokers with rs1800796- GC or CC genotype have the highest CHD risk, compared to never- smokers with rs1800796- GG genotype within IL- 6 gene, OR (95%CI) = 2.57 (1.74 -3.46). Conclusions: We found that the C allele of rs1800796 within IL-6 and T allele of rs2228570 within VDR gene, interaction between rs1800796 and smoking were all associated with increased CHD risk. PMID- 29108240 TI - Nationwide cohort study on the epidemiology and survival outcomes of thyroid cancer. AB - In the past three decades, the thyroid cancer incidence has surged globally. Herein, the Taiwan National Health Insurance database was used to identify thyroid cancer patients and to estimate the prevalence and incidence of thyroid cancer during 1997-2012. The Taiwan Cancer Registry and the National Death Registry databases were crosslinked to obtain information on the histological subtypes and survival rates. Joinpoint regression analysis was used for estimating the average annual percentage changes (APCs) in prevalence, incidence, and survival. The age-standardized incidence of thyroid cancer increased from 5.66 per 100,000 person-years in 1997 to 12.30 per 100,000 person-years in 2012, with an average APC of 5.1 (6.9 in males, 4.6 in females). Thyroid cancer was more prevalent in patients with high socioeconomic status and in urban areas. Papillary carcinoma was the most abundant subtype, with a 2.9-fold increase of incident cases noted during 1998-2012 (from 80.6% to 89.8% of all cases). Among the different treatments, partial thyroidectomy increased the most (average APC, 17.3). The overall survival rates by sex and subtype remained stable over time, with 5-year survival rates of 90.2% in 1997 and 92.4% in 2010. In conclusion, 2.2 and 4.2-fold increases in the incidence and prevalence of thyroid cancer, respectively, were observed during 1997-2012 in Taiwan. The surging incidence of thyroid cancer but stable survival rates, and mainly increased in the papillary subtype, altogether imply enhanced detection of subclinical lesions. A true increase due to environmental carcinogens might also be responsible, but warrant further investigations. PMID- 29108241 TI - Identification of volasertib-resistant mechanism and evaluation of combination effects with volasertib and other agents on acute myeloid leukemia. AB - Volasertib, a selective PLK1 inhibitor, was effective for acute myeloid leukemia (AML) patients in clinical trials. However, its efficacy was limited in mono therapy, and a higher incidence of fatal events was revealed in the combination with low-dose cytarabine. Thus, optimization of combination therapy with volasertib and other agents is necessary for its clinical development, and the predictive factors for response or resistance to volasertib remain largely unknown. In this study, we investigated the resistance mechanism in volasertib resistant cell lines and the combination effects with other agents, such as azacitidine (AZA), on AML cells. We identified that mutations in the ATP-binding domain of PLK1 and expression of MDR1 conferred resistance to volasertib. In the combination therapy, the effects of AZA differed among cells, but were prominent in the cells with higher GI50 values of volasertib in mono-therapy. Furthermore, we identified that the cells in G2/M phase were more sensitive to volasertib, and the PI3K/AKT pathway was up-regulated upon administration of volasertib. Combination therapies with the agents that caused cell cycle accumulation in G2/M phase or with PI3K inhibitor were highly potent against AML cells. Our findings provide strategies for further clinical development of volasertib and PLK inhibitors for AML. PMID- 29108242 TI - Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy. AB - The concept of cancer stem cells has been proposed in various malignancies including colorectal cancer. Recent studies show direct evidence for quiescence slow-cycling cells playing a role in cancer stem cells. There exists an urgent need to isolate and better characterize these slow-cycling cells. In this study, we developed a new model to enrich slow-cycling tumor cells using cell-cycle inducer combined with cell cycle-dependent chemotherapy in vitro and in vivo. Our results show that Short-term exposure of colorectal cancer cells to chemotherapy combined with cell-cycle inducer enriches for a cell-cycle quiescent tumor cell population. Specifically, these slow-cycling tumor cells exhibit increased chemotherapy resistance in vitro and tumorigenicity in vivo. Notably, these cells are stem-cell like and participate in metastatic dormancy. Further exploration indicates that slow-cycling colorectal cancer cells in our model are less sensitive to cytokine-induced-killer cell mediated cytotoxic killing in vivo and in vitro. Collectively, our cell cycle inducer combined chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub population that are resistant to cytokine induced killer cell based immunotherapy. Studying unique signaling pathways in dormant tumor cells enriched by cell cycle inducer combined chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence. PMID- 29108244 TI - TIPE1 function as a prognosis predictor and negative regulator of lung cancer. AB - TIPE1 (tumor necrosis factor-alpha-induced protein 8-like 1 or TNFAIP8L1) belongs to the TIPE (TNFAIP8) family, which act as a regulator of cell death. However, the expression and biologic functions of TIPE1 in lung cancer are largely unknown. Here, we investigated the roles of TIPE1 in lung cancer. Evaluated by qRT-PCR and immunohistochemical staining, lower TIPE1 mRNA and protein expression was found in the lung tumor tissue, compared with adjacent non-tumor tissues, which positively correlated with tumor patient survival. Overexpression of TIPE1 by lentivirus system in TIPE1-downregulated lung cancer cells significantly diminished cell growth and colony formation, companied with proliferation inhibition, apoptosis induction and invasion inhibition. It was identified to be due to TIPE1-regulated Cyclin D1, Cyclin B1, caspase 8, Caspase3, MM2 and MMP9 expression. Consistently, using a homograft tumor model in Balb/c mice, we discovered that TIPE1 prevented the growth and tumor weight of murine lung cancer homografts. Our findings revealed the anti-tumor role of TIPE1 in lung cancer cells and TIPE1 might be a novel prognostic indicator for lung cancer patients. PMID- 29108243 TI - Silencing heme oxygenase-1 increases the sensitivity of ABC-DLBCL cells to histone deacetylase inhibitor in vitro and in vivo. AB - Heme oxygenase-1 (HO-1) can promote tumor growth and reinforce the resistance of diffuse large B-cell lymphoma (DLBCL) cells to chemotherapeutic drug vincristine. We herein found that HO-1 protein expression was higher in high-risk DLBCL patients than in low-risk ones. Silencing HO-1 gene expression resisted vorinostat-induced apoptosis and arrested cell cycle in the G0/G1 phase of LY-10 cells. Western blot, co-immunoprecipitation and chromatin immunoprecipitation assays confirmed that the possible mechanisms may be increased cleaved caspase-3 protein expression, decreased phospho-histone deacetylase 3 protein expression, and activated histone acetylation of P27Kip1 promoter. Moreover, silencing HO-1 gene expression enhanced vorinostat-induced tumor cell apoptosis, prolonged survival time and promoted P27Kip1 protein expression in a xenograft mouse model. In conclusion, HO-1 is a potential therapeutic target of DLBCL. The findings provide a valuable preclinical evidence for sensitizing DLBCL patients with poor prognosis to histone deacetylase inhibitors. PMID- 29108245 TI - Reversion of epithelial-mesenchymal transition by a novel agent DZ-50 via IGF binding protein-3 in prostate cancer cells. AB - Dysregulation of transforming growth factor-beta1 (TGF-beta1) and insulin-like growth factor (IGF) axis has been linked to reactive stroma dynamics in prostate cancer progression. IGF binding protein-3 (IGFBP3) induction is initiated by stroma remodeling and could represent a potential therapeutic target for prostate cancer. In previous studies a lead quinazoline-based Doxazosin(r) derivative, DZ 50, impaired prostate tumor growth by targeting proteins involved in focal adhesion, anoikis resistance and epithelial-mesenchymal-transition (EMT). This study demonstrates that DZ-50 increased expression of the epithelial marker E cadherin, and decreased the mesenchymal marker N-cadherin in human prostate cancer cells. In DU-145 cells, the effect of DZ-50 on EMT towards mesenchymal epithelial transition (MET) was inhibited by talin1 overexpression, a focal adhesion regulator promoting anoikis resistance and tumor invasion. DZ-50 treatment of human prostate cancer cells and cancer-associated fibroblasts (CAFs) downregulated IGFBP3 expression at mRNA and protein level. In TGF-beta1 responsive LNCaPTbetaRII, TGF-beta1 reversed DZ-50-induced MET by antagonizing the drug-induced decrease of nuclear IGFBP3. Furthermore, co-culture with CAFs promoted prostate cancer epithelial cell invasion, an effect that was significantly inhibited by DZ-50. Our findings demonstrate that the lead compound, DZ-50, inhibited the invasive properties of prostate cancer epithelial cells by targeting IGFBP3 and mediating EMT conversion to MET. This study integrated the mechanisms underlying the effect of DZ-50 and further supported the therapeutic value of this compound in the treatment of advanced metastatic prostate cancer. PMID- 29108246 TI - MRP4 regulates ENaC-dependent CREB/COX-2/PGE2 signaling during embryo implantation. AB - Multi-drug resistance protein 4 (MRP4), a potential chemotherapeutic target as well as a transporter for endogenous signaling molecules (e.g. prostaglandins), is known to be expressed in the endometrium, although its possible role(s) in the physiology of the endometrium remains unknown. Here, we show that MRP4 is upregulated at implantation window and localized to the basolateral membrane of the endometrial epithelium, the interface between the epithelium and stroma in mice. In human endometrial epithelial cells, MRP4 expression is upregulated by ENaC activation and the inhibition of MRP4 blocks ENaC-dependent PGE2 release as well as phosphorylation of CREB. Intrauterine injection of MRP4 inhibitor in mice prior to implantation significantly downregulated implantation markers COX-2, Claudin4 and Lif, and reduced implantation rate. These results in together have revealed a previously undefined role of MRP4 in mediating ENaC-dependent CREB/COX 2/PGE2 signaling essential to embryo implantation with implication in cancer progression as well. PMID- 29108247 TI - Regulator of G protein signaling 4 inhibits human melanoma cells proliferation and invasion through the PI3K/AKT signaling pathway. AB - Melanoma is a tumor produced by skin melanocytes, which has a high metastatic rate and poor prognosis. So far, plenty of work has been done on melanoma, but mechanisms underlying melanoma development have not been fully elucidated. Here we identified regulator of G protein signaling 4(RGS4) as novel therapeutic target for malignant melanoma and its regulating effect on melanoma. We found that endogenous RGS4 expression was much lower in melanoma tissues and cells. In A375 cell line with low endogenous RGS4 expression, the function of RGS4 was detected by up-regulation its expression with pcDNA3.1-RGS4 and knockdown its expression with siRNA. Our results showed that RGS4 could significantly reduce the proliferation, migration and invasion of melanoma cells. RGS4 is an important regulator for the apoptosis of melanocyte, and the apoptosis rate is significantly decreased in low RGS4 enviroment. RGS4 induced non-activation of PI3K/AKT pathway, resulting in decreased expression of E2F1 and Cyclin D1, thus constraining cell proliferation and invasion. These results were further confirmed in M14 cell lines. Collectively, our findings show that RGS4 plays an important role in multiple cellular functions of melanoma development and is valuable to be a therapeutic target. PMID- 29108248 TI - Prognostic relevance of androgen receptor expression in renal cell carcinomas. AB - Background: Despite rapid discoveries in molecular biology of renal cell carcinoma (RCC) and advances in systemic targeted therapies, development of new diagnostic and therapeutic strategies is urgently needed. The androgen receptor (AR) has been shown to hold prognostic and predicitve value in several malignancies. Here, we studied a possible association between AR expression and prognosis in patients with RCCs. Results: Low AR expression levels were associated with occurrence of distant metastasis and higher tumor stage in papillary and clear-cell RCCs. Importantly, multivariate Cox regression analyses revealed that AR is an independent prognostic factor for cancer-specific survival. Materials and Methods: The expression of AR was measured by immunohistochemistry and assessed by digital image analysis using a tissue microarray containing tumor tissue of a large and well-documented series of RCC patients with long-term follow-up information. Chi-squared tests, Kaplan-Meier curves and Cox regression models were used to investigate the possible relationship between AR expression and clinico-pathological characteristics and patient survival. Conclusions: Patients affected by AR-positive tumors exhibit a favorable prognosis by multiple Cox regression, while loss of AR expression is related to aggressive disease. Therefore, assessing AR expression offers valuable prognostic information that could improve treatment selection for metastatic disease. Moreover, our findings highlight a potential therapeutic use of AR pharmaceuticals in patients with RCCs. PMID- 29108249 TI - STK38L kinase ablation promotes loss of cell viability in a subset of KRAS dependent pancreatic cancer cell lines. AB - Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. Oncogenic KRAS mutations are found in over 90% of PDACs, playing a central role in tumor progression. Global gene expression profiling of PDAC reveals 3-4 major molecular subtypes with distinct phenotypic traits and pharmacological vulnerabilities, including variations in oncogenic KRAS pathway dependencies. PDAC cell lines of the aberrantly differentiated endocrine exocrine (ADEX) subtype are robustly KRAS-dependent for survival. The KRAS gene is located on chromosome 12p11-12p12, a region amplified in 5-10% of primary PDACs. Within this amplicon, we identified co-amplification of KRAS with the STK38L gene in a subset of primary human PDACs and PDAC cell lines. Therefore, we determined whether PDAC cell lines are dependent on STK38L expression for proliferation and viability. STK38L encodes a serine/threonine kinase, which shares homology with Hippo pathway kinases LATS1/2. We show that STK38L expression is elevated in a subset of primary PDACs and PDAC cell lines displaying ADEX subtype characteristics, including overexpression of mutant KRAS. RNAi-mediated depletion of STK38L in a subset of ADEX subtype cell lines inhibits cellular proliferation and induces apoptosis. Concomitant with these effects, STK38L depletion causes increased expression of the LATS2 kinase and the cell cycle regulator p21. LATS2 depletion partially rescues the cytostatic and cytotoxic effects of STK38L depletion. Lastly, high STK38L mRNA expression is associated with decreased overall patient survival in PDACs. Collectively, our findings implicate STK38L as a candidate targetable vulnerability in a subset of molecularly-defined PDACs. PMID- 29108250 TI - Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients. AB - Background: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy. Methods: AdCD40L is a replication deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival. Results: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood. Conclusions: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment. PMID- 29108251 TI - Clinical significance of lncRNA-ATB expression in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a worldwide health problem and it is important to understand the mechanistic roles of the biomolecules involved in its pathogenesis. Long non-coding RNAs (lncRNAs) are frequently and aberrantly expressed in various human cancers and are known to play a role in cancer pathogenesis. The aim of this study was to analyze the expression of lncRNA-ATB in HCC and investigate the implications for prognoses. In total, 100 samples of HCC tissues and their corresponding, adjacent, non-cancerous liver tissues were collected. Total RNAs were extracted and the expression levels of lncRNA-ATB were measured by qRT-PCR. The association of lncRNA expression with clinicopathological features and patient survival were then analyzed. LncRNA-ATB was significantly upregulated in HCC tissues compared with the levels in corresponding non-cancerous tissues. Expression of lncRNA-ATB was significantly associated with portal vein thrombosis, intrahepatic or extrahepatic metastases, mUICC stage, and the BCLC stage. Large tumors (> 5 cm, HR = 3.851, 95% CI = 1.431 10.364, p = 0.008) and higher lncRNA-ATB expression (HR = 4.158, 95% CI = 1.226 14.107, p = 0.022) were the significant prognostic factors for overall survival. With this novel evidence of the involvement of lncRNA-ATB in HCC pathogenesis and clinical features, lncRNA-ATB can be concluded to have potential as a biomarker for the prognosis of HCC and as a targeted therapy for afflicted patients. PMID- 29108252 TI - Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumor-associated macrophages in colorectal cancer. AB - A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis. The mechanism by which tumor cells communicate with host cells to develop premetastatic niches is unclear. We focused on the role of microRNA (miR) signaling in promoting metastasis. Here, we identified miR 203 as a signaling molecule between tumors and monocytes in metastatic colorectal cancer (CRC) patients. Notably, high expression of serum exosomal miR-203, a major form in circulation, was associated with distant metastasis and an independent poor prognostic factor, whereas low expression in tumor tissues was a poor prognostic factor in CRC patients. We also found that exosomes carrying miR 203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro, suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs). In a xenograft mouse model, miR-203-transfected CRC cells developed more liver metastasis compared to control cells. In conclusion, serum exosomal miR-203 expression is a novel biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Furthermore, we propose the concept of site-dependent functions for miR-203 in tumor progression. PMID- 29108253 TI - Identification of LRP-1 as an endocytosis and recycling receptor for beta1 integrin in thyroid cancer cells. AB - LRP-1 is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP-1 was reported to control focal adhesion turnover to optimize the adhesion-deadhesion balance to support invasion. To better understand how LRP-1 coordinates cell-extracellular matrix interface, we explored its ability to regulate cell surface integrins in thyroid carcinomas. Using an antibody approach, we demonstrated that beta1-integrin levels were increased at the plasma membrane under LRP1 silencing or upon RAP treatment, used as LRP-1 antagonist. Our data revealed that LRP-1 binds with both inactive and active beta1-integrin conformations and identified the extracellular ligand binding domains II or IV of LRP-1 as sufficient to bind beta1-integrin. Using a recombinant beta1-integrin, we demonstrated that LRP-1 acts as a regulator of beta1-integrin intracellular traffic. Moreover, RAP or LRP-1 blocking antibodies decreased up to 36% the number of beta1-integrin-containing endosomes. LRP-1 blockade did not significantly affect the levels of beta1-integrin-containing lysosomes while decreasing localization of beta1-integrin within Rab-11 positive vesicles. Overall, we identified an original molecular process in which LRP-1 acts as a main regulator of beta1-integrin internalization and recycling in thyroid cancer cells. PMID- 29108254 TI - The impacts of genetic polymorphisms in genes of base excision repair pathway on the efficacy and acute toxicities of (chemo)radiotherapy in patients with nasopharyngeal carcinoma. AB - Purpose: To explore whether polymorphisms in base excision repair (BER) pathway genes are predictors of (chemo)radiotherapy outcome in patients with nasopharyngeal carcinoma (NPC). Methods: We genotyped five potentially functional single nucleotide polymorphisms (SNPs) of three genes in the BER pathway in 174 NPC patients who were treated with (chemo)radiotherapy. Sequenom MassArray was used for SNPs analysis. The efficacy at the end of radiotherapy and at 3 months after radiotherapy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Acute radiation toxicity was scored using Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) acute radiation morbidity scoring criteria. Logistic regression was employed to assess the multivariate analyses. Results: We found that the wide genotype GG of X-ray repair cross-complementing 1 (XRCC1) rs25489 (GG vs GA: OR=3.833, 95%CI=1.512-9.714, P=0.005; GG vs GA+AA: OR=3.610, 95%CI=1.496-8.713, P=0.004) and the wide genotype CC of 8-oxoguanine DNA glycosylase (OGG1) rs1052133 (CC vs GG: OR=0.263, 95%CI=0.073-0.951, P=0.042; CC vs CG+GG: OR=0.454, 95%CI=0.195-1.053, P=0.066) were positively and negatively associated with primary tumor efficacy at the end of radiotherapy, respectively. By contrast, no association was found between BER gene polymorphisms and the treatment outcomes at 3 months post-treatment or the treatment-related acute toxicities. Conclusions: The SNPs of the BER genes may act as biomarkers for the curative effect of (chemo)radiotherapy. Further study with long-time follow-up and large population is needed for accurate assessment. PMID- 29108255 TI - Comprehensive bioinformatics analysis of the characterization and determination underlying mechanisms of over-expression and co-expression of genes residing on 20q in colorectal cancer. AB - The Long arm of chromosome 20 (20q) is closely related to the development of colorectal cancer, so identifying the expression profile of genes on 20q through a comprehensive overview is indispensable. In this article, preliminar experimental data, several available databases and bioinformatics tools such as the Cancer Genome Atlas, the Encyclopedia of DNA Elements, the JASPAR database and starBase were combined to analyze the correlation between genes and chromosomal aberrations, microRNA and transcription factors, as well as to explore the expression feature and potential regulative mechanism. The results showed that the most frequently unregulated genes in colorectal cancer arelocated on chromosome 20q, present a significant CNA-mRNA correlation.Furthermore, the genes with mRNA overexpression showed co-expression features and tended to be clustered within the same genomic neighborhoods. Then, several genes were selected to carry out further analysis and demonstrated that shared transcription factors, a conserved bidirectional promoter, and competition for a limited pool of microRNAin the 3'UTR of mRNA may be the underlying mechanisms behind the co expression of physically adjacent genes.Finally, the databases, Lentivirus shRNA, and qPCR were used to find that these adjacent genes with co-expression cooperatively participated in the same biological pathways associated with the pathogenesis and development of colorectal cancer. PMID- 29108256 TI - Sphingosine kinase 1 mediates AGEs-induced fibronectin upregulation in diabetic nephropathy. AB - : Activation of sphingosine kinase 1 (SphK1) signaling pathway mediates fibronectin (FN) upregulation in glomerular mesangial cells (GMCs) under high glucose (HG) condition. However, the roles of SphK1 in advanced glycation end products (AGEs)-induced DN have not been elucidated. Here we show that AGEs upregulated FN and SphK1 and SphK1 activity. Inhibition of SphK1 signaling attenuated AGEs-induced FN synthesis in GMCs. Inhibition of AGE receptor (RAGE) signaling reduced the upregulation of FN and SphK1 and SphK1 activity in GMCs induced by AGEs. Treatment of aminoguanidine ameliorates the renal injury and fibrosis in STZ-induced diabetic mice and attenuated SphK1 expression and activity in diabetic mouse kidneys. The renal injury and fibrosis in diabetic SphK1-/- mice was significantly attenuated than WT mice. Furthermore, AGEs upregulated SphK1 by reducing its degradation and prolonging its half-life. CONCLUSION: SphK1 mediates AGEs-induced FN synthesis in GMCs and diabetic mice under hyperglycemic condition. PMID- 29108257 TI - Regulation of neuroinflammation by matrix metalloproteinase-8 inhibitor derivatives in activated microglia and astrocytes. AB - Matrix metalloproteinases (MMPs) play a pivotal role in neuroinflammation that is associated with neurodegenerative diseases. Our group recently reported that MMP 8 mediates inflammatory reactions by modulating the processing of TNF-alpha. To improve the efficacy of the currently available MMP-8 inhibitor (M8I), we have synthesized structurally modified M8I derivatives (comp 2, 3, 4, 5) and compared their efficacy with original compound (comp 1). Among M8I derivatives, comp 2, 3, and 5 inhibited the production of NO, ROS, and IL-6 more efficiently than the original compound in lipopolysaccharide (LPS)-stimulated microglia. When we compared the anti-inflammatory mechanisms of the most effective derivative, comp 3, with comp 1, comp 3 suppressed the mRNA expression of iNOS and cytokines more efficiently than comp 1. Although comp 1 inhibits only TNF-alpha processing, comp 3 additionally inhibits the expression of TNF-alpha. Both compounds inhibited LPS induced activity of MAP kinases, NF-kappaB, and AP-1, while they increased heme oxygenase-1 expression by upregulating AMPK-Nrf2 signaling. Overall, the effect of comp 3 on anti-inflammatory signaling was much stronger than comp 1. We verified the anti-inflammatory effects of comp 1 and 3 in the LPS-injected mouse brain and primary cultured astrocytes. Comp 1 and 3 suppressed microglial activation, astrogliosis, and proinflammatory gene expression in the brain. Moreover, the compounds inhibited proinflammatory gene expression in the cultured astrocytes. Collectively, our data suggest that the MMP-8 inhibitor may be a promising therapeutic agent for neuroinflammatory disorders. PMID- 29108259 TI - Copy number variations and expression of MPDZ are prognostic biomarkers for clear cell renal cell carcinoma. AB - The vital copy number variation (CNV) plays a crucial role in clear cell renal cell carcinoma (ccRCC). MPDZ inhibit cell polarity associate with osmotic pressure response and cancer-related biological processes. In order to clarify the role of the CNV of MPDZ in the progression of ccRCC, we analyzed the CNV and expression of MPDZ and prognosis in ccRCC patients from The Cancer Genome Atlas data portal. Notably, we found that the deletion of MPDZ was the common CNV, which was present in 28.65% of ccRCC patients. With the development of tumors, the percentage of MPDZ deletion increased significantly (19.38% in stage I; 20.00% in stage II; 40.94% in stage III; and 45.00% in stage IV). The deletion of MPDZ significantly increased ccRCC risk (P=0.0025). Low MPDZ expression associated with its deletion was significantly associated with adverse outcomes in ccRCC patients (P=0.0342). Furthermore, immunohistochemical analysis by tissue microarray showed that MPDZ was expressed at lower levels in tumor tissues compared with adjacent tissues (P<0.01). Kaplan-Meier survival curves showed that ccRCC patients with low MPDZ expression had significantly shorter survival than those with high MPDZ expression (P=0.002). These results indicated that low MPDZ expression associated with CNV is a potential biomarker for the prognosis of ccRCC patients. PMID- 29108258 TI - Transcriptional signature of lymphoblastoid cell lines of BRCA1, BRCA2 and non BRCA1/2 high risk breast cancer families. AB - Approximately 25% of hereditary breast cancer cases are associated with a strong familial history which can be explained by mutations in BRCA1 or BRCA2 and other lower penetrance genes. The remaining high-risk families could be classified as BRCAX (non-BRCA1/2) families. Gene expression involving alternative splicing represents a well-known mechanism regulating the expression of multiple transcripts, which could be involved in cancer development. Thus using RNA-seq methodology, the analysis of transcriptome was undertaken to potentially reveal transcripts implicated in breast cancer susceptibility and development. RNA was extracted from immortalized lymphoblastoid cell lines of 117 women (affected and unaffected) coming from BRCA1, BRCA2 and BRCAX families. Anova analysis revealed a total of 95 transcripts corresponding to 85 different genes differentially expressed (Bonferroni corrected p-value <0.01) between those groups. Hierarchical clustering allowed distinctive subgrouping of BRCA1/2 subgroups from BRCAX individuals. We found 67 transcripts, which could discriminate BRCAX from BRCA1/BRCA2 individuals while 28 transcripts discriminate affected from unaffected BRCAX individuals. To our knowledge, this represents the first study identifying transcripts differentially expressed in lymphoblastoid cell lines from major classes of mutation-related breast cancer subgroups, namely BRCA1, BRCA2 and BRCAX. Moreover, some transcripts could discriminate affected from unaffected BRCAX individuals, which could represent potential therapeutic targets for breast cancer treatment. PMID- 29108260 TI - Angiotensin-converting enzyme-2 overexpression improves atrial electrical remodeling through TRPM7 signaling pathway. AB - Atrial electrical remodeling is an important factor in the development and persistence of atrial fibrillation. The aim of this study was to examine the effects of atrial angiotensin-converting enzyme-2 overexpression on atrial electrical remodeling and to elucidate the molecular mechanisms underlying these effects. Twenty-eight male and female dogs were randomly divided into the following 4 groups: a sham-operation group, a control group, an adenovirus enhanced green fluorescent protein (Ad-EGFP) gene group and an Ad-ACE2 gene group. All dogs in the Ad-EGFP and Ad-ACE2 groups were rhythmized at 450 bpm for 14 days. Two weeks later, all the dogs underwent thoracotomy and epicardial gene painting. On day 21 after gene transfer, all the animals were subjected to electrophysiological and molecular studies. AF induction rates and durations were significantly increased in the control and Ad-EGFP groups compared to the sham operated and Ad-ACE2 groups. Transient receptor potential melastatin 7 (TRPM7) expression levels in the Ad-EGFP and control groups were significantly higher than those in the sham-operated and Ad-ACE2 groups. Basal [Mg2+]i was significantly decreased in siRNA transfected cells compared with control and non silencing siRNA-transfected cells. Our results suggest that ACE2 overexpression suppresses atrial electrical remodeling and improves atrial function through the TRPM7 signaling pathway. PMID- 29108261 TI - The coiled-coil domain of oncogene RASSF 7 inhibits hippo signaling and promotes non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths worldwide, and despite recent improvements in treatment patient prognosis remains dismal. In this study, we examined the role of N-terminal Ras-association domain family 7 (RASSF7) in human non-small cell lung cancer (NSCLC). We found that RASSF7 was overexpressed NSCLC tissues, which correlated with advanced TNM stage, positive lymph node metastasis, and poor prognosis. This RASSF7 overexpression promoted lung cancer cell proliferation, migration, and invasion. We also found that RASSF7 interacted with mammalian Ste20-like kinase 1(MST1) through its C-terminal coiled-coil domain to inhibit MST1 phosphorylation as well as the phosphorylation of large tumor suppressor kinase 1(LATS1) and yes-associated protein (YAP), while promoting the nuclear translocation of YAP. In addition, RASSF7 overexpression inhibited the Hippo signaling pathway both in vitro and vivo and promoted the expression of proteins associated with proliferation and invasion, such as connective tissue growth factor. These results suggest that targeting RASSF7 could be exploited for therapeutic benefit in the treatment of NSCLC. PMID- 29108262 TI - Association of PPP1R13L and CD3EAP polymorphisms with risk and survival of non small cell lung cancer in Chinese non-smoking females. AB - PPP1R13L and CD3EAP were confirmed to play important roles in transcription and apoptosis. SNPs in PPP1R13L and CD3EAP may be associated with lung cancer risk and survival. This study investigated the association of PPP1R13L rs1005165 and CD3EAP rs967591 with non-small cell lung cancer (NSCLC) risk and survival in Chinese non-smoking females. 442 NSCLC cases and 480 cancer-free controls were conducted in the case-control study, and 283 cases were in cohort study. Genotype was determined by Taqman real-time PCR. The statistical analyses were performed by SPSS 22.0 software. We found that rs1005165 and rs967591 were significantly associated with NSCLC risk in Chinese non-smoking females. For rs1005165, compared with homozygous wild CC genotype, carriers of CT or TT genotype had lower risk of NSCLC (adjusted ORs were 0.675 and 0.713, 95% CI were 0.461-0.988 and 0.525-0.968, respectively), adjusted OR for dominant model was 0.702, 95% CI was 0.526-0.937. For rs967591, AA genotype (adjusted OR = 0.721, 95% CI = 0.532 0.978) and at least one A allele (GA+AA) (adjusted OR = 0.716, 95% CI = 0.536 0.956) were significantly correlated with lower risk of NSCLC, compared with GG genotype. But we didn't find correlation between the two SNPs and survival time in Chinese non-smoking NSCLC females. In general, we found PPP1R13L rs1005165 and CD3EAP rs967591 might be associated with lower NSCLC risk in Chinese non-smoking females, but no significant relationship was found with NSCLC survival. PMID- 29108263 TI - ERp29 inhibits tumorigenicity by suppressing epithelial mesenchymal transition in gastric cancer. AB - ERp29 is a novel endoplasmic reticulum (ER) protein that plays an important role in protein unfolding and secretion. Recently, it has been reported to be widely implicated in control of tumorigenesis in some tumors. However, the potential function of ERp29 in gastric cancer remains poorly understood. In this study, we found that the positive rate of ERp29 in gastric cancer tissues was significantly lower than that in adjacent non-tumor tissues. And tumor with high ERp29 expression had inclinations towards smaller tumor size and earlier TNM stage. The in vitro experiments indicated that over-expression of ERp29 in gastric cancer cells significantly suppressed the proliferation and migration of tumor cells, which is consistent with the result of the in vivo animal experiments. Furthermore, our mechanistic investigations revealed that ERp29 reversed EMT process in gastric carcinoma, and its effect was related to the inactivation of ERK1/2 and AKT phosphorylation. Thus, we conclude that ERp29 acts as a tumor suppressor gene in gastric cancer, and is expected to become a novel target of the treatment of GC. PMID- 29108264 TI - lncRNAs PVT1 and HAR1A are prognosis biomarkers and indicate therapy outcome for diffuse glioma patients. AB - Diffuse gliomas are well known malignant brain tumors. Long non-coding RNAs (lncRNAs), a type of RNA transcript with more than 200 nucleotides, involve in tumorigenesis and development of various cancers. This study focused on identifying differentially expressed lncRNAs in gliomas based on gene expression profiling, and chose certain lncRNAs PVT1, CYTOR, HAR1A and MIAT, which changed with significant differences. Further analysis of TCGA and GEO data revealed that the expressions of PVT1 and CYTOR were up-regulated, while HAR1A and MIAT expressions were down-regulated in gliomas. Their expression patterns were validated in an independent cohort containing 98 glioma specimens and 12 non tumor tissue controls. High expression of PVT1 and CYTOR as well as low HAR1A and MIAT expression were associated with high Ki-67 level and more TP53 mutation. Kaplan-Meier survival curve and Cox regression analyses showed that glioma patients with high PVT1 expression or low HAR1A expression had poor survival outcome, aberrantly expressed PVT1 and HAR1A could be the independent prognosis biomarkers for glioma patients. Moreover, down-regulation of PVT1 and up regulation of HAR1A contributed to improve the survival of patients who received chemotherapy and radiotherapy. These results implied that these four lncRNAs might play important role in diffuse gliomas progression, particularly, PVT1 and HAR1A could be explored as promising biomarkers for diagnosis, prognosis and target therapy of diffuse gliomas. PMID- 29108265 TI - Cellular inhibitor of apoptosis protein 2 promotes the epithelial-mesenchymal transition in triple-negative breast cancer cells through activation of the AKT signaling pathway. AB - Triple-negative breast cancer (TNBC) represents approximately 10-17% of all breast cancers, and patients with TNBC show a poorer short-term prognosis than patients with other types of breast cancer. TNBCs also have a higher tendency for early distant metastasis and cancer recurrence due to induction of the epithelial mesenchymal transition (EMT). Several recent reports have suggested that inhibitor of apoptosis (IAP) proteins function as regulators of the EMT. However, the roles of these proteins in TNBC are not clear. Accordingly, we investigated the roles of cIAP2 in TNBC. Among eight IAP genes, only cIAP2 was upregulated in TNBC cells compared with that in other breast cancer subtypes. Analysis of TMAs revealed that expression of cIAP2 was upregulated in TNBCs. In vitro studies showed that cIAP2 was highly expressed in TNBC cells compared with that in other types of breast cancer cells. Furthermore, silencing of cIAP2 in TNBC cells induced mesenchymal-epithelial transition (MET)-like processes and subsequently suppressed the migratory ability and invasion capacity of the cells by regulation of Snail through the AKT signaling pathway. In contrast, ectopic expression of cIAP2 in luminal-type breast cancer cells induced activation of the AKT signaling pathway. These results collectively indicated that cIAP2 regulated the EMT in TNBC via activation of the AKT signaling pathway, contributing to metastasis in TNBC. Our study proposes a novel mechanism through which cIAP2 regulates the EMT involving AKT signaling in TNBC cells. We suggest that cIAP2 may be an attractive candidate molecule for the development of targeted therapeutics in the future. PMID- 29108266 TI - The systemic tumor response to RNase A treatment affects the expression of genes involved in maintaining cell malignancy. AB - Recently, pancreatic RNase A was shown to inhibit tumor and metastasis growth that accompanied by global alteration of miRNA profiles in the blood and tumor tissue (Mironova et al., 2013). Here, we performed a whole transcriptome analysis of murine Lewis lung carcinoma (LLC) after treatment of tumor-bearing mice with RNase A. We identified 966 differentially expressed transcripts in LLC tumors, of which 322 were upregulated and 644 were downregulated after RNase A treatment. Many of these genes are involved in signaling pathways that regulate energy metabolism, cell-growth promoting and transforming activity, modulation of the cancer microenvironment and extracellular matrix components, and cellular proliferation and differentiation. Following RNase A treatment, we detected an upregulation of carbohydrate metabolism, inositol phosphate cascade and oxidative phosphorylation, re-arrangement of cell adhesion, cell cycle control, apoptosis, and transcription. Whereas cancer-related signaling pathways (e.g., TGF-beta, JAK/STAT, and Wnt) were downregulated following RNase A treatment, as in the case of the PI3K/AKT pathway, which is involved in the progression of non-small lung cancer. RNase A therapy resulted in the downregulation of genes that inhibit the biogenesis of some miRNAs, particularly the let-7 miRNA family. Taken together, our data suggest that the antitumor activity and decreased invasion potential of tumor cells caused by RNase A are associated with enhanced energy cascade functioning, rearrangement of cancer-related events regulating cell growth and dissemination, and attenuation of signaling pathways having tumor-promoting activity. Thus, RNase A can be proposed as a potential component of anticancer therapy with multiple modes of action. PMID- 29108267 TI - Beta-catenin represses protein kinase D1 gene expression by non-canonical pathway through MYC/MAX transcription complex in prostate cancer. AB - Down regulation of Protein Kinase D1 (PrKD1), a novel serine threonine kinase, in prostate, gastric, breast and colon cancers in humans leads to disease progression. While the down regulation of PrKD1 by DNA methylation in gastric cancer and by nuclear beta-catenin in colon cancer has been shown, the regulatory mechanisms in other cancers are unknown. Because we had demonstrated that PrKD1 is the only known kinase to phosphorylate threonine 120 (T120) of beta-catenin in prostate cancer resulting in increased nuclear beta-catenin, we explored the role of beta-catenin in gene regulation of PrKD1. An initial CHIP assay identified potential binding sites for beta-catenin in and downstream of PrKD1 promoter and sequencing confirmed recruitment of beta-catenin to a 166 base pairs sequence upstream of exon 2. Co-transfection studies with PrKD1-promoter-reporter suggested that beta-catenin represses PrKD1 promoter. Efforts to identify transcription factors that mediate the co-repressor effects of beta-catenin identified recruitment of both MYC and its obligate heterodimer MAX to the same binding site as beta-catenin on the PrKD1 promoter site. Moreover, treatment with MYC inhibitor rescued the co-repressor effect of beta-catenin on PrKD1 gene expression. Prostate specific knock out of PrKD1 in transgenic mice demonstrated increased nuclear expression of beta-catenin validating the in vitro studies. Functional studies showed that nuclear translocation of beta-catenin as a consequence of PrKD1 down regulation, increases AR transcriptional activity with attendant downstream effects on androgen responsive genes. In silico human gene expression analysis confirmed the down regulation of PrKD1 in metastatic prostate cancer correlated inversely with the expression of MAX, but not MYC, and positively with MXD1, a competing heterodimer of MAX, suggesting that the dimerization of MAX with either MYC or MXD1 regulates PrKD1 gene expression. The study has identified a novel auto-repressive loop that perpetuates PrKD1 down regulation through beta-catenin/MYC/MAX protein complex. PMID- 29108268 TI - Inherent characteristics of metachronous metastatic renal cell carcinoma in the era of targeted agents. AB - Background: To assess the prognostic and predictive factors of time to treatment failure (TTF) and overall survival (OS), respectively, in patients with metachronous metastatic renal cell carcinoma (mRCC) who were treated with targeted agents. Materials and Methods: We retrospectively reviewed metachronous mRCC patients, defined as individuals diagnosed with metastatic disease >3 months after initial nephrectomy, treated at an institute since 2005. Cox proportional hazard regression analysis was performed to discover the most determinant variables associated with TTF and OS. Results: Sarcomatoid features, absence of metastasectomy, multiple site metastasis, time to metastasis <1.5 year, and increased corrected calcium were independent prognostic factors of OS. The low risk group (0-1 risk factors) did not reach the median OS, whereas the OS for the intermediate (2 risk factors) and high risk groups (3-5 risk factors) were 58.6 and 23.6 months, respectively (p<0.001). When a death event was considered the dependent factor, the area under the receiver operating characteristic curve was significantly higher than in the existing International mRCC Database Consortium (IMDC; p=0.010) and Memorial Sloan Kettering Cancer Center (MSKCC; p=0.010) risk criteria models. Conclusion: Initial tumor size or T stage did not affect TTF or OS. Patients who could not undergo metastasectomy and rapidly developed multiple metastases with higher corrected calcium and initial tumors with sarcomatoid features were less likely to benefit from targeted therapy; thus, the new agents under development or clinical trials could be more helpful than the use of standard targeted agents. PMID- 29108269 TI - Microarray analyses reveal genes related to progression and prognosis of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma is a high morbidity and mortality cancer in China. Here are few biomarkers and therapeutic targets. Our study was aimed to identify candidate genes correlated to ESCC. Oncomine, The Cancer Genome Atlas, Gene Expression Omnibus were retrieved for eligible ESCC data. Deregulated genes were identified by meta-analysis and validated by an independent dataset. Survival analyses and bioinformatics analyses were used to explore potential mechanisms. Copy number variant analyses identified upstream mechanisms of candidate genes. In our study, top 200 up/down-regulated genes were identified across two microarrays. A total of 139 different expression genes were validated in GSE53625. Survival analysis found that nine genes were closely related to prognosis. Furthermore, Gene Ontology analyses and Kyoto Encyclopedia of Genes and Genomes analyses showed that different expression genes were mainly enriched in cell division, cell cycle and cell-cell adhesion pathways. Copy number variant analyses indicated that overexpression of ECT2 and other five genes were correlated with copy number amplification. The current study demonstrated that ECT2 and other eight candidate genes were correlated to progression and prognosis of esophageal squamous cell carcinoma, which might provide novel insights to the mechanisms. PMID- 29108270 TI - S-adenosylmethionine and methylthioadenosine inhibit cancer metastasis by targeting microRNA 34a/b-methionine adenosyltransferase 2A/2B axis. AB - MicroRNA-34a (miR-34a) is down-regulated in colorectal cancers (CRC) and required for interleukin-6 (IL-6)-induced CRC metastasis. Mice lacking miR-34a developed more invasive cancer in a colitis-associated cancer model. In the same model, S adenosylmethionine (SAMe) and methylthioadenosine (MTA) inhibited IL-6/STAT3 and lowered tumor burden. SAMe and MTA reduce the expression of methionine adenosyltransferase 2A (MAT2A) and there are consensus binding sites for miR 34a/b in the MAT2A 3'UTR. Here we examined whether SAMe/MTA influence miR-34a/b expression and cancer metastasis. We found SAMe and MTA raised miR-34a/b expression in CRC cell lines, inhibited migration and invasion in vitro and liver metastasis in vivo. Like CRC, MAT2A and MAT2B expression is induced in human pancreas and prostate cancers. Treatment with SAMe, MTA, miR-34a or miR-34b inhibited MAT2A expression mainly at the protein level. MAT2B protein level also fell because MAT2A and MAT2B enhance each other's protein stability. Overexpressing miR-34a or miR-34b inhibited while MAT2A or MAT2B enhanced CRC migration and invasion. Co-expressing either miR-34a/b had minimal to no effect on MAT2A/MAT2B's ability to increase migration, invasion and growth. Taken together, MAT2A and MAT2B are important targets of miR-34a/b and SAMe and MTA target this axis, suppressing MAT2A/MAT2B while raising miR-34a/b expression, inhibiting cancer metastasis. PMID- 29108271 TI - Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer. AB - Purpose: To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer. Patients and Methods: One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell survival, hypoxia, angiogenesis and growth factor, were assessed by immunohistochemistry in pre-treatment samples. A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization. Results: VEGF and GLUT-1 expression were significantly positively associated with complete response (CR) to treatment in all leave-one-out iterations. Bcl-2 expression was inversely correlated with pCR, whilst EPO expression was positively correlated with pathological complete response (pCR). Haemaglobin and HIF-1a nuclear expression were inversely correlated with pCR. HB and HIF-1a expression were associated with a higher risk of relapse and overall survival. Conclusion: Hypoxic biomarkers determines the epirubicin resistance in breast cancer. Assessment of such biomarkers, may be useful for predicting chemosensitivity and also anthracycline based treatment outcome. PMID- 29108272 TI - Up-regulated expression of oxytocin mRNA in peripheral blood lymphocytes from first-episode schizophrenia patients. AB - Schizophrenia (SZ) is a severe neuropsychiatric disorder with significant social cognition impairment. Increasing evidence has suggested that neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are important mediators of complex social cognition and behavior associates with SZ. In the present study, forty three first-episode schizophrenia (FES) patients and forty-seven healthy controls (HC) were included. The peripheral mRNA expression of OXT, OXT receptor (OXTR), AVP, AVP 1a receptor (AVPR1a) and CD38 was determined by real-time quantitative polymerase chain reaction (RT-qPCR). The FES patients have a relatively higher mRNA level of OXT and OXTR genes and lower expression of AVP and CD38 genes than HC. No difference was found for AVPR1a between FES patients and HC. As for the sex difference, the mRNA expression of OXT and OXTR showed no difference in both male and female FES patients compared to HC group. The AVP and CD38 genes in female FES patients showed decreased mRNA expression than female HC. Our findings support disrupted OXT and AVP systems in the FES patients. PMID- 29108273 TI - Sensitive droplet digital PCR method for detection of TERT promoter mutations in cell free DNA from patients with metastatic melanoma. AB - Background: Currently mainly BRAF mutant circulating tumor DNA (ctDNA) is utilized to monitor patients with melanoma. TERT promoter mutations are common in various cancers and found in up to 70% of melanomas, including half of BRAF wild type cases. Therefore, a sensitive method for detection of TERT promoter mutations would increase the number of patients that could be monitored through ctDNA analysis. Methods: A droplet digital PCR (ddPCR) assay was designed for the concurrent detection of chr5:1,295,228 C>T and chr5:1,295,250 C>T TERT promoter mutations. The assay was validated using 39 melanoma cell lines and 22 matched plasma and tumor samples. In addition, plasma samples from 56 metastatic melanoma patients and 56 healthy controls were tested for TERT promoter mutations. Results: The established ddPCR assay detected TERT promoter mutations with a lower limit of detection (LOD) of 0.17%. Total concordance was demonstrated between ddPCR and Sanger sequencing in all cell lines except one, which carried a second mutation within the probe binding-site. Concordance between matched plasma and tumor tissue was 68% (15/22), with a sensitivity of 53% (95% CI, 27%-79%) and a specificity of 100% (95% CI, 59%-100%). A significantly longer PFS (p=0.028) was evident in ctDNA negative patients. Importantly, our TERT promoter mutations ddPCR assay allowed detection of ctDNA in 11 BRAF wild-type cases. Conclusions: The TERT promoter mutation ddPCR assay offers a sensitive test for molecular analysis of melanoma tumors and ctDNA, with the potential to be applied to other cancers. PMID- 29108274 TI - Chromosome preference of disease genes and vectorization for the prediction of non-coding disease genes. AB - Disease-related protein-coding genes have been widely studied, but disease related non-coding genes remain largely unknown. This work introduces a new vector to represent diseases, and applies the newly vectorized data for a positive-unlabeled learning algorithm to predict and rank disease-related long non-coding RNA (lncRNA) genes. This novel vector representation for diseases consists of two sub-vectors, one is composed of 45 elements, characterizing the information entropies of the disease genes distribution over 45 chromosome substructures. This idea is supported by our observation that some substructures (e.g., the chromosome 6 p-arm) are highly preferred by disease-related protein coding genes, while some (e.g., the 21 p-arm) are not favored at all. The second sub-vector is 30-dimensional, characterizing the distribution of disease gene enriched KEGG pathways in comparison with our manually created pathway groups. The second sub-vector complements with the first one to differentiate between various diseases. Our prediction method outperforms the state-of-the-art methods on benchmark datasets for prioritizing disease related lncRNA genes. The method also works well when only the sequence information of an lncRNA gene is known, or even when a given disease has no currently recognized long non-coding genes. PMID- 29108275 TI - Functional imaging in combination with mutation status aids prediction of response to inhibiting B-cell receptor signaling in lymphoma. AB - Aberrant B-cell receptor (BCR) signaling is known to contribute to malignant transformation. Two small molecule inhibitors targeting BCR pathway signaling include ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and idelalisib, a specific Phosphatidylinositol-4,5-bisphosphate 3-kinase delta (PI3Kdelta) inhibitor, both of which have been approved for use in haematological malignancies. Despite the identification of various diffuse large B-cell lymphoma (DLBCL) subtypes, mutation status alone is not sufficient to predict patient response and therapeutic resistance can arise. Herein we apply early molecular imaging across alternative activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL subtypes to investigate the effects of BCR pathway inhibition. Treatment with both inhibitors adversely affected cell growth and viability. These effects were partially predictable based upon mutation status. Accordingly, very early 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (18F-FDG PET) and 3'-deoxy-3'[18F]-fluorothymidine positron emission tomography (18F-FLT PET) reported tumour regression and reductions in tumour metabolism and proliferation upon treatment. Furthermore, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) identified alterations in the proteome of a model of ABC DLBCL upon treatment with ibrutinib or idelalisib. In conclusion we demonstrate that very early molecular imaging adds predictive value in addition to mutational status of DLBCL that may be useful in directing patient therapy. PMID- 29108276 TI - Increased SNAT1 is a marker of human osteosarcoma and potential therapeutic target. AB - Background: SLC38A1/SNAT1 has been found to play an essential role in human development, but its role in osteosarcoma (OS) has yet to be evaluated. The purpose of this study was to assess the expression of SLC38A1/SNAT1 in patients with OS, and further investigate the mechanisms by which it affects tumor growth and metastasis. Methods: Tissue microarray blocks and immunohistochemical studies were carried out to assess the expression of SNAT1 in 165 OS specimens. Its correlation with clinicopathological characteristics was then analyzed. The function of SNAT1 in OS cells was investigated by silencing SNAT1 using SNAT1 shRNA in vitro and in vivo. Results: SNAT1 was highly expressed in 85% OS and significantly closely associated with pulmonary metastasis. Patients with high SNAT1 expression survived for shorter periods than those with low SNAT1 expression. Suppression of endogenous SNAT1 led to inhibition of cell proliferation, cell colony formation, and cell migration in vitro, and retarded tumor growth in xenograft models. Silencing SNAT1 reduced expression of MMP9, vimentin, fibronectin, p-Akt, p-mTOR, and VEGF. Conclusions: Our results indicated that increased expression of SNAT1 is a common event in OS. SNAT1 played an essential role in the development and progression of osteosarcoma, which may serve as a prognostic and therapeutic marker of OS. PMID- 29108277 TI - Exome sequencing identified a novel missense mutation c.464G>A (p.G155D) in Ca2+ binding protein 4 (CABP4) in a Chinese pedigree with autosomal dominant nocturnal frontal lobe epilepsy. AB - The aim of this study was to identify disease-causing gene mutations in a Chinese family affected with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a 4-generation pedigree of 27 members in the Southern Chinese Han population, including 11 individuals diagnosed with ADNFLE. DNA samples were collected from 15 family members, chinese han people, including seven affected and eight unaffected individuals. None of these patients had night blindness or visual disorders. Four affected individuals were screened for mutations using whole exome sequencing, and 13 potentially interesting mutations shared by all the four affected individuals were validated using the Sanger sequencing method. Only one novel missense mutation c.464G>A (p.G155D) in the CABP4 gene, encoding the neuronal Ca2+-binding protein 4 (CaBP4), was present in all seven affected individuals in this family as revealed by PCR with blood DNA samples using CABP4 primers. The mutation was also found in one young unaffected family member, but was absent from 300 unrelated control subjects. The p.G155D mutation, located near the Ca2+ binding motif EF-hand 1 and the L-type Ca2+ channel (Cav1.4) binding motif within the N-terminal lobe of CaBP4, is predicted to affect protein function according to the bioinformatics tools PolyPhen-2 and SIFT. These findings suggest that mutations in the CABP4 gene may be linked to ADNFLE. PMID- 29108278 TI - Epstein-Barr virus BRLF1 induces genomic instability and progressive malignancy in nasopharyngeal carcinoma cells. AB - Nasopharyngeal carcinoma (NPC) is a serious health problem in China and Southeast Asia. Relapse is the major cause of mortality, but mechanisms of relapse are mysterious. Epstein-Barr virus (EBV) reactivation and host genomic instability (GI) have correlated with NPC development. Previously, we reported that lytic early genes DNase and BALF3 induce genetic alterations and progressive malignancy in NPC cells, implying lytic proteins may be required for NPC relapse. In this study, we show that immediate early gene BRLF1 induces chromosome mis-segregation and genomic instability in the NPC cells. Similar phenomenon was also demonstrated in 293 and zebrafish embryonic cells. BRLF1 nuclear localization signal (NLS) mutant still induced genomic instability and inhibitor experiments revealed that BRLF1 interferes with chromosome segregation and induces genomic instability by activating Erk signaling. Furthermore, the chromosome aberrations and tumorigenic features of NPC cells were significantly increased with the rounds of BRLF1 expression, and these cells developed into larger tumor nodules in mice. Therefore, BRLF1 may be the important factor contributing to NPC relapse and targeting BRLF1 may benefit patients. PMID- 29108279 TI - Size-based detection of sarcoma circulating tumor cells and cell clusters. AB - Metastatic disease is the most important factor in determining the survival of sarcoma patients. Since sarcoma metastasis is predominantly hematogenous, we hypothesized that detection and quantification of circulating tumor cells (CTCs) could reflect response to therapy and risk of metastatic relapse. We evaluated the presence of CTCs using a novel animal model and in the blood of patients with high grade sarcomas utilizing the CellSieveTM size-based low pressure microfiltration system. Sarcoma CTCs were identified based on antibody staining patterns and nuclear morphology. Additionally, RNA was extracted from the CTCs for molecular analysis including demonstration of an EWS-FLI1 translocation, identification of a previously unrecognized p53 mutation in a patient with Ewing sarcoma, and single cell RNA sequencing of CTC from a child with alveolar rhabdomyosarcoma. In mouse xenograft models, the presence of CTC correlates with disease burden and with clinically silent metastases. In human patients, CTCs were readily detected at diagnosis, decreased with successful treatment, and were detectable in the blood of patients with no radiographic evidence of disease prior to the development of overt metastasis. Although evaluation of CTC is established in the care of patients with carcinomas, this technology has yet to be effectively applied to the evaluation and treatment of sarcoma patients. Our work demonstrates that the CellSieveTM microfiltration system can be used to study the biology of CTC in both mouse models and human sarcoma patients, with the potential for application to the monitoring of disease response and prediction of metastatic relapse. PMID- 29108280 TI - Trimethylation of H3K27 during human cerebellar development in relation to medulloblastoma. AB - Medulloblastoma (MB), the most common malignant childhood brain tumor, encompasses a collection of four clinically and molecularly distinct tumor subgroups, i.e. WNT, SHH, Group 3 and Group 4. These tumors are believed to originate from precursor cells during cerebellar development. Although the exact etiology of these brain tumors is not yet known, histone modifications are increasingly recognized as key events during cerebellum development and MB tumorigenesis. Recent studies show that key components involved in post translational modifications of histone H3 lysine 27 (H3K27) are commonly deregulated in MB. In this descriptive study, we have investigated the trimethylation status of H3K27, as well as the expression of the H3K27 methylase EZH2 and demethylases KDM6A and KDM6B, during human cerebellum development in relation to MB. H3K27 Trimethylation status differed between the MB subgroups. Moreover, trimethylation of H3K27 and expression of its modifiers EZH2, KDM6A and KDM6B were detected in a spatio-temporal manner during development of the human cerebellum, with consistent high occurrence in the four proliferative zones, which are believed to harbor the precursor cells of the different MB subgroups. Our results suggest that H3K27 trimethylation in MB is deregulated by EZH2, KDM6A and KDM6B. Moreover, we provide evidence that during development of the human cerebellum H3K27me3 and its regulators are expressed in a spatio-temporal manner. PMID- 29108281 TI - Frizzled 8 promotes the cell proliferation and metastasis of renal cell carcinoma. AB - Recent reports have shown a rapid rise in the incidence of renal cell carcinoma (RCC), and Wnt (Wingless-related integration site) signaling pathway is important in RCC. Frizzled 8 (FZD8) is a member of Frizzled (FZD) receptor family which could activate canonical or non-canonical Wnt/beta-catenin pathways. Nevertheless, the role of FZD8 in RCC is poorly investigated. The immunohistochemical analysis showed high expression of FZD8 in RCC tissues compared with peri-tumor tissues. FZD8 knockdown decreased the ability of proliferation and metastasis of RCC cells. Research revealed that the FZD8 regulated the transcription of Cyclin D1, c-Myc, and could promote the epithelial to mesenchymal transition (EMT) by mediating Vimentin and Snail through the Wnt/beta-catenin signaling pathway. In addition, the results of our experiment revealed that FZD8 is involved in the regulation of non-canonical Wnt signaling pathway. These data suggested that the expression of FZD8 may play an important role in the proliferation and metastasis of RCC, and serve as a putative promising drug target for human RCC therapy. PMID- 29108282 TI - IGF-IEc expression is increased in secondary compared to primary foci in neuroendocrine neoplasms. AB - Different Insulin-like growth factor-I (IGF-I) mRNA transcripts are produced by alternative splicing and particularly the IGF-IEc isoform has been implicated in the development and/or progression of various types of cancer. In the present study, we examined the potential role of IGF-IEc expression as a new immunohistochemical marker of aggressiveness in neuroendocrine neoplasms (NENs). We utilized immunohistochemical analysis in tissue specimens of 47 patients with NENs, to evaluate the expression of IGF-IEc (%) and Ki-67 proliferation index (%). Specimens from patients with tumors of different tissue origin, of either primary or metastatic lesions and of different grade were examined. Cytoplasmic IGF-IEc staining was found in 23 specimens of NENs or NECs: 10 pancreatic, 4 small bowel, 3 gastric, 1 lung, 1 uterine and 4 poorly differentiated of unknown primary origin. Ki-67 and IGF-IEc expression was positively correlated in all the samples studied (r=0.31, p=0.03). IGF-1Ec expression was more prevalent in specimens originating from metastatic foci with high Ki-67 compared to primary sites with low Ki-67 expression (p=0.036). These findings suggest a possible role of IGF-IEc in NEN tumorigenesis and progression to metastases that could be used as an additional new marker of a more aggressive behavior and a potential drugable target. PMID- 29108283 TI - Combination of sorafenib and TACE inhibits portal vein invasion for intermediate stage HCC: a single center retrospective controlled study. AB - Purpose: This study aims to investigate the effect of sorafenib plus Transarterial Chemoembolization (TACE) treatment on inhibiting portal vein invasion in patients with intermediate stage HCC. Materials and Methods: The consecutive medical records of patients with HCC were retrospectively analyzed from October 2009 to February 2015. The propensity score matching method was applied into group matching. The Kaplan-Meier method and the Log-Rank Test was used to estimate the median survival time, median time to progression and median time to portal vein invasion. Factors associated with survival benefits were identified by univariate and multivariate Cox-regression model analyses. Results: Of 97 patients enrolled, 19 patients received TACE-sorafenib treatment and 78 patients received TACE treatment. During the follow-up period of 15 months, the median time to portal vein invasion was 14.2 months vs 8.77 months, respectively (p=0.073). And the analysis of the cox's proportional hazard model revealed that patients treated with TACE treatment alone would run greater risk of portal vein invasion compared with TACE-sorafenib treatment (hr=7.49, p=0.021). Early administration of sorafenib was associated with lower risk of portal vein invasion (p=0.021) according to the univariate analysis. Adverse events (AEs) identified in the combined group were mostly classified as Grades 1 and 2, and skin-related reactions and fatigue were the most common. Conclusions: Sorafenib may could inhibit portal vein invasion of hepatoma carcinoma cells. Early administration of sorafenib may bring more survival benefits. PMID- 29108285 TI - Chronic polycyclic aromatic hydrocarbon exposure causes DNA damage and genomic instability in lung epithelial cells. AB - Cell exposure to atmospheric polycyclic aromatic hydrocarbons (PAHs) is closely associated with DNA damage and genomic instability. We assessed the mechanisms of chronic and acute PAH exposure-induced genotoxicity in two human lung epithelial cell lines, A549 and NC-H1975. We sampled atmospheric PAHs at the Xixi Campus, Zhejiang University in Hangzhou, China during August (non-haze episode) and November (haze episode) 2015. We identified vehicle emissions as a dominant anthropogenic PAH source in our study. PAHs were extracted according to the United States Environmental Protection Agency Method TO-13A. We found that chronic PAH exposure saturated lung cell xenobiotic metabolic pathways, promoting intercellular reactive oxygen species production and accumulation. Chronic alteration of the cellular redox status resulted in DNA damage and genomic instability. Chronic PAH exposure also perturbed the cellular DNA damage response, inducing S phase arrest and inhibiting apoptosis. Dysregulation of PAH metabolism and the DNA damage response altered cellular homeostasis and increased cell susceptibility to subsequent PAH exposures, thereby enhancing the likelihood of genomic mutation and instability. PMID- 29108284 TI - Overexpression of miR-26b decreases the cisplatin-resistance in laryngeal cancer by targeting ATF2. AB - Cisplatin is a common used chemotherapeutic drug for the treatment of laryngeal cancer. However, drug-resistance is a major obstacle in platinum-based chemotherapy for laryngeal cancer. Recent studies have demonstrated that dysregulation of microRNAs (miRNAs) is responsible for chemoresistance in multiple cancers including laryngeal cancer, but the potential mechanisms are required to be explored. In the present study, we constantly exposed the laryngeal cancer cell line Hep-2 with cisplatin to establish a cisplatin resistant laryngeal cancer cell model (Hep-2/R). We found that Hep-2/R cells exhibited obvious resistance to cisplatin compared to the Hep-2 cells. However, overexpression of miR-26b significantly decreased the half maximal inhibitory concentration (IC50) of cisplatin to Hep-2/R. Mechanically, miR-26b in Hep-2/R decreased the expression of ATF2, and thus inhibiting the phosphorylation of ATF2 and formation of cellular ATF2-c-Jun complex induced by cisplatin. As the results, Hep-2/R cells failed to overexpress the Bcl-xl which is a key anti apoptotic protein under the cisplatin treatment. Therefore, overexpression of miR 26b was found to be able to promote mitochondrial apoptosis induced by cisplatin. PMID- 29108286 TI - PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway. AB - Mutations in the gene encoding Ca2+-independent phospholipase A2 group 6 (PLA2G6) cause the recessive familial type 14 of Parkinson's disease (PARK14). Mitochondrial dysfunction is involved in the pathogenesis of Parkinson's disease (PD). PLA2G6 is believed to be required for maintaining mitochondrial function. In the present study, rotenone-induced cellular model of PD was used to investigate possible molecular pathogenic mechanism of PARK14 mutant PLA2G6 induced PD. Overexpression of wild-type (WT) PLA2G6 ameliorated rotenone-induced apoptotic death of SH-SY5Y dopaminergic cells. PARK14 mutant (D331Y), (G517C), (T572I), (R632W), (N659S) or (R741Q) PLA2G6 failed to prevent rotenone-induced activation of mitochondrial apoptotic pathway and exert a neuroprotective effect. WT PLA2G6, but not PARK14 mutant PLA2G6, prevented rotenone-induced mitophagy impairment. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 was ineffective in attenuating rotenone-induced decrease in mitochondrial membrane potential and increase in the level of mitochondrial superoxide. WT PLA2G6, but not PARK14 PLA2G6 mutants, restored enzyme activity of mitochondrial complex I and cellular ATP content in rotenone-treated SH-SY5Y dopaminergic cells. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 failed to prevent rotenone-induced mitochondrial lipid peroxidation and cytochrome c release. These results suggest that PARK14 PLA2G6 mutants lose their ability to maintain mitochondrial function and are defective inpreventing mitochondrial dysfunction, ROS production and activation of mitochondrial apoptotic pathway in rotenone-induced cellular model of PD. PMID- 29108287 TI - Prognostic and diagnostic significance of lncRNAs expression in cervical cancer: a systematic review and meta-analysis. AB - Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in cervical cancer (CC) and presumably serve as diagnostic or prognostic markers. We thus performed a systematic review and meta-analysis to evaluate the clinical values of dysregulated lncRNAs in CC. A literature search was performed using the electronic databases PubMed, Embase, and Web of Science. A total of 22 relevant studies were eligible, including 21 on clinicopathological features, 18 on prognosis, and 4 on diagnosis. For clinicopathological features, HOTAIR expression was positively associated with tumor size (odds ratio [OR]=2.19, 95% confidence interval [CI] 1.42-3.38, P=0.000) and lymph node metastasis (OR=6.04, 95% CI 3.51-10.42, P=0.000). For the prognostic values, up-regulated HOTAIR had an unfavorable impact on overall survival ([OS]; hazard ratio [HR]=1.94, 95%CI 1.17-3.22, P=0.011) and disease-free survival (HR=2.61, 95%CI 1.35-5.05, P=0.004), and high PVT1 expression was correlated with shorter OS (HR=1.66, 95%CI 1.21-2.29, P=0.002). For the diagnostic values, the pooled result showed an area under the curve (AUC) of 0.85, with 85% sensitivity and 81% specificity in discriminating patients with CC from healthy controls. Overall, we conclude that lncRNAs might serve as promising indicators for prognostic and diagnostic evaluation of patients with CC. PMID- 29108289 TI - Clinical significance of cripto-1 expression in lung adenocarcinoma. AB - Cripto-1 can promote tumourigenesis and may be a potential prognostic biomarker in several malignancies, yet little is known about this protein in lung adenocarcinoma (LAC). The aim of this study was to evaluate the prognostic value of cripto-1 expression in a cohort of patients with LAC. Tumours from 290 patients with pathologically confirmed LAC were used for an immunohistochemical analysis of cripto-1 expression. The correlation between cripto-1 expression and the clinicopathological parameters of patients, EGFR-TKI sensitivity was analysed. Significant associations between cripto-1 expression and pT status, pN status, pTNM status, E-cadherin expression and EGFR-TKI sensitivity were identified. Compared with patients with low cripto-1 expression, patients with high cripto-1 expression exhibited significantly poorer progression-free survival (PFS) and overall survival (OS). Moreover, multivariate analyses showed that high cripto-1 expression was an independent predictor of worse survival of patients with LAC. The combination of cripto-1 expression and serum CEA level was correlated with both PFS and OS. In conclusion, cripto-1 may be a potential prognostic biomarker of survival in patients with LAC. PMID- 29108290 TI - An endoscopic ultrasonography-guided interstitial brachytherapy based special treatment-planning system for unresectable pancreatic cancer. AB - EUS-guided interstitial brachytherapy is promising in the treatment of unresectable malignant carcinoma adjacent to the digestive tract. The feasible treatment plan is not established. Thus, our study aimed to develop a novel treatment plan and evaluate the feasibility in patients with unresectable pancreatic cancer. A total of 42 patients with unresectable pancreatic cancer (stage III: n = 18; stage IV: n = 24) were retrospectively included. A special treatment-planning system (TPS) for EUS was designed and evaluated by comparing with the traditional TPS. The patients underwent EUS-guided interstitial brachytherapy based on the new software. In the test model, there was no obvious difference of irradiation doses calculated by the two softwares (EUS TPS vs. traditional TPS) (P > 0.05). Under the support of EUS TPS, a novel treatment plan for EUS-guided interstitial brachytherapy was successfully established, which contained seven principles. All patients tolerated the treatment well without any serious complications. In 15 patients (stage III) whose minimal peripheral dose was larger than 90 Gy, partial remission rate was 80% (12/15). Twelve patients (12/18) in stage III were alive for over 12 months with a median peripheral dose of 107.5 Gy. The expected median survival time of the 42 patients was 9.0 months (95%CI 7.6-10.4 months). The results demonstrated that the new EUS TPS will play an important role in EUS-guided interstitial brachytherapy in patients with unresectable pancreatic malignant cancer. PMID- 29108291 TI - A novel "total pituitary hormone index" as an indicator of postoperative pituitary function in patients undergoing resection of pituitary adenomas. AB - The purpose of this study was to investigate the differences between pre- and postoperative pituitary hormone levels in patients undergoing surgical resection of pituitary adenoma and to identify factors associated with preoperative hypopituitarism. Data from 81 patients with histologically confirmed functioning and non-functioning pituitary adenomas (NFPA) who underwent transsphenoidal resection from January 2011 to December 2013 were retrospectively analyzed. Logistic regression was applied to analyze factors associated with preoperative hypopituitarism. In patients with functioning pituitary adenomas, GH and PRL levels declined after the operation; TSH, FSH and LH levels returned to preoperative values after an initial decline at postoperative day 1. In contrast, with the exception of a postoperative reduction in PRL level, NFPA patients had postoperative ACTH, TSH, FSH and LH levels at 4 months follow-up that were similar to preoperative levels. Similarly, a decrease in total hormone index was observed following surgery irrespective of NFPA type and in null-cell type NFPA patients with values increasing over the 4-month follow-up period. A higher percentage of patients receiving partial resection had high PRL levels (>=200 ng/ mL) compared to those receiving complete resection. Age (P = 0.041) and male sex (P = 0.004) were significantly associated with preoperative hypopituitarism. In conclusion, the postoperative total hormone index decreased immediately following surgery in all patients with pituitary adenoma who underwent resection, and then increased over the follow-up period. The extent of surgical resection correlated with PRL levels >200 ng/mL. Age and male sex were also independent risk factors for preoperative hypopituitarism. PMID- 29108288 TI - Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. AB - In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk (p=0.024), large splenomegaly (p=0.017), transfusion dependency (p=0.022), platelet count <200*109/l (p=0.028), and a time-interval between MF diagnosis and RUX start >2 years (p=0.048). Also, patients treated with higher (>=10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (p=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (p<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results. PMID- 29108292 TI - Azacitidine or intensive chemotherapy for older patients with secondary or therapy-related acute myeloid leukemia. AB - The treatment of older patients with acute myeloid leukemia that is secondary to previous myelodysplastic syndrome, myeloproliferative neoplasm, or prior cytotoxic exposure remains unsatisfactory. We compared 92 and 107 patients treated, respectively, with intensive chemotherapy or azacitidine within two centres. Diagnoses were 37.5% post-myelodysplastic syndrome, 17.4% post myeloproliferative neoplasia, and 45.1% therapy-related acute myeloid leukemia. Patients treated by chemotherapy had less adverse cytogenetics, higher white blood-cell counts, and were younger: the latter two being independent factors entered into the multivariate analyses. Median overall-survival times with chemotherapy and azacitidine were 9.6 (IQR: 3.6-22.8) and 10.8 months (IQR: 4.8 26.4), respectively (p = 0.899). Adjusted time-dependent analyses showed that, before 1.6 years post-treatment, there were no differences in survival times between chemotherapy and azacitidine treatments whereas, after this time-point, patients that received chemotherapy had a lower risk of death compared to those that received azacitidine (adjusted HR 0.61, 95%CI: 0.38-0.99 at 1.6 years). There were no interactions between treatment arms and secondary acute myeloid leukemia subtypes in all multivariate analyses, indicating that the treatments had similar effects in all three subtypes. Although a comparison between chemotherapy and azacitidine remains challenging, azacitidine represents a valuable alternative to chemotherapy in older patients that have secondary acute myeloid leukemia because it provides similar midterm outcomes with less toxicity. PMID- 29108293 TI - Gap in gender parity: gender disparities in incidence and clinical impact of chronic total occlusion in non-infarct artery in patients with non-ST-segment elevation myocardial infarction and multivessel coronary artery disease. AB - A chronic total occlusion in a non-infarct-related artery is an independent predictor of mortality in non-ST elevation myocardial infarction. There are no mortality data about the impact of a chronic total occlusion in patients with non ST elevation myocardial infarction according to gender. The purpose of this study was to evaluate the prevalence of the chronic total occlusion in in men and women and examine its impact on clinical outcomes. Data from consecutive patients with multivessel coronary artery disease treated in a high-volume center between 2006 and 2012 were included in a prospective registry and divided according to gender and the presence of chronic total occlusion. All of the analyzed patients were followed up for at least 24 months, with all-cause mortality defined as the primary endpoint. Among the 515 patients who fulfilled the inclusion criteria, 32.8% were female. In the female arm, the 24-month mortality for the groups with and without chronic total occlusion was similar (18.9% and 14.7%, respectively; p = 0.47). In contrast, in the male arm, the occurrence of chronic total occlusion was associated with higher 24-month mortality (24.3% vs. 13.4%; p = 0.009). Multivariate analysis of the male arm revealed a trend toward a positive association between the occurrence of chronic total occlusion and 24-month mortality (HR 1.62; 95% CI 0.93-2.83; p = 0.087). The presence of chronic total occlusion in men is associated with an adverse long-term prognosis, whereas in women this effect was not observed. PMID- 29108294 TI - Predicting level 2 axillary lymph node metastasis in a Chinese breast cancer population post-neoadjuvant chemotherapy: development and assessment of a new predictive nomogram. AB - Background: We aimed to develop a new nomogram to predict the probability of level 2 axillary lymph node metastasis (L-2-ALNM) in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC). Methods: Data were collected from 709 patients who received neoadjuvant chemotherapy and then underwent axillary lymph node (ALN) dissection between May 2009 and December 2015 at the Liaoning Cancer Hospital. The level 2 axillary lymph node metastasis (L-2-ALNM ) nomogram was created from the logistic regression model. An additional set of 141 consecutive patients treated at the same institution between January 2015 and December 2015 were enrolled as the validation group. The predictive accuracy of the L-2-ALNM nomogram was measured by calculating the area under the receiver operating characteristic curve (AUC). Results: In multivariate analysis, age, tumor size, histological grade, skin invasion, and response to neoadjuvant chemotherapy were identified as independent predictors of L-2-ALNM. The new model was accurate and discriminating for both the modeling and validation groups (AUC: 0.819 vs 0.849). The false-negative rates of the L-2-ALNM nomogram were 4.44% and 7.69% for the predicted probability cut-off points of 10% and 20%. Conclusion: The L-2-ALNM nomogram shows reasonable accuracy for making clinical decisions. The omission of level 2 axillary lymph node dissection after neoadjuvant chemotherapy might be possible if the probability of level 2 lymph node involvement was < 10% or < 20% in accordance with the acceptable risk determined by medical staff and patients. PMID- 29108295 TI - Relationship of polymorphisms and haplotype in interleukin-16 and adiponectin gene with late-onset Alzheimer's disease risk. AB - Aims: To investigate the impact of Interleukin-16 (IL- 16) and Adiponectin (ANP) gene single nucleotide polymorphisms (SNPs), gene- gene interactions and haplotype on late-onset Alzheimer's disease (LOAD) risk. Methods: Hardy-Weinberg equilibrium (HWE), haplotype and pairwise linkage disequilibrium (LD) analysis were investigated by using SNPstats (available online at http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to examine interaction among 4 SNPs, odds ratio (OR) and 95% confident interval (95%CI) were calculated by logistic regression model. Results: LOAD risk was significantly higher in carriers of rs266729- G allele than those with CC genotype (CG+ GG versus CC), OR (95%CI) =1.61 (1.26-1.96), and higher in carriers of rs1501299- T allele, OR (95%CI) = 1.62 (1.32-2.12), lower in carriers of rs4072111- T allele, adjusted OR (95%CI) =0.65 (0.44-0.93). We also found a significant gene- gene interaction between rs266729 and rs4072111. Participants with CG or GG of rs266729 and CC of rs4072111 genotype have the highest LOAD risk, OR (95%CI) = 2.62 (1.64 -3.58). Haplotype containing the rs266729- G and rs1501299- T alleles were associated with increased LOAD risk, OR (95%CI)= 1.83 (1.32- 2.43), and haplotype containing the rs1131445- C and rs4072111- T alleles were associated with decreased LOAD risk, OR (95%CI)= 0.53 (0.18- 0.95). Conclusions: We concluded that rs266729 and rs1501299 minor alleles were associated with increased LOAD risk, but rs4072111 minor allele was associated with decreased LOAD risk. We also found that interaction involving rs266729 and rs4072111, and haplotype combinations were associated with LOAD risk. PMID- 29108296 TI - Comparison of two transarterial chemoembolization regimens in patients with unresectable hepatocellular carcinoma: raltitrexed plus oxaliplatin versus 5 fluorouracil plus oxaliplatin. AB - Aims: To compare the safety and efficacy of TACE using raltitrexed, oxaliplatin and epirubicin with 5-fluorouracil, oxaliplatin and epirubicin for patients with unresectable hepatocelluar carcinoma. Results: Median overall survival (OS) was 7.4 months in the raltitrexed group [95% confidence interval (CI): 5.4, 9.4) and 5.8 months in the control group (95% CI: 5.2, 6.4; P = 0.177). The median progression-free survival (PFS) time was significantly higher in the raltitrexed group (3.6 months, 95% CI: 2.8, 4.4) than in the control group (2.6 months, 95% CI: 2.2, 3.0; P = 0.038). The disease control rate (DCR) was higher in the raltitrexed group than in the control group (40% versus 30.4%; P = 0.353). The incidence of adverse events was similar between the two groups. Materials and Methods: From January 2012 to December 2014, 86 patients with unresectable HCC were treated with TACE using the combination of raltitrexed, oxaliplatin and epirubicin (raltitrexed group), and the combination of 5-fluorouracil, oxaliplatin and epirubicin (control group). The primary endpoint was OS, and the secondary endpoints were PFS, DCR and adverse events. Conclusions: Although the study did not meet its primary endpoint, raltitrexed group reach a higher PFS, which suggests that this combination regimen of TACE as alternative may confer some benefits to selected patients. PMID- 29108297 TI - Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer. AB - PURPOSE: To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, <= 8 cycles, with olaparib 400mg bid maintenance. Peripheral blood mononuclear cells were collected for polymorphisms and PAR levels, and paired tumor biopsies (pre-/post-cycle 1) for proteomics and apoptosis endpoints. RESULTS: 28 women were treated (median 5 prior regimens [0-12]). Dose-limiting toxicity was thrombocytopenia, and symptomatic hyponatremia with carboplatin AUC5. The maximum tolerated dose was olaparib 400mg bid+carboplatin AUC4. Grade 3 and 4 adverse events included neutropenia (36%), thrombocytopenia (11%), and anemia (11%). Responses included 1 complete response (CR; 69+months) and 5/27 partial responses (19%; median 4months [4-7]), for a response rate of 22%. Biomarker findings did not correlate with response. The long-term CR patient with prior negative BRCA testing was found to have deletion of BRCA1 exons1-2. CONCLUSIONS: The olaparib/carboplatin combination is tolerable and has modest activity in sporadic TNBC patients. Further evaluation of predictive biomarkers to identify those with BRCA wild type who had response is warranted. PMID- 29108298 TI - Myelodysplastic syndromes: advantages of a combined cytogenetic and molecular diagnostic workup. AB - In this study we present a new diagnostic workup for the myelodysplastic syndromes (MDS) including FISH, aCGH, and somatic mutation assays in addition to the conventional cytogenetics (CC). We analyzed 61 patients by CC, FISH for chromosome 5, 7, 8 and PDGFR rearrangements, aCGH, and PCR for ASXL1, EZH2, TP53, TET2, RUNX1, DNMT3A, SF3B1 somatic mutations. Moreover, we quantified WT1 and RPS14 gene expression levels, in order to find their possible adjunctive value and their possible clinical impact. CC analysis showed 32% of patients with at least one aberration. FISH analysis detected chromosomal aberrations in 24% of patients and recovered 5 cases (13.5%) at normal karyotype (two 5q- syndromes, one del(7) case, two cases with PDGFR rearrangement). The aGCH detected 10 "new" unbalanced cases in respect of the CC, including one with alteration of the ETV6 gene. After mutational analysis, 33 patients (54%) presented at least one mutation and represented the only marker of clonality in 36% of all patients. The statistical analysis confirmed the prognostic role of CC either on overall or on progression-free-survival. In addition, deletions detected by aCGH and WT1 over expression negatively conditioned survival. In conclusion, our work showed that 1) the addition of FISH (at least for chr. 5 and 7) can improve the definition of the risk score; 2) mutational analysis, especially for the TP53 and SF3B1, could better define the type of MDS and represent a "clinical warning"; 3) the aCGH use could be probably applied to selected cases (with suboptimal response or failure). PMID- 29108299 TI - Serum miR-143 levels predict the pathological response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. AB - Recently, several circulating miRNAs have been reported as promising, minimally invasive biomarkers for the diagnosis or prediction of the prognosis in various types of cancer. However, the utility of circulating miRNAs as predictive markers of the cancer response to neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer is still unclear. To identify circulating serum miRNAs useful for predicting a pathological good response to nCRT, total 18 serum miRNAs of interest were analyzed by real-time polymerase chain reaction in 94 rectal cancer patients treated with nCRT and surgery. Pathological complete response (pCR; Dworak TRG4) and near-pCR (TRG3) were obtained in 12 (13%) and 9 (9%) patients respectively, and we regarded them as nCRT-responders. Of the 18 serum miRNAs, only the serum level of miR-143 was identified significantly associated with a pathological response to nCRT in 94 patients; the serum miR-143 level was significantly lower in nCRT-responders than in non-responders. A multivariate analysis incorporating other clinicopathological factors showed that only the serum miR-143 level was an independent predictor of a good pathological response. The circulating serum miR-143 level may be a novel, non-invasive predictive marker of a response to nCRT in locally advanced rectal cancer patients. PMID- 29108300 TI - Different patterns of age-related central olfactory decline in men and women as quantified by olfactory fMRI. AB - Age-related olfactory decline, or presbyosmia, is a prevalent condition with potentially devastating consequences on both quality of life and safety. Despite clear evidence for this decline, it is unknown whether presbyosmia is sex dependent and also whether it is due to central or peripheral olfactory system deterioration. Therefore, the goals of this study were to investigate the neurofunctional substrate of olfactory decline and examine its relationship to age and sex in thirty-seven (18 women, 19 men) healthy older participants using olfactory functional MRI (fMRI). The olfactory fMRI paradigm utilized unique odor+visual and visual-only conditions to contrast peripheral-to-central and central-to-central olfactory processing, respectively. Age was negatively correlated with fMRI activation in olfactory-related regions. Significant aging effects were identifiable in male participants in all target regions. Female participants, however, showed a different pattern of functional decline. Extended unified structural equation modeling (euSEM) analysis revealed that the effective functional connectivity profile was drastically different between male and female participants, with females manifesting a top-down mechanism to offset age-related olfactory activation decline. Our results support the hypotheses that the central olfactory system is involved in age-related olfactory decline, and that resilience to age-related olfactory decline in women may be due to their profuse olfactory network effective connectivity. PMID- 29108301 TI - Cost and cost-effectiveness of adjuvant trastuzumab in the real world setting: A study of the Southeast Netherlands Breast Cancer Consortium. AB - Background: We assessed the real world costs and cost-effectiveness of the addition of trastuzumab in HER2 positive early breast cancer compared to chemotherapy alone in the Dutch daily practice as opposed to the results based on trial data and based on a subset of patients that were treated according to the guidelines. Patients and Methods: In a cohort study, we included all patients with stage I-III invasive breast cancer treated with curative intent in 5 Dutch hospitals between 2005 and 2007 (n=2684).We assessed three scenarios: a real world scenario, a trial scenario and a guideline scenario, with costs and effectiveness based on either the cohort study, the published trials or the guidelines. Incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves (CEACs) were constructed. Results: Costs were ?243,216 and ?239,657 for trastuzumab and no trastuzumab for the real world scenario, ?224,443 and ?218,948 for the guideline scenario and ?253,666 and ?265,116 for the trial scenario. The QALYs were 0.827, 0.861, 0.993 for the real world, guideline and trial scenario. The corresponding ICERs were ?4,304, ?6,382 and dominance, respectively. CEACs showed that the probability that trastuzumab is cost effective is >=99% in each scenario. Conclusion: Adjuvant trastuzumab in the real world can be considered cost-effective. PMID- 29108302 TI - Preoperative lymphocyte-to-monocyte ratio as a strong predictor of survival and recurrence for gastric cancer after radical-intent surgery. AB - Objectives: To evaluate the predictive value of the preoperative lymphocyte-to monocyte ratio (LMR) for the prognosis of patients with gastric cancer (GC) after radical-intent surgery. Methods: We retrospectively analyzed 1,810 patients who underwent radical-intent gastrectomy for primary GC from December 2008 to December 2013. X-tile software was used to identify the optimal value for blood LMR. Nomograms were developed to predict overall survival (OS) and recurrence free survival (RFS) after surgery. Results: LMR was significantly lower in patients with GC than in matched normal volunteers (P<0.001). As shown by forest plots, the long-term outcomes were poorer in the low LMR group than in the high LMR group when considering subgroups separated by clinical characteristics. Cox regression analysis showed that LMR was an independent prognostic factor for OS (P<0.001) and RFS (P=0.001). Nomograms, combining LMR with age, T stage, and N stage, showed better discriminative abilities than the AJCC staging system did in predicting 5-year survival and recurrence from the time of surgery. The recurrence rate was 30.4% (550/1810) and was significantly higher in the low LMR group than in the high LMR group (P<0.05). The LMR was also closely correlated with liver and lymph node metastases (both P<0.05). Conclusion: As an independent prognostic factor for GC, preoperative LMR can improve the predictability of individual survival and recurrence. Furthermore, because liver and lymph node metastases were more commonly observed in patients with low blood LMR before surgery, these patients should be closely followed after the operation. PMID- 29108303 TI - Anesthetic dreaming, anesthesia awareness and patient satisfaction after deep sedation with propofol target controlled infusion: A prospective cohort study of patients undergoing day case breast surgery. AB - Background: Anesthetic dreaming and anesthesia awareness are well distinct phenomena. Although the incidence of intraoperative awareness is more common among patients who reported a dream after surgery, the exact correlation between the two phenomena remains an unsolved rebus. The main purpose of this study was to investigate anesthetic dreaming, anesthesia awareness and psychological consequences eventually occurred under deep sedation. Intraoperative dreaming experiences were correlated with dream features in natural sleep. Methods: Fifty one patients, undergoing surgical excision of fibroadenomas under a Bispectral index-guided deep sedation anesthesia with propofol target controlled infusion, were enrolled into this prospective study. Psychological assessment was performed through the State Trait Anxiety Inventory. A questionnaire was adopted to register dreaming and anesthesia awareness. Data were collected after emergence (t0), 24 hours (t1), 1 month (t2), 6 months (t3). Results: Six patients (12%) reported anesthetic dreaming at t0 confirming the response at each subsequent evaluation. One patient (2%) confirmed dreaming during anesthesia in all, but denied it at t0. There was a high correlation between the intraoperative dream contents and the features of dreams in natural sleep. No cases of anesthesia awareness were detected. A similar level of satisfaction was observed in dreaming and no-dreaming patients. Conclusions: Anesthetic dreaming does not seem to influence satisfaction of patients undergoing deep sedation with propofol target controlled infusion. A psychological assessment would seem to improve the evaluation of possible psychological consequences in dreamer patient. PMID- 29108304 TI - Evaluating the efficacy of post-surgery adjuvant therapies used for ductal carcinoma in situ patients: a network meta-analysis. AB - Objective: Post-surgery adjuvant therapies are very important for patients suffering from ductal carcinoma in situ (DCIS). In this study we conducted a network meta-analysis (NMA) to evaluate the efficacy of different post-surgery adjuvant therapies including tamoxifen, anastrozole and radiation therapy (RT) and their combinations (RT+ tamoxifen and RT+ anastrozole). Methods: We searched several databases, including Embase, MEDLINE / PUBMED, Cochrane Library, and Science Citation Index, for relevant studies. We then extracted the data from eligible studies in order to perform our NMA. We measured the comparative efficacy of each treatment option based on the calculated odds ratios (ORs) and the corresponding 95% credibility interval (95%CrI) for each treatment option. We calculated the surfaces under the cumulative ranking curves (SUCRA) in order to rank the therapies according to their different outcomes. Results: In this study, local recurrence (LC) was chosen as the primary outcome. Metastasis, contralateral-breast cancer (CBC), ipsilateral-breast cancer (IBC) and death were secondary outcomes. Patients treated with RT and RT + tamoxifen exhibited a lower risk of LC compared with control group (OR=0.54, 95%CrI: 0.40-0.73; OR=0.41, 95%CrI: 0.19-0.90). Patients treated by RT and RT + tamoxifen also exhibited a significantly lower risk of IBC compared with control group (OR=0.55, 95%CrI: 0.37-0.82; OR=0.42, 95%CrI: 0.18-0.99). Results from the SUCRA indicated that RT + anastrozole and RT + tamoxifen were potentially the best adjuvant treatments for patients with DCIS. Conclusions: In conclusion, the RT + anastrozole and RT + tamoxifen are recommended for their performance and effectiveness. PMID- 29108306 TI - The prostate health index PHI predicts oncological outcome and biochemical recurrence after radical prostatectomy - analysis in 437 patients. AB - The purpose of this study was to investigate the Prostate-Health-Index (PHI) for pathological outcome prediction following radical prostatectomy and also for biochemical recurrence prediction in comparison to established parameters such as Gleason-score, pathological tumor stage, resection status (R0/1) and prostate specific antigen (PSA). Out of a cohort of 460 cases with preoperative PHI measurements (World Health Organization calibration: Beckman Coulter Access-2 Immunoassay) between 2001 and 2014, 437 patients with complete follow up data were included. From these 437 patients, 87 (19.9%) developed a biochemical recurrence. Patient characteristics were compared by using chi-square test. Predictors were analyzed by multivariate adjusted logistic and Cox regression. The median follow up for a biochemical recurrence was 65 (range 3-161) months. PHI, PSA, [-2]proPSA, PHI- and PSA-density performed as significant variables (p < 0.05) for cancer aggressiveness: Gleason-score <7 or >=7 (ISUP grade 1 or >=2) . Concerning pathological tumor stage discrimination and prediction, variables as PHI, PSA, %fPSA, [-2]proPSA, PHI- and PSA-density significantly discriminated between stages =pT3 with the highest AUC (0.7) for PHI. In biochemical recurrence prediction PHI, PSA, [-2]proPSA, PHI- and PSA-density were the strongest predictors. In conclusion, due to heterogeneity of time spans to biochemical recurrence, longer follow up periods are crucial. This study with a median follow up of more than 5 years, confirmed a clinical value for PHI as an independent biomarker essential for biochemical recurrence prediction. PMID- 29108305 TI - CT-guided microwave ablation through the lungs for treating liver tumors near the diaphragm. AB - Purpose: To explore the short-term efficacy and safety of CT-guided microwave ablation (MWA) for treating liver tumors near the diaphragm. Results: The complete response (CR) rate for CT-guided MWA through the lung was 94.7% (124/131). The incomplete response (ICR) rate was 5.3% (7/131), of which 6 patients with ICRs achieved CRs after MWA. The CR rate for Group I was higher than Group II (99.0% vs. 80.0%, P=0.001). The mean follow-up time was 11.2 +/ 7.50 months. The total local recurrence (LR) rate was 15.3% (20/131). The complication rate was 26.5%, and no severe complications were recorded. All complications were controllable and treatable. The incidence of diaphragmatic thickening during the MWA was 18.8% (P>0.05); the incidence of exudative changes inside the lungs was 6.8% (P>0.05). Conclusions: CT-guided MWA can detect changes in liver tissue, in the diaphragm and nearby lung tissues during the ablation process. It's safe and effective to treat tumors close to the diaphragm by CT guided MWA through the lung. Methods: CT-guided MWA was used on 131 tumors that were close to the diaphragm (distance between tumor and diaphragm <= 5 mm) in 117 patients with liver cancer. The tumors were divided into a < 3.0 cm group (Group I, n= 101) and a >= 3.0 cm group (Group II, n= 30) based on tumor diameters. The complications within 2 weeks following treatment were counted, and the safety and short-term efficacy of MWA were analyzed. PMID- 29108307 TI - Association between obesity and trastuzumab-related cardiac toxicity in elderly patients with breast cancer. AB - Purpose: Trastuzumab can improve the prognosis for patients with breast cancer, but its related cardiac toxicity is concerning. This study aimed to identify the risk factors associated with trastuzumab-related cardiac toxicity in elderly patients with HER2-positive breast cancer. Patients and methods: A total of 133 elderly (>= 65 years) patients who were diagnosed with breast cancer between June 1, 2007, and January 31, 2016, and received trastuzumab treatment were retrospectively reviewed. Cardiac events were defined as: (1) LVEF reduction of >10% from baseline echocardiography, (2) reduction of LVEF to <50%, and (3) signs and symptoms of heart failure as defined by the Common Terminology Criteria for Adverse Events (CTCAE) accompanied by a decrease in the LVEF. Univariate and multivariate regression analyses were used to determine the contribution of different clinical variables to trastuzumab-related cardiac events. Results: The median age of the cohort was 71.0 years (range, 65-81 years). The median follow up period for measurement of left ventricular ejection fraction was 11.0 months (range, 2-71 months). Fifteen patients (11.2%) experienced cardiac events during the follow-up. Multivariate regression analysis revealed that obesity (odd ratio[OR], 4.706; 95% CI, 1.984-10.147; P = 0.002) was a statistically significant risk factor associated with cardiac events. Conclusion: Obesity is an independent risk factor for trastuzumab-related cardiac toxicity in elderly patients with breast cancer, receiving trastuzumab. Further studies are needed to establish the independent predictive value of obesity on cardiotoxicity in these patients. PMID- 29108308 TI - A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. AB - ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naive, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months. One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for >12 months remains disease-free after enrolling on this trial following a re-resection. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target engagement, and DRD2 was expressed in all evaluated archival tumor specimens. In summary, ONC201 is well tolerated and may have single agent activity in recurrent glioblastoma patients. PMID- 29108309 TI - Weekly paclitaxel and cisplatin as neoadjuvant chemotherapy with locally advanced breast cancer: a prospective, single arm, phase II study. AB - There was little evidence of weekly cisplatin regimen either for the locally advanced breast cancer or the metastatic setting. We aimed to evaluate that whether the combination of weekly paclitaxel and cisplatin could improve the efficacy of the neoadjuvant treatment for patients with locally advanced breast cancer. Patients with histologically confirmed large operable breast cancer received paclitaxel 80mg/m2 by weekly for 16 weeks and weekly cisplatin 25mg/m2 on day 1, 8 and 15, out of every 28 days for 4-week cycles. Trastuzumab was allowed for HER2-positive disease as weekly continuous regimen. The primary endpoint was locoregional total pathological complete response (tpCR) in breast and axilla lymph nodes after neoadjuvant treatment. One hundred and thirty-one patients were included in the study, among which 34.4% (45/131) patients achieved tpCR. Rate of pathological complete response (pCR) in the breast was 44.3% and the rate of near-pCR in breast was 48.1%. A significantly higher proportion of tpCR was seen in patients with triple negative breast cancer (64.7%, p = 0.003) and HER2 positive (non-luminal) cancer (52.4%, p = 0.018) compared with those who had luminal type tumors (24.7%). At multivariate analysis, negative estrogen receptor and high ki67 level independently predicted a better response. The most frequent toxicities were anemia, leukopenia and peripheral sensory neuropathy. Neoadjuvant chemotherapy by weekly paclitaxel and cisplatin combination was highly effective and tolerated in this study, especially in the triple negative and HER2 positive tumors. PMID- 29108310 TI - Significance of the thrombo-inflammatory status-based novel prognostic score as a useful predictor for in-hospital mortality of patients with type B acute aortic dissection. AB - Background: Inflammation and thrombosis are associated with development and progression of acute aortic dissection (AAD). The aim of this study was to assess the prognostic significance of Simplified Thrombo-Inflammatory Prognostic Score (sTIPS), in patients with early phase type B AAD. Methods: We retrospectively reviewed 491 patients with type B AAD between November 2012 and September 2015. sTIPS was calculated from the white blood cell count (WBC) and mean platelet volume to platelet count (MPV/PC) ratio, at the time of admission. Patients with both, WBC > 10 (109/L) and MPV/PC ratio > 7.5 (102fL/109L-1) were assigned a score of 2, while patients with high levels of either one or none of the above markers, were assigned scores of 1 and 0 respectively. Multivariable Cox regression analyses were used to investigate the associations between the score and hospital survival. Results: Of the 491 type B AAD patients included in this analysis, 24 patients (4.9%) died during hospitalization. Kaplan-Meier analysis revealed that the cumulative mortality was significantly higher in patients with higher sTIPS (P = 0.001). Multivariable Cox regression analysis further indicated that higher sTIPS was a strong predictor of in-hospital mortality after eliminating all confounding factors (sTIPS 2: hazard ratio 4.704, 95%; confidence interval [CI] 1.184-18.685; P = 0.028; sTIPS 1: hazard ratio 1.918, 95%; CI 1.134 3.537; P = 0.045). Conclusions: sTIPS at admission was a useful tool for stratifying the risk in type B AAD patients, for outcomes such as in-hospital mortality in the early phase. PMID- 29108311 TI - Remote ischemic conditioning for the prevention of contrast-induced acute kidney injury in patients undergoing intravascular contrast administration: a meta analysis and trial sequential analysis of 16 randomized controlled trials. AB - Objective: We conducted this meta-analysis to examine the effect of remote ischemic conditioning (RIC) on contrast-induced acute kidney injury (CI-AKI) in patients undergoing intravascular contrast administrationon. Methods: Pubmed, Embase, and Cochrane Library were comprehensively searched to identify all eligible studies by 15th March, 2017. Risk ratio (RR) and weighted mean difference with the corresponding 95% confidence intervals (CI) were used to examine the treatment effect. The heterogeneity and statistical significance were assessed with Q-test and Z-test, respectively. Results: A total of 16 RCTs including 2175 patients were eventually analyzed. Compared with the control group, RIC could significantly decrease the incidence of CI-AKI (RR=0.58; 95% CI: 0.46, 0.74; P < 0.001), which was further confirmed by the trial sequential analysis. Subgroup analyses showed that remote ischemic preconditioning (RIPrC) and remote ischemic postconditioning (RIPoC) were both obviously effective, and perioperative hydration might enhance the efficiency of RIC. RIC also significantly reduced the major adverse cardiovascular events within six months. Conclusion: RIC, whether RIPrC or RIPoC, could effectively exert renoprotective role in intravascular contrast administration and reduce the incidence of relevant adverse events. PMID- 29108312 TI - Tumor necrosis and complete resection has significant impacts on survival in patients with limited-stage upper aerodigestive tract NK/T cell lymphoma. AB - Tumor necrosis (TN) is associated with worse prognosis in several solid cancers. Whether TN predicts poor outcome in natural killer cell / T cell lymphoma (NKTCL) is unclear. We investigated the clinical impact of TN on survival and other novel prognostic parameters in upper aero-digestive tract (UAT) NKTCL of 100 patients with limited stage. TN was significantly associated with poor performance status (p = 0.049), high Korean Prognostic Index score (p = 0.024), high C-reactive protein/albumin ratio (p = 0.003), higher maximum standard uptake value on positron emission tomography/computed tomography (PET/CT) (p = 0.008) and higher metabolic tumor volume (MTV) on PET/CT (p < 0.001). In univariate and multivariate analyses, progression-free survival and overall survival were independently associated with High MTV status (p = 0.001, p = 0.032), TN (p = 0.018, p = 0.009), local tumor invasiveness (p = 0.007, p = 0.035), complete resection (p = 0.020, p = 0.028) and regional lymph node involvement (p < 0.001, p < 0.001). TN and complete resection are concluded to be novel independent prognostic factors in patients with UAT NKTCL. PMID- 29108313 TI - Skeletal abnormalities detected by SPECT is associated with increased relapse risk in pediatric acute lymphoblastic leukemia. AB - Objectives: Most children with acute lymphoblastic leukemia (ALL) exhibit skeletal abnormalities. This study aimed to investigate bone lesions detected by whole-body bone single-photon emission computed tomography (SPECT) and its prognostic value in children with ALL. Methods: A retrospective analysis was performed using whole-body bone SPECT scans obtained from children with ALL in our department between June 2008 and June 2012. A total of 166 children newly diagnosed with ALL were included, and the patients were divided into two groups: patients with positive and negative SPECT scans. We compared the clinical characteristics of the two groups and analyzed the relationship between the skeletal abnormalities detected by SPECT and prognosis. Results: Among the 166 patients, bone scintigraphic abnormalities was detected by SPECT scan in sixty four patients (38.6%). The most common site was the limbs. There were no significant differences in age, gender, WBC count at diagnosis, risk group and minimal residual disease (MRD) level between SPECT-positive patients and their SPECT-negative counterparts. The event-free and overall survival rates were higher in SPECT-positive patients, but the difference was not statistically significant. However, patients with positive SPECT scans, especially those with multifocal abnormalities (>=3 sites), had a higher rate of relapse (P < 0.05). Multivariate analyses identified that abnormal SPECT scan (HR = 3.547, P = 0.015) was an independent relapse risk. Conclusion: Children with ALL and multiple skeletal abnormalities will suffer from relapse. Abnormal SPECT scan was associated with increased relapse risk which might be a potential relapse marker for ALL children. PMID- 29108314 TI - Utility of endoscopic ultrasound-guided fine-needle aspiration of regional lymph nodes that are proximal to and far from the primary distal esophageal carcinoma. AB - Implications of assessing the proximal and far para-tracheal or sub-carinal nodes (para-tracheal [PTN] or sub-carinal [SCN]) associated with lower primary esophageal carcinomas (ECs) are unclear. To evaluate the value of endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) for PTN and SCN, we analyzed results by positron emission tomography (PET) avidity, 4 EUS node malignancy features, and EUS-FNA results in all patients with Siewert's I or II EC. Of 133 patients (PTN, n=102; SCN, n=31) with EUS-FNA, 47 (35%) patients had malignant node, leading to treatment modifications. EUS-FNA diagnosed significantly more patients with malignant nodes (p=0.02) even when PET and EUS features were combined. Among 94 PET-negative and EUS-negative patients, 9 (10%) had malignant EUS-FNA. At a minimum follow-up of 1 year, only 3 (5%) of 62 patients with benign EUS-FNA had evidence of malignancy in the nodal area of prior EUS-FNA. Patients with malignant EUS-FNA independently had a much shorter overall survival (OS) than those with benign EUS-FNA (p<0.001). Our data suggest that a benign EUS-FNA is highly accurate and need not be pursued further. However, malignant EUS-FNA of PTN/SCN was independently prognostic, conferred a shorter OS, and altered the management of 35% of patients. PMID- 29108315 TI - Prognostic value of systemic inflammation score in patients with hepatocellular carcinoma after hepatectomy. AB - Inflammation plays an important role in cancer progression. In this study, we aimed to investigate the prognostic value of the systemic inflammatory biomarkers in hepatocellular carcinoma (HCC) patients undergoing curative resection. Data from 271 HCC patients who underwent curative resection in Zhongshan Hospital between 2008 and 2011 were included. Kaplan-Meier survival analysis showed that gamma-glutamyltransferase (GGT) and lymphocyte-to-monocyte ratio (LMR) were significantly associated with overall survival(OS) and time to recurrence(TTR). We created a systemic inflammation score (SIS) basing on preoperative serum GGT and LMR. Low SIS was also significantly associated with increased OS and TTR. Univariate and multivariate analyses revealed the LMR, GGT and SIS were independent predictors for OS and TTR. The predictive ability of the SIS, as assessed by area under the receiver operating characteristic curve, was 0.682 (95% CI, 0.618-0.746) for OS, which was higher than GGT and LMR. In conclusion, low preoperative LMR and high preoperative GGT were associated with a poor prognosis in HCC patients after hepatectomy. Our results confirmed that the SIS qualifies as a novel prognostic predictor of HCC patients after hepatectomy. PMID- 29108316 TI - Ultrasound guided percutaneous microwave ablation of benign breast lesions. AB - The benign breast lesions (BBLs) share a high incidence for women and therapy methods with minimal invasion and better cosmetic outcome are thirsted for. In this study, 122 patients with 198 biopsy-proved BBLs were enrolled. Ultrasound (US)-guided microwave ablation (MWA) was performed with local anesthesia from November, 2013 to April, 2016. The mean longest tumor size assessed was 1.6+/-0.7 cm (ranging 0.7-4.9 cm). MWA was successfully performed in all cases including 85 lesions adjacent to the skin, pectoralis and areola. The mean ablation time was 3.2mins (ranging 0.5-18.3 mins). 99.5% of BBLs showed complete ablation when assessed by magnetic resonance imaging and 100% of them by US. At the median 14 month follow-up, the BBLs were not palpable in 45.9 % of the cases (palpable in 90.2 % of the cases before MWA) and the mean volume reduction ratio was 78.4+/ 33.5% for total lesions and 89.3+/-20.8%, 84.7+/-27.6% and 55.9+/-32.9% for <=1.0 cm, 1.1-2.0cm and >2.0 cm lesions in 12-month follow-up, respectively. Cosmesis were reported as good or excellent in 100 % by physician and patients. No side effect was found. The MWA of the BBLs proved feasible and effective, while showing meaningful reduction in volume, palpability and cosmetic satisfying outcomes. PMID- 29108318 TI - Intraoperative use of dexmedetomidine promotes postoperative sleep and recovery following radical mastectomy under general anesthesia. AB - Postoperative sleep disturbance and fatigue following radical mastectomy were high risks for prolonged convalescence in patients with breast cancer. The present study was designed to observe the effect of intraoperative use of dexmedetomidine on postoperative sleep, fatigue and recovery following radical mastectomy under general anesthesia. Forty-seven patients were randomized into two groups that were maintained with propofol/remifentanil/Ringer's solution (Control group), or propofol/remifentanil/Dexmedetomidine (DEX group) for surgery under general anesthesia. During the first night following surgery, patients receiving dexmedetomine spent more time sleeping when compared with those form the Control group. During the first week following operation, when compared with the Control group, patients from the DEX group had a higher score of global 40 item recovery questionnaire on day 3 following operation, and lower 9-question fatigue severity scores on day 3 and day 7 following operation. In conclusion, intraoperative use of dexmedetomidine is sufficient to improve postoperative sleep disorder, promote postoperative recovery. The adverse effect of dexmedetomidine on sleep disturbance might be contributed to its recovery promoting effect. PMID- 29108319 TI - Detection of tumor-derived DNA dispersed in the airway improves the diagnostic accuracy of bronchoscopy for lung cancer. AB - The diagnostic accuracy of bronchoscopy for detecting lung cancer, especially peripheral lung cancer with lesions outside the endoscopically visible range, remains unsatisfactory. The aim of this study was to perform next-generation sequencing on bronchoscopic specimens to determine whether this improves the accuracy of bronchoscopy for diagnosing lung cancer and to identify factors influencing sensitivity. The bronchoscopic sensitivity for diagnosing lung cancer was initially evaluated in 191 patients who underwent lobectomy after bronchoscopy at our hospital. Sputum, bronchial wash fluid, and resected lung cancer specimens were subsequently collected from 18 patients with peripheral small cell lung cancer for genomic analysis. DNA was extracted from formalin fixed, paraffin-embedded surgical tissue specimens and the supernatant and cell fractions of sputum and bronchial wash fluid. Deep sequencing was performed using a lung cancer panel covering all exons of 53 lung cancer-related genes. The bronchoscopic sensitivity for diagnosing lung cancer at our hospital was 60.7%. Multivariate analysis revealed that this was influenced by tumor size and location, but not histological type or lymph node metastasis. The sensitivity was the highest for biopsy followed by curettage and bronchial wash specimens. DNA mutations homologous to those identified in the primary lesions were detected in the bronchial wash fluid of 10 patients (55.6%), while only 2 patients (11.1%) were diagnosed with lung cancer based on conventional cytological examinations. In conclusion, the addition of genomic analysis to routine pathological examinations improves the diagnostic accuracy of bronchoscopy. PMID- 29108317 TI - Prognostic value of number of negative lymph node in patients with stage II and IIIa non-small cell lung cancer. AB - Background: The definitive validation evidence of the implications of lymph node metastases regarding the survival of Non-Small Cell Lung Cancer (NSCLC) patients is lacking. We aimed to evaluate the prognostic impact of several lymph node metastases-associated risk factors including Number of Negative Lymph Node (NLN) and risk-stratify NSCLC patients into subsets with different prognosis. Method: A total of 482 patients with N1 and N2 NSCLC were included in this study. The prognostic importance of a set of risk factors was examined by univariate and multivariate analysis. The cut-off points and 5 years survival rates were calculated to test the best grouping system to stratify the patients with difference outcome. Results: Our analysis indicated that both Ratio of the Metastatic Lymph nodes (RML) and Number of Negative Lymph Node (NLN) were associated with overall survival (OS) and disease free survival (DFS). RML percentage 20% and 55%, and NLN counts 10 and 30 were proved as the optimal cut off points to predict OS by classifying patients into 3 groups, respectively. RML and NLN actually are more powerful in predicting survival outcome for male patients compared to female patients. Stratified survival analyses using combined factors indicated that the 5-year survival rate (5-YSR) is high in RML I + NLN I/III subgroup (5-YSR = 57.1% and 43.3%) and low in RML III + NLN II/III subgroup (5-YSR = 0.0 % each). Conclusions: NLN is a strong prognostic factor for OS and DFS of stage II/IIIa NSCLC patients, and provides a useful classification scheme for NSCLC patients when combined with RML. PMID- 29108320 TI - Can we consider discontinuation of hypomethylating agents in patients with myelodysplastic syndrome : a retrospective study from The Korean Society of Hematology AML/MDS Working Party. AB - It is often difficult to continue treatment with hypomethylating agent(HMA) in clinical practice because of problems such as toxicities, poor economics, etc. We compared clinical outcomes of those patients who continued HMA and those who discontinued HMA because of other causes, and evaluated factors associated with survival in those patients who discontinued HMA. Patients were divided into two groups: treatment failure, those who stopped treatment due to disease progression; and discontinuation, those who discontinued treatment because of other causes. The median progression free survival(PFS) was 9.2 months (range 7.7 - 10.7 months) vs 28.9 months (range 22.6 - 35.2) in the treatment failure and discontinuation groups, respectively (P < 0.001). In a multivariate analysis, a lower risk by WPSS was an independent predictive factor for a longer PFS, and a lower risk by WPSS and median number of HMA cycles greater than seven were independent predictive factors for longer overall survival(OS) only in the discontinuation group. Patients who discontinued HMA without disease progression showed a prolonged survival than those who failed HMA treatment. Especially, a lower risk by WPSS and longer duration of HMA treatment may be predictive factors for a longer PFS and OS in patients who discontinued HMA. PMID- 29108321 TI - Association study of inflammatory cytokine and chemokine expression in hand foot and mouth disease. AB - Objective: To determine the relationship of cytokine/chemokine expression with the clinical presentation of hand, foot and mouth disease (HFMD). Results: All cytokine/chemokine levels were higher in severe HFMD patients than in mild HFMD patients or controls (P < 0.01). RANTES, MCP-1, IL-4, IL-12 and IL-18 levels were higher in mild HFMD patients than in the controls (P < 0.05). In severe HFMD, all levels (except IL-8 and IL-4) were higher in patients with encephalitis plus pulmonary edema than in those with encephalitis alone (P < 0.05). All levels (except IL-8) were higher in EV71-positive patients than in EV71-negative patients (P < 0.05). In mild HFMD, all levels (except IL-8 and IL-4) were higher in EV71-positive patients than in EV71-negative patients (P < 0.05). In severe HFMD, only RANTES, IP-10 and IFN-gamma levels were higher in EV71-positive patients than in EV71-negative patients (P < 0.05). In the EV71-negative group, all levels were higher in severe HFMD than in mild HFMD (P < 0.01). In the EV71 positive group, all levels (except IL-8) were higher in severe HFMD than in mild HFMD (P < 0.01). Materials and Methods: This study involved 28 mild HFMD patients, 44 severe HFMD patients and 26 healthy children. Venous blood was tested for cytokines (IL-4, IL-12, IL-18, TNF-alpha, IFN-gamma) and chemokines (IL-8, RANTES, MCP-1, IP-10). Stool samples from the patients were tested for EV71 nucleic acid using reverse transcription polymerase chain reaction. Conclusions: Cytokines/chemokines participate in HFMD pathogenesis, and could have potential value in monitoring disease progression and predicting prognosis. PMID- 29108322 TI - The predictive efficacy of hypoechoic lesion in ultrasound for prostate cancer in Chinese people: five-year experience in a moderated 10-core transperineal prostate biopsy procedure. AB - We aim to investigate the predictive efficacy of hypoechoic lesion for prostate cancer at different levels of serum PSA in the procedure of transrectal ultrasound guided 10-core trans-perineal prostate biopsy (TP-PBx). In this study, we collected clinical parameters involving age, digital rectal examination (DRE), PSA, prostate volume, pathological diagnosis, Gleason score, novel Gleason group, and numbers of positive cores from 856 patients who had elevated level of PSA above 4 ng/ml or susceptible nodule of prostate gland in DRE received the moderated 10-core TP-PBx procedure. There were 481 cases (56.2%) with no visible lesion of hypoechoic nodule in transrectal ultrasound (TRUS) and 375 cases (43.8%) with the hypoechoic lesion. The total cancer detection rate is 45.56%. The predictive efficacy of hypoechoic lesion for prostate cancer varies among different PSA intervals. For PSA groups of 0-4, 4-10, 10-20, 20-100, > 100 ng/ml, the Youden's indexes are 0.3483, 0.3506, 0.3941, 0.2795 and 0.8667, respectively. Besides, the visible lesions are inclined to be detected in patients with higher Gleason score. We concluded that the hypoechoic lesions in TRUS could improve the predictive accuracy for diagnosing prostate cancer and present different predictive efficacy in the respective PSA intervals. Besides, it was probably associated with more aggressive clinical significance. PMID- 29108323 TI - Skeletal muscle depletion predicts survival of patients with advanced biliary tract cancer undergoing palliative chemotherapy. AB - Background: No prior study has investigated the dynamics of body weight with body muscle mass as a prognostic factor in advanced biliary tract cancer (BTC) patients undergoing palliative chemotherapy. We investigated whether low skeletal muscle mass affects survival in patients with BTC, with a co-analysis of body weight loss and body mass index (BMI). Results: By multivariate analysis, low skeletal muscle mass at diagnosis and decreased SMI during chemotherapy (p = 0.008 and p < 0.001, respectively) were poor prognostic factors for overall survival (OS). Subgroup analysis revealed that low skeletal muscle mass patients who were overweight or obese (BMI >= 25 kg/m2) showed worse OS (p < 0.001). Additionally, patients with both decreased BMI and SMI during chemotherapy had worse OS (p < 0.001). Furthermore, patients with decreased SMI had shorter survival regardless of change in BMI. However, for patients with SMI maintained during chemotherapy, decreased BMI had no effect on survival (p = 0.576). Materials and Methods: We consecutively enrolled 524 patients with advanced BTC who received palliative chemotherapy between 2003 and 2013. Total muscle cross sectional area (cm2) at the L3 level assessed by computed tomography was analyzed. We defined low skeletal muscle mass as a skeletal muscle index (SMI) < 48.5 cm2/m2 (men) and < 39.5 cm2/m2 (women) using ROC curves. Conclusions: Low skeletal muscle mass, obesity and muscle depletion during palliative chemotherapy are meaningful prognostic factors in advanced BTC. Considering muscle depletion with weight change could help to more accurately predict prognoses of patients with BTC. PMID- 29108324 TI - Age-adjusted Charlson comorbidity index score as predictor of survival of patients with digestive system cancer who have undergone surgical resection. AB - Comorbidities have considerable effects on survival outcomes. The primary objective of this retrospective study was to examine the association between age adjusted Charlson comorbidity index (ACCI) score and postoperative in-hospital mortality in patients with digestive system cancer who have undergone surgical resection of their cancers. Using electronic hospitalization summary reports, we identified 315,464 patients who had undergone surgery for digestive system cancer in top-rank (Grade 3A) hospitals in China between 2013 and 2015. The Cox proportional hazard regression model was applied to evaluate the effect of ACCI score on postoperative mortality, with adjustments for sex, type of resection, anesthesia methods, and caseload of each healthcare institution. The postoperative in-hospital mortality rate in the study cohort was 1.2% (3,631/315,464). ACCI score had a positive graded association with the risk of postoperative in-hospital mortality for all cancer subtypes. The adjusted HRs for postoperative in-hospital mortality scores >= 6 for esophagus, stomach, colorectum, pancreas, and liver and gallbladder cancer were 2.05 (95% CI: 1.45 2.92), 2.00 (95% CI: 1.60-2.49), 2.54 (95% CI: 2.02-3.21), 2.58 (95% CI: 1.68 3.97), and 4.57 (95% CI: 3.37-6.20), respectively, compared to scores of 0-1. These findings suggested that a high ACCI score is an independent predictor of postoperative in-hospital mortality in Chinese patients with digestive system cancer who have undergone surgical resection. PMID- 29108325 TI - Ratio of positive lymph nodes: The prognostic value in stage IV thyroid cancer. AB - To assess the prognostic value of lymph node ratio (LNR) in patients with stage IV thyroid cancer based on the Surveillance, Epidemiology, and End Results (SEER) database. A total of 4,940 eligible patients were included for the analysis. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to reveal the effect of LNR on overall survival (OS) and disease specific survival (DSS). The optimal cut-off value of LNR for predicting OS and DSS was determined by the time-dependent Receiver Operating Characteristic analysis. By the univariate Cox proportional hazard regression, LNR was significantly associated with OS and DSS in patients with medullary thyroid cancer (MTC), papillary thyroid cancer and anaplastic thyroid cancer (all P < 0.05). With the optimal cut-off value, Kaplan-Meier analysis showed that MTC patients with LNR>=76.5% were significantly associated with poorer OS (log-rank test: P < 0.0001), and LNR>=40.7% were significantly associated with poorer DSS (log-rank test: P < 0.0001). LNR was an independent prognostic factor of poorer survival in MTC patients after adjusting for other variables by multivariable Cox analysis (OS: hazard ratio [HR] = 2.560, 95% confidence interval [CI] 1.690-3.879, P < 0.0001; DSS: HR=2.781, 95% CI 1.582-4.888, P = 0.0004). Our results demonstrated that LNR could predict clinical outcomes in patients with stage IV MTC, and 76.5% was the optimal cut-off value of LNR to predict OS. LNR, as a function of the nodes positive and the nodes examined, could provide suggestions on the postoperative prognosis of patients with stage IV MTC. PMID- 29108326 TI - Serum dickkopf-1 as a clinical and prognostic factor in non-small cell lung cancer patients with bone metastases. AB - Background: The study was designed to evaluate the association between serum dickkopf-1 (DKK1) and non-small cell lung cancer (NSCLC) bone metastases. Materials and Methods: Serum DKK1 levels were quantified in 470 NSCLC patients, 140 with osseous metastases, 178 with extraosseous metastases, and 152 with early stage in complete remission. The Receiver Operating Characteristic (ROC) curve enabled us to identify a threshold value to distinguish patients with bone metastases. Results: Serum DKK1 levels in patients with osseous metastases were significantly higher than in the other 2 groups (P < 0.001). ROC curves showed that the optimum cutoff was 311.8 pg/ml (area under curve 0.791, 95% confidence interval 0.739-0.843, sensitivity 77.1% and specificity 71.4%). Of interest, serum DKK1 correlated with the number of bone lesions (P = 0.042) and associated with the poor survival in NSCLC patients with osseous metastases (P = 0.029). Conclusions: Our data shows that serum DKK1 can be used for the detection of NSCLC bone metastases. More importantly this is the first report to show that serum DKK1 is a good predictor of poor prognosis in NSCLC patients with bone metastases. PMID- 29108327 TI - Evaluation of the branched-chain amino acid-to-tyrosine ratio prior to treatment as a prognostic predictor in patients with liver cirrhosis. AB - This study evaluated whether the branched-chain amino acid-to-tyrosine ratio (BTR) is a prognostic predictive factor in patients with liver cirrhosis by determining the relationship of the BTR with event-free survival in a retrospective, observational cohort study. The medical records of patients with liver cirrhosis who visited our institution from February 2000 to May 2012 were examined. Events due to liver cirrhosis were defined as death, worsening of esophageal and/or gastric varices, hepatocellular carcinoma, and liver failure. The primary endpoint was the period from the date of BTR measurement until the first onset of these events. Event-free survival was compared between patients with BTR >= 4 and BTR < 4. Relationships between the BTR and other factors predicting prognosis were also examined. Event-free survival was evaluated in patients with and without branched-chain amino acid supplementation using propensity score matching. Significantly longer event-free survival was found in liver cirrhosis patients with BTR >= 4 (n = 425) compared with those with BTR < 4 (n = 105), and the BTR was associated with liver cirrhosis events. The BTR showed significant relationships with other predictive factors evaluated. In subcohorts matched by propensity score, branched-chain amino acid supplementation significantly improved event-free survival in patients with BTR <4. The BTR is clinically useful for predicting prognosis in liver cirrhosis patients. BCAA supplementation may be beneficial in those with BTR < 4. PMID- 29108328 TI - MMP-3 gene polymorphisms are associated with increased risk of osteoarthritis in Chinese men. AB - Osteoarthritis (OA) is the most common late-onset degenerative joint disease., It is characterized by progressive degradation of articular cartilage. We investigated the association between OA occurrence and single nucleotide polymorphisms (SNPs) in the matrix metalloproteinase-3 (MMP-3) gene involved in the breakdown of extra-cellular matrix proteins. The study included 100 male OA patients and 197 healthy men from the north area of China. Eight MMP-3 SNPs were genotyped. Odds ratios (ORs) with 95% confidence intervals (95%CIs) and multivariate logistic regression analysis were used to assess the association. Multivariate logistic regression analysis was used to identify SNPs that correlated with OA susceptibility. We found that rs639752 (dominant, OR = 2.03, 95% CI: 1.03-4.01, P = 0.038; over-dominant, OR = 2.00, 95% CI: 1.03-3.88, P = 0.037); rs520540 (dominant, OR = 2.03, 95% CI: 1.03-4.01, P = 0.038; over dominant, OR = 2.00, 95% CI: 1.03-3.88, P = 0.037); rs602128 (dominant, OR = 2.03, 95% CI: 1.03-4.01, P = 0.038; over-dominant, OR = 2.01, 95% CI: 1.03-3.89, P = 0.037); and rs679620 (dominant, OR = 2.03, 95% CI: 1.03-4.01, P = 0.038; over dominant, OR = 2.04, 95% CI: 1.05-3.96, P = 0.033) were associated with the increased risk of OA. Our results suggest that these SNPs may contribute to OA development, and could serve as molecular markers of OA susceptibility. PMID- 29108329 TI - Risk of acute myocardial infarction in upper tract urothelial carcinoma patients receiving radical nephroureterectomy: a population-based cohort study. AB - Background: The outcomes of upper tract urothelial carcinoma (UTUC) receiving radical nephroureterectomy were usually limited to small sample size, case control studies, and often focused on cancer progression. Risk of acute myocardial infarction (AMI) in these patients was never investigated. Results: The overall incidences of AMI were 3.39, 1.44, and 1.70 per 10,000 person-years in the radical nephroureterectomy, nonnephroureterectomy, and non-UTUC cohorts, respectively. Multivariable Cox proportional hazard regression analysis revealed a significantly higher AMI risk in the radical nephroureterectomy cohort [adjusted HR (aHR) = 1.83, 95% confidence interval (CI) = 1.08-3.11], compared with non-UTUC cohorts. The risk of mortality were the highest in patients with UTUC who had undergone radical nephroureterectomy [adjusted HR (aHR) = 5.37, 95% confidence interval (CI) = 4.80-6.02]. Materials and Methods: From the Taiwan National Health Insurance claims data, 1,359 patients with UTUC who had undergone radical nephroureterectomy and 3,154 patients with UTUC who had undergone nephron sparing surgery and were newly diagnosed between 2000 and 2010 were identified. For each patient, 4 individuals without UTUC were randomly selected and frequency matched by age, sex, and diagnosis year. Conclusions: Patients with UTUC who have undergone radical nephroureterectomy are at a higher risk of developing AMI, compared with those receiving nephron sparing surgery. PMID- 29108330 TI - Surgical management for follicular variant of papillary thyroid carcinoma. AB - Background and Aims: For most patients with follicular variant of papillary thyroid carcinoma (FVPTC), surgery is required, while the surgical management remains controversial. We aim to further understanding of treatment of FVPTC and to determine whether specific features could be identified for the decision of surgical strategy. Materials and Methods: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program database during 2003 and 2013. 26700 patients were eligible and stratified by tumor size or extension. Survival rates were compared using multivariate Cox proportional hazard regressions. Results: Of the total death of 1041, 136 patients died from thyroid cancer. Most patients (79.1%) underwent total thyroidectomy while only a little part of patients (8.2%) underwent lobectomy. Patients receiving radioisotopes had significantly better overall survival (OS) (HR = 0.659, P < 0.001), but showed no differences on disease-specific survival (DSS). No statistical difference was found between total thyroidectomy and lobectomy in multivariate analysis when controlling for tumor size. While for tumor > 2 cm with extrathyroidal extension, lobectomy had significantly worse OS (aHR = 3.364, P = 0.010) and DSS (aHR = 5.494, P = 0.032) compared to total thyroidectomy. Multivariate analysis demonstrated that advanced age, male, higher grade, extrathyroidal extension, lymph nodes metastases and distant metastases had negative effects on OS and DSS controlling for the remaining variables (each P < 0.05). Conclusions: The results of our study revealed total thyroidectomy could benefit the survival for patients whose tumors > 2 cm with extrathyroidal extension, total thyroidectomy should be recommended for those patients. Lots of factors should be taken into consideration on the decision of surgical treatment. PMID- 29108331 TI - The role of frontline autologous stem cell transplantation for primary plasma cell leukemia: a retrospective multicenter study (KMM160). AB - Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell neoplasm, with rapidly progressing clinical course. We evaluated the treatment status and survival outcomes of 69 Korean patients with pPCL. Of them, 59 patients were treated; 15 (25.4%) were treated initially with novel agent-based regimens with upfront autologous stem cell transplantation (ASCT), 7 (11.9%) with conventional chemotherapy with upfront ASCT, 21 (35.6%) with novel agent-based regimens only, and 16 (27.1%) were treated with conventional chemotherapy alone. Overall response rates after initial therapy were significantly higher in patients treated with novel agent-based regimens compared with those treated with conventional chemotherapies (75% vs. 43.4%, P = 0.026). Median progression-free survival (PFS) and overall survival (OS) were 12.2 months and 16.1 months, respectively. The median PFS of the four treatment groups-conventional chemotherapy alone, novel agents alone, conventional chemotherapy with ASCT, and novel agents with ASCT-were 1.2, 9.0, 10.5, and 26.4 months, respectively (P < 0.001); the median OS of the four treatment groups were 2.9, 12.3, 14.1, and 31.1 months, respectively (P < 0.001). The median OS was also significantly better in the patients with novel agents with ASCT versus other patients. In a multivariate analysis, an increased lactate dehydrogenase level, low albumin (< 3.5 g/dL), and non-CR after front-line treatment were independently associated with poor PFS and OS. In conclusion, the use of novel agent-based therapy with ASCT and achieving a deep response to front-line treatment are important in expecting improved PFS and OS in patients with pPCL. PMID- 29108332 TI - Whether low-dose metronomic oral cyclophosphamide improves the response to docetaxel in first-line treatment of non-triple-negative metastatic breast cancer. AB - Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. We initiated the single-center, randomized, open-label, phase II study to determine whether the addition of metronomic cyclophosphamide to docetaxel (T) (w/o trastuzumab) improves overall response rate (ORR) as first-line treatment among patients with non-triple-negative metastatic breast cancer (MBC). Eligible patients with previously untreated non-triple-negative MBC were randomly assigned (1:1) to receive 3-weekly cycles of Metro-TC (T 75mg/m2, d1 plus oral cyclophosphamide 50 mg daily) or T alone. All patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR. Finally, 35 patients were randomized to Metro-TC group while 31 to T group. Median treatment cycles of T for both groups were 8. ORR was not improved by addition of metronomic cyclophosphamide to T (71.4% vs. 51.6%; P = 0.09). There was no statistically significant difference with regard to progression free survival (median 18.5 vs. 11.7 months; P = 0.07) or overall survival (median 33.7 vs. 33.6 months; P = 0.84) between the two group. Grade 3/4 adverse events (eg. neutropenia [100% vs. 100%], febrile neutropenia [29% vs. 29%], and neurotoxicity [6% vs. 3%]) were also comparable. There were no treatment-related deaths. We conclude that concomitant administration of metronomic cyclophosphamide and T does not appear to be a significantly active schedule for first-line treatment of non-triple-negative MBC. PMID- 29108333 TI - Impact of pretreatment plasma D-dimer levels and its perioperative change on prognosis in operable esophageal squamous cell carcinoma. AB - The aim of this study was to investigate the relationship between plasma D-dimer levels and its perioperative change and clinicopathological parameters in patients with operable esophageal squamous cell carcinoma (ESCC). We also analyzed their prognostic significance in ESCC patients. The data of 294 ESCC patients between December 2007 and December 2012 in Mingzhou hospital, Ningbo, China were analyzed retrospectively. Plasma D-dimer levels were measured one week before surgery and on the thirtieth postoperative day. The association between plasma D-dimer levels and clinicopathological parameters was evaluated. Kaplan Meier survival analysis and Cox proportional hazards models were used to estimate the effect of plasma D-dimer levels and its perioperative change on disease-free survival (DFS) and overall survival (OS). Plasma D-dimer levels were above 0.5 ug/mL in 148 patients (50.3%). Plasma D-dimer levels were significantly related with DFS (P < 0.001) and OS (P < 0.001) in univariate analysis. There was significant relationship between plasma D-dimer levels and DFS in patients with N0 (P < 0.001) or N+ (P = 0.003). Multivariate analysis revealed that plasma D dimer levels (P < 0.001), sex (P = 0.012), and T stage (P = 0.033) were independent prognostic factors for DFS. Tumor length (P = 0.018), T stage (P = 0.008) and plasma D-dimer levels (P = 0.001) qualified as independent prognostic factors for OS. Our study suggests that pretreatment plasma D-dimer levels is a powerful independent prognostic factor for operable ESCC. Further studies are needed to prospectively validate this prognostic model and investigate the mechanisms underlying the correlation between elevated plasma D-dimer levels and poor prognosis in operable ESCC. PMID- 29108334 TI - Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer. AB - SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m2. Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade >= 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m2 in the dose expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m2 has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer. PMID- 29108336 TI - Prognostic factors influencing the survival of patients with carcinoma of the gastric cardia receiving preoperative interventional embolization chemotherapy. AB - The purpose of this study was to analyze the characteristics of patients with gastric cardia cancer (GCC) to identify the main factors the influence the survival rate after interventional embolization chemotherapy (IEC). One hundred and fifty-six patients with advanced GCC were treated with IEC via the left gastric artery. Survival time was defined as from the date of diagnosis until death or the end of this study in June 2015. The median survival time was 15 months (range 3 to 29 months). The Cox proportional hazard model found that patients' age (p < 0.001), sex (p = 0.039), weight loss more than 10% in the prior 3 months (p = 0.014), body mass index (BMI) (p = 0.047), and hematocrit value less than 37% (p < 0.001) were correlated with mortality after removal of cases of poorly differentiated carcinoma and undifferentiated carcinoma from the analysis. Kaplan-Meier curves of survival according to patients' age showed significant differences by the log-rank test (p = 0.0015). The median survival time was 17 months among patients of aged < 50 years. In conclusion, BMI, weight loss > 10% in the prior 3 months, albumin, and hematocrit were prognostic indicators for patients with advanced GCC, and patients younger than 50 years have a higher survival rate after IEC. PMID- 29108335 TI - A three gene immunohistochemical panel serves as an adjunct to clinical staging of patients with head and neck cancer. AB - Background: Current management of head and neck squamous cell carcinoma (HNSCC) depends on tumor staging. Despite refinements in clinical staging algorithms, outcomes remain unchanged for the last two decades. In this study, we set out to identify a small, clinically applicable molecular panel to aid prognostication of patients with HNSCC. Materials and Methods: Data from The Cancer Genome Atlas (TCGA) was used to derive copy number aberrations and expression changes to identify putative prognostic genes. To account for cross entity relevance of the biomarkers, HNSCC (n = 276), breast (n = 808) and lung cancer (n = 282) datasets were used to identify robust and reproducible markers with prognostic potential. Validation was performed using immunohistochemistry (IHC) on tissue microarrays of an independent cohort of HNSCC (n = 333). Findings: Using GISTIC algorithm together with gene expression analysis, we identified six putative prognostic genes in at least two out of three cancers analyzed, of which four were successfully optimized for automated IHC. Of these, three were successfully validated; each molecular target being significantly prognostic on univariate analysis. Patients were differentially segregated into four prognostic groups based on the number of genes dysregulated (p < 0.001). The IHC panel remained an independent predictor of survival after adjusting for known survival covariates including clinical staging criteria in a multivariate Cox regression model (p < 0.001). . Interpretation: We have identified and validated a clinically applicable IHC biomarker panel that is independently associated with overall survival. This panel is readily applicable, serving as a useful adjunct to current staging systems and provides novel targets for future therapeutic strategies. PMID- 29108337 TI - Elevated hemoglobin glycation index identify non-diabetic individuals at increased risk of kidney dysfunction. AB - Hemoglobin glycation index (HGI), calculated as the difference between the observed value of HbA1 and the predicted HbA1c based on plasma glucose concentration, is a measure of the individual tendency toward non-enzymatic hemoglobin glycation which has been found to be positively associated with nephropathy in subjects with diabetes. In this cross-sectional study we aimed to evaluate whether higher HGI levels are associated with impaired kidney function also among nondiabetic individuals. The study group comprised 1505 White nondiabetic individuals stratified in quartiles according to HGI levels. Estimated glomerular filtration rate (eGFR) was calculated by using the MDRD equation. Individuals in the intermediate and high HGI groups exhibited a worse metabolic phenotype with increased levels of visceral obesity, total cholesterol, triglycerides, inflammatory biomarkers such as hsCRP and white blood cells count and lower values of HDL and insulin sensitivity assessed by Matsuda index in comparison to the lowest quartile of HGI. Subjects in the intermediate and high HGI groups displayed a graded decrease of eGFR levels in comparison with the lowest quartile of HGI. In a logistic regression analysis individuals in the highest quartile of HGI exhibited a significantly 3.6-fold increased risk of having chronic kidney disease (95% CI: 1.13-11.24, P = 0.03) and a significantly 1.6-fold increased risk of having a mildly reduced kidney function (95% CI: 1.19 2.28, P = 0.003) in comparison to individuals in the lowest HGI group. In conclusion HGI may be a useful tool to identify nondiabetic individuals with an increased risk of having kidney dysfunction. PMID- 29108338 TI - Prevalence of prenatally diagnosed congenital cystic adenomatoid malformation among fetuses in China. AB - The prevalence of congenital cystic adenomatoid malformation among fetuses still varies in different studies in China. The present meta-analysis was intended to evaluate the pooled prevalence of fetuses in China. Four English (Pubmed, Elsevier Science Direct, Web of Science and the Cochrane Library) and four Chinese (the Chinese Biological Medical Literature database, the Chinese National Knowledge Infrastructure database, VIP database and Wanfang Data) databases were searched from inception to July 2016. Meta-analyses were performed using Stata (version 12.0), with prevalence and corresponding 95% confidence intervals using the random effect model. Five studies with 393496 fetuses were chosen for this meta-analysis. The overall pooled prevalence was 4.01/10000 (2.03/10000 - 6.00/10000) fetuses. Sensitivity analysis revealed that the results were stable, and Begg's test and Egg's test showed no potential risk of publication bias. This is, to our knowledge, the first study to systematically evaluate the literature of the prevalence of congenital cystic adenomatoid malformation among fetuses in China. Results showed that the prevalence among fetuses should be considerable. A large-scale multicenter study on the epidemiology across different areas in China is required. PMID- 29108339 TI - Consideration of clinicopathologic features improves patient stratification for multimodal treatment of gastric cancer. AB - Preoperative staging of gastric cancer with computed tomography alone exhibits poor diagnostic accuracy, which may lead to improper treatment decisions. We developed novel patient stratification criteria to select appropriate treatments for gastric cancer patients based on preoperative staging and clinicopathologic features. A total of 5352 consecutive patients who underwent gastrectomy for gastric cancer were evaluated. Preoperative stages were determined according to depth of invasion and nodal involvement on computed tomography. Logistic regression analysis was used to identify clinicopathological factors associated with the likelihood of proper patient stratification. The diagnostic accuracies of computed tomography scans for depth of invasion and nodal involvement were 67.1% and 74.1%, respectively. Among clinicopathologic factors, differentiated tumor histology, tumors smaller than 5 cm, and gross appearance of early gastric cancer on endoscopy were shown to be related to a more advanced stage of disease on preoperative computed tomography imaging than actual pathological stage. Additional consideration of undifferentiated histology, tumors larger than 5 cm, and grossly advanced gastric cancer on endoscopy increased the probability of selecting appropriate treatment from 75.5% to 94.4%. The addition of histology, tumor size, and endoscopic findings to preoperative staging improves patient stratification for more appropriate treatment of gastric cancer. PMID- 29108340 TI - Positive Helicobacter pylori status is associated with better overall survival for gastric cancer patients: evidence from case-cohort studies. AB - Helicobacter pylori (H. pylori) infection increases the gastric cancer risk; however, the influences of H. pylori infection status on the outcomes for gastric cancer patients have not yet clearly defined. Herein, we systematically assessed the epidemiological studies regarding the associations between the H.pylori infection status at diagnosis and the prognosis for gastric cancer patients with the meta-analysis methods. Thirty-three eligibility studies with 8,199 participants that had determined the H.pylori infection status and the outcomes for gastric cancer patients were identified through searching the PubMed and MEDLINE databases updated to March 1st, 2017. The random-effects model suggested that positive H. pylori infection was associated with better overall survival with the pooled hazard ratio (HR) was 0.79 [95% confidence interval (CI) = 0.66 0.93; Q = 134.86, df = 32, P-heterogeneity < 0.001; I2 = 76.3%] compared to negative patients. The association was found to be more prominent in studies with higher quality, longer following-up time and more sensitive detection methods. An inverse but not statistically significant association between the H.pylori status and the disease-free survival of the patients (pooled HR = 0.84, 95% CI = 0.61 1.05;Q = 30.48, df = 11, P-heterogeneity = 0.001; I2 = 63.9%) was found, while no significant association was noticed in any subgroup analyses. These results suggested that gastric cancer patients with positive H.pylori infection status at diagnosis have better overall survival compared to negative; however, more studies are warranted to confirm the results and elucidate the underlying mechanisms. PMID- 29108341 TI - Left-sided primary tumor is a favorable prognostic factor for metastatic colorectal cancer patients receiving surgery. AB - Objective: The role of surgery in metastatic colorectal cancer (mCRC) remains controversial. This study was performed to assess the impact of surgery on survival in metastatic colorectal cancer. Materials and Methods: Information of mCRC patients diagnosed between January 1, 2004, and December 31, 2013, was retrieved from the Surveillance, Epidemiology, and End Results Program database. Patients were classified in three groups: patients undergoing resection of both primary and distant metastatic tumors (group 'PMTR'), patients receiving primary tumor resection alone (group 'PTR') and patients not undergoing any surgery (group 'No resection'). Kaplan-Meier method and multivariate Cox proportional hazard regression analysis were applied to estimate disease specific survival time (DSS) and determine prognostic factors. Results: A total of 38,591 mCRC patients were eligible. Overall, median DSS of group 'PMTR' was significantly longer compared with group 'PTR' and group 'No resection' (28.0 vs 21.0 vs 11.0 months, P < 0.001). Stratified analysis observed that primary tumor in left-sided colorectal cancer (LCRC) was a favorable prognostic factor compared with right sided colorectal cancer (RCRC) (median DSS of LCRC: PMTR, 34 months, PTR, 25 months, No resection, 13 months; median DSS of RCRC: PMTR, 20 months, PTR, 16 months, No resection, 8 months; P < 0.001). Multivariate analysis demonstrated that surgery was an independent prognostic factor for better survival (PMTR, HR = 0.403, 95% CI 0.384-0.423, P < 0.001; PTR, HR = 0.515, 95% CI 0.496-0.534, P < 0.001). Furthermore, in patients undergoing surgery, patients with younger age, female, married status, LCRC and lower CEA level were prone to receiving PMTR. Conclusions: This analysis demonstrated that surgery was an independent prognostic factor for improved survival in mCRC. Patients with LCRC had better survival than patients with RCRC after surgery. PMID- 29108342 TI - Comparison of biological target volume metrics based on FDG PET-CT and 4DCT for primary non-small-cell lung cancer. AB - Fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) and four-dimensional CT (4DCT) are used in several methods for defining the biological target volume (BTV) in primary non-small cell lung cancer (NSCLC). Disagreements between the assessments using these methodologies make the use of BTV for radiotherapy planning controversial. In this study, we compared existing methods with our proposed internal biological target volume (IBTV) metric, derived by combining internal target volume (ITV) and BTV metrics. We defined the IBTV from ITV (IBTVi) or BTV (IBTVb) based on ITV or BTV with symmetrical margin expansion. We detected large differences between IBTV, IBTVi and IBTVb (p < 0.001), but no difference between ITV and BTV. A margin expansion of about 13 mm was necessary for ITV or BTV to encompass > 95% IBTV. The conformity index correlated negatively with IBTV/ITV, IBTV/BTV, IBTVi/ITV, and IBTVb/BTV volume ratios (p < 0.05). VR also increased the margins of IBTVi and IBTVb. Indeed, IBTV was much smaller than IBTVi or IBTVb, suggesting that using IBTV for radiotherapy planning could improve treatment by minimizing the radiation exposure of healthy tissue and organs surrounding tumors. PMID- 29108343 TI - Effect of Amygdalus scoparia kernel oil consumption on lipid profile of the patients with dyslipidemia: a randomized, open-label controlled clinical trial. AB - Background: Amygdalus scoparia kernel (ASK) oil is traditionally used for Hyperlipidemia. Compared to olive oil, it has higher proportion of unsaturated to saturated fatty acid besides exhibiting higher index of oxidative stability. The lipid-lowering effects of ASK oil however, has not been investigated yet. This study is the first one to evaluate such effects in patients with dyslipidemia. Results: Serum triglyceride levels significantly decreased in the intervention compared to control group (24.80 +/- 51.70 vs 3.13 +/- 44.80, p-value = 0.03). Serum total cholesterol, LDL and HDL cholesterol levels did not change significantly (p = 0.28 and p = 0.68 and p = 0.10 respectively). Materials and Methods: In a double arm, open-label, randomized controlled trial,101 hyperlipidemic patients were recruited. The designation of hyperlipidemia was upon meeting either of the three criteria: having serum low-density lipoprotein (LDL) cholesterol level 130-190 (mg/dl), serum triglyceride level 150-400 (mg/dl), and serum high-density lipoprotein (HDL) cholesterol level less than 50 (mg/dl) for women and 40 (mg/dl) for men. Patients who have ever been prescribed with an antihyperlipidemic medication were excluded. They were randomly assigned to intervention group, receiving the ASK oil, for 60 days and control group. Serum lipid measurements were repeated at the end of the intervention period. Conclusions: ASK oil supplementation may have a positive effect in reducing serum triglyceride level in patients with dyslipidemia without significant effect on serum cholesterol levels. PMID- 29108344 TI - Diffusion-weighted MR imaging in prediction of response to neoadjuvant chemotherapy in patients with breast cancer. AB - This study aims to evaluate the potential of apparent diffusion coefficient (ADC) derived from diffusion-weighted MR imaging for predicting the treatment response to neoadjuvant chemotherapy (NACT) in patients with breast cancer. Magnetic resonance imaging was performed prior to NACT and after two cycles of NACT. The correlation between mean ADCpre values, mean ADCpost values, changes in ADC values and changes in tumor diameters after NACT was examined using Spearman rank correlation. A total of 164 breast cancers were enrolled in this study. Mean ADCpre values of responders ([0.85 +/- 0.16] * 10-3 mm2/s) and non-responders ([0.84 +/- 0.21] * 10-3 mm2/s) had no significant difference (P = 0.759). While mean ADCpost value of responders was significantly higher than that of non responders ([1.17 +/- 0.37] * 10-3 mm2/s vs. [1.01 +/- 0.28] * 10-3 mm2/s; P = 0.002). Both mean ADCpost values (r = 0.288, P = 0.000) and changes in mean ADC values (r = 0.222, P = 0.004) were positively correlated to changes in tumor diameter after NACT, except for mean ADCpre values (r = 0.031, P = 0.695). Our results indicated that mean ADCpost values and changes in ADC values after NACT might be a biological marker for assessing the efficacy of chemotherapy. PMID- 29108346 TI - Improved survival with higher radiation dose for esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. AB - Purpose: The optimal radiation dose for patients with esophageal squamous cell carcinoma (ESCC) has long been debated. We undertook the retrospective study to evaluate the survival impact of high dose vs standard dose in patients with stage II-III esophageal cancer treated with definitive chemoradiotherapy (CRT). Results: A total of 137 patients were included in our study, 63 patients classified as standard-dose group and 74 as high-dose group. For the 63 patients in the standard-dose group, the median PFS and the 1-, 2-, and 3-year PFS rates were 12.6 months, 58.0%, 26.0% and 12.0%, respectively; for the 74 patients in the high-dose group, they were 20.0 months, 80.1%, 31.0% and 20.0%, respectively (P = 0.013). The median OS of the patients in the standard-dose group and high dose group groups were 19.0 months and 26.6 months, respectively, and the 1-, 2- and 3-year survival rates were 78.0%, 39.0%, and 24.0% , and 89.0%, 61.0%, and 30.0%, respectively (P = 0.037). Besides the rate of grade >= 3 acute irradiation esophagitis in the high-dose group (10.5% versus. 2.2%, P < 0.01), there were no significantly differ of treatment-related toxicities between the two groups. Materials and Methods: According to the radiation dose, patients from 2010 to 2014 were allocated into either the standard-dose group (50-50.4 Gy) or the high dose group (>= 59.4 Gy). Overall survival (OS), progression-free survival (PFS) and treatment-related toxicities were assessed and compared between the two groups. Conclusions: Our findings suggest that higher radiation dose could perform better outcomes for esophageal squamous cell carcinoma patients. PMID- 29108345 TI - MRI-based evaluation of multiorgan iron overload is a predictor of adverse outcomes in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation. AB - The medical records of 44 pediatric patients who underwent allogeneic transplantation from 2011 to 2015 were retrospectively reviewed. Magnetic resonance imaging was used to measure iron concentrations in the liver, spleen, pancreas and bone. These patients were divided into two groups, 18 with non elevated (< 100 MUmol/g; Group 1) liver iron concentration before transplantation and 26 with elevated (> 100 MUmol/g; Group 2) concentration . We compared transplant-related outcomes in the two groups. Iron overload was a negative prognostic risk factor for sinusoidal obstruction syndrome (OR = 17), osteoporosis (OR = 6.8), pancreatic insufficiency (OR = 17) and metabolic syndrome (OR = 15.1). No statistically significant differences in overall survival, disease-free survival, relapse incidence and incidence of acute or chronic graft-versus host disease were observed between the two groups. Mean times to engraftment of platelets (43.0 +/- 35.3 days vs. 22.1 +/- 9.5 days, p < 0.05) and neutrophils (23.1 +/- 10.4 days vs. 17.8 +/- 4.6 days, p < 0.05) appear significantly longer in Group 2 than in Group 1. Time to platelet engraftment showed statistically significant correlation with pre-transplant liver (r = 0.5775; p < 0.001) and bone iron concentration (r = 0.7305; p < 0.001). Post transplant evaluation pointed out that iron concentration analyzed at the first follow-up peaked in all tissues. The iron accumulation was highest in bone, followed by the spleen, liver and pancreas. One year post transplant 9 of 18 (50%) patients in Group 1 and 6 of 22 (27%) in Group 2 presented with bone and/or spleen iron overload, but not with liver overload. Liver iron concentration is not always a reliable indicator of systemic siderosis or of the efficacy of chelation therapy. PMID- 29108347 TI - Mammography and ultrasound effective features in differentiating basal-like and normal-like subtypes of triple negative breast cancer. AB - The aim of our study was to find effective features of mammography and ultrasound in differentiating Basal-like breast cancer (BBC) and Normal-like breast cancer (NBC), two subtypes of triple negative breast cancer (TNBC). From January 2014 to March 2017, we retrospectively reviewed 91 patients who were pathologically confirmed as TNBC. According to immunohistochemical cytokeratin 5/6 (CK5/6) and Epidermal Growth Factor Receptor (EGFR), TNBCs were classified into BBCs group and NBCs group. Both CK5/6 and EGFR were negative defined to be NBC, whereas if any of CK5/6 or EGFR was positive then defined as BBC. BBCs group concluded 65 (71.4%) cases and NBCs group concluded26 (28.6%) cases. Ultrasound images and mammograms were reevaluated by breast imaging experts according to the breast imaging reporting and data system (BI-RADS) 4th edition. On mammography, masses margins had significant differences between BBCs group and NBCs group (P = 0.024). Most BBCs margins exhibited microlobulated (30/64, 46.9%) or spiculated (25/64, 39.0%), whereas most NBCs margins exhibited microlobulated (17/23, 73.9%). On ultrasound, BBCs were more frequently to present as larger than 20mm lesions (52/65, 80.0%) and more likely to have angular or spiculated margins (35/65, 53.8%), additionally, compared with NBCs, BBCs were less likely to have calcification (1/65, 1.5%). Other mammography and ultrasound features showed no significant differences between the two groups. In conclusion, we have found some effective features of mammography and ultrasound that could be helpful in differentiating BBC and NBC, which will provide some useful references for clinical diagnosis and treatment. PMID- 29108348 TI - Decreased risk of dementia in migraine patients with traditional Chinese medicine use: a population-based cohort study. AB - Patients with migraine are reportedly at increased risk of developing dementia. We aimed to investigate the association between traditional Chinese medicine (TCM) use and dementia risk in migraine patients. This longitudinal cohort study used the Taiwanese National Health Insurance Research Database to identify 32,386 diagnosed migraine patients aged 20 years and above who received treatment from 1997 to 2010. To balance comparability between TCM users and non-TCM users, we randomly selected equal numbers from each group, and compared subgroups compiled based on combinations of age, sex, index year, and year of migraine diagnosis. All enrollees received follow-up until the end of 2013 to measure dementia incidence. We identified 1,402 TCM users and non-TCM users after frequency matching. A total of 134 subjects were newly diagnosed with dementia during the follow-up period. TCM users were significantly less likely to develop dementia than non-TCM users. The most frequently prescribed formulae and single Chinese herbal products were Jia-Wei-Xiao-Yao-San and Yan-Hu-Suo, respectively. This population-based study revealed a decreased dementia risk in migraine patients with TCM use. These findings may provide a reference for dementia prevention strategies, and help integrate TCM into clinical intervention programs that provide a favorable prognosis for migraine patients. PMID- 29108349 TI - Excessive daytime sleepiness and metabolic syndrome in men with obstructive sleep apnea: a large cross-sectional study. AB - Purpose: Excessive daytime sleepiness is a common symptom in obstructive sleep apnea (OSA). Previous studies have showed that excessive daytime sleepiness is associated with some individual components of metabolic syndrome. We performed a large cross-sectional study to explore the relationship between excessive daytime sleepiness and metabolic syndrome in male OSA patients. Methods: A total of 2241 suspected male OSA patients were consecutively recruited from 2007 to 2013. Subjective daytime sleepiness was assessed using the Epworth sleepiness scale. Anthropometric, metabolic, and polysomnographic parameters were measured. Metabolic score was used to evaluate the severity of metabolic syndrome. Results: Among the male OSA patients, most metabolic parameters varied by excessive daytime sleepiness. In the severe group, male OSA patients with excessive daytime sleepiness were more obese, with higher blood pressure, more severe insulin resistance and dyslipidemia than non-sleepy patients. Patients with metabolic syndrome also had a higher prevalence of excessive daytime sleepiness and scored higher on the Epworth sleepiness scale. Excessive daytime sleepiness was independently associated with an increased risk of metabolic syndrome (odds ratio =1.242, 95% confidence interval: 1.019-1.512). No substantial interaction was observed between excessive daytime sleepiness and OSA/ obesity. Conclusions: Excessive daytime sleepiness was related to metabolic disorders and independently associated with an increased risk of metabolic syndrome in men with OSA. Excessive daytime sleepiness should be taken into consideration for OSA patients, as it may be a simple and useful clinical indicator for evaluating the risk of metabolic syndrome. PMID- 29108350 TI - Endostar in combination with postoperative adjuvant chemotherapy prolongs the disease free survival of stage IIIA NSCLC patients with high VEGF expression. AB - Purpose: The aim of this study is to compare the therapeutic effect between endostar plus adjuvant chemotherapy and adjuvant chemotherapy alone in the patients with completely resected non-small cell lung cancer (NSCLC) at stage IB to IIIA. Experimental Design: This is an open, multicenter, randomized (1:1) study with 250 NSCLC patients. Completely resected NSCLC patients at stages IB to IIIA were randomized to receive adjuvant NP plus endostar (Vinorelbine 25 mg/m2 on day 1 and day 8 plus Cisplatin 75 mg/m2 on day 1, and plus endostar 7.5 mg/m2 per day iv for consecutive 14 days) or NP regimen alone. Every 21 days were set as one cycle for 4 cycles. The primary endpoint was disease-free survival (DFS). Secondary endpoints included tumor response rate, overall survival and safety. Results: The two groups had no significant difference in the incidence of toxicity reaction. Endostar plus NP prolonged the DFS of patients with completely resected NSCLC at stage IIIA (19.33+/-3.73 vs 17.10+/-9.68 months) but with no statistical difference compared to NP alone. In the endostar plus NP group, those cases with high expression of vascular endothelial growth factor (VEGF) showed a significantly better DFS than those with low VEGF expression (48.45+/-3.52 vs 40.18+/-4.54 months, P<0.05). Conclusions: Vascular targeted therapy with endostar plus NP prolongs the DFS of patients with complete resectable NSCLC in stage IIIA and significantly extends the DFS of NSCLC patients with high VEGF expression, but does not show benefits in OS for stage IB-IIIA. PMID- 29108351 TI - Generating a robust prediction model for stage I lung adenocarcinoma recurrence after surgical resection. AB - Lung cancer mortality remains high even after successful resection. Adjuvant treatment benefits stage II and III patients, but not stage I patients, and most studies fail to predict recurrence in stage I patients. Our study included 211 lung adenocarcinoma patients (stages I-IIIA; 81% stage I) who received curative resections at Taipei Veterans General Hospital between January 2001 and December 2012. We generated a prediction model using 153 samples, with validation using an additional 58 clinical outcome-blinded samples. Gene expression profiles were generated using formalin-fixed, paraffin-embedded tissue samples and microarrays. Data analysis was performed using a supervised clustering method. The prediction model generated from mixed stage samples successfully separated patients at high vs. low risk for recurrence. The validation tests hazard ratio (HR = 4.38) was similar to that of the training tests (HR = 4.53), indicating a robust training process. Our prediction model successfully distinguished high- from low-risk stage IA and IB patients, with a difference in 5-year disease-free survival between high- and low-risk patients of 42% for stage IA and 45% for stage IB (p < 0.05). We present a novel and effective model for identifying lung adenocarcinoma patients at high risk for recurrence who may benefit from adjuvant therapy. Our prediction performance of the difference in disease free survival between high risk and low risk groups demonstrates more than two fold improvement over earlier published results. PMID- 29108352 TI - Preoperative neutrophil-to-lymphocyte ratio and tumor-related factors to predict microvascular invasion in patients with hepatocellular carcinoma. AB - Small hepatocellular carcinoma (HCC) is less invasive and has a better prognosis, but it still has a high recurrence rate. Microvascular invasion (MVI), as a poor prognostic indicator, is of great importance for treating of patients with HCC. The objective of the present study was to evaluate the predictive value of preoperative neutrophil-to-lymphocyte ratio and possible clinical parameters to MVI in patients with HCC. A total of 157 operable patients with HCC having a tumor diameter of less than or equal to 5 cm were enrolled in this study. The utility of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and other clinical parameters was evaluated using receiver operating characteristic curves. MVI was identified as an independent influencing factor for disease-free survival in patients with HCC who underwent curative resection, using the multivariate Cox proportional hazards regression model. The independent parameters associated with MVI were determined using logistic analysis. Multivariate analyses indicated that the neutrophil-to-lymphocyte ratio [hazard ratio, 1.705; 95% confidence interval, 0.467-6.232; P = 0.022)], platelet-to lymphocyte ratio (hazard ratio, 1.048; 95% confidence interval, 1.006-1.092; P = 0.025), and a-fetoprotein (hazard ratio, 1.012; 95% confidence interval, 1.003 1.021; P = 0.007) were significantly associated with MVI independently. Therefore, this study concluded that the preoperative neutrophil-to-lymphocyte ratio and a-fetoprotein might serve as useful biomarkers for predicting MVI in patients with HCC. PMID- 29108353 TI - Evaluation of real-world treatment outcomes in patients with distant metastatic Merkel cell carcinoma following second-line chemotherapy in Europe. AB - Background and aims: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer; few treatments exist for patients with advanced disease. Once tumors metastasize to distant sites, patients generally receive chemotherapy, but response duration and progression-free survival (PFS) are typically short. Few studies have assessed the efficacy of second-line chemotherapy for metastatic MCC. Here, we studied outcomes in patients who received >= 2 lines of chemotherapy for metastatic MCC. Materials and methods: Patients in an MCC specific registry diagnosed with stage IV MCC between November 1, 2004, and September 15, 2015, and treated with second-line or later chemotherapy were analyzed retrospectively. Patient records, including baseline characteristics, immunocompetent status, and responses to prior chemotherapy, were evaluated. Patients meeting eligibility criteria were followed through December 31, 2015. Results: Of 29 patients with metastatic MCC and immunocompetent status who had received >= 2 lines of chemotherapy, 3 achieved a partial response, for an objective response rate (ORR) of 10.3% (95% CI, 2.2-27.4). In the overall population including patients with immunocompetent and immunocompromised status (n = 34), the ORR was 8.8% (95% CI, 1.9-23.7). The median duration of response was 1.9 months (range, 1.3-2.1 months; 95% CI, 1.3-2.1). In the immunocompetent population, median PFS and overall survival were 3.0 months (95% CI, 2.5-6.0) and 5.3 months (95% CI, 4.3-6.0), respectively. Conclusions: The low response rates and limited durability confirm previous reports of the ineffectiveness of second line or later chemotherapy in patients with metastatic MCC and provide a benchmark for assessing clinical benefit of new treatments. PMID- 29108354 TI - Ultrasound-guided percutaneous microwave ablation assisted by three-dimensional visualization operative treatment planning system and percutaneous transhepatic cholangial drainage with intraductal chilled saline perfusion for larger hepatic hilum hepatocellular (D >= 3 cm): preliminary results. AB - : To assess the clinical efficiency of ultrasound-guided percutaneous microwave ablation (US-PMWA) assisted by three-dimensional (3D) visualization operative treatment planning system and percutaneous transhepatic cholangial drainage with intraductal chilled saline perfusion (PTCD-ICSP) for larger hepatic hilum hepatocellular carcinoma (HH-HCC) (D >= 3 cm). The combination therapy was performed in 14 patients from Sep 2011 to May 2017. The major outcomes for assessment were biliary duct complications, local tumor recurrence, distant recurrence and overall survival rates. Median follow-up period was 26 months. The series of 3D visualization operative treatment planning, PTCD-ICSP and US-PMWA were successfully performed and complete ablation was achieved in all cases. The mean session for one tumor was 1.0 +/- 0.4. The mean ablation time for per tumor was 1805 +/- 567s. The saline volume used for the PTCD-ICSP was 250-450 ml per session. The 1-, 2-, and 3-year local tumor recurrence rates were 7.1%, 14.3%, and 35.7%, the 1-, 2-, and 3-year distant recurrence rates were 0%, 14.3%, and 28.6%, and 1-, 2-, and 3-year overall survival rates were 100%, 92.9%, and 71.4%, respectively. No severe complications related to ablation occurred. Conclusions: US-PMWA assisted by 3D visualization operative treatment planning system and PTCD ICSP appears to be a safe, effective and innovative technique for management for larger HH-HCCs, which improved the prognosis. PMID- 29108356 TI - Radiotherapy for T3N0 glottic carcinoma without cord fixation: elective nodal irradiation or not? AB - Background: Although the T3 category has been changed in the sixth edition of the TNM staging system proposed by the Union for International Cancer Control (UICC), the appropriate clinical target volume (CTV) of elective nodal irradiation (ENI) for T3N0 glottic carcinoma without cord fixation, which was formerly treated as a T1-2N0 disease, is not fully discussed. Materials and Methods: We retrospectively analyzed 64 patients staged or restaged as T3N0 disease without cord fixation. All patients received irradiation to the primary lesion alone using opposed lateral fields. Surgery was performed in 10 patients without tumor regression after the delivery of 40 Gy. The other 54 patients received a median total dose of 66 Gy. Concurrent chemoradiotherapy (CRT) with low-dose cisplatin and UFT (low dose CRT) and docetaxel, cisplatin, and 5-fluorouracil (TPF-CRT) were performed in 23 and 19 patients, respectively. Results: Eighteen (28.1%) patients suffered treatment failure; all were recorded as local failure alone. The 5-year local control rates for RT alone, low-dose CRT, and TPF-CRT groups were 51.7%, 61.6%, and 93.8%, respectively (p = 0.027). The 5-year laryngeal preservation rates for RT alone, low-dose CRT, and TPF-CRT groups were 57.4%, 81.6%, and 89.5%, respectively (p = 0.048). Conclusions: The rate of regional failure was zero when irradiating the primary lesion alone using opposed lateral fields. This treatment technique covers the most level III regions; hence, CTV for ENI should include level III alone. PMID- 29108355 TI - A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. AB - Background: This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. Materials and Methods: Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment. Pharmacokinetic (PK) analysis of 5-FU and oxaliplatin was performed at the MTD in an expanded 6 patient cohort. Results: Twenty-six patients were enrolled and assessed for safety. In the dose-escalation phase, no DLTs were noted in all binimetinib dosing schedules and the MTD of binimetinib in with FOLFOX was 45 mg orally twice daily. There were no significant differences in the PKs of 5-FU or oxaliplatin with or without binimetinib. Continuous dosing of binimetinib produced SD at 2 months in 9 of 13 evaluable patients and a median PFS of 3.5 months. Nine of 10 patients had PD at 2 months on the intermittent arm. Conclusions: Oral binimetinib and FOLFOX has a manageable toxicity profile and showed some evidence of antitumor activity in heavily pretreated mCRC patients. PMID- 29108357 TI - Influence of angiographic spontaneous coronary reperfusion on long-term prognosis in patients with ST-segment elevation myocardial infarction. AB - Objective: To explore the influence of angiographic spontaneous coronary reperfusion (SR) on the short- and long-term outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Materials and Methods: Consecutive patients diagnosed as STEMI and undergoing emergent coronary angiography from January 2009 to August 2010 in a single center were enrolled. Patients whose initial coronary blood flow met Thrombolysis in Myocardial Infarction (TIMI) grade 3 were regarded as angiographic SR. Others (TIMI grade < 3) were included into the NSR group and subsequently underwent primary percutaneous coronary intervention (PCI). Patients' characteristics and outcomes were compared. Results: A total of 207 patients were eligible for analysis. The coincidence rate of patients both with >= 70% ST-segment resolution and >= 70% relief of chest pain and SR was 100%. Patients in the SR group (n = 38) were younger, had more smokers, with higher level of platelet count, lower blood glucose and uric acid, and more distal culprit lesions, as compared to the NSR group (n = 169). Importantly, patients in the SR group had lower rates of in-hospital events (0 vs. 22.5%, p < 0.001) with less stents placed (1.03 +/- 1.05 vs. 1.59 +/- 1.17, p = 0.007). Moreover, there were comparable long-term outcomes (2.6% vs. 6.9%, p = 0.302) between the two groups during 41-month follow ups. Conclusions: Angiographic SR is associated with significantly favorable short-term outcomes. PMID- 29108358 TI - Mid-arm muscle circumference as a surrogate in predicting insulin resistance in non-obese elderly individuals. AB - The homeostatic model assessment of insulin resistance (HOMA-IR) was used to measure the degree of insulin resistance (IR). Previous literature revealed that mid-arm muscle circumference (MAMC) is one of the anthropometric indicators for nutritional status and the relationship between MAMC and HOMA-IR remains uncertain in the obese and non-obese elderly individuals. The present study included 5,607 participants aged between 60 to 84 years old, using data from the 1999 to 2006 National Health and Nutrition Examination Survey (NHANES). To further explore the association between HOMA-IR and MAMC in the obese and non obese elderly population using multivariate Cox regression analyses, we divided the participants into obese (BMI >= 30 kg/m2) group and non-obese (19 <= BMI < 30 kg/m2) group in this study; each group was then divided into quartiles based on their MAMC levels. A positive association was noted between the MAMC and HOMA-IR in all of the designed models initially. After adjusting for multiple covariates, a higher level of the MAMC was significantly associated with elevated HOMA-IR (P < 0.05) in the non-obesity group, which was not the case in the obesity group. Additionally, subjects in the higher quartiles of MAMC tended to have higher HOMA IR with a significant association (P for trend = 0.003 in model 1; P for trend < 0.001 in model 2, 3, and 4). These results demonstrated that the MAMC can be an auxiliary indicator of HOMA-IR in non-obese elderly individuals and may have substantial additional value in screening for IR if well extrapolated. PMID- 29108359 TI - Surgical resection of primary tumor improves survival of pancreatic neuroendocrine tumor with liver metastases. AB - This study investigates survival of patients diagnosed with pancreatic neuroendocrine tumor with liver metastases based on local treatment on the primary tumor. Patients diagnosed with stage IV PNET between 2010 and 2014 were identified from the Surveillance Epidemiology and End Results database. Cancer Specific Survival and Overall Survival were examined. A total of 191 patients with pancreatic neuroendocrine tumor with liver metastases were included in this analysis. There were 47 patients (24.6%) who received surgical resection and 144 (75.4%) who did not. Patients with N1 stage was more likely to be treated with surgical resection. The results showed that surgical resection of primary tumor was associated with Cancer-Specific Survival (p = 0.028) and Overall Survival (p = 0.025) benefit. Not receiving surgery, being unmarried and N1 stage are factors associated with poor survival. This study reveals that local treatment on the primary benefits both Cancer-Specific Survival and Overall Survival in PNET patients with LM. This may be suggestive for the management on this patient population. PMID- 29108360 TI - Prediction of radio-responsiveness with immune-profiling in patients with rectal cancer. AB - We evaluate whether the tumor immune infiltrate (TIL) could be used for prediction of responsiveness to preoperative chemoradiotherapy (PCRT) in rectal cancers. Using formalin-fixed paraffin-embedded slides of pretreatment biopsies, co-stain for CD4, CD8, CD274 (PD-L1), FOXP3, cytokeratin, and DAPI was performed with Opal multi staining kit (Perkin-Elmer, Waltham, MA). Multispectral imaging and digital analysis to visualize and quantify specific immune infiltrates were performed using the Vectra imaging system (Perkin-Elmer). The density (number of cells per mm2) and proportion of total TILs and specific cell types in the stroma were calculated by inFormTM 2.2.1 software (Perkin-Elmer). The density and proportion of total TILs and specific cell types in the stroma were calculated by inFormTM 2.2.1 software (Perkin-Elmer, Waltham, MA). Patients were classified as group with total regression (TR, n = 25) and group with residual disease (near total, moderate, and minimal regression, RD, n = 50). The mean density of T cell infiltration and CD274 (PD-L1)+ lymphocyte were significantly higher in TR (p = 0.005, p = 0.001). The proportion of CD4+ lymphocyte (p=0.042) and CD274 (PD-L1)+ lymphocyte (p = 0.002) were different between 2 groups. The TR group has lower CD4+ and higher CD274 (PD-L1)+ proportions than RD group. The ratio among CD4+, CD8+, CD274 (PD-L1)+, FOXP3+ T cell was different between groups. TR group showed lower CD4/ CD274 (PD-L1) (p = 0.007), CD8/ CD274 (PD-L1) (p = 0.02), and FOXP3/ CD274 (PD-L1) (p = 0.003) ratio than RD group. The determination of the immune infiltrate in biopsies before treatment could be a valuable information for the prediction of responsiveness to PCRT. PMID- 29108361 TI - Loneliness and its impact on quality of life in Chinese heroin-dependent patients receiving methadone maintenance treatment. AB - To date, no studies have examined loneliness in Chinese patients with substance use disorders. This study determined the prevalence and socio-demographic and clinical correlates of loneliness and its impact on quality of life (QOL) in Chinese heroin-dependent patients (HDPs) receiving methadone maintenance treatment (MMT). A total of 603 HDPs were consecutively recruited from three city owned MMT clinics in Wuhan, China, and administered with a standardized questionnaire to collect socio-demographic and clinical data. Loneliness and QOL were assessed with a single-item self-report question and World Health Organization QOL Scale Brief Version, respectively. As high as 55.9% Chinese HDPs of MMT clinics endorsed loneliness. Multiple logistic regression found that non married status, unemployment, religious beliefs, a history of injecting heroin, poor interpersonal relationship, and more depressive symptoms were significant contributors to loneliness. Lonely HDPs had significantly poorer physical and psychological QOL than not lonely HDPs. After controlling for the potential confounding effects of socio-demographic and clinical factors with analysis of covariance, these group-differences in physical (F = 127.169, P < 0.001) and psychological (F = 85.004, P < 0.001) QOL remained statistically significant. Loneliness is prevalent in HDPs receiving MMT and independently associated with poor QOL. To address this serious issue, psychosocial services, including the identification of psychosocial problems, expanded social supports that focus on promoting mental wellbeing, and, when necessary, psychiatric assessment and treatment, should be routinely provided in Chinese MMT settings. PMID- 29108362 TI - Baseline relative eosinophil count as a predictive biomarker for ipilimumab treatment in advanced melanoma. AB - As diverse therapeutic options are now available for advanced melanoma patients, predictive markers that may assist treatment decision are needed. A model based on baseline serum lactate dehydrogenase (LDH), peripheral blood relative lymphocyte counts (RLC) and eosinophil counts (REC) and pattern of distant metastasis, has been recently proposed for pembrolizumab-treated patients. Here, we applied this model to advanced melanoma patients receiving chemotherapy (n = 116) or anti-CTLA-4 therapy (n = 128). Visceral involvement, LDH and RLC were associated with prognosis regardless of treatment. Instead, when compared to chemotherapy-treated patients with REC < 1.5%, those with REC >= 1.5% had improved overall survival when receiving anti-CTLA-4 [Hazard Ratio (HR) = 0.56 (0.4-0.93)] but not chemotherapy [HR = 1.13, (0.74-1.74)], and the treatment-by REC interaction was significant for both overall (p = 0.04) and progression free survival (p = 0.009). These results indicate baseline REC >= 1.5% as a candidate predictive biomarker for benefit from anti-CTLA-4. Further studies are needed to confirm these findings in patients receiving immune-modulating agents. PMID- 29108363 TI - The degree of hepatic arterial blood supply of portal vein tumor thrombus in patients with hepatocellular carcinoma and its impact on overall survival after transarterial chemoembolization. AB - Purpose: To investigate the degree of arterial blood supply of portal vein tumor thrombus (PVTT) in patients with hepatocellular carcinoma (HCC), and to evaluate its impact on overall survival after transarterial chemoembolization using lipiodol +/- gelatin sponge particles (TACE). Results: Of the 10 patients who underwent surgery, the number of patients with good/mild/poor staining of PVTT by methylene blue were 3, 4, and 3, respectively. The degrees of methylene blue staining in these patients correlated well with the degrees of accumulation of lipiodol in PVTT in these patients, i.e. good/mild/poor in 3, 4, and 3 patients, respectively. For the 77 patients who underwent TACE as treatment, they were divided into 2 groups: good accumulation of lipiodol (n = 27) and mild/poor accumulation of lipiodol (n = 50) on CT. The overall median survival between the 2 groups was 10.0 months vs 2.7 months, (p < 0.001). Multi-variable analysis showed degree accumulation of Lipiodol (OR, 2.057; 95% CI,1.414-2.993; p < 0.001) to be an independent prognostic factor. Patients and Methods: Patients with HCC with PVTT who underwent surgical resection received preoperative TACE. At operation, arterial injection of methylene blue into the common hepatic artery was carried out. During the study period, other patients with unresectable HCC with PVTT were treated with TACE. Conclusion: In about 1/3 of patients with HCC with PVTT, the arterial blood supply from the hepatic artery to the PVTT was good. These patients responded better to TACE than those patients with mild/poor arterial supply. PMID- 29108364 TI - The impact of post-radioiodine therapy SPECT/CT on early risk stratification in differentiated thyroid cancer; a bi-institutional study. AB - Objective: SPECT/CT has numerous advantages over planar and traditional SPECT images. The aim of this study was to evaluate the role of post-radioiodine therapy SPECT/CT of patients with differentiated thyroid cancer (DTC) in early risk classification and in prediction of late prognosis. Patients and methods: 323 consecutive patients were investigated after their first radioiodine treatment (1100-3700 MBq). Both whole body scan and SPECT/CT images of the head, neck, chest and abdomen regions were taken 4-6 days after radioiodine therapy. Patients were re-evaluated 9-12 months later as well as at the end of follow up (median 37 months). Results: Post-radioiodine therapy SPECT/CT showed metastases in 22% of patients. Lymph node, lung and bone metastases were detected in 61, 13 and 5 patients, respectively, resulting in early reclassification of 115 cases (36%). No evidence of disease was found in 251 cases at 9-12 months after radioiodine treatment and 269 patients at the end of follow-up. To predict residual disease at the end of follow-up, the sensitivities, specificities and diagnostic accuracies of the current risk classification systems and SPECT/CT were: ATA: 77%, 47% and 53%; ETA: 70%, 62% and 64%; SPECT/CT: 61%, 88% and 83%, respectively. There was no difference between cohorts of the two institutions when data were analyzed separately. Conclusions: Based on our bi-institutional experience, the accuracy of post-radioiodine SPECT/CT outweighs that of the currently used ATA and ETA risk classification systems in the prediction of long term outcome of DTC. PMID- 29108365 TI - A 3-year observation of testosterone deficiency in Chinese patients with chronic heart failure. AB - Testosterone deficiency is present in a certain proportion men with chronic heart failure (CHF). Low testosterone levels in American and European patients with CHF lead to the high mortality and readmission rates. Interestingly, this relationship has not been studied in Chinese patients. To this end, 167 Chinese men with CHF underwent clinical and laboratory evaluations associated with determinations of testosterone levels. Total testosterone (TT) levels and sex hormone-binding globulin were measured by chemiluminescence or immunoassays assays and free testosterone (FT) levels were calculated, Based upon results from these assays, patients were divided into either a low testosterone (LT; n = 93) or normal testosterone (NT; n = 74) group. Subsequently, records from each patient were reviewed over a follow-up duration of at least 3 years. Patients in the LT group experienced worse cardiac function and a higher prevalence of etiology (ischemic vs. no ischemic) and comorbidity (both P < 0.05). In addition, readmission rates of patients in the LT group were higher than that of patients in the NT group (3.32 +/- 1.66 VS 1.57 +/- 0.89). Overall, deficiencies in FT levels were accompanied with increased mortalities (HR = 6.301, 95% CI 3.187 12.459, P < .0001). PMID- 29108366 TI - Neural correlates of childhood trauma with executive function in young healthy adults. AB - The aim of this study was to investigate the relationship among childhood trauma, executive impairments, and altered resting-state brain function in young healthy adults. Twenty four subjects with childhood trauma and 24 age- and gender-matched subjects without childhood trauma were recruited. Executive function was assessed by a series of validated test procedures. Localized brain activity was evaluated by fractional amplitude of low frequency fluctuation (fALFF) method and compared between two groups. Areas with altered fALFF were further selected as seeds in subsequent functional connectivity analysis. Correlations of fALFF and connectivity values with severity of childhood trauma and executive dysfunction were analyzed as well. Subjects with childhood trauma exhibited impaired executive function as assessed by Wisconsin Card Sorting Test and Stroop Color Word Test. Traumatic individuals also showed increased fALFF in the right precuneus and decreased fALFF in the right superior temporal gyrus. Significant correlations of specific childhood trauma severity with executive dysfunction and fALFF value in the right precuneus were found in the whole sample. In addition, individuals with childhood trauma also exhibited diminished precuneus-based connectivity in default mode network with left ventromedial prefrontal cortex, left orbitofrontal cortex, and right cerebellum. Decreased default mode network connectivity was also associated with childhood trauma severity and executive dysfunction. The present findings suggest that childhood trauma is associated with executive deficits and aberrant default mode network functions even in healthy adults. Moreover, this study demonstrates that executive dysfunction is related to disrupted default mode network connectivity. PMID- 29108367 TI - Comparison on efficacy of radical prostatectomy versus external beam radiotherapy for the treatment of localized prostate cancer. AB - Since there was no consensus on treatment options of localized prostate cancer, a meta-analysis was performed to compare the efficacy of radical prostatectomy (RP) versus external beam radiotherapy (EBRT) concluding three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (IMRT). The search of eligible studies was performed on PubMed and Embase databases. The overall survival (OS), cancer-specific survival (CSS) and biochemical disease-free survival (BDFS) were compared by hazard ratio (HR) and odd ratios (OR). Twelve studies with 17137 patients were included. The pooled HR and 95% CI for OS, CSS and BDFS were 1.60 (1.44-1.79), 1.73 (1.34-2.24) and 0.65 (0.51-0.82), respectively. However, according to risk stratification, the HRs of CSS for low- to intermediate-risk patients were not significant. The 5-year and 10-year CSS reported significant OR and 95% CI of 1.96 (1.42-2.72) and 2.44 (1.33-4.48), except for 2-year CSS (P = 0.42). In conclusion, RP was generally associated with decreased risk of overall and cancer-specific mortality as well as better 5-year and 10-year OS and CSS. The EBRT was suggested to be a promising alternative option for low- to intermediate-risk patients. Large-scale prospective studies with risk stratification and adequate follow-up length were needed for further comprehensive comparison. PMID- 29108368 TI - Phase I clinical trial of the base excision repair inhibitor methoxyamine in combination with fludarabine for patients with advanced hematologic malignancies. AB - Purpose: We determined the safety, pharmacokinetics, pharmacodynamics and recommended phase II dose of the base excision repair blocker methoxyamine combined with fludarabine. Materials and Methods: This was a phase I study with intravenous fludarabine (25 mg/m2, days 1-5), and methoxyamine (15 mg/m2-120 mg/m2, once). A maximum of six cycles were given. Adult patients with relapsed/refractory hematologic malignancies, excluding acute myeloid leukemia, were eligible. Results: Twenty patients were treated; diagnoses included CLL/SLL (n = 10), follicular lymphoma (n = 3), DLBCL (n = 3), mantle cell lymphoma (n = 1), anaplastic large cell lymphoma (n = 1) and plasma cell myeloma (n = 2). No DLTs were observed and dose escalation reached the maximum planned dose. Hematologic toxicity was frequent; most common grade 3-4 toxicities were lymphopenia (70%), neutropenia (60%), leukopenia (50%) and anemia (40%). Four patients achieved a partial remission and 8 achieved stable disease. The drug combination resulted in increased DNA damage measured with the Comet assay. Conclusions: Methoxyamine combined with fludarabine was safe and well tolerated. Hematologic toxicity was comparable to single agent fludarabine. Activity appears to correlate with increased levels of DNA damage. Further studies will examine use of this combination of as part conditioning regimens of stem cell transplant and use of methoxyamine as fludarabine dose-sparing agent. PMID- 29108369 TI - Nephroureterectomy increase 5 year survival in patients on dialysis with upper urinary tract urothelial carcinoma. AB - Background: There is a high incidence rate of upper tract urothelial carcinoma (UTUC) in patients on dialysis. However, the studies about nephroureterectomy (NU) in this high surgical risk group are limited. The aim of this study is to investigate the outcomes of NU in this population. Results: There were total 931 patients enrolled and 218, 582, 131 patients were non-NU, unilateral and one stage bilateral NU, respectively. NU provided better 5-year overall survival (66% versus 51% in non-NU, P = 0.001). 19.7% of patients with unilateral NU had successive contralateral NU with a mean interval period of 695 days. Even for the elderly, there were no significant difference in duration of hospitalization, 30- and 90-day mortality between unilateral and bilateral NU. Materials and Methods: Patients on dialysis with UTUC between January 1998 and December 2012 were assessed from the nationwide cohort of Taiwan National Health Insurance Research Database. We classified these patients into non-NU and NU groups. In NU group, we analyzed clinical outcomes of patient groups between different NU types and surgical methods. Conclusions: Although the high surgical risk in patients on dialysis with UTUC, NU provided better 5-year overall survival. One-stage bilateral NU both provides comparable safety profile and avoids 19.7% of successive contralateral NU in less than two years. Even in the elderly, one stage bilateral NU is safe and feasible. PMID- 29108371 TI - Clinical value and indication for the dissection of lymph nodes posterior to the right recurrent laryngeal nerve in papillary thyroid carcinoma. AB - Lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) are common sites of nodal recurrence after the resection of papillary thyroid carcinoma (PTC). However, the indication for LN-prRLN dissection remains debatable. We therefore studied the relationships between LN-prRLN metastasis and the clinicopathological characteristics in 306 patients with right or bilateral PTC who underwent LN-prRLN dissection. We found that LN-prRLN metastasis occurred in 16.67% of PTC and was associated with a number of the clinicopathological features. The receiver-operator characteristic (ROC) analysis showed that the areas under the ROC curves for the prediction of LN-prRLN metastasis by the risk factors age < 35.5 years, right tumor size > 0.85 cm, lymph node (right cervical central VI-1) number > 1.5, metastatic lymph node (right cervical central VI-1) size > 0.45 cm, and lymph node number in the right cervical lateral compartment > 0.5 were 0.601, 0.815, 0.813, 0.725, and 0.743, respectively. In conclusion, the risk factors for LN-prRLN metastasis in patients suffering right thyroid lobe or bilateral PTC include age <= 35.5 years, right tumor size >= 0.85 cm, capsular invasion, metastatic lymph node (right cervical central VI-1) number >= 2, metastatic lymph node (right cervical central VI-1) size >= 0.45 cm, and metastatic lymph node number in the right cervical lateral compartment >= 1. In patients whose risk factors can be identified pre-operatively or intraoperatively, the dissection of LN-pr-RLN should be considered during right cervical central compartment dissection. PMID- 29108372 TI - Aberrant patterns of brain cerebral blood flow in Chinese han first-episode drug naive depressive patients with and without a family history of depression. AB - A positive family history plays a key role in the brain pathology of depression patients and previous research has confirmed that disturbed mood maintenance may be related to abnormal regional cerebral blood flow (rCBF). However, little is known about whether the rCBF is different between depression patients with and without family histories. To address this question, we examined the rCBF in drug naive, first-episode depression patients with and without family histories of depression using a 3D pseudo-continuous arterial spin-labelling technique. We found that decreased rCBF was predominantly observed in the patients without family histories, while decreased and increased rCBF co-existed in patients with family histories. The observed brain regions with altered rCBF were associated with affection processing, such as the prefrontal, occipital and insular areas. However the patterns of rCBF alteration observed in the present study were different from those found in previous studies where patients were compared with healthy controls. Our present findings, together with the findings from previous studies have prompted the need of a long-term follow-up study to characterize the brain features of the developmental trajectory of depression and investigate the targets for precise, personalized treatments. PMID- 29108370 TI - Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study. AB - Background: In cancer patients, malnutrition is associated with treatment toxicity, complications, reduced physical functioning, and decreased survival. The Prevalence of Malnutrition in Oncology (PreMiO) study identified malnutrition or its risk among cancer patients making their first medical oncology visit. Innovatively, oncologists, not nutritionists, evaluated the nutritional status of the patients in this study. Methods: PreMiO was a prospective, observational study conducted at 22 medical oncology centers across Italy. For inclusion, adult patients (>18 years) had a solid tumor diagnosis, were treatment-naive, and had a life expectancy >3 months. Malnutrition was identified by the Mini Nutritional Assessment (MNA), appetite status with a visual analog scale (VAS), and appetite loss with a modified version of Anorexia-Cachexia Subscale (AC/S-12) of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT). Findings: Of patients enrolled (N=1,952), 51% had nutritional impairment; 9% were overtly malnourished, and 43% were at risk for malnutrition. Severity of malnutrition was positively correlated with the stage of cancer. Over 40% of patients were experiencing anorexia, as reported in the VAS and FAACT questionnaire. During the prior six months, 64% of patients lost weight (1-10 kg). Interpretation: Malnutrition, anorexia, and weight loss are common in cancer patients, even at their first visit to a medical oncology center. PMID- 29108373 TI - Conditional survival estimate in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy with/without concurrent radiotherapy. AB - Conditional survival (CS) provides a prognosis of patients who have already survived several years after treatment. We investigated CS in Barcelona Clinic Liver Cancer (BCLC) stage B/C hepatocellular carcinoma (HCC) patients treated with hepatic arterial infusion chemotherapy (HAIC) with or without concurrent radiotherapy (CRT). A total of 181 patients diagnosed with HCC who were treated with HAIC with or without CRT between 2011 and 2015 were retrospectively reviewed. Overall survival (OS) and CS were calculated and a subgroup analysis was performed. The 1- and 5-year survival rates of all patients were 57.0% and 24.3%. OS was significantly higher in patients with BCLC stage B than BCLC stage C patients. Patients who achieved disease control after treatment also showed longer OS than who did not respond to treatment. Provided that the patient had already survived for 0, 1, 2, and 3 years, the CS estimates of surviving an additional 2 years were 35.6%, 55.1%, 82.0%, and 77.4%, respectively. A subgroup analysis was performed to compare BCLC stage B and C patients and revealed that CS has a tendency to increase and the difference in CS between two groups decreased over time. CS reflects the change of prognosis over time and may provide a more accurate prognosis and hopeful message to patients who have already survived with treatment. PMID- 29108374 TI - Long-term postoperative survival prediction in patients with colorectal liver metastasis. AB - Numerous factors affect the prognosis of colorectal liver metastasis (CRLM) patients after hepatic resection. We investigated several factors related to overall survival in patients with CRLM to identify those most likely to benefit from hepatic resection, and produced a rational tumor biology score system. Three hundred CRLM patients treated with preoperative chemotherapy followed by hepatic resection between 2006 and 2016 were enrolled in our study. Clinicopathologic and long-term survival data were collected and assessed. Patient 1-, 3-, and 5-year overall survival rates were 92.7%, 58.3%, and 45.8%, respectively, while 1-, 3-, and 5-year disease-free survival rates were 44.7%, 28.6%, and 24.2%, respectively. Multivariate Cox regression analysis revealed poor preoperative chemotherapy response, Fong clinical risk score > 2, and KRAS mutation to be independent prognostic indicators in CRLM patients. As part of a preoperative staging system in which one point was assigned for each factor, a total score (out of 3) was predictive of long-term survival following surgery. These factors facilitate personalized prognostic assessments in CRLM patients planning for resection. PMID- 29108375 TI - Association between postoperative hyponatremia and renal prognosis in major urologic surgery. AB - Recent evidence for the clinical significance of postoperative hyponatremia after urologic surgeries remains scarce. We examined the incidence, risk factors, and outcomes of electrolyte imbalance in urologic surgery. Patients with newly developed hyponatremia, defined as a sodium level lower than 135 mEq/L within 7 days after surgery, were included in our study group. The primary outcome was progression to end-stage renal disease (ESRD). Secondary outcome was composition of progression to ESRD and creatinine doubling/eGFR halving from baseline. A survival analysis with a multivariable Cox proportional hazard model was performed. We included 9,206 cases of bladder, prostate, ureter, and kidney surgery. Incidence of new-onset postoperative hyponatremia was 15.4% (1,414/9,206). Postoperative hyponatremia mostly developed in patients with high risk perioperative characteristics. The development of postoperative hyponatremia was independently associated with progression to ESRD (adjusted HR 1.343, 95% CI 1.082-1.680, P = 0.007). The secondary outcome was also related to the electrolyte imbalance in prostate (adjusted HR 1.729, 95% CI 1.145-2.612, P = 0.009) and kidney (adjusted HR 1.339, 95% CI 1.099-1.632, P = 0.004) surgery. Postoperative hyponatremia in urologic surgery was a common electrolyte imbalance in patients with high-risk perioperative status, and associated with worse renal prognosis. PMID- 29108376 TI - Pain of methadone-maintained heroin addicts: lonelier individuals feel more intense pain. AB - Managing pain in patients with heroin addiction is challenging, because most pain medications are addictive. A promising way to relieve pain of heroin addicts is to identify and address modifiable psychosocial factors associated with pain. This study examined the association between loneliness and pain intensity in Chinese heroin addicts receiving methadone maintenance treatment (MMT). A consecutive sample of 603 heroin addicts were recruited from three MMT clinics in Wuhan, China. Loneliness was assessed with a single question, and socio demographic and clinical data were collected with a standardized questionnaire. Pain intensity was assessed with the five-point Verbal Rating Scale. Multiple ordinary logistic regression was used to control for potential confounders that may bias the loneliness-pain relationship. There was a significant and positive correlation between pain intensity and loneliness scores among methadone maintained heroin addicts (r = 0.453, P < 0.001). After controlling for potential socio-demographic and clinical confounders, an increase in the level of loneliness was significantly associated with an increase in pain intensity (OR = 1.22, P = 0.042). Loneliness is significantly associated with pain of methadone maintained heroin addicts. Psychosocial interventions aimed at reducing loneliness might prevent or reduce pain of patients receiving MMT. PMID- 29108377 TI - Comparing the efficacy of induction-concurrent with concurrent-adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma: a propensity score matching analysis. AB - Purpose: This study aimed to compare the efficacy of induction-concurrent (IC CCRT) with concurrent-adjuvant (CCRT-AC) chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated by intensity modulated radiotherapy (IMRT). Materials and Methods: Data on 834 patients with newly diagnosed, non-metastatic stage III-IVA (except T3N0) NPC receiving either IC-CCRT or CCRT-AC between July, 2004 and December, 2014 were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between IC-CCRT and CCRT-AC were compared. Results: The median follow-up duration is 45.2 months (range, 1.07-145.4 months). Overall, 309 pairs were selected by PSM. Univariate analysis revealed the CCRT-AC group achieved significantly higher 3-year DFS (83.9% vs. 78.7 %; P = 0.014) and OS (87.6% vs. 87.0%; P = 0.031). Multivariate analysis also identified treatment group (IC-CCRT vs. CCRT-AC) as an independent prognostic factor for 3-year DFS (HR, 1.546; 95% CI, 1.113-2.149; P = 0.009) and OS (HR, 1.487; 95% CI, 1.035-2.136; P = 0.032). Subgroup analysis revealed IC-CCRT was a protective factor for DMFS (HR, 0.145; 95% CI, 0.043 0.488; P = 0.002) in stage III disease; however, it could adversely affected DFS (HR, 2.009; 95% CI, 1.316-3.065; P = 0.001), OS (HR, 1.671; 95% CI, 1.060-2.636; P = 0.027) and DMFS (HR, 1.986; 95% CI, 1.155-3.416; P = 0.013) in stage IVA disease. Conclusions: CCRT-AC may be a more effective treatment modality in patients with stage IVA NPC disease, while IC-CCRT was superior in stage III disease. PMID- 29108378 TI - Preoperative risk factors for massive blood loss in adrenalectomy for pheochromocytoma. AB - Background: This retrospective analysis of patients who underwent adrenalectomy for pheochromocytoma aimed to determine preoperative risk factors for intraoperative massive blood loss. Preoperative identification of patients at high-risk of massive blood loss may be helpful in anesthesia management and preoperative preparation. Materials and Methods: The study involved data of 268 patients who had undergone pheochromocytoma surgery at the Peking Union Medical College Hospital between January 1, 2013 and October 31, 2016. For analysis, the patients were grouped according to intraoperative blood loss: >= 20% of estimated blood volume (group A, n = 38) and < 20% of estimated blood volume (group B, n = 230). Perioperative characteristics were compared between the two groups. Significant variables were selected for a forward stepwise binary logistic regression analysis to determine the independent risk factors for massive blood loss. Results: The two groups showed significant differences in tumor location, tumor size, operative approach, preoperative 24-hour urine level of total noradrenaline, preoperative hemoglobin concentration, phenoxybenzamine maximum daily dose, preoperative preparation time, intraoperative urine volume, crystalloid and colloidal fluid volumes, allogeneic red blood cell transfusion, plasma and autologous blood transfusion volumes, incidence of prolonged hypotension, postoperative drainage volume, lowest and discharge hemoglobin concentrations, length of stay in intensive care unit and length of postoperative hospitalization. Binary logistic regression analysis indicated increased risk of intraoperative massive blood loss in subjects with tumors proximal to vessels or other organs (odds ratio (OR): 4.227), with tumors >= 5 cm (OR: 7.321), or with preoperative preparation time of <= 14 days (OR: 17.747). Conclusions: Tumors proximal to vessels and other organs or with maximum diameter of >= 5 cm (as shown by preoperative radiographic evidence), and preoperative preparation time of <= 14 days were independent risk factors of intraoperative massive blood loss in patients treated with adrenalectomy for pheochromocytoma. PMID- 29108379 TI - Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion. AB - Purpose: Limited studies have compared the efficacy of postoperative adjuvant therapies in HCC patients with microvascular invasion (MVI). In this study we assess the efficacy of postoperative adjuvant conservative therapy (CT), trans catheter arterial chemoembolization (TACE) and radiotherapy (RT) in HCC patients with MVI. Results: Kaplan-Meier survival analysis revealed that patients in the RT group have significantly improved RFS (RT vs TACE: p = 0.011; RT vs CT: p < 0.001) and OS (RT vs. TACE: p = 0.034; RT vs CT: P < 0.001) compared to TACE and CT groups. Further, subgroup analysis based on the degree of MVI and surgical margin width showed that patients with narrow surgical margin have significantly longer RFS and OS after adjuvant RT than the TACE and CT, independent of degree of MVI. Multivariate analysis indicated that MVI classification is the independent prognostic factor associated with RFS and OS. Materials and Methods: Between July 2008 and December 2015, 136 HCC patients with MVI were divided into three groups according to their adjuvant therapies. Survival outcomes namely relapse-free survival (RFS) and overall survival (OS) of the three groups were analyzed. Conclusions: Adjuvant radiotherapy following hepatectomy could result in better survival outcomes for HCC patients with MVI than TACE or CT. PMID- 29108380 TI - Peri-treatment change of anorectal function in patients with rectal cancer after preoperative chemoradiotherapy. AB - Preoperative chemoradiotherapy (PCRT) is a standard treatment for locally advanced rectal cancer. The influence of PCRT on anorectal function has not been objectively assessed. We evaluated the short-term influence of PCRT on anorectal function in patients with locally advanced rectal cancer using anorectal manometry. We included 310 patients with locally advanced mid and lower rectal cancer who underwent PCRT from 2012 to 2015. We compared anorectal function based on anorectal manometry between before and after PCRT according to tumor location, clinical T (cT) stage, and tumor response after PCRT. Lower rectal cancer was common in the cohort of 310 patients (n = 228, 73.5%). Sphincter length (p = 0.003) and maximal resting pressure (p < 0.001) increased and maximal tolerated volume (p = 0.036) decreased after PCRT regardless of tumor location. Maximal squeezing pressure and rectal compliance slightly decreased, without statistical significance. Changes in manometric parameters after PCRT were not associated with changes of cT stage after PCRT. However, minimal sensory volume (p = 0.042) and maximal tolerated volume (p = 0.025) increased significantly in 143 patients (46.1%) with changes in the distance of the cancer from the anal verge after PCRT. PCRT did not impair the overall short-term anorectal manometric parameters in patients with locally advanced rectal cancer. Further study is required to investigate postoperative anorectal function after sphincter-preserving surgery to evaluate the long-term effects of PCRT on anorectal function. PMID- 29108381 TI - Long-term prognosis of Guillain-Barre syndrome not determined by treatment options? AB - Background: The long-term follow-up system for Guillain-Barre syndrome (GBS) is not well established worldwide. In our study, the preliminary data of the long term prognosis of GBS are collected to explore the prognosis of GBS and the effect of intravenous immunoglobulin (IVIg) treatment. Methods: The follow-up data of 186 patients with GBS admitted from 2003 to 2013 were collected in 2015 via phone interview. The GBS disability scale score was ranked by clinician to evaluate the long-term prognosis. The clinical data during the acute phase were also collected. Results: The mortality rates were 2.15%, 5.45% and 7.89% at discharge, 2-5 years and 6-10 years after disease, respectively. The GBS disability scale score improved dramatically from discharge to 2-12 years after the acute phase. The self-limitation, the spontaneous recovery of disease, occurred both at acute phase and 2-5 years after discharge. Comparisons between IVIg-treated patients and GBS patients who only received supportive care revealed no significant difference of long-term prognosis. Conclusion: The long-term prognosis of GBS appears not to be influenced by treatment options. The long-term improvement of IVIg treated-patients might be due to the self-limitation of GBS per se instead of the IVIg treatment. PMID- 29108382 TI - Clinicopathologic features and prognostic factors for patients with colorectal cancer who are 75 years and older. AB - Colorectal cancer (CRC) is common and can be considered as a disease of older adults. About one half of the cases were diagnosed in patients over 70 years of age. Decision-making about treatment for these older patients can be complicated by age-related physiological changes, impaired functional status, limited social support, and comorbidities. Many trials excluded patients using an upper limit of 75 years of age. Little is known about prognostic factors in patients who are over this age limit. In this study, we conducted an analysis in the Surveillance, Epidemiology and End Results (SEER) database to identify specific clinicopathologic features and prognostic factors for these vulnerable cancer patients (N= 293,616). They were predominantly female and had more stage I and II diseases in comparison to younger patients. On average, these patients had lower 5-year cause-specific mortality than younger patients (41.98% vs. 63.14%, P<0.001). Gender, marital status, ethnicity, Tumor-Node-Metastasis stage, grade, histologic subtype, tumor size, status of surgery and radiotherapy were all independent prognostic factors for these elderly CRC patients. In particular, surgery could improve prognosis for all CRC patients with the exception of those who are older than 94 years old and with stage III disease. The identified clinicopathologic features and prognostic factor will help guide treatment decision-making for this oldest old subset of patients with CRC. PMID- 29108383 TI - Prospective evaluation of skin toxicities in patients receiving post-mastectomy irradiation of chest wall, supra/infraclavicular and internal mammary nodes delivered by conventional versus intensity-modulated radiotherapy technique. AB - Background: To determine whether IMRT could decrease skin toxicities in patients undergoing PMRT of chest wall, supra/infraclavicular (SCV), and internal mammary nodes (IMN) as compared to conventional technique. Materials and Methods: Between 2009 and 2013, 106 patients treated with IMRT and 138 treated with conventional technique were followed up regularly. The skin toxicities were graded according to the CTCAE v4.0 issued by the NCI, and compared between groups. Results: Grade 3 radiation dermatitis occurred in 49 patients (35.5%) in the conventional group and 14 (13.2%) in the IMRT group, and the difference was statistically significant (p < 0.001), favoring IMRT. Moist desquamation at the area associated with adjacent fields' junctions or overlaps was observed in 35 patients (71.4%) in the conventional group and none in the IMRT group (p = 0.023). Grade 2 telangiectasia occurred in 32 patients (23.1%) in the conventional group and 9 (8.5%) in the IMRT group; this difference was statistically significant (p = 0.002), in favor of IMRT as well. Telangiectasias at the sub-sites associated with adjacent fields' junctions or overlaps were observed in 26 patients (81.2%) in the conventional group and none in the IMRT group (p < 0.001). Further, 21 in the conventional group, who had initial moist desquamation at the sub-sites associated with adjacent fields' overlaps or junctions, subsequently developed skin telangiectasias at the identical sub-sites. Conclusions: IMRT-based post mastectomy irradiation of chest wall, SCV and IMN might decrease the occurrence of initial moist desquamation as well as subsequent telangiectasia at the subsites associated with adjacent fields' junctions or overlaps as compared to conventional technique. PMID- 29108384 TI - Efficacy, safety and proper dose analysis of PEGylated granulocyte colony stimulating factor as support for dose-dense adjuvant chemotherapy in node positive Chinese breast cancer patients. AB - For high-risk breast cancer patients with positive axillary lymph nodes, dose dense every-two-week epirubicin/cyclophosphamide-paclitaxel (ddEC-P) regimen is the optimal postoperative adjuvant therapy. However, this regimen is limited by the grade 3/4 neutropenia and febrile neutropenia (FN). There is an urgent need to explore the efficacy, safety and proper dosage of PEGylated granulocyte colony stimulating factor (PEG-G-CSF) as support for ddEC-P in Chinese breast cancer patients with positive axillary lymph nodes. Prospectively, 40 women with stage IIIA to IIIC breast cancer received ddEC-P +/- trastuzumab as adjuvant treatment. PEG-G-CSF was injected subcutaneously in a dose of 6 mg or 3 mg on the 2th day of each treatment cycle. With administration of PEG-G-CSF, all of the 40 patients completed 8 cycles of ddEC-P +/- trastuzumab regimen without dose reductions or treatment delays. Moreover, no FN cases were observed. Further analysis showed that the proper dosage of PEG-G-CSF was 6 mg for ddEC treatment, and 3 mg for ddP treatment. PEG-G-CSF exhibits advantages compared with G-CSF in convenient of administration and tolerance for high risk Chinese breast cancer patients. More importantly, the proper dose of PEG-G-CSF for high risk Chinese breast cancer patients during ddEC-P chemotherapy may be 6 mg for ddEC treatment and 3 mg for ddP treatment. PMID- 29108385 TI - Short- and long-term outcomes of laparoscopy-assisted versus open total gastrectomy for gastric cancer: a propensity score-matched analysis. AB - Background: Few studies have been designed to evaluate the short- and long-term outcomes of laparoscopy-assisted total gastrectomy (LATG), and a retrospective study of a large patient cohort is valuable before conducting randomized controlled clinical trials. Results: Among all patients, age, tumor location, histologic type, pT stage, pN stage and pTNM stage significantly differed between the LATG group and OTG group. After the propensity score matching, the clinicopathological characteristics did not significantly differ between groups. The operation time, estimated blood loss, time to first flatus and the number of retrieved lymph nodes (P < 0.05) were better in the LATG group than the OTG group. Morbidity and mortality were lower in the LATG group than the OTG group (P < 0.05) for pre-matched patients. However, significant intergroup differences in morbidity were not identified after propensity matching. Although overall survival did not significantly differ between groups for the pre-matched patients, the 3-year cumulative survival rates were significantly lower in the LATG group (89.9%) than the OTG group (97.7%) for patients with stage I disease (P = 0.028). After propensity score matching, the analysis of the cumulative survival curve did not show a significant difference for any cancer stage. Materials and Methods: We prospectively collected data from 1096 patients who underwent total gastrectomy for gastric cancer. Propensity score matching was applied to compare the covariates between the LATG group and the open total gastrectomy (OTG) group. Operative outcomes and long-term outcomes were compared between the two groups. Conclusions: Implementation of LATG for gastric cancer is a safe, reliable and minimally invasive procedure with long-term outcomes similar to those of OTG. Further randomized controlled clinical trials can be conducted to provide valuable evidence of the safety and efficacy of LATG in treating gastric cancer. PMID- 29108386 TI - Single nucleotide polymorphisms in MLH1 predict poor prognosis of hepatocellular carcinoma in a Chinese population. AB - Hepatocellular carcinoma (HCC) is a malignant cancer causing deleterious health effect worldwide, especially in China. So far clinical cure rate and long-term survival rate of HCC remains low. Most HCC patients after cancer resection have recurrence or metastasis within 5 years. This study aims to explore the genetic association of mutL homolog 1 (MLH1) polymorphisms with HCC risk and prognosis. Four candidate MLH1 polymorphisms, rs1800734, rs10849, rs3774343 and rs1540354 were studied from a hospital-based case-control study including 1,036 cases (HCC patients) and 1,036 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. However, only rs1800734 had significant difference between cases and controls. Compared to the AA genotype, patients with AG, GG and AG/GG genotype of rs1800734 had an increased risk of HCC [ORs (95% CI) = 1.217 (1.074~1.536), 1.745 (1.301~2.591) and 1.291 (1.126~1.687)] and a decreased survival time [co-dominant, HR (95% CI) = 1.553 (1.257~1.920); dominant, HR (95% CI) = 2.207 (1.572~3.100)]. Furthermore, we found that tumor number, tumor staging, metastasis and rs1800734 were associated with the overall survival of HCC patients by multivariate COX regression analysis. No significant difference was found between the other three MLH1 polymorphisms with HCC risk and prognosis. Our study suggests MLH1 SNP, rs1800734 as a new predictor for poor prognosis of HCC patients. PMID- 29108387 TI - A preoperative scoring system to predict the risk of No.10 lymph node metastasis for advanced upper gastric cancer: a large case report based on a single-center study. AB - Purpose: To investigate upper stomach carcinoma risk factors for No. 10 lymph node (LN) metastasis, and establish a preoperative scoring system to predict No.10 LN metastasis. Method: Between January 2011 and December 2014, we prospectively collected and retrospectively analyzed the data of 398 patients with upper-third gastric cancer (GC) who underwent laparoscopic spleen-preserving hilar lymph-node dissection (SHLND). We use the logistics regression analysis risk factors of No. 10 LN metastasis to establish and verify a scoring model. Result: Among the 398 patients examined, 38 patients had No. 10 LN metastasis, yielding a 9.6% transfer rate. The preoperative risk factor analysis for No. 10 LN metastasis in the modeling group showed that tumor size, preoperative T staging, and preoperative N staging are independent risk factors. To establish a scoring system, we divided the modeling group of patients into three levels: low risk, intermediate risk, and high risk. The No. 10 LN metastasis rates of the low risk, intermediate risk and high risk groups were 2.84%, 13.9% and 34.9% respectively, with statistically significant (P < 0.001). The value for the area under the ROC curve of the scoring system was 0.820, and there were no statistically significant differences between the observed and predicted incidence rates for No. 10 LN metastasis in the validation set (P > 0.05). Conclusion: The scoring system comprising the tumor size, preoperative T stage and N stage is a simple and effective method to predict the risk of No. 10 LN metastasis and to preoperatively select cases suitable for laparoscopic spleen preserving SHLND. PMID- 29108388 TI - The impact of delayed commencement of adjuvant chemotherapy (eight or more weeks) on survival in stage II and III colon cancer: a national population-based cohort study. AB - Background: To examine the impact of chemotherapy delay on survival in patients with stage II or III colon cancer and the factors associated with the delay (>=8 weeks) of adjuvant chemotherapy. Methods: Patients undergoing curative resection and adjuvant chemotherapy in a national population-based cohort were included. Results: Among 5355 patients, 154 (2.9%) received chemotherapy more than 8 weeks after surgery. Based on a multivariate analysis, the risk factors associated with chemotherapy delay >=8 weeks were older age [65 to 74 years (hazard ratio [HR]=1.48) and >=75 years (HR=1.69), p=0.0354], medical aid status in the health security system (HR=1.76, p=0.0345), and emergency surgery (HR=2.43, p=0.0002). Using an 8-week cutoff, the 3-year overall survival rate was 89.62% and 80.98% in the <8 weeks and >=8 weeks groups, respectively (p=0.008). Independent prognostic factors for inferior overall survival included chemotherapy delay >=8 weeks (HR=1.49, p=0.0365), older age [65 to 74 years (HR=1.94) and >=75 years (HR=3.41), p<0.0001], TNM stage III (HR=2.46, p<0.0001), emergency surgery (HR=1.89, p<0.0001), American Society of Anesthesiologists score of 3 or higher (HR=1.50, p<0.0001), and higher transfusion amounts (HR=1.09, p=0.0392). Conclusions: This study shows that delayed commencement of adjuvant chemotherapy, defined as >= 8 weeks, is associated with inferior overall survival in colon cancer patients with stage II or III disease. The delay to initiation of adjuvant chemotherapy is influenced by several multidimensional factors, including patient factors (older age), insurance status (medical aid), and treatment-related factors (emergency surgery). PMID- 29108389 TI - Hodgkin lymphoma in adolescent and young adults: insights from an adult tertiary single-center cohort of 349 patients. AB - Background: Adolescent and young adults (AYA) represent one third of patients affected by Hodgkin lymphoma (HL). These patients are frequently treated either with pediatric or adult protocol depending on their physician background. This population has been understudied so far, in terms of HL characteristics and treatment-associated outcomes. Aim: We aimed to extensively describe HL features in the AYA population including HL characteristics, progression-free (PFS) and overall survival (OS). Methods: From 1979 to 2013, consecutive patients with HL aged between 15 to 25 years and followed at Saint-Louis Hospital were prospectively enrolled. Survivals were estimated using the Kaplan-Meier method. Results: 349 patients were included and studied, with a median follow-up of 7 years. The majority of patients were treated with adult protocols (mainly ABVD and BEACOPP). They presented adverse clinical characteristics with a high proportion of stage III and IV according to Ann Arbor classification (45 %), a high rate of B symptoms (46 %) and extra-nodal involvement (36 %). Despite these pejorative clinical features, the prognosis remains good with a 10-year PFS and OS estimated at 81.0 % (95%CI [76.7-85.5]) and 90.7% (95%CI [87.2-94.4]), respectively. In multivariate analysis, stages III and IV according to Ann Arbor classification, mixed cellularity histology, elevated neutrophils and LDH above range were independently associated with a worse PFS. We identified a subgroup of 11 primary refractory patients with a particularly poor prognosis. The toxicity rate was low (7.4 %). Conclusion: Despite their baseline pejorative features, AYA with HL have a good prognosis. Progresses are still needed in order to reduce toxicities. Primary refractory patients with a particularly poor prognosis should be detected early in order to quickly introduce new targeted therapies. PMID- 29108390 TI - High truncated-O-glycan score predicts adverse clinical outcome in patients with localized clear-cell renal cell carcinoma after surgery. AB - Truncated O-glycans, including Tn-antigen, sTn-antigen, T-antigen, sT-antigen, are incomplete glycosylated structures and their expression occur frequently in tumor tissue. The study aims to evaluate the abundance of each truncated O glycans and its clinical significance in postoperative patients with localized clear-cell renal cell carcinoma (ccRCC). We used immunohistochemical testing to analyze the expression of truncated O-glycans in tumor specimens from 401 patients with localized ccRCC. Truncated-O-glycan score was built by integrating the expression level of Tn-, sTn- and sT-antigen. Kaplan-Meier survival and Cox regression analysis were done to compare clinical outcomes in subgroups. Receiver operating characteristic (ROC) was applied to assess the impact of prognostic factors on overall survival (OS) and recurrence-free survival (RFS). The results identified Tn-, sTn-, sT-antigen as independent prognosticators. The OS and RFS were shortened among the 198 (49.4%) patients with high Truncated-O-glycan score than among the 203 (50.6%) patients with low score (hazard ratio for OS, 7.060; 95% confidence interval [CI]: 2.765 to 18.027; p <0.001; for RFS, 4.612; 95% CI: 2.141 to 9.931; p <0.001). There is no difference between low-risk patients and high-risk patients in low score group (p = 0.987). High-risk patients with low score showed a better prognosis than low-risk patient with high score (p = 0.029). The Truncated-O-glycan score showed better prognostic value for OS (AUC: 0.739, p = 0.003) and RFS (AUC: 0.719, p = 0.003) than TNM stage. In summary, the high Truncated-O-glycan score could predict adverse clinical outcome in localized ccRCC patients after surgery. PMID- 29108392 TI - Cauterization of Ozurdex wound for the prevention of scleral leakage in vitrectomized eyes. AB - PURPOSE: To study if cauterization of the scleroconjuctival wound secondary to intravitreal dexamethasone implant in vitrectomized eyes is effective to avoid scleral leakage and hypotony. METHODS: A total of 35 vitrectomized eyes of 35 consecutive patients with macular edema who underwent a single intravitreal dexamethasone implant injection in the operating room at the Eye Clinic of the University of Bari, Italy, from 2013 to 2017 were retrospectively reviewed. At the end of the injection, transconjuctival/scleral bipolar cauterization was applied at the injection site and the presence or absence of leakage or hypotony was studied. RESULTS: At the end of the procedure, no patient showed fluid leakage from the cauterized scleroconjuctival wound. No ocular hypotony of other ophthalmic complications were observed at 1 hour and 1 day from injection and intraocular pressure did not change significantly from baseline at 1 hour and 1 day after injection. CONCLUSIONS: Cauterization of the scleral wound after intravitreal dexamethasone implant injection in vitrectomized eyes is safe and effective to avoid scleral leakage with secondary hypotony, obtaining a watertight wound closure. PMID- 29108393 TI - Anti-vascular endothelial growth factor for unilateral acute idiopathic maculopathy. AB - PURPOSE: To describe a case of unilateral acute idiopathic maculopathy (UAIM) response to intravitreal therapy with aflibercept (Eylea). METHODS: Retrospective case report. RESULTS: A 36-year-old woman with sudden visual impairment and central scotoma was found to have a UAIM in her left eye. Three weeks after continuous worsening of her visual acuity and central scotoma, the patient was treated with intravitreal injections of aflibercept. The visual acuity increased and the macula lesion regressed, causing macula scarring after 2 injections. CONCLUSIONS: Intravitreal injections of aflibercept could be a therapy option in patients with UAIM without signs of spontaneous resolution of the clinical manifestations and visual improvement. PMID- 29108391 TI - Glutathione peroxidases as oncotargets. AB - Oxidative stress is a disturbance in the equilibrium among free radicals, reactive oxygen species, and endogenous antioxidant defense mechanisms. Oxidative stress is a result of imbalance between the production of reactive oxygen and the biological system's ability to detoxify the reactive intermediates or to repair the resulting damage. Mounting evidence has implicated oxidative stress in various physiological and pathological processes, including DNA damage, proliferation, cell adhesion, and survival of cancer cells. Glutathione peroxidases (GPxs) (EC 1.11.1.9) are an enzyme family with peroxidase activity whose main biological roles are to protect organisms from oxidative damage by reducing lipid hydroperoxides as well as free hydrogen peroxide. Currently, 8 sub members of GPxs have been identified in humans, all capable of reducing H2O2 and soluble fatty acid hydroperoxides. A large number of publications has demonstrated that GPxs have significant roles in different stages of carcinogenesis. In this review, we will update recent progress in the study of the roles of GPxs in cancer. Better mechanistic understanding of GPxs will potentially contribute to the development and advancement of improved cancer treatment models. PMID- 29108394 TI - Comparative study of 3 exophthalmometers and computed tomographic biometry. AB - PURPOSE: Accurate and reproducible exophthalmometry is mandatory to diagnose and follow-up orbital patients, especially in Graves disease. However, many variations are described among the different commercially available exophthalmometers. METHODS: Sixty patients, who underwent a cerebral computed tomography (CT) scan, were included. External prebicanthal segments (EPBCS) for right and left eyes (RE and LE), interorbital distance, and globe axial length were recorded by a first observer (O1), more experienced than a second (O2). Intraobserver and interobserver reproducibility were evaluated, using intraclass correlation coefficient (ICC) and Bland and Altman plots. RESULTS: Concordance between each EPBCS measurement for each eye and CT scan biometry was moderate for the Luedde ruler for the 2 observers. For the Hertel exophthalmometer, concordance was moderate for O1 in the 2 eyes and moderate in RE but good in LE for O2. For the Mourits exophthalmometer, this concordance was very good in RE and good in LE for O1, and good whatever the eye for O2. Intraobserver (ICC varying from 0.75 to 0.95 for the 2 observers) and interobserver (ICC from 0.69 to 0.94) reproducibility were high, especially for the Mourits exophthalmometer. Bland and Altman plots showed underestimations when using the Luedde ruler, overestimations when using the Hertel exophthalmometer, and overestimation of small values and underestimation of high values when using the Mourits exophthalmometer when compared to CT scan biometry. CONCLUSIONS: We demonstrated great accuracy to CT scan biometry with 1-prism Mourits exophthalmometer, low accuracy with the Luedde instrument, and intermediate accuracy with the Hertel exophthalmometer, with fair intraobserver and interobserver reproducibility. PMID- 29108395 TI - Active iris vascular tufts bleeding successfully treated with argon laser photocoagulation. AB - PURPOSE: Iris vascular tufts (IVT) are rare biomicroscopic capillary outgrowths from the pupillary margins. Patients are usually asymptomatic until presenting with blurred vision due to spontaneous hyphema or with raised intraocular pressure. CASE REPORT: A 61-year-old woman presented to eye casualty with left eye (LE) blurred vision and discomfort for 1 day. Her external ocular examination was unremarkable and visual acuity was 6/6 in the right eye (RE) and 6/9 in the LE. Biomicroscopic examination revealed a 2-mm hyphema in her LE and bilateral multiple small IVT and active bleeding from IVT at the pupillary margin of the LE at the 5 o'clock position. Diagnosis of LE active bleeding from IVT was made and she underwent argon laser photocoagulation directed at the source of bleeding. The bleeding stopped immediately after the second burn. She was followed up for 3 months; her visual acuity was 6/5 and 6/6 in the RE and LE, respectively, with no further problems. CONCLUSIONS: Iris vascular tufts are benign and recurrent hemorrhages are unlikely. Therefore, definitive argon laser photocoagulation or surgical treatment are reserved to arrest further episodes of hyphema. Our case demonstrates the effective use of argon laser photocoagulation to completely arrest active bleeding from IVT and excellent recovery of hyphema with no further problems for 5 years. PMID- 29108396 TI - Evaluation of pseudophakic cystoid macular edema using optical coherence tomography angiography. AB - PURPOSE: To compare the optical coherence tomography angiography (OCT-A) findings of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in eyes with pseudophakic cystoid macular edema (PCME) with those of fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) and to compare PCME vascular density values of the SCP and DCP with those of healthy eyes. METHODS: In this retrospective observational study, 13 eyes (12 patients) with PCME underwent comprehensive ophthalmologic examinations including visual acuity, FA, SD-OCT, and OCT-A. The vascular density of the SCP and DCP were measured using AngioAnalytics software in all PCME eyes and compared with 46 healthy eyes of 25 subjects. RESULTS: In patients with PCME, at the level of SCP, the mean vascular density in the whole en face image was 44.48 +/- 3.61% while it was 50.27 +/- 5.30% at the level of the DCP. In contrast, the vascular density in the whole en face image was 50.35 +/- 3.22 at the level of SCP while it was 56.15 +/- 3.28 at the level of DCP in 46 healthy eyes of 25 subjects. The vascular density of patients with PCME was significantly lower than in healthy subjects at the SCP (p<0.0001) and at the DCP (p<0.0001). CONCLUSION: We report the OCT-A appearance of PCME and vascular density map with values that can be easily interpreted for quantitative evaluation of retina perfusion status using OCT-A. This approach might be the first step in helping us fully understand the pathophysiologic mechanisms underlying PCME. PMID- 29108397 TI - Internal retinal layer thickness and macular migration after internal limiting membrane peeling in macular hole surgery. AB - PURPOSE: To provide a spectral-domain optical coherence tomography (SD-OCT)-based analysis of retinal layers thickness and nasal displacement of closed macular hole after internal limiting membrane peeling in macular hole surgery. METHODS: In this nonrandomized prospective interventional study, 36 eyes of 32 patients were subjected to pars plana vitrectomy and 3.5 mm diameter internal limiting membrane (ILM) peeling for idiopathic macular hole (IMH). Nasal and temporal internal retinal layer thickness were assessed with SD-OCT. Each scan included optic disc border so that distance between optic disc border and fovea were measured. RESULTS: Thirty-six eyes had a successful surgery with macular hole closure. Total nasal retinal thickening (p<0.001) and total temporal retinal thinning (p<0.0001) were observed. Outer retinal layers increased thickness after surgery (nasal p<0.05 and temporal p<0.01). Middle part of inner retinal layers (mIRL) had nasal thickening (p<0.001) and temporal thinning (p<0.05). The mIRL was obtained by deducting ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thickness from overall thickness of the inner retinal layer. Papillofoveal distance was shorter after ILM peeling in macular hole surgery (3,651 +/- 323 MUm preoperatively and 3,361 +/- 279 MUm at 6 months; p<0.0001). CONCLUSIONS: Internal limiting membrane peel is associated with important alteration in inner retinal layer architecture, with thickening of mIRL and shortening of papillofoveal distance. These factors may contribute to recovery of disrupted foveal photoreceptor and vision improvement after IMH closure. PMID- 29108398 TI - Blockade of p75 Neurotrophin Receptor Reverses Irritability and Anxiety-Related Behaviors in a Rat Model of Status Epilepticus AB - Background: Many recent epidemiological studies have shown that epileptic patients are more likely suffer from depression, anxiety, and irritability. However, the cellular mechanisms of epilepsy-induced psychotic behaviors are not fully elucidated. Neurotrophin receptors have been suggested to be involved in epilepsy and also in psychiatric disorders. Up-regulation of p75NTR expression and activation of p75NTR signalling cascades after the seizure have been shown, but the role of the p75 receptor in epilepsy-induced psychotic behaviors has not been documented so far. Therefore, the present work aimed to investigate the effect of p75 receptor blockade on seizure activity, irritability, and anxiety like behaviors in a rat model of status epilepticus. Methods: Rats were injected with pilocarpine (350 mg/ kg, i.p.) to induce status epilepticus. Then various behavioral tests were performed after the blockade of p75NTR alone or in combination with p75 antagonist and phenobarbital. Molecular analysis by PCR was performed to investigate the expression of p75 and pro-NGF. Results: Molecular findings indicated a high level of mRNA expression for both p75 receptors and pro NGF in the epileptic model group. Results also showed that the administration of p75 antagonist alone or in combination with phenobarbital was able to significantly influence the behavioral responses. Furthermore, 20-hours video monitoring showed a decrease in the frequency and duration of seizures in the rat group receiving p75 antagonist. Conclusion: Taken together, the present study suggests that the blockade of the p75 receptor may affect the irritability and anxiety-related behavior in a rat model of status epilepticus. PMID- 29108399 TI - Effects of Perianal Involvement on Clinical Outcomes in Crohn's Disease over 10 Years. AB - Background/Aims: There was the assumption that Crohn's disease (CD) patients with perianal lesions might have different clinical courses compared to those without. However, quantifiable data comparing the long-term outcomes between the two groups are scarce. Methods: We retrospectively reviewed 221 consecutive patients newly diagnosed with CD and registered at the IBD clinic of Severance Hospital, in Seoul, Korea, between January 1990 and October 2005. We compared patients with perianal CD (PCD) and non-perianal CD (NPCD) in terms of clinical outcomes over 10 years. Results: PCD progressed more frequently from inflammatory to complicated behavior than NPCD. Moreover, corticosteroids were prescribed in 102 patients with PCD and only 57 with NPCD (82.9% vs 58.2%, p<0.001), immunosuppressants in 89 and 42 (72.4% vs 42.9%, p<0.001), and anti-tumor necrosis factor alpha (TNF-alpha) in 37 and 12 (30.1% vs 12.2%, p=0.002). Cumulative hospitalization rates were 82.1% in PCD and 72.4% in NPCD (p=0.086), and surgical intervention rates were 39.8% and 51.0%, respectively (p=0.097). Conclusions: Patients with PCD were more likely than those with NPCD to be administered corticosteroids, immunosuppressants, and anti-TNF-alpha. However, there is no significant difference in the cumulative rates of surgical interventions or hospitalizations. PMID- 29108400 TI - Early experience and favorable clinical outcomes of everolimus-eluting bioresorbable scaffolds for coronary artery disease in Korea. AB - BACKGROUND/AIMS: Compared with metallic drug-eluting stents (DES), bioresorbable vascular scaffolds (BVS) may further improve long-term outcomes of percutaneous coronary intervention (PCI) in patients with coronary artery disease. We report our early experience with BVS in Korea. METHODS: We evaluated 105 consecutive patients with BVS implanted at Asan Medical Center, Korea between October 21, 2015 and June 3, 2016. Angiographic results, and in-hospital and 6-month clinical outcomes were assessed. RESULTS: A total of 134 BVS were implanted to treat 115 lesions. The mean age was 62 +/- 10.5 years; 85 patients (81%) were males, 26 patients (25%) were presented with acute coronary syndrome. Among 115 lesions treated with BVS, 76 (66.1%) were B2/C type, 27 (23.5%) were bifurcation lesions, and four (3.5%) were chronic total occlusion. Pre-dilation and post-dilation using high-pressure non-compliant balloon was performed in 104 lesions (90.4%) and 113 lesions (98.2%), respectively. During the procedure, intravascular imaging was used for all patients (100%; intravascular ultrasound 89 and optical coherence tomography 40 patients). Device success rate was 100%. In-segment and in-scaffold acute again were 1.1 +/- 0.6 and 1.3 +/- 0.5 mm, respectively. Periprocedural myocardial infraction occurred in four patients (3.8%). No deaths, stent thrombosis, or urgent revascularizations occurred either during hospitalization or the follow-up period. CONCLUSION: In this single-center experience, implantation of BVS with intravascular imaging support was feasible and early clinical outcomes were excellent. Evaluation of long-term efficacy and safety of BVS and its feasibility in clinical use for a broader range of lesions is warranted. PMID- 29108402 TI - Clinicopathological features of colorectal polyps in 2002 and 2012. AB - Background/Aims: There are few comparative studies on the historical changes in the clinicopathologic characteristics of colorectal polyps in Korea. This retrospective study compared the clinicopathologic characteristics of colorectal polyps treated at our institution in 2002 and 2012. Methods: The medical records of 1,816 patients who underwent colonoscopy and were found to have colorectal polyps in 2002 (n = 597) or 2012 (n = 1,219) were reviewed retrospectively. Patient characteristics and polyp sizes, gross morphologies, locations, and pathologic results were analyzed and compared. Results: Mean age was older in the 2002 group than in the 2012 group (67.3 +/- 11.1 years vs. 55.4 +/- 10.8 years, p < 0.001). The 1,816 study subjects had a total of 3,723 colorectal polyps, with a mean of 2.05 polyps per patient. Mean polyp size was larger in the 2002 group than in the 2012 group (0.6 +/- 0.4 cm vs. 0.4 +/- 0.3 cm, p < 0.001). The most common histology was tubular adenoma and they were more common in the right colon in both study groups. Although the distribution of total adenoma was not significantly different between groups, the location of advanced adenoma differed significantly and was more common in the right colon in the 2012 group (30.4% vs. 63.2%, p = 0.01). Conclusions: No significant change in total polyps and adenoma distribution was found between 2002 and 2012. However, advanced adenoma was more common in the right colon in 2012, which cautiously suggests a locational shift from the left to right colon. These findings indicate that right colon polyps require more attention. PMID- 29108401 TI - Clinical value of procalcitonin for suspected nosocomial bloodstream infection. AB - BACKGROUND/AIMS: Procalcitonin (PCT) may prove to be a useful marker to exclude or predict bloodstream infection (BSI). However, the ability of PCT levels to differentiate BSI from non-BSI episodes has not been evaluated in nosocomial BSI. METHODS: We retrospectively reviewed the medical records of patients >= 18 years of age with suspected BSI that developed more than 48 hours after admission. RESULTS: Of the 785 included patients, 105 (13.4%) had BSI episodes and 680 (86.6%) had non-BSI episodes. The median serum PCT level was elevated in patients with BSI as compared with those without BSI (0.65 ng/mL vs. 0.22 ng/mL, p = 0.001). The optimal PCT cut-off value of BSI was 0.27 ng/mL, with a corresponding sensitivity of 74.6% (95% confidence interval [CI], 66.4% to 81.7%) and a specificity of 56.5% (95% CI, 52.7% to 60.2%). The area under curve of PCT (0.692) was significantly larger than that of C-reactive protein (CRP; 0.526) or white blood cell (WBC) count (0.518). However, at the optimal cut-off value, PCT failed to predict BSI in 28 of 105 cases (26.7%). The PCT level was significantly higher in patients with an eGFR < 60 mL/min/1.73 m2 than in those with an eGFR >= 60 mL/min/1.73 m2 (0.68 vs. 0.17, p = 0.01). CONCLUSIONS: PCT was more useful for predicting nosocomial BSI than CRP or WBC count. However, the diagnostic accuracy of predicting BSI remains inadequate. Thus, PCT is not recommended as a single diagnostic tool to avoid taking blood cultures in the nosocomial setting. PMID- 29108403 TI - Epidemiology of septic meningitis associated with neuraxial anesthesia: a historical review and meta-analysis. AB - INTRODUCTION: Neuraxial anesthesia in the form of spinal and epidural are two of the most frequent forms of regional anesthesia. We aimed to describe and compare the relevant epidemiological, clinical and microbiological characteristics of all reported cases of septic meningitis associated with the use of spinal and epidural anesthetics. EVIDENCE ACQUISITION: We performed a systematic review of septic meningitis associated with neuraxial anesthesia. We included all relevant case-reports and observational studies in which authors described septic meningitis in association with spinal, epidural or combined neuraxial anesthesia using local anesthetics. EVIDENCE SYNTHESIS: A total of 234 cases of septic meningitis were reported following review of 71 case-report articles and 22 epidemiological studies. In total, there have been 199, 25 and 10 reported cases of septic meningitis associated to spinal, epidural and combined neuraxial anesthesia, respectively. The lack of use of surgical masks was the most common risk factor (41, 16.7%). Streptococcus salivarius was the most common bacteria (17.0%) related to spinal anesthesia and Staphylococcus aureus (26.7%) was the most common one related to epidural. The time to symptom onset was significantly reduced in spinal (median time, 24 hours IQR [8-72] vs. 96 hours IQR [84-240]; P=0.003) compared to epidural anesthesia. The overall mortality rate is 15.3% and 13.3% for reported cases related to spinal and epidural anesthesia, respectively. CONCLUSIONS: While the true incidence remains speculative, this review suggests that given increasing indications for spinals and epidurals, septic meningitis remains an important associated with neuraxial anesthesia. PMID- 29108404 TI - Assessment of rotational thromboelastometry for the prediction of red blood cell requirements in orthotopic liver transplantation. AB - BACKGROUND: In liver transplantation most studies were designed to predict massive transfusion rather than whether or not transfusion is required. We hypothesized that (presurgery) data from thromboelastometry may predict perioperative blood requirements. METHODS: A post-hoc analysis of data from a controlled trial was performed with the primary end point of predicting zero red blood cells. Of the 92 patients studied, 6 were excluded because of incomplete EXTEM and/or FIBTEM data. The multivariate models included preoperative variables with a P value <0.10 in the univariate model: age, MELD score, hemoglobin, plasma fibrinogen, platelet count, activated partial thromboplastin time, INR, EXTEM maximum clot amplitude after 10 minutes, EXTEM an FIBTEM maximum clot firmness, plasma creatinine, and donor data. RESULTS: Blood was transfused to 58% of patients during the surgical procedure and to 34% in the first 24 hours postoperatively. The final model was selected using a backward approach, and fractional polynomials were explored to assess model improvement for the prediction. Hemoglobin was a strong predictor: each 1 g/dL of hemoglobin increase reduced the risk of blood transfusion by 52%. An EXTEM maximum amplitude at 10 min was also a predictor of Red Blood requirement, showing a 64% risk reduction for values between the first quartile (35 mm) and the second quartile (41 mm) but no further improvement for the third and fourth quartiles and resulting in a prediction (ROC AUC of 0.815 [0.771-0.859]). CONCLUSIONS: Presurgical EXTEM maximum amplitude at 10 min <35 mm is highly predictive of red blood administration during liver transplantation. PMID- 29108405 TI - Gabapentin before laparoscopic sleeve gastrectomy reduces postoperative oxycodone consumption in obese patients: a randomized double-blind placebo-controlled trial. AB - BACKGROUND: Postoperative pain can be prevented. Gabapentin may be effective in this role. Our primary objective was to test the hypothesis that a prophylactic administration of gabapentin in obese patients before surgery has an opioid sparing effect and reduces postoperative oxycodone consumption more efficiently than placebo. METHODS: The study enrolled 113 patients undergoing laparoscopic sleeve-gastrectomy under general anesthesia. The patients were randomly allocated to the control or gabapentin group and received a single oral dose of gabapentin 1200 mg or a matching placebo 1 h before surgery. RESULTS: The mean time from the end of anesthesia to the commencement of analgesic therapy was 74.3+/-37.8 minutes in the placebo group and 110.4+/-65.4 minutes with gabapentin (mean difference: -36, 95% CI: 12 to 40, P=0.0004). The mean 12-hour oxycodone consumption was 31.5+/-10 mg with placebo and 26.3+/-10 mg with gabapentin (mean difference: -5.2 mg, 95% CI: -9.08 to -1.35, P=0.0085). The mean NRS pain intensity at 12 hours was 2+/-0.9 in the placebo group and 1.5+/-0.9 with gabapentin (mean difference: -0.5, 95% CI: 0.15 to 0.81, P=0.003). CONCLUSIONS: The demand for oxycodone was delayed in the gabapentin group; also, the total 12 hour dose requirement of oxycodone was lower in the gabapentin group. PMID- 29108406 TI - Intracerebral hemorrhage in Intensive Care Unit: early prognostication fallacies. A single center retrospective study. AB - BACKGROUND: Intracerebral hemorrhage (ICH) admitted to Intensive Care is deem of poor prognosis. The aim of this study was to compare observed and predicted 30 day mortality and to evaluate long term functional outcome in a consecutive ICH cohort. METHODS: Retrospective analysis of prospectively collected data of ICH patients managed in a Neuro-ICU from 2012 to 2015. RESULTS: Out of 136 consecutive patients, 34 (25%) had "withholding of life-sustaining treatment" (WLST) order and 102 (75%) received a "full treatment" (FT). WLST cohort: median (IQR): 72 (70-77) years old, Glasgow Coma Scale (GCS) 4 (3-4) at admission, ICH volume 114 cm3 (68-152); all patients died during neuro-ICU recovery, 28 (82%) patients had brain death diagnosis and 15 (54%) of these were organ donors. FT cohort: 67 (51-73) years old, GCS 9 (6-12) at admission, ICH volume 46 (24-90) cm3, neurosurgery for clot removal in 65 (64%) (P<0.05 vs. WLST cohort for each of previously listed variables); 13 (13%) patients died during neuro-ICU recovery, of these 11 (85%) patients had brain death diagnosis and 4 (36%) of them were organ donors. Overall 30-day observed mortality for FT group was 18% (95% CI: 11-26%). Patients with ICH Score 1, 2, 3, 4+ had 0%, 10%, 16% and 26% 30 day mortality, respectively (P<0.01 vs. ICH Score). Full treatment group 180-day mortality was 32% (95% CI: 24-42%). Modified Rankin Scale (mRS) after one year was <=3 in 35 (35%), i.e. good recovery, and >3 in 64 (65%). Neurosurgery for clot removal was associated with a lower 30 and 180-day mortality (P=0.01 and P=0.03, respectively) and along with GCS at admission it was an independent significant prognostic factor. CONCLUSIONS: Mortality and functional outcome is less severe than predicted in patients with ICH receiving a full medical and/or surgical treatment. PMID- 29108407 TI - Periprocedural analgesic efficacy of a single, pre-emptive administration of propacetamol in catheter ablation for atrial fibrillation: a randomized controlled trial. AB - BACKGROUND: Anesthetic care for termination of atrial fibrillation with catheter ablation poses significant challenges due to significant pain and lengthy procedure. A delicate polypharmacy combining anesthetic agents to minimize respiratory depression and hemodynamic changes and to provide satisfactory sedation and analgesia is needed. METHODS: Ninety-eight patients were randomized into two groups receiving either two grams of propacetamol or normal saline intravenously for 20 minutes before anesthesia. Monitored anesthesia care was provided with midazolam and remifentanil. RESULTS: Total amounts of remifentanil infused were similar between the groups (626+/-251 vs. 597+/-315 MUg, P=0.606). Accounting for the mean duration of the procedure and the elimination half-life of propacetamol, remifentanil requirements were significantly less among patients whose procedure ended within 180 minutes (N.=56) in the propacetamol group than those in the control group (540+/-194 vs. 421+/-164 MUg, P=0.017). In the control group, the incidence of analgesics usage 24 hours after the procedure was significantly greater (43% vs. 23%, P=0.038), and patients exhibited a higher pain score (3.1+/-2.1 vs. 1.9+/-2.1, P=0.007), compared to the propacetamol group. CONCLUSIONS: The addition of a single dose of pre-emptive propacetamol showed promising results in terms of opioid consumption in patients whose procedure ended within 180 minutes. It provided better post-procedural pain control, compared with midazolam plus remifentanil alone. PMID- 29108408 TI - Local anesthetics with additives for single shot nerve block: what are the benefits and risks? PMID- 29108409 TI - Post-anoxic status epilepticus: the prognosis is not always hopeless. PMID- 29108410 TI - "Arterial stiffness": a different approach in the pursuit to assess the intraoperative nociception antinociception balance. PMID- 29108411 TI - Hollow N-Doped Carbon Spheres with Isolated Cobalt Single Atomic Sites: Superior Electrocatalysts for Oxygen Reduction. AB - The search for a low-cost, ultrastable, and highly efficient non-precious metal catalyst substitute for Pt in the oxygen reduction reaction (ORR) is extremely urgent, especially in acidic media. Herein, we develop a template-assisted pyrolysis (TAP) method to obtain a unique Co catalyst with isolated single atomic sites anchored on hollow N-doped carbon spheres (ISAS-Co/HNCS). Both the single sites and the hollow substrate endow the catalyst with excellent ORR performance. The half-wave potential in acidic media approaches that of Pt/C. Experiments and density functional theory have verified that isolated Co sites are the source for the high ORR activity because they significantly increase the hydrogenation of OH* species. This TAP method is also demonstrated to be effective in preparing a series of ISAS-M/HNCS, which provides opportunities for discovering new catalysts. PMID- 29108412 TI - Allium Discoloration: Color Compounds Formed during Greening of Processed Garlic. AB - Structures and formation pathways of compounds responsible for blue-green discoloration of processed garlic were studied in model systems. A procedure was developed for isolation of the color compounds and their tentative identification by high-performance liquid chromatography coupled to a diode array detector and tandem mass spectrometry. It was found that the pigment is a mixture of numerous pyrrole-based purple/blue and yellow species. Experiments with isotope-labeled precursors revealed that two molecules of an amino acid are involved in the formation of each color compound. In the purple/blue species (lambdamax = 565-600 nm), both amino acid molecules are incorporated into two 3,4-dimethylpyrrole derived rings linked together by a propenylidine bridge. On the other hand, the yellow compounds (lambdamax = 420-450 nm) contain only one N-substituted 3,4 dimethylpyrrole ring, to which the second amino acid is bound via a propenylidine side chain. PMID- 29108413 TI - How Equilibrium Gets Mimicked During Kinetic and Thermodynamic Control in Porphyrin and Phthalocyanine Self-Assembled Monolayers. AB - The recent review of Hipps and Mazur is extended to consider the origins and significance of their conclusion that "surface structures vary with relative component concentration in a way that may mimic equilibria but is not". How this situation can arise during self-assembly is discussed, as well as a range of qualitative and quantitative observations and high-level free-energy calculations that document the effect for meso-tetraalkylporphyrins self-assembled monolayer (SAM) polymorphs. This leads to a discussion of modern challenges facing quantification of the effects caused by kinetic control, as well as to the usefulness of equilibrium mimicking in the design and synthesis of SAMs. PMID- 29108414 TI - Highly Efficient Separation of Trivalent Minor Actinides by a Layered Metal Sulfide (KInSn2S6) from Acidic Radioactive Waste. AB - The elimination of trivalent minor actinides (Am3+, Cm3+) is of great concern for the safe management and operation of nuclear waste geological repository and environmental remediation. However, because of the effects of protonation, most of the present sorbents exhibit inferior removal properties toward minor actinides at low pH values. Finding stable ion-exchangers with high sorption capacities, fast kinetics, and good removal toward minor actinides from highly acidic solution remains a great challenge. This work reports a new family member of KMS materials with a robust acid-stable layered metal sulfide structure (KInSn2S6, KMS-5) bearing strong affinity toward trivalent minor actinides. KMS-5 can simultaneously separate trivalent 241Am and 152Eu from acidic solutions below pH 2 with high efficiency (>98%). The ion-exchange kinetics is extremely fast (<10 min) and the largest distribution coefficient is as high as 5.91 * 104 mL/g. KMS-5 is also capable of efficiently removing 241Am from acidic solution containing various competitive cations in large excess. In addition, the ion exchange process of 241Am by KMS-5 is reversible and the loaded material can be easily eluted by high concentration of potassium chloride. This work represents the first case for efficient minor actinides removal from highly acidic solution using layered metal sulfide materials. PMID- 29108415 TI - Distributions of the Stereoisomers of beta-Mercaptoheptanones and beta Mercaptoheptanols in Cooked Bell Pepper (Capsicum annuum). AB - 2-Mercapto-4-heptanone, 4-mercapto-2-heptanone, and the corresponding mercaptoalcohols, previously identified in cooked red bell pepper (Capsicum annuum), were used as examples to determine the distributions of stereoisomers of naturally occurring polyfunctional thiols. The thiols were isolated using simultaneous distillation-extraction and enriched by affinity chromatography. Enantioselective analysis was performed via multidimensional gas chromatography. For the studied cultivar California Wonder, the investigation of different batches of cooked red bell pepper revealed consistent ratios of the stereoisomers independent of origin and date of purchase. Quantitative estimations showed that the stereoisomers were present in cooked red bell peppers at concentrations in the range of 0.04-10.2 MUg/kg. Lower concentrations were observed in cooked green bell peppers. The change from green to red color was also accompanied by shifts in the proportions of stereoisomers in favor of the (S)-enantiomers of the mercaptoheptanones and of the (4S)-configured stereoisomers of 4-mercapto-2 heptanol. PMID- 29108416 TI - Chlorflavonin Targets Acetohydroxyacid Synthase Catalytic Subunit IlvB1 for Synergistic Killing of Mycobacterium tuberculosis. AB - The flavonoid natural compound chlorflavonin was isolated from the endophytic fungus Mucor irregularis, which was obtained from the Cameroonian medicinal plant Moringa stenopetala. Chlorflavonin exhibited strong growth inhibitory activity in vitro against Mycobacterium tuberculosis (MIC90 1.56 MUM) while exhibiting no cytotoxicity toward the human cell lines MRC-5 and THP-1 up to concentrations of 100 MUM. Mapping of resistance-mediating mutations employing whole-genome sequencing, chemical supplementation assays, and molecular docking studies as well as enzymatic characterization revealed that chlorflavonin specifically inhibits the acetohydroxyacid synthase catalytic subunit IlvB1, causing combined auxotrophies to branched-chain amino acids and to pantothenic acid. While exhibiting a bacteriostatic effect in monotreatment, chlorflavonin displayed synergistic effects with the first-line antibiotic isoniazid and particularly with delamanid, leading to a complete sterilization in liquid culture in combination treatment. Using a fluorescent reporter strain, intracellular activity of chlorflavonin against Mycobacterium tuberculosis inside infected macrophages was demonstrated and was superior to streptomycin treatment. PMID- 29108417 TI - Probing the OH Stretch in Different Local Environments in Liquid Water. AB - We use resonant inelastic X-ray scattering (RIXS) to resolve vibrational losses corresponding to the OH stretch where the X-ray absorption process allows us to selectively probe different structural subensembles in liquid water. The results point to a unified interpretation of X-ray and vibrational spectroscopic data in line with a picture of two classes of structural environments in the liquid at ambient conditions with predominantly close-packed high-density liquid (HDL) and occasional local fluctuations into strongly tetrahedral low-density liquid (LDL). PMID- 29108418 TI - Adhesion forces of the sea-water bacterium Paracoccus seriniphilus on titanium: Influence of microstructures and environmental conditions. AB - The bacterial attachment to surfaces is the first step of biofilm formation. This attachment is governed by adhesion forces which act between the bacterium and the substrate. Such forces can be measured by single cell force spectroscopy, where a single bacterium is attached to a cantilever of a scanning force microscope, and force-distance curves are measured. For the productive sea-water bacterium Paracoccus seriniphilus, pH dependent measurements reveal the highest adhesion forces at pH 4. Adhesion forces measured at salinities between 0% and 4.5% NaCl are in general higher for higher salinity. However, there is an exception for 0.9% where a higher adhesion force was measured than expected. These results are in line with zeta potential measurements of the bacterium, which also show an exceptionally low zeta potential at 0.9% NaCl. In the absence of macromolecular interactions, the adhesion forces are thus governed by (unspecific) electrostatic interactions, which can be adjusted by pH and ionic strength. It is further shown that microstructures on the titanium surface increase the adhesion force. Growth medium reduces the interaction forces dramatically, most probably through macromolecular bridging. PMID- 29108419 TI - Serum Potassium Levels and Mortality in Acute Myocardial Infarction: Myth or Fact? PMID- 29108420 TI - Inhibitor Risk Stratification and Individualized Treatment in Patients With Nonsevere Hemophilia A: A Single-Institution Practice Audit. AB - Inhibitor risk in nonsevere hemophilia A increases with cumulative factor VIII (FVIII) exposure days and high-risk mutations. A standardized approach to minimize inhibitor risk is warranted. Following establishment of a systematic approach to reduce inhibitor risk in nonsevere hemophilia, we evaluated the uptake of these strategies into clinical practice. All adult males with nonsevere hemophilia A followed by British Columbia Adult Hemophilia Program from 2004 to 2016 were included in this retrospective audit. Quality-of-care indicators on inhibitor prevention were examined. Of 108 patients, 18 patients had high-risk FVIII mutations for inhibitor development. Rates of FVIII genotyping and 1 deamino-8-d-arginine-vasopressin (DDAVP) testing in mild patients without contraindications were both over 90%, although DDAVP was used for surgical prophylaxis in only 70% of procedures. Inhibitor testing and clinic visits occurred at a median interval of 22 months. Over 80% of patients with high-risk mutations had documentation and education on their inhibitor risk. Our practice audit demonstrated a high level of recognition and patient education of individual inhibitor risk. Impact of our standardized approach on the incidence of inhibitor development is yet to be determined. PMID- 29108422 TI - Unlocking Open Access: How to Comply With Funders' Mandates. PMID- 29108421 TI - Neonatal Arterial Ischemic Stroke: Risk Related to Family History, Maternal Diseases, and Genetic Thrombophilia. AB - The objective of this study was to evaluate the heritability of neonatal arterial ischemic stroke (NAIS) in relation to family history of thromboembolic event, maternal diseases, and thrombophilia in both parents ( F5G1691A, F2G20210A, and MTHFRC677 T mutations). Forty-two consecutive infants >=36 weeks of gestation <28 days of life with acute symptomatic NAIS and their parents, as well as 129 controls, were prospectively recruited. Information on maternal data (age, body mass index, oral contraception, migraine, epilepsy, hypertension, and immune disease) and a 3-generation pedigree regarding myocardial infarction, pulmonary embolism, cerebrovascular event, and deep vein thrombosis were obtained. Thrombophilia and maternal diseases did not differ between cases and controls, except for the use of oral contraceptives (more frequent in mothers of controls). No differences were found regarding each studied antecedent of thromboembolic event in the families. The NAIS group showed a higher presence of positive family history among second-degree maternal relatives than did the control infants (odds ratio 4.10; 95% confidence interval 1.29-12.99). Our study does not support the hypothesis that common genetic thrombophilia or familial predisposition to thromboembolic events is associated with the occurrence of idiopathic NAIS. PMID- 29108423 TI - Linking Nurses' Clinical Leadership to Patient Care Quality: The Role of Transformational Leadership and Workplace Empowerment. AB - Background While improving patient safety requires strong nursing leadership, there has been little empirical research that has examined the mechanisms by which leadership influences patient safety outcomes. Aim To test a model examining relationships among transformational leadership, structural empowerment, staff nurse clinical leadership, and nurse-assessed adverse patient outcomes. Methods A cross-sectional survey was conducted with a randomly selected sample of 378 registered nurses working in direct patient care in acute care hospitals across Ontario, Canada. Structural equation modeling was used to test the hypothesized model. Results The model had an acceptable fit, and all paths were significant. Transformational leadership was significantly associated with decreased adverse patient outcomes through structural empowerment and staff nurse clinical leadership. Discussion This study highlights the importance of transformational leadership in creating empowering practice environments that foster high-quality care. The findings indicate that a more complete understanding of what drives desired patient outcomes warrants the need to focus on how to empower nurses and foster clinical leadership practices at the point of care. Conclusion In planning safety strategies, managers must demonstrate transformational leadership behaviors in order to modify the work environment to create better defenses for averting adverse events. PMID- 29108424 TI - Correct microarray analysis approaches in 'Hsa-circRNA11783-2 in peripheral blood is correlated with coronary artery disease and type 2 diabetes mellitus'. AB - We read with great interest the article by Li et al. The results are illuminating for understanding the relationship among Hsa-circRNA11783-2, coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). However, from our perspective, the bioinformatics analyses need further context as the statistics for differential fold changes in expression data are not explained fully. The authors seem to use unadjusted p values for detecting differentially expressed circular RNA (differentially expressed genes (DEGs)) between the control, CAD and T2DM group. Due to the high false positives caused by a large number of probes and multiple comparisons, it seems essential to analyse microarray data properly to reach a reliable result by a statistical method. Only selecting circular RNA with greater than two fold change with unadjusted p values < 0.05 in expression is not reliable and suitable for high-level microarray analysis. PMID- 29108426 TI - Doctors at war: life and death in a field hospital. PMID- 29108425 TI - Bipolar Disorder Associated with Another Autoimmune Disease-Pemphigus: A Population-based Study. AB - OBJECTIVES: Recent evidence suggests a notable role for inflammation and immune dysregulation in the neuroprogression of bipolar disorders (BD). Several autoimmune comorbidities have been reported in association with BD. However, the epidemiological relationship between pemphigus and BD has not yet been elucidated. We aimed to estimate the association between pemphigus and BD using a large-scale, real-life computerized database. METHODS: Data for this study were retrieved from the database of the Clalit Health Services, the largest, state mandated, health service organization in Israel. This study was designed as a cross-sectional study. The proportion of patients with BD was compared between patients diagnosed with pemphigus and age-, sex-, and ethnicity-matched control subjects. A logistic regression model was performed to estimate how pemphigus and other covariates contributed as risk factors for BD. RESULTS: A total of 1,985 pemphigus cases and 9,874 controls were included in the study. The prevalence of BD was greater in cases with pemphigus than in controls (1.0% v. 0.5%, respectively; P = 0.023). This coexistence was more prominent among patients of Jewish ethnicity. After controlling for confounders, such as age, sex, ethnicity, socioeconomic status, drug abuse, alcohol abuse, smoking, healthcare utilization, and comorbidities, pemphigus demonstrated a substantial independent association with BD (OR, 1.7; 95% CI, 1.0 to 2.9). CONCLUSIONS: Pemphigus is significantly associated with BD. Patients with pemphigus should be assessed for comorbid BD. Experimental research is needed to better recognize the biological mechanisms underlying this observation. PMID- 29108427 TI - What is all this fuss about Tus? Comparison of recent findings from biophysical and biochemical experiments. AB - Synchronizing the convergence of the two-oppositely moving DNA replication machineries at specific termination sites is a tightly coordinated process in bacteria. In Escherichia coli, a "replication fork trap" - found within a chromosomal region where forks are allowed to enter but not leave - is set by the protein-DNA roadblock Tus-Ter. The exact sequence of events by which Tus-Ter blocks replisomes approaching from one direction but not the other has been the subject of controversy for many decades. Specific protein-protein interactions between the nonpermissive face of Tus and the approaching helicase were challenged by biochemical and structural studies. These studies show that it is the helicase-induced strand separation that triggers the formation of new Tus-Ter interactions at the nonpermissive face - interactions that result in a highly stable "locked" complex. This controversy recently gained renewed attention as three single-molecule-based studies scrutinized this elusive Tus-Ter mechanism - leading to new findings and refinement of existing models, but also generating new questions. Here, we discuss and compare the findings of each of the single molecule studies to find their common ground, pinpoint the crucial differences that remain, and push the understanding of this bipartite DNA-protein system further. PMID- 29108428 TI - The Effect of Transarterial Chemoembolization in Combination With Kang'ai Injection on Patients With Intermediate Stage Hepatocellular Carcinoma: A Prospective Study. AB - BACKGROUND: The outcome of patients with intermediate stage hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) remains poor. Search for a more effective therapy is still necessary. OBJECTIVE: This study aimed to investigate the effect of combining TACE with Kang'ai (KA) injection for treating patients with intermediate stage HCC. METHODS: A total of 89 patients with intermediate stage HCC were enrolled and divided into TACE +KA group (n = 48) receiving repeated TACE plus KA injection, and TACE group (n = 41) receiving repeated TACE alone. All patients were prospectively studied. Primary endpoints were overall survival (OS) and time to radiologic progression (TTP). RESULTS: The TACE + KA group had significantly longer median OS (27.0 vs 21.0 months, P = .038) and TTP (12.0 vs 10.0 months, P = .028) than TACE group. The 1-, 2-, and 3 year OS rates in the TACE + KA group were markedly higher than in TACE group (88.5%, 58.8%, and 20.8% vs 81.3%, 44.9%, and 6.7%, respectively, P = .038), while the 1- and 2-year TTP rates in the TACE + KA group were significantly lower than in TACE group (49.3% and 86.9% vs 75.3% and 100%, P = .028). TACE + KA group displayed significantly lower incidences of intrahepatic and extrahepatic metastases, as well as postembolization syndrome than TACE group ( P < .05). Multivariate analyses revealed group ( P = .023), maximum tumor size ( P = .019), and tumor number ( P = .034) as significant predictors for OS, and group ( P = .046), maximum tumor size ( P = .002) and alpha-fetoprotein level ( P = .020) as significant predictors for TTP. Both TACE and KA injection were well tolerated. CONCLUSION: TACE plus KA injection is more effective than TACE alone for treating patients with intermediate stage HCC in this nonrandomized study. Further research is warranted. PMID- 29108431 TI - [Articles of the Hungarian Medical Journal from December, 1968]. PMID- 29108430 TI - Exploration of the Pathophysiology of Chronic Pain Using Quantitative EEG Source Localization. AB - Chronic pain affects more than 35% of the US adult population representing a major public health imperative. Currently, there are no objective means for identifying the presence of pain, nor for quantifying pain severity. Through a better understanding of the pathophysiology of pain, objective indicators of pain might be forthcoming. Brain mechanisms mediating the painful state were imaged in this study, using source localization of the EEG. In a population of 77 chronic pain patients, significant overactivation of the "Pain Matrix" or pain network, was found in brain regions including, the anterior cingulate, anterior and posterior insula, parietal lobule, thalamus, S1, and dorsolateral prefrontal cortex (DLPFC), consistent with those reported with conventional functional imaging, and extended to include the mid and posterior cingulate, suggesting that the increased temporal resolution of electrophysiological measures may allow a more precise identification of the pain network. Significant differences between those who self-report high and low pain were reported for some of the regions of interest (ROIs), maximally on left hemisphere in the DLPFC, suggesting encoding of pain intensity occurs in a subset of pain network ROIs. Furthermore, a preliminary multivariate logistic regression analysis was used to select quantitative-EEG features which demonstrated a highly significant predictive relationship of self-reported pain scores. Findings support the potential to derive a quantitative measure of the severity of pain using information extracted from a multivariate descriptor of the abnormal overactivation. Furthermore, the frequency specific (theta/low alpha band) overactivation in the regions reported, while not providing direct evidence, are consistent with a model of thalamocortical dysrhythmia as the potential mechanism of the neuropathic painful condition. PMID- 29108432 TI - Efficacy and safety of a combination of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis. AB - BACKGROUND: Using network meta-analysis, we assessed the efficacy and safety of a combination regimen of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer. METHODS: We searched the Medline, Embase, and Cochrane Library electronic databases (through December 2016) for phase II/III randomized controlled trials that compared regimens of one or two HER2 targeted agents combined with trastuzumab or chemotherapy. A network meta analysis including direct and indirect analyses was conducted in WinBUGS using fixed and random effects. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. The primary outcome was overall survival. RESULTS: The network meta-analysis incorporated nine HER2-targeted regimens with 9 direct comparisons and 28 indirect comparisons for the main outcomes (8 studies; n = 3976). Combining direct and indirect effects showed significant increased efficacy of trastuzumab and docetaxel plus pertuzumab (TDP) over other regimens as first-line treatment. With indirect comparison of overall safety, TDP, TDM-1, and TDM-1 plus pertuzumab demonstrated a lower risk of grade 3-4 adverse events compared to other regimens. CONCLUSIONS: TDPs are a preferred first-line treatment for HER2-positive metastatic breast cancer compared with other target agent regimens. PMID- 29108433 TI - The human milk oligosaccharides are not affected by pasteurization and freeze drying. AB - OBJECTIVES: Human milk oligosaccharides (HMOs) are known as important factors in neurologic and immunologic development of neonates. Moreover, freeze-drying seems to be a promising storage method to improve the processes of human milk banks. However, the effects of pasteurization and freeze-drying on HMOs were not evaluated yet. The purpose of this study is to analyze and compare the HMOs profiles of human milk collected before and after the pasteurization and freeze drying. METHODS: Totally nine fresh human milk samples were collected from three healthy mothers at the first, second, and third week after delivery. The samples were treated with Holder pasteurization and freeze-drying. HMOs profiles were analyzed by matrix-assisted laser desorption/ionization (MALDI) time-of flight/time-of-flight (TOF/TOF) mass spectrometry and compared between samples collected before and after the treatments. RESULTS: Human milk samples showed significantly different HMO patterns between mothers. However, HMOs were not affected by lactation periods within 3 weeks after delivery (r2 = 0.972-0.999, p < .001). Moreover, both of pasteurization and freeze-drying were found not to affect HMO patterns in a correlation analysis (r2 = 0.989-0.999, p < .001). CONCLUSION: HMO patterns were found not to be affected by pasteurization and freeze-drying of donor milks. We hope that introducing freeze-drying to the human milk banks would be encouraged by the present study. However, the storage length without composition changes of HMOs after freeze-drying needs to be evaluated in the further studies. PMID- 29108434 TI - Carers Victoria response to the low availability of public psychiatric beds. PMID- 29108429 TI - Sources of spontaneous mutagenesis in bacteria. AB - Mutations in an organism's genome can arise spontaneously, that is, in the absence of exogenous stress and prior to selection. Mutations are often neutral or deleterious to individual fitness but can also provide genetic diversity driving evolution. Mutagenesis in bacteria contributes to the already serious and growing problem of antibiotic resistance. However, the negative impacts of spontaneous mutagenesis on human health are not limited to bacterial antibiotic resistance. Spontaneous mutations also underlie tumorigenesis and evolution of drug resistance. To better understand the causes of genetic change and how they may be manipulated in order to curb antibiotic resistance or the development of cancer, we must acquire a mechanistic understanding of the major sources of mutagenesis. Bacterial systems are particularly well-suited to studying mutagenesis because of their fast growth rate and the panoply of available experimental tools, but efforts to understand mutagenic mechanisms can be complicated by the experimental system employed. Here, we review our current understanding of mutagenic mechanisms in bacteria and describe the methods used to study mutagenesis in bacterial systems. PMID- 29108435 TI - Irreproducible data: Problems and solutions for psychiatry. PMID- 29108436 TI - Anorexia nervosa: More than a body image disorder. PMID- 29108437 TI - Latent profiles of early developmental vulnerabilities in a New South Wales child population at age 5 years. AB - OBJECTIVE: Detecting the early emergence of childhood risk for adult mental disorders may lead to interventions for reducing subsequent burden of these disorders. We set out to determine classes of children who may be at risk for later mental disorder on the basis of early patterns of development in a population cohort, and associated exposures gleaned from linked administrative records obtained within the New South Wales Child Development Study. METHODS: Intergenerational records from government departments of health, education, justice and child protection were linked with the Australian Early Development Census for a state population cohort of 67,353 children approximately 5 years of age. We used binary data from 16 subdomains of the Australian Early Development Census to determine classes of children with shared patterns of Australian Early Development Census-defined vulnerability using latent class analysis. Covariates, which included demographic features (sex, socioeconomic status) and exposure to child maltreatment, parental mental illness, parental criminal offending and perinatal adversities (i.e. birth complications, smoking during pregnancy, low birth weight), were examined hierarchically within latent class analysis models. RESULTS: Four classes were identified, reflecting putative risk states for mental disorders: (1) disrespectful and aggressive/hyperactive behaviour, labelled 'misconduct risk' ( N = 4368; 6.5%); (2) 'pervasive risk' ( N = 2668; 4.0%); (3) 'mild generalised risk' ( N = 7822; 11.6%); and (4) 'no risk' ( N = 52,495; 77.9%). The odds of membership in putative risk groups (relative to the no risk group) were greater among children from backgrounds of child maltreatment, parental history of mental illness, parental history of criminal offending, socioeconomic disadvantage and perinatal adversities, with distinguishable patterns of association for some covariates. CONCLUSION: Patterns of early childhood developmental vulnerabilities may provide useful indicators for particular mental disorder outcomes in later life, although their predictive utility in this respect remains to be established in longitudinal follow-up of the cohort. PMID- 29108438 TI - Staging sets trajectory. PMID- 29108439 TI - Research into Australian emergency services personnel mental health and wellbeing: An evidence map. AB - BACKGROUND: Evidence maps are a method of systematically characterising the range of research activity in broad topic areas and are a tool for guiding research priorities. AIMS: 'Evidence-mapping' methodology was used to quantify the nature and distribution of recent peer-reviewed research into the mental health and wellbeing of Australian emergency services personnel. METHODS: A search of the PsycINFO, EMBASE and Cochrane Library databases was performed for primary research articles that were published between January 2011 and July 2016. RESULTS: In all, 43 studies of primary research were identified and mapped. The majority of the research focused on organisational and individual/social factors and how they relate to mental health problems/wellbeing. There were several areas of research where very few studies were detected through the mapping process, including suicide, personality, stigma and pre-employment factors that may contribute to mental health outcomes and the use of e-health. No studies were detected which examined the prevalence of self-harm and/or harm to others, bullying, alcohol/substance use, barriers to care or experience of families of emergency services personnel. In addition, there was no comprehensive national study that had investigated all sectors of emergency services personnel. CONCLUSION: This evidence map highlights the need for future research to address the current gaps in mental health and wellbeing research among Australian emergency services personnel. Improved understanding of the mental health and wellbeing of emergency services personnel, and the factors that contribute, should guide organisations' wellbeing policies and procedures. PMID- 29108440 TI - Cardiopreventive effects of camel milk against carbon tetrachloride induced oxidative stress, biochemical and histological alterations in mice. AB - The present study was designed to examine the preventive effects of camel milk (CM) against the toxic effects of acute exposure to carbon tetrachloride (CCl4) on the heart tissue of mice. Administration of a single dose of CCl4 caused cardio toxicity as monitored by an increase in lipid peroxidation (thiobarbituric acid reactive substances), protein carbonyl level and antioxidant markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione and vitamin C) in the heart tissue. Moreover, CCl4 caused a distinguished rise of plasma aspartate aminotransferase, lactate dehydrogenase, troponin I, and creatine kinase activities. Furthermore, CM ameliorated biochemical and histological parameters as compared to CCl4-treated group. Overall, this study indicates that CM is efficient in inhibiting oxidative stress induced by CCl4 and suggests that the administration of this milk may be helpful in the prevention of cardio toxicity complications. PMID- 29108441 TI - Driven to Support: Individual- and County-Level Factors Associated With Public Support for Active Transportation Policies. AB - PURPOSE: To assess predictors of stated support for policies promoting physically active transportation. DESIGN: Cross-sectional. SETTING: US counties selected on county-level physical activity and obesity health status. PARTICIPANTS: Participants completing random-digit dialed telephone survey (n = 906). MEASURES: Survey measures assessed stated support for 5 policies to promote physically active transportation, access to active transportation facilities, and time spent in a car. County-level estimates included household car dependence and funding for bicycle-pedestrian projects. ANALYSIS: Multivariable generalized linear mixed models using binary distribution and logit link, accounting for clustering within county. RESULTS: Respondents supported policies for accommodating bicyclists and pedestrians through street improvements (89%), school active transportation programs (75%), employer-funded active commuting incentives (67%), and allocation of public funding (68%) and tax support (56%) for building and maintaining public transit. Residents spending >2 h/d (vs <0.7 hours) in cars were more likely to support street (odds ratio [OR]: 1.87; confidence interval [CI]: 1.09-3.22) and public transit (OR: 1.85; CI: 1.24-2.77) improvements. Residents in counties investing >$1.6 million in bicycle and pedestrian improvements expressed greater support for funding (OR: 1.71; CI: 1.04-2.83) and tax increases (OR: 1.73; CI: 1.08-2.75) for transit improvements compared to those with lower prior investments (<$276 100). CONCLUSION: Support for policies to enable active transportation is higher where relevant investments in active transportation infrastructure are large (>$1.6 M), public transit is nearby, and respondents drive >2 h/d. PMID- 29108442 TI - The Effects of Exercise on Memory Function Among Young to Middle-Aged Adults: Systematic Review and Recommendations for Future Research. AB - OBJECTIVE: To systematically summarize the experimental effects of exercise on cognitive-related memory function among young to middle-aged adults, which has yet to be done in the literature. DATA SOURCE: PubMed. STUDY INCLUSION AND EXCLUSION CRITERIA: Studies were included if they were published in the English language, indexed in PubMed, employed an experimental study design (eg, traditional parallel group randomized controlled trial: either acute intervention or chronic/training intervention study), and conducted among human adults. Studies were excluded if nonhumans (ie, animal models) were studied, if children/adolescents (<18 years) or older adults (>50 years) were evaluated, and if select chronic diseases (eg, diabetes and dementia) were present. DATA EXTRACTION: A systematic review approach was employed. DATA SYNTHESIS: An extraction table was created synthesizing the key results, and recommendations for future research are emphasized. RESULTS: Among the 17 evaluated studies, 2 were published before the year 2000 (ie, 1998 and 1999), 2 were published in 2007, and the remaining 13 were published in the years 2011 and beyond. This highlights the emergence of this research topic within this age-group (young to middle-aged adults). Among the 17 evaluated studies, 14 were conducted among healthy samples, with 3 conducted among those with a diagnosis of depression. Among the 17 studies, 4 employed a chronic training protocol, with 13 utilizing an acute exercise protocol. Among the 3 experimental studies in the depressed population, all demonstrated a favorable effect of exercise on memory function. Among the 14 trials in the nondepressed population, 10 (71%) demonstrated a favorable effect of exercise on some aspect of memory function. CONCLUSION: Acute and chronic exercise appears to play a pronounced effect on memory function among young to middle-aged adults. Implications and recommendations for future research are outlined in this systematic review. PMID- 29108443 TI - Translating Healthy Living Messages to Postpartum Women and Their Partners After Gestational Diabetes (GDM): Body Habitus, A1C, Lifestyle Habits, and Program Engagement Results From the Families Defeating Diabetes (FDD) Randomized Trial. AB - PURPOSE: The Families Defeating Diabetes intervention evaluated a postpartum healthy living program for women with recent gestational diabetes mellitus (GDM). DESIGN: Randomized controlled trial. SETTING: Tertiary centers in London, Calgary, and Victoria, Canada. PARTICIPANTS: Women with GDM and partners; 46% of eligible maternal participants agreed to participate. INTERVENTION: Interventional (INT) participants received a healthy living seminar at 3 months; access to a walking group/Website; biweekly e-mails. Control (CON) participants received a contemporary postpartum diabetes prevention handout. MEASURES: Maternal, partner, and offspring demographics at baseline, 3, and 12 months. ANALYSIS: Percentages of women losing >=7% of postpartum weight were compared by chi2 testing; body habitus comparisons by analysis of covariance (ANCOVA); maternal A1C comparisons by unpaired t tests; participant outcome associations by Pearson correlation coefficients. RESULTS: Maternal participants were 170 (89 INT and 81 CON) with 63 partners (30 INT and 33 CON); 103 (73 maternal; 30 partners) were lost to follow-up; 57% of maternal participants completed 12 months; 33% INT women (n = 50) lost >=7% weight versus 25% CON women (n = 47), P = .43. Interventional participant results did not correlate with accession of study elements. Maternal completion was significantly associated with partner involvement, breastfeeding, higher income, and education. Paternal weights correlated significantly with maternal and offspring weights. CONCLUSION: Families Defeating Diabetes outcomes were not significantly different for INT maternal or paternal participants versus CON participants. Secondary outcomes of future value included statistically significant positive associations between paternal participation, socioeconomic indicators, and maternal study completion, significant correlations between maternal, paternal, and offspring weights as well as insights into study component engagement. PMID- 29108444 TI - Outcomes after periviable ultrasound-indicated cerclage. AB - BACKGROUND: Cerclage placed for a sonographically short cervix has been shown to reduce the risk of preterm delivery in women with a history of prior preterm birth. While short cervix is traditionally placed before viability, the threshold gestational age at which viability is achieved continues to decrease, and, as a result, a larger subset of women may be ineligible to receive this potentially beneficial procedure. OBJECTIVE: To evaluate the association between obstetric outcomes and perioperative complications after placement of an ultrasound indicated cerclage at periviability compared to placement in the previable period. METHODS: This retrospective cohort study of patients who underwent ultrasound-indicated cerclage evaluated obstetric outcomes and perioperative complications based on gestational age at cerclage placement. Ultrasound indicated cerclage was considered to have been placed at periviability if placed at 22 to <24 weeks (exposed) and at previability if placed at 16 to <22 weeks gestational age (unexposed). The primary outcome was preterm delivery <36 weeks. Secondary outcomes included mean gestational age at delivery, preterm delivery <32 weeks, <28, and <24 weeks, preterm premature rupture of membranes (PPROM), chorioamnionitis, and perioperative complications. Adjusted analyses were performed to account for demographic and obstetric factors. RESULTS: Of the 426 patients included in the analysis, 94 (22%) had cerclage placed between >=22 weeks to <24 weeks, while 332 (78%) had cerclage placed at <22 weeks. On univariate analysis, women who had a periviable cerclage placed were less likely to have a recurrent preterm delivery <36 weeks compared to women with previable cerclage placement (26.6 versus 38.3%, respectively, p = .04). The adjusted model did not demonstrate a significant difference in risk for preterm delivery <36 weeks associated with periviable versus previable cerclage (odds ratio 0.66, 95%CI 0.37-1.17). Secondary outcomes were similar between the previable and periviable groups, including mean gestational age at delivery (35.1 versus 36.2 weeks, respectively, p = .08) and preterm delivery before 32-week gestation (20.7 versus 13.8%, respectively, p = .17). Intraoperative and postoperative complications were rare and rates were similar between groups. CONCLUSIONS: Obstetric outcomes between patients receiving periviable and previable cerclage are similar. Ultrasound-indicated cerclage placement is associated with a relatively low rate of complications. Given the evidence supporting benefit of cerclage for women with short ultrasound cervical length and prior preterm birth, our findings demonstrate that benefits of placement at >=22 weeks to <24 weeks may outweigh risks. PMID- 29108445 TI - Correction to: Ota et al., Use of hormone therapies in disseminated carcinomatosis of the bone marrow associated with hormone receptor-positive breast cancer. PMID- 29108446 TI - The usefulness of mobile insulator sheets for the optimisation of deep heating area for regional hyperthermia using a capacitively coupled heating method: phantom, simulation and clinical prospective studies. AB - PURPOSE: To evaluate the feasibility and efficacy of deep regional hyperthermia with the use of mobile insulator sheets in a capacitively coupled heating device. MATERIALS AND METHODS: The heat was applied using an 8-MHz radiofrequency capacitive device. The insulator sheet was inserted between the regular bolus and cooled overlay bolus in each of upper and lower side of the electrode. Several settings using the insulator sheets were investigated in an experimental study using an agar phantom to evaluate the temperature distributions. The specific absorption rate (SAR) distributions in several organs were also computed for the three-dimensional patient model. In a clinical prospective study, a total of five heating sessions were scheduled for the pelvic tumours, to assess the thermal parameters. The conventional setting was used during the first, third and fifth treatment sessions, and insulator sheets were used during the second and fourth treatment sessions. RESULTS: In the phantom study, the higher heating area improved towards the centre when the mobile insulator sheets were used. The subcutaneous fat/target ratios for the averaged SARs in the setting with the mobile insulator (median, 2.5) were significantly improved compared with those in the conventional setting (median, 3.4). In the clinical study, the thermal dose parameters of CEM43 degrees CT90 in the sessions with the mobile insulator sheets (median, 1.9 min) were significantly better than those in the sessions using a conventional setting (median, 1.0 min). CONCLUSIONS: Our novel heating method using mobile insulator sheets was thus found to improve the thermal dose parameters. Further investigations are expected. PMID- 29108447 TI - From which level of competition in clubs are adolescents at greater risk of injury compared with outside-of-clubs athletes? A school-based study. AB - OBJECTIVES: Sport practice is a key factor in a person's physical and mental health but, for adolescent athletes, some injuries lead to health problems in the long term. The literature provides multiple factors for understanding injury but does not give information about injury risk related to each level of play in a large sample of multisport athletes. This study investigates this relationship in 14- to 19-year-old adolescents. METHODS: The survey on adolescents and health was conducted in classrooms of France, from February to March 2015. Only sports players were included in the analyses (n = 986). The levels of play were divided into five categories: outside of a club/no competition, club player/no competition, club player/local level, club player/state level and club player/national and higher level. A three-step binary logistic regression analysis with age, sex, type of sport, weekly hours of exposure, and level of play was used. RESULTS: During the past year, 48.1% of the adolescents were injured. Age and sex were not risk factors. The injury risk associated with the increases in level of play is higher than those related to the hours of exposure per week or the type of sport. In clubs, adolescents who do not compete or play at a local level showed no evidence of greater injury risk whereas state-level and national- and higher-level athletes were at greater risk than outside-of-club players (OR = 2.18, 95%CI = 1.13-3.94 and OR = 3.89, 95%CI = 2.07-7.31, respectively). CONCLUSION: Adolescents who play sports in clubs are clearly more exposed to injury than those who play outside of a club, mainly from state level. Age and sex are not related to injury. Future epidemiological studies should control adolescents' level of play. Special attention should be accorded to the injury risk of athletes playing at these levels of competition. PMID- 29108448 TI - The relationship between neutrophil-lymphocyte, platelet-lymphocyte ratio and cognitive functions in bipolar disorder. AB - OBJECTIVE: Inflammation is an important factor in pathophysiology of bipolar disorder. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) analysis are used to predict peripheral inflammation. The aim of this study is to calculate neutrophil-lymphocyte and platelet-lymphocyte ratios, which are inflammatory markers, and investigate their effect on cognitive functions in euthymic patients with objective bipolar disorder. METHOD: Twenty - eight patients with type-I bipolar disorder and 22 healthy controls matched for age, gender and educational status were included in the study. Neuropsychological tests were applied to all participants. Neutrophils, lymphocytes and platelets counts of the participants were measured and NLR and PLR were calculated. RESULTS: There was a significant negative correlation between NLR and Stroop interference score in study group. There was no statistically significant difference in NLR and PLR between study and control group. No significant correlation was found between PLR and neurocognitive test scores. CONCLUSION: This study revealed negative correlation between NLR and Stroop interference scores. We need further prospective studies with larger sample size to investigate role of inflammation on cognitive functions. PMID- 29108449 TI - Iatrogenic Cushing Syndrome in a 47-Year-Old HIV-Positive Woman on Ritonavir and Inhaled Budesonide. AB - Iatrogenic Cushing syndrome (CS) is a well-known complication of treating patients with systemic steroids. More rarely, it has been described in HIV positive patients on ritonavir (RTV) while using the inhaled corticosteroid fluticasone, which is metabolized through the cytochrome P450 3A4 (CYP3A4) enzyme system. In the presence of RTV, a known CYP3A4 enzyme inhibitor, the interaction can result in impaired metabolism and systemic accumulation of inhaled fluticasone resulting in iatrogenic CS. Iatrogenic CS has been less often described with inhaled budesonide compared to inhaled fluticasone. Therefore, inhaled budesonide is often used as an alternative therapy for patients on RTV to avoid iatrogenic CS. We report the fifth case report of budesonide-induced iatrogenic CS in an HIV-positive patient on RTV. We highlight the importance of early recognition of the syndrome and distinguishing it from HIV lipodystrophy. Finally, we review the literature for cases of iatrogenic CS involving RTV and commonly used steroids. PMID- 29108450 TI - Comparing Provider and Client Preferences for HIV Prevention Services in South Africa among Men Who Have Sex with Men. AB - Combination prevention efforts are now recommended toward reducing HIV incidence among men who have sex with men (MSM). Understanding the perceptions of both MSM and service providers is critical to informing the development of prevention packages and ultimately improving intervention effectiveness. This study assessed the preferences of MSM and health service providers in the administration of HIV prevention efforts. Qualitative data were gathered from a series of separate MSM and health care provider focus groups in 2 South African cities. Participants discussed HIV-prevention services and MSM client experiences within South Africa and identified the 3 most important clinic characteristics and 3 most important HIV-prevention services for MSM clients. Priorities indicated by both MSM and health care providers were confidentiality of visit, friendly staff, and condoms, while discrepancies existed between MSM and providers regarding provider consistency and the provision of pre-exposure prophylaxis/post-exposure prophylaxis (PrEP/PEP) and lubricant as prevention methods. Effective interventions must address these discrepancies through the design of intervention and provider training to optimally accommodate MSM. PMID- 29108451 TI - NEDD4-2-dependent control of Na+ homeostasis and renal disease. PMID- 29108452 TI - Comparative study of radioprotective effects of selenium nanoparticles and sodium selenite in irradiation-induced nephropathy of mice model. AB - PURPOSE: The current study was undertaken to evaluate radioprotective effects of selenium (Se) nanoparticles in irradiation-induced nephropathy of mice model compared to sodium selenite. MATERIALS AND METHODS: Forty-five mice were divided into three major groups including control, Se nanoparticle, and sodium selenite. Each major group was further subdivided into three more groups receiving various doses of 0, 2, and 8 Gy gamma irradiation. Both of the supplements were administered intraperitoneally with the dose of 0.1 mg/kg for 14 consecutive days. At the end of each week, the animals were exposed to gamma radiation and 48 h after the last exposure, the animals were humanely euthanized, then blood and renal tissue samples were taken. Serum creatinine, urea, cystatin C, and beta-2 microglobulin levels as well as activities of renal antioxidant enzymes, superoxide dismutase, glutathione peroxidase and catalase, also malondialdehyde level, total antioxidant capacity, renal tissue Se content, and histopathological features were assessed. RESULTS: The results showed that both of the supplements could normalize aforementioned indices. However, selenium nanoparticles (Se-NPs) were more effective than sodium selenite. CONCLUSIONS: Conclusively, Se-NPs as an emerging potent antioxidant agent can protect against irradiation-induced nephropathy. PMID- 29108453 TI - Very low dose of flutamide in the treatment of hyperandrogenism. AB - Hyperandrogenism is a condition affecting 5-10% of adolescents. The aim of this study was to evaluate the efficacy of very low dose of flutamide in the treatment of hyperandrogenism in adolescence. One hundred and fifty-eight patients, presenting severe acne and/or hirsutism, received 62.5 mg/day of flutamide + ethinylestradiol + gestodene for 18 months. The patients were subjected to assessments of hepatic enzymes levels. Thirty subjects treated with drospirenone + ethinylestradiol represented the control group. After 18 months of treatment, it was obtained a decrease of hirsutism (-39.9%), an almost recovery of acne (98% of patients) with better results of those obtained in control group. Only one case of light hypertransaminasemia was recorded, regressed spontaneously. Very low dose of flutamide was successful and safe and in the treatment of hyperandrogenism in adolescence. PMID- 29108455 TI - Better together: Unifying discordant cell-cycle oscillator models. PMID- 29108454 TI - PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer. AB - PTEN phosphorylation at its C-terminal (C-tail) serine/threonine cluster negatively regulates its tumor suppressor function. However, the consequence of such inhibition and its downstream effects in driving lung cancer remain unexplored. Herein, we ascertain the molecular mechanisms by which phosphorylation compromises PTEN function, contributing to lung cancer. Replacement of the serine/threonine residues with alanine generated PTEN-4A, a phosphorylation-deficient PTEN mutant, which suppressed lung cancer cell proliferation and migration. PTEN-4A preferentially localized to the nucleus where it suppressed E2F1-mediated transcription of cell cycle genes. PTEN-4A physically interacted with the transcription factor E2F1 and associated with chromatin at gene promoters with E2F1 DNA-binding sites, a likely mechanism for its transcriptional suppression function. Deletion analysis revealed that the C2 domain of PTEN was indispensable for suppression of E2F1-mediated transcription. Further, we uncovered cancer-associated C2 domain mutant proteins that had lost their ability to suppress E2F1-mediated transcription, supporting the concept that these mutations are oncogenic in patients. Consistent with these findings, we observed increased PTEN phosphorylation and reduced nuclear PTEN levels in lung cancer patient samples establishing phosphorylation as a bona fide inactivation mechanism for PTEN in lung cancer. Thus, use of small molecule inhibitors that hinder PTEN phosphorylation is a plausible approach to activate PTEN function in the treatment of lung cancer. Abbreviations AKT V-Akt Murine Thymoma Viral Oncogene CA Cancer adjacent CDK1 Cyclin dependent kinase 1 CENPC-C Centromere Protein C ChIP Chromatin Immunoprecipitation co-IP Co immunoprecipitation COSMIC Catalog of Somatic Mutations In Cancer CREB cAMP Responsive Element Binding Protein C-tail Carboxy terminal tail E2F1 E2F Transcription Factor 1 ECIS Electric Cell-substrate Impedance Sensing EGFR Epidermal Growth Factor Receptor GSI Gamma Secretase Inhibitor HDAC1 Histone Deacetylase 1 HP1 Heterochromatin protein 1 KAP1/TRIM28 KRAB-Associated Protein 1/Tripartite Motif Containing 28 MAF1 Repressor of RNA polymerase III transcription MAF1 homolog MCM2 Minichromosome Maintenance Complex Component 2 miRNA micro RNA MTF1 Metal-Regulatory Transcription Factor 1 PARP Poly(ADP Ribose) Polymerase PD-1 Programmed Cell Death 1 PD-L1 Programmed Cell Death 1 Ligand 1 PI3K Phosphatidylinositol-4,5-Bisphosphate 3-Kinase PLK Polo-like Kinase pPTEN Phosphorylated PTEN PTEN Phosphatase and Tensin Homolog deleted on chromosome ten PTM Post Translational Modification Rad51 RAD51 Recombinase Rad52 RAD52 Recombinase RPA1 Replication protein A SILAC Stable Isotope Labeling with Amino Acids in Cell Culture SRF Serum Response Factor TKI Tyrosine Kinase inhbitors TMA Tissue Microarray TOP2A DNA Topoisomerase 2A. PMID- 29108456 TI - Cross-task and cross-manipulation stability in shifting the decision criterion. AB - In recognition memory experiments participants must discriminate between old and new items, a judgment influenced by response bias. Research has shown substantial individual differences in the extent to which people will strategically adjust their response bias to diagnostic cues such as the prior probability of an old item. Despite this significant between subject variability, shifts in bias have been found to be relatively predictive within individuals across memory tests. Experiment 1 sought to determine whether this predictability extends beyond memory. Results revealed that the amount a subject shifted response bias in a recognition memory task was significantly predictive of shifting in a visual perception task, suggesting that shifting can generalise outside of a specific testing domain. Experiment 2 sought to determine how predictive shifting would be across two manipulations well known to induce shifts in bias: a probability manipulation and a response payoff manipulation. A modest positive relationship between these two methods was observed, suggesting that shifting behaviour is relatively predictive across different manipulations of shifting. Overall, results from both experiments suggest that response bias shifting, like response bias setting, is a relatively stable behaviour within individuals despite changes in test domain and test manipulation. PMID- 29108457 TI - Screening for depression in Andean Latin America: Factor structure and reliability of the CES-D short form and the PHQ-8 among Bolivian public hospital patients. AB - Objective We assessed the validity and reliability of the Center for Epidemiologic Studies-Depression scale (CES-D) short form and the Patient Health Questionnaire-8 (PHQ-8) (two measures of depressive symptoms) among urban, low income patients from a heavily indigenous area of Andean Latin America. This is a patient population that is in many ways culturally distinct from the populations that have been included in previous Spanish language validation studies of these instruments. Methods We administered the CES-D Yale version short form and the PHQ-8 to 107 outpatients at public hospitals in La Paz and El Alto, Bolivia. We conducted exploratory factor analysis, checked internal reliability, and examined concordance between the two measures in identifying patients with clinically significant depressive symptoms. Results Internal reliability was high for both scales: PHQ-8 (Cronbach's alpha = 0.808) and CES-D (alpha = 0.825). A one-factor solution for the PHQ-8 was maintained after the removal of one poorly loading item. The CES-D showed a two-factor solution, with items for somatic symptoms and interpersonal problems loading on the same factor as negative affect. Using both the cutoff for depression recommended in prior studies and a sample specific cutoff of >=1 standard deviation above the mean, the two scales demonstrated only moderate agreement (kappa = 0.481-0.486). Conclusions The PHQ may be more appropriate for clinical use in the Andean region, given its greater specificity; however, lower than expected agreement between the scales suggests that they also measure different elements of depression. Irregularities with the factor structure of both scales suggest that further research with this population is needed to better understand depressive symptomology and improve screening in the region. PMID- 29108458 TI - A fuzzy logic-based warning system for patients classification. AB - Typically acute deterioration in sick people is preceded by subtle changes in the physiological parameters such as pulse and blood pressure. The Modified Early Warning Score is a scoring system developed to assist hospital staff in gauging these physiological changes and identifying patients in need of urgent medical care to avoid catastrophic deterioration. This work discusses the design and implementation of an equivalent warning system that utilizes fuzzy logic techniques to categorize patients' status. The system is implemented and tested in Rashid Centre for Diabetes and Research in UAE. Results are compared with those obtained using the Modified Early Warning System that is currently used in practice. We demonstrate that the implemented system provides reliable results that are in agreement with the current Modified Early Warning Score system, with the added benefit of a scoring scheme that provides a better insight into the status or medical condition of each patient. PMID- 29108459 TI - Comparison of Medication History Accuracy Between Nurses and Pharmacy Personnel. AB - PURPOSE: To evaluate the differences in medication history errors made by pharmacy technicians, students, and pharmacists compared to nurses at a community hospital. METHODS: One hundred medication histories completed by either pharmacy or nursing staff were repeated and evaluated for errors by a fourth-year pharmacy student. The histories were analyzed for differences in the rate of errors per medication. Errors were categorized by their clinical significance, which was determined by a panel of pharmacists, pharmacy students, and nurses. Errors were further categorized by their origin as either prescription (Rx) or over the counter (OTC). The primary outcome was the difference in the rate of clinically significant errors per medication. Secondary outcomes included the differences in the rate of clinically insignificant errors, Rx errors, and OTC errors. Differences in the types of errors for Rx and OTC medications were also analyzed. Additionally, the number of patients with no errors was compared between both groups. RESULTS: The pharmacy group had a lower clinically significant error rate per medication (0.03 vs 0.09; relative risk [RR] = 0.66; 95% confidence interval [CI]: 0.020-0.093; P = .003). For secondary outcomes, the pharmacy group had a lower total error rate (0.21 vs 0.36, RR = 0.58; 95% CI: 0.041-0.255; P = .007), Rx error rate (0.09 vs 0.27, RR = 0.44; 95% CI: 0.071-0.292; P = .002), and OTC error rate (0.24 vs 0.46; RR = 0.52; 95% CI: 0.057-0.382; P = .009) per medication. The pharmacy group completed 20% more medication histories without Rx errors ( P = .045) and 25% more histories without OTC errors ( P = .041). CONCLUSION: This study demonstrated that expanded use of pharmacy technicians and students improves the accuracy of medication histories in a community hospital. PMID- 29108460 TI - Prior irradiation results in elevated programmed cell death protein 1 (PD-1) in T cells. AB - PURPOSE: In this study we addressed the question whether radiation-induced adverse effects on T cell activation are associated with alterations of T cell checkpoint receptors. MATERIALS AND METHODS: Expression levels of checkpoint receptors on T cell subpopulations were analyzed at multiple post-radiation time points ranging from one to four weeks in mice receiving a single fraction of 1 or 4 Gy of gamma-ray. T cell activation associated metabolic changes were assessed. RESULTS: Our results showed that prior irradiation resulted in significant elevated expression of programmed cell death protein 1 (PD-1) in both CD4+ and CD8+ populations, at all three post-radiation time points. T cells with elevated PD-1 mostly were either central memory or naive cells. In addition, the feedback induction of PD-1 expression in activated T cells declined after radiation. CONCLUSION: Taken together, the elevated PD-1 level observed at weeks after radiation exposure is connected to T cell dysfunction. Recent preclinical and clinical studies have showed that a combination of radiotherapy and T cell checkpoint blockade immunotherapy including targeting the programmed death-ligand 1 (PD-L1)/PD-1 axis may potentiate the antitumor response. Understanding the dynamic changes in PD-1 levels in T cells after radiation should help in the development of a more effective therapeutic strategy. PMID- 29108462 TI - The Effect of Clear Speech on Temporal Metrics of Rhythm in Spanish-Accented Speakers of English. AB - This paper presents a comparative analysis of temporal rhythm in native American English talkers and Spanish-accented English talkers producing clear (hyperarticulated) speech and typical, conversational-style speech. Five acoustic measures of comparative vocalic and consonantal interval duration ("temporal metrics") were obtained from speech samples of 40 adult men and women (half native and half Spanish-accented talkers). In conversational-style speech, vocalic-based metrics differed significantly between native and Spanish-accented talkers, consistent with phonotactic differences between the two native languages. In clear speech, however, all metric values from the Spanish-accented talkers became more English-like and no longer differed significantly from those observed in the native English talkers. Post-hoc analysis revealed that native English talkers increased the duration of both weak and strong vowels in clear speech, whereas the Spanish-accented talkers increased the duration of strong vowels without changing the duration of weak vowels. Listener ease of understanding, as perceived by monolingual English speakers, was significantly improved in clear- compared with conversational-style speech for all talkers. The acoustic data help to explain the changes that result from use of clear speech in nonnative speakers. Together with the improved listener ease of understanding, these data strongly support the further exploration of clear speech as a clinical tool to improve prosody and hence, interpersonal communication, in nonnative speakers. PMID- 29108461 TI - Cdc20 overexpression is involved in temozolomide-resistant glioma cells with epithelial-mesenchymal transition. AB - Glioma remains one of the most aggressive and lethal cancers in central nervous system. Temozolomide (TMZ) is the most commonly used chemotherapeutic agent in gliomas. However, therapeutic benefits of TMZ could be very limited and all patients would finally suffer from tumor progression as the tumors develop resistance to TMZ. In this study, we aim to investigate the underlying mechanism of chemoresistance in glioma cell line and to identify whether there is still a close link between epithelial-mesenchymal transition (EMT) and TMZ resistance in gliomas. The real-time RT-PCR and Western blotting were used to measure the expression of EMT markers in TMZ-resistant cells. The migration and invasion assays were conducted to detect the cell motility activity in TMZ-resistant cells. The transfection was used to down-regulate the Cdc20 expression. The student t-test was applied for data analysis. We established stable TMZ-resistant glioma cells and designated as TR. Our results revealed that TR cells exhibited a significantly increased resistance to TMZ compared with their parental cells. Moreover, TMZ-resistant cells had acquired EMT-like changes. For the mechanism study, we measured a significant increased expression of CDC20 and decreased expression of Bim in TR cells. Moreover, upon suppression of CDC20 by shRNA transfection, TR cells underwent a reverse of EMT features. Importantly, knockdown of CDC20 enhanced the drug sensitivity of TR cells to TMZ. Our results suggested that inactivation of CDC20 could contribute to the future therapy that possibly overcomes drug resistance in human cancers. PMID- 29108463 TI - TD: The case of Diogenes Syndrome-deficit or denial? AB - Diogenes Syndrome (DS) is characterised by extreme self-neglect, domestic squalor, hoarding, social withdrawal, and lack of concern and shame for the individual's residential situation. This paper describes TD who was unable to identify emotional expressions of disgust and was borderline-impaired for facial recognition associated with perceptual difficulties. Problems interpreting expressions of disgust were interesting as TD was living in squalor, neglecting himself, and lacked concern for his circumstances. This led us to question whether the basis of his difficulties were neuropsychological or psychological in nature, which became the objective of this study, with a focus on shame and disgust. TD completed neuropsychological and psychological assessments alongside an experimental task investigating processing of disgust and his living situation. Results highlighted executive dysfunction but understanding of living with the consequences of squalor was spared as was emotion based decision-making. Assessment indicated difficulties with olfactory processing and aspects of interoceptive awareness. TD showed poor awareness of his living conditions and a lack of shame. Disgust sensitivity was unimpaired. It is unclear if TD's difficulties were caused by psychological or neuropsychological impairments, although both likely play a part. Further research is required to understand processes underpinning DS, particularly disgust and shame. PMID- 29108464 TI - Electrocardiographic alterations in patients consuming synthetic cannabinoids. AB - INTRODUCTION: The aim of this study was to investigate the electrocardiographic parameters in patients consuming synthetic cannabinoids. METHODS: Thirty-five patients who were consuming synthetic cannabinoids were enrolled to the study, prospectively. The control group included 35 healthy age and sex-matched volunteers. The standard 12-lead surface electrocardiograms of the study population were recorded. P maximum (Pmax), P minimum (Pmin), P wave dispersion, interatrial duration, P wave area in D2 derivation, abnormal P terminal force in V1 derivation, heart rate, QT interval, corrected QT, QT dispersion, PR interval duration and macrovolt T-wave alternans were evaluated by two experienced cardiologists. The intra-observer and inter-observer variations for all measurements were non-significant. RESULTS: Pmax and Pmin duration was not different between the groups ( p=0.96, p=0.15, respectively). However, P wave dispersion was higher in the patient group compared to control group (34+/-9.4, 29.5+/-6.6, p=0.02, respectively). QT interval was significantly higher in the patient group than the control group (380.3+/-25, 365.6+/-22.8, p=0.01, respectively). Besides, corrected QT was higher in the patient group compared to control group (415+/-36.8, 392+/-15.5, p=0.001, respectively). QT dispersion was also higher in the patient group than the control group (39.8+/-10.0, 29.2+/-5.4, p<0.001, respectively). CONCLUSION: Altered electrocardiography parameters linked with atrial and ventricular arrhythmia development may be observed in patients consuming synthetic cannabinoids. These patients should be evaluated regularly for cardiovascular disease and arrhythmia development. The electrocardiogram, which is a cheap and easy test to apply, can be used to determine the pro arrythmic risk in patients consuming synthetic cannabinoids. PMID- 29108465 TI - PolyMorphine provides extended analgesic-like effects in mice with spared nerve injury. AB - Abstract: Morphine is a well-characterized and effective analgesic commonly used to provide pain relief to patients suffering from both acute and chronic pain conditions. Despite its widespread use and effectiveness, one of the major drawbacks of morphine is its relatively short half-life of approximately 4 h. This short half-life often necessitates multiple administrations of the drug each day, which may contribute to both dependence and tolerance to morphine. Here, we tested the analgesic properties of a new polymer form of morphine known as PolyMorphine. This polymer has monomeric units of morphine incorporated into a poly(anhydride-ester) backbone that has been shown to hydrolyze into free morphine in vitro. Using an animal model of chronic pain, the spared nerve injury surgery, we showed that PolyMorphine is able to block spared nerve injury-induced hypersensitivity in mice for up to 24-h post-administration. Free morphine was shown to only block spared nerve injury-induced hypersensitivity for up to 2-h post-injection. PolyMorphine was also shown to act through the mu opioid receptor due to the ability of naloxone (a mu opioid receptor antagonist) to block PolyMorphine-induced analgesia in spared nerve injury animals pretreated with PolyMorphine. Additionally, we observed that PolyMorphine causes similar locomotor and constipation side effects as free morphine. Finally, we investigated if PolyMorphine had any effects in a non-evoked pain assay, conditioned place preference. Pretreatment of spared nerve injury mice with PolyMorphine blocked the development of conditioned place preference for 2-methyl 6-(phenylethynyl)pyridine (MPEP), a short-lasting mGluR5 antagonist with analgesic-like properties. Free morphine does not block the development of preference for MPEP, suggesting that PolyMorphine has longer lasting analgesic effects compared to free morphine. Together, these data show that PolyMorphine has the potential to provide analgesia for significantly longer than free morphine while likely working through the same receptor. PMID- 29108466 TI - Colchicine alleviates acute postoperative pain but delays wound repair in mice: roles of neutrophils and macrophages. AB - Background: Acute postoperative pain is induced by most incisional surgeries and usually resolves with wound repair. However, many patients experience moderate to severe pain despite receiving currently available postoperative pain relief. Accumulating evidence suggests that inflammatory cells, neutrophils, and macrophages infiltrating the wound site contribute to the acute inflammation, pain, and subsequent wound repair. Colchicine is commonly used to relieve pain in gout by inhibiting the infiltration of granulocytes and other motile cells. In this study, we examined the effects of colchicine on acute postoperative pain and wound repair by correlating the infiltration of neutrophils and macrophages in a mouse model of postoperative pain induced by plantar incision. Furthermore, these effects of colchicine were compared with clodronate liposomes, which selectively deplete circulating macrophages. Results: Plantar incision induced mechanical hypersensitivity in the ipsilateral hind paw that peaked one day and lasted for three days after the surgery. Treatment with colchicine significantly attenuated the early infiltration of Gr1-positive cells (neutrophils) around the incision site and mechanical hypersensitivity, which was accompanied with inhibition of the subsequent infiltration of Iba1-positive cells (macrophages) and macrophage polarization toward the proinflammatory M1 phenotype. By contrast, an intravenous injection of clodronate liposomes significantly inhibited the infiltration of macrophages around the incision site but had little effect on the infiltration of neutrophils or mechanical hypersensitivity. Importantly, colchicine treatment significantly delayed wound closure after the incisional surgery, whereas clodronate liposome administration had no effect on wound closure. Conclusion: These results suggest that colchicine can alleviate acute postoperative pain and also enhance the risk of delayed wound repair, which are associated with the suppression of neutrophil and subsequent proinflammatory M1 macrophage infiltration around the incision site, while the involvement of macrophages may be limited. PMID- 29108467 TI - SPOP-mediated degradation of BRD4 dictates cellular sensitivity to BET inhibitors. AB - Bromodomain and extra-terminal (BET) proteins are frequently overexpressed in various human cancers, therefore have been clinically pursed as attractive therapeutic anti-cancer targets. However, relatively little is known about the mechanism(s) underlying aberrant BET overexpression in human cancers. Recently, we reported that prostate cancer-derived SPOP mutants fail to interact with and promote BRD4 degradation, leading to accumulation of BRD4 in prostate cancer cells. As a result, prostate cancer cells harboring SPOP mutations are more resistant to BET inhibitors. Therefore, our results help to elucidate the tumor suppressor role of SPOP in the prostate cancer setting by negatively controlling BET proteins stability. More importantly, our results also provide a molecular basis for using combination with BET inhibitors and other inhibitors to treat prostate cancer patients with SPOP mutations. PMID- 29108468 TI - Senescence and Telomere Homeostasis Might Be Involved in Placenta Percreta Preliminary Investigation. AB - OBJECTIVE: Placenta percreta (PP) is an abnormal condition of trophoblast maturation and terminal differentiation through the uterine wall. We opted to study telomere homeostasis and senescence expression in trophoblasts from PP, the most severe subgroup of placenta accreta. STUDY DESIGN: Paraffin-embedded placental biopsies from pregnancies with percreta and normal placentation, matched by gestational age at delivery, were assessed for telomere length, aggregates, and senescence-associated heterochromatin foci using quantitative fluorescence in situ hybridization. Cyclin-dependent kinase inhibitors p21, p15, p16, and the tumor suppressor protein p53, known senescence-related markers, were assessed using immunohistochemical staining. RESULTS: Short telomeres were found more often in trophoblasts from the samples of PP (n = 9) compared to controls (n = 8; 54% +/- 20% vs 2.3% +/- 1.16%, respectively; P < .05). More cells with telomere aggregates (18.3% +/- 6.9%) were observed in the PP than in the control group (4.8% +/- 5.4%; P = .0005). The percentage of nucleic senescence-associated heterochromatin foci in the PP and control samples was similar (10.9% +/- 10.4% vs 10.7% +/- 15%, respectively; P = .97). Immunohistochemistry of senescence markers was expressed differently in PP compared to the controls: higher p15 expression (46.42% +/- 15.2% vs 36.63% +/- 12.2%, P = .004), higher p21 expression (59.8% +/- 22.1% vs 47.5% +/- 21.9%, P = .011), lower p16 expression (54.8% +/- 26.3% vs 73.4% +/- 18.9%, P = .000), and lower p53 expression (24.4% +/- 33.8% vs 34% +/- 14.4%, P = .000). CONCLUSION: Placenta percreta exhibits telomere alterations and changes in expression of several senescence markers. These might be related to altered trophoblast invasion maturation and placental detachment postpartum. PMID- 29108469 TI - The incidence of traumatic intracranial hemorrhage in head-injured older adults transported by EMS with and without anticoagulant or antiplatelet use. AB - Field triage guidelines recommend transport of head-injured patients on anticoagulants or antiplatelets to a higher-level trauma center based on studies suggesting a high incidence of traumatic intracranial hemorrhage (tICH). We compared the incidence of tICH in older adults transported by EMS with and without anticoagulation or antiplatelet use and evaluated the accuracies of different sets of field triage criteria to identify tICH. This was a prospective, observational study at 5 EMS agencies and 11 hospitals. Older adults (>=55 years) with head trauma and transported by EMS from Aug 2015 to Sept 2016 were eligible. EMS providers completed standardized data forms and patients were followed through ED or hospital discharge. We enrolled 1,304 patients; 1147 (88%) received a cranial CT scan and were eligible for analysis. 434 (33%) patients had anticoagulant or antiplatelet use and 112 (10%) had tICH. The incidence of tICH in patients with (11%, 95%CI 8-14%) and without (9%, 95%CI 7-11%) anticoagulant or antiplatelet use was similar. Anticoagulant or antiplatelet use was not predictive of tICH on adjusted analysis. Steps 1-3 criteria alone were not sensitive in identifying tICH (27%) while the addition of anticoagulant or antiplatelet criterion improved sensitivity (63%). Other derived sets of triage criteria were highly sensitive (>98%) but poorly specific (<11%). The incidence of tICH was similar between patients with and without anticoagulant or antiplatelet use. Use of anticoagulant or antiplatelet medications was not a risk factor for tICH. We were unable to identify a set of triage criteria that was accurate for trauma center need. PMID- 29108470 TI - The Chinese version of the Brief Assessment of Cognition in Affective Disorders: normative data of a Mandarin-speaking population. AB - OBJECTIVE: The Brief Assessment of Cognition in Affective Disorders (BAC-A) is administered to assess the cognitive impairments in patients with affective disorders. This study aims to develop the normative data and to explore the factor structure of the Chinese version of the BAC-A in a Mandarin-speaking population. METHOD: This cross-sectional study consisted of 220 healthy participants (age range: 19-79 years; mean age: 51.5 +/- 15.9 years, 48.2% male) in communities in Taiwan. We evaluated all participants with the BAC-A, which is a battery of tests containing verbal memory, working memory, motor speed, verbal fluency, attention & processing speed, and executive function, Affective Interference Test (AIT), Affective Interference Delayed Recognition Test (AIT DR), and Emotional Inhibition Test (EIT). We categorized the means and standard deviations of all subtests by age group and gender. Principal component analysis (PCA) was used to examine the factor structure of the BAC-A. RESULTS: Increased age was significantly correlated with reduced performance in all subtests of the BAC-A, except non-affective correct words in the AIT-DR. Compared to females, males exhibited better performance in motor speed, verbal fluency, and executive function, but had worse performance in total non-affective words in the AIT. The results yielded by PCA showed that the indices of the AIT, AIT-DR, and EIT were all correctly categorized, accordingly. CONCLUSIONS: The normative data of the Chinese BAC-A established in this study can serve as a cognitive function reference for Mandarin-speaking populations. Nevertheless, the reliability and validity of the Chinese BAC-A need to be further verified. PMID- 29108471 TI - Intranasally Delivered Wnt3a Improves Functional Recovery after Traumatic Brain Injury by Modulating Autophagic, Apoptotic, and Regenerative Pathways in the Mouse Brain. AB - Traumatic brain injury (TBI) is a prevalent disorder, but no effective therapies currently exist. An underlying pathophysiology of TBI includes the pathological elevation of autophagy. beta-Catenin, a downstream mediator of the canonical Wnt pathway, is a repressor of autophagy. The Wnt/beta-catenin pathway plays a crucial role in cell proliferation and neuronal plasticity/repair in the adult brain. We hypothesized that activation of this pathway could promote neuroprotection and neural regeneration following TBI. In the controlled cortical impact (CCI) model of TBI in C57BL/6 mice (total n = 160), we examined intranasal application of recombinant Wnt3a (2 MUg/kg) in a short-term (1 dose/day for 2 days) and long-term (1 dose/day for 7 days) regimen. Immunohistochemistry was performed at 1 to 14 days post-TBI to assess cell death and neurovascular regeneration. Western blotting measured canonical Wnt3a activity, expression of growth factors, and cell death markers. Longitudinal behavior assays evaluated functional recovery. In short-term experiments, Wnt3a treatment with a 60-min delay post-TBI suppressed TBI-induced autophagic activity in neurons (44.3 +/- 6.98 and 4.25 +/- 2.53 LC3+/NeuN+ double positive cells in TBI+Saline and TBI+Wnt3a mice, respectively; p < 0.0001, n = 5/group), reduced autophagic markers light chain 3 (LC3)-II and Beclin-1, as well as injury markers caspase-3 and matrix metalloproteinase 9 (MMP-9). The Wnt3a treatment reduced cell death and contusion volume (0.72 +/- 0.07 mm2 and 0.26 +/- 0.04 mm2 in TBI+Saline and TBI+Wnt3a mice, respectively; p < 0.001, n = 5/group). The 7-day Wnt3a treatment increased levels of beta-catenin and growth factors glial-derived growth factor (GDNF) and vascular endothelial growth factor (VEGF). This chronic Wnt3a therapy augmented neurogenesis (0.52 +/- 0.09 and 1.25 +/- 0.13 BrdU+/NeuN+ co-labeled cells in TBI+Saline mice and TBI+Wnt3a mice, respectively; p < 0.01, n = 6/group) and angiogenesis (0.26 +/- 0.07 and 0.74 +/- 0.13 BrdU+/GLUT1+ co-labeled cells in TBI+Saline and TBI+Wnt3a mice, respectively; p = 0.014, n = 6/group). The treatment improved performance in the rotarod test and adhesive removal test. Targeting the Wnt pathway implements a unique combination of protective and regenerative approaches after TBI. PMID- 29108472 TI - Maternal and fetal outcomes of emergency obstetric referrals to a Nigerian teaching hospital. AB - Our study sought to determine the maternal and fetal outcomes of emergency obstetric referrals to a Nigerian teaching hospital as well as assess reasons for these referrals. We enrolled women referred or who presented themselves to the emergency obstetric unit for management of complications of pregnancy, labour, delivery or the puerperium. The majority presented late, their mean duration of stay at the referring facility being 22.25 h. Only nine (7.3%) were transported by ambulance. Severe pre-eclampsia and eclampsia (in 33, 26.8%) were the commonest obstetric indications for referral. Stillbirths occurred in 20/122(16.4%). There were eleven maternal deaths, giving an emergency referral fatality rate of 8.9%. Both maternal and fetal outcomes of these emergency obstetric referrals were poor owing mainly to late presentation, this being the result, among other factors, of an inefficient referral system. PMID- 29108473 TI - Caesarean section wound infections and antibiotic use: a retrospective case series in a tertiary referral hospital in The Gambia. AB - Ours is the first published study to examine post-Caesarean section (CS) wound infections in The Gambia. We explored risk factors and clinical management retrospectively at a large referral hospital over a 12-month period. A total of 777 cases were identified and records for 682 (88%) were retrieved. The CS rate was 21.8% and the wound infection rate 13.2%. Risk factors included: length of labour; decision-to-incision time and stillbirth. Only 7.4% of women received preoperative antibiotic prophylaxis, but all women received multiple-dose, postoperative antibiotics. The wound infection rate found is likely to be an underestimate owing to loss to follow-up. The adherence to international guidelines regarding preoperative antibiotic prophylaxis needs to be improved. PMID- 29108475 TI - Innovations in Payer-Community Partnerships: The EmblemHealth Neighborhood Care Program. AB - Comprehensive and innovative strategies are needed to address and manage chronic diseases and conditions and to reduce health disparities. EmblemHealth Neighborhood Care (EHNC) sites provide community-based linkages across payers, health providers, and delivery systems and underserved communities using culturally sensitive methods tailored to meet the needs of the community. This article describes this novel initiative and early indicators of its feasibility. Three EHNC sites were established in New York City: Harlem, Cambria Heights, and Chinatown. Each site provides core health and customer services to members and the community. In addition, sites provide tailored services to meet the unique needs of each community. Preliminary data suggest that program and community members are utilizing the sites and returning for follow-up visits. Sites also demonstrate success in cross referral between EHNC teams. The EHNC program is both feasible from the payer's perspective and acceptable to diverse patient populations and settings. PMID- 29108474 TI - Molecular Testing for Oncogenic Gene Alterations in Pediatric Thyroid Lesions. AB - BACKGROUND: Thyroid nodules are less common in pediatric patients (i.e., those <=18 years) than they are in adults. The Bethesda System for Reporting Thyroid Cytopathology allows for individual risk stratification, but a significant number of nodules are indeterminate. Incorporating gene mutation panels and gene expression classifiers may aid in preoperative diagnosis. The overall aim of this study was to assess the prevalence of oncogene alterations in a representative pediatric population and across a broad-spectrum of thyroid tumor diagnoses. METHODS: This was a retrospective cross-sectional evaluation of 115 archived samples, including: 47 benign (29 follicular adenoma, 11 diffuse hyperplasia, four thyroiditis, and three multinodular goiter), six follicular thyroid carcinomas (FTC), 24 follicular variant of papillary thyroid carcinomas (fvPTC), 27 classic variant of PTC (cPTC), eight diffuse sclerosing variant of PTC (dsvPTC), and three other PTC. Molecular testing was performed by multiplex qualitative polymerase chain reaction followed by bead array cytometry. Oncogene results were analyzed for association with age, sex, histology, lymph node metastasis, and intrathyroidal spread. RESULTS: A mutation in one of the 17 molecular markers evaluated was found in: 2/6 (33%) FTC, 8/24 (33%) fvPTC, 17/27 (63%) cPTC, and 4/8 (50%) dsvPTC. Mutations in RAS or PAX8/PPARG were exclusive to FTC and fvPTC. BRAF was the most common mutation in cPTC (12/17; 71%), and RET/PTC was the only mutation associated with dsvPTC. Overall, a mutation was found in 32/68 (47%) malignant specimens, with a single follicular adenoma positive for PAX8/PPARG. The relative distribution of gene alterations in pediatric lesions was similar to adults. The presence of a BRAF mutation in pediatric cPTC did not predict a more invasive phenotype. CONCLUSIONS: Of 33 nodules with genetic alterations, 32 were malignant. Mutations in RAS were most frequently associated with FTC, RET/PTC rearrangements with dsvPTC, and invasive fvPTC, and BRAF with cPTC. These results suggest a clinical role for mutational analysis of pediatric nodules to guide the surgical approach. PMID- 29108476 TI - Intermittent Catheterization: The Devil Is in the Details. AB - During the last few years, the international community debated urinary tract infection and re-use of catheters when managing neurogenic lower urinary tract dysfunction (NLUTD) among individuals with spinal cord injury (SCI). In this respect, the 2014 Cochrane review by Prieto and colleagues, "Intermittent catheterisation for long-term bladder management," became one of the leading documents that captured the minds and attention of clinicians around the world. Although numerous countries had switched to single-use catheters for management of NLUTD following SCI, the opinion that was expressed in the 2014 Cochrane review had a strong influence on healthcare providers and agencies to recommend re-use of catheters. However, many clinicians have expressed concern regarding the conclusions in the 2014 Cochrane review by Prieto and colleagues. We therefore conducted an independent appraisal of the data and analyses presented in the review. Our appraisal identified crucial discrepancies of data extraction and analyses within the review. In appraisal to that of Prieto and colleagues' review, our analysis revealed a trend to favor single over multiple use of catheters. After addressing our concerns to Cochrane's acting Editor-in-Chief, the most recent version of the 2014 Cochrane review was withdrawn from publication. PMID- 29108478 TI - Evaluation of a computer-based prompting intervention to improve essay writing in undergraduates with cognitive impairment after acquired brain injury. AB - This study evaluated a computer-based prompting intervention for improving expository essay writing after acquired brain injury (ABI). Four undergraduate participants aged 18-21 with mild-moderate ABI and impaired fluid cognition at least 6 months post-injury reported difficulty with the writing process after injury. The study employed a non-concurrent multiple probe across participants, in a single-case design. Outcome measures included essay quality scores and number of revisions to writing counted then coded by type using a revision taxonomy. An inter-scorer agreement procedure was completed for quality scores for 50% of essays, with data indicating that agreement exceeded a goal of 85%. Visual analysis of results showed increased essay quality for all participants in intervention phase compared with baseline, maintained 1 week after. Statistical analyses showed statistically significant results for two of the four participants. The authors discuss external cuing for self-monitoring and tapping of existing writing knowledge as possible explanations for improvement. The study provides preliminary evidence that computer-based prompting has potential to improve writing quality for undergraduates with ABI. PMID- 29108477 TI - Hyperthermia and Mild Traumatic Brain Injury: Effects on Inflammation and the Cerebral Vasculature. AB - Mild traumatic brain injury (mTBI) or concussion represents the majority of brain trauma in the United States. The pathophysiology of mTBI is complex and may include both focal and diffuse injury patterns. In addition to altered circuit dysfunction and traumatic axonal injury (TAI), chronic neuroinflammation has also been implicated in the pathophysiology of mTBI. Recently, our laboratory has reported the detrimental effects of mild hyperthermic mTBI in terms of worsening histopathological and behavioral outcomes. To clarify the role of temperature sensitive neuroinflammatory processes on these consequences, we evaluated the effects of elevated brain temperature (39 degrees C) on altered microglia/macrophage phenotype patterns after mTBI, changes in leukocyte recruitment, and TAI. Sprague-Dawley male rats underwent mild parasagittal fluid percussion injury under normothermic (37 degrees C) or hyperthermic (39 degrees C) conditions. Cortical and hippocampal regions were analyzed using several cellular and molecular outcome measures. At 24 h, the ratio of iNOS-positive (M1 type phenotype) to arginase-positive (M2 type phenotype) cells after hyperthermic mTBI showed an increase compared with normothermia by flow cytometry. Inflammatory response gene arrays also demonstrated a significant increase in several classes of pro-inflammatory genes with hyperthermia treatment over normothermia. The injury-induced expression of chemokine ligand 2 (Ccl2) and alpha-2-macroglobulin were also increased with hyperthermic mTBI. With western blot analysis, an increase in CD18 and intercellular cell adhesion molecule-1 (ICAM-1) with hyperthermia and a significant increase in Iba1 reactive microglia are reported in the cerebral cortex. Together, these results demonstrate significant differences in the cellular and molecular consequences of raised brain temperature at the time of mTBI. The observed polarization toward a M1 phenotype with mild hyperthermia would be expected to augment chronic inflammatory cascades, sustained functional deficits, and increased vulnerability to secondary insults. Mild elevations in brain temperature may contribute to the more severe and longer lasting consequences of mTBI or concussion reported in some patients. PMID- 29108479 TI - Time perception impairment following thalamic stroke: A case study. AB - Impaired time perception is considered to be a relatively unusual and poorly understood consequence of brain injury. This paper presents a case study of altered time perception in JB, a 50-year-old woman who in 2011 had a small thalamic stroke affecting the right anteromedian region. We report on her subjective experience and present results from studies of retrospective timing (i.e., estimating how much time has passed and the clock time) and prospective timing (i.e., producing and reproducing intervals). The results showed that relative to neurologically healthy and brain-injured controls, JB had impaired retrospective timing and impaired prospective time reproduction. However, her prospective time production did not differ significantly from either of the control groups. We interpret this to mean that JB's essential timing functions are intact, and that rather, her time perception impairment stems from a problem in anterograde memory for time intervals. Further, we argue that unlike other cognitive domains, time perception alteration is neither anticipated nor evaluated in most patients, yet these impairments can have a remarkably serious impact on daily life. We encourage further investigation of this topic. PMID- 29108480 TI - Short-Term Homing of Hyaluronan-Primed Cells: Therapeutic Implications for Osteoarthritis Treatment. AB - The evaluation of key factors modulating cell homing following injection can provide new insights in the comprehension of unsolved biological questions about the use of cell therapies for osteoarthritis (OA). The main purpose of this in vivo study was to investigate the biodistribution of an intra-articular injection of mesenchymal stromal cells (MSCs) and bone marrow concentrate (BMC) in a rabbit OA model and whether the additional use of sodium hyaluronate (HA) could modulate their migration and delay joint degeneration. OA was surgically induced in adult male New Zealand rabbits. A group of animals was used to test the biodistribution of labeled cells alone or with HA at 7 and 14 days to investigate cell migration. The efficacy of treatments was evaluated in other experimental groups at 2 months. Histology and immunohistochemistry for markers identifying anabolic and catabolic processes in the cartilage and meniscus, or macrophage subset population in the synovial membrane, were performed. Kruskal-Wallis test, followed by post hoc Dunn's test, and Spearman's rank-order correlation method were used. MSCs and BMC preferentially migrate toward tissue areas showing OA features in the meniscus and cartilage and in detail near inflammatory zones in the synovial membrane. The combination with HA contributed to boost cell migration toward articular cartilage. In general, both labeled cells combined with HA were found near cell cluster and fissures in the cartilage and meniscus, respectively, and close to areas of synovial membrane showing mainly anti inflammatory macrophages. A promotion of joint repair was observed at different levels for all treatments, although BMC-HA treatment resulted as the best strategy to support joint repair. This last, displayed a good protein expression of type II collagen in the cartilage, as well as the presence of anti inflammatory macrophages in the synovial membrane at 2 months from the treatment. Studies tracking cell biodistribution indicate that priming progenitor cells with HA modulated cell homing favoring not only attachment but also their integration within articular cartilage. PMID- 29108481 TI - A fellowship in interim care - the GP Extensivist experience. PMID- 29108482 TI - Spectroscopic, electrochemical, docking and molecular dynamics studies on the interaction of three oxovanadium (IV) Schiff base complexes with bovine serum albumin and their cytotoxicity against cancer. AB - This study was designed to investigate the interaction of three oxovanadium (IV) Schiff base complexes with bovine serum albumin (BSA) by means of various spectroscopic and electrochemical methods along with molecular docking study and molecular dynamics simulations. Binding constants were estimated by fluorescence and UV-Vis spectroscopy. The results indicated a good affinity of the complexes for BSA in which furyl derivative had more activity. Molecular docking study showed that these complexes have the similar binding modes and located within subdomain IB in site III of BSA. The supporting of molecular docking and molecular dynamics results by experimental data, confirms the validity of the interactions data obtained by these methods. Biological activity against cancer cell showed that furyl derivative has higher activity than other complexes. Pharmaceutical analysis also showed that, these complexes potentially can be used as anticancer agents. PMID- 29108483 TI - Bone Therapeutics: Safety Considerations, Session Summary. AB - This session was a series of presentations focused on safety considerations for late stage or currently marketed bone therapeutic agents. The first presentation was an overview of a major regulatory requirement in the nonclinical filing package for bone therapeutics, studies designed to assess the impact of an agent on bone quality. Two presentations focused on safety issues associated with drugs whose primary mechanism of action is inhibition of bone resorption. Typical findings associated with this class of agents in general and reproductive toxicology studies were reviewed, highlighting INHAND (International Harmonization of Nomenclature and Diagnostic Criteria) nomenclature. This was followed by an overview of safety issues that have been identified largely through clinical experience. Similar presentations followed emphasizing safety and regulatory issues associated with classes of drugs whose primary mechanism of action is stimulation of bone formation known broadly as bone anabolic agents. The major focus of these discussions was carcinogenicity risk assessment. The final presentation was an introduction to a rapidly evolving area in bone therapeutics, treatment of rare genetic bone diseases, and the developmental challenges associated with these indications and novel therapeutic modalities. PMID- 29108484 TI - The Validation of Quantitative Mass Spectrometry Assays for Clinical Chemistry Assessments in Animal Models. AB - Mass spectrometry (MS) has become a key platform in the clinical pathology laboratory and is being used more frequently for clinical pathology assessments in preclinical species for drug development studies. MS assays are being utilized for some traditional clinical pathology end points as well as novel biomarker analyses. For effective deployment in drug development toxicology studies, assays must be validated for use, and these validations are not very different from other bioanalytical platforms commonly found in the clinical pathology laboratory. Validations for MS assays include accuracy and precision assessments, analyte stability evaluations, carryover determinations, and recovery measures. The MS platform does present some unique challenges that should be considered, including ion suppression and availability of reference standards with MS data. Understanding the caveats of the MS platform is important for thorough validations and effective deployment. PMID- 29108485 TI - Minimising the risk of Mycobacterium chimaera infection during cardiopulmonary bypass by the removal of heater-cooler units from the operating room. AB - INTRODUCTION: Mycobacterium chimaera ( M. chimaera) is a recently characterised bacterium that can cause life-threatening infections in small numbers of patients who undergo cardiopulmonary bypass during cardiac surgery. The likely mode of transmission is thought to occur through aerosolisation from contaminated water reservoirs. The airborne bacteria then contaminate the surgical field, leading to an infection months or even years later. The preferred practical solution to disrupt the transmission of these airborne bacteria to the patient is to remove the heater-cooler units (HCUs) from the operating room (OR). We describe a process of achieving this in order to provide information to guide other institutions who wish to do a similar thing. METHODS: A multidisciplinary team was assembled to work on the project. The planning phase involved trialling different OR layouts and simulating the alterations in the HCU circuit function. The changes to the OR were made over a weekend to minimise disruption to the operating schedule. RESULTS: The HCU was moved to the dirty utility room adjacent to the OR. Standard operating procedures (SOP) and risk assessments were made to enable this to be used for a dual purpose. One of the ORs was reconfigured to allow the cardiopulmonary bypass machine to be located close to the HCU in the dirty utility room. The total cost of the alterations was L6,158. Although we have provided a physical barrier to interrupt patient exposure to aerosolised M. chimaera from HCUs, we continue to perform cultures and decontamination as per the national recommendations. The SOP was designed to be auditable to ensure compliance with the protocols. CONCLUSIONS: We show a method by which the HCU can be removed from the OR in a relatively low-cost, straightforward and practical manner. PMID- 29108486 TI - Role of insertion sequence Aba-1 and AdeS in reduced tigecycline susceptibility in MDR-Acinetobacter baumannii clinical isolates from Cairo, Egypt. AB - Infections caused by multidrug resistant (MDR) Acinetobacter baumannii (A. baumannii) especially in intensive care units have limited therapeutic options. Overexpression of the adeABC efflux pump may be caused either by the ISAba-1 insertion or by specific point mutations in adeR and adeS, therefore, plays a major role in conferring MDR-A. baumannii. We aimed in our study to monitor the tigecycline (TGC) susceptibility and to study the role of ISAba-1 and the adeS regulator within the AdeABC efflux pump among MDR-A. baumannii clinical isolates. MDR-A. baumannii (63) isolated from ICU patients were identified by detection of OXA-51-like gene. TGC MIC was determined by E-test and broth microdilution. PCR analysis of adeR, adeS, adeB and ISAba1 genes were done with further sequencing of adeS gene. Reduced susceptibility to TGC (MIC: 3-4 mg/L) was noticed in 6/63 (9.5%) MDR-A. baumannii isolates, ISAba-1 was detected in three isolates that two of which showed amino acid substitutions in the adeS operon. We concluded that the amino acids mutations in the adeS gene in presence of insertion ISAba-1 may play a role in conferring reduced TGC susceptibility of MDR-A. baumannii. PMID- 29108487 TI - A clinically meaningful training effect in walking speed using functional electrical stimulation for motor-incomplete spinal cord injury. AB - CONTEXT/OBJECTIVE: The study aimed to investigate the presence of a training effect for rehabilitation of walking function in motor-incomplete spinal cord injury (SCI) through daily use of functional electrical stimulation (FES). SETTING: A specialist FES outpatient centre. PARTICIPANTS: Thirty-five participants (mean age 53, SD 15, range 18-80; mean years since diagnosis 9, range 5 months - 39 years) with drop foot and motor-incomplete SCI (T12 or higher, ASIA Impairment Scale C and D) able to ambulate 10 metres with the use of a walking stick or frame. INTERVENTIONS: FES of the peroneal nerve, glutei and hamstrings as clinically indicated over six months in the community. OUTCOME MEASURES: The data was analysed for a training effect (difference between unassisted ten metre walking speed at baseline and after six months) and orthotic effects (difference between walking speed with and without FES) initially on day one and after six months. The data was further analysed for a minimum clinically important difference (MCID) (>0.06 m/s). RESULTS: A clinically meaningful, significant change was observed for initial orthotic effect (0.13m/s, CI: 0.04 0.17, P = 0.013), total orthotic effect (0.11m/s, CI: 0.04-0.18, P = 0.017) and training effect (0.09m/s, CI: 0.02-0.16, P = 0.025). CONCLUSION: The results suggest that daily independent use of FES may produce clinically meaningful changes in walking speed which are significant for motor-incomplete SCI. Further research exploring the mechanism for the presence of a training effect may be beneficial in targeting therapies for future rehabilitation. PMID- 29108489 TI - Editorial. PMID- 29108488 TI - Validation of Three Scoring Risk-Stratification Models for Thyroid Nodules. AB - BACKGROUND: To minimize potential harm from overuse of fine-needle aspiration, Thyroid Imaging Reporting and Data Systems (TIRADSs) were developed for thyroid nodule risk stratification. The purpose of this study was to perform validation of three scoring risk-stratification models for thyroid nodules using ultrasonography features, a web-based malignancy risk-stratification system, and a model developed by the Korean Society of Thyroid Radiology and the American College of Radiology. METHODS: Using ultrasonography images, radiologists assessed thyroid nodules according to the following criteria: internal content, echogenicity of the solid portion, shape, margin, and calcifications. A total of 954 patients (Mage = 50.8 years; range 13-86 years) with 1112 nodules were evaluated at the authors' institute from January 2013 to December 2014. The discrimination ability of the three models was assessed by estimating the area under the receiver operating characteristic curve. Additionally, Hosmer-Lemeshow goodness-of-fit statistics (calibration ability) were used to evaluate the agreement between the observed and expected number of nodules that were benign or malignant. RESULTS: Thyroid malignancy was present in 37.2% (414/1112) of nodules. According to the 14-point web-based scoring risk-stratification system, malignancy risk ranged from 4.5% to 100.0% and was positively associated with an increase in risk scores. The areas under the receiver operating characteristic curve of the validation set were 0.884 in the web-based model, 0.891 in the Korean Society of Thyroid Radiology model, and 0.875 in the American College of Radiology model. The Hosmer-Lemeshow goodness-of-fit test indicated that the web based scoring system showed the best-calibrated result, with a p-value of 0.078. CONCLUSION: The three scoring risk-stratification models using the ultrasonography features of thyroid nodules to stratify malignancy risk showed acceptable predictive accuracy and similar areas under the curve. The web-based scoring system demonstrated the strongest agreement in calibration ability analysis. The easily accessible automated web-based scoring risk-stratification system may overcome the complexity of the various Thyroid Imaging Reporting and Data System guidelines and provide simplified guidance on personalized and optimal management in real practice. PMID- 29108491 TI - Visuospatial Neglect: Attentional Deficits and Anatomical Correlates. PMID- 29108490 TI - Ethical Dilemmas Encountered by Community-based Occupational Therapists in Home Care Settings. AB - The purpose of the study was to investigate the ethical dilemmas community-based occupational therapists report encountering in home settings. Data was collected from 23 community-based occupational therapists, each of whom provided 1 or 2 narratives, including some ethical dilemmas associated with rehabilitation in home care settings (a total of 40 dilemmas.) The dilemmas were analysed by content analysis, a method of handling qualitative material. The analysis of each dilemma was based on the following questions: "What was the problem?" "Who were the actors?" "What kind of relationship existed between them?" and "What social frameworks or laws shaped their options?" The outcome of these analyses gave rise to six qualitative categories: Category 1. Ethics in home settings. Category 2. Provider-patient relationship. Category 3. Provider-family members relationship. Category 4. Rehabilitation professionals' inter-relationship. Category 5. Law and ethics. Category 6. Allocation of resources. This study, in which some of the ethical dilemmas investigated have been reported in the past and some are new (such as the home setting itself causing problems), showed that ethical problems are indeed likely to occur when rehabilitation takes place in home settings. PMID- 29108492 TI - Professionalization and Rehabilitation: The Case of Swedish Occupational and Physical Therapists. PMID- 29108493 TI - Experience of Therapeutic Occupations in Schizophrenic Subjects: Clinical Observations Organized in Terms of the Flow Theory. AB - Some basic assumptions in occupational therapy theory are that participation in occupations is necessary for human development. Yet the relationship between health and participating in occupations is largely unexplored, and there is a need for concepts to describe this relationship. The purpose of this study was to examine intrinsic motivation and flow experience as an effective agent in therapeutic occupations for persons with schizophrenia. Three persons who had been psychiatric inpatients for more than 5 years participated in the study. The Flow Questionnaire was used to identify flow experiences in their lives and observations were made of the participants performing selected activities based on their interests. Each activity session was followed by an interview aimed to find the participant's experience of the acitivity. Two of the participants managed to identify flow experiences in their lives. During the activity sessions, flow experience was observed in all three participants. In the following interviews this was confirmed. The results suggest that the six elements from the Flow Theory are useful concepts for describing effective components in therapeutic occupation. The method used here makes it possible to conceptualize what happens in therapeutic occupation. PMID- 29108494 TI - The Development of an Assessment of Adjustment Needs in the School Setting for Use with Physically Disabled Students. AB - This study examines the reliability and validity of a new assessment, the School Setting Interview (SSI), which is in process of being developed. The SSI is an interview assessment designed to determine the need for adjustments in the school setting for students with motor disabilities. The approach is descriptive and includes 11 content areas. Forty-five severely disabled students attending their first semester in one of the four Swedish upper secondary schools which have special resources for this group were enrolled in the study. Thirteen occupational therapists employed in the treatment departments assessed all the students using the SSI. Seventeen of the students were randomly chosen for a retest conducted by the first author. The reliability in terms of sensitivity, specificity and interrater reliability was examined. The content validity was also examined. The results show that the SSI is a highly sensitive assessment. According to the calculations, interrater reliability for the content areas is good or very good. The 11 content areas appear to be adequate for the intended purpose of the assessment, although some additional content areas, which could be added to the assessment, were identified. PMID- 29108495 TI - Factors Affecting the Choice of Treatment in Occupational Therapy Practice in Hospital-based Care. AB - The aim of this article was twofold: to describe the occurrence of treatment goals, health-care programmes and type of interventions chosen by occupational therapists; and to investigate relationships between treatment goals, health-care programmes and interventions. A survey on occupational therapy practice was carried out in The Netherlands. A registration form based on the International Classification of Impairments, Disabilities and Handicapts (ICIDH) was filled out for 944 patients. This registration form consisted of three sections: (i) patient characteristics, (ii) occupational therapy diagnosis and treatment goals in terms of ICIDH, and (iii) treatment characteristics. The patients were treated by occupational therapists working in nursing homes, rehabilitation centres or general hospitals. A total of 143 therapists, working in 49 departments of occupational therapy, participated in this study. Relationships existed between treatment goals and health-care programmes on the one hand and interventions on the other. Treatment goals and health-care programmes independently determined the choice of interventions in occupational therapy practice; the choice of interventions was not dependent on specific combinations of goals and programmes. Bases on these results, several profiles of occupational therapy treatment were identified. PMID- 29108496 TI - Validity of Two Self-care Instruments for the Elderly. AB - The aim of this study was to address concurrent and construct validity of two instruments, the Self-care Ability Scale for the Elderly (SASE) and the self report form of the Appraisal of Self-care Agency Scale (ASA-A), by testing them with home-dwelling, elderly Swedish patients. The two self-report instruments, including some additional new questions, were mailed to an age-stratified random sample of 420 elderly subjects and were finally completed by 125 of them. Bivariate and multivariate statistical methods were used in the analyses. An analysis of the non-respondents revealed no significant differences between them and the respondents. Standardized regression coefficients for reported abilities/activities on the scores were 0.71 for SASE (p < 0.0001) and for ASA-A 0.51 (p < 0.0001). SASE and ASA-A were found to measure related but not identical concepts (r = 0.69). Sensitivity and specificity ratings for managing without any help from official and unofficial caregivers were 68% and 72% respectively for SASE, and 50% and 64% for ASA-A. Individuals of 80+ years of age had lower scores than younger respondents on the SASE (p < 0.001) and ASA-A (p < 0.05) scales. Respondents living independently had higher scores on both scales than those living in institutions (p < 0.001). Lower scores on both scales were found for respondents who were not in good health compared with those who were in good health (p < 0.001). A five-factor solution for SASE explained 70.2% of the variances, and an eight-factor solution explained 67.9% of the variances for ASA A. The results of this study confirm that the SASE and ASA-A assessments substantially measured what they were intended to measure in the studied group of lucid, elderly subjects. PMID- 29108498 TI - International Research for School Nursing: Implications for Reviewers. PMID- 29108500 TI - Breastfeeding and Oral Health: Evidence and Methodological Challenges. AB - Breastfeeding is a powerful health-promoting behavior. A 2016 Lancet global collaboration to review the health implications of breastfeeding was among the first to consider oral health outcomes. While a role was suggested for breastfeeding in preventing malocclusion, caries was the only included disease condition unfavorably associated with breastfeeding. The present critical review examines the evidence connecting breastfeeding practices to these outcomes and discusses the methodological challenges inherent in reaching causal conclusions. Published systematic reviews show some evidence of a protective effect of breastfeeding against primary dentition malocclusion but no supportive evidence for mixed dentition and permanent dentition malocclusions. Regarding caries, well conducted studies report a benefit with breastfeeding up to 12 mo but a positive association between caries and breastfeeding of longer duration, at times that vary between 12 and 24 mo, as well as nocturnal feeding. Future studies would be methodologically stronger if focused on specific malocclusion traits that are plausibly associated with sucking movements rather than using general malocclusion indices. Studies should use detailed and consistent terminology for breastfeeding definition, including frequency, intensity, and timing. Analytical studies should be carried out to distinguish between confounders (e.g., prematurity) and mediators (e.g., use of pacifier). Regarding a link to caries, standard terminology for exposures (e.g., nocturnal feeding) is recommended. Statistical analyses must account for known confounding factors (e.g., socioeconomic conditions) but avoid inappropriate adjustment for variables on a causal path between exposure and outcome or for variables not associated with breastfeeding (e.g., tooth brushing), as can be guided using tools such as direct acyclic graphs. For dental practice, the potential caries risk of long-duration breastfeeding should be part of individual patient counseling that incorporates patient values and circumstances. Given the unquestioned overall health benefits of breastfeeding, the dental community should support World Health Organization guidelines that encourage and promote breastfeeding. PMID- 29108499 TI - What Barriers and Facilitators Do School Nurses Experience When Implementing an Obesity Intervention? AB - A recent evaluation of a school nurse-led obesity intervention demonstrated a 5% implementation rate. The purpose of this study was to explore school nurses' perceived barriers to and facilitators of the intervention in order to understand reasons for the low implementation rate. Methods included semi-structured individual interviews with school nurses. Data were analyzed using content analysis and heat mapping. Nineteen nurses participated and eight themes were identified. Parental and administrative gatekeeping, heavy nurse workload, obesogenic environments, and concerns about obesity stigma were barriers to implementation. Teamwork with parents and school staff was a key facilitator of implementation. Nurses also noted the importance of cultural considerations and highlighted the need to tailor the intervention to the unique needs of their school environment and student population. These findings suggest that for school nurses to play a key role in school-based obesity interventions, barriers must be identified and addressed prior to program implementation. PMID- 29108501 TI - Occult Massive Visceral Fat Necrosis Following Therapeutic Hypothermia for Neonatal Encephalopathy. AB - Therapeutic hypothermia (head or whole-body cooling) improves survival and neurodevelopmental outcome in term newborns with moderate-to-severe encephalopathy. Hypothermia treatment is well tolerated; the most common side effect is thrombocytopenia. In about 1% of infants, focal subcutaneous fat necrosis has been reported. We describe a case of clinically unsuspected massive visceral fat necrosis in a term infant with Apgar score 0 at 1 min ("resuscitated apparently stillborn" infant) who was treated with therapeutic hypothermia for 72 h and expired on the 25th day of life following a neonatal course complicated by severe encephalopathy, pulmonary artery hypertension, persistent thrombocytopenia, hypoglycemia, and severe basal ganglia-thalamic abnormalities on magnetic resonance imaging. Postmortem examination revealed extensive visceral (brown) fat necrosis, involving thoracic, abdominal, and retroperitoneal adipose tissue, with distinctive sparing of the subcutaneous (white) fat. The fulminant yet clinically occult-visceral fat necrosis seen in this case suggests that (lesser degrees of) fat necrosis may go unrecognized in hypoxic-ischemic newborns, especially in those treated with hypothermia, and underscores the importance of close monitoring of encephalopathic newborns both in the short and long terms for complications of fat necrosis (hypercalcemia and nephrocalcinosis). PMID- 29108502 TI - Colonic Adventitial Fibromuscular Dysplasia: A Nonspecific Arteriopathy Associated With Hirschsprung Disease and Other Obstructive Disorders. AB - Background Smooth muscle differentiation ("adventitial fibromuscular dysplasia," AFD) was purported as specific to arteries in the transition zone of Hirschsprung disease (HSCR) patients. We investigated AFD in an HSCR population and controls and consider the pathogenesis and significance of the vascular pathology. Design Vascular histology in sections from colonic HSCR resections (n = 55) was compared with age- and site-matched controls with (n = 19) and without (n = 28) non-HSCR obstructive conditions. Vascular pathology was mapped, and correlations were sought between the vascular findings and bowel distension, inflammation, neuromuscular anatomy, preoperative clinical variables, and postsurgical complications. Results One of 2 forms of AFD was identified in 42% (23/55) of the HSCR resections: the previously described "mature" form with adventitial bundles of differentiated smooth muscle cells (7/23, all submucosal) and a newly described "immature" AFD characterized by densely packed myofibroblasts in the arterial adventitia (16/23, 3 submucosal, 3 serosal, and 10 both). Adventitial inflammation and/or medial necrosis was present in the immature form (6/16). Mature submucosal AFD was present in 2/28 (7.1%) nonobstructive and 5/19 (26%) obstructive non-HSCR controls ( P = .10). Immature AFD was only found in less than 1-month-olds, and mature AFD only in older patients, including the 7 affected controls. AFD did not correlate with sex, syndromic status, length of the aganglionic segment, or postoperative complications. AFD was present in grossly dilated (17/23) and narrowed (10/23) regions and in the aganglionic (2/23), ganglionic (14/23), or both (7/23) segments. In several cases, AFD existed proximal to the histological transition zone. Conclusion AFD occurs in HSCR and other obstructive conditions but is significantly less common in the colons of patients with no history of dysmotility. The pathology likely progresses from a reversible accumulation of myofibroblasts in neonates to a stable population of mature smooth muscle cells. The distribution of vascular lesions does not correlate with neuropathological findings and suggests a nonspecific form of vascular injury, possibly related to bowel distension. AFD in HSCR resections has not been shown to be clinically significant and should not influence management. PMID- 29108503 TI - Stress During Development of Experimental Endometriosis Influences Nerve Growth and Disease Progression. AB - PURPOSE: We have previously shown that stress prior to induction worsens clinical presentation and inflammatory parameters in a rat model of endometriosis. This study was designed to examine whether stress during the development of endometriosis can affect the growth of endometriotic implants through nerve growth and immune alterations. METHODS: Endometriosis was surgically induced in female Sprague-Dawley rats by suturing uterine horn implants onto the small intestine mesentery. Two weeks later, one group of rats (endo-stress) was subjected to a 10-day swim stress protocol. Controls had no stress (endo-no stress) or sutures only and stress (sham-stress). On day 60, all rats were killed and examined for the presence of endometriotic vesicles. The size of each vesicle was measured. The uterus and colon were removed and assessed for damage, cell infiltration, and expression of nerve growth factor (NGF), its receptors (p75 and Tropomyosin receptor kinase A (Trk-A)/pTrk-A), and calcitonin gene-related peptide, a sensory fiber marker. A differential analysis of peritoneal fluid white blood cell count was performed. RESULTS: Stress significantly increased endometriotic vesicle size but not colonic damage and increased infiltration of mast cells. Significantly increased expression of NGF and its receptors was found in the uterus of animals with endometriosis receiving stress. CONCLUSIONS: Stress stimulates the development of ectopic endometrial vesicles in an animal model of endometriosis and increases inflammatory cell recruitment to the peritoneum. In addition, stress promotes nerve fiber growth in the uterus. PMID- 29108506 TI - What can we learn from the case of Charlie Gard? Perspectives from an inter disciplinary panel discussion. PMID- 29108507 TI - 'They love us just the way they love a woman': gender identity, power and transactional sex between men who have sex with men and transgender women in Timor-Leste. AB - There has been limited research on the experiences of men who have sex with men and transgender women in Timor-Leste. Previous research has suggested a phenomenon by which same-sex-attracted men and transgender women have sexual and intimate relationships with straight-identifying men or mane-forte. Transactional sex has also been reported to be common. This paper, which complements a larger national size estimation among key populations at risk of HIV, further investigates sexual and social identities and roles, including sexual practices, among men who have sex with men and transgender women in Timor-Leste. Fifteen interviews were conducted with a profile of participants from urban and rural settings. Using inductive thematic analysis, we found that gender identity played a significant role in sexual relationships, with mane-forte having power over their sexual partner(s). Transactional sex was also found to be customary. Some participants experienced stigma, discrimination, sexual coercion and violence, while others, such as mane-forte, did not. Our research suggests that gender identity and power are significant in sexual relationships between men who have sex with men and transgender women in Timor-Leste, have implications for HIV prevention efforts and may reflect gender norms within the broader community. PMID- 29108508 TI - A non-randomised pragmatic trial of a school-based group cognitive-behavioural programme for preventing depression in girls. AB - The aim of this study was to investigate the effectiveness of the DISA-programme in preventing depressive symptoms (DS) in adolescent girls, as implemented in a real-world school setting, accounting for baseline socioeconomic and psychosocial factors, and to investigate whether the effects of these baseline variables on DS differed between intervention participants and non-participants. In this non randomised pragmatic trial, an electronic questionnaire was disseminated in 2011 (baseline) and 2012 (follow-up) in schools in one municipality in northern Sweden. Pupils (total n=275; intervention participants identified in the questionnaire: n=53; non-participants: n=222) were 14-15 years old at baseline. The groups were compared by means of SEM. DISA could not predict differences in DS at follow-up in this real-life setting. In the overall sample, sexual harassment victimisation (SH) at baseline was associated with DS at follow-up and the estimate for SH increased in the DISA-participants compared to the overall sample. PMID- 29108509 TI - Smoking History Is Associated With Adverse Outcomes for Kidney Allograft Recipients. AB - OBJECTIVES: Donor kidney measurements may affect outcomes of transplanted allografts. We tested allograft and recipient measurements on kidney allograft outcomes. In this study, we compared the effects of kidney allograft volumes, which were measured using computed tomographic angiography before transplant, and allograft weight, which was measured during surgery, in relation to the recipient's body weight and body mass index on kidney function at 6 and 12 months after transplant. MATERIAL AND METHODS: We included 74 patients (40 female and 34 male patients, mean age of 50.42 +/-; 9.75 y) in this study. RESULTS: Intraoperative allograft weight was 182.68 +/- 40.33 g (range, 104-266 g). The allograft volume measured using computed tomographic angiography scanning was 123.34 +/- 24.26 mL (range, 78-181 mL). The estimated glomerular filtration rates of the recipients at 6 and 12 months after transplant correlated negatively with age and recipient body mass index but correlated positively with allograft volume/recipient body weight, allograft volume/recipient body mass index, allograft weight, allograft weight/recipient body weight, and allograft weight/recipient body mass index values, as concluded by univariate analyses. From multivariate analyses, we found variables of interest presumed to significantly affect the 12-month estimated glomerular filtration rates, including recipient age, allograft volume/recipient body weight, allograft volume/recipient body mass index, allograft weight, allograft weight/recipient body weight, and allograft weight/recipient body mass index. CONCLUSIONS: Transplanted allograft and recipient body values may be used as predictors of estimated glomerular filtration rates 6 and 12 months after transplant. PMID- 29108510 TI - A Mimic of Posttransplant Lymphoproliferative Disease Following Liver Transplant. AB - Generalized lymphadenopathy after organ transplant is a concerning finding, often indicating the devel-opment of lymphoma. We describe a 52-year-old liver transplant recipient who had clinical symptoms and imaging concerning for posttransplant lymphoproliferative disease. However, histologic evaluation of a lymph node biopsy revealed that the patient actually had a much rarer but relatively benign condition, Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis). We discuss the epidemiology, clinical symptoms, diagnosis, histologic features, and treatment of this uncommon mimic of posttransplant lymphoproliferative disease. PMID- 29108511 TI - Effects of Benign Prostate Hyperplasia on Allografts in Kidney Transplant. AB - OBJECTIVES: Benign prostate hyperplasia is frequently diagnosed in elderly chronic renal failure patients. Although it is asymptomatic because urine flow declines in those with chronic renal failure, it may become symptomatic when urine flow increases after renal transplant. Untreated benign prostate hyperplasia may lead to several complications that adversely affect the kidney allograft. MATERIALS AND METHODS: Our retrospective study investigated data from 286 male transplant patients. Data obtained included medical history, clinical examination, prostate-specific antigen, prostate volume, and residual urine volume results. Patients had completed an International Prostate Symptom Score questionnaire to assess the low urinary symptoms. Creatinine level, residual urine volume, International Prostate Symptom Score, and uroflow-metry results were reviewed. RESULTS: The average age of patients in our group was 54.8 years. Seven patients were diagnosed with benign prostate hyperplasia, and transurethral resection of the prostate was performed. The average creatinine levels before and after transurethral resection were 2.53 +/- 0.76 mg/dL and 1.66 +/- 1.12 mg/dL, respectively. Creatinine levels measured 6 months after transurethral resection versus before resection were statistically significant (P < .018). Furthermore, there was a statistically significant difference (P < .017) in the postmicturition residual urine volume between the preoperative and postoperative values, which were 132.14 +/- 19.33 and 47.6 +/- 18.6 mL, respectively. Maximum urine flow rates before and after transurethral resection were also significantly different (P < .017). CONCLUSIONS: Although the main reasons for graft function loss after renal transplant are rejection and infections, obstructive pathologies should also be considered. Especially for elderly patients, anamnesis, uroflowmetry, and digital rectal examination play critical roles in the evaluation of benign prostate hyperplasia before and after transplant. PMID- 29108512 TI - Individual Surgeon Experience Yields Bimodal Effects on Patient Outcomes After Deceased-Donor Liver Transplant: Results of a Quantile Regression for Survival Data. AB - OBJECTIVES: Data on the relevance of surgeon experience in liver transplant procedures are scarce. In this study, we evaluated the effects of individual surgeon experience on survival outcomes after deceased-donor liver transplant. MATERIALS AND METHODS: In this retrospective analysis of 1193 liver transplant procedures, quantile regression for survival data was performed to assess the effects of surgeon experience. Conditional quantiles of mortality and graft loss were set as primary and secondary outcome measures, respectively, which were categorized as early, midterm, and late. RESULTS: Greater experience of a surgeon performing hepatectomy increased the risk of early mortality (P = .005) and graft loss (P = .025) when the recipient Model for End-Stage Liver Disease was <= 25 and the donor Model for End-Stage Liver Disease was <= 1600. In conventional transplant procedures, greater experience of surgeon performing hepatectomy additionally increased the risk of midterm mortality (P = .027) and graft loss (P = .046). Conversely, a graft implant procedure performed by a more experienced surgeon was associated with better early, midterm, and late outcomes after conventional transplants (all P < .037) and reduced the risk of early graft loss when the donor Model for End-Stage Liver Disease score was > 1600 (P = .027). CONCLUSIONS: Unexpectedly, individual surgeon experience yields bimodal effects on posttransplant outcomes, dependent on the stage of operation, operative technique, severity of recipient status, and transplant risk profile. PMID- 29108513 TI - Reconstruction of Traumatic External Iliac Artery Dissection Due to Vascular Clamping. AB - Traumatic external iliac artery dissection after renal transplant is a rare complication, but it should be urgently managed due to its devastating effects on graft and lower limb circulation. External iliac artery dissection is seen more in recipients with diabetes mellitus and comorbid disease. Recipients with external iliac artery dissection should be treated immediately by percutaneus angioplasty or surgical reconstruction. In this study, we reported the management of 2 kidney transplant cases with external iliac artery dissection due to vascular clamping of the artery. External iliac artery dissection was diagnosed by ultrasonography in both cases. After failed percutaneous interventional angioplasty, we reconstructed the external iliac artery dissection surgically and replaced the external iliac artery with polytetra-fluoroethylene grafts in both patients. Both patients were discharged with normal functioning grafts showing 0.9 and 0.8 mg/dL serum creatinine levels at month 3 posttransplant. Close monitoring of recipients after transplant is mandatory for early diagnosis and early management of external iliac artery dissection to prevent graft loss and preserve lower limb circulation. Routine Doppler ultrasonography is an inexpensive and useful tool for early diagnosis in cases of sudden cessation or decrease in urine. In cases of failed percutaneous interventional angioplasty, reconstruction with synthetic vascular grafts can be safely applied in external iliac artery dissection. PMID- 29108514 TI - Hypothermic Oxygenated Machine Perfusion for Liver Transplantation: An Initial Experience. AB - OBJECTIVES: Due to widespread exploitation of extended criteria donors, machine perfusion is emerging as an alternative to static cold storage for organ preservation. Hypothermic oxygenated machine perfusion has been associated with improved outcomes after liver transplant, both in laboratory and clinical settings. Here, we present our initial experience with hypothermic oxygenated machine perfusion, evaluating incidence of postreperfusion syndrome, early allograft dysfunction, and long-term biliary complications. MATERIALS AND METHODS: End-ischemic dual (hepatic artery and portal vein) hypothermic oxygenated machine perfusion was carried out for 150 to 200 minutes before organ implantation in 4 liver transplants considered at increased risk due to donor, recipient, or matching issues. RESULTS: No device malfunction occurred. Theatre logistics were minimally affected. Incidences of post-reperfusion syndrome and early allograft dysfunction were 25% and 50%. At 6-month follow-up, all patients were alive with normal hepatic function and no evidence of ischemic cholangiopathy. CONCLUSIONS: In our experience, hypothermic oxygenated machine perfusion appeared safe and logistically simple. Further studies are needed to assess the real value of this technique and to identify which subset of patients would benefit from its implementation. PMID- 29108516 TI - Clinical Outcomes of Paramyxovirus Infections in Lung Transplant Recipients Treated With Oral Ribavirin: A Two-Center Case Series. AB - OBJECTIVES: Paramyxoviruses contribute to morbidity and mortality after lung transplant and are associated with bronchiolitis obliterans syndrome. Oral ribavirin has been used off-label for treatment of paramyxoviruses in immunosuppressed patients; however, data supporting its use for this purpose are lacking. MATERIALS AND METHODS: We conducted a retrospective review to evaluate clinical outcomes of lung transplant recipients infected with paramyxoviruses and received treatment with oral ribavirin at 2 tertiary referral centers. Patients who were diagnosed with paramyxovirus infection by polymerase chain reaction testing between January 2011 and December 2014 and who received oral ribavirin were included. Clinical outcomes included pulmonary function testing, infection severity, and adverse events related to treatment. RESULTS: Twenty-six patients were diagnosed with a paramyxovirus and received oral ribavirin. The changes in mean forced expiratory volume 1 second from preinfection to infection onset and from infection onset to postinfection were significant (1.79 +/- 0.13 to 1.61 +/- 0.12 L and 1.61 +/- 0.12L to 1.74 +/- 0.12 L; P = .0001). Similar results were seen in subgroup analysis when respiratory syncytial virus and parainfluenza infections were evaluated independently. CONCLUSIONS: Use of oral ribavirin for treatment of paramyxovirus infections in lung transplant recipients was safe and associated with recovery of lung function. PMID- 29108515 TI - Long-Term Use of Cinacalcet in Kidney Transplant Recipients With Hypercalcemic Secondary Hyperparathyroidism: A Single-Center Prospective Study. AB - OBJECTIVES: Persistent secondary hyperparathyroidism is common after successful kidney transplant, with concomitant hypercalcemia and hypophosphatemia potentially leading to reduced graft survival and increased cardiovascular risk. Cinacalcet, a calcimimetic agent that activates the calcium-sensing receptors in parathyroid glands, is a therapeutic option. In this study, we assessed the long term treatment effects of cinacalcet for a period of up to 5 years in a cohort of kidney transplant recipients. MATERIALS AND METHODS: Forty-seven patients with secondary hyperparathyroidism (intact parathyroid hormone level > 70 pg/mL or 7.43 pmol/L) and hypercalcemia (corrected calcium > 10.4 mg/dL or 2.6 mmol/L) were considered eligible for treatment with cinacalcet and were included in the analysis. Data were recorded at initiation of treatment and every 6 months up to a maximum follow-up of 60 months. A control group of patients treated with placebo, conventional treatment, or surgical treatment was not available for this study. RESULTS: Mean follow-up time was 45 +/- 16 months. Treatment with cinacalcet was initiated at a median of 25 months after renal transplant. Serum calcium decreased by 0.21 mmol/L (2.69 vs 2.48 mmol/L; 95% confidence interval, 0.08-0.345; P < .001) during the first 6 months, and this reduction was sustained during follow-up. Intact parathyroid hormone level decreased by 7.68 pmol/L (32.96 +/- 36.4 vs 25.28 +/- 19.5 pmol/L; 95% confidence interval, -6.42 to 21.75; P = not significant) at 6 months, whereas at the end of follow-up intact parathyroid hormone level decreased further by 20.07 pmol/L (32.96 +/- 36.4 vs 12.89 +/- 5.73 pmol/L; 95% confidence interval, 2.02-38.1; P < .01). Mean starting dose of cinacalcet was 33.5 +/- 10 mg/day. According to the therapeutic response, cinacalcet dose increased steadily and reached 51.1 +/- 33 mg/day at the end of the observation period. Mean serum phosphorus increased significantly, whereas estimated glomerular filtration rate remained virtually stable throughout follow-up. Adverse reactions were observed in 4 patients, comprising mild gastro intestinal complaints. CONCLUSIONS: Long-term treatment with cinacalcet in kidney transplant recipients with secondary hyperparathyroidism is effective in controlling hypercalcemia and correcting hypophosphatemia, without affecting graft function while being well-tolerated. PMID- 29108517 TI - Inferior Long-Term Outcomes for Kidney Transplant Recipients With an Immunologically Mediated Primary Renal Disease. AB - OBJECTIVES: Recurrent glomerulonephritis can negatively affect kidney allograft survival. However, how primary renal disease affects transplant outcomes in the new era of immunosuppression remains unclear. MATERIALS AND METHODS: We categorized 426 kidney transplant recipients (performed from 1996 to 2007) into 4 disease groups: (1) 99 recipients with biopsy-proven immunologically mediated kidney disease, (2) 40 recipients with urologic disease, (3) 67 recipients with polycystic kidney disease, and (4) 220 recipients with other causes of terminal renal failure/uncertain kidney disease. Long-term transplant outcomes were compared between groups at 1, 5, and 10 years of follow-up. RESULTS: Compared with the urologic, polycystic, and other diseases groups, the immunologic group showed significantly lower time of graft survival (9.5 +/- 4 vs 8 +/- 4 vs 8.5 +/ 4 vs 7 +/- 4 years, respectively) and estimated glomerular filtration rate (52.5 +/- 32 vs 49 +/- 22 vs 50 +/- 32 vs 35.5 +/- 30 mL/min; P < .05). Relative risk of 10-year graft loss for the immunologic group was 2.8 (95% confidence interval, 1.6-4.9). Recurrence rate was 12% in the immunologic group versus 1% and 0% in the other diseases and remaining groups (P < .05). The relative risk of 10-year graft loss for patients with recurrence was 2.7 (95% confidence interval, 1.2 6.3). Ten-year graft loss rates for patients with biopsy-proven acute rejection, chronic allograft nephropathy, and recurrent glomerulonephritis were 30%, 23%, and 42% (P < .05). For those with biopsy-proven recurrent glomerulonephritis, 10 year estimated glomerular filtration rate was significantly lower than for those with biopsy-proven acute rejection or chronic allograft nephropathy (14 +/- 6 vs 18 +/- 7 vs 30 +/- 10 mL/min; P < .05). CONCLUSIONS: Kidney transplant recipients with immunologically mediated kidney diseases have inferior long-term allograft survival and function versus patients with other causes of renal failure. Recurrence represents the strongest risk factor for premature loss of function and transplant failure. PMID- 29108518 TI - Pneumatosis Intestinalis and Its Association With Lung Transplant: Alberta Experience. AB - OBJECTIVES: We evaluated the incidence, clinical presentation, laboratory findings, possible causes, and outcomes associated with pneumatosis intestinalis in the setting of lung transplant. MATERIALS AND METHODS: A departmental database showed that, between October 2002 and August 2013, our institution performed 373 lung transplants. The database was queried for all patients who had pneumatosis intestinalis and/or pneumoperitoneum after lung transplant at our institution. For this retrospective chart review, information collected included demographics, baseline variables, symptoms, signs, laboratory parameters, radiologic work-up, medications, including immunosuppressants at presentation, progress and time to resolution, length of hospital stay, and postoperative complications, as well as short-term and midterm outcomes (up to 1 year). RESULTS: The incidence of pneumatosis intestinalis was 2.68% (10/373 patients). Mean age of patients was 52.2 years (range, 34.9-67.9 y). Mean time for development of pneumatosis intestinalis after transplant was 352.8 days (range, 5-2495 d). Abdominal symptoms and signs were present in 6 patients (60%). The large bowel was the site of involvement in all but 1 patient, with predilection for ascending colon (80%) and transverse colon (90%) in most patients. High serum lactate levels were found in 2 patients, and both underwent bowel resection, with surgical specimens revealing evidence of ischemic changes in the gut. Mean dose of prednisone was 22 mg at the time of presentation (range, 0-60 mg). Mean hospital length of stay was 16.9 days (range, 0-40 d). Short-term survival was 100%. Midterm survival at the end of 1 year was 80%. Mean time for pneumatosis to resolve was 18 days (range, 14-35 d). CONCLUSIONS: Pneumatosis intestinalis in bilateral lung transplant recipients can be treated with a minimal amount of imaging, and most patients can be treated conservatively. Survival outcomes are quite good, with 100% during the short term and 80% at 1 year in our series. PMID- 29108519 TI - Rapid Development of De Novo Thoracic Aneurysm After Liver Transplant. AB - The development of aortic aneurysms in post-transplant patients is a rare but potentially lethal problem. De novo aortic aneurysm formation and rapid growth are postulated to result from an imbalance between pro- and anti-inflammatory vascular endothelial factors after transplant. Here, we present a case of de novo thoracic aneurysm formation within 2 months of orthotopic liver transplant. Prompt clinical recognition allowed for successful endovascular repair. Transplant clinicians should be aware of this potentially life-threatening complication and monitor at-risk recipients accordingly. PMID- 29108520 TI - A Proposed Classification System and Therapeutic Strategy for Chyle Leak After Laparoscopic Living-Donor Nephrectomy: A Single-Center Experience and Review of the Literature. AB - OBJECTIVES: Chyle leak or chylous ascites remains a rare complication after laparoscopic living-donor nephrectomy. Its cause and management have not been well elucidated in the literature. Thus, the aim of this study was to review the incidence of chyle leak/chylous ascites after laparoscopic living-donor nephrectomy in our institute and in the literature to propose a classification system with its associated treatment strategy. MATERILAS AND METHODS: In this retrospective review of laparoscopic living-donor nephrectomy patients from January 2005 to April 2016, we identified patients with chyle leak/chylous ascites along with the care performed. A proposed classification system based on our experience and literature is described. RESULTS: Chylous leak developed in 4 donors (2.25%). Of the 4 donors, 3 were treated nonoperatively with diet modification and subcutaneous octreotide injection. One patient required surgical intervention after not responding to second-line therapy with total parenteral nutrition. CONCLUSIONS: Chyle leak/chylous ascites after laparoscopic living donor nephrectomy is rare, but a delayed diagnosis may lead to morbidity secondary to malnutrition and immunosuppression. Meticulous surgical dissection is essential to seal the lymphatic tubes during laparoscopic living-donor nephrectomy. The proposed classification system provides a practical and tailored guide to management based on the drainage volume of chyle leak and a guide to the earlier identification of refractory cases. PMID- 29108521 TI - Minority stressors, rumination, and psychological distress in monozygotic twins discordant for sexual minority status. AB - BACKGROUND: Lesbian, gay, and bisexual (LGB) individuals report higher levels of depression and anxiety than heterosexual people. Genetic factors may be a 'common cause' of sexual minority status and psychological distress. Alternatively, these may be correlated because of non-genetic environmental factors (e.g. minority stressors). This study investigated minority stressors and distress in monozygotic twins discordant for sexual minority status. This design provides a test of the role of non-shared environmental factors while minimizing differences due to genetics. METHODS: Thirty-eight twin pairs in which one was heterosexual and the other was LGB completed a survey. Differences between twin pairs in minority stressors, rumination, psychological distress, and gender non-conformity were examined. Associations between these variables were also tested. RESULTS: Although there were no significant group differences for distress, LGB twins had higher rumination, a vulnerability factor for distress, than heterosexual co twins. LGB twins also had higher scores than heterosexual co-twins on expectations of rejection, active concealment, self-stigma, prejudice events, childhood gender non-conformity, and lower scores on sexual orientation disclosure. Differences between twin pairs in rumination were positively associated with differences in acceptance concerns and self-stigma. Finally, self stigma was positively associated with rumination in the full sample of heterosexual co-twins and microaggressions were positively associated with rumination when looking at exclusively heterosexual co-twins. CONCLUSIONS: These results support environmental factors as a causal explanation for disparities in rumination between LGB and heterosexual individuals. These factors likely include minority stressors. Rumination may also be associated with minority stressors in heterosexual MZ co-twins of LGB individuals. PMID- 29108522 TI - Telling life stories: a dyadic intervention for older Korean couples affected by mild Alzheimer's disease. AB - : ABSTRACTBackground:Dementia has negative consequences for both persons with dementia and their family caregivers. Dyadic interventions in which both groups participate together have shown an effective and promising approach. The Couples Life Story Approach (CLSA) that was recently developed for older couples dealing with dementia in the USA was adapted and implemented for the older Korean population in this study. The purpose of this paper is to understand how older Korean couples dealing with dementia experienced the CLSA. METHOD: Fifty six couples (n = 102) completed the five-week intervention from December 2013 to October 2015. The participants completed a survey including open-ended questions one week after finishing the intervention. A thematic content analysis was conducted to analyze the responses. RESULTS: Qualitative analysis revealed benefits and challenges in the experience of CLSA. Themes related to benefits were: (1) emotional benefits of reminiscing; (2) positive evaluation of life as a couple; (3) gratitude toward spouse; (4) changes in communications or activities with spouse; and (5) changes in relationship quality. Couples' experience varied, with some having mixed feelings about the intervention. Challenges perceived by participants included revival of bitterness and identification of loss. CONCLUSIONS: Findings suggest the CLSA contributes to enhancing the quality of life for couples affected by Alzheimer's disease and improving their relationship. Challenges that emerged in the CLSA will guide future research to identify the sub-population that is appropriate for the couple-oriented intervention in dementia care. PMID- 29108523 TI - Gamma-Glutamyltransferase (GGT) as a biomarker of cognitive decline at the end of life: contrasting age and time to death trajectories. AB - : ABSTRACTBackground:A recently published study suggests that Gamma Glutamyltransferase (GGT) in midlife is related to an increased risk of dementia. In the present longitudinal study, we explore the effects of serum GGT on cognitive decline and dementia also in more advanced ages. METHODS: We analyzed GGT in a sample of 452 individuals, aged 80 years and older at baseline, with the purpose to explore subsequent effects on cognitive performance. We specifically modeled GGT to cognitive change, time to death, and dementia. RESULTS: Our main finding is that a higher level of GGT is associated with cognitive decline prior to death and vascular dementia in late life. These findings were evident across cognitive domains. CONCLUSIONS: This is the first longitudinal study to report on significant associations in late life between GGT, cognitive performance and dementia. Further research is needed to examine the underlying mechanisms of GGT as a marker of age-related cognitive decline. PMID- 29108524 TI - Clinical predictors of conversion to bipolar disorder in a prospective longitudinal familial high-risk sample: focus on depressive features. AB - BACKGROUND: Identifying clinical features that predict conversion to bipolar disorder (BD) in those at high familial risk (HR) would assist in identifying a more focused population for early intervention. METHOD: In total 287 participants aged 12-30 (163 HR with a first-degree relative with BD and 124 controls (CONs)) were followed annually for a median of 5 years. We used the baseline presence of DSM-IV depressive, anxiety, behavioural and substance use disorders, as well as a constellation of specific depressive symptoms (as identified by the Probabilistic Approach to Bipolar Depression) to predict the subsequent development of hypo/manic episodes. RESULTS: At baseline, HR participants were significantly more likely to report ?4 Probabilistic features (40.4%) when depressed than CONs (6.7%; p < .05). Nineteen HR subjects later developed either threshold (n = 8; 4.9%) or subthreshold (n = 11; 6.7%) hypo/mania. The presence of ?4 Probabilistic features was associated with a seven-fold increase in the risk of 'conversion' to threshold BD (hazard ratio = 6.9, p < .05) above and beyond the fourteen-fold increase in risk related to major depressive episodes (MDEs) per se (hazard ratio = 13.9, p < .05). Individual depressive features predicting conversion were psychomotor retardation and ?5 MDEs. Behavioural disorders only predicted conversion to subthreshold BD (hazard ratio = 5.23, p < .01), while anxiety and substance disorders did not predict either threshold or subthreshold hypo/mania. CONCLUSIONS: This study suggests that specific depressive characteristics substantially increase the risk of young people at familial risk of BD going on to develop future hypo/manic episodes and may identify a more targeted HR population for the development of early intervention programs. PMID- 29108525 TI - Who's afraid of institutionalizing health technology assessment (HTA)?: Interests and policy positions on HTA in the Czech Republic. AB - This article identifies the interests and policy positions of key health policy stakeholders regarding the creation of a health technology assessment (HTA) agency in the Czech Republic, and what considerations influenced them. Vested interests have been suggested as a factor mitigating the diffusion of HTA bodies internationally. The Czech Republic recently considered and discarded establishing an HTA agency, making it a good case for studying actors' policy positions throughout the policy debates. Findings are based on in-depth, semi structured expert and elite interviews with 34 key Czech health policy actors, supported by document analysis and extensive triangulation. Findings show that the HTA epistemic community of 'aspiring agents' was the only actor strongly in favor of an HTA body. Payers and the medical device and diagnostics industry were against it; patients and clinicians had no clear preferences. Original decision makers were in favor but a new minister of health opted for a simpler policy alternative to solve his need for expertise. Existing institutions, policy alternatives and the institutional design of a future HTA body influence domestic actors' preferences for or against an HTA agency. Domestic and international proponents of HTA should give serious thought to their concerns when advocating for HTA bodies. PMID- 29108527 TI - Counting the Cost of Cervical Collars. AB - Veljanoski D , Grier G , Wilson MH . Counting the cost of cervical collars. Prehosp Disaster Med. 2017;32(6):701-702. PMID- 29108526 TI - Stabilising sleep for patients admitted at acute crisis to a psychiatric hospital (OWLS): an assessor-blind pilot randomised controlled trial. AB - BACKGROUND: When patients are admitted onto psychiatric wards, sleep problems are highly prevalent. We carried out the first trial testing a psychological sleep treatment at acute admission (Oxford Ward sLeep Solution, OWLS). METHODS: This assessor-blind parallel-group pilot trial randomised patients to receive sleep treatment at acute crisis [STAC, plus standard care (SC)], or SC alone (1 : 1). STAC included cognitive-behavioural therapy (CBT) for insomnia, sleep monitoring and light/dark exposure for circadian entrainment, delivered over 2 weeks. Assessments took place at 0, 2, 4 and 12 weeks. Feasibility outcomes assessed recruitment, retention of participants and uptake of the therapy. Primary efficacy outcomes were the Insomnia Severity Index and Warwick-Edinburgh Mental Wellbeing Scale at week 2. Analyses were intention-to-treat, estimating treatment effect with 95% confidence intervals. RESULTS: Between October 2015 and July 2016, 40 participants were recruited (from 43 assessed eligible). All participants offered STAC completed treatment (mean sessions received = 8.6, s.d. = 1.5). All participants completed the primary end point. Compared with SC, STAC led to large effect size (ES) reductions in insomnia at week 2 (adjusted mean difference -4.6, 95% CI -7.7 to -1.4, ES -0.9), a small improvement in psychological wellbeing (adjusted mean difference 3.7, 95% CI -2.8 to 10.1, ES 0.3) and patients were discharged 8.5 days earlier. One patient in the STAC group had an adverse event, unrelated to participation. CONCLUSIONS: In this challenging environment for research, the trial was feasible. Therapy uptake was high. STAC may be a highly effective treatment for sleep disturbance on wards with potential wider benefits on wellbeing and admission length. PMID- 29108529 TI - High-sensitivity C-reactive protein and cognitive decline: the English Longitudinal Study of Ageing. AB - BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) has been suggested to be involved in the process of cognitive decline. However, the results from previous studies exploring the relationship between hs-CRP concentration and cognitive decline are inconsistent. METHOD: We employed data from wave 2 (2004-2005) to wave 7 (2014-2015) of the English Longitudinal Study of Ageing. Cognitive function was assessed at baseline (wave 2) and reassessed biennially at waves 3 7. RESULTS: A total of 5257 participants (54.9% women, mean age 65.4 +/- 9.4 years) with baseline hs-CRP levels ranged from 0.2 to 210.0 mg/L (median: 2.0 mg/L, interquartile range: 0.9-4.1 mg/L) were studied. The mean follow-up duration was 8.1 +/- 2.8 years, and the mean number of cognitive assessment was 4.9 +/- 1.5. Linear mixed models show that a one-unit increment in natural log transformed hs-CRP was associated with faster declines in global cognitive scores [-0.048 points/year, 95% confidence interval (CI) -0.072 to -0.023], memory scores (-0.022 points/year, 95% CI -0.031 to -0.013), and executive function scores (-0.025 points/year, 95% CI -0.043 to -0.006), after multivariable adjustment. Compared with the lowest quartile of hs-CRP, the multivariable adjusted rate of global cognitive decline associated with the second, third, and highest quartile was faster by -0.043 points/year (95% CI -0.116 to 0.029), 0.090 points/year (95% CI -0.166 to -0.015), -0.145 (95% CI -0.221 to -0.069), respectively (p for trend <0.001). Similarly, memory and executive function also declined faster with increasing quartiles of hs-CRP. CONCLUSIONS: A significant association between hs-CRP concentration and long-term cognitive decline was observed in this study. Hs-CRP might serve as a biomarker for cognitive decline. PMID- 29108528 TI - Problematic alcohol use and hippocampal volume in a female sample: disentangling cause from consequence using a co-twin control study design. AB - BACKGROUND: Although there is extensive evidence that problematic alcohol use is associated with smaller hippocampal volume, the typical cross-sectional study design cannot determine whether hippocampal deviations reflect pre-existing liability toward problematic alcohol use or instead reflect an alcohol exposure related effect. We used the co-twin control study design, which capitalizes upon differences within a twin pair in levels of drinking, to differentiate pre existing liability from an effect of alcohol exposure. METHODS: The sample included 100 female twins, prospectively assessed from ages 11 to 24. Problematic alcohol use was assessed dimensionally and included indicators of quantity, frequency, and density of alcohol use and intoxication. Hippocampal volume was assessed using magnetic resonance imaging. RESULTS: Problematic alcohol use (proximal and cumulative) was associated with significantly smaller left and right hippocampal volume. Follow-up co-twin control analyses that partitioned individual-level alcohol effects into pre-existing, familial liability and non shared alcohol exposure-related effects indicated that this association reflected alcohol exposure. Greater alcohol using twins had smaller hippocampal volume relative to lesser alcohol using co-twins, beyond effects of their shared genetic and environmental liability toward problematic alcohol use. Results held accounting for recent alcohol use, other substance use, externalizing and internalizing psychopathology, personality traits, trauma exposure, and menstrual phase. CONCLUSIONS: The association between problematic alcohol use and smaller hippocampal volume likely reflects an alcohol exposure-related effect. Differentiating pre-existing brain deviations that confer risk for problematic alcohol use from those that reflect effects of alcohol on the brain will inform etiological models of addiction and further prevention and intervention efforts. PMID- 29108530 TI - Battle of plates: a pilot study of an approach-avoidance training for overweight children and adolescents. AB - OBJECTIVE: Approach-avoidance training (AAT) is a promising approach in obesity treatment. The present study examines whether an AAT is feasible and able to influence approach tendencies in children and adolescents, comparing implicit and explicit training approaches. Design/Setting/Subjects Fifty-nine overweight children and adolescents (aged 8-16 years; twenty-six boys) participated in an AAT for food cues, learning to reject snack items and approach vegetable items. Reaction times in the AAT and an implicit association test (IAT) were assessed pre- and post-intervention. RESULTS: A significant increase in the AAT compatibility scores with a large effect (eta 2=0.18) was found. No differences between the implicit and explicit training approaches and no change in the IAT scores were observed. CONCLUSIONS: Automatic tendencies in children can be trained, too. The implementation of AAT in the treatment of obesity might support the modification of an unhealthy nutrition behaviour pattern. Further data from randomized controlled clinical trials are needed. PMID- 29108531 TI - Eating occasions and the contribution of foods to sodium and potassium intakes in adults. AB - OBJECTIVE: To examine dietary Na and K intake at eating occasions in Australian adults and identify the contribution of major food sources to Na and K at different eating occasions. DESIGN: Secondary analysis of 24 h recall diet data from the Australian Health Survey (2011-2013). SETTING: Nationally representative survey in Australia. SUBJECTS: Male and female Australians aged 18-84 years (n 7818). RESULTS: Dinner contributed the greatest proportion to total daily Na intake (33 %) and K intake (35 %). Na density was highest at lunch (380 mg/MJ) and K density highest at between-meal time eating occasions (401 mg/MJ). Between meal time eating occasions provided 20 % of daily Na intake and 26 % of daily K intake. The major food group sources of Na were different at meal times (breads and mixed dishes) compared with between-meal times (cakes, muffins, scones, cake type desserts). The top food group sources of K at meal times were potatoes and unprocessed meat products and dishes. CONCLUSIONS: Foods which contributed to Na and K intake differed according to eating occasion. Major food sources of Na were bread and processed foods. Major food sources of K were potatoes and meat products and dishes. Public health messages that emphasise meal-based advice and diet patterns high in vegetables, fruits and unprocessed foods may also aid reduction in dietary Na intake and increase in dietary K intake. PMID- 29108532 TI - The EAST-Dem study: a pilot cluster randomized controlled trial. AB - ABSTRACTWe recruited eight general practice (GP) practices for a pilot cluster randomized controlled trial (RCT) of a digital versatile disc/leaflet encouraging South Asian people to seek timely help for memory problems. Primary outcomes were feasibility (proportion of patients expressing interest, consenting) and acceptability. Seventy-eight of one hundred and two (76%) potential participants consented; 76/78 (97%) were followed-up. Thirty-seven of forty-one (90%) receiving the intervention rated this acceptable. Only 17/41 (41%) accessed it; they appeared then to be more likely to seek timely help. The intervention was acceptable and feasible but a full-scale RCT would be very expensive. It may be proportionate to make this intervention available without a full-scale RCT. PMID- 29108533 TI - A review of the efficacy and safety of once-daily tiotropium Respimat 2.5 micrograms in adults and adolescents with asthma. AB - BACKGROUND: Despite current guidelines, many patients with asthma remain symptomatic, particularly those intolerant of,unresponsive to, or uncontrolled by long-acting beta 2-agonists (LABAs). Tiotropium bromide, delivered through the Respimatsoft-mist inhaler in 2 puffs of 1.25 micrograms each, is approved for the long-term, maintenance treatment of asthma in patients aged greater than or equal to 6 years. OBJECTIVE: An overview of the use of once-daily tiotropium Respimat 2.5 micrograms in adults and adolescents with varyingdegrees of asthma severity. The role of the parasympathetic nervous system in the pathophysiology of asthma, the developmentof tiotropium for respiratory disease, and the value of the Respimat inhaler are also discussed. METHODS: A literature search of all phase II and phase III trials of once-daily tiotropium Respimat 2.5 micrograms. RESULTS: Once-daily tiotropium Respimat 2.5 micrograms was studied in five phase III studies: three studies in adults andtwo in adolescents aged 12-17 years. Tiotropium Respimat 2.5 micrograms demonstrated efficacy in adults and adolescentswith mild, moderate, or severe asthma, showing significant improvements in lung function and asthma control in patients with uncontrolled asthma despite inhaled corticosteroids (ICS) or ICS plus LABA use. The adverse event profile of tiotropium was very acceptable, with safety similar to placebo. CONCLUSION: Once-daily tiotropium Respimat 2.5 micrograms has positive attributes that include efficacy, a safety profilesimilar to placebo, once-daily dosing, administration by inhalation, and delivery in the easy-to-use and consistent dosing Respimat device. However, more data are needed on the effects of tiotropium on clinical outcomes, patients' day-to-day lives, and real-world effectiveness. PMID- 29108534 TI - [Lengthening temporalis myoplasty in treatment of chronic facial paralysis]. AB - Introducing the lengthening temporalis myoplasty (LTM), a newly implemented surgical treatment of chronic facial paralysis. LTM is a single-stage operation where the temporalis muscle is transposed for dynamic smile reconstruction, hereby serving as an alternative to the more complex two-stage microvascular functional muscle transplantation. This case report demonstrates how LTM can be used to treat patients, who are not motivated or suitable for extensive surgery. The introduction of this technique aims to help a larger number of patients with chronic facial paralysis. PMID- 29108535 TI - [Cardiovascular changes in childhood obesity]. AB - Over the last 35 years there has been an almost 50% increase in childhood obesity worldwide. Childhood obesity is associated with increased cardiovascular morbidity and mortality in adulthood, and in children with overweight or obesity pathologic changes have been found down to the age of two years. These changes are present in vasculature, heart and autonomic nervous system and affect blood pressure control. Overweight and obesity must be prevented, detected and treated at an early age, as even a small weight loss reduces the risk of cardiovascular disease significantly. PMID- 29108536 TI - [Post intensive care syndrome]. AB - Patients surviving severe critical illness commonly develop post intensive care syndrome (PICS). The syndrome consists of a constellation of cognitive dysfunction, depression, anxiety and post-traumatic stress disorder combined with physical weakness. Different contributing risk factors for development of PICS have been identified. Furthermore, close family members of the patient are at risk of developing similar psychiatric manifestations. Focus should be on early preventive measures during hospitalization and post-ICU follow-up with a multidisciplinary approach. PMID- 29108537 TI - [Patients with glenohumeral arthrosis risk delay of treatment]. AB - Referral for shoulder joint replacement in patients with glenohumeral arthrosis may be delayed in the primary sector. When non-surgical first-line treatment has little effect on pain and quality of life, patients should be referred for orthopaedic specialist assessment. New trends regarding shoulder prosthesis are under way as indicated by data from the Danish Shoulder Alloplasty Registry from the latest decade with an increase in number and quality. Changed demographic composition in favour of the elderly makes focus on the importance of shoulder prosthesis regarding research and treatment algorithm. PMID- 29108538 TI - [Upper abdominal pain caused by oesophageal perforation]. AB - Boerhaave's syndrome or spontaneous oesophageal perforation is associated with significant mortality de-pending on time of diagnosis and initiation of treatment. However, the diagnosis is often delayed, as the condition mimics more frequent causes of chest- and abdominal pain. This case report describes a patient with severe upper ab-dominal and back pain following ructus in an effort to loosen a piece of candy stuck in the oesophagus. The case demon-strates, that Boerhaave's syndrome should always be con-sidered in patients presenting with acute chest- or upper abdominal pain. PMID- 29108539 TI - The Pathophysiology of the Male Aging Face and Body. AB - Increasing numbers of men are seeking aesthetic treatments for fat reduction, skin rejuvenation, and other antiaging goals. Compared with women, however, men have distinctly different anatomy and physiologic differences that manifest in the aging process. Given that both anatomy and the aging process affect treatment strategies and clinical outcomes, there is a need for dermatologists to be acutely aware of these male-specific nuances to provide the best clinical care and patient satisfaction. PMID- 29108541 TI - Cosmeceuticals for Male Skin. AB - The male cosmeceutical market is still underdeveloped. Although women embrace skin care as a part of general health, this concept has not gained wide male acceptance. Shaving is probably the most beneficial daily grooming event men commonly undertake for skin appearance and may account for the failure of antiaging cosmeceuticals to attract attention in this segment. In addition, there are many physiologic differences between male and female skin, with less of a need for moisturization and photoprotection in men. This article highlights some of the differences between male and female skin along with the unique product attributes required to address these differences. PMID- 29108540 TI - Cosmetic Concerns Among Ethnic Men. AB - Men of all races are currently more open to requesting and undergoing treatments for a plethora of cosmetic concerns. Among the most common goals are procedures that combat the signs of aging, rejuvenate the skin, even out the color tone, address textural issues such as acne scarring, and improve hair disorders. Given the differences in cultural ideals and anatomic/physiologic differences in ethnic skin, it is important for physicians to be aware and sensitive to the nuances required when providing consultation and treating non-Caucasian men. The main cosmetic concerns of this patient cohort and their optimal management are presented. PMID- 29108542 TI - Energy-Based Devices in Male Skin Rejuvenation. AB - Men seek cosmetic procedures for vastly different reasons than women. Men often seek discrete cosmetic services with little downtime. Male skin structure generally differs from female skin structure. Dermatologists should consider subtle differences in the psyche of the male cosmetic patient. PMID- 29108543 TI - The Use of Neurotoxins in the Male Face. AB - Injection of neurotoxin is the most commonly performed cosmetic procedure in the United States, and the total number of male patients seeking botulinum has steadily increased over the years. Because of their unique aesthetic goals, expectations, and anatomy, men require differing botulinum toxin doses and techniques. This article provides an evidence-based approach to botulinum toxin in men. Each area of the face is discussed separately, focusing on gender differences in anatomy, treatment goals, and injection method. PMID- 29108544 TI - Volumetric Structural Rejuvenation for the Male Face. AB - Fillers and toxins are safe, quick, and require no downtime; the immediately visible results can boost a man's self-esteem, confidence, youthfulness, and sense of competitiveness in the personal and professional realms of the world. The approach to using these agents has changed from ironing out the skin to remove wrinkles and lines to a restructuring of the 3-dimensional face. This new strategy, volumetric structural rejuvenation (VSR), relies on intimate knowledge of facial anatomy and the pathophysiology of aging. It is of essence to know the key anatomic differences between the 2 sexes to avoid potential feminization. PMID- 29108545 TI - Noninvasive Body Contouring: A Male Perspective. AB - Noninvasive body contouring is an attractive therapeutic modality to enhance the ideal male physique. Men place higher value on enhancing a well-defined, strong, masculine jawline and developing a V-shaped taper through the upper body. An understanding of the body contour men strive for allows the treating physician to focus on areas that are of most concern to men, thus enhancing patient experience and satisfaction. This article discusses noninvasive body contouring techniques, taking into account the unique aesthetic concerns of the male patient by combining an analysis of the existing literature with our own clinical experience. PMID- 29108546 TI - Cosmetic Concerns Among Men. AB - Men are interested in reducing signs of aging, while maintaining a masculine appearance. A chief concern among men is maintenance of scalp hair. Men are also concerned with reducing under eye bags and dark circles. The concern of feminization is of significant importance. Neuromodulators remain the most common cosmetic procedure performed in men. Men often prefer a reduction in facial rhytids, as opposed to elimination of the lines. Softening facial lines in men is meant to maintain an appearance of wisdom, without appearing fragile. Men also wish to maintain a taut jawline and a slim waist and reduce breast tissue. PMID- 29108547 TI - Advances in Hair Restoration. AB - Hair loss affects millions of people worldwide and can have devastating effects on an individual's psychological and emotional well-being. Hair restoration technologies have advanced with the use of robotics and manual and motorized follicular unit extraction to provide patients excellent clinical results. Adjuvant modalities such as platelet-rich plasma injections, lasers and stem cells can further enhance the survivability and appearance of hair transplants. PMID- 29108548 TI - New-Generation Therapies for the Treatment of Hair Loss in Men. AB - Hair loss affects millions of people worldwide and can have devastating effects on an individual's psychoemotional well-being. Today hair restoration technologies through hair transplantation have advanced with the use of robots and follicular unit extraction/grafting that can offer patients excellent clinical results. Adjuvant modalities, such as platelet-rich plasma injections, lasers, and stem cells, can further enhance durability, health, and appearance of hair transplants. PMID- 29108549 TI - Combination Therapy for Male Cosmetic Patients. AB - This article reviews the most common male cosmetic procedures that are performed in combination with more than one procedure. Evidence-based medicine for many of these combination therapies is not rampant in the medical literature, but the author uses his current experience to share how combining therapies can be useful for our male population seeking cosmetic improvements in our offices. PMID- 29108550 TI - Liposuction Considerations in Men. AB - Liposuction is the most popular cosmetic surgical procedure performed in men. Aside from traditional liposuction using the tumescent technique, several energy assisted liposuction technologies have emerged and been proven safe and particularly beneficial for the male patient demographic. The differences in fat distribution and unique goals and emotional perspective in men need to be taken into account when performing liposuction, to ensure meeting the patient's needs and expectations for satisfactory results. PMID- 29108551 TI - Cosmetic Dermatology for Men. PMID- 29108552 TI - Effect of body fat and gender on body temperature distribution. AB - It is well known that body composition can influence peripheral heat loss and skin temperature. That the distribution of body fat is affected by gender is well known; however, there is little information on how body composition and gender influences the measure of skin temperature. This study evaluated skin temperature distribution according to body fat percentage (BF%) and gender. A sample of 94 apparently healthy volunteers (47 women and 47 men) was assessed with Dual-Energy X-Ray Absorptiometry (DXA) and infrared thermography (mean, maximum and minimum temperatures - TMean, TMax and TMin). The sample was divided into groups, according to health risk classification, based on BF%, as proposed by the American College of Sports Medicine: Average (n = 58), Elevated (n = 16) or High (n = 20). Women had lower TMean in most regions of interest (ROI). In both genders, group High had lower temperature values than Average and Elevated in the trunk, upper and lower limbs. In men, palms and posterior hands had a tendency (p < 0.05) for increased temperature along with increased BF%. TMean, TMax and TMin of trunk, upper and lower limbs were negatively correlated with BF% and the fat percentage of each segment (upper limbs, lower limbs and trunk). The highest correlations found in women were between posterior trunk and BF% (rho = -0.564, p < 0.001) and, in men, between anterior trunk and BF% (rho = -0.760, p < 0.001). Overall, this study found that women have lower skin temperature than men, which was related with higher BF%. Facial temperature seems not to be influenced by body fat. With the future collection of data on the relationship between BF% and skin temperature while taking into account factors such as body morphology, gender, and ethnicity, we conclude that measurement of BF may be reliably estimated with the use of thermal imaging technology. PMID- 29108553 TI - Rhinarium temperature dynamics in domestic dogs. AB - Many mammals have specialized nose-tips with glabrous and often wet skin, called rhinaria. The function of the rhinarium is unknown in most species. Rhinaria differ not only in shape and skin structure, but also in skin temperature. They are considerably colder in carnivorans than in herbivorous artio- and perissodactyls. Domestic dogs are carnivorans and their noses often feel cold, such that they can be used as an abundant and easily accessible model species. We performed a study on rhinarium temperature in dogs under various ambient temperatures as well as in different behavioral and physiological contexts, breeds, and age groups. The rhinaria of adult, alert, and comfortable dogs are colder than ambient temperature from 30 degrees C (approximately 5 degrees C colder) down to a break point at about 15 degrees C. At an ambient temperature of 0 degrees C, rhinarium temperature is approximately 8 degrees C and the decrease in skin surface temperature with decreasing ambient temperature has not yet leveled off. The dog rhinarium warms up under a number of circumstances. In contrast to the continuously warm rhinaria of herbivores, our results suggest strongly that the cold state is the operating state of the dog rhinarium. PMID- 29108554 TI - Oxidative stress and antioxidant defense responses of Etroplus suratensis to acute temperature fluctuations. AB - Fishes are always exposed to various environmental stresses and the chances of succumbing to such stresses are of great physiological concern. Any change in temperature from the ambient condition can induce various metabolic and physiological changes in the body. The present study evaluates the effects of temperature induced stress on the antioxidant profile of Etroplus suratensis such as superoxide dismutase, catalase, glutathione peroxidase and lipid peroxidation. Fishes of same size were kept in a thermostatized bath at three different temperature regimes viz 16 degrees C, 27 degrees C (ambient temperature) and 38 degrees C for 72h. These temperatures were selected based on the CT Max (Critical Thermal Maximum) and CT Min (Critical Thermal Minimum) exhibited by E. suratensis. Superoxide dismutase and catalase activity was found maximum in brain and muscle respectively during the 48th hour of exposure in fishes kept at 38 degrees C. At 16 degrees C the antioxidant response of glutathione peroxidase was maximum in muscles, whereas the lipid peroxidation rate was found to be high in gills compared to other tissues. The profound increase in the levels of oxidative stress related biomarkers indicate that the thermal stressors severely affected oxidative state of E. suratensis by the second day of experiment. Such down regulation of redox state accompanied with the induction of oxidative stress cascade may lead to physiological damage in various tissues in fishes, in vivo. However current data indicate that a transition to low and high temperature environment from ambient condition severely affected the levels and profile of the antioxidant markers overtime in E. suratensis. PMID- 29108555 TI - Temperature-dependent models of development and survival of an insect pest of African tropical highlands, the coffee antestia bug Antestiopsis thunbergii (Hemiptera: Pentatomidae). AB - The antestia bug Antestiopsis thunbergii (Hemiptera: Pentatomidae) is a major pest of Arabica coffee in African tropical highlands. It feeds on coffee plant vegetative parts and berries leading to a direct reduction in coffee yield and quality. This study aimed to determine A. thunbergii thermal requirements, and to obtain new information on the pest demography as influenced by temperature. Temperature-dependent models were developed using the Insect Life Cycle Modelling software (ILCYM) through a complete life table study at seven constant temperatures in the range 18-32 degrees C. Non-linear functions were fitted to A. thunbergii development, mortality, fecundity and senescence. Model parameters and demographic variables obtained from the models were given for each temperature and development stage. Life table parameters were estimated for nine constant temperatures, from 18 degrees C to 26 degrees C, using stochastic simulations. The minimum temperature threshold (Tmin) and the thermal constant (k) for the development from egg to adult were estimated from a linear function at 12.1 degrees C and 666.67 degrees days, respectively. The maximum temperature threshold (Tmax) was estimated at 33.9 degrees C from a Logan model. The optimum temperature for immature stages' survival was estimated to be between 22.4 and 24.7 degrees C. The maximum fecundity was 147.7 eggs female-1 at 21.2 degrees C. Simulated A. thunbergii life table parameters were affected by temperature, and the maximum value of intrinsic rate of increase (rm) was 0.029 at 22 degrees C and 23 degrees C. In general, the life cycle data, models and demographic parameters we obtained were in line with previous reports for antestia bugs or other stink bug species. The relationships between the pest thermal requirements and ecological preferences in highland coffee were discussed. Our results will contribute to risk prediction under climate change for this important coffee pest. PMID- 29108556 TI - Long-term thermal manipulation in the late incubation period can inhibit breast muscle development by activating endoplasmic reticulum stress in duck (Anasplatyrhynchos domestica). AB - Poultry embryos are easily affected by environmental changings during incubation, thereinto, the temperature modification is the most important one, but the mechanism of temperature effects on bird eggs is not clear. By using RNA-seq, we have previously found that endoplasmic reticulum stress (ERS) may involve in regulating embryonic muscle development of duck under the influence of temperature alteration. To further clarify the role of ERS in the effect, in the present study, we detected the impact of increasing the incubation temperature by 1C during embryonic days 10-27 (E10-27) on the development of duck embryos, and investigated the changes in mRNA and protein expression of ERS marker genes and muscle-related genes under the thermal manipulation (TM). The results of relative weight comparison showed that only the relative weight of breast muscle was steadily decreased by TM from E10 to the first day after hatching (W0). Meanwhile, the real-time PCR and western-blot analysis revealed that raising the incubation temperature stimulated the expression of ERS marker genes in breast muscle at E20. The mRNA expressions of muscle hypertrophy and atrophy-related genes were also detected, and were not changed regularly, however, the protein expressions of hypertrophy-related genes were all decreased at both E20 and W0, and the protein expression of atrophy-related genes were up-regulated at E20. The protein expression of muscle proliferation-related genes were also decreased at E20. Additionally, these results were the same as that in the ERS positive control groups. Taken together, these results indicated that long-term TM during late embryonic period could block the development of duck breast muscle by inhibiting muscle hypertrophy and proliferation, and promoting muscle atrophy at a post-transcriptional level via the activation of ERS. PMID- 29108557 TI - Seasonal energetics and torpor use in North American flying squirrels. AB - Seasonal cold temperatures require mammals to use morphological, behavioural, or physiological traits to survive periods of extreme cold and food shortage. Torpor is a physiological state that minimizes energy requirements by decreasing resting metabolic rate (MR) and body temperature (Tb). Many rodent species are capable of torpor, however, evidence in northern and southern flying squirrels (Glaucomys sabrinus and Glaucomys volans, respectively) has remained anecdotal. We experimentally attempted to induce torpor in wild-caught flying squirrels by lowering ambient temperature (Ta) and measuring MR using open-flow respirometry. We also studied seasonal differences in MR and Tb at various Ta. Both MR and Tb provided evidence for torpor in flying squirrels, but only infrequent, shallow torpor. MR decreased infrequently and any decreases were rarely sustained for longer than one hour. We found a significant positive relationship between Ta and Tb only in G. volans, which suggests that G. volans is more susceptible to low Ta compared with G. sabrinus, possibly due to their small body size. We observed no substantive seasonal or interspecific differences in the relation between MR and Ta, with the exception that northern flying squirrels expended more energy at cold Ta during warm season trials than other species-season combinations. The infrequency of torpor use in our experiments suggests that other energy-saving strategies, such as social thermoregulation, may limit the reliance on torpor in this lineage. PMID- 29108558 TI - Partitioning thermal habitat on a vertical rock, a herculean task. AB - Species occurring in sympatry have to effectively segregate their niche in order to co-exist. In the case of ectotherms in particular, the very important parameter of thermal biology has to be taken into account. Here we investigated the thermoregulatory effectiveness (E) of two endemic Greek lizards (Hellenolacerta graeca and Podarcis peloponnesiacus) that live syntopically on a rocky cliff in the Peloponnese. We presumed that the two species would select different microhabitats, to avoid interspecific competition, and follow a similar thermoregulation pattern as they experience the same conditions. We also expected that E values for both species would differ depending on the season. Overall, we found that the two species had similar E values for each season but differentiated partial thermoregulatory attributes. Though they both occurred in the same types of microhabitat, H. graeca selected higher sites (average 99cm above ground) than P. peloponnesiacus (average 44cm). Also, the latter achieved higher preferred temperatures during summer and winter. Finally, the effectiveness of thermoregulation for both species varied interseasonally and received its highest values during summer, in response to the lowest thermal quality that was observed then. Similar studies stress the importance of thermal shifts for ectotherm co-existence. PMID- 29108559 TI - Zinc nanoparticles potentiates thermal tolerance and cellular stress protection of Pangasius hypophthalmus reared under multiple stressors. AB - A preliminary study was conducted to delineate the ameliorating effect of dietary zinc nanoparticles (Zn-NPs) against thermal stress in Pangasius hypophthalmus reared under concurrent exposure to lead (Pb) and elevated temperature (34 degrees C). Three diets were formulated such as control (no Zn-NPs), Zn-NPs 10 and 20mg/kg diet. Two hundred and thirty four fish were randomly distributed in to six treatments groups in triplicates; such as control group (no Zn-NPs in diet and unexposed to Pb and temperature, Ctr/Ctr), control diet with concurrent exposure to Pb and temperature (Pb-T/Ctr), Zn-NPs 10 and 20mg/kg without stressors (Zn-NPs 10mg/kg, Zn-NPs 20mg/kg), Zn-NPs 10 and 20mg/kg diet with concurrent exposure to Pb and temperature (Pb-T/Zn-NPs 10mg/kg, Pb-T/Zn-NPs 20mg/kg). The Pb in treated water was maintained at the level of 1/21th of LC50 (4ppm) at 34 degrees C temperature in stressors groups. Post 60 days feeding trial, critical thermal minimum (CTmin), lethal thermal minimum (LTmin), and critical thermal maximum (CTmax), lethal thermal maximum (LTmax) and biochemical attributes on P. hypophthalmus were evaluated. The results indicated that, dietary supplementation of Zn-NPs increased the CTmin, LTmin and CTmax, LTmax in P. hypophthalmus. Positive correlations were observed between CTmin LTmin (Y = - 0.495 + 10.08x, R2, 0.896) and CTmax LTmax (Y = - 0.872 + 4.43x, R2, 0.940). At the end of the thermal tolerance study, oxidative stress and lipid peroxidation (LPO) were significantly reduced and neurotransmitter enzyme was significantly increased in the groups fed with Zn-NPs @ 10mg and 20mg/kg diet. Overall results indicated that dietary Zn-NPs can confer protection against thermal stress in P. hypophthalmus. PMID- 29108560 TI - The change in metabolic heat production is a primary mediator of heat acclimation in adults. AB - PURPOSE: This study examined whether heat acclimation (HA) results in either predominate improvements in heat dissipation or reduced endogenous heat production via individual components of the human heat balance equation. METHODS: Twelve healthy inactive subjects (5 females, mean +/- SD): age 28 +/- 6y, 77.9 +/ 2kg), completed a 10-day HA (42 degrees C, 28% RH) hyperthermia clamp (90min/day exercise, ?1.5 degrees C in rectal temperature (Tre)) and control workload matched (CON: 23 degrees C, 42% RH) protocols in a counterbalanced design separated by at least 2 mo. Pre-and post-HA were matched for external work rate (EXWR; day 1 and day 10 first 30min at 118 +/- 29W, last 60min at 11 +/- 5W); and metabolic heat production (Hprod; day 1 and day 9, first 30min at 296 +/- 26Wm-2, last 60min 187 +/- 33Wm-2). RESULTS: When Pre- and post- HA was matched for Hprod, there was no difference during the first 30 or last 60min of exercise for metabolic energy expenditure (MEE 363 +/- 70/ 195 +/- 32Wm-2), Hprod (296 +/- 67/ 187 +/- 33Wm-2) or Tre (?2.1 +/- 0.5 degrees C). When pre- and post-HA was EXWR equivalent, HA significantly attenuated MEE during the first 30 and last 60min (303 +/- 49/ 174 +/- 35Wm-2), Hprod (241 +/- 44/ 168 +/- 33, W.m-2), and ?Tre (?1.3 +/- 0.4 degrees C) (each P < 0.0001). When ?Tre, ?Tsk, ?Tb were each normalized per 100W Hprod, no differences were found for any pre-to post-HA comparison. Heat loss required (Ereq) to maintain steady state internal temperature (Ereq = 220 +/- 32Wm-2), maximal capacity of the climate for evaporative heat loss (Emax = 266 +/- 56Wm-2), evaporative heat loss from skin (Esk = 207 +/- 38Wm-2) or skin wettedness (Ereq/Emax = 0.88 +/- 0.23Wm-2) were not different among each condition during the last 60min. CONCLUSION: The mechanisms that underlie heat acclimation are not wholly attributed to heat dissipation enhancements per se, but are significantly influenced by metabolic heat production alterations under uncompensable heat stress environments. PMID- 29108561 TI - Thermal performance curves under daily thermal fluctuation: A study in helmeted water toad tadpoles. AB - Most research in physiological ecology has focused on the effects of mean changes in temperature under the classic "hot vs cold" acclimation treatment; however, current evidence suggests that an increment in both the mean and variance of temperature could act synergistically to amplify the negative effects of global temperature increase and how it would affect fitness and performance-related traits in ectothermic organisms. We assessed the effects of acclimation to daily variance of temperature on thermal performance curves of swimming speed in helmeted water toad tadpoles (Calyptocephalella gayi). Acclimation treatments were 20 degrees C +/- 0.1 SD (constant) and 20 degrees C +/- 1.5 SD (fluctuating). We draw two key findings: first, tadpoles exposed to daily temperature fluctuation had reduced maximal performance (Zmax), and flattened thermal performance curves, thus supporting the "vertical shift or faster-slower" hypothesis, and suggesting that overall swimming performance would be lower through an examination of temperatures under more realistic and ecologically relevant fluctuating regimens; second, there was significant interindividual variation in performance traits by means of significant repeatability estimates. Our present results suggest that the widespread use of constant acclimation temperatures in laboratory experiments to estimate thermal performance curves (TPCs) may lead to an overestimation of actual organismal performance. We encourage the use of temperature fluctuation acclimation treatments to better understand the variability of physiological traits, which predict ecological and evolutionary responses to global change. PMID- 29108562 TI - Support for the thermal coadaptation hypothesis from the growth rates of Sceloporus jarrovii lizards. AB - The thermal coadaptation hypothesis posits that ectotherms thermoregulate behaviorally to maintain body temperatures (Tb) that maximize performance, such as net energy gain. Huey's (1982) energetics model describes how food availability and Tb interact to affect net energy gain. We tested the thermal coadaptation hypothesis and Huey's energetics model with growth rates of juvenile Yarrow's spiny lizards (Sceloporus jarrovii). We compared the preferred (selected) Tb range (Tsel) of lizards in high and low energy states to their optimal temperature (To) for growth over nine weeks, and determined whether the To for growth depended on food availability. We also measured the same lizards' resting metabolic rate at five Tbs to test the energetics model assumptions that metabolic cost increases exponentially with Tb and does not differ between energy states. The Tsel of lizards on both diets overlapped with the To for growth. The assumptions of the energetics model were verified, but the To for net energy gain did not depend on food availability. Therefore, we found support for the thermal coadaptation hypothesis. We did not find support for the energetics model, but this may have been due to low statistical power. PMID- 29108563 TI - The effect of heat stress on intestinal integrity and Salmonella invasion in broiler birds. AB - The intestinal mucosa works as a barrier to protect the internal environment of the animal from bacteria and bacterial toxins found in the gut lumen. Heat stress may harm this function. Therefore, we designed the current experiment to investigate the effect of heat stress on intestinal integrity, physiological and immunological responses and Salmonella invasion in broiler chickens. At 26 days of age, 72 birds were randomly distributed into 3 treatments, with 8 replicates per treatment and 3 birds per replicate. The three treatments were control treatment; kept at thermoneutral environmental conditions (20 +/- 2 degrees C), chronic heat stress treatment (exposed to 30 +/- 2 degrees C; 24h/day) and acute heat stress treatment (exposed to 35 +/-2 degrees C from 09:00 to 13:00 and kept at 20 +/- 1 degrees C from 13:00 to 09:00). The heat stress exposure was conducted for 10 successive days. Compared with the control treatment, birds subject to chronic and acute heat stress had reduced (P < 0.05) body weight and body gain and increased (P < 0.05) feed conversion ratio. However, feed intake and mortality rate were only increased (P < 0.05) in the acute heat stress treatment. Rectal temperature and Delta rectal temperature ( degrees C/h) increased (P < 0.05) sharply during the first 2 days of exposure followed by gradual decreases until a plateau was achieved. Heat-stressed birds had increased (P < 0.05) serum concentrations of corticosterone, endotoxin lipopolysaccharide and the systemic inflammatory cytokine: TNF-alpha and IL-2, as well as a higher (P < 0.05) prevalence of Salmonella spp. in meat and livers, as compared with control treatment. It can be concluded that heat stress impaired intestinal integrity which resulted in increased intestinal permeability to endotoxin, translocation of intestinal pathogens (Salmonella spp.) and serum inflammatory cytokines. Therefore, avoiding thermal dysfunction of intestinal barrier is a significant factor in maintaining welfare, immune status and meat safety of broiler birds. PMID- 29108565 TI - Analytical Nanoscience and Nanotechnology: Where we are and where we are heading. AB - The main aim of this paper is to offer an objective and critical overview of the situation and trends in Analytical Nanoscience and Nanotechnology (AN&N), which is an important break point in the evolution of Analytical Chemistry in the XXI century as they were computers and instruments in the second half of XX century. The first part of this overview is devoted to provide a general approach to AN&N by describing the state of the art of this recent topic, being the importance of it also emphasized. Secondly, particular but very relevant trends in this topic are outlined: the analysis of the nanoworld, the so "third way" in AN&N, the growing importance of bioanalysis, the evaluation of both nanosensors and nanosorbents, the impact of AN&N in bioimaging and in nanotoxicological studies, as well as the crucial importance of reliability of the nanotechnological processes and results for solving real analytical problems in the frame of Social Responsibility (SR) of science and technology. Several reflections are included at the end of this overview written as a bird's eye view, which is not an easy task for experts in AN&N. PMID- 29108566 TI - Progress in a selective method for the determination of the acetaldehyde-derived DNA adducts by using HILIC-ESI-MS/MS. AB - Acetaldehyde (AA), which is present in tobacco smoke, automobile exhaust gases and alcohol beverage, is a mutagen and carcinogen. AA reacts with 2' deoxyguanosine (dG) in DNA to form N2-ethyl-dG (EtdG) and cyclic, 1, N2-propano dG (CPrdG), which are considered to have a critical role in carcinogenesis induced by AA. In this study, we have developed a highly sensitive method for the quantitation of the two AA-derived DNA adducts by using liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) in which hydrophilic interaction chromatography (HILIC) employing mobile phases of high organic solvent concentration was selected to improve the ionization efficiency in the ESI process. Fourteen times and 11 times larger peak areas for EtdG and CPrdG, respectively, in HILIC-ESI-MS/MS were obtained compared with those in reversed phase (RP)-LC-ESI-MS/MS. Furthermore, 6.9 times (for EtdG) and 2.4 times (for CPrdG) larger peak areas were also obtained as additional enhancement by varying additive compounds in the HILIC mobile phases from ammonium acetate to ammonium bicarbonate. In total, the enhancements in detected MS signal intensities by exchanging from the RP-LC system to the HILIC system are 97 times for EtdG and 26 times for CPrdG, respectively. Three commercially available HILIC columns with different polar functional groups were examined and sufficient separation between normal 2'-deoxynucleosides and the AA-derived DNA adducts was achieved by a carbamoyl-bonded HILIC column. Finally, we applied the established method to quantify EtdG and CPrdG in the damaged calf thymus DNA. PMID- 29108567 TI - A survey of analytical methods employed for monitoring of Advanced Oxidation/Reduction Processes for decomposition of selected perfluorinated environmental pollutants. AB - The monitoring of Advanced Oxidation/Reduction Processes (AO/RPs) for the evaluation of the yield and mechanisms of decomposition of perfluorinated compounds (PFCs) is often a more difficult task than their determination in the environmental, biological or food samples with complex matrices. This is mostly due to the formation of hundreds, or even thousands, of both intermediate and final products. The considered AO/RPs, involving free radical reactions, include photolytic and photocatalytic processes, Fenton reactions, sonolysis, ozonation, application of ionizing radiation and several wet oxidation processes. The main attention is paid to the most commonly occurring PFCs in the environment, namely PFOA and PFOS. The most powerful and widely exploited method for this purpose is without a doubt LC/MS/MS, which allows the identification and trace quantitation of all species with detectability and resolution power depending on the particular instrumental configurations. The GC/MS is often employed for the monitoring of volatile fluorocarbons, confirming the formation of radicals in the processes of C-C and C-S bonds cleavage. For the direct monitoring of radicals participating in the reactions of PFCs decomposition, the molecular spectrophotometry is employed, especially electron paramagnetic resonance (EPR). The UV/Vis spectrophotometry as a detection method is of special importance in the evaluation of kinetics of radical reactions with the use of pulse radiolysis methods. The most commonly employed for the determination of the yield of mineralization of PFCs is ion-chromatography, but there is also potentiometry with ion-selective electrode and the measurements of general parameters such as Total Organic Carbon and Total Organic Fluoride. The presented review is based on about 100 original papers published in both analytical and environmental journals. PMID- 29108568 TI - Comprehensive two-dimensional gas chromatography using partial modulation via a pulsed flow valve with a short modulation period. AB - Partial modulation via a pulsed flow valve for comprehensive two-dimensional (2D) gas chromatography (GC * GC) is demonstrated, producing narrow peak widths, 2Wb, on the secondary separation dimension, 2D, coupled with short modulation periods, PM, thus producing a high peak capacity on the 2D dimension, 2nc. The GC * GC modulator is a pulse flow valve that injects a pulse of carrier gas at the specified PM, at the connection between the primary, 1D, column and the 2D column. Using a commercially available pulse flow valve, this injection technique performs a combination of vacancy chromatography and frontal analysis, whereby each pulse disturbance in the analyte concentration profile as it exits the 1D column results in data that is readily converted into a 2D separation. A three step process converts the raw data into a format analogous to a GC * GC separation, incorporating signal differentiation, baseline correction and conversion to a GC * GC chromatogram representation. A 115-component test mixture with a wide range of boiling points (36-372 degrees C) of nine compound classes is demonstrated using modulation periods of PM = 50, 100, 250, and 500ms, respectively. For the test mixture with a PM of 250ms, peak shapes on 2D are symmetric with apparent 2Wb ranging from 12 to 45ms producing a 2nc of ~ 10. Based on the average peak width of 0.93s on the 1D separation for a time window of 400s, the 1D peak capacity is 1nc ~ 430. Thus, the ideal 2D peak capacity nc,2D is 4300 or a peak capacity production of 650 peaks/min using the PM of 250ms. Additionally, for a PM of 50, 100 and 500ms, the 2nc are 4, 7, and 12, respectively. Retention times on 2D, 2tR, are reproducible having standard deviations less than 1ms. Finally, the processed data is shown to be quantitative, with an average RSD of 4.7% for test analytes. PMID- 29108569 TI - A genome-inspired, reverse selection approach to aptamer discovery. AB - Limitations of Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and related methods that depend upon combinatorial oligonucleotide libraries have hindered progress in this area. Our laboratory has introduced a new approach to aptamer discovery that uses oligonucleotides with sequences drawn from the human genome to capture proteins from biological samples. Specifically, we have focused on capture of proteins in nuclear extracts from human cell lines using G quadruplex (G4) forming genomic sequences. Previous studies identified capture of several proteins both in vitro and in live cells by the Pu28-mer sequence from the ERBB2 promoter region. Here we provide a more comprehensive study of protein capture from BT474 and MCF7 human breast cancer cells using G4-forming sequences from the CMYC, RB, VEGF and ERBB2 human oncogene promoter regions. Mass spectrometric analysis and Western blot analysis of protein capture at oligonucleotide-modified surfaces revealed capture of nucleolin by all three of the oligonucleotides in BT474 and MCF7 cells, and also of ribosomal protein L19 (RPL19) in BT474 cells. Chromatin immunoprecipitation (ChIP) analysis confirmed the interaction of nucleolin with all three promoter sequences in MCF7 cells and with RB in BT474 cells. ChIP also revealed interactions of RPL19 with CMYC in BT474 cells and of both RPL19 and ribosomal protein L14 (RPL14) with ERBB2 in BT474 cells. These results offer the basis for development of new aptamers based on the G4 sequences from the CMYC, RB, VEGF, and ERBB2 promoters toward proteins including nucleolin, RPL19 and RPL14. These interactions also may have biological and therapeutic significance. PMID- 29108570 TI - Liquid chromatography-electrochemical detection for the determination of ethoxyquin and its dimer in pear skin and salmon samples. AB - Ethoxyquin (EQ) is widely used as a synthetic antioxidant in animal feed, an antiscalding agent in apples and pears and as a color preservative in some spices. Since the presence of EQ in food products could cause negative health effects it is necessary to develop reliable analytical methods to evaluate the risk of human exposure. In this work, a sensitive, selective and accurate method based on solid-liquid extraction followed by clean-up with solid sorbent and liquid chromatography-electrochemical detection analysis with boron doped diamond electrode (LC-EC) for the determination of ethoxyquin and its dimer (EQDM) in pear skin and salmon samples, was developed. The method was validated according to the European Commission guidelines. The main variables of extraction were accurately optimized. The amounts of solid sorbents for clean-up procedure were optimized by using experimental design. A Box-Behnken design to obtain the optimum conditions was applied. For validation, a matrix-matched calibration was established and a recovery assay with spiked samples was carried out. The limits of detection (LODs) found were 0.05 and 0.1mgkg-1 for EQ and its dimer, respectively. The precision (as relative standard deviation, RSD) was lower than 15% with recoveries of compounds close to 100% in spiked samples. PMID- 29108571 TI - Wearable non-invasive epidermal glucose sensors: A review. AB - The growing recent interest in wearable and mobile technologies has led to increased research efforts toward development of non-invasive glucose monitoring platforms. Continuous glucose monitoring addresses the limitations of finger stick blood testing and provides the opportunity for optimal therapeutic interventions. This article reviews recent advances and challenges toward the development of non-invasive epidermal electrochemical glucose sensing systems. Recent reports claim success in glucose monitoring in human subjects using skin worn electrochemical sensors. Such epidermal electrochemical biosensors obviate the disadvantages of minimally-invasive subcutaneous glucose biosensors and offer promise for improved glycemic control. The ability of such systems to monitor glucose non-invasively offers an attractive route toward advancing the management of diabetes and achieving improved glycemic control. However, realizing the potential diagnostic impact of these new epidermal sensing strategies would require extensive efforts toward addressing key technological challenges and establishing a reliable correlation to gold standard blood glucose meters. PMID- 29108572 TI - A cost-effective assay for antioxidant using simple cotton thread combining paper based device with mobile phone detection. AB - A cost-effective assay for antioxidant using simple cotton thread combining paper based device with mobile phone detection has been investigated. Standard and sample solutions flow along a bunch of cotton thread treated with sodium hydroxide via microfluidic behaviors without external pumping. The analyte solution reacts with the reagents that have been immobilized on the paper strip fixed at the end of the cotton bunch. The developed platforms were used for the assays of total phenolic content and antioxidant capacity by employing Folin Ciocalteu and 2, 2-diphenyl-1-picryhydrazyl (DPPH) respectively. Simple detection can be made by employing a mobile phone camera (iPhone 4S) with Image J or Photoshop for image processing and evaluation. Gallic acid was used as a reference standard in this work, as its polyphenol structures can be found in many plants. The total phenolic content is expressed as gallic acid equivalents (GAE) (mg/g material). Inhibition capacity is calculated by the equation: % I = [(Io - Is)/ Io] * 100, where Is is the relative magenta intensity (CMYK mode) of sample, and Io the relative magenta intensity of DPPH*. IC50 inhibition can be estimated from the graph and can be used for the antioxidant capacity consideration. Applications to the assay green tea samples were demonstrated. The total phenolic contents in the green tea samples were found to be 48-105mg/g, with %RSD of less than 10 for that of higher 50 GAE mg/g and IC50 values of the samples studied were 25-50mg/L. The results obtained by the developed methods agree with that of the standard methods. PMID- 29108573 TI - Developments of microfluidic paper-based analytical devices (MUPADs) for water analysis: A review. AB - Water pollution is a serious environmental problem affecting millions of people, and the demand for frequent water quality monitoring is increasing. The need for analytical platforms that combine high sensitivity, selectivity and accuracy with low cost, portability and user friendliness remains a challenge. Microfluidic paper-based analytical devices (MUPADs) are recognised as a powerful analytical platform that can satisfy these requirements. The aim of this review is to provide a detailed overview of the MUPADs that have been developed for the determination of important water quality parameters, such as nutrients, metals and organic contaminants, in a range of waters. A description of the fabrication and detection methods selected for these applications is provided, and the performance of the MUPADs with respect to their precision and accuracy is critically assessed. The potential of these devices for real-life applications is also critically examined, particularly if they can determine the concentrations specified in water quality guidelines or the maximum recommended concentrations for various waters, as well as if they are suitable for field applications. PMID- 29108574 TI - Novel method for manipulation of anion-exchange selectivity by derivatizing hydroxyl groups in the proximity of quaternary nitrogen ion-exchange sites with glycidol. AB - A general approach for the manipulation of anion-exchange selectivity through derivatization of hydroxyl groups adjacent to quaternary anion-exchange sites with glycidol is described. Repetitive reactions with glycidol result in dramatic shifts in the retention of divalent anions. Unique selectivities are observed for specific divalent species resulting in shifts in elution order. Modification of anion-exchange materials with glycidol has a small effect on the selectivity of monovalent anions, but in some cases, significant shifts in selectivity are observed. Use of the synthetic approach for modification of commercially available ion-exchange materials is demonstrated. PMID- 29108575 TI - Agarose hydrogel containing immobilized pH buffer microemulsion without increasing permselectivity. AB - A heterogeneous pH buffer based on a colloidal emulsion containing ion-exchanger and lipophilic base is described that can be integrated into hydrogels without affecting their ion-exchange properties. Each sphere works on the basis of reversible ion-exchange of hydrogen ions with solution cations, acting as a pH buffer while staying removed from solution in the nonpolar core of the spheres. The ion-exchange mechanism is supported by titration experiments in aqueous emulsion, showing that the nature and concentration of the exchanging solution cations influences the buffer action, with increasing lipophilicity moving the equilibrium to lower pH values. Agarose gels with entrapped pH buffer emulsions and mounted in a transport cell are shown by zero current potentiometry to exhibit negligible permselective properties above an ionic strength of 1mM, a behavior no different from unmodified agarose, with an observed ion-exchanger concentration of 7mM in dry agarose. This suggests that such pH buffers do not give rise to substantial ion-exchange properties of the gel material. In a first attempt to control the pH in the vicinity of an electrode surface by this approach, the emulsion was entrapped in an agarose gel in direct contact with a pH electrode, demonstrating the ability to buffer such gel films. PMID- 29108576 TI - Continuous measurement of elemental composition of ambient aerosol by induction coupled plasma mass spectrometry. AB - There is presently no instrumentation that can provide (near) real time information on elemental composition of atmospheric aerosols. We describe an arrangement where air is sampled through a cyclone @30L/min with a 50% cutoff @ ~250nm. The particles deposit into a cup through which deionized water is continuously flowing. High purity HNO3 is added downstream and the mixed stream optionally flows through a quartz photo reactor (185nm, ~90 degrees C, tR ~1.2min) and is aspirated by an induction coupled plasma mass spectrometer (ICP MS). Comparative batch experiments in which samples were not photodigested at all or thermally digested off-line for an extended period indicated no statistically significant difference in the results. This observation agrees with early theoretical and experimental work. Some 22 elements were quantifiable (S/N > 10) at all times in the aerosol samples collected in our highly urban sampling location; an additional 4 elements were quantifiable at times of construction activity in the general area. Presently attained system limits of detection (LODs) are orders of magnitude higher than the instrumental LOD, both because of the purity of the acid and pump-induced contamination. These aspects can be vastly improved and will need to be improved to determine background concentrations. PMID- 29108577 TI - Functionalization of mesoporous organosilica nanocarrier for pH/glutathione dual responsive drug delivery and imaging of cancer therapy process. AB - A multifunctional drug nanocarrier is developed by incorporating acetaldehyde modified-cystine (AMC) into mesoporous organosilica nanoparticles (MONs), shortly termed as MONs-AMC. The anticancer drug doxorubicin (DOX) links directly to MONs AMC through electrostatic interaction between DOX and AMC to produce a conjugate, MONs-AMC-DOX, with a drug loading efficiency of 26.24 +/- 1.35%, corresponding to a loading capacity of 0.26 +/- 0.01mgmg-1 for DOX. Schiff base AMC contains a -S S- bond and two -C?N- bonds which cleave in the presence of certain level of GSH and in an acidic medium, providing MONs-AMC-DOX the capability for triggering pH and glutathione (GSH) dual-responsive drug release. Further, the self-fluorescent nature of AMC offers the tracing capability without the need of fluorescent label, which facilitates real-time tracing of the drug delivery and cancer therapy process. With 10mmolL-1 GSH and at pH 5.0, a drug release efficiency of 52.27 +/- 2.84% is achieved. The intracellular drug release process is traced with confocal laser scanning microscope by monitoring the green fluorescence of MONs-AMC-DOX and red fluorescence of DOX with excitation at 408nm and 488nm, respectively. The drug loaded nanocarriers exhibit a time-dependent cellular uptake behavior, providing an enhanced therapeutic effect to A549 cancer cells. PMID- 29108578 TI - Screening arsenic(III)-binding peptide for colorimetric detection of arsenic(III) based on the peptide induced aggregation of gold nanoparticles. AB - A suitable As(III)-binding ligand is the key to realize selective and sensitive As(III) sensing. In this study, phage display technique was used for the screening of As(III)-binding peptide. By negative screening against some representative metal cations and positive screening against target As(III), phages that bind to foreign metal cations were eliminated, while those bearing As(III)-binding peptides were kept and enriched. After DNA sequencing and phage ELISA analysis, 5 sets of As(III)-binding peptides were identified, with high content of N-containing functional groups as their predominate feature. A highly specific peptide (sequence: T-Q-S-Y-K-H-G) with the highest frequency of occurrence and best selectivity for As(III) was finally chosen. This peptide with a cysteine added at the C-terminal induces the aggregation of gold nanoparticles (AuNPs), whereas the competitive binding of As(III) to the peptide prevents the aggregation of AuNPs. Based on this observation, a simple and sensitive colorimetric sensing assay was developed, with a limit of detection (LOD) of 54nM (4MUgL-1) for As(III). The As(III) sensor showed high selectivity over other metal ions including As(V), and was validated by As(III) analysis in certified reference material and environmental water samples. PMID- 29108579 TI - Exploiting the 3-Aminopropyltriethoxysilane (APTES) autocatalytic nature to create bioconjugated microarrays on hydrogen-passivated porous silicon. AB - Porous silicon (pSi) based microarrays are attractive because pSi: (i) can be modified in many ways, (ii) possesses a high surface area, and (iii) exhibits strong photoluminescence (PL). These characteristics make pSi-based microarrays candidates for a host of applications including sensing, optoelectronic devices, and photodetectors. Microarray fabrication requires a high-throughput approach to produce chemically modified, spatially isolated spots on a particular substrate. The most stable platforms are characterized by covalent attachment to the substrate. In this paper we exploit the autocatalytic nature of 3 aminopropyltriethoxysilane (APTES) to contact pin-print APTES directly onto as prepared, H-passivated pSi (ap-pSi) without the need for a formal oxidation step. We assess the APTES-derived spots by using PL and Fourier transform infrared spectroscopy (FT-IR) imaging and determine the spot size and spatial homogeneity. All APTES-derived spots exhibited two distinct regions; a silanized core surrounded by an oxidized halo. By decreasing the APTES concentration and increasing the acid concentration, the oxidized halo size decreased by 60%; however, the silanized core diameter remains APTES and acid concentration independent. Bioconjugation can be achieved to all APTES-derived features; however, the highest biomolecule loading was realized by using pure APTES. Together these experiments demonstrate an easy and simple strategy for creating protein microarrays on pSi. PMID- 29108580 TI - Development of flow systems incorporating membraneless vaporization units and flow-through contactless conductivity detector for determination of dissolved ammonium and sulfide in canal water. AB - Use of membraneless vaporization (MBL-VP) unit with two cone-shaped reservoirs is presented for on-line separation and detection of non-volatile species. A flow system comprising two sets of MBL-VP units with a single in-house capacitively coupled contactless conductivity detector (C4D) was developed for dual determination of ammonium and sulfide ions. Using the continuous-flow section, two zones (280MUL) of a sample, either mixed with sodium hydroxide (for ammonium) or hydrochloric acid (for sulfide), are separately delivered into the donor reservoir of the MBL-VP units. The acceptor reservoir contains either 150MUL of 15MUM HCl solution (for ammonia) or pure water (for hydrogen sulfide), respectively. Vaporization and trapping of the ammonia or hydrogen sulfide gas from the donor reservoir into the liquid acceptor cone occur concurrently in the two separate MBL-VP units. After trapping the gas for 3min, the two 150-MUL liquid acceptors are sequentially aspirated through the C4D flow cell for recording the changes in the conductivity. Linear calibrations were obtained for ammonium from 5 to 80uM (Volt = (0.0134 +/- 0.0003) [NH4+] - (0.01 +/- 0.01), r2 = 0.998) and for sulfide from 5 to 200uM (Volt = (0.0335 +/- 0.0009) [S2-] - (0.13 +/- 0.09), r2 = 0.996). Analysis time for both analytes is only 320s. Our method was applied to analyze canal water samples. The results agree well with membrane gas-diffusion flow injection techniques, using bromothymol blue for ammonium and methylene blue for sulfide. Recoveries ranged from 95% to 104%. PMID- 29108581 TI - Identification of coffee leaves using FT-NIR spectroscopy and SIMCA. AB - Abundant literature has been devoted to coffee beans (green or roasted) chemical description but relatively few studies have been devoted to coffee leaves. Given the fact that coffee leaves are used for food and medicinal consumption, it was of interest to develop a rapid screening method in order to identify coffee leaves taxa. Investigation by Fourier - Transform near infrared spectroscopy (FT NIRS) was performed on nine Coffea taxa leaves harvested over one year in a tropical greenhouse of the Botanic Garden Meise (Belgium). The only process after leaves harvesting was an effective drying and a homogeneous leaves grinding. FT NIRS with SIMCA analysis allowed to discriminate the spectral profiles across taxon, aging stage (mature and senescence coffee leaves) and harvest period. This study showed that it was possible (i) to classify the different taxa, (ii) to identify their aging stage and (iii) to identify the harvest period for the mature stage with a correct classification rate of 99%, 100% and 90%, respectively. PMID- 29108582 TI - Investigation of gas phase absorption spectral similarity for stable-isotopically labeled compounds in the 125-240nm wavelength range. AB - Stable-isotopically-labeled internal standards are commonly incorporated in methods for trace analysis that utilize mass spectrometric detection. They closely mimic the physicochemical properties of the analyte, but their signal is easily differentiable based on a change in molecular mass. To investigate the potential to transfer methods incorporating such internal standards for analysis by vacuum ultraviolet detection, a study was conducted to compare the spectral shape (from 125 to 240nm) of stable-isotopically-labeled compounds with their non labeled counterparts. Gas chromatography - vacuum ultraviolet spectroscopic analysis was performed for a series of benzene isotopologues, as well as for clinically- and environmentally-relevant standard compounds and their deuterated counterparts. The absorption characteristics of the benzene isotopologues were evaluated based on similarity (normalized spectra), as well as on their magnitude of absorption. In general, very minor differences in absorption spectra were observed; however, increasing degree of deuteration did generally increase the spectral difference between labeled and non-labeled analytes. Sum of squared residuals were used as quantitative measures to assess spectral similarity (and dissimilarity). Theoretical computation of absorption spectra for benzene using time-dependent density functional theory was also examined; though, further work is needed in this area to extend the analysis to isotopologue analysis. PMID- 29108583 TI - Metabolomics analysis of human sweat collected after moderate exercise. AB - Sweat is a promising biofluid scarcely used in clinical analysis despite its non invasive sampling. A more frequent clinical use of sweat requires to know its whole composition, especially concerning to non-polar compounds, and the development of analytical strategies for its characterization. The aim of the present study was to compare different sample preparation strategies to maximize the detection of metabolites in sweat from humans collected after practicing moderate exercise. Special emphasis was put on non-polar compounds as they have received scant attention in previous studies dealing with this biofluid. Sample preparation by liquid-liquid extraction (LLE) using extractants with different polarity index was compared to deproteination. Then, derivatization by methoxymation with subsequent silylation was compared to direct analysis of sweat extracts to check the influence of derivatization on the subsequent determination of volatile organic compounds (VOCs). 135 compounds were tentatively identified by combining spectral and retention time information after analysis by gas chromatography coupled to mass spectrometry in high resolution mode (GC-TOF/MS). Lipids, VOCs, benzenoids and other interesting metabolites such as alkaloids and ethanolamines were identified. Among the tested protocols, methyoxiamination plus silylation after LLE with dichloromethane was the best option to obtain a representative snapshot of sweat metabolome collected from different body parts after moderate exercise. Passive and active sweat pools from a cohort of volunteers (n = 6) were compared to detect compositional differences which can be explained by the sampling process and sweating induction. As most of the identified compounds are metabolites involved in key biochemical pathways, this study opens new opportunities to extend the applicability of human sweat as a source of metabolite biomarkers of pathologies or specific processes such as dehydration or nutritional unbalance. PMID- 29108584 TI - Sodium deoxycholate/TRIS-based hydrogels for multipurpose solute delivery vehicles: Ambient release, drug release, and enantiopreferential release. AB - Herein, we report the investigation of sodium deoxycholate (NaDC)/TRIS-based hydrogels as delivery vehicles for a broad range of applications. Three hydrogel formulations were chosen for unique rheological behaviors that suggest a change in internal hydrogel structure with the application of a shear force. In this work, we compare solute release from sheared and non-sheared hydrogels in order to explore the effect of shear force on structure and release kinetics. It was found that the application of a shear force, in addition to changes in temperature, drug solubility, drug concentration, and hydrogel formulation each affected the amount of solute ultimately released from a hydrogel system. Moreover, the use of the inherent chirality of the hydrogel network for enantio preferential drug release was also explored. We show significant enantio preference in the release of model drugs tryptophan and ibuprofen from the hydrogel network. Furthermore, hydrophobic domains within the hydrogel network were exploited to enable ibuprofen loading at ten times the maximum water solubility. Retention of enantio-preference was observed at this higher ibuprofen concentration. Cyclodextrin modification to the hydrogel matrix allowed for enantio-preferential inversion which is an unprecedented observation. PMID- 29108585 TI - Using bead injection to model dispensing of 3-D multicellular spheroids into microtiter plates. AB - Biomedical translational research has relied on two dimensional (2D) cell cultures for drug discovery over the decades, requiring cells to grow on a flat surface which does not always accurately model in vivo biological states. Three dimensional (3D) cell cultures, also known as 3D spheroids or organoids, grow as cellular tissues that are more physiologically relevant especially with respect to emulating cancer tumor-like structures [1]. While attractive, current methods for generating 3D spheroids has yet to replace 2D culturing methods used for drug discovery efforts that employ high-throughput screening (HTS), having limitations with scalability, reproducibility, and compatibility predominantly associated with conventional microtiter plate usage. Presented is a novel use of bead injection for the reproducible placement of spheroids and beads into high density microtiter plates of a 384- and 1536- well format. PMID- 29108586 TI - Exploiting an automated microfluidic hydrodynamic sequential injection system for determination of phosphate. AB - A microfluidic hydrodynamic sequential injection (MUHSI) spectrophotometric system was designed and fabricated. The system was built by laser engraving a manifold pattern on an acrylic block and sealing with another flat acrylic plate to form a microfluidic channel platform. The platform was incorporated with small solenoid valves to obtain a portable setup for programmable control of the liquid flow into the channel according to the HSI principle. The system was demonstrated for the determination of phosphate using a molybdenum blue method. An ascorbic acid, standard or sample, and acidic molybdate solutions were sequentially aspirated to fill the channel forming a stack zone before flowing to the detector. Under the optimum condition, a linear calibration graph in the range of 0.1-6mg P L-1 was obtained. The detection limit was 0.1mgL-1. The system is compact (5.0mm thick, 80mm wide * 140mm long), durable, portable, cost-effective, and consumes little amount of chemicals (83MUL each of molybdate and ascorbic acid, 133MUL of the sample solution and 1.7mL of water carrier/run). It was applied for the determination of phosphate content in extracted soil samples. The percent recoveries of the analysis were obtained in the range of 91.2-107.3. The results obtained agreed well with those of the batch spectrophotometric method. PMID- 29108587 TI - Influence of sample preparation on lipidomics analysis of polar lipids in adipose tissue. AB - The main limitations of lipidomics analysis are the chemical complexity of the lipids, the range of concentrations at which they exist, and the variety of samples usually analyzed. These limitations particularly affect the characterization of polar lipids owing to the interference of neutral lipids, essentially acylglycerides, which are at high concentration and suppress ionization of low concentrated lipids in mass spectrometry detection. The influence of sample preparation on lipidomics analysis of polar lipids in adipose tissue by LC-MS/MS was the aim of this research. Two common extractants used for lipids isolation, methanol:chloroform (MeOH:CHCl3) and methyl tert-butyl ether (MTBE), were qualitatively and quantitatively compared for the extraction of the main families of lipids. The obtained results showed that each family of lipids is influenced differently by the extractant used. However, as a general trend, the use of MTBE as extractant led to higher extraction efficiency for unsaturated fatty acids, glycerophospholipids and ceramides, while MeOH:CHCl3 favored the isolation of saturated fatty acids and plasmalogens. The implementation of a solid-phase extraction (SPE) step for selective isolation of glycerophospholipids prior to LC-MS/MS analysis was assayed to evaluate its influence on lipids detection coverage as compared to direct analysis. This step was critical to enhance the detection coverage of glycerophospholipids by removal of ionization suppression effects caused by acylglycerides. PMID- 29108588 TI - Miniaturized high-performance liquid chromatography instrumentation. AB - Miniaturized high performance liquid chromatography (HPLC) has attracted increasing attention for its potential in high-throughput analyses and point-of care applications. In this review we highlight the recent advancements in HPLC system miniaturization. We focus on the major components that constitute these instruments along with their respective advantages and drawbacks as well as present a few representative miniaturized HPLC systems. We discuss briefly some of the applications and also anticipate the future development trends of these instrumental platforms. PMID- 29108589 TI - The lasting effect of intergenerational wealth transfers: Human capital, family formation, and wealth. AB - Recent evidence indicates that inheritances and other intergenerational wealth transfers have only a limited effect on wealth inequality and the intergenerational transmission of financial well-being. In this study, we explore the role that human capital and family formation play in mediating the relationship between receiving a transfer and building wealth. We examine how educational attainment and family formation determine whether or not households are able to convert inheritances into greater assets, facilitating improved wealth accumulation. Using data from the Panel Study for Income Dynamics (PSID), we examine how these factors moderate wealth accumulation trajectories following a bequest or inter vivos gift. Results reveal that educational attainment and marriage each facilitate wealth accumulation following a transfer. Our evidence suggests that cumulative advantage processes produce divergent wealth accumulation trajectories but these are situated in important turning points in the life course. PMID- 29108590 TI - Multiracial identities, single race history: Contemporary consequences of historical race and marriage laws for racial classification. AB - This work interrogates the role of the law as an "actor" in the spatial patterning of racial classification. Laws governing racial intermarriage represent key ways that rigid distinctions between groups were codified. Critically, there is a great deal of state variation in these laws. We draw on a unique data set that combines samples from the 1990 and 2000 Census (5 percent IPUMS) and the 2009-2011 estimates from the American Community Survey with information on state-specific legal bans against intermarriage. Results from multilevel logistic and multinomial analyses indicate that a past of legal regulation is associated with a lower likelihood of a "mixed" classification for the offspring of black-white interracial unions, particularly in the 2009-11 period. Our results provide evidence that place-specific institutional legacies are imprinted on the classification choices made even in the midst of expanding options. PMID- 29108592 TI - Partisan strength, political trust and generalized trust in the United States: An analysis of the General Social Survey, 1972-2014. AB - The literature on political parties suggests that strong partisan identities are associated with citizens' effective interaction with the political system, and with higher levels of political trust. Traditionally, party identity therefore is seen as a mechanism that allows for political integration. Simultaneously, however, political parties have gained recent attention for their role in promoting societal polarization by reinforcing competing and even antagonistic group identities. This article uses General Social Survey data from 1972 - 2014 to investigate the relationship between partisan strength and both political and generalized trust. The findings show that increases in partisan strength are positively related to political trust, but negatively related to generalized trust. This suggests that while partisan strength is indeed an important linkage mechanism for the political system, it is also associated with a tendency toward social polarization, and this corrosive effect thus far has not gained sufficient attention in literature on party identity. PMID- 29108591 TI - Solamente Mexicanos? Patterns and sources of Hispanic diversity in U.S. metropolitan areas. AB - Rapid Hispanic growth has been a major source of increasing ethnoracial diversity in the United States. However, diversity within the Hispanic population is frequently obscured by the tendency to lump all Latinos together. Our study examines Hispanic diversity at the local level, drawing insights from the Mexican dominance, Caribbean-centric settlement, spatial assimilation, and economic opportunity perspectives. Measures of the magnitude and structure of Hispanic origin-group diversity during the 1990-2010 period are constructed for 363 metropolitan areas based on each area's shares of Mexicans, Puerto Ricans, Cubans, Dominicans, Salvadorans, Guatemalans, Colombians, and 'others'. We find that diversity magnitude varies markedly across metropolitan Hispanic populations. Although the most diverse metro areas lack a majority origin group, Mexicans often constitute a majority or plurality of local Latinos. Diversity levels and structures have remained relatively stable over time. In both 1990 and 2010, metro areas with more diverse, multigroup Hispanic communities are distinguished by their larger size, smaller proportion of Hispanics, location farther from Mexico and closer to the Caribbean, and greater odds of being a military hub. They also exhibit higher rates of housing construction and lower rates of agricultural and manufacturing employment. We use weighted data to show that Dominican metro dwellers experience the highest Hispanic diversity while the average Mexican lives in an area where four-fifths of all Latinos are Mexican. Overall, our results provide primary support for the Mexican dominance perspective but some support for the other three perspectives as well. PMID- 29108593 TI - Radius of trust: Gradient-based conceptualization and measurement. AB - The radius of trust - the width of one's cooperation circle - has been widely cited by scholars from various disciplines as a key factor in the production and maintenance of public good. However, the vagueness in its conceptualization, measurement, and analysis obstructs efficient communication between empirical works, impeding the accumulation of scientific knowledge. This study develops a conceptualization of trust radius as the gradient in the level of trust in specific individuals across social ties of differing strengths. Along with this conceptualization, a new measurement scheme is constructed, which, relative to previous measures, is empirically easy-to-implement and theoretically valid in displaying individual-level variations in trust radius, highlighting trust radius' distinction from generalized trust and affinity with specific trust, and accommodating the differing tie strengths within one's trust network. Finally, this measurement scheme is well integrated in a multilevel modeling framework to study the determinants of trust radius, which is illustrated by two examples. PMID- 29108594 TI - Studying neighborhood crime across different macro spatial scales: The case of robbery in 4 cities. AB - Whereas there is a burgeoning literature focusing on the spatial distribution of crime events across neighborhoods or micro-geographic units in a specific city, the present study expands this line of research by selecting four cities that vary across two macro-spatial dimensions: population in the micro-environment, and population in the broader macro-environment. We assess the relationship between measures constructed at different spatial scales and robbery rates in blocks in four cities: 1) San Francisco (high in micro- and macro-environment population); 2) Honolulu (high in micro- but low in macro-environment population); 3) Los Angeles (low in micro- but high in macro-environment population); 4) Sacramento (low in micro- and macro-environment population). Whereas the socio-demographic characteristics of residents further than 1/2 mile away do not impact robbery rates, the number of people up to 2.5 miles away are related to robbery rates, especially in the two cities with smaller micro environment population, implying a larger spatial scale than is often considered. The results show that coefficient estimates differ somewhat more between cities differing in micro-environment population compared to those differing based on macro-environment population. It is therefore necessary to consider the broader macro-environment even when focusing on the level of crime across neighborhoods or micro-geographic units within an area. PMID- 29108595 TI - Depression in later life: A closer look at the gender gap. AB - Gender differences in depressive symptoms have been extensively documented, with women reporting a higher number of depressive symptoms than men. However, studies offer different explanations for why such a gap exists. The goal of the current paper is to analyze how much of the observed gender gap in depression may be attributed to (1) compositional versus (2) reporting differences or (3) differences in reactivity to adversities. We contribute to this literature by testing, net of compositional differences, whether the relationship between reporting behavior and depressive symptoms is gendered and whether accounting for the possibility of gender-specific reactivity alters the structure of the gender gap at older ages. Our results show that the observed gender gap in depression (1) only partially derives from compositional differences; (2) is not an artifact of a gender-specific reporting style; and remarkably (3) men appear more sensitive to adversities. PMID- 29108596 TI - The relationship between societal change and rising support for gender egalitarianism among men and women: Results from counterfactual analyses in the Netherlands, 1979-2012. AB - This study examines the relationship between important social, cultural, economic, and demographic changes and the rise of support for gender egalitarianism within the Dutch population between 1979 and 2012. Cohort replacement, educational expansion, secularization, and the feminization of the labor force are important processes that have taken place in western societies in ways that may have fostered support for gender egalitarianism. Using unique data from 16 repeated cross-sectional surveys in the Netherlands, we estimate age period-cohort regression models, and the outcomes are subsequently applied in counterfactual simulation designs. Our results show that the social, cultural, economic, and demographic changes explain only a small part of the modest rise in support for gender egalitarianism for men, while they provide a much better explanation of the stronger rise among women. Especially the replacement of older female cohorts by younger ones seems to have propelled support for gender egalitarianism among women throughout the years. PMID- 29108597 TI - Disability and social participation: The case of formal and informal volunteering. AB - People with disabilities in the United States experience lower levels of social integration than people without disabilities. However, less is known about the association between disability and volunteer participation-despite an extensive literature on other disparities in volunteerism. This study uses data from the 2009-2015 Volunteer Supplement of the Current Population Survey to evaluate how working-aged adults with sensory disabilities, cognitive disabilities, physical disabilities, or multiple disabilities access, participate in, and maintain volunteer roles. Net of sociodemographic characteristics, adults with disabilities are no less likely than those without disabilities to report informal volunteering, although the presence of physical and multiple disabilities negatively associates with formal volunteering. Adults with disabilities report no fewer annual hours or weeks than those without disabilities if they are formal volunteers, but the mechanism through which they initially become involved in volunteer organizations varies. People with different types of disability experience different patterns of volunteering, and the sociodemographic characteristics associated with having a disability exacerbate many of these differences. Results suggest that adults with disabilities can-and do-participate in voluntary work, but may face barriers to accessing formal volunteer roles. PMID- 29108598 TI - Disentangling the reciprocal relationship between change in crime and racial/ethnic change. AB - Prior research has found that racial/ethnic change and residential instability are positively related to neighborhood crime. However, the process of racial/ethnic change differentially influences crime above and beyond residential instability. While both processes affect crime through the disruption of existing social ties, racial/ethnic change has additional consequences for crime by heightening racial/ethnic tensions and undercutting cross-group interactions. This means racial/ethnic change is a different process than residential instability, and suggests that neighborhoods experiencing high rates of instability and high rates of racial/ethnic change may be particularly susceptible to crime. Therefore, we examine the influence of racial/ethnic compositional change on change in crime across different levels of residential instability. Further, we argue that demographic change and crime may be influencing each other simultaneously: increases in the crime rate and racial/ethnic compositional change impact each other at the same time. To capture this process, we employ a structural equation model (SEM) that accounts for the reciprocal and simultaneous relationship between racial/ethnic change and violent and property crime rates in Los Angeles, California between 1990 and 2000. We also account for the influence of change in spatially proximate communities. Results show robust evidence that increases in racial/ethnic change contributes to greater violent and property crime rates, but the reciprocal influence of crime on racial/ethnic change is contingent upon the degree to which a neighborhood is experiencing residential instability and crime type. PMID- 29108599 TI - Women's employment trajectories during early adulthood in urban China: A cohort comparison. AB - This study uses retrospective work history data from CGSS 2008 and employs group based trajectory analysis to model the diverse employment trajectories of cohorts of urban Chinese women (born in the 1940s-1970s) during young adulthood (age 20 35). We identify ideal-types of urban women's employment trajectories and explore traits associated with each group type. In particular, we examine whether and how the timing of marriage and fertility as well as socioeconomic background help to distinguish patterns of women's labor force attachment in young adulthood. We also examine how these patterns change across cohorts given China's rapid social transformations in the past few decades. We find that delaying family formation is generally associated with more consistent work attachment, but this relationship is also largely associated with one's socioeconomic background. Our results reveal significant cohort variations in the shape of women's employment trajectories and we discuss how institutional and cultural contexts of different historical periods could have shaped family formation and employment processes differently. Our findings highlight the heterogeneity of urban women's work and family formation patterns in the context of rising gender inequalities and rapid socioeconomic transformation over time. PMID- 29108600 TI - Why does college education matter? Unveiling the contributions of selection factors. AB - This study investigates the contributions of pre-college selection factors that may partially lead to the college degree - health link by using longitudinal data from the National Longitudinal Survey of Youth (1979) cohort. Propensity score matching method finds that the effects of college degree on various health outcomes (self-rated health, physical component summary index, health limitations, CESD scale) are reduced by 51% on average (range: 37%-70%) in the matched sample. Among these observed factors, cognitive skill is the biggest confounder, followed by pre-college health and socioeconomic characteristics (marital aspiration, years of schooling, marriage, fertility, poverty status) and non-cognitive skills (e.g., self-esteem). Rotter Internal-External Locus of Control scale is not significantly associated with all four health measures. The effects of most indicators of family background (parental education, family stability, family size, religious background) on the health of adult children are not direct but through offspring's early adulthood health and socioeconomic status. PMID- 29108601 TI - Childhood social capital and postsecondary educational attainment. PMID- 29108602 TI - Tackling inequalities in political socialisation: A systematic analysis of access to and mitigation effects of learning citizenship at school. AB - This article tackles the issue of social inequalities in voting and identifies how and when differences in learning political engagement are influenced by social background in the school environment between the ages of 11-16 in England. Using Latent Growth Curve Modelling and Regression Analysis on the Citizenship Education Longitudinal (CELS) data this research identifies two elements that influence the political socialisation process: access to political learning and effectiveness in the form of learning in reducing inequalities in political engagement. The results show that there is unequal access by social background to learning political engagement through political activities in school and through an open classroom climate for discussion. However, there is equal access by social background to Citizenship Education in schools and this method of learning political engagement is effective at the age of 15-16 in reducing inequalities in political engagement. PMID- 29108603 TI - Erratum to the Inside Front Cover of Volume 75 (2015). PMID- 29108604 TI - Global issues in allergy and immunology: Parasitic infections and allergy. AB - Allergic diseases are on the increase globally in parallel with a decrease in parasitic infection. The inverse association between parasitic infections and allergy at an ecological level suggests a causal association. Studies in human subjects have generated a large knowledge base on the complexity of the interrelationship between parasitic infection and allergy. There is evidence for causal links, but the data from animal models are the most compelling: despite the strong type 2 immune responses they induce, helminth infections can suppress allergy through regulatory pathways. Conversely, many helminths can cause allergic-type inflammation, including symptoms of "classical" allergic disease. From an evolutionary perspective, subjects with an effective immune response against helminths can be more susceptible to allergy. This narrative review aims to inform readers of the most relevant up-to-date evidence on the relationship between parasites and allergy. Experiments in animal models have demonstrated the potential benefits of helminth infection or administration of helminth-derived molecules on chronic inflammatory diseases, but thus far, clinical trials in human subjects have not demonstrated unequivocal clinical benefits. Nevertheless, there is sufficiently strong evidence to support continued investigation of the potential benefits of helminth-derived therapies for the prevention or treatment of allergic and other inflammatory diseases. PMID- 29108606 TI - Positive Airway Pressure Device Technology Past and Present: What's in the "Black Box"? AB - Since the introduction of continuous positive airway pressure (PAP) for the treatment of obstructive sleep apnea (OSA) in 1981, PAP technology has diversified exponentially. Compact and quiet fixed continuous PAP flow generators, autotitrating PAP devices, and bilevel PAP devices that can treat multiple sleep-disordered breathing phenotypes including OSA, central sleep apnea (CSA), combinations of OSA and CSA, and hypoventilation are available. Adaptive servo-ventilators can suppress Hunter-Cheyne-Stokes breathing and CSA and treat coexisting obstructive events. Volume-assured pressure support PAP apparatus purports to provide a targeted degree of ventilatory assistance while also treating cooccurring OSA and/or CSA. PMID- 29108607 TI - Testing the Performance of Positive Airway Pressure Generators: From Bench to Bedside. AB - Positive airway pressure (PAP) devices use different proprietary algorithms for sleep-disordered breathing event detection and response. Most device evaluations are based on clinical studies, which have obvious limitations. As a complementary approach, bench studies provide an analysis of algorithms in predefined conditions, which allows understanding contradictory results observed in clinical studies. But such studies cannot provide long-term treatment data and physiologic effects of treatment. It is important to understand the advantages and the limitations of both kinds of studies. Combining results of bench tests and clinical studies is essential to improve the management of patients with PAP treatment. PMID- 29108608 TI - Treatment of Obstructive Sleep Apnea: Choosing the Best Positive Airway Pressure Device. AB - Positive airway pressure (PAP) remains primary therapy for most patients with obstructive sleep apnea (OSA). CPAP, APAP, and BPAP are all reasonable therapies that can be used for patients with uncomplicated OSA across the spectrum of disease severity. BPAP should be considered for patients who are nonadherent to CPAP or APAP therapy because of pressure intolerance. Several additional factors should be considered when choosing the type of PAP device for a given patient, including associated symptoms and comorbid medical problems, cost, access to online data management and patient portals, and the portability for the device for patients who travel frequently. PMID- 29108609 TI - Treatment of Obstructive Sleep Apnea: Choosing the Best Interface. AB - Patient interface preference is a key factor in positive airway pressure compliance. Local side effects are common. Proper mask fitting and patient education are important. Masks should seal well and fit comfortably. Nasal, nasal pillow, and oronasal masks can be effective interfaces. Most patients with obstructive sleep apnea prefer a nasal mask. Oronasal masks can be a useful alternative. Nasal pillows can reduce mask size and improve comfort. Oronasal masks may require a higher pressure. A significantly lower pressure may be effective with a nasal interface. Proper mask fitting requires testing the mask seal under the treatment pressure. PMID- 29108610 TI - Treatment of Obstructive Sleep Apnea: Achieving Adherence to Positive Airway Pressure Treatment and Dealing with Complications. AB - Obstructive sleep apnea is a common and treatable condition, but therapeutic adherence is limited by numerous factors. Despite advances in positive airway pressure (PAP) technology and a multitude of effective pharmacologic and behavioral therapeutic interventions to overcome the most common barriers to PAP, adherence has not increased significantly over the past 30 years. This review aims to identify the most important factors that impact adherence, common barriers to treatment, and evidence-based treatment strategies to maximize the effectiveness of PAP treatment. Complications of PAP treatment and mitigation techniques are also discussed. PMID- 29108611 TI - Positive Airway Pressure Therapy for Hyperventilatory Central Sleep Apnea: Idiopathic, Heart Failure, Cerebrovascular Disease, and High Altitude. AB - Central sleep apnea (CSA) and Hunter-Cheyne-Stokes breathing (HCSB) are caused by failure of the pontomedullary pacemaker generating breathing rhythm. CSA/HCSB may complicate several disorders causing recurrent arousals and desaturations. Common causes of CSA in adults are congestive heart failure, stroke, and chronic use of opioids; opioids have hypoventilatory effects. Diagnosis and treatment of hyperventilatory CSA may improve quality of life, and, when associated with heart failure or cerebrovascular disease, reduce morbidity and perhaps mortality. PMID- 29108612 TI - Sleep Disordered Breathing Caused by Chronic Opioid Use: Diverse Manifestations and Their Management. AB - Opioid-induced sleep disordered breathing presents a therapeutic predicament with the increasing incidence of prescription opioid use for noncancer chronic pain in the United States. Central sleep apnea with a Biot or cluster breathing pattern is characteristic of polysomnography studies; however, long-term clinical outcomes and the impact of therapy remain unknown. Novel ampakine-based therapies are being investigated. Randomized controlled trials with therapies that target the underlying pathophysiologic mechanisms of opioid-induced sleep disordered breathing are required. PMID- 29108613 TI - Obesity Hypoventilation Syndrome: Choosing the Appropriate Treatment of a Heterogeneous Disorder. AB - The obesity hypoventilation syndrome (OHS) is associated with significant morbidity and increased mortality compared with simple obesity and eucapnic obstructive sleep apnea. Accurate diagnosis and commencement of early and appropriate management is fundamental in reducing the significant personal and societal burdens this disorder poses. Sleep disordered breathing is a major contributor to the developmental of sleep and awake hypercapnia, which characterizes OHS, and is effectively addressed through the use of positive airway pressure (PAP) therapy. This article reviews the current evidence supporting different modes of PAP currently used in managing these individuals. PMID- 29108614 TI - Noninvasive Mechanical Ventilation in Acute Ventilatory Failure: Rationale and Current Applications. AB - Noninvasive ventilation plays a pivotal role in acute ventilator failure and has been shown, in certain disease processes such as acute exacerbation of chronic obstructive pulmonary disease, to prevent and shorten the duration of invasive mechanical ventilation, reducing the risks and complications associated with it. The application of noninvasive ventilation is relatively simple and well tolerated by patients and in the right setting can change the course of their illness. PMID- 29108615 TI - Noninvasive Positive Pressure Ventilatory Support Begins During Sleep. AB - The goal of sleep doctors has been to titrate away apneas and hypopneas using noninvasive ventilation, a term that has become synonymous with continuous positive airway pressure and bilevel positive airway pressure at the lowest effective bilevel settings. It is now time to appreciate noninvasive ventilatory support as an alternative to invasive mechanical ventilation. This article discusses mechanisms of action, two paradigms, and ancillary techniques for noninvasive ventilatory support. PMID- 29108616 TI - Future of Positive Airway Pressure Technology. AB - This article discusses the future of positive airway pressure (PAP) technology. The focus is on (1) technology improvements in the delivery of PAP; (2) improvements in PAP algorithms; and (3) improvements in PAP informatics. Current limitations of PAP technology and whether technological improvements are sufficient to PAP are discussed. PMID- 29108617 TI - The Development of Positive Airway Pressure Technology and Applications: Faster than Space Travel! PMID- 29108618 TI - Bias...can occur during the research or publication process. PMID- 29108619 TI - Academy of Prosthodontics centennial: The emergence and development of prosthodontics as a specialty. PMID- 29108620 TI - Preface: Pathology and Pharmacology of Atherosclerosis. PMID- 29108621 TI - In vitro biosynthesis of 3-mercaptolactate by lactate dehydrogenases. AB - 3-Mercaptolactate (3ML) is an interesting mercapto compound with special regard to the biosynthesis of new polythioesters (PTEs). Unfortunately, this thioester analog of lactic acid is currently not commercially available. For this reason, we developed an in vitro biosynthesis pathway to convert cysteine to 3 mercaptopyruvate (3MPy), which is then rapidly and efficiently converted to 3ML by suitable lactate dehydrogenases (LDHs). As liver LDH from Rattus norvegicus (LDHRn) was previously described to Exhibit 3MPy reduction activity, in silico studies based on homology to LDHRn were performed and led to the identification of four potentially suitable bacterial LDH candidates from Escherichia coli (LDHEc), Corynebacterium glutamicum (LDHCg), Bacillus cereus (LDHBc) and Gloeobacter violaceus (LDHGv). After heterologous expression in E. coli followed by purification, the enzymes were assessed for their potential to reduce 3MPy to 3ML in comparison to LDHRn. With 3MPy, LDHs from E. coli, C. glutamicum and B. cereus showed no or only very low specific activities of 0.23+/-0.1U/mg (LDHCg) and 0.08+/-0.2U/mg (LDHBc), respectively. In contrast, LDHGv exhibited a remarkable specific activity of 63.6+/-8.1U/mg, being even twice as active as the R. norvegicus LDH. To verify LDH-catalyzed biosynthesis of 3ML we developed and optimized a detection method allowing qualitative analysis and quantification of 3MPy and 3ML by derivatization with Ellman's reagent and liquid chromatography mass spectrometry. This study shows once more the impressive versatility of LDHs and presents a rapid and efficient biosynthesis process for 3ML, a biotechnologically interesting, yet hard-to-obtain, compound. PMID- 29108622 TI - Encapsulation of lipase within metal-organic framework (MOF) with enhanced activity intensified under ultrasound. AB - The enzyme under lower-intensity ultrasonic irradiation leads to favorable conformational changes, thereby enhancing its activity. In this study, lipase activity was augmented upto 1.6-folds after ultrasonic treatment at 22kHz and 11.38Wcm-2 for 25min. This highly activated lipase was encapsulated within zeolite imidazolate framework-8 (ZIF-8) as a metal-organic framework (MOF) material via facile one-step biomineralization method by simply mixing aqueous solution of 2-methylimidazole (13.3mmol) and zinc acetate (1.33mmol) along with sonicated lipase within 10min at room temperature (28+/-2 degrees C). The prepared lipase-MOF was characterized by using FT-IR, FT-Raman, XRD, BET, confocal scanning laser microscopy, TGA and SEM. Further, the thermal stability of lipase embedded MOF was evaluated in the range of 55-75 degrees C on the basis of half-life which showed 3.2 folds increment as against free lipase. In Michaelis-Menten kinetics studies, sonicated lipase entrapped MOF showed nearly same Km and Vmax values as that of sonicated free lipase. Moreover, the immobilized lipase exhibited up to 54% of residual activity after seven successive cycles of reuse, whereas it retained 90% of residual activity till twenty-five days of storage. Finally, the conformational changes occurred in lipase after sonication treatment and encapsulation within MOF were analyzed by using FT-IR data analysis tools and fluorescent spectroscopy. PMID- 29108623 TI - Displaying a recombinant protein on flocs self-produced by Escherichia coli through fused expression with elongation factor Ts. AB - The utility of engineering flocculation is wildly recognized in applied and environmental microbiology. We previously reported self-produced flocculation of Escherichia coli cells by overexpressing the native bcsB gene that encodes a component of the cellulose synthesis pathway. Further experiments clarified that the spontaneous E. coli flocs were proteinous, and elongation factor Ts (Tsf) was the main component. In this study, we demonstrated successful expression of a fusion protein consisting of Tsf and green fluorescence protein (GFP) on E. coli flocs. Interestingly, the percentage of Tsf-GFP in total floc protein reached approximately 15% (w/w). The proposed design of a fusion protein with Tsf enables displaying a recombinant target protein on the floc structure. PMID- 29108624 TI - Rational evolution of the unusual Y-type oxyanion hole of Rhodococcus sp. CR53 lipase LipR. AB - Rhodococcus sp CR-53 lipase LipR was the first characterized member of bacterial lipase family X. Interestingly, LipR displays some similarity with alpha/beta hydrolases of the C. antartica lipase A (CAL-A)-like superfamily (abH38), bearing a Y-type oxyanion hole, never found before among bacterial lipases. In order to explore this unusual Y-type oxyanion hole, and to improve LipR performance, two modification strategies based on site directed or saturation mutagenesis were addressed. Initially, a small library of mutants was designed to convert LipR Y type oxyanion hole (YDS) into one closer to those most frequently found in bacteria (GGG(X)). However, activity was completely lost in all mutants obtained, indicating that the Y-type oxyanion hole of LipR is required for activity. A second approach was addressed to modify the two main oxyanion hole residues Tyr110 and Asp111, previously described for CAL-A as the most relevant amino acids involved in stabilization of the enzyme-substrate complex. A saturation mutagenesis library was prepared for each residue (Tyr110 and Asp111), and activity of the resulting variants was assayed on different chain length substrates. No functional LipR variants could be obtained when Tyr110 was replaced by any other amino acids, indicating that this is a crucial residue for catalysis. However, among the Asp111 variants obtained, LipR D111G produced a functional enzyme. Interestingly, this LipR-YGS variant showed less activity than wild type LipR on short- or mid- chain substrates but displayed a 5.6-fold increased activity on long chain length substrates. Analysis of the 3D model and in silico docking studies of this enzyme variant suggest that substitution of Asp by Gly produces a wider entrance tunnel that would allow for a better and tight accommodation of larger substrates, thus justifying the experimental results obtained. PMID- 29108625 TI - A first glycoside hydrolase family 50 endo-beta-1,3-d-glucanase from Pseudomonas aeruginosa. AB - A novel beta-1,3-glucanase gene (PaBglu50A) from Pseudomonas aeruginosa CAU 342A was cloned and expressed in Escherichia coli. The deduced amino acid sequence of PaBglu50A showed the highest identity of 34% with the beta-agarase belonging to glycoside hydrolase (GH) family 50. The purified PaBglu50A had maximal activity at pH 5.5 and 45 degrees C, respectively. It was stable in the range of pH 4.0 8.0 and at temperatures below 40 degrees C. The Km and Vmax of PaBglu50A for curdlan and laminarin were 94.4mgml-1 and 23.4MUmolmin-1mg-1, 3.65mgml-1 and 8.89MUmolmin-1mg-1, respectively. All characterized members of GH family 50 were only active towards agarose so far. However, the recombinant protein PaBglu50A did not display activity towards agarose but showed activity towards water insoluble curdlan and laminarin. The hydrolysis products for curdlan supported this protein to be an endo-beta-1,3-glucanase, making a significant difference from the reported enzymes of GH family 50. These results suggested that PaBglu50A is the first endo-type beta-1,3-glucanase (EC 3.2.1.39) in GH family 50. PMID- 29108626 TI - Enzymatic esterification of eugenol and benzoic acid by a novel chitosan-chitin nanowhiskers supported Rhizomucor miehei lipase: Process optimization and kinetic assessments. AB - A biotechnological route via enzymatic esterification was proposed as an alternative way to synthesize the problematic anti-oxidant eugenyl benzoate. The new method overcomes the well-known drawbacks of the chemical route in favor of a more sustainable reaction process. The present work reports a Box-Behnken design (BBD) optimization process to synthesize eugenyl benzoate by esterification of eugenol and benzoic acid catalyzed by the chitosan-chitin nanowhiskers supported Rhizomucor miehei lipase (RML-CS/CNWs). Effects of four reaction parameters: reaction time, temperature, substrate molar ratio of eugenol: benzoic acid and enzyme loading were assessed. Under optimum conditions, a maximum conversion yield as high as 66% at 50 degrees C in 5h using 3mg/mL of RML-CS/CNWs, and a substrate molar ratio (eugenol: benzoic acid) of 3:1. Kinetic assessments revealed the RML-CS/CNWs catalyzed the reaction via a ping-pong bi-bi mechanism with eugenol inhibition, characterized by a Vmax of 3.83mMmin-1. The Michaelis Menten constants for benzoic acid (Km,A) and eugenol (Km,B) were 34.04 and 138.28mM, respectively. The inhibition constant for eugenol (Ki,B) was 438.6mM while the turnover number (kcat) for the RML-CS/CNWs-catalyzed esterification reaction was 40.39min-1. RML-CS/CNWs were reusable up to 8 esterification cycles and showed higher thermal stability than free RML. PMID- 29108627 TI - Co-expression of an alcohol dehydrogenase and a cyclohexanone monooxygenase for cascade reactions facilitates the regeneration of the NADPH cofactor. AB - The introduction of a three-enzyme cascade (comprising a cyclohexanone monooxygenase (CHMO), an alcohol dehydrogenase (ADH) and a lipase (CAL-A)) for the production of oligo-epsilon-caprolactone provided self-sufficiency with respect to NADPH-cofactor regeneration and reduced inhibiting effects on the central CHMO enzyme. For further optimization of cofactor regeneration, now a co expression of CHMO and ADH in E. coli using a DuetTM vector was performed. This led to higher conversion values of the substrate cyclohexanol in whole-cell biocatalysis compared to an expression of both enzymes from two separate plasmids. Furthermore, a more advantageous balance of expression levels between the partial cascade enzymes was achieved via engineering of the ribosome binding site. This contributed to an even faster cofactor regeneration rate. PMID- 29108628 TI - Furfural and 5-hydroxymethyl-furfural degradation using recombinant manganese peroxidase. AB - Biomass pretreatment-derived degradation compounds, such as furfural and 5 hydroxymethyl-furfural (HMF), inhibit the growth of fermentation microorganisms that utilize biomass to produce fuels and chemicals. Here we report that recombinant manganese peroxidase (rMnP) produced from the yeast Pichia pastoris can degrade furfural and HMF making them less toxic to microorganisms. Treatment with rMnP or manganese(III) acetate reduced furfural and HMF concentrations in a dose-dependent manner. Furfural disappearance was accompanied by malonate disappearance and accumulation of four distinct degradation products. Furfural was more readily degraded by rMnP and manganese(III) acetate than HMF. Growth assays using Saccharomyces cerevisiae indicated that rMnP treatment reduced the toxicity of furfural and HMF. This work provides an avenue to use rMnP to increase the growth of fermentation microorganisms that are inhibited by toxic compounds derived from pretreatment of biomass. PMID- 29108629 TI - Spontaneous pepsin C-catalyzed activation of human pepsinogen C in transgenic rice cell suspension culture: Production and characterization of human pepsin C. AB - A human pepsinogen C (hPGC) gene was synthesized with rice-optimized codon usage and cloned into a rice expression vector containing the promoter, signal peptide, and terminator derived from the rice alpha-amylase 3D (Ramy3D) gene. In addition, a 6-His tag was added to the 3' end of the synthetic hPGC gene for easy purification. The plant expression vector was introduced into rice calli (Oryza sativa L. cv. Dongjin) mediated by Agrobacterium tumefaciens. The integration of the hPGC gene into the chromosome of the transgenic rice callus and hPGC expression in transgenic rice cell suspensions was verified via genomic DNA polymerase chain reaction amplification and Northern blot analysis. Western blot analysis indicated both hPGC and its mature form, human pepsin C, with masses of 42- and 36-kDa in the culture medium under sugar starvation conditions. Human pepsin C was purified from the culture medium using a Ni-NTA agarose column and the NH2-terminal 5-residue sequences were verified by amino acid sequencing. The hydrolyzing activity of human pepsin C was confirmed using bovine hemoglobin as a substrate. The optimum pH and temperature for pepsin activity were 2.0 and 40 degrees C, respectively. PMID- 29108630 TI - Improved thermostability and enzyme activity of a recombinant phyA mutant phytase from Aspergillus niger N25 by directed evolution and site-directed mutagenesis. AB - We previously constructed three recombinant phyA mutant strains (PP-NPm-8, PP NPep-6A and I44E/T252R-PhyA), showing improved catalytic efficiency or thermostability of Aspergillus niger N25 phytase, by error-prone PCR or site directed mutagenesis. In this study, directed evolution and site-directed mutagenesis were further applied to improve the modified phytase properties. After one-round error-prone PCR for phytase gene of PP-NPep-6A, a single transformant, T195L/Q368E/F376Y, was obtained with the significant improvements in catalytic efficiency and thermostability. The phytase gene of T195L/Q368E/F376Y, combined with the previous mutant phytase genes of PP-NPep-6A, PP-NPm-8 and I44E/T252R-PhyA, was then sequentially modified by DNA shuffling. Three genetically engineered strains with desirable properties were then obtained, namedQ172R, Q172R/K432R andQ368E/K432R. Among them, Q172R/K432R showed the highest thermostability with the longest half-life and the greatest remaining phytase activity after heat treatment, while Q368E/K432R showed the highest catalytic activity. Five substitutions (Q172R, T195L, Q368E, F376Y, K432R) identified from random mutagenesis were added sequentially to the phytase gene of PP-NPep-6A to investigate how the mutant sites influence the properties of phytase. Characterization and structural analysis demonstrated that these mutations could produce cumulative or synergistic improvements in thermostability or catalytic efficiency of phytase. PMID- 29108631 TI - Mesenchymal stromal cells isolated from gestationally diabetic human placenta exhibit insulin resistance, decreased clonogenicity and angiogenesis. AB - Pregnancy is known to be a diabetogenic state. With sedentary lifestyle and wrong dietary choices, gestational diabetes mellitus is on the rise. This raises a concern as placenta is becoming an acceptable choice, as a source of Mesenchymal Stromal Cells (MSCs). In our current study we questioned whether there exists a difference between MSCs isolated from normal and diabetic (Gd-P-MSCs) placenta, as the health of the cells used in therapy is of prime importance. We isolated and verified the Gd-P-MSCs based on their surface markers and differentiation potential. We looked at viability and proliferation and did not see a difference between the two. We analysed the glucose uptake potential of these cells by assessing the remnant glucose in the media, glucose within the cells by 2-NBDG and by glycogen storage. Despite only a slight downregulation of mRNA expression levels of glucose transporters, Gd-P-MSCs exhibited decreased glucose uptake even upon insulin stimulation and decreased glycogen storage, indicative of an insulin resistant state. We then assessed the colony forming ability of the cells and found a decreased clonogenicity in Gd-P-MSCs. We also examined the angiogenic potential of the cells by tube formation. Gd-P-MSCs showed decreased angiogenic potential when compared to normal cells. Thus we show for the first time, the effect of gestational diabetes on cells isolated from the chorionic villi of term placenta. Gd-P-MSCs are indeed insulin resistant, exhibit decreased clonogenicity and angiogenic potential. The present investigation is of relevance to the choice of sample for MSC isolation for therapeutic purposes. PMID- 29108632 TI - Chorionic vascular "fit" in the human placenta: Relationship to fetoplacental outcomes. AB - BACKGROUND: Novel measures of the chorionic plate and vessels are used to test the hypothesis that variation in placental structure is correlated with reduced birth weight (BW) independent of placental weight (PW), suggesting functionally compromised placentas. METHODS: 916 mothers recruited to the Pregnancy, Infection and Nutrition Study delivering singleton live born infants at >30 gestational weeks had placentas collected, digitally photographed and weighed prior to formalin fixation. The fetal-placental weight ratio (FPR) was calculated as birthweight/placental weight. Beta (beta) was calculated as ln(PW)/ln(BW). Chorionic disk perimeter was traced and chorionic surface shape (CS) area was calculated. "Fit" was defined as the ratio of the area of the vascular to the full chorionic surface area. The sites at which chorionic vessels dived beneath the chorionic surface were marked to calculate the chorionic surface vessel (CV) area. The centroids of shapes, the distance between centroids and other measures of shape irregularities were calculated. Principal components analysis (PCA) created three independent factors. Factors were used in regression analyses to explore relations to birth weight, trimmed placental weight, FPR, and beta. Specific measures of shape irregularity were also examined in regression analyses for interrelationships and to predict birth weight, placental weight, FPR, and beta. RESULTS: Variables related to disk size (CS area, perimeter) were correlated with BW, GA, trimmed PW and beta. "Fit" (the ratio of CV area to CS area), measures of shape irregularities, and the distance between the cord insertion and the centroids of surface and vascular areas were also correlated with one or more of the clinical outcome variables. PCA yielded three factors that had independent effects on birth weight, placental weight, the fetal placental weight ratio, and beta (each p < 0.0001). Addition of GA did not alter the factors' associations with outcomes. Chorionic "fit" (ratio of areas), also included within the factor analysis, was a positive predictor of birth weight (p = 0.005) and FPR (p = 0.002) and a negative predictor of beta (p = 0.01). Fit was statistically significantly associated with greater distances between the umbilical cord insertion site and the CS (p < 0.001) and CV centroids (p < 0.001), and to lesser displacement between CS and CV centroids (p < 0.001). CONCLUSIONS: Measures of CS and CV account for variation in placental efficiency defined by beta, independent of GA. Macroscopic placenta measurements can identify suboptimal placental development. PMID- 29108634 TI - Maternal growth restriction and stress exposure in rats differentially alters expression of components of the placental glucocorticoid barrier and nutrient transporters. AB - The placenta plays a major role in the development of fetal growth restriction, which affects 10% of pregnancies and contributes to chronic adult disease risk. We have reported that female rats born small develop cardiometabolic dysfunction only during pregnancy. The physiological tests performed during pregnancy induced a maternal stress response as indicated by increased maternal corticosterone concentrations. This stress effected placental growth compared to females who were unhandled during pregnancy. Maternal stress and growth restriction independently program F2 offspring metabolic dysfunction. This study investigated the effects of maternal stress and growth restriction on placental and fetal metabolic parameters that may contribute to F2 offspring metabolic disease. Maternal growth restriction reduced F2 fetal weight whilst maternal stress reduced placental weight. Stressed mothers had reduced insulin and increased glucose concentrations, changes that were reflected in the fetus. Fetal beta-cell number was reduced by maternal growth restriction, but was increased by stress exposure. Maternal growth restriction reduced placental Slc2a1, Igf2, Slc38a2 and Nr3c1 gene expression. Maternal stress decreased the expression of Slc2a1, Igf2, Slc38a2, Nr3c1, Slc2a3, Slc2a4, Nr3c2, Hsd11b2, Crhr1 and Ogt. Maternal birth weight effects on fetal weight were likely due to changes in placental nutrient transporter and Igf2 expression. On the contrary, maternal stress induced a systemic effect by altering maternal metabolic parameters, placental gene expression and fetal glucose and insulin concentrations. This study highlights the importance of informing pregnant women on effective ways to cope with stress during pregnancy to prevent adverse long-term disease outcomes in their children. PMID- 29108633 TI - Preeclampsia associates with RECK-dependent decrease in human trophoblasts migration and invasion. AB - INTRODUCTION: Preeclampsia is characterized by reduced invasion capacity of trophoblasts involving lower matrix metalloproteinase (MMP) activity. Cell invasion is reduced by reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), a plasma membrane protein that inhibits MMP in several cell types. However, it is unknown whether this mechanism happens in the human placenta from preeclampsia. The hypothesis of this study sustains that RECK expression is increased leading to reduced trophoblasts invasion in preeclampsia. METHODS: RECK expression in the human first trimester trophoblast cell line HTR8/SvNeo and in placentas from normal (n = 4) and preeclampsia (n = 4) pregnancies was evaluated by Western blot and immunofluorescence. MMP-dependent gelatin hydrolyzation was measured by in situ zymography and gelatinase assay in placental and cell extracts. RECK was overexpressed (plasmidial vector transfection) or partially reduced (shRNA) to evaluate its role in HTR8/SVneo cell migration and invasion. RESULTS: RECK was expressed in trophoblasts layer in human placentas. Preeclampsia resulted in higher placental RECK protein abundance, reduced MMP function, and higher level of fibronectin (a MMP substrate) compared with placentas from normal pregnancies. RECK is also expressed in HTR-8/SVneo cells. Reduced RECK expression resulted in higher MMP-dependent gelatin hydrolyzation, associated to higher migration and invasion of HTR8/SVneo cells. However, RECK overexpression associated with reduced hydrolyzation, cell migration and invasion. DISCUSSION: RECK is overexpressed in human trophoblasts from preeclampsia and may be responsible of this disease-associated lower migration and invasion of this cell type. PMID- 29108635 TI - Lipidomic analysis reveals the significant increase in diacylglycerophosphocholines in umbilical cord blood from pregnant women with gestational hypercholesterolemia. AB - Gestational hypercholesterolemia has been recognized as a risk factor of some pregnancy complications. We supposed that maternal hypercholesterolemia modified the lipid profile of the fetus. Thirty pregnant women with hypercholesterolemia and matched controls were recruited and cord blood was sampled. Lipidomic analysis was used to evaluate the lipid profile change between the two groups. The results showed that the content of diacylglycerophosphocholines (PC) was significantly high in cord blood from hypercholesterolemic pregnant women. PC (16:0/20:4) and PC (18:0/20:4) were selected as the most important lipid species in cord plasma and their contents were positively related to the total cholesterol and high-density lipoprotein cholesterol levels in cord blood. The contents of these two PCs were significantly higher in the hypercholesterolemic group than in the control group. These results suggested that gestational hypercholesterolemia might program the phospholipid metabolism in offspring. PMID- 29108636 TI - Dynamic expression of TET1, TET2, and TET3 dioxygenases in mouse and human placentas throughout gestation. AB - INTRODUCTION: Throughout pregnancy, the placenta dynamically changes as trophoblast progenitors differentiate into mature trophoblast cell subtypes. This process is in part controlled by epigenetic regulation of DNA methylation leading to the inactivation of 'progenitor cell' genes and the activation of 'differentiation' genes. TET methylcytosine dioxygenases convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) during DNA demethylation events. Here, we determine the spatiotemporal expression of TET1, TET2, and TET3 in specific trophoblast cell populations of mouse and human placentas throughout gestation, and consider their role in trophoblast cell differentiation and function. METHODS: In situ hybridization analysis was conducted to localize Tet1, Tet2, and Tet3 mRNA at key stages of mouse placental development. The distribution of 5-mC and 5-hmC in these samples was also evaluated. In comparison, expression patterns of TET1, TET2, and TET3 protein in human placentas were determined in first trimester and term pregnancies. RESULTS: In mouse, Tet1-3 mRNA was widely expressed in trophoblast cell populations from embryonic (E) day 8.5 to E12.5 including in progenitor and differentiated cells. However, expression became restricted to specific trophoblast giant cell subtypes by late gestation (E14.5 to E18.5). This coincided with cellular changes in 5-mC and 5-hmC levels. In human, cell columns, extravillous trophoblast and syncytiotrophoblast expressed TET1-3 whereas only TET3 was expressed in villus cytotrophoblast cells in first trimester and term placentas. DISCUSSION: Altogether, our data suggest that TET enzymes may play a dynamic role in the regulation of transcriptional activity of trophoblast progenitors and differentiated cell subtypes in mouse and human placentas. PMID- 29108637 TI - Expression of aquaporin-3 (AQP3) in placentas from pregnancies complicated by preeclampsia. AB - Recently, we have reported that the blocking of AQP3 abrogates the apoptotic response of the trophoblast. Since trophoblast apoptosis is exacerbated in preeclampsia, we hypothesized that placental AQP3 is increased in these placentas in order to trigger the programmed cell death. Here, we examined mRNA levels, protein expression and localization of AQP3 in placentas from pregnancies complicated by preeclampsia and against what we expected, we found that AQP3 expression was significantly reduced, both at protein and mRNA levels, compared to normal placentas. In the light of our results, further studies are required to evaluate whether the decreased expression of AQP3 might be an adaptive response of the placenta to reduce the trophoblast apoptosis, which is related to the clinical manifestations of preeclampsia. PMID- 29108639 TI - Proteomic profiling reveals sub proteomes of the human placenta. AB - Proteomic characterisation of the placenta has largely been focused on effect of disease, anatomical features or specific cell types. We describe an unbiased proteomic mapping analysis to investigate how the placental proteome changes throughout the organ. A transverse slice of a human placenta was sectioned into 1 * 1cm samples. Sections were analysed using label free proteomics. Analysis revealed two distinct sub-proteomes that did not have anatomical significance. One had a muscular proteome and the other had distinct immunomodulation functions. Chorionic plate enriched proteins highlighted the fetal tissues high energy requirements whilst mechanisms of the decidua observed included modulation of cortisone levels. PMID- 29108638 TI - Telomere length heterogeneity in placenta revealed with high-resolution telomere length analysis. AB - INTRODUCTION: Telomeres, are composed of tandem repeat sequences located at the ends of chromosomes and are required to maintain genomic stability. Telomeres can become shorter due to cell division and specific lifestyle factors. Critically shortened telomeres are linked to cellular dysfunction, senescence and aging. A number of studies have used low resolution techniques to assess telomere length in the placenta. In this study, we applied Single Telomere Length Analysis (STELA) which provides high-resolution chromosome specific telomere length profiles to ask whether we could obtain more detailed information on the length of individual telomeres in the placenta. METHODS: Term placentas (37-42 weeks) were collected from women delivering at University Hospital of Wales or Royal Gwent Hospital within 2 h of delivery. Multiple telomere-length distributions were determined using STELA. Intraplacental variation of telomere length was analysed (N = 5). Telomere length distributions were compared between labouring (N = 10) and non-labouring (N = 11) participants. Finally, telomere length was compared between female (N = 17) and male (N = 20) placenta. RESULTS: There were no significant influences of sampling site, mode of delivery or foetal sex on the telomere-length distributions obtained. The mean telomere length was 7.7 kb ranging from 5.0 kb to 11.7 kb across all samples (N = 42) and longer compared with other human tissues at birth. STELA also revealed considerable telomere length heterogeneity within samples. CONCLUSIONS: We have shown that STELA can be used to study telomere length homeostasis in the placenta regardless of sampling site, mode of delivery and foetal sex. Moreover, as each amplicon is derived from a single telomeric molecule, from a single cell, STELA can reveal the full detail of telomere-length distributions, including telomeres within the length ranges observed in senescent cells. STELA thus provides a new tool to interrogate the relationship between telomere length and pregnancy complications linked to placental dysfunction. PMID- 29108640 TI - Placental abnormalities associated with isolated single umbilical artery in small for-gestational-age births. AB - BACKGROUND: Previous studies have shown that pregnancies complicated by placentas with an isolated single umbilical artery (iSUA) are at increased risk for small for-gestational-age (SGA) births. The etiology of SGA in this population, however, remains unknown. OBJECTIVE: The primary objective of this study was to evaluate whether placental abnormalities in pregnancies with SGA births differ according to the presence of iSUA. STUDY DESIGN: This was an observational study of all women with pathologic examination of the placenta after delivering a non anomalous, singleton SGA neonate between January 2009 and August 2015. SGA was defined as birthweight less than 10th percentile for gestational age. Women were categorized according to whether they had an iSUA or a three-vessel cord. The following placental pathologies were compared between the groups using bivariable and multivariable analyses: SGA placenta, maternal vascular malperfusion, high grade fetal vascular malperfusion, and chronic villitis. RESULTS: 1833 women were included in the analysis: 34 with iSUA and 1799 with three-vessel cord. More than 85% of women in both groups had at least one placental abnormality. After adjusting for nulliparity and neonatal gender, the presence of iSUA was associated with increased odds of high grade fetal vascular malperfusion (adjusted odds ratio 2.8, 95% confidence interval 1.1-7.5) and decreased odds of maternal vascular malperfusion (adjusted odds ratio 0.2, 95% confidence interval 0.1-0.9). There was no significant association with other pathologic findings. CONCLUSION: Pathologic placental findings associated with SGA birth differed based on umbilical cord composition. The presence of iSUA in an SGA birth was associated with a higher odds of high grade fetal vascular malperfusion abnormalities and lower odds of maternal vascular malperfusion abnormalities, compared to SGA birth with a 3VC. PMID- 29108641 TI - Editorial. PMID- 29108642 TI - [The 150th anniversary of Marie Curie]. PMID- 29108643 TI - Gastric cancer diagnosis after presentation to the ED: The independent association of presenting location and outcomes. AB - BACKGROUND: The impact of diagnosis location on gastric cancer (GC) outcomes is poorly defined. METHODS: Detailed chart review was conducted to identify presenting location leading to diagnosis and treatment for GC patients at a single institution (2009-2013). Patients treated non-emergently following a diagnosis prompted by an ED visit (EDdx) were compared with those diagnosed at other locations (non-EDdx). RESULTS: EDdx patients comprised 52% of 263 GC patients. They were older, had later cancer stages (stage IV: 50% vs. 24%), more comorbidities (>=3: 68% vs. 47%), and presented with non-specific symptoms like bleeding (21% vs. 5%). Both groups were of similar race and insurance status. In a model adjusted for stage, EDdx was associated with increased mortality (aHR 1.9; 95% CI: 1.2-2.9). CONCLUSION: Half of GC patients had an ED visit prompting diagnosis, which is independently associated with increased mortality. Efforts should focus on reducing EDdx rates to improve GC outcomes. PMID- 29108644 TI - Mesh sutured repairs of contaminated incisional hernias. AB - BACKGROUND: We sought to evaluate the results of a new mesh sutured repair technique for closure of contaminated incisional hernias. METHODS: 48 patients with contaminated hernias 5 cm wide or greater by CT scan were closed with mesh sutures. Surgical site occurrence, infections, and hernia recurrence were compared to similar patient series reported in the literature. RESULTS: Of the 48 patients, 20 had clean-contaminated wounds, 16 had contaminated wounds, and 12 were infected. 69% of the patients underwent an anterior perforator sparing components release for hernias that averaged 10.5 cm transversely (range 5 cm-25 cm). SSO occurred in 27% of patients while SSI was 19%. There were no fistulas or delayed suture sinuses. With a mean follow-up of almost 12 months, 3 midline hernias recurred (6%). In these same patients, three parastomal hernias repaired with mesh sutures failed out of 4 attempted for a total failure rate of 13%. CONCLUSION: Mesh sutured closure represents a simplified and effective surgical strategy for contaminated midline incisional hernia repair. PMID- 29108645 TI - The bidirectional congruency effect of brightness-valence metaphoric association in the Stroop-like and priming paradigms. AB - The conceptual metaphor theory (Lakoff & Johnson, 1980, 1999) postulates a unidirectional metaphoric association between abstract and concrete concepts: sensorimotor experience activated by concrete concepts facilitates the processing of abstract concepts, but not the other way around. However, this unidirectional view has been challenged by studies that reported a bidirectional metaphoric association. In three experiments, we tested the directionality of the brightness valence metaphoric association, using Stroop-like paradigm, priming paradigm, and Stroop-like paradigm with a go/no-go manipulation. Both mean and vincentile analyses of reaction time data were performed. We showed that the directionality of brightness-valence metaphoric congruency effect could be modulated by the activation level of the brightness/valence information. Both brightness-to valence and valence-to-brightness metaphoric congruency effects occurred in the priming paradigm, which could be attributed to the presentation of prime that pre activated the brightness or valence information. However, in the Stroop-like paradigm the metaphoric congruency effect was only observed in the brightness-to valence direction, but not in the valence-to-brightness direction. When the go/no go manipulation was used to boost the activation of word meaning in the Stroop like paradigm, the valence-to-brightness metaphoric congruency effect was observed. Vincentile analyses further revealed that valence-to-brightness metaphoric congruency effect approached significance in the Stroop-like paradigm when participants' reaction times were slower (at around 490ms). The implications of the current findings on the conceptual metaphor theory and embodied cognition are discussed. PMID- 29108646 TI - Allergic Contact Dermatitis Caused by Acrylates in Long-Lasting Nail Polish. AB - The first reported cases of allergic contact dermatitis from acrylates in manicure procedures in relation to the application of porcelain nails were published decades ago. The frequency of sensitization has increased due to the introduction of the so-called permanent nail polish containing photo-bonded acrylates, mainly involving the beauticians who apply them, and to a lesser extent, the consumers. The recent commercialized permanent polish kits for domestic use could trigger even higher degrees of sensitization. In this article, the clinical features, diagnostic procedures, treatment and preventive measures are described. Acrylates are present in a wide range of sources including multiple medical materials. Sensitization caused by a merely aesthetic procedure might end up having an eventual important impact in the future consumer's health which is why restrictive policies should be implemented limiting its use to qualified professionals and banning the indiscriminate sale of domestic kits. PMID- 29108647 TI - Ultrasound-Guided, Minimally Invasive Resection of a Digital Glomus Tumor. PMID- 29108648 TI - Cyclosporin A indirectly attenuates activation of group 2 innate lymphoid cells in papain-induced lung inflammation. AB - Cyclosporin A (CsA) is a well-known immunosuppressant that is used against steroid-resistant asthma. Group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells produce Th2 cytokines including IL-5 and play important roles in asthma pathogenesis. Here, we studied the effects of CsA in allergen-induced lung inflammation in mice and found that CsA decreased the number of lung ILC2s and attenuated papain-induced activation of ILC2s accompanied with IL-5 expression. The ILC2 suppression mediated by CsA was not observed in culture or in lymphocyte deficient Rag2-/- mice. Thus, we propose a new suppressive effect of CsA, i.e., administration of CsA indirectly suppresses maintenance and activation of lung ILC2s in addition to direct suppression of T-cell activation and cytokine production. PMID- 29108650 TI - Biophysical Characterization of Genetically Encoded Voltage Sensor ASAP1: Dynamic Range Improvement. AB - Recent work has introduced a new fluorescent voltage sensor, ASAP1, which can monitor rapid trains of action potentials in cultured neurons. This indicator is based on the Gallus gallus voltage-sensitive phosphatase with the phosphatase domain removed and a circularly permuted GFP placed in the S3-S4 linker. However, many of the biophysical details of this indicator remain unknown. In this work, we study the biophysical properties of ASAP1. Using the cut-open voltage clamp technique, we have simultaneously recorded fluorescence signals and gating currents from Xenopus laevis oocytes expressing ASAP1. Gating charge movement and fluorescence kinetics track closely with each other, although ASAP1 gating currents are significantly faster than those of Ciona intestinalis voltage sensitive phosphatase. Altering the residue before the first gating charge removes a split in the ASAP1 QV curve, but preserves the accelerated kinetics that allow for the faithful tracking of action potentials in neurons. PMID- 29108649 TI - Mapping Hydrophobic Tunnels and Cavities in Neuroglobin with Noble Gas under Pressure. AB - Internal cavities are crucial for conformational flexibility of proteins and can be mapped through noble gas diffusion and docking. Here we investigate the hydrophobic cavities and tunnel network in neuroglobin (Ngb), a hexacoordinated heme protein likely to be involved in neuroprotection, using crystallography under noble gas pressure, mostly at room temperature. In murine Ngb, a large internal cavity is involved in the heme sliding mechanism to achieve binding of gaseous ligands through coordination to the heme iron. In this study, we report that noble gases are hosted by two major sites within the internal cavity. We propose that these cavities could store oxygen and allow its relay in the heme proximity, which could correspond to NO location in the nitrite-reductase function of Ngb. Thanks to a recently designed pressurization cell using krypton at high pressure, a new gas binding site has been characterized that reveals an alternate pathway for gaseous ligands. A new gas binding site on the proximal side of the heme has also been characterized, using xenon pressure on a Ngb mutant (V140W) that binds CO with a similar rate and affinity to the wild-type, despite a reshaping of the internal cavity. Moreover, this study, to our knowledge, provides new insights into the determinants of the heme sliding mechanism, suggesting that the shift at the beginning of helix G precedes and drives this process. PMID- 29108651 TI - Targeting couple and parent-child coercion to improve health behaviors. AB - This phase of the NIH Science of Behavior Change program emphasizes an "experimental medicine approach to behavior change," that seeks to identify targets related to stress reactivity, self-regulation, and social processes for maximal effects on multiple health outcomes. Within this framework, our project focuses on interpersonal processes associated with health: coercive couple and parent-child conflict. Diabetes and poor oral health portend pain, distress, expense, loss of productivity, and even mortality. They share overlapping medical regimens, are driven by overlapping proximal health behaviors, and affect a wide developmental span, from early childhood to late adulthood. Coercive couple and parent-child conflict constitute potent and destructive influences on a wide range of adult and child health outcomes. Such interaction patterns give rise to disturbed environmental stress reactivity (e.g., disrupted sympathetic nervous and parasympathetic nervous systems) and a wide range of adverse health outcomes in children and adults, including dental caries, obesity, and diabetes-related metabolic markers. In this work, we seek to identify/develop/validate assays assessing coercion, identify/develop and test brief interventions to reduce coercion, and test whether changes in coercion trigger changes in health behaviors. PMID- 29108652 TI - Psychosis in a 22-Year-Old Woman With Narcolepsy After Restarting Sodium Oxybate. PMID- 29108653 TI - Effect of asiaticoside on the healing of skin wounds in the carp Cirrhinus mrigala: An immunohistochemical investigation. AB - In the present study effect of asiaticoside, on healing of skin wounds in Cirrhinus mrigala is reported. Skin wound, approx. 2mm in diameter was excised using sterile disposable biopsy punch. Immediately after infliction of the wound, epidermis from wound edge starts migrating as thin sheet toward wound gap. Fronts of migrating epidermis gradually advance, and results in complete epithelialization of wound. Experiments were conducted for 30days and fishes were divided into control, sham, vehicle control and asiaticoside treated groups. Immunohistochemical localization of proliferating cell nuclear antigen positive cells indicating cellular proliferation and caspase 3 positive cells reflecting apoptosis was carried out and their density at different post wound intervals in each fish group was analyzed. Significant increase in cellular proliferation as well as decrease in apoptosis in both epidermis and dermis in fish treated with asiaticoside compared to sham and vehicle control fish is observed at different intervals of wound repair. This suggests that in treated group healing of skin wounds in fish is enhanced than in sham and vehicle control groups. Asiaticoside treatment in healing of skin wounds would greatly be beneficial to fish farmers as it could protect fish from invasion of pathogens and check fish mortality. PMID- 29108655 TI - Proteinase-activated receptor 2 distribution and expression in equine small intestine tracts following herniation through the epiploic foramen. AB - Proteinase-activated receptor 2 (PAR2) is a G-protein-coupled receptor for trypsin and mast cell tryptase; it is highly expressed at the intestinal level with multiple functions, such as epithelial permeability and intestinal motility. The aim of the study was to evaluate the distribution and expression of proteinase-activated receptor 2 in the small intestine during herniation through epiploic foramen. In this prospective clinical study, eight horses admitted for colic and which underwent exploratory laparotomy were considered. During surgery, the jejunum or the ileum was sampled by enterectomy. Morphological examination (histology, PAR2 immunohistochemistry) and molecular biology analysis (western blot and quantitative polymerase chain reaction) were carried out on the resected intestinal samples. The Marginal Injured Tracts (MITs) and Central Injury Tracts (CITs) were defined as the oral and caudal marginal segments of the resected bowel tract and as the geometric centre of the intestinal ischaemic lesion length, respectively. The PAR2 immunoreactivity was particularly evident in the epithelial cells, with higher immunoreactivity in the MIT rather than in the CIT. Moreover, a different immune localisation was observed in the MITs at the cell membrane level and in the CITs in the cytoplasm. No statistical difference was observed in PAR2 mRNA and protein (44kDa) expression between the MIT and the CIT. The PAR2 protein content in the intestinal tracts which were removed from horses with herniation was lower when compared with the control animals. This study provided data concerning the PAR2 presence and distribution in horses with intestinal herniation through the epiploic foramen. PMID- 29108654 TI - Atypical cutaneous melanocytic tumours arising in two patients with Li-Fraumeni syndrome. PMID- 29108656 TI - Hepatocellular carcinoma treatment: ablation and arterial embolization. AB - Percutaneous and endovascular techniques take an important role in the therapeutic management of patients with hepatocarcinoma. Different techniques of percutaneous ablation, especially indicated in tumors up to 2cm diameter offer, at least, similar results to surgical resection. Taking advantage of double hepatic vascularization and exclusive tumor nutrition by the artery, several endovascular techniques of treating the tumor have been developed. Intra-arterial administration of embolizing particles, alone or charged with drug (chemoembolization), will produce ischemia and consequent necrosis with excellent results in selected patients. Certain types of particles may exclusively be carriers of a therapeutic agent when they incorporate a radioisotope that facilitates the direct intratumoral selective irradiation (radioembolization). This technique has demonstrated its efficacy in lesions not susceptible to be treated with other methods and should be considered, together with ablation and chemoembolization, in the therapeutic algorithms of hepatocarcinoma. PMID- 29108657 TI - Imaging biomarkers in liver fibrosis. AB - There is a need for early identification of patients with chronic liver diseases due to their increasing prevalence and morbidity-mortality. The degree of liver fibrosis determines the prognosis and therapeutic options in this population. Liver biopsy represents the reference standard for fibrosis staging. However, given its limitations and complications, different non-invasive methods have been developed recently for the in vivo quantification of fibrosis. Due to their precision and reliability, biomarkers' measurements derived from Ultrasound and Magnetic Resonance stand out. This article reviews the different acquisition techniques and image processing methods currently used in the evaluation of liver fibrosis, focusing on their diagnostic performance, applicability and clinical value. In order to properly interpret their results in the appropriate clinical context, it seems necessary to understand the techniques and their quality parameters, the standardization and validation of the measurement units and the quality control of the methodological problems. PMID- 29108658 TI - Re: Robert J. Motzer, Alain Ravaud, Jean-Jacques Patard, et al. Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2017.09.008. PMID- 29108659 TI - Reply to Aditya Bagrodia, Solomon Woldu, David F. Penson, Alexander Kutikov, and Samuel D. Kaffenberger's Letter to the Editor re: Sophia C. Kamran, Thomas Seisen, Sarah C. Markt, et al. Contemporary Treatment Patterns and Outcomes for Clinical Stage IS Testicular Cancer. Eur Urol 2018;73:262-70. PMID- 29108660 TI - Usefulness of electroencephalography for the management of epilepsy in emergency departments. AB - INTRODUCTION: Electroencephalography (EEG) is an essential diagnostic tool in epilepsy. Its use in emergency departments (ED) is usually restricted to the diagnosis and management of non-convulsive status epilepticus (NCSE). However, EDs may also benefit from EEG in the context of other situations in epilepsy. METHODS: We conducted a retrospective observational study using the clinical histories of patients treated at our hospital's ED for epileptic seizures and suspicion of NCSE and undergoing EEG studies in 2015 and 2016. We collected a series of demographic and clinical variables. RESULTS: Our sample included 87 patients (mean age of 44 years). Epileptic seizures constituted the most common reason for consultation: 59.8% due to the first episode of epileptic seizures (FES), 27.6% due to recurrence, and 12.6% due to suspected NCSE. Interictal epileptiform discharges (IED) were observed in 38.4% of patients reporting FES and in 33.3% of those with a known diagnosis of epilepsy. NCSE was confirmed by EEG in 36.4% of all cases of suspected NCSE. Presence of IED led to administration of or changes in long-term treatment in 59.8% of the patients. CONCLUSIONS: EEG is a useful tool for seizure management in EDs, not only for severe, sudden-onset clinical situations such as NCSE but also for diagnosis in cases of non-affiliated epilepsy and in patients experiencing the first episode of epilepsy. PMID- 29108661 TI - Neurological symptoms as the initial manifestation of IgG4-related disease. PMID- 29108662 TI - Hospital length of stay and cost burden of HIV, tuberculosis, and HIV tuberculosis coinfection among pregnant women in the United States. AB - BACKGROUND: We sought to determine hospital length of stay (LOS) and cost burden associated with hospital admissions among pregnant women with HIV monoinfection, tuberculosis (TB) monoinfection, or HIV-TB coinfection in the United States. METHODS: Analysis covered the period from 2002-2014 using data from the Nationwide Inpatient Sample. Relevant ICD-9-CM codes were used to determine HIV and TB status. Costs associated with hospitalization were calculated and adjusted to 2010 dollars using the medical care component of the Consumer Price Index. RESULTS: We found modest annual average reduction in HIV, TB, and HIV-TB coinfection rates over the study period. The mean LOS was lowest among mothers free of HIV or TB disease and highest among those with HIV-TB coinfection. The average LOS among mothers diagnosed with TB monoinfection was 60% higher than for those with HIV monoinfection. The cost associated with pregnancy-related hospital admissions among mothers with HIV was approximately 30% higher than disease-free mothers, and the cost more than doubled among patients with TB monoinfection or HIV-TB coinfection. CONCLUSIONS: TB significantly increased hospital care cost among HIV-positive and HIV-negative pregnant women. PMID- 29108663 TI - A needs assessment of infection control training for American Red Cross personnel working in shelters. AB - This pilot needs assessment aimed to identify gaps in infection prevention and control (IPC) training of American Red Cross shelter staff through an electronic survey of IPC background, knowledge, and perceived training needs. Respondents (n = 471) noted a greater need for training in several IPC areas, although no significant differences were found in IPC knowledge between those who had recently deployed to a shelter (n = 70) and trained personnel who had never deployed (n = 178). PMID- 29108664 TI - The effect of acute and 7-days dietary nitrate on mechanical efficiency, exercise performance and cardiac biomarkers in patients with chronic obstructive pulmonary disease. AB - BACKGROUND & AIMS: Many COPD patients have a reduced exercise capacity and mechanical efficiency and are at increased cardiometabolic risk. This study aimed to assess acute and 7-days effects of dietary nitrate on mechanical efficiency, exercise performance and cardiac biomarkers in patients with COPD. METHODS: This double-blind, randomized cross-over placebo controlled trial included 20 mild-to moderate COPD patients (66.6 +/- 7.5 years) with moderate exercise impairments and decreased mechanical efficiency, normal BMI (26 +/- 3 kg/m2) but high prevalence of abdominal obesity (83.3%). Subjects were randomly allocated to the treatment order of 7 days sodium nitrate ingestion (~8 mmol/day) and 7 days placebo (NaCl solution) or vice versa, separated by a washout period. Before (Day 1) and after (Day-7) both intervention periods resting metabolic rate and the metabolic response during submaximal cycle ergometry, cycling endurance time, plasma nitrate and nitrite levels, cardiac plasma biomarkers (e.g. cardiac troponin T, Nt-proBNP and creatinine kinase) and blood pressure were measured. Subsequently, gross, net and delta mechanical efficiency were calculated. RESULTS: Plasma nitrate and nitrite concentrations increased at Day-1 and Day-7 after sodium nitrate but not after placebo ingestion. Systolic and diastolic blood pressure did not change following nitrate ingestion. Furthermore, no differences were observed in gross, net, and delta mechanical efficiency during submaximal exercise, cycling endurance time and cardiac biomarkers between nitrate and placebo on Day-1 and Day-7. Meta-analysis of all available studies in COPD also showed no beneficial effect of beetroot juice on systolic and diastolic blood pressure. CONCLUSION: Acute as well as 7-days sodium nitrate supplementation does not modulate mechanical efficiency, blood pressure or cardiac biomarkers in mild-to-moderate COPD patients. PMID- 29108665 TI - Evaluation of a polyvalent foot-and-mouth disease virus vaccine containing A Saudi-95 against field challenge on large-scale dairy farms in Saudi Arabia with the emerging A/ASIA/G-VII viral lineage. AB - In 2015, foot-and-mouth disease (FMD) viruses of the A/ASIA/G-VII lineage emerged from the Indian sub-continent to cause outbreaks in the Middle and Near East. A factor which has been proposed to have contributed to the rapid spread of this lineage is the poor in vitro vaccine-match of field isolates to vaccine strains that are commonly used in the region. This study used data from outbreaks on four large-scale dairy farms using routine vaccination in Saudi Arabia, to evaluate the impact of vaccination and learn how to manage outbreaks more effectively in this setting. This evaluation also included an assessment of vaccine-induced neutralisation titres to the vaccine and field strains on a related farm with no history of FMD that employed an identical vaccination schedule. The incidence risk among exposed groups ranged from 2.6 to 20.1% and was significantly higher among youngstock (18.7%) compared to adults (7.4%). Evidence was found that local isolation of individual sick animals was more effective than whole group isolation and that subclinical infection and undetected circulation may occur on large-scale farms in Saudi Arabia, although both of these points require further evaluation. On the unaffected farm, the mean reciprocal titres for the vaccine and field strains were all above the cut-off supposed to correlate with clinical protection based on evidence from challenge studies. An estimate of vaccination effectiveness was not possible on the affected farms, but the incidence of FMD provides a more realistic estimation of the expected vaccine performance than in vivo studies or r1 value as it is based on field conditions and natural exposure. This study shows that analysis of field data from FMD outbreaks are a useful addition to more conventional challenge and in vitro based evaluations of vaccines and suggests further work is necessary to validate correlates of protection in field conditions. PMID- 29108666 TI - Mycosis fungoides - A cutaneous lymphoproliferative disorder in a patient treated with fingolimod for multiple sclerosis. AB - Fingolimod was the first oral disease-modifying drug approved for the treatment of relapsing-remitting multiple sclerosis (MS). It has previously been associated with rare cases of lymphoma. Here we describe the first case of mycosis fungoides - a cutaneous lymphoproliferative disorder, in an MS patient treated with fingolimod. who developed histologically confirmed mycosis fungoides 3 years after starting fingolimod. The drug was withdrawn and the patient was treated with radiotherapy and surgical excision with remission. This report points to a possible association between fingolimod and skin lymphoproliferative disorder and emphasizes the need for periodic skin examination. PMID- 29108668 TI - The prognostic value of high sensitivity cardiac troponin T in patients with congenital heart disease. AB - BACKGROUND: Cardiac troponin T (cTnT) is a specific marker of myocardial injury that is elevated in patients with coronary artery disease or heart failure; it has been investigated as a prognostic marker. A highly sensitive, commercially available assay has been developed to detect cardiac troponin T (hs-cTnT). This study aimed to evaluate the clinical implications and prognostic value of hs-cTnT in patients with congenital heart disease (CHD). METHODS: We evaluated 122 consecutive patients hospitalized at our institution because of heart failure or scheduled cardiac catheterization. We measured the serum concentration of hs-cTnT at the time of hospitalization, and we prospectively followed-up all patients for 3 years and monitored rates of cardiovascular events (e.g. cardiac death, readmission owing to worsening of heart failure or arrhythmia, and reintervention) as endpoints. RESULTS: We classified the patients according to their hs-cTnT level into non-detectable (ND group, hs-cTnT <0.003ng/mL), detectable normal (DN group, 0.003ng/mL <=hs-cTnT <0.014ng/mL), or elevated (EL group, 0.014ng/mL <=hs-cTnT) group; 20 of 122 (16.4%) patients were in the EL group, in which 17 cardiovascular events occurred during follow-up. In the multivariate Cox proportional hazard analyses, the EL group [p=0.024, hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.1-5.8] was an independent significant predictor of cardiovascular events. A Kaplan-Meier curve revealed a high incidence of cardiovascular events in the EL group (EL vs ND log rank p<0.0001, HR 7.6, 95% CI 3.2-20.0, EL vs DN log rank p<0.0001, HR 4.1, 95% CI 2.1 7.8). CONCLUSIONS: Because the EL group is more likely to have an adverse outcome, elevated hs-cTnT level can be a prognostic marker in patients with CHD. PMID- 29108667 TI - Clinical, electrophysiological, genetic, and imaging features of six Chinese Han patients with hereditary neuropathy with liability to pressure palsies (HNPP). AB - Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. This study summarizes the clinical, electrophysiological, genetic, and imaging features of six unrelated Chinese Han patients with HNPP. Age of onset was within the second decade in five patients, and 46 years of age in one patient. Weakness or numbness in a unilateral lower extremity was the most common symptom in 5 patients, and bilateral sensorineural hearing loss was also detected in one patient. Electrophysiological presentations suggested demyelinating sensory-motor polyneuropathy in the group. Magnetic resonance imaging (MRI) of the cervical and lumbar spine revealed varying degrees of degeneration in five patients, and mild kyphosis of cervical vertebral bodies in 2 teen-aged patients. In addition, cranial MRI of one patient showed scattered demyelination in the frontal lobes. Targeted next-generation-sequencing (NGS) revealed a PMP22 deletion in five patients and a heterozygous c.199G>A mutation in exon 4 of PMP22 in one patient. The I92V variant of lipopolysaccharide-induced tumor necrosis factor (LITAF) gene was found in one patient. There was no relationship between the Ile92Val variant of LITAF and age of onset in this group, albeit the sample size was very small. PMID- 29108669 TI - The health economics of ankle and foot sprains and fractures: A systematic review of English-language published papers. Part 1: Overview and critical appraisal. AB - BACKGROUND: Ankle and foot sprains and fractures are common injuries affecting many individuals, often requiring considerable and costly medical interventions. The objectives of this systematic review are to collect, assess, and critically appraise the published literature on the health economics of ankle and foot injury (sprain and fracture) treatment. METHODS: A systematic literature review of Ovid MEDLINE, EMBASE, Cochrane DSR, ACP Journal Club, AMED, Ovid Healthstar, and CINAHL was conducted for English-language studies on the costs of treating ankle and foot sprains and fractures published from January 1980 to December 2014. Two reviewers assessed the articles for study quality and abstracted data. RESULTS: The literature search identified 2047 studies of which 32 were analyzed. A majority of the studies were published in the last decade. A number of the studies did not report full economic information, including the sources of the direct and indirect costs, as suggested in the guidelines. The perspective used in the analysis was missing in numerous studies, as was the follow-up time period of participants. Only five of the studies undertook a sensitivity analysis which is required whenever there are uncertainties regarding cost data. CONCLUSION: This systematic review found that publications do not consistently report on the components of health economics methodology, which in turn limits the quality of information. Future studies undertaking economic evaluations should ensure that their methods are transparent and understandable so as to yield accurate interpretation for assistance in forthcoming economic evaluations and policy decision-making. PMID- 29108671 TI - Metacognitive Reflection and Insight Therapy for Early Psychosis: A preliminary study of a novel integrative psychotherapy. AB - Poor insight impedes treatment in early phase psychosis (EPP). This manuscript outlines preliminary findings of an investigation of the novel metacognitively oriented integrative psychotherapy, Metacognitive Reflection and Insight Therapy, for individuals with early phase psychosis (MERIT-EP). Twenty adults with EPP and poor insight were randomized to either six months of MERIT-EP or treatment as usual (TAU). Therapists were trained and therapy was successfully delivered under routine, outpatient conditions. Insight, assessed before and after treatment, revealed significant improvement for the MERIT-EP, but not TAU, group. These results suggest MERIT-EP is feasible to deliver, accepted by patients, and leads to clinically significant improvements in insight. PMID- 29108670 TI - Autophagy dysfunction in autoinflammatory diseases. AB - Autoinflammatory diseases (AUIDs) are a genetically heterogeneous group of rheumatic diseases characterized by episodic inflammation linked with dysregulated innate immune responses. In this review, we summarize the molecular mechanisms altered by disease-associated variants in several AUIDs, including NOD2-associated diseases, TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), and highlight the roles dysregulated autophagy plays in disease pathogenesis. Autophagy is a conserved eukaryotic pathway for the elimination of cellular stressors, such as misfolded proteins, damaged organelles, or intracellular microorganisms. It is now recognized that autophagy also functions to control inflammation through regulatory interactions with innate immune signaling pathways. AUID-associated genetic variants are known to directly activate inflammatory signaling pathways. Recent evidence also indicates that these variants may also cause impairment of autophagy, thus augmenting inflammatory responses indirectly. Intriguingly, these variants can impair autophagy by different mechanisms, further implicating the autophagic response pathway in AUIDs. These discoveries provide evidence that autophagy could be investigated as a new therapeutic target for AUIDs. PMID- 29108672 TI - FoxA transcription factor Fork head maintains the intestinal stem/progenitor cell identities in Drosophila. AB - Understanding how somatic stem cells respond to tissue needs is important, since aberrant somatic stem cell behaviors may lead to tissue degeneration or tumorigenesis. Here, from an in vivo RNAi screen targeting transcription factors that regulate intestinal regeneration, we uncovered a requirement for the Drosophila FoxA transcription factor Fork head (Fkh) in the maintenance of intestinal stem/progenitor cell identities. FoxA/Fkh maintains the expressions of stem/progenitor cell markers and is required for stem cell proliferation during intestinal homeostasis and regeneration. Furthermore, FoxA/Fkh prevents the intestinal stem/progenitor cells from precocious differentiation into the Enterocyte lineage, likely in cooperation with the transcription factor bHLH/Daughterless (Da). In addition, loss of FoxA/Fkh suppresses the intestinal tumorigenesis caused by Notch pathway inactivation. To reveal the gene program underlying stem/progenitor cell identities, we profiled the genome-wide chromatin binding sites of transcription factors Fkh and Da, and interestingly, around half of Fkh binding regions are shared by Da, further suggesting their collaborative roles. Finally, we identified the genes associated with their shared binding regions. This comprehensive gene list may contain stem/progenitor maintenance factors functioning downstream of Fkh and Da, and would be helpful for future gene discoveries in the Drosophila intestinal stem cell lineage. PMID- 29108673 TI - beta-Catenin acts in a position-independent regeneration response in the simple eumetazoan Hydra. AB - Wnt/beta-Catenin signaling plays crucial roles in regenerative processes in eumetazoans. It also acts in regeneration and axial patterning in the simple freshwater polyp Hydra, whose morphallactic regenerative capacity is unparalleled in the animal kingdom. Previous studies have identified beta-catenin as an early response gene activated within the first 30min in Hydra head regeneration. Here, we have studied the role of beta-Catenin in more detail. First, we show that nuclear beta-Catenin signaling is required for head and foot regeneration. Loss of nuclear beta-Catenin function blocks head and foot regeneration. Transgenic Hydra tissue, in which beta-Catenin is over-expressed, regenerates more heads and feet. In addition, we have identified a set of putative beta-Catenin target genes by transcriptional profiling, and these genes exhibit distinct expression patterns in the hypostome, in the tentacles, or in an apical gradient in the body column. All of them are transcriptionally up-regulated in the tips of early head and foot regenerates. In foot regenerates, this is a transient response, and expression starts to disappear after 12-36h. ChIP experiments using an anti HydraTcf antibody show Tcf binding at promoters of these targets. We propose that gene regulatory beta-Catenin activity in the pre-patterning phase is generally required as an early regeneration response. When regenerates are blocked with iCRT14, initial local transcriptional activation of beta-catenin and the target genes occurs, and all these genes remain upregulated at the site of both head and foot regeneration for the following 2-3 days. This indicates that the initial regulatory network is followed by position-specific programs that inactivate fractions of this network in order to proceed to differentiation of head or foot structures. brachyury1 (hybra1) has previously been described as early response gene in head and foot regeneration. The HyBra1 protein, however, appears in head regenerating tips not earlier than about twelve hours after decapitation, and HyBra1 translation does not occur in iCRT14-treated regenerates. Foot regenerates never show detectable levels of HyBra1 protein at all. These results suggest that translational control mechanisms may play a decisive role in the head- and foot specific differentiation phase, and HyBra1 is an excellent candidate for such a key regulator of head specification. PMID- 29108674 TI - Effects of Vocal Function Exercises: A Systematic Review. AB - OBJECTIVES: The purpose of the present review was to systematically analyze the evidence for the effectiveness of vocal function exercises (VFEs) in improving voice production. METHODS: A systematic literature search was performed by two independent reviewers using PubMed and EBSCOHost to access relevant databases and to locate outcome studies that used VFEs as an intervention. Articles that met inclusion criteria were appraised based on the American Speech-Language and Hearing Association's levels of evidence. Effect sizes for outcomes were calculated using Hedge's g. Voice outcomes were categorized according to the five domains of voice assessment: visual perceptual analysis, acoustic analysis, aerodynamic analysis, auditory-perceptual analysis, and patient self-report measures. RESULTS: Twenty-one articles were included for the final appraisal. All studies demonstrated positive effects of VFEs as demonstrated by effect sizes across selected voice parameters. Effect sizes across parameters ranged from 0.59 to 1.55. None of the included studies reported adverse voice outcomes as a result of VFEs. CONCLUSIONS: Outcome studies demonstrate that VFEs are efficacious in enhancing vocal function in individuals with normal and disordered voices, presbylaryngeus, and professional voice users. The available research suggests moderate to strong evidence to support the use of VFEs for a variety of voice disorders. PMID- 29108675 TI - A Comparison of Indirect and Direct Methods for Estimating Transglottal Airflow Rate. AB - OBJECTIVE: The purpose of this study was to compare indirect estimates of transglottal airflow rate using measures of phonation quotient with direct measures of mean airflow rate derived from a pneumotachograph. STUDY DESIGN: This study used prospective, repeated measures design. METHODS: Nineteen male and female participants, matched for age, completed tasks for maximum phonation time and vital capacity in addition to the comfortable sustained phonation protocol of the Phonatory Aerodynamic System (PAS), Model 6600. Phonation quotient was calculated from the vital capacity and phonation time measures, whereas actual transglottal airflow was obtained from the flow waveforms recorded on the PAS system. Statistical analyses compared transglottal airflow rate measures as a function of instrument and separately as a function of gender. RESULTS: Statistically significant differences were present only as a function of gender on airflow measures but not as a function of the instrument. There were no interaction effects present between instrument and gender. CONCLUSIONS: Phonation quotient can be used as an estimate of transglottal airflow in the absence of a pneumotachograph-based system. PMID- 29108676 TI - The fatty acid content of plankton is changing in subtropical coastal waters as a result of OA: Results from a mesocosm study. AB - Ocean Acidification (OA) effects on marine plankton are most often considered in terms of inorganic carbon chemistry, but decreasing pH may influence other aspects of cellular metabolism. Here we present the effects of OA on the fatty acid (FA) content and composition of an artificial phytoplankton community (Phaeodactylum tricornutum, Thalassiosira weissflogii, and Emiliania huxleyi) in a fully replicated, ~4 m3 mesocosm study in subtropical coastal waters (Wuyuan Bay, China, 24.52 degrees N, 117.18 degrees E) at present day (400 MUatm) and elevated (1000 MUatm) pCO2 concentrations. Phytoplankton growth occurred in three phases during the 33-day experiment: an initial exponential growth leading to senescence and a subsequent decline phase. Phytoplankton sampled from these mesocosms were fed to mesozooplankton collected by net haul from Wuyuan Bay. Concentrations of saturated fatty acids (SFA) in both phytoplankton and mesozooplankton remained high under acidified and non-acidified conditions. However, polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) increased significantly more under elevated pCO2 during the late exponential phase (Day 13), indicating increased nutritional value for zooplankton and higher trophic levels. Indeed, uptake rates of the essential FA docosahexaenoic acid (C20:5n3, DHA) increased in mesozooplankton under acidified conditions. However, mesozooplankton grazing rates decreased overall with elevated pCO2. Our findings show that these selected phytoplankton species have a relatively high tolerance to acidification in terms of FA production, and local mesozooplankton in these subtropical coastal waters can maintain their FA composition under end of century ocean acidification conditions. PMID- 29108677 TI - Salinity stress results in differential Hsp70 expression in the Exaiptasia pallida and Symbiodinium symbiosis. AB - Abiotic factors affect cnidarian-algal symbiosis and, if severe enough, can result in bleaching. Increased temperature and light are well characterized causes of bleaching, but other factors like salinity can also stress the holobiont. In cnidarian-dinoflagellate systems, the expression of host genes, including heat shock protein 70 (Hsp70), changes due to thermal and light stress. In this experiment, we characterized to what extent salinity stress affects Hsp70 expression in the holobiont by simultaneously measuring host and symbiont Hsp70 expression in response to up to 8 h of hypo- and hypersaline conditions in the sea anemone Exaiptasia pallida and its intracellular symbiont Symbiodinium minutum. We show that E. pallida Hsp70 expression increases (6-11-fold) at high salinities whereas Symbiodinium Hsp70 expression shows little change (1.4-2.6 fold). These data suggest that cnidarian Hsp70 response is similar across multiple abiotic stressors further validating the Hsp70 gene as a biomarker for abiotic stress. PMID- 29108678 TI - Making an Impact: A New Research Prize for Heart, Lung and Circulation. PMID- 29108679 TI - Timing of Surgery for ST-Elevation Myocardial Infarction. PMID- 29108680 TI - Human metabolism and excretion kinetics of the fragrance 7-hydroxycitronellal after a single oral or dermal dosage. AB - 7-Hydroxy-3,7-dimethyl-1-octanal, also known as 7-hydroxycitronellal (7-HC, CAS No. 107-75-5) is a synthetic fragrance widely used in cosmetic and hygiene products. Due to its large scope, 7-HC was selected for the development of a biomonitoring method suitable for the general population within the frame of the cooperation project between the German Federal Ministry for the Environment (BMUB) and the German Chemical Industry Association (VCI). In a human study with 5 healthy subjects who received single dermal and oral doses 7-HC, suitable metabolites and their urinary excretion kinetics was investigated. Two metabolites of 7-hydroxycitronellal were identified in urinary fractions after dermal and oral dosing: The alcohol 7-hydroxycitronellol (7-HCO) and the corresponding acid 7-hydroxycitronellylic acid (7-HCA). Only 7-HCA proved to be a suitable biomarker of exposure to 7-HC, since 7-HCO was quantifiable in only a minority of urine samples collected from the general population. Quantification of 7-HCA was conducted by means of a newly developed UPLC-MS/MS (ultra-high pressure liquid chromatography combined with tandem mass spectrometry) method. Peak excretion of 7-HCA occurred between 3 and 5h after oral application and about 10h after dermal administration. Due to the limited skin absorption of 7 HC, 7-HCA concentrations after dermal application were much lower than levels after oral application. After 24h, about 9% and 50% of the dermally and orally applied dose, respectively, were excreted as 7- HCA. With the conversion factors derived from the controlled human study, we estimated median exposure doses in a group of 40 human volunteers from the general population of approximately 93MUg 7 HC per day. In conclusion, the 7-HC metabolite 7-HCA in urine is a suitable biomarker of exposure and can be applied for biomonitoring of the general population. PMID- 29108681 TI - Legionella contamination in warm water systems: A species-level survey. AB - Legionellae constitute a frequent contamination of warm water systems and can lead to serious infections. Therefore, in many countries it is mandatory to monitor warm water systems for their presence. The method of examination in Germany is regulated by guideline ISO 11731 and DIN EN ISO 11731-2, and the results are reported as concentration of Legionella spp. Only limited information is available on the presence of individual species of Legionellae in the examined systems, since most investigations and research focus solely on Legionella pneumophila as the most important human pathogen. In this study 76,220 samples obtained from 13,397 warm water systems originating from 24 different zip code districts covering an area of more than 71,000km2 in southern Germany were examined. This resulted in the identification of 47,924 Legionella isolates to the species level using a MALDI-TOF mass spectrometry-based method. Legionella species distribution was analyzed with respect to warm water system type, geographic region (defined as zip code district) and temperature during sample taking. Overall, 20.7% of the samples were found positive for Legionella species and 14 different species of Legionella were recovered. These were not equally present throughout the geographic area investigated, but instead an individual regional diversity of Legionella species was observed for the examined zip code districts. Although Legionella pneumophila represented 84% of all contaminations found, depending on the geographical region its proportion varied substantially between 57.5% and 91.2%. The occurrence of other species was also of importance since they accounted for up to 42% of contaminations regionally, with Legionella londiniensis being most prominent representing up to 38.8% of recovered colonies. In addition, the influence of temperature on the individual species was disparate, but the temperature range between 50 degrees C and 59 degrees C was identified as the optimal condition for facilitating emergence of the majority of recovered Legionella species. The identification of Legionella to the species level by MALDI-TOF allowed for a more concise depiction of the regional distribution and the ecology of this genus, and may be of additional value when counter measures need to be initiated. PMID- 29108682 TI - Postchemotherapy lymph node dissection for isolated retroperitoneal nodal recurrences for penile cancer: Is cure possible in highly selected cases? AB - Outcomes for advanced penile carcinoma remain poor with limited options for curative treatment. Nodal recurrences represent worse prognosis and are typically treated with a combination of radiation, chemotherapy, or consolidative resection. Although the ideal management for recurrences remains unknown, there is some evidence supporting the role of chemotherapy followed by consolidative resection. Using a multimodal strategy, we describe the curative potential of postchemotherapy retroperitoneal lymph node dissection for penile cancer patients with isolated locoregional recurrences in the retroperitoneum. PMID- 29108683 TI - Arduino control of a pulsatile flow rig. AB - This note describes the design and testing of a programmable pulsatile flow pump using an Arduino micro-controller. The goal of this work is to build a compact and affordable system that can relatively easily be programmed to generate physiological waveforms. The system described here was designed to be used in an in-vitro set-up for vascular access hemodynamics research, and hence incorporates a gear pump that delivers a mean flow of 900 ml/min in a test flow loop, and a peak flow of 1106 ml/min. After a number of simple identification experiments to assess the dynamic behaviour of the system, a feed-forward control routine was implemented. The resulting system was shown to be able to produce the targeted representative waveform with less than 3.6% error. Finally, we outline how to further increase the accuracy of the system, and how to adapt it to specific user needs. PMID- 29108684 TI - Study of main and cross-over effects on pressure relief among body mass index (BMI), body position and supporting material properties. AB - Pressure ulcers influence people with limited mobility who must spend a long time lying or sitting because these positions create high interfacial pressure between the body and supporting materials. Supporting materials, such as mattresses and cushions, are designed to prevent pressure ulcers by increasing the contact area, reducing the interfacial pressure or reducing the contact time. Foam is the most common supporting material for relieving pressure because it is cheap and easy to change its shape to fit the contour of the body. Past studies showed that BMI, body position and supporting material properties have an impact on relieving pressure; however, there is no study of the main and cross-over effects among these parameters. This study aims to investigate the main and cross-over effects among BMI, body position and supporting material properties on pressure relieving performance using univariate ANOVA and correlation analysis. It was found that body position and foam density were the main effect and BMI and body position, and body position and foam density were the cross-over effects on pressure relief. It was also found that low density Polyurethane (PU) foam of less than 4 cm in thickness as well as the appropriate K2 and K3 moduli are best suited for pressure relief. The actual value of foam thickness and the appropriate K2 and K3 moduli are subject to BMI values and body position. The significance of the outcomes from this study is that it will aid in optimizing the design of supporting materials with varied BMI values and body positions to greatly reduce pressure ulcers for ailing patients. PMID- 29108685 TI - Synovial Sarcoma of the Digits: A Case Report of an Unplanned Excision. AB - Synovial sarcoma is a rare occurrence in the lower extremity, although the presenting symptoms can mimic those of other more common and benign musculoskeletal pathologies. We present the case of a patient who was originally thought to have a Morton's neuroma or ganglionic cyst. The correct diagnosis, synovial sarcoma, was determined only after an unplanned excision. Despite the patient presenting with symptoms similar to those of a compressive neuropathy, a high index of suspicion should be present when a patient presents with any soft tissue mass, especially if it has an unusual clinical appearance to avoid an unplanned excision. PMID- 29108686 TI - Effect of Extracorporeal Shockwave Therapy on Passive Ankle Stiffness in Patients With Plantar Fasciopathy. AB - Plantar fasciopathy (PF) is the most common cause of heel pain. Extracorporeal shockwave therapy (ESWT) improves the gait pattern in patients with PF. However, the effects of ESWT on the biomechanics of the ankle in these patients remains unclear. Sixteen participants were included in the present study. Of the 16 participants, 8 patients with PF were assigned to receive extracorporeal shockwave therapy, and 8 healthy participants served as an external control group. ESWT was applied to the PF group for 1500 pulses at an energy flux of 0.26 mJ/mm2 every 3 weeks for 3 sessions. The biomechanics of the ankle joints were then assessed using an isokinetic dynamometer, and a health-related quality of life questionnaire was administered at baseline and at the final follow-up session 12 weeks after the initial treatment. Passive stiffness was calculated and compared between the foot affected with PF, the opposite foot, and both feet of those in the healthy control group. The Kruskal-Wallis 1-way analysis of variance with repeated measures was performed, and statistical significance was considered present at the 5% (p <= .05) level. Ankle dorsiflexion in the affected limb increased from 14 degrees +/- 3 degrees to 17 degrees +/- 2 degrees after ESWT (p < .05). No statistically significant differences were noted in the strength of dorsiflexion or plantarflexion at baseline and after ESWT. However, a statistically significant increase in the ratio of strength in ankle dorsiflexion versus plantarflexion was found after ESWT (p < .05). No differences in the passive stiffness of the ankle joint were demonstrated. Patients reported an improved physical function score after ESWT (p < .05). An increased dorsiflexion/plantarflexion torque ratio and maximal dorsiflexion associated with decreased pain might contribute to the improved physical function after ESWT for PF. PMID- 29108688 TI - Using additive and coupled spatiotemporal SPDE models: a flexible illustration for predicting occurrence of Culicoides species. AB - This paper formulates and compares a general class of spatiotemporal models for univariate space-time geostatistical data. The implementation of stochastic partial differential equation (SPDE) approach combined with integrated nested Laplace approximation into the R-INLA package makes it computationally feasible to use spatiotemporal models. However, the impact of specifying models with and without space-time interaction is unclear. We formulate an extensive class of additive and coupled spatiotemporal SPDE models and investigate the distinction between them by (1) Extending their temporal effect, allowing a random walk process in time, (2) varying the spatial correlation function and (3) running a simulation study to assess the effect of misspecifying the spatial and temporal models, and to assess the generalizability of our results to a higher number of locations. Our methods are illustrated with Culicoides data from Belgium. The Bayesian spatial predictions showed that the highest prevalence of Culicoides species was found in the Northeastern and central parts of Belgium during summer. PMID- 29108689 TI - Spatial variation in risk for physician diagnosed environmental sensitivity. AB - Multiple chemical sensitivity (MCS) is a chronic condition characterized by recurring and severe symptoms triggered by exposures to low levels of toxicants or anthropogenic pollution. This study investigated the spatial structure of MCS incidence and estimated the contribution of socio-economic deprivation to variations in rates of MCS at the community level in Nova Scotia, Canada. Patient data were used to calculate cumulative incidence rate ratios for treated multiple chemical sensitivities. Poisson regression with a spatially autoregressive random effect was employed to assess spatial variation in MCS. Odds of MSC incidence are greatest among patients from the highest socioeconomic category using the most socioeconomically deprived category as reference (OR: 1.94, CI [2.5-95%] 1.45 2.56). No discernable spatial pattern for MCS risk was evident after controlling for known risk factors. This is the first study to investigate spatial variations in cumulative incidence of multiple chemical sensitivities. The socioeconomic status of the community in which patients live has a significant influence on the geographic patterns of MCS. Future research will include a smartphone application to assess positional and temporal information on environmental exposures to further explain MCS prevalence. PMID- 29108687 TI - Spatial analysis of food insecurity and obesity by area-level deprivation in children in early years settings in England. AB - BACKGROUND: we assessed manager perceptions of food security and obesity in young children attending nurseries across England, assessing spatial differences by area-level deprivation. METHODS: we conducted an adjusted multinomial logistic regression and an adjusted geographically weighted logistic regression examining the odds of a manager perceiving obesity, food insecurity, or both as a problem among children in care measured via a mailed survey. RESULTS: 851 (54.3%) managers returned the survey. A nursery being in the highest tertile of area level deprivation was associated with a 1.89 (95% CI 1.00, 3.57) greater odds of perceiving obesity as a problem, a 3.06 (95% CI 1.94, 4.84) greater odds of perceiving food insecurity as a problem, and a 8.39 (95% CI 4.36, 16.15) greater odds of perceiving both as a problem, compared with the lowest tertile. CONCLUSIONS: we observed differences in manager perception by area-level deprivation, but the relationship was especially pronounced for food insecurity. PMID- 29108690 TI - SpatialEpiApp: A Shiny web application for the analysis of spatial and spatio temporal disease data. AB - During last years, public health surveillance has been facilitated by the existence of several packages implementing statistical methods for the analysis of spatial and spatio-temporal disease data. However, these methods are still inaccesible for many researchers lacking the adequate programming skills to effectively use the required software. In this paper we present SpatialEpiApp, a Shiny web application that integrate two of the most common approaches in health surveillance: disease mapping and detection of clusters. SpatialEpiApp is easy to use and does not require any programming knowledge. Given information about the cases, population and optionally covariates for each of the areas and dates of study, the application allows to fit Bayesian models to obtain disease risk estimates and their uncertainty by using R-INLA, and to detect disease clusters by using SaTScan. The application allows user interaction and the creation of interactive data visualizations and reports showing the analyses performed. PMID- 29108691 TI - Spatial variation in cancer incidence and survival over time across Queensland, Australia. AB - Interpreting changes over time in small-area variation in cancer survival, in light of changes in cancer incidence, aids understanding progress in cancer control, yet few space-time analyses have considered both measures. Bayesian space-time hierarchical models were applied to Queensland Cancer Registry data to examine geographical changes in cancer incidence and relative survival over time for the five most common cancers (colorectal, melanoma, lung, breast, prostate) diagnosed during 1997-2004 and 2005-2012 across 516 Queensland residential small areas. Large variation in both cancer incidence and survival was observed. Survival improvements were fairly consistent across the state, although small for lung cancer. Incidence changes varied by location and cancer type, ranging from lung and colorectal cancers remaining relatively constant over time, to prostate cancer dramatically increasing across the entire state. Reducing disparities in cancer-related outcomes remains a health priority, and space-time modelling of different measures provides an important mechanism by which to monitor progress. PMID- 29108692 TI - A novel nonsense mutation in a patient with Hermansky-Pudlak syndrome type 4. PMID- 29108693 TI - Implementation of the MEDFRAT to Promote Quality Care and Decrease Falls in Community Hospital Emergency Rooms. AB - ABSTRACTPURPOSE: To identify and implement an evidence-based fall-risk assessment tool for use in emergency departments at Essentia Health, a large, primarily rural health care delivery system with 12 emergency departments. METHODS: The Iowa Model of Evidence-Based Practice to Promote Quality Care was used to guide the process. The Memorial Emergency Department Fall-Risk Assessment Tool (MEDFRAT) was programmed into the electronic medical record, along with interventions that could be selected for 2 fall-risk levels. An education session was developed for emergency nurses about falls and MEDFRAT, with planned time for discussion about any concerns in the implementation of MEDFRAT. MEDFRAT was selected for implementation by nursing leadership because it is evidence based and appeared to be conducive to implementation in the diverse emergency departments across 12 sites in 3 states. RESULTS: Education sessions were presented to nurses at 11 of 12 emergency departments. Suggestions to support site-specific implementation were programmed into the electronic health record. Nurses expressed appreciation that they were consulted, and their feedback was incorporated into the tool before it was implemented. Resources needed at each site to implement recommended MEDFRAT interventions in the tool were identified. Needed resources were then provided to the emergency departments before implementation of MEDFRAT. CONCLUSIONS: The Iowa Model was a useful framework to select an evidence-based tool and then engage nurses in the process of implementing evidence-based practice changes in emergency departments across a diverse health care system serving a largely rural population. Ongoing follow-up will determine if this process results in fewer falls. PMID- 29108694 TI - Outdoor air 1,3-butadiene monitoring near a petrochemical industry (Tarragona region) and in several Catalan urban areas using active multi-sorbent bed tubes and analysis through TD-GC/MS. AB - 1,3-Butadiene is a carcinogenic compound that can be emitted to the atmosphere from several sources, such as the combustion of organic matter or traffic. However, petrochemical industry is one of the main origins of this compound. Several campaigns (2013-2017) were conducted in twelve Catalan urban areas to determine 1,3-butadiene concentrations in outdoor air, five of which were close to Tarragona petrochemical region. 1,3-Butadiene was dynamically sampled in multi sorbent bed tubes (Carbotrap, Carbopack X and Carboxen 569) using portable pump equipment. The analysis was performed by automatic thermal desorption coupled with capillary gas chromatography/mass spectrometry detector. El Morell, Perafort and Puigdelfi, located near petrochemical facilities, were the most impacted locations, with average concentrations up to 15+/-33, 33+/-41 and 27+/-39MUgm-3, respectively. Maximum 24h concentrations of 125MUgm-3 were observed in Puigdelfi. However, 1,3-butadiene average and maximum concentrations in the Tarragona petrochemical region diminished significantly (p<=0.05) in a drastic way (40-80%) since the first monitoring program in 2013. On the other hand, average concentrations in the rest of studied Catalan urban areas generally presented average values below 1MUgm-3, ranging from 0.07-1.1MUgm-3. Spain does have neither a monitoring strategy nor standard regulations related to 1,3-butadiene. Taking into account that relevant values can be found in locations near petrochemical facilities, a regulation should be implemented as soon as possible, at least in this specific areas. PMID- 29108695 TI - Stormwater solids removal characteristics of a catch basin insert using geotextile. AB - Suspended solids in urban runoff have multiple adverse environmental impacts and create a wide range of water quality problems in receiving water bodies. Geotextile filtration systems inserted within catch basins have the potential to mitigate these effects, through flow attenuation and pollutant removal. This study modelled a catch basin in a column and assessed the hydraulic and solids removal characteristics of a new type of non-woven geotextile (NWG1) in the capture of solids from stormwater runoff. The new geotextile was compared with two others readily available on the market (NWG2, NWG3). Synthetic stormwater containing TSS (200mg/L) was used with two particle size distributions of 0 180MUm (P1; D50:106MUm) and 0-300MUm (P2; D50:150MUm). The results revealed that the desired stormwater TSS concentration (<30mg/L; ANZECC, 2000) could be achieved with a short ripening process (e.g., 1-2kg/m2 of suspended solids loading) for trials using the larger particle size distribution (P2). In addition, 36% more suspended solids were captured in trials using the soil with the larger range of particle sizes (P2) than for the soil with smaller particle sizes (P1). Geotextile fibre pattern appeared to have a significant influence on the TSS removal capacity. The NWG1 has higher permittivity than NWG3 but similar to NWG2. NWG1 could capture overall more TSS (which also resulted in earlier clogging) than NWG2 and NWG3 because of the special fibre structure of NWG1. The experimental data shows that these geotextiles may start to clog when the hydraulic conductivity reaches below 1.36*10-5m/s. The overall hydraulic performances of geotextiles showed that the NWG1 has better potential for use in CBIs because of its higher strength and multiple reuse capability. PMID- 29108696 TI - Metagenomics for the study of viruses in urban sewage as a tool for public health surveillance. AB - The application of next-generation sequencing (NGS) techniques for the identification of viruses present in urban sewage has not been fully explored. This is partially due to a lack of reliable and sensitive protocols for studying viral diversity and to the highly complex analysis required for NGS data processing. One important step towards this goal is finding methods that can efficiently concentrate viruses from sewage samples. Here the application of a virus concentration method based on skimmed milk organic flocculation (SMF) using 10L of sewage collected in different seasons enabled the detection of many viruses. However, some viruses, such as human adenoviruses, could not always be detected using metagenomics, even when quantitative PCR (qPCR) assessments were positive. A targeted metagenomic assay for adenoviruses was conducted and 59.41% of the obtained reads were assigned to murine adenoviruses. However, up to 20 different human adenoviruses (HAdV) were detected by this targeted assay being the most abundant HAdV-41 (29.24%) and HAdV-51 (1.63%). To improve metagenomics' sensitivity, two different protocols for virus concentration were comparatively analysed: an ultracentrifugation protocol and a lower-volume SMF protocol. The sewage virome contained 41 viral families, including pathogenic viral species from families Caliciviridae, Adenoviridae, Astroviridae, Picornaviridae, Polyomaviridae, Papillomaviridae and Hepeviridae. The contribution of urine to sewage metavirome seems to be restricted to a few specific DNA viral families, including the polyomavirus and papillomavirus species. In experimental infections with sewage in a rhesus macaque model, infective human hepatitis E and JC polyomavirus were identified. Urban raw sewage consists of the excreta of thousands of inhabitants; therefore, it is a representative sample for epidemiological surveillance purposes. The knowledge of the metavirome is of significance to public health, highlighting the presence of viral strains that are circulating within a population while acting as a complex matrix for viral discovery. PMID- 29108697 TI - Editorial: The phantom menace: implications of polyclonality for surgical treatment of primary hyperparathyroidism. PMID- 29108698 TI - Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure. AB - BACKGROUND: Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism. METHODS: We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism. RESULTS: Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 +/- 394 vs 136 +/- 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P < .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P < .001). CONCLUSION: GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2 associated familial isolated hyperparathyroidism. PMID- 29108700 TI - Discussion. PMID- 29108699 TI - Skeletal effects of failed parathyroidectomy. AB - BACKGROUND: Parathyroidectomy improves bone mineral density and decreases risk for fracture in patients with primary hyperparathyroidism. The aim of this study was to determine skeletal consequences of failed parathyroidectomy. METHODS: A retrospective, cohort study of patients with biochemically confirmed primary hyperparathyroidism within a vertically integrated health system was performed (1995-2014). Failed parathyroidectomy was defined by hypercalcemia within 6 months of initial parathyroidectomy. Time-varying Cox regression was used to estimate the risk for any fracture and hip fracture in 3 comparison groups: observation, successful parathyroidectomy, and failed parathyroidectomy. Bone mineral density changes also were compared. RESULTS: The cohort included 7,169 patients, of whom 5,802 (81%) were observed, 1,228 underwent successful parathyroidectomy (17%), and 137 underwent failed parathyroidectomy (2%). The adjusted risk for any fracture (hazard ratio, 1.28; 95% confidence interval, 0.85 1.92) and hip fracture (hazard ratio, 1.63; 95% CI, 0.77-3.45) associated with failed parathyroidectomy was similar to that associated with observation. Successful parathyroidectomy was associated with a decrease in any fracture (hazard ratio, 0.68; 95% confidence interval, 0.57-0.82) and hip fracture (hazard ratio, 0.43; 95% confidence interval, 0.27-0.68) compared with observation. Bone mineral density changes in the failed parathyroidectomy group paralleled those associated with observation. CONCLUSION: Failed parathyroidectomy is associated with a high risk for fracture similar to that seen with observation. PMID- 29108702 TI - Editorial: The use of potassium iodide in Graves' disease. PMID- 29108701 TI - Impact of potassium iodide on thyroidectomy for Graves' disease: Implications for safety and operative difficulty. AB - BACKGROUND: Potassium iodide often is prescribed prior to thyroidectomy for Graves' disease, but the effect of potassium iodide on the ease and safety of thyroidectomy for Graves' is largely unknown. METHODS: We conducted a prospective, cohort study of patients with Graves' disease undergoing thyroidectomy. For the first 8 months, no patients received potassium iodide; for the next 8 months, potassium iodide was added to the preoperative protocol for all patients. Outcomes included operative difficulty (based on the Thyroidectomy Difficulty Scale) and complications. RESULTS: We included a total of 31 patients in the no potassium iodide group and 28 in the potassium iodide group. According to the Thyroidectomy Difficulty Scale, gland vascularity decreased in the potassium iodide group (mean score 2.6 vs 3.3, P = .04), but there were no differences in friability, fibrosis, or size of the thyroid or in overall difficulty of operation (P = not significant for all). Despite similar operative difficulty, patients prescribed potassium iodide were less likely to experience transient hypoparathyroidism (7% vs 26%, P = .018) and transient hoarseness (0% vs 16%, P = .009) compared with the no potassium iodide group. CONCLUSION: Potassium iodide administration decreases gland vascularity, but does not change the overall difficulty of thyroidectomy. Preoperative use of potassium iodide solution was, however, associated with less transient hypoparathyroidism and transient hoarseness, suggesting that potassium iodide improves the safety of thyroidectomy for Graves' disease. PMID- 29108703 TI - Editorial: Implications of implementing NIFTP terminology in the management of patients with thyroid tumors. PMID- 29108704 TI - Editorial: "Skeletal effects of failed parathyroidectomy". PMID- 29108705 TI - Metabolic syndrome is associated with increased postoperative complications and use of hospital resources in patients undergoing laparoscopic adrenalectomy. AB - BACKGROUND: Rates of obesity and metabolic syndrome continue to rise worldwide; however, the impact of metabolic syndrome on outcomes following adrenalectomy has not been described. In this study, we sought to investigate the effects of metabolic syndrome on postoperative 30-day morbidity, mortality, and utilization of hospital resources in a large cohort of patients undergoing elective laparoscopic adrenalectomy. METHODS: Patients who underwent laparoscopic adrenalectomy from 2005 to 2014 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Patients with body mass index >=30 kg/m2 who also had diabetes and hypertension requiring medications were defined as having metabolic syndrome. Univariate and multivariable analyses were performed for the outcomes of 30-day mortality/morbidity, major complications, and utilization of hospital resources (prolonged duration of stay >=3 days and requirement for perioperative blood transfusion). RESULTS: Of the 3,502 patients included in the study, 395 had metabolic syndrome (11.3%). Patients with metabolic syndrome were older (P < .001) and had a greater percentage of preoperative comorbidities (P < .05) than patients without metabolic syndrome. On unadjusted analysis, metabolic syndrome was associated with an increased risk for mortality/morbidity, major complications, duration of stay, operative time, and risk for blood transfusion (all P < .001). On multivariable analysis, metabolic syndrome was an independent predictor of overall mortality/morbidity (odds ratio, 1.86; P < .001), major complications (odds ratio, 1.99; P < .001), pulmonary complications (odds ratio, 1.83; P = .049), the need for blood transfusion (odds ratio, 1.94; P = .04), and prolonged length of stay (odds ratio odds ratio, 1.34; P = .02). CONCLUSION: The presence of metabolic syndrome increased the risk for postoperative complications after laparoscopic adrenalectomy and was associated with 2-fold risk for blood transfusion and 34% increased odds of a prolonged hospital stay. PMID- 29108706 TI - Discussion. PMID- 29108707 TI - Discussion. PMID- 29108708 TI - Discussion. PMID- 29108709 TI - Update on Actinomucor elegans, a mucormycete infrequently detected in human specimens: how combined microbiological tools contribute efficiently to a more accurate medical care. AB - Actinomucor elegans is a fungus belonging to mucormycetes and is still probably underdiagnosed due to misidentification. Based on a recent first case of Actinomucor elegans sinusitis in Europe, in an immunocompromised patient under voriconazole treatment, this paper aims to summarize knowledge about A. elegans mucormycoses. Even if the diagnosis of mucormycosis was made using traditional mycology techniques, precise identification of the fungus could only be achieved using molecular tools. In this observation, the galactomannan dosage was positive until the introduction of treatment and surgical debridement. The patient experienced no relapse after one year. By reviewing the four previous A. elegans reported cases and describing the mycological characteristics of this species, we highlight the need to use a combination of tools to improve the diagnostic strategy in such rare and life-threatening clinical situations. PMID- 29108710 TI - Secreted phospholipases of the lung pathogen Legionella pneumophila. AB - Legionella pneumophila is an intracellular pathogen and the main causative agent of Legionnaires' disease, a potentially fatal pneumonia. The bacteria infect both mammalian cells and environmental hosts, such as amoeba. Inside host cells, the bacteria withstand the multifaceted defenses of the phagocyte and replicate within a unique membrane-bound compartment, the Legionella-containing vacuole (LCV). For establishment and maintenance of the infection, L. pneumophila secretes many proteins including effector proteins by means of different secretion systems and outer membrane vesicles. Among these are a large variety of lipolytic enzymes which possess phospholipase/lysophospholipase and/or glycerophospholipid:cholesterol acyltransferase activities. Secreted lipolytic activities may contribute to bacterial virulence, for example via modification of eukaryotic membranes, such as the LCV. In this review, we describe the secretion systems of L. pneumophila, introduce the classification of phospholipases, and summarize the state of the art on secreted L. pneumophila phospholipases. We especially highlight those enzymes secreted via the type II secretion system Lsp, via the type IVB secretion system Dot/Icm, via outer membrane vesicles, and such where the mode of secretion has not yet been defined. We also give an overview on the complexity of their activities, activation mechanisms, localization, growth phase dependent abundance, and their role in infection. PMID- 29108711 TI - Pseudotumoral cerebellitis with acute hydrocephalus as a manifestation of EBV infection. PMID- 29108712 TI - Cognitive functioning in dyskinetic cerebral palsy: Its relation to motor function, communication and epilepsy. AB - BACKGROUND: Cerebral palsy (CP) is a disorder of motor function often accompanied by cognitive impairment. There is a paucity of research focused on cognition in dyskinetic CP and on the potential effect of related factors. AIM: To describe the cognitive profile in dyskinetic CP and to assess its relationship with motor function and associated impairments. METHOD: Fifty-two subjects with dyskinetic CP (28 males, mean age 24 y 10 mo, SD 13 y) and 52 typically-developing controls (age- and gender-matched) completed a comprehensive neuropsychological assessment. Gross Motor Function Classification System (GMFCS), Communication Function Classification System (CFCS) and epilepsy were recorded. Cognitive performance was compared between control and CP groups, also according different levels of GMFCS. The relationship between cognition, CFCS and epilepsy was examined through partial correlation coefficients, controlling for GMFCS. RESULTS: Dyskinetic CP participants performed worse than controls on all cognitive functions except for verbal memory. Milder cases (GMFCS I) only showed impairment in attention, visuoperception and visual memory. Participants with GMFCS II-III also showed impairment in language-related functions. Severe cases (GMFCS IV-V) showed impairment in intelligence and all specific cognitive functions but verbal memory. CFCS was associated with performance in receptive language functions. Epilepsy was related to performance in intelligence, visuospatial abilities, visual memory, grammar comprehension and learning. CONCLUSION: Cognitive performance in dyskinetic CP varies with the different levels of motor impairment, with more cognitive functions impaired as motor severity increases. This study also demonstrates the relationship between communication and epilepsy and cognitive functioning, even controlling for the effect of motor severity. PMID- 29108714 TI - Not "Z" end of the story: Do Z scores help to guide surgical decisions about the ascending aorta in patients with bicuspid aortic valve? PMID- 29108713 TI - Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. AB - BACKGROUND: Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. METHODS: A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models. RESULTS: Sixteen studies (n=8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3-4 AEs: OR 2.86 (95% CI 2.49-3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39-2.53) for mTOR inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09-5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3-4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52-85.19), stomatitis grade 3-4 for mTOR inhibitors (OR 11.92; 95% CI 3.68-38.57), hyperglycemia grade 3-4 for PI3K inhibitors (OR 40.93; 95% CI 10.08-166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71-20.95). CONCLUSIONS: Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used. PMID- 29108715 TI - The role of reoperative thoracoabdominal surgery in the current era. PMID- 29108716 TI - Eight and counting. PMID- 29108717 TI - Robotic heart surgery: Hype or hope? PMID- 29108718 TI - A new animal model for hyperthermic intraperitoneal chemotherapy (HIPEC) in tumor bearing mice in the treatment of peritoneal carcinomatosis of ovarian origin. AB - AIM OF THE STUDY: We set out to develop and evaluate the morbidity of a non invasive hyperthermic intraperitoneal chemotherapy (HIPEC) procedure in mice. HIPEC has been shown to improve overall survival in treating ovarian cancer with peritoneal carcinomatosis. However, related complications, toxicity and the lack of randomized trials limits its widespread use. To improve the surgical technique, there is a need for animal models that allow teams to work on large groups without burdensome logistics. MATERIALS AND METHODS: To develop the model, we first determined optimal HIPEC conditions in 20 Black Six mice without carcinomatosis. To evaluate HIPEC morbidity, peritoneal carcinomatosis cells of ovarian origin were injected into the peritoneum of 10 pathogen-free Nude mice. The mice underwent HIPEC 21 days later under general anesthesia. An inflow catheter was introduced into the left hypochondria and an outflow catheter was introduced into the left iliac fossa. Bath infusion was oxaliplatin (920mg/m2) at 43 degrees C for 12minutes. The mice were monitored and sacrificed two weeks after the procedure. RESULTS: No deaths were observed during the procedure and infusion was well tolerated throughout the HIPEC. One mouse died the day after the procedure. No major dehydration, hemoperitoneum or evisceration was observed. CONCLUSION: This mouse model of closed abdomen HIPEC has limited morbidity and could be a useful model to study HIPEC regimens and its effects on peritoneal carcinomatosis. PMID- 29108719 TI - Meta-analyses in surgery: Always useful? PMID- 29108720 TI - Main information requests of family members of patients in Intensive Care Units. AB - OBJECTIVE: To compile an inventory of information requests prioritized by the family members, to find out which professionals them consider able to respond these requests, and to explore the differences in perception between family members and professionals. DESIGN: Qualitative analysis of content validation and descriptive cross-sectional study. SCOPE: 41 Spanish ICU. PARTICIPANTS: Relatives, physicians and nurses of critical patients. INTERVENTION: From an initial list of questions extracted from literature review, physicians, nurses, and relatives of critical patients incorporated issues that they considered not included. After analyzing content validity, a new list was obtained, which was again submitted to the participants' assessment to evaluate the level of importance that they assigned to each question and which professional they considered appropriate to answer it. RESULTS: most important questions for the relatives: concern about the clinical situation, measures to be taken, prognosis and information. There was a coincidence between relatives and professionals in the priority issues for families. There were significant differences in the importance given to each question: between doctors and relatives (72/82 questions), and between nurses and relatives (66/82 questions) (P<.05). For the relatives, 63% of the questions could be answered by doctors or nurses, 27% preferably by doctors and 10% by nurses. CONCLUSIONS: The most relevant issues for families were prognosis and severity, but also the need for information. Healthcare professionals tend to underestimate the importance of many of the questions that concern families. Relatives feel that most of their concerns can be resolved either by doctors or nurses. PMID- 29108722 TI - Surgery versus endoscopy for patients with infected pancreatic necrosis. PMID- 29108721 TI - Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial. AB - BACKGROUND: Infected necrotising pancreatitis is a potentially lethal disease and an indication for invasive intervention. The surgical step-up approach is the standard treatment. A promising alternative is the endoscopic step-up approach. We compared both approaches to see whether the endoscopic step-up approach was superior to the surgical step-up approach in terms of clinical and economic outcomes. METHODS: In this multicentre, randomised, superiority trial, we recruited adult patients with infected necrotising pancreatitis and an indication for invasive intervention from 19 hospitals in the Netherlands. Patients were randomly assigned to either the endoscopic or the surgical step-up approach. The endoscopic approach consisted of endoscopic ultrasound-guided transluminal drainage followed, if necessary, by endoscopic necrosectomy. The surgical approach consisted of percutaneous catheter drainage followed, if necessary, by video-assisted retroperitoneal debridement. The primary endpoint was a composite of major complications or death during 6-month follow-up. Analyses were by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN09186711. FINDINGS: Between Sept 20, 2011, and Jan 29, 2015, we screened 418 patients with pancreatic or extrapancreatic necrosis, of which 98 patients were enrolled and randomly assigned to the endoscopic step-up approach (n=51) or the surgical step-up approach (n=47). The primary endpoint occurred in 22 (43%) of 51 patients in the endoscopy group and in 21 (45%) of 47 patients in the surgery group (risk ratio [RR] 0.97, 95% CI 0.62-1.51; p=0.88). Mortality did not differ between groups (nine [18%] patients in the endoscopy group vs six [13%] patients in the surgery group; RR 1.38, 95% CI 0.53-3.59, p=0.50), nor did any of the major complications included in the primary endpoint. INTERPRETATION: In patients with infected necrotising pancreatitis, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing major complications or death. The rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group. The outcome of this trial will probably result in a shift to the endoscopic step-up approach as treatment preference. FUNDING: The Dutch Digestive Disease Foundation, Fonds NutsOhra, and the Netherlands Organization for Health Research and Development. PMID- 29108724 TI - [Levothyrox(r): The teachings of a senseless polemic]. PMID- 29108725 TI - Aplastic anemia in two consecutive pregnancies: obstetric and anesthetic management. AB - Aplastic anemia is a serious condition occasionally coexisting with pregnancy. This pathological process is associated with significant maternal and neonatal morbidity and mortality. Obstetric and anesthetic management are particularly challenging, and treatment requires knowledge of pathophysiologic mechanisms in order to provide safe care to this group of patients. We describe the successful obstetric management and labor analgesia of a patient with a diagnosis of aplastic anemia in two consecutive pregnancies. PMID- 29108726 TI - Distribution and migration of 239+240Pu in abiotic components of the Black Sea ecosystems during the post-Chernobyl period. AB - Distribution of 239,240Pu in abiotic components (water and bottom sediment) of the Black Sea ecosystems was studied during the post-Chernobyl period at different offshore and near-shore locations. The trends of these radionuclides accumulation by sediments were analyzed. The spatial-temporal changes in the 239,240Pu distribution as well as effective half-life for these radionuclides in the Black Sea surface water in deep-sea area are presented. The estimations of the average annual removal fluxes of the 239,240Pu into the bottom sediments were obtained. The Black Sea sediments were characterized by a higher 239,240Pu concentration factor (Cf ~ n.104-n.106) and radiocapacity factor (F(239,240Pu) was about 99.9% on the shelf, 94.5-99.1% on deep-sea basin for silty and 94.6 98.9% on the shelf for sandy bottom sediments) as compared with Cf and F for 137Cs and 90Sr. Silty bottom sediments play the role of 239,240Pu main depot in the Black Sea ecosystem. The studied radioecological characteristics of Pu allowed us to define the type of plutonium biogeochemical behavior in the Black Sea as a pedotropic one. The results of this complex radioecological monitoring of 239+240Pu contamination in the Black Sea and their analysis makes it possible to understand the plutonium redistribution pathways which will enable to carry out the tracing of its migration within the ecosystems. PMID- 29108723 TI - Cardiovascular, respiratory, and related disorders: key messages from Disease Control Priorities, 3rd edition. AB - Cardiovascular, respiratory, and related disorders (CVRDs) are the leading causes of adult death worldwide, and substantial inequalities in care of patients with CVRDs exist between countries of high income and countries of low and middle income. Based on current trends, the UN Sustainable Development Goal to reduce premature mortality due to CVRDs by a third by 2030 will be challenging for many countries of low and middle income. We did systematic literature reviews of effectiveness and cost-effectiveness to identify priority interventions. We summarise the key findings and present a costed essential package of interventions to reduce risk of and manage CVRDs. On a population level, we recommend tobacco taxation, bans on trans fats, and compulsory reduction of salt in manufactured food products. We suggest primary health services be strengthened through the establishment of locally endorsed guidelines and ensured availability of essential medications. The policy interventions and health service delivery package we suggest could serve as the cornerstone for the management of CVRDs, and afford substantial financial risk protection for vulnerable households. We estimate that full implementation of the essential package would cost an additional US$21 per person in the average low-income country and $24 in the average lower-middle-income country. The essential package we describe could be a starting place for low-income and middle-income countries developing universal health coverage packages. Interventions could be rolled out as disease burden demands and budgets allow. Our outlined interventions provide a pathway for countries attempting to convert the UN Sustainable Development Goal commitments into tangible action. PMID- 29108727 TI - Reproducibility of serum oxysterols and lanosterol among postmenopausal women: Results from EPIC-Heidelberg. AB - BACKGROUND: Circulating oxysterols have been proposed as biological markers of disease risk. However, within-person reproducibility of circulating oxysterols over time is not well established. METHODS: We evaluated the one-year reproducibility of 11 oxysterols and lanosterol among 30 postmenopausal women with repeat blood samples in the European Prospective Investigation into Cancer and Nutrition (EPIC) - Heidelberg, Germany cohort. Liquid chromatography-mass spectrometry (LC/MS) was performed to quantify serum concentrations of 22R hydroxycholesterol, 25-hydroxycholesterol, 24S-hydroxycholesterol, 27 hydroxycholesterol, 22S-hydroxycholeterol, 24,25-epoxycholesterol, 5alpha,6beta dihydroxycholestanol, 7alpha-hydroxycholesterol, 5beta,6beta-epoxycholesterol, 5alpha,6alpha-epoxycholesterol, 24-dihydrolanosterol, and lanosterol. We evaluated Spearman correlations and intraclass correlation coefficients (ICCs) between quantifiable concentrations measured in repeat samples taken one-year apart to estimate within-person reproducibility. RESULTS: Spearman correlations (ICCs) over one year ranged from 0 (ICC=0.10) for 5beta,6beta-epoxycholesterol and 0.10 (ICC=0.20) for 5alpha,6alpha-epoxycholesterol, representing low within person stability, to 0.81 (ICC=0.75) for 27-hydroxycholesterol and 0.86 (ICC=0.91) for 24S-hydroxycholesterol, representing relatively high within-person stability. Correlations between oxysterols and lanosterol ranged from 0.01 between 24S-hydroxycholesterol and lanosterol to 0.70 between 5alpha,6alpha epoxycholesterol and 5beta,6beta-epoxycholesterol. CONCLUSIONS: Our results demonstrate that for 27-hydroxycholesterol, 24S-hydroxycholesterol, 25 hydroxycholesterol, 7alpha-hydroxycholesterol and lanosterol, a single serum measurement can reliably estimate average levels over a one-year period. Circulating oxysterols are of increasing interest in epidemiologic studies of chronic disease risk including cancer and cardiovascular disease. Our data suggest that within-person stability of oxysterols differs depending on the individual oxysterol evaluated. We identified four oxysterols and lanosterol as stable over time to inform the use of circulating oxysterols in epidemiologic studies. PMID- 29108728 TI - Molecular biology and functional genomics of immune-endocrine interactions in the Japanese eel, Anguilla japonica. AB - Immune-endocrine interactions are an important pathogen resistance mechanism in fish. We review the immune-endocrine interactions in the Japanese eel, Anguilla japonica, with special reference to high throughput gene sequencing. These data may be relevant to the significant decrease in the eel harvest in recent years and will aid in the selection of appropriate disease-resistant strains for aquaculture. More than 1000 sequences that whose expression in elvers responded to air exposure were identified through comprehensive gene expression analysis using next-generation sequencing. These included transcription factors within the MAPK pathway. Significant changes in expression after air exposure were detected by quantitative polymerase chain reaction analysis in many genes related to disease resistance. These factors include innate immune system factors and cytokines that interact with the endocrine system during the stress response. Other applications of immune-endocrine interactions in eel culture are discussed. PMID- 29108729 TI - Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization, In Vitro Drug Release, and In Vivo Studies. AB - Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB. PMID- 29108730 TI - Sex-specific differences in mortality and the obesity paradox of patients with myocardial infarction ages >70 y. AB - OBJECTIVES: Recent studies suggest an obesity survival paradox in patients with acute myocardial infarction (MI). The aim of this study was to investigate the in hospital mortality of patients aged >=70 y with acute MI relative to sex and obesity. METHODS: We selected patients >=70 y of age with a diagnosis of acute MI based on the International Classification of Diseases (ICD) code I21 in the nationwide database of the Federal Statistical Office of Germany in 2014. We stratified the patients for sex and obesity versus nonobesity, and obesity classes I, II, and III. We compared the in-hospital mortality of these groups. RESULTS: In 2014, 122 607 patients >=70 y of age were diagnosed with acute MI in Germany. Among these inpatients 14 342 (11.7%) died during their in-hospital stay. The calculated incidence was 938.46 per 100 000 citizens. Overall, 7874 MI patients (6.4%) had an additional coded diagnosis of obesity; 513 of these patients (6.5%) died while in the hospital. The number of MI events was higher in men than in women (56.2 versus 43.8%), whereas mortality rate of the women exceeded that of the men (12.7 versus 10.9%). Obesity mitigated sex differences in mortality after MI. Overall mortality after acute MI was distinctly lower in all obesity classes relative to MI patients without coded obesity. Relative mortality risk was 0.45, 0.62, and 0.75 in obesity classes I, II, and III, respectively. The present results point to a pronounced obesity paradox in women. CONCLUSIONS: Obesity is associated with lower in-hospital mortality in patients >=70 y with MI relative to MI patients without coded obesity. Although women showed higher in-hospital mortality, sex differences were significantly attenuated by obesity. Women showed a pronounced obesity paradox in the higher obesity classes. PMID- 29108731 TI - Ratio of the tibial tuberosity-trochlear groove distance to the tibial maximal mediolateral axis: A more reliable and standardized way to measure the tibial tuberosity-trochlear groove distance. AB - BACKGROUND: Tibial tuberosity-trochlear groove distance(TT-TG) is a measurement to assist in the diagnosis and treatment of patellar instability, however it still has some limitations. Our study was to modify the accepted measurement method and seek a more reliable and standardized method. METHODS: The data of 65 healthy controls and 49 patients with bilateral patellar instability from 2010 to 2016 were collected and analyzed by CT. The TT-TG, tibial maximal mediolateral axis (MML), and their ratio [i.e., the modified-TT-TG (M-TT-TG)] were compared between the two groups. RESULTS: The MML (71.9+/-12.0 vs. 71.3+/-10.9) was not significantly different between the two groups (P>0.05). However, the TT TG(18.1+/-6.0 vs. 13.1+/-2.9) and M-TT-TG (0.25+/-0.08 vs. 0.19+/-0.04) were significantly different between the two groups (P<0.05). A TT-TG of >15mm was found in 24.5% of healthy controls and 71.5% of patients. The healthy controls with a TT-TG of >15mm were compared with the patients; although no significant difference was found in the TT-TG (16.8+/-1.5 vs. 18.1+/-6.0), the healthy controls had a significantly larger MML (76.9+/-12.7 vs. 71.9+/-10.9) and significantly smaller M-TT-TG (0.22+/-0.04 vs. 0.25+/-0.08). A total of 53.1% of patients but only 6.9% of healthy controls had an M-TT-TG of >0.25. CONCLUSION: The M-TT-TG is a more reliable and standardized way to measure the effect of the TT-TG with the goal of reducing the false-positive rate associated with the standard measurement technique. The normal M-TT-TG ranges from 0.11 to 0.25, with an M-TT-TG of >0.25 being associated with patellofemoral malalignment. LEVEL OF EVIDENCE: III. PMID- 29108732 TI - [Pigmentary planet]. PMID- 29108733 TI - [Progression of OCT-angiographic signs in paracentral acute middle maculopathy]. PMID- 29108735 TI - Emergency Department Patient Burden from an Electronic Dance Music Festival. AB - BACKGROUND: Electronic dance music (EDM) festivals are increasingly common and psychoactive substance use is prevalent. Although prehospital care can obviate the transfer of many attendees to health care facilities (HCFs), little is known regarding the emergency department (ED) burden of patients presenting from EDM festivals. OBJECTIVES: This study describes the patient volume, length of stay (LOS), and presenting complaints of patients from a 3-day EDM festival in close proximity to an area ED. METHODS: Medical charts of patients presenting to one HCF from an EDM festival were reviewed for substances used, ED LOS, and sedative medications administered. Additionally, preparedness techniques are described. RESULTS: Over the 3-day festival, 28 patients presented to the ED (median age 21 years; range 18-29 years). Twenty-five had complaints related to substance use including ethanol (n = 18), "molly" or "ecstasy" (n = 13), and marijuana (n = 8). Three patients required intensive care or step-down unit admission for endotracheal intubation, rhabdomyolysis, and protracted altered mental status. The median LOS for discharged patients was 265 min (interquartile range 210-347 min). Eleven patients required the use of sedative medications, with cumulative doses of 42 mg of lorazepam and 350 mg of ketamine. All patients presented within the hours of 5:00 pm and 2:15 am. CONCLUSION: The majority of ED visits from an EDM festival were related to substance use. ED arrival times clustered during the evening and were associated with prolonged LOS. Few patients required hospital admission, but admitted patients required high levels of care. HCFs should use these data as a guide in planning for future events. PMID- 29108734 TI - Altered anterior cingulate cortex to hippocampus effective connectivity in response to drug cues in men with cocaine use disorder. AB - Drug-related attentional bias may have significant implications for the treatment of cocaine use disorder (CocUD). However, the neurobiology of attentional bias is not completely understood. This study employed dynamic causal modeling (DCM) to conduct an analysis of effective (directional) connectivity involved in drug related attentional bias in treatment-seeking CocUD subjects. The DCM analysis was conducted based on functional magnetic resonance imaging (fMRI) data acquired from fifteen CocUD subjects while performing a cocaine-word Stroop task, during which blocks of Cocaine Words (CW) and Neutral Words (NW) alternated. There was no significant attentional bias at group level. Although no significant brain activation was found, the DCM analysis found that, relative to the NW, the CW caused a significant increase in the strength of the right (R) anterior cingulate cortex (ACC) to R hippocampus effective connectivity. Greater increase of this connectivity was associated with greater CW reaction time (relative to NW reaction time). The increased strength of R ACC to R hippocampus connectivity may reflect ACC activation of hippocampal memories related to drug use, which was triggered by the drug cues. This circuit could be a potential target for therapeutics in CocUD patients. No significant change was found in the other modeled connectivities. PMID- 29108736 TI - A Randomized Double-Blind Trial Comparing the Effect on Pain of an Oral Sucrose Solution vs. Placebo in Children 1 to 3 Months Old Undergoing Simple Venipuncture. AB - BACKGROUND: Few clinical trials evaluating the efficacy of oral sweet solutions for procedures in the emergency department (ED) have been published. OBJECTIVES: To compare the efficacy of an oral sucrose solution vs. a placebo in reducing pain in infants undergoing venipuncture without cannulation. METHODS: A randomized, double-blinded clinical trial was conducted in a pediatric ED. Infants 1 to 3 months old were randomly allocated to receive 2 mL of 88% sucrose or 2 mL of placebo, 2 min prior to venipuncture. The outcome measures were the difference in pain levels as assessed by the Face, Legs, Activity, Cry and Consolability Pain Scale (FLACC) and Neonatal Infant Pain Scale (NIPS) scores, crying time, and variations in heart rate. RESULTS: Eighty-two participants were recruited. Data were analyzed for 38 patients from each group (excluding protocol deviations). The mean difference in FLACC scores 1 min post venipuncture compared with baseline was 2.84 +/- .64 (sucrose) vs. 2.71 +/- .62 (placebo) (p = 0.98). For the NIPS score, it was 2.32 +/- .47 (sucrose) vs. 1.63 +/- .49 (placebo) (p = 0.60). The difference in the median crying time was not statistically significant between the two groups: 63.0 +/- 3 (sucrose) vs. 48.5 +/- 5 s (placebo) (p = 0.17). No significant difference was found in participants' heart rates 1 min post venipuncture compared with baseline: 33 +/- 6 (sucrose) vs. 24 +/- 5 beats per minute (placebo) (p = 0.44). CONCLUSIONS: In infants 1 to 3 months of age undergoing simple venipuncture, administration of an oral sweet solution did not statistically decrease pain scores, and participants' heart rate variations and crying time were not significantly changed. PMID- 29108737 TI - Seasonal and diel patterns in cetacean use and foraging at a potential marine renewable energy site. AB - Marine renewable energy (MRE) developments often coincide with sites frequented by small cetaceans. To understand habitat use and assess potential impact from development, echolocation clicks were recorded with acoustic click loggers (C PODs) in Swansea Bay, Wales (UK). General Additive Models (GAMs) were applied to assess the effects of covariates including month, hour, tidal range and temperature. Analysis of inter-click intervals allowed the identification of potential foraging events as well as patterns of presence and absence. Data revealed year-round presence of porpoise, with distinct seasonal and diel patterns. Occasional acoustic encounters of dolphins were also recorded. This study provides further evidence of the need for assessing temporal trends in cetacean presence and habitat use in areas considered for development. These findings could assist MRE companies to monitor and mitigate against disturbance from construction, operation and decommissioning activities by avoiding times when porpoise presence and foraging activity is highest in the area. PMID- 29108738 TI - Characterization and flux of marine oil snow settling toward the seafloor in the northern Gulf of Mexico during the Deepwater Horizon incident: Evidence for input from surface oil and impact on shallow shelf sediments. AB - Sediment trap samples from the shelf edge area (400-450m water depth), 58km northeast of the failed Macondo well, were collected before, during and after the Deepwater Horizon oil spill. Detailed chemical analyses of particulates revealed that fluxes of spill-derived TPH (2356MUg/m2/day), total PAH (5.4MUg/m2/day), and hopane (0.89MUg/m2/day) settling to the seafloor directly beneath the surface plume were 19- to 44-times higher during the active spill than pre- and post spill background values. The oil was variably biodegraded, evaporated and photo oxidized indicating that it derived from the sinking of surface oil. The hopane based oil flux that we calculate (10bbl/km2) indicates that at least 76,000bbl of Macondo oil that reached the ocean surface subsequently sank over an area of approximately 7600km2. We explore how this flux of sunken surface oil contributed to the total volume of oil deposited on the seafloor following the Deepwater Horizon incident. PMID- 29108739 TI - Status of vulnerable Cystoseira populations along the Italian infralittoral fringe, and relationships with environmental and anthropogenic variables. AB - We analyzed the occurrence and status of infralittoral fringe populations of Cystoseira spp. (Fucales) at thirteen rocky sites around the Italian coastline, and explored the relationships with relevant environmental and anthropogenic variables. We found Cystoseira populations at 11 sites: most were scattered and comprised monospecific stands of C. compressa, and only 6 sites also supported sparse specimens of either C. amentacea var. stricta or C. brachycarpa. Coastal human population density, Chlorophyll a seawater concentrations, sea surface temperature, annual range of sea surface temperature and wave fetch explained most of the variation of the status of C. compressa. We hypothesize a generally unhealthy state of the Italian Cystoseira infralittoral fringe populations and identify multiple co-occurring anthropogenic stressors as the likely drivers of these poor conditions. Extensive baseline monitoring is needed to describe how Cystoseira populations are changing, and implement a management framework for the conservation of these valuable but vulnerable habitats. PMID- 29108740 TI - Distribution of heavy metals in seafloor sediments on the East China Sea inner shelf: Seasonal variations and typhoon impact. AB - Based on concentrations and distributions of heavy metals, grain size and loss on ignition (LOI) in the seafloor sediments acquired during three surveys in winter and in summer (before and after typhoon Morakot) in the mud deposition center off the Fujian-Zhejiang coast, East China Sea, the seasonal and typhoon-induced variations of heavy metals in seafloor sediments are discussed. It is found that different concentrations of heavy metals occurred in seafloor sediments, but their distribution patterns were similar, gradually decreasing from near-shore to offshore. The distribution of heavy metals was correlated with grain size and LOI in seafloor sediments, which showed significant seasonal variations and typhoon's impact. Based on these results, a conceptual evolution model was built about the seasonal and typhoon's impact on the deposition environment of heavy metals, which has implications for understanding the migration, settling, and burial processes of heavy metals in the sea. PMID- 29108741 TI - The role of smell, taste, flavour and texture cues in the identification of vegetables. AB - It has been shown that the identification of many foods including vegetables based on flavour cues is often difficult. The effect of providing texture cues in addition to flavour cues on the identification of foods and the effect of providing taste cues only on the identification of foods have not been studied. The aim of this study was to assess the role of smell, taste, flavour and texture cues in the identification of ten vegetables commonly consumed in The Netherlands (broccoli, cauliflower, French bean, leek, bell pepper, carrot, cucumber, iceberg lettuce, onion and tomato). Subjects (n = 194) were randomly assigned to one of four test conditions which differed in the sensory cues available for vegetable identification: taste, smell (orthonasal), flavour (taste and smell) and flavour texture (taste, smell and texture). Blindfolded subjects were asked to identify the vegetable from a list of 24 vegetables. Identification was the highest in the flavour-texture condition (87.5%). Identification was significantly lower in the flavour condition (62.8%). Identification was the lowest when only taste cues (38.3%) or only smell cues (39.4%) were provided. For four raw vegetables (carrot, cucumber, onion and tomato) providing texture cues in addition to flavour cues did not significantly change identification suggesting that flavour cues were sufficient to identify these vegetables. Identification frequency increased for all vegetables when perceived intensity of the smell, taste or flavour cue increased. We conclude that providing flavour cues (taste and smell) increases identification compared to only taste or only smell cues, combined flavour and texture cues are needed for the identification of many vegetables commonly consumed in The Netherlands. PMID- 29108742 TI - Gene expression analysis reveals chronic low level exposure to the pesticide diazinon affects psychological disorders gene sets in the adult rat. AB - Chronic low level exposure to organophosphate (OPs) pesticides in adulthood has been linked to adverse neurobehavioural deficits and psychological disorder symptoms, although this remains a contentious issue. The OP-induced biological changes that could underlie these effects are unclear. We assessed gene expression changes following chronic low level exposure to diazinon, a pesticide with a high dietary exposure risk. Adult male rats were orally exposed to diazinon (0, 1, 2mg/kg, 5days a week for 12 weeks). After 4 weeks, marble burying behaviour was lower in diazinon exposed rats than vehicle exposed rats; this difference persisted for 8 weeks. Chronic diazinon exposure did not significantly inhibit acetylcholinesterase activity, the primary mechanism of action of high level OPs. Affymetrix GeneChip(r) HT RG-230 PM Arrays were used for gene profiling followed by Ingenuity Pathway analysis. In the hippocampus, the most significant gene expression changes caused by OP exposure were associated with Psychological Disorders, and Cell-To-Cell Signalling and Interaction functions. Genes encoding the AMPA3 glutamate receptor, glutaminase, dopamine transporter and tyrosine hydroxylase were up-regulated, whereas the gene encoding the GABAB1 receptor was down-regulated. In the dorsal raphe nucleus, genes associated with development and the Psychological Disorders function were significantly affected, including the up-regulation of the gene encoding the alpha1b-adrenoceptor, the major driver of serotoninergic (5-HT) neuronal activity. These data indicate that chronic exposure to diazinon in adulthood, below the threshold to inhibit acetylcholinesterase, stimulates glutamatergic, dopaminergic and serotonergic synaptic transmission which may underlie adverse neurological outcomes. PMID- 29108744 TI - Amblyopia Preferred Practice Pattern(r). PMID- 29108743 TI - Differentially DNA methylation changes induced in vitro by traffic-derived nanoparticulate matter. AB - The cytotoxicity, apoptosis, reactive oxygen species (ROS) and DNA damage induced by the commercial diesel exhaust particulate matter (PM) (SRM2975) with concentrations ranging from 0.1 MUg mL-1 to 20 MUg mL-1 were assessed in human umbilical vein endothelial cells (HUVECs) in vitro. An epigenetics-wide investigation of DNA methylation profiles was also performed using a new methylation beadchip (Illumina 850 K) to identify the health effects of traffic derived nanoparticulate matter (nPM) with a concentration of 20 MUg mL-1. By characterising its physical and chemical properties, we found that SRM2975 is a highly disordered graphitic structure material with a nanometer dimension and a large surface area. Low levels of traffic-derived nPM (<=10 MUg mL-1) induced cell apoptosis and DNA damage as well as increased intracellular ROS levels (p < 0.001). The HUVECs showed a significantly decreased cell viability following their exposure to traffic-derived nPM with a concentration of 20 MUg mL-1 (p < 0.001). A total of 149 significant differential methylated probes between the control and traffic-derived nPM treated-cells were identified, among which 86.6% were hypermethylated. A gene ontology (GO) enrichment analysis of differential methylated genes reported that the majority of the enriched GO terms were related to calcium ion and heart muscle, and further Kyoto encyclopaedia of genes and genomes (KEGG) pathway analysis indicated that the top three enriched pathways were involved in three common subtypes of cardiomyopathy. Overall, these results demonstrated that traffic-derived nPM could induce cytotoxic effects and demonstrate robust associations with cardiomyopathy though differential DNA methylation as well as the physiologic process of ROS, oxidative stress, inflammation, cell death and calcium ion channel. PMID- 29108745 TI - Pediatric Eye Evaluations Preferred Practice Pattern(r): I. Vision Screening in the Primary Care and Community Setting; II. Comprehensive Ophthalmic Examination. PMID- 29108746 TI - Esotropia and Exotropia Preferred Practice Pattern(r). PMID- 29108747 TI - Vision Rehabilitation Preferred Practice Pattern(r). PMID- 29108748 TI - Refractive Errors & Refractive Surgery Preferred Practice Pattern(r). PMID- 29108749 TI - Sensitivity and specificity of QuantiFERON-TB Gold Plus compared with QuantiFERON TB Gold In-Tube and T-SPOT.TB on active tuberculosis in Japan. AB - BACKGROUND: The QuantiFERON-TB Gold Plus (QFT-Plus) was introduced in 2015 as a new generation of interferon-gamma release assays (IGRAs) designed to detect Mycobacterium tuberculosis infection (TB). Examination of its diagnostic accuracy is crucial before it is launched in Japan. METHOD: We examined 99 patients with laboratory-confirmed active TB (patients) and 117 healthy volunteers with no risk of TB infection (controls) at a medical center in Tokyo, Japan. Blood samples were collected from both the patients and controls and tested using three types of IGRAs: the QFT-Plus, the QuantiFERON-TB Gold In-Tube (QFT-GIT), and the T SPOT.TB (T-SPOT). The sensitivity and specificity of each IGRA were examined and compared. RESULTS: The sensitivity of the QFT-Plus was 98.9% (95% confidence interval [CI], 0.934-0.998) and similar to that of the QFT-GIT (97.9%; 95% CI, 0.929-0.998) and T-SPOT (96.9%; 95% CI, 0.914-0.994). The specificity of the QFT Plus was the same as that of the QFT-GIT and T-SPOT (98.1%; 95% CI, 0.934-0.998). One patient with uncontrolled diabetes mellitus showed negative results on all three IGRAs. CONCLUSIONS: The QFT-Plus showed a high degree of agreement with the QFT-GIT and T-SPOT, with high sensitivity and specificity. Severe diabetes mellitus may influence the results of IGRAs. Larger studies are needed to validate the accuracy of the GFT-Plus and determine whether it can contribute as adjunctive method for the early diagnosis of active TB in Japan. PMID- 29108750 TI - New spectrum of the neurologic consequences of Zika. AB - Zika virus infection represents a new neuropathological agent with association to a wide spectrum of neurological complications: a) Congenital Zika Syndrome by affecting the neural stem cells of the human fetal brain; b) Guillain-Barre Syndrome by an autoimmune response against peripheral myelin and/or axonal components or probable direct inflammatory reaction; c) Encephalitis/meningoencephalitis and myelitis by a direct viral inflammatory process on the central nervous system; d) Sensory neuropathy by infecting directly the peripheral neurons and causing substantial cell death and pathogenic transcriptional dysregulation; e) Acute Disseminated Encephalomyelitis and optic neuropathy; f) Seizures and Epilepsy and g) childhood arterial ischemic stroke by probable inflammatory reaction and endothelial injury. PMID- 29108751 TI - Three-dimensional reconstructions of CT scans and cone beam CT of impacted maxillary canines in order to locate areas of ankylosis before orthodontic traction. AB - PURPOSE: The aim of this study was to model impacted maxillary canines and determine whether areas of ankylosis were present before undertaking orthodontic traction. MATERIAL AND METHODS: Amira/ResolveRTTM software, version 5.0, by FEI Company is a meshing and surface-rendering program that was used to produce three dimensional reconstructions from CT scans and cone beam images of the impacted canines of 30 patients (10 cone beam files and 20 CT scan files). RESULTS AND DISCUSSION: The presence of zones of ankylosis on the roots of certain impacted canines is revealed by the inversion of the direction of meshing on the tooth surface and on a larger scale by invagination of bone tissue into the tooth tissue at various densities measured in Hounsfield units by the AMIRATM software program. This observation can guide treatment towards extraction of the impacted tooth, its autotransplantation, or deep alveolar corticotomy, followed by mobilization when the canine is in a vestibular position. CONCLUSION: AMIRATM software made it possible to detect zones of ankylosis on the roots of certain impacted canines and to adopt a treatment program different from conventional surgico-orthodontic traction. The final aim is to reposition the impacted canine without endangering the adjacent teeth. PMID- 29108752 TI - ? PMID- 29108753 TI - Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor. AB - In GPIIb/IIIa mediated arterial thrombosis platelet activation plays a central role. To discover platelet activation inhibitor the pharmacophores of GPIIb/IIIa receptor inhibitors and anti-thrombotic agents were analyzed. This led to the design of (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3 carboxylic acids as GPIIb/IIIa inhibitors. Comparing to (1S,3S)-isomer (1R,3S) isomer had lower cdocker interaction energy. AFM image showed that the minimal effective concentration of (1S,3S)-isomer and (1R,3S)-isomer inhibiting platelet activation were 10-5 M and 10-6 M, respectively. In vivo 1 MUmol/kg of oral (1S,3S)-isomer effectively inhibited the rats to form arterial thrombus and down regulated GPIIb/IIIa expression, but the activities were significantly lower than those of 1 MUmol/kg of oral (1R,3S)-isomer. Both (1S,3S)-isomer and (1R,3S) isomer can be safely used for structural modifications, but (1R,3S)-isomer should be superior to (1S,3S)-isomer. PMID- 29108754 TI - Extracellular adenosine produced by ecto-5'-nucleotidase (CD73) regulates macrophage pro-inflammatory responses, nitric oxide production, and favors Salmonella persistence. AB - Surface enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5' nucleotidase) mediate the synthesis of extracellular adenosine that can regulate immune responses. Adenosine produced by CD39/CD73 acts via adenosine receptors (ARs). CD73 is expressed by a variety of cell types and mediates anti inflammatory responses. Because efficient innate immune responses are required for clearance of Salmonella infection, we investigated the role of CD73 in macrophage function, including phagocytosis, intracellular killing of Salmonella, and anti-bacterial pro-inflammatory responses to Salmonella-whole cell lysate (ST WCL) or Salmonella infection. Additionally, RAW 264.7 macrophage mRNA expression of CD39, CD73, and all ARs were measured by qPCR after ST-WCL treatment. Pro inflammatory cytokine mRNA and nitric oxide (NO) production were quantitated in the ST-WCL treated macrophage with and without CD73-inhibitor (APCP) treatment. Phagocytosis and intracellular killing by peritoneal macrophages from CD73 deficent mice were also evaluated using E. coli BioParticles(r) and GFP Salmonella infection, respectively. CD73, CD39, and A2BAR mRNA were predominantly expressed in RAW cells. ST-WCL treatment significantly reduced CD73 expression, suggesting endogenous down-regulation of CD73, and an enhanced pro-inflammatory response. ST-WCL treated and CD73-inhibited macrophages produced more NO and a higher level of pro-inflammatory cytokines than CD73-competent macrophages (e.g. IL-1beta, TNF-alpha). Phagocytosis of E. coli BioParticles(r) was significantly higher in the macrophages treated with APCP and in the peritoneal macrophages from CD73-deficent mice as compared to APCP-untreated, and CD73-competent macrophages. Internalized bacteria were more efficiently cleared from macrophages in the absence of CD73, as observed by fluorescence-microscopy and Salmonella-DNA measurement by qPCR from the infected cells. CD73 down-regulation or CD73 inhibition of macrophages during Salmonella infection can enhance the production of pro-inflammatory cytokines and NO production, improving intracellular killing and host survivability. Extracellular adenosine synthesized by CD73 suppresses antibacterial responses of macrophages, which may weaken macrophage function and impair innate immune responses to Salmonella infection. PMID- 29108755 TI - Practical guidance for dealing with death abroad. PMID- 29108756 TI - Pulmonary Hypoplasia in a Young Adult. PMID- 29108757 TI - Prevalence and Features of Asthma in Young Adults in Urban Areas of Argentina. AB - OBJECTIVE: To investigate the burden of asthma in a young adult population in urban areas of Argentina. DESIGN: A nationwide telephone survey in subjects aged 20-44 years was performed in urban areas in Argentina. The European Community Respiratory Health Survey questionnaire was used. Asthma was defined as an exacerbation in the last year or use of asthma medications. RESULTS: In total, 1,521 subjects responded (62.4% females, mean age 33 years), of whom 91 were classified as asthmatics (5.9%, 95% CI 4.7-7.1). Prevalence adjusted for age, sex and education level was 6.4% (95% CI 5.1-7.7). Wheezing was reported by 13.9% (95% CI 15.6-12.2) and a diagnosis of asthma by 9.5% (95% CI 8.0-11.0). Among individuals with a diagnosis of asthma (n=154), 71.3% had undergone spirometry. Among those treated (n=77), 51.9% used medications daily and 46.8% as a rescue measure. Of those reporting an exacerbation in the last year (n=60), 55% had attended an emergency department and 23% were admitted. Asthma was associated with rhinitis (OR 11.1, 95% CI 6.2-19.9) and family history (OR 3.6, 95% CI 2.3 5.5). CONCLUSION: Asthma prevalence in young adults in Argentina is similar to Europe. Although attacks and admissions were common, regular use of medications was reported by half of those treated. These results may be useful for other Latin American countries. PMID- 29108758 TI - Pulmonary Mycobacteriosis in a Patient Receiving Chronic Methotrexate Treatment. PMID- 29108759 TI - Clinical practice guidelines or personalized medicine in chronic obstructive pulmonary disease? PMID- 29108760 TI - S. aureus pneumonia and sternoclavicular septic arthritis: An unusual complication. PMID- 29108762 TI - Alveolar Microlithiasis And Its Distinctive Clinical And Radiological Disassociation. PMID- 29108761 TI - Esculetin Attenuates the Growth of Lung Cancer by Downregulating Wnt Targeted Genes and Suppressing NF-kappaB. AB - INTRODUCTION: Esculetin was identified to inhibit cell proliferation and induce apoptosis or cell cycle arrest in several cancer cell lines. However, the effect of esculetin on lung cancer remains elusive. METHODS: The anti-proliferative role of esculetin in murine Lewis lung carcinoma (LLC) cells was evaluated by 3-(4,5 dimethylthiazol-2yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays. BALB/c mice were subcutaneously injected with LLC cells to investigate the inhibitory effect of esculetin on the growth of lung cancer xenograft. Invasive ability was detected in esculetin treated and untreated LLC cells by transwell assay. The association between esculetin and Wnt/beta-catenin signaling, as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), was confirmed by testing the expression of c-myc, Cyclin D1 and NF-kappaB using Western blot. RESULTS: Esculetin treatment in LLC cells led to significant decrease of cell proliferation in a time- and dose-dependent manner. After injection of LLC cells into mice, reduced size and weight of tumors were observed in esculetin treated mice compared to untreated mice. However, no difference in cell invasion was observed between the treated and untreated LLC cells. Notably decreased expression of c-myc, Cyclin D1 and NF-kappaB were observed in LLC cells with esculetin treatment compared to untreated cells. CONCLUSION: Esculetin plays an inhibitory role in the growth of lung cancer by down-regulating c-myc, Cyclin D1 and NF-kappaB. PMID- 29108763 TI - Age estimation in a sub-adult Western Australian population based on the analysis of the pelvic girdle and proximal femur. AB - The accurate and precise estimation of skeletal age by a forensic anthropologist is both a professional and judicial requirement. When unknown skeletal remains are referred to the anthropologist, the estimation of the requisite biological attributes (e.g., age and sex) should accordingly be based on the application of population-specific standards (statistical data). Deviations from the latter practice may result in reduced accuracy and compromised identification. Towards informing appropriate forensic practice, the aim of the present study is to develop statistically quantified age estimation models for a contemporary sub adult Western Australian population based on the timing of fusion in the os coxa and proximal femur. The study sample comprises 562 known age and sex MDCT scans (292 male, 270 female) representing contemporary Western Australian individuals birth through 30 years of age. Scans are viewed in multi-planar reconstructed (MPR) and/or three-dimensionally reconstructed images using OsiriX(r). Fusion status is scored according to a three-stage system across a total of nine sites in the proximal femur and os coxae. Observer accordance, bilateral asymmetry and sex-specific variation in fusion timing are statistically quantified. Polynomial regression is used to formulate age prediction models; transition analysis is used to calculate age ranges and determine the mean age for transition between an unfused, fusing and fused status. Observer accordance in stage assignation is acceptable (kappa=0.79) and there is no significant bilateral variation in fusion timing. It was found that the mean age of commencement of fusion is significantly earlier (~2 years) in females. The accuracy (SEE) of the polynomial models ranges from +/-3.29 to +/-3.80 years and the transition analysis shows that fusion of the iliac crest is delayed in comparison to other attributes of os coxa and proximal femur. Results of the present study confirm that the pelvic girdle and proximal femur can be used to accurately estimate chronological age in the study population. PMID- 29108764 TI - Proposals for harmonization of allergens regulation in the European Union. AB - Allergen medicinal products in the European Union are regulated differently across the different Member States. Thus, whereas in some countries strict quality, safety and efficacy requirements are in place, in others, most allergens are on the market as Named Patient Products, without any regulatory oversight. This situation results on European allergic patients being exposed to totally different standards depending on where they live. Initiatives to correct this situation are needed. PMID- 29108765 TI - Epicutaneous immunotherapy. PMID- 29108766 TI - New insight into cancer immunotherapy. AB - A key point for maintenance of the immune system homeostasis is the balance between the capacity to recognize and fight exogenous molecules and the capacity to avoid auto reactivity. The disruption of this balance induces the progression of several immune diseases such as autoimmune diseases, allergies, infections or cancer. A promising therapeutic approach to treat these diseases is immunotherapy. In cancer, both active and passive immunotherapies have been tested with promising results, such as the blocking of immunological checkpoints like CTLA-4 and PD-1. These treatments, in the market since a few years ago, aim to redirect the patient's immunological response by inhibiting the induction of regulatory T cells, both in the priming and effector phases. This strategy sheds light on the immunological mechanisms that control the regulatory response mediated by T cells and opens new lines of research into other immunological diseases such as allergy, in which the induction of a regulatory response is necessary to avoid allergic progression and which is the main objective of allergen-specific immunotherapies available today. PMID- 29108767 TI - Biologics in the treatment of severe asthma. AB - Severe asthma is defined as asthma which requires treatment with high dose inhaled corticosteroids and with a second controller drug to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy. Patients with uncontrolled severe asthma require additional treatment options as add-on therapy, including biologics. Biologic therapies in asthma are designed to block key immune regulators, such as IgE, or certain pro-inflammatory cytokines, e.g. interleukin (IL)-5, IL-4, IL-13 or IL-17. Patients with severe asthma and eosinophilic phenotype may benefit from biologic therapies aimed at reducing blood and tissue eosinophils, such as mepolizumab, reslizumab and benralizumab. Patients with Th2-high phenotype may also benefit from therapy with anti-IL 4/anti-IL-13 monoclonal antibodies (dupilumab). The main limitations of asthma treatment with biologic agents are the crossover and overlap of the different pathways in the pathogenesis of asthma which may cause lack of complete success of these therapies, in addition of high costs, which make pharmacoeconomic studies necessary to identify the ideal target patient population to receive these biologic drugs. PMID- 29108768 TI - Worldwide allergen immunotherapy guidelines: Evidence and experience-based. PMID- 29108769 TI - Non-allergenic immunotherapy. PMID- 29108770 TI - Predictive biomarkers in allergen specific immunotherapy. PMID- 29108771 TI - Biologics in chronic urticaria. PMID- 29108772 TI - Debates in allergy, regarding the symposium on: "Position Statements and Therapeutic Guidelines". PMID- 29108773 TI - Asiatic acid abridges pre-neoplastic lesions, inflammation, cell proliferation and induces apoptosis in a rat model of colon carcinogenesis. AB - The utmost aim of this present study was to investigate the anti-inflammatory, antiproliferative and proapoptotic potential of Asiatic acid (AA) on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis in experimental rats. Rats were divided into six groups and received modified pellet diet for 32 weeks. Group 1 served as control rats. Group 2 received AA (4 mg/kg b.w. p.o.). Group 3 6 rats received 15 DMH (20 mg/kg b.w., s.c.) injections once a week starting from the 4th week. Besides DMH, rats received AA (4 mg/kg b.w. p.o.) in group 4 starting 2 weeks before carcinogen treatment till the end of the last DMH; group 5 starting 2 days after last DMH till the end of the experiment; and group 6 throughout the experiment. Pre-neoplastic lesions, xenobiotic metabolizing enzymes, inflammation, cell proliferation and apoptotic markers were analysed in our study. Our results ascertained AA supplementation to DMH-exposed rats significantly decreased the incidence of aberrant crypt foci (ACF) and phase I xenobiotic enzymes; and increased the phase II xenobiotic enzymes and mucin content as compared to DMH-alone-exposed rats. Moreover the increased expressions of mast cells, argyrophilic nucleolar organizer regions (AgNORs), proliferating cell nuclear antigen (PCNA) and cyclin D1 observed in the DMH-alone-exposed rats were reverted and were comparable with those of the control rats, when treated with AA. Concordantly AA also induced apoptosis by downregulating the expression of Bcl-2 and upregulating Bax, cytochrome c, caspase-3 and -9 in the DMH-alone exposed rats. Thus AA was able to inhibit DMH-induced colon carcinogenesis by detoxifying the carcinogen, decreasing the preneoplastic lesions by virtue of its anti-inflammatory, antiproliferative and proapoptotic effects. Therefore our findings suggest that AA could be used as an effective chemopreventive agent against DMH induced colon carcinogenesis. PMID- 29108774 TI - Gender-based behavioral and biochemical effects of diphenyl diselenide in Drosophila melanogaster. AB - In the present study we investigated the effects of Diphenyl Diselenide (DPDS) on behavioral and biochemical parameters in Drosophila melanogaster (DM). We also tried to explore the gender differences in response to DPDS treatment. One of the salient features of the present report is that, at the highest tested concentration (3.0 mmol/kg) the survival rate in females was significantly higher (65%) as compared with male subjects (27.5%). However in alive subjects, different results pattern was observed. The locomotor activity of females significantly decreased at all tested concentrations and no statistical difference was observed in males at 0.1 and 1.0 mM. To explore the toxicological pathway of DPDS, different arrays of experiments were performed. DPDS did not cause any significant alteration in total thiol contents (NPSH) in males. While, a significant decrease was observed in females at all tested concentrations (0.1, 1.0 and 3.0 mM; p<0.005). For gender comparison purpose, its important to note that females showed 2.1 and 1.63 folds increase in SOD and CAT m-RNA expression at the highest (3.0 mM) tested concentration (as compared with male subjects). In contrast to m-RNA levels of catalase, the lowest concentration (0.1 mM) of DPDS significantly decreased (P<0.005) the enzymatic activity in females and a noticeable increase (P<0.005) at highest tested concentration (3.0 mM) was observed in male subjects. Statistically no significant change was observed in Glutathione -S- transferase (GST) activity at all tested concentrations in females. However a marked increase at 1.0 and 3.0 mM was observed in males. Furthermore, we also evaluated, HSP70 mRNA levels in females, which were increased by approximately 10.6 fold (P<0.005) as compared to male subjects. These results demonstrated significant gender-differences in terms of acute response to DPDS treatment. Mechanistically thiol oxidase (TOx) potential is one of the proposed pathways of DPDS toxicity, which can not be excluded in the present findings. PMID- 29108775 TI - Facilitation of 9,10-phenanthrenequinone-elicited neuroblastoma cell apoptosis by NAD(P)H:quinone oxidoreductase 1. AB - 9,10-Phenanthrenequinone (PQ), a major quinone component in diesel exhaust particles, is considered to provoke damage of respiratory and vascular cells through highly producing reactive oxygen species (ROS), but little is known about its pathophysiological role in neuronal cell damage. In this study, we found that incubation with 1,2-naphthoquinone, 1,4-naphthoquinone and PQ, major quinone components in diesel exhausts, provokes apoptosis of human neuroblastoma cell lines. SK-N-SH cell treatment with a lethal concentration of PQ facilitated ROS production within 6 h. The treatment also promoted formation of 8-hydroxy deoxyguanosine, p53 activation, elevation of Bax/Bcl-2 ratio, lowering of mitochondrial membrane potential, and resultant activation of caspase-9 and caspase-3, inferring that ROS production, DNA damage and mitochondrial dysfunction are crucial processes of the PQ-triggered SK-N-SH cell apoptosis. The PQ treatment of SK-N-SH cells elevated the level of 4-hydroxynonenal (HNE), a cytotoxic reactive aldehyde generated from lipid peroxidation. The treatment with PQ and HNE also decreased cellular levels of total and reduced glutathiones, and the damage elicited by HNE was ameliorated and deteriorated by pretreating with cell-permeable glutathione analog and the depletor, respectively. Moreover, the treatment with PQ and HNE decreased the proteasomal proteolytic activities, suggesting a contribution of decrease in the antioxidant abilities to the ROS mediated neuroblastoma cell apoptosis. Our comparative analyses of 17 cells showed a positive correlation between the PQ reductase and NAD(P)H:quinone oxidoreductase 1 (NQO1) activities. In addition, overexpression and knockdown of NQO1 augmented and lowered, respectively, the ROS production through PQ redox cycling and the quinone toxicity. Furthermore, the treatment with PQ and HNE up regulated the NQO1 expression. Taken together, PQ exposure produces large amounts of ROS in neuroblastoma cells via NQO1 up-regulation and resultant acceleration of its redox-cycling, followed by activation of the ROS-dependent apoptotic mechanism. PMID- 29108776 TI - Evaluation of chlorpyrifos toxicity through a 28-day study: Cholinesterase activity, oxidative stress responses, parent compound/metabolite levels, and primary DNA damage in blood and brain tissue of adult male Wistar rats. AB - In this 28 day-study, we evaluated the effects of the insecticide chlorpyrifos orally administered to Wistar rats at doses 0.160, 0.015, and 0.010 mg/kg b. w./day. Following treatment, total cholinesterase activity and activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were measured. Oxidative stress responses were evaluated using a battery of endpoints to establish lipid peroxidation, changes in total antioxidant capacity, level of reactive oxygen species (ROS), glutathione (GSH) level and activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase. Using HPLC-UV DAD analysis, levels of the parent compound and its main metabolite 3,5,6 trichloro-2-pyridinol in plasma and brain tissue were measured. The genotoxic effect was estimated using alkaline comet assay in leukocytes and brain tissue. The exposure did not result in significant effects on total cholinesterase, AChE and BChE activity in plasma and brain tissue. Lipid peroxidation slightly increased both in plasma and brain tissue. Total antioxidant capacity, ROS and GSH levels were marginally influenced by the exposure. Treatment led to significant increases of GSH-Px activity in blood, SOD activity in erythrocytes and a slight increase of catalase activity in plasma. HPLC-UV DAD analysis revealed the presence of both the parent compound and its main metabolite in the plasma of all of the experimental animals and brain tissue of the animals treated at the two higher doses. All of the tested doses of chlorpyrifos were slightly genotoxic, both to leukocytes and brain tissue. Our results call for further research using other sensitive biomarkers of effect, along with different exposure scenarios. PMID- 29108777 TI - Antioxidant for treatment of diabetic nephropathy: A systematic review and meta analysis. AB - BACKGROUND: Diabetic nephropathy (DN) is one of the leading causes of morbidity and mortality amongst the diabetes mellitus patients. Oxidative stress played a major role in the pathogenesis of DN. Many studies reported that therapies with antioxidant potential have a beneficial effect on DN but there is conflicting evidence amongst them. OBJECTIVE: To elucidate the association between antioxidant and DN and to develop a robust evidence for clinical decisions by conducting systematic reviews and meta-analysis. PATIENT AND METHODS: A comprehensive systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, CPCI-S, ICTRP, and Google Scholar till February 2017 by two independent researchers. Various outcomes were included and statistical analyses were performed using RevMan V.5.3. RESULTS: There were total 1461 participants identified from twelve studies, of which 882 (60.37%) were monitored on antioxidant treatment. Results indicated that antioxidant treatment was associated with significantly change in Blood Urea Nitrogen (SMD = 1.11, 95% CI: 0.38 to 1.85, p = 0.003), urinary Transforming Growth Factor-beta (SMD = 2.16, 95% CI: -0.01 to 4.33; p = 0.05) and estimated Glomerular filtration Rate (SMD = 0.30, 95% CI: 0.06 to 0.55; p = 0.02) than control group. There was no association of change in urine albumin-to-creatinine ratio, serum creatinine, adverse events and rate of death with antioxidant treatment. CONCLUSION: The findings of this investigation indicate that antioxidant treatment is effective clinically for DN treatment in T2DM patient. However, there is a need of high degree of caution for interpreting the outcomes of the studies with a short duration of antioxidant treatment. PMID- 29108779 TI - Whole-body total lesion glycolysis is an independent predictor in patients with esophageal cancer treated with definitive chemoradiotherapy. AB - BACKGROUND AND PURPOSE: To determine whether pretreatment whole-body total lesion glycolysis (TLGWB) and metabolic tumor volume (MTVWB) are associated with outcomes in patients with esophageal cancer treated with definitive chemoradiotherapy (dCRT). MATERIALS AND METHODS: Ninety patients with stage II or III thoracic esophageal cancer who underwent FDG-PET/CT within 45 days before dCRT between 2005 and 2013 were reviewed. MTV and TLG of the primary lesion (MTVpri and TLGpri) and the sum of MTV and TLG for all lesions (MTVWB and TLGWB) were calculated. Predictors were analyzed using the Cox proportional hazards model. RESULTS: The median follow-up period was 27.7 months. In multivariate analysis, MTVWB > median was an unfavorable predictor for OS (p = 0.027, hazard ratio [HR]: 2.15), LC (p = 0.039, HR: 1.98) and PFS (p = 0.041, HR: 1.96). TLGWB > median was an unfavorable predictor for OS (p = 0.019, HR: 2.26), LC (p = 0.015, HR: 2.36) and PFS (p = 0.014, HR: 2.33). SUVmax was not a predictor, and the HR of TLGWB was higher than that of MTVWB for OS, LC and PFS in multivariate analysis. CONCLUSION: TLGWB and MTVWB are independent predictors in patients with esophageal cancer. PMID- 29108780 TI - [Bayes' syndrome in cardiac surgery: prevalence of interatrial block in patients younger than 65 years undergoing cardiac surgery and association with postoperative atrial fibrillation]. AB - OBJECTIVE: Interatrial block (IAB) is a well-known entity that is associated with an increased risk of atrial fibrillation (AF). This association is called Bayes' syndrome. The aim of our study was to define the prevalence of IAB among patients younger than 65 years undergoing cardiac surgery and determine whether there is an association between the presence of interatrial conduction delay and postoperative atrial fibrillation (POAF). METHOD: A total of 207 patients were enrolled. Partial IAB was defined as P-wave>120ms. Advanced IAB was defined as P wave>120ms+biphasic morphology in the inferior leads. Ocurrence of POAF was assessed and a comparative analysis was conducted between patients that did and did not develop AF. RESULTS: IAB prevalence was 78.3% (partial 66.2%, advanced 12.1%). POAF occurred in 28.5% of all patients, and was more frequent among patients with advanced IAB (44%) compared to 27.7% and 24.4% of POAF among patients with partial IAB and without IAB, respectively. Patients who developed POAF were significantly older, had significantly higher NTproBNP, higher prevalence of atrial enlargement and thyroid disease. After multivariate analysis, advanced IAB was found to be independently associated with POAF. CONCLUSIONS: IAB is a frequent finding among patients undergoing cardiac surgery. According to our results, advanced IAB is independently associated with POAF in younger patients (<65 years) undergoing cardiac surgery. PMID- 29108778 TI - The timing and duration of estradiol treatment in a rat model of the perimenopause: Influences on social behavior and the neuromolecular phenotype. AB - This study tested the effects of timing and duration of estradiol (E2) treatment, factors that are clinically relevant to hormone replacement in perimenopausal women, on social behavior and expression of genes in brain regions that regulate these behaviors. Female rats were ovariectomized (OVX) at 1year of age, roughly equivalent to middle-age in women, and given E2 or vehicle for different durations (3 or 6months) and timing (immediately or after a 3-month delay) relative to OVX. Social and ultrasonic vocalization (USV) behaviors were assessed at the 3 and 6month timepoints, and the rats' brains were then used for gene expression profiling in hypothalamus (supraoptic nucleus, paraventricular nucleus), bed nucleus of the stria terminalis, medial amygdala, and prefrontal cortex using a 48-gene qPCR platform. At the 3-month post-OVX testing period, E2 treatment significantly decreased the number of frequency-modulated USVs emitted. No effects of hormone were found at the 6-month testing period. There were few effects of timing and duration of E2 in a test of social preference of a rat given a choice between her same-sex cagemate and a novel conspecific. For gene expression, effects of timing and duration of E2 were region-specific, with the majority of changes found for genes involved in regulating social behavior such as neuropeptides (Oxt, Oxtr &Avp), neurotransmitters (Drd1, Drd2, Htr2a, Grin2d &Gabbr1), and steroid hormone receptors (Esr2, Ar, Pgr). These data suggest that the mode of E2 treatment has specific effects on social behavior and expression of target genes involved in the regulation of these behaviors. PMID- 29108782 TI - Purulent pericarditis complicating cardiac tamponade in a uremic patient caused by Staphylococcus aureus. PMID- 29108781 TI - Retinoic acid temporally orchestrates colonization of the gut by vagal neural crest cells. AB - The enteric nervous system arises from neural crest cells that migrate as chains into and along the primitive gut, subsequently differentiating into enteric neurons and glia. Little is known about the mechanisms governing neural crest migration en route to and along the gut in vivo. Here, we report that Retinoic Acid (RA) temporally controls zebrafish enteric neural crest cell chain migration. In vivo imaging reveals that RA loss severely compromises the integrity and migration of the chain of neural crest cells during the window of time window when they are moving along the foregut. After loss of RA, enteric progenitors accumulate in the foregut and differentiate into enteric neurons, but subsequently undergo apoptosis resulting in a striking neuronal deficit. Moreover, ectopic expression of the transcription factor meis3 and/or the receptor ret, partially rescues enteric neuron colonization after RA attenuation. Collectively, our findings suggest that retinoic acid plays a critical temporal role in promoting enteric neural crest chain migration and neuronal survival upstream of Meis3 and RET in vivo. PMID- 29108783 TI - Implementation of a national bundle care program to reduce central line associated bloodstream infections in intensive care units in Taiwan. AB - BACKGROUND/PURPOSE: This study assessed the effect of the central line bundle on the rate of central line-associated bloodstream infections (CLABSI) in intensive care units (ICUs) in Taiwan. METHODS: This national study was conducted in 27 ICUs with 404 beds total, including 15 medical ICUs, 11 surgical ICUs, and one mixed ICU. The study period was divided into two phases: a pre-intervention (between June 1, 2011 and October 31, 2011) and intervention phase (between December 1, 2011 and October 31, 2012). Outcome variables, including CLABSI rates (per 1000 catheter-days) and catheter utilization rates, were measured. RESULTS: The overall rate of CLABSI significantly decreased by 12.2% (p < 0.001) from 5.74 per 1000 catheter-days in the pre-intervention phase to 5.04 per 1000 catheter days in the intervention phase. The catheter utilization rate decreased by 1.1% from 55.3% in the pre-intervention phase to 54.2% in the intervention phase. The decline in CLABSI varied significantly among hospital and ICU levels, except surgical ICUs (p = 0.59). CONCLUSIONS: Implementing a multidimensional central line bundle significantly reduced the rates of CLABSI by 12.2% in nearly all participating ICUs, except surgical ICUs. PMID- 29108784 TI - Clinical Outcomes and Return to Sport in Competitive Athletes Undergoing Arthroscopic Iliopsoas Fractional Lengthening Compared With a Matched Control Group Without Iliopsoas Fractional Lengthening. AB - PURPOSE: To compare the minimum 2-year outcomes and return to sports in competitive athletes after arthroscopic iliopsoas fractional lengthening (IFL) and treatment for femoroacetabular impingement (FAI) to competitive athletes treated for FAI who did not undergo IFL. METHODS: Data were prospectively collected and retrospectively reviewed between November 2009 and April 2014. Included patients were high school, collegiate, or professional athletes who underwent arthroscopic IFL, treatment for FAI, and preoperative modified Harris Hip Score, Non-Arthritic Athletic Hip Score, Hip Outcome Score-Sports Specific Subscale, and visual analog scale. Exclusion criteria were patients younger than 16 years, Tonnis grade >1, microfracture, abductor pathology, and previous hip conditions. A subgroup of athletes were matched to athletes who did not undergo IFL by age +/- 5 years, sex, and body mass index +/- 5. RESULTS: There were 75 athletes eligible for inclusion, 60 (80.0%) of whom had minimum 2-year follow-up. All patient-reported outcome (PRO) scores demonstrated significant improvements at latest follow-up (P < .001). Mean satisfaction was 7.9. No patients converted to arthroplasty. Painful snapping was resolved in 55 athletes (91.7%). Nine athletes (15.0%) had nonpainful snapping at follow-up. Thirty-nine (65%) returned to their sport. Forty (66.7%) maintained or improved their competitive abilities. There was one case (1.6%) of temporary postoperative numbness. There were no complaints of weakness in hip flexion. Forty-one IFL athletes were matched to 41 controls. No differences were detected in demographics, follow-up time, intraoperative findings, procedures, mean magnitudes of improvement, or return to sports. CONCLUSIONS: In competitive athletes, IFL during hip arthroscopy is safe and demonstrates favorable improvements in PROs and VAS, high satisfaction, and high rate of symptom resolution at a minimum of 2 years postoperatively. Most patients were able to return to sports and maintain or improve their competitive levels. These results were similar to a control group of athletes not requiring IFL. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 29108785 TI - Semaphorin7A aggravates coxsackievirusB3-induced viral myocarditis by increasing alpha1beta1-integrin macrophages and subsequent enhanced inflammatory response. AB - Semaphorin7A (Sema7A) has been reported to play various roles in nerve axon growth, tumor suppression, and tissue remodeling, as well as regulation of intestinal inflammation diseases. Viral myocarditis (VMC) characterized by viral myocardial-cell necrosis and inflammatory cell infiltration is a common clinical disease of the cardiovascular system. However, the role of Sema7A in coxsackievirus B3 (CVB3)-induced VMC has not been reported. In this study, we generated an acute VMC mouse model by CVB3 infection, and manipulated Sema7A expression by in vivo polyethyleneimine-mediated Sema7A down-regulation. Our results indicated that Sema7A was up-regulated in cardiomyocytes during VMC, and that Sema7A down-regulation following short hairpin RNA interference or mAb neutralization effectively protected mice from VMC. Additionally, reduced inflammatory responses were observed along with Sema7A down-regulation. Furthermore, adoptive transfer of alpha1beta1-integrin macrophages exacerbated CVB3-induced myocarditis, suggesting the significance of alpha1beta1-integrin macrophages in response to VMC. We observed that co-culture of neonatal myocardiocytes with macrophages increased the percentage of alpha1beta1-integrin macrophages, while Sema7A neutralization reduced alpha1beta1-integrin macrophages in heart tissue of VMC mice. These results demonstrated that Sema7A, as an inflammation regulator in CVB3-induced VMC, might interact with alpha1beta1 integrin in macrophages to enhance the inflammatory response and aggravate disease severity. Our findings provided insight into the potential role of Sema7A as a therapeutic treatment for VMC. PMID- 29108787 TI - Spiked helmet pattern ST elevation due to severe abdominal distension. PMID- 29108786 TI - Early Phase Clinical Trial Designs - State of Play and Adapting for the Future. AB - The process of anti-cancer drug development is complex, with high attrition rates. Factors that may optimise this process include well-constructed and relevant pre-clinical testing and use of biomarkers for patient selection. However, the design of early phase clinical trials will probably play a vital role in both the robust clinical investigation of new targeted therapies and in streamlining drug development. In this overview, we assess current concepts in phase I clinical trials, highlighting issues and opportunities to improve their meaningfulness. The particular challenge of how to design combination trials is addressed, with focus on the potential of new adaptive and model-based designs. PMID- 29108788 TI - Peri-procedural ST segment resolution during Primary Percutaneous Coronary Intervention (PPCI) for acute myocardial infarction: predictors and clinical consequences. AB - OBJECTIVE: ECG ST segment resolution (STR) has been used to assess myocardial perfusion in STEMI patients undergoing PPCI. However, in most of the studies ECGs recorded at different time points after the actual procedure have been used, limiting the options of therapeutic interventions while the patient is still in the catheterisation laboratory. The aim of this study was to investigate the presence and clinical consequences of intra-procedural STR during PPCI. METHODS: We analysed 12 lead ECGs recorded at the onset and the end of the PPCI procedure, measuring STR in the lead with maximum ST elevation on the initial recording. STR was defined as good when > 50% compared to baseline. RESULTS: Pre and immediately post PPCI ECGs were recorded in 467 STEMI cases whilst the patient was on the catheter lab table. Mean patient age was 63 (+/- 12) years old and 75% were men. Mean duration of symptoms to admission was 3.8 (+/- 3.4) hours and 51% of infarcts were anterior. Good ST resolution at the end of the procedure was seen in 46.5% of patients and was observed more commonly in inferior compared to anterior infarcts (60.1% vs. 32.6%, p<0.001), and in current smokers (53.2% vs. 42.4%, p=0.031). In patients presenting with symptoms for < 4 hours, good STR was more common (74% vs. 66%, p=0.019). Thrombus aspiration was used more frequently in patients who had good STR (88.5% vs 79.8% p=0.011). Patients with good ST resolution had a shorter mean hospital length of stay (3.8 vs. 4.5 days, p=0.009) and a higher left ventricular ejection fraction (49.9% vs. 44.2%, p<0.001) measured by transthoracic echocardiography prior to discharge. CONCLUSION: Good peri-procedural ST resolution was seen in less than half of STEMI patients undergoing PPCI. There were important clinical consequences of good ST resolution. Identification of suboptimal peri-procedural ST resolution could help identify patients who may benefit from new treatments aimed at protecting the microcirculation, whilst the patients are still in the angiography laboratory. PMID- 29108789 TI - Mauricio B. Rosenbaum and the Argentinian School of Electrocardiography. PMID- 29108790 TI - The association between electrocardiographic R wave peak time and coronary artery disease severity in patients with non-ST segment elevation myocardial infarction and unstable angina pectoris. AB - BACKGROUND: We aimed to evaluate possible association between QRS duration (QRSD), R wave peak time (RWPT), and coronary artery disease severity identified using the SYNTAX score (SS) in patients with unstable angina pectoris (USAP) or non-ST segment elevation myocardial infarction (NSTEMI). METHOD: A total of 176 USAP/NSTEMI patients were enrolled in the study. RESULTS: The high SS group (>22, n:45) patients had a higher prevalence of diabetes mellitus (DM); presence of ST segment depression >=0.5 mm and 1 mm; ST segment elevation in the AVR lead (AVRSTE); longer QRSD and RWPT; and lower left ventricular ejection fraction (LVEF) than the low SS group (<=22, n: 131). The LVEF, AVRSTE, and RWPT (OR: 1.035, 95% CI: 1.003-1.067; p = 0.030) were independent predictors of high SS. CONCLUSION: The present study demonstrated that RWPT and AVRSTE could be used as predictors of high SS. PMID- 29108792 TI - Comparison of the Primary Stability of a Porous Coated Acetabular Revision Cup With a Standard Cup. AB - BACKGROUND: The number of revision hip arthroplasty procedures has been increasing substantially, with the acetabular component requiring component revision in over half of the cases. New porous implant designs attempt to improve outcomes due to improved osseointegration; however, sufficient primary stability is paramount for good osseointegration. METHODS: We compared 2 revision cups of the same geometry, yet different surface properties in an in vitro scenario: a porous titanium surface and a conventional sintered-bead titanium surface. These were tested in 10 cadaveric pelvises under a physiologic cyclic partial weight bearing scenario. Each side was randomly implanted with one of the implants. Relative motion between the bone and cup was measured using an optical measuring device. Statistical evaluation was carried out descriptively using a covariance analysis with repeated measures and a test of fixed effects, with significance determined as P < .05. RESULTS: The conventional cup displayed an average relative motion of 28.02 MUm; and the porous implant displayed an average relative motion of 33.42 MUm. There was no statistically significant difference between the two with regard to the resultant relative motion (P = .2649). The bone mineral density does have a significant influence on resultant relative motion (P = .0406), with higher bone mineral density correlating with less relative motion in both implants. CONCLUSION: The porous implant provides similar primary stability to the conventional implant in the tested scenario; the motion of both implants relative to the bone was within safe limits for osseointegration. Bone stock must be considered when choosing implant type and postoperative care. PMID- 29108791 TI - Improvement of blood loss volume estimation by paramedics using a pictorial nomogram: A developmental study. AB - INTRODUCTION: To propose and evaluate a nomogram to assist paramedics to visually estimate the external blood loss on a non-absorbent surface and to identify whether the nomogram improves visual estimation. METHODS: The study was a prospective, paired-control design (pre-training control group & post-training group), utilizing Emergency Medical Assistant (EMA) I and II trainees from the Hong Kong Fire Services Ambulance Command Training School. A nomogram (blood loss volume to area on a non-absorbent surface) was prepared to aid blood loss estimation. All participants estimated four scenarios of blood pools twice (A: 180mL; B: 470mL;C: 940mL; D: 1550mL) before and after using the nomogram. Every participant received two-minute training on how to use the nomogram correctly. The difference between the estimations and the actual volume in each scenario was calculated. The absolute percentage errors were used for direct comparison and identification of improvement between visual estimation and the use of the nomogram. RESULTS: Sixty-one participants with an average of 3-year paramedic field experience were recruited by convenience sampling. In combining all scenarios, the median of absolute percentage error of 61 participants was 43% (95%CI 38.0-50.9%) in visual estimation, while it was 23% (95%CI 17.4-27.0%) when using the nomogram. There was a significant reduction in absolute percentage error between visual estimation and the use of the nomogram (p<0.0001). CONCLUSION: The nomogram significantly improved the estimation of external blood loss volume. PMID- 29108793 TI - When Does the Knee Feel Normal Again: A Cross-Sectional Study Assessing the Forgotten Joint Score in Patients After Total Knee Arthroplasty. AB - BACKGROUND: The forgotten joint score (FJS) is a recent scoring system that assesses how natural the prosthesis feels after total joint arthroplasty. Although the FJS has been extensively applied in populations with total hip prosthetics, less is known about the patients undergoing total knee arthroplasty (TKA). The purpose of this study is to investigate the temporal relationship between TKA and the FJS. METHODS: We evaluated 566 patients after TKA using the FJS questionnaire. Scores were calculated at the follow-up intervals of 1 (n = 79), 6 (n = 78), 12 (n = 81), 24 (n = 100), 36 (n = 76), 48 (n = 75), and 60 (n = 77) months. The scores ranged from 0-100, with a higher score indicating a more natural or "forgotten" joint. RESULTS: Postoperative FJS averages were 39.3 +/- 27.4 at 1 month, 59.4 +/- 28.3 at 6 months, 72.5 +/- 24.2 at 1 year, 76.4 +/- 23.4 at 2 years, 75.1 +/- 24.2 at 3 years, 68.6 +/- 28.7 at 4 years, and 64.4 +/- 29.0 at 5 years. The average score at 1 month was significantly lower than the average scores at all other intervals. The average score at 6 months was significantly lower than the average scores at 12, 24, and 36 months. The average score at 60 months was significantly lower than the average score at 24 months. CONCLUSION: Based on the findings of this study, patients can expect marked improvement in the natural feel of the prosthesis during the first year after TKA, slight continued improvement at 2 and 3 years, and a decline after 4 years. PMID- 29108794 TI - Comparison of Customized Cutting Block and Conventional Cutting Instrument in Total Knee Arthroplasty: A Randomized Controlled Trial. AB - BACKGROUND: Customized cutting block (CCB) was designed to ensure the accurate alignment of knee prostheses during total knee arthroplasty. Given the paucity of CCB efficacy data, we compare CCB with conventional cutting guide using a randomized controlled trial. METHODS: One hundred eight osteoarthritic knee patients underwent total knee arthroplasty by one experienced surgeon were randomized to receive CCB (n = 54) or conventional cutting instrument (CCI) surgery (n = 54). The primary outcomes were limb alignment, prostheses position, and operative time. The secondary outcomes were hemodynamic alteration after surgery, functional outcomes (modified Western Ontario and McMaster University Osteoarthritis Index) and range of motion at 2 years after surgery. RESULTS: Mean hip-knee-ankle angle in the CCB group was 179.4 degrees +/- 1.8 degrees vs 179.1 degrees +/- 2.4 degrees in the CCI group, Delta = 0 (95% confidence interval [CI] -0.6 to 1.1, P = .55). Mean operative time was faster in the CCB arm: 93 +/- 12 vs 104 +/- 12 minutes, Delta = 11 (95% CI -16.7 to -7.2, P < .0001). There were no differences in hemodynamic parameters, mean blood loss (446 [CCB] vs 514 mL [CCI], Delta = -68 [95% CI -138 to 31 mL, P = .21]), postoperative hemoglobin changes, incidence of hypotension (systolic <90 mm Hg), oliguria, and rates of blood transfusion. Functional outcomes and range of motion were also similar. CONCLUSION: There was no improvement in alignment, hemodynamic changes, blood loss, and knee functional outcomes. CCB reduced surgical time by 11 minutes in our population. CCB cost-effectiveness should be further investigated. PMID- 29108796 TI - Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction. AB - Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation. AD is characterized clinically by cognitive deficit and pathologically by the deposition of beta amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain. Withanone (WS-2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid beta 42 and attenuated the elevated levels of pro-inflammatory cytokines like TNF alpha, IL-1 beta, IL-6, MCP-1, Nitric oxide, lipid peroxidation and both beta- and gamma- secretase enzymatic activity. Administration of WS-2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild-to-moderate AD. WS-2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of Abeta processing, protection against oxidative stress and anti-inflammatory effects. PMID- 29108795 TI - Severity of COPD and its relationship with IL-10. AB - BACKGROUND: The present study was designed to compare inflammatory and metabolic responses according to severity of airflow among patients with COPD and to verify the relationship between pulmonary function, body composition, metabolic and inflammatory profile. METHODS: Fifty-one patients with mild to very severe COPD were recruited and divided according lung function in Mild-moderate (GOLD 1-2) n= 21; Severe (GOLD 3) n=25 and Very severe (GOLD 4) n=5. Patients were submitted to assessments of lung function (spirometry), functional exercise capacity (6-min walk test), body composition (Octopolar bioelectrical impedance), metabolic profile (glucose, triglycerides, total cholesterol, HDL-cholesterol and albumin (colorimetric assay)) and inflammatory profile (cytokines: IL-6, IL-10, TNF-alpha and IL-15 (ELISA)). RESULTS: We found that patients in GOLD 3 group had lower levels of IL-10, triglycerides, visceral fat area, and higher IL-6 and IL-6/IL-10 ratio when compared to GOLD 1-2 patients. Additionally, GOLD 1-2 group presented negative correlation between TNF-alpha and HDL cholesterol (p= .01) and positive correlation between IL-15 and FEV1/FVC (p=.01), while GOLD 3 group showed positive correlation between IL-6 and IL-10 (p< .01), IL-6 and total cholesterol (p<.01) and negative correlation between IL-10 and HDL-cholesterol (p=.01). CONCLUSION: Our findings suggest that patients with severe COPD can exhibit compromised "inflammatory status", characterized by higher IL6, IL-6/IL-10 ratio and lower IL-10 concentration. Furthermore, IL-10 seems to be an interesting cytokine to be investigated in this kind of patients. PMID- 29108798 TI - The unexpected success of NRTIs in second-line treatment. PMID- 29108799 TI - Corrigendum to "Remote management of low- to intermediate-risk chest pain: a case series" (Am J Emerg Med [2017]). PMID- 29108800 TI - Nano- and neurotoxicology: An emerging discipline. AB - The present critical review analyzes the question of how nanoparticles from continuously growing industrial production and use of nanomaterials may impact human brain health. Available evidence suggests incomplete effectiveness of protective barriers of the brain against nanoparticles translocation to the brain. This raises concerns of potential effects of manufactured nanoparticles on brain functions, given that nanoparticle's potential to induce oxidative stress, inflammation, death by apoptosis, or changes in the level of expression of certain neurotransmitters. Most concerns have not been studied sufficiently and many questions are still open: Are the findings in animals transposable to humans? What happens when exposure is chronic or protracted? What happens to the developing brain when exposure occurs in utero? Are some nanoparticles more deleterious, given their ability to alter protein conformations and aggregation? Aside from developments in nanomedicine, the evidence already available fully justifies the need to specifically evaluate the interactions between nanoparticles and the nervous system. The available data clearly indicates the need for original dedicated experimental models and tools for neurotoxicological research on the one hand, and the need for epidemiological studies of neurodegenerative diseases in manufactured nanoparticle-exposed populations, on the other. A combination of nanotoxicology with neurology in a novel discipline, with its specific tools and methods of investigation, should enable answering still unresolved questions. PMID- 29108802 TI - rTMS as an add-on treatment for maladaptive daydreaming over 10 years in patients with schizophrenia: A case report. PMID- 29108797 TI - Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial. AB - BACKGROUND: Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings. METHODS: We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided alpha of 0.025, and superiority with a two-sided alpha of 0.025. The EARNEST trial is registered with ISRCTN, number 37737787. FINDINGS: Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0.07; lower 95% confidence limit for difference 10.2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0.003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification. INTERPRETATION: Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings. FUNDING: European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO. PMID- 29108803 TI - Factor analysis of symptom dimensions (psychotic, affective and obsessive compulsive symptoms) in schizophrenia. AB - AIM: To carryout factor analysis of symptom profile of patients with schizophrenia assessed by using positive and negative syndrome scale (PANSS), Calgary depression rating scale (CDSS), Young mania rating scale (YMRS) and YBOCS checklist. METHODOLOGY: 181 patients of schizophrenia were assessed on PANSS, CDSS, YMRS and YBOCS checklist. RESULTS: Factor analysis of PANSS yielded 3 factor structure (positive, negative, anxiety). When the items of CDSS were added to the PANSS items, total number of factors increased to 4 with depression emerging as a separate factor. Addition of YMRS to PANSS and CDSS led to emergence of 5 factor model. Further addition of YBOCS checklist led to emergence of a 7 factor model (positive, depressive, obsessive compulsive, negative, manic, anxiety and obsessive compulsive-2), which explained 49.85% variance of the data. Positive symptoms emerged as the factor-1. Depressive symptoms loaded on the factor-2, negative symptoms loaded on to factor-4, manic symptoms loaded onto factor-5 and anxiety symptoms loaded onto factor-6. OC symptoms loaded onto factor 3 and 7. CONCLUSIONS: Present study suggests that when multiple scales are used for assessment of various symptoms of schizophrenia, the symptoms separate out into 7 factors. This finding suggests that clinical assessment of schizophrenia should not be limited to core psychotic symptoms only and structured instruments must be used to elicit other symptoms too while monitoring the clinical picture of patients with schizophrenia. PMID- 29108804 TI - Statewide Trends in Utilization and Outcomes of Endovascular Treatment of Acute Ischemic Stroke: Analysis of Minnesota Hospital Association Data (2014 and 2015). AB - BACKGROUND: The study aims at examining the changes in endovascular procedures utilization after the publication of the clinical trials showing their benefit in patients with acute ischemic stroke (AIS). METHODS: Minnesota Hospital Association database from 137 member hospitals was used to calculate the statewide utilization rates for 2 periods: prior to (calendar year 2014) and after (calendar year 2015) the publication of multiple randomized clinical trials showing the efficacy of endovascular therapy. Patients were identified using International Classification of Disease, Clinical Modification, 9th revision (ICD 9) or ICD-10 codes (ICD-10 started October 2015). Utilization rates for endovascular treatment were calculated monthly, quarterly, and annually. RESULTS: Of the 13,043 patients admitted with AIS, 434 patients (mean age 68.5 +/- 15.5 years; 51.2% women) received endovascular treatment. The number of procedures increased from 194 in 2014 to 240 in 2015. Utilization rate was 3.4% in the first quarter of 2014, gradually declined to reach its lowest value (2.6%) the last quarter of 2014, then steadily increased to reach its peak (4%) in the last quarter of 2015. Procedures performed at comprehensive stroke centers increased from 52% of total procedures in 2014 to 57.5% in 2015, whereas those performed at primary stroke centers decreased from 22.6% to 19.5%. In 2015, fewer patients had hypertension (50.4% versus 60.3%; P = .039) and more patients had chronic kidney disease (28.3% versus 15.5%; P = .001) compared with 2014. Intracranial hemorrhage, mortality rate, and rate of home discharge were similar between the 2 years. CONCLUSION: Utilization of endovascular procedures for treatment of AIS has been rapidly influenced by medical literature. PMID- 29108801 TI - Mechanisms of placebo analgesia: A dual-process model informed by insights from cross-species comparisons. AB - Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context. PMID- 29108805 TI - Stroke Risk Is Low after Urgently Treated Transient Ischemic Attack. AB - BACKGROUND: Over the last decades, the approach to patients with transient ischemic attack (TIA) has shifted from treating only patients considered at high risk of recurrent stroke, to referring all patients with TIA to urgent assessment and immediate initiation of preventive treatment. The data on how this change has influenced the stroke rate after TIA are limited. Thus, the primary aim of this study was to identify the incidence of stroke recurrence after TIA. Second, we wanted to evaluate the ABCD2 score as a predictor of recurrent stroke. METHODS: Patients discharged with a diagnosis of TIA from the Stroke Unit at Akershus University Hospital between January 1, 2013 and December 31, 2013 were included in the study. Data were obtained from the electronic medical records. Readmission data to capture recurrent strokes were registered until December 31, 2015. RESULTS: In total, 261 patients were included. Mean age was 70.7 years. Stroke incidence at 1 month, 1 year, and the end of follow-up was 1.5% (n = 4), 3.4% (n = 9), and 4.2% (n = 11), respectively. Median time from TIA until recurrent stroke was 90 days. The ability of the ABCD2 score to predict recurrent stroke was low. CONCLUSIONS: Urgent admission of patients with TIA is followed by a very low risk of early and late recurrent stroke. The ABCD2 score did not identify patients at high risk of recurrent stroke. PMID- 29108806 TI - Cerebral Infarcts by Nonbacterial Thrombotic Endocarditis Associated with Adenomyosis: A Case Report. AB - We report a case of multiple embolic cerebral infarcts associated with nonbacterial thrombotic endocarditis (NBTE) in a patient with adenomyosis. The patient presented with dysarthria, left perioral sensory change, and left-hand weakness. Magnetic resonance imaging revealed multiple vascular territory infarctions involving the bilateral cerebellum and the right precentral gyrus. Magnetic resonance angiography was normal. d-Dimer, carbohydrate antigen (CA) 19 9, and CA125 levels were elevated. Abdominal and pelvic computed tomography with iodine contrast enhancement revealed a huge adenomyosis with left ovarian cyst. Transesophageal echocardiography (TEE) with agitated saline injection test demonstrated shaggy vegetation at the coapting edge of both mitral leaflets and mitral regurgitation. A diagnosis of NBTE was established and treatment with anticoagulation was initiated. Two weeks later, the thrombi reduced significantly on follow-up TEE and transthoracic echocardiography. The patient underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy, and pathological specimens confirmed adenomyosis. The possibility that adenomyosis can be associated with NBTE suggests one of the underlying thromboembolic mechanisms in adenomyosis. Clinicians should be aware of the potential thromboembolic risk of adenomyosis. Further reporting of similar cases is needed to confirm the thromboembolic mechanism. PMID- 29108807 TI - Is the Intensity or Duration of Treadmill Training Important for Stroke Patients? A Meta-Analysis. AB - BACKGROUND: Stroke, the third highest cause of death after cancer and cardiac diseases, is a strong cause of adult disability in most countries. Therefore, the aim of the current meta-analysis was to examine the most effective intensity and duration of treadmill training on motor performance in stroke subjects. METHODS: Suitable studies were recognized from January 1980 to July 2015 using PubMed as the main search engine. There were noticeable biases such as training intensity, training duration (>=2 weeks), relative training intensity, and Vo2max, which were controlled. Subgroup classifications for human studies were prepared based on previous studies and were determined as follows: low intensity (<=.6 m/s)-low volume/duration (<=500 minutes), low intensity (<=.6 m/s)-high volume/duration (>500 minutes), high intensity (>.6 m/s)-low volume/duration (<=500 minutes), and high intensity (>.6 m/s)-high volume/duration (>500 minutes). RESULTS: Forty-nine articles were identified for human studies. This meta-analysis exhibited treadmill training regardless if intensity and volume/duration had a significantly greater recovery of motor function than did no training (standard mean difference [SMD] = .601; 95% confidence interval [CI] = .546-.657; P = .0001). Also, for the low-intensity, low-volume/-duration strategy, training on a treadmill displayed a significantly greater motor function rehabilitation than did no training (SMD = .75; 95% CI = .64-.85; P = .0001). CONCLUSIONS: The current meta-analysis showed that low-intensity (<=.6 m/s)-high-duration/-volume (>500 minutes) treadmill training as a rehabilitation strategy had the highest SMD to ameliorate stroke-induced dysfunctions compared with the other strategies. PMID- 29108808 TI - Fatal Intracranial Aneurysms and Dissections Causing Subarachnoid Hemorrhage: An Epidemiological and Pathological Analysis of 607 Legal Autopsy Cases. AB - BACKGROUND: There are no detailed reports, in terms of epidemiology and pathology, on intracranial aneurysms and on dissections that were found in unexpected fatal subarachnoid hemorrhage (SAH) cases. In this report we analyzed, based on large-sized medicolegal autopsy cases, the detailed epidemiology and pathological aspects of both lesions. METHODS: We analyzed 607 autopsy cases of unexpected fatal SAHs including 496 aneurysms and 111 dissections. RESULTS: The following results were obtained: (1) Patients who died of dissections were younger than those who died of aneurysms; (2) symptom prevalence rates of aneurysms were 31.9%, appearing to be lower than those in previous studies; (3) a significantly higher prevalence of clinical symptoms was found in patients with dissections (60.5%) than patients with aneurysms; (4) hypertensive cardiomegaly was indicated in more than 80%, while no obvious difference in incidence in hypertensive cardiomegaly was noted between aneurysms and dissections; (5) aneurysms were found to occur much more frequently in the anterior communicating artery (31.9%) and vertebral arteries (7.5%), while dissections were found much more commonly in vertebral arteries (93.7%); and (6) the size of aneurysms was much smaller in general than that previously regarded as a risk factor of rupturing. CONCLUSIONS: These data might help in the prompt intervention in SAH and also in the prevention of lethal SAH in clinical settings. PMID- 29108809 TI - Response to Symptoms and Prehospital Delay in Stroke Patients. Is It Time to Reconsider Stroke Awareness Campaigns? AB - BACKGROUND: Despite recent advances in acute stroke care, reperfusion therapies are given to only 1%-8% of patients. Previous studies have focused on prehospital or decision delay. We aim to give a more comprehensive view by addressing different time delays and decisions. METHODS: A total of 382 patients with either acute stroke or transient ischemic attack were prospectively included. Sociodemographic and clinical parameters and data on decision delay, prehospital delay, and first medical contact were recorded. Multivariate logistic regression analyses were conducted to identify factors related to decision delay of 15 minutes or shorter, calling the Extrahospital Emergency Services, and prehospital delay of 60 minutes or shorter and 180 minutes or shorter. RESULTS: Prehospital delay was 60 minutes or shorter in 11.3% of our patients and 180 minutes or shorter in 48.7%. Major vascular risk factors were present in 89.8% of patients. Severity was associated with decision delay of 15 minutes or shorter (odds ratio [OR] 1.08; confidence interval [CI] 1.04-1.13), calling the Extrahospital Emergency Services (OR 1.17; CI 1.12-1.23), and prehospital delay of 180 minutes or shorter (OR 1.08; CI 1.01-1.15). Adult children as witnesses favored a decision delay of 15 minutes or shorter (OR 3.44; CI 95% 1.88-6.27; P < .001) and calling the Extrahospital Emergency Services (OR 2.24; IC 95% 1.20-4.22; P = .012). Calling the Extrahospital Emergency Services favored prehospital delay of 60 minutes or shorter (OR 5.69; CI 95% 2.41-13.45; P < .001) and prehospital delay of 180 minutes or shorter (OR 3.86; CI 95% 1.47-10.11; P = .006). CONCLUSIONS: Severity and the bystander play a critical role in the response to stroke. Calling the Extrahospital Emergency Services promotes shorter delays. Future interventions should encourage immediately calling the Extrahospital Emergency Services, but the target should be redirected to those with known risk factors and their caregivers. PMID- 29108810 TI - Sub-cellular organization of the melanin-concentrating hormone neurons in the hypothalamus. AB - Melanin-concentrating hormone (MCH) is a potent orexigenic and sleep-promoting neuropeptide in mammals produced predominately by hypothalamic neurons which project to a wide variety of brain areas. Several MCH producing neurons contain MCH as the only neuropeptide, while others comprise cocaine- and amphetamine regulated transcript (CART) as well. The intrahypothalamic localization and the projection pattern of these two subpopulations are distinct. To provide structural grounding to understand the mechanism of action of MCH neurons we show here the subcellular localization of the neuropeptides in the two subpopulations within the hypothalamus of healthy young male mice by applying single and double immunofluorescence labelling.; Thick, prominent MCH immunopositive reticulation and fine discrete granules are detected within the perikarya of both CART positive and CART-free MCH neurons. Typically, one or more immunoreactive processes emanate from the perikarya. The bulk of CART immunoreactivity is also centrally positioned, surrounded by sparse immunoreactive granules within the perikarya and in the processes. In double immunopositive neurons, the two neuropeptides seem to colocalize in the heavily labelled central area, while the immunopositive granules in the cell body periphery and in the processes apparently contain either MCH or CART. This spatial arrangement suggests that MCH and CART, after being synthetized and processed in the endoplasmic reticulum/Golgi complex, are sorted into separate dense core vesicles, which then enter into the cell processes. This mechanism allows for both concerted and independent regulation of the transport and release of MCH and CART. PMID- 29108811 TI - The antimicrobial effect of CEN1HC-Br against Propionibacterium acnes and its therapeutic and anti-inflammatory effects on acne vulgaris. AB - Propionibacterium acnes is a commensal bacterium, which is involved in acne inflammation. An antimicrobial peptide named CEN1HC-Br, which was isolated and characterized form the green sea urchin, has been shown to possess broad-spectrum antibacterial activity. Little is known concerning the potential effects of its antibacterial and anti-inflammatory properties against P. acnes. To examine the potency of CEN1HC-Br in acne treatment, we conducted experiments to analyze the antibacterial and anti-inflammatory activities of CEN1HC-Br both in vitro and in vivo. The antimicrobial activity of CEN1HC-Br was evaluated by minimal inhibitory concentration (MIC) assays using the broth dilution method. To elucidate the in vitro anti-inflammatory effect, HaCaT cells and human monocytes were treated with different concentration of CEN1HC-Br after stimulation by P. acnes. The expression of TLR2 and the secretion of the pro-inflammatory cytokines IL-6, IL 8, IL-1beta, TNF-alpha, IL-12, respectively, were measured by enzyme immunoassays. An evaluation of P. acnes-induced ear edema in rat ear was conducted to compare the in vivo antibacterial and anti-inflammatory effect of CEN1HC-Br, the expression of IL-8, TNF-alpha, MMP-2 and TLR2 was evaluated by immunohistochemistry and real time-PCR. CEN1HC-Br showed stronger antimicrobial activity against P. acnes than clindamycin. CEN1HC-Br significantly reduced the expression of interleukin IL-12p40, IL-6, IL-1beta, TNF-alpha and TLR2 in monocytes, but they were not influenced by clindamycin. Both CEN1HC-Br and Clindamycin attenuated P. acnes-induced ear swelling in rat along with pro inflammatory cytokines IL-8, TNF-alpha, MMP-2 and TLR2. Our data demonstrates that CEN1HC-Br is bactericidal against P. acnes and that it has an anti inflammatory effect on monocytes. The anti-inflammatory effect may partially occur through TLR2 down-regulation, triggering an innate immune response and the inhibition of pro-inflammatory cytokines. PMID- 29108813 TI - [Translation, cultural adaptation and validation of the Salt Knowledge Questionnaire to the Spanish language]. AB - INTRODUCTION: In order to reduce salt consumption in Spanish speaking countries it is necessary to know the level of salt knowledge in the population. However, there are no tools in Spanish to measure salt knowledge, but the only valid tool of measurement is the 'Salt Knowledge Questionnaire' (SKQ) developed in Australia, in English. MATERIALS AND METHODS: A validation study was conducted in three phases: (Phase1) Translation of the original Australian version into Spanish; (Phase2) Cultural adaptation based on a Spanish-speaking population such as Peru and following criteria used in the development of the original questionnaire which was evaluated by a panel of experts; (Phase3) Construct validity by comparing the scores of three groups (experts, medical students and non-experts) and reliability by performing a test retest. RESULTS: The translation of the SKQ into Spanish maintained a semantic equivalence with the original questionnaire and a panel of experts accepted the cultural adaptation. The SKQ enables discrimination between those who know and those who do not because differences of scores were found between the group of experts, students and non-experts (P<.001). A good overall internal consistency of the instrument was found (KR20=0.69) and a good overall intraclass correlation (0.79) and no test variations in test-retest (P>.05). CONCLUSIONS: The SKQ questionnaire in Spanish is valid, reliable and is a suitable first tool to measure knowledge about salt in the Spanish language. It is considered possible to adapt it culturally to the Spanish-speaking country that wishes to use it. PMID- 29108812 TI - Correlation of Brown Adipose Tissue with Other Body Fat Compartments and Patient Characteristics: A Retrospective Analysis in a Large Patient Cohort Using PET/CT. AB - RATIONALE AND OBJECTIVES: The objective of this study was to assess the relationship of brown adipose tissue (BAT) activity with different fat compartments of the body, body mass index (BMI), outdoor temperature, thyroid stimulating hormone (TSH) levels, blood glucose, age, and sex in a large patient population using F-18-fluordesoxyglucose positron emission tomography-computer tomography (FDG-PET/CT) scans obtained under thermoneutral conditions. MATERIALS AND METHODS: FDG-PET/CT scans of 4852 patients were retrospectively analyzed for BAT activity. The volumes of the different fat compartments visceral adipose tissue (VAT), subcutaneous adipose tissue (SCAT), and liver fat, were assessed by computed tomography. Age, sex, TSH levels, blood glucose levels, BMI, primary disease, and the outdoor temperature were determined. Multiple linear regression analyses were performed to identify independent relationships between the parameters. RESULTS: The VAT, SCAT, and liver fat content were lower in BAT positive patients than in BAT-negative patients (each P < 0.0001). BAT-positive patients had a lower BMI (P < 0.0001) and were more often female (P < 0.0001), younger (P < 0.0001), and had higher TSH levels (P = 0.0002), whereas the outdoor temperature and the blood glucose level were not different compared to BAT negative patients. Age, sex, VAT, and SCAT were independent factors related to BAT. CONCLUSIONS: Age, sex, and VAT are the most important determinants of BAT activity under thermoneutral conditions. VAT reflects the association between BAT activity and body fat mass more clearly than BMI. The strength of the association between VAT and BAT decreases during aging in men, but increases in women. This may indicate a different importance of BAT activity for obesity in men and in women. PMID- 29108814 TI - Waist-to-height ratio and sedentary lifestyle as predictors of metabolic syndrome in children in Ecuador. AB - OBJECTIVE: To determine the predictors and prevalence of metabolic syndrome (MS) and the presence of vascular inflammation in apparently-normal children (10-15 years) of both sexes in Guayaquil, Ecuador. STUDY DESIGN AND METHODS: We included 395 apparently-healthy students from a middle-income school in a cross-sectional survey. Informed consent was obtained from students and parents. Anthropometric measurements including blood pressure (BP), body mass index (BMI) and waist-to height ratio (WHtR), and blood tests were recorded. Vascular inflammation parameters were assessed. Percentiles of the different parameters were used, and MS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP-ATPIII). Waist circumference>P 75, blood pressure>P 90, glucose>100mg/dl, triglycerides>100mg/dl, HDL<45mg/dl. If 3 of the 5 criteria were present, this was considered MS. RESULTS: The mean age was 12 years (186 boys, 209 girls). The overall prevalence of MS was 9.37% (6.33% in girls, 3.04% in boys). Sustained hypertension was detected in 6.6% of children and pre-hypertension in 7.1%. Obesity was found in 1.8% of subjects, and overweight in 15.2%. Triglycerides has a RR 2.34 (1.97-2.76); HOMA index has a RR 1.97(1.62-2.40); HDL cholesterol has a RR 1.84(1.58-2.13); Insulin level has a RR 1.53(1.40-1.67) and interleukin 6 has RR 1.83(1.20-2.79). Serum glucose, total cholesterol and LDL-Cholesterol had no association with the metabolic syndrome. HDL-Cholesterol<45mg/dl and triglyceride>100mg/dl were present in 70% of subjects with MS. The WHtR threshold>=0.5 was 100% sensitive in both sexes (67% specificity in boys and 69% in girls). There were significant associations between the WHtR and pre-hypertension and sedentary lifestyle (P<0.001 and P<0.003 respectively). A WHtR value of >=0.50 indicated a 2.2-fold increased risk of MS compared with normal WHtR, and normal weight. CONCLUSIONS: A WHtR>=0.5 was 100% sensitive in detecting MS in 10-15 year-old boys and girls in the normal or overweight range of the BMI. This assessment is a simple and practical tool for use in population-based studies of cardiovascular risk. When combined with pre hypertension and a sedentary lifestyle, the WHtR is highly sensitive in predicting MS. PMID- 29108815 TI - Noninvasive BP Monitoring in the Critically Ill: Time to Abandon the Arterial Catheter? AB - Although its reliability is often questioned, noninvasive BP (NIBP)-monitoring with an oscillometric arm cuff is widely used, even in critically ill patients in shock. When correctly implemented, modern arm NIBP devices can provide accurate and precise measurements of mean BP, as well as clinically meaningful information such as identification of hypotension and hypertension and monitoring of patient response to therapy. Even in specific circumstances such as arrhythmia, hypotension, vasopressor infusion, and possibly in obese patients, arm NIBP may be useful, contrary to widespread belief. Hence, postponing the arterial catheter insertion pending the initiation of more urgent diagnostic and therapeutic measures could be a suitable strategy. Given the arterial catheter-related burden, fully managing critically ill patients without any arterial catheter may also be an option. Indeed, the benefit that patients may experience from an arterial catheter has been questioned in studies failing to show that its use reduces mortality. However, randomized controlled trials to confirm that NIBP can safely fully replace the arterial catheter have yet to be performed. In addition to intermittent measurements, continuous NIBP monitoring is a booming field, as illustrated by the release onto the market of user-friendly devices, based on digital volume clamp and applanation tonometry. Although the imperfect accuracy and precision of these devices would probably benefit from technical refinements, their good ability to track, in real time, the direction of changes in BP is an undeniable asset. Their drawbacks and advantages and whether these devices are currently ready to use in the critically ill patient are discussed in this review. PMID- 29108816 TI - Obestatin stimulates the somatotrophic axis activity in sheep. AB - The effects of obestatin (an anorexigenic peripheral peptide) on somatotrophic axis activity in ruminants have not yet been determined. The aim of this study was to investigate the consequence of intracerebroventricular infusions of obestatin on the activity of the somatotrophic axis in peripubertal female sheep. Animals were randomly divided into two groups: control group received intracerebroventricular infusions of the vehicle, and the obestatin group was infused with obestatin (25 ug/120 uL h-1). The series of four hourly infusions on three consecutive days were performed. The blood samples were collected on day 0 and on day 3. Immediately after the end of experiment sheep were slaughtered. Parts of the brains were fixed in situ for further immunohistochemical analysis, while the remaining brains were frozen for Real Time RT-qPCR analysis. Substantial changes in the activity of the somatotrophic axis were observed in obestatin-infused sheep. In those animals obestatin evoked an increase in growth hormone-releasing hormone (GHRH) mRNA expression and a decrease in somatostatin mRNA expression in the anterior hypothalamic area. Moreover, a decrease in somatostatin immunoreactivity in the periventricular nucleus and an increase in somatostatin immunopositive fibers in the median eminence were noted. Changes in the GHRH and somatostatin activity are associated with an increase in growth hormone (GH) gene expression and in the amount of GH immunoreactive material stored in the somatotrophic pituitary cells. Consequently, an increase in GH concentration in the peripheral blood, due to an increase in the number of pulses was observed. It was revealed that obestatin affects the somatostatin/GHRH/GH system at the level of protein synthesis, accumulation and release. It is suggested that obestatin participates in the mechanism modulating somatotrophic axis activity at the central level by stimulating GH release through suppression of somatostatin output. Thereby, it can be concluded that obestatin may be involved in the modulation of growth processes in sheep. PMID- 29108817 TI - Chronic oral methylene blue treatment in a rat model of focal cerebral ischemia/reperfusion. AB - A single acute low-dose methylene blue (MB), an FDA-grandfathered drug, has been shown to ameliorate behavioral deficits and reduces MRI-defined infarct volume in experimental ischemic stroke when administered intravenously or intraperitoneally. The efficacy of chronic MB treatment in ischemic stroke remains unknown. In a randomized, double-blinded and vehicle-controlled design, we investigated the efficacy of chronic oral MB administration in ischemic stroke longitudinally up to 60 days post injury using MRI and behavioral tests, with end point histology. The major findings were chronic oral MB treatment, compared to vehicle, i) improves functional behavioral outcomes starting on day 7 and up to 60 days, ii) reduces MRI-defined total lesion volumes from day 14 and up to 60 days where some initial abnormal MRI-defined core and perfusion-diffusion mismatch were salvaged, iii) reduces white-matter damage, iv) gray matter and white matter damages are consistent with Nissl stains and Black Gold stain histology. These findings provide further evidence that long-term oral administration of low-dose MB is safe and has positive therapeutic effects in chronic ischemic stroke. PMID- 29108818 TI - Tjur's R2 for logistic regression models is the same as Youden's index for a 2*2 diagnostic table. PMID- 29108820 TI - Is undifferentiated spondyloarthritis a discrete entity? A debate. AB - The concept of undifferentiated spondyloarthritis has been introduced recently to describe a clinical setting where the classical features of spondyloarthritis (SpA) are not fully present. Whether this is a discrete entity was the basis of a debate during the 4th International Congress on Controversies in Rheumatology & Autoimmunity held in Bologna, Italy 9-11 March 2017. The pro and con aspects of the debate are presented. The implications of the debate are important ranging from diagnostic aspects to consequences for the society and the payers. PMID- 29108819 TI - Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease. AB - BACKGROUND: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. METHODS: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non carriers), and 3 experimental pulmonary hypertension models. RESULTS: PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). CONCLUSIONS: Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities. PMID- 29108821 TI - Brain diffusion tensor MRI in systematic lupus erythematosus: A systematic review. AB - Diffusion tensor imaging (DTI) maps the brain's microstructure by measuring fractional anisotropy (FA) and mean diffusivity (MD). This systematic review describes brain diffusion tensor Magnetic resonance imaging (MRI) studies in systemic lupus erythematosus (SLE).The literature was reviewed following the PRISMA guidelines and using the terms "lupus", "systemic lupus erythematosus", "SLE", "diffusion tensor imaging", "DTI", "white matter" (WM), "microstructural damage", "tractography", and "fractional anisotropy"; the search included articles published in English from January 2007 to April 2017. The subjects included in the study were selected according to the ACR criteria and included 195 SLE patients with neuropsychiatric manifestation (NPSLE), 299 without neuropsychiatric manifestation (non-NPSLE), and 423 healthy controls (HC). Most studies identified significantly reduced FA and increased MD values in several WM regions of both NPSLE and non-NPSLE patients compared to HC. Subclinical microstructural changes were observed in either regional areas or the entire brain in both the non-NPSLE and NPSLE groups. PMID- 29108822 TI - The immunobiology and clinical features of type 1 autoimmune polyglandular syndrome (APS-1). AB - Autoimmune Polyglandular Syndrome type 1 (APS-1) is a subtype of the autoimmune polyendocrine syndrome characterized by the simultaneous or sequential dysfunction of multiple endocrine or non-endocrine glands. A clinical diagnosis of APS-1 is typically based on the presence of at least two of three following criteria: chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. The first identified causative mutated gene for APS-1 is autoimmune regulator (AIRE) encoding a critical transcription factor, which is primarily expressed in the medullary thymic epithelial cells (mTECs) for generating central immune tolerance. A wide range of chronic, debilitating complications, with no obvious correlation with genetics, makes a diagnosis of APS-1 challenging early in the disease course. Managing APS-1 is difficult due to its complexity, especially the intricate relationships within manifestations and genetic mutations. The past decades have witnessed dramatic progress in elucidating the function of AIRE and conducting large-scale cohort studies in APS 1. However, no clear evidence-based guidelines have been established in APS-1. In this review, we provide a detailed critical overview of the study history, epidemiology, clinical features, and related mechanisms of autoimmunity in APS-1, as well as currently available therapies for this autoimmune disorder. PMID- 29108823 TI - Cocaine and ANCA associated vasculitis-like syndromes - A case series. AB - OBJECTIVES: We analysed the spectrum of clinical manifestations of cocaine associated pseudovasculitis. METHODS: Clinical, serological, radiological and histological features of 14 patients with cocaine pseudovasculitis syndromes were included. RESULTS: Twelve patients had significant sinus thickening or erosive disease. Other multi-system manifestations included vasculitic rashes, pulmonary lesions and peripheral neuropathy. All patients had positive ANCA titres at presentation. All patients were managed with corticosteroids +/- methotrexate and co-trimoxazole, 2 patients received cyclophosphamide. CONCLUSIONS: Advanced erosive nasal septal defects and atypical ANCA patterns are suggestive of cocaine induced pseudovasculitis. Complete drug cessation may negate the need for exposure to potent immunosuppressive agents. PMID- 29108824 TI - Can we withdraw immunosuppressants in patients with lupus nephritis in remission? An expert debate. AB - Lupus nephritis (LN) treatment requires an initial intensive period of therapy followed by a long-term maintenance treatment in order to stabilize disease control and eventually reach renal remission. In this section, Authors discuss the feasibility of safely lowering and even suspending maintenance therapy in LN patients having entered remission, highlighting hurdles in predicting the depth and durability of disease quiescence together with the need for minimizing potentially toxic therapies. Even though no firm conclusions can still be drawn, the treating physician has to find the wise balance between disease control and treatment-related drawbacks by following patients closely and recognizing as early as possible the ones who are likely to reach a deep and durable renal remission; there is consensus that is these are the only patients in whom a potential safe complete withdrawal can be foreseen so far. PMID- 29108825 TI - Targeting interferons and their pathways in systemic lupus erythematosus. AB - Significant advances in the understanding of the molecular basis of innate immunity have led to the identification of interferons (IFNs), particularly IFN alpha, as central mediators in the pathogenesis of Systemic Lupus Erythematosus. Therefore, targeting of IFNs and of their downstream pathways has emerged as important developments for novel drug research in SLE. Based on this, several specific interferon blocking strategies using anti-IFN-alpha antibodies, anti type I interferon receptor antibodies, Interferon-alpha-kinoid, or anti-IFN-gamma antibodies have all been assessed in recent clinical trials. Alternative strategies targeting the plasmacytoid dendritic cells (pDCs), Toll-Like Receptors (TLRs)-7/9 or their downstream pathways such as the myeloid differentiation primary-response protein 88 (MYD88), spleen tyrosine kinase (Syk), Janus-kinases (JAKs), interleukin-1 receptor-associated kinase 4 (IRAK4), or the Tyrosine Kinase 2 (TYK2) are also investigated actively in SLE, at more preliminary clinical development stages, except for JAK inhibitors which have reached phase 2 studies. In a near future, in-depth and personalized functional characterization of IFN pathways may provide further guidance for the selection of the most relevant therapeutic strategy in SLE, tailored at the patient-level. PMID- 29108826 TI - Physical activity and autoimmune diseases: Get moving and manage the disease. AB - Physical activity, by definition, is any skeletal muscle body movement that results in energy expenditure. In the last few decades, a plethora of scientific evidences have accumulated and confirmed the beneficial role of physical activity as a modifiable risk factor for a wide variety of chronic diseases including cardiovascular diseases (CVDs), diabetes mellitus and cancer, among others. Autoimmune diseases are a heterogeneous group of chronic diseases, which occur secondary to loss of self-antigen tolerance. With the advent of biological therapies, better outcomes have recently been noted in the management of autoimmune diseases. Nonetheless, recent research highlights the salient role of modifiable behaviors such as physical inactivity on various aspects of the immune system and autoimmune diseases. Physical activity leads to a significant elevation in T-regulatory cells, decreased immunoglobulin secretion and produces a shift in the Th1/Th2 balance to a decreased Th1 cell production. Moreover, physical activity has been proven to promote the release of IL-6 from muscles. IL 6 released from muscles functions as a myokine and has been shown to induce an anti-inflammatory response through IL-10 secretion and IL-1beta inhibition. Physical activity has been shown to be safe in most of autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel diseases (IBD), as well as others. Additionally, the incidence of RA, MS, IBD and psoriasis has been found to be higher in patients less engaged in physical activity. As a general trend, patients with autoimmune diseases tend to be less physically active as compared to the general population. Physically active RA patients were found to have a milder disease course, better cardiovascular disease (CVD) profile, and improved joint mobility. Physical activity decreases fatigue, enhances mood, cognitive abilities and mobility in patients with MS. In SLE patients, enhanced quality of life and better CVD profile were documented in more physically active patients. Physically active patients with type 1 diabetes mellitus have a decreased risk of autonomic neuropathy and CVD. Both fibromyalgia and systemic sclerosis patients report decreased disease severity, pain, as well as better quality of life with more physical activity. Further, SSc patients improve their grip strength, finger stretching and mouth opening with increased level of exercise. The purpose of this paper is to review the clinical evidence regarding the safety, barriers to engagement, and impact of physical activity on autoimmune diseases. PMID- 29108827 TI - Controversies in Rheumatology and Autoimmunity: Approaching the truth by the discussion. PMID- 29108828 TI - Can we manage lupus nephritis without chronic corticosteroids administration? AB - The outcome of lupus nephritis (LN) has changed since the introduction of glucocorticoids (GCs), which dramatically reduced the mortality related to one of the most severe complications of systemic lupus erythematosus (SLE). Since the 1950's, other immunosuppressants, including biologic drugs (i.e. rituximab) have aided in maintaining remission, preserving kidney function, but not preventing treatment-related toxicity. GCs still remain the cornerstone in the treatment of SLE, including LN, and they are widely used in clinical practice. However, GC administration represents a double-edged sword. Indeed, from one side they allow a fast and effective control of disease activity by dampening inflammation; from the other side, they have many and severe side effects leading to organ damage. In this paper, we will discuss pros and cons of the chronic use of GCs, especially focusing on LN. PMID- 29108829 TI - TNF inhibitors in rheumatoid arthritis and spondyloarthritis: Are they the same? AB - The advent of anti-tumour necrosis factor (TNF) drugs for rheumatoid arthritis (RA) or spondyloarthritis (SpA) has revolutionised the approach to patients with active disease who do not respond to conventional therapy. Although there are differences in their structure, morphology, pharmacokinetic properties and activity, all anti-TNF drugs ultimately neutralise the TNFalpha pathway of inflammation. However, despite their similar clinical efficacy, there are disagreements concerning drug survival and safety, with systematic reviews and meta-analyses confirming one result or the other. The fact that 20-30% of patients fail to respond to TNFalpha inhibitors indicates the possibility of primary resistance or the development of an immune response to the drugs themselves, which may act as antigens. The overall benefit of switching to another anti-TNF drug or a biological agent with a different mechanism of action, may be a valuable option in individual patients. There are few data concerning the use of anti-TNF drugs in patients with SpA but it seems that there are fewer adverse advents and higher drug survival in comparison with patients with RA. PMID- 29108830 TI - Vitamin D and systemic lupus erythematosus - The hype and the hope. AB - Over the past 20years, much has been written about the potential role of vitamin D in on adverse health outcomes. In recent years, evidence has accumulated regarding the effect of vitamin D on the immune system, and its different cells. Some studies have noted lower vitamin D concentrations in patients with SLE. These epidemiological data still not answer the question: is vitamin D deficiency the cause or the effect? To answer this, we will discuss the association between vitamin D deficiency and SLE and review the evidence from interventional studies. PMID- 29108832 TI - Temporal Processing in Audition: Insights from Music. AB - Music is a curious example of a temporally patterned acoustic stimulus, and a compelling pan-cultural phenomenon. This review strives to bring some insights from decades of music psychology and sensorimotor synchronization (SMS) literature into the mainstream auditory domain, arguing that musical rhythm perception is shaped in important ways by temporal processing mechanisms in the brain. The feature that unites these disparate disciplines is an appreciation of the central importance of timing, sequencing, and anticipation. Perception of musical rhythms relies on an ability to form temporal predictions, a general feature of temporal processing that is equally relevant to auditory scene analysis, pattern detection, and speech perception. By bringing together findings from the music and auditory literature, we hope to inspire researchers to look beyond the conventions of their respective fields and consider the cross disciplinary implications of studying auditory temporal sequence processing. We begin by highlighting music as an interesting sound stimulus that may provide clues to how temporal patterning in sound drives perception. Next, we review the SMS literature and discuss possible neural substrates for the perception of, and synchronization to, musical beat. We then move away from music to explore the perceptual effects of rhythmic timing in pattern detection, auditory scene analysis, and speech perception. Finally, we review the neurophysiology of general timing processes that may underlie aspects of the perception of rhythmic patterns. We conclude with a brief summary and outlook for future research. PMID- 29108831 TI - Are the ACR 2010 diagnostic criteria for fibromyalgia better than the 1990 criteria? AB - Fibromyalgia (FM) is difficult to diagnose and manage chronic pain condition whose symptoms have no clear pathophysiological cause, although it is thought that patient hypersensitivity to a range of stimuli may give rise to mechanical hyperalgesia as a result of altered central nociceptive processing. The 1990 American College of Rheumatology (ACR) classification criteria, which have been widely used in clinical practice, require the existence of chronic widespread pain (CWP) for >3months, and the presence of at least 11 out of 18 specified tender points upon digital palpation, although this latter criterion has long been criticised. The newer 2010 ACR diagnostic criteria state that FM can be defined as CWP associated with somatic symptoms, and recommend the use of a widespread pain index and a scale to rate symptom severity. A modified version of the 2010 criteria removed the physician assessment of the extent of somatic symptoms and replaced it by a summary score of three self-reported symptoms, thus making it easier to use while maintaining its sensitivity. This review discusses the advantages and limitations of all of these criteria. PMID- 29108833 TI - Arctiin protects against cardiac hypertrophy through inhibiting MAPKs and AKT signaling pathways. AB - PURPOSE: The mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) pathways have emerged as essential intracellular signaling pathways in eukaryotic cells, particularly as regulators of cardiac hypertrophy. Previous studies indicated that arctiin, an active ingredient of biennial dried ripe burdock, could exhibit potent anti-inflammatory and anti-allergic activities via down regulating the activation of MAPKs and AKT pathways. However, little is known about its effects on cardiac hypertrophy. Therefore, the present study aimed to explore whether arctiin could attenuate cardiac hypertrophy. GENERAL METHODS: Arctiin (80 mg/kg) was administered by oral gavage once daily for 3 weeks from 1 week after surgery. Then, the mice were subjected to either chronic pressure overload generated by aortic banding (AB) or sham surgery (control group). Cardiac function was assessed by echocardiography. FINDINGS: The results indicated that arctiin attenuated cardiac hypertrophy induced by AB, and suppressed cardiac fibrosis and accumulation of collagen in vivo. Arctiin also inhibit the activation of MAPKs and AKT occurs in response to hypertrophic stimuli. Arctiin attenuated phenylephrine-induced hypertrophy of myocytes in vitro. CONCLUSIONS: In conclusion, arctiin can improve cardiac function and prevent the development of cardiac hypertrophy by blocking the MAPKs and AKT signaling pathways. PMID- 29108834 TI - Photodynamic therapy of human biliary cancer cell line using combination of phosphorus porphyrins and light emitting diode. AB - A series of phosphorus porphyrin complexes ([(RO)2P(tpp)]Cl, tpp = tetraphenylporphyrinato group, R = -(CH2CH2O)m(CH2)nH; 1a: m = 2, n = 2; 1b: m = 2, n = 4; 1c: m = 2, n = 6; 1d: m = 3, n = 6) were used for the photodynamic therapy (PDT) of human biliary cancer cell line (NOZ) when exposed to the irradiation of light emitting diodes (LEDs). A Dulbecco's modified Eagle's medium (DMEM) containing NOZ cells (2000 cell well-1) and 1 (0-100 nM) was introduced into a 96-well microplate and incubated for 24 h to accumulate 1 into the NOZ cells and to multiply the NOZ cells until the cell number reached 104 cells well 1. After replacing the DMEM medium containing 1 with a fresh DMEM medium without 1, the plates were irradiated for 30 min at 610 nm. After incubation was performed for 24 h in dark conditions, the cell viability of the NOZ cells was determined using the MTT assay. The half maximum inhibitory concentrations 50 (IC50) of 1a-1d were found to be in the range of 33.7-58.7 nM for NOZ. These IC50 values for the NOZ were one hundredth the IC50 value (7.57 MUM) for mono-l aspartyl chlorin e6 (laserphyrin(r)). Thus, it was found that the PDT activity of 1a-1d was much higher than the mono-l-aspartyl chlorin e6. Similarly, IC50 vales of 1a-1d for HeLa cells were found to be 27.8-52.5 nM. This showed that 1a-1d had high photodynamic activity in cancer cells. At the same time, it was speculated that an LED is a useful light source for deactivating the cancer cells because it can excite the sensitizers with peak width in their absorption spectra using the light of the specified wave length with band width of 10-20 nm; LEDs provide a homogeneous light distribution for the target cells. PMID- 29108836 TI - Inconsistencies in Outcomes of Donor Breast Milk for Preterm Infants. PMID- 29108835 TI - Biomonitoring of perfluorinated compounds in adults exposed to contaminated drinking water in the Veneto Region, Italy. AB - In 2013 a contamination of drinking water by perfluoroalkylated substances (PFASs) was discovered in areas of the Veneto Region (northern Italy). In this study the exposure to PFASs of people living in the aforesaid areas was characterized: contaminant serum concentrations were measured and compared with those of a control population group living in neighboring areas at background exposure (based on available drinking water data). The enrolled population was also genotyped for the OATP1A2*3 allelic variant, possibly affecting PFAS excretion and hence the internal dose. The difference in PFAS concentrations between exposed and not exposed subjects was significantly larger for nine of the 12 substances analyzed, and confirmed that water contamination had resulted in an appreciable high exposure of the residing population over time. Within the group of exposed subjects, subgroups at different exposure levels were identified. The contamination of drinking water of the residence area was found to be the main factor influencing PFAS serum levels; in addition to water contamination, other relevant influencing factors were sex, the years of residence and raising own livestock. No relationship with the genetic trait for the studied renal transporter was evidenced. These results provide a baseline characterization of PFAS exposure of the monitored population groups for further studies, planned to be carried out in the near future. PMID- 29108838 TI - Erratum to'Clinical Therapeutics Supplement: The Proceedings of the 13th Congress of the European Association for Clinical Pharmacology and Therapeutics'Clin Ther. 2017;39:e1-e110. PMID- 29108837 TI - Factors Associated with Type 2 Diabetes Mellitus Treatment Choice Across Four European Countries. AB - PURPOSE: The aim of this analysis was to identify factors associated with the choice of type 2 diabetes mellitus (T2DM) therapy at the time of intensification of antidiabetic treatment across 4 European countries. METHODS: Antidiabetic drug prescription/dispensing records and patients' characteristics were obtained from the electronic health care records of patients with T2DM from the Netherlands (NL), Italy, and Spain (ES) (all, 2007-2011); and the United Kingdom (UK; 2008 2012). Oral monotherapy was defined as first-line; oral dual therapy, as second line; >2 oral treatments or oral combined with an injectable, as third-line; and injectables only, as fourth-line treatment. Treatment intensification was defined as the start of a higher line of treatment. Comedication, comorbidities, clinical parameters, and other factors associated with treatment choice were identified using multivariate relative risk estimation by Poisson regression with robust error variance. FINDINGS: In the 5-year study period, 485,120 patients (79% of the treated T2DM population) underwent treatment intensification. Changes in treatment choice were clearly visible over the study period, such as a decline in the use of thiazolidinediones (NL, ES, UK) and increases in the use of dipeptidyl peptidase-4 inhibitors (DPP4i) (NL, ES, UK) and glucagon-like peptide-1 receptor agonists (UK). With first-line treatment, advanced age and renal comorbidity were associated with the use of sulfonylureas (SUs; all countries), whereas high body mass index (BMI) was inversely associated with SU use in the United Kingdom and Spain. With second-line treatment, advanced age was associated with metformin + SU use (all countries); and renal comorbidity with SU + DPP4i use in the United Kingdom and the Netherlands. High BMI was associated with metformin + thiazolidinedione (TZD) use in the United Kingdom and Spain, and with metformin + DPP4i in the United Kingdom. With third-line treatment, advanced age and renal comorbidity were associated with the use of SU + insulin (NL, ES, UK). Hemoglobin A1c >8.5% was positively associated, and high BMI was inversely associated, with the use of any third-line combination containing insulin. Across treatment lines TZD and metformin were negatively associated with renal and cardiac morbidity. Second and third line treatment choices strongly depended on prior treatments. With fourth-line treatment, women were more likely to receive glucagon-like peptide-1 receptor agonists than were men in the United Kingdom and Spain. IMPLICATIONS: The results suggest that the main factors driving treatment choice at any stage of intensification were age, hemoglobin A1c, BMI, renal and cardiac morbidity, and treatment history. These drivers were consistent with guidelines on, and contraindications of, specific medications. Differences between countries were generally consistent with, but not solely attributable to, differences in local guidelines and reimbursement policies. PMID- 29108839 TI - Association between a MIR499A polymorphism and diabetic neuropathy in type 2 diabetes. AB - AIMS: Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) affect a large percentage of diabetic people and impact severely on quality of life. As it seems that miRNAs and their variations might play a role in these complications, we investigated whether the rs3746444 SNP in the MIR499A gene could be associated with susceptibility to DPN and/or CAN. METHODS: We analyzed 150 participants with type 2 diabetes. DNA was extracted from peripheral blood samples and genotyping was performed by TaqMan genotyping assay. Cardiovascular tests, MNSI-Q and MDNS for neuropathic symptoms and signs, VPT, and thermal thresholds were used for CAN and DPN assessment. We performed a genotype phenotype correlation analysis. RESULTS: We observed that the GG genotype was associated with a higher risk of developing CAN (P=0.002 and OR=16.08, P=0.0005 and OR=35.02, for early and confirmed CAN, respectively) and DPN (P=0.037 and OR=6.56), after correction for BMI, sex, age, HbA1c and disease duration. Moreover, the GG genotype was associated with worse values of MDNS (P=0.017), VPT (P=0.01), thermal thresholds (P=0.01), and CAN score (P<0.001). A logistic multivariate analysis confirmed that MIR499A GG genotype, disease duration and HbA1c contributed to early CAN (R2=0.26), while the same variables and age contributed to DPN (R2=0.21). With a multiple linear regression, we observed that GG genotype (P=0.001) and disease duration (P=0.035) were the main variables contributing to the CAN score (R2=0.35). CONCLUSIONS: We described for the first time that the MIR499A genetic variation could be involved in diabetic neuropathies susceptibility. In particular, patients carrying the rs3746444 GG genotype had a higher risk of CAN development, together with a more severe form of CAN. PMID- 29108840 TI - Use of the Coronary Artery Calcium Score in Discussion of Initiation of Statin Therapy in Primary Prevention. AB - Clinical guidelines for instituting pharmacotherapy for the primary prevention of atherosclerotic cardiovascular disease (ASCVD), specifically lipid management and aspirin, have long been based on absolute risk. However, lipid management in the current era remains challenging to both patients and clinicians in the setting of somewhat discordant recommendations from various organizations. All guidelines endorse the use of statins for primary prevention for those at sufficient absolute risk, and treatment recommendations are generally "risk-based" rather than exclusively targeting specific low-density lipoprotein cholesterol levels. Nonetheless, guidelines differ in relation to the risk threshold for initiation and the intensity of statin treatment. The key concept of the clinician-patient risk discussion introduced in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines is a process that addresses the potential for ASCVD risk reduction with statin treatment, potential for adverse treatment effects, patient preferences, encouragement of heart-healthy lifestyle, and management of other risk factors. However, operationalizing the clinician patient risk discussion requires effective communication of the most accurate and personalized risk information. In this article, we review our treatment approach for the appropriate use of coronary artery calcium testing in the intermediate risk patient to guide shared decision making. The decision to initiate or intensify statin therapy may be uncertain across a broad range of estimated 10 year ASCVD risk of 5% to 20%, and coronary artery calcium testing can reclassify risk upward or downward in approximately 50% of this group to inform the risk discussion. We conclude with 2 case-based examples of uncertain risk and uncertain statin therapeutic benefit to illustrate execution of the clinician patient risk discussion. PMID- 29108841 TI - A Conceptual Framework for Understanding Unintended Prolonged Opioid Use. AB - An urgent need exists to better understand the transition from short-term opioid use to unintended prolonged opioid use (UPOU). The purpose of this work is to propose a conceptual framework for understanding UPOU that posits the influence of 3 principal domains that include the characteristics of (1) individual patients, (2) the practice environment, and (3) opioid prescribers. Although no standardized method exists for developing a conceptual framework, the process often involves identifying corroborative evidence, leveraging expert opinion to identify factors for inclusion in the framework, and developing a graphic depiction of the relationships between the various factors and the clinical problem of interest. Key patient characteristics potentially associated with UPOU include (1) medical and mental health conditions; (2) pain etiology; (3) individual affective, behavioral, and neurophysiologic reactions to pain and opioids; and (4) sociodemographic factors. Also, UPOU could be influenced by structural and health care policy factors: (1) the practice environment, including the roles of prescribing clinicians, adoption of relevant practice guidelines, and clinician incentives or disincentives, and (2) the regulatory environment. Finally, characteristics inherent to clinicians that could influence prescribing practices include (1) training in pain management and opioid use; (2) personal attitudes, knowledge, and beliefs regarding the risks and benefits of opioids; and (3) professionalism. As the gatekeeper to opioid access, the behavior of prescribing clinicians directly mediates UPOU, with the 3 domains interacting to determine this behavior. This proposed conceptual framework could guide future research on the topic and allow plausible hypothesis-based interventions to reduce UPOU. PMID- 29108843 TI - Outcomes following elective resection of congenital pulmonary airway malformations are equivalent after 3 months of age and a weight of 5 kg. AB - PURPOSE: Resection of congenital pulmonary airway malformations (CPAMs) is often performed to reduce the risk of recurrent infection and malignant transformation. However, there is substantial variation in the timing of resection. This study was performed to determine the association of age and weight on outcomes following elective resection of CPAMs. METHODS: The American College of Surgeons National Surgical Quality Improvement Program-Pediatric database from 2012 to 2014 was queried for infants undergoing elective resection of a CPAM. Infants were categorized based on age (0-3months, 3-6months, 6-9months, 9-12months, and >12months) and weight (0-5kg, 5-10kg, and >10kg). Groups were compared for baseline characteristics and outcomes including a morbidity composite of pneumonia, reintubation, ventilator days >0, reoperation, readmission, hospital length of stay >7days, and mortality. RESULTS: A total of 311 infants met study criteria. The morbidity composite was significantly more common among infants <3months of age compared to infants >3months of age (31.3% vs. 15.6%, p=0.01) and among infants <5kg as compared to infants >5kg (37.5% vs. 15.8%, p<0.01). CONCLUSIONS: Infants should be observed until three months of age and a weight of five kilograms prior to elective resection of CPAMs. LEVEL OF EVIDENCE: Level III. PMID- 29108842 TI - Increased Risk of Multimorbidity in Patients With Sarcoidosis: A Population-Based Cohort Study 1976 to 2013. AB - OBJECTIVE: To evaluate the risk and pattern of multimorbidity in patients with sarcoidosis. PATIENTS AND METHODS: A cohort of all residents of Olmsted County, Minnesota, first diagnosed with sarcoidosis between January 1, 1976, and December 31, 2013, was identified through the medical record linkage system of the Rochester Epidemiology Project. Diagnosis was verified by individual medical record review. A cohort of sex- and age-matched comparators without sarcoidosis was assembled from the same population. Data on 18 chronic conditions recommended by the US Department of Health and Human Services for both cases and comparators were retrieved and compared. RESULTS: The prevalence of multimorbidity (ie, the presence of >=2 chronic conditions) was similar between the 2 groups: 111 of 345 cases (32.2%) and 110 of 345 comparators (31.9%) (P=.99). After the index date, 156 cases (43.8%) and 142 comparators (41.2%) developed multimorbidity, corresponding to a hazard ratio of 1.60 (95% CI, 1.27-2.01; P<.001). The cumulative incidence of the presence of >=3, 4, and 5 chronic conditions was also consistently significantly higher in cases than in comparators (P value=.01, .004 and .002, respectively). Analysis by specific type of chronic condition revealed a significantly higher cumulative incidence of coronary artery disease, congestive heart failure, arrhythmia, stroke or transient ischemic attack, arthritis, depression, diabetes, and major osteoporotic fracture. CONCLUSION: In this population, patients with sarcoidosis had a significantly higher risk of developing multimorbidity than did sex- and age-matched individuals without sarcoidosis. PMID- 29108844 TI - Liver transplantation for primary hepatic malignancies of childhood: The UNOS experience. AB - BACKGROUND/PURPOSE: The purpose of this study was to determine factors associated with patient and graft survival following orthotopic liver transplantation (OLT) in children and adolescents with primary hepatic malignancies. METHODS: The United Network for Organ Sharing (UNOS) database was queried for all patients <18years old who received an OLT with a primary malignant liver tumor between 1987 and 2012 (n=544). Five-year patient and graft survival were determined using Kaplan-Meier methodology, and independent predictors of survival were determined using multivariate Cox proportional hazards model. RESULTS: The majority of patients were diagnosed with hepatoblastoma (HB) (n=376, 70%) with 84 (15%) hepatocellular carcinoma (HCC) and 84 (15%) other. HCC patients were older, more often hospitalized at the time of transplant, and more likely to receive a cadaveric organ compared to HB patients. Five-year patient and graft survival for the entire cohort was 73% and 74%, respectively, with the majority of deaths owing to malignancy. On multivariate analysis, independent predictors of 5-year patient and graft survival included diagnosis, transplant era, and medical condition at transplant. CONCLUSIONS: In recent years, there has been significant improvement in posttransplant patient and graft survival for children and adolescents with primary hepatic malignancies. However, patients with HCC continue to have worse outcomes than those with other cancer types. TYPE OF STUDY: Case series with no comparison group. LEVEL OF EVIDENCE: IV. PMID- 29108845 TI - Validation of the age-adjusted shock index using pediatric trauma quality improvement program data. AB - PURPOSE: In adults, shock index (SI; heart rate/systolic blood pressure) >0.9 predicts injury severity and trauma outcomes. However, age-adjusted shock index (SIPA) out-performs SI in blunt trauma patients 4-16years old. We sought to confirm these findings and expand this tool to include penetrating trauma and children aged 1-4years. METHODS: We developed cutoff values for patients 1-3years old using age-based vital signs and queried the 2014 Pediatric Trauma Quality Improvement Program (TQIP) database for patients aged 1-16years sustaining blunt or penetrating trauma. Outcomes measured included injury severity, transfusion within 24h, intensive care unit (ICU) and hospital length of stay (LOS), and mortality. SI and SIPA were compared using Student's t-test and chi-square tests. RESULTS: We identified 22,344 blunt and 613 penetrating trauma patients. SI was elevated in 41.3% and 40.0% of these groups, respectively, whereas SIPA was elevated in 15.6% and 19.4% of patients. SIPA was a significantly better predictor of transfusion needs, injury severity, ICU admission, ventilator use, and mortality for both blunt and penetrating trauma. CONCLUSION: SIPA identifies severe injury and predicts transfusion needs and mortality more effectively than SI for both blunt and penetrating pediatric trauma. Further investigation should evaluate its use as a triage tool. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: II. PMID- 29108846 TI - Predictors of pediatric blunt cerebrovascular injury. AB - BACKGROUND/PURPOSE: Blunt cerebrovascular injury (BCVI) is clinically challenging because these injuries are hard to detect and can have serious neurological consequences, and optimal screening criteria have not been established for children. This study aims to determine risk factors for BCVI in pediatric patients and to evaluate screening practices in a single institutional series. METHODS: A retrospective review of all pediatric blunt trauma patients evaluated over a 10-year period was performed. Demographic, clinical, and radiographic data were reviewed, including the presence of adult risk factors for BCVI. Logistic regression analyses were performed with statistical significance established at p<0.05. RESULTS: Of the 11,596 patients evaluated during the study period, 1018 (8.8%) had at least one adult risk factor for BCVI, but only 62 (6.1% of those with risk factors) underwent angiographic evaluation. Overall, 11 BCVIs were observed, resulting in an incidence of 0.095%. All 11 patients with BCVI had at least one risk factor. Multivariate logistic regression analysis identified cervical spine fracture (OR 36.88 [8.36, 169.95]), GCS score <= 8 (OR 16.42 [2.16, 102.33]), male gender (OR 10.52 [1.33, 363.30]), Le Fort II or III facial fracture (OR 63.71 [2.16, 1124.68]), and ISS (unit OR 1.10 [1.04, 1.17]) as independent risk factors for BCVI. CONCLUSION: Adult screening criteria for BCVI appear appropriate for pediatric patients, but most at-risk children are not being screened. LEVEL OF EVIDENCE: Level III (retrospective case-control study). PMID- 29108847 TI - Effective methods to decrease surgical site infections in pediatric gastrointestinal surgery. AB - BACKGROUND: Gastrointestinal (GI) surgeries represent a significant proportion of the surgical site infection (SSI) burden in pediatric patients, resulting in significant morbidity. Previous studies have shown that perioperative bundles reduce SSIs, but few have focused on pediatric GI operations. We hypothesized that a GI bundle would decrease SSI rates, length of stay (LOS), and hospital charges. METHODS: After establishing baseline SSI rates, a GI bundle was created and implemented in November 2014. We prospectively collected data including demographics, procedure type, LOS, inpatient charges, bundle compliance, and SSI development. We analyzed SSI rates, LOS, and charges using process control charts. RESULTS: The baseline SSI rate for all GI operations was 3.4%, which increased to 7.1%, then decreased to 4.7%. Midgut/hindgut and stoma closure SSI rates decreased from 11.3% to 8.0% (p<0.05) and 21.4% to 7.9%, respectively (p<0.05). Although overall LOS and charges were unchanged, average LOS for midgut/hindgut surgeries and stoma closures decreased from 20.3 to 13.6days (p=0.015) and 12.6 to 7.9days (p=0.04), respectively. Stoma closure charges decreased from $94,262 to $50,088 (p=0.01). CONCLUSIONS: Our perioperative GI bundle decreased SSI rates, primarily among midgut/hindgut operations. Bundle usage decreased LOS and charges most effectively in stoma closures. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: Level 2. PMID- 29108848 TI - Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception. AB - In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles. PMID- 29108849 TI - Enzymatic extract from Ecklonia cava: Acute and subchronic oral toxicity and genotoxicity studies. AB - Ecklonia cava (EC) is known to have antioxidant, anti-inflammatory, antidiabetic, and anticancer properties. Despite its wide use and beneficial properties, comprehensive toxicological information regarding EC extract is currently limited. Therefore, the purpose of this study was to investigate acute toxicity, subchronic toxicity, and genotoxicity of enzymatic EC extract according to test guidelines published by Organization for Economic Cooperation and Development. The acute oral LD50 values of this EC extract administered to rats and dogs were estimated to be more than 3000 mg/kg BW. In an oral 13-week toxicity study, changes in body weights of rats exposed to the EC extract up to 3000 mg/kg BW were found to be normal. In addition, repeated doses of EC extract failed to influence any systematic parameters of treatment-related toxic symptoms such as food/water consumption, mortality, urinalysis, hematology, serum biochemistry, organ weight, or histopathology. These results indicated that the no-observed adverse-effect level for the EC extract was 3000 mg/kg/day for male and female rats. Data obtained from Ames test, chromosome aberration assay, and micronucleus assay indicated that EC extract was not mutagenic or clastogenic. Taken together, these results support the safety of enzymatic EC extract as a potential therapeutic for human consumption against various diseases. PMID- 29108850 TI - Tissue viscoelasticity is related to tissue composition but may not fully predict the apparent-level viscoelasticity in human trabecular bone - An experimental and finite element study. AB - Trabecular bone is viscoelastic under dynamic loading. However, it is unclear how tissue viscoelasticity controls viscoelasticity at the apparent-level. In this study, viscoelasticity of cylindrical human trabecular bone samples (n=11, male, age 18-78 years) from 11 proximal femurs were characterized using dynamic and stress-relaxation testing at the apparent-level and with creep nanoindentation at the tissue-level. In addition, bone tissue elasticity was determined using scanning acoustic microscope (SAM). Tissue composition and collagen crosslinks were assessed using Raman micro-spectroscopy and high performance liquid chromatography (HPLC), respectively. Values of material parameters were obtained from finite element (FE) models by optimizing tissue-level creep and apparent level stress-relaxation to experimental nanoindentation and unconfined compression testing values, respectively, utilizing the second order Prony series to depict viscoelasticity. FE simulations showed that tissue-level equilibrium elastic modulus (Eeq) increased with increasing crystallinity (r=0.730, p=.011) while at the apparent-level it increased with increasing hydroxylysyl pyridinoline content (r=0.718, p=.019). In addition, the normalized shear modulus g1 (r=-0.780, p=.005) decreased with increasing collagen ratio (amide III/CH2) at the tissue-level, but increased (r=0.696, p=.025) with increasing collagen ratio at the apparent-level. No significant relations were found between the measured or simulated viscoelastic parameters at the tissue- and apparent-levels nor were the parameters related to tissue elasticity determined with SAM. However, only Eeq, g2 and relaxation time tau1 from simulated viscoelastic values were statistically different between tissue- and apparent-levels (p<.01). These findings indicate that bone tissue viscoelasticity is affected by tissue composition but may not fully predict the macroscale viscoelasticity in human trabecular bone. PMID- 29108852 TI - Facing the future: a call for higher education in sleep technology. AB - The American Association of Sleep Technologists (AAST) is the national membership organization representing sleep technologists. The Board of Directors of the AAST recognizes that changes in the workforce will result in an increased need for technologists with a higher level of education. In order to meet the needs of members, the AAST has: (1) convened a summit of stakeholders to discuss the changing landscape for sleep technologists; (2) hosted an educational task force to provide ongoing communication and support; and (3) commissioned a survey of members, educators and employers to better define educational gaps and opportunities for sleep technologists. This report summarizes the results of the survey and provides a roadmap for future educational development. Demographic information highlights the diversity of those in the field of sleep technology. The majority of respondents agree that new technical skills will be needed to achieve competence in sleep technology in the near future, but also that clinical and communication skills will be critical in expanding the role of the sleep technologist in the sleep center. These findings led the AAST leadership to propose new directions for the AAST in serving the needs of its members and the field of sleep technology. This will include a continued focus on education, both basic and advanced, and development of diverse pathways for senior sleep technologists as well as those just entering the field. PMID- 29108851 TI - Examining tissue composition, whole-bone morphology and mechanical behavior of GorabPrx1 mice tibiae: A mouse model of premature aging. AB - Gerodermia osteodysplastica (GO) is a segmental progeroid disorder caused by loss of-function mutations in the GORAB gene, associated with early onset osteoporosis and bone fragility. A conditional mouse model of GO (GorabPrx1) was generated in which the Gorab gene was deleted in long bones. We examined the biomechanical/functional relevance of the GorabPrx1 mutants as a premature aging model by characterizing bone composition, tissue-level strains, and whole-bone morphology and mechanical properties of the tibia. MicroCT imaging showed that GorabPrx1 tibiae had an increased anterior convex curvature and decreased cortical cross-sectional area, cortical thickness and moments of inertia, compared to littermate control (LC) tibiae. Fourier transform infrared (FTIR) imaging indicated a 34% decrease in mineral/matrix ratio and a 27% increase in acid phosphate content in the posterior metaphyseal cortex of the GorabPrx1 tibiae (p < .05), suggesting delayed mineralization. In vivo strain gauge measurement and finite element analysis showed ~two times higher tissue-level strains within the GorabPrx1 tibiae relative to LC tibiae when subjected to axial compressive loads of the same magnitude. Three-point bending tests suggested that GorabPrx1 tibiae were weaker and more brittle, as indicated by decreasing whole bone strength (46%), stiffness (55%), work-to-fracture (61%) and post-yield displacement (47%). Many of these morphological and biomechanical characteristics of the GorabPrx1 tibia recapitulated changes in other animal models of skeletal aging. Future studies are necessary to confirm how our observations might guide the way to a better understanding and treatment of GO. PMID- 29108854 TI - SOCS-1 ameliorates smoke inhalation-induced acute lung injury through inhibition of ASK-1 activity and DISC formation. AB - Smoke inhalation leads to acute lung injury (ALI), a devastating clinical problem associated with high mortality. Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of apoptosis and pro-inflammatory cytokine signaling, two major contributors to the pathogenesis of ALI. We have found that SOCS-1 protects lung epithelial cells from smoke-induced apoptosis through two mechanisms. One is that SOCS-1 enhances degradation of ASK-1 and diminishes cleavage of pro-caspase 3 to repress smoke-triggered apoptosis in lung epithelial cells. The other is that SOCS-1 represses smoke-triggered DISC formation through altering TRADD caspase-8 interaction rather than TNFR-1-TRADD interaction or TNFR-1-TRAF-2 interaction. In conclusion, SOCS-1 relieves smoke inhalation-induced lung injury by repressing ASK-1 and DISC-mediated epithelium apoptosis. PMID- 29108853 TI - The biomechanics of subsynovial connective tissue in health and its role in carpal tunnel syndrome. AB - Carpal Tunnel Syndrome (CTS) is the most common surgically treated problem in the hand. Aside from the neuropathy itself, the most common findings are fibrosis of the subsynovial connective tissue (SSCT) and increased intra carpal tunnel pressure. Normally, the SSCT is a multilayer tissue interspersed among the carpal tendons and nerve. As the tendons move, successive SSCT layers are recruited, forming a gliding unit and providing a limit to differential movement. Exceeding this limit, damages the SSCT as has been shown in both cadavers and animal models. This damage leads to a non-inflammatory response with progressive fibrosis and nerve ischemia leaving the SSCT more susceptible to injury. Although the direct consequences for patients are not fully understood, ultrasound research shows that this fibrosis restricts median nerve displacement during tendon loading. This article aims to provide insights into the mechanical properties of SSCT described so far and place it in the context of CTS pathophysiology. A theoretical damage model concerning the SSCT is proposed showing a chain of events and vicious cycles that could lead to the nerve compression as it is found in CTS. Although not complete, this model could explain the pathophysiological pathway of idiopathic CTS. PMID- 29108855 TI - HIV patients, healthy aging and transplant recipients can reveal the hidden footprints of CMV. AB - Cytomegalovirus (CMV) is a beta-herpesvirus. Latent infections are common in all populations. However age-associated increases in levels of CMV-reactive antibody are testament to repeated reactivations and periods of viral replication. CMV has been associated with several diseases of aging, including vasculopathy and neurocognitive impairment. These conditions occur at a younger age in persons with particularly high burdens of CMV - transplant recipients and people living with HIV. Here we define the "clinical footprints" as immunopathologies triggered by CMV that develop over many years. A high burden of CMV also drives accumulation of multifunctional terminally-differentiated alphabeta T-cells, a novel population of Vdelta2- gammadelta T-cells, and a population of CD56lo NK cells lacking a key regulatory molecule. An understanding of these "immunological footprints" of CMV may reveal how they collectively promote the "clinical footprints" of the virus. This is explored here in transplant recipients, HIV patients and healthy aging. PMID- 29108856 TI - Etiology of pediatric acquired blepharoptosis. AB - PURPOSE: To describe the etiology of acquired pediatric blepharoptosis in a large clinical series and to elucidate the causes of the disease. METHODS: The medical records of all patients presenting with acquired blepharoptosis at two specialist ocular plastics practices and a pediatric ophthalmology practice during a period of up to 25 years were reviewed retrospectively and classified according to their diagnosis. Patients were grouped into children (<18 years), younger adults (18-40 years), and older adults (>40 years). RESULTS: A total of 268 patients <18 years of age were identified. The most common identifiable causes of acquired blepharoptosis in children were infantile hemangioma (n = 92 [34.3%]) and trauma (n = 41 [15.3%]). In 42 cases (15.7%) a definite diagnosis could not be made. CONCLUSIONS: The etiology of pediatric acquired blepharoptosis can frequently be determined by history and examination; additional diagnostic tests are sometimes required. A high percentage of pediatric patients have blepharoptosis of unknown cause. PMID- 29108857 TI - Applying inbreeding, hybridization and mutagenesis to improve oxidative stress tolerance and longevity of the entomopathogenic nematode Heterorhabditis bacteriophora. AB - Poor shelf-life and sensitivity to environmental stress of entomopathogenic nematodes (EPNs) are traits, which deserve attention for improvement. Recently, a strong positive correlation between oxidative stress tolerance and longevity of Heterorhabditis bacteriophora dauer juveniles (DJs) has been reported. In this study, the improvement of H. bacteriophora DJ longevity was achieved by hybridization and mutagenesis. A hybrid pool deriving from two oxidative stress tolerant and long-living parental strains was generated. This hybrid AU1 * HU2 survived 2.6 days and 18 days longer than its best parent under oxidative stress and control conditions, respectively. In addition to the natural genetic variability, an EMS-mutant pool (M-OXI) with high longevity was generated and one of the derived mutagenized inbred lines (MOX-IL6) survived 5.8 days and 28.4 days longer than its donor line (IL3) under oxidative stress and control conditions, respectively. A genetic cross between the mutagenized inbred line and its donor line (MOX-IL * IL3) still survived 2.5 days and 18.5 days longer than the donor line under oxidative stress and control conditions, respectively. Concerning virulence and reproductive potential, trade-off effects were not observed as a result of hybridization and mutagenesis. These results underline the potential of classical genetic approaches for trait improvement in the nematode H. bacteriophora. PMID- 29108858 TI - Increased expression of type 1 cannabinoid (CB1) receptor among patients with rotator cuff lesions and shoulder stiffness. AB - BACKGROUND: Shoulder stiffness is a disease manifested by pain, limited range of motion, and functional disability. The inflammatory and fibrosis processes play a substantial role in the pathogenesis of shoulder stiffness. The CB1 receptor has been recognized to mediate the processes of pathologic fibrosis. This study investigated the role of the CB1 pathway in pathogenesis of rotator cuff lesions with shoulder stiffness. METHODS: All of the patients undergoing repair surgery for rotator cuff lesions were recruited and subcategorized into subjects with and without shoulder stiffness. Reverse transcription-polymerase chain reaction assay was used to evaluate the expression level of CB1 and interleukin 1beta (IL-1beta) in the subacromial bursae, and enzyme-linked immunosorbent assay was used to measure the concentration of CB1 and IL-1beta in the subacromial fluid. Tenocytes treated with CB1 agonists and antagonists were also studied for the relationship of CB1 and the inflammatory cytokine IL-1beta. RESULTS: The patients with shoulder stiffness had higher messenger RNA (mRNA) expression (P = .040) and immunohistochemistry staining (P < .001) of CB1 in the subacromial bursa and higher CB1 concentration in the subacromial fluid (P = .008). Tenocytes treated with the CB1 agonist WIN 55,212-2 and antagonist AM251 showed increased expression of IL-1beta mRNA (P = .049) and suppressed expression of IL-1beta mRNA (P = .001), respectively. DISCUSSION: The CB1 pathway is involved in the pathogenesis of shoulder stiffness. It may be a promising target for the treatment of rotator cuff lesions with shoulder stiffness. PMID- 29108859 TI - [Spanish translation and validation of the EMPATHIC-30 questionnaire to measure parental satisfaction in intensive care units]. AB - INTRODUCTION: Few validated surveys measuring parental satisfaction in the Paediatric Intensive Care Unit (PICU) are available, and none of them in Spanish language. The aim of this study is to translate and validate the questionnaire EMpowerment of PArents in THe Intensive Care (EMPATHIC). This questionnaire measures parental perceptions of paediatric intensive care-related satisfaction items in the Spanish language. MATERIAL AND METHODS: A prospective cohort study was carried out using questionnaires completed by relatives of children (range 0 17 years old) admitted into a tertiary PICU. Inclusion criteria were a length of stay more than 24h, and a suitable understanding of Spanish language by parents or guardians. Exclusion criteria were re-admissions and deceased patients. The questionnaire was translated from English to Spanish language using a standardised procedure, after which it was used in a cross-sectional observational study was performed to confirm its validity and consistency. Reliability was estimated using Cronbach's alpha, and content validity using Spearman's correlation analysis. RESULTS: A total of 150 questionnaires were collected. A Cronbach's alpha was obtained for domains greater than 0.7, showing a high internal consistency from the questionnaire. Validity was measured by correlating 5 domains with 4 general satisfaction items, documenting an adequate correlation (Rs: 0.41-0.66, P<.05). CONCLUSIONS: The Spanish version of EMPHATIC 30 is a feasible, easy, and suitable tool in this specific environment, based on the results. EMPATHIC 30 is able to measure parental satisfaction, and may serve as a valid indicator to measure quality of care in Spanish PICUs. PMID- 29108861 TI - A slippery slope: On the origin, role and physiology of mucus. AB - The mucosa of the gastrointestinal tract, eyes, nose, lungs, cervix and vagina is lined by epithelium interspersed with mucus-secreting goblet cells, all of which contribute to their unique functions. This mucus provides an integral defence to the epithelium against noxious agents and pathogens. However, it can equally act as a barrier to drugs and delivery systems targeting epithelial passive and active transport mechanisms. This review highlights the various mucins expressed at different mucosal surfaces on the human body, and their role in creating a mucoid architecture to protect epithelia with specialized functions. Various factors compromising the barrier properties of mucus have been discussed, with an emphasis on how disease states and microbiota can alter the physical properties of mucus. For instance, Akkermansia muciniphila, a bacterium found in higher levels in the gut of lean individuals induces the production of a thickened gut mucus layer. The aims of this article are to elucidate the different physiological, biochemical and physical properties of bodily mucus, a keen appreciation of which will help circumvent the slippery slope of challenges faced in achieving effective mucosal drug and gene delivery. PMID- 29108862 TI - Animal models of smoke inhalation injury and related acute and chronic lung diseases. AB - Smoke inhalation injury leads to various acute and chronic lung diseases and thus is the dominant cause of fire-related fatalities. In a search for an effective treatment and validation of therapies different classes of animal models have been developed, which include both small and large animals. These models have advanced our understanding of the mechanism of smoke inhalation injury, enabling a better understanding of pathogenesis and pathophysiology and development of new therapies. However, none of the animal models fully mirrors human lungs and their pathologies. All animal models have their limitations in replicating complex clinical conditions associated with smoke inhalation injury in humans. Therefore, for a correct interpretation of the results and to avoid bias, a precise understanding of similarities and differences of lungs between different animal species and humans is critical. We have reviewed and presented comprehensive comparison of different animal models and their clinical relevance. We presented an overview of methods utilized to induce smoke inhalation injuries, airway micro /macrostructure, advantages and disadvantages of the most commonly used small and large animal models. PMID- 29108863 TI - Alterations in sperm DNA methylation patterns of oligospermic males. AB - Aberrant in sperm DNA methylation patterns and histone modification play a role in male fecundity decline. This study was prepared to determine whether sperm DNA methylation at CpG dinucleotides is different in oligospermic males compared to proven fertile males and then to evaluate the correlation between the changes in sperm DNA methylation patterns and semen parameters of oligospermic males. A total of 165 males (64 proven fertile males "controls" and 101 oligospermic males "cases") were included in the study. Three CpG sites have the highest difference in methylation levels (cg23081194, cg25750688, and cg04807108) were underwent to further analysis using deep bisulfite sequencing in 125 samples (44 controls and 81 cases). The results of a validation study showed that variation in methylation levels was found in more than one CpG site: there was a significant alteration in methylation levels at all CpGs tested within the UBE2G2 and cg25750688 site related amplicon (p<=0.0001), and at eight CpGs (CpG1, CpG3, CpG6, CpG8, CpG11, CpG13, CpG14, and CpG15) within the cg04807108 site related amplicon (p<=0.0001) in cases compared to controls. Besides, a significant correlation was found between the changes in the methylation levels at different CpGs and semen parameters of case group. In conclusion, this study showed that these sites have a significant alteration in sperm DNA methylation levels in oligospermic males compared to proven fertile males, and these changes correlated with semen parameters. PMID- 29108864 TI - Neuro-glial cannabinoid receptors modulate signaling in the embryonic avian retina. AB - Endocannabinoids are endogenous lipids that activate selective G protein coupled receptors (CB1 and CB2), mostly found at neuronal presynaptic sites in the nervous system. One of the main consequences of the activation of CB receptors is a decrease in GABA or glutamate release, controlling cell excitability. Here we studied the expression of CB1 and CB2 receptors in E8C8 cultured retina cells (embryonic day 8 and 8 days in vitro) using immunocytochemistry and western blot analysis. We also evaluated their functions in terms of cyclic AMP (cAMP) production, single cell calcium imaging (SCCI) and GABA release induced in basal conditions or activated by l-Aspartate (L-ASP) in cell cultures or under ischemia in young chick retina. We show that both cannabinoid receptors are expressed in retinal neurons and glial cells. WIN 55,212-2 (WIN, a CB1/CB2 agonist) decreased cAMP production in cultured avian embryonic retinal cells in basal conditions. WIN also led to a decrease in the number of glial cells that increased Ca2+ levels evoked by ATP, but had no effect in Ca2+ shifts in neuronal cells activated by KCl. Finally, WIN inhibited [3H]-GABA release induced by KCl or L ASP, accumulated in amacrine cells, but had no effect in the amount of GABA released in an oxygen glucose deprivation (OGD) condition. Altogether, our data indicate that cannabinoid receptors function as regulators of avian retina signaling at critical embryonic stages during synapse formation. PMID- 29108865 TI - Insulin expression in cultured astrocytes and the decrease by amyloid beta. AB - Insulin resistance in brain has been reported in Alzheimer's diseases (AD). Insulin signaling is important for homeostasis in brain function and reported to be disturbed in neurons leading to tau phosphorylation and neurofibrillary tangles. Many investigations of insulin in neurons have been reported; however, it has not been reported whether astrocytes also produce insulin. In the present study, we assessed the expression of insulin in astrocytes cultured from rat embryonic brain and the effects of amyloid beta1-42 (Abeta) and lipopolysaccharide (LPS) on the expression. We found that astrocytes expressed preproinsulin mRNAs and insulin protein, and that Abeta or LPS decreased these expressions. Antioxidants, glutathione and N-acetylcysteine, restored the decreases in insulin mRNA expression by Abeta and by LPS. Insulin protein was detected in astrocyte conditioned medium. These results suggest that astrocytes express and secrete insulin. Oxidative stress might be involved in the decreased insulin expression by Abeta or LPS. The insulin decrease by Abeta in astrocytes could be a novel disturbing mechanism for brain insulin signaling in AD. PMID- 29108860 TI - Fibrosis imaging: Current concepts and future directions. AB - Fibrosis plays an important role in many different pathologies. It results from tissue injury, chronic inflammation, autoimmune reactions and genetic alterations, and it is characterized by the excessive deposition of extracellular matrix components. Biopsies are routinely employed for fibrosis diagnosis, but they suffer from several drawbacks, including their invasive nature, sampling variability and limited spatial information. To overcome these limitations, multiple different imaging tools and technologies have been evaluated over the years, including X-ray imaging, computed tomography (CT), ultrasound (US), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). These modalities can provide anatomical, functional and molecular imaging information which is useful for fibrosis diagnosis and staging, and they may also hold potential for the longitudinal assessment of therapy responses. Here, we summarize the use of non invasive imaging techniques for monitoring fibrosis in systemic autoimmune diseases, in parenchymal organs (such as liver, kidney, lung and heart), and in desmoplastic cancers. We also discuss how imaging biomarkers can be integrated in (pre-) clinical research to individualize and improve anti-fibrotic therapies. PMID- 29108866 TI - Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid alpha-glucosidase. AB - Pompe disease is a rare disorder due to deficiency of the acid alpha-glucosidase (GAA) treated by enzyme replacement therapy. The present authorized treatment with rhGAA, the recombinant human enzyme, provides an important benefit in the infantile onset; however, the juvenile and adult forms of the disease corresponding to >80% of the patients are less responsive to this treatment. This resistance has been mainly attributed to an insufficiency of mannose 6-phosphate residues in rhGAA to address lysosomes through the cation-independent mannose 6 phosphate receptor (CI-M6PR). As yet, several attempts to improve the enzyme delivery by increasing the number of mannose 6-phosphate on the enzyme were poorly effective on the late onset form of the disease. Here, we show that chemical conjugation of a synthetic analogue of the mannose 6-phosphate, named AMFA, onto rhGAA improves the affinity for CI-M6PR and the uptake of the enzyme in fibroblasts and myoblasts of adult Pompe patients. More importantly, only the conjugated rhGAA-AMFA was effective in aged Pompe mice when compared to rhGAA. Weekly treatment with 5-20mg.kg-1 rhGAA-AMFA provided major improvements of the motor function and of the myofiber structure, whereas rhGAA was inactive. Finally, AMFA addition did not induce supplementary immune response to the enzyme. This modified enzyme, displaying a muscle recovery in aged Pompe mice that was never attained before, could be considered as a potential therapy for the late onset Pompe disease. PMID- 29108867 TI - Medicolegal issues for the respiratory paediatrician. AB - The legal profession depends on expert witnesses, and indeed the first time an English Court relied on an expert medical witness was in the 14th century. Asking a specialist to comment on the standard of professional practice expected in their own specialty was first introduced in a 1767 case [1]. This article draws on 20 years of experience in medicolegal work relating to paediatric respiratory medicine. It highlights some of the legal principles that lie behind an expert opinion and what constitutes clinical negligence. It aims to set out lessons for medicolegal experts and clinicians, but also offers some advice to lawyers and parents. Finally, it illustrates some issues that arise more commonly in paediatric respiratory practice. PMID- 29108868 TI - Does vitamin E prevent asthma or wheeze in children: A systematic review and meta analysis. AB - Asthma is a heterogeneous disease with multiple phenotypes. Epidemiologic studies suggest a close relationship between vitamin E and the occurrence of asthma, wheezing and atopic conditions during childhood. Previous results on its effects have been conflicting. The aim of this meta-analysis was to critically examine the current evidence on the association of vitamin E with childhood asthma and wheezing. We searched electronic databases for observational studies in English language journals published from 2000 to 2016. The initial search found 420 titles; nineteen studies were eligible according to the abstracts and details, which included reporting asthma or wheeze as an outcome. None of the articles included in this meta-analysis reported side effects of vitamin E supplementation during pregnancy. This meta-analysis found that vitamin E supplementation during pregnancy influenced the risk of asthma. To better understand the effectiveness and safety of vitamin E in children with asthma, large-scale, well-designed and randomized controlled trials are needed. PMID- 29108869 TI - The CADMUS trial - Multi-parametric ultrasound targeted biopsies compared to multi-parametric MRI targeted biopsies in the diagnosis of clinically significant prostate cancer. AB - OBJECTIVE: To compare the proportion of clinically significant prostate cancers (PCa) found in lesions detected by multiparametric MRI (mpMRI) with that found in lesions detected by multiparametric ultrasound (mpUSS), in men at risk. PATIENTS AND METHODS: CADMUS (Cancer Detection by Multiparametric Ultrasound of the prostate) is a prospective, multi-centre paired cohort diagnostic utility study with built-in randomisation of order of biopsies. The trial is registered ISRCTN38541912. All patients will undergo the index test under evaluation (mpUSS+/-biopsies), as well as the standard test (mpMRI+/-biopsies). Eligible men will be those at risk of harbouring prostate cancer usually recommended for prostate biopsy, either for the first time or as a repeat, who have not had any prior treatment for prostate cancer. Men in need of repeat biopsy will include those with prior negative results but ongoing suspicion, and those with an existing prostate cancer diagnosis but a need for accurate risk stratification. Both scans will be reported blind to the results of the other and the order in which the targeted biopsies derived from the two different imaging modalities are taken will be randomised. Comparison will be drawn between biopsy results of lesions detected by mpUSS with those lesions detected by mpMRI. Agreement over position between the two imaging modalities will be studied. DISCUSSION: CADMUS will provide level one evidence on the performance of mpUSS derived targeted biopsies in the identification of clinically significant prostate cancer in comparison to mpMRI targeted biopsies. Recruitment is underway and expected to complete in 2018. PMID- 29108870 TI - Is two-port laparoendoscopic single-site surgery (T-LESS) feasible for pediatric hydroceles? Single-center experience with the initial 59 cases. AB - INTRODUCTION: Although T-LESS is increasingly being used to treat pediatric inguinal hernia, there is no study regarding T-LESS for pediatric hydrocele. OBJECTIVE: To further evaluate the feasibility of T-LESS and present our single center experience for repair of pediatric hydroceles. STUDY DESIGN: From January 2016 to July 2016, all boys undergoing T-LESS for hydrocele in our institute were retrospectively reviewed. A laparoscope and a needle-holding forceps were introduced at umbilicus. A round needle with silk suture was stabbed through the abdominal wall. The peritoneum around the internal ring was sutured continuously in a clockwise direction. After a complete purse-string suture, a triple knot was performed by using a single-instrument tie technique. The contralateral patent processus vaginalis (PPV) was repaired simultaneously if present. RESULTS: Overall, 59 boys with hydrocele were included (22 on the left side, 32 on the right side, and 5 bilaterally) (Table). During the procedure, all hydroceles were observed with a PPV but the fluid needed to be aspired in 39 boys. A contralateral PPV was present in 24 boys with unilateral hydrocele, and finally 88 repairs were performed. Mean operative time was 18.3 min for unilateral repair and 27.5 min for bilateral repair, respectively. All procedures were uneventful besides a minor injury to the inferior epigastric vessels. After a mean follow-up of 10.7 months, neither recurrence nor other postoperative complication was observed. There were no visible scars on the abdominal wall. DISCUSSION: Compared with open repair of pediatric inguinal hernia and hydrocele, laparoscopic surgery had several advantages, such as exploration of contralateral PPV, identification of rare hernias, diminished postoperative pain, improved cosmesis, faster recovery, and fewer complications. Differing from the laparoscopic retroperitoneal approach, T-LESS included no subcutaneous tissue in the ligature, and its knot was completely in the peritoneal cavity which could radically prevent the severe pain and suture granuloma in the ligated region. Furthermore, the skin incisions after T-LESS were hidden in umbilicus, which could achieve an excellent cosmetic result. By performing T-LESS for pediatric hydroceles, the current study showed very satisfactory results, such as high success rate, minor complication, and excellent cosmesis. However, because of the difficult learning curve of T-LESS, some technical details (e.g. avoiding injury to the spermatic cord, completely suturing the peritoneal folds and reducing disturbance between the instruments) still need to be improved in the future. CONCLUSION: T-LESS appears to be a safe and effective method for repair of pediatric hydroceles. PMID- 29108872 TI - Corrigendum to "The possible role of interleukin-35 and its therapeutic potential in pemphigus" [Int. Immunol. 42 (2017) 11-17]. PMID- 29108873 TI - The comparison of the effectiveness of conventional therapeutic exercises and Pilates on pain and function in patients with knee osteoarthritis. AB - The aim of this study was to investigate the effectiveness of two different interventions on pain and disability in patients with knee osteoarthritis (KOA). Forty-one individuals (Mean +/- SD: Age 52.1 +/- 8.9 years, Height 172.8 +/- 6.6 cm, Weight 80.2 +/- 6.9 kg) with KOA were randomly allocated into Pilates (N = 14), conventional therapeutic exercise (CTE) (N = 14), and control (N = 13) groups. Joint position sense (JPS), functional performance, pain, and disability were examined using Biodex system, aggregate time of four daily activities, and Lequesne Index. One-Way ANOVA, and Post Hoc Scheffe test were administrated to analyze the data (P < 0.05). There was a significant (P < 0.001) difference between the experimental groups in all measured outcomes compared to the control. While, regarding pain and disability, more significant (P = 0.003) improvement was observed in participants following Pilates training compared to CTE. It seemed that Pilates training was more effective than the CTE to improve pain and disability in individuals with KOA. PMID- 29108871 TI - Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs. AB - Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2'-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis. PMID- 29108874 TI - Corrigendum to "HMGB1 modulates Lewis cell autophagy and promotes cell survival via RAGE-HMGB1-Erk1/2 positive feedback during nutrient depletion" [Immunobiology 220 May (5) (2015) 539-44]. PMID- 29108875 TI - [The vaccines anti-HPV today in the treatment of the genital infections to HPV]. PMID- 29108876 TI - A fine balancing act: A delicate kinase-phosphatase equilibrium that protects against chromosomal instability and cancer. AB - Cancer cells rewire signalling networks to acquire specific hallmarks needed for their proliferation, survival, and dissemination throughout the body. Although this is often associated with the constitutive activation or inactivation of protein phosphorylation networks, there are other contexts when the dysregulation must be much milder. For example, chromosomal instability is a widespread cancer hallmark that relies on subtle defects in chromosome replication and/or division, such that these processes remain functional, but nevertheless error-prone. In this article, we will discuss how perturbations to the delicate kinase phosphatase balance could lie at the heart of this type of dysregulation. In particular, we will explain how the two principle mechanisms that safeguard the chromosome segregation process rely on an equilibrium between at least two kinases and two phosphatases to function correctly. This balance is set during mitosis by a central complex that has also been implicated in chromosomal instability - the BUB1/BUBR1/BUB3 complex - and we will put forward a hypothesis that could link these two findings. This could be relevant for cancer treatment because most tumours have evolved by pushing the boundaries of chromosomal instability to the limit. If this involves subtle changes to the kinase phosphatase equilibrium, then it may be possible to exacerbate these defects and tip tumour cells over the edge, whilst still maintaining the viability of healthy cells. PMID- 29108877 TI - PIM kinases: From survival factors to regulators of cell motility. AB - PIM kinases are oncogenic serine/threonine kinases, the expression and activities of which are tightly regulated in normal tissues, but upregulated in many types of human malignancies, including both hematological and solid cancers. Since high PIM expression levels have been connected to cancer progression and poor patient survival, PIM kinases have become attractive targets for drug development. Many downstream targets have also been identified, through which PIM kinases promote cell survival, proliferation and metabolism. More recently, PIM kinases have been implicated in regulation of cell motility, which also plays an important role in tumor growth and cancer progression. This review summarizes effects of PIM kinases and their substrates especially on cancer cell migration, invasion and metastatic growth, based on data from cell-based assays, animal experiments and patients. PMID- 29108878 TI - Population genetic data of 22 autosomal STRs in the Guizhou Miao population, southwestern China. PMID- 29108879 TI - Remyelination modulators in multiple sclerosis patients. AB - Multiple Sclerosis (MS) is a complex autoimmune neuro-inflammatory disorder characterized by persistent MS plaques in the central nervous system. Resolution of MS plaques is dependent on the remyelination competence of surviving oligodendrocytes and surrounding environment. Here, we assessed myelination modulators in a 100 MS patients against 77 healthy controls. Plasma fractions were used for the assessment of insulin growth factor binding protein1 (IGFBP1), brain-derived neurotrophic factor (BDNF), and lipocalin2 (LCN2) using a Luminex multiplex assay, whereas neurofilament light chain (NF-L) was assessed with an enzyme-linked immunosorbent assay. Circulating levels of IGFBP1, LCN2 and NF-L were significantly higher in MS patients (p<0.01). Whereas BDNF levels were significantly lower in MS patients (p=0.014). MS Female patients had significantly higher levels of IGFBP1 compared to male MS patients (p=0.006). MS patients treated with fingolimod had higher LCN2 levels compared to those on natalizumab (r=0.25, p=0.03). Higher NF-L levels associated with clinically isolated syndrome's (CIS) conversion into MS (p=0.002). We conclude that low BDNF and high LCN2 and NF-L levels are associated with MS pathogenesis, and high IGFBP1level is a biomarker for female MS only, suggesting different MS progression pathways between the sexes. LCN2 is a candidate predictor of response to natalizumab treatment, and NF-L is a candidate predictor of CIS conversion into MS. PMID- 29108880 TI - Fibroblast growth factor 21 in chronic kidney disease. AB - The association between fibroblast growth factor 21 (FGF21) and kidney function has been extensively studied in recent years in both animal and human studies. However, the exact functional role of FGF21 in the kidney remains unclear. Previous animal studies have shown that administration of FGF21 ameliorates kidney function, morphological glomerular abnormalities, dyslipidemia, hyperglycemia, insulin resistance, oxidative stress and obesity. In human studies, FGF21 levels negatively correlated with estimated glomerular filtration rate. FGF21 levels were elevated in patients with end-stage renal disease. The elevation of FGF21 levels in presence of kidney disease has also raised questions as to whether FGF21 is a potential biomarker for detecting a decline in renal function. In recent clinical trials, an FGF21 analogue reduced insulin levels and body weight, and ameliorated dyslipidemia in patients with type 2 diabetes mellitus and obesity, all of which are well-known risk factors for kidney disease. Thus, FGF21 may be a potential therapeutic target for the treatment of kidney disease, although adverse side effects should also be considered when administering FGF21 since FGF21 may affect bone development and reproduction. This review will assess current knowledge on the relationship between FGF21 and kidney function. PMID- 29108881 TI - Phospholipase C zeta and calcium oscillations at fertilisation: The evidence, applications, and further questions. AB - Oocyte activation is a fundamental event at mammalian fertilisation, initiated by a series of characteristic calcium (Ca2+) oscillations in mammals. This characteristic pattern of Ca2+ release is induced in a species-specific manner by a sperm-specific enzyme termed phospholipase C zeta (PLCzeta). Reduction or absence of functional PLCzeta within sperm underlies male factor infertility in humans, due to mutational inactivation or abrogation of PLCzeta protein expression. Underlying such clinical implications, a significant body of evidence has now been accumulated that has characterised the unique biochemical and biophysical properties of this enzyme, further aiding the unique clinical opportunities presented. Herein, we present and discuss evidence accrued over the past decade and a half that serves to support the identity of PLCzeta as the mammalian sperm factor. Furthermore, we also discuss the potential novel avenues that have yet to be examined regarding PLCzeta mechanism of action in both the oocyte, and the sperm. Finally, we discuss the advances that have been made regarding the clinical therapeutic and diagnostic applications of PLCzeta in potentially treating male infertility as a result of oocyte activation deficiency (OAD), and also possibly more general cases of male subfertility. PMID- 29108882 TI - Brain mechanisms for processing discriminative and affective touch in 7-month-old infants. AB - Affective touch has been associated with affiliative behavior during early stages of infant development; however, its underlying brain mechanisms are still poorly understood. This study used fNIRS (functional near-infrared spectroscopy) to examine both affective and discriminative touch in 7- month-old infants (n=35). Infants were provided affective stimuli on the forearm for 10 sec followed by a 20 sec rest period. The protocol was repeated for discriminative touch, and both affective and discriminative stimuli were given in a counterbalanced order. Brain activation (oxy-hemoglobin and deoxy-hemoglobin levels) in the somatosensory and temporal regions was registered during administration of the stimuli. There was an increase in oxy-hemoglobin and decrease in deoxy-hemoglobin only in the somatosensory region in response to both affective and discriminative touch. No other activations were found. Seven-month-old infants' brain activation in the somatosensory cortex was similar for both discriminative and affective touch, but the stimuli did not elicit any activation in the temporal region/ pSTS. Our study is the first to suggest that 7-month-old infants do not yet recruit socio emotional brain areas in response to affective touch. PMID- 29108884 TI - Peritendinous injection of platelet-rich plasma to treat tendinopathy: A retrospective review. AB - OBJECTIVE: The aim of this study was to determine factors associated with the likelihood of a better clinical outcome after the peritendinous injection of PRP for the treatment of chronic tendinopathy and identify whether PRP represents an effective treatment option for chronic tendinopathies. METHODS: The study included 214 patients (86 males and 128 females; mean age: 39.3 (18-75) years) who received PRP injections for tendinopathy refractory to conventional treatments. The mean duration of symptoms at the moment of the PRP treatment was 8.3 months. Primary outcome measurement was perceived improvement in symptoms for each anatomic compartment for upper and lower limbs at 6 months after treatment. Also, a visual analog scale (VAS) score (pain intensity on a 0-10 scale) was used for pain scoring questionnaire before treatment, 6 weeks and 6 months following the PRP injection(s). To identify factors associated with the likelihood of a better clinical outcome, patients were categorized on the basis of their perceived improvement in symptoms 6 months after the PRP injection(s)-that is, as lower (less than 50% global improvement) or higher (more than 50% global improvement). RESULTS: A visual analogue scale score and perceived improvement in symptoms were significantly lower after peritendinous injection in 6-week and 6 month follow-ups compared with the baseline (P < 0.001) except for peroneal and Achilles tendons. Overall, 83% of patients indicated moderate to complete improvement in symptoms. The most common injection sites were the lateral epicondyle, Achilles, and patellar tendons. Furthermore, 30% of patients received only 1 injection, 30% received 2 injections, and 40% received 3 or more injections. A total of 85% of patients were satisfied (more than 50% global improvement) with the procedure. In addition, upper limb tendons, increase in the age, and female gender were associated with a higher likelihood of perceived improvement in symptoms. CONCLUSIONS: In the present retrospective study assessing PRP injections in the treatment of chronic tendinopathy, a moderate improvement (>50%) in pain symptoms was observed in most of the patients. Our research found that results were most promising with patellar and lateral epicondylar tendinopathy in the short to medium term. Female patients, patients with upper extremity tendinopathy and older patients appeared to benefit more from PRP injection. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 29108885 TI - Management of Dyspnea and Anxiety in Chronic Obstructive Pulmonary Disease: A Critical Review. AB - BACKGROUND: Anxiety and dyspnea, 2 major symptoms in patients with chronic obstructive pulmonary disease (COPD), are associated with high morbidity and mortality. Thus, critically evaluating and synthesizing the existing literature employing pulmonary rehabilitation (PR) and other behavioral therapies in the treatment of anxiety and dyspnea in patients with COPD may help clinicians determine the most efficacious potential treatments. We aim to examine the efficacy of PR and behavioral therapy [eg, cognitive behavioral therapy (CBT) and counseling] and other adjunct modalities used in patients with COPD. METHODS: We extracted relevant studies searching the published literature using an electronic database CINAHL, Medline, PubMed, Science Direct, and the Web of Science was conducted (spanning January 1, 2006 to November 15, 2016). Studies were included if they conducted PR and behavioral therapy (CBT, self-management, yoga) to treat anxiety and/or dyspnea in patients with COPD with or without randomized controlled trial. RESULTS: The 47 studies selected included 4595 participants (PR = 3756 and behavioral therapy = 839), ranging in age from 58 to 75 years. The total number of participants receiving a treatment was 3928, and 667 participants served in control groups. In the majority of studies, PR and CBT are effective in the treatment of anxiety and dyspnea in the short term, but the long-term benefit is limited. In addition, self-management, yoga therapy, and CBT plus PR were beneficial. CONCLUSIONS: PR and CBT reduced both anxiety and dyspnea symptoms in patients with COPD in the short term. However, maintenance programs and the long term benefits of PR and CBT remain inconclusive. Generally, the studies were relatively small and uncontrolled. Thus, prospective and randomized controlled trials with larger sample sizes are needed. PMID- 29108883 TI - An ELISA method to estimate the mono ADP-ribosyltransferase activities: e.g in pertussis toxin and vaccines. AB - ADP-ribosyltransferase activities have been observed in many prokaryotic and eukaryotic species and viruses and are involved in many cellular processes, including cell signalling, DNA repair, gene regulation and apoptosis. In a number of bacterial toxins, mono ADP-ribosyltransferase is the main cause of host cell cytotoxicity. Several approaches have been used to analyse this biological system from measuring its enzyme products to its functions. By using a mono ADP-ribose binding protein we have now developed an ELISA method to estimate native pertussis toxin mono ADP-ribosyltransferase activity and its residual activities in pertussis vaccines as an example. This new approach is easy to perform and adaptable in most laboratories. In theory, this assay system is also very versatile and could measure the enzyme activity in other bacteria such as Cholera, Clostridium, E. coli, Diphtheria, Pertussis, Pseudomonas, Salmonella and Staphylococcus by just switching to their respective peptide substrates. Furthermore, this mono ADP-ribose binding protein could also be used for staining mono ADP-ribosyl products resolved on gels or membranes. PMID- 29108886 TI - Trajectories Over the First Year of Long-Term Care Nursing Home Residence. AB - OBJECTIVES: To describe the trajectories in the first year after individuals are admitted to long-term care nursing homes. DESIGN: Retrospective cohort study. SETTING: US long-term care facilities. PARTICIPANTS: Medicare fee-for-service beneficiaries newly admitted to long-term care nursing homes from July 1, 2012, to December 31, 2013 (N=535,202). MEASUREMENTS: Demographic characteristics were from Medicare data. Individual trajectories were conducted using the Minimum Data Set for determining long-term care stays and community discharge, and Medicare Provider and Analysis Reviews claims data for determining hospitalizations, skilled nursing facility stays, inpatient rehabilitation, long-term acute hospital and psychiatric hospital stays. RESULTS: The median length of stay in a long-term care nursing home over the 1 year following admission was 127 [interquartile range (IQR): 24, 356] days. The median length of stay in any institution was 158 (IQR: 38, 365). Residents experienced a mean of 2.1 +/- 2.8 (standard deviation) transitions over the first year. The community discharge rate was 36.5% over the 1-year follow-up, with 20.8% discharged within 30 days and 31.2% discharged within 100 days. The mortality rate over the first year of nursing home residence was 35.0%, with 16.3% deaths within 100 days. At 12 months post long-term care admission, 36.9% of the cohort were in long-term care, 23.4% were in community, 4.7% were in acute care hospitals or other institutions, and 35.0% had died. CONCLUSION: After a high initial community discharge rate, the majority of patients newly admitted to long-term care experienced multiple transitions while remaining institutionalized until death or the end of 1-year follow-up. PMID- 29108887 TI - Proposed POLST Replacement Creates More Problems than it Solves. PMID- 29108888 TI - The Effect of a 2-Year Intervention Consisting of Diet, Physical Exercise, Cognitive Training, and Monitoring of Vascular Risk on Chronic Morbidity-the FINGER Randomized Controlled Trial. AB - OBJECTIVE: To verify whether a multidomain intervention lowers the risk of developing new chronic diseases in older adults. METHODS: Multicenter, double blind randomized controlled trial started in October 2009, with 2-year follow-up. A total of 1260 people aged 60 to 77 years were enrolled in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Participants were randomly assigned in a 1:1 ratio to a 2-year multidomain intervention (n = 631) (nutritional guidance, exercise, cognitive training, and management of metabolic and vascular risk factors) or a control group (n = 629) (general health advice). Data on most common chronic diseases were collected by a physician at baseline and 2 years later. RESULTS: At 2-year follow-up, the average number of new chronic diseases was 0.47 [standard deviation (SD) 0.7] in the intervention group and 0.58 (SD 0.8) in the control group (P < .01). The incidence rate per 100 person-years for developing 1+ new disease(s) was 17.4 [95% confidence interval (CI) = 15.1-20.1] in the intervention group and 20.5 (95% CI = 18.0-23.4) in the control group; for developing 2+ new diseases, 4.9 (95% CI = 3.7-6.4) and 6.1 (95% CI = 4.8-7.8); and for 3+ new diseases, 0.7 (95% CI = 0.4-1.5) and 1.8 (95% CI = 1.1-2.8), respectively. After adjustment for age, sex, education, current smoking, alcohol intake, and the number of chronic diseases at baseline, the intervention group had a hazard ratio ranging from 0.80 (0.66-0.98) for developing 1+ new chronic disease(s) to 0.38 (0.16-0.88) for developing 3+ new chronic diseases compared to the control group. CONCLUSIONS: Findings from this randomized controlled trial suggest that a multidomain intervention could reduce the risk of developing new chronic diseases in older people. PMID- 29108889 TI - Recall Tests may be Effective to Detect Mild Cognitive Impairment: A Response to Tsoi and Colleagues. PMID- 29108890 TI - Determining the Optimum Physician-to-Resident Ratio in the Nursing Home. PMID- 29108891 TI - Is Fear of Falling Associated With Decline in Global Cognitive Functioning in Older Adults: Findings From the Irish Longitudinal Study on Ageing. AB - BACKGROUND: Fear of falling (FoF) is present in 20% to 85% of older adults and may be an early marker of decline in global cognitive functioning (GCF). We tested the hypothesis that FoF is associated with lower levels of GCF (cross sectional) and greater decline in GCF (prospective) in adults aged 50 and older. DESIGN: Observational cohort study. SETTING: The Irish Longitudinal Study on Ageing, a population-based study. PARTICIPANTS: Data were from 4931 participants (mean age 62.9 +/- 9.1, range 50-98, 54.3% female). MEASUREMENTS: FoF was based on self-report in 2010. GCF was measured with the Montreal Cognitive Assessment (MoCA) and Mini Mental Status Examination (MMSE) in 2010 and 2014. The cross sectional association was examined using linear regression unadjusted and after adjustment for demographic and health factors. The prospective association between FoF and the odds of >1-SD decline in GCF were examined using logistic regression. Interaction with age and mediation by social and physical activities were examined. RESULTS: In 2010, 21.9% of participants reported FoF. In the unadjusted cross-sectional models, those with FoF had lower scores on the MoCA (B -1.15, 95% confidence interval [CI] -1.40 to -0.90) and MMSE (B -0.52, CI -0.67 to -0.37). In the unadjusted prospective models, FoF was associated with a greater odds of decline in MoCA (odds ratio [OR] 1.60, CI 1.26-2.04) and MMSE (OR 1.64, CI 1.29-2.08). After adjustment for covariates, all associations attenuated and were no longer statistically significant, except the association with decline in MoCA (OR 1.32, CI 1.01-1.71). No statistically significant interaction with age was found (P > .37). Additional adjustment for social and physical activity did not change the results. CONCLUSIONS: The findings provide weak evidence for FoF as a predictor of cognitive decline. PMID- 29108892 TI - Antifungal activity of Latarcin 1 derived cell-penetrating peptides against Fusarium solani. AB - Cell-penetrating peptides and antimicrobial peptides share physicochemical characteristics and mechanisms of interaction with biological membranes, hence, termed as membrane active peptides. The present study aims at evaluating AMP activity of CPPs. LDP-NLS and LDP are Latarcin 1 derived cell-penetrating peptides and in the current study we have evaluated antifungal and cell penetrating properties of these CPPs in Fusarium solani. We observed that LDP-NLS and LDP exhibited excellent antifungal activity against the fungus. Cellular uptake experiments with LDP-NLS and LDP showed that LDP-NLS acted as a CPP but LDP uptake into fungal spores and hyphae was negligible. CPP and AMP activity of mutated version of LDP-NLS was also evaluated and it was observed that both the activities of the peptide were compromised, signifying the importance of arginines and lysines present in LDP-NLS for initial interaction of membrane active peptides with biological membranes. Dextrans and Propidium Iodide uptake studies revealed that the mode of entry of LDP-NLS into fungal hyphae is through pore formation. Also, both LDP-NLS and LDP showed no cytotoxicity when infiltered into leaf tissues. Overall, our results suggest that LDP-NLS and LDP are selectively cytotoxic to F. solani and can be a potent peptide based antifungal agents. PMID- 29108893 TI - Bariatric surgery as a treatment for heart failure: review of the literature and potential mechanisms. AB - Heart failure due to severe obesity is a complex disease due to multiple mechanisms, including increased body mass, inflammation, and impaired cardiac metabolism that is complicated by obesity-associated co-morbidities, such as type 2 diabetes and obstructive sleep apnea. Bariatric surgery significantly improves cardiac geometry, function, and symptoms related to obesity cardiomyopathy. There is a consistently positive impact of bariatric surgery on diastolic function with the potential to significantly improve systolic function as measured by ejection fraction in patients with advanced heart failure. For end-stage heart failure patients, including those requiring mechanical circulatory support who are ineligible for organ transplant due to morbid obesity, bariatric surgery has been successfully used for weight loss as a bridge to cardiac transplantation. PMID- 29108894 TI - Improving the side-to-side stapled anastomosis: comparison of staplers for robust crotch formation. AB - BACKGROUND: Few studies have investigated the burst pressure of side-to-side anastomoses comparing different stapling devices that are commercially available. OBJECTIVES: We conducted side-to-side anastomoses with a variety of staplers and compared burst pressure in the crotch of the anastomoses. SETTING: Nagoya City East Medical Center. METHODS: We conducted side-to-side anastomoses with 9 staplers with different shapes and forms. Fresh pig small intestines were used. A side-to-side anastomosis was performed between 2 intestine specimens using a linear stapler. The burst pressure of the anastomosis was recorded. RESULTS: In total, 45 staplers were used for this experiment. The site of leakage in all cases was the crotch. Regarding the influence of the number of staple rows, the burst pressure in 3-row staplers was significantly higher than in 2-row staplers. With regard to the relationship between staple height and burst pressure, staples with a height slightly shorter than the intestinal thickness showed the highest burst pressure. In a comparison of staplers with uniform staple heights and stamplers with staples of 3 different heights, the latter had significantly lower burst pressures. Neoveil significantly increased the burst pressure in the crotch and contributed to the highest burst pressure of all the staplers used in this experiment. CONCLUSIONS: In this experiment, we defined the important factors that influence burst pressure at the crotch of a stapled, side-to-side anastomosis. These factors include the number of staple rows, the height of the staple compared with the thickness of the tissue, uniformity of staple height, and reinforcement of the staple line. In any surgical case requiring intestinal anastomosis, selection of a stapler is a critical step. PMID- 29108895 TI - Changes in bowel habits and patient-scored symptoms after Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch. AB - BACKGROUND: Bariatric procedures are increasingly being used, but data on bowel habits are scarce. OBJECTIVES: To assess changes in gastrointestinal function and patient-scored symptoms after Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion with duodenal switch (BPD/DS). SETTING: University hospital in Sweden. METHODS: We recruited 268 adult patients (mean age of 42.5 yr, body mass index 44.8, 67.9% female) listed for RYGB and BPD/DS. Patients answered validated questionnaires prospectively concerning bowel function, the Fecal Incontinence Quality of Life Scale, and the 36-Item Short Form Health Survey before and after their operation. RESULTS: Postoperatively, 208 patients (78.2% of 266 eligible patients) answered the questionnaires. RYGB patients had fewer bowel motions per week (8 versus 10) and more abdominal pain postoperatively (P<.001). Postoperatively, the 35 BPD/DS patients (69% versus 23%) needed to empty their bowel twice or more than twice daily, reported more flatus and urgency, and increased need for keeping a diet (P<.001). Concerning Fecal Incontinence Quality of Life Scale, coping and behavior was slightly reduced while depression and self perception scores were improved after RYGB. Lifestyle, coping and behavior, and embarrassment were reduced after BPD/DS (P<.05). In the 36-Item Short Form Health Survey, physical scores were markedly improved, while mental scores were largely unaffected. CONCLUSION: RYGB resulted in a reduced number of bowel movements but increased problems with abdominal pain. In contrast, BPD/DS-patients reported higher frequency of bowel movements, more troubles with flatus and urgency, and increased need for keeping a diet. These symptoms affected quality of life negatively, however, general quality of life was markedly improved after both procedures. These results will be of great value for preoperative counseling. PMID- 29108896 TI - Brazilian Intragastric Balloon Consensus Statement (BIBC): practical guidelines based on experience of over 40,000 cases. AB - BACKGROUND: Intragastric balloons (IGBs) are a minimally invasive option for obesity treatment, acting as a space-occupying device and leading to weight loss through increased satiety. This device has been growing in popularity owing to its safety profile and good weight loss results. However, there are no published guidelines that standardize the technical aspects of the procedure. OBJECTIVES: To create a practical guideline for intragastric balloon usage. SETTING: Private and Academic Settings, Brazil. METHODS: A consensus meeting was held in Sao Paulo, Brazil, in June 2016, bringing together 39 Brazilian endoscopists with extensive experience in IGBs from all regions of the country. Topics on patient selection, indications, contraindications, multidisciplinary follow-up, technique, and adverse events were discussed in the form of questions. After electronic voting, a consensus was defined when there was >=70% agreement. Experts were also requested to provide data on their experience with IGBs. RESULTS: The selected experts discussed and reached a consensus on 76 questions, mainly concerning specific indications and contraindications for the procedure; technical details, such as patient preparation, minimum balloon-filling volume, techniques for implant and explant; patient follow-up and recommended medication for the adaptation period; and adverse event management. The overall Brazilian expert data encompassed 41,863 IGBs, with a mean percentage total weight loss of 18.4% +/- 2.9%. The adverse event rate after the adaptation period was 2.5%, the most common being hyperinflation (.9%) and spontaneous deflation (.8%) of the device. The early removal rate due to intolerance was 2.2%. CONCLUSIONS: The present consensus represents practical recommendations for performing IGB procedures and reflects Brazil's significant experience with this device. The experience of over 40,000 cases shows that the device leads to satisfactory weight loss with a low rate of adverse events. PMID- 29108897 TI - Cryoballoon ablation in atrial fibrillation: Advantages and drawbacks. AB - Pulmonary vein isolation is the cornerstone of atrial fibrillation ablation and is effective for preventing arrhythmias recurrences, especially in patients with paroxysmal atrial fibrillation. During the last years, cryoballoon ablation has emerged as an unquestionable alternative approach to radiofrequency ablation. Many non-randomized and randomized trials have proven undoubtedly that cryoballoon ablation displays similar efficacy and overall safety profile, when compared to radiofrequency ablation for the treatment of patients with drug refractory paroxysmal atrial fibrillation. These results have been obtained in all types of pulmonary veins anatomical subsets, which confirms that there is no need to select patients according to the latter. The value of cryoablation in the setting of short persistent atrial fibrillation still needs more evidence. Importantly, cryoballoon ablation seems to be less operator-dependent and more reproducible than radiofrequency for the isolation of pulmonary veins. PMID- 29108900 TI - Irisin and leptin concentrations in relation to obesity, and developing type 2 diabetes: A cross sectional and a prospective case-control study nested in the Normative Aging Study. AB - OBJECTIVE: To investigate the associations between irisin and leptin levels in obesity and insulin resistance in a cross sectional study. To assess the potential role of irisin and leptin as a predictive marker of T2DM using a nested case-control study. METHODS: Both studies were designed within the longitudinal VA NAS cohort. The cross sectional study involved 111 non obese and 105 obese subjects who were subdivided into two groups based on their fasting glucose tolerance. In the nested 1:3 case-control study, 47 subjects with T2DM and 140 non-diabetic controls were selected. Serum samples collected 3-5 years before the diagnosis of T2DM were analyzed. Irisin and leptin concentrations were measured using a validated ELISA and radioimmunoassay respectively. RESULTS: In the cross sectional study, irisin did not differ between groups based on their fasting glucose tolerance. When subjects were grouped based on obesity status, both irisin and leptin concentrations were significantly higher in obese compared to the non-obese group (p=0.03 and <0.001, respectively). Irisin concentrations positively correlated with leptin concentrations (r= 0.392, P < 0.001). In the nested case control study, leptin concentrations were a significant predictor of developing diabetes (p=0.005) in unadjusted models, but not after correcting for BMI, whereas irisin concentrations did not play a role of comparable significance. CONCLUSIONS: Leptin concentrations are higher in the obese group irrespective of their glucose tolerance. Obese individuals with impaired fasting glucose have higher concentrations of circulating irisin compared to non-obese subjects with normal glucose tolerance. Irisin concentrations do not predict risk of developing diabetes prospectively. PMID- 29108899 TI - Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. AB - Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as "overlap genes". Thus, some IGD genes play the role of the modifier genes or "second hits", providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations. The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also "milder" and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD. PMID- 29108898 TI - Thymidine phosphorylase: A potential new target for treating cardiovascular disease. AB - We recently found that thymidine phosphorylase (TYMP), also known as platelet derived endothelial cell growth factor, plays an important role in platelet activation in vitro and thrombosis in vivo by participating in multiple signaling pathways. Platelets are a major source of TYMP. Since platelet-mediated clot formation is a key event in several fatal diseases, such as myocardial infarction, stroke and pulmonary embolism, understanding TYMP in depth may lead to uncovering novel mechanisms in the development of cardiovascular diseases. Targeting TYMP may become a novel therapeutic for cardiovascular disorders. In this review article, we summarize the discovery of TYMP and the potential molecular mechanisms of TYMP involved in the development of various diseases, especially cardiovascular diseases. We also offer insights regarding future studies exploring the role of TYMP in the development of cardiovascular disease as well as in therapy. PMID- 29108901 TI - Keto-adaptation enhances exercise performance and body composition responses to training in endurance athletes. AB - BACKGROUND: Low-carbohydrate diets have recently grown in popularity among endurance athletes, yet little is known about the long-term (>4wk) performance implications of consuming a low-carbohydrate high fat ketogenic diet (LCKD) in well-trained athletes. METHODS: Twenty male endurance-trained athletes (age 33+/ 11y, body mass 80+/-11kg; BMI 24.7+/-3.1kg/m2) who habitually consumed a carbohydrate-based diet, self-selected into a high-carbohydrate (HC) group (n=11, %carbohydrate:protein:fat=65:14:20), or a LCKD group (n=9, 6:17:77). Both groups performed the same training intervention (endurance, strength and high intensity interval training (HIIT)). Prior to and following successful completion of 12 weeks of diet and training, participants had their body composition assessed, and completed a 100km time trial (TT), six second (SS) sprint, and a critical power test (CPT). During post-intervention testing the HC group consumed 30-60g/h carbohydrate, whereas the LCKD group consumed water, and electrolytes. RESULTS: The LCKD group experienced a significantly greater decrease in body mass (HC 0.8kg, LCKD -5.9kg; P=0.006, effect size (ES): 0.338) and percentage body fat percentage (HC -0.7%, LCKD -5.2%; P=0.008, ES: 0.346). Fasting serum beta hydroxybutyrate (betaHB) significantly increased from 0.1 at baseline to 0.5mmol/L in the LCKD group (P=0.011, ES: 0.403) in week 12. There was no significant change in performance of the 100km TT between groups (HC -1.13min.s, LCKD -4.07min.s, P=0.057, ES: 0.196). SS sprint peak power increased by 0.8 watts per kilogram bodyweight (w/kg) in the LCKD group, versus a -0.1w/kg reduction in the HC group (P=0.025, ES: 0.263). CPT peak power decreased by -0.7w/kg in the HC group, and increased by 1.4w/kg in the LCKD group (P=0.047, ES: 0.212). Fat oxidation in the LCKD group was significantly greater throughout the 100km TT. CONCLUSIONS: Compared to a HC comparison group, a 12-week period of keto adaptation and exercise training, enhanced body composition, fat oxidation during exercise, and specific measures of performance relevant to competitive endurance athletes. PMID- 29108902 TI - Development and evaluation of a RT-qPCR assay for fast and sensitive rabies diagnosis. AB - Rabies virus is endemic to Russia, among other countries. It is therefore critical to develop a high-quality and high-precision diagnostic procedure for the control and prevention of infection. The main objective of the research presented here was to develop a reliable RT-qPCR assay for rabies diagnostics. For this purpose, a RABV strains from various biological and geographical origins were used. In addition, rabies-positive and rabies-negative samples, as well as nucleic acids from other viruses and DNA extracted from the brain tissues of mice, dogs, cats, bats and humans, were studied using the developed assay. The analytical sensitivity of the assay, as assessed using armored recombinant positive control dilutions, was 103 copies/ml, and the sensitivity measured using characterized strains was between 0.1 LD50/ml and 1.0 LD50/ml. A broad range of RNA from RABV strains circulating in different regions of Russia, as well as RNA from RABV-positive primary brain samples from 81 animals and two humans, was detected using the developed assay. No false-positive or false-negative results were obtained. Given that high analytical and diagnostic sensitivities and a high specificity were verified for this assay, it has high potential as a screening test that may be suitable for the epizootiological monitoring of animals and for the fast postmortem diagnosis of rabies. PMID- 29108903 TI - ["Fake it until they make it": Practical obstetrical and gynecological ultrasound education nowadays in France]. PMID- 29108904 TI - [Maternal mortality in France: Report from the French confidential enquiry into maternal deaths, 2010-2012. "There have been great advances... but keep on going!"] PMID- 29108905 TI - [Maternal deaths due to infectious cause, results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Over the period 2010-2012, maternal mortality from infectious causes accounted for 5% of maternal deaths by direct causes and 16% of maternal deaths by indirect causes. Among the 22 deaths caused by infection occurred during this period, 6 deaths were attributed to direct causes from genital tract origin, confirming thus the decrease in direct maternal deaths by infection during the last ten years. On the contrary, indirect maternal deaths by infection, from extragenital origin, doubled during the same period, with 16 deaths in the last triennium, dominated by winter respiratory infections, particularly influenza: the 2009-2010 influenza A (H1N1) virus pandemic was the leading cause of indirect maternal mortality by infection during the studied period. The main infectious agents involved in maternal deaths from direct causes were Streptococcus A, Escherichia Coli and Clostridium perfringens: these bacterias were responsible for toxic shock syndrome, severe sepsis, secondary in some cases to cellulitis or necrotizing fasciitis. Of the 6 deaths due to direct infection, 4 were considered avoidable because of inadequate management: delayed or missed diagnosis, delayed or inadequate initiation of a specific medical and/or surgical treatment. Of the 16 indirect maternal deaths due to infection causes, the most often involved infectious agents were influenza A (H1N1) virus and Streptococcus pneumonia with induced purpura fulminans: the absence of influenza vaccination during pregnancy, delayed diagnosis and emergency initiation of a specific treatment, were the main contributory factors to these deaths and their avoidability in 70% of the cases analyzed. PMID- 29108906 TI - Phylogeography and connectivity of molluscan parasites: Perkinsus spp. in Panama and beyond. AB - Panama is a major hub for commercial shipping between two oceans, making it an ideal location to examine parasite biogeography, potential invasions, and the spread of infectious agents. Our goals were to (i) characterise the diversity and genetic connectivity of Perkinsus spp. haplotypes across the Panamanian Isthmus and (ii) combine these data with sequences from around the world to evaluate the current phylogeography and genetic connectivity of these widespread molluscan parasites. We collected 752 bivalves from 12 locations along the coast of Panama including locations around the Bocas del Toro archipelago and the Caribbean and Pacific entrances to the Panama Canal, from December 2012 to February 2013. We used molecular genetic methods to screen for Perkinsus spp. and obtained internal transcribed spacer region (ITS) ribosomal DNA (rDNA) sequences for all positive samples. Our sequence data were used to evaluate regional haplotype diversity and distribution across both coasts of Panama, and were then combined with publicly available sequences to create global haplotype networks. We found 26 ITS haplotypes from four Perkinsus spp. (1-12 haplotypes per species) in Panama. Perkinsus beihaiensis haplotypes had the highest genetic diversity, were the most regionally widespread, and were associated with the greatest number of hosts. On a global scale, network analyses demonstrated that some haplotypes found in Panama were cosmopolitan (Perkinsus chesapeaki, Perkinsus marinus), while others were more geographically restricted (Perkinsus olseni, P. beihaiensis), indicating different levels of genetic connectivity and dispersal. We found some Perkinsus haplotypes were shared across the Isthmus of Panama and several regions around the world, including across ocean basins. We also found that haplotype diversity is currently underestimated and directly related to the number of sequences. Nevertheless, our results demonstrate long-range dispersal and global connectivity for many haplotypes, suggesting that dispersal through shipping probably contributes to these biogeographical patterns. PMID- 29108907 TI - Subclinical sensitization with diphenylcyclopropenone is sufficient for the treatment of alopecia areata: Retrospective analysis of 159 cases. AB - BACKGROUND: Contact immunotherapy with diphenylcyclopropenone (DPCP) is presently considered the treatment of choice for extensive alopecia areata. However, a major concern with contact immunotherapy is that it causes various adverse effects (AEs) that contribute to discontinuation of treatment. OBJECTIVE: We investigated whether a modified DPCP treatment protocol can promote hair regrowth with fewer AEs. METHODS: All patients were sensitized with 0.1% DPCP and began treatment with 0.01% DPCP. Thereafter, the DPCP concentration was slowly increased according to the treatment response and AEs. This was a retrospective review of DPCP treatment with modified protocols in 159 patients with alopecia areata. RESULTS: Of the 159 patients, 46 (28.9%) showed a complete response and 59 (37.1%) showed a partial response. No patients had AEs after sensitization. During the treatment, only 3 patients (1.9%) showed severe AEs, and 55 showed moderate AEs; however, all were well controlled with antihistamines alone or antihistamines and medium-potency topical steroids. There was no association between treatment response and AEs. LIMITATIONS: Sample size, subject composition, and the retrospective study design represent potential limitations. CONCLUSION: A modified DPCP treatment protocol with subclinical sensitization could induce a favorable therapeutic response and result in fewer AEs. PMID- 29108908 TI - Tofacitinib 2% ointment, a topical Janus kinase inhibitor, for the treatment of alopecia areata: A pilot study of 10 patients. PMID- 29108909 TI - A novel, noninvasive anesthetic method for neurotoxin injection for palmar hyperhidrosis. PMID- 29108910 TI - Effects of Nrf2 deficiency on arsenic metabolism in mice. AB - Inorganic arsenic (iAs) is a known toxicant and carcinogen. Worldwide arsenic exposure has become a threat to human health. The severity of arsenic toxicity is strongly correlated with the speed of arsenic metabolism (methylation) and clearance. Furthermore, oxidative stress is recognized as a major mechanism for arsenic-induced toxicity. Nuclear factor-E2-related factor 2 (Nrf2), a key regulator in cellular adaptive antioxidant response, is clearly involved in alleviation of arsenic-induced oxidative damage. Multiple studies demonstrate that Nrf2 deficiency mice are more vulnerable to arsenic-induced intoxication. However, what effect Nrf2 deficiency might have on arsenic metabolism in mice is still unknown. In the present study, we measured the key enzymes involved in arsenic metabolism in Nrf2-WT and Nrf2-KO mice. Our results showed that basal transcript levels of glutathione S-transferase omega 2 (Gsto2) were significantly higher and GST mu 1 (Gstm1) lower in Nrf2-KO mice compared to Nrf2-WT control. Arsenic speciation and methylation rate in liver and urine was then studied in mice treated with 5mg/kg sodium arsenite for 12h. Although there were some alterations in arsenic metabolism enzymes between Nrf2-WT and Nrf2-KO mice, the Nrf2 deficiency had no significant effect on arsenic methylation. These results suggest that the Nrf2-KO mice are more sensitive to arsenic than Nrf2-WT mainly because of differences in adaptive antioxidant detoxification capacity rather than arsenic methylation capacity. PMID- 29108911 TI - Prenatal diagnosis of unicystic ameloblastoma. PMID- 29108912 TI - Autophagy activation is required for influenza A virus-induced apoptosis and replication. AB - Autophagy and apoptosis are two major interconnected host cell responses to viral infection, including influenza A virus (IAV). Thus, delineating these events could facilitate the development of better treatment options and provide an effective anti-viral strategy for controlling IAV infection. We used A549 cells and mouse embryonic fibroblasts (MEF) to study the role of virus-induced autophagy and apoptosis, the cross-talk between both pathways, and their relation to IAV infection [ATCC strain A/Puerto Rico/8/34(H1N1) (hereafter; PR8)]. PR8 infected and mock-infected cells were analyzed by immunoblotting, immunofluorescence confocal microscopy, electron microscopy and flow cytometry (FACS). We found that PR8 infection simultaneously induced autophagy and apoptosis in A549 cells. Autophagy was associated with Bax and Bak activation, intrinsic caspase cleavage and subsequent PARP-1 and BID cleavage. Both Bax knockout (KO) and Bax/Bak double knockout MEFs displayed inhibition of virus induced cytopathology and cell death and diminished virus-mediated caspase activation, suggesting that virus-induced apoptosis is Bax/Bak-dependent. Biochemical inhibition of autophagy induction with 3-methyladenine blocked both virus replication and apoptosis pathways. These effects were replicated using autophagy-refractory Atg3 KO and Atg5 KO cells. Taken together, our data indicate that PR8 infection simultaneously induces autophagy and Bax/caspase-dependent apoptosis, with autophagy playing a role to support PR8 replication, in part, by modulating virus-induced apoptosis. PMID- 29108913 TI - Development and content validation of a preliminary core set of patient- and caregiver-relevant outcomes for inclusion in a potential composite endpoint for Dravet Syndrome. AB - BACKGROUND: Dravet Syndrome (DS) is a rare developmental and epileptic encephalopathy characterized by multiple seizures, frequently prolonged and treatment refractory, with significant developmental disabilities and behavioral and psychiatric disorders. Patients with DS require intensive support and supervision from a caregiver, impacting significantly on both patients' and caregivers' lives. This study aimed to identify core concepts to measure the impact on both patients and caregivers in future DS clinical trials. METHODS: Qualitative concept elicitation interviews were conducted with caregivers and healthcare professionals involved in caring for children with DS (aged 2-18years) in France to identify important concepts related to the global impact of DS. Interviews explored a range of concepts, including triggers, symptoms, impacts, and coping strategies, from which a conceptual model was developed. A Delphi consensus panel with eight international clinical experts aimed to identify important and relevant endpoints. RESULTS: Seizure was the most commonly reported symptom with DS further impacting children's cognitive and behavioral functioning. Caregivers identified impact concepts not reported by healthcare professionals. Both groups described additional impacts on wider family members and home modifications. Clinical experts agreed on the inclusion of five patient- and caregiver-relevant concepts for measurement in future DS clinical trials in a composite endpoint. The five concepts for inclusion were; seizures, expressive communication of the child, receptive communication of the child, impact on daily activities, and social functioning of the caregiver. CONCLUSIONS: This study showed the wider potential impact of DS to extend beyond that of seizures, demonstrating that there is a need for additional patient- and caregiver-relevant concepts to be measured in clinical trials to fully identify the value of therapeutic interventions. PMID- 29108914 TI - Detection and analysis of apoptosis- and autophagy-related miRNAs of mouse vascular endothelial cells in chronic intermittent hypoxia model. AB - Endothelial dysfunction is the main pathogenic mechanism of cardiovascular complications induced by obstructive sleep apnea/hyponea syndrome (OSAHS). Chronic intermittent hypoxia (CIH) is the primary factor of OSAHS-associated endothelial dysfunction. The hypoxia inducible factor (HIF) pathway regulates the expression of downstream target genes and mediates cell apoptosis caused by CIH induced endothelial injury. miRNAs play extensive and important negative regulatory roles in this process at the post-transcriptional level. However, the regulatory mechanism of miRNAs in CIH tissue models remains unclear. The present study established a mouse aortic endothelial cell model of CIH in an attempt to screen out specific miRNAs by using miRNA chip analysis. It was found that 14 miRNAs were differentially expressed. Of them, 6 were significantly different and verified by quantitative real-time PCR (Q-PCR), of which four were up-regulated and two were down-regulated markedly. To gain an unbiased global perspective on subsequent regulation by altered miRNAs, we established signaling networks by GO to predict the target genes of the 6 miRNAs. It was found that the 6 identified miRNAs were apoptosis- or autophagy-related target genes. Down-regulation of miR 193 inhibits CIH induced endothelial injury and apoptosis- or autophagy-related protein expression. In conclusion, our results showed that CIH could induce differential expression of miRNAs, and alteration in the miRNA expression pattern was associated with the expression of apoptosis- or autophagy-related genes. PMID- 29108915 TI - Corrigendum to "Neurobiological correlates of impulsivity in healthy adults: Lower prefrontal gray matter volume and spontaneous eye-blink rate but greater resting-state functional connectivity in basal ganglia-thalamo-cortical circuitry" [Neuroimage 157 (2017) 288-296]. PMID- 29108916 TI - An Evidence-Based Protocol for Antibiotic Use Prior to Cystoscopy Decreases Antibiotic Use without Impacting Post-Procedural Symptomatic Urinary Tract Infection Rates. AB - PURPOSE: Symptomatic urinary tract infection is a complication of office based cystourethroscopy. Studies are mixed regarding the efficacy of antibiotic prophylaxis to prevent urinary tract infections. Our aim was to develop and evaluate an evidence-based protocol that reduces unnecessary antibiotic use while avoiding an increase in urinary tract infections. MATERIALS AND METHODS: We created a clinic antibiogram based on all urology office visits performed during a 2-year period. Bacterial resistance rates, institutional risk related data and clinical guidelines were applied to create a protocol for antibiotic administration before cystourethroscopy. We then analyzed 1,245 consecutive patients without a renal transplant who underwent outpatient cystourethroscopy, including 610 after protocol initiation. Urinary tract infection rates and antibiotic use were analyzed for an association with the protocol change using the Fisher exact test. RESULTS: Cultures had an overall 20% rate of resistance to fluoroquinolones, representing 40% of the cultures that grew Escherichia coli. Before the protocol change 602 of 635 patients (94.8%) received a preprocedural antibiotic compared to 426 of 610 (69.9%) after protocol initiation (p <0.01). A total of 19 patients (3.0%) had a symptomatic urinary tract infection prior to the protocol change while 16 (2.6%) had a urinary tract infection after the change (p = 0.69). Regarding resistance, fluoroquinolone resistant organisms grew in the cultures of 12 of 19 patients (63.2%) with a urinary tract infection before the protocol change compared to 5 of 16 (31.3%) with a urinary tract infection after the change. Recent antibiotic administration, hospitalization and chronic catheterization were associated with urinary tract infection in the entire cohort (all p <=0.01). CONCLUSIONS: A local antibiogram with infection related risk data effectively risk stratifies patients before cystourethroscopy, decreasing the use of antibiotics without increasing the rate of symptomatic urinary tract infection. PMID- 29108917 TI - Subcranial and orthognathic surgery for obstructive sleep apnea in achondroplasia. AB - PURPOSE: Obstructive sleep apnea (OSA) is a common problem in patients with achondroplasia. The purpose of this study was to assess changes in airway volumes following various degrees of facial skeletal advancement. METHODS: This was a retrospective evaluation of patients with achondroplasia who underwent facial skeletal advancement for obstructive sleep apnea. Patients were treated with either an isolated Le Fort III distraction (LF3) or Le Fort II distraction with or without subsequent Le Fort I and bilateral sagittal split osteotomies (LF2 +/- LF1/BSSO). Demographic, cephalometric, volumetric, and polysomnographic variables were recorded pre- and postoperatively. RESULTS: Six patients with achondroplasia underwent midface advancement for treatment of OSA (2 LF2 + LF1/BSSO, 2 LF2, 2 LF3). Patients undergoing LF2 + LF1/BSSO had consistent volumetric improvements at the nasopharyngeal and oropharyngeal levels (Delta >= +347% and >=+253%, respectively). Patients undergoing LF2 alone had consistent improvement in the nasopharyngeal airway alone (Delta >= +214%). Patients undergoing LF3 alone had consistent, but less dramatic, changes in nasopharyngeal volume (Delta >= +97.1%). All patients undergoing LF2 distraction (with or without LF1/BSSO) had a >=50% reduction in the apnea-hypopnea index (AHI) postoperatively; there was no improvement in AHI with LF3 alone. CONCLUSION: In patients with achondroplasia associated OSA there are variable improvements in airway volume. This preliminary report suggests that LF2 distraction, with or without subsequent LF1/BSSO, may provide consistent reductions in AHI relative to LF3 distraction. PMID- 29108918 TI - Donor site morbidity of the anterolateral thigh flap. AB - INTRODUCTION: The purpose of this study was to investigate donor site morbidity after reconstruction of defects in the head and neck region with an anterolateral thigh (ALT) flap. METHODS: From 07/2006 to 12/2015 the anterolateral thigh flap was used for reconstruction of large intra- or extraoral defects in 138 patients. The donor sites were available to examine for morbidity in 51 patients (36.7%). All patients completed a standardized questionnaire, received a physical examination, and underwent isokinetic muscle exercises of the lower extremity with a Dynamometer. RESULTS: The average postoperative follow-up was 29 months and showed significant donor site morbidity in the form of sensory disturbance as well as revealing significant differences in extension and flexion between donor and normal thighs in the isokinetic power test. Range of motion at the hip and knee was moderately compromised. CONCLUSION: The results of this study suggest that dissection of the musculocutaneous perforators can compromise the function of vastus lateralis, which is the largest compartment of the quadriceps group. This could also affect the antagonistic muscles such as the semitendinosus, semimembranosus and biceps femoris. Because of its versatility, adequate tissue stock, possibility of simultaneous two-team approach large and long pedicle and minimal donor site morbidity, the ALT flap has become one of the most preferred transplants for soft tissue reconstruction in the head and neck region. Most authors described the donor site morbidity as minimal (Song et al. 1984; Wolff et al., 2006; Xu et al., 1988; Kimata et al., 1997; Kuo et al., 2001; Collins et al., 2012). In summary, the study shows that functional impairment of the donor thigh can occur but does not affect the patients in their daily life. PMID- 29108920 TI - Correlation of lysosome-associated protein transmembrane-4beta gene overexpression with the malignant phenotypes of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies, for which hepatitis B virus (HBV) chronic infection constitutes a major risk factor. The lysosome-associated protein transmembrane-4 beta gene (LAPTM4B) is a recently identified gene that was found to be overexpressed in several types of cancer. However, the role of LAPTM4B in HCC tumorigenesis and progression has not been clearly determined. The present study demonstrated that the mRNA as well as the protein levels of LAPTM4B were significantly upregulated in HCC specimens. Patients with higher levels of LAPTM4B mRNA in their HCC tissues tended to be of a younger age, HBsAg+, with an advanced Barcelona Clinic Liver Cancer stage. Moreover, LAPTM4B mRNA expression was positively associated with serum alpha -fetoprotein levels. We also observed that LAPTM4B was able to promote HCC cell proliferation, migration and invasion in vitro. In conclusion, our results indicated that LAPTM4B plays an important role in the promotion of hepatocarcinogenesis and cancer progression and may serve as a biomarker for the diagnosis and monitoring of HCC. PMID- 29108919 TI - EGFR immunohistochemistry as biomarker for antibody-based therapy of squamous NSCLC - Experience from the first ring trial of the German Quality Assurance Initiative for Pathology (QuIP(r)). AB - BACKGROUND: EGFR and its downstream signaling pathway are important targets for cancer therapy. Recently, the monoclonal anti-EGFR antibody Necitumumab in combination with gemcitabine and cisplatin was approved (EMA/14106/2016) for first-line treatment of squamous non-small cell carcinoma (SqNSCLC). Eligibility was restricted to cases with positive EGFR expression. In this context, a ring trial of the Quality Assurance Initiative for Pathology (QuIP(r)) was launched to prepare the German pathology community for a reliable and reproducible, immunohistochemically based biomarker test. MATERIALS AND METHODS: The trial was set up by a three-step approach. Two lead institutes were nominated to organize the trial process and to select appropriate cancer samples. These were first tested by the H-score (range 0-300) to identify positive and negative cases. Seven additional pathology institutes with experience in EGFR immunohistochemistry each tested the selected panel of identical cases (internal ring trial) to confirm the suitability of samples and scoring criteria. Then the open ring trial for all institutes of pathology in German speaking countries was announced. RESULTS: For the internal trial 8 EGFR-positive and 2 negative lung sqNSCLC samples were selected. A cut-off value of cell membranous staining in>=1% of tumor cells was introduced to define a case as EGFR negative or positive. Two points were attainable per correctly assessed sample leading to a maximum of 20 points,>=18 points were required for a successful participation. All 7 panel institute passed this barrier, 5 with the maximum of 20 points and two with one error (18 points) being related to one case with incorrect interpretation of cytoplasmic versus membranous staining and one case with an H-score of 2 as being considered EGFR positive. A second cut-off value (H-score>=3) was therefore introduced. In the open ring trial, 34 institutions participated of which 28 were successful according to the above criteria. The trial revealed a high reproducibility despite the use of different EGFR antibodies and detection systems. There was no association between technical parameters and trial failure. Again, one participant misinterpreted the subcellular EGFR localization. CONCLUSIONS: The first nationwide ring test for determination of EGFR IHC expression in sqNSCLC could be successfully performed in a very tight time frame. By this, the national pathology community was prepared to incorporate this marker in the panel of predictive cancer tests in a quality assessed manner and to initiate and accompany future studies on EGFR pathway pathology. PMID- 29108921 TI - MicroRNAs expression pattern related to mast cell activation and angiogenesis in paraffin-embedded salivary gland tumors. AB - : The aim of this study was evaluate the expression profile of microRNAs related to mast cells activation and angiogenesis in salivary glands tumors. METHOD: We have analyzed the expression of miR-9, miR-16, miR-17, miR-132, miR-195 and miR 221 by real-time RT-PCR, in 11 adenoid cystic carcinomas, 9 mucoepidermoid carcinomas and 11 pleomorphic adenomas. Immunohistochemical investigation was performed to detect mast cells tryptase and CD-34 for microvessels biomarkers. miR-16, miR-17, miR-132, miR-195 and miR-221 showed a decreased expression, whereas miR-9 showed an increased expression in most cases compared to normal tissues. However, in all tumors studied only miR-9 showed a statistical significant negative correlation with microvessel density (p=0.001). It was observed a higher density of mast cells in mucoepidermoid carcinomas (10.55 cells/mm2) when compared to adenoid cystic carcinomas (6.27 cells/mm2) and between mucoepidermoid carcinomas and pleomorphic adenomas (5.97celulas/mm2). miR 17, miR-132, miR-195 and miR-221 seem to play an important role as tumor suppressor in salivary gland tumors. In addition, the significant correlation between mast cell and microvessel density contributes to the growth and pathogenesis of these tumors and they may become strong therapeutic targets in the future. PMID- 29108922 TI - Use of erlotinib and thalidomide in advanced NSCLC patients with acquired resistance to erlotinib: A pilot study. AB - Evidences suggested that combined blockade of the VEGF and EGFR pathways can improve the treatment efficacy of non-small-cell lung cancer (NSCLC). In our previously clinical practice, we observed that thalidomide, a potent VEGF inhibitor, can significantly decrease the tumor size of one EGFR-TKI resistance patient with lung cancer cachexia. In this pilot study, we tried to assess the efficacy and toxicity of the combination therapy of erlotinib and thalidomide in advanced NSCLC patients with acquired resistance to erlotinib. In all, 52 NSCLC patients with drug resistance to erlotinib were recruited and treated with this combination therapy. After treatment, 4 patients presented with partial remission (PR), 16 with stable disease (SD) and 32 with progressive disease (PD). The objective response rate (ORR) and disease control rate (DCR) was 7.7% and 38.5%, respectively. In this study, we firstly confirmed that thalidomide can reversion of erlotinib-acquired resistance with a 7 weeks median progression-free survival (PFS); besides, this combination therapy shows acceptable drug tolerance; the most common drug related adverse events were astriction, numbness and sleeve-like feeling in the limbs, no thrombosis occurred in any patient. Those evidences indicate that thalidomide may be a useful candidate for reversion of erlotinib acquired resistance. PMID- 29108923 TI - Combined detection of insulin-like growth factor-binding protein 7 promoter methylation improves the diagnostic efficacy of AFP in hepatitis B virus associated hepatocellular carcinoma. AB - This study quantitatively assessed serum insulin-like growth factor-binding protein 7 (IGFBP7) promoter methylation in hepatocellular carcinoma (HCC), and explored its clinical value. A total of 80 patients with hepatitis B virus associated HCC, 35 patients with chronic hepatitis B (CHB), and 20 healthy controls (HC) were enrolled. MethyLight was used to quantitatively assess the methylation levels of serum IGFBP7 promoter. A logistic regression model was established for the combined evaluation of AFP and serum IGFBP7 promoter methylation. The results showed that mean methylation levels of serum IGFBP7 promoter were significantly higher in HCC (5.33%, interquartile range [IQR] 1.14 15.70%) patients than in individuals with CHB (1.54%, IQR 0.64-2.45%; P<0.01) and HC (0.63%, IQR 0.22-0.98%; P<0.01). In HCC subgroups, patients with vascular invasion, tumor size >3cm and advanced tumor node metastasis (TNM) showed higher methylation levels compared with the remaining groups (P<0.05). Compared with AFP alone, combined determination based on logistic regression analysis significantly improved the area under the receiver operating characteristic (ROC) curve (AUC) (0.759 vs 0.623, P<0.05). In addition, the Youden index was increased from 5.71%, 11.25% and 15.18%, when considering AFP alone at cut-off values of 20, 200, and 400ng/ml, respectively, to 45.71% with IGFBP7 promoter methylation taken into consideration (all P<0.05). These results suggested that combined quantitative measurement of serum IGFBP7 promoter methylation could enhance the diagnostic ability of AFP in distinguishing hepatitis B virus-associated HCC from CHB. PMID- 29108924 TI - Visual cortical activity before and after cochlear implantation: A follow up ERP prospective study in deaf children. AB - ERPs were recorded in response to presentation of static colored patterned stimuli in 25 children (19 to 80months of age at cochlear implantation, CI) with very early prelingual profound deafness (PreLD), 21 postlingual profoundly deaf children (PostLD) (34 to 180months of age at CI) and gender- and age-matched control hearing children. Recording sessions were performed before CI, then 6 and 24months after CI. Results showed that prelingual and, at a lesser degree, postlingual auditory deprivation altered cortical visual neural activity associated to colored shapes from both P1 and N1 cortical processing stages. The P1 and N1 amplitude modifications vanished about 24months after CI in both PreLD and PostLD deaf children. In PreLD the visual processing pattern becomes similar to the typical one essentially by an amplitude decrease of P1 on the left hemisphere together with an amplitude increase of the N1 on the right hemisphere. Finally, in PreLD, increased LH advantage over the RH in N1 amplitude on the cerebellar-occipito-parietal region before CI showed a significant inverse relationship with speech perception outcomes 3years after CI. Investigating early visual processing development and its neural substrates in deaf children would help to understand the variability of CI outcome, because their cortical visual organization diverged from the one of typically developing hearing children, and cannot be predicted from what is observed in deaf adults. PMID- 29108925 TI - Determinants of adherence to hypoglycemic agents and medical visits in patients with type 2 diabetes mellitus. AB - AIM: To assess glycemic control in diabetic patients, to measure the impact on such control of adherence to hypoglycemic agents and to medical visits, and to explore factors that allow for predicting adherence. METHODS: Study of historical cohorts of diabetic patients. The proportion of patients who achieved the target HbA1c levels was estimated. Adherence was assessed using the Haynes-Sackett test. Change in HbA1c from the first to the last visit, adherence, and attendance to visits were analyzed according to comorbidities, cardiovascular risk factors, and treatments used. RESULTS: The study simple consisted of 639 patients (mean follow up time, 11.1+/-11.2 months), of whom 66.6% achieved target HbA1c levels. Change in HbA1c from the first to the last visit was explained in 54.2% of patients by baseline HbA1c (P<0.001), in 13% by treatment adherence (P<0.001), and in 9.6% by visit adherence (P<0.001). Non-insulinization (P=0.011) and smoking cessation (P=0.032) predisposed to greater adherence. Insulinization (P=0.019) and lack of diabetes education (P=0.033) predisposed to visit non-compliance. CONCLUSIONS: Improvement in HbA1c is determined by baseline HbA1c, treatment adherence, and attendance to visits. Patients on insulin have poorer adherence and are more likely to miss the appointments, those who stop smoking adhere more to hypoglycemic agents, and those given therapeutic education are more likely to keep the appointments. PMID- 29108926 TI - A thalidomide-hydroxyurea hybrid increases HbF production in sickle cell mice and reduces the release of proinflammatory cytokines in cultured monocytes. AB - Fetal hemoglobin (HbF) induction by hydroxyurea (HU) therapy is associated with decreased morbidity and mortality in sickle cell anemia (SCA) patients, but not all patients respond to or tolerate HU. This provides a rationale for developing novel HbF inducers to treat SCA. Thalidomide analogs have the ability to induce HbF production while inhibiting the release of tumor necrosis factor-alpha. Molecular hybridization of HU and thalidomide was used to synthesize 3- (1,3 dioxoisoindolin-2-yl) benzyl nitrate (compound 4C). In this study, we show that compound 4C increases HbF production in a transgenic SCA mouse model and reduces the production of pro-inflammatory cytokines by SCA mouse monocytes cultured ex vivo. Therefore, compound 4C is a novel drug designed to treat SCA with a unique combination of HbF-inducing and anti-inflammatory properties. PMID- 29108927 TI - Pemetrexed-induced organizing pneumonia in the treatment of lung adenocarcinoma. PMID- 29108928 TI - Transitioning from first- to second-generation biosimilars: An appraisal of regulatory and post-marketing challenges. AB - Second-generation biosimilars (i.e. monoclonal antibodies or proteins generated by fusion of antibody and receptor moieties) differ in several respects as compared to first-generation ones (e.g. epoetins, bone marrow stimulating factors, somatotropins). In this respect, as second-generation biosimilars are endowed with much greater structural and molecular complexity, which might translate into a number of pharmacological and therapeutic issues, they raise new challenges for manufacturers and regulatory authorities as well as new concerns for clinicians. Based on these arguments, the present article was intended to review information on the main differences between first- and second-generation biosimilars for treatment of immune-mediated inflammatory diseases, as well as their impact on immunogenicity, the design of clinical trials and the critical issue of extrapolation of therapeutic indications. The positions taken by relevant medical associations and the crucial role of pharmacovigilance are also reviewed. According to current knowledge, the initial post-marketing clinical experience with second-generation biosimilars is providing encouraging results, though their long-term safety and efficacy as well as the scientific basis underlying the extrapolation of therapeutic indications are still matter of discussion. There is some consensus that marketing applications should rely on studies supporting the clinical use of biosimilars in their different target diseases and patient populations. In parallel, clinical safety must be ensured by a strict control of the manufacturing processes and a solid pharmacovigilance program. It remains then a responsibility of the physician to drive a proper use of second-generation biosimilars into clinical practice, in accordance with guidelines issued by scientific societies. PMID- 29108929 TI - Development of a New ICT-Based Multisensor Blood Pressure Monitoring System for Use in Hemodynamic Biomarker-Initiated Anticipation Medicine for Cardiovascular Disease: The National IMPACT Program Project. AB - We have developed a multisensor home and ambulatory blood pressure (BP) monitoring system for monitoring 24-h central and brachial BP variability concurrent with physical activity (PA), temperature, and atmospheric pressure. The new BP monitoring system utilizes our recently developed biological and environmental signal monitoring Information Communication Technology/Internet of Things system, which can simultaneously monitor the environment (temperature, illumination, etc.) of different rooms in a house (entryway, bedroom, living room, bathing room, and toilet), and a wrist-type high-sensitivity actigraph for identifying the location of patients. By collecting both data on BP and environmental parameters, the system can assess the brachial and central hemodynamic BP reactivity profiles of patients, such as actisensitivity (BP change with PA), thermosensitivity (with temperature), and atmospheric sensitivity (with atmospheric pressure). We used this new system to monitor ambulatory BP variability in outpatients with one or more cardiovascular disease (CVD) risk factors both in summer and winter. Actisensitivity (the slope of the regression line of ambulatory BP against the log-physical activity) was higher in winter than summer. By multi-level analysis using the parameters monitored by this system, we estimated the ambulatory BPs under different conditions. The individual time-series big data collected by this system will contribute to anticipation medicine for CVD. PMID- 29108931 TI - Binding of human plasminogen by the lipoprotein LipL46 of Leptospira interrogans. AB - Leptospirosis is a widespread zoonosis caused by pathogenic Leptospira. Bacteria disseminate via the bloodstream and colonize the renal tubules of reservoir hosts. Leptospiral surface-exposed proteins are important targets, because due to their location they can elicit immune response and mediate adhesion and invasion processes. LipL46 has been previously reported to be located at the leptospiral outer membrane and recognized by antibodies present in serum of infected hamsters. In this study, we have confirmed the cellular location of this protein by immunofluorescence and FACS. We have cloned and expressed the recombinant protein LipL46 in its soluble form. LipL46 was recognized by confirmed leptospirosis human serum, suggesting its expression during infection. Binding screening of LipL46 with extracellular matrix (ECM) and plasma components showed that this protein interacts with plasminogen. The binding is dose-dependent on protein concentration, but saturation was not reached with the range of protein concentration used. Kringle domains of plasminogen and lysine residues of the recombinant protein are involved in the binding because the lysine analog, amino caproic acid (ACA) almost totally inhibited the reaction. The interaction of LipL46 with plasminogen generates plasmin in the presence of plasminogen activator uPA. Because plasmin generated at the leptospiral surface can degrade ECM molecules and decrease opsonophagocytosis, we tentatively infer that Lip46 has a role in helping the invasion process of pathogenic Leptospira. PMID- 29108930 TI - Effects of age on the courtship, copulation, and fecundity of Pardosa pseudoannulata (Araneae: Lycosidae). AB - According to sexual selection theory, age affects the preference of mate choice, and this preference ultimately influences the fecundity of the female. Pardosa pseudoannulata (Araneae: Lycosidae) is a valued predator in many cropping systems. By determining oviposition rate, egg hatching rate, and also the number and carapace width of the 2nd instar spiderlings of the F1 generation, we explored the effects of age on fecundity of the female spider. There were no significant effects of age on courtship duration, sexual cannibalism rate, mating rate, oviposition rate, egg hatching rate, or the number and carapace width of 2nd instar spiderings of P. pseudoannulata. However, age had a significant effect on courtship latency, courtship intensity, and mating duration of the spider. Courtship latency decreased significantly with an increase in the age of the male, and courtship intensity of the low-age male increased with increasing female age. Increasing age of male and female spiders was associated with significantly prolonged mating duration. The results indicated that low-age male spiders were more inclined to mate with high-age females, and age had no significant effect on sexual cannibalism rate or the fecundity of the female. PMID- 29108932 TI - Improving anti-trypanosomal activity of alkamides isolated from Achillea fragrantissima. AB - In previous studies the aerial parts of Achillea fragrantissima were found to have substantial antileishmanial and antitrypanosomal activity. A bioassay-guided fractionation of a dichloromethane extract yielded the isolation of the essential anti-trypanosomal compounds of the plant. Seven sesquiterpene lactones (including Achillolide-A), two flavonoids, chrysosplenol-D and chrysosplenetine, and four alkamides (including pellitorine) were identified. This is the first report for the isolation of the sesquiterpene lactones 3 and 4, chrysosplenetine and the group of alkamides from this plant. Bioevaluation against Trypanosoma brucei brucei TC221 (T.b brucei) using the Alamar-Blue assay revealed the novel alkamide 13 to have an IC50 value of 40.37MUM. A compound library, derived from the alkamide pellitorine (10), was synthesized and bioevaluated in order to find even more active substances. The most active compounds 26 and 27 showed activities in submicromolar concentrations and selectivity indices of 20.1 and 45.6, respectively, towards macrophage cell line J774.1. Toxicity of 26 and 27 was assessed using the greater wax moth Galleria mellonella larvae as an in vivo model. No significant toxicity was observed for the concentration range of 1.25 20mM. PMID- 29108933 TI - Isolation and identification of a tribenzylisoquinoline alkaloid from Nelumbo nucifera Gaertn, a novel potential smooth muscle relaxant. AB - A new skeleton benzylisoquinoline (BI) named neoliensinine (1) was isolated from embryos of lotus seed (Nelumbo nucifera Gaertn.), a traditional Chinese herb. The tribenzylisoquinoline (TBI) structure of 1 was confirmed by interpreting spectroscopic data of UV, IR, MS, 1D and 2D NMR. The stereo-configurations of the new compound, together with two known bisbenzylisoquinolines (BBI), neferine and isoliensinine were established by analyzing 1H NMR and 13C NMR spectra. The relaxation of 1, neferine, isoliensinine and liensinine in isolated mesenteric vascular smooth muscle (VSM) was evaluated. All the four BIs could efficiently inhibit MVSM contraction induced by 124mM KCl, with IC50 values of 2.407MUM (1), 1.169MUM (neferine), 3.504MUM (isoliensinine) and 3.583MUM (liensinine), respectively, suggesting that they were all potential relaxants for abnormal smooth muscle contractions. Interestingly, VSM treated by the three BBIs could re contract when being stimulated by KCl after the drugs were removed, while VSM dealt with the TBI couldn't. It indicated that 1 has much high affinity with the molecular targets on relaxation of VSM contraction, which may relate to the unique skeleton with three BI groups. PMID- 29108934 TI - Cardiovascular control is associated with pair-bond success in male prairie voles. AB - Social support structures reduce mortality and morbidity in humans, but the mechanisms underlying these reductions are not fully understood. The prevailing hypothesis is that social support buffers stress and reduces allostatic load, thereby increasing longevity. However, the possibility that affiliative social interactions confer health benefits independent of stress buffering is understudied. We examined autonomic function in prairie voles - arguably the premier species for modeling human social affiliation - to assess the possibility that the formation of strong social bonds alters autonomic function and contributes to health benefits. We examined cardiovascular measures in male prairie voles before and after two weeks of cohabitation with a female, during a partner preference test, and during social isolation. There were strong correlations between social contact and heart rate (HR) and heart rate variability (HRV), the latter being an index of autonomic nervous system function. Males that successfully pair-bonded with their partners displayed higher HRV prior to pairing than did unsuccessful males, suggesting higher basal parasympathetic tone in the successful males. HRV increased further still when pair-bonded males huddled quietly with their mates during the partner preference test. Non-pair-bonded males not only had lower baseline parasympathetic activity, but showed a further decrease after pairing. HR increased and HRV decreased during social isolation only in pair-bonded males. Since differences in HRV are thought to reflect the relative influences of the parasympathetic and sympathetic nervous systems on cardiac function, these results suggest that autonomic balance may contribute to social bonding and thus to its health benefits. PMID- 29108935 TI - Effect of the Stroop test performed in supine position on the heart rate variability in both genders. AB - The effect of Stroop test (ST)-induced stress on autonomic nervous system activity is often examined via measurement of heart rate variability (HRV). However, HRV may be significantly affected by interfering factors, including vocalization and inappropriate body position. Surprisingly, published studies ignore these issues, so the aim of our study was to test the innovative procedure for correct HRV measurement in individuals exposed to ST. Moreover, we examined possible gender differences in HRV and heart rate (HR) during ST. Healthy participants (21 men, 34 women) were placed in a supine position (no orthostatic activation) and then exposed to a 5 min relaxation period and a 5 min period of computerized ST (no vocalization). We found significant differences in HR and HRV parameters in both genders during ST when compared to relaxation (baseline) values. On the other hand, there were no significant differences in HR and HRV between males and females (except for a higher baseline HR in women). Also, reactivity to ST stress (difference between baseline and ST value) showed no gender differences. In conclusion, when performed in a supine position and without vocalization, the ST induces significant stress-related changes of HR and HRV in both genders, with no gender differences in the magnitude of reaction to ST stress. This experimental procedure can be used for correct examination of mental stress-related changes in the autonomic nervous system, and is particularly useful for examining mixed-gender experimental groups. PMID- 29108936 TI - Phylogenetic relationships of Deprea: New insights into the evolutionary history of physaloid groups. AB - Deprea is the genus with the second highest species richness in tribe Physalideae (Solanaceae) and comprises 50 species that are mainly distributed in the Andes of South America. The taxonomy of Deprea has been unstable after controversial hypotheses about its position and circumscription. Additionally, biogeographical inferences are only based on observations of the restricted area of distribution of some species and no ancestral area estimation have been performed. Here, we present a phylogenetic analysis and an ancestral area reconstruction of Deprea in order to establish its circumscription, resolve its position within Physalideae, and reconstruct its biogeographical history. Phylogenetic analyses were conducted using Maximum Likelihood and Bayesian approaches. Forty-three Deprea species and 26 related taxa were sampled for three DNA markers (psbA-trnH, ITS, and waxy). A Bayesian binary MCMC model was applied in order to infer ancestral areas. Deprea is resolved as a strongly supported monophyletic group according to its current circumscription and is placed within subtribe Withaninae of Physalideae. The phylogenetic relationships enabled us to solve taxonomic problems including the rejection and acceptance of previous synonyms. The most probable ancestral area for Deprea is the Northern Andes of South America and the Amotape-Huancabamba zone. Our phylogeny provides increased resolution and support for the current position and circumscription of Deprea. Better resolution of interspecific relationships was also obtained, although some affinities remain unclear. The phylogenetic and ancestral area reconstructions provide a framework for addressing taxonomic problems and investigating new evolutionary questions. PMID- 29108937 TI - Is subterranean lifestyle reversible? Independent and recent large-scale dispersal into surface waters by two species of the groundwater amphipod genus Niphargus. AB - Groundwater is an extreme environment due to its absence of light, resource scarcity and highly fragmentary nature. Successful groundwater colonizers underwent major evolutionary changes and exhibit eye and pigment loss (troglomorphies). Consequently, their chances of dispersal and survival in the well-connected surface waters are greatly decreased, resulting in significant endemism. The West Palaearctic subterranean amphipod genus Niphargus comprises hundreds of narrowly endemic and troglomorphic species. Nevertheless, a few are known to occur in surface waters, two of which, N. hrabei and N. valachicus, have extremely large ranges that even exceed those of many surface-water amphipods. We tested if this pattern results from a secondary colonization of the relatively well-connected epigean environment, and whether this ecological shift promoted the large-scale dispersal of these species. Results showed that despite their ecological and zoogeographic similarities, N. hrabei and N. valachicus are not closely related and independently colonized surface waters. Their phylogeographic patterns indicate Middle to Late Pleistocene dispersal episodes throughout the Danube lowlands, and relatively modest yet significant genetic differentiation among populations. Clustering based on morphology revealed that the two species are phenotypically closer to each other than they are to most other epigean congeners. We presume that the ecological shift to surface environments was facilitated by their ability to thrive in hypoxic waters where rheophilic competitors from the family Gammaridae cannot survive. In conclusion, our results indicate that adaptation to groundwater is not a one-way evolutionary path and that troglomorphic species can occasionally recolonize and widely disperse in surface waters. PMID- 29108938 TI - Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. AB - BACKGROUND: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms. METHODS: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 MUg, two puffs twice per day, equivalent to 800 MUg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (<=25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (>=40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279. FINDINGS: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0.071, 95% CI 0.002 to 0.139; p=0.044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%]). INTERPRETATION: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease. FUNDING: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA. PMID- 29108939 TI - FeNO and suspected asthma: better to identify responsiveness to treatment than to label with a diagnosis. PMID- 29108940 TI - Cortical layers, rhythms and BOLD signals. AB - This review investigates how laminar fMRI can complement insights into brain function derived from the study of rhythmic neuronal synchronization. Neuronal synchronization in various frequency bands plays an important role in neuronal communication between brain areas, and it does so on the backbone of layer specific interareal anatomical projections. Feedforward projections originate predominantly in supragranular cortical layers and terminate in layer 4, and this pattern is reflected in inter-laminar and interareal directed gamma-band influences. Thus, gamma-band synchronization likely subserves feedforward signaling. By contrast, anatomical feedback projections originate predominantly in infragranular layers and terminate outside layer 4, and this pattern is reflected in inter-laminar and interareal directed alpha- and/or beta-band influences. Thus, alpha-beta band synchronization likely subserves feedback signaling. Furthermore, these rhythms explain part of the BOLD signal, with independent contributions of alpha-beta and gamma. These findings suggest that laminar fMRI can provide us with a potentially useful method to test some of the predictions derived from the study of neuronal synchronization. We review central findings regarding the role of layer-specific neuronal synchronization for brain function, and regarding the link between neuronal synchronization and the BOLD signal. We discuss the role that laminar fMRI could play by comparing it to invasive and non-invasive electrophysiological recordings. Compared to direct electrophysiological recordings, this method provides a metric of neuronal activity that is slow and indirect, but that is uniquely non-invasive and layer specific with potentially whole brain coverage. PMID- 29108941 TI - Both hyper- and hypo-activation to cognitive challenge are associated with increased beta-amyloid deposition in healthy aging: A nonlinear effect. AB - Beta-amyloid (Abeta) positive individuals hyper-activate brain regions compared to those not at-risk; however, hyperactivation is then thought to diminish as Alzheimer's disease symptomatology begins, evidencing eventual hypoactivation. It remains unclear when in the disease staging this transition occurs. We hypothesized that differential levels of amyloid burden would be associated with both increased and decreased activation (i.e., a quadratic trajectory) in cognitively-normal adults. Participants (N = 62; aged 51-94) underwent an fMRI spatial distance-judgment task and Amyvid-PET scanning. Voxelwise regression modeled age, linear-Abeta, and quadratic-Abeta as predictors of BOLD activation to difficult spatial distance-judgments. A significant quadratic-Abeta effect on BOLD response explained differential activation in bilateral angular/temporal and medial prefrontal cortices, such that individuals with slightly elevated Abeta burden exhibited hyperactivation whereas even higher Abeta burden was then associated with hypoactivation. Importantly, in high-Abeta individuals, Abeta load moderated the effect of BOLD activation on behavioral task performance, where in lower-elevation, greater deactivation was associated with better accuracy, but in higher-elevation, greater deactivation was associated with poorer accuracy during the task. This study reveals a dose-response, quadratic relationship between increasing Abeta burden and alterations in BOLD activation to cognitive challenge in cognitively-normal individuals that suggests 1) the shift from hyper-to hypo-activation may begin early in disease staging, 2) depends, in part, on degree of Abeta burden, and 3) tracks cognitive performance. PMID- 29108942 TI - How landmark suitability shapes recognition memory signals for objects in the medial temporal lobes. AB - A role of perirhinal cortex (PrC) in recognition memory for objects has been well established. Contributions of parahippocampal cortex (PhC) to this function, while documented, remain less well understood. Here, we used fMRI to examine whether the organization of item-based recognition memory signals across these two structures is shaped by object category, independent of any difference in representing episodic context. Guided by research suggesting that PhC plays a critical role in processing landmarks, we focused on three categories of objects that differ from each other in their landmark suitability as confirmed with behavioral ratings (buildings > trees > aircraft). Participants made item-based recognition-memory decisions for novel and previously studied objects from these categories, which were matched in accuracy. Multi-voxel pattern classification revealed category-specific item-recognition memory signals along the long axis of PrC and PhC, with no sharp functional boundaries between these structures. Memory signals for buildings were observed in the mid to posterior extent of PhC, signals for trees in anterior to posterior segments of PhC, and signals for aircraft in mid to posterior aspects of PrC and the anterior extent of PhC. Notably, item-based memory signals for the category with highest landmark suitability ratings were observed only in those posterior segments of PhC that also allowed for classification of landmark suitability of objects when memory status was held constant. These findings provide new evidence in support of the notion that item-based memory signals for objects are not limited to PrC, and that the organization of these signals along the longitudinal axis that crosses PrC and PhC can be captured with reference to landmark suitability. PMID- 29108943 TI - Therapeutic HPV vaccines. AB - High-risk human papillomavirus (HPV) infection is known to be a necessary factor for cervical and anogenital malignancies. Cervical cancers account for over a quarter of a million deaths annually. Despite the availability of prophylactic vaccines, HPV infections remain extremely common worldwide. Furthermore, these vaccines are ineffective at clearing pre-existing infections and associated preinvasive lesions. As cervical dysplasia can regress spontaneously, a therapeutic HPV vaccine that boosts host immunity could have a significant impact on the morbidity and mortality associated with HPV. Therapeutic vaccines differ from prophylactic vaccines in that they are aimed at generating cell-mediated immunity rather than neutralising antibodies. This review will cover various therapeutic vaccine strategies in development for the treatment of HPV-associated lesions and cancers. PMID- 29108944 TI - Optimized expression of the Starmerella bombicola lactone esterase in Pichia pastoris through temperature adaptation, codon-optimization and co-expression with HAC1. AB - The Starmerella bombicola lactone esterase (SBLE) is a novel enzyme that, in vivo, catalyzes the intramolecular esterification (lactonization) of acidic sophorolipids in an aqueous environment. In fact, this is an unusual reaction given the unfavorable conditions for dehydration. This characteristic strongly contributes to the potential of SBLE to become a 'green' tool in industrial applications. Indeed, lactonization occurs normally in organic solvents, an application for which microbial lipases are increasingly used as biocatalysts. Previously, we described the production of recombinant SBLE (rSBLE) in Pichia pastoris (syn. Komagataella phaffii). However, expression was not optimal to delve deeper into the enzyme's potential for industrial application. In the current study, we explored codon-optimization of the SBLE gene and we optimized the rSBLE expression protocol. Temperature reduction had the biggest impact followed by codon-optimization and co-expression of the HAC1 transcription factor. Combining these approaches, we achieved a 32-fold improvement of the yield during rSBLE production (from 0.75 mg/l to 24 mg/L culture) accompanied with a strong reduction of contaminants after affinity purification. PMID- 29108945 TI - Assessing the Ayurvedic prescribing trends on the basis of WHO drug use indicators. AB - BACKGROUND: Ayurvedic prescriptions are often challenged for their rationality. Excessive use of proprietary medicines, rasa preparations, and samshodhana without any justification and deliverable benefits outweighing the other forms of safer, cheaper and less time consuming therapies is putting the Ayurvedic prescribing trends into question. In Ayurvedic practice, prescriptions are often individualized with substantial variability between the choices of drugs. Although being welcomed as an advanced approach of prescription writing by making it tailor made, this method also allows for lapses to creep in thus making it necessary to check common trends of prescribing in Ayurveda and to see whether it raises any caution. OBJECTIVES: The objective of this study was to create a check for common trends of prescribing in Ayurveda and to see if such checks raise any caution. MATERIALS AND METHODS: Present study utilizes the WHO drug use indicators as a preliminary tool for analyzing Ayurvedic prescriptions. RESULTS: It was found that with a small modification, this tool can help immensely in screening of Ayurvedic prescriptions. CONCLUSION: Based on the results obtained through this study, it can be concluded that the WHO drug use indicators, with a small modification, can help in identifying the prescribing trends in Ayurveda and can also help in suggesting remedial measures in case certain anomalies are found. PMID- 29108946 TI - Nuclear ribosomal DNA - ITS region based molecular marker to distinguish the medicinal plant Gmelina arborea Roxb. Ex Sm. from its substitutes and adulterants. AB - Roots of Gmelina arborea (Gambhari) is a medicinally important raw drug traded in India. However, Gmelinaasiatica and Mallotus nudiflorus are also found in the raw drug markets as Gambhari. The current study aims to identify molecular markers based on the nuclear ribosomal DNA - ITS1 region to distinguish the authentic species from substitute/adulterants. The nuclear ribosomal internal transcribed spacer 1 (ITS1) was amplified to identify species-specific markers using universal primers. Based on the sequence of the ITS region, specific primers were designed for G. arborea, G. asiatica and M. nudiflorus which efficiently amplified 142 bp, 93 bp and 150 bp of the ITS1 region of the respective species. The notable feature of this molecular method is that it is technically accurate, practically convenient and suitable for analyzing large numbers of samples. This study demonstrates that the ITS1 region can be used for reliable authentication of medicinal plants and detection of adulterants and substitutes of Gambhari. PMID- 29108947 TI - Antibiotic strategies and clinical outcomes in critically ill patients with pneumonia caused by carbapenem-resistant Acinetobacter baumannii. AB - OBJECTIVES: This study aimed to investigate antibiotic prescribing patterns and effectiveness of different anti-carbapenem-resistant Acinetobacter baumannii (CRAB) strategies for CRAB pneumonia. METHODS: We conducted a multicentre, retrospective study in three hospitals. During 2010-2015, adult ICU patients with CRAB pneumonia treated with at least one antimicrobial agent covering the CRAB isolate in vitro for more than 2 days were included. We used multivariate logistic regression to analyse the associations of anti-CRAB strategies with ICU mortality and other clinical outcomes. RESULTS: Among 238 patients with CRAB pneumonia, tigecycline monotherapy (84, 35.3%) was the most common antibiotic strategy, followed by tigecycline with colistin (43, 18.1%), colistin monotherapy (34, 14.3%), colistin combination without tigecycline (33, 13.9%), tigecycline combination without colistin (32, 13.4%), and sulbactam-based therapy without tigecycline and colistin (12, 5.0%). In multivariate analysis, tigecycline-based therapy was associated with higher ICU mortality than non-tigecycline therapy (adjusted OR 2.30, 95% CI 1.19-4.46). There was no difference between colistin based therapy and non-colistin therapy. Compared with tigecycline monotherapy, colistin monotherapy was associated with lower ICU mortality (aOR 0.30, 95% CI 0.10-0.88). Treatment failure analyses showed similar trends. Tigecycline-based therapy was associated with higher treatment failure rate than non-tigecycline therapy (aOR 2.51, 95% CI 1.39-4.54), whereas colistin-based therapy was associated with lower treatment failure rate than non-colistin-based therapy (aOR 0.48, 95% CI 0.27-0.86). CONCLUSIONS: Tigecycline was commonly prescribed for CRAB pneumonia. However, tigecycline-based therapy was associated with higher ICU mortality and treatment failure. Our study suggests that colistin monotherapy may be a better antibiotic strategy for CRAB pneumonia. PMID- 29108948 TI - Nutrition and infection. PMID- 29108949 TI - World Health Organization "SAVE LIVES: Clean Your Hands" global campaign. PMID- 29108950 TI - Amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis by bacterial and viral aetiology. AB - OBJECTIVE: We aimed to assess the effects of amoxicillin treatment in adult patients presenting to primary care with a lower respiratory tract infection (LRTI) who were infected with a potential bacterial, viral, or mixed bacterial/viral infection. METHODS: This multicentre randomized controlled trial focused on adults with LRTI not suspected for pneumonia. Patients were randomized to receive either antibiotic (amoxicillin 1 g) or placebo three times daily for 7 consecutive days using computer-generated random numbers (follow-up 28 days). In this secondary analysis of the trial, symptom duration (primary outcome), symptom severity (scored 0-6), and illness deterioration (reconsultation with new or worsening symptoms, or hospital admission) were analysed in pre-specified subgroups using regression models. Subgroups of interest were patients with a (strictly) bacterial, (strictly) viral, or combined infection, and patients with elevated values of procalcitonin, C-reactive protein, or blood urea nitrogen. RESULTS: 2058 patients (amoxicillin n = 1036; placebo n = 1022) were randomized. Treatment did not affect symptom duration (n = 1793). Patients from whom a bacterial pathogen only was isolated (n = 207) benefited from amoxicillin in that symptom severity (n = 804) was reduced by 0.26 points (95% CI -0.48 to -0.03). The odds of illness deterioration (n = 2024) was 0.24 (95% CI 0.11 to 0.53) times lower from treatment with amoxicillin when both a bacterial and a viral pathogen were isolated (combined infection; n = 198). CONCLUSIONS: Amoxicillin may reduce the risk of illness deterioration in patients with a combined bacterial and viral infection. We found no clinically meaningful benefit from amoxicillin treatment in other subgroups. PMID- 29108951 TI - Automated time-lapse microscopy a novel method for screening of antibiotic combination effects against multidrug-resistant Gram-negative bacteria. AB - OBJECTIVES: Antibiotic combinations are often used for carbapenemase-producing Enterobacteriaceae (CPE) but more data are needed on the optimal selection of drugs. This study aimed to evaluate the feasibility of a novel automated method based on time-lapse microscopy (the oCelloScope, Philips BioCell A/S, Allerod, Denmark) to determine in vitro combination effects against CPE and to discuss advantages and limitations of the oCelloScope in relation to standard methods. METHODS: Four Klebsiella pneumoniae and two Escherichia coli were exposed to colistin, meropenem, rifampin and tigecycline, alone and in combination. In the oCelloScope experiments, a background corrected absorption (BCA) value of <=8 at 24 h was used as a primary cut-off indicating inhibition of bacterial growth. A new approach was used to determine synergy, indifference and antagonism based on the number of objects (bacteria) in the images. Static time-kill experiments were performed for comparison. RESULTS: The time-kill experiments showed synergy with 12 of 36 regimens, most frequently with colistin plus rifampin. BCA values <=8 consistently correlated with 24-h bacterial concentrations <=6 log10 CFU/mL. The classification of combination effects agreed with the time-kill results for 33 of 36 regimens. In three cases, the interactions could not be classified with the microscopy method because of low object counts. CONCLUSIONS: Automated time-lapse microscopy can accurately determine the effects of antibiotic combinations. The novel method is highly efficient compared with time-kill experiments, more informative than checkerboards and can be useful to accelerate the screening for combinations active against multidrug-resistant Gram-negative bacteria. PMID- 29108952 TI - Mycobacterium tuberculosis and whole-genome sequencing: how close are we to unleashing its full potential? AB - BACKGROUND: Nearly two decades after completion of the genome sequence of Mycobacterium tuberculosis (MTB), and with the advent of next generation sequencing technologies (NGS), whole-genome sequencing (WGS) has been applied to a wide range of clinical scenarios. Starting in 2017, England is the first country in the world to pioneer its use on a national scale for the diagnosis of tuberculosis, detection of drug resistance, and typing of MTB. AIMS: This narrative review critically analyses the current applications of WGS for MTB and explains how close we are to realizing its full potential as a diagnostic, epidemiologic, and research tool. SOURCES: We searched for reports (both original articles and reviews) published in English up to 31 May 2017, with combinations of the following keywords: whole-genome sequencing, Mycobacterium, and tuberculosis. MEDLINE, Embase, and Scopus were used as search engines. We included articles that covered different aspects of whole-genome sequencing in relation to MTB. CONTENT: This review focuses on three main themes: the role of WGS for the prediction of drug susceptibility, MTB outbreak investigation and genetic diversity, and research applications of NGS. IMPLICATIONS: Many of the original expectations have been accomplished, and we believe that with its unprecedented sensitivity and power, WGS has the potential to address many unanswered questions in the near future. However, caution is still needed when interpreting WGS data as there are some important limitations to be aware of, from correct interpretation of drug susceptibilities to the bioinformatic support needed. PMID- 29108953 TI - Investigating the function of Gdt1p in yeast Golgi glycosylation. AB - The Golgi ion homeostasis is tightly regulated to ensure essential cellular processes such as glycosylation, yet our understanding of this regulation remains incomplete. Gdt1p is a member of the conserved Uncharacterized Protein Family (UPF0016). Our previous work suggested that Gdt1p may function in the Golgi by regulating Golgi Ca2+/Mn2+ homeostasis. NMR structural analysis of the polymannan chains isolated from yeasts showed that the gdt1Delta mutant cultured in presence of high Ca2+ concentration, as well as the pmr1Delta and gdt1Delta/pmr1Delta strains presented strong late Golgi glycosylation defects with a lack of alpha 1,2 mannoses substitution and alpha-1,3 mannoses termination. The addition of Mn2+ confirmed the rescue of these defects. Interestingly, our structural data confirmed that the glycosylation defect in pmr1Delta could also completely be suppressed by the addition of Ca2+. The use of Pmr1p mutants either defective for Ca2+ or Mn2+ transport or both revealed that the suppression of the observed glycosylation defect in pmr1Delta strains by the intraluminal Golgi Ca2+ requires the activity of Gdt1p. These data support the hypothesis that Gdt1p, in order to sustain the Golgi glycosylation process, imports Mn2+ inside the Golgi lumen when Pmr1p exclusively transports Ca2+. Our results also reinforce the functional link between Gdt1p and Pmr1p as we highlighted that Gdt1p was a Mn2+ sensitive protein whose abundance was directly dependent on the nature of the ion transported by Pmr1p. Finally, this study demonstrated that the aspartic residues of the two conserved motifs E-x-G-D-[KR], likely constituting the cation binding sites of Gdt1p, play a crucial role in Golgi glycosylation and hence in Mn2+/Ca2+transport. PMID- 29108954 TI - A flexible loop for mannan recognition and activity enhancement in a bifunctional glycoside hydrolase family 5. AB - BACKGROUND: An array of glycoside hydrolases with multiple substrate specificities are required to digest plant cell wall polysaccharides. Cel5E from Clostridium thermocellum and Cel5A from Thermotoga maritima are two glycoside hydrolase family 5 (GH5) enzymes with high sequence and structural similarity, but notably possess different substrate specificities; the former is a bifunctional cellulase/xylanase and the latter is a cellulase/mannanase. A specific loop in TmCel5A, Tmloop, is one of the most structurally divergent regions compared to CtCel5E and interacts with substrates, suggesting the importance for mannan recognition. METHOD: A Tmloop inserted CtCel5E and its related mutants were produced to investigate the role of Tmloop in catalysis. Crystal structure of CtCel5E-TmloopF267A followed by site-direct mutagenesis reveals the mechanism. RtCelB, a homolog with Tmloop was identified to have mannanase activity. RESULT: Tmloop incorporation enables CtCel5E to gain mannanase activity. Tyr270, His277, and Trp282 in the Tmloop are indispensable for CtCel5E-Tmloop catalysis, and weakening hydrophobic environment near the Tmloop enhances enzyme kcat. Using our newly identified loop motif to search for structurally conserved homologs in other subfamilies of GH5, we identified RtCelB. This homolog, originally annotated as a cellulase also possesses mannanase and xylanase activities. CONCLUSION: Our studies show that Tmloop enhances GH5 enzyme promiscuity and plays a role in catalysis. GENERAL SIGNIFICANCE: The study identified a loop of GH5 for mannan recognition and catalysis. Weakening the hydrophobic environment near the loop can also enhance the enzyme catalytic rate. Our findings provide a new insight on mannan recognition and activity enhancement of GH5. PMID- 29108955 TI - Reduced state transition barrier of CDK6 from open to closed state induced by Thr177 phosphorylation and its implication in binding modes of inhibitors. AB - BACKGROUND: CDK6 is considered as a highly validated anticancer drug target due to its essential role in regulating cell cycle progression at G1 restriction point. Activation of CDK6 requires the phosphorylation of Thr177 on A-loop, but the structural insights of the activation mechanism remain unclear. METHODS: Herein, all-atoms molecular dynamics (MD) simulations were used to study the effects of Thr177 phosphorylation on the dynamic structure of CDK6-Vcyclin complex. RESULTS: MD results indicated that the free energy barrier of the transition from open to closed state decreased ~47.2% after Thr177 phosphorylation. Key steps along the state transition process were obtained from a cluster analysis. Binding preference of ten different inhibitors to open or closed state were also investigated through molecular docking along with MD simulations methods. CONCLUSIONS: Our results indicated that Thr177 phosphorylation increased the flexibility around the ATP-binding pocket. The transition of the ATP-binding pocket between open and closed states should be considered for understanding the binding of CDK6 inhibitors. GENERAL SIGNIFICANCE: This work could deepen the understanding of CDKs activation mechanism, and provide useful information for the discovery of new CDKs inhibitors with high affinity and specificity. PMID- 29108956 TI - The mouse Gm853 gene encodes a novel enzyme: Leucine decarboxylase. AB - Ornithine decarboxylase (ODC) is a key enzyme in the biosynthesis of polyamines. ODC-antizyme inhibitors (AZINs) are homologous proteins of ODC, devoid of enzymatic activity but acting as regulators of polyamine levels. The last paralogue gene recently incorporated into the ODC/AZINs family is the murine Gm853, which is located in the same chromosome as AZIN2, and whose biochemical function is still unknown. By means of transfection assays of HEK293T cells with a plasmid containing the coding region of Gm853, we show here that unlike ODC, GM853 was a stable protein that was not able to decarboxylate l-ornithine or l lysine and that did not act as an antizyme inhibitor. However, GM853 showed leucine decarboxylase activity, an enzymatic activity never described in animal cells, and by acting on l-leucine (Km=7.03*10-3M) it produced isopentylamine, an aliphatic monoamine with unknown function. The other physiological branched-chain amino acids, l-valine and l-isoleucine were poor substrates of the enzyme. Gm853 expression was mainly detected in the kidney, and as Odc, it was stimulated by testosterone. The conservation of Gm853 orthologues in different mammalian species, including primates, underlines the possible biological significance of this new enzyme. In this study, we describe for the first time a mammalian enzyme with leucine decarboxylase activity, therefore proposing that the gene Gm853 and its protein product should be named as leucine decarboxylase (Ldc, LDC). PMID- 29108959 TI - Visual and Automated Computer Analysis Differ Substantially in Detection of Acidic Reflux in Multichannel Intraluminal Impedance-pH Monitoring. PMID- 29108958 TI - Novel physical chemistry approaches in biophysical researches with advanced application of lasers: Detection and manipulation. AB - Novel methodologies utilizing pulsed or intense CW irradiation obtained from lasers have a major impact on biological sciences. In this article, recent development in biophysical researches fully utilizing the laser irradiation is described for three topics, time-resolved fluorescence spectroscopy, time resolved thermodynamics, and manipulation of the biological assemblies by intense laser irradiation. First, experimental techniques for time-resolved fluorescence spectroscopy are concisely explained in Section 2. As an example of the recent application of time-resolved fluorescence spectroscopy to biological systems, evaluation of the viscosity of lipid bilayer membranes is described. The results of the spectroscopic experiments strongly suggest the presence of heterogeneous membrane structure with two different viscosity values in liposomes formed by a single phospholipid. Section 3 covers the time-resolved thermodynamics. Thermodynamical properties are important to characterize biomolecules. However, measurement of these quantities for short-lived intermediate species has been impossible by traditional thermodynamical techniques. Recently, development of a spectroscopic method based on the transient grating method enables us to measure these quantities and also to elucidate reaction kinetics which cannot be detected by other spectroscopic methods. The principle of the measurements and applications to some protein reactions are reviewed. Manipulation and fabrication of supramolecues, amino acids, proteins, and living cells by intense laser irradiation are described in Section 4. Unconventional assembly, crystallization and growth, amyloid fibril formation, and living cell manipulation are achieved by CW laser trapping and femtosecond laser-induced cavitation bubbling. Their spatio-temporal controllability is opening a new avenue in the relevant molecular and bioscience research fields. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato. PMID- 29108960 TI - Perioperative morbidity, bowel function and oncologic outcome after radical cystectomy and ileal orthotopic neobladder reconstruction: Studer-pouch versus I pouch. AB - OBJECTIVE: To investigate whether the length of ileum used for ileal orthotopic neobladder (ONB) reconstruction (60 cm vs. 40 cm) after radical cystectomy (RC) for bladder cancer (BC) impacts on bowel function, postoperative complications or survival outcome. MATERIAL AND METHODS: In this retrospective study, we included 56 patients who received an ONB (Studer (S)-Pouch: 23 patients; I-Pouch: 33 patients) after RC for BC between 2003 and 2011. Preoperative comorbidities were assessed by the Charlson Comorbidity Index (CCI) and surgical complications as graded by the Clavien-Dindo classification. Changes of perioperative bowel habits were retrospectively evaluated by the validated Gastrointestinal Quality of Life Index (GIQLI). Kaplan-Meier analyses calculated survival outcomes between both ONB types. RESULTS: Preoperative CCI was comparable between S- and I-pouch patients. No significant differences were observed for 30-day major- (p = 0.33) and minor (p = 0.96) complication rates between both neobladder types. S-Pouch patients reported higher preoperative stool frequencies (S-pouch: mean 2.7; I pouch: mean 3.4; p = 0.049) and tended to suffer from urgency (S: mean 2.9; I: mean 3.4; p = 0.059). No significant differences in postoperative bowel disorders were found between both neobladder types (S-Pouch: 15.9, IQR; I-Pouch: 16.6 IQR; p = 0.84). Furthermore, we observed no overall-, cancer specific- or recurrence free survival advantage for either of both ONB variants (p = 0.81; 0.65 and 0.78), respectively. CONCLUSION: Comorbidities, perioperative complication rates and bowel habits were similar between both ONB substitutes and did not influence survival outcomes. These stratified data suggest that the length of ileum used for ONB reconstruction (60- vs. 40 cm) does not impact per se on postoperative bowel function. PMID- 29108957 TI - Matrix vesicles from chondrocytes and osteoblasts: Their biogenesis, properties, functions and biomimetic models. AB - BACKGROUND: Matrix vesicles (MVs) are released from hypertrophic chondrocytes and from mature osteoblasts, the cells responsible for endochondral and membranous ossification. Under pathological conditions, they can also be released from cells of non-skeletal tissues such as vascular smooth muscle cells. MVs are extracellular vesicles of approximately 100-300nm diameter harboring the biochemical machinery needed to induce mineralization. SCOPE OF THE REVIEW: The review comprehensively delineates our current knowledge of MV biology and highlights open questions aiming to stimulate further research. The review is constructed as a series of questions addressing issues of MVs ranging from their biogenesis and functions, to biomimetic models. It critically evaluates experimental data including their isolation and characterization methods, like lipidomics, proteomics, transmission electron microscopy, atomic force microscopy and proteoliposome models mimicking MVs. MAJOR CONCLUSIONS: MVs have a relatively well-defined function as initiators of mineralization. They bind to collagen and their composition reflects the composition of lipid rafts. We call attention to the as yet unclear mechanisms leading to the biogenesis of MVs, and how minerals form and when they are formed. We discuss the prospects of employing upcoming experimental models to deepen our understanding of MV-mediated mineralization and mineralization disorders such as the use of reconstituted lipid vesicles, proteoliposomes and, native sample preparations and high-resolution technologies. GENERAL SIGNIFICANCE: MVs have been extensively investigated owing to their roles in skeletal and ectopic mineralization. MVs serve as a model system for lipid raft structures, and for the mechanisms of genesis and release of extracellular vesicles. PMID- 29108962 TI - No detriment in taste response or expression in offspring of mice fed representative levels of sucrose or non-caloric sucralose while pregnant. AB - Recent studies in mice indicate that consumption of acesulfame K (a high intensity sweetener) while pregnant, can lead to deficits in taste or enhanced sweet consumption in the offspring, leading to concerns the same may be common in human populations. However, this work employed a relatively unpopular sweetener, fed in quantities amounting to over 20* the FDA's Acceptable Daily Intake (ADI). The aims of this study were to test the effects of sucralose, the USA's most popular high intensity sweetener, along with sucrose, on the taste system of the offspring of mice supplemented at a level commensurate with ADIs while pregnant. The hypothesis was that feeding a dam intensely sweet solutions would produce offspring with enhanced response to sweet taste, when compared to offspring of dams given only water. Females were mated following a 4-week period in which one group was given a measured ration of sucrose or sucralose in addition to chow and water, with the control group given chow and water only. Sucrose and sucralose solutions were removed two weeks after parturition to prevent direct consumption by the offspring. The offspring at 8weeks of age for both the sucrose and sucralose supplementation showed no change in their taste response to sucrose or sucralose. No effect of maternal sweet supplementation was detected at the taste bud level, with fungiform taste bud density and taste bud gene expression remaining unchanged. Overall, this study suggests that sucrose and sucralose consumption at human-relevant levels during pregnancy and lactation do not produce any long-term changes to the offspring's peripheral taste system. PMID- 29108963 TI - Influences of social reward experience on behavioral responses to drugs of abuse: Review of shared and divergent neural plasticity mechanisms for sexual reward and drugs of abuse. AB - Different factors influence the development of drug addiction in humans, including social reward experiences. In animals, experience with social rewards, such as sexual behavior, pair bonding, social and environmental enrichment, can be protective. However, loss or lack of social rewards can lead to a vulnerability to drug-seeking behavior. The effects of social reward experience on drug-seeking behavior are associated with changes in the neural pathways that control drug-related behavior. This review will provide an introduction and overview of the mesolimbic pathway and the influence of social reward experience on drug-seeking behavior in rodents. Moreover, the research from our laboratory on effects of sexual experience and loss of sex reward on psychostimulant and opiate reward will be reviewed. Finally, we will review current knowledge of the neural mechanisms that underlie these interactions. Investigations of the neural underpinnings by which social and drug rewards interact contribute to improved understanding of the neural basis of vulnerability for drug addiction and reward related behaviors in general. PMID- 29108964 TI - Familial early-onset deep venous thrombosis associated with a novel HRG mutation. AB - Deep venous thrombosis (DVT) remains a serious clinical problem that affects millions of people worldwide. Some DVT cases are caused by inherited thrombophilia derived from genetic aberrations and several disease-causing genes have been identified so far. Among them, HRG is an uncommon one with limited related reports. Here, we reported on a family with early-onset DVT where acquired risky conditions were excluded. Whole exome sequencing revealed a novel heterozygous single base pair substitution in exon 2 of HRG gene resulting in a conserved residue replacement of the protein (c. C271T, p. P73S). Sanger sequencing confirmed the co-segregation of the mutation and plasma quantification determined circulating protein deficiency. The mutation might therefore impair hemostatic balance by causing reduced circulating HRG level. Our study broadens the mutation spectrum of the HRG gene and underscores the importance of its function in regulating coagulation pathway. PMID- 29108961 TI - Rare ovarian tumours: Epidemiology, treatment challenges in and outside a network setting. AB - PURPOSE OF THE REVIEW: More than 50% of all gynaecological cancers can be classified as rare tumours (defined as an annual incidence of <6 per 100,000) and such tumours represent an important challenge for clinicians. RECENT FINDINGS: Rare cancers account for more than one fifth of all new cancer diagnoses, more than any of the single common cancers alone. Reviewing the RARECAREnet database, some of the tumours occur infrequently, whilst others because of their natural history have a high prevalence, and therefore appear to be more common, although their incidence is also rare. Harmonization of medical practice, guidelines and novel trials are needed to identify rare tumours and facilitate the development of new treatments. Ovarian tumours are the focus of this review, but we comment on other rare gynaecological tumours, as the diagnosis and treatment challenges faced are similar. FUTURE: This requires European collaboration, international partnerships, harmonization of treatment and collaboration to overcome the regulatory barriers to conduct international trials. Whilst randomized trials can be done in many tumour types, there are some for which conducting even single arm studies may be challenging. For these tumours alternative study designs, robust collection of data through national registries and audits could lead to improvements in the treatment of rare tumours. In addition, concentring the care of patients with rare tumours into a limited number of centres will help to build expertise, facilitate trials and improve outcomes. PMID- 29108966 TI - Dual Task of Fine Motor Skill and Problem Solving in Individuals With Multiple Sclerosis: A Pilot Study. AB - OBJECTIVES: To (1) examine and compare dual-task performance in patients with multiple sclerosis (MS) and healthy controls (HCs) using mathematical problem solving questions that included an everyday competence component while performing an upper extremity fine motor task; and (2) examine whether difficulties in dual task performance are associated with problems in performing an everyday internet task. DESIGN: Pilot study, mixed-design with both a within and between subjects' factor. SETTING: A nonprofit rehabilitation research institution and the community. PARTICIPANTS: Participants (N=38) included persons with MS (n=19) and HCs (n=19) who were recruited from a nonprofit rehabilitation research institution and from the community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participant were presented with 2 testing conditions: (1) solving mathematical everyday problems or placing bolts into divots (single-task condition); and (2) solving problems while putting bolts into divots (dual-task condition). Additionally, participants were required to perform a test of everyday internet competence. RESULTS: As expected, dual-task performance was significantly worse than either of the single-task tasks (ie, number of bolts into divots or correct answers, and time to answer the questions). Cognitive but not motor dual-task cost was associated with worse performance in activities of everyday internet tasks. CONCLUSIONS: Cognitive dual-task cost is significantly associated with worse performance of everyday technology. This was not observed in the motor dual-task cost. The implications of dual-task costs on everyday activity are discussed. PMID- 29108965 TI - IL-1/inhibitory kappaB kinase epsilon-induced glycolysis augment epithelial effector function and promote allergic airways disease. AB - BACKGROUND: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. OBJECTIVES: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. METHODS: We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis. RESULTS: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1beta into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1beta or IL 1alpha resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL 1beta- or IL-1alpha-mediated proinflammatory responses and the stimulatory effects of IL-1beta on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of kappaB kinase epsilon was downstream of HDM or IL-1beta and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1beta levels, and lactate content correlated negatively with lung function. CONCLUSIONS: Collectively, these findings demonstrate that IL-1beta/inhibitory kappaB kinase epsilon signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease. PMID- 29108967 TI - Effect of Rehabilitation Intensity on Mortality Risk After Stroke. AB - OBJECTIVE: To determine the relation between rehabilitation intensity and poststroke mortality. DESIGN: Retrospective cohort study. SETTING: Nationwide claims data. PARTICIPANTS: From Taiwan's National Health Insurance claims databases, patients (N=6737; mean age, 66.9y; 40.3% women) hospitalized between 2001 and 2013 for a first-ever stroke who had mild to moderate stroke and survived the first 90 days of stroke were enrolled. INTERVENTIONS: The intensity of rehabilitation therapy within 90 days after stroke was categorized into low, medium, or high based on the tertile distribution of the number of rehabilitation sessions. MAIN OUTCOME MEASURES: Long-term all-cause mortality. The Cox proportional hazard models with Bonferroni correction were used to assess the association between rehabilitation intensity and mortality, adjusting for age, comorbidities, stroke severity, and other covariates. RESULTS: Patients in the high-intensity group were younger but had a higher burden of comorbidities and greater stroke severity. During follow-up, the high-intensity group was associated with a significantly lower adjusted risk (hazard ratio [HR], .73; 95% confidence interval [CI], .63-.84) of mortality than the low-intensity group, whereas the medium-intensity group carried a similar risk of mortality (HR, 0.94; 95% CI, 0.84-1.06) compared with the low-intensity group. This association was not modified by stroke severity. CONCLUSIONS: Among patients with mild to moderate stroke severity, high-intensity rehabilitation therapy within the first 90 days was associated with a lower mortality risk than low-intensity therapy. Efforts to promote high-intensity rehabilitation therapy for this group of patients with stroke should be encouraged. PMID- 29108968 TI - Identification of a moronecidin-like antimicrobial peptide in the venomous fish Pterois volitans: Functional and structural study of pteroicidin-alpha. AB - The present study characterizes for the first time an antimicrobial peptide in lionfish (Pterois volitans), a venomous fish. Using a peptidomic approach, we identified a mature piscidin in lionfish and called it pteroicidin-alpha. We detected an amidated form (pteroicidin-alpha- CONH2) and a non-amidated form (pteroicidin-alpha-COOH), and then performed their functional and structural study. Interestingly, the two peptides displayed different antibacterial and hemolytic activity levels. Pteroicidin-alpha-CONH2 was bactericidal on human pathogens like Staphylococcus aureus or Escherichia coli, as well as on the fish pathogen Aeromonas salmonicida, while pteroicidin-alpha-COOH only inhibited their growth. Furthermore, the two peptides induced hemolysis of red blood cells from different vertebrates, namely humans, sea bass and lesser-spotted dogfish. Hemolysis occurred with low concentrations of pteroicidin-alpha-CONH2, indicating greater toxicity of the amidated form. Circular dichroism analysis showed that both peptides adopted a helical conformation, yet with a greater alpha-helix content in pteroicidin-alpha-CONH2. Overall, these results suggest that amidation strongly influences pteroicidin-alpha by modifying its structure and its physico chemical characteristics and by increasing its hemolytic activity. PMID- 29108969 TI - Dietary butylated hydroxytoluene improves lipid metabolism, antioxidant and anti apoptotic response of largemouth bass (Micropterus salmoides). AB - A 10-week growth trail was conducted to investigate the efficacy and tolerance of dietary butylated hydroxytoluene (BHT) by evaluating inflammation, apoptosis and hepatic disease related to oxidative stress in largemouth bass (Micropterus salmoides). Four experimental diets were prepared with BHT supplement levels of 0 (B0), 150 (B150), 300 (B300) and 1500 (B1500) mg/kg, in which B150 was at the maximum recommended level established by European Union Regulation, and the B300 and B1500 levels were 2 and 10-fold of B150, respectively. Each diet was fed to 6 replicates with 30 largemouth bass (initial body weight, IBW = 6.20 +/- 0.01 g) in each tank. The BHT inclusion level did not affect the specific growth rate, but fish in the B150 group showed the lowest feed conversion rate (P < 0.05). BHT inclusion significantly decreased the levels of plasma TC, TG, LDL, ALT and AKP, and increased the (HDL-C)/TC ratio (P < 0.05). Plasma MDA was significantly decreased in the B150 group and GSH-Px was extremely enhanced in each BHT inclusion group (P < 0.05). Hepatic T-AOC was significantly enhanced and O2- was significantly decreased in each BHT inclusion group compared to the B0 group (P < 0.05), as well as hepatic MDA was significantly decreased in B1500 group (P < 0.05). Dietary BHT inclusion down-regulated the hepatic mRNA levels of inflammation, apoptosis and fibrosis related genes, including TNFalpha, TGF beta1, alpha-SMA, IL8, IL11beta and caspase-9. Moreover, BHT could improve hepatic lipid metabolism via up-regulating the mRNA levels of APOA1, CYP7A1, CYP8B1, and down-regulating the mRNA levels of PPAR-gamma and APOB. Histological examination of the liver morphology with H&E and Sirius Red staining showed that BHT inclusion decreased necrotic degenerative changes and collagen deposition in largemouth bass. An immunofluorescence examination revealed significantly decreased cleaved caspase-3 signals in the BHT groups. In conclusion, the results demonstrated that ROS induces hepatic cell apoptosis and fibrosis via the intrinsic pathway of apoptosis by activating caspase-9 in the mitochondria and then initiates apoptosis by activating caspase-3. Consuming 2.32-23.80 mg/kg.bw/d (150-1500 mg/kg in diet) of BHT effectively improved the plasma and hepatic lipid metabolism, antioxidant response as well as reduced ROS production, protecting hepatic cells from injury. It is implied that even a 10-fold increase of the maximum level of BHT (150 mg/kg) is safe for the largemouth bass. PMID- 29108970 TI - Inducers of salmon innate immunity: An in vitro and in vivo approach. AB - Maintaining fish health is one of the most important aims in aquaculture. Prevention of fish diseases therefore is crucial and can be achieved by various different strategies, including most often a combination of different methods such as optimal feed and fish density, as well as strengthening the immune system. Understanding the fish innate immune system and developing methods to activate it, in an effort to prevent infections in the first place, has been a goal in recent years. In this study we choose different inducers of the innate immune system and examined their effects in vitro on the salmon cell line CHSE 214. We found that the butyrate derivatives 4-phenyl butyrate (PBA) and beta hydroxy-beta-methyl butyrate (HMB) induce the expression of various innate immune genes differentially over 24-72 h. Similarly, lipids generated from fish oils were found to have an effect on the expression of the antimicrobial peptides cathelicidin and hepcidin, as well as iNOS and the viral receptor RIG-1. Interestingly we found that vitamin D3, similar as in mammals, was able to increase cathelicidin expression in fish cells. The observed induction of these different innate immune factors correlated with antibacterial activity against Aeromonas salmonicida and antiviral activity against IPNV and ISAV in vitro. To relate this data to the in vivo situation we examined cathelicidin expression in juvenile salmon and found that salmon families vary greatly in their basal cathelicidin levels. Examining cathelicidin levels in families known to be resistant to IPNV showed that these QTL-families had lower basal levels of cathelicidin in gills, than non QTL-families. Feeding fish with HMB caused a robust increase in cathelicidin expression in gills, but not skin and this was independent of the fish being resistant to IPNV. These findings support the use of fish cell lines as a tool to develop new inducers of the fish innate immune system, but also highlight the importance of the tissue studied in vivo. Understanding the response of the innate immune system in different tissues and what effect this might have on infections and downstream cellular pathways is an interesting research topic for the future. PMID- 29108971 TI - Hemocytes of the mud crab Scylla paramamosain: Cytometric, morphological characterization and involvement in immune responses. AB - Hemocytes play essential roles in the innate immune system of crustaceans. Characterization of hemocytes from estuary mud crab Scylla paramamosain was performed by flow cytometry and morphological studies such as cytochemical staining and electron microscopy. The hemocyte subsets were further separated using a modified Percoll density gradient centrifugation method. Based on the morphological characteristics of the cells, three distinct categories of hemocytes were identified: granulocytes with abundant large granularity representing 5.27 +/- 0.42%, semigranulocytes with small or less granularity representing 76.03 +/- 3.34%, and hyalinocytes (18.70 +/- 3.92%) which were almost no granularity. The total hemocyte cell count and the percentage of hemocyte subsets varied after pathogen infection, including Vibrio alginolyticus and the viral double-stranded RNA analog Poly (I:C). The phagocytic process is of fundamental importance for crustaceans' cellular immune response as well as development and survival. The results of the in vitro phagocytosis assays analyzed by flow cytometry demonstrated that granulocytes and semigranulocytes had significantly higher phagocytic ability than hyalinocytes. A primary culture system, L-15 medium supplemented with 5-10% fetal bovine serum, was developed to further investigate the immune function of hemocytes. Furthermore, adenovirus can be utilized to effectively transfer GFP gene into hemocytes. Overall, three hemocyte sub-populations of S. paramamosain were successfully discriminated, moreover, their response to pathogen infections, phagocytic activity and adenovirus mediated transfection were also investigated for the first time. This study may contribute to a better understanding of the innate immune system of estuary crabs. PMID- 29108972 TI - Involvement of clip-domain serine protease in the anti-Vibrio immune response of abalone (Haliotis discus hannai)-Molecular cloning, characterization and functional analysis. AB - Vibrio parahemolyticus (V. parahemolyticus) is a major pathogen for abalone, an important economical shellfish in coastal area of China. There is little known about the abalone innate immune system against pathogen infection. Clip-domain serine proteases (cSPs) are increasingly recognized to play important roles in host immune defense in invertebrates. In this study, we cloned a cSP (Hdh-cSP) from abalone (Haliotis discus hannai). We found out that Hdh-cSP was widely expressed in multiple tissues of abalone, with highest level in the immune-like organ, hepatopancreas. V. parahemolyticus infection induced significantly elevated expression of Hdh-cSP in addition to better-characterized innate immune component genes including Rel/NF-kappaB, allograft inflammatory factor (ALInFa), macrophage expressed protein (MEP) and caspase-8. Importantly, the silencing of Hdh-cSP reduced the expression of these genes, suggesting that Hdh-cSP was an upstream regulatory factor in V. parahemolyticus infection. Further analysis showed that apoptosis of hemocytes was inhibited when the transcription of Hdh cSP was knocked down, suggesting that Hdh-cSP participated in cell apoptosis by regulation of caspase 8 expression in V. parahemolyticus infection. Therefore, our study established an important role of cSP in the innate immunity against V. parahemolyticus infection in abalone. PMID- 29108973 TI - Dietary administration of the commercially available probiotics enhanced the survival, growth, and innate immune responses in Mori (Cirrhinus mrigala) in a natural earthen polyculture system. AB - The use of probiotics is considered effective for survival, growth and enhanced immune response in aquaculture. In the current study, effects of commercially available probiotic (Magic Plus) was investigated on survival, growth and immune response of Mori (Cirrhinus mrigala) in a polyculture system. The experiment was conducted for 90 days on 1200 fingerlings in two groups i.e. control and probiotic supplemented groups each having 600 fingerlings. Control group was fed with 35% protein basal diet without any supplements and the other group was supplemented with commercially available probiotic at the rate of (1012 CFU kg-1 diet). After 90 days, probiotic supplemented group was characterized with significant increase (p < 0.05) in growth parameters like, total weight, total length, %weight gain, specific growth rate and survival growth rate. Immunological indices like, lysozyme activity, white blood cells, total plasma protein level and immunoglobulin (IgM) of supplemented group were also significantly (p < 0.05) enhanced. Moreover, digestive enzymes i.e. cellulase, protease and amylase were also found to be significantly (p < 0.05) hyper-active in probiotic supplemented groups. Haematological parameters like, RBCs, Hb, Hct, MCH and MCHC were also significantly (p < 0.05) increased. Thus, the current study strongly suggests that a commercially available probiotic Magic plus may serve as a healthy and immunostimulating feed additive in C. mrigala culture. PMID- 29108974 TI - Analysis of bacterial communities and characterization of antimicrobial strains from cave microbiota. AB - In this study for the first-time microbial communities in the caves located in the mountain range of Hindu Kush were evaluated. The samples were analyzed using culture-independent (16S rRNA gene amplicon sequencing) and culture-dependent methods. The amplicon sequencing results revealed a broad taxonomic diversity, including 21 phyla and 20 candidate phyla. Proteobacteria were dominant in both caves, followed by Bacteroidetes, Actinobacteria, Firmicutes, Verrucomicrobia, Planctomycetes, and the archaeal phylum Euryarchaeota. Representative operational taxonomic units from Koat Maqbari Ghaar and Smasse-Rawo Ghaar were grouped into 235 and 445 different genera, respectively. Comparative analysis of the cultured bacterial isolates revealed distinct bacterial taxonomic profiles in the studied caves dominated by Proteobacteria in Koat Maqbari Ghaar and Firmicutes in Smasse Rawo Ghaar. Majority of those isolates were associated with the genera Pseudomonas and Bacillus. Thirty strains among the identified isolates from both caves showed antimicrobial activity. Overall, the present study gave insight into the great bacterial taxonomic diversity and antimicrobial potential of the isolates from the previously uncharacterized caves located in the world's highest mountains range in the Indian sub-continent. PMID- 29108975 TI - Rapid detection of food-borne Salmonella contamination using IMBs-qPCR method based on pagC gene. AB - Detection of Salmonella is very important to minimize the food safety risk. In this study, the recombinant PagC protein and PagC antibody were prepared and coupled with immunomagnetic beads (IMBs) to capture Salmonella cells from pork and milk samples. And then the SYBR Green qualitative PCR was developed to detect the pathogenic Salmonella. The results showed that the PagC polyclonal antiserum is of good specificity and the capture rate of 0.1mg IMBs for Salmonella tended to be stable at the range of 70-74% corresponding to the concentrations between 101 and 104CFU/mL. The method developed demonstrated high specificity for the positive Salmonella samples when compared to non-specific DNA samples, such as Escherichia coli, Staphylococcus aureus, Yersinia enterocolitica, and Yersinia pseudotuberculosis. The limit of detection of this assay was 18CFU/mL. Detection and quantitative enumeration of Salmonella in samples of pork or milk shows good recoveries of 54.34% and 52.07%. In conclusion, the polyclonal antibody of recombinant PagC protein is effective to capture Salmonella from detected samples. The developed pagC antibody IMBs-qPCR method showed efficiency, sensitivity and specificity for 30 Salmonella detection, enabling detection within 10h, which is a promising rapid method to detect Salmonella in emergency. PMID- 29108976 TI - Orgasmic Dysfunction Following Radical Prostatectomy: Review of Current Literature. AB - INTRODUCTION: The sexual problem after radical prostatectomy (RP) that has received the most focus in the current literature is erectile dysfunction. However, there are orgasmic complications that encompass orgasm-associated urinary incontinence (climacturia), anorgasmia, changes in orgasmic sensation, and painful orgasm (dysorgasmia). Although the body of research is still growing, there remains a need for physician and patient awareness of these potentially problematic complications. AIM: To review the prevalence and management options for different orgasmic dysfunctions after RP. METHODS: A Medline PubMed search was used to identify articles related to orgasmic dysfunction, including climacturia, dysorgasmia, anorgasmia, and altered sensation after RP. MAIN OUTCOME MEASURE: Rates and types of orgasmic dysfunction after RP. RESULTS: Orgasmic dysfunction encompasses a series of conditions that affect men after RP. These include climacturia, dysorgasmia, anorgasmia, and altered sensation. Although the etiologies and management options remain uncertain, their effect on the sexual health of patients is not negligible. CONCLUSION: To provide proper counseling to patients, physicians should be aware of the prevalence of orgasmic side effects after RP. Post-prostatectomy sexual recovery should be focused not only on penile erectile function but also on a satisfactory and healthy sexual life for patients and their partners. Clavell-Hernandez J, Martin C, Wang R. Orgasmic Dysfunction Following Radical Prostatectomy: Review of Current Literature. Sex Med Rev 2018;6:124-134. PMID- 29108977 TI - Sexual Dysfunction in Urethral Reconstruction: A Review of the Literature. AB - INTRODUCTION: Urethral stricture disease accounts for 5,000 hospitalizations and 1.5 million office visits per year. Urethral reconstruction has become more commonplace with the recognition of the poor long-term success of the endoscopic management of stricture disease. Sexual dysfunction related to the surgical management of urethral strictures is an under-recognized sequela. AIM: To characterize and elucidate the various factors that contribute to sexual dysfunction after urethroplasty and hypospadias reconstruction to improve surgical decision making and patient counseling. METHODS: A Medline PubMed search was used to identify articles of interest related to sexual dysfunction and urethral stricture disease. The following were included in the search for articles of interest: "urethroplasty and sexual dysfunction," "urethral stricture and erectile dysfunction," "urethroplasty and ejaculatory dysfunction," and "sexual function and hypospadias." MAIN OUTCOME MEASURE: Rates and types of sexual dysfunction after urethral reconstructive surgery. RESULTS: Urethral reconstructive surgery has the potential to affect many domains of sexual function and thus negatively affect quality of life for patients with urethral stricture disease and hypospadias. These domains include erectile function, ejaculatory function, penile shortening, penile curvature, and altered penile sensation. The etiology, location, length and type of urethral stricture, and importantly the reconstructive technique have different repercussions on sexual function. CONCLUSION: Sexual dysfunction after urethral reconstruction is underappreciated and has a significant consequence on quality of life. Thus, it is important to recognize these sequelae and counsel patients accordingly. Benson CR, Hoang L, Clavell-Hernandez J, Wang R. Sexual Dysfunction in Urethral Reconstruction: A Review of the Literature. Sex Med Rev 2018;6:492-503. PMID- 29108978 TI - Volume of surgery for benign colorectal polyps in the last 11 years. AB - BACKGROUND AND AIMS: Traditionally large, complex colorectal polyps were managed by surgical resection (SR), and in recent years endoscopic resection (ER) has progressed significantly. However, to what extent ER has replaced SR remains largely unknown. We performed a multicenter retrospective cohort study to assess the volume and volume changes of SR for benign colorectal polyps over the past decade. METHODS: Patients who underwent SR for a benign colorectal polyp in the Netherlands between 2005 and 2015 were selected from the prospective nationwide Dutch Pathology Registry (PALGA database). Clinical characteristics were obtained from the charts of patients who underwent SR in the province of Noord-Holland. RESULTS: A total of 5937 patients were treated with SR for a colorectal polyp and the absolute (454-739 per year) and relative volumes (0.20%-0.37% per colonoscopy per year) of SR remained stable. In the province of Noord-Holland, 928 patients (15.6%) underwent SR. In these patients, submucosal lifting and ER were attempted in 19.9% (n = 175) and 15.0% (n = 134). After 2010, patients were more likely to undergo lifting (27.7% vs 11.4%, P < .001) and ER attempts (18.8% vs 10.9%, P = .001) before definitive SR. Twenty-two patients (2.4%) had been referred to another endoscopy clinic. CONCLUSIONS: SR for large, complex colorectal polyps is still frequently performed and has remained stable. A small percentage of patients underwent ER attempts before SR, and referral for an additional ER attempt only occurred in a minority of cases. To increase ER attempts, implementation of a regional multidisciplinary referral network should be considered. PMID- 29108979 TI - Prediction of clinical outcomes in Crohn's disease by using confocal laser endomicroscopy: results from a prospective multicenter study. AB - BACKGROUND AND AIMS: Assessment of prognostic factors in patients with Crohn's disease (CD) is of pivotal importance for early intervention and "treat-to target" strategies. Confocal laser endomicroscopy (CLE) enables on-demand in vivo characterization of mucosal inflammatory and architectural changes during endoscopy. We prospectively assessed the value of CLE for prediction of clinical outcome parameters in CD. METHODS: Consecutive patients with CD undergoing colonoscopy were included in a multicenter study. Confocal imaging focused on 2 highly reproducible histologic hallmarks of active colonic inflammation: focal cryptitis and crypt architectural abnormality. We evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP), and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural adverse events, and CD-related hospitalization or surgery during a 4-year follow-up. RESULTS: Among 49 patients (53% men, median age, 39 years), baseline CRP was >=5 mg/L in 47%, CDEIS >=3 in 75%, and CDAI >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% (CLE+ group). CLE+ patients showed an increased incidence of medical treatment escalation (P < .001; relative risk [RR] = 3.27) and transmural lesions (P = .025; RR = 1.70), whereas patients with CRP >=5 mg/L had increased CD-related hospitalization and surgery (P = .020, RR = 2.71) at 1-year follow-up. No further association with prognostic clinical outcomes was found over the 1-year follow-up as well as for CDEIS and CDAI at any time. CONCLUSIONS: CLE reveals CD-related features of mucosal inflammation and allows for early prediction of relevant clinical outcomes. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients with CD. PMID- 29108980 TI - Radiofrequency ablation combined with biliary stent placement versus stent placement alone for malignant biliary strictures: a systematic review and meta analysis. AB - BACKGROUND AND AIMS: Unresectable malignant biliary strictures are generally managed by palliative stent placement for drainage of biliary tree. Recently, radiofrequency ablation (RFA) has been used to improve the patency of biliary stents in these patients. Several studies have evaluated the effectiveness of biliary stent placement with RFA on stent patency and patient survival with variable results. We performed this meta-analysis to evaluate the efficacy and safety of biliary stent placement with RFA compared with stent placement alone in patients with malignant biliary strictures. METHODS: We performed a comprehensive search of electronic databases for all studies comparing RFA with biliary stent placement versus stent placement only. Measured outcomes included patient survival, stent patency, and procedure-related adverse events. An inverse variance method was used to pool data on stent patency into a random-effects model. Cox-regression analysis was used to calculate hazard ratio for survival analysis. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to interpret our findings. RESULTS: Nine studies (including 2 abstracts) with a total of 505 patients were included in the meta analysis. The pooled weighted mean difference in stent patency was 50.6 days (95% confidence interval [CI], 32.83-68.48), favoring patients receiving RFA. Pooled survival analysis of the reconstructed Kaplan-Meier data showed improved survival in patients treated with RFA (hazard ratio, 1.395; 95% CI, 1.145-1.7; P < .001). However, RFA was associated with a higher risk of postprocedural abdominal pain (31% vs 20%, P = .003). Our analysis did not show significant difference between the RFA and stent placement-only groups with regard to the risk of cholangitis, acute cholecystitis, pancreatitis, and hemobilia. CONCLUSIONS: In the light of this limited data based on observational studies, RFA was found to be safe and was associated with improved stent patency in patients with malignant biliary strictures. In addition, RFA may be associated with improved survival in these patients. PMID- 29108982 TI - Eosinophilic gastritis with involvement of esophageal gastric inlet patch. PMID- 29108981 TI - Outcomes of per-oral endoscopic myotomy for treatment of esophageal achalasia with a median follow-up of 49 months. AB - BACKGROUND AND AIMS: Per-oral endoscopic myotomy (POEM) has received wide acceptance as a highly effective and safe treatment for esophageal achalasia. Short-term and small-scale studies are ample, but long-term large-scale studies are few. The aim of the study was to systematically analyze our long-term results of POEM, with particular emphasis on POEM failures and associated risk factors. METHODS: In this single-center study, consecutive patients treated with POEM between August 2010 and December 2012 were included. The Kaplan-Meier survival function was used to estimate clinical success rate at each year. The Cox proportional hazards model was used to analyze risk factors related to recurrence. RESULTS: A total of 564 patients were included. Major perioperative adverse events occurred in 36 patients (6.4%). After a median follow-up of 49 months (range, 3-68), the Eckardt score and lower esophageal sphincter (LES) pressure were significantly decreased (median Eckardt score, 8 to 2 [P < .05]; median LES pressure, 29.7 mm Hg to 11.9 mm Hg [P < .05]). Fifteen failures occurred within 3 months, 23 between 3 months and 3 years, and 10 after 3 years. The estimated clinical success rates at 1, 2, 3, 4, and 5 years were 94.2%, 92.2%, 91.1%, 88.6%, and 87.1%, respectively. Multivariate Cox regression revealed long disease duration (>=10 years) and history of prior interventions to be risk factors for recurrence. Clinical reflux occurred in 37.3% of patients (155/ 416). CONCLUSIONS: POEM is a highly safe and effective treatment for esophageal achalasia with favorable long-term outcomes. PMID- 29108983 TI - A novel device for improving visualization in an inadequately prepared colon. AB - BACKGROUND AND AIMS: Adequate bowel preparation is crucial for a quality colonoscopy. Poor bowel preparation can result in longer procedural times, missed adenomas, earlier repeat procedures, increase costs, and decreased patient satisfaction. Pure-Vu (MOTUS GI, Tirat Carmel, Israel) is a system that facilitates intraprocedural cleaning of a poorly prepared colon during a colonoscopy by irrigating the colon and evacuating the fluid and feces. The study aims were to evaluate Pure-Vu's cleansing capabilities and its usability and safety in a live animal colon. METHODS: The Pure-Vu system was used by 4 experienced gastroenterologists in 35 Yorkshire cross swine (66% female) that received a reduced bowel preparation to ensure an inadequate bowel preparation at baseline. Before colonoscopy the Pure-Vu was attached to the colonoscope, and the baseline prep was assessed during insertion. The Pure-Vu system was then used to cleanse the colon and the prep then assessed after Pure-Vu use. RESULTS: No adverse effects and no failed or prematurely terminated cases were noted. Fourteen percent of the swine colons were adequately prepped at baseline (median Boston Bowel Preparation Scale [BBPS] score = 0 [25th percentile = 0; 75th percentile = 1; interquartile range = 1]) and improved to 100% after use of Pure Vu (Wilcoxon signed rank test P < .001) (median BBPS score = 3 [25th percentile = 3; 75th percentile = 3; interquartile range = 0]). The physicians found Pure-Vu easy and intuitive to operate. CONCLUSIONS: The Pure-Vu system effectively cleaned inadequately prepped swine colons and proved to be easy to use. The Pure Vu device, applied in clinical practice, may result in improved overall prep quality and a reduction in repeat examinations because of inadequately prepped colons. PMID- 29108985 TI - Serotonergic neurons mediate the anxiolytic effect of l-DOPA: Neuronal correlates in the amygdala. AB - Anxiety in Parkinson's disease is a comorbid non-motor symptom that alters the quality of life of patients. Its neuronal substrates and those of l-Dopa treatment are still poorly known. Using different combinations of monoaminergic system lesions in the rat, we addressed the contribution of these systems in the efficacy of l-DOPA on anxiety and on the neuronal activity of basolateral amygdala (BLA), a brain structure involved in anxiety. Anxiety, locomotor activity and motor performance were assessed using the elevated plus maze, the open field and the skinner box, respectively. The neuronal activity of BLA was electrophysiologically recorded and the loss of dopamine, noradrenaline and serotonin neurons was quantified by immunohistochemistry and stereology. Selective bilateral lesion of dopamine neurons, with or without the additional lesions of noradrenaline and/or serotonin neurons, induced anxiety disorder. l Dopa significantly decreased anxiety in animals with bilateral lesion of dopamine neurons alone or combined with that of noradrenaline neurons. In these two groups, l-DOPA enhanced the firing rate of BLA neurons. However, in animals with combined lesions of dopamine and serotonin neurons or in animals with lesions of the three monoaminergic systems, l-Dopa was no longer able to decrease anxiety behavior or to change the electrophysiological parameters of BLA neurons. Our data provide the first evidence of the key and positive role of the serotonergic system in the combined efficacy of l-Dopa on anxiety and the paralleled BLA neuronal activity, suggesting that the enhancement of the activity of serotonin neurons may boost the anxiolytic action of l-DOPA. PMID- 29108984 TI - Transoral outlet reduction: a comparison of purse-string with interrupted stitch technique. AB - BACKGROUND AND AIMS: Weight regain after Roux-en-Y gastric bypass (RYGB) correlates with dilated gastrojejunal anastomosis (GJA). Endoscopic sutured transoral outlet reduction (TORe) is a safe and effective management and has predominantly been performed by either placing interrupted sutures at the GJA or the creation of a purse-string suture. The aim of the current study was to compare these techniques. METHODS: All patients undergoing TORe for weight regain after RYGB were prospectively enrolled. Primary outcome was mean percent total weight loss (%TWL) at 3 and 12 months. Secondary outcomes included percent excess weight loss (%EWL), percent regained weight lost (%RWL), and total weight loss. Proportions were compared using the Fisher exact test and continuous variables using the Student t test. A P = .05 was significant. Multivariable regression analysis was performed. RESULTS: Two hundred forty-one patients were enrolled (purse string = 187, interrupted = 54). There was no statistical difference between the purse-string and interrupted groups at 3 months in %TWL (8.6 vs 8.0, P = .41), %EWL (20.5 vs 16.7, P = .39), % RWL (44.7 vs 33.3, P = .56), and total weight loss (9.5 vs 11.3, P = .32). At 12 months the purse-string group achieved statistically significant improvement in %TWL (8.6 vs 6.4, P = .02), %EWL (19.8 vs 11.7, P < .001), %RWL (40.2 vs 27.8, P = .02), and total weight loss (9.5 vs 7.8, P = .04). Multivariable regression showed that technique (P = .006) was an independent predictor of %TWL at 12 months. CONCLUSIONS: TORe is effective in treatment of weight regain after failed gastric bypass. The purse-string technique results in greater weight loss at 12 months than the traditional interrupted suture pattern. PMID- 29108986 TI - "I Just Don't Know": An Exploration of Women's Ambivalence about a New Pregnancy. AB - PURPOSE: We sought to examine how ambivalence manifests in women's lives after confirmation of a new pregnancy by exploring women's feelings, attitudes, and experiences regarding pregnancy intentions, the news itself, and related pregnancy decision making. STUDY DESIGN: We recruited women aged 15 to 44 and at less than 24 completed weeks of gestational age from urban, walk-in pregnancy testing clinics in New Haven, Connecticut, from June 2014 to June 2015. We obtained quantitative and qualitative data via an enrollment survey and face-to face, semistructured interviews, respectively. Transcripts were analyzed using framework analysis. RESULTS: The sample included 84 women. Participants had a mean age of 26 years and were on average 7 weeks estimated gestational age at enrollment. Most identified as Black (54%) or Hispanic (20%), were unmarried (92%), and had at least one other child (67%). More than one-half (55%) described feelings of ambivalence regarding their current pregnancy. We identified ambivalence as a frequent and complex thread that represented distinct but overlapping perspectives about pregnancy: ambivalent pregnancy intentions, ambivalent response to new diagnosis of pregnancy, and ambivalence as uncertainty or conflict over pregnancy decision-making. Sources of ambivalence included relationship status, pregnancy timing, and maternal or fetal health problems. CONCLUSIONS: This study improves on previous findings that focus only on ambivalence related to pregnancy intention or to decision making, and explores women's mixed, fluctuating, or unresolved feelings and attitudes about pregnancy before many participants had completed pregnancy decision making. Acknowledging and exploring sources of ambivalence regarding pregnancy may help health providers and policymakers to comprehensively support women with respect to both their experiences and reproductive goals. PMID- 29108987 TI - Insurance-related Practices at Title X-funded Family Planning Centers under the Affordable Care Act: Survey and Interview Findings. AB - INTRODUCTION: Given the recent reforms in the United States health care system, including the passage and implementation of the Affordable Care Act, as well as anticipated upcoming changes to health care coverage, it is critical that publicly funded health care providers understand how to effectively work with their states' Medicaid programs and the private health insurance plans in their service areas to provide high-quality contraceptive care to the millions of women relying on services at these sites annually. METHODS: We collected survey data from a nationally representative sample of 535 clinics providing family planning services that received Title X funding and conducted semistructured interviews with 23 administrators at a subsample of surveyed clinics to explore provider reported experiences working with health plans and to identify barriers to, and practices that lead to, adequate reimbursement for services provided. RESULTS: Providers report that knowledgeable staff are crucial to securing contracts with both public and private insurance plan issuers, and that the contracts they secure often include coverage restrictions on methods or services clinics offer their clients. Good staff relationships with issuers are key to obtaining adequate and consistent reimbursement for all covered services. CONCLUSIONS: Providers are trying to understand how insurance programs in their area knit together. Regardless of how U.S. health policies and delivery systems may change in the coming years, it is imperative that publicly funded family planning centers continue to work with health plans and maximize their third-party revenue to provide services to those in need. PMID- 29108988 TI - Urban/Rural Differences in Breast and Cervical Cancer Incidence: The Mediating Roles of Socioeconomic Status and Provider Density. AB - BACKGROUND: Breast and cervical cancer incidence vary by urbanicity, and several ecological factors could contribute to these patterns. In particular, cancer screening or other sociodemographic and health care system variables could explain geographic disparities in cancer incidence. METHODS: Governmental and research sources provided data on 612 counties in the Surveillance, Epidemiology, and End Results program for rural-urban continuum code, socioeconomic status (SES) quintile, percent non-Hispanic White residents, density of primary care physicians, cancer screening, and breast and cervical cancer incidence rates (2009-2013). Ecological mediation analyses used weighted least squares regression to examine whether candidate mediators explained the relationship between urbanicity and cancer incidence. RESULTS: As urbanicity increased, so did breast cancer incidence (beta^ = 0.23; p < .001). SES quintile and density of primary care physicians mediated this relationship, whereas percent non-Hispanic White suppressed it (all p < .05); county-level mammography levels did not contribute to the relationship. After controlling for these variables, urbanicity and breast cancer incidence were no longer associated (beta^ = 0.11; p > .05). In contrast, as urbanicity increased, cervical cancer incidence decreased (beta^ = -0.33; p < .001). SES quintile and density of primary care physicians mediated this relationship (both p < .05); percent non-Hispanic White and Pap screening levels did not contribute to the relationship. After controlling for these variables, the relationship between urbanicity and cervical cancer incidence remained significant (beta^ = -0.13; p < .05). CONCLUSIONS: County-level SES and density of primary care physicians explained the relationships between urbanicity and breast and cervical cancer incidence. Improving these factors in more rural counties could ameliorate geographic disparities in breast and cervical cancer incidence. PMID- 29108989 TI - Up-regulated lnc-SNHG1 contributes to osteosarcoma progression through sequestration of miR-577 and activation of WNT2B/Wnt/beta-catenin pathway. AB - Long noncoding RNA small nucleolar RNA host gene 1 (lnc-SNHG1) was reported to play an oncogenic role in the progression of cancers. However, the roles of SNHG1 and its molecular mechanism in osteosarcoma (OS) cells are largely unknown. In present study, we found that the expression of SNHG1 was up-regulated in OS tissues and cell lines. OS patients with the high SNHG1 expression were positively correlated with tumor size, TNM stage and lymph node metastasis. In addition, SNHG1 overexpression promoted cell proliferation, cell migration and EMT process in U2OS and MG63 cells and tumor growth in vivo. Furthermore, we also found that miR-577 could act as a ceRNAof SNHG1 in OS cells and the promotion of OS progression induced by lnc-SNHG1 overexpression required the inactivity of miR 577. Besides, we identified that WNT2B acted as a target of miR-577, and WNT2B played the oncogenic role in OS cells by activating Wnt/beta-catenin pathway. In short, our study suggested that lnc-SNHG1 could promote OS progression via miR 577 and WNT2B. The lnc-SNHG1/miR-577/WNT2B/Wnt/beta-catenin axis regulatory network might provide a potential new therapeutic strategy for OS treatment. PMID- 29108990 TI - Laminin-1 induces endocytosis of 67KDa laminin receptor and protects Neuroscreen 1 cells against death induced by serum withdrawal. AB - Although the function of laminin in the basement membrane is known, the function of soluble "neuronal" laminin is unknown. Since laminin is neuroprotective, we determined whether the soluble laminin-1 induces signaling for neuroprotection via its 67KDa laminin-1 receptor (67LR). Treatment of Neuroscreen-1 (NS-1) cells with laminin-1 or YIGSR peptide, which corresponds to a sequence in laminin-1 beta1 chain that binds to 67LR, induced a decrease in the cell-surface expression of 67LR and caused its internalization. Furthermore, intracellular cAMP-elevating agents, dibutyryl-cAMP, forskolin, and rolipram, also induced this internalization. Both soluble laminin-1 and YIGSR induced a sustained elevation of intracellular cAMP under defined conditions, suggesting a causal role of cAMP in the endocytosis of 67LR. This endocytosis was not observed in cells deficient in protein kinase A (PKA) nor in cells treated with either SQ 22536, an inhibitor for adenylyl cyclase, or ESI-09, an inhibitor for the exchange protein directly activated by cAMP (Epac). In addition, when internalization occurred in NS-1 cells, 67LR and adenylyl cyclase were localized in early endosomes. Under conditions in which endocytosis had occurred, both laminin-1 and YIGSR protected NS-1 cells from cell death induced by serum withdrawal. However, under conditions in which endocytosis did not occur, neither laminin-1 nor YIGSR protected these cells. Conceivably, the binding of laminin-1 to 67LR causes initial signaling through PKA and Epac, which causes the internalization of 67LR, along with signaling enzymes, such as adenylyl cyclase, into early endosomes. This causes sustained signaling for protection against cell death induced by serum withdrawal. PMID- 29108991 TI - SETDB1-mediated FosB regulation via ERK2 is associated with an increase in cell invasiveness during anticancer drug treatment of A549 human lung cancer cells. AB - We have determined a functional link to the inverse expression of SETDB1 and FosB following anticancer drug treatment. Doxorubicin treatment caused decreased SETDB1 expression and FosB overexpression both at the mRNA and protein levels. The decreased HMTase activity of SETDB1 coincided with altered occupancy across the promoter region of the FosB gene. SETDB1 overexpression decreased the luciferase reporter activity containing the FosB promoter region, but siSETDB1 increased the luciferase reporter activity, suggesting that SETDB1 directly and negatively regulated FosB expression. In addition, MEK inhibitor (PD98059) blocked the SETDB1 regulation of the FosB promoter activity via ERK2 activation during doxorubicin treatment. A microscopic analysis reveals that FosB expression was observed in living cells in spite of doxorubicin treatment. Ectopic FosB/DeltaFosB expression increased the number of colonies and the migration of A549 cells compared to that in control. These results suggest that the ERK2 SETDB1-FosB signaling pathway might have an anti-therapeutic regulatory mechanism that increases the transformation and migration activity of cancer cells during anticancer drug treatment. PMID- 29108992 TI - miR-32-5p-mediated Dusp5 downregulation contributes to neuropathic pain. AB - Previous studies have demonstrated that microRNAs (miRNAs) play important roles in the pathogenesis of neuropathic pain. In the present study, we found that miR 32-5p was significantly upregulated in rats after spinal nerve ligation (SNL), specifically in the spinal microglia of rats with SNL. Functional assays showed that knockdown of miR-32-5p greatly suppressed mechanical allodynia and heat hyperalgesia, and decreased inflammatory cytokine (IL-1beta, TNF-alpha and IL-6) protein expression in rats after SNL. Similarly, miR-32-5p knockdown alleviated cytokine production in lipopolysaccharide (LPS)-treated spinal microglial cells, whereas its overexpression had the opposite effect. Mechanistic investigations revealed Dual-specificity phosphatase 5 (Dusp5) as a direct target of miR-32-5p, which is involved in the miR-32-5p-mediated effects on neuropathic pain and neuroinflammation. We demonstrated for the first time that miR-32-5p promotes neuroinflammation and neuropathic pain development through regulation of Dusp5. Our findings highlight a novel contribution of miR-32-5p to the process of neuropathic pain, and suggest possibilities for the development of novel therapeutic options for neuropathic pain. PMID- 29108993 TI - Salvianolic acid B inhibits myofibroblast transdifferentiation in experimental pulmonary fibrosis via the up-regulation of Nrf2. AB - Salvianolic acid B (SalB) is one of the most bioactive components extracted from Salvia miltiorrhiza, and its antioxidant capacity corresponds with its protective effects against cell injury from oxidative stress. The aim of the present study was to evaluate the effect of SalB on experimental pulmonary fibrosis and its ability to ameliorate the oxidative/antioxidative imbalance during fibrosis pathogenesis. The anti-fibrotic activity of SalB was first confirmed in Transforming growth factor beta1(TGF-beta1)-stimulated MRC-5 cells. The protection of SalB against oxidative stress during fibrogenesis in vitro was verified by detecting ROS production, the levels of glutathione (GSH) and malondialdehyde (MDA). The Western blot and PCR results indicated that SalB could up-regulate nuclear factor erythroid-derived 2-like 2 (Nrf2) at both the protein and mRNA levels and induce Nrf2 nuclear translocation in vitro, which may be the mechanism underlying the anti-fibrotic capacity of SalB. Furthermore, the anti fibrotic and antioxidant capacities of SalB in vivo were confirmed in rats with BLM-induced pulmonary fibrosis. The immunohistochemistry results showed that Nrf2 was absent in fibroblastic foci (FF) areas, while the SalB treatment could increase the expression of Nrf2 in lung tissues, especially in FF areas. PMID- 29108994 TI - NFkappaB mediated elevation of KCNJ11 promotes tumor progression of hepatocellular carcinoma through interaction of lactate dehydrogenase A. AB - It has been well documented that changes in ion fluxes across cellular membranes is fundamental in maintaining cellular homeostasis. Dysregulation and/or malfunction of ion channels are critical events in the pathogenesis of diverse diseases, including cancers. In this study, we focused on the study of K+ channels in hepatocellular carcinoma (HCC). By data mining TCGA cohort, the expression of 27 K+ channels was investigated and KCNJ11 was identified as a key dysregulated K+ channels in HCC. KCNJ11 was differentially expressed in HCC and predicted a poor prognosis in HCC patients. Inhibition of NFkappaB signaling suppressed KCNJ11 expression in HCC cells. Knockdown of KCNJ11 expression inhibited cell proliferation, promoted cell apoptosis, and reduced cell invasive capacity. Mechanistically, we found that KCNJ11 promotes tumor progression through interaction with LDHA and enhancing its enzymatic activity. Pharmacological inhibition of LDHA largely compromised the oncogenic function of KCNJ11 in cell proliferation, cell apoptosis, and cell invasion. Collectively, our data, as a proof of principle, demonstrate that KCNJ11 acts as an oncogene in HCC though forming a complex with LDHA and suggest that targeting KCNJ11 can be developed as a candidate tool to dampen HCC. PMID- 29108995 TI - CD1d is a novel cell-surface marker for human monocytic myeloid-derived suppressor cells with T cell suppression activity in peripheral blood after allogeneic hematopoietic stem cell transplantation. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that regulate immune responses in cancer and various pathological conditions. However, the phenotypic and functional heterogeneity of human MDSCs represents a major hurdle for the development of therapeutic strategies targeting or regulating MDSCs in tumor progression, inflammation, and graft-versus-host disease (GVHD). We previously shown that circulating HLA-DR-CD14+ monocytic MDSCs are a major contributor to clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we identified, using high throughput screening, a set of surface markers that are strongly expressed in HLA DR-CD14+ monocytic MDSCs isolated from the peripheral blood (PB) of patients receiving allo-HSCT. Subsequent experiments showed the consistent dominant expression of CD1d in monocytic MDSCs of allo-HSCT PB in comparison with granulocytic MDSCs. In addition, CD1d-expressing cells isolated from PB of allo HSCT patients showed the suppressive activity of T cell proliferation and higher expression of MyD88 and IDO compared with CD1d- cells. Our results suggest that CD1d could be a valuable marker for further therapeutic evaluation of human monocytic MDSCs for immune-related diseases, including GVHD. PMID- 29108996 TI - FPLD2 LMNA mutation R482W dysregulates iPSC-derived adipocyte function and lipid metabolism. AB - Lipodystrophies are disorders that directly affect lipid metabolism and storage. Familial partial lipodystrophy type 2 (FPLD2) is caused by an autosomal dominant mutation in the LMNA gene. FPLD2 is characterized by abnormal adipose tissue distribution. This leads to metabolic deficiencies, such as insulin-resistant diabetes mellitus and hypertriglyceridemia. Here we have derived iPSC lines from two individuals diagnosed with FPLD2, and differentiated these cells into adipocytes. Adipogenesis and certain adipocyte functions are impaired in FPLD2 adipocytes. Consistent with the lipodystrophic phenotype, FPLD2-adipocytes appear to accumulate markers of autophagy and catabolize triglycerides at higher levels than control adipocytes. These data are suggestive of a mechanism causing the lack of adipose tissue in FPLD2 patients. PMID- 29108997 TI - Chlamydia pneumoniae exploits adipocyte lipid chaperone FABP4 to facilitate fat mobilization and intracellular growth in murine adipocytes. AB - Fatty acid-binding protein 4 (FABP4), a cytosolic lipid chaperone predominantly expressed in adipocytes and macrophages, modulates lipid fluxes, trafficking, signaling, and metabolism. Recent studies have demonstrated that FABP4 regulates metabolic and inflammatory pathways, and in mouse models its inhibition can improve type 2 diabetes mellitus and atherosclerosis. However, the role of FABP4 in bacterial infection, metabolic crosstalk between host and pathogen, and bacterial pathogenesis have not been studied. As an obligate intracellular pathogen, Chlamydia pneumoniae needs to obtain nutrients such as ATP and lipids from host cells. Here, we show that C. pneumoniae successfully infects and proliferates in murine adipocytes by inducing hormone sensitive lipase (HSL) mediated lipolysis. Chemical inhibition or genetic manipulation of HSL significantly abrogated the intracellular growth of C. pneumoniae in adipocytes. Liberated free fatty acids were utilized to generate ATP via beta-oxidation, which C. pneumoniae usurped for its replication. Strikingly, chemical inhibition or genetic silencing of FABP4 significantly abrogated C. pneumoniae infection induced lipolysis and mobilization of liberated FFAs, resulting in reduced bacterial growth in adipocytes. Collectively, these results demonstrate that C. pneumoniae exploits host FABP4 to facilitate fat mobilization and intracellular replication in adipocytes. This work uncovers a novel strategy used by intracellular pathogens for acquiring energy via hijacking of the host lipid metabolism pathway. PMID- 29108998 TI - Unexpected role of the IMD pathway in Drosophila gut defense against Staphylococcus aureus. AB - In this study, fruit fly of the genus Drosophila is utilized as a suitable model animal to investigate the molecular mechanisms of innate immunity. To combat orally transmitted pathogenic Gram-negative bacteria, the Drosophila gut is armed with the peritrophic matrix, which is a physical barrier composed of chitin and glycoproteins: the Duox system that produces reactive oxygen species (ROS), which in turn sterilize infected microbes, and the IMD pathway that regulates the expression of antimicrobial peptides (AMPs), which in turn control ROS-resistant pathogens. However, little is known about the defense mechanisms against Gram positive bacteria in the fly gut. Here, we show that the peritrophic matrix protects Drosophila against Gram-positive bacteria S. aureus. We also define the few roles of ROS in response to the infection and show that the IMD pathway is required for the clearance of ingested microbes, possibly independently from AMP expression. These findings provide a new aspect of the gut defense system of Drosophila, and helps to elucidate the processes of gut-microbe symbiosis and pathogenesis. PMID- 29108999 TI - Generation of rationally-designed nerve growth factor (NGF) variants with receptor specificity. AB - Nerve growth factor (NGF) is the prototypic member of the neurotrophin family and binds two receptors, TrkA and the 75 kDa neurotrophin receptor (p75NTR), through which diverse and sometimes opposing effects are mediated. Using the FoldX protein design algorithm, we generated eight NGF variants with different point mutations predicted to have altered binding to TrkA or p75NTR. Of these, the I31R NGF variant exhibited specific binding to p75NTR. The generation of this NGF variant with selective affinity for p75NTR can be used to enhance understanding of neurotrophin receptor imbalance in diseases and identifies a key targetable residue for the development of small molecules to disrupt binding of NGF to TrkA with potential uses in chronic pain. PMID- 29109000 TI - 7,8-Dihydroxyflavone ameliorates high-glucose induced diabetic apoptosis in human retinal pigment epithelial cells by activating TrkB. AB - BACKGROUND: In diabetic retinopathy, prolonged high-level blood glucose induced significant impairments among various retinal tissues, including retinal pigment epithelial (RPE) cells. In an in vitro model of human RPE cells, we evaluated whether 7,8-Dihydroxyflavone (DHF) may effectively prevent high glucose-induced diabetic apoptosis among human RPE cells. METHOD: ARPE-19 cells, a Human RPE cell line, were treated with d-glucose (50 mM) to induce apoptosis in vitro. Prior to glucose, ARPE-19 cells were pre-incubated with various concentrations of DHF. The effect of DHF on d-glucose-induced apoptosis was examined by TUNEL assay, in a concentration-dependent manner. The biological effects of DHF on Caspase-9 (Casp 9) and TrkB signaling pathways in d-glucose-injured ARPE-19 cells were evaluated by qRT-PCR and western blot (WB) assays. A TrkB antagonist, K252a, was also applied in DHF and d-glucose treated ARPE-19 cells. Possible effect of K252a blocking TrkB signaling pathway, thus reversing DHF-modulated apoptosis prevention was also examined by TUNEL and WB assays. RESULTS: DHF ameliorated d glucose-induced diabetic apoptosis in ARPE-19 cells. Apoptotic factor Casp-9, at both mRNA and protein levels, were drastically inhibited by DHF in d-glucose injured ARPE-19 cells. Also, DHF activated TrkB signaling pathway through phosphorylation. K252a dramatically reversed the preventive effect of DHF on d glucose-induced apoptosis in ARPE-19 cells. Further investigation showed that K252a functioned through de-activating or de-phosphorylating TrkB signaling pathway. CONCLUSION: This work demonstrates that DHF, through activation of TrkB signaling pathway, has a preventive function in d-glucose-induced apoptosis in PRE cells in diabetic retinopathy. PMID- 29109001 TI - Physician Decision-Making in the Setting of Advanced Illness: An Examination of Patient Disposition and Physician Religiousness. AB - CONTEXT: Little is known about patient and physician factors that affect decisions to pursue more or less aggressive treatment courses for patients with advanced illness. OBJECTIVES: This study sought to determine how patient age, patient disposition, and physician religiousness affect physician recommendations in the context of advanced illness. METHODS: A survey was mailed to a stratified random sample of U.S. physicians, which included three vignettes depicting advanced illness scenarios: 1) cancer, 2) heart failure, and 3) dementia with acute infection. One vignette included experimental variables to test how patient age and patient disposition affected physician recommendations. After each vignette, physicians indicated their likelihood to recommend disease-directed medical care vs. hospice care. RESULTS: Among eligible physicians (n = 1878), 62% (n = 1156) responded. Patient age and stated patient disposition toward treatment did not significantly affect physician recommendations. Compared with religious physicians, physicians who reported that religious importance was "not applicable" were less likely to recommend chemotherapy (adjusted odds ratio [OR] 0.39, 95% CI 0.23-0.66) and more likely to recommend hospice (OR 1.90, 95% CI 1.15-3.16) for a patient with cancer. Compared with physicians who ever attended religious services, physicians who never attended were less likely to recommend left ventricular assist device placement for a patient with congestive heart failure (OR 0.57, 95% CI 0.35-0.92). In addition, Asian ethnicity was independently associated with recommending chemotherapy (OR 1.72, 95% CI 1.13 2.61) and being less likely to recommend hospice (OR 0.59, 95% CI 0.40-0.91) for the patient with cancer; and it was associated with recommending antibiotics for the patient with dementia and pneumonia (OR 1.64, 95% CI 1.08-2.50). CONCLUSION: This study provides preliminary evidence that patient disposition toward more and less aggressive treatment in advanced illness does not substantially factor into physician recommendations. Non-religious physicians appear less likely to recommend disease-directed medical treatment in the setting of advanced illness, although this finding was not uniform and deserves further research. PMID- 29109002 TI - Anesthetic Management of Lung Transplantation: Center Specific Practices and Geographical and Centers Size Differences. PMID- 29109003 TI - Prediction of Postoperative Mechanical Ventilation After Thymectomy in Patients With Myasthenia Gravis: A Myth or Reality. PMID- 29109004 TI - The tubby-like proteins kingdom in animals and plants. AB - Each gene of the tubby-like family is characterized by a signature of C-terminal tubby domain. The wide spread of this family in plants and animals implies they have an important function in various organisms. Even though the tubby-like genes are suggested to be putative transcription factors (TFs), how they execute the function as TFs is not yet clear. The biological functions of most animal tubby like genes have been well studied, especially for vertebrate TUB, TULP1 and TULP3, but not with TULP2 and TULP4. Plants possess more tubby-like genes than animals, but their functions are still elusive except the idea that they are involved in stress responses with indistinct mechanisms. Here we reviewed the current knowledge of the versatile functions and roles of the tubby-like family members in plants and animals. PMID- 29109005 TI - Evaluation of PCSK9 levels and its genetic polymorphisms in women with polycystic ovary syndrome. AB - Dyslipidemia is one of the common metabolic disorders in Polycystic Ovary Syndrome (PCOS). Proprotein convertase subtilisin kexin type 9 (PCSK9) is a new component of lipid metabolism and correlated to the development of dyslipidemia and atherosclerosis. This protein acts by preventing the recycling of LDL receptors (LDL-r) back to the cell surface and thus generates higher levels of LDLc. The objective of this study was to evaluate the PCSK9 polymorphisms rs505151 (c.2009A>G), rs562556 (c.1420A>G) and rs11206510 (T>C) and plasma PCSK9 levels in PCOS. A group of women with PCOS (n=97), and a group of healthy women (control, n=99) were selected. Biochemical parameters were determined by using Vitros system and polymorphisms were assessed by TaqMan SNP Genotyping Assays. Plasma PCSK9 levels or PCSK9 polymorphisms were not associated with PCOS. The genotype rs11206510TT was associated with higher levels of PCSK9 in both groups. The population investigated (PCOS+control groups) with the rs505151AA genotype presented higher HDLc levels. The GG genotype regarding rs562556 polymorphism was associated with higher HDLc in PCOS group, while the AA genotype carriers had higher plasma testosterone levels when evaluated all women in a same group. The results were the same by comparing recessive and dominant model despite PCOS or both groups altogether. Our results suggest that PCSK9 is not altered specifically in PCOS, but it could be associated with in lipid and androgen metabolism in Brazilian women. PMID- 29109006 TI - The rs2292239 polymorphism in ERBB3 gene is associated with risk for type 1 diabetes mellitus in a Brazilian population. AB - The Erb-b2 receptor tyrosine kinase 3 (ERBB3) belongs to a family of epidermal growth factor receptors of protein tyrosine kinases, and regulates cell survival, differentiation and proliferation in several cell types. Previous studies have suggested that ERBB3 contributes to T1DM pathogenesis by modulating antigen presenting cell function, autoimmunity and cytokine-induced beta-cell apoptosis. Accordingly, some genome-wide association studies identified ERBB3 gene as a susceptibility locus for T1DM, with the strongest association signal being observed for the rs2292239 single nucleotide polymorphism (SNP) in intron 7 of the gene. Therefore, the aim of the present study was to replicate the association of the ERBB3 rs2292239 SNP with T1DM in a Brazilian population. We analyzed 421 T1DM patients (cases) and 510 nondiabetic subjects (controls). All subjects were self-declared as white. The ERBB3 rs2292239 (A/C) SNP was genotyped by real-time PCR using TaqMan MGB probes. Genotype (P=0.001) and allele (P=0.002) frequencies of the ERBB3 rs2292239 SNP were differently distributed between T1DM patients and nondiabetic controls. Moreover, the A allele was significantly associated with risk for T1DM when considering recessive (OR=1.58, 95% CI 1.11 2.27; P=0.015), additive (OR=1.78, 95% CI 1.21-2.62; P=0.004), and dominant (OR=1.39, 95% CI 1.07-1.81; P=0.016) models of inheritance. However, after adjustment for presence of high-risk HLA DR/DQ genotypes, the rs2292239 SNP remained independently associated with T1DM only for the additive model (OR=1.62, 95% CI 1.02-2.59; P=0.043). Our results suggest that the A/A genotype of the ERBB3 rs2292239 SNP is associated with risk for T1DM in a white Brazilian population. PMID- 29109007 TI - Roles of DEK in the endometrium of mice in early pregnancy. AB - Embryo implantation is a complex process requiring reciprocal interactions between implantation-competent blastocysts and receptive uteri. Accumulating evidence from Digital Protein Expression Profiling indicates that DEK protein expression at implantation sites (ISs) was much higher than that at inter implantation sites (IISs). In this study, we investigated the expression of DEK in mouse uterus by immunohistochemistry (IHC), Western blotting. We explored its function during decidualization of uterine stromal cells by inhibiting the expression of DEK. In further study of mechanism, the cell proliferation, apoptosis and DNA damage were detected after inhibiting DEK during decidualization of stromal cells. The results suggest that DEK participates in decidualization of stromal cells through mediating cell proliferation, apoptosis and DNA repair. PMID- 29109008 TI - The pathogenic gene screening in a Chinese familial dilated cardiomyopathy pedigree from Hubei. AB - Dilated cardiomyopathy arises from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. In this study, we report a Chinese family with two members affected by TTN. Blood samples were collected from all family members. Genomic DNA was isolated from blood, and all coding exons and adjacent intronic sequences of the TTN gene were examined for mutation analysis using polymerase chain reaction (PCR)-based sequencing. The proband (III3) and his sister (III2) carry a TTN c.100126A>G (p.Thr33376Ala) missense mutation. The proband currently exhibits decreased cardiac function accompanied by malignant arrhythmia, and his sister has no obvious clinical symptoms and no abnormal ultrasound findings. The study found that there is a missense mutation in the TTN gene, c.100126A>G (p.Thr33376Ala), in a family whose members suffer from familial dilated cardiomyopathy in Hubei province. TTN is closely related to dilated cardiomyopathy and is an important causative gene of familial dilated cardiomyopathy. PMID- 29109009 TI - Rapid optimized flow cytometric crossmatch (FCXM) assays: The Halifax and Halifaster protocols. AB - The flow cytometric crossmatch (FCXM) assay, which detects the presence of donor specific HLA antibodies in patient sera, is a cornerstone of HLA compatibility testing. Since relatively long FCXM assay turnaround times may contribute to transplant delays and increased graft ischemia time, we developed and validated two modified crossmatch procedures, namely the Halifax and Halifaster FCXM protocols. These protocols reduce FCXM assay time >60% and simplify their set-up without compromising quality or sensitivity. Optimization of the FCXM (the Halifax protocol) includes a 96-well tray platform, reduced wash times, increased serum to cell suspension volume ratio, shortened incubations and higher incubation temperature. The Halifaster protocol is a further modification, employing methods that improve lymphocyte purity compared to density gradient centrifugation (96 +/- 2.63% vs 69 +/- 19.06%), reduce cell isolation time (by ~40%) and conserve FCXM assay reagents. Importantly, linear regression analysis of the median channel fluorescence shift (MCFS) values revealed excellent concordance (R2 of 0.98-0.99) among all three FCXM protocols (standard vs Halifax vs Halifaster). Finally, a retrospective review of 2013 crossmatches performed using the Halifax protocol demonstrated excellent correlation with the virtual crossmatch (95.7% and 96.8% specificity and sensitivity, respectively) regarding the identification of donor specific antibodies (HLA-A/B/DR) assigned based on the single antigen bead (SAB) assay testing with a 2000 mean fluorescence intensity (MFI) cutoff. Implementation of the Halifax or Halifaster protocols will expedite pre-transplantation work-up and improve patient care. PMID- 29109010 TI - A novel isothermal amplification-based method to detect Mycobacterium tuberculosis complex. AB - Mycobacterium tuberculosis (MTB) is the causative agent of pulmonary tuberculosis. Rapid and accurate diagnosis is crucial to tuberculosis control and prevention. A series of diagnostic methods has been available for MTB detection; however, new rapid, simple and affordable methods are needed. In this study, a multiple cross displacement amplification (MCDA)-based assay was developed to detect the IS6110 gene of the M. tuberculosis complex. Hydroxy naphthol blue (HNB), a colorimetric indicator, was used to detect amplification products. Amplification was carried out at a constant temperature (68 degrees C) for only 40min, followed by direct determination of amplification products through observation of color variations. The entire detection procedure, from processing of specimens to reading of results, required only 85min. Moreover, this assay, hereafter designated MTB-MCDA-HNB, was able to detect as little as 1pg of DNA extracted from the Bacille Calmette-Guerin (BCG) strain of Mycobacterium bovis. No cross-reaction with nontuberculous mycobacteria (NTM) species was observed. Moreover, during testing of clinical samples, the sensitivity and specificity of MCDA results were 94.7% and 92.9%, respectively, when compared to results obtained using the Xpert MTB/RIF method. Therefore, the MTB-MCDA-HNB method developed in this study holds promise for application as an effective point-of care test to detect M. tuberculosis. PMID- 29109011 TI - A temperature-sensitive replicon enables efficient gene inactivation in Pseudomonas aeruginosa. AB - Tools to enable genome editing are essential for understanding physiology. Here we report a gene replacement method in Pseudomonas aeruginosa using a temperature sensitive replicon plasmid that does not require mating or isolation of a merodiploid intermediate. This approach was validated by replacing the non essential ampD gene with a gentamicin resistance cassette. In addition lpxA and lpxD, both located in a complex gene cluster including multiple downstream essential genes, were inactivated when complemented by each target gene in trans. These strains did not grow when expression of the gene in trans was repressed, confirming that both genes are essential for viability. This method facilitates efficient gene inactivation in P. aeruginosa. PMID- 29109012 TI - Ninety six well microtiter plate as microbioreactors for production of itaconic acid by six Aspergillus terreus strains. AB - Itaconic acid (IA) is a building block platform chemical that is currently produced industrially from glucose by fermentation with Aspergillus terreus. However, lignocellulosic biomass has the potential to serve as low cost source of sugars for production of IA. Previously, 100 A. terreus strains were evaluated for production of IA from pentose sugars in shake-flasks. Six selected strains were then investigated for IA production in shake-flasks. But none of the strains grew and produced IA using biomass hydrolyzates. In order to study the factors inhibiting fungal growth and IA production, we have evaluated these six strains for sugar utilization and IA production from glucose, xylose, arabinose, mixed sugars, and both dilute acid and liquid hot water pretreated wheat straw hydrolyzates in microtiter plate (MTP) microbioreactors at 100MUL scale. The results clearly indicate that MTP is very useful as a convenient, reliable and affordable platform to investigate the reasons for inhibition of growth and IA production by the A. terreus strains and should greatly aid in strain development and optimization of IA production by the fungal strains. PMID- 29109013 TI - A decompositional analysis of firearm-related mortality in the United States, 2001-2012. AB - Prior literature reporting increased rates of firearm-related homicide and suicide with increasing firearm availability is limited by only examining the availability of firearms, which is only one component of firearm-related mortality. The objective of the current study is to separate the rates into their respective components and determine which components contribute to mortality rate changes. To address the objective, nationally representative data from 2001 to 2012 was collected from a variety of publicly-available sources. Utilizing decompositional methodology, a negative binomial regression was used to estimate rate ratios for the association between the components and year category, and relative contributions of each component were calculated. From 2001 to 2012, the homicide and unintentional mortality rate decreased while the suicide rate increased. The suicide rate was only the firearm prevalence rate. The unintentional mortality rate was a factor of firearm prevalence, injury incidence, and case fatality rate. The homicide rate was a factor of firearm prevalence, violent crime rate, injury incidence, and case fatality rate. The current results suggest that the contributors of changes in firearm-related mortality are multi-faceted. Future studies should perform a decompositional analysis utilizing more granular data to examine whether the currently reported results are true associations or a factor of ecologic fallacy. PMID- 29109014 TI - Can a selfie promote public engagement with skin cancer? AB - Social media may provide new opportunities to promote skin cancer prevention, but research to understand this potential is needed. In April of 2015, Kentucky native Tawny Willoughby (TW) shared a graphic skin cancer selfie on Facebook that subsequently went viral. We examined the volume of comments and shares of her original Facebook post; news volume of skin cancer from Google News; and search volume for skin cancer Google queries. We compared these latter metrics after TWs announcement against expected volumes based on forecasts of historical trends. TWs skin cancer story was picked up by the media on May 11, 2015 after the social media post had been shared approximately 50,000 times. All search queries for skin cancer increased 162% (95% CI 102 to 320) and 155% (95% CI 107 to 353) on May 13th and 14th, when news about TW's skin cancer selfie was at its peak, and remained higher through May 17th. Google searches about skin cancer prevention and tanning were also significantly higher than expected volumes. In practical terms, searches reached near-record levels - i.e., May 13th, 14th and 15th were respectively the 6th, 8th, and 40th most searched days for skin cancer since January 1, 2004 when Google began tracking searches. We conclude that an ordinary person's social media post caught the public's imagination and led to significant increases in public engagement with skin cancer prevention. Digital surveillance methods can rapidly detect these events in near real time, allowing public health practitioners to engage and potentially elevate positive effects. PMID- 29109015 TI - Factors associated with participation in colorectal cancer screening in Australia: Results from the 45 and Up Study cohort. AB - The Australian Government's National Bowel Cancer Screening Program (NBCSP) was introduced in 2006 to provide free home-based immunochemical faecal occult blood test (iFOBT) to eligible Australians turning 55 and 65years in that year. With the gradual inclusion of additional age cohorts, the rollout of the NBCSP is being implemented in the context of a degree of opportunistic or de facto screening. This study investigated factors associated with self-reported ever uptake of the NBCSP and of any CRC screening using follow-up questionnaire data from 105,897 Australians aged >=45years enrolled in the 45 and Up Study in New South Wales, Australia. Of the 91,968 study participants with information on CRC screening behaviour, 70,444 (76.6%) reported ever-uptake of any CRC screening. 63,777 study participants were eligible for a NBCSP invitation, of these 33,148 (52.0%) reported ever-uptake of screening through the NBCSP. Current smoking (RR=0.86, 0.83-0.90), non-participation in breast cancer screening (female) or PSA testing (male) (RR=0.84, 0.81-0.86), poor self-reported health (RR=0.89, 0.86 0.91), lower levels of education (RR=0.91, 0.90-0.93), and not speaking English at home (RR=0.88, 0.85-0.91) were associated with reduced ever-uptake of screening within the NBCSP and of any CRC screening. Individuals with a family history of CRC were less likely to screen through the NBCSP (RR=0.71, 0.69-0.73), but more likely to participate in any CRC screening (RR=1.18, 1.17-1.19). Smokers, disadvantaged groups and those with non-English speaking backgrounds are less likely to have ever-participated in organised screening through the NBCSP or in any form of CRC screening, supporting efforts to improve participation in these groups. PMID- 29109016 TI - Modifiable predictors of insufficient sleep durations: A longitudinal analysis of youth in the COMPASS study. AB - The purpose of the current study was to simultaneously examine commonly proposed risk and protective factors for sleep deprivation over time among a large cohort of Ontario and Alberta secondary school students. Using 4-year linked longitudinal data from youth in years 1 through 4 (Y1[2012/2013], Y2[2013/2014], Y3[2014/2015], Y4[2015/2016]) of the COMPASS study (n=26,205), the likelihood of students meeting contemporary sleep recommendations was tested based on their self-reported substance use, bullying victimization, physical activity, and homework and screen time. Models controlled for the effect of student-reported gender, race/ethnicity, grade, school clustering, and all other predictor variables. Relative to baseline, students became less likely to meet the sleep recommendations if at follow-up they had initiated binge drinking, experienced cyber bullying victimization, or were spending more time doing homework, with other factors held constant. The likelihood of reporting sufficient sleep increased if students had begun engaging in resistance training at least three times a week. No longitudinal effect was observed when students increased their caffeine consumption (energy drinks, coffee/tea), initiated cannabis or tobacco use, experienced other forms of bullying victimization (physical, verbal, or belongings), engaged in more moderate-vigorous physical activity, or increased their screen use of any type. Few of the commonly purported modifiable risk and protective factors for youth sleep deprivation held in multinomial longitudinal analyses. Causal conclusions appear premature, with further research required to confirm the targets likely to be most effective in assisting more youth in meeting the sleep recommendations. PMID- 29109017 TI - Apoptosis in infection. AB - Apoptosis is one of the principal responses that human cells have at their disposal when faced with changes in their environment. Microbial infection is a massive challenge to a cell, and it is unsurprising that the apoptosis apparatus has been implicated in numerous infections. However, looking at the available data, the impression is one of bewildering complexity. Microbial proteins and other molecules that are often poorly understood interact, with uncertain specificity, with host cell components of varying function, triggering signalling pathways that are ambiguously linked to the apoptotic machinery. Accordingly, many pathogens have been found in different studies both to induce and to inhibit apoptosis. I will here try to present some of the principles of apoptosis and of infection, and to provide a viewpoint on the question how the two are linked. I will further give the reasons for my personal opinion that apoptosis-induction is in most infections beneficial to the host. PMID- 29109018 TI - Effect of Mycobacterium tuberculosis infection on adipocyte physiology. AB - Tuberculosis (TB) remains as a major threat to human health worldwide despite of the availability of standardized antibiotic therapy. One of the characteristic of pathogenic Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis is its ability to persist in the host in a dormant state and develop latent infection without clinical signs of active disease. However, the mechanisms involved in bacterial persistence and the establishment of latency is not well understood. Adipose tissue is emerging as an important niche that favors actively replicating as well as dormant Mtb during acute and latent infection. This also suggests that Mtb can disseminate from the lungs to adipose tissue during aerosol infection and/or from adipose tissue to lungs during reactivation of latent infection. In this study, we report the interplay between key adipokine levels and the dynamics of Mtb pathogenesis in the lungs and adipose tissue using a rabbit model of pulmonary infection with two clinical isolates that produce divergent outcome in disease progression. Results show that markers of adipocyte physiology and function were significantly altered during Mtb infection and distinct patterns of adipokine expression were noted between adipose tissue and the lungs. Moreover, these markers were differentially expressed between active disease and latent infection. Thus, this study highlights the importance of targeting adipocyte function as potential target for developing better TB intervention strategies. PMID- 29109019 TI - Quantifying rotavirus kinetics in the REH tumor cell line using in vitro data. AB - Globally, rotavirus is the most common cause of diarrhea in children younger than 5 years of age, however, a quantitative understanding of the infection dynamics is still lacking. In this paper, we present the first study to extract viral kinetic parameters for in vitro rotavirus infections in the REH cell tumor line. We use a mathematical model of viral kinetics to extract parameter values by fitting the model to data from rotavirus infection of REH cells. While accurate results for some of the parameters of the mathematical model were not achievable due to its global non-identifiability, we are able to quantify approximately the time course of the infection for the first time. We also find that the basic reproductive number of rotavirus, which gives the number of secondary infections from a single infected cell, is much greater than one. Quantifying the kinetics of rotavirus leads not only to a better understanding of the infection process, but also provides a method for quantitative comparison of kinetics of different strains or for quantifying the effectiveness of antiviral treatment. PMID- 29109020 TI - An immortalized microglial cell line (Mocha) derived from rat cochlea. AB - Microglia are glial-immune cells that are essential for the function and survival of the central nervous system. Microglia not only protect neural tissues from immunological insults, but also play a critical role in neural development and repair. However, little is known about the biology of microglia in the cochlea, the auditory portion of the inner ear. In this study, we detected TMEM119+, CD11b+, CD45+ and Iba1+ populations of cells in the rat cochlea, particularly in Rosenthal's canal, inner sulcus and stria vascularis. Next, we isolated and enriched the population of CD11b+ cells from the cochlea and immortalized these cells with the 12S E1A gene of adenovirus in a replication-incompetent retroviral vector to derive a novel microglial cell line, designated Mocha (microglia of the cochlea). The resulting Mocha cells express a number of markers consistent with microglia and respond to lipopolysaccharide (LPS) stimulation by upregulation of genes (Cox2, ICAM-1, Il6r, Ccl2, Il13Ra and Il15Ra) as well as releasing cytokines (IL-1beta, IL-12, IL-13 and RANTES). As evidence of microglial function, Mocha cells phagocytose fluorescent beads at 37 degrees C, but not at 4 degrees C. The expression pattern of microglial markers in Mocha cells suggests that immortalization leads to a more primitive phenotype, a common phenomenon in immortalized cell lines. In summary, Mocha cells display key characteristics of microglia and are now available as a useful model system for the study of cochlear microglial behavior, both in vitro and in vivo. PMID- 29109021 TI - Renal organic anion transporters in drug-drug interactions and diseases. AB - The kidney plays a vital role in maintaining systemic homeostasis. Active tubular secretion and reabsorption, which are mainly mediated by transporters, is an efficient mechanism for retaining glucose, amino acids, and other nutrients and for the clearance of endogenous waste products and xenobiotics. These substances are recognized by uptake transporters located in the basolateral and apical membranes of renal proximal tubule cells and are extracted from plasma and urine. Organic anion transporters (OATs) belong to the solute carrier (SLC) 22 superfamily and facilitate organic anions across the plasma membranes of renal proximal tubule cells. OATs are responsible for the transmembrane transport of anionic and zwitterionic organic molecules, including endogenous substances and many drugs. The alteration in OAT expression and function caused by diseases, drug-drug interactions (DDIs) or other issues can thus change the renal disposition of substrates, induce the accumulation of toxic metabolites, and lead to unexpected clinically outcome. This review summarizes the recent information regarding the expression, regulation, and substrate spectrum of OATs and discusses the roles of OATs in diseases and DDIs. These findings will enables us to have a better understanding of the related disease therapy and the potential risk of DDIs mediated by OATs. PMID- 29109022 TI - Electrically controlled release of ibuprofen from conductive poly(3 methoxydiphenylamine)/crosslinked pectin hydrogel. AB - The pristine pectin hydrogels and conductive polymer/hydrogel blends were prepared by the solution casting using ferrous chloride (FeCl2) and citric acid as the crosslinking agents, and ibuprofen as the model drug and the doping agent. A conductive polymer, poly(3-methoxydiphenylamine), was successfully synthesized and embedded into the pristine pectin hydrogels as the drug encapsulation host. The in-vitro release of ibuprofen from the hydrogels was investigated by a modified Franz diffusion cell filled with a MES buffer solution, with pH of 5.5, at 37 degrees C, for a period of 48h to investigate the effects of the crosslinking agent type, crosslinking mole ratio, mesh size, electric potential, and conductive polymer. The release behavior of ibuprofen from the pectin hydrogels was found to involve 4 modes of release: Fickian diffusion; Anomalous transport; Case-II transport; and Super case II transport. The diffusion coefficient was shown to be significantly improved by two factors: using a FeCl2 as the crosslinking agent and applied electric potential. For both crosslinking agents, the drug diffusion coefficient increased with decreasing crosslinking ratio. Under electric field of 5V, the drug diffusion coefficients of the FeCl2 and citric acid hydrogels were enhanced by more than a factor of two due to the electro-repulsive interaction between ibuprofen and the negatively charged electrode. Moreover, the synthesized poly(3-methoxydiphenylamine) embedded in the pectin hydrogels as the drug encapsulation host was shown to enhance the diffusion coefficients and to reduce the overall release times. PMID- 29109023 TI - Influence of physical activity on tibial bone material properties in laying hens. AB - Laying hens develop a type of osteoporosis that arises from a loss of structural bone, resulting in high incidence of fractures. In this study, a comparison of bone material properties was made for lines of hens created by divergent selection to have high and low bone strength and housed in either individual cages, with restricted mobility, or in an aviary system, with opportunity for increased mobility. Improvement of bone biomechanics in the high line hens and in aviary housing was mainly due to increased bone mass, thicker cortical bone and more medullary bone. However, bone material properties such as cortical and medullary bone mineral composition and crystallinity as well as collagen maturity did not differ between lines. However, bone material properties of birds from the different type of housing were markedly different. The cortical bone in aviary birds had a lower degree of mineralization and bone mineral was less mature and less organized than in caged birds. These differences can be explained by increased bone turnover rates due to the higher physical activity of aviary birds that stimulates bone formation and bone remodeling. Multivariate statistical analyses shows that both cortical and medullary bone contribute to breaking strengthThe cortical thickness was the single most important contributor while its degree of mineralization and porosity had a smaller contribution. Bone properties had poorer correlations with mechanical properties in cage birds than in aviary birds presumably due to the greater number of structural defects of cortical bone in cage birds. PMID- 29109024 TI - AMPK regulates immunometabolism in sepsis. AB - Sepsis and septic shock remain challenging for intensive care units worldwide and have limited treatment options; therefore, identification of targetable key players in systemic inflammation and multiple organ failure is urgently needed. Here, we show that AMP-activated protein kinase (AMPK) is a negative regulator of bioenergetic reprogramming in immune cells and suppresses sepsis development in vivo. Mechanistically, AMPK deficiency increases pyruvate kinase isozyme M2 (PKM2)-dependent aerobic glycolysis, which leads to the release of high mobility group box 1 (HMGB1, a late mediator of lethal systemic inflammation) in macrophages and monocytes. Consequently, activation of AMPK by A-769662 protects whereas depletion of AMPKalpha in myeloid cells promotes endotoxic shock and polymicrobial sepsis in mice. Additionally, administration of the PKM2 inhibitor shikonin reduces lactate production, HMGB1 release, and septic death in AMPKalpha deficient mice. These findings suggest that disruption of the AMPK-dependent immunometabolism pathway may contribute to sepsis development and hence constitute a target for therapeutic intervention. PMID- 29109025 TI - Fish oil feeding attenuates neuroinflammatory gene expression without concomitant changes in brain eicosanoids and docosanoids in a mouse model of Alzheimer's disease. AB - BACKGROUND: Neuroinflammation is a recognized hallmark of Alzheimer's disease, along with accumulation of amyloid-beta plaques, neurofibrillary tangles and synaptic loss. n-3 polyunsaturated fatty acids (PUFA) and molecules derived from them, including eicosapentaenoic acid-derived eicosanoids and docosahexaenoic acid-derived docosanoids, are known to have both anti-inflammatory and pro resolving properties, while human observational data links consumption of these fatty acids to a decreased risk of Alzheimer's disease. Few studies have examined the neuroinflammation-modulating effects of n-3 PUFA feeding in an Alzheimer's disease-related model, and none have investigated whether these effects are mediated by changes in brain eicosanoids and docosanoids. Here, we use both a fat 1 transgenic mouse and a fish oil feeding model to study the impact of increasing tissue n-3 PUFA on neuroinflammation and the production of pro-inflammatory and pro-resolving lipid mediators. METHODS: Fat-1 mice, transgenic animals that can convert n-6 to n-3 PUFA, and their wildtype littermates were fed diets containing either fish oil (high n-3 PUFA) or safflower oil (negligible n-3 PUFA) from weaning to 12 weeks. Animals then underwent intracerebroventricular infusion of either amyloid-beta 1-40 or a control peptide. Hippocampi were collected from non surgery and surgery animals 10 days after infusion. Microarray was used to measure enrichment of inflammation-associated gene categories and expression of genes involved in the synthesis of lipid mediators. Results were validated by real-time PCR in a separate cohort of animals. Lipid mediators were measured via liquid chromatography tandem mass spectrometry. RESULTS: Fat-1 and wildtype mice fed fish oil had higher total hippocampal DHA than wildtype mice fed the safflower oil diet. The safflower-fed mice, but not the fat-1 or fish oil-fed mice, had significantly increased expression in gene ontology categories associated with inflammation in response to amyloid-beta infusion. These effects were independent of changes in the expression of genes involved in the synthesis of eicosanoids or docosanoids in any group. Gene expression was replicated upon validation in the wildtype safflower and fish oil-fed, but not the fat-1 mice. Protectin, maresin and D and E series resolvins were not detected in any sample. There were no major differences in levels of other eicosanoids or docosanoids between any of the groups in response to amyloid-beta infusion. CONCLUSIONS: Fish oil feeding decreases neuroinflammatory gene expression in response to amyloid beta. Neither amyloid-beta infusion or increasing brain DHA affects the brain concentrations of specialized pro-resolving mediators in this model, or the concentrations of most other eicosanoids and docosanoids. PMID- 29109026 TI - A low friction, biphasic and boundary lubricating hydrogel for cartilage replacement. AB - : Partial joint repair is a surgical procedure where an artificial material is used to replace localised chondral damage. These artificial bearing surfaces must articulate against cartilage, but current materials do not replicate both the biphasic and boundary lubrication mechanisms of cartilage. A research challenge therefore exists to provide a material that mimics both boundary and biphasic lubrication mechanisms of cartilage. In this work a polymeric network of a biomimetic boundary lubricant, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), was incorporated into an ultra-tough double network (DN) biphasic (water phase + polymer phase) gel, to form a PMPC triple network (PMPC TN) hydrogel with boundary and biphasic lubrication capability. The presence of this third network of MPC was confirmed using ATR-FTIR. The PMPC TN hydrogel had a yield stress of 26 MPa, which is an order of magnitude higher than the peak stresses found in the native human knee. A preliminary pin on plate tribology study was performed where both the DN and PMPC TN hydrogels experienced a reduction in friction with increasing sliding speed which is consistent with biphasic lubrication. In the physiological sliding speed range, the PMPC TN hydrogel halved the friction compared to the DN hydrogel indicating the boundary lubricating PMPC network was working. A biocompatible, tough, strong and chondral lubrication imitating PMPC TN hydrogel was synthesised in this work. By complementing the biphasic and boundary lubrication mechanisms of cartilage, PMPC TN hydrogel could reduce the reported incidence of chondral damage opposite partial joint repair implants, and therefore increase the clinical efficacy of partial joint repair. STATEMENT OF SIGNIFICANCE: This paper presents the synthesis, characterisation and preliminary tribological testing of a new biomaterial that aims to recreate the primary chondral lubrication mechanisms: boundary and biphasic lubrication. This work has demonstrated that the introduction of an established zwitterionic, biomimetic boundary lubricant can improve the frictional properties of an ultra-tough hydrogel. This new biomaterial, when used as a partial joint replacement bearing material, may help avoid damage to the opposing chondral surface-which has been reported as an issue for other non-biomimetic partial joint replacement materials. Alongside the synthesis of a novel biomaterial focused on complementing the lubrication mechanisms of cartilage, your readership will gain insights into effective mechanical and tribological testing methods and materials characterisation methods for their own biomaterials. PMID- 29109028 TI - Enhancing immunogenicity of antigens through sustained intradermal delivery using chitosan microneedles with a patch-dissolvable design. AB - : Reducing the dosage required for vaccination is highly desirable, particularly in cases of epidemic emergencies. This study evaluated the potential of a chitosan microneedle (MN) system with a patch-dissolvable design for low-dose immunization. This system comprises antigen-loaded chitosan MNs and a hydrophilic polyvinyl alcohol/polyvinyl pyrrolidone supporting array patch, which provides extra strength to achieve complete MN insertion and then quickly dissolves in the skin to reduce patch-induced skin irritation. After insertion, MNs could be directly implanted in the dermal layer as an intradermal (ID) depot to allow a sustained release of the model antigen ovalbumin (OVA) for up to 28 days. We found that rats immunized with MNs containing low-dose OVA (approximately 200 MUg) had persistently high antibody levels for 18 weeks, which were significantly higher than those observed after an intramuscular injection of full-dose OVA (approximately 500 MUg), demonstrating at least 2.5-fold dose sparing. Moreover, OVA-encapsulated chitosan MNs had superior immunogenicity to OVA plus chitosan solution, indicating that MN-based delivery and prolonged skin exposure can further enhance chitosan's adjuvanticity. Therefore, this patch-dissolvable MN system offers a needle-free, accurate, and reliable ID delivery of antigens and has potential as a sustained ID delivery device to improve vaccine efficacy and facilitate dose sparing with existing vaccines. STATEMENT OF SIGNIFICANCE: This study developed implantable chitosan microneedles (MNs) with a patch-dissolvable design for the sustained intradermal (ID) delivery of antigens and demonstrated their antigen dose-sparing potential. We found that rats immunized with chitosan MNs containing low-dose OVA had persistently high antibody levels for 18 weeks, which were significantly higher than those observed after an intramuscular injection of full-dose OVA, demonstrating at least 2.5-fold dose sparing. Our results indicate that chitosan MNs can not only serve as an efficient vaccine delivery system but also exert their promising adjuvant activity by forming an ID depot for prolonged antigen exposure and activating dendritic cells for promoting immune responses. PMID- 29109027 TI - Surface modification of biomaterials and biomedical devices using additive manufacturing. AB - : The demand for synthetic biomaterials in medical devices, pharmaceutical products and, tissue replacement applications are growing steadily due to aging population worldwide. The use for patient matched devices is also increasing due to availability and integration of new technologies. Applications of additive manufacturing (AM) or 3D printing (3DP) in biomaterials have also increased significantly over the past decade towards traditional as well as innovative next generation Class I, II and III devices. In this review, we have focused our attention towards the use of AM in surface modified biomaterials to enhance their in vitro and in vivo performances. Specifically, we have discussed the use of AM to deliberately modify the surfaces of different classes of biomaterials with spatial specificity in a single manufacturing process as well as commented on the future outlook towards surface modification using AM. STATEMENT OF SIGNIFICANCE: It is widely understood that the success of implanted medical devices depends largely on favorable material-tissue interactions. Additive manufacturing has gained traction as a viable and unique approach to engineered biomaterials, for both bulk and surface properties that improve implant outcomes. This review explores how additive manufacturing techniques have been and can be used to augment the surfaces of biomedical devices for direct clinical applications. PMID- 29109029 TI - Transcriptional profile of human macrophages stimulated by ultra-high molecular weight polyethylene particulate debris of orthopedic implants uncovers a common gene expression signature of rheumatoid arthritis. AB - : Osteolysis is a serious postoperative complication of total joint arthroplasty that leads to aseptic loosening and surgical revision. Osteolysis is a chronic destructive process that occurs when host macrophages recognize implant particles and release inflammatory mediators that increase bone-resorbing osteoclastic activity and attenuate bone-formation osteoblastic activity. Although much progress has been made in understanding the molecular responses of macrophages to implant particles, the pathways/signals that initiate osteolysis remain poorly characterized. Transcriptomics and gene-expression profiling of these macrophages may unravel key mechanisms in the pathogenesis of osteolysis and aid the identification of molecular candidates for therapeutic intervention. To this end, we analyzed the transcriptional profiling of macrophages exposed to ultra-high molecular weight polyethylene (UHMWPE) particles, the most common components used in bearing materials of orthopedic implants. Regulated genes in stimulated macrophages were involved in cytokine, chemokine, growth factor and receptor activities. Gene enrichment analysis suggested that stimulated macrophages elicited common gene expression signatures for inflammation and rheumatoid arthritis. Among the regulated genes, tumor necrosis factor superfamily member 15 (TNFSF15) and chemokine ligand 20 (CCL20) were further characterized as molecular targets involved in the pathogenesis of osteolysis. Treatment of monocyte cultures with TNFSF15 and CCL20 resulted in an increase in osteoclastogenesis and bone-resorbing osteoclastic activity, suggesting their potential contribution to loosening between implants and bone tissues. STATEMENT OF SIGNIFICANCE: Implant loosening due to osteolysis is the most common mode of arthroplasty failure and represents a great challenge to orthopedic surgeons and a significant economic burden for patients and healthcare services worldwide. Bone loss secondary to a local inflammatory response initiated by particulate debris from implants is considered the principal feature of the pathogenesis of osteolysis. In the present study, we analyzed the transcriptional profiling of human macrophages exposed to UHMWPE particles and identified a large number of inflammatory genes that were not identified previously in macrophage responses to wear particles. Our data provide a new insight into the molecular pathogenesis of osteolysis and highlights a number of molecular targets with prognostic and therapeutic implications. PMID- 29109030 TI - Layer-by-layer assembly of graphene oxide on thermosensitive liposomes for photo chemotherapy. AB - : Stimuli responsive polyelectrolyte nanoparticles have been developed for chemo photothermal destruction of breast cancer cells. This novel system, called layer by layer Lipo-graph (LBL Lipo-graph), is composed of alternate layers of graphene oxide (GO) and graphene oxide conjugated poly (l-lysine) (GO-PLL) deposited on cationic liposomes encapsulating doxorubicin. Various concentrations of GO and GO PLL were examined and the optimal LBL Lipo-graph was found to have a particle size of 267.9 +/- 13 nm, zeta potential of +43.9 +/- 6.9 mV and encapsulation efficiency of 86.4 +/- 4.7%. The morphology of LBL Lipo-graph was examined by cryogenic-transmission electron microscopy (Cryo-TEM), atomic force microcopy (AFM) and scanning electron microscopy (SEM). The buildup of LBL Lipo-graph was confirmed via ultraviolet-visible (UV-Vis) spectrophotometry, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis. Infra-red (IR) response suggests that four layers are sufficient to induce a gel-to-liquid phase transition in response to near infra-red (NIR) laser irradiation. Light matter interaction of LBL Lipo-graph was studied by calculating the absorption cross section in the frequency domain by utilizing Fourier analysis. Drug release assay indicates that the LBL Lipo-graph releases much faster in an acidic environment than a liposome control. A cytotoxicity assay was conducted to prove the efficacy of LBL Lipo-graph to destroy MD-MB-231 cells in response to NIR laser emission. Also, image stream flow cytometry and two photon microcopy provide supportive data for the potential application of LBL Lipo-graph for photothermal therapy. Study results suggest the novel dual-sensitive nanoparticles allow intracellular doxorubin delivery and respond to either acidic environments or NIR excitation. STATEMENT OF SIGNIFICANCE: Stimuli sensitive hybrid nanoparticles have been synthesized using a layer-by-layer technique and demonstrated for dual chemo-photothermal destruction of breast cancer cells. The hybrid nanoparticles are composed of alternating layers of graphene oxide and graphene oxide conjugated poly-l-lysine coating the surface of a thermosensitive cationic liposome containing doxorubicin as a core. Data suggests that the hybrid nanoparticles may offer many advantages for chemo-photothermal therapy. Advantages include a decrease of the initial burst release which may result in the reduction in systemic toxicity, increase in pH responsivity around the tumor environment and improved NIR light absorption. PMID- 29109031 TI - PGE2 induces apoptosis of hepatic stellate cells and attenuates liver fibrosis in mice by downregulating miR-23a-5p and miR-28a-5p. AB - MicroRNAs (miRNAs), small noncoding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key regulatory molecules in chronic liver diseases, whose end stage is hepatic fibrosis, a major global health burden. Pharmacological strategies for prevention or treatment of hepatic fibrosis are still limited, what makes it necessary to establish a better understanding of the molecular mechanisms underlying its pathogenesis. In this context, we have recently shown that cyclooxygenase-2 (COX-2) expression in hepatocytes restricts activation of hepatic stellate cells (HSCs), a pivotal event in the initiation and progression of hepatic fibrosis. Here, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs on a mouse model of CCl4 and bile duct ligation (BDL)-induced liver fibrosis. Our results provide evidence that COX-2 represses miR-23a-5p and miR-28-5p expression in HSC. The decrease of miR-23a-5p and miR-28-5p expression promotes protection against fibrosis by decreasing the levels of pro-fibrogenic markers alpha-SMA and COL1A1 and increasing apoptosis of HSC. Moreover, we demonstrate that serum levels of miR-28-5p are decreased in patients with chronic liver disease. These results suggest a protective effect exerted by COX-2-derived prostanoids in the process of hepatofibrogenesis. PMID- 29109032 TI - Molecular mechanisms of cardiac pathology in diabetes - Experimental insights. AB - Diabetic cardiomyopathy is a distinct pathology independent of co-morbidities such as coronary artery disease and hypertension. Diminished glucose uptake due to impaired insulin signaling and decreased expression of glucose transporters is associated with a shift towards increased reliance on fatty acid oxidation and reduced cardiac efficiency in diabetic hearts. The cardiac metabolic profile in diabetes is influenced by disturbances in circulating glucose, insulin and fatty acids, and alterations in cardiomyocyte signaling. In this review, we focus on recent preclinical advances in understanding the molecular mechanisms of diabetic cardiomyopathy. Genetic manipulation of cardiomyocyte insulin signaling intermediates has demonstrated that partial cardiac functional rescue can be achieved by upregulation of the insulin signaling pathway in diabetic hearts. Inconsistent findings have been reported relating to the role of cardiac AMPK and beta-adrenergic signaling in diabetes, and systemic administration of agents targeting these pathways appear to elicit some cardiac benefit, but whether these effects are related to direct cardiac actions is uncertain. Overload of cardiomyocyte fuel storage is evident in the diabetic heart, with accumulation of glycogen and lipid droplets. Cardiac metabolic dysregulation in diabetes has been linked with oxidative stress and autophagy disturbance, which may lead to cell death induction, fibrotic 'backfill' and cardiac dysfunction. This review examines the weight of evidence relating to the molecular mechanisms of diabetic cardiomyopathy, with a particular focus on metabolic and signaling pathways. Areas of uncertainty in the field are highlighted and important knowledge gaps for further investigation are identified. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. PMID- 29109033 TI - Predicting and analyzing early wake-up associated gene expressions by integrating GWAS and eQTL studies. AB - Circadian rhythms are endogenous 24-hour rhythmic oscillations affecting human behaviors, such as sleep, blood pressure and other biological processes, the disturbance of which lead to circadian rhythm sleep disorders (CRSDs). In this study, based on the data from genome-wide association studies (GWASs) and expression quantitative trait loci (eQTLs), we tried to identify novel gene expression patterns in brain tissues that were associated with early wake-up. First, the maximum-relevance-minimum-redundancy (mRMR) method was adopted to analyze the involved gene expression patterns, yielding a feature list. Second, the incremental feature selection (IFS) method and the Dagging algorithm were applied to extract important gene expression patterns, which yield the best performance for Dagging. As a result, 4374 gene expression patterns were obtained, and they were further used to build an optimal classifier with a good performance of a Matthews's correlation coefficient of 0.933. Furthermore, the most important 49 gene expression patterns were extensively analyzed. Four genes were found to be related to circadian rhythm, as reported in previous studies. As a first attempt in identifying the target genes whose expression levels are associated with sleep-wake rhythms through integrating GWAS and eQTL results, this study can motivate more investigations in this regard. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. PMID- 29109034 TI - The changing health of Thalidomide survivors as they age: A scoping review. AB - BACKGROUND: In the late 1950s and early 1960s the drug Thalidomide was given to thousands of pregnant women across the world to relieve morning sickness. The drug caused severe birth defects. Much has been written about the drug, its teratogenic effects, and the nature of the damage it caused. There is however, little literature exploring ageing with Thalidomide damage. OBJECTIVES: The aim of the review was to bring together, for the first time, the evidence about the Thalidomide-related health problems Thalidomide survivors are experiencing, as they grow older. METHODS: A systematised review of published and grey literature, in which grounded theory provided a heuristic for the evidence synthesis. RESULTS: Twenty-five relevant papers were found. They included biomedical papers focusing on specific health problems, alongside surveys and mixed method accounts exploring the health of Thalidomide survivors. Most studies had physical health as their primary focus. CONCLUSIONS: The two most frequently reported groups of health problems were musculoskeletal and mental health conditions. There was little discussion about the social consequences of secondary damage being layered onto lifelong impairments or of the implications of co-morbidities. Future research needs a stronger connection to more social models of disability and critical disability studies. PMID- 29109035 TI - "Life behind the mask": Sexual life of Iranian women with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a debilitating and life-long disease that affects the sexual life of people. However, in Iran little attention has been paid to the sexual life of women with MS. OBJECTIVE: The aim of this study was to understand the sexual life and experiences of Iranian women with multiple sclerosis. METHODS: A qualitative study was designed, and face-to-face semi structured interviews were conducted with twenty-five women with MS. The interviews were tape-recorded and transcribed verbatim. Data were analyzed using a content analysis approach and through MAXQDA.10 software. RESULTS: The main themes identified during the analysis were: (1) limited sexual activity, (2) sex life behind the mask, and (3) lack of sexual support during the rehabilitation process. In fact, the participants in this study expressed that their sexual activity was negatively affected by MS. They were trying to hide their sexual problems, and present themselves to their husbands differently from what they are, which can be considered as sex life behind the mask. Furthermore, Iranian women with MS received little sexual support from the rehabilitation team. CONCLUSIONS: Hiding sexual problems from husbands is thought to be a common practice and behavior among Iranian women with MS. Understanding this insight and its consequences can assist the rehabilitation team in helping and solving sexual problems of women with MS. Moreover, sexual awareness and education should be extended, especially among the husbands of women with MS. PMID- 29109036 TI - The role of the P3 and CNV components in voluntary and automatic temporal orienting: A high spatial-resolution ERP study. AB - A main distinction has been proposed between voluntary and automatic mechanisms underlying temporal orienting (TO) of selective attention. Voluntary TO implies the endogenous directing of attention induced by symbolic cues. Conversely, automatic TO is exogenously instantiated by the physical properties of stimuli. A well-known example of automatic TO is sequential effects (SEs), which refer to the adjustments in participants' behavioral performance as a function of the trial-by-trial sequential distribution of the foreperiod between two stimuli. In this study a group of healthy adults underwent a cued reaction time task purposely designed to assess both voluntary and automatic TO. During the task, both post-cue and post-target event-related potentials (ERPs) were recorded by means of a high spatial resolution EEG system. In the results of the post-cue analysis, the P3a and P3b were identified as two distinct ERP markers showing distinguishable spatiotemporal features and reflecting automatic and voluntary a priori expectancy generation, respectively. The brain source reconstruction further revealed that distinct cortical circuits supported these two temporally dissociable components. Namely, the voluntary P3b was supported by a left sensorimotor network, while the automatic P3a was generated by a more distributed frontoparietal circuit. Additionally, post-cue contingent negative variation (CNV) and post-target P3 modulations were observed as common markers of voluntary and automatic expectancy implementation and response selection, although partially dissociable neural networks subserved these two mechanisms. Overall, these results provide new electrophysiological evidence suggesting that distinct neural substrates can be recruited depending on the voluntary or automatic cognitive nature of the cognitive mechanisms subserving TO. PMID- 29109037 TI - Lateralised sleep spindles relate to false memory generation. AB - Sleep is known to enhance false memories: After presenting participants with lists of semantically related words, sleeping before recalling these words results in a greater acceptance of unseen "lure" words related in theme to previously seen words. Furthermore, the right hemisphere (RH) seems to be more prone to false memories than the left hemisphere (LH). In the current study, we investigated the sleep architecture associated with these false memory and lateralisation effects in a nap study. Participants viewed lists of related words, then stayed awake or slept for approximately 90min, and were then tested for recognition of previously seen-old, unseen-new, or unseen-lure words presented either to the LH or RH. Sleep increased acceptance of unseen-lure words as previously seen compared to the wake group, particularly for RH presentations of word lists. RH lateralised stage 2 sleep spindle density relative to the LH correlated with this increase in false memories, suggesting that RH sleep spindles enhanced false memories in the RH. PMID- 29109038 TI - Movements and body ownership: Evidence from the rubber hand illusion after mechanical limb immobilization. AB - There is no consensus on whether, and to what extent, actions contribute to constructing awareness of one's own body. Here we investigated at both physiological and behavioral level whether a prolonged limb immobilization affects body ownership. We tested a group of healthy participants, whose left hand movements were prevented by a cast for one week, and a control group without any movement restriction. In both groups, we measured the strength of the rubber hand illusion (i.e., proprioceptive shift and questionnaire on ownership) and the physiological parameters known to be modulated by short-term arm immobilization (i.e., resting motor threshold, motor evoked potentials and force parameters) before and after the week of immobilization. Our results showed stronger illusory effects on the immobilized hand on both behavioral indexes and weaker illusory effects on the non-immobilized hand on the questionnaire. Additionally, the increased proprioceptive shift was positively correlated to the motor threshold of the contralateral hemisphere. Our findings show at both behavioral and physiological level that altering those movement-related signals which constantly stem from our own body parts, modulates the experience of those body parts as mine. This, in turn, supports the view of a direct role of actions in the developing and maintaining a coherent body ownership. PMID- 29109039 TI - Piperlongumine decreases cell proliferation and the expression of cell cycle associated proteins by inhibiting Akt pathway in human lung cancer cells. AB - Piperlongumine (PL) is an alkaloid of a pepper plant found in Southeast Asia. PL is known to induce selective toxicity towards a variety of cancer cell types. To explore the possible anti-lung cancer effects of PL, A549 cells were treated with PL (0-40 MUM) for 24 h. Alterations in the expression of cell cycle-associated proteins (cyclin D1, cyclin-dependent kinase 4 (CDK4), CDK6 and retinoblastoma (Rb)) and intracellular signaling molecules (extracellular signal receptor activated kinase 1/2 (ERK1/2), Akt, p38 and nuclear factor-kappaB (NF-kappaB)) were examined in cells following treatment of PL using Western blot analysis. Results showed that proliferation of cells were significantly decreased by PL in a dose-dependent manner. Flow cytometry results demonstrated increased number of cells in G1 phase in PL (40 MUM)-treated group. Reactive oxygen species was significantly increased in cells treated with PL at 20-40 MUM. The expression of cyclin D1, CDK4, CDK6 and p-Rb were markedly decreased in cells treated with PL at 40 MUM. Treatment of cells with PL suppressed phosphorylation of Akt but increased ERK1/2 phosphorylation. Treatment of PL significantly decreased nuclear translocation of NF-kappaB p65 in cells. These results suggest that PL possesses antiproliferative properties in A549 cells. PMID- 29109040 TI - Chronic chlorpyrifos exposure elicits diet-specific effects on metabolism and the gut microbiome in rats. AB - Chlorpyrifos is a commonly-used pesticide which was reported to interfere with hormone signaling and metabolism, however, little is known about its effect on gut microbiota. In this study, adult male rats fed a normal (NF) or high fat (HF) diet were exposed to 0.3 or 3.0 mg chlorpyrifos/kg bodyweight/day or vehicle alone for 9 weeks. Effects on bodyweight, serum levels of glucose, lipid, cytokines, and gut microbiome community structure were measured. The effects of chlorpyrifos on metabolism were dose- and diet-dependent, with NF-fed rats administered the low dose showing the largest metabolic changes. NF-fed rats exposed to chlorpyrifos exhibited a pro-obesity phenotype compared with their controls, whereas there was no difference in pro-obesity phenotype between HF-fed groups. Chlorpyrifos exposure significantly reduced serum insulin, C-peptide, and amylin concentrations in NF- and HF-fed rats, leaving serum glucose and lipid profiles unaffected. Chlorpyrifos exposure also significantly altered gut microbiota composition, including the abundance of opportunistic pathogens, short chain fatty acid-producing bacteria and other bacteria previously associated with obese and diabetic phenotypes. The abundance of bacteria associated with neurotoxicity and islet injury was also significantly increased by chlorpyrifos. Our results suggest risk assessments for chlorpyrifos exposure should consider other effects in addition to neurotoxicity. PMID- 29109041 TI - Temporal patterns of caffeine intake in the United States. AB - To investigate whether caffeine intake among adolescents and adults in the U.S. varies across the week or throughout the day, data from a 7-day online beverage consumption survey (2010-2011) were analyzed. Mean (206.8-213.0 mg/day) and 90th percentile (437.4-452.6 mg/day) daily caffeine intakes among consumers 13 years and older were relatively constant across the week with no marked difference among weekdays versus weekend days. Percent consumers of caffeinated beverages likewise remained stable across the week. Mean daily caffeine intake for coffee and energy drink consumers 13 years and older was higher than contributions for tea and carbonated soft drink consumers. Caffeinated beverage consumers (13 + yrs) consumed most of their caffeine in the morning (61% versus 21% and 18% in the afternoon and evening) which was driven by coffee. Caffeinated beverage consumption patterns among adolescents (13-17 yrs) - who typically consume less daily caffeine - were more evenly distributed throughout the day. These findings provide insight into U.S. temporal caffeine consumption patterns among specific caffeinated beverage consumers and different age brackets. These data suggest that while caffeine intakes do not vary from day-to-day, mornings generally drive the daily caffeine intake of adults and is predominantly attributed to coffee. PMID- 29109042 TI - Aldehyde levels in e-cigarette aerosol: Findings from a replication study and from use of a new-generation device. AB - PURPOSE: A recent study identified high aldehyde emissions from e-cigarettes (ECs), that when converted to reasonable daily human EC liquid consumption, 5 g/day, gave formaldehyde exposure equivalent to 604-3257 tobacco cigarettes. We replicated this study and also tested a new-generation atomizer under verified realistic (no dry puff) conditions. DESIGN: CE4v2 atomizers were tested at 3.8 V and 4.8 V, and a Nautilus Mini atomizer was tested at 9.0 W and 13.5 W. All measurements were performed in a laboratory ISO-accredited for EC aerosol collection and aldehyde measurements. RESULTS: CE4v2 generated dry puffs at both voltage settings. Formaldehyde levels were >10-fold lower, acetaldehyde 6-9-fold lower and acrolein 16-26-fold lower than reported in the previous study. Nautilus Mini did not generate dry puffs, and minimal aldehydes were emitted despite >100% higher aerosol production per puff compared to CE4v2 (formaldehyde: 16.7 and 16.5 MUg/g; acetaldehyde: 9.6 and 10.3 MUg/g; acrolein: 8.6 and 11.7 MUg/g at 9.0 W and 13.5 W, respectively). EC liquid consumption of 5 g/day reduces aldehyde exposure by 94.4-99.8% compared to smoking 20 tobacco cigarettes. CONCLUSION: Checking for dry puffs is essential for EC emission testing. Under realistic conditions, new-generation ECs emit minimal aldehydes/g liquid at both low and high power. Validated methods should be used when analyzing EC aerosol. PMID- 29109043 TI - Individual and combined effects of Fusarium toxins on apoptosis in PK15 cells and the protective role of N-acetylcysteine. AB - Deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B1 (FB1) are among the most toxicologically important Fusarium toxins commonly found in nature that lead to nephrotoxicity in animals. The present study investigated that the individual and combined effects of subcytotoxic DON (0.25 MUM), ZEN (20 MUM) and FB1 (10 MUM) on oxidative stress and apoptosis in porcine kidney cells (PK15). In addition, the protective effect of N-acetylcysteine (NAC) against the toxicity of Fusarium toxins was also evaluated. Our results showed that the activities of glutathione reductase (GR) and total superoxide dismutase (SOD) were affected by DON, ZEN and FB1, and this change in activity induced reactive oxygen species (ROS) and malondialdehyde (MDA) production, increased apoptosis and regulated the mRNA expression of Bax, Bcl-2, caspase-3, caspase-9, cytochrome c (cyto c) and P53. This study demonstrated the complexity of combined mycotoxin infection since the combination of toxins exhibited more profound defects in the oxidative stress responses and apoptosis. Moreover, NAC reduced the oxidative damage and inhibited the apoptosis induced by Fusarium toxins. It was concluded that oxidative damage and apoptosis through the mitochondria-dependent channel were the mechanisms of Fusarium toxin mediated toxicity, and NAC reversed these damages to some extent. PMID- 29109044 TI - Target vs non-target analysis to determine pesticide residues in fruits from Saudi Arabia and influence in potential risk associated with exposure. AB - The occurrence of pesticide residues in fruits was determined by a target method for 62 analytes and a wide scope screening method against a database of 500 pesticides. Limits of quantification (LOQs) were from 0.5 to 6.3 MUg kg-1 for the target method and from 0.5 to 119 MUg kg-1 for the non-target. Thirty samples: dates, apples, oranges, tangerines, lemons and grapefruits were selected because their high consumption, except lemons and grapefruits that were to cover all citrus fruits. Using the target method, 15 compounds (mostly insecticides and fungicides) out of 62 pesticides (organophosphorus, carbamates, pyrethroids, chloroacetanilides, triazines, triazoles, imidazoles, etc.) were detected. Residues were in 100% of the samples, 80% contained at or below maximum residue limits (MRLs), and 20% above. Non-target method identified several additional pesticides (cypronil, fludioxonil, boscalid and pyraclostrobin in apples). The highest acute risk were for acrinathrin, chlorpyrifos and imazalil with estimated short-term intake (ESTI) > 100% acute reference dose (ARfD), followed by imidacloprid and thiabendazole with ESTI >= 70% ARfD. The higher chronic risk were for ethion and fluvalinate with estimated daily intakes (EDIs) of 8.8 and 1.5% of the admissible daily intake (ADI), respectively. PMID- 29109045 TI - Identification of the relationship between barriers and facilitators of pharmacist prescribing and self-reported prescribing activity using the theoretical domains framework. AB - BACKGROUND: The scope of pharmacist practice has expanded in many jurisdictions, including Nova Scotia, Canada, to include prescribing of medications. OBJECTIVE: To identify the relationship between barriers and facilitators to pharmacist prescribing and self-reported prescribing activity using the Theoretical Domains Framework version 2 (TDF(v2)). METHODS: The study was a self-administered electronic survey of all registered pharmacists (approximately 1300) in Nova Scotia, Canada. The questionnaire was developed using a consensus process that mapped facilitators and barriers to prescribing with the 14 domains of the TDF(v2). The questionnaire captured information about the type and rate of pharmacists' prescribing activities, pharmacists' perceptions of their prescribing role at the patient, pharmacist, pharmacy organization and health system level, and pharmacist demographics and practice settings. A 5-point Likert scale was used for most TDF(v2) domains. Cronbach's alpha was used to study the internal consistency of responses within each of the TDF(v2) domains and simple logistic regression was used to measure the relationship between TDF(v2) domain responses and self-reported prescribing activity. Open-ended questions were analyzed separately. RESULTS: Eighty-seven pharmacists completed the questionnaire. The majority of respondents were female (70 %), staff pharmacists (52 %) practicing pharmacy for a mean of 18 years. The three domains that respondents most positively associated with prescribing were Knowledge (84 %), Reinforcement (81 %) and Intentions (78 %). The largest effect on prescribing activity was the Skills domain (OR 4.41, 95% CI, 1.34-14.47). CONCLUSIONS: We determined the TDF(v2) domains associated with pharmacist self-reported prescribing behaviours. This understanding can assist the development of policy and program interventions at the pharmacist, pharmacy, and health system levels, to increase the uptake of pharmacist prescribing. Further work is needed to develop and implement interventions based on the domains identified, and to test these in pilot settings and then in large-scale interventions. PMID- 29109046 TI - When Should Infants with Cow's Milk Protein Allergy Use an Amino Acid Formula? A Practical Guide. AB - Cow's milk protein allergy (CMPA) is the most common food allergy in childhood and its prevalence ranges between 1.9% and 4.9%. Most children present with CMPA at age less than 1 year and therefore may require a hypoallergenic formula in the absence of breast milk. Hypoallergenic formulas include both extensively hydrolyzed formula (EHF) and amino acid formula (AAF). For most children with a CMPA, an EHF will be sufficient for symptom resolution, as reflected in current guidelines, but there is a subset of children with CMPA where an AAF may be indicated. The appropriate use of an AAF is a highly debated topic, because there is a significant fiscal burden to either the health care system or the parents. From the literature, the following themes were identified as possible reasons for choosing an AAF: (1) symptoms not fully resolved on EHF, (2) faltering growth/failure to thrive, (3) multiple food eliminations, (4) severe complex gastrointestinal food allergies, (5) eosinophilic esophagitis, (6) food protein induced enterocolitis syndrome, (7) severe eczema, and (8) symptoms while breast feeding. Each of these themes was critically reviewed using all available published data and found that using an AAF in height growth faltering may be indicated. In addition, patients who end up on an AAF often present with multisystem involvement, requiring multiple food eliminations and fall within the more severe spectrum of gastrointestinal allergies. In eosinophilic esophagitis, all current recommendations support the use of an AAF as first-line approach, and in children with anaphylaxis, despite limited evidence an AAF is recommended because of the potential risk for a severe reaction. The use of an AAF in children who are breast-fed remains a highly controversial topic and at all times breast-feeding should be supported in children with CMPA. This article provides a practical guide that is evidence based for health care professionals to the use of AAF. PMID- 29109047 TI - Bioavailability and Cardiovascular Effects of Adrenaline Administered by Anapen Autoinjector in Healthy Volunteers. AB - BACKGROUND: The administration of adrenaline is a life-saving intervention for anaphylactic reactions. However, it has been questioned whether the needle length of the autoinjectors is sufficient to achieve genuine intramuscular delivery and optimal bioavailability. OBJECTIVE: To assess the adequacy of Anapen, which has a relatively short needle length (10.5 mm), through a comparison of the depot localization, plasma pharmacokinetics, and cardiovascular responses of adrenaline delivered via Anapen versus a prefilled syringe with a 25.4-mm needle, which is generally used for intramuscular injections. METHODS: This randomized, open label, crossover study compared the impact of adrenaline administration at 2 sites in the thigh of 18 normal weight male volunteers, using either Anapen or the prefilled syringe; in addition, we studied the treatment of 12 overweight women with Anapen. The depot depth was measured by ultrasonography, plasma adrenaline level was evaluated by ultra performance liquid chromatography-mass spectrometry (UPLC-MS), and heart rates were measured using a Holter monitor. RESULTS: Intramuscular injections were given with both devices at both thigh sites in nonobese men, but not in overweight women. Adrenaline levels showed a double peak, with parallel changes in the heart rate. The first peak, of potential vital importance in anaphylaxis treatment, occurred at approximately 10 minutes postinjection, with maximum concentration and area under the curve significantly higher with Anapen than with prefilled syringes; the magnitude of the second peak did not differ among the various conditions. Unexpectedly, in overweight women treated with Anapen, the magnitude of the first peak was similar to that observed in men, despite the injection being subcutaneous, and the overall bioavailability was enhanced. CONCLUSIONS: Needle length and intramuscular injection are not absolute requirements for autoinjector efficacy, but the monitoring of injection location, biphasic adrenaline levels, and cardiovascular responses is important for the assessment of their therapeutic relevance in anaphylaxis. PMID- 29109048 TI - Increasing hospital presentations for anaphylaxis in the pediatric population in Hong Kong. PMID- 29109049 TI - Combined transcriptomic/proteomic analysis of salivary gland and secreted saliva in three planthopper species. AB - : The planthoppers are piercing-sucking pests that continuously inject saliva into host plants using specialized stylets. However, knowledge on the constituent and function of planthopper saliva proteins was still limited. In this study, the transcriptomic and proteomic approach were adopted to characterize the composition of salivary glands and their secreted saliva in three planthoppers, respectively. Gene repertoires of salivary glands in brown planthopper (Nilaparvata lugens, BPH), white-backed planthopper (Sogatella furcifera, WBPH) and small brown planthopper (Laodelphax striatellus, SBPH) were very similar, which actively involved in protein synthesis and energy metabolism. Comparative analysis of saliva proteome was performed among three planthoppers and other reported insect species. The saliva composition in three planthoppers was diverse, with 55 saliva proteins commonly identified in more than two species. A few proteins, including serine protease, carboxylesterase, aminopeptidase N, lipophorin, elongation factor, carbonic anhydrase, and calcium binding protein were ubiquitous distributed in different insects, indicating conserved function of saliva. While, the majority of saliva proteins were specifically identified in planthoppers, which might be the evolutional adaptation of insects to different hosts. Our work gained insight into the interaction between insect and host plant through salivary approach, and provided a good resource for functional characterization of effectors. BIOLOGICAL SIGNIFICANCE: Secreted saliva from insects is attracting immense research interest on the global level due to the crucial roles in determining the compatibility between the insects and their hosts. The three planthoppers: brown planthopper (Nilaparvata lugens, BPH), small brown planthopper (Laodelphax striatellus, SBPH), and white-backed planthopper (Sogatella furcifera, WBPH) caused serious damage to rice plants throughout Asia. However, knowledge on the composition and function of their secreted saliva proteins was limited. Our study characterizes the global gene expression of salivary glands and their secreted saliva by Illumina sequencing technology and LC-MS/MS analysis, respectively. By comparative analysis, the ubiquitous and specific saliva compounds in different insects were unveiled. PMID- 29109050 TI - Egg structure and outline of embryonic development of the basal mantodean, Metallyticus splendidus Westwood, 1835 (Insecta, Mantodea, Metallyticidae). AB - The egg structure and outline of the embryonic development of Metallyticus splendidus of one of the basal Mantodea representatives, Metallyticidae, were described in the present study. The results obtained were compared with those from the previous studies, to reconstruct and discuss the groundplan of Mantodea and Dictyoptera. In M. splendidus, the egg is spheroidal, it has a convex ventral side at the center in which numerous micropyles are grouped, and it possesses a conspicuous hatching line in its anterior half. These are the groundplan features of mantodean eggs and the "grouped micropyles in the ventral side of the egg" are regarded as an apomorphic groundplan feature of Dictyoptera. A small circular embryo is formed by a simple concentration of blastoderm cells, which then undergoes embryogenesis of the typical short germ band type. Blastokinesis is of the "non-reversion type" and the embryo keeps its original superficial position and original orientation throughout embryonic development. During the middle stages of development, the embryo undergoes rotation around the egg's anteroposterior axis. These features are a part of the groundplan of Mantodea. It is uncertain whether sharing of the "non-reversion type" of blastokinesis by Mantodea and blaberoidean Blattodea can be regarded as homology or homoplasy. PMID- 29109051 TI - Evolving Concepts in the Management of Retinopathy of Prematurity. AB - PURPOSE: The introduction of anti-vascular endothelial growth factor (VEGF) agents has stimulated considerable reexamination of treatment strategies for the management of retinopathy of prematurity (ROP). Herein we summarize and review evolving concepts and provide a personal perspective on clinical management today and future directions of treatment. DESIGN: Literature review. METHODS: To synthesize the evolving management concepts for diagnosis and treatment of retinopathy of prematurity and to provide interpretation and perspective on current emerging therapies. RESULTS: Although initial treatment strategies focused on ablative therapy for threshold ROP, earlier treatment for type 1 or pre-threshold disease has been found to decrease unfavorable visual and structural outcomes. Vascular endothelial growth factor has emerged as a significant contributor to retinal-vascular diseases in the previous 2 decades. The potential role of anti-VEGF treatment for type 1 ROP has become a focus in recent years, but the protracted recurrence of disease and unknown adverse ocular and systemic effects have caused concern from some clinicians. In addition, the use of telemedicine technologies may provide the ability to screen remote areas with a shortage of ROP providers, thereby reducing the burden of disease. CONCLUSIONS: The diagnosis and management of ROP has changed over the past 40 years; the role of anti-VEGF therapy remains to be established in current treatment strategies. Screening for initial disease and progression will likely be impacted by the increasing prevalence of telemedicine and relative shortage of clinicians. PMID- 29109052 TI - Magnetic resonance imaging with RF encoding on curved natural slices. AB - While the idea of using spatial encoding fields (SEM) for image formation has been proven, conventional wisdom still holds that a magnetic resonance imaging (MRI) system begins with a highly uniform magnetic field. In particular, radio frequency (RF) encoding MRIs designed and tested to date have largely used uniform magnetic fields. Here we demonstrate magnetic resonance imaging in a magnetic field with a built-in gradient that gives non-planar slices - curved surfaces - when the nuclear spins are excited with narrow band RF pulses. Image encoding on these naturally occurring non-planar slices was accomplished with RF encoding using a non-linear spatially varying B1 phase gradient. The imaging methods were demonstrated on a small prototype MRI instrument. The MRI has no switched magnetic field gradients - it is "gradient-free". A low field gradient free MRI with low mass permanent magnets and simple, low power, RF encoding hardware is ideal for deployment on the International Space Station for the study of astronaut muscle and bone mass loss. Gradient-free natural slice encoding MRI designs would also be portable enough for application in remote terrestrial locations, in emergency rooms and in operating rooms where they can be used with minimally invasive and robotic surgery. PMID- 29109053 TI - Quantitative assessment of liver function with whole-liver T1rho mapping at 3.0T. AB - OBJECTIVES: To assess the segmental liver function in healthy subjects and liver cirrhosis (LC) patients with different Child-Pugh grades using whole-liver T1rho mapping at 3.0T. METHODS: Thirty-three healthy volunteers and 33 patients with clinically diagnosed LC were examined using a three-dimensional (3D) whole-liver coverage T1rho mapping. T1rho maps were calculated from five respiratory triggered sequences with different spin-lock durations (0, 10, 20, 40, and 60ms). The patients were classified into group A with Child-Pugh A cirrhosis and group B with Child-Pugh B or C cirrhosis. The hepatic T1rho values in different segments of the healthy volunteers and LC patients were compared, and receiver operating characteristic curves (ROC) were plotted to determine the performance of T1rho. RESULTS: The median T1rho value of the patients (Child-Pugh class A: 47.07ms; Child-Pugh classes B and C: 51.09ms) was significantly higher than that of the healthy volunteers (39.37ms, P<0.001). No remarkable variations among different hepatic segments in LC patients with various Child-Pugh grades were found (P>0.05). The T1rho values of the liver parenchyma were significantly correlated with albumin (r=-0.590, P<0.001) and prothrombin time (r=0.601, P<0.001). The T1rho values in patients increased with an increase in the Child-Pugh classification (r=0.574, P<0.001). CONCLUSIONS: The whole-liver coverage T1rho sequence at 3.0T was feasible for the assessment of segmental liver function. T1rho relaxation might be a potential biomarker for the estimation of liver function in LC patients. PMID- 29109054 TI - Assessing the presence of marine toxins in bivalve molluscs from southwest India. AB - The south west coast of India has been showing a steady increase in shellfish cultivation both for local consumption and fishery export, over recent years. Perna viridis and Crassostrea madrasensis are two species of bivalve molluscs which grow in some selected regions of southern Karnataka, close to the city of Mangalore. In the early 1980s, shellfish consumers in the region were affected by intoxication from Paralytic Shellfish Poison present in local bivalves (clams and oysters) resulting in hospitalisation of many, including one fatality. Since then, there have been no further reports of serious shellfish intoxication and there is little awareness of the risks from natural toxins and no routine monitoring programme in place to protect shellfish consumers. This study presents the findings from the first ever systematic assessment of the presence of marine toxins in mussels and oysters grown in four different shellfish harvesting areas in the region. Shellfish were collected and subjected to analysis for ASP, PSP and lipophilic toxins, as well as a suite of non-EU regulated toxins such as tetrodotoxin and selected cyclic imines. Results revealed the presence of low levels of PSP toxins in oysters throughout the study period. Overall, total toxicities reached a maximum of 10% of the EU regulatory limit of 800 MUg STX eq/kg. Toxin profiles were similar to those reported from the 1980 outbreak. No evidence was found for significant levels of ASP and lipophilic toxins, although some cyclic imines were detected, including gymnodimine. The results indicated that the risk to shellfish consumers during this specific study period would have been low. However, with historical evidence for extremely high levels of PSP toxins in molluscs, there is a strong need for routine surveillance of shellfish production areas for marine toxins, in order to mitigate against human health impacts resulting from unexpected harmful algal blooms, with potentially devastating socio-economic consequences. PMID- 29109055 TI - Characterization of oromotor and limb motor dysfunction in the DJ1 -/- model of Parkinson disease. AB - Parkinson disease (PD) is devastating to sensorimotor function that includes cranial/oromotor and limb motor deficits. However, the onset, progression, and neural correlates of PD-related dysfunctions are poorly understood. To address this gap, we used a genetic rat model of PD, DJ1 -/-, and hypothesized that motor deficits would manifest early in the disease process, be progressive in nature, and be related to pathologies in brainstem structures associated with sensorimotor function. The present study compares homozygous DJ1 -/- male rats to age-matched wild type controls. Progressive cranial sensorimotor function (ultrasonic vocalizations and tongue motor performance) and limb motor function (tapered balance beam) was analyzed at 2, 4, 6, and 8 months of age. Additionally, tyrosine hydroxylase cell counts were performed in the locus coeruleus and correlated to behavioral measures. We found that compared to wild type controls, DJ1 -/- show deficits in ultrasonic vocalizations as well as oromotor (tongue) deficits that were progressive. Overtime, DJ1 -/- rats cross a tapered balance beam with significantly decreased speed of traversal. Additionally, in the DJ1 -/-, tyrosine hydroxylase positive cells in the locus coeruleus are significantly reduced and are negatively correlated to oromotor behaviors. Characterizing the DJ1 -/- model of PD provides important foundational work necessary to define behavioral and early-onset biomarkers that parallels early-stage PD pathology in humans. PMID- 29109056 TI - SOD2 gene polymorphism may modulate biochemical responses to a 12-week swimming training. AB - The aim of the study was to analyze the effect of SOD2 Val16Ala polymorphism on blood biochemical response to chronic swimming training. Healthy men (students of physical education) participated in a swimming training program (ST group) or served as a control group (CON group). The swimming training program lasted 12 weeks (1.5h per day; 4 days per week). Fasting blood samples were obtained prior to (pre) and after (post) a 12-week study period, to measure the biomarkers of oxidative stress, muscle damage and lipid profile. No significant changes in the study parameters were documented in CON group after a 12-week study period, either overall or among carriers of specific SOD2 Val16Ala genotypes. In ST group, post-training decrease in serum lipid hydroperoxides (p < 0.05) and creatine kinase activity (p < 0.05) was associated with Ala/Ala genotype of SOD2 Val16Ala polymorphism. In turn, the increase in serum activity of superoxide dismutase (p < 0.05) was associated with Val carriers, and Val/Val genotype additionally predisposed to the post-training increase in total glutathione level in whole blood (p < 0.05). Moreover, in ST group, a 12-week swimming training program induced an increase in serum concentration of total cholesterol (p < 0.05), which resulted from an increase in both high density (p < 0.05) and low density lipoprotein cholesterol (p < 0.05). The change in high density lipoprotein cholesterol level was irrespective of the genotype. Also, a tendency to post-training increase in both total and low density lipoprotein cholesterol was observed in all three genotypes, although these changes were significant solely in Ala/Val genotype carriers (p < 0.05). In conclusion, 12-week swimming training induces changes in oxidative stress and muscle damage parameters, as well as in lipid profile. These changes seem to be associated with the presence of SOD2 Val16Ala polymorphism. Presence of Ala allele, especially as homozygote, is associated with some beneficial post-training changes, such as a decrease in lipid peroxidation and less pronounced muscle damage. In turn, the influence of SOD2 Val16Ala polymorphism on the changes in lipid profile in response to chronic swimming training should be verified in further study. PMID- 29109057 TI - Bronchopleural Fistula After Pneumonectomy: Risk Factors and Management, Focusing on Open-Window Thoracostomy. AB - We evaluated principal risk factors and different therapeutic approaches for post pneumonectomy bronchopleural fistula (BPF), focusing on open-window thoracostomy (OWT). We retrospectively reviewed all patients treated by pneumonectomy for lung cancer from 1999 to 2014; we evaluated preoperative, operative, and postoperative data; time between operation; and fistula formation, size, treatment, and predicting factors of BPF. Cumulative incidence curves for the development of BPF were drawn according to the Kaplan-Meier method. Differences between groups were assessed with the log rank test. Multivariable Cox proportional hazards regression analysis was used to assess the independent risk factors for BPF. P values <0.05 were considered significant. BPF occurred in 60 of 733 patients (8.2%). Bronchial suture with Stapler (EndoGia) (P = 0.02), right side (P = 0.003), and low preoperative albumin levels (< 3.5 g/dL) (P = 0.02) were independent predicting factors of fistula. Early BPF was treated by thoracotomic (12) or thoracoscopic (2) debridement of necrotic tissue and BPF surgical repair. Late BPF was treated by bronchoscopic application of fibrin glue (3) or endobronchial stent (1), chest tube and cavity irrigation by povidone-iodine (15). OWT was performed in 27 patients, followed by muscle flap interposition in 7 of these 27. The survival time of patients after the treatment of BPF was 29.0 months. The overall survival of patients treated by OWT was 50% at 2 years and 27 (8%) at 4 years. Correct management of BPF depends on several factors. In case of failure of different initial therapeutic approaches, we could consider OWT, followed by myoplasty. PMID- 29109058 TI - Homer2 within the central nucleus of the amygdala modulates withdrawal-induced anxiety in a mouse model of binge-drinking. AB - A history of binge-drinking decreases protein expression of the glutamate-related scaffolding protein Homer2 within the central nucleus of the amygdala (CEA), coinciding with behavioral signs of negative affect. To assess the functional relevance of this protein change for withdrawal-induced hyper-anxiety, adult (PND 56) and adolescent (PND 28) male C57BL/6J mice were administered an intra-CEA infusion of an adeno-associated viral vector (AAV) carrying either cDNA to express Homer2 (H2-cDNA) or GFP as control. Mice underwent 14 days of binge drinking under multi-bottle, limited-access conditions and were assayed for behavioral signs of negative affect during withdrawal using the light-dark box, marble burying, and forced swim tests (FST). Following behavioral testing, all animals experienced 5 days of drinking to evaluate the effects of prior alcohol experience and Homer2 manipulation on subsequent alcohol consumption. During protracted (4 weeks) withdrawal, adolescent alcohol-experienced GFP controls showed increased signs of negative affect across all 3 assays, compared to water drinking GFP animals, and also showed elevated alcohol consumption during the subsequent drinking period. Homer2-cDNA infusion in adolescent-onset alcohol drinking animals was anxiolytic and reduced subsequent alcohol consumption. Conversely, Homer2-cDNA was anxiogenic and increased drinking in water-drinking adolescents. Unfortunately, the data from adult-onset alcohol-drinking animals were confounded by low alcohol consumption and negligible behavioral signs of anxiety. Nevertheless, the present results provide novel cause-effect evidence supporting a role for CEA Homer2 in the regulation of both basal anxiety and the time-dependent intensification of negative affective states in individuals with a history of binge-drinking during adolescence. PMID- 29109059 TI - Loop F of the GABAA receptor alpha subunit governs GABA potency. AB - Gamma-amino butyric acid (GABA) is an abundant neurotransmitter in the CNS. GABAergic interneurons orchestrate pyramidal neurons in the cerebral cortex, and thus control learning and memory. Ionotropic receptors for GABA (GABAAR) are heteropentameric complexes of alpha, beta and gamma integral membrane-protein subunits forming Cl- -channels operated by GABA, which are vital for brain function and are important drug targets. However, knowledge on how GABAAR bind GABA is controversial. Structural biology versus functional modelling combined with site-directed mutagenesis suggest markedly different roles for loop F of the extracellular domain of the alpha-subunit when complexed with GABA. Here, we report that contrary to the results of structural studies, loop F of the alpha subunit controls the potency of GABA on GABAAR. We examined the effect of replacing a short, variable segment of loop F of the GABAA alpha5-subunit with the corresponding segment of the alpha2-subunit (GABAA5_LF2) and vice versa (GABAA2-LF5). When compared with their respective wild-type counterparts, GABAA5_LF2 receptors displayed enhanced sensitivity towards GABA, whilst in GABAA2-LF5 sensitivity was diminished. Mice homozygous for the genetic knock-in of the GABAA5_LF2 subunit showed a marked deficit in long- but not short-term object recognition memory. Working memory in place learning, spontaneous alternation and the rewarded T-maze were all normal. The deficit in long-term recognition memory was reversed by an alpha5-GABAA negative allosteric modulator compound. The data show that loop F governs GABA potency in a receptor isoform specific manner in vitro. Moreover, this mechanism of ligand recognition appears to be operative in vivo and impacts cognitive performance. PMID- 29109060 TI - Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling. AB - Binge alcohol (ethanol) drinking is associated with profound adverse effects on our health and society. Rimonabant (SR141716A), a CB1 receptor inverse agonist, was previously shown to be effective for nicotine cessation and obesity. However, studies using rimonabant were discontinued as it was associated with an increased risk of depression and anxiety. In the present study, we examined the pharmacokinetics and effects of AM4113, a novel CB1 receptor neutral antagonist on binge-like ethanol drinking in C57BL/6J mice using a two-bottle choice drinking-in-dark (DID) paradigm. The results indicated a slower elimination of AM4113 in the brain than in plasma. AM4113 suppressed ethanol consumption and preference without having significant effects on body weight, ambulatory activity, preference for tastants (saccharin and quinine) and ethanol metabolism. AM4113 pretreatment reduced ethanol-induced increase in dopamine release in nucleus accumbens. Collectively, these data suggest an important role of CB1 receptor-mediated regulation of binge-like ethanol consumption and mesolimbic dopaminergic signaling, and further points to the potential utility of CB1 neutral antagonists for the treatment of binge ethanol drinking. PMID- 29109061 TI - Extraction, fractionation and re-fractionation of Artemisia nilagirica for anticancer activity and HPLC-ESI-QTOF-MS/MS determination. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants used in traditional medicines are affordable, easily accessible, safer, less toxic and considered as a rich or efficient source of bioactive molecules for modern therapeutics. Artemisia nilagirica (AR) has a long history of use in Indian traditional medicine to combat a wide variety of diseases including cancer. AIM OF THE STUDY: Considering the vast potential of traditional healing plants to deliver safer, less toxic and efficient chemotherapeutics, we have examined anticancer activity of ethanolic extract, bioactive fractions and sub-fractions of AR against different human cancer cell lines along with their phytochemical analysis to understand the insights of novel anticancer activities for further preclinical studies. MATERIALS AND METHODS: Fresh plant material of AR was procured from the wild, dried and ground. The grinded materials was extracted in ethanol (AR-01) and fractionated into butanol (AR-02), ethyl acetate (AR-03), hexane (AR-04) and water (AR-05). The cytotoxicity was evaluated against three different human cancer cell lines, i.e. colon (DLD-1), lung (A-549), and breast (MCF-7) using Sulforhodamine B (SRB) assay along with non-cancerous VERO cells as control and doxorubicin (DOX) as positive control. As we observed strong cytotoxicity of AR 03 and AR-04 fractions against tested cells and marked cytotoxic effects particularly in colon cancer cell lines, we further re-fractionated, AR-03 into (AR-03A, AR-03B, AR-03C, AR-03D, AR-03E) and AR-04 into (AR-04A, AR-04B, AR-04C) sub-fractions by column chromatography and investigated against the same panel of cell lines in addition to one more colon cancer cell line (HT-29). Phytochemical analysis was performed through HPLC-ESI-QTOF-MS/MS fragmentation. RESULTS: Ethyl acetate (AR-03) and hexane (AR-04) fractions were found to be the most cytotoxic against all the tested cell lines. Further, AR-03E and AR-04A sub-fractions were found more specific cytotoxic selectively against DLD-1 cancer cell lines at 100ug/ml concentration. HPLC-ESI-QTOF-MS/MS determination revealed the presence of 17 compounds in AR-01. Among them, 4 compounds were reported for the first time in this species. However, 3 identified compounds (artemorin, beta-santonin and caryophyllene oxide) in AR-03E sub-fraction were commonly present in each bioactive fraction and may be considered as potential and safest cytotoxic agents for anticancer activity. CONCLUSIONS: Experimental evidences reported in this paper for anticancer activity validate the traditional wisdom of Artemisia nilagirica as an anticancer herbal drug. To our knowledge, this is our first novel observation of cytotoxicity and selectivity of ethyl acetate and hexane sub fraction of AR-01 i.e. AR-03E and AR-04A respectively against DLD-1 human cancer cell lines. HPLC-ESI-QTOF-MS/MS determination attributes the identification of cytotoxic compounds which may be used for further preclinical studies. PMID- 29109062 TI - Dural Penetration of Cavernous Hemangioma on Skull: Uncommon Clinical Presentation. AB - BACKGROUND: Cavernous hemangioma (CH) of the bone is a rare, benign neoplasm found usually in the vertebral body. This tumor rarely develops in the calvaria, with predilection to occur in the frontal and temporoparietal bones. CASE DESCRIPTION: A 56-year-old man with a right frontal palpable mass was admitted to our hospital. Magnetic resonance imaging (MRI) revealed a large extra-axial tumor in the right frontal bone. Intraoperatively, the bony mass involved the multilayers composed of extracranium-skull-dura-intradura-cortex. Pathologic examination revealed a typical calvarial CH penetrating dura mater. CONCLUSIONS: This is the second reported case of calvarial CH with complete erosion of the dural plane and extension into subdural space. Although surgical resection is generally safe and easy, the possibility of dural invasion should be kept in mind for safe resection of calvarial CH, especially overlying the eloquent brain area. PMID- 29109063 TI - Patients with a Normal Pressure Hydrocephalus Shunt Have Fewer Complications than Do Patients with Other Shunts. AB - BACKGROUND: Ventriculoperitoneal (VP) shunting is a well-established therapy for hydrocephalus. However, complications are frequent. The incidence of idiopathic normal pressure hydrocephalus (NPH) increases with the aging of the population. We evaluated the functional status of patients and the classification of complications associated with VP shunt procedures in our center. METHODS: We recorded all VP shunt procedures in our prospective patient registry from January 2013 to December 2015. Functional outcome (Karnofsky Performance Status [KPS] and modified Rankin Scale) and complications were compiled from patient records. Any deviation from the normal postoperative course within 3 months after surgery was considered a complication. Complications were classified with the therapy oriented Clavien-Dindo grading system. We evaluated potential risk factors with a logistic regression model. RESULTS: From 285 procedures in the reporting period, 90 were excluded, resulting in 195 patients. Among those patients, 174 (90%) were shunt implantations and 21 (11%) were shunt revisions. Forty-four shunts (23%) were implanted for NPH. Median KPS improved over the first year after surgery. Although some type of complication was observed in 114 patients (58%), 60 of those complications (31%) did not require surgical treatment (Clavien-Dindo grade <3). In 50 patients (26%), the complication concerned the shunt itself. A high KPS at admission and NPH as underlying indication significantly reduced the odds ratio for a complication. CONCLUSIONS: Although shunt surgery has a high general rate of complications, this rate is significantly lower for patients with NPH. The decision for shunting in patients with NPH should consider the low complication rate specific for the group of patients with NPH. PMID- 29109064 TI - Surgical Outcomes After Segmental Limited Surgery for Adjacent Segment Disease: The Consequences of Makeshift Surgery. AB - BACKGROUND: To minimize surgical morbidity, surgeons may opt to perform segmental limited surgery instead of fusion extension for adjacent segment disease (ASD) after lumbar fusion surgery. This study evaluated clinical outcomes from segmental limited surgery without fusion extension for ASD and assessed which clinical factors were associated with reoperation after segmental limited surgery. METHODS: Medical data of 50 patients who underwent segmental limited surgery for ASD after lumbar fusion surgery between 2005 and 2015 were reviewed. Demographic data, ASD type, preoperative disc and facet degeneration, ASD location, and surgical summary were collected. The primary outcome was reoperation rate at 24 months after surgery. RESULTS: Of patients, 28 (56%) experienced recurrent radiculopathy (visual analog scale score >=4). Revision surgery was performed in 22 patients (44%). Reoperation was performed more frequently in multilevel fusion first-surgery cases (15/23; 65.2%) than single level fusion first-surgery cases (7/27; 25.9%; P = 0.005). The lowermost mobile segment group had a lower reoperation-free survival rate than the other group (hazard ratio = 9.85, 95% confidence interval 1.32-73.54, P = 0.01 [log-rank]). The 2-year reoperation-free survival rate for the lowermost mobile segment group was 31.5%, whereas the rate for the other group was 83.3%. CONCLUSIONS: Segmental limited surgery as a treatment for ASD after lumbar fusion surgery is likely to fail frequently and result in a high rate of recurrent radiculopathy and revision surgery. Fusion extension surgery is especially recommended for ASD at the lowermost mobile segment owing to the high failure rate. PMID- 29109065 TI - The Impact of Chronic Kidney Disease on Postoperative Outcomes in Patients Undergoing Lumbar Decompression and Fusion. AB - OBJECTIVE: To determine whether preoperative chronic kidney disease (CKD) is associated with inferior perioperative outcomes in patients undergoing lumbar arthrodesis. METHODS: Medical records of 293 adult (>=18 years old) patients with spine deformity undergoing elective lumbar spine decompression and fusion at a major academic institution from 2006 to 2015 were reviewed. We identified 18 (6.1%) patients with a clinical diagnosis of CKD (CKD group, n = 18; no-CKD group, n = 275). Patient demographics, comorbidities, and intraoperative and postoperative complication rates were collected for each patient. The primary endpoint was incidence of postoperative complications. RESULTS: Patient demographics, including age, sex, and body mass index, and comorbidities were similar between cohorts. The CKD group had a significantly higher prevalence of hypertension, hyperlipidemia, and anemia compared with the no-CKD group. Median number of fusion levels, length of surgery, and estimated blood loss were similar between both cohorts. Postoperative complication profile was significantly different between the cohorts, with the CKD group having a significantly higher proportion of patients transferred to the intensive care unit (52.9% vs. 29.3%, P = 0.04) with episodes of delirium (27.8% vs. 8.4%, P = 0.007), urinary tract infection (27.8% vs. 6.9%, P = 0.0002), and deep vein thrombosis (5.6% vs. 0.4%, P = 0.01). Although not significant, the CKD group had a 2-fold higher rate of 30 day readmissions compared with the no-CKD group (CKD group: 27.8% vs. no-CKD group: 12.7%, P = 0.07). CONCLUSIONS: Our study suggests that patients with CKD may be more likely to develop perioperative complications after lumbar arthrodesis. Future studies are necessary to corroborate our findings. PMID- 29109066 TI - Unplanned Intraoperative Extubations in Pediatric Neurosurgery: Analysis of Case Series to Increase Patient Safety. AB - OBJECTIVE: Unplanned intraoperative extubations (UIEs), rare but high-risk events. Unintentional extubations are used as quality improvement metrics in neonatal and pediatric intensive care units, but intraoperative events have received scant attention in the literature. Complexity of patient positioning and proximity of the operative field to anesthesia make neurosurgical procedures unique. UIEs prolong operative time, increase risk of adverse outcomes, including cardiopulmonary collapse, and potentially require additional procedures. Investigating each event is critical to prevention. We aimed to analyze occurrences of UIEs in the pediatric population. METHODS: We retrospectively reviewed UIE cases (12/2014-4/2017) in pediatric neurosurgical patients at a metropolitan pediatric Level I trauma center. Data were collected on patient demographics, procedure, operating room events before the event, and patient outcomes. RESULTS: Over 27 months, 5 UIEs in pediatric neurosurgical cases occurred, with an event rate of <0.3%. Two occurred in patients <1 year old. Two UIEs occurred in patients undergoing surgery for epilepsy. Root cause analysis identified varied etiologies of UIE: 2 were attributed to endotracheal tube securement, 2 were attributed to lighter anesthesia planes in epilepsy cases with limb movement, and 1 occurred while supinating a prone patient. Postoperative outcomes for these patients were no different from routine cases. CONCLUSIONS: Findings suggest an inverse correlation between patient age and UIE, with patient manipulation and anesthesia depth as risk factors. Meticulous attention to securing the endotracheal tube and streamlined communication between the surgical and anesthesia teams are critical for the goal of zero UIE occurrences. PMID- 29109067 TI - The insertion in the double-stranded RNA binding domain of human Drosha is important for its function. AB - microRNAs (miRNAs) are first transcribed as long, primary transcripts, which are then processed by multiple enzymes and proteins to generate the single-stranded, approximately 22-nucleotide (nt)-long mature miRNAs. A critical step in animal miRNA biogenesis is the cleavage of primary miRNA transcripts (pri-miRNAs) to produce precursor miRNAs (pre-miRNAs) by the enzyme Drosha. How Drosha recognizes its substrates remains incompletely understood. In this study we constructed a series of human Drosha mutants and examined their enzymatic activities and interaction with RNAs. We found that the N-terminal region is required for the nuclear localization and cellular function of Drosha. And in contrast to previous reports, we showed that the double-stranded RNA binding domain (RBD) of Drosha exhibited a weak but noticeable affinity for RNA. Compared to the RBDs of other RNA-binding proteins, the RBD of Drosha has a short insert, whose mutations reduced RNA binding and pri-miRNA cleavage. Overexpression of Drosha RBD mutants in a reporter assay corroborated their deficiencies in Drosha activity in cell cultures. In addition, we found that point mutations in the RNaseIIIb domain of Drosha implicated in Wilms tumors differentially affected cleavage of the 5' and 3' strands of pri-miRNAs in vitro. In conclusion, our results provided important insights into the mechanism of pri-miRNA processing by human Drosha. PMID- 29109068 TI - Obstructive Sleep Apnea in Women: Study of Speech and Craniofacial Characteristics. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder characterized by frequent cessation of breathing lasting 10 seconds or longer. The diagnosis of OSA is performed through an expensive procedure, which requires an overnight stay at the hospital. This has led to several proposals based on the analysis of patients' facial images and speech recordings as an attempt to develop simpler and cheaper methods to diagnose OSA. OBJECTIVE: The objective of this study was to analyze possible relationships between OSA and speech and facial features on a female population and whether these possible connections may be affected by the specific clinical characteristics in OSA population and, more specifically, to explore how the connection between OSA and speech and facial features can be affected by gender. METHODS: All the subjects are Spanish subjects suspected to suffer from OSA and referred to a sleep disorders unit. Voice recordings and photographs were collected in a supervised but not highly controlled way, trying to test a scenario close to a realistic clinical practice scenario where OSA is assessed using an app running on a mobile device. Furthermore, clinical variables such as weight, height, age, and cervical perimeter, which are usually reported as predictors of OSA, were also gathered. Acoustic analysis is centered in sustained vowels. Facial analysis consists of a set of local craniofacial features related to OSA, which were extracted from images after detecting facial landmarks by using the active appearance models. To study the probable OSA connection with speech and craniofacial features, correlations among apnea-hypopnea index (AHI), clinical variables, and acoustic and facial measurements were analyzed. RESULTS: The results obtained for female population indicate mainly weak correlations (r values between .20 and .39). Correlations between AHI, clinical variables, and speech features show the prevalence of formant frequencies over bandwidths, with F2/i/ being the most appropriate formant frequency for OSA prediction in women. Results obtained for male population indicate mainly very weak correlations (r values between .01 and .19). In this case, bandwidths prevail over formant frequencies. Correlations between AHI, clinical variables, and craniofacial measurements are very weak. CONCLUSIONS: In accordance with previous studies, some clinical variables are found to be good predictors of OSA. Besides, strong correlations are found between AHI and some clinical variables with speech and facial features. Regarding speech feature, the results show the prevalence of formant frequency F2/i/ over the rest of features for the female population as OSA predictive feature. Although the correlation reported is weak, this study aims to find some traces that could explain the possible connection between OSA and speech in women. In the case of craniofacial measurements, results evidence that some features that can be used for predicting OSA in male patients are not suitable for testing female population. PMID- 29109069 TI - Subregional Nowcasts of Seasonal Influenza Using Search Trends. AB - BACKGROUND: Limiting the adverse effects of seasonal influenza outbreaks at state or city level requires close monitoring of localized outbreaks and reliable forecasts of their progression. Whereas forecasting models for influenza or influenza-like illness (ILI) are becoming increasingly available, their applicability to localized outbreaks is limited by the nonavailability of real time observations of the current outbreak state at local scales. Surveillance data collected by various health departments are widely accepted as the reference standard for estimating the state of outbreaks, and in the absence of surveillance data, nowcast proxies built using Web-based activities such as search engine queries, tweets, and access of health-related webpages can be useful. Nowcast estimates of state and municipal ILI were previously published by Google Flu Trends (GFT); however, validations of these estimates were seldom reported. OBJECTIVE: The aim of this study was to develop and validate models to nowcast ILI at subregional geographic scales. METHODS: We built nowcast models based on autoregressive (autoregressive integrated moving average; ARIMA) and supervised regression methods (Random forests) at the US state level using regional weighted ILI and Web-based search activity derived from Google's Extended Trends application programming interface. We validated the performance of these methods using actual surveillance data for the 50 states across six seasons. We also built state-level nowcast models using state-level estimates of ILI and compared the accuracy of these estimates with the estimates of the regional models extrapolated to the state level and with the nowcast estimates published by GFT. RESULTS: Models built using regional ILI extrapolated to state level had a median correlation of 0.84 (interquartile range: 0.74-0.91) and a median root mean square error (RMSE) of 1.01 (IQR: 0.74-1.50), with noticeable variability across seasons and by state population size. Model forms that hypothesize the availability of timely state-level surveillance data show significantly lower errors of 0.83 (0.55-0.23). Compared with GFT, the latter model forms have lower errors but also lower correlation. CONCLUSIONS: These results suggest that the proposed methods may be an alternative to the discontinued GFT and that further improvements in the quality of subregional nowcasts may require increased access to more finely resolved surveillance data. PMID- 29109070 TI - Artificial Intelligence Learning Semantics via External Resources for Classifying Diagnosis Codes in Discharge Notes. AB - BACKGROUND: Automated disease code classification using free-text medical information is important for public health surveillance. However, traditional natural language processing (NLP) pipelines are limited, so we propose a method combining word embedding with a convolutional neural network (CNN). OBJECTIVE: Our objective was to compare the performance of traditional pipelines (NLP plus supervised machine learning models) with that of word embedding combined with a CNN in conducting a classification task identifying International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes in discharge notes. METHODS: We used 2 classification methods: (1) extracting from discharge notes some features (terms, n-gram phrases, and SNOMED CT categories) that we used to train a set of supervised machine learning models (support vector machine, random forests, and gradient boosting machine), and (2) building a feature matrix, by a pretrained word embedding model, that we used to train a CNN. We used these methods to identify the chapter-level ICD-10-CM diagnosis codes in a set of discharge notes. We conducted the evaluation using 103,390 discharge notes covering patients hospitalized from June 1, 2015 to January 31, 2017 in the Tri-Service General Hospital in Taipei, Taiwan. We used the receiver operating characteristic curve as an evaluation measure, and calculated the area under the curve (AUC) and F-measure as the global measure of effectiveness. RESULTS: In 5-fold cross-validation tests, our method had a higher testing accuracy (mean AUC 0.9696; mean F-measure 0.9086) than traditional NLP-based approaches (mean AUC range 0.8183-0.9571; mean F-measure range 0.5050-0.8739). A real-world simulation that split the training sample and the testing sample by date verified this result (mean AUC 0.9645; mean F-measure 0.9003 using the proposed method). Further analysis showed that the convolutional layers of the CNN effectively identified a large number of keywords and automatically extracted enough concepts to predict the diagnosis codes. CONCLUSIONS: Word embedding combined with a CNN showed outstanding performance compared with traditional methods, needing very little data preprocessing. This shows that future studies will not be limited by incomplete dictionaries. A large amount of unstructured information from free-text medical writing will be extracted by automated approaches in the future, and we believe that the health care field is about to enter the age of big data. PMID- 29109071 TI - Health Information-Seeking Patterns of the General Public and Indications for Disease Surveillance: Register-Based Study Using Lyme Disease. AB - BACKGROUND: People using the Internet to find information on health issues, such as specific diseases, usually start their search from a general search engine, for example, Google. Internet searches such as these may yield results and data of questionable quality and reliability. Health Library is a free-of-charge medical portal on the Internet providing medical information for the general public. Physician's Databases, an Internet evidence-based medicine source, provides medical information for health care professionals (HCPs) to support their clinical practice. Both databases are available throughout Finland, but the latter is used only by health professionals and pharmacies. Little is known about how the general public seeks medical information from medical sources on the Internet, how this behavior differs from HCPs' queries, and what causes possible differences in behavior. OBJECTIVE: The aim of our study was to evaluate how the general public's and HCPs' information-seeking trends from Internet medical databases differ seasonally and temporally. In addition, we aimed to evaluate whether the general public's information-seeking trends could be utilized for disease surveillance and whether media coverage could affect these seeking trends. METHODS: Lyme disease, serving as a well-defined disease model with distinct seasonal variation, was chosen as a case study. Two Internet medical databases, Health Library and Physician's Databases, were used. We compared the general public's article openings on Lyme disease from Health Library to HCPs' article openings on Lyme disease from Physician's Databases seasonally across Finland from 2011 to 2015. Additionally, media publications related to Lyme disease were searched from the largest and most popular media websites in Finland. RESULTS: Both databases, Health Library and Physician's Databases, show visually similar patterns in temporal variations of article openings on Lyme disease in Finland from 2011 to 2015. However, Health Library openings show not only an increasing trend over time but also greater fluctuations, especially during peak opening seasons. Outside these seasons, publications in the media coincide with Health Library article openings only occasionally. CONCLUSIONS: Lyme disease-related information-seeking behaviors between the general public and HCPs from Internet medical portals share similar temporal variations, which is consistent with the trend seen in epidemiological data. Therefore, the general public's article openings could be used as a supplementary source of information for disease surveillance. The fluctuations in article openings appeared stronger among the general public, thus, suggesting that different factors such as media coverage, affect the information-seeking behaviors of the public versus professionals. However, media coverage may also have an influence on HCPs. Not every publication was associated with an increase in openings, but the higher the media coverage by some publications, the higher the general public's access to Health Library. PMID- 29109075 TI - Atrioesophageal Fistula: Clinical Presentation, Procedural Characteristics, Diagnostic Investigations, and Treatment Outcomes. AB - BACKGROUND: Percutaneous or surgical ablation are increasingly used worldwide in the management of atrial fibrillation. The development of atrioesophageal fistula (AEF) is among the most serious and lethal complications of atrial fibrillation ablation. We sought to characterize the clinical presentation, procedural characteristics, diagnostic investigations, and treatment outcomes of all reported cases of AEF. METHODS AND RESULTS: Electronic searches were conducted in PubMed and Embase for English scientific literature articles. Out of 628 references, 120 cases of AEF were identified using various ablation modalities. Clinical presentation occurred between 0 and 60 days postablation (median 21 days). Fever (73%), neurological (72%), gastrointestinal (41%), and cardiac (40%) symptoms were the commonest presentations. Computed tomography of the chest was the commonest mode of diagnosis (68%), although 7 cases required repeat testing. Overall mortality was 55%, with significantly reduced mortality in patients undergoing surgical repair (33%) compared with endoscopic treatment (65%) and conservative management (97%) (adjusted odds ratio, 24.9; P<0.01, compared with surgery). Multivariable predictors of mortality include presentation with neurological symptoms (adjusted odds ratio, 16.0; P<0.001) and gastrointestinal bleed (adjusted odds ratio, 4.2; P=0.047). CONCLUSIONS: AEF complicating atrial fibrillation ablation is associated with a high mortality. Clinicians should have a high suspicion for the development of AEF in patients presenting with infective, neurological, gastrointestinal, or cardiac symptoms within 2 months of an atrial fibrillation ablation. Investigation by contrast computed tomography of the chest with consideration of repeat testing can lead to prompt diagnosis. Surgical intervention is associated with improved survival rates. PMID- 29109076 TI - Puzzling Challenge of Atrioesophageal Fistula. PMID- 29109072 TI - Factors Associated With Access to HIV Testing and Primary Care Among Migrants Living in Europe: Cross-Sectional Survey. AB - BACKGROUND: There is a heavy and disproportionate burden of human immunodeficiency virus (HIV) infection among migrant communities living in Europe. Despite this, the published evidence related to HIV testing, prevention, and treatment needs for migrants is sparse. OBJECTIVE: The aim of this study was to identify the factors associated with access to primary care and HIV testing among migrant groups living in Europe. METHODS: A Web-based survey (available in 14 languages) was open to all people aged 18 years and older, living outside their country of birth in the World Health Organization (WHO) European area. Community organizations in 9 countries promoted the survey to migrant groups, focusing on those at a higher risk of HIV (sub-Saharan Africans, Latin Americans, gay or bisexual men, and people who inject drugs). Multivariable analysis examined factors associated with access to primary care and previous history of an HIV test. RESULTS: In total, 559 women, 395 heterosexual men, and 674 gay or bisexual men were included in the analysis, and 68.1% (359/527) of women, 59.5% (220/371) of heterosexual men, and 89.6% (596/664) of gay or bisexual men had tested for HIV. Low perceived risk was the reason given for not testing by 62.3% (43/69) of gay or bisexual men and 83.3% (140/168) of women and heterosexual men who reported never having tested for HIV. Access to primary care was >60% in all groups. Access to primary care was strongly positively associated with living in Northern Europe compared with Southern Europe (women: adjusted odds ratio, aOR 34.56 [95% CI 11.58-101]; heterosexual men: aOR 6.93 [95% CI 2.49-19.35], and gay or bisexual men: aOR 2.53 [95% CI 1.23-5.19]), whereas those with temporary residency permits were less likely to have access to primary care (women: aOR 0.41 [95% CI 0.21-0.80] and heterosexual men: aOR 0.24 [95% CI 0.10-0.54] only). Women who had experience of forced sex (aOR 3.53 [95% CI 1.39-9.00]) or postmigration antenatal care (aOR 3.07 [95% CI 1.55-6.07]) were more likely to have tested for HIV as were heterosexual men who had access to primary care (aOR 3.13 [95% CI 1.58-6.13]) or reported "Good" health status (aOR 2.94 [95% CI 1.41 5.88]). CONCLUSIONS: Access to primary care is limited by structural determinants such as immigration and health care policy, which varies across Europe. For those migrants who can access primary care and other health services, missed opportunities for HIV testing remain a barrier to earlier testing and diagnosis for migrants in Europe. Clinicians should be aware of these potential structural barriers to HIV testing as well as low perception of HIV risk in migrant groups. PMID- 29109078 TI - Margaret McCartney: Pointless paperwork, not patients, is what GPs should avoid. PMID- 29109077 TI - Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer. AB - Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ~50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 * 107 or 3 * 108 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152-61. (c)2017 AACR. PMID- 29109079 TI - A three-talk model for shared decision making: multistage consultation process. AB - Objectives To revise an existing three-talk model for learning how to achieve shared decision making, and to consult with relevant stakeholders to update and obtain wider engagement.Design Multistage consultation process.Setting Key informant group, communities of interest, and survey of clinical specialties.Participants 19 key informants, 153 member responses from multiple communities of interest, and 316 responses to an online survey from medically qualified clinicians from six specialties.Results After extended consultation over three iterations, we revised the three-talk model by making changes to one talk category, adding the need to elicit patient goals, providing a clear set of tasks for each talk category, and adding suggested scripts to illustrate each step. A new three-talk model of shared decision making is proposed, based on "team talk," "option talk," and "decision talk," to depict a process of collaboration and deliberation. Team talk places emphasis on the need to provide support to patients when they are made aware of choices, and to elicit their goals as a means of guiding decision making processes. Option talk refers to the task of comparing alternatives, using risk communication principles. Decision talk refers to the task of arriving at decisions that reflect the informed preferences of patients, guided by the experience and expertise of health professionals.Conclusions The revised three-talk model of shared decision making depicts conversational steps, initiated by providing support when introducing options, followed by strategies to compare and discuss trade-offs, before deliberation based on informed preferences. PMID- 29109080 TI - Central leptin regulates heart lipid content by selectively increasing PPAR beta/delta expression. AB - The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein, we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2 ug/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective upregulation of gene and protein expression of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta, encoded by Pparb/d) and their target genes, adipose triglyceride lipase (encoded by Pnpla2, herefater referred to as Atgl), hormone sensitive lipase (encoded by Lipe, herefater referred to as Hsl), pyruvate dehydrogenase kinase 4 (Pdk4) and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization. Besides, central leptin decreased the expression of stearoyl-CoA deaturase 1 (Scd1) and diacylglycerol acyltransferase 1 (Dgat1) involved in TAG synthesis and increased the CPT-1 independent palmitate oxidation, as an index of peroxisomal beta-oxidation. Finally, the pharmacological inhibition of PPARbeta/delta decreased the effects on gene expression and cardiac TAG content induced by leptin. These results indicate that leptin, acting at central level, regulates selectively the cardiac expression of PPARbeta/delta, contributing in this way to regulate the cardiac TAG accumulation in rats, independently of its effects on body weight. PMID- 29109081 TI - Vitamin D, the placenta and early pregnancy: effects on trophoblast function. AB - Pregnancy is associated with significant changes in vitamin D metabolism, notably increased maternal serum levels of active vitamin D, 1,25-dihydroxyvitamin (1,25(OH)2D). This appears to be due primarily to increased renal activity of the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) that catalyzes synthesis of 1,25(OH)2D, but CYP27B1 expression is also prominent in both the maternal decidua and fetal trophoblast components of the placenta. The precise function of placental synthesis of 1,25(OH)2D remains unclear, but is likely to involve localized tissue-specific responses with both decidua and trophoblast also expressing the vitamin D receptor (VDR) for 1,25(OH)2D. We have previously described immunomodulatory responses to 1,25(OH)2D by diverse populations of VDR expressing cells within the decidua. The aim of the current review is to detail the role of vitamin D in pregnancy from a trophoblast perspective, with particular emphasis on the potential role of 1,25(OH)2D as a regulator of trophoblast invasion in early pregnancy. Vitamin D deficiency is common in pregnant women, and a wide range of studies have linked low vitamin D status to adverse events in pregnancy. To date, most of these studies have focused on adverse events later in pregnancy, but the current review will explore the potential impact of vitamin D on early pregnancy, and how this may influence implantation and miscarriage. PMID- 29109082 TI - Prescription Opioids for Pain Management in Patients on Dialysis. PMID- 29109083 TI - Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction. AB - Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm-derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1 deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm-derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1 deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction. PMID- 29109084 TI - Ubiquitin-Binding Protein CG5445 Suppresses Aggregation and Cytotoxicity of Amyotrophic Lateral Sclerosis-Linked TDP-43 in Drosophila. AB - Ubiquitin-mediated protein degradation plays essential roles in proteostasis and is involved in the pathogenesis of neurodegenerative diseases in which ubiquitin positive aberrant proteins accumulate. However, how such aberrant proteins are processed inside cells has not been fully explored. Here, we show that the product of CG5445, a previously uncharacterized Drosophila gene, prevents the accumulation of aggregate-prone ubiquitinated proteins. We found that ubiquitin conjugates were associated with CG5445, the knockdown of which caused the accumulation of detergent-insoluble ubiquitinated proteins. Furthermore, CG5445 rescued eye degeneration caused by the amyotrophic lateral sclerosis (ALS)-linked mutant TAR DNA-binding protein of 43 kDa (TDP-43), which often forms ubiquitin positive aggregates in cells through the capacity of CG5445 to bind to ubiquitin chains. Biochemically, CG5445 inhibited the accumulation of insoluble forms and promoted their clearance. Our results demonstrate a new possible mechanism by which cells maintain ubiquitinated aggregation-prone proteins in a soluble form to decrease their cytotoxicity until they are degraded. PMID- 29109085 TI - More F2 doctors are choosing a career break. PMID- 29109087 TI - Surgical registrar is struck off for refusing to examine three deteriorating patients. PMID- 29109086 TI - Doctors should lead the fight against environmental plastics. PMID- 29109088 TI - Accelerometer-Measured Physical Activity and Sedentary Behavior in Relation to All-Cause Mortality: The Women's Health Study. PMID- 29109089 TI - The TRAPPIII complex activates the GTPase Ypt1 (Rab1) in the secretory pathway. AB - Rab GTPases serve as molecular switches to regulate eukaryotic membrane trafficking pathways. The transport protein particle (TRAPP) complexes activate Rab GTPases by catalyzing GDP/GTP nucleotide exchange. In mammalian cells, there are two distinct TRAPP complexes, yet in budding yeast, four distinct TRAPP complexes have been reported. The apparent differences between the compositions of yeast and mammalian TRAPP complexes have prevented a clear understanding of the specific functions of TRAPP complexes in all cell types. In this study, we demonstrate that akin to mammalian cells, wild-type yeast possess only two TRAPP complexes, TRAPPII and TRAPPIII. We find that TRAPPIII plays a major role in regulating Rab activation and trafficking at the Golgi in addition to its established role in autophagy. These disparate pathways share a common regulatory GTPase Ypt1 (Rab1) that is activated by TRAPPIII. Our findings lead to a simple yet comprehensive model for TRAPPIII function in both normal and starved eukaryotic cells. PMID- 29109090 TI - Impact of Mediterranean Diet on Cancer: Focused Literature Review. AB - BACKGROUND: Cancer is a major public health problem worldwide, and the number of incident cases increases every year expected to reach 17.1 million a year by 2020. There is evidence that people who adhere to the Mediterranean Diet (MediD) have lower incidence of cancer. However, cancers' location and culture studies seem to affect the MediD impact. We aimed to review these discrepant findings. MATERIALS AND METHODS: A critical review from a focused literature search was conducted. A literature search of controlled trials from: EMBASE (1970-), MEDLINE (1950-) and PsycINFO (1960-) was undertaken. Two authors (DF and YB) independently extracted the data. RESULTS: Out of 785 abstracts identified only 583 publications focused solely on MediD and cancer. Of these, 46 were clinical trials published since 2007. Twenty-eight trials with a total of 570,262 participants are included in accordance with inclusion criteria. Only four reported the MediD does not reduce the risk of cancer. Of the negative studies, three were undertaken in non-Mediterranean populations. Cancers of the digestive tract were studied in 11 studies. Except for pancreatic cancer, all other sites along the digestive tract demonstrated significantly reduced rate with the MediD. CONCLUSION: The MediD is associated with reduction in overall cancer rates as well as significantly lower rates of digestive tract cancers. These effects may be accentuated in the Mediterranean countries themselves. Further studies are needed to support or refute the effects of the MediD on other cancer types. PMID- 29109091 TI - Transcriptomic Profiling of MDA-MB-231 Cells Exposed to Boswellia Serrata and 3-O Acetyl-B-Boswellic Acid; ER/UPR Mediated Programmed Cell Death. AB - BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptors (estrogen, progesterone and human epidermal growth factor receptor-2) and a relatively poor prognosis due to inefficacy of hormone receptor-based chemotherapies. It is imperative that we continue to explore natural products with potential to impede growth and metastasis of TNBC. In this study, we screened over 1,000 natural products for capacity to induce cell death in TNBC (MDA-MB -231) cells. MATERIALS AND METHODS: Frankincense (Boswellia serrata extract (BSE)) and 3-O-Acetyl-beta-boswellic acid (3-OAbetaBA) were relatively potent, findings that corroborate the body of existing literature. The effects of BSE and 3-OAbetaBA on genetic parameters in MDA-MB-231 cells were evaluated by examining whole-transcriptomic influence on mRNAs, long intergenic non-coding RNA transcripts (lincRNA) and non-coding miRNAs. RESULTS: Bio statistical analysis demarcates the primary effect of both BSE/3-OAbetaBA on the up-regulation of PERK (protein kinase RNA-like endoplasmic reticulum kinase)- endoplasmic reticulum (ER)/unfolded protein response (UPR) pathways that are closely tied to activated programmed cell death (APCD). Global profiling confirms concomitant effects of BSE/3-OAbetaBA on upwardly expressed ER/URP APCD key components PERK (EIF2AK3), XBP1, C/EBP homologous protein transcription factor (CHOP), ATF3 and DDIT3,4/DNA-damage-inducible transcript 3,4 (GADD34). Further, BSE and/or 3-OAbetaBA significantly down-regulated oncogenes (OG) which, heretofore, lack functional pathway mapping, but are capable of driving epithelial-mesenchymal transition (EMT), cell survival, proliferation, metastasis and drug resistance. Among these are cell migration-inducing protein hyaluronan binding (CEMIP) [-7.22]; transglutaminase 2 [-4.96], SRY box 9 (SOX9) [-4.09], inhibitor of DNA binding 1, dominant negative helix-loop-helix protein (ID1) [ 6.56]; and endothelin 1 (EDN1, [-5.06]). Likewise, in the opposite manner, BSE and/or 3-OAbetaBA induced the robust overexpression of tumor suppressor genes (TSGs), including: glutathione-depleting ChaC glutathione-specific gamma glutamylcyclotransferase 1 (CHAC1) [+21.67]; the mTOR inhibitors - sestrin 2 (SESN2) [+16.4] Tribbles homolog 3 (TRIB3) [+6.2], homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1) [+12.01]; and cystathionine gamma-lyase (CTH) [+11.12]. CONCLUSION: The anti cancer effects of the historically used frankincense sap (BSE) appear to involve major impact on the ER/UPR response, concomitant to effecting multiple targets counter to the growth, proliferation and metastasis of TNBC cancer cells. The microarray data are available at Expression Omnibus GEO Series accession number GSE102891. PMID- 29109092 TI - Screening for Multiple Autoantibodies in Plasma of Patients with Breast Cancer. AB - BACKGROUND/AIM: Autoantibodies have potential as circulating biomarkers for early cancer detection. This study aimed to screen for known autoantibodies in human plasma using an Autoantibody Profiling System (APS) and quantify the levels in plasma of donors with/without breast cancer. MATERIALS AND METHODS: Plasma from nine female donors diagnosed with breast cancer (test group) and nine matched donors with no personal history of cancer (reference group) were screened with an APS containing probes for 30 autoantibodies. Autoantibody levels >=1.5 times the mean concentration of the group were considered elevated, and test/reference ratios >=1.3 were considered higher in the test group compared to the reference group. RESULTS: Twenty percent of the probes detected elevated levels of autoantibodies against proteins involved in different cancer mechanisms. Amongst these, the levels of autoantibodies against interleukin 29 (IL29), osteoprotegerin (OPG), survivin (SUR), growth hormone (GRH) and resistin (RES) were significantly higher in the cancer group compared to the reference group (p<0.05), whereas the level of autoantibody against cytotoxic T-lymphocyte associated antigen-4 (CTLA4) was not significantly different between the two groups (p=0.38). CONCLUSION: Disease-relevant autoantibodies were detected in the plasma of patients with breast cancer and donors without breast cancer. This means that identifying the type and level of autoantibodies in samples will be important in determining their significance in the disease process. A microtiter plate-based array system could be a fast and inexpensive screening method for identifying and quantifying autoantibodies in human plasma. PMID- 29109093 TI - DEK-NUP214-Fusion Identified by RNA-Sequencing of an Acute Myeloid Leukemia with t(9;12)(q34;q15). AB - BACKGROUND/AIM: Given the diagnostic, prognostic, biologic, and even therapeutic impact of leukemia-associated translocations and fusion genes, it is important to detect cryptic genomic rearrangements that may exist in hematological malignancies. CASE REPORT: RNA-sequencing was performed on an acute myeloid leukemia case with the bone marrow karyotype 45,X,-Y,t(9;12) (q34;q15)[16]. RESULTS: The DEK-NUP214 and PRRC2B-DEK fusion genes were found. Reverse transcriptase polymerase chain reaction together with direct sequencing verified the presence of both. Fluorescence in situ hybridization showed that the DEK NUP214 fusion gene was located on the 6p22 band of a seemingly normal chromosome 6. CONCLUSION: RNA-sequencing proved to be a valuable tool for the detection of a fusion of genes DEK and NUP214 in a leukemia that showed cryptic cytogenetic rearrangement of chromosome band 9q34. PMID- 29109094 TI - CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma. AB - BACKGROUND/AIM: Project HOPE (High-tech Omics-based Patient Evaluation) began in 2014 using integrated gene expression profiling (GEP) of cancer tissues as well as diathesis of each patient who underwent operation at our Institution. The aim of this study was to identify novel genes displaying altered gene expression related to the survival and early recurrence after hepatectomy for hepatocellular carcinoma (HCC) using the results of integrated GEP analysis. MATERIALS AND METHODS: The present study included 92 patients. Genes with aberrant expression were selected by the difference of expression levels with >=10-fold change between tumor and non-tumor tissues. RESULTS: GEP analysis showed that down regulation was frequently observed in the PRSS8 (64%), CYP3A4 (61%) and EPCAM (57%) genes. Multivariate analysis revealed tumor stage >=II (p=0.008) and down regulation of the CYP3A4 gene (p=0.036) as independent predictor for overall survival. Furthermore, multivariate analysis identified maximum tumor diameter >=74mm (p=0.008), presence of intrahepatic-metastasis (p=0.020), and down regulation of CYP3A4 gene (p=0.019) as independent predictors for early recurrence. CONCLUSION: CYP3A4 was identified as a novel tumor suppressor gene related to a poor prognosis in HCC. PMID- 29109095 TI - The Association of Flap Endonuclease 1 Genotypes with the Susceptibility of Endometriosis. AB - BACKGROUND/AIM: Flap endonuclease 1 (FEN1), a protein with multiple functions in genome stability maintenance, is important in cancer prevention. The two functional germline variants of FEN1, rs174538 and rs4246215, regarding cancer susceptibility have been reported in lung, breast, liver, esophageal, gastric, colorectal cancer, glioma and leukemia, but not endometriosis. In this study, we firstly aimed at evaluating the contribution of FEN1 genotypes to endometriosis risk in a representative Taiwan population. MATERIALS AND METHODS: In total, 153 patients with endometriosis and 636 non-cancer healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: The genotypes of FEN1 rs174538, but not those of rs4246215, were differently distributed between the endometriosis and control groups. In detail, the AA of FEN1 rs174538 genotypes were significantly less frequently found among endometriosis patients than among controls (odds ratio [OR]=0.43, 95% confidence interval [CI]=0.24-0.78, p=0.0125). The A allele at FEN1 rs174538 was also significantly less frequent among cases than controls (OR=0.65, 95%CI=0.50 0.86, p=0.0021). As for age of first menarche, those with first menarche at the age >12.8 carrying the FEN1 rs174538 AA genotype conferred lower OR of 0.29 (95%CI=0.11-0.78, p=0.0381) for endometriosis. Regarding the full pregnancy status, those without having had a full-term pregnancy carrying the FEN1 rs174538 AA genotype were of lower risk (ORs=0.12, 95%CI=0.03-0.53, p=0.0050). CONCLUSION: The FEN1 rs174538 A allele is a novel protective biomarker for endometriosis and this genotype may have interactions with age- and hormone-related factors on the development of endometriosis. PMID- 29109096 TI - DHPLC Elution Patterns of VDR PCR Products Can Predict Prostate Cancer Susceptibility in African American Men. AB - BACKGROUND/AIM: Denaturing high-performance liquid chromatography (DHPLC) is a technique that is used to detect mutations. The aim of the present study was to determine whether DHPLC elution patterns of vitamin D receptor (VDR) gene PCR products can serve as indicators of susceptibility to prostate cancer (PCa) risk. MATERIALS AND METHODS: DNA samples of PCa cases and controls were screened for mutations and/or polymorphisms in coding exons of VDR gene using DHPLC analysis. Logistic regression, phi-coefficient (phi), and Backward Wald models were used to analyze the data. RESULTS: Similar elution patterns of exons 1, 6, 7 and 9 along with higher prevalence of heteroduplex DNA were observed in PCa samples than in controls. Exons 4 and 8 had highly significant protective effects (p<0.05). Whereas, exons 5, 7, and 9 were perfectly positively correlated with PCa risk (phi=1), thus presenting candidate exons significantly associated with susceptibility to PCa. CONCLUSION: DHPLC elution patterns of the selected exons could be useful to predict susceptibility to develop PCa. PMID- 29109097 TI - Role of Melt Curve Analysis in Interpretation of Nutrigenomics' MicroRNA Expression Data. AB - This article illustrates the importance of melt curve analysis (MCA) in interpretation of mild nutrogenomic micro(mi)RNA expression data, by measuring the magnitude of the expression of key miRNA molecules in stool of healthy human adults as molecular markers, following the intake of Pomegranate juice (PGJ), functional fermented sobya (FS), rich in potential probiotic lactobacilli, or their combination. Total small RNA was isolated from stool of 25 volunteers before and following a three-week dietary intervention trial. Expression of 88 miRNA genes was evaluated using Qiagen's 96 well plate RT2 miRNA qPCR arrays. Employing parallel coordinates plots, there was no observed significant separation for the gene expression (Cq) values, using Roche 480(r) PCR LightCycler instrument used in this study, and none of the miRNAs showed significant statistical expression after controlling for the false discovery rate. On the other hand, melting temperature profiles produced during PCR amplification run, found seven significant genes (miR-184, miR-203, miR-373, miR 124, miR-96, miR-373 and miR-301a), which separated candidate miRNAs that could function as novel molecular markers of relevance to oxidative stress and immunoglobulin function, for the intake of polyphenol (PP)-rich, functional fermented foods rich in lactobacilli (FS), or their combination. We elaborate on these data, and present a detailed review on use of melt curves for analyzing nutigenomic miRNA expression data, which initially appear to show no significant expressions, but are actually more subtle than this simplistic view, necessitating the understanding of the role of MCA for a comprehensive understanding of what the collective expression and MCA data collectively imply. PMID- 29109098 TI - 2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells. AB - BACKGROUND/AIM: According to the reverse Warburg effect, tumor cells may metabolize lactate as an energy source and shuttle L-lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, thus inducing metabolic reprogramming. An increased tumor L-lactate level strictly correlates with increased metastasis, tumor recurrence and a poor outcome. A potent anticancer agent that may act on L-lactate activated cells is 2-metoxyestradiol. Thus, the aim of the study was to evaluate whether a potent anticancer agent, 2 methoxyestradiol, is able to reverse L-lactate-induced metabolic reprogramming in osteosarcoma 143B cells. MATERIALS AND METHODS: We used flow cytometry in order to determine cell death, autophagy, expression of KI-67, mitochondrial membrane depolarization. We performed cell proliferation assay in order to determine cell viability and cell migration assay to determine invasive potential of osteosarcoma cells. While, CalcuSyn software was used in order to evaluate the interaction between 2-methoxyestradiol and L-lactate. RESULTS: We demonstrated that 2-methoxyestradiol abolished L-lactate-induced migration and proliferation of osteosarcoma cells. Moreover, we observed that this effect was associated with regulation of Ki-67 and induction of autophagy. CONCLUSION: 2-Methoxyestradiol is a potent anticancer agent also under metabolic reprogramming conditions. PMID- 29109099 TI - Targeted Gene Sequencing of Gallbladder Carcinoma Identifies High-impact Somatic and Rare Germline Mutations. AB - BACKGROUND: Gallbladder carcinoma (GBC) is a subtype of biliary tract malignancy with poor prognosis and high fatality rate. The present study was designed to uncover somatic and rare germline mutations in GBC to reveal the disease biology and understand the clinical importance of mutation profile in terms of prognostics and actionability. MATERIALS AND METHODS: We performed ultra-deep sequencing across 409 cancer-related genes in 11 GBC patients of North-Indian descent. NGS data analysis was performed using Ion Reporter and several other publicly available resources and databases. RESULTS: We identified 184 nonsynonymous somatic and 60 rare germline mutations in bona-fide cancer drivers such as SMAD family member 4 (SMAD4), lysine methyltransferase 2C (KMT2C), and tumor protein p53 (TP53). All the early-onset cases or hypermutated cases harbored mutation(s) in critical DNA-repair genes. Additionally, we detected 9 novel genes with high-impact somatic mutations in GBC. CONCLUSION: Our results indicated the significance of inherited rare germline mutations in DNA-repair pathway genes in addition to acquired somatic mutations in GB carcinogenesis. PMID- 29109102 TI - Immunoglobulin G Fc glycans are not essential for antibody-mediated immune suppression to murine erythrocytes. PMID- 29109100 TI - High Resolution Proteomic Analysis of the Cervical Cancer Cell Lines Secretome Documents Deregulation of Multiple Proteases. AB - BACKGROUND: Oncogenic infection by HPV, eventually leads to cervical carcinogenesis, associated by deregulation of specific pathways and protein expression at the intracellular and secretome level. Thus, secretome analysis can elucidate the biological mechanisms contributing to cervical cancer. In the present study we systematically analyzed its constitution in four cervical cell lines employing a highly sensitive proteomic technology coupled with bioinformatics analysis. MATERIALS AND METHODS: LC/MS-MS proteomics and bioinformatics analysis were performed in the secretome of four informative cervical cell lines SiHa (HPV16+), HeLa (HPV18+), C33A (HPV-) and HCK1T (normal). RESULTS: The proteomic pattern of each cancer cell line compared to HCK1T was identified and a detailed bioinformatics analysis disclosed inhibition of matrix metalloproteases in cancer cell lines. This prediction was further confirmed via zymography for MMP-2 and MMP-9, western blot analysis for ADAM10 and by MRM for TIMP1. The differential expression of important secreted proteins such as CATD, FUCA1 and SOD2 was also confirmed by western blot analysis. MRM-targeted proteomics analysis confirmed the differential expression of CATD, CATB, SOD2, QPCT and NEU1. CONCLUSION: High resolution proteomics analysis of cervical cancer secretome revealed significantly deregulated biological processes and proteins implicated in cervical carcinogenesis. PMID- 29109104 TI - Advocating for the DREAM Act: Why Pediatricians Should Care and What They Can Do. PMID- 29109103 TI - Hepatocyte nuclear factor 1A deficiency causes hemolytic anemia in mice by altering erythrocyte sphingolipid homeostasis. AB - The hepatocyte nuclear factor (HNF) family regulates complex networks of metabolism and organ development. Human mutations in its prototypical member HNF1A cause maturity-onset diabetes of the young (MODY) type 3. In this study, we identified an important role for HNF1A in the preservation of erythrocyte membrane integrity, calcium homeostasis, and osmotic resistance through an as-yet unrecognized link of HNF1A to sphingolipid homeostasis. HNF1A-/- mice displayed microcytic hypochromic anemia with reticulocytosis that was partially compensated by avid extramedullary erythropoiesis at all erythroid stages in the spleen thereby excluding erythroid differentiation defects. Morphologically, HNF1A-/- erythrocytes resembled acanthocytes and displayed increased phosphatidylserine exposure, high intracellular calcium, and elevated osmotic fragility. Sphingolipidome analysis by mass spectrometry revealed substantial and tissue specific sphingolipid disturbances in several tissues including erythrocytes with the accumulation of sphingosine as the most prominent common feature. All HNF1A-/ erythrocyte defects could be simulated by exposure of wild-type (WT) erythrocytes to sphingosine in vitro and attributed in part to sphingosine induced suppression of the plasma-membrane Ca2+-ATPase activity. Bone marrow transplantation rescued the anemia phenotype in vivo, whereas incubation with HNF1A-/- plasma increased the osmotic fragility of WT erythrocytes in vitro. Our data suggest a non-cell-autonomous erythrocyte defect secondary to the sphingolipid changes caused by HNF1A deficiency. Transcriptional analysis revealed 4 important genes involved in sphingolipid metabolism to be deregulated in HNF1A deficiency: Ormdl1, sphingosine kinase-2, neutral ceramidase, and ceramide synthase-5. The considerable erythrocyte defects in murine HNF1A deficiency encourage clinical studies to explore the hematological consequences of HNF1A deficiency in human MODY3 patients. PMID- 29109105 TI - Understanding the Highs and Lows of Adolescent Marijuana Use. PMID- 29109106 TI - Prevalence and Attitudes Regarding Marijuana Use Among Adolescents Over the Past Decade. AB - BACKGROUND: Adolescent marijuana prevalence has not increased since 2005 despite a substantial decrease in the percentage of adolescents who believe marijuana use leads to great risk of harm. This finding calls into question the long-standing, inverse connection between marijuana prevalence and perceived risk of use, a connection central to many arguments opposing marijuana legalization. We tested 2 hypotheses for why marijuana prevalence did not increase after 2005: (1) decreases in adolescent use of cigarettes and alcohol reduced risk for marijuana use and counteracted the expected risk in marijuana prevalence, and/or (2) perceived risk of harm now plays a smaller role in marijuana use. METHODS: Data came from the annual, nationally-representative Monitoring the Future study from 1991 to 2016, in which 1 100 000 US students in eighth, 10th, and 12th grade were surveyed. RESULTS: The entire sample was stratified into 3 mutually exclusive and exhaustive groups on the basis of cigarette and alcohol use. Within each of the 3 groups, marijuana prevalence increased from 2005 to 2016. Paradoxically, when the 3 groups were combined into 1 analysis pool, overall marijuana prevalence did not increase. The seeming paradox results from a decline in the percentage of adolescents who used cigarettes; as this group grew smaller, so too did its disproportionately large contribution to overall marijuana prevalence. Perceived risk of harm from marijuana remained a strong indicator of use throughout 2005 to 2016. CONCLUSIONS: Perceived risk of marijuana remains tightly associated with use, and adolescent marijuana prevalence today would be at or near record highs if cigarette use had not declined since 2005, according to study projections. PMID- 29109108 TI - Ophthalmologists should be able to prescribe bevacizumab, says royal college. PMID- 29109107 TI - Web-based Social Media Intervention to Increase Vaccine Acceptance: A Randomized Controlled Trial. AB - BACKGROUND: Interventions to address vaccine hesitancy and increase vaccine acceptance are needed. This study sought to determine if a Web-based, social media intervention increases early childhood immunization. METHODS: A 3-arm, randomized controlled trial was conducted in Colorado from September 2013 to July 2016. Participants were pregnant women, randomly assigned (3:2:1) to a Web site with vaccine information and interactive social media components (VSM), a Web site with vaccine information (VI), or usual care (UC). Vaccination was assessed in infants of participants from birth to age 200 days. The primary outcome was days undervaccinated, measured as a continuous and dichotomous variable. RESULTS: Infants of 888 participants were managed for 200 days. By using a nonparametric rank-based analysis, mean ranks for days undervaccinated were significantly lower in the VSM arm versus UC (P = .02) but not statistically different between the VI and UC (P = .08) or between VSM and VI arms (P = .63). The proportions of infants up-to-date at age 200 days were 92.5, 91.3, and 86.6 in the VSM, VI, and UC arms, respectively. Infants in the VSM arm were more likely to be up-to-date than infants in the UC arm (odds ratio [OR] = 1.92; 95% confidence interval [CI], 1.07 3.47). Up-to-date status was not statistically different between VI and UC arms (OR = 1.62; 95% CI, 0.87-3.00) or between the VSM and VI arms (OR = 1.19, 95% CI, 0.70-2.03). CONCLUSIONS: Providing Web-based vaccine information with social media applications during pregnancy can positively influence parental vaccine behaviors. PMID- 29109109 TI - Letter to the Editor: Pulmonary toxicity of electronic cigarettes: more doubts than certainties. PMID- 29109110 TI - Reply to "Letter to the Editor: Pulmonary toxicity of electronic cigarettes: more doubts than certainties". PMID- 29109111 TI - Letter to the Editor: The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice. PMID- 29109112 TI - Reply to "Letter to the Editor: The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice". PMID- 29109113 TI - Generation and Characterization of SULT4A1 Mutant Mouse Models. AB - Sulfotransferase 4A1 (SULT4A1) belongs to the cytosolic sulfotransferase (SULT) superfamily of enzymes that catalyze sulfonation reactions with a variety of endogenous and exogenous substrates. Of the SULTs, SULT4A1 was shown to have the highest sequence homology between vertebrate species, yet no known function or enzymatic activity has been identified for this orphan SULT. To better understand SULT4A1 function in mammalian brain, two mutant SULT4A1 mouse strains were generated utilizing clustered regulatory interspaced short palindromic repeats (CRISPR)-content-addressable storage (Cas) 9 technology. The first strain possessed a 28-base pair (bp) deletion (Delta28) in exon 1 that resulted in a frameshift mutation with premature termination. The second strain possessed a 12 bp in-frame deletion (Delta12) immediately preceding an active site histidine111 common to the SULT family. Homozygous pups of both strains present with severe and progressive neurologic symptoms, including tremor, absence seizures, abnormal gait, ataxia, decreased weight gain compared with littermates, and death around postnatal days 21-25. SULT4A1 immunostaining was decreased in brains of heterozygous pups and not detectable in homozygous pups of both SULT4A1 mutants. SULT4A1 localization in subcellular fractions of mouse brain showed SULT4A1 associated with mitochondrial, cytosolic, and microsomal fractions, a novel localization pattern for SULTs. Finally, primary cortical neurons derived from embryonic (E15) CD-1 mice expressed high levels of SULT4A1 throughout the cell except in nuclei. Taken together, SULT4A1 appears to be an essential neuronal protein required for normal brain function, at least in mammals. Mouse models will be valuable in future studies to investigate the regulation and functions of SULT4A1 in the mammalian brain. PMID- 29109114 TI - Pointers to earlier diagnosis of endometriosis: a nested case-control study using primary care electronic health records. AB - BACKGROUND: Endometriosis is a condition with relatively non-specific symptoms, and in some cases a long time elapses from first-symptom presentation to diagnosis. AIM: To develop and test new composite pointers to a diagnosis of endometriosis in primary care electronic records. DESIGN AND SETTING: This is a nested case-control study of 366 cases using the Practice Team Information database of anonymised primary care electronic health records from Scotland. Data were analysed from 366 cases of endometriosis between 1994 and 2010, and two sets of age and GP practice matched controls: (a) 1453 randomly selected females and (b) 610 females whose records contained codes indicating consultation for gynaecological symptoms. METHOD: Composite pointers comprised patterns of symptoms, prescribing, or investigations, in combination or over time. Conditional logistic regression was used to examine the presence of both new and established pointers during the 3 years before diagnosis of endometriosis and to identify time of appearance. RESULTS: A number of composite pointers that were strongly predictive of endometriosis were observed. These included pain and menstrual symptoms occurring within the same year (odds ratio [OR] 6.5, 95% confidence interval [CI] = 3.9 to 10.6), and lower gastrointestinal symptoms occurring within 90 days of gynaecological pain (OR 6.1, 95% CI = 3.6 to 10.6). Although the association of infertility with endometriosis was only detectable in the year before diagnosis, several pain-related features were associated with endometriosis several years earlier. CONCLUSION: Useful composite pointers to a diagnosis of endometriosis in GP records were identified. Some of these were present several years before the diagnosis and may be valuable targets for diagnostic support systems. PMID- 29109115 TI - Use of an electronic consultation system in primary care: a qualitative interview study. AB - BACKGROUND: The level of demand on primary care continues to increase. Electronic or e-consultations enable patients to consult their GP online and have been promoted as having potential to improve access and efficiency. AIM: To evaluate whether an e-consultation system improves the ability of practice staff to manage workload and access. DESIGN AND SETTING: A qualitative interview study in general practices in the West of England that piloted an e-consultation system for 15 months during 2015 and 2016. METHOD: Practices were purposefully sampled by location and level of e-consultation use. Clinical, administrative, and management staff were recruited at each practice. Interviews were transcribed and analysed thematically. RESULTS: Twenty-three interviews were carried out across six general practices. Routine e-consultations offered benefits for the practice because they could be completed without direct contact between GP and patient. However, most e-consultations resulted in GPs needing to follow up with a telephone or face-to-face appointment because the e-consultation did not contain sufficient information to inform clinical decision making. This was perceived as adding to the workload and providing some patients with an alternative route into the appointment system. Although this was seen as offering some patient benefit, there appeared to be fewer benefits for the practices. CONCLUSION: The experiences of the practices in this study demonstrate that the technology, in its current form, fell short of providing an effective platform for clinicians to consult with patients and did not justify their financial investment in the system. The study also highlights the challenges of remote consultations, which lack the facility for real time interactions. PMID- 29109116 TI - Mitochondrial dynamics and respiration within cells with increased open pore cytoskeletal meshes. AB - The cytoskeletal architecture directly affects the morphology, motility, and tensional homeostasis of the cell. In addition, the cytoskeleton is important for mitosis, intracellular traffic, organelle motility, and even cellular respiration. The organelle responsible for a majority of the energy conversion for the cell, the mitochondrion, has a dependence on the cytoskeleton for mobility and function. In previous studies, we established that cytoskeletal inhibitors altered the movement of the mitochondria, their morphology, and their respiration in human dermal fibroblasts. Here, we use this protocol to investigate applicability of power law diffusion to describe mitochondrial locomotion, assessment of rates of fission and fusion in healthy and diseased cells, and differences in mitochondria locomotion in more open networks either in response to cytoskeletal destabilizers or by cell line. We found that mitochondria within fibrosarcoma cells and within fibroblast cells treated with an actin-destabilizing toxin resulted in increased net travel, increased average velocity, and increased diffusion of mitochondria when compared to control fibroblasts. Although the mitochondria within the fibrosarcoma travel further than mitochondria within their healthy counterparts, fibroblasts, the dependence on mitochondria for respiration is much lower with higher rates ofhydrogen peroxide production and was confirmed using the OROBOROS O2K. We also found that rates of fission and fusion of the mitochondria equilibrate despite significant alteration of the cytoskeleton. Rates ranged from 15% to 25%, where the highest rates were observed within the fibrosarcoma cell line. This result is interesting because the fibrosarcoma cell line does not have increased respiration metrics including when compared to fibroblast. Mitochondria travel further, faster, and have an increase in percent mitochondria splitting or joining while not dependent on the mitochondria for a majority of its energy production. This study illustrates the complex interaction between mitochondrial movement and respiration through the disruption of the cytoskeleton. PMID- 29109117 TI - Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients: mRNA Signatures of Duodenal Neoplasia. AB - To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months (P < 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNgamma) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. Cancer Prev Res; 11(1); 4-15. (c)2017 AACRSee related editorial by Shureiqi, p. 1. PMID- 29109118 TI - Evidence-based framework for a pathomechanical model of patellofemoral pain: 2017 patellofemoral pain consensus statement from the 4th International Patellofemoral Pain Research Retreat, Manchester, UK: part 3. PMID- 29109119 TI - Causes and consequences of chromosome segregation error in preimplantation embryos. AB - Errors in chromosome segregation are common during the mitotic divisions of preimplantation development in mammalian embryos, giving rise to so-called 'mosaic' embryos possessing a mixture of euploid and aneuploid cells. Mosaicism is widely considered to be detrimental to embryo quality and is frequently used as criteria to select embryos for transfer in human fertility clinics. However, despite the clear clinical importance, the underlying defects in cell division that result in mosaic aneuploidy remain elusive. In this review, we summarise recent findings from clinical and animal model studies that provide new insights into the fundamental mechanisms of chromosome segregation in the highly unusual cellular environment of early preimplantation development and consider recent clues as to why errors should commonly occur in this setting. We furthermore discuss recent evidence suggesting that mosaicism is not an irrevocable barrier to a healthy pregnancy. Understanding the causes and biological impacts of mosaic aneuploidy will be pivotal in the development and fine-tuning of clinical embryo selection methods. PMID- 29109121 TI - Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation. AB - The decision between T cell activation and tolerance is governed by the spatial and temporal integration of diverse molecular signals and events occurring downstream of TCR and costimulatory or coinhibitory receptor engagement. The PI3K protein kinase B (PKB; also known as Akt) signaling pathway is a central axis in mediating proximal signaling events of TCR and CD28 engagement in T cells. Perturbation of the PI3K-PKB pathway, or the loss of negative regulators of T cell activation, such as the E3 ubiquitin ligase Cbl-b, have been reported to lead to increased susceptibility to autoimmunity. In this study, we further examined the molecular pathway linking PKB and Cbl-b in murine models. Our data show that the protein kinase GSK-3, one of the first targets identified for PKB, catalyzes two previously unreported phosphorylation events at Ser476 and Ser480 of Cbl-b. GSK-3 inactivation by PKB abrogates phosphorylation of Cbl-b at these two sites and results in reduced Cbl-b protein levels. We further show that constitutive activation of PKB in vivo results in a loss of tolerance that is mediated through the downregulation of Cbl-b. Altogether, these data indicate that the PI3K-PKB-GSK-3 pathway is a novel regulatory axis that is important for controlling the decision between T cell activation and tolerance via Cbl-b. PMID- 29109120 TI - CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy. AB - CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27-transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcgammaRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcgammaRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen. PMID- 29109122 TI - The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice. AB - Type 1 diabetes (T1D) has a strong genetic component. The insulin dependent diabetes (Idd)22 locus was identified in crosses of T1D-susceptible NOD mice with the strongly T1D-resistant ALR strain. The NODcALR-(D8Mit293-D8Mit137)/Mx (NOD Idd22) recombinant congenic mouse strain was generated in which NOD mice carry the full Idd22 confidence interval. NOD-Idd22 mice exhibit almost complete protection from spontaneous T1D and a significant reduction in insulitis. Our goal was to unravel the mode of Idd22-based protection using in vivo and in vitro models. We determined that Idd22 did not impact immune cell diabetogenicity or beta cell resistance to cytotoxicity in vitro. However, NOD-Idd22 mice were highly protected against adoptive transfer of T1D. Transferred CTLs trafficked to the pancreatic lymph node and proliferated to the same extent in NOD and NOD Idd22 mice, yet the accumulation of pathogenic CTLs in the islets was significantly reduced in NOD-Idd22 mice, correlating with disease resistance. Pancreatic endothelial cells from NOD-Idd22 animals expressed lower levels of adhesion molecules, even in response to inflammatory stimuli. Lower adhesion molecule expression resulted in weaker adherence of T cells to NOD-Idd22 endothelium compared with NOD-derived endothelium. Taken together, these results provide evidence that Idd22 regulates the ability of beta cell-autoreactive T cells to traffic into the pancreatic islets and may represent a new target for pharmaceutical intervention to potentially prevent T1D. PMID- 29109123 TI - A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen Induced Liver Injury. AB - Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury. IL-22 binding protein (IL-22BP, IL-22Ra2) is a soluble inhibitor of IL-22 that regulates IL-22 activity. However, the significance of endogenous IL-22BP in acute liver injury is unknown. We hypothesized that IL-22BP may play a role in acute liver injury. To test this hypothesis, we used Il22bp-deficient mice and murine models of acute liver damage induced by ischemia reperfusion and N-acetyl-p-aminophenol (acetaminophen) administration. We found that Il22bp-deficient mice were more susceptible to acute liver damage in both models. We used Il22 * Il22bp double deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of Cxcl10 by hepatocytes, and consequently increased infiltration of inflammatory CD11b+Ly6C+ monocytes into the liver in Il22bp-deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of Il22bp deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22-induced Cxcl10 expression. PMID- 29109125 TI - Reevaluation of Positivity Cutoff Values for the Pneumococcal Urinary Antigen Detection Assay. PMID- 29109126 TI - Effect of Breastfeeding and Additional Household Children on Cytomegalovirus Seroprevalence among U.S. Children 1 to 5 Years of Age. PMID- 29109124 TI - Endogenous Calcitriol Synthesis Controls the Humoral IgE Response in Mice. AB - The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)2D3 (calcitriol), is synthesized by the essential enzyme 25-hydroxyvitamin D3-1alpha hydroxylase (CYP27B1), which can be expressed by activated immune cells. The role of endogenous calcitriol synthesis for the regulation of IgE has not been proven. In this study, we investigated IgE-responses in Cyp27b1-knockout (KO) mice following sensitization to OVA or intestinal infection with Heligmosomoides polygyrus Specific Igs and plasmablasts were determined by ELISA and ELISpot, Cyp27b1 expression was measured by quantitative PCR. The data show elevated specific IgE and IgG1 concentrations in the blood of OVA-sensitized Cyp27b1-KO mice compared with wild-type littermates (+898 and +219%). Accordingly, more OVA specific IgG1-secreting cells are present in spleen and fewer in the bone marrow of Cyp27b1-KO mice. Ag-specific mechanisms are suggested as the leucopoiesis is in general unchanged and activated murine B and T lymphocytes express Cyp27b1 Accordingly, elevated specific IgE concentrations in the blood of sensitized T cell-specific Cyp27b1-KO mice support a lymphocyte-driven mechanism. In an independent IgE-inducing model, i.e., intestinal infection with H. polygyrus, we validated the increase of total and specific IgE concentrations of Cyp27b1-KO compared with wild-type mice, but not those of IgG1 or IgA. We conclude that endogenous calcitriol has an impact on the regulation of IgE in vivo. Our data provide genetic evidence supporting previous preclinical and clinical findings and suggest that vitamin D deficiency not only promotes bone diseases but also type I sensitization. PMID- 29109127 TI - A complex genomic locus drives mtDNA replicase POLG expression to its disease related nervous system regions. AB - DNA polymerase gamma (POLG), the mtDNA replicase, is a common cause of mitochondrial neurodegeneration. Why POLG defects especially cause central nervous system (CNS) diseases is unknown. We discovered a complex genomic regulatory locus for POLG, containing three functional CNS-specific enhancers that drive expression specifically in oculomotor complex and sensory interneurons of the spinal cord, completely overlapping with the regions showing neuronal death in POLG patients. The regulatory locus also expresses two functional RNAs, LINC00925-RNA and MIR9-3, which are coexpressed with POLG The MIR9-3 targets include NR2E1, a transcription factor maintaining neural stem cells in undifferentiated state, and MTHFD2, the regulatory enzyme of mitochondrial folate cycle, linking POLG expression to stem cell differentiation and folate metabolism. Our evidence suggests that distant genomic non-coding regions contribute to regulation of genes encoding mitochondrial proteins. Such genomic arrangement of POLG locus, driving expression to CNS regions affected in POLG patients, presents a potential mechanism for CNS-specific manifestations in POLG disease. PMID- 29109129 TI - Histopathological nature of myofascial trigger points at different stages of recovery from injury in a rat model. AB - OBJECTIVE: To investigate the histopathological nature of myofascial trigger points (MTrPs) or spots (MTrSs) at different stages of recovery from injury in a rat model. METHODS: Forty Sprague-Dawley rats were randomly divided into two groups: a control group (CG) and experimental group (EG). The CG was further randomly subdivided into CG1 and CG2 subgroups. The CG2 was used for palpating the taut band and CG1 as a blank. EG was subdivided into three groups according to recovery times: 4 weeks (4W), 8 weeks (8W) and 12 weeks (12W); these groups consisted of eight rats each. All CG rats received no intervention, whereas the intervention in EG rats was by a blunt strike to the vastus medialis and eccentric exercise for 8 weeks. The taut bands with spontaneous electrical activity were then detected in the muscle to guide a muscle biopsy. The histopathological findings were investigated under optical and electron microscopes in all groups. RESULTS: Under optical microscopy, the differently augmented sizes of round fibres (contracture knots) with deep staining in the transverse section and fusiform shapes in a longitudinal view were clearly seen in CG2 and EGs with a large diameter; the number of contracture knots was significantly more in EGs than in CGs. Under an electron microscope, the mitochondria in EGs significantly decreased with abnormal structures. The sarcomeres were significantly shortened in the 8W and 12W EGs. CONCLUSION: An injury can cause activation of MTrSs in a muscle and an activated level of MTrPs depending on the number of contracture knots in muscle with impaired energy production. PMID- 29109128 TI - SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis. AB - Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis. PMID- 29109130 TI - Effects of electroacupuncture at BL33 on detrusor smooth muscle activity in a rat model of urinary retention. AB - BACKGROUND: Detrusor smooth muscle (DSM) underactivity may lead to urinary retention (UR). Electroacupuncture (EA) at BL33 may be effective in improving DSM contractions. OBJECTIVES: This study aimed to investigate: (1) the effect of EA at BL33; and (2) the effect of different manipulation methods at BL33 on the modulation of DSM contractions in UR rats. METHODS: 30 male Sprague-Dawley rats were anaesthetised with urethane and modelled by urethral outlet obstruction. First, 2 Hz EA at BL33, SP6 and LI4 wasrandomly applied to the UR rats for 5 min to observe the immediate effects (n=10); second, manual acupuncture (MA) (n=10) and 100 Hz EA (n=10) were applied with the same programme. DSM electromyography (EMG) and cystometrogram data were evaluated. RESULTS: (1) 2 Hz EA at BL33 and SP6 significantly increased DSM discharging frequency (0.80+/-0.10 Hz, P<0.001, and 0.22+/-0.14 Hz, P=0.038), shortened micturation intervals (65.67+/-20.65 s, P=0.008, and 35.62+/-15.84 s, P=0.042), prolonged the duration of voiding (2.13+/ 0.61 s, P=0.005, and 0.47+/-0.16 s, P=0.015), and reduced residual pressure ( 0.91+/-0.31 mmHg, P=0.019, and -0.66+/-0.27 mmHg, P=0.046). EA at LI4 was not associated with any functional effects (P>0.05). Compared with SP6, EA at BL33 had greater positive effects on DSM discharging frequency, duration of discharging, and duration of voiding (all P<0.05). (2) No statistically significant differences were shown between MA, 2 Hz EA and 100 Hz EA interventions when stimulating at BL33, SP6 or LI4. CONCLUSIONS: EA at BL33 improved DSM contractions to a greater degree than EA at SP6 or LI4. There were no differences in effect when stimulating using 2 Hz EA, 100 Hz EA and MA. PMID- 29109131 TI - Carbidopa: a selective Ah receptor modulator (SAhRM). AB - The aryl hydrocarbon receptor (AhR) was discovered as the intracellular receptor that bound with high affinity to the environmental toxicant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), and the AhR is required for mediating the toxicity induced by TCDD. Subsequent studies show that the AhR binds structurally diverse chemicals including plant-derived compounds that promote health and several AhR-active pharmaceuticals that exhibit anticancer activity. In this issue, there is a report that carbidopa, a drug used for treating Parkinson's disease, is also an AhR ligand, and this compound inhibits pancreatic cancer cell and tumor growth. These results are consistent with activities of other AhR active compounds that inhibit carcinogenesis. Like carbidopa, these chemicals are selective AhR modulators with potential clinical applications that are AhR dependent. PMID- 29109132 TI - Granulocytic sarcoma of the choroid plexus complicating acute leukemia. PMID- 29109133 TI - Ping-pong gaze and ocular nodding in bacterial meningitis. PMID- 29109134 TI - Editors' Note. PMID- 29109135 TI - Letter re: Evaluating the safety of beta-interferons in MS: A series of nested case-control studies. PMID- 29109136 TI - Author response: Evaluating the safety of beta-interferons in MS: A series of nested case-control studies. PMID- 29109137 TI - Letter re: Education Research: Positive effect of scheduled faculty modeling on clerkship student bedside skills exposure and learning. PMID- 29109138 TI - Author response: Education Research: Positive effect of scheduled faculty modeling on clerkship student bedside skills exposure and learning. PMID- 29109139 TI - Clinical Reasoning: A patient with a history of encephalomyelitis and recurrent optic neuritis. PMID- 29109140 TI - Teaching NeuroImages: Sucking candy sign in Bell palsy. PMID- 29109141 TI - Teaching NeuroImages: Craniofacial fibrous dysplasia: Loss of vision after head trauma. PMID- 29109142 TI - Teaching Video NeuroImages: Upbeat and horizontal gaze-evoked nystagmus in bilateral medial medullary infarction. PMID- 29109143 TI - MicroRNA-874-mediated inhibition of the major G1/S phase cyclin, CCNE1, is lost in osteosarcomas. AB - The tumor microenvironment is characterized by nutrient-deprived conditions in which the cancer cells have to adapt for survival. Serum starvation resembles the growth factor deprivation characteristic of the poorly vascularized tumor microenvironment and has aided in the discovery of key growth regulatory genes and microRNAs (miRNAs) that have a role in the oncogenic transformation. We report here that miR-874 down-regulates the major G1/S phase cyclin, cyclin E1 (CCNE1), during serum starvation. Because the adaptation of cancer cells to the tumor microenvironment is vital for subsequent oncogenesis, we tested for miR-874 and CCNE1 interdependence in osteosarcoma cells. We observed that miR-874 inhibits CCNE1 expression in primary osteoblasts, but in aggressive osteosarcomas, miR-874 is down-regulated, leading to elevated CCNE1 expression and appearance of cancer-associated phenotypes. We established that loss of miR 874-mediated control of cyclin E1 is a general feature of osteosarcomas. The down regulation of CCNE1 by miR-874 is independent of E2F transcription factors. Restoration of miR-874 expression impeded S phase progression, suppressing aggressive growth phenotypes, such as cell invasion, migration, and xenograft tumors, in nude mice. In summary, we report that miR-874 inhibits CCNE1 expression during growth factor deprivation and that miR-874 down-regulation in osteosarcomas leads to CCNE1 up-regulation and more aggressive growth phenotypes. PMID- 29109144 TI - Autophagic clearance of proteasomes in yeast requires the conserved sorting nexin Snx4. AB - Turnover of the 26S proteasome by autophagy is an evolutionarily conserved process that governs cellular proteolytic capacity and eliminates inactive particles. In most organisms, proteasomes are located in both the nucleus and cytoplasm. However, the specific autophagy routes for nuclear and cytoplasmic proteasomes are unclear. Here, we investigate the spatial control of autophagic proteasome turnover in budding yeast (Saccharomyces cerevisiae). We found that nitrogen starvation-induced proteasome autophagy is independent of known nucleophagy pathways but is compromised when nuclear protein export is blocked. Furthermore, via pharmacological tethering of proteasomes to chromatin or the plasma membrane, we provide evidence that nuclear proteasomes at least partially disassemble before autophagic turnover, whereas cytoplasmic proteasomes remain largely intact. A targeted screen of autophagy genes identified a requirement for the conserved sorting nexin Snx4 in the autophagic turnover of proteasomes and several other large multisubunit complexes. We demonstrate that Snx4 cooperates with sorting nexins Snx41 and Snx42 to mediate proteasome turnover and is required for the formation of cytoplasmic proteasome puncta that accumulate when autophagosome formation is blocked. Together, our results support distinct mechanistic paths in the turnover of nuclear versus cytoplasmic proteasomes and point to a critical role for Snx4 in cytoplasmic agglomeration of proteasomes en route to autophagic destruction. PMID- 29109145 TI - Jumpstarting the cytochrome P450 catalytic cycle with a hydrated electron. AB - Cytochrome P450cam (CYP101Fe3+) regioselectively hydroxylates camphor. Possible hydroxylating intermediates in the catalytic cycle of this well-characterized enzyme have been proposed on the basis of experiments carried out at very low temperatures and shunt reactions, but their presence has not yet been validated at temperatures above 0 degrees C during a normal catalytic cycle. Here, we demonstrate that it is possible to mimic the natural catalytic cycle of CYP101Fe3+ by using pulse radiolysis to rapidly supply the second electron of the catalytic cycle to camphor-bound CYP101[FeO2]2+ Judging by the appearance of an absorbance maximum at 440 nm, we conclude that CYP101[FeOOH]2+ (compound 0) accumulates within 5 MUs and decays rapidly to CYP101Fe3+, with a k440 nm of 9.6 * 104 s-1 All processes are complete within 40 MUs at 4 degrees C. Importantly, no transient absorbance bands could be assigned to CYP101[FeO2+por*+] (compound 1) or CYP101[FeO2+] (compound 2). However, indirect evidence for the involvement of compound 1 was obtained from the kinetics of formation and decay of a tyrosyl radical. 5-Hydroxycamphor was formed quantitatively, and the catalytic activity of the enzyme was not impaired by exposure to radiation during the pulse radiolysis experiment. The rapid decay of compound 0 enabled calculation of the limits for the Gibbs activation energies for the conversions of compound 0 -> compound 1 -> compound 2 -> CYP101Fe3+, yielding a DeltaG? of 45, 39, and 39 kJ/mol, respectively. At 37 degrees C, the steps from compound 0 to the iron(III) state would take only 4 MUs. Our kinetics studies at 4 degrees C complement the canonical mechanism by adding the dimension of time. PMID- 29109146 TI - Peptide splicing by the proteasome. AB - The proteasome is the major protease responsible for the production of antigenic peptides recognized by CD8+ cytolytic T cells (CTL). These peptides, generally 8 10 amino acids long, are presented at the cell surface by major histocompatibility complex (MHC) class I molecules. Originally, these peptides were believed to be solely derived from linear fragments of proteins, but this concept was challenged several years ago by the isolation of anti-tumor CTL that recognized spliced peptides, i.e. peptides composed of fragments distant in the parental protein. The splicing process was shown to occur in the proteasome through a transpeptidation reaction involving an acyl-enzyme intermediate. Here, we review the steps that led to the discovery of spliced peptides as well as the recent advances that uncover the unexpected importance of spliced peptides in the composition of the MHC class I repertoire. PMID- 29109147 TI - Structural and dynamical characterization of the pH-dependence of the pectin methylesterase-pectin methylesterase inhibitor complex. AB - Pectin methylesterases (PMEs) catalyze the demethylesterification of pectin, one of the main polysaccharides in the plant cell wall, and are of critical importance in plant development. PME activity generates highly negatively charged pectin and mutates the physiochemical properties of the plant cell wall such that remodeling of the plant cell can occur. PMEs are therefore tightly regulated by proteinaceous inhibitors (PMEIs), some of which become active upon changes in cellular pH. Nevertheless, a detailed picture of how this pH-dependent inhibition of PME occurs at the molecular level is missing. Herein, using an interdisciplinary approach that included homology modeling, MD simulations, and biophysical and biochemical characterizations, we investigated the molecular basis of PME3 inhibition by PMEI7 in Arabidopsis thaliana Our complementary approach uncovered how changes in the protonation of amino acids at the complex interface shift the network of interacting residues between intermolecular and intramolecular. These shifts ultimately regulate the stability of the PME3-PMEI7 complex and the inhibition of the PME as a function of the pH. These findings suggest a general model of how pH-dependent proteinaceous inhibitors function. Moreover, they enhance our understanding of how PMEs may be regulated by pH and provide new insights into how this regulation may control the physical properties and structure of the plant cell wall. PMID- 29109148 TI - HDAC8 substrate selectivity is determined by long- and short-range interactions leading to enhanced reactivity for full-length histone substrates compared with peptides. AB - Histone deacetylases (HDACs) catalyze deacetylation of acetyl-lysine residues within proteins. To date, HDAC substrate specificity and selectivity have been largely estimated using peptide substrates. However, it is unclear whether peptide substrates accurately reflect the substrate selectivity of HDAC8 toward full-length proteins. Here, we compare HDAC8 substrate selectivity in the context of peptides, full-length proteins, and protein-nucleic acid complexes. We demonstrate that HDAC8 catalyzes deacetylation of tetrameric histone (H3/H4) substrates with catalytic efficiencies that are 40-300-fold higher than those for corresponding peptide substrates. Thus, we conclude that additional contacts with protein substrates enhance catalytic efficiency. However, the catalytic efficiency decreases for larger multiprotein complexes. These differences in HDAC8 substrate selectivity for peptides and full-length proteins suggest that HDAC8 substrate preference is based on a combination of short- and long-range interactions. In summary, this work presents detailed kinetics for HDAC8 catalyzed deacetylation of singly-acetylated, full-length protein substrates, revealing that HDAC8 substrate selectivity is determined by multiple factors. These insights provide a foundation for understanding recognition of full-length proteins by HDACs. PMID- 29109149 TI - Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA binding protein TDP-43, a modification linked to neurodegeneration. AB - Oxidative and endoplasmic reticulum (ER) stresses are hallmarks of the pathophysiology of ALS and other neurodegenerative diseases. In these stresses, different kinases phosphorylate eukaryotic initiation factor eIF2alpha, enabling the translation of stress response genes; among these is GADD34, the protein product of which recruits the alpha-isoform of protein phosphatase 1 catalytic subunit (PP1alpha) and eIF2alpha to assemble a phosphatase complex catalyzing eIF2alpha dephosphorylation and resumption of protein synthesis. Aberrations in this pathway underlie the aforementioned disorders. Previous observations indicating that GADD34 is induced by arsenite, a thiol-directed oxidative stressor, in the absence of eIF2alpha phosphorylation suggest other roles for GADD34. Here, we report that arsenite-induced oxidative stress differs from thapsigargin- or tunicamycin-induced ER stress in promoting GADD34 transcription and the preferential translation of its mRNA in the absence of eIF2alpha phosphorylation. Arsenite also stabilized GADD34 protein, slowing its degradation. In response to oxidative stress, but not ER stress, GADD34 recruited TDP-43, and enhanced cytoplasmic distribution and cysteine modifications of TDP 43 promoted its binding to GADD34. Arsenite also recruited a TDP-43 kinase, casein kinase-1epsilon (CK1epsilon), to GADD34. Concomitant with TDP-43 aggregation and proteolysis after prolonged arsenite exposure, GADD34-bound CK1epsilon catalyzed TDP-43 phosphorylations at serines 409/410, which were diminished or absent in GADD34-/- cells. Our findings highlight that the phosphatase regulator, GADD34, also functions as a kinase scaffold in response to chronic oxidative stress and recruits CK1epsilon and oxidized TDP-43 to facilitate its phosphorylation, as seen in TDP-43 proteinopathies. PMID- 29109150 TI - Role of salt bridges in the dimer interface of 14-3-3zeta in dimer dynamics, N terminal alpha-helical order, and molecular chaperone activity. AB - The 14-3-3 family of intracellular proteins are dimeric, multifunctional adaptor proteins that bind to and regulate the activities of many important signaling proteins. The subunits within 14-3-3 dimers are predicted to be stabilized by salt bridges that are largely conserved across the 14-3-3 protein family and allow the different isoforms to form heterodimers. Here, we have examined the contributions of conserved salt-bridging residues in stabilizing the dimeric state of 14-3-3zeta. Using analytical ultracentrifugation, our results revealed that Asp21 and Glu89 both play key roles in dimer dynamics and contribute to dimer stability. Furthermore, hydrogen-deuterium exchange coupled with mass spectrometry showed that mutation of Asp21 promoted disorder in the N-terminal helices of 14-3-3zeta, suggesting that this residue plays an important role in maintaining structure across the dimer interface. Intriguingly, a D21N 14-3-3zeta mutant exhibited enhanced molecular chaperone ability that prevented amorphous protein aggregation, suggesting a potential role for N-terminal disorder in 14-3 3zeta's poorly understood chaperone action. Taken together, these results imply that disorder in the N-terminal helices of 14-3-3zeta is a consequence of the dimer-monomer dynamics and may play a role in conferring chaperone function to 14 3-3zeta protein. PMID- 29109151 TI - Peropsin modulates transit of vitamin A from retina to retinal pigment epithelium. AB - Peropsin is a non-visual opsin in both vertebrate and invertebrate species. In mammals, peropsin is present in the apical microvilli of retinal pigment epithelial (RPE) cells. These structures interdigitate with the outer segments of rod and cone photoreceptor cells. RPE cells play critical roles in the maintenance of photoreceptors, including the recycling of visual chromophore for the opsin visual pigments. Here, we sought to identify the function of peropsin in the mouse eye. To this end, we generated mice with a null mutation in the peropsin gene (Rrh). These mice exhibited normal retinal histology, normal morphology of outer segments and RPE cells, and no evidence of photoreceptor degeneration. Biochemically, Rrh-/- mice had ~2-fold higher vitamin A (all-trans retinol (all-trans-ROL)) in the neural retina following a photobleach and 5-fold lower retinyl esters in the RPE. This phenotype was similar to those reported in mice that lack interphotoreceptor retinoid-binding protein (IRBP) or cellular retinol-binding protein, suggesting that peropsin plays a role in the movement of all-trans-ROL from photoreceptors to the RPE. We compared the phenotypes in mice lacking both peropsin and IRBP with those of mice lacking peropsin or IRBP alone and found that the retinoid phenotype was similarly severe in each of these knock out mice. We conclude that peropsin controls all-trans-ROL movement from the retina to the RPE or may regulate all-trans-ROL storage within the RPE. We propose that peropsin affects light-dependent regulation of all-trans-ROL uptake from photoreceptors into RPE cells through an as yet undefined mechanism. PMID- 29109152 TI - Prodomain-growth factor swapping in the structure of pro-TGF-beta1. AB - TGF-beta is synthesized as a proprotein that dimerizes in the endoplasmic reticulum. After processing in the Golgi to cleave the N-terminal prodomain from the C-terminal growth factor (GF) domain in each monomer, pro-TGF-beta is secreted and stored in latent complexes. It is unclear which prodomain and GF monomer are linked before proprotein convertase cleavage and how much conformational change occurs following cleavage. We have determined a structure of pro-TGF-beta1 with the proprotein convertase cleavage site mutated to mimic the structure of the TGF-beta1 proprotein. Structure, mutation, and model building demonstrate that the prodomain arm domain in one monomer is linked to the GF that interacts with the arm domain in the other monomer in the dimeric structure (i.e. the prodomain arm domain and GF domain in each monomer are swapped). Swapping has important implications for the mechanism of biosynthesis in the TGF-beta family and is relevant to the mechanism for preferential formation of heterodimers over homodimers for some members of the TGF-beta family. Our structure, together with two previous ones, also provides insights into which regions of the prodomain-GF complex are highly structurally conserved and which are perturbed by crystal lattice contacts. PMID- 29109153 TI - Structure-function analyses reveal key features in Staphylococcus aureus IsdB associated unfolding of the heme-binding pocket of human hemoglobin. AB - IsdB is a receptor on the surface of the bacterial pathogen Staphylococcus aureus that extracts heme from hemoglobin (Hb) to enable growth on Hb as a sole iron source. IsdB is critically important both for in vitro growth on Hb and in infection models and is also highly up-regulated in blood, serum, and tissue infection models, indicating a key role of this receptor in bacterial virulence. However, structural information for IsdB is limited. We present here a crystal structure of a complex between human Hb and IsdB. In this complex, the alpha subunits of Hb are refolded with the heme displaced to the interface with IsdB. We also observe that atypical residues of Hb, His58 and His89 of alphaHb, coordinate to the heme iron, which is poised for transfer into the heme-binding pocket of IsdB. Moreover, the porphyrin ring interacts with IsdB residues Tyr440 and Tyr444 Previously, Tyr440 was observed to coordinate heme iron in an IsdB.heme complex structure. A Y440F/Y444F IsdB variant we produced was defective in heme transfer yet formed a stable complex with Hb (Kd = 6 +/- 2 MUm) in solution with spectroscopic features of the bis-His species observed in the crystal structure. Haptoglobin binds to a distinct site on Hb to inhibit heme transfer to IsdB and growth of S. aureus, and a ternary complex of IsdB.Hb.Hp was observed. We propose a model for IsdB heme transfer from Hb that involves unfolding of Hb and heme iron ligand exchange. PMID- 29109154 TI - Hierarchical protein targeting and secretion is controlled by an affinity switch in the type III secretion system of enteropathogenic Escherichia coli. AB - Type III secretion (T3S), a protein export pathway common to Gram-negative pathogens, comprises a trans-envelope syringe, the injectisome, with a cytoplasm facing translocase channel. Exported substrates are chaperone-delivered to the translocase, EscV in enteropathogenic Escherichia coli, and cross it in strict hierarchical manner, for example, first "translocators", then "effectors". We dissected T3S substrate targeting and hierarchical switching by reconstituting them in vitro using inverted inner membrane vesicles. EscV recruits and conformationally activates the tightly membrane-associated pseudo-effector SepL and its chaperone SepD. This renders SepL a high-affinity receptor for translocator/chaperone pairs, recognizing specific chaperone signals. In a second, SepD-coupled step, translocators docked on SepL become secreted. During translocator secretion, SepL/SepD suppress effector/chaperone binding to EscV and prevent premature effector secretion. Disengagement of the SepL/SepD switch directs EscV to dedicated effector export. These findings advance molecular understanding of T3S and reveal a novel mechanism for hierarchical trafficking regulation in protein secretion channels. PMID- 29109155 TI - Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle. AB - Cellular metabolic demands change throughout the cell cycle. Nevertheless, a characterization of how metabolic fluxes adapt to the changing demands throughout the cell cycle is lacking. Here, we developed a temporal-fluxomics approach to derive a comprehensive and quantitative view of alterations in metabolic fluxes throughout the mammalian cell cycle. This is achieved by combining pulse-chase LC MS-based isotope tracing in synchronized cell populations with computational deconvolution and metabolic flux modeling. We find that TCA cycle fluxes are rewired as cells progress through the cell cycle with complementary oscillations of glucose versus glutamine-derived fluxes: Oxidation of glucose-derived flux peaks in late G1 phase, while oxidative and reductive glutamine metabolism dominates S phase. These complementary flux oscillations maintain a constant production rate of reducing equivalents and oxidative phosphorylation flux throughout the cell cycle. The shift from glucose to glutamine oxidation in S phase plays an important role in cell cycle progression and cell proliferation. PMID- 29109156 TI - Improving Genomic Prediction in Cassava Field Experiments Using Spatial Analysis. AB - Cassava (Manihot esculenta Crantz) is an important staple food in sub-Saharan Africa. Breeding experiments were conducted at the International Institute of Tropical Agriculture in cassava to select elite parents. Taking into account the heterogeneity in the field while evaluating these trials can increase the accuracy in estimation of breeding values. We used an exploratory approach using the parametric spatial kernels Power, Spherical, and Gaussian to determine the best kernel for a given scenario. The spatial kernel was fit simultaneously with a genomic kernel in a genomic selection model. Predictability of these models was tested through a 10-fold cross-validation method repeated five times. The best model was chosen as the one with the lowest prediction root mean squared error compared to that of the base model having no spatial kernel. Results from our real and simulated data studies indicated that predictability can be increased by accounting for spatial variation irrespective of the heritability of the trait. In real data scenarios we observed that the accuracy can be increased by a median value of 3.4%. Through simulations, we showed that a 21% increase in accuracy can be achieved. We also found that Range (row) directional spatial kernels, mostly Gaussian, explained the spatial variance in 71% of the scenarios when spatial correlation was significant. PMID- 29109157 TI - An ultraprocessive, accurate reverse transcriptase encoded by a metazoan group II intron. AB - Group II introns and non-LTR retrotransposons encode a phylogenetically related family of highly processive reverse transcriptases (RTs) that are essential for mobility and persistence of these retroelements. Recent crystallographic studies on members of this RT family have revealed that they are structurally distinct from the retroviral RTs that are typically used in biotechnology. However, quantitative, structure-guided analysis of processivity, efficiency, and accuracy of this alternate RT family has been lacking. Here, we characterize the processivity of a group II intron maturase RT from Eubacterium rectale (E.r), for which high-resolution structural information is available. We find that the E.r. maturase RT (MarathonRT) efficiently copies transcripts at least 10 kb in length and displays superior intrinsic RT processivity compared to commercial enzymes such as Superscript IV (SSIV). The elevated processivity of MarathonRT is at least partly mediated by a loop structure in the finger subdomain that acts as a steric guard (the alpha-loop). Additionally, we find that a positively charged secondary RNA binding site on the surface of the RT diminishes the primer utilization efficiency of the enzyme, and that reengineering of this surface enhances capabilities of the MarathonRT. Finally, using single-molecule sequencing, we show that the error frequency of MarathonRT is comparable to that of other high-performance RTs, such as SSIV, which were tested in parallel. Our results provide a structural framework for understanding the enhanced processivity of retroelement RTs, and they demonstrate the potential for engineering a powerful new generation of RT tools for application in biotechnology and research. PMID- 29109158 TI - Metabolic Mitigation of Staphylococcus aureus Vancomycin Intermediate-Level Susceptibility. AB - Staphylococcus aureus is a major human pathogen whose infections are increasingly difficult to treat due to increased antibiotic resistance, including resistance to vancomycin. Vancomycin-intermediate S. aureus (VISA) strains develop resistance to vancomycin through adaptive changes that are incompletely understood. Central to this adaptation are metabolic changes that permit growth in the presence of vancomycin. To define the metabolic changes associated with adaptive resistance to vancomycin in S. aureus, the metabolomes of a vancomycin sensitive and VISA strain pair isolated from the same patient shortly after vancomycin therapy began and following vancomycin treatment failure were analyzed. The metabolic adaptations included increases in acetogenesis, carbon flow through the pentose phosphate pathway, wall teichoic acid and peptidoglycan precursor biosynthesis, purine biosynthesis, and decreased tricarboxylic acid (TCA) cycle activity. The significance of these metabolic pathways for vancomycin intermediate susceptibility was determined by assessing the synergistic potential of human-use-approved inhibitors of these pathways in combination with vancomycin against VISA strains. Importantly, inhibitors of amino sugar and purine biosynthesis acted synergistically with vancomycin to kill a diverse set of VISA strains, suggesting that combinatorial therapy could augment the efficacy of vancomycin even in patients infected with VISA strains. PMID- 29109159 TI - Overtreatment of Asymptomatic Candiduria among Hospitalized Patients: a Multi institutional Study. AB - Candiduria is common in hospitalized patients, and asymptomatic candiduria contributes to antifungal overuse. The guidelines for management of asymptomatic candiduria do not recommend antifungal use, but rather the elimination of predisposing factors. It is unknown whether these recommendations are being followed. The primary objective of this study was to characterize candiduria management among hospitalized patients. This was a retrospective cohort study of a random sample of 305 hospitalized patients with candiduria at four U.S. medical centers from January 2010 to December 2013. Patients were classified as asymptomatic or symptomatic based on established criteria, and data were collected by chart review. Infectious Diseases Society of America (IDSA) treatment guideline adherence and its association with clinical outcomes, including candiduria recurrence (short- and long-term) and 30-day readmission, were assessed. Eighty percent of patients were classified as having asymptomatic candiduria. Overall, 143 (47%) patients were not managed according to recommended guidelines, including 105/243 (43%) in the asymptomatic candiduria group and 38/62 (61%) in the symptomatic group (P = 0.01). Discordance among asymptomatic patients was driven by overtreatment with an antifungal (98/105 [93%]). Thirty three percent of patients with asymptomatic candiduria not managed according to the guidelines were treated for over 7 days, and 5% received over 14 days of therapy. Fluconazole was the most commonly used empirical antifungal among asymptomatic candiduria patients (96%), followed by micafungin (4%). Asymptomatic candiduria patients not managed according to the guidelines had a trend toward higher 30-day readmission (35% versus 26%, P = 0.27). Inappropriate management of candiduria among hospitalized patients was high, leading to overtreatment with antifungal therapy. PMID- 29109160 TI - Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC Producing Carbapenem-Resistant Enterobacteriaceae. AB - Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with meropenem MICs ranging from <=0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae. PMID- 29109161 TI - Combating Multidrug-Resistant Pathogens with Host-Directed Nonantibiotic Therapeutics. AB - Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral Clostridium difficile infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with Klebsiella pneumoniae when it was administered at the time of infection or at 24 h postinfection. Using the same in vitro cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against K. pneumoniae For Acinetobacter baumannii, 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern. PMID- 29109162 TI - Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis. AB - Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean +/- standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (Cmax), 1.5 +/- 0.5 versus 2.7 +/- 1.1 mg/liter (P = 0.005); time to Cmax (Tmax) (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) (P = 0.003); half life (t1/2), 9.1 +/- 3.6 versus 8.9 +/- 2.2 h (P = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC p ), 18.5 +/- 9.7 versus 28.7 +/- 9.6 mg . h/liter (P = 0.004). The tissue area under the concentration-time curve (AUC t ) for the dosing interval was 3.4 +/- 1.5 versus 5.2 +/- 1.6 mg . h/liter (P = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) (P = 0.351). Despite lower plasma Cmax and delayed Tmax values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI. PMID- 29109163 TI - Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model. AB - The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model. PMID- 29109164 TI - Zika Virus Replication Is Substantially Inhibited by Novel Favipiravir and Interferon Alpha Combination Regimens. AB - Zika virus (ZIKV) is a major public health concern due to its overwhelming spread into the Americas. Currently, there are neither licensed vaccines nor antiviral therapies available for the treatment of ZIKV. We aimed to identify and rationally optimize effective therapeutic regimens for ZIKV by evaluating the antiviral potentials of the approved broad-spectrum antiviral agents favipiravir (FAV), interferon alpha (IFN), and ribavirin (RBV) as single agents and in combinations. For these studies, Vero cells were infected with ZIKV in the presence of increasing concentrations of FAV, IFN, or/and RBV for 4 days. Supernatants were harvested daily, and the viral burden was quantified by a plaque assay on Vero cells. The time course of the viral burden during treatment in vitro was characterized by a novel translational, mechanism-based model, which was subsequently used to rationally optimize combination dosage regimens. The combination regimen of FAV plus IFN provided the greatest extent of viral inhibition without cytotoxicity, reducing the viral burden by 4.4 log10 PFU/ml at concentrations of 250 MUM FAV and 100 IU/ml IFN. Importantly, these concentrations are achievable in humans. The translational, mechanism-based model yielded unbiased and reasonably precise curve fits. Simulations with the model predicted that clinically relevant regimens of FAV plus IFN would markedly reduce viral burdens in humans, resulting in at least a 10,000-fold reduction in the amount of the virus during the first 4 days of treatment. These findings highlight the substantial promise of rationally optimized combination dosage regimens of FAV plus IFN, which should be further investigated to combat ZIKV. PMID- 29109166 TI - Acinetobacter pittii from Companion Animals Coharboring blaOXA-58, the tet(39) Region, and Other Resistance Genes on a Single Plasmid. PMID- 29109165 TI - Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites. AB - Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicoplast in the blood stage of the parasite life cycle, and IPP supplementation rescues parasites from apicoplast-perturbing drugs. Hence, any drug that kills parasites when IPP is supplied in culture must have a nonapicoplast target. Here, we use IPP supplementation to discriminate whether 23 purported apicoplast-targeting drugs are on- or off-target. We demonstrate that a prokaryotic DNA replication inhibitor (ciprofloxacin), several prokaryotic translation inhibitors (chloramphenicol, doxycycline, tetracycline, clindamycin, azithromycin, erythromycin, and clarithromycin), a tRNA synthase inhibitor (mupirocin), and two IPP synthesis pathway inhibitors (fosmidomycin and FR900098) have apicoplast targets. Intriguingly, fosmidomycin and FR900098 leave the apicoplast intact, whereas the others eventually result in apicoplast loss. Actinonin, an inhibitor of bacterial posttranslational modification, does not produce a typical delayed-death response but is rescued with IPP, thereby confirming its apicoplast target. Parasites treated with putative apicoplast fatty acid pathway inhibitors could not be rescued, demonstrating that these drugs have their primary targets outside the apicoplast, which agrees with the dispensability of the apicoplast fatty acid synthesis pathways in the blood stage of malaria parasites. IPP supplementation provides a simple test of whether a compound has a target in the apicoplast and can be used to screen novel compounds for mode of action. PMID- 29109167 TI - Cloning and Expression of Novel Aminoglycoside Phosphotransferase Genes from Campylobacter and Their Role in the Resistance to Six Aminoglycosides. AB - Nine aph genes, including aph(2")-Ib, aph(2")-Ic, aph(2")-Ig, aph(2")-If, aph(2") If1, aph(2")-If3, aph(2")-Ih, aac(6')-Ie-aph(2")-Ia, and aac(6')-Ie-aph(2")-If2, were previously identified in Campylobacter To measure the contribution of these alleles to aminoglycoside resistance, we cloned nine genes into the pBluescript and expressed them in Escherichia coli DH5alpha. The nine aph expressed in E. coli showed various levels of resistance to gentamicin, kanamycin, and tobramycin. Three genes, aac(6")-Ie-aph(2")-Ia, aph2"-If1, and aph2"-Ig, showed increased MICs to amikacin, and five aph genes were transferrable. PMID- 29109168 TI - Risk Factors and Outcomes for Ineffective Empiric Treatment of Sepsis Caused by Gram-Negative Pathogens: Stratification by Onset of Infection. AB - Sepsis and septic shock remain serious consequences of infections, with reported mortality rates in excess of 40 percent. Timely antibiotic therapy in cases of sepsis and septic shock is recognized as an important determinant of outcome. However, the administration of ineffective empirical treatment (IET) (an initial antibiotic regimen that is not active against the identified pathogen[s] based on in vitro susceptibility testing results) is associated with excess mortality compared to effective empirical treatment (EET). We examined all hospitalized patients at Barnes-Jewish Hospital with a sterile site (blood or pleural, abdominal, cerebrospinal, synovial, and pericardial fluid) culture positive for Gram-negative (GN) bacteria combined with a primary or secondary ICD-9-CM code for severe sepsis (995.92) or septic shock (785.52) between January 2010 and October 2015. Variables significantly associated with early-onset (<48 h of hospitalization) IET of GN sterile site sepsis and septic shock included age, recent hospitalization, and prior intravenous antibiotics. Late-onset IET was associated with increasing numbers of hospitalization days before infection onset and prior intravenous antibiotic administration. For patients with early-onset infection, we found no difference in rates of survival between patients receiving IET and EET. However, patients in the late-onset infection group receiving IET had a statistically lower rate of survival than those receiving EET. These data suggest that risk factors and outcomes for IET can vary based on the time of onset of infection. Our results also highlight the importance of prior intravenous antibiotic exposure as a risk factor for IET in infections by GN bacteria regardless of the time of onset of infection. PMID- 29109169 TI - Environmental Triazole Induces Cross-Resistance to Clinical Drugs and Affects Morphophysiology and Virulence of Cryptococcus gattii and C. neoformans. AB - Cryptococcus gattii and Cryptococcus neoformans are environmental fungi that cause cryptococcosis, which is usually treated with amphotericin B and fluconazole. However, therapeutic failure is increasing because of the emergence of resistant strains. Because these species are constantly isolated from vegetal materials and the usage of agrochemicals is growing, we postulate that pesticides could be responsible for the altered susceptibility of these fungi to clinical drugs. Therefore, we evaluated the influence of the pesticide tebuconazole on the susceptibility to clinical drugs, morphophysiology, and virulence of C. gattii and C. neoformans strains. The results showed that tebuconazole exposure caused in vitro cross-resistance (CR) between the agrochemical and clinical azoles (fluconazole, itraconazole, and ravuconazole) but not with amphotericin B. In some strains, CR was observed even after the exposure ceased. Further, tebuconazole exposure changed the morphology, including formation of pseudohyphae in C. neoformans H99, and the surface charge of the cells. Although the virulence of both species previously exposed to tebuconazole was decreased in mice, the tebuconazole-exposed colonies recovered from the lungs were more resistant to azole drugs than the nonexposed cells. This in vivo CR was confirmed when fluconazole was not able to reduce the fungal burden in the lungs of mice. The tolerance to azoles could be due to increased expression of the ERG11 gene in both species and of efflux pump genes (AFR1 and MDR1) in C. neoformans Our study data support the idea that agrochemical usage can significantly affect human pathogens present in the environment by affecting their resistance to clinical drugs. PMID- 29109171 TI - Postovulatory aging causes the deterioration of porcine oocytes via induction of oxidative stress. AB - Negative effects of postovulatory aging on fertilization ability and subsequent embryo development have been reported in rodents; however, the molecular and cellular changes during this process have not been fully defined. Here, we used porcine oocytes, a model that is physiologically and developmentally similar to humans, to explore the molecular mechanisms that underlie how postovulatory aging affects oocyte quality and fertilization capacity. We found that postovulatory aging caused the morphologic change of porcine oocytes by exhibiting the incompact expansion of cumulus cells and an increased occurrence of fragmentation. Aging also impaired oocyte quality by disrupting organelle structures, including the spindle assembly, actin polymerization, and mitochondrial integrity. Moreover, postovulatory aging led to the abnormal distribution of cortical granules and ovastacin, which, in turn, resulted in defective sperm binding and consequently compromised fertilization potential. Of note, we observed that postovulatory aging induced oxidative stress with a high level of reactive oxygen species and apoptotic rate in oocytes, thereby resulting in the deterioration of critical factors in the maintenance of oocyte quality and fertilization capacity. Taken together, our findings demonstrate that postovulatory aging perturbs a variety of molecular and cellular changes in porcine oocytes by inducing oxidative stress.-Miao, Y., Zhou, C., Cui, Z., Zhang, M., ShiYang, X., Lu, Y., Xiong, B. Postovulatory aging causes the deterioration of porcine oocytes via induction of oxidative stress. PMID- 29109170 TI - L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis. AB - Ethanol causes fetal alcohol spectrum disorders (FASDs) partly by inhibiting cell adhesion mediated by the L1 neural cell adhesion molecule. Ethanol interacts with an alcohol binding pocket in the L1 extracellular domain (ECD), and dephosphorylation of S1248 in the L1 cytoplasmic domain (CD) renders L1 adhesion insensitive to inhibition by ethanol (L1 insensitive). The mechanism underlying this inside-out signaling is unknown. Here we show that phosphorylation of the human L1-CD at S1152, Y1176, S1181, and S1248 renders L1 sensitive to ethanol by promoting L1 coupling with ankyrin-G and the spectrin-actin cytoskeleton. Knockdown of ankyrin-G or L1 mutations that uncouple L1 from ankyrin reduce L1 sensitivity to ethanol, but not methanol, consistent with a small conformational change in the extracellular alcohol binding pocket. Phosphorylation of Y1176 and ankyrin-G coupling with L1 are higher in NIH/3T3 clonal cell lines in which ethanol inhibits L1 adhesion than in ethanol-resistant NIH/3T3 clonal cell lines. Similarly, phosphorylation of Y1176 is higher in C57BL/6J mice that are sensitive to ethanol teratogenesis than in ethanol resistant C57BL/6N mice. Finally, polymorphisms in genes that encode ankyrin-G and p90rsk, a kinase that phosphorylates S1152, are linked to facial dysmorphology in children with heavy prenatal ethanol exposure. These findings indicate that genes that regulate L1 coupling to ankyrin may influence susceptibility to FASD.-Dou, X., Menkari, C., Mitsuyama, R., Foroud, T., Wetherill, L., Hammond, P., Suttie, M., Chen, X., Chen, S.-Y., Charness, M. E., Collaborative Initiative on Fetal Alcohol Spectrum Disorders. L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis. PMID- 29109172 TI - Development of Subunit Vaccines that Provide High Level Protection and Sterilizing Immunity Against Acute Inhalational Melioidosis. AB - Burkholderia pseudomallei, the etiologic agent of melioidosis, causes severe disease in humans and animals. Diagnosis and treatment of melioidosis can be challenging and no licensed vaccines currently exist. Several studies have shown that this pathogen expresses a variety of structurally conserved protective antigens that include cell-surface polysaccharides and cell-associated/-secreted proteins. Based on this, such antigens have become important components of the subunit vaccine candidates that we are currently developing. In the present study, the 6-deoxyheptan capsular polysaccharide (CPS) from B. pseudomallei was purified, chemically activated and covalently linked to recombinant CRM197 diphtheria toxin mutant (CRM197) to produce CPS-CRM197. Additionally, tandem nickel-cobalt affinity chromatography was used to prepare highly purified recombinant B. pseudomallei Hcp1 and TssM proteins. Immunization of C57BL/6 mice with CPS-CRM197 produced high-titer IgG and opsonizing antibody responses against the CPS component of the glycoconjugate while immunization with Hcp1 and TssM produced high titer IgG and robust IFN-gamma secreting T cell responses against the proteins. Extending upon these studies, we found that when vaccinated with a combination of CPS-CRM197 plus Hcp1, 100% of the mice survived a lethal inhalational challenge of B. pseudomallei Remarkably, 70% of the survivors had no culturable bacteria in their lungs, livers or spleens indicating that the vaccine formulation had generated sterilizing immune responses. Collectively, these studies help to better establish surrogates of antigen-induced immunity against B. pseudomallei as well as provide valuable insights towards the development of a safe, affordable and effective melioidosis vaccine. PMID- 29109174 TI - Orientia tsutsugamushi modulates endoplasmic reticulum-associated degradation to benefit its growth. AB - Orientia tsutsugamushi, an obligate intracellular bacterium that is auxotrophic for the aromatic amino acids and histidine, causes scrub typhus, a potentially deadly infection that threatens one billion people. O. tsutsugamushi growth is minimal during the first 24 to 48 h of infection, but becomes logarithmic thereafter. How the pathogen modulates cellular functions to support its growth is poorly understood. The unfolded protein response (UPR) is a cytoprotective pathway that relieves endoplasmic reticulum (ER) stress by promoting ER associated degradation (ERAD) of misfolded proteins. Here we show that O. tsutsugamushi invokes the UPR in the first 48 h and benefits from ER stress in an amino acid-dependent manner. O. tsutsugamushi also impedes ERAD during this time period. By 72 h, ER stress is alleviated and ERAD proceeds unhindered. Sustained inhibition of ERAD using RNA interference results in an O. tsutsugamushi growth defect at 72 h that can be rescued by amino acid supplementation. Thus, O. tsutsugamushi temporally stalls ERAD until ERAD-derived amino acids are needed to support its growth. The O. tsutsugamushi effector, Ank4, is linked to this phenomenon. Ank4 interacts with Bat3, a eukaryotic chaperone that is essential for ERAD, and is transiently expressed by O. tsutsugamushi during the infection period when it inhibits ERAD. Ectopically expressed Ank4 blocks ERAD to phenocopy O. tsutsugamushi infection. Our data reveal a novel mechanism by which an obligate intracellular bacterial pathogen modulates ERAD to satisfy its nutritional virulence requirements. PMID- 29109173 TI - The Homolog of the Gene bstA of the BTP1 Phage from Salmonella enterica Serovar Typhimurium ST313 Is an Antivirulence Gene in Salmonella enterica Serovar Dublin. AB - In a previous study, a novel virulence gene, bstA, identified in a Salmonella enterica serovar Typhimurium sequence type 313 (ST313) strain was found to be conserved in all published Salmonella enterica serovar Dublin genomes. In order to analyze the role of this gene in the host-pathogen interaction in S Dublin, a mutant where this gene was deleted (S Dublin DeltabstA) and a mutant which was further genetically complemented with bstA (S Dublin 3246-C) were constructed and tested in models of in vitro and in vivo infection as well as during growth competition assays in M9 medium, Luria-Bertani broth, and cattle blood. In contrast to the results obtained for a strain of S Typhimurium ST313, the lack of bstA was found to be associated with increased virulence in S Dublin. Thus, S Dublin DeltabstA showed higher levels of uptake than the wild-type strain during infection of mouse and cattle macrophages and higher net replication within human THP-1 cells. Furthermore, during mouse infections, S Dublin DeltabstA was more virulent than the wild type following a single intraperitoneal infection and showed an increased competitive index during competitive infection assays. Deletion of bstA did not affect either the amount of cytokines released by THP-1 macrophages or the cytotoxicity toward these cells. The histology of the livers and spleens of mice infected with the wild-type strain and the S Dublin DeltabstA mutant revealed similar levels of inflammation between the two groups. The gene was not important for adherence to or invasion of human epithelial cells and did not influence bacterial growth in rich medium, minimal medium, or cattle blood. In conclusion, a lack of bstA affects the pathogenicity of S Dublin by decreasing its virulence. Therefore, it might be regarded as an antivirulence gene in this serovar. PMID- 29109176 TI - Candidalysin drives epithelial signaling, neutrophil recruitment, and immunopathology at the vaginal mucosa. AB - Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen Candida albicans, is a disease of immunocompetent and otherwise healthy women. Despite its prevalence, the fungal factors responsible for initiating symptomatic infection remain poorly understood. One of the hallmarks of vaginal candidiasis is the robust recruitment of neutrophils to the site of infection, which seemingly do not clear the fungus, but rather exacerbate disease symptomatology. Candidalysin, a newly discovered peptide toxin secreted by C. albicans hyphae during invasion, drives epithelial damage, immune activation and phagocyte attraction. Therefore, we hypothesized that Candidalysin is crucial for vulvovaginal candidiasis immunopathology.Anti-Candida immune responses are anatomical site specific, as effective gastrointestinal, oral, and vaginal immunity is uniquely compartmentalized. Thus, we aimed to identify the immunopathologic role of Candidalysin and downstream signaling events at the vaginal mucosa. Microarray analysis of C. albicans-infected human vaginal epithelium in vitro revealed signaling pathways involved in epithelial damage responses, barrier repair, and leukocyte activation. Moreover, treatment of A431 vaginal epithelial cells with Candidalysin induced dose-dependent pro inflammatory cytokine responses (including IL-1alpha, IL-1beta and IL-8), damage, and activation of c-Fos and mitogen activated protein kinase (MAPK) signaling, consistent with fungal challenge. Mice intravaginally challenged with C. albicans strains deficient in Candidalysin exhibited no differences in colonization as compared to isogenic controls. However, significant decreases in neutrophil recruitment, damage, and pro-inflammatory cytokine expression were observed with these strains. Our findings demonstrate that Candidalysin is a key hypha associated virulence determinant responsible for the immunopathogenesis of C. albicans vaginitis. PMID- 29109177 TI - Medical regulators could merge in government shake up. PMID- 29109175 TI - The Streptococcus agalactiae Stringent Response Enhances Virulence and Persistence in Human Blood. AB - Streptococcus agalactiae (group B Streptococcus [GBS]) causes serious infections in neonates. We previously reported a transposon sequencing (Tn-seq) system for performing genomewide assessment of gene fitness in GBS. In order to identify molecular mechanisms required for GBS to transition from a mucosal commensal lifestyle to bloodstream invasion, we performed Tn-seq on GBS strain A909 with human whole blood. Our analysis identified 16 genes conditionally essential for GBS survival in blood, of which 75% were members of the capsular polysaccharide (cps) operon. Among the non-cps genes identified as conditionally essential was relA, which encodes an enzyme whose activity is central to the bacterial stringent response-a conserved adaptation to environmental stress. We used blood coincubation studies of targeted knockout strains to confirm the expected growth defects of GBS deficient in capsule or stringent response activation. Unexpectedly, we found that the relA knockout strains demonstrated decreased expression of beta-hemolysin/cytolysin, an important cytotoxin implicated in facilitating GBS invasion. Furthermore, chemical activation of the stringent response with serine hydroxamate increased beta-hemolysin/cytolysin expression. To establish a mechanism by which the stringent response leads to increased cytotoxicity, we performed transcriptome sequencing (RNA-seq) on two GBS strains grown under stringent response or control conditions. This revealed a conserved decrease in the expression of genes in the arginine deiminase pathway during stringent response activation. Through coincubation with supplemental arginine and the arginine antagonist canavanine, we show that arginine availability is a determinant of GBS cytotoxicity and that the pathway between stringent response activation and increased virulence is arginine dependent. PMID- 29109179 TI - Scientific Society Journals: By Scientists for Science. PMID- 29109178 TI - A Hard(y) Look at B-1 Cell Development and Function. AB - A small population of B cells exists in lymphoid tissues and body cavities of mice that is distinct in development, phenotype, and function from the majority (B-2) B cell population. This population, originally termed "Ly-1" and now "B-1," has received renewed interest as an innate-like B cell population of fetal derived hematopoiesis, responsible for natural Ab production and rapid immune responses. Molecular analyses have begun to define fetal and adult hematopoiesis, while cell-fate mapping studies have revealed complex developmental origins of B 1 cells. Together the studies provide a more detailed understanding of B-1 cell regulation and function. This review outlines studies that defined B-1 cells as natural Ab- and cytokine-producing B cells of fetal origin, with a focus on work conducted by R.R. Hardy, an early pioneer and codiscoverer of B-1 cells, whose seminal contributions enhanced our understanding of this enigmatic B cell population. PMID- 29109180 TI - Isolation of Aggressive Behavior Mutants in Drosophila Using a Screen for Wing Damage. AB - Aggression is a complex social behavior that is widespread in nature. To date, only a limited number of genes that affect aggression have been identified, in large part because the complexity of the phenotype makes screening difficult and time-consuming regardless of the species that is studied. We discovered that aggressive group-housed Drosophila melanogaster males inflict damage on each other's wings, and show that wing damage negatively affects their ability to fly and mate. Using this wing-damage phenotype, we screened males from ~1400 chemically mutagenized strains and found ~40 mutant strains with substantial wing damage. Five of these mutants also had increased aggressive behavior. To identify the causal mutation in one of our top aggressive strains, we used whole-genome sequencing and genomic duplication rescue strategies. We identified a novel mutation in the voltage-gated potassium channel Shaker (Sh) and show that a nearby previously identified Sh mutation also results in increased aggression. This simple screen can be used to dissect the molecular mechanisms underlying aggression. PMID- 29109181 TI - Achievements of an eradication programme against caprine arthritis encephalitis virus in South Tyrol, Italy. AB - Small ruminant lentivirus infections in goats affect both production and animal welfare. This represents a threat to the qualitative and quantitative growth of goat farming, recently observed in mountainous regions such as the Autonomous Province of Bolzano - South Tyrol (Italy). To monitor and eradicate the caprine arthritis encephalitis virus in this goat population, a compulsory eradication campaign was launched, based on a strict census of small ruminants and yearly serological testing of all animals, followed by the consequent culling of seropositive individuals. The campaign succeeded in completely eliminating cases of clinical disease in goats, while drastically reducing the seroprevalence at the herd as well as individual animal level. The serological outcome of the introduced control measures was determined using commercially available ELISA kits, demonstrating their suitability for use in this type of campaign, aimed at reducing seroprevalence as well as clinical manifestations of these infections. However, this clear success is diminished by the failure to achieve a complete eradication of these viruses. The reasons leading to the observed tailing phenomenon and the occurrence of new infections in already sanitised flocks are discussed and implementation of further measures are proposed. PMID- 29109182 TI - Characterization of an Aldolase Involved in Cholesterol Side Chain Degradation in Mycobacterium tuberculosis. AB - The heteromeric acyl coenzyme A (acyl-CoA) dehydrogenase FadE28-FadE29 and the enoyl-CoA hydratase ChsH1-ChsH2, encoded by genes within the intracellular growth (igr) operon of Mycobacterium tuberculosis, catalyze the dehydrogenation of the cholesterol metabolite 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA), with a 3 carbon side chain, and subsequent hydration of the product 3-oxo-4,17-pregnadiene 20-carboxyl-CoA (3-OPDC-CoA) to form 17-hydroxy-3-oxo-4-pregnene-20-carboxyl-CoA (17-HOPC-CoA). The gene downstream of chsH2, i.e., ltp2, was expressed in recombinant Rhodococcus jostii RHA1 in combination with other genes within the igr operon. His-tagged Ltp2 copurified with untagged ChsH1-ChsH2, ChsH2, or the C terminal domain of ChsH2, which contains a domain of unknown function (DUF35). Ltp2 in association with ChsH1-ChsH2 or just the DUF35 domain of ChsH2 was shown to catalyze the retroaldol cleavage of 17-HOPC-CoA to form androst-4-ene-3,17 dione and propionyl-CoA. Steady-state kinetic analysis using the Ltp2-DUF35 complex showed that the aldolase had optimal activity at pH 7.5, with a Km of 6.54 +/- 0.90 MUM and a kcat of 159 +/- 8.50 s-1 ChsH1-ChsH2 could hydrate only about 30% of 3-OPDC-CoA, but this unfavorable equilibrium could be overcome when the aldolase was present to remove the hydrated product, providing a rationale for the close association of the aldolase with the hydratase. Homologs of ChsH1, ChsH2, and Ltp2 are found in steroid-degrading Gram-positive and Gram-negative bacteria, suggesting that side chains of diverse steroids may be cleaved by aldolases in the bacteria.IMPORTANCE The C-C bond cleavage of the D-ring side chain of cholesterol was shown to be catalyzed by an aldolase. The aldolase associates with the hydratase that catalyzes the preceding reaction in the cholesterol side chain degradation pathway. These enzymes are encoded by genes within the intracellular growth (igr) operon of M. tuberculosis, and the operon was demonstrated previously to be linked to the pathogenicity and persistence of the bacteria in macrophages and in mice. PMID- 29109184 TI - Untangling Flavobacterium johnsoniae Gliding Motility and Protein Secretion. AB - Flavobacterium johnsoniae exhibits rapid gliding motility over surfaces. At least 20 genes are involved in this process. Seven of these, gldK, gldL, gldM, gldN, sprA, sprE, and sprT, encode proteins of the type IX protein secretion system (T9SS). The T9SS is required for surface localization of the motility adhesins SprB and RemA, and for secretion of the soluble chitinase ChiA. Here, we demonstrate that the gliding motility proteins GldA, GldB, GldD, GldF, GldH, GldI, and GldJ are also essential for secretion. Cells with mutations in the genes encoding any of these seven proteins had normal levels of gldK mRNA but dramatically reduced levels of the GldK protein, which may explain the secretion defects of the motility mutants. GldJ is necessary for stable accumulation of GldK, and each mutant lacked the GldJ protein. F. johnsoniae cells that produced truncated GldJ, lacking eight to 13 amino acids from the C terminus, accumulated GldK but were deficient in gliding motility. SprB was secreted by these cells but was not propelled along their surfaces. This C-terminal region of GldJ is thus required for gliding motility but not for secretion. The identification of mutants that are defective for motility but competent for secretion begins to untangle the F. johnsoniae gliding motility machinery from the T9SS.IMPORTANCE Many members of the phylum Bacteroidetes secrete proteins using T9SSs. T9SSs appear to be confined to members of this phylum. Many of these bacteria also glide rapidly over surfaces using a motility machine that is also confined to the Bacteroidetes and appears to be intertwined with the T9SS. This study identifies F. johnsoniae proteins that are required for both T9SS function and gliding motility. It also provides an explanation for the link between secretion and gliding and identifies mutants with defects in motility but not secretion. PMID- 29109183 TI - Mutation and Suppressor Analysis of the Essential Lipopolysaccharide Transport Protein LptA Reveals Strategies To Overcome Severe Outer Membrane Permeability Defects in Escherichia coli. AB - In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the robust permeability barrier of the outer membrane (OM), preventing the entry of toxic molecules, such as detergents and antibiotics. LPS is transported from the inner membrane (IM) to the OM by the Lpt multiprotein machinery. Defects in LPS transport compromise LPS assembly at the OM and result in increased antibiotic sensitivity. LptA is a key component of the Lpt machine that interacts with the IM protein LptC and chaperones LPS through the periplasm. We report here the construction of lptA41, a quadruple mutant in four conserved amino acids potentially involved in LPS or LptC binding. Although viable, the mutant displays increased sensitivity to several antibiotics (bacitracin, rifampin, and novobiocin) and the detergent SDS, suggesting that lptA41 affects LPS transport. Indeed, lptA41 is defective in Lpt complex assembly, and its lipid A carries modifications diagnostic of LPS transport defects. We also selected and characterized two phenotypic bacitracin-resistant suppressors of lptA41 One mutant, in which only bacitracin sensitivity is suppressed, harbors a small in frame deletion in mlaA, which codes for an OM lipoprotein involved in maintaining OM asymmetry by reducing accumulation of phospholipids in the outer leaflet. The other mutant, in which bacitracin, rifampin, and SDS sensitivity is suppressed, harbors an additional amino acid substitution in LptA41 and a nonsense mutation in opgH, encoding a glycosyltransferase involved in periplasmic membrane-derived oligosaccharide synthesis. Characterization of the suppressor mutants highlights different strategies adopted by the cell to overcome OM defects caused by impaired LPS transport.IMPORTANCE Lipopolysaccharide (LPS) is the major constituent of the outer membrane (OM) of most Gram-negative bacteria, forming a barrier against antibiotics. LPS is synthesized at the inner membrane (IM), transported across the periplasm, and assembled at the OM by the multiprotein Lpt complex. LptA is the periplasmic component of the Lpt complex, which bridges IM and OM and ferries LPS across the periplasm. How the cell coordinates the processes involved in OM biogenesis is not completely understood. We generated a mutant partially defective in lptA that exhibited increased sensitivity to antibiotics and selected for suppressors of the mutant. The analysis of two independent suppressors revealed different strategies adopted by the cell to overcome defects in LPS biogenesis. PMID- 29109185 TI - Genome-wide screens reveal new gene products that influence genetic competence in Streptococcus mutans. AB - A network of genes and at least two peptide signaling molecules tightly control when Streptococcus mutans becomes competent to take up DNA from its environment. Widespread changes in the expression of genes occur when S. mutans is presented with competence signal peptides in vitro, including increased production of the alternative sigma factor, ComX, which activates late competence genes. Still, the way that gene products that are regulated by competence peptides influence DNA uptake and cellular physiology are not well understood. Here, we developed and employed comprehensive transposon mutagenesis of the S. mutans genome with a screen to identify mutants that aberrantly expressed comX, coupled with transposon sequencing (Tn-seq) to gain a more thorough understanding of the factors modulating comX expression and progression to the competent state. The screens effectively identified genes known to affect competence, e.g. comR, comS, comD, comE, cipB, clpX, rcrR, ciaH, but disclosed an additional 20 genes that were not previously competence-associated. The competence phenotypes of mutants were characterized, including using fluorescence microscopy to determine at which stage the mutants were impaired for comX activation. Among the novel genes studied were those implicated in cell division, sensing of cell envelope stress, cell envelope biogenesis, and RNA stability. Our results provide a platform for determining the specific chemical and physical cues that are required for genetic competence in S. mutans, while highlighting the effectiveness of using Tn-seq in S. mutans to discover and study novel biological processes.IMPORTANCEStreptococcus mutans acquires DNA from its environment by becoming genetically competent, a physiologic state triggered by cell-cell communication using secreted peptides. Competence is important for acquiring novel genetic traits and has a strong influence on the expression of virulence associated traits of S. mutans Here, we used transposon mutagenesis and genomic technologies to identify novel genes involved in competence development. In addition to identifying genes previously known to be required for comX expression, 20 additional genes were identified and characterized. The findings create opportunities to diminish the pathogenic potential of S. mutans, while validating technologies that can rapidly advance our understanding of the physiology, biology and genetics of S. mutans and related pathogens. PMID- 29109186 TI - Insights into biofilm dispersal regulation from the crystal structure of the PAS GGDEF-EAL region of RbdA from Pseudomonas aeruginosa. AB - RbdA is a positive Regulator of biofilm dispersal of Pseudomonas aeruginosa Its cytoplasmic region (cRbdA) comprises a N-terminal PAS domain followed by a diguanylate cyclase (GGDEF) and an EAL domain, whose phosphodiesterase activity is allosterically stimulated by GTP binding to the GGDEF domain. We report crystal structures of cRbdA and of two binary complexes: with GTP/Mg2+ bound to the GGDEF active site and with the EAL domain bound to the c-di-GMP substrate. These structures unveil a 2-fold symmetric dimer, stabilized by a closely packed N-terminal PAS domain and a non-canonical EAL dimer. The auto-inhibitory switch is formed by an alpha helix (S-helix) immediately N-terminal to the GGDEF domain that interacts with the EAL dimerization helix (alpha6-E) of the other EAL monomer and maintains the protein in a locked conformation. We propose that local conformational changes in cRbdA upon GTP binding lead to a structure with the PAS domain and S-helix shifted away from the GGDEF-EAL domains, as suggested by SAXS experiments. Domain reorientation should be facilitated by the presence of a alpha-helical lever (H-helix) that tethers the GGDEF and EAL regions, allowing the EAL domain to rearrange into an active dimeric conformation.IMPORTANCEBiofilm formation by bacterial pathogens increases resistance to antibiotics. RbdA positively regulates biofilm dispersal of Pseudomonas aeruginosa The crystal structures of the cytoplasmic region of RbdA protein presented here reveal that two evolutionary-conserved helices play an important role in regulating the activity of RbdA, with implications for other dual GGDEF-EAL domains that are abundant in the proteomes of several bacterial pathogens. Thus, this work could assist the development of small molecules that would promote bacterial biofilm dispersal. PMID- 29109187 TI - Homologous VapC Toxins Inhibit Translation and Cell Growth by Sequence-Specific Cleavage of tRNAfMet. AB - Type II toxin-antitoxin (TA) systems play a critical role in the establishment and maintenance of bacterial dormancy. They are composed of a protein toxin and its cognate protein antitoxin. They function to regulate growth under conditions of stress, such as starvation or antibiotic treatment. As cellular proteases degrade the antitoxin, which normally binds and neutralizes the toxin, this frees the toxin to act on its cellular targets and arrest bacterial growth. TA systems are of particular concern in regard to pathogenic organisms, such as nontypeable Haemophilus influenzae (NTHi), as dormancy may lead to chronic infections and failure of antibiotic treatment. Many targets of VapC toxins have not been identified, to date, and this knowledge is crucial to understanding how toxins control the establishment and maintenance of bacterial dormancy. Accordingly, we characterized the target specificity of the VapC toxins from the two paralogous NTHi vapBC TA systems. RNA sequencing and Northern blot analysis revealed that VapC1 and VapC2 cleave tRNAfMet in the anticodon loop. Overexpression of tRNAfMet suppresses VapC toxicity, suggesting that translation inhibition results from the depletion of tRNAfMet These experiments also identified base pairs in the tRNAfMet anticodon stem that play a key role in VapC-specific cleavage of the tRNA. Together these findings suggest the potential for NTHi VapC1 and VapC2 to induce dormancy by sequence-specific cleavage of tRNAfMetIMPORTANCE Bacterial persistence is a significant concern in regard to pathogenic organisms, such as nontypeable Haemophilus influenzae, as it can result in recurrent and chronic infections. Toxin-antitoxin systems can lead to persistence by causing bacteria to enter a slow-growing state that renders them antibiotic tolerant. Type II toxin components affect a wide variety of bacterial targets in order to elicit dormancy, and for many toxin-antitoxin systems, these mechanisms are not well understood. Thus, in order to understand how vapBC toxin-antitoxin systems cause dormancy, it is crucial to investigate the substrate specificity of VapC toxins. This study identifies the target of the VapC1 and VapC2 toxins from NTHi and takes important steps toward understanding the specificity of these toxins for their tRNA target. PMID- 29109189 TI - Regulation of Proteolysis in the Gram-Negative Bacterial Envelope. AB - Proteolysis is carefully regulated to prevent the untimely destruction of critical proteins. In this issue of the Journal of Bacteriology, Kim and colleagues identify YjfN as a proteolytic regulator that stimulates the activity of the DegP/HtrA protease of Escherichia coli (S. Kim, I. Song, G. Eom, and S. Kim, J Bacteriol 200:e00519-17, 2018, https://doi.org/10.1128/JB.00519-17). The suicide destruction and transcriptional regulation of YjfN limit its activity to conditions in which there are likely to be many misfolded substrate proteins present. PMID- 29109188 TI - Zinc Acquisition Mechanisms Differ between Environmental and Virulent Francisella Species. AB - Zinc is an essential nutrient for bacterial growth. Because host cells can restrict pathogen access to zinc as an antimicrobial defense mechanism, intracellular pathogens such as Francisella must sense their environment and acquire zinc in response. In many bacteria, the conserved transcription factor Zur is a key regulator of zinc acquisition. To identify mechanisms of zinc uptake in Francisella novicida U112, transcriptome sequencing of wild-type and putative zur mutant bacteria was performed. Only three genes were confirmed as directly regulated by Zur and zinc limitation by quantitative reverse transcription-PCR. One of these genes, FTN_0879, is predicted to encode a protein with similarity to the zupT family of zinc transporters, which are not typically regulated by Zur. While a putative znuACB operon encoding a high-affinity zinc transporter was identified in U112, expression of this operon was not controlled by Zur or zinc concentration. Disruption of zupT but not znuA in U112 impaired growth under zinc limitation, suggesting that ZupT is the primary mechanism of zinc acquisition under these conditions. In the virulent Francisella tularensis subsp. tularensis Schu S4 strain, zupT is a pseudogene, and attempts to delete znuA were unsuccessful, suggesting that it is essential in this strain. A reverse TetR repression system was used to knock down the expression of znuA in Schu S4, revealing that znuA is required for growth under zinc limitation and contributes to intracellular growth within macrophages. Overall, this work identifies genes necessary for adaptation to zinc limitation and highlights nutritional differences between environmental and virulent Francisella strains.IMPORTANCEFrancisella tularensis is a tier 1 select agent with a high potential for lethality and no approved vaccine. A better understanding of Francisella virulence factors is required for the development of therapeutics. While acquisition of zinc has been shown to be required for the virulence of numerous intracellular pathogens, zinc uptake has not been characterized in Francisella This work characterizes the Zur regulon in F. novicida and identifies two transporters that contribute to bacterial growth under zinc limitation. In addition, these data identify differences in mechanisms of zinc uptake and tolerance to zinc limitation between F. tularensis and F. novicida, highlighting the role of znuA in the growth of Schu S4 under zinc limitation. PMID- 29109190 TI - TRPV4 (Transient Receptor Potential Vanilloid 4) Mediates Endothelium-Dependent Contractions in the Aortas of Hypertensive Mice. AB - The role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular contraction in hypertensive mice is poorly established. We tested the hypothesis that TRPV4 regulates endothelium-dependent contractions in aortas from hypertensive mice through the activation of cytosolic cPLA2 (phospholipase A2) and COX2 (cyclooxygenase 2) and identified the possible endothelium-derived contracting factor generated by COX2. Using myography, we demonstrated that GSK1016790A (a TRPV4 agonist) and acetylcholine (ACh) trigger endothelium dependent contractions in aortas from hypertensive mice, and the contractions were abolished with TRPV4 deletion. PLA2 assay and Western blotting showed that cPLA2 activity was higher in salt-induced hypertension and HC067047 or a Ca2+ chelator inhibited cPLA2 activity. Contractions induced by TRPV4 and ACh were inhibited by the cPLA2 inhibitor or removal of extracellular Ca2+ COX2 expression was enhanced in the endothelium from hypertensive mice and contractions induced by TRPV4 or ACh were inhibited by the COX2 inhibitor. Enzyme immunoassay showed that the release of prostaglandin F2alpha (PGF2alpha) was increased in hypertensive mice. GSK1016790A or ACh triggered the release of PGF2alpha and this was inhibited by HC067047, the cPLA2 inhibitor, and COX2 inhibitor. GSK1016790A, ACh, and PGF2alpha induced contractions were significantly reduced by S18886 in salt-induced hypertensive mice. The present study demonstrates that PGF2alpha generated by COX2 in the endothelium is the most likely endothelium-derived contracting factor underlying endothelium-dependent, TRPV4-mediated contraction in hypertensive mice. This contraction involved increased intracellular Ca2+ concentrations and cPLA2 activity. These results suggested an important role of TRPV4 in endothelium-dependent contraction in mice during hypertension. PMID- 29109193 TI - The Value of Preoperative Assessment Before Noncardiac Surgery in the Era of Value-Based Care. PMID- 29109192 TI - Turning Dilatation to Constriction: Endothelial TRPV4 (Transient Receptor Potential Vanilloid 4) Matters. PMID- 29109191 TI - Calneuron 1 Increased Ca2+ in the Endoplasmic Reticulum and Aldosterone Production in Aldosterone-Producing Adenoma. AB - Aldosterone production is initiated by angiotensin II stimulation and activation of intracellular Ca2+ signaling. In aldosterone-producing adenoma (APA) cells, the activation of intracellular Ca2+ signaling is independent of the renin angiotensin-aldosterone systems. The purpose of our study was to clarify molecular mechanisms of aldosterone production related to Ca2+ signaling. Transcriptome analysis revealed that the CALN1 gene encoding calneuron 1 had the strongest correlation with CYP11B2 (aldosterone synthase) among genes encoding Ca2+-binding proteins in APA. CALN1 modulation and synthetic or fluorescent compounds were used for functional studies in human adrenocortical carcinoma (HAC15) cells. CALN1 expression was 4.4-fold higher in APAs than nonfunctioning adrenocortical adenomas. CALN1 expression colocalized with CYP11B2 expression as investigated using immunohistochemistry in APA and zona glomerulosa of male rats fed by a low-salt diet. CALN1 expression was detected in the endoplasmic reticulum (ER) by using GFP-fused CALN1, CellLight ER-RFP, and the corresponding antibodies. CALN1-overexpressing HAC15 cells showed increased Ca2+ in the ER and cytosol fluorescence-based studies. Aldosterone production was potentiated in HAC15 cells by CALN1 expression, and dose-responsive inhibition with TMB-8 showed that CALN1-mediated Ca2+ storage in ER involved sarcoendoplasmic reticulum calcium transport ATPase. The silencing of CALN1 decreased Ca2+ in ER, and abrogated angiotensin II- or KCNJ5 T158A-mediated aldosterone production in HAC15 cells. Increased CALN1 expression in APA was associated with elevated Ca2+ storage in ER and aldosterone overproduction. Suppression of CALN1 expression prevented angiotensin II- or KCNJ5 T158A-mediated aldosterone production in HAC15 cells, suggesting that CALN1 is a potential therapeutic target for excess aldosterone production. PMID- 29109194 TI - Primary Prevention Implantable Cardioverter Defibrillators in Patients With Nonischemic Cardiomyopathy: Diminishing Returns With Advancing Age? PMID- 29109196 TI - Highlights From the Circulation Family of Journals. PMID- 29109197 TI - An Asymptomatic Man With an Abnormal ECG. PMID- 29109198 TI - Impact of Heart Outcomes Prevention Evaluation Trial on Statin Eligibility for the Primary Prevention of Cardiovascular Disease: Insights from the National Health and Nutrition Examination Survey. PMID- 29109195 TI - Sleep Apnea and Cardiovascular Disease: Lessons From Recent Trials and Need for Team Science. AB - Emerging research highlights the complex interrelationships between sleep disordered breathing and cardiovascular disease, presenting clinical and research opportunities as well as challenges. Patients presenting to cardiology clinics have a high prevalence of obstructive and central sleep apnea associated with Cheyne-Stokes respiration. Multiple mechanisms have been identified by which sleep disturbances adversely affect cardiovascular structure and function. Epidemiological research indicates that obstructive sleep apnea is associated with increases in the incidence and progression of coronary heart disease, heart failure, stroke, and atrial fibrillation. Central sleep apnea associated with Cheyne-Stokes respiration predicts incident heart failure and atrial fibrillation; among patients with heart failure, it strongly predicts mortality. Thus, a strong literature provides the mechanistic and empirical bases for considering obstructive sleep apnea and central sleep apnea associated with Cheyne-Stokes respiration as potentially modifiable risk factors for cardiovascular disease. Data from small trials provide evidence that treatment of obstructive sleep apnea with continuous positive airway pressure improves not only patient-reported outcomes such as sleepiness, quality of life, and mood but also intermediate cardiovascular end points such as blood pressure, cardiac ejection fraction, vascular parameters, and arrhythmias. However, data from large scale randomized controlled trials do not currently support a role for positive pressure therapies for reducing cardiovascular mortality. The results of 2 recent large randomized controlled trials, published in 2015 and 2016, raise questions about the effectiveness of pressure therapies in reducing clinical end points, although 1 trial supported the beneficial effect of continuous positive airway pressure on quality of life, mood, and work absenteeism. This review provides a contextual framework for interpreting the results of recent studies, key clinical messages, and suggestions for future sleep and cardiovascular research, which include further consideration of individual risk factors, use of existing and new multimodality therapies that also address adherence, and implementation of trials that are sufficiently powered to target end points and to support subgroup analyses. These goals may best be addressed through strengthening collaboration among the cardiology, sleep medicine, and clinical trial communities. PMID- 29109199 TI - Letter by Tzanis et al Regarding Article, "Stress Testing in Asymptomatic Aortic Stenosis". PMID- 29109200 TI - Response by Redfors and Genereux to Letter Regarding Article, "Stress Testing in Asymptomatic Aortic Stenosis". PMID- 29109201 TI - Letter by Maltais et al Regarding Article, "Hemocompatibility-Related Outcomes in the MOMENTUM 3 Trial at 6 Months: A Randomized Controlled Study of a Fully Magnetically Levitated Pump in Advanced Heart Failure". PMID- 29109202 TI - Response by Mehra et al to Letter Regarding Article, "Hemocompatibility-Related Outcomes in the MOMENTUM 3 Trial at 6 Months: A Randomized Controlled Study of a Fully Magnetically Levitated Pump in Advanced Heart Failure". PMID- 29109203 TI - Correction to: Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure: A Scientific Statement From the American Heart Association. PMID- 29109204 TI - Correction to: American Heart Association's Call to Action for Payment and Delivery System Reform. PMID- 29109205 TI - Correction to: A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization. PMID- 29109206 TI - Quantitative cell biology: uniting disciplines to understand the cell. PMID- 29109207 TI - Need for equity in treatment of substance use among Indigenous people in Canada. PMID- 29109209 TI - Making the most of the federal investment of $5 billion for mental health. PMID- 29109208 TI - The Cedar Project: mortality among young Indigenous people who use drugs in British Columbia. AB - BACKGROUND: Young Indigenous people, particularly those involved in the child welfare system, those entrenched in substance use and those living with HIV or hepatitis C, are dying prematurely. We report mortality rates among young Indigenous people who use drugs in British Columbia and explore predictors of mortality over time. METHODS: We analyzed data collected every 6 months between 2003 and 2014 by the Cedar Project, a prospective cohort study involving young Indigenous people who use illicit drugs in Vancouver and Prince George, BC. We calculated age-standardized mortality ratios using Indigenous and Canadian reference populations. We identified predictors of mortality using time-dependent Cox proportional hazard regression. RESULTS: Among 610 participants, 40 died between 2003 and 2014, yielding a mortality rate of 670 per 100 000 person-years. Young Indigenous people who used drugs were 12.9 (95% confidence interval [CI] 9.2-17.5) times more likely to die than all Canadians the same age and were 7.8 (95% CI 5.6-10.6) times more likely to die than Indigenous people with Status in BC. Young women and those using drugs by injection were most affected. The leading causes of death were overdose (n = 15 [38%]), illness (n = 11 [28%]) and suicide (n = 5 [12%]). Predictors of mortality included having hepatitis C at baseline (adjusted hazard ratio [HR] 2.76, 95% CI 1.47-5.16), previous attempted suicide (adjusted HR 1.88, 95% CI 1.01-3.50) and recent overdose (adjusted HR 2.85, 95% CI 1.00-8.09). INTERPRETATION: Young Indigenous people using drugs in BC are dying at an alarming rate, particularly young women and those using injection drugs. These deaths likely reflect complex intersections of historical and present-day injustices, substance use and barriers to care. PMID- 29109210 TI - Essential tremor. PMID- 29109211 TI - Mechanic's hands and hiker's feet in antisynthetase syndrome. PMID- 29109212 TI - Is referral necessary for abnormal bleeding? PMID- 29109213 TI - The authors respond to "Is referral necessary for abnormal bleeding?" PMID- 29109214 TI - Mixed news for doctors as feds pivot on tax reforms. PMID- 29109215 TI - World Medical Association updates ethical code for physicians. PMID- 29109216 TI - Health on the hill: Six health bills to watch. PMID- 29109217 TI - Feds further limit scope of tax reforms affecting most doctors. PMID- 29109218 TI - Just get on with improving palliative care, plead experts. PMID- 29109219 TI - Variation in recombination frequency and distribution across eukaryotes: patterns and processes. AB - Recombination, the exchange of DNA between maternal and paternal chromosomes during meiosis, is an essential feature of sexual reproduction in nearly all multicellular organisms. While the role of recombination in the evolution of sex has received theoretical and empirical attention, less is known about how recombination rate itself evolves and what influence this has on evolutionary processes within sexually reproducing organisms. Here, we explore the patterns of, and processes governing recombination in eukaryotes. We summarize patterns of variation, integrating current knowledge with an analysis of linkage map data in 353 organisms. We then discuss proximate and ultimate processes governing recombination rate variation and consider how these influence evolutionary processes. Genome-wide recombination rates (cM/Mb) can vary more than tenfold across eukaryotes, and there is large variation in the distribution of recombination events across closely related taxa, populations and individuals. We discuss how variation in rate and distribution relates to genome architecture, genetic and epigenetic mechanisms, sex, environmental perturbations and variable selective pressures. There has been great progress in determining the molecular mechanisms governing recombination, and with the continued development of new modelling and empirical approaches, there is now also great opportunity to further our understanding of how and why recombination rate varies.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109220 TI - Evolution of recombination rates between sex chromosomes. AB - In species with genetic sex-determination, the chromosomes carrying the sex determining genes have often evolved non-recombining regions and subsequently evolved the full set of characteristics denoted by the term 'sex chromosomes'. These include size differences, creating chromosomal heteromorphism, and loss of gene functions from one member of the chromosome pair. Such characteristics and changes have been widely reviewed, and underlie molecular genetic approaches that can detect sex chromosome regions. This review deals mainly with the evolution of new non-recombining regions, focusing on how certain evolutionary situations select for suppressed recombination (rather than the proximate mechanisms causing suppressed recombination between sex chromosomes). Particularly important is the likely involvement of sexually antagonistic polymorphisms in genome regions closely linked to sex-determining loci. These may be responsible for the evolutionary strata of sex chromosomes that have repeatedly formed by recombination suppression evolving across large genome regions. More studies of recently evolved non-recombining sex-determining regions should help to test this hypothesis empirically, and may provide evidence about whether other situations can sometimes lead to sex-linked regions evolving. Similarities with other non recombining genome regions are discussed briefly, to illustrate common features of the different cases, though no general properties apply to all of them.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109221 TI - Coevolution between transposable elements and recombination. AB - One of the most striking patterns of genome structure is the tight, typically negative, association between transposable elements (TEs) and meiotic recombination rates. While this is a highly recurring feature of eukaryotic genomes, the mechanisms driving correlations between TEs and recombination remain poorly understood, and distinguishing cause versus effect is challenging. Here, we review the evidence for a relation between TEs and recombination, and discuss the underlying evolutionary forces. Evidence to date suggests that overall TE densities correlate negatively with recombination, but the strength of this correlation varies across element types, and the pattern can be reversed. Results suggest that heterogeneity in the strength of selection against ectopic recombination and gene disruption can drive TE accumulation in regions of low recombination, but there is also strong evidence that the regulation of TEs can influence local recombination rates. We hypothesize that TE insertion polymorphism may be important in driving within-species variation in recombination rates in surrounding genomic regions. Furthermore, the interaction between TEs and recombination may create positive feedback, whereby TE accumulation in non-recombining regions contributes to the spread of recombination suppression. Further investigation of the coevolution between recombination and TEs has important implications for our understanding of the evolution of recombination rates and genome structure.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109222 TI - Recombination rate plasticity: revealing mechanisms by design. AB - For over a century, scientists have known that meiotic recombination rates can vary considerably among individuals, and that environmental conditions can modify recombination rates relative to the background. A variety of external and intrinsic factors such as temperature, age, sex and starvation can elicit 'plastic' responses in recombination rate. The influence of recombination rate plasticity on genetic diversity of the next generation has interesting and important implications for how populations evolve. Further, many questions remain regarding the mechanisms and molecular processes that contribute to recombination rate plasticity. Here, we review 100 years of experimental work on recombination rate plasticity conducted in Drosophila melanogaster We categorize this work into four major classes of experimental designs, which we describe via classic studies in D. melanogaster Based on these studies, we highlight molecular mechanisms that are supported by experimental results and relate these findings to studies in other systems. We synthesize lessons learned from this model system into experimental guidelines for using recent advances in genotyping technologies, to study recombination rate plasticity in non-model organisms. Specifically, we recommend (1) using fine-scale genome-wide markers, (2) collecting time-course data, (3) including crossover distribution measurements, and (4) using mixed effects models to analyse results. To illustrate this approach, we present an application adhering to these guidelines from empirical work we conducted in Drosophila pseudoobscuraThis article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109223 TI - What drives the evolution of condition-dependent recombination in diploids? Some insights from simulation modelling. AB - While the evolutionary advantages of non-zero recombination rates have prompted diverse theoretical explanations, the evolution of essential recombination features remains underexplored. We focused on one such feature, the condition dependence of recombination, viewed as the variation in within-generation sensitivity of recombination to external (environment) and/or internal (genotype) conditions. Limited empirical evidence for its existence comes mainly from diploids, whereas theoretical models show that it only easily evolves in haploids. The evolution of condition-dependent recombination can be explained by its advantage for the selected system (indirect effect), or by benefits to modifier alleles, ensuring this strategy regardless of effects on the selected system (direct effect). We considered infinite panmictic populations of diploids exposed to a cyclical two-state environment. Each organism had three selected loci. Examining allele dynamics at a fourth, selectively neutral recombination modifier locus, we frequently observed that a modifier allele conferring condition-dependent recombination between the selected loci displaced the allele conferring the optimal constant recombination rate. Our simulations also confirm the results of theoretical studies showing that condition-dependent recombination cannot evolve in diploids on the basis of direct fitness-dependent effects alone. Therefore, the evolution of condition-dependent recombination in diploids can be driven by indirect effects alone, i.e. by modifier effects on the selected system.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109224 TI - Low recombination rates in sexual species and sex-asex transitions. AB - In most sexual, diploid eukaryotes, at least one crossover occurs between each pair of homologous chromosomes during meiosis, presumably in order to ensure proper segregation. Well-known exceptions to this rule are species in which one sex does not recombine and specific chromosomes lacking crossover. We review other possible exceptions, including species with chromosome maps of less than 50 cM in one or both sexes. We discuss the idea that low recombination rates may favour sex-asex transitions, or, alternatively may be a consequence of it. We then show that a yet undescribed species of brine shrimp Artemia from Kazakhstan (A sp. Kazakhstan), the closest known relative of the asexual Artemia parthenogenetica, has one of the shortest genetic linkage maps known. Based on a family of 42 individuals and 589 RAD markers, we find that many linkage groups are considerably shorter than 50 cM, suggesting either no obligate crossover or crossovers concentrated at terminal positions with little effect on recombination. We contrast these findings with the published map of the more distantly related sexual congener, A. franciscana, and conclude that the study of recombination in non-model systems is important to understand the evolutionary causes and consequences of recombination.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109226 TI - The Red Queen model of recombination hot-spot evolution: a theoretical investigation. AB - In humans and many other species, recombination events cluster in narrow and short-lived hot spots distributed across the genome, whose location is determined by the Zn-finger protein PRDM9. To explain these fast evolutionary dynamics, an intra-genomic Red Queen model has been proposed, based on the interplay between two antagonistic forces: biased gene conversion, mediated by double-strand breaks, resulting in hot-spot extinction, followed by positive selection favouring new PRDM9 alleles recognizing new sequence motifs. Thus far, however, this Red Queen model has not been formalized as a quantitative population-genetic model, fully accounting for the intricate interplay between biased gene conversion, mutation, selection, demography and genetic diversity at the PRDM9 locus. Here, we explore the population genetics of the Red Queen model of recombination. A Wright-Fisher simulator was implemented, allowing exploration of the behaviour of the model (mean equilibrium recombination rate, diversity at the PRDM9 locus or turnover rate) as a function of the parameters (effective population size, mutation and erosion rates). In a second step, analytical results based on self-consistent mean-field approximations were derived, reproducing the scaling relations observed in the simulations. Empirical fit of the model to current data from the mouse suggests both a high mutation rate at PRDM9 and strong biased gene conversion on its targets.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109225 TI - The consequences of sequence erosion in the evolution of recombination hotspots. AB - Meiosis is initiated by a double-strand break (DSB) introduced in the DNA by a highly controlled process that is repaired by recombination. In many organisms, recombination occurs at specific and narrow regions of the genome, known as recombination hotspots, which overlap with regions enriched for DSBs. In recent years, it has been demonstrated that conversions and mutations resulting from the repair of DSBs lead to a rapid sequence evolution at recombination hotspots eroding target sites for DSBs. We still do not fully understand the effect of this erosion in the recombination activity, but evidence has shown that the binding of trans-acting factors like PRDM9 is affected. PRDM9 is a meiosis specific, multi-domain protein that recognizes DNA target motifs by its zinc finger domain and directs DSBs to these target sites. Here we discuss the changes in affinity of PRDM9 to eroded recognition sequences, and explain how these changes in affinity of PRDM9 can affect recombination, leading sometimes to sterility in the context of hybrid crosses. We also present experimental data showing that DNA methylation reduces PRDM9 binding in vitro Finally, we discuss PRDM9-independent hotspots, posing the question how these hotspots evolve and change with sequence erosion.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109227 TI - The impact of recombination on human mutation load and disease. AB - Recombination promotes genomic integrity among cells and tissues through double strand break repair, and is critical for gamete formation and fertility through a strict regulation of the molecular mechanisms associated with proper chromosomal disjunction. In humans, congenital defects and recurrent structural abnormalities can be attributed to aberrant meiotic recombination. Moreover, mutations affecting genes involved in recombination pathways are directly linked to pathologies including infertility and cancer. Recombination is among the most prominent mechanism shaping genome variation, and is associated with not only the structuring of genomic variability, but is also tightly linked with the purging of deleterious mutations from populations. Together, these observations highlight the multiple roles of recombination in human genetics: its ability to act as a major force of evolution, its molecular potential to maintain genome repair and integrity in cell division and its mutagenic cost impacting disease evolution.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109228 TI - Connecting theory and data to understand recombination rate evolution. AB - Meiotic recombination is necessary for successful gametogenesis in most sexually reproducing organisms and is a fundamental genomic parameter, influencing the efficacy of selection and the fate of new mutations. The molecular and evolutionary functions of recombination should impose strong selective constraints on the range of recombination rates. Yet, variation in recombination rate is observed on a variety of genomic and evolutionary scales. In the past decade, empirical studies have described variation in recombination rate within genomes, between individuals, between sexes, between populations and between species. At the same time, theoretical work has provided an increasingly detailed picture of the evolutionary advantages to recombination. Perhaps surprisingly, the causes of natural variation in recombination rate remain poorly understood. We argue that empirical and theoretical approaches to understand the evolution of recombination have proceeded largely independently of each other. Most models that address the evolution of recombination rate were created to explain the evolutionary advantage of recombination rather than quantitative differences in rate among individuals. Conversely, most empirical studies aim to describe variation in recombination rate, rather than to test evolutionary hypotheses. In this Perspective, we argue that efforts to integrate the rich bodies of empirical and theoretical work on recombination rate are crucial to moving this field forward. We provide new directions for the development of theory and the production of data that will jointly close this gap.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109229 TI - Are the effects of elevated temperature on meiotic recombination and thermotolerance linked via the axis and synaptonemal complex? AB - Meiosis is unusual among cell divisions in shuffling genetic material by crossovers among homologous chromosomes and partitioning the genome into haploid gametes. Crossovers are critical for chromosome segregation in most eukaryotes, but are also an important factor in evolution, as they generate novel genetic combinations. The molecular mechanisms that underpin meiotic recombination and chromosome segregation are well conserved across kingdoms, but are also sensitive to perturbation by environment, especially temperature. Even subtle shifts in temperature can alter the number and placement of crossovers, while at greater extremes, structural failures can occur in the linear axis and synaptonemal complex structures which are essential for recombination and chromosome segregation. Understanding the effects of temperature on these processes is important for its implications in evolution and breeding, especially in the context of global warming. In this review, we first summarize the process of meiotic recombination and its reliance on axis and synaptonemal complex structures, and then discuss effects of temperature on these processes and structures. We hypothesize that some consistent effects of temperature on recombination and meiotic thermotolerance may commonly be two sides of the same coin, driven by effects of temperature on the folding or interaction of key meiotic proteins.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109231 TI - Correction to 'Overexpression of plastid terminal oxidase in Synechocystis sp. PCC 6803 alters cellular redox state'. PMID- 29109230 TI - Background selection as null hypothesis in population genomics: insights and challenges from Drosophila studies. AB - The consequences of selection at linked sites are multiple and widespread across the genomes of most species. Here, I first review the main concepts behind models of selection and linkage in recombining genomes, present the difficulty in parametrizing these models simply as a reduction in effective population size (Ne) and discuss the predicted impact of recombination rates on levels of diversity across genomes. Arguments are then put forward in favour of using a model of selection and linkage with neutral and deleterious mutations (i.e. the background selection model, BGS) as a sensible null hypothesis for investigating the presence of other forms of selection, such as balancing or positive. I also describe and compare two studies that have generated high-resolution landscapes of the predicted consequences of selection at linked sites in Drosophila melanogaster Both studies show that BGS can explain a very large fraction of the observed variation in diversity across the whole genome, thus supporting its use as null model. Finally, I identify and discuss a number of caveats and challenges in studies of genetic hitchhiking that have been often overlooked, with several of them sharing a potential bias towards overestimating the evidence supporting recent selective sweeps to the detriment of a BGS explanation. One potential source of bias is the analysis of non-equilibrium populations: it is precisely because models of selection and linkage predict variation in Ne across chromosomes that demographic dynamics are not expected to be equivalent chromosome- or genome-wide. Other challenges include the use of incomplete genome annotations, the assumption of temporally stable recombination landscapes, the presence of genes under balancing selection and the consequences of ignoring non crossover (gene conversion) recombination events.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'. PMID- 29109232 TI - Recombination: the good, the bad and the variable. AB - Recombination, the process by which DNA strands are broken and repaired, producing new combinations of alleles, occurs in nearly all multicellular organisms and has important implications for many evolutionary processes. The effects of recombination can be good, as it can facilitate adaptation, but also bad when it breaks apart beneficial combinations of alleles, and recombination is highly variable between taxa, species, individuals and across the genome. Understanding how and why recombination rate varies is a major challenge in biology. Most theoretical and empirical work has been devoted to understanding the role of recombination in the evolution of sex-comparing between sexual and asexual species or populations. How recombination rate evolves and what impact this has on evolutionary processes within sexually reproducing organisms has received much less attention. This Theme Issue focusses on how and why recombination rate varies in sexual species, and aims to coalesce knowledge of the molecular mechanisms governing recombination with our understanding of the evolutionary processes driving variation in recombination within and between species. By integrating these fields, we can identify important knowledge gaps and areas for future research, and pave the way for a more comprehensive understanding of how and why recombination rate varies. PMID- 29109233 TI - Advance care planning for patients with chronic respiratory diseases: a systematic review of preferences and practices. AB - BACKGROUND: Advance care planning (ACP) supports patients in identifying and documenting their preferences and timely discussing them with their relatives and healthcare professionals (HCPs). Since the British Thoracic Society encourages ACP in chronic respiratory disease, the objective was to systematically review ACP practice in chronic respiratory disease, attitudes of patients and HCPs and barriers and facilitators related to engagement in ACP. METHODS: We systematically searched 12 electronic databases for empirical studies on ACP in adults with chronic respiratory diseases. Identified studies underwent full review and data extraction. RESULTS: Of 2509 studies, 21 were eligible: 10 were quantitative studies. Although a majority of patients was interested in engaging in ACP, ACP was rarely carried out. Many HCPs acknowledged the importance of ACP but were hesitant to initiate it. Barriers to engagement in ACP were the complex disease course of patients with chronic respiratory diseases, HCPs' concern of taking away patients' hopes and lack of continuity of care. The identification of trigger points and training of HCPs on how to communicate sensitive topics were identified as facilitators to engagement in ACP. CONCLUSIONS: In conclusion, ACP is surprisingly uncommon in chronic respiratory disease, possibly due to the complex disease course of chronic respiratory diseases and ambivalence of both patients and HCPs to engage in ACP. Providing patients with information about their disease can help meeting their needs. Additionally, support of HCPs through identification of trigger points, training and system-related changes can facilitate engagement in ACP. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42016039787. PMID- 29109234 TI - Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury. AB - Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI. PMID- 29109235 TI - Glial Draper Rescues Abeta Toxicity in a Drosophila Model of Alzheimer's Disease. AB - Pathological hallmarks of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques, neurofibrillary tangles, and reactive gliosis. Glial cells offer protection against AD by engulfing extracellular Abeta peptides, but the repertoire of molecules required for glial recognition and destruction of Abeta are still unclear. Here, we show that the highly conserved glial engulfment receptor Draper/MEGF10 provides neuroprotection in an AD model of Drosophila (both sexes). Neuronal expression of human Abeta42arc in adult flies results in robust Abeta accumulation, neurodegeneration, locomotor dysfunction, and reduced lifespan. Notably, all of these phenotypes are more severe in draper mutant animals, whereas enhanced expression of glial Draper reverses Abeta accumulation, as well as behavioral phenotypes. We also show that the signal transducer and activator of transcription (Stat92E), c-Jun N-terminal kinase (JNK)/AP-1 signaling, and expression of matrix metalloproteinase-1 (Mmp1) are activated downstream of Draper in glia in response to Abeta42arc exposure. Furthermore, Abeta42-induced upregulation of the phagolysosomal markers Atg8 and p62 was notably reduced in draper mutant flies. Based on our findings, we propose that glia clear neurotoxic Abeta peptides in the AD model Drosophila brain through a Draper/STAT92E/JNK cascade that may be coupled to protein degradation pathways such as autophagy or more traditional phagolysosomal destruction methods.SIGNIFICANCE STATEMENT Alzheimer's disease (AD) and similar dementias are common incurable neurodegenerative disorders in the aging population. As the primary immune responders in the brain, glial cells are implicated as key players in the onset and progression of AD and related disorders. Here we show that the glial engulfment receptor Draper is protective in a Drosophila model of AD, reducing levels of amyloid beta (Abeta) peptides, reversing locomotor defects, and extending lifespan. We further show that protein degradation pathways are induced downstream of Draper in AD model flies, supporting a model in which glia engulf and destroy Abeta peptides to reduce amyloid-associated toxicity. PMID- 29109236 TI - History-Dependent Odor Processing in the Mouse Olfactory Bulb. AB - In nature, animals normally perceive sensory information on top of backgrounds. Thus, the neural substrate to perceive under background conditions is inherent in all sensory systems. Where and how sensory systems process backgrounds is not fully understood. In olfaction, just a few studies have addressed the issue of odor coding on top of continuous odorous backgrounds. Here, we tested how background odors are encoded by mitral cells (MCs) in the olfactory bulb (OB) of male mice. Using in vivo two-photon calcium imaging, we studied how MCs responded to odors in isolation versus their responses to the same odors on top of continuous backgrounds. We show that MCs adapt to continuous odor presentation and that mixture responses are different when preceded by background. In a subset of odor combinations, this history-dependent processing was useful in helping to identify target odors over background. Other odorous backgrounds were highly dominant such that target odors were completely masked by their presence. Our data are consistent in both low and high odor concentrations and in anesthetized and awake mice. Thus, odor processing in the OB is strongly influenced by the recent history of activity, which could have a powerful impact on how odors are perceived.SIGNIFICANCE STATEMENT We examined a basic feature of sensory processing in the olfactory bulb. Specifically, we measured how mitral cells adapt to continuous background odors and how target odors are encoded on top of such background. Our results show clear differences in odor coding based on the immediate history of the stimulus. Our results support the argument that odor coding in the olfactory bulb depends on the recent history of the sensory environment. PMID- 29109237 TI - Sleep Deprivation Promotes Habitual Control over Goal-Directed Control: Behavioral and Neuroimaging Evidence. AB - Sleep is one of the most fundamental processes of life, playing an important role in the regulation of brain function. The long-term lack of sleep can cause memory impairments, declines in learning ability, and executive dysfunction. In the present study, we evaluated the effects of sleep deprivation on instrumental learning behavior, particularly goal-directed and habitual actions in humans, and investigated the underlying neural mechanisms. Healthy college students of either gender were enrolled and randomly divided into sleep deprivation group and sleep control group. fMRI data were collected. We found that one night of sleep deprivation led to greater responsiveness to stimuli that were associated with devalued outcomes in the slips-of-action test, indicating a deficit in the formation of goal-directed control and an overreliance on habits. Furthermore, sleep deprivation had no effect on the expression of acquired goal-directed action. The level of goal-directed action after sleep deprivation was positively correlated with baseline working memory capacity. The neuroimaging data indicated that goal-directed learning mainly recruited the ventromedial PFC (vmPFC), the activation of which was less pronounced during goal-directed learning after sleep deprivation. Activation of the vmPFC during goal-directed learning during training was positively correlated with the level of goal-directed action performance. The present study suggests that people rely predominantly on habits at the expense of goal-directed control after sleep deprivation, and this process involves the vmPFC. These results contribute to a better understanding of the effects of sleep loss on decision-making.SIGNIFICANCE STATEMENT Understanding the cognitive consequences of sleep deprivation has become extremely important over the past half century, given the continued decline in sleep duration in industrialized societies. Our results provide novel evidence that goal-directed action may be particularly vulnerable to sleep loss, and the brain mechanism underlying this effect was explored. Elucidation of the effects of sleep deprivation on decision-making will deepen our understanding of the function of sleep, emphasizing the role of sleep in cognitive impairments and mental health. PMID- 29109238 TI - Extensive Tonotopic Mapping across Auditory Cortex Is Recapitulated by Spectrally Directed Attention and Systematically Related to Cortical Myeloarchitecture. AB - Auditory selective attention is vital in natural soundscapes. But it is unclear how attentional focus on the primary dimension of auditory representation acoustic frequency-might modulate basic auditory functional topography during active listening. In contrast to visual selective attention, which is supported by motor-mediated optimization of input across saccades and pupil dilation, the primate auditory system has fewer means of differentially sampling the world. This makes spectrally-directed endogenous attention a particularly crucial aspect of auditory attention. Using a novel functional paradigm combined with quantitative MRI, we establish in male and female listeners that human frequency band-selective attention drives activation in both myeloarchitectonically estimated auditory core, and across the majority of tonotopically mapped nonprimary auditory cortex. The attentionally driven best-frequency maps show strong concordance with sensory-driven maps in the same subjects across much of the temporal plane, with poor concordance in areas outside traditional auditory cortex. There is significantly greater activation across most of auditory cortex when best frequency is attended, versus ignored; the same regions do not show this enhancement when attending to the least-preferred frequency band. Finally, the results demonstrate that there is spatial correspondence between the degree of myelination and the strength of the tonotopic signal across a number of regions in auditory cortex. Strong frequency preferences across tonotopically mapped auditory cortex spatially correlate with R1-estimated myeloarchitecture, indicating shared functional and anatomical organization that may underlie intrinsic auditory regionalization.SIGNIFICANCE STATEMENT Perception is an active process, especially sensitive to attentional state. Listeners direct auditory attention to track a violin's melody within an ensemble performance, or to follow a voice in a crowded cafe. Although diverse pathologies reduce quality of life by impacting such spectrally directed auditory attention, its neurobiological bases are unclear. We demonstrate that human primary and nonprimary auditory cortical activation is modulated by spectrally directed attention in a manner that recapitulates its tonotopic sensory organization. Further, the graded activation profiles evoked by single-frequency bands are correlated with attentionally driven activation when these bands are presented in complex soundscapes. Finally, we observe a strong concordance in the degree of cortical myelination and the strength of tonotopic activation across several auditory cortical regions. PMID- 29109239 TI - Graded Elevation of c-Jun in Schwann Cells In Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination. AB - Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/+ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/+ mice, in which c-Jun is elevated ~6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyelinating neuropathies. The tumor suppressor P19ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/+ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury.SIGNIFICANCE STATEMENT In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling beneficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury. PMID- 29109240 TI - Deficiency of the Thyroid Hormone Transporter Monocarboxylate Transporter 8 in Neural Progenitors Impairs Cellular Processes Crucial for Early Corticogenesis. AB - Thyroid hormones (THs) are essential for establishing layered brain structures, a process called corticogenesis, by acting on transcriptional activity of numerous genes. In humans, deficiency of the monocarboxylate transporter 8 (MCT8), involved in cellular uptake of THs before their action, results in severe neurological abnormalities, known as the Allan-Herndon-Dudley syndrome. While the brain lesions predominantly originate prenatally, it remains unclear how and when exactly MCT8 dysfunction affects cellular processes crucial for corticogenesis. We investigated this by inducing in vivo RNAi vector-based knockdown of MCT8 in neural progenitors of the chicken optic tectum, a layered structure that shares many developmental features with the mammalian cerebral cortex. MCT8 knockdown resulted in cellular hypoplasia and a thinner optic tectum. This could be traced back to disrupted cell-cycle kinetics and a premature shift to asymmetric cell divisions impairing progenitor cell pool expansion. Birth-dating experiments confirmed diminished neurogenesis in the MCT8-deficient cell population as well as aberrant migration of both early-born and late-born neuroblasts, which could be linked to reduced reelin signaling and disorganized radial glial cell fibers. Impaired neurogenesis resulted in a reduced number of glutamatergic and GABAergic neurons, but the latter additionally showed decreased differentiation. Moreover, an accompanying reduction in untransfected GABAergic neurons suggests hampered intercellular communication. These results indicate that MCT8-dependent TH uptake in the neural progenitors is essential for early events in corticogenesis, and help to understand the origin of the problems in cortical development and function in Allan-Herndon-Dudley syndrome patients.SIGNIFICANCE STATEMENT Thyroid hormones (THs) are essential to establish the stereotypical layered structure of the human forebrain during embryonic development. Before their action on gene expression, THs require cellular uptake, a process facilitated by the TH transporter monocarboxylate transporter 8 (MCT8). We investigated how and when dysfunctional MCT8 can induce brain lesions associated with the Allan-Herndon Dudley syndrome, characterized by psychomotor retardation. We used the layered chicken optic tectum to model cortical development, and induced MCT8 deficiency in neural progenitors. Impaired cell proliferation, migration, and differentiation resulted in an underdeveloped optic tectum and a severe reduction in nerve cells. Our data underline the need for MCT8-dependent TH uptake in neural progenitors and stress the importance of local TH action in early development. PMID- 29109241 TI - Optogenetic Activation of the fruitless-Labeled Circuitry in Drosophila subobscura Males Induces Mating Motor Acts. AB - It remains an enigma how the nervous system of different animal species produces different behaviors. We studied the neural circuitry for mating behavior in Drosophila subobscura, a species that displays unique courtship actions not shared by other members of the genera including the genetic model D. melanogaster, in which the core courtship circuitry has been identified. We disrupted the D. subobscura fruitless (fru) gene, a master regulator for the courtship circuitry formation in D. melanogaster, resulting in complete loss of mating behavior. We also generated frusoChrimV , which expresses the optogenetic activator Chrimson fused with a fluorescent marker under the native fru promoter. The fru-labeled circuitry in D. subobscura visualized by frusoChrimV revealed differences between females and males, optogenetic activation of which in males induced mating behavior including attempted copulation. These findings provide a substrate for neurogenetic dissection and manipulation of behavior in non-model animals, and will help to elucidate the neural basis for behavioral diversification.SIGNIFICANCE STATEMENT How did behavioral specificity arise during evolution? Here we attempted to address this question by comparing the parallel genetically definable neural circuits controlling the courtship behavior of Drosophila melanogaster, a genetic model, and its relative, D. subobscura, which exhibits a courtship behavioral pattern unique to it, including nuptial gift transfer. We found that the subobscura fruitless circuit, which is required for male courtship behavior, was slightly but clearly different from its melanogaster counterpart, and that optogenetic activation of this circuit induced subobscura-specific behavior, i.e., regurgitating crop contents, a key element of transfer of nuptial gift. Our study will pave the way for determining how and which distinctive cellular elements within the fruitless circuit determine the species-specific differences in courtship behavior. PMID- 29109242 TI - Why Do Irrelevant Alternatives Matter? An fMRI-TMS Study of Context-Dependent Preferences. AB - Both humans and animals are known to exhibit a violation of rationality known as "decoy effect": introducing an irrelevant option (a decoy) can influence choices among other (relevant) options. Exactly how and why decoys trigger this effect is not known. It may be an example of fast heuristic decision-making, which is adaptive in natural environments, but may lead to biased choices in certain markets or experiments. We used fMRI and transcranial magnetic stimulation to investigate the neural underpinning of the decoy effect of both sexes. The left ventral striatum was more active when the chosen option dominated the decoy. This is consistent with the hypothesis that the presence of a decoy option influences the valuation of other options, making valuation context-dependent even when choices appear fully rational. Consistent with the idea that control is recruited to prevent heuristics from producing biased choices, the right inferior frontal gyrus, often implicated in inhibiting prepotent responses, connected more strongly with the striatum when subjects successfully overrode the decoy effect and made unbiased choices. This is further supported by our transcranial magnetic stimulation experiment: subjects whose right inferior frontal gyrus was temporarily disrupted made biased choices more often than a control group. Our results suggest that the neural basis of the decoy effect could be the context dependent activation of the valuation area. But the differential connectivity from the frontal area may indicate how deliberate control monitors and corrects errors and biases in decision-making.SIGNIFICANCE STATEMENT Standard theories of rational decision-making assume context-independent valuations of available options. Motivated by the importance of this basic assumption, we used fMRI to study how the human brain assigns values to available options. We found activity in the valuation area to be consistent with the hypothesis that values depend on irrelevant aspects of the environment, even for subjects whose choices appear fully rational. Such context-dependent valuations may lead to biased decision making. We further found differential connectivity from the frontal area to the valuation area depending on whether biases were successfully overcome. This suggests a mechanism for making rational choices despite the potential bias. Further support was obtained by a transcranial magnetic stimulation experiment, where subjects whose frontal control was temporarily disrupted made biased choices more often than a control group. PMID- 29109243 TI - Expression of Concern. The IR1152 Mutant Insulin Receptor Selectively Impairs Insulin Action in Skeletal Muscle but Not in Liver. Diabetes 2000;49:1194-1202. DOI: https://doi.org/10.2337/diabetes.49.7.1194. PMID: 10909978. PMID- 29109244 TI - Expression of Concern. Prep1 Controls Insulin Glucoregulatory Function in Liver by Transcriptional Targeting of SHP1 Tyrosine Phosphatase. Diabetes 2011;60:138 147. DOI: 10.2337/db10-0860. PMID: 20864515. PMID- 29109245 TI - Expression of Concern. Protein Kinase C (PKC)-alpha Activation Inhibits PKC-zeta and Mediates the Action of PED/PEA-15 on Glucose Transport in the L6 Skeletal Muscle Cells. Diabetes 2001;50:1244-1252. DOI: https://doi.org/10.2337/diabetes.50.6.1244. PMID: 11375323. PMID- 29109246 TI - Scale-dependent climatic drivers of human epidemics in ancient China. AB - A wide range of climate change-induced effects have been implicated in the prevalence of infectious diseases. Disentangling causes and consequences, however, remains particularly challenging at historical time scales, for which the quality and quantity of most of the available natural proxy archives and written documentary sources often decline. Here, we reconstruct the spatiotemporal occurrence patterns of human epidemics for large parts of China and most of the last two millennia. Cold and dry climate conditions indirectly increased the prevalence of epidemics through the influences of locusts and famines. Our results further reveal that low-frequency, long-term temperature trends mainly contributed to negative associations with epidemics, while positive associations of epidemics with droughts, floods, locusts, and famines mainly coincided with both higher and lower frequency temperature variations. Nevertheless, unstable relationships between human epidemics and temperature changes were observed on relatively smaller time scales. Our study suggests that an intertwined, direct, and indirect array of biological, ecological, and societal responses to different aspects of past climatic changes strongly depended on the frequency domain and study period chosen. PMID- 29109247 TI - Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology. AB - Implantable electrical probes have led to advances in neuroscience, brain-machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases. PMID- 29109248 TI - DGR mutagenic transposition occurs via hypermutagenic reverse transcription primed by nicked template RNA. AB - Diversity-generating retroelements (DGRs) are molecular evolution machines that facilitate microbial adaptation to environmental changes. Hypervariation occurs via a mutagenic retrotransposition process from a template repeat (TR) to a variable repeat (VR) that results in adenine-to-random nucleotide conversions. Here we show that reverse transcription of the Bordetella phage DGR is primed by an adenine residue in TR RNA and is dependent on the DGR-encoded reverse transcriptase (bRT) and accessory variability determinant (Avd ), but is VR independent. We also find that the catalytic center of bRT plays an essential role in site-specific cleavage of TR RNA for cDNA priming. Adenine-specific mutagenesis occurs during reverse transcription and does not involve dUTP incorporation, indicating it results from bRT-catalyzed misincorporation of standard deoxyribonucleotides. In vivo assays show that this hybrid RNA-cDNA molecule is required for mutagenic transposition, revealing a unique mechanism of DNA hypervariation for microbial adaptation. PMID- 29109249 TI - Hominid butchers and biting crocodiles in the African Plio-Pleistocene. AB - Zooarchaeologists have long relied on linear traces and pits found on the surfaces of ancient bones to infer ancient hominid behaviors such as slicing, chopping, and percussive actions during butchery of mammal carcasses. However, such claims about Plio-Pleistocene hominids rely mostly on very small assemblages of bony remains. Furthermore, recent experiments on trampling animals and biting crocodiles have shown each to be capable of producing mimics of such marks. This equifinality-the creation of similar products by different processes-makes deciphering early archaeological bone assemblages difficult. Bone modifications among Ethiopian Plio-Pleistocene hominid and faunal remains at Asa Issie, Maka, Hadar, and Bouri were reassessed in light of these findings. The results show that crocodiles were important modifiers of these bone assemblages. The relative roles of hominids, mammalian carnivores, and crocodiles in the formation of Oldowan zooarchaeological assemblages will only be accurately revealed by better bounding equifinality. Critical analysis within a consilience-based approach is identified as the pathway forward. More experimental studies and increased archaeological fieldwork aimed at generating adequate samples are now required. PMID- 29109251 TI - Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. AB - The metabolic programs of functionally distinct T cell subsets are tailored to their immunologic activities. While quiescent T cells use oxidative phosphorylation (OXPHOS) for energy production, and effector T cells (Teffs) rely on glycolysis for proliferation, the distinct metabolic features of regulatory T cells (Tregs) are less well established. Here we show that the metabolic sensor LKB1 is critical to maintain cellular metabolism and energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early-onset autoimmune disorder. Tregs lacking Lkb1 have defective mitochondria, compromised OXPHOS, depleted cellular ATP, and altered cellular metabolism pathways that compromise their survival and function. Furthermore, we demonstrate that the function of LKB1 in Tregs is largely independent of the AMP-activated protein kinase, but is mediated by the MAP/microtubule affinity-regulating kinases and salt-inducible kinases. Our results define a metabolic checkpoint in Tregs that couples metabolic regulation to immune homeostasis and tolerance. PMID- 29109252 TI - Poaceae-specific MS1 encodes a phospholipid-binding protein for male fertility in bread wheat. AB - Male sterility is an essential trait in hybrid seed production for monoclinous crops, including rice and wheat. However, compared with the high percentage of hybrid rice planted in the world, little commercial hybrid wheat is planted globally as a result of the lack of a suitable system for male sterility. Therefore, understanding the molecular nature of male fertility in wheat is critical for commercially viable hybrid wheat. Here, we report the cloning and characterization of Male Sterility 1 (Ms1) in bread wheat by using a combination of advanced genomic approaches. MS1 is a newly evolved gene in the Poaceae that is specifically expressed in microsporocytes, and is essential for microgametogenesis. Orthologs of Ms1 are expressed in diploid and allotetraploid ancestral species. Orthologs of Ms1 are epigenetically silenced in the A and D subgenomes of allohexaploid wheat; only Ms1 from the B subgenome is expressed. The encoded protein, Ms1, is localized to plastid and mitochondrial membranes, where it exhibits phospholipid-binding activity. These findings provide a foundation for the development of commercially viable hybrid wheat. PMID- 29109250 TI - Molecular basis of tactile specialization in the duck bill. AB - Tactile-foraging ducks are specialist birds known for their touch-dependent feeding behavior. They use dabbling, straining, and filtering to find edible matter in murky water, relying on the sense of touch in their bill. Here, we present the molecular characterization of embryonic duck bill, which we show contains a high density of mechanosensory corpuscles innervated by functional rapidly adapting trigeminal afferents. In contrast to chicken, a visually foraging bird, the majority of duck trigeminal neurons are mechanoreceptors that express the Piezo2 ion channel and produce slowly inactivating mechano-current before hatching. Furthermore, duck neurons have a significantly reduced mechano activation threshold and elevated mechano-current amplitude. Cloning and electrophysiological characterization of duck Piezo2 in a heterologous expression system shows that duck Piezo2 is functionally similar to the mouse ortholog but with prolonged inactivation kinetics, particularly at positive potentials. Knockdown of Piezo2 in duck trigeminal neurons attenuates mechano current with intermediate and slow inactivation kinetics. This suggests that Piezo2 is capable of contributing to a larger range of mechano-activated currents in duck trigeminal ganglia than in mouse trigeminal ganglia. Our results provide insights into the molecular basis of mechanotransduction in a tactile-specialist vertebrate. PMID- 29109253 TI - A transient dopamine signal encodes subjective value and causally influences demand in an economic context. AB - The mesolimbic dopamine system is strongly implicated in motivational processes. Currently accepted theories suggest that transient mesolimbic dopamine release events energize reward seeking and encode reward value. During the pursuit of reward, critical associations are formed between the reward and cues that predict its availability. Conditioned by these experiences, dopamine neurons begin to fire upon the earliest presentation of a cue, and again at the receipt of reward. The resulting dopamine concentration scales proportionally to the value of the reward. In this study, we used a behavioral economics approach to quantify how transient dopamine release events scale with price and causally alter price sensitivity. We presented sucrose to rats across a range of prices and modeled the resulting demand curves to estimate price sensitivity. Using fast-scan cyclic voltammetry, we determined that the concentration of accumbal dopamine time locked to cue presentation decreased with price. These data confirm and extend the notion that dopamine release events originating in the ventral tegmental area encode subjective value. Using optogenetics to augment dopamine concentration, we found that enhancing dopamine release at cue made demand more sensitive to price and decreased dopamine concentration at reward delivery. From these observations, we infer that value is decreased because of a negative reward prediction error (i.e., the animal receives less than expected). Conversely, enhancing dopamine at reward made demand less sensitive to price. We attribute this finding to a positive reward prediction error, whereby the animal perceives they received a better value than anticipated. PMID- 29109254 TI - let-7 miRNA controls CED-7 homotypic adhesion and EFF-1-mediated axonal self fusion to restore touch sensation following injury. AB - Neuronal injury often leads to devastating consequences such as loss of senses or locomotion. Restoration of function after injury relies on whether the injured axons can find their target cells. Although fusion between injured proximal axon and distal fragment has been observed in many organisms, its functional significance is not clear. Here, using Caenorhabditis elegans mechanosensory neurons, we address this question. Using two femtosecond lasers simultaneously, we could scan and sever posterior lateral microtubule neurons [posterior lateral microtubules (PLMs)] on both sides of the worm. We showed that axotomy of both PLMs leads to a dramatic loss of posterior touch sensation. During the regenerative phase, only axons that fuse to their distal counterparts contribute to functional recovery. Loss of let-7 miRNA promotes functional restoration in both larval and adult stages. In the L4 stage, loss of let-7 increases fusion events by increasing the mRNA level of one of the cell-recognition molecules, CED 7. The ability to establish cytoplasmic continuity between the proximal and distal ends declines with age. Loss of let-7 overcomes this barrier by promoting axonal transport and enrichment of the EFF-1 fusogen at the growing tip of cut processes. Our data reveal the functional property of a regenerating neuron. PMID- 29109255 TI - HIF and HOIL-1L-mediated PKCzeta degradation stabilizes plasma membrane Na,K ATPase to protect against hypoxia-induced lung injury. AB - Organisms have evolved adaptive mechanisms in response to stress for cellular survival. During acute hypoxic stress, cells down-regulate energy-consuming enzymes such as Na,K-ATPase. Within minutes of alveolar epithelial cell (AEC) exposure to hypoxia, protein kinase C zeta (PKCzeta) phosphorylates the alpha1 Na,K-ATPase subunit and triggers it for endocytosis, independently of the hypoxia inducible factor (HIF). However, the Na,K-ATPase activity is essential for cell homeostasis. HIF induces the heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), which leads to PKCzeta degradation. Here we report a mechanism of prosurvival adaptation of AECs to prolonged hypoxia where PKCzeta degradation allows plasma membrane Na,K-ATPase stabilization at ~50% of normoxic levels, preventing its excessive down-regulation and cell death. Mice lacking HOIL-1L in lung epithelial cells (CreSPC/HOIL-1Lfl/fl ) were sensitized to hypoxia because they express higher levels of PKCzeta and, consequently, lower plasma membrane Na,K-ATPase levels, which increased cell death and worsened lung injury. In AECs, expression of an alpha1-Na,K-ATPase construct bearing an S18A (alpha1-S18A) mutation, which precludes PKCzeta phosphorylation, stabilized the Na,K-ATPase at the plasma membrane and prevented hypoxia-induced cell death even in the absence of HOIL-1L. Adenoviral overexpression of the alpha1-S18A mutant Na,K-ATPase in vivo rescued the enhanced sensitivity of CreSPC/HOIL-1Lfl/fl mice to hypoxic lung injury. These data suggest that stabilization of Na,K-ATPase during severe hypoxia is a HIF-dependent process involving PKCzeta degradation. Accordingly, we provide evidence of an important adaptive mechanism to severe hypoxia, whereby halting the exaggerated down-regulation of plasma membrane Na,K-ATPase prevents cell death and lung injury. PMID- 29109256 TI - GPCR-controlled membrane recruitment of negative regulator C2GAP1 locally inhibits Ras signaling for adaptation and long-range chemotaxis. AB - Eukaryotic cells chemotax in a wide range of chemoattractant concentration gradients, and thus need inhibitory processes that terminate cell responses to reach adaptation while maintaining sensitivity to higher-concentration stimuli. However, the molecular mechanisms underlying inhibitory processes are still poorly understood. Here, we reveal a locally controlled inhibitory process in a GPCR-mediated signaling network for chemotaxis in Dictyostelium discoideum We identified a negative regulator of Ras signaling, C2GAP1, which localizes at the leading edge of chemotaxing cells and is activated by and essential for GPCR mediated Ras signaling. We show that both C2 and GAP domains are required for the membrane targeting of C2GAP1, and that GPCR-triggered Ras activation is necessary to recruit C2GAP1 from the cytosol and retains it on the membrane to locally inhibit Ras signaling. C2GAP1-deficient c2gapA- cells have altered Ras activation that results in impaired gradient sensing, excessive polymerization of F actin, and subsequent defective chemotaxis. Remarkably, these cellular defects of c2gapA cells are chemoattractant concentration dependent. Thus, we have uncovered an inhibitory mechanism required for adaptation and long-range chemotaxis. PMID- 29109257 TI - Ribonucleotides incorporated by the yeast mitochondrial DNA polymerase are not repaired. AB - Incorporation of ribonucleotides into DNA during genome replication is a significant source of genomic instability. The frequency of ribonucleotides in DNA is determined by deoxyribonucleoside triphosphate/ribonucleoside triphosphate (dNTP/rNTP) ratios, by the ability of DNA polymerases to discriminate against ribonucleotides, and by the capacity of repair mechanisms to remove incorporated ribonucleotides. To simultaneously compare how the nuclear and mitochondrial genomes incorporate and remove ribonucleotides, we challenged these processes by changing the balance of cellular dNTPs. Using a collection of yeast strains with altered dNTP pools, we discovered an inverse relationship between the concentration of individual dNTPs and the amount of the corresponding ribonucleotides incorporated in mitochondrial DNA, while in nuclear DNA the ribonucleotide pattern was only altered in the absence of ribonucleotide excision repair. Our analysis uncovers major differences in ribonucleotide repair between the two genomes and provides concrete evidence that yeast mitochondria lack mechanisms for removal of ribonucleotides incorporated by the mtDNA polymerase. Furthermore, as cytosolic dNTP pool imbalances were transmitted equally well into the nucleus and the mitochondria, our results support a view of the cytosolic and mitochondrial dNTP pools in frequent exchange. PMID- 29109258 TI - Definition of the hypothalamic GnRH pulse generator in mice. AB - The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARNKISS) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARNKISS neuron population exhibits brief (~1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARNKISS population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARNKISS neurons for 1 min generated pulses of LH in freely behaving mice, whereas inhibition with archaerhodopsin for 30 min suppressed LH pulsatility. Experiments aimed at resetting the activity of the ARNKISS neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARNKISS neurons as the long-elusive hypothalamic pulse generator driving fertility. PMID- 29109259 TI - Proof of region-specific multipotent progenitors in human breast epithelia. AB - The human breast parenchyma consists of collecting ducts and terminal duct lobular units (TDLUs). The TDLU is the site of origin of most breast cancers. The reason for such focal susceptibility to cancer remains poorly understood. Here, we take advantage of a region-specific heterogeneity in luminal progenitors to interrogate the differentiation repertoire of candidate stem cells in TDLUs. We show that stem-like activity in serial passage culture and in vivo breast morphogenesis relies on the preservation of a myoepithelial phenotype. By enrichment for region-specific progenitors, we identify bipotent and multipotent progenitors in ducts and TDLUs, respectively. We propose that focal breast cancer susceptibility, at least in part, originates from region-specific myoepithelial progenitors. PMID- 29109260 TI - Natural language indicators of differential gene regulation in the human immune system. AB - Adverse social conditions have been linked to a conserved transcriptional response to adversity (CTRA) in circulating leukocytes that may contribute to social gradients in disease. However, the CNS mechanisms involved remain obscure, in part because CTRA gene-expression profiles often track external social environmental variables more closely than they do self-reported internal affective states such as stress, depression, or anxiety. This study examined the possibility that variations in patterns of natural language use might provide more sensitive indicators of the automatic threat-detection and -response systems that proximally regulate autonomic induction of the CTRA. In 22,627 audio samples of natural speech sampled from the daily interactions of 143 healthy adults, both total language output and patterns of function-word use covaried with CTRA gene expression. These language features predicted CTRA gene expression substantially better than did conventional self-report measures of stress, depression, and anxiety and did so independently of demographic and behavioral factors (age, sex, race, smoking, body mass index) and leukocyte subset distributions. This predictive relationship held when language and gene expression were sampled more than a week apart, suggesting that associations reflect stable individual differences or chronic life circumstances. Given the observed relationship between personal expression and gene expression, patterns of natural language use may provide a useful behavioral indicator of nonconsciously evaluated well-being (implicit safety vs. threat) that is distinct from conscious affective experience and more closely tracks the neurobiological processes involved in peripheral gene regulation. PMID- 29109261 TI - Scale-dependent portfolio effects explain growth inflation and volatility reduction in landscape demography. AB - Population demography is central to fundamental ecology and for predicting range shifts, decline of threatened species, and spread of invasive organisms. There is a mismatch between most demographic work, carried out on few populations and at local scales, and the need to predict dynamics at landscape and regional scales. Inspired by concepts from landscape ecology and Markowitz's portfolio theory, we develop a landscape portfolio platform to quantify and predict the behavior of multiple populations, scaling up the expectation and variance of the dynamics of an ensemble of populations. We illustrate this framework using a 35-y time series on gypsy moth populations. We demonstrate the demography accumulation curve in which the collective growth of the ensemble depends on the number of local populations included, highlighting a minimum but adequate number of populations for both regional-scale persistence and cross-scale inference. The attainable set of landscape portfolios further suggests tools for regional population management for both threatened and invasive species. PMID- 29109262 TI - Myoanatomy of the velvet worm leg revealed by laboratory-based nanofocus X-ray source tomography. AB - X-ray computed tomography (CT) is a powerful noninvasive technique for investigating the inner structure of objects and organisms. However, the resolution of laboratory CT systems is typically limited to the micrometer range. In this paper, we present a table-top nanoCT system in conjunction with standard processing tools that is able to routinely reach resolutions down to 100 nm without using X-ray optics. We demonstrate its potential for biological investigations by imaging a walking appendage of Euperipatoides rowelli, a representative of Onychophora-an invertebrate group pivotal for understanding animal evolution. Comparative analyses proved that the nanoCT can depict the external morphology of the limb with an image quality similar to scanning electron microscopy, while simultaneously visualizing internal muscular structures at higher resolutions than confocal laser scanning microscopy. The obtained nanoCT data revealed hitherto unknown aspects of the onychophoran limb musculature, enabling the 3D reconstruction of individual muscle fibers, which was previously impossible using any laboratory-based imaging technique. PMID- 29109263 TI - Phosphatidylserine save-me signals drive functional recovery of severed axons in Caenorhabditis elegans. AB - Functional regeneration after axonal injury requires transected axons to regrow and reestablish connection with their original target tissue. The spontaneous regenerative mechanism known as axonal fusion provides a highly efficient means of achieving targeted reconnection, as a regrowing axon is able to recognize and fuse with its own detached axon segment, thereby rapidly reestablishing the original axonal tract. Here, we use behavioral assays and fluorescent reporters to show that axonal fusion enables full recovery of function after axotomy of Caenorhabditis elegans mechanosensory neurons. Furthermore, we reveal that the phospholipid phosphatidylserine, which becomes exposed on the damaged axon to function as a "save-me" signal, defines the level of axonal fusion. We also show that successful axonal fusion correlates with the regrowth potential and branching of the proximal fragment and with the retraction length and degeneration of the separated segment. Finally, we identify discrete axonal domains that vary in their propensity to regrow through fusion and show that the level of axonal fusion can be genetically modulated. Taken together, our results reveal that axonal fusion restores full function to injured neurons, is dependent on exposure of phospholipid signals, and is achieved through the balance between regenerative potential and level of degeneration. PMID- 29109264 TI - Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3beta signaling. AB - Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14 (15) epoxyeicosatrienoic acid [14 (15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/reperfusion (I/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated I/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the I/R-caused reduction in glycogen synthase kinase 3beta (GSK3beta) phosphorylation in murine kidney, dose dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3beta phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3beta phosphorylation in mRTECs. In addition, 19 (20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in I/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3beta phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions. PMID- 29109265 TI - Diminished Ost3-dependent N-glycosylation of the BiP nucleotide exchange factor Sil1 is an adaptive response to reductive ER stress. AB - BiP (Kar2 in yeast) is an essential Hsp70 chaperone and master regulator of endoplasmic reticulum (ER) function. BiP's activity is regulated by its intrinsic ATPase activity that can be stimulated by two different nucleotide exchange factors, Sil1 and Lhs1. Both Sil1 and Lhs1 are glycoproteins, but how N glycosylation regulates their function is not known. Here, we show that N glycosylation of Sil1, but not of Lhs1, is diminished upon reductive stress. N glycosylation of Sil1 is predominantly Ost3-dependent and requires a functional Ost3 CxxC thioredoxin motif. N-glycosylation of Lhs1 is largely Ost3-independent and independent of the CxxC motif. Unglycosylated Sil1 is not only functional but is more effective at rescuing loss of Lhs1 activity than N-glycosylated Sil1. Furthermore, substitution of the redox active cysteine pair C52 and C57 in the N terminus of Sil1 results in the Doa10-dependent ERAD of this mutant protein. We propose that reductive stress in the ER inhibits the Ost3-dependent N glycosylation of Sil1, which regulates specific BiP functions appropriate to the needs of the ER under reductive stress. PMID- 29109266 TI - Climate extremes and predicted warming threaten Mediterranean Holocene firs forests refugia. AB - Warmer and drier climatic conditions are projected for the 21st century; however, the role played by extreme climatic events on forest vulnerability is still little understood. For example, more severe droughts and heat waves could threaten quaternary relict tree refugia such as Circum-Mediterranean fir forests (CMFF). Using tree-ring data and a process-based model, we characterized the major climate constraints of recent (1950-2010) CMFF growth to project their vulnerability to 21st-century climate. Simulations predict a 30% growth reduction in some fir species with the 2050s business-as-usual emission scenario, whereas growth would increase in moist refugia due to a longer and warmer growing season. Fir populations currently subjected to warm and dry conditions will be the most vulnerable in the late 21st century when climatic conditions will be analogous to the most severe dry/heat spells causing dieback in the late 20th century. Quantification of growth trends based on climate scenarios could allow defining vulnerability thresholds in tree populations. The presented predictions call for conservation strategies to safeguard relict tree populations and anticipate how many refugia could be threatened by 21st-century dry spells. PMID- 29109267 TI - Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model. AB - Psoriasis is a chronic inflammatory skin disease characterized by the infiltration of T cell and other immune cells to the skin in response to injury or autoantigens. Conventional, as well as unconventional, gammadelta T cells are recruited to the dermis and epidermis by CCL20 and other chemokines. Together with its receptor CCR6, CCL20 plays a critical role in the development of psoriasiform dermatitis in mouse models. We screened a panel of CCL20 variants designed to form dimers stabilized by intermolecular disulfide bonds. A single atom substitution yielded a CCL20 variant (CCL20 S64C) that acted as a partial agonist for the chemokine receptor CCR6. CCL20 S64C bound CCR6 and induced intracellular calcium release, consistent with G-protein activation, but exhibited minimal chemotactic activity. Instead, CCL20 S64C inhibited CCR6 mediated T cell migration with nominal impact on other chemokine receptor signaling. When given in an IL-23-dependent mouse model for psoriasis, CCL20 S64C prevented psoriatic inflammation and the up-regulation of IL-17A and IL-22. Our results validate CCR6 as a tractable therapeutic target for psoriasis and demonstrate the value of CCL20 S64C as a lead compound. PMID- 29109268 TI - Syntenin mediates SRC function in exosomal cell-to-cell communication. AB - The cytoplasmic tyrosine kinase SRC controls cell growth, proliferation, adhesion, and motility. The current view is that SRC acts primarily downstream of cell-surface receptors to control intracellular signaling cascades. Here we reveal that SRC functions in cell-to-cell communication by controlling the biogenesis and the activity of exosomes. Exosomes are viral-like particles from endosomal origin that can reprogram recipient cells. By gain- and loss-of function studies, we establish that SRC stimulates the secretion of exosomes having promigratory activity on endothelial cells and that syntenin is mandatory for SRC exosomal function. Mechanistically, SRC impacts on syndecan endocytosis and on syntenin-syndecan endosomal budding, upstream of ARF6 small GTPase and its effector phospholipase D2, directly phosphorylating the conserved juxtamembrane DEGSY motif of the syndecan cytosolic domain and syntenin tyrosine 46. Our study uncovers a function of SRC in cell-cell communication, supported by syntenin exosomes, which is likely to contribute to tumor-host interactions. PMID- 29109269 TI - Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin alphaVbeta8. AB - Human regulatory T cells (Tregs) suppress other T cells by converting the latent, inactive form of TGF-beta1 into active TGF-beta1. In Tregs, TGF-beta1 activation requires GARP, a transmembrane protein that binds and presents latent TGF-beta1 on the surface of Tregs stimulated through their T cell receptor. However, GARP is not sufficient because transduction of GARP in non-Treg T cells does not induce active TGF-beta1 production. RGD-binding integrins were shown to activate TGF-beta1 in several non-T cell types. Here we show that alphaVbeta8 dimers are present on stimulated human Tregs but not in other T cells, and that antibodies against alphaV or beta8 subunits block TGF-beta1 activation in vitro. We also show that alphaV and beta8 interact with GARP/latent TGF-beta1 complexes in human Tregs. Finally, a blocking antibody against beta8 inhibited immunosuppression by human Tregs in a model of xenogeneic graft-vs.-host disease induced by the transfer of human T cells in immunodeficient mice. These results show that TGF beta1 activation on the surface of human Tregs implies an interaction between the integrin alphaVbeta8 and GARP/latent TGF-beta1 complexes. Immunosuppression by human Tregs can be inhibited by antibodies against GARP or against the integrin beta8 subunit. Such antibodies may prove beneficial against cancer or chronic infections. PMID- 29109270 TI - M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment. AB - Alterations in synaptic input, persisting for hours to days, elicit homeostatic plastic changes in the axon initial segment (AIS), which is pivotal for spike generation. Here, in hippocampal pyramidal neurons of both primary cultures and slices, we triggered a unique form of AIS plasticity by selectively targeting M type K+ channels, which predominantly localize to the AIS and are essential for tuning neuronal excitability. While acute M-current inhibition via cholinergic activation or direct channel block made neurons more excitable, minutes to hours of sustained M-current depression resulted in a gradual reduction in intrinsic excitability. Dual soma-axon patch-clamp recordings combined with axonal Na+ imaging and immunocytochemistry revealed that these compensatory alterations were associated with a distal shift of the spike trigger zone and distal relocation of FGF14, Na+, and Kv7 channels but not ankyrin G. The concomitant distal redistribution of FGF14 together with Nav and Kv7 segments along the AIS suggests that these channels relocate as a structural and functional unit. These fast homeostatic changes were independent of l-type Ca2+ channel activity but were contingent on the crucial AIS protein, protein kinase CK2. Using compartmental simulations, we examined the effects of varying the AIS position relative to the soma and found that AIS distal relocation of both Nav and Kv7 channels elicited a decrease in neuronal excitability. Thus, alterations in M-channel activity rapidly trigger unique AIS plasticity to stabilize network excitability. PMID- 29109271 TI - Periodic production of retinoic acid by meiotic and somatic cells coordinates four transitions in mouse spermatogenesis. AB - Mammalian spermatogenesis is an elaborately organized differentiation process, starting with diploid spermatogonia, which include germ-line stem cells, and ending with haploid spermatozoa. The process involves four pivotal transitions occurring in physical proximity: spermatogonial differentiation, meiotic initiation, initiation of spermatid elongation, and release of spermatozoa. We report how the four transitions are coordinated in mice. Two premeiotic transitions, spermatogonial differentiation and meiotic initiation, were known to be coregulated by an extrinsic signal, retinoic acid (RA). Our chemical manipulations of RA levels in mouse testes now reveal that RA also regulates the two postmeiotic transitions: initiation of spermatid elongation and spermatozoa release. We measured RA concentrations and found that they changed periodically, as also reflected in the expression patterns of an RA-responsive gene, STRA8; RA levels were low before the four transitions, increased when the transitions occurred, and remained elevated thereafter. We found that pachytene spermatocytes, which express an RA-synthesizing enzyme, Aldh1a2, contribute directly and significantly to RA production in testes. Indeed, chemical and genetic depletion of pachytene spermatocytes revealed that RA from pachytene spermatocytes was required for the two postmeiotic transitions, but not for the two premeiotic transitions. We conclude that the premeiotic transitions are coordinated by RA from Sertoli (somatic) cells. Once germ cells enter meiosis, pachytene spermatocytes produce RA to coordinate the two postmeiotic transitions. In combination, these elements underpin the spatiotemporal coordination of spermatogenesis and ensure its prodigious output in adult males. PMID- 29109272 TI - Structure and mechanotransmission mechanism of the MacB ABC transporter superfamily. AB - MacB is an ABC transporter that collaborates with the MacA adaptor protein and TolC exit duct to drive efflux of antibiotics and enterotoxin STII out of the bacterial cell. Here we present the structure of ATP-bound MacB and reveal precise molecular details of its mechanism. The MacB transmembrane domain lacks a central cavity through which substrates could be passed, but instead conveys conformational changes from one side of the membrane to the other, a process we term mechanotransmission. Comparison of ATP-bound and nucleotide-free states reveals how reversible dimerization of the nucleotide binding domains drives opening and closing of the MacB periplasmic domains via concerted movements of the second transmembrane segment and major coupling helix. We propose that the assembled tripartite pump acts as a molecular bellows to propel substrates through the TolC exit duct, driven by MacB mechanotransmission. Homologs of MacB that do not form tripartite pumps, but share structural features underpinning mechanotransmission, include the LolCDE lipoprotein trafficking complex and FtsEX cell division signaling protein. The MacB architecture serves as the blueprint for understanding the structure and mechanism of an entire ABC transporter superfamily and the many diverse functions it supports. PMID- 29109273 TI - Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. AB - The TGF-beta family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit. PMID- 29109274 TI - Near-infrared remotely triggered drug-release strategies for cancer treatment. AB - Remotely controlled, localized drug delivery is highly desirable for potentially minimizing the systemic toxicity induced by the administration of typically hydrophobic chemotherapy drugs by conventional means. Nanoparticle-based drug delivery systems provide a highly promising approach for localized drug delivery, and are an emerging field of interest in cancer treatment. Here, we demonstrate near-IR light-triggered release of two drug molecules from both DNA-based and protein-based hosts that have been conjugated to near-infrared-absorbing Au nanoshells (SiO2 core, Au shell), each forming a light-responsive drug delivery complex. We show that, depending upon the drug molecule, the type of host molecule, and the laser illumination method (continuous wave or pulsed laser), in vitro light-triggered release can be achieved with both types of nanoparticle based complexes. Two breast cancer drugs, docetaxel and HER2-targeted lapatinib, were delivered to MDA-MB-231 and SKBR3 (overexpressing HER2) breast cancer cells and compared with release in noncancerous RAW 264.7 macrophage cells. Continuous wave laser-induced release of docetaxel from a nanoshell-based DNA host complex showed increased cell death, which also coincided with nonspecific cell death from photothermal heating. Using a femtosecond pulsed laser, lapatinib release from a nanoshell-based human serum albumin protein host complex resulted in increased cancerous cell death while noncancerous control cells were unaffected. Both methods provide spatially and temporally localized drug-release strategies that can facilitate high local concentrations of chemotherapy drugs deliverable at a specific treatment site over a specific time window, with the potential for greatly minimized side effects. PMID- 29109275 TI - Engineering of a membrane-triggered activity switch in coagulation factor VIIa. AB - Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. To exploit these properties of TF, a covalent complex between FVIIa and the soluble ectodomain of TF (sTF) was engineered by introduction of a nonperturbing cystine bridge (FVIIa Q64C-sTF G109C) in the interface. Upon coexpression, FVIIa Q64C and sTF G109C spontaneously assembled into a covalent complex with functional properties similar to the noncovalent wild-type complex. Additional introduction of a FVIIa M306D mutation to uncouple the sTF-mediated allosteric stimulation of FVIIa provided a final complex with FVIIa-like activity in solution, while exhibiting a two to three orders-of-magnitude increase in activity relative to FVIIa upon exposure to a procoagulant membrane. In a mouse model of hemophilia A, the complex normalized hemostasis upon vascular injury at a dose of 0.3 nmol/kg compared with 300 nmol/kg for FVIIa. PMID- 29109276 TI - Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. AB - H3N2 viruses continuously acquire mutations in the hemagglutinin (HA) glycoprotein that abrogate binding of human antibodies. During the 2014-2015 influenza season, clade 3C.2a H3N2 viruses possessing a new predicted glycosylation site in antigenic site B of HA emerged, and these viruses remain prevalent today. The 2016-2017 seasonal influenza vaccine was updated to include a clade 3C.2a H3N2 strain; however, the egg-adapted version of this viral strain lacks the new putative glycosylation site. Here, we biochemically demonstrate that the HA antigenic site B of circulating clade 3C.2a viruses is glycosylated. We show that antibodies elicited in ferrets and humans exposed to the egg-adapted 2016-2017 H3N2 vaccine strain poorly neutralize a glycosylated clade 3C.2a H3N2 virus. Importantly, antibodies elicited in ferrets infected with the current circulating H3N2 viral strain (that possesses the glycosylation site) and humans vaccinated with baculovirus-expressed H3 antigens (that possess the glycosylation site motif) were able to efficiently recognize a glycosylated clade 3C.2a H3N2 virus. We propose that differences in glycosylation between H3N2 egg-adapted vaccines and circulating strains likely contributed to reduced vaccine effectiveness during the 2016-2017 influenza season. Furthermore, our data suggest that influenza virus antigens prepared via systems not reliant on egg adaptations are more likely to elicit protective antibody responses that are not affected by glycosylation of antigenic site B of H3N2 HA. PMID- 29109277 TI - Gut microbiomes and reproductive isolation in Drosophila. AB - Experimental studies of the evolution of reproductive isolation (RI) in real time are a powerful way in which to reveal fundamental, early processes that initiate divergence. In a classic speciation experiment, populations of Drosophila pseudoobscura were subjected to divergent dietary selection and evolved significant positive assortative mating by diet. More recently, a direct role for the gut microbiome in determining this type of RI in Drosophila melanogaster has been proposed. Manipulation of the diet, and hence the gut microbiome, was reported to result in immediate assortative mating by diet, which could be eliminated by reducing gut microbes using antibiotics and recreated by adding back Lactobacillus plantarum We suggest that the evolutionary significance of this result is unclear. For example, in D. melanogaster, the microbiome is reported as flexible and largely environmentally determined. Therefore, microbiome-mediated RI would be transient and would break down under dietary variation. In the absence of evolutionary coassociation or recurrent exposure between host and microbiome, there are no advantages for the gut bacteria or host in effecting RI. To explore these puzzling effects and their mechanisms further, we repeated the tests for RI associated with diet-specific gut microbiomes in D. melanogaster Despite observing replicable differences in the gut microbiomes of flies maintained on different diets, we found no evidence for diet-associated RI, for any role of gut bacteria, or for L. plantarum specifically. The results suggest that there is no general role for gut bacteria in driving the evolution of RI in this species and resolve an evolutionary riddle. PMID- 29109278 TI - Coordinated regulation of heterochromatin inheritance by Dpb3-Dpb4 complex. AB - During DNA replication, chromatin is disrupted ahead of the replication fork, and epigenetic information must be restored behind the fork. How epigenetic marks are inherited through DNA replication remains poorly understood. Histone H3 lysine 9 (H3K9) methylation and histone hypoacetylation are conserved hallmarks of heterochromatin. We previously showed that the inheritance of H3K9 methylation during DNA replication depends on the catalytic subunit of DNA polymerase epsilon, Cdc20. Here we show that the histone-fold subunit of Pol epsilon, Dpb4, interacts an uncharacterized small histone-fold protein, SPCC16C4.22, to form a heterodimer in fission yeast. We demonstrate that SPCC16C4.22 is nonessential for viability and corresponds to the true ortholog of Dpb3. We further show that the Dpb3-Dpb4 dimer associates with histone deacetylases, chromatin remodelers, and histones and plays a crucial role in the inheritance of histone hypoacetylation in heterochromatin. We solve the 1.9-A crystal structure of Dpb3-Dpb4 and reveal that they form the H2A-H2B-like dimer. Disruption of Dpb3-Dpb4 dimerization results in loss of heterochromatin silencing. Our findings reveal a link between histone deacetylation and H3K9 methylation and suggest a mechanism for how two processes are coordinated during replication. We propose that the Dpb3-Dpb4 heterodimer together with Cdc20 serves as a platform for the recruitment of chromatin modifiers and remodelers that mediate heterochromatin assembly during DNA replication, and ensure the faithful inheritance of epigenetic marks in heterochromatin. PMID- 29109279 TI - Ultrafast 25-fs relaxation in highly excited states of methyl azide mediated by strong nonadiabatic coupling. AB - Highly excited electronic states are challenging to explore experimentally and theoretically-due to the large density of states and the fact that small structural changes lead to large changes in electronic character with associated strong nonadiabatic dynamics. They can play a key role in astrophysical and ionospheric chemistry, as well as the detonation chemistry of high-energy density materials. Here, we implement ultrafast vacuum-UV (VUV)-driven electron-ion coincidence imaging spectroscopy to directly probe the reaction pathways of highly excited states of energetic molecules-in this case, methyl azide. Our data, combined with advanced theoretical simulations, show that photoexcitation of methyl azide by a 10-fs UV pulse at 8 eV drives fast structural changes and strong nonadiabatic coupling that leads to relaxation to other excited states on a surprisingly fast timescale of 25 fs. This ultrafast relaxation differs from dynamics occurring on lower excited states, where the timescale required for the wavepacket to reach a region of strong nonadiabatic coupling is typically much longer. Moreover, our theoretical calculations show that ultrafast relaxation of the wavepacket to a lower excited state occurs along one of the conical intersection seams before reaching the minimum energy conical intersection. These findings are important for understanding the unique strongly coupled non-Born Oppenheimer molecular dynamics of VUV-excited energetic molecules. Although such observations have been predicted for many years, this study represents one of the few where such strongly coupled non-Born-Oppenheimer molecular dynamics of VUV excited energetic molecules have been conclusively observed directly, making it possible to identify the ultrafast reaction pathways. PMID- 29109280 TI - Oxalate-curcumin-based probe for micro- and macroimaging of reactive oxygen species in Alzheimer's disease. AB - Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that has a progression that is closely associated with oxidative stress. It has long been speculated that the reactive oxygen species (ROS) level in AD brains is much higher than that in healthy brains. However, evidence from living beings is scarce. Inspired by the "chemistry of glow stick," we designed a near-IR fluorescence (NIRF) imaging probe, termed CRANAD-61, for sensing ROS to provide evidence at micro- and macrolevels. In CRANAD-61, an oxalate moiety was utilized to react with ROS and to consequentially produce wavelength shifting. Our in vitro data showed that CRANAD-61 was highly sensitive and rapidly responsive to various ROS. On reacting with ROS, its excitation and emission wavelengths significantly shifted to short wavelengths, and this shifting could be harnessed for dual-color two-photon imaging and transformative NIRF imaging. In this report, we showed that CRANAD-61 could be used to identify "active" amyloid beta (Abeta) plaques and cerebral amyloid angiopathy (CAA) surrounded by high ROS levels with two-photon imaging (microlevel) and to provide relative total ROS concentrations in AD brains via whole-brain NIRF imaging (macrolevel). Lastly, we showed that age-related increases in ROS levels in AD brains could be monitored with our NIRF imaging method. We believe that our imaging with CRANAD-61 could provide evidence of ROS at micro- and macrolevels and could be used for monitoring ROS changes under various AD pathological conditions and during drug treatment. PMID- 29109281 TI - Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in mice with particular MHC types. AB - Autoantibodies to citrullinated proteins (ACPAs) are present in two-thirds of patients with rheumatoid arthritis (RA). ACPAs are produced in the absence of identified T cell responses for each citrullinated protein. Peptidyl arginine deiminase 4 (PAD4), which binds proteins and citrullinates them, is the target of autoantibodies in early RA. This suggests a model for the emergence of ACPAs in the absence of detectable T cells specific for citrullinated antigens: ACPAs could arise because PADs are recognized by T cells, which help the production of autoantibodies to proteins bound by PADs, according to a "hapten/carrier" model. Here, we tested this model in normal mice. C3H are healthy mice whose IEbetak chain is highly homologous to the beta1 chain HLA-DRB1*04:01, the allele most strongly associated with RA in humans. C3H mice immunized with PADs developed antibodies and T cells to PAD and IgG antibodies to citrullinated fibrinogen peptides, in the absence of a T cell response to fibrinogen. To analyze the MHC background effect on hapten/carrier immunization, we immunized DBA/2 mice (whose IEbetad chain is similar to that of HLA-DRB1*04:02, an HLA-DR4 subtype not associated with RA). DBA/2 mice failed to develop antibodies to citrullinated fibrinogen peptides. Thus, T cell immunization to PAD proteins may trigger ACPAs through a hapten/carrier mechanism. This may constitute the basis for a new mouse model of ACPA-positive RA. PMID- 29109282 TI - Aggregation control in natural brush-printed conjugated polymer films and implications for enhancing charge transport. AB - Shear-printing is a promising processing technique in organic electronics for microstructure/charge transport modification and large-area film fabrication. Nevertheless, the mechanism by which shear-printing can enhance charge transport is not well-understood. In this study, a printing method using natural brushes is adopted as an informative tool to realize direct aggregation control of conjugated polymers and to investigate the interplay between printing parameters, macromolecule backbone alignment and aggregation, and charge transport anisotropy in a conjugated polymer series differing in architecture and electronic structure. This series includes (i) semicrystalline hole-transporting P3HT, (ii) semicrystalline electron-transporting N2200, (iii) low-crystallinity hole transporting PBDTT-FTTE, and (iv) low-crystallinity conducting PEDOT:PSS. The (semi-)conducting films are characterized by a battery of morphology and microstructure analysis techniques and by charge transport measurements. We report that remarkably enhanced mobilities/conductivities, as high as 5.7*/3.9*, are achieved by controlled growth of nanofibril aggregates and by backbone alignment, with the adjusted R2 (R2adj) correlation between aggregation and charge transport as high as 95%. However, while shear-induced aggregation is important for enhancing charge transport, backbone alignment alone does not guarantee charge transport anisotropy. The correlations between efficient charge transport and aggregation are clearly shown, while mobility and degree of orientation are not always well-correlated. These observations provide insights into macroscopic charge transport mechanisms in conjugated polymers and suggest guidelines for optimization. PMID- 29109283 TI - SIRPalpha+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen. AB - In secondary lymphoid organs, development and homeostasis of stromal cells such as podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) are regulated by hematopoietic cells, but the cellular and molecular mechanisms of such regulation have remained unclear. Here we show that ablation of either signal regulatory protein alpha (SIRPalpha), an Ig superfamily protein, or its ligand CD47 in conventional dendritic cells (cDCs) markedly reduced the number of CD4+ cDCs as well as that of Pdpn+ FRCs and T cells in the adult mouse spleen. Such ablation also impaired the survival of FRCs as well as the production by CD4+ cDCs of tumor necrosis factor receptor (TNFR) ligands, including TNF-alpha, which was shown to promote the proliferation and survival of Pdpn+ FRCs. CD4+ cDCs thus regulate the steady-state homeostasis of FRCs in the adult spleen via the production of TNFR ligands, with the CD47-SIRPalpha interaction in cDCs likely being indispensable for such regulation. PMID- 29109284 TI - Enzyme stabilization via computationally guided protein stapling. AB - Thermostabilization represents a critical and often obligatory step toward enhancing the robustness of enzymes for organic synthesis and other applications. While directed evolution methods have provided valuable tools for this purpose, these protocols are laborious and time-consuming and typically require the accumulation of several mutations, potentially at the expense of catalytic function. Here, we report a minimally invasive strategy for enzyme stabilization that relies on the installation of genetically encoded, nonreducible covalent staples in a target protein scaffold using computational design. This methodology enables the rapid development of myoglobin-based cyclopropanation biocatalysts featuring dramatically enhanced thermostability (DeltaTm = +18.0 degrees C and DeltaT50 = +16.0 degrees C) as well as increased stability against chemical denaturation [DeltaCm (GndHCl) = 0.53 M], without altering their catalytic efficiency and stereoselectivity properties. In addition, the stabilized variants offer superior performance and selectivity compared with the parent enzyme in the presence of a high concentration of organic cosolvents, enabling the more efficient cyclopropanation of a water-insoluble substrate. This work introduces and validates an approach for protein stabilization which should be applicable to a variety of other proteins and enzymes. PMID- 29109285 TI - Limiting (zero-load) speed of the rotary motor of Escherichia coli is independent of the number of torque-generating units. AB - Rotation of the bacterial flagellar motor is driven by multiple torque-generating units (stator elements). The torque-generating dynamics can be understood in terms of the "duty ratio" of the stator elements, that is, the fraction of time a stator element engages with the rotor during its mechanochemical cycle. The dependence of the limiting speed (zero-load speed) of the motor on the number of stator elements is the determining test of the duty ratio, which has been controversial experimentally and theoretically over the past decade. Here, we developed a method combining laser dark-field microscopy and optical trapping to resolve this controversy. We found that the zero-load speed is independent of the number of stator elements for the bacterial flagellar motor in Escherichia coli, demonstrating that these elements have a duty ratio close to 1. PMID- 29109286 TI - Circadian clock cryptochrome proteins regulate autoimmunity. AB - The circadian system regulates numerous physiological processes including immune responses. Here, we show that mice deficient of the circadian clock genes Cry1 and Cry2 [Cry double knockout (DKO)] develop an autoimmune phenotype including high serum IgG concentrations, serum antinuclear antibodies, and precipitation of IgG, IgM, and complement 3 in glomeruli and massive infiltration of leukocytes into the lungs and kidneys. Flow cytometry of lymphoid organs revealed decreased pre-B cell numbers and a higher percentage of mature recirculating B cells in the bone marrow, as well as increased numbers of B2 B cells in the peritoneal cavity of Cry DKO mice. The B cell receptor (BCR) proximal signaling pathway plays a critical role in autoimmunity regulation. Activation of Cry DKO splenic B cells elicited markedly enhanced tyrosine phosphorylation of cellular proteins compared with cells from control mice, suggesting that overactivation of the BCR-signaling pathway may contribute to the autoimmunity phenotype in the Cry DKO mice. In addition, the expression of C1q, the deficiency of which contributes to the pathogenesis of systemic lupus erythematosus, was significantly down-regulated in Cry DKO B cells. Our results suggest that B cell development, the BCR-signaling pathway, and C1q expression are regulated by circadian clock CRY proteins and that their dysregulation through loss of CRY contributes to autoimmunity. PMID- 29109287 TI - Charged residues in the H-NS linker drive DNA binding and gene silencing in single cells. AB - Nucleoid-associated proteins (NAPs) facilitate chromosome organization in bacteria, but the precise mechanism remains elusive. H-NS is a NAP that also plays a major role in silencing pathogen genes. We used genetics, single-particle tracking in live cells, superresolution microscopy, atomic force microscopy, and molecular dynamics simulations to examine H-NS/DNA interactions in single cells. We discovered a role for the unstructured linker region connecting the N-terminal oligomerization and C-terminal DNA binding domains. In the present work we demonstrate that linker amino acids promote engagement with DNA. In the absence of linker contacts, H-NS binding is significantly reduced, although no change in chromosome compaction is observed. H-NS is not localized to two distinct foci; rather, it is scattered all around the nucleoid. The linker makes DNA contacts that are required for gene silencing, while chromosome compaction does not appear to be an important H-NS function. PMID- 29109288 TI - An RNA structure-mediated, posttranscriptional model of human alpha-1-antitrypsin expression. AB - Chronic obstructive pulmonary disease (COPD) affects over 65 million individuals worldwide, where alpha-1-antitrypsin deficiency is a major genetic cause of the disease. The alpha-1-antitrypsin gene, SERPINA1, expresses an exceptional number of mRNA isoforms generated entirely by alternative splicing in the 5' untranslated region (5'-UTR). Although all SERPINA1 mRNAs encode exactly the same protein, expression levels of the individual mRNAs vary substantially in different human tissues. We hypothesize that these transcripts behave unequally due to a posttranscriptional regulatory program governed by their distinct 5' UTRs and that this regulation ultimately determines alpha-1-antitrypsin expression. Using whole-transcript selective 2'-hydroxyl acylation by primer extension (SHAPE) chemical probing, we show that splicing yields distinct local 5'-UTR secondary structures in SERPINA1 transcripts. Splicing in the 5'-UTR also changes the inclusion of long upstream ORFs (uORFs). We demonstrate that disrupting the uORFs results in markedly increased translation efficiencies in luciferase reporter assays. These uORF-dependent changes suggest that alpha-1 antitrypsin protein expression levels are controlled at the posttranscriptional level. A leaky-scanning model of translation based on Kozak translation initiation sequences alone does not adequately explain our quantitative expression data. However, when we incorporate the experimentally derived RNA structure data, the model accurately predicts translation efficiencies in reporter assays and improves alpha-1-antitrypsin expression prediction in primary human tissues. Our results reveal that RNA structure governs a complex posttranscriptional regulatory program of alpha-1-antitrypsin expression. Crucially, these findings describe a mechanism by which genetic alterations in noncoding gene regions may result in alpha-1-antitrypsin deficiency. PMID- 29109289 TI - Host-based lipid inflammation drives pathogenesis in Francisella infection. AB - Mass spectrometry imaging (MSI) was used to elucidate host lipids involved in the inflammatory signaling pathway generated at the host-pathogen interface during a septic bacterial infection. Using Francisella novicida as a model organism, a bacterial lipid virulence factor (endotoxin) was imaged and identified along with host phospholipids involved in the splenic response in murine tissues. Here, we demonstrate detection and distribution of endotoxin in a lethal murine F. novicida infection model, in addition to determining the temporally and spatially resolved innate lipid inflammatory response in both 2D and 3D renderings using MSI. Further, we show that the cyclooxygenase-2-dependent lipid inflammatory pathway is responsible for lethality in F. novicida infection due to overproduction of proinflammatory effectors including prostaglandin E2. The results of this study emphasize that spatial determination of the host lipid components of the immune response is crucial to identifying novel strategies to effectively address highly pathogenic and lethal infections stemming from bacterial, fungal, and viral origins. PMID- 29109291 TI - Observation of a remarkable reduction of correlation effects in BaCr2As2 by ARPES. AB - The superconducting phase in iron-based high-[Formula: see text] superconductors (FeSC), as in other unconventional superconductors such as the cuprates, neighbors a magnetically ordered one in the phase diagram. This proximity hints at the importance of electron correlation effects in these materials, and Hund's exchange interaction has been suggested to be the dominant correlation effect in FeSCs because of their multiband nature. By this reasoning, correlation should be strongest for materials closest to a half-filled [Formula: see text] electron shell (Mn compounds, hole-doped FeSCs) and decrease for systems with both higher (electron-doped FeSCs) and lower (Cr-pnictides) [Formula: see text] counts. Here we address the strength of correlation effects in nonsuperconducting antiferromagnetic BaCr2As2 by means of angle-resolved photoemission spectroscopy (ARPES) and first-principles calculations. This combination provides us with two handles on the strength of correlation: First, a comparison of the experimental and calculated effective masses yields the correlation-induced mass renormalization. In addition, the lifetime broadening of the experimentally observed dispersions provides another measure of the correlation strength. Both approaches reveal a reduction of electron correlation in BaCr2As2 with respect to systems with a [Formula: see text] count closer to five. Our results thereby support the theoretical predictions that Hund's exchange interaction is important in these materials. PMID- 29109290 TI - Sea anemone model has a single Toll-like receptor that can function in pathogen detection, NF-kappaB signal transduction, and development. AB - In organisms from insects to vertebrates, Toll-like receptors (TLRs) are primary pathogen detectors that activate downstream pathways, specifically those that direct expression of innate immune effector genes. TLRs also have roles in development in many species. The sea anemone Nematostella vectensis is a useful cnidarian model to study the origins of TLR signaling because its genome encodes a single TLR and homologs of many downstream signaling components, including the NF-kappaB pathway. We have characterized the single N. vectensis TLR (Nv-TLR) and demonstrated that it can activate canonical NF-kappaB signaling in human cells. Furthermore, we show that the intracellular Toll/IL-1 receptor (TIR) domain of Nv TLR can interact with the human TLR adapter proteins MAL and MYD88. We demonstrate that the coral pathogen Vibrio coralliilyticus causes a rapidly lethal disease in N. vectensis and that heat-inactivated V. coralliilyticus and bacterial flagellin can activate a reconstituted Nv-TLR-to-NF-kappaB pathway in human cells. By immunostaining of anemones, we show that Nv-TLR is expressed in a subset of cnidocytes and that many of these Nv-TLR-expressing cells also express Nv-NF-kappaB. Additionally, the nematosome, which is a Nematostella-specific multicellular structure, expresses Nv-TLR and many innate immune pathway homologs and can engulf V. coralliilyticus Morpholino knockdown indicates that Nv-TLR also has an essential role during early embryonic development. Our characterization of this primitive TLR and identification of a bacterial pathogen for N. vectensis reveal ancient TLR functions and provide a model for studying the molecular basis of cnidarian disease and immunity. PMID- 29109292 TI - Selective deuteration illuminates the importance of tunneling in the unimolecular decay of Criegee intermediates to hydroxyl radical products. AB - Ozonolysis of alkenes, an important nonphotolytic source of hydroxyl (OH) radicals in the atmosphere, proceeds through unimolecular decay of Criegee intermediates. Here, we report a large kinetic isotope effect associated with the rate-limiting hydrogen-transfer step that releases OH radicals for a prototypical Criegee intermediate, CH3CHOO. IR excitation of selectively deuterated syn CD3CHOO is shown to result in deuterium atom transfer and release OD radical products. Vibrational activation of syn-CD3CHOO is coupled with direct time resolved detection of OD products to measure a 10-fold slower rate of unimolecular decay upon deuteration in the vicinity of the transition state barrier, which is confirmed by microcanonical statistical theory that incorporates quantum mechanical tunneling. The corresponding kinetic isotope effect of ~10 is attributed primarily to the decreased probability of D-atom vs. H-atom transfer arising from tunneling. Master equation modeling is utilized to compute the thermal unimolecular decay rates for selectively and fully deuterated syn methyl-substituted Criegee intermediates under atmospheric conditions. At 298 K (1 atm), tunneling is predicted to enhance the thermal decay rate of syn CH3CHOO compared with the deuterated species, giving rise to a significant kinetic isotope effect of ~50. PMID- 29109293 TI - Ion pair particles at the air-water interface. AB - Although the role of methanesulfonic acid (HMSA) in particle formation in the gas phase has been extensively studied, the details of the HMSA-induced ion pair particle formation at the air-water interface are yet to be examined. In this work, we have performed Born-Oppenheimer molecular dynamics simulations and density functional theory calculations to investigate the ion pair particle formation from HMSA and (R1)(R2)NH (for NH3, R1 = R2 = H; for CH3NH2, R1 = H and R2 = CH3; and for CH3NH2, R1 = R2 = CH3) at the air-water interface. The results show that, at the air-water interface, HMSA deprotonates within a few picoseconds and results in the formation of methanesulfonate ion (MSA-)??H3O+ ion pair. However, this ion pair decomposes immediately, explaining why HMSA and water alone are not sufficient for forming stable particles in atmosphere. Interestingly, the particle formation from the gas-phase hydrogen-bonded complexes of HMSA with (R1)(R2)NH on the water droplet is observed with a few femtoseconds, suggesting a mechanism for the gas to particle conversion in aqueous environments. The reaction involves a direct proton transfer between HMSA and (R1)(R2)NH, and the resulting MSA-??(R1)(R2)NH2+ complex is bound by one to four interfacial water molecules. The mechanistic insights gained from this study may serve as useful leads for understanding about the ion pair particle formation from other precursors in forested and polluted urban environments. PMID- 29109295 TI - Effect of paleoseawater composition on hydrothermal exchange in midocean ridges. AB - Variations in the Mg, Ca, Sr, and SO4 concentrations of paleoseawater can affect the chemical exchange between seawater and oceanic basalt in hydrothermal systems at midocean ridges (MOR). We present a model for evaluating the nature and magnitude of these previously unappreciated effects, using available estimates of paleoseawater composition over Phanerozoic time as inputs and 87Sr/86Sr of ophiolite epidosites and epidote-quartz veins as constraints. The results suggest that modern hydrothermal fluids are not typical due to low Ca and Sr relative to Mg and SO4 in modern seawater. At other times during the last 500 million years, particularly during the Cretaceous and Ordovician, hydrothermal fluids had more seawater-derived Sr and Ca, a prediction that is supported by Sr isotope data. The predicted 87Sr/86Sr of vent fluids varies cyclically in concert with ocean chemistry, with some values much higher than the modern value of ~0.7037. The seawater chemistry effects can be expressed in terms of the transfer efficiency of basaltic Ca and Sr to seawater in hydrothermal systems, which varies by a factor of ~1.6 over the Phanerozoic, with minima when seawater Mg and SO4 are low. This effect provides a modest negative feedback on seawater composition and 87Sr/86Sr changes. For the mid-Cretaceous, the low 87Sr/86Sr of seawater requires either exceptionally large amounts of low-temperature exchange with oceanic crust or that the weathering flux of continentally derived Sr was especially small. The model also has implications for MOR hydrothermal systems in the Precambrian, when low-seawater SO4 could help explain low seawater 87Sr/86Sr. PMID- 29109294 TI - Key amino acid residues conferring enhanced enzyme activity at cold temperatures in an Antarctic polyextremophilic beta-galactosidase. AB - The Antarctic microorganism Halorubrum lacusprofundi harbors a model polyextremophilic beta-galactosidase that functions in cold, hypersaline conditions. Six amino acid residues potentially important for cold activity were identified by comparative genomics and substituted with evolutionarily conserved residues (N251D, A263S, I299L, F387L, I476V, and V482L) in closely related homologs from mesophilic haloarchaea. Using a homology model, four residues (N251, A263, I299, and F387) were located in the TIM barrel around the active site in domain A, and two residues (I476 and V482) were within coiled or beta sheet regions in domain B distant to the active site. Site-directed mutagenesis was performed by partial gene synthesis, and enzymes were overproduced from the cold-inducible cspD2 promoter in the genetically tractable Haloarchaeon, Halobacterium sp. NRC-1. Purified enzymes were characterized by steady-state kinetic analysis at temperatures from 0 to 25 degrees C using the chromogenic substrate o-nitrophenyl-beta-galactoside. All substitutions resulted in altered temperature activity profiles compared with wild type, with five of the six clearly exhibiting reduced catalytic efficiency (kcat/Km) at colder temperatures and/or higher efficiency at warmer temperatures. These results could be accounted for by temperature-dependent changes in both Km and kcat (three substitutions) or either Km or kcat (one substitution each). The effects were correlated with perturbation of charge, hydrogen bonding, or packing, likely affecting the temperature-dependent flexibility and function of the enzyme. Our interdisciplinary approach, incorporating comparative genomics, mutagenesis, enzyme kinetics, and modeling, has shown that divergence of a very small number of amino acid residues can account for the cold temperature function of a polyextremophilic enzyme. PMID- 29109296 TI - Reply to Fattori et al.: Action of SP and IL-33 on mast cells. PMID- 29109297 TI - IL-33/ST2 signaling boosts inflammation and pain. PMID- 29109298 TI - Severity of Neuropathy Is Associated With Long-term Spinal Cord Stimulation Outcome in Painful Diabetic Peripheral Neuropathy: Five-Year Follow-up of a Prospective Two-Center Clinical Trial. AB - OBJECTIVE: Evidence from prospective studies for long-term treatment efficacy of spinal cord stimulation (SCS) in painful diabetic peripheral neuropathy (PDPN) is not available. We report prospective data on the effect of SCS on pain ratings, treatment success and failure, and complications during a 5-year follow-up in patients with PDPN. RESEARCH DESIGN AND METHODS: Patients with PDPN (n = 48) were included in this prospective multicenter study. The Michigan Diabetic Neuropathy Score (MDNS) was used to assess the severity of neuropathy. Numerical rating scale (NRS) score for pain, Patient's Global Impression of Change (PGIC), and treatment success (50% reduction of NRS score or significant PGIC) during 5 years of follow-up were evaluated. Complications of SCS were reported, and associations between baseline characteristics and SCS trial success or failure during a 5-year follow-up were investigated by using survival analyses. RESULTS: Treatment success was observed in 55% of patients after 5 years. Median duration of SCS treatment was 60 months (minimum 1 month, maximum 60 months), and 80% of patients with a permanent implant still used their SCS device after 5 years. Higher MDNS was associated with treatment failure during the 5-year follow-up (hazard ratio 3.9 [95% CI 1.3-11.6]; P = 0.014). CONCLUSIONS: SCS is successful in reducing chronic pain symptoms in the lower extremities of patients with PDPN up to 5 years after initiation of treatment. Furthermore, 80% of patients with PDPN still use their SCS device after 5 years. Moreover, the severity of neuropathy is associated with a higher chance of long-term treatment failure during a 5-year follow-up. PMID- 29109299 TI - Long-term Trends in Antidiabetes Drug Usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes. AB - OJBECTIVE: To explore temporal trends in antidiabetes drug (ADD) prescribing and intensification patterns, along with glycemic levels and comorbidities, and possible benefits of novel ADDs in delaying the need for insulin initiation in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes aged 18-80 years, who initiated any ADD, were selected (n = 1,023,340) from the U.S. Centricity Electronic Medical Records. Those who initiated second-line ADD after first-line metformin were identified (subcohort 1, n = 357,482); the third-line therapy choices were further explored. RESULTS: From 2005 to 2016, first-line use increased for metformin (60-77%) and decreased for sulfonylureas (20-8%). During a mean follow-up of 3.4 years post metformin, 48% initiated a second ADD at a mean HbA1c of 8.4%. In subcohort 1, although sulfonylurea usage as second-line treatment decreased (60-46%), it remained the most popular second ADD choice. Use increased for insulin (7-17%) and dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.4-21%). The rates of intensification with insulin and sulfonylureas did not decline over the last 10 years. The restricted mean time to insulin initiation was marginally longer in second-line DPP-4i (7.1 years) and in the glucagon-like peptide 1 receptor agonist group (6.6 years) compared with sulfonylurea (6.3 years, P < 0.05). CONCLUSIONS: Most patients initiate second-line therapy at elevated HbA1c levels, with highly heterogeneous clinical characteristics across ADD classes. Despite the introduction of newer therapies, sulfonylureas remained the most popular second-line agent, and the rates of intensification with sulfonylureas and insulin remained consistent over time. The incretin-based therapies were associated with a small delay in the need for therapy intensification compared with sulfonylureas. PMID- 29109300 TI - The shifted balance between circulating follicular regulatory T cells and follicular helper T cells in patients with ulcerative colitis. AB - B-cell immunity participates in the pathogenesis of ulcerative colitis (UC). The immune balance between follicular regulatory T (TFR) cells and follicular helper T (TFH) cells is important in regulating B-cell responses. However, the alteration of TFR/TFH balance in UC remains unclear. Peripheral blood from 25 UC patients and 15 healthy controls was examined for the frequencies of circulating TFR, TFH, and regulatory T (Treg) cells by flow cytometry. Levels of serum cytokines were measured using cytometric bead array (CBA). Disease activity was evaluated by the Mayo Clinic Score. Compared with controls, UC patients exhibited significant reductions in circulating Foxp3+CXCR5+ TFR cells, the subset interleukin (IL)-10+Foxp3+CXCR5+ cells, and Treg cells, but significant expansions in Foxp3-CXCR5+ TFH cells and IL-21+Foxp3-CXCR5+ cells. UC patients also had reduced levels of serum IL-10 and elevated levels of serum IL-21. The values of Mayo Clinic Score, C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR) in UC patients were negatively correlated with circulating TFR cells, serum IL-10 level, and TFR/TFH ratio, while positively correlated with circulating TFH cells and serum IL-21 level. Alterations in circulating TFR and TFH cells shift the balance from immune tolerance to immune responsive state, contributing to dysregulated B-cell immunity and the pathogenesis of UC. PMID- 29109302 TI - Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases. AB - Cardiovascular disease remains a major medical and socioeconomic burden in developed and developing societies, and will increase with an aging and increasingly sedentary society. Vascular disease and atherosclerotic vascular syndromes are essentially inflammatory disorders, and transcriptional and post transcriptional processes play essential roles in the ability of resident vascular and inflammatory cells to adapt to environmental stimuli. The regulation of mRNA translocation, stability, and translation are key processes of post transcriptional regulation that permit these cells to rapidly respond to inflammatory stimuli. For the most part, these processes are controlled by elements in the 3'-UTR of labile, proinflammatory transcripts. Since proinflammatory transcripts almost exclusively contain AU-rich elements (AREs), this represents a tightly regulated and specific mechanism for initiation and maintenance of the proinflammatory phenotype. RNA-binding proteins (RBPs) recognize cis elements in 3'-UTR, and regulate each of these processes, but there is little literature exploring the concept that RBPs themselves can be directly regulated by inflammatory stimuli. Conceptually, inflammation-responsive RBPs represent an attractive target of rational therapies to combat vascular inflammatory syndromes. Herein we briefly describe the cellular and molecular etiology of atherosclerosis, and summarize our current understanding of RBPs and their specific roles in regulation of inflammatory mRNA stability. We also detail RBPs as targets of current anti-inflammatory modalities and how this may translate into better treatment for vascular inflammatory diseases. PMID- 29109303 TI - Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD? AB - Whether non-alcoholic fatty liver disease (NAFLD) precedes insulin resistance (IR) or IR preludes/causes NAFLD has been long debated. Recent studies have shown that there are two phenotypes of NAFLD, 'genetic' vs 'metabolic' NAFLD. The former patients are more at risk of hepatocellular carcinoma and chronic liver disease the latter are more IR and at increased risk of type 2 diabetes (T2D). Even if they are not yet diabetics, from a metabolic point of view having NAFLD is equivalent to T2D with reduced peripheral glucose disposal and impaired suppression of hepatic glucose production, but without fasting hyperglycaemia. T2D develops only when hepatic autoregulation is lost and glucose production exceeds the capacity of muscle glucose disposal.In NAFLD adipocytes are resistant to the effect of insulin, lipolysis is increased and excess plasma free fatty acids (FFA) are taken up by other organs (mainly liver) where they are stored as lipid droplets or oxidized. Increased adiposity is associated with worsen severity of both 'genetic' and 'metabolic' NAFLD. FFA oxidative metabolism is increased in NAFLD and not shifted towards glucose during insulin infusion. Although this reduced metabolic flexibility is an early predictor of T2D, it can be seen also as a protective mechanism against excess FFA.In conclusion, IR precedes and causes 'metabolic' NAFLD, but not 'genetic' NAFLD. Reduced metabolic flexibility in NAFLD might be seen as a protective mechanism against FFA overflow, but together with IR remains a strong risk factor for T2D that develops with the worsening of hepatic regulation of glucose production. PMID- 29109304 TI - Corrigendum. PMID- 29109301 TI - Personalized medicine-a modern approach for the diagnosis and management of hypertension. AB - The main goal of treating hypertension is to reduce blood pressure to physiological levels and thereby prevent risk of cardiovascular disease and hypertension-associated target organ damage. Despite reductions in major risk factors and the availability of a plethora of effective antihypertensive drugs, the control of blood pressure to target values is still poor due to multiple factors including apparent drug resistance and lack of adherence. An explanation for this problem is related to the current reductionist and 'trial-and-error' approach in the management of hypertension, as we may oversimplify the complex nature of the disease and not pay enough attention to the heterogeneity of the pathophysiology and clinical presentation of the disorder. Taking into account specific risk factors, genetic phenotype, pharmacokinetic characteristics, and other particular features unique to each patient, would allow a personalized approach to managing the disease. Personalized medicine therefore represents the tailoring of medical approach and treatment to the individual characteristics of each patient and is expected to become the paradigm of future healthcare. The advancement of systems biology research and the rapid development of high throughput technologies, as well as the characterization of different -omics, have contributed to a shift in modern biological and medical research from traditional hypothesis-driven designs toward data-driven studies and have facilitated the evolution of personalized or precision medicine for chronic diseases such as hypertension. PMID- 29109305 TI - Breath-based diagnosis of fungal infections. AB - Invasive aspergillosis and other invasive fungal infections are associated with significant morbidity and mortality in immunocompromised patients, in large part due to limitations of existing diagnostic methods for these infections. Detection of species-specific volatile sesquiterpene metabolites of fungal origin in the breath of patients with invasive fungal infections allows the diagnosis and monitoring of these infections in vivo, non-invasively and more rapidly than possible with current diagnostic methods. While detection of exogenous microbial volatile metabolites in the breath has opened up a new and exciting dimension of diagnostic research and development in infectious diseases, we discuss the daunting challenges to volatile diagnostic biomarker discovery and clinical development. PMID- 29109306 TI - Hierarchy and scaling behaviour of multi-rank domain patterns in ferroelectric K0.9Na0.1NbO3 strained films. AB - The formation process of a ferroelectric multi-rank domain pattern in the thickness range of 7 to 52 nm is investigated for monoclinic K0.9Na0.1NbO3 strained epitaxial films on (110) NdScO3 substrates. Although the elastic strain energy density is degenerated for two pseudocubic orientations, a distinctive hierarchy of domain evolution is observed with exclusive in-plane a1a2 domains for very thin films and the retarded onset of a ferroelectric MC phase at larger film thickness. This is accompanied by a thickness dependent transformation from stripe domains to a herringbone pattern and, eventually, for the thickest film, to a checkerboard-like structure. These transformations in the domain arrangement and width are correlated to energetic aspects as depolarization field and anisotropic strain relaxation in the film. While for the MC domains plastic strain relaxation is throughout observed, the a1a2 domains show a two-step strain relaxation mechanism starting with an in-plane elastic shearing, which is followed by plastic lattice relaxation. Our results highlight a pathway for engineering and patterning of periodic ferroelectric domain structures. PMID- 29109307 TI - Is the Pen really Mightier than the Scalpel? AB - One of the most crucial aspects of cancer diagnosis and treatment is to determine the thin boundary between lesional and normal tissues. So it is important to assess an accurate negative margin and to completely excise the tumor for a prolonged disease-free state and increase the overall survival of the patient. PMID- 29109308 TI - Triclosan: Hazards of Overuse are not limited to Antibiotics. AB - Antibiotic abuse by patients and overprescription by some dentists are problems in modern healthcare practice. Less understood are the deleterious effects of antiseptics in oral care products marketed for routine home use. Ample literature exists to condemn the routine use of mouthrinses, but criticism focuses on alcohol content and its effects on oral mucosa.1 We highlight the more insidious problem of triclosan, which is added as an antiseptic to toothpastes and mouthrinses. PMID- 29109309 TI - Prevalence of Dental Caries and Oral Hygiene Status among Juvenile Prisoners in the Kingdom of Saudi Arabia. AB - AIM: The aim of the study was to determine the prevalence of dental caries and oral hygiene status among juvenile prisoners in Riyadh, Kingdom of Saudi Arabia. MATERIALS AND METHODS: A total of 105 prisoners aged between 12 and 17 years of age from the Juvenile Detention Center were included in the study. Any prisoner with systemic illness and being noncooperative were excluded from the study. Clinical examinations were performed under an artificial light source using a disposable mouth mirror and explorer while seated on a portable chair. The dental caries experience was measured as the number of decayed, missing, or filled permanent teeth (DMFT) using DMFT score. The oral hygiene index (OHI) was assessed by the Greene and Vermillion method. The data collected were analyzed using Statistical Package for the Social Sciences version 16. RESULTS: The mean age of the sample was 16.33 years, with 74.3% of the prisoners in the 16 to 17 year-old group. The dental caries index measured by calculating the mean DMFT of the juvenile prisoners increased with age. The DMFT scores of 9.09 (4.388) for 78 juvenile prisoners aged 16 to 17 years followed by 9.00 (2.925) for 19 prisoners aged 14 to 15 years and 7.13 (1.808) for 8 prisoners aged 12 to 13 years were observed. The oral hygiene status of the prisoners showed that more than half of the juvenile prisoners included in the study had poor (53.3%) oral hygiene and less than half had fair (45.7%) oral hygiene and only one participant demonstrated good oral hygiene. CONCLUSION: The juvenile prisoners had high prevalence of dental caries and fair-to-bad oral hygiene, indicating poor oral health status. Furthermore, the study emphasizes the need for special attention from the concerned health authorities, voluntary organizations, and surrounding dental colleges in meeting the oral health needs of this group. CLINICAL SIGNIFICANCE: The study provides an important database for decision makers to take on the challenge of reducing dental caries among juvenile prisoners. PMID- 29109310 TI - In situ Effect of Nanohydroxyapatite Paste in Enamel Teeth Bleaching. AB - AIM: Evaluate in situ the effect of nanohydroxyapatite paste (nano-HAP) before bleaching with hydrogen peroxide 35% (HP35%) by ion chromatography (IC) Knoop hardness number (KHN) and tristimulus colorimetry (TC). MATERIALS AND METHODS: A total of 60 fragments were obtained from third molars included (3 mm * 3 mm * 3 mm) and the specimens were divided into three groups (n = 20): Gas chromatography (CG) (negative control group) = no bleaching; HP35% (positive control group) = HP35% whitening (whiteness HP35%); nano-HAP = application for 10 minutes before bleaching treatment + HP35%. The specimens were fixed to the volunteers' molars. The KHN and TC were measured before and after bleaching. For IC, the dentin layer was removed, leaving the enamel that was crushed, and autoclaved for chemical quantification (calcium, fluorine, and phosphorus). The results of KHN and TC were analyzed statistically by analysis of variance (ANOVA) followed by Tukey test (p < 0.05). RESULTS: The HP35% group showed reduction of the Ca, F, and P ions. The initial and final KHN mean of the CG and nano-HAP did not differ statistically; however, the group of HP35% did differ statistically. The mean DeltaE of the HP35% and nano-HAP groups did not differ statistically from each other. However, they differed from the CG. CONCLUSION: The nano-HAP paste preserved the KHN, promoted the lower loss of Ca and P ions and an increase of F ions when compared with the CG, but did not influence the effectiveness of the bleaching treatment. CLINICAL SIGNIFICANCE: Nano-HA is a biomaterial that has shown positive results in the prevention of deleterious effects on the enamel by the action of the office bleaching treatment. PMID- 29109311 TI - Antimicrobial Effect of Ginger, Garlic, Honey, and Lemon Extracts on Streptococcus mutans. AB - AIM: The aim of this study was to evaluate the effect of lemon, ginger, garlic, and honey extracts on Streptococcus mutans. MATERIALS AND METHODS: Commercially obtained honey, ginger, garlic, and lemon were included in the study to evaluate its efficacy in isolation and in combination against S. mutans. The efficacies of extracts were tested using well diffusion method, and its effect was evaluated by measuring the zone of inhibition around the well. Antimicrobial activity of the extracts was carried out individually and compared considering triplicates of all the extracts. RESULTS: When individual comparison of the extracts was made, garlic showed greatest antimicrobial activity with a mean zone of inhibition (34.9 +/- 0.58 mm) and honey showed least antimicrobial activity (0.5 +/- 0.6 mm). When combinations of extracts were tested against S. mutans, lemon and garlic combination showed the greatest zone of inhibition (27.6 +/- 0.43 mm) compared with other combinations, and ginger + lemon combinations showed the least zone of inhibition (12.6 +/- 0.43 mm). CONCLUSION: This study concluded that garlic showed a greatest antimicrobial effect against S. mutans when compared with other preparations individually and garlic and lemon showed greatest zone of inhibition in combination than other preparations. CLINICAL SIGNIFICANCE: Antibiotics and other chemical agents are mainly used to treat the common dental infections. However, due to the excessive use, it can result in antibiotic resistance. Hence, herbal medicines with medicinal values should be replaced with conventional methods. PMID- 29109312 TI - Dissolution of Enamel on Exposure to Various Commercial Beverages Available in India. AB - AIM: The study was aimed to estimate the pH of the commonly available soft drinks in the Indian market and to assess the detrimental effects of the juices and beverages on the tooth surface by measuring the weight loss of the tooth sample. MATERIALS AND METHODS: The study was done with eight different types of commercially available carbonated drink and fruit juices available in the Indian market among which six were carbonated drinks and two were juices. Carbonated drinks experimented were Coca-Cola, Pepsi, Fanta, Mirinda, 7Up and Sprite, and two fruit juices were Tropicana orange juice and real orange juice. Ten different bottles from each category were obtained, and the pH was estimated. Each of the beverages was divided into batch of 10 containers containing the tooth sample. Weight of all samples was measured at 24, 48, 72, 96, and 120 hours with subsequently changing each solution at an interval of 24 hours. RESULTS: The mean pH of the beverages was found ranging from 2.13 +/- 0.02 in Pepsi to 3.41 +/- 0.02 in Tropicana on opening. The mean pH of water was found to be 6.98 +/- 0.01. Among carbonated drinks, the mean weight loss after 24 hours was highest in Coca Cola and least in 7Up. Tropicana fruit juice had a higher tooth loss than real orange juices. When compared with water, the tooth loss was significantly higher in Coca-Cola after all specified time (hours). CONCLUSION: The pH of both carbonated drinks and fruit juices was below the critical pH. The weight loss was also seen after every 24 hours in all the carbonated drinks and beverages. The study showed that these commercial beverages are harmful to the tooth structures, and hence, the health professionals play a major role in educating the population about its effects and advising them to use these products precisely. CLINICAL SIGNIFICANCE: The change in lifestyle has increased the demand of soft drinks and artificial juice in Indian market. The use of these carbonated drinks and fruit juices causes damage to the tooth structure in all ages, especially in young mass. Our study provides an idea about the deleterious effects of these commercial drinks on dental hard tissues. PMID- 29109313 TI - Evaluation of the Antifungal Effect of Chicory Extracts on Candida Glabrata and Candida Krusei in a Laboratory Environment. AB - AIM: This research has evaluated the extract's antifungal effects on Candida glabrata and Candida krusei in a laboratory environment. MATERIALS AND METHODS: In this research, to evaluate the antifungal effect and the minimal inhibitory concentration (MIC) determination of chicory extract, the Clinical and Laboratory Standards Institute (CLSI) was used. Candida glabrata and C. krusei funguses were procured from the Tehran Pasteur Institute; they were grown in the relative growing environment according to the required conditions. Also for further assurance about the macrodilution method reality, the agar well diffusion method was used. Finally, the obtained results were analyzed using the Statistical Package for the Social Sciences version 16 software. RESULTS: The MIC for the chicory extract was 50 MUg/mL for C. krusei and 100 MUg/mL for C. glabrata. On the contrary, in the evaluation of different concentrations of the chicory extract by the agar well diffusion method, C. krusei's lack of growth in similar concentrations was greater than that of C. glabrata. As a result, the findings related to both the methods of agar well diffusion and MIC prevention concentration maximization proved that C. krusei sensitivity to the chicory extract is more compared with the sensitivity of C. glabrata. CONCLUSION: Chicory extract has the benefits of low price, accessibility, and proper taste as compared with nystatin. It also has fewer side effects, and after a clinical test, it could be considered a proper candidate as an antifungal drug against infections caused by C. krusei and C. glabrata. CLINICAL SIGNIFICANCE: The results obtained from this research have shown that chicory extract has antifungal features and is the best choice as an antifungal drug because of its low price, accessibility, and proper taste as compared with nystatin. PMID- 29109314 TI - A Cross-sectional Study to assess the Perception of Psychosocial Elements among Pediatric Patients visiting Dental Clinics. AB - INTRODUCTION: Children with high dental fear and perception usually encounter high prevalence of dental caries. Data showed that individuals with dental fear will probably defer dental appointments which may result in the formation of a setup of an endless loop of dental fear. Present study was aimed to assess different psycho-social parameters among pediatric patients visiting dental clinics. MATERIALS AND METHODS: In the present cross-sectional study, the data of 200 schoolchildren were collected and analyzed by means of a questionnaire. Evaluation of the oral health status was done by experienced pedodontists. All the answers were recorded and analyzed by Statistical Package for the Social Sciences (SPSS) software. RESULTS: Nearly 120 were regular attendees while remaining 80 were found to be irregular attendees. Significant difference was observed while comparing the decayed, missing, and filled teeth (DMFT) index, decayed teeth, dental fear, cognitive vulnerability, and dental prevention belief between the regular and irregular group. Significant correlation was observed between higher number of decayed teeth and increasing level of dental fear. CONCLUSION: Various psychosocial parameters, by affecting the dental visits, are associated with outcome of oral health measures. CLINICAL SIGNIFICANCE: Special attention should be paid to the pediatric patients with such kind of behavior so that their psy-chosocial attitude could be modified in favor of dental treatment. PMID- 29109315 TI - Assessment of Alteration in Capnometry Monitoring during Intravenous Sedation with Midazolam for Oral Surgical Procedures. AB - INTRODUCTION: Capnography is routinely used for monitoring of patients subjected to sedation for different surgical procedures. There is still paucity of data highlighting the capnographic assessment of patients on midazolam sedation undergoing oral surgical procedures. Hence, we planned the present study to assess the alterations occurring in the end-tidal carbon dioxide (ETCO2) values monitored during intravenous (IV) sedation with midazolam during various oral surgical procedures. MATERIALS AND METHODS: The present study included assessment of alteration in ETCO2 values occurring during oral surgical procedure. After meeting the inclusion and exclusion criteria, a total of 40 participants were included in the present study. Pulse oximeter with capnograph (EmcoMeditek Pvt., Ltd., India) device was used for assessment of respiratory rate (RR) and ETCO2 values. The mean of 12 readings over a period of 1 minute before the starting of first infusion was referred to as baseline time. By evaluating the first four readings at an interval of 15 seconds during the 1st minute of infusion, we obtained the 1 minute average reading. All the data were compiled and recorded and assessed by the Statistical Package for the Social Sciences (SPSS) software. RESULTS: A total of 40 participants were included, out of which, 20 were males and 20 were females. At the baseline time, mean value of ETCO2 was 31 mm Hg, while mean value of oxygen saturation (SpO2) was 36%. Out of total 40 participants, 15 showed the presence of respiratory depression. Out of these 15 participants, ETCO2 changes from baseline were observed in 13 participants. CONCLUSION: No oxygen should be delivered, unless until required, to the healthy participants undergoing dental sedation procedures, for marinating the sensitivity of pulse oximetry during assessment of respiratory depression. CLINICAL SIGNIFICANCE: In patients undergoing sedation procedures, various monitoring techniques should be employed as respiratory depression is a commonly encountered risk factor. PMID- 29109316 TI - Evaluation and Comparison between Formocresol and Sodium Hypochlorite as Pulpotomy Medicament: A Randomized Study. AB - INTRODUCTION: Pulpotomy is the most common treatment to preserve vitality of cariously exposed molars. Various pulpotomy medicaments used should be antimicrobial, should help in healing without damaging surrounding tissue, and should not affect eruption of permanent teeth. Thus, this study was conducted to evaluate and compare the clinical and radiographic outcomes of formocresol (FC) and sodium hypochlorite (NaOCl) in primary molars. The aim of this randomized study was to compare the clinical and radiographic success rate of FC and 5% NaOCl as a pulpotomy medicament in primary molars. MATERIALS AND METHODS: Forty children aged 4 to 9 years with primary carious molar were selected and randomly assigned into two groups: FC and NaOCl. Pulpotomy procedure was then performed followed by restoration with stainless steel crowns. Clinical and radiographic evaluation was done at an interval of 3 to 6 months. RESULTS: Clinical success rate at 3 and 6 months was 100% for both groups. Radiographic success rate for FC was 95% at 3 months and 90% at 6 months, whereas for NaOCl, it was 90% at 3 months and 85% at 6 months. CONCLUSION: Based on this study, result of 5% NaOCl and FC showed no significant difference in their success rate. Hence, NaOCl can be used as pulpotomy medicament; however, further clinical trials with long follow-up period are required. CLINICAL SIGNIFICANCE: Sodium hypochlorite is a potential clinical substitute of FC for vital pulpotomy treatment in primary teeth because of its exceptional biological compatibility and to evade carcinogenic effect of FC. PMID- 29109317 TI - Prevalence of Dental Malocclusions in Patients admitted to the Department of Orthodontics, School of Dentistry, Tabriz, in 2016. AB - AIM: This study is aimed at investigating the prevalence of disorders among patients referred to Tabriz Dental School in 2016. MATERIALS AND METHODS: This research was conducted in a cross-section method and taken from all patients admitted during this period. Classification of dental occlusion in patients was based on Angle's definition, skeletal classification was based on Steiner's analysis, and overjet and overbite values and other patient-related information were imported from the records in the extractive sector and in specific forms. After reviewing the data, the forms of individual patients were inputted into the computer and analyzed. RESULTS: In terms of dental condition, the prevalence of malocclusion CL.I, malocclusion CL.II, and malocclusion CL.III was respectively, 50, 36.8, and 13.2%. In terms of overjet condition, 13.9% of patients had normal overjet, 67.1% had increased overjet, 8.9% had reduced overjet, and 10.1% had reversed overjet. In terms of overbite, 17.7% of patients had normal overbite, 53.2% had increased overbite, 8.9% had decreased overbite, 15.2% had open bite, and 5.1% had deep bite. Skeletally, 24.1% of patients had skeletal abnormalities CL.I, 62% had skeletal deformities CL.II, and 13.9% had skeletal CL.III. CONCLUSION: The most common dental malocclusion among patients was related to CL.I and the most common skeletal malocclusion was related to CL.II, and malocclusions of CL.III had the least prevalence both dentally and skeletally. There was no significant relationship between dental and skeletal malocclusions and also between different malocclusions and gender. CLINICAL SIGNIFICANCE: Knowledge of the prevalence of different types of dental and jaw anomalies is considered as the first step in the evaluation and treatment of these disorders. It is worth mentioning that the results of the study can be used in treatment planning required in the province and even in the country. PMID- 29109318 TI - Extrusion of Debris from Primary Molar Root Canals following Instrumentation with Traditional and New File Systems. AB - INTRODUCTION: To assess the amount of debris extruded apically during instrumentation of distal canals of extracted primary molars by three instrument systems [ProTaper Universal (PTU), ProTaper NEXT (PTN), and self-adjusting file (SAF)] compared with conventional stainless steel hand K-files (HF, control). MATERIALS AND METHODS: Primary mandibular molars (n = 120) with a single distal canal were selected and randomly divided into four groups (n = 30) for root canal instrumentation using group I, HF (to size 0.30/0.02 taper), group II, PTU (to size F3), group III, PTN (to size X3), and group IV, SAF. Debris extruded during instrumentation was collected in preweighed Eppendorf tubes, stored in an incubator at 70 degrees C for 5 days and then weighed. Statistical analysis was performed by one-way analysis of variance (ANOVA), followed by Turkey's post hoc test (p = 0.05). RESULTS: All the groups resulted in extrusion of debris. There was statistically significant difference (p < 0.001) in the debris extrusion between the three groups: HF (0.00133 +/- 0.00012), PTU (0.00109 +/- 0.00005), PTN (0.00052 +/- 0.00008), and SAF (0.00026 +/- 0.00004). CONCLUSION: Instrumentation with SAF resulted in the least debris extrusion when used for shaping root canals of primary molar teeth. CLINICAL SIGNIFICANCE: Debris extrusion in primary teeth poses an adverse effect on the stem cells and may also alter the permanent dental germ. Debris extrusion is rarely reported for primary teeth and it is important for the clinician to know which endodontic instrumentation leads to less extrusion of debris. PMID- 29109319 TI - Histological Evaluation of the Effect of Platelet-rich Plasma on Pulp Regeneration in Nonvital Open Apex Teeth: An Animal Study. AB - AIM: Platelet-rich plasma (PRP), which is a concentration of growth factors found in platelets, may be a suitable material for pulp regeneration. The aim of this animal study was a histological evaluation of PRP on pulp regeneration in nonvital teeth with immature apices. MATERIALS AND METHODS: A total of 40 premolar dogs' teeth were chosen for this study. After general anesthesia, the teeth were exposed, and subsequently, pulps were removed and the cavities were opened to the oral cavity. After 2 weeks, root canals were irrigated and disinfected with sodium hypochlorite with noninstrumentation technique, and triple antibiotic paste was placed inside the canals. Cavities were sealed with a temporary restoration. About 4 weeks later, canals were irrigated again and the teeth were randomly divided into three groups. Bleeding was evoked with overinstrumentation, then experimental materials for each group [PRP, mineral trioxide aggregate (MTA), and parafilm respectively] were placed over the bleeding, and orifices were sealed with MTA and glass ionomer. After 3 months, dogs were sacrificed and the teeth were separated from the jaws and sections prepared for histological evaluation. RESULTS: Regeneration was shown in 44.7% of the samples. About 47.3% of the samples in the MTA group and 42.1% of the samples in the PRP group showed regeneration; however, no regeneration was observed in the parafilm group. Chi-square test showed no significant difference between groups I and II. The soft regenerative tissue included pulp-like tissue and vessels. Mineralized regenerative tissue included cementum-like, periodontal ligament-like, and bone-like tissues. No normal pulp and nerve tissue were observed. CONCLUSION: Both PRP and MTA may be ideal scaffolds to accelerate the regeneration process. CLINICAL SIGNIFICANCE: Pulp repair in immature permanent teeth with weak roots has a better outcome than replacement of the pulp with gutta-percha or biomaterials. PMID- 29109320 TI - Effects of the Ratio between Pigment and Bleaching Gel on the Fracture Resistance and Dentin Microhardness of endodontically treated Teeth. AB - INTRODUCTION: The aim of this study was to evaluate the effects of bleaching gel using 35% hydrogen peroxide (HP), associated with red carmine pigment (RC), in the 3:1 or 1:1 ratio, on fracture resistance and dentin microhardness of endodontically treated teeth. MATERIALS AND METHODS: A total of 40 lower incisors were endodontically treated and divided into four groups (n = 10), according to the bleaching protocol: G1 (HP3), 35% HP + RC (3:1); G2 (HP1), 35% HP + RC (1:1); G3 (positive), 38% HP; and G4 (negative), unbleached. Four dental bleaching sessions were performed. The dental crowns were restored after the last session and submitted to the fracture resistance test. Totally, 60 specimens from the endodontically treated lower incisor crowns were prepared to evaluate the effects on dentin microhardness. The analysis was measured (in Knoop) prior to and after the last dental bleaching session using similar bleaching protocols. RESULTS: G2 presented the lowest fracture resistance (p < 0.05). The other groups were similar to each other (p > 0.05). No difference was observed in the reduction of dentin microhardness among the groups (p > 0.05). CONCLUSION: A 1:1 ratio (bleaching gel:pigment) caused a significant fracture resistance reduction in relation to the other protocols. No effect on the dentin microhardness reduction was observed. CLINICAL SIGNIFICANCE: The pigment addition to the bleaching agent accelerates the bleaching chemical reaction. However, no studies have evaluated the ideal proportion to optimize tooth bleaching. PMID- 29109321 TI - Epidemiological and Clinicopathological Analysis of 92 Odontogenic Tumors: A 5 year Retrospective Study. AB - INTRODUCTION: Odontogenic tumors (OTs) are a heterogeneous group of lesions that are derived from odontogenic apparatus comprised of odontogenic epithelium, ectomesenchyme, and/ or mesenchymal elements. The OTs show marked geographical variation. This study was conducted to analyze the epidemiology and clinicopathological presentation of OTs based on age, sex, and site. MATERIALS AND METHODS: This study was conducted in Department of Oral Pathology and Microbiology. Records were reviewed retrospectively for all the lesions of oral cavity from January 2010 to December 2015. A total of 92 lesions were found to be OTs and were classified into benign and malignant tumors. They were further subdivided into three subtypes based on the types of odontogenic tissues involved. These were epithelial OTs (EOTs), mixed OTs (MIXOTs), and mesenchymal OTs (MOTs). RESULTS: Of 92 OTs, 84 were benign (males 48, females 36) and 8 were malignant (male 2, females 6). The most common benign tumor was ameloblastoma (AME) (20), followed by keratocystic OT (KCOT) (17), calcifying EOT (CEOT) (14), compound odontome (OD-Cd) (12), complex odontome (OD-Cx) (10), odontogenic fibroma (OF) (5), odontogenic myxoma (OM) (4), and cementoblastoma (CB) (2). The most common malignant tumor was primary intraosseous squamous cell carcinoma (PIOSCC) (3) followed by fibrosarcoma (FS) (3) and ameloblastic carcinoma (AC). CONCLUSION: Author concluded that there was geographic and demographic variation in distribution of OTs, which may be attributed to socioeconomic and genetic factors. CLINICAL SIGNIFICANCE: Literature showing prevalence of OTs in India is negligible. By this article, we have analyzed the frequency of various OTs according to sex, age, and site. A comprehensive record of OTs should be started so that pathologists and surgeons would be able to acquire the information about the tumor for reference in the future. PMID- 29109322 TI - Self-disinfecting Alginate vs Conventional Alginate: Effect on Surface Hardness of Gypsum Cast-An in vitro Study. AB - INTRODUCTION: For the construction of any dental prosthesis, accurate impressions are necessary. Hence, we undertook the present study to evaluate and compare the surface hardness of gypsum casts poured from impressions made using conventional alginate and self-disinfecting alginate. MATERIALS AND METHODS: A total of 30 impressions of stainless steel die were made, out of which 15 impressions were made with conventional alginate and 15 were made with self-disinfecting alginate and poured using Type III dental stone. Thirty stone specimens were subjected for hardness testing. Data were analyzed using independent samples t-test to compare the mean surface hardness. RESULTS: Difference in surface hardness was statistically insignificant (p > 0.05). CONCLUSION: Surface hardness of gypsum casts poured using impressions made from self-disinfecting alginate and conventional alginates were comparable. CLINICAL SIGNIFICANCE: Self-disinfecting alginates may be employed in clinical practice as safe and effective materials to overcome the infection control issues without compromising on the properties of the material. PMID- 29109323 TI - Impact of Root Dentin Thickness on the in vitro Compressive Strength of Teeth treated with Recent Post and Core Systems. AB - INTRODUCTION: Endodontically treated teeth dry with time, and its dentin undergoes changes making the teeth brittle and friable. The main function of a post is to strengthen or reinforce a weakened root. However, doing a post and core frequently requires the removal of sound tooth tissue. Recent materials introduced in the market for post and cores have been promising. AIM: The aim of this study is to evaluate the fracture resistance of endodontically treated extracted permanent teeth with variable remaining root dentin thickness after post space preparation. MATERIALS AND METHODS: A total of 270 freshly extracted permanent maxillary central incisors with fully formed apices were selected, decoronated at cementoenamel junction, and divided into three main groups according to remaining root dentin thickness, determined using a Vernier caliper into 0.5, 1, and 1.50 mm after post space preparation. Each group was further divided into three subgroups (subgroup a: Custom-made cobalt-chromium alloy post and core; subgroup b: Prefabricated glass fiber post and composite core; and subgroup c: EverStick fiber post). Each specimen was subjected to compressive load using universal testing machine. The force required to fracture was recorded and data were analyzed using analysis of variance (ANOVA) test. RESULTS: Analysis of variance revealed that compressive strength of the tooth is significantly affected by the increase in the remaining dentin thickness after post space preparation (p < 0.05). Furthermore, teeth with custom fabricated posts showed a significantly higher compressive strength (p < 0.05) than prefabricated glass fiber post and EverStick fiber post groups except the group with minimum remaining dentin thickness. CONCLUSION: The present in vitro study revealed that compressive strength of the post and core systems is directly related to the amount of healthy remaining dentin thickness. Hence, efforts to maximize the preservation of natural dentin should be taken during post space preparation. PMID- 29109324 TI - Potential Predictor of Tobacco Cessation among Factory Workers: A Baseline Data of Worksite Tobacco Cessation Programs in the Central Part of India. AB - AIM: Our study aimed to evaluate the prevalence of tobacco use among factory workers and identify the predicting factors for quitting tobacco use. MATERIALS AND METHODS: In this cross-sectional study, a total of 640 factory workers were included and divided into the quitter group and who had never quit the tobacco habit in the past. Data were collected by standardized and validated questionnaire pro forma, which comprised the demographic profile, smoking history, and Fagerstrom scale to check the nicotine dependence. Data were analyzed using descriptive analysis and Chi-squares test, whereas logistic regression was used to predict the factor for quitting the tobacco habit. All tests were applied using Statistical Package for the Social Sciences (SPSS) version 17.0. RESULTS: The mean age among the quitters was comparatively low than the never-quit group. Out of 640 participants, the majority of quitters and those who never quit were found to consume smokeless tobacco (232 [93.5]; 288 [73.5]). As per logistic regression analysis, gender of participants, age of starting tobacco use, and frequency of tobacco use can be considered as good predictors to quit smoking/chewing tobacco. CONCLUSION: The present study found that participants in the quitter group were less dependent on tobacco, and these participants were more likely to quit smoking if behavioral support was provided at the early days of the quitting attempt. CLINICAL SIGNIFICANCE: This study's result provides valuable insight into the current tobacco usage and potential predicting factors for quitting tobacco use among factory workers in India. These data can help in developing a policy for the implementation of tobacco cessation programs at the worksite. PMID- 29109325 TI - Effect of Interimplant Distance and Cyclic Loading on the Retention of Overdenture Attachments. AB - AIM: The purpose of this in vitro study was to investigate the effect of interimplant distance and cyclic loading on the retention of two locator attachment systems. MATERIALS AND METHODS: A total of 72 acrylic resin blocks were fabricated and divided into six groups of six pairs each. Locators of DIO and 3i implant systems were positioned on analogs in three different interimplant distances (19, 23, and 29 mm). The blocks were attached to a universal testing machine, and 1,440 dislodging cycles by the force of 136 N were applied. After 0, 120, 360, 720, and 1,440 cycles, the retention was recorded. Three-way analysis of variance (ANOVA) was used to test for differences in retention between the various combinations of the locator, interimplant distance, and cyclic loadings. RESULTS: Interimplant distance was significantly associated with retention, independent of the locator system used, and dislodge-ment force cycles. Mean retention was significantly higher under the 3i system relative to the DIO system (p < 0.0001). This association varied with both interimplant distance (p > 0.0001) and dislodgement force (p < 0.0001) as well as across the various combinations of distance and cycle (p < 0.0001). CONCLUSION: Interimplant distances could affect the initial retention of locator attachments. There was little difference in retention between distances of 23 and 29 mm across all cycles when both locator systems were combined. Distance of 23 mm was associated with superior retention in the DIO system. With regard to the speed of retention decrease, the 23 mm distance was associated with better performance. CLINICAL SIGNIFICANCE: Interimplant distance could play a significant role in overdenture retention with locator attachments. PMID- 29109326 TI - Effect of Periodontal Therapy on Crevicular Fluid Interleukin-18 Level in Periodontal Health and Disease in Central Maharashtra (India) Population. AB - AIM: The incidence and progression of the periodontal disease depend on periodontal microflora and the multifaceted response of the host, and these interactions are mediated by cytokines and chemokines. Interleukin-18 (IL-18) is a proinflammatory cytokine of the IL-1 superfamily. The aim of the present study was the assessment of the periodontal therapy in IL-18 level in periodontal disease and health. MATERIALS AND METHODS: Based on clinical attachment loss (CAL), probing pocket depth (PPD), gingival index (GI), and plaque index (PI) patients were divided into three groups: Group I with healthy patients, group II with chronic periodontitis, and group III with posttreatment patients having periodontitis. RESULTS: Mean PI, PPD, CAL, and gingival crevicular fluid (GCF) volume were significantly higher in groups II and III compared with group I. However, there were no significant differences between GI in groups I, II, and III. The total amount of IL-18 in GCF was significantly higher in group II when compared with groups I and III (p < 0.05). CONCLUSION: The present study confirmed that the IL-18 level in GCF was lower in healthy patients, higher in periodontally involved patients, and reduced at baseline, 3 and 6 weeks after nonsurgical periodontal therapy. CLINICAL SIGNIFICANCE: The IL-18 might be hypothetically beneficial in distinguishing health from disease and monitoring periodontal disease activity. PMID- 29109327 TI - Evolution of Nickel-titanium Alloys in Endodontics. AB - : To improve clinical use of nickel-titanium (NiTi) endodontic rotary instruments by better understanding the alloys that compose them. A large number of engine driven NiTi shaping instruments already exists on the market and newer generations are being introduced regularly. While emphasis is being put on design and technique, manufacturers are more discreet about alloy characteristics that dictate instrument behavior. Along with design and technique, alloy characteristics of endodontic instruments is one of the main variables affecting clinical performance. Modification in NiTi alloys is numerous and may yield improvements, but also drawbacks. Martensitic instruments seem to display better cyclic fatigue properties at the expense of surface hardness, prompting the need for surface treatments. On the contrary, such surface treatments may improve cutting efficiency but are detrimental to the gain in cyclic fatigue resistance. Although the design of the instrument is vital, it should in no way cloud the importance of the properties of the alloy and how they influence the clinical behavior of NiTi instruments. CLINICAL SIGNIFICANCE: Dentists are mostly clinicians rather than engineers. With the advances in instrumentation design and alloys, they have an obligation to deal more intimately with engineering consideration to not only take advantage of their possibilities but also acknowledge their limitations. PMID- 29109328 TI - Semi-automated carotid lumen segmentation in computed tomography angiography images. AB - Carotid artery stenosis causes narrowing of carotid lumens and may lead to brain infarction. The purpose of this study was to develop a semi-automated method of segmenting vessel walls, surrounding tissues, and more importantly, the carotid artery lumen by contrast computed tomography angiography (CTA) images and to define the severity of stenosis and present a three-dimensional model of the carotid for visual inspection. In vivo contrast CTA images of 14 patients (7 normal subjects and 7 patients undergoing endarterectomy) were analyzed using a multi-step segmentation algorithm. This method uses graph cut followed by watershed and Hessian based shortest path method in order to extract lumen boundary correctly without being corrupted in the presence of surrounding tissues. Quantitative measurements of the proposed method were compared with those of manual delineation by independent board-certified radiologists. The results were quantitatively evaluated using spatial overlap surface distance indices. A slightly strong match was shown in terms of dice similarity coefficient (DSC) = 0.87+/-0.08; mean surface distance (Dmsd) = 0.32+/-0.32; root mean squared surface distance (Drmssd) = 0.49+/-0.54 and maximum surface distance (Dmax) = 2.14+/-2.08 between manual and automated segmentation of common, internal and external carotid arteries, carotid bifurcation and stenotic artery, respectively. Quantitative measurements showed that the proposed method has high potential to segment the carotid lumen and is robust to the changes of the lumen diameter and the shape of the stenosis area at the bifurcation site. The proposed method for CTA images provides a fast and reliable tool to quantify the severity of carotid artery stenosis. PMID- 29109329 TI - Role of apolipoproteins, ABCA1 and LCAT in the biogenesis of normal and aberrant high density lipoproteins. AB - In this review, we focus on the pathway of biogenesis of HDL, the essential role of apoA-I, ATP binding cassette transporter A1 (ABCA1), and lecithin: cholesterol acyltransferase (LCAT) in the formation of plasma HDL; the generation of aberrant forms of HDL containing mutant apoA-I forms and the role of apoA-IV and apoE in the formation of distinct HDL subpopulations. The biogenesis of HDL requires functional interactions of the ABCA1 with apoA-I (and to a lesser extent with apoE and apoA-IV) and subsequent interactions of the nascent HDL species thus formed with LCAT. Mutations in apoA-I, ABCA1 and LCAT either prevent or impair the formation of HDL and may also affect the functionality of the HDL species formed. Emphasis is placed on three categories of apoA-I mutations. The first category describes a unique bio-engineered apoA-I mutation that disrupts interactions between apoA-I and ABCA1 and generates aberrant prebeta HDL subpopulations that cannot be converted efficiently to alpha subpopulations by LCAT. The second category describes natural and bio-engineered apoA-I mutations that generate prebeta and small size alpha4 HDL subpopulations, and are associated with low plasma HDL levels. These phenotypes can be corrected by excess LCAT. The third category describes bio-engineered apoA-I mutations that induce hypertriglyceridemia that can be corrected by excess lipoprotein lipase and also have defective maturation of HDL. The HDL phenotypes described here may serve in the future for diagnosis, prognoses and potential treatment of abnormalities that affect the biogenesis and functionality of HDL. PMID- 29109330 TI - Vanishing cerebral vasculitis in a patient with Lewy pathology. AB - Immune-mediated mechanisms are involved in the pathogenesis of both cerebral vasculitis and Parkinson's disease (PD, brainstem-predominant Lewy pathology), but the presentation of cerebral vasculitis with comorbid Lewy pathology has not yet been reported. Here we present a case of pathologically confirmed vasculitis in a 73-year-old male patient whose postmortem examination revealed Lewy pathology diagnostic of PD. This case study suggests a comorbidity of cerebral vasculitis and Lewy pathology, as well as potential pathogenic interactions between these two disorders with immune-mediated mechanisms. PMID- 29109331 TI - MKL1 mediates TNF-alpha induced pro-inflammatory transcription by bridging the crosstalk between BRG1 and WDR5. AB - Tumor necrosis factor alpha (TNF-alpha) is a cytokine that can potently stimulate the synthesis of a range of pro-inflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) is associated with a histone H3K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-alpha. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of pro-inflammatory genes. In contrast, silencing of WDR5 attenuates TNF-alpha induced production of pro-inflammatory mediators and erases the H3K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-alpha induced pro-inflammatory transcription in macrophages. PMID- 29109332 TI - Hydrogen-enriched water eliminates fine particles from the lungs and blood by enhancing phagocytic activity. AB - Particulate matters (PM) are one of the major body burdens leading to diseases. We investigated the capacities of a hydrogen-enriched water (HW) eliminating carbon nanoparticles (CNP) and carbon microparticles (CMP) from the lungs and blood, respectively. In CNP-elimination test, rats were orally administered with purified water (PW) or HW (10 or 30 mL/kg/day) for 10 weeks. At the time point of 4 weeks, the rats were challenged with intratracheal instillation of CNP (4 mg). CNP accumulated in the airways and alveoli, and induced inflammatory lesions. Such pneumoconiosis was markedly improved by feeding HW, while PW was ineffective. CNP-induced pneumoconiosis caused systemic hematological alterations, decreasing major inflammatory cells, but markedly increasing eosinophils, indicative of an allergic reaction, which were attenuated by treatment with HW. Such PM-eliminating and anti-allergic effects of HW reduced body burden as confirmed from the facilitated recovery of body and lung weights. In CMP-clearance test, mice were orally administered with PW or HW for 7 days, and intravenously injected with CMP (300 mg/kg). CMP was rapidly eliminated from the blood in HW-fed mice. Indeed, the phagocytic indices increased to 3.5 and 6.7 folds at 10 and 30 mL/kg of HW, in comparison with a negligible effect of PW. As a mechanism study, only HW significantly inhibited lipid peroxidation in vitro Fenton reaction-mediated .OH-generating system. Collectively, the results indicate that HW not only effectively eliminated PM from the lungs and blood by enhancing phagocytic activity, but also attenuated the lung injuries by inhibiting lipid peroxidation. PMID- 29109333 TI - Mitochondrial Dysfunction and Left Ventricular Structural Remodeling After Acute Myocardial Infarction - Usefulness of Leukocyte Mitochondrial Copy Number. PMID- 29109334 TI - Comparison of Archaeal Communities in Mineral Soils at a Boreal Forest in Finland and a Cold-Temperate Forest in Japan. AB - Archaeal communities in mineral soils were compared between a boreal forest in Finland and cold-temperate forest in Japan using 16S rRNA gene-targeted high throughput sequencing. In boreal soils, Thaumarchaeota Group 1.1c archaea predominated and Thaumarchaeota Group 1.1a-associated and Group 1.1b archaea were also detected. In temperate soils, Thaumarchaeota Group 1.1a-associated and Group 1.1b archaea were dominant members at the subsurface, whereas their dominancy was replaced by Thermoplasmata archaea at the subsoil. An analysis of the ammonia monooxygenase subunit A gene of Archaea also indicated the distribution of Thaumarchaeota Group 1.1a-associated and Group 1.1b archaea in these soils. PMID- 29109335 TI - [The type IX secretion system and the type V pilus in the phylum Bacteroidetes]. AB - Many bacteria symbiotic and parasitic in humans are included in the genera Bacteroides, Prevotella, Porphyromonas and others, which belong to the phylum Bacteroidetes. We have been studying gingipain, a major secretory protease of Porphyromonas gingivalis which is a periodontopathogenic bacterium belonging to the genus Porphyromonas, and pili which contribute to host colonization in the bacterium. In the process, it was found that gingipain was secreted by a system not reported previously. Furthermore, this secretion system was found to exist widely in the Bacteroidetes phylum bacteria and closely related to the gliding motility of bacteroidete bacteria, and it was named the Por secretion system (later renamed the type IX secretion system). Regarding P. gingivalis pili, it was found that the pilus protein is transported as a lipoprotein to the cell surface, and the pilus formation occurs due to degradation by arginine-gingipain. Pili with this novel formation mechanism was found to be widely present in bacteria belonging to the class Bacteroidia in the phylum Bacteroidetes and was named the type V pili. PMID- 29109336 TI - Corrosion resistance and mechanical properties of titanium nitride plating on orthodontic wires. AB - Titanium nitride (TiN) coating by ion plating has properties such as high hardness, wear resistance, corrosion resistance, and surface lubricity, therefore TiN coating is often used in various dental appliances and materials. In this study, we evaluated the corrosion behaviors and mechanical properties of TiN coated stainless steel (SS) and nickel titanium (Ni-Ti) orthodontic wires prepared by ion plating. TiN coating by ion plating improves the corrosion resistance of orthodontic wires. The corrosion pitting of the TiN coated wire surface become small. The tensile strength and stiffness of SS wire were increased after TiN coating. In contrast, its elastic force, which is a property for Ni-Ti wire, was decreased. In addition, TiN coating provided small friction forces. The low level of friction may increase tooth movement efficiently. Therefore, TiN coated SS wire could be useful for orthodontics treatment. PMID- 29109337 TI - Effect of ethanol treatment on mechanical properties of heat-polymerized polymethyl methacrylate denture base polymer. AB - This laboratory study was assessing the nano-mechanical properties (NMP), surface roughness (Sa), and topographic changes caused by ethanol on the surface of heat polymerized denture base polymers at different time past dough stage. Specimens of heat polymerizing acrylic resin (Interacryl Hot, Interdent, Celje, Slovenia) of size 10*10*3 mm were prepared, wet ground, and polished for uniform smoothness and treated with ethanol in concentrations of 40, 70, and 99.9% for 30, 60, and 120 s and statistical analysis was done. Some statistical significance for Sa were highest with 120 s exposure to 40% ethanol. NMP were the highest for specimens treated with 99.9% ethanol concentration for 120 s, on specimens prepared 30 min past the dough stage. This study suggested that heat-polymerized denture base polymers are prone for changes by ethanol which alters mechanical properties and surface topography. Dough time influenced the ethanol resistance. PMID- 29109338 TI - Effect of dentin surface modification using carbon nanotubes on dental bonding and antibacterial ability. AB - This study developed carbon nanotube coatings for the dentin surface and investigated the bonding strength and the in vitro antibacterial properties of carbon nanotube-coated dentin. Single-walled carbon nanotubes and multi-walled carbon nanotubes were first modified and then characterized using Fourier transform infrared spectroscopy, scanning electron microscope, and transmission electron microscopy. Second, dentin samples were coated using either single walled carbon nanotubes or multi-walled carbon nanotubes and observed under a scanning electron microscope. Then, the shear bonding strength and antibacterial properties of the dentin samples were tested. The results showed that both modified single-walled carbon nanotubes and multi-walled carbon nanotubes formed a stable coating on the dentin surface without affecting the shear bonding strength. Moreover, the antibacterial properties of the single-walled carbon nanotube-coated samples was obviously superior to those of the multi-walled carbon nanotube-coated samples. Consequently, single-walled carbon nanotube coating may be an antibacterial agent for potential application in the dental bonding field. PMID- 29109339 TI - Effects of surface microtopography of titanium disks on cell proliferation and differentiation of osteoblast-like cells isolated from rat calvariae. AB - The surface topography of implant fixture is an important factor affecting the osseointegration. We herein demonstrated the effects of surface microtopography of titanium disks on proliferation and differentiation of osteoblast-like cells isolated from rat calvariae. Titanium disks with machine surface (MS), rough surface (R1) and rough surface combined with small cavities (R2) were used in an in vitro culture system. Rough surfaces (R1 and R2 disks) induced stronger osteoblast proliferation and differentiation (BGP and sclerostin mRNA expressions and calcium content) than the smooth surface (MS disk). Furthermore, surface microtopography of R2 disk, which was rough with small cavities, more strongly induced cell proliferation and mineralized bone matrix production than R1 disk. Our results suggest that surface microtopography influences osteoblast proliferation and differentiation. R2 disk, which is rough with small cavities, may be used in implant fixtures to increase osseointegration. PMID- 29109340 TI - Effect of three metal priming agents on the bond strength of adhesive resin cement to Ag-Zn-Sn-In alloy and component metals. AB - The aim of this study was to investigate the effect of three metal priming agents on the bond strength of adhesive resin cement to Silver-Zinc-Tin-Indium (Ag-Zn-Sn In) alloy and pure Ag, Zn, Sn, and In. The specimens were air-abraded with alumina and then primed with one of three metal priming agents: V-Primer, Estenia Opaque Primer, or Alloy Primer. The metal disks were bonded with adhesive resin cement (Super-Bond Bulk-mix technique). Shear bond strengths (n=10/group) were determined before and after 50,000 thermocycles for Ag-Zn-Sn-In alloy as well as after 5,000 thermocycles for pure Ag, Zn, Sn and In. For Ag-Zn-Sn-In alloy, the post-thermocycling bond strength of the Alloy Primer group was significantly higher than that of the other primers. It can be concluded that Alloy Primer containing both the vinyl-thione monomer (VBATDT) and hydrophobic phosphate monomer (MDP) is effective for bonding Ag-Zn-Sn-In alloy and pure Ag, Zn and Sn. PMID- 29109341 TI - [Gastrointestinal lymphomas:recent topics in diagnosis and treatment]. PMID- 29109342 TI - [Pathology of malignant lymphoma in gastric intestinal tracts]. PMID- 29109343 TI - [Diagnosis and treatment of gastric malignant lymphoma]. PMID- 29109344 TI - [Clinicopathological characteristics and therapeutic strategy in intestinal lymphoma]. PMID- 29109345 TI - [Analysis of the gray-zone cutoff values of new serum Helicobacter pylori antibody kits using latex immunoassay]. AB - The serum Helicobacter pylori titers are good markers for population-based H. pylori screening and treatment programs because the tests used to estimate these titers are noninvasive, inexpensive, and convenient. However, the reference range of 3-10U/mL, which is used as a standard in commercially available serum H. pylori antibody kit E plate Eiken H. pylori antibody II, is regarded as a gray zone cutoff value to indicate H. pylori infection status. We aimed to clarify the gray-zone cutoff values of H. pylori infection status with new serum H. pylori antibody kits using latex immunoassay. We enrolled 256 patients who underwent endoscopic examination and H. pylori tests at the Inui Clinic of Internal Medicine or IMS Ota Central General Hospital between January 2013 and December 2015. Serum H. pylori titers were measured using Type L Wako H. pylori antibody J (Wako-LIA), H. pylori-latex Seiken (Denka-LIA), and LZ test Eiken H. pylori antibody (Eiken-LZ). In patients with a positive diagnosis of H. pylori infection, the positive diagnostic values (sensitivity, specificity, and positive predictive value) using Wako-LIA, Denka-LIA, and Eiken-LZ were (94.6%, 86.0%, and 79.1%), (95.7%, 90.2%, and 84.6%), and (85.9%, 92.1%, and 85.9%), respectively;in patients with a negative diagnosis of H. pylori infection, the diagnostic values (sensitivity, specificity, and negative predictive value) using Wako-LIA, Denka LIA, and Eiken-LZ were (96.9%, 83.5%, and 85.6%), (96.9%, 78.7%, and 82.2%) and (95.3%, 67.7%, and 75.0%), respectively. In this study, the gray-zone cutoff value indicating H. pylori infection status was between 4.0 and 8.7U/mL for Wako LIA, between 10.0 and 15.2U/mL for Denka-LIA, and between 5.6 and 10.0U/mL for Eiken-LZ. Therefore, we propose that lower titers of the positive antibody are important to diagnose H. pylori infection using Wako-LIA and Denka-LIA. However, when using Eiken-LZ, high titers of the negative antibody should be considered diagnostically important. PMID- 29109346 TI - [A case of metastatic uveal melanoma of the liver and digestive tract]. AB - Metastasis of uveal melanoma of the digestive tract is rare. We report a case of a patient with metastatic uveal melanoma of the liver and digestive tract. A 68 year-old man was admitted with primary complaint of appetite loss and fatigue. Abdominal computed tomography revealed a 13-cm diameter tumor in the right lobe of the liver. We diagnosed him with metastatic uveal melanoma. We performed a liver tumor biopsy and diagnosed metastatic melanoma;we found distant metastases in the stomach, duodenum, and rectum on endoscopic biopsy. We administered systemic chemotherapy [DACa-Tam therapy (Dacarbazine, 220mg/m2*3 days;Nimustine, 60mg/m2*1 day;Carboplatin area under the curve (AUC) =4*1 day;Tamoxifen, 40mg/day*3 days)]. Prognosis is unfavorable in approximately half of the patients with liver metastases that occur through blood circulation. The patient died of liver failure two months after the diagnosis. PMID- 29109347 TI - [A case of long-term survival in stage IV squamous cell carcinoma of the anal canal with multidisciplinary treatment]. AB - A 60-year-old female presented to our hospital with anal pain. Colonoscopy (CS) revealed a tumor in the anal canal, which was diagnosed as squamous cell carcinoma by biopsy. Computed tomography (CT) showed multiple liver metastases. From these findings, we diagnosed the anal tumor as stage IV squamous cell carcinoma of the anal canal. Although CS and CT indicated disappearance of the primary tumor and liver metastases following chemoradiotherapy, brain metastasis developed during the disease course and was treated with radiotherapy and surgical resection. Administration of S-1 as adjuvant chemotherapy was continued, and the patient has remained alive for approximately six years without recurrence. To the best of our knowledge, this case can be considered as having the longest-term survival in stage IV squamous cell carcinoma of the anal canal. PMID- 29109348 TI - [A case of gastric follicular lymphoma resected and diagnosed with laparoscopy and endoscopy cooperative surgery]. AB - A woman in her 70s was diagnosed with a protruding mucosa-associated lymphoid tissue (MALT) lymphoma during a secondary health examination. After eradication of Helicobacter pylori, a biopsy revealed gastric follicular lymphoma (FL) and the lesion was still protruding one year later. 18F-fluorodeoxyglucose positron emission tomography showed focal nodular hypermetabolic activity, suggesting that FL may have transformed into a diffuse large B-cell lymphoma. Upper gastrointestinal endoscopy, colonoscopy, and capsule endoscopy showed no other lesions in the gastrointestinal tract, and bone marrow biopsy showed no permeation into the marrow. Therefore, this lesion, which appeared as a submucosal tumor, was limited to the stomach. Laparoscopy and endoscopy cooperative surgery was performed, because it allows for correct pathological diagnosis while removing only a minimal portion of the stomach wall. Histological findings showed follicular structures consisting of abnormal lymphoid cells. Immunohistochemical analysis revealed that neoplastic cells were positive for CD20, CD79a, Bcl-2, CD10, and c-MYC, but negative for CD3, CD5, and cyclin D1. Finally, we diagnosed this lesion as a primary gastric FL. PMID- 29109349 TI - [A case of an elderly patient with inverted Meckel's diverticulum with small intestinal bleeding detected using capsule and double-balloon endoscopies]. AB - An 80-year-old man was examined with esophagogastroduodenoscopy and colonoscopy because of digestive tract hemorrhage;however, no specific cause was found. Small intestinal capsule endoscopy revealed a reddish elevated lesion in the ileum. This lesion was also detected using double-balloon endoscopy as a 5-cm reddish elevated lesion covered with normal villous architecture in the 95-cm part of the Bauhin valve on the oral side. The lesion was laparoscopically resected and diagnosed as inverted Meckel's diverticulum based on pathological examination. This was a rare case where Meckel's diverticulum was inverted, and the lesion was observed using capsule and double-balloon endoscopies before surgery. Although complications of Meckel's diverticulum are rare in the elderly, it is necessary to identify this disease as a cause of small intestinal bleeding, even in elderly patients. PMID- 29109350 TI - [Spontaneous regression of pancreatic arteriovenous malformation under the influence of severe acute pancreatitis: a case report]. AB - A 49-year-old man was diagnosed with severe acute pancreatitis because of pancreatic arteriovenous malformation (AVM). The pancreatic AVM spontaneously regressed during conservative treatment for severe acute pancreatitis. Transarterial embolization of an aneurysm in an artery branch flowing into the pancreatic AVM was performed using metallic coils, following amelioration of severe acute pancreatitis. The complete elimination of the pancreatic AVM was confirmed 1 year after embolization, and the patient has had no recurrence of pancreatic AVM and pancreatitis for over 6 years. Most cases of pancreatic AVMs with acute pancreatitis require surgical resection. This is a rare case in which the pancreatic AVM spontaneously regressed under the influence of acute severe pancreatitis. PMID- 29109351 TI - Chronological differential effects of pro-inflammatory cytokines on RANKL-induced osteoclast differentiation of canine bone marrow-derived macrophages. AB - The aim of this study was to investigate osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Bone marrow-derived macrophages from five healthy dogs were stimulated with the macrophage colony-stimulating factor, receptor activator of nuclear factor-kappaB ligand and inflammatory cytokines such as interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-17. Osteoclasts (OC) formation and function were enhanced with TNF-alpha regardless of temporal differences. But in contrast, IL 1beta suppressed the osteoclastogenesis at early phase of the process while upregulating at the late phase. Furthermore, differentiation of OC precursors into OC was suppressed at high concentrations of IL-17. Collectively, the results revealed that suppressing TNF-alpha would be a promising strategy to inhibit inflammation-associated bone destruction in dogs. PMID- 29109352 TI - Mapping of KNDy neurons and immunohistochemical analysis of the interaction between KNDy and substance P neural systems in goat. AB - A population of neurons in the arcuate nucleus (ARC) coexpresses kisspeptin, neurokinin B (NKB), and dynorphin, and therefore they are referred to as KNDy neurons. It has been suggested that KNDy neurons participate in several brain functions, including the control of reproduction. The present study aimed to advance our understanding of the anatomy of the KNDy neural system. We first produced an antiserum against goat kisspeptin. After confirming its specificity, the antiserum was used to histochemically detect kisspeptin-positive signals. Using the colocalization of kisspeptin and NKB immunoreactivity as a marker for KNDy neurons, we mapped distributions of their cell somata and fibers in the whole brain (except the cerebellum) of ovariectomized (OVX) goats. KNDy neuronal somata were distributed throughout the ARC, and were particularly abundant in its caudal aspect. KNDy neuronal fibers projected into several areas within the septo preoptic-hypothalamic continuum, such as the ARC, median eminence, medial preoptic nucleus, and bed nucleus of the stria terminalis. Kisspeptin immunoreactivity was not found outside of the continuum. We then addressed to the hypothesis that substance P (SP) is also involved in the KNDy neural system. Double-labeling immunohistochemistry for kisspeptin and SP revealed that KNDy neurons did not coexpress SP, but nearly all of the KNDy neuronal somata were surrounded by fibers containing SP in the OVX goats. The present results demonstrate anatomical evidence for a robust association between the KNDy and SP neural systems. PMID- 29109353 TI - Intranasal immunization with a recombinant outer membrane protein H based Haemorrhagic septicemia vaccine in dairy calves. AB - Haemorrhagic septicemia (HS) is a contagious disease in cattle with high morbidity and mortality rates. HS vaccine in Thailand is an oil-adjuvant formulation, and is difficult to administer. The present study aimed to formulate and evaluate the protection in dairy calves conferred by immunization with an in house intranasal HS vaccine. The intranasal vaccine was formulated in a total volume of 500 ul containing either 50 or 100 ug of the recombinant outer membrane protein H (rOmpH) of Pasteurella multocida strain M-1404 (serovar B:2), and 10 ug of Cytosine-phosphate-guanosine oligodeoxynucleotides (CpG-ODN) as a mucosal adjuvant. Intranasal immunizations were conducted three times at three-week intervals. The antibodies post-immunization were detected by indirect ELISA and demonstrated efficient in vitro activity in suppressing a P. multocida strain from the complement-mediated killing assay. An intranasal vaccine induced both the serum IgG and secretory IgA levels that were significantly higher than the level conferred by the parenteral vaccine (P<0.05). Challenge exposure was conducted with a P. multocida strain M-1404 at day 72 of the experiments. The immunized calves had reduced clinical signs after challenge exposure that would normally result in disease proliferation. We conclude that intranasal vaccination of calves with rOmpH with CpG-ODN 2007 stimulated serum and secretory antibodies to rOmpH and whole cells of P. multocida strain M-1404 antigen. Moreover, it would result in protection in calves against artificial P. multocida infection. PMID- 29109354 TI - Early development of pleuroperitoneal fold of the diaphragm in the rat fetus. AB - The embryonic diaphragm comprises four major structural components derived from the transverse septum, the dorsal foregut mesentery, the pleuroperitoneal folds (PPFs), and the body wall. In this study, the appearance of PPFs and related factors were investigated using light microscopy of horizontal sections of rat fetuses from embryonic day 12 to 13. In rat fetuses, the sign of PPF projection was noted in the sidewall of the pericardioperitoneal canal at embryonic day 12, and was confirmed as folds at embryonic day 12.25. Expressions of GATA4, COUP TF2, and FOG2 were detected in PPF at the early stage of formation. Localizations of these factors suggested that COUP-TF2 and FOG2 are the main factors in PPF appearance and that GATA4 is unlikely to be a main factor, although it is necessary for PPF formation. PMID- 29109355 TI - Intraspecific variation of the interparietal suture closure in Siberian roe deer Capreolus pygargus from Jeju Island. AB - The sequence of cranial suture closure among cervids is reported to be generally species-specific and highly conservative within species. On the other hand, it is known that intraspecific variation often exists to some extent in other mammalian taxa. Here we studied the cranial suture closures of Capreolus pygargus from Jeju Island and compared it with other cervid species. We found that the timing of the interparietal suture closure is highly variable within C. pygargus. Capreolus capreolus similarly shows intraspecific variation of the interparietal suture closure, whereas other cervid species studied to date do not show any intraspecific variation in the sequence of cranial suture closure. Such high intraspecific variation of the interparietal suture may be a derived character for Capreolus. PMID- 29109356 TI - Intrauterine infection with bovine leukemia virus in pregnant dam with high viral load. AB - Enzootic bovine leukemia is caused by the bovine leukemia virus (BLV). BLV is transmitted vertically or horizontally through the transfer of infected cells via direct contact, through milk, insect bites and contaminated iatrogenic procedures. However, we lacked direct evidence of intrauterine infection. The purpose of this study was to confirm intrauterine BLV infection in two pregnant dams with high viral load by cesarean delivery. BLV was detected in cord and placental blood, and the BLV in the newborns showed 100% nucleotide identity with the BLV-env sequence from the dams. Notably, a newborn was seropositive for BLV but had no colostral antibodies. In this study, we presented a direct evidence of intrauterine BLV transmission in pregnant dam with a high proviral load. These results could aid the development of BLV control measures targeting viral load. PMID- 29109357 TI - Occupational exposure to electromagnetic fields from medical sources. AB - High exposures to electromagnetic fields (EMF) can occur near certain medical devices in the hospital environment. A systematic assessment of medical occupational EMF exposure could help to clarify where more attention to occupational safety may be needed. This paper seeks to identify sources of high exposure for hospital workers and compare the published exposure data to occupational limits in the European Union. A systematic search for peer-reviewed publications was conducted via PubMed and Scopus databases. Relevant grey literature was collected via a web search. For each publication, the highest measured magnetic flux density or internal electric field strength per device and main frequency component was extracted. For low frequency fields, high action levels may be exceeded for magnetic stimulation, MRI gradient fields and movement in MRI static fields. For radiofrequency fields, the action levels may be exceeded near devices for diathermy, electrosurgery and hyperthermia and in the radiofrequency field inside MRI scanners. The exposure limit values for internal electric field may be exceeded for MRI and magnetic stimulation. For MRI and magnetic stimulation, practical measures can limit worker exposure. For diathermy, electrosurgery and hyperthermia, additional calculations are necessary to determine if SAR limits may be exceeded in some scenarios. PMID- 29109358 TI - Burnout syndrome as an occupational disease in the European Union: an exploratory study. AB - The risk of psychological disorders influencing the health of workers increases in accordance with growing requirements on employees across various professions. This study aimed to compare approaches to the burnout syndrome in European countries. A questionnaire focusing on stress-related occupational diseases was distributed to national experts of 28 European Union countries. A total of 23 countries responded. In 9 countries (Denmark, Estonia, France, Hungary, Latvia, Netherlands, Portugal, Slovakia and Sweden) burnout syndrome may be acknowledged as an occupational disease. Latvia has burnout syndrome explicitly included on the List of ODs. Compensation for burnout syndrome has been awarded in Denmark, France, Latvia, Portugal and Sweden. Only in 39% of the countries a possibility to acknowledge burnout syndrome as an occupational disease exists, with most of compensated cases only occurring in recent years. New systems to collect data on suspected cases have been developed reflecting the growing recognition of the impact of the psychosocial work environment. In agreement with the EU legislation, all EU countries in the study have an action plan to prevent stress at the workplace. PMID- 29109359 TI - Heat stress assessment in artistic glass units. AB - Heat stress in glass industry is mainly studied in large and highly mechanized manufacturing Units. To the contrary, few studies were carried out in small factories specialized in hand-made products. To stress the need of combined objective and medical surveys in these environments, this paper deals with a simultaneous climatic and physiological investigation of working conditions in artistic crystal glass factories in Tuscany (Italy). The microclimatic monitoring, through a continuous survey has been carried out in early spring. The main physiological parameters (metabolic rate, heart rate, tympanic temperature and water loss) were measured over the whole shifts. The results show that, despite the arduousness of the working conditions, the heat stress levels are physiologically tolerable. The predictions made using the PHS model at the Analysis level described in ISO 15265 agree closely to the observed values, validating the use of PHS model in these conditions. This model was then used to analyse what is likely to be the situation during the summer. It is concluded that the heat constraint will be very high and that some steps must be taken from the spring to monitor closely the exposed workers in the summer and take measures to prevent any heat accident. PMID- 29109360 TI - Investigation of the pronounced erythropoietin-induced reduction in hyperglycemia in type 1-like diabetic rats. AB - Erythropoietin (EPO) is known to stimulate erythropoiesis after binding with its specific receptor. In clinics, EPO is widely used in hemodialyzed patients with diabetes. However, changes in the expression of the erythropoietin receptor (EPOR) under diabetic conditions are still unclear. Therefore, we investigated EPOR expression both in vivo and in vitro. Streptozotocin-induced type 1-like diabetic rats (STZ rats) were used to evaluate the blood glucose-lowering effects of EPO. The expression and activity of the transducer and activator of transcription 3 (STAT3), the potential signaling molecule, was investigated in cultured rat skeletal myoblast (L6) cells incubated in high-glucose (HG) medium to mimic the in vivo changes. The EPO-induced reduction in hyperglycemia was more pronounced in diabetic rats. The increased EPOR expression in the soleus muscle of diabetic rats was reversed by the reduction in hyperglycemia. Glucose uptake was also increased in high-glucose (HG)-treated L6 cells. Western blotting results indicated that the EPO-induced hyperglycemic activity was enhanced mainly through an increase in EPOR expression. Increased EPOR expression was associated with the enhanced nuclear expression of STAT3 in HG-exposed L6 cells. In addition, treatment with siRNA specific to STAT3 reversed the increased expression of EPOR observed in these cells. Treatment with Stattic at a dose sufficient to inhibit STAT3 reduced the expression level of EPOR in STZ rats. In conclusion, the increased expression of EPOR by hyperglycemia is mainly associated with an augmented expression of nuclear STAT3, which was identified both in vivo and in vitro in the present study. PMID- 29109361 TI - Anaerobic Reduction of Nitrate to Nitrous Oxide Is Lower in Bradyrhizobium japonicum than in Bradyrhizobium diazoefficiens. AB - When soil oxygen levels decrease, some bradyrhizobia use denitrification as an alternative form of respiration. Bradyrhizobium diazoefficiens (nos+) completely denitrifies nitrate (NO3-) to dinitrogen, whereas B. japonicum (nos-) is unable to reduce nitrous oxide to dinitrogen. We found that anaerobic growth with NO3- as the electron acceptor was significantly lower in B. japonicum than in B. diazoefficiens, and this was not explained by the absence of nos in B. japonicum. Our results indicate that the reason for the limited growth of B. japonicum is weak NO3- reduction due to impaired periplasmic nitrate reductase activity, which may rely on posttranscriptional events. PMID- 29109362 TI - PAPOLB/TPAP regulates spermiogenesis independently of chromatoid body-associated factors. AB - Mutant mice lacking a testis-specific cytoplasmic poly(A) polymerase, PAPOLB/TPAP, exhibit spermiogenesis arrest and male infertility. However, the mechanism by which PAPOLB regulates spermiogenesis remains unclear. In this study, we examined the relationships between PAPOLB and other spermiogenesis regulators present in the chromatoid body (CB). The loss of PAPOLB had no impact either on the abundance of CB components such as PIWIL1, TDRD6, YBX2, and piRNAs, or on retrotransposon expression. In addition, localization of CB proteins and CB architecture were both normal in PAPOLB-null mice. No interactions were observed between PAPOLB and PIWIL1 or YBX2. While PIWIL1 and YBX2 were associated with translationally inactive messenger ribonucleoproteins and translating polyribosomes, PAPOLB was present almost exclusively in the mRNA-free fractions of sucrose gradients. These results suggest that PAPOLB may regulate spermiogenesis through a pathway distinct from that mediated by CB-associated factors. PMID- 29109363 TI - Efficacy and safety of two doses of Norditropin(r) (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients. AB - This randomized double-blind multicenter trial (NCT01927861) evaluated the growth promoting effect and safety of Norditropin(r) (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3 <11 years (boys) or 3-<10 years (girls) with Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was -3.24. Estimated change in HSDS [95% CI] after 104 weeks' treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p < 0.0001. Rates and patterns of adverse events (AEs) were similar between groups. Most were mild and reported as unlikely to be related to Norditropin(r). There were no withdrawals due to AEs. Insulin-like growth factor-I SDS increased from 1.71 to -0.64 (0.033 mg/kg/day) and to 0.63 (0.066 mg/kg/day). HbA1c increased slightly (0.033 mg/kg/day: +0.14%; 0.066 mg/kg/day: +0.13%); glucose profiles were almost unchanged; insulin profiles increased in both groups in the oral glucose tolerance test. There were no clinically significant abnormal electrocardiogram or echocardiography findings. We conclude that Norditropin(r) at doses of 0.033 mg/kg/day or 0.066 mg/kg/day for 104 weeks increases height in Japanese children with short stature due to Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day. PMID- 29109364 TI - Trend of Prevalence of Atrial Fibrillation and use of Oral Anticoagulation Therapy in Patients With Atrial Fibrillation in South Korea (2002-2013). AB - BACKGROUND: This study examined the annual prevalence of atrial fibrillation (AF) and its associated comorbidities, as well as the prevalence of warfarin therapy in South Korean patients with AF. METHODS: The National Health Insurance Service National Sample Cohort database was searched for subjects aged >=30 years diagnosed with AF from 2002-2013. The prevalence of AF was analyzed by sex and age, as was the current status of warfarin therapy in AF patients according to CHA2DS2-VASc score and comorbidities. RESULTS: The age-standardized prevalence of AF in men and women was 0.15% and 0.14%, respectively, in 2002, increasing to 0.54% and 0.39%, respectively, in 2013. In 2013, the prevalence of AF in men and women aged 30-39 years was 0.08% and 0.03%, respectively, increasing to 2.35% and 1.71%, respectively, in those in aged >=60 years. During 2002-2013, the prevalence of AF in men significantly increased among subjects aged >=30 years and increased in women aged >=60 years. The age-standardized prevalence of hypertension and diabetes mellitus among AF patients were markedly increased during 2002-2013. Of these AF patients, 86.1% had a CHA2DS2-VASc score of >=2; however, only 39.1% of these were receiving warfarin. CONCLUSIONS: The age standardized prevalence of AF increased 2.89-fold over the 12-year study period. The total number of patients with AF in South Korea has been drastically increasing, due to not only aging society but also increasing age-specific prevalence of AF, especially in middle-aged and elderly individuals. The rate of warfarin therapy increased slightly over the study period but remains low. PMID- 29109366 TI - Recent Trends in the Prevalence of Underweight, Overweight, and Obesity in Korean Adults: Korean National Health and Nutrition Examination Survey From 1998 to 2013 [J Epidemiol 27 (9) (2017) 413-419]. PMID- 29109365 TI - Improvement in 5-Year Relative Survival in Cancer of the Corpus Uteri From 1993 2000 to 2001-2006 in Japan. AB - BACKGROUND: Medical circumstances in Japanese patients with cancer of the corpus uteri have greatly changed since the late 1990s, including the introduction of concomitant therapy with taxane and platinum. We evaluated changes in survival rates for this cancer following these advances by analyzing data from population based cancer registries in Japan. METHODS: Data were available for 8562 cases of cancer of the corpus uteri from six prefectural cancer registries. We defined the two periods of 1993-2000 (1st period) and 2001-2006 (2nd period). Relative survival (RS) in each period was calculated to assess changes using an excess mortality model, with adjustment for age group (15-54, 55-69, and 70-99 years), extent of disease (localized, regional, and distant), and histological subtype. RESULTS: Overall 5-year RS improved from 77.7% in the 1st period to 80.2% in the 2nd period, with an excess hazard ratio (EHR) of 0.785 (95% confidence interval [CI], 0.705-0.873). Five-year RS significantly improved in the group aged 55-69 years, in all groups by extent of disease, and in the endometrioid adenocarcinoma group. In particular, 5-year RS significantly improved in patients with endometrioid adenocarcinoma, from 84.5% to 89.7%, with an EHR of 0.698 (95% CI, 0.560-0.870). CONCLUSION: Overall 5-year RS for cancer of the corpus uteri in Japan improved from the 1990s to early 2000s. These improvements might have been aided by the comprehensive medical development of management for this cancer, including the spread of concomitant therapy with taxane and platinum as a standard adjuvant chemotherapy in the early 2000s. PMID- 29109367 TI - Asperflavin, an Anti-Inflammatory Compound Produced by a Marine-Derived Fungus, Eurotium amstelodami. AB - In the present study, 16 marine-derived fungi were isolated from four types of marine materials including float, algae, animals and drift woods along with the coast of Jeju Island, Korea and evaluated for anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW 24.7 cells. The broth and mycelium extracts from the 16 fungi were prepared and the broth extract (BE) of Eurotium amstelodami (015-2) inhibited nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells without cytotoxicity. By further bioassay-guided isolation, three compounds including asperflavin, neoechinulin A and preechinulin were successfully isolated from the BE of E. amstelodami. It was revealed that asperflavin showed no cytotoxicity up to 200 MUM and significantly inhibited LPS induced NO and PGE2 production in a dose-dependent manner. In the western blot results, asperflavin suppressed only inducible NOS (iNOS), but COX-2 were slightly down-regulated. Asperflavin was also observed to inhibit the production of pro-inflammatory cytokines including TNF-alpha, IL-1beta, and IL-6. In conclusion, this study reports a potential use of asperflavin isolated from a marine fungus, E. amstelodami as an anti-inflammatory agent via suppression of iNOS and pro-inflammatory cytokines as well as no cytotoxicity. PMID- 29109368 TI - Zinc Ion-Dependent Peptide Nucleic Acid-Based Artificial Enzyme that Cleaves RNA Bulge Size and Sequence Dependence. AB - In this report, we investigate the efficiency and selectivity of a Zn2+-dependent peptide nucleic acid-based artificial ribonuclease (PNAzyme) that cleaves RNA target sequences. The target RNAs are varied to form different sizes (3 and 4 nucleotides, nt) and sequences in the bulge formed upon binding to the PNAzyme. PNAzyme-promoted cleavage of the target RNAs was observed and variation of the substrate showed a clear dependence on the sequence and size of the bulge. For targets that form 4-nt bulges, we identified systems with an improved efficacy (an estimated half-life of ca 7-8 h as compared to 11-12 h for sequences studied earlier) as well as systems with an improved site selectivity (up to over 70% cleavage at a single site as compared to 50-60% with previous targets sequences). For targets forming 3-nt bulges, the enhancement compared to previous systems was even more pronounced. Compared to a starting point of targets forming 3-nt AAA bulges (half-lives of ca 21-24 h), we could identify target sequences that were cleaved with half-lives three times lower (ca 7-8 h), i.e., at rates similar to those found for the fastest 4-nt bulge system. In addition, with the 3-nt bulge RNA target site selectivity was improved even further to reach well over 80% cleavage at a specific site. PMID- 29109369 TI - Effects of Melatonin on Glucose Homeostasis, Antioxidant Ability, and Adipokine Secretion in ICR Mice with NA/STZ-Induced Hyperglycemia. AB - Diabetes is often associated with decreased melatonin level. The aim was to investigate the effects of different dosage of melatonin on glucose hemostasis, antioxidant ability and adipokines secretion in diabetic institute for cancer research (ICR) mice. Forty animals were randomly divided into five groups including control (C), diabetic (D), low-dosage (L), medium-dosage (M), and high dosage (H) groups. Groups L, M, and H, respectively, received oral melatonin at 10, 20, and 50 mg/kg of BW (body weight) daily after inducing hyperglycemia by nicotinamide (NA)/ streptozotocin (STZ). After the six-week intervention, results showed that melatonin administration increased insulin level and performed lower area under the curve (AUC) in H group (p < 0.05). Melatonin could lower hepatic Malondialdehyde (MDA) level in all melatonin-treated groups and increase superoxide dismutase activity in H group (p < 0.05). Melatonin-treated groups revealed significant higher adiponectin in L group, and lower leptin/adiponectin ratio and leptin in M and H groups (p < 0.05). Melatonin could lower cholesterol and triglyceride in liver and decrease plasma cholesterol and low-density lipoprotein-cholesterol (LDL-C) in L group, and increase plasma high-density lipoprotein-cholesterol (HDL-C) in H group (p < 0.05). Above all, melatonin could decrease oxidative stress, increase the adiponectin level and improve dyslipidemia, especially in H group. These data support melatonin possibly being a helpful aid for treating hyperglycemia-related symptoms. PMID- 29109370 TI - Olive (Olea europaea L.) Biophenols: A Nutriceutical against Oxidative Stress in SH-SY5Y Cells. AB - Plant biophenols have been shown to be effective in the modulation of Alzheimer's disease (AD) pathology resulting from free radical-induced oxidative stress and imbalance of the redox chemistry of transition metal ions (e.g., iron and copper). On the basis of earlier reported pharmacological activities, olive biophenols would also be expected to have anti-Alzheimer's activity. In the present study, the antioxidant activity of individual olive biophenols (viz. caffeic acid, hydroxytyrosol, oleuropein, verbascoside, quercetin, rutin and luteolin) were evaluated using superoxide radical scavenging activity (SOR), hydrogen peroxide (H2O2) scavenging activity, and ferric reducing ability of plasma (FRAP) assays. The identification and antioxidant activities in four commercial olive extracts-Olive leaf extractTM (OLE), Olive fruit extractTM (OFE), Hydroxytyrosol ExtremeTM (HTE), and Olivenol plusTM (OLP)-were evaluated using an on-line HPLC-ABTS*+ assay, and HPLC-DAD-MS analysis. Oleuropein and hydroxytyrosol were the predominant biophenols in all the extracts. Among the single compounds examined, quercetin (EC50: 93.97 MUM) and verbascoside (EC50: 0.66 mM) were the most potent SOR and H2O2 scavengers respectively. However, OLE and HTE were the highest SOR (EC50: 1.89 MUg/mL) and H2O2 (EC50: 115.8 MUg/mL) scavengers among the biophenol extracts. The neuroprotection of the biophenols was evaluated against H2O2-induced oxidative stress and copper (Cu)-induced toxicity in neuroblastoma (SH-SY5Y) cells. The highest neuroprotection values (98% and 92%) against H2O2-induced and Cu-induced toxicities were shown by the commercial extract HTETM. These were followed by the individual biophenols, caffeic acid (77% and 64%) and verbascoside (71% and 72%). Our results suggest that olive biophenols potentially serve as agents for the prevention of neurodegenerative diseases such as AD, and other neurodegenerative ailments that are caused by oxidative stress. PMID- 29109371 TI - Seasonal Patterns of Japanese Encephalitis and Associated Meteorological Factors in Taiwan. AB - The persistent transmission of Japanese encephalitis virus (JEV) in Taiwan necessitates exploring the risk factors of occurrence of Japanese encephalitis (JE). The purpose of this study was to assess the relationship between meteorological factors and the incidence of JE in Taiwan. We collected data for cases of JE reported to the Taiwan Centers for Disease Control (Taiwan CDC) from 2000 to 2014. Meteorological data were obtained from the Taiwan Central Weather Bureau. The relationships between weather variability and the incidence of JE in Taiwan were determined via Poisson regression analysis and a case-crossover methodology. During the 15-year study period, a total of 379 cases of JE were reported. The incidence of JE showed significant seasonality, with the majority of cases occurring in summertime (for oscillation, p < 0.001). The number of JE cases started to increase at temperatures of 22 degrees C (r2 = 0.88, p < 0.001). Similarly, the number of JE cases began to increase at a relative humidity of 70-74% (r2 = 0.75, p < 0.005). The number of JE cases was positively associated with mean temperature and relative humidity in the period preceding the infection. In conclusion, the occurrence of JE is significantly associated with increasing temperature and relative humidity in Taiwan. Therefore, these factors could be regarded as warning signals indicating the need to implement preventive measures. PMID- 29109372 TI - Marine Algae as Source of Novel Antileishmanial Drugs: A Review. AB - Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the Leishmania genus and transmitted by the female Phlebotomus and Lutzomyia sand flies. The currently prescribed therapies still rely on pentavalent antimonials, pentamidine, paromomycin, liposomal amphotericin B, and miltefosine. However, their low efficacy, long-course treatment regimen, high toxicity, adverse side effects, induction of parasite resistance and high cost require the need for better drugs given that antileishmanial vaccines may not be available in the near future. Although most drugs are still derived from terrestrial sources, the interest in marine organisms as a potential source of promising novel bioactive natural agents has increased in recent years. About 28,000 compounds of marine origin have been isolated with hundreds of new chemical entities. Recent trends in drug research from natural resources indicated the high interest of aquatic eukaryotic photosynthetic organisms, marine algae in the search for new chemical entities given their broad spectrum and high bioactivities including antileishmanial potential. This current review describes prepared extracts and compounds from marine macroalgae along with their antileishmanial activity and provides prospective insights for antileishmanial drug discovery. PMID- 29109373 TI - Development of a Lethal Intranasal Exposure Model of Ebola Virus in the Cynomolgus Macaque. AB - Ebola virus (EBOV) is a filovirus that can cause Ebola virus disease (EVD). No approved vaccines or therapies exist for filovirus infections, despite an urgent need. The development and testing of effective countermeasures against EBOV requires use of animal models and a thorough understanding of how the model aligns with EVD in humans. The majority of published studies report outcomes of parenteral exposures for emulating needle stick transmission. However, based on data from EVD outbreaks, close contact exposures to infected bodily fluid seems to be one of the primary routes of EBOV transmission. Thus, further work is needed to develop models that represent mucosal exposure. To characterize the outcome of mucosal exposure to EBOV, cynomolgus macaques were exposed to EBOV via intranasal (IN) route using the LMA(r) mucosal atomization device (LMA(r) MAD). For comparison, four non-human primates (NHPs) were exposed to EBOV via intramuscular (IM) route. This IN exposure model was uniformly lethal and correlated with a statistically significant delay in time to death when compared to exposure via the IM route. This more closely reflects the timeframes observed in human infections. An IN model of exposure offers an attractive alternative to other models as it can offer insight into the consequences of exposure via a mucosal surface and allows for screening countermeasures via a different exposure route. PMID- 29109375 TI - Model-Based Localization and Tracking Using Bluetooth Low-Energy Beacons. AB - We introduce a high precision localization and tracking method that makes use of cheap Bluetooth low-energy (BLE) beacons only. We track the position of a moving sensor by integrating highly unreliable and noisy BLE observations streaming from multiple locations. A novel aspect of our approach is the development of an observation model, specifically tailored for received signal strength indicator (RSSI) fingerprints: a combination based on the optimal transport model of Wasserstein distance. The tracking results of the entire system are compared with alternative baseline estimation methods, such as nearest neighboring fingerprints and an artificial neural network. Our results show that highly accurate estimation from noisy Bluetooth data is practically feasible with an observation model based on Wasserstein distance interpolation combined with the sequential Monte Carlo (SMC) method for tracking. PMID- 29109376 TI - Physicochemical and Sensory Characteristics of Spreadable Liver Pates with Annatto Extract (Bixa orellana L.) and Date Palm Co-Products (Phoenix dactylifera L.). AB - Two novel ingredients were incorporated into spreadable liver pates to study their effect on physicochemical and sensory characteristics and their possible use in the meat industry. Fresh date (Phoenix dactylifera, cv. Confitera) co products, as a paste (0, 2.5 and 7.5%), and annatto (Bixa orellana) extract (0 and 128 mg/kg), as a colourant, and their combinations were incorporated into liver pates to study their effect on the final quality. The six formulations were analysed for chemical composition, physicochemical characteristics (pH, aw, colour, emulsion stability, and texture), and sensory properties. Pates tolerated suitable incorporation of date paste, providing emulsifying activity and being able to counteract to some extent the emulsion destabilisation caused by the annatto. All formulations showed an acceptable sensory quality, particularly pates with annatto and 7.5% date paste, which was softer, juicier, and presented redness values similar to the control as well as better emulsion stability. The combined use of these novel ingredients could be used as natural ingredients. PMID- 29109374 TI - Therapeutic Versatility of Resveratrol Derivatives. AB - Resveratrol, a natural phytoalexin, exhibits a remarkable range of biological activities, such as anticancer, cardioprotective, neuroprotective and antioxidant properties. However, the therapeutic application of resveratrol was encumbered for its low bioavailability. Therefore, many researchers focused on designing and synthesizing the derivatives of resveratrol to enhance the bioavailability and the pharmacological activity of resveratrol. During the past decades, a large number of natural and synthetic resveratrol derivatives were extensively studied, and the methoxylated, hydroxylated and halogenated derivatives of resveratrol received particular more attention for their beneficial bioactivity. So, in this review, we will summarize the chemical structure and the therapeutic versatility of resveratrol derivatives, and thus provide the related structure activity relationship reference for their practical applications. PMID- 29109377 TI - Sensitizing Black Adult and Youth Consumers to Targeted Food Marketing Tactics in Their Environments. AB - Food marketing environments of Black American consumers are heavily affected by ethnically-targeted marketing of sugar sweetened beverages, fast foods, and other products that may contribute to caloric overconsumption. This qualitative study assessed Black consumers' responses to targeted marketing. Black adults (2 mixed gender groups; total n = 30) and youth (2 gender specific groups; total n = 35) from two U.S. communities participated before and after a sensitization procedure a critical practice used to understand social justice concerns. Pre-sensitization focus groups elicited responses to scenarios about various targeted marketing tactics. Participants were then given an informational booklet about targeted marketing to Black Americans, and all returned for the second (post sensitization) focus group one week later. Conventional qualitative content analysis of transcripts identified several salient themes: seeing the marketer's perspective ("it's about demand"; "consumers choose"), respect for community ("marketers are setting us up for failure"; "making wrong assumptions"), and food environments as a social justice issue ("no one is watching the door"; "I didn't realize"). Effects of sensitization were reflected in participants' stated reactions to the information in the booklet, and also in the relative occurrence of marketer-oriented themes and social justice-oriented themes, respectively, less and more after sensitization. PMID- 29109378 TI - Evolutionary Conserved Cysteines Function as cis-Acting Regulators of Arabidopsis PIN-FORMED 2 Distribution. AB - Coordination of plant development requires modulation of growth responses that are under control of the phytohormone auxin. PIN-FORMED plasma membrane proteins, involved in intercellular transport of the growth regulator, are key to the transmission of such auxin signals and subject to multilevel surveillance mechanisms, including reversible post-translational modifications. Apart from well-studied PIN protein modifications, namely phosphorylation and ubiquitylation, no further post-translational modifications have been described so far. Here, we focused on root-specific Arabidopsis PIN2 and explored functional implications of two evolutionary conserved cysteines, by a combination of in silico and molecular approaches. PIN2 sequence alignments and modeling predictions indicated that both cysteines are facing the cytoplasm and therefore would be accessible to redox status-controlled modifications. Notably, mutant pin2C-A alleles retained functionality, demonstrated by their ability to almost completely rescue defects of a pin2 null allele, whereas high resolution analysis of pin2C-A localization revealed increased intracellular accumulation, and altered protein distribution within plasma membrane micro-domains. The observed effects of cysteine replacements on root growth and PIN2 localization are consistent with a model in which redox status-dependent cysteine modifications participate in the regulation of PIN2 mobility, thereby fine-tuning polar auxin transport. PMID- 29109379 TI - Development of a Shipboard Remote Control and Telemetry Experimental System for Large-Scale Model's Motions and Loads Measurement in Realistic Sea Waves. AB - Wave-induced motion and load responses are important criteria for ship performance evaluation. Physical experiments have long been an indispensable tool in the predictions of ship's navigation state, speed, motions, accelerations, sectional loads and wave impact pressure. Currently, majority of the experiments are conducted in laboratory tank environment, where the wave environments are different from the realistic sea waves. In this paper, a laboratory tank testing system for ship motions and loads measurement is reviewed and reported first. Then, a novel large-scale model measurement technique is developed based on the laboratory testing foundations to obtain accurate motion and load responses of ships in realistic sea conditions. For this purpose, a suite of advanced remote control and telemetry experimental system was developed in-house to allow for the implementation of large-scale model seakeeping measurement at sea. The experimental system includes a series of technique sensors, e.g., the Global Position System/Inertial Navigation System (GPS/INS) module, course top, optical fiber sensors, strain gauges, pressure sensors and accelerometers. The developed measurement system was tested by field experiments in coastal seas, which indicates that the proposed large-scale model testing scheme is capable and feasible. Meaningful data including ocean environment parameters, ship navigation state, motions and loads were obtained through the sea trial campaign. PMID- 29109382 TI - Determination of Chloride Content in Cementitious Materials: From Fundamental Aspects to Application of Ag/AgCl Chloride Sensors. AB - This paper reports on the advantages and drawbacks of available test methods for the determination of chloride content in cementitious materials in general, and the application of Ag/AgCl chloride sensors in particular. The main factors that affect the reliability of a chloride sensor are presented. The thermodynamic behaviour of silver in the presence or absence of chloride ions is described and kinetic restrictions are addressed. The parameters that can affect the activity of chloride ions in the medium and/or the rate of ion exchange and dissolution/precipitation processes at the sensor's surface are also considered. In this regard, the contribution of morphology and microstructure of the AgCl layer, binding of chloride ions and the compactness of hydration products around the chloride sensor are highlighted. The important parameters for a reliable sensor's response are discussed and the possible causes of inaccuracies are evaluated. PMID- 29109381 TI - Epileptogenic Brain Malformations and Mutations in Tubulin Genes: A Case Report and Review of the Literature. AB - Malformations of the cerebral cortex are an important cause of developmental disabilities and epilepsy. Neurological disorders caused by abnormal neuronal migration have been observed to occur with mutations in tubulin genes. The alpha- and beta-tubulin genes encode cytoskeletal proteins, which play a role in the developing brain. TUBA1A mutations are associated with a wide spectrum of neurological problems, which are characterized by peculiar clinical details and neuroradiologic patterns. This manuscript describes the case of a nine-year-old girl with microcephaly, mild facial dysmorphisms, epileptic seizures, and severe developmental delay, with a de novo heterozygous c.320A>G [p.(His 107 Arg)] mutation in TUBA1A gene, and the clinical aspects and neuroimaging features of "lissencephaly syndrome" are summarized. This case shows that TUBA1A mutations lead to a variety of brain malformations ranging from lissencephaly with perisylvian pachygyria to diffuse posteriorly predominant pachygyria, combined with internal capsule dysgenesis, cerebellar dysplasia, and callosal hypotrophy. This peculiar neuroradiological pattern, in combination with the usually severe clinical presentation, suggests the need for future molecular studies to address the mechanisms of TUBA1A mutation-induced neuropathology. PMID- 29109383 TI - Synthesis and Antitumor Activity of Novel Arylpiperazine Derivatives Containing the Saccharin Moiety. AB - Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145) cancer cell lines for their anticancer activities. The majority of the compounds exhibited excellent selective activity for the tested cancer cells. Compounds 4 and 12 exhibited strong cytotoxic activities against DU145 cells (half maximal inhibitory concentration (IC50) < 2 MUM). The structure-activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data. This work provides a potential lead compound for anticancer agent development focusing on prostate cancer therapy. PMID- 29109384 TI - An Adaptive Transmitting Scheme for Interrupted Sampling Repeater Jamming Suppression. AB - The interrupted sampling repeater jamming (ISRJ) based on a digital radio frequency memory (DRFM) device is a new type of coherent jamming. This kind of jamming usually occurs as main-lobe jamming and has the advantages of low power requirements and easy parameter adjustment, posing a serious threat to the modern radar systems. In order to suppress the ISRJ, this paper proposes an adaptive transmitting scheme based on a phase-coded signal. The scheme firstly performs jamming perception to estimate the jamming parameters, then, on this basis, optimizes the waveform with genetic algorithm. With the optimized waveform, the jamming signal is orthogonal to the target echo, thus it can be easily suppressed with pulse compression. Simulation experiments are performed to verify the effectiveness of the scheme and the results suggest that the peak-to-side-lobe ratio (PSR) and integrated side-lobe level (ISL) of the pulse compression can be improved by about 16 dB and 15 dB, respectively, for the case where the jamming to-signal ratio (JSR) is 13 dB. PMID- 29109380 TI - Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps? AB - Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines. PMID- 29109385 TI - Motion-Blur-Free High-Speed Video Shooting Using a Resonant Mirror. AB - This study proposes a novel concept of actuator-driven frame-by-frame intermittent tracking for motion-blur-free video shooting of fast-moving objects. The camera frame and shutter timings are controlled for motion blur reduction in synchronization with a free-vibration-type actuator vibrating with a large amplitude at hundreds of hertz so that motion blur can be significantly reduced in free-viewpoint high-frame-rate video shooting for fast-moving objects by deriving the maximum performance of the actuator. We develop a prototype of a motion-blur-free video shooting system by implementing our frame-by-frame intermittent tracking algorithm on a high-speed video camera system with a resonant mirror vibrating at 750 Hz. It can capture 1024 * 1024 images of fast moving objects at 750 fps with an exposure time of 0.33 ms without motion blur. Several experimental results for fast-moving objects verify that our proposed method can reduce image degradation from motion blur without decreasing the camera exposure time. PMID- 29109386 TI - Design, Synthesis and Bioactivity Evaluation of Novel beta-carboline 1,3,4 oxadiazole Derivatives. AB - A series of novel beta-carboline 1,3,4-oxadiazole derivatives were designed and synthesized, and the in vitro cytotoxic activity against Sf9 cells and growth inhibitory activity against Spodoptera litura were evaluated. Bioassay results showed that most of these compounds exhibited excellent in vitro cytotoxic activity. Especially, compound 37 displayed the best efficacy in vitro (IC50 = 3.93 MUM), and was five-fold more potent than camptothecin (CPT) (IC50 = 18.95 MUM). Moreover, compounds 5 and 37 could induce cell apoptosis and cell cycle arrest and stimulate Sf-caspase-1 activation in Sf9 cells. In vivo bioassay also demonstrated that compounds 5 and 37 could significantly inhibit larvae growth of S. litura with decreasing the weight of larvae and pupae. Based on these bioassay results, compounds 5 and 37 emerged as lead compounds for the development of potential insect growth inhibitions. PMID- 29109387 TI - Diet Quality and Satisfaction with Life, Family Life, and Food-Related Life across Families: A Cross-Sectional Pilot Study with Mother-Father-Adolescent Triads. AB - Family is a major determinant of children's and adolescents' eating behavior. The objectives of the present study were to assess diet quality, eating habits, satisfaction with life, family life, and food-related life in mother-father adolescent triads, and to identify profiles of families according to family members' diet quality. Questionnaires were administered to a sample of 300 two parent families with one child over the age of 10 in the city of Temuco (Chile), including the Adapted Healthy Eating Index (AHEI), Satisfaction with Life Scale (SWLS), Satisfaction with Food-related Life (SWFoL) scale, Satisfaction with Family Life (SWFaL) scales, and questions relating to their eating habits. Positive relationships were found between the diet quality of the family members, particularly between mothers and adolescents. Three family profiles with different diet qualities were identified: "families with an unhealthy diet" (39.3%), "families in which mothers and adolescents have healthy diets, but the fathers' diets require changes" (14.3%), and "families that require changes in their diet" (46.4%). These findings stress the key role of mothers in determining family diet quality and suggest a positive relationship between diet quality and satisfaction with life. PMID- 29109388 TI - Electrical and Self-Sensing Properties of Ultra-High-Performance Fiber-Reinforced Concrete with Carbon Nanotubes. AB - This study examined the electrical and self-sensing capacities of ultra-high performance fiber-reinforced concrete (UHPFRC) with and without carbon nanotubes (CNTs). For this, the effects of steel fiber content, orientation, and pore water content on the electrical and piezoresistive properties of UHPFRC without CNTs were first evaluated. Then, the effect of CNT content on the self-sensing capacities of UHPFRC under compression and flexure was investigated. Test results indicated that higher steel fiber content, better fiber orientation, and higher amount of pore water led to higher electrical conductivity of UHPFRC. The effects of fiber orientation and drying condition on the electrical conductivity became minor as sufficiently high amount of steel fibers, 3% by volume, was added. Including only steel fibers did not impart UHPFRC with piezoresistive properties. Addition of CNTs substantially improved the electrical conductivity of UHPFRC. Under compression, UHPFRC with a CNT content of 0.3% or greater had a self sensing ability that was activated by the formation of cracks, and better sensing capacity was achieved by including greater amount of CNTs. Furthermore, the pre peak flexural behavior of UHPFRC was precisely simulated with a fractional change in resistivity when 0.3% CNTs were incorporated. The pre-cracking self-sensing capacity of UHPFRC with CNTs was more effective under tensile stress state than under compressive stress state. PMID- 29109389 TI - Overlooked Short Toxin-Like Proteins: A Shortcut to Drug Design. AB - Short stable peptides have huge potential for novel therapies and biosimilars. Cysteine-rich short proteins are characterized by multiple disulfide bridges in a compact structure. Many of these metazoan proteins are processed, folded, and secreted as soluble stable folds. These properties are shared by both marine and terrestrial animal toxins. These stable short proteins are promising sources for new drug development. We developed ClanTox (classifier of animal toxins) to identify toxin-like proteins (TOLIPs) using machine learning models trained on a large-scale proteomic database. Insects proteomes provide a rich source for protein innovations. Therefore, we seek overlooked toxin-like proteins from insects (coined iTOLIPs). Out of 4180 short (<75 amino acids) secreted proteins, 379 were predicted as iTOLIPs with high confidence, with as many as 30% of the genes marked as uncharacterized. Based on bioinformatics, structure modeling, and data-mining methods, we found that the most significant group of predicted iTOLIPs carry antimicrobial activity. Among the top predicted sequences were 120 termicin genes from termites with antifungal properties. Structural variations of insect antimicrobial peptides illustrate the similarity to a short version of the defensin fold with antifungal specificity. We also identified 9 proteins that strongly resemble ion channel inhibitors from scorpion and conus toxins. Furthermore, we assigned functional fold to numerous uncharacterized iTOLIPs. We conclude that a systematic approach for finding iTOLIPs provides a rich source of peptides for drug design and innovative therapeutic discoveries. PMID- 29109390 TI - Promoter Methylation Status of WNT2 in Placenta from Patients with Preeclampsia. AB - BACKGROUND Preeclampsia is a serious multisystem disorder of human gestation, affecting up to 10% of pregnant women worldwide, and results in maternal morbidity and mortality. The aim of this study was to determine the gene expression pattern and methylation status of the promoter of the WNT2 gene in placentas from patients with preeclampsia and to evaluate the potential role of the WNT2 pathway in the pathogenesis of preeclampsia. MATERIAL AND METHODS Real time quantitative polymerase chain reaction (PT-PCR) was used to determine the WNT2 gene expression level. Western blot analysis was used to identify alterations in wnt2 protein expression. RESULTS The mRNA and protein expression levels of the WNT2 gene were reduced in placentas from patients with preeclampsia when compared with placentas from healthy women. The average methylation level of the promoter of the WNT2 gene was elevated in the placentas from patients with preeclampsia compared with the controls placentas from healthy women. CONCLUSIONS The findings of this study have shown that molecular mechanisms, including aberrant activation of the WNT2 gene signaling pathway, may be involved in the pathogenesis of preeclampsia. Promoter hypermethylation and reduced expression of the WNT2 gene requires further study to determine a potential role in the diagnosis and treatment of preeclampsia. PMID- 29109391 TI - Occult Spigelian Hernia Presenting as Inability to Complete Colon Cancer Screening in a Patient with a History of Rectal Cancer. AB - BACKGROUND While it is well known that abdominal wall hernias can pose obstacles for colonoscopy, these may not be obvious in obese patients, particularly when the hernia is in an unusual place. CASE REPORT A 62-year-old man presented with inability to complete colon cancer screening by means of colonoscopy or barium enema. On exam, he was noted to have a Spigelian hernia present in his left lower quadrant abdominal wall. CT colonography identified incarcerated sigmoid colon within the hernia accounting for his inability to complete colonoscopy or barium enema. Repair of his Spigelian hernia was thus performed, allowing for ease of future colorectal cancer screening. CONCLUSIONS Colorectal cancer screening is an evidence-based benchmark for effective primary care, but is often ordered and interpreted like a blood test, without reference to the technical aspects of the procedure. Failure of colonoscopy requires examination of the patient and consideration of why the procedure failed. In particular, patients in whom colonoscopy fails must be carefully evaluated for occult partially obstructing hernias. PMID- 29109392 TI - Silica nanoparticle aggregation in calcite replacement reactions. AB - Natural nanoparticles are fundamental building blocks of Earth's bio- and geosphere. Amorphous silica nanoparticles are ubiquitous in nature, but fundamental knowledge of their interaction mechanisms and role in mineral replacement reactions is limited. Here we show how silica nanoparticles replace Cretaceous calcite bivalve shells in a volume- and texture-preserving process. Electron tomography reveals that mineral replacement transfers calcite crystallographic orientations to twinned photonic crystals composed of face centered cubic silica sphere stacks. During the face-specific replacement process, silica nanoparticles continuously nucleate, aggregate, and form a lattice of uniform spheres parallel to calcite low-energy facets. We explain the replacement process with a new model that unifies recently proposed, probably universal mechanisms of interface-coupled dissolution-precipitation and aggregation-based crystallization; both key mechanisms in geological processes and nanomaterials design and synthesis. PMID- 29109394 TI - Colloidal zinc oxide-copper(I) oxide nanocatalysts for selective aqueous photocatalytic carbon dioxide conversion into methane. AB - Developing catalytic systems with high efficiency and selectivity is a fundamental issue for photochemical carbon dioxide conversion. In particular, rigorous control of the structure and morphology of photocatalysts is decisive for catalytic performance. Here, we report the synthesis of zinc oxide-copper(I) oxide hybrid nanoparticles as colloidal forms bearing copper(I) oxide nanocubes bound to zinc oxide spherical cores. The zinc oxide-copper(I) oxide nanoparticles behave as photocatalysts for the direct conversion of carbon dioxide to methane in an aqueous medium, under ambient pressure and temperature. The catalysts produce methane with an activity of 1080 MUmol gcat-1 h-1, a quantum yield of 1.5% and a selectivity for methane of >99%. The catalytic ability of the zinc oxide-copper(I) oxide hybrid catalyst is attributed to excellent band alignment of the zinc-oxide and copper(I) oxide domains, few surface defects which reduce defect-induced charge recombination and enhance electron transfer to the reagents, and a high-surface area colloidal morphology. PMID- 29109395 TI - Holocene sea ice variability driven by wind and polynya efficiency in the Ross Sea. AB - The causes of the recent increase in Antarctic sea ice extent, characterised by large regional contrasts and decadal variations, remain unclear. In the Ross Sea, where such a sea ice increase is reported, 50% of the sea ice is produced within wind-sustained latent-heat polynyas. Combining information from marine diatom records and sea salt sodium and water isotope ice core records, we here document contrasting patterns in sea ice variations between coastal and open sea areas in Western Ross Sea over the current interglacial period. Since about 3600 years before present, an increase in the efficiency of regional latent-heat polynyas resulted in more coastal sea ice, while sea ice extent decreased overall. These past changes coincide with remarkable optima or minima in the abundances of penguins, silverfish and seal remains, confirming the high sensitivity of marine ecosystems to environmental and especially coastal sea ice conditions. PMID- 29109393 TI - Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. AB - Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1* coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have >=10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with >=10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing. PMID- 29109396 TI - Electricity generation from digitally printed cyanobacteria. AB - Microbial biophotovoltaic cells exploit the ability of cyanobacteria and microalgae to convert light energy into electrical current using water as the source of electrons. Such bioelectrochemical systems have a clear advantage over more conventional microbial fuel cells which require the input of organic carbon for microbial growth. However, innovative approaches are needed to address scale up issues associated with the fabrication of the inorganic (electrodes) and biological (microbe) parts of the biophotovoltaic device. Here we demonstrate the feasibility of using a simple commercial inkjet printer to fabricate a thin-film paper-based biophotovoltaic cell consisting of a layer of cyanobacterial cells on top of a carbon nanotube conducting surface. We show that these printed cyanobacteria are capable of generating a sustained electrical current both in the dark (as a 'solar bio-battery') and in response to light (as a 'bio-solar panel') with potential applications in low-power devices. PMID- 29109397 TI - Planar Hall effect from the surface of topological insulators. AB - A prominent feature of topological insulators (TIs) is the surface states comprising of spin-nondegenerate massless Dirac fermions. Recent technical advances have made it possible to address the surface transport properties of TI thin films by tuning the Fermi levels of both top and bottom surfaces. Here we report our discovery of a novel planar Hall effect (PHE) from the TI surface, which results from a hitherto-unknown resistivity anisotropy induced by an in plane magnetic field. This effect is observed in dual-gated devices of bulk insulating Bi2-x Sb x Te3 thin films, where the field-induced anisotropy presents a strong dependence on the gate voltage with a characteristic two-peak structure near the Dirac point. The origin of PHE is the peculiar time-reversal-breaking effect of an in-plane magnetic field, which anisotropically lifts the protection of surface Dirac fermions from backscattering. The observed PHE provides a useful tool to analyze and manipulate the topological protection of the TI surface. PMID- 29109398 TI - Numerical Investigation of Tunable Plasmonic Tweezers based on Graphene Stripes. AB - We are proposing tunable plasmonic tweezers, consisting two parallel graphene stripes, which can be utilized to effectively trap and sort nanoparticles. We show that by electrostatically tuning the chemical potential of a graphene stripe by about 100 meV (equivalent to DeltaV G ~ 4.4 V), the plasmonic force can be switched efficiently, without a need to switch the laser intensity. This enables high speed and low power switching with a large number of switching cycles. By applying two independent and appropriate gate bias voltages to the stripes, the direction of the plasmonic force can be reversed, which leads to separation of nanoparticles that satisfy the trapping conditions. Numerical simulations show that the potential depths obtained for polystyrene nanoparticles of refractive index n = 1.5717 and radii r >= 50 nm is deeper than -10 k B T , confirming the ability of the proposed system to effectively separate such nanoparticles. This capability holds for smaller nanoparticles with larger refractive indices. Finally, performing thermal simulations, we have demonstrated that the heat induced by the illumination increases the fluid temperature by at most 9 degrees C, having negligible effect on the trapping mechanism. The proposed system opens up new possibilities in developing tunable on-chip manipulation devices, suitable for biological applications. PMID- 29109399 TI - Competition between crystal and fibril formation in molecular mutations of amyloidogenic peptides. AB - Amyloidogenic model peptides are invaluable for investigating assembly mechanisms in disease related amyloids and in protein folding. During aggregation, such peptides can undergo bifurcation leading to fibrils or crystals, however the mechanisms of fibril-to-crystal conversion are unclear. We navigate herein the energy landscape of amyloidogenic peptides by studying a homologous series of hexapeptides found in animal, human and disease related proteins. We observe fibril-to-crystal conversion occurring within single aggregates via untwisting of twisted ribbon fibrils possessing saddle-like curvature and cross-sectional aspect ratios approaching unity. Changing sequence, pH or concentration shifts the growth towards larger aspect ratio species assembling into stable helical ribbons possessing mean-curvature. By comparing atomistic calculations of desolvation energies for association of peptides we parameterise a kinetic model, providing a physical explanation of fibril-to-crystal interconversion. These results shed light on the self-assembly of amyloidogenic peptides, suggesting amyloid crystals, not fibrils, represent the ground state of the protein folding energy landscape. PMID- 29109400 TI - Ullmann Coupling Reactions on Ag(111) and Ag(110); Substrate Influence on the Formation of Covalently Coupled Products and Intermediate Metal-Organic Structures. AB - On-surface reactions based on Ullmann coupling are known to proceed on coinage metal substrates (e.g. Au, Ag, Cu), with the chemistry of the surface strongly influencing the reaction progression. In addition, the topography of the surface may be expected to affect the local adsorption geometry of the reactants as well as the intermediate and final structures. Here, we investigate the effect of two different surface facets of silver, Ag(111) and Ag(110) on the formation of organometallic and covalent structures for Ullmann-type coupling reactions. Deposition of 4,4"-diiodo-m-terphenyl molecules onto either Ag(111) or Ag(110) surfaces leads to the scission of C-I bonds followed by the formation of organometallic zigzag structures, consisting of molecules connected by coordination bonds to Ag adatoms. The covalently coupled product is formed by annealing each surface, leading to the removal of Ag atoms and the formation of covalently bonded zigzag poly(m-phenylene) structures. Comparisons of the adsorption model of molecules on each surface before and after annealing reveal that on Ag(111), structures rearrange by rotation and elongation of bonds in order to become commensurate with the surface, whereas for the Ag(110) surface, the similarity in adsorption geometry of the intermediate and final states means that no rotation is required. PMID- 29109401 TI - Smad3 initiates oxidative stress and proteolysis that underlies diaphragm dysfunction during mechanical ventilation. AB - Prolonged use of mechanical ventilation (MV) leads to atrophy and dysfunction of the major inspiratory muscle, the diaphragm, contributing to ventilator dependence. Numerous studies have shown that proteolysis and oxidative stress are among the major effectors of ventilator-induced diaphragm muscle dysfunction (VIDD), but the upstream initiator(s) of this process remain to be elucidated. We report here that periodic diaphragm contraction via phrenic nerve stimulation (PNS) substantially reduces MV-induced proteolytic activity and oxidative stress in the diaphragm. We show that MV rapidly induces phosphorylation of Smad3, and PNS nearly completely prevents this effect. In cultured cells, overexpressed Smad3 is sufficient to induce oxidative stress and protein degradation, whereas inhibition of Smad3 activity suppresses these events. In rats subjected to MV, inhibition of Smad3 activity by SIS3 suppresses oxidative stress and protein degradation in the diaphragm and prevents the reduction in contractility that is induced by MV. Smad3's effect appears to link to STAT3 activity, which we previously identified as a regulator of VIDD. Inhibition of Smad3 suppresses STAT3 signaling both in vitro and in vivo. Thus, MV-induced diaphragm inactivity initiates catabolic changes via rapid activation of Smad3 signaling. An early intervention with PNS and/or pharmaceutical inhibition of Smad3 may prevent clinical VIDD. PMID- 29109402 TI - Machine learning model for sequence-driven DNA G-quadruplex formation. AB - We describe a sequence-based computational model to predict DNA G-quadruplex (G4) formation. The model was developed using large-scale machine learning from an extensive experimental G4-formation dataset, recently obtained for the human genome via G4-seq methodology. Our model differentiates many widely accepted putative quadruplex sequences that do not actually form stable genomic G4 structures, correctly assessing the G4 folding potential of over 700,000 such sequences in the human genome. Moreover, our approach reveals the relative importance of sequence-based features coming from both within the G4 motifs and their flanking regions. The developed model can be applied to any DNA sequence or genome to characterise sequence-driven intramolecular G4 formation propensities. PMID- 29109403 TI - Identification of unusual peptides with new Cys frameworks in the venom of the cold-water sea anemone Cnidopus japonicus. AB - Sea anemones (Actiniaria) are intensely popular objects of study in venomics. Order Actiniaria includes more than 1,000 species, thus presenting almost unlimited opportunities for the discovery of novel biologically active molecules. The venoms of cold-water sea anemones are studied far less than the venoms of tropical sea anemones. In this work, we analysed the molecular venom composition of the cold-water sea anemone Cnidopus japonicus. Two sets of NGS data from two species revealed molecules belonging to a variety of structural classes, including neurotoxins, toxin-like molecules, linear polypeptides (Cys-free), enzymes, and cytolytics. High-throughput proteomic analyses identified 27 compounds that were present in the venoms. Some of the toxin-like polypeptides exhibited novel Cys frameworks. To characterise their function in the venom, we heterologously expressed 3 polypeptides with unusual Cys frameworks (designated CjTL7, CjTL8, and AnmTx Cj 1c-1) in E. coli. Toxicity tests revealed that the CjTL8 polypeptide displays strong crustacean-specific toxicity, while AnmTx Cj 1c 1 is toxic to both crustaceans and insects. Thus, an improved NGS data analysis algorithm assisted in the identification of toxins with unusual Cys frameworks showing no homology according to BLAST. Our study shows the advantage of combining omics analysis with functional tests for active polypeptide discovery. PMID- 29109404 TI - Neural basis of forward flight control and landing in honeybees. AB - The impressive repertoire of honeybee visually guided behaviors, and their ability to learn has made them an important tool for elucidating the visual basis of behavior. Like other insects, bees perform optomotor course correction to optic flow, a response that is dependent on the spatial structure of the visual environment. However, bees can also distinguish the speed of image motion during forward flight and landing, as well as estimate flight distances (odometry), irrespective of the visual scene. The neural pathways underlying these abilities are unknown. Here we report on a cluster of descending neurons (DNIIIs) that are shown to have the directional tuning properties necessary for detecting image motion during forward flight and landing on vertical surfaces. They have stable firing rates during prolonged periods of stimulation and respond to a wide range of image speeds, making them suitable to detect image flow during flight behaviors. While their responses are not strictly speed tuned, the shape and amplitudes of their speed tuning functions are resistant to large changes in spatial frequency. These cells are prime candidates not only for the control of flight speed and landing, but also the basis of a neural 'front end' of the honeybee's visual odometer. PMID- 29109405 TI - Application of Cre-lox gene switch to limit the Cry expression in rice green tissues. AB - The presence of genetically modified (GM) protein in the endosperm is important information for the public when considering the biological safety of transgenic rice. To limit the expression of GM proteins to rice green tissues, we developed a modified Cre-lox gene switch using two cassettes named KEY and LOCK. KEY contains a nuclear-localized Cre recombinase driven by the green-tissue-specific promoter rbcS. LOCK contains a Nos terminator (NosT), which is used to block the expression of the gene of interest (GOI), bounded by two loxP sites. When KEY and LOCK are pyramided into hybrid rice, a complete gene switch system is formed. The Cre recombinase from KEY excises loxP-NosT in LOCK and unlocks the GOI in green tissues but keeps it locked in the endosperm. This regulatory effect was demonstrated by eYFP and Bt expression assays. The presence of eYFP and Cre were confirmed in the leaf, sheath, stem, and glume but not in the root, anther or seed of the gene-switch-controlled eYFP hybrids. Meanwhile, gene switch controlled Bt hybrid rice not only confined the expression of Bt protein to the green tissues but also showed high resistance to striped stem borers and leaffolders. PMID- 29109406 TI - New microbial resource: microbial diversity, function and dynamics in Chinese liquor starter. AB - Traditional Chinese liquor (Baijiu) solid state fermentation technology has lasted for several thousand years. The microbial communities that enrich in liquor starter are important for fermentation. However, the microbial communities are still under-characterized. In this study, 454 pyrosequencing technology was applied to comprehensively analyze the microbial diversity, function and dynamics of two most-consumed liquor starters (Jiang- and Nong-flavor) during production. In total, 315 and 83 bacterial genera and 72 and 47 fungal genera were identified in Jiang- and Nong-flavor liquor starter, respectively. The relatively high diversity was observed when the temperature increased to 70 and 62 degrees C for Jiang- and Nong-flavor liquor starter, respectively. Some thermophilic fungi have already been isolated. Microbial communities that might contribute to ethanol fermentation, saccharification and flavor development were identified and shown to be core communities in correlation-based network analysis. The predictively functional profile of bacterial communities showed significant difference in energy, carbohydrate and amino acid metabolism and the degradation of aromatic compounds between the two kinds of liquor starters. Here we report these liquor starters as a new functionally microbial resource, which can be used for discovering thermophilic and aerobic enzymes and for food and feed preservation. PMID- 29109407 TI - Paper-Based Sensing Device for Electrochemical Detection of Oxidative Stress Biomarker 8-Hydroxy-2'-deoxyguanosine (8-OHdG) in Point-of-Care. AB - This work presents a cost-effective, label-free in point-of-care (POC) biosensor for the sensitive detection of 8-hydroxy-2'-deoxyguanosine (8-OHdG), the most abundant oxidative product of DNA, that may allow a premature assessment of cancer disease, thereby improving diagnosis, prognostics and survival rates. The device targets the direct detection of 8-OHdG by using for the first time a carbon-ink 3-electrode on a paper substrate coupled to Differential Pulse Voltammetry readings. This design was optimized by adding nanostructured carbon materials to the ink and the conducting polymer PEDOT, enhancing the electrocatalytic properties of the sensor towards 8-OHdG detection. Meanwhile, the ability of this oxidative stress biomarker to undertake an oxidation reaction enabled the development of the sensing electrochemical device without the need of chemical probes and long incubation periods. This paper-modified sensor presented high electrochemical performance on the oxidation of 8-OHdG with a wide linear range (50-1000 ng/ml) and a low detection limit (14.4 ng/ml). Thus, our results showed the development of a direct and facile sensor with good reproducibility, stability, sensitivity and more importantly, selectivity. The proposed carbon based electrochemical sensor is a potential candidate to be miniaturized to small portable size, which make it applicable for in-situ 8-OHdG sensing in real biological samples. PMID- 29109408 TI - Small infrarenal aortic diameter associated with lower-extremity peripheral artery disease in Chinese hypertensive adults. AB - Several studies suggest that infrarenal aortic diameter is associated with lower extremity peripheral artery disease (LE-PAD). However, data regarding the associations between infrarenal aortic diameter and LE-PAD are limited, especially in large sample populations and Asian or Chinese populations. Our analysis included 17279 Chinese hypertensive adults comprising 6590 men and 10689 women with a mean age of 64.74 +/- 7.41 years. Participants were selected from 22693 candidates from two large population-based cohort-studies. The primary noninvasive test for diagnosis of LE-PAD is the ankle-brachial index (ABI) at rest and typically an ABI <= 0.90 is used to define LE-PAD. The prevalence of LE PAD was found to significantly decrease as the aortic diameter increased according to the tertile of the aortic diameter. LE-PAD was significantly more prevalent in the lowest tertile (OR = 1.58, 95% CI = 1.29-1.94, p < 0.001) and similarly prevalent in the highest tertile (OR = 0.92, 95% CI = 0.73-1.16, p = 0.49) when compared with the median tertile. No significant interactions between the aortic diameter and any of the stratified variables were found (all p > 0.05). In conclusion, Small aortic diameter (as opposed to large aortic diameter) is significantly associated with LE-PAD in Chinese hypertensive adults. PMID- 29109409 TI - Candidate proteins from predegenerated nerve exert time-specific protection of retinal ganglion cells in glaucoma. AB - Glaucoma is thought to be the main cause of severe visual impairment or permanent loss of vision. Current therapeutic strategies are not sufficient to protect against glaucoma. Thus, new therapies and potential novel therapeutic targets must be developed to achieve progress in the treatment of this insidious disease. This study was undertaken to verify whether the time of administration of an extract from predegenerated rat sciatic nerves as well as exposure time of this extract onto retinal ganglion cells (RGCs) influences the survival of RGCs in a rat glaucoma model. We have demonstrated that extract obtained from the predegenerated sciatic nerves protects RGCs in a rat glaucoma model. The neuroprotective effect depends mostly on the time of administration of the extract and less clearly on the time of exposure to the extract and is associated with stimulation of endogenous BDNF expression both in RGCs and glial cells. The 14th day following glaucoma induction represents a therapeutic window for effective treatment in a glaucoma model. Mass Spectrometry analysis demonstrated that metallothionein 2 (MT2) may be a key molecule responsible for neuroprotective effects on RGC survival. PMID- 29109410 TI - Changes in the soil bacterial community along a pedogenic gradient. AB - Current research on the influence of environmental and physicochemical factors in shaping the soil bacterial structure has seldom been approached from a pedological perspective. We studied the bacterial communities of eight soils selected along a pedogenic gradient at the local scale in a Mediterranean calcareous mountain (Sierra de Maria, SE Spain). The results showed that the relative abundance of Acidobacteria, Canditate division WPS-1, and Armatimonadetes decreased whereas that of Actinobacteria, Bacteroidetes, and Proteobacteria increased from the less-developed soils (Leptosol) to more developed soils (Luvisol). This bacterial distribution pattern was also positively correlated with soil-quality parameters such as organic C, water stable aggregates, porosity, moisture, and acidity. In addition, at a lower taxonomic level, the abundance of Acidobacteria Gp4, Armatimonadetes_gp4, Solirubrobacter, Microvirga, Terrimonas, and Nocardioides paralleled soil development and quality. Therefore, our work indicates that the composition of bacterial populations changes with pedogenesis, which could be considered a factor influencing the communities according to the environmental and physicochemical conditions during the soil formation. PMID- 29109412 TI - Mutation accumulation under UV radiation in Escherichia coli. AB - Mutations are induced by not only intrinsic factors such as inherent molecular errors but also by extrinsic mutagenic factors such as UV radiation. Therefore, identifying the mutational properties for both factors is necessary to achieve a comprehensive understanding of evolutionary processes both in nature and in artificial situations. Although there have been extensive studies on intrinsic factors, the mutational profiles of extrinsic factors are poorly understood on a genomic scale. Here, we explored the mutation profiles of UV radiation, a ubiquitous mutagen, in Escherichia coli on the genomic scale. We performed an evolution experiment under periodic UV radiation for 28 days. The accumulation speed of the mutations was found to increase so that it exceeded that of a typical mutator strain with deficient mismatch repair processes. The huge contribution of the extrinsic factors to all mutations consequently increased the risk of the destruction of inherent error correction systems. The spectrum of the UV-induced mutations was broader than that of the spontaneous mutations in the mutator. The broad spectrum and high upper limit of the frequency of occurrence suggested ubiquitous roles for UV radiation in accelerating the evolutionary process. PMID- 29109413 TI - Plasticity in leader-follower roles in human teams. AB - In humans, emergence of leaders and followers is key to group performance, but little is known about the whys and hows of leadership. A particularly elusive question entails behavioral plasticity in leadership across social contexts. Addressing this question requires to eliminate social feedback between focal individuals and their partners in experiments that could illuminate the spontaneous emergence of social roles. We investigated plasticity in leader follower roles in cooperation, where members choose the task toward a shared goal, and coordination, where members adjust their actions in real time based on social responsiveness. Through a computer-programmed virtual partner, we demonstrate adaptive plasticity in leader-follower roles. Humans increased their followership to cooperate when the partner led more in the choice of the task, whereas they showed only weak leadership when the partner followed more. We leveraged the information-theoretic notion of transfer entropy to quantify leadership and followership in coordination from their movements. When exhibiting stronger followership in task cooperation, humans coordinated more with the partner's movement, with greater information being transferred from the partner to humans. The evidence of behavioral plasticity suggests that humans are capable of adapting their leader-follower roles to their social environments, in both cooperation and coordination. PMID- 29109411 TI - Structural basis for receptor recognition of pollen tube attraction peptides. AB - Transportation of the immobile sperms directed by pollen tubes to the ovule enclosed female gametophytes is important for plant sexual reproduction. The defensin-like (DEFL) cysteine-rich peptides (CRPs) LUREs play an essential role in pollen tube attraction to the ovule, though their receptors still remain controversial. Here we provide several lines of biochemical evidence showing that the extracellular domain of the leucine-rich repeat receptor kinase (LRR-RK) PRK6 from Arabidopsis thaliana directly interacts with AtLURE1 peptides. Structural study reveals that a C-terminal loop of the LRR domain (AtPRK6LRR) is responsible for recognition of AtLURE1.2, mediated by a set of residues largely conserved among PRK6 homologs from Arabidopsis lyrata and Capsella rubella, supported by in vitro mutagenesis and semi-in-vivo pollen tube growth assays. Our study provides evidence showing that PRK6 functions as a receptor of the LURE peptides in A. thaliana and reveals a unique ligand recognition mechanism of LRR-RKs. PMID- 29109414 TI - Involvement of autophagy in the outcome of mitotic catastrophe. AB - Evading cell death is a major driving force for tumor progression that is one of the main problems in current cancer research. Mitotic catastrophe (MC) represents attractive platform compromising tumor resistance to current therapeutic modalities. MC appeared as onco-suppressive mechanism and is defined as a stage driving the cell to an irreversible destiny, i.e. cell death via apoptosis or necrosis. Our study highlights that MC induction in colorectal carcinoma cell lines ultimately leads to the autophagy followed by apoptosis. We show that autophagy suppression in Atg 13 knockout non-small cell lung carcinoma cells lead to the dramatic decrease of MC rate. Furthermore, mitochondria-linked anti apoptotic proteins Mcl-1 and Bcl-xL play a crucial role in the duration of MC and a cross-talk between autophagy and apoptosis. Thus, the suppression of apoptosis by overexpression of Mcl-1 or Bcl-xL affected MC and lead to a significant induction of autophagy in HCT116 wt and HCT116 14-3-3sigma-/- cells. Our data demonstrate that MC induction is a critical stage, in which a cell decides how to die, while mitochondria are responsible for the maintaining the balance between MC - autophagy - apoptosis. PMID- 29109415 TI - The Correlation of Pirani and Dimeglio Scoring Systems for Ponseti Management at Different Levels of Deformity Severity. AB - The Pirani and Dimeglio scoring systems both have excellent inter-observer and intra-observer reliability, but no research has been conducted to determine their inter-observer reliability and their relationship at different levels of deformity. A total of 173 idiopathic clubfoot cases were reviewed using Pirani and Dimeglio scoring systems, and the number of casts needed was also recorded. For clubfeet with a cast number equal to 2 or 7 and 8, the inter-observer reliability of the two scoring systems was poor or moderate, and there was no correlation between the two scoring systems. There was also no correlation between the Dimeglio scoring score with the number of casts for grade II or IV clubfeet. A binary regression of the number of casts on initial Pirani or Dimeglio scores showed that there was a Quadratic or Cubic relation between the scores and the cast numbers. In conclusion, in the case of mild and very severe clubfoot deformity, the interobserver reliability and its ability to predict the number of casts needed for clubfoot deformity correction was poor. A more objective evaluation system may be required. PMID- 29109416 TI - Mixed-quantum-dot solar cells. AB - Colloidal quantum dots are emerging solution-processed materials for large-scale and low-cost photovoltaics. The recent advent of quantum dot inks has overcome the prior need for solid-state exchanges that previously added cost, complexity, and morphological disruption to the quantum dot solid. Unfortunately, these inks remain limited by the photocarrier diffusion length. Here we devise a strategy based on n- and p-type ligands that judiciously shifts the quantum dot band alignment. It leads to ink-based materials that retain the independent surface functionalization of quantum dots, and it creates distinguishable donor and acceptor domains for bulk heterojunctions. Interdot carrier transfer and exciton dissociation studies confirm efficient charge separation at the nanoscale interfaces between the two classes of quantum dots. We fabricate the first mixed quantum-dot solar cells and achieve a power conversion of 10.4%, which surpasses the performance of previously reported bulk heterojunction quantum dot devices fully two-fold, indicating the potential of the mixed-quantum-dot approach. PMID- 29109417 TI - The comprehensive expression analysis of circular RNAs in gastric cancer and its association with field cancerization. AB - Circular RNAs comprise a new class of long noncoding RNAs characterized by their 5' and 3' ends covalently joined. Previous studies have demonstrated that some circular RNAs act as microRNA sponges, and are associated with cellular proliferation in cancer. We were the first to analyze the global expression of circular RNAs in samples of patients without gastric cancer, gastric cancer, and matched tumor-adjacent gastric tissue. Among the samples, we identified 736 previously annotated circular RNAs by RNA-Seq. The tumor-adjacent tissue presented the higher abundance of circular RNAs and could not be considered as a normal tissue, reinforcing the notion of field effect in gastric cancer. We identified five differentially expressed circular RNAs that may be potential biomarkers of this type of cancer. We also predicted candidate microRNAs targets of the highest expressed circular RNAs in gastric tissues and found five miRNAs. Overall, our results support the hypothesis of circular RNAs representing a novel factor in the dynamic epigenetic network of gene regulation, which involves the microRNAs, its mRNAs targets, and the circular RNAs-derived genes. Further studies are needed to elucidate the roles and the functional relevance of the circular RNAs in human diseases. PMID- 29109418 TI - Extremely low frequency pulsed electromagnetic fields cause antioxidative defense mechanisms in human osteoblasts via induction of *O2- and H2O2. AB - Recently, we identified a specific extremely low-frequency pulsed electromagnetic field (ELF-PEMF) that supports human osteoblast (hOBs) function in an ERK1/2 dependent manner, suggesting reactive oxygen species (ROS) being key regulators in this process. Thus, this study aimed at investigating how ELF-PEMF exposure can modulate hOBs function via ROS. Our results show that single exposure to ELF PEMF induced ROS production in hOBs, without reducing intracellular glutathione. Repetitive exposure (>3) to ELF-PEMF however reduced ROS-levels, suggesting alterations in the cells antioxidative stress response. The main ROS induced by ELF-PEMF were *O2- and H2O2, therefore expression/activity of antioxidative enzymes related to these ROS were further investigated. ELF-PEMF exposure induced expression of GPX3, SOD2, CAT and GSR on mRNA, protein and enzyme activity level. Scavenging *O2- and H2O2 diminished the ELF-PEMF effect on hOBs function (AP activity and mineralization). Challenging the hOBs with low amounts of H2O2 on the other hand improved hOBs function. In summary, our data show that ELF-PEMF treatment favors differentiation of hOBs by producing non-toxic amounts of ROS, which induces antioxidative defense mechanisms in these cells. Thus, ELF-PEMF treatment might represent an interesting adjunct to conventional therapy supporting bone formation under oxidative stress conditions, e.g. during fracture healing. PMID- 29109419 TI - Metal Solidification Imaging Process by Magnetic Induction Tomography. AB - There are growing number of important applications that require a contactless method for monitoring an object surrounded inside a metallic enclosure. Imaging metal solidification is a great example for which there is no real time monitoring technique at present. This paper introduces a technique - magnetic induction tomography - for the real time in-situ imaging of the metal solidification process. Rigorous experimental verifications are presented. Firstly, a single inductive coil is placed on the top of a melting wood alloy to examine the changes of its inductance during solidification process. Secondly, an array of magnetic induction coils are designed to investigate the feasibility of a tomographic approach, i.e., when one coil is driven by an alternating current as a transmitter and a vector of phase changes are measured from the remaining of the coils as receivers. Phase changes are observed when the wood alloy state changes from liquid to solid. Thirdly, a series of static cold phantoms are created to represent various liquid/solid interfaces to verify the system performance. Finally, a powerful temporal reconstruction method is applied to realise real time in-situ visualisation of the solidification and the measurement of solidified shell thickness, a first report of its kind. PMID- 29109420 TI - Passage-dependent accumulation of somatic mutations in mesenchymal stromal cells during in vitro culture revealed by whole genome sequencing. AB - Human mesenchymal stromal cells (MSCs) have served as a major cellular resource for cell-based immunomodulatory and regenerative therapies. However, genomic instability may accumulate during ex vivo expansion of MSCs, thereby increasing the potential of malignant transformation. Here, we performed whole genome sequencing of two peripheral blood-derived MSC lines (MSC1 and MSC2) at various passages (passage 1 [P1] to P9). The majority of single-nucleotide variations (SNVs) occurred in later passages; specifically, 90% and 70% of all SNVs in MSC1 and MSC2 were observed in P9 and P7/P9, respectively. These late-occurring SNVs were enriched with C > A transversions and were overrepresented in intronic regions compared to intergenic regions, suggesting that the mutational forces are not constant across the passages. Clonality analyses also distinguished early occurring, subclonal SNVs from late-occurring, clonally fixed SNVs. In addition, MSCs were largely devoid of copy number alterations (CNAs) (i.e., 0-2 CNAs per passage), with one exception (MSC2-P3) harboring 29 passage-specific CNAs. Our findings suggest that the SNVs found to be abundant at later passages likely resulted from the accumulation of replication stress, which can be associated with proliferation activity. Thus, the genomic instability associated with proliferation records should be considered for clinical applications of MSCs. PMID- 29109421 TI - High-level heterologous production and Functional Secretion by recombinant Pichia pastoris of the shortest proline-rich antibacterial honeybee peptide Apidaecin. AB - Drug resistance is a major problem in antibacterial chemotherapy. Apidaecins, which refer to a series of small, proline-rich antimicrobial peptides, are predominantly active against many drug-resistant bacteria. The apidaecins have special antibacterial mechanisms, and are non-toxic for human cells, a prerequisite for using them as novel antibiotic drugs. However, no efficient non tagged apidaecin expression system has been reported, which is the limiting factor for their application. Here we successfully generated a Pichia pastoris transformant expressing and secreting apidaecin. However, expression was unstable and poor. Analysis of this revealed that the integration plasmid was frequently lost and that apidaecin expression resulted in cell death. Using N-methyl-N-nitro N-nitroso-guanidine mutagenesis and selection, a mutant strain Apmu4 was derived, in which the rate of loss of the integration plasmid was much lower after induction, and which produced improved titres of apidaecin. Additionally, we discovered that using glucose as the sole carbon source to pre-culture the strain before induction could greatly enhance apidaecin production. A pilot-scale 10 L fermentation yielded 418 mg/L of recombinant apidaecin, which represents the highest reported yield of apidaecin. Consequently, this study reports the first super heterologous expression and secretion of apidaecin in yeast. PMID- 29109422 TI - Periodic squeezing in a polariton Josephson junction. AB - The use of a Kerr nonlinearity to generate squeezed light is a well-known way to surpass the quantum noise limit along a given field quadrature. Nevertheless, in the most common regime of weak nonlinearity, a single Kerr resonator is unable to provide the proper interrelation between the field amplitude and squeezing required to induce a sizable deviation from Poissonian statistics. We demonstrate experimentally that weakly coupled bosonic modes allow exploration of the interplay between squeezing and displacement, which can give rise to strong deviations from the Poissonian statistics. In particular, we report on the periodic bunching in a Josephson junction formed by two coupled exciton-polariton modes. Quantum modeling traces the bunching back to the presence of quadrature squeezing. Our results, linking the light statistics to squeezing, are a precursor to the study of nonclassical features in semiconductor microcavities and other weakly nonlinear bosonic systems. PMID- 29109423 TI - Transcriptomic profiling in human mesangial cells using patient-derived lupus autoantibodies identified miR-10a as a potential regulator of IL8. AB - Autoantibody-mediated inflammation directed at resident kidney cells mediates lupus nephritis (LN) pathogenesis. This study investigated the role of miRNA in human mesangial cells (HMCs) stimulated with auto anti-dsDNA immunoglobulin (Ig)G antibodies. HMCs were treated with antibodies purified from active LN patients or non-specific IgG controls in the presence of normal serum. Aberrant miRNA was screened using high throughput sequencing. Anti-dsDNA IgG up-regulated 103 miRNAs and down-regulated 30 miRNAs. The miRNAs regulated genes in the cell cycle, catabolic processes, regulation of transcription and apoptosis signalling. miR 10a was highly abundant in HMCs but was specifically downregulated upon anti dsDNA IgG induction. Interestingly, the expression of miR-10a in kidney biopsies from class III and IV LN patients (n = 26) was downregulated compared with cadaveric donor kidneys (n = 6). Functional studies highlighted the downstream regulator of miR-10a in the chemokine signalling and cell proliferation or apoptosis pathways. Luciferase assay confirmed for the first time that IL8 was a direct target of miR-10a in HMCs. In conclusion, anti-dsDNA IgG Ab down-regulated miR-10a expression in HMCs resulting in the induction of various target genes involved in HMC proliferation and chemokine expression. PMID- 29109425 TI - Landscape-scale conservation design across biotic realms: sequential integration of aquatic and terrestrial landscapes. AB - Systematic conservation planning has been used extensively throughout the world to identify important areas for maintaining biodiversity and functional ecosystems, and is well suited to address large-scale biodiversity conservation challenges of the twenty-first century. Systematic planning is necessary to bridge implementation, scale, and data gaps in a collaborative effort that recognizes competing land uses. Here, we developed a conservation planning process to identify and unify conservation priorities around the central and southern Appalachian Mountains as part of the Appalachian Landscape Conservation Cooperative (App LCC). Through a participatory framework and sequential, cross realm integration in spatial optimization modeling we highlight lands and waters that together achieve joint conservation goals from LCC partners for the least cost. This process was driven by a synthesis of 26 multi-scaled conservation targets and optimized for simultaneous representation inside the program Marxan to account for roughly 25% of the LCC geography. We identify five conservation design elements covering critical ecological processes and patterns including interconnected regions as well as the broad landscapes between them. Elements were then subjected to a cumulative threats index for possible prioritization. The evaluation of these elements supports multi-scaled decision making within the LCC planning community through a participatory, dynamic, and iterative process. PMID- 29109424 TI - Enhancing reading performance through action video games: the role of visual attention span. AB - Recent studies reported that Action Video Game-AVG training improves not only certain attentional components, but also reading fluency in children with dyslexia. We aimed to investigate the shared attentional components of AVG playing and reading, by studying whether the Visual Attention (VA) span, a component of visual attention that has previously been linked to both reading development and dyslexia, is improved in frequent players of AVGs. Thirty-six French fluent adult readers, matched on chronological age and text reading proficiency, composed two groups: frequent AVG players and non-players. Participants performed behavioural tasks measuring the VA span, and a challenging reading task (reading of briefly presented pseudo-words). AVG players performed better on both tasks and performance on these tasks was correlated. These results further support the transfer of the attentional benefits of playing AVGs to reading, and indicate that the VA span could be a core component mediating this transfer. The correlation between VA span and pseudo-word reading also supports the involvement of VA span even in adult reading. Future studies could combine VA span training with defining features of AVGs, in order to build a new generation of remediation software. PMID- 29109426 TI - Fault-tolerant interface between quantum memories and quantum processors. AB - Topological error correction codes are promising candidates to protect quantum computations from the deteriorating effects of noise. While some codes provide high noise thresholds suitable for robust quantum memories, others allow straightforward gate implementation needed for data processing. To exploit the particular advantages of different topological codes for fault-tolerant quantum computation, it is necessary to be able to switch between them. Here we propose a practical solution, subsystem lattice surgery, which requires only two-body nearest-neighbor interactions in a fixed layout in addition to the indispensable error correction. This method can be used for the fault-tolerant transfer of quantum information between arbitrary topological subsystem codes in two dimensions and beyond. In particular, it can be employed to create a simple interface, a quantum bus, between noise resilient surface code memories and flexible color code processors. PMID- 29109427 TI - The Dependence of CNT Aerogel Synthesis on Sulfur-driven Catalyst Nucleation Processes and a Critical Catalyst Particle Mass Concentration. AB - The floating catalyst chemical vapor deposition (FC-CVD) process permits macro scale assembly of nanoscale materials, enabling continuous production of carbon nanotube (CNT) aerogels. Despite the intensive research in the field, fundamental uncertainties remain regarding how catalyst particle dynamics within the system influence the CNT aerogel formation, thus limiting effective scale-up. While aerogel formation in FC-CVD reactors requires a catalyst (typically iron, Fe) and a promotor (typically sulfur, S), their synergistic roles are not fully understood. This paper presents a paradigm shift in the understanding of the role of S in the process with new experimental studies identifying that S lowers the nucleation barrier of the catalyst nanoparticles. Furthermore, CNT aerogel formation requires a critical threshold of FexCy > 160 mg/m3, but is surprisingly independent of the initial catalyst diameter or number concentration. The robustness of the critical catalyst mass concentration principle is proved further by producing CNTs using alternative catalyst systems; Fe nanoparticles from a plasma spark generator and cobaltocene and nickelocene precursors. This finding provides evidence that low-cost and high throughput CNT aerogel routes may be achieved by decoupled and enhanced catalyst production and control, opening up new possibilities for large-scale CNT synthesis. PMID- 29109428 TI - Serial-omics of P53-/-, Brca1-/- Mouse Breast Tumor and Normal Mammary Gland. AB - This study demonstrates a liquid-liquid extraction for the sequential tandem mass spectrometry (LC-MS/MS) analysis of non-polar lipids, polar metabolites, proteins and phosphorylation sites from a single piece of tissue. Extraction of 10 mg BRCA /-, p53-/- breast tumor tissue or normal mammary gland tissue with methyl-tert butyl ether (MTBE) results in three phases: an upper non-polar phase containing 1,382 lipids, a lower polar phase with 805 metabolites and a precipitated protein pellet with 4,792 proteins with 1,072 phosphorylation sites. Comparative analysis revealed an activated AKT-mTOR pathway in tumors. Tumors also showed a reduction of phosphorylation sites involved in transcription and RNA splicing and decreased abundance of enzymes in lipid synthesis. Analysis of polar metabolites revealed a reduction in glycolysis, pentose phosphate pathway, polyamines and nucleotides, but an increase in TCA and urea cycle intermediates. Analysis of lipids revealed a shift from high triglycerides in mammary gland to high phospholipid levels in tumors. The data were integrated into a model showing breast tumors exhibit features on the proteomic, lipidomic and metabolomic level that are distinct from normal breast tissue. Our integrative technique lends itself to samples such as tumor biopsies, dried blood spots and fluids including urine and CSF to develop biomarkers of disease. PMID- 29109429 TI - Knockdown of amyloid precursor protein increases calcium levels in the endoplasmic reticulum. AB - Familial Alzheimer's disease (AD) is caused by mutations in the genes that encode amyloid precursor protein (APP) and presenilins. Disturbances in calcium homeostasis have been observed in various cellular and animal models of AD and are proposed to underlie the pathogenesis of the disease. Furthermore, wildtype presenilins were shown to regulate endoplasmic reticulum (ER) calcium homeostasis, although their precise mechanism of action remains controversial. To investigate whether APP also affects ER calcium levels, we used RNA interference to target the APP gene in cultured T84 cells in combination with two types of ER calcium sensors. Using a genetically encoded calcium indicator, GEM-CEPIA1er, we found that APP-deficient cells exhibited elevated resting calcium levels in the ER and prolonged emptying of ER calcium stores upon the cyclopiazonic acid induced inhibition of sarco-endoplasmic reticulum calcium-ATPase. These effects could be ascribed to lower ER calcium leakage rates. Consistent with these results, translocation of the endogenous ER calcium sensor STIM1 to its target channel Orai1 was delayed following ER calcium store depletion. Our data suggest a physiological function of APP in the regulation of ER calcium levels. PMID- 29109431 TI - Waterlogging accelerates the loss of soil organic carbon from abandoned paddy fields in the hilly terrain in subtropical China. AB - Paddy soils have been widely recognized as important carbon sinks. However, paddy field abandonment is increasing in the hilly area in subtropical China. Soil waterlogging and weed burning are common practices in abandoned paddy fields, which could affect vegetation cover and carbon sequestration. An rice cultivation experiment was ceased in 2006, and four new treatments were applied as waterlogging (W), drainage (D), waterlogging combined with burning (WB), and drainage combined with burning (DB). Waterlogging altered the vegetation cover and caused an associated change in biomass. Paspalum paspaloides, Murdannia triquetra, and Bidens frondosa dominated W and WB plots, and Microstegium vimineum and Bidens frondosa dominated D and DB plots. Abandonment of paddy fields led to a rapid decrease in soil organic carbon (SOC), and waterlogging accelerates SOC loss which should be attributed mainly to alteration of the vegetation cover. Six years' rice cultivation increased SOC content by 13.5% (2.4 g kg-1) on average. In contrast, six years' abandonment reduced SOC content by 14.5% (3.0 g kg-1) on average. Decline rate of SOC was 0.38, 0.64, 0.30, and 0.65 g kg-1 a-1 for D, W, DB, and WB, respectively. Such results indicate a significant risk of SOC loss from abandoned paddy fields. PMID- 29109430 TI - The first draft reference genome of the American mink (Neovison vison). AB - The American mink (Neovison vison) is a semiaquatic species of mustelid native to North America. It's an important animal for the fur industry. Many efforts have been made to locate genes influencing fur quality and color, but this search has been impeded by the lack of a reference genome. Here we present the first draft genome of mink. In our study, two mink individuals were sequenced by Illumina sequencing with 797 Gb sequence generated. Assembly yielded 7,175 scaffolds with an N50 of 6.3 Mb and length of 2.4 Gb including gaps. Repeat sequences constitute around 31% of the genome, which is lower than for dog and cat genomes. The alignments of mink, ferret and dog genomes help to illustrate the chromosomes rearrangement. Gene annotation identified 21,053 protein-coding sequences present in mink genome. The reference genome's structure is consistent with the microsatellite-based genetic map. Mapping of well-studied genes known to be involved in coat quality and coat color, and previously located fur quality QTL provide new knowledge about putative candidate genes for fur traits. The draft genome shows great potential to facilitate genomic research towards improved breeding for high fur quality animals and strengthen our understanding on evolution of Carnivora. PMID- 29109432 TI - ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export. AB - Mutations in Matrin 3 have recently been linked to ALS, though the mechanism that induces disease in these patients is unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS. PMID- 29109433 TI - Hf/Sb co-doping induced a high thermoelectric performance of ZrNiSn: First principles calculation. AB - Previous experiments showed that Hf/Sb co-doping in ZrNiSn impressively improved the electrical conductivity (sigma). To explore the physical reasons for this improvement, the electronic structures of HfxZr1-xNiSn1-ySby (x = 0, 0.25, 0.5; y = 0, 0.02) have been systematically investigated by using the first-principles method and semiclassical Boltzmann transport theory. 50% Hf doping at Zr site in ZrNiSn simultaneously increases the degeneracy and dispersion of energy bands near the conduction band edge, which are helpful to optimizing Seebeck coefficient and slightly improving sigma. Furthermore, 2% Sb co-doping at Sn site in Hf0.5Zr0.5NiSn not only increases total density of states near the Fermi energy but also retains high mobility, and N v reaches eleven at the conduction band minimum, thereby inducing a large improvement in sigma. Additionally, the Bader charge analysis shows the reason why Sb co-doping supplies more electrons. It is most likely derived from that Sb loses more electrons and Sb-Ni has a stronger hybridization than Sn-Ni. Moreover, we predict that the ZT of Hf0.5Zr0.5NiSn0.98Sb0.02 at 1000 K can reach 1.37 with the carrier concentration of 7.56 * 1018 cm-3, indicating that Hf/Sb co-doping may be an effective approach in optimizing thermoelectric properties of ZrNiSn alloy compounds. PMID- 29109434 TI - New concept of pump-less forward osmosis (FO) and low-pressure membrane (LPM) process. AB - We tested the possibility of energy-saving water treatment methods by using a pump-less forward osmosis (FO) and low-pressure membrane (LPM) hybrid process (FO LPM). In this pump-less FO-LPM, permeate migrates from the feed solution (FS) to the draw solution (DS) through the FO membrane by use of osmotic pressure differences. At the same time, within the closed DS tank, inner pressure increases as the DS volume increases. By using the DS tank's internal pressure, the LPM process works to re-concentrate the diluted DS, maintaining the DS concentration and producing clean water. In this study, a polymer - polystyrene sulfonate (PSS) was used as a draw solute. Based on the results of each individual portion of the process, the optimal range of the PSS DS was determined. The performance of the pump-less FO-LPM process was lower than that of a single process; however, we observed that the hybrid process can be operated without a pump for regeneration of a diluted DS. This research highlights the feasibility and applicability of pump-less FO-LPM processes using a polymeric DS for water treatment. Additionally, it is suggested that this novel process offers a breakthrough in FO technology that is often limited by operation and management cost. PMID- 29109435 TI - Developing a Black Carbon-Substituted Multimedia Model for Simulating the PAH Distributions in Urban Environments. AB - A multimedia fugacity model with spatially resolved environmental phases at an urban scale was developed. In this model, the key parameter, organic matter, was replaced with black carbon (BC) and applied to simulate the distributions of phenanthrene (Phe), pyrene (Pyr) and benzo[alpha]pyrene (BaP) in Nanjing, China. Based on the estimated emissions and measured inflows of air and water, the Phe, Pyr and BaP concentrations in different environment media were calculated under steady-state assumptions. The original model (OC-Model), BC-inclusive model (dual C-Model) and improved model (BC-Model) were validated by comparing observed and predicted Phe, Pyr and BaP concentrations. Our results suggested that lighter polycyclic aromatic hydrocarbons (PAHs) were more affected by BC substitution than their heavier counterparts. We advocate the utilization of sorption with BC in future multimedia fate models for lighter PAHs based on the comparison of the calculated and observed values from measured and published sources. The spatial distributions of the Phe, Pyr and BaP concentrations in all phases were rationally mapped based on the calculated concentrations from the BC-Model, indicating that soil was the dominant sink of PAHs in terrestrial systems, while sediment was the dominant sink of PAHs in aquatic systems. PMID- 29109436 TI - Discovering geothermal supercritical fluids: a new frontier for seismic exploration. AB - Exploiting supercritical geothermal resources represents a frontier for the next generation of geothermal electrical power plant, as the heat capacity of supercritical fluids (SCF),which directly impacts on energy production, is much higher than that of fluids at subcritical conditions. Reconnaissance and location of intensively permeable and productive horizons at depth is the present limit for the development of SCF geothermal plants. We use, for the first time, teleseismic converted waves (i.e. receiver function) for discovering those horizons in the crust. Thanks to the capability of receiver function to map buried anisotropic materials, the SCF-bearing horizon is seen as the 4km-depth abrupt termination of a shallow, thick, ultra-high (>30%) anisotropic rock volume, in the center of the Larderello geothermal field. The SCF-bearing horizon develops within the granites of the geothermal field, bounding at depth the vapor filled heavily-fractured rock matrix that hosts the shallow steam-dominated geothermal reservoirs. The sharp termination at depth of the anisotropic behavior of granites, coinciding with a 2 km-thick stripe of seismicity and diffuse fracturing, points out the sudden change in compressibility of the fluid filling the fractures and is a key-evidence of deep fluids that locally traversed the supercritical conditions. The presence of SCF and fracture permeability in nominally ductile granitic rocks open new scenarios for the understanding of magmatic systems and for geothermal exploitation. PMID- 29109437 TI - mir-355 Functions as An Important Link between p38 MAPK Signaling and Insulin Signaling in the Regulation of Innate Immunity. AB - We performed a systematic identification of microRNAs (miRNAs) involved in the control of innate immunity. We identified 7 novel miRNA mutants with altered survival, colony forming in the body, and expression pattern of putative antimicrobial genes after Pseudomonas aeruginosa infection. Loss-of-function mutation of mir-45, mir-75, mir-246, mir-256, or mir-355 induced resistance to P. aeruginosa infection, whereas loss-of-function mutation of mir-63 or mir-360 induced susceptibility to P. aeruginosa infection. DAF-2 in the insulin signaling pathway acted as a target for intestinal mir-355 to regulate innate immunity. mir 355 functioned as an important link between p38 MAPK signaling pathway and insulin signaling pathway in the regulation of innate immunity. Our results provide an important molecular basis for further elucidation of the functions of various miRNAs in the regulation of innate immunity. PMID- 29109438 TI - VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism. AB - Exacerbation of macrophage-mediated inflammation contributes to pathogenesis of various inflammatory diseases, but the immunometabolic programs underlying regulation of macrophage activation are unclear. Here we show that V-set immunoglobulin-domain-containing 4 (VSIG4), a B7 family-related protein that is expressed by resting macrophages, inhibits macrophage activation in response to lipopolysaccharide. Vsig4 -/- mice are susceptible to high-fat diet-caused obesity and murine hepatitis virus strain-3 (MHV-3)-induced fulminant hepatitis due to excessive macrophage-dependent inflammation. VSIG4 activates the PI3K/Akt STAT3 pathway, leading to pyruvate dehydrogenase kinase-2 (PDK2) upregulation and subsequent phosphorylation of pyruvate dehydrogenase, which results in reduction in pyruvate/acetyl-CoA conversion, mitochondrial reactive oxygen species secretion, and macrophage inhibition. Conversely, interruption of Vsig4 or Pdk2 promotes inflammation. Forced expression of Vsig4 in mice ameliorates MHV-3 induced viral fulminant hepatitis. These data show that VSIG4 negatively regulates macrophage activation by reprogramming mitochondrial pyruvate metabolism. PMID- 29109439 TI - Crystal structure of tripartite-type ABC transporter MacB from Acinetobacter baumannii. AB - The MacA-MacB-TolC tripartite complex is a transmembrane machine that spans both plasma membrane and outer membrane and actively extrudes substrates, including macrolide antibiotics, virulence factors, peptides and cell envelope precursors. These transport activities are driven by the ATPase MacB, a member of the ATP binding cassette (ABC) superfamily. Here, we present the crystal structure of MacB at 3.4-A resolution. MacB forms a dimer in which each protomer contains a nucleotide-binding domain and four transmembrane helices that protrude in the periplasm into a binding domain for interaction with the membrane fusion protein MacA. MacB represents an ABC transporter in pathogenic microorganisms with unique structural features. PMID- 29109440 TI - The subpolar gyre regulates silicate concentrations in the North Atlantic. AB - The North Atlantic is characterized by diatom-dominated spring blooms that results in significant transfer of carbon to higher trophic levels and the deep ocean. These blooms are terminated by limiting silicate concentrations in summer. Numerous regional studies have demonstrated phytoplankton community shifts to lightly-silicified diatoms and non-silicifying plankton at the onset of silicate limitation. However, to understand basin-scale patterns in ecosystem and climate dynamics, nutrient inventories must be examined over sufficient temporal and spatial scales. Here we show, from a new comprehensive compilation of data from the subpolar Atlantic Ocean, clear evidence of a marked pre-bloom silicate decline of 1.5-2 uM throughout the winter mixed layer during the last 25 years. This silicate decrease is primarily attributed to natural multi-decadal variability through decreased winter convection depths since the mid-1990s, a weakening and retraction of the subpolar gyre and an associated increased influence of nutrient-poor water of subtropical origin. Reduced Arctic silicate import and the projected hemispheric-scale climate change-induced weakening of vertical mixing may have acted to amplify the recent decline. These marked fluctuations in pre-bloom silicate inventories will likely have important consequences for the spatial and temporal extent of diatom blooms, thus impacting ecosystem productivity and ocean-atmosphere climate dynamics. PMID- 29109441 TI - Buildup of a highly twisted magnetic flux rope during a solar eruption. AB - The magnetic flux rope is among the most fundamental magnetic configurations in plasma. Although its presence after solar eruptions has been verified by spacecraft measurements near Earth, its formation on the Sun remains elusive, yet is critical to understanding a broad spectrum of phenomena. Here we study the dynamic formation of a magnetic flux rope during a classic two-ribbon flare. Its feet are identified unambiguously with conjugate coronal dimmings completely enclosed by irregular bright rings, which originate and expand outward from the far ends of flare ribbons. The expansion is associated with the rapid ribbon separation during the flare main phase. Counting magnetic flux through the feet and the ribbon-swept area reveals that the rope's core is more twisted than its average of four turns. It propagates to the Earth as a typical magnetic cloud possessing a similar twist profile obtained by the Grad-Shafranov reconstruction of its three dimensional structure. PMID- 29109443 TI - Shining a Psychoanalytic Light on Alienation, Otherness, and Xenophobia. PMID- 29109444 TI - Highly Performance Core-Shell TiO2(B)/anatase Homojunction Nanobelts with Active Cobalt phosphide Cocatalyst for Hydrogen Production. AB - In this paper, a highly efficient core-shell structure of TiO2(B)/anatase photocatalyst with CoP cocatalyst has been synthesized via hydrothermal processes and a mechanical milling method. The designed core-shell TiO2(B)/anatase photocatalysts exhibit excellent performance by compared with pure TiO2(B) and anatase phase. With the participation of CoP particles, there is drastically enhanced photocatalytic activity of TiO2(B)/anatase, and the H2-production rate can be up to 7400 MUmol.g-1, which is about 3.2 times higher than TiO2(B)/anatase photocatalyst. The improved activity is attributed to the contribution of the well-matched core-shell structure and cooperative effect of CoP cocatalyst. The photogenerated holes of anatase can migrate more promptly to the adjacent TiO2(B) core than the photogenerated electrons, which result in an accumulation of electrons in the anatase, and CoP nanoparticles can contribute significantly to transferring electrons from the surface of TiO2(A). It was found that the efficient separation of electron-hole pairs greatly improved the photocatalytic hydrogen evolution in water under UV light irradiation. PMID- 29109445 TI - Half a century of coastal temperature records reveal complex warming trends in western boundary currents. AB - Accelerated warming of western boundary currents due to the strengthening of subtropical gyres has had cascading effects on coastal ecosystems and is widely expected to result in further tropicalization of temperate regions. Predicting how species and ecosystems will respond requires a better understanding of the variability in ocean warming in complex boundary current regions. Using three >=50 year temperature records we demonstrate high variability in the magnitude and seasonality of warming in the Southwest Pacific boundary current region. The greatest rate of warming was evident off eastern Tasmania (0.20 degrees C decade 1), followed by southern New Zealand (0.10 degrees C decade-1), while there was no evidence of annual warming in northeastern New Zealand. This regional variability in coastal warming was also evident in the satellite record and is consistent with expected changes in regional-scale circulation resulting from increased wind stress curl in the South Pacific subtropical gyre. Warming trends over the satellite era (1982-2016) were considerably greater than the longer-term trends, highlighting the importance of long-term temperature records in understanding climate change in coastal regions. Our findings demonstrate the spatial and temporal complexity of warming patterns in boundary current regions and challenge widespread expectations of tropicalization in temperate regions under future climate change. PMID- 29109446 TI - Bruton's tyrosine kinase and RAC1 promote cell survival in MLL-rearranged acute myeloid leukemia. PMID- 29109447 TI - Opto-electric investigation for Si/organic heterojunction single-nanowire solar cells. AB - Recently, silicon single nanowire solar cells (SNSCs) serving as the sustainable self-power sources have been integrated into optoelectronic nanodevices under the driver of technology and economy. However, conventional SNSC cannot provide the minimum energy consumption for the operation of nanodevices due to its low power conversion efficiency (PCE). Here, we propose an innovative approach to combine the n-type silicon nanowires (SiNWs) with p-type poly(3,4 ethylthiophene):poly(styrenesulfonate) (PEDOT:PSS) to form the p + n heterojunction, which shows superior opto-electric performances. Besides, PEDOT:PSS also acts as a natural anti-reflection coating (ARC) with an excellent light-trapping capability, especially in the short-wavelength range. Importantly, the photovoltaic performances of Si/PEDOT:PSS SNSC can be well maintained even in large surface recombination velocity, due to the efficient field-effect passivation of PEDOT:PSS. The minority carrier concentration at outer surface of shallow p + n heterojunction is greatly reduced by the electric field, drastically suppressing the surface recombination compared to the conventional p i-n homojunction SNSC. Furthermore, larger junction area of p + n heterojunction facilitates the separation of photo-generated charge carriers. These results demonstrate that the Si/PEDOT:PSS SNSC is a promising alternative for micro power application. PMID- 29109448 TI - Identification of claudin-4 binder that attenuates tight junction barrier function by TR-FRET-based screening assay. AB - Claudins are key functional and structural components of tight junctions (TJs) in epithelial cell sheets. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds to claudin-4 and reversibly modulates intestinal TJ seals, thereby enhancing paracellular transport of solutes. However, the use of C CPE as an absorption enhancer is limited by the molecule's immunogenicity and manufacturing cost. Here, we developed a high-throughput screening system based on the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method to identify claudin-4 binders in a library collection of 32,560 compounds. Thiostrepton, identified from the screen, decreased transepithelial electrical resistance and increased flux of 4-kDa fluorescein isothiocyanate-labelled dextran (FD-4) in Caco-2 cell monolayers, a model of intestinal epithelium. Thiostrepton changed the expression, but not the localisation, of TJ components. Treatment of rat jejunum with thiostrepton increased the absorption of FD-4 without tissue toxicity, indicating that thiostrepton is a novel claudin-4 binder that enhances intestinal permeability. The screening system may therefore be a useful tool for identifying claudin-4 binders to enhance drug absorption in mucosa. PMID- 29109449 TI - Protein profiling identified key chemokines that regulate the maintenance of human pluripotent stem cells. AB - Microenvironment (or niche)-providing chemokines regulate many important biological functions of tissue-specific stem cells. However, to what extent chemokines influence human pluripotent stem cells (hPSCs) is not yet completely understood. In this study, we applied protein array to screen chemokines found within the cytokine pool in the culture supernatant of hPSCs. Our results showed that chemokines were the predominant supernatant components, and came from three sources: hPSCs, feeder cells, and culture media. Chemotaxis analysis of IL-8, SDF 1alpha, and IP-10 suggested that chemokines function as uniform chemoattractants to mediate in vitro migration of the hPSCs. Chemokines mediate both differentiated and undifferentiated states of hPSCs. However, balanced chemokine signaling tends to enhance their stemness in vitro. These results indicate that chemokines secreted from both stem cells and feeder cells are essential to mobilize hPSCs and maintain their stemness. PMID- 29109450 TI - Interactive phenotyping of large-scale histology imaging data with HistomicsML. AB - Whole-slide imaging of histologic sections captures tissue microenvironments and cytologic details in expansive high-resolution images. These images can be mined to extract quantitative features that describe tissues, yielding measurements for hundreds of millions of histologic objects. A central challenge in utilizing this data is enabling investigators to train and evaluate classification rules for identifying objects related to processes like angiogenesis or immune response. In this paper we describe HistomicsML, an interactive machine-learning system for digital pathology imaging datasets. This framework uses active learning to direct user feedback, making classifier training efficient and scalable in datasets containing 108+ histologic objects. We demonstrate how this system can be used to phenotype microvascular structures in gliomas to predict survival, and to explore the molecular pathways associated with these phenotypes. Our approach enables researchers to unlock phenotypic information from digital pathology datasets to investigate prognostic image biomarkers and genotype-phenotype associations. PMID- 29109451 TI - SIM2l attenuates resistance to hypoxia and tumor growth by transcriptional suppression of HIF1A in uterine cervical squamous cell carcinoma. AB - Despite chemoradiotherapy being one of the most important modalities in advanced cervical cancer, there is a lack of both usable biomarkers to predict treatment outcome and of knowledge about the mechanism of refractoriness to the therapy. Here we identified a transcriptional factor Single-minded homolog 2 (SIM2) as an independent predictive biomarker for uterine cervical squamous cell carcinoma (CvSCC). The retrospective study showed that high expression level of SIM2 was correlated to good survival in CvSCC patients. SIM2 knockdown in CvSCC cell lines showed resistance to hypoxia with increased expression of HIF1A and its target genes. Loss of SIM2 also caused growth promotion, resistance to ROS, and radiation in 3D culture. Furthermore, SIM2 knockdown suppressed tumor growth with increased HIF-1alpha expression and angiogenesis in vivo. On the other hand, SIM2 long isoform (SIM2l)-overexpressed cells had contrary results, indicating the long isoform plays a key role for maintenance of these phenotypes. These data indicated that SIM2l has a potential to be precision medicine for CvSCC patients and that anti-angiogenesis therapy might be usable for SIM2lLow poor survivors. PMID- 29109452 TI - A digital microfluidic system for loop-mediated isothermal amplification and sequence specific pathogen detection. AB - A digital microfluidic (DMF) system has been developed for loop-mediated isothermal amplification (LAMP)-based pathogen nucleic acid detection using specific low melting temperature (Tm) Molecular Beacon DNA probes. A positive temperature-coefficient heater with a temperature sensor for real-time thermal regulation was integrated into the control unit, which generated actuation signals for droplet manipulation. To enhance the specificity of the LAMP reaction, low-Tm Molecular Beacon probes were designed within the single-stranded loop structures on the LAMP reaction products. In the experiments, only 1 MUL of LAMP reaction samples containing purified Trypanosoma brucei DNA were required, which represented over a 10x reduction of reagent consumption when comparing with the conventional off-chip LAMP. On-chip LAMP for unknown sample detection could be accomplished in 40 min with a detection limit of 10 copies/reaction. Also, we accomplished an on-chip melting curve analysis of the Molecular Beacon probe from 30 to 75 degrees C within 5 min, which was 3x faster than using a commercial qPCR machine. Discrimination of non-specific amplification and lower risk of aerosol contamination for on-chip LAMP also highlight the potential utilization of this system in clinical applications. The entire platform is open for further integration with sample preparation and fluorescence detection towards a total micro-analysis system. PMID- 29109453 TI - A multi-component discrete Boltzmann model for nonequilibrium reactive flows. AB - We propose a multi-component discrete Boltzmann model (DBM) for premixed, nonpremixed, or partially premixed nonequilibrium reactive flows. This model is suitable for both subsonic and supersonic flows with or without chemical reaction and/or external force. A two-dimensional sixteen-velocity model is constructed for the DBM. In the hydrodynamic limit, the DBM recovers the modified Navier Stokes equations for reacting species in a force field. Compared to standard lattice Boltzmann models, the DBM presents not only more accurate hydrodynamic quantities, but also detailed nonequilibrium effects that are essential yet long neglected by traditional fluid dynamics. Apart from nonequilibrium terms (viscous stress and heat flux) in conventional models, specific hydrodynamic and thermodynamic nonequilibrium quantities (high order kinetic moments and their departure from equilibrium) are dynamically obtained from the DBM in a straightforward way. Due to its generality, the developed methodology is applicable to a wide range of phenomena across many energy technologies, emissions reduction, environmental protection, mining accident prevention, chemical and process industry. PMID- 29109454 TI - 8000-year monsoonal record from Himalaya revealing reinforcement of tropical and global climate systems since mid-Holocene. AB - We provide the first continuous Indian Summer Monsoon (ISM) climate record for the higher Himalayas (Kedarnath, India) by analyzing a 14C-dated peat sequence covering the last ~8000 years, with ~50 years temporal resolution. The ISM variability inferred using various proxies reveal striking similarity with the Greenland ice core (GISP2) temperature record and rapid denitrification changes recorded in the sediments off Peru. The Kedarnath record provides compelling evidence for a reorganization of the global climate system taking place at ~5.5 ka BP possibly after sea level stabilization and the advent of inter-annual climate variability governed by the modern ENSO phenomenon. The ISM record also captures warm-wet and cold-dry conditions during the Medieval Climate Anomaly and Little Ice Age, respectively. PMID- 29109455 TI - Various response of Pinus tabulaeformis Carr. regeneration in artifical gaps. AB - Understanding the influence of gaps in promoting canopy recruitment will help to maintain structural stability and achieve continuous forest cover. We established three control plots and experimental plots with three replications each (gap sizes L-I, L-II, L-III, and L-IV) in a Chinese pine (Pinus tabulaeformis Carr.) plantation to test the short-term effects of gap size on the age distribution, density and growth, and annual height and ground diameter growth for regeneration established before (REBG) and after (REAG) gap creation. Age distribution exhibited an approximately normal distribution, with the numbers of REBG and REAG decreasing and increasing, respectively, as the age increased. Although there was no difference in density among gap size classes, regeneration growth positively responded to gap size, with maximum values observed in class L-III. Annual average height growth after (AAH-A) gap creation was significantly greater than that before (AAH-B) gap creation for REBG among gap sizes, suggesting that gaps promote the rapid growth of regeneration. However, the responses of height and ground diameter growth in REBG to gap size were not immediate and exhibited a response delay of 2-4 years. Similarly, for the height and ground diameter growth of REAG, significant differences were first observed within years 2-4 after germination in the same growing season for all gap size classes. PMID- 29109456 TI - Indication of band flattening at the Fermi level in a strongly correlated electron system. AB - Using ultra-high quality SiGe/Si/SiGe quantum wells at millikelvin temperatures, we experimentally compare the energy-averaged effective mass, m, with that at the Fermi level, m F , and verify that the behaviours of these measured values are qualitatively different. With decreasing electron density (or increasing interaction strength), the mass at the Fermi level monotonically increases in the entire range of electron densities, while the energy-averaged mass saturates at low densities. The qualitatively different behaviour reveals a precursor to the interaction-induced single-particle spectrum flattening at the Fermi level in this electron system. PMID- 29109457 TI - Non-alcoholic fatty liver disease is an influencing factor for the association of SHBG with metabolic syndrome in diabetes patients. AB - Metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) have been identified as risk factors affecting serum sex hormone binding globulin (SHBG) levels. We conducted this cross-sectional study to delineate whether MS or NAFLD has more impact on circulating SHBG levels in type 2 diabetes (T2D) patients. Anthropometric and biochemical parameters including serums SHBG, testosterone (TT), liver enzymes, lipids, insulin, C-peptide and plasma glucose were measured. Regardless of the MS status, SHBG level was significantly lower in NAFLD patients than in non-NAFLD patients (P < 0.001). In the multiple linear regression analysis, lower serum SHBG level was strongly correlated with a higher incidence of NAFLD, but not MS components. In logistic regression analyses, after adjusted for age, sex, duration of diabetes, smoking status, and alcohol use, the ORs and 95%CI for presence of MS was 2.26 (95%CI 1.91-2.68) and for presence of NAFLD was 6.36 (95%CI 4.87-8.31) with per one SD decrease in serum SHBG (both P < 0.001). In conclusion, lower serum SHBG is associated with a higher prevalence of NAFLD, compared with MS and other metabolic disorders, in T2D patients. NAFLD might be an important influencing factor for the association of circulating SHBG with MS in T2D patients. PMID- 29109458 TI - Shifts in pore connectivity from precipitation versus groundwater rewetting increases soil carbon loss after drought. AB - Droughts and other extreme precipitation events are predicted to increase in intensity, duration, and extent, with uncertain implications for terrestrial carbon (C) sequestration. Soil wetting from above (precipitation) results in a characteristically different pattern of pore-filling than wetting from below (groundwater), with larger, well-connected pores filling before finer pore spaces, unlike groundwater rise in which capillary forces saturate the finest pores first. Here we demonstrate that pore-scale wetting patterns interact with antecedent soil moisture conditions to alter pore-scale, core-scale, and field scale C dynamics. Drought legacy and wetting direction are perhaps more important determinants of short-term C mineralization than current soil moisture content in these soils. Our results highlight that microbial access to C is not solely limited by physical protection, but also by drought or wetting-induced shifts in hydrologic connectivity. We argue that models should treat soil moisture within a three-dimensional framework emphasizing hydrologic conduits for C and resource diffusion. PMID- 29109459 TI - Selectivity of Cobalt Corrole for CO vs. O2 and N2 in Indoor Pollution. AB - Coal combustion causes indoor pollution of CO. In this work, DFT calculations on cobalt corrole (Co(Cor)) with three most common indoor gas molecules (N2, O2 and CO) were performed. The Mulliken spin densities show that the ground states of Co(N2)(Cor), Co(CO)(Cor) and Co(OC)(Cor) have an anti-ferromagnetic coupling fashion of the electrons on the Co 3d z2 orbital and the pi orbital of the corrole ring. However, Co(O2)(Cor) has a triplet ground state. With the spin contamination corrections, the Co(N2)(Cor) binding energy was obtained at -50.6 kcal mol-1 (B3LYP-D3). While CO can interact with Co(Cor) in two different ways, and their binding energies were -22.8 and -10.9 kcal mol-1 (B3LYP-D3) for Co(CO)(Cor) and Co(OC)(Cor), respectively. The natural bond orbital charges on the axial ligands (NO, CO, OC) are increased upon the chemical bond formation. These are the cause of the shorten metal-ligand bond and the increase of the wavenumber of the metal-ligand bond vibrational transitions. While the charges for O2 are decreased, leading to bond elongation as well as the decrease of the wavenumber upon complexation. Overall, O2 was found to be hardly coordinated with Co(Cor). This study provides a detailed molecular understanding of interactions between a gas sensor and gaseous indoor air-pollutants. PMID- 29109460 TI - Molecular-trapping in Emulsion's Monolayer: A New Strategy for Production and Purification of Bioactive Saponins. AB - Saponins from defatted root-extract of Securidaca longipedunculata were systematically entrapped in emulsion monolayer-barrier and finally recovered in pure form through demulsification. First, their molecules were dispersed in water to engineer a monomolecular film architecture, via self-assembly. Emulsifying with ethyl-ether resulted in swollen micelles and engendered phase-inversion and phase-separation, by disrupting the thermodynamic equilibrium. As positive outcome, a Winsor II system was obtained, having saponin-rich upper phase (ethyl ether) and impurities bound lower phase (aqueous). Saponin particles underwent transition in insoluble ethyl-ether, precipitated and recovered as solids. The entire process was bioactivity-guided and validated using pooled fractions of securidaca saponins, purified by TLC (RP-C18, F254S). TEM and SEM revealed interesting morphologies and particle sizes between nanometer and micron. At the end, purity output of 90% and total recovery of 94% were achieved. Here we show that "molecular-trapping in emulsion's monolayer" is an effective method for recovery, production and purification of saponins of plant origin. PMID- 29109461 TI - Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation. AB - Cannabidiol (CBD) and ?9-tetrahydrocannabinol (THC) have well documented immunomodulatory effects in vitro, but not following oral administration in humans. Here we show that oral co-administration of cannabinoids with lipids can substantially increase their intestinal lymphatic transport in rats. CBD concentrations in the lymph were 250-fold higher than in plasma, while THC concentrations in the lymph were 100-fold higher than in plasma. Since cannabinoids are currently in clinical use for the treatment of spasticity in multiple sclerosis (MS) patients and to alleviate nausea and vomiting associated with chemotherapy in cancer patients, lymphocytes from those patients were used to assess the immunomodulatory effects of cannabinoids. The levels of cannabinoids recovered in the intestinal lymphatic system, but not in plasma, were substantially above the immunomodulatory threshold in murine and human lymphocytes. CBD showed higher immunosuppressive effects than THC. Moreover, immune cells from MS patients were more susceptible to the immunosuppressive effects of cannabinoids than those from healthy volunteers or cancer patients. Therefore, administering cannabinoids with a high-fat meal or in lipid-based formulations has the potential to be a therapeutic approach to improve the treatment of MS, or indeed other autoimmune disorders. However, intestinal lymphatic transport of cannabinoids in immunocompromised patients requires caution. PMID- 29109462 TI - Intravascular Optical Coherence Tomography for Characterization of Atherosclerosis with a 1.7 Micron Swept-Source Laser. AB - The main cause of acute coronary events, such as thrombosis, is the rupture of atherosclerotic plaques. Typical intravascular optical coherence tomography (IVOCT) imaging systems that utilize a 1.3 MUm swept source laser are often used for identifying fibrous cap thickness of plaques, yet cannot provide adequate depth penetration to resolve the size of the lipid pool. Here, we present a novel IVOCT system with a 1.7 MUm center wavelength swept light source that can readily penetrate deeper into the tissue because of the longer wavelength and allows for better identification of plaques due to the lipid absorption spectrum at 1.7 MUm. Using this system, we have imaged a human coronary artery to evaluate the performance of the novel OCT system and verified the results by hematoxylin and eosin (H&E) histology. The significantly improved imaging depth and better identification sensitivity suggest that the 1.7 MUm OCT system holds great potential that can be further translated for in-vivo applications of atherosclerosis characterization. PMID- 29109463 TI - A role for small secreted proteins (SSPs) in a saprophytic fungal lifestyle: Ligninolytic enzyme regulation in Pleurotus ostreatus. AB - Small secreted proteins (SSPs), along with lignocellulose degrading enzymes, are integral components of the secretome of Pleurotus ostreatus, a white rot fungus. In this study, we identified 3 genes (ssp1, 2 and 3) encoding proteins that are annotated as SSPs and that exhibited of ~4,500- fold expression, 24 hr following exposure to the toxic compound 5-hydroxymethylfurfural (HMF). Homologues to genes encoding these SSPs are present in the genomes of other basidiomycete fungi, however the role of SSPs is not yet understood. SSPs, aryl-alcohol oxidases (AAO) and the intracellular aryl-alcohol dehydrogenases (AAD) were also produced after exposure to other aryl-alcohols, known substrates and inducers of AAOs, and during idiophase (after the onset of secondary metabolism). A knockdown strain of ssp1 exhibited reduced production of AAO-and AAD-encoding genes after HMF exposure. Conversely, a strain overexpressing ssp1 exhibited elevated expression of genes encoding AAOs and ADD, resulting in a 3-fold increase in enzymatic activity of AAOs, as well as increased expression and protein abundance of versatile peroxidase 1, which directly degrades lignin. We propose that in addition to symbionts and pathogens, SSPs also have roles in saprophytes and function in P. ostreatus as components of the ligninolytic system. PMID- 29109464 TI - New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kalpha Complexed with a Potent Lead Compound. AB - Phosphatidylinositol 3-kinase alpha is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kalpha inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110alpha-YXY-4F and apo p110alpha complexes showed that YXY-4F induced additional space by promoting a flexible conformational change in residues Ser773 and Ser774 in the PI3Kalpha ATP catalytic site. Specifically, residue 773(S) in PI3Kalpha is quite different from that of PI3Kbeta (D), gamma (A), and delta (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kalpha. PMID- 29109465 TI - Evidence for Human Streptococcus pneumoniae in wild and captive chimpanzees: A potential threat to wild populations. AB - Habituation of wild great apes for tourism and research has had a significant positive effect on the conservation of these species. However, risks associated with such activities have been identified, specifically the transmission of human respiratory viruses to wild great apes, causing high morbidity and, occasionally, mortality. Here, we investigate the source of bacterial-viral co-infections in wild and captive chimpanzee communities in the course of several respiratory disease outbreaks. Molecular analyses showed that human respiratory syncytial viruses (HRSV) and human metapneumoviruses (HMPV) were involved in the etiology of the disease. In addition our analysis provide evidence for coinfection with Streptococcus (S.) pneumoniae. Characterisation of isolates from wild chimpanzees point towards a human origin of these bacteria. Transmission of these bacteria is of concern because - in contrast to HRSV and HMPV - S. pneumoniae can become part of the nasopharyngeal flora, contributing to the severity of respiratory disease progression. Furthermore these bacteria have the potential to spread to other individuals in the community and ultimately into the population. Targeted vaccination programs could be used to vaccinate habituated great apes but also human populations around great ape habitats, bringing health benefits to both humans and wild great apes. PMID- 29109467 TI - Determine the timing. PMID- 29109466 TI - Haplotype selection as an adaptive mechanism in the protozoan pathogen Leishmania donovani. AB - The parasite Leishmania donovani causes a fatal disease termed visceral leishmaniasis. The process through which the parasite adapts to environmental change remains largely unknown. Here we show that aneuploidy is integral for parasite adaptation and that karyotypic fluctuations allow for selection of beneficial haplotypes, which impact transcriptomic output and correlate with phenotypic variations in proliferation and infectivity. To avoid loss of diversity following karyotype and haplotype selection, L. donovani utilizes two mechanisms: polyclonal selection of beneficial haplotypes to create coexisting subpopulations that preserve the original diversity, and generation of new diversity as aneuploidy-prone chromosomes tolerate higher mutation rates. Our results reveal high aneuploidy turnover and haplotype selection as a unique evolutionary adaptation mechanism that L. donovani uses to preserve genetic diversity under strong selection. This unexplored process may function in other human diseases, including fungal infection and cancer, and stimulate innovative treatment options. PMID- 29109468 TI - A statistical estimator for determining the limits of contemporary and historic phenology. AB - Climate change affects not just where species are found, but also when species' key life-history events occur-their phenology. Measuring such changes in timing is often hampered by a reliance on biased survey data: surveys identify that an event has taken place (for example, the flower is in bloom), but not when that event happened (for example, the flower bloomed yesterday). Here, we show that this problem can be circumvented using statistical estimators, which can provide accurate and unbiased estimates from sparsely sampled observations. We demonstrate that such methods can resolve an ongoing debate about the relative timings of the onset and cessation of flowering, and allow us to place modern observations reliably within the context of the vast wealth of historical data that reside in herbaria, museum collections, and written records. We also analyse large-scale citizen science data from the United States National Phenology Network and reveal not just earlier but also potentially more variable flowering in recent years. Evidence for greater variability through time is important because increases in variation are characteristic of systems approaching a state change. PMID- 29109469 TI - Temporal niche expansion in mammals from a nocturnal ancestor after dinosaur extinction. AB - Most modern mammals, including strictly diurnal species, exhibit sensory adaptations to nocturnal activity that are thought to be the result of a prolonged nocturnal phase or 'bottleneck' during early mammalian evolution. Nocturnality may have allowed mammals to avoid antagonistic interactions with diurnal dinosaurs during the Mesozoic. However, understanding the evolution of mammalian activity patterns is hindered by scant and ambiguous fossil evidence. While ancestral reconstructions of behavioural traits from extant species have the potential to elucidate these patterns, existing studies have been limited in taxonomic scope. Here, we use an extensive behavioural dataset for 2,415 species from all extant orders to reconstruct ancestral activity patterns across Mammalia. We find strong support for the nocturnal origin of mammals and the Cenozoic appearance of diurnality, although cathemerality (mixed diel periodicity) may have appeared in the late Cretaceous. Simian primates are among the earliest mammals to exhibit strict diurnal activity, some 52-33 million years ago. Our study is consistent with the hypothesis that temporal partitioning between early mammals and dinosaurs during the Mesozoic led to a mammalian nocturnal bottleneck, but also demonstrates the need for improved phylogenetic estimates for Mammalia. PMID- 29109470 TI - A global picture of biological invasion threat on islands. AB - Biological invasions are among the main drivers of biodiversity losses. As threats from biological invasions increase, one of the most urgent tasks is to identify areas of high vulnerability. However, the lack of comprehensive information on the impacts of invasive alien species (IAS) is a problem especially on islands, where most of the recorded extinctions associated with IAS have occurred. Here we provide a global, network-oriented analysis of IAS on islands. Using network analysis, we structured 27,081 islands and 437 threatened vertebrates into 21 clusters, based on their profiles in term of invasiveness and shared vulnerabilities. These islands are mainly located in the Southern Hemisphere and many are in biodiversity hotspots. Some of the islands share similar characteristics regarding their connectivity that could be useful for understanding their response to invasive species. The major invaders found in these clusters of islands are feral cats, feral dogs, pigs and rats. Our analyses reveal those IAS that systematically act alone or in combination, and the pattern of shared IAS among threatened species, providing new information to implement effective eradication strategies. Combined with further local, contextual information this can contribute to global strategies to deal with IAS. PMID- 29109471 TI - The meaning of intragenomic conflict. AB - Recent years have seen an explosion of interest in genes that function for their own good and to the detriment of other genes that reside in the same genome. Such intragenomic conflicts are increasingly recognized to underpin maladaptation and disease. However, progress has been impeded by a lack of clear understanding regarding what intragenomic conflict actually means, and an associated obscurity concerning its fundamental drivers. Here we develop a general theory of intragenomic conflict in which genes are viewed as inclusive-fitness-maximizing agents that come into conflict when their inclusive-fitness interests disagree. This yields a classification of all intragenomic conflicts into three categories according to whether genes disagree about where they have come from, where they are going, or where they currently are. We illustrate each of these three basic categories, survey and classify all known forms of intragenomic conflict, and discuss the implications for organismal maladaptation and human disease. PMID- 29109472 TI - Proteomic analysis reveals an impaired Ca2+/AQP5 pathway in the submandibular gland in hypertension. AB - Hypertension is a systemic disorder that affects numerous physiological processes throughout the body. Improper sodium transport is a common comorbidity of hypertension, and sodium transport is also critical for maintaining the secretion of submandibular glands, whether the function of submandibular glands is affected by hypertension remains unclear. To determine whether hypertension induces changes in the protein expression of submandibular glands, we compared the proteome of submandibular glands from 14-week-old spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats using LC-MS/MS. The results revealed that 95 proteins displayed different levels of expression between the submandibular glands from the SHRs and WKYs. Among these, 35 proteins were more abundant, and 60 proteins were less abundant in the SHR compared with the WKY rats. Specifically, aquaporin 5 and parvalbumin, which are correlated with water transport and intracellular Ca2+ signal transduction, were verified to exhibit differences in protein abundance. Impaired Ca2+ response to carbachol was confirmed in the acinar cells from SHRs, and hyposecretion by the submandibular glands was further confirmed by in vivo saliva collection. In conclusion, the proteomic analysis of the submandibular glands of SHRs revealed novel changes in protein abundance that provides possible mechanisms connecting hypertension and hyposecretion in submandibular glands. PMID- 29109473 TI - The shape of density dependence in fragmented landscapes explains an inverse buffer effect in a migratory songbird. AB - It is well known that forest fragmentation reduces fecundity in several avian species, including wood thrush, Hylocichla mustelina, a migratory songbird that has been declining for several decades. However, I found that landscape-scale density in wood thrush was lower and population declines steeper in higher quality, less-fragmented landscapes (an inverse buffer effect) than in poor quality landscapes. These patterns suggest that wood thrush was not limited by availability of breeding habitat but that declines were primarily driven by non breeding season events. A two-season model predicts that if this hypothesis is correct, breeding population trends will be negatively related to the strength of density dependence (b') in the breeding season. To test this, a site-dependence model was used to construct fecundity-density curves and showed that landscape fragmentation affected the shape of density dependence. In good quality landscapes, the onset of strong density dependence was much more abrupt than in poorer quality landscapes and the realized strength of density dependence, b', was lower in good quality landscapes. Population trends were negatively associated with b', providing support for the non-breeding limitation hypothesis. The combination of the negative associations of trends with b' and b' with landscape quality explain the inverse buffer effect. PMID- 29109474 TI - Current-induced viscoelastic topological unwinding of metastable skyrmion strings. AB - In the MnSi bulk chiral magnet, magnetic skyrmion strings of 17 nm in diameter appear in the form of a lattice, penetrating the sample thickness, 10-1000 MUm. Although such a bundle of skyrmion strings may exhibit complex soft-matter-like dynamics when starting to move under the influence of a random pinning potential, the details remain highly elusive. Here, we show that a metastable skyrmion string lattice is subject to topological unwinding under the application of pulsed currents of 3-5 * 106 A m-2 rather than being transported, as evidenced by measurements of the topological Hall effect. The critical current density above which the topological unwinding occurs is larger for a shorter pulse width, reminiscent of the viscoelastic characteristics accompanying the pinning-creep transition observed in domain-wall motion. Numerical simulations reveal that current-induced depinning of already segmented skyrmion strings initiates the topological unwinding. Thus, the skyrmion-string length is an element to consider when studying current-induced motion. PMID- 29109475 TI - Ultra-broadband Asymmetric Light Transmission and Absorption Through The Use of Metal Free Multilayer Capped Dielectric Microsphere Resonator. AB - In this paper, we propose a simple design with an excellent performance to obtain high contrast in transmission asymmetry based on dielectric microspheres. Initially, we scrutinize the impact of the sphere radius on forward and backward transmissions. Afterward, by introducing a capping layer on top of the sphere, transmission response for the backward illuminated light will be blocked. In the next step, in order to replace the reflecting metal cap with a metal free absorbing design, we adopt a modeling approach based on the transfer matrix method (TMM) to explore an ideal material to achieve metal free perfect absorption in a multilayer configuration of material-insulator-material-insulator (MIMI). As a result of our investigations, it is found that Titanium Nitride (TiN) is an excellent alternative to replace metal in a MIMI multilayer stack. Setting this stack as the top capping coating, we obtain a high contrast between forward and backward light transmission where in an ultra-broadband range of 400 nm-1000 nm, forward transmission is above 0.85 while its backward response stays below 0.2. Moreover, due to the existence of multilayer stack, a high asymmetry is also observed for absorption profiles. This design has a relatively simple and large scale compatible fabrication route. PMID- 29109476 TI - The major targets of acute norovirus infection are immune cells in the gut associated lymphoid tissue. AB - Noroviruses are the leading cause of food-borne gastroenteritis outbreaks and childhood diarrhoea globally, estimated to be responsible for 200,000 deaths in children each year 1-4 . Thus, reducing norovirus-associated disease is a critical priority. Development of vaccines and therapeutics has been hindered by the limited understanding of basic norovirus pathogenesis and cell tropism. While macrophages, dendritic cells, B cells and stem-cell-derived enteroids can all support infection of certain noroviruses in vitro 5-7 , efforts to define in vivo norovirus cell tropism have generated conflicting results. Some studies detected infected intestinal immune cells 8-12 , other studies detected epithelial cells 13 , and still others detected immune and epithelial cells 14-16 . Major limitations of these studies are that they were performed on tissue sections from immunocompromised or germ-free hosts, chronically infected hosts where the timing of infection was unknown, or following non-biologically relevant inoculation routes. Here, we report that the dominant cellular targets of a murine norovirus inoculated orally into immunocompetent mice are macrophages, dendritic cells, B cells and T cells in the gut-associated lymphoid tissue. Importantly, we also demonstrate that a norovirus can infect T cells, a previously unrecognized target, in vitro. These findings represent the most extensive analyses to date of in vivo norovirus cell tropism in orally inoculated, immunocompetent hosts at the peak of acute infection and thus they significantly advance our basic understanding of norovirus pathogenesis. PMID- 29109477 TI - Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes. AB - The causative agent of malaria, Plasmodium, replicates inside a membrane-bound parasitophorous vacuole (PV), which shields this intracellular parasite from the cytosol of the host cell 1 . One common threat for intracellular pathogens is the homeostatic process of autophagy, through which cells capture unwanted intracellular material for lysosomal degradation 2 . During the liver stage of a malaria infection, Plasmodium parasites are targeted by the autophagy machinery of the host cell, and the PV membrane (PVM) becomes decorated with several autophagy markers, including LC3 (microtubule-associated protein 1 light chain 3) 3,4 . Here we show that Plasmodium berghei parasites infecting hepatic cells rely on the PVM transmembrane protein UIS3 to avoid elimination by host-cell-mediated autophagy. We found that UIS3 binds host LC3 through a non-canonical interaction with a specialized surface on LC3 where host proteins with essential functions during autophagy also bind. UIS3 acts as a bona fide autophagy inhibitor by competing with host LC3-interacting proteins for LC3 binding. Our work identifies UIS3, one of the most promising candidates for a genetically attenuated vaccine against malaria 5 , as a unique and potent mediator of autophagy evasion in Plasmodium. We propose that the protein-protein interaction between UIS3 and host LC3 represents a target for antimalarial drug development. PMID- 29109478 TI - A bacterial pioneer produces cellulase complexes that persist through community succession. AB - Cultivation of microbial consortia provides low-complexity communities that can serve as tractable models to understand community dynamics. Time-resolved metagenomics demonstrated that an aerobic cellulolytic consortium cultivated from compost exhibited community dynamics consistent with the definition of an endogenous heterotrophic succession. The genome of the proposed pioneer population, 'Candidatus Reconcilibacillus cellulovorans', possessed a gene cluster containing multidomain glycoside hydrolases (GHs). Purification of the soluble cellulase activity from a 300litre cultivation of this consortium revealed that ~70% of the activity arose from the 'Ca. Reconcilibacillus cellulovorans' multidomain GHs assembled into cellulase complexes through glycosylation. These remarkably stable complexes have supramolecular structures for enzymatic cellulose hydrolysis that are distinct from cellulosomes. The persistence of these complexes during cultivation indicates that they may be active through multiple cultivations of this consortium and act as public goods that sustain the community. The provision of extracellular GHs as public goods may influence microbial community dynamics in native biomass-deconstructing communities relevant to agriculture, human health and biotechnology. PMID- 29109480 TI - Detection of subclonal L1 transductions in colorectal cancer by long-distance inverse-PCR and Nanopore sequencing. AB - Long interspersed nuclear elements-1 (L1s) are a large family of retrotransposons. Retrotransposons are repetitive sequences that are capable of autonomous mobility via a copy-and-paste mechanism. In most copy events, only the L1 sequence is inserted, however, they can also mobilize the flanking non repetitive region by a process known as 3' transduction. L1 insertions can contribute to genome plasticity and cause potentially tumorigenic genomic instability. However, detecting the activity of a particular source L1 and identifying new insertions stemming from it is a challenging task with current methodological approaches. We developed a long-distance inverse PCR (LDI-PCR) based approach to monitor the mobility of active L1 elements based on their 3' transduction activity. LDI-PCR requires no prior knowledge of the insertion target region. By applying LDI-PCR in conjunction with Nanopore sequencing (Oxford Nanopore Technologies) on one L1 reported to be particularly active in human cancer genomes, we detected 14 out of 15 3' transductions previously identified by whole genome sequencing in two different colorectal tumour samples. In addition we discovered 25 novel highly subclonal insertions. Furthermore, the long sequencing reads produced by LDI-PCR/Nanopore sequencing enabled the identification of both the 5' and 3' junctions and revealed detailed insertion sequence information. PMID- 29109479 TI - Viral and cellular N6-methyladenosine and N6,2'-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. AB - N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) modifications (m6A/m) of messenger RNA mediate diverse cellular functions. Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) has latent and lytic replication phases that are essential for the development of KSHV-associated cancers. To date, the role of m6A/m in KSHV replication and tumorigenesis is unclear. Here, we provide mechanistic insights by examining the viral and cellular m6A/m epitranscriptomes during KSHV latent and lytic infection. KSHV transcripts contain abundant m6A/m modifications during latent and lytic replication, and these modifications are highly conserved among different cell types and infection systems. Knockdown of YTHDF2 enhanced lytic replication by impeding KSHV RNA degradation. YTHDF2 binds to viral transcripts and differentially mediates their stability. KSHV latent infection induces 5' untranslated region (UTR) hypomethylation and 3'UTR hypermethylation of the cellular epitranscriptome, regulating oncogenic and epithelial-mesenchymal transition pathways. KSHV lytic replication induces dynamic reprogramming of epitranscriptome, regulating pathways that control lytic replication. These results reveal a critical role of m6A/m modifications in KSHV lifecycle and provide rich resources for future investigations. PMID- 29109481 TI - Pelagic barite precipitation at micromolar ambient sulfate. AB - Geochemical analyses of sedimentary barites (barium sulfates) in the geological record have yielded fundamental insights into the chemistry of the Archean environment and evolutionary origin of microbial metabolisms. However, the question of how barites were able to precipitate from a contemporary ocean that contained only trace amounts of sulfate remains controversial. Here we report dissolved and particulate multi-element and barium-isotopic data from Lake Superior that evidence pelagic barite precipitation at micromolar ambient sulfate. These pelagic barites likely precipitate within particle-associated microenvironments supplied with additional barium and sulfate ions derived from heterotrophic remineralization of organic matter. If active during the Archean, pelagic precipitation and subsequent sedimentation may account for the genesis of enigmatic barite deposits. Indeed, barium-isotopic analyses of barites from the Paleoarchean Dresser Formation are consistent with a pelagic mechanism of precipitation, which altogether offers a new paradigm for interpreting the temporal occurrence of barites in the geological record. PMID- 29109482 TI - First Evidence of Coherent Bands of Strong Turbulent Layers Associated with High Wavenumber Internal-Wave Shear in the Upstream Kuroshio. AB - The upstream Kuroshio flows through Okinawa Trough and the Tokara island chain, the region near the continental shelf of the East China Sea and shallow seamounts, where the Kuroshio can induce strong mixing over the shallow topography. Also, tidal currents over the rough topography may produce internal tides, and associated turbulence. The previous observations show energetic high vertical wavenumber near-inertial wave shear in the Kuroshio thermocline, which implies strong turbulent mixing. However, direct turbulence measurements in this region are very scarce. Using high lateral resolution (1-2 km) direct turbulence measurements, we show here, for the first time, that strong turbulent layers form spatially coherent banded structures with lateral scales of >O(10 km), associated with bands of near-inertial wave/diurnal internal tide shear of high vertical wavenumber in the upstream Kuroshio. The turbulent kinetic energy dissipation rates within these turbulent layers are >O(10-7 W kg-1), and estimated vertical eddy diffusivity shows >O(10-4 m2 s-1) on average. These results suggest that the high vertical wavenumber near-inertial waves propagating in the upstream Kuroshio could have large impacts on the watermass modifications, momentum mixing, nutrient supply, and associated biogeochemical responses in its downstream. PMID- 29109483 TI - Safety of Nonporous Silica Nanoparticles in Human Corneal Endothelial Cells. AB - Nonporous silica nanoparticles (SiNPs) are promising drug carrier platforms for intraocular drug delivery. In this study, we investigated the safety of three different sizes of SiNPs (50, 100, and 150 nm) in a human corneal endothelial cell (HCEC) line, B4G12. The HCECs were exposed to different concentrations (0, 25, 50, and 100 ug/ml) of three sizes of SiNPs for up to 48 h. Cellular viability, autophagy, lactate dehydrogenase (LDH) assay, and mammalian target of rapamycin (mTOR) pathway activation were evaluated. Intracellular distribution of the SiNPs was evaluated with transmission electron microscopy (TEM). TEM revealed that the SiNPs were up-taken by the HCECs inside cytoplasmic vacuoles. No mitochondrial structural damage was observed. Both cellular viability and LDH level remained unchanged with up to 100 ug/mL of SiNP treatment. Autophagy showed a significant dose-dependent activation with 50, 100, and 150 nm SiNPs. However, the mTOR activation remained unchanged. Human corneal tissue culture with 100 ug/ml concentrations of SiNPs for 72 h revealed no significant endothelial toxicity. In vivo corneal safety of the SiNPs (0.05 ml intracameral injection, 200 mg/ml concentration) was also verified in rabbit models. These findings suggested that 50, 100, and 150 nm SiNPs did not induce acute significant cytotoxicity in corneal endothelial cells at concentrations up to 100 ug/mL. However, long-term toxicity of SiNPs remains unknown. PMID- 29109485 TI - Continuing Medical Education Questions: November 2017: Complications of Bariatric Surgery: What You Can Expect to See in Your GI Practice. PMID- 29109484 TI - Beyond Bell's theorem: realism and locality without Bell-type correlations. AB - The long-lasting view of entanglement as the characteristic trait of quantum mechanics has been recently challenged by experimental demonstrations of non quantum entanglement. This motivates a review of the meaning of Bell violations, which have been widely taken to prove the impossibility of a realistic interpretation of quantum mechanics and as a manifestation of its non-local character. This work provides new theoretical evidence for the need of reviewing the meaning of Bell violations, especially when they occur outside the quantum framework. We present a local-realistic model that reproduces quantum predictions concerning Bell tests. We claim that local-realism is fully compatible with correlations that are not of the Bell type and therefore lie outside the scope of Bell's theorem. Most experimental Bell tests involve either spin vectors spanning the Bloch sphere or Stokes vectors spanning the Poincare sphere. A suitable statistical tool that allows assessing correlations between vectors is given by inner-product-type correlations. Using them, it is possible to reproduce quantum predictions for all Bell states, thereby explaining experimental results of Bell tests within a local-realistic framework. PMID- 29109486 TI - Continuing Medical Education: November 2017: Complications of Bariatric Surgery: What You Can Expect to See in Your GI Practice. PMID- 29109487 TI - Inflammatory Bowel Disease in an Elderly Woman After Nivolumab Administration. PMID- 29109488 TI - Enteral Nutrition in the Treatment of Crohn's Disease: Overlooked and Underutilized. PMID- 29109489 TI - The First Case of Mumps-Associated Achalasia. PMID- 29109490 TI - Lower-Extremity Vasospasm Caused by Carcinoid Syndrome. PMID- 29109491 TI - Cyclic Vomiting Syndrome: Randomized Controlled Trials Are also Needed in Adults. PMID- 29109493 TI - Continuing Medical Education Questions: November 2017: Systematic Review: Disease Activity Indices in Eosinophilic Esophagitis. PMID- 29109492 TI - Yes, We Are Still Talking about Cylosporin vs. Infliximab in Steroid Resistant Acute Severe Ulcerative Colitis. AB - The Spanish IBD Registry (ENEIDA) is reporting in this issue of the Journal on a retrospective assessment of outcomes of cyclosporine use and infliximab use to treat steroid refractory acute severe ulcerative colitis (SR-ASUC) between 1989 and 2013. Overall, they found similar outcomes in terms of 3 month and 1 year colectomy rates. Serious adverse events were lower in cyclosporine users. While this study does not meet the standard of a prospective randomized controlled trial, it does remind us that cyclosporine can be effective in (SR-ASUC) and should be considered in those who have already failed antibody to tumor necrosis factor therapy or as a bridge to immunomodulators that have a slower onset of action. PMID- 29109494 TI - Not Too Hot, Not Too Cold, but "Just Right". AB - When ordering diagnostic tests, physicians are faced with a problem of not too many tests, not too few, but 'just right'. However, in medical diagnostics 'just right' may be very difficult to identify. Such is the conundrum presented in study by Rubenstein and colleagues regarding appropriate use of repeat esophagogastroduodenoscopy (EGD) in Veterans Health Administration (VHA) medical facilities. The important message of this paper is that out of 235,855 patients with an index EGD, 36% underwent repeat EGD over 5 years, of which only 9% (range 3-18%a cross VHA facilities) were classified as probable overuse. PMID- 29109495 TI - A Pitfall in Suspected (refractory) Celiac Disease: Losartan-Induced Enteropathy. PMID- 29109496 TI - No Results? No Problem! Why We Are Publishing Methods of a Landmark Study With Results Still Pending. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the United States, and screening for CRC is a national health-care priority. In this issue, investigators from the CONFIRM study group report on the aims and study design of a large, multicenter, randomized prospective study of whether screening colonoscopy is superior to an annual fecal immunochemical test (FIT). CONFRIM hopes to enroll 50,000 individuals, aged 50-75 years, from 46 Veterans Affairs Medical Centers and monitor them for 10 years. This article is unique in that no results are presented as the study is not yet complete. We have taken this unusual step as we believe the topic of CRC screening is critically important for our readers and that the results of this massive study have the potential to change clinical practice throughout all fields of medicine. PMID- 29109497 TI - Response to Miner et al. PMID- 29109499 TI - Cost-Effective but Unaffordable and Unequal Hepatitis C Treatment in the US. PMID- 29109500 TI - Fluoroscopic-Assisted, EUS-Guided Trans-Sigmoidal Pancreas Biopsy in a Patient with Surgically Altered Anatomy. PMID- 29109501 TI - Endocytoscopy of Superficial Nonampullary Duodenal Epithelial Tumor: Two Cases of Tubular Adenocarcinoma and Adenoma. PMID- 29109502 TI - Direct-Acting Antivirals and Mixed Cryoglobulinemia Vasculitis: Long-Term Outcome of Patients Achieving HCV Eradication. PMID- 29109503 TI - Continuing Medical Education: November 2017: Systematic Review: Disease Activity Indices in Eosinophilic Esophagitis. PMID- 29109504 TI - Response to Currie et al. PMID- 29109505 TI - Response to Liu et al. PMID- 29109506 TI - Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship. AB - Cigarette smoking is an established environmental risk factor for Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease, although a mechanistic basis remains largely unknown. We aimed at investigating how smoking affects blood DNA methylation in MS patients, by assaying genome-wide DNA methylation and comparing smokers, former smokers and never smokers in two Swedish cohorts, differing for known MS risk factors. Smoking affects DNA methylation genome-wide significantly, an exposure-response relationship exists and the time since smoking cessation affects methylation levels. The results also show that the changes were larger in the cohort bearing the major genetic risk factors for MS (female sex and HLA risk haplotypes). Furthermore, CpG sites mapping to genes with known genetic or functional role in the disease are differentially methylated by smoking. Modeling of the methylation levels for a CpG site in the AHRR gene indicates that MS modifies the effect of smoking on methylation changes, by significantly interacting with the effect of smoking load. Alongside, we report that the gene expression of AHRR increased in MS patients after smoking. Our results suggest that epigenetic modifications may reveal the link between a modifiable risk factor and the pathogenetic mechanisms. PMID- 29109507 TI - Chemometric Evaluation of THz Spectral Similarity for the Selection of Early Drug Candidates. AB - In this paper we discuss the link between the domain of physical parameters - molecular descriptors of a drug, and terahertz (THz) spectra. We measured the derivatives of the well-known anti-inflammatory drug Piroxicam using THz spectroscopy and employed Principal Component Analysis to build similarity maps in the molecular descriptor and spectral domains. We observed, that the spatial neighborhood on the molecular descriptors map is highly correlated with the spectral neighbourhood within a group of structurally-similar molecules. We built a Partial Least Squares (PLS) predictive model to quantify the relationship between the spectra and the melting point, which can guide the selection of early drug candidates. PMID- 29109508 TI - Mice in social conflict show rule-observance behavior enhancing long-term benefit. AB - Disorderly resolution of conflict is costly, whereas orderly resolution by consent rules enables quick settlement. However, it is unclear whether non-human animals can make and observe rules to resolve conflict without aggression. Here we report a new behavioral paradigm for mice: a modified two-armed maze that uses wireless electrical brain stimulation as reward. First, the mice were individually operant-trained to initiate and then receive the reward at the signaled arm. Next, two mice were coupled and had to cooperate to initiate reward but then to compete over reward allocation. Mice develop and observe a rule of reward zone allocation that increases the total amount of reward and reward equity between the pair. In the mutual rule-observance behavior, positive reciprocity and tolerance to the other's violation are also observed. These findings suggest that rodents can learn to make and observe rules to resolve conflict, enhancing long-term benefit and payoff equity. PMID- 29109509 TI - Centimeter-wide worm-like fossils from the lowest Cambrian of South China. AB - The trace fossil record implies that large worm-like animals were in place along with the skeletonizing organisms during the initial stage of the Cambrian explosion. Body fossils of large worms, however, have so far not been found. Here, we describe a large, soft-bodied, worm-like organism, Vittatusivermis annularius gen. et sp. nov. from the lowest Cambrian of South China, which is constrained to the Fortunian Age (541-529 Ma) of the Cambrian Period. The elongate body of Vittatusivermis was large enough to have supported organ systems and a fluid skeleton that facilitated peristaltic locomotion, thus allowing for more complex patterns of movement than those of flatworms. Its occurrence on the same bedding surface as trace fossils suggests that Vittatusivermis might have produced epichnial trails and shallow burrows on and within sediments. Therefore, Vittatusivermis is likely to have been one of the long expected producers of trace fossils in the earliest Cambrian. PMID- 29109510 TI - 3d-4f coupling and multiferroicity in frustrated Cairo Pentagonal oxide DyMn2O5. AB - In solid state science, multifunctional materials and especially multiferroics have attracted a great deal of attention, as they open the possibility for next generation spintronic and data storage devices. Interestingly, while many of them host coexisting 3d and 4f elements, the role of the coupling between these two magnetic entities has remained elusive. By means of single crystal neutron diffraction and inelastic neutron scattering experiments we shed light on this issue in the particular case of the multiferroic oxide DyMn2O5. This compound undergoes a first order magnetic transition from a high temperature incommensurate phase to a low temperature commensurate one. Our investigation reveals that although these two phases have very different magnetic structures, the spin excitations are quite similar indicating a fragile low temperature ground state with respect to the high temperature one. Such a rare scenario is argued to be a manifestation of the competition between the exchange interaction and 4f magnetic anisotropy present in the system. It is concluded that the magnetic structure, hence the ferroelectricity, can be finely tuned depending on the anisotropy of the rare earth. PMID- 29109511 TI - ASH1L histone methyltransferase regulates the handoff between damage recognition factors in global-genome nucleotide excision repair. AB - Global-genome nucleotide excision repair (GG-NER) prevents ultraviolet (UV) light induced skin cancer by removing mutagenic cyclobutane pyrimidine dimers (CPDs). These lesions are formed abundantly on DNA wrapped around histone octamers in nucleosomes, but a specialized damage sensor known as DDB2 ensures that they are accessed by the XPC initiator of GG-NER activity. We report that DDB2 promotes CPD excision by recruiting the histone methyltransferase ASH1L, which methylates lysine 4 of histone H3. In turn, methylated H3 facilitates the docking of the XPC complex to nucleosomal histone octamers. Consequently, DDB2, ASH1L and XPC proteins co-localize transiently on histone H3-methylated nucleosomes of UV exposed cells. In the absence of ASH1L, the chromatin binding of XPC is impaired and its ability to recruit downstream GG-NER effectors diminished. Also, ASH1L depletion suppresses CPD excision and confers UV hypersensitivity. These findings show that ASH1L configures chromatin for the effective handoff between damage recognition factors during GG-NER activity. PMID- 29109512 TI - Modulating medial septal cholinergic activity reduces medial entorhinal theta frequency without affecting speed or grid coding. AB - Medial septal inputs to the hippocampal system are crucial for aspects of temporal and spatial processing, such as theta oscillations and grid cell firing. However, the precise contributions of the medial septum's cholinergic neurones to these functions remain unknown. Here, we recorded neuronal firing and local field potentials from the medial entorhinal cortex of freely foraging mice, while modulating the excitability of medial septal cholinergic neurones. Alteration of cholinergic activity produced a reduction in the frequency of theta oscillations, without affecting the slope of the non-linear theta frequency vs running speed relationship observed. Modifying septal cholinergic tone in this way also led mice to exhibit behaviours associated with novelty or anxiety. However, grid cell firing patterns were unaffected, concordant with an absence of change in the slopes of the theta frequency and firing rate speed signals thought to be used by grid cells. PMID- 29109513 TI - Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer. AB - Androgen receptor (AR) is widely expressed in different subtypes of breast cancer (BC). However, it is unclear how AR functions in HER2 positive (+) BC. Knockdown of AR with shRNAs and a new generation anti-androgen drug, Enzalutamide, were used to explore the involvement of AR on the growth of HER2 + BC cells (HCC1954 and SKBR3). AR shRNA or Enzalutamide inhibited the growth of SKBR3 cells at a similar extend compared to trastuzumab, an approved HER2 targeted drug. Combining Enzalutamide with trastuzumab further decreased the growth of HCC1954 and SKBR3 cells compared with single agent alone in vitro. Biochemical analysis revealed that inhibiting AR resulted in decreased HER2 phosphorylation and activation of Erk and Akt, without affecting the HER2 and HER3 expression. The in vivo efficacy of Enzalutamide was further tested using the HCC1954 xenograft model. Enzalutamide impaired the growth of HCC1954 tumor at a level comparable to that by trastuzumab. Enzalutamide decreased Ki67 staining and increased activated caspase3 staining compared with vehicle control in HCC1954 tumors. Our results indicate AR plays an important role in promoting the growth of HER2 + BC by cross talking with the HER2 signaling. AR drug may be used as an alternative second line therapy for treating HER2 + BC. PMID- 29109514 TI - Violet Light Transmission is Related to Myopia Progression in Adult High Myopia. AB - Myopia is increasing worldwide. Although the exact etiology of myopia is unknown, outdoor activity is one of the most important environmental factors for myopia control. We previously reported that violet light (VL, 360-400 nm wavelength), which is abundant in the outdoor environment, suppressed myopia progression for individuals under 20 years of age. However, whether VL is also effective for adult high myopia, which can be sight-threatening, has remained unknown. To investigate the influence of VL for adult myopia, we retrospectively compared the myopic progression and the axial length elongation over five years in adult high myopic patients over 25 years of age after two types (non-VL transmitting and VL transmitting) of phakic intraocular lens (pIOL) implantation. We found that high myopic patients with the non-VL transmitting pIOLs implanted are almost two times more myopic in the change of refraction and four times longer in the change of axial length, compared to those implanted with the VL transmitting pIOLs. This result indicated that the VL transmitting pIOL suppressed myopia progression and axial length elongation compared with the non-VL transmitting one. In conclusion, our study showed the VL possibly has an anti-myopia effect for human adults with high myopia. PMID- 29109515 TI - Chemical Similarity Enrichment Analysis (ChemRICH) as alternative to biochemical pathway mapping for metabolomic datasets. AB - Metabolomics answers a fundamental question in biology: How does metabolism respond to genetic, environmental or phenotypic perturbations? Combining several metabolomics assays can yield datasets for more than 800 structurally identified metabolites. However, biological interpretations of metabolic regulation in these datasets are hindered by inherent limits of pathway enrichment statistics. We have developed ChemRICH, a statistical enrichment approach that is based on chemical similarity rather than sparse biochemical knowledge annotations. ChemRICH utilizes structure similarity and chemical ontologies to map all known metabolites and name metabolic modules. Unlike pathway mapping, this strategy yields study-specific, non-overlapping sets of all identified metabolites. Subsequent enrichment statistics is superior to pathway enrichments because ChemRICH sets have a self-contained size where p-values do not rely on the size of a background database. We demonstrate ChemRICH's efficiency on a public metabolomics data set discerning the development of type 1 diabetes in a non obese diabetic mouse model. ChemRICH is available at www.chemrich.fiehnlab.ucdavis.edu. PMID- 29109516 TI - Cytotoxicity of Aconitum alkaloid and its interaction with calf thymus DNA by multi-spectroscopic techniques. AB - The cytotoxicities of three aconitum alkaloids- aconitine, hypaconitine and mesaconitine, and their abilities to bind DNA have been explored. Rat myocardial cells H9c2 were treated with aconitum alkaloids and assessed the cytotoxicities by using MTT assay and flow cytometry. Apoptosis was evidenced by the results of the annexin V/propidium iodide (PI) assay. Aconitine was found to be the most toxic in rat myocardial cells H9c2 in three aconitum alkaloids. At the same time, DNA adducts were isolated and then analyzed by UV-Vis spectroscopy after exposure to alkaloids, which indicated that three alkaloids could bind to DNA in rat myocardial cells H9c2. Furthermore, their binding modes were investigated by UV Visible, fluorescence, DNA melting studies and ionic strength effect. Results indicated that the interaction between three alkaloids and DNA were intercalation coupled with electrostatic effect. The estimated binding constants were between 4.83 * 105 M-1 to 9.85 * 105 M-1 for three alkaloids at 298 K. PMID- 29109517 TI - Workplace violence among female sex workers who use drugs in Vancouver, Canada: does client-targeted policing increase safety? AB - Workplace violence, by clients or predators, poses serious negative health consequences for sex workers. In 2013, the Vancouver (British Columbia), Canada Police Department changed their guidelines with the goal of increasing safety for sex workers by focusing law enforcement on clients and third parties, but not sex workers. We sought to examine the trends and correlates of workplace violence among female sex workers (FSW) before and after the guideline change, using data collected from prospective cohorts of persons who use illicit drugs in Vancouver, Canada. Among 259 FSW, 21.0% reported workplace violence at least once during the study period between 2008 and 2014. There was no statistically significant change in rates of workplace violence after the guideline change. In our multivariable analysis, daily heroin use was independently associated with workplace violence. The 2013 policing guideline change did not appear to have resulted in decreased reports of workplace violence. Increased access to opioid agonist therapies may reduce workplace violence among drug-using FSW. PMID- 29109518 TI - Birth outcomes in Flint in the early stages of the water crisis. AB - Following Flint's switching from the Detroit Water Authority to the Flint River as the source of its tap water, we show, using birth records, that there were lower average birthweights and higher incidence of low birthweight (< 2500 g) among infants. We compare these observed reductions in Flint birthweights to a series of counterfactuals. We find that among white mothers, there was a 71 g reduction in birthweight and a 26% increase in the incidence of low birthweight relative to what would have likely occurred without the water change. For infants of black mothers, we were unable to verify that the smaller reduction in birthweight was statistically different than what would have occurred without the water change. We consider lead contamination and stress as potential causes of the poor birth outcomes, as well as the reasons for the null effect among the infants of black mothers. PMID- 29109519 TI - Network-pharmacology-based validation of TAMS/CXCL-1 as key mediator of XIAOPI formula preventing breast cancer development and metastasis. AB - Network pharmacology has become a powerful means of understanding the mechanisms underlying the action of Chinese herbs in cancer treatment. This study aims to validate the preventive effects and molecular mechanisms of a clinical prescription XIAOPI formula against breast cancer. In vivo breast cancer xenograft data showed that XIAOPI delayed breast cancer development and efficiently inhibited lung metastasis, accompanied by prolonged survival benefits and decreased cancer stem cell subpopulations. However, similar phenomenon were not observed in a cell model. The herb-ingredient-target network analysis further identified a total of 81 genes closely correlated with the breast cancer chemoprevention effects of XIAOPI. Cytokine array analysis further validated CXCL 1 as the key target of XIAOPI both in vitro and in vivo. Evaluation of the mechanism demonstrated that CXCL-1 administration significantly abrogated the metastatic inhibition effects of XIAOPI on breast cancer migration, invasion, stem cells subpopulations, epithelial-mesenchymal transition(EMT), or mammosphere formation abilities. Overall, our study provides experimental evidence and molecular mechanisms that may facilitate the safe and effective use of herbal medicine for the prevention of breast cancer growth or metastasis, and may lead to CXCL-1-based therapeutic strategies for mammary malignancies. PMID- 29109520 TI - A perfusion incubator liver chip for 3D cell culture with application on chronic hepatotoxicity testing. AB - Liver chips have been developed to recapitulate in vivo physiological conditions to enhance hepatocyte functions for assessing acute responses to drugs. To develop liver chips that can assess repeated dosing chronic hepatotoxicity, we need to ensure that hepatocyte functions be maintained at constant values over two weeks in stable culture conditions of sterility, temperature, pH, fluidic flow of culture media and drugs. We have designed a perfusion-incubator-liver chip (PIC) for 3D cell culture, that assures a tangential flow of the media over the spheroids culture. Rat hepatocyte spheroids constrained between a cover glass and a porous-ultrathin Parylene C membrane experienced optimal mass transfer and limited shear stress from the flowing culture media; maintained cell viability over 24 days. Hepatocyte functions were significantly improved and maintained at constant values (urea, albumin synthesis, and CYP450 enzyme activities) for 14 days. The chip act as an incubator, having 5% CO2 pressure-driven culture-media flow, on-chip heater and active debubbler. It operates in a biosafety cabinet, thus minimizing risk of contamination. The chronic drug response to repeated dosing of Diclofenac and Acetaminophen evaluated in PIC were more sensitive than the static culture control. PMID- 29109521 TI - Enhanced Attentional Bias Variability in Post-Traumatic Stress Disorder and its Relationship to More General Impairments in Cognitive Control. AB - Hypervigilance towards threat is one of the defining features of post-traumatic stress disorder (PTSD). This symptom predicts that individuals with PTSD will be biased to attend to potential dangers in the environment. However, cognitive tasks designed to assess visual-spatial attentional biases have shown mixed results. A newer proposal suggests that attentional bias is not a static phenomenon, but rather is characterized by fluctuations towards and away from threat. Here, we tested 28 combat Veterans with PTSD and 28 control Veterans on a dot probe task with negative-neutral word pairs. Combat-related words and generically negative words were presented in separate blocks. Replicating previous results, neither group showed a bias to attend towards or away from threat, but PTSD patients showed greater attentional bias variability (ABV), which correlated with symptom severity. However, the cognitive processes indexed by ABV are unclear. The present results indicated that ABV was strongly correlated with standard deviation at the reaction time (RT) level and with excessively long RTs (ex-Gaussian tau) related to cognitive failures. These findings suggest an overall increase in response variability unrelated to threat related biases in spatial attention, and support a disruption in more general cognitive control processes in PTSD. PMID- 29109522 TI - Cancer genomics: The driving force of cancer evolution. PMID- 29109523 TI - Gene expression: Principles of gene regulation across tissues. PMID- 29109525 TI - Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6. AB - A portion of newly synthesized transmembrane domain proteins tend to fail to assemble correctly in the lumen of the endoplasmic reticulum, thus resulting in the production of a signal sequence-uncleaved form of the defective species. Although the efficient degradation of these mistargeted polypeptides is crucial, the molecular mechanism of their elimination pathway has not been adequately characterized. In this study, we focused on one such cryptic portion of a defective transmembrane domain protein, HLA-A, and show that a part of HLA-A is produced as a signal sequence-uncleaved labile species that is immediately targeted to the degradation pathway. We found that both BAG6 and proteasomes are indispensable for elimination of mislocalized HLA-A species. Furthermore, defective HLA-A is subjected to BAG6-dependent solubilization in the cytoplasm. These observations suggest that BAG6 acts as a critical factor for proteasome mediated degradation of mislocalized HLA-A with a non-cleaved signal sequence at its N-terminus. PMID- 29109524 TI - Navigating complexity to breed disease-resistant crops. AB - Plant diseases are responsible for substantial crop losses each year and pose a threat to global food security and agricultural sustainability. Improving crop resistance to pathogens through breeding is an environmentally sound method for managing disease and minimizing these losses. However, it is challenging to breed varieties with resistance that is effective, stable and broad-spectrum. Recent advances in genetic and genomic technologies have contributed to a better understanding of the complexity of host-pathogen interactions and have identified some of the genes and mechanisms that underlie resistance. This new knowledge is benefiting crop improvement through better-informed breeding strategies that utilize diverse forms of resistance at different scales, from the genome of a single plant to the plant varieties deployed across a region. PMID- 29109527 TI - The RNA binding protein La/SS-B promotes RIG-I-mediated type I and type III IFN responses following Sendai viral infection. AB - La/SS-B (or La) is a 48 kDa RNA-binding protein and an autoantigen in autoimmune disorders such as systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). La involvement in regulating the type I interferon (IFN) response is controversial - acting through both positive and negative regulatory mechanisms; inhibiting the IFN response and enhancing viral growth, or directly inhibiting viral replication. We therefore sought to clarify how La regulates IFN production in response to viral infection. ShRNA knockdown of La in HEK 293 T cells increased Sendai virus infection efficiency, decreased IFN-beta, IFN-lambda1, and interferon-stimulated chemokine gene expression. In addition, knockdown attenuated CCL-5 and IFN-lambda1 secretion. Thus, La has a positive role in enhancing type I and type III IFN production. Mechanistically, we show that La directly binds RIG-I and have mapped this interaction to the CARD domains of RIG I and the N terminal domain of La. In addition, we showed that this interaction is induced following RIG-I activation and that overexpression of La enhances RIG I-ligand binding. Together, our results demonstrate a novel role for La in mediating RIG-I-driven responses downstream of viral RNA detection, ultimately leading to enhanced type I and III IFN production and positive regulation of the anti-viral response. PMID- 29109526 TI - Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability. AB - Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, to identify potential targets for personalized treatment, we perform integrative genome-wide and epigenome-wide analyses. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are detected. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies promising therapeutic targets in ACC for drugs recently approved for precision cancer therapy. PMID- 29109528 TI - Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) - an 11-Year Prospective Study. AB - Liver fat can be non-invasively measured by proton magnetic resonance spectroscopy (1H-MRS) and fibrosis estimated as stiffness using transient elastography (FibroScan). There are no longitudinal data on changes in liver fat in Europids or on predictors of liver stiffness using these methods. We determined liver fat (1H-MRS) and clinical characteristics including features of insulin resistance at baseline and after a median follow-up period of 11.3 (range 7.3-13.4) years in 97 Finnish subjects. Liver stiffness was measured at 11.3 years. Liver fat content decreased by 5% (p < 0.05) over time. Values at baseline and 11.3 years were closely interrelated (r = 0.81, p < 0.001). Baseline liver fat (OR 1.32; 95%CI: 1.15-1.50) and change in BMI (OR 1.67; 95%CI: 1.24-2.25) were independent predictors of liver fat at 11.3 years (AUROC 0.90; 95%CI: 0.83 0.96). Baseline liver fat (AUROC 0.84; 95%CI: 0.76-0.92) predicted liver fat at 11.3 years more accurately than routinely available parameters (AUROC 0.76; 95%CI: 0.65-0.86, p = 0.02). At 11.3 years, 29% of the subjects had increased liver stiffness. Baseline liver fat (OR 2.17; 95%CI: 1.05-4.46) was an independent predictor of increased liver stiffness. These data show that liver fat is more important than the associated metabolic abnormalities as the predictor of future liver fat and fibrosis. PMID- 29109529 TI - Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo. AB - : Changes in miRNA expression glomerular of capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes. A better understanding could lead to novel diagnostic tools and reveal novel therapeutic targets. We explored deregulated miRNAs in an glomeruloendothelial in vitro model of ABMR due to class I human leukocyte antigen (HLA) with and without complement activation. We studied a set of 16 promising candidate miRNAs in microdissected glomeruli a confirmation set of 20 human transplant biopsies (DSA+) compared to 10 matched controls without evidence for ABMR. Twelve out of these 16 glomerulocapillary miRNAs could successfully be confirmed as dysregulated in vivo with 10 upregulated (let-7c-5p, miR-28-3p, miR-30d-5p, miR-99b-5p, miR-125a-5p, miR-195-5p, miR-374b-3p, miR-484, miR-501-3p, miR-520e) and 2 downregulated (miR29b-3p, miR-885-5p) in DSA+ vs. CONTROLS: A random forest analysis based on glomerular miRNAs identified 18/20 DSA+ and 8/10 controls correctly. This glomerulocapillary miRNA signature associated with HLA class I-DSA could improve our understanding of ABMR and be useful for diagnostic or therapeutic purposes. PMID- 29109531 TI - A robust single-beam optical trap for a gram-scale mechanical oscillator. AB - Precise optical control of microscopic particles has been mastered over the past three decades, with atoms, molecules and nano-particles now routinely trapped and cooled with extraordinary precision, enabling rapid progress in the study of quantum phenomena. Achieving the same level of control over macroscopic objects is expected to bring further advances in precision measurement, quantum information processing and fundamental tests of quantum mechanics. However, cavity optomechanical systems dominated by radiation pressure - so-called 'optical springs' - are inherently unstable due to the delayed dynamical response of the cavity. Here we demonstrate a fully stable, single-beam optical trap for a gram-scale mechanical oscillator. The interaction of radiation pressure with thermo-optic feedback generates damping that exceeds the mechanical loss by four orders of magnitude. The stability of the resultant spring is robust to changes in laser power and detuning, and allows purely passive self-locking of the cavity. Our results open up a new way of trapping and cooling macroscopic objects for optomechanical experiments. PMID- 29109532 TI - N-Myc-Interacting Protein Negatively Regulates TNF-alpha-Induced NF-kappaB Transcriptional Activity by Sequestering NF-kappaB/p65 in the Cytoplasm. AB - NF-kappaB is a major regulator of gene transcription involved in immune, inflammation, apoptosis and stress responses. However, the regulation of NF kappaB is not completely understood. Here, we report that the N-Myc and STATs Interactor (NMI), an IFN-inducible protein, is an important negative regulator of NF-kappaB activity. We found that NMI negatively regulates TNF-alpha-induced IL-6 and IL-1beta production in HeLa cells. Overexpression of NMI inhibits NF-kappaB transcriptional activity, in contrast, depletion of NMI by shRNA increases NF kappaB transcriptional activity. Mechanistically, NMI associates with NF kappaB/p65 and inhibits NF-kappaB/p65 nuclear translocation and thereby negatively regulates NF-kappaB/p65 transcriptional activity. Taken together, our results demonstrate that NMI modulates the NF-kappaB signaling pathway by sequestering NF-kappaB/p65 in the cytoplasm, resulting in reduced IL-6 and IL 1beta production after TNF-alpha stimulation. Treatment with IFNalpha in the presence of NMI leads to increased apoptosis in tumor cells. These findings reveal a novel mechanism by which NMI regulates NF-kappaB activity. PMID- 29109530 TI - A clinical-scale BioArtificial Liver, developed for GMP, improved clinical parameters of liver function in porcine liver failure. AB - Liver failure, whether arising directly from acute liver failure or from decompensated chronic liver disease is an increasing problem worldwide and results in many deaths. In the UK only 10% of individuals requiring a liver transplant receive one. Thus the need for alternative treatments is paramount. A BioArtificial Liver machine could temporarily replace the functions of the liver, buying time for the patient's liver to repair and regenerate. We have designed, implemented and tested a clinical-scale BioArtificial Liver machine containing a biomass derived from a hepatoblastoma cell-line cultured as three dimensional organoids, using a fluidised bed bioreactor, together with single-use bioprocessing equipment, with complete control of nutrient provision with feedback BioXpert recipe processes, and yielding good phenotypic liver functions. The methodology has been designed to meet specifications for GMP production, required for manufacture of advanced therapy medicinal products (ATMPs). In a porcine model of severe liver failure, damage was assured in all animals by surgical ischaemia in pigs with human sized livers (1.2-1.6 kg liver weights). The BioArtificial liver (UCLBAL) improved important prognostic clinical liver related parameters, eg, a significant improvement in coagulation, reduction in vasopressor requirements, improvement in blood pH and in parameters of intracranial pressure (ICP) and oxygenation. PMID- 29109533 TI - Bipolar configuration with twisted loop defect in chiral nematic droplets under homeotropic surface anchoring. AB - Optical textures and appropriate orientational structures have been studied within droplets of chiral nematic dispersed in polymer assigning the homeotropic anchoring. The helix axis of the chiral structure inside droplets forms the bipolar configuration. The optical droplet textures were analysed in the unpolarised light, analyser switching-off scheme and in crossed polarisers. The twisted loop defect reveals itself convincingly in all schemes. Its appearance at the optical patterns of the chiral nematic droplets has been examined depending on their size and the aspect direction. The existence of the defect has been verified by the structural and optical calculations. The effect of an electric field on both the defect line shape and the orientational structure of chiral nematic has been studied. PMID- 29109534 TI - Natural history of Helicobacter pylori VacA toxin in human gastric epithelium in vivo: vacuoles and beyond. AB - Uptake, intracellular trafficking and pathologic effects of VacA toxin from Helicobacter pylori have been widely investigated in vitro. However, no systematic analysis investigated VacA intracellular distribution and fate in H. pylori-infected human gastric epithelium in vivo, using ultrastructural immunocytochemistry that combines precise toxin localization with analysis of the overall cell ultrastructure and intercompartimental/interorganellar relationships. By immunogold procedure, in this study we investigated gastric biopsies taken from dyspeptic patients to characterize the overall toxin's journey inside human gastric epithelial cells in vivo. Endocytic pits were found to take up VacA at sites of bacterial adhesion, leading to a population of peripheral endosomes, which in deeper (juxtanuclear) cytoplasm enlarged and fused each other to form large VacA-containing vacuoles (VCVs). These directly opened into endoplasmic reticulum (ER) cisternae, which in turn enveloped mitochondria and contacted the Golgi apparatus. In all such organelles we found toxin molecules, often coupled with structural damage. These findings suggest direct toxin transfer from VCVs to other target organelles such as ER/Golgi and mitochondria. VacA-induced cytotoxic changes were associated with the appearance of auto(phago)lysosomes containing VacA, polyubiquitinated proteins, p62/SQSTM1 protein, cathepsin D, damaged mitochondria and bacterial remnants, thus leading to persistent cell accumulation of degradative products. PMID- 29109535 TI - Prevalence and factors associated with chronic kidney disease and end-stage renal disease in HIV-1-infected Asian patients in Tokyo. AB - This single-center cross-sectional study determined the prevalence and factors associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD) in HIV-1-infected Asian patients at the largest HIV clinic in Japan. HIV-1 infected patients who visited the clinic between September and December 2016 were analyzed. CKD was defined as estimated glomerular filtration rate of <60 ml/min/1.73 m2 or proteinuria >=1+, observed at least over three months. A logistic regression model was used to estimate the effects of various variables on CKD. The study included 1,990 patients; with 97% Asians, 34% aged of >=50 years, and 94% had HIV-1 load <50 copies/ml. The median time from HIV-1 diagnosis to study enrollment and duration of ART were 9.1 years (IQR4.8-14.2) and 7.35 years (IQR3.28-12), respectively. CKD and ESRD were diagnosed in 256 (13%) and 9 (0.5%) patients, respectively. The prevalence of CKD was 18.6% for age 50-59, 28.5% for 60-69, and 47% for over 70. Older age, heavier body weight, diabetes mellitus, hypertension, and longer duration of ART, but not duration of TDF exposure, were associated with CKD. The traditional risk factors, rather than HIV 1-related variables, were associated with CKD, suggesting the importance of management of such comorbidities in maintenance of renal function. PMID- 29109537 TI - Neuroprotective effect of Ruminococcus albus on oxidatively stressed SH-SY5Y cells and animals. AB - Recent evidence shows that the gut microbiota has an important role in gut-brain crosstalk and is linked to neuronal disorders. The aim of this study was to investigate the effects of intestinal Ruminococcus albus with probiotic potential on neuroprotection in oxidatively stressed SH-SY5Y neuroblastoma cells and animals. To investigate these effects, conditioned medium was prepared using Caco 2 cells cultured with heat-killed R. albus (CRA-CM). Caco-2 cells cultured with heat-killed R. albus showed increased BDNF expression and BDNF protein levels increased in CRA-CM. CRA-CM up-regulated the protein expression levels of SRF, C fos and CDK2. In addition, CRA-CM protected SH-SY5Y cells from H2O2-induced cell death. CRA-CM significantly decreased the Bax/Bcl-2 ratio in oxidatively stressed SH-SY5Y cells. Animal experiments showed that oral administration of heat-killed R. albus for 15 days attenuated the oxidative stress induced by sodium arsenate. Treatment with heat-killed R. albus reduced the level of ROS, and the levels of SOD and GSH increased in oxidatively stressed brains. In conclusion, the secretome prepared from Caco-2 cells cultured with heat-killed R. albus might promote neuronal proliferation through the activation of cell proliferation related proteins, and heat-killed R. albus protects neurons from oxidative damage by reducing ROS levels and increasing SOD and GSH levels. PMID- 29109536 TI - Self-patterning of rostral-caudal neuroectoderm requires dual role of Fgf signaling for localized Wnt antagonism. AB - The neuroectoderm is patterned along a rostral-caudal axis in response to localized factors in the embryo, but exactly how these factors act as positional information for this patterning is not yet fully understood. Here, using the self organizing properties of mouse embryonic stem cell (ESC), we report that ESC derived neuroectoderm self-generates a Six3+ rostral and a Irx3+ caudal bipolarized patterning. In this instance, localized Fgf signaling performs dual roles, as it regulates Six3+ rostral polarization at an earlier stage and promotes Wnt signaling at a later stage. The Wnt signaling components are differentially expressed in the polarized tissues, leading to genome-wide Irx3+ caudal-polarization signals. Surprisingly, differentially expressed Wnt agonists and antagonists have essential roles in orchestrating the formation of a balanced rostral-caudal neuroectoderm pattern. Together, our findings provide key processes for dynamic self-patterning and evidence that a temporally and locally regulated interaction between Fgf and Wnt signaling controls self-patterning in ESC-derived neuroectoderm. PMID- 29109538 TI - Two novel diterpenoid heterodimers, Bisebracteolasins A and B, from Euphorbia ebracteolata Hayata, and the cancer chemotherapeutic potential of Bisebracteolasin A. AB - Rare ent-abietane-rosane diterpenoid heterodimers, Bisebracteolasins A and B (1 and 2, respectively), were isolated from the roots of Euphorbia ebracteolata Hayata. Their structures and absolute configurations were elucidated from spectroscopic data and X-ray diffraction analysis. Compounds 1 and 2 exhibited moderate cytotoxic effects against five cancer cell lines. Compound 1 showed more effective antiproliferative activities against human tumour cells, HL-60 and SMMC 7721, with IC50 values of 2.61 and 4.08 MUM, respectively, than 2. Both compounds 1 and 2 inhibit the colorectal cancer stem cell line P6C with IC50 values of 16.48 and 34.76 MUM, respectively. Moreover, preliminary biological tests showed compound 1 exhibited inhibitory activity towards tumoursphere formation and migration of the P6C cell line. Overall, we identified two novel diterpenoid heterodimers, and Bisebracteolasin A exhibits therapeutic potential in impeding tumour growth and metastatic ability of cancer stem cells. PMID- 29109540 TI - Inflammation: Inflammatory memory is skin deep. PMID- 29109541 TI - Immunometabolism: T cells activate the fear. PMID- 29109539 TI - Controllable molecular motors engineered from myosin and RNA. AB - Engineering biomolecular motors can provide direct tests of structure-function relationships and customized components for controlling molecular transport in artificial systems 1 or in living cells 2 . Previously, synthetic nucleic acid motors 3-5 and modified natural protein motors 6-10 have been developed in separate complementary strategies to achieve tunable and controllable motor function. Integrating protein and nucleic-acid components to form engineered nucleoprotein motors may enable additional sophisticated functionalities. However, this potential has only begun to be explored in pioneering work harnessing DNA scaffolds to dictate the spacing, number and composition of tethered protein motors 11-15 . Here, we describe myosin motors that incorporate RNA lever arms, forming hybrid assemblies in which conformational changes in the protein motor domain are amplified and redirected by nucleic acid structures. The RNA lever arm geometry determines the speed and direction of motor transport and can be dynamically controlled using programmed transitions in the lever arm structure 7,9 . We have characterized the hybrid motors using in vitro motility assays, single-molecule tracking, cryo-electron microscopy and structural probing 16 . Our designs include nucleoprotein motors that reversibly change direction in response to oligonucleotides that drive strand-displacement 17 reactions. In multimeric assemblies, the controllable motors walk processively along actin filaments at speeds of 10-20 nm s-1. Finally, to illustrate the potential for multiplexed addressable control, we demonstrate sequence-specific responses of RNA variants to oligonucleotide signals. PMID- 29109543 TI - Penicillin induces alterations in glutamine metabolism in Streptococcus pneumoniae. AB - Penicillin is a bactericidal antibiotic that inhibits the synthesis of the peptidoglycan by targeting penicillin-binding proteins. This study aimed to assess through transcriptional profiling the stress response of S. pneumoniae strains after exposure to lethal penicillin concentrations to understand further the mode of action of penicillin. Two experimental designs (time-course and dose response) were used for monitoring the effect of penicillin on the transcriptional profile. The expression of some genes previously shown to be modulated by penicillin was altered, including ciaRH, pstS and clpL. Genes of the glnRA and glnPQ operons were among the most downregulated genes in the three strains. These genes are involved in glutamine synthesis and uptake and LC-MS work confirmed that penicillin treatment increases the intracellular glutamine concentrations. Glutamine conferred a protective role against penicillin when added to the culture medium. Glutamine synthetase encoded by glnA catalyses the transformation of glutamate and ammonium into glutamine and its chemical inhibition by the inhibitor L-methionine sulfoximine is shown to sensitize S. pneumoniae to penicillin, including penicillin-resistant clinical isolates. In summary, a combination of RNA-seq and metabolomics revealed that penicillin interferes with glutamine metabolism suggesting strategies that could eventually be exploited for combination therapy or for reversal of resistance. PMID- 29109542 TI - How poverty affects diet to shape the microbiota and chronic disease. AB - Here, we discuss the link between nutrition, non-communicable chronic diseases and socio-economic standing, with a special focus on the microbiota. We provide a theoretical framework and several lines of evidence from both animal and human studies that support the idea that income inequality is an underlying factor for the maladaptive changes seen in the microbiota in certain populations. We propose that this contributes to the health disparities that are seen between lower income and higher-income populations in high-income countries. PMID- 29109544 TI - Mapping and phasing of structural variation in patient genomes using nanopore sequencing. AB - Despite improvements in genomics technology, the detection of structural variants (SVs) from short-read sequencing still poses challenges, particularly for complex variation. Here we analyse the genomes of two patients with congenital abnormalities using the MinION nanopore sequencer and a novel computational pipeline-NanoSV. We demonstrate that nanopore long reads are superior to short reads with regard to detection of de novo chromothripsis rearrangements. The long reads also enable efficient phasing of genetic variations, which we leveraged to determine the parental origin of all de novo chromothripsis breakpoints and to resolve the structure of these complex rearrangements. Additionally, genome-wide surveillance of inherited SVs reveals novel variants, missed in short-read data sets, a large proportion of which are retrotransposon insertions. We provide a first exploration of patient genome sequencing with a nanopore sequencer and demonstrate the value of long-read sequencing in mapping and phasing of SVs for both clinical and research applications. PMID- 29109545 TI - The lunar core can be a major reservoir for volatile elements S, Se, Te and Sb. AB - The Moon bears a striking compositional and isotopic resemblance to the bulk silicate Earth (BSE) for many elements, but is considered highly depleted in many volatile elements compared to BSE due to high-temperature volatile loss from Moon forming materials in the Moon-forming giant impact and/or due to evaporative loss during subsequent magmatism on the Moon. Here, we use high-pressure metal silicate partitioning experiments to show that the observed low concentrations of volatile elements sulfur (S), selenium (Se), tellurium (Te), and antimony (Sb) in the silicate Moon can instead reflect core-mantle equilibration in a largely to fully molten Moon. When incorporating the core as a reservoir for these elements, their bulk Moon concentrations are similar to those in the present-day bulk silicate Earth. This suggests that Moon formation was not accompanied by major loss of S, Se, Te, Sb from Moon-forming materials, consistent with recent indications from lunar carbon and S isotopic compositions of primitive lunar materials. This is in marked contrast with the losses of other volatile elements (e.g., K, Zn) during the Moon-forming event. This discrepancy may be related to distinctly different cosmochemical behavior of S, Se, Te and Sb within the proto lunar disk, which is as of yet virtually unconstrained. PMID- 29109546 TI - Chronic kidney disease: Intensive blood pressure reduction lowers mortality in CKD. PMID- 29109547 TI - Skin to e-skin. PMID- 29109548 TI - How to build an educational bridge. PMID- 29109549 TI - High-performance semiconductor quantum-dot single-photon sources. AB - Single photons are a fundamental element of most quantum optical technologies. The ideal single-photon source is an on-demand, deterministic, single-photon source delivering light pulses in a well-defined polarization and spatiotemporal mode, and containing exactly one photon. In addition, for many applications, there is a quantum advantage if the single photons are indistinguishable in all their degrees of freedom. Single-photon sources based on parametric down conversion are currently used, and while excellent in many ways, scaling to large quantum optical systems remains challenging. In 2000, semiconductor quantum dots were shown to emit single photons, opening a path towards integrated single photon sources. Here, we review the progress achieved in the past few years, and discuss remaining challenges. The latest quantum dot-based single-photon sources are edging closer to the ideal single-photon source, and have opened new possibilities for quantum technologies. PMID- 29109551 TI - Modular endolysin of Burkholderia AP3 phage has the largest lysozyme-like catalytic subunit discovered to date and no catalytic aspartate residue. AB - Endolysins are peptidoglycan-degrading enzymes utilized by bacteriophages to release the progeny from bacterial cells. The lytic properties of phage endolysins make them potential antibacterial agents for medical and industrial applications. Here, we present a comprehensive characterization of phage AP3 modular endolysin (AP3gp15) containing cell wall binding domain and an enzymatic domain (DUF3380 by BLASTP), both widespread and conservative. Our structural analysis demonstrates the low similarity of an enzymatic domain to known lysozymes and an unusual catalytic centre characterized by only a single glutamic acid residue and no aspartic acid. Thus, our findings suggest distinguishing a novel class of muralytic enzymes having the activity and catalytic centre organization of DUF3380. The lack of amino acid sequence homology between AP3gp15 and other known muralytic enzymes may reflect the evolutionary convergence of analogous glycosidases. Moreover, the broad antibacterial spectrum, lack of cytotoxic effect on human cells and the stability characteristics of AP3 endolysin advocate for its future application development. PMID- 29109552 TI - Butyrate and propionate inhibit antigen-specific CD8+ T cell activation by suppressing IL-12 production by antigen-presenting cells. AB - Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune responses. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8+ T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8+ T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8+ T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8+ T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8+ T cell function with possible implications in anti-cancer immunotherapy. PMID- 29109553 TI - NMR relaxation properties of the synthetic malaria pigment beta-hematin. AB - 200 million patients suffer from malaria, a parasitic disease caused by protozoans of the genus Plasmodium. Reliable diagnosis is crucial since it allows the early detection of the disease. The development of rapid, sensitive and low cost diagnosis tools is an important research area. Different studies focused on the detection of hemozoin, a major by-product of hemoglobin detoxification by the parasite. Hemozoin and its synthetic analog, beta-hematin, form paramagnetic crystals. A new detection method of malaria takes advantage of the paramagnetism of hemozoin through the effect that such magnetic crystals have on Nuclear Magnetic Resonance (NMR) relaxation of water protons. Indeed, magnetic microparticles cause a shortening of the relaxation times. In this work, the magnetic properties of two types of beta-hematin are assessed at different temperatures and magnetic fields. The pure paramagnetism of beta-hematin is confirmed. The NMR relaxation of beta-hematin suspensions is also studied at different magnetic fields and for different echo-times. Our results help to identify the best conditions for beta-hematin detection by NMR: T 2 must be selected, at large magnetic fields and for long echo-times. However, the effect of beta-hematin on relaxation does not seem large enough to achieve accurate detection of malaria without any preliminary sample preparation, as microcentrifugation. PMID- 29109554 TI - The evolution of seasonal influenza viruses. AB - This corrects the article DOI: 10.1038/nrmicro.2017.118. PMID- 29109556 TI - Management of mechanical ventilation in patients with hospital-acquired pneumonia: A retrospective, observational study. AB - BACKGROUND: Hospital-acquired pneumonia (HAP) in intensive care patients is a frequent reason for mechanical ventilation (MV). The management of MV and ventilator weaning vary, depending on the type of lung inflammation. This retrospective, observational study screened the data from all patients admitted to the intensive care unit (ICU) of the Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc between 2011 and 2016. The aims were to determine the parameters of pressure-controlled ventilation, the frequencies of tracheostomy, bronchoscopy, reconnection to MV, the length of ICU and hospital stay and the mortality in subgroups with early-/late-onset HAP compared to a subgroup with community acquired pneumonia (CAP) and patients with MV without pneumonia. The primary outcome of this study was MV length. RESULTS: Over the study period, a total of 2672 patients were hospitalised. Excluded were 137 organ donors, 66 patient without MV and 20 patients placed on volume-controlled ventilation. The cohort comprised 2.447 patients requiring MV. A total of 1.927 patients (78.7%) were indicated for MV without signs of pneumonia. CAP was diagnosed in 131 patients (5.4%). The criteria for HAP were met by 389 patients (16.0%). Early-onset and late-onset HAP was diagnosed in 63 (2.6%) and 326 (13.3%) patients, respectively. In the subgroups without pneumonia, with CAP, early- and late-onset HAP, the median MV times were 3, 6, 6 and 12 days, respectively, and the median peak inspiratory pressure (Pinsp) of MV was 20, 25, 25 and 27 cm H2O, respectively. The median positive end-expiratory pressure (PEEP) was 5, 8, 8 and 11 cm H2O, respectively. The median inspired oxygen concentrations (FiO2) were 0.45, 0.7, 0.7 and 0.8, respectively. The median length of hospital stays was 8, 15, 15 and 17 days. The mortality rates were 11.4%, 3.8%, 9.5% and 31.3%, respectively. CONCLUSIONS: During MV, the late-onset HAP subgroup was shown to have the highest Pinsp, PEEP and FiO2, the longest MV time, ICU and hospital stay, the highest frequency of tracheostomy, reconnection to MV, pulmonary hygiene bronchoscopy and the highest mortality compared to the early-onset HAP and CAP subgroups. The lowest values were found in the mechanically ventilated patients without pneumonia. The differences were due to the severity of lung damage that is graduated from CAP over early-onset HAP after late-onset HAP. PMID- 29109557 TI - Creating an Arms Race? Examining School Costs and Motivations for Providing NAPLEX and PCOA Preparation. AB - Objective. To examine the extent of financial and faculty resources dedicated to preparing students for NAPLEX and PCOA examinations, and how these investments compare with NAPLEX pass rates. Methods. A 23-item survey was administered to assessment professionals in U.S. colleges and schools of pharmacy (C/SOPs). Institutions were compared by type, age, and student cohort size. Institutional differences were explored according to the costs and types of NAPLEX and PCOA preparation provided, if any, and mean NAPLEX pass rates. Results. Of 134 C/SOPs that received the survey invitation, 91 responded. Nearly 80% of these respondents reported providing some form of NAPLEX preparation. Significantly higher 2015 mean NAPLEX pass rates were found in public institutions, schools that do not provide NAPLEX prep, and schools spending less than $10,000 annually on NAPLEX prep. Only 18 schools reported providing PCOA preparation. Conclusion. Investment in NAPLEX and PCOA preparation resources vary widely across C/SOPs but may increase in the next few years, due to dropping NAPLEX pass rates and depending upon how PCOA data are used. PMID- 29109555 TI - Pathogenesis of HIV-1 and Mycobacterium tuberculosis co-infection. AB - Co-infection with Mycobacterium tuberculosis is the leading cause of death in individuals infected with HIV-1. It has long been known that HIV-1 infection alters the course of M. tuberculosis infection and substantially increases the risk of active tuberculosis (TB). It has also become clear that TB increases levels of HIV-1 replication, propagation and genetic diversity. Therefore, co infection provides reciprocal advantages to both pathogens. In this Review, we describe the epidemiological associations between the two pathogens, selected interactions of each pathogen with the host and our current understanding of how they affect the pathogenesis of TB and HIV-1/AIDS in individuals with co infections. We evaluate the mechanisms and consequences of HIV-1 depletion of T cells on immune responses to M. tuberculosis. We also discuss the effect of HIV-1 infection on the control of M. tuberculosis by macrophages through phagocytosis, autophagy and cell death, and we propose models by which dysregulated inflammatory responses drive the pathogenesis of TB and HIV-1/AIDS. PMID- 29109558 TI - Associations Between Pharmacy Students' Attitudes Toward Debt, Stress, and Student Loans. AB - Objective. To assess graduating pharmacy students' attitudes toward debt and determine associations with stress, student loan debt, financial need, current employment, post-graduation plans, and expected length of time to repay loans. Methods. Survey was conducted using an attitudes-toward-debt scale (sub-scales: tolerant attitudes toward debt; contemplation and knowledge about loans; fear of debt), Perceived Stress Scale, and questions concerning current employment, estimated total student loan debt, post-graduation plans, and expected length of time to repay loans. Federal loan data were collected using financial aid records. Independent samples t-test, ANOVA, and Pearson's r correlations were conducted. Results. There were 147 students (96.7%) who participated. The majority were female (59.2%), white (69.4%), and had federal student loans (90.5%). Mean total loan amount was $153,276 (SD $59,810), which included federal students loans accumulated before and during pharmacy school. No significant differences were noted on attitudes toward debt or stress based on whether respondents had federal student loans. Greater "fear of debt" was correlated with increased stress, estimated total student loan debt, total federal loan debt, and pharmacy school loan debt. Greater "contemplation and knowledge about loans" was correlated with lower estimated total student loan debt, total federal loan amount, and pharmacy school loan amount. Students with higher "contemplation and knowledge" scores expected to repay loans within a shorter time frame than students with lower scores. Conclusion. Increased fear of debt was related to greater perceived stress and higher student loan amounts borrowed, while increased contemplation and knowledge about loans was associated with lower amounts borrowed. Educational programming concerning loans, debt, and personal financial management may help reduce stress and amount borrowed. PMID- 29109559 TI - Curriculum in Psychiatry and Neurology for Pharmacy Programs. AB - Objective. To describe pharmacy curricula in psychiatry and neurology and to report on neuropsychiatric pharmacy specialists' views on optimal curriculum. Methods. Design and administer one electronic survey to accredited pharmacy programs asking them to report information on curricula in psychiatry and neurology for the 2014-2015 academic year. Design and administer a separate electronic survey to board certified pharmacists with an academic affiliation who are members of the College of Psychiatric and Neurologic Pharmacists (CPNP) asking about their teaching activities and their opinion on optimal curricula. Results. Fifty-six percent of pharmacy programs and 65% of CPNP members responded to the surveys. The program survey revealed greater than 80% of topics were taught by full-time faculty. Didactic lecturing, team-based learning, and case studies were the most common teaching methods. Programs dedicated the most didactics (3 to 5+ hours) to epilepsy, depression, schizophrenia, substance use disorders, and pain. Autism, traumatic brain injury, personality, and eating disorders were either not taught or given <= 1 hour of didactics in most programs. Inpatient psychiatry had the most APPE placements with a mean of 19.6, range 0-83. APPE electives in psychiatry outnumbered those in neurology 5 to 1. CPNP member survey results showed 2 out of 3 members agreed that curriculum could be improved with additional APPEs in psychiatry and neurology. Conclusion. Didactic hour distribution in psychiatry and neurology could be improved to better align with board certification in psychiatric pharmacy (BCPP) recommendations and disorder prevalence and complexity. Specialists recommend an experiential component in neurology and psychiatry to combat stigma and improve pharmacist knowledge and skills. PMID- 29109561 TI - A Review of Contemporary Diversity Literature in Pharmacy Education. AB - Objective. To review and categorize published educational research concerning diversity within colleges and schools of pharmacy. Methods. The Three Models of Organizational Diversity Capabilities in Higher Education framework was used to guide the review efforts. Of the 593 documents retrieved, 11 met the inclusion criteria for review. Each included article was individually reviewed and coded according to the framework. Results. The reviewed articles were primarily influenced by contemporary drivers of change (eg, shifting demographics in the United States), focused on enhancing the compositional diversity of colleges and schools of pharmacy, examined the experiences of underrepresented groups, and suggested process improvement recommendations. Conclusion. There is limited published educational research concerning diversity within schools and colleges of pharmacy. Contemporary drivers of change are influencing this research, but more attention must be given to the focus of the research, individuals targeted, and recommendations suggested. PMID- 29109560 TI - Educational Attainment and Academic Profile of Deans and Chairs at US Pharmacy Schools. AB - Objective. To characterize educational attainment and experiences of current US pharmacy school deans and chairs. Methods. A cross-sectional study using a publicly available listing of accredited schools and information. Results. Among 134 deans and 301 chairs, 79.9% and 65.5% held a professional degree (BSPharm and/or PharmD), 33.6% and 26.2% completed PGY-1 residencies, 12.7% and 15.6% completed post-PharmD fellowships, 23.1% and 33.9% completed post-doctoral fellowships, and 13.4% and 18.3% held BPS certification, respectively. Fewer than 1 in 5 were employed at an alma mater. Ninety (20.7%) deans and chairs completed AACP's Academic Leadership Fellows Program. Average current tenure was 5.7 and 5.1 years for deans and chairs, respectively. Conclusion. The majority of deans and chairs held a pharmacy professional degree and the prevalence of post graduate educational and leadership training is increasing. Future research should apply mixed methods to investigate educational attainment and employment experience of deans and chairs, institutional hiring trends, and how these characteristics compare between newer and established programs. PMID- 29109562 TI - A Systematic Meta-ethnographic Review of the Beneficial Outcomes of International Internships to Student Pharmacists. AB - Objective. To describe the benefits that pharmacy students gain by completing international internships as a part of their pharmacy education. Methods. A systematic literature search was conducted from database inception to November 2016. Articles that reported on any measure of outcome or impact on student learning were included in the study. A meta-ethnographic approach was used to translate and synthesize findings. Results. Analysis of the reported outcomes produced nine distinct themes: cultural awareness, collaboration, communication, clinical skills, knowledge, adaptability, compassion, confidence, and personal growth. Conclusion. Pharmacy students experienced many benefits that align with program competencies. The most frequently described benefits were development of clinical skills and compassion. PMID- 29109563 TI - Evaluating the Changing Financial Burdens for Graduating Pharmacists. AB - Objective. To compare new practitioners in 2009 and 2014 by modeling net income from available salary, expenditure, and student loan data. Methods. A Monte Carlo simulation with probabilistic sensitivity analysis was conducted to model net income for graduating pharmacists in 2009 and 2014. Mean and standard deviations were recorded for each model parameter. Student t-tests were used to compare the mean differences between 2009 and 2014 cohorts. Results. Pharmacist salary and disposable income were higher on average in 2014 compared with 2009. Consumer expenditures were higher in 2014, offsetting the higher salary resulting in a 2014 discretionary income that was less than in 2009 [95% CI: -$2,336, -$1,587]. Net income decreased from 2009 to 2014 for all pharmacy school types. Conclusion. Regardless of loan payment strategy, net incomes for pharmacists graduating from public and private institutions were less in 2014 compared with 2009. PMID- 29109564 TI - Discrepancies in Lesbian, Gay, Bisexual, and Transgender Patient Care and How Pharmacists Can Support an Evolved Practice. AB - We live in an increasingly multicultural society with people from different ethnicities and beliefs. In recent years, we have witnessed a growing group of people who identify as having diverse sexual orientations and gender identities. Members of the lesbian, gay, bisexual, and transgender (LGBT) community have historically been marginalized by the health care industry. The disproportionate prevalence of LGBT health concerns and cultural prejudices may be overlooked by many practitioners. As pharmacists, we are in an optimal position to affect meaningful changes in how we treat, counsel, and interact with all our patients, including with those whose sexual orientation or gender identity differ from ours. It is important for student and practicing pharmacists alike to receive adequate education and training that identifies the role of a pharmacist in LGBT health and fosters culturally competent and equitable patient care. Clinical and cultural competence should be reflective of inclusive pharmacy programs that embrace and incorporate LGBT health. The objectives of this commentary are to identify the role of a pharmacist in LGBT health, recognize specific concerns with mental and sexual health, describe gender-transitioning pharmacotherapy, and discuss the current stance of LGBT health in pharmacy education. PMID- 29109565 TI - Creating Student Organizations to Promote Careers in Academic Pharmacy. PMID- 29109566 TI - Educational Gaming for Pharmacy Students - Design and Evaluation of a Diabetes themed Escape Room. AB - Objective. To design an educational game that will increase third-year professional pharmacy students' knowledge of diabetes mellitus disease management and to evaluate their perceived value of the game. Methods. Faculty members created an innovative educational game, the diabetes escape room. An authentic escape room gaming environment was established through the use of a locked room, an escape time limit, and game rules within which student teams completed complex puzzles focused on diabetes disease management. To evaluate the impact, students completed a pre-test and post-test to measure the knowledge they've gained and a perception survey to identify moderating factors that could help instructors improve the game's effectiveness and utility. Results. Students showed statistically significant increases in knowledge after completion of the game. A one-sample t-test indicated that students' mean perception was statistically significantly higher than the mean value of the evaluation scale. This statically significant result proved that this gaming act offers a potential instructional benefit beyond its novelty. Conclusion. The diabetes escape room proved to be a valuable educational game that increased students' knowledge of diabetes mellitus disease management and showed a positive perceived overall value by student participants. PMID- 29109567 TI - Design, Implementation, and Outcomes of a Three-week Pharmacy Bridging Course. AB - Objective. To evaluate the design, implementation, and outcomes of a three-week pharmacy bridging course (PBC) covering five math and science areas for first year doctor of pharmacy students in fall 2015. Methods. Each topic was taught as a separate module. All five modules used pre- and post-module assessments to measure student knowledge and confidence. Course grades for subsequent first-year courses (PY1) were collected to examine relationships between PBC and PY1 courses. Results. Scores on the post-knowledge assessments increased for all five subject areas compared to scores on pre-PBC knowledge assessments. Student confidence also increased pre-/post- in applied mathematics, biostatistics, and organic chemistry. Students agreed that PBC enhanced their level of academic preparation and increased their motivation to continue in the program. PBC performance was strongly correlated with first-year grade point average. Conclusion. A bridging course is both feasible and effective for helping students prepare for and transition into a doctor of pharmacy degree program. PMID- 29109568 TI - An Illustrated Guide to Poster Design. PMID- 29109569 TI - "The Farmer and the Cowman Should be Friends": Surviving a Curricular Revision Through Interprofessional Cooperation. PMID- 29109570 TI - Mentors and Lessons Learned. PMID- 29109571 TI - Medication Therapy Management - It's Complicated. PMID- 29109572 TI - The Pharmacy Student Population: Applications Received 2015-16, Degrees Conferred 2015-16, Fall 2016 Enrollments. PMID- 29109573 TI - 2016 Annual Report of the Accreditation Council for Pharmacy Education. PMID- 29109574 TI - Obesity: The Next Public Health Challenge. PMID- 29109575 TI - ? PMID- 29109576 TI - Baseline Competency Assessment of Pharmacists Prescribing and Managing Vancomycin Therapy in the Regina Qu'Appelle Health Region. AB - Background: Pharmacists in the Regina Qu'Appelle Health Region (RQHR), Saskatchewan, independently dose, monitor, and adjust vancomycin therapy. No framework exists for ongoing competency assessment of pharmacists. Objectives: The primary objective was to determine pharmacists' overall level of competency for all components of the vancomycin prescribing procedure. The secondary objectives were to determine competency for individual prescribing phases, to stratify overall competency in relation to pharmacist and patient factors, and to identify the 3 most frequent errors. Methods: A retrospective chart audit was performed of patients who received a prescription for vancomycin between November 1, 2015, and January 31, 2016. Patients were included if they received pharmacist prescribed vancomycin as an inpatient or outpatient of an RQHR facility. Patients under the care of a pediatrician, those receiving vancomycin for surgical prophylaxis or via any route other than the IV route, and those whose vancomycin was prescribed by a current pharmacy resident were excluded. A rubric was created that assigned a numeric value for the appropriate completion of various procedure criteria. Results: A total of 326 patients received vancomycin during the study period, of whom 200 met the inclusion criteria, representing 511 discrete episodes of prescribing by 42 pharmacists. The median overall competency rate, for all phases of prescribing, was 100% (interquartile range [IQR] 90.1%-100%). The median competency rates for the empiric therapy and monitoring phases were 94.4% (IQR 88.9%-100%) and 100% (IQR 87.5%-100%), respectively. No statistically significant differences were found in relation to pharmacists' experience or postbaccalaureate education, patients' level of acuity, or timing of prescribing. The competency score was significantly higher among pharmacists prescribing for patients with normal renal function than among those prescribing for patients with reduced renal function (p = 0.008). The 3 most common errors were failure to document risk factors for nephrotoxicity, failure to document requirement to obtain future trough levels, and failure to document that samples for trough levels had been drawn correctly. Conclusions: During the study period, pharmacists at RQHR showed competency in all phases of vancomycin prescribing using the approved procedure. Documentation of clinical plans and assessments was identified as an area for improvement. PMID- 29109577 TI - Creation of a Natural Health Products Database for Assessing Safety for Patients with Chronic Kidney Disease or Renal Transplant. AB - Introduction: There is a lack of published safety information on the use of natural health products (NHPs) for patients with chronic kidney disease (CKD) or renal transplant. Objective: To create an online database to provide evidence based safety recommendations for commonly used NHPs, specific to patients with CKD or renal transplant. Methods: NHPs used by CKD and transplant patients in British Columbia were identified from the records of the BC Provincial Renal Agency. For each NHP, several databases (MEDLINE, Embase, Lexi-Natural Products, PubMed Dietary Supplement Subset, and Natural Medicines) were searched for any information pertaining to dosage, adverse drug reactions, drug interactions, immunomodulatory effects, and pharmacokinetics in patients with renal disease. Each NHP was given 1 of 4 safety ratings: likely safe, possibly safe, possibly unsafe, and likely unsafe. An NHP was classified as "possibly unsafe" for patients with renal transplant if it had demonstrated in vitro immunomodulatory effects and/or significant interactions with transplant medications due to effects on the cytochrome P450 3A4 isozyme. Results: Of the 19 627 BC-registered patients with renal disease (as of August 2014), 4122 (21%) were using one or more NHPs. The Herbal-CKD website (www.herbalckd.com) was created in 2015 to provide information about 47 commonly used NHPs and 2 known nephrotoxins (aristolochic acid and silver). This website provides a systematic evaluation of safety information for selected NHPs for patients with CKD (both nondialysis and dialysis-dependent) and kidney transplant. The most common NHP safety classification was "possibly safe", reflecting the paucity of studies in renal populations and the availability of safety data for the general population. Limitations of the website include difficulty in interpreting and generalizing the safety literature because most NHP formulations are not standardized, and others are combination products. Conclusion: The website www.herbalckd.com provides an easy-to-use, evidence-based tool for health care professionals to assess the safety of NHPs for CKD and transplant patients. PMID- 29109578 TI - Provincial Comparison of Pharmacist Prescribing in Canada Using Alberta's Model as the Reference Point. AB - Background: In the past decade, pharmacist practice has evolved tremendously in Canada, but the scope of practice varies substantially from one province to another. Objective: To describe pharmacists' scopes of practice relevant to prescribing within various jurisdictions of Canada, using the prescribing model in Alberta (authors' province) as the reference point. Methods: This cross sectional survey consisted of clinical scenarios for emergency prescribing, adapting or renewing a prescription, and initial-access prescribing for a chronic disease. Pharmacists were asked about their ability to administer injections and to order or access the results of laboratory tests, as well as certification and training requirements and reimbursement models. Results: Thirteen pharmacists representing Canadian provinces other than Alberta were surveyed in late 2015, for comparison with Alberta. With specific reference to the scenarios presented, pharmacists were able to prescribe in an emergency in 9 of the 10 provinces, renew prescriptions in all provinces, and adapt prescriptions in 6 provinces. Three provinces required that pharmacists have collaborative practice agreements identifying a specific practice area in order to initiate a prescription for a chronic disease (with 6-12 pharmacists per province having such agreements). Alberta required pharmacists to have authorization, based on a detailed application, in order to initiate any provincially regulated drug (with about 1150 pharmacists having this authorization). Pharmacists were allowed to administer vaccines in 9 provinces, and 5 provinces allowed pharmacists to administer drugs by injection. Three provinces had systems in place for pharmacists to access laboratory test results, and 2 allowed pharmacists to order laboratory tests. Five provinces had government-reimbursed programs in place for select prescribing services; however, all 9 provinces with public vaccination programs reimbursed pharmacists for this service. Conclusions: Pharmacist prescribing differs among Canadian provinces. Although most provinces allow emergency prescribing and renewal or adaptation of prescriptions by pharmacists, only 4 provinces allow prescription initiation, with variable criteria and scope. Despite some progress to enhance patient flow through the health care system (e.g., by allowing pharmacists to extend prescriptions), further work should be pursued to harmonize clinical practices across Canada and to enable pharmacists to initiate and manage drug therapy. PMID- 29109579 TI - Program to Manage New and Expensive Drugs in Pediatrics: Profile of a New Drug Policy and a 12-Month Descriptive Study. AB - Background: With growing financial pressure and the range of new and expensive drugs, hospital administrators, clinicians, and pharmacy directors are facing tough decisions on how to manage drug budgets. At a Canadian mother-child hospital, a policy for new and expensive drugs was developed, with the goal of managing their use and costs. Objectives: To describe the development and implementation of a policy for new and expensive drugs in a mother-child teaching hospital and to describe the profile of requests for these therapies over a 12 month period. Methods: A brainstorming session was conducted with members of the pharmacy and therapeutics committee to define the criteria for new and expensive drugs at the study hospital and a new process to evaluate requests for these drugs. Over the 12-month period following implementation of the policy, all requests for new and expensive drugs were evaluated through collection and analysis of relevant data. Results: The new drug policy was launched on October 1, 2014. Over the following 12-month period, a total of 58 requests for new and expensive drugs were discussed, but only 47 request forms were completed and signed by a physician and a clinical pharmacist. Conclusions: New and expensive drugs represent a challenge for clinicians and hospital stakeholders. This study illustrates the implementation of a new policy for these drugs in a mother-child teaching hospital over a 12-month period. PMID- 29109581 TI - Choosing Wisely: Experience of a Community Academic Hospital Pharmacy in Identifying Opportunities and Implementing Changes. PMID- 29109580 TI - Fosfomycin Susceptibility in Multidrug-Resistant Enterobacteriaceae Species and Vancomycin-Resistant Enterococci Urinary Isolates. AB - Background: Broad-spectrum antibiotics are often used to treat urinary tract infections (UTIs) due to drug-resistant species of Enterobacteriaceae and Enterococcus (e.g., organisms producing extended-spectrum beta-lactamase [ESBL] or AmpC beta-lactamase, as well as vancomycin-resistant enterococci [VRE]). However, this type of therapy can promote selection of resistant organisms and may necessitate venous access. Fosfomycin is an orally administered, single-dose antibiotic for the treatment of uncomplicated UTI. Little is known about its microbiologic activity against urinary isolates, including in southwestern Ontario, since fosfomycin susceptibility testing is not routinely performed. Objective: To explore a cost-effective alternative for the treatment of lower UTIs caused by multidrug-resistant Enterobacteriaceae and VRE organisms resistant to usual first-line therapies by determining fosfomycin susceptibility rates. Methods: Urinary isolates were collected prospectively from November 2015 to April 2016 at 3 hospitals in southwestern Ontario. Susceptibility testing was completed according to guidelines of the Clinical and Laboratory Standards Institute, with interpretation by zone of inhibition (as diameter in millimetres). Patients 18 years of age or older with isolation of multidrug resistant Enterobacteriaceae or VRE were eligible for inclusion. Urinary isolates from these patients were subjected to susceptibility testing. The primary outcome was the rate of fosfomycin susceptibility of these isolates. Results: A total of 137 urinary isolates were tested: 106 positive for ESBL-or AmpC beta-lactamase producing Enterobacteriaceae (95 Escherichia coli, 11 Klebsiella spp.) and 31 positive for vancomycin-resistant Enterococcus faecium. Susceptibility rates for ESBL- and AmpC beta-lactamase-producing E. coli were 100% for ertapenem, 96% for fosfomycin, 83% for nitrofurantoin, 72% for gentamicin, 56% for trimethoprim sulfamethoxazole, and 14% for ciprofloxacin. Susceptibility rates of vancomycin resistant E. faecium urinary isolates were 100% for linezolid, 81% for fosfomycin, 68% for tetracycline, 6% for ampicillin, 3% for penicillin, and 0% for both nitrofurantoin and ciprofloxacin. Conclusion: Given susceptibility rates at the study institutions, fosfomycin was deemed the most reliable oral option for the treatment of lower UTI in patients with suspected or documented multidrug resistant uropathogens. PMID- 29109582 TI - Pharmacy in Brazil: Progress and Challenges on the Road to Expanding Clinical Practice. PMID- 29109583 TI - Should Digoxin Continue To Be Used for the Management of Atrial Fibrillation? PMID- 29109584 TI - Ensuring Accurate, Timely Medication Orders and Reducing Errors: Assessment of a Read-Back Tactic. PMID- 29109585 TI - Nonformulary Medication Orders and Discharge Discrepancies. PMID- 29109587 TI - Choosing Excellence. PMID- 29109586 TI - ? PMID- 29109589 TI - Biochar additions can enhance soil structure and the physical stabilization of C in aggregates. PMID- 29109588 TI - Electrochemical performance of Ti3C2Tx MXene in aqueous media: towards ultrasensitive H2O2 sensing. AB - An extensive characterization of pristine and oxidized Ti3C2Tx (T: =O, -OH, -F) MXene showed that exposure of MXene to an anodic potential in the aqueous solution oxidizes the nanomaterial forming TiO2 layer or TiO2 domains with subsequent TiO2 dissolution by F- ions, making the resulting nanomaterial less electrochemically active compared to the pristine Ti3C2Tx. The Ti3C2Tx could be thus applied for electrochemical reactions in a cathodic potential window i.e. for ultrasensitive detection of H2O2 down to nM level with a response time of approx. 10 s. The manuscript also shows electrochemical behavior of Ti3C2Tx modified electrode towards oxidation of NADH and towards oxygen reduction reactions. PMID- 29109590 TI - Motion of a nano-spheroid in a cylindrical vessel flow: Brownian and hydrodynamic interactions. AB - We study the motion of a buoyant or a nearly neutrally buoyant nano-sized spheroid in a fluid filled tube without or with an imposed pressure gradient (weak Poiseuille flow). The fluctuating hydrodynamics approach and the deterministic method are both employed. We ensure that the fluctuation dissipation relation and the principle of thermal equipartition of energy are both satisfied. The major focus is on the effect of the confining boundary. Results for the velocity and the angular velocity autocorrelations (VACF and AVACF), the diffusivities and the drag and the lift forces as functions of the shape, the aspect ratio, the inclination angle and the proximity to the wall are presented. For the parameters considered, the boundary modifies the VACF and AVACF such that three distinct regimes are discernible - an initial exponential decay followed by an algebraic decay culminating in a second exponential decay. The first is due to the thermal noise, the algebraic regime is due both to the thermal noise and the hydrodynamic correlations, while the second exponential decay shows the effect of momentum reflection from the confining wall. Our predictions display excellent comparison with published results for the algebraic regime (the only regime for which earlier results exist). We also discuss the role of the off-diagonal elements of the mobility and the diffusivity tensors that enable the quantifications of the degree of lift and margination of the nanocarrier. Our study covers a range of parameters that are of wide applicability in nanotechnology, microrheology and in targeted drug delivery. PMID- 29109591 TI - The experience of acting and the structure of consciousness. PMID- 29109593 TI - Legality, Racialization, and Immigrants' Experience of Ethnoracial Harassment in Russia. AB - Using data from a structured survey and in-depth interviews in three Russian cities, our study engages the scholarship on immigration legal regimes and racialization practices to examine the experiences of ethnoracially motivated harassment among working migrant women from Kyrgyzstan, Tajikistan, and Uzbekistan in Russia. The results of statistical analyses show that regularized legal status is associated with a significantly lower likelihood of experiencing harassment at the hands of law enforcement agents and other actors alike. Regardless of legal status, however, the analyses reveal significant variations across the three migrant groups, with members of the group that is seen as racially most distinct from the host population having the highest odds of reporting harassment. The analysis of in-depth interviews confirms and expands on these patterns, providing additional insights into the complex expressions and interplay of legality and race in migrants' everyday experiences. The study findings are situated within the cross-national literature on migrants' legal and ethnoracial exclusion in receiving contexts. PMID- 29109594 TI - ARMA Cholesky Factor Models for the Covariance Matrix of Linear Models. AB - In longitudinal studies, serial dependence of repeated outcomes must be taken into account to make correct inferences on covariate effects. As such, care must be taken in modeling the covariance matrix. However, estimation of the covariance matrix is challenging because there are many parameters in the matrix and the estimated covariance matrix should be positive definite. To overcomes these limitations, two Cholesky decomposition approaches have been proposed: modified Cholesky decomposition for autoregressive (AR) structure and moving average Cholesky decomposition for moving average (MA) structure, respectively. However, the correlations of repeated outcomes are often not captured parsimoniously using either approach separately. In this paper, we propose a class of flexible, nonstationary, heteroscedastic models that exploits the structure allowed by combining the AR and MA modeling of the covariance matrix that we denote as ARMACD. We analyze a recent lung cancer study to illustrate the power of our proposed methods. PMID- 29109592 TI - Nanomaterial-based biosensors for detection of prostate specific antigen. AB - Screening serum for the presence of prostate specific antigen (PSA) belongs to the most common approach for the detection of prostate cancer. This review (with 156 refs.) addresses recent developments in PSA detection based on the use of various kinds of nanomaterials. It starts with an introduction into the field, the significance of testing for PSA, and on current limitations. A first main section treats electrochemical biosensors for PSA, with subsections on methods based on the use of gold electrodes, graphene or graphene-oxide, carbon nanotubes, hybrid nanoparticles, and other types of nanoparticles. It also covers electrochemical methods based on the enzyme-like activity of PSA, on DNA-, aptamer- and biofuel cell-based methods, and on the detection of PSA via its glycan part. The next main section covers optical biosensors, with subsections on methods making use of surface plasmon resonance (SPR), localized SPR and plasmonic ELISA-like schemes. This is followed by subsections on methods based on the use of fiber optics, fluorescence, chemiluminescence, Raman scattering and SERS, electrochemiluminescence and cantilever-based methods. The most sensitive biosensors are the electrochemical ones, with lowest limits of detection (down to attomolar concentrations), followed by mass cantilever sensing and electrochemilumenescent strategies. Optical biosensors show lower performance, but are still more sensitive compared to standard ELISA. The most commonly applied nanomaterials are metal and carbon-based ones and their hybrid composites used for different amplification strategies. The most attractive sensing schemes are summarized in a Table. The review ends with a section on conclusions and perspectives. PMID- 29109595 TI - The Role of Hematological Indices in Patients with Acute Coronary Syndrome. AB - An increased systemic and local inflammation plays a key role in the pathophysiology of acute coronary syndrome (ACS). This review will discuss the role of hematological indices: white blood cells (WBC), neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and platelet indices, that is, platelet to lymphocyte ratio (PLR), mean platelet volume (MPV), and platelet distribution width (PDW) in the case of ACS. In recent years, a strong interest has been drawn to these indices, given that they may provide independent information on pathophysiology, risk stratification, and optimal management. Their low-cost and consequent wide and easy availability in daily clinical practice have made them very popular in the laboratory testing. Furthermore, many studies have pointed at their effective prognostic value in all-cause mortality, major cardiovascular events, stent thrombosis, arrhythmias, and myocardial perfusion disorders in terms of acute myocardial infarction and unstable angina. The most recent research also emphasizes their significant value in the combined analysis with other markers, such as troponin, or with GRACE, SYNTAX, and TIMI scores, which improve risk stratification and diagnosis in ACS patients. PMID- 29109597 TI - Suicidality: prevention, detection and intervention. PMID- 29109596 TI - Soluble Urokinase Plasminogen Activator Receptor and the Risk of Coronary Artery Disease in Young Chinese Patients. AB - Background: Soluble urokinase plasminogen activator receptor (suPAR) is a novel marker of chronic inflammation and is considered to be a risk factor for coronary artery disease (CAD) in Caucasians. This study investigated the role of suPAR in young Chinese patients with CAD. Methods: The study involved a total of 196 consecutive young (age <= 55 years) patients with angiographically proven CAD and 188 age-matched non-CAD individuals as controls. Traditional risk factors were evaluated using conventional assays, and levels of suPAR were measured by sandwich enzyme-linked immunosorbent assays. Results: Levels of suPAR were significantly correlated with age (r = 0.20, P = 0.04), smoking (r = 0.33, P = 0.008), body mass index (r = 0.21, P = 0.03), and high-sensitivity C-reactive protein (hs-CRP; r = 0.31, P = 0.01). Multivariate logistic regression analysis showed that male sex (odds ratio (OR) = 3.12; 95% confidence interval (CI) = 1.18 8.25, P = 0.02), smoking (OR = 3.41, 95% CI = 1.55-7.50, P = 0.002), triglyceride (OR = 1.89, 95% CI = 1.10-3.25, P = 0.02), high-sensitivity C-reactive protein (OR = 1.24, 95% CI = 1.02-0.03, P = 0.03), and suPAR (OR = 1.37, 95% CI = 1.09 1.72, P = 0.007) were independently associated with CAD risk in young patients. Conclusions: SuPAR is a novel independent risk factor for CAD in young Chinese patients. Further studies evaluating the effect of anti-inflammatory treatment on the suPAR levels and the risk of CAD are needed. PMID- 29109598 TI - Drugs and genetics. PMID- 29109599 TI - Medication management on sick days. PMID- 29109600 TI - Prescribing for frail older people. PMID- 29109601 TI - Treatment of fibromyalgia. PMID- 29109602 TI - Antibiotic prophylaxis for dental procedures. PMID- 29109603 TI - Drug dosing in obese adults. PMID- 29109604 TI - Access to unregistered drugs in Australia. PMID- 29109605 TI - Brexpiprazole for schizophrenia. PMID- 29109606 TI - Pegvisomant for acromegaly. PMID- 29109607 TI - Sofosbuvir with velpatasvir. PMID- 29109608 TI - It's the Patient's Fault. PMID- 29109610 TI - How Similar Are Biosimilars? What Do Clinicians Need to Know About Biosimilar and Follow-On Insulins? AB - IN BRIEF As more patents on biological medicines expire, increased numbers of biologic copies, referred to as "biosimilars," will likely become available in the United States in the coming years. With greater availability and the drive for health care savings, the use of biosimilars and of "follow-on" biological products is likely to increase in routine clinical practice. Health care practitioners need to be fully aware of these products and accompanying considerations if they are to make informed decisions together with their patients. PMID- 29109609 TI - End-Stage Renal Disease Increases Rates of Adverse Glucose Events When Treating Diabetic Ketoacidosis or Hyperosmolar Hyperglycemic State. AB - IN BRIEF Treatment guidelines for diabetic emergencies are well described in patients with normal to moderately impaired kidney function. However, management of patients with end-stage renal disease (ESRD) is an ongoing challenge. This article describes a retrospective study comparing the rates of adverse glucose events (defined as hypoglycemia or a decrease in glucose >200 mg/dL/h) between patients with ESRD and those with normal kidney function who were admitted with diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS). These results indicate that current treatment approaches to DKA or HHS in patients with ESRD are suboptimal and require further evaluation. PMID- 29109611 TI - Socioeconomic Status and Care Metrics for Women Diagnosed With Gestational Diabetes Mellitus. AB - IN BRIEF Appropriate management of hyperglycemia can significantly attenuate perinatal risks associated with a diagnosis of gestational diabetes mellitus (GDM). This article reports on a study evaluating the independent associations of maternal income and education with select measures of GDM management. This exploratory study demonstrates notable socioeconomic differences in select measures of GDM management. Additional studies are needed to determine the reasons for these differences and whether they exist in broader populations. PMID- 29109612 TI - Pilot Study for Managing Complex Chronic Care Medicaid Patients With Diabetes Using a Mobile Health Application Achieves "Triple Aim" Improvement in a Primary Care Setting. AB - IN BRIEF Cost-effective innovations to improve health and health care in patients with complex chronic diseases are urgently needed. Mobile health (mHealth) remote monitoring applications (apps) are a promising technology to meet this need. This article reports on a study evaluating patients' use of a tablet device with an mHealth app and a cellular-enabled glucose meter that automatically uploaded blood glucose values to the app. Improvements were observed across all three components of the Patient Protection and Affordable Care Act's "triple aim." Self rated wellness and numerous quality-of-care metrics improved, billed charges and paid claims decreased, but no changes in clinical endpoints were observed. PMID- 29109613 TI - International Classification of Diseases, 10th Revision, Coding for Diabetes. PMID- 29109614 TI - Providing Lifelong Education and Support: Updates in the 2017 National Standards for Diabetes Self-Management Education and Support. PMID- 29109616 TI - GOOD TO KNOW: Information from the American Diabetes Association for people with diabetes. PMID- 29109615 TI - Fixed-Ratio Combinations. PMID- 29109617 TI - Euglycemic Diabetic Ketoacidosis Accompanied by Severe Hypophosphatemia During Recovery in a Patient With Type 2 Diabetes Being Treated With Canagliflozin/Metformin Combination Therapy. PMID- 29109618 TI - Mysterious Hyperglycemia: Disease Versus Device. PMID- 29109619 TI - Nonobese, Nonketotic Childhood-Onset Diabetes: Look for Lipodystrophies. PMID- 29109620 TI - Erratum: Stigma in People With Type 1 or Type 2 Diabetes. Clinical Diabetes 2017;35:27-34. DOI: 10.2337/cd16-0020. AB - [This corrects the article on p. 27 in vol. 35, PMID: 28144043.]. PMID- 29109621 TI - Mediators of Allergic Asthma and Rhinosinusitis. PMID- 29109623 TI - Stay calm and register your trial... its time. PMID- 29109622 TI - Pretreatment Liver Injury Predicts Poor Prognosis of DLBCL Patients. AB - Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction. PMID- 29109624 TI - Axillary vein cannulation for central access: A newer look below the clavicle! PMID- 29109625 TI - Postoperative delirium in elderly citizens and current practice. AB - Postoperative delirium (POD) represents an acute brain dysfunction in the postsurgical period. Perioperative physicians caring for the older adults are familiar with the care of dysfunction of organs such as lungs, heart, liver, or kidney in the perioperative setting, but they are less familiar with management of brain dysfunction. As early detection and prompt treatment of inciting factors are utmost important to prevent or minimize the deleterious outcomes of delirium. The purpose of this review is to prepare perioperative physicians with a set of current clinical practice recommendations to provide optimal perioperative care of older adults, with a special focus on specific perioperative interventions that have been shown to prevent POD. On literature search in EMBASE, CINAHL, and PUBMED between January 2000 and September 2015 using search words delirium, POD, acute postoperative confusion, and brain dysfunction resulted in 9710 articles. Among them, 73 articles were chosen for review, in addition, National Institute for Health and Clinical Excellence guidelines, American Geriatric Society guidelines, hospital elderly life program-confusion assessment method training manual, New York geriatric nursing protocols, World Health Organization's International Classification of Diseases, 10th Revision classification of mental disorders, Food and Drug Administration requests boxed warnings on older class of antipsychotic drugs 2008 and delirium in Miller's text book of anesthesia were reviewed and relevant information presented in this article. PMID- 29109626 TI - Action and resistance mechanisms of antibiotics: A guide for clinicians. AB - Infections account for a major cause of death throughout the developing world. This is mainly due to the emergence of newer infectious agents and more specifically due to the appearance of antimicrobial resistance. With time, the bacteria have become smarter and along with it, massive imprudent usage of antibiotics in clinical practice has resulted in resistance of bacteria to antimicrobial agents. The antimicrobial resistance is recognized as a major problem in the treatment of microbial infections. The biochemical resistance mechanisms used by bacteria include the following: antibiotic inactivation, target modification, altered permeability, and "bypass" of metabolic pathway. Determination of bacterial resistance to antibiotics of all classes (phenotypes) and mutations that are responsible for bacterial resistance to antibiotics (genetic analysis) are helpful. Better understanding of the mechanisms of antibiotic resistance will help clinicians regarding usage of antibiotics in different situations. This review discusses the mechanism of action and resistance development in commonly used antimicrobials. PMID- 29109627 TI - Temperature management under general anesthesia: Compulsion or option. AB - Administration of general anesthesia requires continuous monitoring of vital parameters of the body including body temperature. However, temperature continues to be one of the least seriously monitored parameters perioperatively. Inadvertent perioperative hypothermia is a relatively common occurrence with both general and regional anesthesia and can have significant adverse impact on patients' outcome. While guidelines for perioperative temperature management have been proposed, there are no specific guidelines regarding the best site or best modality of temperature monitoring and management intraoperatively. Various warming and cooling devices are available which help maintain perioperative normothermia. This article discusses the physiology of thermoregulation, effects of anesthesia on thermoregulation, various temperature monitoring sites and methods, perioperative warming devices, guidelines for perioperative temperature management and inadvertent temperature complications (hypothermia/hyperthermia) and measures to control it in the operating room. PMID- 29109628 TI - Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery. AB - Background and Aims: The aim is to evaluate the association between the use of intraoperative dexmedetomidine with an increase in recurrence-free survival (RFS) and overall survival (OS) after nonsmall cell lung cancer (NSCLC) surgery. Material and Methods: This was a propensity score-matched (PSM) retrospective study. Single academic center. The study comprised patients with Stage I through IIIa NSCLC. Patients were excluded if they were younger than 18 years. Primary outcomes of the study were RFS and OS. RFS and OS were evaluated using univariate and multivariate Cox proportional hazards models after PSM (n = 251/group) to assess the association between intraoperative dexmedetomidine use and the primary outcomes. The value of P < 0.05 was considered statistically significant. Results: After PSM and adjusting for significant covariates, the multivariate analysis demonstrated no association between the use of dexmedetomidine and RFS (hazard ratio [HR] [95% confidence interval (CI)]: HR = 1.18, 95% CI: 0.91-1.53; P = 0.199). The multivariate analysis also demonstrated an association between the administration of dexmedetomidine and reduced OS (HR = 1.28, 95% CI: 1.03 1.59; P = 0.024). Conclusions: This study demonstrated that the intraoperative use of dexmedetomidine to NSCLC patients was not associated with a significant impact on RFS and but worsening OS. A randomized controlled study should be conducted to confirm the results of this study. PMID- 29109629 TI - Peripartum hysterectomy in a tertiary care hospital: Epidemiology and outcomes. AB - Background and Aims: Peripartum hysterectomy is associated with significant maternal morbidity and mortality. We reviewed all peripartum hysterectomies at our institute over a 1-year period. The aim of this study was to determine the incidence, surgery and anesthesia-related issues of peripartum hysterectomies and to compare outcomes of emergency and electively planned peripartum hysterectomies. Material and Methods: This was a retrospective analysis of records of women who underwent emergency or elective peripartum hysterectomy in a tertiary care hospital. The study included all women who underwent peripartum hysterectomy in a teaching hospital and referral institute in North India over a span of 1 year (April 1, 2014, to March 31, 2015). Association of variables was based on Chi-square test, Fisher's exact test, and comparison on "t" statistics (normal distribution) and Mann-Whitney (nonnormal distribution). Results: Forty women underwent peripartum hysterectomy during the study period. The incidence was 6.9/1000 deliveries. In 16 (40%) cases, peripartum hysterectomy was planned electively while emergency hysterectomy was done in 24 (60%) cases. Main indications of peripartum hysterectomies were placenta accreta (60%), atonic postpartum hemorrhage (PPH) (27.5%), and uterine rupture (7.5%). Intensive care management was required in 35% women postoperatively. The common maternal complications were febrile morbidity, bladder injury, disseminated intravascular coagulation, and wound infection. There were 4 maternal deaths following emergency peripartum hysterectomy done for atonic PPH whereas no mortality occurred in elective hysterectomy group. Conclusions: The most common indication for peripartum hysterectomy was placenta accrete. Electively planned peripartum hysterectomies with a multidisciplinary team approach had better outcomes and no mortality as compared to emergency peripartum hysterectomies. PMID- 29109630 TI - Improving outcomes for peripartum hysterectomy: Still a long way to go! PMID- 29109631 TI - Comparative evaluation of midazolam, dexmedetomidine, and propofol as Intensive Care Unit sedatives in postoperative electively ventilated eclamptic patients. AB - Background and Aims: Eclampsia is a common hypertensive disorder of pregnancy and treatment often includes termination of pregnancy with elective postoperative mechanical ventilation. The present study was aimed to compare midazolam, propofol, and dexmedetomidine for sedation and antihypertensive requirements of such patients admitted to Intensive Care Unit (ICU) after termination of pregnancy. Material and Methods: A total of ninety eclamptic patients administered general anesthesia for the termination of pregnancy through cesarean section and who also required postoperative ventilation were taken up for the study and were randomly allocated into three groups. All patients received MgSO4 (loading dose, 4 g intravenous) following first seizure episode followed by a continuous infusion for next 24 h. Midazolam group (GrM) received 0.05 mg/kg loading dose of midazolam, followed by infusion of 0.05-0.3 mg/kg/h, propofol group (GrP) received 1 mg/kg loading dose of propofol followed by infusion of 2-8 mg/kg/h, and dexmedetomidine group (GrD) received dexmedetomidine loading dose at 1 mcg/kg followed by infusion of 0.2-1.2 mcg/kg/h. Postoperatively, patients were assessed for hemodynamic stability, requirement of antihypertensive and analgesics, duration of sedation and stop sedation-discharge, and total time spent in the ICU. Results: Mean heart rate and mean arterial pressure recorded at different time intervals were lowest in GrD. Nearly 70% (n = 21) patients in the GrM required antihypertensive, 50% (n = 15) in GrP, and 36.6% (n = 11) in the GrD (P < 0.05). Duration of stop sedation-discharge from ICU was least in GrD. A number of patients demanding additional analgesics was also least in GrD. Conclusion: Sedation with dexmedetomidine produced better hemodynamic stability in eclamptic patients, and there was a significant reduction in requirement of additional analgesics (P = 0.035) and antihypertensive (P = 0.004). Total duration of ICU stay was also less in this group of patients. PMID- 29109632 TI - A manikin-based evaluation of a teaching modality for ultrasound-guided infraclavicular longitudinal in-plane axillary vein cannulation in comparison with ultrasound-guided internal jugular vein cannulation: A pilot study. AB - Background and Aims: Ultrasound (US)-guided infraclavicular approach for axillary vein (AXV) cannulation has gained popularity in the last decade. Material and Methods: In this manikin study, we evaluated the feasibility of a training model for teaching AXV cannulation. The learning pattern with this technique was assessed among attending anesthesiologists and residents in training. Results: A faster learning pattern was observed for AXV cannulation among the attending anesthesiologists and residents in training, irrespective of their prior experience with US. It was evident that a training modality for this technique could be easily established with a phantom model and that hands-on training motivates trainees to embrace US-based central venous cannulation. Conclusion: A teaching model for US-guided infraclavicular longitudinal in-plane AXV cannulation can be established using a phantom model. A focused educational program would result in an appreciable change in preference in embracing US-based cannulation techniques among residents. PMID- 29109633 TI - Comparison of ease of intubation in sniffing position and further neck flexion. AB - Background and Aims: Optimization of patient's head and neck position for the best laryngeal view is the most important step before laryngoscopy and intubation. The objective of this prospective crossover study was to determine the differences, if any, between the gold standard sniffing position (SP) and the further head elevation (HE) (neck flexion) with regard to the incidence of difficult laryngoscopy, intubation difficulty, and variables of the I ntubation Difficulty Scale (IDS) in adult patients undergoing elective surgery under general anesthesia. Material and Methods: In the "SP" the neck must be flexed on the chest by elevating the head with a cushion under the occiput and extending the head at the atlanto-occipital joint. Our study was carried out to evaluate the glottic view in SP compared to further HE by 1.5 inches during direct laryngoscopy in elective surgeries. Patients were randomly assigned to either Group A ("SP" during first laryngoscopy and "HE" during second laryngoscopy) or vice versa in Group B. The effect of patient position on ease of intubation was assessed using a quantitative scale - The intubation difficulty scale (IDS). Results: There were significant differences with regard to glottic visualization (P = 0.00), number of operators (P = 0.001), laryngeal pressure (P = 0.00), and lifting force (P = 0.00) required for intubation and IDS (P = 0.00), thus favoring further HE position. Conclusion: We conclude that the HE position is superior to standard SP with regard to ease of intubation as assessed by IDS. PMID- 29109634 TI - Accuracy of ultrasound imaging versus manual palpation for locating the intervertebral level. AB - Background and Aims: Efficacy of epidural analgesia depends on placement of the epidural catheter at the appropriate level. Manual palpation using surface landmarks to identify the desired intervertebral level may not be a reliable method. Ultrasonography (USG) is an alternative technique but requires training and may increase procedure time. The objective of this study was to compare the accuracy of ultrasound (US) imaging with manual palpation for locating the intervertebral level. Material and Methods: We included postoperative adult patients without an epidural catheter who were scheduled to have a chest radiograph in the recovery room. A radio-opaque marker was placed at random at an intervertebral space along the thoracic or lumbar spine of the patient (in the field of the chest radiograph). The level of intervertebral space corresponding to the radio-opaque marker was determined by palpation technique by one anesthetist. Two other anesthetists (A and B) blinded to the result of manual palpation, independently used USG to determine the level of intervertebral space. A consultant radiologist assessed the radiographs to determine the correct position of the marker, which was judged to be the accurate space. Results: We recruited a total of 71 patients, of which 64 patients were included in the final analysis. Accurate identification by manual method was 31/64 (48%), by US A was 27/64 (42%) and by US B was 22/64 (34%). The difference in accuracy between manual palpation and US imaging was not statistically significant (P = 0.71). Conclusion: US imaging may not be superior to manual palpation for identifying intervertebral level. PMID- 29109635 TI - Correlation between preoperative ultrasonographic airway assessment and laryngoscopic view in adult patients: A prospective study. AB - Background and Aims: Difficult tracheal intubation is associated with serious morbidity and mortality and cannot be always predicted based on preoperative airway assessment using conventional clinical predictors. Ultrasonographic airway assessment could be a useful adjunct, but at present, there are no well-defined sonographic criteria that can predict the possibility of encountering a difficult airway. The present study was conducted with the aim of finding some correlation between preoperative sonographic airway assessment parameters and the Cormack Lehane (CL) grade at laryngoscopic view in adult patients. Material and Methods: This was a prospective, double-blinded study on 130 patients undergoing elective surgery under general anesthesia. Preoperative clinical and ultrasonographic assessment of the airway was done to predict difficult intubation and was correlated with the CL grade noted at laryngoscopy. The sensitivity, specificity, positive predictive value, and negative predictive values of the parameters were assessed. Results: The incidence of difficult intubation was 9.2%. Among the clinical predictors, the modified Mallampati classification had the maximum sensitivity and specificity, and among the sonographic parameters, the skin to epiglottis distance had the maximum sensitivity and specificity to predict difficult laryngoscopy. A combination of these two tests improved the sensitivity in predicting a difficult laryngoscopy. Conclusions: The skin to epiglottis distance, as measured at the level of the thyrohyoid membrane, is a good predictor of difficult laryngoscopy. When combined with the modified Mallampati classification, the sensitivity of the combined parameter was found to be greater than any single parameter taken alone. PMID- 29109636 TI - Comparison of polyvinyl chloride, curved reinforced, and straight reinforced endotracheal tubes for tracheal intubation through AirtraqTM laryngoscope in anesthetized patients. AB - Background and Aims: The AirtraqTM video laryngoscope facilitates tracheal intubations in patients with difficult airway or cervical spine immobilization. However, curved reinforced tracheal tube and straight reinforced tracheal tubes are useful where neck of the patient is likely to be moved or flexed or if patient is in prone position, wherein nonreinforced endotracheal tube (ETT) might get kinked and/or compressed. We compared intubation success rate of curved and straight reinforced tracheal tubes with polyvinyl chloride (PVC) tracheal tube using AirtaqTM laryngoscope in paralyzed and anesthetized patients. Material and Methods: Totally, 120 patients underwent random allocation to one of the three groups using computer-generated randomization table. Patients were intubated with appropriate size and type of ETT using AirtraqTM after obtaining optimal glottis view. Experienced anesthesiologist performed endotracheal intubation and unblinded observer noted down success and ease of intubation. Results: Patients intubated with PVC tube (100%) had higher rates of successful intubation and shorter intubation time (4 s), in comparison to intubation with curved reinforced (92.5%) and straight reinforced tubes (SRTs) (85%) using AirtraqTM laryngoscope (AL). However, there was no statistical difference in the incidence of airway trauma among all the three groups. Conclusions: PVC tracheal tube is significantly superior to both curved and SRTs for intubation using AL. PMID- 29109637 TI - An observational study of feasibility of tracheal intubation using Airtraq in pediatric population. AB - Background and Aim: There is a paucity of observational studies for the use of Airtraq (AT) in children, especially infants. We undertook a prospective observational study to compare ease of use of infant (size 0), pediatric (size 1), and small (size 2) AT. Material and Methods: AT was used for endotracheal intubation in healthy pediatric patients of 3 months to 18 years age. The primary outcome was success of intubation which was noted as number (%) and analyzed using Fisher's exact test. The secondary outcomes were percentage of glottis opening (POGO) score, visual analog scale (VAS) for field of view, time to best view (TTBV), time to intubation (TTI), and VAS for ease of use and were presented as median (interquartile range) in each subgroup of sizes and analyzed using Kruskal-Wallis test. Results: Overall POGO score was 100 (100, 100 [50-100]) %, VAS field of view was 10 (10, 10 [5-10]), and TTBV was 6 (4, 10 [1.5-24]) s. There was no statistically significant difference in any of the subgroups. The success rate of intubation with AT was 100% with AT size 1 and 2, whereas 45% with AT 0, P < 0.001. VAS for ease of use was 5 (4, 10 [3-10]) with AT 0 compared to 10 (10, 10 [9-10]) with AT 1 and 10 (10, 10 [6-10]) with AT 2 (P < 0.001). TTI was 28 (20, 36 [11.8-59]) s in those who could be successfully intubated. Conclusions: All sizes of AT provide quick, easy, and excellent glottic visualization. However, failure rate for intubation with infant (size 0) is high compared to nil with pediatric (size 1) and small (size 2). PMID- 29109638 TI - Evaluation of optimum time for intravenous cannulation after sevoflurane induction of anesthesia in different pediatric age groups. AB - Background and Aims: The ideal time for intravenous (IV) cannulation following inhalational induction in children is debatable. The effect of age on this time has not been studied. We evaluated the optimum time for IV cannulation after sevoflurane induction of anesthesia in different pediatric age groups. Material and Methods: A prospective interventional study based on Dixon's sequential up and down method was conducted in children of age 1-10 years. They were grouped according to their age - Group 1: 1-3 years, Group 2: >3-7 years, and Group 3: >7 10 years. Anesthesia was induced with 8% sevoflurane in 5 L of 100% oxygen. IV cannulation was attempted at 3.5 min in the first child in each group. The time for cannulation in the next child was stepped up or down by 30 s depending on positive or negative response, respectively, in the previous child. Children were recruited till a minimum of six pairs of failure-success sequence which was obtained in each group. The mean of midpoints of the failure-success sequence was calculated to obtain the time for cannulation in 50% of the children in each group. Results: Total number of children in Groups 1, 2, and 3 were 24, 23, and 24, respectively. The mean (95% confidence level) time for IV cannulation after sevoflurane induction in Groups 1, 2, and 3 was 53.6 (40.0-67.1), 105 (62.6 147.4), and 143.6 (108.8-178.4) s, respectively. This time was significantly shorter in Group 1 compared to those in Groups 2 and 3. Conclusion: The optimum time for IV cannulation in 50% of the children after sevoflurane induction of anesthesia was shorter in children of age 1-3 years than in older children. PMID- 29109639 TI - Evaluation of the efficacy of desflurane with or without labetalol for hypotensive anesthesia in middle ear microsurgery. AB - Background and Aims: Hypotensive anesthesia technique is used to reduce intraoperative bleeding and to improve the visibility of the operative field. The aim was to evaluate the efficacy of desflurane with and without labetalol for producing hypotensive anesthesia. Material and Methods: Sixty adult patients undergoing elective middle ear surgery were administered general anesthesia and randomly divided into two groups - Group D and Group L. The target mean arterial pressure (MAP) was 55-65 mmHg during hypotensive period. Group D patients received an increasing concentration of desflurane alone. Group L patients received 3% desflurane plus labetalol (loading dose 0.3 mg/kg intravenously, followed by 10 mg increments every 10 min). Student's t-test and paired t-test were used to compare the hemodynamic parameters. Visibility of the operative field, anesthetic and rescue drug requirement, partial pressure of oxygen in arterial blood, time taken for induction and reversal of hypotension and recovery characteristics were noted. Results: Target MAP was achieved in both the groups. Group D was associated with a higher mean heart rate compared with Group L (77.3 +/- 11.0/min vs. 70.5 +/- 2.5/min, respectively; P < 0.001) during the hypotensive period, along with a higher requirement for desflurane (P = 0.000) and metoprolol (P = 0.01). Time taken to achieve target MAP was lesser in Group L compared with Group D (33.7 +/- 7.1 vs. 39.8 +/- 6.2 min, respectively; P = 0.000). Time taken to return to baseline MAP was faster in Group D (P = 0.03). Emergence time was longer with desflurane alone (P = 0.000) resulting in greater sedation (P = 0.000) in the immediate postoperative period. Conclusion: Although desflurane is effective for inducing deliberate hypotension in middle ear microsurgery, the combination of desflurane with labetalol is associated with decreased requirement of desflurane, absence of reflex tachycardia, faster induction of hypotension, faster recovery from anesthesia, and less postoperative sedation. PMID- 29109640 TI - Obstetric critical care requirements felt by the obstetricians: An experience based study. AB - Background and Aims: Pregnancy is a state of physiological stress to a woman's health. Concomitant complications and infections during pregnancy may necessitate intensive monitoring and management of such patients in critical care settings. This study aims to determine the perceptions about the requirement of obstetric critical care based on the experience of obstetricians. Material and Methods: An observational, questionnaire-based study was conducted in 200 obstetricians working in various settings, who were approached during obstetric conferences. The questionnaire consisted of twenty items and was designed to determine the views of obstetricians, based on their clinical experience, regarding problems at the time of medical or surgical crisis in obstetric patients due to nonavailability of the intensive care services. Results: Seventeen percent of the participating obstetricians had a facility of dedicated obstetric Intensive Care Unit (ICU) at their institution. In the opinion of 62% of the respondents, ICU bed was made available in cases of crisis. Forty-two percent of the obstetricians reported that it took <10 min for the intensivist to reach the critically ill parturient. According to 32% of respondents, the intensivist could not reach within 20 min. There was a delay of more than 30 min in providing critical care services according to almost half (49%) of the respondents. Postpartum hemorrhage (24%) was the leading cause of ICU admission, followed by pregnancy-induced hypertension (14%) and acute respiratory distress syndrome (12%). A majority (87%) of the obstetricians were strongly in favor of a dedicated obstetric ICU. Conclusions: Need for a dedicated obstetric ICU is felt by most of the obstetricians to improve patient care. PMID- 29109641 TI - Comparative efficacy of clonidine versus magnesium sulfate as an adjunct to lignocaine in intravenous regional anesthesia for postoperative analgesia: A prospective, randomized, double-blind study. AB - Background and Aims: Intravenous regional anesthesia (IVRA) is a very good technique to be used in unstable patients. Various adjuvants have been added, but till date, there is no ideal adjuvant. Clonidine is one of the most widely used adjuvants in IVRA. However, it has many side effects. Hence, the search continues for a better adjuvant. The aim of the present study was to compare the efficacy of clonidine versus MgSO4 as an adjunct to lignocaine in IVRA for postoperative analgesia and to compare their side effect profile. Material and Methods: This prospective double-blind randomized controlled study was conducted in a tertiary care institute. Forty adult patients were included. Patients were assigned into two groups; Group 1 (n = 20) received 3 mg/kg of 2% lignocaine + 50% MgSO4 1.5 g diluted with normal saline to 40 ml. Group 2 (n = 20) received 3 mg/kg of 2% lignocaine + clonidine 150 MUg diluted with normal saline to 40 ml. Pain score, time to first rescue analgesic (TTFA), total number of rescue analgesics required, and the side effects of the two drugs were compared for 24 h postoperatively. Results: The mean TTFA was significantly longer in Group 1 (193.9 +/- 38.4 min) than in Group 2 (169.5 +/- 33.3 min); P < 0.05. The mean number of rescue analgesics required was 1.6 +/- 0.7 in Group 1 as compared to 2.1 +/- 0.8 in Group 2 (P < 0.05). More serious side effects such as hypotension and bradycardia were noted with clonidine, although all patients experienced transient pain during intravenous injection of MgSO4. Conclusion: MgSO4 provides better postoperative analgesia as compared to clonidine when used as an adjunct to lignocaine in IVRA with fewer side effects. PMID- 29109642 TI - Comparison of intra-articular analgesics in arthroscopic anterior cruciate ligament reconstruction surgeries: A randomized controlled trial. AB - Background and Aims: Arthroscopic anterior cruciate ligament reconstruction (ACLR) is one of the most common knee surgeries done worldwide today. It involves immense pain at sites of graft harvest, tibial, and femoral tunnels, thereby delaying recovery and increased patient morbidity, and delayed rehabilitation. Various drugs and combination of drugs administered intra-articularly have been studied for analgesic efficacy. Our study gives an insight if there is any added advantage of additives morphine or clonidine to bupivacaine when compared to administering bupivacaine alone. Material and Methods: After obtaining the Institute Ethics Committee approval, ninety American Society of Anesthesiology I II patients undergoing arthroscopic ACLR under spinal anesthesia were randomly assigned to one of three groups (Group B - bupivacaine alone 0.25%, Group BM - bupivacaine 0.25% with morphine 5 mg, Group BC - bupivacaine 0.25% with clonidine 150 mcg). At the end of procedure, 20 mL of the respective drug was administered intra-articularly and postoperative time duration to rescue analgesia, 24 h analgesic requirement, visual analog scale (VAS) score findings at rest and on movement were observed. Results: The mean duration of time to request for first rescue analgesia in minutes was significantly longer in Group BC 341.55 (103.66 SD) with P < 0.001. The VAS scores at that time point were least in Group BM 6.1 (1.7 SD), but not statistically significant. The 24 h analgesic consumption was least in Group B 2.24 (0.79 SD), but not statistically significant. Conclusion: Combination of bupivacaine and clonidine administered intra-articularly provided a longer duration of analgesia though the quality of analgesia was comparable between the three groups. PMID- 29109643 TI - Perianesthetic dental considerations. PMID- 29109644 TI - Xylometazoline nasal drops induced anaphylaxis: An atypical perioperative complication. AB - Xylometazoline nasal drops used for nasal decongestion can have side-effect in the form of palpitation, hypertension, headache, and tremors. Anaphylaxis to xylometazoline nasal drops is a relatively unrecognized complication. We encountered a patient posted for tonsillectomy who developed serious anaphylaxis upon administration of a commercially available preparation of xylometazoline nasal drops and required aggressive management for stabilization. Further evaluation and literature search indicated toward the preservative (benzylalkonium chloride) as the cause of this adverse event. PMID- 29109645 TI - Neostigmine induced coronary artery spasm: A case report and literature review. AB - Neostigmine is a cholinesterase inhibitor which does not cross the blood brain barrier and a commonly used for reversal of nondepolarizing muscle relaxants. In the following case report, we present a patient who developed coronary artery spasm, after the administration of repeated doses of neostigmine. Ours is the first case to demonstrate such a longstanding coronary artery vasospasm that lasted several hours in response to neostigmine, resulting in myocardial damage and left ventricular dysfunction. We would like to draw the attention of the anesthesiologists to this rare effect that may lead to perioperative cardiac complications. PMID- 29109646 TI - Ludwig's angina in children anesthesiologist's nightmare: Case series and review of literature. AB - Ludwig's angina is potentially lethal, rapidly spreading cellulitis of the floor of mouth and neck. The anticipated difficult airway becomes even more challenging when it occurs in children. In children, the larynx is positioned relatively higher in the neck, and one does not have the option for blind nasal intubation or awake fiberoptic, which otherwise is the technique of choice in adult patients. We present the clinical course of 16 children and highlight various problems encountered during the anesthetic management of six children who required emergency surgical drainage under general anesthesia. PMID- 29109647 TI - An unusual airway challenge in a patient with acromegaly. PMID- 29109649 TI - Persistent postoperative hypercyanotic spells in an adult with surgically untreated tetralogy of Fallot: Use of ketamine infusion. PMID- 29109648 TI - Effect of dexmedetomidine on blood glucose during surgery. PMID- 29109650 TI - Anesthetic management of congenital methemoglobinemia in an emergency cesarean section. PMID- 29109651 TI - Can dexmedetomidine be used as sole maintenance anesthetic agent at standard sedative doses? PMID- 29109652 TI - Conscious sedation in a psychiatric patient: A challenge. PMID- 29109653 TI - Combined spinal-epidural anesthesia for cesarean section in a parturient with congenitally corrected transposition of the great arteries. PMID- 29109654 TI - Bilateral vocal fold granulomas following double-lumen endotracheal tube placement. PMID- 29109655 TI - Antithymocyte globulin-induced refractory hypotension in renal transplantation recipient. PMID- 29109656 TI - Reply...Is it time to separate consent for anesthesia from consent for surgery? PMID- 29109657 TI - Impact of Physical Abuse on Internalizing Behavior Across Generations. AB - This study investigated the multigenerational impact of mothers' own exposure to physical maltreatment on internalizing symptoms in her child after accounting for her parenting practices, depression, and the child's own exposure to stressful life events. Children (n = 101, ages 5-16), predominantly African American, were recruited into this cross sectional study using ethnographic mapping and targeted sampling for high-risk neighborhoods. Mothers reported retrospectively on their own exposure to physical maltreatment in childhood, their parenting practices, as well as current depressive symptoms. Maternal report of her child's exposure to stressful life events and child behavior was also collected. Maternal childhood exposure to physical maltreatment was significantly associated with her child's internalizing symptoms (p = .004); this effect remained after accounting for child sex, maternal depressive symptoms, harsh parenting practices, and the child's own exposure to stressful life events. Formal tests of mediation through these pathways were non-significant. Findings suggest mothers' experience of childhood maltreatment contributes uniquely to children's internalizing symptoms, potentially through previously uncharacterized pathways. Examination of additional behavioral, psychosocial and biological pathways may help better describe the multi-generational effects of child maltreatment. PMID- 29109659 TI - Amblyopia in Children: Analysis Among Preschool and School Children in the City of Tuzla, Bosnia and Herzegovina. AB - Aim: This study measured the prevalence of amblyopia in preschool and school children between 4 and 15 years of age in Tuzla, Bosnia and Herzegovina and as well and to examine its relations with anisometropia and strabismus. Methods: Children from eight daycare centers and twenty four elementary schools were screened for amblyopia by volunteer personnel (medical students), any child who failed to pass the screening examination, was referred to the ophthalmologist for complete examination at University Clinic Center Tuzla. The examination included VA, stereopsis, cover testing, refractive retinoscopy, and examination of the red reflex and posterior pole. Results: Total of 7415 children, which included 3790 males and 3625 females, in the age range of 3 to 15 years from 24 schools and 8 preschool were screened. Fifty night children (1.9%) were diagnosed with amblyopia, unilateral in 28 and bilateral in 31. Conclusion: Prevalence of significant refractive errors is high enough to justify a school eye screening program solely for this purpose. preschool and school screening program in children in critical period of development of amblyopia must be conducted to find out the ametropias and amblyopia in time; and treat them earlier. PMID- 29109658 TI - Single-Needle Arthrocentesis with Upper Compartment Distension versus Conventional Two-Needle Arthrocentesis: Randomized Clinical Trial. AB - The objective of this study was to compare single-needle arthrocentesis with distension of the upper compartment of the temporomandibular joint (TMJ) with the conventional two-needle arthrocentesis. Twenty-six patients with articular disc displacement without reduction (DDWOR) were included in the study and assigned to two groups (n = 13): single-needle arthrocentesis with distension of the upper compartment of the TMJ (1N) and conventional two-needle arthrocentesis (2N). The maximum interincisal distance (MID) and TMJ pain as measured by the visual analog scale (VAS) were compared. MID and VAS data were obtained: before (T1), seven days after (T2), fifteen days after (T3), one month after (T4), three months after (T5), six months after (T6), nine months after (T7), and one year after the arthrocentesis procedures (T8). Considering each group individually, results of the VAS scores and MID measurements showed a significant difference between T1 and T2-T8 (p < 0.001) in both groups. Between two groups, results show no significant differences (p > 0.05). Both techniques tested were effective in reducing pain and increasing MID. Due to the advantages over the conventional two needle arthrocentesis, single-needle arthrocentesis with distension of the upper compartment should be considered as the first treatment option for patients with painful hypomobilized TMJ of DDWOR. PMID- 29109660 TI - The Quality of Life in Chronic Patients in the Process of Rehabilitation. AB - Objective: The aim of this study was to examine whether there is a correlation between self-evaluated quality of life, anxiety, depression, motivation, subjective-rated financial status, education, age and autonomous movements in patients with chronic conditions. Respondents and Methods: The study consecutively included 68 chronically ill patients, the average chronological age of 56.21 years. The Hospital Anxiety and Depression Scale for self-evaluation of the quality of life of respondents was used to evaluate the presence of anxiety and depression, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form was used for self-evaluation of the quality of life, and the Visual analogue scale of motivation was used for self-evaluation of the level of motivation. Results: It was found that anxiety, depression, education, financial status, chronological age and mobility have a significant impact on the sense of satisfaction with the quality of life of patients with chronic diseases. Conclusions: These results are important for clinical practice, planning and delivery of health services, evaluation of the implemented public health measures. PMID- 29109661 TI - Comparison of Responsiveness Level in Iranian Public and Private Physiotherapy Clinics: a Cross-Sectional Multi-center Study. AB - Introduction: Responsiveness is a main goal of health systems. Responsiveness focus on the non-medical aspects of health services delivery. This study was aimed to assess responsiveness level in public and private physiography clinics. Methods: In this multicenter cross sectional study, 403 patients refers to 16 public and 64 private physical therapy clinics were studied randomly in Ahvaz, Iran, from 2013 to 2014. Data were collected based on a valid health system responsiveness questionnaire that was developed by WHO. Health system responsiveness questionnaire for outpatients care includes seven components and 25 questions. Statistical relationship between responsiveness level of centers and patients characteristics was analyzed using Pearson coefficient, Independent t-test and one-way ANOVA. Results: Out of 403 patients, 299 (74.19%) patients were women. The mean (+/-SD) age of the patients was 42(+/-14.18) years and 92.1% of patients were 65> years. Responsiveness status in private and public physiotherapy clinics was assessed excellent (26.93+/-5.2) and very well (21.08+/ 5.8) respectively. In private clinics, the mean score of communication dimension (3.96+/-1) and autonomy dimension (3.95+/-0.9) was higher than other dimensions. In public clinics the mean score of dignity (3.30+/-0.8), autonomy (3.16+/-0.9), and prompt attention (3.12+/-1) was higher than other areas respectively. In public and private clinics, quality of basic amenities area had the lowest score. Conclusions: The results showed that the some patients and center characteristics such as gender and work shift were factors affecting assessment of responsiveness. Responsiveness level in private centers was better than publics. PMID- 29109662 TI - Budget Impact of Introducing Linagliptin into Bosnia and Herzegovina Health Insurance Drug Reimbursement List in 2016-2018. AB - Introduction: Diabetes is reaching epidemiological scales worldwide. Beside health implications diabetes bears significant financial impact on health systems. Different treatment options aiming to prevent diabetes complications are available. Dipeptidyl-peptidase-IV (DPP-4) inhibitors like linagliptin are usually add-on therapy to metformin in order to achieve glycemic control. Expenditure for oral antidiabetic medicines in Bosnia and Herzegovina (B&H) is low accounting for only 2.53% of the total drug market expenditure. Linagliptin is not reimbursed in B&H mainly due to it's perception of high cost medication. Aim: To assess budget impact (BI) of introducing linagliptin into health insurance reimbursement list in B&H through development of the budget impact model (BIM). Material and methods: Budget impact model was developed using Microsoft Excel 2010 based on current legislation and practice in B&H. Local epidemiology data and data on drug consumption from government reports in 2014 were used. Two scenarios with three-year time horizon have been developed: 1) without and 2) with linagliptin reimbursed and compared. Results: Inclusion of linagliptin into reimbursement list in Canton Sarajevo and Canton Tuzla would have positive budget impact on national level of B&H resulting in total savings of 18,194?, 235,570? and 699,472?, in 2016, 2017 and 2018, respectively. Conclusion: Introduction of linagliptin into reimbursement list would decrease total costs for DPP-4 inhibitors and is favorable for positive decision on reimbursement in B&H. Applying BIM in decision making would assure better allocation and planning of resources at any region or administrative level in B&H. PMID- 29109663 TI - Hemodialysis Patients' Information and Associated Characteristics. AB - Introduction: of this study was to explore characteristics associated with hemodialysis patients' degree of information. Material and Methods: The sample of the study included 650 patients undergoing hemodialysis. For data collection a questionnaire specially designed for the needs of the research was used. More specifically, socio-demographic, clinical and other patients' characteristics were associated with the degree of information as it was reported by patients. Results: of the 650 participants, 55.4% was men while 58.6% of the sample was aged over 60 years. Regarding information level, results showed that only 9.8% was "little" or "not all" informed about their health problem, 61,7% was "enough" informed whereas 28.5% were "very" informed. Statistically significant association was observed between degree of information and age (p=<0.001), family status (p=0.005), education (p=0.001), job (p=0.005) and number of children (p=0.019). In terms of clinical characteristics, statistically significant association was observed between the degree of information and whether patients had other disease or not (p=0.037), whether patients reported adherence to treatment guidelines (p=<0.001). Finally, statistically significant association was observed between the degree of information and relations with nursing staff (p=<0.001), doctors (p=0.007) and other patients (p=0.003), and whether patients faced difficulties in social (p=0.001) and family environment (p=0.002). Conclusion: Health professionals when planning information interventions for orienting hemodialysis patients is increasingly important to evaluate socio demographic, clinical and other patients ' characteristics and incorporate them in their project. PMID- 29109664 TI - A Cross-Sectional study of Psychiatric disorders in Medical Sciences Students. AB - Introduction: Aim of article was to investigate the prevalence of psychiatric disorders (depression, social dysfunction, anxiety and somatic symptoms) and some of its influencing factors in freshmen at Ahvaz Jundishapur University of Medical Sciences. Methods: This was a cross-sectional study which has conducted among 781 new students of all faculties of University in 2014. A study tool was the General Health Questionnaire (GHQ28). Results: Founding of this study has shown that from 781 students under study (33% male and 67% female). 27.9% of students have been suspected of some degree of mental disorders. The average total score of the questionnaire for male students was18.04+/-12.02 and for female students was18.69+/-12.13, but no significant difference was observed between the average score of mental health and sex(p<0.05). The average overall score in Ph.D students was higher than this score in undergraduates and masters that it shows there is more mental disorders in this group. But no significant difference between level of education and average mental health score, anxiety and health problems was observed(p<0.05). In terms of depression subscale(p<0.05) and social adjustment(p<0.001), this difference was significant. Conclusion: Due to high prevalence of mental disorders in these students, counseling and therapeutic interventions to eliminate or reduce these problems must be designed. PMID- 29109665 TI - Communication Skills of Physicians and Patients' Satisfaction. AB - Background: The communication skills of physicians is an effective step of making effective relationship between doctor and patient. It plays essential role through diagnosis and treatment processes. This current study was performed to investigate the impact of communication skillfulness of physicians on patients' satisfaction. Methods: A cross-sectional descriptive study was done to determine the impact of communication capability of practitioners on patients' satisfaction. The DiMatto's Patient Satisfaction Scale was administered among patients referring to the all 8 specialized clinics of Tabriz University of Medical Sciences. The validity and reliability of Persian translation of questionnaire of DiMatto's Patient Satisfaction was verified by 10 specialists. The validity of the questionnaire was measured by content and structural analysis, and Cronbach's alpha coefficients. The data were analyzed by software package of SPSS version 16 using Pearson's correlation coefficient, U Mann Whitney, Kruskal-wallis Test, Regression. Results: The study showed that there was a significant correlation between patients' satisfaction and the communication skills of physicians (devoting the appropriate time for visiting the patients, explaining diagnosis and treatment procedures). In addition, the therapeutic skills of physicians, their friendly manners, respecting the patients' feelings, and careful examination of patients by physician, revealed a significant correlation with patient satisfaction (P <0.05). However, we did not find strong correlation between effective listening to patients and patient's satisfaction. Conclusion: Communication skills of physician play an important role on patients' satisfaction; therefore, we propose strongly to improve the communication skills of physicians by improving the communication skills through related training courses. PMID- 29109666 TI - Prevalence of Pressure Ulcer and Nutritional Factors Affecting Wound Closure Success in Thailand. AB - Introduction: The authors aimed to estimate the prevalence of pressure ulcers and to explore the nutritional effects of the prognostic factors on successful pressure ulcer closure in a public tertiary care hospital in Thailand. Patients and Methods: The study was a retrospective cohort analysis of seven-year census (2008 - 2014) at Surin hospital in Thailand. There were 424 of total 240,826 patients aged over than 15 years admitted to surgery, orthopedics and medicine wards during the study period with documented pressure ulcers (ICD 10TM). We analyzed four hundred and ten patients after excluding 14 patients with non pressure ulcers (due to burning/ diabetic/ ischemic neuropathic ulcers, and less than 24 hours of admission) and loss medical record. We selected independent factors from demographic data, nutritional factors, pressure ulcer characteristics, and management data. The outcome of interest was successful pressure ulcer closure. The analysis method was the semi-parametric Cox regression model and reported as Hazard Ratios (HR) with 95% confidence interval (95% CI). Results: The total hospital admission was 240,826 patients between 2008 - 2014. 410 patients were developing pressure ulcers, of these, 7% (28/410) success in ulcer closure, and 77% (314/410) failure in closure requiring for additional procedures (excisional debridement). The rest of patients (16%, 68/410) was non-operative care. The prevalence of pressure ulcers was 1.7 per 1,000 person-year. The multivariable model found that only the Nottingham Hospital Screening Tool (NS) score was a statistically significant nutritional variable, and additional subgroup analysis of two models of sepsis and spinal cord co-morbidities was also significant. Adjusted hazard ratios (HR) for NS score = 0.355 (95% CI: 0.187, 0.674), p=0.002), for sepsis = 0.312 (95% CI: 0.140, 0.695), p=0.004), and for spinal cord co-morbidity = 0.420 (95% CI: 0.184, 0.958), p=0.039). Conclusions: The annual prevalence was 1.7 per 1,000 persons. NS score was strongly associated with ulcer closure success. PMID- 29109667 TI - Health System Reform Plan and Performance of Hospitals: an Iranian Case Study. AB - Background: Health system reform is essential to make desired Changes. In Iran, first phase of Health Reform Plan (HRP) was implemented in hospitals affiliated with Ministry of Health and Medical Education (MHME) in 2014. Aim: The present study was carried out to evaluate the performance of hospitals affiliated with Urmia University of Medical Sciences at the time of the implementation of HRP. Methods: This cross-sectional study carried out in two stages, before (2012- 2013) and during (2014- 2015) implementation of the HRP in district and teaching hospitals. Data collection and evaluation of performance of hospitals was performed using indices issued by MHME using graphical and statistical analysis. Results: Average bed occupancy rate and bed turnover rate increased and the average length of stay decreased in the majority of hospitals during the study period. The highest and lowest bed occupancy rate was observed in district hospitals. All hospitals were shifted toward the third zone in Pabon Lasso (PL) diagram. Conclusion: This study confirmed that the implementation of the defined package of HRP in hospitals affiliated with UUMS resulted in increased admissions and hospitalization and improved performance. PMID- 29109668 TI - Early Screening of Balkan Endemic Nephropathy. AB - Introduction: Balkan endemic nephropathy (BEN) is a chronic irreversible interstitial sclerosis, for which over the last 25 years, chronic exposure to aristolochic acid from the contaminated cereal seeds has been considered the most likely cause. The aim of our research is to reevaluate trends of disease and to try to obtain new information about practical implementing of in-field screening of BEN, and to find indicators or a reliable biomarker for an early detection of the disease, especially for in field conditions. Patients and methods: Study was conducted in two phases (two groups of respondents). The first group related to respondents with BEN and microalbuminuria in the family. After filling out the questionnaire and following the consent of the respondents, their medical records were taken, and they were subjected to clinical examination and laboratory tests as well as to abdominal ultrasound and urinary tract examination. Results: For a long time, the disease is asymptomatic, with no hypertension, anemia or disturbed glucoregulation. Only A1M values were increased in the second group (16.22 mg), whereas A1M/CrUrine value was normal in both groups. Renal function in form of creatinine clearence and size of kidneys were in their referent values. Conclusion: The early stages of the disease are nonspecific, with no hypertension and disturbed glucoregulation, with normal renal function and blood count. The kidney size was in referent values. The only reliable symptom in the early stage of the renal disease was microalbuminuria. PMID- 29109670 TI - Assessment of Hygiene Habits in Acrylic Denture Wearers: a Cross-sectional Study. AB - Objectives: To assess the denture hygiene habits in a population of Lebanese denture wearers. Materials and Methods: One hundred and thirty-two (132) patients [71 women (53.8%) and 61 men (46.2%)] wearing their acrylic dentures for more than two years were included in this study. The hygiene methods related to their dentures were evaluated and the data obtained were analyzed statistically using the IBM(r) SPSS(r) statistics 20.0 (USA) statistical package. Results: Regardless of the cleaning technique, the big majority of our participants [123 out of 132 (93.1%)] cleaned their dentures daily. The two mostly used denture cleaning techniques were rinsing with tap water (34.1%) and brushing with toothpaste (31.8%). Nearly half of our patients (45.5%) soaked their dentures during the night; most of them with cleansing tablets dissolved in water (28.8%). Conclusions: Within the limitations of our study, it was concluded that in a sample of Lebanese population surveyed about denture hygiene habits, the daily frequency of denture cleaning is satisfactory, but the techniques and products used were self-estimated and, consequently, not sufficient. PMID- 29109669 TI - Mental Illness Related Internalized Stigma: Psychometric Properties of the Brief ISMI Scale in Greece. AB - Aims: Since evaluation regarding the impact of mental illness related internalized stigma is scarce, there is a great need for psychometric instruments which could contribute to understanding its adverse effects among Greek patients with severe mental illness. The Brief Internalized Stigma of Mental Illness (ISMI) scale is one of the most widely used measures designed to assess the subjective experience of stigma related to mental illness. The present study aimed to investigate the psychometric properties of the Greek version of the Brief ISMI scale. In addition to presenting psychometric findings, we explored the relationship of the Greek version of the Brief ISMI subscales with indicators of self-esteem and quality of life. Methods: 272 outpatients (108 males, 164 females) meeting the DSM-IV TR criteria for severe mental disorder (schizophrenia, bipolar disorder, major depression) completed the Brief ISMI, the RSES and the WHOQOL-BREF scales. Patients reported age and educational level. A retest was conducted with 124 patients. Results: The Chronbach's alpha coefficient was 0 0.83. The test-retest reliability coefficients varied from 0.81 to 0.91, indicating substantial agreement. The ICC was for the total score 0.83 and for the two factors, 0.69 and 0.77 respectively. Factor analysis provided strong evidence for a two factor model. Factors 1 and 2 were named respectively "how others view me" and "how I view myself". They were negatively correlated with both RSES and WHOQOL-BREF scales, as well as with educational level. Factor 2 was significantly associated with the type of diagnosis. Conclusions: The Greek version of the Brief ISMI scale can be used as a reliable and valid tool for assessing mental illness related internalized stigma among Greek patients with severe mental illness. PMID- 29109671 TI - The Role and Characteristics of Collections of Folk Recepies in the Folk and Traditional Medicine of Bosnia and Herzegovina. AB - Introduction: Folk medicine represents part of the folk culture, when we first think about the rural culture with characteristic of the rural population in the pre-industrial period. The difference between official and folk medicine is manifested in the education, knowledge and social status of those practicing folk medicine as well as their patients. The most common ways of treating were the treatment by use of herbs, magic and treatments based on religious beliefs. So, it is of no surprise that folk medicine was the main form of treatment for the inhabitants of Bosnia and Herzegovina (B&H) in the past. In addition to many herbalists, quacks and religious officials who treated the patients with records, there were also spells, i.e. women who, by pronouncing various magic formulas, treated the patients. Each village had at least one person who practiced this type of treatment. Discussion: Numerous, original documents and records have been stored in the archives of the monastery throughout B&H, including very valuable literature in the field of medicine and pharmacy, which testifies of the very important role of Franciscans in the treatment of the population in Bosnia and Herzegovina. The most extensive health service of the Franciscans since their arrival in Bosnia in 1291 was the decadent era of Turkish rule, mostly from the 17th century until the Austro-Hungarian occupation of Bosnia and Herzegovina in 1978. In the sources of national thought, and on the basis of professional medical books, the Franciscans created recipes for the treatment of certain diseases, which they then collected in so-called "Ljekaruse" (Collections of folk recipes), and over time there was a lot of them. Most of the ljekarusa are hand printed booklets, for some it is known the time and place of creation, and less often the author of the text. Ljekarusa is a very important source of information about our medical past. Some of them were processed and recorded, while a significant part of these manuscripts remained unknown to the general public. They included recipes for various diseases and the names they were called by the people. Professional terms were not used, nor were the illnesses and the recipes ordered in any order or systematic manner. We learn from them that our people were once treated in the absence of doctors and pharmacists. Most commonly mentioned are various herbs, animal parts, mineral substances, and some of these recipes can be even applied today. All medicines continue to be transcribed by the people and valued as good old medical receipts. Conclusion: This review article presents a book (ljekaruse) that was archived in several famous monasteries in Bosnia and Herzegovina. PMID- 29109672 TI - Towards a Developmentally Integrative Model of Personality Change: A Focus on Three Potential Mechanisms. AB - While the overall stability of personality across the lifespan has been well documented, one does see incremental changes in a number of personality traits, changes that may impact overall life trajectories in both positive and negative ways. In this chapter, we present a new, developmentally-oriented and integrative model of the factors that might lead to personality change, drawing from the theoretical and empirical work of prior models (e.g. Caspi & Roberts, 2001; Roberts et al., 2005) as well as from our own longitudinal studies of personality change and risky behavior engagement in children, adolescents, and young adults (Boyle et al., 2016; Riley & Smith, 2016; Riley et al., 2016). We focus on change in the trait of urgency, which is a high-risk personality trait that represents the tendency to act rashly when highly emotional. We explore processes of both biologically-based personality change in adolescence, integrating neurocognitive and puberty-based models, as well as behavior-based personality change, in which behaviors and the personality traits underlying those behaviors are incrementally reinforced and shaped over time. One implication of our model for clinical psychology is the apparent presence of a positive feedback loop of risk, in which maladaptive behaviors increase high-risk personality traits, which in turn further increase the likelihood of maladaptive behaviors, a process that continues far beyond the initial experiences of maladaptive behavior engagement. Finally, we examine important future directions for continuing work on personality change, including trauma-based personality change and more directive (e.g., therapeutic) approaches aimed at shaping personality. PMID- 29109673 TI - Commentary: On the joys of perceiving: Affect as feedback for perceptual predictions. PMID- 29109675 TI - Editorial: The Physiological Functions of the APP Gene Family. PMID- 29109674 TI - Adult Neurogenesis in Sheep: Characterization and Contribution to Reproduction and Behavior. AB - Sheep have many advantages to study neurogenesis in comparison to the well-known rodent models. Their development and life expectancy are relatively long and they possess a gyrencephalic brain. Sheep are also seasonal breeders, a characteristic that allows studying the involvement of hypothalamic neurogenesis in the control of seasonal reproduction. Sheep are also able to individually recognize their conspecifics and develop selective and lasting bonds. Adult olfactory neurogenesis could be adapted to social behavior by supporting recognition of conspecifics. The present review reveals the distinctive features of the hippocampal, olfactory, and hypothalamic neurogenesis in sheep. In particular, the organization of the subventricular zone and the dynamic of neuronal maturation differs from that of rodents. In addition, we show that various physiological conditions, such as seasonal reproduction, gestation, and lactation differently modulate these three neurogenic niches. Last, we discuss recent evidence indicating that hypothalamic neurogenesis acts as an important regulator of the seasonal control of reproduction and that olfactory neurogenesis could be involved in odor processing in the context of maternal behavior. PMID- 29109676 TI - Oxytocin Removes Estrous Female vs. Male Preference of Virgin Male Rats: Mediation of the Supraoptic Nucleus Via Olfactory Bulbs. AB - Social functions of oxytocin (OT) have been explored extensively; however, relationship between the effect of intranasally applied OT (nasal OT) on the social preference (SP) and intracerebral actions of endogenous OT remains unclear. To resolve this question, we first observed effects of nasal OT on the SP of virgin young adult male rats toward unfamiliar virgin estrous female (EF) vs. virgin male rats. The results showed that the test male rats exhibited significantly more times and longer duration accessing the female than the male, which were acutely eliminated by nasal OT. Then, we examined the approaches mediating nasal OT effects on the activity of potential brain targets in Western blots and found that nasal OT activated the olfactory bulbs (OBs) and the supraoptic nucleus (SON), but not the piriform cortex, amygdala and hippocampus as shown by significant changes in the expression of c-Fos and/or phosphorylated extracellular signal-regulated protein kinase (pERK) 1/2. Moreover, microinjection of TTX into the OBs blocked nasal OT-evoked increases in pERK1/2 levels as well as the molecular association between ERK1/2 and OT-neurophysin in the SON. Electrolytic lesions of the lateral olfactory tract did not significantly change the basal levels of pERK 1/2 in the SON; however, upon nasal OT, pERK 1/2 levels in the SON reduced significantly. Lastly, microinjection of L aminoadipic acid (gliotoxin) into the SON to reduce OT levels reduced the duration of the test male's accessing the EF and blocked the nasal OT-evoked increase in the duration of test male's accessing the male while significantly increasing pERK1/2 levels in the amygdala. These findings reveal for the first time that nasal OT acutely eliminates virgin males' SP to EFs via the OB-SON route and that OT neurons could mediate the social effects of nasal OT by suppressing social phobia generated in the amygdala. PMID- 29109677 TI - Mechanisms of Long Non-Coding RNAs in the Assembly and Plasticity of Neural Circuitry. AB - The mechanisms underlying development processes and functional dynamics of neural circuits are far from understood. Long non-coding RNAs (lncRNAs) have emerged as essential players in defining identities of neural cells, and in modulating neural activities. In this review, we summarized latest advances concerning roles and mechanisms of lncRNAs in assembly, maintenance and plasticity of neural circuitry, as well as lncRNAs' implications in neurological disorders. We also discussed technical advances and challenges in studying functions and mechanisms of lncRNAs in neural circuitry. Finally, we proposed that lncRNA studies would advance our understanding on how neural circuits develop and function in physiology and disease conditions. PMID- 29109679 TI - Extracellular Electrophysiological Measurements of Cooperative Signals in Astrocytes Populations. AB - Astrocytes are neuroglial cells that exhibit functional electrical properties sensitive to neuronal activity and capable of modulating neurotransmission. Thus, electrophysiological recordings of astroglial activity are very attractive to study the dynamics of glial signaling. This contribution reports on the use of ultra-sensitive planar electrodes combined with low noise and low frequency amplifiers that enable the detection of extracellular signals produced by primary cultures of astrocytes isolated from mouse cerebral cortex. Recorded activity is characterized by spontaneous bursts comprised of discrete signals with pronounced changes on the signal rate and amplitude. Weak and sporadic signals become synchronized and evolve with time to higher amplitude signals with a quasi periodic behavior, revealing a cooperative signaling process. The methodology presented herewith enables the study of ionic fluctuations of population of cells, complementing the single cells observation by calcium imaging as well as by patch-clamp techniques. PMID- 29109678 TI - Identification of Genes that Maintain Behavioral and Structural Plasticity during Sleep Loss. AB - Although patients with primary insomnia experience sleep disruption, they are able to maintain normal performance on a variety of cognitive tasks. This observation suggests that insomnia may be a condition where predisposing factors simultaneously increase the risk for insomnia and also mitigate against the deleterious consequences of waking. To gain insight into processes that might regulate sleep and buffer neuronal circuits during sleep loss, we manipulated three genes, fat facet (faf), highwire (hiw) and the GABA receptor Resistance to dieldrin (Rdl), that were differentially modulated in a Drosophila model of insomnia. Our results indicate that increasing faf and decreasing hiw or Rdl within wake-promoting large ventral lateral clock neurons (lLNvs) induces sleep loss. As expected, sleep loss induced by decreasing hiw in the lLNvs results in deficits in short-term memory and increases of synaptic growth. However, sleep loss induced by knocking down Rdl in the lLNvs protects flies from sleep-loss induced deficits in short-term memory and increases in synaptic markers. Surprisingly, decreasing hiw and Rdl within the Mushroom Bodies (MBs) protects against the negative effects of sleep deprivation (SD) as indicated by the absence of a subsequent homeostatic response, or deficits in short-term memory. Together these results indicate that specific genes are able to disrupt sleep and protect against the negative consequences of waking in a circuit dependent manner. PMID- 29109680 TI - Diversity of Evoked Astrocyte Ca2+ Dynamics Quantified through Experimental Measurements and Mathematical Modeling. AB - Astrocytes are a major cell type in the mammalian brain. They are not electrically excitable, but generate prominent Ca2+ signals related to a wide variety of critical functions. The mechanisms driving these Ca2+ events remain incompletely understood. In this study, we integrate Ca2+ imaging, quantitative data analysis, and mechanistic computational modeling to study the spatial and temporal heterogeneity of cortical astrocyte Ca2+ transients evoked by focal application of ATP in mouse brain slices. Based on experimental results, we tune a single-compartment mathematical model of IP3-dependent Ca2+ responses in astrocytes and use that model to study response heterogeneity. Using information from the experimental data and the underlying bifurcation structure of our mathematical model, we categorize all astrocyte Ca2+ responses into four general types based on their temporal characteristics: Single-Peak, Multi-Peak, Plateau, and Long-Lasting responses. We find that the distribution of experimentally recorded response types depends on the location within an astrocyte, with somatic responses dominated by Single-Peak (SP) responses and large and small processes generating more Multi-Peak responses. On the other hand, response kinetics differ more between cells and trials than with location within a given astrocyte. We use the computational model to elucidate possible sources of Ca2+ response variability: (1) temporal dynamics of IP3, and (2) relative flux rates through Ca2+ channels and pumps. Our model also predicts the effects of blocking Ca2+ channels/pumps; for example, blocking store-operated Ca2+ (SOC) channels in the model eliminates Plateau and Long-Lasting responses (consistent with previous experimental observations). Finally, we propose that observed differences in response type distributions between astrocyte somas and processes can be attributed to systematic differences in IP3 rise durations and Ca2+ flux rates. PMID- 29109682 TI - Robust Sex Differences in Jigsaw Puzzle Solving-Are Boys Really Better in Most Visuospatial Tasks? AB - Sex differences are consistently reported in different visuospatial tasks with men usually performing better in mental rotation tests while women are better on tests for memory of object locations. In the present study, we investigated sex differences in solving jigsaw puzzles in children. In total 22 boys and 24 girls were tested using custom build tablet application representing a jigsaw puzzle consisting of 25 pieces and featuring three different pictures. Girls outperformed boys in solving jigsaw puzzles regardless of the picture. Girls were faster than boys in solving the puzzle, made less incorrect moves with the pieces of the puzzle, and spent less time moving the pieces around the tablet. It appears that the strategy of solving the jigsaw puzzle was the main factor affecting differences in success, as girls tend to solve the puzzle more systematically while boys performed more trial and error attempts, thus having more incorrect moves with the puzzle pieces. Results of this study suggest a very robust sex difference in solving the jigsaw puzzle with girls outperforming boys by a large margin. PMID- 29109683 TI - Two Mechanisms of Sensorimotor Set Adaptation to Inclined Stance. AB - Orientation of posture relative to the environment depends on the contributions from the somatosensory, vestibular, and visual systems mixed in varying proportions to produce a sensorimotor set. Here, we probed the sensorimotor set composition using a postural adaptation task in which healthy adults stood on an inclined surface for 3 min. Upon returning to a horizontal surface, participants displayed a range of postural orientations - from an aftereffect that consisted of a large forward postural lean to an upright stance with little or no aftereffect. It has been hypothesized that the post-incline postural change depends on each individual's sensorimotor set: whether the set was dominated by the somatosensory or vestibular system: Somatosensory dominance would cause the lean aftereffect whereas vestibular dominance should steer stance posture toward upright orientation. We investigated the individuals who displayed somatosensory dominance by manipulating their attention to spatial orientation. We introduced a distraction condition in which subjects concurrently performed a difficult arithmetic subtraction task. This manipulation altered the time course of their post-incline aftereffect. When not distracted, participants returned to upright stance within the 3-min period. However, they continued leaning forward when distracted. These results suggest that the mechanism of sensorimotor set adaptation to inclined stance comprises at least two components. The first component reflects the dominant contribution from the somatosensory system. Since the postural lean was observed among these subjects even when they were not distracted, it suggests that the aftereffect is difficult to overcome. The second component includes a covert attentional component which manifests as the dissipation of the aftereffect and the return of posture to upright orientation. PMID- 29109684 TI - Antimicrobial, Anthelmintic, and Antiviral Activity of Plants Traditionally Used for Treating Infectious Disease in the Similipal Biosphere Reserve, Odisha, India. AB - In the present study, we tested in vitro different parts of 35 plants used by tribals of the Similipal Biosphere Reserve (SBR, Mayurbhanj district, India) for the management of infections. From each plant, three extracts were prepared with different solvents (water, ethanol, and acetone) and tested for antimicrobial (E. coli, S. aureus, C. albicans); anthelmintic (C. elegans); and antiviral (enterovirus 71) bioactivity. In total, 35 plant species belonging to 21 families were recorded from tribes of the SBR and periphery. Of the 35 plants, eight plants (23%) showed broad-spectrum in vitro antimicrobial activity (inhibiting all three test strains), while 12 (34%) exhibited narrow spectrum activity against individual pathogens (seven as anti-staphylococcal and five as anti candidal). Plants such as Alangium salviifolium, Antidesma bunius, Bauhinia racemosa, Careya arborea, Caseria graveolens, Cleistanthus patulus, Colebrookea oppositifolia, Crotalaria pallida, Croton roxburghii, Holarrhena pubescens, Hypericum gaitii, Macaranga peltata, Protium serratum, Rubus ellipticus, and Suregada multiflora showed strong antibacterial effects, whilst Alstonia scholaris, Butea monosperma, C. arborea, C. pallida, Diospyros malbarica, Gmelina arborea, H. pubescens, M. peltata, P. serratum, Pterospermum acerifolium, R. ellipticus, and S. multiflora demonstrated strong antifungal activity. Plants such as A. salviifolium, A. bunius, Aporosa octandra, Barringtonia acutangula, C. graveolens, C. pallida, C. patulus, G. arborea, H. pubescens, H. gaitii, Lannea coromandelica, M. peltata, Melastoma malabathricum, Millettia extensa, Nyctanthes arbor-tristis, P. serratum, P. acerifolium, R. ellipticus, S. multiflora, Symplocos cochinchinensis, Ventilago maderaspatana, and Wrightia arborea inhibit survival of C. elegans and could be a potential source for anthelmintic activity. Additionally, plants such as A. bunius, C. graveolens, C. patulus, C. oppositifolia, H. gaitii, M. extensa, P. serratum, R. ellipticus, and V. maderaspatana showed anti-enteroviral activity. Most of the plants, whose traditional use as anti-infective agents by the tribals was well supported, show in vitro inhibitory activity against an enterovirus, bacteria (E. coil, S. aureus), a fungus (C. albicans), or a nematode (C. elegans). PMID- 29109681 TI - Tenascins in Retinal and Optic Nerve Neurodegeneration. AB - Tenascins represent key constituents of the extracellular matrix (ECM) with major impact on central nervous system (CNS) development. In this regard, several studies indicate that they play a crucial role in axonal growth and guidance, synaptogenesis and boundary formation. These functions are not only important during development, but also for regeneration under several pathological conditions. Additionally, tenascin-C (Tnc) represents a key modulator of the immune system and inflammatory processes. In the present review article, we focus on the function of Tnc and tenascin-R (Tnr) in the diseased CNS, specifically after retinal and optic nerve damage and degeneration. We summarize the current view on both tenascins in diseases such as glaucoma, retinal ischemia, age related macular degeneration (AMD) or diabetic retinopathy. In this context, we discuss their expression profile, possible functional relevance, remodeling of the interacting matrisome and tenascin receptors, especially under pathological conditions. PMID- 29109686 TI - Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists. AB - We investigated the effect of pre- "race" ingestion of a 1,3-butanediol acetoacetate diester on blood ketone concentration, substrate metabolism and performance of a cycling time trial (TT) in professional cyclists. In a randomized cross-over design, 10 elite male cyclists completed a ~31 km laboratory-based TT on a cycling ergometer programmed to simulate the 2017 World Road Cycling Championships course. Cyclists consumed a standardized meal [2 g/kg body mass (BM) carbohydrate (CHO)] the evening prior to a trial day and a CHO breakfast (2 g/kg BM CHO) with 200 mg caffeine on the morning of a trial day. Cyclists were randomized to consume either the ketone diester (2 * 250 mg/kg) or a placebo drink, followed immediately by 200 mL diet cola, given ~ 30 min before and immediately prior to commencing a 20 min incremental warm-up. Blood samples were collected prior to and during the warm-up, pre- and post- TT and at regular intervals after the TT. Urine samples were collected pre- and post- warm-up, immediately post TT and 60 min post TT. Pre-exercise ingestion of the diester resulted in a 2 +/- 1% impairment in TT performance that was associated with gut discomfort and higher perception of effort. Serum beta-hydroxybutyrate, serum acetoacetate, and urine ketone concentrations increased from rest following ketone ingestion and were higher than placebo throughout the trial. Ketone ingestion induces hyperketonemia in elite professional cyclists when in a carbohydrate fed state, and impairs performance of a cycling TT lasting ~50 min. PMID- 29109685 TI - Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors. AB - The mechanism of action of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB2 receptors (CB2Rs) it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs); however, CBD does not bind with high affinity to the orthosteric site of any GPCR. To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB2R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB2R. Using membrane preparations from CB2R-expressing HEK-293T (human embryonic kidney 293T) cells, we confirmed that CBD does not bind with high affinity to the orthosteric site of the human CB2R where the synthetic cannabinoid, [3H]-WIN 55,212-2, binds. CBD was, however, able to produce minor but consistent reduction in the homogeneous binding assays in living cells using the fluorophore-conjugated CB2R selective compound, CM-157. The effect on binding to CB2R-expressing living cells was different to that exerted by the orthosteric antagonist, SR144528, which decreased the maximum binding without changing the KD . CBD at nanomolar concentrations was also able to significantly reduce the effect of the selective CB2R agonist, JWH133, on forskolin-induced intracellular cAMP levels and on activation of the MAP kinase pathway. These results may help to understand CBD mode of action and may serve to revisit its therapeutic possibilities. PMID- 29109688 TI - Weak Relationships between Stint Duration, Physical and Skilled Match Performance in Australian Football. AB - Australian Rules football comprises physical and skilled performance for more than 90 min of play. The cognitive and physiological fatigue experienced by participants during a match may reduce performance. Consequently, the length of time an athlete is on the field before being interchanged (known as a stint), is a key tactic which could maximize the skill and physical output of the Australian Rules athlete. This study developed two methods to quantify the relationship between athlete time on field, skilled and physical output. Professional male athletes (n = 39) from a single elite Australian Rules football club participated, with physical output quantified via player tracking systems across 22 competitive matches. Skilled output was calculated as the sum of involvements performed by each athlete, collected from a commercial statistics company. A random intercept and slope model was built to identify how a team and individuals respond to physical outputs and stint lengths. Stint duration (mins), high intensity running (speeds >14.4 km . hr-1) per minute, meterage per minute and very high intensity running (speeds >25 km.hr-1) per minute had some relationship with skilled involvements. However, none of these relationships were strong, and the direction of influence for each player was varied. Three conditional inference trees were computed to identify the extent to which combinations of physical parameters altered the anticipated skilled output of players. Meterage per minute, player, round number and duration were all related to player involvement. All methods had an average error of 10 to 11 involvements, per player per match. Therefore, other factors aside from physical parameters extracted from wearable technologies may be needed to explain skilled output within Australian Rules football matches. PMID- 29109689 TI - Molecular Plasticity under Ocean Warming: Proteomics and Fitness Data Provides Clues for a Better Understanding of the Thermal Tolerance in Fish. AB - Ocean warming is known to alter the performance and fitness of marine organisms albeit the proteome underpinnings of species thermal tolerance are still largely unknown. In this 1-month experiment we assessed the vulnerability of the gilt head sea bream Sparus aurata, taken here as a biological model for some key fisheries species, to ocean warming (control 18 degrees C, nursery ground temperature 24 degrees C and heat wave 30 degrees C). Survival was impaired after 28 days, mainly at 30 degrees C although fishes' condition was unaltered. Muscle proteome modulation was assessed at 14 and 21 days, showing that protein expression profiles were similar between fish exposed to 18 and 24 degrees C, differing from fish exposed to 30 degrees C. Fish subjected to 24 degrees C showed an enhanced glycolytic potential and decreased glycogenolysis mainly at 14 days of exposure. Fish subjected to 30 degrees C also showed enhanced glycolytic potential and up-regulated proteins related to gene expression, cellular stress response (CSR), and homeostasis (mostly cytoskeletal dynamics, acid-base balance, chaperoning). However, inflammatory processes were elicited at 21 days along with a down-regulation of the tricarboxylic acid cycle. Thus, juvenile fish seem able to acclimate to 24 degrees C but possibly not to 30 degrees C, which is the predicted temperature for estuaries during heat waves by the year 2100. This may be related with increasing constraints on organism physiology associated with metabolic scope available for performance and fitness at higher temperatures. Consequently, recruitment of commercial sea breams may be in jeopardy, highlighting the need for improved management plans for fish stocks. PMID- 29109690 TI - Comorbid Mental Disorders and 6-Month Symptomatic and Functioning Outcomes in Chinese University Students at Clinical High Risk for Psychosis. AB - Background: High rates of non-psychotic psychopathological symptoms have been observed in clinical population at clinical high risk (CHR) for psychosis. These comorbid disorders affected the baseline functional level of CHR patients. However, little is known about the comorbid mental disorder in CHR individuals in non-clinical adolescent population. This study aimed to investigate the comorbid mental disorder in non-clinical CHR adolescents and the impact on attenuated psychosis symptoms (APS) as well as clinical outcome. Methods: The sample consisted of 32 CHR students, who were screened from 2,800 university students. CHR status was evaluated with the Structured Interview of Prodromal Syndromes, comorbid mental disorder diagnoses with the International Neuropsychiatric Interview. Results: In the CHR sample, 46.9% was found at least one non-psychotic comorbid mental disorder. The CHR participants presenting comorbid mental disorder had significantly more severity of APS than those without comorbid mental disorders, and the remission rate at 6-month follow-up is significantly higher in the individuals without comorbid mental disorders at baseline. Conclusion: In the non-clinical sample of individuals at CHR, non-psychotic comorbid mental disorders are common and anxiety disorder is most frequent. Copresence of anxiety and/or depression is related to higher level of attenuated psychotic symptoms and unfavorable clinical outcome at 6-month follow-up. Assessment and intervention in anxiety and depression for non-clinical CHR adolescents are suggested. PMID- 29109691 TI - Adaptive Personality Traits and Psychosocial Correlates among Living Kidney Donors. AB - Since living kidney donors have repeatedly been shown to be mentally more healthy compared to the general population, they might also exhibit more adaptive personality characteristics. We investigated the personality traits of 315 living kidney donors (202 female and 113 male donors) on average 7.1 years after donation using the NEO-Five Factor Inventory, a frequently used personality inventory measuring the "big five" dimensions of personality (neuroticism, extraversion, openness, agreeableness, and conscientiousness). In addition, levels of depression, anxiety, and fatigue were assessed with the Patient Health Questionnaire-Depression Scale, GAD-7, and Multidimensional Fatigue Inventory. Kidney donors showed more adaptive personality traits with higher agreeableness and lower neuroticism scores compared to the German general population. This was even more pronounced in living kidney donors with a high motivation to donate again (non-regreters). Scores for depression, anxiety, and fatigue did not differ from general population values and were significantly correlated with most personality dimensions. The more adaptive personality characteristics of living kidney donors might either be a selection effect or the consequence of the experience of donation and improved health of the close relative. Regardless of the causal relationship, adaptive personality traits might positively influence both physical and psychosocial well-being of the donor. Longitudinal studies should investigate if living donation might lead to persistent adaptive changes in personality traits. PMID- 29109692 TI - In an Unpredictable and Changing Environment: Intrapreneurial Self-Capital As a Key Resource for Life Satisfaction and Flourishing. AB - The twenty-first century is characterized by an unpredictable and challenging work environment, and the Intrapreneurial Self-Capital (ISC) career and life construct can be seen as a core of individual intrapreneurial resources that enables people to cope with ongoing challenges, changes, and transitions founding innovative solutions when confronted with the constraints imposed by such an environment. The ISC is a challenging construct since it can enhance behavior and attitudes through specific training, unlike personality traits, which are considered substantially stable in the literature. Against this background, the present study examined the relationship between ISC and well-being (hedonic well being and eudaimonic well-being) controlling for the effects of personality traits. The Big Five Questionnaire (BFQ), the Intrapreneurial Self-Capital Scale (ISCS), the Satisfaction With Life Scale (SWLS), and the Flourishing Scale (FS) were administered to 258 Italian workers. Hierarchical regression analyses showed that ISC explained a percentage of incremental variance beyond that explained by personality traits in relation to both life satisfaction and flourishing. These results indicate that ISC is a key resource for hedonic well-being and eudaimonic well-being and that it offers new research and intervention opportunities. PMID- 29109687 TI - Low-Intensity Ultrasound-Induced Anti-inflammatory Effects Are Mediated by Several New Mechanisms Including Gene Induction, Immunosuppressor Cell Promotion, and Enhancement of Exosome Biogenesis and Docking. AB - Background: Low-intensity ultrasound (LIUS) was shown to be beneficial in mitigating inflammation and facilitating tissue repair in various pathologies. Determination of the molecular mechanisms underlying the anti-inflammatory effects of LIUS allows to optimize this technique as a therapy for the treatment of malignancies and aseptic inflammatory disorders. Methods: We conducted cutting edge database mining approaches to determine the anti-inflammatory mechanisms exerted by LIUS. Results: Our data revealed following interesting findings: (1) LIUS anti-inflammatory effects are mediated by upregulating anti-inflammatory gene expression; (2) LIUS induces the upregulation of the markers and master regulators of immunosuppressor cells including MDSCs (myeloid-derived suppressor cells), MSCs (mesenchymal stem cells), B1-B cells and Treg (regulatory T cells); (3) LIUS not only can be used as a therapeutic approach to deliver drugs packed in various structures such as nanobeads, nanospheres, polymer microspheres, and lipidosomes, but also can make use of natural membrane vesicles as small as exosomes derived from immunosuppressor cells as a novel mechanism to fulfill its anti-inflammatory effects; (4) LIUS upregulates the expression of extracellular vesicle/exosome biogenesis mediators and docking mediators; (5) Exosome-carried anti-inflammatory cytokines and anti-inflammatory microRNAs inhibit inflammation of target cells via multiple shared and specific pathways, suggesting exosome mediated anti-inflammatory effect of LIUS feasible; and (6) LIUS-mediated physical effects on tissues may activate specific cellular sensors that activate downstream transcription factors and signaling pathways. Conclusions: Our results have provided novel insights into the mechanisms underlying anti-inflammatory effects of LIUS, and have provided guidance for the development of future novel therapeutic LIUS for cancers, inflammatory disorders, tissue regeneration and tissue repair. PMID- 29109693 TI - The Effectiveness of Eye Movement Desensitization and Reprocessing Integrative Group Protocol with Adolescent Survivors of the Central Italy Earthquake. AB - Earthquakes, which can cause widespread territorial and socio-economic destruction, are life-threatening, unexpected, unpredictable, and uncontrollable events caused by the shaking of the surface of the earth. The psychological consequences, such as PTSD, anxiety, depression, and suicidal ideation, are well known to clinicians and researchers. This study was conducted with the aim of evaluating the use of the Eye Movement Desensitization and Reprocessing (EMDR) Integrative Group Treatment Protocol on a sample of adolescents, after the earthquake in Central Italy on 24 August 2016. The objective of the EMDR intervention was to reduce PTSD symptoms. Before and after EMDR, specific assessment to find changes in PTSD symptoms was made using the Impact of Event Scale-Revised and through the analyses of the Subjective Units of Disturbance. The EMDR treatment was given in three sessions (T1, T2, and T3), each lasting 90 min, and the results at follow-up phase (T4) were also monitored. The results are very encouraging, showing significantly reduced PTSD symptoms in the majority of the subjects. The clinical implications and limitations will be discussed. PMID- 29109694 TI - Teaching Semantic Radicals Facilitates Inferring New Character Meaning in Sentence Reading for Nonnative Chinese Speakers. AB - This study investigates the effects of teaching semantic radicals in inferring the meanings of unfamiliar characters among nonnative Chinese speakers. A total of 54 undergraduates majoring in Chinese Language from a university in Hanoi, Vietnam, who had 1 year of learning experience in Chinese were assigned to two experimental groups that received instructional intervention, called "old-for new" semantic radical teaching, through two counterbalanced sets of semantic radicals, with one control group. All of the students completed pre- and post tests of a sentence cloze task where they were required to choose an appropriate character that fit the sentence context among four options. The four options shared the same phonetic radicals but had different semantic radicals. The results showed that the pre-test and post-test score increases were significant for the experimental groups, but not for the control group. Most importantly, the experimental groups successfully transferred the semantic radical strategy to figure out the meanings of unfamiliar characters containing semantic radicals that had not been taught. The results demonstrate the effectiveness of teaching semantic radicals for lexical inference in sentence reading for nonnative speakers, and highlight the ability of transfer learning to acquire semantic categories of sub-lexical units (semantic radicals) in Chinese characters among foreign language learners. PMID- 29109696 TI - Low-Dose Alkylphenol Exposure Promotes Mammary Epithelium Alterations and Transgenerational Developmental Defects, But Does Not Enhance Tumorigenic Behavior of Breast Cancer Cells. AB - Fetal and neonatal exposure to long-chain alkylphenols has been suspected to promote breast developmental disorders and consequently to increase breast cancer risk. However, disease predisposition from developmental exposures remains unclear. In this work, human MCF-10A mammary epithelial cells were exposed in vitro to a low dose of a realistic (4-nonylphenol + 4-tert-octylphenol) mixture. Transcriptome and cell-phenotype analyses combined to functional and signaling network modeling indicated that long-chain alkylphenols triggered enhanced proliferation, migration ability, and apoptosis resistance and shed light on the underlying molecular mechanisms which involved the human estrogen receptor alpha 36 (ERalpha36) variant. A male mouse-inherited transgenerational model of exposure to three environmentally relevant doses of the alkylphenol mix was set up in order to determine whether and how it would impact on mammary gland architecture. Mammary glands from F3 progeny obtained after intrabuccal chronic exposure of C57BL/6J P0 pregnant mice followed by F1-F3 male inheritance displayed an altered histology which correlated with the phenotypes observed in vitro in human mammary epithelial cells. Since cellular phenotypes are similar in vivo and in vitro and involve the unique ERalpha36 human variant, such consequences of alkylphenol exposure could be extrapolated from mouse model to human. However, transient alkylphenol treatments combined to ERalpha36 overexpression in mammary epithelial cells were not sufficient to trigger tumorigenesis in xenografted Nude mice. Therefore, it remains to be determined if low-dose alkylphenol transgenerational exposure and subsequent abnormal mammary gland development could account for an increased breast cancer susceptibility. PMID- 29109695 TI - The Role of Thromboinflammation in Delayed Cerebral Ischemia after Subarachnoid Hemorrhage. AB - Delayed cerebral ischemia (DCI) is a major determinant of patient outcome following aneurysmal subarachnoid hemorrhage. Although the exact mechanisms leading to DCI are not fully known, inflammation, cerebral vasospasm, and microthrombi may all function together to mediate the onset of DCI. Indeed, inflammation is tightly linked with activation of coagulation and microthrombi formation. Thromboinflammation is the intersection at which inflammation and thrombosis regulate one another in a feedforward manner, potentiating the formation of thrombi and pro-inflammatory signaling. In this review, we will explore the role(s) of inflammation and microthrombi in subarachnoid hemorrhage (SAH) pathophysiology and DCI, and discuss the potential of targeting thromboinflammation to prevent DCI after SAH. PMID- 29109697 TI - Circulating Endothelial Progenitor Cells in Type 1 Diabetic Patients: Relation with Patients' Age and Disease Duration. AB - Objectives: Circulating endothelial progenitor cells (cEPCs) have been reported to be dysfunctional in diabetes mellitus (DM) patients, accounting for the vascular damage and the ensuing high risk for cardiovascular disease (CVD) characteristic of this disease. The aim of the present study was to evaluate the number of circulating cEPCs in type 1 DM (T1DM) patients, without clinical vascular damage, of different ages and with different disease duration. Methods: An observational, clinical-based prospective study was performed on T1DM patients enrolled in two clinical centers. cEPCs were determined by flow cytometry, determining the number of CD34/CD133/VEGFR2-positive cells within peripheral blood mononuclear cells (PBMCs). Results: The number of cEPCs was lower in adult T1DM patients, whilst higher in childhood/young patients, compared to controls of the same age range. When patients were grouped into two age groups (>= or <20 years) (and categorized on the basis of the duration of the disease), the number of cEPCs in young (<20 years) patients was higher compared with older subjects, regardless of disease duration. A subset of patients with very high cEPCs was identified in the <20 years group. Conclusion: There is an association between the number of cEPCs and patients' age: childhood/young T1DM patients have significantly higher levels of cEPCs, respect to adult T1DM patients. Such difference is maintained also when the disease lasts for more than 10 years. The very high levels of cEPCs, identified in a subset of childhood/young patients, might protect vessels against endothelial dysfunction and damage. Such protection would be less operative in older subjects, endowed with lower cEPC numbers, in which complications are known to develop more easily. PMID- 29109698 TI - The Emerging Facets of Non-Cancerous Warburg Effect. AB - The Warburg effect (WE), or aerobic glycolysis, is commonly recognized as a hallmark of cancer and has been extensively studied for potential anti-cancer therapeutics development. Beyond cancer, the WE plays an important role in many other cell types involved in immunity, angiogenesis, pluripotency, and infection by pathogens (e.g., malaria). Here, we review the WE in non-cancerous context as a "hallmark of rapid proliferation." We observe that the WE operates in rapidly dividing cells in normal and pathological states that are triggered by internal and external cues. Aerobic glycolysis is also the preferred metabolic program in the cases when robust transient responses are needed. We aim to draw attention to the potential of computational modeling approaches in systematic characterization of common metabolic features beyond the WE across physiological and pathological conditions. Identification of metabolic commonalities across various diseases may lead to successful repurposing of drugs and biomarkers. PMID- 29109699 TI - Multiple Sclerosis, Melatonin, and Neurobehavioral Diseases. PMID- 29109700 TI - Exploring the Genome and Phenotype of Multi-Drug Resistant Klebsiella pneumoniae of Clinical Origin. AB - Klebsiella pneumoniae is an important nosocomial pathogen with an extraordinary resistant phenotype due to a combination of acquired resistant-elements and efflux mechanisms. In this study a detailed molecular characterization of 11 K. pneumoniae isolates of clinical origin was carried out. Eleven clinical isolates were tested for their susceptibilities, by disk diffusion and broth microdilution and interpreted according to CLSI guidelines. Efflux activity was determined by measuring the extrusion of ethidium bromide and biofilm formation was assessed following static growth in Mueller-Hinton and minimal media M9 broths at two temperatures and time points. Template DNA from all 11 isolates was extracted and sequenced. The study collection was found to be resistant to several (extended spectrum beta-lactam) ESBL-type compounds along with several (fluoro)quinolones (FQ). Resistance to tetracycline accounted for 55% of the study collection (n = 6) and three of the 11 isolates were resistance to carbapenems. Genotyping identified blaCTX-M-15 (82%), blaSHV-12 (55%), and blaTEM-1B (45%) ESBL encoding genes and FQ resistance was associated the presence of the oqxAB operon, identified in 10 of the 11 isolates and qnrB gene in one isolate. The polymorphisms detected in the quinolone resistance-determining regions (QRDRs) were associated with isolates of the clonal group CG15. Sequence types (ST) identified were representative of previously described clonal groups including CG258 (n = 7), CG15 (n = 3), and CG147 (n = 1). Plasmid replicon type databases were queried indicating the presence of IncFII and IncFIB replicon types in the majority of the isolates (91%), followed by IncFIA (45%), and IncR (45%). Two of the 11 isolates were found positive for yersiniabactin siderophore-encoding genes. No differences in the ability to efflux ethidium bromide were identified. Biofilm formation was stronger when the isolates were grown under stressed conditions at 37 degrees C for a period up to 96 h. These data confirm the fact that well-recognized clonal groups of K. pneumoniae of importance to human health carries a diverse repertoire of antimicrobial resistance determinants, particularly related to critically important drugs in the ESBL and FQ classes. The capacity of most isolates to form strong biofilms, when stressed under laboratory-simulated conditions, supports the risk to human health associated with nosocomial infections deriving from indwelling medical devices. PMID- 29109702 TI - Genomic Comparison among Lethal Invasive Strains of Streptococcus pyogenes Serotype M1. AB - Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a human pathogen that causes diverse human diseases including streptococcal toxic shock syndrome (STSS). A GAS outbreak occurred in Brasilia, Brazil, during the second half of the year 2011, causing 26 deaths. Whole genome sequencing was performed using Illumina platform. The sequences were assembled and genes were predicted for comparative analysis with emm type 1 strains: MGAS5005 and M1 GAS. Genomics comparison revealed one of the invasive strains that differ from others isolates and from emm 1 reference genomes. Also, the new invasive strain showed differences in the content of virulence factors compared to other isolated in the same outbreak. The evolution of contemporary GAS strains is strongly associated with horizontal gene transfer. This is the first genomic study of a Streptococcal emm 1 outbreak in Brazil, and revealed the rapid bacterial evolution leading to new clones. The emergence of new invasive strains can be a consequence of the injudicious use of antibiotics in Brazil during the past decades. PMID- 29109701 TI - Microbial Community and Biochemical Dynamics of Biological Soil Crusts across a Gradient of Surface Coverage in the Central Mojave Desert. AB - In this study, we expand upon the biogeography of biological soil crusts (BSCs) and provide molecular insights into the microbial community and biochemical dynamics along the vertical BSC column structure, and across a transect of increasing BSC surface coverage in the central Mojave Desert, CA, United States. Next generation sequencing reveals a bacterial community profile that is distinct among BSCs in the southwestern United States. Distribution of major phyla in the BSC topsoils included Cyanobacteria (33 +/- 8%), Proteobacteria (26 +/- 6%), and Chloroflexi (12 +/- 4%), with Phormidium being the numerically dominant genus. Furthermore, BSC subsurfaces contained Proteobacteria (23 +/- 5%), Actinobacteria (20 +/- 5%), and Chloroflexi (18 +/- 3%), with an unidentified genus from Chloroflexi (AKIW781, order) being numerically dominant. Across the transect, changes in distribution at the phylum (p < 0.0439) and genus (p < 0.006) levels, including multiple biochemical and geochemical trends (p < 0.05), positively correlated with increasing BSC surface coverage. This included increases in (a) Chloroflexi abundance, (b) abundance and diversity of Cyanobacteria, (b) OTU level diversity in the topsoil, (c) OTU-level differentiation between the topsoil and subsurface, (d) intracellular ATP abundances and catalase activities, and (e) enrichments in clay, silt, and varying elements, including S, Mn, Co, As, and Pb, in the BSC topsoils. In sum, these studies suggest that BSCs from regions of differing surface coverage represent early successional stages, which exhibit increasing bacterial diversity, metabolic activities, and capacity to restructure the soil. Further, these trends suggest that BSC successional maturation and colonization across the transect are inhibited by metals/metalloids such as B, Ca, Ti, Mn, Co, Ni, Mo, and Pb. PMID- 29109703 TI - The Temperature Dependence of Phytoplankton Stoichiometry: Investigating the Roles of Species Sorting and Local Adaptation. AB - The elemental composition of phytoplankton (C:N:P stoichiometry) is a critical factor regulating nutrient cycling, primary production and energy transfer through planktonic food webs. Our understanding of the multiple direct and indirect mechanisms through which temperature controls phytoplankton stoichiometry is however incomplete, increasing uncertainty in the impacts of global warming on the biogeochemical functioning of aquatic ecosystems. Here, we use a decade-long warming experiment in outdoor freshwater ponds to investigate how temperature-driven turnover in species composition and shifts in stoichiometric traits within species through local thermal adaptation contribute to the effects of warming on seston stoichiometry. We found that experimental warming increased seston C:P and N:P ratios, while the C:N ratio was unaffected by warming. Temperature was also the dominant driver of seasonal variation in seston stoichiometry, correlating positively with both C:P and N:P ratios. The taxonomic composition of the phytoplankton community differed substantially between the warmed and ambient treatments indicating that warming resulted in differential sorting of species from the regional pool. Furthermore, taxonomic composition also changed markedly over the year within each of the warmed and ambient treatments, highlighting substantial temporal turnover in species. To investigate whether local adaptation also played an important role in shaping the effects of warming on seston stoichiometry, we isolated multiple strains of the cosmopolitan alga, Chlamydomonas reinhardtii from across the warmed and ambient mesocosms. We found that warmed isolates had higher C:P and N:P ratios, shifts that were comparable in direction and magnitude to the effects of warming on seston stoichiometry. Our results suggest that both species sorting and local adaptation are likely to play important roles in shaping the effects of warming on bulk phytoplankton stoichiometry and indicate that major shifts in aquatic biogeochemistry should be expected in a warmer world. PMID- 29109704 TI - Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal. AB - New diagnostic tests for enteric fever are urgently needed to assist with timely antimicrobial treatment of patients and to measure the efficacy of prevention measures such as vaccination. In a novel translational approach, here we use two recently developed controlled human infection models (CHIM) of enteric fever to evaluate an antibody-in-lymphocyte supernatant (ALS) assay, which can detect recent IgA antibody production by circulating B cells in ex vivo mononuclear cell culture. We calculated the discriminative ability of the ALS assay to distinguish diagnosed cases in the two CHIM studies in Oxford, prior to evaluating blood culture-confirmed diagnoses of patients presenting with fever to hospital in an endemic areas of Kathmandu, Nepal. Antibody responses to membrane preparations and lipopolysaccharide provided good sensitivity (>90%) for diagnosing systemic infection after oral challenge with Salmonella Typhi or S. Paratyphi A. Assay specificity was moderate (~60%) due to imperfect sensitivity of blood culture as the reference standard and likely unrecognized subclinical infection. These findings were augmented through the translation of the assay into the endemic setting in Nepal. Anti-MP IgA responses again exhibited good sensitivity (86%) but poor specificity (51%) for detecting blood culture-confirmed enteric fever cases (ROC AUC 0.79, 95%CI 0.70-0.88). Patients with anti-MP IgA ALS titers in the upper quartile exhibited a clinical syndrome synonymous with enteric fever. While better reference standards are need to assess enteric fever diagnostics, routine use of this ALS assay could be used to rule out infection and has the potential to double the laboratory detection rate of enteric fever in this setting over blood culture alone. PMID- 29109705 TI - Complete Genome Sequence of Vibrio campbellii LMB 29 Isolated from Red Drum with Four Native Megaplasmids. AB - Vibrio spp. are the most common pathogens for animals reared in aquaculture. Vibrio campbellii, which is often involved in shrimp, fish and mollusks diseases, is widely distributed in the marine environment worldwide, but our knowledge about its pathogenesis and antimicrobial resistance is very limited. The existence of this knowledge gap is at least partially because that V. campbellii was originally classified as Vibrio harveyi, and the detailed information of its comparative genome analysis to other Vibrio spp. is currently lacking. In this study, the complete genome of a V. campbellii predominant strain, LMB29, was determined by MiSeq in conjunction with PacBio SMRT sequencing. This genome consists of two circular DNA chromosomes and four megaplasmids. Comparative genome analysis indicates that LMB29 shares a 96.66% similarity (average nucleotide identity) with the V. campbellii ATCC strain BAA-1116 based on a 75% AF (average fraction) calculations, and its functional profile is very similar to V. campbellii E1 and V. campbellii CAIM115. Both type III secretion system (T3SS) and type VI secretion system (T6SS), along with the tlh gene which encodes a thermolabile hemolysin, are present in LMB29 which may contribute to the bacterial pathogenesis. The virulence of this strain was experimental confirmed by performing a LDH assay on a fish cell infection model, and cell death was observed as early as within 3 h post infection. Thirty-seven antimicrobial resistance genes (>45% identity) were predicted in LMB29 which includes a novel rifampicin ADP ribosyltransferase, arr-9, in plasmid pLMB157. The gene arr-9 was predicted on a genomic island with horizontal transferable potentials which may facilitate the rifampicin resistance dissemination. Future researches are needed to explore the pathogenesis of V. campbellii LMB29, but the availability of this genome sequence will certainly aid as a basis for further analysis. PMID- 29109706 TI - A Novel TetR-Like Transcriptional Regulator Is Induced in Acid-Nitrosative Stress and Controls Expression of an Efflux Pump in Mycobacteria. AB - Mycobacterium tuberculosis has the ability to survive inside macrophages under acid-nitrosative stress. M. tuberculosis Rv1685c and its ortholog in M. smegmatis, MSMEG_3765, are induced on exposure to acid-nitrosative stress. Both genes are annotated as TetR transcriptional regulators, a family of proteins that regulate a wide range of cellular activities, including multidrug resistance, carbon catabolism and virulence. Here, we demonstrate that MSMEG_3765 is co transcribed with the upstream genes MSMEG_3762 and MSMEG_3763, encoding efflux pump components. RTq-PCR and GFP-reporter assays showed that the MSMEG_3762/63/65 gene cluster, and the orthologous region in M. tuberculosis (Rv1687c/86c/85c), was up-regulated in a MSMEG_3765 null mutant, suggesting that MSMEG_3765 acts as a repressor, typical of this family of regulators. We further defined the MSMEG_3765 regulon using genome-wide transcriptional profiling and used reporter assays to confirm that the MSMEG_3762/63/65 promoter was induced under acid nitrosative stress. A putative 36 bp regulatory motif was identified upstream of the gene clusters in both M. smegmatis and M. tuberculosis and purified recombinant MSMEG_3765 protein was found to bind to DNA fragments containing this motif from both M. smegmatis and M. tuberculosis upstream regulatory regions. These results suggest that the TetR repressor MSMEG_3765/Rv1685c controls expression of an efflux pump with an, as yet, undefined role in the mycobacterial response to acid-nitrosative stress. PMID- 29109707 TI - Genomic Comparisons Reveal Microevolutionary Differences in Mycobacterium abscessus Subspecies. AB - Mycobacterium abscessus, a rapid-growing non-tuberculous mycobacterium, has been the cause of sporadic and outbreak infections world-wide. The subspecies in M. abscessus complex (M. abscessus, M. massiliense, and M. bolletii) are associated with different biologic and pathogenic characteristics and are known to be among the most frequently isolated opportunistic pathogens from clinical material. To date, the evolutionary forces that could have contributed to these biological and clinical differences are still unclear. We compared genome data from 243 M. abscessus strains downloaded from the NCBI ftp Refseq database to understand how the microevolutionary processes of homologous recombination and positive selection influenced the diversification of the M. abscessus complex at the subspecies level. The three subspecies are clearly separated in the Minimum Spanning Tree. Their MUMi-based genomic distances support the separation of M. massiliense and M. bolletii into two subspecies. Maximum Likelihood analysis through dN/dS (the ratio of number of non-synonymous substitutions per non synonymous site, to the number of synonymous substitutions per synonymous site) identified distinct genes in each subspecies that could have been affected by positive selection during evolution. The results of genome-wide alignment based on concatenated locally-collinear blocks suggest that (a) recombination has affected the M. abscessus complex more than mutation and positive selection; (b) recombination occurred more frequently in M. massiliense than in the other two subspecies; and (c) the recombined segments in the three subspecies have come from different intra-species and inter-species origins. The results lead to the identification of possible gene sets that could have been responsible for the subspecies-specific features and suggest independent evolution among the three subspecies, with recombination playing a more significant role than positive selection in the diversification among members in this complex. PMID- 29109708 TI - Differential Identification of Mycobacterial Species Using High-Resolution Melting Analysis. AB - Infections caused by non-tuberculous mycobacteria (NTM) is increasing wordwide. Due to the difference in treatment of NTM infections and tuberculosis, rapid species identification of mycobacterial clinical isolates is necessary for the effective management of mycobacterial diseases treatment and their control strategy. In this study, a cost-effective technique, real-time PCR coupled with high-resolution melting (HRM) analysis, was developed for the differentiation of Mycobacterial species using a novel rpoBC sequence. A total of 107 mycobacterial isolates (nine references and 98 clinical isolates) were subjected to differentiation using rpoBC locus sequence in a real-time PCR-HRM assay scheme. From 98 Mycobacterium clinical isolates, 88 species (89.7%), were identified at the species level by rpoBC locus sequence analysis as a gold standard method. M. simiae was the most frequently encountered species (41 isolates), followed by M. fortuitum (20 isolates), M. tuberculosis (15 isolates), M. kansassi (10 isolates), M. abscessus group (5 isolates), M. avium (5 isolates), and M. chelonae and M. intracellulare one isolate each. The HRM analysis generated six unique specific groups representing M. tuberculosis complex, M. kansasii, M. simiae, M. fortuitum, M. abscessus-M. chelonae group, and M. avium complex. In conclusion, this study showed that the rpoBC-based real-time PCR followed by HRM analysis could differentiate the majority of mycobacterial species that are commonly encountered in clinical specimens. PMID- 29109709 TI - Vanillin Promotes the Germination of Antrodia camphorata Arthroconidia through PKA and MAPK Signaling Pathways. AB - Wild fruiting bodies of medicinal mushroom Antrodia camphorata are only found on the endemic species bull camphor tree, Cinnamomum kanehirae, in Taiwan. Despite the evident importance of the host components in promoting the growth of A. camphorata, insights into the underlying mechanisms are still lacking. Here, we first evaluated effects of the compounds from C. kanehirai, C. camphora, and A. camphorata, and their structural analogs on the germination rate of A. camphorata arthroconidia. Among the 54 tested compounds, vanillin (4-hydroxy-3 methoxybenzaldehyde) was determined as the optimum germination promoter, while o vanillin and 1-octen-3-ol as major negative regulators of arthroconidia germination. Second, the protein patterns of arthroconidia after 24 h of incubation in the presence or absence of vanillin were compared via isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics. Via bioinformatic analysis, it was found that 61 proteins might relate to the germination of arthroconidia, in which 16 proteins might involve in two potential protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signaling pathways in the vanillin-promoted germination of A. camphorata arthroconidia. Last, the mRNA expression levels of the 16 germination-related genes in the potential PKA and MAPK signaling pathways were analyzed by quantitative real time PCR. Together, our results are beneficial for the elucidation of molecular mechanisms underlying the germination of A. camphorata arthroconidia. PMID- 29109710 TI - Aedes aegypti Molecular Responses to Zika Virus: Modulation of Infection by the Toll and Jak/Stat Immune Pathways and Virus Host Factors. AB - Zika (ZIKV) and dengue virus (DENV) are transmitted to humans by Aedes mosquitoes. However, the molecular interactions between the vector and ZIKV remain largely unexplored. In this work, we further investigated the tropism of ZIKV in two different Aedes aegypti strains and show that the virus infection kinetics, tissue migration, and susceptibility to infection differ between mosquito strains. We also compare the vector transcriptome changes upon ZIKV or DENV infection demonstrating that 40% of the mosquito's midgut infection responsive transcriptome is virus-specific at 7 days after virus ingestion. Regulated genes included key factors of the mosquito's anti-viral immunity. Comparison of the ZIKV and DENV infection-responsive transcriptome data to those available for yellow fever virus and West Nile virus identified 26 genes likely to play key roles in virus infection of Aedes mosquitoes. Through reverse genetic analyses, we show that the Toll and the Jak/Stat innate immune pathways mediate increased resistance to ZIKV infection, and the conserved DENV host factors vATPase and inosine-5'-monophosphate dehydrogenase are also utilized for ZIKV infection. PMID- 29109711 TI - miPepBase: A Database of Experimentally Verified Peptides Involved in Molecular Mimicry. AB - Autoimmune diseases emerge due to several reasons, of which molecular mimicry i.e., similarity between the host's and pathogen's interacting peptides is an important reason. In the present study we have reported a database of only experimentally verified peptide sequences, which exhibit molecular mimicry. The database is named as miPepBase (Mimicry Peptide Database) and contains comprehensive information about mimicry proteins and peptides of both host (and model organism) and pathogen. It also provides information about physicochemical properties of protein and mimicry peptides, which might be helpful in predicting the nature of protein and optimization of protein expression. The miPepBase can be searched using a keyword or, by autoimmune disease(s) or by a combination of host and pathogen taxonomic group or their name. To facilitate the search of proteins and/or epitope in miPepBase, which is similar to the user's interest, BLAST search tool is also incorporated. miPepBase is an open access database and available at http://proteininformatics.org/mkumar/mipepbase. PMID- 29109712 TI - Anaerobic Oxidation of Ethane, Propane, and Butane by Marine Microbes: A Mini Review. AB - The deep ocean and its sediments are a continuous source of non-methane short chain alkanes (SCAs) including ethane, propane, and butane. Their high global warming potential, and contribution to local carbon and sulfur budgets has drawn significant scientific attention. Importantly, microbes can use gaseous alkanes and oxidize them to CO2, thus acting as effective biofilters. A relative decrease of these gases with a concomitant 13C enrichment of propane and n-butane in interstitial waters vs. the source suggests microbial anaerobic oxidation. The reported uncoupling of sulfate-reduction (SR) from anaerobic methane oxidation supports their microbial consumption. To date, strain BuS5 isolated from the sediments of Guaymas Basin, Gulf of California, is the only pure culture that can anaerobically degrade propane and n-butane. This organism belongs to a metabolically diverse cluster within the Deltaproteobacteria called Desulfosarcina/Desulfococcus. Other phylotypes involved in gaseous alkane degradation were identified based on stable-isotope labeling and fluorescence in situ hybridization. A novel syntrophic association of the archaeal genus, Candidatus Syntrophoarchaeum, and a thermophilic SR bacterium, HotSeep-1 was recently discovered from the Guaymas basin, Gulf of California that can anaerobically oxidize n-butane. Strikingly, metagenomic data and the draft genomes of ca. Syntrophoarchaeum suggest that this organism uses a novel mechanism for n-butane oxidation, distinct from the well-established fumarate addition mechanism. These recent findings indicate that a lot remains to be understood about our understanding of anaerobic SCA degradation. This mini-review summarizes our current understanding of microbial anaerobic SCA degradation, and provides an outlook for future research. PMID- 29109714 TI - Characteristics of a Regulator of G-Protein Signaling (RGS) rgsC in Aspergillus fumigatus. AB - The regulator of G-protein signaling (RGS) proteins have a conserved RGS domain that facilitates the intrinsic GTPase activity of an activated Galpha subunit of heterotrimeric G protein, thereby attenuating signal transduction. Among six predicted RGS proteins in the opportunistic human pathogenic fungus Aspergillus fumigatus, only three (FlbA, GprK, and Rax1) have been studied. The unexplored RgsC composed of the Phox-associated (PXA), RGS, Phox homology (PX), and Nexin_C superfamily domains is highly conserved in many ascomycete fungi, suggesting a crucial role of RgsC in fungal biology. To address this, we have investigated functions of the rgsC gene. The deletion (Delta) of rgsC causes impaired vegetative growth and asexual development coupled with reduced expression of key developmental regulators. Moreover, DeltargsC results in accelerated and elevated conidial germination regardless of the presence or absence of an external carbon source. Furthermore, DeltargsC causes reduced conidial tolerance to oxidative stress. In addition, activities and expression of catalases and superoxide dismutases (SODs) are severely decreased in the DeltargsC mutant. The deletion of rgsC results in a slight reduction in conidial tolerance to cell wall damaging agents, yet significantly lowered mRNA levels of cell wall integrity/biogenesis transcription factors, indicating that RgsC may function in proper activation of cell wall stress response. The DeltargsC mutant exhibits defective gliotoxin (GT) production and decreased virulence in the wax moth larvae, Galleria mellonella. Transcriptomic studies reveal that a majority of transporters is down-regulated by DeltargsC and growth of the DeltargsC mutant is reduced on inorganic and simple nitrogen medium, suggesting that RgsC may function in external nitrogen source sensing and/or transport. In summary, RgsC is necessary for proper growth, development, stress response, GT production, and external nutrients sensing. PMID- 29109713 TI - Basin Scale Variation on the Composition and Diversity of Archaea in the Pacific Ocean. AB - The Archaea are a widely distributed group of prokaryotes that inhabit and thrive in many different environments. In the sea, they play key roles in various global biogeochemical processes. Here, in order to investigate the vertical profiles of archaeal community across a large geographic distance, the compositions of archaeal communities in seven seawater columns in the Pacific Ocean were investigated using high throughput 454 pyrosequencing of the 16S rRNA gene. The surface archaeal communities showed lower diversity and greater variability than those in the deeper layers. Two of the major archaeal phyla that displayed different depth preferences were Thaumarchaeota and Euryarchaeota. The majority of Thaumarchaeota belonged to Marine Group I (MGI), which had high relative abundance in deep water. In contrast, Euryarchaeota, which mainly consisted of Marine Group II (MGII) and III (MGIII), were dominant in the surface layer. Compared with MGI and MGII, MGIII were less abundant in seawater and generally absent from the surface water of the subarctic Pacific. In addition, niche separation in the MGI, MGII, and MGIII subgroups was also observed. For example, MGI.C and MGII.A (the major subgroups of MGI and MGII, respectively) displayed a strong negative correlation with each other. The highest level of archaeal diversity was found in the core of an oxygen minimum zone (OMZ) located off Costa Rica, which resulted from the co-occurrence of both anaerobic and aerobic archaea. For example, methanotrophic archaea ANME-2, methanogenic archaea and several sediment origin archaea, such as Marine Benthic Group A (MBGA) and Bathyarchaeota, were all detected at relatively high abundance in the OMZ. Together, our findings indicate that vertical heterogeneities along water columns and latitudinal differentiation in the surface waters are ubiquitous features of archaeal communities in the Pacific Ocean, and the OMZ off Costa Rica is an archaeal biodiversity hot-spot. PMID- 29109715 TI - Specific Detection of Serum Antibodies against BKPyV, A Small DNA Tumour Virus, in Patients Affected by Choroidal Nevi. AB - Ocular or choroidal nevus (CN) is a rare benign neoplastic lesion of the eye. The cause of CN onset/progression, which arises from the transformation of ocular melanocytes, is not known. A fraction of CN patients may develop uveal melanoma. The objective of this study was to investigate the association between CN and BK polyomavirus (BKPyV), a small DNA tumor virus. Serum IgG antibodies which react with BKPyV antigens were analyzed. An indirect E.L.I.S.A. using synthetic peptides that mimic BKPyV antigens was employed. Serum antibodies against BKPyV were also investigated by haemagglutination inhibition (HAI) assay. Sera were from CN patients and healthy subject (HS) were the control. A statistically significant higher prevalence of antibodies against BKPyV capsid protein antigens in serum samples from CN patients was detected, compared to HS, using two independent techniques, indirect E.L.I.S.A. and HAI (87.3% CN vs. 62.1% HS and 91.5% CN vs. 64.4% HS, respectively; p < 0.005). Our data suggest an association exists between CN and BKPyV indicating that this small DNA tumor virus could be responsible in the onset of this benign neoplastic lesion affecting eye melanocytes. This investigation reports the association between choroidal nevi and BKPyV infection for the first time. These data are innovative in this field and may represent a starting point for further investigation into the putative role of BKPyV in CN onset/progression. PMID- 29109716 TI - Expression of Genes for a Flavin Adenine Dinucleotide-Binding Oxidoreductase and a Methyltransferase from Mycobacterium chlorophenolicum Is Necessary for Biosynthesis of 10-Methyl Stearic Acid from Oleic Acid in Escherichia coli. AB - In living organisms, modified fatty acids are crucial for the functions of the cellular membranes and storage lipids where the fatty acids are esterified. Some bacteria produce a typical methyl-branched fatty acid, i.e., 10-methyl stearic acid (19:0Me10). The biosynthetic pathway of 19:0Me10 in vivo has not been demonstrated clearly yet. It had been speculated that 19:0Me10 is synthesized from oleic acid (18:1Delta9) by S-adenosyl-L-methionine-dependent methyltransfer and NADPH-dependent reduction via a methylenated intermediate, 10-methyelene octadecanoic acid. Although the recombinant methyltransferases UmaA and UfaA1 from Mycobacterium tuberculosis H37Rv synthesize 19:0Me10 from 18:1Delta9 and NADPH in vitro, these methyltransferases do not possess any domains functioning in the redox reaction. These findings may contradict the two-step biosynthetic pathway. We focused on novel S-adenosyl-L-methionine-dependent methyltransferases from Mycobacterium chlorophenolicum that are involved in 19:0Me10 synthesis and selected two candidate proteins, WP_048471942 and WP_048472121, by a comparative genomic analysis. However, the heterologous expression of these candidate genes in Escherichia coli cells did not produce 19:0Me10. We found that one of the candidate genes, WP_048472121, was collocated with another gene, WP_048472120, that encodes a protein containing a domain associated with flavin adenine dinucleotide-binding oxidoreductase activity. The co-expression of these proteins (hereafter called BfaA and BfaB, respectively) led to the biosynthesis of 19:0Me10 in E. coli cells via the methylenated intermediate. PMID- 29109717 TI - Corrigendum: Molecular Cloning, Characterization, and Anti-avian Pathogenic Escherichia coli Innate Immune Response of the Cherry Valley Duck CIITA Gene. AB - [This corrects the article on p. 1629 in vol. 8, PMID: 28878764.]. PMID- 29109718 TI - SIgA, TGF-beta1, IL-10, and TNFalpha in Colostrum Are Associated with Infant Group B Streptococcus Colonization. AB - Background: Group B Streptococcus (GBS) is a major cause of mortality and morbidity in infants and is associated with transmission from a colonized mother at birth and via infected breastmilk. Although maternal/infant colonization with GBS is common, the majority of infants exposed to GBS remain unaffected. The association between breastmilk immune factors and infant colonization and disease prevention has not been elucidated. Objectives: We have investigated the association between SIgA and cytokines in breastmilk and infant GBS colonization and clearance. Methods: Mother/infant GBS colonization was determined in a prospective cohort of 750 Gambian mother/infant pairs followed to day 89 of life. Anti-GBS secretory IgA bound to the surface of whole bacteria was assessed by flow cytometry and a panel of 12 cytokines quantified by mesoscale discovery in colostrum, breastmilk and serum. Results: Compared with infants receiving low anti-GBS SIgA in colostrum, infants receiving high anti-GBS SIgA were at decreased risk of GBS colonization for serotypes III and V. Infants colonized at day 6 were twice as likely to receive colostrum with high TGF-beta1, TNFalpha, IL10, and IL-6 compared to uncolonized infants. Infants receiving high colostral TGF-beta1, TNFalpha, and IL-6 had two-fold enhanced GBS clearance between birth and day 89. Conclusion: Our results suggest that the infant GBS colonization risk diminishes with increasing anti-GBS SIgA antibody in breastmilk and that key maternally derived cytokines might contribute to protection against infant colonization. These findings might be leveraged to develop interventions including maternal vaccination that may reduce infant GBS colonization. PMID- 29109719 TI - Phenotypic Characterization of Human Monocytes following Macronutrient Intake in Healthy Humans. AB - Background: Three subsets of human monocytes in circulation have been identified and their characterization is still ill-defined. Although glucose and lipid intakes have been demonstrated to exert pro-inflammatory effects on mononuclear cells (MNCs) of healthy subjects, characterization of monocytes phenotypes following macronutrient (glucose, protein, and lipid) intake in humans remains to be determined. Methods: Thirty-six healthy, normal weight volunteers were recruited in the study. Subjects were randomly assigned into three groups, each group consisting of 12 participants. Each group drank equal calories (300 kcal) of either glucose or lipids or whey proteins. Each subject served as his own control by drinking 300 mL of water 1 week before or after the caloric intake. Baseline blood samples were drawn at 0, 1, 2, and 3-h intervals post caloric or water intakes. MNCs were isolated, and the expression levels of different cluster of differentiation (CD) markers (CD86, CD11c, CD169, CD206, CD163, CD36, CD68, CD11b, CD16, and CD14) and IL-6 were measured by RT-qPCR. Results: Equicaloric intake of either glucose or lipids or whey proteins resulted in different monocyte phenotypes as demonstrated by changes in the expression levels of CD and polarization markers. Whey proteins intake resulted in significant mRNA upregulation in MNCs of CD68 and CD11b at 1, 2, and 3 h post intake while mRNA of IL-6 was significantly inhibited at 1 h. Lipids intake, on the other hand, resulted in mRNA upregulation of CD11b at 2 and 3 h and CD206 at 1, 2, and 3 h. There were no significant changes in the other CD markers measured (CD86, CD163, CD169, CD36, CD16, and CD14) following either whey proteins or lipids intakes. Glucose intake did not alter mRNA expression of any marker tested except CD206 at 3 h. Conclusion: Macronutrient intake alters the expression levels of polarization markers in MNCs of human subjects. A distinct population of different monocytes phenotypes may result in human circulation following the intake of different macronutrients. Further studies are required to characterize the immunomodulatory effects of macronutrients intake on monocytes phenotypes and their characteristics in humans. PMID- 29109720 TI - An Organismal Model for Gene Regulatory Networks in the Gut-Associated Immune Response. AB - The gut epithelium is an ancient site of complex communication between the animal immune system and the microbial world. While elements of self-non-self receptors and effector mechanisms differ greatly among animal phyla, some aspects of recognition, regulation, and response are broadly conserved. A gene regulatory network (GRN) approach provides a means to investigate the nature of this conservation and divergence even as more peripheral functional details remain incompletely understood. The sea urchin embryo is an unparalleled experimental model for detangling the GRNs that govern embryonic development. By applying this theoretical framework to the free swimming, feeding larval stage of the purple sea urchin, it is possible to delineate the conserved regulatory circuitry that regulates the gut-associated immune response. This model provides a morphologically simple system in which to efficiently unravel regulatory connections that are phylogenetically relevant to immunity in vertebrates. Here, we review the organism-wide cellular and transcriptional immune response of the sea urchin larva. A large set of transcription factors and signal systems, including epithelial expression of interleukin 17 (IL17), are important mediators in the activation of the early gut-associated response. Many of these have homologs that are active in vertebrate immunity, while others are ancient in animals but absent in vertebrates or specific to echinoderms. This larval model provides a means to experimentally characterize immune function encoded in the sea urchin genome and the regulatory interconnections that control immune response and resolution across the tissues of the organism. PMID- 29109722 TI - Editorial: Neuroimmune Interface in Health and Diseases. PMID- 29109721 TI - The C-Type Lectin Mincle: Clues for a Role in Crohn's Disease Adjuvant Reaction. PMID- 29109723 TI - Inhibition of Pro-inflammatory and Anti-apoptotic Biomarkers during Experimental Oral Cancer Chemoprevention by Dietary Black Raspberries. AB - Oral cancer continues to be a significant public health problem worldwide. Recently conducted clinical trials demonstrate the ability of black raspberries (BRBs) to modulate biomarkers of molecular efficacy that supports a chemopreventive strategy against oral cancer. However, it is essential that a preclinical animal model of black raspberry (BRB) chemoprevention which recapitulates human oral carcinogenesis be developed, so that we can validate biomarkers and evaluate potential mechanisms of action. We therefore established the ability of BRBs to inhibit oral lesion formation in a carcinogen-induced rat oral cancer model and examined potential mechanisms. F344 rats were administered 4-nitroquinoline 1-oxide (4NQO) (20 ug/ml) in drinking water for 14 weeks followed by regular drinking water for 6 weeks. At week 14, rats were fed a diet containing either 5 or 10% BRB, or 0.4% ellagic acid (EA), a BRB phytochemical. Dietary administration of 5 and 10% BRB reduced oral lesion incidence and multiplicity by 39.3 and 28.6%, respectively. Histopathological analyses demonstrate the ability of BRBs and, to a lesser extent EA, to inhibit the progression of oral cancer. Oral lesion inhibition by BRBs was associated with a reduction in the mRNA expression of pro-inflammatory biomarkers Cxcl1, Mif, and Nfe2l2 as well as the anti-apoptotic and cell cycle associated markers Birc5, Aurka, Ccna1, and Ccna2. Cellular proliferation (Ki-67 staining) in tongue lesions was inhibited by BRBs and EA. Our study demonstrates that, in the rat 4NQO oral cancer model, dietary administration of BRBs inhibits oral carcinogenesis via inhibition of pro-inflammatory and anti-apoptotic pathways. PMID- 29109725 TI - Early Events of the Reaction Elicited by CSF-470 Melanoma Vaccine Plus Adjuvants: An In Vitro Analysis of Immune Recruitment and Cytokine Release. AB - In a previous work, we showed that CSF-470 vaccine plus bacillus Calmette-Guerin (BCG) and granulocyte macrophage colony-stimulating factor (GM-CSF) as adjuvants resulted in a significant benefit in the distant metastasis-free survival when comparing vaccinated vs. IFN-alpha2b-treated high-risk cutaneous melanoma patients in a Phase II study. Immune monitoring demonstrated an increase in anti tumor innate and adaptive immunities of vaccinated patients, with a striking increase in IFN-gamma secreting lymphocytes specific for melanoma antigens (Ags). In an effort to dissect the first steps of the immune response elicited by CSF 470 vaccine plus adjuvants, we evaluated, in an in vitro model, leukocyte migration, cytokine production, and monocyte phagocytosis of vaccine cells. Our results demonstrate that leukocytes recruitment, mostly from the innate immune system, is an early event after CSF-470 vaccine plus BCG plus GM-CSF interaction with immune cells, possibly explained by the high expression of CCL2/MCP-1 and other chemokines by vaccine cells. Early release of TNF-alpha and IL-1beta pro inflammatory cytokines and efficient tumor Ags phagocytosis by monocytes take place and would probably create a favorable context for Ag processing and presentation. Although the presence of the vaccine cells hampered cytokines production stimulated by BCG in a mechanism partially mediated by TGF-beta and IL 10, still significant levels of TNF-alpha and IL-1beta could be detected. Thus, BCG was required to induce local inflammation in the presence of CSF-470 vaccine cells. PMID- 29109724 TI - Actors and Factors in the Resolution of Intestinal Inflammation: Lipid Mediators As a New Approach to Therapy in Inflammatory Bowel Diseases. AB - In the last few decades, the pathogenesis of inflammatory bowel disease (IBD) in genetically predisposed subjects susceptible to specific environmental factors has been attributed to disturbance of both the immune and non-immune system and/or to the imbalanced interactions with microbes. However, increasing evidences support the idea that defects in pro-resolving pathways might strongly contribute to IBD onset. The resolution of inflammation is now recognized as a dynamic event coordinated by specialized pro-resolving lipid mediators (LMs), which dampen inflammation-sustaining events, such as angiogenesis, release of pro inflammatory cytokines, clearance of apoptotic cells, and microorganisms. Among these pro-resolving molecules, those derived from essential polyunsaturated fatty acids (PUFAs) have been shown to induce favorable effects on a plethora of human inflammatory disorders, including IBD. Here, we offer a summary of mechanisms involving both cellular and molecular components of the immune response and underlying the anti-inflammatory and pro-resolving properties of PUFAs and their derivatives in the gut, focusing on both omega-3 and omega-6 LMs. These fatty acids may influence IBD progression by: reducing neutrophil transmigration across the intestinal vasculature and the epithelium, preventing the release of pro inflammatory cytokines and the up-regulation of adhesion molecules, and finally by promoting the production of other pro-resolving molecules. We also discuss the numerous attempts in using pro-resolving PUFAs to ameliorate intestinal inflammation, both in patients with IBD and mouse models. Although their effects in reducing inflammation is incontestable, results from previous works describing the effects of PUFA administration to prevent or treat IBD are controversial. Therefore, more efforts are needed not only to identify and explain the physiological functions of PUFAs in the gut, but also to unveil novel biosynthetic pathways of these pro-resolving LMs that may be dysregulated in these gut-related disorders. We suppose that either PUFAs or new medications specifically promoting resolution-regulating mediators and pathways will be much better tolerated by patients with IBD, with the advantage of avoiding immune suppression. PMID- 29109726 TI - IL-36alpha Regulates Tubulointerstitial Inflammation in the Mouse Kidney. AB - IL-36alpha, a member of the IL-1 family, is a crucial mediator of inflammatory responses. We previously found that IL-36alpha was overexpressed in injured distal tubules (DTs); however, its pathological function remains unclear. Herein, unilateral ureter obstruction (UUO) or folic acid (FA) injection was performed in mouse kidneys to assess the role of IL-36alpha in kidney injury. IL-36alpha mRNA and protein expression significantly increased in the kidneys within 24 h after UUO. IL-36alpha localized to dilated DTs. IL-36alpha expression significantly correlated with the progression of tubulointerstitial cell infiltration and tubular epithelium cell death in UUO kidneys and with renal dysfunction in FA induced acute kidney injury mice. At 24 h after UUO, IL-36alpha+ DT epithelial cells showed loose intercellular digitations. IL-1RL2, an IL-36alpha receptor protein, localized to podocytes, proximal tubules, and DTs in the healthy kidney. IL-1RL2 was expressed in interstitial cells and platelets or extended primary cilia of DT epithelial cells in UUO kidneys. IL-36alpha stimulation promoted the production of IL-6 and Prss35, an inflammatory cytokine and collagen remodeling associated enzyme, respectively, in cultured NIH3T3 fibroblasts. UUO-treated IL 36alpha-knockout (KO) mice showed milder kidney injury features than wild-type (WT) mice did. In UUO kidneys from IL-36alpha-KO mice, the expression of genes associated with inflammatory response and sensory perception was significantly different from that in WT mice. Altogether, our data indicate an association between intrarenal IL-36alpha overexpression and the progression of tubulointerstitial inflammations and morpho-functional alterations of DT epithelial cells. IL-36alpha may be a novel kidney injury marker useful for evaluating DT damages. PMID- 29109727 TI - Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response. AB - There is growing interest in the use of tolerogenic dendritic cells (tolDCs) as a potential target for immunotherapy. However, the molecular bases that drive the differentiation of monocyte-derived DCs (moDCs) toward a tolerogenic state are still poorly understood. Here, we studied the transcriptional profile of moDCs from healthy subjects, modulated with dexamethasone (Dex) and activated with monophosphoryl lipid A (MPLA), referred to as Dex-modulated and MPLA-activated DCs (DM-DCs), as an approach to identify molecular regulators and pathways associated with the induction of tolerogenic properties in tolDCs. We found that DM-DCs exhibit a distinctive transcriptional profile compared to untreated (DCs) and MPLA-matured DCs. Differentially expressed genes downregulated by DM included MMP12, CD1c, IL-1B, and FCER1A involved in DC maturation/inflammation and genes upregulated by DM included JAG1, MERTK, IL-10, and IDO1 involved in tolerance. Genes related to chemotactic responses, cell-to-cell signaling and interaction, fatty acid oxidation, metal homeostasis, and free radical scavenging were strongly enriched, predicting the activation of alternative metabolic processes than those driven by counterpart DCs. Furthermore, we identified a set of genes that were regulated exclusively by the combined action of Dex and MPLA, which are mainly involved in the control of zinc homeostasis and reactive oxygen species production. These data further support the important role of metabolic processes on the control of the DC-driven regulatory immune response. Thus, Dex and MPLA treatments modify gene expression in moDCs by inducing a particular transcriptional profile characterized by the activation of tolerance-associated genes and suppression of the expression of inflammatory genes, conferring the potential to exert regulatory functions and immune response modulation. PMID- 29109729 TI - In Vitro Maturation of a Humanized Shark VNAR Domain to Improve Its Biophysical Properties to Facilitate Clinical Development. AB - Molecular engineering to increase the percentage identity to common human immunoglobulin sequences of non-human therapeutic antibodies and scaffolds has become standard practice. This strategy is often used to reduce undesirable immunogenic responses, accelerating the clinical development of candidate domains. The first humanized shark variable domain (VNAR) was reported by Kovalenko and colleagues and used the anti-human serum albumin (HSA) domain, clone E06, as a model to construct a number of humanized versions including huE06v1.10. This study extends this work by using huE06v1.10 as a template to isolate domains with improved biophysical properties and reduced antigenicity. Random mutagenesis was conducted on huE06v1.10 followed by refinement of clones through an off-rate ranking-based selection on target antigen. Many of these next generation binders retained high affinity for target, together with good species cross-reactivity. Lead domains were assessed for any tendency to dimerize, tolerance to N- and C-terminal fusions, affinity, stability, and relative antigenicity in human dendritic cell assays. Functionality of candidate clones was verified in vivo through the extension of serum half-life in a typical drug format. From these analyses the domain, BA11, exhibited negligible antigenicity, high stability and high affinity for mouse, rat, and HSA. When these attributes were combined with demonstrable functionality in a rat model of PK, the BA11 clone was established as our clinical candidate. PMID- 29109728 TI - Invariant Natural Killer T Cells in Immune Regulation of Blood Cancers: Harnessing Their Potential in Immunotherapies. AB - Invariant natural killer T (iNKT) cells are a unique innate T lymphocyte population that possess cytolytic properties and profound immunoregulatory activities. iNKT cells play an important role in the immune surveillance of blood cancers. They predominantly recognize glycolipid antigens presented on CD1d, but their activation and cytolytic activities are not confined to CD1d expressing cells. iNKT cell stimulation and subsequent production of immunomodulatory cytokines serve to enhance the overall antitumor immune response. Crucially, the activation of iNKT cells in cancer often precedes the activation and priming of other immune effector cells, such as NK cells and T cells, thereby influencing the generation and outcome of the antitumor immune response. Blood cancers can evade or dampen iNKT cell responses by downregulating expression of recognition receptors or by actively suppressing or diverting iNKT cell functions. This review will discuss literature on iNKT cell activity and associated dysregulation in blood cancers as well as highlight some of the strategies designed to harness and enhance iNKT cell functions against blood cancers. PMID- 29109730 TI - T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection. AB - T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh-B cell interactions. PMID- 29109732 TI - CCL3 Enhances Antitumor Immune Priming in the Lymph Node via IFNgamma with Dependency on Natural Killer Cells. AB - Lymph node (LN) plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2). Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell-antigen-presenting cell (APC) encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3-5). In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs) of a CCL3-secreting CT26 colon tumor (L3TU) as compared to wild-type tumor (WTTU) during the priming phase of an antitumor response (<=10 days). In comparison to WTTU, inoculation of L3TU resulted in suppressed tumor growth, a phenomenon that is accompanied by altered in vivo inflammatory responses on several fronts. Autologous tumor-derived CCL3 (aCCL3) secretion by L3TU bolstered the recruitment of T- and B-lymphocytes, tissue-migratory CD103+ dendritic cells (DCs), and CD49b+ natural killer (NK) cells, resulting in significant increases in the differentiation and activation of multiple Interferon-gamma (IFNgamma)-producing leukocytes in the TDLN. During this early phase of immune priming, NK cells constitute the major producers of IFNgamma in the TDLN. CCL3 also enhances CD8+ T cell proliferation and differentiation by augmenting DC capacity to drive T cell activation in the TDLN. Our results revealed that CCL3-dependent IFNgamma production and CCL3-induced DC maturation drive the priming of effective antitumor immunity in the TDLN. PMID- 29109731 TI - GM-CSF Monocyte-Derived Cells and Langerhans Cells As Part of the Dendritic Cell Family. AB - Dendritic cells (DCs) and macrophages (Mph) share many characteristics as components of the innate immune system. The criteria to classify the multitude of subsets within the mononuclear phagocyte system are currently phenotype, ontogeny, transcription patterns, epigenetic adaptations, and function. More recently, ontogenetic, transcriptional, and proteomic research approaches uncovered major developmental differences between Flt3L-dependent conventional DCs as compared with Mphs and monocyte-derived DCs (MoDCs), the latter mainly generated in vitro from murine bone marrow-derived DCs (BM-DCs) or human CD14+ peripheral blood monocytes. Conversely, in vitro GM-CSF-dependent monocyte derived Mphs largely resemble MoDCs whereas tissue-resident Mphs show a common embryonic origin from yolk sac and fetal liver with Langerhans cells (LCs). The novel ontogenetic findings opened discussions on the terminology of DCs versus Mphs. Here, we bring forward arguments to facilitate definitions of BM-DCs, MoDCs, and LCs. We propose a group model of terminology for all DC subsets that attempts to encompass both ontogeny and function. PMID- 29109733 TI - Plant Growth Promoting Rhizobacteria in Amelioration of Salinity Stress: A Systems Biology Perspective. AB - Salinity affects plant growth and is a major abiotic stress that limits crop productivity. It is well-understood that environmental adaptations and genetic traits regulate salinity tolerance in plants, but imparting the knowledge gained towards crop improvement remain arduous. Harnessing the potential of beneficial microorganisms present in the rhizosphere is an alternative strategy for improving plant stress tolerance. This review intends to elucidate the understanding of salinity tolerance mechanisms attributed by plant growth promoting rhizobacteria (PGPR). Recent advances in molecular studies have yielded insights into the signaling networks of plant-microbe interactions that contribute to salt tolerance. The beneficial effects of PGPR involve boosting key physiological processes, including water and nutrient uptake, photosynthesis, and source-sink relationships that promote growth and development. The regulation of osmotic balance and ion homeostasis by PGPR are conducted through modulation of phytohormone status, gene expression, protein function, and metabolite synthesis in plants. As a result, improved antioxidant activity, osmolyte accumulation, proton transport machinery, salt compartmentalization, and nutrient status reduce osmotic stress and ion toxicity. Furthermore, in addition to indole-3-acetic acid and 1-aminocyclopropane-1-carboxylic acid deaminase biosynthesis, other extracellular secretions of the rhizobacteria function as signaling molecules and elicit stress responsive pathways. Application of PGPR inoculants is a promising measure to combat salinity in agricultural fields, thereby increasing global food production. PMID- 29109735 TI - Clostridium difficile in Inflammatory Bowel Disease: A Retrospective Study. AB - Aim: To investigate the epidemiology and risk factors of Clostridium difficile infections (CDI) in patients with inflammatory bowel disease (IBD). Methods: This is a retrospective study of patients diagnosed with IBD. 1006 charts were screened and 654 patients met the inclusion criteria. Patients were divided into 2 cohorts based on the presence of prior diagnosis of CDI. Statistical analysis with Pearson's chi-squared and two-sample t-test was performed. Results: The incidence of CDI among IBD patients was 6.7%. There was equal prevalence of CDI among Crohn's disease (CD) (n = 21, 49%) and ulcerative colitis (UC) (n = 22, 51%). IBD patients acquired CDI at a mean age of 42.7 years, with 56% of infections acquired in the community and only 28% associated with healthcare. Only 30% of IBD patients with CDI had prior antibiotic use, and 16% had prior steroid use. IBD patients were significantly more likely to require biologic therapy (57% versus 37%, p < 0.01) and have extraintestinal manifestations of IBD (43% versus 28%, p < 0.02). Conclusions: IBD patients are more susceptible to CDI at a younger age and often lack traditional risk factors. IBD patients with at least one CDI were more likely to require biologic therapy and had greater rates of extraintestinal manifestations. PMID- 29109734 TI - Similar Genetic Architecture with Shared and Unique Quantitative Trait Loci for Bacterial Cold Water Disease Resistance in Two Rainbow Trout Breeding Populations. AB - Bacterial cold water disease (BCWD) causes significant mortality and economic losses in salmonid aquaculture. In previous studies, we identified moderate-large effect quantitative trait loci (QTL) for BCWD resistance in rainbow trout (Oncorhynchus mykiss). However, the recent availability of a 57 K SNP array and a reference genome assembly have enabled us to conduct genome-wide association studies (GWAS) that overcome several experimental limitations from our previous work. In the current study, we conducted GWAS for BCWD resistance in two rainbow trout breeding populations using two genotyping platforms, the 57 K Affymetrix SNP array and restriction-associated DNA (RAD) sequencing. Overall, we identified 14 moderate-large effect QTL that explained up to 60.8% of the genetic variance in one of the two populations and 27.7% in the other. Four of these QTL were found in both populations explaining a substantial proportion of the variance, although major differences were also detected between the two populations. Our results confirm that BCWD resistance is controlled by the oligogenic inheritance of few moderate-large effect loci and a large-unknown number of loci each having a small effect on BCWD resistance. We detected differences in QTL number and genome location between two GWAS models (weighted single-step GBLUP and Bayes B), which highlights the utility of using different models to uncover QTL. The RAD SNPs detected a greater number of QTL than the 57 K SNP array in one population, suggesting that the RAD-SNPs may uncover polymorphisms that are more unique and informative for the specific population in which they were discovered. PMID- 29109736 TI - Identification of Neuroprotective Factors Associated with Successful Ageing and Risk of Cognitive Impairment among Malaysia Older Adults. AB - The increase of ageing population has raised public attention on the concept of successful ageing. Studies have shown that vitamin D, telomere length, and brain derived neurotrophic factor (BDNF) have been associated with cognitive function. Therefore, this study aimed to identify neuroprotective factors for cognitive decline in different ageing groups. A total of 300 older adults aged 60 years and above were recruited in this population based cross-sectional study. Participants were categorized into three groups: mild cognitive impairment (MCI) (n = 100), usual ageing (UA) (n = 100), and successful ageing (SA) (n = 100). Dietary vitamin D intake was assessed through Diet History Questionnaire (DHQ). Out of the 300 participants, only 150 were subjected to fasting blood sample collection. These samples were used for serum vitamin D and plasma BDNF measurements. Whole blood telomere length was measured using RT-PCR method. The results show that the reduction of the risk of MCI was achieved by higher serum vitamin D level (OR: 0.96, 95% CI: 0.92-0.99, p < 0.05), higher plasma BDNF level (OR: 0.51, 95% CI: 0.30-0.88, p < 0.05), and longer telomere (OR: 0.97, 95% CI: 0.95-0.99, p < 0.001). In conclusion, participants with higher vitamin D level, higher BDNF level, and longer telomere length were more likely to age successfully. PMID- 29109737 TI - Associations of Salivary BPIFA1 Protein in Chronic Periodontitis Patients with Type 2 Diabetes Mellitus. AB - Aims: To explore the differences in salivary BPI fold containing family A, member 1 (BPIFA1) concentration among type 2 diabetes mellitus (T2DM) subjects with various severities of chronic periodontitis and to determine whether BPIFA1 in saliva can be used as a potential biomarker of T2DM. Methods: Unstimulated saliva samples were collected from 44 subjects with T2DM and 44 without T2DM (NDM). Additionally, demographic data and general health parameters, including fasting blood glucose (FBG) and body mass index (BMI), were collected. We also detected full-mouth clinical periodontal parameters including probing pocket depth (PPD), clinical attachment level (CAL), bleeding index (BI), and plaque index (PLI). Salivary BPIFA1, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL 6) concentrations were also detected. Results: BPIFA1 in saliva was detected at relatively high levels. T2DM subjects had decreased salivary BPIFA1 concentrations (P = 0.031). In T2DM subjects with nonperiodontitis or severe periodontitis, the level of BPIFA1 was significantly lower compared with that of NDM. Salivary TNF-alpha concentration displayed a similar trend to BPIFA1 in the NDM group. Conclusions: BPIFA1 protein is rich in saliva and might be used as a potential predictive biomarker of T2DM, especially in patients with severe periodontitis and nonperiodontitis. This trial is registered with ChiCTR-ROC 17010310. PMID- 29109738 TI - Association between Sex Hormone and Blood Uric Acid in Male Patients with Type 2 Diabetes. AB - The association between serum uric acid (SUA) level and sexual dysfunction in patients with diabetes is not well characterized. Type 2 diabetes mellitus (T2DM) causes metabolic disorders, including abnormal serum uric acid (SUA) levels. In this study, we enrolled 205 male patients with T2DM and investigated the relationship between sex hormone levels and SUA. Patients were divided into four groups based on SUA quartiles. On the other hand, based on the total testosterone (TT) level, patients were divided into three groups; SUA and other laboratory indices were determined. Increase in SUA level was significantly associated with decreased levels of TT, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, and increased levels of dehydroepiandrosterone, age, body mass index (BMI), waist circumference, glycated hemoglobin, serum creatinine, and HOMA-IR levels. SUA, waist circumference, BMI, and HOMA-IR showed a negative correlation with TT level, while age showed a positive correlation with TT level. SUA and body mass index were found to be risk factors for gonadal dysfunction. Therefore, we conclude that hypogonadism of male patients with T2DM is related to SUA level. PMID- 29109739 TI - A Case of Polyarteritis Nodosa Presenting as Rapidly Progressing Intermittent Claudication of Right Leg. AB - Background: Polyarteritis nodosa (PAN) is a medium vessel vasculitis which causes significant morbidity and mortality. Usually, it presents with constitutional symptoms with angiographic evidence of aneurysms or segmental stenosis of arteries of mesenteric or renal vasculature. It is exceedingly uncommon for PAN to present with symptomatic progressive intermittent claudication. Case Presentation: We describe a 60-year-old male who presented with rapidly progressive intermittent claudication of his right leg. He did not have any significant atherosclerotic risk factors. He had recent onset hypertension and loss of weight. He also had mononeuropathy of right common peroneal nerve and livedo reticularis rash. With negative autoimmune markers and suggestive histology in deep punch skin biopsy and angiographic evidence of segmental stenosis of femoral and renal arteries, we diagnosed PAN. We treated him with aggressive immunosuppressants and vascular bypass surgery of right femoral vessels; he showed a good response. Conclusion: Rapidly progressive unilateral intermittent claudication could be a very rare, but noteworthy presentation of PAN. With suggestive histology and exclusion of other comorbidities aggressive immunosuppressants should be instituted. Vascular bypass surgery for critical ischaemia of the limbs is an option that could be considered for limb-threatening disease. PMID- 29109740 TI - Simple Meets Single: The Application of CRISPR/Cas9 in Haploid Embryonic Stem Cells. AB - The CRISPR/Cas9 system provides a powerful method for the genetic manipulation of the mammalian genome, allowing knockout of individual genes as well as the generation of genome-wide knockout cell libraries for genetic screening. However, the diploid status of most mammalian cells restricts the application of CRISPR/Cas9 in genetic screening. Mammalian haploid embryonic stem cells (haESCs) have only one set of chromosomes per cell, avoiding the issue of heterozygous recessive mutations in diploid cells. Thus, the combination of haESCs and CRISPR/Cas9 facilitates the generation of genome-wide knockout cell libraries for genetic screening. Here, we review recent progress in CRISPR/Cas9 and haPSCs and discuss their applications in genetic screening. PMID- 29109741 TI - Functional Test Scales for Evaluating Cell-Based Therapies in Animal Models of Spinal Cord Injury. AB - Recently, spinal cord researchers have focused on multifaceted approaches for the treatment of spinal cord injury (SCI). However, as there is no cure for the deficits produced by SCI, various therapeutic strategies have been examined using animal models. Due to the lack of standardized functional assessment tools for use in such models, it is important to choose a suitable animal model and precise behavioral test when evaluating the efficacy of potential SCI treatments. In the present review, we discuss recent evidence regarding functional recovery in various animal models of SCI, summarize the representative models currently used, evaluate recent cell-based therapeutic approaches, and aim to identify the most precise and appropriate scales for functional assessment in such research. PMID- 29109743 TI - The clinical and metabolic effects of subgingival application of xanthan-based chlorhexidine gel in Type 2 diabetic patients with chronic periodontitis. AB - Background: There is a two-way relationship between periodontal disease and diabetes. The purpose of this study was to evaluate the clinical and metabolic effects of a xanthan-based chlorhexidine (CHX) gel used as an adjunct to nonsurgical periodontal therapy in Type II diabetic patients with chronic periodontitis. Materials and Methods: Sixty-eight diabetic patients with moderate to advanced periodontitis and glycated hemoglobin (HbA1c) >=6% were selected. The test group (n = 34) received scaling and root planning (SRP) plus xanthan-based CHX gel. The control group (n = 34) received single SRP. Fasting blood sugar (FBS) and HbA1c tests were done at the baseline and after 3 and 6 months. Data from the study were analyzed using descriptive statistics (mean +/- standard deviation and frequency), ANOVA test by SPSS.15 software (SPSS Inc. Chicago, IL, USA). P < 0.05 was considered statistically significant. Results: Patients in test group exhibited a decrease in FBS from the baseline (227 +/- 64.97) to the 3 and 6 months follow-up (208 +/- 61.95 and 201 +/- 61.33; P < 0.001). HbA1cb levels decreased from 7.72 +/- 0.99 to 6.20 +/- 0.97 and 6.06 +/- 1.04 after 3 and 6 months follow-up (P < 0.001), respectively. Reduction of FBS and HbA1c was statistically significant after 3 and 6 months in the control group (P < 0.001). Conclusion: Considering the limitations of this study, the application of CHX gel might improve the effects of nonsurgical periodontal treatment in diabetic patients with periodontitis. PMID- 29109742 TI - Effects of Neuropeptide Y on Stem Cells and Their Potential Applications in Disease Therapy. AB - Neuropeptide Y (NPY), a 36-amino acid peptide, is widely distributed in the central and peripheral nervous systems and other peripheral tissues. It takes part in regulating various biological processes including food intake, circadian rhythm, energy metabolism, and neuroendocrine secretion. Increasing evidence indicates that NPY exerts multiple regulatory effects on stem cells. As a kind of primitive and undifferentiated cells, stem cells have the therapeutic potential to replace damaged cells, secret paracrine molecules, promote angiogenesis, and modulate immunity. Stem cell-based therapy has been demonstrated effective and considered as one of the most promising treatments for specific diseases. However, several limitations still hamper its application, such as poor survival and low differentiation and integration rates of transplanted stem cells. The regulatory effects of NPY on stem cell survival, proliferation, and differentiation may be helpful to overcome these limitations and facilitate the application of stem cell-based therapy. In this review, we summarized the regulatory effects of NPY on stem cells and discussed their potential applications in disease therapy. PMID- 29109745 TI - Evaluation of myofibroblasts in oral submucous fibrosis and oral squamous cell carcinoma: The pathogenesis and correlation. AB - Background: Oral submucous fibrosis (OSMF) is a chronic debilitating disease of the oral cavity having premalignant potential and unclear pathogenesis. Recently, myofibroblast has been postulated to play an important role in its pathogenesis and in the process of carcinogenesis. The purpose of this study was to evaluate and compare the presence of myofibroblasts in normal mucosa, different grades of OSMF, and oral squamous cell carcinoma (OSCC). Materials and Methods: The present in vitro cross-sectional descriptive study sample consisted of three groups, including 40 OSCCs, 40 OSMF, and 10 sections of normal oral epithelium taken as control group. Alpha-smooth muscle actin was used to identify myofibroblasts using immunohistochemical technique. P < 0.05 was taken as statistically significant. Results: The presence of myofibroblasts was significantly higher in OSMF cases when compared with normal epithelium specimens. The presence of myofibroblasts was significantly higher in OSCC compared to OSMF cases. A significant difference was not observed between the different grades of OSCC. Conclusion: These findings favor the possibility that OSMF actually represents an abnormal healing process in response irritation caused by areca nut. A significant increase in myofibroblasts in OSCC as compared to OSMF also highlights the possible role it may play in the malignant transformation of OSMF. PMID- 29109744 TI - Selective nitric oxide synthase inhibitor promotes bone healing. AB - Background: Nitric oxide (NO) has many functions in wound healing and bone metabolism. This study sought to assess the local effect of aminoguanidine (AG), a selective inducible NO synthase (iNOS) inhibitor, on the rate of bone healing. Materials and Methods: This experimental interventional study was conducted on 36 rats, which were randomly divided into three groups of control, placebo, and AG. Bone defects measuring 5 mm * 5 mm were created in the femur. In control group, bone defects remained empty. A placebo gel was applied to defects in the placebo group. AG gel was placed in bone defects in AG group. New bone formation and healing were assessed using histological and histomorphometric analyses. The healing score and the percentage of new bone formation (total bone mass, immature bone, and mature bone) were compared among the three groups using the Kruskal Wallis test and analysis of variance, respectively. A P < 0.05 was statistically significant. Results: The mean healing score in AG group (3.17 +/- 0.577) was significantly higher than that in control (2.67 +/- 0.49) and the placebo (2.58 +/- 0.515) groups (P = 0.036). The percentage of new mature (lamellar) bone in AG group (22.06 +/- 1.90) was significantly higher than that in control (20.94 +/- 2.03) and the placebo (20.53 +/- 1.20) groups (P = 0.008). Conclusion: The rate of bone healing was faster in the AG compared to the other two groups. Local application of selective iNOS inhibitors like AG may be efficient as an adjunct in the clinical setting where local bone formation is required. PMID- 29109746 TI - Comparative evaluation of root canal morphology of mandibular premolars using clearing and cone beam computed tomography. AB - Background: Different techniques are used to evaluate the anatomy of root canal system. The present study was aimed to evaluate the root canal morphology of mandibular premolars using clearing and cone beam computed tomography (CBCT) techniques. Materials and Methods: A total of 182 mandibular first and second premolars were evaluated in vitro using 100 MUm CBCT cross sections. The root canal morphology of the teeth was determined based on Vertucci classification in relation to the prevalence of C-shaped canals, lateral canals, and furcation location. Having removed the pulp tissue with NaOCl solution and staining the root canals with India ink, the samples were decalcified with 5% nitric acid and dehydrated with isopropyl alcohol. Finally, the samples were cleared with methyl salicylate. Data were analyzed by SPSS 16 software using McNamara, t-test, and Kappa coefficient. Results: After Type I, the most frequent morphologies in both first and second premolars were Type V followed by Type IV. The prevalence rates of C-shaped morphology in first premolars using clearing and CBCT were 4.4% and 6.6%, respectively. However, no C-shaped morphology was found in second premolars. The maximum and minimum levels of agreement between the two techniques were observed in Type IV and Type V root canal morphologies, respectively. Extra root canals were identified in 25% and 13% of the first and second premolars, respectively. Conclusion: CBCT showed a higher accuracy in determining C-shaped root canal morphology than the clearing technique. It also showed the least accuracy in diagnosing lateral root canals. PMID- 29109747 TI - Effect of finishing/polishing techniques and time on surface roughness of esthetic restorative materials. AB - Background: Surface roughness associated with improper finishing/polishing of restorations can result in plaque accumulation, gingival irritation, surface staining, and poor esthetic of restored teeth. The study aimed to evaluate the efficiency of various finishing and polishing systems and time using various procedures on surface roughness of some esthetic restorative materials. Materials and Methods: In this in vitro study, samples of two composite materials, compomer and glass ionomer cement (GIC) materials, were fabricated. Finishing and polishing were done immediately (n = 40) and after 1 week (n = 40) using four systems (diamond bur + soflex discs; diamond bur + Astropol polishing brush; tungsten carbide bur + soflex discs; tungsten carbide bur + Astropol polishing brush). Surface roughness was measured using surface profilometer. Data were statistically analyzed by t-test (for each material and time period) and one-way analysis of variance followed by Tukey's post hoc (for finishing and polishing systems) at a significant level of P < 0.05. Results: Analysis of time period, irrespective of finishing and polishing system showed that Ra values were greater (P < 0.05) in delayed polishing in GIC > Z100 > Filtek P90 > Dyract AP, suggesting immediate polishing is better. Among the materials, Filtek P90 had the least Ra values indicating the smoothest surface among all materials, followed by Z100, Dyract AP, and GIC. Comparison of polishing and finishing systems irrespective of materials showed that Ra values were lower (P > 0.05) in diamond + Astropol combination whereas diamond + soflex had the greatest Ra values. Conclusion: It might be concluded that: (i) Filtek P90 showed least Ra values followed by < Z100 < Dyract < GIC; (ii) immediate (24 h) finishing/polishing of materials is better than delayed; and (iii) among all these polishing systems, diamond bur-Astropol and Astrobrush showed good surface finish. PMID- 29109748 TI - Do increased drilling speed and depth affect bone viability at implant site? AB - Background: The aim of this study was to assess the effect of increasing the drilling speed and depth during implant site preparation on bone viability. Materials and Methods: In this prospective cohort study, participants were divided into four groups based on the speed and depth of drilling at the first molar site in the mandible. Participants underwent drilling at Group 1: 1000 rpm and 10 mm depth, Group 2: 1500 rpm and 10 mm, Group 3: 1000 rpm and 13 mm, and Group 4: 1500 rpm and 13 mm. Obtained specimens were assessed histologically to the qualitative measurement of bone viability, and the percentage of vital bone were evaluated by histomorphometric analysis. ANOVA was used to compare age and the mean percentage of vital bone and Tukey's test as post hoc was applied for pairwise comparison of groups. Results: A total of 100 participants were studied in four groups (25 subjects in each group). Histological evaluation revealed a low level of bone viability maintenance in all groups. Histomorphometric analysis showed the mean percentage of vital bone was 9.5 +/- 3.91% in Group 1, 8.86 +/- 3.84% in Group 2, 8.32 +/- 3.80% in Group 3, and 4.27 +/- 3.22% in Group 4. A significant difference was noted in the mean percentage of bone viability among the four groups (P = 0.001). Conclusion: It seems that increasing the drilling speed or depth during dental implant site preparation does not affect the mean percentage of cell viability, while the increase in both depth and speed may decrease the percentage of viable cells. PMID- 29109749 TI - Push-out bond strength of different intracanal posts in the anterior primary teeth according to root canal filling materials. AB - Background: This study was carried out to evaluate the effect of root canal filling on the bond strength of three intracanal posts in the primary incisors. Materials and Methods: Sixty primary incisors were prepared and then divided into two groups (n = 30). The first group canals obturated with zinc oxide eugenol (ZOE) and Group 2 canals obturated with Metapex. Further, the two group categories were divided into three subgroups (n = 10): (1) short composite post (SCP), (2) glass fiber posts (GFPs) cemented with flowable composite, and (3) GFP with glass ionomer cement (GFP + GIC). The push-out test was performed with a universal testing machine. The results were statistically analyzed with two-way analysis of variance.(alpha = 0.05). Results: The mean bond strength of the first group obturated with ZOE was lower than that of the second group obturated with Metapex (P = 0.046). Moreover, from a statistical point of view, in all three subgroups, the correlation of mean push-out bond strength between SCP and GFP coated with flowable composite was not substantial at P = 0.97. However, the mean bond strength of SCP was in fact significantly greater than that of the GFP coated with GIC since P = 0.034. Conclusion: Using ZOE resulted in the significant reduction of the mean bond strength of the intracanal posts when utilized in the primary anterior teeth. Likewise, SCP and GFP coated with flowable composite showed higher push-out bond strengths for restoring primary anterior teeth. PMID- 29109750 TI - Microbial microleakage assessment of class V cavities restored with different materials and techniques: A laboratory study. AB - Background: The aim of this study was to compare microbial microleakage of class V cavities restored with different materials and techniques using a microbial leakage assessment method. Materials and Methods: One hundred extracted, caries free, human maxillary premolars were randomly divided into five groups. Group 1: Resin-modified glass ionomer (RMGI), Group 2: Closed sandwich with flowable composite + nanohybrid composite, Group 3: Nanohybrid composite, Group 4: Closed sandwich with RMGI + nanohybrid composite, and Group 5: Flowable composite + nanohybrid composite that were co-cured together ("snow-plow" technique). A microbial penetration method utilizing Streptococcus mutans as an indicator was tested for leakage assessment. Data were analyzed and the significance level was alpha =0.05. Results: The log-rank test indicated a statistically significant difference in leakage rates among the five groups (P = 0.008). Mantel-Cox log rank test indicated statistically significant differences in microleakage rates between Groups 1 and 3 (P = 0.029), between Groups 2 and 5 (P = 0.005), and between Groups 3 and 5 (P = 0.002). Conclusion: With respect to the limitations of an in vitro study, our findings suggest that adding a thin layer of flowable composite or RMGI under nanohybrid composite in class V cavities did not decrease the bacterial leakage rate, whereas use of the "snow-plow" technique caused an increase in the microleakage rate. PMID- 29109751 TI - The relation of preoperative stress and anxiety on patients' satisfaction after implant placement. AB - Background: There are some factors which can affect preoperative patient anxiety such as the necessity of procedure, postoperative pain, and patient's conception of his body image. The aim of this study was to assess the relation of patients' preoperative anxiety and postoperative patients' satisfaction in dental implant surgery. Materials and Methods: Dental implants were placed in 40 patients (19 male and 21 female) who were referred to Dental Implant Surgery Department in Imam Reza clinic, during March-December of 2014 in Shiraz. The procedures were performed with or without bone regeneration. Preoperative anxiety was evaluated using Corah Dental Anxiety Scale, and postoperative satisfaction was determined on the basis of pain intensity, bleeding tendency, inability to eating, and overall satisfaction by filling a questionnaire in the 2nd or 3rd week after surgery. Data were collected and analyzed using Mann-Whitney test. Results: Preoperative anxiety was detected as high in 10%, mild in 85%, and moderate in 5% of patients. Anxiety and depression score did not differ in both genders. There was no statistical difference between neither level of anxiety nor depression in both high and low educated patients. Postoperative bleeding, difficulty in eating, and overall satisfaction was nearly the same in both genders. Statistical analysis demonstrated a lower pain level and higher pain threshold in men than women (P = 0.007). Patients' age was not related to anxiety, depression, amount of bleeding, pain, and difficulty in eating. Overall dental care satisfaction was similar in both men and women. Conclusion: The results of the study indicated that while anxiety does play a role in the perception of pain by patients undergoing implant surgery, overall patient satisfaction and post surgical outcomes did not significantly differ. PMID- 29109752 TI - Management of exaggerated gag reflex in dental patients using intravenous sedation with dexmedetomidine. AB - Pharmacological sedation is one of the effective ways of prevention of gag reflex development in patients experiencing anxiety and fright before dental treatment. We are reporting a case where we could successfully eliminate exaggerated gag reflex (intravenous [IV] Gagging Severity Index) in a dental patient using IV sedation with dexmedetomidine. IV administration of dexmedetomidine provided elimination of gag reflex at a depth of sedation for the patient with the Richmond Agitation-Sedation Scale score of -2 and -1. The patient received dexmedetomidine 1.0 MUg/kg for 10 min and then a continuous infusion of dexmedetomidine 0.4 MUg/kg/h. The use of dexmedetomidine for sedation may be an alternative to other pharmacological agents in patients with dental anxiety accompanied by exaggerated gag reflex. PMID- 29109753 TI - Agenesis of permanent canines: Rare case report. AB - Agenesis of permanent canines is a rare condition, and that of both maxillary and mandibular permanent canines is extremely rare. It may occur either isolated or in association with other dental anomalies. Reports of such cases are very scarce in the literature. Need for early diagnosis of such conditions should be emphasized because of functional, esthetic, and psychological problems which should be evaluated and treated appropriately. The present paper presents a report of bilaterally missing permanent maxillary and mandibular canines. This case might contribute in the future studies of incidence of agenesis of permanent canines. PMID- 29109755 TI - Geometrical frustration yields fiber formation in self-assembly. AB - Controlling the self-assembly of supramolecular structures is vital for living cells, and a central challenge for engineering at the nano- and microscales [1, 2]. Nevertheless, even particles without optimized shapes can robustly form well defined morphologies. This is the case in numerous medical conditions where normally soluble proteins aggregate into fibers [3, 4]. Beyond the diversity of molecular mechanisms involved [5, 6], we propose that fibers generically arise from the aggregation of irregular particles with short-range interactions. Using a minimal model of ill-fitting, sticky particles, we demonstrate robust fiber formation for a variety of particle shapes and aggregation conditions. Geometrical frustration plays a crucial role in this process, and accounts for the range of parameters in which fibers form as well as for their metastable character. PMID- 29109754 TI - Understanding the impact of hypoglycemia on the cardiovascular system. AB - Introduction: Hypoglycemia occurs commonly in insulin requiring individuals with either Type 1 or Type 2 Diabetes. Areas Covered: This article will review recent information on the pro-inflammatory and pro-atherothrombotic effects of hypoglycemia. Additionally, effects of hypoglycemia on arrhythmogenic potential and arterial endothelial dysfunction will be discussed. Effects of hypoglycemia on cardiovascular morbidity and mortality from large clinical studies in Type 1 and Type 2 DM will also be reviewed. Expert Commentary: The relative and absolute risk of severe hypoglycemia leading to death and serious adverse events in both cardiovascular and other organ systems has been highlighted following the publication of recent large clinical trials focused on glucose control and outcomes. It would be helpful if future studies could develop broader end points to include minor and moderate hypoglycemia as well as more robust methods for capturing hypoglycemia contemporaneously with adverse events. In addition, perhaps consideration of including hypoglycemia as a primary outcome, may help identify the possible cause and effect of hypoglycemia on cardiovascular morbidity and mortality. PMID- 29109756 TI - Imaging Acetaldehyde Formation During Ethanol Metabolism in Living Cells using a Hydrazinyl Naphthalimide Fluorescent Probe. AB - The metabolism of ethanol to acetaldehyde has been visualized in living lung epithelial cells using a hydrazinyl naphthalimide fluorescent probe. Utilizing a condensation reaction between carbonyls and a hydrazine moeity, we demonstrate that the fluorescent probe (Aldehydefluor-1) AF1 reacts with a range of reactive carbonyl species including formaldehyde, acetaldehyde, glyoxylic acid, and methyl glyoxal. With AF1, it is possible to directly visualize endogenous carbonyl metabolites. Here, we have applied it towards the visualization of acetaldehyde generated from alcohol dehydrogenase mediated ethanol metabolism, validating it as a useful tool to study the roles of alcohol in respiratory disease and other pathological mechanisms. PMID- 29109757 TI - Evaluation of the efficacy of Ajuga decumbens extract supplement in individuals with knee discomfort associated with physical activity: A randomized, double blind, placebo-controlled study. AB - The aim of the present study was to assess the efficacy and safety of the oral administration of Ajuga decumbens extract (ADE) supplement to individuals with knee discomfort associated with physical activity. A randomized, double-blind, placebo-controlled study was conducted using 48 subjects. The subjects were randomly allocated to an ADE diet group (oral administration of ADE-containing diet, n=24) or a placebo group (n=24), and the intervention was conducted for 12 weeks. A total of 22 subjects in the placebo group and 22 subjects in the ADE diet group were assessed to be eligible for assessment of the efficacy of supplement. Knee function was assessed by changes in the scores of the Japanese Knee Osteoarthritis Measure (JKOM) questionnaire and the scores of the Japan Orthopedic Association (JOA) criteria, as well as by analyzing the levels of type II collagen synthesis and degradation biomarkers (procollagen II C-terminal propeptide, cross-linked C-telopeptide of type II collagen, collagen type II cleavage and matrix metalloproteinase-13). Outcomes were measured at the baseline and at 4, 8 and 12 weeks from the start of administration. Subscale II (joint flexion/stiffness) of the JOA criteria was markedly improved in the ADE diet group compared with the placebo group at 8 and 12 weeks during the intervention. Furthermore, in the subgroup analyses using subjects with mild knee discomfort, subscale II (pain/stiffness) and IV (general activities) scores of JKOM were significantly improved (P<0.05) and total JKOM score was markedly improved in the ADE diet group compared with the placebo group at week 8 of the intervention. No adverse effects were identified for the administration of ADE. In conclusion, these observations suggest that the administration of an ADE-containing diet is safe and improves joint function (flexion and stiffness) and general activity in subjects with mild knee discomfort. Therefore, ADE could be a promising candidate as a functional food that is beneficial to joint health. PMID- 29109759 TI - Overexpression of epithelial cell transforming 2 protein in colorectal carcinoma predicts a poor prognosis. AB - Epithelial cell transforming 2 (Ect2) protein is a member of the human diffuse B cell lymphoma family of guanine nucleotide exchange factors, which activate the Ras homolog gene family of small GTPases; however, the clinical implications of Ect2 in colorectal carcinoma (CRC) are unclear. The present study aimed to determine the relationship between Ect2 expression and prognosis in patients with CRC. Western blot analysis and immunohistochemistry assays were used to determine the expression of Ect2 in CRC and paired non-cancerous tissues from 66 patients. The correlation between Ect2 expression and clinicopathological parameters was assessed using chi2 tests. Patient survival was determined using the Kaplan-Meier method and log-rank test. Cox regression was used for multivariate analysis of prognostic factors. Results demonstrated that Ect2 protein was highly expressed in human CRC samples [29/45 (64.45%)] and significantly correlated with a poor prognosis (P<0.05). Compared with normal tissues, CRC tissues demonstrated higher expression levels of Ect2 mRNA [44/66 (66.67%)]. In addition, highly-expressed Ect2 was significantly associated with recurrence (P=0.023) and invasion (P=0.008) of CRC. High Ect2 expression levels in patients were associated with poorer overall survival (OS) and disease-free survival (DFS) compared with lower expression levels of Ect2. Based on multivariate analysis, Ect2 overexpression was significantly correlated with OS and DFS (P=0.015 and 0.020, respectively). In conclusion, Ect2 overexpression is an independent and important prognostic factor for OS and DFS in patients with CRC. PMID- 29109758 TI - Antitumor and immunomodulating activities of six Phellinus igniarius polysaccharides of different origins. AB - The aim of the current study was to compare the antitumor efficiency of Phellinus igniarius polysaccharides (PIP) from six different origins and preliminarily investigate its potential mechanisms. PIP was extracted using the microwave extraction method. The corresponding in vivo antitumor efficacy was assessed in Kunming mice bearing H22 tumors and Gansu PIP (GPIP) was identified to have a significantly higher antitumor efficacy compared with the control group (P<0.05), while no significant difference was observed following treatment with PIP from different origins (P>0.05). The spleen index of the GPIP group significantly increased compared with the saline and CTX groups (P<0.01). The in vitro MTT assay of GPIP on HepG2 cells indicated that GPIP had no direct cytotoxicity. The serum immune cytokines of interleukin-2, interleukin-12 and interferon-gamma were assessed using the ELISA method. The concentration of all three serum cytokines significantly increased compared with saline and CTX groups (P<0.01) indicating that activating the immune system may be a potential antitumor mechanism. These results demonstrated that GPIP has great potential as a natural antitumor agent with immunomodulatory activity. PMID- 29109760 TI - Influence of serum HMW adiponectin level in patients with pregnancy-induced hypertension syndrome on the occurrence of eclampsia in secondary pregnancy. AB - In the present study, we studied the influence of serum high-molecular weight adiponectin (HMWA) levels in patients with pregnancy-induced hypertension (PIH) on the occurrence of eclampsia in secondary pregnancy and its related mechanisms. In total, 130 patients who were diagnosed with PIH for the first time were selected for this study; the median interval of the secondary pregnancy was 28.5 months. The serum HMWA and leptin levels both times were detected, and the insulin resistance indexes (HOMA-IR) were calculated. The serum inflammatory indexes in the secondary pregnancy included interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels, and the oxidative stress indexes included methane dicarboxylic aldehyde (MDA) and oxidized low-density lipoprotein (ox-LDL) levels. The expression levels of adiponectin receptor 2 and cyclooxygenase-2 (COX-2) in placental tissue were detected. In secondary pregnancy, there were a total of 20 cases of eclampsia (15.38%), including 2 cases of mild PIH, 8 cases of moderate PIH and 10 cases of severe PIH; differences were statistically significant when compared to patients without eclampsia (p<0.001). The serum HMWA levels in patients with severe PIH in the first pregnancy were significantly lower than those in patients with mild and moderate PIH, and the serum levels in patients with mild PIH were the highest. The leptin levels in patients with severe PIH were significantly higher than those in patients with mild and moderate PIH, and the leptin levels in patients with mild PIH were the lowest (p<0.05). The HMWA levels in patients with eclampsia in the secondary pregnancy was significantly lower than those in patients without eclampsia, and the leptin levels in patients with eclampsia were significantly increased. The HMWA levels in patients with eclampsia in the secondary pregnancy were lower than that in the first pregnancy, whereas the leptin levels were higher than that in the first pregnancy (p<0.05). HOMA-IR, IL 6, TNF-alpha, MDA and ox-LDL levels in patients with eclampsia were significantly higher than those in patients without eclampsia (p<0.05), and the adiponectin receptor 2 and COX-2 expression levels in the placental tissue were significantly higher than those in patients without eclampsia (p<0.05). Therefore, the serum HMWA levels are closely related to the occurrence of eclampsia in PIH patients in secondary pregnancy, and it influences insulin resistance, inflammatory response and oxidative stress response, which is correlated with increased adiponectin receptor 2 and COX-2 protein expression in placental tissue. Consequently, HMWA may be an important target for the intervention of preventing eclampsia for PIH patients in secondary pregnancy. PMID- 29109761 TI - Analysis of the correlation between adiponectin gene polymorphism and metabolic syndrome incidence and its relationship with the degree of atherosclerosis in patients. AB - The aim of the present study was to determine the correlation between adiponectin (APN) gene polymorphism, metabolic syndrome incidence, and degree of atherosclerosis in patients with this disease. The study was conducted on 369 unrelated patients, diagnosed with metabolic abnormalities. The patients were divided into the metabolic syndrome group (MS group, n=182), the metabolic abnormality group (n=187) and the control group with metabolic normality (n=134), as per the degree of metabolic abnormality. The gene polymorphism of rs121917815 site of APN gene was detected by TaqMAN probe technique, and the OR values of different genotypes and alleles were calculated. The APN protein, C-reactive protein (CRP), IL-1 and high-density lipoprotein (HDL) 2a and 2b expression level changes were detected by immunoblotting. The atherosclerosis index (AI) of each allele in patients with MS was calculated. Compared with the control group, the expression levels of APN protein in the metabolic abnormality and MS groups were significantly decreased. However, there was no distinct difference in the comparison of gene polymorphism between the control and metabolic abnormality groups. The CC genotype frequency and C allele frequency of rs121917815 polymorphic site in the MS group were significantly increased, compared with the control group. The TT genotype frequency and T allele frequency were significantly decreased and the OR values of the CC genotype and C allele were increased. The results of immunoblotting showed that there was no obvious change of CRP, IL-1, HDL-2a and HDL-2b in the three groups, and there was no statistically significant difference in the comparison of AI between the MS and control groups as well as the metabolic abnormality group. The APN gene polymorphic site rs121917815 is associated with MS. The occurrence of CC genotype and C allele increased the incidence of MS, but it did not increase the degree of atherosclerosis in MS patients. PMID- 29109762 TI - Stability analysis on the radioactive iodine-labelled prostate cancer-specific recombinant oncolytic adenovirus. AB - The aim of the present study was to construct the 125I-replication-selective oncolytic adenovirus (RSOAds)-human telomerase reverse transcriptase (hTERT)/prostate specific antigen (PSA) nuclide-oncolytic virus marker by labelling the hTERT/PSA double-regulation replicative oncolytic adenovirus with 125I nuclide, and investigate the influence of viral markers under various reaction conditions on labelling efficiency. N-bromosuccinimide (NBS) was used as the oxidizer for 125I labelling, and the best conditions for labelling were identified through the reactions between oncolytic adenovirus at various concentrations and NBS. Dosage of 125I, reaction duration, pH values and reaction volume were respectively evaluated to determine their effects on the labelling efficiency of 125I-RSOAds-hTERT/PSA nuclide-oncolytic adenovirus markers. Purified nuclide-oncolytic adenovirus markers were isolated by gel-filtration chromatography; paper chromatography was performed to assay the radiochemical purity of 125I-RSOAds-hTERT/PSA markers at various time points. Radiochemical purity of 125I-RSOAds-hTERT/PSA was >95%, and could be maintained at 4 degrees C for 7 days. The best reaction conditions were set as follows: 0.5 ul of 125I (~0.2 m Ci, 7.4 MBq); 25 qg of NBS; 100 ul of 8*109 VP/ml 125I-RSOAds-hTERT/PSA virus solution; 30 min of reaction duration; pH 7.5; 120 ul of PBS. Labelling hTERT/PSA double-regulation replicative oncolytic adenovirus with 125I was identified to be available, and the radiochemical purity of acquired virus markers could be maintained under specific conditions. PMID- 29109763 TI - Survivin and XIAP expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas. AB - There is considerable evidence that the inhibitor of apoptosis protein (IAP) family serves a role in tumorigenesis. The most studied IAP family members, survivin and X-linked inhibitor of apoptosis (XIAP), have been demonstrated to serve as biomarkers in distinct tumor entities. Thus, the present study aimed to investigate the expression levels of both IAPs in the tumor center, invasion front and lymph node metastases of surgically resected gastric cancer (GC) specimens. Tissue microarrays containing samples from 201 primary GCs were analyzed. IAP expression was detected using immunohistochemistry in different tumor compartments, normal mucosa and lymph node metastases. In addition, the association between the expression levels of these proteins, and clinicopathological parameters and overall survival was investigated. High levels of survivin and XIAP were evident in GC, when compared with normal mucosa, and were correlated with intestinal-type and well-differentiated GC, as well as low International Union Against Cancer stages. Increased XIAP expression was detected in lymph node metastases as compared with corresponding primary tumors. XIAP overexpression was identified to be an independent negative prognostic marker in diffuse and mixed type GC. These results suggest a potential role of survivin and XIAP in the early phase of gastric carcinogenesis. In addition, increased XIAP expression in lymph node metastases supports the observation that IAPs serve an essential role in metastatic tumor disease. Since XIAP expression was identified to be associated with poor survival in diffuse and mixed type GC, XIAP may serve as a novel therapeutic target in these types of GC. PMID- 29109764 TI - Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities. AB - Immunotherapy is rapidly emerging as the cornerstone for the treatment of several forms of metastatic cancer, as well as for a host of other pathologies. Meanwhile, several new high-profile studies have uncovered remarkable linkages between the central nervous and immune systems. With these recent developments, harnessing the immune system for the treatment of brain pathologies is a promising strategy. Here, we contend that MR image-guided focused ultrasound (FUS) represents a noninvasive approach that will allow for favorable therapeutic immunomodulation in the setting of the central nervous system. One obstacle to effective immunotherapeutic drug delivery to the brain is the blood brain barrier (BBB), which refers to the specialized structure of brain capillaries that prevents transport of most therapeutics from the blood into brain tissue. When applied in the presence of circulating microbubbles, FUS can safely and transiently open the BBB to facilitate the delivery of immunotherapeutic agents into the brain parenchyma. Furthermore, it has been demonstrated that physical perturbations of the tissue microenvironment via FUS can modulate immune response in both normal and diseased tissue. In this review article, we provide an overview of FUS energy regimens and corresponding tissue bioeffects, followed by a review of the literature pertaining to FUS for therapeutic antibody delivery in normal brain and preclinical models of brain disease. We provide an overview of studies that demonstrate FUS-mediated immune modulation in both the brain and peripheral settings. Finally, we provide remarks on challenges facing FUS immunotherapy and opportunities for future expansion in this area. PMID- 29109765 TI - Presenilin Mutation Suppresses Lung Tumorigenesis via Inhibition of Peroxiredoxin 6 Activity and Expression. AB - Some epidemiological studies suggest an inverse correlation between cancer incidence and Alzheimer's disease (AD). In this study, we demonstrated experimental evidences for this inverse relationship. In the co-expression network analysis using the microarray data and GEO profile of gene expression omnibus data analysis, we showed that the expression of peroxiredoxin 6 (PRDX6), a tumor promoting protein was significantly increased in human squamous lung cancer, but decreased in mutant presenilin 2 (PS2) containing AD patient. We also found in animal model that mutant PS2 transgenic mice displayed a reduced incidence of spontaneous and carcinogen-induced lung tumor development compared to wildtype transgenic mice. Agreed with network and GEO profile study, we also revealed that significantly reduced expression of PRDX6 and activity of iPLA2 in these animal models. PS2 mutations increased their interaction with PRDX6, thereby increasing iPLA2 cleavage via increased gamma-secretase leading to loss of PRDX6 activity. However, knockdown or inhibition of gamma-secretase abolished the inhibitory effect of mutant PSs. Moreover, PS2 mutant skin fibroblasts derived from patients with AD showed diminished iPLA2 activity by the elevated gamma-secretase activity. Thus, the present data suggest that PS2 mutations suppress lung tumor development by inhibiting the iPLA2 activity of PRDX6 via a gamma-secretase cleavage mechanism and may explain the inverse relationship between cancer and AD incidence. PMID- 29109766 TI - Cancer Nanomedicines Stabilized by pi-pi Stacking between Heterodimeric Prodrugs Enable Exceptionally High Drug Loading Capacity and Safer Delivery of Drug Combinations. AB - Combination therapy using distinct mode-of-action drugs has sparked a rapidly growing interest because this paradigm holds promise for improving the therapeutic efficacy of anticancer therapy. However, the current drug combination therapy refers to administering individual drugs together, which is far from a perfect regimen for cancer patients. The aim of this work was to demonstrate that synergistic delivery of two chemotherapeutic drugs in a single nanoparticle reservoir could be achieved through the rational chemical ligation of the drugs followed by supramolecular nano-assembly via blending of the drugs with a minimal amount of matrix. Choosing 7-ethyl-10-hydroxycamptothecin and taxanes, which are rich in aromatic structures, as model compounds, we show that the heterodimeric conjugates of the two agents are miscible with lipids to form systemically injectable nanomedicines. The compatibility between the prodrug conjugates and lipid carriers is substantially augmented by the intermolecular pi-pi stacking and alleviated polarity, thus enabling an exceptionally high drug loading (DL) capacity (~92%) and a gratifyingly long drug retention time within the micellar core. We further observed superior therapeutic outcomes in a mouse tumor model without detecting accompanying systemic toxicity. This structure-based, self assembled cancer nanomedicine increased the potency and drug tolerability in animals and thus offers a robust strategy for simultaneously formulating two or more drugs in single nanovehicles. PMID- 29109767 TI - Dexamethasone-loaded Polymeric Nanoconstructs for Monitoring and Treating Inflammatory Bowel Disease. AB - Corticosteroids, such as dexamethasone (DEX), are the mainstays for the treatment of moderate to severe inflammatory bowel disease (IBD). However, their relatively poor bioavailability and lack of specificity is often the origin of short and long-term adverse effects. Here, spherical polymeric nanoconstructs (SPNs) encapsulating dexamethasone are proposed for the systemic treatment of IBD. In a mouse model of colitis, the accumulation of SPNs within the inflamed intestine is firstly assessed using near infra-red fluorescent (NIRF) imaging at different stages of the disease - 5, 7 and 10 days of Dextran Sulfate Sodium (DSS) administration. Then, the efficacy of DEX-SPNs is tested in vitro over macrophages and in vivo by monitoring the animal weight, food and water intake; expression of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6); intestinal density of macrophages; rectal bleeding and histological scoring. 150 nm DEX-SPNs are shown to deposit within the hyper-permeable inflamed intestine in a disease severity-dependent fashion. DEX-SPNs exposed to LPS-stimulated RAW 264.7 cells reduce the expression of inflammatory cytokines as rapidly as free DEX. In DSS administered mice, DEX-SPNs treatments improve weight loss, reduce the macrophage infiltration, expression of inflammatory cytokines, rectal bleeding and histological scoring, as compared to free DEX. Moreover, DEX-SPNs exert a strong systemic anti-inflammatory effect and facilitate animal recovery. This work confirms the benefits of using sufficiently small nanoconstructs for targeting inflamed, hyper-permeable tissues and efficiently delivering high doses of corticosteroids for the treatment of intestinal and systemic inflammation. PMID- 29109769 TI - Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma. AB - We synthesized a novel aryl-guanidino compound, DCZ3301, and found that it has potent cytotoxicity against multiple human cancer cell lines. The anticancer activity was most potent against multiple myeloma (MM). DCZ3301 induced cytotoxicity in MM cell lines, as well as patient myeloma cells, in part by decreasing mitochondrial membrane potential to induce apoptosis. In contrast, DCZ3301 had no cytotoxic effect on normal cells. DCZ3301 also inhibited cell cycling and caused a G2/M accumulation that corresponded with downregulation of Cdc25C, CDK1, and Cyclin B1. DCZ3301 retained its activity against MM cells in the presence of exogenous cytokines (IL-6 or VEGF) or bone marrow stromal cells (BMSCs) and reduced activity of multiple signaling pathways (STAT3, NFkappaB, AKT, ERK1/2) in MM but not normal cells. The STAT3 pathway played an important role in modulating DCZ3301-mediated cytotoxicity. Knockdown of STAT3 using siRNA in MM cells enhanced DCZ3301-induced cytotoxicity, whereas overexpression of STAT3 in MM cells partially protected them from apoptosis. In addition, DCZ3301 inhibited VEGF and IL-6 secretion in a dose-dependent fashion in a co-culture of MM cells and BMSCs. Combining DCZ3301 with bortezomib induced synergistic cytotoxicity in MM cell lines and primary MM cells. Finally, in vivo efficacy of DCZ3301 was confirmed in an MM xenograft mouse model. Together, these results provide a rationale for translation of this small-molecule inhibitor, either alone or in combination, to the clinic against MM. PMID- 29109770 TI - Epiregulin Promotes Lung Metastasis of Salivary Adenoid Cystic Carcinoma. AB - Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8. We also show that epiregulin can be delivered via exosomes and was enriched in exosomes derived from epiregulin overexpressing SACC cells. Furthermore, treating immunodeficient mice with these epiregulin-enriched exosomes greatly enhanced SACC metastasis to lung. These epiregulin-enriched exosomes significantly enhanced angiogenesis in the neighboring tumor microenvironment and increased vascular permeability in the pre metastatic lung microenvironment in vivo. Therefore, epiregulin, as well as epiregulin-containing exosomes, may be a novel target for controlling SACC lung metastasis. PMID- 29109768 TI - Strategies for Preparing Albumin-based Nanoparticles for Multifunctional Bioimaging and Drug Delivery. AB - Biosafety is the primary concern in clinical translation of nanomedicine. As an intrinsic ingredient of human blood without immunogenicity and encouraged by its successful clinical application in Abraxane, albumin has been regarded as a promising material to produce nanoparticles for bioimaging and drug delivery. The strategies for synthesizing albumin-based nanoparticles could be generally categorized into five classes: template, nanocarrier, scaffold, stabilizer and albumin-polymer conjugate. This review introduces approaches utilizing albumin in the preparation of nanoparticles and thereby provides scientists with knowledge of goal-driven design on albumin-based nanomedicine. PMID- 29109771 TI - Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy. AB - Fetal growth restriction (FGR) in pregnancy is commonly caused by impaired uteroplacental blood flow. Vasodilators enhance uteroplacental perfusion and fetal growth in humans and animal models; however, detrimental maternal and fetal side effects have been reported. We hypothesised that targeted uteroplacental delivery of a vasodilator would enhance drug efficacy and reduce the risks associated with drug administration in pregnancy. Phage screening identified novel peptides that selectively accumulated in the uteroplacental vasculature of pregnant mice. Following intravenous injection, the synthetic peptide CNKGLRNK selectively bound to the endothelium of the uterine spiral arteries and placental labyrinth in vivo; CNKGLRNK-decorated liposomes also selectively bound to these regions. The nitric oxide donor 2-[[4-[(nitrooxy)methyl]benzoyl]thio]-benzoic acid methyl ester (SE175) induced significant relaxation of mouse uterine arteries and human placental arteries in vitro; thus, SE175 was encapsulated into these targeted liposomes and administered to healthy pregnant C57BL/6J mice or endothelial nitric oxide synthase knockout (eNOS-/-) mice, which exhibit impaired uteroplacental blood flow and FGR. Liposomes containing SE175 (0.44mg/kg) or PBS were administered on embryonic (E) days 11.5, 13.5, 15.5 and 17.5; fetal and placental weights were recorded at term and compared to mice injected with free PBS or SE175. Targeted uteroplacental delivery of SE175 had no effect on fetal weight in C57BL/6J mice, but significantly increased fetal weight and mean spiral artery diameter, and decreased placental weight, indicative of improved placental efficiency, in eNOS-/- mice; free SE175 had no effect on fetal weight or spiral artery diameter. Targeted, but not free SE175 also significantly reduced placental expression of 4-hydroxynonenal, cyclooxygenase-1 and cyclooxygenase-2, indicating a reduction in placental oxidative stress. These data suggest that exploiting vascular targeting peptides to selectively deliver SE175 to the uteroplacental vasculature may represent a novel treatment for FGR resulting from impaired uteroplacental perfusion. PMID- 29109772 TI - The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin Based Hydrogels on Hepatocellular Carcinoma. AB - Background and Aims: Recently we reported that direct injection of M1 macrophages significantly caused tumor regression in vivo. Despite the promising result, a major limitation in translating this approach is the induction of acute inflammatory response. To improve the strategy, a biocompatible scaffold for cell presentation and support is essential to control cell fate. Here, we aimed to elucidate the anti-tumor effects of a poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) cross-linked hydrogels capsulated with M1 macrophages in both in vitro and in vivo disease models. Methods: Hydrogels were made at 0.5% (w/v) Iragcure 2959 photoinitiator, 10% (w/v) PEGdA, and 10% (w/v) Gel-PEG-Cys. Monocytic THP-1 cells were loaded into hydrogels and differentiated into M1 macrophages with lipopolysaccharide (LPS) and interferon gamma (IFN-gamma). The M1 hydrogels were then cocultivated with HCC cell-lines Hep3B and MHCC97L to investigate the anti-tumor capacities and the associated molecular profiles in vitro. A nude mice ectopic liver cancer model with dorsal window chamber (DWC) and a subcutaneous tumor model were both performed to validate the in vivo application of M1 hydrogels. Results: M1 hydrogels significantly decreased the viability of HCC cells (MHCC97L: -46%; Hep3B: -56.9%; P<0.05) compared to the control in vitro. In response to HCC cells, the hydrogel embedded M1 macrophages up-regulated nitrite and tumor necrosis factor alpha (TNF-alpha) activating caspase-3 induced apoptosis in the tumor cells. Increased tumor necrosis was observed in DWC filled with M1 hydrogels. In addition, mice treated with M1 hydrogels exhibited a significant 2.4-fold decrease in signal intensity of subcutaneous HCC tumor compared to control (P=0.036). Conclusion: M1 hydrogels induced apoptosis in HCC cells and tumor regression in vivo. Continuous development of the scaffold-based cancer immunotherapy may provide an alternative and innovative strategy against HCC. PMID- 29109773 TI - Quantitative Three-Dimensional Dynamic Contrast-Enhanced Ultrasound Imaging: First-In-Human Pilot Study in Patients with Liver Metastases. AB - Purpose: To perform a clinical assessment of quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) feasibility and repeatability in patients with liver metastasis, and to evaluate the extent of quantitative perfusion parameter sampling errors in 2D compared to 3D DCE-US imaging. Materials and Methods: Twenty consecutive 3D DCE-US scans of liver metastases were performed in 11 patients (45% women; mean age, 54.5 years; range, 48-60 years; 55% men; mean age, 57.6 years; range, 47-68 years). Pairs of repeated disruption-replenishment and bolus DCE-US images were acquired to determine repeatability of parameters. Disruption-replenishment was carried out by infusing 0.9 mL of microbubbles (Definity; Latheus Medical Imaging) diluted in 35.1 mL of saline over 8 min. Bolus consisted of intravenous injection of 0.2 mL microbubbles. Volumes-of-interest (VOI) and regions-or-interest (ROI) were segmented by two different readers in images to extract 3D and 2D perfusion parameters, respectively. Disruption-replenishment parameters were: relative blood volume (rBV), relative blood flow (rBF). Bolus parameters included: time-to peak (TP), peak enhancement (PE), area-under-the-curve (AUC), and mean-transit time (MTT). Results: Clinical feasibility and repeatability of 3D DCE-US using both the destruction-replenishment and bolus technique was demonstrated. The repeatability of 3D measurements between pairs of repeated acquisitions was assessed with the concordance correlation coefficient (CCC), and found to be excellent for all parameters (CCC > 0.80), except for the TP (0.74) and MTT (0.30) parameters. The CCC between readers was found to be excellent (CCC > 0.80) for all parameters except for TP (0.71) and MTT (0.52). There was a large Coefficient of Variation (COV) in intra-tumor measurements for 2D parameters (0.18-0.52). Same-tumor measurements made in 3D were significantly different (P = 0.001) than measurements made in 2D; a percent difference of up to 86% was observed between measurements made in 2D compared to 3D in the same tumor. Conclusions: 3D DCE-US imaging of liver metastases with a matrix array transducer is feasible and repeatable in the clinic. Results support 3D instead of 2D DCE US imaging to minimize sampling errors due to tumor heterogeneity. PMID- 29109774 TI - Dual Functioned Pegylated Phospholipid Micelles Containing Cationic Antimicrobial Decapeptide for Treating Sepsis. AB - Despite intensive investigation of molecular mechanisms underlying the pathogenesis of sepsis, many aspects of sepsis remain unresolved; this hampers the development of appropriate therapeutics. In the present study, we developed a biologic nanomedicine containing a cationic antimicrobial decapeptide KSLW (KKVVFWVKFK), self-associated with biocompatible and biodegradable PEGylated phospholipid micelles (PLM), and analyzed its efficacy for treating sepsis. KSLW was modified with polyethylene glycol (PEG)-aldehyde or was conjugated with distearoylphosphatidylethanolamine (DSPE) -PEG-aldehyde. We compared the antibacterial and antiseptic effects of PEG-KSLW and PLM-KSLW with those of unmodified KSLW both in vitro and in vivo. We found that the PLM-KSLW improved the survival rate of sepsis mouse models without undesired immune responses, and inhibited lipopolysaccharide (LPS)-induced severe vascular inflammatory responses in human umbilical vein endothelial cells compared with unmodified KSLW or PEG KSLW. Furthermore, PLM-KSLW dramatically reduced the bacterial count and inhibited bacterial growth. We also found a new role of PLM-KSLW in tightening vascular barrier integrity by binding to the glycine/tyrosine-rich domain of occludin (OCLN). Our results showed that PLM-KSLW had a more effective antiseptic effect than KSLW or PEG-KSLW, possibly because of its high affinity toward OCLN. Moreover, PLM-KSLW could be potentially used to treat severe vascular inflammatory diseases, including sepsis and septic shock. PMID- 29109775 TI - The Bidirectional Regulation between MYL5 and HIF-1alpha Promotes Cervical Carcinoma Metastasis. AB - Myosin light chains (MLC) serve important regulatory functions in a wide range of cellular and physiological processes. Recent research found that MLC are also chromatin-associated nuclear proteins which regulate gene transcription. In this study, the MLC member myosin regulatory light chain 5 (MYL5) expression was upregulated in late stage cervical cancer patients, positively correlated with pelvic lymph node metastasis, and identified as a poor survival indicator. MYL5 overexpression promoted metastasis in cervical cancer in vitro and in vivo models, whereas MYL5 silencing had the converse effect. We demonstrated a bidirectional regulation between MYL5 and hypoxia inducible factor-1alpha (HIF 1alpha). HIF-1alpha activates MYL5 via binding to the hypoxia response element (HRE) in the promoter of MYL5, and MYL5 could sustain HIF-1alpha expression by tethering to recognition sequence AGCTCC in the HIF-1alpha promoter region. Clinical data confirmed a positive correlation between MYL5 and HIF-1alpha. In summary, our data show that MYL5 may act as a prognosis predictive factor in cervical carcinoma, and strategies that inhibit the interaction of MYL5 and HIF 1alpha may benefit the cervical carcinoma patients with metastasis. PMID- 29109776 TI - Sequential Delivery of Cyclopeptide RA-V and Doxorubicin for Combination Therapy on Resistant Tumor and In Situ Monitoring of Cytochrome c Release. AB - A programmed drug delivery system that can achieve sequential release of multiple therapeutics under different stimulus holds great promise to enhance the treatment efficacy and overcome multi-drug resistance (MDR) in tumor. Herein, multi-organelle-targeted and pH/ cytochrome c (Cyt c) dual-responsive nanoparticles were designed for combination therapy on resistant tumor. In this system (designated DGLipo NPs), doxorubicin (Dox) was intercalated into the DNA duplex containing a Cyt c aptamer, which subsequently loaded in the dendrigraftpoly-L-lysines (DGL) cores of DGLipo NPs, while cyclopeptide RA-V was doped into the pH-sensitive liposomal shells. After dual modification with c(RGDfK) and mitochondria-penetrating peptide (MPP), DGLipo NPs could successively deliver the two drugs into lysosome and mitochondria of cancer cells, and achieve sequential drug release in virtue of the unique characteristic of these two organelles. The organelle-specific and spatiotemporally controlled release of Dox and RA-V led to enhanced therapeutic outcomes in MDR tumor. More significantly, the DGLipo NPs were successfully applied to monitor Cyt c release during mitochondria-mediated apoptotic process. This work represents a versatile strategy for precise combination therapy against resistant tumor with spatiotemporal control, and provides a potential tool for Cyt c-related apoptotic studies. PMID- 29109777 TI - Improved Tumor Targeting and Longer Retention Time of NIR Fluorescent Probes Using Bioorthogonal Chemistry. AB - The traditional labeling method for targeted NIR fluorescence probes requires directly covalent-bonded conjugation of targeting domains and fluorophores in vitro. Although this strategy works well, it is not sufficient for detecting or treating cancers in vivo, due to steric hindrance effects that relatively large fluorophore molecules exert on the configurations and physiological functions of specific targeting domains. The copper-free, "click-chemistry"-assisted assembly of small molecules in living systems may enhance tumor accumulation of fluorescence probes by improving the binding affinities of the targeting factors. Here, we employed a vascular homing peptide, GEBP11, as a targeting factor for gastric tumors, and we demonstrate its effectiveness for in vivo imaging via click-chemistry-mediated conjugation with fluorescence molecules in tumor xenograft mouse models. This strategy showed higher binding affinities than those of the traditional conjugation method, and our results showed that the tumor accumulation of click-chemistry-mediated probes are 11-fold higher than that of directly labeled probes. The tracking life was prolonged by 12-fold, and uptake of the probes into the kidney was reduced by 6.5-fold. For lesion tumors of different sizes, click-chemistry-mediated probes can achieve sufficient signal-to background ratios (3.5-5) for in vivo detection, and with diagnostic sensitivity approximately 3.5 times that of traditional labeling probes. The click-chemistry assisted detection strategy utilizes the advantages of "small molecule" probes while not perturbing their physiological functions; this enables tumor detection with high sensitivity and specific selectivity. PMID- 29109778 TI - A H2O2-Responsive Theranostic Probe for Endothelial Injury Imaging and Protection. AB - Overproduction of H2O2 causes oxidative stress and is the hallmark of vascular diseases. Tracking native H2O2 in the endothelium is therefore indispensable to gain fundamental insights into this pathogenesis. Previous fluorescent probes for H2O2 imaging were generally arylboronates which were decomposed to emissive arylphenols in response to H2O2. Except the issue of specificity challenged by peroxynitrite, boric acid by-produced in this process is actually a waste with unknown biological effects. Therefore, improvements could be envisioned if a therapeutic agent is by-produced instead. Herein, we came up with a "click-to release-two" strategy and demonstrate that dual functional probes could be devised by linking a fluorophore with a therapeutic agent via a H2O2-responsive bond. As a proof of concept, probe AP consisting of a 2-(2'-hydroxyphenyl) benzothiazole fluorophore and an aspirin moiety has been prepared and confirmed for its theranostic effects. This probe features high specificity towards H2O2 than other reactive species including peroxynitrite. Its capability to image and ameliorate endothelial injury has been verified both in vitro and in vivo. Noteworthy, as a result of its endothelial-protective effect, AP also works well to reduce thrombosis formation in zebrafish model. PMID- 29109779 TI - Serum Immune Profiling for Early Detection of Cervical Disease. AB - BACKGROUND: The most recent (2012) worldwide estimates from International Agency for Research on Cancer indicate that approximately 528,000 new cases and 270,000 deaths per year are attributed to cervical cancer worldwide. The disease is preventable with HPV vaccination and with early detection and treatment of pre invasive cervical intraepithelial neoplasia, CIN. Antibodies (Abs) to HPV proteins are under investigation as potential biomarkers for early detection. METHODS: To detect circulating HPV-specific IgG Abs, we developed programmable protein arrays (NAPPA) that display the proteomes of two low-risk HPV types (HPV6 and 11) and ten oncogenic high-risk HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52 and 58). Arrays were probed with sera from women with CIN 0/I (n=78), CIN II/III (n=84), or invasive cervical cancer (ICC, n=83). RESULTS: Abs to any early (E) HPV protein were detected less frequently in women with CIN 0/I (23.7%) than women with CIN II/III (39.0%) and ICC (46.1%, p<0.04). Of the E Abs, anti-E7 Abs were the most frequently detected (6.6%, 19.5%, and 30.3%, respectively). The least frequently detected Abs were E1 and E2-Abs in CIN 0/I (1.3%) and E1-Abs in CIN II/III (1.2%) and ICC (7.9%). HPV16-specific Abs correlated with HPV16 DNA detected in the cervix in 0% of CIN 0/I, 21.2% of CIN II/III, and 45.5% of ICC. A significant number (29 - 73%) of E4, E7, L1, and L2 Abs had cross-reactivity between HPV types. CONCLUSION: HPV protein arrays provide a valuable high throughput tool for measuring the breadth, specificity, and heterogeneity of the serologic response to HPV in cervical disease. PMID- 29109780 TI - Metabolomic Profiling of Extracellular Vesicles and Alternative Normalization Methods Reveal Enriched Metabolites and Strategies to Study Prostate Cancer Related Changes. AB - : Body fluids are a rich source of extracellular vesicles (EVs), which carry cargo derived from the secreting cells. So far, biomarkers for pathological conditions have been mainly searched from their protein, (mi)RNA, DNA and lipid cargo. Here, we explored the small molecule metabolites from urinary and platelet EVs relative to their matched source samples. As a proof-of-concept study of intra-EV metabolites, we compared alternative normalization methods to profile urinary EVs from prostate cancer patients before and after prostatectomy and from healthy controls. METHODS: We employed targeted ultra-performance liquid chromatography-tandem mass spectrometry to profile over 100 metabolites in the isolated EVs, original urine samples and platelets. We determined the enrichment of the metabolites in the EVs and analyzed their subcellular origin, pathways and relevant enzymes or transporters through data base searches. EV- and urine derived factors and ratios between metabolites were tested for normalization of the metabolomics data. RESULTS: Approximately 1 x 1010 EVs were sufficient for detection of metabolite profiles from EVs. The profiles of the urinary and platelet EVs overlapped with each other and with those of the source materials, but they also contained unique metabolites. The EVs enriched a selection of cytosolic metabolites including members from the nucleotide and spermidine pathways, which linked to a number of EV-resident enzymes or transporters. Analysis of the urinary EVs from the patients indicated that the levels of glucuronate, D-ribose 5-phosphate and isobutyryl-L-carnitine were 2-26-fold lower in all pre-prostatectomy samples compared to the healthy control and post prostatectomy samples (p < 0.05). These changes were only detected from EVs by normalization to EV-derived factors or with metabolite ratios, and not from the original urine samples. CONCLUSIONS: Our results suggest that metabolite analysis of EVs from different samples is feasible using a high-throughput platform and relatively small amount of sample material. With the knowledge about the specific enrichment of metabolites and normalization methods, EV metabolomics could be used to gain novel biomarker data not revealed by the analysis of the original EV source materials. PMID- 29109781 TI - A Circular RNA Binds To and Activates AKT Phosphorylation and Nuclear Localization Reducing Apoptosis and Enhancing Cardiac Repair. AB - As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio protective role in cardiovascular disease. Here we describe a circular RNA, circ Amotl1 that is highly expressed in neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to AKT1 phosphorylation and nuclear translocation. In primary cardiomyocytes, epithelial cells, and endothelial cells, we found that forced circ-Amotl1 expression increased the nuclear fraction of pAKT. We further detected increased nuclear pAKT in circ-Amotl1-treated hearts. In vivo, circ Amotl1 expression was also found to be protective against Doxorubicin (Dox) induced cardiomyopathy. Putative PDK1- and AKT1-binding sites were then identified in silico. Blocking oligonucleotides could reverse the effects of exogenous circ-Amotl1. We conclude that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT. PMID- 29109783 TI - Oxygen breathing challenge- the simplest theranostic. AB - Multispectral optoacoustic tomography provides insights into tumor vascular oxygenation with high temporal and spatial resolution non-invasively. New work indicates that a simple oxygen breathing challenge can reveal differences in tumor, potentially as a prognostic biomarker. PMID- 29109782 TI - Berunda Polypeptides: Multi-Headed Fusion Proteins Promote Subcutaneous Administration of Rapamycin to Breast Cancer In Vivo. AB - Recombinant Elastin-Like Polypeptides (ELPs) serve as attractive scaffolds for nanoformulations because they can be charge-neutral, water soluble, high molecular weight, monodisperse, biodegradable, and decorated with functional proteins. We recently reported that fusion of the FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) reduces rapamycin (Rapa) toxicity and enables intravenous (IV) therapy in both a xenograft breast cancer model and a murine autoimmune disease model. Rapa has poor solubility, which leads to variable oral bioavailability or drug precipitation following parenteral administration. While IV administration is routine during chemotherapy, cytostatic molecules like Rapa would require repeat administrations in clinical settings. To optimize FKBP/Rapa for subcutaneous (SC) administration, this manuscript expands upon first generation FSI nanoparticles (Rh ~ 25 nm) and compares them with two second generation carriers (FA and FAF) that: i) do not self-assemble; ii) retain a hydrodynamic radius (Rh ~ 7 nm) above the renal filtration cutoff; iii) increase tumor accumulation; and iv) have either one (FA) or two (FAF) drug-binding FKBP domains per ELP protein. Methods: The carriers were compared and evaluated for temperature-concentration phase behavior by UV-Vis spectrophotometry; equilibrium binding and thermodynamics by Isothermal Titration Calorimetry; drug retention and formulation stability by Dialysis and Dynamic Light Scattering; in vitro efficacy using a cell proliferation assay; in vivo efficacy in human MDA-MB-468 orthotopic breast cancer xenografts; downstream target inhibition using western blot; tissue histopathology; and bio-distribution via optical imaging in the orthotopic xenograft mouse model. Results: Named after the two-headed bird in Hindu mythology, the 'Berunda polypeptide' FAF with molecular weight of 97 kDa and particle size, Rh ~ 7 nm demonstrated polypeptide conformation of a soluble hydrated coiled polymer, retained formulation stability for one month post Rapa loading, eliminated toxicity observed with free Rapa after SC administration, suppressed tumor growth, decreased phosphorylation of a downstream target, and increased tumor accumulation in orthotopic breast tumor xenografts. Conclusion: This comprehensive manuscript demonstrates the versatility of recombinant protein polymers to investigate drug carrier architectures. Furthermore, their facilitation of SC administration of poorly soluble drugs, like Rapa, may enable chronic self-administration in patients. PMID- 29109784 TI - Multimodal Assessment of Mesenchymal Stem Cell Therapy for Diabetic Vascular Complications. AB - Peripheral arterial disease (PAD) is a debilitating complication of diabetes mellitus (DM) that leads to thousands of injuries, amputations, and deaths each year. The use of mesenchymal stem cells (MSCs) as a regenerative therapy holds the promise of regrowing injured vasculature, helping DM patients live healthier and longer lives. We report the use of muscle-derived MSCs to treat surgically induced hindlimb ischemia in a mouse model of type 1 diabetes (DM-1). We serially evaluate several facets of the recovery process, including alphaVbeta3 -integrin expression (a marker of angiogenesis), blood perfusion, and muscle function. We also perform microarray transcriptomics experiments to characterize the gene expression states of the MSC-treated is- chemic tissues, and compare the results with those of non-ischemic tissues, as well as ischemic tissues from a saline treated control group. The results show a multifaceted impact of mMSCs on hindlimb ischemia. We determined that the angiogenic activity one week after mMSC treatment was enhanced by approximately 80% relative to the saline group, which resulted in relative increases in blood perfusion and muscle strength of approximately 42% and 1.7-fold, respectively. At the transcriptomics level, we found that several classes of genes were affected by mMSC treatment. The mMSCs appeared to enhance both pro-angiogenic and metabolic genes, while suppressing anti-angiogenic genes and certain genes involved in the inflammatory response. All told, mMSC treatment appears to exert far-reaching effects on the microenvironment of ischemic tissue, enabling faster and more complete recovery from vascular occlusion. PMID- 29109785 TI - Overexpression of miR-194 Reverses HMGA2-driven Signatures in Colorectal Cancer. AB - : Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide with increasing incidence and mortality in developed countries. Oncogenes and microRNAs regulate key signaling pathways in CRC and are known to be deregulated. Oncogenic transcriptional regulator high-mobility group AT-hook 2 (HMGA2) participates in the transformation of several cancers including CRC and exhibits strong correlation with poor prognosis and distal metastasis. Evidence of HMGA2 and its co-regulated miRs contributing to tumor progression remains to be clarified. METHODS: We performed gene-set enrichment analysis on the expression profiles of 70 CRC patients and revealed HMGA2 correlated genes that are targeted by several miRs including miR-194. To eliminate the oncogenic effects in HMGA2 driven CRC, we re-expressed miR-194 and found that miR-194 functions as a tumor suppressor by reducing cell proliferation and tumor growth in vitro and in vivo. RESULTS: As a direct upstream inhibitory regulator of miR-194, overexpression of HMGA2 reduced miR-194 expression and biological activity, whereas re-expressing miR-194 in cells with high levels of HMGA2 impaired the effects of HMGA2, compromising cell survival, the epithelial-mesenchymal transition process, and drug resistance. CONCLUSION: Our findings demonstrate that novel molecular correlations can be discovered by revisiting transcriptome profiles. We uncover that miR-194 is as important as HMGA2, and both coordinately regulate the oncogenesis of CRC with inverted behaviors, revealing alternative molecular therapeutics for CRC patients with high HMGA2 expression. PMID- 29109787 TI - Emerging Advances in Nanotheranostics with Intelligent Bioresponsive Systems. AB - The confluence of therapeutics and diagnostics based on the advantages of nanotechnology offers significant opportunities for personalized and precision medicine. Intelligent nanotheranostics based on bioresponsive systems have recently emerged and offer the promise of high specificity and efficiency via "on demand" activation of both therapeutic and diagnostic capabilities. PMID- 29109786 TI - "One-Pot" Fabrication of Highly Versatile and Biocompatible Poly(vinyl alcohol) porphyrin-based Nanotheranostics. AB - Nanoparticle-based theranostic agents have emerged as a new paradigm in nanomedicine field for integration of multimodal imaging and therapeutic functions within a single platform. However, the clinical translation of these agents is severely limited by the complexity of fabrication, long-term toxicity of the materials, and unfavorable biodistributions. Here we report an extremely simple and robust approach to develop highly versatile and biocompatible theranostic poly(vinyl alcohol)-porphyrin nanoparticles (PPNs). Through a "one pot" fabrication process, including the chelation of metal ions and encapsulation of hydrophobic drugs, monodispersenanoparticle could be formed by self-assembly of a very simple and biocompatible building block (poly(vinyl alcohol)-porphyrin conjugate). Using this approach, we could conveniently produce multifunctional PPNs that integrate optical imaging, positron emission tomography (PET), photodynamic therapy (PDT), photothermal therapy (PTT) and drug delivery functions in one formulation. PPNs exhibited unique architecture-dependent fluorescence self-quenching, as well as photodynamic- and photothermal- properties. Near-infrared fluorescence could be amplified upon PPN dissociation, providing feasibility of low-background fluorescence imaging. Doxorubicin (DOX) loaded PPNs achieved 53 times longer half-life in blood circulation than free DOX. Upon irradiation by near infrared light at a single excitation wavelength, PPNs could be activated to release reactive oxygen species, heat and drugs simultaneously at the tumor sites in mice bearing tumor xenograft, resulting in complete eradication of tumors. Due to their organic compositions, PPNs showed no obvious cytotoxicity in mice via intravenous administration during therapeutic studies. This highly versatile and multifunctional PPN theranostic nanoplatform showed great potential for the integration of multimodal imaging and therapeutic functions towards personalized nanomedicine against cancers. PMID- 29109788 TI - Decrease in Lymphoid Specific Helicase and 5-hydroxymethylcytosine Is Associated with Metastasis and Genome Instability. AB - DNA methylation is an important epigenetic modification as a hallmark in cancer. Conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by ten eleven translocation (TET) family enzymes plays an important biological role in embryonic stem cells, development, aging and disease. Lymphoid specific helicase (LSH), a chromatin remodeling factor, is regarded as a reader of 5-hmC. Recent reports show that the level of 5-hmC is altered in various types of cancers. However, the change in 5-hmC levels in cancer and associated metastasis is not well defined. We report that the level of 5-hmC was decreased in metastatic tissues of nasopharyngeal carcinoma, breast cancer, and colon cancer relative to that in non-metastasis tumor tissues. Furthermore, our data show that TET2, but not TET3, interacted with LSH, whereas LSH increased TET2 expression through silencing miR-26b-5p and miR-29c-5p. Finally, LSH promoted genome stability by silencing satellite expression by affecting 5-hmC levels in pericentromeric satellite repeats, and LSH was resistant to cisplatin-induced DNA damage. Our data indicate that 5-hmC might serve as a metastasis marker for cancer and that the decreased expression of LSH is likely one of the mechanisms of genome instability underlying 5-hmC loss in cancer. PMID- 29109790 TI - Aptamer-Based Therapeutic Approaches to Target Cancer Stem Cells. AB - Cancer stem cells (CSCs) are believed to be a principal cellular source for tumour progression and therapeutic drug resistance as they are capable of self renewal and can differentiate into cancer cells. Importantly, CSCs acquire the ability to evade the killing effects of cytotoxic agents through changes at the genetic, epigenetic and micro-environment levels. Therefore, therapeutic strategies targeting CSCs hold great potential as an avenue for cancer treatment. Aptamers or "chemical antibodies" are a group of single-stranded nucleic acid (DNA or RNA) oligonucleotides with distinctive properties such as smaller size, lower toxicity and less immunogenicity compared to conventional antibodies. They have been frequently used to deliver therapeutic payloads to cancer cells and have achieved encouraging anti-tumour effects. This review discusses progress in CSC evolution theory and the role of aptamers to target CSCs for cancer treatment. Challenges of aptamer-mediated CSC targeting approaches are also discussed. PMID- 29109789 TI - Nucleic Acid-Based Theranostics for Tackling Alzheimer's Disease. AB - Nucleic acid-based technologies have received significant interest in recent years as novel theranostic strategies for various diseases. The approval by the United States Food and Drug Administration (FDA) of Nusinersen, an antisense oligonucleotide drug, for the treatment of spinal muscular dystrophy highlights the potential of nucleic acids to treat neurological diseases, including Alzheimer's disease (AD). AD is a devastating neurodegenerative disease characterized by progressive impairment of cognitive function and behavior. It is the most common form of dementia; it affects more than 20% of people over 65 years of age and leads to death 7-15 years after diagnosis. Intervention with novel agents addressing the underlying molecular causes is critical. Here we provide a comprehensive review on recent developments in nucleic acid-based theranostic strategies to diagnose and treat AD. PMID- 29109791 TI - Can molecular profiling enhance radiotherapy? Impact of personalized targeted gold nanoparticles on radiosensitivity and imaging of adenoid cystic carcinoma. AB - Personalized molecular profiling has an established role in selection of treatment for metastatic disease; however, its role in improving radiosensitivity and functional imaging has not been evaluated. In the current study, we examined molecular profiling as a tool for designing personalized targeted gold nanoparticles (GNP) to serve as dual-modal tumor radiosensitizers and functional imaging enhancers. To this end, molecular profiling of a patient's salivary gland adenoid cystic carcinoma (ACC) was performed, and anaplastic lymphoma kinase (ALK) mutation was detected. The extracted tumor was subcutaneously injected into mice, which were then treated either with radiation, the specific ALK inhibitor crizotinib, or a combination of therapies. One of these combinations, namely, ALK targeted GNP (via crizotinib coating), was found to enhance radiation treatment, as demonstrated by a significant decrease in tumor volume over 24 days. In parallel, ALK-targeted GNP substantially augmented tumor visualization via computed tomography. The mechanism of radiosensitivity enhancement was mostly related to a diminished cell repair mechanism in tumors, as demonstrated by proliferating cell nuclear antigen staining. These findings indicate that personalized molecular profiling is an effective technique for enhancing cancer theranostics. PMID- 29109792 TI - MiR-205/YAP1 in Activated Fibroblasts of Breast Tumor Promotes VEGF-independent Angiogenesis through STAT3 Signaling. AB - Tumor microenvironment contributes to tumor angiogenesis. However, the role of the activated cancer associated-fibroblasts (CAFs) in angiogenesis is still unclear. Here we report that miR-205/YAP1 signaling in the activated stromal fibroblasts plays a critical role in VEGF-independent angiogenesis in breast tumor. Methods: miR-205 expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR); YAP1 expression by qRT-PCR, western blotting and immunohistochemistry; IL11 and IL15 expression by qRT-PCR, western blotting and ELISA. Tube formation and three-dimensioned sprouting assays in vitro, and orthotopic Xenografts in vivo were conducted as angiogenesis experiments. The mechanism of miR-205/YAP1-mediated tumor angiogenesis was analyzed via overexpression and shRNA, siRNA, or antibody neutralization experiments in combination with anti-VEGF antibody or Axitinib. Results: miR-205/YAP1 signaling axis activates breast normal fibroblasts (NFs) into CAFs, promotes tubule formation and sprouting of Human Umbilical Vein Endothelial Cells (HUVECs). Rescue of miR-205 in CAFs blunts angiogenesis processes. YAP1, a target of miR 205, does not regulate VEGF expression but specifically enhances IL11 and IL15 expressions, maintaining tumor angiogenesis even in the presence of Axitinib or after exhaustion of VEGF by neutralizing VEGF antibody. IL11 and IL15 released from CAFs activate STAT3 signaling in HUVECs. Blockage of IL11 and IL15 expression in CAFs results in the inactivation of STAT3-signaling in HUVECs and repression of the CAF-induced angiogenesis. The blunt angiogenesis halts the invasion and metastasis of breast cancer cells in vivo. Conclusions: These results provide a novel insight into breast CAF-induced tumor angiogenesis in a VEGF-independent manner. PMID- 29109793 TI - Acute Inflammatory Response Following Increased Blood-Brain Barrier Permeability Induced by Focused Ultrasound is Dependent on Microbubble Dose. AB - Rationale: Focused ultrasound (FUS), in conjunction with circulating microbubbles (MBs), can be used to transiently increase the permeability of the blood-brain barrier (BBB) in a targeted manner, allowing therapeutic agents to enter the brain from systemic circulation. While promising preclinical work has paved the way for the initiation of 3 human trials, there remains concern regarding neuroinflammation following treatment. The aim of this study was to assess the magnitude of this response following sonication and explore the influence of MB dose. Methods: Differential expression of NFkappaB signaling pathway genes was assessed in rats at 6 h and 4 days following a FUS-mediated increase in BBB permeability. Three sonication schemes were tested: (1) a clinical imaging dose of MBs + peak negative pressure (PNP) controlled by acoustic feedback, (2) 10x clinical imaging dose of MBs + constant PNP of 0.290 MPa, and (3) 10x clinical imaging dose of MBs + PNP controlled by acoustic feedback. Follow-up magnetic resonance imaging (MRI) was performed to assess edema and hemorrhage. Hematoxylin and eosin histology was used to evaluate general tissue health. Results: MB dose has a significant impact on the expression of several key genes involved in acute inflammation and immune activation, including Tnf, Birc3, and Ccl2. At a clinical imaging dose of MBs, there were no significant changes detected in the expression of any NFkappaB signaling pathway genes. Conversely, a high MB dose resulted in a clear activation of the NFkappaB signaling pathway, accompanied by edema, neuronal degeneration, neutrophil infiltration, and microhemorrhage. Results also suggest that post-FUS gadolinium enhancement may hold predictive value in assessing the magnitude of inflammatory response. Conclusion: While a significant and damaging inflammatory response was observed at high MB doses, it was demonstrated that FUS can be used to induce increased BBB permeability without an associated upregulation of NFkappaB signaling pathway gene expression. This emphasizes the importance of employing optimized FUS parameters to mitigate the chances of causing injury to the brain at the targeted locations. PMID- 29109794 TI - Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt FoxO1 Interaction. AB - Rationale: Glucagon is involved in hepatic gluconeogenesis, playing a key role in type 2 diabetes. Ginsenosides are reported to have antidiabetic activities. Ginsenoside Rg1 is a major propanaxatriol-type saponin in ginseng. This study aims to investigate the regulatory effects of Rg1 on glucagon-induced hepatic glucose production. Methods: The effects of Rg1 were investigated in high-fat diet (HFD)-fed mice and glucagon-challenged C57BL/6J mice. Glucose metabolism was evaluated by oral glucose tolerance test and pyruvate tolerance test. The role of Rg1 on the regulation of Akt-FoxO1 interaction was performed using immunofluorescence, immunoprecipitation, siRNA silencing, pharmacological inhibitor and active-site mutant in primary hepatocytes or HepG2 cells. Results: Abnormally elevated fasting glucagon levels were observed in HFD-fed mice, contributing significantly to increased fasting plasma glucose levels. Inappropriate fasting glucagon secretion inactivated Akt and promoted hepatic glucose production via upregulation of FoxO1 activity. Rg1 preserved glucagon impaired Akt activation partly by binding to Akt at Ser473 site. Rg1 also promoted Akt binding to FoxO1 and inactivated FoxO1 by phosphorylation. Consequently, Rg1 decreased the hepatic glucose production through a decrease in transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase). Both siRNA silencing of Akt and Akt inhibitor triciribine attenuated the effects of Rg1 in response to fasting hormone glucagon. Conclusion: Akt phosphorylation at Ser473 by ginsenoside Rg1 is critical for its gluconeogenesis-lowering effect, suggesting a potential for pharmaceutical intervention in response to fasting hormone glucagon. PMID- 29109795 TI - The Use of PET Imaging for Prognostic Integrin alpha2beta1 Phenotyping to Detect Non-Small Cell Lung Cancer and Monitor Drug Resistance Responses. AB - PURPOSE: Growing evidence has demonstrated that aberrant expression of integrin alpha2beta1 might contribute to the invasion, metastasis and drug resistance of non-small cell lung cancer (NSCLC). Thus, the integrin alpha2beta1 targeting 68Ga DOTA-A2B1 tracer was validated in NSCLC in contrast to accumulation of the clinically used 18F-FDG PET tracer to see if 68Ga-DOTA-A2B1-PET imaging can offer a valuable and critical diagnostic imaging criterion for the identification of phenotypes of aggressive lung cancer. METHODS: To verify the prognostic value of integrin alpha2beta1, several quantitative and functional in vitro assays were validated in different NSCLC cell lines (CL1-0, CL1-5, A549 and selected A549++ cells). Positron emission tomography (PET) imaging studies using both standard 18F-FDG and a newly developed 68Ga-labeled integrin alpha2beta1 (68Ga-DOTA-A2B1) tracer were sequentially performed on mice with lung tumor xenografts in different anatomic locations (subcutaneous, orthotopic and osseous) to validate the targeting capability of the 68Ga-DOTA-A2B1 tracers. Treatment responses were monitored by injecting animals with metastatic bone tumors with 5 mg/kg doxorubicin. All in vivo treatment responses in each treatment subgroup were monitored with a PET imaging system to evaluate the up-regulation of integrin expression at the earliest stage of treatment (6 h). RESULTS: The PET and computed tomography (CT) images from NSCLC xenograft animals unambiguously demonstrated accumulation of the integrin tracer 68Ga-DOTA-A2B1 in the tumor lesions at all locations. The average tumor uptake and tumor-to-normal (T/N) ratio were 2.51 +/- 0.56 %ID/g and T/N = 2.82, 3.40 +/- 0.42 %ID/g and T/N = 1.52, and 1.58 +/- 0.108 %ID/g and T/N = 2.31 in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05). The xenograft tumors were all clearly visible. In contrast, the accumulation of 18F-FDG reached 3.6 +/- 0.76 %ID/g, 1.39 +/- 0.075 %ID/g and 3.78 +/- 0.73 %ID/g in subcutaneous, orthotopic and osseous tumors, respectively (n = 5; p < 0.05). However, due to the high background uptake by normal tissue, the T/N values were less than or close to 1, making the tumors almost indistinguishable in the PET imaging analysis. Furthermore, 68Ga-DOTA-A2B1-PET imaging of the treated osseous tumor model demonstrated more than 19% tracer uptake in A549 lesions (1.72 +/- 0.95 %ID/g vs. pretreatment 1.44 +/- 0.12 %ID/g,p = 0. 015) 6 h post-treatment with doxorubicin. The elevated intensity of tracer uptake was in accordance with the results of in vitroWestern blot and ex vivo integrin staining, demonstrating elevated integrin alpha2beta1 expression. CONCLUSION: In this study, integrin alpha2beta1 was identified as a biomarker of aggressive malignant NSCLC. Thus, efforts should be devoted to validating integrin alpha2beta1 as a potential target for non-invasive diagnosis and as a predictive marker for monitoring treatment responses using a preclinical PET imaging system. PMID- 29109796 TI - Investigating the Effect of Chemical Structure of Semiconducting Polymer Nanoparticle on Photothermal Therapy and Photoacoustic Imaging. AB - The donor-acceptor semiconducting polymers (SPs) have robust absorbance in near infrared (NIR) region, great photostability, high photothermal conversion efficiency, and good biocompatibility. Thus, the SPs exhibit great potentials for photothermal therapy (PTT) and photoacoustic imaging (PAI). However, poor understanding of the underlying mechanisms and the correlation between the SP polymer chemical structures and their performances of PTT and PAI have significantly hindered their biomedical application. Herein, a series of acceptor pi-acceptor type (A1-pi-A2) type SPs were synthesized. The diketopyrrolopyrrole (DPP) and thiophene are used as A1 electron accepting block and pi-bridge, and the chemical structure of A2 unit was variable. The SPs were formulated into PEGylated nanoparticles, which ensured these SP-based nanoparticles (SP@NPs) exhibited similar size, shape, and physiological stability. Thus, the chemical structure of A2 unit was the only variable. The effects of the SP chemical structures are carefully and comprehensively evaluated through both in vitro and in vivo experiments. Our results demonstrated the chemical structure of A2 unit simultaneously impact their absorption spectra and photothermal (PT) conversion efficiency, which finally determined their PTT and PAI performances. Among these A2 acceptors, thieno[3,2-b]thiophene (TT) unit exhibited the best in vitro and in vivo anticancer efficacies and PAI performances. This study not only provides molecular insights into the design of efficient SPs for PTT and PAI but also highlights the flexibility and potential of SP@NPs for biomedical application. Thus, SP@NPs can act as a versatile nanoplatform for the development of novel light intensive imaging and therapeutic approaches. PMID- 29109799 TI - Draft genome sequence of a biosurfactant producing, Bacillus aquimaris strain SAMM MCC 3014 isolated from Indian Arabian coastline sea water. AB - Bacillus aquimaris strain SAMM, a biosurfactant producing moderately halophilic marine bacterium was isolated from Indian Arabian coastline sea water. The strain was found to tolerate up to 2.7 M NaCl indicating osmotic stress sustainable physiological systems. We report here the draft genome sequence of B. aquimaris SAMM, as a candidate bacterium for bioactive surfactant producer. The whole genome sequence with 161 scaffolds, 4,414,932 bp and 44.8% of G+C content for SAMM was obtained using Illumina MiSeq sequencing technology. Annotation was added by the PGAP and RAST prokaryotic genome annotation service and shown 4,247 coding sequences, 123 RNAs genes, classified in 453 subsystems. Several genes encoding enzymatic activities against the high molecular weight polysaccharides, osmotic stress response and siderophore synthesis of potential biotechnological importance were identified in the genome. PMID- 29109797 TI - Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-alpha. AB - The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor alpha expression (ERalpha). Identification of the key regulator that governs the luminal phenotype of breast cancer will clarify the pathogenic mechanism and provide novel therapeutic strategies for this subtype of cancer. ERalpha signaling pathway sustains the epithelial phenotype and inhibits the epithelial-mesenchymal transition (EMT) of breast cancer. In this study, we demonstrate that Notch3 positively associates with ERalpha in both breast cancer cell lines and human breast cancer tissues. We found that overexpression of Notch3 intra-cellular domain, a Notch3 active form (N3ICD), in ERalpha negative breast cancer cells re-activated ERalpha, while knock-down of Notch3 reduced ERalpha transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ERalpha. Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ERalpha promoter and activates ERalpha expression. Moreover, Notch3 suppressed EMT, while suppression of Notch3 promoted EMT in cellular assay. Overexpressing N3ICD in triple-negative breast cancer suppressed tumorigenesis and metastasis in vivo. Conversely, depletion of Notch3 in luminal breast cancer promoted metastasis in vivo. Furthermore, Notch3 transcripts were significantly associated with prolonged relapse-free survival in breast cancer, in particular in ERalpha positive breast cancer patients. Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ERalpha expression in breast cancer. These findings delineate the role of a Notch3/ERalpha axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ERalpha negative or low-expressing breast cancers to hormone therapy. PMID- 29109798 TI - Multiplexed Nucleic Acid Programmable Protein Arrays. AB - Rationale: Cell-free protein microarrays display naturally-folded proteins based on just-in-time in situ synthesis, and have made important contributions to basic and translational research. However, the risk of spot-to-spot cross-talk from protein diffusion during expression has limited the feature density of these arrays. Methods: In this work, we developed the Multiplexed Nucleic Acid Programmable Protein Array (M-NAPPA), which significantly increases the number of displayed proteins by multiplexing as many as five different gene plasmids within a printed spot. Results: Even when proteins of different sizes were displayed within the same feature, they were readily detected using protein-specific antibodies. Protein-protein interactions and serological antibody assays using human viral proteome microarrays demonstrated that comparable hits were detected by M-NAPPA and non-multiplexed NAPPA arrays. An ultra-high density proteome microarray displaying > 16k proteins on a single microscope slide was produced by combining M-NAPPA with a photolithography-based silicon nano-well platform. Finally, four new tuberculosis-related antigens in guinea pigs vaccinated with Bacillus Calmette-Guerin (BCG) were identified with M-NAPPA and validated with ELISA. Conclusion: All data demonstrate that multiplexing features on a protein microarray offer a cost-effective fabrication approach and have the potential to facilitate high throughput translational research. PMID- 29109800 TI - Exploring Effects of Sex and Diet on Drosophila melanogaster Head Gene Expression. AB - Gene expression depends on sex and environment. We stringently explored the contributions of these effects in Drosophila melanogaster by rearing three distinct wildtype genotypes on isocaloric diets either high in protein or sugar followed by expression profiling of heads from the sexes. By using different genotypes as replicates we developed robust sex- and diet-biased expression responses. PMID- 29109801 TI - The Osteometry of Equine Third Phalanx by the Use of Three-Dimensional Scanning: New Measurement Possibilities. AB - This study consisted in analyzing the asymmetry between bilateral third phalanges (coffin bones) in cold-blood horses based on the angle range of the plantar margin of the bone. The study employed a scanner projecting a hybrid set of images, consisting of sinusoidal stripes preceded by a Gray code sequence. As it turned out, three-dimensional scanning can be used to effectively determine the angle range for a selected portion of the studied bone. This provides broad possibilities for osteometric studies, as it enables the determination of angle distribution in a given fragment. The results obtained indicate a weak correlation between age and bilateral third-phalanx asymmetry in terms of the angle range of the plantar margins and no correlation between body weight and the asymmetry described. PMID- 29109802 TI - Effect of Ta Additions on the Microstructure, Damping, and Shape Memory Behaviour of Prealloyed Cu-Al-Ni Shape Memory Alloys. AB - The influence of Ta additions on the microstructure and properties of Cu-Al-Ni shape memory alloys was investigated in this paper. The addition of Ta significantly affects the green and porosity densities; the minimum percentage of porosity was observed with the modified prealloyed Cu-Al-Ni-2.0 wt.% Ta. The phase transformation temperatures were shifted towards the highest values after Ta was added. Based on the damping capacity results, the alloy of Cu-Al-Ni-3.0 wt.% Ta has very high internal friction with the maximum equivalent internal friction value twice as high as that of the prealloyed Cu-Al-Ni SMA. Moreover, the prealloyed Cu-Al-Ni SMAs with the addition of 2.0 wt.% Ta exhibited the highest shape recovery ratio in the first cycle (i.e., 100% recovery), and when the number of cycles is increased, this ratio tends to decrease. On the other hand, the modified alloys with 1.0 and 3.0 wt.% Ta implied a linear increment in the shape recovery ratio with increasing number of cycles. Polarization tests in NaCl solution showed that the corrosion resistance of Cu-Al-Ni-Ta SMA improved with escalating Ta concentration as shown by lower corrosion current densities, higher corrosion potential, and formation of stable passive film. PMID- 29109803 TI - Effect of Fluoride Varnish Containing CPP-ACP on Preventing Enamel Erosion. AB - This study aimed to investigate the effect of a fluoride varnish with added casein phosphopeptide-amorphous calcium phosphate treatment on the prevention of enamel erosion, and it compared the results with those of other fluoride varnishes. Fifty enamel specimens obtained from bovine incisors were randomly divided into five groups (n = 10) based on the type of surface pretreatment used: intact enamel (Group 1); intact enamel+erosive cycles (Group 2); intact enamel+MI varnish+erosive cycles (Group 3); intact enamel+Clinpro White varnish+erosive cycles (Group 4); and intact enamel+Duraphat varnish+erosive cycles (Group 5). The specimens were subjected to erosive cycles for five days. The surface roughness was evaluated using atomic force microscopy. The results were statistically analyzed using one-way ANOVA and Tukey's tests. Group 1 had the smoothest surfaces. After the erosive cycles, the greatest surface roughness values were observed in Group 2, followed by Groups 5, 4, and 3, respectively. Statistically significant differences were observed among all groups (p < 0.05). The application of fluoride varnishes had some positive effects on preventing enamel erosion; however, the most effective agent was fluoride varnish with added casein phosphopeptide-amorphous calcium phosphate. PMID- 29109804 TI - Effects of Tumor Necrosis Factor-alpha on Morphology and Mechanical Properties of HCT116 Human Colon Cancer Cells Investigated by Atomic Force Microscopy. AB - Chronic inflammation orchestrates the tumor microenvironment and is strongly associated with cancer. Tumor necrosis factor-alpha (TNFalpha) is involved in tumor invasion and metastasis by inducing epithelial to mesenchymal transition (EMT). This process is defined by the loss of epithelial characteristics and gain of mesenchymal traits. The mechanisms of TNFalpha-induced EMT in cancer cells have been well studied. However, mechanical properties have not yet been probed. In this work, atomic force microscopy (AFM) was applied to investigate the morphology and mechanical properties of EMT in HCT116 human colon cancer cells. A remarkable morphological change from cobblestone shape to spindle-like morphology was observed. In parallel, AFM images showed that the cellular cytoskeleton was rearranged from a cortical to a stress-fiber pattern. Moreover, cell stiffness measurements indicated that Young's modulus of cells gradually reduced from 1 to 3 days with TNFalpha-treatment, but it has an apparent increase after 4 days of treatment compared with that for 3 days. Additionally, Young's modulus of the cells treated with TNFalpha for 4 days is slightly larger than that for 1 or 2 days, but still less than that of the untreated cells. Our work contributes to a better understanding of colorectal cancer metastasis induced by inflammation. PMID- 29109805 TI - Experimental Study on the Behavior of TiN and Ti2O3 Inclusions in Contact with CaO-Al2O3-SiO2-MgO Slags. AB - TiN and Ti2O3 are the predominant inclusion types in Ti-alloyed ferritic chromium stainless steels. In order to ensure the required steel cleanness level, an effective removal of such inclusions in the slag during secondary metallurgy is essential. This inclusion removal predominantly takes place via dissolution of the inclusion in the slag. The dissolution behavior of TiN and Ti2O3 in CaO-SiO2 Al2O3-MgO slags as well as their agglomeration behavior in the liquid steel is investigated using High Temperature Laser Scanning Confocal Microscopy and Tammann Furnace experiments. Thermodynamic calculations are performed using FactSage 7.0. The behavior of TiN is observed to be completely different to that of oxides. Ti2O3 dissolves quickly in slags, and its dissolution behavior is comparable to that of other already well examined oxides. In contrast, TiN shows a very intense gas reaction which is attributed to the release of nitrogen during contact with slag. Slags with higher SiO2 content show a significantly higher ability for the dissolution of TiN as compared to Al2O3-rich slags. The gas reaction is found to also significantly influence the final steel cleanness. Despite the easy absorption of TiN in the slag, the formed nitrogen supports the formation of pinholes in the steel. PMID- 29109806 TI - Growth and Characterization of M-Plane GaN Thin Films Grown on gamma-LiAlO2 (100) Substrates. AB - M-plane GaN thin films were grown on LiAlO2 substrates under different N/Ga flux ratios by plasma-assisted molecular beam epitaxy. An anisotropic growth of M plane GaN was demonstrated against the N/Ga flux ratio. As the N/Ga flux ratio decreased by increasing Ga flux, the GaN surface trended to a flat morphology with stripes along [11[Formula: see text]0]. According to high-resolution X-ray diffraction analysis, Li5GaO4 was observed on the interface between GaN and LiAlO2 substrate. The formation of Li5GaO4 would influence the surface morphology and crystal quality. PMID- 29109807 TI - Ultrasonic Spray Pyrolysis Deposited Copper Sulphide Thin Films for Solar Cell Applications. AB - Polycrystalline copper sulphide (Cu x S) thin films were grown by ultrasonic spray pyrolysis method using aqueous solutions of copper chloride and thiourea without any complexing agent at various substrate temperatures of 240, 280, and 320 degrees C. The films were characterized for their structural, optical, and electrical properties by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive analysis of X-rays (EDAX), atomic force microscopy (AFM), contact angle (CA), optical absorption, and current-voltage (I-V) measurements. The XRD analysis showed that the films had single or mixed phase polycrystalline nature with a hexagonal covellite and cubic digenite structure. The crystalline phase of the films changed depending on the substrate temperature. The optical band gaps (Eg ) of thin films were 2.07 eV (CuS), 2.50 eV (Cu1.765S), and 2.28 eV (Cu1.765S-Cu2S). AFM results indicated that the films had spherical nanosized particles well adhered to the substrate. Contact angle measurements showed that the thin films had hydrophobic nature. Hall effect measurements of all the deposited Cu x S thin films demonstrated them to be of p type conductivity, and the current-voltage (I-V) dark curves exhibited linear variation. PMID- 29109808 TI - SEM Analysis of Surface Impact on Biofilm Antibiotic Treatment. AB - The aim of this work was to use scanning electron microscopy (SEM) to investigate the effect of ampicillin treatment on Escherichia coli biofilms formed on two surface materials with different properties, silicone (SIL) and glass (GLA). Epifluorescence microscopy (EM) was initially used to assess biofilm formation and killing efficiency on both surfaces. This technique showed that higher bacterial colonization was obtained in the hydrophobic SIL than in the hydrophilic GLA. It has also shown that higher biofilm inactivation was attained for GLA after the antibiotic treatment (7-log reduction versus 1-log reduction for SIL). Due to its high resolution and magnification, SEM enabled a more detailed analysis of the antibiotic effect on biofilm cells, complementing the killing efficiency information obtained by EM. SEM micrographs revealed that ampicillin-treated cells have an elongated form when compared to untreated cells. Additionally, it has shown that different materials induced different levels of elongation on cells exposed to antibiotic. Biofilms formed on GLA showed a 37% higher elongation than those formed on SIL. Importantly, cell elongation was related to viability since ampicillin had a higher bactericidal effect on GLA formed biofilms. These findings raise the possibility of using SEM for understanding the efficacy of antimicrobial treatments by observation of biofilm morphology. PMID- 29109809 TI - Automated Axis Alignment for a Nanomanipulator inside SEM and Its Error Optimization. AB - In the motion of probing nanostructures, repeating position and movement is frequently happing and tolerance for position error is stringent. The consistency between the axis of manipulators and image is very significant since the visual servo is the most important tool in the automated manipulation. This paper proposed an automated axis alignment method for a nanomanipulator inside the SEM by recognizing the position of a closed-loop controlling the end-effector, which can characterize the relationship of these two axes, and then the rotation matrix can be calculated accordingly. The error of this method and its transfer function are also calculated to compare the iteration method and average method. The method in this paper can accelerate the process of axis alignment to avoid the electron beam induced deposition effect on the end tips. Experiment demonstration shows that it can achieve a 0.1-degree precision in 90 seconds. PMID- 29109810 TI - Microscopic Examination of Cold Spray Cermet Sn+In2O3 Coatings for Sputtering Target Materials. AB - Low-pressure cold spraying is a newly developed technology with high application potential. The aim of this study was to investigate potential application of this technique for producing a new type of transparent conductive oxide films target. Cold spraying technique allows the manufacture of target directly on the backing plate; therefore the proposed sputtering target has a form of Sn+In2O3 coating sprayed onto copper substrate. The microstructure and properties of the feedstock powder prepared using three various methods as well as the deposited ones by low pressure cold spraying coatings were evaluated, compared, and analysed. Produced cermet Sn+In2O3 targets were employed in first magnetron sputtering process to deposit preliminary, thin, transparent conducting oxide films onto the glass substrates. The resistivity of obtained preliminary films was measured and allows believing that fabrication of TCO (transparent conducting oxide) films using targets produced by cold spraying is possible in the future, after optimization of the deposition conditions. PMID- 29109811 TI - Characterization of Dielectric Nanocomposites with Electrostatic Force Microscopy. AB - Nanocomposites physical properties unexplainable by general mixture laws are usually supposed to be related to interphases, highly present at the nanoscale. The intrinsic dielectric constant of the interphase and its volume need to be considered in the prediction of the effective permittivity of nanodielectrics, for example. The electrostatic force microscope (EFM) constitutes a promising technique to probe interphases locally. This work reports theoretical finite elements simulations and experimental measurements to interpret EFM signals in front of nanocomposites with the aim of detecting and characterizing interphases. According to simulations, we designed and synthesized appropriate samples to verify experimentally the ability of EFM to characterize a nanoshell covering nanoparticles, for different shell thicknesses. This type of samples constitutes a simplified electrostatic model of a nanodielectric. Experiments were conducted using either DC or AC-EFM polarization, with force gradient detection method. A comparison between our numerical model and experimental results was performed in order to validate our predictions for general EFM-interphase interactions. PMID- 29109812 TI - Nanoscale Mechanical Properties of Nanoindented Ni48.8Mn27.2Ga24 Ferromagnetic Shape Memory Thin Film. AB - The structure and nanoscale mechanical properties of Ni48.8Mn27.2Ga24 thin film fabricated by DC magnetron sputtering are investigated systematically. The thin film has the austenite state at room temperature with the L21 Hesuler structure. During nanoindentation, stress-induced martensitic transformation occurs on the nanoscale for the film annealed at 823 K for 1 hour and the shape recovery ratio is up to 85.3%. The associated mechanism is discussed. PMID- 29109813 TI - Relationship between Microstructure and Properties of Cu-Cr-Ag-(Ce) Alloy Using Microscopic Investigation. AB - Microstructure, precipitation hardening response, and mechanical and physical properties of Cu-Cr-Ag alloy and Cu-Cr-Ag-Ce alloy have been investigated using transmission electron microscopy, scanning electron microscope, optical microscope, electrical conductivity analysis, and tensile test. The influence of element Ce on the matrix refinement, impurity removal, and precipitation in the Cu-Cr-Ag alloys has been analyzed. The experimental results show that the strength and electrical conductivity of Ce containing alloys are greater than those of Ce-free alloys after each processing step. Improvement of strength and electrical conductivity of the Cu-Cr-Ag alloy by adding Ce element is attributed to removing oxygen and sulfur from as-cast alloy. PMID- 29109815 TI - Description of Changes in Crystal Orientations by the Elements of Logarithm of a Rotation Matrix. AB - The logarithm ln?R of rotation matrix R is a skew symmetric tensor consisting of three independent elements of real numbers. In addition to the Euler angles and the axis/angle pair, the elements of ln?R called the log angles are also the set of three parameters of R. In this paper, we will show that the concept of the log angles is also useful to discuss changes in crystal orientations. The changes in R as a function of the position are given by the changes in the log angles. As an example, orientation changes caused by arrays of dislocations in a plastically deformed Cu single crystal are discussed. PMID- 29109814 TI - Evaluation of Dentin Defect Formation during Retreatment with Hand and Rotary Instruments: A Micro-CT Study. AB - The purpose of this study was to compare the incidence and longitudinal propagation of dentin defects after gutta-percha removal with hand and rotary instruments using microcomputed tomography. Twenty mandibular incisors were prepared using the balanced-force technique and scanned in a 19.9 MUm resolution. Following filling with the lateral compaction technique, gutta-percha was removed with ProTaper Universal Retreatment (PTUR) or hand instruments. After rescanning, a total of 24,120 cross-sectional images were analyzed. The numbers, types, and longitudinal length changes of defects were recorded. Defects were observed in 36.90% of the cross sections. A total of 73 defects were comprised of 87.67% craze lines, 2.73% partial cracks, and 9.58% fractures. No significant difference in terms of new defect formation was detected between the retreatment groups. The apical and middle portions of the roots had more dentin defects than the coronal portions. Defects in three roots of the PTUR instrument group increased in length. Under the conditions of this in vitro study, gutta-percha removal seemed to not increase the incidence of dentin defect formation, but the longitudinal defect propagation finding suggests possible cumulative dentinal damage due to additional endodontic procedures. Hand and rotary instrumentation techniques caused similar dentin defect formation during root canal retreatment. PMID- 29109816 TI - Contrast of Backscattered Electron SEM Images of Nanoparticles on Substrates with Complex Structure. AB - This study is concerned with backscattered electron scanning electron microscopy (BSE SEM) contrast of complex nanoscaled samples which consist of SiO2 nanoparticles (NPs) deposited on indium-tin-oxide covered bulk SiO2 and glassy carbon substrates. BSE SEM contrast of NPs is studied as function of the primary electron energy and working distance. Contrast inversions are observed which prevent intuitive interpretation of NP contrast in terms of material contrast. Experimental data is quantitatively compared with Monte-Carlo- (MC-) simulations. Quantitative agreement between experimental data and MC-simulations is obtained if the transmission characteristics of the annular semiconductor detector are taken into account. MC-simulations facilitate the understanding of NP contrast inversions and are helpful to derive conditions for optimum material and topography contrast. PMID- 29109817 TI - Diagnosis of the Diatom Community upon Biofilm Development on Stainless Steels in Natural Freshwater. AB - This paper reports the development of biofilms on stainless steels (SS) upon exposure in a natural freshwater ecosystem for about six months and focuses on the composition of diatom populations. By using environmental scanning electron microscopy (ESEM) technique, we provide a detailed description regarding diatom identification at species level as well as their main characteristics, including type, morphology, ability to form colony, and motility. Results reveal the presence of both prostrate (initial colonizers) and stalked (late colonizers) forms. Pennate diatoms, Cocconeis placentula and Amphora coffeaeformis, and a centric diatom, Melosira varians, are shown to be the abundant forms regardless of the SS type. Pennate diatoms dominate the community and are directly attached to the substratum, whereas the centric form is entangled in the biofilm matrix in a significant number. The dominance of adnate forms suggests that these cells are sturdy and successfully maintaining their population. In situ monitoring of the electrochemical response of immersed materials showed ennoblement of the open circuit potential, which seems to be due to the biogenic production of H2O2, detected in a significant amount within the biofilms. The substantial enrichment of biofilms with diatoms potentially suggests the implication of these microorganisms in the process of ennoblement. A mechanism is proposed in this paper describing the possible interactions of diatom community with SS in the studied ecosystem. PMID- 29109818 TI - Effect of Red Light-Emitting Diodes Irradiation on Hemoglobin for Potential Hypertension Treatment Based on Confocal Micro-Raman Spectroscopy. AB - Red light-emitting diodes (LED) were used to irradiate the isolated hypertension hemoglobin (Hb) and Raman spectra difference was recorded using confocal micro Raman spectroscopy. Differences were observed between the controlled and irradiated Hb by comparing the spectra records. The Raman spectrum at the 1399 cm 1 band decreased following prolonged LED irradiation. The intensity of the 1639 cm-1 band decreased dramatically in the first five minutes and then gradually increased in a time-dependent manner. This observation indicated that LED irradiation increased the ability of oxygen binding in Hb. The appearance of the heme aggregation band at 1399 cm-1, in addition to the oxygen marker band at 1639 cm-1, indicated that, in our study, 30 min of irradiation with 15.0 mW was suitable for inhibiting heme aggregation and enhancing the oxygen-carrying capacity of Hb. Principal component analysis showed a one-to-one relationship between irradiated Hb at different time points and the corresponding Raman spectra. Our approach could be used to analyze the hemoglobin from patients with confocal micro-Raman spectroscopy and is helpful for developing new nondrug hypertension therapy. PMID- 29109819 TI - Characterization of the Resistance and Force of a Carbon Nanotube/Metal Side Contact by Nanomanipulation. AB - A high contact resistance restricts the application of carbon nanotubes (CNTs) in fabrication of field-effect transistors (FETs). Thus, it is important to decrease the contact resistance and investigate the critical influence factors such as the contact length and contact force. This study uses nanomanipulation to characterize both the resistance and the force at a CNT/Au side-contact interface inside a scanning electron microscopy (SEM). Two-terminal CNT manipulation methods, and models for calculating the resistance and force at contact area, are proposed to guide the measurement experiments of a total resistance and a cantilever's elastic deformation. The experimental results suggest that the contact resistance of CNT/Au interface is large (189.5 kOmega) when the van der Waals force (282.1 nN) dominates the contact force at the interface. Electron beam-induced deposition (EBID) is then carried out to decrease the contact resistance. After depositing seven EBID points, the resistance is decreased to 7.5 kOmega, and the force increases to 1339.8 nN at least. The resistance and force at the contact area where CNT was fixed exhibit a negative exponential correlation before and after EBID. The good agreement of this correlation with previous reports validates the proposed robotic system and methods for characterizing the contact resistance and force. PMID- 29109820 TI - Time of Application of Sodium Ascorbate on Bonding to Bleached Dentin. AB - This study examined the effects of different application times of sodium ascorbate (SA) on the bond strength of composite resin to bleached dentin. Specimens with an exposed dentin surface were divided into 3 groups according to the type of bleaching agent used: Group A, mixture of sodium perborate (SP) and distilled water (DW); Group B, mixture of SP and hydrogen peroxide (HP); control group, no bleaching. Each group was classified into 10 subgroups. Subgroups IB and DB underwent immediate bonding and delayed bonding, respectively. 10% SA was applied to 3, 5, 10, and 30 minutes and 1, 24, 48, and 72 hours, respectively. Microtensile bond strength (MUTBS) was measured after restoration, and the data was analyzed by one-way ANOVA and Scheffe's test. Before restoration, the dentin surfaces were examined by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). SEM showed that most dentin surfaces were filled with crystals when SA was applied to more than 24 hours. EDS revealed peaks of calcium, carbon, oxygen, and sodium. The application of SA for 5 minutes to 48 hours or for 30 minutes to 24 hours is suggested when a mixture of SP and DW or HP is used, respectively. PMID- 29109821 TI - In Situ SEM Torsion Test of Metallic Glass Microwires Based on Micro Robotic Manipulation. AB - Microwires, such as metallic, semiconductor, and polymer microwires and carbon fibers, have stimulated great interest due to their importance in various structural and functional applications. Particularly, metallic glass (MG) microwires, because of their amorphous atoms arrangement, have some unique mechanical properties compared with traditional metals. Despite the fact that substantial research efforts have been made on the mechanical characterizations of metallic glass microwires under tension or flexural bending, the mechanical properties of microwires under torsional loading have not been well studied, mainly due to the experimental difficulties, such as the detection of torsion angle, quantitative measurement of the torsional load, and the alignment between the specimen and torque meter. In this work, we implemented the in situ SEM torsion tests of individual La50Al30Ni20 metallic glass (MG) microwires successfully based on a self-developed micro robotic mechanical testing system. Unprecedented details, such as the revolving vein-pattern along the torsion direction on MG microwires fracture surface, were revealed. Our platform could provide critical insights into understanding the deformation mechanisms of other microwires under torsional loading and can even be further used for robotic micromanufacturing. PMID- 29109822 TI - The Effect of Various Types of Mechanical and Chemical Preconditioning on the Shear Bond Strength of Orthodontic Brackets on Zirconia Restorations. AB - The purpose of this study was to investigate the combined effect of mechanical and chemical treatments on the shear bond strength (SBS) of metal orthodontic brackets on zirconia restoration. The zirconia specimens were randomly divided into 12 groups (n = 10) according to three factors: AL (Al2O3) and CO (CoJetTM) by sandblasting material; SIL (silane), ZPP (Zirconia Prime Plus), and SBU (Single Bond Universal) by primer; and N (not thermocycled) and T (thermocycled). The specimens were evaluated for shear bond strength, and the fractured surfaces were observed using a stereomicroscope. Scanning electron microscopy images were also obtained. CO-SBU combination had the highest bond strength after thermocycling (26.2 MPa). CO-SIL showed significantly higher SBS than AL-SIL (p < 0.05). CO-ZPP resulted in lower bond strength than AL-ZPP before thermocycling, but the SBS increased after thermocycling (p > 0.05). Modified Adhesive Remnant Index (ARI) scoring and SEM figures were consistent with the results of the surface treatments. In conclusion, CO-SBU, which combines the effect of increased surface area and chemical bonding with both 10-MDP and silane, showed the highest SBS. Sandblasting with either material improved the mechanical bonding by increasing the surface area, and all primers showed clinically acceptable increase of shear bond strength for orthodontic treatment. PMID- 29109823 TI - Numerical Study of Hydrodynamic Forces for AFM Operations in Liquid. AB - For advanced atomic force microscopy (AFM) investigation of chemical surface modifications or very soft organic sample surfaces, the AFM probe tip needs to be operated in a liquid environment because any attractive or repulsive forces influenced by the measurement environment could obscure molecular forces. Due to fluid properties, the mechanical behavior of the AFM cantilever is influenced by the hydrodynamic drag force due to viscous friction with the liquid. This study provides a numerical model based on computational fluid dynamics (CFD) and investigates the hydrodynamic drag forces for different cantilever geometries and varying fluid conditions for Peakforce Tapping (PFT) in liquids. The developed model was verified by comparing the predicted values with published results of other researchers and the findings confirmed that drag force dependence on tip speed is essentially linear in nature. We observed that triangular cantilever geometry provides significant lower drag forces than rectangular geometry and that short cantilever offers reduced flow resistance. The influence of different liquids such as ultrapure water or an ethanol-water mixture as well as a temperature induced variation of the drag force could be demonstrated. The acting forces are lowest in ultrapure water, whereas with increasing ethanol concentrations the drag forces increase. PMID- 29109824 TI - u-XRF Studies on the Colour Brilliance in Ancient Wool Carpets. AB - Many handmade ancient and recent oriental wool carpets show outstanding brilliance and persistence of colour that is not achieved by common industrial dyeing procedures. Anthropologists have suggested the influence of wool fermentation prior to dyeing as key technique to achieve the high dyeing quality. By means of MU-XRF elemental mapping of mordant metals we corroborate this view and show a deep and homogenous penetration of colourants into fermented wool fibres. Furthermore we are able to apply this technique and prove that the fermentation process for ancient specimens cannot be investigated by standard methods due to the lack of intact cuticle layers. This finding suggests a broad range of further investigations that will contribute to a deeper understanding of the development of traditional dyeing techniques. Spectroscopic studies add information on the oxidation states of the metal ions within the respective mordant-dye-complexes and suggest a partial charge transfer as basis for a significant colour change when Fe mordants are used. PMID- 29109825 TI - Manipulations of Wavefront Propagation: Useful Methods and Applications for Interferometric Measurements and Scanning. AB - Phase measurements obtained by high-coherence interferometry are restricted by the 2pi ambiguity, to height differences smaller than lambda/2. A further restriction in most interferometric systems is for focusing the system on the measured object. We present two methods that overcome these restrictions. In the first method, different segments of a measured wavefront are digitally propagated and focused locally after measurement. The divergent distances, by which the diverse segments of the wavefront are propagated in order to achieve a focused image, provide enough information so as to resolve the 2pi ambiguity. The second method employs an interferogram obtained by a spectrum constituting a small number of wavelengths. The magnitude of the interferogram's modulations is utilized to resolve the 2pi ambiguity. Such methods of wavefront propagation enable several applications such as focusing and resolving the 2pi ambiguity, as described in the article. PMID- 29109826 TI - Application of Environmental Scanning Electron Microscope-Nanomanipulation System on Spheroplast Yeast Cells Surface Observation. AB - The preparation and observations of spheroplast W303 cells are described with Environmental Scanning Electron Microscope (ESEM). The spheroplasting conversion was successfully confirmed qualitatively, by the evaluation of the morphological change between the normal W303 cells and the spheroplast W303 cells, and quantitatively, by determining the spheroplast conversion percentage based on the OD800 absorbance data. From the optical microscope observations as expected, the normal cells had an oval shape whereas spheroplast cells resemble a spherical shape. This was also confirmed under four different mediums, that is, yeast peptone-dextrose (YPD), sterile water, sorbitol-EDTA-sodium citrate buffer (SCE), and sorbitol-Tris-Hcl-CaCl2 (CaS). It was also observed that the SCE and CaS mediums had a higher number of spheroplast cells as compared to the YPD and sterile water mediums. The OD800 absorbance data also showed that the whole W303 cells were fully converted to the spheroplast cells after about 15 minutes. The observations of the normal and the spheroplast W303 cells were then performed under an environmental scanning electron microscope (ESEM). The normal cells showed a smooth cell surface whereas the spheroplast cells had a bleb-like surface after the loss of its integrity when removing the cell wall. PMID- 29109827 TI - Registration of Partially Focused Images for 2D and 3D Reconstruction of Oversized Samples. AB - Methods of fracture surface 3D reconstruction from a series of partially focused images acquired in a small field of view (e.g., by confocal microscope or CCD camera) are well known. In this case, projection rays can be considered parallel and recorded images do not differ in any geometrical transformation from each other. In the case of larger samples (oversized for microscope or CCD camera), it is necessary to use a wider viewing field (e.g., standard cameras); taken images primarily differ in scaling but may also differ in shifting and rotation. These images cannot be used for reconstruction directly; they must be registered; that is, we must determine all transformations in which the images differ and eliminate their effects. There are several ways to do this. This paper deals with the registration based on phase correlation. PMID- 29109828 TI - Enhancement of Dye-Sensitized Solar Cells Efficiency Using Mixed-Phase TiO2 Nanoparticles as Photoanode. AB - Dye-sensitized solar cell (DSSC) is a potential candidate to replace conventional silicon-based solar cells because of high efficiency, cheap cost, and lower energy consumption in comparison with silicon chip manufacture. In this report, mixed-phase (anatase and rutile nanoparticles) TiO2 photoanode was synthesized to investigate material characteristics, carriers transport, and photovoltaic performance for future DSSC application. Field-emission scanning electron microscope (SEM), X-ray diffraction (XRD), photoluminescence (PL), and UV-visible spectroscopy were used to characterize mixed TiO2 particles. Subsequently, various mixed-phase TiO2 anodes in DSSC devices were measured by electrical impedance spectra (EIS) and energy efficiency conversion. The overall energy conversion efficiency of DSSC chip was improved as a result of the increase of rutile phase of TiO2 (14%) in anatase matrix. Synergistic effects including TiO2 crystallization, reduction of defect density level in energy band, longer lifetime of photoexcited electrons, and lower resistance of electron pathway all contributed to high efficiency of light energy conversion. PMID- 29109829 TI - Cytotoxicity of Etch-and-Rinse, Self-Etch, and Universal Dental Adhesive Systems in Fibroblast Cell Line 3T3. AB - The aim of this study was to evaluate in fibroblast cultures the direct cytotoxic effects of etch-and-rinse, self-etch, and universal adhesive systems. The sterile glass cover slips (n = 3) were then immersed in culture medium to obtain the eluates for the experimental groups: (1) AdperTM Single Bond 2; (2) Ambar; (3) AdperTM ScotchbondTM Multi-Purpose; (4) ScotchbondTM Universal; (5) Ambar Universal; and (6) OptiBond All-In-One. As a negative control, sterile glass cover slips were immersed in culture medium only. After 24 h, the eluate obtained was applied on fibroblast culture. Cell viability and cell morphology were evaluated by MTT assay and SEM, respectively. Data were analyzed by Kruskal Wallis and Mann-Whitney tests (alpha = 0.05). All adhesive systems except universal reduced cell viability in 3T3 cells to between 26.04% and 56.57%, and Scotchbond Universal and Ambar Universal reduced cell viability to 2.13% and 3.57%, respectively, when compared to the negative control. Cytoplasmic membrane shrinkage and cell-free areas with residual membrane fragments from dead cells were observed. In conclusion, improvements in universal adhesive system formulations and their mechanisms of action are not accompanied by increased toxicity compared with those in other systems, warranting commitment to the use of these dentin-pulp complexes. PMID- 29109830 TI - Cross-Sectional Information on Pore Structure and Element Distribution of Sediment Particles by SEM and EDS. AB - The interaction between pollutants and sediment particles often occurs on the particle surface, so surface properties directly affect surface reaction. The physical and chemical processes occurring on sediment particle surfaces are microscopic processes and as such need to be studied from a microscopic perspective. In this study, field emission scanning electron microscopy (SEM) and energy dispersive X-ray spectrometer (EDS) were adopted to observe and analyze the pore structure and element distribution of sediment particles. In particular, a special method of sample preparation was used to achieve the corresponding cross-sectional information of sediment particles. Clear images of a particle profile and pore microstructure were obtained by high-resolution SEM, while element distribution maps of sediment particles were obtained by EDS. The results provide an intuitive understanding of the internal microenvironment and external behavior of sediment particles, in addition to revealing a significant role of pore microstructure in the adsorption and desorption of pollutants. Thus, a combination of different experimental instruments and observation methods can provide real images and information on microscopic pore structure and element distribution of sediment particles. These results should help to improve our understanding of sediment dynamics and its environmental effects. PMID- 29109833 TI - Magnesium and Other Biometals in Oxidative Medicine and Redox Biology. PMID- 29109832 TI - Cardioprotective Effect of Resveratrol in a Postinfarction Heart Failure Model. AB - Despite great advances in therapies observed during the last decades, heart failure (HF) remained a major health problem in western countries. In order to further improve symptoms and survival in patients with heart failure, novel therapeutic strategies are needed. In some animal models of HF resveratrol (RES), it was able to prevent cardiac hypertrophy, contractile dysfunction, and remodeling. Several molecular mechanisms are thought to be involved in its protective effects, such as inhibition of prohypertrophic signaling molecules, improvement of myocardial Ca2+ handling, regulation of autophagy, and the reduction of oxidative stress and inflammation. In our present study, we wished to further examine the effects of RES on prosurvival (Akt-1, GSK-3beta) and stress signaling (p38-MAPK, ERK 1/2, and MKP-1) pathways, on oxidative stress (iNOS, COX-2 activity, and ROS formation), and ultimately on left ventricular function, hypertrophy and fibrosis in a murine, and isoproterenol- (ISO-) induced postinfarction heart failure model. RES treatment improved left ventricle function, decreased interstitial fibrosis, cardiac hypertrophy, and the level of plasma BNP induced by ISO treatment. ISO also increased the activation of P38 MAPK, ERK1/2Thr183-Tyr185, COX-2, iNOS, and ROS formation and decreased the phosphorylation of Akt-1, GSK-3beta, and MKP-1, which were favorably influenced by RES. According to our results, regulation of these pathways may also contribute to the beneficial effects of RES in HF. PMID- 29109831 TI - MicroRNA-93 Regulates Hypoxia-Induced Autophagy by Targeting ULK1. AB - The expression of the core autophagy kinase, Unc51-like kinase 1 (ULK1), is regulated transcriptionally and translationally by starvation-induced autophagy. However, how ULK1 is regulated during hypoxia is not well understood. Previously, we showed that ULK1 expression is induced by hypoxia stress. Here, we report a new ULK1-modulating microRNA, miR-93; its transcription is negatively correlated with the translation of ULK1 under hypoxic condition. miR-93 targets ULK1 and reduces its protein levels under hypoxia condition. miR-93 also inhibits hypoxia induced autophagy by preventing LC3-I to LC3-II transition and P62 degradation; these processes are reversed by the overexpression of an endogenous miR-93 inhibitor. Re-expression of ULK1 without miR-93 response elements restores the hypoxia-induced autophagy which is inhibited by miR-93. Finally, we detected the effects of miR-93 on cell viability and apoptosis in noncancer cell lines and cancer cells. We found that miR-93 sustains the viability of MEFs (mouse embryonic fibroblasts) and inhibits its apoptosis under hypoxia. Thus, we conclude that miR-93 is involved in hypoxia-induced autophagy by regulating ULK1. Our results provide a new angle to understand the complicated regulation of the key autophagy kinase ULK1 during different stress conditions. PMID- 29109834 TI - Mechanism of Mechanical Trauma-Induced Extracellular Matrix Remodeling of Fibroblasts in Association with Nrf2/ARE Signaling Suppression Mediating TGF beta1/Smad3 Signaling Inhibition. AB - Stress urinary incontinence (SUI) is a common hygienic problem affecting the quality of women's life worldwide. In this research, we revealed the involvement and regulation of extracellular matrix (ECM) remodeling, oxidative damage, and TGF-beta1 signaling in the pathological mechanisms of mechanical trauma-induced SUI. We found that excessive mechanical strain significantly increased apoptosis rate, decreased cell viability and ECM production, and broke the balance of MMPs/TIMPs compared with the nonstrain control (NC) group. The expression levels of TGFbeta1, p-Smad3, Nrf2, GPx1, and CAT were downregulated, the production of ROS, 8-OHdG, 4-HNE, and MDA was increased, and the nuclear translocation of Smad2/3 was suppressed after 5333 MUstrain's treatment. Both mTGF-beta1 pretreatment and Nrf2 overexpression could reverse mechanical injury-induced TGFbeta1/Smad3 signaling inhibition and ECM remodeling, whereas mTGF-beta1 had no effect on Nrf2 expression. Nrf2 overexpression significantly alleviated mechanical injury-induced ROS accumulation and oxidative damage; in contrast, Nrf2 silencing exhibited opposite effects. Besides, vaginal distention- (VD-) induced in vivo SUI model was used to confirm the in vitro results; Nrf2 knockout aggravates mechanical trauma-induced LPP reduction, ECM remodeling, oxidative damage, and TGF-beta1/Smad3 suppression in mice. Therefore, we deduce that mechanical injury-induced ECM remodeling might be associated with Nrf2/ARE signaling suppression mediating TGF-beta1/Smad3 signaling inhibition. This might reflect a new molecular target for SUI researches. PMID- 29109835 TI - Anterior Submandibular Approach for Transmylohyoid Endotracheal Intubation: A Reappraisal with Prospective Study in 206 Cases of Craniomaxillofacial Fractures. AB - Despite a paradigm shift in anesthesia and trauma airway management, the craniomaxillofacial fracture (CMF) patients continue to pose a challenge. A prospective study was planned between April 2007 and March 2015 to investigate the safety, efficacy, utility, and complications of anterior submandibular approach for transmylohyoid intubation (TMI) in CMFs using an armored endotracheal tube (ETT). Out of 1,207 maxillofacial trauma cases reported, this study recruited 206 patients (152 males and 54 females) aged between 21 and 60 years. No episode of oxygen desaturation was noted intraoperatively. Mean time to perform TMI was 6 +/- 2 minutes. The mean transmylohyoid ETT withdrawal time/disconnection time from ventilator was approximately 1.5 minutes. Accidental partial extubation of ETT was noted in two patients (0.97%), and three patients (1.45%) developed abscess formations at anterior submandibular site which were managed by incision and drainage. The anterior submandibular approach for TMI was successfully used and provided stable airway in all elective CMF surgery cases, where oral or nasal intubations were not indicated/feasible and long-term ventilation support was not required. It permitted simultaneous dental occlusion guided reduction and fixation of all the facial fractures without interference from the tube during the surgery with unhindered maintenance of the anesthesia and airway. The advantages include easy, swift, efficient, and reliable approach with a small learning curve. PMID- 29109836 TI - Pedicle Flaps Contribute to Endoscopic Skull-Base Surgery and Facial Soft-Tissue Repair: The Diuturnity of Johannes Fredericus Samuel Esser (1877-1946). AB - Pedicle flaps based on the external maxillary (facial) artery were introduced during the World War I, precisely a century ago. Today they remain effective tools in facial soft-tissue repair. Recently, pedicle flaps based on the internal maxillary (sphenopalatine) artery have been chosen to reliably close dural defects after endoscopic skull-base surgery. Pedicle flaps, "biologic" to the extent they are based on a defined arterial blood supply, are the lasting contributions-the diuturnity-of Johannes ("Jan") Fredericus Samuel Esser (1877 1946) of Leiden, Holland, and Chicago (IL). PMID- 29109837 TI - Comparing Plastic Surgery and Otolaryngology Management in Cleft Care: An Analysis of 4,999 Cases. AB - Care for patients with cleft lip and palate is best managed by a craniofacial team consisting of a variety of specialists, including surgeons, who are generally plastic surgeons or otolaryngologists trained in the United States. The goal of this study was to compare the surgical approaches and management algorithms of cleft lip, cleft palate, and nasal reconstruction between plastic surgeons and otolaryngologists. We performed a retrospective analysis of the American College of Surgeons' National Surgical Quality Improvement Program Pediatric database between 2012 and 2014 to identify patients undergoing primary repair of cleft lip, cleft palate, and associated rhinoplasty. Two cohorts based on primary specialty, plastic surgeons and otolaryngologists, were compared in relation to patient characteristics, 30-day postoperative outcomes, procedure type, and intraoperative variables. Plastic surgeons performed the majority of surgical repairs, with 85.5% ( n = 1,472) of cleft lip, 79.3% ( n = 2,179) of cleft palate, and 87.9% ( n = 465) of rhinoplasty procedures. There was no difference in the age of primary cleft lip repair or rhinoplasty. However, plastic surgeons performed primary cleft palate repair earlier than otolaryngologists ( p = 0.03). Procedure type varied between the specialties. In rhinoplasty, otolaryngologists were more likely to use septal or ear cartilage, whereas plastic surgeons preferred rib cartilage. Results were similar, with no statistically significant difference in terms of mortality, reoperation, readmission, or complications. Significant variation exists in the treatment of cleft lip and palate based on specialty service with regard to procedure timing and type. However, short-term rates of mortality, wound occurrence, reoperation, readmission, and surgical or medical complications remain similar. PMID- 29109838 TI - Treatment Outcomes for Isolated Maxillary Complex Fractures with Maxillomandibular Screws. AB - Intermaxillary fixation (IMF) is a basic and fundamental principle in the management of patients with fractures of the maxillomandibular complex. There are several shortcomings related to the conventionally recommended tooth-mounted devices that are used to achieve IMF. To circumvent these, the use of bone-borne screws has been advocated. We present a series of maxillary fractures treated with IMF screws. Over a 12-month period, 15 cases of maxillary fracture were managed with open reduction and bone plate fixation. IMF screws were used to achieve IMF intraoperatively and for a short duration postoperatively. Eight cortical titanium screws were inserted transmucosally, two for each quadrant at the junction of the attached and mobile mucosa. Satisfactory occlusion was achieved in all the patients with few complications. IMF screw fixation was observed to be a safe and quick method for open reduction of maxillary fractures. Tooth-borne devices are associated with problems such as poor oral hygiene and periodontal health, extrusion of teeth, loss of tooth vitality, traumatic ulcers of buccal and labial mucosa, and needle stick injury to the operator. These procedures are also time consuming. The use of cortical bone screws is a quicker and safe alternative for achieving satisfactory IMF. PMID- 29109839 TI - Hearing and Mortality Outcomes following Temporal Bone Fractures. AB - The aim of this article is to determine hearing and mortality outcomes following temporal bone fractures. Retrospective chart review was performed of 152 patients diagnosed with a temporal bone fracture presenting to the emergency room at a tertiary care referral center over a 10-year period. Utilizing Patients' previously obtained temporal bone computed tomographic scans and audiograms, fractures were classified based on several classification schemes. Correlations between fracture patterns, mortality, and hearing outcomes were analyzed using chi2 tests. Ossicular chain disruption was seen in 11.8% of patients, and otic capsule violation was seen in 5.9%; 22.7% of patients presented for audiologic follow-up. Seventeen patients with conductive hearing loss had air-bone gaps of 26 +/- 7.5 dB (500 Hz), 27 +/- 6.8 dB (1,000 Hz), 18 +/- 6.2 dB (2,000 Hz), and 32 +/- 7.7 dB (4,000 Hz). Two cases of profound sensorineural hearing loss were associated with otic capsule violation. No fracture classification scheme was predictive of hearing loss, although longitudinal fractures were statistically associated with ossicular chain disruption ( p < 0.01). Temporal bone fractures in patients older than 60 years carried a relative risk of death of 3.15 compared with those younger than 60 years. The average magnitude of conductive hearing loss resulting from temporal bone fracture ranged from 18 to 32 dB in this cohort. Classification of fracture type was not predictive of hearing loss, despite the statistical association between ossicular chain disruption and longitudinal fractures. This finding may be due to the low follow-up rates of this patient population. Physicians should make a concerted effort to ensure that audiological monitoring is executed to prevent and manage long-term hearing impairment. PMID- 29109840 TI - Identical Twins with Crouzon Syndrome: Eight-Year Follow-up, Genetic Considerations, and Operative Management. AB - A case report of monozygotic (MZ) twins with Crouzon syndrome was previously published to highlight variables in clinical presentation. The postnatal and epigenetic causes for this variation are not well understood. An 8-year follow-up discusses their pertinent clinic course with consideration of genetic and nongenetic variables. The phenotypic and symptomatic obstacles encountered since their initial assessment are reviewed, and the use of three-dimensional Medical Modeling (Golden, CO) as a preoperative planning strategy is addressed. Analyzing the longitudinal clinical course of MZ twins with syndromic craniosynostosis will help better predict and provide optimal treatment. PMID- 29109841 TI - Mandibular Reconstruction with Lateral Tibial Bone Graft: An Excellent Option for Oral and Maxillofacial Surgery. AB - Autogenous bone grafts are the gold standard for reconstruction of atrophic jaws, pseudoarthroses, alveolar clefts, orthognathic surgery, mandibular discontinuity, and augmentation of sinus maxillary. Bone graft can be harvested from iliac bone, calvarium, tibial bone, rib, and intraoral bone. Proximal tibia is a common donor site with few reported problems compared with other sites. The aim of this study was to evaluate the use of proximal tibia as a donor area for maxillofacial reconstructions, focusing on quantifying the volume of cancellous graft harvested by a lateral approach and to assess the complications of this technique. In a retrospective study, we collected data from 31 patients, 18 women and 13 men (mean age: 36 years, range: 19-64), who were referred to the Department of Oral and Maxillofacial Surgery at the Servidores do Estado Federal Hospital. Patients were treated for sequelae of orthognathic surgery, jaw fracture, nonunion, malunion, pathology, and augmentation of bone volume to oral implant. The technique of choice was lateral access of proximal tibia metaphysis for graft removal from Gerdy tubercle under general anesthesia. The mean volume of bone harvested was 13.0 +/- 3.7 mL (ranged: 8-23 mL). Only five patients (16%) had minor complications, which included superficial infection, pain, suture dehiscence, and unwanted scar. However, none of these complications decreases the result and resolved completely. We conclude that proximal tibia metaphysis for harvesting cancellous bone graft provides sufficient volume for procedures in oral and maxillofacial surgery with minimal postoperative morbidity. PMID- 29109842 TI - Submental Perforator Flap for Soft-Tissue Reconstruction in Bisphosphonate Related Osteonecrosis of the Jaws. AB - Bisphosphonate-related osteonecrosis of the jaws (BRONJ) has emerged as an important and increasingly common comorbidity, especially in patients undergoing long-term treatment with high doses of bisphosphonates. The management of BRONJ remains controversial. Surgical treatment is necessary in severe cases. Treatment of the bone requires sequestrectomy or resection. Given the lack of sufficient mucosa to perform the operation and fragility of margins in many patients, local flaps are crucial. We report two cases of stage-3 BRONJ presenting secondary infection with Actinomyces , receiving treatment consisting of marginal resection of the necrotic bone, reinforcement with a reconstruction plate, and reconstruction of soft tissues using a submental perforator artery flap ipsilateral to the lesion. Total cure was achieved in both cases, achieving favorable aesthetic and functional outcomes. PMID- 29109843 TI - Posttraumatic Parotid Sialocele Complicating a Mandibular Fracture: A Case Report. AB - Blunt trauma to the parotid resulting in the formation of a sialocele is rare, with only three cases identified in the literature. We present a unique case involving a 32-year-old man with blunt trauma resulting in a left mandibular angle fracture. The patient underwent open reduction and internal fixation of the left mandibular angle fracture via transoral approach. At follow-up, after resolution of the edema from the injury, a sialocele was noted in the region of the left anterior parotid gland. The patient was treated conservatively with antisialagogues, pressure dressings, and multiple percutaneous aspirations that ultimately resulted in resolution of the sialocele. PMID- 29109844 TI - Porcine Urinary Bladder Extracellular Matrix for the Salvage of Fibula Free Flap Skin Paddle: Technical Note and Description of a Case. AB - This report establishes a novel application of a commercially available porcine urinary bladder extracellular matrix, MatriStem (ACell, Inc., Columbia, MD), in the salvage of partial loss of the skin paddle of a fibula osteoseptocutaneous free flap that was utilized for mandibular reconstruction. PMID- 29109845 TI - Le Fort I-Type Osteotomy Retractor. AB - A new instrument for retracting the maxilla after mobilization is described. It does neither compress nor inadvertently pierce the lower lip and it does neither obliterate the view nor hinder access to bone removing instruments. PMID- 29109846 TI - New Management in Bilateral Masseter Muscle Hypertrophy. AB - Bilateral masseter muscle hypertrophy is an alteration in shape and thickness of the masseter muscles that can modify the width of the lower face causing aesthetic and functional problems. A 21-year-old man was referred to the Department of Maxillofacial Surgery at the Civil Hospital in Brescia by his dentist for an evaluation of his facial appearance with a square-face type. To reduce the undesirable facial appearance, a surgical intraoral approach was performed; the procedure includes the bilateral dissection of the masseter muscle, partial lipectomy, and the ostectomy of the mandibular angle assisted by a surgical guide built on a stereolithographic model. The patient was satisfied with the functional and aesthetic outcomes of both the profile and the frontal views. There was no evidence of complication at a 1-year follow-up. This new method yields optimal aesthetic results with an enhanced outline of the lower face. PMID- 29109847 TI - The Pull-Through Technique: A Viable Option for Preserving the Inferior Alveolar Nerve during Surgical Resection. AB - The aim of this study was to present a new surgical technique used to remove benign mandibular tumors with minimal damage to the inferior alveolar nerve. The pull-through technique was shown using an ameloblastoma surgical resection as an example. This technique consisted in the reconstruction of the lower jaw associating the resection of the lesion with nerve repair at the same surgical time. The resection was performed using the pull-through technique and the inferior alveolar nerve was preserved. After 6 months, the patient presented a recovery of approximately 80% of sensory function. The surgical technique presented should be considered an important method by which to produce a higher functional outcome to remove benign mandibular tumors with minimal damage to the inferior alveolar nerve and allows the maintenance of quality of life for the patient, as the consequences of this type of surgery are minimized. PMID- 29109848 TI - A Hemangioma of the Zygomatic Bone: Management Ensuring Good Reconstructive and Aesthetic Results. AB - Hemangiomas are benign tumors representing only 0.7 to 1% of all bone tumors; those that arise in the zygomatic region are rarely described in the literature. Here, we describe the case of a 55-year-old woman with a mass in the right orbitozygomatic region. She was diagnosed on the basis of preoperative clinical manifestations, data from an earlier histopathological examination, and computed tomography (CT). The CT scan revealed a lesion in the right zygomatic region at the level of the cancellous component. This caused thinning and remodeling of the deformed cortex both medially and laterally. Surgery was performed. We describe the clinical characteristics of our case with an emphasis on surgical management of the lesion using a titanium grid prepared by reference to a stereolithographic model. PMID- 29109849 TI - Current concepts and future strategies in the antimicrobial therapy of emerging Gram-positive spontaneous bacterial peritonitis. AB - Spontaneous bacterial peritonitis (SBP) is the most common infection in end-stage liver disease patients. SBP is defined as an ascitic fluid infection with a polymorphonuclear leucocyte count >= 250/mm3 without an evident intra-abdominal surgically treatable source. Several mechanisms contribute to SBP occurrence, including translocation of gut bacteria and their products, reduced intestinal motility provoking bacterial overgrowth, alteration of the gut's barrier function and local immune responses. Historically, Gram-negative enteric bacteria have been the main causative agents of SBP, thereby guiding the empirical therapeutic choice. However, over the last decade, a worryingly increasing prevalence of Gram positive and multi-drug resistant (MDR) SBP has been seen. Recently, the microbiological spectrum of SBP seems to have changed in Europe due to a high prevalence of Gram-positive bacteria (48%-62%). The overall proportion of MDR bacteria is up to 22%-73% of cases. Consequently, empirical therapy based on third-generation cephalosporins or amoxicillin/clavulanic acid, can no longer be considered the standard of care, as these drugs are associated with poor outcomes. The aim of this review is to describe, with an epidemiological focus, the evidence behind this rise in Gram-positive and MDR SBP from 2000 to present, and illustrate potential targeted therapeutic strategies. An appropriate treatment protocol should include daptomycin plus ceftaroline and meropenem, with prompt stepdown to a narrower spectrum when cultures and sensitivity data are available in order to reduce both cost and potential antibiotic resistance development. PMID- 29109851 TI - Safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in hepatitis C virus/human immunodeficiency virus co-infected patients. AB - AIM: To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection in an urban HIV clinic. METHODS: A retrospective cohort study of 40 subjects co-infected with HIV-1 and HCV treated with the fixed-dose combination of ledipasvir and sofosbuvir for 12 wk from 2014 to 2016. All patients included were receiving antiretroviral therapy (ART) with HIV RNA values of 100 copies/mL or fewer regardless of baseline HCV RNA level. The primary end point was a sustained virologic response of HCV at 12 wk (SVR12) after the end of therapy. RESULTS: Of the 40 patients enrolled, 55% were black, 22.5% had been previously treated for HCV, and 25% had cirrhosis. The patients were on a wide range of ART. Overall, 39 patients (97.5%) had a SVR 12 after the end of therapy, including rates of 97.1% in patients with HCV genotype 1a and 100% in those with HCV genotype 1b. One patient with HCV genotype 3a was included and achieved SVR12. Rates of SVR12 were similar regardless of previous treatment or the presence of compensated cirrhosis. Only 1 patient experienced relapse at week 12 following treatment and deep sequencing didn't reveal any resistance associated mutation in the NS5A or NS5B region. Interestingly, 7 (17.5%) patients who were adherent to ART experienced HIV viral breakthrough which resolved after continuing the same ART regimen. Two (5%) patients experienced HIV-1 virologic rebound due to noncompliance with HIV therapy, which resolved after resuming the same ART regimen. No severe adverse events were observed and no patient discontinued treatment because of adverse events. The most common adverse events included headache (12.5%), fatigue (10%), and diarrhea (2.5%). CONCLUSION: This retrospective study demonstrated the high rates of SVR12 of ledipasvir/sofosbuvir on HCV eradication in patients co-infected with HCV and HIV, regardless of HCV baseline levels, HCV treatment history or cirrhosis condition. The oral combination of ledipasvir/sofosbuvir represents a safe and well tolerated HCV treatment option that does not require modification for many of the common HIV ART. Occasional HIV virologic rebound occurred but later resolved without the need to change ART. PMID- 29109850 TI - Liver cystic echinococcosis and human host immune and autoimmune follow-up: A review. AB - Cystic echinococcosis (CE) is an infectious disease caused by the larvae of parasite Echinococcus granulosus (E. granulosus). To successfully establish an infection, parasite release some substances and molecules that can modulate host immune functions, stimulating a strong anti-inflammatory reaction to carry favor to host and to reserve self-survival in the host. The literature was reviewed using MEDLINE, and an open access search for immunology of hydatidosis was performed. Accumulating data from animal experiments and human studies provided us with exciting insights into the mechanisms involved that affect all parts of immunity. In this review we used the existing scientific data and discuss how these findings assisted with a better understanding of the immunology of E. granulosus infection in man. The aim of this study is to point the several facts that challenge immune and autoimmune responses to protect E. granulosus from elimination and to minimize host severe pathology. Understanding the immune mechanisms of E. granulosus infection in an intermediate human host will provide, we believe, a more useful treatment with immunomodulating molecules and possibly better protection from parasitic infections. Besides that, the diagnosis of CE has improved due to the application of a new molecular tool for parasite identification by using of new recombinant antigens and immunogenic peptides. More studies for the better understanding of the mechanisms of parasite immune evasion is necessary. It will enable a novel approach in protection, detection and improving of the host inflammatory responses. In contrast, according to the "hygiene hypothesis", clinical applications that decrease the incidence of infection in developed countries and recently in developing countries are at the origin of the increasing incidence of both allergic and autoimmune diseases. Thus, an understanding of the immune mechanisms of E. granulosus infection is extremely important. PMID- 29109852 TI - Mortality and morbidity in necrotizing pancreatitis managed on principles of step up approach: 7 years experience from a single surgical unit. AB - AIM: To determine percentage of patients of necrotizing pancreatitis (NP) requiring intervention and the types of interventions performed. Outcomes of patients of step up necrosectomy to those of direct necrosectomy were compared. Operative mortality, overall mortality, morbidity and overall length of stay were determined. METHODS: After institutional ethics committee clearance and waiver of consent, records of patients of pancreatitis were reviewed. After excluding patients as per criteria, epidemiologic and clinical data of patients of NP was noted. Treatment protocol was reviewed. Data of patients in whom step-up approach was used was compared to those in whom it was not used. RESULTS: A total of 41 interventions were required in 39% patients. About 60% interventions targeted the pancreatic necrosis while the rest were required to deal with the complications of the necrosis. Image guided percutaneous catheter drainage was done in 9 patients for infected necrosis all of whom required further necrosectomy and in 3 patients with sterile necrosis. Direct retroperitoneal or anterior necrosectomy was performed in 15 patients. The average time to first intervention was 19.6 d in the non step-up group (range 11-36) vs 18.22 d in the Step-up group (range 13 25). The average hospital stay in non step-up group was 33.3 d vs 38 d in step up group. The mortality in the step-up group was 0% (0/9) vs 13% (2/15) in the non step up group. Overall mortality was 10.3% while post-operative mortality was 8.3%. Average hospital stay was 22.25 d. CONCLUSION: Early conservative management plays an important role in management of NP. In patients who require intervention, the approach used and the timing of intervention should be based upon the clinical condition and local expertise available. Delaying intervention and use of minimal invasive means when intervention is necessary is desirable. The step-up approach should be used whenever possible. Even when the classical retroperitoneal catheter drainage is not feasible, there should be an attempt to follow principles of step-up technique to buy time. The outcome of patients in the step-up group compared to the non step-up group is comparable in our series. Interventions for bowel diversion, bypass and hemorrhage control should be done at the appropriate times. PMID- 29109853 TI - Mesenteric vein thrombosis following impregnation via in vitro fertilization embryo transfer. AB - Pregnancy is an acquired hypercoagulable state. Most patients with thrombosis that develops during pregnancy present with deep vein leg thrombosis and/or pulmonary embolism, whereas the development of mesenteric vein thrombosis (MVT) in pregnant patients is rare. We report a case of MVT in a 34-year-old woman who had achieved pregnancy via in vitro fertilization-embryo transfer (IVF-ET). At 7 wk of gestation, the patient was referred to us due to abdominal pain accompanied by vomiting and hematochezia, and she was diagnosed with superior MVT. Following resection of the gangrenous portion of the small intestine, anticoagulation therapy with unfractionated heparin and thrombolysis therapy via a catheter placed in the superior mesenteric artery were performed, and the patient underwent an artificial abortion. Oral estrogen had been administered for hormone replacement as part of the IVF-ET procedure, and additional precipitating factors related to thrombosis were not found. Pregnancy itself, in addition to the administered estrogen, may have caused MVT in this case. We believe that MVT should be included in the differential diagnosis of a pregnant patient who presents with an acute abdomen. PMID- 29109854 TI - Correction to "Acute calculous cholecystitis: Review of current best practices". AB - [This corrects the article on p. 5 in vol. 9, PMID: 28603584.]. PMID- 29109855 TI - Miller Fisher syndrome with sinus arrest. PMID- 29109856 TI - Knowledge and quality of adolescents reproductive health communication between parents and their adolescents children in Ibadan, Nigeria. PMID- 29109857 TI - An optimum allocation sampling based feature extraction scheme for distinguishing seizure and seizure-free EEG signals. AB - Epileptic seizure is the common neurological disorder, which is generally identified by electroencephalogram (EEG) signals. In this paper, a new feature extraction methodology based on optimum allocation sampling (OAS) and Teager energy operator (TEO) is proposed for detection of seizure EEG signals. The OAS scheme selects the finite length homogeneous sequence from non-homogeneous recorded EEG signal. The trend of selected sequence by OAS is still non-linear, which is analyzed by non-linear operator TEO. The TEO convert non-linear but homogenous EEG sequence into amplitude-frequency modulated (AM-FM) components. The statistical measures of AM-FM components used as input features to least squares support vector machine classifier for classification of seizure and seizure-free EEG signals. The proposed methodology is evaluated on a benchmark epileptic seizure EEG database. The experimental results demonstrate that the proposed scheme has capability to effectively distinguish seizure and seizure free EEG signals. PMID- 29109858 TI - Using neutrosophic graph cut segmentation algorithm for qualified rendering image selection in thyroid elastography video. AB - Recently, elastography has become very popular in clinical investigation for thyroid cancer detection and diagnosis. In elastogram, the stress results of the thyroid are displayed using pseudo colors. Due to variation of the rendering results in different frames, it is difficult for radiologists to manually select the qualified frame image quickly and efficiently. The purpose of this study is to find the qualified rendering result in the thyroid elastogram. This paper employs an efficient thyroid ultrasound image segmentation algorithm based on neutrosophic graph cut to find the qualified rendering images. Firstly, a thyroid ultrasound image is mapped into neutrosophic set, and an indeterminacy filter is constructed to reduce the indeterminacy of the spatial and intensity information in the image. A graph is defined on the image and the weight for each pixel is represented using the value after indeterminacy filtering. The segmentation results are obtained using a maximum-flow algorithm on the graph. Then the anatomic structure is identified in thyroid ultrasound image. Finally the rendering colors on these anatomic regions are extracted and validated to find the frames which satisfy the selection criteria. To test the performance of the proposed method, a thyroid elastogram dataset is built and totally 33 cases were collected. An experienced radiologist manually evaluates the selection results of the proposed method. Experimental results demonstrate that the proposed method finds the qualified rendering frame with 100% accuracy. The proposed scheme assists the radiologists to diagnose the thyroid diseases using the qualified rendering images. PMID- 29109860 TI - Development and application of an indirect ELISA for the detection of antibodies against encephalomyocarditis virus. AB - Encephalomyocarditis virus (EMCV) can cause acute myocarditis in young pigs or reproductive failure in sows. It has been recognized worldwide as a pathogen infecting many species and causes substantial economic losses. In the present study, an indirect ELISA was developed for the detection of antibodies to EMCV. The VP1 gene of EMCV was amplified by reverse transcription-quantitative polymerase chain reaction and expressed in Escherichia coli with 49.3 kDa under the condition of isopropyl-beta-d-thiogalactoside. Following this, the authors obtained the recombinant protein VP1 as a coating antigen. The antigen concentration and serum dilution were optimized using a checkerboard titration. Compared with viral neutralization tests, the sensitivity and specificity of the indirect ELISA was 95.7% and 92.9%, respectively. A total of 265 clinical swine serum samples from different pig farms in China were used to a serological survey. The seropositive rate of the serum samples was 81.9%. In conclusion, the developed indirect ELISA assay is sensitive and specific, which will be useful for large-scale serological survey in EMCV infection and monitoring antibodies titers against EMCV. PMID- 29109859 TI - Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer. AB - Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC. PMID- 29109862 TI - Comparative analysis of thyroid function parameters in pregnant women. AB - The aim of the present study was to investigate the serum levels of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) during pregnancy and comparative analysis of serum markers levels in non pregnant women and pregnant women. Pregnant women were divided into four groups according to their gestational age: 8-14, 15-20, 21-36 and >=37 weeks. Non pregnant women were divided into three groups according to their age: 20-40, 41 55 and 56-85 years, and women of reproductive age (20-40 years) as control, which match their age and body mass index with pregnant women. The levels of serum markers were measured by magnetic microparticle chemiluminescence immunoassay and compared among different gestational weeks or with the control. In pregnant women, from 8-14 to >=37 weeks, FT3 and FT4 levels declined, and significant differences were identified between each group, except for FT4 at 21-36 weeks, when compared with >=37 weeks. While TSH was increased and significant differences were identified between each group. Compared with the control group, the concentrations of FT3, FT4 and TSH were lower in pregnant women for all weeks except for TSH in >=37 weeks. Reference intervals of FT3, FT4 and TSH in pregnant women are much lower than that of the control women. Pregnant women are likely to have lower thyroid hormone levels throughout pregnancy. The current reference intervals of thyroid hormones were not feasible for pregnant women and pregnancy specific reference intervals should be established according to a local Chinese pregnant women database. PMID- 29109861 TI - Association of smoking with prevalence of common diseases and metabolic abnormalities in community-dwelling Japanese individuals. AB - Smoking is a significant risk factor for cardiovascular diseases (CVDs). Given that certain common pathologies, including hypertension, dyslipidemia and type 2 diabetes mellitus, are major risk factors for CVDs, the association of smoking with CVDs may be attributable, at least in part, to its effects on common diseases. The aim of the present study was to determine the association of smoking with the prevalence of common diseases and metabolic abnormalities in community-dwelling Japanese individuals. The study included 5,959 subjects (1,302 current smokers, 1,418 past smokers and 3,239 nonsmokers) recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. Various metabolic parameters and prevalence of common diseases were compared between smokers and nonsmokers using multivariable regression or logistic regression analysis with adjustments for age. Analysis indicated significantly higher serum concentrations of triglycerides and lower concentrations of high-density lipoprotein (HDL) cholesterol in current smokers compared with nonsmokers in men and women. Serum concentrations of creatinine and systolic blood pressure were significantly lower and estimated glomerular filtration rate was higher in male current smokers. In addition, body weight was higher in female current smokers. In multivariable logistic regression analysis, smoking was significantly associated with the prevalence of dyslipidemia [P=6.3*10-10; odds ratio (OR), 1.81], hypertriglyceridemia (P=2.3*10-20; OR, 2.39), hypo-HDL-cholesterolemia (P=2.0*10 9; OR, 2.14), metabolic syndrome (P=0.0003; OR, 1.61) and chronic kidney disease (P=4.4*10-15; OR, 0.54) in men, but not in women. The results indicated that smoking is significantly associated with various metabolic abnormalities and prevalence of common diseases in Japanese individuals, with certain sex differences, which may lead to accelerated development of CVDs. PMID- 29109863 TI - Pattern of gynaecological malignancies in south western region of Pakistan: An overview of 12 years. AB - Gynaecological malignancies contribute significantly to cancer burden and have a higher rate of mortality and morbidity. The aim of this retrospective study was to determine the pattern of gynaecological malignancies identified between January, 2000 and December, 2011, at the Centre for Nuclear Medicine and Radiotherapy (CENAR). At CENAR 5,072 female patients were registered with different malignancies, of which 632 cases were gynaecological malignancies. Ovarian cancer (47%) was the most common gynaecological malignancy, followed by cervical cancer (29%), uterine cancer (14%), vulvar and vaginal cancer (6%), and gestational trophoblastic neoplasm (4%). Of the ovarian cancer cases, 72.5% had epithelial while 26.5% had non-epithelial cancer. Squamous cell carcinoma was 75.9% in cervix and 87.8% in vulva and vagina while endometrial carcinoma (75.9%) was more frequent in uterus. For gestational trophoblastic neoplasm, 69.2% of patients had choriocarcinoma. Ovarian cancer was the most common type for the age range of 50-59 years. In the case of cervical and gestational trophoblastic neoplasm the majority of patients presented at the ages of 40-49 and 30-39 years while uterus, vulvar and vaginal tumor presented in the elderly (>60 years). Thus, ovarian cancer is the leading gynecological malignancy in Pakistan. PMID- 29109864 TI - Induction of autophagy by sphingosine kinase 1 inhibitor PF-543 in head and neck squamous cell carcinoma cells. AB - Sphingosine kinase 1 (SphK1) overexpressed in head and neck squamous cell carcinoma (SCC) regulates tumor growth. The effects of PF-543, a specific SphK1 inhibitor, on human SCC cells were examined. The proportion of viable cells after PF-543 treatment decreased in a time- and dose-dependent manner, and cell death occurred in SphK1-expressing SCC cells. Flow cytometry analysis revealed that PF 543 induced both necrosis and apoptosis. PF-543 also induced granular accumulation of LC3 and conversion from LC3-I to LC3-II, which was blocked by autophagy inhibitors, wortmannin, 3-methyladenine (3-MA), and bafilomycin A1. Treatment of head and neck SCC cells with autophagy inhibitors and PF-543 increased the proportion of cells with necrosis and apoptosis, indicating that autophagy acts to promote cell survival. Reactive oxygen species (ROS) scavenger reduced the cytotoxicity of PF-543. These results demonstrated that PF-543 induces apoptosis, necrosis, and autophagy in human head and neck SCC cells, and that autophagy antagonizes either necrosis or apoptosis. PMID- 29109865 TI - OM-101 Decreases the Fibrotic Response Associated with Proliferative Vitreoretinopathy. AB - Purpose: This study aimed to investigate the effect of OM-101 on the fibrotic response occurring in proliferative vitreoretinopathy (PVR) in an animal model. Methods: Antifibrotic effect of OM-101 was investigated in vivo. As control, eight weeks old c57black mice underwent intravitreal injection with Hepes (group A) or dispase (0.3 units), to induce retinal detachment (RD) and PVR. The dispase injected mice were randomly divided into two groups B and C (N = 25 mice); in group C, the eyes were treated with intravitreal injection of OM-101 (3 MUl), and group B with PBS, as a control. After additional five days, mice were injected with the same initial treatment. Three days later, mice were euthanized, and the eyes were enucleated and processed for histological analysis. Results: Intravitreal injection of dispase caused RD in 64% of the mice in group B, and 93% of those mice had PVR. Only 32% of mice treated with OM-101 and dispase (group C) developed RD, and only 25% of those developed PVR. Conclusions: OM-101 was found effective in reducing the incidence of RD and PVR maintaining the normal architecture of the retina. This study suggests that OM-101 is a potentially effective and safe drug for the treatment of PVR patients. PMID- 29109866 TI - Correlation between Choroidal Neovascularization Shown by OCT Angiography and Choroidal Thickness in Patients with Chronic Central Serous Chorioretinopathy. AB - Purpose: To assess the occurrence of choroidal neovascularization (CNV) secondary to chronic central serous chorioretinopathy (CSCR) using optical coherence tomography angiography (OCTA) and correlate these findings with choroidal thickness (CT). Materials and Methods: This retrospective study included 25 consecutive patients (43 eyes), mean age 48.12 +/- 7.8 years, diagnosed with persistent CSCR. All patients underwent a complete ophthalmic examination, fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography, and OCTA. Results: CNV was confirmed in 18.6% of eyes using FA and ICGA and in 25.6% of eyes using OCTA. All cases of CNV were associated with irregular retinal pigment epithelial detachment. CT was increased in the affected eyes (mean 491.05 +/- 91.98), but there were no statistically significant correlations between CT and CNV and PED occurrence (p = 0.661 and p = 0.614, resp.) and between CT and duration of the disease (p = 0.940). Conclusions: OCTA detected CNV more frequently than other imaging modalities. CNV coexisted with irregular PED in all cases. CT was increased in eyes with chronic CSCR, but without any correlation with CNV occurrence; therefore, CT cannot be considered as a predictor of CNV occurrence. Further studies with a larger number of patients are needed to confirm these findings. PMID- 29109867 TI - Clinical Profile of Unilateral Proptosis in a Tertiary Care Centre. AB - Proptosis, the forward protrusion of the eyeball, is a common manifestation of a wide variety of diseases inside the orbit and its spaces. Its diagnosis is usually a combined effort of the ophthalmologist, otolaryngologist, neurosurgeon, and radiologist. A clinical study of twenty-five cases with unilateral proptosis were studied in different age groups over a period of about 3 years under different headings like distribution, clinical features, radiological features, histopathological aspects, management, and outcomes of diseases. Proptosis measurement was done by simple/plastic ruler exophthalmometry, and diagnosis was made after a detailed clinical examination and ancillary tests. Treatment modality was decided based on radiological and histopathological examination reports, which included medical surgery, radiotherapy, and chemotherapy or a combination of all. In our study, most of the patients were in the age group of more than 60 years. The M : F ratio is 3 : 1. One case had a large proptosis of 18 mm above normal and 2 cases were as small as 3 mm. Diagnosis was mainly done by clinical features and confirmed by radiological and histopathological features. Most of them were treated medically (13 cases, i.e., 52%) and the rest by surgery with a combination of radiotherapy/chemotherapy (12 cases, i.e., 48%). PMID- 29109868 TI - Visual Quality Assessment of Posterior Capsule Opacification Using Optical Quality Analysis System (OQAS). AB - Objective: To evaluate intraocular scattering in eyes with posterior capsule opacification by means of an objective scatter index (OSI) obtained from double pass images of optical quality assessment system (OQAS TM II) and to determine the indication for laser capsulotomy when patients report visual disturbances without decreased visual acuity. Methods: In this prospective, observational, and nonconsecutive case series study, a total of 32 eyes of 29 patients are diagnosed with posterior capsule opacification after age-associated cataract were analyzed. Patient examination included age, the period after cataract surgery, logMAR best corrected visual acuity (BCVA), and OSI. Results: We found a significant decrease in the BCVA and increase in the OSI with the development of posterior capsule opacification. The decrease of BCVA was statistically correlated with the increase of OSI (r = 0.812, P < 0.01). In patients who reported visual disturbances without decreased visual acuity, OSI decreased to <1.3 and subjective symptoms were resolved in all cases although there was no significant improvement in visual acuity after laser capsulotomy. Conclusions: The results of our study showed that OSI is also a useful parameter for objectively evaluating posterior capsule opacification. OSI may help predict laser capsulotomy in patients who report visual disturbances without decreased visual acuity. PMID- 29109869 TI - Postintervention Dyspnea after Radiofrequency Catheter Ablation: Think of a Phrenic Nerve Injury. AB - Phrenic nerve injury (PNI) is a rare complication of catheter ablation therapy, most commonly observed in cryoablation of the right side pulmonary veins. We present a case of PNI after radiofrequency catheter ablation that developed acute dyspnea 24 hours after the intervention. Dyspnea is the main symptom of PNI, so the diagnosis should always be suspected if it appears after any type of catheter ablation involving the trajectory of the phrenic nerve. There is no specific treatment for PNI. The only maneuver that has been reported to accelerate the recovery of PNI is early stopping of the ablation therapy. PMID- 29109870 TI - Acute-Onset Panhypopituitarism Nearly Missed by Initial Cosyntropin Testing. AB - Introduction: Diagnosis of adrenal crisis and panhypopituitarism in patients with septic shock is difficult but crucial for outcome. Case: A 66-year-old woman with metastasized breast cancer presented to the ED with respiratory insufficiency and septic shock after a 2-day history of the flu. After transfer to the ICU, corticosteroids were started in addition to antibiotics, as the patient was vasopressor-nonresponsive. Diabetes insipidus was diagnosed due to polyuria and treated with 4 mg desmopressin. Thereafter, norepinephrine could be tapered rapidly. On day 2, basal cortisol was 136 nmol/L with an increase to 579 nmol/L in low-dose cosyntropin testing. Polyuria had not developed again. Therefore, corticosteroids were stopped. On day 3, the patient developed again nausea, vomiting, and polyuria. Adrenal crisis and diabetes insipidus were postulated. Corticosteroids and desmopressin were restarted. Further testing confirmed panhypopituitarism. MRI showed a new sellar metastasis. After 2 weeks, stimulated cortisol in cosyntropin testing reached only 219 nmol/l, confirming adrenal insufficiency. Discussion: The time course showed that the adrenal glands took 2 weeks to atrophy after loss of pituitary ACTH secretion. Therefore, a misleading result of the cosyntropin test in the initial phase with low basal cortisol and allegedly normal response to exogenous ACTH may be seen. Cosyntropin testing in the critically ill should be interpreted with caution and in the corresponding clinical setting. PMID- 29109872 TI - Severe Decompression Illness: Case Report, Prehospital Recognition, and Regional Transport Considerations. AB - A 46-year-old male presented to our tertiary care emergency department (ED) with shortness of breath and chest pain following an uneventful four-hour SCUBA dive at 100 feet. His prehospital emergency medical services (EMS) assessment revealed transient hypotension and hypoxia. He later developed progressive skin mottling. Serology was significant for acute kidney injury, transaminitis, hemoconcentration, and hypoxia on an arterial blood gas. Computed tomography (CT) angiography demonstrated intravascular gas throughout the mesenteric and pulmonary arteries as well as the portal venous system. No abnormality was seen on head CT and the patient had normal mental status. Prehospital nonrebreather oxygen therapy was changed to continuous positive airway pressure (CPAP) upon ED arrival, and the patient was intubated prior to transfer to a hyperbaric facility. However, within 24 hours the patient was found to have multiorgan failure, diffuse cerebral edema, and brain death despite no further episodes of hypotension or hypoxia. No intracranial gas was seen on repeat head CT. Our case demonstrates the importance of early recognition of decompression illness by EMS personnel, consideration of ground versus flight transportation of these patients to the nearest hyperbaric center, and the possible use of prehospital CPAP as an alternative to enhance oxygenation. PMID- 29109871 TI - Unusual Etiology and Diagnosis of Oroantral Communication due to Late Implant Failure. AB - Oroantral communication (OAC) rarely occurs long after implant placement. The present report describes the rare etiology and the difficulty of the diagnosis of an uncommon OAC occurring 10 years after the implant placement in the posterior maxilla. The difficulty of the diagnosis lies in the absence of clinical symptoms of sinusitis and presence of multiunit prosthesis hiding implant failure. This case report supports the need for sinus check-up during a routine implant examination. PMID- 29109873 TI - The Traumatic Tube: Bleeding Rectal Ulcer Caused by Flexi-Seal Device. AB - Diarrhea and fecal incontinence are common in critically ill patients and present a challenging problem in patient management. The Flexi-Seal(r) Fecal Management System is a device to divert the stools away from the patient, thus improving the care to patients with fecal incontinence. There have been only few case reports describing the complications with the use of this device. Here, we present a case of a 77-year-old woman who was admitted due to massive hematochezia while on anticoagulation. She was found to have a large rectal ulcer caused by the Flexi Seal device, used during the last hospital stay for fecal incontinence. Flexi Seal device can be effective for the management of incontinence; however, caution should be exercised during handling and pressure from the retention balloon should be relieved periodically. PMID- 29109874 TI - Esophageal Lichen Planus: Understanding a Potentially Severe Stricturing Disease. AB - A 67-year-old woman with a long-standing history of recurrent dysphagia and esophageal strictures failed to respond to aggressive antireflux management. She required multiple dilations for symptomatic strictures that were discovered throughout the esophagus. Intralesional, topical, and systemic glucocorticoid therapies were utilized without resolution in symptoms. Several years after initial presentation, histopathology ultimately demonstrated lichenoid features and a diagnosis of esophageal lichen planus (ELP) was confirmed. However, as her symptoms had already become significantly disabling with severe strictures that carried an increased risk of endoscopic complications with dilation, she ultimately decided to undergo an esophagectomy for definitive treatment. Moreover, ELP may often go unrecognized for several years. Clinicians should consider ELP in the differential for dysphagia in middle- to elderly-aged women with or without a known history of lichen planus (LP) especially for those with findings of multiple or proximal strictures. PMID- 29109875 TI - A Severe Case of Tuberculosis Radiologically and Endoscopically Mimicking Colorectal Cancer with Peritoneal Carcinomatosis. AB - Although generally rising in incidence, intestinal tuberculosis is still rare in western countries and due to unspecific manifestations mainly as ulcerations on endoscopy, diagnosis of intestinal tuberculosis is challenging. Within this report, we describe a case of severe intestinal tuberculosis radiologically and endoscopically masquerading as colorectal cancer with peritoneal carcinomatosis. Our case exemplifies that intestinal tuberculosis needs to be considered as a differential diagnosis in patients at risk and that undelayed and sensitive diagnosis of intestinal tuberculosis is of central importance for avoiding unfavorable disease outcome. PMID- 29109876 TI - Debut of Gastroesophageal Reflux Concomitant with Administration of Sublingual Immunotherapy. AB - Gastroesophageal reflux disease (GORD) is an often debilitating condition characterised by retrograde flow of content from stomach into the oesophagus, where the low pH of the stomach acid irritates the mucosa of the oesophagus. The most dominant symptoms in GORD are pyrosis, regurgitation, and dysphagia. Sublingual immunotherapy (SLIT) was first described in 1986. Following this description, the use has greatly increased in the treatment of allergic rhinitis, as an alternative to subcutaneously administered immunotherapy. Side effects are commonly of oropharyngeal and gastrointestinal nature, for example, swelling, itching, irritation, ulceration of the oropharynx and nausea, abdominal pain, vomiting, and diarrhoea. More serious side effects are dominated by respiratory tract and systemic manifestations. A 30-year-old male experienced refractory, relentless, and debilitation GORD subsequent to administration of sublingual immunotherapy for house dust mite in allergic rhinitis. The patient had to stop the SLIT after two weeks of administration due to GORD. The cessation resulted in rapid resolution of symptoms. PMID- 29109877 TI - PAX5-Negative Classical Hodgkin Lymphoma: A Case Report of a Rare Entity and Review of the Literature. AB - Classical Hodgkin lymphoma (CHL) is recognized as a B-cell neoplasm arising from germinal center or postgerminal center B-cells. The hallmark of CHL is the presence of CD30 (+) Hodgkin and Reed-Sternberg (HRS) cells with dim expression of PAX5. Nearly all of the HRS cells are positive for PAX5. However, a small minority of HRS cells may lack PAX5 expression, which can cause a diagnostic dilemma. Herein we describe two cases of PAX5-negative CHL and review of the English literature on this very rare entity. It is crucial to be aware of this phenomenon, which in some cases may lead to misdiagnosis and may ultimately adversely affect patient's management. PMID- 29109878 TI - Bilateral Neck Pyomyositis Caused by Staphylococcus capitis and Staphylococcus saccharolyticus in a Diabetic Adult. AB - We report a case of pyomyositis of the paraspinal neck muscles caused by two coagulase-negative staphylococci: Staphylococcus capitis and Staphylococcus saccharolyticus. Inflammation in the spermatic cords was an additional feature of this infection. Treatment with six weeks of first-generation cephalosporin therapy resulted in complete clinical and radiological resolution. PMID- 29109879 TI - Legionnaires' Disease Complicated with Rhabdomyolysis and Acute Kidney Injury in an AIDS Patient. AB - Objective: To present a case of an uncommon triad of Legionella pneumonia, rhabdomyolysis, and renal failure, with review of the relevant literature. Case: A 51-year-old with a history of human immunodeficiency virus (HIV), chronic obstructive pulmonary disease (COPD), and hypertension presented with fever, cough, and shortness of breath over four days. Chest X-ray showed consolidation in left lower lung field; urine was positive for Legionella antigen and myoglobin; creatine kinase was 51092U/L; creatine was 6.9 mg/dL, and his CD4 count was 41 cells/ul. He was managed with azithromycin and levofloxacin and further required dialysis and ventilatory support in the intensive care unit due to renal failure and respiratory failure. He responded well to the treatment and made a complete recovery. Legionella pneumophila infection is a recognized but rare cause of rhabdomyolysis with high morbidity and mortality when there is extrapulmonary involvement. Early diagnosis and appropriate treatment is essential to improve outcomes. Conclusion: Physicians should consider Legionella pneumonia in patients with rhabdomyolysis, renal failure, and respiratory symptoms. Early diagnosis and treatment have been shown to have good clinical response. Timely intensive care management, together with early and judicious use of dialysis in patients complicated with rhabdomyolysis and renal failure, may lead to good outcomes. PMID- 29109880 TI - An Unusual Subcutaneous Mass in an Otherwise Healthy Patient: A Case Report of Localized Histoplasmosis Diagnosed on Excisional Biopsy. AB - Patients are commonly referred to general surgery clinics for evaluation of soft tissue masses of the trunk and extremities. The primary goal of surgical referral is to confirm the presence of a mass, to assess the need for additional imaging and/or testing, and to gauge amenability to surgical biopsy, whether incisional or excisional. This is a case of a 67-year-old woman who was referred to surgery clinic for a small soft-tissue mass near her left elbow that had increased in size and pain over the past year. The mass had been present for several years. After MRI imaging revealed a nonspecific process, an excisional biopsy was performed. Following a careful review of the patient's history, risk factors, and histological results, a diagnosis of localized subcutaneous Histoplasma capsulatum var. capsulatum infection was made. Without signs or symptoms of active, systemic disease, no further treatment was recommended. The patient was provided risk factor counseling for symptoms or signs of active histoplasmosis and outpatient follow-up. Histologically, most masses will return as benign and mesenchymal in origin. However, soft-tissue masses may arise from uncommon etiologies and a broad differential is needed to ensure appropriate management and recommendations. PMID- 29109881 TI - Hypothermia with Extreme Bradycardia following Spinal Cord Infarction of Septic Origin. AB - Among other autonomic dysfunctions complicating acute spinal cord injury, deep hypothermia is rare but may induce serious cardiovascular complications. There are few pharmacological options to influence hypothermia. A 66-year-old woman was transferred to the intensive care unit (ICU) for serious cardiac arrhythmias (atrial fibrillation and asystole) in the context of a deep hypothermia (axillary temperature below 32 degrees C). She had been admitted to the hospital two months before for an acute L4-L5 infectious spondylodiscitis without any initial neurological deficit. After surgery for epidural abscess drainage, she became paraplegic due to spinal cord infarction (from C7 to T6 levels) in the upper territory of the anterior spinal artery. In the ICU, the patient experienced several episodes of asystole and hypotension associated with a core body temperature below 35 degrees C. Common causes of hypothermia (drugs, hypothyroidism, etc.) were excluded. A definitive pacemaker had to be inserted, but hypotension persisted. The prescription of oral progesterone (200 mg.d-1) helped to maintain a core temperature higher than 35 degrees C, with a withdrawal of vasopressors. This case report illustrates that patients with incomplete spinal cord injury may present with delayed and deep hypothermia leading to serious cardiovascular complications. Progesterone could be able to influence positively central and peripheral thermal regulation. PMID- 29109882 TI - Successful Mechanical Thrombectomy of a Middle Cerebral Artery Occlusion 14 Hours after Stroke Onset. AB - A 54-year-old patient presented with mild right-sided weakness of hand and face with a National Institutes of Health Stroke Scale (NIHSS) of 2 and occlusion of the left middle cerebral artery (MCA) in the M1 segment with a large perfusion deficit on computed tomography (CT). Due to mild neurological deficits no IVT was performed. Nine hours after symptom onset the patient gradually deteriorated with a NIHSS fluctuating between 9 and 15. MRI showed a persistent occlusion of the MCA with a large diffusion-perfusion mismatch. Immediate endovascular thrombectomy was performed 14 hours after symptom onset with complete recanalization and complete clinical recovery. Although mechanical thrombectomy is generally considered an effective alternative strategy up to 8 hours after stroke onset, selected patients with a large diffusion/perfusion mismatch and small infarct cores may benefit from an expanded therapeutic window. PMID- 29109883 TI - Nd:YAG Laser Photodisruption for Multilevel Premacular Hemorrhage due to Isolated Retinal Venous Macroaneurysm. AB - A 55-year-old man presented with sudden deterioration of vision in the right eye. His visual acuity was reduced to hand motion because of a large multilevel premacular hemorrhage. Nd:YAG laser was performed to drain the entrapped hemorrhage under the internal limiting membrane (ILM) and posterior hyaloid face in the macula into the vitreous. Immediately after laser treatment, streaming of red blood cells into the vitreous gel through the perforation site was observed. At the first-month follow-up, BCVA improved to 20/25 and ILM wrinkling was observed at the macula where the preretinal hemorrhage cleared. Fluorescein angiography revealed an isolated retinal venous macroaneurysm located on the macular branch of the superotemporal vein at the bifurcation site. In contrast to retinal arterial macroaneurysms, retinal venous macroaneurysms are quite rare. To the best of our knowledge, this is the first case reported with multilevel premacular hemorrhage caused by an isolated retinal venous macroaneurysm. PMID- 29109884 TI - Natural Remission of Major Periprosthetic Osteolysis following Total Hip Arthroplasty with Metal-on-Metal Bearings. AB - The natural course of adverse events following the use of metal-on-metal (MoM) bearings in total hip arthroplasty (THA) is not well known. In this article, we report the case of a patient with asymptomatic major acetabular osteolysis following MoM THA that diminished gradually without any surgical intervention. A 58-year-old male underwent one-stage bilateral MoM THA for bilateral osteoarthritis. Four years after THA, major acetabular osteolysis developed in his right hip without any local or systemic symptoms. The patient underwent a careful radiographic and clinical observation without any surgical intervention because he did not want to undergo revision surgery. The lesion gradually diminished after 7 years, and most of the osteolytic area was replaced by newly formed bone at 10 years. He continues to be followed with no evidence of cup loosening or migration. Our observation suggests that a periprosthetic osteolytic change related to the use of MoM bearings has the potential for natural remission. PMID- 29109885 TI - Sacral Stress Fracture in an Amateur Badminton Player. AB - Sacral stress fractures are rare among athletes but have been reported most frequently in long distance runners. We report herein the first case of a sacral stress fracture in an amateur badminton player. A 16-year-old, left-handed adolescent girl, who had just started to play badminton 3 months previously, complained of acute left buttock pain when she received a shuttlecock. Magnetic resonance imaging revealed a linear lesion of the left sacrum with low signal intensity on T1- and high signal intensity on T2-weighted images, which was consistent with a stress fracture. Conservative treatment with rest relieved her symptoms. Her fracture was considered to have occurred due to repetition of an exercise that caused excessive vertical power. PMID- 29109886 TI - Radiofrequency-Targeted Vertebral Augmentation: Case Report of a Patient with 7 Osteoporotic Vertebral Fractures in a Variant of Osteogenesis Imperfecta. AB - Introduction: Radiofrequency-targeted vertebral augmentation (RF-TVA) is a recognized treatment for painful compression fractures. RF-TVA in a patient with multiple compression fractures due to type I osteogenesis imperfecta (OI) has not been previously reported. Case Presentation: A 54-year-old patient with type I OI is presented with a segmental thoracic hyperkyphosis and 7 recent vertebral compression fractures. Because of persistent severe thoracolumbar back pain despite conservative therapy, RF-TVA was indicated. Nocturnal back pain was almost completely relieved at all postoperative time points evaluated. However, overall pain relief dropped only slightly from 7 to 5 on the numerical rating scale (NRS) at the 6-week follow-up, and there was only a small decrease in the Oswestry Disability Index (ODI) from 72% to 63%. An MRI at the 3-month follow-up revealed hyperintensity at levels T11 and T12, indicating slight recollapsing. At the 6-month follow-up, the ODI improved to 55%, although overall pain had worsened to 6 on the NRS. Pain at rest remained at a very low level. Conclusion: Despite the remaining lumbago, RF-TVA may be a good option for patients with OI who have multiple fractures. However, fractures at multiple levels and segmental thoracic hyperkyphosis may increase the risk for recollapsing and ongoing pain. PMID- 29109887 TI - Usefulness of Sacral Sublaminar Wire for Low Transverse Sacral Fractures: Two Cases' Report. AB - Low transverse sacral fractures are rare, with only two published reports regarding their surgery. The complication associated with surgery for sacral fractures is the prominence of implants. In addition, screw fixation below S3 is impractical. We performed posterior sacral fixation using S2 alar iliac (S2AI) screws and sacral sublaminar wires for low transverse sacral fractures. Case 1 was 65-year-old male with an S2-3 transverse sacral fracture. We performed laminectomy (S2-3) and passed ultrahigh molecular weight polyethylene (UHMWPE) cables from laminectomy area to the third posterior sacral foramina. We inserted S2AI screws and connected rods. We also tightened the UHMWPE cables. The implants did not protrude into skin. One year after surgery, the sacral fracture healed without any displacement. Case 2 was a 42-year-old female with an S2 transverse sacral fracture. We performed laminectomy (S1-3) and passed UHMWPE cables from laminectomy area to the third and fourth posterior sacral foramina. We inserted S1 pedicular screws and S2AI screws and connected rods. We also tightened UHMWPE cables. The implants did not protrude into skin. One year after surgery, the sacral fracture healed without any displacement. We consider sacral sublaminar wires to be useful bone anchors in lower sacrum. PMID- 29109888 TI - Melanotic Schwannomas Are Rarely Seen Pigmented Tumors with Unpredictable Prognosis and Challenging Diagnosis. AB - Melanotic Schwannoma (MS) is rarely seen and potentially malignant neoplasm that is categorized as a variant of Schwannoma. MS most frequently involves intracranial structures followed by posterior nerve roots in the spinal canal. Approximately 50% of the cases with MS have psammomatous calcifications and this type of MS is related to Carney complex with autosomal dominant inheritance. Most cases of MS are benign, though 10% of them are malignant with metastatic potential. MS mimics melanoma and the differential diagnosis should be made excluding other melanin producing neoplasms especially melanoma. Case 1. A 42 year-old hypertensive male presented for checkup. He had a well-defined extraspinal oval lesion measuring 3.5 * 2.5 cm near right adrenal. Case 2. A 22 year-old female presented with neurofibromatosis-2, bilateral acoustic schwannomas and cafe au lait lesions on sacrococcygeal region. She had an intradural extramedullary lesion measuring 6.1 * 2.0 cm at L1-2 level. MS is a rare neoplasm composed of Schwann cells and melanin pigment. These tumors are usually benign but they may become aggressive. The biologic behavior of MS is difficult to predict; the patients have to be followed up for a longer period due to its malignant potential. PMID- 29109889 TI - A Case Report on VT from TV: DVT and PE from Prolonged Television Watching. AB - Pulmonary embolus (PE) and deep vein thrombosis are diagnoses that are commonly made in the emergency department. Well known risk factors for thromboembolic events include immobility, malignancy, pregnancy, surgery, and acquired or inherited thrombophilias, obesity, cigarette smoking, and hypertension. We present a case of a 59-year-old female who watched TV and developed leg swelling and was found to have PE and DVT. PMID- 29109890 TI - Gossypiboma Resection after Eight Years in a Patient with Rheumatoid Arthritis and Diabetes. AB - Gossypiboma is the term used to refer to a mass formed by surgical material left in the body cavity after surgery. We present the case of a middle-aged woman with a history of rheumatoid arthritis controlled with corticosteroids and biologic therapies, uncontrolled type II diabetes mellitus, and cesarean section with postoperative bleeding eight years earlier, who presents with right lower quadrant abdominal pain and is found to have a gossypiboma from her previous operation. A subsequent operation is undertaken to remove the gossypiboma. After the procedure, our patient's diabetes and chronic back pain greatly improve, raising the question of gossypiboma's role in these diseases. A review of our patient's records found that a correct sponge count was recorded after her cesarean section, raising questions about the operating room policies regarding surgical counts, the presence of falsely correct counts, and the need for postoperative plain films in procedures with an increased risk of a retained object. Our patient's presentation eight years after the inciting surgery raises questions about the involvement her immunosuppressive therapy may have had in cloaking the gossypiboma. Our case also raises the question of surgical culpability, including the ethical and legal considerations for apology from the culpable surgeon. PMID- 29109892 TI - Topography and Higher Order Corneal Aberrations of the Fellow Eye in Unilateral Keratoconus. AB - Objectives: Comparison of topography and corneal higher order aberrations (HOA) data of fellow normal eyes of unilateral keratoconus patients with keratoconus eyes and control group. Materials and Methods: The records of 196 patients with keratoconus were reviewed. Twenty patients were identified as unilateral keratoconus. The best corrected visual acuity (BCVA), topography and aberration data of the unilateral keratoconus patients' normal eyes were compared with their contralateral keratoconus eyes and with control group eyes. For statistical analysis, flat and steep keratometry values, average corneal power, cylindrical power, surface regularity index (SRI), surface asymmetry index (SAI), inferior superior ratio (I-S), keratoconus prediction index, and elevation-depression power (EDP) and diameter (EDD) topography indices were selected. Results: Mean age of the unilateral keratoconus patients was 26.05+/-4.73 years and that of the control group was 23.6+/-8.53 years (p>0.05). There was no statistical difference in BCVA between normal and control eyes (p=0.108), whereas BCVA values were significantly lower in eyes with keratoconus (p=0.001). Comparison of quantitative topographic indices between the groups showed that all indices except the I-S ratio were significantly higher in the normal group than in the control group (p<0.05). The most obvious differences were in the SRI, SAI, EDP, and EDD values. All topographic indices were higher in the keratoconus eyes compared to the normal fellow eyes. There was no difference between normal eyes and the control group in terms of spherical aberration, while coma, trefoil, irregular astigmatism, and total HOA values were higher in the normal eyes of unilateral keratoconus patients (p<0.05). All HOA values were higher in keratoconus eyes than in the control group. Conclusion: According to our study, SRI, SAI, EDP, EDD values, and HOA other than spherical aberration were higher in the clinically and topographically normal fellow eyes of unilateral keratoconus patients when compared to a control group. This finding may be due to the mild asymmetric and morphologic changes in the subclinical stage of keratoconus leading to deterioration in the indicators of corneal irregularity and elevation changes. Therefore, these eyes may be exhibiting the early form of the disease. PMID- 29109891 TI - Adipose tissue autophagy and homeostasis in alcohol-induced liver injury. AB - Alcohol consumption leads to injury in multiple organs and systems, including the liver, brain, heart, skeletal muscle, pancreas, bone, immune system, and endocrine system. Emerging evidence indicates that alcohol also promotes adipose tissue dysfunction, which may contribute to injury progression in other organs and systems. Autophagy is a lysosomal degradation pathway that has been shown to regulate adipose tissue homeostasis and adipogenesis. Increasing evidence also demonstrates that alcohol consumption affects autophagy in multiple tissues. This review summarizes current knowledge regarding the effect of autophagy on adipose tissue and its potential roles in alcohol-induced adipose tissue atrophy as well as its contribution to alcohol-induced liver injury. PMID- 29109893 TI - Correlation of Corneal Endothelial Cell Density with Corneal Tomographic Parameters in Eyes with Keratoconus. AB - Objectives: To examine changes in corneal endothelial cell density (ECD) in different stages of keratoconus and evaluate its correlation with corneal tomographic parameters. Materials and Methods: Two hundred six patients with keratoconus were enrolled in the study. Corneal topography was performed by Sirius (CSO, Italy), which has a rotating Scheimpflug camera and a Placido disc topographer. Automatic endothelial analysis was done with the non-contact endothelial microscope (20x probe) of Confoscan-4 (NIDEK, Japan). The eyes were classified into stages based on steepest keratometric value as follows: mild <45 D; moderate 45-52 D; severe >52 D and according to thinnest cornea thickness (TCT) as <400 MUm, 400-450 MUm, and >450 MUm. Tomographic and endothelial cell parameters were compared among the groups using Kruskal-Wallis test and the correlations between them were analyzed using Spearman correlation. Results: The study included 391 eyes of 100 male (24.29+/-7.7 years, range 11-47 years) and 106 female (26.26+/-7.5 years, range 13-45 years) patients (p=0.07). Mean ECD values were 2628+/-262 cells/mm2, 2541.9+/-260.4 cells/mm2, and 2414.6+/-384.3 cells/mm2 in mild, moderate, and severe keratoconus, respectively (p<0.001) and 2592.3+/-277 cells/mm2, 2502+/-307 cells/mm2 and 2348+/-296 cells/mm2 in corneas with TCT values >450 um, 400-450 um, and <400 um, respectively (p<0.001). ECD showed significant negative correlation with keratometric and elevation parameters and positive correlation with pachymetric parameters (p<0.05). Conclusion: As endothelial cell numbers seem to decrease with the progression of keratoconus, specular/confocal microscopy screening should be carried out, especially in eyes with advanced stages and corneas with TCT <400 um. PMID- 29109894 TI - Vitreomacular Interface Disorders in Behcet's Uveitis. AB - Objectives: To determine the prevalence of vitreomacular interface (VMI) disorders in patients with Behcet's uveitis and assess the relationship between VMI disorders and clinical characteristics. Materials and Methods: The macular optical coherence tomography (OCT) images of 160 eyes of 96 patients with Behcet's uveitis who were being followed in the Uvea-Behcet's clinic were assessed retrospectively for VMI disorders including posterior vitreous detachment (PVD), epiretinal membrane (ERM), vitreomacular adhesion (VMA), vitreomacular traction (VMT), full-thickness macular hole (FTMH), lamellar hole (LH) and pseudohole. Results: Twenty-four patients (25%) with unilateral and 72 patients with bilateral uveitis were included in the study. Six (30%) of 20 eyes with anterior uveitis and 57 (40.7%) of 140 eyes with posterior uveitis, in total 63 (39.4%) eyes of 160 eyes had at least one VMI disorder. PVD was detected in 4 eyes (2.5%), ERM in 48 eyes (30%), VMA in 12 eyes (7.5%), and LH in 1 eye (0.6%). None of the eyes had VMT, FTMH, or pseudohole. ERM was detected in 13 eyes (8.1%) on fundus examination and 48 (30%) eyes by OCT (p=0.001). VMI was detected in 12 (50%) of 24 eyes with prior intraocular surgery and 51 (37.5%) of 136 eyes without. The mean duration of uveitis was 7.3+/-5.8 years in patients with VMI disorders and 5.8+/-7.7 years in patients without (p=0.04). There was no relation between VMI disorders and anatomic location of uveitis, history of past ocular surgery, number of ocular/periocular steroid injections, or visual acuity. Conclusion: VMI disorders are common in patients with Behcet's uveitis. Their frequency increases with the duration of uveitis. OCT is more sensitive than fundus examination in the detection of VMI disorders. PMID- 29109895 TI - Are All Retinal Nerve Fiber Layer Defects on Optic Coherence Tomography Glaucomatous? AB - Objectives: In this study, we investigated the patients who were referred to our clinic with a prediagnosis of glaucoma based on retinal nerve fiber layer (RNFL) defects on optic coherence tomography (OCT) but were determined to have nonglaucomatous RNLF defects upon detailed examination. Materials and Methods: The ophthalmic examination notes, OCT images, Heidelberg retinal tomography (HRT) II and fundus photographs of 357 patients were retrospectively evaluated. Final diagnoses of these patients were investigated. Results: Of the 357 patients, 216 (60.5%) were diagnosed as open angle glaucoma, 33 (9.2%) as low-tension glaucoma, 39 (10.9%) as pre-perimetric glaucoma. The ophthalmic examinations of 14 patients (3.9%) were normal and there were no RNFL defects in OCT examinations after dilatation. In 39 patients (10.9%), the ophthalmic and optic disc examinations were completely normal and no etiologic factor explaining RNFL defects was found. Twenty-two eyes of 16 patients (4.5%) were included in this study (the mean age was 53.8+/-11.5 years; 9 men and 7 women). After detailed questioning of the medical history and systemic and neurologic examinations, a diagnosis of ischemic optic neuropathy was made in 11 eyes (10 patients) (2.8%), optic neuritis in 3 eyes (2 patients) (0.6%), optic disc drusen in 4 eyes (2 patients) (0.6%), pseudotumor cerebri in 2 eyes (1 patient) (0.3%), and cerebral palsy in 2 eyes (1 patient) (0.3%). Conclusion: Decrease in RNFL thickness on OCT images alone may be misleading in glaucoma examination. In cases where optic disc cupping is not evident, diagnosis should not be based on OCT RNFL examinations alone, and the patient's medical history, detailed ophthalmic examination, OCT optic disc parameters, HRT, and visual field tests should all be carefully evaluated together. PMID- 29109896 TI - Outcomes of Intravitreal Dexamethasone Implant in the Treatment of Recalcitrant Diabetic Macular Edema. AB - Objectives: To investigate the efficacy and safety of intravitreal dexamethasone (OZURDEX(r)) implantation in patients with recalcitrant diabetic macular edema. Materials and Methods: This is a retrospective non-randomized study of patients who underwent intravitreal dexamethasone implantation for recalcitrant diabetic macular edema. Main outcome measures included changes in best corrected visual acuity (BCVA), central macular thickness (CMT), and incidence of ocular side effects. Results: Fifty-seven eyes of thirty-eight patients (20 females, 18 males; mean age 65+/-7 years) were included in the study. The mean hemoglobin A1c level was 7.9+/-1.7%. Before entering the study, patients had undergone 5.71+/ 3.40 anti-vascular endothelial growth factor (anti-VEGF) and 3.44+/-2.46 intravitreal triamcinolone acetonide injections. The mean duration of diabetes and diabetic macular edema was 17.2+/-6.4 years and 60.2+/-17.6 months, respectively. At baseline, mean CMT was 506.76+/-166.74 um, and the mean BCVA was 0.68+/-0.38 LogMAR. Mean CMT significantly decreased to 341.36+/-146.26 um (p<0.001), 324.41+/-114.58 um (p<0.001), and 384.82+/-151 um (p<0.001) at 1, 3, and 4 months of follow-up and increased again to 462.29+/-152.87 um at 5 months. Sixteen eyes (28%) received second injections after mean of 7.4+/-2.3 months and mean CMT was again significantly decreased at 7, 8, and 9 months. Significant improvement in mean BCVA (0.54+/-0.41 LogMAR; p<0.001) occurred only at 1 month after implantation. However, subgroup analysis revealed significant BCVA improvement in the pseudophakic group at 1, 3, and 4 months. Among phakic patients, 50% showed cataract progression and 28% had elevated intraocular pressure increase which was managed medically. Conclusion: Intravitreal dexamethasone implantation was effective for the first 4 months in eyes with recalcitrant diabetic macular edema. However, it is hard to displace anti-VEGF agents as first-line therapy due to steroid-related complications. PMID- 29109897 TI - Optic Coherence Angiography Findings in Type-2 Macular Telangiectasia. AB - Objectives: To evaluate the vascular changes of idiopathic macular telangiectasia type 2 (MacTel 2) patients with optical coherence tomography angiography (OCTA) and correlate these changes with the findings of spectral domain optical coherence tomography (SD-OCT). Materials and Methods: Simultaneous SD-OCT and OCTA images of 10 eyes of 6 patients who were diagnosed as MacTel 2 in Ankara University Faculty of Medicine, Department of Ophthalmology were obtained and graded according to the OCTA grading system for MacTel 2. Results: Ten eyes of 6 patients were included. Four (66%) patients were female and 2 (34%) were male. The disease was grade 0 in 2 eyes, grade 1 in 2 eyes, grade 2 in 3 eyes, grade 3 in 1 eye, grade 4 in 1 eye, and grade 5 in 1 eye. The most common findings in grade 1, 2, and 3 non-proliferative disease were thinning of the outer retinal layers, presence of intraretinal hyporeflective layers and inner limiting membrane draping. In cases with subretinal choroidal neovascularisation (CNV) in OCTA, CNV or CNV scar was present in the B-scan SD-OCT images. In a case in which OCT was within normal limits, vascular changes consistent with grade 1 disease were observed in OCTA. On the contrary, 2 patients with significant foveal atrophy and macular hole in B-scan showed changes of early disease in OCTA. In some of the eyes, OCTA revealed an intact superficial vascular layer despite visible changes in the deep layer and the presence of neovascularisation. Conclusion: OCTA yields findings which are important for understanding the pathogenesis of the disease and providing better follow-up. Contrary to fundus fluorescein angiography, changes in the deep arterial plexus in the early disease and CNV can be clearly observed with OCTA. To achieve the best results in clinical practice, en face flow maps should be evaluated together with B-scan SD OCT images. PMID- 29109899 TI - Diagnosis of Nephropathic Cystinosis in a Child During Routine Eye Exam. AB - We present a 7-year-old patient who was diagnosed with asymptomatic nephropathic cystinosis following the detection of the pathognomonic corneal white crystalline opacities during a routine eye examination. PMID- 29109898 TI - Limbal Stem Cell Deficiency and Treatment with Stem Cell Transplantation. AB - The cornea is the outermost tissue of the eye and it must be transparent for the maintenance of good visual function. The superficial epithelium of the cornea, which is renewed continuously by corneal stem cells, plays a critical role in the permanence of this transparency. These stem cells are localized at the cornea conjunctival transition zone, referred to as the limbus. When this zone is affected/destroyed, limbal stem cell deficiency ensues. Loss of limbal stem cell function allows colonization of the corneal surface by conjunctival epithelium. Over 6 million people worldwide are affected by corneal blindness, and limbal stem cell deficiency is one of the main causes. Fortunately, it is becoming possible to recover vision by autologous transplantation of limbal cells obtained from the contralateral eye in unilateral cases. Due to the potential risks to the donor eye, only a small amount of tissue can be obtained, in which only 1-2% of the limbal epithelial cells are actually limbal stem cells. Vigorous attempts are being made to expand limbal stem cells in culture to preserve or even enrich the stem cell population. Ex vivo expanded limbal stem cell treatment in limbal stem cell deficiency was first reported in 1997. In the 20 years since, various protocols have been developed for the cultivation of limbal epithelial cells. It is still not clear which method promotes effective stem cell viability and this remains a subject of ongoing research. The most preferred technique for limbal cell culture is the explant culture model. In this approach, a small donor eye limbal biopsy is placed as an explant onto a biocompatible substrate (preferably human amniotic membrane) for expansion. The outgrowth (cultivated limbal epithelial cells) is then surgically transferred to the recipient eye. Due to changing regulations concerning cell-based therapy, the implementation of cultivated limbal epithelial transplantation in accordance with Good Laboratory Practice using xenobiotic-free systems is becoming widely accepted both in Turkey and worldwide. PMID- 29109900 TI - Preventable Diving-related Ocular Barotrauma: A Case Report. AB - The mystical beauty of the subaquatic world is undoubtedly attractive, and many techniques and forms of equipment have been developed in the last few decades to allow us to explore the underwater world. A swimmer or diver needs swimming goggles or a diving mask to have clear vision because of the refraction problem between the eye and the water interface. Although these items are effective for clear vision, they can result in "ocular or facial barotrauma of descent" during diving. It is possible to prevent these types of barotrauma with correct techniques and precautions, thus enabling the continuation of recreational diving without recurrence. In this paper, we report a case of subconjunctival hemorrhage caused by breath-hold diving and discuss the causes of ocular barotrauma of descent and preventive measures. PMID- 29109901 TI - Posterior Polar Central Choroidal Dystrophy: A Case Report. AB - A 52-year-old male presented with a 25-year history of decreasing vision. Best corrected visual acuity was 0.3 in his right and 0.2 in his left eye. Fundoscopic examination showed bilateral symmetric atrophy of the retinal pigment epithelium and choriocapillaris in the posterior polar areas between vascular arcades and surrounding the optic disc. On fluorescein angiography, the large choroidal vessels beneath these affected regions were easily seen. Fundus autofluorescence imaging showed clearly defined hypoautofluorescent areas that corresponded to the aforementioned lesions. Atrophy of the choriocapillaris and outer retinal layer were detected in optical coherence tomography. Photopic and scotopic responses were subnormal in flash electroretinogram (ERG), and responses were also minimal in pattern ERG and multifocal ERG. The patient was diagnosed with posterior polar central choroidal dystrophy. We aimed to present the results of fluorescein angiography, fundus autofluorescence imaging, optical coherence tomography, and electrophysiological tests in this rare case of posterior polar central choroidal dystrophy. PMID- 29109902 TI - Assessment of Spectral-Domain Optical Coherence Tomography Findings in Three Cases of X-Linked Juvenile Retinoschisis in the Same Family. AB - X-linked juvenile retinoschisis (XLRS) is an X-linked hereditary retinal dystrophy characterized by splitting of the neurosensory retina. On fundus examination, the macula often has a spoke wheel appearance with foveal cystic lesions, and separation of the retinal layers is typical on spectral-domain optical coherence tomography (SD-OCT). Patients with XLRS can exhibit different clinical courses, stages, and SD-OCT findings, even among members of the same family. SD-OCT is an important imaging method that allows us to achieve more detailed information about XLRS. In this study, we report three patients in the same family who have different clinical features and SD-OCT findings. PMID- 29109903 TI - The Diagnostic Role of Multimodal Imaging Techniques in Isolated Foveal Hypoplasia. AB - To report a case of bilateral isolated foveal hypoplasia in which multimodal imaging was used to confirm the diagnosis. Fundus autofluorescence imaging, optical coherence tomography (OCT), and fundus fluorescein angiography were used to describe the typical findings of a patient with isolated foveal hypoplasia. Spectral domain OCT showed absence of foveal depression and persistent inner retinal layers in the fovea. Fundus autofluorescence did not reveal foveal hypoautofluorescence in the presumed foveal area. Clinical diagnosis of foveal hypoplasia may be difficult due to the subtle nature of fundus findings. Fundus autofluorescence imaging may help to diagnose these patients. Foveal hypoplasia should be considered in the differential diagnosis of absence of foveal hypoautofluorescence. PMID- 29109904 TI - Visible-Light Photocatalytic Decarboxylation of alpha,beta-Unsaturated Carboxylic Acids: Facile Access to Stereoselective Difluoromethylated Styrenes in Batch and Flow. AB - The development of synthetic methodologies which provide access to both stereoisomers of alpha,beta-disubstituted olefins is a challenging undertaking. Herein, we describe the development of an operationally simple and stereoselective synthesis of difluoromethylated styrenes via a visible-light photocatalytic decarboxylation strategy using fac-Ir(ppy)3 as the photocatalyst. Meta- and para-substituted cinnamic acids provide the expected E-isomer. In contrast, ortho-substituted cinnamic acids yield selectively the less stable Z product, whereas the E-isomer can be obtained via continuous-flow processing through accurate control of the reaction time. Furthermore, our protocol is amenable to the decarboxylative difluoromethylation of aryl propiolic acids. PMID- 29109905 TI - Abnormalities of Eye-Hand Coordination in Patients with Writer's Cramp: Possible Role of the Cerebellum. AB - Background: Writer's cramp (WC) is one of the commonly observed focal dystonias. The pathophysiology of WC has not been fully understood. The role of the cerebellum has been increasingly recognized in the pathogenesis of dystonia. As the cerebellum is crucial for maintaining accurate eye-hand coordination (EHC), its role in the pathogenesis of WC can be investigated by studying the EHC in patients with WC. Methods: Fifteen patients with WC (women:men, 3:12) and 15 age- and gender-matched controls performed oculomotor and EHC tasks. A visually guided stimulus (VGS) task was first performed with eye-only condition (EOC) and then with EHC. Results: A significant interaction between the groups (controls and patients) and tasks (EOC and EHC) with age as a covariate confirmed that the two groups reacted differently to the tasks in saccadic latency (F(1,27) = 4.8; p = 0.039) and average saccade acceleration (F(1,27) = 10.6; p = 0.003). The curvature index of acceleration of the hand was significantly more in patients compared to controls (patients vs. controls, 2.4+/-0.4 vs. 1.8+/-0.2, p = 0.01). While performing the EHC task, there was a significant correlation of the Writer's Cramp Rating Score with the average saccadic speed (-0.61, p = 0.016), peak saccadic deceleration (0.59, p = 0.019) and average saccadic acceleration ( 0.63, p = 0.012). Discussion: Saccadic acceleration and latency are abnormal while performing EHC tasks in patients with WC. Our study gives further insights into the possible role of the cerebellum in the pathogenesis of WC. PMID- 29109906 TI - The Movement Disorder of Brain-Lung-Thyroid Syndrome Can be Responsive to Methylphenidate. PMID- 29109907 TI - A Temporal White Noise Analysis for Extracting the Impulse Response Function of the Human Electroretinogram. AB - Purpose: We introduce a method for determining the impulse response function (IRF) of the ERG derived from responses to temporal white noise (TWN) stimuli. Methods: This white noise ERG (wnERG) was recorded in participants with normal trichromatic vision to full-field (Ganzfeld) and 39.3 degrees diameter focal stimuli at mesopic and photopic mean luminances and at different TWN contrasts. The IRF was obtained by cross-correlating the TWN stimulus with the wnERG. Results: We show that wnERG recordings are highly repeatable, with good signal-to noise ratio, and do not lead to blink artifacts. The wnERG resembles a flash ERG waveform with an initial negativity (N1) followed by a positivity (P1), with amplitudes that are linearly related to stimulus contrast. These N1 and N1-P1 components showed commonalties in implicit times with the a- and b-waves of flash ERGs. There was a clear transition from rod- to cone-driven wnERGs at ~1 photopic cd.m-2. We infer that oscillatory potentials found with the flash ERG, but not the wnERG, may reflect retinal nonlinearities due to the compression of energy into a short time period during a stimulus flash. Conclusion: The wnERG provides a new approach to study the physiology of the retina using a stimulation method with adaptation and contrast conditions similar to natural scenes to allow for independent variation of stimulus strength and mean luminance, which is not possible with the conventional flash ERG. Translational Relevance: The white noise ERG methodology will be of benefit for clinical studies and animal models in the evaluation of hypotheses related to cellular redundancy to understand the effects of disease on specific visual pathways. PMID- 29109908 TI - Extraocular Muscle Repair and Regeneration. AB - Purpose of Review: The goal of this review is to summarize the unique regenerative milieu within mature mammalian extraocular muscles (EOMs). This will aid in understanding disease propensity for and sparing of EOMs in skeletal muscle diseases as well as the recalcitrance of the EOM to injury. Recent Findings: The EOMs continually remodel throughout life and contain an extremely enriched number of myogenic precursor cells that differ in number and functional characteristics from those in limb skeletal muscle. The EOMs also contain a large population of Pitx2-positive myogenic precursor cells that provide the EOMs with many of their unusual biological characteristics, such as myofiber remodeling and skeletal muscle disease sparing. This environment provides for rapid and efficient remodeling and regeneration after various types of injury. In addition, the EOMs show a remarkable ability to respond to perturbations of single muscles with coordinated changes in the other EOMs that move in the same plane. Summary: These data will inform Ophthalmologists as they work toward developing new treatments for eye movement disorders, new approaches for repair after nerve or direct EOMs injury, as well as suggest potential explanations for the unusual disease propensity and disease sparing characteristics of human EOM. PMID- 29109909 TI - Estrogen therapy offsets thermal impairment of vitellogenesis, but not zonagenesis, in maiden spawning female Atlantic salmon (Salmo salar). AB - In female Atlantic salmon (Salmo salar), exposure to warm summer temperatures causes a reduction in plasma 17beta-estradiol (E2), which impairs downstream vitellogenesis and zonagenesis, and reduces egg fertility and embryo survival. The aim of the present study was to determine whether E2-treatment could offset thermal impairment of endocrine function and maintain egg quality in maiden (first-time-spawning) S. salar reared at 22 degrees C. Treatment with E2 at 22 degrees C stimulated vitellogenin (vtg) gene expression and subsequent protein synthesis which promoted oocyte growth and increased egg size relative to untreated fish at 14 and 22 degrees C. However, E2-treatment at 22 degrees C was not associated with an increase in egg fertility and embryo survival relative to untreated fish at 22 degrees C, despite the positive effects of E2-treatment on vitellogenesis and oocyte growth. As there was no evidence to suggest that the estrogen receptor alpha expression was suppressed by high temperature, this could be due to the lack of stimulation on zonagenesis by E2-treatment observed at high temperature during oocyte development. Our results demonstrate that treatment with E2 is not able to maintain zonagenesis or egg quality in maiden S. salar at high temperature, even when vtg gene expression, protein synthesis and subsequent oocyte growth is promoted. This implies that the mechanisms regulating zonagenesis, but not vitellogenesis are impaired at elevated temperature in female S. salar broodstock, and highlights the remarkable complexity of thermally induced endocrine disruption in fish. PMID- 29109910 TI - Effects of graded concentrations of supplemental lead on lead concentrations in tissues of pigs and prediction equations for estimating dietary lead intake. AB - The objectives of this experiment were to determine the effects of graded dietary lead (Pb) concentrations on body weight and Pb concentrations in blood, hair, soft tissues, and urine from pigs and to generate equations for estimating daily Pb intake. Sixteen barrows with initial body weight 36.3 kg (standard deviation = 2.3) were allotted to four dietary treatments that consisted of graded supplemental Pb concentrations (0, 10, 25, and 250 mg/kg of diet). Daily feed allowances for each pig were 1 kg for first two weeks and 2 kg for last two weeks. The hair and blood of pigs were collected on d 14 and 28. At the end of experiment, the pigs were euthanized, and the liver, kidneys, muscle, and urine samples were collected. The prediction equations for estimating daily Pb intake of pigs were generated using Pb concentration of blood, hair, tissues, or urine as an independent variable. The Pb concentrations in the blood, hair, liver, kidneys, muscle, and urine linearly increased (P < 0.01) with increasing dietary Pb concentrations. There were quadratic effects (P < 0.05) of increasing dietary Pb concentration on Pb concentrations in the blood, hair, and muscle. There were highly positive correlations between dietary Pb concentration and Pb concentrations in the blood, hair, liver, kidneys, muscle, and urine (r > 0.83; P < 0.01). The equations were significant (P < 0.01) and showed high r2 (>0.83), except the equation using Pb concentration in the muscle as an independent variable. In conclusion, the dietary Pb concentration was highly correlated with Pb concentrations in the blood, hair, soft tissues, and urine of pigs. The total dietary Pb intake can be estimated from the Pb concentrations in the blood, hair, soft tissues, or urine for pigs. PMID- 29109911 TI - Can 9q34.2 rs633862 polymorphism predict survival in epithelial ovarian cancer? AB - Objective: Our previous genome-wide association study (GWAS) identified that the ABO rs633862 variant in chromosome 9q34.2 was associated with the risk of epithelial ovarian cancer (EOC) in Chinese Han women. The aim of the present study was to evaluate its prognostic effect on EOC. Methods: A total of 669 EOC patients were enrolled for the genotyping of rs633862 variant in 9q34.2. We used Kaplan-Meier survival curves, univariate and multivariate Cox proportional hazard models to evaluate the association of rs633862 with overall survival (OS) in EOC patients. Results: We found that rs633862 variant AG/GG genotypes were significantly associated with a longer OS by using univariate Cox proportional hazards regression analysis, compared with the rs633862 AA genotype (HR = 0.69, 95% CI [0.49-0.98], p = 0.035), albeit with a boardline significance in the multivariate analysis. Similar findings were observed in the subgroup of high grade serous ovarian carcinoma. Further expression quantitative trait loci (eQTL) analysis indicated that the rs633862 AA genotype was associated with an increased level of ABO mRNA expression (p = 1.8 * 10-11). Conclusions: Supplementary to the previous GWAS, our study provides additional evidence on the prognostic value of the 9q34.2 rs633862 variant in EOC patients, and this variant may function by regulating the ABO mRNA expression. PMID- 29109912 TI - Genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry. AB - Background: Currently, there is limited knowledge about the genetics underlying pigmentary traits in East Asian populations. Here, we report the results of the first genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry. Methods: We obtained quantitative skin pigmentation measures (M-index) in the inner upper arm of the participants using a portable reflectometer (N = 305). Quantitative measures of iris color (expressed as L*, a* and b* CIELab coordinates) were extracted from high resolution iris pictures (N = 342). We also measured the color differences between the pupillary and ciliary regions of the iris (e.g., iris heterochromia). DNA samples were genotyped with Illumina's Infinium Multi-Ethnic Global Array (MEGA) and imputed using the 1000 Genomes Phase 3 samples as reference haplotypes. Results: For skin pigmentation, we did not observe any genome-wide significant signal. We followed-up in three independent Chinese samples the lead SNPs of five regions showing multiple common markers (minor allele frequency >= 5%) with good imputation scores and suggestive evidence of association (p-values < 10-5). One of these markers, rs2373391, which is located in an intron of the ZNF804B gene on chromosome 7, was replicated in one of the Chinese samples (p = 0.003). For iris color, we observed genome-wide signals in the OCA2 region on chromosome 15. This signal is driven by the non-synonymous rs1800414 variant, which explains 11.9%, 10.4% and 6% of the variation observed in the b*, a* and L* coordinates in our sample, respectively. However, the OCA2 region was not associated with iris heterochromia. Discussion: Additional genome-wide association studies in East Asian samples will be necessary to further disentangle the genetic architecture of pigmentary traits in East Asian populations. PMID- 29109913 TI - Comparative analysis of the microRNA transcriptome between yak and cattle provides insight into high-altitude adaptation. AB - Extensive and in-depth investigations of high-altitude adaptation have been carried out at the level of morphology, anatomy, physiology and genomics, but few investigations focused on the roles of microRNA (miRNA) in high-altitude adaptation. We examined the differences in the miRNA transcriptomes of two representative hypoxia-sensitive tissues (heart and lung) between yak and cattle, two closely related species that live in high and low altitudes, respectively. In this study, we identified a total of 808 mature miRNAs, which corresponded to 715 pre-miRNAs in the two species. The further analysis revealed that both tissues showed relatively high correlation coefficient between yak and cattle, but a greater differentiation was present in lung than heart between the two species. In addition, miRNAs with significantly differentiated patterns of expression in two tissues exhibited co-operation effect in high altitude adaptation based on miRNA family and cluster. Functional analysis revealed that differentially expressed miRNAs were enriched in hypoxia-related pathways, such as the HIF 1alpha signaling pathway, the insulin signaling pathway, the PI3K-Akt signaling pathway, nucleotide excision repair, cell cycle, apoptosis and fatty acid metabolism, which indicated the important roles of miRNAs in high altitude adaptation. These results suggested the diverse degrees of miRNA transcriptome variation in different tissues between yak and cattle, and suggested extensive roles of miRNAs in high altitude adaptation. PMID- 29109914 TI - Revisiting the tryptophan-serotonin deficiency and the inflammatory hypotheses of major depression in a biopsychosocial approach. AB - Background: The aim of this cross-sectional study was to identify important biopsychosocial correlates of major depression. Biological mechanisms, including the inflammatory and the tryptophan-serotonin deficiency hypotheses of major depression, were investigated alongside health-related quality of life, life satisfaction, and social support. Methods: The concentrations of plasma tryptophan, plasma kynurenine, plasma kynurenic acid, serum quinolinic acid, and the tryptophan breakdown to kynurenine were determined alongside health-related quality of life (Medical Outcome Study Form, SF-36), life satisfaction (Life Satisfaction Questionnaire, FLZ), and social support (Social Support Survey, SSS) in 71 depressive patients at the time of their in-patient admittance and 48 healthy controls. Results: Corresponding with the inflammatory hypothesis of major depression, our study results suggest a tryptophan breakdown to kynurenine in patients with major depression, and depressive patients had a lower concentration of neuroprotective kynurenic acid in comparison to the healthy controls (Mann-Whitney-U: 1315.0; p = 0.046). Contradicting the inflammatory theory, the concentrations of kynurenine (t: -0.945; df = 116; p = 0.347) and quinolinic acid (Mann-Whitney-U: 1376.5; p = 0.076) in depressive patients were not significantly different between depressed and healthy controls. Our findings tend to support the tryptophan-serotonin deficiency hypothesis of major depression, as the deficiency of the serotonin precursor tryptophan in depressive patients (t: -3.931; df = 116; p < 0.001) suggests dysfunction of serotonin neurotransmission. A two-step hierarchical linear regression model showed that low tryptophan concentrations, low social support (SSS), occupational requirements (FLZ), personality traits (FLZ), impaired physical role (SF-36), and impaired vitality (SF-36) predict higher Beck Depression Inventory (BDI-II) scores. Discussion: Our study results argue for the validity of a biopsychosocial model of major depression with multiple pathophysiological mechanisms involved. PMID- 29109915 TI - Mechanisms of oat (Avena sativa L.) acclimation to phosphate deficiency. AB - Background: Deficiency of available forms of phosphorus is common in most soils and causes reduction of crop plants growth and yield. Recently, model plants responses to phosphate (Pi) deficiency have been intensively studied. However, acclimation mechanisms of cereals like oat (Avena sativa L.), to low Pi stress remains not fully understood. Oat plants have been usually cultured on poor soils, with a low nutrient content, but their responses to such conditions are not well known, therefore the main goal of the study was to investigate the mechanisms that enable oat plants to grow under low Pi conditions. Methods: Four oat cultivars (A. sativa, cv. Arab, Krezus, Rajtar and Szakal) were grown for three weeks in a nutrient media with various P sources: inorganic-KH2PO4 (control), organic-phytate (PA) and with no phosphate (-P). The effects of Pi deficiency on the level of P, oat growth parameters, intensity of photosynthesis, plant productivity, root exudation ability, localization, activity and isoforms of acid phosphatases, enzymes involved in Pi mobilization, were estimated. In addition, the effect of mycorrhization on plant growth was also observed. Results: All studied oat cultivars grown on Pi-deficient media had significantly decreased Pi content in the tissues. Pi deficiency caused inhibition of shoot growth, but generally it did not affect root elongation; root diameter was decreased, root/shoot ratios increased, whereas PA plants showed a similar growth to control. Photosynthesis rate and productivity parameters decreased under low Pi nutrition, however, sugar content generally increased. Studied oat cultivars did not respond to low Pi via increased exudation of carboxylates from the roots, as pH changes in the growth media were not observed. Pi starvation significantly increased the activity of extracellular and intracellular acid phosphatases (APases) in comparison to the control plants. Three major APase isoforms were detected in oat tissues and the isoform pattern was similar in all studied conditions, usually with a higher level of one of the isoforms under Pi starvation. Generally no significant effects of mycorrhizal colonization on growth of oat cultivars were observed. Discussion: We postulated that acid phosphatases played the most important role in oat cultivars acclimation to Pi deficiency, especially extracellular enzymes involved in Pi acquisition from soil organic P esters. These APases are mainly located in the epidermis of young roots, and may be released to the rhizosphere. On the other hand, intracellular APases could be involved in fast Pi remobilization from internal sources. Our study showed that oat, in contrast to other plants, can use phytates as the sole source of P. The studied oat cultivars demonstrated similar acclimation mechanisms to Pi deficiency, however, depending on stress level, they can use different pools of acid phosphatases. PMID- 29109916 TI - Self-medication practices and rational drug use habits among university students: a cross-sectional study from Kahramanmaras, Turkey. AB - Background: Self-medication refers to the use of medicines to treat self diagnosed diseases without consulting any healthcare professionals. Irrational drug use and self-medication have serious negative consequences both on health and economy. Therefore, the aim of this study is to assess the habits related to rational use of drugs (RUD) and to estimate the prevalence of self-medication practices among university students. Methods: This cross-sectional study was conducted on university students in Kahramanmaras. From May 2017 to June 2017 a total of 960 students filled a "Rational Use of Drugs Questionnaire". Results: The prevalence of practicing self-medication in students was 63.4%. The most common medicines that the students had consumed without prescription were analgesics by 39.5%, antibiotics by 36.9% and cold remedies by 24.0%. The rate of students who declared that they were familiar with RUD and "rational use of antibiotics" (RUA) was 45.9%. Reading/checking the instructions in the prospectus (OR = 1.529, 95% CI [1.176-1.990]), understanding the context of the prospectus (OR = 1.893, 95% CI [1.387-2.584]), compliance with the duration of antibiotic treatment (OR = 1.597, 95% CI [1.231-2.071]) and consulting a physician in case of a side effect (OR = 1.350, 95% CI [1.037-1.757]) were significantly higher among students who were familiar with RUD as compared to who were not. Discussion: Since the awareness of RUD among university students was found to be inadequate, it has critical importance to hold educational activities with the cooperation of physicians, health organizations, universities, non-governmental organizations and media to avoid negative consequences of irrational drug use and self-medication. PMID- 29109917 TI - Scaldiporia vandokkumi, a new pontoporiid (Mammalia, Cetacea, Odontoceti) from the Late Miocene to earliest Pliocene of the Westerschelde estuary (The Netherlands). AB - Background: The family Pontoporiidae (Cetacea, Odontoceti, Inioidea) is currently represented in our oceans by just one species of diminutive dolphin (Pontoporia blainvillei, franciscana). Although P. blainvillei is limited to coastal waters of the South Atlantic along Brazil, Uruguay and Argentina, multiple Miocene and Pliocene fossils indicate the past presence of members of the family in the South Atlantic, South Paciifc and North Atlantic oceans. Our comprehension of the origin and diversity of this clade and of the relationships of its members with other inioids is hampered by the fact that part of the described fossil specimens, especially from the North Atlantic realm, are cranial fragments often associated to limited stratigraphic information. Methods: Based on an almost complete fossil cranium of pontoporiid from the Westerschelde estuary, The Netherlands, whose preservation allows for detailed morphological observations, we describe a new genus and species. The latter is compared to other pontoporiids, as well as a few non-pontoporiid inioids. A phylogenetic analysis is performed to investigate the relationship of S. vandokkumi with the best-known extinct and extant inioids. Palynological analysis of the sediment associated to the holotype is used to assess its geological age. Results and discussion: The new genus and species Scaldiporia vandokkumi is characterized among others by greatly thickened premaxillary eminences reaching the level of the antorbital notch. Palynologically dated from the late Tortonian-earliest Zanclean (7.6-5 Ma, Late Miocene-earliest Pliocene), this new pontoporiid confirms the surprising past diversity of marine inioids in the North Atlantic area. Finally the content of the pontoporiid subfamily Brachydelphininae is briefly discussed. PMID- 29109918 TI - Microsatellites for Phytolacca acinosa (Phytolaccaceae), a traditional medicinal herb. AB - Premise of the study: Phytolacca acinosa (Phytolaccaceae) is a traditional Chinese herb with multiple medicinal uses and is an important pigment source. Due to excessive human harvesting, the population numbers and sizes have decreased dramatically. Methods and Results: Using an enriched genomic library, we developed and characterized 15 microsatellite primers for P. acinosa, 13 of which were polymorphic. The number of alleles varied from two to seven. The observed heterozygosity and expected heterozygosity per locus ranged from 0.267 to 1.000 and 0.331 to 0.743, respectively. All of the primers that were developed were also successfully applied in P. americana. Conclusions: These markers should be useful in probing the genetic diversity, genetic structure, and mating systems of P. acinosa, which could provide information about protecting and sustainably harvesting this species. PMID- 29109920 TI - Using genomic data to develop chloroplast DNA SSRs for the Neotropical liana Stizophyllum riparium (Bignonieae, Bignoniaceae). AB - Premise of the study: We developed chloroplast microsatellite markers (cpSSRs) to be used to study the patterns of genetic structure and genetic diversity of populations of Stizophyllum riparium (Bignonieae, Bignoniaceae). Methods and Results: We used genomic data obtained through an Illumina HiSeq sequencing platform to develop a set of cpSSRs for S. riparium. A total of 36 primer pairs were developed, of which 28 displayed polymorphisms across 59 individuals from three populations. Two to 12 alleles were recorded, and the unbiased haploid diversity per locus ranged from 0.037 to 0.905. All 28 cpSSRs presented transferability to two closely related species, S. inaequilaterum and S. perforatum. Conclusions: We report a set of 28 cpSSRs for S. riparium. All markers were shown to be variable in S. riparium, indicating that these markers will be valuable for population genetic studies across S. riparium and congeneric species. PMID- 29109921 TI - Development and characterization of EST-SSR markers via transcriptome sequencing in Brainea insignis (Aspleniaceae s.l.). AB - Premise of the study: Brainea insignis (Aspleniaceae) is an endangered tree fern in China whose wild populations have been seriously damaged due to overexploitation. Expressed sequence tag-simple sequence repeat (EST-SSR) primers were developed to investigate its genetic diversity and provide resources for future conservation studies. Methods and Results: We obtained 72,897 unigenes of B. insignis using transcriptome sequencing and detected 15,006 SSRs in 12,058 unigenes. Based on these results, we designed 100 EST-SSR primer pairs and successfully amplified 52 of them in six individuals; 27 demonstrated polymorphisms after amplification against 72 individuals across three populations. Allele numbers ranged from three to 10, and the observed and expected heterozygosities ranged from 0.105 to 1.000 and from 0.523 to 0.865, respectively, in the tested populations. Most of these primers could be successfully amplified in two other fern species (Blechnumorientale and Chieniopteris harlandii). Conclusions: These selected EST-SSRs are valuable for genetic diversity and conservation studies in B. insignis and other related fern species. PMID- 29109919 TI - The unexpected depths of genome-skimming data: A case study examining Goodeniaceae floral symmetry genes. AB - Premise of the study: The use of genome skimming allows systematists to quickly generate large data sets, particularly of sequences in high abundance (e.g., plastomes); however, researchers may be overlooking data in low abundance that could be used for phylogenetic or evo-devo studies. Here, we present a bioinformatics approach that explores the low-abundance portion of genome skimming next-generation sequencing libraries in the fan-flowered Goodeniaceae. Methods: Twenty-four previously constructed Goodeniaceae genome-skimming Illumina libraries were examined for their utility in mining low-copy nuclear genes involved in floral symmetry, specifically the CYCLOIDEA (CYC)-like genes. De novo assemblies were generated using multiple assemblers, and BLAST searches were performed for CYC1, CYC2, and CYC3 genes. Results: Overall Trinity, SOAPdenovo Trans, and SOAPdenovo implementing lower k-mer values uncovered the most data, although no assembler consistently outperformed the others. Using SOAPdenovo Trans across all 24 data sets, we recovered four CYC-like gene groups (CYC1, CYC2, CYC3A, and CYC3B) from a majority of the species. Alignments of the fragments included the entire coding sequence as well as upstream and downstream regions. Discussion: Genome-skimming data sets can provide a significant source of low-copy nuclear gene sequence data that may be used for multiple downstream applications. PMID- 29109922 TI - Isolation and characterization of microsatellite markers for Hypochaeris incana (Asteraceae) and close relatives. AB - Premise of the study: We developed microsatellite markers to study clonal growth and interspecific hybridization in the Patagonian and subantarctic plant Hypochaeris incana (Asteraceae) and its closest relatives. Methods and Results: We developed primers for microsatellite loci from 454 sequence reads of genomic DNA of H. incana. We tested them on individuals of H. acaulis, H. hookeri, H. incana, H. palustris, and H. tenuifolia. We selected 15 polymorphic microsatellite loci, which delivered clearly scorable fragments in most or all species. With mean values between 0.7 and 0.8, the expected heterozygosity in populations of H. incana is high. Conclusions: Due to high levels of polymorphism, the developed markers make it possible to distinguish between genets and ramets in H. incana. In some markers, null alleles complicate the scoring of genotypes in tetraploids. All of the developed markers are suitable to study interspecific hybridization among this group of closely related species. PMID- 29109923 TI - Development and characterization of genomic SSR markers for Anneslea fragrans (Pentaphylacaceae). AB - Premise of the study: The genus Anneslea (Pentaphylacaceae) contains four species and six varieties, most of which are locally endemic. Here, simple sequence repeat (SSR) markers were developed for the conservation of these species. Methods and Results: The genome of A. fragrans was sequenced and de novo assembled into 445,162 contigs, of which 30,409 SSR loci were detected. Primers for 100 SSR loci were validated with PCR amplification in three populations of A. fragrans. Seventy-nine loci successfully amplified, and 30 were polymorphic. The mean number of alleles, observed heterozygosity, and expected heterozygosity were 7.01 +/- 1.60, 0.817 +/- 0.241, and 0.796 +/- 0.145, respectively. Most primers could be amplified in Ternstroemia gymnanthera, T. kwangtungensis, and Cleyerapachyphylla. Conclusions: Our study demonstrated that shotgun genome sequencing is an efficient way to develop genomic SSR markers for nonmodel species. These genomic SSR loci will be valuable in population genetic studies in Anneslea and its relatives. PMID- 29109924 TI - The frontier of data discoverability: Why we need to share our data. AB - We are now in an era where sharing and making data widely accessible are not only expected within many disciplines, but also required by federal granting agencies and many scientific journals. In addition, there are practical reasons why authors should deposit their data into permanent data repositories: (1) it prevents data loss due to accidents, theft, or death of the researcher; (2) it enables published research to be reproduced by others; (3) publications associated with accessible data sets can have higher citation rates; (4) deposited data sets are increasingly recognized for scholarly recognition and professional advancement; and (5) stored and accessible data can be used in the future for projects that are unanticipated today. Applications in Plant Sciences requires that data underlying its articles be publicly accessible as a condition of publication to promote the continued advancement of the field of plant biology. PMID- 29109925 TI - Saccharification of citrus wastes by immobilized polygalacturonase in an improved alginate matrix. AB - Enzyme immobilization using hydrogels is a low-cost and effective system for the degradation of bulk pectin derived from orange industry residues. Polygalacturonases obtained from four different bacterial strains of Streptomyces genus were immobilized in alginate gel and assayed for pectin hydrolysis. The enzyme from Streptomyces halstedii ATCC 10897 proved to be superior and more stable within the alginate matrix. Furthermore, a new strategy to improve alginate bead stability using a mixture of calcium and strontium is reported; this technique allowed enhancing the mechanical properties by combining different amounts of these cations for ionotropic gelation. The developed biocatalyst showed maximum hydrolysis at 2 h, generating 1.54 mg/mL of reducing sugars and decreasing the viscosity of polygalacturonic acid by 98.9%. Reusability up to 29 successive reactions (58 h) demonstrated a very stable performance. The heterogeneous biocatalyst was used in the enzymatic saccharification of orange peel albedo (2.23 mg/mL) for adding value to this agro-waste by industrial exploitation. PMID- 29109926 TI - Modified microplate method for rapid and efficient estimation of siderophore produced by bacteria. AB - In this study, siderophore production by various bacteria amongst the plant growth-promoting rhizobacteria was quantified by a rapid and efficient method. In total, 23 siderophore-producing bacterial isolates/strains were taken to estimate their siderophore-producing ability by the standard method (chrome azurol sulphonate assay) as well as 96 well microplate method. Production of siderophore was estimated in percent siderophore unit by both the methods. It was observed that data obtained by both methods correlated positively with each other proving the correctness of microplate method. By the modified microplate method, siderophore production by several bacterial strains can be estimated both qualitatively and quantitatively at one go, saving time, chemicals, making it very less tedious, and also being cheaper in comparison with the method currently in use. The modified microtiter plate method as proposed here makes it far easier to screen the plant-growth-promoting character of plant-associated bacteria. PMID- 29109927 TI - Low-Intensity Pulsed Ultrasound and Halo Immobilization Is an Effective Treatment for Nonunion Following Traumatic Spondylolisthesis of the Axis. AB - This case report describes a unique case involving traumatic spondylolisthesis of the axis that resulted in nonunion, angulation, and displacement after conservative treatment with a cervical collar, but which was successfully achieved union with halo immobilization and low-intensity pulsed ultrasound (LIPUS). Halo immobilization of a traumatic spondylolisthesis in a 20-year-old patient, that previously failed to improve after wearing a cervical collar for 3 months, was immediately followed by treatment with a LIPUS device (SAFHS 4000J; Teijin Pharma, Tokyo, Japan) 20 minutes once daily to the right and left fracture sites which were located using fluoroscopic guidance. Radiographs and computed tomography showed conclusive evidence of bone union after 10 weeks of treatment with halo immobilization. No adverse events were observed. To the best of our knowledge, this is the first report describing that the combination of halo immobilization and LIPUS therapy might be a safe, effective, and feasible method by which to treat cervical spine fractures. PMID- 29109928 TI - Ventriculoperitoneal Shunt-Associated Vancomycin-Resistant Meningitis Complicating a Patient Undergoing Plasmapheresis for Presumed Systemic Lupus Erythematosus-Associated Transverse Myelitis. AB - Objectives We report a patient who had a working diagnosis of transverse myelitis secondary to a lupus exacerbation. As his clinical course evolved, continued vigilance clarified that he was in fact suffering from a nosocomial infection caused by vancomycin-resistant Enterococcus (VRE). Methods We performed a retrospective review of the patient's medical record. Results Despite radiographic improvement, he did not improve clinically following immunosuppressive therapy including plasma exchange. Once meningitis was diagnosed and treated, he improved rapidly. Conclusion The prospect of transverse myelitis may confound the diagnosis of VRE meningitis, a uniquely treated and potentially deadly infection. PMID- 29109930 TI - Error assessment in molecular dynamics trajectories using computed NMR chemical shifts. AB - Accurate chemical shifts for the atoms in molecular mechanics (MD) trajectories can be obtained from quantum mechanical (QM) calculations that depend solely on the coordinates of the atoms in the localized regions surrounding atoms of interest. If these coordinates are correct and the sample size is adequate, the ensemble average of these chemical shifts should be equal to the chemical shifts obtained from NMR spectroscopy. If this is not the case, the coordinates must be incorrect. We have utilized this fact to quantify the errors associated with the backbone atoms in MD simulations of proteins. A library of regional conformers containing 169,499 members was constructed from 6 model proteins. The chemical shifts associated with the backbone atoms in each of these conformers was obtained from QM calculations using density functional theory at the B3LYP level with a 6-311+G(2d,p) basis set. Chemical shifts were assigned to each backbone atom in each MD simulation frame using a template matching approach. The ensemble average of these chemical shifts was compared to chemical shifts from NMR spectroscopy. A large systematic error was identified that affected the 1H atoms of the peptide bonds involved in hydrogen bonding with water molecules or peptide backbone atoms. This error was highly sensitive to changes in electrostatic parameters. Smaller errors affecting the 13Ca and 15N atoms were also detected. We believe these errors could be useful as metrics for comparing the force-fields and parameter sets used in MD simulation because they are directly tied to errors in atomic coordinates. PMID- 29109931 TI - Clinical trials and healthcare needs in India: A difficult balancing act but opportunities abound! PMID- 29109929 TI - Opportunities for Therapeutic Intervention During Machine Perfusion. AB - Purpose of review: There is a vast discrepancy between the number of patients waiting for organ transplantation and the available donor organs. Ex vivo machine perfusion (MP) has emerged in an effort to expand the donor pool, by improving organ preservation, providing diagnostic information, and more recently, acting as a platform for organ improvement. This article reviews the current status of MP with a focus on its role in organ preconditioning and therapeutic interventions prior to transplantation. Recent findings: MP has allowed longer organ preservation compared to conventional static cold storage and allowed the use of organs that might otherwise have been discarded. Moreover, experimental studies have investigated the role of MP in reducing ischemia reperfusion injury of lungs, kidneys and livers by applying mesenchymal stem cells (MSCs), anti inflammatory agents, cytotopic anticoagulants, and defatting cocktails. Summary: MP has opened a new era in the field of organ transplantation and tissue medication. PMID- 29109932 TI - International Council for Harmonisation E6(R2) addendum: Challenges of implementation. AB - The International Council for Harmonisation (ICH) E6 - good clinical practice (GCP) (R2) addendum - was released in 2016 to encourage implementation of improved approaches for the management of clinical trials. The changes in different sections include new approaches - quality management system, risk-based monitoring with emphasis on human subject protection, and data integrity. The article discusses challenges in adoption and implementation of the changes in ICH GCP guideline for clinical trial stakeholders. PMID- 29109933 TI - A study comparing trial registry entries of randomized controlled trials with publications of their results in a high impact factor journal: The Journal of the American Medical Association. AB - Purpose: The International Committee of Medical Journal Editors mandates trial registration as a precondition for publication. Growing evidence indicates that information in registry may not correlate with eventual publication. The present study was carried out with the objective of comparing content of Randomized Controlled Trials (RCTs) published in one year in the Journal of the American Medical Association (JAMA), with the information contained in trial registries. Methods: All RCTs published in JAMA in 2013 were included. 11 data set items were matched for content between registry entry and published RCT: Title, Primary and Secondary Objectives, Study type, Inclusion and Exclusion Criteria, Treatment Age Group, Follow up, Sample Size, Primary and Secondary Outcomes. A fully correct match was scored 2, partially correct 1 and incorrect 0. Thus, maximum possible score for each paper was number of items multiplied by 2, i.e., 22. Results: The median [range] total score achieved by RCTs was 15. No RCT achieved a perfect score of 22. The largest proportion of RCTs reported secondary objectives, study type, treatment age group, follow up, sample size and primary outcomes fully correctly. However, only 13.5 %, 12 % and 13.5 % of RCTs were a perfect match with registry entries in terms of title, primary objective and secondary outcomes respectively. Almost three quarters did not match perfectly in selection criteria. Conclusion: There exist discrepancies between trial registration and published paper even in a high impact factor journal. Both authors and editors should adhere to CONSORT guidelines to ensure transparency of published research. PMID- 29109934 TI - Do clinical trials conducted in India match its healthcare needs? An audit of the Clinical Trials Registry of India. AB - Background: India continues to contribute disproportionately to the global burden of disease and public health research output from India is also known to be not commensurate with her healthcare needs. We carried out the present study to assess if clinical trials were in line with the health care needs of the country by auditing the clinical trials registry of India. Materials and Methods: All the clinical studies registered in CTRI between July 20, 2007 and December 31, 2015 were searched in the "Trial Search" section. The total number of studies, their phases of development, and therapeutic areas were assessed. Trials in each therapeutic area was compared with the disease burden (DALYs) in that area taken from Global Health Estimates [2014] Summary Tables of the WHO. The number of trials conducted per state in India was also compared with the population of that state [Census 2011]. Results: A total of 6474 studies were registered of which 3325 (51.4%) were clinical trials. The state of Maharashtra had the highest number trials [16.4%] followed by Karnataka (11.6%) and Tamil Nadu (10%). Populous states like Uttar Pradesh (5.3%) and Bihar (1.4%) had far fewer trials. The largest number of trials was in the area of cancer (16.4%), followed by diabetes (12.1%) and cardiovascular diseases (10.1%). Infectious and parasitic diseases had the highest DALYs (82,681) and ranked first in disease burden but accounted for only 5% of the total trials and ranked 7th according to number of trials. Cancer ranked first in the number of trials (16.4%), but ranked 6th based on DALYs. Conclusion: Clinical trials conducted in India are not in consonance with her health care needs. Strengthening the capacity for conducting trials in the populous states and the north-eastern part of the country is necessary to allow a more equitable selection of participants. The government should introduce policies to encourage new drug development in areas where needed the most. PMID- 29109935 TI - Striking balance between expedited review and expecting efficacious anticancer drug and biologics: An ongoing challenge. AB - Objective: The objective of this study is to assess the postmarketing status: Efficacy and safety drugs and biologics related with cancer approved under expedited review. Methods: This observational, analytical study was carried between January and April 2016 by the Department of Pharmacology and Medical Oncology, Saveetha Medical College. Drugs approved under expedited review, fast track status and its association with anti-cancer effects, postmarketing efficacy and safety, propensity to induce the second tumor was noted. Drug approval status and average time of review process were obtained from the United States-Food and Drug Administration (FDA), Center for Drugs and Biologics Center (Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research). Postmarketing adverse events and safety issues were collected FDA adverse effects reporting system. Further, evidence efficacy and safety of drugs were taken from various meta-analysis, reports on BioMed journals, and Cochrane systematic reviews. Results: In the last 5 years, 166 products were approved by expedited review. Out of 166, 48 (28.9%) drugs/biologics are anticancer drugs and drugs used in precancerous conditions. The average time of review varies from19 months to 8.2 months. Out of these 48 molecules, 37 (77%) molecules received serious adverse event alert. Positive correlation is seen between average time of review and number of adverse events reported. Seven (14.5%) drugs were proven to induce second tumor among receivers. Conclusion: Although expedited review facilitates faster approval of drugs; selection and assessment criteria should be stringent to prevent clinical failure, serious adverse effects of such drugs exposed to many individuals. Focus should be given developing chemosensitizing molecule and evaluation of metronomic regimen which is being more optimistic in current cancer therapeutics. PMID- 29109937 TI - Common pitfalls in statistical analysis: Measures of agreement. AB - Agreement between measurements refers to the degree of concordance between two (or more) sets of measurements. Statistical methods to test agreement are used to assess inter-rater variability or to decide whether one technique for measuring a variable can substitute another. In this article, we look at statistical measures of agreement for different types of data and discuss the differences between these and those for assessing correlation. PMID- 29109936 TI - A study of harmful drug-drug interactions due to polypharmacy in hospitalized patients in Goa Medical College. AB - Introduction: Concomitant use of multiple drugs is often indicated to manage comorbid conditions and enhance efficacy. Such concomitant use of multiple drugs (five or more drugs) has been defined as "polypharmacy." Polypharmacy has been associated with adverse consequences such as greater healthcare costs, increased risk of adverse drug events, drug-drug interactions (DDIs), medication nonadherence, reduced functional capacity, and multiple geriatric syndromes. This study evaluated number of potential harmful DDIs due to polypharmacy. Materials and Methods: A prospective, cross-sectional, observational study was performed from July 2011 to June 2012. Approval was obtained from the Institutional Ethics Committee, Goa Medical College. Drug interactions were identified using a computerized DDI database system Lexi-Comp version: 2.4.1. Quantitative data analysis was done by the SPSS for Windows version 17.0. Results: Seven hundred and fifty-one out of 5424 (13.85%) prescriptions were observed to have polypharmacy with highest rates observed in the Department of Medicine. The median age of patients was 55.60 +/- 13.86 (range 10-108 years). A total number of drugs per prescription ranged from minimum of 5 to maximum of 16 drugs, with an average of 7.96 +/- 1.75. A large number of 596 prescriptions contained 6-9 drugs per prescription. Drugs involved in potential DDIs in our study included aspirin, antacids, beta-blockers, 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, calcium channel blockers, angiotensin-converting enzyme inhibitors, ondansetron, and H2 blockers. Conclusion: Patients taking multiple medications experience unique pharmacotherapy. Personalized drug prescribing strategies and close monitoring of patients taking drugs with potential DDIs are keys to optimal therapeutic result. PMID- 29109938 TI - A day in the life of a pharmacovigilance case processor. AB - Pharmacovigilance (PV) has grown significantly in India in the last couple of decades. The etymological roots for the word "pharmacovigilance" are "Pharmakon" (Greek for drug) and "Vigilare" (Latin for to keep watch). It relies on information gathered from the collection of individual case safety reports and other pharmacoepidemiological data. The PV data processing cycle starts with data collection in computerized systems followed by complete data entry which includes adverse event coding, drug coding, causality and expectedness assessment, narrative writing, quality control, and report submissions followed by data storage and maintenance. A case processor plays an important role in conducting these various tasks. The case processor should also manage drug safety information, possess updated knowledge about global drug safety regulations, summarize clinical safety data, participate in meetings, write narratives with medical input from a physician, report serious adverse events to the regulatory authorities, participate in the training of operational staff on drug safety issues, quality control work of other staff in the department, and take on any other task as assigned by the manager or medical director within the capabilities of the drug safety associate. There can be challenges while handling all these tasks at a time, hence the associate will have to maintain a balance to overcome them and keep on updating their knowledge on drug safety regulations, which in turn, would help in increasing their learning curve. PMID- 29109939 TI - Is it easy to be an Ethics Committee member? (Experiences as an Ethics Committee member). PMID- 29109940 TI - Erratum: Relationship of admission mean platelet volume, platelet distribution width and white blood cells with ST resolution in patients with acute ST segment elevation myocardial infarction treated with streptokinase without history of previous cardiovascular surgery. AB - [This corrects the article on p. 125 in vol. 4, PMID: 23833737.]. PMID- 29109941 TI - Corrigendum: Clinical and Research Activities at the CATANA Facility of INFN-LNS: From the Conventional Hadrontherapy to the Laser-Driven Approach. AB - [This corrects the article on p. 223 in vol. 7, PMID: 28971066.]. PMID- 29109943 TI - Evaluation of mandibular lingula and foramen location using 3-dimensional mandible models reconstructed by cone-beam computed tomography. AB - Background: The positions of the mandibular lingula and foramen have been set as indexes for inferior alveolar nerve (IAN) block and ramus osteotomies in orthognathic surgery. This study aimed to evaluate the anatomical structures of mandibular ramus, especially the mandibular lingula and foramen, by analyzing the cone-beam computed tomography (CBCT) data of young adults. Methods: We evaluated 121 sides of hemi-mandibular CBCT model of 106 patients (51 male and 55 female patients; 18 to 36 years old). All the measurements were performed using the 2- and 3-dimensional rulers of OnDemand3D(r) software. Results: Statistical analysis of the data revealed that there was no significant difference in the mandibular angle between the genders. The mandibular lingula was found to be located at the center of ramus in males, but a little posterior in relation to the center in females. The mandibular lingula was rarely located below the occlusal plane; however, the position of the mandibular foramen was more variable (84.3% below, 12.4% above, and 3.3% at the level of the occlusal plane). Conclusions: The results of this study provide a valuable guideline for IAN block anesthesia and orthognathic surgery. CBCT can be considered effective and accurate in evaluating the fine structures of the mandible. PMID- 29109944 TI - Surgical excision of osteochondroma on mandibular condyle via preauricular approach with zygomatic arch osteotomy. AB - Background: Osteochondroma is a benign tumor that tends to develop in mandibular condyle and coronoid process in the craniofacial region. If tumor mass has grown from condyle into the infratemporal space with zygomatic arch obstructing the access, there are risks associated with surgical exposure and local resection of these masses. Case presentation: This study reports on a case of osteochondroma on mandibular condylar head where we treated with surgical excision via preauricular approach with 3D analysis. After the local resection, there were no surgical and post-operative complications until 8-month follow-up period. Conclusions: In local excision of osteochondroma, our method is a minimally invasive method. It is a good example of osteochondroma treatment. PMID- 29109942 TI - Ductal Carcinoma In Situ Biology, Biomarkers, and Diagnosis. AB - Ductal carcinoma in situ (DCIS) is an often-diagnosed breast disease and a known, non-obligate, precursor to invasive breast carcinoma. In this review, we explore the clinical and pathological features of DCIS, fundamental elements of DCIS biology including gene expression and genetic events, the relationship of DCIS with recurrence and invasive breast cancer, and the interaction of DCIS with the microenvironment. We also survey how these various elements are being used to solve the clinical conundrum of how to optimally treat a disease that has potential to progress, and yet is also likely over-treated in a significant proportion of cases. PMID- 29109945 TI - Lumbosacral Soft Tissue Mass in a Newborn: A Clinical Case with a Difficult Diagnosis. AB - Many types of dorsal neoplasm of early infancy are described in literature ranging from benign to aggressive. Some are more common while others quite unusual. Here, we describe a newborn with a lumbosacral soft tissue mass. Positivity of S-100 and vimentin was compatible with the neural cell line and the high proliferation rate of major activity cells (biopsy Ki67 20%) suggests an aggressive nature. An exclusively surgical approach was chosen and no clinical or radiological signs of recurrence have been observed after 2 years of follow-up. This case is atypical for location, histological pattern, radiological aspect, and clinical behavior. Diagnosis is hard to define and limited to a mesenchymal neoplasia with myxoid tracts. The described aspects raise concerns about clinical and therapeutic approach, classification, and radiological follow-up of sacral tissue masses in newborns. PMID- 29109946 TI - The Binding Mode of the Sonic Hedgehog Inhibitor Robotnikinin, a Combined Docking and QM/MM MD Study. AB - Erroneous activation of the Hedgehog pathway has been linked to a great amount of cancerous diseases and therefore a large number of studies aiming at its inhibition have been carried out. One leverage point for novel therapeutic strategies targeting the proteins involved, is the prevention of complex formation between the extracellular signaling protein Sonic Hedgehog and the transmembrane protein Patched 1. In 2009 robotnikinin, a small molecule capable of binding to and inhibiting the activity of Sonic Hedgehog has been identified, however in the absence of X-ray structures of the Sonic Hedgehog-robotnikinin complex, the binding mode of this inhibitor remains unknown. In order to aid with the identification of novel Sonic Hedgehog inhibitors, the presented investigation elucidates the binding mode of robotnikinin by performing an extensive docking study, including subsequent molecular mechanical as well as quantum mechanical/molecular mechanical molecular dynamics simulations. The attained configurations enabled the identification of a number of key protein ligand interactions, aiding complex formation and providing stabilizing contributions to the binding of the ligand. The predicted structure of the Sonic Hedgehog-robotnikinin complex is provided via a PDB file as Supplementary Material and can be used for further reference. PMID- 29109948 TI - Hemodynamic and Pathologic Characterization of the TASK-1-/- Mouse Does Not Demonstrate Pulmonary Hypertension. AB - Introduction: Pulmonary hypertension (PH) carries significant associated morbidity and mortality and the underlying molecular mechanisms of PH are not well understood. Loss-of-function mutations in TASK-1 potassium channels are associated with PH in humans. Although TASK-1 has been considered in the development of PH for over a decade, characterization of TASK-1 knockout mice has been limited to in vitro studies or in vivo studies in room air at isolated time points. The purpose of this study was twofold. First, we sought to determine if TASK-/- male and female mice developed PH over the span of one year. Second, we sought to determine the effect of chronic hypoxia, a stimulus for PH, and its recovery on PH in TASK-1-/- mice. Methods: We measured right ventricular systolic pressure (RVSP) and vascular remodeling in male and female C57BL/6 WT and TASK-1 /- mice at separate time points: 20-24 weeks and 1 year of age. Additionally, we measured RVSP and vascular remodeling in TASK-1-/- and wild-type mice between 13 and 16 weeks of age exposed to 10% hypoxia for 3 weeks followed by recovery to room air conditions for an additional 6 weeks. Results: RVSP was similar between WT and TASK-/- mice. Male and female WT and TASK-1-/- mice all demonstrated age related increases in RVSP, which correlated to age-related vascular remodeling in male mice but not in female mice. Male TASK-1-/- and WT mice exposed to chronic hypoxia demonstrated increased RVSP, which decreased following room air recovery. WT and TASK-1-/- male mice demonstrated vascular remodeling upon exposure to hypoxia that persisted in room air recovery. Conclusion: Female and male TASK-1-/ mice do not develop hemodynamic or vascular evidence for PH, but RVSP rises in an age-dependent manner independent of genotype. TASK-1-/- and WT male mice develop hypoxia-induced elevations in RVSP that decrease to baseline after recovery in room air. TASK-1-/- and WT male mice demonstrate vascular remodeling after exposure to hypoxia that persists despite recovery to room air conditions and does not correlate with RVSP normalization. PMID- 29109947 TI - Acute Exacerbation in Interstitial Lung Disease. AB - Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has been defined as an acute, clinically significant deterioration that develops within less than 1 month without obvious clinical cause like fluid overload, left heart failure, or pulmonary embolism. Pathophysiologically, damage of the alveoli is the predominant feature of AE-IPF which manifests histopathologically as diffuse alveolar damage and radiologically as diffuse, bilateral ground-glass opacification on high-resolution computed tomography. A growing body of literature now focuses on acute exacerbations of interstitial lung disease (AE ILD) other than idiopathic pulmonary fibrosis. Based on a shared pathophysiology it is generally accepted that AE-ILD can affect all patients with interstitial lung disease (ILD) but apparently occurs more frequently in patients with an underlying usual interstitial pneumonia pattern. The etiology of AE-ILD is not fully understood, but there are distinct risk factors and triggers like infection, mechanical stress, and microaspiration. In general, AE-ILD has a poor prognosis and is associated with a high mortality within 6-12 months. Although there is a lack of evidence based data, in clinical practice, AE-ILD is often treated with a high dose corticosteroid therapy and antibiotics. This article aims to provide a summary of the clinical features, diagnosis, management, and prognosis of AE-ILD as well as an update on the current developments in the field. PMID- 29109949 TI - The Impact of Frailty on the Risk of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: Evidences from a 5-Year Observational Study. AB - The frailty construct has increasingly been adopted in the field of cognitive disorders. The aim of the present study was to measure frailty in a cohort of individuals with mild cognitive impairment (MCI) and to explore whether frailty measures may consent to predict the risk of conversion to dementia. We retrospectively reviewed the clinical charts of outpatients with amnesic MCI (aMCI) consecutively recruited at our Department, and followed-up for 5 years. Individual frailty status was measured by means of a frailty index (FI) consisting of 39 deficits (including signs, symptoms, diagnoses, and disabilities). Univariate analyses were used to compare the socio-demographic and clinical characteristics between subjects converting or not converting to probable Alzheimer's disease (AD) dementia over the follow-up. Risk for conversion to AD dementia was assessed using Cox regression models. Ninety-one subjects with aMCI (mean age 72.7, SD 7.1 years; women 49.5%) were consecutively recruited over a period of 12 months. Low levels of frailty were documented in the sample (mean FI score 10.0, SD 5.3). A statistically significant correlation between age and FI was observed. Overall, 58 participants converted to AD dementia over time. The Cox regression analysis showed that age (HR: 1.04, 95% CI: 1.00-1.08), male sex (HR: 0.52, 95% CI: 0.30-0.91), Mini-Mental State Examination score (HR: 0.85, 95% CI: 0.77-0.94), and FI (HR: 1.11, 95% CI: 1.05 1.18) were all significantly associated with the probability of MCI conversion. Individual's frailty status may increase the risk of conversion from a condition of MCI to overt AD dementia. The adoption of constructs comprehensively reflecting the biological decline of the aging subject may add useful estimates and information in the clinical approach to cognitive disorders. PMID- 29109950 TI - Paget's Breast Disease: A Case Report and Review of the Literature. AB - Paget's disease of the breast is a rare cancer. This typical clinical case illustrates the different epidemiological, clinical, histological, therapeutic, and evolving aspects of the disease. We report a case of Paget's disease in a 43 year-old woman who presented eczema of the nipple. Mammography and ultrasounds did reveal a lesion in situ. The patient was scheduled for mastectomy and sentinel node biopsy. She had chosen a radical bilateral surgery. The histological diagnosis was Paget's disease of the breast with a carcinoma in situ. There was no metastasis in either of the sentinel nodes. Paget's disease must be considered with the presence of a persistent eczematous involvement of the nipple, which does not respond to local treatment. Ultrasounds, mammography, and magnetic resonance imaging can allow searching an underlying cancer and guiding the surgical management. There is no evidence at this time that one of the two surgical techniques (conservative or mastectomy) would improve survival. The prognosis depends on the presence of a palpable mass and the invasiveness of the cancer. PMID- 29109951 TI - RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate. AB - mRNA metabolism is tightly orchestrated by highly-regulated RNA Binding Proteins (RBPs) that determine mRNA fate, thereby influencing multiple cellular functions across biological contexts. Here, we review the interplay between six well-known RBPs (TTP, AUF-1, KSRP, HuR, TIA-1, and TIAR) that recognize AU-rich elements (AREs) at the 3' untranslated regions of mRNAs, namely ARE-RBPs. Examples of the links between their cross-regulations and modulation of their targets are analyzed during mRNA processing, turnover, localization, and translational control. Furthermore, ARE recognition can be self-regulated by several factors that lead to the prevalence of one RBP over another. Consequently, we examine the factors that modulate the dynamics of those protein-RNA transient interactions to better understand the final consequences of the regulation mediated by ARE-RBPs. For instance, factors controlling the RBP isoforms, their conformational state or their post-translational modifications (PTMs) can strongly determine the fate of the protein-RNA complexes. Moreover, mRNA specific sequence and secondary structure or subtle environmental changes are also key determinants to take into account. To sum up, the whole understanding of such a fine tuned regulation is a challenge for future research and requires the integration of all the available structural and functional data by in vivo, in vitro and in silico approaches. PMID- 29109952 TI - Is TB Testing Associated With Increased Blood Interferon-Gamma Levels? AB - The Republic of Ireland reports a relatively low prevalence of Johne's disease (JD) compared to international counterparts. Postulated reasons for this include a lower average herd size and a grass-based production system. Ireland also engages in high levels of bovine tuberculosis (bTB) testing. As interferon-gamma (IFN-gamma) is believed to play a key role in protecting against JD, it is our hypothesis that administration of purified protein derivative (PPD), as part of the bTB test, is associated with a systemic increase in IFN-gamma production, which may potentially limit clinical progression of the disease. We studied 265 cows (202 Friesian and 63 "Non-Friesian," e.g., JerseyX, Norwegian Red) to assess IFN-gamma levels and Mycobacterium avium subspecies paratuberculosis (MAP) antibody response before and after the bTB test. As part of the compulsory annual bTB test, avian and bovine PPD were administered at two separate cervical sites. To assess IFN-gamma production, blood samples were taken before and 72 h after PPD administration. MAP antibody response was assessed before and 10 days post PPD administration. A significant increase in MAP antibody response was identified post-bTB compared to pre-bTB response (p < 0.001). Additionally, IFN gamma production significantly increased at the post-bTB time point (p < 0.001) compared to the pre-bTB test readings. This may indicate a beneficial effect of bTB testing in controlling JD. PMID- 29109953 TI - Processing Challenges and Opportunities of Camel Dairy Products. AB - A review on the challenges and opportunities of processing camel milk into dairy products is provided with an objective of exploring the challenges of processing and assessing the opportunities for developing functional products from camel milk. The gross composition of camel milk is similar to bovine milk. Nonetheless, the relative composition, distribution, and the molecular structure of the milk components are reported to be different. Consequently, manufacturing of camel dairy products such as cheese, yoghurt, or butter using the same technology as for dairy products from bovine milk can result in processing difficulties and products of inferior quality. However, scientific evidence points to the possibility of transforming camel milk into products by optimization of the processing parameters. Additionally, camel milk has traditionally been used for its medicinal values and recent scientific studies confirm that it is a rich source of bioactive, antimicrobial, and antioxidant substances. The current literature concerning product design and functional potential of camel milk is fragmented in terms of time, place, and depth of the research. Therefore, it is essential to understand the fundamental features of camel milk and initiate detailed multidisciplinary research to fully explore and utilize its functional and technological properties. PMID- 29109954 TI - Role of Periapical Diseases in Medication-Related Osteonecrosis of the Jaws. AB - Objective: The present study aimed to investigate the role of periapical diseases in inducing medication-related osteonecrosis of the jaws (MRONJ) using an ovariectomized (OVX) mice model. Materials and Methods: Twenty C57BL/6N female mice were randomly assigned to two groups. All mice were subjected to bilateral ovariectomy and then treated with oncologic dose of zoledronic acid (ZA) or vehicle for twelve weeks. Eight weeks after commence of drug administration, a pulpal exposure (PE) operation was performed on the first right lower molar to induce periapical periodontitis; the contralateral non-PE tooth was used as control. All animals were sacrificed four weeks after pulpal exposure, and the mandibles were harvested for radiological and histomorphometrical analysis. Results: Micro computed tomography (MU-CT) examination demonstrated that periapical diseases significantly increased alveolar bone resorption, and the resorption was greatly attenuated by ZA treatment. Concurrent ZA therapy significantly increased bone density and histological osteocyte necrosis in the presence of periapical lesions. Conclusion: ZA treatment reduced bone absorption resulting from periapical disease but increased the risk of developing MRONJ in the ovariectomized mouse model. PMID- 29109955 TI - Fibroblast Growth Factor 21 Promotes C2C12 Cells Myogenic Differentiation by Enhancing Cell Cycle Exit. AB - Fibroblast growth factor 21 (FGF21), a secretion protein, functions as a pivotal regulator of energy metabolism and is being considered as a therapeutic candidate in metabolic syndromes. However, the roles of FGF21 in myogenic differentiation and cell cycle remain obscure. In this study, we investigated the function of FGF21 in myogenesis and cell cycle exit using C2C12 cell line. Our data showed that the expression of myogenic genes as well as cell cycle exit genes was increased after FGF21 overexpression, and FGF21 overexpression induces cell cycle arrest. Moreover, cell cycle genes were decreased in FGF21 overexpression cells while they were increased in FGF21 knockdown cells. Further, FGF21/P53/p21/Cyclin CDK has been suggested as the key pathway for cell cycle exit mediated by FGF21 in C2C12 cells. Also, we deduce that FGF21 promotes the initiation of myogenic differentiation mainly through enhancing cell cycle exit of C2C12 cells. Taken together, our results demonstrated that FGF21 promotes cell cycle exit and enhances myogenic differentiation of C2C12 cells. This study provided new evidence that FGF21 promotes myogenic differentiation, which could be useful for better understanding the roles of FGF21 in myogenesis. PMID- 29109956 TI - Incidental Extracardiac Findings and Their Characterization on Cardiac MRI. AB - Background: Cardiac magnetic resonance imaging (cMRI) has recently emerged as a new noninvasive imaging modality that offers superior structural and functional assessment of the heart. cMRI benefits from a large field of view but, consequently, may capture incidental extracardiac findings (IEFs). We aimed to evaluate the frequency and significance of IEFs reported from clinically indicated cMRI scans. Methods: 742 consecutive patients (402 males and 340 females) referred to the Cardiac Magnetic Resonance Center of our University Hospital between January 2015 and December 2016 for clinically indicated cMRI were retrospectively enrolled for the evaluation of IEF prevalence and relevance. The median age of the subjects was 51 years (range: 5-85 years). Results: A significant number of patients who underwent cMRI had incidental and clinically significant IEFs (2% of the population, 11.4% of cases). cMRI allowed a correct diagnosis in 116/131 cases with a diagnostic accuracy value of 88.5%. Conclusions: IEFs on cMRI are not uncommon and lesions with mild or no clinical significance represent the most frequent findings. cMRI can characterize incidental findings with high accuracy in most cases. PMID- 29109957 TI - "Gold" Pressed Essential Oil: An Essay on the Volatile Fragment from Citrus Juice Industry By-Products Chemistry and Bioactivity. AB - Present essay explores the potentials of Citrus juice industry's by-products as alternative bioactive natural products resources. Four crude Cold Pressed Essential Oils (CPEOs), derived from orange, lemon, grapefruit, and mandarin, were studied. All CPEOs were subjected to water distillation, in order to obtain the volatile fragment, which was further fractionated with respect to distillation period in two parts, concluding to eight samples. These samples along with the four original CPEOs were assessed in relation to their phytochemical content and their repellent and larvicidal properties against Asian Tiger Mosquito. The volatiles recovery rates ranged from 74% to 88% of the CPEO. Limonene presented a significant increase in all samples ranging from 8% to 52% of the respective CPEO's content and peaked in mandarin's 2nd volatile fragment which comprised 97% of the essential oil. The refinement process presented clear impacts on both bioassays: a significant increase in larvicidal potency was observed, annotated best by the improvement by 1100% and 1300% of the grapefruit volatile fractions; repellence testing provided only one significant result, the decrease of landings by 50% as a response to mandarin's second volatile fraction. The applied methodology thus may be considered for the improvement of Citrus juice industry's by-products chemistry and bioactivity. PMID- 29109958 TI - Deterioration of Cerebral Oxygenation by Aortic Arch Calcification Progression in Patients Undergoing Hemodialysis: A Cross-Sectional Study. AB - Background: Near-infrared spectroscopy revealed that the regional saturation of oxygen (rSO2) in cerebral tissue is lower in hemodialysis (HD) patients than in healthy subjects. However, no study has examined the changes in cerebral oxygenation by aortic arch calcification (AAC) progression in HD patients. Methods: A total of 104 HD patients were divided into four groups by AAC grade determined using chest radiography: 23 patients at grade 0, 24 at grade 1, 30 at grade 2, and 27 at grade 3. Differences in clinical parameters, including cerebral rSO2, among AAC grades were investigated and atherosclerotic parameters affecting cerebral rSO2 values were identified. Results: Cerebral rSO2 significantly decreased as AAC progressed (AAC grade 3 versus grade 0, p < 0.01 versus grade 1, p < 0.05). Multivariate logistic regression analysis was performed using parameters with p values < 0.20 in univariate analysis between cerebral rSO2 values less than the mean and atherosclerotic parameters. AAC grades 2 and 3, serum phosphate level, and history of smoking were factors associated with the cerebral rSO2 decrease. Conclusions: Cerebral rSO2 significantly decreased as AAC progressed and was independently associated with higher AAC grade, serum phosphate level, and history of smoking. PMID- 29109960 TI - Expression Pattern of G-Protein-Coupled Estrogen Receptor in Myometrium of Uteri with and without Adenomyosis. AB - Objective: To compare the expression of G-protein-coupled estrogen receptor (GPER) in the junctional zone and outer myometrium of the proliferative and secretory phases of women with and without adenomyosis. Methods: A total of 76 women were included in this study, 42 with adenomyosis (proliferative phase, n = 23; secretory phases, n = 19) and 34 controls (proliferative phase, n = 16; secretory phases, n = 18). Protein and total RNA were extracted from the junctional zone (JZ) and outer myometrium (OM). GPER protein and mRNA expression levels were evaluated by the use of western blotting and real-time quantitative polymerase chain reaction (RT-qPCR). Results: The expression of GPER protein and mRNA in women with adenomyosis was significantly higher than that of control subjects, both in the junctional zone and in the outer myometrium and both in the proliferative and in the secretory phases. Conclusion: The significant and consistent increase in GPER expression in adenomyosis compared with control subjects, regardless of whether it was in the proliferative or secretory phases and regardless of whether it was in the JZ or OM, suggests that GPER plays an important role in the pathogenesis of the adenomyosis. PMID- 29109959 TI - Probiotic Bacteria for Healthier Aging: Immunomodulation and Metabolism of Phytoestrogens. AB - Age-related degeneration gives rise to a number of pathologies, many of them associated with imbalances of the microbiota and the gut-associated immune system. Thus, the intestine is considered a key target organ to improve the quality of life in senescence. Gut microbiota can have a powerful impact in the deterioration linked to aging by its nutritional and immunomodulatory activity. Reduced numbers of beneficial species and low microbial biodiversity in the elderly have been linked with pathogenesis of many diseases. A healthy lifestyle with an elderly customized diet including probiotics can contribute to reducing the chronic proinflammatory status and other age-related pathologies. Beneficial effects of probiotic lactic acid bacteria and bifidobacteria to alleviate some of these disorders based on their immunomodulatory properties as well as their capacity to produce bioactive metabolites from dietary phytoestrogens are summarized. On one hand, the preservation of gut barrier integrity and an increased ability to fight infections are the main reported immune benefits of probiotics. On the other hand, the intake of a diet rich in phytoestrogens along with the presence of selected probiotic bacteria may lead to the production of equol, enterolignans, and urolithins, which are considered protective against chronic diseases related to aging. PMID- 29109962 TI - Micronutrient Intake in a Cohort of Italian Adults with Type 1 Diabetes: Adherence to Dietary Recommendations. AB - Micronutrients are of fundamental importance in maintaining health status. However, data on their dietary intake are few particularly in persons with diabetes. The aim of this study was to evaluate in adults with type 1 diabetes (T1DM) attending a tertiary-level diabetes center in Southern Italy the intake of micronutrients (both vitamins and minerals) and the adherence to recommendations. Seven-day food records of 60 T1DM patients were analyzed. Micronutrient intake was evaluated based on the Italian food composition tables and expressed as amount per 1000 kcal of energy intake to adjust for possible underreporting. Adherence to recommendations for vitamins A, B6, B12, and C and niacin was acceptable in both sexes (ranging from 77% to 100%). Half of the patients did not adhere to folate recommendation, even less to vitamin E, and no patient reached the recommended intake for vitamin D. As for minerals, adherence was low for potassium and selenium (0-23%); intermediate for zinc, copper, and magnesium; low and intermediate for calcium in men and women, respectively; and low for iron in women. In conclusion, the diet followed by T1DM patients may not have a sufficient content of different micronutrients. Therefore, an adequate intake of low-fat dairy products, fish, legumes, and vegetables should be encouraged as components of a healthier dietary pattern. PMID- 29109961 TI - The Incorporation of Strontium in a Sodium Alginate Coating on Titanium Surfaces for Improved Biological Properties. AB - Orthopedic implant failure is mainly attributed to the poor bonding of the implant to bone tissue. An effective approach to minimize the implant failure would be modifying the surface of the implant. Strontium (Sr) can stimulate the proliferation and differentiation of osteoblasts and reduce the activity of osteoclasts. In this study, a titanium (Ti) surface was successively functionalized by covalently grafting dopamine, sodium alginate (SA), and Sr2+ via the electrostatic immobilization method. The as-prepared coatings on the Ti surface were characterized by using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT IR), and contact angle. The results indicated that the Sr-incorporated coatings were successfully prepared and that Sr distributed uniformly on the surface. A long-lasting and sustained Sr release had been observed in Sr2+ release studies. The Ti/DOPA/SA/Sr exhibited little cytotoxicity and a robust effect of Sr incorporation on the adhesion and spreading of MG63 cells. The proliferation and alkaline phosphatase (ALP) activity of MG63 cells were enhanced by immobilizing Sr2+ on the SA-grafted Ti. The Sr-containing coatings, which displayed excellent biocompatibility and osteogenic activity, may provide a promising solution for promoting the tissue integration of implants. PMID- 29109963 TI - Cytokine Profile of Patients with Allergic Rhinitis Caused by Pollen, Mite, and Microbial Allergen Sensitization. AB - Allergic rhinitis (AR) is especially prevalent among the population of large cities. Immunologically, the airway epithelium is a region where the population of allergen-presenting cells concentrates. These cells actively express a group of receptors of the innate immune system. A specific cytokine profile is its representation. The study was aimed at evaluating the cytokine profile in patients with seasonal and perennial allergic rhinitis. The cytokine profile of nasal secretion and blood serum of 44 patients with AR was studied. 24 of them had seasonal allergic rhinitis (SAR), and 20 patients suffered from perennial allergic rhinitis (PAR). The patients' age ranged from 4 to 60 years. It was determined in our study that the activation of the GM-CSF production retained in patients with PAR sensitized to mite allergen components (Dermatophagoides pteronyssinus). There was a higher production profile of TNF-alpha and TSLP in nasal secretion in the patients with perennial allergic rhinitis and additional high sensitization to SEs. Sensitization to mold fungal allergen components significantly increases in patients with seasonal allergic rhinitis. They demonstrated high level of sensitization to the Aspergillus fumigatus component m3. Thus, along with other clinical trials, the study performed would clarify some aspects of molecular pathogenesis of human allergic rhinitis. PMID- 29109964 TI - Immunotherapy as a Promising Treatment for Prostate Cancer: A Systematic Review. AB - Prostate cancer treatment is currently based on surgical removal, radiotherapy, and hormone therapy. In recent years, another therapeutic method has emerged immunological treatment. Immunotherapy modulates and strengthens one's immune responses against cancer. Neoplastic cells naturally escape from the control of the immune system, and the main goal of immune therapy is to bring the control back. Satisfying outcomes after treatment of advanced melanoma and lung cancer suggest a great potential of immunotherapy as an approach for other tumors' treatment, especially in patients primarily introduced to palliative care. After initial clinical trials, immunotherapy seems to have different side effects than chemotherapy. Prostate cancer was the first neoplasm in which a specific vaccine significantly improved survival. There is a tremendous potential for synergistic combinations of immunotherapy with conventional cancer treatments. A combination of several drugs or methods can be a key in radical treatment of metastatic prostate cancer as demonstrated by preliminary studies. PMID- 29109965 TI - Estimating the carbohydrate content of various forms of tobacco by phenol sulfuric acid method. AB - BACKGROUND: Due to consumption of various forms of tobacco in large amounts by Indian population, it has become a cause of concern for major oral diseases. In 2008, the WHO named tobacco as the world's single greatest cause of preventable death. It is also known that certain amount of carbohydrates are incorporated in processed tobacco to make it acceptable for consumption. Thus, its role in oral diseases becomes an important question at this point of time. Through this study, it is attempted to find out the carbohydrate content of various forms of tobacco by phenol-sulfuric acid method. MATERIALS AND METHODS: Tobacco products selected for the study were Nandi hookah tambakhu (A), photo brand budhaa Punjabi snuff (B), Miraj (C), Gai-chhap tambakhu (D), Hanuman-chhap Pandharpuri tambakhu (E), and Hathi-chhap Bidi (F). The samples were decoded and transported to laboratory and tested at various concentrations by phenol-sulfuric acid method followed by ultraviolet spectrophotometry to determine their absorbance. RESULTS: The present study showed Hathi-chhap bidi/sample F had a maximum absorbance (1.995) at 10 MUg/ml which is a smoking form of tobacco followed by rest all smokeless forms of tobacco, i.e. sample C (0.452), sample B (0.253), sample D (0.077), sample E ( 0.018), and sample A (-0.127), respectively. CONCLUSION: As the concentration of tobacco sample increases, their absorbance increases which in turn is suggestive of increase in its carbohydrate concentration. Carbohydrates in the form of sugars, either inherently present or added in it during manufacturing can serve as a risk factor for higher incidence of dental caries. PMID- 29109966 TI - Mixed emotions in the predictive brain. AB - Understanding complex or mixed emotions first requires an exploration of the human nervous system underlying emotions, and indeed all experience. We review current research in neuroscience, which describes the brain as a predictive, internal model of the world that flexibly combines features from past experience to construct emotions. We argue that "mixed emotions" result when these features of past experience correspond to multiple emotion categories. Integrating event perception and cognitive linguistic theories, we propose that "mixed emotions" are perceived as an episode of distinct, linked emotional events due to attentional shifts which update the predicted model of experience. These proposed mechanisms have profound implications for the study of emotion; we conclude by suggesting methodological improvements for future research. PMID- 29109967 TI - Explaining Continuance Intention of Fruit and Vegetable Consumption among the Rural Elderly: An Application of the Expectancy Confirmation Model. AB - Background and Aim: Healthy aging is the permanent right of all people. Thus, the purpose of this work was to investigate the expectation confirmation model constructs on intention of continuing to consume fruit and vegetables among the rural elderly. Materials and Methods: This cross-sectional study was conducted on 332 elderly. The expectation confirmation model served as a theoretical framework. A random sampling was recruited. Data were collected through face-to face visit in the second 6 months of 2016. The data were then analyzed using LISREL 8.5 and SPSS 16 software. Results: This model could explain 79% of intention to continue fruit and vegetable consumption. The usefulness and satisfaction had the most effect on the intention to continue the consumption of fruit and vegetables. Conclusion: Expectation confirmation model depicted a proper application in explaining the intention to continue the consumption of fruit and vegetables in the elderly. Since perceived benefits were the most important factor in determining the intention to continue F&V consumption in this study, it is required that policymakers utilize suitable efficient strategies to promote the perception of benefits of F&V consumption in the elderly by means of campaigns in the society, organizations, and families. PMID- 29109968 TI - Tracking post-trauma psychopathology using mobile applications: A usability study. AB - Trauma exposure markedly increases risk for psychopathology including posttraumatic stress disorder (PTSD). Understanding the course by which PTSD develops after a traumatic event is critical to enhancing early intervention. Although prior work has explored the course of PTSD symptoms in the subsequent months, relatively few studies have explored the course of symptoms in the acute post-trauma period, defined as the 30 days after a traumatic event. A key challenge to conducting such studies is the lack of efficient means to collect data that does not impose significant burden on the participant during this time. The present study evaluated the use of a mobile phone application to collect symptom data during the acute post trauma period. Data was obtained from 23 individuals who experienced a Criterion A traumatic event and were recruited from the Emergency Department of a Level 1 Trauma Center. Participants completed 44.93% of daily assessments across a 30-day period. Responses rates were uncorrelated with PTSD symptoms or depression symptoms at 1-month and 3-month posttrauma. Participants reported that the surveys were moderately helpful and posed minimal burden. These findings suggest that mobile applications can be used to learn about the course of post-trauma recovery. PMID- 29109969 TI - Mapping Language Networks Using the Structural and Dynamic Brain Connectomes. AB - Lesion-symptom mapping is often employed to define brain structures that are crucial for human behavior. Even though poststroke deficits result from gray matter damage as well as secondary white matter loss, the impact of structural disconnection is overlooked by conventional lesion-symptom mapping because it does not measure loss of connectivity beyond the stroke lesion. This study describes how traditional lesion mapping can be combined with structural connectome lesion symptom mapping (CLSM) and connectome dynamics lesion symptom mapping (CDLSM) to relate residual white matter networks to behavior. Using data from a large cohort of stroke survivors with aphasia, we observed improved prediction of aphasia severity when traditional lesion symptom mapping was combined with CLSM and CDLSM. Moreover, only CLSM and CDLSM disclosed the importance of temporal-parietal junction connections in aphasia severity. In summary, connectome measures can uniquely reveal brain networks that are necessary for function, improving the traditional lesion symptom mapping approach. PMID- 29109970 TI - Dynamics of GnRH Neuron Ionotropic GABA and Glutamate Synaptic Receptors Are Unchanged during Estrogen Positive and Negative Feedback in Female Mice. AB - Inputs from GABAergic and glutamatergic neurons are suspected to play an important role in regulating the activity of the gonadotropin-releasing hormone (GnRH) neurons. The GnRH neurons exhibit marked plasticity to control the ovarian cycle with circulating estradiol concentrations having profound "feedback" effects on their activity. This includes "negative feedback" responsible for suppressing GnRH neuron activity and "positive feedback" that occurs at mid-cycle to activate the GnRH neurons to generate the preovulatory luteinizing hormone surge. In the present study, we employed brain slice electrophysiology to question whether synaptic ionotropic GABA and glutamate receptor signaling at the GnRH neuron changed at times of negative and positive feedback. We used a well characterized estradiol (E)-treated ovariectomized (OVX) mouse model to replicate negative and positive feedback. Miniature and spontaneous postsynaptic currents (mPSCs and sPSCs) attributable to GABAA and glutamatergic receptor signaling were recorded from GnRH neurons obtained from intact diestrous, OVX, OVX + E (negative feedback), and OVX + E+E (positive feedback) female mice. Approximately 90% of GnRH neurons exhibited spontaneous GABAA-mPSCs in all groups but no significant differences in the frequency or kinetics of mPSCs were found at the times of negative or positive feedback. Approximately 50% of GnRH neurons exhibited spontaneous glutamate mPSCs but again no differences were detected. The same was true for spontaneous PSCs in all cases. These observations indicate that the kinetics of ionotropic GABA and glutamate receptor synaptic transmission to GnRH neurons remain stable across the different estrogen feedback states. PMID- 29109972 TI - The changing hydrology of a dammed Amazon. AB - Developing countries around the world are expanding hydropower to meet growing energy demand. In the Brazilian Amazon, >200 dams are planned over the next 30 years, and questions about the impacts of current and future hydropower in this globally important watershed remain unanswered. In this context, we applied a hydrologic indicator method to quantify how existing Amazon dams have altered the natural flow regime and to identify predictors of alteration. The type and magnitude of hydrologic alteration varied widely by dam, but the largest changes were to critical characteristics of the flood pulse. Impacts were largest for low elevation, large-reservoir dams; however, small dams had enormous impacts relative to electricity production. Finally, the "cumulative" effect of multiple dams was significant but only for some aspects of the flow regime. This analysis is a first step toward the development of environmental flows plans and policies relevant to the Amazon and other megadiverse river basins. PMID- 29109971 TI - alpha2delta-1 Signaling Drives Cell Death, Synaptogenesis, Circuit Reorganization, and Gabapentin-Mediated Neuroprotection in a Model of Insult Induced Cortical Malformation. AB - Developmental cortical malformations (DCMs) result from pre- and perinatal insults, as well as genetic mutations. Hypoxia, viral infection, and traumatic injury are the most common environmental causes of DCMs, and are associated with the subsyndromes focal polymicrogyria and focal cortical dysplasia (FCD) Type IIId, both of which have a high incidence of epilepsy. Understanding the molecular signals that lead to the formation of a hyperexcitable network in DCMs is critical to devising novel treatment strategies. In a previous study using the freeze-lesion (FL) murine model of DCM, we found that levels of thrombospondin (TSP) and the calcium channel auxiliary subunit alpha2delta-1 were elevated. TSP binds to alpha2delta-1 to drive the formation of excitatory synapses during development, suggesting that overactivation of this pathway may lead to exuberant excitatory synaptogenesis and network hyperexcitability seen in DCMs. In that study, antagonizing TSP/alpha2delta-1 signaling using the drug gabapentin (GBP) reduced many FL-induced pathologies. Here, we used mice with a genetic deletion of alpha2delta-1 to determine how alpha2delta-1 contributes to cell death, elevated excitatory synapse number, and in vitro network function after FL and to examine the molecular specificity of GBP's effects. We identified a critical role for alpha2delta-1 in FL-induced pathologies and in mediating the neuroprotective effects of GBP. Interestingly, genetic deletion of alpha2delta-1 did not eliminate GBP's effects on synaptogenesis, suggesting that GBP can have alpha2delta-1-independent effects. Taken together these studies suggests that inhibiting alpha2delta-1 signaling may have therapeutic promise to reduce cell death and network reorganization associated with insult-induced DCMs. PMID- 29109973 TI - Adaptability as the key to success for the ubiquitous marine nitrite oxidizer Nitrococcus. AB - Nitrite-oxidizing bacteria (NOB) have conventionally been regarded as a highly specialized functional group responsible for the production of nitrate in the environment. However, recent culture-based studies suggest that they have the capacity to lead alternative lifestyles, but direct environmental evidence for the contribution of marine nitrite oxidizers to other processes has been lacking to date. We report on the alternative biogeochemical functions, worldwide distribution, and sometimes high abundance of the marine NOB Nitrococcus. These largely overlooked bacteria are capable of not only oxidizing nitrite but also reducing nitrate and producing nitrous oxide, an ozone-depleting agent and greenhouse gas. Furthermore, Nitrococcus can aerobically oxidize sulfide, thereby also engaging in the sulfur cycle. In the currently fast-changing global oceans, these findings highlight the potential functional switches these ubiquitous bacteria can perform in various biogeochemical cycles, each with distinct or even contrasting consequences. PMID- 29109974 TI - Laboratory unraveling of matter accretion in young stars. AB - Accretion dynamics in the formation of young stars is still a matter of debate because of limitations in observations and modeling. Through scaled laboratory experiments of collimated plasma accretion onto a solid in the presence of a magnetic field, we open a first window on this phenomenon by tracking, with spatial and temporal resolution, the dynamics of the system and simultaneously measuring multiband emissions. We observe in these experiments that matter, upon impact, is ejected laterally from the solid surface and then refocused by the magnetic field toward the incoming stream. This ejected matter forms a plasma shell that envelops the shocked core, reducing escaped x-ray emission. This finding demonstrates one possible structure reconciling current discrepancies between mass accretion rates derived from x-ray and optical observations, respectively. PMID- 29109975 TI - Genomic models predict successful coral adaptation if future ocean warming rates are reduced. AB - Population genomic surveys suggest that climate-associated genetic variation occurs widely across species, but whether it is sufficient to allow population persistence via evolutionary adaptation has seldom been quantified. To ask whether rapid adaptation in reef-building corals can keep pace with future ocean warming, we measured genetic variation at predicted warm-adapted loci and simulated future evolution and persistence in a high-latitude population of corals from Rarotonga, Cook Islands. Alleles associated with thermal tolerance were present but at low frequencies in this cooler, southerly locality. Simulations based on predicted ocean warming in Rarotonga showed rapid evolution of heat tolerance resulting in population persistence under mild warming scenarios consistent with low CO2 emission plans, RCP2.6 and RCP4.5. Under more severe scenarios, RCP6.0 and RCP8.5, adaptation was not rapid enough to prevent extinction. Population adaptation was faster for models based on smaller numbers of additive loci that determine thermal tolerance and for higher population growth rates. Finally, accelerated migration via transplantation of thermally tolerant individuals (1 to 5%/year) sped adaptation. These results show that cool water corals can adapt to warmer oceans but only under mild scenarios resulting from international emissions controls. Incorporation of genomic data into models of species response to climate change offers a promising method for estimating future adaptive processes. PMID- 29109976 TI - Wind causes Totten Ice Shelf melt and acceleration. AB - Totten Glacier in East Antarctica has the potential to raise global sea level by at least 3.5 m, but its sensitivity to climate change has not been well understood. The glacier is coupled to the ocean by the Totten Ice Shelf, which has exhibited variable speed, thickness, and grounding line position in recent years. To understand the drivers of this interannual variability, we compare ice velocity to oceanic wind stress and find a consistent pattern of ice-shelf acceleration 19 months after upwelling anomalies occur at the continental shelf break nearby. The sensitivity to climate forcing we observe is a response to wind driven redistribution of oceanic heat and is independent of large-scale warming of the atmosphere or ocean. Our results establish a link between the stability of Totten Glacier and upwelling near the East Antarctic coast, where surface winds are projected to intensify over the next century as a result of increasing atmospheric greenhouse gas concentrations. PMID- 29109978 TI - Dust formation and wind acceleration around the aluminum oxide-rich AGB star W Hydrae. AB - Dust grains, formed around asymptotic giant branch (AGB) stars, are accelerated by stellar radiation to drive stellar winds, which supply freshly synthesized nuclides to the Galaxy. Silicate is the dominant dust species in space, but ~40% of oxygen-rich AGB stars are thought to have comparable amounts of aluminum oxide dust. Dust formation and the wind-driving mechanism around these oxygen-rich stars, however, are poorly understood. We report on the spatial distributions of AlO and 29SiO molecules around an aluminum oxide-rich M-type AGB star, W Hydrae, based on observations obtained with the Atacama Large Millimeter/submillimeter Array. AlO molecules were only observed within three stellar radii (Rstar), whereas 29SiO was distributed in the accelerated wind beyond 5 Rstar without significant depletion. This strongly suggests that condensed aluminum oxide dust plays a key role in accelerating the stellar wind and in preventing the efficient formation of silicate dust around W Hydrae. PMID- 29109977 TI - Prior alcohol use enhances vulnerability to compulsive cocaine self administration by promoting degradation of HDAC4 and HDAC5. AB - Addiction to cocaine is commonly preceded by experiences with legal or decriminalized drugs, such as alcohol, nicotine, and marijuana. The biological mechanisms by which these gateway drugs contribute to cocaine addiction are only beginning to be understood. We report that in the rat, prior alcohol consumption results in enhanced addiction-like behavior to cocaine, including continued cocaine use despite aversive consequences. Conversely, prior cocaine use has no effect on alcohol preference. Long-term, but not short-term, alcohol consumption promotes proteasome-mediated degradation of the nuclear histone deacetylases HDAC4 and HDAC5 in the nucleus accumbens, a brain region critical for reward based memory. Decreased nuclear HDAC activity results in global H3 acetylation, creating a permissive environment for cocaine-induced gene expression. We also find that selective degradation of HDAC4 and HDAC5, facilitated by the class II specific HDAC inhibitor MC1568, enhances compulsive cocaine self-administration. These results parallel our previously reported findings that the gateway drug nicotine enhances the behavioral effects of cocaine via HDAC inhibition. Together, our findings suggest a shared mechanism of action for the gateway drugs alcohol and nicotine, and reveal a novel mechanism by which environmental factors may alter the epigenetic landscape of the reward system to increase vulnerability to cocaine addiction. PMID- 29109979 TI - Na+-induced structural transition of MotPS for stator assembly of the Bacillus flagellar motor. AB - The bacterial flagellar motor consists of a rotor and a dozen stator units and regulates the number of active stator units around the rotor in response to changes in the environment. The MotPS complex is a Na+-type stator unit in the Bacillus subtilis flagellar motor and binds to the peptidoglycan layer through the peptidoglycan-binding (PGB) domain of MotS to act as the stator. The MotPS complex is activated in response to an increase in the Na+ concentration in the environment, but the mechanism of this activation has remained unknown. We report that activation occurs by a Na+-induced folding and dimer formation of the PGB domain of MotS, as revealed in real-time imaging by high-speed atomic force microscopy. The MotPS complex showed two distinct ellipsoid domains connected by a flexible linker. A smaller domain, corresponding to the PGB domain, became structured and unstructured in the presence and absence of 150 mM NaCl, respectively. When the amino-terminal portion of the PGB domain adopted a partially stretched conformation in the presence of NaCl, the center-to-center distance between these two domains increased by up to 5 nm, allowing the PGB domain to reach and bind to the peptidoglycan layer. We propose that assembly of the MotPS complex into a motor proceeds by means of Na+-induced structural transitions of its PGB domain. PMID- 29109981 TI - Variable Damping Force Tunnel for Gait Training Using ALEX III. AB - Haptic feedback affects not only the quality of training but can also influence the physical design of robotic gait trainers by determining how much force needs to be applied to the user and the nature of the force. This paper presents the design of a variable damping force tunnel and explores the effect of the shape and strength of the damping field using ALEX III, a treadmill-based exoskeleton developed at Columbia University. The study consists of 32 healthy subjects who were trained for 40 minutes in the device. The subjects were trained to follow a footpath with a 50% increase in step height, so the foot would have 1.5 times the ground clearance. Subjects were assigned to one of four groups: linear high, linear low, parabolic high, and parabolic low. Linear or parabolic denotes the shape of the damping field, and high or low denotes the rate of change (strength) of the field based on error. It is shown that the new controller is capable of inducing gait adaptations in healthy individuals while walking in the device. All groups showed adaptations in step height, while only the high strength groups showed changes in normalized error area, a measure of how closely the desired path was followed. PMID- 29109980 TI - The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts. AB - Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML). TML levels correlated with histone H3 trimethylation at Lys9 and Lys27, and methylation at these sites was also enhanced in efficiently metastasizing tumors. Erasing either of these marks by genetically or pharmacologically silencing the histone methyltransferase SETDB1 or EZH2 had no effect on primary tumor growth but reduced cellular invasiveness and metastatic spread. Thus, metabolite profiling can uncover targetable epigenetic requirements for the metastasis of human melanoma cells. PMID- 29109984 TI - Scaling relations for the interactions between curved graphene sheets in water. AB - The effect of curvature and relative orientation between two curved graphene sheets in aqueous media is quantified by calculating the potential of mean force using molecular dynamics simulations and thermodynamic perturbation. The potential of mean force between two curved graphene sheets is found to scale as UCG ~ R0.5d-4.5, where R is the sheet radius of curvature and d is the inter sheet distance. Further, a simple analytical calculation based on classical Hamaker theory and the Derjaguin approximation also arrives at the same scaling of interaction energy with respect to R and d. For the case where a misorientation, theta, exists between the two curved graphene sheets, the simulation results strongly suggest an inverse dependence of the potential of mean force on sin theta for theta > 30 degrees . This result is very similar to the scaling predicted by the Derjaguin approximation for two cylinders crossed at an angle theta with respect to each other. PMID- 29109982 TI - Hepatic Lipophagy: New Insights into Autophagic Catabolism of Lipid Droplets in the Liver. AB - The liver is a central fat-storage organ, making it especially susceptible to steatosis as well as subsequent inflammation and cirrhosis. The mechanisms by which the liver mobilizes stored lipid for energy production, however, remain incompletely defined. The catabolic process of autophagy, a well-known process of bulk cytoplasmic recycling and cellular self-regeneration, is a central regulator of lipid metabolism in the liver. In the past decade, numerous studies have examined a selective form of autophagy that specifically targets a unique neutral lipid storage organelle, the lipid droplet, to better understand the function for this process in hepatocellular fatty acid metabolism. In the liver (and other oxidative tissues), this specialized pathway, lipophagy, likely plays as important of a role in lipid turnover as conventional lipase-driven lipolysis. In this review, we will highlight several recent studies that have contributed to our understanding about the regulation and effects of hepatic lipophagy. PMID- 29109985 TI - Near infrared photoluminescence modulation by defect site design using aryl isomers in locally functionalized single-walled carbon nanotubes. AB - We newly introduce positional isomeric structures at the defect sites of locally functionalized single-walled carbon nanotubes (lf-SWNTs) showing unique near infrared photoluminescence (PL). The observed PL is significantly different from that of typical para-aryl modified lf-SWNTs; i.e., (i) an extraordinary PL wavelength shift of the meta-aryl modified lf-SWNTs, and (ii) remarkably red shifted PL from the ortho-aryl modified lf-SWNTs are revealed. PMID- 29109986 TI - Bifunctional organic sponge photocatalyst for efficient cross-dehydrogenative coupling of tertiary amines to ketones. AB - A novel bifunctional organic sponge photocatalyst can enable the efficient coupling of tertiary amines with ketones in water. The asymmetric transformation can be also achieved by using this sponge photocatalyst. PMID- 29109987 TI - Direct screening for ribozyme activity in mammalian cells. AB - Engineered ribozymes are powerful tools for manipulating gene expression in living cells. However, identification of active ribozymes in mammalian cells has relied on empirical assays of a limited number of arbitrarily chosen ribozymes. Here, we synthesized 376 natural and 2625 synthetic variants of pistol ribozymes, and screened for active variants directly in mammalian cells, greatly expanding the ribozyme toolbox for biological applications. PMID- 29109988 TI - Embedded nanoparticle dynamics and their influence on switching behaviour of resistive memory devices. AB - Resistively switching Conductive Bridge Random Access Memories (CBRAMs) rely on the controlled formation and dissolution of metallic filaments within a solid insulator, and are emerging building blocks for beyond von Neumann computing architectures and neuromorphic computing. A lack of understanding of the underlying switching mechanisms currently prevents further device utilisation and optimisation. We present a study of lateral and vertical CBRAM model devices that allow us to systematically relate important switching properties and their statistics to a direct characterisation of their critical switching region by scanning and transmission electron microscopy, i.e. to the physical nature of metal filaments and inclusions on all relevant length scales. We find that filaments are composed of metallic clusters and show how filament dynamics link to migration effects of embedded nanoparticles under voltage bias stress. The formation of metal clusters is promoted by a dynamic interplay of cation mobility and redox rate during switching. These clusters are not completely removed from the switching material matrix upon RESET and appear to grow by consumption of smaller clusters. We discuss in detail the interfacial stress of the nanoparticles in the context of their interaction with the switching material and ambient atmosphere. This allows us to consistently interpret previous literature and to suggest future device improvements. PMID- 29109990 TI - An unexpected journey from highly tunable phosphorescence to novel photochemistry of 1,2,3-triazole-based complexes. AB - The photophysical properties of transition metal complexes have long attracted interest in the literature with significant research activity during the past two to three decades due to the potential exploitation of these materials in solar energy conversion, light-emitting technology, luminescence biological imaging and photodynamic therapeutic applications to name but a few. Since the advent of the facile preparation of 1,2,3-triazole-based compounds through copper(i)-catalysed cycloaddition, ligands based on this heterocycle have received widespread attention in coordination chemistry. Inevitably, their ability to be used as pyridine-like analogues has resulted in significant attention on the photophysical properties of their resultant complexes. There are, however, two sides to this tale; on the one hand, routes to 1,2,3-triazoles have enabled the realisation of highly tunable and efficient phosphors and photosensitisers. On the other hand, 1,2,3-triazole-based complexes have allowed highly novel photochemical processes to be explored offering insights into hitherto unappreciated excited state dynamics. This Perspective review covers the developments of photophysically active triazole-based complexes over the last decade, highlighting some of the key discoveries from our own laboratory as well as seminal contributions from other groups who are active in the area. We also identify possible new avenues for investigation and exploitation stemming from the work so far. PMID- 29109991 TI - Synthetic approaches to the C11-C27 fragments of bryostatins. AB - The modified Julia reaction and acyl carbanion chemistry, especially reactions of 2-lithiated dithianes, have been investigated for the synthesis of intermediates that are the synthetic equivalents of the C11-C27 fragments of bryostatins. The modified Julia reaction using 2-benzothiazolylsulfones was found to be more useful for the formation of the C16-C17 double-bond than the classical Julia reaction using phenylsulfones, and bulky sulfones gave very good (E) stereoselectivity. The alkylation of a dithiane monoxide that corresponded to a C19-acyl carbanion using (E)-1-bromobut-2-ene was efficient but the use of a more complex allylic bromide corresponding to the C20-C27 fragment of the bryostatins was unsuccessful, possibly due to competing elimination reactions. This meant that the use of C19 dithianes for the synthesis of 20-deoxybryostatins would have to involve the stepwise assembly of the C20-C27 fragment from simpler precursors. However, lithiated C19 dithianes gave good yields of adducts with aldehydes and conditions were developed for the stereoselective conversion of the major adducts into methoxyacetals that corresponded to the C17-C27 fragment of 20-oxygenated bryostatins. A convergent synthesis of the C11-C27 fragment of a 20 deoxybryostatin was subsequently achieved using a 2-benzothiazolylsulfone corresponding to the intact C17-C27 fragment. PMID- 29109992 TI - Correction: Photodissociation dynamics of fulvenallene and the fulvenallenyl radical at 248 and 193 nm. AB - Correction for 'Photodissociation dynamics of fulvenallene and the fulvenallenyl radical at 248 and 193 nm' by Isaac A. Ramphal et al., Phys. Chem. Chem. Phys., 2017, DOI: . PMID- 29109993 TI - Exploration of an easily synthesized fluorescent probe for detecting copper in aqueous samples. AB - An easily synthesized fluorescent probe for detecting copper in aqueous samples, with a short response time and at neutral pH, has been investigated. Through the chelation of Cu2+ ions or by binding to CuO nanoparticles, the fluorescence emission of the 2-(aminomethyl)aniline derivative H2L is quenched by over 50%. Spectroscopic determination of the association constants of H2L with some metal ions showed that the ligand has a higher affinity toward Cu2+ than toward other d block metal ions. The comparative bonding ability of the aniline-based fluorescent probe in d-block metal complexes was studied in solution by a combination of UV-Vis, 1H NMR and mass spectrometry analyses. Besides these, the bonding behavior has been investigated in the solid state by X-ray diffraction, FT-IR spectroscopy and elemental analysis. The crystal structures of Pd2(L)2 and Co(L)(HL)(H2O) were elucidated. PMID- 29109994 TI - Macroscopic supramolecular assembly to fabricate multiplexed DNA patterns for potential application in DNA chips. AB - Macroscopic supramolecular assembly (MSA) is a newly established methodology to construct supramolecular materials directly from large building blocks. Demonstrations of MSA for various functions are urgently needed to advance MSA from fundamental studies to practical uses. Here we propose the fabrication of DNA microarrays by combining MSA and magnetic-assisted localization. PMID- 29109995 TI - Total synthesis of 7-des-O-pivaloyl-7-O-benzylbryostatin 10. AB - The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17-C27 fragment with aldehydes corresponding to the C1-C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1-C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling. A more efficient synthesis of the C17-C27 sulfone was developed in which a key step was the bismuth mediated coupling of an allylic bromide with an aldehyde in the presence of an acrylate moiety in the allylic bromide. A scalable synthesis of an advanced macrolide was completed using the modified Julia reaction followed by selective deprotection and macrolactonisation. The final stages of the synthesis required selective hydroxyl deprotection and the introduction of the sensitive C19-C21 unsaturated keto-ester functionality. Unexpected selectivities were observed during studies of the hydroxyl group deprotections. In particular, cleavage of tri-isopropylsilyl ethers of the exocyclic primary allylic alcohols was observed in the presence of the triethylsilyl ether of the secondary alcohol at C19. Model studies helped in the design of the methods used to introduce the C19-C21 keto-ester functionality and led to the completion of a total synthesis of a close analogue of bryostatin 10 in which a benzyloxy group rather than the pivaloyloxy group was present at C7. PMID- 29109996 TI - Simulational insights into the mechanical response of prestretched double network filled elastomers. AB - This paper deals with molecular-dynamics simulations of the mechanical properties of prestretched double network filled elastomers. To this end, we firstly validated the accuracy of this method, and affirmed that the produced stress strain characteristics were qualitatively consistent with Lesser's experimental results on the prestretched tri-block copolymers with a competitive double network. Secondly, we investigated the effect of the crosslinking network ratio on the mechanical properties of the prestretched double network homopolymers under uniaxial tension. We found that the prestretched double network contributes greatly to the enhanced tensile stress and ultimate strength at fracture, as well as to the lower permanent set (the residual strain) and dynamic hysteresis loss, both parallel and perpendicular to the prestretching direction. Notably, though, an anisotropic behavior was observed: in the parallel direction, both the first and the second crosslinked networks bore the external force; whereas in the perpendicular direction, only the second crosslinked network was relevantly effective. Finally, the polymer nanocomposites with a prestretched double network exhibited tensile mechanical properties similar to those of the studied homopolymers with prestretched double networks. Summing up the results, it can be concluded that the incorporation of prestretched double networks with a specified crosslinking network ratio seems to be a promising method for manipulating the mechanical properties of elastomers and their nanocomposites, as well as for introducing anisotropy in their mechanical response. PMID- 29109997 TI - Foreign In3+ treatment improving the photoelectrochemical performance of a hematite nanosheet array for water splitting. AB - In this work, we found that foreign metallic ion (In3+) treatment enhanced the photoelectrochemical (PEC) activity of hematite nanosheets aligning on a substrate without joining the host lattice. Scanning electron microscopy (SEM) observation indicated that the In3+ ion treatment nearly did not change the size and thickness of the hematite nanosheets during solvothermal synthesis. However, the treatment reduced nanosheet stacking and increased the active surface area of the hematite photoanode. Careful combined analyses involving Energy Dispersive X ray (EDX) spectroscopy, X-ray photoelectron spectroscopy (XPS) and powder X-ray diffraction (XRD) confirmed that In3+ ions were not doped in the hematite nanosheets. Interestingly, after the In3+ treatment, the photoelectrochemical properties of the hematite nanosheets were highly enhanced when they were used as a photoanode for water splitting. The photocurrent density at 1.23 V (versus reversible hydrogen electrode) was 2.6 times as high as that of the hematite without In3+-treatment. The improved PEC activity was deduced to be associated with the increased active surface area for higher light absorption and more photoelectrode/electrolyte junctions, as well as higher carrier density after the In3+-treatment. Furthermore, the efficiencies of the surface charge separation and charge transfer for the In3+-treated hematite nanosheets also increased much more. PMID- 29109998 TI - Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling. AB - Anaplastic lymphoma kinase (ALK) has been regarded as a promising drug target in the treatment of tumors and the mutation L1196M induces different levels of drug resistance toward the existing inhibitors. Free energy perturbation (FEP) coupled with umbrella sampling simulation is used to investigate the conformational change of ALK induced by L1196M and drug-resistant mechanisms of L1196M on four inhibitors VGH, 3U9, 5P8 and IV7. Dynamics analysis shows that L119M produces significant influences on the flexibility of the loops L1 and L2 in ALK. FEP calculations suggest that the drug-resistant intensity of L1196M toward inhibitors decreases in the order 3U9 > VGH > 5P8 > IV7, in accordance with the experimentally determined results. Moreover, statistical analysis of hydrophobic contacts of inhibitors with separate residues in ALK further demonstrates that the decrease in the hydrophobic interactions of inhibitors with L1256 mostly drives drug resistance of L1196M toward inhibitors. The calculations of potential of mean force (PMF) based on umbrella sampling simulations indicate that the free energies of inhibitor-L1196M ALKs are lower than those of inhibitor-wild ALKs. This study is expected to provide significant theoretical support which would help in the design of potent inhibitors alleviating the drug resistance of L1196M in ALK. PMID- 29109999 TI - Enhanced directional cell migration induced by vaccinia virus on a microfluidic based multi-shear cell migration assay platform. AB - Virus-induced cell migration plays important roles in the direct and rapid spread of virus particles. As cell migration is also regulated by shear stress, it is necessary to explore the cell migration behavior influenced by multiple factors including a virus and shear stress. In this report, a three-layer microfluidic chip with symmetric channels was designed and fabricated to investigate vaccinia virus-induced cell migration in different shear stress environments. Regular "exclusion zones" without cell damage were formed by microvalves. The results showed that infected cells were more elongated and tended to migrate along the flow direction compared to the random cell migration under static conditions. Meanwhile, shear stress enhanced the natural directional persistence and accelerated the velocity of infected cell migration. Moreover, reduced peripheral lamellae and the axial lamella being confined to the flow direction were responsible for the increased directionality of cell migration under shear stress. Interestingly, in the presence of shear stress, the Golgi complex reoriented and relocated behind the nucleus and aligned to the flow direction in infected migratory cells accompanied by the rearrangement of the cytoskeleton. Our report reveals the cell migration behavior in the multi-environment of virus infection and shear stress based on the microfluidic cell migration assay platform. It helps us to deeply understand the interactions between the virus, host cells, and surrounding microenvironment. PMID- 29110000 TI - Carbon dots: promising biomaterials for bone-specific imaging and drug delivery. AB - Bone-related diseases and dysfunctions are heavy burdens on our increasingly aged society. One important strategy to relieve this problem is through early detection and treatment of bone-related diseases. Towards this goal, there has been constant interest in developing novel bone-specific materials for imaging and drug delivery. Currently, however, materials that have high affinity and specificity towards bone are very limited. Carbon dots (C-dots) synthesized from carbon nanopowder bind to calcified bones in vivo with high affinity and specificity. In this study we show that bone binding is highly unique to a specific type of C-dot, and that this binding is non-toxic. Significantly, C-dots derived from other raw materials did not show any bone binding properties. These differences are attributed to the differences in surface chemistry of C-dot preparations, highlighting the heterogeneous nature of C-dots. Importantly, bone binding by carbon nanopowder derived C-dots is not significantly altered by chemical functionalization of their surface. These unique properties indicate the potential applications of carbon nanopowder-derived C-dots as highly bone specific bioimaging agents and drug carriers. PMID- 29110001 TI - Probing the chaotic boundary of a membrane resonator with nanowire arrays. AB - Mechanically induced nonlinearities in nano-electromechanical systems (NEMSs) are typically avoided in design due to their unpredictable nature; however, by incorporating these normally unwanted nonlinear and chaotic phenomena, the performance of NEMS devices displays substantially different characteristics opening a broad new range of potential applications for their use. In this work, experiments have been conducted for probing the chaotic boundary of a circular membrane mechanical resonator with and without a silicone nanowire array (Si NWA). The NWA resonator can transition from linear to nonlinear quasi-periodic behaviour, and further transition into a chaotic state at resonance. Moreover, the NWA resonator demonstrated a high level of complex nonlinear behaviours, as the device expands the power spectral response from a single frequency at a linear regime to a wideband continuous frequency spectrum when chaotic behaviour was initiated; the threshold power of this transition decreased with a smaller NWA diameter. It was also observed that the NWA resonator had higher damping compared to the resonator without a NWA; however, as the vibration velocity of the NWA resonator increased, complex air damping and thin squeeze film damping lowered the threshold for probing the chaotic boundary condition of the NWA resonator. PMID- 29110002 TI - Excited state dynamics for hybridized local and charge transfer state fluorescent emitters with aggregation-induced emission in the solid phase: a QM/MM study. AB - Highly efficient organic light-emitting diodes (OLEDs) based on fluorescent emitters with a hybridized local and charge transfer (HLCT) state have attracted significant attention. Recently, a near-infrared fluorescent compound, 2,3-bis(4' (diphenylamino)-[1,1'-biphenyl]-4-yl)fumaronitrile (TPATCN), with an HLCT state has been synthetized, and the features of OLEDs based on this compound have been explored. In this study, excited state dynamics of TPATCN in the solid phase has been theoretically studied through a combined quantum mechanics and molecular mechanics (QM/MM) method. By analyzing the changes in geometry, the Huang-Rhys factor, and reorganization energy, non-radiative consumption ways through the torsional motions of diphenylamino and central fumaronitrile in low frequency regions (<200 cm-1) are effectively hindered by the restricted intramolecular rotation (RIR) effect in the solid phase. The fluorescence efficiency of the OLED has been quantitatively calculated. The results show that the fluorescence efficiency is greatly enhanced from 0.16% in the gas phase to 52.1% in the solid phase; this demonstrates the aggregation-induced emission (AIE) mechanism for the OLED. Furthermore, by combining the dynamics of the excited states and the adiabatic energy structures calculated in the solid phase, the so-called hot exciton process from higher triplet states to a singlet state has been illustrated. Our investigation elucidates the experimental measurement and helps understand the AIE mechanism for HLCT compounds, which is beneficial for developing highly efficient emitters. PMID- 29110003 TI - Approximate solution of coupled cluster equations: application to the coupled cluster doubles method and non-covalent interacting systems. AB - We have developed a simplified coupled cluster (SCC) methodology, using the basic idea of scaled MP2 methods. The scheme has been applied to the coupled cluster double equations and implemented in three different non-iterative variants. This new method (especially the SCCD[3] variant, which utilizes a spin-resolved formalism) has been found to be very efficient and to yield an accurate approximation of the reference CCD results for both total and interaction energies of different atoms and molecules. Furthermore, we demonstrate that the equations determining the scaling coefficients for the SCCD[3] approach can generate non-empirical SCS-MP2 scaling coefficients which are in good agreement with previous theoretical investigations. PMID- 29110004 TI - Asymmetric formal synthesis of (+)-cycloclavine. AB - The asymmetric synthesis of Szantay's amine (+)-2, the pivotal precursor for direct access to (+)-cycloclavine (1), is described for the first time in eleven steps with 19.7% overall yield from the commercially available 4-bromoindole. The strategy features an asymmetric induction by Ellman's sulfinimine and rhodium catalysed isomerization of the C[double bond, length as m-dash]C bond. PMID- 29110005 TI - Effect of donor to acceptor ratio on electrochemical and spectroscopic properties of oligoalkylthiophene 1,3,4-oxadiazole derivatives. AB - A structure-property study across a series of donor-acceptor-donor structures composed of mono- and bi-(1,3,4-oxadiazole) units symmetrically substituted with alkyl functionalized bi-, ter- and quaterthiophene segments is presented. Synthetically tailoring the ratio of electron-withdrawing 1,3,4-oxadiazole to electron-releasing thiophene units and their alkyl grafting pattern permitted us to scrutinize the impact of these structural factors on the redox, absorptive and emissive properties of these push-pull molecules. Contrasting trends of redox potentials were observed, with the oxidation potential closely following the donor-to-acceptor ratio, whereas the reduction potential being tuned independently by either the number of acceptor units or the conjugation length of the donor-acceptor system. Increasing the thiophene unit contribution delivered a shift from blue to green luminescence, while the structural rigidity afforded by intramolecular non-covalent interactions between 1,3,4-oxadiazole and the thiophene moieties has been identified as the prime factor determining the emission efficiency of these molecules. All six structures investigated electro polymerize easily, yielding electroactive and electrochromic polymers. The polymer doping process is largely influenced by the length of the oligothiophene repeating unit and the alkyl chain grafting density. Polymers with relatively short oligothiophene segments are able to support polarons and polaron-pairs, whereas those with segments longer than six thiophene units could also stabilize diamagnetic charge carries - bipolarons. Increasing the alkyl chain grafting density improved the reversibility and broadened the working potential window of the p-doping process. Stable radical anions have also been investigated, bringing detailed information about the conjugation pattern of these electron-surplus species. This study delivers interesting clues towards the conscious structural design of bespoke frontier energy level oligothiophene functional materials and their polymers by incorporating a structurally matching 1,3,4-oxadiazole unit. PMID- 29110006 TI - Porous germanene as a highly efficient gas separation membrane. AB - Using a gas separation membrane as a simple gas separation device has an obvious advantage because of the low energy consumption and pollution-free manufacturing. The first-principles calculations used in this work show that germanene with its divacancy is an excellent material for use as a hydrogen (H2) and helium (He) separation membrane, and that it displays an even better competitive advantage than porous graphene and porous silicene. Porous germanene with its divacancy is chemically inert to gas molecules, because it lacks additional atoms to protect the edged dangling germanium atoms in defects, and thus shows great advantages for gas separation over previously prepared graphene. The energy barriers to H2 and He penetrating porous germanene are quite low, and the permeabilities to H2 and He are high. Furthermore, the selectivities of porous germanene for H2 and He relative to other gas molecules are high, up to 1031 and 1027, respectively, which are superior to those of porous graphene (1023) and porous silicene (1013); thus the separation efficiency of porous germanene is much higher than that of porous graphene and porous silicene. Therefore, germanene is a favorable candidate as a gas separation membrane material. At the same time, the successful synthesis of germanene in the laboratory means that it is possible to use it in real applications. PMID- 29110007 TI - Recent development of luminescent rhenium(i) tricarbonyl polypyridine complexes as cellular imaging reagents, anticancer drugs, and antibacterial agents. AB - There has been fast-growing interest in the exploitation of the photophysical and photochemical properties of luminescent transition metal complexes in biological applications, with a focus on both diagnostic and therapeutic aspects. In particular, the design of luminescent rhenium(i) tricarbonyl polypyridine complexes as cellular imaging reagents and anticancer drugs has received considerable attention for a number of reasons. First, most rhenium(i) tricarbonyl polypyridine complexes possess diverse photophysical and photochemical properties through the coordination of functionalized ligands. The typical photophysical properties of the complexes such as large Stokes shifts, long emission lifetimes, and high photostability allow them to serve as attractive candidates for optical imaging. Also, the cellular uptake of the complexes can be readily quantified by atomic absorption spectroscopy and inductively coupled plasma-mass spectrometry. Additionally, owing to the characteristic infrared absorption bands and the isostructural relationship between rhenium and technetium-99m, rhenium(i) tricarbonyl complexes have been exploited as multimodal imaging reagents for vibrational and radio-imaging, respectively. Furthermore, the facile photosensitizing properties and the three carbon monoxide (CO) ligands render rhenium(i) tricarbonyl complexes promising candidates as photodynamic therapy reagents and photoactivatable CO-releasing molecules, respectively, for cancer treatment. In this Perspective, we describe the recent development of luminescent rhenium(i) tricarbonyl polypyridine complexes as cellular imaging reagents, anticancer drugs, and antibacterial agents. PMID- 29110008 TI - Effects of UV-B radiation on the infectivity of Magnaporthe oryzae and rice disease-resistant physiology in Yuanyang terraces. AB - The traditional rice variety "Baijiaolaojing" was planted in Yuanyang terraces (1600 m altitude) under field conditions. The effects of enhanced UV-B radiation (0 kJ m-2, 2.5 kJ m-2, 5.0 kJ m-2 and 7.5 kJ m-2) on the rice-Magnaporthe oryzae system were studied with respect to the Magnaporthe oryzae infection, the disease resistance physiology of the rice and the rice blast disease condition. The results showed that under enhanced UV-B radiation, the infectivity of Magnaporthe oryzae was decreased, which could significantly inhibit its growth and sporulation. The activities of rice leaf disease-resistance-related enzymes (phenylalanine ammonia-lyase, lipoxygenase, chitinase and beta-1,3-glucanase) were significantly increased under enhanced UV-B radiation. Following inoculation with Magnaporthe oryzae, levels of disease-resistance-related substances in the rice leaves were significantly increased. Among the results, it was found that leaves after UV-B radiation had a more significant resistance response. The level of UV-B irradiation showed a parabolic relationship with the rice blast index (r2 = 0.85, P < 0.01; in the control group, r2 = 0.88, P < 0.01). The disease index decreased with increase in irradiation. The DI was at a minimum with enhanced UV B irradiance of 4 kJ m-2; thereafter, it increased with increasing irradiation. The enhanced UV-B radiation had a direct impact on the growth of rice and Magnaporthe oryzae, and it indirectly changed the rice-Magnaporthe oryzae system. UV-B radiation could reduce the harmful impact of rice blast. PMID- 29110009 TI - Theoretical design of conjugated diradicaloids as singlet fission sensitizers: quinones and methylene derivatives. AB - The electronic structures of 206 carbonyls and methylene derivatives based on conjugated cyclic hydrocarbons are computationally studied in this work using theoretical methods of quantum chemistry. The singlet open-shell nature of the ground state and its influence on the low-lying excited states is analyzed for 90 carbonyl (quinone, Q), 90 methylene (quinone dimethide, QDM) and 26 carbonyl methylene (quinone methide, QM) mixed derivatives in the pursuit of new promising candidates for singlet fission sensitizers. Non-negligible diradical character is observed for most of the studied molecules, which is mainly determined by the nature and the relative position of the substituting groups in the bare rings. In general, the methylene group enhances to a greater extent the diradical character and the following trend is observed: y0(QDM) > y0(QM) > y0(Q). This feature leads to a decrease in the energy of the S0 -> S1 and, especially, the S0 -> T1 transitions, facilitating the accomplishment of the singlet fission energetic conditions: 2T1-S1 <= 0 (C1) and 2T1-T2 < 0 (C2). For all the methylene derivatives, these transitions have pi -> pi* character, while some carbonyl containing molecules, in particular those with low diradical character, show transitions with n -> pi* character, due to the presence of the lone pairs of the oxygen atom. From the total set of 206 molecules analyzed, 10 molecules with intermediate diradical character may be considered as potential candidates to undergo singlet fission efficiently. PMID- 29110012 TI - A look at the density functional theory zoo with the advanced GMTKN55 database for general main group thermochemistry, kinetics and noncovalent interactions. AB - We present the GMTKN55 benchmark database for general main group thermochemistry, kinetics and noncovalent interactions. Compared to its popular predecessor GMTKN30 [Goerigk and Grimme J. Chem. Theory Comput., 2011, 7, 291], it allows assessment across a larger variety of chemical problems-with 13 new benchmark sets being presented for the first time-and it also provides reference values of significantly higher quality for most sets. GMTKN55 comprises 1505 relative energies based on 2462 single-point calculations and it is accessible to the user community via a dedicated website. Herein, we demonstrate the importance of better reference values, and we re-emphasise the need for London-dispersion corrections in density functional theory (DFT) treatments of thermochemical problems, including Minnesota methods. We assessed 217 variations of dispersion corrected and -uncorrected density functional approximations, and carried out a detailed analysis of 83 of them to identify robust and reliable approaches. Double-hybrid functionals are the most reliable approaches for thermochemistry and noncovalent interactions, and they should be used whenever technically feasible. These are, in particular, DSD-BLYP-D3(BJ), DSD-PBEP86-D3(BJ), and B2GPPLYP-D3(BJ). The best hybrids are omegaB97X-V, M052X-D3(0), and omegaB97X-D3, but we also recommend PW6B95-D3(BJ) as the best conventional global hybrid. At the meta-generalised-gradient (meta-GGA) level, the SCAN-D3(BJ) method can be recommended. Other meta-GGAs are outperformed by the GGA functionals revPBE D3(BJ), B97-D3(BJ), and OLYP-D3(BJ). We note that many popular methods, such as B3LYP, are not part of our recommendations. In fact, with our results we hope to inspire a change in the user community's perception of common DFT methods. We also encourage method developers to use GMTKN55 for cross-validation studies of new methodologies. PMID- 29110013 TI - Metal-organic frameworks based membranes for liquid separation. AB - Metal-organic frameworks (MOFs) represent a fascinating class of solid crystalline materials which can be self-assembled in a straightforward manner by the coordination of metal ions or clusters with organic ligands. Owing to their intrinsic porous characteristics, unique chemical versatility and abundant functionalities, MOFs have received substantial attention for diverse industrial applications, including membrane separation. Exciting research activities ranging from fabrication strategies to separation applications of MOF-based membranes have appeared. Inspired by the marvelous achievements of MOF-based membranes in gas separations, liquid separations are also being explored for the purpose of constructing continuous MOFs membranes or MOF-based mixed matrix membranes. Although these are in an emerging stage of vigorous development, most efforts are directed towards improving the liquid separation efficiency with well-designed MOF-based membranes. Therefore, as an increasing trend in membrane separation, the field of MOF-based membranes for liquid separation is highlighted in this review. The criteria for judicious selection of MOFs in fabricating MOF-based membranes are given. Special attention is paid to rational design strategies for MOF-based membranes, along with the latest application progress in the area of liquid separations, such as pervaporation, water treatment, and organic solvent nanofiltration. Moreover, some attractive dual-function applications of MOF-based membranes in the removal of micropollutants, degradation, and antibacterial activity are also reviewed. Finally, we define the remaining challenges and future opportunities in this field. This Tutorial Review provides an overview and outlook for MOF-based membranes for liquid separations. Further development of MOF-based membranes for liquid separation must consider the demands of strict separation standards and environmental safety for industrial application. PMID- 29110014 TI - TMAO mediates effective attraction between lipid membranes by partitioning unevenly between bulk and lipid domains. AB - Under environmental duress, many organisms accumulate large amounts of osmolytes molecularly small organic solutes. Osmolytes are known to counteract stress, driving proteins to their compact native states by their exclusion from protein surfaces. In contrast, the effect of osmolytes on lipid membranes is poorly understood and widely debated. Many fully membrane-permeable osmolytes exert an apparent attractive force between lipid membranes, yet all proposed models fail to fully account for the origin of this force. We follow the quintessential osmolyte trimethylamine N-oxide (TMAO) and its interaction with dimyristoyl phosphatidylcholine (DMPC) membranes in aqueous solution. We find that by partitioning away from the inter-bilayer space, TMAO pushes adjacent membranes closer together. Experiments and simulations further show that the partitioning of TMAO away from the volume between bilayers stems from its exclusion from the lipid-water interface, similar to the mechanism of protein stabilization by osmolytes. We extend our analysis to show that the preferential interaction of other physiologically relevant solutes (including sugars and DMSO) also correlates with their effect on membrane bilayer interactions. Our study resolves a long-standing puzzle, explaining how osmolytes can increase membrane-membrane attraction or repulsion depending on their preferential interactions with lipids. PMID- 29110015 TI - Fractional Carbon Dioxide Laser as an "Add-on" Treatment for Vitiligo: A Meta analysis with Systematic Review. AB - Treatment of vitiligo is challenging and requires a multidisciplinary approach. Fractional carbon dioxide (CO2) laser as an add-on to conventional treatment has been reported to be effective, but there is no consensus on its use. A systematic review was performed by searching major databases for relevant publications to February 2017. Six studies with 85 participants were included. For those with refractory vitiligo, the addition of fractional CO2 laser to routine treatment modalities was superior to conventional treatment alone in terms of > 50% re pigmentation (risk ratio (RR) 4.90, 95% confidence interval (95% CI), 1.15-20.93; p = 0.03), physician improvement score (mean difference (MD) 0.81, 95% CI 0.33 1.29; p < 0.001), < 25% re-pigmentation (RR 0.64, 95% CI, 0.49-0.85; p=0.002) and patient satisfaction (MD 1.61, 95% CI 0.73-2.49; p< 0.001). Side-effects were minor. These results provide evidence supporting that fractional CO2 laser is a valuable treatment modality for patients with vitiligo, especially for those with refractory vitiligo. PMID- 29110016 TI - Allergic Contact Dermatitis Due to Ripasudil Hydrochloride Hydrate in Eye-drops: A Case Report. PMID- 29110017 TI - Infectious Cellulitis Caused by Streptococcus halichoeri. PMID- 29110018 TI - Estimation of Direct Melanoma-related Costs by Disease Stage and by Phase of Diagnosis and Treatment According to Clinical Guidelines. AB - Cutaneous melanoma is a major concern in terms of healthcare systems and economics. The aim of this study was to estimate the direct costs of melanoma by disease stage, phase of diagnosis, and treatment according to the pre-set clinical guidelines drafted by the AIOM (Italian Medical Oncological Association). Based on the AIOM guidelines for malignant cutaneous melanoma, a highly detailed decision-making model was developed describing the patient's pathway from diagnosis through the subsequent phases of disease staging, surgical and medical treatment, and follow-up. The model associates each phase potentially involving medical procedures with a likelihood measure and a cost, thus enabling an estimation of the expected costs by disease stage and clinical phase of melanoma diagnosis and treatment according to the clinical guidelines. The mean per-patient cost of the whole melanoma pathway (including one year of follow-up) ranged from ?149 for stage 0 disease to ?66,950 for stage IV disease. The costs relating to each phase of the disease's diagnosis and treatment depended on disease stage. It is essential to calculate the direct costs of managing malignant cutaneous melanoma according to clinical guidelines in order to estimate the economic burden of this disease and to enable policy-makers to allocate appropriate resources. PMID- 29110019 TI - Correlation Between Dermatology Life Quality Index and Psoriasis Area and Severity Index in Patients with Psoriasis Treated with Ustekinumab. AB - Monitoring of biological treatment efficacy for psoriasis is based on clinical evaluation and patient's quality of life. However, long-term correlation between Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) in real life has not been studied in patients treated with ustekinumab. All patients with psoriasis treated with ustekinumab at our department were included (n = 120) in this study. Correlation analyses between the change in PASI and DLQI and the individual subquestions in DLQI were performed using Spearman's rank correlation coefficient. A correlation value of 0.57 (p-value <0.001) and 0.45 (p-value < 0.001) between PASI and DLQI were found in the period baseline - 4 months and baseline - 12 months, respectively. In DLQI subquestions, the greatest association was found for the questions on "Symptoms and feelings". Objective improvements in the severity of psoriasis were weakly to moderately associated with improvements in quality of life in patients with psoriasis treated with ustekinumab. PMID- 29110020 TI - Granuloma Annulare and Morphea: Correlation with Borrelia burgdorferi Infections and Chlamydia-related Bacteria. AB - A retrospective study of 109 skin biopsies with granuloma annulare (GA) or morphea histology from patients with suspected tick bite was performed. Biopsies were tested for cutaneous Borrelia burgdorferi DNA using PCR. The same biopsies were analysed for tick-borne novel agents, Chlamydia-related bacteria (members of the Chlamydiales order), using a PCR-based method. Borrelia DNA was detected in 7/73 (9.6%) biopsies with GA and in 1/36 (2.8 %) biopsies with morphea, while Chlamydiales DNA was found in 53/73 (72.6%) biopsies with GA and 25/34 (73.4%) biopsies with morphea. All Borrelia DNA-positive GA samples were also positive for Chlamydiales DNA. The Chlamydiales sequences detected in GA were heterogeneous and contained Waddliaceae and Rhabdochlamydiaceae bacteria, which are also present in Ixodes ricinus ticks, while the Chlamydiales sequences detected in morphea closely resembled those found in healthy skin. In conclusion, tick-mediated infections can trigger GA in some cases, while correlation of either Borrelia or Chlamydiales with morphea is unlikely. PMID- 29110021 TI - Search for RASA1 Variants in Capillary Malformations of the Legs in 113 Children: Results from the French National Paediatric Cohort CONAPE. AB - Patients with an inherited autosomal-dominant disorder, capillary malformation arteriovenous malformation (CM-AVM), frequently have mutations in Ras P21 protein activator 1 (RASA1). The aims of this study were to determine the prevalence of germline RASA1 variants in a French multicentre national cohort of children, age range 2-12 years, with sporadic occurrence of capillary malformation (CM) of the legs, whatever the associated abnormalities, and to identify genotype-phenotype correlates. DNA was extracted from leukocytes in blood samples, purified and amplified, and all exons of the RASA1 gene were analysed. Among 113 children analysed, 7 had heterozygous variants (6.1%). Four different variants were identified; 2 were new. In children with RASA1 variants, CMs were more frequently bilateral and multifocal. In conclusion, RASA1 variants are rarely found in children with sporadic CM of lower limbs without CM-AVM syndrome. CMs in this study were heterogeneous, and no disease-causing relationship could be proven. PMID- 29110022 TI - Patients' and Physicians' Preferences for Systemic Psoriasis Treatments: A Nationwide Comparative Discrete Choice Experiment (PsoCompare). AB - Systemic antipsoriatic treatment options are increasing rapidly. The aim of this nationwide discrete choice experiment was to compare patients' (n = 222) and physicians' (n = 78) preferences for outcome and process attributes of systemic antipsoriatics using Relative Importance Scores (RIS). Both groups considered Psoriasis Area and Severity Index 90 (PASI 90) to be most important (RIS 21.4 and 20.8, respectively). Moreover, patients were highly concerned about mild and severe adverse events (RIS = 18.2 and 14.2), physicians about severe adverse events (RIS = 14.9) and cost (RIS = 13.8). Compared to physicians, patients worried more about mild adverse events and treatment location, but less about cost and frequency of laboratory tests. Physicians' preferences were influenced by work experience and percentage of biological prescriptions, patients' preferences by age, disease duration and severity. Older and less severely affected patients recruited via a patient organization focused more on safety, but less on efficacy and time until response than did patients from study centres. In conclusion, these differences in trade-offs should be integrated into a shared decision-making. PMID- 29110023 TI - [Modern treatment of primary biliary cholangitis]. AB - For nearly 30 years ursodeoxycholic acid (UDCA) represented the only pharmacological treatment option available for primary biliary cholangitis (PBC). This changed at the end of 2016 when obeticholic acid was licensed in Europe for PBC patients not responding to UDCA. Novel treatment concepts involving the modulation of nuclear receptor signaling in cholestatic and other liver diseases have led to a host of new potential options, studies and drug candidates for the treatment of PBC. The analysis of large multinational cohorts has additionally confirmed the effectiveness of UDCA in slowing PBC progression, and has led to the development of new definitions for the risk assessment of PBC patients under therapy, which will be an asset for clinical decision making. One issue that remains unresolved is the therapeutic management of extrahepatic symptoms associated with PBC, namely fatigue and pruritus, which are the main factors influencing the quality of life of affected individuals. Their pathophysiological basis is poorly understood and treatment remains unsatisfactory. PMID- 29110025 TI - Medication errors with tramadol drops in children. PMID- 29110026 TI - piRNAs and Evolutionary Trajectories in Genome Size and Content. PMID- 29110024 TI - Parenting style and mental disorders in a nationally representative sample of US adolescents. AB - PURPOSE: We examined associations between parenting style and past-year mental disorders in a nationally representative cross-sectional survey of US adolescents and whether the associations differed by adolescent demographic characteristics. METHODS: The sample included 6483 adolescents aged 13-18 years who were interviewed for a full range of DSM-IV mental disorders. Parenting style was assessed by adolescent-reported maternal and paternal care and control using items from the Parental Bonding Instrument. We controlled for socio-demographics, parental history of mental disorders, stressful life events, sexual violence, inter-parental conflict, and household composition. We also tested for two-way interactions between parental care and control and adolescent age, sex, and race/ethnicity. RESULTS: In adjusted models, high maternal care was associated with lower odds of depressive, eating, and behavioral disorders, and high maternal control was associated with greater odds of depressive, anxiety, eating, and behavioral disorders. High paternal care was associated with lower odds of social phobia and alcohol abuse/dependence. High paternal control was associated with greater odds of agoraphobia and alcohol abuse/dependence but with lower odds of attention-deficit/hyperactivity disorder. Associations of maternal and paternal control with anxiety disorders and substance abuse/dependence differed by sex. High paternal care was associated with lower odds of anxiety disorders only among Hispanics and non-Hispanic blacks. CONCLUSIONS: Perceived parental care and control were associated with adolescent mental disorders after controlling for multiple potential confounders. Differential patterns of association were found according to adolescent sex and race/ethnicity. Findings have implications for prevention and intervention programs that incorporate familial contextual factors. PMID- 29110027 TI - Human papillomavirus vaccine uptake in adolescence and adherence to cervical cancer screening in Switzerland: a national cross-sectional survey. AB - OBJECTIVES: The objectives were to measure uptake of and factors associated with human papillomavirus (HPV) vaccination initiation and to determine whether HPV vaccination reduced the uptake of cervical cancer screening. METHODS: We conducted a cross-sectional survey in a random sample of Swiss women aged 18-49 years in 2014 (N = 3588). RESULTS: Vaccination initiation was 69.3% and full coverage (three doses) 54.1% for 18-20-year olds, respectively, 42.4% and 33.9% for 21-24-year olds. Women with >= 10 lifetime sexual partners were less likely to have received any HPV vaccination than women with <= 2 partners (18-20 years OR 0.2, 21-24 years OR 0.5). Amongst 1000 unvaccinated women (18-24 years), reasons for not having initiated vaccination were lack of information (22.5%) and fear of vaccine side effects (18.1%). Vaccination status was not associated with adherence to cervical cancer screening recommendations (OR 1.3). 95.4% of all vaccinated participants knew about the continued need for screening. CONCLUSIONS: Our data suggest that HPV vaccination is not associated with reduced uptake of cervical cancer screening. This study provides information that can be used to improve HPV vaccination uptake in Switzerland. PMID- 29110028 TI - Quantification of dehydroepiandrosterone in human serum on a routine basis: development and validation of a tandem mass spectrometry method based on a surrogate analyte. AB - In the clinical laboratories, dehydroepiandrostenedione (DHEA) is usually quantified by immunoassay-based methods, which are often affected by cross reactivity with endogenous interferences, such as 4-androsten-3beta-ol-17-one. The interfering compounds lead to a poor accuracy of the measurements, mainly at a low concentration level. The present paper describes a validated method based on tandem mass spectrometry coupled to liquid chromatography, for the accurate quantification of DHEA in serum. The peculiarity of this method is the use of calibrators and quality controls prepared by adding measured amounts of DHEA-D5, a stable isotope-labeled analogue of DHEA, to real serum from healthy subjects. DHEA-D5 is used in place of DHEA, which is usually present in unstripped serum at physiological levels, as it has the same basic structure, provides an equivalent instrumental response, and can be easily distinguish by DHEA by mass spectrometry due to its different m/z value. The method proved to be sensitive, with a LLOD of 0.09 ng/mL and a LLOQ of 0.23 ng/mL, and selective, with overall performances that allow its use on a routine basis. PMID- 29110029 TI - ABC Spotlight on paper-based strips analytics. PMID- 29110031 TI - Upper and lower limb muscle atrophy in critically ill patients: an observational ultrasonography study. PMID- 29110030 TI - The emerging roles for the chromatin structure regulators CTCF and cohesin in neurodevelopment and behavior. AB - Recent genetic and technological advances have determined a role for chromatin structure in neurodevelopment. In particular, compounding evidence has established roles for CTCF and cohesin, two elements that are central in the establishment of chromatin structure, in proper neurodevelopment and in regulation of behavior. Genetic aberrations in CTCF, and in subunits of the cohesin complex, have been associated with neurodevelopmental disorders in human genetic studies, and subsequent animal studies have established definitive, although sometime opposing roles, for these factors in neurodevelopment and behavior. Considering the centrality of these factors in cellular processes in general, the mechanisms through which dysregulation of CTCF and cohesin leads specifically to neurological phenotypes is intriguing, although poorly understood. The connection between CTCF, cohesin, chromatin structure, and behavior is likely to be one of the next frontiers in our understanding of the development of behavior in general, and neurodevelopmental disorders in particular. PMID- 29110032 TI - The lessons learned from the EAT ICU study. PMID- 29110033 TI - Pump head thrombosis in extracorporeal membrane oxygenation (ECMO). PMID- 29110034 TI - Authors' reply to the comment by Petros et al. on "Retropubic versus transobturator MUS: Time to revisit?" by Lose and Klarskov. PMID- 29110035 TI - [New aspects on giant cell tumor of bone]. AB - A giant cell tumor of bone (GCTB) is one of the giant cell-rich lesions of bone and has to be differentiated from non-ossifying fibroma, aneurysmatic bone cyst, chondroblastoma, "brown tumor" and osteosarcoma containing giant cells. A hallmark of GCTB is the presence of the distinct histone 3 (H3F3A) mutation G34W and its detection either by sequencing methods or using immunohistochemistry with a novel antibody against this mutational site. Worrisome is the fact that under denosumab therapy a histological change of the lesions can be seen and there are first reports of sarcomas arising after therapy. When diagnosing giant cell-rich lesions, pathologists should be aware of the various differential diagnoses and morphological spectrum within GCTB. PMID- 29110036 TI - Papillary puncture: no way! PMID- 29110038 TI - Palytoxin congeners. AB - Palytoxin, isolated from a zoanthid of the genus Palythoa, is the most potent marine toxin known. Intoxication by palytoxin leads to vasoconstriction, hemorrhage, ataxia, muscle weakness, ventricular fibrillation, pulmonary hypertension, ischemia and death. Palytoxin and its numerous derivatives (congeners) may enter the food chain and accumulate mainly in fishes and crabs, causing severe human intoxication and death following ingestion of contaminated products. Furthermore, toxic effects in individuals exposed via inhalation or skin contact to marine aerosol in coincidence with Ostreopsis blooms, have been reported. Blooms of the benthic dinoflagellate Ostreopsis cf. ovata are a concern in the Mediterranean Sea, since this species produces a wide range of palytoxin like compounds listed among the most potent marine toxins. Thus, the formerly unsuspected broad distribution of the benthic dinoflagellate Ostreopsis spp. has recently posed a problem of risk assessment for human health. Palytoxin has a strong potential for toxicity in humans and animals, and currently this toxin is of great concern worldwide. This review summarized and discussed the pharmacology and toxicology data of palytoxin and its congeners, including their cytotoxicity, human and animal toxicities. Moreover, the risk assessment and their control strategies including prevention and treatment assays were evaluated. PMID- 29110037 TI - A novel, integrated in vitro carcinogenicity test to identify genotoxic and non genotoxic carcinogens using human lymphoblastoid cells. AB - Human exposure to carcinogens occurs via a plethora of environmental sources, with 70-90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens' adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention. PMID- 29110039 TI - [Endoscopic and surgical treatment of early gastric and esophageal carcinoma]. AB - BACKGROUND: The treatment of early gastric (EGC) and esophageal carcinomas (EEC) is an interdisciplinary challenge. The risk of lymph node metastasis (LNM) is the crucial point in choosing the correct treatment option. OBJECTIVE: This article gives an overview of the current treatment options and provides help in choosing the correct therapy. METHOD: Current concepts and therapy algorithms are presented on the basis of a literature review and data from our own center. RESULTS: Endoscopic submucosal dissection (ESD) is recommended for mucosal gastric cancer with good or moderate differentiation (G1,2) without macroscopic ulceration, in elevated type lesions smaller than 2 cm in size or depressed lesions smaller than 1 cm in size. In additional chromoendoscopy should be carried out. The extent of surgical resection is defined by the location of the tumor. A safety margin of at least 3 cm should be applied in distal gastric resections whereas the first line goal in gastrectomy is to achieve an R0 resection. In cN0 tumors a D1 lymphadenectomy (LA) seems to be sufficient. Minimally invasive techniques currently show promising results especially for a subtotal resection. The treatment strategy in EEC differs depending on the tumor entity. Mucosal squamous cell carcinoma with high risk factors (L1,V1) and all cN0 submucosal tumors without the detection of LNM should be referred to primary surgical resection. Early stage cN+ squamous cell carcinomas should be preoperatively treated with chemoradiotherapy. Adenocarcinoma with infiltration of the deeper submucosa (sm2,3) and high-risk sm1 tumors require surgical treatment. The standard operating procedure for EEC is an Ivor Lewis esophagectomy with 2-field LA preferably performed as a hybrid or by a completely minimally invasive procedure. The procedure of choice in endoscopic resection of EEC is resection with the suck and cut technique. PMID- 29110040 TI - [Surgical strategy in multimodal treatment of gastric and esophageal cancer]. AB - The majority of curatively treatable esophageal and gastric carcinomas are currently diagnosed in a locally advanced stage in Western Europe. The vast majority of patients in Western Europe and the USA are now treated in multimodal treatment protocols. These protocols consist of neoadjuvant chemoradiation or perioperative chemotherapy plus radical surgical resection including lymphadenectomy. Radical esophagectomy and gastrectomy are still the main curative therapeutic step in these multimodal protocols. The current surgical recommendations and guidelines were, however, based on experience and studies from almost exclusively unimodal treatment of patient groups. The validity for the patients, particularly those who undergo multimodal treatment, therefore urgently needs to be reviewed. In particular, there are results and indirect indications from recent studies that show a difference between unimodal surgical therapy and multimodal therapy in the efficacy of radical lymphadenectomy on the oncological results. Against the background of these studies, the question arises whether it is possible to adapt surgical resection to the multimodal overall concept under the influence of the additional therapeutic modalities. Future prospective randomized surgical trials should have a tailor-made adaptation to the multimodal therapy concepts concerning primary tumor and locoregional tumor compartments. The different histological tumor entities of the upper gastrointestinal tract must also be included. PMID- 29110041 TI - [Unusual intraoperative cystic findings in laparoscopic hernioplasty (TAPP) for scrotal hernia]. PMID- 29110042 TI - [Acne inversa/hidradenitis suppurativa: A challenge for the future]. AB - Acne inversa (AI)/hidradenitis suppurativa is a chronic recurrent inflammatory dermatosis with signs of a systemic disease. AI is characterized by typical skin alterations in body areas bearing apocrine glands. The care of the AI patients in Germany is still inadequate. This situation might be significantly improved through the following efforts: (i) shortening of the time between the disease onset and the diagnosis/start of therapy; (ii) the in-depth investigation of AI pathogenesis with the aim of identifying innovative therapeutic targets and blood biomarkers; (iii) establishing a method for quantifying the severity of the disease, which takes into account both the clinical assessment and objective laboratory parameters and the self-assessment of the patient (e.g., Dermatology Life Quality Index [DLQI]); (iv) the elaboration of a clear algorithm for the interdisciplinary treatment of patients, which, in addition to the therapy of skin lesions, also includes lifestyle-modification measures and takes into consideration the systemic character of AI. This article describes the current problems of medical care for AI patients and outlines how we can achieve the predetermined goals. PMID- 29110043 TI - [Axillary and perimamillary Fox-Fordyce disease (apocrine miliaria) in a 19-year old woman]. AB - Fox-Fordyce disease (FFD), also known as apocrine miliaria, is a rare and chronic skin disease characterized by itching and skin-colored, light brown or yellowish papules. FFD typically affects postpubertal young women between 13 and 35 years. The etiology is not completely known, but a hormonal component is in discussion. Furthermore, exacerbating factors like laser hair removal and hyperhidrosis have been described. Treatment of FFD is quite challenging, as the reported modalities mostly show limited success. PMID- 29110044 TI - Correction to: community-acquired pneumonia in children - a changing spectrum of disease. AB - The published version of this article unfortunately contained an error. Corresponding author information included only the mailing address but not the affiliations. Full corresponding author information is given below. The publisher apologizes. PMID- 29110045 TI - [The Hessian Landgrave Philipp the Magnanimous (1504-1567) : His diseases and their political consequences]. AB - Landgrave Philipp of Hesse was one of the leading figures of the reformation period. His morganatic marriage to a young Saxonian lady resulted in a massive impairment of his importance and initiated the division of his territory among his four legitimate sons. Triorchidism ascribed to him was more likely a misdiagnosed spermatozele, and also, there is no reliable account for his syphilis infection. The foundation of the Hessian Grand Hospitals, housing the poor, sick and disabled from the countryside, was his major social-medical achievement. PMID- 29110046 TI - [Supplementary optical techniques for the detection of nonmuscle invasive bladder cancer]. AB - White light cystoscopy (WL) is the gold standard for the detection of bladder cancer. It can be performed using a rigid or flexible urethrocystoscope. With the more recent introduction of high definition (HD) techniques, WL cystoscopy has been decisively improved. Supplementary optical techniques are also used to improve the detection of bladder cancer. Among these are photodynamic diagnosis (PDD), narrow-band imaging (NBI), S-technologies of IMAGE1 S, optical coherence tomography (OCT), confocal laser endomicroscopy (CLE), and Raman spectroscopy. The aim of the present work is to introduce the techniques and to discuss their current role and future potential in the detection of bladder cancer. PMID- 29110048 TI - Detection of femoroplasty on pre- and post-arthroscopic comparison radiographs following treatment of femoroacetabular impingement syndrome: multi-reader accuracy and agreement study. AB - OBJECTIVE: To assess diagnostic accuracy and agreement among radiologists in detecting femoroplasty on pre- and post-arthroscopic comparison frog lateral and anteroposterior (AP) pelvic radiographs after treatment of femoroacetabular impingement (FAI) syndrome. MATERIALS AND METHODS: In this retrospective, cross sectional study, 86 patients underwent hip arthroscopy (52 with and 34 without femoroplasty) for treatment of FAI syndrome. Three radiologists blinded to clinical data and chronological order of the pre- and post-arthroscopic comparison radiographs independently examined AP pelvis and frog lateral radiographs to detect femoroplasty changes. Statistical analysis outputs included diagnostic accuracy parameters and inter- and intra-observer agreement. RESULTS: Identification of femoroplasty in the frog lateral projection has mean sensitivity 70%, specificity 82%, inter-observer agreement kappa 0.74-0.76 and intra-observer agreement kappa 0.72-0.85. Using the AP pelvis projection to detect femoroplasty has mean sensitivity 32%, specificity 71%, inter-observer agreement kappa 0.47-0.65, and intra-observer agreement kappa, 0.56-0.84. CONCLUSIONS: Radiologists are only moderately sensitive, though more specific, in femoroplasty detection in the frog lateral projection. The AP pelvis projection yields lower sensitivity and specificity. Both projections have moderate inter- and intra-observer agreement. PMID- 29110047 TI - Hip shape is symmetric, non-dependent on limb dominance and gender-specific: implications for femoroacetabular impingement. A 3D CT analysis in asymptomatic subjects. AB - OBJECTIVE: To determine the reference intervals (RefInt) of the quantitative morphometric parameters of femoroacetabular impingement (FAI) in asymptomatic hips with computed tomography (CT) and determine their dependence on age, side, limb dominance and sex. METHODS: We prospectively included 590 patients and evaluated 1111 hips with semi-automated CT analysis. We calculated overall, side- and sex-specific parameters for imaging signs of cam [omega and alpha angle (alpha degrees )] and pincer-type morphology [acetabular version (ACvers), lateral centre-edge angle (LCEA) and cranio-caudal coverage]. RESULTS: Hip shape was symmetrical and did not depend on limb dominance. The 95% RefInt limits were sex-different for all cam-type parameters and extended beyond current abnormal thresholds. Specifically, the upper limits of RefInt for alpha degrees at 12:00, 1:30 and 3:00 o'clock positions were 56 degrees , 70 degrees and 58 degrees , respectively, and 45 degrees for LCEA. Acetabular morphology varied between age groups, with a trend toward an LCEA/ACvers increase over time. CONCLUSION: Our morphometric measurements can be used to estimate normal hip morphology in asymptomatic individuals. Notably they extended beyond current thresholds used for FAI imaging diagnosis, which was most pronounced for cam-type parameters. We suggest the need to reassess alpha degrees RefInt and consider a 60 degrees threshold for the 12:00/3:00 positions and 65-70 degrees for other antero superior positions. KEY POINTS: * Hip shape is symmetrical regardless of limb dominance. * Pincer/cam morphology is frequent in asymptomatic subjects (20 and 71%, respectively). * LCEA and acetabular version increases with age (5-7 degrees between opposite age groups). * Femoral morphology is stable after physeal closure (in the absence of pathology). * Alpha and omega angle thresholds should be set according to sex. PMID- 29110049 TI - Diagnostic accuracy of low-dose versus ultra-low-dose CT for lumbar disc disease and facet joint osteoarthritis in patients with low back pain with MRI correlation. AB - OBJECTIVE: To compare the image quality, radiation dose, and diagnostic performance between low-dose (LD) and ultra-low-dose (ULD) lumbar-spine (L-spine) CT with iterative reconstruction (IR) for patients with chronic low back pain (LBP). METHODS: In total, 260 patients with chronic LBP who underwent L-spine CT between November 2015 and September 2016 were prospectively enrolled. Of these, 143 underwent LD-CT with IR and 117 underwent ULD-CT with IR. The patients were divided according to their body mass index (BMI) into BMI1 (<22.9 kg/m2), BMI2 (23.0-24.9 kg/m2), and BMI3 (>=25 kg/m2) groups. Two blinded radiologists independently evaluated the signal-to-noise ratio (SNR), qualitative image quality, and final diagnoses (lumbar disc disease and facet joint osteoarthritis). L-spine MRIs interpreted by consensus were used as the reference standard. All data were statistically analyzed. RESULTS: ULD protocol showed significantly lower SNR for all patients (p < 0.001) except the vertebral bodies and lower qualitative image quality for BMI3 patients (p <= 0.033). There was no statistically significant difference between ULD (sensitivity, 95.1-98.1%; specificity, 92.5-98.7%; accuracy, 94.6-98.0%) and LD protocols (sensitivity, 95.6-100%; specificity, 95.5-98.9%; accuracy, 97.4-98.1%), (all p>=0.1) in the BMI1 and BMI2; while dose was 60-68% lower with the ULD protocol. Interobserver agreements were excellent or good with regard to image quality and final diagnoses. CONCLUSIONS: For the BM1 and BMI2 groups, ULD-CT provided an acceptable image quality and exhibited a diagnostic accuracy similar to that of LD-CT. These findings suggest that it is a useful diagnostic tool for patients with chronic LBP who exhibit a BMI of <25 kg/m2. PMID- 29110050 TI - Frequency of inflammatory-like MR imaging findings in asymptomatic fingers of healthy volunteers. AB - OBJECTIVE: To describe the frequency of inflammatory-like findings on MR imaging in asymptomatic volunteers and compare them with patients with known rheumatoid arthritis and psoriatic arthritis. MATERIALS AND METHODS: MR images of fingers in 42 asymptomatic volunteers and 33 patients with rheumatoid/psoriatic arthritis were analyzed. The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid/Psoriatic Arthritis MRI Scoring System (RAMRIS/PsAMRIS) and tenosynovitis scoring system were used to assess: bone marrow edema (BME), erosions, tendon sheath fluid/tenosynovitis, joint effusion, and soft-tissue edema. Findings and scores were compared between volunteers and patients. Inter reader agreement was calculated (intraclass correlation coefficients, ICC). RESULTS: In volunteers, tendon sheath fluid was very common in at least one location (42/42 volunteers for reader 1, 34/42 volunteers for reader 2). BME, erosions, joint effusion, and soft-tissue edema were absent (except one BME in the 3rd proximal phalanx for reader 1). Tendon sheath fluid scores in volunteers and tenosynovitis scores in patients were high (reader 1, 7.17 and 5.39; reader 2, 2.31 and 5.45). Overall, inter-reader agreement was substantial (ICC = 0.696 0.844), except for tendon sheath fluid (ICC = 0.258). CONCLUSION: Fluid in the finger flexor tendon sheaths may be a normal finding and without gadolinium administration should not be interpreted as tenosynovitis. Bone marrow edema, erosions, joint effusion, and soft-tissue edema in the fingers most likely reflect pathology if present. PMID- 29110051 TI - Diffusion-weighted imaging in hemorrhagic abdominal and pelvic lesions: restricted diffusion can mimic malignancy. AB - Diffusion-weighted imaging (DWI) is an increasingly utilized sequence in the assessment of abdominal and pelvic lesions. Benign lesions containing hemorrhagic products, with conglomerates of tightly packed blood cells or fibers, can have restricted water diffusion on DWI and apparent diffusion coefficient maps. Such lesions can have restricted diffusion erroneously attributed to malignancy. This review illustrates benign hemorrhagic lesions displaying restricted diffusion, with histopathologic correlation in relevant cases. PMID- 29110052 TI - Contrast-enhanced ultrasonography for assessment of tubular atrophy/interstitial fibrosis in immunoglobulin A nephropathy: a preliminary clinical study. AB - PURPOSE: To investigate the potential of contrast-enhanced ultrasonography (CEUS) for evaluating the severity of tubular atrophy/interstitial fibrosis (TA/IF) in immunoglobulin A nephropathy (IgAN) patients. MATERIALS AND METHODS: A total of 80 patients with IgAN and 33 healthy adults were investigated. Patients were divided into three groups according to the TA/IF (T) grade of the Oxford classification: T0 (n = 28), T1 (n = 35), and T2 (n = 17). Patients and control subjects underwent conventional ultrasound (US) and CEUS. Time-intensity curves of CEUS were drawn for regions of interest located in the renal cortex and medulla using QLab software. Conventional US and CEUS quantitative parameters were analyzed. One-way analysis of variance (ANOVA), binary logistic regression, and receiver operating characteristic (ROC) curves were used. RESULTS: There were no significant differences in renal size, cortical thickness, and medullary perfusion parameters (P > 0.05), whereas the differences in peak intensity (PI), area under the time-intensity curve (AUC) and wash-in slope (WIS) of cortical perfusion parameters between the control subjects and patients were significant (P < 0.05). PI was significantly lower with the increasing degree of T (P < 0.05). PI was associated independently with the degree of T in IgAN patients (P < 0.05). ROC analysis revealed that using the optimal cutoff values of 15.38 dB for diagnosis of T0-T1 (sensitivity 83.30% and specificity 63.00%) and 14.69 dB for diagnosis of T2 (sensitivity 100.00% and specificity 66.70%), the corresponding areas under the ROC curve were found to be 0.782 and 0.952, respectively. CONCLUSIONS: CEUS can potentially be used as a noninvasive imaging marker to evaluate the severity of TA/IF in IgAN patients. PMID- 29110054 TI - Diffusion-weighted imaging and pathology of chronic kidney disease: initial study. AB - PURPOSE: To investigate the value of diffusion-weighted imaging (DWI) for assessing histopathologic changes observed in chronic kidney disease (CKD). METHODS: Fifty-two patients with CKD underwent DWI before renal biopsy. The renal apparent diffusion coefficient (ADC) values and histopathologic changes were analyzed. The pathologic changes were scored using a semi-quantitative method (no lesion as 0, mild lesion as 1, moderate lesion as 2, and severe lesion as 3). The relationships between renal histopathologic scores, types, classification, and right renal ADCs were analyzed using ANOVA and Pearson's or Spearman's correlation tests. RESULTS: Negative correlations were found between the right renal ADCs and scores of tubulointerstitial lesions (r = - 0.354, P = 0.012), the severity of tubular atrophy (r = - 0.439, P = 0.002), and the severity of interstitial fibrosis (r = - 0.272, P = 0.049). There were no correlations between the ADCs and scores of glomeruli and peritubular vessel lesions (P > 0.05). There were significant differences among groups based on pathology types (P = 0.009). There was no significant relationship between renal ADCs and the pathologic classification (P > 0.05). CONCLUSIONS: DWI may be helpful to detect tubulointerstitial injury, including tubular atrophy and interstitial fibrosis. DWI may have the potential to serve as an effective auxiliary method to help nephrologists to evaluate patients with CKD. PMID- 29110053 TI - The role of imaging in the clinical practice of radiation oncology for pancreatic cancer. AB - Advances in technology have enabled the delivery of high doses of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) with low rates of toxicity. Although the role of radiation for pancreatic cancer continues to evolve, encouraging results with newer techniques indicate that radiation may benefit selected patient populations. Imaging has been central to the modern successes of radiation therapy for PDAC. Here, we review the role of diagnostic imaging, imaging-based planning, and image guidance in radiation oncology practice for PDAC. PMID- 29110055 TI - Reproducible imaging features of biologically aggressive gastrointestinal stromal tumors of the small bowel. AB - PURPOSE: To identify reproducible CT imaging features of small bowel gastrointestinal stromal tumors (GIST) that are associated with biologic aggressiveness. METHODS: Patients with histologically proven small bowel GISTs and CT enterography or abdominopelvic CT were included. Biologic aggressiveness was established based on initial histologic grading (very low risk to malignant), with "malignant" assigned if recurrence or metastases developed subsequently. CT exams were independently evaluated by three gastrointestinal radiologists for tumor size, growth pattern, enhancement, tumor borders, necrosis, calcification, ulceration, multiplicity, internal air or enteric contrast, nodal metastasis, liver metastasis, peritoneal metastasis, ascites, and draining vein size. Inter observer variability and imaging features associated with high-grade and malignant small bowel GISTs were determined. RESULTS: Of 78 patients with small bowel GISTs, 10/78 (13%) were high grade and 18/78 (23%) were malignant. There was moderate to substantial inter-observer agreement (Kappa > 0.4) for all findings except tumor border, ulceration, and nodal metastases. Tumor size, irregular or invasive tumor border, necrosis, liver metastasis, ascites, and iso enhancement were associated with high-grade/malignant small bowel GISTs (p < 0.04). Internal air or enteric contrast and peritoneal metastases additionally predicted malignant behavior (p < 0.03). When imaging features predicting malignant small bowel GISTs were absent and size was <= 3 cm, 0% (0/16), 5% (1/19), and 5% (1/17) of patients had high grade, and 0% (0/16, 0/19, and 0/17) had malignant tumors for the three readers, respectively. CONCLUSION: Multiple, reproducibly identified, small bowel GIST imaging features suggest biologic aggressiveness. The absence of these imaging features may identify small tumors that can be followed in asymptomatic or high-risk patients. PMID- 29110056 TI - Efficacy and safety of balloon-occluded retrograde transvenous obliteration of gastric varices with lauromacrogol foam sclerotherapy: initial experience. AB - PURPOSE: Balloon-occluded retrograde transvenous obliteration (BRTO) is a widely accepted treatment for gastric varices (GVs). The purpose of this study was to evaluate the efficacy and safety of BRTO with lauromacrogol foam sclerotherapy. MATERIALS AND METHODS: Between May 2014 and June 2015, 32 patients were treated with lauromacrogol foam. Lauromacrogol foam was made using a combination of agents, with a 2:1:1 ratio of room air: lauromacrogol: contrast media. Patients were followed up using contrast-enhanced computed tomography (CT) and endoscopy. RESULTS: Technical success was achieved in 31 of 32 patients (96.9%). Portal vein thrombosis occurred in two patients and resolved spontaneously. No other major complications were observed. The overall mean dose of lauromacrogol used was 12.4 mL (range, 8-20 mL). Complete obliteration of GVs was confirmed in all 31 patients (100%) on follow-up CT. Seven of the 31 patients (22.6%) experienced worsening of esophageal varices. Rupture of esophageal varices occurred in three patients and was treated successfully with band ligation. Five patients (16.1%) experienced worsening of ascites and responded well to diuretic therapy. CONCLUSION: BRTO utilizing lauromacrogol foam appears to be a safe and useful treatment option in patients with GVs in the short term. PMID- 29110057 TI - Mosaic architecture of hepatocellular carcinoma. PMID- 29110058 TI - The "chain of lakes" sign. PMID- 29110059 TI - Differentiating focal nodular hyperplasia from hepatocellular adenoma: Is hepatobiliary phase MRI (HBP-MRI) using linear gadolinium chelates always useful? AB - PURPOSE: To assess the value of Hepatobiliary phase MRI (HPB-MRI) to differentiate FNH and HCA, and evaluate its impact on diagnostic accuracy, diagnostic confidence, inter-observer variability, and patient clinical management. METHODS: Forty-nine patients referred for Gd-BOPTA-enhanced MRI were retrospectively included in this IRB-approved study, with a total of 119 lesions 90 FNH and 29 HCA. Two observers separately assessed in 2 distinct randomized reading sessions the performance of MRI with (HBP-MRI) or without (conventional MRI) the use of HBP images. Each lesion was ranked with a 5-point scale (from 1 Typical FNH to 5 Certainly not a FNH). Sensitivity, specificity, overall accuracy, and inter-observer agreement for the differentiation of FNH from HCA were calculated and compared between conventional and HBP-MRI. RESULTS: Both sensitivity (respective values of 38.9% and 97.8%), overall accuracy (respective values of 53.8% and 98.3%), and inter-observer agreement (respective values of Kappa 0.56 and 0.88) were significantly higher using HBP-MRI than with conventional MRI, with unchanged specificity (100%). The sensitivity of conventional MRI for the diagnosis of FNH was significantly lower in lesions <= 3 cm (20% vs. 88%). Overall, HBP could have changed lesion management in 59/119 cases (49.5%), including 53 FNH and 6 HCA with no impact in 60/119 lesions (50.5%) including all 35 lesions classified as scores 1 and 2 for the diagnosis of FNH. CONCLUSIONS: The clinical impact of HBP-MRI is mostly important for smaller than 3-cm FNH, and more limited in larger FNH lesions as well as for HCA diagnosis for which conventional MRI is already accurate. The use of extracellular contrast agents upfront could limit the required use of linear HBP contrast agents for benign hepatocellular lesion characterization. On HBP, all FNH appeared hypointense compared to adjacent liver while close to 97% of HCA appeared hypointense. PMID- 29110060 TI - Community Response and Engagement During Extreme Water Events in Saskatchewan, Canada and Queensland, Australia. AB - Technology alone cannot address the challenges of how societies, communities, and individuals understand water accessibility, water management, and water consumption, particularly under extreme conditions like floods and droughts. At the community level, people are increasingly aware challenges related to responses to and impacts of extreme water events. This research begins with an assessment of social and political capacities of communities in two Commonwealth jurisdictions, Queensland, Australia and Saskatchewan, Canada, in response to major flooding events. The research further reviews how such capacities impact community engagement to address and mitigate risks associated with extreme water events and provides evidence of key gaps in skills, understanding, and agency for addressing impacts at the community level. Secondary data were collected using template analysis to elucidate challenges associated with education (formal and informal), social and political capacity, community ability to respond appropriately, and formal government responses to extreme water events in these two jurisdictions. The results indicate that enhanced community engagement alongside elements of an empowerment model can provide avenues for identifying and addressing community vulnerability to negative impacts of flood and drought. PMID- 29110061 TI - The impact of GI events on persistence and adherence to osteoporosis treatment: 3 , 6-, and 12-month findings in the MUSIC-OS study. AB - : The goal of this multinational, prospective, observational study was to examine the relationship between gastrointestinal (GI) events and self-reported levels of medication adherence and persistence in postmenopausal women. A total of 73.9% of patients remained on their osteoporosis (OP) therapy at month 12, although the presence of a GI event at baseline, month 3, and month 6 significantly reduced month 12 persistence among new users. The odds of a month-12 ADEOS score >= 20 were significantly lower among patients who experienced a GI event between baseline and month 6. The occurrence of GI events was observed to be associated with a lower likelihood of patient adherence and persistence to OP medication. INTRODUCTION: This study examines the relationship between gastrointestinal (GI) events and self-reported adherence and persistence with initial osteoporosis (OP) therapy over the course of the first 12 months of treatment. METHODS: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study was a multinational, prospective, observational study examining the impact of GI events on OP management in postmenopausal women. Information regarding GI events was collected at the time of enrollment and at months 3, 6, and 12 of follow-up. Patients reported GI events and medication persistence and completed the 12-item Adherence Evaluation of Osteoporosis treatment (ADEOS) questionnaire. Multivariate logistic and general linear models examined the association between GI events at various time points and persistence and adherence at month 12. RESULTS: The study enrolled 2943 women; 22.8% were classified as new users of OP therapy and the remainder were considered experienced users. Across all patients, 68.1% reported GI events at baseline; by month 12, over 80% of subjects who completed follow-up reported at least one GI problem. The majority of patients (86.7%) were treated only with bisphosphonates at baseline. At month 12, 73.9% of patients remained on therapy; logistic regression revealed that those with GI problems by month 6 were significantly less likely to persist with treatment, after adjusting for other factors. The odds of a month 12 ADEOS score >= 20 (considered predictive of adherence) were significantly lower among patients who experienced a GI event between baseline and month 6. CONCLUSIONS: The occurrence of GI events was associated with a lower likelihood of patient adherence to and persistence with OP medication. PMID- 29110062 TI - Osteoporosis and bone mineral density in patients with Wilson's disease: a systematic review and meta-analysis. AB - This systematic review aims to assess the occurrence and risks of osteopenia and osteoporosis in patientswith Wilson's disease (WD). A literature search was conducted utilizing EMBASE and MEDLINE frominception through April 2017. Studies assessing the occurrence or risk of osteopenia and/or osteoporosis inWD patients were included. Effect estimates from the individual study were extracted and combined usingrandom-effect, generic inverse variance method of DerSimonian and Laird. Of 754 studies, four studies with283 WD patients met the eligibility criteria and were included in the data analysis. The pooled prevalencerates of osteopenia and osteoporosis in WD patients were 36.5% (95% confidence interval [CI]: 14.8%-65.7%) and 27.7% (95%CI: 8.6%-60.9%), respectively. When meta analysis was limited only to adults, the estimated prevalence rates of osteopenia, osteoporosis, and vertebral fracture were 50.0% (95%CI: 42.0%-58.0%), 17.6% (95%CI: 6.7%-38.6%) and 8.01% (95%CI: 4.05%-15.2%), respectively. Meta regressionshowed significant impacts of age (negative correlation; P=0.002) and male status (positive correlation;P < 0.001) on the prevalence of osteoporosis. The data on risks of osteopenia and osteoporosis in WDpatients were limited. We suggests that there are potential associations of WD with osteopenia and/orosteoporosis. Also, young age and male status are correlated with the higher prevalence of osteoporosis inWD patients. PMID- 29110063 TI - The effect of icariin on bone metabolism and its potential clinical application. AB - Osteoporosis is a bone disease characterized by reduced bone mass, which leads to increased risk of bone fractures, and poses a significant risk to public health, especially in the elderly population. The traditional Chinese medicinal herb Epimedii has been utilized for centuries to treat bone fracture and bone loss. Icariin is a prenylated flavonol glycoside isolated from Epimedium herb, and has been shown to be the main bioactive component. This review provides a comprehensive survey of previous studies on icariin, including its structure and function, effect on bone metabolism, and potential for clinical application. These studies show that icariin promotes bone formation by stimulating osteogenic differentiation of BMSCs (bone marrow-derived mesenchymal stem cells), while inhibiting osteoclastogenic differentiation and the bone resorption activity of osteoclasts. Furthermore, icariin has been shown to be more potent than other flavonoid compounds in promoting osteogenic differentiation and maturation of osteoblasts. A 24-month randomized double-blind placebo-controlled clinical trial reported that icariin was effective in preventing postmenopausal osteoporosis with relatively low side effects. In conclusion, icariin may represent a class of flavonoids with bone-promoting activity, which could be used as potential treatment of postmenopausal osteoporosis. PMID- 29110064 TI - The Impact of the Diurnal Cycle on the Microbial Transcriptome in the Rhizosphere of Barley. AB - While root exudation follows diurnal rhythms, little is known about the consequences for the microbiome of the rhizosphere. In this study, we used a metatranscriptomic approach to analyze the active microbial communities, before and after sunrise, in the rhizosphere of barley. We detected increased activities of many prokaryotic microbial taxa and functions at the pre-dawn stage, compared to post-dawn. Actinomycetales, Planctomycetales, Rhizobiales, and Burkholderiales were the most abundant and therefore the most active orders in the barley rhizosphere. The latter two, as well as Xanthomonadales, Sphingomonadales, and Caulobacterales showed a significantly higher abundance in pre-dawn samples compared to post-dawn samples. These changes in taxonomy coincide with functional changes as genes involved in both carbohydrate and amino acid metabolism were more abundant in pre-dawn samples compared to post-dawn samples. This study significantly enhances our present knowledge on how rhizospheric microbiota perceives and responds to changes in the soil during dark and light periods. PMID- 29110065 TI - Fungi in Gastrointestinal Tracts of Human and Mice: from Community to Functions. AB - Fungi are often ignored in studies on gut microbes because of their low level of presence (making up only 0.1% of the total microorganisms) in the gastrointestinal tract (GIT) of monogastric animals. Recent studies using novel technologies such as next generation sequencing have expanded our understanding on the importance of intestinal fungi in humans and animals. Here, we provide a comprehensive review on the fungal community, the so-called mycobiome, and their functions from recent studies in humans and mice. In the GIT of humans, fungi belonging to the phyla Ascomycota, Basidiomycota and Chytridiomycota are predominant. The murine intestines harbor a more diverse assemblage of fungi. Diet is one of the major factors influencing colonization of fungi in the GIT. Presence of the genus Candida is positively associated with dietary carbohydrates, but are negatively correlated with dietary amino acids, proteins, and fatty acids. However, the relationship between diet and the fungal community (and functions), as well as the underlying mechanisms remains unclear. Dysbiosis of intestinal fungi can cause invasive infections and inflammatory bowel diseases (IBD). However, it is not clear whether dysbiosis of the mycobiome is a cause, or a result of IBD. Compared to non-inflamed intestinal mucosa, the abundance and diversity of fungi is significantly increased in the inflamed mucosa. The commonly observed commensal fungal species Candida albicans might contribute to occurrence and development of IBD. Limited studies show that Candida albicans might interact with immune cells of the host intestines through the pathways associated with Dectin-1, Toll-like receptor 2 (TLR2), and TLR4. This review is expected to provide new thoughts for future studies on intestinal fungi and for new therapies to fungal infections in the GIT of human and animals. PMID- 29110066 TI - Ecological Patterns Among Bacteria and Microbial Eukaryotes Derived from Network Analyses in a Low-Salinity Lake. AB - Microbial communities are comprised of complex assemblages of highly interactive taxa. We employed network analyses to identify and describe microbial interactions and co-occurrence patterns between microbial eukaryotes and bacteria at two locations within a low salinity (0.5-3.5 ppt) lake over an annual cycle. We previously documented that the microbial diversity and community composition within Lake Texoma, southwest USA, were significantly affected by both seasonal forces and a site-specific bloom of the harmful alga, Prymnesium parvum. We used network analyses to answer ecological questions involving both the bacterial and microbial eukaryotic datasets and to infer ecological relationships within the microbial communities. Patterns of connectivity at both locations reflected the seasonality of the lake including a large rain disturbance in May, while a comparison of the communities between locations revealed a localized response to the algal bloom. A network built from shared nodes (microbial operational taxonomic units and environmental variables) and correlations identified conserved associations at both locations within the lake. Using network analyses, we were able to detect disturbance events, characterize the ecological extent of a harmful algal bloom, and infer ecological relationships not apparent from diversity statistics alone. PMID- 29110067 TI - Prognostic value of 18F-choline PET/CT metabolic parameters in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide. AB - PURPOSE: The role of 18F-choline positron emission tomography/computed tomography (FCH-PET/CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) has been firmly established in recent years. We analyzed the prognostic value of functional parameters such as mean standardized uptake volume (SUVmean), maximum standardized uptake volume (SUVmax), metabolic total volume (MTV; the volume of interest consisting of all spatially connected voxels within a fixed threshold of 40% of the SUVmax), and total lesion activity (TLA: the product of MTV and mean standardized uptake value) estimated with FCH-PET/CT in mCRPC patients in progression after docetaxel and treated with new antiandrogen receptor therapies, abiraterone or enzalutamide. METHODS: We retrospectively studied 94 mCRPC patients, mean age 74 years (range 42-90), previously treated with docetaxel who were treated with either abiraterone (n = 52) or enzalutamide (n = 42). An FCH-PET/CT was performed at baseline, and patients were evaluated on a monthly basis for serological PSA response and every 3 months for radiological response. We measured MTV, SUVmean, SUVmax and TLA for each lesion and analyzed the sum of MTV (SMTV), SUVmean (SSUVmean), SUVmax (SSUVmax) and TLA (STLA) values for a maximum of 20 lesions. Univariate analysis was used to correlate these data with PFS and OS. RESULTS: We observed a median SMTV of 130 cm3, median SSUVmax of 106.5 and a median STLA of 495,070. All of these parameters were significant for PFS and OS in univariate analysis, while only STLA was significant for PFS and OS in multivariate analysis after adjusting for lesion and age (p < 0.0001 and p = 0.001, respectively). Baseline PSA values maintained a certain reliability for OS (p = 0.034). CONCLUSIONS: Semiquantitative parameters of FCH-PET/CT play a prognostic role in mCRCP patients treated with abiraterone or enzalutamide. PMID- 29110068 TI - Prognostic value of metabolic indices and bone marrow uptake pattern on preoperative 18F-FDG PET/CT in pediatric patients with neuroblastoma. AB - PURPOSE: To evaluate the prognostic value of metabolic parameters and bone marrow uptake (BMU) patterns on pretherapeutic 18-F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in pediatric patients with neuroblastoma (NB). PATIENTS AND METHODS: Forty-seven pediatric patients with newly diagnosed neuroblastoma who underwent 18F-FDG PET/CT were retrospectively reviewed. Clinicopathological factors and metabolic parameters including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and bone marrow uptake patterns on PET/CT were compared to predict recurrence-free survival (RFS) and overall survival (OS) by univariate and multivariate analysis. RESULTS: During the follow-up period, 27 (57.4%) patients experienced recurrence. MTV (P = 0.001), TLG (P = 0.004) and BMU patterns (P = 0.025) remained significant predictive factors for tumor recurrence, along with tumor size, histology, stage, lactate dehydrogenase (LDH) and other distant metastasis (except bone metastasis). Univariate analysis showed that histology, stage, tumor size (>37.25 cm), other distant metastasis, MTV (>88.10cm3) and TLG (>1045.2 g) and BMU patterns correlated with both RFS and OS (P < 0.05). On multivariate analysis, TLG remained the only independent prognostic factor for RFS (P = 0.016) and OS (P = 0.012), and BMU patterns and MTV were statistically significant for OS (P = 0.024 and P = 0.038, respectively). CONCLUSION: Pretherapeutic 18F-FDG PET/CT can provide reliable prognostic information for neuroblastoma pediatric patients, and patients with high MTV, TLG and focal bone marrow (unifocal and multifocal) uptake on PET/CT may have inferior outcomes during subsequent treatment. PMID- 29110069 TI - Correction to: A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. AB - The published online version contains mistake in Acknowledgment Section. The author name "Steve Gorin, M.D." should have been "Steven Gorin, D.O, M.S.Ed.". PMID- 29110071 TI - Retrieved 16S rRNA and nifH sequences reveal co-dominance of Bradyrhizobium and Ensifer (Sinorhizobium) strains in field-collected root nodules of the promiscuous host Vigna radiata (L.) R. Wilczek. AB - In the present study, the relative distribution of endophytic rhizobia in field collected root nodules of the promiscuous host mung bean was investigated by sequencing of 16S ribosomal RNA (rRNA) and nifH genes, amplified directly from the nodule DNA. Co-dominance of the genera Bradyrhizobium and Ensifer was indicated by 32.05 and 35.84% of the total retrieved 16S rRNA sequences, respectively, and the sequences of genera Mesorhizobium and Rhizobium comprised only 0.06 and 2.06% of the recovered sequences, respectively. Sequences amplified from rhizosphere soil DNA indicated that only a minor fraction originated from Bradyrhizobium and Ensifer strains, comprising about 0.46 and 0.67% of the total retrieved sequences, respectively. 16S rRNA gene sequencing has also identified the presence of several non-rhizobial endophytes from phyla Proteobacteria, Actinobacteria, Bacteroides, and Firmicutes. The nifH sequences obtained from nodules also confirmed the co-dominance of Bradyrhizobium (39.21%) and Ensifer (59.23%) strains. The nifH sequences of the genus Rhizobium were absent, and those of genus Mesorhizobium comprised only a minor fraction of the sequences recovered from the nodules and rhizosphere soil samples. Two bacterial isolates, identified by 16S rRNA gene sequence analysis as Bradyrhizobium strain Vr51 and Ensifer strain Vr38, successfully nodulated the original host (mung bean) plants. Co-dominance of Bradyrhizobium and Ensifer strains in the nodules of mung bean indicates the potential role of the host plant in selecting specific endophytic rhizobial populations. Furthermore, successful nodulation of mung bean by the isolates showed that strains of both the genera Bradyrhizobium and Ensifer can be used for production of inoculum. PMID- 29110070 TI - Dietary and metabolic modulators of hepatic immunity. AB - The liver is the central metabolic organ of the organism and is thus constantly exposed to gut-derived dietary and microbial antigens. The liver maintains homoeostatic tolerance to these mostly harmless antigens. However, the liver also functions as a barrier organ to harmful pathogens and is thus permissive to liver inflammation. The regulation of the delicate balance between liver tolerance and liver inflammation is of vital importance for the organism. In recent years, a general role for dietary components and metabolites as immune mediators has been emerging. However, although the liver is exposed to a great deal of metabolic mediators, surprisingly, little is known about their actual role in the regulation of hepatic immune responses. Here, we will explore the possible impacts of metabolic mediators for homoeostatic and pathological immunity in the liver, by highlighting selected examples of metabolic immune regulation in the liver. PMID- 29110073 TI - Vasovagal syncope is associated with poor prognosis in patients with left ventricular dysfunction. AB - Vasovagal syncope (VVS) is known to have a benign prognosis and be associated with enhanced contraction and activation of the left ventricular (LV) mechanoreceptors. However, a little is known about VVS in patients with LV dysfunction. The present study aimed to investigate the prevalence and prognosis of VVS in patients with LV dysfunction. We enrolled 368 patients with unexplained syncope. In 7 of these patients, LV ejection fraction was lower than 40%. The results of a head-up tilt test (HUT) and the recurrence of syncope were compared between these 7 patients with LV dysfunction and the remaining patients. Positive HUT was obtained in the 6 patients (86%) with LV dysfunction; this rate tended to be higher as compared with normal cardiac function (192/361, 53%, P = 0.069). In patients with LV dysfunction, response in HUT was mostly vasodepressor type (62%); however, most of HUT responses were mixed type in patients with normal LV function (67%). Among patients with positive HUT, the recurrent rate of syncope after HUT was higher in those with LV dysfunction than in those with normal LV function (67 vs. 21%, P = 0.008). VVS in patients with LV dysfunction may be refractory to treatment and could be associated with poor prognosis. PMID- 29110072 TI - The genetic and molecular basis of crop height based on a rice model. AB - MAIN CONCLUSION: This review presents genetic and molecular basis of crop height using a rice crop model. Height is controlled by multiple genes with potential to be manipulated through breeding strategies to improve productivity. Height is an important factor affecting crop architecture, apical dominance, biomass, resistance to lodging, tolerance to crowding and mechanical harvesting. The impressive increase in wheat and rice yield during the 'green revolution' benefited from a combination of breeding for high-yielding dwarf varieties together with advances in agricultural mechanization, irrigation and agrochemical/fertilizer use. To maximize yield under irrigation and high fertilizer use, semi-dwarfing is optimal, whereas extreme dwarfing leads to decreased yield. Rice plant height is controlled by genes that lie in a complex regulatory network, mainly involved in the biosynthesis or signal transduction of phytohormones such as gibberellins, brassinosteroids and strigolactones. Additional dwarfing genes have been discovered that are involved in other pathways, some of which are uncharacterized. This review discusses our current understanding of the regulation of plant height using rice as a well characterized model and highlights some of the most promising research that could lead to the development of new, high-yielding varieties. This knowledge underpins future work towards the genetic improvement of plant height in rice and other crops. PMID- 29110074 TI - What are the odds of anxiety disorders running in families? A family study of anxiety disorders in mothers, fathers, and siblings of children with anxiety disorders. AB - This family study investigated (1) the prevalence of anxiety disorders (ADs) in parents and siblings of children (n = 144) aged 8-18 years with ADs compared to control children (n = 49), and (2) the specificity of relationships between child mother, child-father, and child-sibling ADs. Clinical interviews were used to assess current DSM-IV-TR ADs in children and siblings, and lifetime and current ADs in parents. Results showed that children with ADs were two to three times more likely to have at least one parent with current and lifetime ADs than the control children (odds ratio (OR) = 2.04 and 3.14). Children with ADs were more likely to have mothers with current ADs (OR = 2.51), fathers with lifetime ADs (OR = 2.84), but not siblings with ADs (OR = 0.75). Specific relationships between mother-child ADs were found for Social Anxiety Disorder (SAD, OR = 3.69) and Generalized Anxiety Disorder (OR = 3.47). Interestingly, all fathers and siblings with SAD came from families of children with SAD. Fathers of children with SAD were more likely to have lifetime ADs themselves (OR = 2.86). Findings indicate that children with ADs more often have parents with ADs, and specifically SAD is more prevalent in families of children with SAD. Influence of parent's (social) ADs should be considered when treating children with ADs. PMID- 29110075 TI - Maternal experience and soil origin influence interactions between resident species and a dominant invasive species. AB - Invasive species dominance in invaded communities may not be long-lasting due to regulatory processes, such as plant-soil feedbacks and neighboring species adaptation. Further, the change in species competitive ability may be contingent upon neighbor identity (i.e., specialized response) or consistent across neighbors (i.e., generalized response). Specialized responses can facilitate overall coexistence, while generalized responses may result in competitive exclusion. We set up a greenhouse experiment to test, in three species, the effect of soil conditions (non-invaded vs. invaded soil) and maternal experience (offspring of maternal plants from invaded vs. non-invaded areas) on species competitive ability against the invader Bromus inermis and conspecifics. If changes in species competitive ability against B. inermis were also evident when interacting with conspecifics, it would suggest a generalized increased/decreased competitive ability. Maternal experience resulted in reduced suppression of B. inermis in the three species and no change in tolerance. On the other hand, tolerance to B. inermis was enhanced when plants grew in soil from invaded areas, compared to non-brome soil. Importantly, both the decreased suppression due to maternal experience with B. inermis and the increased tolerance in invaded soil appear to be invader specific, as no such effects were observed when interacting with conspecifics. Specialized responses should facilitate coexistence, as no individual/species is a weaker or stronger competitor against all other neighbors or under all local soil conditions. Further, the negative plant-soil feedback for B. inermis should facilitate native species recovery in invaded areas and result in lower B. inermis performance and dominance over time. PMID- 29110076 TI - Testing hypoxia: physiological effects of long-term exposure in two freshwater fishes. AB - Hypoxic or oxygen-free zones are linked to large-scale mortalities of fauna in aquatic environments. Studies investigating the hypoxia tolerance of fish are limited and focused on marine species and short-term exposure. However, there has been minimal effort to understand the implications of long-term exposure on fish and their ability to acclimate. To test the effects of long-term exposure (months) of fish to hypoxia we devised a novel method to control the level of available oxygen. Juvenile golden perch (Macquaria ambigua ambigua), and silver perch (Bidyanus bidyanus), two key native species found within the Murray Darling Basin, Australia, were exposed to different temperatures (20, 24 and 28 degrees C) combined with normoxic (6-8 mgO2 L-1 or 12-14 kPa) and hypoxic (3-4 mgO2 L-1 or 7-9 kPa) conditions. After 10 months, fish were placed in individual respirometry chambers to measure standard and maximum metabolic rate (SMR and MMR), absolute aerobic scope (AAS) and hypoxia tolerance. Golden perch had a much higher tolerance to hypoxia exposure than silver perch, as most silver perch died after only 1 month exposure. Golden perch acclimated to hypoxia had reduced MMR at 20 and 28 degrees C, but there was no change to SMR. Long-term exposure to hypoxia improved the tolerance of golden perch to hypoxia, compared to individuals held under normoxic conditions suggesting that golden perch can acclimate to levels around 3 mgO2 L-1 (kPa ~ 7) and lower. The contrasting tolerance of two sympatric fish species to hypoxia highlights our lack of understanding of how hypoxia effects fish after long-term exposure. PMID- 29110077 TI - Exploring the relationship between threat-related changes in anxiety, attention focus, and postural control. AB - Individuals report directing attention toward and away from multiple sources when standing under height-related postural threat, and these changes in attention focus are associated with postural control modifications. As it is unknown whether these changes generalize to other types of threat situations, this study aimed to quantify changes in attention focus and examine their relationship with postural control changes in response to a direct threat to stability. Eighty young adults stood on a force plate fixed to a translating platform. Three postural threat conditions were created by altering the expectation of, and prior experience with, a postural perturbation: no threat of perturbation, threat without perturbation experience, and threat with perturbation experience. When threatened, participants were more anxious and reported directing more attention to movement processes, threat-related stimuli, and self-regulatory strategies, and less to task-irrelevant information. Postural sway amplitude and frequency increased with threat, with greater increases in frequency and smaller increases in amplitude observed with experience. Without experience, threat-related changes in postural control were accounted for by changes in anxiety; larger changes in anxiety were related to larger changes in sway amplitude. With experience, threat related postural control changes were accounted for by changes in attention focus; increases in attention to movement processes were related to greater forward leaning and increases in sway amplitude, while increases in attention to self-regulatory strategies were related to greater increases in sway frequency. Results suggest that relationships between threat-related changes in anxiety, attention focus, and postural control depend on the context associated with the threat. PMID- 29110078 TI - Joint cognition and the role of human agency in random number choices. AB - Joint cognition refers to the mental systems that support group performance when carrying out a shared, or jointly owned task. We focused here on understanding the social configurations that underpin key phenomena in joint cognition, in particular, whether individual cognition in task-sharing environments is mostly shaped by social factors or not. To this end, we investigated, first and mainly, whether human presence is necessary for the creation of joint performance; second and separately, whether prior experience of task sharing has an adaptive influence on subsequent individual choices; and third and additionally, whether individual differences in a social trait mediate joint performance. We describe an experiment in which participants combined with another human or a computer as they attempted to generate a paired sequence that was as random as possible. First, we found little difference in joint performance with regard to whether a human or a computer was the co-participant, except for immediate repetitive response. Second, we found evidence for choice adaptation, but only under the lower time pressure. Third, we replicated previous research in which no systematic link was established between social desirability and joint performance. We conclude that joint cognition phenomena may be rooted primarily in turn-taking configurations rather than in social dynamics per se. PMID- 29110080 TI - Pemphigus trigger factors: special focus on pemphigus vulgaris and pemphigus foliaceus. AB - Pemphigus is a general term for a rare group of autoimmune diseases which result in the formation of blisters on the skin and oral cavity. Although there is no way to prevent autoimmune diseases, some factors may trigger pemphigus initiation in susceptible individuals or be exacerbated in affected patients. Recognition of these triggers, based on the latest studies and experiences is essential and should be updated every few years. In this study, several triggers, including different drugs and treatments, diseases, vaccines, genetic factors, nutrients, micronutrients, pregnancy, stress, and various other triggers have been discussed. Some possible triggers, such as blood antigens and the effect of seasons have also been discussed briefly. Moreover, some protective factors against pemphigus have been reviewed. Considering the molecular mechanism of pemphigus and immune response alteration during this disease, some possible triggers have been suggested and discussed. Although those triggers may be a real threat, more studies are needed to support these hypotheses. PMID- 29110079 TI - Old and emerging concepts on adrenal chromaffin cell stimulus-secretion coupling. AB - The chromaffin cells (CCs) of the adrenal medulla play a key role in the control of circulating catecholamines to adapt our body function to stressful conditions. A huge research effort over the last 35 years has converted these cells into the Escherichia coli of neurobiology. CCs have been the testing bench for the development of patch-clamp and amperometric recording techniques and helped clarify most of the known molecular mechanisms that regulate cell excitability, Ca2+ signals associated with secretion, and the molecular apparatus that regulates vesicle fusion. This special issue provides a state-of-the-art on the many well-known and unsolved questions related to the molecular processes at the basis of CC function. The issue is also the occasion to highlight the seminal work of Antonio G. Garcia (Emeritus Professor at UAM, Madrid) who greatly contributed to the advancement of our present knowledge on CC physiology and pharmacology. All the contributors of the present issue are distinguished scientists who are either staff members, external collaborators, or friends of Prof. Garcia. PMID- 29110081 TI - An interprofessional approach to managing children with treatment-resistant enuresis: an educational review. AB - Enuresis (intermittent urinary incontinence during sleep in a child aged >= 5 years) is commonly seen in paediatric practice. Despite the availability of effective interventions, treatment resistance is encountered in up to 50% of children. In this educational review we attempt to provide insight into the causes of treatment resistance, and offer practical suggestions for addressing this condition using an interprofessional approach. We explore the pathophysiology of and standard treatments for enuresis and discuss why standard treatments may fail. An interprofessional approach to treatment resistance is proposed which utilises the expertise of professionals from different disciplines to address the problems and barriers to treatment. The two interprofessional approaches include a multidisciplinary approach that involves the patient being sent to experts in different disciplines at different times to address their treatment resistance utilising the skills of the respective experts, and an interdisciplinary approach that involves a patient being managed by members of interdisciplinary team who integrate their separate discipline perspectives into a single treatment plan. Although an interdisciplinary approach is ideal, interdisciplinary teams may not be available in all circumstances. Understanding the roles of other disciplines and engaging clinicians from other disciplines when appropriate can still be helpful when treatment resistance is encountered. PMID- 29110083 TI - Yellow sac spiders. PMID- 29110082 TI - Continuous monitoring of the recurrent laryngeal nerve. AB - OBJECTIVE: The objective of this study was to assess the safety and utility of continuous intraoperative neuromonitoring for the prevention of recurrent laryngeal nerve injury during thyroidectomy. METHODS: A prospective cohort study was conducted in consecutive patients undergoing thyroidectomy. Variations in amplitude and distal latency of the electromyogram (EMG) were assessed. In the case of suspicious events, restorative manoeuvers were performed to attempt to recover the potentials. Associations were explored between findings in laryngoscopy 24 h after surgery and intraoperative neurophysiological events. RESULTS: In the study, 248 consecutive thyroidectomies were included, which were carried out between January 2012 and December 2015. Continuous vagal nerve monitoring was not associated with adverse cardiopulmonary events. Among the 400 at-risk recurrent laryngeal nerves (RLNs), there were eight nerves showing temporary palsy (2%). While an increase in distal latency of > 10% did not provide any relevant information, a decrease in the amplitude of the EMG of > 50% was associated with a higher risk of RLN palsy. A decrease in the amplitude of the EMG of > 50% was associated with negative and positive predictive values of 100 and 47%, respectively. Recovery manoeuvers reversed the decline in the amplitude of potentials in 80% of cases. CONCLUSIONS: Continuous vagal nerve monitoring is safe and allows us to assess nerve function intraoperatively. A decrease of more than 50% in the amplitude of the potentials from EMG baseline is a warning sign of the development of a nerve injury. Nevertheless, this decrease is reversible with restorative manoeuvers, making it possible to minimise RLN injuries. PMID- 29110084 TI - The development of a post-mortem interval estimation for human remains found on land in the Netherlands. AB - The decomposition process of human remains can be used to estimate the post mortem interval (PMI), but decomposition varies due to many factors. Temperature is believed to be the most important and can be connected to decomposition by using the accumulated degree days (ADD). The aim of this research was to develop a decomposition scoring method and to develop a formula to estimate the PMI by using the developed decomposition scoring method and ADD.A decomposition scoring method and a Book of Reference (visual resource) were made. Ninety-one cases were used to develop a method to estimate the PMI. The photographs were scored using the decomposition scoring method. The temperature data was provided by the Royal Netherlands Meteorological Institute. The PMI was estimated using the total decomposition score (TDS) and using the TDS and ADD. The latter required an additional step, namely to calculate the ADD from the finding date back until the predicted day of death.The developed decomposition scoring method had a high interrater reliability. The TDS significantly estimates the PMI (R 2 = 0.67 and 0.80 for indoor and outdoor bodies, respectively). When using the ADD, the R 2 decreased to 0.66 and 0.56.The developed decomposition scoring method is a practical method to measure decomposition for human remains found on land. The PMI can be estimated using this method, but caution is advised in cases with a long PMI. The ADD does not account for all the heat present in a decomposing remain and is therefore a possible bias. PMID- 29110085 TI - Safety of first-line triple therapy with a potassium-competitive acid blocker for Helicobacter pylori eradication in children. AB - BACKGROUND: Helicobacter pylori infection is a risk factor for gastric cancer, and it has been reported that eradication of H. pylori is effective for preventing such cancer. Recently, H. pylori eradication has been performed in children as first-line therapy against gastric cancer. Here, we report use of triple therapy with a potassium-competitive acid blocker (P-CAB) for H. pylori eradication in children. METHODS: H. pylori infection testing and eradication therapy began in fiscal year 2015 in junior high school students located in Yurihonjo city and Nikaho city, Akita prefecture, Japan. Urine-based immunochromatography, stool antigen enzyme-linked immunosorbent assay tests, and serum antibody tests were performed as the initial screening examination. Those who tested positive on one of the three examinations then underwent a urea breath test (13C-UBT). Those who tested positive on 13C-UBT and expressed the desire to undergo H. pylori eradication then received eradication therapy comprising 20 mg P-CAB, 750 mg amoxicillin, and 200 mg clarithromycin twice a day for 7 days. At least 8 weeks after treatment, eradication success was evaluated using 13C-UBT. RESULTS: A total of 118 students received eradication therapy. Eradication rates were 81.3% (95% confidence interval: 74.3-88.4, 96/118) in ITT analysis and 85.7% (95% confidence interval: 79.1-92.9 96/112) in PP analysis. Adverse effects associated with eradication therapy were observed in 25 of 118 subjects (21.1%), seven of whom required hospital treatment (rash in five, vomiting in two). All seven subjects either discontinued therapy or were administered anti-allergy drugs, which resulted in swift alleviation of symptoms. CONCLUSIONS: First-line triple therapy with a P-CAB for H. pylori eradication in children was found to be safe. PMID- 29110086 TI - Acute and chronic fluid misdirection syndrome: pathophysiology and treatment. AB - PURPOSE: To summarize our current understanding of the specific pathogenic mechanisms of the fluid misdirection syndrome and possible treatment methods. METHODS: We used the PubMed web platform to find relevant studies using the following keywords: infusion misdirection syndrome, aqueous misdirection syndrome, ciliary block, ciliovitreal block, capsular block, intraoperative fluid misdirection, subcapsular fluid entrapment, acute intraoperative rock-hard eye syndrome, positive vitreous pressure glaucoma, and malignant glaucoma. Other publications were also considered as a potential source of information when referenced in relevant articles. RESULTS: We collected and analyzed 55 articles dated from 1951 to 2016. Acute intraoperative rock-hard eye syndrome is characterized by a very shallow anterior chamber with the absence of suprachoroidal effusion or hemorrhage and no noticeable pathology of the iris lens diaphragm. It usually occurs during uneventful phacoemulsification, particularly in hyperopic eyes. The pathophysiology of acute fluid misdirection syndrome is based on inappropriate movement of balanced salt solution via the zonular fibers. This syndrome has also been described as occurring from hours to months, or years, after the initial surgery. The pathophysiology of malignant glaucoma is based on similar mechanisms of cilio-lenticular block of aqueous flow leading to the misdirection of aqueous posteriorly into or besides the vitreous gel. Faced with these situations, vitreous decompression is required, preferably with hyaloido-capsulo-iridectomy. In phakic eyes, concomitant cataract extraction would be desirable. CONCLUSIONS: We believe both of these clinical conditions should be considered as one syndrome. We suggest the term acute fluid misdirection syndrome for the cascade of events during phacoemulsification surgery. Chronic fluid misdirection syndrome better describes the nature of malignant glaucoma. PMID- 29110087 TI - Outcomes of open versus laparoscopic surgery in patients with rectal cancer. AB - PURPOSE: The goal of this study was to compare the effectiveness of laparoscopic with that of open surgery up to 2 years after intervention in patients with rectal cancer. METHODS: This is a prospective cohort study of patients with rectal cancer who underwent surgery (laparoscopic or open) between June 2010 and December 2012 in 22 acute hospitals. Main outcomes were mortality, complications, reoperation, readmission, and patient-reported outcome measures (PROMs), as measured using the EuroQol-5D (EQ-5D), European Organisation for Research and Treatment of Cancer (EORTC) QLQ-Q30 and Q29, the Barthel Index (BI), and the Duke UNC Functional Social Support Questionnaire at baseline, 1 year, and 2 years after surgery. Multivariable multilevel logistic regression and generalized linear models were used in the analyses after adjusting for specific propensity scores developed for each outcome and time point. RESULTS: In the multivariable analysis, rates of some medical complications after surgery during admission (renal failure and paralytic ileus) and infectious (urinary tract infection, septic shock, and localized intra-abdominal infection) and at 1 year (renal and heart failure) were higher among patients who underwent open surgery than among those who underwent laparoscopic surgery. There were no differences between the two surgical approaches in all other parameters assessed at the different time points or in all PROMs evaluated. CONCLUSIONS: Laparoscopic surgery and open surgery provide quite similar results in patients with rectal cancer up to 2 years after intervention in most outcomes, though the rates of certain medical and infectious complications at admission and up to 1 year after the intervention were higher in open surgery. PMID- 29110088 TI - Carbohydrate active enzyme domains from extreme thermophiles: components of a modular toolbox for lignocellulose degradation. AB - Lignocellulosic biomass is a promising feedstock for the manufacture of biodegradable and renewable bioproducts. However, the complex lignocellulosic polymeric structure of woody tissue is difficult to access without extensive industrial pre-treatment. Enzyme processing of partly depolymerised biomass is an established technology, and there is evidence that high temperature (extremely thermophilic) lignocellulose degrading enzymes [carbohydrate active enzymes (CAZymes)] may enhance processing efficiency. However, wild-type thermophilic CAZymes will not necessarily be functionally optimal under industrial pre treatment conditions. With recent advances in synthetic biology, it is now potentially possible to build CAZyme constructs from individual protein domains, tailored to the conditions of specific industrial processes. In this review, we identify a 'toolbox' of thermostable CAZyme domains from extremely thermophilic organisms and highlight recent advances in CAZyme engineering which will allow for the rational design of CAZymes tailored to specific aspects of lignocellulose digestion. PMID- 29110089 TI - Impact of surgical treatment after sorafenib therapy for advanced hepatocellular carcinoma. AB - BACKGROUND: For advanced hepatocellular carcinoma (HCC), surgical treatment after sorafenib induction has rarely been reported. We examined the survival benefit of additional surgical treatment in sorafenib-treated patients. METHODS: Thirty-two advanced HCC patients were given sorafenib from July 2009 to July 2012, and we statistically analyzed the relevant predictive factors of the long-term survival. The institutional review board of Kumamoto University Hospital approved this study (Approval number 1038). RESULTS: The median duration of sorafenib administration was 56.5 days (range 5-945). The cumulative overall survival rate was 44.6, 33.4, 26.0 and 17.8% at 1, 2, 3 and 5 years, respectively. The median survival time was 11.2 months. A survival of more than 3 years after the initiation of sorafenib induction was observed in seven patients, five of whom were subjected to additional surgical intervention. Additional surgery was the most significant factor predicting a survival exceeding 3 years (P < 0.0001) and represents an independent prognostic factor [hazard ratio (HR) 0.07; P = 0.01], followed by the total dose of sorafenib. The surgical interventions comprised two hepatic resections +/- radiofrequency ablation, two radiofrequency ablations and one lung resection. CONCLUSIONS: A long-term survival might be obtained for select HCC patients given adequate additional surgical treatment, even after sorafenib induction. PMID- 29110090 TI - Assessing the economic advantage of laparoscopic vs. open approaches for colorectal cancer by a propensity score matching analysis. AB - PURPOSES: This study investigated the surgical outcomes and potential economic advantage of open vs. laparoscopic surgery for colorectal cancer using a propensity score matching analysis. METHODS: We examined the surgical and economic outcomes of patients undergoing laparoscopic (N = 127) and open surgery (N = 253) for colorectal cancer and then compared these outcomes in two groups (N = 103 each) using a propensity score matching analysis. RESULTS: Compared to open surgery, the laparoscopic approach was associated with a significantly lower overall morbidity rate (14 vs. 40%; P < 0.001) and shorter mean (+/- standard deviation) postoperative hospital stay (12.6 +/- 8.3 vs. 16.8 +/- 9.9 days, respectively; P = 0.001). Despite generating higher mean surgical costs (Japanese yen) (985,000 +/- 215,000 vs. 812,000 +/- 222,000 yen; P < 0.001), utilizing a laparoscopic approach significantly reduced the non-surgical costs (773,000 +/- 440,000 vs. 1075,000 +/- 508,000 yen; P < 0.001). The mean total cost of laparoscopic-assisted surgery (1758,000 +/- 576,000 yen) was decreased by approximately 130,000 yen compared with open surgery (1886,000 +/- 619,000 yen), although the difference was not statistically significant (P = 0.125). CONCLUSIONS: Laparoscopic surgery for colorectal cancer is advantageous in reducing morbidity and facilitating an early discharge and does not increase hospital costs. These findings are consistent with the general consensus supporting the benefits of laparoscopic surgery as a minimally invasive approach. PMID- 29110091 TI - Tree species identity and diversity drive fungal richness and community composition along an elevational gradient in a Mediterranean ecosystem. AB - Ecological and taxonomic knowledge is important for conservation and utilization of biodiversity. Biodiversity and ecology of fungi in Mediterranean ecosystems is poorly understood. Here, we examined the diversity and spatial distribution of fungi along an elevational gradient in a Mediterranean ecosystem, using DNA metabarcoding. This study provides novel information about diversity of all ecological and taxonomic groups of fungi along an elevational gradient in a Mediterranean ecosystem. Our analyses revealed that among all biotic and abiotic variables tested, host species identity is the main driver of the fungal richness and fungal community composition. Fungal richness was strongly associated with tree richness and peaked in Quercus-dominated habitats and Cistus-dominated habitats. The highest taxonomic richness of ectomycorrhizal fungi was observed under Quercus ilex, whereas the highest taxonomic richness of saprotrophs was found under Pinus. Our results suggest that the effect of plant diversity on fungal richness and community composition may override that of abiotic variables across environmental gradients. PMID- 29110092 TI - Tracking posttraumatic hemianopia. AB - Hemianopia after traumatic brain injury is not infrequent and results from retro chiasmatic lesions. Differentiating optic pathway lesions can be challenging with classic imaging. Advanced imaging techniques as an investigational tool for posttraumatic hemianopia are discussed and their pitfalls highlighted through an illustrative case study. In a patient with posttraumatic hemianopia, MRI at 8 weeks and 2 years after trauma were analyzed. Diffusion tensor imaging (DTI) and morphometric analysis of the primary visual cortex (V1) were performed. Optical coherence tomography (OCT) was performed 2 years after trauma. DTI at 8 weeks showed a decrease in fractional anisotropy (FA) of the left optic tract together with a decrease in FA in the right optic tract and optic radiation. At 2 years, an isolated decrease of the left optic tract FA values was noticed together with signs of Wallerian degeneration on classic MR imaging. OCT showed thinning of the retina congruent with the visual field deficit. While DTI abnormalities were also present in the early scan, they were more diffuse and also encompassed functionally intact structures. Results of advanced imaging techniques need to be interpreted with caution and can vary according to the timing of imaging due to Wallerian degeneration. PMID- 29110093 TI - Evaluation of inter- and intra-observer reliability of current classification systems for subtrochanteric femoral fractures. AB - INTRODUCTION: To evaluate the inter- and intra-observer reliability of the Russell Taylor, Seinsheimer and AO classification systems, and to investigate whether or not the experience of the surgeon had any effect on the classification. PATIENTS AND METHODS: All the radiographs of 35 patients with subtrochanteric femur fracture were classified by 16 observers using the Russell Taylor, Seinsheimer and 31-AO classifications. Two groups of observers were formed of eight orthopedic surgeons, each with at least five-year experience and eight orthopedic assistants, from six different hospitals, who were invited to participate in the study. All the observers reviewed all the X-rays at this first evaluation. At 6 weeks after the first evaluation, the same radiographs were presented to each observer again in a random order and all the observers were requested to classify the fractures again. To evaluate the inter- and intra observer reliability, the Fleiss kappa and Cohen's kappa values were used. RESULTS: In the inter-observer reliability, the mean values of the two evaluations for the Russell Taylor classification were determined to be kappa:0.724 (substantial) for the specialists and kappa:0.722 (substantial) for the assistants. Using the Seinsheimer classification, the mean values were kappa:0.691 (substantial) for the specialists and kappa:0.629 (substantial) for the assistants, and for the AO classification, the mean values were kappa:0.279 (fair) for the specialists and kappa:0.291 (fair) for the assistants. In the intra-observer reliability, the median values for the Russell Taylor classification were determined to be kappa:0.955 (almost perfect) for the specialists and kappa:0.855 (almost perfect) for the assistants. Using the Seinsheimer classification, the median values were kappa:0.915 (almost perfect) for the specialists and kappa:0.900 (almost perfect) for the assistants, and for the AO classification, the median values were kappa:0.665 (substantial) for the specialists and kappa:0.695 (substantial) for the assistants. CONCLUSIONS: As both the Russell Taylor and Seinsheimer classifications were found to be more reliable and reproducible than the AO classification for subtrochanteric femoral fractures, they can be considered to be more valuable in clinical practice and communication. The experience of the surgeons was not found to have any significance in the evaluation of these three classification systems in these types of fractures. PMID- 29110095 TI - Gender Dysphoria in the Military. AB - PURPOSE OF REVIEW: With the announcement that members of the military who identify as transgender are allowed to serve openly, the need for Department of Defense behavioral health providers to be comfortable in the assessment, diagnosis, and treatment of this population becomes quickly evident. This population has been seeking care in the community and standards have been developed to help guide decision-making, but a comparable document does not exist for the military population. RECENT FINDINGS: Previously published papers were written in anticipation of the policy allowing for open service. The civilian sector has treatment guidelines and evidence supporting the same for reference. There is no similar document for the military population, likely due to the recent change and ongoing development. This paper attempts to provide an overview of the recent Department of Defense policy and walks the reader through key considerations when providing care to a transgender member of the military as it relates to those who are currently serving in the military through the use of a case example. The military transgender population faces some unique challenges due to the need to balance readiness and deployability with medically necessary health care. Also complicating patient care is that policy development is ongoing as of this publication, the decision has not yet been made regarding how people who identify as transgender will access into the military nor is there final approval regarding coverage for surgical procedures. Unique circumstances of this population are brought up to generate more discussion and encourage further evaluation and refinement of the process. PMID- 29110094 TI - Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing. AB - GPR88 is an orphan G-protein coupled receptor originally characterized as a striatal-enriched transcript and is a potential target for neuropsychiatric disorders. At present, gene knockout studies in the mouse have essentially focused on striatal-related functions and a comprehensive knowledge of GPR88 protein distribution and function in the brain is still lacking. Here, we first created Gpr88-Venus knock-in mice expressing a functional fluorescent receptor to fine-map GPR88 localization in the brain. The receptor protein was detected in neuronal soma, fibers and primary cilia depending on the brain region, and remarkably, whole-brain mapping revealed a yet unreported layer-4 cortical lamination pattern specifically in sensory processing areas. The unique GPR88 barrel pattern in L4 of the somatosensory cortex appeared 3 days after birth and persisted into adulthood, suggesting a potential function for GPR88 in sensory integration. We next examined Gpr88 knockout mice for cortical structure and behavioral responses in sensory tasks. Magnetic resonance imaging of live mice revealed abnormally high fractional anisotropy, predominant in somatosensory cortex and caudate putamen, indicating significant microstructural alterations in these GPR88-enriched areas. Further, behavioral analysis showed delayed responses in somatosensory-, visual- and olfactory-dependent tasks, demonstrating a role for GPR88 in the integration rather than perception of sensory stimuli. In conclusion, our data show for the first time a prominent role for GPR88 in multisensory processing. Because sensory integration is disrupted in many psychiatric diseases, our study definitely positions GPR88 as a target to treat mental disorders perhaps via activity on cortical sensory networks. PMID- 29110096 TI - Role of Platinum in Early-Stage Triple-Negative Breast Cancer. AB - OPINION STATEMENT: Triple-negative breast cancer (TNBC) is both a clinically and genomically heterogeneous disease, with distinct molecular subtypes; however, most epidemiologic and clinical studies to date have defined it under a "one disease" umbrella. This is an important point, since one therapeutic approach for all TNBCs is unlikely to be successful given the underlying biological diversity. In this review, we explore the role of platinums in the treatment of TNBC, as well as the potential for biomarkers to predict patient response to these agents. The results of neoadjuvant TNBC trials, with addition of platinum to anthracycline/taxane-based chemotherapies, have been very encouraging given increases in pathologic complete response (pCR) rates. However, we do not have any evidence yet that these agents would lead to improvement in disease-free and overall survival. Moreover, addition of platinums increases toxicity and can compromise current standard chemotherapy doses, which further impedes their use in all TNBC patients. Therefore, the addition of platinums to standard chemotherapy should be used with caution and in discussion with patients after a careful assessment of risks and benefits. Clinical trials addressing the role of platinums in TNBC further remain of significant value. PMID- 29110097 TI - Geographic region, socioeconomic position and the utilisation of primary total joint replacement for hip or knee osteoarthritis across western Victoria: a cross sectional multilevel study of the Australian Orthopaedic Association National Joint Replacement Registry. AB - : Compared to urban residents, those in rural/regional areas often experience inequitable healthcare from specialist service providers. Independent of small between-area differences in utilisation, socially advantaged groups had the greatest uptake of joint replacement. These data suggest low correlation between 'need' vs. 'uptake' of surgery in rural/regional areas. BACKGROUND AND PURPOSE: Compared to urban residents, those in rural and regional areas often experience inequitable healthcare from specialist service providers, often due to geographical issues. We investigated associations between socioeconomic position (SEP), region of residence and utilisation of primary total knee replacement (TKR) and/or total hip replacement (THR) for osteoarthritis. DESIGN AND METHODS: As part of the Ageing, Chronic Disease and Injury study, we extracted data from the Australian Orthopaedic Association National Joint Replacement Registry (2011 2013) for adults that utilised primary TKR (n = 4179; 56% female) and/or THR (n = 3120; 54% female). Residential addresses were matched with the Australian Bureau of Statistics (ABS) 2011 census data: region of residence was defined according to local government areas (LGAs), and area-level SEP (quintiles) defined using an ABS-derived composite index. The ABS-determined control population (n = 591,265; 51% female) excluded individuals identified as cases. We performed multilevel logistic regression modelling using a stratified two-stage cluster design. RESULTS: TKR was higher for those aged 70-79 years (AOR 1.4 95%CI 1.3-1.5; referent = 60-69 years) and in the most advantaged SEP quintile (AOR 2.1, 95%CI 1.8-2.3; referent = SEP quintile 3); results were similar for THR (70-79 years = AOR 1.7, 95%CI 1.5-1.8; SEP quintile 5 = AOR 2.5, 95%CI 2.2-2.8). Total variances contributed by the variance in LGAs were 2% (SD random effects +/- 0.28) and 3% (SD +/- 0.32), respectively. CONCLUSION: Independent of small between-LGA differences in utilisation, and in contrast to the expected greater prevalence of osteoarthritis in disadvantaged populations, we report greater TKR and THR in more advantaged groups. Further research should investigate whether more advantaged populations may be over-serviced. PMID- 29110098 TI - Do hydrodynamically assisted binary collisions lead to orientational ordering of microswimmers? AB - We have investigated the onset of collective motion in systems of model microswimmers, by performing a comprehensive analysis of the binary collision dynamics using three-dimensional direct numerical simulations (DNS) with hydrodynamic interactions. From this data, we have constructed a simplified binary collision model (BCM) which accurately reproduces the collective behavior obtained from the DNS for most cases. Thus, we show that global alignment can mostly arise solely from binary collisions. Although the agreement between both models (DNS and BCM) is not perfect, the parameter range in which notable differences appear is also that for which strong density fluctuations are present in the system (where pseudo-sound mound can be observed (N. Oyama et al., Phys. Rev. E 93, 043114 (2016))). PMID- 29110099 TI - Response to the correspondence "Preservation of vaginal elasticity is essential for avoiding mesh complications after prolapse surgery" by P Petros and P Richardson. PMID- 29110100 TI - Gills as morphological biomarkers in extensive and intensive rainbow trout (Oncorhynchus mykiss, Walbaum 1792) production technologies. AB - We investigated environmental impacts on rainbow trout (Oncorhynchus mykiss) reared at fish farms with either extensive technology, in a flow-through system (FTS, n = 3), or intensive technology, in a recirculating aquaculture system (RAS, n = 3). All fish were fed the same rations. Fish were caught in spring and autumn (body mass, 501-750 g) from these six farms. We performed macroscopic (intact fish) and microscopic (gills stained with haematoxylin/eosin) examinations. Lesions were categorised based on the type and location of structural abnormalities. The histopathological index (HAI) was calculated, and each lesion was scored. Fish reared in FTS or RAS were compared for the prevalence of morphological lesions. Gill epithelial hypertrophy and hyperplasia comprised 73% (RAS) to 79% (FTS) of all morphological abnormalities. In spring and autumn, lesions comprised, respectively, 11 and 18% (FTS) and 16 and 10% (RAS) mucous and chloride cell abnormalities and 8 and 4% (FTS) and 10 and 3% (RAS) blood vessel abnormalities. Diffuse, irreversible gill lesions were observed sporadically in all fish. Gill epithelium received the most exposure to environmental pathogens. HAIs indicated that normal gill architecture and minor lesions predominated in all fish. However, among trout caught in spring, moderate and extensive changes in gills occurred more commonly with RAS (34%) than with FTS (17%). Trout caught in autumn displayed no great differences. These results indicated that FTS prepared fish better than RAS for wintering. Moreover, we showed that gills were an excellent biomarker for analysing the impact of extensive and intensive production environments on rainbow trout. PMID- 29110101 TI - Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors. AB - Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8-16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis. PMID- 29110102 TI - Pediatric Delirium: Recognition, Management, and Outcome. AB - PURPOSE OF REVIEW: This review seeks to provide an update on the diagnosis, management, and outcome of pediatric delirium. RECENT FINDINGS: Care of patients with delirium depends on correct diagnosis and treatment of its underlying cause. A variety of instruments are available to aid diagnosis. Management of delirium currently depends on atypical antipsychotics, while avoiding agents that may precipitate or exacerbate it. While most critically ill children survive delirium, many children die or have worsening function after their illness. The longer the duration of delirium, the more severe its subsequent problems including postintensive care syndrome and posttraumatic stress disorder. Possible serious long-term consequences emphasize the importance of efforts to improve diagnosis and outcome in critically ill children suffering from delirium. PMID- 29110103 TI - CT Imaging of the Vulnerable Plaque. AB - OPINION STATEMENT: Acute coronary syndromes are most often the result of vulnerable atherosclerotic plaque events. Plaques events occur when intimal fibroatheroma in the coronary artery wall becomes vulnerable to erosion or rupture. Such vulnerable plaques can be distinguished from quiescent atheroma by features that have been defined through histopathology and invasive imaging. A challenge for coronary CT angiography has been to identify vulnerable plaques non invasively. Were this possible, CT angiography could offer comprehensive vessel assessment including stenosis severity and plaque characteristics with the hope of reducing acute coronary events through timely intervention. Over the past decade, advances in invasive imaging techniques have enabled unstable coronary plaques to be accessed more readily. In this fashion it has been possible to correlate invasive appearances to CT angiographic findings in an unprecedented manner. Several CT defined plaque characteristic have now been described to reliably identify unstable plaques. Retrospective studies have demonstrated the utility of these plaque features to predict future acute coronary events. If these can be confirmed in prospective studies, the intrinsic benefits of non invasive imaging will position coronary CT angiography firmly in our armamentarium to image coronary arteries and help prevent acute coronary events. PMID- 29110104 TI - Characterization of a beta-glucosidase from Bacillus licheniformis and its effect on bioflocculant degradation. AB - Bacillus licheniformis CGMCC 2876, an aerobic spore-forming bacterium, produces a polysaccharide bioflocculant that is biodegradable and harmless. The present study determined that beta-glucosidase played a negative role in bioflocculant synthesis. The gene encoding beta-glucosidase was cloned and expressed in Escherichia coli BL21. This gene consists of 1437 bp and encodes 478 amino acid residues. The recombinant beta-glucosidase (Bgl.bli1) was purified and showed a molecular mass of 53.4 kDa by SDS-PAGE. The expression and reaction conditions of Bgl.bli1 were optimized; the activity of beta-glucosidase reached a maximum at 45.44 U/mL. Glucose clearly inhibited the activity of beta-glucosidase. The purified recombinant Bgl.bli1 hydrolysed polysaccharide bioflocculant in vitro and synergised with other cellulases. The ability of Bgl.bli1 to hydrolyse polysaccharide bioflocculant was the reason for the decrease in flocculating activity and indicated the utility of this enzyme for diverse industrial processes. PMID- 29110105 TI - Recent Issues in Pediatric Clostridium difficile Infection. AB - PURPOSE OF REVIEW: We focus on two recent aspects of Clostridium difficile infection (CDI) in children, namely the emergence of community-associated CDI (CA CDI) and the incidence and prevention of recurrent CDI. RECENT FINDINGS: Current surveys suggest that a large proportion of all pediatric CDI is acquired in the community. Risk factors and frequency estimates of pediatric CA-CDI, however, are confounded in babies and toddlers by a high rate of asymptomatic excretion, whose detection likely is exaggerated by the wide use of highly sensitive nucleic acid amplification tests. Recurrent diarrhea occurs in up to 25% of children with CDI. Preventative strategies for recurrent CDI in adults, namely pulse and taper antibiotic dosing, use of anti-CDI drugs with mild effect on the colonic microbiome, fecal microbiota transplantation, and passive immune therapy, currently are being tested in children. Future studies are required to better characterize community acquisition of CDI in children and to define the safety and effectiveness of preventative strategies for recurrent CDI. PMID- 29110106 TI - Diversity and distribution of heterotrophic dinoflagellates from the coastal waters of Port Blair, South Andaman. AB - The interaction between the environment and heterotrophic dinoflagellates inhabiting coastal waters of South Andaman was studied based on year round collections made during September 2012-August 2013 in the bay, eastern, and western region of South Andaman. The distribution pattern of microzooplankton in South Andaman showed high abundance in eutrophic waters (bay region) and gradually decreased towards the off shore region. Microzooplankton community comprised of six different taxa, viz. tintinnids, heterotrophic dinoflagellates, non-loricate ciliates, Foraminifera, Rotifera, and Copepoda (nauplii). Tintinnids were the major component of the microzooplankton (43.8 +/- 7%) followed by heterotrophic dinoflagellates (34 +/- 12%) and copepod nauplii (18.8 +/- 4.0%). This study focused on heterotrophic dinoflagellates which ranked next to tintinnids in overall abundance and contributed 38-42% in the bay, 22-37% in the eastern, and 15-29% in the western region to the microzooplankton community. Dinoflagellates showed a positive correlation with salinity and a negative correlation with dissolved oxygen and chlorophyll a (r = - 0.3). Abundance of heterotrophic dinoflagellates in this area may be due to their diverse and advantageous mode of nutrition. A total of 35 species belonging to 8 genera of heterotrophic dinoflagellates were recorded during the study period. Heterotrophic dinoflagellates showed a great potential to thrive in low oxygenated and low productive area (p < 0.001, Mann-Whitney test). Relatively higher diversity (H') in the dinoflagellates population was found in the bay region (avg. H' = 3.46). PMID- 29110107 TI - Effect of light conditions and chemical characteristics of water on dissipation of glyphosate in aqueous medium. AB - The present study was conducted to determine the effect of light conditions and chemical properties of water on dissipation of glyphosate. The residues of glyphosate and aminomethylphosphonic acid (AMPA) were quantified using fluorescence spectrophotometer after derivatization with 9 fluoroenylmethoxycarbonyl chloride (FMOC-Cl) and orthopthaldehyde (OPA). Average percent recoveries of glyphosate and AMPA from distilled, tap, and ground water ranged from 87.5 to 94.9, 87.3 to 93.7, and 80.6 to 92.0, respectively, with relative standard deviation less than 10%. The limit of detection and limit of quantification of glyphosate and AMPA from different water matrices ranged from 0.001 to 0.03 MUg mL-1 and 0.003 to 0.01 MUg mL-1, respectively. The dissipation of glyphosate followed the first-order kinetics, and half-life varied from 1.56 to 14.47 and 13.14 to 42.38 days under UV and sunlight, respectively. The pH and electrical conductivity (EC) of water has differential influence on dissipation of glyphosate, and it increased with increase in pH and EC. PMID- 29110108 TI - Universality of domain growth in antiferromagnets with spin-exchange kinetics. AB - We study phase ordering kinetics in symmetric and asymmetric binary mixtures, undergoing an order-disorder transition below the critical temperature. Microscopically, we model the kinetics via the antiferromagnetic Ising model with Kawasaki spin-exchange kinetics. This conserves the composition while the order parameter (staggered magnetization) is not conserved. The order-parameter correlation function and structure factor show dynamical scaling, and the scaling functions are independent of the mixture composition. The average domain size shows a power-law growth: [Formula: see text]. The asymptotic growth regime has [Formula: see text], though there can be prolonged transients with [Formula: see text] for asymmetric mixtures. Our unambiguous observation of the asymptotic universal regime is facilitated by using an accelerated Monte Carlo technique. We also obtain the coarse-grained free energy from the Hamiltonian, as a function of two order parameters. The evolution of these order parameters is modeled by using Model C kinetics. As for the microscopic dynamics, the average domain size of the nonconserved order-parameter (staggered magnetization) field exhibits a power-law growth: [Formula: see text] at later times, irrespective of the mean value of the conserved order-parameter (composition) field. PMID- 29110109 TI - Can we have an overall osteoarthritis severity score for the patellofemoral joint using magnetic resonance imaging? Reliability and validity. AB - This work aimed to assess inter-rater reliability and agreement of a magnetic resonance imaging (MRI)-based Kellgren and Lawrence (K&L) grading for patellofemoral joint osteoarthritis (OA) and to validate it against the MRI Osteoarthritis Knee Score (MOAKS). MRI scans from people aged 45 to 75 years with chronic knee pain participating in a randomised clinical trial evaluating dietary supplements were utilised. Fifty participants were randomly selected and scored using the MRI-based K&L grading using axial and sagittal MRI scans. Raters conducted inter-rater reliability, blinded to clinical information, radiology reports and other rater results. Intra- and inter-rater reliability and agreement were evaluated using the intra-class correlation coefficient (ICC) and Cohen's weighted kappa. There was a 2-week interval between the first and second readings for intra-rater reliability. Validity was assessed using the MOAKS and evaluated using Spearman's correlation coefficient. Intra-rater reliability of the K&L system was excellent: ICC 0.91 (95% CI 0.82-0.95); weighted kappa (K = 0.69). Inter-rater reliability was high (ICC 0.88; 95% CI 0.79-0.93), while agreement between raters was moderate (K = 0.49-0.57). Validity analysis demonstrated a strong correlation between the total MOAKS features score and the K&L grading system (rho = 0.62-0.67) but weak correlations when compared with individual MOAKS features (rho = 0.19-0.61). The high reliability and good agreement show consistency in grading the severity of patellofemoral OA with the MRI-based K&L score. Our validity results suggest that the scale may be useful, particularly in the clinical environment. Future research should validate this method against clinical findings. PMID- 29110110 TI - Changes and clinical significance of CD8+CD122+ T cells in the peripheral blood of patients with ankylosing spondylitis. AB - The aim of our study was to explore the relationship between circulating T cells and ankylosing spondylitis (AS) and to find the role of the CD8+CD122+ T cells in the pathogenesis and progression of AS. With the method of case-control design, flow cytometry was performed to quantitatively determine the percentage of circulating CD8+CD122+ T cells in peripheral blood mononuclear cells from established AS patients and age- and gender-matched healthy controls. Serum levels of inflammatory cytokines like interleukin-2, interleukin-10, interleukin 15, TGF-beta1, and TNF-alpha were detected by enzyme-linked immunosorbent assay. The t test was used to compare differences between groups, correlation analysis with Spearman rank test and Pearson correlation was performed. The percentage of circulating CD8+CD122+ T cells were significantly increased in AS patients compared with controls (Z = - 4.917, P = 0.001). Plasma IL-2, IL-10, IL-15, TGF beta1, and TNF-alpha levels between cases and controls were analyzed but no statistically significant differences were found. The percentage of circulating CD8+CD122+ T cells were not significantly different in the two groups of patients with AS whether they were treated or not. In addition, the percentage of circulating CD8+CD122+ T cells was positively correlated with disease duration, CRP, and ASDAS-CRP. The CD8+CD122+ T cells in the peripheral blood of AS patients may be involved in the development of AS, and they may coordinate regulate inflammation and immune dysregulation in patients with AS, which may play an important role in the pathogenesis and prognosis of AS. PMID- 29110111 TI - Forest fire risk assessment-an integrated approach based on multicriteria evaluation. AB - The present study deals with application of the weighted linear combination method for zoning of forest fire risk in Dohezar and Sehezar region of Mazandaran province in northern Iran. In this study, the effective criteria for fires were identified by the Delphi method, and these included ecological and socioeconomic parameters. In this regard, the first step comprised of digital layers; the required data were provided from databases, related centers, and field data collected in the region. Then, the map of criteria was digitized in a geographic information system, and all criteria and indexes were normalized by fuzzy logic. After that, the geographic information system (GIS 10.3) was integrated with the Weighted Linear Combination and the Analytical Network Process, to produce zonation of the forest fire risk map in the Dohezar and Sehezar region. In order to analyze accuracy of the evaluation, the results obtained from the study were compared to records of former fire incidents in the region. This was done using the Kappa coefficient test and a receiver operating characteristic curve. The model showing estimations for forest fire risk explained that the prepared map had accuracy of 90% determined by the Kappa coefficient test and the value of 0.924 by receiver operating characteristic. These results showed that the prepared map had high accuracy and efficacy. PMID- 29110112 TI - Random field Ising model in a uniform magnetic field: Ground states, pinned clusters and scaling laws. AB - In this paper, we study the random field Ising model (RFIM) in an external magnetic field h . A computationally efficient graph-cut method is used to study ground state (GS) morphologies in this system for three different disorder types: Gaussian, uniform and bimodal. We obtain the critical properties of this system and find that they are independent of the disorder type. We also study GS morphologies via pinned-cluster distributions, which are scale-free at criticality. The spin-spin correlation functions (and structure factors) are characterized by a roughness exponent [Formula: see text]. The corresponding scaling function is universal for all disorder types and independent of h. PMID- 29110113 TI - Depressive Symptoms and Condomless Sex Among Men Who Have Sex with Men Living with HIV: A Curvilinear Association. AB - Depressive symptoms are highly prevalent among HIV-positive men who have sex with men (MSM) and may contribute to risky health behaviors. However, research linking depressed mood to condomless sex in HIV-positive MSM has yielded mixed findings and has focused primarily on testing for a linear association. In the current study, we tested both linear and curvilinear models to assess the association of depressive symptoms to condomless anal sex for the most recent sexual episode in a sample of MSM living with HIV (N = 96, M age = 44, 57% Caucasian). Participants completed the Center for Epidemiological Studies-Depression Scale and self reported on their sexual behaviors. Findings confirmed a curvilinear association of depressive symptoms with condomless anal sex for encounters involving non primary partner: MSM with moderate levels of depressed mood were more likely to report non-condom use compared to those with low and high levels of depressive symptoms. Future research should test whether treatment for depression can serve to enhance the impact of sexual health promotion interventions for MSM. PMID- 29110114 TI - Medical Humanities Teaching in North American Allopathic and Osteopathic Medical Schools. AB - Although the AAMC requires annual reporting of medical humanities teaching, most literature is based on single-school case reports and studies using information reported on schools' websites. This study sought to discover what medical humanities is offered in North American allopathic and osteopathic undergraduate medical schools. An 18-question, semi-structured survey was distributed to all 146 (as of June 2016) member schools of the American Association of Medical Colleges and the American Association of Colleges of Osteopathic Medicine. The survey sought information on required and elective humanities content, hours of humanities instruction, types of disciplines, participation rates, and humanities administrative structure. The survey was completed by 134 schools (145 AAMC; 31 AACOM). 70.8% of schools offered required and 80.6% offered electives in humanities. Global health and writing were the most common disciplines. Schools required 43.9 mean (MD 45.4; DO 37.1) and 30 (MD 29; DO 37.5) median hours in humanities. In the first two years, most humanities are integrated into other course work; most electives are offered as stand-alone classes. 50.0% of schools report only 0-25% of students participating in humanities electives. Presence of a certificate, concentration or arts journal increased likelihood of humanities content but decreased mean hours. Schools with a medical humanities MA had a higher number of required humanities hours. Medical humanities content in undergraduate curriculum is lower than is indicated in the AAMC annual report. Schools with a formal structure have a greater humanities presence in the curriculum and are taken by more students. PMID- 29110115 TI - DNM1L Variant Alters Baseline Mitochondrial Function and Response to Stress in a Patient with Severe Neurological Dysfunction. AB - Mitochondria play vital roles in brain development and neuronal activity, and mitochondrial dynamics (fission and fusion) maintain organelle function through the removal of damaged components. Dynamin-like protein-1 (DRP-1), encoded by DNM1L, is an evolutionarily conserved GTPase that mediates mitochondrial fission by surrounding the scission site in concentric ring-like structures via self oligomerization, followed by GTPase-dependant constriction. Here, we describe the clinical characteristics and cellular phenotype of a patient with severe neurological dysfunction, possessing a homozygous DNM1L variant c.305C>T (p.T115M) in the GTPase domain. For comparative analysis, we also describe a previously identified heterozygous variant demonstrating a rapidly fatal neurocognitive phenotype (c.261dup/c.385:386del, p.W88M*9/E129K*6). Using patient generated fibroblasts, we demonstrated both DNM1L variants undergo adverse alterations to mitochondrial structure and function, including impaired mitochondrial fission, reduced membrane potential, and lower oxidative capacity including an increased cellular level of reactive oxygen species (ROS) and dsDNA breaks. Mutation of DNM1L was also associated with impaired responses to oxidative stress, as treatment with hydrogen peroxide dramatically increased cellular ROS, with minimal exacerbation of already impaired mitochondrial function. Taken together, our observations indicate that homozygous p.T115M variant of DNM1L produces a neurological and neurodevelopmental phenotype, consistent with impaired mitochondrial architecture and function, through a diminished ability to oligomerize, which was most prevalent under oxidative stress. PMID- 29110116 TI - Do Genetic Factors Explain the Links Between Callous-Unemotional, Attention Hyperactivity and Oppositional Defiant Problems in Toddlers? AB - Research demonstrates that callous-unemotional (CU) behaviors, Attention Deficit Hyperactivity Disorder (ADHD) and Oppositional Defiant Problems (ODD) are related, but little is known about the sources of covariation among the three externalizing behaviors. The present study looked at genetic and environmental links between all three behavioral domains in twins at ages 2 and 3 years (MZ = 145, DZ = 169), a time when CU behaviors are beginning to emerge. CU, ADHD, and ODD behaviors as assessed using the Child Behavior Checklist 1.5-5 (Achenbach and Rescorla 2000) were strongly interrelated at both ages. Genetic factors primarily explained the covariation among the three behavioral domains via a common externalizing factor; however, there were also genetic factors unique to each behavior. Furthermore, the majority of nonshared environmental influences on each externalizing behavior were behavior-specific. The heritable externalizing factor was highly stable across age, largely due to genetic factors shared across ages 2 and 3 years. Despite their extensive phenotypic and genetic overlap, CU, ADHD, and ODD behaviors have unique genetic and nonshared environmental influences as early as toddlerhood. This supports phenotypic research showing that the three are related but distinct constructs in very young children. PMID- 29110117 TI - Successful treatment of acute promyelocytic leukemia in pregnancy with single agent all-trans retinoic acid. AB - PURPOSE: The diagnosis of acute promyelocytic leukemia (APL) in pregnancy is an uncommon, life-threatening emergency. Choice of treatment and management of complications are challenging. METHODS: We report the case of a patient with diagnosis of APL at gestational age (GA) 24 + 4. We describe the interdisciplinary management during pregnancy and delivery and provide a 2-year follow-up. Existing reports on APL in pregnancy are summarized. RESULTS: Single agent induction therapy with all-trans retinoic acid (ATRA) was started and resulted in normalization of blood cell counts after 32 days. Vaginal delivery of a healthy baby occurred at GA 34 + 4. Consolidation therapy consisted of four courses of ATRA and arsenic trioxide (ATO). Less than 100 cases of APL in pregnancy are published. Misdiagnosis as HELLP syndrome with fatal outcome may occur. Combination therapies (ATRA-plus anthracyclines) were used in the majority of reports. CONCLUSIONS: Diagnosis and treatment of APL during pregnancy continues to be a challenge requiring interdisciplinary team work. Single-agent ATRA therapy may evolve as a safe and less-toxic treatment modality. PMID- 29110119 TI - Metformin synergistically enhances antitumor activity of cisplatin in gallbladder cancer via the PI3K/AKT/ERK pathway. AB - Metformin (Met) is a widely used antidiabetic drug and has demonstrated interesting anticancer effects in various cancer models, alone or in combination with chemotherapeutic drugs. The aim of the present study is to investigate the synergistic effect of Met with cisplatin (Cis) on the tumor growth inhibition of gallbladder cancer cells (GBC-SD and SGC-996) and explore the underlying mechanism. Cells were treated with Met and/or Cis and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay and immunohistochemistry. The results demonstrated that Met and Cis inhibited the proliferation of gallbladder cancer cells, and combination treatment with Met and Cis resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with Met and Cis caused G0/G1 phase arrest by upregulating P21, P27 and downregulating CyclinD1, and induced apoptosis through decreasing the expression of p-PI3K, p-AKT, and p-ERK. In addition, pretreatment with a specific AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of Met + Cis, suggesting the key role of AKT in this process. More importantly, in nude mice model, Met and Cis in combination displayed more efficient inhibition of tumor weight and volume in the SGC-996 xenograft mouse model than Met or Cis alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which is consistent with our in vitro results. In conclusion, our findings indicate that the combination therapy with Met and Cis exerted synergistic antitumor effects in gallbladder cancer cells through PI3K/AKT/ERK pathway, and combination treatment with Met and Cis would be a promising therapeutic strategy for gallbladder cancer patients. PMID- 29110118 TI - MicroRNA in gastrointestinal cell signalling. AB - Our gut forms an important organ and its formation, functioning and homeostasis are maintained by several factors including cell signalling pathways and commensal microflora. These factors affect pathological, physiological and immunological parameters to maintain gut health and prevent its inflammation. Among these, different intracellular signalling pathways play an important role in regulating gut homeostasis. These pathways are in turn regulated by various microRNAs that play a key role in maintaining the balance between tolerance and inflammation. This review highlights the importance of various cell signalling pathways in modulating gut homeostasis and the role specific miRNAs play in their regulation. PMID- 29110120 TI - [Analysis of spectacle lens prescriptions shows no increase of myopia in Germany from 2000 to 2015]. AB - OBJECTIVE: To determine whether the prevalence and magnitude of myopia among children and young adults wearing spectacles has increased in Germany from 2000 to 2015. MATERIAL AND METHODS: A total of 1,223,410 refraction values from 278,432 male and 333,273 female subjects between 5 and 30 years of age were analyzed. All subjects had received a new pair of spectacles between 1 January 2000 and 31 December 2015. The parameter studied was the spherical equivalent averaged over both eyes of each subject (N = 611,705). In order to identify temporal changes, the entire period of 16 years was divided into 4 time intervals of 4 years each. In the subjects three evaluation criteria were studied as a function of age: a) the frequency of myopic subjects among all spectacle wearers, b) the mean spherical equivalent and c) the distribution of the individual spherical equivalents. RESULTS: a) The frequency of myopic corrections among all spectacle wearers did not increase from 2000 to 2015. At 5 years of age, 9% of all children wearing glasses were myopic (<=-0.5 D) and 80% were hyperopic (>=+0.5 D). At the age of 10, 20 and 25 years, 46%, 75% and 79%, respectively, of all spectacle wearers were myopic and 42%, 13% and 10% hyperopic. b) The mean spherical equivalent, averaged across all spectacle wearers of the same age, did not show a myopic shift from 2000 to 2015. At the age of 5, 10.3 and 27 years, the mean spherical equivalent all subjects wearing glasses was +1.74 D, 0.0 D and -1.91D. c) The refractive power distribution of the individual spherical equivalents did not change significantly from 2000 to 2015. Neither low nor high myopias were more abundant in the period 2012-2015 compared to the previous years. CONCLUSION: The frequency and the refractive power of myopia did not increase in Germany over the last 16 years. PMID- 29110121 TI - [Nanoparticles as drug delivery systems in ophthalmology]. AB - Nanoparticles are perfectly suited as drug delivery systems due to their size and the diversity of materials used. They are able to penetrate biological barriers, can directly deliver drugs to the target site and provide a sustained release profile. Having long been established in oncology, in the last decade research has started to take a closer look at the potential of nanoparticles for ocular drug delivery. Obstacles, such as poor delivery of drugs via eye drops and the side effects of invasive methods, such as placing implants as drug depots could be overcome. Among the most relevant investigated structures are polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles, dendrimers and cyclodextrins. Besides the composition of the nanoparticle itself, its efficacy and stability can be optimized through coatings; however, long-term stability, standardization of production and toxicity remain the major challenges. The preclinical and partly clinical results obtained so far will hopefully give impulse to the idea of applying nanoparticles for optimized ocular drug delivery in the near future. PMID- 29110123 TI - [Acute onset of ptosis in a 23-year-old female patient]. PMID- 29110124 TI - [Who visits an ophthalmologist and how often? Results of the German nationwide adult health survey (DEGS1)]. AB - BACKGROUND: The prevalence of eye diseases increases in the second half of life, especially cataract, glaucoma and age-related macular degeneration. In this study we examined the influencing factors for visiting an ophthalmologist in the last 12 months. METHODS: Visits to an ophthalmologist's practice in the last 12 months and the frequency were surveyed in the German nationwide adult health survey wave 1 (DEGS1) study (baseline examination from 2008 to 2011, N = 7987, 52.6% women, age 18-79 years). Data on utilization were processed by taking the complex study design into consideration. Multivariable logistic regression analysis was used to determine associated factors including age, sex, socioeconomic status, place of residence, type of health insurance (e.g. statutory or private) and diabetes. RESULTS: Between the ages of 18 and 79 years, 29.3% of survey participants in Germany visited an ophthalmologist in the last year, while after the age of 60 years this was only 50.4%. Multivariable logistic regression analysis showed an association with female sex (odds ratio OR = 1.51, p < 0.001), older age, type of health insurance (private vs. statutory: OR = 0.77, p = 0.006) and diabetes (OR = 3.84, p < 0.001), but no association with socioeconomic status (p = 0.29) or place of residence (p = 0.06). CONCLUSION: Approximately one third of the German population visit an ophthalmologist at least once a year. Especially diabetics showed a high utilization of ophthalmological consultations, which could be based on the interdisciplinary guidelines for early detection of diabetic eye complications. PMID- 29110122 TI - [Suprachoroidal minimally invasive glaucoma surgery : Procedures and clinical outcome]. AB - The uveoscleral outflow route is via the ciliary muscles into the suprachoroidal spaces and then to the orbital blood and lymph systems. The main driving force behind this uveoscleral outflow is the high oncotic pressure in the choroidal vessels. Currently, the CyPass microstent is the only available suprachoroidal device for ab interno minimally invasive glaucoma surgery. The CyPass achieves a maximum reduction of intraocular pressure (IOP) to 16-17 mm Hg over 12-24 months and is approved for mild to moderate primary open-angle glaucoma. The CyPass is an easy to use minimally invasive glaucoma surgery stent operation and has few intraoperative as well as short and long-term complications. Postoperative management is unproblematic and the postoperative burden for patients is low, which leads to rapid recovery of patients; however, the correct selection of glaucoma patients is crucial for maintaining a sustainable success rate. Long term studies are necessary to demonstrate the persistence of the IOP lowering effect. PMID- 29110125 TI - [Laser-assisted blepharoplasty]. AB - Blepharoplasty is one of the most frequently performed plastic cosmetic interventions. For this purpose the CO2 laser is an instrument that can be used as a laser scalpel to cut as well as in its ablative function to remove skin irregularities, such as scars and tumors and also to treat changes of the skin due to aging. Fractionated laser irradiation reduces the duration of skin redness and the postoperative rehabilitation time after a resurfacing. The advantages of the CO2 laser are a gentle intraoperative preparation and less postoperative swelling due to an additional cauterization of blood vessels. Disadvantages are an increased occurrence of wound dehiscence and the high cost of instrumentation. Before performing a blepharoplasty an exact analysis of changes of the eyelid and also the wishes of the patients are necessary to establish the most suitable surgical procedure and the correct dosage. In addition to skin and fat resection, depending on the original situation it is possible to tighten slack skin with a resurfacing, to shift the fat compartments, to change the position of the eyebrows, to correct a ptosis and also to modulate the tension of the lid. The frequency of complications can be reduced by good planning of the surgical intervention. In the case of occurrence of complications, suitable treatment strategies should be available. PMID- 29110126 TI - [Lamellar macular holes with hyporeflective epiretinal proliferation : OCT diagnostics and clinical course]. AB - BACKGROUND: High-resolution spectral domain optical coherence tomography (SD-OCT) is the standard examination for assessment of lamellar macular holes (LMH). According to the current SD-OCT classification of LMHs, they are characterized by (1) an irregular foveal contour, (2) a defect in the inner fovea, and (3) a separation of inner retinal layers from outer retinal layers of the fovea leading to an intraretinal splitting with loss of retinal tissue. OBJECTIVE: The article aims to give an overview on the current knowledge of retinal imaging in LMH diagnostics and clinical course of disease. MATERIALS AND METHODS: This review is based on current literature and analyses of data from different case series from the Department of Ophthalmology, Ludwig-Maximilian University Munich, Germany. RESULTS: In eyes with LMH, a homogenous atypical, hyporeflective epiretinal tissue has been described in addition to conventional tractional epiretinal membranes (ERM). By SD-OCT, this named lamellar hole-associated epiretinal proliferation (LHEP) does not show common signs of traction and is characterized as a thick homogenous layer of moderately reflective material. LHEP has been demonstrated to be related to the occurrence of photoreceptor layer defects, enlargement of LMH diameter and poor visual acuity. CONCLUSION: The correlation of SD-OCT and en-face OCT can help to identify LMH subgroups and morphology progression early on. FAF enables detection of structural changes at a subclinical stage without visual deterioration. With regard to a high variability of intraretinal changes in LMHs and epimacular fibro-cellular proliferation, the current classification of LMH should be discussed and re-evaluated. PMID- 29110127 TI - [Atypical retinal vasculitis]. PMID- 29110130 TI - Improved diagnostic performance of transluminal attenuation gradient in combination with morphological evaluation of coronary artery stenosis using 320 row computed tomography. AB - PURPOSE: To assess the utility of transluminal attenuation gradient (TAG) in combination with coronary computed tomography angiography (CTA) for detecting obstructive coronary artery stenosis. MATERIALS AND METHODS: We retrospectively evaluated coronary CTA data in 35 consecutive patients who underwent invasive coronary angiography (ICA). We compared the diagnostic performance of TAG with that of quantitative coronary angiography, which we used as the reference standard. For the combination of TAG and coronary CTA, we designed a logical conjunction model (CCTA&&TAG) as well as a logical disjunction model (CCTA||TAG), and evaluated their diagnostic accuracies. RESULTS: Among 130 vessels of 35 patients, 30 lesions (23%) showed significant stenosis on ICA. TAG predicted significant coronary artery stenosis with a sensitivity of 75%, specificity of 63%, positive predictive value of 40%, negative predictive value of 89%, and accuracy of 66%, and had a cutoff value of - 15.4 HU/10 mm. The respective values for CCTA&&TAG were 73, 98, 88, 90, and 90%; those for CCTA||TAG were 94, 61, 56, 94, and 72%. CCTA&&TAG improved the diagnostic accuracy significantly more than CCTA||TAG. CONCLUSION: TAG in conjunction with coronary CTA improves the diagnostic accuracy of coronary CTA. PMID- 29110128 TI - Endoscopic treatments for portal hypertension. AB - Acute esophageal variceal hemorrhage is a dreaded complication of portal hypertension. Its management has evolved rapidly in recent years. Endoscopic therapy is often employed to arrest bleeding varices as well as to prevent early rebleeding. The combination of vasoconstrictor and endoscopic therapy is superior to vasoconstrictor or endoscopic therapy alone for control of acute esophageal variceal hemorrhage. After control of acute variceal bleeding, combination of banding ligation and beta-blockers is generally recommended to prevent variceal rebleeding. To prevent the catastrophic event of acute variceal bleeding, endoscopic banding ligation is an important tool in the prophylaxis of first bleeding. Endoscopic obturation with cyanoacrylate is usually utilized to arrest acute gastric variceal hemorrhage as well as to prevent rebleeding. It can be concluded that endoscopic therapies play a pivotal role in management of portal hypertensive bleeding. PMID- 29110129 TI - Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience. AB - PURPOSE AND PATIENTS: The M.O.S.CA.TI. (Metastases of the Skeleton from CArcinoma of the ThyroId) is a multicenter, retrospective study investigating the real-life outcome and management of bone metastases (BM) in 143 patients (63 M, 80 F; median age 64 years, range 11-87) with differentiated thyroid carcinoma (DTC). RESULTS: Radio-active iodine (RAI) treatment was performed in 131 patients (91.6%), surgical approach and/or external radiotherapy in 68 patients (47.6%), and anti-resorptive bone-active drugs in 32 patients (22.4%; in 31 zoledronate and in one denosumab). At the start of treatment, 24 patients (75.0%) receiving anti-resorptive bone-active drugs had at least one clinical skeletal-related event (SRE) (p < 0.001). One or more clinical SREs (pathological fractures and/or malignant hypercalcemia and/or spinal cord compression) developed in 53 patients (37.1%). Development of SREs was significantly associated with metachronous BM (hazard ratio (HR) 2.04; p = 0.04), localization of BM to cervical spine (HR 3.89; p = 0.01), and lack of avid RAI uptake (HR 2.66; p = 0.02). Thirty-nine patients (27.3%) died in correlation with development of SREs (HR 6.97; p = 0.006) and localization of BM to the hip (HR 3.86; p = 0.02). Moreover, overall mortality was significantly decreased by RAI therapy (HR 0.10; p = 0.02), whereas no significant effects were induced by bone-active drugs (p = 0.36), external radiotherapy (p = 0.54), and surgery (p = 0.43) of BM. CONCLUSIONS: SREs are very frequent in BM from DTC and they impact patient survival. In the real life, the use of bone-active drugs is currently limited to zoledronate in patients with pre existing SREs. In this clinical setting, RAI therapy, but not zoledronate, decreased mortality. PMID- 29110132 TI - Novel Mesenchymal Stem Cell Strategy in Alleviating Toll-Like Receptor-4, p53 and Nrf2 Signaling in Isoproterenol-Induced Myocardial Infarction in Rat Model. AB - Mesenchymal stem cells (MSCs) are multipotent stromal cells that merit the differentiation into various cell types. The present study was designed to test the hypothesis that the cardioprotective effect of MSCs transplantation and digoxin treatment is mediated via the regulation of messenger RNA gene expression of pro-inflammatory cytokines and apoptotic markers. Myocardial infarction was induced in Wistar rats via isoproterenol injection in a dose of (85 mg/kg, subcutaneously, twice at an interval of 24 h). Four weeks post-MSCs transplantation and digoxin treatment a significant reduction in serum cardiac markers, aspartate aminotransferase, creatine kinase-MB and troponine II was observed. Meanwhile, isoproterenol significantly reduced the gene and protein expression of the oxidative stress marker nuclear-related factor-2 (Nrf2) with a concomitant elevation in (MDA) level and inflammatory markers toll-like receptor 4 (TLR-4), intercellular adhesion molecules (ICAMs) and (VCAM-1). Moreover, apoptotic marker (P53) was significantly down-regulated. This was confirmed by histopathological investigations. It was hypothesized that MSCs transplantation was superior over digoxin treatment regimen in improving heart function. PMID- 29110131 TI - What Controls the Acute Viral Infection Following Yellow Fever Vaccination? AB - Does target cell depletion, innate immunity, or adaptive immunity play the dominant role in controlling primary acute viral infections? Why do some individuals have higher peak virus titers than others? Answering these questions is a basic problem in immunology and can be particularly difficult in humans due to limited data, heterogeneity in responses in different individuals, and limited ability for experimental manipulation. We address these questions for infections following vaccination with the live attenuated yellow fever virus (YFV-17D) by analyzing viral load data from 80 volunteers. Using a mixed effects modeling approach, we find that target cell depletion models do not fit the data as well as innate or adaptive immunity models. Examination of the fits of the innate and adaptive immunity models to the data allows us to select a minimal model that gives improved fits by widely used model selection criteria (AICc and BIC) and explains why it is hard to distinguish between the innate and adaptive immunity models. We then ask why some individuals have over 1000-fold higher virus titers than others and find that most of the variation arises from differences in the initial/maximum growth rate of the virus in different individuals. PMID- 29110133 TI - Recurrent pulmonary alveolar proteinosis in an immunocompromised host. PMID- 29110134 TI - Pneumomediastinum and pneumoperitoneum following partial sphincterotomy for choledocholithiasis. PMID- 29110135 TI - The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation. AB - The vestibulo-ocular reflex (VOR) is the main retinal image stabilising mechanism during rapid head movement. When the VOR does not stabilise the world or target image on the retina, retinal image slip occurs generating an error signal that drives the VOR response to increase or decrease until image slip is minimised, i.e. VOR adaptation occurs. Visual target contrast affects the human smooth pursuit and optokinetic reflex responses. We sought to determine if contrast also affected VOR adaptation. We tested 12 normal subjects, each over 16 separate sessions. For sessions 1-14, the ambient light level (lx) during adaptation training was as follows: dark, 0.1, 0.2, 0.3, 0.5, 0.7, 1, 2, 8, 16, 32, 64, 128 and 255 lx (light level for a typical room). For sessions 15-16, the laser target power (related to brightness) was halved with ambient light at 0 and 0.1 lx. The adaptation training lasted 15 min and consisted of left/right active head impulses. The VOR gain was challenged to increment, starting at unity, by 0.1 every 90 s for rotations to the designated adapting side and fixed at unity towards the non-adapting side. We measured active and passive VOR gains before and after adaptation training. We found that for both the active and passive VOR, there was a significant increase in gain only towards the adapting side due to training at contrast level 1.5 k and above (2 lx and below). At contrast level 261 and below (16 lx and above), adaptation training resulted in no difference between adapting and non-adapting side gains. Our modelling suggests that a contrast threshold of ~ 1000, which is 60 times higher than that provided by typical room lighting, must be surpassed for robust active and passive VOR adaptation. Our findings suggest contrast is an important factor for adaptation, which has implication for rehabilitation programs. PMID- 29110136 TI - Social participation and heat-related behavior in older adults during heat waves and on other days. AB - BACKGROUND: High indoor temperatures require behavioral adaptation, especially among vulnerable older adults. There are uncertainties as to the degree to which people adapt to these challenging conditions. OBJECTIVE: The aim of this study was to describe the degree of adaptation of social participation and other heat related behavior with respect to higher indoor temperatures. METHODS: In this study 81 residents from 10 sheltered living facilities (84% women, mean age 80.9 years) were visited every 4 weeks from May to October 2015 and additionally during 2 heat waves in July and August 2015. The indoor temperature, drinking and clothing and social participation were documented. Baseline documentation of gait speed and residential area were used to create subgroups of people with high or low gait speed and with facility location in a garden city/suburb or city/city center. RESULTS: Social participation and clothing decreased with -4.53 in the World Health Organization participation score units (95% confidence interval CI 5.32; -3.74) and -0.41 for clothing units (95% CI -0.46; -0.37) and volume of drinking increased (0.65 l/day; 95% CI 0.52; 0.77) per increase of indoor temperature by 10 degrees C. The negative association between indoor temperature and social life participation was stronger if functional capacity was low or if the facility was located in the city/city center. Not all older adults displayed temperature-related adaptive behavior. CONCLUSION: For older adults the negative association between indoor temperature and social life participation was stronger in the city/city center or if their functional capacity was low. Frequent personal contact and motivation of those who are frail might be helpful to support their adaptive behavior of drinking and clothing during heat stress. PMID- 29110137 TI - [Dementia friendly care services in general hospitals : Representative results of the general hospital study (GHoSt)]. AB - BACKGROUND: Mostly model projects report on special care services and procedures for general hospital patients with cognitive impairment. The objective of this study was to determine the frequency of special care services and procedures in general hospitals on the basis of a representative cross-sectional study. METHODS: From a list of all general hospitals in southern Germany we randomly selected a specified number of hospitals und somatic wards. The hospitals were visited and all older patients on the selected wards on that day were included in the study. Information about care services and their utilization was collected with standardized instruments. RESULTS: A total of 33 general hospitals and 172 wards participated in the study. The patient sample included 1469 persons over 65 (mean age 78.6 years) and 40% of the patients showed cognitive impairments. The staff reported that the most frequent measures for patients with cognitive impairments concerned patients with wandering behavior (63.1%), efforts to involve the patients' relatives to help with their daily care (60.1%), conducting nonintrusive interviews to identify cognitive impairments (59.9%), allocation to other rooms (58%) and visual aids for place orientation of patients (50.6%). In accordance with earlier studies our results show that other dementia friendly services implemented in pilot projects were rare. The existing special services for patients with cognitive impairment were rarely used by the patients or their relatives. DISCUSSION: The results demonstrate the urgent need to improve special care services and routines for identification of elderly patients with cognitive impairment and risk of delirium in general hospitals. PMID- 29110138 TI - Early plant growth and biochemical responses induced by Azospirillum brasilense Sp245 lipopolysaccharides in wheat (Triticum aestivum L.) seedlings are attenuated by procyanidin B2. AB - This study analyzes the effects of procyanidin B2 on early wheat plant growth and plant biochemical responses promoted by lipopolysaccharides (LPS) derived from the rhizobacteria Azospirillum brasilense Sp245. Measurements of leaf, root length, fresh weight, and dry weight showed in vitro plant growth stimulation 4 days after treatment with A. brasilense as well as LPS. Superoxide anion (O2.-) and hydrogen peroxide (H2O2) levels increased in seedling roots treated with LPS (100 MUg mL-1). The chlorophyll content in leaf decreased while the starch content increased 24 h after treatment in seedling roots. The LPS treatment induced a high increase in total peroxidase (POX) (EC 1.11.1.7) activity and ionically bound cell wall POX content in roots, when compared to respective controls. Early plant growth and biochemical responses observed in wheat seedlings treated with LPS were inhibited by the addition of procyanidin B2 (5 MUg mL-1), a B type proanthocyanidin (PAC), plant-derived polyphenolic compound with binding properties of LPS. All results suggest first that the ionically bound cell wall POX enzymes could be a molecular target of A. brasilense LPS, and second that the recognition or association of LPS by plant cells is required to activate plant responses. This last event could play a critical role during plant growth regulation by A. brasilense LPS. PMID- 29110140 TI - Economic Evaluation of Implementing a Novel Pharmacogenomic Test (IDgenetix(r)) to Guide Treatment of Patients with Depression and/or Anxiety. AB - BACKGROUND: The response to therapeutics varies widely in patients with depression and anxiety, making selection of an optimal treatment choice challenging. IDgenetix(r), a novel pharmacogenomic test, has been shown to improve outcomes by predicting the likelihood of response to different psychotherapeutic medications. OBJECTIVE: The objective of this study was to estimate the cost effectiveness of implementing a novel pharmacogenomic test (IDgenetix(r)) to guide treatment choices in patients with depression and/or anxiety compared with treatment as usual from the US societal perspective. METHODS: We developed a discrete event simulation to compare clinical events, quality-adjusted life-years, and costs of the two treatment strategies. Target patients had a Hamilton Rating Scale for Depression Score >= 20 and/or a Hamilton Rating Scale for Anxiety score >= 18 at baseline. Remission, response, and no response were simulated based on the observed rates in the IDgenetix(r) randomized controlled trial. Quality-adjusted life-years and direct and indirect costs attributable to depression and anxiety were estimated and compared over a 3 year time horizon. We conducted extensive deterministic and probabilistic sensitivity analyses to assess the robustness of the results. RESULTS: The model predicted cumulative remission rates of 78 and 66% in IDgenetix(r) and treatment as usual groups, respectively. Estimated discounted quality-adjusted life-years were 2.09 and 1.94 per patient for IDgenetix(r) and treatment as usual, respectively, which resulted in 0.15 incremental quality-adjusted life-years (95% credible interval 0.04-0.28). The total costs after accounting for a US$2000 test cost were US$14,124 for IDgenetix(r) compared with US$14,659 for treatment as usual, suggesting a US$535 (95% credible interval - 2902 to 1692) cost saving per patient in the IDgenetix(r) group. Incremental quality-adjusted life-year gain (0.49) and cost savings (US$6800) were substantially larger in patients with severe depression (Hamilton Rating Scale for Depression score >= 25). CONCLUSION: Using the IDgenetix(r) test to guide the treatment of patients with depression and anxiety may be a dominant strategy, as it improves quality-adjusted life years and decreases overall costs over a 3-year time horizon. PMID- 29110139 TI - The Place of Antipsychotics in the Therapy of Anxiety Disorders and Obsessive Compulsive Disorders. AB - PURPOSE OF REVIEW: The purpose of this review was to assess and present the findings up to this date on the efficacy of antipsychotics in the treatment of generalized anxiety disorders (GAD), social anxiety disorders (SAD), panic disorders (PD), and obsessive-compulsive disorders (OCD), mostly based on published randomized controlled trials (RCTs) or on open-label studies when RCT were lacking. RECENT FINDINGS: Quetiapine could be recommended in patients with GAD. The efficacy of aripiprazole in two open-label studies on patients with antidepressant-refractory GAD should be assessed in RCTs. Despite preliminary positive results in open studies, there are currently no strong evidence for the effectiveness of antipsychotics in refractory SAD and in refractory PD. Conversely, risperidone and aripiprazole can be used for the treatment of refractory OCD as augmentation agents to antidepressants. Contrary to SAD and PD, this review found evidence for the use of second-generation antipsychotics in GAD and OCD. Otherwise, first-generation antipsychotics cannot be recommended in anxiety disorders and OCD. PMID- 29110141 TI - Oncology Modeling for Fun and Profit! Key Steps for Busy Analysts in Health Technology Assessment. AB - In evaluating new oncology medicines, two common modeling approaches are state transition (e.g., Markov and semi-Markov) and partitioned survival. Partitioned survival models have become more prominent in oncology health technology assessment processes in recent years. Our experience in conducting and evaluating models for economic evaluation has highlighted many important and practical pitfalls. As there is little guidance available on best practices for those who wish to conduct them, we provide guidance in the form of 'Key steps for busy analysts,' who may have very little time and require highly favorable results. Our guidance highlights the continued need for rigorous conduct and transparent reporting of economic evaluations regardless of the modeling approach taken, and the importance of modeling that better reflects reality, which includes better approaches to considering plausibility, estimating relative treatment effects, dealing with post-progression effects, and appropriate characterization of the uncertainty from modeling itself. PMID- 29110142 TI - An outbreak of skin infections in neonates due to a Staphylococcus aureus strain producing the exfoliative toxin A. AB - PURPOSE: Staphylococcus aureus is an important cause of infections in hospitalized neonates. Preterm or low birthweight infants are especially at risk to develop a S. aureus infection due to the immaturity of the immune system, length of hospital stay and invasive procedures. Exfoliative toxin (ET)-producing S. aureus is often responsible for neonatal infections, causing clinical manifestations such as staphylococcal scalded skin syndrome, characterized by both localized blisters or generalized exfoliation of the skin. METHODS: We describe an outbreak due to an S. aureus strain producing ETA occurring in a local hospital in Northern Italy. Molecular typing of the isolates included spa typing and multilocus sequence typing. DNA microarray hybridization was also performed on one representative strain. RESULTS: In the period from July 2013 to February 2014, 12 neonates presented with skin infections, mainly bullae or pustules. Cultures of skin swabs yielded methicillin-susceptible S. aureus (MSSA). By molecular typing, an epidemic strain (t1393/ST5) was identified in nine neonates; microarray analysis and PCR revealed that it contained the ETA encoding gene. Screening of staff, mothers and healthy neonates and environmental cultures did not reveal the presence of the epidemic strain. However, the father of an infected neonate was found to be a carrier of MSSA t1393 five months after the outbreak started. CONCLUSION: Implementation of hygiene procedures and sanitization of the ward twice terminated the outbreak. Timely surveillance of infections, supported by molecular typing, is fundamental to prevent similar episodes among neonates. PMID- 29110144 TI - New formulation and approach for mucoadhesive buccal film of rizatriptan benzoate. AB - Mucoadhesive buccal film is developed as a promising dosage form, which has prominent advantages because of drug delivery through buccal mucosa. New formulation of buccal films containing rizatriptan benzoate (RB) was prepared by solvent casting method using various concentrations of hydroxypropyl methylcellulose (HPMC K4M), polyvinyl alcohol (PVA), polyethylene oxide (PEO), glycerol, stevia, and goat buccal mucosa used as a model membrane. In this work, the effect of polymers and plasticizer concentrations on drug release profile, disintegration and dissolution time, mechanical properties, and mucoadhesive characteristics of films was studied. Scanning electron microscopy analysis revealed uniform distribution of RB in film formulations. Chemical compounds and thermal analysis of the films were studied by Fourier transform infrared spectroscopy and differential scanning calorimetry, respectively. The buccal films produced were uniform in drug content and thickness. All formulations have in vitro release of 98-102% between 40 and 80 min. Also ex vivo mucoadhesion strength was in the range of 0.205 +/- 0.035 to 0.790 +/- 0.014 N for all formulations. A formulation consisting RB (50 mg), HPMC K4M, PVA, and PEO (63 mg), glycerol (1.5 ml), stevia (5 mg) was selected as our optimum composition. More satisfactory results were obtained in terms of disintegration and dissolution time, mechanical properties, and mucoadhesive characteristics. In addition, it showed about 99.89% RB released in 45 min. The results suggest that RB-loaded mucoadhesive buccal films could be a potential candidate to achieve optimum drug release for effective treatment of migraine. PMID- 29110145 TI - Cohort Measures of Internal Migration: Understanding Long-Term Trends. AB - Internal migration intensities fluctuate over time, but both migration levels and trends show great diversity. The dynamics underpinning these trends remain poorly understood because they are analyzed almost exclusively by applying period measures to cross-sectional data. This article proposes 10 cohort measures that can be applied to both prospective and retrospective data to systematically examine long-term trends. To demonstrate their benefits, the proposed measures are applied to retrospective survey data for England that provide residential histories from birth to age 50 for cohorts born between 1918 and 1957. The analysis reveals stable lifetime migration for men but increased lifetime migration for women associated with earlier ages at moving in adulthood and a compression of intervals between consecutive moves. The proposed cohort measures provide a more comprehensive picture of migration behavior and should be used to complement period measures in exploring long-term trends. Increasing availability of retrospective and longitudinal survey data means that researchers can now apply the proposed measures to a wide range of countries. PMID- 29110143 TI - Pharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review. AB - PURPOSE: Ceftazidime-avibactam is an antimicrobial association active against several Enterobacteriaceae species, including those resistant to carbapenem. Considering the importance of this drug in the current panorama of multidrug resistant bacteria, we performed a systematic review about ceftazidime-avibactam with emphasis on clinical and pharmacological published data. METHODS: A systematic search of the medical literature was performed. The databases searched included MEDLINE, EMBASE and Web of Science (until September 2017). The search terms used were 'avibactam', 'NXL104' and 'AVE1330A'. Bibliographies from those studies were also reviewed. Ceftazidime was not included as a search term, once relevant studies about avibactam in association with other drugs could be excluded. Only articles in English were selected. No statistical analysis or quality validation was included in this review. RESULTS: A total of 151 manuscripts were included. Ceftazidime-avibactam has limited action against anaerobic bacteria. Avibactam is a potent inhibitor of class A, class C, and some class D enzymes, which includes KPC-2. The best pharmacodynamic profile of ceftazidime-avibactam is fT > MIC, validated in an animal model of soft tissue infection. Three clinical trials showed the efficacy of ceftazidime-avibactam in patients with intra-abdominal and urinary infections. Ceftazidime-avibactam has been evaluated versus meropenem/doripenem in hospitalized adults with nosocomial pneumonia, neutropenic patients and pediatric patients. CONCLUSION: Ceftazidime avibactam has a favorable pharmacokinetic profile for severe infections and highly active against carbapenemases of KPC-2 type. PMID- 29110147 TI - Correction to: Villaret syndrome as clinical presentation of occult metastatic breast cancer. AB - The author's given name and family name were initially interchanged inadvertently. The correct names have been corrected above. The original article was corrected. PMID- 29110146 TI - Atherosclerosis, Periodontal Disease, and Treatment with Resolvins. AB - PURPOSE OF REVIEW: This review aims to discuss the existing evidence on the link between atherosclerosis and periodontitis by particularly presenting new findings that link the pathology and therapy of these diseases. Acute vascular ischemic events that can lead to stroke or myocardial infarction are initiated by inflammatory processes leading to rupture or erosion of plaques susceptible to thrombosis ("high risk" or "vulnerable"). These are highly inflamed plaques residing in the media and adventitia that may not be detected by angiography measurments of luminal narrowing. Statistically significant excess risk for atherosclerotic cardiovascular disease has been reported in persons with periodontitis independent of established risk factors. We hypothesized that the systemic pathologic links also represent potential therapeutic links. RECENT FINDINGS: We recently demonstrated that periodontal inflammation promotes atherosclerotic plaque inflammation and destabilization. As discrete pathological regions, these plaques with a high susceptibility to rupture can be imaged and differentiated from lower risk plaques. In cholesterol-fed rabbits with periodontal disease, circulating inflammatory mediators were also significantly elevated thereby contributing to "vulnerable blood," a systemic characteristic of high risk for cardiovascular events. New studies show that certain lipid mediators, including lipoxins and resolvins, are potent in preventing and possibly treating a number of inflammation-associated diseases, including periodontitis and vascular inflammation. The concept of the vulnerable patient and the pro-resolving approach open new terrain for discovery of paradigm changing therapies for the prevention and treatment of two of the most common diseases of man. Importantly, lipoxins and resolvins are natural receptor agonists that do not exhibit the same pro-atherogenic side effects attributed to anti-inflammatory medications (e.g., NSAIDs) but rather coordinate resolution of inflammation and a return to homeostasis. PMID- 29110148 TI - Association between VDR polymorphisms and multiple sclerosis: systematic review and updated meta-analysis of case-control studies. AB - Vitamin D receptor (VDR) polymorphisms have been inconsistently investigated in multiple sclerosis (MS). However, published studies demonstrated differences concerning design and effect size. A meta-analysis is necessary to determine the magnitude of the association between VDR polymorphisms and MS risk. The aim of the current study was to quantify the magnitude of the association between BsmI, FokI, ApaI, and TaqI VDR polymorphisms and MS risk. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic search and meta-analysis of the VDR gene polymorphisms and the risk of MS. The pooled odds ratios (OR) and 95% confidence interval (CI) were calculated by using Stata Version 11.0 with dominant and recessive models and allele analyses. A total of 4013 cases and 4218 controls in 24 case-control studies were included in the meta-analyses. The results did not indicate an association between any of the VDR polymorphisms and the risk of MS among overall populations, Asians, and Caucasians. However, our subgroup analysis suggests that the A allele was associated with MS risk in Asian populations (P = 0.005, OR = 1.267, 95% CI 1.074-1.496). Interestingly, the sensitivity analysis excluding studies with controls not in HWE showed insignificant association between the A allele and MS risk (P = 0.211), which was different from those in the non sensitivity analysis. Our preliminary results indicate the VDR gene ApaI, BsmI, FokI, and TaqI polymorphisms may not be associated with elevated MS risk among overall populations. But ApaI polymorphism may confer different susceptibility to MS among different populations, and more well-designed studies with a large sample size are still needed to validate our results. PMID- 29110150 TI - The effect of an aerobic exercise bout 24 h prior to each doxorubicin treatment for breast cancer on markers of cardiotoxicity and treatment symptoms: a RCT. AB - PURPOSE: In rodents, a single exercise bout performed 24 h prior to a single doxorubicin treatment provides cardio-protection. This study investigated whether performing this intervention prior to every doxorubicin treatment for breast cancer reduced subclinical cardiotoxicity and treatment symptoms. METHODS: Twenty four women with early stage breast cancer were randomly assigned to perform a 30 min, vigorous-intensity treadmill bout 24 h prior to each of four doxorubicin containing chemotherapy treatments or to usual care. Established echocardiographic and circulating biomarkers of subclinical cardiotoxicity, as well as blood pressure and body weight were measured before the first and 7-14 days after the last treatment. The Rotterdam symptom checklist was used to assess patient-reported symptoms. RESULTS: The exercise and usual care groups did not differ in the doxorubicin-related change in longitudinal strain, twist, or cardiac troponin. However, the four total exercise bouts prevented changes in hemodynamics (increased cardiac output, resting heart rate, decreased systemic vascular resistance, p < 0.01) and reduced body weight gain, prevalence of depressed mood, sore muscles, and low back pain after the last treatment (p < 0.05) relative to the usual care group. No adverse events occurred. CONCLUSIONS: An exercise bout performed 24 h prior to every doxorubicin treatment did not have an effect on markers of subclinical cardiotoxicity, but had a positive systemic effect on hemodynamics, musculoskeletal symptoms, mood, and body weight in women with breast cancer. A single exercise bout prior to chemotherapy treatments may be a simple clinical modality to reduce symptoms and weight gain among women with breast cancer. PMID- 29110151 TI - Patient-reported factors associated with adherence to adjuvant endocrine therapy after breast cancer: an integrative review. AB - BACKGROUND: Adjuvant endocrine therapy (AET) significantly reduces recurrence and mortality in women with breast cancer (BrCa). Despite the efficacy of AET in improving BrCa outcomes, up to 50% of women do not adhere to prescribed AET regimens. While numerous demographic and clinical predictors influence adherence and persistence, few studies have identified the patient-reported factors that influence AET adherence and persistence. PURPOSE: The aim was to examine the patient-reported personal, social, and structural factors influencing BrCa survivors' adherence and persistence with AET. METHODS: An integrative review was undertaken wherein PubMed, Medline, CINAHL, Embase, and PsycINFO databases were searched using keyword descriptors and database subject headings. Inclusion criteria included quantitative or qualitative peer-reviewed studies written in English that assessed AET adherence and/or persistence through objective measurement or self-report and included patient-reported factors found to influence adherence and/or persistence. The data extracted from eligible studies were entered into a matrix, and systematically compared and iteratively analyzed using relational autonomy as an organizing theoretical framework. RESULTS: A total of 43 manuscripts (9 qualitative and 34 quantitative) were reviewed. Several personal, social, and structural factors were identified that influenced AET adherence and persistence, including side effects, necessity beliefs, self efficacy, the patient-healthcare provider relationship, social support, and continuity of follow-up care. CONCLUSIONS: An increasing number of studies have focused on identifying the patient-reported factors that influence AET adherence and persistence. This review highlights important personal, social, and structural factors that act as facilitators and barriers in adhering to and persisting with long-term AET. Acknowledging and addressing these factors is key to providing women with the care needed to improve suboptimal adherence and persistence. PMID- 29110152 TI - Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. AB - PURPOSE: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy. PATIENTS AND METHODS: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER) positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR). RESULTS: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006). CONCLUSION: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy. PMID- 29110153 TI - Protection by mTOR Inhibition on Zymosan-Induced Systemic Inflammatory Response and Oxidative/Nitrosative Stress: Contribution of mTOR/MEK1/ERK1/2/IKKbeta/IkappaB-alpha/NF-kappaB Signalling Pathway. AB - Mammalian target of rapamycin (mTOR), a serine/threonine kinase regulate variety of cellular functions including cell growth, differentiation, cell survival, metabolism, and stress response, is now appreciated to be a central regulator of immune responses. Because mTOR inhibitors enhanced the anti-inflammatory activities of regulatory T cells and decreased the production of proinflammatory cytokines by macrophages, mTOR has been a pharmacological target for inflammatory diseases. In this study, we examined the role of mTOR in the production of proinflammatory and vasodilator mediators in zymosan-induced non-septic shock model in rats. To elucidate the mechanism by which mTOR contributes to non-septic shock, we have examined the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system caused by mTOR/mitogen-activated protein kinase kinase (MEK1)/extracellular signal-regulated kinase (ERK1/2)/inhibitor kappaB kinase (IKKbeta)/inhibitor of kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF kappaB) signalling pathway activation. After 1 h of zymosan (500 mg/kg, i.p.) administration to rats, mean arterial blood pressure (MAP) was decreased and heart rate (HR) was increased. These changes were associated with increased expression and/or activities of ribosomal protein S6, MEK1, ERK1/2, IKKbeta, IkappaB-alpha and NF-kappaB p65, and NADPH oxidase system activity in cardiovascular and renal tissues. Rapamycin (1 mg/kg, i.p.), a selective mTOR inhibitor, reversed these zymosan-induced changes in these tissues. These observations suggest that activation of mTOR/MEK1/ERK1/2/IKKbeta/IkappaB-alpha/NF kappaB signalling pathway with proinflammatory and vasodilator mediator formation and NADPH oxidase system activity contributes to systemic inflammation in zymosan induced non-septic shock. Thus, mTOR may be an optimal target for the treatment of the diseases characterized by the severe systemic inflammatory response. PMID- 29110155 TI - Streptomyces swartbergensis sp. nov., a novel tyrosinase and antibiotic producing actinobacterium. AB - As part of an antibiotic screening program, an actinobacterium, strain HMC13T, was isolated from soil collected from the banks of the Gamka River, Western Cape Province, South Africa. The isolate was found to produce branched mycelia that differentiated into spiral spore chains with spiny spores. 16S rRNA gene sequence analysis showed the strain to be closely related to Streptomyces caelestis NRRL 2418T (99.72%) and Streptomyces azureus NBRC 12744T (99.51%). Chemotaxonomic analyses confirmed the classification of the strain as a member of the genus Streptomyces: LL-DAP in the peptidoglycan, no diagnostic sugars in the whole cell sugar pattern, dominant menaquinones including MK9(H8), MK9(H6), and the polar lipids detected included phosphatidylethanolamine. The fatty acid profile revealed the presence of mostly branched, saturated fatty acids: iso-C15:0 (14.4%), anteiso-C15:0 (21.1%), iso-C16:0 (16.8%), C16:1omega7c/2-OH iso-C15:0 (5.8%), C16:0 (6.2%), iso-C17:1omega9c (5.8%), iso-C17:0 (5.9%), and anteiso C17:0 (9.6%). Strain HMC13T is a tyrosinase producer and exhibits very strong antibiosis against Mycobacterium aurum A+ and Staphylococcus aureus subsp. aureus ATCC 33591 (methicillin resistant), while only weak activity was observed against Bacillus cereus ATCC 10876, Enterococcus faecium VanA (vancomycin resistant), Enterococcus faecalis ATCC 51299 (vancomycin resistant) and Candida tropicalis ATCC 750T. Strain HMC13T (= LMG 28849T = NRRL B-65294T) is proposed as the type strain of a new species, to be named Streptomyces swartbergensis sp. nov. PMID- 29110154 TI - RX-207, a Small Molecule Inhibitor of Protein Interaction with Glycosaminoglycans (SMIGs), Reduces Experimentally Induced Inflammation and Increases Survival Rate in Cecal Ligation and Puncture (CLP)-Induced Sepsis. AB - The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis. PMID- 29110156 TI - Microbiota associated with tubes of Escarpia sp. from cold seeps in the southwestern Atlantic Ocean constitutes a community distinct from that of surrounding marine sediment and water. AB - As the depth increases and the light fades in oceanic cold seeps, a variety of chemosynthetic-based benthic communities arise. Previous assessments reported polychaete annelids belonging to the family Siboglinidae as part of the fauna at cold seeps, with the 'Vestimentifera' clade containing specialists that depend on microbial chemosynthetic endosymbionts for nutrition. Little information exists concerning the microbiota of the external portion of the vestimentiferan trunk wall. We employed 16S rDNA-based metabarcoding to describe the external microbiota of the chitin tubes from the vestimentiferan Escarpia collected from a chemosynthetic community in a cold seep area at the southwestern Atlantic Ocean. The most abundant operational taxonomic unit (OTU) belonged to the family Pirellulaceae (phylum Planctomycetes), and the second most abundant OTU belonged to the order Methylococcales (phylum Proteobacteria), composing an average of 21.1 and 15.4% of the total reads on tubes, respectively. These frequencies contrasted with those from the surrounding environment (sediment and water), where they represent no more than 0.1% of the total reads each. Moreover, some taxa with lower abundances were detected only in Escarpia tube walls. These data constitute on the first report of an epibiont microbial community found in close association with external surface of a cold-seep metazoan, Escarpia sp., from a chemosynthetic community in the southwestern Atlantic Ocean. PMID- 29110157 TI - Streptomyces thermoalkaliphilus sp. nov., an alkaline cellulase producing thermophilic actinomycete isolated from tropical rainforest soil. AB - During an investigation exploring potential sources of novel thermophilic species and natural products, a novel thermophilic and alkaliphilic actinomycete with alkaline cellulase producing ability, designated strain 4-2-13T, was isolated from soil of a tropical rainforest in Xishuangbanna, Yunnan province, China. The morphological and chemotaxonomic characteristics of strain 4-2-13T are consistent with those of the members of the genus Streptomyces. The strain forms extensively branched aerial mycelia and substrate mycelia. Spiral spore chains were observed on aerial mycelia; spores were oval to cylindrical, with smooth surfaces. The organism was found to contain LL-diaminopimelic acid as the diagnostic diamino acid in the cell wall peptidoglycan. The whole cell hydrolysates were found to contain glucose and ribose. The cellular fatty acid profile mainly consists of anteiso-C17:0 and iso-C16:0. The menaquinones were identified as MK-9(H8), MK 10(H6) and MK-9(H6). The polar lipids profile were found to consist of diphosphatidylglycerol, phosphatidylmethylethanolamine, a ninhydrin-positive glycophospholipid, phosphatidylinositol, phosphatidylglycerol and unidentified glycolipids. The 16S rRNA gene sequence analysis showed that the organism belongs to the genus Streptomyces and in the 16S rRNA gene tree it formed a distinct phyletic line together with the closely related type strain Streptomyces burgazadensis Z1R7T (95.2% sequence similarity). However, the phenotypic characteristics of strain 4-2-13T are significantly different from those of S. burgazadensis Z1R7T. Based on the phenotypic, chemotaxonomic and phylogenetic characteristics, strain 4-2-13T represents a novel species in the genus Streptomyces, for which the name Streptomyces thermoalkaliphilus sp. nov. is proposed. The type strain is 4-2-13T (= DSM 42159T = CGMCC 4. 7205T). PMID- 29110158 TI - Factors Predicting Ethiopian Anesthetists' Intention to Leave Their Job. AB - BACKGROUND: Ethiopia has rapidly expanded training programs for associate clinician anesthetists in order to address shortages of anesthesia providers. However, retaining them in the public health sector has proven challenging. This study aimed to determine anesthetists' intentions to leave their jobs and identify factors that predict turnover intentions. METHODS: A nationally representative, cross-sectional survey of 251 anesthetists working in public sector hospitals in Ethiopia was conducted in 2014. Respondents were asked whether they planned to leave the job in the next year and what factors they considered important when making decisions to quit. Bivariate and multivariable logistic regressions were conducted to investigate 16 potential predictors of turnover intentions, including personal and facility characteristics as well as decision-making factors. RESULTS: Almost half (n = 120; 47.8%) of anesthetists planned to leave their jobs in the next year, and turnover intentions peaked among those with 2-5 years of experience. Turnover intentions were not associated with the compulsory service obligation. Anesthetists rated salary and opportunities for professional development as the most important factors in decisions to quit. Five predictors of turnover intentions were significant in the multivariable model: younger age, working at a district rather than regional or referral hospital, the perceived importance of living conditions, opportunities for professional development, and conditions at the workplace. CONCLUSIONS: Human resources strategies focused on improving living conditions for anesthetists and expanding professional development opportunities may increase retention. Special attention should be focused on younger anesthetists and those posted at district hospitals. PMID- 29110159 TI - Measuring Decision-Making During Thyroidectomy: Validity Evidence for a Web-Based Assessment Tool. AB - BACKGROUND: Errors in judgment during thyroidectomy can lead to recurrent laryngeal nerve injury and other complications. Despite the strong link between patient outcomes and intraoperative decision-making, methods to evaluate these complex skills are lacking. The purpose of this study was to develop objective metrics to evaluate advanced cognitive skills during thyroidectomy and to obtain validity evidence for them. METHODS: An interactive online learning platform was developed ( www.thinklikeasurgeon.com ). Trainees and surgeons from four institutions completed a 33-item assessment, developed based on a cognitive task analysis and expert Delphi consensus. Sixteen items required subjects to make annotations on still frames of thyroidectomy videos, and accuracy scores were calculated based on an algorithm derived from experts' responses ("visual concordance test," VCT). Seven items were short answer (SA), requiring users to type their answers, and scores were automatically calculated based on their similarity to a pre-populated repertoire of correct responses. Test-retest reliability, internal consistency, and correlation of scores with self-reported experience and training level (novice, intermediate, expert) were calculated. RESULTS: Twenty-eight subjects (10 endocrine surgeons and otolaryngologists, 18 trainees) participated. There was high test-retest reliability (intraclass correlation coefficient = 0.96; n = 10) and internal consistency (Cronbach's alpha = 0.93). The assessment demonstrated significant differences between novices, intermediates, and experts in total score (p < 0.01), VCT score (p < 0.01) and SA score (p < 0.01). There was high correlation between total case number and total score (rho = 0.95, p < 0.01), between total case number and VCT score (rho = 0.93, p < 0.01), and between total case number and SA score (rho = 0.83, p < 0.01). CONCLUSION: This study describes the development of novel metrics and provides validity evidence for an interactive Web-based platform to objectively assess decision-making during thyroidectomy. PMID- 29110160 TI - Disability at Work: A Look Back and Forward. AB - Purpose This article presents new evidence on employment barriers and workplace disparities facing employees with disabilities, linking the disparities to employee attitudes. Methods Analyses use the 2006 General Social Survey to connect disability to workplace disparities and attitudes in a structural equation model. Results Compared to employees without disabilities, those with disabilities report: lower pay levels, job security, and flexibility; more negative treatment by management; and, lower job satisfaction but similar organizational commitment and turnover intention. The lower satisfaction is mediated by lower job security, less job flexibility, and more negative views of management and co-worker relations. Conclusion Prior research and the present findings show that people with disabilities experience employment disparities that limit their income, security, and overall quality of work life. Technology plays an increasingly important role in decreasing employment disparities. However, there also should be increased targeted efforts by government, employers, insurers, occupational rehabilitation providers, and disability groups to address workplace barriers faced by employees with disabilities, and by those with disabilities seeking to return to work. PMID- 29110161 TI - Association Between Small Intestinal Bacterial Overgrowth by Glucose Breath Test and Coronary Artery Disease. AB - BACKGROUND: A possible role of gut bacteria and their metabolic by-products in the development of coronary artery disease (CAD) is suspected. There is a lack of studies evaluating the association of small intestinal bacterial overgrowth (SIBO) with the development of CAD. AIM: To evaluate the frequency and risk factors for angiography-confirmed CAD in patients with or without SIBO. METHODS: A total of 1059 patients tested for SIBO using the glucose hydrogen/methane breath test from 2006 to 2014 were evaluated. In total, 160 had coronary artery angiography and were included in the study. SIBO-positive patients were compared to SIBO-negative patients. Demographic, clinical, and laboratory variables and the presence of CAD on coronary angiography were analyzed. RESULTS: Patients with SIBO had a higher frequency of CAD (78.9 vs. 38.6%, p < 0.001), diabetes mellitus (40.0 vs. 22.9%, p = 0.016), chronic kidney disease (26.7 vs. 12.9%, p = 0.025), use of angiotensin conversion enzyme inhibitor/blocker (45.5 vs. 32.9%, p = 0.008), and statins (75.6 vs. 61.4%, p = 0.004). Patients with SIBO had an increased number of coronary arteries affected compared to SIBO-negative patients (1-vessel disease 67.2 vs. 32.8%, p < 0.001; 2-vessel disease 85.7 vs. 14.3%, p < 0.001; and 3-vessel disease 82.4 vs. 17.6%, p < 0.001, respectively). In the stepwise multivariate logistic regression analysis, SIBO remained an independent risk factor for CAD (odds ratio 7.18, 95% confidence interval 3.09-16.67; p < 0.001). CONCLUSION: SIBO was found to be associated with CAD and with the number of coronary arteries involved in this study from a single tertiary center. Further studies are necessary to confirm the association of SIBO with CAD. In the presence of risk factors, patients with SIBO may benefit from assessment for CAD. PMID- 29110163 TI - Selenite removal and reduction by growing Aspergillus sp. J2. AB - In this study, the removal and reduction of selenite [Se(IV)] by growing Aspergillus sp. J2 were investigated. The lag phase, growth rate and biomass of J2 was not significantly influenced by the presence of 100 mg/L Se(IV). A rapid Se(IV) removal process took place from the 3rd to the 4th day during the growth of J2. Scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy and X-ray diffraction analyses showed that the Se(IV) did not cause any visible effects on cell morphology and the reduced amorphous elemental selenium [Se(0)] nanoparticles were mainly on the surface of the mycelial cell walls. The macromolecules containing amine groups also interact with Se(IV) and could play an important role in Se(IV) removal by J2. PMID- 29110164 TI - Study on a Novel Binary Zn n Eu Layered Double Hydroxide with Excellent Fluorescence. AB - A group of binary ZnnEu-LDHs with Zn2+/Eu3+ molar ratios of 5.0, 6.0, 7.0, and 8.0 have been obtained in ammonia water media by hydrothermal treatment. The structure, composition, and fluorescent property of samples have been investigated using various techniques. Compositional analyses revealed that the composition of samples was in agreement with that of the initial reactants. X-ray diffraction (XRD) suggested that the ZnnEu-LDHs exhibited typical layered structure with orthorhombic symmetry. All the ZnnEu-LDHs appeared strong red emissions attributed to 5D0 -> 7F J (J = 1, 2) transitions of Eu3+. Moreover, the intensity of emissions due to 5D0 -> 7FJ (J = 1, 2) transitions of Eu3+ tended to increase with the Zn2+/Eu3+ molar ratio varied from 8.0, 7.0 to 6.0, then decreased as the Zn2+/Eu3+ molar ratio reduced to 5.0. The strongest fluorescence was found to be at Zn2+/Eu3+ molar ratio of 6.0. Further the fluorescence decay spectra show that the Zn n Eu-LDH have similar behavior of fluorescent decay and decayed more slowly than that of the Eu(OH)3. These results indicate that the novel binary ZnnEu-LDHs have better fluorescent property and may be potential application as fluorescent materials. PMID- 29110165 TI - Spectral Properties and Possibilities of meso-Substituted BODIPY Usage in Sol-Gel Process and Materials. AB - Hybrid materials based on organically modified silica with immobilized boron dipyrrins (BODIPY) dyes were obtained. Spectral characteristics of the dyes were measured during the matrix formation and in obtained materials. It was stated, that immobilization does not affect the character of the absorption and fluorescence spectra of the dye, but due to the effect of fluorescent molecular rotor observed for meso-substituted BODIPY, the fluorescent quantum yields were found to increase during the matrix sealing. Quantum yield increase is linear for all of the investigated matrices except phenyl-substituted one, where the pi-pi interactions of the dye molecule with matrix could be observed. This effect could be used for fine control of the matrix formation process and leads to increase of the dye emission in the final material for further practical applications. All obtained hybrid materials were found to be stable upon UV light irradiation, hence immobilization enhance the stability of the dye in comparison with the BODIPY in organic solvents. PMID- 29110162 TI - Recent Advances in the Pharmacological Management of Gastroesophageal Reflux Disease. AB - The management of proton pump inhibitor-refractory GERD (rGERD) is a challenge in clinical practice. Since up to one-third of patients with typical GERD symptoms (heartburn and/or acid regurgitation) are not satisfied with proton pump inhibitor (PPI) therapy, new drug development targeting different pathophysiologies of GERD is imperative. At present, no other drugs serve as a more potent acid suppression agent than PPIs. As an add-on therapy, histamine type-2 receptor antagonists, alginates, prokinetics and transient lower esophageal sphincter relaxation inhibitors have some impact on the subgroups of rGERD, but greater effectiveness and fewer adverse effects for widespread use are required. Visceral hypersensitivity also contributes to the perception of GERD symptoms, and neuromodulators including antidepressants play a role in this category. Esophageal pH-impedance monitoring helps to distinguish functional heartburn from true GERD, and psychologic medication and cognitive behavior therapy are further therapy options instead of PPIs. PMID- 29110166 TI - Effect of battery longevity on costs and health outcomes associated with cardiac implantable electronic devices: a Markov model-based Monte Carlo simulation. AB - INTRODUCTION: The effects of device and patient characteristics on health and economic outcomes in patients with cardiac implantable electronic devices (CIEDs) are unclear. Modeling can estimate costs and outcomes for patients with CIEDs under a variety of scenarios, varying battery longevity, comorbidities, and care settings. The objective of this analysis was to compare changes in patient outcomes and payer costs attributable to increases in battery life of implantable cardiac defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-D). METHODS AND RESULTS: We developed a Monte Carlo Markov model simulation to follow patients through primary implant, postoperative maintenance, generator replacement, and revision states. Patients were simulated in 3-month increments for 15 years or until death. Key variables included Charlson Comorbidity Index, CIED type, legacy versus extended battery longevity, mortality rates (procedure and all-cause), infection and non-infectious complication rates, and care settings. Costs included procedure-related (facility and professional), maintenance, and infections and non-infectious complications, all derived from Medicare data (2004-2014, 5% sample). Outcomes included counts of battery replacements, revisions, infections and non-infectious complications, and discounted (3%) costs and life years. An increase in battery longevity in ICDs yielded reductions in numbers of revisions (by 23%), battery changes (by 44%), infections (by 23%), non-infectious complications (by 10%), and total costs per patient (by 9%). Analogous reductions for CRT-Ds were 23% (revisions), 32% (battery changes), 22% (infections), 8% (complications), and 10% (costs). CONCLUSION: Based on modeling results, as battery longevity increases, patients experience fewer adverse outcomes and healthcare costs are reduced. Understanding the magnitude of the cost benefit of extended battery life can inform budgeting and planning decisions by healthcare providers and insurers. PMID- 29110167 TI - Assessment of autonomic nervous system modulation after novel catheter ablation techniques for atrial fibrillation using multiple short-term electrocardiogram recordings. AB - PURPOSE: The effect of novel catheter ablation techniques for atrial fibrillation (AF) on the autonomic nervous system (ANS) is unclear. This study aimed to assess the ANS after three novel catheter ablation techniques for paroxysmal AF by evaluating heart rate variability (HRV) parameters using a 3-min electrocardiogram recording. METHODS: Two hundred and thirty-five patients who underwent catheter ablation for paroxysmal AF (119 in irrigated-tip, 51 in contact-force sensing-guided, and 65 patients in second-generation cryoballoon ablation) were included. HRV analysis was performed at baseline and 1, 3, 6, and 12 months after the ablation. RESULTS: The three ablation groups had similarly decreased HRV parameters after the ablation, and this change was maintained > 1 year. A reduction in parasympathetic nervous function was more apparent after the ablation, compared to changes in the sympathetic nervous function. Of the total population, 45 patients had recurrence. Ln high frequency (HF) 12 months after the ablation was significantly higher in the recurrence group than in the non recurrence group (1.52 +/- 0.47 vs. 1.26 +/- 0.57 ms2, p = 0.007). Multivariate analysis demonstrated that AF duration (hazards ratio 1.09, 95% confidence interval 1.04-1.15, p = 0.001) and ln HF 12 months after ablation (hazards ratio 1.91, 95% confidence interval 1.12-3.25, p = 0.017) were independent predictors of AF recurrence after the ablation. CONCLUSIONS: ANS modulation after the three catheter ablation methods was similar and maintained > 1 year after the procedure. Higher parasympathetic nervous function at 1 year after ablation was associated with AF recurrence after the ablation. PMID- 29110168 TI - Caregiver Quality of Life with Tyrosinemia Type 1. AB - Tyrosinemia type I (HT1) is an inborn error of metabolism (IEM). Current management guidelines include lifelong specialized diet and use of the orphan drug, nitisinone. This study explores the quality of life (QOL) of caregivers of children with HT1. Caregivers for 26 children with HT1 completed a questionnaire (TYR-QOL) adapted to this patient population from an existing validated QOL questionnaire (PKU-QOL). Responses were analyzed via domain scores, based on predetermined scoring guidelines. Results suggest HT1 has a moderate overall impact on caregiver QOL, with emotional aspects of the disease having the greatest impact. HT1 diet and specialized formula also had an impact on caregiver QOL, with the vast majority feeling guilt if their child's diet and specialized formula plan were not followed. Management of nitisinone did not impact caregiver QOL. Results were compared to the phenylketonuria (PKU) population. Domain scores for the emotional, practical, social, and overall impact on QOL were higher for HT1 than for mild PKU, indicating a greater impact on QOL. Domain scores for practical and social aspects were similarly higher for HT1 than for classic PKU, though emotional and overall impacts were comparable. This is the first questionnaire to assess QOL in caregivers of children with HT1. Results can be used to better understand psychosocial implications of HT1 and assist healthcare professionals in addressing treatment issues. PMID- 29110169 TI - Ticks (Acari: Ixodidae) infesting some small mammals from Northern Turkey with new tick-host associations and locality records. AB - Ticks are obligate ectoparasites of a vast range of terrestrial vertebrates which may play an important role in the transmission of many zoonotic pathogens to humans and animals. In the current study, we performed an investigation on ticks infesting some small mammals captured from Samsun and Tokat provinces, Northern Turkey. One hundred forty-five mammalian samples belonging to four species, namely Cricetulus migratorius (n = 1), Apodemus flavicollis (n = 17), Crocidura suaveolens (n = 102) and Sorex volnuchini (n = 25), were examined for the presence of tick infestations. A total of 273 (74 larvae, 194 nymphs, 5 females) hard ticks were collected from 88 mammalian samples. Ticks were identified as Ixodes laguri (1 nymph), I. redikorzevi (22 larvae, 186 nymphs, 5 females), I. ricinus (52 larvae, 4 nymphs) and Rhipicephalus turanicus (3 nymphs). Here, we also provided new tick mammalian host associations for Turkey. In addition, I. laguri and I. redikorzevi ticks were recorded for the first time in Samsun province of Turkey. PMID- 29110170 TI - Distribution and host associations of ixodid ticks collected from wildlife in Florida, USA. AB - A tick survey was conducted to document tick-host associations with Florida (USA) wildlife, and to determine the relative abundance and distribution of ixodid ticks throughout the state. The survey was conducted using collection kits distributed to licensed Florida hunters as well as the examination of archived specimens from ongoing state wildlife research programs. Collected tick samples were obtained from 66% of Florida counties and were collected from nine wildlife hosts, including black bear, bobcat, coyote, deer, gray fox, Florida panther, raccoon, swine, and wild turkey. In total, 4176 ticks were identified, of which 75% were Amblyomma americanum, 14% Ixodes scapularis, 8% A. maculatum, 3% Dermacentor variabilis, and < 1% were I. affinis and I. texanus. americanum, D. variabilis, and I. scapularis had the broadest host range, while A. maculatum, D. variabilis, and I. scapularis had the widest geographic distribution. While the survey data contribute to an understanding of tick-host associations in Florida, they also provide insight into the seasonal and geographic distribution of several important vector species in the southeastern USA. PMID- 29110171 TI - Experimental efficacy of a vaccine against Rhipicephalus australis. AB - Despite several decades of chemical use the cattle tick, Rhipicephalus australis, still represents an important threat for breeders of tick susceptible cattle under tropical conditions. The intense use of acaricides has lead to the development of multi-resistant strains of ticks and alternative means of control need to be developed to maintain control. A vaccine against ticks, based on the Boophilus microplus Bm86 protein, is one of the promising alternative means of tick control. In this investigation, an experimental vaccine was developed based on the orthologous R. australis Bm86 sequence identified from local R. australis strains and a recombinant protein expressed in Escherichia coli. The efficacy of this vaccine against a local strain of R. australis was assessed under controlled conditions. Vaccinated cattle presented 40.3% fewer ticks than unvaccinated cattle and tick reproductive performance was also affected by the vaccine. Ticks that engorged on vaccinated animals laid 51.2% less egg mass and tick fertility decreased by 18.8% compared to the control group. The use of the vaccine reduced the tick population by 74.2% at each generation. The tick vaccine can be used in an integrated tick control program. PMID- 29110172 TI - When Doctors and Parents Don't Agree: The story of Charlie Gard. AB - This discussion follows a series of high profile cases involving a terminally ill child, Charlie Gard. These cases are significant as they trace the complexities that arise when parents and medical teams do not agree as well as addressing the question of whether there is a right to access experimental treatment. PMID- 29110173 TI - Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer. AB - Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-GloTM Luminescent cell viability assay, synergy index analysis and Western blotting. The nuclear localization of AR was examined via immunocytochemical staining in 22Rv1 cells and primary tumor cells from a patient with CRPC. Results Combination treatment with HDACIs (vorinostat or CG200745) and docetaxel synergistically inhibited the growth of 22Rv1 and VCaP cells. Consistently, the combination treatment decreased the levels of full-length AR (AR-FL), AR splice variants (AR-Vs), prostate specific antigen (PSA), and anti-apoptotic Bcl-2 proteins more efficiently compared with docetaxel or vorinostat alone. Moreover, the combination treatment accelerated the acetylation and bundling of tubulin, which significantly inhibited the nuclear accumulation of AR in 22Rv1 cells. The cytoplasmic colocalization of AR-FL and AR-V7 with microtubule bundles increased after combination treatment in primary tumor cells from a patient with CRPC. Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC. PMID- 29110174 TI - Murine myoblast migration: influence of replicative ageing and nutrition. AB - Cell migration is central to skeletal muscle repair following damage. Leucine and beta-Hydroxy beta-methylbutyric acid (HMB) are supplements consumed for recovery from muscle damaging exercise in humans, however, their impact on muscle cell migration with age is not yet understood. We hypothesised that replicatively aged ("aged"; P46-P48) myoblasts would be less efficient at basal and supplemented repair versus parental controls ("control"; P12-P16). Aged and control myoblasts were scratch-damaged and migration velocity, directionality and distance assessed over 48 h in the absence and presence of leucine (10 mM) or HMB (10 mM) +/- PI3K/Akt (LY294002 10 MUM), ERK (PD98059 5 MUM) or mTOR (rapamycin 0.5 MUM) inhibition. Opposing our hypothesis, aged cells displayed increased velocities, directionality and distance migrated (P < 0.001) versus control. Leucine and HMB significantly increased (P < 0.001) the same parameters in control cells. The supplements were with smaller, albeit significant impact on aged cell velocity (P < 0.001) and in the presence of HMB only, distance (P = 0.041). Inhibitor studies revealed that, PI3K and ERK activation were essential for velocity, directionality and migration distance of aged cells in basal conditions, whereas mTOR was important for directionality only. While PI3K activation was critical for all parameters in control cells (P < 0.001), inhibition of ERK or mTOR improved, rather than reduced, control cell migration distance. Enhanced basal velocity, directionality and distance in aged cells required ERK and PI3K activation. By contrast, in control cells, basal migration was underpinned by PI3K activation, and facilitated by leucine or HMB supplementation, to migration levels seen in aged cells. These data suggest that replicatively aged myoblasts are not anabolically resistant per se, but are capable of efficient repair, underpinned by altered signaling pathways, compared with unaged control myoblasts. PMID- 29110175 TI - Optimization and Verification of Droplet Digital PCR Even-Specific Methods for the Quantification of GM Maize DAS1507 and NK603. AB - In recent years, digital polymerase chain reaction (dPCR), a new molecular biology technique, has been gaining in popularity. Among many other applications, this technique can also be used for the detection and quantification of genetically modified organisms (GMOs) in food and feed. It might replace the currently widely used real-time PCR method (qPCR), by overcoming problems related to the PCR inhibition and the requirement of certified reference materials to be used as a calibrant. In theory, validated qPCR methods can be easily transferred to the dPCR platform. However, optimization of the PCR conditions might be necessary. In this study, we report the transfer of two validated qPCR methods for quantification of maize DAS1507 and NK603 events to the droplet dPCR (ddPCR) platform. After some optimization, both methods have been verified according to the guidance of the European Network of GMO Laboratories (ENGL) on analytical method verification (ENGL working group on "Method Verification." (2011) Verification of Analytical Methods for GMO Testing When Implementing Interlaboratory Validated Methods). Digital PCR methods performed equally or better than the qPCR methods. Optimized ddPCR methods confirm their suitability for GMO determination in food and feed. PMID- 29110176 TI - Avascular necrosis after long-term glucocorticoid treatment in MELAS: a cautionary note. PMID- 29110177 TI - Role of protein carbonylation in diabetes. AB - Diabetes mellitus is a metabolic disease characterized by, among others, elevated blood glucose levels. Hyperglycaemia as well as enhanced levels of glucose derived reactive metabolites contribute to the development of diabetic complications partly via increased generation of reactive oxygen species (ROS). ROS are not only part of signaling pathways themselves but also lead to carbonylation of particular amino acid side chains by direct metal-catalyzed oxidation. In addition, carbonyl groups can be introduced into proteins indirectly by non-oxidative covalent adduction of reactive carbonyl species generated by the oxidation of lipids or carbohydrates. Both direct and indirect carbonylation mechanisms may affect protein conformation, activity, and function. Herein we introduce the different mechanisms of the carbonylation reaction, discuss degradation mechanisms, and the fate of proteins modified this way and how the overall degree of carbonylation affects protein homeostasis and function differently. The role of protein carbonylation in metabolic control systems and cell signaling are also summarized. Finally, current diagnostic and antioxidant therapeutic options in diabetes are discussed. PMID- 29110178 TI - Priapism in a Fabry disease mouse model is associated with upregulated penile nNOS and eNOS expression. AB - Fabry disease is a glycosphingolipidosis caused by deficient activity of alpha galactosidase A; it is one of a few diseases that are associated with priapism, an abnormal prolonged erection of the penis. The goal of this study was to investigate the pathogenesis of Fabry disease-associated priapism in a mouse model of the disease. We found that Fabry mice develop late-onset priapism. Neuronal nitric oxide synthase (nNOS), which was predominantly present as the 120 kDa N-terminus-truncated form, was significantly upregulated in the penis of 18 month-old Fabry mice compared to wild type controls (~fivefold). Endothelial NOS (eNOS) was also upregulated (~twofold). NO level in penile tissues of Fabry mice was significantly higher than wild type controls at 18 months. Gene transfer mediated enzyme replacement therapy reversed abnormal nNOS expression in the Fabry mouse penis. The penile nNOS level was restored by antiandrogen treatment, suggesting that hyperactive androgen receptor signaling in Fabry mice may contribute to nNOS upregulation. However, the phosphodiesterase-5A expression level and the adenosine content in the penis, which are known to play roles in the development of priapism in other etiologies, were unchanged in Fabry mice. In conclusion, these data suggested that increased nNOS (and probably eNOS) content and the consequential elevated NO production and high arterial blood flow in the penis may be the underlying mechanism of priapism in Fabry mice. Furthermore, in combination with previous findings, this study suggested that regulation of NOS expression is susceptible to alpha-galactosidase A deficiency, and this may represent a general pathogenic mechanism of Fabry vasculopathy. PMID- 29110179 TI - A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome. AB - BACKGROUND: Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. METHODS AND RESULTS: This was a two-site, randomized crossover trial of 23 patients (age 35-73 years; 63% men) who received triheptanoin or vegetable oil as placebo. The trial took place over 1 year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389 +/- 164 m (range 95-672; n = 19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on triheptanoin versus placebo was 6 m; 95% confidence interval (CI) -11 to 22; p = 0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4 years. CONCLUSIONS: We cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity. ClinicalTrials.gov Identifier: NCT00947960. PMID- 29110180 TI - Correlation between the molecular effects of mutations at the dimer interface of alanine-glyoxylate aminotransferase leading to primary hyperoxaluria type I and the cellular response to vitamin B6. AB - Primary hyperoxaluria type I (PH1) is a rare disease caused by the deficit of liver alanine-glyoxylate aminotransferase (AGT). AGT prevents oxalate formation by converting peroxisomal glyoxylate to glycine. When the enzyme is deficient, progressive calcium oxalate stones deposit first in the urinary tract and then at the systemic level. Pyridoxal 5'-phosphate (PLP), the AGT coenzyme, exerts a chaperone role by promoting dimerization, as demonstrated by studies at protein and cellular level. Thus, variants showing a destabilized dimeric structure should, in principle, be responsive to vitamin B6, a precursor of PLP. However, models to predict the extent of responsiveness of each variant are missing. We examined the effects of pathogenic interfacial mutations by combining bioinformatic predictions with molecular and cellular studies on selected variants (R36H, G42E, I56N, G63R, and G216R), in both their holo- (i.e., with bound PLP) and apo- (i.e., without bound PLP) form. We found that all variants displayed structural alterations mainly related to the apoform and consisting of an altered tertiary and quaternary structure. G216R also shows a strongly reduced catalytic efficiency. Moreover, all but G216R respond to vitamin B6, as shown by their increased specific activity and expression level in a cellular disease model. A global analysis of data unraveled a possible inverse correlation between the degree of destabilization/misfolding induced by a mutation and the extent of B6 responsiveness. These results provide a first explanation of factors influencing B6 response in PH1, a model possibly valuable for other rare diseases caused by protein deficits. PMID- 29110181 TI - C-myb Plays an Essential Role in the Protective Function of IGF-1 on Cytotoxicity Induced by Abeta25-35 via the PI3K/Akt Pathway. AB - There have been numerous reports about neurodegenerative diseases, including Alzheimer's disease. Nevertheless, the molecules responsible for the neurodegeneration in Alzheimer's disease are basically unknown. Recent findings indicate that the cellular myeloblastosis (c-myb) regulates neural progenitor cell proliferation. In the current study, the function of insulin-like growth factor-1 (IGF-1) against cell toxicity in SH-SY5Y cells induced by beta-amyloid 25-35 (Abeta25-35) and its molecular mechanism were investigated. It was found that p25 protein production was raised by Abeta25-35 (25 MUM), similar to the increased expression of MU-calpain. The results also showed that Abeta25-35 reduced c-myb, elevated tau hyper-phosphorylation, and induced death of SH-SY5Y cells. Loss of cell viability and apoptosis of SH-SY5Y cells induced by Abeta25 35 were attenuated by IGF-1 pretreatment in a dose-dependent manner. In addition, IGF-1 blocked MU-calpain expression, which was induced by Abeta25-35 and reduced p25 formation and tau hyper-phosphorylation. Moreover, the expression of c-myb in SH-SY5Y cells was increased by combining IGF-1 with Abeta25-35 or IGF-1 alone. The neuroprotective function of IGF-1 was attenuated in the SH-SY5Y cells, which were transfected with a c-myb small interfering RNA. Furthermore, LY294002, a specific PI3K inhibitor, reduced c-myb expression and abolished IGF-1's protective function in SH-SY5Y cell apoptosis induced by Abeta25-35. The facts above indicate that c-myb has a role in IGF-1-mediated protection from Abeta25-35 induced cytotoxicity via the PI3K/Akt pathway. PMID- 29110182 TI - New complexity measures reveal that topographic loops of human alpha phase potentials are more complex in drowsy than in wake. AB - A number of measures, stemming from nonlinear dynamics, exist to estimate complexity of biomedical objects. In most cases they are appropriate, but sometimes unconventional measures, more suited for specific objects, are needed to perform the task. In our present work, we propose three new complexity measures to quantify complexity of topographic closed loops of alpha carrier frequency phase potentials (CFPP) of healthy humans in wake and drowsy states. EEG of ten adult individuals was recorded in both states, using a 14-channel montage. For each subject and each state, a topographic loop (circular directed graph) was constructed according to CFPP values. Circular complexity measure was obtained by summing angles which directed graph edges (arrows) form with the topographic center. Longitudinal complexity was defined as the sum of all arrow lengths, while intersecting complexity was introduced by counting the number of intersections of graph edges. Wilcoxon's signed-ranks test was used on the sets of these three measures, as well as on fractal dimension values of some loop properties, to test differences between loops obtained in wake vs. drowsy. While fractal dimension values were not significantly different, longitudinal and intersecting complexities, as well as anticlockwise circularity, were significantly increased in drowsy. Graphical abstract An example of closed topographic carrier frequency phase potential (CFPP) loops, recorded in one of the subjects in the wake (A) and drowsy (C) states. Lengths of loop graph edges, r(c j, c j + 1), plotted against the series of EEG channels with decreasing CFPP values, c j , in the wake (B) and drowsy (D) states. Conventional fractal analysis did not reveal any difference between them; therefore, three new complexity measures were introduced. PMID- 29110183 TI - Integrated cross-network connectivity of amygdala, insula, and subgenual cingulate associated with facial emotion perception in healthy controls and remitted major depressive disorder. AB - Emotion perception deficits could be due to disrupted connectivity of key nodes in the salience and emotion network (SEN), including the amygdala, subgenual anterior cingulate cortex (sgACC), and insula. We examined SEN resting-state (rs )fMRI connectivity in rMDD in relation to Facial Emotion Perception Test (FEPT) performance. Fifty-two medication-free people ages 18 to 23 years participated. Twenty-seven had major depressive disorder (MDD) in remission (rMDD, 10 males), as MDD is associated with emotion perception deficits and alterations in rsfMRI. Twenty-five healthy controls (10 males) also participated. Participants completed the FEPT during fMRI, in addition to an 8-minute eyes-open resting-state scan. Seed regions of interest were defined in the amygdala, anterior insula and sgACC. Multiple regression analyses co-varied diagnostic group, sex and movement parameters. Emotion perception accuracy was positively associated with connectivity between amygdala seeds and regions primarily in the SEN and cognitive control network (CCN), and also the default mode network (DMN). Accuracy was also positively associated with connectivity between the sgACC seeds and other SEN regions, and the DMN, particularly for the right sgACC. Connectivity negatively associated with emotion perception was mostly with regions outside of these three networks, other than the left insula and part of the DMN. This study is the first to our knowledge to demonstrate relationships between facial emotion processing and resting-state connectivity with SEN nodes and between SEN nodes and regions located within other neural networks. PMID- 29110184 TI - Individual differences in social desirability are associated with white-matter microstructure of the external capsule. AB - Humans tend to present themselves in a positive light to gain social approval. This behavioral trait, termed social desirability, is important for various types of social success. Surprisingly, investigation into the neural underpinnings of social desirability has been limited and focused only on interindividual differences in dopamine receptor binding. These studies revealed reduced dopamine receptor binding in the striatum of individuals who are high in trait social desirability. Interestingly, high dopamine signaling has been associated with low white-matter integrity, irrespective of social desirability. Based on these findings, we hypothesized that a positive association exists between trait social desirability and the white-matter microstructure of the external capsule, which carries fibers to the striatum from the prefrontal cortex. To test this hypothesis, we collected diffusion tensor imaging data and examined the relationship between fractional anisotropy of the external capsule and participants' social desirability-our analysis revealed a positive association. As a second exploratory step, we examined the association between social desirability and white-matter microstructure throughout the whole brain. Our whole-brain analysis revealed associations within multiple major white-matter tracts, demonstrating that socially desirable behavior relies on connectivity between distributed brain regions. PMID- 29110185 TI - Positioning error of custom 3D-printed surgical guides for the radius: influence of fitting location and guide design. AB - PURPOSE: Utilization of 3D-printed patient-specific surgical guides is a promising navigation approach for orthopedic surgery. However, navigation errors can arise if the guide is not correctly positioned at the planned bone location, compromising the surgical outcome. Quantitative measurements of guide positioning errors are rarely reported and have never been related to guide design and underlying bone anatomy. In this study, the positioning accuracy of a standard and an extended guide design with lateral extension is evaluated at different fitting locations (distal, mid-shaft and proximal) on the volar side of the radius. METHODS: Four operators placed the surgical guides on 3D-printed radius models obtained from the CT scans of six patients. For each radius model, every operator positioned two guide designs on the three fitting locations. The residual positioning error was quantified with a CT-based image analysis method in terms of the mean target registration error (mTRE), total translation error ([Formula: see text]) and total rotation error ([Formula: see text]) by comparing the actual guide position with the preoperatively planned position. Three generalized linear regression models were constructed to evaluate if the fitting location and the guide design affected mTRE, [Formula: see text] and [Formula: see text]. RESULTS: mTRE, [Formula: see text] and [Formula: see text] were significantly higher for mid-shaft guides ([Formula: see text]) compared to distal guides. The guide extension significantly improved the target registration and translational accuracy in all the volar radius locations ([Formula: see text]). However, in the mid-shaft region, the guide extension yielded an increased total rotational error ([Formula: see text]). CONCLUSION: Our study demonstrates that positioning accuracy depends on the fitting location and on the guide design. In distal and proximal radial regions, the accuracy of guides with lateral extension is higher than standard guides and is therefore recommended for future use. PMID- 29110186 TI - Patient safety ward round checklist via an electronic app: implications for harm prevention. AB - INTRODUCTION: Patient safety is a value at the core of modern healthcare. Though awareness in the medical community is growing, implementing systematic approaches similar to those used in other high reliability industries is proving difficult. The aim of this research was twofold, to establish a baseline for patient safety practices on routine ward rounds and to test the feasibility of implementing an electronic patient safety checklist application. METHODS: Two research teams were formed; one auditing a medical team to establish a procedural baseline of "usual care" practice and an intervention team concurrently was enforcing the implementation of the checklist. The checklist was comprised of eight standard clinical practice items. The program was conducted over a 2-week period and 1 month later, a retrospective analysis of patient charts was conducted using a global trigger tool to determine variance between the experimental groups. Finally, feedback from the physician participants was considered. RESULTS: The results demonstrated a statistically significant difference on five variables of a total of 16. The auditing team observed low adherence to patient identification (0.0%), hand decontamination (5.5%), and presence of nurse on ward rounds (6.8%). Physician feedback was generally positive. CONCLUSIONS: The baseline audit demonstrated significant practice bias on daily ward rounds which tended to omit several key-proven patient safety practices such as prompting hand decontamination and obtaining up to date reports from nursing staff. Results of the intervention arm demonstrate the feasibility of using the Checklist App on daily ward rounds. PMID- 29110188 TI - Percutaneous balloon compression for persistent or recurrent trigeminal neuralgia after microvascular decompression: personal experience of 28 patients. AB - The objective of this study is to investigate the long-term effects of percutaneous balloon compression (PBC) for treating persistent or recurrent trigeminal neuralgia (TN) after microvascular decompression (MVD). The clinical features, surgical findings, outcomes, and complications of 28 patients underwent PBC for TN in Nanjing Drum Tower Hospital between April 2011 and March 2015 were analyzed retrospectively. All the patients had received MVD before but they did not get cured or the symptom relapsed during follow-up. Twenty-six patients (92.9%) experienced immediate pain relief; one patient (3.6%) improved but still had occasional pain. The other one (3.6%) had no pain relief and repeat PBC was performed with complete resolution of the symptom. With a mean follow-up of 39.9 months, ranging from 24 to 65 months after surgery, 24 (85.7%) patients remained pain-free; three patients (11.1%) had a relapse. Surgical complications included facial numbness in 27 patients (96.4%), masseter muscle weakness in 10 patients (35.7%), and diplopia secondary to abducens nerve palsy in one patient (3.6%). None of the patients had serious surgical morbidities. PBC is a minimally invasive, safe, and effective treatment for trigeminal neuralgia, especially suitable for patients with persistent or recurrent TN after MVD. PMID- 29110187 TI - Outcomes from a community-based hypertension educational programme: the West of Ireland Hypertension study. AB - BACKGROUND: Hypertension is a leading modifiable risk factor for premature cardiovascular disease. Research indicates a growing prevalence of hypertension among adults worldwide, with accompanying low levels of patient knowledge, and sub-optimal clinical management. AIMS: This study aims to explore the impact of a structured hypertension educational intervention on patient knowledge, lifestyle behaviours and blood pressure control. DESIGN: An observational, prospective cohort design was selected. METHODS: Participants were recruited through a public blood pressure screening event in a community-based setting. They were asked to complete a self-report questionnaire followed by an assessment of their blood pressure. Participants with high blood pressure were randomly assigned to either a control group or an intervention group. Those in the intervention group received an educational intervention on hypertension 4 weeks later. Both groups were recalled 4 months later for a repeat of the same initial assessment. RESULTS: Eighty-one participants with a mean age of 64 years were included in this study. There were no significant differences in the baseline measures between the two groups. Significant improvements were found in the intervention group compared with the control group in levels of hypertension knowledge and awareness (p = <0.001), exercise levels (p = 0.002) and weight (p = 0.003). Participants who underwent the intervention showed a greater reduction in both systolic (SBP) and diastolic (DBP) blood pressure (SBP 158.8 to 141.6 mmHg, p < 0.0001 and DBP 84.7 to 77.7 mmHg, p < 0.001). CONCLUSION: Providing a tailored educational intervention can positively impact on hypertension knowledge, self care management and control within community-based settings. PMID- 29110189 TI - Ciclosporin Ophthalmic Emulsion 0.1%: A Review in Severe Dry Eye Disease. AB - Ciclosporin ophthalmic emulsion 0.1% (hereafter referred to as ciclosporin 0.1%) [Ikervis(r)] is an unpreserved cationic emulsion formulation containing an 0.1% concentration of ciclosporin. It has been approved in various countries worldwide, including those of the EU, for the treatment of severe keratitis in adults with dry eye disease, which has not improved despite treatment with tear substitutes. In a multinational, phase III study in this patient population, once daily ciclosporin 0.1% was associated with statistically significant and clinically relevant improvements in the signs (corneal surface damage and ocular surface inflammation) of dry eye disease relative to vehicle during the first 6 month treatment period. These beneficial effects were maintained or improved in a subsequent 6-month period, with data suggesting sustainability following treatment discontinuation in a 24-month, phase III extension study. Ciclosporin 0.1% was well tolerated in these studies, with instillation-site pain (which was mostly mild in severity) being the most frequently reported ocular treatment related adverse event. There were no findings to suggest the systemic absorption of ciclosporin. Thus, once-daily ciclosporin 0.1% is an effective and well tolerated option for the treatment of severe keratitis in adults with dry eye disease. PMID- 29110190 TI - Pomalidomide: A Review in Relapsed and Refractory Multiple Myeloma. AB - Pomalidomide (Imnovid(r); Pomalyst(r)), an analogue of thalidomide, is an immunomodulatory agent, with several mechanisms of action (both direct and indirect) thought to be involved in its anti-myeloma activity. Oral pomalidomide is available in several countries for use in combination with low-dose dexamethasone in adults with relapsed and refractory multiple myeloma. In multinational, phase II or III studies in patients with refractory, or relapsed and refractory multiple myeloma who had received >= 2 prior treatment regimens (including >= 2 cycles of both lenalidomide and bortezomib), pomalidomide plus low-dose dexamethasone was associated with prolonged progression-free survival (PFS) and overall survival and an improved overall response rate. Pomalidomide plus low-dose dexamethasone had a manageable tolerability profile, with neutropenia, infections, anaemia and thrombocytopenia being the most frequently reported grade 3 or 4 treatment-emergent adverse events. In conclusion, pomalidomide plus low-dose dexamethasone extends the treatment options available for the management of relapsed and refractory multiple myeloma in a patient population that has very limited treatment options. PMID- 29110191 TI - Epithelioid Angiomyolipoma of the Liver. PMID- 29110192 TI - Endoscopic Sleeve Gastroplasty, Laparoscopic Sleeve Gastrectomy, and Laparoscopic Band for Weight Loss: How Do They Compare? AB - BACKGROUND: Endoscopic sleeve gastroplasty (ESG) is a novel endobariatric procedure. Initial studies demonstrated an association of ESG with weight loss and improvement of obesity-related comorbidities. Our aim was to compare ESG to laparoscopic sleeve gastrectomy (LSG) and laparoscopic adjustable gastric banding (LAGB). METHODS: We included 278 obese (BMI > 30) patients who underwent ESG (n = 91), LSG (n = 120), or LAGB (n = 67) at our tertiary care academic center. Primary outcome was percent total body weight loss (%TBWL) at 3, 6, 9, and 12 months. Secondary outcome measures included adverse events (AE), length of stay (LOS), and readmission rate. RESULTS: At 12-month follow-up, LSG achieved the greatest %TBWL compared to LAGB and ESG (29.28 vs 13.30 vs 17.57%, respectively; p < 0.001). However, ESG had a significantly lower rate of morbidity when compared to LSG or LAGB (p = 0.01). The LOS was significantly less for ESG compared to LSG or LAGB (0.34 +/- 0.73 vs 3.09 +/- 1.47 vs 1.66 +/- 3.07 days, respectively; p < 0.01). Readmission rates were not significantly different between the groups (p = 0.72). CONCLUSION: Although LSG is the most effective option for weight loss, ESG is a safe and feasible endobariatric option associated with low morbidity and short LOS in select patients. PMID- 29110193 TI - Paraneoplastic Stiff Person Syndrome Secondary to Pancreatic Adenocarcinoma. PMID- 29110194 TI - White matter fiber bundle lengths are shorter in cART naive HIV: an analysis of quantitative diffusion tractography in South Africa. AB - This study examines white matter microstructure using quantitative tractography diffusion magnetic resonance imaging (qtdMRI) in HIV+ individuals from South Africa who were naive or early in the initiation of antiretroviral therapy. Fiber bundle length (FBL) metrics, generated from qtdMRI, for whole brain and six white matter tracts of interest (TOI) were assessed for 135 HIV+ and 21 HIV- individuals. The association between FBL metrics, measures of disease burden, and neuropsychological performance were also investigated. Results indicate significantly reduced sum of whole brain fiber bundle lengths (FBL, p < 0.001), but not average whole brain FBL in the HIV+ group compared to the HIV- controls. The HIV+ group exhibited significantly shorter sum of FBL in all six TOIs examined: the anterior thalamic radiation, cingulum bundle, inferior and superior longitudinal fasciculi, inferior frontal occipital fasciculus, and the uncinate fasciculus. Additionally, average FBLs were significantly shorter select TOIs including the inferior longitudinal fasciculus, cingulum bundle, and the anterior thalamic radiation. Shorter whole brain FBL sum metrics were associated with poorer neuropsychological performance, but were not associated with markers of disease burden. Taken together these findings suggest HIV affects white matter architecture primarily through reductions in white matter fiber numbers and, to a lesser degree, the shortening of fibers along a bundle path. PMID- 29110195 TI - A transposition-active Phyllostachys edulis long terminal repeat (LTR) retrotransposon. AB - Due to infrequent sexual reproduction, moso bamboo breeding by hybridization is extremely technically difficult. Insertional mutagenesis based on endogenous active transposons may thus serve as an alternative method to create new germplasm of moso bamboo. In the present study, using LTR-STRUC, a full-length intact long terminal repeat (LTR) retrotransposon was identified in the moso bamboo genome and was named PHRE2 (Phyllostachys edulis retrotransposon 2). The 5' and 3' LTR sequences of PHRE2 were highly (98.39%) similar. PHRE2 contains all domains necessary for transposition such as gag, pr, rt, rh, and int. The coding frames of these essential domains were complete and had no apparent mutations. In addition, PHRE2 possessed a prime binding site (PBS), a polypurine tract (PPT), and two typical sequences of LTR retrotransposons. A genome-wide scan showed that the moso bamboo genome has only one full-length sequence of PHYRE2. After its transfer to Arabidopsis thaliana, an increase in PHRE2 copy number occurred in the T3 plants compared to in the T2 plants. After moso bamboo seedlings were grown in tissue culture or treated by irradiation or plant hormones, the copy number of PHRE2 significantly increased. These findings indicate that PHRE2 has the capacity for transposition, which can be induced by environmental conditions. PMID- 29110196 TI - Challenges for molecular and serological ZIKV infection confirmation. AB - BACKGROUND: Zika Virus (ZIKV), member of Flaviviridae family and Flavivirus genus, has recently emerged as international public health emergency after its association with neonatal microcephaly cases. Clinical diagnosis hindrance involves symptom similarities produced by other arbovirus infections, therefore laboratory confirmation is of paramount importance. DISCUSSION: The most reliable test available is based on ZIKV RNA detection from body fluid samples. However, short viremia window periods and asymptomatic infections diminish the success rate for RT-PCR positivity. Beyond molecular detection, all serology tests in areas where other Flavivirus circulates proved to be a difficult task due to the broad range of cross-reactivity, especially with dengue pre-exposed individuals. CONCLUSION: Altogether, lack of serological diagnostic tools brings limitations to any retrospective evaluation. Those studies are central in the context of congenital infection that could occur asymptomatically and mask prevalence and risk rates. PMID- 29110197 TI - Zika virus infection in children: epidemiology and clinical manifestations. AB - PURPOSE: The purpose of this review is to comprehensively review Congenital Zika Syndrome in regard to their epidemiology and clinical manifestations. METHODS: This subject review of congenital Zika syndrome was composed after conducting a thorough review of the available literature on this topic using PubMed and other primary sources. RESULTS: The first epidemic of Zika virus infection in Brazil was followed by an unexpected sharp increase in the incidence of infants born with microcephaly and the description of a new disease, the congenital Zika syndrome. This review focuses on the epidemiological and clinical aspects of Zika infection in children. We conducted a brief historical account of the virus description in 1947, the rare cases of Zika infection occurring up to 2007, and the first epidemics in the Pacific between 2007 and 2014. We also discussed the isolation of the virus in Brazil in 2015 and its spread in the Americas, the microcephaly outbreak in Brazil and its association with Zika virus, and the current epidemiological panorama. We address the known clinical spectrum of Zika virus infection in the pediatric population, including manifestations of acute infection and congenital Zika syndrome, with emphasis on cranial, ophthalmic, and orthopedic abnormalities. CONCLUSION: While much has been learned about congenital Zika syndrome, the full spectrum of this infection is not yet known. This review is based on current, limited data about Zika virus infection. As more information becomes available, we will have a more accurate picture of this new disease. PMID- 29110198 TI - Surgical management of craniosynostosis in the setting of a ventricular shunt: a case series and treatment algorithm. AB - PURPOSE: Cerebrospinal fluid diversion via ventricular shunt is a common treatment for hydrocephalus. Change in cranial morphology associated with a sutural fusion has been termed shunt-related or induced craniosynostosis (SRC) or craniocerebral disproportion (CCD). We present a series of patients with SRC who underwent cranial vault remodeling (CVR) and our treatment algorithm. METHODS: Thirteen patients were retrospectively reviewed who had SRC and CVR; 92% of patients had a ventriculoperitoneal (VP) shunt placed for largely intraventricular hemorrhage of prematurity (69% of patients) at a mean age of 2.2 months. The shunt revision rate was 38.4%, and 54% of patients had a programmable shunt placed initially. RESULTS: The mean age at time of CVR was 3.6 years old. The most commonly affected sutures (CT confirmed) were the sagittal and coronal sutures, with three patients exhibiting pancraniosynostosis. The mean time from placement of the shunt to CT evidence of sutural fusion was 2.0 years. Abnormal head shape was noted in all 13 patients; 11 of these also had either chronic headaches, papilledema, seizures, or behavioral changes in the setting of functional shunt. Mean follow-up after the initial CVR was 3.3 years. No shunt infections were attributed to the CVR. The families of all patients were contacted and reported improvement in head shape with 60% of families reporting improvement in behavior, 75% reported improvement in headaches, and 40% reported decrease in seizure frequency or intensity. Shunt setting or type was not routinely changed after CVR. CONCLUSIONS: Our threshold for CVR in SRC is met when shunt malfunction has been ruled out and there are (1) radiographic evidence of craniosynostosis, (2) signs of increased ICP clinically or radiographically, and (3) cranial dysmorphism, i.e., dolichocephaly. The majority of cases of SRC result in improved cranial morphology in addition to some abatement of the symptoms of increased intracranial pressure. Early involvement of an experienced craniofacial/neurosurgical team could allow for early diagnosis and intervention which may prevent progression to more severe deformities. SRC is a complex entity, with multiple etiologies, and a future study is needed. PMID- 29110199 TI - Epidermoid cyst of the fourth ventricle in a child. PMID- 29110200 TI - Maintaining the Public Trust in Journals with Ethical Publishing. PMID- 29110201 TI - Dexamethasone Intravitreal Implant in Diabetic Macular Edema: Real-Life Data from a Prospective Study and Predictive Factors for Visual Outcome. AB - INTRODUCTION: The purpose of the study was to evaluate the long-term anatomical and functional outcomes in patients with diabetic macular edema (DME) treated with intravitreal dexamethasone implant and to determine the predictive factors for the final visual outcome. METHODS: The study included 54 patients with DME refractory to previous antivascular endothelial growth factor (anti-VEGF) who were treated with intravitreal dexamethasone implant. Predictive factors for visual outcome were assessed. In addition, the change in best-corrected visual acuity (BCVA) and the percentage of patients with edema resolution were evaluated. RESULTS: At the end of the 12-month follow-up, patients with DME gained + 5.2 letters (about 1 Snellen line), while 57.4% of patients presented total resolution of macular edema. Negative predictive factors for the final visual outcome were found to be increasing age, increasing macular thickness, phakic status, the presence of intraretinal fluid, hyperreflective foci, hard exudates, as well as external limiting membrane and ellipsoid zone disruption. The mean number of injections was 2.1. CONCLUSIONS: The various predictive factors that determine the visual outcome and possibly define patient prognosis after dexamethasone intravitreal implant in DME cases have been studied. The long follow-up showed that dexamethasone intravitreal implant seems to be a safe and effective treatment for this disease, requiring a limited number of injections. PMID- 29110202 TI - Religiosity as a Substance Use Protective Factor Among Female College Students. AB - Research exists about religiosity as a substance use protective factor. However, there is little attention of this issue regarding Israeli female college students. Undergraduate religious and secular students were studied. Religious students reported lower last month tobacco, alcohol, cannabis and non-medical prescription drug use. Secular females who smoked, missed class because of party habits and reported easy access to cannabis had a higher probability of binge drinking. This study contributes to knowledge about religiosity and college student substance use, and it provides useful information for their mental health and well-being. PMID- 29110203 TI - The Coping Mechanisms and Strategies of Hypertension Patients in Ghana: The Role of Religious Faith, Beliefs and Practices. AB - This qualitative study explored the role of religious faith, belief and practice systems in the coping mechanisms and strategies of essential hypertension patients in Accra, Ghana. Six participants were recruited for participation, of which five were Christians and one was a Muslim. Interviews were conducted and interpretative phenomenological analysis was used to analyze the data. Results showed that participants used their religious faith, beliefs and practices as coping resources. Participants used a deferring-collaborative style of religious coping, which seemed to have provided them with an avoidance strategy that protected the participants from conscious confrontation with their illness. Religious faith and beliefs also afforded the participants a sense of coherence that enabled the participants to manage their stress, reflect on their external and internal resources to promote effective coping and adaptive functioning in a health promoting manner. Implications of a deferring-collaborative style of religious coping and religious re-appraisal are discussed. PMID- 29110204 TI - Shiite Perspective on the Moral Status of the Early Human Embryo: A Critical Review. AB - According to Shiite perspective, the relative inviolability of the human embryo starts at the time of implantation and attains complete ethical status at ensoulment. Different paradigms of embryology have been influential on the understanding of Shiite jurists of the relevant Qur'anic verses. This paper provides a critical review of the process of issuing religious decrees on issues related to the early human life and concludes that Shiite jurisprudence needs to obtain consistency in its adopted account of embryology and adopt a proactive approach toward the bioethical new-emerging issues. PMID- 29110205 TI - Psychobiography and the Psychology of Religion: A Tribute to the Work of Donald Capps. AB - This article examines Donald Capps's work on the psychology of major religious figures and the social forces that informed their psychic lives, spiritual worldviews, and teachings. Drawing on four texts that were published between 2000 and 2014, the essay explores Capps's views on the importance of psychobiography to the study of religion and the specific contributions his thinking has made to a greater understanding of the historical Jesus. The article considers Capps's analysis of Jesus's illegitimacy and his role as healer within the society in which he lived and preached. Building on Capps's work, the article also expands on feminist and postcolonial theories that offer insight into the psychosocial development of religious figures whose teachings and beliefs emerged out of their individual life circumstances and the larger socio-political culture in which they lived. PMID- 29110206 TI - Incorporating Islamic Creed into Islamic Counselling Process: A Guideline to Counsellors. AB - This article is a concept paper that reviewed the main principles of Islamic creed (aqidah) related to counselling. Islamic creed has been regarded as the root of Islam; thus, it should be the fundamental composition of Islamic counselling. The objectives of this review are to demonstrate the relationship between counselling and Islamic creed and to establish a guideline for the practitioners of Islamic counselling when consulting with their clients in matters related to creed. The review was conducted by suggesting methods to incorporate Islamic creed into three stages of counselling process. The major references for this review were the verses in the Quran, the Prophet Tradition (hadith) and literatures on Islamic counselling. This review revealed that there is a strong relationship between counselling and Islamic creed and there are six aspects of Islamic creed associated to counselling that should be observed by the Islamic counselling practitioners. PMID- 29110207 TI - Ameliorating Effect of Osteopontin on H2O2-Induced Apoptosis of Human Oligodendrocyte Progenitor Cells. AB - Recently our group used oligodendrocyte progenitor cells (OPCs) as appropriate model cells to pinpoint the mechanism of the progress of neurodegenerative disorders. In the present study, we focused on the therapeutic role of osteopontin (OPN), a secreted glycosylated phosphoprotein, involved in a number of physiological events including bone formation and remodeling, immune responses, and tumor progression. Protective role of OPN, as a negative regulator of tumorigenesis, has already been clarified. Human embryonic stem cell-derived OPCs were pretreated with OPN before induction of apoptosis by H2O2. Data indicated that OPN prohibited cell death and enhanced OPC viability. This effect is achieved through reduction of apoptosis and induction of anti-apoptosis markers. In addition OPN induces expression of several integrin subunits, responsible for OPN interaction. Notably, our findings showed that expression of alphaV beta1/beta3/beta5 and beta8 integrins increased in response to OPN, while treatment with H2O2 down-regulated alphaV beta1/beta5 and beta8 integrins expression significantly. In conclusion, OPN may act via alphaV integrin signaling and trigger suppression of P53-dependent apoptotic cascades. Therefore OPN therapy may be considered as a feasible process to prevent progress of neurodegenerative diseases in human. PMID- 29110209 TI - Agency attributions of mental effort during self-regulated learning. AB - Previous results suggest that the monitoring of one's own performance during self regulated learning is mediated by self-agency attributions and that these attributions can be influenced by poststudy effort-framing instructions. These results pose a challenge to the study of issues of self-agency in metacognition when the objects of self-regulation are mental operations rather than motor actions that have observable outcomes. When participants studied items in Experiment 1 under time pressure, they invested greater study effort in the easier items in the list. However, the effects of effort framing were the same as when learners typically invest more study effort in the more difficult items: Judgments of learning (JOLs) decreased with effort when instructions biased the attribution of effort to nonagentic sources but increased when they biased attribution to agentic sources. However, the effects of effort framing were constrained by parameters of the study task: Interitem differences in difficulty constrained the attribution of effort to agentic regulation (Experiment 2) whereas interitem differences in the incentive for recall constrained the attribution of effort to nonagentic sources (Experiment 3). The results suggest that the regulation and attribution of effort during self-regulated learning occur within a module that is dissociated from the learner's superordinate agenda but is sensitive to parameters of the task. A model specifies the stage at which effort framing affects the effort-JOL relationship by biasing the attribution of effort to agentic or nonagentic sources. The potentialities that exist in metacognition for the investigation of issues of self-agency are discussed. PMID- 29110208 TI - Expression of Gas1 in Mouse Brain: Release and Role in Neuronal Differentiation. AB - Growth arrest-specific 1 (Gas1) is a pleiotropic protein that induces apoptosis of tumor cells and has important roles during development. Recently, the presence of two forms of Gas1 was reported: one attached to the cell membrane by a GPI anchor; and a soluble extracellular form shed by cells. Previously, we showed that Gas1 is expressed in different areas of the adult mouse CNS. Here, we report the levels of Gas1 mRNA protein in different regions and analyzed its expressions in glutamatergic, GABAergic, and dopaminergic neurons. We found that Gas1 is expressed in GABAergic and glutamatergic neurons in the Purkinje-molecular layer of the cerebellum, hippocampus, thalamus, and fastigial nucleus, as well as in dopaminergic neurons of the substantia nigra. In all cases, Gas1 was found in the cell bodies, but not in the neuropil. The Purkinje and the molecular layers show the highest levels of Gas1, whereas the granule cell layer has low levels. Moreover, we detected the expression and release of Gas1 from primary cultures of Purkinje cells and from hippocampal neurons as well as from neuronal cell lines, but not from cerebellar granular cells. In addition, using SH-SY5Y cells differentiated with retinoic acid as a neuronal model, we found that extracellular Gas1 promotes neurite outgrowth, increases the levels of tyrosine hydroxylase, and stimulates the inhibition of GSK3beta. These findings demonstrate that Gas1 is expressed and released by neurons and promotes differentiation, suggesting an important role for Gas1 in cellular signaling in the CNS. PMID- 29110210 TI - Unmasking the component-general and component-specific aspects of primary and secondary memory in the immediate free recall task. AB - The immediate free recall (IFR) task has been commonly used to estimate the capacities of the primary memory (PM) and secondary memory (SM) components of working memory (WM). Using this method, the correlation between estimates of the PM and SM components has hovered around zero, suggesting that PM and SM represent fully distinct and dissociable components of WM. However, this conclusion has conflicted with more recent studies that have observed moderately strong, positive correlations between PM and SM when separate attention and retrieval tasks are used to estimate these capacities, suggesting that PM and SM represent at least some related capacities. The present study attempted to resolve this empirical discrepancy by investigating the extent to which the relation between estimates of PM and SM might be suppressed by a third variable that operates during the recall portion of the IFR task. This third variable was termed "strength of recency" (SOR) in the present study as it reflected differences in the extent to which individuals used the same experimentally-induced recency recall initiation strategy. As predicted, the present findings showed that the positive correlation between estimates of PM and SM grew from small to medium when the indirect effect of SOR was controlled across two separate sets of studies. This finding is important because it provides stronger support for the distinction between "component-general" and "component-specific" aspects of PM and SM; furthermore, a proof is presented that demonstrates a limitation of using regression techniques to differentiate general and specific aspects of these components. PMID- 29110211 TI - Is the superior verbal memory span of Mandarin speakers due to faster rehearsal? AB - It is well established that digit span in native Chinese speakers is atypically high. This is commonly attributed to a capacity for more rapid subvocal rehearsal for that group. We explored this hypothesis by testing a group of English speaking native Mandarin speakers on digit span and word span in both Mandarin and English, together with a measure of speed of articulation for each. When compared to the performance of native English speakers, the Mandarin group proved to be superior on both digit and word spans while predictably having lower spans in English. This suggests that the Mandarin advantage is not limited to digits. Speed of rehearsal correlated with span performance across materials. However, this correlation was more pronounced for English speakers than for any of the Chinese measures. Further analysis suggested that speed of rehearsal did not provide an adequate account of differences between Mandarin and English spans or for the advantage of digits over words. Possible alternative explanations are discussed. PMID- 29110212 TI - Selective Blockade of the Sigma 1 Receptor Has Beneficial Effects on Both Acute and Chronic Oxaliplatin-Induced Peripheral Neuropathy. PMID- 29110213 TI - Correction to: Neuroimmune Response in Ischemic Preconditioning. AB - Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of pro- and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammatory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke. PMID- 29110214 TI - SOX2-mediated inhibition of miR-223 contributes to STIM1 activation in phenylephrine-induced hypertrophic cardiomyocytes. AB - Stromal interaction molecule 1 (STIM1) is the key molecule responsible for store operated Ca2+ entry (SOCE). Numerous studies have demonstrated that STIM1 levels appeared to be enhanced during cardiac hypertrophy. However, the mechanism underlining this process remains to be clarified. In this study, phenylephrine (PE) was employed to establish a model of hypertrophic neonatal rat cardiomyocytes (HNRCs) in vitro, and low expression of primary and mature miR-223 was detected in PE-induced HNRCs. Our results have revealed that downregulation of miR-223 by PE contributed to the increase of STIM1, which in turn induced cardiac hypertrophy. As expected, overexpression of miR-223 could prevent the increase in cell surface and reduce the mRNA levels of ANF and BNP in cardiomyocytes. To address the mechanism triggering downregulation of miR-223 under PE, we demonstrated that PE-induced inhibition of GSK-3beta activity led to the activation of beta-catenin, which initiates the transcription of SOX2. Increased expression of SOX2 occupied the promoter region of primary miR-223 and suppressed its transcription. Therefore, miR-223 appears to be a promising candidate for inhibiting cardiomyocyte hypertrophy, and miR-223/STIM1 axis might be one of interesting targets for the clinical treatment of hypertrophy. PMID- 29110215 TI - Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. AB - Commensal microbiota inhabit all the mucosal surfaces of the human body. It plays significant roles during homeostatic conditions, and perturbations in numbers and/or products are associated with several pathological disorders. Angiogenesis, the process of new vessel formation, promotes embryonic development and critically modulates several biological processes during adulthood. Indeed, deregulated angiogenesis can induce or augment several pathological conditions. Accumulating evidence has implicated the angiogenic process in various microbiota associated human diseases. Herein, we critically review diseases that are regulated by microbiota and are affected by angiogenesis, aiming to provide a broad understanding of how angiogenesis is involved and how microbiota regulate angiogenesis in microbiota-associated human conditions. PMID- 29110216 TI - Punto Seguro: A Randomized Controlled Pilot Using Conditional Economic Incentives to Reduce Sexually Transmitted Infection Risks in Mexico. AB - Randomized controlled pilot evaluated effect of conditional economic incentives (CEIs) on number of sex partners, condom use, and incident sexually transmitted infections (STIs) among male sex workers in Mexico City. Incentives were contingent on testing free of new curable STIs and/or clinic attendance. We assessed outcomes for n = 227 participants at 6 and 12 months (during active phase with incentives), and then at 18 months (with incentives removed). We used intention-to-treat and inverse probability weighting for the analysis. During active phase, CEIs increased clinic visits (10-13 percentage points) and increased condom use (10-15 percentage points) for CEI groups relative to controls. The effect on condom use was not sustained once CEIs were removed. CEIs did not have an effect on number of partners or incident STIs. Conditional incentives for male sex workers can increase linkage to care and retention and reduce some HIV/STI risks such as condomless sex, while incentives are in place. PMID- 29110217 TI - Aggressive intrahepatic therapies for synchronous hepatocellular carcinoma with pulmonary metastasis. AB - PURPOSE: Prognosis of synchronous hepatocellular carcinoma (HCC) patients with pulmonary metastasis (PM) was poor, while aggressive intrahepatic therapies remained controversial. This study aimed to investigate the significance of aggressive intrahepatic therapies for synchronous PM-HCC. METHODS: Synchronous PM HCC patients were retrospectively enrolled from Sun Yat-sen Memorial Hospital of Sun Yat-sen University during January 2000 and December 2015. Univariate and multivariate analysis were performed to investigate the prognostic factors. Patients were grouped according to different HCC treatment modalities including liver resection (LR), ablation, transarterial chemoembolization (TACE), systemic therapy (ST, systemic chemotherapy or sorafenib) and supportive care (SC). Case control studies were achieved using propensity score matching (PSM) analysis to further investigate the significance of LR, ablation and TACE. RESULTS: Eighty one patients were enrolled, and the median overall survival (OS) was 4.5 months. Serum alpha fetal protein (AFP) >= 400 ng/ml, multiple HCC lesions and no intrahepatic therapies (LR/Ablation/TACE) were inferior independent prognostic factors. Patients were divided into LR group (n = 9), Ablation/TACE group (n = 24) and ST/SC group (n = 48). After PSM analysis, survival outcome was superior in LR group compared to Ablation/TACE group (19.6 vs. 6.9 months) (p = 0.023) or ST/SC group (19.6 vs. 2.8 months) (p = 0.034), while no significant difference was found between -Ablation/TACE and ST/SC group (5.1 vs. 3.2 months) (p = 0.338). CONCLUSIONS: Prognosis of synchronous PM-HCC patients was poor. Serum AFP >= 400 ng/ml, multiple HCC lesions and no aggressive intrahepatic therapies were inferior prognostic factors. LR might provide survival benefits in well-selected patients, while the significance of ablation or TACE remained to be further investigated. PMID- 29110219 TI - Reduction and fixation of displaced U-shaped sacral fractures using lumbopelvic fixation: technical recommendations. AB - PURPOSE: U-shaped sacral fractures are extremely rare injuries that usually occur as a result of falls from considerable heights. Almost all treatment methods described to date aim solely at stabilizing the fracture but do not contribute to supporting the reduction of such fractures. Using existing implants the purpose of this study is to present a surgical technique that facilitates both the reduction and the stabilization of these injuries. The presented technique was evaluated in a series of three cases. METHODS: Polyaxial pedicle screws were placed through vertebral bodies L4 and L5. Two long pedicle screws were implanted in the posterior iliac spine. The lumbar pedicle screws were held with two longitudinal rods, and the pelvic screws with one transverse connecting rod. The lumbar longitudinal and pelvic transverse rods were connected via two hinge-like connecting elements. First, distraction was performed between lumbar pedicle screws L5 and the sacral transverse rod. Lordosis was then restored via the hinge joint, thereby eliminating kyphosis. After tightening all moving elements, the fracture was reduced and stabilized. RESULTS: Computed tomography documented anatomical reduction and fracture healing was achieved in all cases. Two of three patients could be fully mobilized immediately; mobilization of the third patient was delayed due to multiple injuries. Two patients showed neurological symptoms. In one case, complete remission was achieved within 3 weeks, while in the other patient a clear improvement was observed. In all cases, the implant was removed after 8-12 months. There were no post-operative complications, such as infections, wound-healing disorders, neurological deterioration, implant failure, or premature loosening. CONCLUSIONS: The surgical procedure was successful, since it considerably facilitated reduction, thereby shortening surgery time. The stabilization was sufficient to fully mobilize the patients. The procedure is based on existing implant components and is thus routinely available. PMID- 29110218 TI - Cervical sagittal balance: a biomechanical perspective can help clinical practice. AB - PURPOSE: In this article, we summarize our work on understanding the influence of cervical sagittal malalignment on the mechanics of the cervical spine. METHODS: Biomechanical studies were performed using an ex vivo laboratory model to study the kinematic and kinetic response of human cervical spine specimens in the setting of cervical sagittal imbalance. The model allowed controlled variations of C2-C7 Sagittal Vertical Alignment (C2-C7 SVA) and T1-Slope so that clinically relevant sagittally malaligned profiles could be prescribed, while maintaining horizontal gaze, and their biomechanical consequences studied. RESULTS: Our results demonstrated that increasing C2-C7 SVA caused flexion of lower cervical (C2-C7) segments and hyperextension of suboccipital (C0-C1-C2) segments to maintain horizontal gaze. An increase in C2-C7 SVA increased the lower cervical neural foraminal areas. Conversely, increasing T1-slope predominantly influenced subaxial cervical lordosis and, as a result, decreased cervical neural foraminal areas. Therefore, we believe patients with increased upper thoracic kyphosis and radicular symptoms may respond with increased forward head posture (FHP) as a compensatory mechanism to increase their lower cervical neural foraminal area and alleviate nerve root compression as well as reduce the burden on posterior muscles and soft and bony structures of the cervical spine. Increasing FHP (i.e., increased C2-C7 SVA) was associated with shortening of the cervical flexors and occipital extensors and lengthening of the cervical extensors and occipital flexors, which corresponds to C2-C7 flexion and C0-C2 extension. The greatest shortening occurred in the suboccipital muscles, suggesting considerable load bearing of these muscles during chronic FHP. Regardless, there was no evidence of nerve compression within the suboccipital triangle. Finally, cervical sagittal imbalance may play a role in exacerbating adjacent segment pathomechanics after multilevel cervical fusion and should be considered during surgical planning. CONCLUSIONS: The results of our biomechanical studies have improved our understanding of the impact of cervical sagittal malalignment on pathomechanics of the cervical spine. We believe this improved understanding will assist in clinical decision-making. PMID- 29110220 TI - Retrotransverse foramen of the atlas: prevalence and bony variations. AB - PURPOSE: To analyze the prevalence of the retrotransverse foramen (RTF) and its bony variations. METHODS: One hundred ten atlases of living adult subjects, 161 twentieth century dry adult cervical atlases and four dry adult cervical atlases from medieval skeletons were studied to detect the RTF and its abnormal bony variations. The 110 living adult subjects underwent a computed tomography study to detect the RTF. RESULTS: In the in vivo sample (n = 110; 100%), the RTF was found in four (3.6%) atlases. It was bilateral in all cases, but three (2.7%) patients showed complete RTF and the other patient presented a complete RTF in the left transverse process and an unclosed RTF in the right transverse process. In addition, the RTF was observed in combination with an unclosed transverse foramen in two cases (1.8%). In the twentieth century skeletal sample (n = 206; 100%) the RTF was found in 15 (7.3%) C1 vertebrae. It was bilateral in three (1.5%) vertebrae and unilateral in another 12 (5.8%) vertebrae. In the medieval skeletal sample (n = 4; 100%) one cadaveric atlas (25%) presented a bilateral RTF with special bony characteristics which presented an unexpected spicula in the left RTF. CONCLUSIONS: The RTF is a nonmetric variant of the atlas vertebra that can present non-degenerative and non-traumatic spiculae or it can be unclosed. In addition, it can be associated with the presence of unclosed transverse foramina. PMID- 29110221 TI - Transoral robotic surgery for oncocytic ductal cyst of hypopharynx: a lesion with a high probability of recurrence. AB - Hypopharyngeal cysts are very uncommon pathology. They are presented in adult people over 60 years. Although oncocytic cysts are benign tumors, an incomplete resection causes recurrence. The symptoms are not specific, but the more frequent are dyspnea and foreign body sensation upon swallowing. Diagnosis usually is under general anesthesia during intubation. A flexible fiberoptic laryngoscopy could be insufficient; the trumpet maneuver during this examination can reveled occult cysts. To perform a total resection, the surgeon must have a complete exposition of the operative field. We present a new case of a patient with a symptomatic hypopharyngeal cyst successfully treated with transoral robotic extirpation; our view was tridimensional magnified and the robotic instruments provided great range of movement that permitted complete and safe removal hypopharyngeal lesion. PMID- 29110222 TI - Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development. AB - Anti-drug antibodies (ADA) pose a potential risk to patient safety and efficacy and are routinely monitored during clinical trials. Pre-existing drug-reactive antibodies are present in patients without prior drug exposure and are defined by their ability to bind to a component of the drug. These pre-existing drug reactive antibodies are frequently observed and could represent an adaptive immune response of an individual who has been previously exposed to antigens with structural similarities to the biotherapeutic. Clinical consequences of these antibodies can vary from no impact to adverse effects on patient safety, exposure, and efficacy, and are highly dependent on biotherapeutic modality, disease indications, and patient demographics. This paper describes how the immunogenicity risk assessment of a biotherapeutic integrates the existence of pre-existing drug-reactive antibodies, and provides recommendations for risk based strategies to evaluate treatment-emergent ADA responses. PMID- 29110224 TI - Role of VEGF, CD105, and CD31 in the Prognosis of Colorectal Cancer Cases. AB - INTRODUCTION: Colorectal cancer (CRC) incidence is increasing globally. It is ranked as the second most common cancer in women and the third most in men. Angiogenesis plays a significant role in the development and spread of colorectal cancer. Angiogenesis has been proposed as a prognostic marker in a variety of human neoplasms. In this regard, markers of angiogenic endothelial cells are emerging as targets for cancer therapy. AIM OF THE WORK: The aim of this study is to evaluate the prognostic impact of tumor angiogenesis assessed by microvessel density (MVD) counting using CD31 and CD105 along with VEGF immunostaining in colorectal cancer patients. METHODS: VEGF, CD31, and CD105 expressions were evaluated using immunohistochemical staining in 50 patients with colorectal cancer. The relationship between their expressions and clinicopathological factors and outcome of patients were analyzed. RESULTS: The VEGF expression (70% of the cases) correlated significantly with larger tumor size, higher grade, and advanced tumor stage (p = 0.006, p < 0.001, p < 0.001), respectively. The mean MVD was 24.2 +/- VMD by CD105 (p = 0.10.65 019 for CD105, 19.2 +/- 8.41 for CD31, respectively. MVD by CD31 (p = 0.023)) and was significant predictive factors for overall survival. Furthermore, the VEGF expression (p = < 0.001) was a significant predictive factor for DFS. There was a statistically significant association between the recurrence rates with both VEGF and CD105 (p < 0.001) but not significant with CD31. CONCLUSION: CRC patients with high VEGF, CD105, and CD31 expression showed poor prognosis. The immunohistochemical markers could be used for stratification of patients into low-risk and high-risk groups. PMID- 29110225 TI - A Deregulated PI3K-AKT Signaling Pathway in Patients with Colorectal Cancer. AB - BACKGROUND: Molecular switches in phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway may serve as potential targets for the treatment of colorectal cancer (CRC). This study aims to profile the gene alterations involved in PI3K AKT signaling pathway in patients with CRC. METHODS: Tumoral and matched peritumoral tissues were collected from 15 CRC patients who went routine surgery. A human PI3K-AKT signaling pathway polymerase chain reaction (PCR) array, which profiled the transcriptional changes of a total number of 84 genes involved in the PI3K-AKT pathway, was then applied to determine the gene alterations in CRC tumoral tissue with matched peritumoral tissue as a healthy control. Subsequent real-time reverse transcription PCR and western blot (WB) with different subgroups of CRC patients were then performed to further validate the array findings. RESULTS: The PCR array identified 14 aberrantly expressed genes involved in the PI3K-AKT signaling pathway in CRC tumoral tissue, among which 12 genes, CCND1, CSNK2A1, EIF4E, EIF4EBP1, EIF4G1, FOS, GRB10, GSK3B, ILK, PTK2, PTPN11, and PHEB were significantly up-modulated (> two fold) while the remaining two, PDK1 and PIK3CG, were down-regulated (> two fold). These genes involve in the regulation of gene transcription and translation, cell cycle, and cell growth, proliferation, and differentiation. The real-time reverse transcription PCR validation agreed with the array data towards the tested genes, CCND1, EIF4E, FOS, and PIK3CG, while it failed to obtain similar result for PDK1. Interestingly, the WB analyses were further consistent with the PCR results that the protein levels of CCND1, EIF4E, and FOS were apparently up-regulated and that protein PIK3CG was down-modulated. CONCLUSION: Taken together, the present study identified a deregulated PI3K-AKT signaling pathway in CRC patients, which might serve as therapeutic target(s). PMID- 29110223 TI - The effectiveness and cost-effectiveness of plant sterol or stanol-enriched functional foods as a primary prevention strategy for people with cardiovascular disease risk in England: a modeling study. AB - This study appraises the effectiveness and cost-effectiveness of consumption of plant sterol-enriched margarine-type spreads for the prevention of cardiovascular disease (CVD) in people with hypercholesterolemia in England, compared to a normal diet. A nested Markov model was employed using the perspective of the British National Health Service (NHS). Effectiveness outcomes were the 10-year CVD risk of individuals with mild (4-6 mmol/l) and high (above 6 mmol/l) cholesterol by gender and age groups (45-54, 55-64, 65-74, 75-85 years); CVD events avoided and QALY gains over 20 years. This study found that daily consumption of enriched spread reduces CVD risks more for men and older age groups. Assuming 50% compliance, 69 CVD events per 10,000 men and 40 CVD events per 10,000 women would be saved over 20 years. If the NHS pays the excess cost of enriched spreads, for the high-cholesterol group, the probability of enriched spreads being cost-effective is 100% for men aged over 64 years and women over 74, at L20,000/QALY threshold. Probabilities of cost-effectiveness are lower at younger ages, with mildly elevated cholesterol and over a 10-year time horizon. If consumers bear the full cost of enriched spreads, NHS savings arise from reduced CVD events. PMID- 29110226 TI - Is Watchful Waiting an Option in Margin-Positive Solid Pseudopapillary Neoplasms of the Pancreas? PMID- 29110228 TI - Regulatory Fluctuation of WNT16 Gene Expression Is Associated with Human Gastric Adenocarcinoma. AB - INTRODUCTION: Gastric cancer is one of the most serious and lethal kinds of cancer in the world. It is a multi-step, multi-factor, and elaborated process that is associated to gene abnormal expression. This study intended to investigate the WNT16 gene's expression in human gastric tumor and the margin tissues of the stomach (normal tissues). METHODS: Correspondingly, 40 samples (20 tumoral tissues and 20 non tumoral or margins tissues) were investigated in Imam Khomeini Hospital in Sari City, Mazandaran Province, Iran. In this way, real-time PCR, Taqman assay was employed to evaluate the upregulation and downregulation of this gene in both tissues in triplicate form. The GAPDH gene was selected as housekeeping gene. RESULTS: Conspicuously, the results have shown a remarkable modification in tumoral tissues, and the gene expression increased significantly in tumoral tissue. CONCLUSIONS: Conclusively, the upregulation of WNTt16 gene expression in tumoral tissues was impressive and the P value was 0.005 and the SE range was 0.064-142.154. PMID- 29110227 TI - Clinical Factors as a Component of the Personalized Treatment Approach to Advanced Pancreatic Cancer: a Systematic Literature Review. AB - INTRODUCTION: Pancreatic cancer is often diagnosed at late stages, where disease is either locally advanced unresectable or metastatic. Despite advances, long term survival is relatively non-existent. DISCUSSION: This review article discusses clinical factors commonly encountered in practice that should be incorporated into the decision-making process to optimize patient outcomes, including performance status, nutrition and cachexia, pain, psychological distress, medical comorbidities, advanced age, and treatment selection. CONCLUSION: Identification and optimization of these clinical factors could make a meaningful impact on the patient's quality of life. PMID- 29110229 TI - Recurrence of Metastatic Pro-insulinoma Nearly 50 Years After Subtotal Pancreatectomy. PMID- 29110230 TI - Colonic Adenocarcinoma with Florid Vascular Proliferation Related to Intussusception. PMID- 29110232 TI - How important is woody tissue photosynthesis in EuCahetus dunnii Maiden and Osmanthus fragrans (Thunb.) Lour. under O3 stress? AB - Numerous studies have demonstrated the negative effects of elevated O3 on leaf photosynthesis. Within trees, a portion of respired CO2 is assimilated by woody tissue photosynthesis, but its response to elevated O3 remains unclear. Saplings of two evergreen tree species, EuCahetus dunnii Maiden (E. dunnii) and Osmanthus fragrans (Thunb.) Lour. (O. fragrans), were exposed to non-filtered air (NF), 100 nmol mol-1 O3 air (E1) and 150 nmol mol-1 O3 air (E2) in open-top chambers from May 5 to September 5, 2016 (8 h a day; 7 days a week) in subtropical China. In this study, O3 fumigation significantly reduced leaf net photosynthesis rate in both two tree species on most measurements. However, compared with leaf net photosynthesis rate, woody tissue gross photosynthesis rate showed less negative response to O3 fumigation and was even stimulated to increase. Refixation rate reflects the utilization efficiency of the respired CO2 by woody tissue photosynthesis. During the experiment period, E1 and E2 both increased refixation rate in O. fragrans compared with NF. Whereas for E. dunnii, E1 increased refixation rate until 81 days after starting of fumigation and then decreased it, and E2 decreased it all the time. Refixation rate had a significant positive correlation with woody tissue chlorophyll contents, indicating that the response of refixation rate to elevated O3 may relate to chlorophyll contents. All these suggested that under O3 fumigation, when atmospheric CO2 uptake and fixation by leaf is limited, woody tissue photosynthesis can contribute more to the total carbon assimilation in trees. The findings help to understand the significance of woody tissue photosynthesis under elevated O3 conditions. PMID- 29110231 TI - Treatment of synthetic textile wastewater containing dye mixtures with microcosms. AB - The aim was to assess the ability of microcosms (laboratory-scale shallow ponds) as a post polishing stage for the remediation of artificial textile wastewater comprising two commercial dyes (basic red 46 (BR46) and reactive blue 198 (RB198)) as a mixture. The objectives were to evaluate the impact of Lemna minor L. (common duckweed) on the water quality outflows; the elimination of dye mixtures, organic matter, and nutrients; and the impact of synthetic textile wastewater comprising dye mixtures on the L. minor plant growth. Three mixtures were prepared providing a total dye concentration of 10 mg/l. Findings showed that the planted simulated ponds possess a significant (p < 0.05) potential for improving the outflow characteristics and eliminate dyes, ammonium-nitrogen (NH4 N), and nitrate-nitrogen (NO3-N) in all mixtures compared with the corresponding unplanted ponds. The removal of mixed dyes in planted ponds was mainly due to phyto-transformation and adsorption of BR46 with complete aromatic amine mineralisation. For ponds containing 2 mg/l of RB198 and 8 mg/l of BR46, removals were around 53%, which was significantly higher than those for other mixtures: 5 mg/l of RB198 and 5 mg/l of BR46 and 8 mg/l of RB198 and 2 mg/l of BR46 achieved only 41 and 26% removals, respectively. Dye mixtures stopped the growth of L. minor, and the presence of artificial wastewater reduced their development. PMID- 29110233 TI - Preparation and application of unhairing enzyme using solid wastes from the leather industry-an attempt toward internalization of solid wastes within the leather industry. AB - Usage of the animal fleshing waste as the source of carbon and nitrogen for animal skin unhairing protease (EC 3.4.21) production along with agro-industrial wastes like wheat bran has been investigated. Thermal hydrolysis of delimed fleshing waste for 3 h yielded a fleshing hydrolysate (FH) having a protein content of 20.86 mg/mL and total solids of 46,600 ppm. The FH was lyophilized and spray dried to obtain fleshing hydrolysate powder (FHP) to be used along with wheat bran and rice bran for protease production. The carbon, nitrogen, hydrogen, and sulfur contents of the FHP were found to be 40.1, 13.8, 5.4, and 0.2%. The control solid-state fermented (SSF) medium without FHP showed a maximum activity of only 550 U/g. A maximum protease activity of 956 U/g was obtained by using 6% FHP (taken based on the combined total weight of wheat bran and rice bran) after 96 h of fermentation, resulting in a 1.7-fold increase in the protease activity. The total cost of producing 1 kg of FHP and the cost of producing 1000 kU of protease using FHP along with wheat bran and rice bran were found to be USD 24.62 and USD 2.08, respectively; 25% of SSF protease along with 40% water was found to be capable of unhairing the sheepskins in 7 h eliminating the hazardous conventional lime sulfide unhairing system. Thus, the leather industry's solid waste internalized for the production of unhairing enzyme resulted in a sustainable solution for pollution problems. Graphical abstract ?. PMID- 29110234 TI - Soil ecological criteria for nickel as a function of soil properties. AB - Scientific information for the chemistry and ecotoxicology of metals in soils has been obtained in the research conducted in recent years. However, the latest "science" obtained from this research has not yet been translated into "regulations" in China. In the present study, the predicted no effect concentrations (PNECs) for Ni which denoted as soil ecological criteria for Ni were derived based on the effects of soil properties on bioavailability/ecotoxicity of Ni, incorporating the differences in species sensitivity as well as in laboratory and field conditions. First, collected all ecotoxicity data of Ni from bioassays in Chinese soils and filtered with given criteria to obtain reliable data. Second, corrected the compiled data with either aging factor or leaching and aging factors simultaneously to eliminate the discrepancy caused by difference between laboratory and realistic field conditions. Prior to being put into a species sensitivity distribution (SSD) method to fit SSD curves, the corrected Ni ecotoxicity data were normalized with Ni ecotoxicity predictive models to modify the variation in Ni ecotoxicity caused by different soil properties. Then, the hazardous concentration for x% of the species (HCx) was figured out from the Ni SSD curve and the ecological criterion of Ni (PNEC) was set equal to HCx. Finally, predictive models for HCx were developed by quantifying the relationship between the Ni HCx and soil properties. Soil pH was the major factor controlling the values of HCx for Ni, with HC5 varying from 6.5 mg/kg in an acidic soil (pH 5.0) to 218.8 mg/kg in an alkaline soil (pH 8.5). The predictive models with parameters of soil pH and organic carbon (%) could calculate HCx with determination coefficients (R2) of 0.90-0.95. When soil cation exchange capacity was taken into account the third parameter, the predictive models could predict HCx more accurate with R2 values of 0.94 0.99. PMID- 29110235 TI - Automotive brake wear: a review. AB - Road transport systems generate toxic particulate matter (PM) when in motion, that ultimately finds its way to the atmosphere. The PM produced by road transport systems can be broadly classified as exhaust and non-exhaust emissions. Exhaust emission is primarily due to product of combustion, as is the case of internal combustion engines and the PM is released to the atmosphere through the tail. Non-exhaust PM sources can be classified as sources such as emissions due to brake wear, tyre wear, road surface wear and resuspension. Both exhaust and non-exhaust sources generate PM of various sizes and shapes that has an impact on our health. Strict legislations by authorities have led to reduced exhaust emissions; however, due to the nature of complexity of PM generation by non exhaust sources, effective control of non-exhaust emission still needs to be developed. Thus, as exhaust emissions are being controlled, non-exhaust is becoming a significant source of PM emission. The present paper reviews work done by previous researchers on non-exhaust PM and specifically, brake wear from road transport systems as this is one of the most important non-exhaust source of PM in the environment. The finding of the paper would be beneficial to policy makers and researchers. PMID- 29110236 TI - Correction to: X-linked hypophosphatemia and growth. AB - The authors of the article would like to note an error in the acknowledgements section of this paper. PMID- 29110237 TI - Prevalence of African swine fever virus and classical swine fever virus antibodies in pigs in Benue State, Nigeria. AB - This study investigated the prevalence of African swine fever virus (ASFV) and classical swine fever virus (CSFV) antibodies in pigs in Benue State, Nigeria. Serum samples were collected from a total of 460 pigs, including 416 from 74 piggeries and 44 from Makurdi slaughter slab. The samples were analysed using indirect enzyme-linked immunosorbent assay (ELISA) test kit to detect the presence of ASFV antibodies, while competitive ELISA test kit was used to detect antibodies to CSFV. Our findings showed a total ASF prevalence of 13 (2.8%), while prevalences of 7 (1.7%) and 6 (13.6%) were observed in piggeries and in Makurdi slaughter slab, respectively. However, no CSFV antibody sera were detected in this study. Relatively higher ASFV antibody-positive pigs were detected in the slaughter slab than in piggeries. The difference in prevalence of ASF between the two locations was significantly associated (p = 0.017). These findings suggest the presence of ASFV antibody-positive pig in Benue State, Nigeria. Continuous surveillance and monitoring of these diseases among pigs in Nigeria to prevent any fulminating outbreak are recommended. PMID- 29110238 TI - Herbage intake of dairy cows in mixed sequential grazing with breeding ewes as followers. AB - This study aimed to evaluate the hypothesis that mixed sequential grazing of dairy cows and breeding ewes is beneficial. During the seasons of spring-summer 2013 and autumn-winter 2013-2014, 12 (spring-summer) and 16 (autumn-winter) Holstein Friesian cows and 24 gestating (spring-summer) and lactating (autumn winter) Pelibuey ewes grazed on six (spring-summer) and nine (autumn-winter) paddocks of alfalfa and orchard grass mixed pastures. The treatments "single species cow grazing" (CowG) and "mixed sequential grazing with ewes as followers of cows" (MixG) were evaluated, under a completely randomized design with two replicates per paddock. Herbage mass on offer (HO) and residual herbage mass (RH) were estimated by cutting samples. The estimate of herbage intake (HI) of cows was based on the use of internal and external markers; the apparent HI of ewes was calculated as the difference between HO (RH of cows) and RH. Even though HO was higher in CowG, the HI of cows was higher in MixG during spring-summer and similar in both treatments during autumn-winter, implying that in MixG the effects on the cows HI of higher alfalfa proportion and herbage accumulation rate evolving from lower residual herbage mass in the previous cycle counteracted that of a higher HO in CowG. The HI of ewes was sufficient to enable satisfactory performance as breeding ewes. Thus, the benefits of mixed sequential grazing arose from higher herbage accumulation, positive changes in botanical composition, and the achievement of sheep production without negative effects on the herbage intake of cows. PMID- 29110239 TI - T 2 mapping of cerebrospinal fluid: 3 T versus 7 T. AB - OBJECT: Cerebrospinal fluid (CSF) T 2 mapping can potentially be used to investigate CSF composition. A previously proposed CSF T 2-mapping method reported a T 2 difference between peripheral and ventricular CSF, and suggested that this reflected different CSF compositions. We studied the performance of this method at 7 T and evaluated the influence of partial volume and B 1 and B 0 inhomogeneity. MATERIALS AND METHODS: T 2-preparation-based CSF T 2-mapping was performed in seven healthy volunteers at 7 and 3 T, and was compared with a single echo spin-echo sequence with various echo times. The influence of partial volume was assessed by our analyzing the longest echo times only. B 1 and B 0 maps were acquired. B 1 and B 0 dependency of the sequences was tested with a phantom. RESULTS: T 2,CSF was shorter at 7 T compared with 3 T. At 3 T, but not at 7 T, peripheral T 2,CSF was significantly shorter than ventricular T 2,CSF. Partial volume contributed to this T 2 difference, but could not fully explain it. B 1 and B 0 inhomogeneity had only a very limited effect. T 2,CSF did not depend on the voxel size, probably because of the used method to select of the regions of interest. CONCLUSION: CSF T 2 mapping is feasible at 7 T. The shorter peripheral T 2,CSF is likely a combined effect of partial volume and CSF composition. PMID- 29110240 TI - Manipulating transmit and receive sensitivities of radiofrequency surface coils using shielded and unshielded high-permittivity materials. AB - OBJECTIVE: To use high-permittivity materials (HPM) positioned near radiofrequency (RF) surface coils to manipulate transmit/receive field patterns. MATERIALS AND METHODS: A large HPM pad was placed below the RF coil to extend the field of view (FOV). The resulting signal-to-noise ratio (SNR) was compared with that of other coil configurations covering the same FOV in simulations and experiments at 7 T. Transmit/receive efficiency was evaluated when HPM discs with or without a partial shield were positioned at a distance from the coil. Finally, we evaluated the increase in transmit homogeneity for a four-channel array with HPM discs interposed between adjacent coil elements. RESULTS: Various configurations of HPM increased SNR, transmit/receive efficiency, excitation/reception sensitivity overlap, and FOV when positioned near a surface coil. For a four-channel array driven in quadrature, shielded HPM discs enhanced the field below the discs as well as at the center of the sample as compared with other configurations with or without unshielded HPM discs. CONCLUSION: Strategically positioning HPM at a distance from a surface coil or array can increase the overlap between excitation/reception sensitivities, and extend the FOV of a single coil for reduction of the number of channels in an array while minimally affecting the SNR. PMID- 29110241 TI - Relative enhanced diffusivity: noise sensitivity, protocol optimization, and the relation to intravoxel incoherent motion. AB - OBJECTIVE: To explore the relationship between relative enhanced diffusivity (RED) and intravoxel incoherent motion (IVIM), as well as the impact of noise and the choice of intermediate diffusion weighting (b value) on the RED parameter. MATERIALS AND METHODS: A mathematical derivation was performed to cast RED in terms of the IVIM parameters. Noise analysis and b value optimization was conducted by using Monte Carlo calculations to generate diffusion-weighted imaging data appropriate to breast and liver tissue at three different signal-to noise ratios. RESULTS: RED was shown to be approximately linearly proportional to the IVIM parameter f, inversely proportional to D and to follow an inverse exponential decay with respect to D*. The choice of intermediate b value was shown to be important in minimizing the impact of noise on RED and in maximizing its discriminatory power. RED was shown to be essentially a reparameterization of the IVIM estimates for f and D obtained with three b values. CONCLUSION: RED imaging in the breast and liver should be performed with intermediate b values of 100 and 50 s/mm2, respectively. Future clinical studies involving RED should also estimate the IVIM parameters f and D using three b values for comparison. PMID- 29110242 TI - Perioperative Mortality Following Bariatric Surgery in Australia. AB - BACKGROUND: Bariatric surgery is the most effective method of sustainable weight loss for the treatment of morbid obesity. Low mortality associated with these procedures has been reported internationally; however, Australian outcomes are yet to be published. Despite its efficacy, limited access to bariatric surgery exists in Australian public hospitals. This retrospective data analysis was conducted for two reasons. Firstly, to determine the perioperative mortality rate (POMR) associated with bariatric procedures in Australia, and secondly, to compare public and private hospital bariatric surgery admission demographics and outcomes. METHOD: A retrospective review of de-identified patient data from the National Hospital Morbidity Database, held by the Australian Institute of Health and Welfare (AIHW), was conducted using codes relating to bariatric procedures. POMR calculations were established using AIHW admission data from 1 July 2005 to 30 June 2013. RESULTS: From 1 July 2005 to 30 June 2013, 113,929 patient admissions occurred for patients undergoing a bariatric procedure. Thirty-nine deaths occurred nationally, with an overall average POMR of 0.03%. A higher POMR was associated with public admissions and secondary procedures. A higher proportion of secondary procedures were performed in public hospitals. Primary bariatric procedure incidence increased throughout the study period while secondary bariatric procedure incidence decreased. CONCLUSION: This study demonstrates the Australian bariatric procedure POMR to be substantially lower than internationally reported figures. Public hospitals were shown to perform far fewer bariatric procedures at a higher POMR than private hospitals. Public hospitals performed a higher proportion of secondary revision procedures. PMID- 29110243 TI - Problematic Alcohol Use and Associated Characteristics Following Bariatric Surgery. AB - PURPOSE: Evidence suggests that a significant minority of individuals who undergo Roux-en-Y gastric bypass (RYGB) experience problematic alcohol and substance use following surgery. However, little research has examined characteristics, drinking patterns, and possible risk factors within this population. To provide descriptive information of a sample of adults with self-identified alcohol use problems following bariatric surgery, this study examined (1) alcohol and substance use symptoms using standardized assessments, (2) current and past psychiatric comorbidity, (3) subjective changes in alcohol sensitivity following surgery, and (4) specific patterns of alcohol use prior to and following bariatric surgery. MATERIALS AND METHODS: Adult participants (N = 26) completed a series of structured diagnostic interviews and self-report assessments (e.g., Alcohol Use Disorders Identification Test [AUDIT], Michigan Alcohol Screening Test [MAST], Drug Abuse Screening Test [DAST]) by telephone 1 to 4 years following a RYGB or sleeve gastrectomy. RESULTS: All participants met objective criteria for current problematic alcohol use based on AUDIT and MAST cutoff scores, reported increased subjective sensitivity to alcohol following surgery, and evidenced significant current and past psychiatric comorbidities, most notably previous major depression (45.5%). Approximately one third of participants evidenced new-onset Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) alcohol use or dependence following surgery. Preoperative drinking frequencies and quantities were similar to those reported during the period of the heaviest postoperative alcohol use. CONCLUSIONS: Findings have implications for pre- and postoperative prevention and intervention efforts. Additional research is needed to further elucidate risk factors for problematic alcohol use following bariatric surgery. PMID- 29110244 TI - The Effect of 6 and 12 months Duodenal-Jejunal Bypass Liner Treatment on Obesity and Type 2 Diabetes: a Crossover Cohort Study. AB - OBJECTIVE: The aim of this research was to study the duodenal-jejunal bypass liner (DJBL) treatment for obesity and type 2 diabetes mellitus (T2DM) in patients after dietary treatment in a cross-over design. BACKGROUND: DJBL treatment has been proven effective for treatment of obesity and T2DM. However, data on safety and efficacy of a 12-month DJBL treatment is limited. METHODS: In 2014, our research group reported on a multicenter randomized clinical trial. Patients were randomized to DJBL or dietary treatment (control group). Twenty eight patients crossed over after their dietary treatment and received up to 12 months of DJBL treatment. Patient visits were conducted at baseline, during DJBL treatment (1 week, 1-6, 9, 12 months) and 6 months after removal of the liner. Patients underwent a standard physical examination, blood sampling, assessment of adverse events, nutritional and diabetes counseling, and a standardized meal tolerance test. RESULTS: Of the 28 patients included in this study, 24 patients completed 6 months of treatment. Eighteen patients were extended to 12 months of DJBL treatment; 13 patients completed this treatment period. After 6 months of DJBL treatment, a significant increase in excess weight loss (EWL) and decrease in weight, BMI, HbA1c, fasting glucose, cholesterol, HDL and LDL improved significantly. After 12 months of DJBL treatment, these parameters stabilized. CONCLUSIONS: The DJBL is an effective, minimally invasive treatment option. Even after successful treatment with dietary restrictions, the DJBL is still capable of significantly reducing weight and improving cardiovascular and type 2 diabetes mellitus parameters in obese patients. PMID- 29110245 TI - Quality Assessment of Information on Bariatric Surgery Websites. AB - OBJECTIVE: The aim of this study was to assess the quality of patient information on bariatric surgery in the internet using the modified Ensuring Quality Information for Patients (EQIP) tool. METHODS: Systematic review of information on bariatric surgery in the internet by entering common search terms into five search engines. The top 100 websites of every search term and search engine were assessed using the validated EQIP tool (maximum score, 36), which entails points for content, structure, and identification data of a given website. Websites at or above the 99th percentile were analyzed separately (n = 8). RESULTS: The median EQIP score of all included websites (n = 463) was 17 (IQR 15-19). While information on the medical problem, the indication for surgery, or the treatment alternatives was present in 84% of all websites, only 10% of the included websites contained adequate information on postoperative complications. Although quantitative information on incidence (37.5%) and treatment of complications (12.5%) was significantly better in the top 99th percentile websites, the content of relevant information such as occurrence and treatment of complications was still very limited. CONCLUSION: The overall quality of patient information on bariatric surgery in the internet is relatively poor. Especially incidence of complications and their treatment are rarely reported even on websites with a 99th percentile EQIP score. PMID- 29110246 TI - Preparation of Palladium(II) Ion-Imprinted Polymeric Nanospheres and Its Removal of Palladium(II) from Aqueous Solution. AB - Three kinds of functional monomers, 4-vinylpridine(4-VP), 2-(allylthio)nicotinic acid(ANA), and 2-Acetamidoacrylic acid(AAA), were used to synthetize palladium(II) ion-imprinted polymeric nanospheres (Pd(II) IIPs) via precipitation polymerization method in order to study the effects of different functional monomers on the adsorption properties of ion-imprinted materials. The results of UV spectra in order to study the interaction between template ion PdCl42- and functional monomers showed that there were great differences in structure after the template reacted with three functional monomers, 4-VP and ANA caused a large structural change, while AAA basically did not change. Further results on the adsorption performance of Pd(II) IIPs on Pd(II) confirmed 4-VP was the most promising candidate for the synthesis of Pd(II) IIPs with an adsorption capacity of 5.042 mg/g as compared with ANA and AAA. The influence of operating parameters on Pd(II) IIP's performance on Pd(II) adsorption was investigated. There was an increase in the adsorption capacity of Pd(II) IIPs at higher pH, temperature, and initial concentration of Pd(II). The results of multi-metal competitive adsorption experiments showed that Pd(II) IIPs had selectivity for Pd(II). An adsorption equilibrium could be reached at 180 min. Kinetic analysis showed that the adsorption test data fitted best to the pseudo-second order kinetic model, and the theoretical equilibrium adsorption capacity was about 5.085 mg/g. The adsorption isotherms of Pd(II) by Pd(II) IIPs agreed well with the Freundlich equation, suggesting a favorable adsorption reaction under optimal conditions. These results showed that Pd(II) IIPs have potential application in the removal of Pd(II) from aqueous solutions and may provide some information for the selection of functional monomers in the preparation of Pd(II) IIPs. PMID- 29110247 TI - The effect of pre-cueing on spatial attention across perception and action. AB - It is well established that processes of perception and action interact. A key question concerns the role of attention in the interaction between perception action processes. We tested the hypothesis that spatial attention is shared by perception and action. We created a dual-task paradigm: In one task, spatial information is relevant for perception (spatial-input task) but not for action, and in a second task, spatial information is relevant for action (spatial-output task) but not for perception. We used endogenous pre-cueing, with two between subjects conditions: In one condition the cue was predictive only for the target location in the spatial-input task; in a second condition the cue was predictive only for the location of the response in the spatial-output task. In both conditions, the cueing equally affected both tasks, regardless of the information conveyed by the cue. This finding directly supports the shared input-output attention hypothesis. PMID- 29110248 TI - Why target the tumor stroma in melanoma? AB - Melanoma metastasis is fatal. Melanoma cells are often characterized by an activated extracellular signal-regulated kinase (ERK) pathway downstream of mutations in BRAF. Therapies targeting these BRAF mutations are useful for a while; however, patients ultimately develop resistance to these therapies. Recent evidence suggests that this resistance occurs when tumor cells leave their microenvironment and migrate on a stiff, activated tumor stroma; that is, this resistance is linked to the presence of an extracellular matrix reminiscent of a fibrotic micronvironment. These data suggest that agents targeting fibrosis might be used to treat melanoma. We therefore discuss what is known about the tumor stroma in melanoma. An emergent target, CCN2 (CTGF), that is required for fibrosis, may also be a good target for drug-resistant melanoma. Intriguingly, anti-CCN2 antibodies are currently under clinical development. PMID- 29110249 TI - TRIM proteins in blood cancers. AB - Post-translational modification of proteins with ubiquitin plays a central role in regulating numerous cellular processes. E3 ligases determine the specificity of ubiquitination by mediating the transfer of ubiquitin to substrate proteins. The family of tripartite motif (TRIM) proteins make up one of the largest subfamilies of E3 ligases. Accumulating evidence suggests that dysregulation of TRIM proteins is associated with a variety of diseases. In this review we focus on the involvement of TRIM proteins in blood cancers. PMID- 29110250 TI - Treatment with the PPARgamma Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats. AB - Neurogenesis is essential for a good post-stroke outcome. Exogenous stem cells are currently being tested to promote neurogenesis after stroke. Elsewhere, we demonstrated that treatment with the PPARgamma agonist pioglitazone (PGZ) before cerebral ischemia induction reduced brain damage and activated survival-related genes in ovariectomized (OVX) rats. Here, we tested our hypothesis that post ischemia treatment with PGZ inhibits brain damage and contributes to neurogenesis via activated stem cells. Bone marrow (BM) cells of 7-week-old Wistar female rats were replaced with BM cells from green fluorescent protein-transgenic (GFP+BM) rats. Three weeks later, they were ovariectomized (OVX/GFP+BM rats). We subjected 7-week-old Wistar male and 13-week-old OVX/GFP+BM rats to 90-min cerebral ischemia. Male and OVX/GFP+BM rats were divided into two groups, one was treated with PGZ (2.5 mg/kg/day) and the other served as the vehicle control (VC). In both male and OVX/GFP+BM rats, post-ischemia treatment with PGZ reduced neurological deficits and the infarct volume. In male rats, PGZ decreased the mRNA level of IL-6 and M1-like macrophages after 24 h. In OVX/GFP+BM rats, PGZ augmented the proliferation of resident stem cells in the subventricular zone (SVZ) and the recruitment of GFP+BM stem cells on days 7-14. Both types of proliferated stem cells migrated from the SVZ into the peri-infarct area. There, they differentiated into mature neurons, glia, and blood vessels in association with activated Akt, MAP2, and VEGF. Post-ischemia treatment with PGZ may offer a new avenue for stroke treatment through contribution to neuroprotection and neurogenesis. PMID- 29110251 TI - Inhibition of two gastric cancer cell lines induced by fucoxanthin involves downregulation of Mcl-1 and STAT3. AB - Fucoxanthin is a natural carotenoid that had never been previously demonstrated to have anti-tumor effect on human gastric adenocarcinoma SGC-7901 or BGC-823 cells. Here it was found to inhibit proliferation and induce apoptosis through JAK/STAT signal pathway in these cells; the mechanism by which this occurred was investigated. We find that fucoxanthin significantly increased the number of apoptotic cells by propidium iodide (PI) dye staining and flow cytometry. Fucoxanthin (50 or 75 MUM) induced SGC-7901 cells cycle arrest at S phase, while BGC-823 cells arrest at G2/M phase. RT-PCR and western blot analysis revealed that the expressions of Mcl-1, STAT3 and p-STAT3 were obviously decreased by fucoxanthin in a dose-dependent manner. Synthetic siRNA targeting Mcl-1 was transfected into cells which had no effect on expressions of STAT3. After pretreatment with AG490 (50 MUM) which led to blocking of the JAK/STAT signal pathway, the reductive expressions of Mcl-1, STAT3 and p-STAT3 caused by fucoxanthin were inhibited. This is the first analysis of effects on SGC-7901 and BGC-823 cells by fucoxanthin. Fucoxanthin can induce cell-cycle arrest and apoptosis in these cells. These effects involved downregulation of Mcl-1, STAT3 and p-STAT3. This work is significant for better understanding of mechanisms leading to human gastric adenocarcinoma formation and informing exploitation of anti-tumor marine drug, and for providing Mcl-1 and STAT3 as potential therapeutic targets for gastric adenocarcinoma. PMID- 29110252 TI - Risk of Psoriasis Following Terbinafine or Itraconazole Treatment for Onychomycosis: A Population-Based Case-Control Comparative Study. AB - INTRODUCTION: Several case studies have reported an association between antifungal drug use and psoriasis risk. OBJECTIVE: The objective of this study was to investigate the association between terbinafine/itraconazole exposure and psoriasis incidence. METHODS: Among patients with onychomycosis in the Taiwan National Health Insurance Research Database, 3831 incident psoriasis cases were identified during 2004-2010 and compared with 3831 age- and sex-matched controls with the same look-back period. Multivariate conditional logistic regression was used for the analysis. RESULTS: The psoriasis cases were significantly more likely than matched controls to have used terbinafine or itraconazole (59.85 vs. 42.70%, respectively; p < 0.0001). After adjusting for potential confounders and cumulative duration of antifungal drug prescription, terbinafine/itraconazole use was associated with an increased psoriasis risk (adjusted odds ratio 1.33, 95% confidence interval 1.15-1.54). The association was stronger for more recent drug exposure (adjusted odds ratio 2.96, 95% confidence interval 2.25-3.90 for <= 90 days before the sampling date; adjusted odds ratio 1.04, 95% confidence interval 0.89-1.22 for > 360 days). In a comparison of patients receiving terbinafine or itraconazole only, psoriasis risk was higher for itraconazole (adjusted odds ratio 1.21, 95% confidence interval 1.05-1.40). CONCLUSION: This large population based case-control analysis showed that exposure to terbinafine or itraconazole is associated with an increased risk of incident psoriasis. The finding of an increased psoriasis risk for antifungal drug users, particularly for itraconazole, deserves attention in clinical practice although further prospective studies are necessary to confirm our findings and clarify the biological mechanisms that underlie these associations. PMID- 29110254 TI - Socialization Goals, Parental Psychological Control, and Youth Anxiety in Chinese Students: Moderated Indirect Effects based on School Type. AB - With rates of adolescent anxiety on the rise in China, it is imperative to investigate whether certain parenting beliefs and practices may be related to anxiety. Specifically, we tested whether parents' socialization goals relate to parental psychological control, and subsequently, adolescents' anxiety. We also tested if attending a "key" school (i.e., more competitive and achievement oriented) or typical school moderated relations. Two hundred forty-seven high school students (Mage = 15.62, 57.5% girls) and a caregiver (59.5% mothers) participated. Caregivers completed measures of their socialization goals and their own psychological control. Adolescents reported on their perceptions of parental psychological control and their own anxiety. Psychological control was positively related to youth anxiety. Moderated indirect effects were found. For youth in typical schools, parents who strongly value academic achievement (i.e., achievement oriented goals) and those who strongly value broadening one's experiences in new places and with new people (i.e., self-development in context goals) had youth who experienced more anxiety, and this relation occurred indirectly through greater parental psychological control. For youth in key schools, only parents' achievement oriented goals were related to youth anxiety indirectly through parental psychological control. Parents' interdependence oriented socialization goals were unrelated to either psychological control or anxiety. PMID- 29110256 TI - Philosophy of medicine 2017: reviewing the situation. AB - In this introduction to a special subsection of Theoretical Medicine and Bioethics comprising separate reviews of the Springer Handbook of the Philosophy of Medicine, The Routledge Companion to Philosophy of Medicine, and The Bloomsbury Companion to Contemporary Philosophy of Medicine, I compare the three texts with respect to their overall organization and their approach to the relation between the science and the art of medicine. I then indicate two areas that merit more explicit attention in developing a comprehensive philosophy of medicine going forward: health economics and systematic relations within the field as a whole. The reviews that follow speak for themselves. PMID- 29110259 TI - Antifungal Activity of Lactobacillus pentosus LOCK 0979 in the Presence of Polyols and Galactosyl-Polyols. AB - The antifungal activity of Lactobacillus pentosus LOCK 0979 depends both on the culture medium and on the fungal species. In the control medium, the strain exhibited limited antagonistic activity against indicator food-borne molds and yeasts. However, the supplementation of the bacterial culture medium with polyols (erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol) or their galactosyl derivatives (gal-erythritol, gal-sorbitol, gal-xylitol) enhanced the antifungal properties of Lactobacillus pentosus LOCK 0979. Its metabolites were identified and quantified by enzymatic methods, HPLC, UHPLC-MS coupled with QuEChERS, and GC MS. The presence of polyols and gal-polyols significantly affected the acid metabolite profile of the bacterial culture supernatant. In addition, lactitol and mannitol were used by bacteria as alternative carbon sources. A number of compounds with potential antifungal properties were identified, such as phenyllactic acid, hydroxyphenyllactic acid, and benzoic acid. Lactobacillus bacteria cultivated with mannitol synthesized hydroxy-fatty acids, including 2 hydroxy-4-methylpentanoic acid, a well-described antifungal agent. Scanning electron microscopy (SEM) and light microscopy confirmed a strong antifungal effect of L. pentosus LOCK 0979. PMID- 29110261 TI - The Significance of Long Non-coding RNA HULC in Predicting Prognosis and Metastasis of Cancers: a Meta-Analysis. AB - Long non-coding RNAs (lncRNAs) have been demonstrated that they not only play important roles in tumorgenicity but also associate with cancer prognosis. Recently, highly up-regulated in liver cancer (HULC) is abnormally expressed in liver cancer and other cancers, and participated in cancers progression; however, it is unclear whether its expression is associated with prognosis. Here, we performed a meta-analysis and systematic review to evaluate the prognostic value and metastasis of HULC in various cancer patients. The meta-analysis was performed using a systematic search of PubMed, Web of Science, ScienceDirect and Wiley Online Library database to eligible studies. The pooled hazard ratios (HRs) with a 95% confidence interval (95% CI) were calculated to assess its prognosis and metastasis in human cancer. A total of 1134 patients from 11 studies were included. The results indicated that overexpression of HULC was associated with poor overall survival (OS) (HR = 1.89, 95% CI: 1.32-2.47). Furthermore, subgroup analysis showed that cancer type (digestive system cancer or non-digestive system cancers) and sample size (more or less than 100) significantly associated between HULC and OS. In addition, overexpression of HULC expression was significantly associated with metastasis in cancers (HR = 2.67, 95% CI: 0.94-4.39). The meta analysis indicated that lncRNA HULC could serve as a new molecular marker for cancer prognosis and metastasis. PMID- 29110260 TI - Disparities in reproductive outcomes according to the endometrial preparation protocol in frozen embryo transfer : The risk of early pregnancy loss in frozen embryo transfer cycles. AB - PURPOSE: The purpose of this study was to determine the effect of stimulated and artificial endometrial preparation protocols on reproductive outcomes in frozen embryo transfer (FET) cycles. METHODS: We performed a retrospective study of 1926 FET cycles over a 3.5-year period in the Fertility Unit at a University Hospital. Stimulated and artificial protocols were used for endometrial preparation. The embryos for FET were obtained from either in vitro fertilization or intracytoplasmic sperm injection cycles. Live birth rate and early pregnancy loss rates were retrospectively compared. In artificial protocols, oral or vaginal administration of oestradiol 2 mg two or three times a day was followed by vaginal supplementation with progesterone 200 mg two or three times a day. In stimulated protocols, recombinant follicle-stimulating hormone was administered from day 4 onward. Vaginal ultrasound was used for endometrial and ovarian monitoring. A pregnancy test was performed 14 days after FET. If it was positive, oestradiol and progesterone were administered up until the 12th week of gestation in artificial cycles. We defined early pregnancy losses as biochemical pregnancies (preclinical losses) and miscarriages. RESULTS: Data on 865 artificial cycles (45% of the total) and 1061 stimulated cycles (55%) were collected. Early pregnancy loss rate was significantly lower for stimulated cycles (34.2%) than for artificial cycles (56.9%), and the live birth rate was significantly higher for stimulated cycles (59.7%) than for artificial cycles (29.1%). CONCLUSION: In frozen embryo transfer, artificial cycles were associated with more early pregnancy loss and lower live birth rate than stimulated cycles. PMID- 29110262 TI - Mutational Diversity of Lung Cancer and Associated Lymph Nodes. An Exploratory Prospective Study of 4 Resected cIIIA-N2. AB - Mutational heterogeneity could explain different metastatic patterns among IIIA N2 lung cancer and influence prognosis. The identification of subclonal mutations using deep sequencing to evaluate the degree of molecular heterogeneity may improve IIIA-N2 classification. The aim of this prospective study was to assess mutational and immunohistochemical characteristics in primary tumours and involved lymph nodes (LN) in operated patients. Four patients operated for primary lung carcinoma and unisite N2 mediastinal involvement were consecutively selected. Samples (tumour and paired LN) were analysed for PD1, PD-L1 and CD8 immunostaining. Somatic mutation testing was performed by deep targeted next generation sequencing (NGS), with the AmpliSeqTM Colon and Lung Cancer Panel (LifeTechnology). A total of 9 primary lung cancer samples and 10 LN stations were analysed. For each cancer, we found 2 mutations, with allelic ratios from 3% to 72%. Mutational patterns were heterogeneous for 2 primary tumours. In 3 cases, mutations observed in the primary tumour were not found in LN metastases (ALK, FGFR3, MET). Inversely, in 1 case, a KRAS mutation was found in LN but not in the primary tumour. All primary tumours were found PD-L1 positive while CD8+ T cells infiltrate varied. In the different examined LN samples, PD-L1 expression, CD8+ and PD1+ T cells infiltrate were not similar to the primary tumour. This preliminary prospective study shows the diversity of intra-tumour and LN mutations using routinely-used targeted NGS, concerning both mutated gene and allelic ratio. Further studies are needed to evaluate its prognostic impact. PMID- 29110263 TI - Long-term meditation: the relationship between cognitive processes, thinking styles and mindfulness. AB - The aim of this study is to examine the relationship between meditation and cognitive functions. More in depth the purpose is to demonstrate that long-term meditation practice improves attention skills and cognitive flexibility. Eighteen long-term meditation practitioners were compared to a matched control group, who never practiced meditation. Each subject was tested, using computerized software (Presentation Software 9.90), which measured: attention, visual search abilities, working memory and Stroop's interference tasks. Furthermore, we examined the relationship between long-term meditation practice, mindfulness skills and thinking styles, namely styles of processing information. The results showed significant differences between the two groups, demonstrating that long-term meditation is linked to improvements of attentional functions, working memory and cognitive flexibility. PMID- 29110264 TI - Optimization of Drug Prescription and Medication Management in Older Adults with Cardiovascular Disease. AB - Cardiovascular disease increases incrementally with age and elderly patients concomitantly sustain multimorbidities, with resultant prescription of multiple medications. Despite conforming with disease-specific cardiovascular clinical practice guidelines, this polypharmacy predisposes many elderly individuals with cardiovascular disease to adverse drug events and non-adherence. Patient-centered care requires that the clinician explore with each patient his or her goals of care and that this shared decision-making constitutes the basis for optimization of medication management. This approach to aligning therapies with patient preferences is likely to promote patient satisfaction, to limit morbidity, and to favorably affect healthcare costs. PMID- 29110265 TI - Correction to: Impact Performance of Modern Football Helmets. AB - This erratum is to correct headings listing the impact location and speed in Figs. 5 and 6. The following provides corrected Figs. 5 and 6. The data is unchanged. The authors apologize for any inconvenience this might have caused. PMID- 29110266 TI - Reparative Effects of Poloxamer P188 in Astrocytes Exposed to Controlled Microcavitation. AB - Blast-induced traumatic brain injury (bTBI) is a neurological dysfunction that can result from a sudden exposure to shockwave and lead to adverse health consequences. Currently, there are no preventive measures that specifically target bTBI. Several hypotheses have been formulated to explain such injuries, including the generation of microcavitation (e.g., microbubbles) in the brain that subsequently collapses with high pressure. This study was designed to explore and elucidate potential therapeutic effects of surfactants (poloxamers P188) to partially repair the damaged brain tissue due to bTBI. A controlled electrical discharge system was designed and validated to generate microbubbles of 20-30 MUm in size. Using this system, we tested the hypothesis that the P188 can partially rescue astrocytes exposed to collapsing microbubbles. The immediate impact of the collapse of microbubbles created a crater-like region in which astrocytes detached from the substrate. Of those cells that survived the initial mechanical assault, the poloxamer P188 demonstrated reparative potential by partially restoring calcium spiking and minimizing the production of reactive oxygen species. The FDA-approved P188 may offer a potential therapeutic treatment for those exposed to a blast and suffered bTBI. PMID- 29110267 TI - The Journal and 15 Years. PMID- 29110268 TI - Eliminating the Glass Ceiling in Academic Psychiatry. PMID- 29110269 TI - Perspectives of Religion and Spirituality in Psychiatry: a Comparison of Students, Residents, and Attending Physicians. PMID- 29110270 TI - Development and Implementation of a Residency Area-of-Distinction in Lesbian, Gay, Bisexual, and Transgender Mental Health. PMID- 29110272 TI - Impact of County Rurality and Urologist Density on the Practice of Inguinal Lymph Node Dissection and Mortality in Patients Diagnosed with Squamous Cell Carcinoma of the Penis. AB - BACKGROUND: Inguinal lymphadenectomy (LND) is influential in reducing the mortality of squamous cell carcinoma of the penis (SCCP). We investigated the impact of urologic workforce density (UD) and rural residence (RR) on the practice of LND and mortality of SCCP (SCCP-RM). MATERIALS AND METHODS: UD was determined from the 2014 to 2015 Area Health Resource File data, while RR was determined using the 2003 rural-urban continuum codes. All cases of SCCP within the surveillance, epidemiology, and end results 18 registry with known county codes were used for analysis (n = 2863). RESULTS: Overall, 48.69% of cases lived in a county with less than the mean UD, 8.38% lived in counties with no urologists, 14.60% lived in a rural county, and 19.2% (n = 550) had LND performed. UD and RR had no impact on the prevalence of LND, number of lymph nodes examined, or the mean number of lymph nodes positive for SCCP (all p > 0.05). Adjusted analysis indicated that older patients and patients with regional stage of cancer were at a greater risk for post-LND SCCP-RM (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.28-2.21, and HR 4.32, 95% CI 3.09-6.06, respectively). There was no difference in the HR of SCCP-RM dependent on race, marital status, education, RR, UD, or LND. CONCLUSION: While demand on the urologist workforce has increased in rural demographics, no impact of limited access to urologists on the practice of LND in SCCP could be identified in this study. In addition, there was no significant difference in the risk of SCCP specific mortality related to lower UD or RR. PMID- 29110271 TI - Induced Bias Due to Crossover Within Randomized Controlled Trials in Surgical Oncology: A Meta-regression Analysis of Minimally Invasive versus Open Surgery for the Treatment of Gastrointestinal Cancer. AB - BACKGROUND: Randomized controlled trials (RCTs) inform clinical practice and have provided the evidence base for introducing minimally invasive surgery (MIS) in surgical oncology. Crossover (unplanned intraoperative conversion of MIS to open surgery) may affect clinical outcomes and the effect size generated from RCTs with homogenization of randomized groups. OBJECTIVES: Our aims were to identify modifiable factors associated with crossover and assess the impact of crossover on clinical endpoints. METHODS: A systematic review was performed to identify all RCTs comparing MIS with open surgery for gastrointestinal cancer (1990-2017). Meta-regression analysis was performed to analyze factors associated with crossover and the influence of crossover on endpoints, including 30-day mortality, anastomotic leak rate, and early complications. RESULTS: Forty RCTs were included, reporting on 11,625 patients from 320 centers. Crossover was shown to affect one in eight patients (mean 12.6%, range 0-45%) and increased with American Society of Anesthesiologists score (beta = + 0.895; p = 0.050). Pretrial surgeon volume (beta = - 2.344; p = 0.037), composite RCT quality score (beta = - 7.594; p = 0.014), and site of tumor (beta = - 12.031; p = 0.021, favoring lower over upper gastrointestinal tumors) showed an inverse relationship with crossover. Importantly, multivariate weighted linear regression revealed a statistically significant positive correlation between crossover and 30-day mortality (beta = + 0.125; p = 0.033), anastomotic leak rate (beta = + 0.550; p = 0.004), and early complications (beta = + 1.255; p = 0.001), based on intention to-treat analysis. CONCLUSIONS: Crossover in trials was associated with an increase in 30-day mortality, anastomotic leak rate, and early complications within the MIS group based on intention-to-treat analysis, although our analysis did not assess causation. Credentialing surgeons by procedural volume and excluding high comorbidity patients from initial trials are important in minimizing crossover and optimizing RCT validity. PMID- 29110273 TI - Vitamin D Levels Affect Breast Cancer Survival Rates. PMID- 29110274 TI - Does Red Blood Cell Distribution Width Really Have a Prognostic Role in Upper Tract Urothelial Carcinoma? PMID- 29110275 TI - Impact of Cellularity on Oncologic Outcomes Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Pseudomyxoma Peritonei. AB - BACKGROUND: The Peritoneal Surface Oncology Group International (PSOGI) recommends pathologic reporting of tumor cellularity in patients with pseudomyxoma peritonei (PMP) undergoing cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC). We investigated the prognostic significance of PMP cellularity, or lack thereof (acellular mucin), following CRS HIPEC. METHODS: We reviewed clinical data for 310 CRS-HIPEC procedures in low grade (American Joint Committee on Cancer grade G1) PMP with acellular mucin (n = 19), scant cellularity (n = 30), or moderate cellularity (n = 242). Kaplan-Meier survival curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes. RESULTS: Compared with patients with acellular mucin, those with scant and moderate cellularity had higher PCI and less-frequent complete macroscopic resection. After an estimated median follow-up of 49 months, 4 patients (14%) with scant cellularity and 127 patients (56%) with moderate cellularity progressed, while none of the patients with acellular mucin progressed. While the median progression-free survival (PFS) was not reached for patients with acellular mucin or scant cellularity (estimated 5-year PFS probability of 100 and 83%, respectively), patients with moderate cellularity demonstrated a median PFS of 32 months (estimated 5-year PFS probability of 27%). In a multivariate model, degree of disease cellularity, or lack thereof (acellular mucin), was an independent predictor of PFS but not overall survival. CONCLUSIONS: Early disease progression is unlikely in patients with acellular mucin undergoing CRS-HIPEC, as opposed to a 14% recurrence rate with scant cellularity. Thorough pathologic assessment for cellularity, or lack thereof (acellular mucin), is vital for accurate prognostication of disease progression for patients with low-grade PMP undergoing CRS-HIPEC. PMID- 29110276 TI - Do Lumpectomy Cavity Shaved Margins Really Not Impact Re-Excision Rates in Breast Cancer? A Reply. PMID- 29110277 TI - Meta-Analysis of Local Invasive Breast Cancer Recurrence After Electron Intraoperative Radiotherapy. AB - BACKGROUND: Electron intraoperative radiotherapy (IORT) can be used during breast conserving surgery to treat early-stage invasive breast cancer. Using data from current clinical and observational studies, this study aimed to assess the impact of single-fraction electron IORT on local recurrence rates. METHODS: Studies on single-fraction electron IORT during breast conserving surgery were identified through a search of PubMed and Google Scholar, as well as through secondary referencing. Local recurrence rate was the main outcome of interest. A meta analysis of proportions using a binomial distribution to model the within-study variability and a random effects model was conducted to estimate a pooled local recurrence rate. To estimate a 5-year recurrence rate, a single-sample Poisson normal model was applied to model the probability of events occurring during a fixed period (60 months). RESULTS: The study identified 13 publications. The analysis demonstrated a pooled monthly local recurrence rate of 0.02% per person month (95% confidence interval CI 0.00-0.06%) for the studies with a follow-up period shorter than 5 years, 0.03% per person-month (95% CI 0.02-0.06%) for studies with a follow-up period of 5 years or longer, and 0.02% per person-month (95% CI 0.01-0.04%) overall. Based on this model, the predicted 5-year local recurrence rate was 2.7% (range 1.9-3.7%). CONCLUSIONS: According to the published literature, the rate of breast cancer local recurrence after electron IORT was 0.02% per person-month, with an adjusted 5-year recurrence rate of 2.7%. These findings support the recent guidelines from the American Society for Radiation Oncology (ASTRO) supporting the use of electron IORT for low-risk patients. PMID- 29110278 TI - The Imperative for Research to Promote Health Equity in Indigenous Communities. AB - Health disparities exact a devastating toll upon Indigenous people in the USA. However, there has been scant research investment to develop strategies to address these inequities in Indigenous health. We present a case for increased health promotion, prevention, and treatment research with Indigenous populations, providing context to the recent NIH investment in the Intervention Research to Improve Native American Health (IRINAH) network. We discuss the disproportionate costs and consequences of disparities borne by Indigenous groups, the limited evidence base on effective intervention for this population, how population uniqueness often makes transfer of existing intervention models difficult, and additional challenges in creating interventions for Indigenous settings. Given the history of colonial disruption that has included genocide, forced removal from lands, damaging federal, state and local policies and practices, environmental contamination, and most recently, climate change, we conclude research that moves beyond minor transformations of existing majority population focused interventions, but instead truly respects Indigenous wisdom, knowledge, traditions, and aspirations is needed, and that investment in intervention science to address Indigenous health disparities represent a moral imperative. PMID- 29110279 TI - Metoprolol, propranolol, carvedilol, or labetalol for patients with Takotsubo syndrome? PMID- 29110280 TI - Body weight and mortality in COPD: focus on the obesity paradox. AB - : The positive association between overweight, obesity, and cardiovascular and all-cause mortality is well established, even though this relation is typically U shaped with an increased risk also in low-weight subjects. However, being overweight or obese has been associated with a better prognosis in subjects suffering from chronic diseases, id est the "obesity paradox". In both community dwelling and hospitalized patients with COPD, several studies have reported a significant protective effect of obesity on all-cause mortality, indicating that also in obstructive pulmonary diseases, an obesity paradox may be present. Interestingly, the "paradox" is more evident for subjects with severe bronchial obstruction (i.e., a lower FEV1), while in mild-moderate conditions, the weight related mortality shows a behavior similar to that observed in the general population. Several factors may confound the relation between COPD, obesity and mortality. The lower FEV1 found in obese people may be linked to a restrictive defect rather than to an obstructive one. Due to the modified chest wall mechanical properties-related to increased fat mass-obese COPD patients may present, respect to their lean counterpart, a lower lung hyperinflation which is associated with higher mortality. The traditional classification of COPD attributes to obese "blue bloaters" a low-grade emphysema in opposition to lean "pink puffers"; the fact that emphysema extent is related to mortality may bias the relationship between weight and survival. It is also to underline that the majority of the studies, consider BMI rather than body composition (a better predictor of mortality) when studying the intriguing relation between weight, COPD, and mortality. Reverse bias has also to be taken into account, hypothesizing that an unintentional weight loss may be the deleterious factor related to mortality, rather than considering obesity a protective one. Further prospective studies are needed to shed light on the complexity of this emerging issue. LEVEL OF EVIDENCE: Level V: Narrative Review. PMID- 29110281 TI - The effect of vitamin D supplementation in combination with low-calorie diet on anthropometric indices and androgen hormones in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial. AB - PURPOSE: Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in reproductive age women. The aim of this studywas to evaluate the effects of vitamin D supplementation in combination with low-calorie diet on anthropometric indices, reproductive hormones and menstrual regularity in overweight and obese PCOS women. METHODS: In this randomized controlled clinical trial, 60 PCOS women with vitamin D insufficiency were randomly assigned to 12 weeks of either (1) weight-loss intervention + 50,000 IU/week oral vitamin D3 or (2) weight-loss intervention + placebo. At the beginning and end of the study, the anthropometric indices, body composition, 25-hydroxyvitamin D, total testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and free androgen index (FAI) were measured and regularity of menses was compared among the two groups. RESULT: After 12-week intervention, median of serum 25-hydroxyvitamin D3 significantly increased from 18.5 (10.75-20) ng/ml to 42.69 (34-53.25) ng/ml in vitamin D group compared to placebo group (p < 001). Moreover, there was a significant improvement in frequency regular menstrual cycle (p = 0.01). Mean of weight, body mass index, fat mass, waist and hip circumference and waist-to-hip ratio significantly decreased in both groups, but was not different between two groups. Mean of total testosterone insignificantly decreased from 0.7 to 0.5 ng/ml in vitamin D group (p = 0.18). In addition, we did not observe significant differences regarding DHEAS, FAI and SHBG between two groups. CONCLUSIONS: In women with PCOS, androgen profile did not change with vitamin D supplementation when combined with low-calorie diet, but menstrual frequency significantly improved. CLINICAL TRIAL REGISTRATION NUMBER: IRCT2016062710826N19. PMID- 29110282 TI - Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one: a non-selective alpha-adrenoceptor antagonist. AB - PURPOSE: Previous studies have shown that several components of the metabolic syndrome, such as hypertension, obesity or imbalanced lipid and carbohydrate homeostasis, are associated with the sympathetic nervous system overactivity. Therefore, the inhibition of the adrenergic nervous system seems to be a reasonable and appropriate therapeutic approach for the treatment of metabolic disturbances. It has been suggested that non-selective adrenoceptor antagonists could be particularly beneficial, since alpha1-adrenoceptor antagonists can improve disrupted lipid and carbohydrate profiles, while the inhibition of the alpha2-adrenoceptor may contribute to body weight reduction. The aim of the present study was to investigate the metabolic benefits deriving from administration of a non-selective alpha-adrenoceptor antagonist from the group of pyrrolidin-2-one derivatives. The aim of the present study was to investigate the potential metabolic benefits deriving from chronic administration of a non selective alpha-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives. METHODS: The alpha1- and alpha2-adrenoreceptor affinities of the tested compound-1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one had been investigated previously by means of the radioligand binding assay. In the present study, we extended the pharmacological profile characteristics of the selected molecule by additional intrinistic activity assays. Next, we investigated the influence of the tested compound on body weight, hyperglycemia, hypertriglyceridemia, blood pressure in the animal model of obesity induced by a high-fat diet, and additionally we measured the spontaneous activity and body temperature. RESULTS: The intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of alpha1B and alpha2A adrenoceptors. After the chronic administration of the tested compound, we observed reduced level of triglycerides and glucose in the rat plasma. Interestingly, the tested did not reduce the body weight and did not influence the blood pressure in normotensive animals. Additionally, the administration of the tested compound did not change the animals' spontaneous activity and body temperature. CONCLUSION: Non-selective alpha-adrenoceptor antagonist seems to carry potential benefits in the improvement of the reduction of elevated glucose and triglyceride level. The lack of influence on blood pressure suggests that compounds with such a pharmacological profile may be particulary beneficial for the patients with disturbed lipid and carbohydrate profile, who do not suffer from hypertension. These results are particulary valuable, since currently there are no safe alpha2A-adrenoceptor antagonist drugs available in clinical use with the ability to modulate hyperglycemia that would not affect blood pressure. PMID- 29110283 TI - EphA2 Targeted Doxorubicin-Nanoliposomes for Osteosarcoma Treatment. AB - PURPOSE: To employ Doxorubicin-loaded liposomes, modified with YSA-peptide to target EphA2, to reduce adverse effects against primary bone cells and maximize toxicity against Saos-2 osteosarcoma cells. METHODS: PEGylated liposomes were prepared by thin film method using Dipalmitoylphosphatidylcholine (DPPC), cholesterol and distearylphosphatidylethanolamine-polyethyleneglycol conjugate (DSPE-mPEG) in 67.9:29.1:3 M ratios, and loaded with DOX (L-DOX) by pH-gradient method. Targeted liposomes (YSA-L-DOX), were prepared by conjugating YSA-peptide to DSPE-mPEG. Liposomes were physicochemically characterized and tested in cellular toxicity assays. RESULTS: YSA conjugation efficiency was >98%. Size and polydispersity index of both L-DOX and YSA-L-DOX were around 88 nm and 0.188, respectively. Both had similar zeta potential, and 85% DOX loading efficiencies. DOX release kinetics followed the Korsmeyer-Peppa model, and showed comparable release for both formulations from 1-8 h, and a plateau of 29% after 48 h. Both formulations could be stably stored for >=6 months at 4 degrees C in the dark. Toxicity assays showed a significant 1.91-fold higher cytotoxicity compared to free DOX in the Saos-2 cells, and 2-fold lesser toxicity in primary bone cells compared to the Saos-2 cells. Cellular uptake studies showed higher and more nuclear uptake in YSA-L-DOX compared to L-DOX treated cells. CONCLUSIONS: YSA-L DOX vesicles might be effective for targeted treatment of osteosarcoma. PMID- 29110284 TI - Folate Conjugated Hybrid Nanocarrier for Targeted Letrozole Delivery in Breast Cancer Treatment. AB - PURPOSE: Letrozole as a steroidal anticancer drug with hydrophobic nature is usually administrated by oral route for patient treatment and the injectable formulation for this drug has not still been reported. In this study, a new letrozole incorporated folate-conjugated polymer - lipid hybrid nanoparticles - is introduced for cancer treatment. METHODS: Nanoparticles were fabricated via modified oil in water ionic gelation method using optimization parameters and then were coupled to folic acid using carbodiimide activation. The physicochemical characterization in vitro drug release, cytotoxicity, and then ex vivo study of obtained carrier was investigated. RESULTS: Both thermal and crystallography studies proved the amorphous loading of drug in the nanocarrier. The cytotoxicity investigation with an average IC50 value of 79 +/- 2.40 nM proved the efficiency of the coupled folic acid carrier for the intracellular uptake of letrozole on the breast cancer line. Ex vivo, the study proved the positive effect of the letrozole entrapment on the drug bioavailability. CONCLUSIONS: The obtained targeted nanocarrier could overcome the limitations associated with the LTZ as a potent non-steroidal drug. Both the entrapment and therapeutic efficiency of letrozole in the amphiphilic carrier were increased using the lipid nanoparticles and the surface modification, respectively. PMID- 29110285 TI - Chemical and Biophysical Characteristics of Monoclonal Antibody Solutions Containing Aggregates Formed during Metal Catalyzed Oxidation. AB - PURPOSE: To physicochemically characterize and compare monoclonal antibody (mAb) solutions containing aggregates generated via metal catalyzed oxidation (MCO). METHODS: Two monoclonal IgG2s (mAb1 and mAb2) and one monoclonal IgG1 (rituximab) were exposed to MCO with the copper/ascorbic acid oxidative system, by using several different methods. The products obtained were characterized by complementary techniques for aggregate and particle analysis (from oligomers to micron sized species), and mass spectrometry methods to determine the residual copper content and chemical modifications of the proteins. RESULTS: The particle size distribution and the morphology of the protein aggregates generated were similar for all mAbs, independent of the MCO method used. There were differences in both residual copper content and in chemical modification of specific residues, which appear to be dependent on both the protein sequence and the protocol used. All products showed a significant increase in the levels of oxidized His, Trp, and Met residues, with differences in extent of modification and specific amino acid residues modified. CONCLUSION: The extent of total oxidation and the amino acid residues with the greatest oxidation rate depend on a combination of the MCO method used and the protein sequence. PMID- 29110287 TI - A Novel Hypergraph-Based Genetic Algorithm (HGGA) Built on Unimodular and Anti homomorphism Properties for DNA Sequencing by Hybridization. AB - The sequencing by hybridization (SBH) of determining the order in which nucleotides should occur on a DNA string is still under discussion for enhancements on computational intelligence although the next generation of DNA sequencing has come into existence. In the last decade, many works related to graph theory-based DNA sequencing have been carried out in the literature. This paper proposes a method for SBH by integrating hypergraph with genetic algorithm (HGGA) for designing a novel analytic technique to obtain DNA sequence from its spectrum. The paper represents elements of the spectrum and its relation as hypergraph and applies the unimodular property to ensure the compatibility of relations between l-mers. The hypergraph representation and unimodular property are bound with the genetic algorithm that has been customized with a novel selection and crossover operator reducing the computational complexity with accelerated convergence. Subsequently, upon determining the primary strand, an anti-homomorphism is invoked to find the reverse complement of the sequence. The proposed algorithm is implemented in the GenBank BioServer datasets, and the results are found to prove the efficiency of the algorithm. The HGGA is a non classical algorithm with significant advantages and computationally attractive complexity reductions ranging to [Formula: see text] with improved accuracy that makes it prominent for applications other than DNA sequencing like image processing, task scheduling and big data processing. PMID- 29110286 TI - The Better Understanding and Recognition of the Disconnects, Experiences, and Needs of Patients with Chronic Idiopathic Constipation (BURDEN-CIC) Study: Results of an Online Questionnaire. AB - INTRODUCTION: There is limited literature comparing the experiences and attitudes of patients with chronic idiopathic constipation (CIC) to those of healthcare professionals (HCPs) treating CIC patients. The BURDEN-CIC study was conducted to better understand the experiences and ongoing needs of CIC patients and to assess their alignment versus disconnection with the perceptions and needs of HCPs who treat CIC patients. METHODS: The BURDEN-CIC study was an author-developed, online questionnaire that used KnowledgePanel(r) to survey individuals with CIC (n = 1223). HCPs who treat CIC patients were recruited separately and participated in a complementary online questionnaire (n = 331). RESULTS: Most patients had used (58%) or were using (51%) over-the-counter treatments for their CIC, with only 16% currently on prescription therapy. More than half (59%) of current CIC prescription users were not satisfied/completely satisfied with their current chronic treatment. Many patients (42%) felt frustrated regarding their CIC, and a similar percentage (40%) expressed acceptance that CIC was part of their daily life. The majority of HCPs agreed that CIC patients were frustrated (72%), stressed (50%), or fed up (43%) with current treatment options but were relatively unaware (21%) that patients were accepting of their CIC. HCPs reported the greatest challenges in treating CIC patients as response rates to current therapies (55%), treatment adherence (55%), management of treatment-related diarrhea (34%), and lack of treatment options (34%). CONCLUSION: BURDEN-CIC identified that many patients and HCPs are frustrated and not satisfied with current CIC treatments due to lack of efficacy and side effects, such as diarrhea. The survey identified that many patients are "accepting" of their disease, potentially compromising treatment outcomes. More dialogue is needed between HCPs and CIC patients, especially regarding management of treatment expectations and side effects. Further, additional treatment options would be useful for both patients and HCPs. FUNDING: Synergy Pharmaceuticals Inc. PMID- 29110289 TI - Dyssynchrony: a risk marker for ventricular arrhythmias? PMID- 29110290 TI - Relationship between left ventricular dyssynchrony and scar burden in the genesis of ventricular tachyarrhythmia. AB - BACKGROUND: Left ventricular (LV) ejection fraction (EF) has poor predictive value for ventricular tachyarrhythmia (VT). Other parameters such as LV dyssynchrony (LVD), and LV scar burden have also been individually associated with VT, but the interplay of these factors in the genesis of VT has not been explored. This retrospective study sought to evaluate the relationship between LVD and imaging characteristics of the myocardial substrate in predicting VT. METHODS: We identified 183 patients (150 men; mean age: 64 +/- 14 years and mean LVEF: 23% +/- 7%), who received an implantable cardioverter defibrillator (ICD) for primary prevention and who underwent a gated single-photon emission computed tomography (GSPECT) myocardial perfusion scan prior to ICD implantation. LVD was determined by phase analysis of the GSPECT images. Occurrence of VTs was established through routine ICD interrogations and review of electronic medical records. RESULTS: LVD was present in 136 (74%) patients. VT occurred in 48 (26%) patients. Ninety-eight percent of patient who experienced VT had LVD. Patients without LVD had a significantly better survival free of both sustained and non sustained VT (HR, 95% CI 4.90, 2.12-11.20; P < 0.0001). The combination of LVD and myocardial scar occupying > 6% of LV myocardium accounted for 83% of all VT events. CONCLUSIONS: LVD assessment by GSPECT is strongly associated with incident VT in patients with low LVEF. The combination of LVD and scar burden predicted the majority of VT events. PMID- 29110288 TI - Myocardial perfusion imaging: Lessons learned and work to be done-update. AB - As the second term of our commitment to Journal begins, we, the editors, would like to reflect on a few topics that have relevance today. These include prognostication and paradigm shifts; Serial testing: How to handle data? Is the change in perfusion predictive of outcome and which one? Ischemia-guided therapy: fractional flow reserve vs perfusion vs myocardial blood flow; positron emission tomography (PET) imaging using Rubidium-82 vs N-13 ammonia vs F-18 Flurpiridaz; How to differentiate microvascular disease from 3-vessel disease by PET? The imaging scene outside the United States, what are the differences and similarities? Radiation exposure; Special issues with the new cameras? Is attenuation correction needed? Are there normal databases and are these specific to each camera system? And finally, hybrid imaging with single-photon emission tomography or PET combined with computed tomography angiography or coronary calcium score. We hope these topics are of interest to our readers. PMID- 29110291 TI - Non-ionic Surfactant Based In Situ Forming Vesicles as Controlled Parenteral Delivery Systems. AB - Non-ionic surfactant (NIS) based in situ forming vesicles (ISVs) present an affordable alternative to the traditional systems for the parenteral control of drug release. In this work, NIS based ISVs encapsulating tenoxicam were prepared using the emulsion method. Tenoxicam-loaded ISVs were prepared using a 22.31 full factorial experimental design, where three factors were evaluated as independent variables; type of NIS (A), molar ratio of NIS to Tween(r)80 (B), and phase ratio of the internal ethyl acetate to the external Captex(r) oil phase (C). Percentage drug released after 1 h, particle size of the obtained vesicles and mean dissolution time were chosen as the dependent variables. Selected formulation was subjected to morphological investigation, injectability, viscosity measurements, and solid state characterization. Optimum formulation showed spherical nano vesicles in the size of 379.08 nm with an initial drug release of 37.32% in the first hour followed by a sustained drug release pattern for 6 days. DSC analysis of the optimized formulation confirmed the presence of the drug in an amorphous form with the nano-vesicles. Biological evaluation of the selected formulation was performed on New Zealand rabbits by IM injection. The prepared ISVs exhibited a 45- and 28-fold larger AUC and MRT values, respectively, compared to those of the drug suspension. The obtained findings boost the use of ISVs for the treatment of many chronic inflammatory conditions. PMID- 29110292 TI - Development of Chitosan-Based pH-Sensitive Polymeric Micelles Containing Curcumin for Colon-Targeted Drug Delivery. AB - pH-sensitive N-naphthyl-N,O-succinyl chitosan (NSCS) and N-octyl-N,O-succinyl chitosan (OSCS) polymeric micelles carriers have been developed to incorporate curcumin (CUR) for colon-targeted drug delivery. The physical entrapment methods (dialysis, co-solvent evaporation, dropping, and O/W emulsion) were applied. The CUR-loaded micelles prepared by the dialysis method presented the highest loading capacity. Increasing initial amount of CUR from 5 to 40 wt% to polymer resulted in the increase in loading capacity of the polymeric micelles. Among the hydrophobic cores, there were no significant differences in the loading capacity of CUR-loaded micelles. The particle sizes of all CUR-loaded micelles were in the range of 120-338 nm. The morphology of the micelles changed after being contacted with medium with different pH values, confirming the pH-responsive properties of the micelles. The release characteristics of curcumin from all CUR-loaded micelles were pH-dependent. The percent cumulative release of curcumin from all CUR-loaded micelles in simulated gastric fluid (SGF) was limited to about 20%. However, the release amount was significantly increased after contacted with simulated intestinal fluid (SIF) (50-55%) and simulated colonic fluid (SCF) (60 70%). The released amount in SIF and SCF was significantly greater than the release of CUR from CUR powder. CUR-loaded NSCS exhibited the highest anti-cancer activity against HT-29 colorectal cancer cells. The stability studies indicated that all CUR-loaded micelles were stable for at least 90 days. Therefore, the colon targeted, pH-sensitive NSCS micelles may have potential to be a prospective candidate for curcumin delivery to the colon. PMID- 29110294 TI - Chemometric Methods to Quantify 1D and 2D NMR Spectral Differences Among Similar Protein Therapeutics. AB - NMR spectroscopy is an emerging analytical tool for measuring complex drug product qualities, e.g., protein higher order structure (HOS) or heparin chemical composition. Most drug NMR spectra have been visually analyzed; however, NMR spectra are inherently quantitative and multivariate and thus suitable for chemometric analysis. Therefore, quantitative measurements derived from chemometric comparisons between spectra could be a key step in establishing acceptance criteria for a new generic drug or a new batch after manufacture change. To measure the capability of chemometric methods to differentiate comparator NMR spectra, we calculated inter-spectra difference metrics on 1D/2D spectra of two insulin drugs, Humulin R(r) and Novolin R(r), from different manufacturers. Both insulin drugs have an identical drug substance but differ in formulation. Chemometric methods (i.e., principal component analysis (PCA), 3-way Tucker3 or graph invariant (GI)) were performed to calculate Mahalanobis distance (D M) between the two brands (inter-brand) and distance ratio (D R) among the different lots (intra-brand). The PCA on 1D inter-brand spectral comparison yielded a D M value of 213. In comparing 2D spectra, the Tucker3 analysis yielded the highest differentiability value (D M = 305) in the comparisons made followed by PCA (D M = 255) then the GI method (D M = 40). In conclusion, drug quality comparisons among different lots might benefit from PCA on 1D spectra for rapidly comparing many samples, while higher resolution but more time-consuming 2D-NMR data-based comparisons using Tucker3 analysis or PCA provide a greater level of assurance for drug structural similarity evaluation between drug brands. PMID- 29110293 TI - Evaluation of Streptococcus thermophilus IFFI 6038 Microcapsules Prepared Using an Ultra-fine Particle Processing System. AB - Microencapsulation technology has the potential to protect probiotics and to deliver them to the gut, and extrusion is one of the most commonly used methods. However, the rather large diameters of 1~5 mm produced tend to cause oral grittiness and result in low compliance. In this article, Streptococcus thermophilus IFFI 6038 (IFFI 6038) microcapsules were prepared using an ultra fine particle processing system (UPPS) previously developed by this research group. IFFI 6038 suspension was pumped by a peristaltic pump to the feeding inlet nozzle and then dispersed into micro-droplets by a rotating disk, followed by solidification. Trehalose (16%) was used as a cryoprotectant to protect IFFI 6038 from damage by lyophilization used in the process. Alginate (3%) resulted in IFFI 6038 microcapsules with a median particle diameter (d 50) of 29.32 +/- 0.12 MUm and a span value of 1.00 +/- 0.02, indicating uniform particle size distribution. To evaluate the potential of microencapsulation in protecting IFFI 6038 from the gastric conditions, the viable counts of IFFI 6038 following incubation of IFFI 6038 microcapsules in simulated gastric juices for 120 min were determined and compared with those of free IFFI 6038. The stability of microencapsulated IFFI 6038 upon storage for 3 months at 4 degrees C and 25 degrees C, respectively, was also determined. The results showed that microcapsules prepared by UPPS protected IFFI 6038 from gastric conditions. The results from a rat diarrhea model showed that microcapsules prepared by the UPPS method were able to effectively improve the diarrhea conditions in rats. PMID- 29110295 TI - Prevalence and Variability in Medications Contributing to Polypharmacy in Long Term Care Facilities. AB - BACKGROUND: Research into which medications contribute to polypharmacy and the variability in these medications across long-term care facilities (LTCFs) has been minimal. OBJECTIVE: Our objective was to investigate which medications were more prevalent among residents with polypharmacy and to determine the variability in prescribing of these medications across LTCFs. METHODS: This was a cross sectional study of 27 LTCFs in regional and rural Victoria, Australia. An audit of the medication charts and medical records of 754 residents was performed in May 2015. Polypharmacy was defined as nine or more regular medications. Logistic regression was performed to determine the association between medications and resident characteristics with polypharmacy. Analyses were adjusted for age, sex and Charlson's comorbidity index. Variability in the use of the ten most prevalent medication classes was explored using funnel plots. Characteristics of LTCFs with low (< 30%), moderate (30-49%) and high (>= 50%) polypharmacy prevalence were compared. RESULTS: Polypharmacy was observed in 272 (36%) residents. In adjusted analyses, each of the top ten most prevalent medication classes, with the exception of antipsychotics, were associated with polypharmacy. Between 7 and 23% of LTCFs fell outside the 95% control limits for each of the ten most prevalent medications. LTCFs with >= 50% polypharmacy prevalence were predominately smaller. CONCLUSION: Polypharmacy was associated with nine of the ten most prevalent medication classes. There was greater than fourfold variability in nine of the ten most prevalent medications across LTCFs. Further studies are needed to investigate the clinical appropriateness of the variability in polypharmacy. PMID- 29110296 TI - The combined and individual impact of diabetes and smoking on key subgingival periodontal pathogens in patients with chronic periodontitis. AB - BACKGROUND AND OBJECTIVE: Comprehension of the similarities and differences in the composition of the subgingival microbiota of patients with diabetes mellitus (DM), smokers or smokers with DM is an important step in developing therapies specific for these groups at risk for periodontitis. Therefore, the aim of this study was to compare the combined and individual effects of DM and smoking on the levels and prevalence of key subgingival periodontal pathogens in patients with chronic periodontitis. MATERIAL AND METHODS: One hundred patients with generalized chronic periodontitis were allocated into one of the following groups: DM (n = 25, non-smokers with type 2 DM); S (n = 25, non-diabetic smokers); SDM (n = 25, smokers with type 2 DM); and control (n = 25, non-diabetic non-smokers). Two subgingival biofilm samples from healthy sites (probing depth and clinical attachment level <=3 mm and no bleeding) and 2 from diseased sites (probing depth and clinical attachment level >=5 mm and bleeding on probing) were analyzed by quantitative polymerase chain reaction for Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Eubacterium nodatum, Parvimonas micra, Fusobacterium nucleatum ssp. and Prevotella intermedia. RESULTS: There were no differences among groups in the mean counts of the bacterial species studied, considering all sampled sites (healthy plus diseased sites). There were also no differences among groups regarding the prevalence of any bacteria species in healthy and diseased sites (P > .05). The mean P. micra count was significantly higher in the healthy sites of both smoking groups, than in those of the control group (P < .05). CONCLUSION: The subgingival levels and prevalence of the bacterial species studied are not significantly different in subjects with chronic periodontitis presenting DM, smokers or smokers with DM. In addition, DM and smoking, jointly and individually, do not considerably affect the subgingival levels of target periodontal pathogens in patients with chronic periodontitis. PMID- 29110297 TI - Concurrent variable-interval variable-ratio schedules in a dynamic choice environment. AB - Most studies of operant choice have focused on presenting subjects with a fixed pair of schedules across many experimental sessions. Using these methods, studies of concurrent variable- interval variable-ratio schedules helped to evaluate theories of choice. More recently, a growing literature has focused on dynamic choice behavior. Those dynamic choice studies have analyzed behavior on a number of different time scales using concurrent variable-interval schedules. Following the dynamic choice approach, the present experiment examined performance on concurrent variable-interval variable-ratio schedules in a rapidly changing environment. Our objectives were to compare performance on concurrent variable interval variable-ratio schedules with extant data on concurrent variable interval variable-interval schedules using a dynamic choice procedure and to extend earlier work on concurrent variable-interval variable-ratio schedules. We analyzed performances at different time scales, finding strong similarities between concurrent variable-interval variable-interval and concurrent variable interval variable- ratio performance within dynamic choice procedures. Time-based measures revealed almost identical performance in the two procedures compared with response-based measures, supporting the view that choice is best understood as time allocation. Performance at the smaller time scale of visits accorded with the tendency seen in earlier research toward developing a pattern of strong preference for and long visits to the richer alternative paired with brief "samples" at the leaner alternative ("fix and sample"). PMID- 29110298 TI - Long-term Genoprotection Effect of Sechium edule Fruit Extract Against UVA Irradiation in Keratinocytes. AB - Photoprotection is essential to prevent the long-term deleterious effects of ultraviolet (UV), including skin cancer and photoaging. So far, there has been an increase in the use of natural bioactive phytochemicals for the development of more effective skin photoprotective agents. However, the molecular mechanisms underlying the photochemoprotection activity of such compounds remain largely unknown. The objective of this study was to investigate the effects of a Sechium edule fruit extract (SEE) in terms of photoprotection against UVA in primary human keratinocytes. We found that SEE protected keratinocytes against UVA induced cytotoxicity, decreased the intracellular amounts of reactive oxygen species, and reduced oxidatively induced DNA lesions after UVA exposure. Furthermore, SEE decreased the induction of CPD lesions in UVA-irradiated keratinocytes and exhibited increased DNA repair of such photoproducts at 24 h postexposure. Finally, using DNA repair biochips, we demonstrated that SEE treated keratinocytes had DNA enzymatic repair activities more efficient for abasic sites, CPD and thymine glycols. Therefore, the benefits of SEE against UVA could be explained by a combination of antioxidant activity, the reduction in DNA damage, and the enhancement of DNA repair capacities. PMID- 29110299 TI - Long non-coding RNA MALAT1 expression in patients with gestational diabetes mellitus. AB - OBJECTIVE: To monitor the expression of long non-coding RNAs (lncRNAs) and changes in metabolic profiles among patients with gestational diabetes mellitus (GDM). METHODS: A retrospective case-control study was conducted using data for women treated at a hospital in China between October 8, 2014, and April 15, 2015. Patients diagnosed with GDM using an oral glucose tolerance test at 24-28 weeks of pregnancy (n=50) were included. The control group comprised pregnant women without GDM (n=47). Serum levels of lncRNA MALAT1, lncRNA p21, and lncRNA H19 were assessed using the reverse transcription polymerase chain reaction. Plasma glucose and lipid levels were assessed biochemically. RESULTS: The expression level of lncRNA MALAT1 was higher among the cases than the controls (P=0.007). Expression of IncRNA MALAT1 among the patients with GDM correlated with both lncRNA p21 (r=0.333, P=0.018) and lncRNA H19 (r=0.314, P=0.030). Levels of triglycerides and total cholesterol differed between the control group and patients with GDM (3.6 +/- 2.6 mmol/L vs 3.8 +/- 1.5 mmol/L and 6.54 +/- 1.30 mmol/L vs 7.40 +/- 0.90 mmol/L, respectively; P<0.05). The area under the receiver operating characteristic curve was 0.654 (95% confidence interval 0.543 0.768, P<0.001). CONCLUSION: Expression of lncRNA MALAT1 could offer a novel biomarker to predict GDM. PMID- 29110300 TI - Dissociation of intramyocellular lipid storage and insulin resistance in trained athletes and type 2 diabetes patients; involvement of perilipin 5? AB - KEY POINTS: Intramyocellular lipid storage is negatively associated with insulin sensitivity. However, endurance trained athletes and type 2 diabetes mellitus (T2DM) patients store similar amounts of lipids in their muscle; the so-called athlete's paradox. Compared to T2DM, trained athletes possess higher levels of perilipin 5 (PLIN5), a lipid droplet (LD) coating protein. We examined whether coating LD with PLIN5 affects the pattern of muscle lipid (LD size and number) in relation to the athlete's paradox. Despite differences in PLIN5 protein content, we observed that coating the LD with PLIN5 could not explain the observed differences in LD size and number between athletes and T2DM. PLIN5-coated LDs were positively associated with oxidative capacity but not with insulin sensitivity. We conclude that coating of LDs with PLIN5 cannot causally explain the athlete's paradox. ABSTRACT: Intramyocellular lipid (IMCL) hampers insulin sensitivity, albeit not in endurance-trained athletes (Trained). Compared to type 2 diabetes mellitus (T2DM) patients, Trained subjects have high levels of perilipin 5 (PLIN5). In the present study, we tested whether the fraction of PLIN5-coated lipid droplets (LDs) is a determinant of skeletal muscle insulin sensitivity and contributes to the athlete's paradox. Muscle biopsies were taken from eight Trained, Lean sedentary, Obese and T2DM subjects. Trained, Obese and T2DM subjects were matched for total IMCL content. Confocal images were analysed for lipid area fraction, LD size and number and PLIN5+ and PLIN5- LDs were measured. A stepwise linear regression was performed to identify factors explaining observed variance in glucose infusion rate (GIR). Trained and T2DM subjects stored IMCL differently; Trained subjects had a higher number of LDs compared to T2DM subjects (0.037 +/- 0.004 MUm-2 vs. 0.023 +/- 0.003 MUm-2 , P = 0.024) that were non-significantly smaller (0.27 +/- 0.01 MUm2 vs. 0.32 +/- 0.02 MUm2 , P = 0.197, Trained vs. T2DM). Even though total PLIN5 protein content was almost double in Trained vs. T2DM subjects (1.65 +/- 0.21 AU vs. 0.89 +/- 0.09 AU, P = 0.004), PLIN5 coating did not affect LD number or size significantly. Of the observed variance in GIR, the largest fraction by far (70.2%) was explained by maximal oxygen uptake. Adding PLIN5 protein content or PLIN5+ LDs increased the explained variance in GIR (74.7% and 80.7% for PLIN5 protein content and PLIN5+ LDs, respectively). Thus, the putative relationship between PLIN5 and insulin sensitivity is at best indirect and is apparent only in conjunction with maximal oxygen uptake. Hence, PLIN5 abundance cannot be causally linked to the athlete's paradox. PMID- 29110302 TI - Coimmunoprecipitation of reversibly glycosylated polypeptide with sucrose synthase from developing castor oilseeds. AB - The sucrose synthase (SUS) interactome of developing castor oilseeds (COS; Ricinus communis) was assessed using coimmunoprecipitation (co-IP) with anti-(COS RcSUS1)-IgG followed by proteomic analysis. A 41-kDa polypeptide (p41) that coimmunoprecipitated with RcSUS1 from COS extracts was identified as reversibly glycosylated polypeptide-1 (RcRGP1) by LC-MS/MS and anti-RcRGP1 immunoblotting. Reciprocal Far-western immunodot blotting corroborated the specific interaction between RcSUS1 and RcRGP1. Co-IP using anti-(COS RcSUS1)-IgG and clarified extracts from other developing seeds as well as cluster (proteoid) roots of white lupin and Harsh Hakea consistently recovered 90 kDa SUS polypeptides along with p41/RGP as a SUS interactor. The results suggest that SUS interacts with RGP in diverse sink tissues to channel UDP-glucose derived from imported sucrose into hemicellulose and/or glycoprotein/glycolipid biosynthesis. PMID- 29110303 TI - Diets and trophic niches of the main commercial fish species from the Celtic Sea. AB - The characterization and quantification of diets of nine commercially important Celtic Sea fish species (black-bellied angler Lophius budegassa, blue whiting Micromesistius poutassou, Atlantic cod Gadus morhua, haddock Melanogrammus aeglefinus, European hake Merluccius merluccius, megrim Lepidorhombus whiffiagonis, European plaice Pleuronectes platessa, common sole Solea solea and whiting Merlangius merlangus) was undertaken November 2014 and November 2015 to gain a better understanding of fish feeding strategies, prey preferences, competition for resources and, more generally, increases knowledge of marine ecosystem functioning. Prey were classified into 39 taxonomic groups. A feeding overlap index and multivariate analyses were used to classify the fishes into four main trophic groups where interspecific competition for resources may be important: piscivorous species, omnivorous species, planktivorous species and invertebrate benthic feeders. Ontogenetic changes in diet were also considered for L. budegassa, G. morhua, M. aeglefinus, M. merluccius and M. merlangus through partitioning into size classes. This revealed an important shift in the diet of M. merluccius from omnivory to piscivory, whereas M. aeglefinus exhibited no significant ontogenetic change in diet, remaining an invertebrate benthic feeder. Feeding strategies of these species were also investigated using the Shannon niche-breadth index and other descriptors, such as the total number of taxonomic groups of prey and the mean number of prey in gut contents. PMID- 29110301 TI - Studies of cortical connectivity using optical circuit mapping methods. AB - An important consideration when probing the function of any neuron is to uncover the source of synaptic input onto the cell, its intrinsic physiology and efferent targets. Over the years, electrophysiological approaches have generated considerable insight into these properties in a variety of cortical neuronal subtypes and circuits. However, as researchers explore neuronal function in greater detail, they are increasingly turning to optical techniques to bridge the gap between local network interactions and behaviour. The application of optical methods has increased dramatically over the past decade, spurred on by the optogenetic revolution. In this review, we provide an account of recent innovations, providing researchers with a primer detailing circuit mapping strategies in the cerebral cortex. We will focus on technical aspects of performing neurotransmitter uncaging and channelrhodopsin-assisted circuit mapping, with the aim of identifying common pitfalls that can negatively influence the collection of reliable data. PMID- 29110304 TI - Beta-blockers for preventing aortic dissection in Marfan syndrome. AB - BACKGROUND: Marfan syndrome is a hereditary disorder affecting the connective tissue and is caused by a mutation of the fibrillin-1 (FBN1) gene. It affects multiple systems of the body, most notably the cardiovascular, ocular, skeletal, dural and pulmonary systems. Aortic root dilatation is the most frequent cardiovascular manifestation and its complications, including aortic regurgitation, dissection and rupture are the main cause of morbidity and mortality. OBJECTIVES: To assess the long-term efficacy and safety of beta blocker therapy as compared to placebo, no treatment or surveillance only in people with Marfan syndrome. SEARCH METHODS: We searched the following databases on 28 June 2017; CENTRAL, MEDLINE, Embase, Science Citation Index Expanded and the Conference Proceeding Citation Index - Science in the Web of Science Core Collection. We also searched the Online Metabolic and Molecular Bases of Inherited Disease (OMMBID), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 June 2017. We did not impose any restriction on language of publication. SELECTION CRITERIA: All randomised controlled trials (RCTs) of at least one year in duration assessing the effects of beta-blocker monotherapy compared with placebo, no treatment or surveillance only, in people of all ages with a confirmed diagnosis of Marfan syndrome were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for inclusion, extracted data and assessed trial quality. Trial authors were contacted to obtain missing data. Dichotomous outcomes will be reported as relative risk and continuous outcomes as mean differences with 95% confidence intervals. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: One open-label, randomised, single-centre trial including 70 participants with Marfan syndrome (aged 12 to 50 years old) met the inclusion criteria. Participants were randomly assigned to propranolol (N = 32) or no treatment (N = 38) for an average duration of 9.3 years in the control group and 10.7 years in the treatment group. The initial dose of propranolol was 10 mg four times daily and the optimal dose was reached when the heart rate remained below 100 beats per minute during exercise or the systolic time interval increased by 30%. The mean (+/- standard error (SE)) optimal dose of propranolol was 212 +/- 68 mg given in four divided doses daily.Beta-blocker therapy did not reduce the incidence of all-cause mortality (RR 0.24, 95% CI 0.01 to 4.75; participants = 70; low-quality evidence). Mortality attributed to Marfan syndrome was not reported. Non-fatal serious adverse events were also not reported. However, study authors report on pre defined, non-fatal clinical endpoints, which include aortic dissection, aortic regurgitation, cardiovascular surgery and congestive heart failure. Their analysis showed no difference between the treatment and control groups in these outcomes (RR 0.79, 95% CI 0.37 to 1.69; participants = 70; low-quality evidence).Beta-blocker therapy did not reduce the incidence of aortic dissection (RR 0.59, 95% CI 0.12 to 3.03), aortic regurgitation (RR 1.19, 95% CI 0.18 to 7.96), congestive heart failure (RR 1.19, 95% CI 0.18 to 7.96) or cardiovascular surgery, (RR 0.59, 95% CI 0.12 to 3.03); participants = 70; low-quality evidence.The study reports a reduced rate of aortic dilatation measured by M-mode echocardiography in the treatment group (aortic ratio mean slope: 0.084 (control) vs 0.023 (treatment), P < 0.001). The change in systolic and diastolic blood pressure, total adverse events and withdrawal due to adverse events were not reported in the treatment or control group at study end point.We judged this study to be at high risk of selection (allocation concealment) bias, performance bias, detection bias, attrition bias and selective reporting bias. The overall quality of evidence was low. We do not know whether a statistically significant reduced rate of aortic dilatation translates into clinical benefit in terms of aortic dissection or mortality. AUTHORS' CONCLUSIONS: Based on only one, low quality RCT comparing long-term propranolol to no treatment in people with Marfan syndrome, we could draw no definitive conclusions for clinical practice. High quality, randomised trials are needed to evaluate the long-term efficacy of beta blocker treatment in people with Marfan syndrome. Future trials should report on all clinically relevant end points and adverse events to evaluate benefit versus harm of therapy. PMID- 29110305 TI - Wellington Playgrounds Uncovered: An Examination of Solar Ultraviolet Radiation and Shade Protection in New Zealand. AB - Providing effective shade in summer recreation spaces can reduce children's risk of skin cancer. This study explored the quantity and protective quality of shade in Wellington, New Zealand playgrounds. Two researchers visited 50 randomly selected playgrounds during peak ultraviolet radiation (UVR) hours in summer and recorded the mean shade cover of playground equipment, seats, tables and open areas. A solar meter was used to calculate the proportion of UVR blocked by each built structure and tree. The results found that 95% of playground equipment and 64% of sitting and eating areas had no shade protection. Trees blocked a mean of 80.1% (95% CI: 66.0-94.1) of direct solar UVR, but mostly covered open areas, not playground equipment, seats and tables. The findings demonstrate that Wellington playgrounds have insufficient shade available. Increased shade in Wellington playgrounds is urgently needed to protect children from harmful UVR exposure, particularly through planting trees with heavy foliage and building structures with large, protective roofing. This may well be the case for other regions of NZ and for other countries where UVR exposure is dangerous. The method used in this study provides a reliable means to evaluate shade. PMID- 29110308 TI - Exploring plant root traits and fungal interactions governing plant community structure: re-focusing long standing questions. PMID- 29110306 TI - Coping strategies and perceived social support in fibromyalgia syndrome: Relationship with alexithymia. AB - Fibromyalgia (FM) is a chronic pain syndrome characterized by high levels of psychological distress and alexithymia, a personality disposition affecting emotional self-awareness. The main aim of the present study was to investigate for the first time the relationship between alexithymia and coping strategies on the one hand, and alexithymia and perceived social support on the other, in a sample of FM patients. To reach this aim, 153 FM patients completed a battery of tests assessing coping strategies, perceived social support, alexithymia, psychological distress and pain intensity. Four regression analyses were performed to assess whether alexithymia was still a significant predictor of coping strategies and perceived social support, after controlling for psychological distress. High levels of both psychological distress and alexithymia were found in our sample of FM patients. Regarding coping strategies, FM patients reported higher scores on problem-focused coping, with respect to the other two coping strategies. The regression analyses showed that the externally oriented thinking factor of alexithymia significantly explained both problem- and emotion-focused coping, while the difficulty-describing feelings factor of alexithymia proved to be a significant predictor of perceived social support. Only the variance of dysfunctional coping ceased to be uniquely explained by alexithymia (difficulty identifying feelings factor), after controlling for psychological distress, particularly anxiety. These results highlight a negative relationship between alexithymia and both the use of effective coping strategies and the levels of perceived social support in FM patients. An adequate assessment of both alexithymia and psychological distress should therefore be included in clinical practice with these patients. PMID- 29110309 TI - Revealing the water uptake pathways of seeds with high resolution magnetic resonance imaging. PMID- 29110310 TI - Stan D. Wullschleger. PMID- 29110311 TI - Teresa Rosas. PMID- 29110312 TI - Trait covariance: the functional warp of plant diversity? PMID- 29110313 TI - Sleep problems in Dravet syndrome: a modifiable comorbidity. AB - AIM: Many children with severe developmental and epileptic encephalopathies experience significant sleep disturbance, causing major disruption to the family's quality of life. We aimed to determine the frequency and nature of sleep problems in individuals with Dravet syndrome. METHODS: The Sleep Disturbance Scale for Children and a seizure questionnaire were distributed to the parents/guardians of 96 patients with Dravet syndrome. Sixteen patients had two nights of home oximetry. RESULTS: Fifty-seven out of 96 questionnaires were completed. Forty-three out of 57 (75%) individuals had sleep problems. Twenty five out of 57 (44%) individuals had an abnormal total sleep score, with difficulty initiating and maintaining sleep (22 out of 57, 39%), sleep-wake transition disorders (20 out of 57, 35%), and sleep breathing disorders (19 out of 57, 33%). Twenty-two out of 57 (39%) individuals took medication to assist sleep, predominantly melatonin (n=14). Thirty out of 57 (53%) recently had nocturnal seizures. Overnight oximetry showed 14 out of 16 (88%) had a higher oxygen desaturation index (>3%), and six out of 16 (38%) had higher mean pulse rates than normative values. Home oximetry was normal or inconclusive in all patients. INTERPRETATION: Seventy-five per cent of individuals with Dravet syndrome had sleep problems, highlighting the importance of routinely assessing sleep and initiating appropriate behavioural and pharmacological interventions to improve the patient and family's quality of life. A high oxygen desaturation index and mean pulse rates on pulse oximetry may reflect unrecognized nocturnal seizures. WHAT THIS PAPER ADDS: More than 70% of patients with Dravet syndrome have sleep problems. Difficulty initiating and maintaining sleep was most common, particularly in those older than 20 years. Second most common were sleep-wake transition disorders, affecting more than 50% of those younger than 5 years. Sleep breathing disorders were a frequent problem across all age groups. Oximetry was not diagnostic of sleep-disordered breathing or obvious seizures. PMID- 29110314 TI - Post-irradiation morphoea of the breast: a case report and review of the literature. AB - We describe a 44-year-old female with triple-negative breast cancer who developed skin erythaema, sclerosis and contracture of her entire right breast 15 months after completion of post-lumpectomy chemotherapy and radiotherapy, consistent with post-irradiation morphoea (PIM). PIM is a rare complication of breast irradiation that impairs a patient's quality of life. PIM is located usually at the radiation port or in the surrounding tissue. Clinically, PIM is misdiagnosed commonly as lymphoedema and cellulitis in the early inflammatory phase, and recurrent breast cancer, chronic radiodermatitis (CRD), radiation-induced fibrosis (RIF), post-irradiation pseudosclerodermatous panniculitis (PIPP), atypical vascular lesions (AVL) or angiosarcoma (AS) in the late burnout phase. Arriving at the correct diagnosis typically requires a multidisciplinary approach, including a skin biopsy for confirmation. To date, satisfactory treatment of this condition has been challenging. and the clinical outcome after therapy is often unsatisfactory. PMID- 29110315 TI - NAD(P)H-quinone oxidoreductase 1 silencing aggravates hormone-induced prostatic hyperplasia in mice. AB - NAD(P)H-quinone oxidoreductase 1 (NQO1) is a highly inducible flavoprotein known to involve in various cellular defence mechanisms. In this study, we explored whether NQO1 deletion affects hormone-induced prostatic hyperplasia. Testosterone propionate (3 mg/kg, IP) was injected into wild-type (WT) and NOQ1 knockout C57BL/6 mice (NQO1-/- ) for 14 consecutive days, and the samples were collected for biological and histochemical studies. The testosterone-treated NQO1-/- showed about 140% higher prostate weight than the testosterone-treated WT, with enhanced connective tissue and hyperplastic glands formations. However, increased dihydrotestosterone level after testosterone treatment was not significantly different between the WT and NQO1-/- . In contrast, the enhanced nuclear expression of proliferating cell nuclear antigen in NQO1-/- prostate confirmed aggravated prostatic hyperplasia in NQO1-/- . Moreover, the expression of heat shock protein (HSP) 90-alpha was markedly increased in the NQO1-/- , and this was supported by increased testosterone-induced nuclear androgen receptor expression in NQO1-silenced LNCaP cells. Testosterone-induced prostate-specific antigen expression was not reversed in NOQ1-silenced cells after finasteride treatment. Although the exact role of NQO1 in prostatic hyperplasia remains unclear, the hyperplasia exacerbation due to NQO1 deletion might be independent of type 2 5alpha-reductase and might be related to enhanced androgen receptor affinity due to enhanced HSP90-alpha expression. PMID- 29110316 TI - Asymptotic distributions of kappa statistics and their differences with many raters, many rating categories and two conditions. AB - In clinical research and in more general classification problems, a frequent concern is the reliability of a rating system. In the absence of a gold standard, agreement may be considered as an indication of reliability. When dealing with categorical data, the well-known kappa statistic is often used to measure agreement. The aim of this paper is to obtain a theoretical result about the asymptotic distribution of the kappa statistic with multiple items, multiple raters, multiple conditions, and multiple rating categories (more than two), based on recent work. The result settles a long lasting quest for the asymptotic variance of the kappa statistic in this situation and allows for the construction of asymptotic confidence intervals. A recent application to clinical endoscopy and to the diagnosis of inflammatory bowel diseases (IBDs) is shortly presented to complement the theoretical perspective. PMID- 29110317 TI - Fetal growth standards in gastroschisis: Reference values for ultrasound measurements. AB - OBJECTIVES: The objectives of this study were to create growth curves based on ultrasonography biometric parameters of fetuses with gastroschisis, comparing them with normal growth standards, and to analyze umbilical artery (UA) Doppler velocimetry patterns. METHODS: A cohort study of 72 fetuses with gastroschisis, at gestational ages between 14 and 39 weeks was designed. Mean and standard deviation were calculated, with the 5th, 10th, 50th, 90th, and 95th centiles being established for biometric parameters according to gestational age. Curves were obtained, comparing with normal reference via the Mann-Whitney test. UA Doppler velocimetry patterns were obtained. RESULTS: A total of 434 examinations were performed, and centiles were established for biparietal diameter, head circumference, abdominal circumference, femur length, and estimated fetal weight. A significant difference was observed between the gastroschisis measurements when compared to control, with all curves shifted downwards. Abdominal circumference was the parameter presenting the largest difference. Estimated fetal weight was also lower, with mean difference of 256.3 +/- 166.8 g for the 50th centile (P < .0001). UA Doppler velocimetry was normal in 97.5%. CONCLUSIONS: Fetuses with gastroschisis show symmetrical growth deficits in the second and third trimesters, with normal UA Doppler velocimetry. These results reinforce the hypothesis that they are constitutionally smaller, yet not restricted because of placental insufficiency. PMID- 29110318 TI - Simultaneous determination and pharmacokinetic study of giraldoid a, giraldoid B in rat plasma after oral administration of Daphne giraldii Nitsche extracts by LC MS/MS. AB - A simple sensitive LC-MS/MS method has been developed for the simultaneous determination of giraldoid A and giraldoid B in rat plasma. The method was applied to pharmacokinetics studies of the two compounds from Daphne giraldii Nitsche. Chromatographic separation was accomplished on an Acquity UPLCTM BEH C18 column (100 * 2.1 mm, 1.7 mm) by gradient elution with a flow rate of 0.2 mL min 1. The method was linear over the concentration range of 1.0-1000 ng mL-1 , and the lower limits of quantification were 1.04 +/- 0.10 and 1.04 +/- 0.09 ng mL-1 , respectively. The intra- and inter-day precisions (RSD) were <10.14 and 9.96%. The extraction recovery of the analytes was acceptable. Stability studies demonstrated that the two compounds were stable in the preparation and analytical process. The maximum plasma concentration was 687.78 +/- 243.62 ng mL-1 for giraldoid A and 952.38 +/- 131.99 ng mL-1 for giraldoid B. The time to reach the maximum plasma concentration was 0.50 +/- 0.37 h for giraldoid A and 0.50 +/- 0.66 h for giraldoid B. The validated method was successfully applied to investigate the concentration-time profiles of giraldoid A and giraldoid B. PMID- 29110319 TI - Effects of Chlamydia trachomatis infection on sperm chromatin condensation and DNA integrity. AB - The present study was performed to investigate the relation of Chlamydia trachomatis infection to sperm chromatin/DNA integrity in a population of infertile men (male partner of infertile couples) from Iran. Blood, semen and first-void urine samples were obtained from 250 infertile men. Data were analysed with regard to the results of (i) serological analysis for specific antibodies to C. trachomatis in serum; (ii) the presence of C. trachomatis and DNA in first void urine; and (iii) in the semen sample of the male partner, in addition to sperm analysis, four different tests (aniline blue, chromomycin A3, acridine orange and TUNEL) were used to detect sperm chromatin and DNA abnormalities. The main conclusions of the results were: (i) no evidence of C. trachomatis infection in semen samples was found; (ii) sperm DNA fragmentation and chromatin studies were not correlated with C. trachomatis diagnosis; (iii) the percentage of DNA fragmentation is positively correlated with the percentage of immotile sperm but negatively with semen volume, normal morphology; and (iv) in sperm chromatin evaluations, only the percentage of chromatin protamination was related to male age. PMID- 29110320 TI - A general framework for constraint approaches to adjusted risk differences. AB - The risk difference is an intelligible measure for comparing disease incidence in two exposure or treatment groups. Despite its convenience in interpretation, it is less prevalent in epidemiological and clinical areas where regression models are required in order to adjust for confounding. One major barrier to its popularity is that standard linear binomial or Poisson regression models can provide estimated probabilities out of the range of (0,1), resulting in possible convergence issues. For estimating adjusted risk differences, we propose a general framework covering various constraint approaches based on binomial and Poisson regression models. The proposed methods span the areas of ordinary least squares, maximum likelihood estimation, and Bayesian inference. Compared to existing approaches, our methods prevent estimates and confidence intervals of predicted probabilities from falling out of the valid range. Through extensive simulation studies, we demonstrate that the proposed methods solve the issue of having estimates or confidence limits of predicted probabilities out of (0,1), while offering performance comparable to its alternative in terms of the bias, variability, and coverage rates in point and interval estimation of the risk difference. An application study is performed using data from the Prospective Registry Evaluating Myocardial Infarction: Event and Recovery (PREMIER) study. PMID- 29110321 TI - Effect of nordihydroguaiaretic acid on spermatogenesis and fertility in rats. AB - Nordihydroguaiaretic acid (NDGA) is a naturally occurring lignan with potent antioxidant activity. Currently, it is in clinical trials as anticancer agent. As there is no earlier report on the effect of NDGA on spermatogenesis and fertility, this study was designed to investigate this aspect. Administration of NDGA to rats for 60 days produced degenerative changes in testis but had no effect on sperm DNA integrity test and androgen receptor expression. Ultrastructural studies revealed loss of integrity of cells in seminiferous tubules, vacuolation and presence of apoptotic bodies. Derangement of the outer dense fibres was noted in some sperm flagella. Acrosome formation appears to be normal. About 13.7% of epididymal spermatozoa had deformations like short tail or rounded head. This may explain the lower fertility index in NDGA-treated group. No external deformations in newborns were noted. In conclusion, NDGA may have adverse effects on spermatogenesis. PMID- 29110322 TI - In silico size selection is effective in reducing false positive NIPS cases of monosomy X that are due to maternal mosaic monosomy X. AB - OBJECTIVES: The aim of this study was to establish maternal contribution to false positive noninvasive prenatal DNA screening (NIPS) results and develop the method to distinguish maternal and fetal origin of high-risk monosomy X NIPS calls including mosaic maternal cases. METHOD: A total of 906 women carrying singleton pregnancies have been recruited. Maternal plasma DNA semiconductor massive parallel sequencing was performed to detect common aneuploidies. For the case of high monosomy X risk call, analysis method to distinguish fetal and maternal monosomy X has been additionally applied. RESULTS: According to NIPS results, 18 patients had a high risk of fetal monosomy X. In 11 (61%) cases, fetal aneuploidy was confirmed by karyotyping. Other 7 cases were false positives. In 3 out of 7 cases, additional analysis based on in silico size selection was allowed to assume maternal monosomy X. In these cases, fluorescence in situ hybridization analysis confirmed mosaic monosomy X in maternal blood cells. CONCLUSION: The prevalence of mosaic monosomy X karyotype is 0.3% (3/906)-10 times higher than published before. Additional in silico size-selection and data analysis increases PPV for monosomy X from 61% to 73% for studied population. PMID- 29110323 TI - Prenatal diagnosis and prognosis of isolated subependymal cysts: A retrospective cohort study. AB - OBJECTIVE: The objective of this study was to investigate the significance of prenatal diagnosis of subependymal cysts (SEC). Diagnoses were made by brain ultrasonography (bUS) and confirmed by fetal brain magnetic resonance imaging (MRI). METHODS: We reviewed all the cases of isolated SEC diagnosed antenatally in our center from January 1, 2014, to December 31, 2015, and confirmed by fetal MRI. We followed up their evolution throughout pregnancy and the neonatal neurodevelopment at 3, 6, and 12 months using the Gesell Developmental Schedule. RESULTS: Among the 91 cases in the cohort, 74 were bilateral and 17 unilateral. The SEC were significantly smaller in unilateral than bilateral cases (P < .001). Among the 35 cases with repeated bUS, SEC remained stable or decreased in size with advancing gestational age in 86% of cases. After excluding terminations of pregnancy (n = 13), neurodevelopment was normal in 75/78 (96%) cases with developmental quotient ?85. CONCLUSION: Isolated SEC are usually a benign finding. Accurate diagnosis is important to differentiate SEC from other pathologic brain conditions with a combination of brain ultrasonography and MRI. PMID- 29110324 TI - CntA oxygenase substrate profile comparison and oxygen dependency of TMA production in Providencia rettgeri. AB - CntA oxygenase is a Rieske 2S-2Fe cluster-containing protein that has been previously described as able to produce trimethylamine (TMA) from carnitine, gamma-butyrobetaine, glycine betaine, and in one case, choline. TMA found in humans is exclusively of bacterial origin, and its metabolite, trimethylamine oxide (TMAO), has been associated with atherosclerosis and heart and renal failure. We isolated four different Rieske oxygenases and determined that there are no significant differences in their substrate panels. All three had high activity toward carnitine/gamma-butyrobetaine, medium activity toward glycine betaine, and very low activity toward choline. We tested the influence of low oxygen concentrations on TMA production in CntA-containing Providencia rettgeri cell cultures and discovered that this process, although dependent on the amount of oxygen, is still feasible in environments with 1 and 0.2% oxygen, which is comparable to oxygen levels in some parts of the digestive system. PMID- 29110325 TI - A case of segmental stiff skin syndrome treated with systemic losartan. AB - Stiff skin syndrome (SSS) is a rare, autosomal dominant cutaneous disorder with progressive, symmetric, sclerotic skin changes of the shoulders, hips, and thighs. In a recent publication, a distinct segmental variant of SSS was proposed. In this report we discuss the case of a boy with segmental SSS and review the current literature. PMID- 29110326 TI - In-depth insight into the methods of plasma protein-drug interaction studies: Comparison of capillary electrophoresis-frontal analysis, isothermal titration calorimetry, circular dichroism and equilibrium dialysis. AB - Plasma protein-drug binding assays are routinely performed during the early stages of drug discovery and development, which creates demand for an automated high-throughput screening assay to increase laboratory efficiency. A comprehensive comparison of the four methods typically used for determining the binding parameters is presented in this study with respect to the above demand. Capillary electrophoresis-frontal analysis, isothermal titration calorimetry, circular dichroism and equilibrium dialysis were used to study the affinity of human serum albumin for diclofenac and lidocaine. These model drugs were chosen due to their different physico-chemical properties and different binding sites on the albumin molecule, also resulting in different binding strength. The binding parameters estimated under the conditions as similar as possible were comparable among all these approaches as well as to the literature values. Besides this, the comparison of the results and especially other considerations demonstrated the benefits and drawbacks of the selected methods, with capillary electrophoresis frontal analysis being the best candidate for such studies. PMID- 29110327 TI - Caries risk assessment tool and prevention protocol for public health nurses in mother and child health centers, Israel. AB - OBJECTIVES: Dental caries is the most prevalent chronic disease in children. Caries risk assessment tools enable the dentists, physicians, and nondental health care providers to assess the individual's risk. Intervention by nurses in primary care settings can contribute to the establishment of oral health habits and prevention of dental disease. In Israel, Mother and Child Health Centers provide free preventive services for pregnant women and children by public health nurses. MATERIALS AND METHODS: A caries prevention program in health centers started in 2015. Nurses underwent special training regarding caries prevention. A customized Caries Risk Assessment tool and Prevention Protocol for nurses, based on the AAPD tool, was introduced. A two-step evaluation was conducted which included a questionnaire and in-depth phone interviews. RESULTS: Twenty-eight (out of 46) health centers returned a completed questionnaire. Most nurses believed that oral health preventive services should be incorporated into their daily work. In the in-depth phone interviews, nurses stated that the integration of the program into their busy daily schedule was realistic and appropriate. The lack of specific dental module for computer program was mentioned as an implementation difficulty. DISCUSSION: The wide use of our tool by nurses supports its simplicity and feasibility which enables quick calculation and informed decision making. The nurses readily embraced the tool and it became an integral part of their toolkit. CONCLUSION: We provide public health nurses with a caries risk assessment tool and prevention protocol thus integrating oral health into general health of infants and toddlers. PMID- 29110328 TI - Development of novel radionuclides for medical applications. AB - Medical radionuclide production technology is well established. There is, however, a constant need for further development of radionuclides. The present efforts are mainly devoted to nonstandard positron emitters (eg, 64 Cu, 86 Y, 124 I, and 73 Se) and novel therapeutic radionuclides emitting low-range beta- particles (eg, 67 Cu and 186 Re), conversion or Auger electrons (eg, 117m Sn and 77 Br), and alpha particles (eg, 225 Ac). A brief account of various aspects of development work (ie, nuclear data, targetry, chemical processing, and quality control) is given. For each radionuclide under consideration, the status of technology for clinical scale production is discussed. The increasing need of intermediate-energy multiple-particle accelerating cyclotrons is pointed out. PMID- 29110329 TI - Transplantation of feeder-free human induced pluripotent stem cell-derived cortical neuron progenitors in adult male Wistar rats with focal brain ischemia. AB - The use of human induced pluripotent stem cells (hiPSCs) eliminates the ethical issues associated with fetal or embryonic materials, thus allowing progress in cell therapy research for ischemic stroke. Strict regulation of cell therapy development requires the xeno-free condition to eliminate clinical complications. Maintenance of hiPSCs with feeder-free condition presents a higher degree of spontaneous differentiation in comparison with conventional cultures. Therefore, feeder-free derivation might be not ideal for developing transplantable hiPSC derivatives. We developed the feeder-free condition for differentiation of cortical neurons from hiPSCs. Then, we evaluated the cells' characteristics upon transplantation into the sham and focal brain ischemia on adult male Wistar rats. Grafts in lesioned brains demonstrated polarized reactivity toward the ischemic border, indicated by directional preferences in axonal outgrowth and cellular migration, with no influence on graft survival. Following the transplantation, forelimb asymmetry was better restored compared with controls. Herein, we provide evidence to support the use of the xeno-free condition for the development of cell therapy for ischemic stroke. PMID- 29110331 TI - Radioligands for positron emission tomography imaging of cannabinoid type 2 receptor. AB - The cannabinoid type 2 (CB2) receptor is an immunomodulatory receptor mainly expressed in peripheral cells and organs of the immune system. The expression level of CB2 in the central nervous system under physiological conditions is negligible, however under neuroinflammatory conditions an upregulation of CB2 protein or mRNA mainly colocalized with activated microglial cells has been reported. Consequently, CB2 agonists have been confirmed to play a role in neuroprotective and anti-inflammatory processes. A suitable positron emission tomography radioligand for imaging CB2 would provide an invaluable research tool to explore the role of CB2 receptor expression in inflammatory disorders. In this review, we provide a summary of so far published CB2 radioligands as well as their in vitro and in vivo binding characteristics. PMID- 29110330 TI - Multiethnic polygenic risk scores improve risk prediction in diverse populations. AB - Methods for genetic risk prediction have been widely investigated in recent years. However, most available training data involves European samples, and it is currently unclear how to accurately predict disease risk in other populations. Previous studies have used either training data from European samples in large sample size or training data from the target population in small sample size, but not both. Here, we introduce a multiethnic polygenic risk score that combines training data from European samples and training data from the target population. We applied this approach to predict type 2 diabetes (T2D) in a Latino cohort using both publicly available European summary statistics in large sample size (Neff = 40k) and Latino training data in small sample size (Neff = 8k). Here, we attained a >70% relative improvement in prediction accuracy (from R2 = 0.027 to 0.047) compared to methods that use only one source of training data, consistent with large relative improvements in simulations. We observed a systematically lower load of T2D risk alleles in Latino individuals with more European ancestry, which could be explained by polygenic selection in ancestral European and/or Native American populations. We predict T2D in a South Asian UK Biobank cohort using European (Neff = 40k) and South Asian (Neff = 16k) training data and attained a >70% relative improvement in prediction accuracy, and application to predict height in an African UK Biobank cohort using European (N = 113k) and African (N = 2k) training data attained a 30% relative improvement. Our work reduces the gap in polygenic risk prediction accuracy between European and non-European target populations. PMID- 29110332 TI - Is MBL serum concentration a reliable predictor for recurrent vulvovaginal candidiasis? AB - BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC) is acommon opportunistic, mucosal fungal infection, predominantly caused by the fungus Candida albicans.Mannose-binding lectin (MBL) is an acute-phase protein that plays a key role in the innate immunity defense against infectious disease. OBJECTIVES: The present study was conducted to evaluate the relationship between the MBL serum level and the relative expression of MBL mRNA in RVVC using real-time PCR for the first time. PATIENTS/METHODS: The case-control study included 40 female participants suffering from RVVC and 40 healthy individuals. The MBL serum level was measured using a commercial ELISA kit. The relative mRNA expression of the MBL gene was quantified using real-time PCR. Data analysis was done by SPSS software. RESULTS: The MBL concentration was significantly higher in the participants suffering from RVVC compared to the control group (0.330 ng/ml versus 0.253 ng/ml). The prognostic value (P<0.001) for RVVC diagnosis has been calculated. Quantitative RT-PCR results from 35 samples showed a low to significant values for mRNA levels corresponding to MBL gene expression (1-352 folds) (P<0.001). CONCLUSION: The results of this study suggest that MBL plays a main role in the innate immunity and it is also affected by environmental factors and other genetic variations. Therefore, the MBL gene expression profile does not reflect precise phenotypic levels in the serum. This article is protected by copyright. All rights reserved. PMID- 29110333 TI - Development and validation of a novel sensitive UV-direct capillary electrophoresis method for quantification of alendronate in release studies from biomaterials. AB - A simple, highly sensitive, and robust CE method applied to the determination of alendronate (ALN) was developed from matrices for tissue engineering, characterized by being highly complex systems. The novel method was based on the ALN derivatization with o-phthalaldehyde and 2-mercaptoethanol for direct ultraviolet detection at 254 nm. The BGE consisted of 20 mM sodium borate buffer at pH 10, and the electrophoretic parameters were optimized.The method was validated in terms of specificity, linearity, LOD, LOQ, precision, accuracy, and robustness. The LOD and LOQ obtained were 0.8 and 2.7 MUg/mL, respectively. In addition, the method offers higher sensitivity and specificity compared to other CE and HPLC methods using UV-detectors, as well as low cost and simplicity that allowed the rapid and simple quantitation of ALN from bone regeneration matrices. PMID- 29110334 TI - Frontotemporal dementia with trans-activation response DNA-binding protein 43 presenting with catatonic syndrome. AB - Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder. At the age of 58, the patient had a sudden onset of disorganized behavior and meaningless speech. Psychotropic drugs were effective for catatonic symptoms. However, after remission apathy, hyperorality, socially inappropriate behavior, hoarding, and an instinctive grasp reaction appeared and persisted. Brain MRI showed significant atrophy of the bilateral fronto-temporal lobes. A neuropathological examination revealed extensive trans activation response DNA-binding protein 43 (TDP-43) positive neurocytoplasmic inclusions and dystrophic neurites in the brain, including the cerebral cortex, basal ganglia, and brainstem. Pathological diagnosis was frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) type C, which was also confirmed by the band pattern of C-terminal fragments of TDP-43 on western blotting of sarkosyl-insoluble fractions extracted from the frozen brain. Dysfunction of the thalamus, globus pallidus, supplementary motor area, amygdala and cingulate cortex have been said to be related to the catatonic syndrome. In this case, these areas were affected, showing abnormal TDP-43-positive structures. Further studies are expected to confirm further clinical - pathological correlations to FTLD. PMID- 29110336 TI - Electronic and vibrational exciton coupling in oxidized trianglimines. AB - Readily available chiral trianglimine and their (poly)oxygenated congeners represent a unique class of macrocyclic rigid compounds optimal for testing electronic and vibrational circular dichroism exciton chirality methods. Electronic and vibrational circular dichroism spectra of such trianglimines are strongly affected by polar substituents in macrocycle skeletons. Double substitution by OH groups in each aromatic fragment of the macrocycle causes sign reversal of the exciton couplet in the region of the strongest UV absorption. On the other hand, electronic circular dichroism spectrum of the macrocycle having 2 methoxy groups shows 2 exciton couplets-the long-wavelength positive and the second of the negative sign, observed at the shorter wavelengths. VCD spectra of macrocyclic imines show vibrational exciton couplets in the region of strong C=N stretches. The signs of these couplets are positive and the opposite of the diamine chirality. For trianglimine macrocycles the interpretation of VCD spectra in terms of excitons is much more convincing than for electronic circular dichroism spectra. By contrast, trans-1,2-diaminocyclohexane-based vicinal diimines, being a one-third of the respective macrocycle, do not exhibit any vibrational exciton effect. Experimental data were confronted with DFT calculations. We observed good-to-excellent agreement between experimental and computed data. PMID- 29110335 TI - Correlation between fungal sensitisation in childhood persistent asthma and disease severity. AB - Fungal sensitisation in adults is associated with severe asthma but prevalence and clinical significance of fungal sensitisation remains unclear in paediatric population. The aim of this study was to study the association of fungal sensitisation with disease severity in children with persistent asthma. One hundred children with persistent asthma in age group 7-15 years, symptom duration >2 years and forced expiratory volume in first second >50% of expected were enrolled. Skin prick test (SPT) to 8 fungal antigens and total serum immunoglobulin E (IgE) were done. Fungal sensitisation was described as positive SPT (wheel diameter more than 3 mm larger than the negative control) to any of the fungal antigens and total serum IgE >200 ng/mL. Seventeen patients showed evidence of fungal sensitisation, of which, 6 demonstrated sensitisation to multiple fungi. 17.6% patients with fungal sensitisation had severe asthma as compared to 2.4% patients without fungal sensitisation (P value .032). Significant increase in family history of allergic comorbidities was noted among patients with fungal sensitisation (47.1% vs 21.7%, P value .03). The most common implicated organism in fungal sensitised patients was Aspergillus flavus (47.1%). The results of this study, a first among Indian children with asthma, suggest that children with fungal sensitisation have more severe asthma as compared to children without fungal sensitisation. PMID- 29110337 TI - Pituitary atypical teratoid rhabdoid tumor in a patient with prolactinoma: A unique description. AB - Atypical teratoid rhabdoid tumor (ATRT) is an aggressive tumor of the CNS and characteristically occurs in the pediatric age. In adulthood, ATRT is rare and it is mainly localized in the cerebral hemispheres. Only 16 cases of ATRT have been described in the sellar region up to now. Interestingly, all sellar ATRTs occurred in adult female patients. Herein we report a novel case of sellar ATRT in a patient with previous history of lactotroph adenoma. Similar to other sellar ATRTs, this case occurred in a female adult patient. At histological examination, it was characterized by a small number of rhabdoid cells. In addition, it did not have homozygous deletion of SMARCB1 gene, but it rather showed a frameshift mutation at exon 4 of SMARCB1 which had not been previously found in ATRT. Clinico-pathological and molecular findings observed in this case confirm previous evidence that sellar ATRT seems to be a distinct entity. Association with previous prolactin-secreting pituitary adenoma is discussed. PMID- 29110338 TI - Use of viscoelastic tests to predict clinical thromboembolic events: A systematic review and meta-analysis. AB - We aimed to assess whether whole-blood viscoelastic tests are useful to identify patients who are hypercoagulable and at increased risk of thromboembolism. Two investigators independently analyzed studies in the MEDLINE, EMBASE, and Cochrane controlled trial register databases to determine the ability of viscoelastic tests to identify a hypercoagulable state that is predictive of objectively proven thromboembolic events. Forty-one eligible studies, including 10,818 patients, were identified and subject to meta-analysis. The majority of the studies (n = 36, 88%) used the maximum clot strength to identify a hypercoagulable state which had a moderate ability to differentiate between patients who developed thromboembolic events and those who did not (area under the summary receiver operating characteristic [sROC] curve = 0.70, 95% confidence interval [CI]: 0.65-0.75). The pooled sensitivity, specificity, and diagnostic odds ratio to predict thromboembolism were 56% (95%CI: 44-67), 76% (95%CI: 67 83), and 3.6 (95%CI: 2.6-4.9), respectively. The predictive performance did not vary substantially between patient populations, and publication bias was not observed. Current evidence suggests that whole-blood viscoelastic tests have a moderate ability to identify a variety of patient populations with an increased risk of thromboembolic events and can be considered as a useful adjunct to clinical judgment to stratify a patient's risk of developing thromboembolism. PMID- 29110339 TI - Role of Dectin-1 receptor on cytokine production by human monocytes challenged with Paracoccidioides brasiliensis. AB - Fungal recognition by Dectin-1 receptor triggers a series of cellular mechanisms involved in a protective activation of the immune system. In this study, we aimed to evaluate the participation of Dectin-1 receptor in the induction of IL-8, TNF alpha, IL-12, IL-10 and IL-17A secretion by human monocytes activated with different cytokines, and challenged in vitro with Paracoccidioides brasiliensis (P. brasiliensis). Our results show that monocytes challenged with P. brasiliensis (Pb265) are able to produce IL-12, IL-8, IL-17, IL-10 and TNF-alpha. Dectin-1 receptor blockage decreased the IL-12, IL-17, IL-10 and TNF-alpha levels indicating the participation of such receptor in the induction of these cytokines. Only IL-8 production was not affected by the blockage. Cells activation with different cytokines showed that GM-CSF was able to induce secretion of all cytokines and the receptor blockage prior to the challenge also decreased the cytokine secretion, except IL-8. Monocytes activated with TNF-alpha promoted IL-8, IL-10 and TNF-alpha production, whereas stimulation with IFN-gamma promoted mainly IL-12 and TNF-alpha. Thus, these findings bring new and important knowledge about Dectin-1 participation in cytokines production by monocytes challenged with Pb265. PMID- 29110340 TI - Effect of topical fluoride application on enamel after in-office bleaching, as evaluated using a novel hardness tester and a transverse microradiography method. AB - This study evaluated the effect of topical fluoride application on enamel hardness after in-office bleaching. Twelve human incisors were cut along the long axis, resulting in 24 halves used in four treatment groups (n = 6 in each group): (i) untreated group (C); (ii) in-office bleaching material (B); (iii) treatment with surface reaction-type prereacted glass-ionomer varnish after in-office bleaching (B+PRG); and (iv) treatment with acidulated phosphate fluoride solution after bleaching (B+F). All specimens were subjected to pH-cycling for 4 wk. Knoop hardness was measured using a Cariotester. The decalcification of enamel was assessed quantitatively by measuring the integrated mineral loss (DeltaIML). Games-Howell analysis was used to assess statistical significance of between group differences. The Knoop hardness decreased significantly after bleaching for all groups. In treatment groups B+PRG and B+F, the Knoop hardness returned to the original unbleached values after the first pH cycle and did not change afterwards. In treatment groups C and B there was a gradual decrease in the Knoop hardness until the fourth pH cycle. The integrated mineral loss, DeltaIML, was significantly higher in treatment group B+F after 2 wk than in the other treatment groups. After 4 wk, the DeltaIML in treatment group B was significantly higher than in treatment group B+PRG. The application of fluoride-containing materials after bleaching results in recuperation of hardness to levels similar to those of unbleached enamel. PMID- 29110341 TI - Hemin and bile pigments are the secondary structure regulators of intrinsically disordered antimicrobial peptides. AB - The interaction of protoporphyrin compounds of human origin with the major bee venom component melittin (26 a.a., Z +6) and its hybrid derivative (CM15, 15 a.a., Z +6) were studied by a combination of various spectroscopic methods. Throughout a two-state, concentration-dependent process, hemin and its metabolites (biliverdin, bilirubin, bilirubin ditaurate) increase the parallel beta-sheet content of the natively unfolded melittin, suggesting the oligomerization of the peptide chains. In contrast, alpha-helix promoting effect was observed with the also disordered but more cationic CM15. According to fluorescence quenching experiments, the sole Trp residue of melittin is the key player during the binding, in the vicinity of which the first pigment molecule is accommodated presumably making indole-porphyrin pi-pi stacking interaction. As circular dichroism titration data suggest, cooperative association of additional ligands subsequently occurs, resulting in multimeric complexes with an apparent dissociation constant ranged from 20 to 65 MUM. Spectroscopic measurements conducted with the bilirubin catabolite urobilin and stercobilin refer to the requirement of intact dipyrrinone moieties for inducing secondary structure transformations. The binding topography of porphyrin rings on a model parallel beta-sheet motif was evaluated by absorption spectroscopy and computational modeling showing a slipped-cofacial binding mode responsible for the red shift and hypochromism of the Soret band. Our results may aid to recognize porphyrin responsive binding motifs of biologically relevant, intrinsically disordered peptides and proteins, where transient conformations play a vital role in their functions. PMID- 29110342 TI - Production of (R)-1-(1,3-benzodioxol-5-yl)ethanol in high enantiomeric purity by Lactobacillus paracasei BD101. AB - Piperonyl ring is found in a number of naturally occurring compounds and possesses enormous biological activities. There are many studies in the literature with compounds containing a piperonyl ring, but there are very few studies on the synthesis of chiral piperonyl carbinol. The objective of this study was to determine the microbial reduction ability of bacterial strains and to reveal the effects of different physicochemical parameters on this reduction ability. A total of 15 bacterial isolates were screened for their ability to reduce 1-(benzo[d][1,3]dioxol-5-yl) ethanone 1 to its corresponding alcohol. Among these isolates Lactobacillus paracasei BD101 was found to be the most successful biocatalyst to reduce the ketone containing piperonyl ring to the corresponding alcohol. The reaction conditions were systematically optimized for the reducing agent L paracasei BD101, which showed high enantioselectivity and conversion for the bioreduction. The preparative scale study was performed, and a total of 3.72 g of (R)-1-(1,3-benzodioxol-5-yl) ethanol in high enantiomeric form (>99% enantiomeric excess) was produced in a mild, cheap, and environment friendly process. This study demonstrates that L paracasei BD101 can be used as a biocatalyst to obtain chiral carbinol with excellent yield and selectivity. PMID- 29110343 TI - A possible way to assess tidal exhaled nitric oxide in neonates and infants treated with nasal continuous positive airway pressure. PMID- 29110345 TI - Pyometra and unilateral uterine horn torsion in a sheep. AB - A 13-year-old Romanov sheep presented for evaluation of vaginal discharge, depression and anorexia. Blood work demonstrated mature neutrophilia and marked hyperlactatemia. Transrectal and transabdominal ultrasound revealed echogenic fluid (pus) within the uterus. Purulent uterine fluid culture yield Escherichia coli. A diagnosis of pyometra was made. After medical treatment without clinical improvement, an exploratory laparotomy was performed, and a 360-degree uterine left horn torsion was identified with the pyometra and multiple corpora lutea on both ovaries. Ovariohysterectomy was performed and the ewe recovered uneventfully. PMID- 29110346 TI - On meta- and mega-analyses for gene-environment interactions. AB - Gene-by-environment (G * E) interactions are important in explaining the missing heritability and understanding the causation of complex diseases, but a single, moderately sized study often has limited statistical power to detect such interactions. With the increasing need for integrating data and reporting results from multiple collaborative studies or sites, debate over choice between mega- versus meta-analysis continues. In principle, data from different sites can be integrated at the individual level into a "mega" data set, which can be fit by a joint "mega-analysis." Alternatively, analyses can be done at each site, and results across sites can be combined through a "meta-analysis" procedure without integrating individual level data across sites. Although mega-analysis has been advocated in several recent initiatives, meta-analysis has the advantages of simplicity and feasibility, and has recently led to several important findings in identifying main genetic effects. In this paper, we conducted empirical and simulation studies, using data from a G * E study of lung cancer, to compare the mega- and meta-analyses in four commonly used G * E analyses under the scenario that the number of studies is small and sample sizes of individual studies are relatively large. We compared the two data integration approaches in the context of fixed effect models and random effects models separately. Our investigations provide valuable insights in understanding the differences between mega- and meta analyses in practice of combining small number of studies in identifying G * E interactions. PMID- 29110344 TI - Current technical approaches to brain energy metabolism. AB - Neuroscience is a technology-driven discipline and brain energy metabolism is no exception. Once satisfied with mapping metabolic pathways at organ level, we are now looking to learn what it is exactly that metabolic enzymes and transporters do and when, where do they reside, how are they regulated, and how do they relate to the specific functions of neurons, glial cells, and their subcellular domains and organelles, in different areas of the brain. Moreover, we aim to quantify the fluxes of metabolites within and between cells. Energy metabolism is not just a necessity for proper cell function and viability but plays specific roles in higher brain functions such as memory processing and behavior, whose mechanisms need to be understood at all hierarchical levels, from isolated proteins to whole subjects, in both health and disease. To this aim, the field takes advantage of diverse disciplines including anatomy, histology, physiology, biochemistry, bioenergetics, cellular biology, molecular biology, developmental biology, neurology, and mathematical modeling. This article presents a well-referenced synopsis of the technical side of brain energy metabolism research. Detail and jargon are avoided whenever possible and emphasis is given to comparative strengths, limitations, and weaknesses, information that is often not available in regular articles. PMID- 29110347 TI - Treatment with the MAPK kinase inhibitor U0126 during the first two hours of in vitro maturation improves bovine oocyte developmental competence. AB - This study examined the effects of treatment with U0126, which inhibits MAPK by inhibiting MAPK kinase, during the first 2 hr of in vitro maturation on bovine developmental competence and on gap junction (GAPJ) communication between the oocyte and cumulus cells. The percentage of oocytes developing to the blastocyst stage in the group treated with 5 MUM U0126 (28%) was significantly higher than that in controls (15%, p < .05), while that in the group treated with 10 MUM U0126 (18%) was not. Breakdown of the GAPJs was delayed in the group treated with 5 MUM U0126 when compared to controls, as estimated by immunohistochemical examination of connexin 43, which is a primary constituent of the GAPJs. These results indicate that treatment with 5 MUM U0126 during in vitro maturation delays GAPJ breakdown and improves bovine oocyte developmental competence. PMID- 29110349 TI - Sequence Controlled Polymers from a Novel beta-Cyclodextrin Core. AB - In this work the synthesis and use of a novel beta-cyclodextrin-based single electron transfer-living radical polymerization (SET-LRP) initiator are reported. Three different approaches toward the synthesis of this initiator, based on several "click"-like reactions (copper(I)-catalyzed azide-alkyne cycloaddition, nucleophilic thiol-ene reaction, and radical thiol-ene reaction), are explored and discussed. Synthesis via radical thiol-ene proves to be most successful in achieving this. The beta-cyclodextrin-based initiator is subsequently used for the polymerization of several acrylates in a controlled fashion, yielding 7-arm multiblock copolymers. The achieved sequence-controlled polymers exhibit low dispersities (<=1.12) and are completed under 6.5 h at high monomer conversion (>=95%) for each block. PMID- 29110348 TI - Evaporative cooling in late gestation heat-stressed Murrah buffaloes increases efficiency of next reproductive cycle. AB - Evaporative cooling during late gestation period improves post-partum reproductive performance in Murrah buffaloes. To prove this hypothesis, sixteen pregnant dry Murrah buffaloes at sixty days pre-partum were selected and divided into two groups of eight animals each. Group 1 of buffaloes (Cooled/CL) was managed under fan and mist cooling during dry period, whereas second group of buffaloes (non-cooled/NCL) remained without the provision of cooling. After parturition, all the animals were managed under evaporative cooling till the end of experimental period. Reproductive performance in cooled (CL) and non-cooled (NCL) groups, respectively, viz. 1st and 2nd ovulation from calving (48.63 +/- 2.41, 69.25 +/- 2.34 days and 57.75 +/- 3.35, 93.63 +/- 2.84 days); calving to conception interval (117.88 +/- 4.21 days and 117.88+/- 4.21 days); conception rate (87.5% +/- 2.16% and 57% +/- 2.26%); and follicular diameter at the time of 1st and 2nd ovulation (14.84 +/- 0.16, 15.75 +/- 0.13 mm and 12.65 +/- 0.13, 13.35 +/- 0.11 mm) varied significantly (p < .05). Total peak oestrogen concentration was significantly (p < .05) higher in cooled (26.7 +/- 1.32 pg/ml) relative to non-cooled (20.7 +/- 1.22 pg/ml) buffaloes. Time from onset of oestrus to ovulation varied significantly (p < .05) in cooled (32 +/- 2.22 hr) and non-cooled (40 +/- 2.86 hr) buffaloes. The peak progesterone concentration reached to (4.25 ng/ml) in cooled group and (4.16 ng/ml) in non-cooled group after first ovulation. PMID- 29110350 TI - Fertilizing ability of canine spermatozoa cryopreserved with skim milk-based extender in a retrospective study. AB - We previously reported that skim milk (SM) is an effective cryoprotectant for cryopreservation of canine spermatozoa instead of egg yolk (EY), which is the conventional cryoprotectant. In this study, the fertilizing ability and practical use of frozen canine spermatozoa prepared with SM were evaluated by transcervical insemination. Frozen-thawed spermatozoa were inseminated one to four times on days 2-9 after the LH surge. In SM group, a single transcervical insemination (TCI) on Day 5 led to higher delivery rate (83%) than any other days (33%-50%) post-LH surge. In EY group, delivery rate in double TCI on days 5 and 6 (71%) was higher compared to any other experimental groups (0%-44%). Regardless of single or double, TCI on Day 5 or Day 6 led to higher litter sizes in SM or EY groups, respectively. The breeding efficiency and litter size of single TCI on Day 5 (4.2) and double TCI on Day 5 and Day 6 (3.7) were significantly higher than in the other experimental groups in SM and EY groups, respectively (p < .05). These findings suggest that skim milk is a suitable alternative to egg yolk for cryopreservation of canine spermatozoa, and the suitable timing for insemination might be on Day 5 post-LH surge. PMID- 29110351 TI - Posaconazole liquid vs tablet formulation in lung transplant recipients. AB - Posaconazole is an extended-spectrum triazole antifungal used in the treatment and prophylaxis of Aspergillus infections. It is available as oral suspension (POS-Liq) and delayed-release tablets (POS-Tab). The aim of this longitudinal, retrospective study was to compare the clinical effectiveness, toxicity and pharmacokinetics of POS-Liq vs POS-Tab in lung transplant recipients (LTx recipients), who were treated with both formulations subsequently. Twenty-four consecutive LTx-recipients with 191 documented posaconazole trough levels (PTLs) for POS-Liq or POS-Tab were included. The administered daily doses were 300 mg for POS-Tab and 600 mg (prophylaxis) or 800 mg (therapy) for POS-Liq. Target PTLs were >=700 ng/mL (prophylaxis) and >=1250 ng/mL (therapy). The overall prophylactic and therapeutic response rates were 78% and 67%, respectively. No cases of hepatotoxicity or QT-prolongation were observed with either formulation. The achieved target PTLs were tripled under POS-Tab compared to POS-Liq with fewer risk factors for sub-therapeutic PTLs. Concomitant administration of POS Tab significantly reduced the tacrolimus concentration-to-dose ratio (P = .001). We suggest the use of POS-Tab is appropriate for prophylaxis and therapy of Aspergillus infections in LTx-recipients, since POS-Tab displayed more reliable PTLs with no added adverse events. However, we recommend regular drug monitoring for POS-Liq and for therapy with POS-Tab and that immunosuppressant levels are monitored closely when the posaconazole formulation is switched. PMID- 29110352 TI - The Screen for Cognitive Impairment in Psychiatry: Proposal for a polytomous scoring system. AB - The Screen for Cognitive Impairment in Psychiatry is a simple, fast, and easy to administer scale that has been validated in clinical and community samples. The aim of this study was to propose a polytomous scoring system for the Screen for Cognitive Impairment in Psychiatry and to demonstrate its functioning, thus providing new and complementary information regarding the utility and precision of this screening tool. Three hundred seventy-six Spanish patients diagnosed with schizophrenia spectrum disorder were evaluated. A polytomous scoring system was generated and analyzed by means of the partial credit model. Category assessment revealed optimal functioning after collapsing the 7-category system to 1 with either 5 or 4 categories, depending on the item. The proposed polytomous scoring system shows good psychometric properties and an adequate fit to the partial credit model. These results provide further confirmation of the test's utility in clinical settings and of its suitability for detecting cognitive impairment. PMID- 29110354 TI - Landscape features along migratory routes influence adaptive genomic variation in anadromous steelhead (Oncorhynchus mykiss). AB - Organisms typically show evidence of adaptation to features within their local environment. However, many species undergo long-distance dispersal or migration across larger geographic regions that consist of highly heterogeneous habitats. Therefore, selection may influence adaptive genetic variation associated with landscape features at residing sites and along migration routes in migratory species. We tested for genomic adaptation to landscape features at natal spawning sites and along migration paths to the ocean of anadromous steelhead trout (Oncorhynchus mykiss) in the Columbia River Basin. Results from multivariate ordination, gene-environment association and outlier analyses using 24,526 single nucleotide polymorphisms (SNPs) provided evidence that adaptive allele frequencies were more commonly associated with landscape features along migration paths than features at natal sites (91.8% vs. 8.2% of adaptive loci, respectively). Among the 45 landscape variables tested, migration distance to the ocean and mean annual precipitation along migration paths were significantly associated with adaptive genetic variation in three distinct genetic groups. Additionally, variables such as minimum migration water temperature and mean migration slope were significant only in inland stocks of steelhead that migrate up to 1,200 km farther than those near the coast, indicating regional differences in migratory selective pressures. This study provides novel approaches for investigating migratory corridors and some of the first evidence that environment along migration paths can lead to substantial divergent selection. Consequently, our approach to understand genetic adaptation to migration conditions can be applied to other migratory species when migration or dispersal paths are generally known. PMID- 29110353 TI - Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia. AB - OBJECTIVE: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D2/3 receptor (D2/3 R) blockade by antipsychotics. METHODS: Data from 41 older schizophrenia patients (mean age: 60.2 +/- 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D2/3 R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate. RESULTS: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: beta = .38, t = -2.48, P = .01; left: beta = -.31, t = -2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (beta = -.43, t = -0.26, P = .03). CONCLUSION: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3 R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit. PMID- 29110355 TI - Long non-coding RNAs in rheumatoid arthritis. AB - Rheumatoid arthritis, a disabling autoimmune disease, is associated with altered gene expression in circulating immune cells and synovial tissues. Accumulating evidence has suggested that long non-coding RNAs (lncRNAs), which modulate gene expression through multiple mechanisms, are important molecules involved in immune and inflammatory pathways. Importantly, many studies have reported that lncRNAs can be utilized as biomarkers for disease diagnosis and prognostication. Recently, dysregulation of lncRNAs in rheumatoid arthritis and other autoimmune diseases has been revealed. Experimental studies also confirmed their crosstalk with matrix metalloproteinases, nuclear factor-kappaB signalling and T-cell response pertinent to autoimmunity and inflammation. Circulating lncRNAs, such as HOTAIR, differentiated patients with rheumatoid arthritis from healthy subjects. Taken together, lncRNAs are good candidates as biomarkers and therapeutic targets in rheumatoid arthritis. Further investigation on in vivo delivery of these regulatory molecules and large-cohort validation of their clinical applicability may be useful. PMID- 29110356 TI - Quantitation of Tolyporphins, Diverse Tetrapyrrole Secondary Metabolites with Chlorophyll-Like Absorption, from a Filamentous Cyanobacterium-Microbial Community. AB - INTRODUCTION: Tolyporphins are unusual tetrapyrrole macrocycles produced by a non axenic filamentous cyanobacterium (HT-58-2). Tolyporphins A-J, L, and M share a common dioxobacteriochlorin core, differ in peripheral substituents, and exhibit absorption spectra that overlap that of the dominant cyanobacterial pigment, chlorophyll a. Identification and accurate quantitation of the various tolyporphins in these chlorophyll-rich samples presents challenges. OBJECTIVE: To develop methods for the quantitative determination of tolyporphins produced under various growth conditions relative to that of chlorophyll a. METHODOLOGY: Chromatographic fractionation of large-scale (440 L) cultures afforded isolated individual tolyporphins. Lipophilic extraction of small-scale (25 mL) cultures, HPLC separation with an internal standard, and absorption detection enabled quantitation of tolyporphin A and chlorophyll a, and by inference the amounts of tolyporphins A-M. Absorption spectroscopy with multicomponent analysis of lipophilic extracts (2 mL cultures) afforded the ratio of all tolyporphins to chlorophyll a. The reported absorption spectral data for the various tolyporphins required re-evaluation for quantitative purposes. RESULTS AND DISCUSSION: The amount of tolyporphin A after 50 days of illumination ranged from 0.13 nmol/mg dry cells (media containing nitrate) to 1.12 nmol/mg (without nitrate), with maximum 0.23 times that of chlorophyll a. Under soluble-nitrogen deprivation after 35-50 days, tolyporphin A represents 1/3-1/2 of the total tolyporphins, and the total amount of tolyporphins is up to 1.8-fold that of chlorophyll a. CONCLUSIONS: The quantitative methods developed herein should facilitate investigation of the biosynthesis of tolyporphins (and other tetrapyrroles) as well as examination of other strains for production of tolyporphins. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29110357 TI - The administration of blood components: a British Society for Haematology Guideline. PMID- 29110358 TI - Temporal variation in brain transcriptome is associated with the expression of female mimicry as a sequential male alternative reproductive tactic in fish. AB - Distinct patterns of gene expression often underlie intra- and intersexual differences, and the study of this set of coregulated genes is essential to understand the emergence of complex behavioural phenotypes. Here, we describe the development of a de novo transcriptome and brain gene expression profiles of wild caught peacock blenny, Salaria pavo, an intertidal fish with sex-role reversal in courtship behaviour (i.e., females are the courting sex) and sequential alternative reproductive tactics in males (i.e., larger and older nest-holder males and smaller and younger sneaker males occur). Sneakers mimic both female's courtship behaviour and nuptial coloration to get access to nests and sneak fertilizations, and later in life transition into nest-holder males. Thus, this species offers the unique opportunity to study how the regulation of gene expression can contribute to intersex phenotypes and to the sequential expression of male and female behavioural phenotypes by the same individual. We found that at the whole brain level, expression of the sneaker tactic was paralleled by broader and divergent gene expression when compared to either females or nest holder males, which were more similar between themselves. When looking at sex biased transcripts, sneaker males are intersex rather than being either nest holder or female-like, and their transcriptome is simultaneously demasculinized for nest-holder-biased transcripts and feminized for female-biased transcripts. These results indicate that evolutionary changes in reproductive plasticity can be achieved through regulation of gene expression, and in particular by varying the magnitude of expression of sex-biased genes, throughout the lifetime of the same individual. PMID- 29110359 TI - Identification of Functional Peptide Sequences to Lead the Design of Precision Polymers. AB - Peptide sciences developed dramatically as a result of routine use of solid-phase peptide synthesis and nowadays offer a rich set of well-established strategies to design and identify functional peptide sequences for advanced applications in materials sciences. Appropriate sequences for a wide range of interesting material targets, ranging from molecules to materials surfaces and internal interfaces, can be selected via combinatorial means, and sequence specificities within the resulting peptide-target interactions can be routinely investigated. Based on this understanding, macromolecular sciences can define new polymer structures that meet required functionalities or functional sequences with fully synthetic, nonpeptidic precision polymers to endeavor toward information-based design of next-generation, purpose-adapted macromolecules. PMID- 29110360 TI - Enhancing engineered vascular networks in vitro and in vivo: The effects of IGF1 on vascular development and durability. AB - OBJECTIVES: Creation of functional, durable vasculature remains an important goal within the field of regenerative medicine. Engineered biological vasculature has the potential to restore or improve human tissue function. We hypothesized that the pleotropic effects of insulin-like growth factor 1 (IGF1) would enhance the engineering of capillary-like vasculature. MATERIALS AND METHODS: The impact of IGF1 upon vasculogenesis was examined in in vitro cultures for a period of up to 40 days and as subcutaneous implants within immunodeficient mice. Co-cultures of human umbilical vein endothelial cells and human bone marrow-derived mesenchymal stem cells in collagen-fibronectin hydrogels were supplemented with either recombinant IGF1 protein or genetically engineered cells to provide sustained IGF1. Morphometric analysis was performed on the vascular networks that formed in four concentrations of IGF1. RESULTS: IGF1 supplementation significantly enhanced de novo vasculogenesis both in vitro and in vivo. Effects were long-term as they lasted the duration of the study period, and included network density, vessel length, and diameter. Bifurcation density was not affected. However, the highest concentrations of IGF1 tested were either ineffective or even deleterious. Sustained IGF1 delivery was required in vivo as the inclusion of recombinant IGF1 protein had minimal impact. CONCLUSION: IGF1 supplementation can be used to produce neovasculature with significantly enhanced network density and durability. Its use is a promising methodology for engineering de novo vasculature to support regeneration of functional tissue. PMID- 29110362 TI - Plant traits determine the phylogenetic structure of arbuscular mycorrhizal fungal communities. AB - Functional diversity in ecosystems has traditionally been studied using aboveground plant traits. Despite the known effect of plant traits on the microbial community composition, their effects on the microbial functional diversity are only starting to be assessed. In this study, the phylogenetic structure of arbuscular mycorrhizal (AM) fungal communities associated with plant species differing in life cycle and growth form, that is, plant life forms, was determined to unravel the effect of plant traits on the functional diversity of this fungal group. The results of the 454 pyrosequencing showed that the AM fungal community composition differed across plant life forms and this effect was dependent on the soil collection date. Plants with ruderal characteristics tended to associate with phylogenetically clustered AM fungal communities. By contrast, plants with resource-conservative traits associated with phylogenetically overdispersed AM fungal communities. Additionally, the soil collected in different seasons yielded AM fungal communities with different phylogenetic dispersion. In summary, we found that the phylogenetic structure, and hence the functional diversity, of AM fungal communities is dependent on plant traits. This finding adds value to the use of plant traits for the evaluation of belowground ecosystem diversity, functions and processes. PMID- 29110361 TI - Hairy cell leukemia 2018: Update on diagnosis, risk-stratification, and treatment. AB - DISEASE OVERVIEW: Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B-cell disorders, characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment. DIAGNOSIS: Diagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation. RISK STRATIFICATION: Progression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. VH4-34 positive HCL cases are associated with poor prognosis RISK ADAPTED THERAPY: Purine analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option. MANAGEMENT OF PROGRESSIVE OR REFRACTORY DISEASE: It is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors. PMID- 29110363 TI - Synthesis, receptor binding studies, optical spectroscopic and in silico structural characterization of morphiceptin analogs with cis-4-amino-L-proline residues. AB - Three novel morphiceptin analogs, in which Pro in position 2 and/or 4 was replaced by cis-4-aminoproline connected with the preceding amino acid through the primary amino group, were synthesized. The opioid receptor affinities, functional assay results, enzymatic degradation studies and experimental and in silico structural analysis of such analogs are presented. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 29110364 TI - Low-Valent Ate Complexes Formed in Cobalt-Catalyzed Cross-Coupling Reactions with 1,3-Dienes as Additives. AB - The combination of CoCl2 and 1,3-dienes is known to catalyze challenging alkyl alkyl cross-coupling reactions between Grignard reagents and alkyl halides, but the mechanism of these valuable transformations remains speculative. Herein, electrospray-ionization mass spectrometry is used to identify and characterize the elusive intermediates of these and related reactions. The vast majority of detected species contain low-valent cobalt(I) centers and diene molecules. Charge tagging, deuterium labeling, and gas-phase fragmentation experiments elucidate the likely origin of these species and show that the diene not only binds to Co as a pi ligand, but also undergoes migratory insertion reactions into Co-H and Co R bonds. The resulting species have a strong tendency to form anionic cobalt(I) ate complexes, the superior nucleophilicity of which should render them highly reactive toward electrophilic substrates and, thus, presumably is the key to the high catalytic efficiency of the system under investigation. Upon the reaction of the in situ formed cobalt(I) ate complexes with organyl halides, only the final cross-coupling product could be detected, but no cobalt(III) species. This finding implies that this reaction step proceeds in a direct manner without any intermediate or, alternatively, that it involves an intermediate with a very short lifetime. PMID- 29110365 TI - Magnetic resonance imaging features of canine gliomatosis cerebri. AB - A retrospective, case series study was undertaken to identify magnetic resonance imaging (MRI) characteristics of gliomatosis cerebri in dogs. Fourteen dogs were included by review of histopathological records and contemporaneous MRI. On MRI, all lesions presented as ill-defined, intraaxial lesions within the left and right forebrain hemispheres with involvement of white and gray matter. Lesions presented as hyperintense areas on T2-weighted and FLAIR sequences and as hypointense or isointense areas on T1-weighted images, with mild parenchymal contrast enhancement in three dogs. Signal changes were noted in three to 10 cerebral lobes. Other most commonly affected structures were the thalamus (13), caudate nucleus (13), interthalamic adhesion (11), hypothalamus (11), callosal commissure (10), hippocampus (9), and quadrigeminal plate (8). Abnormalities within the caudal fossa were noted in 10 dogs. Solid tumor portions were identified in five dogs. The histopathological examination demonstrated in all dogs a widespread diffuse infiltration with neoplastic glial cells in white and gray matter with meningeal infiltration. Comparison between MRI and histopathology showed that all areas with signal changes on MRI corresponded to diffuse and dense infiltration with neoplastic cells. The signal intensity on T2 weighted and FLAIR images reflected the density of neoplastic cells. In all dogs, MRI underestimated lesion extent and meningeal infiltration. Involvement of the caudal fossa was not seen on MRI in three dogs. Despite this, MRI allowed identification of lesions extending into at least three cerebral lobes and therefore satisfying the criteria used for diagnosis of diffuse glioma with gliomatosis cerebri growth pattern in humans. PMID- 29110366 TI - Energy dissipation differs between females with and without chronic ankle instability. AB - Chronic ankle instability (CAI) is associated with altered energy dissipation patterns, but comparisons to lateral ankle sprain (LAS) copers have not been explored. The purpose of this study was to examine differences in relative sagittal plane energy dissipation during a single-leg landing between female CAI and LAS coper participants. We separated 33 females (23.6 +/- 4.6 years, 164.3 +/ 6.2 cm, 69.4 +/- 13.7 kg) into CAI (n = 17) and LAS coper (n = 16) groups. Participants completed 5 single-leg landings followed by a 5-second stabilization. We collected sagittal plane kinematics and joint moments at the ankle, knee, hip, and proximal joints (knee and hip) combined then calculated each joint's energy dissipation at 50, 100, 150, and 200 ms post-landing. We compared the percentage of total energy dissipated by the ankle, knee, hip, and proximal joints during each interval utilizing independent t tests and Cohen's d effect sizes. Statistical significance was set a priori at P < .05. The CAI group had lower relative energy dissipation from the ankle at 50 (24.7 +/- 11.5% vs 39.2 +/- 11.8%, P < .01, d = 1.25 [0.47, 1.95]), 100 (66.9 +/- 19.4% vs 77.7 +/- 6.5%, P = .04, d = 0.74 [0.01, 1.42]), and 150 ms (70.7 +/- 17.8% vs 81.0 +/- 5.7%, P = .03, d = 0.77 [0.04, 1.46]) compared to LAS copers. The CAI group had a greater hip contribution through 150 ms (17.9 +/- 10.7% vs 11.7 +/- 4.4%, P = .04, d =-0.75 [-1.44, -0.03]) and the proximal joints at 50 (75.3 +/- 11.5% vs 60.8 +/- 11.8%, P < .01, d = -1.25 [-1.96, -0.47]), 100 (33.1 +/- 19.4% vs 22.3 +/- 6.5%, P = .04, d = -0.74 [-1.42, -0.01]), and 150 ms (29.3 +/- 17.8 vs 19.0 +/- 5.7%, P = .03, d =-0.77 [-1.46, -0.04]) compared to LAS copers. Females with CAI may benefit from therapeutic exercises designed to correct a single-leg energy dissipation strategy that relies less on the ankle joint. PMID- 29110367 TI - Copper- or Thermally Induced Divergent Outcomes: Synthesis of 4-Methyl 2H Chromenes and Spiro-4H-Pyrazoles. AB - An unprecedented divergent outcome transformation of alkyne tethered N-sulfonyl hydrazones is reported, which provides a direct and effective access to 4-methyl 2H-chromene derivatives and spiro-4H-pyrazoles in the presence of copper catalyst or under thermal conditions, respectively. The notable features of this process include readily available starting materials, an inexpensive copper catalyst, mild reaction conditions, broad substrate scope, diverse transformations and potential applications of these generated products. Mechanistic studies indicate that the 3H-pyrazole, which is generated via direct [3+2] cycloaddition, is the communal key intermediate of these two divergent transformations. To the best of our knowledge, this is the only example of sulfonation reaction that goes through a cascade process involving 3H-pyrazole, which was isolated and confirmed by single crystal X-ray diffraction analysis for the first time. PMID- 29110369 TI - Author's reply to comments on "A taxonomy of estimands for regulatory clinical trials with discontinuations". PMID- 29110370 TI - Learning curve estimation in medical devices and procedures: hierarchical modeling. PMID- 29110368 TI - Kv channels and vascular smooth muscle cell proliferation. AB - Kv channels are present in virtually all VSMCs and strongly influence contractile responses. However, they are also instrumental in the proliferative, migratory, and secretory functions of synthetic, dedifferentiated VSMCs upon PM. In fact, Kv channels not only contribute to all these processes but also are active players in the phenotypic switch itself. This review is focused on the role(s) of Kv channels in VSMC proliferation, which is one of the best characterized functions of dedifferentiated VSMCs. VSMC proliferation is a complex process requiring specific Kv channels at specific time and locations. Their identification is further complicated by their large diversity and the differences in expression across vascular beds. Of interest, both conserved changes in some Kv channels and vascular bed-specific regulation of others seem to coexist and participate in VSMC proliferation through complementary mechanisms. Such a system will add flexibility to the process while providing the required robustness to preserve this fundamental cellular response. PMID- 29110371 TI - Comments on "A taxonomy of estimands for regulatory clinical trials with discontinuations". PMID- 29110372 TI - Correction. PMID- 29110373 TI - Correction. PMID- 29110375 TI - Modulation of immunogenicity of poly(sarcosine) displayed on various nanoparticle surfaces due to different physical properties. AB - Poly(sarcosine) displayed on polymeric micelle is reported to trigger a T cell independent type2 reaction with B1a cells in the mice to produce IgM and IgG3 antibodies. In addition to polymeric micelle, three kinds of vesicles displaying poly(sarcosine) on surface were prepared here to evaluate the amounts and avidities of IgM and IgG3, which were produced in mice, to correlate them with physical properties of the molecular assemblies. The largest amount of IgM was produced after twice administrations of a polymeric micelle of 35 nm diameter (G1). On the other hand, the production amount of IgG3 became the largest after twice administrations of G3 (vesicle of 229 nm diameter) or G4 (vesicle of 85 nm diameter). The augmented avidity of IgG3 after the twice administrations compared with that at the single administration was the highest with G3. These differences in immune responses are discussed in terms of surface density of poly(sarcosine) chains, nanoparticle size, hydrophobic component of poly(L-lactic acid) or (Leu- or Val-Aib)n , and membrane elasticity of the nanoparticles. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 29110376 TI - Asymmetric Synthesis of Less Accessible alpha-Tertiary Amines from Alkynyl Z Ketimines. AB - A highly stereoselective synthesis of hitherto less accessible chiral alpha tertiary amines with multiple structurally similar linear carbon chains was achieved through chiral auxiliary mediated addition of organolithium reagents to the geometrically well-controlled alkynyl Z-ketimines. This stereoselective nucleophilic addition offers a general approach to the asymmetric synthesis of nitrogen-containing chiral materials. PMID- 29110374 TI - Towards understanding the mechanisms of actions of carcinoembryonic antigen related cell adhesion molecule 6 in cancer progression. AB - Human carcinoembryonic antigen (CEA) is the prototypic member of a family of highly related cell surface glycoproteins that includes carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6) and others. CEACAM6 (formerly NCA), which belongs to the immunoglobulin superfamily, is a cell adhesion protein of the CEA family. It is normally expressed on the epithelial surfaces and on the surface of myeloid cells (CD66c). CEACAM6 is a multi-functional glycoprotein that mediates homotypic binding with other CEA family members and heterotypic binding with integrin receptors. It functions by organizing tissue architecture and regulating different signal transduction, while aberrant expression leads to the development of human malignancies. It was first discovered in proliferating cells of adenomas and hyperplastic polyps in comparison to benign colonic tissue when overexpressed on the surface of various cell types in model systems. CEACAM6 functions as a pan-inhibitor of cell differentiation and cell polarization, and it also causes distortion of tissue architecture. Moreover, overexpression of CEACAM6 modulates cancer progression through aberrant cell differentiation, anti apoptosis, cell growth and resistance to therapeutic agents. In addition, CEACAM6 overexpression in multiple malignancies promotes cell invasion and metastasis, thereby representing an acquired advantage of tumor cells directly responsible for an invasive phenotype. This review focuses on the findings supporting the mechanisms of actions linking the oncogenic potential of CEACAM6 to the onset of cancer progression and pathogenesis, especially in breast cancer, and to validating CEACAM6 as a target to pave the way towards the design of efficient therapeutic strategies against breast cancer. PMID- 29110377 TI - Abnormal esophageal acid exposure on high-dose proton pump inhibitor therapy is common in systemic sclerosis patients. AB - BACKGROUND: Esophageal dysfunction and gastro-esophageal reflux disease (GERD) are common among patients with systemic sclerosis (SSc). Although high-dose proton pump inhibitors (PPIs) typically normalize esophageal acid exposure, the effectiveness of PPI therapy has not been systematically studied in SSc patients. The aim of this study was to characterize reflux in SSc patients on high-dose PPI using esophageal pH-impedance testing. METHODS: In this case-controlled retrospective analysis, 38 patients fulfilling 2013 American College of Rheumatology SSc criteria who underwent esophageal pH-impedance testing on twice daily PPI between January 2014 and March 2017 at a tertiary referral center were compared with a control-cohort of 38 non-SSc patients matched for PPI formulation and dose, hiatal hernia size, age, and gender. Patient clinical characteristics, including endoscopy and high-resolution manometry findings, were assessed via chart review. KEY RESULTS: On pH-impedance, SSc patients had higher acid exposure times (AETs) than controls. Sixty-one percent of the SSc patients and 18% of the control patients had a total AET >=4.5% (P < .001). Systemic sclerosis patients also had significantly longer AETs, longer median bolus clearance, and lower nocturnal impedance values. CONCLUSIONS & INFERENCES: Abnormal esophageal acid exposure despite high-dose PPI therapy was common among patients with SSc. The lack of increased reflux episodes in the SSc patients, and longer bolus clearance times and lower nocturnal impedance, supports ineffective clearance as the potential mechanism. Systemic sclerosis patients may require adjunctive therapies to PPIs to control acid reflux. PMID- 29110379 TI - A comparison of honeybee (Apis mellifera) queen, worker and drone larvae by RNA Seq. AB - Honeybees (Apis mellifera) have haplodiploid sex determination: males develop from unfertilized eggs and females develop from fertilized ones. The differences in larval food also determine the development of females. Here we compared the total somatic gene expression profiles of 2-day and 4-day-old drone, queen and worker larvae by RNA-Seq. The results from a co-expression network analysis on all expressed genes showed that 2-day-old drone and worker larvae were closer in gene expression profiles than 2-day-old queen larvae. This indicated that for young larvae (2-day-old) environmental factors such as larval diet have a greater effect on gene expression profiles than ploidy or sex determination. Drones had the most distinct gene expression profiles at the 4-day larval stage, suggesting that haploidy, or sex dramatically affects the gene expression of honeybee larvae. Drone larvae showed fewer differences in gene expression profiles at the 2-day and 4-day time points than the worker and queen larval comparisons (598 against 1190 and 1181), suggesting a different pattern of gene expression regulation during the larval development of haploid males compared to diploid females. This study indicates that early in development the queen caste has the most distinct gene expression profile, perhaps reflecting the very rapid growth and morphological specialization of this caste compared to workers and drones. Later in development the haploid male drones have the most distinct gene expression profile, perhaps reflecting the influence of ploidy or sex determination on gene expression. PMID- 29110378 TI - Generation of embryonic stem-like cells from in vivo-derived porcine blastocysts at a low concentration of basic fibroblast growth factor. AB - Although basic fibroblast growth factor (bFGF) is an essential factor supporting the maintenance of porcine embryonic stem (ES) cell self-renewal and pluripotency, its high cost has limited previous studies, and the development of a low-cost culture system is required. For these systems, in vivo blastocysts were progressively cultured under various conditions consisting of different culture mediums and/or different feeder cell numbers at a low concentration of bFGF. As the results, the sequential culture of in vivo-derived porcine blastocysts on 5.0 * 105 mouse embryonic fibroblast (MEF) feeder cells in alpha minimum essential medium-based medium for primary culture, on 2.5 * 105 MEF feeder cells in Mixture medium for the 1st subpassage, and on 2.5 * 105 MEF feeder cells in DMEM/Ham's F10-based medium for the post-2nd subpassage could support the establishment and maintenance of porcine ES-like cells at the low concentration of bFGF. The established porcine ES-like cells showed ES cell specific characteristics such as self-renewal and pluripotency. We confirmed that porcine ES-like cells could be generated from in vivo-derived porcine blastocysts at a low concentration of bFGF. PMID- 29110380 TI - Room-Temperature-Phosphorescence-Based Dissolved Oxygen Detection by Core-Shell Polymer Nanoparticles Containing Metal-Free Organic Phosphors. AB - The highly sensitive optical detection of oxygen including dissolved oxygen (DO) is of great interest in various applications. We devised a novel room-temperature phosphorescence (RTP)-based oxygen detection platform by constructing core-shell nanoparticles with water-soluble polymethyloxazoline shells and oxygen-permeable polystyrene cores crosslinked with metal-free purely organic phosphors. The resulting nanoparticles show a very high sensitivity for DO with a limit of detection (LOD) of 60 nm and can be readily used for oxygen quantification in aqueous environments as well as the gaseous phase. PMID- 29110382 TI - Transcriptional profile and differential fitness in a specialist milkweed insect across host plants varying in toxicity. AB - Interactions between plants and herbivorous insects have been models for theories of specialization and co-evolution for over a century. Phytochemicals govern many aspects of these interactions and have fostered the evolution of adaptations by insects to tolerate or even specialize on plant defensive chemistry. While genomic approaches are providing new insights into the genes and mechanisms insect specialists employ to tolerate plant secondary metabolites, open questions remain about the evolution and conservation of insect counterdefences, how insects respond to the diversity defences mounted by their host plants, and the costs and benefits of resistance and tolerance to plant defences in natural ecological communities. Using a milkweed-specialist aphid (Aphis nerii) model, we test the effects of host plant species with increased toxicity, likely driven primarily by increased secondary metabolites, on aphid life history traits and whole-body gene expression. We show that more toxic plant species have a negative effect on aphid development and lifetime fecundity. When feeding on more toxic host plants with higher levels of secondary metabolites, aphids regulate a narrow, targeted set of genes, including those involved in canonical detoxification processes (e.g., cytochrome P450s, hydrolases, UDP glucuronosyltransferases and ABC transporters). These results indicate that A. nerii marshal a variety of metabolic detoxification mechanisms to circumvent milkweed toxicity and facilitate host plant specialization, yet, despite these detoxification mechanisms, aphids experience reduced fitness when feeding on more toxic host plants. Disentangling how specialist insects respond to challenging host plants is a pivotal step in understanding the evolution of specialized diet breadths. PMID- 29110381 TI - Update in respiratory sleep disorders: Epilogue to a modern review series. PMID- 29110383 TI - Asymmetric Traceless Petasis Borono-Mannich Reactions of Enals: Reductive Transposition of Allylic Diazenes. AB - The traceless Petasis borono-Mannich reaction of enals, sulfonylhydrazines, and allylboronates, catalyzed by chiral biphenols, results in an asymmetric reductive transposition of the in situ generated allylic diazene. Acyclic 1,4-diene products bearing either alkyl- or aryl-substituted benzylic stereocenters are afforded in excellent yields and enantiomeric ratios of up to 99:1. The use of crotylboronates in the reaction results in concomitant formation of two stereocenters in either a 1,4-syn or anti relationship from the corresponding E- or Z-crotylboronate used in the reaction. The use of beta-monosubstituted enals in the asymmetric traceless Petasis borono-Mannich reaction of crotylboronates installs tertiary methyl-bearing stereocenters in good yields and high enantioselectivities. PMID- 29110384 TI - Long-term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus. AB - AIM: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin. MATERIALS AND METHODS: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values. RESULTS: The changes from baseline (mean +/- standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were -1.09% +/- 0.85% and -0.88% +/- 0.86% for HbA1c, 1.40% +/- 2.54% and -2.14% +/- 2.75% for body weight, and 7.84% +/- 14.37% and 8.91% +/- 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period. CONCLUSIONS: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients. PMID- 29110385 TI - Vitamin D and progression of carotid intima-media thickness in HIV-positive Canadians. AB - OBJECTIVES: Based on a growing body of evidence implicating low vitamin D status in the development of cardiovascular disease (CVD), we hypothesized that in Canadian HIV-positive adults, low 25-hydroxyvitamin D (25(OH)D) concentration would be associated with increased subclinical vascular disease progression. METHODS: We prospectively studied the relationship between baseline 25(OH)D and subsequent progression of carotid intima-media thickness (CIMT) between 2002 and 2011, in the Canadian HIV Vascular Study using stored blood specimens. RESULTS: Of the 128 participants, 89.1% were men, the mean age (standard deviation [SD]) was 46.5 (8.2) years, 93.8% were white, and 36.7% were current smokers. Mean (SD) annual CIMT follow-up was 5.9 (1.8) years (maximum 8.5 years), providing approximately 750 patient-years of follow-up. Mean (SD) CIMT progression was 0.027 (0.030) mm/year. Mean (SD) 25(OH)D was 95.0 (46.9) nmol/L. Only 13.3% of participants were vitamin D deficient (25(OH)D < 50 nmol/L), whereas 61.7% had a 25(OH)D exceeding the sufficiency threshold (75 nmol/L). Vitamin D quartiles were inversely associated with body mass index (BMI) (P = 0.034), total cholesterol to high-density lipoprotein (HDL) cholesterol ratio (P = 0.001) and parathyroid hormone concentration (P = 0.003), but not efavirenz exposure (P = 0.141). In linear regression analyses, baseline 25(OH)D as a continuous variable was inversely associated with CIMT progression in univariable (P < 0.001) and multivariable (P < 0.001) models. CONCLUSIONS: Baseline 25(OH)D was associated with CIMT progression in this relatively vitamin D replete, predominately white and male, Canadian HIV-positive population. Future research needs to establish causality as this may warrant more targeted screening or supplementation. PMID- 29110386 TI - Selective Functionalization of Aromatic C(sp2 )-H Bonds in the Presence of Benzylic C(sp3 )-H Bonds by Electron-Deficient Carbenoids Generated from 4-Acyl-1 Sulfonyl-1,2,3-Triazoles. AB - A rhodium(II)-catalyzed reaction of newly prepared 4-acyl-1-sulfonyl-1,2,3 triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4-acyltriazoles undergo selective insertion at aromatic C(sp2 )-H bonds in the presence of benzylic C(sp3 )-H bonds to produce N sulfonylenaminones. PMID- 29110388 TI - Corrigendum. PMID- 29110387 TI - Cholesterol-alpha-glucosyltransferase gene is present in most Helicobacter species including gastric non-Helicobacter pylori helicobacters obtained from Japanese patients. AB - BACKGROUND: Non-Helicobacter pylori helicobacters (NHPHs) besides H. pylori infect human stomachs and cause chronic gastritis and mucosa-associated lymphoid tissue lymphoma. Cholesteryl-alpha-glucosides have been identified as unique glycolipids present in H. pylori and some Helicobacter species. Cholesterol-alpha glucosyltransferase (alphaCgT), a key enzyme for the biosynthesis of cholesteryl alpha-glucosides, plays crucial roles in the pathogenicity of H. pylori. Therefore, it is important to examine alphaCgTs of NHPHs. MATERIALS AND METHODS: Six gastric NHPHs were isolated from Japanese patients and maintained in mouse stomachs. The alphaCgT genes were amplified by PCR and inverse PCR. We retrieved the alphaCgT genes of other Helicobacter species by BLAST searches in GenBank. RESULTS: alphaCgT genes were present in most Helicobacter species and in all Japanese isolates examined. However, we could find no candidate gene for alphaCgT in the whole genome of Helicobacter cinaedi and several enterohepatic species. Phylogenic analysis demonstrated that the alphaCgT genes of all Japanese isolates show high similarities to that of a zoonotic group of gastric NHPHs including Helicobacter suis, Helicobacter heilmannii, and Helicobacter ailurogastricus. Of 6 Japanese isolates, the alphaCgT genes of 4 isolates were identical to that of H. suis, and that of another 2 isolates were similar to that of H. heilmannii and H. ailurogastricus. CONCLUSIONS: All gastric NHPHs examined showed presence of alphaCgT genes, indicating that alphaCgT may be beneficial for these helicobacters to infect human and possibly animal stomachs. Our study indicated that NHPHs could be classified into 2 groups, NHPHs with alphaCgT genes and NHPHs without alphaCgT genes. PMID- 29110389 TI - Equivalence testing for similarity in bioassays using bioequivalence criteria on the relative bioactivity. AB - Similarity in bioassays means that the test preparation behaves as a dilution of the standard preparation with respect to their biological effect. Thus, similarity must be investigated to confirm this biological property. Historically, this was typically conducted with traditional hypothesis testing, but this has received substantial criticism. Failing to reject similarity does not imply that the 2 preparations are similar. Also, rejecting similarity when bioassay variability is small might simply demonstrate a nonrelevant deviation in similarity. To remedy these concerns, equivalence testing has been proposed as an alternative to traditional hypothesis testing, and it has found its way in the official guidelines. However, similarity has been discussed mainly in terms of the parameters in the dose-response curves of the standard and test preparations, but the consequences of nonsimilarity on the relative bioactivity have never been investigated. This article provides a general equivalence approach to evaluate similarity that is directly related to bioequivalence on the relative bioactivity of the standard and test preparations. Bioequivalence on the relative bioactivity can only be guaranteed for positive (only nonblanks) and finite dose intervals. The approach is demonstrated on 4 case studies in which we also show how to calculate a sample size and how to investigate the power of equivalence on similarity. PMID- 29110390 TI - A novel three-dimensional printed guiding device for electrode implantation of sacral neuromodulation. AB - AIM: The aim was to test the feasibility of a novel three-dimensional (3D) printed guiding device for electrode implantation of sacral neuromodulation (SNM). METHOD: A 3D printed guiding device for electrode implantation was customized to patients' anatomy of the sacral region. Liquid photopolymer was selected as the printing material. The details of the device designation and prototype building are described. The guiding device was used in two patients who underwent SNM for intractable constipation. Details of the procedure and the outcomes are given. RESULTS: With the help of the device, the test needle for stimulation was placed in the target sacral foramen successfully at the first attempt of puncture in both patients. The time to implant a tined SNM electrode was less than 20 min and no complications were observed. At the end of the screening phase, symptoms of constipation were relieved by more than 50% in both patients and permanent stimulation was established. CONCLUSION: The customized 3D printed guiding device for implantation of SNM is a promising instrument that facilitates a precise and quick implantation of the electrode into the target sacral foramen. PMID- 29110391 TI - Th2 axis-related cytokines in patients with neuromyelitis optica spectrum disorders. AB - AIMS: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system. Increasing evidence indicates that NMOSD is a Th2- and Th17-dominant disease. IL-25, IL-31, and IL-33 are three newly found Th2-related cytokines, and their roles in the pathogenesis of NMOSD have not been studied. This study aimed to measure the serum levels of IL-25, IL 31, and IL-33 in patients with NMOSD and evaluate their clinical implications. METHODS: Serum was collected from patients with NMOSD (n = 48) and healthy controls (HC, n = 28). Serum level measurements of IL-25, IL-31, IL-33, IL-17A, and IL-6 were performed using enzyme-linked immunoassay (ELISA) method. RESULTS: The serum levels of IL-25, IL-31, and IL-33 were significantly higher in patients with NMOSD as compared to HC. The serum level of IL-31 was significantly correlated with IL-17A (r = 0.382,P = 0.009) in patients with NMOSD; the latter is a critical cytokine in the pathogenesis of NMOSD. The serum level of IL-33 was higher in patients with characteristic brain lesions than patients without (307 pg/mL vs 166 pg/mL, P = 0.028). Furthermore, the serum level of IL-33 in the acute phase of the disease was positively correlated with annualized relapse rate (r = 0.364, P = 0.04). CONCLUSION: We found higher serum levels of IL-25, IL-31, and IL-33 in patient with NMOSD as compared to healthy controls. The serum level of IL-33 during acute phase was associated with more past attacks in patients with NMOSD. PMID- 29110392 TI - Na+ /H+ exchanger 3 blockade ameliorates type 2 diabetes mellitus via inhibition of sodium-glucose co-transporter 1-mediated glucose absorption in the small intestine. AB - AIM: To elucidate the role of Na+ /H+ exchanger 3 (NHE3) in sodium-glucose co transporter 1 (SGLT1)-mediated small intestinal brush border membrane (BBM) glucose absorption and its functional implications in type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Human jejunal samples were obtained from patients undergoing gastrectomy. 14 C-glucose absorption was measured by liquid scintillation counting. NHE3 expression was suppressed by siRNA-mediated knockdown or augmented in Caco2 cells. Glucose and insulin tolerance in db/db and m+/db mice was assessed with oral and intraperitoneal glucose tolerance tests, and an intraperitoneal insulin tolerance test. Insulin resistance and beta-cell function were assessed using homeostatic model assessment of insulin resistance and beta-cell function. RESULTS: NHE3 expression was upregulated in db/db mouse jejunal BBM and high-glucose-treated Caco2 cells. NHE3 blockade impaired SGLT1 mediated glucose absorption in human jejunum, m+/db and db/db mouse jejunums, and Caco2 cells, via serum/glucocorticoid-regulated kinase 1 (SGK1). NHE3 knockdown suppressed SGLT1-mediated glucose uptake and reduced mRNA and protein levels of SGK1 and SGLT1, which were conversely enhanced by NHE3 overexpression. Chronic S3226 treatment diminished postprandial glucose levels and ameliorated glucose intolerance in db/db mice. CONCLUSION: NHE3 is essential in the modulation of small intestinal BBM glucose absorption. Our findings provide a rationale for future possible clinical application of NHE3 for treatment of T2DM through reducing intestinal glucose uptake and counteracting postprandial hyperglycaemia. PMID- 29110393 TI - Oocyte holding in the Iberian red deer (Cervus elaphus hispanicus): Effect of initial oocyte quality and epidermal growth factor addition on in vitro maturation. AB - Current in vitro embryo production protocols in the Iberian red deer (Cervus elaphus hispanicus) need to be optimized; oocyte harvesting in situ followed by overnight holding could reduce the human effort and shipping costs. In our work, post-mortem ovaries were retrieved, and the oocytes were harvested and allocated to G1 group (good quality) or G2 + G3 group (low quality). The oocytes were separately subjected to immediate in vitro maturation (IVM) or held overnight in a holding medium composed of 40% of TCM 199 with Earle's salts, 40% TCM 199 with Hanks' salts and 20% fetal bovine serum (FBS), at room temperature (16 hr). In vitro maturation was carried out in a basal medium supplemented or not with 50 ng/ml of epidermal growth factor (EGF). Our data showed that addition of EGF to the maturation medium increases the percentage of G1 oocytes reaching metaphase II (3.9% vs. 50%, basal vs. EGF; p < .001) and decreased their degeneration rate (69.9% vs. 22.2%, basal vs. EGF; p < .01) when oocytes were immediately matured. Overnight holding increased the meiotic competence of G1 oocytes (37.5% matured in basal medium) and EGF increased prophase arrest in G2 + G3 oocytes (16.1% vs. 38.8% in germinal vesicle [GV] stage in basal medium vs. EGF added medium; p < .05). Our data demonstrate that oocyte holding can be used in Iberian red deer oocytes. Interestingly, EGF addition increases the oocytes' meiotic competence in immediately matured oocytes but not after oocyte holding depending upon initial oocyte quality. PMID- 29110394 TI - Methylisothiazolinone may induce cell death and inflammatory response through DNA damage in human liver epithelium cells. AB - Methylisothiazolinone (MIT) is a powerful biocide and preservative, which is widely used alone or in a 1:3 ratio with methylchloroisothiazolinone (MCIT) under the trade name of Kathons in the manufacture of numerous personal and household products. Considering that Kathons injected intravenously is distributed in the blood and then in the liver, we explored the toxic mechanism of MIT on human liver epithelium cells. At 24 h after exposure, MIT bound to the plasma membrane and the inner wall of vacuoles in the cells, and rupture of the cell membrane and nuclear envelop, autophagosome-like vacuoles formation and mitochondrial damage were observed. Cell viability dose-dependently decreased accompanying an increase of apoptotic cells, and the level of LDH, NO, IFN-gamma, IL-10 and IL-8, but not IL-1beta, significantly increased in the culture media of cells exposed to MIT. Additionally, expression of autophagy-, membrane damage- and apoptosis-related proteins was notably enhanced, and the produced ATP level dose-dependently decreased with the reduced mitochondrial activity. Furthermore, the increased DNA damage and the decreased transcription activity were observed in MIT-treated cells. Meanwhile, the intracellular ROS level did not show dose-dependent change at the same time-point. Then we explored the role of autophagy in MIT-induced cytotoxicity by inhibiting or inducing the autophagic signal. Intriguingly, no additional cell death induced by autophagic modulation occurred when MIT was treated. Taken together, we suggest that MIT may induce multiple pathways of cell death and inflammatory response through DNA damage caused by rupture of the nuclear envelope. PMID- 29110395 TI - Antiretroviral pill count and clinical outcomes in treatment-naive patients with HIV infection. AB - OBJECTIVES: Treatment guidelines recommend single-tablet regimens for patients with HIV infection starting antiretroviral therapy. These regimens might be as effective and cost less if taken as separate drugs. We assessed whether the one pill once a day combination of efavirenz, emtricitabine and tenofovir reduces the risk of disease progression compared with multiple-pill formulations of the same regimen. METHODS: We selected treatment-naive patients starting one-, two- or three-pill formulations of this regimen in data from the Antiretroviral Therapy Cohort Collaboration. These patients were followed until an AIDS event or death or until they modified their regimen. We analysed these data using Cox regression models, then used our models to predict the potential consequences of exposing a future population to either a one-pill regimen or a three-pill regimen. RESULTS: Among 11 739 treatment-naive patients starting the regimen, there were 386 AIDS events and 87 deaths. Follow-up often ended when patients switched to the same regimen with fewer pills. After the first month, two pills rather than one was associated with an increase in the risk of AIDS or death [hazard ratio (HR) 1.39; 95% confidence interval (CI) 1.01-1.91], but three pills rather than two did not appreciably add to that increase (HR 1.19; 95% CI 0.84-1.68). We estimate that 77 patients would need to be exposed to a one-pill regimen rather than a three-pill regimen for 1 year to avoid one additional AIDS event or death. CONCLUSIONS: This particular single-tablet regimen is associated with a modest decrease in the risk of AIDS or death relative to multiple-pill formulations. PMID- 29110396 TI - Using cognitive mapping to understand Senegalese infant and young child feeding decisions. AB - Caregivers make decisions about how to feed their infants and young children based on complex interactions of knowledge, beliefs, and values, as well as assessments of situational determinants, including economic and social constraints and opportunities. Because of the relationship of these factors to the adoption of new feeding behaviours, the development of nutrition interventions for this age group must be grounded in knowledge about the target population. This paper presents the results of a study that used cognitive mapping techniques to gain insight into mothers' knowledge and perceptions of foods for infants and young children and examine their significance for feeding decisions in Saint-Louis, northern Senegal. Guided by mixed-methods protocols from the Focused Ethnographic Study for Infant and Young Child Feeding Manual, in depth interviews that included qualitative discussions and cognitive mapping techniques were conducted with 46 mothers in rural and peri-urban communities. We explored mothers' perceptions about five dimensions that affect food decision making-healthiness, convenience, child acceptance, appeal, and modernity-and the relationship of these dimensions to 38 local food items. Data analysis entailed a combination of qualitative thematic analysis and descriptive statistics. In both communities, "healthiness" was the most valued dimension for food decision-making by a large margin, followed by child acceptance, appeal, modernity, and convenience. We explore how different interpretations and definitions of these dimensions, and their relationship to specific local food items, may influence the design and planning of nutrition interventions. The results support the importance of mixed-methods formative research to illuminate the emic perspectives of caregivers. PMID- 29110398 TI - Teaching Targeted Drug Discovery and Development to Healthcare Professionals. PMID- 29110399 TI - De Novo Sequencing of Peptides from High-Resolution Bottom-Up Tandem Mass Spectra using Top-Down Intended Methods. AB - Despite high-resolution mass spectrometers are becoming accessible for more and more laboratories, tandem (MS/MS) mass spectra are still often collected at a low resolution. And even if acquired at a high resolution, software tools used for their processing do not tend to benefit from that in full, and an ability to specify a relative mass tolerance in this case often remains the only feature the respective algorithms take advantage of. We argue that a more efficient way to analyze high-resolution MS/MS spectra should be with methods more explicitly accounting for the precision level, and sustain this claim through demonstrating that a de novo sequencing framework originally developed for (high-resolution) top-down MS/MS data is perfectly suitable for processing high-resolution bottom up datasets, even though a top-down like deconvolution performed as the first step will leave in many spectra at most a few peaks. PMID- 29110400 TI - Spaghetti, a homolog of human RPAP3 (RNA polymerase II-associated protein 3), determines the fate of germline stem cells in Drosophila ovary. AB - The Drosophila ovary provides an attractive model for studying the extrinsic or intrinsic factors that regulate the fate of germline stem cells (GSCs). Using this model, we identified a new role for Drosophila spaghetti (spag), encoding a homolog of human RNA polymerase II-associated protein 3 (RPAP3), in regulating the fate of ovarian GSCs. Results from spag knockdown and genetic mosaic studies suggest that spag functions as an intrinsic factor for GSCs maintenance. Loss of Spag by, either spag RNAi or null mutation failed to trigger apoptosis in ovarian GSCs. Overexpression of spag led to negligible increases in the number of GSC/Cystoblast (CB) cells, suggesting that an excess of Spag is not sufficient to accelerate the proliferation of GSCs or delay CBs' differentiation. Our study provides evidence supporting that spag is involved in adult stem cells maintenance. In addition, the RNAi screen results showed that knockdown of Hsp90, one of known Spag interacting partners, led to loss of ovarian GSCs in Drosophila. Heterozygous mutations in hsp90 (hsp90/+) dramatically accelerated the GSC loss in spag RNAi ovaries, suggesting that the Spag-contained complex possibly plays an essential role in controlling the GSCs fate. PMID- 29110401 TI - Absolute configuration of the diterpenoids icetexone and conacytone from Salvia ballotaeflora. AB - Detailed literature inspections regarding the diterpenoids icetexone (1) and conacytone (3) reveal that the absolute configuration (AC) of these natural occurring compounds is not rigorously proven, despite they were originally isolated in 1976. This task is now completed by single-crystal X-ray diffraction Flack and Hooft parameters determination after processing data collected with Cu Kalpha graphite monochromated radiation. The AC of both compounds is further determined by vibrational circular dichroism measurements performed on icetexone acetate (2) and conacytone triacetate (4) since the solubility of 1 and 3 is limited. Comparison of the substituent chemical shifts (SCS) induced by acetylation of 1 and 3 to afford 2 and 4, respectively, reveals that in the case of icetexone, all six SCS values of the quinone ring are in excellent agreement with the expected values, while in the case of conacytone, three agree and three do not agree due to the presence of additional acetates near the quinone ring. Density functional theory calculations performed on 3-hydroxythymoquinone (6) and its tautomer 4-hydroxy-1,2-quinone 7, on 6-hydroxythymoquinone (8) and its tautomer ortho-quinone 9, and on icetexone (1) and the claimed natural occurring ortho-quinone tautomer romulogarzone (5) indicate that 2-hydroxy-1,4-quinones are more stable, by some 11-14 kcal/mol, than their 4-hydroxy-1,2-quinone tautomers, and therefore, romulogarzone (5) is inexistent. PMID- 29110402 TI - High rate of adaptive evolution in two widespread European pines. AB - Comparing related organisms with differing ecological requirements and evolutionary histories can shed light on the mechanisms and drivers underlying genetic adaptation. Here, by examining a common set of hundreds of loci, we compare patterns of nucleotide diversity and molecular adaptation of two European conifers (Scots pine and maritime pine) living in contrasted environments and characterized by distinct population genetic structure (low and clinal in Scots pine, high and ecotypic in maritime pine) and demographic histories. We found higher nucleotide diversity in Scots pine than in maritime pine, whereas rates of new adaptive substitutions (omegaa ), as estimated from the distribution of fitness effects, were similar across species and among the highest found in plants. Sample size and population genetic structure did not appear to have resulted in significant bias in estimates of omegaa . Moreover, population contraction-expansion dynamics for each species did not affect differentially the rate of adaptive substitution in these two pines. Several methodological and biological factors may underlie the unusually high rate of adaptive evolution of Scots pine and maritime pine. By providing two new case studies with contrasting evolutionary histories, we contribute to disentangling the multiple factors potentially affecting adaptive evolution in natural plant populations. PMID- 29110403 TI - Live Cell Labeling with Terpyridine Derivative Proligands to Measure Cytotoxicity Mediated by Immune Cells. AB - Immunotherapy using immune checkpoint inhibitors and CAR-T cells has revolutionized treatment for patients with malignant tumors. However, measuring tumor cell cytotoxicity mediated by immune effector cells in clinical laboratories has been difficult due to the requirement for radioactive substances. In this study, a series of novel terpyridine derivative proligands were synthesized, and a non-radioactive cellular cytotoxicity assay using the newly synthesized compounds was developed for use in preclinical and clinical studies for cancer immunotherapy. Once internalized into target cells, the compounds are hydrolyzed by esterases, resulting in the intracellular accumulation of the negatively charged terpyridine derivatives. When the labeled target cells are recognized and killed by immune effector cells, the integrity of the cell membrane is disrupted, and the terpyridine derivatives are released. Upon combining the culture supernatant with europium (Eu3+ ), the cytotoxicity of immune effector cells for the target cells can be quantitatively determined by measuring the intensity of the Eu3+ /ligand-derived time-resolved fluorescence. Thus, the assay developed in this study would facilitate the development of novel cancer immunotherapies. PMID- 29110404 TI - Antimicrobial resistance trends in Escherichia coli isolated from diseased food producing animals in France: A 14-year period time-series study. AB - Antimicrobial resistance (AMR) among bacteria isolated from food-producing animals is a growing concern with implications for public health. AMR surveillance is essential to identify resistance trends and help in the design of effective and efficient control strategies. The aim of the study was to describe the antimicrobial susceptibility of pathogenic Escherichia coli isolated from three livestock productions in France (cattle, swine and poultry). The trend in resistance to the most commonly prescribed antibiotics in animal health was analysed as follows: amoxicillin (penicillin), spectinomycin or streptomycin (aminoglycoside), tetracycline and trimethoprim-sulfamethoxazole/Enrofloxacin and ceftiofur were also taken into account as members of critically important antimicrobial families in human and veterinary medicine, that is fluoroquinolones and third-generation cephalosporins, respectively. Data collected between 2002 and 2015 by the French national surveillance network of AMR referred to as RESAPATH were analysed. Resistance trends were investigated using non-linear analysis (generalized additive models) applied to time-series stratified by livestock production and antibiotic. Irrespective of the species and the antibiotic considered, resistance signals over time showed no significant annual cycle. Resistance to third-generation cephalosporins emerged during the period of the study, with a peak at 22% [20.5; 24.0] in poultry in 2010, decreasing afterwards, while it remained consistently below 10% for the other species. The proportion of resistance to fluoroquinolones was broadly similar between species and remained under 30%, with a slight decreasing trend after 2009. Resistances to tetracycline and amoxicillin remained high, between 90% and 40% over time in cattle and swine. After 2010, there was a decrease in resistance to these antibiotics for all species, especially to tetracycline for poultry with a drop from 84% in 2009 to 43% in 2015. These results contribute to risk assessment and constitute objective evidence on which to evaluate the efficacy of control measures implemented to limit AMR occurrence. PMID- 29110405 TI - Nested PUF Proteins: Extending Target RNA Elements for Gene Regulation. AB - RNA-binding proteins recognizing unique sequences within large transcriptomes serve as a powerful tool to control RNA metabolism. Pumilio and fem-3 mRNA binding factor (PUF) proteins are considered good candidates for such tools, because they are typically composed of eight highly homologous repeat segments and can be designed to recognize arbitrary 8 nt RNA sequences. However, a specific 8 nt RNA sequence is found at multiple sites in various RNAs in the transcriptome, making it difficult to specifically target a single RNA. Designer PUF proteins recognizing longer RNA sequences should achieve more selective binding. Here, we propose an approach for creating 16-repeat PUFs capable of targeting a single, unique mRNA in the transcriptome. Our design is simple and involves either the tandem alignment of two PUF segments or the nesting of one PUF segment within another. Designed 16-repeat PUFs bound to the target RNA sequence without partial recognition derived from the original 8-repeat PUF. Furthermore, based on our strategy, expression of an endogenous mRNA was selectively and effectively modulated, demonstrating the applicability of 16 repeat PUF proteins for regulating endogenous RNA metabolism. PMID- 29110407 TI - Acupuncture inhibits TXNIP-associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats. AB - AIMS: Oxidative stress and inflammation have been implicated in the pathogenesis of vascular dementia (VD). Thioredoxin-interacting protein (TXNIP) plays a vital role in oxidative stress and NOD-like receptor protein 3 (NLRP3) inflammasome activation. There is evidence that acupuncture has an antioxidative and neuroprotective effect in VD. In this study, we investigated whether acupuncture can attenuate cognitive impairment via inhibiting TXNIP-associated oxidative stress and inflammation in VD rats. METHODS: Both common carotid arteries were occluded (2-vessel occlusion [2VO]) in rats to model VD. The neuroprotective effect of acupuncture was assessed by the Morris water maze and Nissl staining. Oxidative stress was assessed by detecting levels of reactive oxygen species, DNA oxidation, and antioxidase. Western blot, real-time PCR, and immunofluorescence were used to detect the expression of TXNIP, NLRP3, caspase-1, and IL-1beta. A TXNIP siRNA intraventricular injection was applied to investigate whether acupuncture mimicked the effect of TXNIP inhibitor. RESULTS: Our findings demonstrated that VD rats treated with acupuncture had reduced hippocampal neuronal loss and oxidative stress. The upregulation of TXNIP, NLRP3, caspase-1, and IL-1beta induced by 2VO was also reversed by acupuncture. Furthermore, TXNIP siRNA had a similar effect as acupuncture on cognition, hippocampal neurons, and ROS production in VD rats. CONCLUSION: In conclusion, our study suggests that the neuroprotective effects of acupuncture in VD are mediated through reducing expression of TXNIP-associated oxidative stress and inflammation. PMID- 29110406 TI - Switching from low-dose thiazide diuretics to sodium-glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension. AB - AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors function to increase urinary glucose excretion and improve glycemic control in individuals with type 2 diabetes mellitus. SGLT2 inhibitors, as well as diuretics, increase urinary volume, which leads to the reduction of blood pressure. The aim of the present study was to compare the effects of SGLT2 inhibitor and thiazide diuretic on blood pressure, metabolic parameters and body mass composition. MATERIALS AND METHODS: A total of 31 participants were enrolled in the present study. We switched from thiazide diuretics to an SGLT2 inhibitor, ipragliflozin, in participants with type 2 diabetes and hypertension whose blood pressure was controlled with thiazide diuretics. Three months after the switch, we evaluated the effects of such switching on blood pressure, various metabolic parameters and body mass composition. RESULTS: There was no significant difference in blood pressure from baseline to 3 months later. However, glycated hemoglobin, fasting plasma glucose and uric acid were significantly decreased after the switch. Body mass index and visceral fat area were also significantly reduced after the switch. Furthermore, urinary albumin excretion was also significantly decreased after the switch. CONCLUSIONS: Switching from thiazide diuretic to an SGLT2 inhibitor, ipragliflozin, markedly improved various metabolic parameters and body mass composition without affecting blood pressure in participants with type 2 diabetes and hypertension. PMID- 29110410 TI - How to deal with neglected tropical diseases in the light of an African ethic. AB - Many countries in Africa, and more generally those in the Global South with tropical areas, are plagued by illnesses that the wealthier parts of the world (mainly 'the West') neither suffer from nor put systematic effort into preventing, treating or curing. What does an ethic with a recognizably African pedigree entail for the ways various agents ought to respond to such neglected diseases? As many readers will know, a characteristically African ethic prescribes weighty duties to aid on the part of those in a position to do so, and it therefore entails that there should have been much more contribution from the Western, 'developed' world. However, what else does it prescribe, say, on the part of sub-Saharan governments and the African Union, and are they in fact doing it? I particularly seek to answer these questions here, by using the 2013-16 Ebola crisis in West Africa to illustrate what should have happened but what by and large did not. PMID- 29110408 TI - Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir. AB - The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S) Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir-resistant HIV-1 variants. An X-ray structure of inhibitor 3g in complex with HIV-1 protease revealed key interactions in the S2' subsite. PMID- 29110411 TI - Incidence of new-onset benign anal disorders after bariatric surgery. AB - New-onset benign anal disorders (NBADs) represent a potential complication following bariatric surgery, although their incidence in this population is not well studied. The preoperative characteristics, weight loss, bowel habits and NBADs data of 196 patients with bariatric surgery were collected by telephone interviews and medical records review and evaluated retrospectively. Ninety-nine patients had undergone gastric bypass (GBP) and 97 had a modified biliopancreatic diversion (MBPD). Fifty-nine patients were excluded. The mean follow-up of the remaining 137 patients was 87.8 months, and 51 of them (37.2%) developed NBADs. Haemorrhoids were the most common diagnosis and 27.5% of the patients that developed NBADs were treated surgically. Patients who developed NBADs had a longer follow-up time (92.5 vs. 85.1 months, P = 0.003), and those with an abnormal bowel habit (diarrhoea or constipation) had a higher percentage of NBADs (54.5 vs. 28.3%, P = 0.003). NBADs were more frequent after MBPD (52.9%) than after GBP (21.7%) (P < 0.001). Multivariate analysis found that only an abnormal bowel habit was associated with NBADs, with an odds ratio of 3.2 (95% CI: 1.5 6.9, P = 0.003). As NBADs are a common complication after bariatric surgery, further studies should be performed to find the reasons for these complications. PMID- 29110409 TI - Coronary microvascular Kv1 channels as regulatory sensors of intracellular pyridine nucleotide redox potential. AB - Smooth muscle voltage-gated potassium (Kv) channels are important regulators of microvascular tone and tissue perfusion. Recent studies indicate that Kv1 channels represent a key component of the physiological coupling between coronary blood flow and myocardial oxygen demand. While the mechanisms by which metabolic changes in the heart are transduced to alter coronary Kv1 channel gating and promote vasodilation are unclear, a growing body of evidence underscores a pivotal role of Kv1 channels in sensing the cellular redox status. Here, we discuss current knowledge of mechanisms of Kv channel redox regulation with respect to pyridine nucleotide modulation of Kv1 function via ancillary Kvbeta proteins as well as direct modulation of channel activity via reactive oxygen and nitrogen species. We identify areas of additional research to address the integration of regulatory processes under altered physiological and pathophysiological conditions that may reveal insights into novel treatment strategies for conditions in which the matching of coronary blood supply and myocardial oxygen demand is compromised. PMID- 29110412 TI - Dual Functionalization of White Phosphorus: Formation, Characterization, and Reactivity of Rare-Earth-Metal Cyclo-P3 Complexes. AB - The [3+1] fragmentation reaction of rare-earth metallacyclopentadienes 1 a-c with 0.5 equivalents of P4 affords a series of rare-earth metal cyclo-P3 complexes 2 a c and a phospholyl anion 3. 2 a-c demonstrate an unusual eta3 coordination mode with one P-P bond featuring partial pi-bonding character. 2 a-c are the first cyclo-P3 complexes of rare-earth metals, and also the first organo-substituted polyphosphides in the category of Group 3 and f-block elements. Rare-earth metallacyclopentadienes play a dual role in the combination of aromatization and Diels-Alder reaction. Compounds 2 a-c can coordinate to one or two [W(CO)5 ] units, yielding 4 a-c or 5 c, respectively. Furthermore, oxidation of 2 a with p benzoquinone produces its corresponding phospholyllithium and regenerated P4 . PMID- 29110414 TI - Renal glucosuria in schoolchildren: Clinical characteristics. AB - BACKGROUND: We conducted an annual urine glucose screening program at schools, and diagnosed schoolchildren with diabetes at an early stage of the disease. We also identified some cases of renal glucosuria (RG), based on positive urine glucose with normal glucose tolerance. METHODS: During 2000-2015, 3 309 631 schoolchildren participated in the screening program. The positive rate for glucosuria in the first test was approximately 0.1%, whereas on repeat urine test it was approximately 0.05%. In total 350 schoolchildren were positive for glucosuria on detailed examination. Oral glucose tolerance test (OGTT) was also used to evaluate glucose intolerance. RESULTS: One hundred and two schoolchildren (29.7%) were diagnosed with diabetes, whereas RG was identified in 246 (70.3%) with normal glucose metabolism. In regard to the characteristics of RG, the percentage of boys was 50.3%, and the mean age at diagnosis was 11.2 +/- 2.4 years. Twenty-eight children (11.4%) were overweight (body mass index standard deviation score [BMI-SDS] > +2.0 SD), whereas five (2.0%) were underweight (BMI SDS < -2.0 SD). First-degree family history was suspected in 176 cases (71.5%). All RG subjects had normal glucose tolerance in the absence of insulin resistance and decreased insulin secretion (homeostasis model assessment for beta-cell function, 78.8 +/- 59.5%) on OGTT. CONCLUSIONS: RG is not rare in Japanese schoolchildren with glucosuria. This disorder seems to have a strong genetic background, and to involve less growth retardation and weight loss than expected despite continuous excretion of glucose in urine. PMID- 29110413 TI - Successful heart transplantation in patients with total artificial heart infections. AB - BACKGROUND: Data are limited on clinical outcomes in patients awaiting heart transplant (HT) with total artificial heart (TAH) infections. METHODS: We retrospectively reviewed all TAH recipients at our center. TAH infection was classified as definite if a microorganism was isolated in cultures from the exit site or deep tissues around the TAH; as probable in patients without surgical or microbiologic evidence of infection but no other explanation for persistent or recurrent bloodstream infection (BSI); or possible in patients with clinical suspicion and radiographic findings suggestive of TAH infection, but without surgical intervention or microbiologic evidence. RESULTS: From 2012 to 2015, a total of 13 patients received a TAH, with a median age at implantation of 52 years (range: 28-60). TAH infection occurred in nine patients (seven definite, one probable, one possible) a median of 41 days after implant (range: 17-475). The majority of TAH infections were caused by Staphylococcus species. Seven of nine patients underwent HT (four had pre-HT mediastinal washout, and five had positive HT operative cultures). Three patients had an active BSI caused by the same pathogen causing TAH infection at the time of HT, with one developing a post HT BSI with the same bacteria. No patient developed post-HT surgical site infection caused by the TAH infection pathogen. No deaths among HT recipients were attributed to infection. CONCLUSION: TAH infection is frequently associated with BSI and mediastinitis and Staphylococcus was the most common pathogen. A multimodal approach of appropriate pre- and post-HT antimicrobial therapy, surgical drainage, and heart transplantation with radical mediastinal debridement was successful in curing infection. PMID- 29110415 TI - Structural and functional studies of differentially O-glycosylated analogs of a thrombin inhibitory peptide - variegin. AB - Variegin is a 32-amino acid long thrombin inhibitory peptide isolated from the salivary gland extract of tropical bont tick Amblyomma variegatum. It was identified to be O-glycosylated on its Thr-14 side chain, and this glycosylated form was 14-fold more potent than that of its non-glycosylated form. However, as the identity of this glycosylation remained elusive, the mechanistic details underlying its functional impact are not yet known. In this report, we synthesized four different O-glycosylated analogs of variegin bearing physiologically relevant sugars on its Thr-14. Functional characterization of these analogs by enzyme inhibitory kinetics and surface plasmon resonance methods showed that all the synthesized glycopeptides are strong thrombin inhibitors. Structural studies by macromolecular docking identified that the sugar moiety of these peptides can potentially mediate favorable interactions with amino acids at the base of thrombin's autolysis loop. This report, for the first time, describes the impact of differential glycosylation on the function of a thrombin inhibitory peptide and tries to provide structural insights into the relevance of peptide glycosylation in thrombin inhibition. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 29110416 TI - Rarity and persistence. AB - Rarity is a population characteristic that is usually associated with a high risk of extinction. We argue here, however, that chronically rare species (those with low population densities over many generations across their entire ranges) may have individual-level traits that make populations more resistant to extinction. The major obstacle to persistence at low density is successful fertilisation (union between egg and sperm), and chronically rare species are more likely to survive when (1) fertilisation occurs inside or close to an adult, (2) mate choice involves long-distance signals, (3) adults or their surrogate gamete dispersers are highly mobile, or (4) the two sexes are combined in a single individual. In contrast, external fertilisation and wind- or water-driven passive dispersal of gametes, or sluggish or sedentary adult life habits in the absence of gamete vectors, appear to be incompatible with sustained rarity. We suggest that the documented increase in frequency of these traits among marine genera over geological time could explain observed secular decreases in rates of background extinction. Unanswered questions remain about how common chronic rarity actually is, which traits are consistently associated with chronic rarity, and how chronically rare species are distributed among taxa, and among the world's ecosystems and regions. PMID- 29110417 TI - Stability of Residual Oxides in Oxide-Derived Copper Catalysts for Electrochemical CO2 Reduction Investigated with 18 O Labeling. AB - Oxide-derived (OD) Cu catalysts have high selectivity towards the formation of multi-carbon products (C2 /C3 ) for aqueous electrochemical CO2 reduction (CO2 R). It has been proposed that a large fraction of the initial oxide can be surprisingly resistant to reduction, and these residual oxides play a crucial catalytic role. The stability of residual oxides was investigated by synthesizing 18 O-enriched OD Cu catalysts and testing them for CO2 R. These catalysts maintain a high selectivity towards C2 /C3 products (ca. 60 %) for up to 5 h in 0.1 m KHCO3 at -1.0 V vs. RHE. However, secondary-ion mass spectrometry measurements show that only a small fraction (<1 %) of the original 18 O content remains, showing that residual oxides are not present in significant amounts during CO2 R. Furthermore, we show that OD Cu can reoxidize rapidly, which could compromise the accuracy of ex situ methods for determining the true oxygen content. PMID- 29110418 TI - A Molecular Hybrid for Mitochondria-Targeted NO Photodelivery. AB - The design, synthesis, spectroscopic and photochemical properties, and biological evaluation of a novel molecular hybrid that is able to deliver nitric oxide (NO) into mitochondria are reported. This molecular conjugate unites a tailored o-CF3 p-nitroaniline chromophore, for photo-regulated NO release, and a rhodamine moiety, for mitochondria targeting, in the same molecular skeleton via an alkyl spacer. A combination of steady-state and time-resolved spectroscopic and photochemical experiments demonstrate that the two chromogenic units preserve their individual photophysical and photochemical properties in the conjugate quite well. Irradiation with violet light triggers NO release from the nitroaniline moiety and photoionization in the rhodamine center, which also retains considerable fluorescence efficiency. The molecular hybrid preferentially accumulates in the mitochondria of A549 lung adenocarcinoma cells where it induces toxicity at a concentration of 1 MUm, exclusively upon irradiation. Comparative experiments, carried out with ad-hoc-synthesized model compounds, suggest that the phototoxicity observed at such a low concentration is probably not due to NO itself, but rather to the formation of the highly reactive peroxynitrite that is generated from the reaction of NO with the superoxide anion. PMID- 29110420 TI - Empathy revisited. PMID- 29110421 TI - The value of mentorship in academic medicine. PMID- 29110422 TI - Student societies and medical leadership. PMID- 29110424 TI - Increasing drought and diminishing benefits of elevated carbon dioxide for soybean yields across the US Midwest. AB - Elevated atmospheric CO2 concentrations ([CO2 ]) are expected to increase C3 crop yield through the CO2 fertilization effect (CFE) by stimulating photosynthesis and by reducing stomatal conductance and transpiration. The latter effect is widely believed to lead to greater benefits in dry rather than wet conditions, although some recent experimental evidence challenges this view. Here we used a process-based crop model, the Agricultural Production Systems sIMulator (APSIM), to quantify the contemporary and future CFE on soybean in one of its primary production area of the US Midwest. APSIM accurately reproduced experimental data from the Soybean Free-Air CO2 Enrichment site showing that the CFE declined with increasing drought stress. This resulted from greater radiation use efficiency (RUE) and above-ground biomass production at elevated [CO2 ] that outpaced gains in transpiration efficiency (TE). Using an ensemble of eight climate model projections, we found that drought frequency in the US Midwest is projected to increase from once every 5 years currently to once every other year by 2050. In addition to directly driving yield loss, greater drought also significantly limited the benefit from rising [CO2 ]. This study provides a link between localized experiments and regional-scale modeling to highlight that increased drought frequency and severity pose a formidable challenge to maintaining soybean yield progress that is not offset by rising [CO2 ] as previously anticipated. Evaluating the relative sensitivity of RUE and TE to elevated [CO2 ] will be an important target for future modeling and experimental studies of climate change impacts and adaptation in C3 crops. PMID- 29110425 TI - Therapeutic response to domperidone in gastroparesis: A prospective study using the GCSI-daily diary. AB - : Common symptoms of gastroparesis include nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain. Domperidone is used for treatment of gastroparesis. Daily symptom scoring may help document efficacy. AIM: To determine the effectiveness of domperidone for gastroparesis symptoms using the gastroparesis cardinal symptom index-daily diary (GCSI-DD) and to determine which symptoms improve and when with domperidone treatment. METHODS: Symptomatic patients with diabetic or idiopathic gastroparesis were enrolled. Gastric emptying was performed using 4 hour scintigraphy. GCSI-DD recorded symptoms at baseline and during six weeks of treatment with domperidone 10 mg TID. GCSI-DD records severity of nausea, early satiety, postprandial fullness, upper abdominal pain, overall gastroparesis symptoms on a scale of 0 (no symptom) to 4 (very severe) and records the number of vomiting episodes per day. RESULTS: Thirty-four patients with gastroparesis (5 diabetic, 29 idiopathic) participated in this open label study. Treatment duration averaged 36.9 +/- 7.6 days. Improvement in overall gastroparesis symptoms occurred on day 3 of treatment and maintained during the treatment. Early satiety, postprandial fullness, and overall symptom severity significantly improved from baseline to the final week of treatment (P < .05 for all), whereas nausea had borderline improvement (P = .055). Side effects included palpitations (5 patients), headache (5), breast tenderness (2), menstrual bleeding (2), dizziness (1), drowsiness (1), chest pain (1), swelling (1), constipation (1). CONCLUSIONS: Domperidone improves symptoms of gastroparesis, reducing overall gastroparesis symptom severity and decreasing early satiety, postprandial fullness, and nausea. GCSI-DD is useful to document efficacy of therapy for gastroparesis. PMID- 29110426 TI - Functional near-infrared spectroscopy to probe sensorimotor region activation during electrical stimulation-evoked movement. AB - : This study used non-invasive functional near-infrared spectroscopy (fNIRS) neuroimaging to monitor bilateral sensorimotor region activation during unilateral voluntary (VOL) and neuromuscular electrical stimulation (NMES)-evoked movements. METHODS: In eight healthy male volunteers, fNIRS was used to measure relative changes in oxyhaemoglobin (O2 Hb) and deoxyhaemoglobin (HHb) concentrations from a cortical sensorimotor region of interest in the left (LH) and right (RH) hemispheres during NMES-evoked and VOL wrist extension movements of the right arm. RESULTS: NMES-evoked movements induced significantly greater activation (increase in O2 Hb and concomitant decrease in HHb) in the contralateral LH than in the ipsilateral RH (O2 Hb: 0.44 +/- 0.16 MUM and 0.25 +/ 0.22 MUM, P = 0.017; HHb: -0.19 +/- 0.10 MUM and -0.12 +/- 0.09 MUM, P = 0.036, respectively) as did VOL movements (0.51 +/- 0.24 MUMU and 0.34 +/- 0.21 MUM, P = 0.031; HHb: -0.18 +/- 0.07 MUMU and -0.12 +/- 0.04 MUMU, P = 0.05, respectively). There was no significant difference between conditions for O2 Hb (P = 0.144) and HHb (P = 0.958). CONCLUSION: fNIRS neuroimaging enables quantification of bilateral sensorimotor regional activation profiles during voluntary and NMES evoked wrist extension movements. PMID- 29110428 TI - Xenon-augmented pediatric anesthesia: A small step closer? PMID- 29110430 TI - Judging causal associations in observational research on caudal anesthesia and hypospadias repair. PMID- 29110431 TI - Reply to Adam Adler and Arvind Chandrakantan regarding their comment "Nursing initiated tracheal extubation in PACU, the risk of delegating critical anesthesiology tasks in the interest of speed". PMID- 29110432 TI - Comment on: "Galvez et al.: Interactive pediatric emergency checklists to the palm of your hand - How the pedi crisis app traveled around the world". PMID- 29110434 TI - Caution with the Posey(r) CufflatorTM cuff pressure manometers. PMID- 29110435 TI - Infant spinal anesthesia: Do girls need a larger dose of local anesthetic? PMID- 29110436 TI - Ultra-modified Rapid Sequence Induction. PMID- 29110437 TI - The Finnish national guideline for diagnosis, treatment and follow-up of patients with wet age-related macular degeneration. PMID- 29110438 TI - Comparison of noncycloplegic and cycloplegic autorefraction in categorizing refractive error data in children. AB - PURPOSE: To systematically analyse the differences between cycloplegic and noncycloplegic refractive errors (RE) in children and to determine if the predictive value of noncycloplegic RE in categorizing RE can be improved. METHODS: Random cluster sampling was used to select 6825 children aged 4-15 years. Autorefraction was performed under both noncycloplegic and cycloplegic (induced with 1% cyclopentolate drops) conditions. Paired differences between noncycloplegic and cycloplegic spherical equivalent (SE) RE were determined. A general linear model was developed to determine whether cycloplegic SE can be predicted using noncycloplegic SE, age and uncorrected visual acuity (UCVA). RESULTS: Compared to cycloplegia, noncycloplegia resulted in a more myopic SE (paired difference: -0.63 +/- 0.65D, 95% CI: -0.612 to -0.65D, 6017 eligible right eyes) with greater differences observed in younger participants and in eyes with more hyperopic RE and smaller AL. Using raw noncycloplegic data resulted in only 61% of the eyes being correctly classified as myopic, emmetropic or hyperopic. Using age and uncorrected VA in the model, the association improved and 77% of the eyes were classified correctly. However, predicted cycloplegic SE continued to show large residual errors for low myopic to hyperopic RE. Applying the model to only those eyes with uncorrected VA <6/6 resulted in an improvement (R2 = 0. 93), with 80% of the eyes correctly classified. A higher VA cut-off (i.e., <=6/18) resulted in 97.5% of eyes classified correctly. CONCLUSION: Noncycloplegic assessment of RE in children overestimates myopia and results in a high error rate for emmetropic and hyperopic RE. Adjusting for age and applying uncorrected VA cut-offs to noncycloplegic assessments improves detection of myopic RE and may help in identifying myopic RE in situations where cycloplegia is not available but does not help in identifying the magnitude of refractive error and therefore is of limited value. PMID- 29110439 TI - Iontophoretic collagen cross-linking versus epithelium-off collagen cross-linking for early stage of progressive keratoconus - 3 years follow-up study. AB - PURPOSE: To compare 3-year iontophoretic corneal collagen cross-linking (I-CXL) outcomes with epithelium-off corneal collagen cross-linking (epi-off CXL) for early stage of progressive keratoconus. METHODS: Eighty eyes of 80 patients with early progressive keratoconus treated by I-CXL (n = 40) or epi-off CXL (n = 40) were included in this study. Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction, corneal topography and pachymetry were assessed at baseline and at 1, 3, 6, 12, 24 and 36 months of follow-up. RESULTS: Visual acuity (VA) showed a significant improvement (p < 0.05) at the end of follow-up in both groups. In the I-CXL group, the UDVA showed a rapid recovery after 3 months (p = 0.04). There was a statistically significant different trend in CDVA between groups with a more favourable outcome for the standard CXL group (p < 0.01). The cylinder improved beginning with 3 months after CXL in both groups. Maximum keratometry showed a significant reduction by 0.9 dioptres (D) in the I CXL group and by 1.2 D in the epi-off CXL group after 36 months (p = 0.283). Pachymetry values decreased at 3 months while a statistically significant increase occurred in both groups at 24 months. Progression occurred to one patient (2.5%) in I-CXL group. Adverse effects occurred to eight eyes (20%) in the epi-off CXL group. CONCLUSION: Iontophoretic corneal collagen cross-linking (I-CXL) is non-inferior to epi-off CXL for stopping the progression of keratoconus in its early stages with a higher degree of safety for the patients and a faster recovery of VA. PMID- 29110441 TI - Human case of bubonic plague resulting from the bite of a wild Gunnison's prairie dog during translocation from a plague-endemic area. AB - Plague is a zoonotic disease (transmitted mainly by fleas and maintained in nature by rodents) that causes severe acute illness in humans. We present a human plague case who became infected by the bite of a wild Gunnison's prairie dog, and a good practical example of the One Health approach that resulted in a rapid public health response. The exposure occurred while the animal was being transported for relocation to a wildlife refuge after being trapped in a plague enzootic area. This is the first report of a human plague case resulting from the bite of a Gunnison's prairie dog. Additionally, we present an observation of a longer incubation period for plague in captive prairie dogs, leading to a recommendation for a longer quarantine period for prairie dogs during translocation efforts. PMID- 29110442 TI - Cyclophilin A promotes non-small cell lung cancer metastasis via p38 MAPK. AB - BACKGROUND: Cyclophilin A (CypA) is associated with metastasis in diverse cancers; however, its role in lung cancer metastasis and the underlying mechanisms remain poorly understood. Our study investigated the effect of CypA on non-small cell lung cancer (NSCLC) metastasis in vitro and in vivo to determine its mechanisms. METHODS: In this study, A549 and H1299 cell lines with downregulated and overexpressed CypA, respectively, were constructed by lentivirus transfection of NSCLC cells. in vitro experiments, including wound healing and transwell assays and Western blotting, showed that CypA promoted cancer cell migration and epithelial-mesenchymal transition in NSCLC. Lung metastasis mouse models were used for the first time to confirm that CypA promoted NSCLC metastasis in vivo. The p38 inhibitor SB203580 was used to show that p38 MAPK is involved in CypA-mediated NSCLC metastasis. RESULTS: Wound healing and transwell assays showed that the migration of both A549 and H1299 cells decreased in the CypA downregulated group and increased in the CypA overexpressed group. CypA also positively promoted the expression of epithelial mesenchymal transition-relevant proteins. Results of mouse models confirmed that the tumor metastasis rate was much higher in the CypA overexpressed than in the CypA downregulated group. In addition, SB203580 inhibited NSCLC cell migration significantly in the CypA overexpressed group, while the difference in the CypA downregulated group was not significant. CONCLUSIONS: In conclusion, this study demonstrated that CypA promotes NSCLC cancer metastasis via p38 MAPK. PMID- 29110444 TI - Noninvasive in vivo optical characterization of blood flow and oxygen consumption in the superficial plexus of skin. AB - Assessing the metabolic activity of a tissue, whether normal, damaged, aged, or pathologic, is useful for diagnosis and evaluating the effects of drugs. This report describes a handheld optical fiber probe that contacts the skin, applies pressure to blanch the superficial vascular plexus of the skin, then releases the pressure to allow refill of the plexus. The optical probe uses white light spectroscopy to record the time dynamics of blanching and refilling. The magnitude and dynamics of changes in blood content and hemoglobin oxygen saturation yield an estimate of the oxygen consumption rate (OCR) in units of attomoles per cell per second. The average value of OCR on nine forearm sites on five subjects was 10+/-5 (amol/cell/s). This low-cost, portable, rapid, noninvasive optical probe can characterize the OCR of a skin site to assess the metabolic activity of the epidermis or a superficial lesion. PMID- 29110445 TI - Monitoring early phases of orthodontic treatment by means of Raman spectroscopies. AB - Gingival crevicular fluid (GCF) is a site-specific exudate in the gingival sulcus. GCF composition changes in response to diseases or mechanical stimuli, such as those occurring during orthodontic treatments. Raman microspectroscopy (MU-RS) and surface-enhanced Raman spectroscopy (SERS) were adopted for a GCF analysis during different initial phases of orthodontic force application. GCF samples were pooled from informed patients using paper cones. SERS spectra were obtained from GCF extracted from these cones, whereas MU-RS spectra were directly acquired on paper cones without any manipulation. The spectral characteristics of the main functional groups and the changes in cytochrome, amide III, and amide I contributions were highlighted in the different phases of orthodontic treatment with both SERS and MU-RS analysis. MU-RS directly performed on the paper cones together with proper statistical methods can offer an effective approach for the development of a tool for monitoring the processes occurring during orthodontic treatments, which may help the clinician in the choice of type of treatment individually for each patient and accelerate and improve the orthodontic therapy. PMID- 29110446 TI - Dense concentric circle scanning protocol for measuring pulsatile retinal blood flow in rats with Doppler optical coherence tomography. AB - The variability in the spatial orientation of retinal blood vessels near the optic nerve head (ONH) results in imprecision of the measured Doppler angle and therefore the pulsatile blood flow (BF), when those parameters are evaluated using Doppler OCT imaging protocols based on dual-concentric circular scans. Here, we utilized a dense concentric circle scanning protocol and evaluated its precision for measuring pulsatile retinal BF in rats for different numbers of the circular scans. An spectral domain optical coherence tomography (SD-OCT) system operating in the 1060-nm spectral range with image acquisition rate of 47,000 A scans/s was used to acquire concentric circular scans centered at the rat's ONH, with diameters ranging from 0.8 to 1.0 mm. A custom, automatic blood vessel segmentation algorithm was used to track the spatial orientation of the retinal blood vessels in three dimensions, evaluate the spatially dependent Doppler angle and calculate more accurately the axial BF for each major retinal blood vessel. Metrics such as retinal BF, pulsatility index, and resistance index were evaluated for each and all of the major retinal blood vessels. The performance of the proposed dense concentric circle scanning protocols was compared with that of the dual-circle scanning protocol. Results showed a 3.8+/-2.2 deg difference in the Doppler angle calculation between the two approaches, which resulted in ~7% difference in the calculated retinal BF. PMID- 29110447 TI - Evidence based position paper on Physical and Rehabilitation Medicine (PRM) professional practice for ageing people with disabilities. The European PRM position (UEMS PRM Section). AB - Ageing people with disabilities (APwDs) are faced with challenges of ageing which is straightforwardly related to disability that adds to the burden related to their early-onset disability. The aim of the paper is to improve Physical and Rehabilitation Medicine (PRM) physicians' professional practice for APwDs (as a distinct group from those who are disabled due to the ageing process) in order to promote their functioning properties and to reduce activity limitations and/or participation restrictions. A systematic review of the literature and a Consensus procedure by means of a Delphi process have been performed involving the delegates of all European countries represented in the UEMS PRM Section. The systematic literature review is reported together with the 30 recommendations resulting from the Delphi procedure. The professional role of PRM physicians in relation to APwDs is extending, expanding and/or improving health-related rehabilitation services worldwide in various settings (getting beyond the rehabilitation facilities) emphasizing the concept of integrated care with collaboration across other sectors to meet the specific needs of APwDs. This evidence based position paper (EBPP) represents the official position of the European Union through the UEMS PRM Section and designates the professional role of PRM physicians in APwDs. PMID- 29110448 TI - Cochrane Rehabilitation Corners in the European Journal of Physical and Rehabilitation Medicine. PMID- 29110449 TI - Cochrane Rehabilitation Methodology Committee: an international survey of priorities for future work. AB - Cochrane Rehabilitation aims to improve the application of evidence-based practice in rehabilitation. It also aims to support Cochrane in the production of reliable, clinically meaningful syntheses of evidence related to the practice of rehabilitation, while accommodating the many methodological challenges facing the field. To this end, Cochrane Rehabilitation established a Methodology Committee to examine, explore and find solutions for the methodological challenges related to evidence synthesis and knowledge translation in rehabilitation. We conducted an international online survey via Cochrane Rehabilitation networks to canvass opinions regarding the future work priorities for this committee and to seek information on people's current capabilities to assist with this work. The survey findings indicated strongest interest in work on how reviewers have interpreted and applied Cochrane methods in reviews on rehabilitation topics in the past, and on gathering a collection of existing publications on review methods for undertaking systematic reviews relevant to rehabilitation. Many people are already interested in contributing to the work of the Methodology Committee and there is a large amount of expertise for this work in the extended Cochrane Rehabilitation network already. PMID- 29110451 TI - Ultraviolet Wavelength-Dependent Optoelectronic Properties in Two-Dimensional NbSe2-WSe2 van der Waals Heterojunction-Based Field-Effect Transistors. AB - Atomically thin two-dimensional (2D) van der Waals (vdW) heterostructures are one of the very important research issues for stacked optoelectronic device applications. In this study, using the transferred and stacked NbSe2-WSe2 films as electrodes and a channel, we fabricated the field-effect transistor (FET) devices based on 2D-2D vdW metal-semiconductor heterojunctions (HJs) and systematically studied their ultraviolet (UV) wavelength-dependent electrical and photoresponse properties. Upon the exposure to UV light with a wavelength of 365 nm, the NbSe2-WSe2 vdW HJFET devices exhibited threshold voltage shift toward positive gate bias direction, a current increase, and a nonlinear photocurrent increase upon applying a gate bias due to the contribution of the photogenerated hole current. In contrast, for the 254 nm UV-irradiated FET devices, the drain current was decreased dramatically and the threshold voltage was negatively shifted. The time-resolved photoresponse properties showed that the device current after turning off the 254 nm UV light was completely and much more rapidly recovered compared with the case of the persistent photocurrent after turning off the 365 nm UV light. Interestingly, we found that the wettability of the WSe2 surface was changed with increasing irradiation time only after 254 nm UV irradiation. The measured wetting behavior on the WSe2 surface provided direct evidence that the experimentally observed UV-wavelength-dependent phenomena was attributed to the UV-induced dissociative adsorption of oxygen and water molecules, leading to the modulation of charge trap states on the photogenerated and intrinsic carriers in the p-type WSe2 channel. This study will help provide an understanding of the influence of environmental and electrical measurement conditions on the electrical and optical properties of 2D-2D vdW HJ devices for a variety of device applications through the stacking of 2D heterostructures. PMID- 29110450 TI - Three-Dimensional Framework of Graphene Nanomeshes Shell/Co3O4 Synthesized as Superior Bifunctional Electrocatalyst for Zinc-Air Batteries. AB - The synthesis of durable and low-cost electrocatalyst is crucial but challenging. Here, we developed a one-pot pyrolysis approach toward the preparation of heteroatom-doped hierarchical porous three-dimensional (3D) graphene frameworks decorated with multilayer graphene shell-coated cobalt oxide nanocrystal. Large literal sheet size of graphene nanomeshes may stimulate rapid thermolysis with cobalt-oleate complex to form Co3O4 nanocrystals and in situ growth of multilayer graphene coating co-doped by boron and nitrogen with controlling heating rate up to 600 degrees C. This new material worked as superior bifunctional electrocatalyst on oxygen reduction reaction and oxygen evolution reaction to commercial Pt/C with better onset potential/half-wave potentials, larger current density, better stability, and stronger methanol tolerance. The heteroatom co doping into porous/curved graphene confined nanocrystals in 3D porous walls provided adequate accessibility of created catalytic active sites and ideal mass transport route for the excellent catalytic activity on redox reaction of oxygen. The synthesized material-based Zn-air battery further confirmed its superior electrolytic activity with high specific capacity and smaller overpotential. This one-pot pyrolysis method shows a great potential of scalable synthesis of high performance practical electrocatalyst for metal-air batteries and fuel cells at a low cost. PMID- 29110452 TI - Schiff Base as Additive for Preventing Gas Evolution in Li4Ti5O12-Based Lithium Ion Battery. AB - Lithium titanium oxide (Li4Ti5O12)-based electrodes are very promising for long life cycle batteries. However, the surface reactivity of Li4Ti5O12 in organic electrolytes leading to gas evolution is still a problem that may cause expansion of pouch cells. In this study, we report the use of Schiff base (1,8 diazabicyclo[5.4.0]undec-7-ene) as an additive that prevents gas evolution during cell aging by a new mechanism involving the solid electrolyte interface on the anode surface. The in situ ring opening polymerization of cyclic carbonates occurs during the first cycles to decrease gas evolution by 9.7 vol % without increasing the internal resistance of the battery. PMID- 29110453 TI - Development of Embedded Fiber-Optic Evanescent Wave Sensors for Optical Characterization of Graphite Anodes in Lithium-Ion Batteries. AB - The development, fabrication, and embedment of fiber-optic evanescent wave sensors (FOEWSs) to monitor the state of charge (SOC) and the state of health (SOH) of lithium-ion batteries (LIBs) are presented. Etching of FOEWSs is performed using a solution of 40 wt % ammonium fluoride (NH4F) and 49 wt % hydrofluoric acid (HF) (6:1), which is found to be superior to an etching solution containing just 49 wt % HF. FOEWSs were characterized using glycerol and found to have the highest sensitivity in a lithium-ion battery when they lose 92% of their transmittance in the presence of glycerol on their sensing region. The physical effect that the FOEWS has on the graphite anode is also investigated and is found to be much more significant in Swagelok cells compared to that in in house-fabricated pouch cells, mainly due to pressure variation. The FOEWS was found to be most sensitive to the changes in the LIB when it was completely embedded using a slurry of graphite anode material within a pouch cell. The optimized fabrication process of the embedded FOEWS demonstrates the potential of using such sensors commercially for real-time monitoring of the SOC and SOH of LIBs while in operation. PMID- 29110454 TI - Metal-Organic Framework-Stabilized CO2/Water Interfacial Route for Photocatalytic CO2 Conversion. AB - Here, we propose a CO2/water interfacial route for photocatalytic CO2 conversion by utilizing a metal-organic framework (MOF) as both an emulsifier and a catalyst. The CO2 reduction occurring at the CO2/water interface produces formate with remarkably enhanced efficiency as compared with that in conventional solvent. The route is efficient, facile, adjustable, and environmentally benign, which is applicable for the CO2 transformation photocatalyzed by different kinds of MOFs. PMID- 29110455 TI - Natural Attenuation of Nonionic Surfactants Used in Hydraulic Fracturing Fluids: Degradation Rates, Pathways, and Mechanisms. AB - Hydraulic fracturing fluids are injected into shales to extend fracture networks that enhance oil and natural gas production from unconventional reservoirs. Here we evaluated the biodegradability of three widely used nonionic polyglycol ether surfactants (alkyl ethoxylates (AEOs), nonylphenol ethoxylates (NPEOs), and polypropylene glycols (PPGs)) that function as weatherizers, emulsifiers, wetting agents, and corrosion inhibitors in injected fluids. Under anaerobic conditions, we observed complete removal of AEOs and NPEOs from solution within 3 weeks regardless of whether surfactants were part of a chemical mixture or amended as individual additives. Microbial enzymatic chain shortening was responsible for a shift in ethoxymer molecular weight distributions and the accumulation of the metabolite acetate. PPGs bioattenuated the slowest, producing sizable concentrations of acetone, an isomer of propionaldehyde. Surfactant chain shortening was coupled to an increased abundance of the diol dehydratase gene cluster (pduCDE) in Firmicutes metagenomes predicted from the 16S rRNA gene. The pduCDE enzymes are responsible for cleaving ethoxylate chain units into aldehydes before their fermentation into alcohols and carboxylic acids. These data provide new mechanistic insight into the environmental fate of hydraulic fracturing surfactants after accidental release through chain shortening and biotransformation, emphasizing the importance of compound structure disclosure for predicting biodegradation products. PMID- 29110456 TI - General Two-Dimensional Absorption-Mode J-Resolved NMR Spectroscopy. AB - Two-dimensional (2D) J-resolved NMR technique offers a natural solution for disentangling complex mixtures that suffer from crowded spectra in 1D NMR. The applicability of classical 2D J-resolved spectroscopy is inevitably limited by phase-twist lineshapes and strong coupling artifacts. Here, a general and robust NMR method is proposed to record 2D absorption-mode J-resolved spectra in rapid acquisition manner. This method can also reduce the impact of strong coupling artifacts, thus achieving full considerations for applications. Intuitively, this method delivers pure chemical shifts along one dimension and orthogonally adds J couplings along the other dimension, free of 45 degrees spectral shearing. It may provide a powerful tool for structural and configurational studies as well as biological analyses. PMID- 29110457 TI - Electrical Homogeneity of Large-Area Chemical Vapor Deposited Multilayer Hexagonal Boron Nitride Sheets. AB - Large-area hexagonal boron nitride (h-BN) can be grown on polycrystalline metallic substrates via chemical vapor deposition (CVD), but the impact of local inhomogeneities on the electrical properties of the h-BN and their effect in electronic devices is unknown. Conductive atomic force microscopy (CAFM) and probe station characterization show that the tunneling current across the h-BN stack fluctuates up to 3 orders of magnitude from one substrate (Pt) grain to another. Interestingly, the variability in the tunneling current across the h-BN within the same substrate grain is very low, which may enable the use of CVD grown h-BN in ultra scaled technologies. PMID- 29110458 TI - Simultaneous Rayleigh/Mie and Raman/Fluorescence Characterization of Molecularly Functionalized Colloids by Correlative Single-Particle Real-Time Imaging in Suspension. AB - Many applications of nano- and microparticles require molecular functionalization. Assessing the heterogeneity of a colloidal sample in terms of its molecular functionalization is highly desirable but not accessible by conventional ensemble experiments. Retrieving this information necessitates single-particle experiments which simultaneously detect both functionalized and nonfunctionalized particles via two separate imaging channels. In this contribution, we present an optical setup for performing correlative single particle imaging using laser light-sheet illumination: the first detection channel records elastic light scattering (Rayleigh/Mie), while the second channel detects inelastic light scattering (Raman) or fluorescence. The instrument is tested with Raman reporter-functionalized SERS-active metal nanoparticles (core/satellite silver nanoparticles, dimers and monomers of gold nanoparticles) and fluorophore-functionalized colloids (fluorescent polymer microparticles, dye labeled protein on gold nanoparticles). PMID- 29110459 TI - In Vivo Oxidative Stress Monitoring Through Intracellular Hydroxyl Radicals Detection by Recyclable Upconversion Nanoprobes. AB - Oxidative stress, as an essential cause to many diseases via irreversible biomolecule oxidation, can be induced by casual-contacted nanomaterials, which can generate hydroxyl radical (*OH) due to their active surface capacity. Herein, we report a novel upconversion nanoprobe for ratiometric *OH detection and monitoring titanium oxide nanomaterial-induced oxidative stress. Unlike previously developed nanoprobes, the *OH-responsive acceptor in these nanoprobes can be rapidly prepared and easily recycled. With a detection limit of ~2 nM and a broad linear range of 4 nM-16 MUM, the nanoprobe is suitable for both in vitro and in vivo applications. The facile preparation and recyclable strategy provide a new method for developing novel nanoprobes that can directly detect hazardous molecules in biological samples and systems. PMID- 29110460 TI - Illustrating the Mass-Transport Effect on Enzyme Cascade Reaction Kinetics by Use of a Rotating Ring-Disk Electrode. AB - Electrochemical biosensors based on enzymatic reaction have been applied to a wide range of fields. As the trend continues to grow, these biosensors are approaching the limit imposed by physics and chemistry. To further improve the performance of biosensors, the interplay of mass transport and enzymatic reaction kinetics, especially in enzyme cascade systems, should be considered in the design of biosensors. Herein, we propose a simple approach to studying the influence of mass transport and enzyme molecule motion on the kinetics of enzyme cascade reactions. beta-Galactosidase (beta-Gal) and glucose oxidase (GOx) of the enzyme cascade reaction are precisely immobilized onto the disk and ring electrodes, respectively, of a rotating ring-disk electrode (RRDE) via covalent attachment. At a low rotating speed (<600 rpm), convective transport promotes the enzyme cascade reaction. When the rotating speed is higher than 600 rpm, the cascade reaction becomes kinetically controlled. Further increase of the rotating speed results in a slow decline in reaction rate, possibly due to the production inhibition effect. In addition, the effect of conformation change of the enzyme at higher centrifugal forces on enzyme activity should be considered. This study would shine light on the effect of convective force on regulation of kinetics of enzyme cascade reaction, offering an ideal platform for studying other enzyme cascade reactions and providing fundamentals to design high-performance biosensors, biofuel cells, and bioelectronics. PMID- 29110461 TI - NMR Quantification of Carbohydrates in Complex Mixtures. A Challenge on Honey. AB - The knowledge of carbohydrate composition is greatly important to determine the properties of natural matrices such as foodstuff and food ingredients. However, because of the structural similarity and the multiple isomeric forms of carbohydrates in solution, their analysis is often a complex task. Here we propose an NMR analytical procedure based on highly selective chemical shift filters followed by TOCSY, which allows us to acquire specific background-free signals for each sugar. The method was tested on raw honey samples dissolved in water with no other pretreatment. In total, 22 sugars typically found in honey were quantified: 4 monosaccharides (glucose, fructose, mannose, rhamnose), 11 disaccharides (sucrose, trehalose, turanose, maltose, maltulose, palatinose, melibiose and melezitose, isomaltose, gentiobiose nigerose, and kojibiose), and 7 trisaccharides (raffinose, isomaltotriose, erlose, melezitose, maltotriose, panose, and 1-kestose). Satisfactory results in terms of limit of quantification (0.03-0.4 g/100g honey), precision (% RSD: 0.99-4.03), trueness (bias % 0.4-4.2), and recovery (97-104%) were obtained. An accurate control of the instrumental temperature and of the sample pH endows an optimal chemical shift reproducibility, making the procedure amenable to automation and suitable to routine analysis. While validated on honey, which is one of the most complex natural matrices in terms of saccharides composition, this innovative approach can be easily transferred to other natural matrices. PMID- 29110462 TI - Aerobic Soil Biodegradation of Bisphenol (BPA) Alternatives Bisphenol S and Bisphenol AF Compared to BPA. AB - Pressures to ban bisphenol A (BPA) has led to the use of alternate chemicals such as BPA analogues bisphenol S (BPS) and bisphenol AF (BPAF) in production of consumer products; however, information on their environmental fate is scarce. In this study, aerobic degradation of BPA, BPAF, and BPS at 100 MUg/kg soil and 22 +/- 2 degrees C was monitored for up to 180 days in a forest soil and an organic farm soil. At each sampling point, soils were extracted three times and analyzed by liquid chromatography high resolution mass or time-of-flight mass spectrometry. Based on compound mass recovered from soils compared to the mass applied, BPS had short half-lives of <1 day in both soils similar to BPA. BPAF was much more persistent with observed half-lives of 32.6 and 24.5 days in forest and farm soils, respectively. To our knowledge, this is the first report on BPAF degradation. For all three compounds, half-lives were longer in the higher organic carbon (OC) forest soil which correlates well to sorption studies showing higher sorption with higher OC. Metabolites identified for all three bisphenols support degradation pathways that include meta-cleavage as well as ortho cleavage, which has not been previously shown. PMID- 29110463 TI - 8-Nitro-cGMP Attenuates the Interaction between SNARE Complex and Complexin through S-Guanylation of SNAP-25. AB - 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is the second messenger in nitric oxide/reactive oxygen species redox signaling. This molecule covalently binds to protein thiol groups, called S-guanylation, and exerts various biological functions. Recently, we have identified synaptosomal associated protein 25 (SNAP-25) as a target of S-guanylation, and demonstrated that S-guanylation of SNAP25 enhanced SNARE complex formation. In this study, we have examined the effects of S-guanylation of SNAP-25 on the interaction between the SNARE complex and complexin (cplx), which binds to the SNARE complex with a high affinity. Pull-down assays and coimmunoprecipitation experiments have revealed that S-guanylation of Cys90 in SNAP-25 attenuates the interaction between the SNARE complex and cplx. In addition, blue native-PAGE followed by Western blot analysis revealed that the amount of cplx detected at a high molecular weight decreased upon 8-nitro-cGMP treatment in SH-SY5Y cells. These results demonstrated for the first time that S-guanylation of SNAP-25 attenuates the interaction between the SNARE complex and cplx. PMID- 29110464 TI - Joule Heating-Induced Dispersion in Open Microfluidic Electrophoretic Cytometry. AB - While protein electrophoresis conducted in capillaries and microchannels offers high-resolution separations, such formats can be cumbersome to parallelize for single-cell analysis. One approach for realizing large numbers of concurrent separations is open microfluidics (i.e., no microchannels). In an open microfluidic device adapted for single-cell electrophoresis, we perform 100s to 1000s of simultaneous separations of endogenous proteins. The microscope slide sized device contains cells isolated in microwells located in a ~40 MUm polyacrylamide gel. The gel supports protein electrophoresis after concurrent in situ chemical lysis of each isolated cell. During electrophoresis, Joule (or resistive) heating degrades separation performance. Joule heating effects are expected to be acute in open microfluidic devices, where a single, high conductivity buffer expedites the transition from cell lysis to protein electrophoresis. Here, we test three key assertions. First, Joule heating substantially impacts analytical sensitivity due to diffusive losses of protein out of the open microfluidic electrophoretic (EP) cytometry device. Second, increased analyte diffusivity due to autothermal runaway Joule heating is a dominant mechanism that reduces separation resolution in EP cytometry. Finally, buffer exchange reduces diffusive losses and band broadening, even when handling single-cell lysate protein concentrations in an open device. We develop numerical simulations of Joule heating-enhanced diffusion during electrophoresis and observe ~50% protein loss out of the gel, which is reduced using the buffer exchange. Informed by analytical model predictions of separation resolution (with Joule heating), we empirically demonstrate nearly fully resolved separations of proteins with molecular mass differences of just 4 kDa or 12% (GAPDH, 36 kDa; PS6, 32 kDa) in each of 129 single cells. The attained separation performance with buffer exchange is relevant to detection of currently unmeasurable protein isoforms responsible for cancer progression. PMID- 29110465 TI - Rayleigh Instability-Assisted Satellite Droplets Elimination in Inkjet Printing. AB - Elimination of satellite droplets in inkjet printing has long been desired for high-resolution and precision printing of functional materials and tissues. Generally, the strategy to suppress satellite droplets is to control ink properties, such as viscosity or surface tension, to assist ink filaments in retracting into one drop. However, this strategy brings new restrictions to the ink, such as ink viscosity, surface tension, and concentration. Here, we report an alternative strategy that the satellite droplets are eliminated by enhancing Rayleigh instability of filament at the break point to accelerate pinch-off of the droplet from the nozzle. A superhydrophobic and ultralow adhesive nozzle with cone morphology exhibits the capability to eliminate satellite droplets by cutting the ink filament at breakup point effectively. As a result, the nozzles with different sizes (10-80 MUm) are able to print more inks (1 < Z < 38), for which the nozzles are super-ink-phobic and ultralow adhesive, without satellite droplets. The finding presents a new way to remove satellite droplets via designing nozzles with super-ink-phobicity and ultralow adhesion rather than restricting the ink, which has promising applications in printing electronics and biotechnologies. PMID- 29110466 TI - Degradation of Organic UV filters in Chlorinated Seawater Swimming Pools: Transformation Pathways and Bromoform Formation. AB - Organic ultraviolet (UV) filters are used in sunscreens and other personal-care products to protect against harmful effects of exposure to UV solar radiation. Little is known about the fate of UV filters in seawater swimming pools disinfected with chlorine. The present study investigated the occurrence and fate of five commonly used organic UV filters, namely dioxybenzone, oxybenzone, avobenzone, 2-ethylhexyl-4-methoxycinnamate, and octocrylene, in chlorinated seawater swimming pools. Pool samples were collected to monitor the variation of UV filter concentrations during pool opening hours. Furthermore, laboratory controlled chlorination experiments were conducted in seawater spiked with UV filters to investigate the reactivity of UV filters. Extracts of chlorination reaction samples were analyzed using high-resolution mass spectrometry and electron-capture detection to identify the potentially formed byproducts. In the collected pool samples, all the UV filters except dioxybenzone were detected. Chlorination reactions showed that only octocrylene was stable in chlorinated seawater. The four reactive UV filters generated brominated transformation products and disinfection byproducts. This formation of brominated products resulted from reactions between the reactive UV filters and bromine, which is formed rapidly when chlorine is added to seawater. Based on the identified byproducts, the transformation pathways of the reactive UV filters were proposed for the first time. Bromoform was generated by all the reactive UV filters at different yields. Bromal hydrate was also detected as one of the byproducts generated by oxybenzone and dioxybenzone. PMID- 29110467 TI - Development of PM2.5 Source Profiles Using a Hybrid Chemical Transport-Receptor Modeling Approach. AB - Laboratory-based or in situ PM2.5 source profiles may not represent the pollutant composition for the sources in a different study location due to spatially and temporally varying characteristics, such as fuel or crustal element composition, or due to differences in emissions behavior under ambient versus laboratory conditions. In this work, PM2.5 source profiles were estimated for 20 sources using a novel optimization approach that incorporates observed concentrations with source impacts from a chemical transport model (CTM) to capture local pollutant characteristics. Nonlinear optimization was used to minimize the error between source profiles, CTM source impacts, and observations. In a 2006 U.S. application, spatial and seasonal variability was seen for coal combustion, dust, fires, metals processing, and other source profiles when compared to the reference profiles, with variability in species fractions over 400% (calcium in dust) compared to mean contributions of the same species. Revised profiles improved the spatial and temporal bias in modeled concentrations of several trace metal species, including Na, Al, Ca, Mn, Cu, As, Se, Br, and Pb. In an application of the CMB-iteration model for two U.S. cities, revised profiles estimated higher biomass burning and dust impacts for summer compared with previous studies. Source profile optimization can be useful for source apportionment studies that have limited availability of source profile data for the location of interest. PMID- 29110468 TI - Redox-Triggered Bonding-Induced Emission of Thiol-Functionalized Gold Nanoclusters for Luminescence Turn-On Detection of Molecular Oxygen. AB - Most optical sensors for molecular oxygen were developed based on the quenching effect of the luminescence of oxygen-sensitive probes; however, the signal turn off mode of these probes is undesirable to quantify and visualize molecular oxygen. Herein, we report a novel luminescence turn-on detection strategy for molecular oxygen via the specific oxygen-triggered bonding-induced emission of thiol-functionalized gold nanoclusters. Thiol-functionalized gold nanoclusters were prepared by a facile one-step synthesis, and as-prepared gold nanoclusters possess significant aggregation-induced emission (AIE) property. It is the first time to discover the oxygen-triggered bonding-induced emission (BIE) behavior of gold nanoclusters, which results in disulfide-linked covalent bonding assemblies with intensely red luminescence. This specific redox-triggered BIE is capable of quantitatively detecting dissolved oxygen in aqueous solution in a light-up manner, and trace amount of dissolved oxygen at ppb level is achieved based on this detection method. A facile and convenient test strip for oxygen detection was also developed to monitor molecular oxygen in a gas matrix. Covalent bonding induced emission is proven to be a more efficient way to attain high brightness of AIEgens than a physical aggregation-induced emission process, and provides a more convenient and desirable detection method for molecular oxygen than the previous sensors. PMID- 29110469 TI - Comparative Analysis of Whey N-Glycoproteins in Human Colostrum and Mature Milk Using Quantitative Glycoproteomics. AB - Glycosylation is a ubiquitous post-translational protein modification that plays a substantial role in various processes. However, whey glycoproteins in human milk have not been completely profiled. Herein, we used quantitative glycoproteomics to quantify whey N-glycosylation sites and their alteration in human milk during lactation; 110 N-glycosylation sites on 63 proteins and 91 N glycosylation sites on 53 proteins were quantified in colostrum and mature milk whey, respectively. Among these, 68 glycosylation sites on 38 proteins were differentially expressed in human colostrum and mature milk whey. These differentially expressed N-glycoproteins were highly enriched in "localization", "extracellular region part", and "modified amino acid binding" according to gene ontology annotation and mainly involved in complement and coagulation cascades pathway. These results shed light on the glycosylation sites, composition and biological functions of whey N-glycoproteins in human colostrum and mature milk, and provide substantial insight into the role of protein glycosylation during infant development. PMID- 29110471 TI - Microscale Dynamics of Oil Droplets at a Membrane Surface: Deformation, Reversibility, and Implications for Fouling. AB - Despite their excellent capabilities, wide implementation of membranes for oil/water emulsion separation is limited due to severe fouling. To date, microscale dynamics of the oil-water-membrane system are poorly understood. The present study uses confocal microscopy at unprecedented resolution for direct observation of oil droplet deposition, deformation, and detachment during separation and cleaning, respectively. The 3D shape of the droplets was imaged as a function of the permeation rate, J, droplet radius, R, membrane permeance, k, water viscosity, MU, and the water/oil interfacial tension coefficient, sigma. These parameters yield a modified capillary number, [Formula: see text] = MUVR1/2/sigmak1/2, which accounts for the extra viscous "suction" at close proximity to the membrane surface. A clear correlation was observed between the degree of droplet deformation and an increasing [Formula: see text]. Furthermore, the reversibility of droplet deposition and membrane performance were assessed through microscopic surface coverage and flux recovery analysis. In general, operation at a low flux (3.9 MUm/s) yields spherical droplets that are easily removed by crossflow cleaning, whereas a high flux (85 MUm/s) leads to significant deformation and mostly irreversible deposition. These results shed important new insight on the influence of hydrodynamic conditions on fouling reversibility during emulsion separation, and may guide better design of surface modified membranes. PMID- 29110472 TI - Enzymatic Purification of Microplastics in Environmental Samples. AB - Micro-Fourier transform infrared (micro-FTIR) spectroscopy and Raman spectroscopy enable the reliable identification and quantification of microplastics (MPs) in the lower micron range. Since concentrations of MPs in the environment are usually low, the large sample volumes required for these techniques lead to an excess of coenriched organic or inorganic materials. While inorganic materials can be separated from MPs using density separation, the organic fraction impedes the ability to conduct reliable analyses. Hence, the purification of MPs from organic materials is crucial prior to conducting an identification via spectroscopic techniques. Strong acidic or alkaline treatments bear the danger of degrading sensitive synthetic polymers. We suggest an alternative method, which uses a series of technical grade enzymes for purifying MPs in environmental samples. A basic enzymatic purification protocol (BEPP) proved to be efficient while reducing 98.3 +/- 0.1% of the sample matrix in surface water samples. After showing a high recovery rate (84.5 +/- 3.3%), the BEPP was successfully applied to environmental samples from the North Sea where numbers of MPs range from 0.05 to 4.42 items m-3. Experiences with different environmental sample matrices were considered in an improved and universally applicable version of the BEPP, which is suitable for focal plane array detector (FPA)-based micro-FTIR analyses of water, wastewater, sediment, biota, and food samples. PMID- 29110470 TI - Emerging Functional Differences between the Synaptotagmin and Ferlin Calcium Sensor Families. AB - The ferlin family proteins have emerged as multi-C2 domain regulators of calcium triggered membrane fusion and fission events. While initially determined to share many of the features of members of the synaptotagmin family of calcium sensors, ferlins in more recent studies have been found to interact directly with non neuronal voltage-gated calcium channels and nucleate the assembly of membrane trafficking protein complexes, functions that distinguish them from the more well studied members of the synaptotagmin family. Here we highlight some of the recent findings that have advanced our understanding of ferlins and their functional differences with the synaptotagmin family. PMID- 29110474 TI - Migration of Constituent Protons in Hybrid Organic-Inorganic Perovskite Triggers Intrinsic Doping. AB - The crucial separation of photocarriers in solar cells can be efficiently driven by contacting semiconductor phases with differing doping levels. Here we show that intrinsic doping surges in methylammonium lead iodide (MAPbI3) crystals as a response to environmental basicity. MAPbI3 crystals were passivated with polybases to induce the deprotonation of its methylammonium ions (MA+). Stable crystals showed marked increases in photoluminescence and radiative decay, attributed to the presence of unbalanced charges acting as doped carriers. This emulates in a controlled manner the proton-withdrawing conditions of polycrystalline films, where excess basic precursors are found between grains. Raman spectroscopy showed the collective alignment of MA+ cations within the intrinsically doped lattices, thus revealing the buildup of electric fields. On this basis, we propose a mechanism for the formation of doping-gradients toward grain boundaries, potentially explaining the extended photocarrier lifetimes and diffusion lengths observed in perovskite solar cells. PMID- 29110473 TI - Cycloreversion Reaction of a Diarylethene Derivative at Higher Excited States Attained by Two-Color, Two-Photon Femtosecond Pulsed Excitation. AB - Two-color, two-pulse femtosecond pulsed excitation was applied to the elucidation of the dynamics and mechanism of cycloreversion reaction of a diarylethene derivative in the higher excited states. Transient absorption spectroscopy under one-photon visible excitation revealed that the 1B state produced by the excitation undergoes the internal conversion into the 2A state with a time constant of 200 fs. Geometrical rearrangement of the 2A state takes place concomitantly with the vibrational cooling with a time constant of 3 ps. The resultant 2A state undergoes the transition into the conical intersection point in competition with nonradiative as well as radiative deactivation into the ground state with a time constant of 12 ps. The second pulse excitation of the 2A state, especially the geometrically relaxed 2A state, led to the significant enhancement of the cycloreversion reaction through the large reaction quantum yield of ca. 50-90% in the higher excited state (Sn state), while the excitation of the 1B state, leading to the Sn' state, did not induce such enhancement. By integrating with the excitation wavelength dependence of the second pump laser pulse, we discussed the chemical reactivity of diarylethene derivatives in terms of the symmetry of the electronic states. PMID- 29110475 TI - Preslaughter Transport Effect on Broiler Meat Quality and Post-mortem Glycolysis Metabolism of Muscles with Different Fiber Types. AB - Preslaughter transport has been reported to decrease the quality of breast meat but not thigh meat of broilers. However, tissue-specific difference in glycogen metabolism between breast and thigh muscles of transported broilers has not been well studied. We thus investigated the differences in meat quality, adenosine phosphates, glycolysis, and bound key enzymes associated with glycolysis metabolism in skeletal muscles with different fiber types of preslaughter transported broilers during summer. Compared to a 0.5 h transport, a 3 h transport during summer decreased ATP content, increased AMP content and AMP/ATP ratio, and accelerated glycolysis metabolism via the upregulation of glycogen phosphorylase expression accompanied by increased activities of bound glycolytic enzymes (hexokinase, pyruvate kinase, and lactate dehydrogenase) in pectoralis major muscle, which subsequently increased the likelihood of pale, soft, and exudative-like breast meat. On the other hand, a 3 h transport induced only a moderate glycolysis metabolism in tibialis anterior muscle, which did not cause any noticeable changes in the quality traits of the thigh meat. PMID- 29110476 TI - Certain Perfluoroalkyl and Polyfluoroalkyl Substances Associated with Aqueous Film Forming Foam Are Widespread in Canadian Surface Waters. AB - The presence of perfluoroalkyl and polyfluoroalkyl substances (PFASs) commonly associated with aqueous film forming foams (AFFFs) at sites without known AFFF contamination is a largely unexplored area, which may reveal widespread environmental contaminants requiring further investigation. Sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening for 23 classes of PFASs, followed by quantitative analysis was used to investigate surface waters from rural, urban, and AFFF-impacted sites in Canada. The PFASs detected included perfluorohexane sulfonamide (FHxSA), 6:2 fluorotelomer sulfonamide (FTSAm), fluorotelomer sulfonamide alkylbetaines (FTABs), fluorotelomer betaines (FTBs), 6:2 fluorotelomer mercaptoalkylamido sulfonate sulfone (FTSAS-SO2), 6:2 fluorotelomerthiohydroxyl ammonium sulfoxide (FTSHA-SO), 6:2 fluorotelomer sulfonamide alkylamine (FTAA) and C3 to C6 perfluoroalkane sulfonamido amphoterics. Detection of FHxSA in all urban and AFFF-impacted sites (0.04-19 ng/L) indicates the widespread presence of rarely considered perfluorohexanesulfonate (PFHxS) precursors in Canadian waters. FTABs and FTBs were especially abundant with up to 16-33 ng/L of 6:2 FTAB in urban and AFFF impacted water suggesting it may have additional applications, while FTBs were only in AFFF-impacted sites (qualitative; ?FTBs 80 ng/L). The distributions of PFASs moving downstream along the AFFF-impacted Welland River and between water and sediment suggested differences in the persistence of various AFFF components and enhanced sorption of long-chain fluorotelomer betaines. Total organofluorine combustion-ion chromatography (TOF-CIC) revealed that fluorotelomer betaines were a substantial portion of the organofluorine in some waters and 36-99.7% of the total organofluorine was not measured in the targeted analysis. PMID- 29110477 TI - Transition-Metal-Free C-S Bond Formation: Synthesis of Polysubstituted Diaryl Sulfides and alpha-Thioarylcarbonyl Compounds. AB - A transition-metal-free protocol for the construction of C-S bonds has been developed. Acetylacetone acts as a new and green aryl source for the synthesis of polysubstituted diarylsulfides bearing a free hydroxy group and a ketone group, which provides a new access to a series of flavonoids containing a thioaryl group. In addition, a series of alpha-thioarylcarbonyl compounds are obtained in good to excellent yields. PMID- 29110478 TI - Rotationally Assisted Spin-State Inversion in Carbene-Metal-Amides Is an Artifact. AB - High-level quantum chemical calculations, presented in this Letter, show that the unusual luminescence properties of the high-performance thermally activated delayed fluorescence emitter CMA1, observed recently by Di et al. [ Science 2017, 356, 159-163 ], can be explained without resorting to the rotationally assisted spin-state inversion mechanism proposed by these authors. Multiconfiguration and relativistic effects lead to fast and efficient thermal equilibration of the excited singlet and triplet populations of this linear gold complex even for coplanar orientations of the ligands. The calculations predict S1 ? T1 intersystem crossing outcompetes the submicrosecond fluorescence by 2 orders of magnitude, thus quenching prompt fluorescence. The significant time- and environment-dependent shifts of the CMA1 luminescence, observed in experiment, are attributed to effects of (hindered) solvent reorganization. PMID- 29110479 TI - Synthesis of a Nonracemic C2-Symmetric Tetrahydro-1,4-azaborine and Evaluation of Hydroboration Enantioselectivity. AB - Tetrahydro-1,4-azaborines were accessed by hydroboration of N,N diprenyltoluenesulfonamide 4. Conversion to the methylborinates 11 and 12 followed by heating with l-alanine and crystallization afforded (R,R,S)-13 (27%). Reduction of borinic acid (R,R)-18 with Soderquist's KH* gave (R,R)-19, and hydride abstraction by TMSCl in the presence of alkenes resulted in hydroboration, 84-86% ee for (Z)-alkenes, but (E)-alkenes or 1,1-disubstituted alkenes gave <5% ee. PMID- 29110480 TI - Lewis Acid Triggered Vinylcyclopropane-Cyclopentene Rearrangement. AB - We report a mild Lewis acid induced isomerization of donor-acceptor cyclopropanes, containing an alkenyl moiety and diverse electron-withdrawing group(s) at the adjacent positions, into substituted cyclopentenes. We have found that 1,1,2-trisubstituted cyclopent-3-enes were exclusively obtained in yield of 51-99% when cyclopropanes with a 2-substituted alkenyl group as a donor underwent isomerization. For cyclopropanes bearing a trisubstituted alkenyl group either the corresponding cyclopent-3-enes or isomeric cyclopent-2-enes having two acceptor groups at the C(1) atom were formed, with the reaction selectivity being determined by the applied Lewis acid. We have shown that the reactivity of the donor-acceptor cyclopropane increases with the increase of the electron-donating character of (hetero)aromatic group attached to the alkenyl moiety. The synthetic utility of the developed methodology was also demonstrated through the synthesis of polysubstituted cyclopentane and piperidine derivatives. PMID- 29110481 TI - Theoretical Insights into Unexpected Molecular Core Level Shifts: Chemical and Surface Effects. AB - A set of density-functional theory based tools is employed to elucidate the influence of chemical and surface-induced changes on the core level shifts of X ray photoelectron spectroscopy experiments. The capabilities of our tools are demonstrated by analyzing the origin of an unpredicted component in the N 1s core level spectra of metal phthalocyanine molecules (in particular ZnPc) adsorbed on Cu(110). We address surface induced effects, such as splitting of the lowest unoccupied molecular orbital or local electrostatic effects, demonstrating that these cannot account for the huge core level shift measured experimentally. Our calculations also show that, when adsorbed at low temperatures, these molecules might capture hydrogen atoms from the surface, giving rise to hydrogenated molecular species and, consequently, to an extra component in the molecular core level spectra. Only upon annealing, and subsequent hydrogen release, would the molecules recover their nominal structural and electronic properties. PMID- 29110482 TI - Rapidly Recoverable Thixotropic Hydrogels from the Racemate of Chiral OFm Monosubstituted Cyclo(Glu-Glu) Derivatives. AB - Both chiral OFm monosubstituted cyclo(l-Glu-l-Glu) and cyclo(d-Glu-d-Glu) display a robust gelation ability in a variety of organic solvents and water. In contrast to an individual enantiomer, their racemate can form rapidly recoverable thixotropic hydrogels with a remarkably shorter thixotropic recovery time. This unexpected thixotropic behavior is induced by the random arrangement of d- and l enantiomers in the cell units, leading to the formation of "pseudoracemate", noncrystalline self-assemblies in the resulting 3D fibrous network. PMID- 29110483 TI - Stable Graphene-Two-Dimensional Multiphase Perovskite Heterostructure Phototransistors with High Gain. AB - Recently, two-dimensional (2D) organic-inorganic perovskites emerged as an alternative material for their three-dimensional (3D) counterparts in photovoltaic applications with improved moisture resistance. Here, we report a stable, high-gain phototransistor consisting of a monolayer graphene on hexagonal boron nitride (hBN) covered by a 2D multiphase perovskite heterostructure, which was realized using a newly developed two-step ligand exchange method. In this phototransistor, the multiple phases with varying bandgap in 2D perovskite thin films are aligned for the efficient electron-hole pair separation, leading to a high responsivity of ~105 A W-1 at 532 nm. Moreover, the designed phase alignment method aggregates more hydrophobic butylammonium cations close to the upper surface of the 2D perovskite thin film, preventing the permeation of moisture and enhancing the device stability dramatically. In addition, faster photoresponse and smaller 1/f noise observed in the 2D perovskite phototransistors indicate a smaller density of deep hole traps in the 2D perovskite thin film compared with their 3D counterparts. These desirable properties not only improve the performance of the phototransistor, but also provide a new direction for the future enhancement of the efficiency of 2D perovskite photovoltaics. PMID- 29110484 TI - Metal-Free Aerobic Oxidative Cyanation of Tertiary Amines: Azobis(isobutyronitrile) (AIBN) as a Sole Cyanide Source. AB - An aerobic oxidative cyanation for the synthesis of alpha-aminonitriles was reported. The formation of C(sp3)-CN bonds was achieved under a metal-free condition by utilizing azobis(isobutyronitrile) as a sole organic cyanide source with the combination of pivalic acid and sodium acetate as additives. PMID- 29110485 TI - Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2). AB - Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure-activity relationship for neuroprotective activity. Several derivatives were identified that possess greater protective effect in human induced pluripotent stem cell-derived neurons, protecting up to 80% of neurons against etoposide-induced apoptosis at concentrations as low as 100 nM. The developed aromatic carbamates possess physicochemical properties desirable for CNS therapeutics. The primary known mechanisms of action of the parent scaffold are not responsible for the observed neuroprotective activity. Herein, we demonstrate that neuroprotective aromatic carbamates function to increase the Bcl 2/Bax ratio to an antiapoptotic state and activate autophagy through induction of beclin 1. PMID- 29110487 TI - Assembly of PCBM and tn-ZnPc Molecular Domains and Phase Separation of Molecular Mixtures from Liquid Solution on Si(111). AB - We present the results of investigations aimed at understanding the mechanisms by which small, mutually immiscible organic molecules self-assemble into domains during phase separation from liquid solutions in the presence of a solid substrate. As an example system, we investigated molecular mixtures of tetranitro zinc-phthalocyanine (tn-ZnPc), an electron donor, and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), an electron acceptor, in chloroform solution, deposited onto native oxide-covered Si(111) substrates. We found qualitatively different behavior in the formation of domains of the two types of molecules, seemingly because of a large difference in their solubilities in the solvent. The morphology of PCBM molecule domains varies widely depending on the solvent evaporation rate, the presence/absence of tn-ZnPc molecules in the solution, solvent annealing conditions, and seemingly the presence/absence of trace impurities. By contrast, we find evidence that the shape of the tn-ZnPc domains is insensitive to evaporation; these form while in liquid suspension, and the assembly of domains into clusters varies according to the rate and mode of solvent evaporation. PMID- 29110486 TI - Impact of Detergents on Membrane Protein Complex Isolation. AB - Detergents play an essential role during the isolation of membrane protein complexes. Inappropriate use of detergents may affect the native fold of the membrane proteins, their binding to antibodies, or their interaction with partner proteins. Here we used cadherin-11 (Cad11) as an example to examine the impact of detergents on membrane protein complex isolation. We found that mAb 1A5 could immunoprecipitate Cad11 when membranes were solubilized by dodecyl maltoside (DDM) but not by octylglucoside, suggesting that octylglucoside interferes with Cad11-mAb 1A5 interaction. Furthermore, we compared the effects of Brij-35, Triton X-100, cholate, CHAPSO, Zwittergent 3-12, Deoxy BIG CHAP, and digitonin on Cad11 solubilization and immunoprecipitation. We found that all detergents except Brij-35 could solubilize Cad11 from the membrane. Upon immunoprecipitation, we found that beta-catenin, a known cadherin-interacting protein, was present in Cad11 immune complex among the detergents tested except Brij-35. However, the association of p120 catenin with Cad11 varied depending on the detergents used. Using isobaric tag for relative and absolute quantitation (iTRAQ) to determine the relative levels of proteins in Cad11 immune complexes, we found that DDM and Triton X-100 were more efficient than cholate in solubilization and immunoprecipitation of Cad11 and resulted in the identification of both canonical and new candidate Cad11-interacting proteins. PMID- 29110488 TI - Atomistic Modeling of Quantum Dots at Experimentally Relevant Scales Using Charge Equilibration. AB - Quantum dots (QDs) have been successfully employed within a vast array of fundamental and applied studies spanning all subdisciplines of chemistry. However, ab initio models of QD behavior are inherently limited by computational cost due to the large number of atoms within QDs of experimentally relevant size. This work builds upon the method of charge equilibration (qEQ) to account for system interactions unique to QDs (QD-qEQ) and demonstrates accuracy through calculated per-QD energies and dipole moments that agree generally with ab initio calculations and experimental observation, respectively. By forgoing electronic structure information, QD-qEQ exhibits a distinct advantage in its exceptionally low computational cost, which affords consideration of over 35,000 unique spherical wurtzite CdSe structures with radii <=12.5 A. A comparison of QD-qEQ calculations with experimental data relating to the phenomenon of CdSe magic size crystals (MSCs) affords statistical and structural insight into why MSCs are observed. Consideration of structures <=12.5 A reveals QD sizes corresponding with local minima in QD energy, correlating closely with experimentally observed MSCs. The physical origin of observed energy minima is assigned to QD structures with surfaces exhibiting large fractions of highly coordinated atoms, a physical trait postulated to yield fewer reaction sites for stepwise growth, resulting in MSC stability. The low computational cost along with the per-atom and per structure electrostatic data afforded by QD-qEQ makes this method an enticing approach to address dynamic QD behavior and enables potential applications within a broad range of fields concomitant to those in which QD inclusion has already proven useful. PMID- 29110489 TI - Comparative Study of the Adsorption of Thiols and Selenols on Au(111) and Au(100). AB - The effect of the Au crystalline plane on the adsorption of different thiols and selenols is studied via reductive desorption (RD) and X-ray photoelectron spectroscopy (XPS) measurements. Self-assembled monolayers (SAMs) using aliphatic (ATs) and aromatic thiols (ArTs) on both Au(111) and Au(100) were prepared. The electrochemical stability of these SAMs on both surfaces is evaluated by comparing the position of the RD peaks. The longer the AT chain the more stable the SAM on Au(100) when compared to Au(111). By means of XPS measurements, we determine that the binding energy (BE) of the S 2p signal corresponding to the S atoms at the thiol/Au interface, commonly assigned at 162.0 eV, shifts 0.2 eV from Au(111) to Au(100) for SAMs prepared using thiols with the C* (C atom bonded to S) in sp3 hybridization, such as ATs. However, when the thiol presents the C* with an sp2 hybridization, such as in the case of ArTs, the BE remains at 162.0 eV regardless of the surface plane. Selenol-based SAMs were characterized comparatively on both Au(100) and Au(111). Our results show that selenol SAMs become even more electrochemically stable on Au(100) with respect to Au(111) than the analogue sulfur-based SAM. According to our results, we suggest that the electronic distribution around the Au-S/Se bond could be responsible for the different structural arrangements reported in the literature (gold adatoms, etc.), which should be dependent on the crystalline face (Au(hkl)-S) and the chemical nature of the environment of the adsorbates (sp3-C* vs sp2-C* and Au-SR vs Au-SeR). PMID- 29110490 TI - Ferroelectricity in Ruddlesden-Popper Chalcogenide Perovskites for Photovoltaic Application: The Role of Tolerance Factor. AB - Chalcogenide perovskites with optimal band gap and desirable light absorption are promising for photovoltaic devices, whereas the absence of ferroelectricity limits their potential in applications. On the basis of first-principles calculations, we reveal the underlying mechanism of the paraelectric nature of Ba3Zr2S7 observed in experiments and demonstrate a general rule for the appearance of ferroelectricity in chalcogenide perovskites with Ruddlesden-Popper (RP) A3B2X7 structures. Group theoretical analysis shows that the tolerance factor is the primary factor that dominates the ferroelectricity. Both Ba3Zr2S7 and Ba3Hf2S7 with large tolerance factor are paraelectric because of the suppression of in-phase rotation that is indispensable to hybrid improper ferroelectricity. In contrast, Ca3Zr2S7, Ca3Hf2S7, Ca3Zr2Se7, and Ca3Hf2S7 with small tolerance factor exhibit in-phase rotation and can be stable in the ferroelectric Cmc21 ground state with nontrivial polarization. These findings not only provide useful guidance to engineering ferroelectricity in RP chalcogenide perovskites but also suggest potential ferroelectric semiconductors for photovoltaic applications. PMID- 29110493 TI - [Articles of the Hungarian Medical Journal from April, 1994]. PMID- 29110492 TI - Observation of Effective Pseudospin Scattering in ZrSiS. AB - 3D Dirac semimetals are an emerging class of materials that possess topological electronic states with a Dirac dispersion in their bulk. In nodal-line Dirac semimetals, the conductance and valence bands connect along a closed path in momentum space, leading to the prediction of pseudospin vortex rings and pseudospin skyrmions. Here, we use Fourier transform scanning tunneling spectroscopy (FT-STS) at 4.5 K to resolve quasiparticle interference (QPI) patterns at single defect centers on the surface of the line nodal semimetal zirconium silicon sulfide (ZrSiS). Our QPI measurements show pseudospin conservation at energies close to the line node. In addition, we determine the Fermi velocity to be hvF = 2.65 +/- 0.10 eV A in the Gamma-M direction ~300 meV above the Fermi energy EF and the line node to be ~140 meV above EF. More importantly, we find that certain scatterers can introduce energy-dependent nonpreservation of pseudospin, giving rise to effective scattering between states with opposite pseudospin deep inside valence and conduction bands. Further investigations of quasiparticle interference at the atomic level will aid defect engineering at the synthesis level, needed for the development of lower-power electronics via dissipationless electronic transport in the future. PMID- 29110491 TI - Deep Learning Accurately Predicts Estrogen Receptor Status in Breast Cancer Metabolomics Data. AB - Metabolomics holds the promise as a new technology to diagnose highly heterogeneous diseases. Conventionally, metabolomics data analysis for diagnosis is done using various statistical and machine learning based classification methods. However, it remains unknown if deep neural network, a class of increasingly popular machine learning methods, is suitable to classify metabolomics data. Here we use a cohort of 271 breast cancer tissues, 204 positive estrogen receptor (ER+), and 67 negative estrogen receptor (ER-) to test the accuracies of feed-forward networks, a deep learning (DL) framework, as well as six widely used machine learning models, namely random forest (RF), support vector machines (SVM), recursive partitioning and regression trees (RPART), linear discriminant analysis (LDA), prediction analysis for microarrays (PAM), and generalized boosted models (GBM). DL framework has the highest area under the curve (AUC) of 0.93 in classifying ER+/ER- patients, compared to the other six machine learning algorithms. Furthermore, the biological interpretation of the first hidden layer reveals eight commonly enriched significant metabolomics pathways (adjusted P-value <0.05) that cannot be discovered by other machine learning methods. Among them, protein digestion and absorption and ATP-binding cassette (ABC) transporters pathways are also confirmed in integrated analysis between metabolomics and gene expression data in these samples. In summary, deep learning method shows advantages for metabolomics based breast cancer ER status classification, with both the highest prediction accuracy (AUC = 0.93) and better revelation of disease biology. We encourage the adoption of feed-forward networks based deep learning method in the metabolomics research community for classification. PMID- 29110495 TI - [Articles of the Hungarian Medical Journal from October, 1986]. PMID- 29110494 TI - [Articles of the Hungarian Medical Journal from November, 1998]. PMID- 29110496 TI - [Articles of the Hungarian Medical Journal from October, 1968]. PMID- 29110497 TI - [Articles of the Hungarian Medical Journal from March, 1967]. PMID- 29110498 TI - [Articles of the Hungarian Medical Journal from July, 1968]. PMID- 29110499 TI - [Articles of the Hungarian Medical Journal from December, 1998]. PMID- 29110500 TI - [Articles of the Hungarian Medical Journal from April, 2003]. PMID- 29110501 TI - First Metatarsal Head Osteochondral Defect Treatment With Particulated Juvenile Cartilage Allograft Transplantation: A Case Series. AB - BACKGROUND: Focal damage to articular cartilage, also called an osteochondral defect (OCD), can be a cause of pain and decreased range of motion. Recent advancements have led to transplantation techniques using particulated juvenile articular cartilage allograft. This technique has been applied to the first metatarsal head to a very limited degree, with no published results to our knowledge. The aim of this study was to review the clinical results of patients who underwent particulated juvenile cartilage allograft implantation for first metatarsal head OCDs. METHODS: We performed a retrospective consecutive case series study. Nine patients, at an average age of 41 years, were treated for symptomatic focal osteochondral defects of the first metatarsal head with particulate cartilage grafting from 2010 to 2016. Patients were contacted by phone to assess interest in returning to the office for follow-up, where weightbearing radiographs of the foot were obtained and a foot examination was performed. RESULTS: At an average follow-up of 3.3 years, 7 of 9 patients reported no pain with recreational activities and no patient required further operations. This patient cohort was physically active, with 6 of 9 listing running as a regular activity. The average overall American Orthopaedic Foot & Ankle Society (AOFAS) Hallux Metatarsophalangeal-Interphalangeal Scale questionnaire score was 85 (maximum 100), AOFAS pain 35.6 (maximum 40), and AOFAS function 40.1 (maximum 45). Patient satisfaction surveys correlated with the AOFAS scores and revealed that 7 of 9 patients were very satisfied with their results, 1 was satisfied, and 1 patient was very dissatisfied. CONCLUSION: Particulated juvenile cartilage allograft transplantation is a promising treatment option for symptomatic first metatarsophalangeal focal articular cartilage lesions. Further study is needed to demonstrate which lesions respond better to this type of cartilage graft versus traditional marrow-stimulating procedures. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29110502 TI - Daily vision testing can expose the prodromal phase of migraine. AB - Background Several visual tasks have been proposed as indirect assays of the balance between cortical inhibition and excitation in migraine. This study aimed to determine whether daily measurement of performance on such tasks can reveal perceptual changes in the build up to migraine events. Methods Visual performance was measured daily at home in 16 non-headache controls and 18 individuals with migraine using a testing protocol on a portable tablet device. Observers performed two tasks: luminance increment detection in spatial luminance noise and centre surround contrast suppression. Results Luminance thresholds were reduced in migraine compared to control groups ( p < 0.05), but thresholds did not alter across the migraine cycle; while headache-free, centre-surround contrast suppression was stronger for the migraine group relative to controls ( p < 0.05). Surround suppression weakened at around 48 hours prior to a migraine attack and strengthened to approach their headache-free levels by 24 hours post-migraine (main effect of timing, p < 0.05). Conclusions Daily portable testing of vision enabled insight into perceptual performance in the lead up to migraine events, a time point that is typically difficult to capture experimentally. Perceptual surround suppression of contrast fluctuates during the migraine cycle, supporting the utility of this measure as an indirect, non-invasive assay of the balance between cortical inhibition and excitation. PMID- 29110503 TI - CGRP, a target for preventive therapy in migraine and cluster headache: Systematic review of clinical data. AB - Introduction Migraine and cluster headache are challenging to manage, with no tailored preventive medications available. Targeting the calcitonin gene-related peptide (CGRP) pathway to treat these headaches may be the first focused therapeutic option to date, with the potential for promising efficacy. Methods We systematically searched PubMed and clinicaltrials.gov for randomized controlled trials investigating the preventive potential of monoclonal antibodies against the CGRP pathway in the treatment of migraine and cluster headache. Results The literature search returned a total of 136 records, of which 32 were eligible for review. Discussion Clinical data from phase II and III trials of the four monoclonal antibodies targeting the CGRP pathway: Eptinezumab, erenumab, fremanezumab, and galcanezumab, collectively show a positive effect in the preventive treatment of episodic and chronic migraine. Multiple phase II and III trials are under way to further determine the efficacy and safety of this new drug class. It may be particularly important to assess the cardiovascular effects of long-term CGRP blockade. Phase III trials are also currently in progress for the preventive treatment of cluster headache. Conclusion Efficacy of anti-CGRP monoclonal antibodies spells a promising future for the many patients suffering from migraine, and possibly also for the smaller but severely-affected population with cluster headache. PMID- 29110505 TI - Effects of contrast-enhancement on diffusion weighted imaging and apparent diffusion coefficient measurements in 3-T magnetic resonance imaging of breast lesions. AB - Background The effect of gadolinium-based contrast agents on diffusion-weighted imaging (DWI) measurements of breast lesions is still not clear. Purpose To investigate gadolinium effects on DWI and apparent diffusion coefficient (ADC) in breast lesions and normal parenchyma with 3 Tesla contrast-enhanced MRI. Material and Methods Pre- and post-contrast DWI (b = 0 and b = 1000 s/mm2) were acquired in 47 patients. Measured ADC values, pre- and post-contrast T2 signal intensity (T2 SI) and contrast-to-noise ratio (CNR) were compared with Wilcoxon signed-rank and rank-sum test ( P < 0.05). Results Post-contrast ADC was reduced only in malignant lesions (-34%), T2 SI was reduced both in malignant (-50%) and benign ( 36%) lesions. Post-contrast CNR was reduced in all groups except for benign lesions. Conclusion Gadolinium-based contrast agent causes a significant reduction in ADC values of malignant breast lesions. PMID- 29110506 TI - Mouse population-based evaluation of urinary protein and miRNA biomarker performance associated with cisplatin renal injury. AB - Discovery and qualification of novel biomarkers with improved specificity and sensitivity for detection of xenobiotic-induced injuries is an area of active research across multiple sectors. However, the majority of efforts in this arena have used genetically limited rodent stocks that lack variability in xenobiotic responses inherent to genetically heterogeneous human populations. In this study, genetically diverse Diversity Outbred (DO) mice were used as a surrogate for human clinical populations to investigate performance of urinary kidney biomarkers against classical preclinical kidney injury biomarkers (blood urea nitrogen [BUN] and serum creatinine). In this study, cisplatin was used as a paradigm kidney toxicant, with female adult DO mice exposed to a single injection (5 mg/kg) of cisplatin or vehicle and necropsied 72 h post-exposure and 18 h following overnight urine collection. Interindividual variability in kidney toxicity was observed, with DO mice experiencing either no tubule cell necrosis or minimal-mild necrosis. A panel of urinary protein biomarkers and profiled miRNAs were assessed by receiver-operating characteristic curves as to their ability to distinguish non-responder versus responder animals, as defined by histopathological evidence of renal tubule cell necrosis. A surprising outcome of these studies was that BUN was elevated alongside of urinary miRNA and protein biomarkers in animals with grade 2 proximal tubular cell necrosis; but not elevated with grade 1 necrosis. These studies demonstrate a novel approach for using a rodent population to better assess sensitivity of candidate biomarkers, especially for proposed clinical applications. Impact statement Recent studies have indicated that several urinary proteins and miRNA species may be suitable as biomarkers for acute kidney injury. A major focus on biomarker qualification is demonstrating improved specificity and sensitivity over gold standard tests. In this study, a mouse population model, Diversity Outbred mice, was used to demonstrate that neither the urinary protein markers nor the miRNA species assayed in urine could reliably detect low severity kidney injury better than blood urea nitrogen. This study has implications for use of these biomarkers in the clinic, where interindividual heterogeneity is present within patient populations and for which the underlying tissue pathology may not be known. PMID- 29110508 TI - Implementation of the Early Start Denver Model in an Italian community. AB - Identifying effective, community-based specialized interventions for young children with autism spectrum disorder is an international clinical and research priority. We evaluated the effectiveness of the Early Start Denver Model intervention in a group of young children with autism spectrum disorder living in an Italian community compared to a group of Italian children who received treatment as usual. A total of 22 young children diagnosed with autism spectrum disorder received the Early Start Denver Model in a center-based context for 6 h per week over 6 months. The Early Start Denver Model group was compared to a group of 70 young children diagnosed with autism spectrum disorder who received treatment as usual for an average of 5.2 h over 6 months. Children in both groups improved in cognitive, adaptive, and social skills after 3 months and 6 months of treatment. Children in the Early Start Denver Model group made larger gains in cognitive and social skills after 3 and 6 months of treatment. The Early Start Denver Model group made larger gains in adaptive skills after 3 months of treatment. Our results are discussed in terms of implications for intervention research and clinical practice. Our study supports the positive impact of the Early Start Denver Model in a non-English-speaking community. PMID- 29110507 TI - Regulatory landscapes for biomarkers and diagnostic tests: Qualification, approval, and role in clinical practice. AB - While the term 'biomarker' is relatively new, the concept is millennia old. However, with the introduction of new technologies to discover potential biomarkers comes the need to assess their utility and veracity for any given use. This is particularly true for the use of biomarkers to support regulatory decisions in medical product development. Hence the US Food and Drug Administration has developed processes for the qualification of biomarkers and other medical product development tools, processes that are underscored by recent legislation (i.e. the 21st Century Cures Act). In addition to these qualification processes, diagnostic tests that measure a biomarker may follow a process for regulatory decision through the processes that evaluate companion diagnostics. This mini-review provides an overview of these processes and their role in pharmaceutical development and clinical use. Impact statement This work summarizes very recent developments in the US FDA's biomarker qualification program. Furthermore, it contrasts biomarker qualification with companion diagnostic evaluation. As such, it will be highly informative for researches considering taking a biomarker discovery farther along the road to validation. PMID- 29110509 TI - Stress management for headaches in children and adolescents: A review and practical recommendations for health promotion programs and well-being. AB - Stress is considered to be the most common factor reported to trigger headaches in children and adolescents. Although tension-type headache and migraine are the two most common types of headache in children and adolescents, they are often untreated, ignoring their stressful background. We provide a narrative review of the available evidence for health-care professionals involved in stress-related headache management and health promotion programs. An integrative plan is delivered through lifestyle improvement and biopsychosocial modifying stress response techniques. Healthy dietary choices, sleep hygiene, and regular exercise, although limited, are effective for young sufferers. Biopsychosocial therapies such as relaxation, biofeedback, hypnosis, yoga, cognitive behavioral therapy, and acupuncture focus at stress physiological and behavioral relief. Our purpose is to suggest a stress-related headache management to empower children to make healthy choices in order to improve their lifelong well-being and quality of life. We aim to authorize relationship between nurses and other health-care providers with background knowledge around stress management for pediatric headache populations. PMID- 29110510 TI - gamma-irradiation from radiotherapy improves the virulence potential of Candida tropicalis. AB - AIM: To evaluate if radiation used in radiotherapy can cause changes in the virulence potential of Candida tropicalis ATCC 750. MATERIALS & METHODS: C. tropicalis was exposed in vitro to identical dose and scheme of irradiation would be used in patients with head and neck cancer. Some virulence parameters were analyzed before and after irradiation. RESULTS: Colony morphologies were irreversibly affected by irradiation. Increase in growth rate, filamentation, adhesion on cell lines and phagocytosis process were also observed. Overall the irradiated C. tropicalis cells became more efficient at causing systemic infection in mice. CONCLUSION: gamma-radiation induced important changes in C. tropicalis increasing its virulence profile, which could directly affect the relationship between yeasts and hosts. PMID- 29110511 TI - Decision Algorithms for the Retreatment with Viscosupplementation in Patients Suffering from Knee Osteoarthritis: Recommendations from the EUROpean VIScosupplementation COnsensus Group (EUROVISCO). AB - Background Viscosupplementation (VS) is a symptomatic treatment of knee osteoarthritis. Although systematic reviews of its repeat use showed favorable benefit/risk ratio, no study has focused on the indication of retreatment. Methods A task force was created to look at issues regarding retreatment with VS in knee osteoarthritis. An attempt was made to reach consensus on several issues: (1) to define treatment "success" and "failure," (2) to determine when to retreat patients successfully treated by a previous VS, (3) to determine how to retreat patients in whom VS failed, (4) to define what to do in case of adverse reaction following previous VS, and (5) to examine the interests of soluble biomarkers to manage retreatment. After debate and review of literature the working group voted on 88 issues. Two "decision trees" were built based on the results of the votes. Results In case of failure, the authors draw attention to the need of a rigorous clinical and radiological analysis, and consider evidence-based medicine. When VS was previously successful, retreatment can be considered after recurrence or increase in pain. However, in subjects with high risk of disease progression, in young patients, and in professional sportsmen, retreatment could be considered systematically, because of the probability of hyaluronic acid to slow osteoarthritis progression. Evidence on soluble biomarkers was not considered as enough strong to support their use as decision tools for patient retreatment. Conclusion The decision algorithms are intended to facilitate consideration of the therapeutic options, in patients with knee osteoarthritis previously treated with VS. PMID- 29110512 TI - Short-term Clinical and Radiographic Results of the Salto Mobile Total Ankle Prosthesis. AB - BACKGROUND: The mobile-bearing Salto total ankle prosthesis has been reported to have promising outcomes. However, clinical reports on this prosthesis are few, and most have been published by the inventors and disclosed consultants. METHODS: We retrospectively reviewed 59 patients who received Salto prosthesis unilaterally. The average follow-up was 35.9 (range, 6-56) months. Clinical and radiologic results were evaluated. Clinical results were evaluated according to visual analog scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, Ankle Osteoarthritis Scale (AOS) pain and disability score, and ankle range of motion (ROM) in dorsiflexion/plantarflexion. In the radiographic evaluation, we measured the tibial angle (TA), talar angle (TAL), tibial slope, and talocalcaneal angle (TCA) on weightbearing radiographs. RESULTS: By the last follow-up, 7 of 59 patients (11.9%) had undergone reoperation, and 3 of 59 implants (5.1%) had been removed. The prosthesis survival was 94.9% (95% CI, 89.1%-100%). With any reoperation as the endpoint of follow-up, the clinical success rate was 88.1% (95% CI, 79.4%-96.9%). The mean postoperative visual analog scale score, AOFAS ankle-hindfoot score, and Ankle Osteoarthritis Scale pain and disability score improved significantly ( P < .001). The ankle range of motion also improved from preoperative 33.4 +/- 16.6 to 40.3 +/- 15.5 postoperatively ( P < .001); however, there was no statistically significant change in plantarflexion ( P = .243). Radiolucent areas and osteolysis were found in 28 (47.5%) and 27 (45.8%) patients, respectively. Heterotopic ossification was observed in 13 patients (22.0%). CONCLUSIONS: In this series, early clinical and radiographic outcomes of this prosthesis were promising. We believe the early radiolucent lines were probably due to the gap at the implant and bone interface, and they disappeared at the time of osseous integration. However, longer follow-up is necessary to determine the long-term durability and survivorship of this implant, particularly given the high incidence of postoperative osteolysis. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29110514 TI - [Articles of the Hungarian Medical Journal from June, 2003]. PMID- 29110513 TI - Ankaferd Influences mRNA Expression of Iron-Regulated Genes During Iron Deficiency Anemia. AB - Ankaferd Blood Stopper (ABS) comprises a mixture of plants and stops bleeding via forming a protein network by erythroid aggregation. Bleeding causes reduction of iron levels in body. It has been indicated that ABS contains significant amount of iron. Thus, we investigated the biological activity of ABS-derived iron on iron-regulated genes during iron-deficiency anemia (IDA). IDA We selected Caco-2 and HepG2 cell lines as in vitro models of human intestine and liver, respectively. Iron deficiency anemia was induced by deferoxamine. The cells were treated with ferric ammonium citrate (FAC) and ABS. Messenger RNA levels of iron regulated genes were analyzed by quantitative reverse transcription polymerase chain reaction to elucidate whether iron in ABS behaved similar to inorganic iron (FAC) during IDA. The results showed that ABS-derived iron influenced transcriptions of iron-regulated marker genes, including divalent metal transporter ( Dmt1), transferrin receptor ( TfR), ankyrin repeat domain 37 ( Ankrd37), and hepcidin ( Hamp) in IDA-induced Caco-2 and HepG2 cells. Our results suggest that when ABS is used to stop tissue bleeding, it might have an ability to reduce levels of IDA. PMID- 29110515 TI - Monitoring Zika virus infection associated cardiovascular problem. PMID- 29110517 TI - Functions of reminiscence in later life: Predicting change in the physical and mental health of older adults over time. AB - OBJECTIVE: Research has repeatedly shown that reminiscence affects the mental health and well-being of older adults contemporaneously and over time. Cross sectional research also points to a link between reminiscence and physical health. The direction of this relationship is unclear, however. Does physical health affect how and why older adults think of themselves in the past? Or conversely, do various functions of reminiscence affect both mental and physical health now, and in future? METHODS: Online responses were collected from a primarily Canadian sample of 411 older adults at three time points, separated by eight months on average. Participants responded to the Reminiscence Functions Scale at baseline and reported their health conditions, perceived state of health, life satisfaction, and psychological distress at subsequent points of measurement. A structural equation model was computed to identify direct and indirect associations between reminiscence functions and health over time. RESULTS: Self-negative reminiscence functions at baseline (T1) predicted physical health 8 months later (T2), whereas self-positive reminiscence functions at T1 predicted both physical health and psychological distress at T2. The associations among self-positive functions and subsequent physical and mental health were maintained over time. Additionally, longitudinal crossover was observed in which psychological distress at T2 predicted physical health at T3, controlling for physical and mental health at T2. CONCLUSIONS: Findings confirm longitudinal associations among reminiscence functions and subsequent indicators of health. For older adults, this extends to both physical and mental health. Future research should examine the physiological mechanisms by which autobiographical memory affects health over time. PMID- 29110516 TI - Minimally Invasive Distal Metatarsal Diaphyseal Osteotomy (DMDO) for Chronic Plantar Diabetic Foot Ulcers. AB - BACKGROUND: The aims of this prospective study were first to evaluate the safety and effectiveness of minimally invasive distal metatarsal diaphyseal osteotomies (DMDOs) for treating a consecutive series of diabetic patients with chronic plantar diabetic foot ulcers (CPDFUs) and second to assess their clinical functional and radiographic outcomes. METHODS: A consecutive series of patients affected by diabetes mellitus with CPDFUs, not responsive to previous nonoperative management, underwent DMDO. The CPDFUs were evaluated using the University of Texas Diabetic Wound Classification System (UTDWC). Demographic parameters, Foot & Ankle Society (AOFAS) scores, visual analog scale (VAS) scores, healing times, and complications were recorded. Maestro et al criteria and bone callus formation were analyzed radiologically. Statistical analysis was carried out ( P < .05). Thirty consecutive enrolled patients with a mean age of 66.7 (range, 53-75) years presented 35 CPDFUs with a mean diameter of 16.3 mm and a mean duration of 10.3 months. The most frequent grade of the UTDWC was IIIB (42.9%). RESULTS: All ulcers recovered with a mean healing time of 7.9 +/- 4.0 (range, 4-17) weeks. AOFAS scores improved significantly from 55.3 to 81.4 points ( P < .001). At a mean follow-up of 25.3 months (range, 18-71), no cases of ulcer recurrence were recorded, while a major complication or a wound infection required longer healing time. CONCLUSION: Minimally invasive DMDO was a safe and effective method in promoting CPDFU healing, regardless of the grade of severity, by the reduction of the high plantar pressure under the metatarsal heads. This technique improved functional and radiographic outcomes with few complications. LEVEL OF EVIDENCE: IV, case series. PMID- 29110518 TI - Age-appropriate preparations for children with cancer undergoing radiotherapy: A feasibility study. AB - The aim of this study was to test age-appropriate information and preparation procedures for children with cancer undergoing radiotherapy (RT) for feasibility and effectiveness in terms of the need for general anesthesia (GA) and anxiety. In a quasi-experimental controlled clinical trial, 17 children aged 3-18 years receiving age-appropriate preparation were compared with 16 children in a control group. Feasibility in terms of recruitment, compliance, and acceptability was assessed. Effectiveness was assessed by the number of children who underwent treatment without GA and their respective fractions and validated instruments measured the children's anxiety and emotional behavior. The preparation parts were delivered as intended without any additional personnel and without dropouts in the intervention group (IG) and therefore found feasible and acceptable. No statistic significances were found concerning the number of children receiving GA or anxiety. However, three children planned for GA in the IG completed their treatments, including 73 fractions awake. Children receiving GA, regardless of group, showed significantly higher negative emotional behavior. Giving children individualized preparation may decrease the need for GA during RT, which gives benefits in terms of fewer risks and restrictions in life for the child and lower costs for health care. PMID- 29110519 TI - Caring for infants with posterior urethral valves: A qualitative study of parents' experiences. AB - This study aimed to explore the perspectives and experiences of parents caring for an infant with posterior urethral valves (PUVs). Eight parents participated in a semi-structured, individual telephone interview, with qualitative data collected and analysed thematically using NVivo11 software. Two main themes emerged as interconnecting aspects of parents' experiences: (1) trying to face the challenges and (2) learning to cope. Parents felt challenged by the need to attend to their child's medical care, while developing a bond with their baby, trying to maintain positivity for their child's future and managing the impact of the condition on their family. Nevertheless, parents developed strategies to cope with these challenges, such as seeking support, normalizing the experience and focusing on the positives. This preliminary understanding of parents' experiences provides direction for improving care pathways for infants with PUV and their parents as well as guides further research in this previously unexplored area. PMID- 29110520 TI - Parental concerns and attributions of food pickiness and its consequences for the parent-child relationship: A qualitative analysis. AB - A qualitative study was conducted to identify how parents describe and attribute their toddler's food pickiness, a common pediatric problem during childhood. Parental strategies to respond to picky behaviors were also explored in this study. Focus groups were used with 38 parents of children aged 18-38 months. Results highlighted several consequences of child pickiness such as parental concerns about child's growth and health, conflicts at mealtime, and feelings of guilt. Parents attributed food pickiness mainly as a manifestation of opposition and assertiveness by their child. Some strategies known to be effective were applied by parents (such as repeated exposure, modeling, co-preparing meals, and using a flavor-based approach) but some strategies that are counterproductive were also highlighted (such as rewards for eating). Parents need to be better informed about food pickiness and the strategies that help to overcome it. Understanding parental beliefs may help pediatricians to offer appropriate guidance adapted to parental experiences and feelings. PMID- 29110521 TI - What makes parents act and react? Parental views and considerations relating to 'child health' during infancy. AB - Lifestyle factors and behaviours are adopted very early in life and tend to persist throughout life. Considering that the parents are the primary gatekeepers for their child's health, there is a need to gain more knowledge and deeper understanding about what causes parents to act and react in order for early preventive efforts to have any effect. The aim was to explore the parental views and considerations concerning 'child health' among parents with infants 8-10 months old. The sample was strategic and 16 parents (aged 23-41) were recruited from three child health centres in Sweden. Open-ended interviews were conducted and a qualitative, manifest content analysis approach was utilized. The parents described the subject 'child health' as a large, multifaceted concept. Three categories emerged during data analysis: developing a sixth sense, being affected by perceptions and believing health and ill health as a continuum. The parents perceived food and feeding issues as one of the most worrying aspects and a significant indicator of 'child health'. In order to meet the parents on their turf, the 'healthy health message' conveyed needs to take the parental perspective into consideration rather than attempting to educate the parents from predetermined assumption, belief and values. PMID- 29110522 TI - Gender differences in the experience of pain dismissal in adolescence. AB - This study examined physician-generated pain dismissal experiences in adolescence between males and females. Young adults (ages 18-24, N = 178) with chronic or recurrent pain reported at least one pain dismissal experience in adolescence and answered a series of questions regarding the experience during this time period. Females were significantly more likely to report pain dismissal and a physician as the dismisser. Males were more likely to report that the dismisser expressed hostility toward them, feeling ambivalent regarding the dismissal experience, and a desire to avoid the dismisser. Females were more likely to report a desire to plead for understanding with the dismisser. Results suggest that female adolescents are more likely to report a pain dismissal experience with physicians, raising concerns that adolescent females may receive, or at least perceive, differential treatment for their chronic pain. PMID- 29110523 TI - Access to primary care child weight management programs: Urban parent barriers and facilitators to participation. AB - The prevalence and comorbidities of childhood obesity among low-income urban children are a significant health issue in the United States. Programs designed to assist families are underutilized. The aim of this study is to describe barriers and facilitators relevant to intervention program participation from the perspective of parents who have children who are overweight or obese. Systematic thematic analysis of focus groups and semi-structured interviews with parents from multiple urban pediatrics and family medicine practices were used to gather data. A framework analysis approach was used and a codebook of themes was developed. Transcripts were coded independently by the research team and consensus among researchers was reached. Forty-eight parents participated in the study. Perceived barriers to participation included (1) varied referral process (lack of follow-up or varying referral experience), (2) costs (time and program fee), (3) logistics (location and program schedule), and (4) child motivation. Perceived facilitators to participation included (1) systematic referral process (in-office referral and timely follow-up), (2) program content and organization, and (3) no cost. Multiple barriers and facilitators affect weight management program participation among families, which should be specifically targeted in future obesity interventions in order to effectively reach urban, minority parents and children. PMID- 29110525 TI - Behavioural correlates of energy drink consumption among adolescents: A review of the literature. AB - Despite regulatory measures on the labelling of energy drinks (EDs), their consumption among adolescents continues to grow in popularity, but teachers increasingly report significant behavioural concerns among students who disclose habitual ED consumption. A review of papers published between January 2010 and October 2016 was undertaken to determine whether an association between adverse behaviour and consumption of ED exists. Findings indicate that ED consumption among adolescents is associated with alcohol and substance use, risky behaviours and psychological states including sensation seeking, depression and anxiety symptoms. ED consumption impacts negatively on executive functions and increases hyperactivity/inattention symptoms among adolescents. An inverse association between ED consumption and sleep duration exists. The findings highlight the need for greater awareness of the potential risk of ED consumption among adolescents. PMID- 29110524 TI - The Faces Emotional Coping Scale as a self-reporting instrument for coping with needle-related procedures: An initial validation study with children treated for type 1 diabetes. AB - The aim of this study was to determine the concurrent and content validity, sensitivity and inter-rater reliability of the Faces Emotional Coping Scale (FECS) to evaluate the children's anticipation of the level of emotional coping in conjunction with a venepuncture. A total of 153 children with type 1 diabetes and 86 of their parents participated in the study. The age of the children, 76 of whom were boys, ranged from 7 to 18 years. The child and his or her parent reported the child's coping ability, and the child reported the pain intensity and unpleasantness of a venepuncture. The child also wrote a short narrative about his or her experience of the needle procedure. The FECS correlated negatively with the Coloured Analogue Scale and the Facial Affective Scale and positively with the FECS by proxy. The narratives of 90 children correlated negatively with the FECS. Younger children reported significantly lower scores than older children did regarding their ability to cope with a venepuncture. The children's scores on the FECS showed good agreement with the parents' scores. In this study, the FECS was deemed valid for measuring children's ability to cope with their emotions when undergoing needle-related procedures like venepuncture. PMID- 29110526 TI - Mental health screening of fathers attending early parenting services in Australia. AB - Paternal perinatal depression and anxiety is a common, though under-recognized mental health condition experienced by men during their transition to fatherhood. An opportunity to screen for paternal mental health issues occurs when parents present for assistance with the care of their baby at early parenting services (EPSs). There are 10 EPSs located across Australia that provide specialist, multidisciplinary interventions to support parents experiencing complex parenting difficulties. Using structured telephone interviews, this qualitative study explored the views of 18 professional staff from nine EPSs regarding screening, referral processes and acceptability of screening fathers for mental health issues. A thematic analysis revealed that most EPSs screened fathers for depression. Participants agreed screening was important and that routine approaches to screening would help normalize the process for both men and services. Despite this, no uniform, comprehensive approach to identifying the mental health needs of fathers was found. EPSs provide a unique opportunity to address the mental health needs of fathers. Results from this study point to the need for a national approach to the development of father-specific screening guidelines for EPSs to improve family well-being, in parallel to those informing the Australian National Perinatal Mental Health Initiative for mothers. PMID- 29110527 TI - Improving health in at-risk youth through Photovoice. AB - Photovoice is a practical method to allow at-risk youth to express the environmental influences in their lives at school, at home, and in their community. This project emerged from an interprofessional collaboration between social work and nursing that focused on school health. The purpose was to explore the factors influencing the mental and emotional health using photographs by students in a largely Hispanic middle school. Ten students were recruited and consented but only eight completed the project. The SHOWeD method was used to assist the students to formally reflect upon their photographs. Data analysis was conducted using content analysis to identify themes presented the students' reflections. The themes were staying healthy, stress dealing with anger/frustration, maintaining friendships and communication, recognizing bullying, and planning for the future. Reflections aided students to provide rich details about how the school environment influences their mental and emotional health. The use of Photovoice is a reasonable method for at-risk youth to explore and describe their environment. Nurses, social workers, parents, and school leaders can use the new knowledge about how the school environment influences the health of students to develop tools to support a healthy school and community environment. PMID- 29110528 TI - Parental conceptions of the rotavirus vaccine during implementation in Stockholm: A phenomenographic study. AB - In 2014, Stockholm became the first Swedish county to introduce the rotavirus vaccine, which is given from as early as six weeks of age. The aim of this study was to describe parental conceptions of rotavirus infection and vaccination during its implementation as part of the child immunization program, as their support is vital for any new vaccine. The study followed a descriptive, qualitative design with a phenomenographic approach. Ten in-depth interviews with parents were conducted in Stockholm County, transcribed and analyzed to describe qualitatively different conceptions of rotavirus infection and vaccination. Four main categories were identified: to vaccinate without doubt, hesitant to vaccinate, risky to vaccinate, and unnecessary to vaccinate. All the parents had in common the desire to protect their children from suffering, either by vaccinating their child in order to avoid rotavirus infection or by not vaccinating their child because of concerns about the side effects. It is important that child health-care professionals understand the variations of conceptions that influence the parents' decisions and that these conceptions may differ considerably. Individualized parental information about rotavirus infection and vaccination would help to achieve a successful implementation of the vaccination program. PMID- 29110529 TI - Impaired mobility associated with an increased likelihood of death in children: A systematic review. AB - Improved identification of children with an increased likelihood of death can support appropriate provision of integrated palliative care. This systematic review aims to consider immobility and the associated likelihood of death in children with disabilities, living in high-income countries. Two reviewers independently searched MEDLINE, Embase, Cochrane Library, OpenGrey and Science Citation Index (1990-2016) for studies that reported hazard ratios (HRs) and relative risk for the likelihood of death related to impaired mobility. Nine papers were included. Three studies reported functioning using the Gross Motor Function Classification Scale (GMFCS) and the remaining studies reported measures of functioning unique to the study. The strongest single prognostic factor for the likelihood of death was 'lack of sitting ability at 24 months', HR 44.4 (confidence interval (CI) 6.1-320.8) followed by GMFCS V HR 16.3 (CI 5.6-47.2) and 11.4 (CI 3.76-35.57) and 'not able to cruise by 24 months', HR 14.4 (CI 3.5 59.2). Immobility is associated with an increased risk of dying over study periods, but different referent groups make clinical interpretation challenging. Overall, the quality of evidence is moderate. The findings suggest that immobility can support identification of children who may benefit from integrated palliative care. PMID- 29110530 TI - Parenting children with Down syndrome: Societal influences. AB - Most studies of parenting children with Down syndrome (DS) have been conducted in industrialized countries. They suggest that sensitive communication on the part of professionals, and social support, can lead to acceptance and positive adjustments in the family. This study examined the impact of a diagnosis of DS on Ecuadorian families, in particular at how the diagnosis had been communicated and received, as well as the feelings and experiences which followed. Despite considerable progress in recent years, Ecuador is still marked by discriminatory attitudes which affect children with disabilities and their families, and by the persistence of widespread poverty. This qualitative study, conducted in Cuenca, Ecuador's third largest city, is based on a focus group discussion and four in depth interviews with Ecuadorian parents of DS children attending a specialist center in the city. The study shows that, reflecting the effects of status differences and lack of appropriate training, professionals rarely communicate a DS diagnosis in an appropriate manner. Further, it is shown that lack of social support, and the widespread stigmatization confronting children with DS and their families, hinder development of positive and empowering adjustments that would best serve the child's and the family's interest. PMID- 29110531 TI - The possibilities and challenges in providing pediatric spiritual care. AB - The purpose of this article was to present discussions on how pediatric nurses can perform spiritual care to children and adolescents and discuss the challenges of integrating such care in health-care settings. Based on the literature, the article presents an overview of spiritual care in pediatric settings highlighting the assessment of spirituality, expected outcomes, and the corresponding nursing interventions. Spiritual care provided to children and adolescents should take into account all aspects of the developmental stage, life experiences, and familiar and sociocultural contexts. Different approaches can be used to perform spiritual care. However, lack of knowledge and time are highlighted as the main challenges in integrating spiritual care into the clinical practice. Spiritual care is crucial to the well-being of children and adolescents in times of illness and hospitalization when the goal is to provide holistic care. PMID- 29110532 TI - Psychometric testing of the Turkish version of the Health Literacy for School Aged Children Scale. AB - This study aimed to assess the validity and reliability of the Turkish version of the Health Literacy for School-Aged Children (HLSAC-T) scale. This study was a cross-sectional and methodological design. The sample consisted of 563 sixth and ninth grade students in Izmir, Turkey. Data were collected with the socio demographic characteristics questionnaire, HLSAC-T, and Turkish version of the Adolescent Lifestyle Profile. Cronbach's alpha for the scale was .77 and item total correlations were between .49 and .61 ( p < .001). The model fit indices were determined to be the root mean square error of approximation at .035, the goodness of fit index at .99, and the comparative fit index at .99. The concordance validity and convergent validity were supported and the discriminant validity suggested that the scale successfully discriminated students who cared about healthy lifestyle from the students who did not. The HLSAC-T showed an adequate reliability and validity for determining the subjective health literacy of Turkish school-aged children. The results showed promise that the scale could be translated into other languages. PMID- 29110533 TI - Childhood language skills and adolescent self-esteem in preterm survivors. AB - Fifty-seven percent of children with poor language skills are affected by socio emotional problems. Despite the importance of language skills to interpersonal functioning and school performance, relatively little is known about how they affect self-esteem in adolescence. Data on youth at high risk for language problems (e.g. those born extremely low birth weight (ELBW; <1000 grams)) are even more scarce. This prospective study examined associations between language skills at age 8 and self-esteem during adolescence (12-16 years) in individuals born at ELBW ( N = 138) or normal birth weight (NBW; >2500 grams) ( N = 111). Participants' language skills were assessed using the Verbal Scale of the Wechsler Intelligence Scale for Children-Revised and the Token Test at age 8. In adolescence, participants completed the Harter Self-Perception Profile for Adolescents. Birth weight status was found to moderate associations between childhood language and adolescent global self-esteem (Token Test ( p = .006), Verbal Intelligence Quotient ( p = .033)) such that better language skills were associated with higher self-esteem in adolescent ELBW survivors, but not in NBW participants. Language skills may play a protective role in the development and maintenance of self-esteem in ELBW youth and could be an important target for optimizing their functioning, particularly before transitioning to the critical adolescent period. PMID- 29110534 TI - Flavonol glycosides from the fruits of Evodia rutaecarpa. AB - Two new flavonol glycosides, limocitrin 3-O-beta-D-xylopyranosyl(1->2)-beta-D glucopyranoside (1) and limocitrin 3-O[2-O-beta-D-xylopyranosyl-6-O-alpha-L rhamnopyranosyl]-beta-D-glucopyranoside (2), together with eight known analogs (3 10), were isolated from the fruits of Evodia rutaecarpa. Their structures were elucidated on the basis of spectroscopic analyses and chemical evidences. Meanwhile, Nrf2 inducing abilities of seven isolated compounds were evaluated, and compounds 1, 2, 6, 7, and 8 exhibited moderate effect on Nrf2. PMID- 29110535 TI - Dental stem cells in tooth regeneration and repair in the future. AB - INTRODUCTION: Human dental stem cells can be obtained from postnatal teeth, extracted wisdom teeth or exfoliated deciduous teeth. Due to their differentiation potential, these mesenchymal stem cells are promising for tooth repair. Therefore, the development of dental tissue regeneration represents a suitable but challenging, target for dental stem cell therapies. Areas covered: In this review, the authors provide an overview of human dental stem cells and their properties for regeneration medicine. Numerous preclinical studies have shown that dental stem cells improve bone augmentation and healing of periodontal diseases. Clinical trials are ongoing to validate the clinical feasibility of these approaches. Dental stem cells are also important for basic research. Expert opinion: Dental stem cells offer numerous advantages for tooth repair and regeneration. Data obtained from different studies are encouraging. In the next few years, investigations on dental stem cells in basic research, pre-clinical research and clinical studies will pave the way to optimizing patient-tailored treatments for repair and regeneration of dental tissues. PMID- 29110536 TI - Histone acetyltransferase encoded by NGG1 is required for morphological conversion and virulence of Candida albicans. AB - AIM: To assess the function of Ngg1 in Candida albicans and reveal the role of NGG1 in the morphological conversion and virulence of C. albicans. MATERIALS & METHODS: C. albicans NGG1 gene was deleted in the wild-type strain SC5314 and the function of Ngg1 was assessed by western blot analysis. The phenotypes and the virulence of the ngg1 mutants were examined. Microarray analysis was performed to explore the mechanism. RESULTS: The ngg1 mutants attenuated acetylated histone H3, obviously reduced filamentous growth and showed significantly diminished pathogenicity in all the infection models. CONCLUSION: This study suggested the histone acetyltransferase activity of C. albicans Ngg1 and revealed the important role of NGG1 in morphological conversion and virulence of C. albicans. [Formula: see text]. PMID- 29110538 TI - Victims' Attitudes Toward Sex Offenders and Sex Offender Legislation. AB - It is commonly assumed that victims of sexual abuse feel more negatively toward sex offenders and advocate for harsher punishments than individuals who have not been victimized. This belief was examined by comparing attitudes toward sex offenders and their treatment, support of registration, notification, and residence restriction policies, as well as general knowledge about sex offenders between a sample of 129 individuals who reported sexual victimization and a sample of 841 individuals who did not report sexual victimization. Overall, we found that victims of sexual abuse reported more positive attitudes toward sex offenders and were more supportive of mandated treatment compared with nonvictims. However, while victims showed decreased support for the community notification laws, there were no differences in support of residence restrictions laws compared with those who reported no victimization. Finally, knowledge about sex offenders predicted attitudes regardless of victim status. These findings are discussed as they pertain to sex offender treatment and legislation. PMID- 29110537 TI - Novel c(RGDyK)-based conjugates of POPAM and 5-fluorouracil for integrin-targeted cancer therapy. AB - AIM: Alkylating agents and antimetabolites are cytotoxic drugs commonly used in cancer treatment. These medications are often associated with serious side effects on normal tissues and organs. METHODOLOGY: To improve the pharmacological profile of the alkylating agent POPAM and the antimetabolite 5-fluorouracil, novel integrin-targeted delivery systems based on c(RGDyK) were successfully synthesized. The new conjugates were tested in vitro against different cancer cells such as PC3, SKOV3, A549, MCF7 and MBA-MB-321. RESULTS & CONCLUSION: The c(RGDyK) conjugates of POPAM demonstrated better inhibitory effects and selectivity compared with c(RGDyK) and POPAM. The c(RGDyK) conjugates of 5-FUA demonstrated diverse inhibitory effects compared with c(RGDyK) and 5-FUA related to the levels of integrin expression, the conjugate stability and sensitivity of cancer cells to 5-FUA. PMID- 29110539 TI - Nutritional and bioactive compounds of commercialized algae powders used as food supplements. AB - The main nutritional/bioactive compounds (protein; aminoacids, AA; fucose; minerals; vitamins B12 and C; and total phenolic content, TPC) of nine commercial algae powders, used as food supplements, were studied. Undaria pinnatifida showed the highest protein/aminoacid contents (51.6/54.4 g 100 g-1). Among brown macroalgae, Himanthalia elongata showed the highest fucose content (26.3 g kg-1) followed by Laminaria ochroleuca (22.5 g kg-1). Mineral contents of 15-24% were observed in the algae, being particularly excellent sources of iodine (69.0-472.0 mg kg-1). Porphyra spp. and Palmaria palmata showed the highest vitamin B12 contents (667-674 ug kg-1). Vitamin C ranged among 490.4-711.8 mg kg-1. H. elongata showed the highest total phenolic content (14.0 g kg-1). In conclusion, the studied algae are excellent sources of protein, AA, minerals, vitamin C and some of them presented particularly high vitamin B12 and fucose contents, which may have a potential use as food supplements. PMID- 29110540 TI - A Qualitative Analysis of Selected Stakeholders' Viewpoints on Tobacco Control in Nigeria. AB - Nigeria is a signatory to the Framework Convention on Tobacco Control. However, tobacco control efforts have been fraught with challenges. These challenges cannot be presumed to be independent of tobacco industry manipulation. We examined submissions and viewpoints from prominent tobacco control stakeholders across social, administrative, and political strata to identify convergence with tobacco industry viewpoints. We illustrate how these convergences pose a threat to effective tobacco control in Nigeria. A thematic analysis of stakeholder viewpoints was conducted on submissions to the national assembly during the Tobacco Control Bill public hearings and various industry documents. Areas of convergence with tobacco industry narratives were then explored. Significant convergence in views was observed between government agencies, social groups, and the tobacco industry. These were for narratives on constitution of a National Tobacco Control Committee, use of automated vending machines, designation of smoking areas, report to regulatory agencies, and negative effect of tobacco control on trade and poverty. There was evidence of tobacco industry interference in tobacco control efforts, which manifested in some prominent tobacco control stakeholders adopting the narratives of the tobacco industry. We advocate a constant watchfulness over the activities of these stakeholders and a proactive engagement with evidence-based antitobacco dialogue. PMID- 29110541 TI - Three new cytotoxic oleanane triterpenoid saponins from Cylindrokelupha dalatensis. AB - Three new minor oleanane triterpenoid saponins, cylindrosides B (1), C (2), and D (3), were isolated from the seed of Cylindrokelupha dalatensis using chromatographic method. Their structures were established on the basis of the chemical and spectroscopic evidences. They displayed significant antitumor activity in vitro against HL60 cancer cell lines and IC50 values were 7.15 +/- 0.63, 10.07 +/- 0.97, and 4.74 +/- 0.57 MUM, respectively, by MTT method. PMID- 29110542 TI - Allergen immunotherapy in atopic dermatitis. AB - INTRODUCTION: Atopic dermatitis (AD) is a chronic relapsing skin disease, characterized by flare-up due to the exposure to allergens in patients sensitized to them. Currently, therapy of AD is mainly based on symptomatic treatment and avoidance of irritating/allergenic factors, house dust mites being particularly important. Allergen immunotherapy (AIT) is suggested to be the only etiologic treatment, to modify the natural history of the disease. Areas covered: The aim of this review is investigating the putative role of AIT in AD through the evaluation of the most recent scientific literature. Several studies have been conducted since 1970, with promising results in improving the clinical outcome of AD, but they often lack the necessary scientific rigorousness. Moreover, heterogeneity of the studies makes it very difficult to compare and to analyze data in a systematic review or meta-analysis. Expert commentary: As a result of the above-mentioned limitations, the treatment of AD with causative aeroallergen can nowadays be suggested only as an add-on therapy in selected patients who are non-responsive to the traditional therapy. PMID- 29110543 TI - Police Legitimacy and Compliance With the Law Among Chinese Youth. AB - The process-based model of policing garnered considerable support in the discourse on police legitimacy. However, findings are largely based on Western contexts, and little attention has been paid to the model advanced by Tyler that police legitimacy helps promote compliance. Using a high school sample ( N = 711) from China, we follow Tankebe's operationalization and examine the role of legitimacy in youth support for the police and whether legitimacy helps predict compliance with the law. Findings indicate that procedural justice and shared values are strong predictors of youth support to the police, and this support positively predicts compliance with the law. Distributive fairness exerts an independent effect on compliance while having been questioned by the police is negatively related to compliance. PMID- 29110544 TI - Containment strategies to address the expanding threat of multidrug-resistant Candida auris. AB - INTRODUCTION: Candida auris is an emerging multidrug resistant human yeast pathogen associated with nosocomial transmission and high mortality. The organism can be a challenge to diagnose, may be even more difficult to treat, and continues to pose an expanding threat to patients. Areas covered: Our medical center and others in the surrounding area have seen a concerning rise in confirmed cases of C. auris infection and substantial resources have been dedicated to containment measures. We draw on our in vitro and in vivo work with this organism to examine the most effective ways to curb the current outbreak. Expert commentary: We explore novel strategies to halt the spread C. auris, including enhanced molecular diagnostics, novel therapeutics, and epidemiologic studies to determine risk factors for infection and transmission. PMID- 29110546 TI - Problem Gambling Among Australian Male Prisoners: Lifetime Prevalence, Help Seeking, and Association With Incarceration and Aboriginality. AB - Prisoners represent a group containing the highest problem gambling (PG) rate found in any population. PG is of particular concern among Indigenous Australians. Little data exist concerning PG rates among Indigenous Australian prisoners. The present study aimed to address this gap in the literature by examining the lifetime prevalence of PG among male prisoners, whilst identifying prisoners of Aboriginal background. The EIGHT Gambling Screen (Early Intervention Gambling Health Test) was administered to 296 prisoners across three male prisons in South Australia. Previous help-seeking behaviour and forms of gambling were also examined. Sixty percent of prisoners indicated a lifetime prevalence of PG with 18% reporting they were incarcerated due to offending relating to their gambling problem. Indigenous Australian prisoners indicated a significantly higher prevalence of PG (75%) than non-Indigenous prisoners (57%) and reported less than half the rate of help-seeking. Given the high levels of PG and overall low rates of help-seeking among prisoners, prisons may provide an important opportunity to engage this high-risk population with effective treatment programs, in particular culturally appropriate targeted interventions for Australian Indigenous prisoners. PMID- 29110545 TI - Serum from CCl4-induced acute rat injury model induces differentiation of ADSCs towards hepatic cells and reduces liver fibrosis. AB - Cellular therapies hold promise to alleviate liver diseases. This study explored the potential of allogenic serum isolated from rat with acute CCl4 injury to differentiate adipose derived stem cells (ADSCs) towards hepatic lineage. Acute liver injury was induced by CCl4 which caused significant increase in serum levels of VEGF, SDF1alpha and EGF. ADSCs were preconditioned with 3% serum isolated from normal and acute liver injury models. ADSCs showed enhanced expression of hepatic markers (AFP, albumin, CK8 and CK19). These differentiated ADSCs were transplanted intra-hepatically in CCl4-induced liver fibrosis model. After one month of transplantation, fibrosis and liver functions (alkaline phosphatase, ALAT and bilirubin) showed marked improvement in acute injury group. Elevated expression of hepatic (AFP, albumin, CK 18 and HNF4a) and pro survival markers (PCNA and VEGF) and improvement in liver architecture as deduced from results of alpha smooth muscle actin, Sirius red and Masson's trichome staining was observed. PMID- 29110547 TI - Robotic exoskeletons for reengaging in everyday activities: promises, pitfalls, and opportunities. AB - PURPOSE: Media images and marketing materials suggest a future in which individuals with spinal cord injury (SCI) can utilize robotic exoskeletons to reengage in everyday activities, yet these narratives may not align with the current technological realities. The purpose of this paper is to present and describe the current use of robotic exoskeletons in rehabilitation and home settings and discuss the benefits and limitations of the devices. MATERIALS AND METHODS: We provide an overview of the features and limitations of the four robotic exoskeleton products (EKSO Bionics, ReWalk, Rex Bionics, and Indego) that are currently being used in in the United States in rehabilitation settings. We follow by suggesting ways that these devices fall short of fulfilling the promise of reengage in everyday activities in real-world life contexts. RESULTS AND DISCUSSION: Available devices appear to be better suited for rehabilitation settings than for home use. Device weight, the need for upper extremity supports, supervision requirements, and a limited range of movements are all issues that limit functionality and restrict opportunities for using such devices in real world contexts. Designing the next generation of exoskeletons to be more useful in everyday life will require further collaboration among engineers, clinicians, and patients. Implications for Rehabilitation Exoskeletons offer the promise of allowing individuals with neurological injury to reengage in everyday activities from a standing position. Several exoskeleton devices are currently available for use in the United States. Weight of exoskeleton devices, the need for upper extremity supports, supervision requirements of hone units, and a limited range of movements are issues that restrict opportunities for using such devices in real-world contexts. Further development of exoskeleton technologies is warranted to improve the devices for real-world use. PMID- 29110548 TI - New targets and therapies for gastrointestinal stromal tumors. AB - INTRODUCTION: The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence. Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics. Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using 'liquid biopsy'. PMID- 29110549 TI - A 104-week pulmonary toxicity assessment of long and short single-wall carbon nanotubes after a single intratracheal instillation in rats. AB - We compared long-term pulmonary toxicities after a single intratracheal instillation of two types of dispersed single-wall carbon nanotubes (SWCNTs), namely, those with relatively long or short linear shapes with average lengths of 8.6 and 0.55 um, respectively. Both types of SWCNTs were instilled intratracheally in male F344 rats at 0.2 or 1.0 mg/kg (long SWCNTs) or 1.0 mg/kg (short SWCNTs). Pulmonary responses were characterized at 26, 52 and 104 weeks after a single instillation. Inflammatory changes, test substance deposition, test substance engulfment by macrophages, and alveolar wall fibrosis were observed in the lungs of almost all test rats at 52 and 104 weeks after short nanotube instillation. The incidences of these changes were much lower in the long nanotube-treated groups. In almost all rats of the long nanotube-treated groups, fibrosis and epithelium loss in the terminal bronchiole with test substance deposition were observed. These bronchiolar changes were not observed after administering short nanotubes. Both bronchiolo-alveolar adenoma and carcinoma were found in the negative-control group, the high-dose long-nanotube group, and the short-nanotube group at 104 weeks post-instillation, although the incidences were not statistically different. The genotoxicity of the SWCNTs was also evaluated by performing in vivo comet assays with lung cells obtained 26 weeks post-instillation. No significant changes in the percent tail deoxyribonucleic acid were found in any group. These findings suggested that most long SWCNTs were deposited at the terminal bronchioles and that a considerable amount of short SWCNTs reached the alveolus, resulting in chronic inflammatory responses, but no genotoxicity in the lungs. PMID- 29110551 TI - Management of osseous cystic echinococcosis. AB - INTRODUCTION: Osseous cystic echinococcosis (CE) is one of the most complicated and devastating conditions caused by Echinococcus granulosus. Its management is difficult and there is scant literature about it. Areas covered: A literature review was performed to provide an update on its diagnosis, treatment and follow up. Expert commentary: In most cases diagnosis of osseous CE can only be confirmed by surgery. Osseous CE should be managed by experienced physicians and addressed as a chronic disease with therapies must be aimed at controlling the disease and its sequels or complications, rather than with a curative intent. PMID- 29110552 TI - Antibiotic Resistance in Diabetic Foot Soft Tissue Infections: A Series From Greece. AB - Diabetic foot infections are a common and serious problem for all health systems worldwide. The aim of this study was to examine the resistance to antibiotics of microorganisms isolated from infected soft tissues of diabetic foot ulcers, using tissue cultures. We included 113 consecutive patients (70 men, 43 women) with a mean age of 66.4 +/- 11.2 years and a mean diabetes duration of 14.4 +/- 7.6 years presenting with diabetic foot soft tissue infections. Generally, no high antibiotic resistance was observed. Piperacillin-tazobactam exhibited the lowest resistance in Pseudomonas, as well as in the other Gram-negative pathogens. In methicillin-resistant Staphylococcus aureus isolates, there was no resistance to anti-Staphylococcus agents. Of note, clindamycin, erythromycin, and amoxycillin/clavulanic acid exhibited high resistance in Gram-positive cocci. These results suggest that antibiotic resistance in infected diabetic foot ulcers in our area is not high and they are anticipated to prove potentially useful in the initial choice of antibiotic regimen. PMID- 29110553 TI - The Punitive Woman? Gender Differences in Public Attitudes Toward Parole Among an Australian Sample. AB - Research exploring gender differences in public attitudes toward parole is limited, despite a large body of literature showing that men and women have diverging views on other criminal justice issues, including capital punishment and offender rehabilitation and treatment. Drawing on an Australian national survey of community views on parole, the current study examines whether men and women differ in their support for the release of prisoners on parole. The results indicate that gender does predict parole attitudes, with Australian women significantly more likely to hold nonsupportive views on parole than Australian men. The results also reveal that women are more likely to take a neutral position toward parole, rather than supporting it. Together, these findings indicate there may be something about being a woman in Australia that prevents one from being willing to support the early release of prisoners. The implications of these findings for future research are discussed. PMID- 29110554 TI - Proceedings of the 2017 Autumn Meeting of the Society of British Neurological Surgeons. PMID- 29110555 TI - Oxidative stress or redox signalling - new insights into the effects of a proprietary multifunctional botanical dietary supplement. AB - Recent interest has focused on maintenance of healthy levels of redox signalling and the related oxidants; these parameters are crucial for providing us with concrete nutritional targets that may help us to better understand and maintain "optimal health". Following the above hypothesis, we performed a pilot double blind, crossover, placebo-controlled, single dose study to measure the dose dependent effects of a proprietary plant-based dietary supplement labelled here as S7 (SPECTRA7), related to how it affected the cellular metabolic index (CMI) in healthy human participants (n = 8). We demonstrated using the electron spin resonance/electron paramagnetic resonance spectrometer NOXYSCAN that the administration S7 resulted in statistically significant, long-term, dose dependent inhibition of mitochondrial and cellular reactive oxygen species generation by as much as 9.2 or 17.7% as well as 12.0 or 14.8% inhibition in extracellular nicotinamide-dinucleotide-phosphate oxidase system-dependent generation of O2*-, and 9.5 or 44.5% inhibition of extracellular H2O2 formation. This was reflected with dose-dependent 13.4 or 17.6% inhibition of tumour necrosis factor alpha induced cellular inflammatory resistance and also 1.7 or 2.3-times increases of bioavailable NO concentration. In this pilot study, we demonstrated the ability of a natural supplement to affect cellular redox signalling, which is considered by many researchers as oxidative stress. The design and activity of this proprietary plant-based material, in combination with the newly developed "CMI" test, demonstrates the potential of using dietary supplements to modulate redox signalling. This opens the door to future research into the use of S7 for modulation of inflammatory markers, for sports endurance or recovery applications. PMID- 29110556 TI - The impact of biologic agents on health-related quality of life outcomes in patients with psoriasis. AB - INTRODUCTION: Psoriasis is a common, immune-mediated skin disease often associated with significant physical and psychosocial impairment. Antipsoriatic biologic agents offer patients unparalleled treatment potential in regard to greater skin clearance and overall improved quality of life. Evaluation of the therapeutic efficacy of biologic agents on the full psoriasis disease burden must account for their impact on both physical symptoms, as well as patient-reported, health-related quality of life (HRQoL) measurements. Areas covered: Results from numerous clinical trials demonstrate the significant clinical efficacy of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) and the interleukin (IL)-12/23 and IL-17 immune pathways. However, relatively limited data is available evaluating their full effect on quality of life outcomes. This review will discuss the most relevant and up-to-date clinical data on HRQoL measurements related to treatment with these aforementioned biologic agents. Expert commentary: Patient-reported outcomes (i.e. Dermatology Life Quality Index) are being used with increasing frequency in clinical trials, and provide valuable information on the impact of psoriasis on numerous aspects of day-to-day living. These outcomes must also be incorporated in clinical practice, in addition to physical assessment of disease severity, treatment decisions, and therapeutic response in the psoriasis patient population. PMID- 29110557 TI - Post discharge issues identified by a call-back program: identifying improvement opportunities. AB - OBJECTIVES: The period following discharge from the hospital is one of heightened vulnerability. Discharge instructions serve as a guide during this transition. Yet, clinicians receive little feedback on the quality of this document that ties into the patients' experience. We reviewed the issues voiced by discharged patients via a call-back program and compared them to the discharge instructions they had received. METHODS: At our institution, patients receive an automated call forty-eight hours following discharge inquiring about progress. If indicated by the response to the call, they are directed to a nurse who assists with problem solving. We reviewed the nursing documentation of these encounters for a period of nine months. The issues voiced were grouped into five categories: communication, medications, durable medical equipment/therapies, follow up and new or ongoing symptoms. The discharge instructions given to each patient were reviewed. We retrieved data on the number of discharges from each specialty from the hospital over the same period. RESULTS: A total of 592 patients voiced 685 issues. The numbers of patients discharged from medical or surgical services identified as having issues via the call-back line paralleled the proportions discharged from medical and surgical services from the hospital during the same period. Nearly a quarter of the issues discussed had been addressed in the discharge instructions. The most common category of issues was related to communication deficits including missing or incomplete information which made it difficult for the patient to enact or understand the plan of care. Medication prescription related issues were the next most common. Resource barriers and questions surrounding medications were often unaddressed. CONCLUSIONS: Post discharge issues affect patients discharged from all services equally. Data from call back programs may provide actionable targets for improvement, identify the inpatient team's 'blind spots' and be used to provide feedback to clinicians. PMID- 29110558 TI - Being a donor-child: wishes for parental support, peer support and counseling. AB - OBJECTIVES: We aimed at exploring the wishes of Dutch donor-conceived offspring for parental support, peer support and counseling and sought to contribute to the improvement of health care for all parties involved with assisted reproductive technologies. METHODS: We held semi-structured in-depth interviews with 24 donor conceived offspring (Mage = 26.9, range 17-41) born within father-mother, two mother and single mother families. The majority of the donor offspring was conceived with semen of anonymous donors. All offspring were recruited by network organizations and snowball sampling. The interviews were fully transcribed and analyzed using the constant comparative method. RESULTS: Donor-conceived offspring wished that their parents had talked openly about donor conception and had missed parental support. They wished that their parents would have received counseling before donor sperm treatment on how to talk with their children about donor conception in several stages of life. They valued the availability of peer contact to exchange stories with other donor-conceived offspring and would have liked assistance in getting access to trustworthy information about characteristics and identifying information of their donor. Donor-conceived offspring wished to know where to find specialist counseling when needed. CONCLUSIONS: Peer support and counseling by professionals for donor-conceived offspring should be available for those who need it. The findings also support professional counseling for intended parents before treatment to improve parental support for donor-children. PMID- 29110559 TI - Injury Among Home Care Workers in Washington State. AB - Home Care Aides (HCAs) have nearly four times the rate of injury as the general U.S. work force. In 2015, the Service Employees International Union 775 Benefits Group conducted a health and safety survey with 672 HCAs in Washington State. The goal was to identify the risk factors for injury and to better assess injury rates through self-report. Quantitative analyses assessed injury prevalence and barriers in reporting injury. Overall, 13 percent responded that they had ever had an injury that required medical attention while working as an HCA. These rates are significantly higher for HCAs employed by home care agencies compared with HCAs who work independently. Over a third reported moderate to high levels of hesitancy in reporting an on-the-job injury; these rates were even higher for independent providers. Study findings suggest that HCAs are well informed about appropriate next steps following workplace injury, but strong barriers may prevent them from attempting the reporting process. PMID- 29110560 TI - The Job Content, Context, and Requirements of Regulated Home-Based Childcare Workers. AB - Contrary to a large and growing literature on center-based childcare workers, we know little about the work and health experiences of those providing childcare services in their homes. This study examines the job content, context, and requirements of regulated Home-Based Childcare workers in Canada. It is based on the qualitative analysis of eleven individual semistructured interviews. These workers perform business administration tasks and more housekeeping and domestic work than those in the center-based childcare, which affect their health and well being. In addition, they reported factors related to the context and the content of their job such as the high physical and mental efforts, the absence of contact with other adults during working hours, the lack of external help, the exposure to noise and bad odors, the interference of work with personal and family life, the precarious remuneration, and the lack of benefits as potential factors that may affect their health. PMID- 29110561 TI - Efficacy of zonisamide on interictal electroencephalography in familial spontaneous epileptic cats. AB - Objectives The effectiveness of zonisamide (ZNS) against spontaneous epilepsy in cats has not yet been described. The purpose of this study was to investigate the effect of ZNS on interictal paroxysmal discharges (PDs) using scalp electroencephalography (EEG) in familial spontaneous epileptic cats (FSECs). Methods Eight FSECs were evaluated (six males and two females). Scalp EEG measurements were performed once a week for 3 weeks before ZNS administration (Pre-ZNS). Thereafter, administration of ZNS was started and an adjustment period was instituted until the drug in plasma achieved the steady state. When ZNS in plasma was confirmed to be within 10-40 MUg/ml, scalp EEG measurements were performed once a week for 3 weeks (Post-ZNS). The number of PDs (counts/min) were compared between Pre-ZNS and Post-ZNS treatment. Results The median number of PDs for Pre-ZNS and Post-ZNS were 0.43/min (0.13-0.82/min) and 0.28/min (0.07 0.87/min), respectively. The number of PDs Post-ZNS was significantly reduced compared with Pre-ZNS ( P = 0.02). Conclusions and relevance This study showed that ZNS, within the recommended therapeutic range suggested for use in humans and dogs (10-40 ug/ml), reduced the number of PDs recorded on EEG in FSECs that are considered a model for cats with idiopathic epilepsy. Although phenobarbital is the antiepileptic drug of choice for epileptic cats, the results of this research provide evidence to support the use of ZNS in cats with phenobarbital resistant epilepsy or for cats that cannot use phenobarbital due to adverse side effects. PMID- 29110562 TI - Report of the 13th International Family Nursing Conference: The Art and Science of Family Nursing: Transforming Health for Families, Pamplona, Spain, 2017. PMID- 29110563 TI - Increased Beta Activity Links to Impaired Emotional Control in ADHD Adults With High IQ. AB - OBJECTIVE: The present study investigated the neuropathology of everyday-life executive function (EF) deficits in adults with ADHD with high IQ. METHOD: Forty adults with ADHD with an IQ >= 120 and 40 controls were recruited. Ecological EFs were measured, and eyes-closed Electroencephalograph (EEG) signals were recorded during a resting-state condition; EEG power and correlations with impaired EFs were analyzed. RESULTS: Compared with controls, the ADHD group showed higher scores on all clusters of EF. The ADHD group showed globally increased theta, globally decreased alpha, and increased central beta activity. In the ADHD group, central beta power was significantly related to emotional control ratings, while no such correlation was evident in the control group. CONCLUSION: The results suggest that resting-state beta activity might be involved in the neuropathology of emotional control in adults with ADHD with high IQ. PMID- 29110564 TI - Resilience Among Nepali Widows After the Death of a Spouse: "That Was My Past and Now I Have to See My Present". AB - Responses to the death of a spouse vary; although some are at increased risk of poorer physical and mental health outcomes, others have more resilient responses. In light of the limited scope of research on widows' experiences in Nepal, a setting where widows are often marginalized, we explore themes of resilience in Nepali widows' lives. Drawing from a larger qualitative study of grief and widowhood, a thematic narrative analysis was performed on narratives from four widows that reflected resilient outcomes. Individual assets and social resources contributed to these widows' resilient outcomes. Forgetting, acceptance, and moving forward were complemented by confidence and strength. Social support and social participation were key to widows' resilient outcomes. These four narratives reflect the sociocultural context that shape widows' resilient outcomes in Nepal. Future studies on the emergent themes from this exploratory study will help identify how best to encourage resilient outcomes among widows. PMID- 29110565 TI - Impact of Biopsy Modality on the Management of Cutaneous Melanoma of the Head and Neck. AB - Objective The purpose of this study was to examine how biopsy modality affects the treatment course and outcomes of patients with cutaneous melanoma of the head and neck. Specifically, we investigated if partial biopsy techniques are associated with positive margins on definitive wide local excision (DWLE), the need for early reoperation to obtain adequate margins or sentinel lymph node biopsy, and survival. Study Design Retrospective case series. Setting Tertiary care academic center. Subjects and Methods Subjects (N = 170) included all patients who were surgically treated for primary cutaneous melanoma of the head and neck at the University of Missouri-Columbia between January 1, 2000, and December 31, 2015. For analysis, patients were divided into 4 groups based on biopsy modality: shave (n = 61), excisional (n = 62), punch (n = 33), and incisional (n = 14). Results The shave biopsy group ( P = .0324) and the punch biopsy group ( P = .0479) were significantly more likely to have positive margins on DWLE. The shave biopsy group ( P = .0042) and the punch biopsy group ( P = .0479) were also significantly more likely to need early reoperation. The mean number of sentinel nodes and incidence of positive sentinel nodes detected on pathologic examination did not differ significantly across biopsy modality ( P = .3600). Overall survival ( P = .4605) and disease-free survival ( P = .5011) did not differ significantly among the groups. Conclusions Patients diagnosed with shave and punch biopsy techniques are significantly more likely to have positive margins after DWLE and more frequently require early reoperation. Biopsy modality does not appear to influence the number of sentinel nodes detected, the incidence of detecting regional metastases in sentinel nodes, the overall survival, or the disease-free survival. PMID- 29110566 TI - Predicting the Outcome after Acute Unilateral Vestibulopathy: Analysis of Vestibulo-ocular Reflex Gain and Catch-up Saccades. AB - Objectives (1) To describe the relationships among the main instrumental features characterizing an acute unilateral vestibulopathy and (2) to clarify the role of the video head impulse test in predicting the development of chronic vestibular insufficiency. Study Design Case series with chart review. Setting Tertiary referral center. Subjects and Methods Sixty patients suffering from acute unilateral vestibulopathy were retrospectively analyzed: 30 who recovered spontaneously (group 1) and 30 who needed a vestibular rehabilitation program (group 2). The main outcome measures included Dizziness Handicap Inventory score, canal paresis, high-velocity vestibulo-oculomotor reflex gain, and catch-up saccade parameters. The tests were all performed between 4 and 8 weeks from the onset of symptoms. Results The high-velocity vestibulo-oculomotor reflex gain correlated with the Dizziness Handicap Inventory score ( P = .004), with the amplitude of covert and overt saccades ( P < .001), and with the prevalence of overt saccades ( P < .001). Patients in need for vestibular rehabilitation programs had a significantly lower gain ( P < .001) and a higher prevalence and amplitude of overt saccades ( P = .002 and P = .008, respectively). Conversely, we found no differences in terms of response to the caloric test ( P = .359). Conclusions Lower values of high-velocity vestibulo-oculomotor reflex gain and a high prevalence of overt saccades are related to a worse prognosis after acute unilateral vestibulopathy. This is of great interest to clinicians in identifying which patients are less likely to recover and more likely to need a vestibular rehabilitation program. PMID- 29110567 TI - Efficacy and tolerability of a new ibuprofen 200mg plaster in patients with acute sports-related traumatic blunt soft tissue injury/contusion. AB - BACKGROUND: Ibuprofen is used for the treatment of non-serious pain. This study assessed the efficacy and safety of a new ibuprofen plaster for the treatment of pain associated with acute sports impact injuries/contusions. METHODS: In this randomised, double-blind, multi-centre, placebo controlled, parallel group study, adults (n = 130; 18-58 years of age) diagnosed with acute sports-related blunt soft tissue injury/contusion were randomized to receive either ibuprofen 200 mg plaster or placebo plaster. Plasters were administered once daily for five consecutive days. The primary assessment was area under the visual analogue scale (VAS) of pain on movement (POM) over 0 to three days (VAS AUC0-3d). Other endpoints included algometry AUC from 0 to three days (AUC0-3d) and 0 to five days (AUC0-5d), to evaluate improvement of sensitivity at the injured site, and patient and investigator global assessment of efficacy. Safety was monitored throughout the study. RESULTS: The ibuprofen plaster resulted in superior reduction in AUC0-3d compared with placebo; the Least Squares (LS) mean difference was 662.82 mm*h in favour of the ibuprofen 200mg plaster (P = 0.0011). The greater improvement in VAS AUC of POM was also observed after 12 h, 24 h, and five days of therapy. Tenderness also significantly improved with the ibuprofen plaster compared with placebo; LS mean difference in algometry/tenderness AUC0-3d was 1.87 N/cm2*d and AUC0-5d was 1.87 N/cm2*d (P values <=0.0004). At all study timepoints, a greater percentage of patients and investigators rated the effectiveness of the ibuprofen 200 mg plaster as good/excellent than the placebo plaster. Treatment-emergent adverse events for the ibuprofen plaster were few (<=1.5%) and were mild in severity. CONCLUSIONS: The results of this study indicate 200 mg plaster is effective and safe for the treatment of pain due to acute sports-related traumatic blunt soft tissue injury/contusion in adults. PMID- 29110568 TI - Foxtail Ingestion in an Asymptomatic Child: A True Emergency? PMID- 29110569 TI - Beliefs about smoking-related lung cancer risk among low socioeconomic individuals: the role of smoking experience and interpersonal communication. AB - INTRODUCTION: Previous research has documented that smoking prevalence is generally high among low socioeconomic groups and that tobacco industries continue to target these population groups. However, little research has investigated the beliefs of individuals with low socioeconomic position (SEP) about the association between smoking and cancer risks. In this study, we examined beliefs about smoking-related lung cancer risk and the role of smoking experience, mass media exposure and health-related interpersonal communication among a sample of low SEP population. METHODS: Data were gathered from 324 urban poor recruited from adult education centers in the greater Boston area, Massachusetts, USA as part of a larger project called Click to Connect. While we collected a variety of data at baseline and follow-up, the data for this study come from the baseline survey alone. RESULTS: We found that individuals with smoking experience tend to be better than those without in perceiving the lung cancer risks of smoking. Moreover, we found that health-related interpersonal communication with friends and family members is positively associated with beliefs about the link between smoking and lung cancer. CONCLUSION: Our findings suggest that low SEP individuals with smoking experience might be more exposed to anti-tobacco messages than are low SEP individuals without smoking experience. This could suggest that anti-tobacco interventions thus far may have done very little in raising the awareness of low SEP nonsmokers about the dangers of smoking and that they may have little potential to avert the initiation of smoking in this population. PMID- 29110570 TI - So pretty! The neural correlates of self-other vs familiar-other attractiveness comparisons. AB - Previous research has demonstrated that comparing two persons activates a frontoparietal network associated with numbers and nonsocial magnitudes. However, it is unclear whether this network is also recruited by comparisons involving the self. Self-reflection engages self-serving motivations (e.g., the maintenance of a positive self-image) and is associated with specific brain structures, such as the medial prefrontal cortex (MPFC), the anterior insula (AI) and the anterior cingulate cortex (ACC). Self-other comparisons may thus rely on distinct neural activity. To clarify this question, we used fMRI and asked female participants to compare their own attractiveness (or the attractiveness of a familiar woman) to pictures of unknown women. Participants were slower for comparisons with targets whose attractiveness was similar to their own (or their familiar other). Yet although this behavioral result resembles the distance effect reported for nonsocial magnitudes, at the brain level, it was linked to the activity of the AI, the ACC and the MPFC. The effect of distance in these regions was stronger for self-other than familiar-other comparisons. We interpret these results in relation to previous literature in social psychology and social neuroscience. PMID- 29110571 TI - IgG4-related disease. PMID- 29110572 TI - Tracheostomy as a Comfort Measure in Children With Life-Limiting Conditions. AB - Palliative care for children who can expect only a short life has expanded over the last decade. Greater understanding of the measures required to ensure comfort and acceptable quality of life within the critical care environment has grown in tandem. Some more invasive interventions may be considered a "step too far" by some practitioners, including feeding gastrostomy, contracture release, and tracheostomy. Tracheostomy can facilitate a number of measures, which may enhance the brief life of the child and their family. However, tracheostomy is associated with some challenges, which may make it less suitable for some families. We discuss 3 cases where this intervention was carried out. PMID- 29110573 TI - The Impact of Integrated Multidisciplinary Palliative Care Program on Symptoms in Patients at the Palliative Care Ward-An Audit and a Protocol of Prospective Controlled Investigation. AB - An integrated multidisciplinary palliative care (IMPC) program is a promising tool to improve symptom control in patients at the end of life. The aim was to study the feasibility of the IMPC program in patients at the palliative care (PC) ward. A retrospective audit, using the extended Edmonton Symptom Assessment Scale (ESAS), was conducted on the PC ward of the university hospital. Consecutive patients who were admitted for the IMPC program during 1 year were considered. One hundred forty-eight cases (93% with underlying cancer) were analyzed. The intensity of pain levels, nausea, vomiting, shortness of breath, and sleep disorders decreased at least by 50% ( P < .0001) during the 13 (median) days of IMPC. Integrated multidisciplinary PC program was associated with symptom improvements in patients at the PC ward. The information generated supports sample size calculation for a prospective controlled trial. PMID- 29110574 TI - Comparison of Medical Therapy Alone to Medical Therapy with Surgical Treatment of Peritonsillar Abscess. AB - Objective This study was performed to determine whether the efficacy and safety of medical management of uncomplicated peritonsillar abscess (PTA) presenting in the emergency department is equivalent to medical plus surgical therapy. Study Design Case series with chart review. Setting Southern California Permanente Medical Group (SCPMG). Subjects and Methods Upon successful completion of a prospective study comparing medical treatment (MT) to surgical treatment (ST) of PTA in 2008, MT was adopted by 12 SCPMG centers while 7 centers continued standard surgical drainage. Clinical outcomes are now reviewed on a random sampling of 211 patients with PTA treated with MT and 96 patients treated with ST between 2008 and 2013 at the respective medical centers. Patients were treated with intravenous (IV) fluids, weight-appropriate IV ceftriaxone, clindamycin, and dexamethasone, and then discharged on clindamycin * 10 days (MT). Patients in the ST group received MT but also surgical drainage. Primary end points were complication rates and failure rates. Results MT and ST resulted in no significant difference in treatment success or complications. However, patients in the MT group obtained significantly less liquid opioid prescriptions (MT, 30.8 +/- 5.65; ST, 77.75 +/- 13.41; P < .0001), reported fewer sore days (MT, 4.48 +/- 0.27; ST, 5.77 +/- 0.49; P = .0004), and required less days off from work (MT, 3.4 +/- 0.44; ST, 4.9 +/- 0.82; P = .044). Conclusions Compared to ST, MT appears to be equally safe and efficacious, with less pain, opioid use, and days off work, especially if patients with PTA present without trismus. MT for PTAs reduces the possibility of surgical complications, as well as the cost and inconvenience associated with ST. PMID- 29110575 TI - Utility of Neck, Height, and Tonsillar Size to Screen for Obstructive Sleep Apnea among Obese Youth. AB - Objectives To determine whether neck:height ratio combined with adenoid and tonsillar size is a good predictive tool for obstructive sleep apnea in obese youth. Study Design Cross-sectional study. Setting Sleep clinics at the Hospital for Sick Children, Toronto, Canada. Subjects and Methods Consented obese individuals aged 8 to 18 years were recruited between 2013 and 2015. Anthropometric measures were obtained by a trained research coordinator in a standardized manner. Otolaryngologists evaluated adenoid and tonsil sizes. Obstructive sleep apnea was diagnosed with an overnight polysomnogram as an obstructive apnea-hypopnea index >=2. Multivariable logistic regressions investigated the relationship between potential predictors and obstructive sleep apnea. The C-statistic measured the predictive ability. Results Of the 53 subjects (median age, 13 years; 55% males), 28 (53%) were diagnosed with obstructive sleep apnea, with a median index of 10.6 per hour. In a logistic regression controlling for adenoid size, enlarged tonsils were significantly associated with the presence of obstructive sleep apnea ( P < .01). Adding neck:height ratio into the model improved the model predictive ability (C-index increased from 0.73 to 0.84). Controlling for tonsil and adenoid sizes, an increase in neck:height ratio was significantly associated with the presence of obstructive sleep apnea ( P = .01). Conclusion Our study suggests that neck:height ratio combined with tonsillar hypertrophy may have a strong predictive ability for obstructive sleep apnea and may be useful in an ambulatory setting to screen obese youth at high risk. These findings should be confirmed in a larger study. PMID- 29110576 TI - Universal Health Coverage: an urgent need for collaborative learning and technology in primary care. PMID- 29110577 TI - Moral Economy and Moral Capital in the Community of Clinical Practice. AB - This New Zealand study used focused ethnography to explore the activities of communities of clinical practice (CoCP) in a community-based long-term conditions management program within a large primary health care clinic. CoCP are the informal vehicles by which patient care was delivered within the program. Here, we describe the CoCP as a micro-level moral economy within which values such as trust, respect, authenticity, reciprocity, and obligation circulate as a kind of moral capital. As taxpayers, citizens who become patients are credited with moral capital because the public health system is funded by taxes. This moral capital can be paid forward, accrued, banked, redeemed, exchanged, and forfeited by patients and their health care professionals during the course of a patient's journey. The concept of moral capital offers another route into the "black box" of clinical work by providing an alternative theoretic for explaining the relational aspects of patient care. PMID- 29110578 TI - Effects of combined alpha-galactosidase and xylanase supplementation on nutrient digestibility and growth performance in growing pigs. AB - Two experiments were conducted to investigate the effect of combined supplementation of alpha-galactosidase and xylanase on nutrient digestibility and growth performance in growing pigs. Experiment 1 had a 2 * 2 Latin square design, where eight barrows (45.0 +/- 0.52 kg body weight [BW]) were fitted with a simple T-cannula in the distal ileum and received a basal diet without or with supplementation of alpha-galactosidase (12 U/kg diet) and xylanase (15 AXC/kg diet) within two periods of 10 d. The apparent ileal digestibility (AID) and apparent total tract digestibility of nutrients, pH, viscosity of digesta and digestive enzyme activities were assessed. In Experiment 2, a total of 432 growing pigs (initial BW 44.7 +/- 0.66 kg) were allocated to four treatments. Diets were based on corn and soybean meal and had a normal or reduced nutrient level (reduced by 0.42 kJ digestible energy [DE] per kg and 0.8% crude protein). Both diets were offered without or with supplementation of alpha-galactosidase and xylanase. The growth performance was assessed within a 43-d feeding period, where at the end, biochemical serum indices were estimated. In Experiment 1, the enzyme-supplemented diet had a greater contents of DE and DE/gross energy ratio (p < 0.05), and a higher AID of Arg, raffinose, stachyose and arabinoxylan (p < 0.05). In Experiment 2, the low nutrient level caused lower daily gain (p < 0.05), which was partially compensated by enzyme addition. Enzyme addition also increased the serum concentration of Lys (p < 0.05). Moreover, it appears that the tested enzyme supplementation could increase dietary DE, serum total amino acid concentrations and decrease serum urea nitrogen. PMID- 29110580 TI - Clinical Significance of Low 2-Methoxyestradiol Levels in Serum and Tissue of Recurrent Juvenile-Onset Laryngeal Papillomatosis. AB - Objective We aim to explore the correlation between serum and tissue 2 methoxyestradiol (2-ME-2) levels and recurrence of juvenile-onset respiratory papillomatosis (JORRP). Study Design Retrospective cohort studies. Settings Laboratory of Otolaryngology, Department of Head and Neck Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University. Subjects and Methods Sixty-four patients diagnosed with JORRP in our department from January 2007 to December 2012 were enrolled. Patients were divided into recurrence and nonrecurrence groups, with 32 patients in each group. ELISA detected the concentration of 2-ME-2 in serum and tissue samples collected during the first surgical procedure. Mann-Whitney analysis, receiver operating characteristic curves, logistic regression model, and Kaplan-Meier method were used for data processing. Results There was no difference in the serum 2-ME-2 concentration between the groups ( P = .237), while the tissue 2-ME-2 concentration of the recurrent group was significantly lower than that of the nonrecurrence group ( P = .0001). When the area under the curve was 0.752, the cutoff value of tissue 2 ME-2 at 670.02 pg/mL yielded the highest predictive sensitivity (71.9%) and specificity (71.9%). Regrouped by this cutoff point, patients with a lower tissue 2-ME-2 level (n = 26) had shorter disease-free survival and a higher recurrence odds ratio than patients with a higher tissue 2-ME-2 level (n = 38; P = .0408, odds ratio = 7.667). Conclusion A low tissue 2-ME-2 level is associated with a higher recurrence rate of JORRP. Tissue 2-ME-2 may be an effective target for JORRP treatment and a convenient measure for recurrence monitoring. PMID- 29110579 TI - Effects of glyphosate residues and different concentrate feed proportions on performance, energy metabolism and health characteristics in lactating dairy cows. AB - The aim of this study was to examine the influence of glyphosate (GL) residues in feedstuffs on performance, energy balance and health-related characteristics of lactating dairy cows fed diets with different concentrate feed proportions. After an adaption period, 64 German Holstein cows (207 +/- 49 d in milk; mean +/- SD) were assigned to either groups receiving a GL contaminated total mixed ration (TMR) (GL groups) or an uncontaminated TMR (CON groups) during a 16 weeks trial. Contaminated feedstuffs used were legally GL-treated peas and wheat (straw and grain). GL and CON groups were subdivided into a "low concentrate" group (LC) fed on dry matter (DM) basis of 21% maize silage, 42% grass silage, 7% straw and 30% concentrate and a "high concentrate" group (HC) composed of 11% maize silage, 22% grass silage, 7% straw and 60% concentrate for ad libitum consumption. Body condition score, body weight, DM intake and milk performance parameters were recorded. In blood serum, beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA) and glucose were measured and energy balance was calculated. Milk was analysed for GL residues. At week 0, 7 and 15, general health status was evaluated by a modified clinical score. The average individual GL intake amounted for Groups CONLC, CONHC, GLLC and GLHC to 0.8, 0.8, 73.8 and 84.5 mg/d, respectively. No GL residues were detected in milk. GL contamination did not affect body condition score, body weight, DM intake, nutrient digestibility, net energy intake, net energy balance or BHB, glucose, NEFA and milk performance parameters; whereas concentrate feed proportion and time did affect most parameters. The clinical examination showed no adverse effect of GL-contaminated feedstuffs on cows' health condition. In the present study, GL-contaminated feedstuffs showed no influence on performance and energy balance of lactating dairy cows, irrespective of feed concentrate proportion. PMID- 29110581 TI - Outcomes of Drug-Induced Sleep Endoscopy-Directed Surgery for Pediatric Obstructive Sleep Apnea. AB - Objectives To determine the effectiveness of pediatric drug-induced sleep endoscopy (DISE)-directed surgery for children with infant obstructive sleep apnea (OSA) or OSA after adenotonsillectomy. Study Design Case series with chart review. Setting Tertiary care pediatric hospital. Subjects and Methods We included 56 children undergoing DISE from October 2013 to September 2015 who underwent subsequent surgery to address OSA. The primary outcome was successful response to DISE-directed surgery based on the postoperative obstructive Apnea Hypopnea Index (oAHI). Wilcoxon matched-pairs signed-ranks tests were used to compare polysomnography variables before and after surgery, and regression was used to model response to surgery. Results We evaluated 56 patients with a mean age of 5.9 +/- 5.5 years (range, 0.1-17.4) and mean body mass index of 21.2 +/- 7.9 kg/m2 (percentile, 77 +/- 30). The most commonly performed surgical procedures were adenoidectomy (48%, n = 27), supraglottoplasty (38%, n = 21), tonsillectomy (27%, n = 15), lingual tonsillectomy (13%, n = 7), nasal surgery (11%, n = 6), pharyngoplasty (7%, n = 4), and partial midline glossectomy (7%, n = 4). Mean oAHI improved from 14.9 +/- 13.5 to 10.3 +/- 16.2 events/hour, with 54% (30 of 56) of children with oAHI <5 and 16.1% (9 of 56) with oAHI <1. There was a significant improvement in oAHI ( P = .001) and saturation nadir ( P < .001) but not in time with end tidal carbon dioxide >50 mm Hg ( P = .14). Multivariable modeling, controlling for age, race, body mass index, sex, and baseline polysomnography variables, revealed that white race predicted success of DISE-directed surgery. Conclusion Fifty-four percent of children with infant OSA or persistent OSA after adenotonsillectomy had oAHI <5 events per hour after DISE directed surgery. Only white race was predictive of oAHI <5 events per hour. PMID- 29110582 TI - Establishment of cholangiocarcinoma cell lines from patients in the endemic area of liver fluke infection in Thailand. AB - Cholangiocarcinoma is a rare type of cancer which is an increasingly discernible health threat. The disease is usually very difficult in diagnosis and various treatment modalities are typically not effective. Cholangiocarcinoma is a complex and very heterogeneous malignancy characterized by tumor location, different risk factors, molecular profiling, and prognosis. Cancer cell lines represent an important tool for investigation in various aspects of tumor biology and molecular therapeutics. We established two cell lines, KKU-452 and KKU-023, which were derived from patients residing in the endemic area of liver fluke infection in Thailand. Both of tumor tissues have gross pathology of perihilar and intrahepatic mass-forming cholangiocarcinoma. Two cell lines were characterized for their biological, molecular and genetic properties. KKU-452 and KKU-023 cells are both adherent cells with epithelium morphology, but have some differences in their growth pattern (a doubling time of 17.9 vs 34.8 h, respectively) and the expression of epithelial bile duct markers, CK7 and CK19. Cytogenetic analysis of KKU-452 and KKU-023 cells revealed their highly complex karyotypes; hypertriploid and hypotetraploid, respectively, with multiple chromosomal aberrations. Both cell lines showed mutations in p53 but not in KRAS. KKU-452 showed a very rapid migration and invasion properties in concert with low expression of E-cadherin and high expression of N-cadherin, whereas KKU-023 showed opposite characters. KKU-023, but not KKU-452, showed in vivo tumorigenicity in xenografted nude mice. Those two established cholangiocarcinoma cell lines with unique characters may be valuable for better understanding the process of carcinogenesis and developing new therapeutics for the patients. PMID- 29110583 TI - Beta-mangostin from Cratoxylum arborescens activates the intrinsic apoptosis pathway through reactive oxygen species with downregulation of the HSP70 gene in the HL60 cells associated with a G0/G1 cell-cycle arrest. AB - Xanthones are phytochemical compounds found in a number of fruits and vegetables. Characteristically, they are noted to be made of diverse properties based on their biological, biochemical, and pharmacological actions. Accordingly, the apoptosis mechanisms induced by beta-mangostin, a xanthone compound isolated from Cratoxylum arborescens in the human promyelocytic leukemia cell line (HL60) in vitro, were examined in this study. The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay was done to estimate the cytotoxicity effect of beta-mangostin on the HL60 cell line. Acridine orange/propidium iodide and Hoechst 33342 dyes and Annexin V tests were conducted to detect the apoptosis features. Caspase-3 and caspase-9 activities; reactive oxygen species; real-time polymerase chain reaction for Bcl-2, Bax, caspase-3, and caspase-9 Hsp70 genes; and western blot for p53, cytochrome c, and pro- and cleavage-caspase-3 and caspase-9 were assessed to examine the apoptosis mechanism. Cell-cycle analysis conducted revealed that beta-mangostin inhibited the growth of HL60 at 58 uM in 24 h. The administration of beta-mangostin with HL60 caused cell morphological changes related to apoptosis which increased the number of early and late apoptotic cells. The beta-mangostin-catalyzed apoptosis action through caspase-3, caspase-7, and caspase-9 activation overproduced reactive oxygen species which downregulated the expression of antiapoptotic genes Bcl-2 and HSP70. Conversely, the expression of the apoptotic genes Bax, caspase-3, and caspase-9 were upregulated. Meanwhile, at the protein level, beta-mangostin activated the formation of cleaved caspase-3 and caspase-9 and also upregulated the p53. beta mangostin arrested the cell cycle at the G0/G1 phase. Overall, the results for beta-mangostin showed an antiproliferative effect in HL60 via stopping the cell cycle at the G0/G1 phase and prompted the intrinsic apoptosis pathway. PMID- 29110584 TI - MicroRNA-target cross-talks: Key players in glioblastoma multiforme. AB - The role of microRNAs in brain cancer is still naive. Some act as oncogene and others as tumor suppressors. Discovery of efficient biomarkers is mandatory to debate that aggressive disease. Bioinformatically selected microRNAs and their targets were investigated to evaluate their putative signature as diagnostic and prognostic biomarkers in primary glioblastoma multiforme. Expression of a panel of seven microRNAs (hsa-miR-34a, hsa-miR-16, hsa-miR-17, hsa-miR-21, hsa-miR-221, hsa-miR-326, and hsa-miR-375) and seven target genes ( E2F3, PI3KCA, TOM34, WNT5A, PDCD4, DFFA, and EGFR) in 43 glioblastoma multiforme specimens were profiled compared to non-cancer tissues via quantitative reverse transcription polymerase chain reaction. Immunohistochemistry staining for three proteins (VEGFA, BAX, and BCL2) was performed. Gene enrichment analysis identified the biological regulatory functions of the gene panel in glioma pathway. MGMT ( O-6 methylguanine-DNA methyltransferase) promoter methylation was analyzed for molecular subtyping of tumor specimens. Our data demonstrated a significant upregulation of five microRNAs (hsa-miR-16, hsa-miR-17, hsa-miR-21, hsa-miR-221, and hsa-miR-375), three genes ( E2F3, PI3KCA, and Wnt5a), two proteins (VEGFA and BCL2), and downregulation of hsa-miR-34a and three other genes ( DFFA, PDCD4, and EGFR) in brain cancer tissues. Receiver operating characteristic analysis revealed that miR-34a (area under the curve = 0.927) and miR-17 (area under the curve = 0.900) had the highest diagnostic performance, followed by miR-221 (area under the curve = 0.845), miR-21 (area under the curve = 0.836), WNT5A (area under the curve = 0.809), PDCD4 (area under the curve = 0.809), and PI3KCA (area under the curve = 0.800). MGMT promoter methylation status was associated with high miR-221 levels. Moreover, patients with VEGFA overexpression and downregulation of TOM34 and BAX had poor overall survival. Nevertheless, miR-17, miR-221, and miR-326 downregulation were significantly associated with high recurrence rate. Multivariate analysis by hierarchical clustering classified patients into four distinct groups based on gene panel signature. In conclusion, the explored microRNA-target dysregulation could pave the road toward developing potential therapeutic strategies for glioblastoma multiforme. Future translational and functional studies are highly recommended to better understand the complex bio-molecular signature of this difficult-to-treat tumor. PMID- 29110585 TI - Cell-free DNA levels and correlation to stage and outcome following treatment of locally advanced rectal cancer. AB - Accurate staging of rectal cancer remains essential for optimal patient selection for combined modality treatment, including radiotherapy, chemotherapy and surgery. We aimed at examining the correlation of cell free DNA with the pathologic stage and subsequent risk of recurrence for patients with locally advanced rectal cancer undergoing preoperative chemoradiation. We examined 75 patients with locally advanced rectal cancer receiving preoperative chemoradiation. Blood samples for translational use were drawn prior to rectal surgery. The level of cell free DNA was quantified by digital droplet PCR and expressed as copy number of beta 2 microglobulin. We found a median level of cell free DNA in the AJCC stages I-III of 3100, 8300, and 10,700 copies/mL respectively. For patients with 12 sampled lymph nodes or above, the median level of cell free DNA were 2400 copies/mL and 4400 copies/mL (p = 0.04) for node negative and node positive disease respectively. The median follow-up was 39 months and 11 recurrences were detected (15%). The median level for patients with recurrent disease was 13,000 copies/mL compared to 5200 copies/mL for non recurrent patients (p = 0.08). We have demonstrated a correlation between the level of total cell free DNA and the pathologic stage and nodal involvement. Furthermore, we have found a trend towards a correlation with the risk of recurrence following resection of localized rectal cancer. PMID- 29110586 TI - Genetic variants of SULT1A1 and XRCC1 genes and risk of lung cancer in Bangladeshi population. AB - Lung cancer is one of the most frequently occurring cancers throughout the world as well as in Bangladesh. This study aimed to correlate the prognostic and/or predictive value of functional polymorphisms in SULT1A1 (rs9282861) and XRCC1 (rs25487) genes and lung cancer risk in Bangladeshi population. A case-control study was conducted which comprises 202 lung cancer patients and 242 healthy volunteers taking into account the age, sex, and smoking status. After isolation of genomic DNA, genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method and the lung cancer risk was evaluated as odds ratio that was adjusted for age, sex, and smoking status. A significant association was found between SULT1A1 rs9282861 and XRCC1 rs25487 polymorphisms and lung cancer risk. In case of rs9282861 polymorphism, Arg/His (adjusted odds ratio = 5.06, 95% confidence interval = 3.05-8.41, p < 0.05) and His/His (adjusted odds ratio = 3.88, 95% confidence interval = 2.20-6.82, p < 0.05) genotypes were strongly associated with increased risk of lung cancer in comparison to the Arg/Arg genotype. In case of rs25487 polymorphism, Arg/Gln heterozygote (adjusted odds ratio = 4.57, 95% confidence interval = 2.79-7.46, p < 0.05) and Gln/Gln mutant homozygote (adjusted odds ratio = 4.99, 95% confidence interval = 2.66-9.36, p < 0.05) were also found to be significantly associated with increased risk of lung cancer. This study demonstrates that the presence of His allele and Gln allele in case of SULT1A1 rs9282861 and XRCC1 rs25487, respectively, involve in lung cancer prognosis in Bangladeshi population. PMID- 29110587 TI - Momordica charantia extracts ameliorate insulin resistance by regulating the expression of SOCS-3 and JNK in type 2 diabetes mellitus rats. AB - CONTEXT: Momordica charantia L. (Cucurbitaceae) has long been widely used as a traditional remedy for diabetes mellitus in some countries. However, detailed antidiabetic mechanisms are largely unknown. OBJECTIVES: This study clarified the ameliorating effects of M. charantia ethanol extracts (MCE) on the insulin resistance in type 2 diabetes mellitus (T2DM) rats. MATERIALS AND METHODS: T2DM rat model was established by high-fat diet and streptozotocin (STZ) injection. Diabetic rats were randomized into five groups: the model control group (n = 8) (common diet), the high-fat diet metformin (50 mg/kg/d), and the three-dose MCE (100, 200, and 400 mg/kg/d) groups (n = 8 each). After 8 weeks, the fasting serum glucose, insulin, TNF-alpha, and IL-6 were measured, and the relevant factors of glucose and insulin were monitored by glycogen dyeing, RT-PCR, and western blot, respectively. RESULTS: The 8-week treatment of 400 mg/kg MCE significantly lowered body weight (330.1 versus 365.9 g), serum glucose (7.41 versus 16.63 mmol/L), insulin (12.06 versus 15.89 mIU/L), TNF-alpha (52.72 versus 81.83 ng/L), and IL-6 (104.81 versus 135.74 ng/L) in comparison with those of the diabetic control group (p < 0.05). It was the same for skeletal muscle glucose transporter 4 (GLUT-4) protein, and glycogen level, suppressor of cytokine signaling-3 (SOCS-3), c-Jun N-terminal kinase (JNK), and Akt expression at both protein and mRNA levels in liver (p < 0.05). CONCLUSIONS: MCE can ameliorate insulin resistance in T2DM rats. This effect may be related to the regulation of mRNA and protein levels of SOCS-3 and JNK. PMID- 29110589 TI - Antimicrobial Peptides of Marine Crustaceans: The Potential and Challenges of Developing Therapeutic Agents. AB - The alarming increase of antimicrobial resistance has led to a growing number of studies aiming to develop novel antimicrobial therapeutics. Natural antimicrobial peptides possess a potent and broad-spectrum antimicrobial activity combined with diverse and unique structural motifs, which confer their different mechanisms of action. These peptides are ubiquitous in organisms and are integral to the innate immune system. Recently, identification of antimicrobial peptides from marine crustaceans has become the centre of attention of many researchers. This increasing interest stems from the remarkable diversity in the structural and genetic composition of these peptides compared to terrestrial counterparts. Thus, peptides from marine crustaceans can serve as future templates for novel antimicrobial agents. Here, we provide an overview of various antimicrobial peptides from the marine crustaceans, their antimicrobial activity and structure- activity relationships. We also discuss the potential and challenges of their development as new antimicrobial agents. PMID- 29110590 TI - New strategy on antimicrobial-resistance: inhibitors of DNA replication enzymes. AB - Antimicrobial resistance is found in all microorganisms and has become one of the biggest threats to global health. New antimicrobials with different action mechanisms from existing drugs are effective weapons to fight antibiotic resistance. DNA replication universally exists in all living organisms and is a complicated process involving in multiple enzymes. Enzymes in bacterial DNA replication of initiation and elongation phases bring abundant targets for antimicrobial development as they are conserved and indispensable. In this review, enzyme inhibitors of DNA helicase, DNA primase, topoisomerases, DNA polymerase and DNA ligase were discussed. Special attentions were paid to structures, activities and action modes of these enzyme inhibitors to find potential drugs which can be further developed into clinic. Also, this review can provide clues for developing more effective antimicrobials. PMID- 29110591 TI - Optical Sensors for Detection of Amino Acids. AB - BACKGROUND: Amino acids are crucially involved in a myriad of biological processes. Any aberrant changes in physiological level of amino acids often manifest in common metabolic disorders, serious neurological conditions and cardiovascular diseases. Thus, devising methods for detection of trace amounts of amino acids becomes highly elemental to their efficient clinical diagnosis. Recently, the domain of developing optical sensors for detection of amino acids has witnessed significant activity which is the focus of the current review article. METHODS: We undertook a detailed search of the peer-reviewed literature that primarily deals with optical sensors for amino acids and focuses on the use of different type of materials as a sensing platform. RESULTS: Ninety-five papers have been included in the review, majority of which deal with optical sensors. We attempt to systematically classify these contributions based on the applications of various chemical and biological scaffolds such as polymers, supramolecular assemblies, nanoparticles, DNA, heparin etc for the sensing of amino acids. This review identifies that supramolecular assemblies and nanomaterial continue to be commonly used platforms to devise sensors for amino acids followed by surfactant assemblies. CONCLUSION: The broad implications of amino acids in human health and diagnosis have stirred a lot of interest to develop optimized optical detection systems for amino acids in recent years, using different materials based on chemical and biological scaffolds. We have also attempted to highlight the merits and demerits of some of the noteworthy sensor systems to instigate further efforts for constructing amino acids sensor based on unconventional concepts. PMID- 29110592 TI - Recent Developments on Phenstatins as Potent Antimitotic Agents. AB - BACKGROUND: Phenstatin and their derivatives display remarkable antiproliferative activity toward a wide variety of preclinical tumor models. Structural simplicity and excellent stability of phenstatins offer a stimulating premise for developing various derivatives with profound antimitotic activity and excellent cytotoxicity. OBJECTIVE: To do analysis of literature that phenstatins derivatives inhibit tubulin polymerization through their interaction at the colchicine binding site of microtubules and arrest the G2/M phase of the cell cycle. In addition, phenstatin derivatives are undergoing clinical evaluation as vascular targeting/disrupting agents and also exhibit direct antiangiogenic properties. METHODS: An organised well designed and appropriately managed search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/ exclusion criteria has been done for this article. CONCLUSION: In this review article, the synthesis and structure-activity relationships of phenstatin and a wide number of their reported analogues with modifications to ring A, ring B, and to the keto position are discussed in the perspective of medicinal chemistry with proper conclusion. PMID- 29110593 TI - Spirolactones: Recent Advances in Natural Products, Bioactive Compounds and Synthetic Strategies. AB - BACKGROUND: The spirocyclic compounds have always aroused a great interest because this motif is present as structural core in a number of natural products and bioactive compounds. In particular, the spirolactone moiety has been recognized in a wide array of natural and non-natural scaffolds showing a variety of useful pharmacological properties. METHODS: Extensive literature search using SciFinder (Databases: CA Plus, CAS Registry, CAS React, Chemlist, Chemcat and Medline) and Web of Science (Database: Web of Science Core Collection) was conducted. RESULTS: Nowadays, many efforts are being devoted to the discovery of new natural products containing the promising spirolactone framework and to the disclosure of the potential bioactivities of these chemical entities. Moreover, the medicinal relevance of many spirolactones makes these scaffolds attractive targets for the design and development of innovative and efficient synthetic strategies, enabling the construction of complex and variably substituted products. CONCLUSION: This review gives an overview on the recent advances in the spirolactones field, in terms of new compounds isolated from natural sources, recently determined bioactivity profiles and innovative synthetic approaches. The collected data demonstrate the key role played by spirolactones in medicinal chemistry and the great attention still devoted by the scientific community to these compounds. PMID- 29110594 TI - Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier. AB - BACKGROUND: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. METHODS: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. RESULTS: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. CONCLUSION: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development. PMID- 29110595 TI - The impact of ultraviolet radiation on barrier function in human skin: Molecular mechanisms and topical therapeutics. AB - A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However, studies in mice and more limited work in humans suggest that the epidermal barrier becomes more permeable, as measured by increased transepidermal water loss, in response UVR, at doses sufficiently high to induce erythema. The mechanisms may include disturbance in the organisation of lipids in the stratum corneum (the outermost layer of the epidermis) and reduction in tight junction function in the granular layer (the first living layer of the skin). By contrast, suberythemal doses of UVR appear to have positive effects on epidermal barrier function. Topical sunscreens have direct and indirect protective effects on the barrier through their ability to block UV and also due to their moisturising or occlusive effects, which trap water in the skin, respectively. Some topical agents such as specific botanical extracts have been shown to prevent the loss of water associated with high doses of UVR. In this review we discuss the current literature and suggest that the biology of UVR induced barrier dysfunction, and the use of topical products to protect the barrier, are areas worthy of further investigation. PMID- 29110597 TI - The in silico drug discovery toolbox: applications in lead discovery and optimization. AB - Discovery and development of a new drug is a long lasting and expensive journey that takes around 15 years from starting idea to approval and marketing of new medication. Despite the R&D expenditures have been constantly increasing in the last few years, number of new drugs introduced into market has been steadily declining. This is mainly due to preclinical and clinical safety issues, which still represent about 40% of drug discontinuation. From this point of view, it is clear that if we want to increase drug-discovery success rate and reduce costs associated with development of a new drug, a comprehensive evaluation/prediction of potential safety issues should be conducted as soon as possible during early drug discovery phase. In the present review, we will analyse the early steps of drug-discovery pipeline, describing the sequence of steps from disease selection to lead optimization and focusing on the most common in silico tools used to assess attrition risks and build a mitigation plan. PMID- 29110596 TI - gamma-AApeptides as a new strategy for therapeutic development. AB - A new class of peptidomimetics termed "gamma-AApeptides" was recently developed by our group. Similar to other peptidomimetics, gamma-AApeptides are resistant to proteolytic degradation, and possess limitless potential to introduce chemically diverse functional groups. gamma-AApeptides have shown great promise in biomedical applications. In this article, we will review a few examples of gamma AApeptides with biological potential. Certain gamma-AApeptides can permeate cell membranes and therefore they can be used as potential drug carrier. gamma AApeptides can also bind to HIV RNA with high specificity and affinity, suggesting their potential application as anti-HIV agents. Moreover, they can mimic host-defense peptides and display potent and broad-spectrum activity towards a range of drug-resistant bacterial pathogens. They are also potential anti-cancer agents. For instance, they have shown great promise in targeted imaging of tumor in mouse model, and they are also capable of disrupting p53/DNA interactions, and thus antagonize STAT3 signaling pathway. Recently, from combinatorial screening, gamma-AApeptides are identified to inhibit A? peptide aggregation, and thus they can be developed into potential anti-Alzheimer's Disease agent. PMID- 29110598 TI - SIRT1 as a Therapeutic Target in Diabetic Complications. AB - BACKGROUND: Sirtuin1 is an epigenetic enzyme involved in histone and nonhistone protein deacetylation. It acts primarily as a metabolic sensor, which responses to changing energy status by deacetylating crucial transcription factors and cofactors. In this way, Sirtuin1 regulates mitochondrial function and biogenesis, oxidative stress, inflammation, apoptosis and cellular senescence. Disturbance of all of these phenomena promotes the pathogenesis of diabetic complications. These disorders are inseparably connected with chronic hyperglycemia, which possesses a strong epigenetic determinant. OBJECTIVE: To summarize the contemporary knowledge regarding the role of Sirtuin1 in the development, progression and therapy of diabetic complications. METHODS: We extensively searched literature describing the importance of Sirtuin1 in pathophysiology and treatment of all kinds of diabetic complications till September 2017. We focused on the examples of synthetic and natural compounds-mediated Sirtuin1 upregulation along with Sirtuin1-associated epigenetics. RESULTS: Reduction of Sirtuin1 is implicated in endothelial dysfunction and metabolic memory, underlying the development of micro and macrovascular complications. Declined Sirtuin1 also participates in diabetic testicular and erectile dysfunction. Sirtuin1 is elevated by naturally occurring anti-oxidant and anti-inflammatory compounds such as resveratrol, trans-delta viniferin, vitamin D and more. Similarly, Sirtuin1 level increases after treatment with standard antihyperglycemic (metformin, exenatide, liraglutide), antihypertensive (sartans), lipid-lowering (fibrates, statins) and anticoagulant (fidarestat) drugs. Regarding epigenetics, a number of miRNAs trigger Sirtuin1 decrease, which further contributes to histone acetylation of Sirtuin1-regulated and relevant for diabetes genes. CONCLUSION: Evidence strongly suggest that Sirtuin1 upregulation may serve as a potent therapeutic approach against development and progression of diabetic complications. PMID- 29110599 TI - Effect of Metformin on Plasma Fibrinogen Concentrations: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. AB - OBJECTIVE: Fibrinogen is a key mediator of thrombosis and it has been implicated in the pathogenesis of atherosclerosis. Because metformin has shown a potential protective effect on different atherothrombotic risk factors, we assessed in this meta-analysis its effect on plasma fibrinogen concentrations. METHODS: A systematic review and meta-analysis was carried out to identify randomized placebo-controlled trials evaluating the effect of metformin administration on fibrinogen levels. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases (by June 2, 2017) and quality of studies was performed according to Cochrane criteria. Quantitative data synthesis was conducted using a random-effects model and sensitivity analysis by the leave-one out method. Meta-regression analysis was performed to assess the modifiers of treatment response. RESULTS: Meta-analysis of data from 9 randomized placebo controlled clinical trials with 2302 patients comprising 10 treatment arms did not suggest a significant change in plasma fibrinogen concentrations following metformin therapy (WMD: -0.25 g/L, 95% CI: -0.53, 0.04, p = 0.092). The effect size was robust in the leave-one-out sensitivity analysis and remained non significant after omission of each single study from the meta-analysis. CONCLUSION: No significant effect of metformin on plasma fibrinogen concentrations was demonstrated in the current meta-analysis. PMID- 29110600 TI - Editorial: Polymeric Nanocarriers as Robust Platforms for Cancer Therapy. PMID- 29110601 TI - Drug Release from Porous Matrixes based on Natural Polymers. AB - BACKGROUND: This review provides a report on recent advances in the field of drug release from matrixes made of natural polymers. Herein, the properties of natural polymers such as proteins and polysaccharides are discussed in general. Selected detailed examples of drug release profiles from biopolymer matrixes have also been collected from scientific literature and practical work, and commented on. In this review, the most common natural polymers, i.e. collagen, elastin, chitosan, hyaluronic acid and sodium alginate have been discussed as biopolymers that can be potentially applied in drug delivery systems. METHODOLOGY: The most rapidly developing field of the biomaterials science is the one dealing with their application as matrixes in drug release systems. Such systems show numerous advantages when compared to conventional ones. They improve medical treatment efficiency due to the fact that drugs are placed directly into the infected part. Moreover, the drug release systems reduce toxic reactions because the drug does not pass through the body and, as a result, does not affect the healthy tissues. Such systems also improve the patient's comfort during the treatment. RESULT: Biocompatibility, bioresorbability and non-toxicity are the significant properties characteristic for natural polymers. Natural polymers can be used to obtain biomaterials which can further find their applications in the production of bones or soft tissues implants as well as dressing materials placed on damaged skin. Nevertheless, the disadvantages of biomaterials made of natural polymers, e.g., high solubility and low thermal stability, limit the range of their potential applications. Therefore, it is necessary to modify material properties by carrying out the cross-linking process. CONCLUSION: Recently, a rapidly growing interest in the use of porous materials as controlled drug delivery matrixes has been observed since they present several positive features. The drug release from polymeric matrixes is based on the carrier degradation process which depends on dissolving and diffusion processes. The selection of a polymeric matrix depends on its compatibility with the drug as well as the manufacturing process which needs to be considered. The proper adjustment of the drug release rate is necessary to obtain the best results during medical treatment. Numerous classes of hydrophilic as well as hydrophobic drugs can be released from polymeric matrixes which is beneficial to medical treatment. The research of different drug release systems has already been carried out, and the results can be found in scientific literature. PMID- 29110602 TI - Pharmacometabonomics Technique to Identify Warfarin Response Using Nuclear Magnetic Resonance Spectroscopy. AB - BACKGROUND: Warfarin, an anticoagulant medication, is prescribed regularly despite of its bleeding tendency for the prevention and/or treatment of various thromboembolic conditions, such as deep vein thrombosis, and complications associated with atrial fibrillation, and myocardial infarction, but because of its narrow therapeutic window, it has a lot of interactions with drugs and diet. METHODS: Warfarin relies on regular monitoring of International Normalized Ratio which is a standardized test to measure prothrombin time and appropriate dose adjustment. Pharmacometabonomics is a novel scientific field which deals with identification and quantification of the metabolites present in the metabolome using spectroscopic techniques such as Nuclear Magnetic Resonance (NMR). Pharmacometabonomics helps to indicate perturbation in the levels of metabolites in the cells and tissues due to drug or ingestion of any substance. NMR is one of the most widely-used spectroscopic techniques in metabolomics because of its reproducibility and speed. RESULTS: There are many factors that influence the metabolism of warfarin, making changes in drug dosage common, and clinical factors like drug-drug interactions, dietary interactions and age explain for the most part the variability in warfarin dosing. Some studies have showed that pharmacogenetic testing for warfarin dosing does not improve health outcomes, and around 26% of the variation in warfarin dose requirements remains unexplained yet. CONCLUSION: Many recent pharmacometabonomics studies have been conducted to identify novel biomarkers of drug therapies such as paracetamol, aspirin and simvastatin. Thus, a technique such as NMR based pharmacometabonomics to find novel biomarkers in plasma and urine might be useful to predict warfarin outcome. PMID- 29110604 TI - Editorial: View of Cellular Biology through the Eye. PMID- 29110603 TI - Characterization of Polyethersulfone Membranes for Tear Fluid Collection. AB - BACKGROUND: The sampling of tear fluids is essential for the reproducibility of tear assays. But, an operable, efficient and stable method for tear collection has not been widely established. This study evaluated the utility of polyethersulfone membranes (PESms) for tear collection and compared it with two frequently employed approaches: the use of Schirmer test paper (STP) and capillary tube (CaT). METHODS: STP and PESms (0.45 and 0.65 um) were examined using scanning electron microscopy(SEM), applied to soak up water, bovine albumin and cellular lysates, and employed to collect tear fluids from rabbits. The proteins in the cellular lysates and tear fluid were characterized through band profiling of SDS-polyacrylamide electrophoresis (PAGE) gels. Western blot analyses with antibodies against vinculin and lysozyme C were used to compare rabbit tear fluids sampling with CaT, STP and PESm. Rabbit ocular surfaces and eye blinking were evaluated under different conditions. RESULTS: The SEM examination showed that PESms exhibited much smoother surfaces and smaller pores than STP. PESm65 exhibited the highest water absorption and water recovery in vitro. Although SDS-PAGE revealed no obvious differences in the cellular or tear protein band patterns, the highest Dice's similarity coefficient and lowest variance in the differences in peak heights(i.e. band intensities) were observed in the PESm65 samples. The Western blot showed that the band intensities of vinculin protein in tear fluids obtained using CaT, STP and PESm65 are in order of CaTPESm65>STP. PESm65 exhibited less blinks and conjunctival injuries than STP during sampling-rabbit tears. CONCLUSION: Tear collection using PESm has less variance in protein components and is easily operable than traditional STP. PESm possesses the potential for clinical utilization in diagnostic tear assays. PMID- 29110605 TI - Glutathiolation Triggers Proteins for Degradation by the Ubiquitin- Proteasome Pathway. AB - BACKGROUND: Glutathione is a small antioxidant peptide in cells and it plays an important role in maintaining a reducing intracellular environment. Glutathione is also involved in the dynamic regulation of specific protein functions by reversible glutathiolation of certain proteins in response to oxidative stress. OBJECTIVE: The purpose of this work is to mechanistically investigate the effects of glutathiolation on the susceptibility of proteins to degradation by the ubiquitinproteasome pathway (UPP). METHODS AND RESULTS: The data show that gammaC crystallin and carbonic anhydrase III were barely degraded by the UPP without modifications, but both were rapidly degraded by the UPP after glutathiolation. Modifications of sulfhydryls by other thiol-modification reagents, such as iodoacetamide, also increased the degradation of gammaC-crystallin, but not as effectively as glutathiolation. Biophysical analysis showed that glutathiolation caused reversible conformational changes of these proteins, including a significant increase in protein surface hydrophobicity and a decrease in thermal stability. The modified protein regained its native conformation and its resistance to degradation upon removal of the glutathione moiety. A cataract causing T5P mutant gammaC-crystallin shares many biophysical characteristics as glutathiolated gammaC-crystallin, including increased surface hydrophobicity and decreased thermal stability. T5P mutant gammaC-crystallin was also rapidly degraded. Comparison of the conformational changes and the susceptibility to degradation of glutathiolated gammaC-crystallin with other forms of modified gammaC-crystallin suggests that the glutathiolation-induced exposure of hydrophobic patches, rather than the modification per se, serves as the signal for degradation by the UPP. Consistent with this hypothesis, masking the surface hydrophobicity of glutathiolated and T5P mutant gammaC-crystallins significantly reduced their susceptibility to degradation by the UPP. CONCLUSION: This work demonstrates that glutathiolation is a novel mechanism for the UPP to recognize substrates in response to oxidative stress. PMID- 29110606 TI - The Fate of In Situ Lens Regeneration is Determined by Capsulorhexis Size. AB - BACKGROUND AND OBJECTIVE: Lens regeneration is an optimal strategy for cataract patients to regain visual acuity with accommodation. We recently designed a novel, minimally invasive capsulorhexis surgical method for cataract removal that achieved functional lens regeneration in human infants. However, small anterior capsulorhexis requires advanced surgical expertise. To examine whether the quality of the regenerated lens can be maintained with enlarged anterior capsulorhexis, we investigated the shape and transparency of the regenerated lenses with different anterior capsulorhexis diameters (ACDs). METHODS: Thirty six 4-week-old New Zealand albino rabbits were randomly divided into three groups which underwent lens extraction with different ACDs (Group A: 2.0+/-0.5 mm, Group B: 4.0+/-0.5 mm, Group C: 6.0+/-0.5 mm). The anterior capsule opening area (ACOA) was quantified, and the morphology, weight, and histological characteristics of the regenerated lenses were examined. RESULTS: Lens regeneration was observed in all three groups. In Group A, the regenerated lenses were relatively complete and transparent. In Groups B and C, the regenerated lenses were doughnut-shaped and opaque. The speed of lens regeneration in Group A was significantly faster than that in Groups B and C. The ACOA in Group A healed quickly and completely approximately 2 weeks after surgery. However, in Groups B and C, ACOA did not heal completely until 12 weeks after surgery. Histological examination showed that in Group A, most of the lens epithelial cells differentiated into well organized lens fibers. However, in Groups B and C, the regenerated lens fibers were disorganized. CONCLUSION: Capsulorhexis size is a critical determinant of integrity and transparency in lens regeneration. PMID- 29110607 TI - Serum Carotenoids and Risks of Diabetes and Diabetic Retinopathy in a Chinese Population Sample. AB - OBJECTIVE: Diabetes mellitus (DM) and diabetic retinopathy (DR) are associated with oxidative stress and carotenoids have antioxidant properties. This study aimed to test the relationship between serum carotenoid concentrations and the risk for DM and DR. METHODS: This is a cross-sectional study of the Chinese urban population. A total of 747 subjects, consisting of 272 DR patients, 190 diabetic patients without retinopathy, and 285 non-diabetes mellitus healthy controls, were recruited to this study. Demographic and lifestyle characteristics were ascertained by questionnaire. General physical and ophthalmic examinations were completed for all participants. Serum carotenoids were measured by high performance liquid chromatography (HPLC). The associations of serum carotenoids with DM and DR were assessed by logistic regression with adjustment of known risk factors. The correlation analyses of serum carotenoids with the candidate influence factors were assessed using the single variable linear regression. RESULTS: Both pro-vitamin A (PVA) carotenoids and non-PVA carotenoids in the serum were measured and compared between different groups. Levels of alpha carotene were significantly lower in DR patients and beta-carotene were significantly lower in DM patients as compared to non DM healthy control group. In contrast, levels of beta-cryptoxanthin, lycopene, lutein and zeaxanthin were comparable among different groups. After adjusting for confounding factors, beta carotene concentration was associated with reduced risk for DM (OR (95%CI): 0.56 (0.34, 0.91), P=0.02) and alpha-carotene was associated with reduced risk for DR in non-smokers (OR (95%CI): 0.41 (0.17, 0.99), P=0.048). No significant association was found between hemoglobin A1c and any carotenoids (P>0.05). Significantly associations with serum carotenoids were found in age, sex, BMI, smoking, and exercise (P<0.05). CONCLUSION: Serum beta-carotene may have a protective effect on DM and alpha-carotene may be a protective factor for DR in non-smokers. PMID- 29110608 TI - The Profile of Angiogenic Factors in Vitreous Humor of the Patients with Proliferative Diabetic Retinopathy. AB - OBJECTIVE: To explore the expression profile of angiogenic factors associated with proliferative diabetic retinopathy (PDR). METHODS: Undiluted vitreous humor samples were obtained from 10 diabetic patients with PDR (10 eyes) and 9 non diabtic patients (9 eyes). The concentrations of 60 angiogenic factors in the vitreous humor samples were measured by RayBio Angiogenic Cytokine Antibody Array. Some differentially expressed factors were further confirmed in vitreous humor by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the non-diabetic controls, 20 differentially expressed factors with more than 1.50 fold changes were detected in patients with PDR. The median concentration of vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), angiopoietin (ANG)-1, ANG-2, urokinase-type plasminogen activator receptor (uPAR), Follistatin and matrix metalloproteinases 9 (MMP-9) was significantly increased in vitreous samples from PDR compared to controls (P < 0.05). However, (MCP)-1, Angiogenin and Leptin was significantly lower in PDR eyes compared to controls (P < 0.05). In the verification assay using ELISA, ANG-1, ANG-2, IL-6, VEGF, MMP-9, hepatocyte growth factor (HGF) and placenta growth factor (PIGF) concentration were increased in patients with PDR compared to controls (all P-values < 0.05). CONCLUSION: This is the first report of a comprehensive multiplex analysis to identify angiogenic factors associated with PDR. These angiogenic factors may contribute to the pathogenesis of PDR and may be targets for therapeutic strategies of PDR. PMID- 29110609 TI - bmp3 is Required for Integrity of Blood Brain Barrier by Promoting Pericyte Coverage in Zebrafish Embryos. AB - BACKGROUND: The compromise of blood brain barrier (BBB) integrity is often associated with human hemorrhage stroke and neurodegeneration diseases, including retina diseases, such as age-related macular degeneration and diabetic retinopathy. Brain pericytes play pivotal roles in regulation and maintenance of BBB integrity. However, the mechanisms underlying brain pericyte development to establish BBB integrity remain unclear. METHODS: Zebrafish transgenic lines Tg(flk1:GFP; gata1:dsRed), Tg(flk1:GFP), Tg(fli1:GFP) and Tg(BRE:GFP) were used in this work. The functional studies of bmp3 were performed by mopholino oligonucleotide (MO) injection, dye-based permeability assay, RT-PCR, in vivo imaging, immunofluorescence staining and statics analysis. RESULTS: Here we report that bmp3 regulates BBB integrity in zebrafish brain by promoting pericyte development. Knockdown of bmp3 with injection of bmp3-MO causes intracerebral hemorrhage in zebrafish embryos. Meanwhile, disruption of bmp3 function by bmp3 MO injection impairs cerebral pericyte coverage in zebrafish embryos. Mechanistically, knockdown of bmp3 disrupts the pattern and activities of BMP signaling in zebrafish brain, thus probably disrupting the balance of TGFbeta/BMP signaling in zebrafish embryos. CONCLUSION: In summary, our data shows that bmp3 regulates BBB integrity potentially by promoting pericyte development. PMID- 29110610 TI - VEGFR1 Signaling Regulates IL-4-Mediated Arginase 1 Expression in Macrophages. AB - BACKGROUND: Macrophages undergo polarization or activation in response to environmental stimuli, an essential process for proper immune response. Meanwhile, excessive activation of macrophages causes autoimmune diseases. It is therefore crucial to prevent over-activation of macrophage in order to maintain the proper immune response. Arginase 1 (Arg-1) plays a critical role in coordinating the immune response by regulating availability of arginine. OBJECTIVE: To understand the mechanism of Arg-1 regulation. METHODS: Real-time PCR and Western Blot analysis were utilized to examine the Arg-1 levels expressed from the VEGFR1-deleted and VEGFR1-TK-deficient bone marrowderived macrophages (BMDMs). RESULTS: The VEGFR1-mediated signaling suppressed IL-4-induced Arg-1 expression. Deletion of VEGFR1 resulted in elevated Arg-1 expression and the tyrosine kinase domain of VEGFR1 was required for the suppression. Each of three ligands of VEGFR1, VEGF-A, VEGF-B and PIGF, mediated the inhibition to the similar degree. CONCLUSION: Our findings identified a novel function of the VEGFR1 signaling in avoiding over-expression of Arginase 1 potentially to maintain the proper innate immune response. PMID- 29110611 TI - Curcumin Inhibits Proliferation and Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells Via Multiple Pathways. AB - BACKGROUND: Proliferative vitreoretinopathy (PVR) is a disease caused by dedifferentiation, translocation and proliferation of several types of local cells. These cells form fibrocellular membranes resulting in detachment of retinal and vision loss. PVR occurs in 8%-10% of patients undergoing primary retinal detachment (RD) surgery and becomes a major obstacle for successful RD repair. Retinal pigment epithelial (RPE) cells are among the major cells which consist of fibrocellular membranes. Reproliferation and Epithelial-mesenchymal transition (EMT) are the primary pathological alteration of RPE cells in PVR. METHODS: RPE cells were treated with curcumin at different concentrations for 24, 48 and 72 hours. The viable cells were detected by MTT assay. The apoptosis of RPE was stained by Multicaspase/7-AAD and detected using flow cytometry. Cell cycle analysis was quantified by PI staining. The mRNA levels were detected by real-time PCR. The protein levels were detected by western blot. RESULTS: We found a compound curcumin significantly inhibited proliferation and EMT of RPE cells in vitro. Further study showed curcumin induced cell cycle arrest by activating G2 checkpoint through p53 pathway. Meanwhile, we found that curcumin suppressed the AKT, MAPK and TGF-beta pathways in RPE cells which may also affect proliferation and EMT. Our research identified curcumin a potential novel agent for the PVR prevention and treatment. Curcumin induces cell cycle arrest by activating G2 checkpoint. CONCLUSION: Our results in this study also provide the insights to broaden the application of curcumin in research and probably clinics. PMID- 29110612 TI - Influence of Implants Composition on Melatonin Release from Ethylcellulose Matrix. AB - BACKGROUND: Melatonin release from Ethylcellulose matrix has never been studied on the whole range of compositions. OBJECTIVE: To perform a comprehensive study about the influence of the melatonin loading on its release from solid ethylcellulose implants, from both a kinetic and structural point of view. METHOD: Cylindrical implants differing in their Melatonin:Ethylcellulose ratio were fabricated to cover a large range of compositions. Drug release was assayed by in vitro dissolution tests in CTAB micellar solutions. The 2D imaging of implant chemical composition during Melatonin release was performed by confocal Raman spectroscopy. FT-IR spectroscopy and Karl-Fisher technique were employed to study implants hydration. RESULTS: A drug radial leakage, whatever the implant composition, is imaged. The apparent diffusion coefficient, D of melatonin was evaluated considering Fickian radial diffusion: its value ranges from 2 to 6 10 12 cm2/s depending on the EC content. The variation of the characteristic drug delivery time with composition was non-monotonous and two different regimes were identified. CONCLUSION: A micellar transport of Melatonin was found. The two regimes in drug release were interpreted considering the polymer barrier effect, the initial porosity and M domains connectivity. PMID- 29110613 TI - A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials. AB - BACKGROUND: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. METHOD: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. RESULTS: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8+/-4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. CONCLUSION: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer's disease. PMID- 29110614 TI - The Correlations between Postmortem Brain Pathologies and Cognitive Dysfunction in Aging and Alzheimer's Disease. AB - BACKGROUND: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. OBJECTIVE: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. METHOD: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the "ABC" score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. RESULTS: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-beta (Abeta) deposits (A score) present no significant correlation with any of ECog domains. CONCLUSION: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank. PMID- 29110616 TI - Diallyl Disulfide Inhibits Breast Cancer Stem Cell Progression and Glucose Metabolism by Targeting CD44/PKM2/AMPK Signaling. AB - BACKGROUND: It has been reported that diallyl disulfide (DADS) has anti proliferative activity in many cancers. OBJECTIVE: The purpose of this study was to investigate the functions of DADS and the underlying mechanisms of its effect in breast cancer stem cells (BCSCs). METHOD: Mammosphere formation assay, glucose consumption assay, lactate production assay and mouse xenograft experiments were performed to explore the functions of DADS in BCSCs. ATPase activity assay, western blotting and immunohistochemistry (IHC) assay were conduct to explore the mechanisms underlying the effects of DADS in BCSCs. RESULTS: The results showed that DADS suppressed cell stemness and glucose metabolism in BCSCs. In vivo mouse xenograft experiments showed that DADS inhibited the proliferation and metastasis of BCSCs. Then, we continued to explore the mechanisms underlying the effects of DADS in BCSCs and found that DADS acts by targeting CD44, Pyruvate kinase M2 (PKM2) and AMP-activated protein kinase (AMPK) signaling pathways. IHC analysis of 125 breast cancer patients' tissues demonstrated that CD44, PKM2 and AMPK expression levels were positively correlated. In addition, positive CD44, PKM2 and AMPK expression was associated with poor patient overall survival (OS) and disease-free survival (DFS). CONCLUSION: In summary, DADS suppresses cell stemness, proliferation, metastasis and glucose metabolism in BCSCs partly through the inhibition of CD44/PKM2/AMPK. DADS may be used as a potential therapy for breast cancer treatment. PMID- 29110615 TI - Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment. AB - BACKGROUND: Oxidative stress is one of the causative factors in the pathogenesis of neurodegenerative diseases including mild cognitive impairment (MCI) and dementia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant. OBJECTIVE: We assess the effects of drinking H2-water (water infused with H2) on oxidative stress model mice and subjects with MCI. METHODS: Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a dementia model. The mice with enhanced oxidative stress were allowed to drink H2-water. For a randomized double-blind placebo-controlled clinical study, 73 subjects with MCI drank ~300 mL of H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year. RESULTS: In mice, drinking H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the H2-water group was longer than that of the control group. In MCI subjects, although there was no significant difference between the H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4) genotype in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cog score). CONCLUSION: H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI. PMID- 29110617 TI - Degradation of Androgen Receptor through Small Molecules for Prostate Cancer. AB - Prostate cancer is the most common carcinoma among aged males in western countries and more aggressive and lethal castration resistant prostate cancer often occurs after androgen deprivation therapy. The high expression of androgens and androgen receptor is closely related to prostate cancer. Efficient androgen receptor antagonists, such as enzalutamide and ARN-509, could be employed as potent anti-prostate cancer agents. Nevertheless, recent studies have revealed that F876L mutation in androgen receptor converts the action of enzalutamide and ARN-509 from an antagonist to agonist, so that novel strategies are urgent to address this resistance mechanism. In this review, we focus on the discussion about some novel strategies, which targets androgen receptor mainly through the degrading pathway as potential treatments for prostate cancer. PMID- 29110619 TI - Influence of Antipsychotic Drug Risperidone on Human Serum Albumin Affinity to Organic Anions. AB - BACKGROUND: Risperidone is an antipsychotic drug. In blood, this drug binds mainly to human serum albumin (HSA) and is also transported by HSA. METHOD: To study certain details of the interaction between risperidone and HSA, a fluorescent dye CAPIDAN was used as a reporter. This dye specifically fluoresces from HSA in serum and is highly sensitive to structural changes in HSA including pathology-induced changes. Interaction of CAPIDAN with HSA has been studied using time-resolved fluorescence techniques. RESULT: The addition of phenylbutazone, a marker for the HSA drug-binding site I, leads to displacement of CAPIDAN from this site due to direct competition between phenylbutazone and the dye. The addition of risperidone induces a response of CAPIDAN fluorescence that is highly similar to its response to phenylbutazone. This response depends strongly on ionic strength and is very similar in both cases, phenylbutazone and risperidone. This similarity suggests that risperidone binds to HSA in the region of site I. In this site, the risperidone molecule probably covers the positive charge of Arginine 218 or Arginine 222 preventing their interaction with the CAPIDAN negatively charged carboxyl group. This effect was observed both in isolated HSA and in serum, suggesting similarity of the interaction. CONCLUSION: Thus, risperidone is able to prevent binding of organic anions (i.e. CAPIDAN as a drug like molecule) to HSA. PMID- 29110620 TI - Vitamins Based Novel Target Pathways/Molecules as Possible Emerging Drug Targets for the Management of Tuberculosis. AB - BACKGROUND: Tuberculosis (TB) is a deadly infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). Approximately, 1.8 and 1.3 million people are infected and die, from TB each year as estimated by the World Health Organization. Due to increase in the incidence of drug-resistant strains of Mtb, there is an urgent need to accelerate research which focuses on the development of new drugs with novel mechanism of action that can treat both drugsensitive and resistant TB infections. OBJECTIVE: The purpose of this review study was to describe vitamins as drug target that can be explored to develop new anti tubercular drugs that can treat both drug-sensitive and resistant TB infections. METHOD: The methodological approaches include literature review which is performed in the databases like PubMed, Web of Science, Scopus, Springer and Science Direct, etc. On the basis of evaluation of literature sources, the review was complied. RESULTS: This review study demonstrated that vitamins biosynthesis pathway could be used in the development of novel drug targets. Further sequencing of the Mtb genome facilitated research in target identification and validation that make possible the discovery of novel anti-TB agent with new mechanisms of action. Several compounds were identified, which target vitamin biosynthesis pathway /enzymes. Some other new targets were also identified and can be explored for the identification of novel structural moiety. CONCLUSION: Further exploration of these compounds which have been identified to target these vitamins related novel target pathways /molecules could led to the development of antitubercular drug which can be used in the treatment of drug sensitive and resistant TB. PMID- 29110621 TI - Functional Germ Cells From Non-Testicular Adult Stem Cells: A Dream or Reality? AB - BACKGROUND: Some research studies provided evidence for the differentiation capacity of adult stem cells (ASCs) into germ cells (GCs). Since the generation of GCs from stem cells (SCs) has been proposed as a potential way for treatment of infertility, many research groups have begun their creative studies on generation of new GCs both in vitro and in vivo, and utilized different ASC types such as bone marrow mesenchymal stem cells (BM-MSCs), skin stem cells, pancreatic stem cells, and adipose tissue MSCs. Despite many interesting reports with promising results, an obvious problem in the research projects was the functionality of the produced GCs. OBJECTIVE: In this paper, we have reviewed the results of almost all previously published reports on derivation of male and female GCs from ASCs to provide a better insight into this field of research. RESULTS: The most evaluated papers have shown that ASCs from various tissues can differentiate into GCs but rarely were the produced GCs functional and could form fertile gametes neither in vitro, nor in vivo (after transplantation into the gonads). CONCLUSION: There are still so many unknown issues about gametogenesis. Perhaps making alterations in treatment methods and utilizing creative techniques like tissue engineering and gene targeting help to achieve a standard method of in vitro GC production from ASCs. PMID- 29110618 TI - Cognitive Effects of Nicotine: Recent Progress. AB - BACKGROUND: Cigarette smoking is the main cause of preventable death in developed countries. While the direct positive behavioral reinforcing effect of nicotine has historically been considered the primary mechanism driving the development of TUD, accumulating contemporary research suggests that the cognitive-enhancing effects of nicotine may also significantly contribute to the initiation and maintenance of TUD, especially in individuals with pre-existing cognitive deficits. METHODS: We provide a selective overview of recent advances in understanding nicotine's effects on cognitive function, a discussion of the role of cognitive function in vulnerability to TUD, followed by an overview of the neurobiological mechanisms underlying the cognitive effects of nicotine. RESULTS: Preclinical models and human studies have demonstrated that nicotine has cognitiveenhancing effects. Attention, working memory, fine motor skills and episodic memory functions are particularly sensitive to nicotine's effects. Recent studies have demonstrated that the alpha4, beta2, and alpha7 subunits of the nicotinic acetylcholine receptor (nAChR) participate in the cognitive enhancing effects of nicotine. Imaging studies have been instrumental in identifying brain regions where nicotine is active, and research on the dynamics of large-scale networks after activation by, or withdrawal from, nicotine hold promise for improved understanding of the complex actions of nicotine on human cognition. CONCLUSION: Because poor cognitive performance at baseline predicts relapse among smokers who are attempting to quit smoking, studies examining the potential efficacy of cognitive-enhancement as strategy for the treatment of TUD may lead to the development of more efficacious interventions. PMID- 29110622 TI - Recent Development of Sulfonyl or Sulfonamide Hybrids as Potential Anticancer Agents: A Key Review. AB - Cancer is the second leading cause of death worldwide. There is always a huge demand for novel anticancer drugs and diverse new natural or synthetic compounds are developed continuously by scientists. Presently, a large number of drugs in clinical practice have showed pervasive side effect and multidrug resistance. Sulfonyl or sulfonamide hybrids became one of the most attractive subjects due to their broad spectrum of pharmacological activities. Sulfonyl hybrids were broadly explored for their anticancer activities and it was found that they possess minimum side effect along with multi-drug resistance activity. This review describes the most recent applications of sulfonyl hybrid analogues in anticancer drug discovery and further discusses the mechanistic insights, structure-activity relationships and molecular docking studies for the potent derivatives. PMID- 29110623 TI - A Review of the Components of Seaweeds as Potential Candidates in Cancer Therapy. AB - The marine natural products (MNPs) isolated from seaweeds-associated microbial communities have received substantial attention owing to their exceptional nutritional and pharmacology application, such as antiviral, anticancer, antiprotozoal, antifungal, and antibacterial properties and so on. Particularly, there are several MNPs that have been displayed attractive value for the development of novel anticancer agents. This review covers the literature published in the recent 5 years on the novel anticancer MNPs discovered originating from seaweeds, and focused on the chemistry and relative anticancer activities of new MNPs which categorize their source organisms. These seaweed derived MNPs are categorized based on their origin as brown algae, red algae, cyanobacteria, chlorophyta and others. PMID- 29110624 TI - Recent Advancements in Organotin(IV) Complexes as Potential Anticancer Agents. AB - Cancer is a multistep disease incorporating physical, chemical, environmental, metabolic and genetic factors, which play direct or indirect role in the induction and deterioration of cancer. Many of the platinum based drugs were synthesized but due to their systemic toxicity, broad spectrum of action, intrinsic and acquired drug resistivity, it has become necessary to search for the effective anticancer drugs with superior efficiency. Among non-platinum metal compounds with antitumor activity, organotin complexes have proven effective management of toxicity, specific targeted drug uptake by the cancerous cell line and significant potential in the pharmaceutical chemistry. So this article provides a critical review from 2010 onwards of the anticancer activity of the organotin complexes reported by the authors worldwide and explores the landmarks for their future projection as novel anticancer chemotypes with high therapeutic indices. PMID- 29110625 TI - Combined Evaluation of Expression of CXCR4 and Nrf2 as Prognostic Factor for Patients with Gastric Carcinoma. AB - BACKGROUND: CXC Chemokine Receptor 4 (CXCR4) and NFE-related factor 2 (Nrf2) have been observed implicated with cell malignant behavior of human cancers. AIMS: In this study, we detected their expression in gastric carcinoma (GC) tissue specimens and related the result with clinicopathological data and patient survival. METHODS: 120 GC and compared normal tissue specimens were processed to analyse the expression of CXCR4 and Nrf2. We found that the expression of CXCR4 and Nrf2 was dramatically increased in GC tissues when compared to the distant non-cancer tissues (P<0.05). CXCR4 overexpression was associated with the depth of invasion (P= 0.006), Histological grade (P=0.018), TNMstage (P= 0.021), lymph node metastasis (P < 0.001) and distant metastasis (P=0.026), whereas overexpression of Nrf2 protein was significantly associated with tumor size (P=0.045), Histological grade (P=0.026), TNMstage (P= 0.020), lymph node metastases (P < 0.001) and distant metastasis (P=0.008). Furthermore, we observed a significant co-expression of CXCR4 and Nrf2 expression in GC specimens. RESULTS: In the survival part, we found that GC patients with CXCR4+ and Nrf2+ had worse outcomes. The significant prognostic indicators are age, tumor size, histological grade, TNMstage, CXCR4, Nrf2, and coexpression of CXCR4 and Nrf2 in GC patients. Multivariate analysis showed that TNMstage and CXCR4+/Nrf2+ expression were risk factors. Above all we come to the conclusion that the expression of CXCR4 might partly be regulated by the level of Nrf2 and both positive expressions suggest poor prognosis of GC patients. PMID- 29110626 TI - The Rationale for Repurposing Sildenafil for Lung Cancer Treatment. AB - There is now a considerable body of evidence for sildenafil possessing anticancer properties. In this article, we argue the case for testing sildenafil as a lung cancer therapy chemoadjuvant. Currently, lung cancer is a disease with insufficient treatment options, with only 20% of patients responding to systemic chemotherapy, and even incremental potential improvements should be explored. We review the literature concerning the biochemical, physiological and metabolic effects on cancer cells by sildenafil alone, and when combined with chemotherapeutic agents. Most studies have shown that sildenafil is cytotoxic to cancer cells, both as a monotherapy and as a chemoadjuvant. Sildenafil enhances cancer cell apoptosis when used as a chemoadjuvant both in vitro and in vivo. In particular, in rodent experiments sildenafil has decreased tumour size compared to chemotherapy alone. Sildenafil has also been proven as an agent to decrease drug-efflux by cancer cells and increases blood perfusion to lung tissue, which can potentially increase the dosage of chemotherapeutic agents delivered to lung cancer cells compared to healthy tissue. In addition, the proven clinical effects of sildenafil on other lung diseases suggest that it could improve other patient outcomes, such as right ventricular function and quality of life. Sildenafil may also extend the half-life of docetaxel and some small molecule inhibitors used in lung cancer treatment by acting as an inhibitor of CYP3A4. We conclude that the evidence strongly warrants clinical investigation into the use of sildenafil as an agent for the treatment of lung-cancer. PMID- 29110627 TI - The Impact of Translational Research in Breast Cancer Care: Can we Improve the Therapeutic Scenario? AB - Traditionally, breast cancer (BC) is divided into different subtypes defined by immunohistochemistry (IHC) according to the expression of hormone receptors and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), with crucial therapeutic implications. In the last few years, the definition of different BC molecular subgroups within the IHC-defined subtypes and the identification of the important role that molecular heterogeneity can play in tumor progression and treatment resistance have inspired the search for personalized therapeutic approaches. In this scenario, translational research represents a key strategy to apply knowledge from cancer biology to the clinical setting, through the study of all the tumors "omics", including genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Importantly, the introduction of new high-throughput technologies, such as next generation sequencing (NGS) for the study of cancer genome and transcriptome, greatly amplifies the potential and the applications of translational research in the oncology field. Moreover, the introduction of new experimental approaches, such as liquid biopsy, as well as new-concept clinical trials, such as biomarker driven adaptive studies, may represent a turning point for BC translational research. It is likely that translational research will have in the near future a significant impact on BC care, especially by giving us the possibility to dissect the complexity of tumor cell biology and develop new personalized treatment strategies. PMID- 29110628 TI - Synthesis of Biotinylated 2-methoxystypandrone and Identification of JAK2 and IKK as its Targets. AB - BACKGROUND: 2-Methoxystypandrone (2-MS), isolated from the roots of Polygonum cuspidatum, is a potent dual inhibitor of the STAT3 and NF-kappaB pathways. OBJECTIVE: To investigate the molecular targets and mechanisms of 2-MS. METHOD: A biotin-conjugated 2-MS analog, named 2-MS-Biotin, was designed and synthesized. The effects of 2-MS-Biotin on the STAT3 and NF-kappaB pathways were examined by Western blotting. The cytotoxicity of 2- MS-Biotin was evaluated using real-time cell analysis system. Proteins directly bound to 2-MS-Biotin were pulled down through streptavidin agarose beads and were detected using Western blotting. RESULTS: 2-MS-Biotin retained the inhibition activities of the parent compound 2 MS on the STAT3 and NF-kappaB pathways as well as on cancer cell growth. Also, JAK2 and IKK proteins can be effectively pulled down by 2- MS-Biotin. CONCLUSION: Using 2-MS-Biotin as a tool, both JAK2 and IKK were identified as the targets of 2-MS. PMID- 29110629 TI - Commentary: Endophenotypes as Disease Modifiers: Decoding the Biology of Alzheimer's by Genome-wide Association Studies. PMID- 29110630 TI - Genotoxicity of 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4] triazolo[4,3-a]pyrazine, a Potent H4 Receptor Antagonist for the Treatment of Allergy: Evidence of Glyoxal Intermediate Involvement. AB - BACKGROUND: 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3 e][1,2,4]triazolo[4,3-a]pyrazine (1) is a small-molecule which demonstrated a sub nM inhibitory potency toward the histamine H4 receptor (H4R). However, it was found to be mutagenic in an in vitro Ames assay. Metabolic bioactivation of 1 could potentially arise from the piperazine moiety by forming reactive intermediates such as glyoxal, aldehyde-imine and/or iminium ion, which could all lead to genotoxicity. The aim of this study was to investigate bioactivation of 1 to determine the potential causes of the genotoxicity and mitigate liabilities in this scaffold. METHODS: 1 was investigated for its genotoxicity in phenobarbital and beta-naphthoflavone induced Sprague Dawley rat liver S9 fractions. Trapping agents such as o-phenylenediamine was used postincubation. RESULTS: Following metabolic profiling of 1, two oxidative metabolites were observed and identified in phenobarbital- and beta -naphthoflavone induced Sprague Dawley rat liver S9 fractions. Metabolic pathway of 1 was primarily mediated by the metabolism of the piperazine moiety. The trapped glyoxal was identified by using high resolution LC MS instrument. Structural characterization of the trapped glyoxal was determined by comparison of retention time, accurate mass measurement and Collision Induced Dissociation (CID) spectra to authentic standard. CONCLUSION: In the present investigation, a novel method was developed to trap glyoxal, which may potentially be liberated from piperazine moiety. These findings led to modifications on the piperazine ring to mitigate the bioactivation pathways leading to mutagenicity. Subsequently, the next generation compounds with modified piperazine moiety, retained H4R inhibitory potency in vitro and were not genotoxic in the Ames mutagenicity assay. PMID- 29110631 TI - Preparation of Mesalamine Nanoparticles Using a Novel Polyurethane- Chitosan Graft Copolymer. AB - BACKGROUND: Chitosan nanoparticle, a potential vehicle, is used as a hydrophilic carrier system since it can deliver drugs to specific sites and also control the drug release rate. Moreover, controlled release systems are designed to minimize systemic absorption and to achieve optimum delivery of the biologically active mesalamine to the distal small intestine and the colon. OBJECTIVE: The current study investigated the development of new nanoparticulate drug delivery systems based on polyurethane-chitosan copolymers. The copolymer shows good biodegradablity and biocompatiblity properties and thus can be considered as a potential carrier for drug delivery systems. METHOD: In this work, Polyurethane was obtained from the condensation reaction between polypropylene glycol (PPG) as prepolymerpolyol, 1, 4-butanediol (BD) as diol, dimethylol propionic acid (DMPA) as chain extender and also isophoronediisocyanate (IPDI). The synthesized polyurethane was grafted onto the prepared chitosan through a covalent binding and preparation of nanoparticles was done further through a coprecipitation process. The particle size of the prepared samples was evaluated with dynamic light scattering (DLS) technique. RESULTS: The obtained particle size of the samples was 80+/-0.05 nm. Characterization of the synthesized chitosan polyurethane copolymer was performed by FT-IR spectroscopy, 13CNMR and 11HNMR spectroscopy. The morphology of the synthesized polyurethane-chitosan copolymers and the amount of the loaded drug were also examined using SEM images and UV visible spectroscopy, respectively. Moreover, drug release behavior was examined in PBS (pH 7.4) at 37 degrees C. It was concluded that the mesalamine release from polyurethane-chitosan was sustained and no initial burst release (burst effect) was observed and the percentage of mesalamine released from nanoparticles was 92.19+/-0.2% within 72 hrs. CONCLUSION: The results of the drug loaded nanoparticles showed that the drug loading process was performed successfully. As a result, polyurethane-chitosan copolymer can be a good candidate for drug delivery systems. PMID- 29110632 TI - RNA inverse folding using Monte Carlo tree search. AB - BACKGROUND: Artificially synthesized RNA molecules provide important ways for creating a variety of novel functional molecules. State-of-the-art RNA inverse folding algorithms can design simple and short RNA sequences of specific GC content, that fold into the target RNA structure. However, their performance is not satisfactory in complicated cases. RESULT: We present a new inverse folding algorithm called MCTS-RNA, which uses Monte Carlo tree search (MCTS), a technique that has shown exceptional performance in Computer Go recently, to represent and discover the essential part of the sequence space. To obtain high accuracy, initial sequences generated by MCTS are further improved by a series of local updates. Our algorithm has an ability to control the GC content precisely and can deal with pseudoknot structures. Using common benchmark datasets for evaluation, MCTS-RNA showed a lot of promise as a standard method of RNA inverse folding. CONCLUSION: MCTS-RNA is available at https://github.com/tsudalab/MCTS-RNA . PMID- 29110633 TI - Network analysis for count data with excess zeros. AB - BACKGROUND: Undirected graphical models or Markov random fields have been a popular class of models for representing conditional dependence relationships between nodes. In particular, Markov networks help us to understand complex interactions between genes in biological processes of a cell. Local Poisson models seem to be promising in modeling positive as well as negative dependencies for count data. Furthermore, when zero counts are more frequent than are expected, excess zeros should be considered in the model. METHODS: We present a penalized Poisson graphical model for zero inflated count data and derive an expectation-maximization (EM) algorithm built on coordinate descent. Our method is shown to be effective through simulated and real data analysis. RESULTS: Results from the simulated data indicate that our method outperforms the local Poisson graphical model in the presence of excess zeros. In an application to a RNA sequencing data, we also investigate the gender effect by comparing the estimated networks according to different genders. Our method may help us in identifying biological pathways linked to sex hormone regulation and thus understanding underlying mechanisms of the gender differences. CONCLUSIONS: We have presented a penalized version of zero inflated spatial Poisson regression and derive an efficient EM algorithm built on coordinate descent. We discuss possible improvements of our method as well as potential research directions associated with our findings from the RNA sequencing data. PMID- 29110634 TI - JS-MS: a cross-platform, modular javascript viewer for mass spectrometry signals. AB - BACKGROUND: Despite the ubiquity of mass spectrometry (MS), data processing tools can be surprisingly limited. To date, there is no stand-alone, cross-platform 3-D visualizer for MS data. Available visualization toolkits require large libraries with multiple dependencies and are not well suited for custom MS data processing modules, such as MS storage systems or data processing algorithms. RESULTS: We present JS-MS, a 3-D, modular JavaScript client application for viewing MS data. JS-MS provides several advantages over existing MS viewers, such as a dependency free, browser-based, one click, cross-platform install and better navigation interfaces. The client includes a modular Java backend with a novel streaming.mzML parser to demonstrate the API-based serving of MS data to the viewer. CONCLUSIONS: JS-MS enables custom MS data processing and evaluation by providing fast, 3-D visualization using improved navigation without dependencies. JS-MS is publicly available with a GPLv2 license at github.com/optimusmoose/jsms. PMID- 29110635 TI - A modified endoscopic submucosal dissection for a superficial hypopharyngeal cancer: a case report and technical discussion. AB - BACKGROUND: Adequate working space and a clear view for the dissected lesion are crucial for endoscopic submucosal dissection (ESD). Pharyngeal ESD requires that an otorhinolaryngologist creates working space by lifting the larynx with a curved laryngoscope. However, many countries do not have this kind of curved laryngoscope, and the devices could interfere with endoscope because of the narrow space of the pharynx. To overcome these issues, we used a transparent hood (Elastic Touch, slit and hole type, M (long), Top company, Tokyo Japan) instead of the curved laryngoscope to create adequate working space by pushing the larynx, and pharyngeal ESD could be done by gastroenterologists. CASE PRESENTATION: A 64-year-old male patient was admitted to our hospital because of chronic persistent swallowing dysfunction for 2 years. Oesophagogastroduodenoscopy showed a superficial hypopharyngeal cancer in the right pyriform sinus. We used a transparent hood (Elastic Touch, slit and hole type, M (long), Top company, Tokyo Japan) instead of the curved laryngoscope to create adequate working space by pushing the larynx, and dental floss tied to a haemoclip was applied to create counter traction during ESD. The lesion was pathologically confirmed as superficial squamous cell carcinoma and resected completely. CONCLUSIONS: This is the first report of modified ESD for a superficial hypopharyngeal cancer. The modified ESD enables early pharyngeal superficial cancer to be removed completely under endoscope by gastroenterologist. PMID- 29110636 TI - Phenotypic and genotypic aspects of Townes-Brock syndrome: case report of patient in southern Brazil with a new SALL1 hotspot region nonsense mutation. AB - BACKGROUND: Townes-Brocks syndrome (TBS) is a rare autosomal dominant condition characterized by renal, anal, limb, and auditory abnormalities. TBS diagnosis can be challenging in settings where genetic analysis is not readily available. TBS traits overlap with those of Goldenhar and VACTERL syndromes. CASE PRESENTATION: Here, we present the case of a 5-year-old Brazilian boy born with an anorectal abnormality, limb and external ears malformations, genitourinary anomalies, and a congenital heart defect. Genetic analysis revealed a SALL1 nonsense mutation. The case is discussed in the context of the current literature. CONCLUSIONS: Because of the variability in TBS clinical presentation, genetic analysis is key to the differential diagnosis of TBS relative to phenotypically similar syndromes. PMID- 29110637 TI - Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report. AB - BACKGROUND: Multiple Myeloma is a cancer of plasma cells associated with significantly reduced survival. Long term survivorship from myeloma is very rare and despite advances in its treatment the disease is generally considered incurable. We report a patient diagnosed with myeloma carrying a germline mutation of a tumour suppressor gene who has effectively been cured. CASE PRESENTATION: A 36-year-old woman was diagnosed with IgG lambda myeloma in 1985. She was treated with melphalan chemotherapy followed by high-dose melphalan and autologous stem cell rescue and since remained in complete remission despite not having received any additional therapy. After eliciting a prior history of multiple primary melanomas and breast cancer, she was tested for and shown to be a carrier for a germline mutation in CDKN2A. CONCLUSIONS: This is the second case report of germline mutation of CDKN2A being associated with myeloma. CDKN2A is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo sensitivity due to impairment of the DNA repair pathway. PMID- 29110638 TI - Application of the 2016 diagnostic approach for autoimmune encephalitis from Lancet Neurology to Chinese patients. AB - BACKGROUND: A unified clinical approach to diagnose autoimmune encephalitis was published in Lancet Neurology in 2016. Purpose of our study is to examine the feasibility and reasonability of the 2016 "A clinical approach to diagnosis of autoimmune encephalitis" in China with a retrospective study. METHODS: We retrospectively collected 95 cases of autoimmune encephalitis and non autoimmune encephalitis cases with detailed clinical data from Beijing Tongren Hospital and the China National Knowledge Infrastructure (CNKI). All cases were analysed stepwise according to the approach in Lancet Neurology to compare the new diagnosis with the final clinical diagnosis. RESULTS: The disease course of these 95 cases ranged from 2 to 540 days. Initial symptoms include fever, headache, seizure, mental and behavioral disorders, memory deterioration and illusion. Based on symptoms and signs when the patient came to the hospital, the sensitivity and specificity of criteria were as follows: possible autoimmune encephalitis (pAE) 84% and 94%, definite autoimmune limbic encephalitis (dALE) 38% and 96%, probable anti-N-methyl-D-aspartate receptor encephalitis (prNMDARE) 49% and 98%. The sensitivities of the above three criteria and the specificity of pAE were low during early disease stage, while the specificities of dALE and prNMDAER remained relatively high in different time periods. CONCLUSIONS: This new autoimmune encephalitis diagnostic approach can recognize possible autoimmune encephalitis. The chances of a case being autoimmune-mediated following classification as autoimmune encephalitis with the new criteria are high. The flowchart is recommended to use as a whole. At the early disease stage, criteria with low sensitivity and high specificity, such as dALE and prNMDARE, lead most cases to enter subsequent diagnosis steps, namely autoantibody detection in the flowchart. Final diagnoses can only be made by autoantibody tests. These factors may make it challenging for clinicians to make diagnosis promptly and to begin immune-modulating therapy immediately. Moreover, the criteria for patients with paraneoplastic syndromes (PNSs) should be considered to avoid diagnosis omission. For Chinese patients, a multi-centre, prospective study on the clinical manifestations, laboratory diagnostic technology, therapy, and prognosis is greatly needed. PMID- 29110639 TI - A comparison of licensed and un-licensed artisanal and small-scale gold miners (ASGM) in terms of socio-demographics, work profiles, and injury rates. AB - BACKGROUND: Artisanal and small-scale gold mining (ASGM) represents one of the most hazardous work environments. While formalization of this sector has been suggested (e.g., Minamata Convention) as a means to improve working conditions, we are unaware of empirical evidence that supports this notion. This study aimed to compare sociodemographic profiles, work profiles, and injury rates among miners working in licensed versus un-licensed ASGM sites. METHODS: In the Tarkwa mining region of Ghana, 404 small-scale miners were recruited in 2014 and interviewed regarding their occupational injury experiences over the preceding 10 years. Workers were drawn from 9 mining sites, of which 5 were licensed and 4 were not licensed. RESULTS: Sociodemographic characteristics of miners from the two groups were relatively similar. Those currently working in an un-licensed mine have spent more time in the ASGM sector than those currently working in a licensed mine (94 vs. 70 months). Miners working in an un-licensed site tended to experience more injury episodes (e.g., 26% vs. 8% had 3 or more injury events) and not use personal protective equipment during the time of an injury (92% indicated to not using vs. 73%) when compared to miners working in a licensed site. A total of 121 injury episodes were recorded for 2245 person years of ASGM work. The injury rate for those working in un-licensed mines was 5.9 per 100 person years (59 injuries in 995 person years) versus 5.0 (62 injuries in 1250 person-years) in the licensed mines. When focusing on the male miners, there was a significant difference in injury rates between those working in a licensed mine (4.2 per 100 person years) versus an un-licensed mine (6.1 per 100 person years). CONCLUSIONS: These findings advance our understanding of injuries amongst ASGM workers, and help identify important differences in socio-demographics, work profiles, and injury rates between miners working in a licensed versus and un licensed site. The findings suggest that certain working conditions in a licensed site may be safer. PMID- 29110640 TI - Prevalence and molecular characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates from Southern China. AB - BACKGROUND: Pyrazinamide (PZA) plays a unique role in the treatment for multidrug resistant tuberculosis (MDR-TB) in both first- and second-line regimens. The aim of this study was to investigate the prevalence and molecular characterization of PZA resistance among MDR-TB isolates collected in Chongqing municipality. METHODS: A total of 133 MDR-TB isolates were collected from the smear-positive tuberculosis patients who were registered at local TB dispensaries of Chongqing. PZA susceptibility testing was determined with a Bactec MGIT 960 system. In addition, the genes conferring for PZA resistance were screened by DNA sequencing. RESULTS: Of these 133 MDR-TB isolates, 83 (62.4%) were determined as PZA-resistant by MGIT 960. In addition, streptomycin- (83.1% vs. 56.0%, P < 0.01), ofloxacin- (51.8% vs. 18.0%, P < 0.01), kanamycin- (22.9% vs. 2.0%, P < 0.01), amikacin- (18.1% vs. 2.0%, P = 0.01), capromycin-resistance (12.0% vs. 2.0%, P = 0.05), were more frequently observed among PZA-resistant isolates compared with PZA-susceptible isolates. Sequence analysis revealed that 73 out of 83 (88.0%) MDR strains harbored a mutation located in the pncA gene, including 55 (75.3%, 55/73) of single nucleotide substitutions and 18 (24.7%, 18/73) of frameshift mutation, while no genetic mutation associated with PZA resistance was found in the rpsA gene. The pncA expression of strains harboring substitution from A to G at position -11 in the promoter region of pncA was significantly lower than that of H37Rv (P < 0.01). CONCLUSIONS: In conclusion, our data have demonstrated that the analysis of the pncA gene rather than rpsA gene provides rapid and accurate information regarding PZA susceptibility for MDR-TB isolates in Chongqing. In addition, loss of pncA expression caused by promoter mutation confers PZA resistance in MDR-TB isolates. PMID- 29110641 TI - Correction to: The effectiveness of a life style modification and peer support home blood pressure monitoring in control of hypertension: protocol for a cluster randomized controlled trial. AB - After publication of the article [1], it has been brought to our attention that the methodology outlined in the original article was not able to be fully carried out. The article planned a two armed randomized control trial. However, due to a lower response than expected and one housing complex dropping out from the study, the method was changed to pre- and post-intervention with no control group. All other methods were conducted as outlined in the original article. PMID- 29110642 TI - In vivo functional analysis of L-rhamnose metabolic pathway in Aspergillus niger: a tool to identify the potential inducer of RhaR. AB - BACKGROUND: The genes of the non-phosphorylative L-rhamnose catabolic pathway have been identified for several yeast species. In Schefferomyces stipitis, all L rhamnose pathway genes are organized in a cluster, which is conserved in Aspergillus niger, except for the lra-4 ortholog (lraD). The A. niger cluster also contains the gene encoding the L-rhamnose responsive transcription factor (RhaR) that has been shown to control the expression of genes involved in L rhamnose release and catabolism. RESULT: In this paper, we confirmed the function of the first three putative L-rhamnose utilisation genes from A. niger through gene deletion. We explored the identity of the inducer of the pathway regulator (RhaR) through expression analysis of the deletion mutants grown in transfer experiments to L-rhamnose and L-rhamnonate. Reduced expression of L-rhamnose induced genes on L-rhamnose in lraA and lraB deletion strains, but not on L rhamnonate (the product of LraB), demonstrate that the inducer of the pathway is of L-rhamnonate or a compound downstream of it. Reduced expression of these genes in the lraC deletion strain on L-rhamnonate show that it is in fact a downstream product of L-rhamnonate. CONCLUSION: This work showed that the inducer of RhaR is beyond L-rhamnonate dehydratase (LraC) and is likely to be the 2-keto-3-L deoxyrhamnonate. PMID- 29110643 TI - Perceived coercion in psychiatric hospital admission: validation of the French language version of the MacArthur Admission Experience Survey. AB - BACKGROUND: The MacArthur Admission Experience Survey (AES) is a widely used tool to evaluate the level of perceived coercion experienced at psychiatric hospital admission. The French-language AES was prepared using a translation/back translation procedure. It consists of 16 items and 3 subscores (perceived coercion, negative pressures and voice). This study aimed to assess the psychometric properties of the French-language AES. METHODS: 152 inpatients were evaluated. Reliability was estimated using internal consistency coefficients and a test-retest procedure. Internal validity was assessed using a two-parameter logistic item response model. Convergent validity was estimated using correlations between the AES scores and the Coercion Ladder (CL), the Coercion Experience Scale (CES) and the Global Assessment of Functioning (GAF) scale. Discriminatory power was evaluated by comparing the scores of patients undergoing voluntary or compulsory admission. RESULTS: The French-language AES showed good internal consistency and test-retest reliability. Internal validity of the three factor model was excellent. Correlations between AES and CL, CES and GAF scores suggested good convergent validity. AES scores were significantly higher among patients subject to compulsory psychiatric hospital admission than among those admitted voluntarily. CONCLUSIONS: Overall, the French-language version of the AES demonstrated very good psychometric proprieties. PMID- 29110644 TI - The protective role of religiosity against problem gambling: findings from a five year prospective study. AB - BACKGROUND: Little research has examined the potential protective influence of religiosity against problem gambling; a common addictive behavior, and one with a host of associated negative health and social outcomes. The aims of this study were to examine (1) the potential longitudinal association between religiosity and problem gambling among adults and (2) the potential moderating role of gender on this association. METHODS: Data were from five waves of the Quinte Longitudinal Study (QLS), between 2006 and 2010. Participants were Canadian adults from Belleville, Ontario, Canada (n = 4121). A multiple group (based on gender) latent growth curve analysis was conducted to examine the overall trajectory of problem gambling severity. Two models were tested; the first examined the influence of past-year religious service attendance, and the second examined an overall measure of personal religiosity on the trajectory of problem gambling. The Problem and Pathological Gambling Measure (PPGM) was used as a continuous measure. The Rohrbaugh-Jessor Religiosity Scale (RJRS) was used to assess past-year frequency of religious service attendance and personal religiosity. Religious affiliation (Protestant, Catholic, Atheist/Agnostic, Other, Prefer not to say) was also included in the models. RESULTS: At baseline, higher frequency of past-year religious service attendance (males: beta= -0.54, females: beta= -0.68, p < 0.001 for both) and greater overall personal religiosity (males: beta= -0.17, females: beta= -0.13, p < 0.001 for both) were associated with lower PPGM scores. The moderating effect of gender indicated that the influence of past-year religious service attendance was greater among females (chi2diff(44) = 336.8, p < 0.001); however, the effect of overall religiosity was greater among males (chi2diff(36) = 213.4, p < 0.001). Findings were mixed with respect to religious affiliation. No measures of religiosity or religious affiliation were associated with the overall decline in problem gambling severity. CONCLUSIONS: These findings suggest that religiosity may act as a static protective factor against problem gambling severity but may play a less significant role in predicting change in problem gambling severity over time. PMID- 29110645 TI - Long intergenic non-protein-coding RNA 1567 (LINC01567) acts as a "sponge" against microRNA-93 in regulating the proliferation and tumorigenesis of human colon cancer stem cells. AB - BACKGROUND: Cancer stem cells (CSCs) are considered to be the major factor in tumor initiation, progression, metastasis, recurrence and chemoresistance. Maintaining the stemness and promoting differentiation of these cells involve various factors. Recently, long non-coding RNAs (lncRNAs) have been identified as new regulatory factors in human cancer cells. However, the function of lncRNAs in colon CSCs is still unknown. METHODS: Primary colon cancer cells were maintained in serum-free medium to form spheres and CD133+/CD166+/CD44+ spheroid cells were selected using FACS technique. Then we detected growth curve, colony formation, invasion and migration ability, and tumorigenicity of CD133+/CD166+/CD44+ cells. LOCCS-siRNA and pcDNA-LOCCS plasmid vectors were constructed and transfected to evaluate impact of the lncRNA. We also performed dual luciferase reporter assay to verify the interaction of LOCCS and miR-93. RESULTS: The research explored lncRNA expression and the regulatory role of novel lncRNAs in colon CSCs. Using the stem cell markers CD133, CD166 and CD44, we found a subpopulation of highly tumorigenic human colon cancer cells. They displayed some characteristics of stem cells, including the ability to proliferate and form colonies, to resist chemotherapeutic drugs, and to produce xenografts in nude mice. We also found an lncRNA, LOCCS, with obviously upregulated expression in colon CSCs. Knockdown of LOCCS reduced cell proliferation, invasion, migration, and generation of tumor xenografts. Furthermore, microRNA-93 (miR-93) and Musashi-1 mediated the tumor suppression of LOCCS knockdown. CONCLUSIONS: There was reciprocal repression between LOCCS and miR-93. Research on mechanisms suggested direct binding, as a predicted miR-93 binding site was identified in LOCCS. This comprehensive analysis of LOCCS in colon CSCs provides insight for elucidating important roles of the lncRNA-microRNA functional network in human colon cancer. PMID- 29110646 TI - High-impact exercise in adulthood and vertebral dimensions in midlife - the Northern Finland Birth Cohort 1966 study. AB - BACKGROUND: Vertebral size and especially cross-sectional area (CSA) are independently associated with vertebral fracture risk. Previous studies have suggested that physical activity and especially high-impact exercise may affect vertebral strength. We aimed to investigate the association between high-impact exercise at 31 and 46 years of age and vertebral dimensions in midlife. METHODS: We used a subsample of 1023 individuals from the Northern Finland Birth Cohort 1966 study with records of self-reported sports participation from 31 and 46 years and MRI-derived data on vertebral dimensions from 46 years. Based on the sports participation data, we constructed three impact categories (high, mixed, low) that represented longitudinal high-impact exercise activity in adulthood. We used linear regression and generalized estimating equation (GEE) models to analyse the association between high-impact exercise and vertebral CSA, with adjustments for vertebral height and body mass index. RESULTS: Participation in high-impact sports was associated with large vertebral CSA among women but not men. The women in the 'mixed' group had 36.8 (95% confidence interval 11.2-62.5) mm2 larger CSA and the women in the 'high' group 43.2 (15.2-71.1) mm2 larger CSA than the 'low' group. CONCLUSIONS: We suggest that participation (>= 1/week) in one or more high-impact sports in adulthood is associated with larger vertebral size, and thus increased vertebral strength, among middle-aged women. PMID- 29110647 TI - A randomized, placebo-controlled clinical trial evaluating the safety and efficacy of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus inadequately controlled by glimepiride and metformin. AB - BACKGROUND: Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride. METHODS: Patients with T2D and HbA1c >=7.5% and <=10.5% while on metformin (>=1500 mg/day) and glimepiride (>=4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of <7% and <6.5%. RESULTS: From a mean baseline HbA1c of 8.5% (omarigliptin) and 8.6% (placebo), the least squares (LS) mean change from baseline in HbA1c at Week 24 was -0.67% in the omarigliptin group and -0.06% in the placebo group, with a between-group difference (95% CI) of -0.61% (-0.85, -0.38). Treatment with omarigliptin resulted in a significantly greater reduction in FPG relative to placebo (LS mean difference [95% CI] -0.9 mmol/L [-1.4, -0.4]; p < 0.001). The proportion of patients achieving glycemic goals of <7.0% and <6.5% was higher in the omarigliptin group relative to the placebo group. The overall incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuations were generally similar between treatment groups. The incidence of symptomatic hypoglycemia was 10.5% in the omarigliptin group and 8.5% in the placebo group. Relative to baseline, omarigliptin and placebo treatments were associated with LS mean changes in body weight of -0.1 kg and -0.9 kg, respectively. CONCLUSION: In patients with T2D and inadequate glycemic control on dual therapy with metformin and glimepiride, compared with placebo, once-weekly omarigliptin provided greater improvement in glycemic control and was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01704261 , EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012. PMID- 29110648 TI - Prospective study of 11C-methionine PET for distinguishing between recurrent brain metastases and radiation necrosis: limitations of diagnostic accuracy and long-term results of salvage treatment. AB - BACKGROUND: On conventional diagnostic imaging, the features of radiation necrosis (RN) are similar to those of local recurrence (LR) of brain metastases (BM). 11C-methionine positron emission tomography (MET-PET) is reportedly useful for making a differential diagnosis between LR and RN. In this prospective study, we aimed to investigate the diagnostic performance of MET-PET and the long-term results of subsequent patient management. METHODS: The eligible subjects had enlarging contrast-enhanced lesions (>1 cm) on MR imaging after any form of radiotherapy for BM, suggesting LR or RN. However, it was difficult to differentiate LR from RN in these cases. From August 2013 to February 2017, MET PET was performed for 37 lesions in 32 eligible patients. Tracer accumulation in the regions of interest was analysed as the standardised uptake value (SUV) and maximal lesion SUV/maximal normal tissue SUV ratios (LNR) were calculated. The cut-off value for LNR was provisionally set at 1.40. Salvage treatment strategies determined based on MET-PET diagnosis and treatment results were investigated. The diagnostic accuracy of MET-PET was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: The median interval from primary radiotherapy to MET-PET was 19 months and radiotherapy had been performed twice or more for 13 lesions. The MET-PET diagnoses were LR in 19 and RN in 18 lesions. The mean values and standard deviation of LNRs for each diagnostic category were 1.70 +/- 0.30 and 1.09 +/- 0.25, respectively. At the median follow-up time of 18 months, final diagnoses were confirmed histologically for 17 lesions and clinically for 20 lesions. ROC curve analysis indicated the optimal LNR cut-off value to be 1.40 (area under the curve: 0.84), and the sensitivity and specificity were 0.82 and 0.75, respectively. The median survival times of patient groups with LR and RN based on MET-PET diagnosis were 14.8 months and 35.1 months, respectively (P = 0.035, log-rank test). CONCLUSIONS: MET-PET showed apparently reliable diagnostic performance for distinguishing between LR and RN. The provisional LNR cut-off value of 1.4 in our institution was found to be appropriate. Limitations of diagnostic accuracy should be recognised in cases with LNR close to this cut-off value. PMID- 29110650 TI - Group-based developmental BMI trajectories, polycystic ovary syndrome, and gestational diabetes: a community-based longitudinal study. AB - BACKGROUND: Obesity is common in young women, increasing insulin resistance (IR) and worsening pregnancy complications, including gestational diabetes (GDM). Women with polycystic ovary syndrome (PCOS) are commonly obese, which aggravates the severity of PCOS clinical expression. Relationships between these common insulin-resistant conditions, however, remain unclear. METHODS: We conducted a secondary analysis of the Australian Longitudinal Study on Women's Health (ALSWH) database, including data from 8009 women aged 18-36 years across six surveys. We used latent-curve growth modelling to identify distinct body mass index (BMI) trajectories and multinomial logistic regression to explore sociodemographic and health variables characterizing BMI group membership. Logistic regression was used to assess independent risk of GDM. RESULTS: A total of 662 women (8.29%, 95% CI 7.68-8.89) reported PCOS. Three distinct BMI trajectories emerged, namely low stable (LSG) (63.8%), defined as an average trajectory remaining at ~25 kg/m2; moderately rising (MRG) (28.8%), a curvilinear trajectory commencing in a healthy BMI and terminating in the overweight range; and high-rising (HRG) (7.4%), a curvilinear trajectory starting and terminating in the obese range. A high BMI in early reproductive life predicted membership in higher trajectories. The HRG BMI trajectory was independently associated with GDM (OR 2.50, 95% CI 1.80-3.48) and was a stronger correlate than PCOS (OR 1.89, 95% CI 1.41-2.54), maternal age, socioeconomic status, or parity. CONCLUSION: Our results suggest heterogeneity in BMI change among Australian women of reproductive age, with and without PCOS. Reducing early adult life weight represents an ideal opportunity to intervene at an early stage of reproductive life and decreases the risk of long-term metabolic complications such as GDM. PMID- 29110649 TI - Associations between physical activity and motivation, competence, functioning, and apathy in inhabitants with mental illness from a rural municipality: a cross sectional study. AB - BACKGROUND: There is increasing evidence for physical activity (PA) having a positive impact on physical and mental health as well as illness symptoms in individuals with severe mental illness (SMI). However, individuals with SMI experience several barriers that makes it difficult to take advantage of the benefits associated with PA. One barrier consistently reported to impede PA is motivational issues. Thus, the main aim of the present study was to examine associations between PA and motivation for PA, perceived competence for PA, functioning, apathy, and demographic variables among individuals with SMI. This was conducted within a larger study aiming at including all inhabitants with SMI in one particular small, rural municipality. METHOD: A total of 106 participants were recruited to the study. Questionnaire-based interviews conducted by two mental health nurses assessed self-reported PA, motivation and competence for PA, functioning, and apathy. Additionally, 71 participants accepted to wear an accelerometer-equipped wristwatch yielding an objective assessment of PA. RESULTS: The participants engaged in little PA. However, they did not lack motivation, as over 90% stated that they would like to be more active, and participants across PA level displayed high scores of a motivation reflecting that they valued the benefits of PA. Results showed that higher self-reported PA level was associated with higher levels of integrated regulated motivation and perceived competence for PA while it was unrelated to functioning and apathy. In the subpopulation with objectively measured PA, integrated regulated motivation for PA remained significantly associated with PA level, whereas poor scores on functioning lowered the odds ratio for higher PA level. CONCLUSION: The results show that PA specific motivation is associated with PA even when controlling for functioning and apathy. This highlight the importance of facilitating context specific motivation (i.e., motivation for PA) and that health care practitioners should emphasise helping people with SMI develop more intrinsic forms of motivation. PMID- 29110651 TI - Variability in market uptake of psychotropic medications in Europe reflects cultural diversity. AB - BACKGROUND: In the last 20-30 years, many international studies have found substantial differences in the use of (older) psychotropic medication between European countries. The majority mentioned an important role for attitudes and beliefs towards psychotropic medication. So far, no studies have looked into the effects of cultural diversity on the use of new medications entering the market. As national cultures relate deeply to held values regarding, for example, what is seen as effective versus ineffective or safe versus dangerous, (cultural) diversity in decision making around the role of new medications in clinical practice may already be expected from the first day after market authorization. METHODS: This study examined the relation between cultural diversity, described in Hofstede's model of cultural dimensions (Power Distance, Individualism, Masculinity, Uncertainty Avoidance, Indulgence and Long-Term Orientation) and utilization of three new psychotropic medications, namely aripiprazole, duloxetine and pregabalin in Europe. Country level sales data of the case study medications were correlated to country-specific scores of Hofstede's cultural dimensions. IMS Health's MIDAS database has been used for sales data (converted to Defined Daily Doses/1000 inhabitants/day) for the case study medications from the market authorization date in 2004 until December 2009 for 23 EU member states. RESULTS: Consumption of the case study medications was seen in all countries. In general, pregabalin was used more often than aripiprazole and duloxetine. In 2 years after market authorization, approximately 80% of all countries have reported use of all three molecules. Correlations between Hofstede dimensions individualism, long-term orientation and indulgence and total use of the case study medications tended to become stronger over time, but they were only statistically significant for indulgence at two years after market authorization (rho = 0.51, p = 0.014) and three years after market authorization (rho = 0.54, p = 0.008). A more detailed analysis showed (slight) variation by molecule. CONCLUSIONS: This study is a first step in including cultural dimensions when explaining cross-national variation in the use of new medications. The results indicate that indulgence, however marginally, is a cultural aspect that relates to the utilization of new psychotropic medications, suggesting that within the cultural context, less regulation of social norms is a main factor in explaining cross-national variation in uptake of these medications. PMID- 29110652 TI - Open subpectoral biceps tenodesis in patients over 65 does not result in an increased rate of complications. AB - BACKGROUND: Long head biceps tendon pathology is a common cause of anterior shoulder pain and is often associated with other shoulder conditions, such as rotator cuff tears and osteoarthritis. It is well accepted that older patients are at increased risk for major and minor peri- and postoperative complications. The purpose of this study is to investigate patients over 65 years old who underwent subpectoral biceps tenodesis and compare the complication rates of this group to those of patients younger than 65 years old. The hypothesis is, that there would be no difference in complication rates and that clinical outcome scores for patients over 65 were satisfying and showed improvements over time. METHODS: There were 337 patients who underwent open subpectoral biceps tenodesis, between January 2005 and June 2015, 23 were identified as being over the age of 65 with a minimum follow up of 12 months. All patients over the age of 65 were evaluated pre- and postoperatively using Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES), Constant-Murley (CM) and Single Assessment Numeric Evaluation (SANE). Intraoperative and postoperative adverse events (fracture, infection, wound opening, rupture/failure and neurovascular injuries) related to the tenodesis procedure and to the surgery itself were collected from all 337 patients in a routine postoperative follow-up. RESULTS: The under 65 group (range 27-64 years) at an average follow up (FU) of 30 months (range 12-91 months) showed a 5.4% (17 out of 314) post-operative complication rate related to the subpectoral tenodesis, whereas the group over 65 (range 65-77 years) at an average follow up of 33 months (range 12-79 months) showed an 8.7% (2 out of 23) complication rate. CONCLUSION: This study demonstrates that in patients over the age of 65, biceps tenodesis is a successful procedure when performed for biceps tendinopathy and concomitantly with other surgical procedures of the shoulder, and does not result in an increased rate of complications when compared to a group of patients under the age of 65. PMID- 29110653 TI - Brief reasons for living inventory: a psychometric investigation. AB - BACKGROUND: The present study aimed at validating the German version of the Brief Reasons for Living inventory (BRFL). METHODS: Validity and reliability were established in a community (n = 339) and a clinical sample (n = 272). Convergent and discriminant validity were investigated, and confirmatory factor analyses were conducted for the complete BRFL as well as for a 10-item version excluding conditional items on child-related concerns. Furthermore, it was assessed how BRFL scores moderate the association between depression and suicide ideation. RESULTS: Results indicated an adequate fit of the data to the original factor structure. The total scale and the subscales of the German version of the BRFL had sufficient internal consistency, as well as good convergent and divergent validity. The BRFL demonstrated clinical utility by differentiating between participants with vs. without suicide ideation. Reasons for living proved to moderate the association between depression and suicide ideation. CONCLUSIONS: Results provide preliminary evidence that the BRFL may be a reliable and valid measure of adaptive reasons for living that can be used in clinic and research settings. PMID- 29110654 TI - Correction to: The GREENH-City interventional research protocol on health in all policies. AB - After publication of the article [1], it has been brought to our attention that in the original publication the third author's name was spelt incorrectly. The correct spelling is "Emmanuelle Faure". This was previously spelt as "Emmannuelle Faure". The original article has been revised to reflect this. PMID- 29110655 TI - Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series. AB - BACKGROUND: Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1-2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. METHODS: Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6 week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. RESULTS: We identified 9 paediatric/young adult patients (aged 11-21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to >73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. CONCLUSION: The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment. PMID- 29110656 TI - In-patient Tolvaptan use in SIADH: care audit, therapy observation and outcome analysis. AB - BACKGROUND: Indications for use of tolvaptan in SIADH-associated hyponatraemia remain controversial. We audited our local guidelines for Tolvaptan use in this situation to review treatment implications including drug safety, hospital admission episode analysis (episodes of liver toxicity, CNS myelinolysis, sodium related re-admission rates), morbidity; mortality and underlying aetiologies. METHODS: We report a retrospective case series analysis of on-going treatment outcomes (case-note review) for 31 patients (age 73.3 +/- 10.5 years, 55% females) consecutively treated with Tolvaptan as in-patient for confirmed SIADH with persistent S/Na+ < 125 mmol/L despite removal of reversible causes and 24-48 h fluid restriction, and include longer-term outcome data (re treatment/readmissions/mortality) for up to 4 years of follow-up. A minimum of 6 months follow-up data were reviewed unless the patient died before that period. RESULTS: Short-term outcomes were favourable; 94%-achieved treatment targets after a mean of 3.48 +/- 2.46 days. There was statistically significant rise in S/Na+ level after Tolvaptan treatment (before treatment: mean sodium 117.8 +/- 3.73, 108-121 mmol/L and after treatment: mean sodium 128.7 +/- 3.67, 125-135.2 mmol/L, P < .001). Although the target S/Na+ level was >125 mmol/L in fact one third (35%) of the patients achieved a S/Na+ level of >130 mmol/L by the time of hospital discharge. No patient experienced S/Na+ rise >12 mmol/L/24 h, drug associated liver injury or CNS-myelinolysis. The average length of hospital stay following start of Tolvaptan treatment was 3.2 days. Relapse of hyponatraemia occurred in 26% of the patients, requiring retreatment with Tolvaptan. In all patients where either relapse of hyponatraemia occurred or readmission was necessary, SIADH was associated with malignancy, which was present overall in 60% of the group studied. CONCLUSIONS: This study confirms the safety and efficacy of Tolvaptan in the treatment of SIADH-related significant, symptomatic hyponatraemia when used under specialist guidance and strict monitoring. A sodium level relapsing below the treatment threshold by 1 week after discontinuation is a good indicator of a patient group with re-treatment/longer-term therapy needs, all of whom had underlying malignancy. The criteria set locally in our trust to initiate Tolvaptan use also identifies a group where further investigation for underlying malignancy should be considered. PMID- 29110657 TI - Social capital and health in China: exploring the mediating role of lifestyle. AB - BACKGROUND: Although social capital as a key determinant of health has been well established in various studies, little is known about how lifestyle factors mediate this relationship. Understanding the cross-relationships between social capital, health, and lifestyle factors is important if health promotion policies are to be effective. The purpose of this study is to explore whether different dimensions of social capital and lifestyle factors are related, and whether lifestyle factors mediate the association between social capital and self-rated health (SRH) and psychological well-being (PWB) in China. METHODS: This study used nationally representative data from the 2014 China Family Panel Studies (n = 28,916). The data reported on three dimensions of individual-level social capital: social trust, social relationship and Chinese Communist Party (CCP) membership. Health was assessed using SRH and PWB. Five lifestyle indicators were recorded: healthy diet, physical activity, smoking, sleeping, and non-overweight status. Logistic regression was used to examine the associations between social capital and lifestyle factors, and whether there was a mediating role of lifestyle. Odds ratios relating health status to social capital were reported before and after adjustment for lifestyle factors. Mediation analysis was then used to calculate the total, direct and indirect effects of social capital on SRH and PWB. RESULTS: The results show that social trust was significantly associated with all five lifestyle factors. Social relationship was significantly associated with four of the five: healthy diet, physical activity, sleeping and non overweight. CCP membership was only significantly associated with two lifestyle factors: physical activity and non-overweight. Social trust and social relationship were significantly related to both SRH and PWB. CCP membership was only significantly related to SRH. Mediation analysis found modest evidence that lifestyle factors influenced the relationship between all three types of social capital and SRH. In contrast, only social trust and social relationship, but not CCP membership, were mediated by lifestyle factors with respect to PWB. CONCLUSIONS: This study is the first to explore the mediating role of lifestyle factors in the relationship between social capital and health in China. The overall findings suggest that lifestyle factors modestly mediate the association between social capital and health. The degree of mediating effect varies across different dimensions of social capital. Social capital-based health promotion policies would benefit from taking lifestyle factors into account. PMID- 29110658 TI - Effect of primary Phacoviscocanalostomy/ Viscocanalostomy on intraocular pressure of normal tension glaucoma patients: 3-year results. AB - BACKGROUND: The objective of this study was to evaluate the efficacy of Viscocanalostomy/Phacoviscocanalostomy (VC/PVC) in lowering intraocular pressure (IOP) in Normal Tension Glaucoma (NTG) patients. METHODS: Retrospective electronic database review of patients who underwent VC/PVC for NTG between December 2009 and November 2011 at Stanley eye unit in Abergele Hospital. Goldmann applanation tonometry (GAT) was used for all IOP measurements which were taken at the time of listing for surgery and at 1 day, 1 week, 1 month, then 3 monthly up to 1 year, then half-yearly up to 3 years post operatively. Statistical analysis was performed using unpaired t-test. A P value of <0.05 was accepted as the level of significance. RESULTS: Operations were performed on 94 eyes from 67 patients over the study period. The mean age at the time of surgery was 76.4 years. Pre-operative IOP was 17.75 +/- 2.19 mmHg (range 12-21 mmHg). 3 year follow-up showed a mean IOP of 13.41 +/- 2.22 mmHg (range 8-18 mmHg). By year 3, 17 patients needed laser goniopuncture and 25 patients needed antiglaucoma drops. IOP was reduced by 24.4% at 3 years post-surgery, which was statistically significant (p < 0.0001). CONCLUSIONS: From our results, which show a 24.5% reduction in IOP at 3 years with 12% complication rate, we propose that a logical surgical management for NTG patients would be viscocanalostomy, thereby keeping trabeculectomy as an alternative. PMID- 29110659 TI - Validation and comparison of the molecular classifications of pancreatic carcinomas. AB - Four molecular classifications of pancreatic ductal adenocarcinoma (PDAC), biologically and clinically relevant and based on gene expression profiles, were established in the recent years, including the Collisson's, Moffitt's ("tumor" and "stroma" classifications), and Bailey's classifications. The aim of this study was to validate the prognostic value of the Moffitt's classifications and to compare the Collisson's, Moffitt's, and Bailey's classifications in a large series of samples. We collected clinical and gene expression data of PDAC samples from 15 public data sets, resulting in a total of 846 primary cancer samples, including 601 with survival annotation. All samples were classified according to each of the four multigene classifiers. We confirmed the independent prognostic value of the Moffitt "tumor", Moffitt "stroma", and Bailey's classifications, but not that of the Collisson's classification. Despite a relatively low gene overlap, all classifications were associated with pathological grade, an important prognostic feature and reflect of intrinsic molecular characteristics of tumors. The concordance rate in term of "good-prognosis" vs. "poor-prognosis" prediction by classifiers was relatively high (from 73 to 86%) between the three "tumor" classifications based on tumor gene lists (Collisson, Moffitt "tumor", Bailey), but low (from 50 to 60%) with the Moffitt's stroma classification based on stroma genes. Multivariate analysis incorporating the four classifiers together retained as significant variables the Moffitt "stroma" and Bailey classifications, highlighting the complementarity of classifiers based on tumor epithelium (Bailey) and tumor stroma (Moffitt stroma). Our results reinforce the clinical validity of subtyping in PDAC, which should be regarded as a collection of separate diseases. Beside their clinical utility that remains to be demonstrated, the clinical interest of the subtypes, notably those from Bailey's and Moffitt's "stroma" classifiers that show independent prognostic value, will be reinforced by the identification of new biomarkers and/or therapeutic targets in each subtype for designing and testing novel specific targeted therapies. PMID- 29110661 TI - Correction to: Opportunities for reproductive tourism: cost and quality advantages of Turkey in the provision of in-vitro Fertilization (IVF) services. AB - ?. PMID- 29110660 TI - Characterization of respiratory dendritic cells from equine lung tissues. AB - BACKGROUND: Dendritic cells (DCs) are professional antigen-presenting cells that have multiple subpopulations with different phenotypes and immune functions. Previous research demonstrated that DCs have strong potential for anti-viral defense in the host. However, viruses including alphaherpesvirinae have developed strategies to interfere with the function or maturation of DCs, causing immune dysfunction and avoidance of pathogen elimination. The goal of the present study was to isolate and characterize equine lung-derived DCs (L-DCs) for use in studies of respiratory viruses and compare their features with equine blood derived DCs (B-DCs), which are currently used for these types of studies. RESULTS: We found that L-DCs were morphologically similar to B-DCs. Overall, B DCs demonstrated higher expression of CD86 and CD172alpha than L-DCs, but both cell types expressed high levels of MHC class II and CD44, as well as moderate amounts of CD163, CD204, and Bla36. In contrast, the endocytic activity of L-DCs was elevated compared to that of B-DCs. Finally, mononuclear cells isolated from lung (L-MCs), which are used as precursors for L-DCs, expressed more antigen presenting cell-associated markers such as MHC class II and CD172alpha compared to their counterparts from blood. CONCLUSIONS: Our results indicate that L-DCs may be in an earlier differentiation stage compared to B-DCs. Concurrent with this observation, L-MCs possessed significantly more antigen-uptake capacity compared to their counterparts from blood. It is likely that L-DCs play an important role in antigen uptake and processing of respiratory pathogens and are major contributors to respiratory tract immunity and may be ideal tools for future in vitro or ex vivo studies. PMID- 29110662 TI - Reliability of Multiple Mini-Interviews and traditional interviews within and between institutions: a study of five California medical schools. AB - BACKGROUND: Many medical schools use admissions Multiple Mini-Interviews (MMIs) rather than traditional interviews (TIs), partly because MMIs are thought to be more reliable. Yet prior studies examined single-school samples of candidates completing either an MMI or TI (not both). Using data from five California public medical schools, the authors examined the within- and between-school reliabilities of TIs and MMIs. METHODS: The analyses included applicants interviewing at >=1 of the five schools during 2011-2013. Three schools employed TIs (TI1, TI2, TI3) and two employed MMIs (MMI1, MMI2). Mixed linear models accounting for nesting of observations within applicants examined standardized TI and MMI scores (mean = 0, SD = 1), adjusting for applicant socio-demographics, academic metrics, year, number of interviews, and interview date. RESULTS: A total of 4993 individuals (completing 7516 interviews [TI = 4137, MMI = 3379]) interviewed at >=1 school; 428 (14.5%) interviewed at both MMI schools and 687 (20.2%) at more than one TI school. Within schools, inter-interviewer consistency was generally qualitatively lower for TI1, TI2, and TI3 (Pearson's r 0.07, 0.13, and 0.29, and Cronbach's alpha, 0.40, 0.44, and 0.61, respectively) than for MMI1 and MMI 2 (Cronbach's alpha 0.68 and 0.60, respectively). Between schools, the adjusted intraclass correlation coefficient was 0.27 (95% CI 0.20-0.35) for TIs and 0.47 (95% CI 0.41-0.54) for MMIs. CONCLUSIONS: Within and between-school reliability was qualitatively higher for MMIs than for TIs. Nonetheless, TI reliabilities were higher than anticipated from prior literature, suggesting TIs may not need to be abandoned on reliability grounds if other factors favor their use. PMID- 29110663 TI - Redressing or entrenching social and health inequities through policy implementation? Examining personalised budgets through the Australian National Disability Insurance Scheme. AB - BACKGROUND: Increasing attention is being given to political agenda setting for the social determinants of health. While designing policies that can improve the social determinants of health is critical, so too is ensuring these policies are appropriately administered and implemented. Many policies have the potential to entrench or even expand inequities during implementation. At present little attention has been given to this in the social determinants of health literature. There is an international trend in the personalisation of funding for care services, from the National Health Service in the England to the Brukerstyrt Personlig Assistanse in Norway. Part of this trend is the Australian National Disability Insurance Scheme (NDIS). The NDIS has the potential to secure gains in health for hundreds of thousands of Australians living with a disability. However, policies are only as good as their implementation. METHODS: As part of a longitudinal study on the implementation of the Australian NDIS, we conducted a systematic document search of policy documents pertaining to the Scheme on the websites of government departments with auspice over the design and implementation of the scheme with the aim of examining issues of equity. RESULTS AND DISCUSSION: Scheme architects have argued that the NDIS has the potential to replace a piecemeal and fragmented set of state-determined services with an empowering model of user choice and control. However, without careful attention to both existing inequities and, diversity and difference across populations (e.g. different disability types and different localities), market based approaches such as the NDIS have the serious potential to entrench or even widen inequities. CONCLUSIONS: The research concluded that 'personalisation' approaches can widen inequities and inequalities unless careful consideration is given at both policy design and implementation stages. PMID- 29110664 TI - Correction to: Absence of Plasmodium inui and Plasmodium cynomolgi, but detection of Plasmodium knowlesi and Plasmodium vivax infections in asymptomatic humans in the Betong division of Sarawak, Malaysian Borneo. AB - After publication of the article [1], it has been brought to our attention that two of the labels on Figure 4 have transposed. The labels "S-type SSU rRNA" and "A-type SSU rRNA" should be in opposite places. PMID- 29110665 TI - Correction to: Design and initial implementation of the WHO FP umbrella project- to strengthen contraceptive services in the sub Saharan Africa. AB - CORRECTION: After publication of the original article [1], it came to the authors' attention that the Acknowledgements section was not completed correctly. The Acknowledgements of the article should have been as follows. PMID- 29110666 TI - Development of real-time recombinase polymerase amplification assay for rapid and sensitive detection of canine parvovirus 2. AB - BACKGROUND: Canine parvovirus 2, a linear single-stranded DNA virus belonging to the genus Parvovirus within the family Parvoviridae, is a highly contagious pathogen of domestic dogs and several wild canidae species. Early detection of canine parvovirus (CPV-2) is crucial to initiating appropriate outbreak control strategies. Recombinase polymerase amplification (RPA), a novel isothermal gene amplification technique, has been developed for the molecular detection of diverse pathogens. In this study, a real-time RPA assay was developed for the detection of CPV-2 using primers and an exo probe targeting the CPV-2 nucleocapsid protein gene. RESULTS: The real-time RPA assay was performed successfully at 38 degrees C, and the results were obtained within 4-12 min for 105-101 molecules of template DNA. The assay only detected CPV-2, and did not show cross-detection of other viral pathogens, demonstrating a high level of specificity. The analytical sensitivity of the real-time RPA was 101 copies/reaction of a standard DNA template, which was 10 times more sensitive than the common RPA method. The clinical sensitivity of the real-time RPA assay matched 100% (n = 91) to the real-time PCR results. CONCLUSION: The real-time RPA assay is a simple, rapid, reliable and affordable method that can potentially be applied for the detection of CPV-2 in the research laboratory and point-of-care diagnosis. PMID- 29110667 TI - A complex intervention to improve implementation of World Health Organization guidelines for diagnosis of severe illness in low-income settings: a quasi experimental study from Uganda. AB - BACKGROUND: To improve management of severely ill hospitalized patients in low income settings, the World Health Organization (WHO) established a triage tool called "Quick Check" to provide clinicians with a rapid, standardized approach to identify patients with severe illness based on recognition of abnormal vital signs. Despite the availability of these guidelines, recognition of severe illness remains challenged in low-income settings, largely as a result of infrequent vital sign monitoring. METHODS: We conducted a staggered, pre-post quasi-experimental study at four inpatient health facilities in western Uganda to assess the impact of a multi-modal intervention for improving quality of care following formal training on WHO "Quick Check" guidelines for diagnosis of severe illness in low-income settings. Intervention components were developed using the COM-B ("capability," "opportunity," and "motivation" determine "behavior") model and included clinical mentoring by an expert in severe illness care, collaborative improvement meetings with external support supervision, and continuous audits of clinical performance with structured feedback. RESULTS: There were 5759 patients hospitalized from August 2014 to May 2015: 1633 were admitted before and 4126 during the intervention period. Designed to occur twice monthly, collaborative improvement meetings occurred every 2-4 weeks at each site. Clinical mentoring sessions, designed to occur monthly, occurred every 4-6 months at each site. Audit and feedback reports were implemented weekly as designed. During the intervention period, there were significant increases in the site-adjusted likelihood of initial assessment of temperature, heart rate, blood pressure, respiratory rate, mental status, and pulse oximetry. Patients admitted during the intervention period were significantly more likely to be diagnosed with sepsis (4.3 vs. 0.4%, risk ratio 10.1, 95% CI 3.0-31.0, p < 0.001) and severe respiratory distress (3.9 vs. 0.9%, risk ratio 4.5, 95% CI 1.8-10.9, p = 0.001). CONCLUSIONS: Theory-informed quality improvement programs can improve vital sign collection and diagnosis of severe illness in low-income settings. Further implementation, evaluation, and scale-up of such interventions are needed to enhance hospital-based triage and severe illness management in these settings. TRIAL REGISTRATION: Severe illness management system (SIMS) intervention development, ISRCTN46976783. PMID- 29110668 TI - Measuring the bias against low-income country research: an Implicit Association Test. AB - BACKGROUND: With an increasing array of innovations and research emerging from low-income countries there is a growing recognition that even high-income countries could learn from these contexts. It is well known that the source of a product influences perception of that product, but little research has examined whether this applies also in evidence-based medicine and decision-making. In order to examine likely barriers to learning from low-income countries, this study uses established methods in cognitive psychology to explore whether healthcare professionals and researchers implicitly associate good research with rich countries more so than with poor countries. METHODS: Computer-based Implicit Association Test (IAT) distributed to healthcare professionals and researchers. Stimuli representing Rich Countries were chosen from OECD members in the top ten (>$36,000 per capita) World Bank rankings and Poor Countries were chosen from the bottom thirty (<$1000 per capita) countries by GDP per capita, in both cases giving attention to regional representation. Stimuli representing Research were descriptors of the motivation (objective/biased), value (useful/worthless), clarity (precise/vague), process (transparent/dishonest), and trustworthiness (credible/unreliable) of research. IAT results are presented as a Cohen's d statistic. Quantile regression was used to assess the contribution of covariates (e.g. age, sex, country of origin) to different values of IAT responses that correspond to different levels of implicit bias. Poisson regression was used to model dichotomized responses to the explicit bias item. RESULTS: Three hundred twenty one tests were completed in a four-week period between March and April 2015. The mean Implicit Association Test result (a standardized mean relative latency between congruent and non-congruent categories) for the sample was 0.57 (95% CI 0.52 to 0.61) indicating that on average our sample exhibited moderately strong implicit associations between Rich Countries and Good Research. People over 40 years of age were less likely to exhibit pro-poor implicit associations, and being a peer reviewer contributes to a more pro-poor association. CONCLUSIONS: The majority of our participants associate Good Research with Rich Countries, compared to Poor Countries. Implicit associations such as these might disfavor research from poor countries in research evaluation, evidence-based medicine and diffusion of innovations. PMID- 29110669 TI - A comparison of cardiovascular magnetic resonance and single photon emission computed tomography (SPECT) perfusion imaging in left main stem or equivalent coronary artery disease: a CE-MARC substudy. AB - BACKGROUND: Assessment of left main stem (LMS) stenosis has prognostic and therapeutic implications. Data on assessment of LMS disease by cardiovascular magnetic resonance (CMR) and single photon emission computed tomography (SPECT) are limited. CE-MARC is the largest prospective comparison of CMR and SPECT against quantitative invasive coronary angiography (QCA) for detection of coronary artery disease (CAD), and provided the framework for this evaluation. The aims of this study were to compare diagnostic accuracy of visual and quantitative perfusion CMR to SPECT in patients with LMS stable CAD. METHODS: Fifty-four patients from the CE-MARC study were included: 27 (4%) with significant LMS or LMS-equivalent disease on QCA, and 27 age/sex-matched patients with no flow-limiting CAD. All patients underwent multi-parametric CMR, SPECT and QCA. Performance of visual and quantitative perfusion CMR by Fermi-constrained deconvolution to detect LMS disease was compared with SPECT. RESULTS: Of 27 patients in the LMS group, 22 (81%) had abnormal CMR and 16 (59%) had abnormal SPECT. All patients with abnormal CMR had abnormal perfusion by visual analysis. CMR demonstrated significantly higher area under the curve (AUC) for detection of disease (0.95; 0.85-0.99) over SPECT (0.63; 0.49-0.76) (p = 0.0001). Global mean stress myocardial blood flow (MBF) by CMR in LMS patients was significantly lower than controls (1.77 +/- 0.72 ml/g/min vs. 3.28 +/- 1.20 ml/g/min, p < 0.001). MBF of <2.08 ml/g/min had sensitivity of 78% and specificity of 85% for diagnosis of LMS disease, with an AUC (0.87; 0.75-0.94) not significantly different to visual CMR analysis (p = 0.18), and more accurate than SPECT (p = 0.003). CONCLUSION: Visual stress perfusion CMR had higher diagnostic accuracy than SPECT to detect LMS disease. Quantitative perfusion CMR had similar performance to visual CMR perfusion analysis. PMID- 29110671 TI - Residual microcalcifications after neoadjuvant chemotherapy for locally advanced breast cancer: comparison of the accuracies of mammography and MRI in predicting pathological residual tumor. AB - BACKGROUND: The aims of this study were to correlate residual mammographic microcalcifications after neoadjuvant chemotherapy (NAC) with pathological results and to compare the accuracy of mammography (MG) and magnetic resonance imaging (MRI) in predicting the size of residual tumors. METHODS: The imaging findings and pathological results for 29 patients with residual microcalcifications after NAC were reviewed. We compared the agreement of the measured extent of residual microcalcifications based on MG and residual enhancement based on MRI with the residual tumor size based on pathology. RESULTS: At final pathology, residual microcalcifications were malignant in 55.2% of cases and benign in 44.8% of cases. In 36% of non-pCR cases, the remaining microcalcifications were benign. Compared with the measurements of residual tumor obtained from pathology, MG showed poor agreement, and MRI showed moderate agreement, for the entire group (concordance correlation coefficient [CCC] = 0.196 vs. 0.566). Regarding the receptor status, the agreement of measurements obtained by MG was superior to that obtained by MRI (CCC = 0.5629, 0.5472 vs. 0.4496, 0.4279) for ER(+) and HER2(-) tumors. In ER(-) tumors, the measurements obtained by MG showed the lowest agreement with the pathological tumor size, which had the highest agreement with those obtained by MRI (CCC = - 0.0162 vs. 0.8584). CONCLUSIONS: Residual mammographic microcalcifications after NAC did not correlate with malignancy in 44.8% of cases. Residual microcalcifications on MG were poorly correlated with pathological tumor size, and MRI might be more reliable for predicting residual tumor size after NAC. Tumor receptor status affected the accuracy of both MG and MRI for predicting residual tumor size after NAC. TRIAL REGISTRATION: CRIS, KCT0002281 ; registered 6 April 2015, retrospectively registered. PMID- 29110670 TI - Indoor and outdoor malaria vector surveillance in western Kenya: implications for better understanding of residual transmission. AB - BACKGROUND: The widespread use of indoor-based malaria vector control interventions has been shown to alter the behaviour of vectors in Africa. There is an increasing concern that such changes could sustain residual transmission. This study was conducted to assess vector species composition, feeding behaviour and their contribution to indoor and outdoor malaria transmission in western Kenya. METHODS: Anopheles mosquito collections were carried out from September 2015 to April 2016 in Ahero and Iguhu sites, western Kenya using CDC light traps (indoor and outdoor), pyrethrum spray catches (PSCs) (indoor) and pit shelters (outdoor). Species within Anopheles gambiae s.l. and Anopheles funestus s.l. were identified using polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was used to determine mosquito blood meal sources and sporozoite infections. RESULTS: A total of 10,864 female Anopheles mosquitoes comprising An. gambiae s.l. (71.4%), An. funestus s.l. (12.3%), Anopheles coustani (9.2%) and Anopheles pharoensis (7.1%) were collected. The majority (61.8%) of the anopheline mosquitoes were collected outdoors. PCR result (n = 581) revealed that 98.9% An. arabiensis and 1.1% An. gambiae s.s. constituted An. gambiae s.l. in Ahero while this was 87% An. gambiae s.s. and 13% An. arabiensis in Iguhu. Of the 108 An. funestus s.l. analysed by PCR, 98.1% belonged to An. funestus s.s. and 1.9% to Anopheles leesoni. The human blood index (HBI) and bovine blood index (BBI) of An. arabiensis was 2.5 and 73.1%, respectively. Anopheles gambiae s.s. had HBI and BBI of 50 and 28%, respectively. The HBI and BBI of An. funestus was 60 and 22.3%, respectively. Forage ratio estimate revealed that An. arabiensis preferred to feed on cattle, An. gambiae s.s. showed preference for both human and cattle, while An. funestus preferred human over other hosts. In Ahero, the sporozoite rates for An. arabiensis and An. funestus were 0.16 and 1.8%, respectively, whereas in Iguhu, the sporozoite rates for An. gambiae s.s. and An. funestus were 2.3 and 2.4%, respectively. In Ahero, the estimated indoor and outdoor entomological inoculation rate (EIR) was 108.6 infective bites/person/year (79.0 from An. funestus and 29.6 from An. arabiensis) and 43.5 infective bites/person/year (27.9 from An. arabiensis and 15.6 from An. funestus), respectively. In Iguhu, the estimated indoor and outdoor EIR was 24.5 infective bites/person/year (18.8 from An. gambiae s.s. and 5.7 from An. funestus) and 5.5 infective bites/person/year (all from An. gambiae s.s.), respectively. CONCLUSION: Anopheles gambiae s.s. showed an increasing tendency to feed on cattle. Anopheles arabiensis was highly zoophagic, whereas An. funestus showed anthropophagic behaviour. While the majority of malaria transmission occurred indoor, the magnitude of outdoor transmission was considerably high. Additional control tools that complement the existing interventions are required to control residual transmission. PMID- 29110672 TI - The Onset of ADL Difficulties and Changes in Health-Related Quality of Life. AB - BACKGROUND: The effect of the onset of difficulties with activities of daily living (ADLs) on the health-related quality of life (HRQoL) of older adults is not well understood. We identified strong longitudinal associations between ADL onset and HRQoL changes for older adults in Medicare Advantage Organizations (MAOs). METHODS: We analyzed 473,282 age-eligible MAO beneficiaries in the 2008 2013 Medicare Health Outcomes Surveys (M-HOS) who reported no ADL difficulties at baseline and completed their two-year follow-ups in 2010-2015. The four HRQoL measures were the physical and mental health component scores (PCS and MCS) from the SF-12V, and the CDC's counts of physically unhealthy and mentally unhealthy days (PUD and MUD) in the past month. Ordinary least squares (OLS) and zero inflated negative binomial regressions were used. RESULTS: The onset of difficulty/inability in bathing, dressing, eating, getting in/out of chairs, walking, and using the toilet significantly reduced PCS scores by 10.84, 11.29, 9.18, 8.98, 9.49 and 10.67 points, and MCS scores by 7.93, 8.72, 10.13, 5.34, 4.37 and 9.00 points, respectively. The onset of difficulty/inability in bathing, dressing, eating, getting in/out of chairs, walking, and using the toilet increased PUD days by 6.24, 6.83, 6.34, 4.93, 4.96 and 6.72 days, and MUD days by 3.00, 3.19, 3.54, 2.26, 2.07 and 3.27 days, respectively. CONCLUSIONS: There is robust evidence that the onset of ADL difficulties/inabilities significantly and substantially reduced age-eligible MAO beneficiaries' HRQoL. Prevention strategies focused on ADLs would benefit the performance of MAOs. PMID- 29110673 TI - Clinical outcomes of graves' ophthalmopathy treated with intensity modulated radiation therapy. AB - BACKGROUND: Radiation for Graves' ophthalmopathy (GO) has traditionally utilized lateral opposing fields (LOF) or three-dimensional conformal radiotherapy (3DCRT) technique. The current study was conducted to report clinical outcomes and therapeutic effects of intensity modulated radiation therapy (IMRT) in treating GO patients. METHODS: One hundred sixteen patients with GO were treated with IMRT as initial local therapy between July 2010 and August 2013, with a median follow up of 62 months (range 45-81 months). Radiotherapy dose was 20 Gy in 10 fractions within two to three weeks. The immediate and long-term response to IMRT was evaluated in GO severity score and in each category of symptoms. Acute and long term complications were recorded to assess its safety. RESULTS: Symptom severity score significantly fell from the start of treatment to 4- or 6- month post-IMRT (P < 0.01). In total, 85 patients (73.3%) experienced improvement of GO symptoms in the first half-year, and only 4 of them (4.7%) suffered recurrence of the GO symptoms during the subsequent follow-ups. Orbital pain, tearing and extraocular muscle dysfunction had the best treatment reaction to IMRT, while proptosis and blurred vision were the most refractory symptoms. Acute complications were slight and self-limited, mainly including intermittent eye redness in 9 patients (7.8%), sideburns hair loss in 19 patients (16.4%), increased milphosis or madarosis in 23 patients (19.8%) and pseudo-progression of GO symptoms in 15 patients (12.9%). For long-term complications, chronic xerophthalmias occurred in 7 patients (6.03%), cataract developed in 2 patients (1.72%), and all were well-managed by medical interventions. Radiation retinopathy and secondary malignancy was not presented in the cohort. CONCLUSION: The study demonstrated that IMRT could serve as a viable option in treating GO patients, with a satisfactory symptom control ability, and relatively slight and acceptable post-radiotherapeutic complications. PMID- 29110674 TI - Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study. AB - BACKGROUND: Cannabis-based drugs have been shown to be effective in inflammatory diseases. A number of endocannabinoids including N- arachidonoylethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) with activity at the cannabinoid receptors (CBR) CBR1 and CBR2, have been identified. Other structurally related endogenous fatty acid compounds such as oleoylethanolamide (OEA) and palmitoyl ethanolamide (PEA) have been identified in biological tissues. These compounds do not bind to CBR but might be involved in facilitating the actions of directly acting endocannabinoids and thus are commonly termed "entourage" compounds due to their ability to modulate the endocannabinoid system. The aim of this study was to evaluate the presence of endocannabinoids and entourage compounds in the synovial fluid of dogs with osteoarthritis subjected to arthrotomy of the knee joint. Cytokines and cytology were studied as well. RESULTS: AEA, 2-AG, OEA and PEA were all present in the synovial fluid of arthritic knees and in the contralateral joints; in addition, a significant increase of OEA and 2AG levels were noted in SF from OA knees when compared to the contralateral joints. CONCLUSION: The identification and quantification of endocannabinoids and entourage compounds levels in synovial fluids from dogs with OA of the knee is reported for the first time. Our data are instrumental for future studies involving a greater number of dogs. Cannabinoids represent an emerging and innovative pharmacological tool for the treatment of OA and further studies are warranted to evaluate the effectiveness of cannabinoids in veterinary medicine. PMID- 29110675 TI - Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic childhood malnutrition, as manifested by stunted linear growth, remains a persistent barrier to optimal child growth and societal development. Environmental enteric dysfunction (EED) is a significant underlying factor in the causal pathway to stunting, delayed cognitive development, and ultimately morbidity and mortality. Effective therapies against EED and stunting are lacking and further clinical trials are warranted to effectively identify and operationalize interventions. METHODS/DESIGN: A prospective randomized placebo controlled parallel-group randomized controlled trial will be conducted to determine if a daily supplement of lactoferrin and lysozyme, two important proteins found in breast milk, can decrease the burden of EED and stunting in rural Malawian children aged 12-23 months old. The intervention and control groups will have a sample size of 86 subjects each. All field and laboratory researchers will be blinded to the assigned intervention group, as will the subjects and their caregivers. The percentage of ingested lactulose excreted in the urine (Delta%L) after 4 h will be used as the biomarker for EED and linear growth as the measure of chronic malnutrition (stunting). The primary outcomes of interest will be change in Delta%L from baseline to 8 weeks and to 16 weeks. Intention-to-treat analyses will be used. DISCUSSION: A rigorous clinical trial design will be used to assess the biologically plausible use of lactoferrin and lysozyme as dietary supplements for children at high risk for EED. If proven effective, these safe proteins may serve to markedly reduce the burden of childhood malnutrition and improve survival. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02925026 . Registered on 4 October 2016. PMID- 29110677 TI - Using meta-quality to assess the utility of volunteered geographic information for science. AB - BACKGROUND: Volunteered geographic information (VGI) has strong potential to be increasingly valuable to scientists in collaboration with non-scientists. The abundance of mobile phones and other wireless forms of communication open up significant opportunities for the public to get involved in scientific research. As these devices and activities become more abundant, questions of uncertainty and error in volunteer data are emerging as critical components for using volunteer-sourced spatial data. METHODS: Here we present a methodology for using VGI and assessing its sensitivity to three types of error. More specifically, this study evaluates the reliability of data from volunteers based on their historical patterns. The specific context is a case study in surveillance of tsetse flies, a health concern for being the primary vector of African Trypanosomiasis. RESULTS: Reliability, as measured by a reputation score, determines the threshold for accepting the volunteered data for inclusion in a tsetse presence/absence model. Higher reputation scores are successful in identifying areas of higher modeled tsetse prevalence. A dynamic threshold is needed but the quality of VGI will improve as more data are collected and the errors in identifying reliable participants will decrease. CONCLUSIONS: This system allows for two-way communication between researchers and the public, and a way to evaluate the reliability of VGI. Boosting the public's ability to participate in such work can improve disease surveillance and promote citizen science. In the absence of active surveillance, VGI can provide valuable spatial information given that the data are reliable. PMID- 29110676 TI - Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017. AB - This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers. PMID- 29110678 TI - Utilization of biodiesel derived-glycerol for 1,3-PD and citric acid production. AB - Today, biofuels represent a hot topic in the context of petroleum and adjacent products decrease. As biofuels production increase, so does the production of their major byproduct, namely crude glycerol. The efficient usage of raw glycerol will concur to the biodiesel viability. As an inevitable waste of biodiesel manufacturing, glycerol is potentially an attractive substrate for the production of value-added products by fermentation processes, due to its large amounts, low cost and high degree of reduction. One of the most important usages of glycerol is its bioconversion through microbial fermentation to value-added materials like 1,3-propanediol and citric acid. There is a considerable industrial interest in 1,3-propanediol and citric acid production based on microbial fermentations, as it seems to be in competition with traditional technologies utilized for these products. In the present work, yields and concentrations of 1,3-propanediol and citric acid registered for different isolated strains are also described. Microbial bioconversion of glycerol represents a remarkable choice to add value to the biofuel production chain, allowing the biofuel industry to be more competitive. The current review presents certain ways for the bioconversion of crude glycerol into citric acid and 1,3-propanediol with high yields and concentrations achieved by using isolated microorganisms. PMID- 29110679 TI - High-throughput gadobutrol-enhanced CMR: a time and dose optimization study. AB - BACKGROUND: Reducing time and contrast agent doses are important goals to provide cost-efficient cardiovascular magnetic resonance (CMR) imaging. Limited information is available regarding the feasibility of evaluating left ventricular (LV) function after gadobutrol injection as well as defining the lowest dose for high quality scar imaging. We sought to evaluate both aspects separately and systematically to provide an optimized protocol for contrast-enhanced CMR (CE CMR) using gadobutrol. METHODS: This is a prospective, randomized, single-blind cross-over study performed in two different populations. The first population consisted of 30 patients with general indications for a rest CE-CMR who underwent cine-imaging before and immediately after intravenous administration of 0.1 mmol/kg body-weight of gadobutrol. Quantitative assessment of LV volumes and function was performed by the same reader in a randomized and blinded fashion. The second population was composed of 30 patients with indication to late gadolinium enhancement (LGE) imaging, which was performed twice at different gadobutrol doses (0.1 mmol/kg vs. 0.2 mmol/kg) and at different time delays (5 and 10 min vs. 5, 10, 15 and 20 min), within a maximal interval of 21 days. LGE images were analysed qualitatively (contrast-to-noise ratio) and quantitatively (LGE%-of-mass). RESULTS: Excellent correlation between pre- and post-contrast cine-imaging was found, with no difference of LV stroke volume and ejection fraction (p = 0.538 and p = 0.095, respectively). End-diastolic-volume and end systolic-volume were measured significantly larger after contrast injection (p = 0.008 and p = 0.001, respectively), with a mean difference of 3.7 ml and 2.9 ml, respectively. LGE imaging resulted in optimal contrast-to-noise ratios 10 min post-injection for a gadobutrol dose of 0.1 mmol/kg body-weight and 20 min for a dose of 0.2 mmol/kg body-weight. At these time points LGE quantification did not significantly differ (0.1 mmol/kg: 11% (16.4); 0.2 mmol/kg: 12% (14.5); p = 0.059), showing excellent correlation (ICC = 0.957; p < 0.001). CONCLUSION: A standardized CE-CMR rest protocol giving a dose of 0.1 mmol/kg of gadobutrol before cine-imaging and performing LGE 10 min after injection represents a fast low-dose protocol without significant loss of information in comparison to a longer protocol with cine-imaging before contrast injection and a higher dose of gadobutrol. This approach allows to reduce examination time and costs as well as minimize contrast-agent exposure. PMID- 29110680 TI - Fraction of high-grade cervical intraepithelial lesions attributable to genotypes targeted by a nonavalent HPV vaccine in Galicia, Spain. AB - BACKGROUND: Human papillomavirus (HPV) bivalent and quadrivalent vaccines have been widely implemented in worldwide organized immunization programs. A nonavalent HPV vaccine is now available in several countries. The objective was to describe the fraction of squamous non-invasive high-grade cervical intraepithelial lesions attributable to genotypes targeted by bi-quadrivalent vaccines and by nonavalent vaccine according to age and diagnosis in women living in the city of Vigo (Galicia, Spain). METHODS: Cervical scrapings (2009-2014) of women with histological diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2, n = 145) and grade 3-carcinoma in situ (CIN3-CIS, n = 244) were tested with Linear Array HPV Genotyping test (Roche diagnostics, Mannheim, Germany). Hierarchical estimation of the fraction attributable to HPV 16/18 or HPV 31/33/45/52/58 detected alone or in combination was calculated. Absolute additional fraction attributable to genotypes targeted by nonavalent vaccine compared to genotypes targeted by bi-quadrivalent vaccines was calculated as the increment of attributable cases with respect to all studied cases. Age group 1, 2 and 3 included women 18 to 34, 35-44 and >=45 years old, respectively. EPIDAT 3.1 was used. RESULTS: Fraction attributable to genotypes targeted by bi-quadrivalent vaccines was 59% CIN2 vs. 69% CIN3-CIS (p < 0.001). It was 63/51/50% of CIN2 and 78/66/45% of CIN3-CIS in age group 1, 2, 3, respectively. Fraction attributable to genotypes targeted by nonavalent vaccine was 86% CIN2 and 86% CIN3-CIS. It was 87/91/75% of CIN2 and 90/86/76% of CIN3-CIS in age group 1, 2, 3, respectively. Fraction attributable to genotypes targeted by these vaccines tended to decrease as age increased (p-trend <0.05). Globally, absolute additional attributable fraction was 16%, 26% and 29% in age group 1, 2 and 3, respectively (p < 0.005). CONCLUSIONS: Absolute additional fraction of CIN2 and CIN3-CIS attributable to genotypes targeted by nonavalent vaccine was observed in women of any age, especially in those over 35 years old. PMID- 29110681 TI - Treatment of sleep disturbances in trauma-affected refugees: Study protocol for a randomised controlled trial. AB - BACKGROUND: Sleep disturbances are often referred to as a hallmark and as core symptoms of post-traumatic stress disorder (PTSD). Untreated sleep disturbances can contribute to the maintenance and exacerbation of PTSD symptoms, which may diminish treatment response and constitute a risk factor for poor treatment outcome. Controlled trials on treatment of sleep disturbances in refugees suffering from PTSD are scarce. The present study aims to examine sleep-enhancing treatment in refugees with PTSD. We aim to assess if add-on treatment with mianserin and/or Imagery Rehearsal Therapy (IRT) to treatment as usual (TAU) for PTSD improves sleep disturbances. We will study the relation between sleep disturbances, PTSD symptoms, psychosocial functioning and quality of life. METHODS: The study is a randomised controlled superiority trial with a 2 * 2 factorial design. The study will include 230 trauma-affected refugees. The patients are randomised into four groups. All four groups receive TAU - an interdisciplinary treatment approach covering a period of 6-8 months with pharmacological treatment, physiotherapy, psychoeducation and manual-based cognitive behavioural therapy within a framework of weekly sessions with a physician, physiotherapist or psychologist. One group receives solely TAU, serving as a control group, while the three remaining groups are active-treatment groups receiving add-on treatment with either mianserin, IRT or a combination of both. Treatment outcome is evaluated using self-administered rating scales, observer ratings and actigraph measurements at baseline, during treatment and post treatment. The primary outcome is subjective sleep quality using the Pittsburgh Sleep Quality Index. Secondary outcome measures are objective sleep length, nightmares, PTSD severity, symptoms of depression and anxiety, pain, quality of life and psychosocial functioning. DISCUSSION: This trial will be the first randomised controlled trial to examine sleep-enhancing treatment in trauma affected refugees, as well as the first trial to investigate the effect of IRT and mianserin in this population. Therefore, this trial may optimise treatment recommendations for sleep disturbances in trauma-affected refugees. Based on our findings, we expect to discuss the effect of treatment, focussing on sleep disturbances. Furthermore, the results will provide new information regarding the association between sleep disturbances, PTSD symptoms, psychosocial functioning and quality of life in trauma-affected refugees. TRIAL REGISTRATION: EudraCT registration under the name 'Treatment of sleep disturbances in trauma-affected refugees - a randomised controlled trial', registration number: 2015-004153-40 , registered on 13 November 2015. ClinicalTrials.gov, ID: NCT02761161. Registered on 27 April 2016. PMID- 29110682 TI - TAGLN2 is a candidate prognostic biomarker promoting tumorigenesis in human gliomas. AB - BACKGROUND: Transgelin-2 (TAGLN2) is a member of the calponin family of actin bundling proteins that is involved in the regulation of cell morphology, motility, and cell transformation. Here, the clinical significance and potential function of TAGLN2 in malignant gliomas were investigated. METHODS: Molecular and clinical data was obtained from The Cancer Genome Atlas (TCGA) database. Gene ontology and pathway analysis was used to predict potential functions of TAGLN2. RNA knockdown was performed using siRNA or lentiviral contructs in U87MG and U251 glioma cell lines. Cells were characterized in vitro or implanted in vivo to generate orthotopic xenografts in order to assess molecular status, cell proliferation/survival, and invasion by Western blotting, flow cytometry, and 3D tumor spheroid invasion assay, respectively. RESULTS: Increased TAGLN2 expression was associated with increasing tumor grade (P < 0.001), the mesenchymal molecular glioma subtype and worse prognosis in patients (P < 0.001). Immunohistochemistry performed with anti-TAGLN2 on an independent cohort of patients (n = 46) confirmed these results. Gene silencing of TAGLN2 in U87MG and U251 significantly inhibited invasion and tumor growth in vitro and in vivo. Western blot analysis revealed that epithelial-mesenchymal transition (EMT) molecular markers, such as N-cadherin, E-cadherin, and Snail, were regulated in a manner corresponding to suppression of the EMT phenotype in knockdown experiments. Finally, TAGLN2 was induced ~ 2 to 3-fold in U87MG and U251 cells by TGFbeta2, which was also elevated in GBM and highly correlated with TAGLN2 mRNA levels (P < 0.001). CONCLUSIONS: Our findings indicate that TAGLN2 exerts a role in promoting the development of human glioma. The regulation and function of TAGLN2 therefore renders it as a candidate molecular target for the treatment of GBM. PMID- 29110683 TI - Array comparative genomic hybridization of 18 pancreatic ductal adenocarcinomas and their autologous metastases. AB - BACKGROUND: Mortality rates of pancreatic cancer remain high, which is mainly due to advanced disease and metastasis. We hypothesized that genomic copy number alterations are enriched in metastatic cells compared to autologous primary tumors, which may inform on cancer-related pathways possibly serving as potential targets for specific therapies. We investigated 18 pancreatic ductal adenocarcinomas, including 39 lymph node and 5 distant metastases after surgical resection. Analysis was performed with array-based comparative genomic hybridization (aCGH). RESULTS: Metastases acquire a higher frequency of copy number alterations with the highest in distant metastasis (median = 42, lymph node metastases: median = 23, primary tumors: median = 17). In lymph node metastases, gains were prevalent on chromosome bands 8q11.23-q24.3, 12q14.1, 17p12.1, 21q22.12, and losses on 3p21.31, 4p14, 8p23.3-p11.21,17p12-11.2. Genes on amplified regions are involved in cancer-related pathways such as WNT signaling, also involved in metastasis. CONCLUSIONS: Pancreatic cancers show a high degree of intratumor heterogeneity, which could lead to resistance of chemotherapy and worse outcome. ACGH analysis reveals regions preferentially gained or lost in synchronous metastases encoding for genes involved in cancer related pathways, which could lead to novel therapeutic opportunities. PMID- 29110685 TI - Lingual metastasis as an initial presentation of renal cell carcinoma: a case report. AB - BACKGROUND: Renal cell carcinoma is the third most common tumor that metastasizes to the head and neck, after breast and lung carcinomas. Tongue metastasis as an initial presentation of renal cell carcinoma is extremely rare, and very few cases have been reported. The prognosis is poor. We present a rare case of metastatic renal cell carcinoma that initially presented as a tongue lesion. CASE PRESENTATION: We report the case of a 55-year-old white man who presented with a large exophytic lesion on his tongue. A biopsy was taken, and pathologic examination showed a poorly differentiated carcinoma including a sarcomatoid component. Subtotal glossectomy with neck dissection were planned, but a positron emission tomographic-computed tomography scan showed a left kidney mass. Immunohistochemical evaluation of the tongue lesion was performed, and it was compatible with metastasis from primary renal cell carcinoma. The biopsy of the renal lesion showed a high-grade unclassified renal cell carcinoma. Although our patient underwent systemic therapy, he died of hemorrhagic complications 3 months after the initiation of therapy. CONCLUSION: Tongue lesions require a complete assessment to distinguish a metastasis from a primary cancer in order to give the appropriate treatment. PMID- 29110686 TI - Oncology practitioners' perspectives and practice patterns of post-treatment cancer survivorship care in the Asia-Pacific region: results from the STEP study. AB - BACKGROUND: Most efforts to advance cancer survivorship care have occurred in Western countries. There has been limited research towards gaining a comprehensive understanding of survivorship care provision in the Asia-Pacific region. This study aimed to establish the perceptions of responsibility, confidence, and frequency of survivorship care practices of oncology practitioners and examine their perspectives on factors that impede quality survivorship care. METHODS: A cross-sectional survey of hospital-based oncology practitioners in 10 Asia-Pacific countries was undertaken between May 2015 October 2016. The participating countries included Australia, Hong Kong, China, Japan, South Korea, Thailand, Singapore, India, Myanmar, and The Philippines. The survey was administered using paper-based or online questionnaires via specialist cancer care settings, educational meetings, and professional organisations. RESULTS: In total, 1501 oncology practitioners participated in the study. When comparing the subscales of responsibility perception, frequency and confidence, Australian practitioners had significantly higher ratings than practitioners in Hong Kong, Japan, Thailand, and Singapore (all p < 0.05). Surprisingly, practitioners working in Low- and Mid- Income Countries (LMICs) had higher levels of responsibility perception, confidence and frequencies of delivering survivorship care than those working in High-Income Countries (HICs) (p < 0.001), except for the responsibility perception of care coordination where no difference in scores was observed (p = 0.83). Physicians were more confident in delivering most of the survivorship care interventions compared to nurses and allied-health professionals. Perceived barriers to survivorship care were similar across the HICs and LMICs, with the most highly rated items for all practitioners being lack of time, dedicated educational resources for patients and family members, and evidence-based practice guidelines informing survivorship care. CONCLUSIONS: Different survivorship practices have been observed between HICs and LMICs, Australia and other countries and between the professional disciplines. Future service planning and research efforts should take these findings into account and overcome barriers identified in this study. PMID- 29110684 TI - Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer's disease. AB - BACKGROUND: Oligodendrocytes (OLs) and myelin are critical for normal brain function and have been implicated in neurodegeneration. Several lines of evidence including neuroimaging and neuropathological data suggest that Alzheimer's disease (AD) may be associated with dysmyelination and a breakdown of OL-axon communication. METHODS: In order to understand this phenomenon on a molecular level, we systematically interrogated OL-enriched gene networks constructed from large-scale genomic, transcriptomic and proteomic data obtained from human AD postmortem brain samples. We then validated these networks using gene expression datasets generated from mice with ablation of major gene expression nodes identified in our AD-dysregulated networks. RESULTS: The robust OL gene coexpression networks that we identified were highly enriched for genes associated with AD risk variants, such as BIN1 and demonstrated strong dysregulation in AD. We further corroborated the structure of the corresponding gene causal networks using datasets generated from the brain of mice with ablation of key network drivers, such as UGT8, CNP and PLP1, which were identified from human AD brain data. Further, we found that mice with genetic ablations of Cnp mimicked aspects of myelin and mitochondrial gene expression dysregulation seen in brain samples from patients with AD, including decreased protein expression of BIN1 and GOT2. CONCLUSIONS: This study provides a molecular blueprint of the dysregulation of gene expression networks of OL in AD and identifies key OL- and myelination-related genes and networks that are highly associated with AD. PMID- 29110688 TI - Evaluation of physicochemical and antioxidant properties of two stingless bee honeys: a comparison with Apis mellifera honey from Nsukka, Nigeria. AB - OBJECTIVE: Several physical, biochemical and antioxidant properties of two Nigerian stingless bee honey varieties (Melipona sp. and Hypotrigona sp.) were compared with Apis mellifera honey using standard analytical procedures. RESULTS: The mean pH of Apis mellifera, Hypotrigona sp. and Melipona sp. honeys were 4.24 +/- 0.28, 3.75 +/- 0.11 and 4.21 +/- 0.37 respectively. The mean moisture contents of the honeys were 11.74 +/- 0.47, 17.50 +/- 0.80, and 13.86 +/- 1.06%. Honey samples from Hypotrigona sp. when compared with other honey samples had the highest mean total dissolved solids (370.01 +/- 22.51 ppm), hydroxymethylfurfural (16.58 +/- 0.37 mg/kg), total acidity (35.57 +/- 0.42 meq/kg), protein content (16.58 +/- 0.37 g/kg), phenol content (527.41 +/- 3.60 mg/kg), and ascorbic acid (161.69 +/- 6.70 mg/kg), antioxidant equivalent-ascorbic acid assay value (342.33 +/- 0.78 mg/kg) as well as ferric reducing power (666.88 +/- 1.73 MUM Fe(II)/100 g) (p < 0.05). Several strong correlations were observed among some of the parameters of the honeys. This is the first study to compare the properties of Nigerian honey bees. Our results suggested that these honeys (specifically Hypotrigona sp. honey) is a good source of antioxidants comparable to A. mellifera honey. PMID- 29110687 TI - Effects of high-frequency transcranial magnetic stimulation on functional performance in individuals with incomplete spinal cord injury: study protocol for a randomized controlled trial. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been investigated as a new tool in neurological rehabilitation of individuals with spinal cord injury (SCI). However, due to the inconsistent results regarding the effects of rTMS in people with SCI, a randomized controlled double-blind crossover trial is needed to clarify the clinical utility and to assess the effect size of rTMS intervention in this population. Therefore, this paper describes a study protocol designed to investigate whether the use of rTMS can improve the motor and sensory function, as well as reduce spasticity in patients with incomplete SCI. METHODS: A double-blind randomized sham-controlled crossover trial will be performed by enrolling 20 individuals with incomplete SCI. Patients who are at least six months post incomplete SCI (aged 18-60 years) will be recruited through referral by medical practitioners or therapists. Individuals will be randomly assigned to either group 1 or group 2 in a 1:1 ratio, with ten individuals in each group. The rTMS protocol will include ten sessions of high frequency rTMS (5 Hz) over the bilateral lower-limb motor area positioned at the vertex (Cz). Clinical evaluations will be performed at baseline and after rTMS active and sham. DISCUSSION: rTMS has produced positive results in treating individuals with physical impairments; thus, it might be promising in the SCI population. The results of this study may provide new insights to motor rehabilitation thereby contributing towards the better usage of rTMS in the SCI population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02899637 . Registered on 25 August 2016. PMID- 29110689 TI - Multicriteria plan optimization in the hands of physicians: a pilot study in prostate cancer and brain tumors. AB - BACKGROUND: The purpose of this study was to demonstrate the feasibility of physician driven planning in intensity modulated radiotherapy (IMRT) with a multicriteria optimization (MCO) treatment planning system and template based plan optimization. Exploiting the full planning potential of MCO navigation, this alternative planning approach intends to improve planning efficiency and individual plan quality. METHODS: Planning was retrospectively performed on 12 brain tumor and 10 post-prostatectomy prostate patients previously treated with MCO-IMRT. For each patient, physicians were provided with a template-based generated Pareto surface of optimal plans to navigate, using the beam angles from the original clinical plans. We compared physician generated plans to clinically delivered plans (created by dosimetrists) in terms of dosimetric differences, physician preferences and planning times. RESULTS: Plan qualities were similar, however physician generated and clinical plans differed in the prioritization of clinical goals. Physician derived prostate plans showed significantly better sparing of the high dose rectum and bladder regions (p(D1) < 0.05; D1: dose received by 1% of the corresponding structure). Physicians' brain tumor plans indicated higher doses for targets and brainstem (p(D1) < 0.05). Within blinded plan comparisons physicians preferred the clinical plans more often (brain: 6:3 out of 12, prostate: 2:6 out of 10) (not statistically significant). While times of physician involvement were comparable for prostate planning, the new workflow reduced the average involved time for brain cases by 30%. Planner times were reduced for all cases. Subjective benefits, such as a better understanding of planning situations, were observed by clinicians through the insight into plan optimization and experiencing dosimetric trade-offs. CONCLUSIONS: We introduce physician driven planning with MCO for brain and prostate tumors as a feasible planning workflow. The proposed approach standardizes the planning process by utilizing site specific templates and integrates physicians more tightly into treatment planning. Physicians' navigated plan qualities were comparable to the clinical plans. Given the reduction of planning time of the planner and the equal or lower planning time of physicians, this approach has the potential to improve departmental efficiencies. PMID- 29110690 TI - Autologous-cell-derived, tissue-engineered cartilage for repairing articular cartilage lesions in the knee: study protocol for a randomized controlled trial. AB - BACKGROUND: Spontaneous recovery from articular cartilage injury is difficult, and the ongoing progression of disease can eventually lead to osteoarthritis. Currently, there is no effective non-surgical treatment for articular cartilage injury. Arthroscopic debridement and microfracture surgery are performed for fibrocartilage repair. But fibrocartilage is different from normal articular cartilage, and functional recovery is not satisfactory. Therefore, it is necessary to develop more effective techniques for articular cartilage repair. Progress in material science, cell biology, biomechanics, and bioreactor technology has allowed the development of biomimetic, tissue-engineered osteochondral composites that have shown potential for the repair of damaged cartilage. We prepared biomimetic, tissue-engineered cartilage scaffolds optimized for biochemical composition and structural characteristics. Based on the experience of our pre-clinical studies on animals, a human articular cartilage acellular matrix scaffold was prepared and is in clinical use. The combination of autologous chondrocytes and scaffolds has shown satisfactory results in repairing cartilage defects in preliminary experiments. METHODS: This is a prospective randomized controlled trial. One hundred patients with full thickness cartilage injury of the knee will be randomly divided into two groups to receive treatment with either tissue-engineered cartilage constructed using biomimetic cartilage extracellular-matrix-oriented scaffolds combined with autologous chondrocytes, or arthroscopic debridement and microfracture surgery. There will be five visiting time points: at baseline, then at 3, 6, 12, and 18 months postoperatively. The primary outcome will be therapeutic efficacy as assessed by the Lysholm score at 12 months postoperatively. The secondary outcomes will be the International Knee Documentation Committee score, Visual Analog Scale score, and cartilage injury and repair as assessed by magnetic resonance imaging as well as the incidence of postoperative adverse events. DISCUSSION: This trial will attempt to verify the use of tissue-engineered cartilage constructed using autologous chondrocytes combined with allogeneic, acellular cartilage matrix for the repair of cartilage defects, thereby providing favorable evidence for its use in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02770209 . Registered on 11 May 2016. PMID- 29110691 TI - On the complexity of measuring forests microclimate and interpreting its relevance in habitat ecology: the example of Ixodes ricinus ticks. AB - BACKGROUND: Ecological field research on the influence of meteorological parameters on a forest inhabiting species is confronted with the complex relations between measured data and the real conditions the species is exposed to. This study highlights this complexity for the example of Ixodes ricinus. This species lives mainly in forest habitats near the ground, but field research on impacts of meteorological conditions on population dynamics is often based on data from nearby official weather stations or occasional in situ measurements. In addition, studies use very different data approaches to analyze comparable research questions. This study is an extensive examination of the methodology used to analyze the impact of meteorological parameters on Ixodes ricinus and proposes a methodological approach that tackles the underlying complexity. METHODS: Our specifically developed measurement concept was implemented at 25 forest study sites across Baden-Wurttemberg, Germany. Meteorological weather stations recorded data in situ and continuously between summer 2012 and autumn 2015, including relative humidity measures in the litter layer and different heights above it (50 cm, 2 m). Hourly averages of relative humidity were calculated and compared with data from the nearest official weather station. RESULTS: Data measured directly in the forest can differ dramatically from conditions recorded at official weather stations. In general, data indicate a remarkable relative humidity decrease from inside to outside the forest and from ground to atmosphere. Relative humidity measured in the litter layer were, on average, 24% higher than the official data and were much more balanced, especially in summer. CONCLUSIONS: The results illustrate the need for, and benefit of, continuous in situ measurements to grasp the complex relative humidity conditions in forests. Data from official weather stations do not accurately represent actual humidity conditions in forest stands and the explanatory power of short period and fragmentary in situ measurements is extremely limited. However, it is still an open question to what kind of meteorological data are necessary to answer specific questions in tick research. The comparison of research findings was hindered by the variety of information provided, which is why we propose details for future reporting. PMID- 29110692 TI - Identification of a novel genetic locus underlying tremor and dystonia. AB - BACKGROUND: Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Human brain sub-region cDNA libraries were used to study the expression pattern of CAMTA2 transcript variants. RESULTS: Linkage analysis and homozygozity mapping localized the disease allele to a 2.1 Mb interval on chromosome 17 with a LOD score of 4.58. Whole exome sequencing identified a G>A change in the transcript variant 2 5'UTR of CAMTA2 that was only 6 bases upstream of the translation start site (c.-6G > A) (NM_001171166.1) and segregated with disease in an autosomal recessive manner. Transfection of wild type and mutant 5'UTR-linked fluorescent reporters showed no impact upon mRNA levels but a significant reduction in the protein fluorescent activity implying translation inhibition. CONCLUSIONS: Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia. PMID- 29110693 TI - Management of organ motion in scanned ion beam therapy. AB - Scanned ion beam therapy has special demands for treatment of intra-fractionally moving tumors such as lesions in lung or liver. Interplay effects between beam and organ motion can in those settings lead to under-dosage of the target volume. Dedicated treatment techniques such as gating or abdominal compression are required. In addition 4D treatment planning should be used to determine strategies for patient specific treatment planning such as an increased beam focus or the use of internal target volumes incorporating range changes.Several work packages of the Clinical Research Units 214 and 214/2 funded by the German Research Council investigated the management of organ motion in scanned ion beam therapy. A focus was laid on 4D treatment planning using TRiP4D and the development of motion mitigation strategies including their quality assurance. This review focuses on the activity in the second funding period covering adaptive treatment planning strategies, 4D treatment plan optimization, and the application of motion management in pre-clinical research on radiation therapy of cardiac arrhythmias. PMID- 29110694 TI - Effects of freezer storage time on levels of complement biomarkers. AB - BACKGROUND: There is uncertainty regarding how stable complement analytes are during long-term storage at - 80 degrees C. As part of our work program we have measured 17 complement biomarkers (C1q, C1 inhibitor, C3, C3a, iC3b, C4, C5, C9, FB, FD, FH, FI, TCC, Bb, sCR1, sCR2, Clusterin) and the benchmark inflammatory marker C-reactive protein (CRP) in a large set of plasma samples (n = 720) that had been collected, processed and subsequently stored at - 80 degrees C over a period of 6.6-10.6 years, prior to laboratory analysis. The biomarkers were measured using solid-phase enzyme immunoassays with a combination of multiplex assays using the MesoScale Discovery Platform and single-plex enzyme-linked immunosorbent assays (ELISAs). As part of a post hoc analysis of extrinsic factors (co-variables) affecting the analyses we investigated the impact of freezer storage time on the values obtained for each complement analyte. RESULTS: With the exception of five analytes (C4, C9, sCR2, clusterin and CRP), storage time was significantly correlated with measured plasma concentrations. For ten analytes: C3, FI, FB, FD, C5, sCR1, C3a, iC3b, Bb and TCC, storage time was positively correlated with concentration and for three analytes: FH, C1q, and C1 inhibitor, storage time was negatively correlated with concentration. CONCLUSIONS: The results suggest that information on storage time should be regarded as an important co-variable and taken into consideration when analysing data to look for associations of complement biomarker levels and disease or other outcomes. PMID- 29110695 TI - Unifying interdisciplinary education: designing and implementing an intern simulation educational curriculum to increase confidence in critical care from PGY1 to PGY2. AB - BACKGROUND: A longitudinal, multidisciplinary critical care simulation curriculum was developed and implemented within a teaching hospital to address the need for consistent, safe, efficient, and unified critical care training within graduate medical education. Primary goals were to increase learner confidence in critical care topics and procedural skills across all specialties. Secondary goals included improving communication skills and obtaining a high level of learner satisfaction. All interns caring for adult patients within our hospital participated in three 4-h simulation-based sessions scheduled over the second half of their intern year. Pre- and postcurricular surveys evaluated self confidence in critical care topics, procedures, and communication skills. The Debriefing Assessment for Simulation in Healthcare Student Version (DASH-SV) Short Form was used to evaluate facilitator debriefing. Data were compared with Wilcoxon rank sum and signed rank test. RESULTS: Pre- and postcurricular surveys were collected from 51 of 52 interns (98% response rate) in curricular year 1 and 59 of 59 interns (100% response rate) in curricular year 2 in six programs within the hospital. Resident confidence significantly improved in all areas (p < .05). DASH-SV demonstrated overall effective facilitator debriefing and > 75% of interns in both curricular years 1 and 2 expressed a desire for future educational sessions. CONCLUSIONS: The implemented curriculum increased learner confidence in select critical care topics, procedures, and communication skills and demonstrated a high level of learner satisfaction. The curriculum has expanded to learners from three other teaching hospitals within our system to unify critical care education for all interns caring for adult patients. PMID- 29110696 TI - A randomized controlled trial on the effects of collagen sponge and topical tranexamic acid in posterior spinal fusion surgeries. AB - BACKGROUND: This is a randomized controlled trial research to assess the hemostatic efficacy of gelatin sponge, collagen sponge, and topical use of tranexamic acid (TXA) on postoperative blood loss in posterior spinal fusion surgeries. METHODS: We recruited patients with spinal degenerative diseases into the study from November 2013 to October 2016. All the participants were assigned to 3 groups using a simple, equal-probability randomization scheme: group A is a control group utilizing gelatin sponge, while groups B and C are experimental groups, applying collagen hemostatic sponge and topical TXA respectively. Postoperative blood loss, rates of transfusion, and hospitalization were compared among the 3 groups. RESULTS: In our study, the volume of drainage and blood content in drainage on the first postoperative day (POD 1) of patients in the experimental groups were significantly less than those in the control group, as well as rates of transfusion and postoperative hospitalization (P < 0.05). When compared with the control group, the volume of drainage decreased by 22.7% in group B and 56.2% in group C, while the blood content in drainage decreased by 28.8 and 75% respectively. CONCLUSIONS: In this study, collagen and topical use of TXA have both proven to be effective and safe for patients undergoing posterior spinal fusion surgeries, while TXA has exhibited better efficacy. The total amount of perioperative blood loss reduced significantly without increasing incidence of related complications. TRIAL REGISTRATION: A randomized controlled trial for effects of collagen sponge and topical tranexamic acid in posterior lumbar fusion surgeries. ChiCTR-IIR-17010785. PMID- 29110697 TI - ExUTR: a novel pipeline for large-scale prediction of 3'-UTR sequences from NGS data. AB - BACKGROUND: The three prime untranslated region (3'-UTR) is known to play a pivotal role in modulating gene expression by determining the fate of mRNA. Many crucial developmental events, such as mammalian spermatogenesis, tissue patterning, sex determination and neurogenesis, rely heavily on post transcriptional regulation by the 3'-UTR. However, 3'-UTR biology seems to be a relatively untapped field, with only limited tools and 3'-UTR resources available. To elucidate the regulatory mechanisms of the 3'-UTR on gene expression, firstly the 3'-UTR sequences must be identified. Current 3'-UTR mining tools, such as GETUTR, 3USS and UTRscan, all depend on a well-annotated reference genome or curated 3'-UTR sequences, which hinders their application on a myriad of non-model organisms where the genomes are not available. To address these issues, the establishment of an NGS-based, automated pipeline is urgently needed for genome-wide 3'-UTR prediction in the absence of reference genomes. RESULTS: Here, we propose ExUTR, a novel NGS-based pipeline to predict and retrieve 3'-UTR sequences from RNA-Seq experiments, particularly designed for non model species lacking well-annotated genomes. This pipeline integrates cutting edge bioinformatics tools, databases (Uniprot and UTRdb) and novel in-house Perl scripts, implementing a fully automated workflow. By taking transcriptome assemblies as inputs, this pipeline identifies 3'-UTR signals based primarily on the intrinsic features of transcripts, and outputs predicted 3'-UTR candidates together with associated annotations. In addition, ExUTR only requires minimal computational resources, which facilitates its implementation on a standard desktop computer with reasonable runtime, making it affordable to use for most laboratories. We also demonstrate the functionality and extensibility of this pipeline using publically available RNA-Seq data from both model and non-model species, and further validate the accuracy of predicted 3'-UTR using both well characterized 3'-UTR resources and 3P-Seq data. CONCLUSIONS: ExUTR is a practical and powerful workflow that enables rapid genome-wide 3'-UTR discovery from NGS data. The candidates predicted through this pipeline will further advance the study of miRNA target prediction, cis elements in 3'-UTR and the evolution and biology of 3'-UTRs. Being independent of a well-annotated reference genome will dramatically expand its application to much broader research area, encompassing all species for which RNA-Seq is available. PMID- 29110698 TI - Impact of radiographer immediate reporting of chest X-rays from general practice on the lung cancer pathway (radioX): study protocol for a randomised control trial. AB - BACKGROUND: Diagnostic capacity and suboptimal logistics are consistently identified as barriers to timely diagnosis of cancer, especially lung cancer. Immediate chest X-ray (CXR) reporting for patients referred from general practice is advocated in the National Optimal Lung Cancer Pathway to improve time to diagnosis of lung cancer and to reduce inappropriate urgent respiratory medicine referral for suspected cancer (2WW) referrals. The aim of radioX is to examine the impact of immediate reporting by radiographers of CXRs requested by general practice (GP) on lung cancer patient pathways. METHODS: A two-way comparative study that will compare the time to diagnosis of lung cancer for patients. Internal comparison will be made between those who receive an immediate radiographer report of a GP CXR compared to standard radiographer GP CXR reporting over a 12-month period. External comparison will be made with a similar, neighbouring hospital trust that does not have radiographer CXR reporting. Primary outcome is the effect on the speed of the lung cancer pathway (diagnosis of cancer or discharge). Secondary outcomes include the effect of the pathway on efficiency including the number of repeat CXRs performed in a timely fashion for suspected infection and the effect of immediate reporting of GP CXRs on patient satisfaction. DISCUSSION: The radioX trial will examine the hypothesis that immediate reporting of CXRs referred from GP reduces the time to diagnosis of lung cancer or discharge from the lung cancer pathway. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN21818068 . Registered on 20 June 2017. PMID- 29110699 TI - Extensively drug resistant tuberculosis in Mali: a case report. AB - BACKGROUND: Drug resistant tuberculosis presents a major public health challenge. CASE PRESENTATION: We present here the first two patients diagnosed with extensively drug resistant tuberculosis in Bamako, Mali. Genotypic findings suggest possible nosocomial transmission from the first patient to the second one, resulting in superinfection of the second patient. After being diagnosed with extensively drug resistant tuberculosis in August 2016, the patients only started receiving appropriate treatment 10 months later. CONCLUSION: The identification of these patients highlights the need for improved diagnostic and treatment algorithms for better surveillance and management of drug resistance in Mali. In the interest of these as well as future patients suffering from resistant tuberculosis, all steps recommended for programmatic management of drug resistant tuberculosis must be urgently prioritized in order to strengthen the multidrug resistant tuberculosis program. PMID- 29110700 TI - Transcatheter arterial chemoembolization plus sorafenib versus transcatheter arterial chemoembolization alone to treat advanced hepatocellular carcinoma: a meta-analysis. AB - BACKGROUND: Many studies have combined sorafenib with transcatheter arterial chemoembolization (TACE) to treat patients with advanced hepatocellular carcinoma (HCC), but the results are disputable. Thus, we conducted this meta-analysis to assess the efficacy and safety of the combination treatment in patients with advanced HCC. METHODS: Clinical data were collected from a computer search of literature published from January 2009 to June 2016 in PubMed, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang and the China Science and Technology Journal Database (CSTJ). The final analysis included 14 studies and 1670 patients. The primary endpoints were overall survival (OS), the objective response rate (ORR) and the disease control rate (DCR). RESULTS: The combination group exhibited significantly more improvement than the group treated with TACE alone in ORR (RR =1.62, 95% confidence interval (CI) = 1.34-1.94, p < 0.00001), DCR (RR = 1.43, 95% CI = 1.26-1.62, p < 0.00001), 0.5-year OS (OR = 2.60, 95% CI = 1.57-4.29, p = 0.0002) and 1-year OS (OR = 1.88, 95% CI =1.39-2.53, p < 0.0001). The incidence of adverse events from combination therapy was increased compared to that from treatment with TACE alone, and the most commonly reported adverse events were fatigue, hand-foot skin reaction and diarrhoea, which were bearable. CONCLUSIONS: The meta-analysis indicated that combination therapy is safe and efficient for clinical application. PMID- 29110701 TI - Large-scale analysis reveals that the genome features of simple sequence repeats are generally conserved at the family level in insects. AB - BACKGROUND: Simple sequence repeats (SSR), also called microsatellites, have been widely used as genetic markers, and have been extensively studied in some model insects. At present, the genomes of more than 100 insect species are available. However, the features of SSRs in most insect genomes remain largely unknown. RESULTS: We identified 15.01 million SSRs across 136 insect genomes. The number of identified SSRs was positively associated with genome size in insects, but the frequency and density per megabase of genomes were not. Most insect SSRs (56.2 93.1%) were perfect (no mismatch). Imperfect (at least one mismatch) SSRs (average length 22-73 bp) were longer than perfect SSRs (16-30 bp). The most abundant insect SSRs were the di- and trinucleotide types, which accounted for 27.2% and 22.0% of all SSRs, respectively. On average, 59.1%, 36.8%, and 3.7% of insect SSRs were located in intergenic, intronic, and exonic regions, respectively. The percentages of various types of SSRs were similar among insects from the same family. However, they were dissimilar among insects from different families within orders. We carried out a phylogenetic analysis using the SSR frequencies. Species from the same family were generally clustered together in the evolutionary tree. However, insects from the same order but not in the same family did not cluster together. These results indicated that although SSRs undergo rapid expansions and contractions in different populations of the same species, the general genomic features of insect SSRs remain conserved at the family level. CONCLUSION: Millions of insect SSRs were identified and their genome features were analyzed. Most insect SSRs were perfect and were located in intergenic regions. We presented evidence that the variance of insect SSRs accumulated after the differentiation of insect families. PMID- 29110702 TI - Partially absorbed cataractous lens in the anterior chamber revealing neglected severe ocular contusion: a case report. AB - BACKGROUND: Ocular contusion can produce severe lesions, which if not treated appropriately and promptly, can lead to visual impairment. Ocular contusion in childhood may not be reported by children. CASE PRESENTATION: A 27 year old female presented with a partially absorbed cataractous lens that was dislocated into the anterior chamber of her left eye. There was mild anterior chamber reaction. She reported no history of ocular trauma; but associated findings and further investigations were in favour of a post-traumatic aetiology. CONCLUSION: All ocular injuries require a detailed ophthalmological examination to assess vision and the extent of lesions. PMID- 29110703 TI - Effectiveness of a theory-based multicomponent intervention (Movement Coaching) on the promotion of total and domain-specific physical activity: a randomised controlled trial in low back pain patients. AB - BACKGROUND: The promotion of physical activity is a major field in rehabilitation and health promotion but evidence is lacking on what method or strategy works best. Ensuing from this research gap, the present study compared the effectiveness of a comprehensive theory based multicomponent intervention (Movement Coaching) to a low intensity intervention in low back pain patients. METHODS: A monocenter randomized controlled trial with three measuring points (T0 = baseline, T1 = six month follow-up, T2 = twelve month follow-up) was conducted. N = 412 chronic low back pain patients participated. The Movement Coaching group (n = 201) received a comprehensive multicomponent intervention with small-group intervention, phone- and web 2.0-intervention. The low intensity control (n = 211) received two oral presentations that were available for download afterwards. Main outcome was total physical activity measured by Global Physical Activity Questionnaire at 12 month follow-up. Additionally, workplace, leisure time and transportation activities were compared. A split-plot anova was conducted for evaluating repeated measure effects and between group effects. RESULTS: At six and twelve month follow-up there were no statistically significant between group differences in total (T1: p = 0.79; T2: p = 0.30) as well as domain-specific physical activity (workplace (T1: p = 0.16; T2: p = 0.65), leisure time (T1: p = 0.54; T2: p = 0.89), transportation (T1: p = 0.29; T2: p = 0.77) between Movement Coaching and the control group. In both groups, workplace physical activity showed the highest proportion of total physical activity. From baseline to twelve month follow-up the results showed a decline in total physical activity (Movement Coaching: p = 0.04; control group: p = 0.50). CONCLUSIONS: The comprehensive Movement Coaching intervention was not found to be more effective than a low intensity intervention in promoting total and domain-specific physical activity in chronic low back pain patients. TRIAL REGISTRATION: This study is registered at German Clinical Trials Register (DRKS)-ID: DRKS00004878 . PMID- 29110705 TI - Pneumomediastinum following a prolonged second stage of labor - an emphasis on early diagnosis and conservative management: a case report. AB - BACKGROUND: Esophageal rupture is an extremely rare condition to occur to a pregnant or postnatal woman. Esophageal ruptures have been previously described in the literature; however, they are most common in the setting of hyperemesis gravidarum. CASE PRESENTATION: This case report describes a 27-year-old white woman who began complaining of central chest pain and shortness of breath 3 hours after a normal vaginal delivery, with no history of vomiting antenatally or intrapartum. A chest X-ray and computed tomography pulmonary angiogram confirmed surgical emphysema and pneumomediastinum, and a diagnosis of esophageal rupture was made based on these findings. She was stable and conservative management was initiated; she improved over 4 days. Resolution of surgical emphysema was demonstrated on serial chest X-rays without requiring contrast swallow or surgical intervention. CONCLUSIONS: This case exemplifies the importance of a timely diagnosis of esophageal rupture in ensuring a positive outcome for the patient. Delay in diagnosis can lead to an increase in morbidity and mortality. PMID- 29110704 TI - Endobronchial one-way valves for treatment of persistent air leaks: a systematic review. AB - Persistent air leak (PAL) is associated with significant morbidity and mortality, prolonged hospitalization and increased health-care costs. It can arise from a number of conditions, including pneumothorax, necrotizing infection, trauma, malignancies, procedural interventions and complications after thoracic surgery. Numerous therapeutic options, including noninvasive and invasive techniques, are available to treat PALs. Recently, endobronchial one-way valves have been used to treat PAL. We conducted a systematic review based on studies retrieved from PubMed, EMbase and Cochrane library. We also did a hand-search in the bibliographies of relevant articles for additional studies. 34 case reports and 10 case series comprising 208 patients were included in our review. Only 4 patients were children, most of the patients were males. The most common underlying disease was COPD, emphysema and cancer. The most remarkable cause was pneumothorax. The upper lobes were the most frequent locations of air leaks. Complete resolution was gained within less than 24 h in majority of patients. Complications were migration or expectoration of valves, moderate oxygen desaturation and infection of related lung. No death related to endobronchial one way valves implantation has been found. The use of endobronchial one-way valve adds to the armamentarium for non-invasive treatments of challenging PAL, especially those with difficulties of anesthesia, poor condition and high morbidity. Nevertheless, prospective randomized control trials with large sample should be needed to further evaluate the effects and safety of endobronchial one way valve implantation in the treatment of PAL. PMID- 29110706 TI - Correction to: Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma. PMID- 29110707 TI - Correction to: Effects of a multi-level intervention on the pattern of physical activity among in-school adolescents in Oyo state Nigeria: a cluster randomised trial. AB - CORRECTION: After publication of the article [1], it has been brought to our attention that there is an error in figure 1. The number of excluded secondary schools should read "50" and not "72". The rest of the data in the figure is accurate. PMID- 29110708 TI - Co-expression of 1alpha-hydroxylase and vitamin D receptor in human articular chondrocytes. AB - BACKGROUND: The aim was to investigate whether resident chondrocytes in human articular cartilage and in subculture express vitamin D receptor (VDR) and the enzyme that hydroxylates the prohormone 25(OH)D3 to the active hormone 1alpha,25(OH)2D3, namely 1alpha-hydroxylase (CYP27B1). Any putative effects of vitamin D on chondrocytes were also explored. METHODS: Cartilage from human osteoarthritic knee joints, cultured chondrocytes and cells grown in 3D spheroids were examined for the expression of VDR and 1alpha-hydroxylase by PCR, Western blots and immunolabelling. Receptor engagement was judged by visualizing nuclear translocation. The effects of 25(OH)D3 and 1alpha,25(OH)2D3 on chondrocyte functions were assessed in proliferation-, chondrogenesis- and cartilage signature-gene expression assays. The capability of chondrocytes to hydroxylate 25(OH)D3 was determined by measuring the concentration of metabolites. Finally, a putative regulation of receptor and enzyme expression by 1alpha,25(OH)2D3 or interleukin (IL)-1beta, was investigated by Western blot. RESULTS: Gene expression was positive for VDR in freshly isolated cells from native cartilage, cells subcultured in monolayers and in spheroids, whereas protein expression, otherwise judged low, was apparent in monolayers. Nuclear translocation of VDR occurred upon 1alpha,25(OH)2D3 treatment. Transcripts for 1alpha-hydroxylase were detected in freshly isolated cells, cultured cells and spheroids. Western blots and immunolabelling detected 1alpha-hydroxylase protein in all materials, while staining of tissue appeared confined to cells at the superficial layer. A dose dependent 1alpha,25(OH)2D3 production was measured when the enzyme substrate was supplied to cell cultures. Western blots revealed that the VDR, but not 1alpha hydroxylase, was induced by IL-1beta treatment in adherent cells. Proliferation in monolayers was enhanced by both 25(OH)D3 and 1alpha,25(OH)2D3, and both compounds had negative effects on chondrogenesis and cartilage-matrix genes. CONCLUSIONS: VDR expression in resident cartilage chondrocytes, generally considered differentiated cells, is elusive. A similar pattern applies for redifferentiated chondrocytes in spheroid cultures, whereas dedifferentiated cells, established in monolayers, stably express VDR. Both 25(OH)D3 and 1alpha,25(OH)2D3 are able to potentiate cell proliferation but have a negative impact in proteoglycan synthesis. Chondrocytes express 1alpha-hydroxylase and may contribute to the production of 1alpha,25(OH)2D3 into the joint environment. Effects of vitamin D could be unfavourable in the context of cartilage matrix synthesis. PMID- 29110709 TI - The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study. AB - BACKGROUND: Prophylaxis for high-risk populations, such as forest workers, could be one component for malaria elimination in the Greater Mekong Sub-region. A study was conducted to assess the malaria incidence in forest rangers and the feasibility of malaria prophylaxis for rangers sleeping in forest camps. METHODS: Forest rangers deployed in the Bu Gia Map National Park, Vietnam were invited to participate in the study. Plasmodium infections were cleared using presumptive treatment, irrespective of malaria status, with a 3-day course dihydroartemisinin/piperaquine (DP) and a 14-day course of primaquine. Before returning to the forest, study participants were randomly allocated to a 3-day course of DP or placebo. Fifteen days after returning from their forest deployment the participants were tested for Plasmodium infections using uPCR. RESULTS: Prior to treatment, 30 of 150 study participants (20%) were found to be infected with Plasmodium. Seventeen days (median) after enrolment the rangers were randomized to DP or placebo 2 days before returning to forest camps where they stayed between 2 and 20 days (median 9.5 days). One ranger in the DP prophylaxis arm and one in the placebo arm were found to be infected with Plasmodium falciparum 15 days (median) after returning from the forest. The evaluable P. falciparum isolates had molecular markers indicating resistance to artemisinins (K13-C580Y) and piperaquine (plasmepsin), but none had multiple copies of pfmdr1 associated with mefloquine resistance. CONCLUSION: Anti-malarial prophylaxis in forest rangers is feasible. The findings of the study highlight the threat of multidrug-resistant malaria. Trial registration NCT02788864. PMID- 29110710 TI - Potential effectiveness of Chinese herbal medicine Yu ping feng san for adult allergic rhinitis: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Chinese herbal medicine formula Yu ping feng san (YPFS) is commonly used for allergic rhinitis (AR). Previous review had summarized the effectiveness and safety of YPFS, however without any subgroup analysis performed to provide detailed evidence for guiding clinical practice. YPFS was recommended for the management of AR by Chinese medicine clinical practice guideline, but the treatment duration of YPFS was also not specified. The aim of this study is to evaluate the effectiveness and safety of YPFS in treating adult AR with the most recent evidence, and attempt to specify the duration of utilisation through subgroup meta-analyses. METHODS: Seven databases were searched from their inceptions to September 2017. Randomized controlled trials (RCTs) evaluating YPFS for adult AR were included. Methodological quality of studies was assessed using the Cochrane risk of bias tool. Meta-analysis and subgroup meta-analyses were conducted for evaluating the effectiveness of YPFS. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used for rating the quality of evidence. RESULTS: Twenty-two RCTs involving 23 comparisons were included in this review. YPFS was compared to placebo, pharmacotherapy, and used as an add-on treatment compared to pharmacotherapy. Meta-analyses were feasible for the outcomes of four individual nasal symptom scores and "effective rate". Four individual nasal symptom scores decreased after YPFS' combination treatment: itchy nose (MD-0.46, 95% CI[-0.50, -0.42]), sneezing (MD-0.41, 95% CI[-0.47, -0.35]), blocked nose (MD-0.46, 95% CI[-0.54, -0.39]) and runny nose (MD-0.42, 95% CI[-0.58, -0.26]). Based on "effective rate", meta analysis showed that YPFS did not achieve better effect than pharmacotherapy (RR1.07, 95%CI [0.94, 1.22), but its combination with pharmacotherapy seemed more effective than pharmacotherapy alone (RR1.27, 95%CI [1.19, 1.34]) (low quality). Subgroup analysis suggested that YPFS was not superior to the second-generation antihistamine (RR1.04, 95%CI [0.90, 1.19]) (low quality). Further, YPFS' combination treatment seemed more beneficial when it was used for more than three weeks (RR1.15, 95%CI [1.01, 1.32]). In addition, YPFS was well-tolerated for treating adult AR. CONCLUSION: Chinese herbal medicine formula YPFS seems beneficial for adult AR. This potential benefit need to be further evaluated by more rigorous RCTs. PMID- 29110711 TI - Radial extracorporeal shock wave therapy is efficient and safe in the treatment of fracture nonunions of superficial bones: a retrospective case series. AB - BACKGROUND: A substantial body of evidence supports the use of focused extracorporeal shock wave therapy (fESWT) in the non-invasive treatment of fracture nonunions. On the other hand, virtually no studies exist on the use of radial extracorporeal shock wave therapy (rESWT) for this indication. METHODS: We retrospectively analyzed 22 patients treated with rESWT for fracture nonunions of superficial bones that failed to heal despite initial surgical fixation in most cases. Radial extracorporeal shock wave therapy was applied without anesthesia in three rESWT sessions on average, with one rESWT session per week and 3000 radial extracorporeal shock waves at an energy flux density of 0.18 mJ/mm2 per session. Treatment success was monitored with radiographs and clinical examinations. RESULTS: Six months after rESWT radiographic union was confirmed in 16 out of 22 patients (73%), which is similar to the success rate achieved in comparable studies using fESWT. There were no side effects. The tibia was the most common treatment site (10/22) and 70% of tibia nonunions healed within 6 months after rESWT. Overall, successfully treated patients showed a mean time interval of 8.8 +/- 0.8 (mean +/- standard error of the mean) months between initial fracture and commencement of rESWT whereas in unsuccessfully treated patients the mean interval was 26.0 +/- 10.1 months (p < 0.05). In unsuccessful tibia cases, the mean interval was 43.3 +/- 13.9 months. CONCLUSIONS: Radial extracorporeal shock wave therapy appears to be an effective and safe alternative in the management of fracture nonunions of superficial bones if diagnosed early and no fESWT device is available. The promising preliminary results of the present case series should encourage the implementation of randomized controlled trials for the early use of rESWT in fracture nonunions. PMID- 29110712 TI - Ultrasonographically determined renal values and comparisons to serum biochemistry renal variables in aged semi-captive cheetahs (Acinonyx jubatus). AB - BACKGROUND: Cheetahs in captivity have a high prevalence of chronic renal diseases. We ultrasonographically evaluated the renal volumes, a variety of renal dimensions, interarcuate artery resistive indices (RI) as well as aortic diameters and the length of the ventral aspect of the 6th lumbar vertebrae in 27 aged semi-captive anesthetized cheetahs. Renal size, dimensions and ratios were compared to urine specific gravity, serum creatinine and urea values. RESULTS: There were minimal differences for all values between left and right kidneys. Mean kidney length was 65.1 mm (range 55.2-76.9) with left kidney length ratios to L6 length being 1.60 (range 1.27-2.06) and to the aortic diameter 7.69 (range 4.54-10.72). Significant correlations between left renal length as well as length:L6 ratio to creatinine values were found ((r - 0.66) and (r - 0.60) respectively). The mean RI values of the different sedation/anesthetic protocols ranged from 0.46-0.55. CONCLUSIONS: Left renal length and L6 ventral vertebral body length as well as left kidney RI values should be routinely measured in all cheetah abdominal ultrasound examinations. These measurements, together with serum creatinine, urea and urine specific gravity values may be relatively sensitive indicators of early renal pathology in the absence of gross ultrasonographic changes. PMID- 29110713 TI - Temporal and spatial distribution of lumpy skin disease outbreaks in Ethiopia in the period 2000 to 2015. AB - BACKGROUND: Lumpy skin disease (LSD) is an infectious viral disease of cattle caused by a virus of the genus Capripoxvirus. LSD was reported for the first time in Ethiopia in 1981 and subsequently became endemic. This time series study was undertaken with the aims of identifying the spatial and temporal distribution of LSD outbreaks and to forecast the future pattern of LSD outbreaks in Ethiopia. RESULTS: A total of 3811 LSD outbreaks were reported in Ethiopia between 2000 and 2015. In this period, LSD was reported at least once in 82% of the districts (n = 683), 88% of the administrative zones (n = 77), and all of the regional states or city administrations (n = 9 and n = 2) in the country. The average incidence of LSD outbreaks at district level was 5.58 per 16 years (0.35 year-1). The incidence differed between areas, being the lowest in hot dry lowlands and highest in warm moist highland. The occurrence of LSD outbreaks was found to be seasonal. LSD outbreaks generally have a peak in October and a low in May. The trend of LSD outbreaks indicates a slight, but statistically significant increase over the study period. The monthly precipitation pattern is the reverse of LSD outbreak pattern and they are negatively but non-significantly correlated at lag 0 (r = -0.05, p = 0.49, Spearman rank correlation) but the correlation becomes positive and significant when the series are lagged by 1 to 6 months, being the highest at lag 3 (r = 0.55, p < 0.001). The forecast for the period 2016-2018 revealed that the highest number of LSD outbreaks will occur in October for all the 3 years and the lowest in April for the year 2016 and in May for 2017 and 2018. CONCLUSION: LSD occurred in all major parts of the country. Outbreaks were high at the end of the long rainy season. Understanding temporal and spatial patterns of LSD and forecasting future occurrences are useful for indicating periods when particular attention should be paid to prevent and control the disease. PMID- 29110714 TI - Subjectively and objectively assessed social and physical environmental correlates of preschoolers' accelerometer-based physical activity. AB - BACKGROUND: Overweight and low levels of physical activity (PA) in preschoolers are major public health concerns. However, to date only few studies have investigated subjective and objective correlates of PA across different socioecological domains in preschoolers. We therefore simultaneously investigate associations between preschoolers' objectively measured leisure-time PA and a comprehensive set of subjective and objective potential PA correlates across the behavioral, social and physical environmental domains on both family- and community-level. METHODS: In this cross-sectional study time spent in moderate-to vigorous PA (MVPA) and total PA (TPA) were measured by combined accelerometry and heart rate monitoring in 735 3-6 year-old children from 52 preschools in Southern Germany. Family- and community-level potential correlates of PA from different domains (behavioral, social and physical environmental) were subjectively (i.e. by parent proxy-report) and objectively assessed. Their associations with PA on weekend days and weekday afternoons were tested by covariate-adjusted multilevel regression models. RESULTS: While none of the objective social and physical environmental factors showed associations with PA, subjective parental traffic safety perceptions were positively associated with MVPA and TPA on weekends. Also, preschoolers' participation in organized sports was positively correlated with MVPA (on weekends) and TPA (both on weekends and weekday afternoons). CONCLUSION: Subjective traffic safety perceptions and participation in organized sports, an indicator and a result of parental support towards PA - i.e. subjective parental perceptions of environmental factors and family-level correlates which are more proximal to preschoolers - might be more central to PA in preschool age than objectively assessed community-level environmental features which tend to be more distal correlates. If replicable, targeting parental perceptions of environmental factors and parental support for PA in preschool age might be powerful leverages for public health policy. PMID- 29110715 TI - Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis. AB - BACKGROUND: Macrophages play a pivotal role in atherosclerotic plaque development. Recent evidence has suggested the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can attenuate pro-inflammatory responses in macrophages. We hypothesized that liraglutide could limit atherosclerosis progression in vivo via modulation of the inflammatory response. METHODS: Human THP-1 macrophages and bone marrow-derived macrophages, from both wild-type C57BL/6 (WT) and apolipoprotein E null mice (ApoE-/-) were used to investigate the effect of liraglutide on the inflammatory response in vitro. In parallel, ApoE-/- mice were fed a high-fat (60% calories from fat) high-cholesterol (1%) diet for 8 weeks to induce atherosclerotic disease progression with/without daily 300 MUg/kg liraglutide administration for the final 6 weeks. Macrophages were analysed for MPhi1 and MPhi2 macrophage markers by Western blotting, RT-qPCR, ELISA and flow cytometry. Atherosclerotic lesions in aortae from ApoE-/- mice were analysed by en face staining and monocyte and macrophage populations from bone marrow derived cells analysed by flow cytometry. RESULTS: Liraglutide decreased atherosclerotic lesion formation in ApoE-/- mice coincident with a reduction in pro-inflammatory and increased anti-inflammatory monocyte/macrophage populations in vivo. Liraglutide decreased IL-1beta in MPhi0 THP-1 macrophages and bone marrow-derived macrophages from WT mice and induced a significant increase in the MPhi2 surface marker mannose receptor in both MPhi0 and MPhi2 macrophages. Significant reduction in total lesion development was found with once daily 300 MUg/kg liraglutide treatment in ApoE-/- mice. Interestingly, liraglutide inhibited disease progression at the iliac bifurcation suggesting that it retards the initiation and development of disease. These results corresponded to attenuated MPhi1 markers (CCR7, IL-6 and TNF-alpha), augmented MPhi2 cell markers (Arg-1, IL-10 and CD163) and finally decreased MPhi1-like monocytes and macrophages from bone marrow-derived cells. CONCLUSIONS: This data supports a therapeutic role for liraglutide as an atheroprotective agent via modulating macrophage cell fate towards MPhi2 pro-resolving macrophages. PMID- 29110716 TI - Postoperative survival of EGFR-TKI-targeted therapy in non-small cell lung cancer patients with EGFR 19 or 21 mutations: a retrospective study. AB - BACKGROUND: The aim of this retrospective study is to identify epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer patients and to compare the long-term postoperative outcomes in different EGFR-TKI-targeted therapy effects between the different EGFR mutation groups. METHODS: A total of 2094 postoperative non-small cell lung cancer (NSCLC) patients with EGFR gene detection were collected in the Department of Pathology in the Cancer Hospital Chinese Academy of Medical Sciences from January 2003 to January 2014. Three hundred sixty-three patients were treated with EGFR tyrosine kinase inhibitor (TKI) after surgery: 184 harbored the exon 19 deletion mutation and 179 cases carried the exon 21 L858R point mutation. The end points included progression free survival (PFS), overall survival (OS), and the response rate. RESULTS: OS was increased in the EGFR exon 19 deletion group compared with the exon 21 L858R point mutation group (92 vs. 65 months; P < 0.001). But the median PFS did not differ between two groups (12 vs 14 months). The objective response rate (ORR) in 19 deletion group was increased compared with L858R mutation patients (28.35 vs. 22.73%). The disease control rate (DCR) of patients with 19 deletion benefited more from targeted therapy, compared with L858R group (93.71 vs. 84.31%, P = 0.014). In 19 deletion group, a high ORR and DCR were noted in patients treated with icotinib, 16 out of 18 achieved stable disease (SD), and the DCR in this population was 100%. CONCLUSIONS: EGFR subtypes could influence the postoperative survival of NSCLC patients with TKI-targeted therapy. PMID- 29110717 TI - Bayesian intravoxel incoherent motion parameter mapping in the human heart. AB - BACKGROUND: Intravoxel incoherent motion (IVIM) imaging of diffusion and perfusion in the heart suffers from high parameter estimation error. The purpose of this work is to improve cardiac IVIM parameter mapping using Bayesian inference. METHODS: A second-order motion-compensated diffusion weighted spin echo sequence with navigator-based slice tracking was implemented to collect cardiac IVIM data in early systole in eight healthy subjects on a clinical 1.5 T CMR system. IVIM data were encoded along six gradient optimized directions with b values of 0-300 s/mm2. Subjects were scanned twice in two scan sessions one week apart to assess intra-subject reproducibility. Bayesian shrinkage prior (BSP) inference was implemented to determine IVIM parameters (diffusion D, perfusion fraction F and pseudo-diffusion D*). Results were compared to least-squares (LSQ) parameter estimation. Signal-to-noise ratio (SNR) requirements for a given fitting error were assessed for the two methods using simulated data. Reproducibility analysis of parameter estimation in-vivo using BSP and LSQ was performed. RESULTS: BSP resulted in reduced SNR requirements when compared to LSQ in simulations. In-vivo, BSP analysis yielded IVIM parameter maps with smaller intra-myocardial variability and higher estimation certainty relative to LSQ. Mean IVIM parameter estimates in eight healthy subjects were (LSQ/BSP): 1.63 +/- 0.28/1.51 +/- 0.14.10-3 mm2/s for D, 13.13 +/- 19.81/13.11 +/- 5.95% for F and 201.45 +/- 313.23/13.11 +/- 14.53.10-3 mm2/s for D *. Parameter variation across all volunteers and measurements was lower with BSP compared to LSQ (coefficient of variation BSP vs. LSQ: 9% vs. 17% for D, 45% vs. 151% for F and 111% vs. 155% for D *). In addition, reproducibility of the IVIM parameter estimates was higher with BSP compared to LSQ (Bland-Altman coefficients of repeatability BSP vs. LSQ: 0.21 vs. 0.26.10-3 mm2/s for D, 5.55 vs. 6.91% for F and 15.06 vs. 422.80.10-3 mm2/s for D*). CONCLUSION: Robust free-breathing cardiac IVIM data acquisition in early systole is possible with the proposed method. BSP analysis yields improved IVIM parameter maps relative to conventional LSQ fitting with fewer outliers, improved estimation certainty and higher reproducibility. IVIM parameter mapping holds promise for myocardial perfusion measurements without the need for contrast agents. PMID- 29110718 TI - Cardiac patients' perceptions of neighboring patients' risk: influence on psychological stress in the ED and subsequent posttraumatic stress. AB - BACKGROUND: As many as 12% of acute coronary syndrome (ACS) patients screen positive for post-traumatic stress disorder (PTSD) symptoms due to their cardiac event, and emergency department (ED) factors such as overcrowding have been associated with risk for PTSD. We tested the association of patients' perceptions of their proximity to a critically ill patient during ED evaluation for ACS with development of posttraumatic stress symptoms (PSS) in the month after hospital discharge. METHODS: Participants were enrolled in the REactions to Acute Care and Hospitalization (REACH) study during evaluation for ACS in an urban ED. Participants reported whether they perceived a patient near them was close to death. They also reported their current fear, concern they may die, perceived control, and feelings of vulnerability on an Emergency Room Perceptions questionnaire. One month later, participants reported on PTSD symptoms specific to the cardiac event and ED hospitalization. RESULTS: Of 763 participants, 12% reported perceiving a nearby patient was likely to die. In a multivariate linear regression model [F(9757) = 19.69, p < .001, R2 adjusted = .18] with adjustment for age, sex, GRACE cardiac risk score, discharge ACS diagnosis, Charlson comorbidity index, objective ED crowding, and depression symptoms at baseline, perception of a nearby patients' likely death was associated with a 2.33 point (95% CI, 0.60-4.61) increase in 1 month PTSD score. A post hoc mediation analysis with personal threat perceptions [F(10,756) = 25.28, p < .001, R2 adjusted = .24] showed increased personal threat perceptions during the ED visit, B = 0.71 points on the PCL per point on the personal threat perception questionnaire, beta = 0.27, p = .001, fully mediated association of participants' perceptions of nearby patients' likely death with 1-month PTSD score (after adjustment for ED threat perceptions,) B = 0.89 (95% CI, -1.33 to 3.12), beta = 0.03, p = .43, accounting for 62% of the adjusted effect and causing the main effect to become statistically nonsignificant. CONCLUSIONS: We found patients who perceived a nearby patient was likely to die had significantly greater PTSD symptoms at 1 month. Awareness of this association may be helpful for designing ED patient management procedures to identify and treat patients with an eye to post-ACS psychological care. PMID- 29110719 TI - Plague risk in vulnerable community: assessment of Xenopsylla cheopis susceptibility to insecticides in Malagasy prisons. AB - BACKGROUND: Prisons in Madagascar are at high risk of plague outbreak. Occurrence of plague epidemic in prisons can cause significant episode of urban plague through the movement of potentially infected humans, rodents and fleas. Rodent and flea controls are essential in plague prevention, by reducing human contact with plague reservoirs and vectors. Insecticide treatment is the key step available for the control of rat fleas which transmit the disease from infected rodents to human. The implementation of an adapted flea control strategy should rely on the insecticide susceptibility status of the targeted population. For the purpose of plague prevention campaign in prisons, we conducted insecticide resistance survey on Xenopsylla cheopis, the rat flea. METHODS: Fleas were collected on rats caught in six prisons of Madagascar. They were exposed to insecticide treated filter papers and mortality was recorded following World Health Organization protocol. RESULTS: The fleas collected in the prisons had different resistance patterns, while a high level of resistance to insecticides tested was described in the Antanimora prison, located in the heart of Antananarivo, the capital of Madagascar. CONCLUSIONS: This finding is alarming in the context of public health, knowing that the effectiveness of flea control could be jeopardized by insecticide resistance. In order to establish more accurate rat fleas control in prisons, the main recommendations are based on continuous monitoring insecticide susceptibility of flea, insecticide rotation, and the development of a new method for flea control. PMID- 29110720 TI - First intraindividual comparison of contrast-enhanced MRI, FET- and DOTATOC- PET in patients with intracranial meningiomas. AB - BACKGROUND: For irradiation treatment planning of meningiomas the use of PET scans is well established. The most frequently used tracers are either based on amino acids or the somatostatin receptor ligand DOTATOC. Since up to now no inter institutionally accepted standard PET-tracer has been defined, the aim of this study was to evaluate the influence of these different types of PET-tracers on the GTV-definition. METHODS: Twenty-one patients suffering from intracranial meningiomas underwent CT, MRI, FET- and DOTATOC-PET. First, tumour extension was delineated after image-fusion of CT and MRI (GTVCT/MRI). Then distinct GTVs based either on FET- or DOTATOC-PET were contoured and compared with each other as well with GTVCT/MRI. RESULTS: Every tumour showed typical enhancement of DOTATOC, but two meningiomas remained FET-negative. The mean relative overlap volume of GTVFET and GTVDOTATOC was only 41.9% and there was a significantly stronger correlation between GTVCT/MRI and GTVDOTATOC than between GTVCT/MRI and GTVFET . CONCLUSIONS: Further investigations are necessary to clarify the minor conformity of DOTATOC- and FET-PET in meningiomas. Because of the receptor targeting, DOTATOC is known to be more specific for meningiomas and will remain the standard in our institution with the known limitation in areas nearby the pituitary gland. PMID- 29110721 TI - Prevalence of markers of HIV infection among febrile adults and children in Bo, Sierra Leone, 2012-2013. AB - OBJECTIVE: The goal of this study was to examine the prevalence of HIV among febrile patients seeking care in Mercy Hospital, Bo, Sierra Leone, in 2012-2013. RESULTS: A total of 1207 febrile persons were tested for HIV with DetermineTM and SD Bioline rapid diagnostic tests kits that detect the presence of HIV antibodies and HIV p24 antigens. The overall prevalence of HIV among the tested patients was 8.9%, which is considerably higher than the < 2% prevalence of HIV reported previously in the general population. While these results are not sufficient to prove a causal relationship, the obtained data imply that HIV positive individuals may be more likely to suffer from febrile infectious diseases than individuals without HIV infection. Increasing the availability and use of HIV testing services will allow antiretroviral therapy to be accessed in a timely manner and improve health status among people living with HIV. PMID- 29110722 TI - Molecular markers for artemisinin and partner drug resistance in natural Plasmodium falciparum populations following increased insecticide treated net coverage along the slope of mount Cameroon: cross-sectional study. AB - BACKGROUND: Drug resistance is one of the greatest challenges of malaria control programmes, with the monitoring of parasite resistance to artemisinins or to Artemisinin Combination Therapy (ACT) partner drugs critical to elimination efforts. Markers of resistance to a wide panel of antimalarials were assessed in natural parasite populations from southwestern Cameroon. METHODS: Individuals with asymptomatic parasitaemia or uncomplicated malaria were enrolled through cross-sectional surveys from May 2013 to March 2014 along the slope of mount Cameroon. Plasmodium falciparum malaria parasitaemic blood, screened by light microscopy, was depleted of leucocytes using CF11 cellulose columns and the parasite genotype ascertained by sequencing on the Illumina HiSeq platform. RESULTS: A total of 259 participants were enrolled in this study from three different altitudes. While some alleles associated with drug resistance in pfdhfr, pfmdr1 and pfcrt were highly prevalent, less than 3% of all samples carried mutations in the pfkelch13 gene, none of which were amongst those associated with slow artemisinin parasite clearance rates in Southeast Asia. The most prevalent haplotypes were triple mutants Pfdhfr I 51 R 59 N 108 I 164(99%), pfcrt- C72V73 I 74 E 75 T 76 (47.3%), and single mutants PfdhpsS436 G 437K540A581A613(69%) and Pfmdr1 N86 F 184D1246 (53.2%). CONCLUSIONS: The predominance of the Pf pfcrt CVIET and Pf dhfr IRN triple mutant parasites and absence of pfkelch13 resistance alleles suggest that the amodiaquine and pyrimethamine components of AS-AQ and SP may no longer be effective in their role while chloroquine resistance still persists in southwestern Cameroon. PMID- 29110723 TI - Molecular and serological detection of bovine babesiosis in Indonesia. AB - BACKGROUND: Bovine babesiosis, mainly caused by Babesia bovis and B. bigemina, is a huge threat to the livestock industry. In Indonesia, the current distribution of the disease is unknown due to a lack of scientific study. METHODS: In the present study, 487 blood samples were collected from cattle with different breeding and age groups in a broad geographical area across the archipelago. The presence of antibodies and current infections of B. bovis and B. bigemina were determined using enzyme-linked immunosorbent assay (ELISA), immunochromatographic test (ICT), and nested PCR (nPCR) targeting B. bovis SBP-4 and B. bigemina RAP-1a genes. Sequence analysis was performed to the amplicon of B. bovis SBP-4, B. bigemina RAP-1a, and internal transcribed spacer (ITS) region of ribosomal RNA of both Babesia species. RESULTS: In total, B. bovis positives were detected by ELISA, single-ICT, dual-ICT and nPCR in 340 (69.8%), 317 (65.1%), 307 (63.0%) and 247 (50.7%) samples, respectively. For B. bigemina, the positive samples were detected in 134 (27.5%), 130 (26.7%), 127 (26.1%) and 93 (19.1%), respectively. Furthermore, mixed infections were found in 125 (25.7%), 113 (23.2%), 109 (22.4%) and 52 (10.7%) samples, respectively, which occurred only by chance and were not influenced by additional factors. The obtained nucleotide sequences of B. bovis SBP-4 and B. bigemina RAP-1a genes showed a high homology with other isolates from different countries. Further nucleotide sequence analysis using ITS region showed a great genetic diversity of B. bovis isolates among sampling locations; a lower diversity was found in B. bigemina ITS isolates. CONCLUSIONS: These data revealed the current distribution of B. bovis and B. bigemina infection in cattle in Indonesia. The rate of infection varied among sampling locations, cattle breeds and age groups. Furthermore, B. bovis ITS isolates from Indonesia were found to be more genetically diverse than B. bigemina ITS isolates. The data presented in this study are necessary to develop an effective strategy for controlling the disease in the country. PMID- 29110724 TI - Quantifying the intensity of permethrin insecticide resistance in Anopheles mosquitoes in western Kenya. AB - BACKGROUND: The development and spread of resistance among local vectors to the major classes of insecticides used in Long-Lasting Insecticidal Nets (LLINs) and Indoor Residual Spraying (IRS) poses a major challenge to malaria vector control programs worldwide. The main methods of evaluating insecticide resistance in malaria vectors are the WHO tube bioassay and CDC bottle assays, with their weakness being determination of resistance at a fixed dose for variable populations. The CDC bottle assay using different insecticide dosages has proved applicable in ascertaining the intensity of resistance. METHODS: We determined the status and intensity of permethrin resistance and investigated the efficacy of commonly used LLINs (PermaNet(r) 2.0, PermaNet(r) 3.0 and Olyset(r)) against 3 5 day-old adult female Anopheles mosquitoes from four sub-counties; Teso, Bondo, Rachuonyo and Nyando in western Kenya. Knockdown was assessed to 4 doses of permethrin; 1* (21.5 MUg/ml), 2* (43 MUg/ml), 5* (107.5 MUg/ml) and 10* (215 MUg/ml) using CDC bottle assays. RESULTS: Mortality for 0.75% permethrin ranged from 23.5% to 96.1% in the WHO tube assay. Intensity of permethrin resistance was highest in Barkanyango Bondo, with 84% knockdown at the 30 min diagnostic time when exposed to the 10* dose. When exposed to the LLINs, mortality ranged between 0-39% for Olyset(r), 12-88% for PermaNet(r) 2.0 and 26-89% for PermaNet(r) 3.0. The efficacy of nets was reduced in Bondo and Teso. Results from this study show that there was confirmed resistance in all the sites; however, intensity assays were able to differentiate Bondo and Teso as the sites with the highest levels of resistance, which coincidentally were the two sub-counties with reduced net efficacy. CONCLUSIONS: There was a reduced efficacy of nets in areas with high resistance portraying that at certain intensities of resistance, vector control using LLINs may be compromised. It is necessary to incorporate intensity assays in order to determine the extent of threat that resistance poses to malaria control. PMID- 29110725 TI - Tendon split lengthening technique for flexor hallucis longus tendon rupture. AB - BACKGROUND: Flexor hallucis longus (FHL) tendon rupture is a challenging injury to lead with clawing of the great toe when the FHL tendon is repaired too tight. When the diagnosis is delayed, the tendon ends may not be opposable because of contracture or poor tendon tissue. METHODS: A technique to reconstruct FHL tendon rupture without a free tendon graft is described. A split tendon lengthening is performed at the midfoot around the knot of Henry. Ankle block anesthesia is used to allow the patient's active movement of the interphalangeal (IP) joint to determine the appropriate length of the reconstructed tendon for maintaining balance and preventing the tendon from being too tight or too loose. Between May 2012 and September 2015, five patients with a total rupture of the FHL tendon, having tendon defect distal to the knot of Henry, were treated with split tendon lengthening. RESULTS: Four patients could actively plantarflex the great toe IP joint. One patient who was operated under spinal anesthesia could not actively plantarflex the great toe IP joint, but did not have extension deformity and did not want another procedure. The mean American Orthopedic Foot and Ankle Society (AOFAS) score at a mean follow-up of 44 months was 92 points (range, 80-100). CONCLUSIONS: This technique is described to overcome the difficulty of reconstructing the FHL tendon with tendon defect. The tendon defect could be repaired after split tendon lengthening without a free tendon graft. PMID- 29110726 TI - Coix lacryma-jobi var. ma-yuen Stapf sprout extract has anti-metastatic activity in colon cancer cells in vitro. AB - BACKGROUND: Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf has been used in China as an herbal medicine. Many studies of this plant have reported anti proliferative and apoptotic activities on human cancer cell lines. Therefore, this study of the anti-metastatic effect of Coix lacryma-jobi var. ma-yuen Stapf sprout extract (CLSE) in colorectal cancer cells may provide a scientific basis for exploring anti-cancer effects of edible crops. METHODS: To evaluate the effect of CLSE on cell proliferation and signaling, we performed a Cell Counting Kit-8 (CCK-8) assay in HCT116 cells and used western blot analysis. Furthermore, scratch-wound healing, transwell migration, matrigel invasion, and adhesion assays were conducted to elucidate the anti-metastatic effects of CLSE under hypoxic conditions in colon cancer cells. RESULTS: First, CLSE decreased deferoxamine (DFO)-induced migration of colon cancer cells by 87%, and blocked colon cancer cell migration by 80% compared with hypoxia control cells. Second, CLSE treatment resulted in a 54% reduction in hypoxia-induced invasiveness of colon cancer cells, and 50% inhibition of adhesive potency through inactivation of the extracellular signal-regulated kinase (ERK) 1/2 and protein kinase b (AKT) pathways. Third, conditioned medium collected from CLSE-treated HCT116 cells suppressed tube formation of human umbilical vein endothelial cells (HUVECs) by 91%. CONCLUSIONS: CLSE inhibited migration, invasion, and adhesion of colon cancer cells and tube formation by HUVECs via repression of the ERK1/2 and AKT pathways under hypoxic conditions. Therefore, CLSE may be used to treat patients with colon cancer. PMID- 29110727 TI - The nonstructural proteins of Pneumoviruses are remarkably distinct in substrate diversity and specificity. AB - BACKGROUND: Interferon (IFN) inhibits viruses by inducing several hundred cellular genes, aptly named 'interferon (IFN)-stimulated genes' (ISGs). The only two RNA viruses of the Pneumovirus genus of the Paramyxoviridae family, namely Respiratory Syncytial Virus (RSV) and Pneumonia Virus of Mice (PVM), each encode two nonstructural (NS) proteins that share no sequence similarity but yet suppress IFN. Since suppression of IFN underlies the ability of these viruses to replicate in the host cells, the mechanism of such suppression has become an important area of research. This Short Report is an important extension of our previous efforts in defining this mechanism. RESULTS: We show that, like their PVM counterparts, the RSV NS proteins also target multiple members of the ISG family. While significantly extending the substrate repertoire of the RSV NS proteins, these results, unexpectedly, also reveal that the target preferences of the NS proteins of the two viruses are entirely different. This is surprising since the two Pneumoviruses are phylogenetically close with similar genome organization and gene function, and the NS proteins of both also serve as suppressors of host IFN response. CONCLUSION: The finding that the NS proteins of the two highly similar viruses suppress entirely different members of the ISG family raises intriguing questions of pneumoviral NS evolution and mechanism of action. PMID- 29110729 TI - Penile metastasis from rectal adenocarcinoma: a case report. AB - BACKGROUND: Despite its rich vasculature, the penis is rarely involved by metastasis. Since the first description of penile metastasis in 1870, fewer than 500 cases have been reported in the literature. The pelvic organs are the main source of primary tumors that metastasize to the penis. CASE PRESENTATION: We report a case of a 46-year-old Arabic man who presented with erectile dysfunction and painful induration of the penile root. Eight months ago, he had undergone abdomino-perineal resection for rectal adenocarcinoma after neo-adjuvant chemotherapy. The histological evaluation of the resected specimen disclosed a ypT3N0 tumor with a poor therapeutic response (around 5%). An adjuvant chemotherapy by XELOX (oxaliplatin plus capecitabine) regimen has been prescribed for the patient. The magnetic resonance imaging (MRI) showed tumoral infiltration of penile structures and a biopsy of the corpora cavernosa was performed. The histological examination disclosed a penile metastasis from the patient's previous rectal adenocarcinoma. The patient is still alive and continues his adjuvant therapy. CONCLUSION: Penile secondary tumors are very rare and usually occur in patients with advanced tumor stages. A diagnosis of penile metastasis should be considered in patients with a history of malignancies who present with genitourinary symptoms. These patients have a dismal prognosis as they often die in the year after the diagnosis. PMID- 29110730 TI - A meta-science for a global bioethics and biomedicine. AB - BACKGROUND: As suggested by Shook and Giordano, understanding and therefore addressing the urgent international governance issues around globalizing bio medical/technology research and applications is limited by the perception of the underlying science. METHODS: A philosophical methodology is used, based on novel and classical philosophical reflection upon existent literature, clinical wisdoms and narrative theory to discover a meta-science and telos of humankind for the development of a relevant and defendable global biomedical bioethics. RESULTS: In this article, through pondering an integrative systems approach, I propose a biomedical model that may provide Western biomedicine with leadership and interesting insight into the unity beyond the artificial boundaries of its traditional divisions and the limit between physiological and pathological situations (health and disease). A unified biomedicine, as scientific foundation, might then provide the basis for dissolution of similar reflected boundaries within bioethics. A principled and communitarian cosmopolitan bioethics may then be synonymous with a recently proposed principled and communitarian cosmopolitan neuroethics based on a novel objective meta-ethics. In an attempt to help facilitate equal and inclusive participation in inter-, multi-, and transdisciplinary intercultural discourse regarding the aforementioned international governance issues, I offer: (1) a meta-science derived through considering the general behaviour of activity, plasticity and balance in biology and; (2) a novel thought framework to encourage and enhance the ability for self evaluation, self-criticism, and self-revision aimed at broadening perspective, as well as acknowledging and responding to the strengths and limitations of extant knowledge. CONCLUSIONS: Through classical philosophical reflection, I evolve a theory of medicine to discover a telos of humankind which in turn provides an 'internal' moral grounding for a proposed global biomedical bioethics. PMID- 29110731 TI - Level of asthma control and risk factors for poor asthma control among clinic patients seen at a Referral Hospital in Addis Ababa, Ethiopia. AB - OBJECTIVE: Uncontrolled asthma negatively impacts patients, families, and the community. The level of symptom control among asthmatics in Ethiopia has not been well studied. We investigated the level of asthma control and risk factors for poor asthma control in clinic patients seen in the largest public hospital in Ethiopia. RESULTS: In this cross-sectional study, we studied all 182 consecutive subjects with a physician diagnosis of asthma who were seen in chest clinic at Tikur Anbessa Specialized Hospital between July and December 2015. Of the 182 subjects, 68.1% were female. The mean age was 52 +/- 12 years and the median duration of asthma was 20 +/- 12.7 years. One hundred and seventeen subjects (64.3%) had nighttime awakening due to asthma. Fifty-eight (31%) were not using controller medications and 62 (34.6%) had improper inhaler technique. Only 44 (24.2%) subjects had well-controlled asthma. On multivariate analysis, variables associated with uncontrolled asthma included: use of biomass fuel for cooking, longer duration of asthma (> 30 year), incorrect inhalation technique, and asthma exacerbation in the last 12 months. Most asthmatics attending in the largest public hospital in Ethiopia, had uncontrolled asthma. Several risk factors for poor asthma control were identified. Improved asthma control is possible through directed interventions. PMID- 29110732 TI - Normal lung sparing Tomotherapy technique in stage III lung cancer. AB - PURPOSE: Radiation pneumonitis (RP) has been a challenging obstacle in treating stage III lung cancer patients. Beam angle optimization (BAO) technique for Tomotherapy was developed to reduce the normal lung dose for stage III non-small cell lung cancer (NSCLC). Comparative analyses on plan quality by 3 different Intensity-modulated radiation therapy (IMRT) methods with BAO were done. MATERIALS AND METHODS: Ten consecutive stage IIIB NSCLC patients receiving linac based static IMRT (L-IMRT) with total 66 Gy in 33 fractions to the PTV were selected. Two additional Tomotherapy-based IMRT plans (helical beam (TH-IMRT) and static beam (TD-IMRT)) were generated on each patient. To reduce the normal lung dose, Beam angles were optimized by using complete and directional block functions in Tomotherapy based on knowledge based statistical analysis. Plan quality was compared with target coverage, normal organ sparing capability, and normal tissue complication probability (NTCP). Actual beam delivery times and risk of RP related with planning target volume (PTV) were also evaluated. RESULTS: The best PTV coverage measured by conformity index and homogeneity index was achievable by TH-IMRT (0.82 and 1.06), followed by TD-IMRT (0.81 and 1.07) and L-IMRT (0.75 and 1.08). Mean lung dose was the lowest in TH-IMRT plan followed by TD-IMRT and L-IMRT, all of which were <=20 Gy. TH-IMRT plan could significantly lower the lung volumes receiving low to medium dose levels: V5~30 when compared to L-IMRT plan; and V5~20 when compared to TD-IMRT plan, respectively. TD-IMRT plan was significantly better than L-IMRT with respects to V20 and V30 and there was no significant difference with respect to V40 among three plans. The NTCP of the lung was the lowest in TH-IMRT plan, followed by TD IMRT and L-IMRT (6.42% vs. 6.53% vs. 8.11%). Beam delivery time was the shortest in TD-IMRT plan followed by L-IMRT. As PTV length increased, NTCP and Mean lung dose proportionally increased significantly in all three plans. CONCLUSION: Advantageous profiles by TH-IMRT could be achieved by BAO by complete and directional block functions. Current observation could help radiation oncologists to make wise selection of IMRT method for stage IIIB NSCLC. PMID- 29110733 TI - Sigmoid volvulus in children: a case report. AB - BACKGROUND: Sigmoid volvulus is frequently reported in the "volvulus belt" (Middle East, Africa, the Indian subcontinent, Turkey, and South America) and is the third leading cause of large bowel obstruction in North America. It is an uncommon problem in children and adolescents, and is rarely considered a diagnosis in this group. A high index of suspicion is necessary to diagnose sigmoid volvulus in children. CASE PRESENTATION: We present a 13-year-old Arabian girl who came with features suggestive of intestinal obstruction. Plain abdominal film revealed classic omega (coffee bean) sign of sigmoid volvulus. The volvulus was successfully decompressed by means of a rectal tube in our emergency department. The next day during the same admission the volvulus recurred and was successfully decompressed by endoscopy. She was discharged home on her parents' request; she presented again 1 month later. This time the volvulus could not be decompressed non-operatively, so she underwent sigmoidectomy with primary anastomosis. Postoperatively she developed paralytic ileus that resolved after 10 days. Following that she did well and was discharged home. She is still free of symptoms 1 year after the resection. CONCLUSIONS: Sigmoid volvulus is an uncommon problem in children and adolescents, and is rarely considered a diagnosis in this group as a cause of intestinal obstruction. Pediatric surgeons should maintain a high index of suspicion, in order not to miss this important diagnosis, as any delay in instituting treatment has a devastating effect on morbidity as well as mortality. Early diagnosis and prompt treatment confer an excellent prognosis. PMID- 29110734 TI - Socioeconomic and behavioural determinants of malaria among the migrants in gold mining, rubber and oil palm plantation areas in Myanmar. AB - BACKGROUND: Malaria is a major public health problem in Myanmar. Migrant populations are at high risk of contracting malaria and its control is more difficult than for settled population. Studies on malaria and migration are rare in Myanmar. This study was undertaken with the main objective of identifying socioeconomic and behavioural determinants of malaria among the migrant workers involved in gold mining, rubber and oil palm plantations. METHODS: A cross sectional analytic study was conducted using pretested interview-administered questionnaires among internal migrants (n = 406) in the malaria endemic townships of Shwegyin, Bago Region, Thanbyuzayat, Mon State and Kawthaung, Taninthayi Region from August to November, 2015. Data were collected by well-trained Basic Health Staff members in study areas, and then analysed by SPSS version 16.0 using Chi-square tests with significant level at 0.05. RESULTS: Majority of participants were male, Bahmar nationals, married and with primary basic education level and below. The mean duration of migratory work was 4.51 years. 43.1% of them gave definite previous history of malaria within last two years during migration. 92.9% (377/406) of them always used bed nets. Malaria determinants found were male gender (OR = 1.84, 95% CI: 1.22-2.77; P = 0.0040), habit of going out at dawn (OR = 2.36, 95% CI: 1.58-3.52; P < 0.001), usual sleeping indoors (OR = 2.14, 95% CI: 1.04-4.42; P = 0.036), torn bed net or net with large hole(s) (OR = 2.0, 95% CI: 1.21-3.3; P = 0.006), habit of not always sleeping under a bed net at night (OR = 2.02, 95% CI: 1.15-3.52; P = 0.014), alcohol drinking (OR = 2.71, 95% CI: 1.73-4.26; P < 0.001) and failure to attend malaria health talk (OR = 1.78, 95% CI: 1.2-2.65; P = 0.004). CONCLUSIONS: The present study highlighted that it is warranted to launch an effective health education programme for malaria, and to encourage the proper use of insecticide treated bed nets, blankets and/or mufflers and mosquito repellents to reduce the occurrence of malaria among the migrants. PMID- 29110728 TI - How a diverse research ecosystem has generated new rehabilitation technologies: Review of NIDILRR's Rehabilitation Engineering Research Centers. AB - Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a "total approach to rehabilitation", combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970's, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program. PMID- 29110735 TI - Development of interstitial pneumonia during treatment with eribulin: a case report. AB - BACKGROUND: Eribulin is typically used to treat patients with advanced breast cancer, and anti-cancer agents often cause the development of interstitial pneumonia in Japanese patients with advanced cancer. However, few case reports have addressed eribulin-induced interstitial pneumonia. Herein, we report a rare case of interstitial pneumonia-specifically, organized pneumonia-during treatment with eribulin in a patient with advanced breast cancer. CASE PRESENTATION: A 52 year-old Japanese woman was diagnosed as having advanced breast cancer 3 years before the admission described in the present report. She had received eribulin as third-line chemotherapy. Five days after her second treatment with eribulin, she was admitted to our hospital with dyspnea and dry cough. Upon admission, a chest computed tomography scan showed consolidation, with air bronchograms along the bronchovascular bundle of both lower lobes. The patient's serum levels of sialylated carbohydrate antigen Krebs von den Lungen-6 were high, as were her surfactant protein-D levels. There was no evidence of heart failure, renal failure, or infection. Based on the clinical cause, as well as on the findings of organized pneumonia, the patient was diagnosed as having interstitial pneumonia and treated with corticosteroids. After the initiation of steroid treatment, her respiratory condition and chest radiological findings improved. CONCLUSIONS: This case reveals an association between eribulin treatment and interstitial pneumonia. To our knowledge, this is the first case report to describe eribulin induced organized pneumonia. Clinicians should be aware that interstitial pneumonia can develop during treatment with anti-cancer agents. PMID- 29110736 TI - Wireless intraoral tongue control of an assistive robotic arm for individuals with tetraplegia. AB - BACKGROUND: For an individual with tetraplegia assistive robotic arms provide a potentially invaluable opportunity for rehabilitation. However, there is a lack of available control methods to allow these individuals to fully control the assistive arms. METHODS: Here we show that it is possible for an individual with tetraplegia to use the tongue to fully control all 14 movements of an assistive robotic arm in a three dimensional space using a wireless intraoral control system, thus allowing for numerous activities of daily living. We developed a tongue-based robotic control method incorporating a multi-sensor inductive tongue interface. One abled-bodied individual and one individual with tetraplegia performed a proof of concept study by controlling the robot with their tongue using direct actuator control and endpoint control, respectively. RESULTS: After 30 min of training, the able-bodied experimental participant tongue controlled the assistive robot to pick up a roll of tape in 80% of the attempts. Further, the individual with tetraplegia succeeded in fully tongue controlling the assistive robot to reach for and touch a roll of tape in 100% of the attempts and to pick up the roll in 50% of the attempts. Furthermore, she controlled the robot to grasp a bottle of water and pour its contents into a cup; her first functional action in 19 years. CONCLUSION: To our knowledge, this is the first time that an individual with tetraplegia has been able to fully control an assistive robotic arm using a wireless intraoral tongue interface. The tongue interface used to control the robot is currently available for control of computers and of powered wheelchairs, and the robot employed in this study is also commercially available. Therefore, the presented results may translate into available solutions within reasonable time. PMID- 29110737 TI - A microdeletion in the GRHL2 Gene in two unrelated patients with congenital fibrosis of the extra ocular muscles. AB - OBJECTIVE: Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is known to be caused by mutations in KIF21A or TUBB3 or other known genes (SALL4, CHN1, HOXA1). However, affected children may harbor other genetic defects. Therefore, a candidate gene analysis (KIF21A, TUBB3 SALL4, CHN1, HOXA1) and a high-resolution array comparative genomic hybridization (arrayCGH) was performed in two unrelated children with sporadic CFEOM1. RESULTS: Two unrelated Saudi patients did not have any mutation(s) after sequencing the full coding regions of SALL4, CHN1, HOXA1, and TUBB3 genes; and exons 8, 20, and 21 of the KIF21A gene. However, arrayCGH revealed a 3.17 Kb deletion at chromosome 8p22 with copy number state equal to 1, indicating a heterozygous deletion. This deletion was absent in proband's mother or father or 220 unrelated healthy individuals of similar ethnicity. The deletion encompassed only one functional gene, GRHL2, which encodes a transcription factor. In humans, defects in this gene are a cause of non-syndromic sensorineural deafness, autosomal dominant type 28 (DFNA28). We speculate that GRHL2 gene may have a role in orbital innervations and the defect in this gene (deletion) may be related to the CFEOM1 phenotype in these two children. PMID- 29110739 TI - Urgent hybrid palliation for interrupted aortic arch in a preterm infant. AB - In patients with ductal-dependent CHD, ductal restriction can be life threatening. We present the use of urgent hybrid palliation involving placement of bilateral pulmonary artery bands and ductus arteriosus stent implantation in a 1.5 kg premature infant with interrupted aortic arch and ductal restriction. PMID- 29110738 TI - What can we learn from simulation-based training to improve skills for end-of life care? Insights from a national project in Israel. AB - BACKGROUND: Simulation-based training improves residents' skills for end-of-life (EOL) care. In the field, staff providers play a significant role in handling those situations and in shaping practice by role modeling. We initiated an educational intervention to train healthcare providers for improved communication skills at EOL using simulation of sensitive encounters with patients and families. METHODS: Hospital physicians and nurses (n = 1324) attended simulation based workshops (n = 100) in a national project to improve EOL care. We analyzed perceptions emerging from group discussions following simulations, from questionnaires before and after each workshop, and from video-recorded simulations using a validated coding system. We used the simulation setting as a novel tool for action research. We used a participatory inquiry paradigm, with repetitive cycles of exploring barriers and challenges with participants in an iterative pattern of observation, discussion and reflection - including a description of our own responses and evolution of thought as well as system effects. RESULTS: The themes transpiring included lack of training, knowledge and time, technology overuse, uncertainty in decision-making, poor skills for communication and teamwork. Specific scenarios demonstrated lack of experience at eliciting preferences for EOL care and at handling conflicts or dilemmas. Content analysis of simulations showed predominance of cognitive utterances - by an order of magnitude more prevalent than emotional expressions. Providers talked more than actors did and episodes of silence were rare. Workshop participants acknowledged needs to improve listening skills, attention to affect and teamwork. They felt that the simulation-based workshop is likely to ameliorate future handling of EOL situations. We observed unanticipated consequences from our project manifested as a field study of preparedness to EOL in nursing homes, followed by a national survey on quality of care, leading to expansion of palliative care services and demand for EOL care education in various frameworks and professional areas. CONCLUSIONS: Reflective simulation exercises show barriers and paths to improvement among staff providers. When facing EOL situations, physicians and nurses use cognitive language far more often than emotions related expressions, active listening, or presence in silence. Training a critical mass of staff providers may be valuable to induce a cultural shift in EOL care. PMID- 29110740 TI - Electrophysiological Investigations in Orthostatic Myoclonus: Preliminary Findings. AB - We report the clinical and electrophysiological findings in seven patients with orthostatic myoclonus (OM) associated with gait initiation failure and falls. OM is one of the causes of unsteadiness of stance and gait, and it may develop as a symptom of neurodegenerative disorders. Both positive myoclonic bursts and negative myoclonus may be seen in electrophysiological recordings, and electrophysiological analysis suggests a subcortical origin for OM. PMID- 29110741 TI - Effect of fibre additions to flatbread flour mixes on glucose kinetics: a randomised controlled trial. AB - We previously found that guar gum (GG) and chickpea flour (CPF) added to flatbread wheat flour lowered postprandial blood glucose (PPG) and insulin responses dose dependently. However, rates of glucose influx cannot be determined from PPG, which integrates rates of influx, tissue disposal and hepatic glucose production. The objective was to quantify rates of glucose influx and related fluxes as contributors to changes in PPG with GG and CPF additions to wheat-based flatbreads. In a randomised cross-over design, twelve healthy males consumed each of three different 13C-enriched meals: control flatbreads (C), or C incorporating 15 % CPF with either 2 % (GG2) or 4 % (GG4) GG. A dual isotope technique was used to determine the time to reach 50 % absorption of exogenous glucose (T 50 %abs, primary objective), rate of appearance of exogenous glucose (RaE), rate of appearance of total glucose (RaT), endogenous glucose production (EGP) and rate of disappearance of total glucose (RdT). Additional exploratory outcomes included PPG, insulin, glucose-dependent insulinotropic peptide and glucagon-like peptide 1, which were additionally measured over 4 h. Compared with C, GG2 and GG4 had no significant effect on T 50 %abs. However, GG4 significantly reduced 4-h AUC values for RaE, RaT, RdT and EGP, by 11, 14, 14 and 64 %, respectively, whereas GG2 showed minor effects. Effect sizes over 2 and 4 h were similar except for significantly greater reduction in EGP for GG4 at 2 h. In conclusion, a soluble fibre mix added to flatbreads only slightly reduced rates of glucose influx, but more substantially affected rates of postprandial disposal and hepatic glucose production. PMID- 29110742 TI - Development and validation of anthropometric prediction equations for lean body mass, fat mass and percent fat in adults using the National Health and Nutrition Examination Survey (NHANES) 1999-2006. AB - Quantification of lean body mass and fat mass can provide important insight into epidemiological research. However, there is no consensus on generalisable anthropometric prediction equations to validly estimate body composition. We aimed to develop and validate practical anthropometric prediction equations for lean body mass, fat mass and percent fat in adults (men, n 7531; women, n 6534) from the National Health and Nutrition Examination Survey 1999-2006. Using a prediction sample, we predicted each of dual-energy X-ray absorptiometry (DXA) measured lean body mass, fat mass and percent fat based on different combinations of anthropometric measures. The proposed equations were validated using a validation sample and obesity-related biomarkers. The practical equation including age, race, height, weight and waist circumference had high predictive ability for lean body mass (men: R 2=0.91, standard error of estimate (SEE)=2.6 kg; women: R 2=0.85, SEE=2.4 kg) and fat mass (men: R 2=0.90, SEE=2.6 kg; women: R 2=0.93, SEE=2.4 kg). Waist circumference was a strong predictor in men only. Addition of other circumference and skinfold measures slightly improved the prediction model. For percent fat, R 2 were generally lower but the trend in variation explained was similar. Our validation tests showed robust and consistent results with no evidence of substantial bias. Additional validation using biomarkers demonstrated comparable abilities to predict obesity-related biomarkers between direct DXA measurements and predicted scores. Moreover, predicted fat mass and percent fat had significantly stronger associations with obesity-related biomarkers than BMI did. Our findings suggest the potential application of the proposed equations in various epidemiological settings. PMID- 29110743 TI - Rosmarinic acid: modes of action, medicinal values and health benefits. AB - The supplementation of livestock rations with herbs containing bioactive components, such as rosmarinic acid (RA), have shown promising results as a natural feed additive in promoting growth, productive and reproductive performance, feed utilization, fertility, anti-oxidant status and immunologic indices. Furthermore, RA reportedly reduces the risks of various animal diseases and mitigates side effects of chemical and synthetic drugs. RA is a natural polyphenol present in several Lamiaceae herbs like Perilla frutescens, and RA is becoming an integral component of animal nutrition as it counters the effect of reactive oxygen species induced in the body as a consequence of different kinds of stressors. Studies have further ascertained the capability of RA to work as an anti-microbial, immunomodulatory, anti-diabetic, anti-allergic, anti inflammatory, hepato- and renal-protectant agent, as well as to have beneficial effects during skin afflictions. Additionally, RA is favored in meat industries due to enhancing the quality of meat products by reportedly improving shelf-life and imparting desirable flavor. This review describes the beneficial applications and recent findings with RA, including its natural sources, modes of action and various useful applications in safeguarding livestock health as well as important aspects of human health. PMID- 29110744 TI - Biochemical characterization a digestive trypsin in the midgut of large cabbage white butterfly, Pieris brassicae L. (Lepidoptera: Pieridae). AB - A comprehensive study on digestive trypsin was undertaken in the larval midgut of Pieris brassicae L. Results of enzymatic compartmentalization showed a significantly higher activity of crude trypsin in the anterior larval midgut rather than posterior-midgut. Using Diethylaminoethyl cellulose fast flow column chromatography a purified trypsin was obtained by specific activity of 21 U mg-1 protein, recovery of 22%, purification fold of 28-fold and molecular weight of 25 kDa. This purified enzyme showed the highest activity at pH 8 and the corresponding temperature of 40 degrees C. However, the specific inhibitors used including 4-(2-Aminoethyl) benzenesulfonyl fluroride hydrochloride, N-p-Tosyl-L lysine methyl ester hydrochloride and Soybean Trypsin Inhibitor significantly lowered the activity of the purified enzyme in vitro. Moreover, the activity of trypsin and likewise the nutritional indices were significantly altered in the larval midgut feeding upon the leaves treated by 1 mM concentration of each inhibitor in comparison with control. Determination of enzymatic characteristics of insect trypsins is crucial in paving the path for controlling pests by potential natural compounds via transgenic plants. PMID- 29110745 TI - An unusual course of anti-Ro antibody-mediated fetal complete heart block. AB - Fetal hydrops is a serious complication of immune-mediated congenital complete atrioventricular block. We present the case of a fetus with severe hydrops and profound bradycardia and an unusual favourable outcome. This case enhances the importance of considering the contribution of ventricular ectopic beats to the cardiac output when counselling and predicting outcome of complete heart block. PMID- 29110746 TI - Lead promotes abnormal angiogenesis induced by CCM3 gene defects via mitochondrial pathway. AB - Lead is one of the environmental pollutants with cardiovascular toxicity. The embryos are particularly sensitive to lead exposure, because it can move through the blood-placental barrier and the blood-brain barrier easily during embryonic development. Cerebral cavernous malformations 3 (CCM3) gene plays an important role in cardiovascular development, mainly affecting cell proliferation, differentiation and apoptosis. In this study, we established a blood vessel development model of mouse embryos in order to imitate human people with CCM3 genes defects and exposing to environment toxin Pb in utero. We would like to determine the interaction of Pb and CCM3 gene on vascular development, and to explore the mechanisms. We found that the yolk sac of CCM3 heterozygous mice embryo showed abnormal morphology at E11.5 after lead treatment comparing with wild type (WT) mice without lead exposure, meanwhile it showed more angiogenesis and vascular remodeling in the hematoxylin and eosin stained sections of the CCM3+/- yolk sac with lead exposure. We also found that the similar effect of Pb and CCM3 gene on mitochondrial DNA (mtDNA) copy number in vivo and in vitro. Mitochondrial morphology and function also changed in primary human umbilical vein endothelial cells after lead exposure. Besides, it was found that the HIF 1alpha and TFAM which have close relationship with mtDNA biogenesis showed similarly increasing messenger RNA expression in both human and mouse-derived primary cells with lead treated and CCM3 gene knockout. All of the above results indicated that lead and CCM3 might damage endothelial cells through mitochondria pathway and eventually both affected angiogenesis. PMID- 29110747 TI - Deep Brain Stimulation, Authenticity and Value-CORRIGENDUM. PMID- 29110748 TI - Perinatal maternal high-fat diet induces early obesity and sex-specific alterations of the endocannabinoid system in white and brown adipose tissue of weanling rat offspring. AB - Perinatal maternal high-fat (HF) diet programmes offspring obesity. Obesity is associated with overactivation of the endocannabinoid system (ECS) in adult subjects, but the role of the ECS in the developmental origins of obesity is mostly unknown. The ECS consists of endocannabinoids, cannabinoid receptors (cannabinoid type-1 receptor (CB1) and cannabinoid type-2 receptor (CB2)) and metabolising enzymes. We hypothesised that perinatal maternal HF diet would alter the ECS in a sex-dependent manner in white and brown adipose tissue of rat offspring at weaning in parallel to obesity development. Female rats received standard diet (9 % energy content from fat) or HF diet (29 % energy content from fat) before mating, during pregnancy and lactation. At weaning, male and female offspring were killed for tissue harvest. Maternal HF diet induced early obesity, white adipocyte hypertrophy and increased lipid accumulation in brown adipose tissue associated with sex-specific changes of the ECS's components in weanling rats. In male pups, maternal HF diet decreased CB1 and CB2 protein in subcutaneous adipose tissue. In female pups, maternal HF diet increased visceral and decreased subcutaneous CB1. In brown adipose tissue, maternal HF diet increased CB1 regardless of pup sex. In addition, maternal HF diet differentially changed oestrogen receptor across the adipose depots in male and female pups. The ECS and oestrogen signalling play an important role in lipogenesis, adipogenesis and thermogenesis, and we observed early changes in their targets in adipose depots of the offspring. The present findings provide insights into the involvement of the ECS in the developmental origins of metabolic disease induced by inadequate maternal nutrition in early life. PMID- 29110749 TI - Salivary leptin and TAS1R2/TAS1R3 polymorphisms are related to sweet taste sensitivity and carbohydrate intake from a buffet meal in healthy young adults. AB - The influence of sweet taste sensitivity on food intake is not well understood. We investigated the involvement of salivary leptin and SNP of the sweet taste receptor genes (TAS1R2/TAS1R3) on sweet taste sensitivity, sensory-specific satiety (SSS) and macronutrient intake in healthy human adults. In all, nineteen high sweet sensitivity (HS) and eleven low sweet sensitivity (LS) subjects were classified based on the sweetness perception of one solution (9 mm sucrose) forced-choice triangle test. All participants completed a randomised crossover design experiment where they consumed one of three iso-energetic soup preloads differing in primary taste quality (sweet, non-sweet taste-control or no-taste energy-control). A period of 1 h after the preload, participants were offered a buffet meal consisting of foods varying in taste (sweet or non-sweet) and fat content. Subjective measures included hunger/fullness and SSS for sweetness. Saliva and buccal cells were collected to measure leptin level and to study the TAS1R2/TAS1R3 specific SNP, respectively. Salivary leptin concentrations were significantly higher in LS than HS participants (P<0.05). In addition, HS showed stronger sweet SSS compared with LH participants (P<0.05), and consumed less carbohydrate (% energy) and more non-sweet foods than LS (P<0.01 and P<0.05, respectively). Alleles from each TAS1R2 locus (GG compared with AA alleles of rs12033832, and CT/CC compared with TT alleles of rs35874116) were related to higher consumption of carbohydrates (% energy) and higher amount of sweet foods, respectively (P<0.05). In contrast, no associations were found for the TAS1R3 alleles. These results contribute to understand the links between taste sensitivity, macronutrient appetite and food consumption. PMID- 29110750 TI - Aortic elasticity and carotid intima-media thickness in children with mitral valve prolapse. AB - : Aim We aimed to study the dimensions, systolic and diastolic functions of the left ventricle; dimensions and elasticity of the aorta; and carotid intima-media thickness and flow-mediated dilatation of the brachial artery in mitral valve prolapse. METHODS: The study group consisted of 43 patients (mean age=13.3+/-3.9) and 42 healthy children (mean age=12.9+/-3.4). Left ventricular end-diastolic, end-systolic, left atrial diameters, interventricular septum, and left ventricular posterior wall thickness were measured. Ejection and shortening fractions were calculated by M-mode. Measurements were adjusted to the body surface area. Mitral annulus, and systolic and diastolic diameters of the aortic annulus and aorta at each level were obtained; z-scores, aortic strain, distensibility, stiffness index were calculated. Carotid intima-media thickness and flow-mediated dilatation were studied. Patients were classified as classical/non-classical mitral valve prolapse and younger/older patients. RESULTS: Left ventricular end-systolic, end-diastolic, and left atrial diameters (p=0.009, p=0.024, p=0.001) and aortic z-scores at annulus, sinus valsalva, and sinotubuler junction were larger (p=0.008, p=0.003, p=0.002, respectively) in the mitral valve prolapse group. Aortic strain and distensibility increased and stiffness decreased at the ascending aorta in the patient group (p=0.012, 0.020, p=0.019, respectively). Classical mitral valve prolapse had lower strain and distensibility and higher stiffness of the aorta at sinus valsalva level (p=0.010, 0.027, 0.004, respectively). Carotid intima-media thickness was thinner in the patient group, especially in the non-classical mitral valve prolapse group (p=0.037). Flow-mediated dilatation did not differ among the groups. CONCLUSION: Mitral valve prolapse is a systemic disease of the connective tissue causing enlarged cardiac chambers and increased elasticity of the aorta. Decreased carotid intima-media thickness in this group may indicate low atherosclerosis risk. PMID- 29110751 TI - Actinobacillus pleuropneumoniae biofilms: Role in pathogenicity and potential impact for vaccination development. AB - Actinobacillus pleuropneumoniae is a Gram-negative bacterium that belongs to the family Pasteurellaceae. It is the causative agent of porcine pleuropneumonia, a highly contagious respiratory disease that is responsible for major economic losses in the global pork industry. The disease may present itself as a chronic or an acute infection characterized by severe pathology, including hemorrhage, fibrinous and necrotic lung lesions, and, in the worst cases, rapid death. A. pleuropneumoniae is transmitted via aerosol route, direct contact with infected pigs, and by the farm environment. Many virulence factors associated with this bacterium are well characterized. However, much less is known about the role of biofilm, a sessile mode of growth that may have a critical impact on A. pleuropneumoniae pathogenicity. Here we review the current knowledge on A. pleuropneumoniae biofilm, factors associated with biofilm formation and dispersion, and the impact of biofilm on the pathogenesis A. pleuropneumoniae. We also provide an overview of current vaccination strategies against A. pleuropneumoniae and consider the possible role of biofilms vaccines for controlling the disease. PMID- 29110752 TI - Heritability and GWAS Analyses of Acne in Australian Adolescent Twins. AB - Acne vulgaris is a skin disease with a multifactorial and complex pathology. While several twin studies have estimated that acne has a heritability of up to 80%, the genomic elements responsible for the origin and pathology of acne are still undiscovered. Here we performed a twin-based structural equation model, using available data on acne severity for an Australian sample of 4,491 twins and their siblings aged from 10 to 24. This study extends by a factor of 3 an earlier analysis of the genetic factors of acne. Acne severity was rated by nurses on a 4 point scale (1 = absent to 4 = severe) on up to three body sites (face, back, chest) and on up to three occasions (age 12, 14, and 16). The phenotype that we analyzed was the most severe rating at any site or age. The polychoric correlation for monozygotic twins was higher (r MZ = 0.86, 95% CI [0.81, 0.90]) than for dizygotic twins (r DZ = 0.42, 95% CI [0.35, 0.47]). A model that includes additive genetic effects and unique environmental effects was the most parsimonious model to explain the genetic variance of acne severity, and the estimated heritability was 0.85 (95% CI [0.82, 0.87]). We then conducted a genome wide analysis including an additional 271 siblings - for a total of 4,762 individuals. A genome-wide association study (GWAS) scan did not detect loci associated with the severity of acne at the threshold of 5E-08 but suggestive association was found for three SNPs: rs10515088 locus 5q13.1 (p = 3.9E-07), rs12738078 locus 1p35.5 (p = 6.7E-07), and rs117943429 locus 18q21.2 (p = 9.1E 07). The 5q13.1 locus is close to PIK3R1, a gene that has a potential regulatory effect on sebocyte differentiation. PMID- 29110753 TI - A multicentre, randomised controlled trial of position during the late stages of labour in nulliparous women with an epidural: clinical effectiveness and an economic evaluation (BUMPES). AB - BACKGROUND: Epidural analgesia leads to increased risk of instrumental vaginal delivery (IVD). There is debate about whether or not posture in second-stage labour influences the incidence of spontaneous vaginal birth (SVB). OBJECTIVES: In nulliparous women with epidural analgesia, does a policy of adopting an 'upright position' throughout second-stage labour increase the incidence of SVB compared with a policy of adopting a 'lying-down' position? DESIGN: Two-arm randomised controlled trial. SETTING: Maternity units in England and Wales. PARTICIPANTS: Nulliparous women aged >= 16 years, at >= 37 weeks' gestation with singleton cephalic presentation and intended SVB, in second-stage labour with an epidural providing effective pain relief. INTERVENTIONS: (1) Upright position to maintain the pelvis in as vertical a plane as possible; and (2) lying-down position to maintain the pelvis in as horizontal a plane as possible. MAIN OUTCOME MEASURES: The primary outcome measure was incidence of SVB. Secondary outcomes included augmentation, interventions to maintain blood pressure, duration of labour, episiotomy, genital tract trauma, post-partum haemorrhage, maternal satisfaction, neonatal metabolic acidosis, 5-minute Apgar score of < 4, resuscitation at birth and admission to neonatal unit. At 1 year for (1) women: urinary or faecal incontinence, dyspareunia and health-related quality of life; (2) for infants: major morbidity. A cost-consequences analysis with a time horizon of 1 year after the birth from a NHS perspective. RESULTS: Between October 2010 and January 2014, 3236 women were randomised from 41 centres in England and Wales. There was a statistically significant difference in the incidence of SVB between groups, with 35.2% of women achieving a SVB in the upright group, compared with 41.1% in the lying-down group (adjusted risk ratio 0.86, 95% confidence interval 0.78 to 0.94). There was no evidence of differences in most of the secondary maternal or neonatal outcomes, or in long-term outcomes at the 12-month follow-up. No significant overall cost differences were observed between upright and lying-down positions for mothers or their babies. LIMITATIONS: Measurement of adherence was challenging in this unmasked trial, and adherence could be influenced by midwives' beliefs about the allocated positions. If adherence was poor, this would have diluted the difference between the two groups. CONCLUSIONS: There is clear evidence of the benefit of adopting a lying down position in second-stage labour in nulliparous women with epidural analgesia, with no apparent disadvantages in either short- or long-term outcomes for mother or baby, and this is cost neutral for the NHS. FUTURE WORK: Questions remain about whether or not other positions could increase the incidence of SVB further in this group of women. The results also raise questions about the role of maternal position in second-stage labour in women without an epidural. TRIAL REGISTRATION: Current Controlled Trials ISRCTN35706297. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in Health Technology Assessment, Vol 21, No. 65. See the NIHR Journals Library website for further project information. PMID- 29110755 TI - Introduction: APOL1-Associated Kidney Disease. PMID- 29110756 TI - APOL1 Nephropathy: A Population Genetics and Evolutionary Medicine Detective Story. AB - Common DNA sequence variants rarely have a high-risk association with a common disease. When such associations do occur, evolutionary forces must be sought, such as in the association of apolipoprotein L1 (APOL1) gene risk variants with nondiabetic kidney diseases in populations of African ancestry. The variants originated in West Africa and provided pathogenic resistance in the heterozygous state that led to high allele frequencies owing to an adaptive evolutionary selective sweep. However, the homozygous state is disadvantageous and is associated with a markedly increased risk of a spectrum of kidney diseases encompassing hypertension-attributed kidney disease, focal segmental glomerulosclerosis, human immunodeficiency virus nephropathy, sickle cell nephropathy, and progressive lupus nephritis. This scientific success story emerged with the help of the tools developed over the past 2 decades in human genome sequencing and population genomic databases. In this introductory article to a timely issue dedicated to illuminating progress in this area, we describe this unique population genetics and evolutionary medicine detective story. We emphasize the paradox of the inheritance mode, the missing heritability, and unresolved associations, including cardiovascular risk and diabetic nephropathy. We also highlight how genetic epidemiology elucidates mechanisms and how the principles of evolution can be used to unravel conserved pathways affected by APOL1 that may lead to novel therapies. The APOL1 gene provides a compelling example of a common variant association with common forms of nondiabetic kidney disease occurring in a continental population isolate with subsequent global admixture. Scientific collaboration using multiple experimental model systems and approaches should further clarify pathomechanisms further, leading to novel therapies. PMID- 29110757 TI - A Brief History of APOL1: A Gene Evolving. AB - APOL1 kidney risk variants lead to high rates of kidney disease in people of recent African ancestry. These risk variants are very common and confer a large increase in risk of kidney disease. This unusual combination of high frequency and large effect size occurs because the risk variants also appear to have beneficial properties. The risk variants show enhanced protective effects against certain pathogens, particularly the trypanosomes that cause African sleeping sickness. Here, we consider the origins and evolution of the primate-only APOL1 gene. Human genetics, mouse models, biochemistry, and comparative genomics suggest that APOL1 is an innate immunity gene and that the risk variants have the potential for heightened immunity that comes at the cost of toxicity to the kidneys. A better understanding of the evolution of APOL1 may help illuminate how APOL1 causes kidney disease in individuals who harbor the high-risk variants. PMID- 29110754 TI - Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium. AB - The human gastrointestinal tract is immature at birth, yet must adapt to dramatic changes such as oral nutrition and microbial colonization. The confluence of these factors can lead to severe inflammatory disease in premature infants; however, investigating complex environment-host interactions is difficult due to limited access to immature human tissue. Here, we demonstrate that the epithelium of human pluripotent stem-cell-derived human intestinal organoids is globally similar to the immature human epithelium and we utilize HIOs to investigate complex host-microbe interactions in this naive epithelium. Our findings demonstrate that the immature epithelium is intrinsically capable of establishing a stable host-microbe symbiosis. Microbial colonization leads to complex contact and hypoxia driven responses resulting in increased antimicrobial peptide production, maturation of the mucus layer, and improved barrier function. These studies lay the groundwork for an improved mechanistic understanding of how colonization influences development of the immature human intestine. PMID- 29110758 TI - APOL1 Renal Risk Variants: Fertile Soil for HIV-Associated Nephropathy. AB - Apolipoprotein L1 (APOL1) genetic variants are potent risk factors for glomerular disease, but one or more additional factors are required for expression of glomerular disease. Uncontrolled or poorly controlled human immunodeficiency virus (HIV) infection is the most potent susceptibility factor for APOL1 nephropathy that has been identified to date. APOL1 variants are associated with HIV-associated nephropathy (HIVAN), a podocyte disease, but not with HIV-immune complex disease, primarily a disease of the mesangium. The mechanism by which HIV brings out the latent glomerular disease risk remains to be defined. There are at least two classes of candidate mechanisms to explain the potent interaction between HIV-1 and APOL1. First, APOL1 variant proteins and HIV accessory proteins implicated in HIVAN may target the same or related intracellular pathways in podocytes. Recent data suggest roles for interleukin 1b and transcription factor EB. Second, features of uncontrolled HIV infection, including increased circulating factors such as interferon, may drive APOL1 gene transcription or act upon podocytes in other ways. Deeper probing of APOL1-HIV interactions may yield insights that will aid in understanding HIVAN, APOL1 nephropathy, and podocyte biology. PMID- 29110759 TI - The Expanding Role of APOL1 Risk in Chronic Kidney Disease and Cardiovascular Disease. AB - Variants of the APOL1 gene, found primarily in individuals of African descent, are associated with various forms of kidney disease and kidney disease progression. Recent studies evaluating the association of APOL1 with cardiovascular disease have yielded conflicting results, and the potential role in cardiovascular disease remains unclear. In this review, we summarize the observational studies linking the APOL1 risk variants with chronic kidney and cardiovascular disease among persons of African descent. PMID- 29110760 TI - Apolipoprotein L1 Gene Effects on Kidney Transplantation. AB - The pathogenesis of many common etiologies of nephropathy has been informed by recent molecular genetic breakthroughs. It now is apparent that the ethnic disparity in the risk for nondiabetic chronic kidney disease between African Americans and European Americans is explained largely by variation in the apolipoprotein L1 gene (APOL1). The presence of two APOL1 renal risk variants markedly increases an individual's risk for kidney disease. In transplantation, kidneys from deceased African Americans with two APOL1 renal risk variants have shorter survival intervals after engraftment, regardless of the ethnicity of the recipient. Precision medicine will transform the clinical practice of nephrology and kidney transplantation, and play an important role in the allocation of kidneys from deceased and living kidney donors with recent African ancestry. This article reviews existing data on APOL1 in deceased-donor and living-donor kidney transplantation. It considers the impact of including APOL1 genotyping in decisions on the allocation and discard of deceased-donor kidneys, as well as the selection of living donors. PMID- 29110761 TI - The Cell Biology of APOL1. AB - The association of variants in the APOL1 gene, which encodes apolipoprotein L1 (APOL1), with progressive nondiabetic kidney diseases in African Americans has prompted intense investigation into the function(s) of APOL1. APOL1 is an innate immune effector that protects human beings from infection by some trypanosomal parasites. We review the data characterizing APOL1 trypanolytic function, which has been a basis for studies of APOL1 function in mammalian cells. Subsequently, we discuss the studies that use animal models, mammalian cell culture models, and kidney biopsy tissue to discover the mechanisms of variant APOL1-associated kidney diseases. PMID- 29110764 TI - RECALMIN II: Information for improving the country's Internal Medicine Services. PMID- 29110763 TI - Clinical Genetic Testing for APOL1: Are we There Yet? AB - End-stage renal disease (ESRD) disproportionately affects African Americans, who are two to four times more likely than European Americans to develop ESRD. Two independent variants of the apolipoprotein L1 (APOL1) gene, G1 and G2, have been associated with a 7- to 10-fold greater risk of developing nondiabetic ESRD in African Americans. Those who inherit two risk variants (G1/G1, G2/G2, or G1/G2) are also more likely to develop ESRD at a younger age and to have progression of chronic kidney disease. Currently, it is not known what proportion of persons with high-risk genotypes will develop ESRD in the general population, the exact mechanism of injury for APOL1-related risk, its relation to environmental exposures, or whether patients with comorbid conditions are more likely to develop ESRD. To address the above uncertainties, research that includes assessment of APOL1 status is needed before guidelines for general testing can be endorsed. Currently, APOL1 testing has been proposed as part of kidney transplant protocols both for living donors and recipients. However, because of uncertainties regarding the clinical implications of APOL1 variants, testing could generate confusion, anxiety, or stigma. Multiple forms of evidence, including the views of community members, are needed to support responsible approaches to providing information about APOL1 status as part of clinical care or in population screening. Informed consent with subsequent counseling regarding the risks and benefits of APOL1 testing should be considered for patients at high risk. PMID- 29110765 TI - High-intensity plaques as a novel surrogate marker of vulnerable coronary lesions? PMID- 29110762 TI - APOL1 Nephrotoxicity: What Does Ion Transport Have to Do With It? AB - Apolipoprotein L1 (APOL1) protein is the human serum factor that protect human beings against Trypanosoma brucei brucei, the cause of trypanosomiasis. Subspecies of T b brucei that cause human sleeping sickness-T b gambiense and T b rhodesiense evolved molecular mechanisms that enabled them to evade killing by APOL1. Sequence changes (termed G1 and G2) in the APOL1 gene that restored its ability to kill T b rhodesiense also increase the risk of developing glomerular diseases and accelerate progression to end-stage kidney disease. To lyse trypanosome parasites, APOL1 forms pores in the trypanosome endolysosomal and mitochondrial membranes, resulting in rapid membrane depolarization. However, the molecular mechanism underlying APOL1 nephropathy is unknown. Recent experimental evidence has shown that aberrant efflux of intracellular potassium is an early event in APOL1-induced death of human embryonic kidney cells. Here, we discuss the possibility that abnormal efflux of cellular potassium or other cations may be relevant to the pathogenesis of APOL1 nephropathy. PMID- 29110766 TI - Cerebrospinal fluid in Creutzfeldt-Jakob disease. AB - Cerebrospinal fluid (CSF) contains a dynamic and complex mixture of proteins, which reflects physiologic or pathologic states of the central nervous system. Changes in CSF proteome have been described in various neurodegenerative disorders. Earliest publications came from the field of prion disease. Two major approaches have been followed aiming to detect the pathologic form of prion protein (PrPSc) in various peripheral tissues on one hand, but also looking for surrogate parameters as a consequence of the underlying neurodegenerative process. First observations were made using two-dimensional gel electrophoresis for proteins named p130/131, identified as belonging to the 14-3-3 protein family group. This protein became known as the first "wet" biomarker part of clinical diagnostic criteria. Other proteins were identified; most of the work in addition to 14-3-3 has been done on tau/p-tau. The development of PrPSc-based biomarkers was hampered by technical problems and detection limits. A novel technique which uses an amplification procedure followed by an aggregation step (real-time quaking-induced conversion: RT-QuIC) emerged and allows the detection of abnormally folded PrPSc in the CSF. This chapter summarizes the current knowledge of biomarker development in prion disease and discusses perspectives for new approaches. PMID- 29110767 TI - Cerebrospinal fluid findings in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathies. AB - The classic immunologic alteration of the cerebrospinal fluid (CSF) in Guillain Barre syndrome (GBS), albuminocytologic dissociation, has been known since the original paper by Guillain, Barre, and Strohl. Albuminocytologic dissociation has been also described in other forms of the GBS spectrum, such as axonal motor or motor-sensory forms (AMAN, AMSAN), the anti-GQ1b spectrum of Miller Fisher syndrome, and Bickerstaff brainstem encephalitis. Cytokines, chemokines, antibodies, complement components, and molecules with a putative neuroprotective role or indicating axonal damage have also been examined using different methods. Besides these candidate approaches, proteomics has been recently applied to discover potential biomarkers. The overall results support the immunopathogenesis of GBS, but albuminocytologic dissociation remained the only consistent CSF biomarker supporting the diagnosis of GBS. Chronic inflammatory neuropathies also comprise a heterogeneous group of diseases. Increased protein in the CSF is a supportive factor of chronic inflammatory demyelinating polyneuropathy, especially in the absence of definite electrophysiologic criteria. A number of other markers have also been investigated in the CSF of patients with chronic inflammatory neuropathies, similar to GBS. However, none has been used in supporting diagnosis, differentiating among syndromes, or predicting the clinical course and treatment responses. PMID- 29110768 TI - Cerebrospinal fluid biomarkers of malignancies located in the central nervous system. AB - CNS malignancies include primary tumors that originate within the CNS as well as secondary tumors that develop as a result of metastatic cancer. The delicate nature of the nervous systems makes tumors located in the CNS notoriously difficult to reach, which poses several problems during diagnosis and treatment. CSF can be acquired relatively easy through lumbar puncture and offers an important compartment for analysis of cells and molecules that carry information about the malignant process. Such techniques have opened up a new field of research focused on the identification of specific biomarkers for several types of CNS malignancies, which may help in diagnosis and monitoring of tumor progression or treatment response. Biomarkers are sought in DNA, (micro)RNA, proteins, exosomes and circulating tumor cells in the CSF. Techniques are rapidly progressing to assess these markers with increasing sensitivity and specificity, and correlations with clinical parameters are being investigated. It is expected that these efforts will, in the near future, yield clinically relevant markers that aid in diagnosis, monitoring and (tailored) treatment of patients bearing CNS tumors. This chapter provides a summary of the current state of affairs of the field of biomarkers of different types of CNS tumors. PMID- 29110769 TI - Impaired cerebrospinal fluid pressure. AB - Abnormalities of cerebrospinal fluid (CSF) pressure are relatively common and may lead to a variety of symptoms, with headache usually being the most prominent one. The clinical presentation of alterations in CSF pressure may vary significantly and show a striking similitude to several primary headache syndromes. While an increase in CSF pressure may be of primary or secondary origin, a pathologic decrease of CSF pressure is usually the result of a meningeal rupture with a resulting leakage of CSF. The pathophysiologic mechanisms of idiopathic intracranial hypertension (IIH) remain largely unknown. However recent evidence indicates that an abnormality in CSF outflow and absorption is likely to play a significant role. Treatment usually consists of a combination of weight loss and a pharmacologic approach using carbonic anhydrase inhibitors. Recent results of the first randomized, double-blind, placebo controlled trial (RCT) with acetazolamide proved its efficacy in reducing headache and visual disturbances. Clinical evidence suggests efficacy for topiramate and furosemide but no RCT has been conducted to date to confirm these results. In contrast to IIH, spontaneous intracranial hypotension frequently remits spontaneously without specific treatment. If necessary, treatment options range from conservative methods to epidural blood or fibrin sealant patches and surgical interventions. PMID- 29110770 TI - CSF in acute and chronic infectious diseases. AB - Infections of the nervous system are an important and challenging aspect of clinical neurology. Immediate correct diagnosis enables to introduce effective therapy, in conditions that without diagnosis may leave the patient with severe neurological incapacitation and sometimes even death. The cerebrospinal fluid (CSF) is a mirror that reflects nervous system pathology and can promote early diagnosis and therapy. The present chapter focuses on the CSF findings in neuro infections, mainly viral and bacterial. Opening pressure, protein and glucose levels, presence of cells and type of the cellular reaction should be monitored. Other tests can also shed light on the causative agent: serology, culture, staining, molecular techniques such as polymerase chain reaction. Specific examination such as panbacterial and panfungal examinations should be examined when relevant. Our chapter is a guide-text that combines clinical presentation and course with CSF findings as a usuaful tool in diagnosis of neuroinfections. PMID- 29110771 TI - Vascular diseases and bleedings. AB - Diseases of the central nervous system that are caused by an underlying vascular pathology typically result in either hemorrhage or ischemia. Most prominent entities include spontaneous subarachnoid hemorrhage, spontaneous intracerebral hemorrhage, and ischemic stroke. For anatomic reasons, cerebrospinal fluid (CSF) qualifies as body fluid for the exploration of biomarkers in these disorders. Even though in subarachnoid hemorrhage a few CSF parameters have been established for routine diagnostic purposes, there is still an unmet need and broad interest in the identification of molecules that would allow further insight into disease mechanisms and supplement patients' medical care. This chapter provides an overview on what is presently known about CSF biomarkers in spontaneous subarachnoid hemorrhage, spontaneous intracerebral hemorrhage, and ischemic stroke. We recapitulate current evidence on established diagnostic tests, discuss the role of various CSF molecules in the pathophysiology of these diseases, and illuminate their potential use in future clinical practice. Furthermore, we address methodologic aspects as well as shortcomings of research in this field. PMID- 29110772 TI - The cerebrospinal fluid and barriers - anatomic and physiologic considerations. AB - The cerebrospinal fluid (CSF) space consists of the intracerebral ventricles, subarachnoid spaces of the spine and brain (e.g., cisterns and sulci), and the central spinal cord canal. The CSF protects the central nervous system (CNS) in different ways involving metabolic homeostasis, supply of nutrients, functioning as lymphatic system, and regulation of intracranial pressure. CSF is produced by the choroid plexus, brain interstitium, and meninges, and it circulates in a craniocaudal direction from ventricles to spinal subarachnoid space from where it is removed via craniocaudal lymphatic routes and the venous system. The CSF is renewed 3-5 times daily and its molecular constituents are mainly blood-derived (80%), while the remainder consists of brain-derived and intrathecally produced molecules (20%). The CSF space is separated from the vascular system by the blood CSF barrier (BCB), whereas the blood-brain barrier (BBB), responsible for maintaining the homeostasis of the brain, is located between brain parenchyma and vascular system. Although both barriers have similar functions, they differ with regard to their morphologic and functional properties. Both barrier systems are permeable not only for small molecules, but also for macromolecules and circulating cells. The transport of molecules across the BBB and BCB is regulated by passive diffusion (e.g., albumin, immunoglobulins) and facilitated or active transport (e.g., glucose). The extracellular space volume, potassium buffering, CSF circulation, and interstitial fluid absorption are mainly regulated by aquaporin-4 channels, which are abundantly located at the blood-brain and brain CSF interfaces. The composition of CSF shows a high dynamic range, and the levels of distinct proteins vary due to several influencing factors, such as site of production (brain or blood-derived), site of sampling (ventricular or lumbar), CSF flow rate (BCB function), diurnal fluctuations of CSF production rate, and finally, molecular size of blood-derived proteins (IgM vs. albumin) and circadian rhythm (glucose, prostaglandin D synthase). Alterations of lumbar CSF are mainly influenced by processes of the CNS located adjacent to the ventricular and spinal CSF space and less by pathologies in cortical areas remote from the ventricles. PMID- 29110773 TI - Cerebrospinal fluid and brain extracellular fluid in severe brain trauma. AB - Traumatic brain injury is a major cause of morbidity and mortality worldwide. Pathophysiologic mechanisms of secondary brain injury are complex and still not fully understood. Cerebrospinal fluid deserves attention to detect infectious complications and to identify biomarkers of disease severity and impending secondary brain injury. As an adjunct, cerebral microdialysis (CMD) allows online measurements of biomarkers derived directly from brain extracellular fluid. We critically review relevant literature related to infectious complications detectable in the cerebrospinal fluid in trauma patients. We then address the current role of CMD in clinical practice in the identification and prediction of secondary brain injury after severe trauma. Moreover we discuss the role of CMD derived biomarkers in prognostication. Finally we challenge common treatment strategies and provide novel treatment concepts using brain-derived biomarkers as endpoints. We suggest a personalized treatment strategy for individual patients with severe traumatic brain injury. PMID- 29110774 TI - Epilepsy. AB - Epilepsy is worldwide one of the most common neurologic diseases (prevalence 0.5 1%). The diagnostic procedure following a first epileptic seizure includes cerebral imaging, blood examinations, electroencephalography, and an investigation of the cerebrospinal fluid (CSF) in patients seen soon after a seizure in order to exclude dangerous causes which require immediate treatment. Basic CSF investigation comprises the determination of cell counts, glucose, and lactate levels in serum and CSF and of albumin, immunoglobulins, and their quotients. Taken together recent studies show that otherwise unexplained liquor pleocytosis following an epileptic seizure is a rare and transient phenomenon, mainly observed in the first 72 hours. Blood-CSF barrier disruption, however, is observed in a considerable percentage of patients with epileptic seizures and plays a critical role in epileptogenesis and also is observed as a sequel of epileptic activity, in particular in status epilepticus. Similarly, elevated tau protein and lactate levels are commonly seen after epileptic seizures and depend on seizure duration. Whereas elevated lactate levels are transient and observed only up to 72 hours after a seizure, tau levels and albumin quotients remain increased for 9-14 days. Intrathecal immunoglobulin synthesis is increasingly observed in patients with focal cryptogenic epilepsy. Systematic prospective clinical and experimental trials are required to identify antigenic targets and to select patients for whom immunotherapy might be a therapeutic option. PMID- 29110775 TI - Primary headaches. AB - Headache disorders, characterized by recurrent headache, are among the most common disorders of the nervous system. Primary headache disorders are by definition not the result of any other underlying disease or process. In this chapter the current status of cerebrospinal fluid (CSF) research and applications for clinical practice for the three main primary headaches - migraine, cluster headache, and tension-type headache - will be described. Primary headaches are clinically diagnosed disorders, with typically normal routine CSF measurements. Research in these headaches has been focused on identifying pathophysiologic pathways with a wide array of measured molecules. CSF research in the headache field is still in the discovery phase, with most studies performed in migraine and with unreplicated findings for most of the identified molecules. From a clinical standpoint it would be of great value if CSF biomarkers could be used as disorder-specific biomarkers for difficult primary headache cases, or to predict treatment responsiveness or risk for headache chronification. These applications are currently not yet feasible. For future research into CSF biomarkers for primary headache disorders, two different strategies should be employed: hypothesis-driven and nonhypothesis-driven biochemical research, to show new avenues for treatment strategies and develop prediction models for clinical use. PMID- 29110776 TI - Psychiatric syndromes other than dementia. AB - There is wide variability in how psychiatry guidelines and textbooks address the question of cerebrospinal fluid (CSF) diagnostics in the screening of psychiatric disorders. A United States-based textbook confirms that there is no consensus about which laboratory investigation should be routinely performed in psychiatric patients, but with respect to CSF diagnostics, the differences are even more striking. A survey among European experts showed a wide variety of opinions regarding clinical use and criteria in various countries of Europe and worldwide: some psychiatrists, mostly university hospital-based, recommended performing CSF diagnostics in every patient first experiencing severe mental illness (SMI), but especially in patients from the schizophrenia spectrum, whereas others almost never perform CSF examinations themselves and usually refer patients to neurology departments if necessary. Minor neurologic signs are generally frequent in SMI, mainly in affective and schizophrenic disorders. Even with neurologic signs present, there are no clear guidelines regarding CSF evaluation, leaving doctors with experience-based decision making. However, the field is evolving. A recent review provides helpful yellow and red flags for differential diagnosis of SMI from autoimmune encephalitis; interestingly, minor CSF abnormalities are considered a red flag, suggesting that CSF should be routinely performed in acute psychiatric patients. There are reports of single cases identified as an established neurologic disorder: patients within affective and schizophrenic spectrum disorders systematically underwent CSF examination, and were rediagnosed based on CSF results. This was often to the surprise of the psychiatric doctors. Overall, an increasing number of psychiatrists believe that CSF is too rarely examined in psychiatric patients. This chapter provides an overview of differential diagnostic issues in SMI, particularly for new-onset cases. The general recommendations regarding CSF examination procedures can be found in other chapters of this book. Here we focus on specific aspects of differential diagnosis in SMI. Also, there will be an overview of admittedly limited CSF research efforts in psychiatric disorders, focusing on more recent CSF studies. CSF studies in SMI performed with state-of-the-art methods, for example proteomics or assessments of cytokines, were intriguing but difficult to interpret and required critical considerations regarding respective methodology, an undertaking which is outside the scope of this chapter. PMID- 29110778 TI - More than a drainage fluid: the role of CSF in signaling in the brain and other effects on brain tissue. AB - Current progress in neuroscience demonstrates that the brain is not an isolated organ and is influenced by the systemic environment and extracerebral processes within the body. In view of this new concept, blood and cerebrospinal fluid (CSF) are important body fluids linking extracerebral and intracerebral processes. For decades, substantial evidence has been accumulated indicating that CSF modulates brain states and influences behavior as well as cognition. This chapter provides an overview of how CSF directly modulates the function of different types of brain cells, such as neurons, neural stem cells, and CSF-contacting cells. Alterations in CSF content occur in most pathologic central nervous system (CNS) conditions. In a classic view, the function of CSF is to drain waste products and detrimental factors derived from diseased brain parenchyma. This chapter presents examples for how intra- and extracerebral pathologic processes lead to alterations in the CSF content. Current knowledge about how pathologically altered CSF influences the functionality of brain cells will be presented. Thereby, it becomes evident that CSF has more than a drainage function and has a causal role for the etiology and pathogenesis of different CNS diseases. PMID- 29110777 TI - The use of cerebrospinal fluid in biomarker studies. AB - Cerebrospinal fluid (CSF) is an extremely useful matrix for biomarker research for several purposes, such as diagnosis, prognosis, monitoring, and identification of prominent leads in pathways of neurologic diseases. Such biomarkers can be identified based on a priori hypotheses around prominent protein changes, but also by applying -omics technologies. Proteomics is widely used, but metabolomics and transcriptomics are rapidly revealing their potential for CSF studies. The basis of such studies is the availability of high-quality biobanks. Furthermore, profound knowledge and consequent optimization of all aspects in biomarker development are needed. Here we discuss current knowledge and recently developed protocols for successful biomarker studies, from collection of CSF by lumbar puncture, processing, and biobanking protocols, preanalytic confounding factors, and cost-efficient development and validation of assays for implementation into clinical practice or research. PMID- 29110779 TI - Dosing, collection, and quality control issues in cerebrospinal fluid research using animal models. AB - Cerebrospinal fluid (CSF) is a complex fluid filling the ventricular system and surrounding the brain and spinal cord. Although the bulk of CSF is created by the choroid plexus, a significant fraction derives from the interstitial fluid in the brain and spinal cord parenchyma. For this reason, CSF can often be used as a source of pharmacodynamic and prognostic biomarkers to reflect biochemical changes occurring within the brain. For instance, CSF biomarkers can be used to diagnose and track progression of disease as well as understand pharmacokinetic and pharmacodynamic relationships in clinical trials. To facilitate the use of these biomarkers in humans, studies in preclinical species are often valuable. This review summarizes methods for preclinical CSF collection for biomarkers from mice, rats, and nonhuman primates. In addition, dosing directly into CSF is increasingly being used to improve drug levels in the brain. Therefore, this review also summarizes the state of the art in CSF dosing in these preclinical species. PMID- 29110780 TI - Multiple sclerosis, and other demyelinating and autoimmune inflammatory diseases of the central nervous system. AB - Multiple sclerosis (MS) is characterized by a substantial degree of heterogeneity in relation to clinical manifestations, disease course, radiologic findings, histopathologic characteristics of brain lesions, and response to treatment. In this scenario, there is a strong need in MS for biomarkers that reliably capture these diverse aspects of disease heterogeneity and assist, for instance, in disease diagnosis and stratification, in the prediction of disease course, or in the identification of new and effective therapies for the disease. Due to its close proximity to sites of inflammatory lesions, biomarkers measured in cerebrospinal fluid (CSF) are likely to be more informative compared to other body fluid sources such as peripheral blood or urine. This chapter will review the current knowledge existing on CSF molecular biomarkers in MS and also neuromyelitis optica, a pathologic condition originally considered to be a form of MS, following a classification of biomarkers based on the predominant pathophysiologic processes taking place in these two diseases: activation/inflammatory biomarkers; oxidative stress biomarkers; neuroaxonal damage biomarkers; and remyelination and demyelination biomarkers. PMID- 29110781 TI - Cerebrospinal fluid in the dementias. AB - Alzheimer disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia are the most common central nervous system disorders that cause progressive neurocognitive dysfunction and ultimately dementia. A number of biomarkers for pathologies reflecting each condition have been developed. Here, we review these and give an overview of the current state of practice and research regarding cerebrospinal fluid biomarkers for these disorders. The chapter discusses both established (most of which are tau- and amyloid beta related) and upcoming biomarkers and details, wherever appropriate, clinical use and differential diagnostics aspects. PMID- 29110782 TI - Biomarkers in cerebrospinal fluid for synucleinopathies, tauopathies, and other neurodegenerative disorders. AB - The incidence of neurodegenerative disorders is increasing due to worldwide population aging. In general, sporadic forms account for 90% of total cases with neurodegenerative disorders and the reasons underlying initiation or progression of these diseases remain unknown for almost all disorders. To date, diagnosis is mainly based on clinical symptoms and neuroimaging, which is in many cases insufficient due to overlap in clinical symptoms among several neurodegenerative disorders. Therefore, postmortem neuropathologic confirmation remains the gold standard diagnostic technique for many disorders. Biomarkers that could help in defining the clinical diagnosis, or predict disease progression and response to treatment, would therefore be very useful. In this chapter, we discuss potential biomarkers in cerebrospinal fluid studied in synucleinopathies, tauopathies, and other neurodegenerative disorders, and their possible application for clinical practice. Dementias are excluded in this analysis as these are discussed in Chapter 6. PMID- 29110783 TI - Preface. PMID- 29110784 TI - Foreword. PMID- 29110785 TI - Big-5 Quasi-Experimental designs. PMID- 29110786 TI - Corrigendum to "The Mini-OAKHQOL for knee and hip osteoarthritis quality of life was obtained following recent shortening guidelines" [J Clin Epidemiol 2016;69:70 78]. PMID- 29110788 TI - Worldwide trends in heart and lung transplantation: Guarding the most precious gift ever. AB - Transplantation is sadly a therapy to die for. The survival of a recipient with end-stage heart or lung disease requires the demise of a human being through brain death or cessation of circulation, with the noblest final act of offering one's organs to another. However, transplantation is constrained by severe hemodynamic, regulatory, inflammatory, and metabolic stresses in the donor, rendering the majority of offered organs unsuitable for transplantation. Coupled with our inability to acquire exact molecular and cellular information and missed opportunities for effectively modulating deteriorations of donors and allografts, anesthesia and critical care contributes to ongoing organ shortages. Progress is made with improving waiting lists by bridging patients for transplantation using mechanical support. However, this represents more complex recipients, higher risk transplant operations, and increased resource utilization. The advent of ex vivo perfusion allows implementing novel diagnostic and therapeutic strategies with real potential of reconditioning less ideal organs. This review advocates a paradigm change in critical care management of the potential donor for improving retrieval practices and for more intellectual involvement of our specialties in organ preservation, ex vivo evaluation and reconditioning, and the need for great advancement in our efficiency in converting unacceptable allografts to suitable donor organs. PMID- 29110790 TI - Long-term management of patients with end-stage lung diseases. AB - Long-term management of end-stage lung disease differs from interstitial lung disease to chronic obstructive pulmonary disease to cystic fibrosis to pulmonary vascular disease. The management includes pharmacological therapy that is disease specific such as antibiotic therapy for cystic fibrosis, antifibrotic drugs in idiopathic pulmonary fibrosis; long-acting beta-agonists, long-acting muscarinic antagonist, and inhaled corticosteroids in chronic obstructive pulmonary disease; and vasodilators in pulmonary arterial hypertension. Moreover, non pharmacological therapy is essential in the treatment of these diseases, in particular, rehabilitation and supportive therapy, which are necessary in all end stage lung diseases and specific intervention such as non-invasive ventilation in chronic obstructive pulmonary disease and cystic fibrosis, surgical therapy in chronic obstructive pulmonary disease, and airway clearance in cystic fibrosis. The goal is not only to prolong survival, but it is fundamental to keep patients in good general conditions for transplantation. Transplantation, indeed, remains the only therapeutic option that could prolong survival in patients with terminal lung disease when medical or surgical therapies are not available or not effective anymore. PMID- 29110789 TI - Long-term management of end-stage heart failure. AB - End-stage heart failure manifests as severe and often relentless symptoms that define the clinical syndrome of heart failure, namely congestion and hypoperfusion. These patients suffer from dyspnea, fatigue, abdominal discomfort, and ultimately cardiac cachexia. Renal and hepatic dysfunction frequently further complicates the process. Recurrent hospitalizations, cardiac arrhythmias, and intolerance to standard heart failure therapies are common as the disease progresses. Management focuses on controlling symptoms, correcting precipitants, avoiding triggers, and maximizing therapies with demonstrable survival benefit. Among appropriate candidates, advanced therapies such as orthotopic heart transplant (OHT) can significantly extend survival and improve the quality of life. Left ventricular assist devices have been used with increasing frequency as a bridge to OHT or as a destination therapy in appropriately selected candidates where they have a demonstrable mortality benefit over medical therapy. Importantly, a multidisciplinary patient-centered approach is crucial when considering these advanced therapies. PMID- 29110791 TI - Preanesthetic evaluation of the patient with end-stage heart failure. AB - Heart failure (HF) currently affects more than 5 million patients in the United States [1]. Advanced HF is associated with high mortality and poor quality of life. It is estimated that between 5% and 10% of all patients with HF have an advanced form of the disease [1]. Orthotopic heart transplantation (OHT) is an accepted therapy for stage D HF [3] (Fig. 1). Unfortunately, the number of patients with the disease exceeds the number of available organs. This makes appropriate patient selection vital in the field of heart transplantation. Anesthetic evaluation of the patient presenting for OHT or mechanical circulatory support (MCS) implantation is a vital component of the patient's perioperative course. Patients often have had extensive diagnostic testing and assessment prior to being listed for OHT or considered for MCS implantation. Because of the often urgent nature of these procedures, the cardiac anesthesiologist must conduct a focused review of the relevant information and perform a focused patient interview and physical exam. PMID- 29110792 TI - Anesthetic management of the patient undergoing heart transplantation. AB - Cardiac transplantation is the treatment of choice for patients with end-stage heart failure. Over the years, significant advances in patient selection, donor optimization and selection, and optimization of immunosuppression strategies have markedly improved outcomes. In this review, we highlight patient selection, donor management and procurement, heart transplantation procedure, and intraoperative and postoperative management of heart transplants. PMID- 29110793 TI - Postoperative management of heart transplantation patients. AB - Heart transplant recipients are at risk for a number of post-transplantation complications such as graft dysfunction, rejection, and infection. The rates of many complications are decreasing over time, and prognosis is improving. However, these patients continue to experience significant morbidity and mortality. This review focuses on the optimal management of heart transplant recipients in the postoperative period, based on current knowledge. More information is needed about the best ways to predict, prevent, and treat primary graft dysfunction, right ventricular failure, and cellular and antibody-mediated rejection. PMID- 29110794 TI - Anesthetic management of the patient with a ventricular assist device. AB - The use of long- and short-term mechanical circulatory support in the form of ventricular assist device (VAD) has increased over the last decade. Although cardiothoracic anesthesiologists care for these patients during device placement, increasingly higher numbers of general anesthesiologists are involved in the management of VAD patients during noncardiac surgery and procedures. An understanding of devices, their indications, and complications is essential to the anesthesiologists caring for these patients. We review the anesthetic considerations for the implantation of these devices and concerns when caring for patients with durable and short-term devices already in place. PMID- 29110795 TI - Anesthetic management of the patient with extracorporeal membrane oxygenator support. AB - The use of short-term mechanical circulatory support in the form of extracorporeal membrane oxygenation (ECMO) in adult patients has increased over the last decade. Cardiothoracic anesthesiologists may care for these patients during ECMO placement and for procedures while ECMO support is in place. An understanding of ECMO capabilities, indications, and complications is essential to the anesthesiologist caring for these patients. Below we review the anesthetic considerations for the implantation of ECMO and concerns when caring for patients on ECMO. PMID- 29110796 TI - Long-term outcomes and management of the heart transplant recipient. AB - Cardiac transplantation remains the gold standard in the treatment of advanced heart failure. With advances in immunosuppression, long-term outcomes continue to improve despite older and higher risk recipients. The median survival of the adult after heart transplantation is currently 10.7 years. While early graft failure and multiorgan system dysfunction are the most important causes of early mortality, malignancy, rejection, infection, and cardiac allograft vasculopathy contribute to late mortality. Chronic renal dysfunction is common after heart transplantation and occurs in up to 68% of patients by year 10, with 6.2% of patients requiring dialysis and 3.7% undergoing renal transplant. Functional outcomes after heart transplantation remain an area for improvement, with only 26% of patients working at 1-year post-transplantation, and are likely related to the high incidence of depression after cardiac transplantation. Areas of future research include understanding and managing primary graft dysfunction and reducing immunosuppression-related complications. PMID- 29110797 TI - Pre-anaesthetic evaluation of the patient with end-stage lung disease. AB - Lung transplantation is a viable alternative for end-stage lung diseases, which offers good quality of life and survival outcomes for recipients. The aims of pre assessment for potential lung transplant recipients are to assess fitness for surgery, optimise co-morbidities, commence interventions or investigations, weigh risk-benefit ratio, plan appropriate analgesia and obtain informed consent. The assessment information is gathered from the medical record, patient interview, physical examination and pre-operative tests. A comprehensive workup includes cardiopulmonary evaluation, haematological, biochemical, microbiological and immunological investigations. Most of the evidence regarding lung transplantation is gleaned from retrospective data from single, multi-centre or multinational registries. The lack of good quality evidence means that the guidelines are based on expert consensus. PMID- 29110798 TI - Intraoperative anesthetic management of lung transplantation patients. AB - Lung transplantation is a high-risk procedure that requires a highly trained cardiothoracic anesthesiologist and a considerable degree of vigilance. In the 50 years since the first lung transplantation, improvements in immunosuppression, preservation solutions, and surgical techniques and technologies have led to increased survival rates. The development of the extracorporeal circulatory membrane oxygenation allowed for bridge to transplantation and for donor organ recovery from primary graft dysfunction post transplantation [1]. In addition, changes in the criteria for lung allocation will cause the anesthesiologist to encounter older recipients with comorbidities that would have been disqualifying for transplantation a decade ago [2]. PMID- 29110799 TI - Acute postoperative management after lung transplantation. AB - Despite many advances in the field of lung transplantation, lung transplant recipients have the lowest median survival of any solid organ transplant population. Complications such as reperfusion injury, graft rejection, infection, and anastomotic breakdown increase morbidity and mortality during the immediate postoperative period. Ventilator management with lung protective strategies can not only minimize ventilator time and mitigate the risk of ventilator-associated pneumonia, but it may also decrease the risk of primary graft dysfunction and graft failure. Maintaining fluid balance, pain control, and preserving renal function also decrease postoperative complications. Advancements in immunotherapy with the use of calcineurin inhibitors and monoclonal antibodies have been shown to decrease the incidence of acute rejection. However, when unexpected complications occur, appropriately timed rescue therapies such as the initiation of extra-corporeal membrane oxygenation, retransplantation, and plasmapheresis are important considerations geared toward a positive transplant outcome. PMID- 29110800 TI - Long-term outcomes and management of lung transplant recipients. AB - Lung transplantation is an established treatment for patients with end-stage lung disease. Improvements in immunosuppression and therapeutic management of infections have resulted in improved long-term survival and a decline in allograft rejection. Allograft rejection continues to be a serious complication following lung transplantation, thereby leading to acute graft failure and, subsequently, chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS), the most common phenotype of CLAD, is the leading cause of late mortality and morbidity in lung recipients, with 50% having developed BOS within 5 years of lung transplantation. Infections in lung transplant recipients are also a significant complication and represent the most common cause of death within the first year. The success of lung transplantation depends on careful management of immunosuppressive regimens to reduce the rate of rejection, while monitoring recipients for infections and complications to help identify problems early. The long-term outcomes and management of lung transplant recipients are critically based on modulating natural immune response of the recipient to prevent acute and chronic rejection. Understanding the immune mechanisms and temporal correlation of acute and chronic rejection is thus critical in the long term management of lung recipients. PMID- 29110801 TI - Enhanced Electrical Field Stimulated Nitrergic and Purinergic Vasoreactivity in Distal vs Proximal Internal Pudendal Arteries. AB - BACKGROUND: The internal pudendal arteries (IPAs) supply blood to the penis and are highly susceptible to vascular remodeling in rodent models of diabetes, hypertension, aging, and chronic kidney disease, thus contributing to erectile dysfunction. Interestingly, vascular remodeling primarily occurs in the distal and not in the proximal IPA, suggesting distinct local physiologic signaling differences within the IPA. AIM: To examine the role of purinergic signaling and neurotransmitter release by electrical field stimulation (EFS) in the regulation of proximal and distal IPA vascular tone. METHODS: Proximal and distal IPAs were mounted in wire myographs and vascular responses to phenylephrine, acetylcholine, and 2-(N,N-diethylamino)-diazenolate-2-oxide, diethyl-ammonium salt (DEA NONOate) were measured. EFS-mediated contraction and non-adrenergic non-cholinergic (NANC) relaxation were evaluated in the absence and presence of a nitric oxide synthase antagonist. Purinergic agonist and NANC relaxation responses were assessed in the presence and absence of P2X1 and P2Y1 antagonists. Protein expression of P2X1 and P2Y1 receptors was measured by western blot. MAIN OUTCOME MEASURES: Proximal and distal IPA contraction and relaxation were measured during increasing agonist administration and EFS in the presence and absence of antagonists. RESULTS: Proximal and distal IPA concentration response curves to phenylephrine, acetylcholine, and DEA NONOate did no differ. Interestingly, distal IPA exhibited greater EFS-mediated contraction and NANC relaxation compared with proximal IPA. Nitric oxide synthase inhibition completely inhibited distal IPA NANC relaxation but did not affect proximal IPA relaxation. P2X1 or P2Y1 receptor antagonism during NANC relaxation increased distal IPA relaxation but decreased proximal IPA relaxation. Combined P2X1 and P2Y1 receptor antagonism had no effect on proximal IPA relaxation but significantly increased distal IPA NANC relaxation. CLINICAL TRANSLATION: Understanding neurovascular regulation of IPA vascular tone through nitrergic and purinergic mechanisms could yield new therapeutic targets to improve IPA blood flow and treat vasculogenic erectile dysfunction. STRENGTHS AND LIMITATIONS: This study is the first to illustrate the differences in mechanisms responsible for regulating vascular tone in the proximal and distal IPAs. All presented findings are currently limited to ex vivo vascular function. CONCLUSION: The regulation of vascular tone differs regionally in the IPA. The distal IPA is controlled through neurotransmitter-mediated NO-dependent mechanisms and increased sensitivity to purinergic P2X1 and P2Y1 receptor inhibition. Odom MR, Pak ES, Brown DA, Hannan JL. Enhanced Electrical Field Stimulated Nitrergic and Purinergic Vasoreactivity in Distal vs Proximal Internal Pudendal Arteries. J Sex Med 2017;14:1285-1296. PMID- 29110802 TI - Testosterone Therapy and Risk of Acute Myocardial Infarction in Hypogonadal Men: An Administrative Health Care Claims Study. AB - BACKGROUND: There are some ongoing debates on the potential link between testosterone therapy (TT) and risk of acute myocardial infarction (MI). AIM: To investigate the association between acute MI and TT use compared with non-use in men having documented hypogonadism (diagnostic International Classification of Diseases, Ninth Revision codes 257.2, 257.8, 257.9, 758.7) in patient claims records. METHODS: This retrospective cohort study used a real-world US-based administrative health care claims database (MarketScan 2004-2013; Truven Health Analytics, Ann Arbor, MI, USA) to compare MI rates between TT-treated men and a cohort of untreated hypogonadal men matched by a calendar time-specific propensity score. Subgroup analyses were performed by route of administration, age, and prior cardiovascular disease (CVD). OUTCOMES: Incidence rates of MI (per 1,000 person-years) and hazard ratio. RESULTS: After 1:1 calendar time-specific propensity score matching, 207,176 TT-treated men and 207,176 untreated hypogonadal men were included in the analysis (mean age = 51.8 years). Incidence rates of MI were 4.20 (95% CI = 3.87-4.52) in the TT-treated cohort and 4.67 (95% CI = 4.43-4.90) in the untreated hypogonadal cohort. Cox regression model showed no significant association between TT use and MI when comparing TT-treated with untreated hypogonadal men overall (hazard ratio = 0.99, 95% CI = 0.89-1.09), by age, or by prior CVD. A significant association was observed when comparing a subgroup of injectable (short- and long-acting combined) TT users with untreated hypogonadal men (hazard ratio = 1.55, 95% CI = 1.24-1.93). CLINICAL IMPLICATION: In this study, there was no association between TT (overall) and risk of acute MI. STRENGTHS AND LIMITATIONS: Strengths included the use of a comprehensive real world database, sophisticated matching based on calendar blocks of 6 months to decrease potential bias in this observational study, carefully chosen index dates for the untreated cohort to avoid immortal time bias, and implemented sensitivity analysis to further investigate the findings (stratification by administration route, age, and prior CVD). Key limitations included no information about adherence, hypogonadism condition based solely on diagnosis (no information on clinical symptoms or testosterone levels), lack of information on disease severity, inability to capture diagnoses, medical procedures, and medicine dispensing if corresponding billing codes were not generated and findings could contain biases or fail to generalize well to other populations. CONCLUSION: This large, retrospective, real-world observational study showed no significant association between TT use and acute MI when comparing TT-treated with untreated hypogonadal men overall, by age, or by prior CVD; the suggested association between injectable TT and acute MI deserves further investigation. Li H, Mitchell L, Zhang X, et al. Testosterone Therapy and Risk of Acute Myocardial Infarction in Hypogonadal Men: An Administrative Health Care Claims Study. J Sex Med 2017;14:1307-1317. PMID- 29110803 TI - Sexual Dysfunction in Primary Care: An Exploratory Descriptive Analysis of Medical Record Diagnoses. AB - BACKGROUND: The prevalence of sexual dysfunction (SDx) diagnoses in primary care settings is not well known, which is a concern because of the high prevalence of comorbid chronic health conditions in patients diagnosed with SDx. AIM: To explore the relation of SDx diagnosis, chronic health conditions, and prescription medications commonly associated with SDx for men and women in primary care using medical records diagnoses. METHODS: Exploratory descriptive analyses were used to interpret secondary data from a primary care patient database. The database included patient data from 3 family and internal medicine clinics in the St Louis metropolitan area from July 1, 2008 to June 30, 2015. Analysis included key demographic variables, chronic illness, and health conditions of hypertension, pain, prostate disorder, menopause, substance abuse, depression, anxiety, and associated medications. Analysis of the database yielded 30,627 adult patients (men: n = 12,097, mean age = 46.8 years, 65.6% white race; women: n = 18,530, mean age = 46.6 years, 59.2% white race) with significant comorbid associations between SDx and other chronic illness, health conditions, and medication prescription. RESULTS: Depression, anxiety, pain, hypertension, diabetes, and psychotropic medication use were significantly associated with SDx for men and women. Examination of specific SDx diagnoses showed erectile dysfunction to be significantly associated with all tested variables for men. For women, pain-related SDx diagnoses were associated more with chronic illness, health conditions, and medication use than were psychosexual SDx diagnoses (eg, orgasm), except for menopause. Prevalence varied by sex, with a higher prevalence rate of any SDx for men (13.5%) than for women (1.0%), although sex comparisons were not part of the analytics. CLINICAL TRANSLATION: This study suggests the diagnosis of SDx is closely associated with other common chronic illness and health conditions and could go underdiagnosed in women in primary care. STRENGTHS AND LIMITATIONS: The cross-sectional nature of the study limits the ability to draw causal conclusions related to the nature of the associated conditions with SDx diagnoses. The generalizability of the findings also might be limited given the specific demographic or health makeup of the St Louis area where the study was conducted. CONCLUSION: The high comorbidity of SDx with mental health, chronic pain and illnesses, and medication use adds to the growing evidence that sexual health and functioning are essential components of overall well-being and holistic care for men and women. Heiden-Rootes KM, Salas J, Gebauer S, et al. Sexual Dysfunction in Primary Care: An Exploratory Descriptive Analysis of Medical Record Diagnoses. J Sex Med 2017;14:1318-1326. PMID- 29110804 TI - Association Between Marijuana Use and Sexual Frequency in the United States: A Population-Based Study. AB - BACKGROUND: Marijuana use is increasingly prevalent in the United States. Effects of marijuana use on sexual function are unclear, with contradictory reports of enhancement and detriment existing. AIM: To elucidate whether a relation between marijuana use and sexual frequency exists using a nationally representative sample of reproductive-age men and women. METHODS: We analyzed data from cycle 6 (2002), cycle 7 (2006-2010), and continuous survey (2011-2015) administrations of the National Survey of Family Growth, a nationally representative cross-sectional survey. We used a multivariable model, controlling for demographic, socioeconomic, and anthropographic characteristics, to evaluate whether a relationship between marijuana use and sexual frequency exists. OUTCOMES: Sexual frequency within the 4 weeks preceding survey administration related to marijuana use and frequency in the year preceding survey administration. RESULTS: The results of 28,176 women (average age = 29.9 years) and 22,943 men (average age = 29.5) were analyzed. More than 60% of men and women were Caucasian, and 76.1% of men and 80.4% of women reported at least a high school education. After adjustment, female monthly (incidence rate ratio [IRR] = 1.34, 95% CI = 1.07 1.68, P = .012), weekly (IRR = 1.36, 95% CI = 1.15-1.60, P < .001), and daily (IRR = 1.16, 95% CI = 1.01-1.32, P = .035) marijuana users had significantly higher sexual frequency compared with never users. Male weekly (IRR = 1.22, 95% CI = 1.06-1.41, P = .006) and daily (IRR = 1.36, 95% CI = 1.21-1.53, P < .001) users had significantly higher sexual frequency compared with never users. An overall trend for men (IRR = 1.08, 95% CI = 1.05-1.11, P < .001) and women (IRR = 1.07, 95% CI = 1.04-1.10, P < .001) was identified showing that higher marijuana use was associated with increased coital frequency. CLINICAL IMPLICATIONS: Marijuana use is independently associated with increased sexual frequency and does not appear to impair sexual function. STRENGTHS AND LIMITATIONS: Our study used a large well-controlled cohort and clearly defined end points to describe a novel association between marijuana use and sexual frequency. However, survey responses were self-reported and represent participants only at a specific point in time. Participants who did not answer questions related to marijuana use and sexual frequency were excluded. CONCLUSION: A positive association between marijuana use and sexual frequency is seen in men and women across all demographic groups. Although reassuring, the effects of marijuana use on sexual function warrant further study. Sun AJ, Eisenberg ML. Association Between Marijuana Use and Sexual Frequency in the United States: A Population-Based Study. J Sex Med 2017;14:1342-1347. PMID- 29110805 TI - A Population-Based Epidemiologic Study of Female Sexual Dysfunction Risk in Mainland China: Prevalence and Predictors. AB - BACKGROUND: Epidemiologic data on female sexual dysfunction in China are sparse. AIM: To assess the prevalence of risk of female sexual dysfunction in mainland China and its regional and sociodemographic variations and physiologic, pathologic, and behavioral risk factors. METHODS: A survey of the general female population was conducted in mainland China from February 2014 through January 2016. Women were randomly selected using multistage, stratified, cluster sampling. The prevalence rate of sexual dysfunction, as measured by the Female Sexual Function Index and a score lower than 23.45 as the cutoff threshold, was determined. Multivariate logistical regression models were used to examine the effects of sociodemographic, physiologic, pathologic, and behavioral factors on women's risk of experiencing sexual dysfunction and domain-specific sexual problems. OUTCOMES: The questionnaire on sexual dysfunction was completed by 25,446 women 20 to 70 years old. RESULTS: The prevalence of sexual dysfunction in women 20 to 70 years old in mainland China was estimated at 29.7% (99% CI = 28.9 30.4), with large regional variations. The prevalence rates of potential domain specific sexual problems were 21.6% (99% CI = 20.9-22.2) for low desire, 21.5 (99% CI = 20.8-22.2) for arousal disorder, 18.9% (99% CI = 18.3-19.6) for lubrication disorder, 27.9% (99% CI = 27.2-28.7) for orgasm disorder, and 14.1% (99% CI = 13.6-14.7) for sexual pain. Higher educational attainment and urban residency were associated with a decreased risk of sexual dysfunction. Women of ethnic minorities (or non-Han ethnicity) had fewer reports of sexual dysfunction than women of Han ethnicity (odds ratio = 0.67, 99% CI = 0.47-0.97). Diabetes, cancers, pelvic inflammatory disease, and pelvic organ prolapse significantly increased the reports of sexual dysfunction. CLINICAL TRANSLATION: This survey provided the prevalence and risk factors of female sexual dysfunction in China, information that could be useful for potential prevention and clinical treatment. STRENGTHS AND LIMITATIONS: This is the first large-scale, nationally based epidemiologic study of female sexual dysfunction in mainland China. The limitations of the study design included an overpowered study caused by the large sample, the under-representation of younger and unmarried women, and no information on the women's partners, their values and knowledge, and detailed medical conditions. CONCLUSIONS: The prevalence rate of female sexual dysfunction in mainland China was modest overall, although variations existed across regions and social groups. Zhang C, Tong J, Zhu L, et al. A Population-Based Epidemiologic Study of Female Sexual Dysfunction Risk in Mainland China: Prevalence and Predictors. J Sex Med 2017;14:1348-1356. PMID- 29110806 TI - Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2 Arachidonoylglycerol in Humans. AB - BACKGROUND: Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied. AIM: To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers. OUTCOMES: Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm. METHODS: In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design. RESULTS: In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2. CLINICAL TRANSLATION: Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions. STRENGTHS AND LIMITATIONS: We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study. CONCLUSION: Our data indicate that the endocannabinoid 2-AG is involved in the human sexual response cycle and we hypothesize that 2-AG release plays a role in the rewarding consequences of sexual arousal and orgasm. Fuss J, Bindila L, Wiedemann K, et al. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans. J Sex Med 2017;14:1372 1379. PMID- 29110807 TI - Psychobiological Correlates of Vaginismus: An Exploratory Analysis. AB - BACKGROUND: Evidence concerning the determinants of vaginismus (V), in particular medical conditions, is inconclusive. AIM: To investigate, in a cohort of subjects consulting for female sexual dysfunction, whether there is a difference in medical and psychosocial parameters between women with V and women with other sexual complaints. METHODS: A series of 255 women attending our clinic for female sexual dysfunction was consecutively recruited. V was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Lifelong and acquired V cases were included. OUTCOMES: Patients underwent a structured interview and physical, gynecologic, laboratory, and clitoral ultrasound examinations; they completed the Female Sexual Function Index (FSFI), the Middlesex Hospital Questionnaire, the Female Sexual Distress Scale-Revised (FSDS), and the Body Uneasiness Test. RESULTS: V was diagnosed in 20 patients (7.8%). Women with V were significantly younger than the rest of the sample (P < .05). No differences were found for traditional risk factors such as a history of sexual abuse, relational parameters, or gynecologic diseases or for newly investigated parameters (ie, neurologic, hormonal, and metabolic alterations). Women with V showed significantly higher histrionic-hysterical symptoms and traits (as detected by MHQ-H score; P < .05) compared with subjects with other sexual complaints. When the scores of all MHQ subscales were simultaneously introduced in a logistic model, the association between V and MHQ H score was confirmed (P = .013). Women with V also showed higher FSFI pain and FSDS total scores, even after adjusting for age (P < .05). In an age-adjusted model, FSDS total score increased as a function of the years of duration of V (P = .032) but not as a function of its severity. All observations were confirmed in a case-control study (ratio = 1:3). CLINICAL IMPLICATIONS: Our data demonstrate that some novel contributors of V should be investigated, namely histrionic hysterical traits. This psychological comorbidity could offer valuable insights for intervention and managing complications. STRENGTHS AND LIMITATIONS: This is the first study to assess the role of many metabolic and hormonal parameters as potential determinants of V. The main limitation is its exploratory and cross sectional nature; our data need to be confirmed in larger, more systematic analyses. CONCLUSION: V was associated with histrionic-hysterical traits, FSFI pain domain, and sex-related distress. A history of abuse, relational parameters, gynecologic diseases, and hormonal and metabolic alterations do not seem to play a role in the development of V. Maseroli E, Scavello I, Cipriani S, et al. Psychobiological Correlates of Vaginismus: An Exploratory Analysis. J Sex Med 2017;14:1392-1402. PMID- 29110809 TI - Addressing complexity in health research, a big issue. PMID- 29110808 TI - How Big is Too Big? The Girth of Bestselling Insertive Sex Toys to Guide Maximal Neophallus Dimensions. AB - BACKGROUND: In our practice we have encountered 4 female-to-male transgender patients seeking neophallus revision surgery for girth precluding penetrative vaginal or anal intercourse. Despite this, there is little evidence available to guide transitioning patients in neophallus sizing. In this work we examined the dimensions of bestselling realistic dildos, presuming that the most popular dimensions would reflect population preferences for penetrative toys and phalluses. AIM: To determine a maximal upper limit for girth compatible with penetrative intercourse based on measurements of bestselling realistic dildos and published erect penile dimensions. METHODS: We collected measurements for "realistic dildos" designated as bestsellers for the top 5 Alexa.com-rated online adult retailers in the United States and for Amazon.com. We compared these with measurements of dildos available at Good Vibrations in San Francisco and with studies of erect natal dimensions. We compared all data with measurements of 4 index patients whose neophallus girth prevented penetrative intercourse. OUTCOMES: Length and circumference of overall bestselling and largest bestselling realistic dildos as reported on top websites and measured by investigators. RESULTS: The average insertive length of the compiled dildos (16.7 +/- 1.6 cm) was 1 SD longer than natal functional erect penile length as reported in the literature (15.7 +/- 2.6 cm); however, their average circumference (12.7 +/- 0.8 cm) mirrored natal erect penile girth (12.3 +/- 1.3). The average girth of vendors' top 3 largest-girth dildos was 15.1 +/- 0.9 cm, 2 SD wider than natal erect penile girth. Index patients had an average length of 16.3 +/- 3.2 cm and an average girth of 17.6 +/- 1.3 cm. Index patient girth was 4 to 5 SD wider than the average natal erect girth. CLINICAL IMPLICATIONS: Based on our data, we suggest that a surgically created neophallus should have a girth no wider than 15.1 cm after implantation of an inflatable penile prosthesis. This corresponds to 2 SD wider than the average natal man's erect girth. STRENGTHS AND LIMITATIONS: Strengths include in-person measurements of patients whose girth prevented penetrative intercourse, the large number of dildos assessed, and correlations with in-person measurements. Limitations include the inability to account for the pliability of different materials, whether dildos were used for vaginal and/or anal insertion, the limited sample of 4 transmen for in-person measurement, and the absence of implanted inflatable penile prostheses in index neophalluses. CONCLUSIONS: Neophallus girth wider than 15.1 cm could lead to difficulty in penetrative intercourse for many individuals. A conservative recommendation for neophallus girth is 13 to 14 cm, or 0.5 to 1.5 SD wider than natal erect penile girth. Isaacson D, Aghili R, Wongwittavas N, Garcia M. How Big is Too Big? The Girth of Bestselling Insertive Sex Toys to Guide Maximal Neophallus Dimensions. J Sex Med 2017;14:1455-1461. PMID- 29110810 TI - Trauma in pregnancy: an underappreciated cause of maternal death. PMID- 29110811 TI - The link between cell-free DNA, inflammation and the initiation of spontaneous labor at term. PMID- 29110812 TI - Prophylactic bilateral salpingectomy at vaginal hysterectomy: time for a "policy"? PMID- 29110813 TI - Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - To evaluate the efficacy and safety of long-duration dual antiplatelet therapy (L DAPT) compared to short-duration dual antiplatelet therapy (S-DAPT) after drug eluting stent implantation. We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials assessing the clinical effect of L-DAPT vs S-DAPT after drug-eluting stent. Efficacy end points were all-cause mortality, cardiac mortality, myocardial infarction (MI), stent thrombosis (ST), and target vessel revascularization (TVR). Safety end points were TIMI major bleeding and stroke. Event rates were compared using a random-effects model. We identified 11 randomized controlled trials in which 33,520 patients were randomized to S-DAPT (N = 16,687) and L-DAPT (n = 16,833), respectively. Compared with L-DAPT, S-DAPT was associated with higher rate of MI and lower rate of TIMI major bleeding (1.40 [1.08-1.81] and 0.60 [0.41-0.89], respectively), without any significant differences in the rate of all-cause mortality, cardiac mortality, ST, TVR, and stroke (0.88 [0.75-1.04], 0.98 [0.79-1.22], 1.54 [0.95-2.50], 0.99 [0.73-1.34], and 1.01 [0.78-1.32], respectively). Our results showed that compared with L-DAPT, S-DAPT was associated with higher rate of MI and lower rate of major bleeding without any significant difference in the rates of all-cause mortality, cardiac mortality, ST, TVR, and stroke. PMID- 29110814 TI - Exploratory reports: A new article type for Cortex. PMID- 29110815 TI - Bioactive natural products. PMID- 29110816 TI - Forgetting to Be Addicted: Reconsolidation and the Disconnection of Things Past. PMID- 29110817 TI - Cocaine Rearranges the Neuronal Epigenome. PMID- 29110818 TI - Decision Making in Alcoholic Patients and Its Contribution to Relapse. PMID- 29110819 TI - Metabolism and Memory: Obesity, Diabetes, and Dementia. PMID- 29110820 TI - Rapid Cocaine-Induced Spine Changes in the Nucleus Accumbens. PMID- 29110821 TI - Corrigendum to "Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function" Neurobiology of Disease 105 (2017) 194-212. PMID- 29110822 TI - Preface. PMID- 29110823 TI - Assessment and significance of long-term outcomes in pediatric surgery. AB - Treatment modalities for newborns with anatomical congenital anomalies have greatly improved over the past decades, with a concomitant increase in survival. This review will briefly discuss specific long-term outcomes to illustrate, which domains deserve to be considered in long-term follow-up of patients with anatomical congenital anomalies. Apart from having disease-specific morbidities these children are at risk for impaired neurodevelopmental problems and school failure, which may affect participation in society in later life. There is every reason to offer them long-term multidisciplinary follow-up programs. We further provide an overview of the methodology of long-term follow-up, its significance and discuss ways to improve care for newborns with anatomical congenital anomalies from childhood into adulthood. Future initiatives should focus on transition of care, risk stratification, and multicenter collaboration. PMID- 29110824 TI - Long-term psychosocial consequences of surgical congenital malformations. AB - Surgical congenital malformations often represent years of treatment, large number of hospital stays, treatment procedures, and long-term functional sequels affecting patients' psychosocial functioning. Both functional defects and psychosocial difficulties that occur commonly in childhood may pass through adolescence on to adulthood. This overview presents reports published over the past 3 decades to elucidate the long-term psychosocial consequences of surgical congenital malformations. Literature searches conducted on PubMed database revealed that less than 1% of all the records of surgical congenital malformations described long-term psychosocial consequences, but with diverse findings. This inconsistency may be due to methodological differences or deficiencies; especially in study design, patient sampling, and methods. Most of the studies revealed that the functional deficits may have great impact on patients' mental health, psychosocial functioning, and QoL; both short- and long term negative consequences. Factors other than functional problems, e.g., repeated anesthesia, multiple hospitalization, traumatic treatment procedures, and parental dysfunctioning, may also predict long-term mental health and psychosocial functioning. Through multidisciplinary approach, pediatric surgeons should also be aware of deficits in emotional and psychosocial functioning. To achieve overall optimal psychosocial functioning, the challenge is to find a compromise between physically optimal treatment procedures and procedures that are not psychologically detrimental. PMID- 29110825 TI - Long-term outlook in biliary atresia. AB - The oldest survivors from the Kasai portoenterostomy originate in Sendai, Japan and are approaching their 60th birthday. These represent the tip of an expanding cohort of adults born with this previously fatal condition. Increasingly transition to adult-biased hepatologists and physicians will be the expectation of many with this condition. However unlike their usual patients with alcohol, drugs, virally mediated liver disease these are different with different expectations of health and quality of life. Cure is not on the cards for most of these and they survive still with impaired bile flow and increased liver fibrosis and cirrhosis with the threat of cholangitis and portal hypertension still apparent. We review the reported statistics on long-term survival essentially from Japan and Western Europe (such as the UK and France) and the range of complications that may still beset this group. PMID- 29110826 TI - Long-term morbidity of congenital diaphragmatic hernia: A plea for standardization. AB - Congenital diaphragmatic hernia (CDH) survivors present long-term morbidities in several systems, including the neurodevelopmental, gastrointestinal, pulmonary, and musculoskeletal ones, and CDH long-term sequelae are increasingly being recognized. Due to high co-morbidity, health related quality of life in a significant proportion of CDH patients might be compromised. As a consequence of consciousness on the long-term sequelae of CDH survivors, and their consequences for life, several follow-up programs were brought to life worldwide. In this review, we will summarize the long-term sequelae of CDH survivors, the impact of new treatments, and analyze the consistency of follow-up programs. PMID- 29110828 TI - Late sequelae and long-term outcomes of vascular anomalies. AB - Vascular anomalies are classified as tumors and malformations depending on their clinical characteristics, pathological diagnosis and recent genomic information. Diagnosis can still be challenging because of the heterogeneity of clinical presentation. Thus, the best care is provided by an interdisciplinary team of specialists. An updated classification system has helped provide more consistent terminology with the addition of new diagnoses and genomic discovery. Historically, treatment of vascular anomalies was primarily surgical and or interventional with limited medical therapies. The field of vascular anomalies lacked prospective clinical trials in both medical treatments as well as surgical and interventional therapeutic options. Recent interdisciplinary collaboration has led to collaborative studies in which short- and long-term outcomes are being prospectively evaluated. Specifically, discoveries of pharmacologic agents effective in treating vascular anomalies have broadened our medical therapeutic options, which has led to innovative approaches in combined treatment of vascular anomalies and has stressed the need to prospectively assess long-term outcomes and sequelae for these patients which has been lacking in this field. PMID- 29110827 TI - Long-term outcomes of congenital lung malformations. AB - Congenital lung malformations comprise a group of anatomical abnormalities of the respiratory tree including congenital cystic malformations, bronchopulmonary sequestrations, bronchogenic cyst, bronchial atresia, and congenital lobar emphysema. These anomalies are detected with increasing frequency by pre-natal sonography, but may also present for the first time with symptoms in childhood or later life. When symptomatic, there is little controversy that resection is indicated, which is usually curative. When a lesion is asymptomatic there is greater debate regarding the benefit of resection versus continued observation. This article provides an overview of the spectrum of disorders, the management options available and the long-term outcomes associated with each treatment option. PMID- 29110829 TI - Hirschsprung disease-Bowel function beyond childhood. AB - Hirschsprung disease is a developmental defect of the enteric nervous system characterized by lack of enteric neurons in the distal hindgut. There are numerous reports on short-term outcomes indicating that impaired bowel function is common. Recently, several controlled studies show that bowel function outcomes are affected beyond childhood, in adolescents and adults, compared with healthy control subjects. Constipation and fecal incontinence are common. The impaired bowel function appears to have a negative impact on quality of life, although, a majority of patients have adapted to their symptoms. On the other hand, Hirschsprung disease seems to have limited impact on education and occupation in adult life. The aim of this review was to summarize current knowledge of bowel function outcome beyond childhood in patients with Hirschsprung disease. PMID- 29110830 TI - Long-term outcomes of pediatric intestinal failure. AB - Management of pediatric intestinal failure has evolved in recent decades, with improved survival since the advent of specialized multidisciplinary intestinal failure centers. Though sepsis and intestinal failure associated liver disease still contribute to mortality, we now have growing data on the long-term outcomes for this population. While intestinal adaptation and parenteral nutrition weaning is most rapid during the first year on parenteral support, achievement of enteral autonomy is possible even after many years as energy and protein requirements decline dramatically with age. Intestinal transplant is an option for patients experiencing complications of long-term parenteral nutrition who are expected to have permanent intestinal failure, but outcomes are hindered by immunosuppression related complications. Much of the available data comes from single center retrospective reports, with variable inclusion criteria, intestinal failure definitions, and follow-up durations; this limits the ability to analyze outcomes and identify best practices. As most children now survive long-term, the focus of management has shifted to the avoidance and management of comorbidities, support of normal growth and development, and optimization of quality of life for these medically and surgically complex patients. PMID- 29110831 TI - Long-term bowel function, quality of life and sexual function in patients with anorectal malformations treated during the PSARP era. AB - Anorectal malformations are an important group of congenital anomalies that vary widely in their anatomical characteristics and complexity. Understanding the long term functional outcomes after modern treatments, and how these compare to the general population, are essential for ensuring that patients receive optimal, evidence-based care. With increasing appreciation of the wider impact of the illness on patients and their families, minimizing social disability from fecal incontinence and enabling normal social integration from the outset are key management concerns. This review summarizes the current knowledge on the functional outcomes by type of malformation, reflecting on the literature, and our institutional experience over a follow-up period of nearly 30 years. PMID- 29110832 TI - Thromboelastometric Profile and Acute Coagulopathy of the Polytraumatized Patient: Clinical and Prognostic Implications. AB - INTRODUCTION: About 25-35% of polytraumatized patients have a profound alteration of hemostasis on arrival at the hospital (acute traumatic coagulopathy [CAT]). Viscoelastic tests (ROTEM(r)) measure the hemostatic capacity and provide an early detection of CAT. The objectives of this study are to describe the initial thromboelastogram of these patients and to determine the prevalence of CAT according to predefined thromboelastographic profiles. METHODS: Single-center, observational, prospective study in polytraumatic patients. Initial blood and thromboelastographic test (ROTEM(r)) were made, and pre-hospital, hospital, transfusion, initial surgical/angiographic interventions, cardiac arrest and mortality data were collected. ROTEM(r)-based, patients were classified as: normal, hypercoagulable, hypocoagulable, hipocoagulable +hyperfibrinolytic and isolated hyperfibrinolysis. RESULTS: One hundred and twenty-three patients were analyzed. 32 cases (26%) with CAT: 15 patients with hypocoagulability, 9 with hyperfibrinolysis alone and 8 with hypocoagulability +hyperfibrinolysis. The CAT group, related to the normal group, presented higher ISS (23 vs. 16, P<.01), higher blood products transfusion (2.5 vs. 0; P=.001), more cardiac arrest (19 vs. 1%, P<.01), and higher mortality (34 vs. 5%, P<.01). The subgroup with hypocoagulability/hyperfibrinolysis, related to the groups with hypocoagulability or hyperfibrinolysis alone, presented a higher ISS (41 vs. 25 vs. 15, P<.01), higher angiographic procedures (62% vs. 13% vs. 0%, P<.01) and higher mortality (75% vs. 33% vs. 0%, P=.05). CONCLUSIONS: Twenty-six percent of the polytrauma patients presented early coagulopathy assessed by thromboelastography. It is associated with higher consumption of blood products and lower survival. The presence of hypocoagulability +hyperfibrinolysis is associated with greater severity and a higher requirement of blood products. PMID- 29110833 TI - State of the Art Update and Next Questions: Acute Myeloid Leukemia. AB - As our general understanding regarding the complex nature of acute myeloid leukemia (AML) is expanding, so is our ability to translate this biological data into clinically relevant information. The use of whole genome and whole exome sequencing has begun to shed light on the importance of a variety of somatic mutations that are frequently identified in AML. In turn, this has allowed the field to incorporate mutational data into prognostic classifications which can guide treatment decisions. Furthermore, minimal residual disease (MRD) monitoring in AML is more commonplace as the prognostic relevance of MRD at various time points during treat is becoming clear. Many novel treatments have recently been approved, or are expected to gain approval in the near future, and this is opening the door to a more personalized approach to the management of AML. PMID- 29110834 TI - Short communication: Diagnosis of lung cancer increases during the annual southeast Asian haze periods. AB - There have been few but timely studies examining the role of air pollution in lung cancer and survival. The Southeast Asia haze is a geopolitical problem that has occurred annually since 1997 in countries such as Malaysia, Singapore and Indonesia. To date, there has been no study examining the impact of the annual haze in the presentation of lung cancer. Data on all lung cancers and respiratory admissions to Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from 1st January 2010 to 31th October 2015 were retrospectively collected and categorized as presentation during the haze and non-haze periods defined by the Department of Environment Malaysia. We report a lung cancer incidence rate per week of 4.5 cases during the haze compared to 1.8 cases during the non-haze period (p<0.01). The median survival for subjects presenting during the haze was 5.2 months compared to 8.1 months for the non-haze period (p<0.05). The majority of subjects diagnosed during the haze period initially presented with acute symptoms. Although this study could not suggest a cause and effect relationship of the annual haze with the incidence of lung cancer, this is the first study reporting a local air pollution-related modifiable determinant contributing to the increase in presentation of lung cancer in Southeast Asia. PMID- 29110835 TI - PD-L1 IHC in NSCLC with a global and methodological perspective. AB - In summary, the PD-L1 biomarker discussed here highlights the importance of understanding the practice of IHC. This can be used to the patients advantage, with appropriate usage. The currently available literature on PD-L1 IHC from a methodologic point of view has not shown that different assays are comparable. The route of laboratory developed test and commercial test validation is the same: challenging and complex. Executing this process along proper methodologic lines is needed to ensure that patients receive the most accurate and representative test outcomes. PMID- 29110836 TI - Next-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs. AB - OBJECTIVES: Despite initial responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant non-small cell lung cancer, patients invariably develop acquired resistance. In this study, we performed next generation sequencing in pre- and post-EGFR-TKI tumor samples to identify novel resistance mechanisms to EGFR-TKIs. MATERIAL AND METHODS: We collected tumor tissues before EGFR-TKI treatment and after progression from 19 NSCLC patients to analyze genomic alterations in 409 cancer related genes. Bioinformatics analyses were used to identify mutations in which the allele frequencies are significantly changed, or newly appeared after progression. RESULTS: Overall, mutation rates and compositions were similar between pre- and post-EGFR-TKI tumors. We identified EGFR T790M as the most common mechanism of acquired resistance (63.2%). No pre-EGFR-TKI tumor had a preexisting T790M mutation, suggesting that tumors acquired T790M mutations following progression on EGFR-TKIs. Compared to T790M-positive tumors, T790M-negative tumors showed relatively high tumor mutation burden and shorter survival, suggesting T790M-negative patients as a potential candidate for immune checkpoint inhibitors. TP53 mutation was also significantly enriched in the T790M-negative tumors. Finally, we described here for the first time a novel missense mutation (T263P), which occurred concurrently with an activating G719A mutation, in the extracellular domain II of EGFR in a patient with poor response to erlotinib. Ba/F3 cells harboring EGFR T263P/G719A mutation showed higher sensitivity to afatinib, compared to gefitinib due to inhibition of EGFR/HER2 heterodimerization. CONCLUSION: Comprehensive genomic analysis of post-EGFR-TKI tumors can provide novel insight into the complex molecular mechanisms of acquired resistance to EGFR-TKIs. PMID- 29110837 TI - The burden of neutropenic sepsis in patients with advanced non-small cell lung cancer treated with single-agent docetaxel: A retrospective study. AB - OBJECTIVES: To describe rates of confirmed and suspected neutropenic sepsis (NS) and associated hospital resource utilisation in patients with non-small cell lung cancer (NSCLC) treated with docetaxel monotherapy following relapse after >=1 line of chemotherapy in routine UK clinical practice. MATERIALS AND METHODS: A multi-centre, retrospective, observational research study was conducted in seven centres across England and Wales. Adult patients with stage III/IV NSCLC initiated on docetaxel monotherapy between 2010 and 2016 in routine clinical practice (aged >=18 years at initiation) following failure of first-line chemotherapy were eligible. Data were collected from hospital medical records between May 2016 and July 2016, on all episodes of confirmed or suspected NS related to docetaxel monotherapy, including patient characteristics. Episodes of confirmed NS were defined as documented absolute neutrophil count <1.0*109/L, plus temperature >38 degrees C or other signs/symptoms of sepsis, otherwise episodes were classified as suspected NS. RESULTS: 121 patients were included (median age 65.5 years; 57.9% male; median 4.0 cycles of docetaxel; 19.8% treated with prophylactic granulocyte-colony stimulating factor). Episodes of confirmed or suspected NS were recorded in 21/121 (17.4%) patients (11 confirmed episodes in 11 [9.1%] patients and 11 suspected episodes in 10 [8.3%] patients). Resource utilisation data were available for 21/22 episodes; the mean length of stay for confirmed NS admissions (n=11) was 9.2 (SD: 9.2) days and for suspected NS admissions (n=10) was 4.7 (SD: 4.6) days. The most commonly prescribed treatment for NS was piperacillin/tazobactam therapy (46.5% of all documented treatments). The mean total costs of managing patients with confirmed NS (n=11) and suspected NS (n=9) were L3163 (SD: L2921) and L1790 (SD: L1585) per patient, respectively. CONCLUSION: Rates of confirmed NS in UK clinical practice were broadly similar to those reported in clinical trials; however, the burden of suspected NS, not routinely reported elsewhere, is also substantial. PMID- 29110838 TI - CD13 as target for tissue factor induced tumor vascular infarction in small cell lung cancer. AB - OBJECTIVES: Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease. MATERIAL AND METHODS: CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF NGR on tumor growth were tested. RESULTS AND CONCLUSION: In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection. PMID- 29110839 TI - Challenging a dogma; AJCC 8th staging system is not sufficient to predict outcomes of patients with malignant pleural mesothelioma. AB - BACKGROUND: The 8th edition of malignant pleural mesothelioma (MPM) American Joint Committee on Cancer (AJCC) staging system has been published. The current analysis aims to evaluate its performance in a population-based setting among patients recorded within the surveillance, epidemiology and end results (SEER) database. METHODS: SEER database (2004-2013) has been accessed through SEER*Stat program and AJCC 8th edition stage groups were reconstructed. Survival analyses (overall and cancer-specific) were conducted according to 6th and 8th editions through Kaplan-Meier analysis. Cox-regression multivariate model was also utilized for pair wise comparisons between different prognostic groups for overall and cancer-specific survival. RESULTS: A total of 5382 patients with MPM were identified in the period from 2004 to 2013. According to the 6th edition, significant pair wise P values for overall survival included: IA vs. III (P=0.027); IA vs. IV: P<0.0001; IB vs. IV: P<0.0001; II vs. III: P<0.0001; II vs. IV: P<0.0001; III vs. IV: P<0.0001). According to the 8th edition, significant pair wise P values for overall survival included: all stages vs. IV: P<0.0001; IA vs. II: P=0.046; IA vs. IIIA: P=0.022; IA vs. IIIB: P <0.0001; IB vs. II: P<0.0001; IB vs. IIIB: P<0.0001; II vs. IIIA: P<0.0001; IIIA vs. IIIB: P<0.0001). C-index for 6th edition was 0.539 (SE: 0.008; 95% CI: 0.524-0.555); while C-index for 8th edition was 0.540 (SE: 0.008; 95% CI: 0.525-0.556). Based on the above findings, a simplified staging system was proposed and overall and cancer specific survivals were evaluated according to the simplified system. For overall and cancer-specific survival assessment, P values for all pair wise comparisons among different stages were significant (<0.01). CONCLUSION: The prognostic performance of both the 6th and 8th AJCC editions is unsatisfactory; there is a need for a more practical and prognostically relevant staging system for MPM. PMID- 29110840 TI - Immunohistochemical and genetic characteristics of lung cancer mimicking organizing pneumonia. AB - INTRODUCTION: Lung cancer mimicking organizing pneumonia (LCOP) is a novel radiological entity of lung adenocarcinoma that could be misdiagnosed as inflammatory lesions. However, the characteristic biological and genetic features of LCOP are not fully clarified. MATERIALS AND METHODS: We used thin-section CT images to select cases of (LCOP) among surgically resected lung adenocarcinoma patients. We compared the clinicopathological characteristics and the immunophenotypes of LCOP (n=44) and other lepidic-predominant adenocarcinomas (non-LCOP, n=56). We also analyzed the genomic mutation features of LCOP (n=4) by whole-exome sequencing (WES). RESULTS: All LCOP lesions were lepidic-predominant invasive adenocarcinoma. Patients with LCOP had significantly superior recurrence free survival, compared to non-LCOP patients (95.5% and 74.4%; P=0.006, respectively). Vascular invasion and lymph node metastasis were less frequent in LCOP than in non-LCOP patients (P=0.001 and P=0.03, respectively). The cancer cell expression levels of aggressiveness-related molecules, including ezrin, ALDH 1, laminin-5 were similar between LCOP and non-LCOP. On the contrary, the number of tumor promoting stromal cells, i.e., podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor associated macrophages, was significantly lower in LOCP (P=0.021 and P=0.037, respectively). WES revealed that ABCB1, DNAH3, MSI2, and SLITRK2 were specifically mutated in LCOP. CONCLUSIONS: Our results indicate that LCOP is characterized by fewer tumor-promoting stromal cells, which may contribute to the better prognosis of LCOP patients. Moreover, recognition of specific somatic mutations of LCOP patients may provide information regarding the development and progression of this type of lung cancer. PMID- 29110841 TI - Heterogeneous resistance mechanisms in an EGFR exon 19-mutated non-small cell lung cancer patient treated with erlotinib: Persistent FGFR3-mutation, localized transformation to EGFR-mutated SCLC, and acquired T790M EGFR-mutation. AB - Patients with epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer (NSCLC) obtain substantial clinical benefit from EGFR tyrosine-kinase inhibitors (TKIs), but will ultimately develop TKI-resistance resulting in median progression-free survival of 9-15 months during first-line TKI-therapy. However, type and timing of TKI-resistance cannot be predicted and several mechanisms may simultaneously/subsequently occur during TKI-treatment. In this respect, we present a 49 year-old Caucasian male ex-smoker with metastatic pulmonary adenocarcinoma (ADC) that concomitantly harbored an EGFR exon 19-mutation (p.E746_A750delELREA) and a previously unreported 2bp frame-shift microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. Interestingly, FGFR3-mutations have previously been described in other cancer types of Caucasian patients and may represent an alternative pathway to EGFR signaling. The patient received first-line erlotinib but after only 7 weeks showed metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) that retained the EGFR- and FGFR3-mutations was identified. Consequently, standard carboplatin-etoposide regimen for SCLC combined with erlotinib continuation was implemented obtaining significant objective response. However, after completing 6 cycles of this combination, new pulmonary and hepatic metastases appeared and showed persistence of the original EGFR- and FGFR3 mutated ADC phenotype together with acquisition of the erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased. Thus, this advanced EGFR-mutated NSCLC displayed very rapid onset and heterogeneous genetic and phenotypic mechanisms of TKI-resistance occurring at different times and locations of metastatic disease: concomitant FGFR3-mutation before and during TKI treatment as potential intrinsic mechanism for the rapid progression; transformation to SCLC at first progression during TKI-therapy; acquired T790M EGFR-mutation at second progression. Our case also underlines that, when achievable, rebiopsies of progressive sites during TKI-treatment are important for identifying heterogeneous histopathological and molecular resistance mechanisms and better defining possible treatment modifications. PMID- 29110842 TI - Patient-reported outcome measures (PROMs) in the management of lung cancer: A systematic review. AB - Lung cancer is often associated with a poor quality of life, as reflected by patient-reported outcome measures (PROMs). The aim of this paper is to describe and compare the PROMs that are available. In this manuscript, we review the impact of PROMs on the management of lung cancer. Quality of the study and risk of bias were assessed using the appraisal tools recommended by the Dutch Cochrane Center. Out of 51 studies included in this review, ten instruments were identified and categorized as either generic, cancer- or lung cancer-specific. PROMs are primarily applied in scientific research to compare the therapy outcomes and in drug development to support labeling claims. The interest for the routine use of PROMs in daily practice is growing, which has positive effects on the communication with the patient, mutual decision making and the monitoring and managing of the patient. Besides that, PROMs have an independent prognostic value for survival in lung cancer and economic evaluations can be conducted using their results. Electronic platforms simplify the implementation of PROMs in the daily clinic. The EORTC QLQ-C30 and its lung cancer-specific module QLQ-LC13 are the most frequently used instruments in lung cancer patients. PROMs have the potential to improve the quality of care with a proper implementation in the routine practice. PROMS are needed to value and understand the experience of the patient. PMID- 29110843 TI - Frequency and clinical impact of preoperative circulating tumor cells in resectable non-metastatic lung adenocarcinomas. AB - OBJECTIVES: Despite successful surgery, 30-50% of patients with resectable non small cell lung cancer develop tumor recurrence within 5 years of surgery. MATERIALS AND METHODS: In this prospective study, we performed CTC enumerations in 40 patients with non-metastatic lung adenocarcinoma (NMLA) using a size-based microfilter. Additionally, cfDNA isolated from plasma was analyzed in 35 out of 40 patients. RESULTS: CTCs were identified in 15 out of 40 patients (37.5%) with a range of 1-44 cells, whereas mutated cfDNA was only detected in 3 out of 35 patients (8.6%). Disease-free survival (DFS) was significantly associated with CTC positivity (log-rank p=0.025), grading (log-rank p=0.019), tumor stage (log rank p=0.025) and lymph node status (log-rank p=0.029). Multivariate analysis, including tumor stage and grading, showed that CTC positivity (p=0.006), grading (0.039) and tumor stage (p=0.022) were independently associated with DFS. CONCLUSION: Our study found that microfilter-based CTC enumeration in NMLA patients is an independent predictor of worse DFS. The used NGS-based cfDNA characterization had limited sensitivity to be clinically informative in our study cohort. CTC assessment before surgery can thus identify NMLA patients at high risk of disease recurrence. PMID- 29110844 TI - Genetic polymorphisms and lung cancer risk: Evidence from meta-analyses and genome-wide association studies. AB - A growing number of studies investigating the association between Single Nucleotide Polymorphisms (SNPs) and lung cancer risk have been published since over a decade ago. An updated integrative assessment on the credibility and strength of the associations is required. We searched PubMed, Medline, and Web of Science on or before August 29th, 2016. A total of 198 articles were deemed eligible for inclusion, which addressed the associations between 108 variants and lung cancer. Among the 108 variants, 63 were reported to be significantly associated with lung cancer while the remaining 45 were reported non-significant. Further evaluation integrating the Venice Criteria and false-positive report probability (FPRP) was performed to determine the strength of cumulative epidemiological evidence for the 63 significant associations. As a result, 15 SNPs on or near 12 genes and one miRNA with strong evidence of association with lung cancer risk were identified, including TERT (rs2736098), CHRNA3 (rs1051730), AGPHD1 (rs8034191), CLPTM1L (rs401681 and rs402710), BAT3 (rs3117582), TRNAA (rs4324798), ERCC2 (Lys751Gln), miR-146a2 (rs2910164), CYP1B1 (Arg48Gly), GSTM1 (null/present), SOD2 (C47T), IL-10 (-592C/A and -819C/T), and TP53 (intron 6). 19 SNPs were given moderate rating and 17 SNPs were rated as having weak evidence. In addition, all of the 29 SNPs identified in 12 genome-wide association studies (GWAS) were proved to be noteworthy based on FPRP value. This review summarizes and evaluates the cumulative evidence of genetic polymorphisms and lung cancer risk, which can serve as a general and useful reference for further genetic studies. PMID- 29110845 TI - An international epidemiological analysis of young patients with non-small cell lung cancer (AduJov-CLICaP). AB - BACKGROUND: A proportion of patients with NSCLC is diagnosed at 40 years or younger. These patients tend to be never-smokers, usually present with stage IV adenocarcinoma, and have somatic genomic alterations. Few studies have documented and analyzed epidemiological characteristics of this population. MATERIALS AND METHODS: We performed an international epidemiological analysis of 389 young patients with NSCLC. Data was collected from centers participating in the Latin American Consortium for Lung Cancer Research (AduJov-CLICaP). Patients were identified and data was retrospectively collected from different Latin American countries and Canada (Argentina=6, Canada=19, Colombia=29, Costa Rica=9, Mexico=219, Nicaragua=2, Panama=19, Peru=76 and Venezuela=10). The period of study was from 2012 to 2017. Inclusion criteria were: age 40 years or less and a histologically confirmed NSCLC. Clinical data was obtained, and EGFR mutation status and EML4-ALK translocation were collected. RESULTS: NSCLC patients aged 40 years or less accounted for approximately 4% of the total NSCLC population. Female patients accounted for 54.5%, while median age was of 37 years. Adenocarcinoma accounted for 86.1% (n=335/389), 72.5% (n=282/389; unknown=5) of patients were non-smokers, and 90.3% (n=351/389) had stage IV disease. Site of metastasis was obtained from 260/351 (unknown=91) stage IV patients (lung metastasis=40.0%, CNS metastasis=35.7%, and bone metastasis=31.5%). OS for the total population was 17.3 months (95%CI=13.9-20.7). OS for EGFRm(+)=31.4months (95%CI=11.6-51.3), EGFRm(-)=14.5months (95%CI=11.0-17.9) (p=0.005). OS for alk(+)=9.8months (95%CI=3.1-16.5) and alk(-)=5.6months (95%CI=3.9-7.3) (p=0.315). CONCLUSIONS: Patients aged 40 years or less account for a small but important proportion of NSCLC cases. Younger patients may have different characteristics compared to the older population. EGFRm and EML4-alk translocation frequency is higher than that of the general population. PMID- 29110847 TI - Symptomatic pseudo-progression followed by significant treatment response in two lung cancer patients treated with immunotherapy. AB - In the setting of pseudo-progression in a cancer patient who receives immunotherapeutic treatment, discontinuation of therapy is recommended if the patient is symptomatic. Here, we present two patients with advanced adenocarcinoma of the lung who developed massive tumor growth after initiation of treatment with the anti-PD-1 antibody pembrolizumab. Even though clinical deterioration occurred in the form of severe dyspnea and weight loss, pembrolizumab therapy was continued, as the speed of tumor growth suggested pseudo-progression and the tumors showed marked PD-L1 expression. This approach was successful, and both patients experienced impressive treatment responses within a few weeks. PMID- 29110846 TI - EGFR mutation prevalence in Asia-Pacific and Russian patients with advanced NSCLC of adenocarcinoma and non-adenocarcinoma histology: The IGNITE study. AB - OBJECTIVES: Limited understanding exists of epidermal growth factor receptor (EGFR) mutation frequency in less common subgroups of advanced non-small-cell lung cancer (aNSCLC) (e.g. squamous cell carcinoma [SCC]), and to what extent local practices exclude patients from EGFR testing based on their clinical characteristics. MATERIALS AND METHODS: IGNITE (non-comparative/-interventional; NCT01788163) was conducted in 90 centres (Asia-Pacific/Russia). Eligible patients: local/metastatic aNSCLC; chemotherapy-naive, newly-diagnosed/recurrent disease after resection; ineligible for curative treatment. Patients provided a tissue/cytology (all) and a blood plasma (China/Russia/South Korea/Taiwan) sample. Primary endpoint: EGFR mutation frequency in aNSCLC patients (adenocarcinoma [ADC]/non-ADC), as per local practices. RESULTS: 3382 patients were enrolled. EGFR mutation frequencies for evaluable tissue/cytology samples in Asia-Pacific and Russian patients: 49.3% (862/1749) and 18.0% (90/500) for ADC tumours; 14.1% (74/525) and 3.7% (15/402) for non-ADC; 9.9% (40/403) and 3.7% (13/349) for SCC. Of Russian patients with SCC tumours harbouring common, activating EGFR mutations, 6/9 were never-/former-smokers. Mutation status concordance between 2581 matched tissue/cytology and plasma samples: 80.5% (sensitivity 46.9%, specificity 95.6%). CONCLUSION: EGFR mutation testing should be considered in all Asian aNSCLC patients. Also, as activating EGFR mutations were observed in a small number of Caucasian squamous NSCLC patients, testing here may be appropriate, particularly in those with no/remote smoking history. Circulating free tumour-derived DNA is feasible for mutation analysis employing well-validated and sensitive methods, when tumour samples are unavailable. PMID- 29110848 TI - Relationship between nodule count and lung cancer probability in baseline CT lung cancer screening: The NELSON study. AB - OBJECTIVES: To explore the relationship between nodule count and lung cancer probability in baseline low-dose CT lung cancer screening. MATERIALS AND METHODS: Included were participants from the NELSON trial with at least one baseline nodule (3392 participants [45% of screen-group], 7258 nodules). We determined nodule count per participant. Malignancy was confirmed by histology. Nodules not diagnosed as screen-detected or interval cancer until the end of the fourth screening round were regarded as benign. We compared lung cancer probability per nodule count category. RESULTS: 1746 (51.5%) participants had one nodule, 800 (23.6%) had two nodules, 354 (10.4%) had three nodules, 191 (5.6%) had four nodules, and 301 (8.9%) had>4 nodules. Lung cancer in a baseline nodule was diagnosed in 134 participants (139 cancers; 4.0%). Median nodule count in participants with only benign nodules was 1 (Inter-quartile range [IQR]: 1-2), and 2 (IQR 1-3) in participants with lung cancer (p=NS). At baseline, malignancy was detected mostly in the largest nodule (64/66 cancers). Lung cancer probability was 62/1746 (3.6%) in case a participant had one nodule, 33/800 (4.1%) for two nodules, 17/354 (4.8%) for three nodules, 12/191 (6.3%) for four nodules and 10/301 (3.3%) for>4 nodules (p=NS). CONCLUSION: In baseline lung cancer CT screening, half of participants with lung nodules have more than one nodule. Lung cancer probability does not significantly change with the number of nodules. Baseline nodule count will not help to differentiate between benign and malignant nodules. Each nodule found in lung cancer screening should be assessed separately independent of the presence of other nodules. PMID- 29110849 TI - Continued use of afatinib with the addition of cetuximab after progression on afatinib in patients with EGFR mutation-positive non-small-cell lung cancer and acquired resistance to gefitinib or erlotinib. AB - OBJECTIVES: In a phase Ib trial, afatinib plus cetuximab demonstrated promising clinical activity (objective response rate [ORR]: 29%; median progression-free survival [PFS]: 4.7 months) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with acquired resistance to erlotinib or gefitinib. Here, a separate cohort exploring afatinib plus cetuximab after progression on afatinib is reported. MATERIALS AND METHODS: Patients with EGFR mutation-positive NSCLC who progressed on erlotinib or gefitinib received afatinib 40mg daily until progression, followed by afatinib daily plus cetuximab 500mg/m2 every 2 weeks until progression or intolerable adverse events (AEs). Endpoints included safety, ORR, and PFS. RESULTS: Thirty seven patients received afatinib monotherapy. Two (5%) patients responded; median PFS was 2.7 months. Thirty-six patients transitioned to afatinib plus cetuximab. Four (11%) patients responded; median PFS was 2.9 months. Median PFS with afatinib plus cetuximab for patients who received afatinib monotherapy for >=12 versus <12 weeks was 4.9 versus 1.8 months (p=0.0354), and for patients with T790M-positive versus T790M-negative tumors was 4.8 versus 1.8 months (p=0.1306). Fifty percent of patients receiving afatinib plus cetuximab experienced drug related grade 3/4 AEs. The most frequent drug-related AEs (any grade) were diarrhea (70%), rash (49%), and fatigue (35%) with afatinib monotherapy and rash (69%), paronychia (39%), and dry skin (36%) with afatinib plus cetuximab. CONCLUSION: Sequential EGFR blockade with afatinib followed by afatinib plus cetuximab had a predictable safety profile and demonstrated modest activity in patients with EGFR mutation-positive NSCLC with resistance to erlotinib or gefitinib. CLINICALTRIALS. GOV IDENTIFIER: NCT01090011. PMID- 29110850 TI - Nanoparticle targeted folate receptor 1-enhanced photodynamic therapy for lung cancer. AB - OBJECTIVE: Despite modest improvements, the prognosis of lung cancer patients has still remained poor and new treatment are urgently needed. Photodynamic therapy (PDT), the use of light-activated compounds (photosensitizers) is a treatment option but its use has been restricted to central airway lesions. Here, we report the use of novel porphyrin-lipid nanoparticles (porphysomes) targeted to folate receptor 1 (FOLR1) to enhance the efficacy and specificity of PDT that may translate into a minimally-invasive intervention for peripheral lung cancer and metastatic lymph nodes of advanced lung cancer. MATERIALS AND METHODS: The frequency of FOLR1 expression in primary lung cancer and metastatic lymph nodes was first analyzed by human tissue samples from surgery and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA). Confocal fluorescence microscopy was then used to confirm the cellular uptake and fluorescence activation in lung cancer cells, and the photocytotoxicity was evaluated using a cell viability assay. In vivo fluorescence activation and quantification of uptake were investigated in mouse lung orthotopic tumor models, followed by the evaluation of in vivo PDT efficacy. RESULTS: FOLR1 was highly expressed in metastatic lymph node samples from patients with advanced lung cancer and was mainly expressed in lung adenocarcinomas in primary lung cancer. Expression of FOLR1 in lung cancer cell lines corresponded with the intracellular uptake of folate-porphysomes in vitro. When irradiated with a 671nm laser at a dose of 10J/cm2, folate-porphysomes showed marked therapeutic efficacy compared with untargeted porphysomes (28% vs. 83% and 24% vs. 99% cell viability in A549 and SBC5 lung cancer cells, respectively). Systemically-administered folate porphysomes accumulated in lung tumors with significantly enhanced disease-to normal tissue contrast. Folate-porphysomes mediated PDT successfully inhibited tumor cell proliferation and activated tumor cell apoptosis. CONCLUSION: Folate porphysome based PDT shows promise in selectively ablating lung cancer based on FOLR1 expression in these preclinical models. PMID- 29110851 TI - Acquired resistance to crizotinib in advanced lung adenocarcinoma with MET exon 14 skipping. PMID- 29110852 TI - Radiological classification of multiple lung cancers and the prognostic impact based on the presence of a ground glass opacity component on thin-section computed tomography. AB - OBJECTIVES: Revised TNM classification has proposed a new clinical classification of lung cancers with multiple pulmonary sites. However, definition of the radiological findings and their prognostic impacts are still controversial. Therefore, we evaluated the prognostic impact of multiple lung cancers based on the radiologic classifications concluded from findings on thin-section computed tomography. METHODS: Among surgically resected 1440 c-stage I lung cancer patients, 246 (17.1%) with multiple lung tumors were reviewed. All tumors were classified into 3 groups based on the extent of ground glass opacity (GGO), i.e., consolidation tumor ratio (CTR); GGO-dominant (GD; 0<=CTR<0.5), solid-dominant (SD; 0.5<=CTR<1.0) and pure-solid (PS; CTR=1.0). Multiple lung tumors were divided radiologically into 6 groups, and their prognoses were compared with that of c-stage I lung cancer using Cox's proportional hazard model. RESULTS: Of all, 198 patients (80.5%) were surgically resected more than two tumors and determined as multiple lung cancers pathologically. The number of patients with GD+GD=73 (30%), GD+SD=54 (22%), GD+PS=53 (21%), SD+SD=12 (5%), SD+PS=20 (8%) and PS+PS=34 (14%). A multivariate analysis revealed that PS+PS group consisted of independently significant prognosticator (p<0.001). The overall survival (OS) was 97.3% in GD+GD, 98.2% in GD+SD, 84.8% in GD+PS, 90.9% in SD+SD, 78.7% in SD+PS and 41.8% in PS+PS groups, showing a significant difference between PS+PS group and the other groups. Furthermore, the OS of 1194 c-stage I lung cancer patients was 78.2%, and the prognosis of PS+PS group was significantly poor compared with that of c-stage I (p<0.001), while OS of the other groups were almost equivalent or much better than the c-stage I. CONCLUSIONS: Among multiple lung cancers, PS+PS group is associated with poor survival, which would contribute to the upstaging of T descriptors. The presence of GGO is extremely important when considering the correlation between radiological classification of multiple lung cancers and its prognosis. PMID- 29110853 TI - CD44 variant-dependent regulation of redox balance in EGFR mutation-positive non small cell lung cancer: A target for treatment. AB - OBJECTIVES: The regulation of redox balance in cancer cells is an important factor in tumor development and chemoresistance, with oncogene activation having been shown to induce the generation of reactive oxygen species (ROS). Activating mutations of the epidermal growth factor receptor gene (EGFR) are oncogenic drivers in non-small cell lung cancer (NSCLC), but it has remained unknown whether ligand-independent EGFR signaling conferred by EGFR mutation triggers ROS generation in NSCLC cells. MATERIALS AND METHODS: HEK293T cells were transfected with an expression vector for mutant EGFR. The expression of CD44 variant (CD44v) isoforms in NSCLC cell lines was evaluated by flow cytometry. Cells were depleted of CD44v by RNA interference and assayed for ROS and glutathione (GSH) levels. The effect of CD44v on cisplatin sensitivity was evaluated in vitro with the MTS assay. RESULTS: EGFR signaling due to EGFR mutation increased ROS levels in transfected HEK293T cells. The expression of CD44v isoforms was found to be inversely correlated with basal ROS levels in EGFR mutation-positive NSCLC cell lines. Knockdown of CD44v induced depletion of intracellular GSH and increased ROS levels in EGFR-mutated NSCLC cells that express CD44v at a high level (CD44vhigh). In addition, depletion of GSH by treatment with buthionine-[S, R] sulfoximine induced marked accumulation of ROS and enhanced the cytotoxicity of cisplatin in CD44vhighEGFR-mutated NSCLC cells but not in corresponding CD44vlow cells. This enhancement of cisplatin cytotoxicity by GSH depletion was prevented by treatment with the antioxidant N-acetyl-l-cysteine. Knockdown of CD44v also enhanced cisplatin cytotoxicity in CD44vhighEGFR mutation-positive NSCLC cells but not in CD44vlow cells. CONCLUSION: Our results thus implicate CD44v in redox adaptation and as a potential target for treatment in CD44vhighEGFR-mutated NSCLC cells. PMID- 29110855 TI - Predictors for chemotherapy in early stage small cell lung carcinoma (SCLC): A National Cancer Database (NCDB) analysis. PMID- 29110854 TI - Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI). AB - PURPOSE: To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. PATIENTS AND METHODS: Patients with progressive refractory NSCLC who had previously benefitted from erlotinib (objective response or stable disease >8weeks) were randomized to receive treatment with either erlotinib and sorafenib (400mg orally twice daily) or sorafenib alone. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. RESULTS: Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. CONCLUSIONS: These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804. PMID- 29110856 TI - External validation of prognostic indices for overall survival of malignant pleural mesothelioma. AB - OBJECTIVE: There are several prognostic indices (PIs) to predict overall survival (OS) in malignant pleural mesothelioma (MPM) patients. Before using a clinical prediction model in the actual clinical setting, empiric evaluation of its performance based on datasets that were not used to develop the model (i.e., external validation) is essential. The purpose of this study was to conduct an external validation of the PIs for MPM. MATERIALS AND METHODS: A retrospective cohort study was performed on MPM patients treated at 2 tertiary hospitals in Japan between 2007 and 2015. The primary outcome was OS. Harrell's c-index, and was calculated to examine the discrimination of three models. The bootstrapping technique was used to evaluate optimism. RESULTS: The participants comprised 183 patients who underwent surgical treatment (n=61), chemotherapy (n=101), and best supportive care (BSC, n=21). The median OS rates were 1014days for surgery, 690days for chemotherapy, and 545days for best supportive care (BSC). The respective discriminations (95% confidence interval) of the Eastern Cooperative Oncology Group Performance Status, the European Organisation for Research and Treatment of Cancer index, regimen, PS, histology or stage (rPHS) index, and Tagawa index for the OS of MPM patients were 0.532 (0.444-0.620), 0.560 (0.472 0.648), 0.584 (0.452-0.716), and 0.525 (0.453-0.596) for surgery; 0.632 (0.539 0.724), 0.622 (0.548-0.696), 0.677 (0.587-0.766), and 0.545 (0.436-0.653) for chemotherapy; and 0.504 (0.365-0.644), 0.583 (0.456--0.710), 0.704 (0.508-0.899), and 0.583 (0.436-0.730) for BSC. CONCLUSIONS: Each PI showed poor discrimination for MPM patients who underwent surgical treatment. The rPHS index showed moderate discrimination for patients given chemotherapy and BSC. PMID- 29110857 TI - Inter-relationship between PD-L1 expression and clinic-pathological features and driver gene mutations in pulmonary sarcomatoid carcinomas. AB - INTRODUCTION: Pulmonary Sarcomatoid Carcinoma (PSC) is a rare subset of NSCLC, associated with worse prognosis and resistant to platinum-based regimens. Recent investigations have shown high levels of PD-L1 expression in PSC, providing a rationale for the potential use of immunotherapy. In this study, we investigated whether the PD-L1 expression was related to clinico-pathologic and molecular characteristics. MATERIALS AND METHODS: Fortythree surgically-resected PSCs were selected from 2006 to 2014 and clinical information retrieved. PD-L1 expression was analyzed by immunohistochemistry and correlated with the clinic-pathologic features and driver gene mutations analyzed by Next-Generation-Sequencing. Correlation of clinical, pathological and genetic variants with PD-L1 expression positivity were tested by Fisher's exact test analysis. RESULTS: About 25% of PSCs showed a significant expression of PD-L1 (positive staining defined as staining in >=10% of tumor cells). PD-L1 expression was associated with aggressive pathological features of PSCs including N2-involvement (PD-L1 positive in 83.3% of N2-PSCs vs in 16.2% of N0/N1-PSCs, p=0.003) and presence of either local (p=0.038) and distant metastases (p=0.022). Furthermore, PD-L1 expression was significantly associated with the overall mutational load of the tumors (PD L1 positivity only in PSCs with at least one mutational event) and in particular with the presence of KRAS mutation (PD-L1 positive in 44.4% of KRAS-Mut PSCs vs 12.0% in KRAS-Wild PSCs). The correlation between PD-L1 expression and KRAS mutation were found at univariate analysis (p=0.031), even considering PD-L1 as a continuous variable (p=0.018), and confirmed at multivariate analysis (p=0.035). The mutational status of the other genes explored in the NGS-panel (EGFR, APC, PTEN, PIK3CA, TP53 and STK11) did not correlate with PD-L1 expression. CONCLUSIONS: PD-L1 expression significantly correlates with overall mutational load and KRAS mutational status in pulmonary sarcomatoid carcinomas. PMID- 29110860 TI - Incidence and prevalence rates of diabetes mellitus in Saudi Arabia: An overview. AB - OBJECTIVE: This study aimed to report on the trends in incidence and prevalence rates of diabetes mellitus in Saudi Arabia over the last 25 years (1990-2015). DESIGN: A descriptive review. METHODS: A systematic search was conducted for English-language, peer reviewed publications of any research design via Medline, EBSCO, PubMed and Scopus from 1990 to 2015. Of 106 articles retrieved, after removal of duplicates and quality appraisal, 8 studies were included in the review and synthesised based on study characteristics, design and findings. FINDINGS: Studies originated from Saudi Arabia and applied a variety of research designs and tools to diagnosis diabetes. Of the 8 included studies; three reported type 1 diabetes and five on type 2 diabetes. Overall, findings indicated that the incidence and prevalence rate of diabetes is rising particularly among females, older children/adolescent and in urban areas. CONCLUSION: Further development are required to assess the health intervention, polices, guidelines, self-management programs in Saudi Arabia. PMID- 29110861 TI - 'Before reaching the last mile'- Knowledge, attitude, practice and perceived barriers related to tuberculosis directly observed therapy among ASHA workers in Central India: A mixed method study. AB - INTRODUCTION: Community-based direct observed treatment (DOT) providers are an important bridge for the national tuberculosis programme in India to reach the unreached. The present study has explored the knowledge, attitude, practice and barriers perceived by the community-based DOT providers. METHODS: Mixed-methods study design was used among 41 community-based DOT providers (Accredited Social Health Activist (ASHAs)) working in 67 villages from a primary health center in Raisen district of Madhya Pradesh, India. The cross-sectional quantitative component assessed the knowledge and practices and three focus-group discussions explored the attitude and perceived barriers related to DOT provision. RESULT: 'Adequate knowledge' and 'satisfactory practice' related to DOT provision was seen in 14 (34%) and 13 (32%) ASHAs respectively. Only two (5%) received any amount of honorarium for completion of DOT in last 3years. The focus-group discussions revealed unfavourable attitude; inadequate training and supervision, non-payment of honorarium, issues related to assured services after referral and patient related factors as the barriers to satisfactory practice of DOT. CONCLUSION: Study revealed inadequate knowledge and unsatisfactory practice related to DOT provision among ASHAs. Innovations addressing the perceived barriers to improve practice of DOT provision by ASHAs are urgently required. PMID- 29110862 TI - Low pre-diagnosis attrition but high pre-treatment attrition among patients with MDR-TB: An operational research from Chennai, India. AB - BACKGROUND: Worldwide, there's concern over high pre-diagnosis and pre-treatment attritions or delays in Multidrug resistant tuberculosis (MDR-TB) diagnosis and treatment pathway (DTP). We conducted this operational research among patients with presumptive MDR-TB in north and central Chennai, India to determine attrition and turnaround times (TAT) at various steps of DTP and factors associated with attrition. METHODS: Study was conducted in Revised National Tuberculosis Control Programme setting. It was a retrospective cohort study involving record review of all patients with presumptive MDR-TB (eligible for DST) in 2014. RESULTS: Of 628 eligible for DST, 557 (88%) underwent DST and 74 (13%) patients were diagnosed as having MDR-TB. Pre-diagnosis and pre-treatment attrition was 11% (71/628) and 38% (28/74) respectively. TAT [median (IQR)] to test from eligibility for DST and initiate DR-TB treatment from diagnosis were 14 (9,27) and 18 (13,36) days respectively. Patients with smear negative TB and detected in first quarter of 2014 were less likely to undergo DST. Patients in first quarter of 2014 had significantly lower risk of pre-treatment attrition. CONCLUSION: There was high uptake of DST. However, urgent attention is required to reduce pre-treatment attrition, improve TAT to test from eligibility for DST and improve DST among patients with smear-negative TB. PMID- 29110863 TI - Assessment of metabolic syndrome in Kashmiri population with type 2 diabetes employing the standard criteria's given by WHO, NCEPATP III and IDF. AB - BACKGROUND: Around 20-25 percent of the world's adult populations have the metabolic syndrome and they are twice as likely to die from heart attack or stroke compared with people without the syndrome. The World Health Organization proposed a definition for the metabolic syndrome in 1998 and later on NCEP ATPIII and IDF provided new definitions of this syndrome in 2001 and 2003 respectively. Very few studies have compared the different definitions to diagnose the metabolic syndrome in type two diabetics in India while as for Kashmir valley no such documented study has been carried out till date. OBJECTIVE: To study the prevalence of metabolic syndrome in type 2 Kashmir diabetics and to find out the degree of agreement between three different criteria given by WHO, NCEPATPIII and IDF for diagnosis of metabolic syndrome. MATERIALS AND METHOD: A cross sectional study was conducted in one of the two tertiary care hospitals of Kashmir, India. About 1000 patients were selected and their demographic, clinical and biochemical parameters were studied after obtaining informed consent from each patient. RESULTS: Prevalance of metabolic syndrome was found to be highest(84.5%) while using WHO definition.Kappa statistic between WHO, ATP III and WHO, IDF definitions was 0.697 (95% CI 0.637-0.754) and 0.775 (95%CI 0.72-0.82) respectively while the degree of agreement between IDF and ATP III definitions was highest with kappa of 0.851 (95%CI 0.810-0.889). CONCLUSION: Our study warrants for interventions to prevent the progression towards this syndrome among type 2 diabetics as early as the diagnosis of diabetes is made. PMID- 29110864 TI - Pulmonary tuberculosis in Patna, India: Durations, delays, and health care seeking behaviour among patients identified through household surveys. AB - BACKGROUND: Delays in accessing effective health care plays a pivotal role in increasing Tuberculosis (TB) transmission within the community. Patna, North India, with high levels of poverty and weak public health system, faces huge challenges for achieving effective TB control. The study aims to determine delays that occur from onset of TB symptoms until initiation of pulmonary TB (PTB) treatment among patients in Patna. METHODS: Of the 109 self-reporting TB patients identified through an active household survey, 64 PTB patients were interviewed. First care seeking, TB diagnostic and treatment initiation durations were calculated and delays defined for new and retreatment patients and minors and adults. Outliers exhibiting extreme delays were additionally identified. RESULTS: A cross sMean total pathway duration for TB care was 40days, with diagnostic duration contributing to 58% of the duration. No significant differences were noted between new and retreatment patients. Minors, comprising of 30% of total PTB patients accessed care faster than adults, but showed significantly higher diagnostic duration (38days vs. 17days). Preference for private sector, chemists and allopaths was seen throughout the pathway. DISCUSSION: Patna requires a more effective harnessing of the private sector augmented with reliable diagnostic investigations and a focus on quality. PMID- 29110866 TI - Prenatal care utilization in Zimbabwe: Examining the role of community-level factors. AB - This paper assesses the importance of community-level factors on prenatal care utilization in Zimbabwe. The analysis is performed using data from the two most recent rounds of the nationally representative Demographic and Health Survey for Zimbabwe conducted in 2005/06 and 2010/11 linked with other community-level data. We use logistic, generalized linear regressions as well as multilevel mixed models to examine the factors associated with the frequency, timing and quality of prenatal care. Our results suggest that contraceptive prevalence, religious composition, density of nurses, health expenditures per capita and availability of government hospitals in communities are important predictors of prenatal care use in Zimbabwe. These findings have important implications for public health policy in Zimbabwe - a country with unfavorable maternal and child health outcomes. PMID- 29110865 TI - Establishing a cohort in a developing country: Experiences of the diabetes tuberculosis treatment outcome cohort study. AB - BACKGROUND: Prospective cohort studies are instrumental in generating valid scientific evidence based on identifying temporal associations between cause and effect. Researchers in a developing country like Pakistan seldom undertake cohort studies hence little is known about the challenges encountered while conducting them. We describe the retention rates among tuberculosis patients with and without diabetes, look at factors associated with loss to follow up among the cohort and assess operational factors that contributed to retention of cohort. METHODS: A prospective cohort study was initiated in October 2013 at the Gulab Devi Chest Hospital, Lahore, Pakistan. We recruited 614 new adult cases of pulmonary tuberculosis, whose diabetic status was ascertained by conducting random and fasting blood glucose tests. The cohort was followed up at the 2nd, 5th and 6th month while on anti-tuberculosis therapy (ATT) and 6months after ATT completion to determine treatment outcomes among the two groups i.e. patients with diabetes and patients without diabetes. RESULTS: The overall retention rate was 81.9% (n=503), with 82.3% (93/113) among patients with diabetes and 81.8% (410/501) among patients without diabetes (p=0.91). Age (p=0.001), area of residence (p=0.029), marital status (p=0.001), educational qualification (p=<0.001) and smoking (p=0.026) were significantly associated with loss to follow up. Respondents were lost to follow up due to inability of research team to contact them as either contact numbers provided were incorrect or switched off (44/111, 39.6%). CONCLUSION: We were able to retain 81.9% of PTB patients in the diabetes tuberculosis treatment outcome (DITTO) study for 12months. Retention rates among people with and without diabetes were similar. Older age, rural residence, illiteracy and smoking were associated with loss to follow up. The study employed gender matched data collectors, had a 24-h helpline for patients and sent follow up reminders through telephone calls rather than short messaging service, which might have contributed to retention of cohort. PMID- 29110867 TI - Characterization of SCCmec and spa types of methicillin-resistant Staphylococcus aureus isolates from health-care and community-acquired infections in Kerman, Iran. AB - Spread of methicillin-resistant Staphylococcus aureus (MRSA) isolates is a worldwide problem. Molecular typing is a useful tool to understand MRSA epidemiology. Herein, we determined vancomycin-resistant, SCCmec and spa types among MRSA isolates recovered from healthcare and community-acquired infections in Kerman, Iran. A total of 170 S. aureus isolates were collected from different patients who were admitted to affiliated hospitals of Kerman University of Medical science. MRSA and vancomycin-resistant S. aureus (VRSA) isolates were detected by phenotypic methods. Polymerase chain reaction (PCR) technique was used for detection of mecA, vanA and vanB genes. Staphylococcal cassette chromosomemec (SCCmec) and spa typing were used for molecular typing of among MRSA isolates. Overall, 53% of isolates were considered as MRSA. Two MRSA isolates were resistant to vancomycin and vanA was detected in only one of VRSA isolates. SCCmec type III belonged to spa types t030 and t459 which they were the dominant spa types among community-associated MRSA (CA-MRSA) and healthcare acquired MRSA (HA-MRSA) isolates. Our findings showed that the SCCmec type I and III spread from hospital settings to community, although the SCCmec type IV spread from community to healthcare systems. We have also reported VRSA isolates from hospitalized patients, therefore, appropriate policies should be enforced in order to prevent the spread of antibiotic resistance isolates in hospitals settings. PMID- 29110868 TI - Effect of exclusive cigarette smoking and in combination with waterpipe smoking on lipoproteins. AB - OBJECTIVE: A significant increase in total cholesterol and LDL-C is well shown in tobacco users, as compared to non-tobacco users. The additive effects of waterpipe and cigarette smoking on LDL levels have not been studied. The study's objective was to assess the correlation between cigarette smoking and LDL levels in Lebanese cigarette smokers and to check the interaction effect of waterpipe and cigarette smoking on LDL levels. METHODS: This cross-sectional study was conducted between October 2016 and February 2017 in 4 different laboratories, enrolling 308 patients (188 non-smokers, 105 cigarette smokers, 15 previous smokers). RESULTS: Current cigarette smoking (Beta=25.57; p<0.0001) was significantly associated with higher LDL levels and higher total cholesterol levels (Beta=53.29; p<0.0001) in exclusive cigarette smokers. Among current cigarette smokers who were current waterpipe smokers, a significant increase in LDL level was observed relative to current cigarette smokers who were not waterpipe smokers (Beta=66.64 vs Beta=37.37; p<0.0001). CONCLUSION: Among Lebanese current cigarette smokers, LDL levels increased relative to nonsmokers, consistent with findings in other populations. In addition, among Lebanese current cigarette smokers, current waterpipe smoking might increase adverse lipid profiles associated with adverse coronary effects more than cigarette smoking alone. The direct cause responsible for these observed variations in our study remains unidentified, with the hope that future research will reveal it. PMID- 29110870 TI - Evidence of ongoing brucellosis in livestock animals in North West Libya. AB - Animal brucellosis is thought to be present in small ruminants, cattle, and camels in Libya, particularly in the west coastal strip. Before the system collapsed due to political unrest in 2011, prevalence of the disease did not exceed 0.2% in cattle, 0.1% in camels, 8.3% in sheep, and 14.8% in goats. The aim of this study was to highlight outbreaks of disease that took place during the 18 month period from November 2014 to April 2016. A total of 1612 serum samples, collected opportunistically from 29 herds in 12 different localities in the northwest region of Libya, were investigated for brucellosis. The samples were screened for Brucella antibodies using the Rose Bengal test, and confirmed with either indirect enzyme linked immunosorbent assay in the case of sheep, and/or a serum agglutination test, followed with a complement fixation test, in the case of cattle and camels. Our results showed the highest rates of brucellosis seropositivity in goats (33.4%) and sheep (9.2%). The overall percentage of brucellosis seropositivity was 21%. The high level of brucellosis identified by this study, particularly in small ruminants, strongly suggests re-emergence of the disease in the region. Re-evaluation of intervention measures applied to the control of brucellosis is highly recommended. PMID- 29110869 TI - Prevalence of zoonotic tuberculosis and associated risk factors in Central Indian populations. AB - In the present study, we aimed to estimate the occurrence of bovine tuberculosis (TB) and examine the determinants of distribution of the disease in three high risk populations of Central India. A prospective cohort study was conducted in Central India between March 2014 and June 2015. Based on the requisite inclusion criteria, we recruited a total of 301 participants whose blood samples were subjected to polymerase chain reaction-based detection and differentiation of Mycobacterium bovis and Mycobacterium tuberculosis. M. bovis was detected in 11.4%, 8.9%, and 12.6% of the recruited participants belonging to three distinct population groups (Groups A, B, and C, respectively). The highest proportion of cases infected with M. bovis was observed in Group C, who lived in the high TB endemic region. Previous contact with active TB cases (odds ratio=3.7; 95% confidence interval, 0.9612-14.4533) and raw milk consumption (odds ratio=5.3472; 95% confidence interval, 1.9590-14.5956) were found to be important determinants of bovine TB in this population. The high incidence rates of bovine TB in the Central Indian populations indicate the substantial consequences of this disease for some population groups and settings. However, more research is necessary to identify the main transmission drivers in these areas. PMID- 29110871 TI - Prevalence of rifampicin-resistant Mycobacterium tuberculosis among human immunodeficiency-virus-seropositive patients and their treatment outcomes. AB - Multidrug resistant (MDR) and extensively drug resistant tuberculosis (TB) are a threat to the TB control programs in developing countries, and the situation is worsened by the human immunodeficiency virus (HIV) pandemic. This study was performed to correlate treatment outcome with the resistance patterns in HIV seropositive patients coinfected with pulmonary TB. Sputum specimens were collected from 1643 HIV-seropositive patients and subjected to microscopy and liquid culture for TB. The smear- and culture-positive Mycobacterium tuberculosis isolates were subjected to Genotype MTBDRplus assay version 2.0. The M. tuberculosis culture-positivity rate was 39.44% (648/1643) among the 1643 HIV seropositive patients and the overall MDR-TB rate was 5.6% (36/648). There were 421 newly diagnosed and 227 previously treated patients, among whom, MDR-TB was associated with 2.9% and 10.57% cases, respectively. The rate of rifampicin monoresistant TB among the cases of MDR-TB was 2.31% (15/648) and the rate of combined rifampicin and isoniazid resistance was 3.24% (21/648). The cure and death rates among the 20 registered cases were 30% (6/20) and 35% (7/20), respectively. Five cases were on treatment and two cases were defaulters among the 20 registered cases. High death rate (13, 36.1%, 95% confidence interval 20.8 53.8) was observed in this study among the patients who had mutations at the 530 533 codons. The present study emphasized the prerequisite to monitor the trend of drug-resistant TB in various mutant populations in order to timely implement appropriate interventions to curb the threat of MDR-TB. PMID- 29110872 TI - Venous thromboembolism risks and prophylaxis in King Fahad Hospital, Madinah, Saudi Arabia. AB - OBJECTIVE: To evaluate the risk factors, physician's compliance, and implementation of the American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) prophylaxis at our hospital. METHODS: A retrospective cohort study was conducted in King Fahad Hospital, Madinah, Saudi Arabia, from July 2015 to September 2015. We used the ACCP 2012 guidelines to assess the VTE risk and to determine whether patients had received the recommended prophylaxis. All hospital inpatients aged 14years or older were assessed for risk of VTE by reviewing the hospital chart. The primary endpoint was the rate of appropriate thromboprophylaxis. RESULTS: A total of 414 patients were studied. Their mean age was 47.74+/-20.4years, and 208 (50.2%) were female. There were 292 (70.5%) patients at high risk and 73 (17.6%) at moderate risk. As per the ACCP criteria, 375 (90.5%) patients were at risk for VTE and qualified for prophylaxis. Although 227 (60.5%) received some form of prophylaxis, only 144 (38.4%) of them received ACCP-recommended VTE prophylaxis. CONCLUSION: In our hospital, most of the patients are at high risk for developing VTE. The VTE prophylaxis guideline is not properly implemented and is underutilized. Strategies should be developed and implemented to ensure patient safety. PMID- 29110873 TI - Predictors of healthcare seeking delays among children with chronic musculoskeletal disorders in Nepal. AB - BACKGROUND: Healthcare seeking behaviors among children with musculoskeletal disorders are poorly understood. We sought to analyze healthcare seeking delays among children with chronic musculoskeletal conditions in Nepal and identify predictors of clinically significant delays. METHODS: A cross-sectional study was conducted at a large pediatric musculoskeletal rehabilitation center in Nepal. Baseline sociodemographic data and healthcare seeking behaviors were assessed via interviews with 75 randomly selected caregivers. Delays of at least 3 months between disease recognition and presentation to a health worker were considered clinically significant. Predictors of significant delay were assessed via multivariable logistic regression. RESULTS: Clubfoot was the most common condition seen in the study sample (N = 33; 37%). Mean and median presentation delays were 33 months and 14 months, respectively. Sixty-seven percent of children were delayed at least 3 months and 40% were delayed at least 2 years. Caregiver occupation in agriculture or unskilled labor was associated with an increased risk of delayed presentation (adjusted OR = 4.05; 95% CI: 1.36-12.09). CONCLUSIONS: Children with chronic musculoskeletal disorders in Nepal face significant delays in accessing healthcare. This poses a major clinical problem as the delayed diagnosis and treatment of childhood musculoskeletal disorders can complicate management options and decrease long-term quality of life. PMID- 29110874 TI - Diarrheagenic Escherichia coli infections among the children of Andaman Islands with special reference to pathotype distribution and clinical profile. AB - Diarrhoeagenic E. coli (DEC) is one of the most common causes of diarrhoeal death in children less than five years globally. It is responsible for 30%-40% of all diarrhoeal episodes in developing countries. It is estimated that 0.12million children died of diarrhoea caused by DEC in 2011 globally. There is no baseline data on the occurrence of DEC diarrhoea in Andaman Islands, the remote islands of India. The study is particularly important as these strains are the emerging enteric pathogen in both developed and developing countries. DEC was screened from E. coli isolates obtained from diarrhoeal stool samples by multiplex PCR with specific primers using stasndard protocols. During the study period, among the 1394 stool samples collected, 95 (6.82%) patients were found infected with DEC. Of the 97 isolates from 95 patients, 68 (70.1%) were EAEC, 19 (19.6%) were EPEC and 10 (10.3%) were ETEC. Of the 19 EPEC isolates, 63.2% were atypical EPEC which is the emerging enteric pathogen among the children in developing as well as developed countries. More than 80% of the patients had watery diarrhoea and 6% of them had invasive diarrhoea. Persistent diarrhoea was also found in three infected children. This study documents the occurrence and type of DEC diarrhoea in Andaman Islands first time and highlights the significant proportions of E. coli diarrhoea being caused by EAEC and atypical EPEC strains. PMID- 29110875 TI - Special issue on "Distributed coordination control for multi-agent systems in engineering applications". PMID- 29110876 TI - Corrigendum to "RNCR3: A regulator of diabetes mellitus-related retinal microvascular dysfunction" [Biochem. Biophys. Res. Commun. 482 (2017) 777-783]. PMID- 29110877 TI - Impact on Quality of Life in Dermatology Patients Attending an Emergency Department. AB - INTRODUCTION: Dermatological complaints have been estimated to represent up to 5 10% of all the visits to emergency departments. The main objective of our study was to determine how affected is the Health related Quality of Life (HRQL) in a series of patients attending an emergency department due to skin symptoms. PATIENTS AND METHODS: A prospective study during one month (July 2016) was conducted in a hospital with full-time on-call dermatologists. The Short-Form SF 12v2 Health Survey and the Dermatology Life Quality Index (DLQI) were offered to all the patients over 18 years old attending the emergency department with cutaneous complaints. Clinical and epidemiological characteristics were also collected. RESULTS: In total 108 patients completed the study. Mean age found was 45.1+/-16.1 years. Mean DLQI score found was 10.56+/-6.12. Fifty-three patients (49%) had a score of 11 or higher in the DLQI questionnaire. Most affected subscales were "Symptoms and Feelings" in DLQI scale and "Overall Health" and "Vitality" for the SF-12. A very significant difference (p<0.0001) was found between women's (12.4+/-5.7) and men's (7.5+/-5.6) DLQI mean score (mean difference of 4.9; 95% confidence interval of the difference: 2.7-7.1). CONCLUSIONS: Patients visiting emergency units with cutaneous complaints seem to feel a moderate-large impact on their quality of life which is mainly related to the symptoms and feelings that they are experiencing. This impact is significantly higher among women. PMID- 29110878 TI - Tumour size, volume, and marker expression during radiation therapy can predict survival of cervical cancer patients: a multi-institutional retrospective analysis of KROG 16-01. AB - OBJECTIVE: The aim of this multi-institutional study was to determine the prognostic impact of tumour parameters, such as tumour size (TS), tumour volume (TV), and marker expression, on survival during radiation therapy (RT) for cervical cancer patients. METHODS: A total of 231 patients with histologically confirmed cervical cancer, classified as Federation of Gynecology and Obstetrics (FIGO) Ib2-IVa, were enrolled in this study. Pre- and mid-RT pelvic magnetic resonance imaging (MRI) and squamous cell carcinoma antigen (SCC-ag) analysis were performed twice, during RT and just before brachytherapy. RESULTS: The median follow-up time was 27.8months (range, 2-116months). Multivariate analysis revealed that stage (odds ratio [OR], 2.936 and 95% confidence interval [CI], 1.119-7.707; P=0.029), tumour volume reduction rate (TVRR) (OR, 3.435 and 95% CI, 1.062-11.106; P=0.039), and SCC-ag reduction rate (SCCRR) (OR, 5.104 and 95% CI, 1.769-14.727; P=0.003) were independently associated with overall survival (OS), while pre-RT TS (OR, 2.148 and 95% CI, 1.221-3.810; P=0.009), mid-RT TV (OR, 3.106 and 95% CI, 1.685-5.724; P<0.0001) and SCCRR (OR, 1.954 and 95% CI, 1.133 3.369; P=0.016) were associated with progression-free survival (PFS). Based on the prognostic factor analysis, patients with the highest prognostic risk score of 3 showed poorer overall survival and progression free survival than patients with lower prognostic risk scores. CONCLUSION: We identified that tumour parameters such as TVRR, SCCRR, pre-RT TS, and mid-RT TV areindependent and strong prognostic parameters for patients with cervical cancer receiving RT. This scoring system-based prognostic factor analysis could be used to help develop optimized treatment plans for cervical cancer patients during RT. PMID- 29110879 TI - A diagnostic approach to bone tumours. AB - In this review we discuss an approach to diagnosing primary bone tumours, namely the cartilaginous, bone-forming, giant cell-rich, fibro-osseous and round cell neoplasms. Less common lesions including chordoma are also discussed. The value of integrating clinical, histopathological and relevant radiological features is emphasised with a view to providing the general histopathologist with a methodical approach to reaching an accurate diagnosis. PMID- 29110880 TI - Primary pulmonary myxoid sarcoma, a potential mimic of metastatic extraskeletal myxoid chondrosarcoma. PMID- 29110882 TI - Substantial disease exacerbation in a patient with relapsing-remitting multiple sclerosis after withdrawal from siponimod. AB - Among patients with multiple sclerosis, discontinuing highly effective disease modifying treatments can potentially lead to severe disease recurrence, especially cessation of natalizumab and fingolimod. Similar to fingolimod, siponimod is a sphingosine-1-phosphate receptor modulator that inhibits the egress of a lymphocyte subpopulation from lymph nodes. In the present case report, we describe a patient with MS who experienced substantial disease exacerbation after withdrawal from siponimod. PMID- 29110881 TI - The influence of microorganisms in allergic diseases. PMID- 29110883 TI - Linear and nonlinear parameters of heart rate variability in ischemic stroke patients. AB - INTRODUCTION: Cardiovascular system presents cortical modulation. Post-stroke outcome can be highly influenced by autonomic nervous system disruption. Heart rate variability (HRV) analysis is a simple non-invasive method to assess sympatho-vagal balance. OBJECTIVES: The purpose of this study was to investigate cardiac autonomic activity in ischemic stroke patients and to asses HRV nonlinear parameters beside linear ones. METHODS: We analyzed HRV parameters in 15 right and 15 left middle cerebral artery ischemic stroke patients, in rest condition and during challenge (standing and deep breathing). Data were compared with 15 age- and sex-matched healthy controls. RESULTS: There was an asymmetric response after autonomic stimulation tests depending on the cortical lateralization in ischemic stroke patients. In resting state, left hemisphere stroke patients presented enhanced parasympathetic control of the heart rate (higher values for RMSSD, pNN50 and HF in normalized units). Right hemisphere ischemic stroke patients displayed a reduced cardiac parasympathetic modulation during deep breathing test. Beside time and frequency domain, using short-term ECG monitoring, cardiac parasympathetic modulation can also be assessed by nonlinear parameter SD1, that presented strong positive correlation with time and frequency domain parameters RMSSD, pNN50, HFnu, while DFA alpha1 index presented negative correlation with the same indices and positive correlation with the LFnu and LF/HF ratio, indicating a positive association with the sympatho-vagal balance. CONCLUSIONS: Cardiac monitoring in clinical routine using HRV analysis in order to identify autonomic imbalance may highlight cardiac dysfunctions, thus helping preventing potential cardiovascular complications, especially in right hemisphere ischemic stroke patients with sympathetic hyperactivation. PMID- 29110884 TI - Looking back to go forward: Promoting single case studies. PMID- 29110885 TI - The NIH Science of Behavior Change Program: Transforming the science through a focus on mechanisms of change. AB - The goal of the NIH Science of Behavior Change (SOBC) Common Fund Program is to provide the basis for an experimental medicine approach to behavior change that focuses on identifying and measuring the mechanisms that underlie behavioral patterns we are trying to change. This paper frames the development of the program within a discussion of the substantial disease burden in the U.S. attributable to behavioral factors, and details our strategies for breaking down the disease- and condition-focused silos in the behavior change field to accelerate discovery and translation. These principles serve as the foundation for our vision for a unified science of behavior change at the NIH and in the broader research community. PMID- 29110886 TI - The Incidence of Primary vs Secondary Focal Segmental Glomerulosclerosis: A Clinicopathologic Study. AB - OBJECTIVES: To describe the change in the incidence rates of primary and secondary focal segmental glomerulosclerosis (FSGS) from 1994 through 2013 in Olmsted County, Minnesota, and to identify the clinical and biopsy characteristics that distinguish primary from secondary FSGS. PATIENTS AND METHODS: Olmsted County adult residents with native kidney biopsy from January 1, 1994, through December 31, 2013, and FSGS as the only glomerulopathy were identified. The clinical and pathologic characterstics of primary and secondary FSGS were described and compared, and incidence rates were calculated. RESULTS: Of 370 adults biopsied, 281 had glomerular diseases, of which 46 (16%) had FSGS. From 1994-2003 to 2004-2013, there were significant increases in kidney biopsy rates (14.7 [95% CI, 12.1-17.3] vs 22.9 [95% CI, 20.0-25.7] per 100,000 person years, 17% increase per 5 years; P<.001) and total FSGS rates (1.4 [95% CI, 0.6 2.2] vs 3.2 [95% CI, 2.1-4.3] per 100,000 person-years, 41% increase per 5 years; P=.02). Compared with patients with limited foot process effacement (<80%), patients with diffuse effacement (>=80%) without an identifiable cause had lower serum albumin levels (P<.001), had higher proteinuria (P<.001), and were more likely to have nephrotic syndrome (100% vs 4%; P<.001). Patients with diffuse effacement without an identifiable cause were classified as primary FSGS, which accounted for 3 of 12 patients (25%) during 1994-2003 and 9 of 34 (26%) during 2004-2013. CONCLUSION: Although the incidence of FSGS has increased, the proportions of primary and secondary FSGS have remained stable. PMID- 29110887 TI - Managing Peripheral Facial Palsy. PMID- 29110888 TI - [Knowledge and attitudes of health professionals towards advance directives]. AB - OBJECTIVE: To evaluate the degree of knowledge and attitudes of medical and nursing professionals in two health departments to advance directives, as well as to examine their association with the sociodemographic and occupational variables of the professionals. METHODS: A cross-sectional survey on 329 health professionals was carried out through the internet and a standardised procedure. The knowledge and attitudes of the professionals about advance directives were examined using two validated questionnaires of 17 and 12 items, respectively. Sociodemographic and professional data were also collected from the participants. RESULTS: 45% of the professionals were physicians, with X-=13,1 (SD: 8.3) years of professional experience. Sixty-seven point five percent were women and the mean age was 38.9 (SD: 9.2) years. Professionals had very positive attitudes towards the advance directives document (X-=75.37;SD: 11.97;R=0-90), although their level of knowledge about them was medium-low (X-=9.31;SD: 2.73;R=0-18). Both the level of knowledge and self-perception were associated with previous training in palliative care, experience with document management, reading, or the demand for information. Completing the document related to self-perception of knowledge. Attitudes towards the document related to experience in its use and a positive attitude toward training. CONCLUSIONS: The professionals showed positive attitudes towards the advance directive document although low knowledge about it. Experience with the document was the only variable associated with both the knowledge and the attitudes of the professionals. PMID- 29110889 TI - A risk adjustment approach to estimating the burden of skin disease in the United States. AB - Direct insurance claims tabulation and risk adjustment statistical methods can be used to estimate health care costs associated with various diseases. In this third manuscript derived from the new national Burden of Skin Disease Report from the American Academy of Dermatology, a risk adjustment method that was based on modeling the average annual costs of individuals with or without specific diseases, and specifically tailored for 24 skin disease categories, was used to estimate the economic burden of skin disease. The results were compared with the claims tabulation method used in the first 2 parts of this project. The risk adjustment method estimated the direct health care costs of skin diseases to be $46 billion in 2013, approximately $15 billion less than estimates using claims tabulation. For individual skin diseases, the risk adjustment cost estimates ranged from 11% to 297% of those obtained using claims tabulation for the 10 most costly skin disease categories. Although either method may be used for purposes of estimating the costs of skin disease, the choice of method will affect the end result. These findings serve as an important reference for future discussions about the method chosen in health care payment models to estimate both the cost of skin disease and the potential cost impact of care changes. PMID- 29110890 TI - Experience in the management of ECMO therapy as a mortality risk factor. AB - INTRODUCTION: The extracorporeal oxygenation membrane (ECMO) is a system that provides circulatory and respiratory assistance to patients in cardiac or respiratory failure refractory to conventional treatment. It is a therapy with numerous associated complications and high mortality. Multidisciplinary management and experienced teams increase survival. OBJECTIVE: Our purpose is to evaluate and analyse the effect of the learning curve on mortality. METHODS: Retrospective and observational study of 31 patients, from January 2012 to December 2015. Patients were separated into 2periods. These periods were divided by the establishment of an ECMO protocol. We compared the quantitative variables by performing the Mann-Whitney U test. For the categorical qualitative variables we performed the chi-square test or Fisher exact statistic as appropriate. The survival curve was computed using the Kaplan-Meier method, and the analysis of statistical significance using the Log-rank test. Data analysis was performed with the STATA programme 14. RESULTS: Survival curves show the tendency to lower mortality in the subsequent period (P=0.0601). The overall mortality rate in the initial period was higher than in the subsequent period (P=0.042). In another analysis, we compared the characteristics of the 2groups and concluded that they were homogeneous. CONCLUSION: The degree of experience is an independent factor for mortality. The application of a care protocol is fundamental to facilitate the management of ECMO therapy. PMID- 29110891 TI - How academic physicians can benefit from social media. PMID- 29110892 TI - Behaviour of trace metals in the anoxic environment of Veraval harbour, India. AB - The purpose of the present study is to investigate the behaviour of trace metals in anoxic environment. Water column of the harbour was found to be anoxic (DO <0.2mgl-1) with high concentration of NH4+-N (av. 459+/-21MUmoll-1) and H2S (av.73+/-2.5MUmoll-1) irrespective of season and tide. High concentrations of Fe, Mn in bottom water indicated that Fe, Mn were diagenetically mobilized under the anoxic conditions prevailing in the harbour. In harbour sediments significant correlation of metals with TOC and TS indicated their diagenetic immobilization in anoxic environment. Fe was positively correlated with TS suggesting FeS formation in anoxic condition. TOC/TN ratio of sediments was higher (16+/-5.2) than the normal marine planktonic sediments suggesting an increased burden of terrestrial carbon in the harbour. A sediment core collected 10km away from the shore indicated build-up of trace metals in recent years, showing diagenetically upward movement of metals. PMID- 29110893 TI - Use of the sea hare (Aplysia fasciata) in marine pollution biomonitoring of harbors and bays. AB - Our study evaluated heavy metal concentrations in soft tissues of sea hare, Aplysia fasciata, from the Lower Laguna Madre, Texas. Heavy metals in tissues followed Se>As>Pb>Cd. Concentrations ranged As (BDL-28.08), Cd (BDL-5.50), Pb (BDL-12.85) and Se (4.25-93.43ppm). Median As, Cd, Pb, and Se tissue levels exceeded exposure levels. Significant relationships occurred in metal-metal (AsCd, AsPb, CdPb, CdSe, and PbSe), metal-tissue (significant Se uptake by inhalant and exhalant siphons and As in the hepatopancreas), and metal-metal within tissue (AsPb in the hepatopancreas and CdPb in the digestive cecum) analyses (p<0.05). Bioaccumulation factors (BAF) suggested the inhalant siphon, hepatopancreas, and digestive cecum function as macroconcentrators of Cd, hepatopancreas and digestive cecum as macroconcentrators of Pb, and all tissues were deconcentrators for As and Se. As a bioaccumulator of heavy metals, Aplysia was evaluated as a bioindicator of marine pollution in harbors and bays. PMID- 29110894 TI - Cadmium determination in Chilean blue mussels Mytilus chilensis: Implications for environmental and agronomic interest. AB - Cadmium is present in agricultural soil composition and is assimilated by plants. The mussel industry generates large volumes of calcareous valves as a byproduct of processing in factories. This solid waste is ground, stored and disposed of in the form of agricultural supplies near production areas in almost all regions of the world. Cd content was recorded in these calcareous substrate by-products of industrial processes. In this study, mussel shells were investigated in three areas in the sea of Chile; two areas with high aquaculture activity and one in a non-production area. Mass Spectrometry was used for [Cd] readings. There are no significant differences (p=0.92) in [Cd] between the studied areas. Additionally, the [Cd] observed in valves was also similar relative to different depths. The low [Cd] observed in valves (~0.014+/-0.0049mgCdkg-1 dry) suggests the potential use of this industrial byproduct in agricultural applications. PMID- 29110895 TI - Cadmium accumulation in edible flowering cabbages in the Pearl River Delta, China: Critical soil factors and enrichment models. AB - Although many previous studies have reported the soil pH and organic matter to be the most critical factors that affect the transfer of Cd in soil-crop systems in temperate zones, the behavior of Cd transfer is different in the Pearl River Delta (PRD), which is located in a subtropical zone with different climate and soil conditions. Therefore, we must determine the critical environmental factors that influence the transfer of Cd in the soil-vegetable system in the PRD region. Such knowledge can improve the safety of vegetables. In this study, the soil geochemical properties are investigated to explore the key soil factors that control the uptake of Cd by flowering cabbage, a popular leaf vegetable in China, from soils in the PRD region. The Cd contents in vegetables were most positively correlated to soil oxalate-Cd (p < 0.01), which indicates that amorphous Cd is the most available form for uptake into the cabbages. With the characteristics of rich in Fe oxide and Al oxide in the PRD soils, soil Fe and Al oxides were found to be the most relevant to the transfer factors of Cd from the soils to the cabbages. Soil secondary minerals are the key factor that affects the transfer of Cd, thereby influencing the migration and fate of Cd in soil-cabbage systems, with DCB-Fe significantly decreasing the Cd accumulation in cabbages. Additionally, models were developed to predict the enrichment of Cd in flowering cabbages, in which oxalate-Cd, DCB-Fe, and NaOAc-Al in soils were determined to be the most important factors that affect the Cd enrichment in flowering cabbages. In this study, we determine the important role of soil secondary minerals in affecting the transfer of Cd in soil-cabbage systems in the PRD. These observations are important to evaluate the accumulation of Cd in vegetables in subtropical zones. PMID- 29110897 TI - Iatrogenic lesions of soft tissue and bone. PMID- 29110896 TI - New year's greetings. PMID- 29110898 TI - Successful pregnancies from vitrified embryos in the dromedary camel: Avoidance of a possible toxic effect of sucrose on embryos. AB - Successful embryo cryopreservation facilitates the wider application of assisted reproduction technologies and also provides a useful method for gene banking of valuable genetics. Unfortunately attempts to establish an effective cryopreservation protocol for camelid embryos have been unsuccessful. In the current study, a modified vitrification protocol with three steps was investigated, whereby embryos were exposed to solutions containing increasing amounts of glycerol and ethylene glycol for fixed time periods. Embryos were then loaded into an Open Pull Straw (OPS) and plunged directly into liquid nitrogen for storage. Three experiments were designed to investigate the effect of 1) artificial shrinkage (AS) of embryos, 2) the addition of sucrose to the vitrification solutions, and 3) the replacement of sucrose by galactose in the warming solution, on the outcome of vitrification. The results showed that neither AS of hatched embryos prior to vitrification, nor the addition of sucrose into vitrification solutions improves the outcome of vitrification, while replacement of sucrose with galactose in warming solution increases the survival and developmental rates of vitrified embryos in culture. Transfer of vitrified embryos that were warmed in galactose resulted in a pregnancy rate of 42.8% per embryo or 46.1% per recipient. Collectively, these results suggest a possible species-specific toxic effect of sucrose on camel embryos, and that avoiding its use either in vitrification or warming solution is critical for establishing an effective protocol. This study may also be applicable to the vitrification of embryos of other camelid species including alpaca and llamas. PMID- 29110900 TI - Evaluation of novel chemical additive that colorizes chlorine-based disinfectants to improve visualization of surface coverage. PMID- 29110899 TI - The Role of the Hippocampus in Predicting Future Posttraumatic Stress Disorder Symptoms in Recently Traumatized Civilians. AB - BACKGROUND: Understanding the neurobiological mechanisms that predict posttraumatic stress disorder (PTSD) in recent trauma survivors is important for early interventions. Impaired inhibition of fear or behavioral responses is thought to be central to PTSD symptomatology, but its role in predicting PTSD is unknown. Here we examine whether brain function during response inhibition early after a civilian trauma can predict future PTSD symptoms. METHODS: Participants (original sample, n = 27; replication sample, n = 31) were recruited in the emergency department within 24 hours of trauma exposure. PTSD symptoms were assessed in the emergency department and 1, 3, and 6 months posttrauma. A Go/NoGo procedure in a 3T magnetic resonance imaging scanner was used to measure neural correlates of response inhibition 1 to 2 months posttrauma. Elastic net regression was used to define the most optimal model to predict PTSD symptoms at 3 and 6 months among demographic, clinical, and imaging measures. RESULTS: Less hippocampal activation was a significant predictor in the model predicting PTSD symptoms at 3 months (F11,22 = 4.33, p = .01) and 6 months (F9,19 = 4.96, p = .01). Other significant predictors in the model were race and pain level in the emergency department (3 months), and race and baseline depression symptoms (6 months). Using these predictors in a linear regression in the replication sample again resulted in significant models (3 months [F3,23 = 3.03, p = .05], 6 months [F3,20 = 5.74, p = .007]) with hippocampal activation predicting PTSD symptoms at 3 and 6 months. CONCLUSIONS: Decreased inhibition-related hippocampal activation soon after trauma predicted future PTSD symptom severity. This finding may contribute to early identification of at-risk individuals and reveals potential targets for intervention or symptom prevention in the aftermath of trauma. PMID- 29110901 TI - Gut microbiota and obesity: Concepts relevant to clinical care. AB - The composition and function of gut microbiota play a role in obesity and metabolic disease, yet the mechanisms have not been fully described. As new discoveries and advances in the field have occurred, the relevance of gut microbiota in clinical care has become more substantial. There is promising potential for manipulation of the gut microbiota as treatment of obesity and associated health complications, both as a standalone therapy and as part of interventions such as weight loss. In this review we have compiled knowledge and concepts that are important in the consideration of gut microbiota for clinical care. PMID- 29110902 TI - [Endometrial cancer: Predictive models and clinical impact]. AB - In France, in 2015, endometrial cancer (CE) is the first gynecological cancer in terms of incidence and the fourth cause of cancer of the woman. About 8151 new cases and nearly 2179 deaths have been reported. Treatments (surgery, external radiotherapy, brachytherapy and chemotherapy) are currently delivered on the basis of an estimation of the recurrence risk, an estimation of lymph node metastasis or an estimate of survival probability. This risk is determined on the basis of prognostic factors (clinical, histological, imaging, biological) taken alone or grouped together in the form of classification systems, which are currently insufficient to account for the evolutionary and prognostic heterogeneity of endometrial cancer. For endometrial cancer, the concept of mathematical modeling and its application to prediction have developed in recent years. These biomathematical tools have opened a new era of care oriented towards the promotion of targeted therapies and personalized treatments. Many predictive models have been published to estimate the risk of recurrence and lymph node metastasis, but a tiny fraction of them is sufficiently relevant and of clinical utility. The optimization tracks are multiple and varied, suggesting the possibility in the near future of a place for these mathematical models. The development of high-throughput genomics is likely to offer a more detailed molecular characterization of the disease and its heterogeneity. PMID- 29110903 TI - Spinal dural arteriovenous fistulas: the most frequent vascular malformations of the spinal cord. AB - Spinal dural arteriovenous fistulas are produced by direct communication between the arterial and venous systems of the spinal cord, causing hypertension in the latter with spinal cord dysfunction. It is a rare pathology with unknown etiology and non-specific clinical symptoms that usually results in a delayed diagnosis. Often radiologists are the first to guide the disease towards an adequate diagnosis. Characteristic findings can be seen through MR or MR angiography, and may even locate the fistula in a high percentage of cases, although the pathology must be confirmed by spinal angiography. There are two treatment modalities: endovascular and surgical therapy. Endovascular treatment has improved in recent years with the advantages of a less invasive approach and is therefore usually chosen as primary therapy. In this article we review the main clinical manifestations, imaging findings and treatment of this pathology. PMID- 29110904 TI - Retention of gadolinium compounds used in magnetic resonance imaging: a critical review and the recommendations of regulatory agencies. AB - The Spanish Agency for Drugs and Healthcare Products (AEMPS), based on the recommendations of the European Committee for Risk Assessment in Pharmacovigilance, established on 13 March 2017 that linear gadolinium-based MR contrast media, such as MultiHance, Omniscan, Magnevist (currently not marketed) and Optimark (no longer marketed in Spain), the clinical benefits do not outweigh the potential risks derived from their use. AEMPS recommends to suspend its marketing for general use based on the retention of these compounds in the brain. On the other hand, the AEMPS justifies the maintenance of Primovist and MultiHance for liver studies, and Magnevist of intra-articular administration (not commercialized in Spain), and justified the almost exclusive use of macrocyclic structure contrasts (Gadovist, ProHance and Dotarem). However, this retention is known to be different for each of the contrast media. All existing gadolinium contrasts agents have a distribution phase with tissue retention, due to a very slow exchange, in the interstitium of bone, skin, kidney, brain and other organs. The existence of histological effects or clinical symptoms associated with the accumulation of these trace amounts of gadolinium has not been demonstrated. The major toxicological concern with these contrast agents is related to nephrogenic systemic fibrosis (NSF). Since the safety profiles are mainly related to the interstitial retention space in the tissues, it does not seem justified to actually exclude contrast media that do not have cases related to the NSF. Based on all of this, we disagree with the latest AEMPS recommendation suggesting the marketing stoppage of linear agents without considering the individual retention profiles. This recommendation is not based neither on the data nor existing knowledge about the retention, relaxivity and clinical efficiency of the Gd compounds. It is therefore necessary to carry out prospective studies on the histological and clinical relevance of these organic Gd deposits. PMID- 29110905 TI - Extra-articular hip impingement: a review of the literature. AB - Hip and groin pain is a common clinical problem. Multiple causes can generate hip or groin pain, often sharing clinical and demographic characteristics. Diagnostic imaging tests play an important role in the etiological diagnosis. New forms of extra-articular hip impingement have recently been recognized as a cause of hip pain and limited function especially in young active patients. These conditions include ischiofemoral impingement, anterior inferior iliac spine and subspine impingement, iliopsoas impingement and greater trochanteric-pelvic impingement. In general, they are caused by a mechanical conflict with an abnormal or excessive contact between the proximal femur and pelvis and/or soft tissue between them. In this manuscript we review the physiopathology, clinical presentation, the most common radiologic findings and treatment of these forms of extra-articular hip impingement. PMID- 29110906 TI - Memory-focused interventions for people with cognitive disorders: A systematic review and meta-analysis of randomized controlled studies. AB - BACKGROUND: A better understanding of people with cognitive disorders improves performance on memory tasks through memory-focused interventions are needed. OBJECTIVES: The purpose of this study was to assess the effect of memoryfocused interventions on cognitive disorders through a meta-analysis. DESIGN: Systematic review and meta-analysis. DATA SOURCES: The online electronic databases PubMed, the Cochrane Library, Ovid-Medline, CINHAL, PsycINFO, Ageline, and Embase (up to May 2017) were used in this study. No language restriction was applied to the search. REVIEW METHODS: Objective memory (learning and memory function, immediate recall, delayed recall, and recognition) was the primary indicator and subjective memory performance, global cognitive function, and depression were the secondary indicators. The Hedges' g of change, subgroup analyses, and meta-regression were analyzed on the basis of the characteristics of people with cognitive disorders. RESULTS: A total of 27 studies (2177 participants, mean age=75.80) reporting RCTs were included in the meta-analysis. The results indicated a medium-to-large effect of memory-focused interventions on learning and memory function (Hedges' g=0.62) and subjective memory performance (Hedges' g=0.67), a small-to-medium effect on delayed recall and depression, and a small effect on immediate recall and global cognitive function (all p<0.05) compared with the control. Subgroup analysis and meta-regression indicated that the effects on learning and memory function were more profound in the format of memory training, individual training, shorter treatment duration, and more than eight treatment sessions, and the effect size indicated the MMSE score was the most crucial indicator (beta= 0.06, p=0.04). CONCLUSIONS: This is first comprehensive meta-analysis of special memory domains in people with cognitive disorders. The results revealed that memory-focused interventions effectively improved memory-related performance in people with cognitive disorders. An appropriately designed intervention can effectively improve memory function, reduce disability progression, and improve mood state in people with cognitive disorders. Additional randomized controlled trials including measures of recognition, global cognitive function, and depression should be conducted and analyzed. PMID- 29110907 TI - What is the impact of professional nursing on patients' outcomes globally? An overview of research evidence. AB - BACKGROUND: Nursing is an integral part of all healthcare services, and has the potential of having a wide and enduring impact on health outcomes for a global ageing population. Over time nurses have developed new roles and assumed greater responsibilities. It is increasingly important to demonstrate the safety and overall impact of nurses' practice through research, to support the case for greater investment and development of nursing services around the world. OBJECTIVE: To provide an overview of existing research evidence on the impact of nursing on patient outcomes, identify gaps in evidence, and point to future priorities for global research. Specifically to address two questions: what is the evidence that nursing contributes to improving the health and well-being of populations?; and where should research activity be focused to strengthen the evidence base for the impact of nursing? METHODS: A search of the literature from 1996 using CINAHL, MEDLINE, the Cochrane Library, Google Scholar and the NICE evidence databases using the key words: nursing, nurse led, nursing interventions and patient outcomes. Initial analysis of the retrieved citations to reveal clusters of evidence of nursing impact in clinical areas which had been subject to systematic/integrative reviews or meta-analyses. Further analysis of these reviews to provide an overview of the research evidence for nurses' contributions to healthcare to inform discussion on future research agendas. We use the terms low, moderate and high quality evidence to reflect the assessments made by the review authors whose work is presented throughout. RESULTS: Analysis of 61 reviews, including ten Cochrane reviews and two scoping/selective reviews to provide a summary of the research evidence for nurses' contributions to healthcare in the following areas of practice: nursing in acute care settings; nurses' involvement in public health; the contribution of specialist nurse and nurse-led services to the management of chronic disease; comparison of care provided by nurses and doctors; and task shifting to invasive procedures. CONCLUSIONS: There is evidence that adequate numbers of well-educated nurses working in acute care areas can reduce the risk of patient mortality, although the evidence for this is confined to studies in high income countries and the evidence is not sufficiently robust to draw up definitive nurse: patient ratios. There is also moderate evidence that well trained nurses can produce health outcomes that are equivalent to those of doctors for patients with a range of chronic health problems, particularly for those patients managed in primary care, and that nurse-led care may be more effective than medical care in promoting patient adherence to treatment and patient satisfaction. There is low to moderate evidence for the benefits of parenting support programmes delivered by nurses on a range of health outcomes; and for the impact of home visiting on improving function and other health service outcomes for older people. The wider societal benefits of home visiting by nurses and the impact of this on long term outcomes and related cost-effectiveness of home visiting has not been established. There is limited available information regarding the wider global impact of increasing the numbers of nurses and their contribution to healthcare through improved education. Moreover there is very little evidence for the cost-effectiveness of changing care providers from doctors to nurses and as the majority of cost data available has tended to come from studies based in higher income countries, their external validity in terms of applicability to settings in low and middle income countries is questionable. In addition to effectiveness, cost and safety, future research needs to address how implementing expanded nursing roles and task shifting impacts on the morale, retention, and professional development of nurses and the other workforces, and the longer term implications of these developments both locally and internationally. PMID- 29110908 TI - Corrigendum to "MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism" [Exp. Cell Res. (2017) 292-302]. PMID- 29110909 TI - Radiologists Are Actually Well Positioned to Innovate in Patient Experience. AB - Patient experience is becoming increasingly prioritized, most notably as a component of recently passed health care legislation that aims to link physician reimbursement to quality of care and cost-effectiveness. For several reasons, radiologists are better positioned to seize opportunities to enhance patient experience than is readily apparent. We propose that discrete components along the imaging value chain can be evaluated specifically for their effect on patient experience and improved to this end. We also emphasize that the field of radiology has traditionally been the earliest adopter and a serial innovator in health information technology, and we suggest possible ways to leverage the newest technological tools to improve patient experience. Finally, we discuss how carefully vetted opportunities for direct patient interaction might expand the reach of diagnostic radiologists as members of integrated health systems. We believe that emerging patient experience metrics present unconventional opportunities for radiologists to make imaging even more meaningful for the many patients who entrust us with their care. SIX SUMMARY POINTS. PMID- 29110910 TI - Treatment of giant cell tumor of distal radius with limited soft tissue invasion: Curettage and cementing versus wide excision. AB - BACKGROUND: Intralesional curettage and adjuvant versus wide en bloc excision (WEE) as the best treatment method of giant cell tumor (GCT) of distal radius with limited soft tissue extension is a controversial topic. METHODS: Prospectively, 13 patients who had GCT of distal radius with perforation of either volar or dorsal cortex of the bone and soft tissue extension which was confined to one plane were enrolled in the study. Six patients treated with ICC and seven cases cured by WEE technique and proximal fibular arthroplasty. The results were evaluated based on recurrence, range of motion of the wrist joint, rotation of the forearm, grip and pinch power. RESULTS: The mean age of the patients treated with ICC and WEE techniques were 32.7 (range: 23-43) and 34.5 (range: 28-44), respectively. Mean follow-up period was 72 months (range: 28 148). Local recurrence was seen in 4 of 6 patients (66.7%) underwent ICC technique but in none of the 7 subjects treated with WEE technique (P value = 0.021). The overall range of flexion/extension and supination/pronation in the WEE group were 83% and 92% of the ICC group, respectively. Both of pinch and grip power were 14% less in the WEE group compared to the ICC group. CONCLUSIONS: In GCT lesion of distal radius even with limited soft tissue extension, WEE and proximal fibular arthroplasty may be a more reasonable suggestion when the patient seeks a one-shot surgery. PMID- 29110911 TI - Blau syndrome with good Reponses to Tocilizumab: A case report and focused literature review. AB - OBJECTIVES: Blau syndrome (BS), a rare auto-inflammatory granulomatous disease, is a progressive disorder. Usually the maintenance dose of glucocorticoid may not be tapered below 15 mg per day while immunosuppressives is used. There has been some experience with biologic agents in refractory BS patients. The objective of this study is to describe the case of a BS patient benefiting from Tocilizumab, a humanized monoclonal antibody against interleukin 6 receptor. METHODS: We report the first Chinese patient with BS who was resistant to currently available therapies but had rapid quiescence after using Tocilizumab. We also conducted a systematic literature review about the current treatments of BS. RESULTS: A 13 year-old Chinese boy with BS, whose uveitis got worsened when treated with Infliximab, was well-controlled after taking Tocilizumab and prednisone was tapered off to a dose of 8mg per day. We identified 29 manuscripts providing 45 BS cases. Among these patients, 24 underwent biological treatments and 22 of them recovered. In these 29 manuscripts, the biological agents used to treat refractory BS included Etanercept, Infliximab, Adalimumab, Canakinumab and Anakinra. CONCLUSIONS: Case reports on the use of biological agents have yielded mixed results. The diversity of the symptoms may be due to functional differences in NOD2 mutations. For BS patients with fever, lymphadenopathy and hepatosplenomegaly, Tocilizumab may be a better choice. PMID- 29110912 TI - In Reply to Drs Lipman and Hackett. PMID- 29110913 TI - Pristinamycin-induced arthralgia and myalgia: Analysis of the French Pharmacovigilance Database. AB - INTRODUCTION: Pristinamycin is an antibiotic of the streptogramin family; few adverse effects of this drug are reported, only cutaneous and digestive ones. Arthralgia and myalgia may however be observed although not mentioned in the summary of product characteristics. OBJECTIVE: Description and analysis of cases of pristinamycin-induced arthralgia and/or myalgia registered in the French database of pharmacovigilance. METHOD: We carried out a targeted search of the database, selecting case patients presenting with arthralgia and muscle pain and excluding those associated with sensitivities or allergies to pristinamycin. RESULTS: We retrieved 15 case patients of pristinamycin-induced arthralgia and myalgia. Pristinamycin was the only potentially incriminated drug for seven case patients. CONCLUSION: Although not serious, this adverse effect deserves to be better known by physicians to optimize therapeutic management. PMID- 29110914 TI - [Multifocal tuberculosis with involvement of the calvaria diagnosed by molecular biology]. PMID- 29110915 TI - Plain Language and Health Literacy for the Oncology Family Caregiver: Examining an English/Spanish mHealth Resource. AB - OBJECTIVES: To explore an mHealth resource to support the limited-English proficient cancer family caregiver. DATA SOURCES: Structured interviews with oncology clinic providers to assess a nurse-delivered resource to support health literacy and decision-making along the cancer trajectory. CONCLUSION: Limitations in communicating about oncology care with limited-English caregivers is evident. The mHealth resource examined here shows promise to improve relational health literacy between the oncology nurse and family caregiver. IMPLICATIONS FOR NURSING PRACTICE: Communicating with limited-English-proficient family caregivers invites oncology nurses to seek out resources to create shared understanding. PMID- 29110916 TI - Kidney transplantation in the Intensive Care Unit: Graft evaluation using imaging tests. PMID- 29110917 TI - Response to the letter to the editor regarding comment on: "The outcomes of overlay myringoplasty: Endoscopic versus microscopic approach". PMID- 29110918 TI - In response to the commentary of Dr. Lou on treatment of laryngopharyngeal reflux using a sleep positioning device: A prospective cohort study. PMID- 29110919 TI - Effects of intratympanic dexamethasone on noise-induced hearing loss: An experimental study. AB - AIM: Aim of the study was to evaluate the effect of intratympanic steroid treatment on hearing based on oto-acoustic emission. METHODS: A total of 16 healthy female Wistar albino rats weighing were used in this study. They were divided in to 2 groups and each group was exposed to noise at 110dB for 25min to induce acoustic trauma. Intratympanic dexamethasone was administered to the middle ears of animals in the experimental group on the same day as exposure to noise. The control group was given 0.09% saline solution. Distortion product otoacoustic emission measurements were performed on days 7 and 10. RESULTS: There were no differences between the emission results of two groups before treatment at 4004, 4761, 5652, 6726, and 7996Hz. There were significant group differences on measurement days 7 and 10 at all frequencies. CONCLUSION: Our study revealed a significant difference in DPOAE measurements on days 7 and 10 between the experimental and control groups. We detected a positive effect of dexamethasone on noise-induced hearing loss. PMID- 29110920 TI - Flow generation by the corona ciliata in Chaetognatha - quantification and implications for current functional hypotheses. AB - The corona ciliata of Chaetognatha (arrow worms) is a circular or elliptical groove lined by a rim from which multiple lines of cilia emanate, located dorsally on the head and/or trunk. Mechanoreception, chemosensation, excretion, respiration, and support of reproduction have been suggested to be its main functions. Here we provide the first experimental evidence that the cilia produce significant water flow, and the first visualisation and quantification of this flow. In Spadella cephaloptera, water is accelerated toward the corona ciliata from dorsal and anterior of the body in a funnel-shaped pattern, and expelled laterally and caudally from the corona, with part of the water being recirculated. Maximal flow speeds were approximately 140MUms-1 in adult specimens. Volumetric flow rate was Q=0.0026MUls-1. The funnel-shaped directional flow can possibly enable directional chemosensation. The flow measurements demonstrate that the corona ciliata is well suited as a multifunctional organ. PMID- 29110922 TI - Cost-effectiveness of Trifluridine/tipiracil for Previously Treated Metastatic Colorectal Cancer in England and Wales. AB - BACKGROUND: Treatment options at third-line and beyond for patients with late line metastatic colorectal cancer (mCRC) are limited, and outcomes are poor with best supportive care (BSC). This study investigated the cost-effectiveness of trifluridine/tipiracil and regorafenib relative to BSC alone in patients with mCRC who have been previously treated with, or are not considered candidates for, standard chemotherapies. MATERIALS AND METHODS: A partitioned survival model was constructed to assess the lifetime costs and benefits accrued by patients. Clinical data were derived from the pivotal phase III (Randomized, Double-Blind, Phase 3 Study of TAS-102 plus Best Supportive Care [BSC] versus Placebo plus BSC in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapies [RECOURSE]) and supporting phase II (J003-10040030) randomized controlled trial of trifluridine/tipiracil + BSC versus placebo + BSC, as well as the phase III Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy (CORRECT) randomized controlled trial of regorafenib, and were extrapolated to estimate lifetime outcomes. Costs were taken from published sources, and health effects sourced from previous mCRC studies. RESULTS: Trifluridine/tipiracil was associated with a 0.27 incremental life year versus BSC alone, which corresponds to a 0.17 quality-adjusted life year gain. The incremental cost of treatment with trifluridine/tipiracil was L8,479, resulting in an incremental cost-effectiveness ratio of L51,194 per quality-adjusted life year gained. Trifluridine/tipiracil was shown to dominate regorafenib (improve outcomes with reduced costs). Sensitivity analyses showed principal areas of uncertainty were survival estimates and patient utility. CONCLUSIONS: The results show that trifluridine/tipiracil is more clinically and cost-effective than regorafenib, with clinical outcomes greatly exceeding those for patients treated with BSC alone. Based on the results of the analysis, trifluridine/tipiracil offers an important new treatment option for patients with mCRC maintaining good performance status at the end of life. PMID- 29110921 TI - 3D printed versus conventionally cured provisional crown and bridge dental materials. AB - OBJECTIVES: To optimize the 3D printing of a dental material for provisional crown and bridge restorations using a low-cost stereolithography 3D printer; and compare its mechanical properties against conventionally cured provisional dental materials. METHODS: Samples were 3D printed (25*2*2mm) using a commercial printable resin (NextDent C&B Vertex Dental) in a FormLabs1+ stereolithography 3D printer. The printing accuracy of printed bars was determined by comparing the width, length and thickness of samples for different printer settings (printing orientation and resin color) versus the set dimensions of CAD designs. The degree of conversion of the resin was measured with FTIR, and both the elastic modulus and peak stress of 3D printed bars was determined using a 3-point being test for different printing layer thicknesses. The results were compared to those for two conventionally cured provisional materials (Integrity(r), Dentsply; and Jet(r), Lang Dental Inc.). RESULTS: Samples printed at 90 degrees orientation and in a white resin color setting was chosen as the most optimal combination of printing parameters, due to the comparatively higher printing accuracy (up to 22% error), reproducibility and material usage. There was no direct correlation between printing layer thickness and elastic modulus or peak stress. 3D printed samples had comparable modulus to Jet(r), but significantly lower than Integrity(r). Peak stress for 3D printed samples was comparable to Integrity(r), and significantly higher than Jet(r). The degree of conversion of 3D printed samples also appeared higher than that of Integrity(r) or Jet(r). SIGNIFICANCE: Our results suggest that a 3D printable provisional restorative material allows for sufficient mechanical properties for intraoral use, despite the limited 3D printing accuracy of the printing system of choice. PMID- 29110923 TI - Malignant triton tumor of the gluteal region in a patient unaffected by neurofibromatosis: A case report. AB - Malignant triton tumor (MTT) is a rare variant of malignant peripheral nerve sheath tumor (MPNST) made up of both malignant schwannoma cells and malignant rhabdomyoblasts. A 26-years-old male patient was admitted with an asymptomatic gluteal mass. Magnetic resonance imaging showed heterogeneous soft tissue mass and he underwent open biopsy. Malignant peripheral nerve sheath tumor was diagnosed. He was given adjuvant chemotherapy following the removal of the tumor with hip disarticulation. The tumor was diagnosed as "malignant triton tumor" based on pathological examination including immunohistochemical studies. There were no signs of metastasis but recurrence was observed at 9 months follow up. MTT is usually associated with Neurofibromatosis 1 and located in head, neck region. In this case sporadic involvement of gluteal region and aggressive behavior of the lesion despite radical surgery was demonstrated. PMID- 29110924 TI - Intramedullary elastic nailing of the displaced radial neck fractures in children. AB - OBJECTIVE: The aim of this study was to report the clinical and radiological results of 11 patients with Judet type 3 severely displaced radial neck fractures, who were treated with intramedullary elastic nail fixation with the help of percutaneous K-wire reduction maneuver (Metaizeau technique). METHODS: A total of 11 children (4 boys and 7 girls with a mean age of 7.7 (6-10) years) with Judet type 3 radial neck fractures were treated in our clinic between February 2013 and August 2015. The fractures were evaluated according to Judet classification system modified by Metaizeau. Reduction and fixation was performed within the first 24 h after injury in all patients. All fractures were treated by closed reduction using distal elastic intramedullary nail. Clinical evaluation was performed by measuring elbow range of motion (ROM) with goniometer, radiological evaluation by assessing fracture healing and functional evaluation by using Mayo Elbow Performance Score (MEPS). RESULTS: The mean MEPS score increased from 15 points preoperatively to 88 points postoperatively (range, 12 95 points). Radiological evaluation revealed that all fractures healed with excellent or good alignment. The mean flexion was 150 degrees (range, 145-154 degrees ), extension 1 degrees (range, 0-2 degrees ), supination 82 degrees (range, 80-86 degrees ), and pronation 83 degrees (range, 80-85 degrees ). CONCLUSION: Reduction and osteosynthesis of radial neck fractures by intramedullary nailing with the help of percutaneous K-wire manipulation appears to be a simple, safe and effective treatment method in children. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 29110925 TI - A novel IMRT planning study by using the fixed-jaw method in the treatment of peripheral lung cancer with mediastinal lymph node metastasis. AB - Intensity-modulated radiotherapy (IMRT) is an important technology in cancer radiotherapy. In the current planning system, such as in the Pinnacle3 system, jaw positions are automatically set to cover all target volumes, and many medical centers in developing countries are not equipped with linear accelerators with a jaw tracing function. As solitary lesions are often located in patients, the resulting radiation leakage and transmission increase the dose exposure in surrounding critical organs, although blocked by multileaf collimator (MLC) leaves. We therefore designed a method to manually fix jaw positions, which further reduces doses. We particularly focused on the patients of peripheral lung cancer combined with mediastinal lymph node metastasis, as our medical center mainly targets lung cancer. We designed 2 treatment plans for each patient with the same optimization parameters, i.e., the plan of automatically chosen jaw positions (jaw auto-chosen plan) and the plan of fixed-jaw positions (fixed-jaw plan). In the latter plan, jaws were manually fixed for tumors in lung and in mediastinal lymph node metastases, respectively. We found that both plans met the clinical requirements, and the D2, D98, conformation number (CN), and homogeneity index (HI) for planning target volume (PTV) had no significant differences between the 2 plans. Importantly, the machine units (MUs) for fixed-jaw plans were 50%~60% more than routine jaw auto-chosen plans, whereas the V5, V10, V20, V30, and the mean dose in the total lung and the ipsilateral lung were less than the routine jaw auto-chosen plans. Dose-volume values D1 for the spinal cord and D2, V40, V60 for the heart existed no significant differences for 2 plans. In the fixed-jaw method, the total lung TLV5-?Vab and TLV10-?Vab values had a moderate positive correlation with the lung radiation leakage and the transmission area reduction. We concluded that the fixed-jaw plan is superior to the routine jaw auto-chosen plan in reducing the radiation exposure of surrounding critical organs, which will benefit the IMRT application. PMID- 29110927 TI - Fever of unknown origin in a laboratory worker. PMID- 29110926 TI - Study for reducing lung dose of upper thoracic esophageal cancer radiotherapy by auto-planning: volumetric-modulated arc therapy vs intensity-modulated radiation therapy. AB - This study aimed to investigate the dosimetric differences and lung sparing between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) in the treatment of upper thoracic esophageal cancer with T3N0M0 for preoperative radiotherapy by auto-planning (AP). Sixteen patient cases diagnosed with upper thoracic esophageal cancer T3N0M0 for preoperative radiotherapy were retrospectively studied, and 3 plans were generated for each patient: full arc VMAT AP plan with double arcs, partial arc VMAT AP plan with 6 partial arcs, and conventional IMRT AP plan. A simultaneous integrated boost with 2 levels was planned in all patients. Target coverage, organ at risk sparing, treatment parameters including monitor units and treatment time (TT) were evaluated. Wilcoxon signed-rank test was used to check for significant differences (p < 0.05) between datasets. VMAT plans (pVMAT and fVMAT) significantly reduced total lung volume treated above 20 Gy (V20), 25 Gy (V25), 30 Gy (V30), 35 Gy (V35), 40 Gy (V40), and without increasing the value of V10, V13, and V15. For V5 of total lung value, pVMAT was similar to aIMRT, and it was better than fVMAT. Both pVMAT and fVMAT improved the target dose coverage and significantly decreased maximum dose for the spinal cord, monitor unit, and TT. No significant difference was observed with respect to V10 and V15 of body. VMAT AP plan was a good option for treating upper thoracic esophageal cancer with T3N0M0, especially partial arc VMAT AP plan. It had the potential to effectively reduce lung dose in a shorter TT and with superior target coverage and dose homogeneity. PMID- 29110928 TI - Direct bacterial identification from positive blood cultures using matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry: A systematic review and meta-analysis. AB - INTRODUCTION: The rapid identification of bacteraemia-causing pathogens could assist clinicians in the timely prescription of targeted therapy, thereby reducing the morbidity and mortality of this infection. In recent years, numerous techniques that rapidly and directly identify positive blood cultures have been marketed, with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) being one of the most commonly used. METHODS: The aim of this systematic review and meta-analysis was to evaluate the accuracy of MALDI TOF (Bruker(r)) for the direct identification of positive blood culture bottles. RESULTS: A meta-analysis was performed to summarize the results of the 32 studies evaluated. The overall quality of the studies was moderate. For Gram-positive bacteria, overall rates of correct identification of the species ranged from 0.17 to 0.98, with a cumulative rate (random-effects model) of 0.72 (95% CI: 0.64 0.80). For Gram-negative bacteria, correct identification rates ranged from 0.66 to 1.00, with a cumulative effect of 0.92 (95% CI: 0.88-0.95). For Enterobacteriaceae, the rate was 0.96 (95% CI: 0.94-0.97). CONCLUSION: MALDI-TOF mass spectrometry shows high accuracy for the correct identification of Gram negative bacteria, particularly Enterobacteriaceae, directly from positive blood culture bottles, and moderate accuracy for the identification of Gram-positive bacteria (low for some species). PMID- 29110929 TI - Reply to "Observations on native valve endocarditis caused by Kocuria kristinae". PMID- 29110931 TI - Publication of Vascular Surgical Registry Data: Strengths and Limitations. PMID- 29110930 TI - Determinants of Acute Kidney Injury and Renal Function Decline After Endovascular Abdominal Aortic Aneurysm Repair. AB - OBJECTIVE/BACKGROUND: Endovascular aneurysm repair (EVAR) may be associated with renal injury and more insight is needed into potential risk factors. The aim was to identify clinical, anatomical, and peri-procedural parameters as potential risk factors for the occurrence of acute kidney injury (AKI) and to evaluate chronic kidney disease (CKD) after EVAR. METHODS: A cohort of 212 consecutive patients who underwent elective EVAR for abdominal aortic aneurysm from January 2009 to October 2016 was included. A subgroup of 149 patients with 2 years follow up was compared with a set of 135 non-operated aneurysm patients with smaller aneurysms (similar cardiovascular risk profile) to assess CKD. Primary outcomes were AKI (Acute Kidney Injury Network criteria) and CKD measured by estimated glomerular filtration rate (Kidney Disease Improving Global Outcomes guidelines). For AKI, candidate risk factors were identified by univariate and multivariate logistic regression analysis; for chronic renal function decline, risk factors were identified using Cox regression analysis. RESULTS: AKI occurred in 30 patients (15%). On multivariate analysis, the use of angiotensin II blocker (odds ratio [OR] 4.08, 95% confidence interval [CI] 1.38-12.07) and peri-operative complications (OR 3.12, 95% CI 1.20-8.10) were independent risk factors for AKI, whereas statin use was a protective factor (OR 0.19, 95% CI 0.07-0.52). EVAR resulted in a significant increase (23.5%) in the occurrence of CKD compared with the control group (6.7%; p <.001). On univariate and multivariate Cox regression the risk factors: aortic neck diameter (per mm increase) (hazard ratio [HR] 1.13, 95% CI 1.02-1.25), renal artery stenosis >50% (HR 2.24, 95% CI 1.05-4.79), and the occurrence of AKI (HR 2.19, 95% CI 0.99-4.85) were significant predictors of CKD. CONCLUSION: This study identified use of angiotensin II blockers and peri operative complications as risk factors for AKI. In addition, the problem of renal function decline after EVAR is highlighted, which indicates that prolonged protective measures (e.g., in those patients at high risk) over time are needed to improve patient outcomes. PMID- 29110932 TI - Dengue vaccine supplies under endemic and epidemic conditions in three dengue endemic countries: Colombia, Thailand, and Vietnam. AB - BACKGROUND: Dengue fever has been a major public health concern in Colombia, Thailand, and Vietnam. Unlike other infectious diseases, dengue vaccines had not been available for a long time, causing difficulties to control the disease. However, the first live attenuated, tetravalent dengue vaccine (CYD-TDV) became available in 2016 and has been already licensed in some dengue-endemic countries. Because several second-generation dengue vaccines are also in the pipeline, it is critical to understand the efficient allocation of dengue vaccines considering the geographical variation of the disease. METHODS: The Climate Risk Factor (CRF) index was created using the climate and non-climate factors in the three countries. A random-coefficient negative binomial model was chosen to validate the relationship between the CRF index and dengue incidence proxy. Given the statistical significance of the CRF index, high risk areas for dengue fever were identified at the 5 km by 5 km resolution and used to estimate vaccination coverage rates and the number of doses required for various types of vaccination scenarios by country. RESULTS AND CONCLUSIONS: Based upon a three-dose scheme, the estimated number of vaccines required for routine vaccination targeting 9 years old ranged from 1 to 2.6 million doses across the countries during the first year of introduction. A one-off catch-up campaign targeting the age group of 10-17 year olds would require 8 to 18 million additional doses. Routine vaccination (with or without a catch-up campaign) covered 63%, 90%, and 91% of the targeted age group populations in Colombia, Thailand, and Vietnam respectively. Given that many dengue-endemic countries face limited resources and that the costs for mass vaccination campaigns may not be trivial, the findings of this study can guide the decision makers in the three countries regarding the efficient distribution of vaccines by identifying populations at high risk at 5 km by 5 km resolution. PMID- 29110933 TI - Temporal association of rotavirus vaccination and genotype circulation in South Africa: Observations from 2002 to 2014. AB - BACKGROUND: Rotavirus vaccination has reduced diarrhoeal morbidity and mortality globally. The monovalent rotavirus vaccine was introduced into the public immunization program in South Africa (SA) in 2009 and led to approximately 50% reduction in rotavirus hospitalization in young children. The aim of this study was to investigate the rotavirus genotype distribution in SA before and after vaccine introduction. MATERIALS AND METHODS: In addition to pre-vaccine era surveillance conducted from 2002 to 2008 at Dr George Mukhari Hospital (DGM), rotavirus surveillance among children <5 years hospitalized for acute diarrhoea was established at seven sentinel sites in SA from April 2009 to December 2014. Stool specimens were screened by enzyme immunoassay and rotavirus positive specimens genotyped using standardised methods. RESULTS: At DGM, there was a significant decrease in G1 strains from pre-vaccine introduction (34%; 479/1418; 2002-2009) compared to post-vaccine introduction (22%; 37/170; 2010-2014; p for trend <.001). Similarly, there was a significant increase in non-G1P[8] strains at this site (p for trend <.001). In expanded sentinel surveillance, when adjusted for age and site, the odds of rotavirus detection in hospitalized children with diarrhoea declined significantly from 2009 (46%; 423/917) to 2014 (22%; 205/939; p<.001). The odds of G1 detection declined significantly from 2009 (53%; 224/421) to 2010-2011 (26%; 183/703; aOR=0.5; p<.001) and 2012-2014 (9%; 80/905; aOR=0.1; p<.001). Non-G1P[8] strains showed a significant increase from 2009 (33%; 139/421) to 2012-2014 (52%; 473/905; aOR=2.5; p<.001). CONCLUSIONS: Rotavirus vaccination of children was associated with temporal changes in circulating genotypes. Despite these temporal changes in circulating genotypes, the overall reduction in rotavirus disease in South Africa remains significant. PMID- 29110934 TI - Letter to Editor. PMID- 29110935 TI - Successful percutaneous retrieval of a leadless pacemaker due to an acute rise in pacing threshold. AB - Leadless cardiac pacemakers (LCP) have become available recently. Both its acute and long-term performance in a large population of patients remain to be tested. Subacute rise in pacing threshold has been reported as an uncommon complication. On the other hand, the retrieval technique for LCP with passive fixation mechanism has not been previously described in details. Herein we report a newly recognized complication of an acute rise in pacing threshold very soon after implantation of an LCP without radiographic dislodgement. Percutaneous retrieval of this LCP with passive fixation mechanism was successful using a novel technique with the cryoballoon steerable sheath and a snare. PMID- 29110936 TI - RIght VErsus Left Apical transvenous pacing for bradycardia: Results of the RIVELA randomized study. AB - AIMS: To compare cardiac function when pacing from the right or left ventricular apex in patients with preserved left ventricular systolic function, at 1-year follow-up. METHODS: Prospective, multicentre centre randomizing conventional right ventricular apical (RVA) versus left ventricular apical (LVA) pacing using a coronary sinus lead in patients requiring ventricular pacing for bradycardia. Follow-up was performed using 3D-echocardiography at 6 and 12 months. RESULTS: A total of 36 patients (age 75.4 +/- 8.7 years, 21 males) were enrolled (17 patients in the RVA group and 19 patients in the LVA group). A right ventricular lead was implanted in 8 patients in the LVA group, mainly because of high capture thresholds. There were no differences in the primary endpoint of LVEF at 1 year (60.4 +/- 7.1% vs 62.1 +/- 7.2% for the RVA and LVA groups respectively, P = 0.26) nor in any of the secondary endpoints (left ventricular dimensions, left ventricular diastolic function, right ventricular systolic function and tricuspid/mitral insufficiency). LVEF did not change significantly over follow-up in either group. Capture thresholds were significantly higher in the LVA group, and two patients had unexpected loss of capture of the coronary sinus lead during follow-up. CONCLUSIONS: Left univentricular pacing seems to be comparable to conventional RVA pacing in terms of ventricular function at up to 1 year follow up, and is an option to consider in selected patients (e.g. those with a tricuspid valve prosthesis). PMID- 29110937 TI - Ocean acidification does not impair predator recognition but increases juvenile growth in a temperate wrasse off CO2 seeps. AB - Fish behavioural effects under Ocean Acidification (OA) rely on changes expected to occur in brain function, which can be reversed by gabazine, a GABA-A antagonist. Here, using standard two-channel choice flume, we assessed OA effects on the predator recognition ability of both gabazine-treated and -untreated Symphodus ocellatus post-settlers living off CO2 seeps in the Mediterranean Sea. To estimate the post-settlers background predation risk we evaluated the density of their predator in the wild and through otolith aging techniques we assessed their post-settlement growth. Results showed that: 1) post-settlers predator recognition was unaffected under OA; 2) post-settlers living in elevated CO2 were on average 15% bigger in size than those from ambient conditions. Our results support fish behavioural tolerance to OA, potentially mediated by pre-exposure to high-risk predation levels, and speculate that by increasing body size, juvenile fish might more efficiently avoid their predators. PMID- 29110938 TI - Torrefaction of landfill food waste for possible application in biomass co firing. AB - Greenhouse gas emissions and municipal solid waste management have presented challenges globally. This study aims to produce a high-quality biochar with properties close to bituminous coal from landfill food waste (FW). FW was analyzed by proximate and ultimate analyses to determine its fuel properties and elemental composition before torrefaction. Temperature was varied from 200 to 300 degrees C at a constant residence time of 40 min and 10 degrees C/min heating rate. Calorific value, mass yield, energy yield and energy density were computed and used to determine the quality of the resulting biochar. Quality of raw food waste was also determined by elemental analysis. Thermal evolution was then investigated using hyphenated Thermogravimetric Analysis (TGA) and Fourier Transform Infra-Red Spectrometry (FTIR). Torrefaction was done at 225 degrees C, 275 degrees C and 300 degrees C. The calorific value was upgraded from 19.76 MJ/kg for dried raw food waste to 26.15 MJ/kg for torrefied food waste at the appropriate conditions which were 275 degrees C, 40 min and 10 degrees C/min. The higher heating value was comparable to that of bituminous coal from Anglo Mafube in South Africa. Elemental analysis of biochar showed an increase in carbon content with temperature due to loss of oxygen containing volatiles. This agreed with TG curves and FTIR spectra which confirmed release of H2O, CO and CO2. This resulted in a more hydrophobic solid fuel with high energy density. Food waste can therefore be upgraded to a biochar with similar fuel properties as pulverized coal used in coal fired boilers. PMID- 29110939 TI - Analysis of landfill design variables based on scientific computing. AB - The optimal design of waste landfills is a complex, still unsolved issue. Each design variable influences the rest and it is difficult to quantify their interactions. Recent advances in scientific computing, however, allow this problem to be approached from a new perspective. Thus, in this paper a new method is proposed for the analysis and optimization of design variables in waste landfills. This method is based on the computer simulation of multiple models and the systematic analysis of the resulting data to extract knowledge. It can be extended to the optimization of other complex systems with a direct impact on the environment. Its efficacy is tested by studying the effect of five common design variables on landfill hydrology. The main results show the benefits of temporary surface lining and intermediate covers on the volume of leachate generated. Intermediate covers, however, may jeopardize landfill stability and significantly affect the variability of the leachate flow. The case studied demonstrates the usefulness of the proposed method to improve the design and operation of waste landfills. It also shows the need to analyse multiple scenarios in order to generalize the conclusions obtained. PMID- 29110940 TI - Process for recycling mixed-cathode materials from spent lithium-ion batteries and kinetics of leaching. AB - A "grave-to-cradle" process for the recycling of spent mixed-cathode materials (LiCoO2, LiCo1/3Ni1/3Mn1/3O2, and LiMn2O4) has been proposed. The process comprises an acid leaching followed by the resynthesis of a cathode material from the resulting leachate. Spent cathode materials were leached in citric acid (C6H8O7) and hydrogen peroxide (H2O2). Optimal leaching conditions were obtained at a leaching temperature of 90 degrees C, a H2O2 concentration of 1.5 vol%, a leaching time of 60 min, a pulp density of 20 g L-1, and a citric acid concentration of 0.5 M. The leaching efficiencies of Li, Co, Ni, and Mn exceeded 95%. The leachate was used to resynthesize new LiCo1/3Ni1/3Mn1/3O2 material by using a sol-gel method. A comparison of the electrochemical properties of the resynthesized material (NCM-spent) with that synthesized directly from original chemicals (NCM-syn) indicated that the initial discharge capacity of NCM-spent at 0.2 C was 152.8 mA h g-1, which was higher than the 149.8 mA h g-1 of NCM-syn. After 160 cycles, the discharge capacities of the NCM-spent and NCM-syn were 140.7 mA h g-1 and 121.2 mA h g-1, respectively. After discharge at 1 C for 300 cycles, the NCM-spent material remained a higher capacity of 113.2 mA h g-1 than the NCM-syn (78.4 mA h g-1). The better performance of the NCM-spent resulted from trace Al doping. A new formulation based on the shrinking-core model was proposed to explain the kinetics of the leaching process. The activation energies of the Li, Co, Ni, and Mn leaching were calculated to be 66.86, 86.57, 49.46, and 45.23 kJ mol-1, respectively, which indicates that the leaching was a chemical reaction-controlled process. PMID- 29110941 TI - Lanthanide-alkali double sulfate precipitation from strong sulfuric acid NiMH battery waste leachate. AB - In NiMH battery leaching, rare earth element (REE) precipitation from sulfate media is often reported as being a result of increasing pH of the pregnant leach solution (PLS). Here we demonstrate that this precipitation is a phenomenon that depends on both Na+ and SO42- concentrations and not solely on pH. A two-stage leaching for industrially crushed NiMH waste is performed: The first stage consists of H2SO4 leaching (2 M H2SO4, L/S = 10.4, V = 104 ml, T = 30 degrees C) and the second stage of H2O leaching (V = 100 ml, T = 25 degrees C). Moreover, precipitation experiments are separately performed as a function of added Na2SO4 and H2SO4. During the precipitation, higher than stoichiometric quantities of Na to REE are utilized and this increase in both precipitation reagent concentrations results in an improved double sulfate precipitation efficiency. The best REE precipitation efficiencies (98-99%) - achieved by increasing concentrations of H2SO4 and Na2SO4 by 1.59 M and 0.35 M, respectively - results in a 21.8 times Na (as Na2SO4) and 58.3 times SO4 change in stoichiometric ratio to REE. Results strongly indicate a straightforward approach for REE recovery from NiMH battery waste without the need to increase the pH of PLS. PMID- 29110942 TI - Adjuvant therapy for locally advanced renal cell carcinoma: A meta-analysis and systematic review. AB - OBJECTIVES: Many adjuvant therapies have been widely used in an attempt to reduce the local recurrence or distant metastasis of locally advanced renal cell carcinoma (RCC) after surgical resection. However, the benefits of adjuvant therapy remain controversial. Thus, we performed this study to analyze the role and safety of adjuvant therapy in renal cancer setting. METHODS AND METHODS: We comprehensively searched PubMed, EMBASE, Web of Science, and the Cochrane Library for published randomized controlled trials comparing adjuvant therapy (chemotherapy, vaccine therapy, immune therapy, and targeted therapy) versus no active treatment after surgery among patients with locoregional RCC. Outcomes of interest were disease-free survival, overall survival, and severe toxicities. Different kinds of adjuvant therapy were evaluated separately. RESULTS: Twelve studies (5,936 patients) were included in the present analysis. Adjuvant therapy did not contribute to overall survival (HR = 1.04; 95% CI: 0.95-1.15; P = 0.395; I2 = 0%) or disease-free survival (HR = 1.00; 95% CI: 0.92-1.08; P = 0.971; I2 = 35%) when compared to placebo or observation. No survival benefit was observed according to subgroup analyses (targeted therapy, vaccine therapy, and immune therapy). Moreover, adjuvant therapy increased obviously the risk of toxicities. CONCLUSIONS: The addition of adjuvant therapy provided no survival benefit but increased the rates of adverse events for locally advanced RCC patients. PMID- 29110943 TI - Differentiation between hepatic alveolar echinococcosis and primary hepatic malignancy with diffusion-weighted magnetic resonance imaging. AB - PURPOSE: To determine the value of diffusion-weighted magnetic resonance imaging (DW-MRI) in discriminating between hepatic alveolar echinococcosis (AE) and hepatocellular carcinoma and intrahepatic cholangiocarcinoma. METHODS: We included 49 patients (27 men, 22 women; mean age: 52.02+/-9.76 [SD] years; range: 25-72years) with 57 histopathologically confirmed hepatic AE lesions. Fifty patients (18 men, 32 women; mean age: 58.93+/-8.42 [SD] years; range: 42-71years) with 61 histopathologically confirmed hepatocellular carcinoma and 50 patients (24 men, 26 women; mean age: 50.11+/-7.70 [SD] years; range: 38-69years) with 54 histopathologically confirmed intrahepatic cholangiocarcinoma lesions were used as control groups. All patients had MRI examination of the liver that included conventional MRI sequences and DW-MRI using b values of 50, 400 and 800s/mm2. Two radiologists evaluated conventional MRI and DW-MRI images and calculated ADC values of hepatic lesions. RESULTS: The mean ADC value of solid components of hepatic AE lesions was 1.34+/-0.41*10-3 mm2/s (range: 0.9-1.59*10-3 mm2/s) and was significantly higher than that of the solid components of hepatocellular carcinoma lesions (mean ADC value, 0.99+/-0.29*10-3 mm2/s; range: 0.7-1.15*10-3 mm2/s) and of intrahepatic cholangiocarcinoma lesions (mean ADC value, 1.05+/ 0.22*10-3 mm2/s; range: 0.86-1.18*10-3 mm2/s) (P<0.001). CONCLUSION: In general ADC values can help discriminate between AE and hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, the use of ADC values cannot help differentiating Type 4 AE from hepatocellular carcinoma or intrahepatic cholangiocarcinoma. PMID- 29110944 TI - Botulinum Toxin A for the Treatment of Photophobia and Dry Eye. PMID- 29110945 TI - The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration. AB - Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to progressive and irreversible loss of visual function. Geographic atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the perifoveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggests that specific characteristics may be important in predicting disease progression and outcomes. This review synthesizes current understanding of GA progression in AMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement are discussed. Overall, GA progression rates reported in the literature for total study populations range from 0.53 to 2.6 mm2/year (median, ~1.78 mm2/year), assessed primarily by color fundus photography or fundus autofluorescence (FAF) imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multifocality, FAF patterns, and fellow eye status. Because best-corrected visual acuity does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including microperimetry, low-luminance visual acuity, reading speed assessments, and patient-reported outcomes. Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis. PMID- 29110946 TI - Assessment of the Electronic Retinal Implant Alpha AMS in Restoring Vision to Blind Patients with End-Stage Retinitis Pigmentosa. AB - PURPOSE: To report the initial efficacy results of the Retina Implant Alpha AMS (Retina Implant AG, Reutlingen, Germany) for partial restoration of vision in end stage retinitis pigmentosa (RP). DESIGN: Prospective, single-arm, investigator sponsored interventional clinical trial. Within-participant control comprising residual vision with the retinal implant switched ON versus OFF in the implanted eye. PARTICIPANTS: The Retina Implant Alpha AMS was implanted into the worse seeing eye of 6 participants with end-stage RP and no useful perception of light vision. Eligibility criteria included previous normal vision for >=12 years and no significant ocular or systemic comorbidity. METHODS: Vision assessments were scheduled at 1, 2, 3, 6, 9, and 12 months postimplantation. They comprised tabletop object recognition tasks, a self-assessment mobility questionnaire, and screen-based tests including Basic Light and Motion (BaLM), grating acuity, and greyscale contrast discrimination. A full-field stimulus test (FST) was also performed. MAIN OUTCOME MEASURES: Improvement in activities of daily living, recognition tasks, and assessments of light perception with the implant ON compared with OFF. RESULTS: All 6 participants underwent successful implantation. Light perception and temporal resolution with the implant ON were achieved in all participants. Light localization was achieved with the implant ON in all but 1 participant (P4) in whom the chip was not functioning optimally because of a combination of iatrogenic intraoperative implant damage and incorrect implantation. Implant ON correct grating detections (which were at chance level with implant OFF) were recorded in the other 5 participants, ranging from 0.1 to 3.33 cycles/degree on 1 occasion. The ability to locate high-contrast tabletop objects not seen with the implant OFF was partially restored with the implant ON in all but 1 participant (P4). There were 2 incidents of conjunctival erosion and 1 inferotemporal macula-on retinal detachment, which were successfully repaired, and 2 incidents of inadvertent damage to the implant during surgery (P3 and P4). CONCLUSIONS: The Alpha AMS subretinal implant improved visual performance in 5 of 6 participants and has exhibited ongoing function for up to 24 months. Although implantation surgery remains challenging, new developments such as OCT microscope guidance added refinements to the surgical technique. PMID- 29110947 TI - Autorefraction-Based Prescription and Mailed Delivery of Eyeglasses. PMID- 29110948 TI - Bioprosthetic aortic valve replacement: Revisiting prosthesis choice in patients younger than 50 years old. AB - OBJECTIVE: Aortic prosthesis choice is controversial in young adults because robust comparative outcome data are lacking. We therefore compared mortality and morbidity in young adults after bioprosthetic versus mechanical aortic valve replacement. METHODS: This was a retrospective analysis of 5111 patients aged 18 to 50 years undergoing primary aortic valve replacement in California and New York State from 1997 to 2006. Median follow-up time was 11.8 years (maximum 18.9 years). The primary endpoint was mortality; secondary endpoints were stroke, bleeding, and reoperation. Propensity score matching yielded 1175 patient pairs. RESULTS: Bioprosthetic valves increased from 14% to 47% of aortic valve replacements between 1997 and 2014 (P < .001). There was no survival difference with bioprosthetic versus mechanical aortic valves in the propensity score matched cohort: actuarial 15-year survival was 79.0% (95% confidence interval [CI], 75.8%-81.8%) versus 81.5% (95% CI, 78.5%-84.2%) respectively (hazard ratio [HR], 1.14; 95% CI, 0.93-1.40, P = .20). No interaction was found between age and prosthesis choice on survival (Pinteraction = 0.16). After bioprosthetic valve replacement, stroke rates were lower (5.4% [95% CI, 3.8%-7.2%] vs 8.1% [95% CI, 6.3%-10.2%], HR 0.62 [95% CI 0.43-0.91]), bleeding rates were lower (4.2% [95% CI, 3.0-5.6%] vs 8.4% [95% CI, 6.6-10.4%], HR 0.48 [95% CI, 0.33-0.69]), but reoperation rates were greater (24.5% [95% CI, 21.3%-27.8%] vs 9.3% [95% CI, 7.2% 11.7%], HR 5.9 [95% CI 3.2-11.0]) at 15 years versus mechanical valve replacement. CONCLUSIONS: Although lifetime risks are represented incompletely, these findings suggest that in adults aged 18-50 years, bioprostheses are a reasonable alternative to mechanical valves for aortic valve replacement. PMID- 29110949 TI - del Nido cardioplegia: Passing fad or here to stay? PMID- 29110950 TI - Validity of the updated European Society of Thoracic Surgeons staging guideline in lung cancer patients. AB - OBJECTIVE: The European Society of Thoracic Surgeons (ESTS) has proposed a revised preoperative lymph node staging guideline for patients with potentially resectable non-small cell lung cancer (NSCLC). We aimed to assess the validity of this revised ESTS guideline and survival results in our patient cohort. METHODS: A total of 571 patients with potentially resectable NSCLC seen between January 2004 and November 2013 were included in the study. The preoperative mediastinal staging was performed by video-assisted cervical mediastinoscopy or video assisted mediastinoscopic lymphadenectomy in all patients except those with peripheral cT1N0 nonadenocarcinoma tumors. Resection via thoracotomy or video assisted thoracoscopic surgery was done in patients with no mediastinal lymph node metastasis. Surgical pathological results were compared with the ESTS staging guideline, and the validity of the guideline was tested. RESULTS: In this series, mediastinal lymph node metastasis was revealed preoperatively in 266 patients (46.6%). A total of 305 patients underwent anatomic lung resection. The sensitivity, specificity, positive and negative predictive values, and accuracy of the guidelines were calculated as 95.0%, 100%, 100%, 94.6%, and 97.2%, respectively. CONCLUSIONS: The ESTS revised preoperative lymph node staging guidelines for patients with NSCLC seem to be effective and valid, and may provide high survival following resectional surgery. PMID- 29110951 TI - Valve-sparing repair to alleviate pulmonary regurgitation may lead to as much right ventricular dilatation as a transannular patch: A catch-22? PMID- 29110952 TI - Discussion. PMID- 29110953 TI - A functional pulmonary valve after tetralogy of Fallot repair: A fool's errand? PMID- 29110954 TI - Effect of motor subtypes of delirium in the intensive care unit on fast-track failure after cardiac surgery. AB - OBJECTIVE: The purpose of the study was to evaluate the association between motor subtypes of postoperative delirium in the intensive care unit and fast-track failure (a composite outcome of prolonged stay in the intensive care unit >48 hours, intensive care unit readmission, and 30-day mortality) after cardiac surgery. METHODS: This was a secondary analysis of a prospective cohort study of 600 consecutive adults undergoing cardiac surgery at a university hospital in Hong Kong (July 2013 to July 2015). The motor subtypes of delirium were classified using the Richmond Agitation Sedation Score and Confusion Assessment Method intensive care unit assessments performed by trained bedside nurses. A generalized estimating equation was used to estimate a common relative risk of fast-track failure associated with motor subtypes. RESULTS: The incidences of hypoactive, hyperactive, and mixed motor subtypes were 4.3% (n = 26), 4.0% (n = 24), and 5.5% (n = 33), respectively. Fast-track failure occurred in 88 patients (14.7%). There was an association between delirium (all subtypes) and fast-track failure (P = .048); hyperactive delirium (relative risk, 1.95; 95% confidence interval, 0.96-3.94); hypoactive delirium (relative risk, 2.79; 95% confidence interval, 1.34-5.84); and mixed delirium (relative risk, 2.55; 95% confidence interval, 1.11-5.88). Hypoactive and mixed subtypes were associated with prolonged intensive care unit stay (both P = .001). CONCLUSIONS: Patients with pure hypoactive delirium had a similar risk of developing fast-track failure as other motor subtypes. Differentiation of motor subtypes is unlikely to be clinically important for prognostication of fast-track failure. However, because delirium is associated with poor outcomes, potential treatment strategies should address all subtypes equally. PMID- 29110955 TI - [Furosemide induced agranulocytosis in heart failure, what else?] PMID- 29110956 TI - Activation inhibitors of nuclear factor kappa B protect neurons against the NMDA induced damage in the rat retina. AB - We reported that high-mobility group Box-1 (HMGB1) was involved in excitoneurotoxicity in the retina. HMGB1 is known to activate nuclear factor kappa B (NF-kappaB). However, the role of NF-kappaB in excitotoxicity is still controversial. Here, we demonstrated that NF-kappaB activation induced by NMDA led to the retinal neurotoxicity. Male Sprague-Dawley rats were used, and NMDA (200 nmol/eye) and bovine HMGB1 (15 MUg/eye) were intravitreally injected. Triptolide (500 pmol/eye), BAY 11-7082 (500 pmol/eye), and IMD-0354 (7.5 nmol/eye), NF-kappaB inhibitors, were co-injected with NMDA or HMGB1. Retinal sections were obtained seven days after intravitreal injection. Cell loss in the ganglion cell layer was observed in the HMGB1- and the NMDA-treated retina. All of the NF-kappaB inhibitors used in this study reduced the damage. BAY 11-7082 reduced the expression of phosphorylated NF-kappaB 12 h after NMDA injection, upregulation of GFAP immunoreactivity induced by NMDA 12 and 48 h after NMDA injection, and the number of TUNEL-positive cells 48 h after NMDA injection. The results suggest that NF-kappaB activation is one of the mechanisms of the retinal neuronal death that occurs 48 h after NMDA injection or later. Prevention of NF kB activation is a candidate for the treatment of retinal neurodegeneration associated with excitotoxicity. PMID- 29110957 TI - A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy. AB - The kidney expresses protease-activated receptor-1 (PAR-1). PAR-1 is known as a thrombin receptor, but its role in kidney injury is not well understood. In this study, we examined the contribution of PAR-1 to kidney glomerular injury and the effects of its inhibition on development of nephropathy. Mice were divided into 3 groups: control, doxorubicin + vehicle (15 mg/kg doxorubicin and saline) and doxorubicin + Q94 (doxorubicin at 15 mg/kg and the PAR-1 antagonist Q94 at 5 mg/kg/d) groups. Where indicated, doxorubicin was administered intravenously and PAR-1 antagonist or saline vehicle by subcutaneous osmotic mini-pump. PAR-1 expression was increased in glomeruli of mice treated with doxorubicin. Q94 treatment significantly suppressed the increased albuminuria in these nephropathic mice. Pathological analysis showed that Q94 treatment significantly attenuated periodic acid-Schiff and desmin staining, indicators of podocyte injury, and also decreased glomerular levels of podocin and nephrin. Furthermore, thrombin increased intracellular calcium levels in podocytes. This increase was suppressed by Q94 and Rox4560, a transient receptor potential cation channel (TRPC)3/6 antagonist. In addition, both Q94 and Rox4560 suppressed the doxorubicin-induced increase in activities of caspase-9 and caspase-3 in podocytes. These data suggested that PAR-1 contributes to development of podocyte and glomerular injury and that PAR-1 antagonists have therapeutic potential. PMID- 29110958 TI - Low-level arsenic exposure during pregnancy and its association with postpartum depression: A cohort study of women from Arica, Chile. AB - BACKGROUND: While the relationship between inorganic arsenic exposure and psychological impairment has been studied previously, the association between low level arsenic exposure during pregnancy and postpartum depression has not yet been examined. The objective is to estimate the association between low-level arsenic exposure during pregnancy and the Edinburgh score. METHODS: A sample of 223 women was collected from five public health services in Arica, Chile. Participation was voluntary and written consent was mandatory. Sociodemographic data related to arsenic exposure and urine samples for total inorganic arsenic assessments were collected during the second trimester. Postpartum depression symptoms were estimated by the Edinburgh Postpartum Depression scale. We examined descriptive statistics and ran multiple linear regressions. The modifying effect of age and depression history was evaluated separately. RESULTS: The median for total urinary inorganic arsenic was 14.6MUg/L (range: 2-69.2MUg/L), the median for postpartum depression score was 8 points (range: 0-27 points) and 20.6% of women were considered as postpartum depressed. For women older than 25years old without depression history, the adjusted coefficient for the total urinary natural logarithm of inorganic arsenic in multiple linear regressions was -2.51 (95% CI: -4.54, -0.48; P-value=0.02). For women older than 25years old with a depression history, this value was 2.09 (95% CI: -0.90, 5.08; P-value=0.16). CONCLUSIONS: In this cohort, the number of children, physical perception, depression history, stressful maternity, and age were associated with postpartum depression score. The Edinburgh score was associated with inorganic arsenic in women older than 25years without depression history. PMID- 29110959 TI - [Taxation of traditional rums in French overseas territories and public health: The example of Reunion Island]. AB - BACKGROUND: France has a complex system for the taxation of alcoholic beverages. In the French overseas territories (FOT), the system includes little-known specificities whose purpose is to preserve the sugar-cane-rum sector, a pillar for the weak economies in these territories. Taxes are reduced for traditional rums produced and sold locally. This favors the marketing of alcoholic spirits at low prices. In metropolitan France, on the contrary, spirits are heavily taxed drinks and their share in consumption is minor. Reunion Island (RI) is a FOT confronted with significant socioeconomic precariousness and with one of the highest national morbidity and mortality rates associated with alcohol abuse. Spirits account for half of the total consumption of pure alcohol, with a strong predominance for local traditional rums. These products are preferentially consumed by vulnerable subjects, often affected by an alcohol-use disorder. METHODS: This study consists of three parts. First, a comparative analysis of alcoholic beverage prices between RI and mainland France. Second, an analysis of the bibliography on the consequences of preferential consumption of spirits. Third, a literature review on the impact of taxation on alcohol-related morbidity and mortality. RESULTS: In France, the cheapest gram of pure alcohol is found in the FOT. The preferential consumption of spirits is associated with more frequent and more rapid complications. It is correlated with the level of alcoholic psychoses. Taxation is effective in reducing damage caused by the abuse of alcoholic beverages. The World Health Organization recommends the application of a minimum price for alcohol and tax increases. CONCLUSION: The reduced taxation of the traditional rums of the FOT does not take into account public health data. Its purpose is economic. In RI, it contributes to a high level of consumption of spirits and encourages excess mortality through alcohol abuse. It constitutes an inequality of health for these populations. Changes in this tax system is desirable in order to reduce the harm caused by alcohol. It should be closer to the tax system in force in metropolitan France. Alcohol lobbies and lack of political courage have so far inhibited this change to the detriment of the health of the populations. PMID- 29110960 TI - The clinical role of fractional exhaled nitric oxide in asthma control. AB - BACKGROUND: The potential role and characteristics of fractional exhaled nitric oxide (FeNO) remain unclear in the treatment of asthma. OBJECTIVE: To explore the clinical role of FeNO in asthmatic treatment. METHODS: We evaluated whether the mean or change of FeNO levels in the treatment period is associated with other conventional control parameters and predicted some clinical outcomes of asthma. We retrospectively analyzed the mean and percentage change of FeNO levels in the first 5 measurements at our hospital. RESULTS: The study found a significantly strong correlation between FeNO level at diagnosis and the largest changes of FeNO values from diagnosis. No significant correlations were observed between FeNO levels and other parameters (Asthma Control Test [ACT] score or forced expiratory volume in one second [FEV1]) in mean and percentage change of values under treatment of asthma; however, significant positive correlations were found between ACT scores and FEV1. The mean FeNO level revealed a significant negative correlation with an annual change in FEV1 in individuals with asthma who were followed up for more than 2 years. Both the mean ACT score and percent predicted FEV1 revealed a significant negative correlation with occasional use of systemic corticosteroids. CONCLUSION: During conventional treatment of asthma, the largest changes of FeNO values from diagnosis were strongly correlated with FeNO levels at diagnosis. As for the unlikely conventional parameters, no significant associations were observed between FeNO levels and deterioration of asthma during the treatment periods. An elevated mean FeNO level may be a marker of decreased lung function in individuals with asthma. PMID- 29110961 TI - The surgeons should express their suggestions clearly during patients' shared decision making(SDM) process. PMID- 29110962 TI - Role of diuretics in the harmful effects of beta blockers in patients with ascites. Author's reply. PMID- 29110963 TI - Gastric preparation for magnetically controlled capsule endoscopy: A prospective, randomized single-blinded controlled trial. AB - BACKGROUND AND AIMS: Magnetically controlled capsule endoscopy (MCE) is a novel technique for which there is no agreed gastric preparation. We aimed to determine an optimal standardized gastric preparation regimen. METHODS: 120 patients referred for MCE were randomly assigned to gastric preparation with either water alone (A), water with simethicone (B) or water, simethicone and pronase (C). Image quality was assessed using cleanliness and visualization scores, higher scores equating to better image quality. RESULTS: The total cleanliness scores were (mean+/-SD) 15.83+/-2.41 (A), 21.35+/-1.23 (B), and 20.82+/-1.90 (C). The total visualization scores (mean+/-SD) were 10.75+/-2.02 (A), 15.20+/-1.32 (B), and 15.08+/-1.86 (C). While the image quality of the whole stomach in groups B and C were significantly better than group A (P<0.0001), there was no statistical difference between group B and C (P>0.05). MCE detected positive findings in 21 (52.5%), 27 (67.5%) and 21 (53.8%) patients in group A, B and C respectively, with no significant difference between groups (P>0.5). CONCLUSIONS: Simethicone swallowed with water prior to MCE produced the optimal gastric mucosal image quality. The addition of pronase had no demonstrable additional benefit. PMID- 29110965 TI - Response to Er and Tez: the use of artificial neural networks in medical prognostication. PMID- 29110964 TI - 'Basic and Applied Thermogenesis Research' Bridging the Gap. AB - Obesity is a major health problem without satisfactory pharmacological treatment. A promising strategy is to promote energy dissipation by activating brown/beige adipose tissue. However, for this strategy to succeed it requires improving the transferability amongst cellular, murine, and human systems and bridging the gap between basic and clinical research. PMID- 29110966 TI - Longitudinal development of initial, chronic and mucoid Pseudomonas aeruginosa infection in young children with cystic fibrosis. AB - BACKGROUND: While the emergence of chronic and mucoid Pseudomonas aeruginosa (Pa) infection are both associated with poorer outcomes among CF patients, their relationship is poorly understood. We examined the longitudinal relationship of incident, chronic and mucoid Pa in a contemporary, young CF cohort in the current era of Pa eradication therapy. METHODS: This retrospective cohort was comprised of patients in the U.S. CF Foundation Patient Registry born 2006-2015, diagnosed before age 2, and with at least 3 respiratory cultures annually. Incidence and age-specific prevalence of Pa infection stages (initial and chronic [>= 3Pa+cultures in prior year]) and of mucoid Pa were summarized. Transition times and the interaction between Pa stage and acquisition of mucoid Pa were examined via Cox models. RESULTS: Among the 5592 CF patients in the cohort followed to a mean age of 5.5years, 64% (n=3580) acquired Pa. Of those, 13% (n=455) developed chronic Pa and 17% (n=594) cultured mucoid Pa. Among those with mucoid Pa, 36% (211/594) had it on their first recorded Pa+culture, while mucoid Pa emerged at or after entering the chronic stage in 12% (73/594). Mucoidy was associated with significantly increased risk of transition to chronic Pa infection (HR=2.59, 95% CI 2.11, 3.19). CONCLUSIONS: Two-thirds of early-diagnosed young children with CF acquired Pa during a median 5.6years of follow up, among whom 13% developed chronic Pa and 17% acquired mucoid Pa. Contrary to our hypothesis, 87% of young children who developed mucoid Pa did so before becoming chronically infected. PMID- 29110967 TI - Experience of using MOSFET detectors for dose verification measurements in an end to-end 192Ir brachytherapy quality assurance system. AB - PURPOSE: Establishment of an end-to-end system for the brachytherapy (BT) dosimetric chain could be valuable in clinical quality assurance. Here, the development of such a system using MOSFET (metal oxide semiconductor field effect transistor) detectors and experience gained during 2 years of use are reported with focus on the performance of the MOSFET detectors. METHODS AND MATERIALS: A bolus phantom was constructed with two implants, mimicking prostate and head & neck treatments, using steel needles and plastic catheters to guide the 192Ir source and house the MOSFET detectors. The phantom was taken through the BT treatment chain from image acquisition to dose evaluation. During the 2-year evaluation-period, delivered doses were verified a total of 56 times using MOSFET detectors which had been calibrated in an external 60Co beam. An initial experimental investigation on beam quality differences between 192Ir and 60Co is reported. RESULTS: The standard deviation in repeated MOSFET measurements was below 3% in the six measurement points with dose levels above 2 Gy. MOSFET measurements overestimated treatment planning system doses by 2-7%. Distance dependent experimental beam quality correction factors derived in a phantom of similar size as that used for end-to-end tests applied on a time-resolved measurement improved the agreement. CONCLUSIONS: MOSFET detectors provide values stable over time and function well for use as detectors for end-to-end quality assurance purposes in 192Ir BT. Beam quality correction factors should address not only distance from source but also phantom dimensions. PMID- 29110968 TI - A quantitative assessment of the effectiveness of USDA's AgrAbility project. AB - BACKGROUND: There is evidence that the combination of assistive technology and education increases ability to live and work independently, which in turn increases the quality of life (QOL) levels of adults with disabilities. No previously published treatment-comparison group intervention studies were found with adult farmers and ranchers with disabilities. Knowing how effective USDA's AgrAbility Project is at increasing this population's QOL and independent living and working (ILW) levels will reinforce and inform change in AgrAbility and will provide outcomes for stakeholders and public decision makers to better address agricultural communities' needs. OBJECTIVES: To assess whether or not AgrAbility is effective for enhancing QOL and ILW levels of agricultural producers with functional limitations and to assess intervention-comparison group differences. METHODS: Intervention group participants (N = 225) included ranchers and farmers from 12 states with various disabilities who participated in AgrAbility. Comparison group participants (N = 100) from 17 states also included farmers and ranchers with various disabilities; they received no on-site visits or other AgrAbility services. RESULTS: In this 10-year, 27-state study, AgrAbility participants reported statistically significant presurvey-postsurvey improvements in QOL levels (mean presurvey = 5.56; mean postsurvey = 7.13) while comparison group participants reported no change in QOL (mean presurvey = 5.10; mean postsurvey = 4.91). AgrAbility group mean ILW scores rose from 2.86 to 3.71 while comparison group mean ILW scores rose slightly from 3.24 to 3.50. CONCLUSIONS: These results suggest that AgrAbility was effective as compared with a no treatment comparison group on improving QOL and ILW levels. PMID- 29110969 TI - How do patients describe their disabilities? A coding system for categorizing patients' descriptions. AB - BACKGROUND: To provide care that meets the values and preferences of patients with disabilities, health care providers need to understand patients' perceptions and understanding of their disability. No studies have explored patients' definitions of disability within the healthcare setting. OBJECTIVE: The aim of the study was to understand how patients' define their disability in the healthcare setting and to develop a coding system for categorizing how they describe their disability. METHODS: In 2000 all new outpatients at Mayo Clinic, Rochester, MN completed a form that inquired if they had a disability and if so, to write in the disability. The research team categorized the responses by disability type (e.g.: visual or physical) and how the patient described his disability or "disability narrative" (e.g.: diagnosis or activity). RESULTS: Within 128,636 patients, 14,908 reported a disability. For adults, lower limb (26%) and chronic conditions (24%) were the most frequent disability type and activity limitations (56%) were the most frequent disability narrative category. For pediatric patients, developmental disabilities (43%) were the most frequently reported disability type and diagnoses (83%) were the most frequent disability narrative category. Patients used different disability narrative categories to describe different disability types. For example, most adults reporting a mental health listed a diagnosis (97%), compared to only 13% of those with lower limb disabilities. CONCLUSIONS: Patients had diverse descriptions of their disabilities. In order for providers and healthcare organizations to provide high quality care, they should engage patients in developing a consistent, patient centered language around disability. PMID- 29110971 TI - The effects of enzalutamide and abiraterone on skeletal related events and bone radiological progression free survival in castration resistant prostate cancer patients: An indirect comparison of randomized controlled trials. AB - Two new drugs, the CYP17 inhibitor abiraterone acetate and the androgen receptor (AR) antagonist enzalutamide, have recently shown to prolong OS prior chemotherapy or in docetaxel treated mCRPC patients, using steroidal therapy or placebo as control group. Updated analyses underlined the role of these new agents on two prostate-specific endpoints as radiographic progression-free survival (rPFS) and time to first skeletal-related event (tSRE). On the basis of these reports, we made an indirect comparison between abiraterone and enzalutamide. We obtained a clinically but not significant difference favouring enzalutamide over abiraterone in terms of rPFS (HR 0.48, 95% CI 0.22-1.02). No significant difference was shown in term of tSRE (HR 0.99, 95% CI 0.83-1.17). In conclusion, abiraterone and enzalutamide have both demonstrated to significantly delay the bone progression resulting in similar improvements in bone-related endpoints in patients with mCRPC. PMID- 29110972 TI - Patient-reported Outcomes in Patients with Type 2 Diabetes Treated with Dulaglutide Added to Titrated Insulin Glargine (AWARD-9). AB - PURPOSE: This 28-week, randomized, double-blind study compared a once-weekly injection of dulaglutide 1.5 mg to placebo, both added to titrated once-daily insulin glargine (with or without metformin), in patients with type 2 diabetes mellitus and inadequate glycemia control (control defined as hemoglobin A1c, >=7% and <=10.5%). Patient-reported outcomes were assessed as an exploratory objective to further understand patients' physical, psychological, and social aspects of well-being and injection-device experience. METHODS: Patients not naive to injectable therapy were randomly assigned (1:1) to receive dulaglutide/glargine or placebo/glargine; glargine was titrated to a fasting plasma glucose target of 71 to 99 mg/dL. The Impact of Weight on Self-Perceptions (IW-SP), the EQ-5D-5L (measure of health status), the 18-item Diabetes Health Profile (DHP-18), and the Medication Device Delivery Assessment (MDDAB) instruments for assessing the dulaglutide Single-Use Pen (SUP) and glargine-delivery device were administered at baseline and 28 weeks, and also at 6 or 12 weeks for some measures. A mixed model for repeated measures was used for analyzing changes from baseline scores. FINDINGS: At 28 weeks, improvements observed in the transformed total scores on the IW-SP and DHP-18 Disinhibited Eating domain were significantly greater with dulaglutide/glargine compared with placebo/glargine (least squares mean differences, +6.06 [P = 0.019] and -4.50 [P = 0.017], respectively). There were no significant overall between-treatment differences in quality of life as measured by the EQ-5D-5L or the Barriers to Activities and Psychological Distress domains of the DHP-18. Of all patients, 95% reported that overall, the dulaglutide SUP was "easy" or "very easy" to use at 28 weeks. Device-features scores showed that most patients liked the dulaglutide SUP features, with the 3 highest-rated items relating specifically to features of the needle (not having to touch the needle, not having to attach the needle, and automatic insertion). The majority of patients (~90%) "agreed" or "strongly agreed" that they were satisfied with the overall dulaglutide SUP injection experience at 28 weeks. IMPLICATIONS: Dulaglutide/glargine-treated patients had greater improvements in weight-related quality-of-life measures compared with placebo/glargine-treated patients, which may be clinically relevant when evaluating treatment options for insulin-requiring patients who often gain weight with insulin monotherapy. Results from the MDDAB indicated overall satisfaction with the dulaglutide SUP injection experience, which may be an important factor in some patients when initiating parenteral therapy. ClinicalTrials.gov identifier: NCT02152371. PMID- 29110970 TI - Perinatal weight and risk of prenatal and postpartum depressive symptoms. AB - PURPOSE: Prepregnancy obesity and weight changes accompanying pregnancy (gestational weight gain and postpartum weight retention) may be associated with risk of maternal depressive symptoms during pregnancy and in the postpartum. The few studies that have examined these relationships report conflicting findings. METHODS: We studied pregnant (n = 2112) and postpartum (n = 1686) women enrolled in Project Viva. We used self-reported prepregnancy and postpartum weight and measured prenatal weight to calculate prepregnancy body mass index (BMI), gestational weight gain (GWG), and postpartum weight retention at 6 months after birth. We assessed elevated depressive symptoms (EDS) with the Edinburgh Postnatal Depression Scale (>=13 on 0-30 scale) at midpregnancy and 6 months postpartum. We used logistic regression to estimate the odds of prenatal and postpartum EDS in relation to prepregnancy BMI, GWG, and postpartum weight retention. RESULTS: A total of 214 (10%) participants experienced prenatal EDS and 151 (9%) postpartum EDS. Neither prepregnancy BMI nor GWG was associated with prenatal EDS. Prepregnancy obesity (BMI >= 30 kg per m2) was associated with higher odds of postpartum EDS (odds ratio = 1.69, 95% confidence interval, 1.01 2.83) compared to normal prepregnancy weight in a model adjusted for age, race/ethnicity, nativity, education, marital status, household income, parity, pregnancy intention, and smoking. CONCLUSIONS: Prepregnancy obesity is associated with elevated depressive symptoms in the postpartum period. Given the current obesity epidemic in the US and the consequences of perinatal depression, additional prevention and screening efforts in this population may be warranted. PMID- 29110973 TI - Galton, reversion and the quincunx: The rise of statistical explanation. AB - Over the last six decades there has been a consistent trend in the philosophy literature to emphasize the role of causes in scientific explanation. The emphasis on causes even pervades discussions of non-causal explanations. For example, the concern of a recent paper by Marc Lange (2013b) is whether purported cases of statistical explanation are "really statistical" or really causal. Likewise, Michael Strevens (2011) argues that the main task of statistical idealizations is to distinguish between the causal factors that make a difference to the phenomenon to be explained and those that do not. But, the philosophy literature poorly reflects the history of the development of statistical explanation in the sciences. Francis Galton's (19th century) explanation for the laws of heredity is our case. Galton's statistical explanation was both innovative for his time and influential to our contemporary sciences. The key points to understanding Galton's statistical explanation for reversion is that it is autonomous from the real-world biological properties that make up an instance of reversion while still being approximately true of many real-world biological phenomena. Ours is an expanded discussion of ideas originated in Hacking (1990) and Sober (1980). We will articulate these features and compare our account with that of Lange and Strevens. PMID- 29110974 TI - The psychoneuroimmunology of pregnancy. AB - Pregnancy is associated with a number of significant changes in maternal physiology. Perhaps one of the more notable changes is the significant alteration in immune function that occurs during pregnancy. This change in immune function is necessary to support a successful pregnancy, but also creates a unique period of life during which a female is susceptible to disease and, as we'll speculate here, may also contribute to mental health disorders associated with pregnancy and the postpartum period. Here, we review the known changes in peripheral immune function that occur during pregnancy and the postpartum period, while highlighting the impact of hormones during these times on immune function, brain or neural function, as well as behavior. We also discuss the known and possible impact of pregnancy-induced immune changes on neural function during this time and briefly discuss how these changes might be a risk factor for perinatal anxiety or mood disorders. PMID- 29110975 TI - Traumatic Perforation of the Tympanic Membrane: A Review of 80 Cases. AB - BACKGROUND: Traumatic perforation of the tympanic membrane (TPTM) is often encountered in primary care or in the emergency department (ED). Several therapeutic interventions have been described, but conservative follow-up until spontaneous complete recovery is the most common choice. OBJECTIVE: Our goal was to analyze the trauma mechanism, perforation characteristics, and outcome of patients with TPTM. METHODS: The study included patients examined in the ED of a tertiary, university-affiliated medical center because of TPTM between 2012 and 2016. Their medical records were retrospectively reviewed for demographics, trauma mechanism, clinical characteristics, and outcome. A phone survey was performed to obtain the missing information of all the patients who did not continue their follow-up in our outpatient clinic. RESULTS: We reviewed the histories of 80 patients with a mean age of 26.7 +/- 14.6 years (20 children; 25%). TPTM was caused by blunt trauma in 45 patients (56%) and penetrating trauma in 35 patients (44%). Thirty-five patients (44%) completed their follow-up in the hospital outpatient clinic, with a mean duration of 6.2 weeks. Twenty-five patients (38%) completed their follow-up in a community-based otolaryngology clinic, 6 patients (9%) chose not to complete their follow-up, and 14 patients were lost to follow-up. Of the 60 patients who completed follow-up, 56 patients recovered spontaneously, 3 patients underwent successful tympanoplasty, and 1 patient was referred to surgery but was lost to follow-up. All children healed spontaneously. CONCLUSION: TPTM was more common in young males with main mechanisms of blunt trauma (an assault) or cleaning the ear canal. All children demonstrated complete spontaneous recovery. PMID- 29110976 TI - Emergency Medicine Myths: Ectopic Pregnancy Evaluation, Risk Factors, and Presentation. AB - BACKGROUND: Ectopic pregnancy (EP) is an important cause of morbidity and mortality in females of reproductive age. Proper diagnosis and treatment are critical, as complications such as rupture, hemorrhagic shock, and even death can occur. OBJECTIVE: EP is a condition emergency physicians are trained to detect, yet there are multiple myths concerning its evaluation and diagnosis. This article reviews several of these myths in order to improve emergency department (ED) evaluation and diagnosis. DISCUSSION: EP is a difficult diagnosis and may be missed on initial ED visit. While the diagnosis is often delayed simply due to very early presentations, it can also be missed because patients may not have all the same risk factors or demonstrate the same symptoms. They may also not demonstrate the same serum B-human chorionic gonadotropin levels and trends or have the same ultrasound findings at equivalent gestational ages. Some patients with early EP may have positive ultrasound findings with serum beta-hCG levels under a defined discriminatory zone (DZ). On the other hand, some patients with an early viable intrauterine pregnancy may have no visible findings on initial ultrasound, but have serum beta-hCG (quantitative) levels well above the DZ. Although rare, EP has even been demonstrated in women with negative urine beta hCG tests or low serum beta-hCG levels. CONCLUSIONS: While EP may be a challenging diagnosis, understanding the myths surrounding EP may help emergency physicians consider it, even when patient risk factors, symptoms, or ED laboratory or imaging studies do not initially or easily define the diagnosis. PMID- 29110977 TI - Clinical Mimics: An Emergency Medicine-Focused Review of Syncope Mimics. AB - BACKGROUND: Syncope is an event that causes a transient loss of consciousness (LOC) secondary to global cerebral hypoperfusion. The transient nature of the event can make diagnosis in the emergency department (ED) difficult, as symptoms have often resolved by time of initial presentation. The symptoms and presentation of syncope are similar to many other conditions, which can lead to difficulty in establishing a diagnosis in the ED. OBJECTIVE: This review evaluates patients presenting with a history concerning for possible syncope, mimics of syncope, and approach to managing syncope mimics. DISCUSSION: Syncope is caused by transient LOC secondary to global cerebral hypoperfusion. Many conditions can present similarly to syncope, making diagnosis in the ED difficult. Some of the most emergent conditions include seizures, stroke, metabolic disorders, and head trauma. Other nonemergent conditions include cataplexy, pseudosyncope, or deconditioning. Many laboratory studies and imaging can be nondiagnostic during ED evaluation. For patients presenting with apparent syncope, immediate treatment should focus on identifying and treating life threatening conditions. History and physical examination can help guide further diagnostic evaluation and management. CONCLUSIONS: Patients with apparent syncope should be evaluated for potential immediate life-threatening conditions. A thorough history and physical examination can aid in distinguishing syncope from common mimics and help identify and subsequently treat life-threatening conditions. PMID- 29110978 TI - Mumps: An Emergency Medicine-Focused Update. AB - BACKGROUND: Mumps is a Paramyxoviridae virus. This disease was rampant prior to introduction of the measles, mumps, and rubella vaccine, resulting in decreased incidence. This disease has demonstrated several outbreaks. OBJECTIVE: This review provides a focused evaluation of mumps, an update on outbreaks, management recommendations, and ways to decrease transmission. DISCUSSION: Clusters of mumps outbreaks continue to occur. The virus is a paramyxovirus, a single-stranded RNA virus. The vaccine can provide lifelong immunity if administered properly, though prior to 1967 and introduction of the vaccine, the virus was common. In the past decade, there have been several notable outbreaks. Humans are the only known hosts, with disease spread through exposure to droplets and saliva. Factors affecting transmission include age, compromised immunity, time of year, travel, and vaccination status. Upper respiratory symptoms, fever, and headache are common, with unilateral or bilateral parotitis, and the virus may spread to other systems. Diagnosis is clinical, though polymerase chain reaction and immunoglobulin testing are available. This review provides several recommendations for vaccine in pregnancy, patients living in close quarters, health care personnel, and those immunocompromised. Treatment is generally supportive, with emphasis on proper isolation to prevent widespread outbreaks. Although reporting regulations and procedures vary by state, mumps is reportable in most states. CONCLUSIONS: Mumps is an easily spread virus. Although vaccination is the most effective way to prevent transmission, early recognition of the disease is crucial. As an emergency physician, it is important to recognize the clinical presentation, recommended testing, treatment, and isolation procedures. PMID- 29110979 TI - Complications from Administration of Vasopressors Through Peripheral Venous Catheters: An Observational Study. AB - BACKGROUND: The placement of a central venous catheter for the administration of vasopressors is still recommended and required by many institutions because of concern about complications associated with peripheral administration of vasopressors. OBJECTIVE: Our aim was to determine the incidence of complications from the administration of vasopressors through peripheral venous catheters (PVC) in patients with circulatory shock, and to identify the factors associated with these complications. METHODS: This was a prospective, observational study conducted in the emergency department (ED) of a tertiary care medical center. Patients presenting to the ED with circulatory shock and in whom a vasopressor was started through a PVC were included. Research fellows examined the i.v. access site for complications twice daily during the period of peripheral vasopressor administration, then daily up to 48 h after treatment discontinuation or until the patient expired. RESULTS: Of the 55 patients that were recruited, 3 (5.45% overall, 6% of patients receiving norepinephrine) developed complications; none were major. Two developed local extravasation and one developed local thrombophlebitis. All three complications occurred during the vasopressor infusion, none in the 48 h after discontinuation, and none required any medical or surgical intervention. Two of the three complications occurred in the hand, and all occurred in patients receiving norepinephrine and with 20-gauge catheters. CONCLUSIONS: The incidence of complications from the administration of vasopressors through a PVC is small and did not result in significant morbidity in this study. Larger prospective studies are needed to better determine the factors that are associated with these complications, and identify patients in whom this practice is safe. PMID- 29110980 TI - Benign Migratory Glossitis. PMID- 29110981 TI - Distributive Shock in a Neonate with Diffuse Infantile Hepatic Hemangioma. AB - BACKGROUND: Hemangiomas are common cutaneous findings on healthy infants. These vascular malformations are generally benign, though in rare circumstances they can potentially be fatal. This is particularly true when the hemangiomas are large or numerous and occurring in visceral organs. Previously unrecognized visceral hemangiomas are part of the differential for any neonate presenting unexpectedly in shock. CASE REPORT: A 10-day-old neonate presented to the pediatric emergency department with difficulty breathing. On examination, he appeared to be in respiratory distress and in shock. Echocardiography showed cardiomegaly, and an abdominal ultrasound showed a massive and heterogeneous liver. Magnetic resonance imagine performed after stabilization in the pediatric intensive care unit verified the presence of diffuse infantile hepatic hemangiomas. This case demonstrates how numerous visceral hemangiomas can generate high-volume vascular steal, distributive shock, and cardiac failure. Our patient was subsequently noted to have bruits over his liver. WHY AN EMERGENCY PHYSICIAN SHOULD BE AWARE OF THIS?: Diffuse hemangiomas and arteriovenous malformations are rare causes of extrinsic cardiogenic shock in the neonate. Targeted palpation of an enlarged liver or auscultation of a right upper quadrant bruit can raise suspicion of this diagnosis. PMID- 29110982 TI - Point-of-Care Ultrasound is Associated With Decreased Length of Stay in Children Presenting to the Emergency Department With Soft Tissue Infection. AB - BACKGROUND: Point-of-care ultrasound (POCUS) is increasingly being used to differentiate cellulitis from abscess in the pediatric emergency department (ED). POCUS has also been shown to decrease length of stay (LOS) for other applications among adult patients. OBJECTIVE: We sought to determine if ED LOS differed for children presenting with skin and soft tissue infections who received POCUS versus radiology-performed ultrasound. METHODS: We performed a retrospective cohort study of children presenting to an urban pediatric ED between January 2011 and June 2013 with a diagnosis of cellulitis or abscess who underwent soft tissue ultrasound. Patients who received a surgical consult, had significant medical comorbidities, or had a lesion located on the face, hands, feet, or groin were excluded. We compared ED LOS among children who received radiology-performed ultrasound to children who received POCUS, adjusting for relevant clinical variables. RESULTS: Among 3094 children with a diagnosis of cellulitis or abscess, we identified 202 who underwent a POCUS and 118 who underwent radiology performed ultrasound. The POCUS group had a shorter median LOS than the radiology performed ultrasound group (adjusted median difference -73 min; 95% confidence interval -93.6 to -52.4 min). In the subset of patients discharged from the ED, this difference was more pronounced (adjusted median difference -89 min; 95% confidence interval -109.9 to -68.1 min). CONCLUSION: Among children presenting to a pediatric ED with superficial skin and soft tissue infections, children receiving POCUS experienced shorter LOS compared to children receiving radiology performed ultrasound. PMID- 29110983 TI - View From the Top: Point-of-Care Ultrasound Diagnosis of Type A Aortic Dissection Using the Suprasternal View. PMID- 29110984 TI - In honour of the 60th birthday of Professor Bezhan Chankvetadze. PMID- 29110986 TI - The synthesis of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as potent CRTh2 antagonists. AB - New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay. PMID- 29110987 TI - Corrigendum to "A novel intestinal-restricted FXR agonist" [Bioorg Med Chem Lett 27 (2017) 3386-3390]. PMID- 29110985 TI - Cyclotides, a versatile ultrastable micro-protein scaffold for biotechnological applications. AB - Cyclotides are fascinating microproteins (~30-40 residues long) with a unique head-to-tail cyclized backbone, stabilized by three disulfide bonds forming a cystine knot. This unique topology makes them exceptionally stable to chemical, thermal and biological degradation compared to other peptides of similar size. Cyclotides have been also found to be highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, able to cross cellular membranes and modulate intracellular protein-protein interactions both in vitro and in vivo. These properties make them ideal scaffolds for many biotechnological applications. This article provides and overview of the properties of cyclotides and their applications as molecular imaging agents and peptide-based therapeutics. PMID- 29110988 TI - Resveratrol analogues like piceatannol are potent antioxidants as quantitatively demonstrated through the high scavenging ability against reactive oxygen species and methyl radical. AB - Resveratrol (RSV) analogues have attracted much attention because of the expected health functions including antioxidant activities. We have carried out a quantitative determination of the scavenging abilities of six trans-RSV analogues against various reactive oxygen species and methyl radical (hydroxyl radical, superoxide, alkoxyl radical, peroxyl radical, methyl radical, and singlet oxygen). RSV analogues are in general more potent scavenger than the parent RSV. Furthermore, piceatannol (PIC) having two OH groups in the ortho position of resveratrol was found to show 11 times higher scavenging ability against peroxyl radical than parent resveratrol. With the aid of previous theoretical studies, the enhanced antioxidant ability was interpreted based on the effects of substituent that modifies the original resveratrol structure and function. PMID- 29110990 TI - Transjugular intrahepatic portosystemic shunt as a bridge to non-hepatic surgery in cirrhotic patients with severe portal hypertension: a systematic review. AB - BACKGROUND: Portal hypertension (PHTN) increases the risk of non-hepatic surgery in cirrhotic patients. This first systematic review analyzes the place of transjugular intrahepatic portosystemic shunt (TIPS) in preparation for non hepatic surgery in such patients. METHODS: Medline, EMBASE, and Scopus databases were searched from 1990 to 2017 to identify reports on outcomes of non-hepatic surgery in cirrhotic patients with PHTN prepared by TIPS. Feasibility of TIPS and the planned surgery, and the short- and long-term outcomes of the latter were assessed. RESULTS: Nineteen studies (64 patients) were selected. TIPS was indicated for past history of variceal bleeding and/or ascites in 22 (34%) and 33 (52%) patients, respectively. The planned surgery was gastrointestinal tract cancer in 38 (59%) patients, benign digestive or pelvic surgery in 21 (33%) patients and others in 4 (6%) patients. The TIPS procedure was successful in all, with a nil mortality rate. All patients could be operated within a median delay of 30 days from TIPS (mortality rate = 8%; overall morbidity rate = 59.4%). One year overall survival was 80%. CONCLUSIONS: TIPS allows non-hepatic surgery in cirrhotic patients deemed non operable due to PHTN. Further evidence in larger cohort of patients is essential for wider applicability. PMID- 29110989 TI - Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases. AB - To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram positive bacterial strains. PMID- 29110991 TI - Using GPS, accelerometry and heart rate to predict outdoor graded walking energy expenditure. AB - OBJECTIVES: To determine the best method and combination of methods among global positioning system (GPS), accelerometry, and heart rate (HR) for estimating energy expenditure (EE) during level and graded outdoor walking. DESIGN: Thirty adults completed 6-min outdoor walks at speeds of 2.0, 3.5, and 5.0kmh-1 during three randomized outdoor walking sessions: one level walking session and two graded (uphill and downhill) walking sessions on a 3.4% and a 10.4% grade. EE was measured using a portable metabolic system (K4b2). Participants wore a GlobalSat(r) DG100 GPS receiver, an ActiGraphTM wGT3X+ accelerometer, and a Polar(r) HR monitor. Linear mixed models (LMMs) were tested for EE predictions based on GPS speed and grade, accelerometer counts or HR-related parameters (alone and combined). Root-mean-square error (RMSE) was used to determine the accuracy of the models. Published speed/grade-, count-, and HR-based equations were also cross-validated. RESULTS: According to the LMMs, GPS was as accurate as accelerometry (RMSE=0.89-0.90kcalmin-1) and more accurate than HR (RMSE=1.20kcalmin-1) for estimating EE during level walking; GPS was the most accurate method for estimating EE during both level and uphill (RMSE=1.34kcalmin 1)/downhill (RMSE=0.84kcalmin-1) walking; combining methods did not increase the accuracy reached using GPS (or accelerometry for level walking). The cross validation results were in accordance with the LMMs, except for downhill walking. CONCLUSIONS: Our study provides useful information regarding the best method(s) for estimating EE with appropriate equations during level and graded outdoor walking. PMID- 29110992 TI - Letter to the editor. PMID- 29110993 TI - Anterior temporal artery to posterior cerebral artery bypass for revascularization of the posterior circulation: An anatomical study. AB - We describe a novel intracranial-to-intracranial bypass technique between the anterior temporal artery and the posterior cerebral artery for revascularization of the posterior circulation. Four formalin-fixed human heads were examined to demonstrate the detailed anatomy of the middle cerebral artery and the posterior cerebral artery, and to illustrate the step-by-step bypass procedure. The anterior temporal artery, a branch of the middle cerebral artery, can be anastomosed to the P2 segment of the posterior cerebral artery as an alternative to extracranial bypass donor segments for treatment of complex aneurysms requiring revascularization. The anastomosis of the anterior temporal artery as a pedicled donor to the posterior cerebral artery provides a shorter graft, due to its close anatomical position to the posterior cerebral artery, for posterior circulation revascularization. PMID- 29110994 TI - Spinal cord involvement in primary CNS lymphoma. AB - LETM is a common syndrome and the diagnosis of CNS lymphoma is not usually considered in the list of differentials. Primary CNS lymphoma can present as longitudinally extensive transverse myelopathy. Failure to suspect and evaluate leads to delay in diagnosis and treatment. PCNSL may be non contrast enhancing on gadolinium enhanced MRI. CSF analysis should be done preferably before starting corticosteroids as it is usual practice in treatment of transverse myelitis, as steroids may lead to transient improvement and mask the correct diagnosis. Repeated CSF examinations may be needed to clinch the diagnosis. PMID- 29110995 TI - On the road to atrial fibrillation. PMID- 29110997 TI - Spinal nerve involvement in early Guillain-Barre syndrome: The Haymaker and Kernohan's legacy. AB - Pathological studies of early Guillain-Barre syndrome (GBS), defined as of 10days of disease onset, are scanty making it difficult to interpret the physiopathology of clinical and electrophysiological features. In 1949, Webb Haymaker and James Kernohan reported 50 clinico-pathological studies of fatal GBS cases, 32 of them having died between days 2 and 10 after onset. They established that the brunt of initial lesions, consisting of endoneurial oedema interpreted as degenerative, relied on spinal nerves. That this oedema was inflammatory was soon thereafter recognized. Two decades later, however, the pathogenic role of endoneurial oedema was disputed. In experimental allergic neuritis, considered an animal model of GBS, the initial lesion appearing on day 4 post-inoculation is marked inflammatory oedema in the sciatic nerve and lumbosacral nerve roots. Additional detailed clinico-pathological studies corroborated that the appearance of epi perineurium at the subarachnoid angle, where anterior and posterior roots join to form the spinal nerve, is a pathological hotspot in early GBS, there developing inflammatory oedema, incipient demyelination and endoneurial ischemic zones with axonal degeneration. Furthermore, nerve ultrasonography has demonstrated predominant spinal nerve changes in early GBS, either demyelinating or axonal. Other outstanding Haymaker and Kernohan's contributions were to clarify the complex nosology of the syndrome bringing under the same rubric Landry's paralysis, acute febrile polyneuritis and GBS, and critically analyzing GBS exclusion criteria by then prevailing. It is concluded that the authors' legacy remains as relevant as ever. PMID- 29110996 TI - Atrial ectopy as a mediator of the association between race and atrial fibrillation. AB - BACKGROUND: Blacks have a lower risk of atrial fibrillation (AF) despite having more AF risk factors, but the mechanism remains unknown. Premature atrial contraction (PAC) burden is a recently identified risk factor for AF. OBJECTIVE: The purpose of this study was to determine whether the burden of PACs explains racial differences in AF risk. METHODS: PAC burden (number per hour) was assessed by 24-hour ambulatory electrocardiographic (ECG) monitoring in a randomly selected subset of patients in the Cardiovascular Health Study. Participants were followed prospectively for the development of AF, diagnosed by study ECG and hospital admission records. RESULTS: Among 938 participants (median age 73 years; 34% black; 58% female), 206 (22%) developed AF over a median follow-up of 11.0 years (interquartile range 6.1-13.4). After adjusting for age, sex, body mass index, coronary disease, congestive heart failure, diabetes, hypertension, alcohol consumption, smoking status, and study site, black race was associated with a 42% lower risk of AF (hazard ratio 0.58, 95% confidence interval [CI] 0.40 0.85; P = .005). The baseline PAC burden was 2.10 times (95% CI 1.57-2.83; P <.001) higher in whites than blacks. There was no detectable difference in premature ventricular contraction (PVC) burden by race. PAC burden mediated 19.5% (95% CI 6.3-52.5) of the adjusted association between race and AF. CONCLUSION: On average, whites exhibited more PACs than blacks, and this difference statistically explains a modest proportion of the differential risk of AF by race. The differential PAC burden, without differences in PVCs, by race suggests that identifiable common exposures or genetic influences might be important to atrial pathophysiology. PMID- 29110998 TI - Total small vessel disease burden and brain network efficiency in cerebral amyloid angiopathy. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with hemorrhagic and nonhemorrhagic markers small vessel disease (SVD). A composite score to quantify the total burden of SVD on MRI specifically for CAA patients was recently developed. Brain network alterations related to individual MRI markers of SVD in CAA were demonstrated. OBJECTIVES: Considering diffusion based network measures sensitive to detect different relevant SVD-related brain injury, we investigated if increased overall SVD injury on MRI corresponds to worse global brain connectivity in CAA. METHODS: Seventy-three patients (79.5% male, mean age 70.58+/-8.22years) with a diagnosis CAA were considered. SVD markers in total MRI SVD score included: lobar cerebral microbleeds, cortical superficial siderosis (cSS), white matter hyperintensities (WMH) and centrum semiovale-enlarged perivascular spaces. Diffusion imaging based network reconstruction was made. The associations between total MRI SVD score and global network efficiency (GNE) were analyzed. RESULTS: A modest significant inverse correlation between total MRI SVD score and GNE existed (p=0.013; R2=0.07). GNE was related with the presence of cSS and moderate-severe WMHs. CONCLUSIONS: An increased burden of SVD neuroimaging markers corresponds to more reductions in global brain connectivity, implying a possible cumulative effect of overall SVD markers on disrupted physiology. GNE was related with some components of the score, specifically cSS and moderate-severe WMHs. PMID- 29110999 TI - About 30% of wake-up stroke patients may be candidate for the tPA therapy using Negative-FLAIR as a "tissue clock". AB - BACKGROUND AND PURPOSE: Recent studies using magnetic resonance imaging (MRI) have reported that wake-up stroke (WUS) patients may be able to be treated using tissue-plasminogen activator (tPA) when showing no ischemia on fluid-attenuated inversion recovery (Negative-FLAIR). We investigated the frequency of WUS and calculated what percentage of WUS patients with Negative-FLAIR meets most of the conventional tPA criteria. We did not include a time parameter in this study. METHODS: Consecutive patients with acute stroke affecting the anterior circulation who presented within 12h of onset were enrolled. All patients were examined using diffusion-weighted imaging (DWI) and FLAIR. As large infarctions are excluded from tPA therapy, an Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) of <=3 was used as the upper limit for exclusion. RESULTS: A total of 816 consecutive patients were included in the study and were separated into two groups; 163 (20%) WUS patients as the WUS group, and 653 (80%) non-WUS patients as the non-WUS group. The median National Institutes of Health Stroke Scale (NIHSS) score on admission was 7 (interquartile range, 3-17) in the WUS group and 8 (3-16) in the non-WUS group (p=0.313). MRI study revealed Negative-FLAIR in 67 (41%) of 163 patients in the WUS group. Of the 67 patients with Negative-FLAIR, 19 patients were excluded from tPA therapy. Therefore, 48 (29%) of the 163 wake-up stroke patients met the tPA criteria. CONCLUSIONS: About 30% of WUS patients may be candidates for tPA therapy based upon Negative-FLAIR findings. PMID- 29111000 TI - Natural history and predictors of survival in progressive supranuclear palsy. AB - BACKGROUND: Progressive supranuclear palsy is a neurodegenerative disorder characterized by high functional disability and rapidly progressive dependency. The predictors of survival are still unclear. METHODS: The predictors of survival were evaluated in a group of clinically diagnosed PSP patients, focusing primarily on extensive cognitive assessment. RESULTS: The mean survival time from symptom onset was 8.25+/-3.0years. Sex, age at onset, education, occupation and severity of extrapyramidal symptoms did not correlate with survival. The only factor associated with a shorter life expectancy in our cohort was the presence of dementia at diagnosis. Impairment of executive functions was the best predictor of an unfavorable outcome. CONCLUSIONS: Our findings suggest that dementia and executive functions need to be evaluated in order to define survival probability in PSP patients. PMID- 29111001 TI - The professional practice and training of neurology in the Asian and Oceanian Region: A cross-sectional survey by the Asian and Oceanian Association of Neurology (AOAN). AB - OBJECTIVE: To survey AOAN member countries regarding their organizational structure, postgraduate neurology training program, and resources for neurological care provision. METHODOLOGY: A cross-sectional survey using a 36 item questionnaire was conducted among country representatives to AOAN from August 2015 to August 2016. RESULTS: A total of 18/20 AOAN member countries participated in the survey. All the countries have organized association with regular meetings, election of officers and neurology training program. In 9/18 countries, professionals other than neurologists were eligible for affiliation. In 11/18 countries, prior Internal medicine training (or equivalent postgraduate housemanship) is prerequisite to neurology program. Recertification examination is not a practice, but submission of CME is required in 7/18 countries to maintain membership. 12/18 countries publish peer-reviewed journals with at least 1 issue per year. Subspecialty training is offered in 14/18 countries. The ratio of neurologist to population ranges from 1:14,000 to as low as 1:32 million with 9/18 having <1 neurologist per 100,000 population. 6/18 countries have at least 1 specialized center solely for neurological diseases. In government-funded hospitals, the lag time to be seen by a neurologist and/or obtain neuroimaging scan ranges from 1day to 3months. All except one country have several medical- and lay- advocacy or support groups for different neurological conditions. IMPLICATIONS: The data generated can be used for benchmarking to improve neurological care, training, collaborative work and research in the field of neurosciences among the AOAN member countries. The paper presented several strategies used by the different organizations to increase their number of neurologists and improve the quality of training. Sharing of best practices, academic networking, exchange programs and use of telemedicine have been suggested. PMID- 29111002 TI - Free fatty acid as a determinant of ischemic lesion volume in nonarterial-origin embolic stroke. AB - GOALS: This study aimed to determine whether the plasma levels of free fatty acid (FFA) are associated with ischemic lesion characteristics in nonarterial-origin embolic stroke. MATERIALS AND METHODS: We prospectively recruited 254 patients with acute cerebral infarction caused by cardioembolic stroke (CES, n=121) or with embolic stroke of undetermined source (ESUS, n=133). Plasma levels of FFA were measured during the acute stage (median of 2days after stroke onset). Acute ischemic lesions on diffusion-weighted imaging were measured in terms of size, composition, and pattern. Transthoracic echocardiography parameters were evaluated in all patients. FINDINGS: Plasma levels of FAA were not different in CES and ESUS patients (mEq/L, 0.78+/-0.52 vs. 0.67+/-0.61, P=0.120). Echocardiography parameters, including left atrium volume index and E/e', were higher, and the ischemic lesion volume was larger in patients with CES than in those with ESUS. The ischemic lesion volume and the proportion of patients with mixed (small and large) and large cortical lesions increased with FFA quartile in both CES and ESUS groups. In a multivariable analysis, FFA level (coefficient, 5.249; standard error, 3.447; P=0.001), atrial fibrillation (coefficient, 7.673; standard error, 1.855; P<0.001), and fasting glucose (coefficient, 0.104; standard error, 0.023; P<0.001) were associated with ischemic lesion volume in nonarterial-origin embolic stroke. CONCLUSION: Elevated plasma FFA levels are associated with larger ischemic lesion volumes and a higher prevalence of large cortical infarcts in patients with nonarterial-origin embolic stroke regardless of the presence of a high-risk cardioembolic source. PMID- 29111003 TI - Early and late seizures associated to Niccolo Paganini's viral encephalitis. PMID- 29111004 TI - Fluctuating ataxia and nystagmus in association with anti-GQ1b antibody in HIV infection. PMID- 29111005 TI - Impact of non-guideline-based treatment of status epilepticus. AB - BACKGROUND: This retrospective study analyzed benzodiazepine usage patterns in relation to guideline recommendations for the treatment of generalized convulsive status epilepticus (GCSE) as practiced by emergency medical services (EMS) and the emergency department (ED) of an inner-city hospital. Secondary outcomes of interest were adverse events and admission/discharge outcomes. METHODS: Records of all patients>=18years old diagnosed with GCSE between June 2012 and September 2015 and transported by EMS to our hospital ED were reviewed. RESULTS: Of 44 patients analyzed, 43 (98%) had a history of epilepsy. Benzodiazepine utilization varied; EMS preferred midazolam (69% of cases) while the ED utilized lorazepam (91% of cases). Benzodiazepine dosages used were lower than guideline recommendations. Seizure activity was aborted with benzodiazepines alone in 22 (50%) patients. Twelve patients (27%) experienced seizure recurrence following SE treatment and achievement of seizure cessation. Twenty-three (52%) patients required intubation after arrival to ED. All 44 patients were admitted; 30 (68%) required admission to the intensive care unit. CONCLUSIONS: There was consistent underdosing of benzodiazepines in treatment of GCSE in both EMS and ED settings likely resulting in underachievement of seizure cessation, while intubation rates were higher than reported when compared to previous studies. Prospective studies are needed to identify barriers to optimal benzodiazepine usage in GCSE patients. PMID- 29111006 TI - A complex association between ABCA7 genotypes and blood lipid levels in Southern Chinese Han patients of sporadic Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive cognitive decline. It can be divided into familial AD (FAD) and sporadic AD (SAD) based on the family history. Recently dysregulation of cholesterol homeostasis has been implicated in the development of late-onset AD. ATP-binding cassette transporter A7 (ABCA7) gene, regulating the transport of cholesterol, has been recently identified as a susceptible gene of AD by several large genome-wide association studies. To test the genetic effect of ABCA7 rs3764650 on blood lipid levels in Southern Chinese Han population and investigate the risk factors of SAD, a total of 118 SAD patients and 120 healthy matched controls were recruited and the genotyping in ABCA7 rs3764650 was conducted on the Sequenom MassARRAY iPLEX platform. Meanwhile, the levels of fasting lipid profile and mini-mental state examination (MMSE) scores were tested. There was significant difference in genotype distribution between SAD patients and controls (p=0.001). While the difference of ABCA7 rs3764650 allele distribution between SAD patients and controls was only significant in APOEepsilon4-noncarriers (p=0.039). The association between blood lipid levels and ABCA7 rs3764650 genotypes was influenced by APOEepsilon4 status. In APOEepsilon4-noncarriers of SAD, the total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels in GG genotype group were significantly lower than those in GT and TT genotype groups (all p<0.05). Whereas no significant difference of blood lipid levels was found among three genotypes in APOEepsilon4-carriers of SAD and controls. Additionally, logistic regression analysis showed that lower high-density lipoprotein cholesterol (HDL-C) levels (p=0.015, OR=5.669) and GG genotype (p=0.013, OR=8.318) were positively associated with SAD. Our results suggest that GG genotype of ABCA7 rs3764650 was a risk factor of SAD in Southern Chinese Han population as well as lipid homeostasis. PMID- 29111007 TI - Performed and perceived walking ability in relation to the Expanded Disability Status Scale in persons with multiple sclerosis. AB - BACKGROUND: The severity of walking impairment in persons with multiple sclerosis (pwMS) at different levels on the expanded disability status scale (EDSS) is unclear. Furthermore, it is unclear if the EDSS is differently related to performed- and perceived walking capacity tests. AIMS: To quantify walking impairment and perceived impact of MS on walking according to EDSS scores and to examine the relations between these parameters in pwMS. METHODS: EDSS was collected by neurologists and walking was assessed by the timed 25ft walk test (T25FWT), two minute walk test (2MWT), six minute walk test (6MWT) and the 12 item MS walking scale (MSWS-12) in 474 PwMS with mild (EDSS 1-4: n=200) to moderate (EDSS 4.5-6.5: n=274) MS. Magnitude of walking impairment was calculated and related to EDSS. RESULTS: Compared to predicted values in healthy controls, walking speed was reduced by 41.5+/-25.8% in the 6MWT for the total MS group and by 21.8+/-20.2% and 55.8+/-19.1% in the mild and moderate MS subgroups, respectively. The EDSS score showed the strongest relationship to the 2MWT and the 6MWT in the total MS group (r=-0.76, p<0.0001), to the MSWS-12 score in the mild MS group (r=0.56, p<0.0001), and to the 2MWT in the moderate MS group (r= 0.50, p<0.0001). CONCLUSION: In pwMS (EDSS scores 1-6.5), walking speed is on average reduced by ~40% when compared to predicted values in healthy controls, and impairments are already present at early disease stages, suggesting early initiation of rehabilitation. The 2MWT and 6MWT show the strongest relationship to EDSS, but the MSWS-12 identify impairments more gradually at low EDSS scores. PMID- 29111008 TI - Management of blood pressure in acute stroke: Comparison of current prescribing patterns with AHA/ASA guidelines in a Sub-Saharan African referral hospital. AB - BACKGROUND: High blood pressure (HBP) is common at acute phase of stroke. It may reflect untreated or uncontrolled hypertension before stroke, or it may relate to stress response. The present study was designed to compare current American Stroke Association (ASA) guidelines with actual prescribing patterns for management of HBP at the acute phase of stroke, in a tertiary care Hospital in Douala, Cameroon. METHODS: This cross-sectional study was conducted in the Cardiology and Neurology department of the Douala Laquintinie Hospital. Consenting patients with sign of stroke, confirmed by a brain CT-scan, who consented to participate in the study were recruited from March to July 2012. The use of antihypertensive medications (type, dose, routes of administration, BP recordings) in the first three days after admission was noted. RESULTS: One hundred and eleven patients were recruited including 59 men (53.1%). The mean age of patients was 60.9+/-12.3years, 70 patients (63%) had ischemic stroke and 41 (37%) hemorrhagic. Sixty two (55.8%) patients had hypertension severe enough to warrant treatment upon arrival. There was an overtreatment rate of 46.9% and undertreatment rate of 9.7%. CONCLUSION: The ASA guidelines were broadly respected by practitioners for patients who required treatment, but those who do not need treatment were overtreated. These findings support the need for more research to improve treatment guidelines as well as patient management. PMID- 29111010 TI - Writing tremor: Should we look for a TOR1A mutation? PMID- 29111009 TI - Novel biallelic missense mutations in CTC1 gene identified in a Chinese family with Coats plus syndrome. AB - BACKGROUND: Coats plus syndrome is a recently described, very rare multisystem disorder. The clinical phenotype is wide and variable, which making the diagnosis more difficulty. The genetic study of Coats plus syndrome has been reported recently. The biallelic heterozygous mutations in CTC1 gene, encoding conserved telomere maintenance component 1, were identified in families with Coats plus from different ancestry (European, American, and African). To data, there has not been a report about genetically confirmed Coats plus syndrome from China. RESULTS: We firstly identify a novel biallelic heterozygous missense variants (c.775G>A p.V259M and c.2066A>G p.Y689C) of CTC1 gene in a Chinese family with Coats plus. The c.2066A>G mutation (p.Y689C) in CTC1 is a novel variant. Such variant was not found in any of the 85 healthy individuals in the same community. CONCLUSION: This is the first report of a genetically confirmed case of Coats plus from China. Targeted sequencing of CTC1 gene is useful for genetic diagnosis in Coats plus and differential diagnosis for other patients with similar disease manifestations. PMID- 29111011 TI - Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: A 3-year follow-up multicentric study. AB - BACKGROUND: Health-related quality of life (HRQoL) is impaired in multiple sclerosis (MS) but can be improved by disease-modifying therapies such as natalizumab. However, the predictive factors and neuropsychiatric correlates of HRQoL improvement are unknown. METHODS: In this study, 48 patients with relapsing remitting MS were included in a 3-year open-label, single group, multicenter, clinical trial (NCT01392872). HRQoL was measured by the disease-specific MusiQoL questionnaire, together with physical disability, cognition, fatigue, anxiety and depression scores at baseline, 6months, 12months, 18months and 36months after starting natalizumab therapy. RESULTS: Compared to baseline, global HRQoL, as measured with the index of the MusiQoL, was significantly increased 6months after the beginning of natalizumab therapy, with medium effect-size (58.6+/-16.2 vs 69.8+/-18.9, p<0.001, Cohen's d=0.63). This improvement was maintained over time for up to 3years and mainly concerned activity of daily living, psychological well-being, symptoms and coping (p<0.001 for every dimensions). The variation of global HRQoL after 3years was negatively correlated with the variation of fatigue score (r=-0.44, p=0.015). Furthermore, a higher fatigue score at baseline was correlated with improvement in global HRQoL 3years afterwards (r=0.34, p=0.041), independently of age, educational level, disease duration and disability at baseline (beta=2.45, p=0.020). Disability at baseline, cognitive impairment, anxiety and depression failed to predict or correlate with global HRQoL improvement in multivariate analyses. CONCLUSION: Natalizumab improved HRQoL quickly and sustainably in patients with relapsing-remitting MS. In terms of HRQoL, natalizumab seems to benefit mostly patients with more marked fatigue at baseline. PMID- 29111013 TI - Genotype-phenotype and OCT correlations in Autosomal Dominant Optic Atrophy related to OPA1 gene mutations: Report of 13 Italian families. AB - Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n=60) and Optical Coherence Tomography (OCT) (n=12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age. Presence of plus phenotypes was investigated. We found four known mutations, the most common being missense c.1034G>A, and a new missense mutation, c1193A>C, the latter in a 54-yrs old female with late-onset phenotype. Visual acuity, colour sensitivity, and optic disc atrophy were sensitive indicators of disease. OCT RNFL thickness was reduced in OPA1 compared to controls. OPA-M showed worst visual acuity than OPA-H, but not more frequent plus-phenotype, observed only in four OPA-H patients. In both groups, visual acuity worsened with age. Our data confirm worst vision in OPA-M, but not increased plus-phenotype. Since most patients belonged to nine families from south-eastern Sicily (a famous region for the cult of St. Lucy, patron of the blinds) local genetic and environmental factors might have accounted for the low occurrence of plus-phenotypes. PMID- 29111012 TI - Advancing stroke genomic research in the age of Trans-Omics big data science: Emerging priorities and opportunities. AB - BACKGROUND: We systematically reviewed the genetic variants associated with stroke in genome-wide association studies (GWAS) and examined the emerging priorities and opportunities for rapidly advancing stroke research in the era of Trans-Omics science. METHODS: Using the PRISMA guideline, we searched PubMed and NHGRI- EBI GWAS catalog for stroke studies from 2007 till May 2017. RESULTS: We included 31 studies. The major challenge is that the few validated variants could not account for the full genetic risk of stroke and have not been translated for clinical use. None of the studies included continental Africans. Genomic study of stroke among Africans presents a unique opportunity for the discovery, validation, functional annotation, Trans-Omics study and translation of genomic determinants of stroke with implications for global populations. This is because all humans originated from Africa, a continent with a unique genomic architecture and a distinctive epidemiology of stroke; as well as substantially higher heritability and resolution of fine mapping of stroke genes. CONCLUSION: Understanding the genomic determinants of stroke and the corresponding molecular mechanisms will revolutionize the development of a new set of precise biomarkers for stroke prediction, diagnosis and prognostic estimates as well as personalized interventions for reducing the global burden of stroke. PMID- 29111015 TI - MOG-IgG-positive multifocal myelitis with intrathecal IgG synthesis as a spectrum associated with MOG autoimmunity: Two case reports. PMID- 29111014 TI - Negative myoclonus induced by gabapentin and pregabalin: A case series and systematic literature review. AB - INTRODUCTION: Negative myoclonus is a jerky, brief, and sudden interruption of voluntary muscle contraction. Although gabapentin and pregabalin have been reported to induce positive myoclonus in some patients with impaired renal function, there are only a few studies describing pregabalin- or gabapentin induced negative myoclonus. This study reviewed patients who had developed pregabalin- or gabapentin-induced negative myoclonus. METHODS: We collected the patients with negative myoclonus who were referred to the department of neurology at a university-affiliated hospital and selected pregabalin- or gabapentin induced negative myoclonus. Then reviewed the literature with respect to pregabalin- or gabapentin-induced negative myoclonus. RESULTS: A total of 77 patients with negative myoclonus were reviewed. Among them, 21 neuropathic pain patients who were prescribed and developed negative myoclonus induced by pregabalin (9 cases) or gabapentin (12 cases). To prove causality of the drug, probable and certain level of category according to the WHO-UMC criteria were recruited. Of the 21 patients, 3 had impaired renal function, while 18 had normal renal function. Review of the literature identified 7 further cases (6 had normal renal function) with pregabalin- or gabapentin-induced negative myoclonus. CONCLUSION: Pregabalin- and gabapentin-induced negative myoclonus can develop even in patients with normal renal function. Physicians should keep in mind the possibility of patients developing negative myoclonus under treatment of pregabalin or gabapentin even in short period of time and with low dosage, and in the normal range of renal function. Further prospective study investigating incidence and risk factors is warranted. PMID- 29111016 TI - MOG antibody-associated optic neuritis in the setting of acute CMV infection. PMID- 29111017 TI - Dopamine agonist withdrawal syndrome in Parkinson's disease. PMID- 29111018 TI - Embolic stroke of undetermined source: The role of the nonstenotic carotid plaque. AB - Cryptogenic stroke, or stroke of undetermined cause, presents a remarkably challenging dilemma for the treating physician as there are limited therapeutic options to prevent recurrence. Roughly one third of transient ischemic attacks (TIAs) and ischemic strokes are classified as cryptogenic, with an even greater proportion in young patients. While classification systems have been successfully used in trials to refine therapeutic approaches specific to subtype, there has been little progress made in secondary prevention of cryptogenic stroke. The cryptogenic stroke/ESUS International Working Group recently proposed a new entity under the realm of cryptogenic stroke called embolic stroke of undetermined source (ESUS). This clinical construct emerged from data suggesting thromboembolism as the primary etiology of cryptogenic strokes. While current trials are addressing covert atrial fibrillation as a significant source of embolism, more recent population data has called this hypothesis into question and illustrated the heterogeneity, and often multiplicity, of embolic sources. The importance of carotid artery plaques which do not cause significant stenosis as a source of emboli to the brain has generally been ignored given the long standing focus of using percent stenosis measurements as the primary criterion for defining high-risk carotid atherosclerotic disease. As part of the required diagnostic workup to define ESUS, vascular imaging, and advances therein, provides a unique opportunity to prospectively determine a subset of patients who may benefit from aggressive medical therapy or endovascular interventions in the prevention of recurrent ESUS. Here we review the role of the nonstenotic, and potentially vulnerable, carotid plaque in ESUS. PMID- 29111019 TI - A case report of multiple system atrophy treated with an Abelson tyrosine kinase inhibitor. PMID- 29111020 TI - Status epilepticus causing extensive microvacuolar change with astrocytosis and diffusion MRI abnormalities in the subcortical white matter. PMID- 29111021 TI - Differences in clinical characteristics when REM sleep behavior disorder precedes or comes after the onset of Parkinson's disease. AB - OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is important not only as a preclinical symptom of Parkinson's disease (PD), but also as an aggravating symptom of PD. However, it is not known whether the onset of RBD in relation to PD affects the clinical characteristics of PD. A cross-sectional study comparing clinical characteristics of PD between patients with RBD occurring before and after the onset of PD was conducted. METHODS: Interviews regarding RBD symptoms were conducted and polysomnography was performed on 136 patients with PD. Patients with PD were divided into a group with RBD and a group without RBD. Moreover, the group with RBD was subdivided into those with RBD before the onset of PD (RBD->PD) and those with RBD after the onset of PD (PD >RBD). Clinical characteristics of the patients with and without RBD, and PD with RBD->PD and PD->RBD were compared. RESULTS: Patients with RBD (47 PD patients) had more severe parkinsonian symptoms, autonomic dysfunction, and cognitive impairment than those without RBD (89 PD patients). Moreover, 38 PD patients with PD->RBD had greater cognitive impairment including Mini-metal examination than 9 with RBD->PD in spite of similar motor and autonomic dysfunction with similar dopaminergic agents. CONCLUSION: The occurrence of RBD after the onset of PD might be an important factor aggravating cognitive function. PMID- 29111022 TI - Association of freezing of gait with nigral iron accumulation in patients with Parkinson's disease. AB - BACKGROUND AND PURPOSE: The objective of this work was to investigate whether patients with and without freezing of gait (FOG) in Parkinson's disease (PD) have differences in iron accumulation in substantia nigra using R2* relaxometry. MATERIALS AND METHODS: This study included seventeen PD patients with FOG [FOG (+)], equal number of age and gender matched patients without FOG [FOG (-)] and 34 healthy controls (HC). T2* images were obtained from a 3-Tesla MRI system using multi-echo sequence. R2* values were extracted from Substantia Nigra (SN) and red nucleus and were compared among the three groups and correlated with clinical findings. RESULTS: R2* values were increased in PD group as a whole compared to HC in rostral and caudal segments of Substantia Nigra pars compacta (SNc) and in Substantia Nigra pars reticulata (SNr) but not in red nucleus. Within PD subgroups, FOG (+) group had increased iron accumulation in SNc compared to FOG (-) and HC. FOG score positively correlated with R2* values in the caudal region of SNc in FOG (+) group. CONCLUSIONS: Our study reveals higher nigral iron content in FOG (+) compared to FOG (-) and HCs. In addition, we observed positive correlation of FOG score with iron accumulation in SNc. Results of this study emphasize possible role of higher nigral iron content in the pathogenesis of FOG in PD. PMID- 29111023 TI - Can fibrinolytic system components explain cognitive impairment in multiple sclerosis? AB - BACKGROUND: The fibrinolytic system is capable of modulating inflammatory and degenerative events within the central nervous system. Specifically, the plasminogen activator inhibitor-1 (PAI-1) has been associated with different pathological conditions in multiple sclerosis (MS) and its role in cognitive functioning is also known. OBJECTIVES AND METHODS: To study the association between plasma levels and the polymorphic variants of the PAI-1 gene and cognitive performance in MS. 176 patients were studied. Neuropsychological evaluation was performed with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). A Polymerase Chain Reaction (PCR) was used to determine PAI-1 4G/5G polymorphisms and quantification was performed using an Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: Participants were categorized as not cognitively impaired (NCI; n=114) and cognitively impaired (CI; n=62). The NCI group had a higher percentage of heterozygous subjects but no statistical differences were found between the CI and NCI group. Neuropsychological functioning did not correlate with plasma levels of PAI-1 or its genetic polymorphism. It is noteworthy that PAI-1 plasma levels were related to neurological impairment. DISCUSSION: Cognitive impairment in MS is due to strategic focal lesions affecting regions and tracts involved in cognitive processes and to diffuse damage in the white and gray matter. This complex etiology could explain the absence of a relationship between the cognitive functioning and PAI-1 in patients with MS that has been found in vascular dementia or Alzheimer's disease. Plasma curves of PAI-1 and its measures in cerebrospinal fluid could help elucidate the role of PAI-1 in MS. PMID- 29111024 TI - Cognition and quality of life in clinically isolated syndrome patients starting a disease modifying therapy in the QUALICIS study may not predict treatment response at one year. AB - Cognition and health-related quality of life (HRQoL) are early involved in multiple sclerosis (MS). The aim of QUALICIS study was to monitor cognition and HRQoL prospectively in a cohort of clinically isolated syndrome (CIS) patients starting a treatment with subcutaneous beta-1b interferon as a first disease modifying treatment (DMT), and to assess their correlation with the clinical outcome 6years later. Relapse history, EDSS and yearly standardized brain MRI data were also collected. 37 patients were included. Cognition and HRQoL remained stable over treatment period. At baseline, we found that SDMT was moderately correlated to T2 lesion load (r=-0.47, p=0.04). Baseline SDMT was predictive of HRQoL at year 2 (r=0.53, p=0.02). Regarding 6-year outcome, the most specific predictive factor of favorable outcome was achieving "No Evidence of Disease Activity" (NEDA) status at year 1. In this group, all the patients had a stable EDSS score and none switched to a second line therapy. In the "non-NEDA" group, 44% of patients experienced EDSS worsening and 38.9% switched to a second line therapy. The number of gadolinium enhancing lesions on baseline scan was the only predictive factor of poor outcome in this subgroup of patients (2 vs. 0.13, p=0.03). Our results suggest that NEDA at 1year could be used to predict long term outcome after initiation of DMT in CIS. For non-NEDA patients, monitoring SDMT and brain atrophy could be potentially relevant, but this should be confirmed on a larger sample. PMID- 29111025 TI - Orthostatic hypotension associated with executive dysfunction in mild cognitive impairment. AB - INTRODUCTION: Midlife hypertension is associated with dementia in longitudinal studies while chronic hypotension in the elderly is associated with dementia onset. Orthostatic hypotension could influence cognitive performance in the elderly. The objective of this study was to assess the relationship between orthostatic hypotension and cognitive functions. METHODS: Consecutive participants with complete neuropsychological evaluation from a Memory Clinic were included. Orthostatic hypotension (OH) was defined by a fall>=20/10mmHg systolic/diastolic pressure. Participants were classified into one of 3 groups: 1) subjective cognitive impairment (SCI), 2) mild cognitive impairment (MCI), and 3) dementia. Neuropsychological tests were analyzed for patients with and without OH. RESULTS: One hundred and twenty participants were included, of which 16 (13%) were classified as SCI, 42 (35%) as MCI, and 63 (52%) with dementia. Prevalence of OH was 0% for the SCI group, 26% (n=11) for the MCI group, and 38% (n=24) for the dementia group. Age, sex, education, and brief cognitive test scores (MMSE & MoCA) were not different between groups with or without OH. In the MCI group, OH was associated with lower cognitive performance in several executive functions tests: visual working memory (p<0.001), processing speed (p=0.006), Stroop flexibility (p=0.030) and Trail-Making Test part B (p=0.024). There was no difference in episodic memory performance. OH was associated with a diagnosis of hypertension and the use of antihypertensive medication. No differences were observed in vascular brain injury between groups with and without OH. CONCLUSIONS: This study found that orthostatic hypotension prevalence is correlated to severity of cognitive deficits in a Memory Clinic. In MCI, OH is associated with lower performance in executive functions. OH could represent an under-recognized correlate of cognitive performance. PMID- 29111026 TI - A retrospective study of acetylcholine receptor antibody positive ocular myasthenia in the West of Scotland. AB - Ocular myasthenia is the milder end of the myasthenia gravis spectrum but treatment can be challenging especially in older patients. We retrospectively studied all patients on our database with ocular myasthenia (OMG), positive for acetylcholine receptor (AChR) antibodies. We identified 93 patients (64 men and 29 women). The mean age at disease onset was 63y, median 68y. Most (72%) experienced ptosis with diplopia; 19% experienced ptosis alone, while 7.5% complained of diplopia without ptosis. As expected, pyridostigmine was commenced early at diagnosis in the majority (69%) and 20% were still receiving pyridostigmine at final review. Immunosuppression was prescribed in 50%. Seven patients had ptosis repair surgery; 20 patients used prisms at some stage. >75% had several comorbidities. Our OMG cohort is an older population with several comorbidities. Final outcomes in those who received immunosuppression were similar to those who had not. PMID- 29111027 TI - Sequence configuration of spinocerebellar ataxia type 8 repeat expansions in a Japanese cohort of 797 ataxia subjects. AB - Spinocerebellar ataxia type 8 (SCA8), an autosomal dominant neurodegenerative disorder showing slowly progressive cerebellar ataxia, is caused by a tri nucleotide CTG repeat expansion (CTGexp) in the SCA8 gene. As the CTGexp is not fully penetrant, the significance of screening CTGexp in ataxia subjects remains obscure. We tested SCA8 CTGexp in a cohort of 797 ataxia subjects, and if present, its sequence configuration was analyzed. CTGexp was found in 16 alleles from 14 individuals, 2 of which was homozygous for CTGexp. Nucleotide sequencing disclosed 3 types of CTGexp sequence configurations: uninterrupted CTGexp, tri nucleotide CTA interruption and CCG interruption. The 2 individuals with homozygous expansions were both sporadic cases with clinical features compatible with SCA8, supporting gene dosage effect. Seven out of 14 CTGexp-positive subjects were also carriers of other SCA expansions [Machado-Joseph disease (n=1), SCA6 (n=3) and SCA31 (n=3)], whereas 7 others were not complicated with such major SCAs. Ages of onset in subjects with pure CTGexp tended to be earlier than those with interrupted CTGexp among the 7 subjects not complicated by major SCAs, suggesting that pure CTGexp have stronger pathogenic effect than interrupted CTGexps. The present study underscores importance of disclosing sequence configuration when testing SCA8. PMID- 29111028 TI - CSF biomarkers beta-amyloid, tau proteins and a-synuclein in the differential diagnosis of Parkinson-plus syndromes. AB - INTRODUCTION: Differential diagnosis of Parkinson-plus patients (PSP, CBD, MSA) and Parkinson's disease (PD) patients is often not straightforward, particularly in atypical cases or at the initial stages of the diseases. Classic CSF biomarkers (amyloid-beta - Abeta42, tau protein - tauT and phosphorylated tau protein - tauP-181) are established biomarkers in the diagnosis of Alzheimer's disease (AD). CSF a-synuclein (alpha-syn) has emerged as a promising biomarker in patients with Parkinsonism. The aim of this study was to analyze the CSF biochemical profile of patients with Parkinsonism. METHODS: We analyzed the CSF biomarker profile (Abeta42, tauT, tauP-181, alpha-syn) and all relevant ratios in 68 patients with Parkinsonism (19 PSP, 15 MSA, 17 CBD, 17 PD) and 18 controls, diagnosed by latest established diagnostic criteria. RESULTS: CBD patients exhibited elevated tauT and decreased Abeta42 compared to the other groups. Five CBD, one PSP patient and one control had a typical AD CSF profile. After exclusion of these patients, the tauT/Abeta42 ratio was significantly elevated in MSA patients compared to PD patients and provided excellent specificity and adequate sensitivity in their differential diagnosis. CONCLUSION: CSF biochemical profile analysis is important in distinguishing AD patients with a CBS phenotype from non-AD CBS patients. The tauT/Abeta42 ratio is useful in the differential diagnosis of MSA from PD. PMID- 29111029 TI - Hematoma volume is a predictive factor of disturbed autoregulation after spontaneous intracerebral hemorrhage. AB - BACKGROUND: Dynamic cerebral autoregulation (dCA) is probably disturbed after spontaneous intracerebral hemorrhage (ICH) and could be an independent predictor of clinical outcome. Clinical determinants of dCA status after ICH need to be further elucidated. METHODS: We finally enrolled 53 patients diagnosed with supratentorial ICH within 6days from onset. DCA was assessed 4-6days after ICH onset by monitoring middle cerebral artery blood flow velocities and simultaneous arterial blood pressure continuously, utilizing transcranial Doppler combined with a servo-controlled finger plethysmograph. Cerebral autoregulation was evaluated by phase difference (PD) in low frequency (0.06-0.12Hz) range derived from transfer function analysis. The previous clinical history was collected including hypertension, diabetes mellitus, prior stroke, smoking, heavy drinking history. Laboratory results during hospitalization were utilized for further risk factors screening, including fasting blood glucose, glycosylated hemoglobin A (1C), total cholesterol, low density lipoprotein cholesterol and homocysteine, etc. Computed tomography scans were performed to collect neuroimaging data, including hematoma location, volume and presence of intraventricular hemorrhage. Univariate and multivariate linear analyses were adopted to explore the relationship between clinical and laboratory variables and bilateral PD respectively. RESULTS: In ICH patients, PD was lower (indicating disturbed autoregulation) both on the ipsilateral (37.53+/-17.78 degree, P<0.001) and contralateral (34.45+/-14.92 degree, P<0.001) side of hematoma compared with healthy controls (56.13+/-16.11 degree). Hematoma volume was independently associated with ipsilateral PD according to multivariate analysis (beta=-0.383, P=0.024) after adjustment for clinical and laboratory factors. CONCLUSIONS: DCA is bilaterally disturbed after supratentorial ICH. Larger hematoma volume is likely to independently predict poorer cerebral autoregulation status ipsilateral to hematoma. PMID- 29111030 TI - Corrigendum to "Sulfoethylated nanofibrillated cellulose: Production and properties" [Carbohydr. Polym. 169 (2017) 515-523]. PMID- 29111031 TI - A dextran with unique rheological properties produced by the dextransucrase from Oenococcus kitaharae DSM 17330. AB - A gene encoding a novel dextransucrase was identified in the genome of Oenococcus kitaharae DSM17330 and cloned into E. coli. With a kcat of 691s-1 and a half-life time of 111h at 30 degrees C, the resulting recombinant enzyme -named DSR-OK- stands as one of the most efficient and stable dextransucrase characterized to date. From sucrose, this enzyme catalyzes the synthesis of a quasi linear dextran with a molar mass higher than 1*109g.mol-1 that presents uncommon rheological properties such as a higher viscosity than that of the most industrially used dextran from L. mesenteroides NRRL-B-512F, a yield stress that was never described before for any type of dextran, as well as a gel-like structure. All these properties open the way to a vast array of new applications in health, food/feed, bulk or fine chemicals fields. PMID- 29111032 TI - Injectable hydrogels based on the hyaluronic acid and poly (gamma-glutamic acid) for controlled protein delivery. AB - Injectable hydrogels have great potential in minimally invasive delivery. In this work, novel injectable hydrogels were prepared via self-crosslinking of aldehyde hyaluronic acid (HA-CHO) and hydrazide-modified poly (gamma-glutamic acid) (gamma PGA-ADH) for proteins delivery. The HA/gamma-PGA hydrogels could be formed in situ as fast as 9s with high swelling ratios. Rheological properties illustrated a wide processing range and good mechanical properties, which were reflected by broad linear viscoelastic region and higher threshold shear stress (sigmac) and storage modulus (G'). Meanwhile, the gelation time, swelling ratio, rheological properties, as well as the protein release behavior could be modulated conveniently. Bovine serum albumin (BSA) was designed as a model drug to study the release behavior. We found that the release mechanisms were either diffusion or Case-II relaxation depending on the different hydrogel components. The HA/gamma-PGA hydrogels also showed good biocompatibility. Therefore, the HA/gamma PGA hydrogels have great potential as promising injectable biomaterials for controlled protein delivery. PMID- 29111033 TI - Water-Induced shape memory effect of nanocellulose papers from sisal cellulose nanofibers with graphene oxide. AB - A novel water-induced shape memory nanocomposites were prepared by introducing graphene oxide (GO), which was based on microcrystalline cellulose nanofibers (MSF-g-COOH) extracting from sisal fibers. The results showed that the water induced shape memory properties of MSF-g-COOH were significantly improved by the strong hydrogen bonding interaction between MSF-g-COOH and GO, It leads to some additional physically cross-linked points in MSF-g-COOH. On the other hand, at 0.5wt% GO loading, tensile strength and Young modulus of the nanocomposite increased from 139 to 184MPa, and from 5.77 to 8.54GPa, respectively, compared to those of pure MSF-g-COOH. Furthermore, a water-induced model was proposed to discuss the water-induced shape memory behaviors of the MSF-g-COOH/GO nanocomposites. This study provides a framework for developing a cellulose based shape memory polymers (CSMPs) and better understanding the shape recovery mechanism in water-induced CSMPs. PMID- 29111034 TI - Poly (vinyl alcohol) as a capping agent in oven dried cellulose nanofibrils. AB - Commercialization of cellulose nanofibrils (CNFs) involves addressing various challenges. Among them, wet storage and transport of CNFs due to their irreversible agglomeration when dehydrated (i.e., hornification) is a pressing issue, as it increases transportation costs. Various alternatives have been proposed in literature, some of which require the use of high-energy treatments to facilitate their redispersion after drying, while others may be inadequate when applied to food and pharmaceutical applications. The present work examines a new approach that involves using poly (vinyl alcohol) (PVA) as a capping agent to redisperse CNFs. Different CNF to PVA ratios were used, and redispersed samples were analyzed in terms of their morphological, physicochemical and rheological properties to assess changes occurring during processing. Results show that the ratio of CNFs to PVA affects the final properties of the redispersed product, when the ratio 1:2.5 was used, the redispersed product closely resembles the never dried sample. PMID- 29111035 TI - Effect of in situ modification of bacterial cellulose with carboxymethylcellulose on its nano/microstructure and methotrexate release properties. AB - Bacterial cellulose/carboxymethylcelullose (BC/CMC) biocomposites with different DS-CMC (DS from 0.7 to 1.2) were developed in order to evaluate their impact as a drug delivery system. Biocomposites were loaded with methotrexate (MTX) as an alternative for the topical treatment of psoriasis. Scanning electron microscopy and atomic force microscopy showed that the CMC coated the cellulose nanofibers, leading to the decrease of the elastic modulus as the DS of CMC increased. BC/CMC0.9 exhibited the lower liquid uptake (up to 11 times lower), suggesting that the more linear structure of the intermediate substitute CMC grade (0.9) was able to interact more strongly with BC, resulting in a denser structure. All samples showed a typical burst release effect in the first 15min of test, however the BC/CMC0.9 biocomposite promoted a slight lowering of MTX release rates, suggesting that the DS of CMC can be considered the key factor to modulate the BC properties. PMID- 29111037 TI - Filament spinning of unbleached birch kraft pulps: Effect of pulping intensity on the processability and the fiber properties. AB - Man-made lignocellulosic fibres were successfully prepared from unbleached birch kraft pulps by using the Ioncell-F technology. Pulps with different lignin content were produced by tailored kraft pulping with varying intensity. The degree of polymerization of the pulps was adjusted by acid-catalyzed hydrolysis and electron beam treatment. All substrates were completely soluble in 1,5 diazabicyclo[4.3.0]non-5-enium acetate ([DBNH]OAc) and the respective solutions were spinnable to yield fibres with good to excellent mechanical properties despite the use of only mildly refined wood pulp. The tensile properties decreased gradually as the lignin concentration in the fibres increased. Changes in the chemical composition also affected the structure and morphology of the fibres. Both the molecular orientation and the crystallinity decreased while the presence of lignin enhanced the water accessibility. The effects of the crystallite size and lignin content on monolayer water adsorption are discussed. PMID- 29111036 TI - GABAB receptor ligand-directed trimethyl chitosan/tripolyphosphate nanoparticles and their pMDI formulation for survivin siRNA pulmonary delivery. AB - The effect of gene silencing by survivin siRNA (siSurvivin) on the proliferation and apoptosis of lung tumor has been attracted more interest. GABAB receptor ligand-directed nanoparticles consisting of baclofen functionalized trimethyl chitosan (Bac-TMC) as polymeric carriers, tripolyphosphate (TPP) as ionic crosslinker, and siSurvivin as therapeutic genes, were designed to enhance the survivin gene silencing. GABAB receptor agonist baclofen (Bac) was initially introduced into TMC as a novel ligand. This Bac-TMC/TPP nanoparticles increased the uptake of survivin siRNA through the interaction with GABAB receptor, further resulted in efficient cell apoptosis and gene silencing. For siRNA-loaded nanoparticles pulmonary delivery, mannitol was utilized for it delivery into pressurized metered dose inhalers (pMDI). The fine particle fractions of this formulation was (45.39+/-2.99)% indicating the appropriate deep lung deposition. These results revealed that this pMDI formulation containing Bac-TMC/TPP nanoparticles would be a promising siRNA delivery system for lung cancer treatment. PMID- 29111038 TI - Hybrid composite membranes of chitosan/sulfonated polyaniline/silica as polymer electrolyte membrane for fuel cells. AB - A series of novel ionic cross-linked chitosan (CS) based hybrid nanocomposites were prepared by using polyaniline/nano silica (PAni/SiO2) as inorganic filler and sulfuric acid as an ionic cross-linking agent. The CS-PAni/SiO2 nanocomposites show enhanced mechanical properties and improved oxidative stabilities. These nanocomposites can be effectively used as environmental friendly proton exchange membranes. Incorporation of PAni/SiO2 into CS matrix enhances water uptake and facilitates the phase separation which enables the formation of hydrophilic domains and improves the proton transport. Moreover, the doped polyaniline also provides some additional pathways for proton conduction. The membrane containing 3wt% loading of PAni/SiO2 in chitosan (CS-PAni/SiO2-3) exhibits high proton conductivity at 80 degrees C (8.39*10-3Scm-1) in fully hydrated state due to its excellent water retention properties. Moreover, methanol permeability of the ionic cross-linked CS-PAni/SiO2 nanocomposite membranes significantly reduces with the addition of PAni/SiO2 nano particles. The CS-PAni/SiO2-3 composite membrane displays the best overall performance as a polymer electrolyte membrane. PMID- 29111039 TI - Ultralight electrospun cellulose sponge with super-high capacity on absorption of organic compounds. AB - Three-dimensional, cost-effective, and renewable/recyclable absorbent materials with high capacities on absorption of organic compounds are urgently in demand. Herein, a facile while innovative approach is reported to develop ultralight electrospun cellulose sponge (UECS). The prepared UECS exhibits super-high absorption capacity (up to 232 times of its own weight) towards absorption of organic compounds due to high porosity (99.57%), low density (6.45mg/cm3), and hydrophobic surface feature (with water contact angle of 141.2 degrees ). Furthermore, the UECS is mechanically robust thus can be readily cut into different shapes; and it also possesses excellent stability against various organic compounds. Intriguingly, upon absorption of an organic compound, the shape-stable UECS organic gel can be formed. Hence, the developed UECS would be promising as environmental friendly absorbent on high-performance separation of organic compounds from aqueous systems; while the UECS organic gel could be utilized for the applications such as drug delivery and sensor. PMID- 29111040 TI - Gut microbiota fermentation of marine polysaccharides and its effects on intestinal ecology: An overview. AB - The gut microbiota that resides in the mammalian intestine plays a critical role in host health, nutrition, metabolic and immune homeostasis. As symbiotic bacteria, these microorganisms depend mostly on non-digestible fibers and polysaccharides as energy sources. Dietary polysaccharides that reach the distal gut are fermented by gut microbiota and thus exert a fundamental impact on intestinal ecology. Marine polysaccharides contain a class of dietary fibers that are widely used in food and pharmaceutical industries (e.g., agar and carrageenan). In this regard, insights into fermentation of marine polysaccharides and its effects on intestinal ecology are of vital importance for understanding the beneficial effects of these glycans. Here, in this review, to provide an overlook of current advances and facilitate future studies in this field, we describe and summarize up-to-date findings on how marine polysaccharides are metabolized by gut microbiota and what effects these polysaccharides have on intestinal ecology. PMID- 29111041 TI - The effect of hydration on the material and mechanical properties of cellulose nanocrystal-alginate composites. AB - Alginate is commonly used in the form of hydrogels in biomedical applications. It is known to be highly sensitive to liquid exposure and can degrade or solubilize easily. This study attempts to improve the mechanical and material properties in various humidity conditions and in liquid immersion of thin alginate films with the addition of unmodified and oxidized cellulose nanocrystals (CNCs, CNC-Ts). CNCs and CNC-Ts were added to alginate composites in varying amounts, and the material and mechanical properties were measured in dry, humid, and liquid conditions. It was shown that the properties can be enhanced with the addition of nanocellulose as tested by liquid uptake, and mechanical testing. These results suggest that the addition of TEMPO-oxidized nanocellulose crystals improves the performance and longevity of alginate when exposed to phosphate buffer solution (PBS) compared to deionized water. This improved performance was shown to have a limited effect on the adhesion of mesenchymal stem cells (MSCs) to the surface of the nanocomposites. PMID- 29111042 TI - Fabrication and stabilization of biocompatible selenium nanoparticles by carboxylic curdlans with various molecular properties. AB - In this study, carboxylic curdlans (Cur-4, Cur-8, and Cur-24) with different molecular properties and chain conformations were used as stabilizer and capping agent to fabricate stable and water-dispersible selenium nanoparticles (SeNPs). Results showed that molecular properties and chain conformations of carboxylic curdlans remarkably influenced the size, morphology, structure, and stability of SeNPs and the carboxylic curdlan was ligated to SeNPs via OH?Se interaction. The as-prepared SeNPs was amorphous and showed homogeneous and monodisperse spherical structure with size of ~50-90nm. The Cur-8-decorated SeNPs (SeNPs@Cur-8) exhibited smaller particle size (~56nm) and greater stability than those of the others. The carboxylic curdlan-stabilized SeNPs exhibited excellent antioxidant capacities compared to the control SeNPs. Specifically, SeNPs@Cur-8 with smaller particle size possessed strong antioxidant efficacy. SeNPs@Cur-8 also exhibited low cytotoxic activity against SPCA-1 and HeLa cell lines in vitro. PMID- 29111043 TI - Investigation of an elutable N-propylphosphonic acid chitosan derivative composition with a chitosan matrix prepared from carbonic acid solution. AB - Porous chitosan composites using CO2 dissolution procedure and including water soluble N-propylphosphonic chitosan derivative (p-CHI) were obtained and characterized. In contrast to the control material, composites containing modified chitosan distinguished by a rapid moisture absorption and good adhesion to the skin. The FTIR analysis confirmed the presence of propylphosphonic group in the structure of the polymer. The porosity of the materials was in the range 55-77% and decreased with increasong amount of modified chitosan in materials. Solubility of composites was dependent on the content of p-CHI in scaffolds (40%, 25% and 15%) and reached values 11%, 9% and 6,5%, respectively. The values of other parameters like swelling degree (30g/g) good antioxidant and antimicrobial properties (almost 100% reduction of S.aureus, E.coli and C. albicans growth) and low in vitro cytotoxicity against fibroblasts were highly advantageous for possible biomedical applications of the composites. PMID- 29111044 TI - Structural and physicochemical changes in guar gum by alcohol-acid treatment. AB - The aim of this study was to evaluate the effects of alcohol-acid degradation on the structural and physicochemical characteristics of guar gum. Guar gum (50wt.%) was treated with methanol, ethanol, 2-propanol, or 1-butanol containing 1 or 2mL 36% hydrochloric acid at 75 degrees C for 30-240min. The linear relationship between 1/Mw and time suggested that alcohol-acid degradation followed first order kinetics with rate constants varying directly with the number of alcohol carbon atoms and acid concentration. Alcohol-acid treatment exerted no effect on the chemical and crystal structure of guar but significantly decreased shear viscosity, slightly increased solubility, mildly reduced thermostability, and dramatically darkened colour. This study extended the knowledge of the effect of alcohol on the acid hydrolysis of guar and will contribute to the development of a large-scale procedure for guar gum degradation. PMID- 29111045 TI - Physical properties and antioxidant capacity of chitosan/epigallocatechin-3 gallate films reinforced with nano-bacterial cellulose. AB - Films with antioxidant activity were prepared by combining chitosan (CH) and epigallocatechin-3-gallate (EGCG) with nano-bacterial cellulose (BC) as a reinforcement agent. Results showed that BC addition improved the qualities of films jeopardized by EGCG. Fourier Transform Infrared (FTIR) spectroscopy analysis confirmed that there were intermolecular interactions among BC, CH and EGCG though hydrogen bonding. Consequently, BC addition increased the crystallinity and thermal stability of CH-BC5/10-EGCG15/30 films analyzed by X ray diffraction (XRD) and thermogravimetric (TGA) analysis. BC addition also significantly decreased water solubility (WS), from 26.54% to 20.80%, increased tensile strength (TS), from 18.71 to 44.17MPa, and increased elongation at break (EAB), from 2.72% to 7.34%. Moreover, BC and EGCG had high affinity for each other, as BC addition lowered the release of EGCG from CH films with a higher ABTS radical scavenging ability. Therefore, BC can be used as a sustained release carrier of EGCG in antioxidant active films. PMID- 29111046 TI - Surface functionalization of cellulose with poly(3-hexylthiophene) via novel oxidative polymerization. AB - Surface functionalization of cellulose with poly(3-hexylthiophene) (P3HT) was conducted with FeCl3 as an oxidant in three different solvents: acetonitrile, chloroform, and hexane. Of these three solvents, hexane best promoted the grafting P3HT to cellulose with a high grafting ratio and molecular weight. The maxima of the UV-vis absorption and fluorescent spectra, observed at around 500 and 600nm, respectively, represented the build-up of the conjugated chain length formed by the grafting of P3HT onto the cellulose surface. The HOMO level of cellulose as determined by photoemission yield spectroscopy decreased from 4.83 to 4.67eV after modification with P3HT. Grafting P3HT onto the surface of cellulose provided super-hydrophobic property with a lotus effect. The conductivity of cellulose also improved significantly, from 10-9 to 10-6S/cm when P3HT was present on the surface. The thermal stability and crystallinity of cellulose decreased slightly upon graft polymerization with P3HT. PMID- 29111047 TI - Characterization, genetic regulation and production of cyanobacterial exopolysaccharides and its applicability for heavy metal removal. AB - Cyanobacteria are uniquely suited for the development of sustainable bioproduction platforms but are currently underutilized due to lack of genetic tools. Exopolysaccharide (EPS) is of significant biotechnological importance due to their technological application in various industries. It has been found that most of the research works are focused on isolation and characterization of new exopolysaccharides from microbial sources. The exopolysaccharides from cyanobacteria have been poorly explored despite their original structural features associated with specific biological and physicochemical properties. However, it could increase in a near future through the use of inexpensive cyanobacterial platform as well as available information on the structural data and specific properties of these biopolymers. This review covers genetic regulation for production of exopolysaccharide, analytical strategies for their characterization, evaluation of structure property relationship and design of extraction protocol from cyanobacterial biomass. In addition applications of exopolysaccharide for removal of heavy metal from wastewater are critically reviewed. PMID- 29111048 TI - Ultra-high mechanical properties of porous composites based on regenerated cellulose and cross-linked poly(ethylene glycol). AB - The ultra-high mechanical, biocompatible and biodegradable porous regenerated cellulose/poly(ethylene glycol) (RC/PEG) composites with double network structure were fabricated via an simple method to dissolve cellulose followed by UV irradiation. The porous structure of RC/PEG was sensitively altered by PEG contents, which led to the porous structure morphology transition from 3D fibrillar network to close-grained sheet-like-network with the loading of cross linked PEG. The porous RC/PEG showed excellent mechanical properties, i.e., the compressive strength can reach 33 times higher than that of neat RC (0.07MPa) at the compressive strain of 30%. Porous RC/PEG also displayed outstanding properties with openly porous structure and structural stabilization. Besides, porous RC/PEG exhibited good water absorbency, which the water absorbency ratio at equilibrium state was 83% higher than that of porous RC. This work provides an environmentally friendly and simple pathway to prepare non-toxic and biocompatible porous regenerated cellulose-based composites with high strength, structural stabilization and good water absorbency, which could be useful for packaging, biomedical applications, sewage purification, etc. PMID- 29111049 TI - Assessing cellulose nanofiber production from olive tree pruning residue. AB - Pruning operation in olive trees generates a large amount of biomass that is normally burned causing severe environmental concern. Therefore, the transformation of this agricultural residue into value-added products is imperative but still remains as a technological challenge. In this study, olive tree pruning (OTP) residue is evaluated for the first time to produce cellulose nanofibers (CNF). The OTP bleached pulp was treated by TEMPO-mediated oxidation and subsequent defibrillation in a microfluidizer. The resulting CNF was characterized and compared to CNF obtained from a commercial bleached eucalyptus kraft pulp using the same chemi-mechanical procedure. CNF from OTP showed higher carboxylate content but lower fibrillation yield and optical transmittance as compared to eucalyptus CNF. Finally, the visco-elastic gel obtained from OTP was stronger than that produced from eucalyptus. Therefore, the properties of CNF from OTP made this nanomaterial suitable for several applications. CNF from OTP showed higher carboxylate content as compared to eucalyptus CNF (1038 vs. 778MUmol/g) but lower fibrillation yield (48% vs. 96%) and optical transmittance. Finally, the visco-elastic gel obtained from OTP was stronger than that produced from eucalyptus. Therefore, the properties of CNF from OTP made this nanomaterial suitable for several applications. PMID- 29111050 TI - Xyloglucan-based hydrogel films for wound dressing: Structure-property relationships. AB - Thin xyloglucan-based hydrogel films have been synthetized and characterized in the prospect of producing wound dressings. Polyvinyl alcohol (PVA) and glycerol (Gro) were added to have an optimal combination of softness, conformability and resilience. Physical hydrogels have been transformed into permanent covalent hydrogels by reaction with glutaraldehyde (GA). Network structure-process property relationships are discussed on the account of the results of several complementary characterizations: FTIR, rheology, thermal analysis, morphological analysis, moisture retention and swelling measurements. Selected formulations were also subjected to preliminary in vitro cytotoxicity tests. The physical and mechanical properties of some of the xyloglucan-based hydrogel films produced, combined with absence of cytotoxicity, make them suitable candidates for integration with sensors to monitor the wound healing process and further biological investigations in animal models. PMID- 29111051 TI - Antimicrobial activity of catechol functionalized-chitosan versus Staphylococcus epidermidis. AB - Protein mussel-inspired adhesive polymers, characterized by the presence of catechol groups, possess superior muco-adhesive properties and have great potentiality in wound healing. Suitable materials for wound dressing should properly combine muco-adhesiveness and antimicrobial activity. In this work, catechol-functionalized chitosan was obtained by reaction with hydrocaffeic acid (HCAF), in order to investigate how catechol introduction at different content could affect the intrinsic antimicrobial activity of the polymer itself. Unexpectedly, an enhancement of chitosan antimicrobial activity was observed after catechol functionalization, with a fourfold reduction in the polymer minimum inhibitory concentration versus Staphylococcus epidermidis. Additionally, a commercial wound dressing coated with one of the synthesized CS-HCAF derivatives showed a significant reduction in the adhesion of S. epidermidis compared to the uncoated dressing (3-log reduction). The CS-HCAF derivatives also showed an interesting antioxidant property (EC50 ranging from 20 to 60MUg/mL), which further confirms the potentiality of these materials as wound dressings. PMID- 29111052 TI - Bio-based products from xylan: A review. AB - Obtaining chemicals and materials in sustainable ways is of growing importance. A potential source of sustainable chemicals and materials is lignocellulosic biomass residues generated as waste from agriculture. Hemicellulose which is a large component in lignocellulosic biomass residues, provides many potential applications such as the generation of chemicals, packaging materials, drug delivery and biomedical applications. This review deals with the various techniques which can be used for the extraction of hemicellulose from biomass residues, purification and some potential applications of the extracted hemicellulose. The methods that have been used to further produce chemicals from extracted hemicellulose as well as their applications are discussed. PMID- 29111053 TI - Pectin from Husk Tomato (Physalis ixocarpa Brot.): Rheological behavior at different extraction conditions. AB - A rheological study was carried out to evaluate formulations of test dispersions and gels of high methoxyl pectins (HTHMP) obtained at different conditions from husk tomato waste (Physalis ixocarpa Brot.). The effect of extraction agent (hydrochloric acid or citric acid), blanching time (10 or 15min) and extraction time (15, 20 or 25min) on the rheology of the tested samples was evaluated. Flow behavior and activation energy were evaluated on the test dispersions, while (Ea) frequency sweeps, temperature sweep, creep-recovery test and penetration test were performed on the gels. HTHMP dispersions showed shear thinning flow behavior, while showing a good fit to Cross model. Extraction agent, blanching time and extraction time did not have effect on Cross parameters (etaz, etainfinity, C, and m). Ea decreased as blanching time and extraction time increased. Frequency sweeps revealed high dependence on frequency for both G' and G", while temperature sweeps (25- 95 degrees C) showed thermostable husk tomato pectin gels. Hydrocloric acid (HCl) extracted pectin gels showed stronger structure than citric acid (CA) gels. PMID- 29111054 TI - Interaction of industrially relevant cationic starches with cellulose. AB - Industrially relevant, commercially available cationic starches have been investigated towards their interaction capacity with cellulose thin films derived from trimethylsilyl cellulose (TMSC). The starches used in this study stem from different sources (potato, pea, corn) and featured rather low degrees of substitution ranging from 0.030 to 0.062. The interaction of those starches with cellulose thin films was studied by surface plasmon resonance spectroscopy under flow conditions using concentrations of 1.0mgml-1 and a flow rate of 25MUlmin-1. All the investigated starches employed in this study were capable to efficiently interact with the slightly negatively charged cellulose surface leading to irreversible deposition on the surface. As complementary techniques atomic force microscopy and x-ray photoelectron spectroscopy were used to confirm the presence of the starches on the cellulose film surface. Further, dynamic light scattering and size exclusion chromatography measurements were performed to correlate adsorbed amount, particle size and molecular weight of the starches to their interaction behavior. PMID- 29111055 TI - All cellulose composites based on cellulose diacetate and nanofibrillated cellulose prepared by alkali treatment. AB - Cellulose diacetate (CDA) composite films were synthesized by incorporation of nanofibrillated celluloses (NFCs), using a casting/evaporation technique. Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM) characterization indicated the presence of interaction and certain compatibility between CDA and NFCs. The CDA and NFCs were converted to cellulose II by an alkaline treatment which resulted in the formation of all cellulose composite (ACC) films, as indicated by the FTIR and XRD characterization. Significant changes were observed in their structural, thermal, mechanical, and optical transparency properties. The SEM images revealed the excellent compatibility among the constituents of the ACC films. The tensile strength, Young's modulus, and strain at break of the ACC films with 15wt% NFCs content were increased to 102.3MPa, 5.8GPa, 14.7% respectively. This work provides a promising pathway for manufacturing high performance ACC materials. PMID- 29111056 TI - Optimization of tenofovir release from mucoadhesive vaginal tablets by polymer combination to prevent sexual transmission of HIV. AB - The use of sustained-release mucoadhesive vaginal tablets of antiretroviral drugs as microbicidal formulations can be an effective strategy for reducing the sexual transmission of HIV from men to women, which is a main problem particularly in low- and middle-income countries. Different polymers (hydroxypropylmethyl cellulose (HPMC), chitosan, guar gum and Eudragit(r) RS) have proven some good features for this purpose. At this work, these polymers have been combined in pairs in different proportions to enhance the advantages offered by each one individually. The in vitro release of tenofovir from the matrices, ex vivo mucoadhesive capacity (evaluated on vaginal mucosa) and the degree of swelling in simulated vaginal fluid have been assessed. A multimodal pore size distribution is observed in porosimetry studies -carried out with swelling witnesses-, due to the contribution of polymers with different swelling behaviour to the pore formation, and it is corroborated by scanning electron microscopy. X-ray diffraction technique confirms the changes in crystallinity of the formulation after swelling. We can report that the combination of HPMC and chitosan in the same formulation may be useful for the prevention of sexual transmission of HIV, since tablets can be obtained that remain adhered to the vaginal mucosa for 96h, so the drug is released in a sustained manner for 72h. When the formulation contains more chitosan than HPMC the swelling is moderate, making it more comfortable for women to apply. PMID- 29111057 TI - Resol based chitosan/nano-hydroxyapatite nanoensemble for effective bone tissue engineering. AB - It is the first report where different amounts of resol resin (RS) were incorporated with chitosan-hydroxyapatite (CHA) to develop a triconstituent nanoensemble CHA-RS(0.5,1,2), via simple co-precipitation method. The results of SEM, TEM, TGA and mechanical analysis revealed irregular interconnected rough morphology with homogenous distribution of needle shaped particles having average size ranging between 12 and 19nm, possessing higher thermal stability and mechanical strength, respectively relative to CHA (binary) nanocomposite. The CHA 1RS nanocomposite showed enhanced protein adsorption and ALP activity with excellent apatite formation ability compared to CHA-RS(0.5,2) and CHA nanocomposites. Thus, CHA-1RS nanocomposite was selectively tested as bare implant in the repair of critical-size calvarium defect (8mm) in albino rat. The histopathological and radiological investigations indicated that CHA-1RS prompted the bone regeneration ability as early as 2 weeks postimplantation demonstrating remarkably faster healing of calvarial defect relative to Cerabone. These findings have placed CHA-1RS on the pedestal to be employed as a potential alternative biomaterial for bone tissue engineering. PMID- 29111058 TI - The performance of chitosan with bentonite microparticles as wet-end additive system for paper reinforcement. AB - In this research, the effect of bentonite micro-particles on the performance of chitosan as a new additive system for improving the dry strengths of acidic papermaking was studied. Chitosan, an abundant carbohydrate biopolymer, in 4 dosages (0, 0.75, 1.25 and 2% based on dry weight of pulp) was applied with bentonite in 4 dosages (0, 0.3, 0.6 and 0.9% based on oven-dry weight of pulp). Although the addition of chitosan up to 0.75% (without bentonite) improved tensile index and burst index, but the addition of more chitosan decreased all mechanical properties in comparison with the control sample. The application of bentonite in combination with chitosan had a significant impact on chitosan performance in mechanical properties. The best results were obtained with 0.3% bentonite consumption. Visual formation ranking had a proper correlation with this obtained results. The micro-kjeldahl indirectly confirmed chitosan retention in the treated paper with chitosan/bentonite. PMID- 29111059 TI - Highly flexible cross-linked cellulose nanofibril sponge-like aerogels with improved mechanical property and enhanced flame retardancy. AB - Cellulose nanofibril (CNF) aerogel is highly flammable and its mechanical strength is very soft, which is unfavourable due to safety concerns and impractical when used as the thermal insulation material. In this work, we used N methylol dimethylphosphonopropionamide (MDPA) and 1,2,3,4-butanetetracarboxylic acid (BTCA) as co-additives and then prepared lightweight flame resistant CNF sponge-like aerogels via an eco-friendly freeze-drying and post cross-linking method. The CNF/BTCA/MDPA aerogel exhibited a better flame retardant performance, outstanding self-extinguishing behaviour and significantly increased char residue (by as much as 268%) compared with the neat CNF aerogel. Meanwhile, the resilience of the aerogel samples improved significantly as the flexibility decreased slightly. Furthermore, the aerogel samples still exhibited excellent thermal insulating properties with thermal conductivity as low as 0.03258W/(m k). The combination of these characteristics makes the CNF-based aerogel a promising insulation candidate for thermal protective equipment (e.g., fire-protection clothing or advanced spacesuit elements) in the future. PMID- 29111060 TI - Hydrothermal synthesis of bacterial cellulose-copper oxide nanocomposites and evaluation of their antimicrobial activity. AB - In this work, for the first time bacterial cellulose (BC) hydrogel membranes were used for the fabrication of antimicrobial cellulosic nanocomposites by hydrothermal deposition of Cu derivative nanoparticles (i.e.Cu(0) and CuxOy species). BC-Cu nanocomposites were characterized by FTIR, SEM, AFM, XRD and TGA, to study the effect of hydrothermal processing time on the final physicochemical properties of final products. XRD result show that depending on heating time (3 48h), different CuxOy phases were achieved. SEM and AFM analyses unveil the presence of the Cu(0) and copper CuxOy nanoparticles over BC fibrils while the surface of 3D network became more compact and smother for longer heating times. Furthermore, the increase of heating time placed deleterious effect on the structure of BC network leading to decrease of BC crystallinity as well as of the on-set degradation temperature. Notwithstanding, BC-Cu nanocomposites showed excellent antimicrobial activity against E. coli, S. aureus and Salmonella bacteria suggesting potential applications as bactericidal films. PMID- 29111061 TI - Synthesis of fructooligosaccharides (FosA) and inulin (InuO) by GH68 fructosyltransferases from Bacillus agaradhaerens strain WDG185. AB - Fructooligosaccharides (FOS) and inulin, composed of beta-2-1 linked fructose units, have a broad range of industrial applications. They are known to have various beneficial health effects and therefore have broad application potential in nutrition. For (modified) inulin also for non-food purposes more applications are arising. Examples are carboxymethylated inulin as anti-scalant and carboymlated inulin as emulsifiers. Various plants synthesize FOS and/or inulin type of fructans. However, isolating of FOS and inulin from plants is challenging due to for instance varying chains length. There is an increasing demand for FOS and inulin oligosaccharides and alternative procedures for their synthesis are attractive. We identified and characterized two fructosyltransferases from Bacillus agaradhaerens WDG185. FosA, a beta-fructofuranosidase, synthesises short chain fructooligosaccharides (GF2-GF4) at high sucrose concentration, whereas InuO, an inulosucrase, synthesises a broad range of inulooligosaccharides (GF2 GF24) from sucrose, very similar to plant derived inulin. FosA and InuO showed activity over a broad pH range from 6 to 10 and optimal temperature at 60 degrees C. Calcium ions and EDTA were found to have no effect on the activity of both enzymes. Kinetic analysis showed that only at relatively low substrate concentrations both enzymes showed Michaelis-Menten type of kinetics for total and transglycosylation activity. Both enzymes showed increased transglycosylation upon increasing substrate concentrations. These are the first examples of the molecular and biochemical characterization of a beta-fructofuranosidase (FosA) and an inulosucrase enzyme (InuO) and its product from a Bacillus agaradhaerens strain. PMID- 29111062 TI - Plasma-treated poly(ethylene oxide) nanofibers containing tea tree oil/beta cyclodextrin inclusion complex for antibacterial packaging. AB - This work describes the effect of cold nitrogen plasma to enhance the antibacterial activity of poly(ethylene oxide) (PEO) nanofibers containing antibacterial agent. Beta-cyclodextrin (beta-CD) and tea tree oil (TTO) were used as a host-guest to form water-soluble inclusion complex. The encapsulation efficiency of TTO in inclusion complex could reach 73.23% at 60 degrees C. As antibacterial agent, the inclusion complex was encapsulated into PEO matrix by electrospun. After plasma treatment, the release efficiency of antibacterial agent from PEO nanofibers was improved. As a result, the antibacterial activity of PEO nanofibers was enhanced accordingly. The plasma-treated nanofiber membranes achieved the highest antibacterial activity against Escherichia coli O157:H7, which was tested on the beef for 7d, with inhibition efficiently of 99.99% whether at 4 degrees C or 12 degrees C. The plasma-treated PEO nanofiber membranes containing TTO/beta-CD inclusion complex (TTO/beta-CD-IC) can prolong the shelf-life of beef, suggesting it has potential application in active food packaging. PMID- 29111063 TI - Fabrication and characterization of copper(II)-chitosan complexes as antibiotic free antibacterial biomaterial. AB - We produced and characterized copper(II)-chitosan complexes fabricated via in situ precipitation as antibiotic-free antibacterial biomaterials. Copper was bound to chitosan from a dilute acetic acid solution of chitosan and copper(II) chloride exploiting the ability of the polysaccharide to chelate metal ions. The influence of copper(II) ions on the morphology, structure and hydrophobicity of the complexes was evaluated using scanning electron microscopy, energy-dispersive X-ray spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy and static contact-angle measurements. To assess the biological response to the materials, cell viability and antibacterial assays were performed using mouse embryonic fibroblasts and both Gram-positive and -negative bacteria. Combined analysis of cell and bacterial studies identified a threshold concentration at which the material shows outstanding antibacterial properties without significantly affecting fibroblast viability. This key outcome sets copper(II)- chitosan as a promising biomaterial and encourages further investigation on similar systems toward the development of new antibiotic-free antibacterial technologies. PMID- 29111064 TI - Quantification of food polysaccharide mixtures by 1H NMR. AB - Polysaccharides are food ingredients that critically determine rheological properties and shelf life. A qualitative and quantitative assessment on food specific polysaccharide mixtures by 1H NMR is presented. The method is based on the identification of intact polysaccharides, combined with a quantitative analysis of their monosaccharide constituents. Identification of the polysaccharides is achieved by 1H NMR line shape fitting with pure compound spectra. The monomeric composition was determined using the Saeman hydrolysis procedure, followed by direct monosaccharide quantification by 1H NMR. In the quantification, both the monosaccharide degradation during hydrolysis, as well as a correction for the non-instantaneous polysaccharide dissolution were taken into account. These factors were particularly important for the quantification of pectins. The method showed overall good repeatability (RSDr=4.1+/-0.9%) and within-laboratory reproducibility (RSDR=6.1+/-1.4%) for various food polysaccharides. Polysaccharide mixtures were quantitatively resolved by a non negative least squares estimation, using identified polysaccharides and their molar monosaccharide stoichiometry as prior knowledge. The accuracy and precision of the presented method make it applicable to a wide range of food polysaccharide mixtures with complex and overlapping 1H NMR spectra. PMID- 29111065 TI - Complexes between methyltestosterone and beta-cyclodextrin for application in aquaculture production. AB - The inclusion complexes between 17-alpha-methyltestosterone (MT) and beta cyclodextrin (bCD) were prepared and characterized in dissolution and solid phase. The complex promoted a sixfold increment in solubility of the hormone. It has a limited solubility and stoichiometry of 2:1 (bCD:MT) determined by DSC, NMR and solubility experiments, the association constant Ka=2846Lmol-1 and complex fraction of 76% (assessed by DOSY-NMR, in (1:3) DMSO/D2O). The association constant obtained in water by the solubility isotherms is 7540Lmol-1. 2D-ROESY experiments indicate the intermolecular orientation (complete inclusion of the hormone in the cavity). Simulations by molecular dynamics agreed with the formation of the inclusion complex 2:1. Release tests showed the slower release for the complexes, with 50% for lyophilization and 56% for malaxation. These results clearly demonstrate the complexation of MT in bCD, which formulations are promising for further applications involving this steroid in aquaculture, both for sexual reversal and in technologies of hormone in water sequestration. PMID- 29111066 TI - Homogenous isolation of individualized bacterial nanofibrillated cellulose by high pressure homogenization. AB - Varying levels of high pressure homogenization (HPH) were applied to disintegrate bacterial nanofibrillated cellulose (BNFC) from bacterial cellulose (BC). HPH was considered as a simple, non-toxic and highly efficient physical method for nanofibrillated cellulose extraction. The blended BC passed through chambers at high pressures of 68, 138 and 207MPa for 30 cycles. The particle size confirmed disintegration of the BC network fibers to bundles of BNFC and the atomic force microscopy images showed the decreased diameter of individual BNFC in the range 36-67nm. Fourier transform infrared spectroscopy measurement indicated there were no change in the chemical functional groups of the BNFC compared with BC. The decreased crystallinity index and crystallite size of BNFC with increased pressure confirmed the effect of HPH on the BNFC. Nevertheless, BNFC at 207MPa had the lowest thermal stability due to having the highest surface area, which resulted in the minimum nanofiber diameter. PMID- 29111067 TI - Gums induced microstructure stability in Ca(II)-alginate beads containing lactase analyzed by SAXS. AB - Previous works show that the addition of trehalose and gums in beta-galactosidase (lactase) Ca(II)-alginate encapsulation systems improved its intrinsic stability against freezing and dehydration processes in the pristine state. However, there is no available information on the evolution in microstructure due to the constraints imposed by the operational conditions. The aim of this research is to study the time course of microstructural changes of Ca(II)-alginate matrices driven by the presence of trehalose, arabic and guar gums as excipients and to discuss how these changes influence the diffusional transport (assessed by LF NMR) and the enzymatic activity of the encapsulated lactase. The structural modifications at different scales were assessed by SAXS. The incorporation of gums as second excipients induces a significant stabilization in the microstructure not only at the rod scale, but also in the characteristic size and density of alginate dimers (basic units of construction of rods) and the degree of interconnection of rods at a larger scale, improving the performance in terms of lactase activity. PMID- 29111068 TI - Microwave assisted synthesis of binary grafted psyllium and its utility in anticancer formulation. AB - A binary grafted copolymer of Psyllium mucilage (Psy) with acrylic acid (AA) and acrylonitrile (An) has been successfully synthesized under microwave conditions for in vitro drug release study. The grafting was confirmed by FTIR spectroscopy, XRD, SEM, EDX, TGA analytical techniques and the intrinsic viscosity study. The swelling behavior of grafted material has been studied in solution of different pH and time. We also prepare Psy-g-Poly (AA-co-An) based beads with anti-cancer drug [(2-Chloro-3-(4-hydroxyphenylamino) naphthalene-1, 4-dione)]. The drug release behavior of Psy-g-Poly (AA-co-An) based beads has been determined in aqueous medium at different pH. It has been observed that highest drug release at pH 1.6. The drug release kinetics was analysed using the different models. This study demonstrates that the release of drug depends on the composition of beads and pH of release medium. Kinetics of drug release from beads is best fitted by zero order and first order model. PMID- 29111069 TI - Chitosan and thiolated chitosan: Novel therapeutic approach for preventing corneal haze after chemical injuries. AB - Corneal haze, commonly caused by deep physical and chemical injuries, can greatly impair vision. Growth factors facilitate fibroblast proliferation and differentiation, which leads to haze intensity. In this study, the potential effect of chitosan (CS) and thiolated-chitosan (TCS) nanoparticles and solutions on inhibition of fibroblast proliferation, fibroblast to myofibroblast differentiation, neovascularization, extracellular matrix (ECM) deposition, and pro-fibrotic cytokine expression was examined. Transforming growth factor beta-1 (TGFbeta1) was induced by interleukin-6 (IL6) in human corneal fibroblasts and expression levels of TGFbeta1, Platelet-derived growth factor (PDGF), alpha smooth muscle actins (alpha-SMA), collagen type I (Col I), fibronectin (Fn) and vascular endothelial growth factor (VEGF) were quantified using qRT-PCR. To assess wound-healing capacity, TCS-treated mice were examined for alpha-SMA positive cells, collagen deposition, inflammatory cells and neovascularization through pathological immunohistochemistry. The results revealed that CS and TCS could down-regulate the expression levels of TGFbeta1 and PDGF comparable to that of TGFbeta1 knockdown experiment. However, down-regulation of TGFbeta1 was not regulated through miR29b induction. Neovascularization along with alpha-SMA and ECM deposition were significantly diminished. According to these findings, CS and TCS can be considered as potential anti-fibrotic and anti-angiogenic therapeutics. Furthermore, TCS, thiolated derivative of CS, will increase mucoadhesion of the polymer at the corneal surface which makes the polymer efficient and non-toxic therapeutic approach for corneal injuries. PMID- 29111070 TI - In vitro fermentability of xylo-oligosaccharide and xylo-polysaccharide fractions with different molecular weights by human faecal bacteria. AB - Xylo-oligosaccharides and xylo-polysaccharides (XOS, XPS) produced by autohydrolysis of the fibre from oil palm empty fruit bunches (OPEFB) were purified using gel filtration chromatography to separate the XOS and XPS from the crude autohydrolysis liquor. Six mixed fractions of refined XOS and XPS with average degree of polymerisation (avDP) of 4-64 were obtained. These were characterised in terms of their composition and size by HPLC, MALDI-ToF-MS (selected fractions) and carbohydrate gel electrophoresis (PACE). They were assessed in batch culture fermentations using faecal inocula to determine their ability to modulate the human faecal microbiota in vitro by measuring the bacterial growth, organic acid production and the XOS assimilation profile. The gut microbiota was able to utilise all the substrates and there was a link between the avDP with the fermentation properties. In general, XOS/XPS preparations of lower avDP promote better Bifidobacterium growth and organic acid production. PMID- 29111071 TI - Biocompatible chitosan based hydrogels for potential application in local tumour therapy. AB - A series of hydrogels based on chitosan polyamine and nitrosalicylaldehyde were prepared via dynamic covalent chemistry (DCC), by imination and transimination reactions towards ordered clusters which play the role of crosslinking nodes of the chitosan network. The hydrogelation mechanism has been proved through NMR and FTIR spectroscopy, X-ray diffraction and polarized light microscopy. The successful preparation of the hydrogels and their mechanical properties were further investigated using rheological measurements. By electron scanning microscopy, the hydrogels exhibited a channels microstructure morphology which critically influenced their fast swelling by capillarity. The hydrogels cytotoxicity was explored in vitro on HeLa cancer cells and their biocompatibility was monitored in vivo by subcutaneous implantation on rats. The novel hydrogels proved good in vitro cytotoxicity on the HeLa cells and also in vivo biocompatibility in rats. Thus, these novel biomaterials promise to be suitable for local cancer therapy. PMID- 29111072 TI - Phase behavior, rheological characteristics and microstructure of sodium caseinate-Persian gum system. AB - In this study, the phase behavior of sodium caseinate-Persian gum mixtures was investigated. The effect of thermodynamic incompatibility on phase distribution of sodium caseinate fractions as well as the flow behavior and microstructure of the biopolymer mixtures were also studied. The phase diagram clearly demonstrated the dominant effect of Persian gum on the incompatibility of the two biopolymers. SDS-PAGE electrophoresis indicated no selective fractionation of sodium caseinate subunits between equilibrium phases upon de-mixing. The microstructure of mixtures significantly changed depending on their position within the phase diagram. Fitting viscometric data to Cross and Bingham models revealed that the apparent viscosity, relaxation time and shear thinning behavior of the mixtures is greatly influenced by the volume ratio and concentration of the equilibrium phases. There is a strong dependence of the flow behavior of sodium caseinate Persian gum mixtures on the composition of the equilibrium phases and the corresponding microstructure of the system. PMID- 29111073 TI - Combined effect of cellulose nanocrystals and poly(butylene succinate) on poly(lactic acid) crystallization: The role of interfacial affinity. AB - Poly (lactic acid) (PLA)/cellulose nanocrystals (CNC), poly(butylene succinate) (PBS)/CNC and PLA/PBS/CNC composite films were prepared using a solution-casting technique. CNCs can be used to enhance the crystallization of PLA by offering more nucleation sites, and PBS can increase spherulite growth rate of PLA by providing flexible chains. However, CNCs and PBS together tend to interfere with each other and thus enhancement in the crystallization of PLA is lost. FTIR, contact-angle measurements, and dissolution experiments were used to characterize the materials. It was found that the interfacial affinity was greater in the CNC PBS system than the CNC-PLA system. It was therefore concluded that the PBS chains occupy most of the CNC surfaces in the molten state before cooling. Consequently, PLA was mainly blocked from the CNCs and the nucleation effect was greatly weakened. The binary and ternary composite systems are discussed in terms of their crystallization processes. PMID- 29111074 TI - Biodegradable regenerated cellulose-dispersed composites with improved properties via a pickering emulsion process. AB - Reinforcement of biodegradable polymers with nanocellulose is attractive yet the effectiveness is often compromised by uneven dispersion. In this work, a general method of preparing reinforced biodegradable composites using regenerated cellulose (RC) was developed. From an oil-in-water Pickering emulsion of PLA/methylene chloride stabilized with RC, uniformly dispersed RC/PLA composites was obtained. The resulting RC/PLA composites showed enhanced crystallization and tensile strength of up to 34% compared with the native PLA, while the transmittance in the visible range remained above 70%. The Pickering emulsion based composition procedure is simple, environment friendly and cost effectively, which could be applied to preparation of other RC-reinforced biodegradable composites. PMID- 29111075 TI - Humidity-activated shape memory effect on plasticized starch-based biomaterials. AB - Humidity-activated shape memory behavior of plasticized starch-based films reinforced with the innovative combination of starch nanocrystals (SNCs) and catechin as antioxidant were studied. In a previous work, we reported the processing of gelatinized starch-based films filled with SNCs and catechin as antioxidant agent, and we observed that this novel combination leads to starch based film with enhanced thermal and mechanical performance. In this work, the humidity-activated shape memory behavior of the previous developed starch-based films was characterized. The moisture loss as well as the moisture absorption were studied since they are essential parameters in humidity-activated shape memory polymers to fix the temporary shape and to recover the original shape, respectively. Therefore, the effect of the incorporation of SNCs and catechin on the humidity-activated shape memory properties of plasticized starch was also studied. Moreover, the effectiveness of catechin to increase the polymer stability under oxidative atmosphere and the thermo-mechanical relaxation of all the starch-based materials were studied. The combination of plasticized starch matrix loaded with both, SNCs and catechin, leads to a multifunctional starch based films with increased hydrophilicity and with excellent humidity-activated shape memory behavior with interest for potential biomedical applications. PMID- 29111076 TI - Electroconvulsive therapy for depression with comorbid borderline personality disorder or post-traumatic stress disorder: A matched retrospective cohort study. AB - BACKGROUND: The impact of comorbid borderline personality disorder (BPD) or post traumatic stress disorder (PTSD) on clinical and cognitive outcomes of electroconvulsive therapy (ECT) in patients with major depressive episodes (MDE) is unknown. OBJECTIVE: Compare clinical response and adverse cognitive effects for MDE patients with comorbid BPD or PTSD to MDE only. METHODS: In a matched retrospective cohort study of 75 patients treated with ECT at an academic psychiatric hospital with DSM-IV MDE and either comorbid BPD, PTSD or both (MDE + BPD/PTSD), 75 MDE patients without BPD or PTSD (MDE-only) were matched. We reviewed clinical records to determine treatment response by estimating clinical global impression of improvement (c-CGI) and presence of adverse cognitive effects based on subjective distress or objective impairment. We explored factors associated with response and cognitive effects in the MDE + BPD/PTSD group. RESULTS: There was no difference in c-CGI response rates between groups (p > 0.017). Secondary analysis of inpatients found lower response rates for MDE + BPD (55.4%) and MDE + BPD + PTSD (55.8%) than MDE-only (82.5%), but not MDE + PTSD (65.0%). There was no difference in adverse cognitive effects in the MDE + BPD/PTSD (23.3%-26.8%) group compared to MDE-only (25.0%). In the MDE + BPD/PTSD group, factors associated with higher response rate were: referral indications other than failed pharmacotherapy, greater number of ECT treatments, presence of adverse cognitive effects, and seizure duration >30 s. CONCLUSIONS: Despite a lower c-CGI response for inpatients with MDE + BPD, ECT is a viable treatment option for patients in the MDE + BPD/PTSD group with similar adverse cognitive effect profiles to MDE-only. PMID- 29111078 TI - Electroconvulsive therapy, depression, the immune system and inflammation: A systematic review. AB - BACKGROUND: The management and treatment of major depressive disorder are major public health challenges, the lifetime prevalence of this illness being 4.4%-20% in the general population. Major depressive disorder and treatment resistant depression appear to be, in part, related to a dysfunction of the immune response. Among the treatments for depression ECT occupies an important place. The underlying cerebral mechanisms of ECT remain unclear. OBJECTIVES/HYPOTHESIS: The aim of this review is to survey the potential actions of ECT on the immuno inflammatory cascade activated during depression. METHODS: A systematic search of the literature was carried out, using the bibliographic search engines PubMed and Embase. The search covered articles published up until october 2017. The following MESH terms were used: Electroconvulsive therapy AND (inflammation OR immune OR immunology). RESULTS: Our review shows that there is an acute immuno inflammatory response immediately following an ECT session. There is an acute stress reaction. Studies show an increase in the plasma levels of cortisol and of interleukins 1 and 6. However, at the end of the course of treatment, ECT produces, in the long term, a fall in the plasma level of cortisol, a reduction in the levels of TNF alpha and interleukin 6. LIMITATIONS: One of the limitations of this review is that a large number of studies are relatively old, with small sample sizes and methodological bias. CONCLUSION: Advances in knowledge of the immuno-inflammatory component of depression seem to be paving the way towards models to explain the mechanism of action of ECT. PMID- 29111079 TI - Phytosterol-enriched milk lowers LDL-cholesterol levels in Brazilian children and adolescents: Double-blind, cross-over trial. AB - BACKGROUND AND AIMS: Despite evidence of the lipid-lowering effect of plant sterols among adults with hypercholesterolemia, data regarding phytosterol use in children are limited. In this paper, we examined the effects of daily consumption of a phytosterol-enriched milk compound on the lipid profiles of Brazilian children and adolescents with dyslipidemia. METHODS AND RESULTS: This was a randomized, double blind, crossover clinical trial. Twenty eight dyslipidemics outpatients (aged 6-9 years) from an University Hospital were randomly allocated to control or intervention group. The intervention group received milk enriched with 1.2 g/day of plant sterol and the control group received the equivalent amount of skim milk during the period of 8 weeks. Changes from baseline in the mean lipid profile, including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) concentrations. Serum lipid profiles, glucose levels, dietary and anthropometric data were determined at weeks 0, 4, 8, 16, and 20. Details regarding the safety and tolerance of phytosterol were obtained, using an open-ended questionnaire. Intention-to-treat analysis were performed, using the proc mixed procedure in SAS. After 8 weeks, the mean concentrations of TC and LDL-C were significantly reduced in the intervention group as compared to the control group with reductions of 5.9% (p = 0.09) and 10.2% (p = 0.002), respectively. In addition, TG concentrations were reduced by 19.7% (p = 0.09). No serious side effects were reported during the study. CONCLUSION: Our results confirm that plant sterols are an effective and safe treatment of infantile dyslipidemia. TRIAL REGISTRATION: RBR-3h7f9k. PMID- 29111077 TI - International randomized-controlled trial of transcranial Direct Current Stimulation in depression. AB - BACKGROUND: Evidence suggests that transcranial Direct Current Stimulation (tDCS) has antidepressant effects in unipolar depression, but there is limited information for patients with bipolar depression. Additionally, prior research suggests that brain derived neurotrophic factor (BDNF) Val66Met genotype may moderate response to tDCS. OBJECTIVE: To examine tDCS efficacy in unipolar and bipolar depression and assess if BDNF genotype is associated with antidepressant response to tDCS. METHODS: 130 participants diagnosed with a major depressive episode were randomized to receive active (2.5 milliamps (mA), 30 min) or sham (0.034 mA and two 60-second current ramps up to 1 and 0.5 mA) tDCS to the left prefrontal cortex, administered in 20 sessions over 4 weeks, in a double-blinded, international multisite study. Mixed effects repeated measures analyses assessed change in mood and neuropsychological scores in participants with at least one post-baseline rating in the unipolar (N = 84) and bipolar (N = 36) samples. RESULTS: Mood improved significantly over the 4-week treatment period in both unipolar (p = 0.001) and bipolar groups (p < 0.001). Among participants with unipolar depression, there were more remitters in the sham treatment group (p = 0.03). There was no difference between active and sham stimulation in the bipolar sample. BDNF genotype was unrelated to antidepressant outcome. CONCLUSIONS: Overall, this study found no antidepressant difference between active and sham stimulation for unipolar or bipolar depression. However, the possibility that the low current delivered in the sham tDCS condition was biologically active cannot be discounted. Moreover, BDNF genotype did not moderate antidepressant outcome. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT01562184. PMID- 29111080 TI - Morbidity and mortality among "big" babies who develop necrotizing enterocolitis: A prospective multicenter cohort analysis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is classically a disease of prematurity, with less reported regarding morbidity and mortality of this disease among other infants. METHODS: Data were prospectively collected from 2009 to 2015 at 252 Vermont Oxford Network member centers on neonates with birth weight>2500g admitted to a participating NICU within 28days of birth. RESULTS: Of 1629 neonates with NEC, gestational age was 37 (36, 39) weeks, and 45% had major congenital anomalies, most commonly gastrointestinal defects (20%), congenital heart defects (18%), and chromosomal anomalies (7%). For the 23% of infants who had surgery for NEC, mortality and length of stay were 23% and 63 (36, 94) days versus 8% and 34 (22, 61) days in medical NEC. Independent predictors of mortality were congenital heart defects (p<0.0001), chromosomal abnormalities (p<0.05), other congenital malformations (p<0.001), surgical NEC (p<0.0001), and sepsis (p<0.05). All of these in addition to gastrointestinal defects were independent predictors of increased length of stay. Nutritional morbidity at discharge included 6% receiving no enteral feeds and 27% who were <10th percentile weight-for-age. CONCLUSIONS: Major congenital anomalies are present in nearly half of >2500g birth weight infants diagnosed with necrotizing enterocolitis. Morbidity and mortality increase with sepsis, surgical disease, and congenital anomalies. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: Level II. PMID- 29111081 TI - Timing of mortality in pediatric trauma patients: A National Trauma Data Bank analysis. AB - BACKGROUND/PURPOSE: The classic "trimodal" distribution of death has been described in adult patients, but the timing of mortality in injured children is not well understood. The purpose of this study was to define the temporal distribution of mortality in pediatric trauma patients. METHODS: A retrospective cohort of patients with mortality from the National Trauma Data Bank (2007-2014) was analyzed. Categorical comparison of 'dead on arrival', 'death in the emergency department', and early (<=24h) or late (>24h) inpatient death was performed. Secondary analyses included mortality by pediatric age, predictors of early mortality, and late complication rates. RESULTS: Children (N=5463 deaths) had earlier temporal distribution of death compared to adults (n=104,225 deaths), with 51% of children dead on arrival or in ED compared to 44% of adults (p<0.001). For patients surviving ED resuscitation, children and adolescents had a shorter median time to death than adults (1.2 d and 0.8 days versus 1.6 days, p<0.001). Older age, penetrating mechanism, bradycardia, hypotension, tube thoracostomy, and thoracotomy were associated with early mortality in children. CONCLUSIONS: Injured children have higher incidence of early mortality compared to adults. This suggests that injury prevention efforts and strategies for improving early resuscitation have potential to improve mortality after pediatric injury. LEVEL OF EVIDENCE: Level III: Retrospective cohort study. PMID- 29111082 TI - Safety culture among pediatric surgeons: A national survey of attitudes and perceptions of patient safety. AB - PURPOSE: Improving the culture of safety within health care is an essential component of preventing errors and improving overall health care quality. The purpose of this study was to characterize the attitudes and perceptions of patient safety among pediatric surgeons. METHODS: We conducted a cross-sectional online survey of American Pediatric Surgery Association members. Survey items assessed surgeons' knowledge, attitudes, and perceptions of patient safety. We performed descriptive statistics and evaluated associations between respondent characteristics and survey responses. RESULTS: Response rate was 38% (353/928). Surgeons in academic practice (96% vs 83% private, P=0.01) and in leadership positions (98% vs 92%, P=0.03) were more likely to feel actively engaged in patient safety initiatives. Surgeons in private practice were less likely to feel safe having their own children undergo surgery at their institution (80% vs 96% academic, P<0.005). CONCLUSION: Pediatric surgeons have disparate attitudes and perceptions of patient safety within their hospitals. Significant variation exists based on surgeon characteristics. These findings underscore the need to identify barriers to surgeon engagement and develop educational initiatives to empower surgeons as leaders in improving patient safety culture. LEVEL OF EVIDENCE: V. PMID- 29111083 TI - Postoperative outcomes in vedolizumab-treated pediatric patients undergoing abdominal operations for inflammatory bowel disease. AB - INTRODUCTION: Recent studies have found vedolizumab to be an independent predictor of increased rates of postoperative complications and surgical site infections (SSIs) in adults with inflammatory bowel disease (IBD), but studies in the pediatric surgical population are lacking. We sought to determine the 30-day postoperative infectious complication rate among pediatric IBD patients who received vedolizumab within 12weeks of a major abdominal operation. METHODS: A retrospective chart review was performed on pediatric IBD patients who underwent an abdominal operation between 5/20/2014 and 6/1/2017. The study cohort was comprised of pediatric patients (<=18years) who received vedolizumab within 12weeks prior to their abdominal operation. The control cohort was all patients operated on for IBD during the same time on anti-TNF therapy within 12weeks of their abdominal operation. RESULTS: Thirteen pediatric patients (5 female) received vedolizumab within 12weeks of an abdominal operation and 36 patients received anti TNF therapy (20 female). There were no differences in the vedolizumab and anti-TNF therapy with regard to sex, median age of diagnosis or operation, IBD type, body mass index (BMI), smoking status, diabetes mellitus (DM), preoperative serum laboratory values, steroid or immunomodulatory use. The number of biologics previously exposed to was significantly higher in the vedolizumab treated patients (p<0.0001). There were no significant differences in operative characteristics including laparoscopic versus open surgery, construction of an anastomosis, or diversion of an anastomosis. There were also no significant differences found in 30-day postoperative complications including nonsurgical site infections (SSIs), all SSIs, small bowel obstruction (SBO)/ileus, hospital readmission, or return to the operating room (ROR). There were four RORs in total: one in the vedolizumab group was for a missed enterotomy and stoma revision; three in the anti-TNF cohort were for ileostomy revisions. CONCLUSIONS: None of the thirteen pediatric patients who received vedolizumab within 12weeks of an abdominal operation experienced a 30-day postoperative SSI or non SSI infectious complication, suggesting that vedolizumab is safe in the perioperative period for pediatric patients with IBD. Owing to the small sample size, future study, perhaps multi-institutional, will be important to confirm these findings. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 29111084 TI - A model for humanitarian outreach in today's world. AB - The traditional model for humanitarian work for surgeons has been a few long-term people and a larger number of volunteers on short-term missions to needy places for one or two weeks with limited opportunity for follow-up. While a great deal of good has resulted from these efforts, in the long term not much has changed. Recent studies like the U.N. Millennium Development Goals and the Lancet Commission Report, Surgery 2030, have pointed out that the burden of surgical disease is the major public health issue in the world, such that an estimated five billion people worldwide do not have access to safe surgery and anesthesia, with the largest number being in Africa where almost half of the population is less than age 18years. These and other reports related to essential surgery conclude that the key element in this problem is an extreme shortage of a capable, well-trained physician workforce, without which none of the Millennium Goals can be accomplished. For these reasons, we have directed our efforts to the development of a humanitarian model that meets the modern day need to expand the surgeon and anesthesia workforces using a Western university model adapted to locoregional African needs. The goal is to train the trainers in order to magnify the physician output rapidly over wide geographical areas and to train teams of surgeons and anesthesiologists who will work together. Although we have worked primarily in East Africa, particularly in Kenya, we feel that this model is widely applicable. While this effort is in its early stages, resident trainees from the home program in Kenya are now in Uganda, Rwanda, Ethiopia, Sierra Leone, Cameroon, and Madagascar, and they are in the process of developing their own residency training programs. It is our vision that with the expansion of the surgeon-anesthesiologist workforce, more people will have access to safe surgery and anesthesia, including obstetrical care, a humanitarian model in today's context. PMID- 29111085 TI - IL-37 and leprosy: A novel cytokine involved in the host response to Mycobacterium leprae infection. AB - Leprosy is a chronic infectious granulomatous disease caused by Mycobacterium leprae, in which the clinical outcome depends on the pattern of the host immune response. Because it is a spectral disease, leprosy is a good model for studying the immunology of the pathogen-host relationship. Although previous studies have characterized the participation of cytokine profiles such as Th1, Th2, Th7, Treg, Th9, and Th22 responses in leprosy, the role of new cytokines such as IL-37 have not yet been described for the spectral model of the disease. Here, we used an immunohistochemical technique to evaluate IL-37 expression in the skin of patients with leprosy. The expression of this cytokine was observed in the keratinocytes, endothelial cells, macrophages, and lymphocytes. Moreover, the IL 37 expression level was increased in patients with the tuberculoid (TT) form when compared to those with the lepromatous leprosy (LL) form in keratinocytes, endotheliocytes, and lymphocytes. However, in the macrophages, the cytokine expression was more intense in the LL form of the disease. These results point to the effective participation of IL-37 in the immunopathogenesis of leprosy, which is expressed in both the epidermal cells and the dermis. PMID- 29111086 TI - Role of interleukin 17 in TGF-beta signaling-mediated renal interstitial fibrosis. AB - BACKGROUND: Several studies suggest IL-17 is involved in the pathogenesis of organ fibrosis. The exact role of IL-17 in renal interstitial fibrosis has not been fully elucidated. METHODS: We compared the histopathology of renal fibrosis as well as profibrotic TGF-beta signaling in wild-type (WT) and IL-17 knock-out (IL-17-/-) mice using UUO as the disease model. To find out the possible mechanisms involved in the exacerbated renal fibrosis happened to IL-17-/- mice, we analyzed the pattern of ECM synthesis by different fibroblasts cultured with IL-17 and associated signaling mediators. RESULTS: On day3 and day7, IL-17-/- mice developed more severe renal fibrosis compared with WT mice. IL-17 had an inhibitory factor in TGF-beta-induced renal fibroblast activation and ECM synthesis, and sequentially in renal interstitial fibrosis, via down-regulation of Smad -independent pathway (p38MAPK and AKT phosphorylations). CONCLUSION: IL 17 acts an inhibitory factor in TGF-beta-induced renal fibroblast activation and ECM synthesis, and sequentially in renal interstitial fibrosis, via down regulation of Smad-independent pathway (p38MAPK and AKT phosphorylations). Clarifying the novel regulatory mechanisms of fibrosis by the cytokine IL-17 may lead to a new therapeutic approach for progressive renal disease and fibrosis. PMID- 29111087 TI - Angiogenic factor screening in women with mild preeclampsia - New and significant proteins in plasma. AB - INTRODUCTION: The aim of this study was to analyse a panel of 60 angiogenic factors (pro-angiogenic and antiangiogenic) in the plasma of women with mild preeclampsia. MATERIALS AND METHODS: We recruited 21 women between 25 and 40 weeks gestation with diagnosed mild preeclampsia into the study group and 27 healthy women with uncomplicated pregnancies of corresponding gestational age to that of the study to the control group. We used a quantitative protein macroarray method that allowed for analysis of 60 angiogenic proteins per sample simultaneously. RESULTS: We showed a statistically significant increase in the concentration of 8 proteins, interferon gamma (IFN-gamma), interleukin 6 (IL-6), leukaemia inhibitory factor (LIF), heparin-binding EGF-like growth factor (HB EGF), hepatocyte growth factor (HGF), C-X-C motif chemokine 10 (IP-10), leptin and platelet-derived growth factor BB (PDGF-BB), as well as a significant decrease in the concentration of 3 proteins, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and follistatin, in the plasma of women with preeclampsia. CONCLUSION: Based on our findings, it seems that protein factors may play an important role in the pathogenesis of preeclampsia, and there are many proteins that have not been studied in PE to date. There are no previous studies assessing the LIF, follistatin, HGF, HB-EGF and PDGF-BB concentrations in the plasma of women with PE; therefore, our obtained results indicate that these proteins are new factors that can play an important role in the pathomechanisms of PE. PMID- 29111088 TI - State Laws Are Associated with School Lunch Duration and Promotion Practices. AB - BACKGROUND: The changes in school meal programs stemming from the Healthy, Hunger Free Kids Act of 2010 have expanded interest in strategies that increase student participation in school lunch and reduce plate waste. However, it remains unclear what factors are associated with schools' use of such strategies. OBJECTIVE: This study examines whether state laws are associated with two types of school meal related practices: (a) using promotional strategies (ie, taste tests, using posters or announcements) and (b) duration of lunch periods. DESIGN: This cross sectional study utilized the nationally representative 2014 School Health Policies and Practices Study, combined with corresponding state laws gathered by the National Wellness Policy Study. School data were available from 414 public schools in 43 states. MAIN OUTCOME MEASURES: Outcome measures included 16 strategies to promote school meals and the amount of time students had to eat lunch after being seated. STATISTICAL ANALYSES PERFORMED: Multivariate logistic regression and Poisson regression were used to examine associations between state laws and school practices, after accounting for school demographic characteristics. RESULTS: Compared to schools in states with no law about engaging stakeholders in meal programs, schools in states with a law were more likely to conduct taste tests (64% vs 44%, P=0.016), collect suggestions from students (67% vs 50%, P=0.017), and invite family members to a school meal (71% vs 53%, P=0.015). Schools used more promotion strategies in states with a law than in states without a law (mean=10.4 vs 8.8, P=0.003). Schools were more likely to provide students at least 30 minutes to eat lunch after being seated in states with laws that addressed a minimum amount of time for lunch duration (43% vs 27%, P=0.042). CONCLUSIONS: State-level policy provisions are associated with school practices. Policy development in more states may support school practices that promote lunch participation and consumption. PMID- 29111089 TI - Benefits, Barriers, and Motivators to Training Dietetic Interns in Clinical Settings: A Comparison between Preceptors and Nonpreceptors. AB - BACKGROUND: The shortage of supervised practice sites in dietetics is associated with fewer numbers of preceptors available to supervise interns, especially in the clinical setting. OBJECTIVE: To identify clinical dietitians' perceived benefits and challenges of training dietetic interns and to determine key motivators that would entice nonpreceptors to volunteer for the role. DESIGN: Registered dietitian nutritionists working in clinical settings completed a semi structured, audiotaped interview followed by a brief questionnaire. PARTICIPANTS: Clinical dietitians working in hospitals, long-term care facilities, and outpatient clinics (n=100) participated: 54 preceptors and 46 nonpreceptors. STATISTICAL ANALYSIS: Qualitative analysis was conducted using an iterative process to identify and code common themes. T tests were used to compare mean differences between the opinions of preceptors and nonpreceptors. RESULTS: Preceptors had approximately 5 more years of experience (mean=14.27+/-12.09 years) than nonpreceptors (mean=8.83+/-9.72 years) (P< 0.01). Furthermore, preceptors reported twice as many benefits to mentoring interns (mean=6.7 mentions/participant) as nonpreceptors (mean=3.4 mentions/participant), including knowledge gains and staying current. Lack of time was consistently noted as a barrier in interviews and rated as the greatest barrier in the survey. Both groups rated receiving continuing professional education units (CPEUs) for precepting as the greatest potential motivator for taking on interns. CONCLUSIONS: Incentive programs should be developed to entice nonpreceptors to take on interns. These programs should include extensive training on the preceptor role and how to alleviate the burden of time spent supervising interns and should provide a significant number of CPEUs to make the added workload worthwhile. PMID- 29111090 TI - Diet Quality as Assessed by the Healthy Eating Index, Alternate Healthy Eating Index, Dietary Approaches to Stop Hypertension Score, and Health Outcomes: An Updated Systematic Review and Meta-Analysis of Cohort Studies. AB - BACKGROUND: Diets of the highest quality have been associated with a significantly lower risk of noncommunicable diseases. OBJECTIVE: It was the aim of this study to update a previous systematic review investigating the associations of diet quality as assessed by the Healthy Eating Index (HEI), Alternate Healthy Eating Index (AHEI), and Dietary Approaches to Stop Hypertension (DASH) score and multiple health outcomes. As an additional topic, the associations of these diet quality indices with all-cause mortality and cancer mortality among cancer survivors were also investigated. DESIGN: A literature search for prospective cohort studies that were published up to May 15, 2017 was performed using the electronic databases PubMed, Scopus, and Embase. Summary risk ratios (RRs) and 95% CIs were estimated using a random effects model for high vs low adherence categories. RESULTS: The updated review process showed 34 new reports (total number of reports evaluated=68; including 1,670,179 participants). Diets of the highest quality, as assessed by the HEI, AHEI, and DASH score, resulted in a significant risk reduction for all-cause mortality (RR 0.78, 95% CI 0.77 to 0.80; I2=59%; n=13), cardiovascular disease (incidence or mortality) (RR 0.78, 95% CI 0.76 to 0.80; I2=49%; n=28), cancer (incidence or mortality) (RR 0.84, 95% CI 0.82 to 0.87; I2=66%; n=31), type 2 diabetes (RR 0.82, 95% CI 0.78 to 0.85; I2=72%; n=10), and neurodegenerative diseases (RR 0.85, 95% CI 0.74 to 0.98; I2=51%; n=5). Among cancer survivors, the association between diets for the highest quality resulted in a significant reduction in all cause mortality (RR 0.88, 95% CI 0.81 to 0.95; I2=38%; n=7) and cancer mortality (RR 0.90, 95% CI 0.83 to 0.98; I2=0%; n=7). CONCLUSIONS: In the updated meta analyses, diets that score highly on the HEI, AHEI, and DASH were associated with a significant reduction in the risk of all-cause mortality, cardiovascular disease, cancer, type 2 diabetes, and neurodegenerative disease by 22%, 22%, 16%, 18%, and 15%, respectively. Moreover, high-quality diets were inversely associated with overall mortality and cancer mortality among cancer survivors. PMID- 29111091 TI - Participant Satisfaction with a Food Benefit Program with Restrictions and Incentives. AB - BACKGROUND: Policy makers are considering changes to the Supplemental Nutrition Assistance Program (SNAP). Proposed changes include financially incentivizing the purchase of healthier foods and prohibiting the use of funds for purchasing foods high in added sugars. SNAP participant perspectives may be useful in understanding the consequences of these proposed changes. OBJECTIVE: To determine whether food restrictions and/or incentives are acceptable to food benefit program participants. DESIGN: Data were collected as part of an experimental trial in which lower-income adults were randomly assigned to one of four financial food benefit conditions: (1) Incentive: 30% financial incentive on eligible fruits and vegetables purchased using food benefits; (2) Restriction: not allowed to buy sugar-sweetened beverages, sweet baked goods, or candies with food benefits; (3) Incentive plus Restriction; or (4) Control: no incentive/restriction. Participants completed closed- and open-ended questions about their perceptions on completion of the 12-week program. PARTICIPANTS/SETTING: Adults eligible or nearly eligible for SNAP were recruited between 2013 and 2015 by means of events or flyers in the Minneapolis/St Paul, MN, metropolitan area. Of the 279 individuals who completed baseline measures, 265 completed follow-up measures and are included in these analyses. STATISTICAL ANALYSIS: chi2 analyses were conducted to assess differences in program satisfaction. Responses to open-ended questions were qualitatively analyzed using principles of content analysis. RESULTS: There were no statistically significant or meaningful differences between experimental groups in satisfaction with the program elements evaluated in the study. Most participants in all conditions found the food program helpful in buying nutritious foods (94.1% to 98.5%) and in buying the kinds of foods they wanted (85.9% to 95.6%). Qualitative data suggested that most were supportive of restrictions, although a few were dissatisfied. Participants were uniformly supportive of incentives. CONCLUSIONS: Findings suggest a food benefit program that includes incentives for purchasing fruits and vegetables and/or restrictions on the use of program funds for purchasing foods high in added sugars appears to be acceptable to most participants. PMID- 29111092 TI - Quantitative neuroimaging in mucopolysaccharidoses clinical trials. AB - The mucopolysaccharidosis (MPS) disorders are rare lysosomal storage disorders caused by mutations in lysosomal enzymes involved in glycosaminoglycan (GAG) degradation. The resulting intracellular accumulation of GAGs leads to widespread tissue and organ dysfunction. In addition to somatic signs and symptoms, patients with MPS can present with neurological manifestations such as cognitive decline, behavioral problems (e.g. hyperactivity and aggressiveness), sleep disturbances, and/or epilepsy. These are associated with significant abnormalities of the central nervous system (CNS), including white and gray matter lesions, brain atrophy, ventriculomegaly, and spinal cord compression. In order to effectively manage and develop therapies for MPS that target neurological disease, it is important to visualize and quantify these CNS abnormalities. This review describes optimal approaches for conducting magnetic resonance imaging assessments in multi-center clinical studies, and summarizes current knowledge from neuroimaging studies in MPS disorders. The content of the review is based on presentations and discussions on these topics that were held during a meeting of an international group of experts. PMID- 29111093 TI - Biomarkers of cerebral microembolic signals. AB - Stroke is a major cause of mortality and morbidity around the world. Microembolic signals (MES), as the markers of unstable atherosclerotic plaque, can predict the occurrence and prognosis of ischemic stroke (IS). MES can also assess the efficacy of antithrombotic agents and predict the recurrence probability of IS. Unstable plaques are the main source of MES; thus, numerous biomarkers of atherosclerotic plaque instability are highly likely to predict the presence of MES. This study aims to review recent biomarker candidates for MES or microembolism. Current research indicates that the following are independent markers for positive MES: high level of serum soluble P-selectin, chemokine (C-X C motif) ligand 16 (CXCL16) and fibrinogen, high neutrophil count, reduced ratio of CD4+CD25high regulatory T cells (Tregs) and the C allele of tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) rs3102735. However, a more integrated profile of biomarkers for MES is needed to improve the stratification of patients with carotid stenosis and enhance the effectiveness of therapeutic interventions and prevention for IS. PMID- 29111094 TI - Real-time PCR-based method for the rapid detection of extended RAS mutations using bridged nucleic acids in colorectal cancer. AB - Mutations in RAS and BRAF are predictors of the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). Therefore, simple, rapid, cost-effective methods to detect these mutations in the clinical setting are greatly needed. In the present study, we evaluated BNA Real-time PCR Mutation Detection Kit Extended RAS (BNA Real-time PCR), a real-time PCR method that uses bridged nucleic acid clamping technology to rapidly detect mutations in RAS exons 2-4 and BRAF exon 15. Genomic DNA was extracted from 54 formalin-fixed paraffin-embedded (FFPE) tissue samples obtained from mCRC patients. Among the 54 FFPE samples, BNA Real-time PCR detected 21 RAS mutations (38.9%) and 5 BRAF mutations (9.3%), and the reference assay (KRAS Mutation Detection Kit and MEBGENTM RASKET KIT) detected 22 RAS mutations (40.7%). The concordance rate of detected RAS mutations between the BNA Real-time PCR assay and the reference assays was 98.2% (53/54). The BNA Real-time PCR assay proved to be a more simple, rapid, and cost-effective method for detecting KRAS and RAS mutations compared with existing assays. These findings suggest that BNA Real-time PCR is a valuable tool for predicting the efficacy of early anti-EGFR therapy in mCRC patients. PMID- 29111095 TI - Multi-arm Clinical Trials - Teams within Teams. PMID- 29111096 TI - Multinodular and vacuolating neuronal tumor of the cerebrum. A rare entity. New case and review of the literature. AB - BACKGROUND: Multinodular and vacuolating neuronal tumor has been recently described and included in the World Health Organization Classification of Tumors of The Central Nervous System, even though its consideration as a true tumor is controversial. Patients with these lesions usually present with refractory seizures and inconclusive imaging findings that may be confused with other more common diagnoses such as dysembryoplastic neuroepithelial tumors or low-grade gliomas. Therefore, surgical resection is warranted to reach a pathologic diagnosis and seizure control. To the best of our knowledge, only 16 cases have been published in the English literature. CASE DESCRIPTION: We present the case of a 52-year-old male who presented at our institution with a 2-year-history of absence of seizures. Brain MRI showed a T2-hyperintense lesion with no contrast enhancement affecting his temporal lobe. Temporal craniotomy and microsurgical resection was scheduled. The procedure was uneventful and a grayish, gluey mass was sent for pathologic analysis. The tumor was formed by immature neuronal cells organized in nodules with a vacuolated matrix. A thorough immunohistochemical analysis showed positivity for: Protein Gene Product 9.5. ATRX. OLIG2. SOX10. p16. Nestin. Synaptophysin. The findings were consistent with multinodular and vacuolating neuronal tumor. The patient has been seizure-free after surgery and with no signs of tumor progression. CONCLUSION: We present a thorough review addressing this uncommon tumor along with a description of the 17th reported case of MVNT, a tumor that was described for the first time in 2013. Further studies and case studies are necessary to establish a well-defined morphological and immunohistochemical profile along with knowledge about its natural history. PMID- 29111097 TI - Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications. AB - During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology. Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers. In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well. PMID- 29111099 TI - Prediction of human percutaneous absorption from in vitro and in vivo animal experiments. AB - Although anatomical and structural similarities between the skin of minipigs and humans are often reported, few percutaneous pharmacokinetic studies have been conducted in minipigs. The objective of this study was to clarify the usefulness of minipigs for estimating the percutaneous absorption of various drugs in humans. The absorption of several marketed drugs was observed in mice, rats and minipigs both in vivo and in vitro, and results were compared with those in humans. For all six model drugs, after percutaneous administration in vivo, fraction of dose absorbed (F) from the skin was the lowest in minipigs among the four species studied, including humans. In vitro drug permeation results were similar, with the lowest permeability observed in minipigs. However, combined use of both in vitro permeation and in vivo absorption data from minipigs using triple pack approach resulted in better prediction of human F values than data obtained from mice. These results suggest some qualitative, but not quantitative, similarities between the drug absorption process across the skin of minipigs and humans. In conclusion, minipigs appear to be a promising model animal for predicting percutaneous drug absorption in humans, however, more in vivo and in vitro studies are needed to improve predictability. PMID- 29111098 TI - Development of pre-activated alpha-cyclodextrin as a mucoadhesive excipient for intra-vesical drug delivery. AB - The study was designed to synthesize and characterize pre-activated alpha cyclodextrin (alpha-CD) derivatives as mucus adhering excipients for intra vesical drug delivery. Sodium periodate (NaIO4) was used to oxidize alpha-CD and subsequently cysteamine was covalently attached to carbonyl groups of oxidized alpha-CD via reductive amination to produce thiolated alpha-CD. l-cysteine-2 mercaptonicotinic acid conjugate (Cys-MNA) was covalently attached to carbonyl groups of oxidized alpha-CD to produce pre-activated alpha-CD having enhance stability against oxidation at higher pH. Thiolated and pre-activated alpha-CD derivatives were quantitatively assayed for the attached thiol groups and MNA groups, respectively. Cell viability and tolerability was evaluated via resazurin assay and via red blood cells (RBC) lysis assay, respectively. Mucoadhesive properties were evaluated on porcine bladder mucosa. Trimethoprim (TMP) was encapsulated into thiolated and pre-activated alpha-CD derivatives and the dissolution behavior was evaluated in vitro. Thiol groups attached to thiolated alpha-CD derivatives alpha-CD-SH780 and alpha-CD-SH1426 were 780+/-68MUmol/g and 1426+/-66MUmol/g, respectively. For the entirely pre-activated alpha-CD derivatives, alpha-CD-MNA3609 and alpha-CD-MNA4285 number of attached MNA groups were 3609+/-19MUmol/g and 4285+/-43MUmol/g, respectively. Thiolated and pre activated derivatives of alpha-CD did not show adverse effects to cells determined via resazurin and RBC lysis assays. Mucoadhesion on porcine bladder mucosa was significantly improved for thiolated and pre-activated alpha-CD derivatives. Thiolated alpha-CD-SH1426 showed 15-fold and pre-activated alpha-CD MNA4285 showed 25-fold improved mucoadhesion compared to unmodified alpha-CD. Further, pre-activated alpha-CD-MNA4285 showed 2-fold enhanced dissolution of encapsulated TMP compared to free TMP over 3 h. The study shows that pre activated alpha-CD could be an excipient of the choice for the formulations of mucoadhesive intra-vesical drug delivery systems. PMID- 29111100 TI - Systemic cell cycle activation is induced following complex tissue injury in axolotl. AB - Activation of progenitor cells is crucial to promote tissue repair following injury in adult animals. In the context of successful limb regeneration following amputation, progenitor cells residing within the stump must re-enter the cell cycle to promote regrowth of the missing limb. We demonstrate that in axolotls, amputation is sufficient to induce cell-cycle activation in both the amputated limb and the intact, uninjured contralateral limb. Activated cells were found throughout all major tissue populations of the intact contralateral limb, with internal cellular populations (bone and soft tissue) the most affected. Further, activated cells were additionally found within the heart, liver, and spinal cord, suggesting that amputation induces a common global activation signal throughout the body. Among two other injury models, limb crush and skin excisional wound, only limb crush injuries were capable of inducing cellular responses in contralateral uninjured limbs but did not achieve activation levels seen following limb loss. We found this systemic activation response to injury is independent of formation of a wound epidermis over the amputation plane, suggesting that injury-induced signals alone can promote cellular activation. In mammals, mTOR signaling has been shown to promote activation of quiescent cells following injury, and we confirmed a subset of activated contralateral cells is positive for mTOR signaling within axolotl limbs. These findings suggest that conservation of an early systemic response to injury exists between mammals and axolotls, and propose that a distinguishing feature in species capable of full regeneration is converting this initial activation into sustained and productive growth at the site of regeneration. PMID- 29111101 TI - Multiresidue determination of pesticides in crop plants by the quick, easy, cheap, effective, rugged, and safe method and ultra-high-performance liquid chromatography tandem mass spectrometry using a calibration based on a single level standard addition in the sample. AB - In this study, a QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method, optimized by a 23 full factorial design, was developed for the determination of 72 pesticides in plant parts of carrot, corn, melon, rice, soy, silage, tobacco, cassava, lettuce and wheat by ultra-high-performance liquid chromatographic tandem mass spectrometry (UHPLC-MS/MS). Considering the complexity of these matrices and the need of use calibration in matrix, a new calibration approach based on single level standard addition in the sample (SLSAS) was proposed in this work and compared with the matrix-matched calibration (MMC), the procedural standard calibration (PSC) and the diluted standard addition calibration (DSAC). All approaches presented satisfactory validation parameters with recoveries from 70 to 120% and relative standard deviations<=20%. SLSAS was the most practical from the evaluated approaches and proved to be an effective way of calibration. Method limit of detection were between 4.8 and 48MUgkg-1 and limit of quantification were from 16 to 160MUgkg-1. Method application to different kinds of plants found residues of 20 pesticides that were quantified with z-scores values<=2 in comparison with other calibration approaches. The proposed QuEChERS method combined with UHPLC-MS/MS analysis and using an easy and effective calibration procedure presented satisfactory results for pesticide residues determination in different crop plants and is a good alternative for routine analysis. PMID- 29111102 TI - Quantitative assessment of the learning curve for cleft lip repair using LC CUSUM. AB - The first step in cleft lip repair is the precise positioning of anatomical landmarks and tracing of the incisions on the patient's lip at the beginning of the procedure. The aim of this study was to evaluate progress made in learning cleft lip repair tracing using a quantitative assessment of learning curves: LC CUSUM (learning curve - cumulative sum). Eight surgical residents were enrolled and asked to trace lip repair incisions on five cases of unilateral left cleft lip over 5 consecutive weeks. Results were compared to a reference tracing based on the positioning of nine anatomical landmarks and assessed using LC-CUSUM. Competence was defined as the accurate positioning of the nine landmarks (less than 1.4mm deviation from the reference positions, with an accepted 15% failure rate). After five tracing sessions, competence was not achieved evenly for all trainees, or for all landmarks, underlining differences in inter-individual learning ability even with similar training. However, despite an initial marked lack of theoretical and practical training in lip repair techniques, repeated drawings of cleft lip incisions allowed a satisfactory level of competence to be reached for most landmarks and most trainees. Nevertheless it was found that not all landmarks are understood by students with similar ease, and that landmark positioning reveals significant inter-individual differences. This approach allowed a global assessment of the teaching of cleft repair and will help to focus training on specific problematic points for which competence was not obtained according to the LC-CUSUM test. PMID- 29111105 TI - PIM activity in tumours: A key node of therapy resistance. AB - The PIM kinases are proto-oncogenes which have been shown to facilitate cell survival and proliferation to drive malignancy and resistance post-therapy. They are able to suppress cell death signals, sustain PI3K/AKT/mTORC1 pathway activity and regulate the MYC oncogenic program. Recent work has revealed PIM kinase essentiality for advanced tumour maintenance and described tumour sensitivity to small molecule inhibitors targeting PIM kinase in multiple malignancies. PMID- 29111104 TI - Carotid-femoral pulse wave velocity in a healthy adult sample: The ELSA-Brasil study. AB - BACKGROUND: Aging declines essential physiological functions, and the vascular system is strongly affected by artery stiffening. We intended to define the age- and sex-specific reference values for carotid-to-femoral pulse wave velocity (cf PWV) in a sample free of major risk factors. METHODS AND RESULTS: The ELSA-Brasil study enrolled 15,105 participants aged 35-74years. The healthy sample was achieved by excluding diabetics, those over the optimal and normal blood pressure levels, body mass index <=18.5 or >=25kg/m2, current and former smokers, and those with self-report of previous cardiovascular disease. After exclusions, the sample consisted of 2158 healthy adults (1412 women). Although cf-PWV predictors were similar between sex (age, mean arterial pressure (MAP) and heart rate), cf PWV was higher in men (8.74+/-1.15 vs. 8.31+/-1.13m/s; adjusted for age and MAP, P<0.001) for all age intervals. When divided by MAP categories, cf-PWV was significantly higher in those which MAP >=85mmHg, regardless of sex, and for all age intervals. Risk factors for arterial stiffening in the entire ELSA-Brasil population (n=15,105) increased by twice the age-related slope of cf-PWV growth, regardless of sex (0.0919+/-0.182 vs. 0.0504+/-0.153m/s per year for men, 0.0960+/-0.173 vs. 0.0606+/-0.139m/s per year for women). CONCLUSIONS: cf-PWV is different between men and women and even in an optimal and normal range of MAP and free of other classical risk factors for arterial stiffness, reference values for cf-PWV should take into account MAP levels. Also, the presence of major risk factors in the general population doubles the age-related rise in cf-PWV. PMID- 29111103 TI - Muscle-specific knockout of general control of amino acid synthesis 5 (GCN5) does not enhance basal or endurance exercise-induced mitochondrial adaptation. AB - OBJECTIVE: Lysine acetylation is an important post-translational modification that regulates metabolic function in skeletal muscle. The acetyltransferase, general control of amino acid synthesis 5 (GCN5), has been proposed as a regulator of mitochondrial biogenesis via its inhibitory action on peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha). However, the specific contribution of GCN5 to skeletal muscle metabolism and mitochondrial adaptations to endurance exercise in vivo remain to be defined. We aimed to determine whether loss of GCN5 in skeletal muscle enhances mitochondrial density and function, and the adaptive response to endurance exercise training. METHODS: We used Cre-LoxP methodology to generate mice with muscle-specific knockout of GCN5 (mKO) and floxed, wildtype (WT) littermates. We measured whole-body energy expenditure, as well as markers of mitochondrial density, biogenesis, and function in skeletal muscle from sedentary mice, and mice that performed 20 days of voluntary endurance exercise training. RESULTS: Despite successful knockdown of GCN5 activity in skeletal muscle of mKO mice, whole-body energy expenditure as well as skeletal muscle mitochondrial abundance and maximal respiratory capacity were comparable between mKO and WT mice. Further, there were no genotype differences in endurance exercise-mediated mitochondrial biogenesis or increases in PGC-1alpha protein content. CONCLUSION: These results demonstrate that loss of GCN5 in vivo does not promote metabolic remodeling in mouse skeletal muscle. PMID- 29111106 TI - 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure. AB - Since the inception of the Canadian Cardiovascular Society heart failure (HF) guidelines in 2006, much has changed in the care for patients with HF. Over the past decade, the HF Guidelines Committee has published regular updates. However, because of the major changes that have occurred, the Guidelines Committee believes that a comprehensive reassessment of the HF management recommendations is presently needed, with a view to producing a full and complete set of updated guidelines. The primary and secondary Canadian Cardiovascular Society HF panel members as well as external experts have reviewed clinically relevant literature to provide guidance for the practicing clinician. The 2017 HF guidelines provide updated guidance on the diagnosis and management (self-care, pharmacologic, nonpharmacologic, device, and referral) that should aid in day-to-day decisions for caring for patients with HF. Among specific issues covered are risk scores, the differences in management for HF with preserved vs reduced ejection fraction, exercise and rehabilitation, implantable devices, revascularization, right ventricular dysfunction, anemia, and iron deficiency, cardiorenal syndrome, sleep apnea, cardiomyopathies, HF in pregnancy, cardio-oncology, and myocarditis. We devoted attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care. Recognition and treatment of advanced HF is another important aspect of this update, including how to select advanced therapies as well as end of life considerations. Finally, we acknowledge the remaining gaps in evidence that need to be filled by future research. PMID- 29111107 TI - Mind the Gap: Current Challenges and Future State of Heart Failure Care. AB - The past decade has seen many advances in the management of heart failure (HF) that have improved survival and quality of life for patients living with this condition. A number of gaps remain in our understanding of the pathophysiology of HF, and the application of emerging treatment strategies is an exciting but daunting challenge. It is possible that advances in genetic evaluation of cardiomyopathy will provide a more refined approach to characterizing HF syndromes, whereas large-scale clinical trials on the horizon should further clarify the role of novel pharmacologic agents and invasive therapies. Cardiac repair and regeneration hold great promise, but a number of pragmatic issues will limit clinical application in the near term. Replacing cardiac function with ventricular assist devices represents significant progress in the management of advanced disease; however, unacceptable rates of complications and costs need to be addressed before broader use in the general HF population is feasible. The ability to personalize care is limited, and the optimal model of disease management in the Canadian context remains uncertain. The emergence of biomarker guided management and remote monitoring technologies might facilitate a more personalized approach to care in an effort to maintain health and stability and to prevent worsening HF. Ultimately, a greater understanding of how and when to intervene in the setting of acute HF should translate into improved outcomes for the highest-risk subgroup of patients. This review highlights key challenges in the management of HF and highlights the progress toward an ideal future state. PMID- 29111109 TI - Failing at Heart Failure Therapies: Are Health Behaviours to Blame? PMID- 29111108 TI - The Need for Heart Failure Advocacy in Canada. PMID- 29111110 TI - Impact of Injectable Furosemide Hospital Shortage on Congestive Heart Failure Outcomes: A Time Series Analysis. AB - BACKGROUND: Beginning in February 2012, there was a shortage of injectable furosemide in the province of Ontario, Canada. The objective of this study was to assess the effects of the furosemide shortage on heart failure outcomes in Ontario, Canada. METHODS: We determined which hospitals experienced a shortage of injectable furosemide using an online survey. We then used health administrative data to identify all patients who presented to those hospitals with congestive heart failure. Using 40 months of data from before the shortage, we determined the proportion of patients with heart failure expected to die each month. We then used time series analysis to forecast the 30-day mortality rate during the shortage period and compared it with the observed rate. Secondary outcomes included length of hospital stay, transfer to an intensive care unit, mechanical ventilation during the hospital stay, and risk of 30-day readmission for heart failure. RESULTS: Survey results were obtained for 82% of hospitals, 28 of which experienced a severe shortage of injectable furosemide in the year 2012. The 30 day mortality among patients presenting to these hospitals with congestive heart failure before the shortage period was 11.2%. We forecasted a mortality rate of 11.3% (95% confidence interval, 8.2-14.4) for the shortage period, which was not significantly different from the observed rate of 10.9%. Similarly, we found no significant effect of the shortage on secondary outcomes. CONCLUSIONS: A severe shortage of injectable furosemide did not increase the risk of adverse outcomes among patients who presented to the hospital with congestive heart failure. PMID- 29111111 TI - Anti-aggregation effect of aroxyalkyl derivatives of 2-methoxyphenylpiperazine is due to their 5-HT2A and alpha2-adrenoceptor antagonistic properties. A comparison with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239. AB - Serotonin (5-HT) and adrenaline acting at platelet 5-HT2A-serotoninergic and alpha2-adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5-HT2A, alpha2A-, and alpha2B-adrenoceptors as well as an anti-aggregation effect of aroxyalkyl derivatives of 2 methoxyphenylpiperazine and compared them with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239 (2-[2-[4-(o-methoxyphenyl)-piperazin-1-yl]-ethyl] 4,4-dimethyl-1,3-(2H,4H)-isoquinolindione). Functional bioassays at cells expressing human receptors, revealed studied compounds to be moderate antagonists of 5-HT2A and alpha2-adrenoceptors, with around 2-7 times stronger antagonistic effect at alpha2B subtype than alpha2A subtype. Further, studied compounds inhibited 5-HT2A-mediated contraction in isolated rat aortic rings and 5-HT vasopressor response in rat in vivo. Studied compounds inhibited collagen stimulated whole rat blood aggregation with compound MH-77 (1-[(2,3 dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride) being more potent than sarpogrelate or yohimbine. They also inhibited 5-HT/adrenaline-, amplified ADP- or collagen- induced platelet aggregation. Simultaneous, moderate blockade of 5-HT2A serotonin and alpha2-adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy. PMID- 29111112 TI - Anti-migraine effect of ?9-tetrahydrocannabinol in the female rat. AB - Current anti-migraine treatments have limited efficacy and many side effects. Although anecdotal evidence suggests that marijuana is useful for migraine, this hypothesis has not been tested in a controlled experiment. Thus, the present study tested whether administration of ?9-tetrahydrocannabinol (THC) produces anti-migraine effects in the female rat. Microinjection of the TRPA1 agonist allyl isothiocyanate (AITC) onto the dura mater produced migraine-like pain for 3h as measured by depression of home cage wheel running. Concurrent systemic administration of 0.32 but not 0.1mg/kg of THC prevented AITC-induced depression of wheel running. However, 0.32mg/kg was ineffective when administered 90min after AITC. Administration of a higher dose of THC (1.0mg/kg) depressed wheel running whether rats were injected with AITC or not. Administration of a CB1, but not a CB2, receptor antagonist attenuated the anti-migraine effect of THC. These data suggest that: 1) THC reduces migraine-like pain when administered at the right dose (0.32mg/kg) and time (immediately after AITC); 2) THC's anti-migraine effect is mediated by CB1 receptors; and 3) Wheel running is an effective method to assess migraine treatments because only treatments producing antinociception without disruptive side effects will restore normal activity. These findings support anecdotal evidence for the use of cannabinoids as a treatment for migraine in humans and implicate the CB1 receptor as a therapeutic target for migraine. PMID- 29111113 TI - Understanding the relationship between brain and upper limb function in children with unilateral motor impairments: A multimodal approach. AB - : Atypical brain development and early brain injury have profound and long lasting impact on the development, skill acquisition, and subsequent independence of a child. Heterogeneity is present at the brain level and at the motor level; particularly with respect to phenomena of bilateral activation and mirrored movements (MMs). In this multiple case study we consider the feasibility of using several modalities to explore the relationship between brain structure and/or activity and hand function: Electroencephalography (EEG), both structural and functional Magnetic Resonance Imaging (sMRI, fMRI), diffusion tensor imaging (DTI), transcranial magnetic stimulation (TMS), Electromyography (EMG) and hand function assessments. METHODS: 15 children with unilateral CP (ages: 9.4 +/- 2.5 years) undertook hand function assessments and at least two additional neuroimaging and/or neurophysiological procedures: MRI/DTI/fMRI (n = 13), TMS (n = 11), and/or EEG/EMG (n = 8). During the fMRI scans and EEG measurements, a motor task was performed to study cortical motor control activity during simple hand movements. DTI tractography analysis was used to study the corpus-callosum (CC) and cortico-spinal tracts (CST). TMS was used to study cortico-spinal connectivity pattern. RESULTS: Type and range of severity of brain injury was evident across all levels of manual ability with the highest radiological scores corresponded to children poorer manual ability. Evidence of MMs was found in 7 children, mostly detected when moving the affected hand, and not necessarily corresponding to bilateral brain activation. When moving the affected hand, bilateral brain activation was seen in 6/11 children while 3/11 demonstrated unilateral activation in the contralateral hemisphere, and one child demonstrated motor activation predominantly in the supplementary motor area (SMA). TMS revealed three types of connectivity patterns from the cortex to the affected hand: a contralateral (n = 3), an ipsilateral (n = 4) and a mixed (n = 1) connectivity pattern; again without clear association with MMs. No differences were found between children with and without MMs in lesion scores, motor fMRI laterality indices, CST diffusivity values, and upper limb function. In the genu, midbody, and splenium of the CC, higher fractional anisotropy values were found in children with MMs compared to children without MMs. The EEG data indicated a stronger mu-restoration above the contralateral hemisphere in 6/8 children and above the ipsilateral hemisphere in 2/8 children. CONCLUSION: The current results demonstrate benefits from the use of different modalities when studying upper limb function in children with CP; not least to accommodate to the variations in tolerance and feasibility of implementation of the differing methods. These exposed multiple individual brain-reorganization patterns corresponding to different functional motor abilities. Additional research is warranted to understand the transactional influences of early brain injury, neuroplasticity and developmental and environmental factors on hand function in order to develop targeted interventions. PMID- 29111114 TI - Motor dysfunction in NF1: Mediated by attention deficit or inherent to the disorder? AB - AIM: Attention deficit and compromised motor skills are both prevalent in Neurofibromatosis type 1 (NF1), but the relationship is unclear. We investigated motor function in children with NF1 and in children with Attention Deficit/Hyperactivity Disorder (ADHD), and explored if, in patients with NF1, attention deficit influences motor performance. METHODS: Motor performance was measured using the Movement Assessment Battery for Children (M-ABC) in 71 children (26 with NF1 plus ADHD, 14 with NF1 without ADHD, and 31 with ADHD without NF1) aged 6-12 years. RESULTS: There was a significant effect of group on motor performance. Both NF1 groups scored below children with ADHD without NF1. Attention performance mediated motor performance in children with ADHD without NF1, but not in children with NF1. CONCLUSIONS: Motor function is not mediated by attention performance in children with NF1. While in ADHD, attention deficit influences motor performance, motor problems in NF1 seem to be independent from attention deficit. This argues for different pathomechanisms in these two groups of developmental disorders. PMID- 29111116 TI - Coevolution takes the sting out of it: Evolutionary biology and mechanisms of toxin resistance in animals. AB - Understanding how biotic interactions shape the genomes of the interacting species is a long-sought goal of evolutionary biology that has been hampered by the scarcity of tractable systems in which specific genomic features can be linked to complex phenotypes involved in interspecific interactions. In this review we present the compelling case of evolved resistance to the toxic challenge of venomous or poisonous animals as one such system. Animal venoms and poisons can be comprised of few or of many individual toxins. Here we show that resistance to animal toxins has evolved multiple times across metazoans, although it has been documented more often in phyla that feed on chemically-armed animals than in prey of venomous predators. We review three types of gene-product based resistance: 1) toxin scavenging, where molecules produced by the envenomed organism bind and inactivate the toxins; 2) target-site insensitivity, including landmark cases of convergent changes that make the molecules normally targeted by animal toxins refractory, and; 3) off-target repurposing, where envenomed organisms overcome toxicity by exploiting the function of toxins to alter their physiological effect. We finish by discussing the evolutionary processes that likely played a role in the origin and maintenance of toxin resistance. We conclude that antagonistic interactions involving poisonous or venomous animals are unparalleled models for investigating microevolutionary processes involved in coevolution and linking them to macroevolutionary patterns. PMID- 29111117 TI - Identification of B cell recognized linear epitopes in a snake venom serine proteinase from the central American bushmaster Lachesis stenophrys. AB - Snake venom serine proteinases are toxins that perturb hemostasis acting on proteins from the blood coagulation cascade, the fibrinolytic or the kallikrein kinin system. Despite the relevance of these enzymes in envenomations by viper bites, the characterization of the antibody response to these toxins at the molecular level has not been previously addressed. In this work surface-located B cell recognized linear epitopes from a Lachesis stenophrys venom serine proteinase (UniProt accession number Q072L7) were predicted using an artificial neuronal network at the ABCpred server, the corresponding peptides were synthesized and their immunoreactivity was analyzed against a panel of experimental and therapeutic antivenoms. A molecular model of the L. stenophrys enzyme was built using as a template the structure of the D. acutus Dav-PA serine proteinase (Q9I8X1), which displays the highest degree of sequence similarity to the L. stenophrys enzyme among proteins of known 3D structure, and the surface located epitopes were identified in the protein model using iCn3D. A total of 13 peptides corresponding to the surface exposed predicted epitopes from L. stenophrys serine proteinase were synthesized and, their reactivity with a rabbit antiserum against the recombinant enzyme and a panel of antivenoms was evaluated by a capture ELISA. Some of the epitopes recognized by monospecific and polyspecific antivenoms comprise sequences overlapping motifs conserved in viper venom serine proteinases. The identification and characterization of relevant epitopes recognized by B cells in snake venom toxins may provide valuable information for the preparation of immunogens that help in the production of improved therapeutic antivenoms. PMID- 29111118 TI - Hsp90 and Thioredoxin-Thioredoxin Reductase enable the catalytic activity of Clostridial neurotoxins inside nerve terminals. AB - Botulinum (BoNTs) and tetanus (TeNT) neurotoxins are the most toxic substances known and form the growing family of Clostridial neurotoxins (CNT), the etiologic agents of botulism and tetanus. CNT are composed of a metalloprotease light chain (L), linked via a disulfide bond to a heavy chain (H). H mediates the binding to nerve terminals and the membrane translocation of L into the cytosol, where its substrates, the three SNARE proteins, are localized. L translocation is accompanied by unfolding and, once delivered on the cytosolic side of the endosome membrane, it has to be reduced and reacquire the native fold to be active. The Thioredoxin-Thioredoxin Reductase system (Trx-TrxR) specifically reduces the interchain disulfide bond while the cytosolic chaperone protein Hsp90 mediates L refolding. Both steps are essential for CNT activity and their inhibition efficiently blocks the neurotoxicity in cultured neurons and mice. Trx and its reductase physically interact with Hsp90 and are loosely bound to the cytosolic side of synaptic vesicles, the organelle exploited by CNT to enter nerve terminals and wherefrom L is translocated into the cytosol. Therefore, Trx, TrxR and Hsp90 orchestrate a chaperone-redox molecular machinery that enables the catalytic activity of the L inside nerve terminals. Given the fundamental role of L reduction and refolding, this machinery represents a rational target for the development of mechanism-based antitoxins. PMID- 29111115 TI - Aprepitant Has Mixed Effects on Nausea and Reduces Other Symptoms in Patients With Gastroparesis and Related Disorders. AB - BACKGROUND & AIMS: There are few effective treatments for nausea and other symptoms in patients with gastroparesis and related syndromes. We performed a randomized trial of the ability of the neurokinin-1 receptor antagonist aprepitant to reduce symptoms in patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome. METHODS: We conducted a 4-week multicenter, double-masked trial of 126 patients with at least moderate symptoms of chronic nausea and vomiting of presumed gastric origin for a minimum of 6 months. Patients were randomly assigned to groups given oral aprepitant (125 mg/day, n = 63) or placebo (n = 63). The primary outcome from the intention-to treat analysis was reduction in nausea, defined as a decrease of 25 mm or more, or absolute level below 25 mm, on a daily patient-reported 0-to-100 visual analog scale (VAS) of nausea severity. We calculated relative risks of nausea improvement using stratified Cochran-Mental-Haenszel analysis. RESULTS: Aprepitant did not reduce symptoms of nausea, based on the primary outcome measure (46% reduction in the VAS score in the aprepitant group vs 40% reduction in the placebo group; relative risk, 1.2; 95% CI, 0.8-1.7) (P = .43). However, patients in the aprepitant group had significant changes in secondary outcomes such as reduction in symptom severity (measured by the 0-5 Gastroparesis Clinical Symptom Index) for nausea (1.8 vs 1.0; P = .005), vomiting (1.6 vs 0.5; P = .001), and overall symptoms (1.3 vs 0.7; P = .001). Adverse events, predominantly mild or moderate in severity grade, were more common in aprepitant (22 of 63 patients, 35% vs 11 of 63, 17% in the placebo group) (P = .04). CONCLUSIONS: In a randomized trial of patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome, aprepitant did not reduce the severity of nausea when reduction in VAS score was used as the primary outcome. However, aprepitant had varying effects on secondary outcomes of symptom improvement. These findings support the need to identify appropriate patient outcomes for trials of therapies for gastroparesis, including potential additional trials for aprepitant. ClinicalTrials.gov no: NCT01149369. PMID- 29111119 TI - Direct central nervous system effects of botulinum neurotoxin. AB - Local intramuscular injections of botulinum neurotoxin type A (BoNT/A) are effective in the treatment of focal dystonias, muscle spasms, and spasticity. However, not all clinical effects of BoNT/A may be explained by its action at peripheral nerve terminals. For example, the therapeutic benefit may exceed the duration of the peripheral neuroparalysis induced by the neurotoxin. In cellular and animal models, evidence demonstrates retrograde transport of catalytically active BoNT/A in projection neurons. This process of long-range trafficking is followed by transcytosis and action at second-order synapses. In humans, several physiological changes have been described following intramuscular delivery of BoNT/A. In particular, clinical studies have documented a decrease in Renshaw cell-mediated inhibition (i.e., recurrent inhibition), which may be important therapeutically for normalizing uncoordinated movements and overflow of muscle activity. In this review, we present data obtained in animal and experimental models that support direct central actions of BoNT/A mediated via retrograde axonal trafficking. We also discuss the reorganization of central circuitry induced by BoNT/A in patients, and the potential contribution of these effects to the therapeutic efficacy of the neurotoxin. PMID- 29111120 TI - Abnormal Coronary Flow Velocity Reserve and Decreased Myocardial Contractile Reserve Are Main Factors in Relation to Physical Exercise Capacity in Cardiac Amyloidosis. AB - BACKGROUND: The aim of the present study was to evaluate the clinical importance of echocardiographic coronary flow velocity reserve (CFVR), resting and exercise left ventricular global longitudinal strain (LVGLS), and myocardial work efficiency (MWE) in patients with cardiac amyloidosis (CA). METHODS: The study population comprised 69 subjects: group A, 27 patients with CA confirmed by endomyocardial biopsy (CA positive); group B, 42 healthy control subjects. The amyloid phenotype in group A was as follows: patients with wild-type transthyretin-related amyloidosis (n = 10), carriers of the Danish familial transthyretin amyloidosis mutation with cardiac involvement (n = 5), and patients with amyloid light chain amyloidosis with cardiac involvement (n = 12). All subjects underwent comprehensive echocardiographic evaluation during rest and during symptom-limited, semisupine exercise testing. Furthermore, CFVR was assessed using Doppler echocardiography. RESULTS: Patients with CA had significantly lower CFVR (1.7 +/- 0.6 vs 3.9 +/- 0.8, P < .0001), MWE (1.9 +/- 1.0 vs 3.0 +/- 0.7, P < .0001), and LVGLS magnitude (11% [10%-14%] vs 20% [18% 21%], P < .0001) than control subjects. Patients with CA showed severely reduced deformation and efficiency reserve compared with control subjects (DeltaLVGLS 0.9 +/- 2.8% vs 5.6 +/- 2.3%, P < .0001; DeltaMWE 2.5 +/- 2.8 vs 8.8 +/- 2.6, P < .0001). In patients with CA, a strong relation was seen between physical capacity by the metabolic equivalent of tasks test and CFVR (r = 0.55, P < .01), peak exercise LVGLS (r = 0.64, P < .0001), and peak exercise MWE (r = 0.60, P < .01). CONCLUSIONS: Patients with CA had a profound lack of CFVR and longitudinal myocardial deformation reserve compared with healthy control subjects. Both parameters were significantly associated with exercise capacity and may prove useful for evaluating cardiac performance in patients with CA. PMID- 29111121 TI - Invasive Validation of the Echocardiographic Assessment of Left Ventricular Filling Pressures Using the 2016 Diastolic Guidelines: Head-to-Head Comparison with the 2009 Guidelines. AB - BACKGROUND: Recent American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) guidelines for echocardiographic evaluation of left ventricular (LV) diastolic function provide a practical, simplified diagnostic algorithm for estimating LV filling pressure. The aim of this study was to test the accuracy of this algorithm against invasively measured pressures and compare it with the accuracy of the previous 2009 guidelines in the same patient cohort. METHODS: Ninety patients underwent transthoracic echocardiography immediately before left heart catheterization. Mitral inflow E/A ratio, E/e', tricuspid regurgitation velocity, and left atrial volume index were used to estimate LV filling pressure as normal or elevated using the ASE/EACVI algorithm. Invasive LV pre-A pressure was used as a reference, with >12 mm Hg defined as elevated. RESULTS: Invasive LV pre-A pressure was elevated in 40 (44%) and normal in 50 (56%) patients. The 2016 algorithm resulted in classification of 9 of 90 patients (10%) as indeterminate but estimated LV filling pressures in agreement with the invasive reference in 61 of 81 patients (75%), with sensitivity of 0.69 and specificity of 0.81. The 2009 algorithm could not definitively classify 4 of 90 patients (4.4%), but estimated LV filling pressures in agreement with the invasive reference in 64 of 86 patients (74%), with sensitivity of 0.79 and specificity of 0.70. CONCLUSIONS: The 2016 ASE/EACVI guidelines for estimation of filling pressures are more user friendly and efficient than the 2009 guidelines and provide accurate estimates of LV filling pressure in the majority of patients when compared with invasive measurements. The simplicity of the new algorithm did not compromise its accuracy and is likely to encourage its incorporation into clinical decision making. PMID- 29111122 TI - Contrast-Enhanced Echocardiography Has the Greatest Impact in Patients with Reduced Ejection Fractions. AB - BACKGROUND: Contrast-enhanced echocardiography (CE) helps to improve image quality in patients with suboptimal acoustic windows. Despite current recommendations, contrast use remains low. The aim of this study was to identify populations that would benefit more from contrast use. METHODS: A total of 176 subjects (137 men; mean age, 60.8 +/- 13.7 years) with technically difficult transthoracic echocardiographic studies who received clinically indicated intravenous contrast were prospectively studied. The impact on clinical decision making (including alterations in medical therapy, referral, imaging, or clinical procedures) was evaluated. RESULTS: The use of CE enabled biplane left ventricular (LV) ejection fraction measurement in 97.2% of studies and the interpretation of regional wall motion in 95% of studies. CE allowed definitive assessment of the presence or absence of LV thrombus in 99% of the cases. In the 174 patients whose ordering physicians could be reached at the time of image interpretation, changes in management occurred in 51% of subjects. There was no difference in the proportion of management changes between inpatients and outpatients (60.0% vs 48.1%, P = .225). Subjects with heart failure, cardiomyopathy, and arrhythmia had a higher proportion of changes (61.4% vs 44.2% [P = .031], 62.5% vs 45.0% [P = .028], and 72.0% vs 47.7% [P = .030], respectively). The proportion of management change after CE increased as pre-CE estimated ejection fraction decreased. Logistic regression showed that pre-CE estimated LV ejection fraction < 50% was the only significant predictor of change of management after contrast (P = .004). CONCLUSIONS: The use of CE has a significant impact on clinical decision making in patients with suboptimal acoustic windows, especially in those with depressed pre-CE LV ejection fractions. PMID- 29111124 TI - ? PMID- 29111123 TI - Prognostic and Added Value of Two-Dimensional Global Longitudinal Strain for Prediction of Survival in Patients with Light Chain Amyloidosis Undergoing Autologous Hematopoietic Cell Transplantation. AB - BACKGROUND: Autologous hematopoietic cell transplantation (HCT) is a first-line therapy for prolonging survival in patients with light-chain (AL) amyloidosis. Cardiac involvement is the most important determinant of survival. However, patients with advanced cardiac involvement have often been excluded from HCT because of high risk for transplantation-related mortality and poor overall survival. Whether baseline left ventricular global longitudinal strain (GLS) can provide additional risk stratification and predict survival after HCT in this high-risk population remains unclear. The aim of this study was to evaluate the prognostic implication of baseline GLS and the added value of GLS beyond circulating cardiac biomarkers for risk stratification in patients with AL amyloidosis undergoing HCT. METHODS: Eighty-two patients with newly diagnosed AL amyloidosis who underwent upfront HCT between January 2007 and April 2014 were included in the study. Clinical, echocardiographic, and serum cardiac biomarker data were collected at baseline and 12 months following HCT. GLS measurements were performed using a vendor-independent offline system. The median follow-up time for survivors was 58 months. RESULTS: Sixty-four percent of patients were in biomarker-based Mayo stage II or III. GLS, brain natriuretic peptide, troponin, and mitral E/A ratio were identified as the strongest predictors of survival (P < .0001). Other predictors included sex, creatinine, free AL, wall thickness, and ejection fraction. Mayo stage was significantly associated with outcome, with 5 year survival of 93%, 72% and 31% in stage I, II, and III patients, respectively. GLS of 17% was identified as the value that best discriminated survivors from nonsurvivors, and the application of this cutoff value provided further mortality risk stratification within each Mayo stage. CONCLUSIONS: GLS is a strong predictor of survival in patients with AL amyloidosis undergoing HCT, potentially providing incremental value over serum cardiac biomarkers for risk stratification. GLS should be considered as a standard parameter along with serum cardiac biomarkers when evaluating eligibility for HCT or other investigational therapies. PMID- 29111125 TI - ? PMID- 29111126 TI - Mandibular response and directional forces with a new functional orthopedic appliance - A clinical case treated with a "Paolone-Kaitsas (PK) appliance". AB - Class II/1 malocclusion needs strict vertical control in order to obtain a mandibular response and correction of the sagittal discrepancy. These objectives can be achieved not only in one-stage treatments but also in two stages, when clinicians decide to perform functional therapy for psychological, traumatological or social reasons. This paper reports on expression of mandibular response and directional forces in a two-stage class II/1 malocclusion using a new functional appliance. The Paolone-Kaitsas (PK) appliance provides vertical control and occlusal plane management during the very first phases of treatment. It prepares the anchorage of the denture used in the second phase of treatment. PMID- 29111127 TI - A five-year follow-up of a root fracture in a ten-year-old boy. AB - The management of horizontal root fracture still presents a challenge to clinicians. The case of a 10-year-old boy with a horizontal root fracture in the left maxillary central incisor (tooth number 21) is described here. The fracture was present at the junction of the apical and the middle thirds. We report both the emergency care and the 5-year follow-up. At the same time, an orthodontic treatment was planned for a retained maxillary cuspid (tooth number 23), first composed of a high-pull headgear and then by a fixed multi-bracket appliance. Today, the tooth number 21 remains vital and symptomless. This report highlights the successful management of a horizontally fractured tooth requiring orthodontic treatment. Our work also underlines the advantages of 3D images [cone-beam computed tomography (CBCT)] in positive and differential diagnosis especially in the event of a suspicion of post-traumatic complication. PMID- 29111128 TI - ? PMID- 29111129 TI - ? PMID- 29111130 TI - Effect of sandblasting and enamel deproteinization on shear bond strength of resin-modified glass ionomer. AB - INTRODUCTION: The purpose of this study was to compare, in vitro, the shear bond strength of resin-modified glass ionomer (RMGI) bonded to an enamel surface prepared by either sandblasting with 50MUm of aluminium oxide particles, deproteinization with 5.25% NaOCl, or by combining both techniques. MATERIAL AND METHODS: One hundred and fifty human premolars were cleaned and randomly divided into five groups. In group 1, the teeth were etched using 37% phosphoric acid and bonded with Transbond XT. In group 2, the teeth were etched using 37% phosphoric acid and bonded with Fuji Ortho LC. In group 3, the teeth were deproteinized with 5.25% NaOCl for one minute then etched with 37% phosphoric acid and bonded with Fuji Ortho LC. In group 4, the enamel was sandblasted with 50MUm of aluminium oxide particles for 5seconds prior to etching and bonding with Fuji Ortho LC. In group 5, the teeth were both sandblasted with 50MUm of aluminium oxide particles for 5seconds and deproteinized with 5.25% NaOCl for one minute prior to etching using 37% phosphoric acid and bonding with Fuji Ortho LC. The shear bond strength was tested using a universal testing machine with a crosshead speed of 1.0mm/min. The adhesive remnant index (ARI) index was also determined for each group. RESULTS: The mean shear bond strengths were as follows: group 1: 11.33+/-2.60MPa, group 2: 8.14+/-2.09, group 3: 9.57+/-3.25MPa, group 4: 9.49+/-1.99MPa and group 5: 9.76+/-2.29MPa (P=0.0001). CONCLUSION: The results show that pre-treating the enamel with either sandblasting, NaOCl, or both, could give a significantly higher shear bond strength than using RMGI with acid etch alone. PMID- 29111131 TI - Association between condylar position and vertical skeletal craniofacial morphology: A cone beam computed tomography study. AB - OBJECTIVE: Condylar position may play an important role in the establishment of different craniofacial morphologies. The aim of the present study was to determine the possible association between condylar position and vertical skeletal craniofacial morphology in subjects with normal sagittal skeletal pattern using CBCT. METHOD AND MATERIAL: The CBCT images of 45 patients with Class I sagittal skeletal pattern were classified into three balanced groups on the basis of SN-MP angle. Each group contained 15 subjects: low angle, normal angle and high angle. The condylar position was determined for the left and right joints. Chi square test was applied to assess the association between condylar position and vertical skeletal growth pattern. RESULTS: The condyles were more anteriorly-positioned in patients with high angle vertical pattern than in those with normal and low angle vertical pattern. No significant differences were found in condylar position between low angle and normal angle subjects. CONCLUSION: A significant correlation between condylar position and vertical skeletal pattern was found in the present study. This relationship can be considered for predicting and establishing a proper treatment plan for temporomandibular diseases during orthodontic treatment. PMID- 29111132 TI - Age-Related Repetitive Transcranial Magnetic Stimulation Effects on Executive Function in Depression: A Systematic Review. AB - OBJECTIVE: The aims of the current review were to: 1) examine whether the rTMS effects on executive function increase as age advances; 2) to examine the potential of rTMS to remediate executive function in older depressed patients; and 3) to assess the relationship between the executive function and mood benefits from rTMS in depression. METHODS: Randomized or matched-groups, blind, sham-controlled studies (12 studies, 347 participants) on excitatory rTMS applied to left DLPFC in depression were reviewed. RESULTS: A series of meta-regressions found no evidence of greater rTMS effects on executive functions as age advances. Similarly, meta-analyses showed no significant rTMS effects on executive functions in older depressed individuals. However, meta-regression analyses showed that the size of the executive function benefits from rTMS in depression are positively related to the effect size of mood symptom reduction. Despite its correlational nature, this finding is consistent with the idea that improvement in executive function may play a critical role in depression recovery. CONCLUSIONS: The authors consider these findings preliminary because of the modest number of available studies. Based on a qualitative review, the authors describe methodologic modifications that may increase rTMS efficacy for both executive functions and mood in late-life depression. PMID- 29111134 TI - The Ethical Importance of Assessing End-of-Life Care Preferences in Patients with Severe and Persistent Mental Illness. PMID- 29111133 TI - In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults. AB - OBJECTIVE: Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. METHODS: Positron emission tomography (PET) scans with 2-(1 {6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. RESULTS: Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (eta2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. CONCLUSIONS: By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders. PMID- 29111136 TI - Factors Associated With Response to Biofeedback Therapy for Dyssynergic Defecation. AB - BACKGROUND & AIMS: Biofeedback therapy is effective for dyssynergic defecation (DD), but it is not widely available or reimbursed, and is labor intensive. It is therefore important to select the appropriate patients for this treatment. We investigated symptoms and demographic, manometric, and other factors associated with outcomes of biofeedback therapy in patients with DD. METHODS: We performed a post hoc analysis of 2 prospective studies of biofeedback therapy in 127 adult outpatients (18-75 years old, 120 female) with chronic constipation who failed to respond to treatment with dietary fiber or laxatives (>1 year) and were diagnosed with DD based on standard criteria. In each study, patients received 1-hour, biweekly office biofeedback therapy (6 sessions) or home biofeedback therapy with a device. A therapist used visual feedback, postural, and diaphragmatic breathing techniques to teach subjects to improve defecation. Treatment success was defined by a composite of normalization of dyssynergia pattern and increase of 20 mm in baseline bowel satisfaction score. Factors were compared between the treatment success and failure groups. Intention-to-treat analysis was performed. RESULTS: Of the 127 patients enrolled, 77 (61%) had treatment success. Dyssynergia was corrected in 78% of patients and bowel satisfaction improved in 64% of patients. Baseline demographic features, constipation symptoms, manometric and sensory parameters, balloon expulsion time, and colonic transit results were similar between treatment failure and success groups. Patients with lower baseline bowel satisfaction score (P = .008) and patients who used digital maneuvers (P = .04) were more likely to have successful biofeedback therapy. CONCLUSIONS: Biofeedback therapy is successful in more than 60% of patients with DD. Patients who used digital maneuvers and patients with lower baseline levels of bowel satisfaction were more likely to have treatment success, whereas other factors were not associated with success. Biofeedback therapy should be offered to all patients with DD, irrespective of baseline symptoms or anorectal physiology findings. PMID- 29111135 TI - Digital gene atlas of neonate common marmoset brain. AB - Interest in the common marmoset (Callithrix jacchus) as a primate model animal has grown recently, in part due to the successful demonstration of transgenic marmosets. However, there is some debate as to the suitability of marmosets, compared to more widely used animal models, such as the macaque monkey and mouse. Especially, the usage of marmoset for animal models of human cognition and mental disorders, is still yet to be fully explored. To examine the prospects of the marmoset model for neuroscience research, the Marmoset Gene Atlas (https://gene atlas.bminds.brain.riken.jp/) provides a whole brain gene expression atlas in the common marmoset. We employ in situ hybridization (ISH) to systematically analyze gene expression in neonate marmoset brains, which allows us to compare expression with other model animals such as mouse. We anticipate that these data will provide sufficient information to develop tools that enable us to reveal marmoset brain structure, function, cellular and molecular organization for primate brain research. PMID- 29111137 TI - Biogenic silver nanoparticles inducing Leishmania amazonensis promastigote and amastigote death in vitro. AB - American Cutaneous Leishmaniasis (ACL) is a zoonosis caused by Leishmania protozoa. The ACL chemotherapy available is unsatisfactory motivating researches to seek alternative treatments. In this study, we investigated the action of biogenic silver nanoparticle (AgNp-bio) obtained from Fusarium oxysporium, against Leishmania amazonensis promastigote and amastigote forms. The AgNp-bio promastigote treatment results in promastigote death leading to apoptosis-like events due an increased production of reactive oxygen species (ROS), loss of mitochondrial integrity, phosphatidylserine exposure and damage on promastigotes membrane. In L. amazonensis infected macrophages, AgNp-bio treatment was still able to reduce the percentage of infected macrophages and the amount of amastigotes per macrophage, consequently, the amount of promastigotes recovered. This leishmanicidal effect was also accompanied by a decrease in the levels of ROS and nitric oxide. By observing the ultrastructural integrity of the intracellular amastigotes, we found that the AgNp-bio treatment made a significant damage, suggesting that the compound has a direct effect on intracellular amastigotes. These results demonstrated that AgNp-bio had a direct effect against L. amazonensis forms and acted on immunomodulatory ability of infected macrophages, reducing the infection without inducing the synthesis of inflammatory mediators, which continuous stimulation can generate and aggravate leishmaniotic lesions. Overall, our findings suggest that the use of AgNp-bio stands out as a new therapeutic option to be considered for further in vivo investigations representing a possible treatment for ACL. PMID- 29111138 TI - KIR-like activating natural killer cell receptors and their association with complicated malaria in north India. AB - Killer immunoglobulin-like receptors (KIRs) genomic regions have been suggested to influence malaria pathogenesis and infection susceptibility. KIRs are known as activating natural killer (NK) cell receptors, which upon binding to their corresponding human leukocyte antigen (HLA) ligands cause lysis of any infected cell. We have examined the potential association of KIR genes with complicated malaria (CM) among north Indians in this study and further evaluated the KIR receptor-HLA ligand association on the severity of the disease considering the uncomplicated malaria (UCM) subjects as control. Molecular profiling of KIR and HLA was carried out using the PCR-SSP method. Susceptible association was found for individuals possessing KIR2DS2 (OR=1.76, p-value=0.0390), KIR2DL1 (OR=2.87, p value=0.0005) and KIR2DL3 (OR=2.74, p-value=0.0011) genes with CM. This was supported by the strong linkage disequilibrium observed for 2DS2-2DL2 (D=0.87, r2=0.54) with CM. Whereas the receptor-ligand association has revealed risk association against KIR2DS2-HLAC1 (OR=2.08, p-value=0.0229), KIR2DL3-HLAC1 (OR=1.79, p-value=0.0301), and KIR2DL1-HLAC2 (OR=2.10, p-value=0.0175) combinations for complicated malaria. The frequency of different KIR genes are more or less similar to that observed in African population showing not much genetic diversity at KIR level in context to malarial infection. In conclusion, our data indicates KIR gene loci differentially influenced the malarial outcome in north Indians and in particular the KIR2DS2 gene appeared to be associated with disease severity. PMID- 29111139 TI - Seroprevalence of Schmallenberg virus in dairy cattle in Ethiopia. AB - Schmallenberg virus (SBV) is a recently identified member of the genus Orthobunyavirus of the family Bunyaviridae. It is an arbovirus transmitted by different members of Culicoides spp of biting midges. The virus is more recognized for its effect on reproductive disorders in ruminants characterised by abortion, stillbirth and birth of congenitally defective newborns with hydranencephaly-arthrogryposis syndrome. The current study was undertaken with the objectives of exploring the presence of SBV exposure and identification of factors affecting its distribution among dairy cattle in Ethiopia. A cross sectional study was conducted on 1379 dairy cattle sampled from 149 dairy herds in central, southern and western Ethiopia during September 2011 to May 2012. Serum samples were examined using competitive enzyme linked immunosorbent assay (cELISA). Data on hypothesised risk factors were collected from farm records where available and semi-structured questionnaire-based interview. The apparent seroprevalence of exposure to SBV was 56.6% (95% confidence interval (CI): 53.9 59.3). True prevalence adjusted for sensitivity and specificity of the cELISA kit used was 58.3% (95% CI 55.7-60.9). Among the sampled herds, 82.6% (95% CI: 75.5 88.3) had at least one seropositive animal. Seropositive cattle were found in all of the 15 conurbations studied. Adult dairy cows [odds ratio (OR)=1.6] were more commonly affected than young heifers. Dairy cattle kept in commercial (OR=1.6) and breeding farms (OR=3.5) and Midland agroecology (OR=2.5) showed statistically significant seroconversion than cattle kept under small-holder dairy farms and Highland agroecology respectively (p<0.05). Reproductive disorders including abortion, retention of the fetal membranes, and metritis were associated with serostatus of SBV. In conclusion, the seroprevalence of SBV is high and widely distributed in the studied parts of Ethiopia. This being the first study of its kind on SBV in Ethiopia, further longitudinal studies on isolation of the virus and its impact on reproductive disorders are recommended. PMID- 29111140 TI - Genomics and molecular epidemiology of Cryptosporidium species. AB - Cryptosporidium is one of the most widespread protozoan parasites that infects domestic and wild animals and is considered the second major cause of diarrhea and death in children after rotavirus. So far, around 20 distinct species are known to cause severe to moderate infections in humans, of which Cryptosporidium hominis and Cryptosporidium parvum are the major causative agents. Currently, ssurRNA and gp60 are used as the optimal markers for differentiating species and subtypes respectively. Over the last decade, diagnostic tools to detect and differentiate Cryptosporidium species at the genotype and subtype level have improved, but our understanding of the zoonotic and anthroponotic transmission potential of each species is less clear, largely because of the paucity of high resolution whole genome sequencing data for the different species. Defining which species possess an anthroponotic vs. zoonotic transmission cycle is critical if we are to limit the spread of disease between animals and humans. Likewise, it is unclear to what extent genetic hybridization impacts disease potential or the emergence of outbreak strains. The development of high resolution genetic markers and whole genome sequencing of different species should provide new insights into these knowledge gaps. The aim of this review is to outline currently available molecular epidemiology and genomics data for different species of Cryptosporidium. PMID- 29111141 TI - Self-stigma and its associations with stress, physical health, and health care satisfaction in adults who stutter. AB - PURPOSE: The aim of this study was to identify potential relationships between self-stigma (stigma awareness and stigma application) and stress, physical health, and health care satisfaction among a large sample of adults who stutter. It was hypothesized that both stigma awareness and stigma application would be inversely related to measures of physical health and health care satisfaction, and positively related to stress. Furthermore, it was anticipated that stress mediated the relationship between self-stigma and physical health. METHOD: A sample of adults who stutter in the United States (n=397) completed a web survey that assessed levels of stigma awareness and stigma application, stress, physical health, and health care satisfaction. Correlational analyses were conducted to determine the relationships between these variables. RESULTS: Higher levels of stigma awareness and stigma application were associated with increased stress, decreased overall physical health, and decreased health care satisfaction (i.e., discomfort obtaining health care due to stuttering, and adverse health care outcomes due to stuttering), and these relationships were statistically significant. Stress was identified as a mediator between stigma application and physical health. CONCLUSION: Because adults who stutter with higher levels of self-stigma are at risk for decreased physical health through increased stress, and lower satisfaction with their health care experiences as a result of stuttering, it is important for professionals to assess and manage self-stigma in clients who stutter. Self-stigma has implications for not only psychological well being, but stress, physical health, and health care satisfaction as well. PMID- 29111142 TI - Hypertension Treatment Controversies in the Oldest Old. PMID- 29111143 TI - Neurodegeneration in histiocytoses might start in utero. PMID- 29111144 TI - Reply to Pirus Ghadjar and Thomas Wiegel's Letter to the Editor re: Daniel E. Spratt, Robert T. Dess, Zachary S. Zumsteg, et al. A Systematic Review and Framework for the Use of Hormone Therapy with Salvage Radiation Therapy for Recurrent Prostate Cancer. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2017.06.027: Salvage Radiotherapy and Hormone Therapy: Change Is Coming, Just Not Quite Yet. PMID- 29111145 TI - Risk of operative delivery for intrapartum fetal compromise in small-for gestational-age fetuses at term: an internally validated prediction model. AB - BACKGROUND: Small-for-gestational-age fetuses are at an increased risk of intrapartum fetal compromise requiring operative delivery. Factors associated with the risk of intrapartum fetal compromise are yet to be established, and a comprehensive model accounting for both the antenatal and intrapartum variables is lacking. OBJECTIVE: We aimed to develop and validate a predictive model for the risk of operative delivery for presumed intrapartum fetal compromise in fetuses suspected to be small for gestational age at term. STUDY DESIGN: This was a single-center cohort study of small-for-gestational-age fetuses, defined as estimated fetal weight below the 10th centile in singleton pregnancies at term. The variables included known risk factors for operative delivery because of fetal compromise: maternal characteristics, estimated fetal weight, abdominal circumference, Doppler parameters, gestational age at delivery, induction of labor, and intrapartum risk factors (presence of meconium, augmentation of labor using oxytocin, the use of epidural analgesia, intrapartum pyrexia, and hemorrhage). The receiver-operating characteristics curve analysis was used to investigate the predictive accuracy. Internal validation of the models was performed with bootstrapped data sets. RESULTS: A total of 927 term pregnancies with 18.7% operative deliveries were included. The antenatal model (area under the curve, 0.69; 95% confidence interval, 0.65-0.73) using only the antenatal risk factors included parity, abdominal circumference centile, gestational age at delivery beyond 39 weeks' gestation, and the cerebroplacental ratio multiples of median. The combined model (area under the curve, 0.76; 95% confidence interval, 0.72-0.80), using both the antenatal and intrapartum risk factors, included the gestational age at delivery beyond 39 weeks' gestation (odds ratio, 1.62; 95% confidence interval, 1.14-2.56), the cerebroplacental ratio multiples of median (odds ratio, 0.38; 95% confidence interval, 0.18-0.79), parity (odds ratio 0.35; 95% confidence interval, 0.22-0.54), induction of labor (odds ratio 1.63; 95% confidence interval, 1.11-2.40), augmentation using oxytocin (odds ratio, 1.84; 95% confidence interval, 1.23-2.73) and the use of epidural analgesia (odds ratio, 2.80; 95% confidence interval, 1.94-4.04). The results indicate that the model has good discrimination and, according to the Hosmer-Lemeshow test, has good fit (P = .591). CONCLUSION: The prediction model demonstrates 6 important risk factors that are associated with the risk of operative delivery for fetal compromise in small-for-gestational-age fetuses at term. The model shows good discrimination and fit and has the potential to be used for clinical decision making and to counsel women about their individual intrapartum risk. PMID- 29111146 TI - Medical contraindications to estrogen and contraceptive use among women veterans. AB - BACKGROUND: Women veterans have high rates of medical comorbidities and may be particularly vulnerable to adverse health outcomes associated with unintended pregnancy. OBJECTIVES: The objective of the study was to estimate the prevalence of medical contraindications to estrogen-containing combined hormonal contraception among women veterans of reproductive age and to evaluate the relationship between contraindications and contraceptive use. STUDY DESIGN: This was a secondary analysis of data from a cross-sectional, telephone-based survey with a national sample of 2302 female veterans, aged 18-45 years, who use the Veterans Administration Healthcare System for primary care. This analysis included women at risk of unintended pregnancy, defined as heterosexually active and not pregnant or trying to conceive and with no history of hysterectomy or infertility. Seven contraindications to combined hormonal contraception were identified using survey data or medical diagnosis codes: hypertension; coronary artery disease; active migraine in women older than 35 years or migraine with aura; smoking in women older than 35 years; and a history of thromboembolism, stroke, or breast cancer. Outcomes were current use of combined hormonal contraception and contraceptive method type (combined hormonal contraception, and other prescription methods, nonprescription methods or no method). Multivariable logistic and multinomial regression were used to assess the relationship between contraindications and combined hormonal contraception use and method type, respectively. RESULTS: Among 1169 women veterans at risk of unintended pregnancy, 339 (29%) had at least 1 contraindication to combined hormonal contraception. The most prevalent conditions were hypertension (14.9%) and migraine (8.7%). In adjusted analyses, women with contraindications were less likely than women without contraindications to report use of combined hormonal contraception (adjusted odds ratio, 0.54, 95% confidence interval, 0.37-0.79). Relative to use of combined hormonal contraception, women with contraindications were more likely than women without contraindications to use other prescription methods (adjusted odds ratio, 1.74, 95% confidence interval, 1.17-2.60), nonprescription methods (adjusted odds ratio, 1.96, 95% confidence interval, 1.19-3.22), and no method (adjusted odds ratio, 2.29, 95% confidence interval, 1.35-3.89). CONCLUSION: Women veterans at risk of unintended pregnancy have a high burden of medical contraindications to estrogen. Women with contraindications were less likely to use combined hormonal contraceptive methods but were more likely to use no method, suggesting an unmet need for contraception in this medically vulnerable population. PMID- 29111147 TI - A novel RT-PCR for the detection of Helicobacter pylori and identification of clarithromycin resistance mediated by mutations in the 23S rRNA gene. AB - In this study we evaluated the commercially available LightMix(r) RT-PCR assay for Helicobacter pylori detection and identification of clarithromycin (CLR) resistance in culture and clinical specimens (gastric biopsies and stool). The H. pylori LightMix(r) RT-PCR detects a 97bp long fragment of the 23S rRNA gene and allows the identification of 3 distinct point mutations conferring CLR resistance via melting curve analysis. The performance of the H. pylori LightMix(r) RT-PCR was evaluated using a set of 60 H. pylori strains showing phenotypical CLR susceptibility or CLR resistance (Minimum inhibitory concentrations from 0.016 to 256mg/L). We found high concordance (95%) between phenotypical CLR resistance screening by E-Test(r) and the Lightmix(r) RT-PCR. Discrepant results were verified by sequencing of the 23S rRNA gene that always confirmed the results obtained by Lightmix(r) RT-PCR. Furthermore, H. pylori was detected in clinical biopsy and stool specimens by Lightmix(r) RT-PCR that identified the correct H. pylori genotype. The LightMix(r) RT-PCR is an accurate, sensitive and easy to use test for H. pylori and CLR resistance detection and can therefore be readily implemented in any diagnostic laboratory. PMID- 29111148 TI - Effects of opioid and nonopioid analgesics on canine wheal formation and cultured human mast cell degranulation. AB - : Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures. METHODS: Dogs were anesthetized with IV propofol and received intradermal (ID) injections (50MUL). Flare diameters were measured at 30min. Drugs showing flare responses were tested after intramuscular (IM) cromolyn (10mg/kg), a MC stabilizer. Human primary MCs (human cord blood CD34+/CD45+ cells) were employed and beta-hexosaminidase in cell-free supernatants were measured to assess degranulation. RESULTS: A significant skin flare for several classes of agents was observed including opioids, ziconotide, ketamine, ST-91, neostigmine, adenosine, bupivacaine, lidocaine, MK-801 and 48/80. Tizanidine, fentanyl, alfentanil, gabapentin and baclofen produced no flare. Flare produced by all ID agents, except adenosine, bupivacaine and lidocaine, was reduced by cromolyn. Naloxone had no effect upon opiate or 48/80 evoked flares. In hMC studies, 48/80 resulted in a concentration-dependent release of beta hexosaminidase. The rank order of drug-induced hMC beta-hexosaminidase release was similar to that for flares. CONCLUSIONS: A variety of therapeutically useful drugs degranulate MCs. This action may account for side effects such as the intrathecal granuloma resulting from spinally-delivered opioids. This degranulating effect may be useful in predicting potential intrathecal toxicity in the development of novel agents. PMID- 29111149 TI - Systematic approaches for biodiagnostics using exhaled air. AB - The 21st century is witnessing a revolution in understanding the composition of human exhaled breath more deeply, as the "breathe-print" can provide significant information of various diseases and disorders. This review elucidates various breath analytical techniques applied in medical diagnosis. A quick, portable, simple, accurate, non-invasive and relatively inexpensive approach of this technique is the reason of its evolution as a new frontier in disease diagnosis. This review emphasizes on breath biomarkers and traditional approaches in techniques used for breath biosensors like GC-MS, SIFT-MS, PTR-MS, IMS, Optical Absorption, Sensor Arrays and Electronic noses along with other new approaches such as Enzyme Immunoassay, Fluorescent Bead Immunoassays, Polymerase Chain Reaction, Antibody Microarray. It also includes the approaches using nanotechnology to improve the sensitivity and portability of breath biosensors. Still there is a lack of sensitive, standardized and accurate technique for the validation of biosensor. Hence future research is needed to overcome the loopholes in the present techniques. PMID- 29111150 TI - Small molecule delivery to solid tumors with chitosan-coated PLGA particles: A lesson learned from comparative imaging. AB - For polymeric nanoparticles (NPs) to deliver more drugs to tumors than free drug solution, it is critical that the NPs establish interactions with tumor cells and avoid removal from the tumors. Since traditional polyethylene glycol (PEG) surface layer interferes with the cell-NP interaction in tumors, we used a water soluble and blood-compatible chitosan derivative called zwitterionic chitosan (ZWC) as an alternative surface coating for poly(lactic-co-glycolic acid) (PLGA) NPs. The ZWC-coated PLGA NPs showed pH-dependent surface charge profiles and differential cellular interactions according to the pH of the medium. The in vivo delivery of ZWC-coated NPs was evaluated in mice bearing LS174T-xenografts using magnetic resonance (MR) imaging and fluorescence whole body imaging, which respectively tracked iron oxide particles and indocyanine green (ICG) encapsulated in the NPs as tracers. MR imaging showed that ZWC-coated NPs were more persistent in tumors than PEG-coated NPs, in agreement with the in vitro results. However, the fluorescence imaging indicated that the increased NP retention in tumors by the ZWC coating did not significantly affect the ICG distribution in tumors due to the rapid release of the dye. This study shows that stable drug retention in NPs during circulation is a critical prerequisite to successful translation of the potential benefits of surface-engineered NPs. PMID- 29111151 TI - Experimental optimization of Lornoxicam liposomes for sustained topical delivery. AB - The purpose of the present investigation is to formulate liposomes of Lornoxicam for topical delivery using Central Composite Design, to provide a sustained release of the drug and thereby extend its elimination half-life. Liposomes were prepared by thin film hydration method with pH induced vesiculation. The liposomes were assessed for their particle size, charge, morphology and drug entrapment and characterized using TGA-DSC and FTIR analysis, to assess the interaction between the drug and excipients. The in vitro release study was performed using modified USP dissolution apparatus-I using three different dissolution media and the ex vivo release study was performed using goat skin. The cytotoxicity of Lornoxicam liposomes were studied on NIH 3T3 cells by MTT assay. The optimized formulation with particle size ranging from 100-200nm provided sustained release for 8h. The characterization studies proved very less interactions between the drug and the excipients. The ex vivo studies showed flux value of 23.29MUg/cm2/h and Kp 0.011645cm/h. The cytotoxicity study showed increase in toxicity with increase in concentration more than 0.5MUg/mL. The in vivo skin toxicity studies and histopathology analysis showed absence of toxic lesions, which confirmed the suitability of the formulation for topical application. Lornoxicam liposomes with good skin permeation and sustained release of drug were finally optimized by the experimental design. PMID- 29111152 TI - Vegetarian or meat? Food choice modeling of main dishes occurs outside of awareness. AB - It is well established that the amount eaten by other people affects how much we eat, but unanswered questions exist regarding how much the food choices of other people affect the types of food that we choose. Past research on food choice modeling has primarily been conducted in controlled laboratory situations and has focused on snack foods. The current research examines the extent to which food choice modeling of a main dish occurs in a real-life context and whether people are aware of being influenced by others. The lunch orders of cafe patrons were surreptitiously tracked and participants were recruited after they paid for their lunch. Participants were asked what they ordered, whether they were influenced by the prior order, and what their relationship was to the person ahead of them in line. We analyzed the data of participants who were not acquainted with the person ahead of them (N = 174). As hypothesized, participants' main-dish lunch orders matched the choice of the person ordering ahead of them in line at rates significantly higher than chance. A significant modeling effect was observed even among participants who reported that their order was not influenced by the prior order. This research provided evidence of main-dish choice modeling occurring in real-life eating situations and outside of conscious awareness - demonstrating a powerful social influence on eating behaviours. PMID- 29111153 TI - Guilty pleasures: The effect of perceived overeating on food addiction attributions and snack choice. AB - Despite being widely debated throughout the scientific community, the concept of food addiction remains a popular explanation for overeating and obesity amongst the lay public. Overeating is often accompanied by feelings of guilt and dietary concern, and this may lead people to attribute their eating to an addiction in order to minimise personal responsibility. Research also indicates that food addiction attributions and dietary concern may lead people to limit their exposure to tempting foods. To test these ideas, we examined the effect of perceived overeating on food addiction attributions and snack choice. Subjective ratings of guilt and dietary concern were indirectly manipulated by leading female participants (N=90) to believe they had eaten more than (overeating condition), less than (undereating condition), or roughly the same (control condition) amount of palatable foods in relation to their own estimated consumption and to previous participants. Participants then rated the relative importance of a list of explanations for their eating (including "the foods were really addictive") and selected a snack to take home with them. Ratings of guilt and dietary concern were highest in the overeating condition, and lowest in the undereating condition, indicating that the manipulation had been successful. However, findings revealed no effect of condition on food addiction attributions. As predicted, participants in the overeating condition selected less tempting snacks than in the undereating condition. However, this effect was not mediated by guilt/dietary concern. There was also no association between food-addiction attributions and snack choice. These findings suggest that perceived overeating affects snack choice but not food addiction attributions. Future research should investigate whether food addiction attributions may be driven by feelings of guilt and dietary concern following longer-term disinhibited eating patterns. PMID- 29111154 TI - Robot-assisted Partial Nephrectomy: 5-yr Oncological Outcomes at a Single European Tertiary Cancer Center. AB - BACKGROUND: Nowadays, there is a debate about which surgical treatment should be best for clinical T1 renal tumors. If the oncological outcomes are considered, there are many open and laparoscopic series published. As far as robotic series are concerned, only a few of them report 5-yr oncological outcomes. OBJECTIVE: The aim of this study was to analyze robot-assisted partial nephrectomy (RAPN) midterm oncological outcomes achieved in a tertiary robotic reference center. DESIGN, SETTING, AND PARTICIPANTS: Between April 2009 and September 2013, 123 consecutive patients with clinical T1-stage renal masses underwent RAPN in our tertiary cancer center. Inclusion criteria were as follows: pathologically confirmed renal cell carcinomas (RCCs) and follow-up for >12 mo. Eighteen patients were excluded due to follow-up of <12 mo and 15 due to benign final pathology. Median follow-up was 59 mo (interquartile range 44-73 mo). Patients were followed according to guideline recommendations and institutional protocol. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were measured by time to disease progression, overall survival, or time to cancer-specific death. Kaplan Meier method was used to estimate survival; log-rank tests were applied for pair wise comparison of survival. RESULTS AND LIMITATIONS: From the 90 patients included, 66 (73.3%) had T1a, 12 (13.3%) T1b, three (3.3%) T2a, and nine (10%) T3a tumors. Predominant histological type was clear cell carcinoma: 67 (74.5%). Fuhrmann grade 1 and 2 was found in 73.3% of all malignant tumors. Two patients (2.2%) had positive surgical margins, and complication rate was 17.8%. Relapse rate was 7.7%, including two cases (2.2%) of local recurrences and five (5.5%) distant metastasis. Five-year disease-free survival was 90.9%, 5-yr cancer specific survival was 97.5%, and 5-yr overall survival was 95.1%. CONCLUSIONS: Midterm oncological outcomes after RAPN for localized RCCs (predominantly T1a tumors of low anatomic complexity) were shown to be good, adding significant evidence to support the oncological efficacy and safety of RAPN for the treatment of this type of tumors. PATIENT SUMMARY: Robot-assisted partial nephrectomy seems to be the most promising minimally invasive approach in the treatment of renal masses suitable for organ-sparing surgery as midterm (5 yr) oncological outcomes are excellent. PMID- 29111155 TI - Drift and Behavior of E. coli Cells. AB - Chemotaxis of the bacterium Escherichia coli is well understood in shallow chemical gradients, but its swimming behavior remains difficult to interpret in steep gradients. By focusing on single-cell trajectories from simulations, we investigated the dependence of the chemotactic drift velocity on attractant concentration in an exponential gradient. Whereas maxima of the average drift velocity can be interpreted within analytical linear-response theory of chemotaxis in shallow gradients, limits in drift due to steep gradients and finite number of receptor-methylation sites for adaptation go beyond perturbation theory. For instance, we found a surprising pinning of the cells to the concentration in the gradient at which cells run out of methylation sites. To validate the positions of maximal drift, we recorded single-cell trajectories in carefully designed chemical gradients using microfluidics. PMID- 29111156 TI - Genetics of human susceptibility to active and latent tuberculosis: present knowledge and future perspectives. AB - Tuberculosis is an ancient human disease, estimated to have originated and evolved over thousands of years alongside modern human populations. Despite considerable advances in disease control, tuberculosis remains one of the world's deadliest communicable diseases with 10 million incident cases and 1.8 million deaths in 2015 alone based on the annual WHO report, due to inadequate health service resources in less-developed regions of the world, and exacerbated by the HIV/AIDS pandemic and emergence of multidrug-resistant strains of Mycobacterium tuberculosis. Recent findings from studies of tuberculosis infection and of patients with Mendelian predisposition to severe tuberculosis have started to reveal human loci influencing tuberculosis outcomes. In this Review, we assess the current understanding of the contribution of host genetics to disease susceptibility and to drug treatment. Despite remarkable progress in technology, only a few associated genetic variants have so far been identified, strongly indicating the need for larger global studies that investigate both common and under-represented rare variants to develop new approaches to combat the disease. Pharmacogenomic discoveries are also likely to lead to more efficient drug design and development, and ultimately safer and more effective therapies for tuberculosis. PMID- 29111157 TI - Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis. AB - Angiogenesis is an organized series of events, beginning with vessel destabilization, followed by endothelial cell re-organization, and ending with vessel maturation. The formation of a mature vascular network requires precise spatial and temporal regulation of a large number of angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor (PDGF). VEGF aids in vascular permeability and endothelial cell recruitment, FGF-2 activates endothelial cell proliferation and migration while PDGF stimulates vascular stability. Accordingly, VEGF may inhibit vessel stabilization while PDGF may inhibit endothelial cell recruitment. Therefore, a new polymeric system was prepared by the supercritical carbon dioxide foaming technology, which realized sequential delivery of two or more growth factors with the controlled dose and rate. Increased release of VEGF (71.10%) and FGF-2 (69.76%) compared to PDGF (43.17%) was observed for the first 7 days. Thereafter, up till 21 days, an increased rate of release of BMP-2 compared to VEGF 165 was observed. The effects of PDGF PLAms/VEGF-FGF-2-PLGA scaffolds on angiogenesis were investigated by human umbilical vein endothelial cells (HUVECs) angiogenic differentiation in vitro and chorioallantoic membrane (CAM) angiogenesis in vivo. Sequential delivery of VEGF, FGF-2 and PDGF from structural polymer scaffolds with distinct kinetics resulted in significant angiogenic differentiation of HUVECs and rapid formation of mature vascular networks in chorioallantoic membrane. This study reported a composite scaffold with distinct release kinetics, and these results clearly indicated the importance of sequential delivery of multiple growth factors in tissue regeneration and engineering. PMID- 29111158 TI - Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool. AB - Kupffer cells (KCs) and monocyte-derived macrophages are implicated in non alcoholic steatohepatitis (NASH) pathogenesis but their functions remain unclear due to the lack of specific markers to distinguish between the different cell types. Additionally, it is unclear if multiple subsets of KCs are present during NASH. Here, we characterized the liver macrophage subsets during methionine/choline deficient (MCD) diet-induced NASH and recovery. We observed a significant reduced contribution of Ly6CloClec4F+Tim4+KCs to the hepatic macrophage pool in MCD fed mice, which normalized during recovery. Ly6CloClec4F Tim4- monocyte-derived macrophages increased during MCD feeding and returned to baseline during recovery. Ly6CloClec4F+Tim4- monocyte-derived KCs developed during initial recovery but did not self-renew as their numbers were reduced after full recovery. Initial recovery from MCD diet feeding was further characterized by increased proportions of Ki-67+ proliferating KCs. In conclusion, the hepatic macrophage pool undergoes substantial albeit transient changes during NASH and recovery, with the KC pool being maintained by proliferation and differentiation of short-lived monocyte-derived KCs. PMID- 29111159 TI - The association between leisure-time physical activity and lung function in older adults: The English longitudinal study of ageing. AB - The longitudinal association between physical activity and lung function is unclear. Therefore, we examined said association over eight years. This study included data from 2966 participants in English Longitudinal Study of Ageing (63+/-7years [mean+/-SD]), a prospective study of initially healthy, community dwelling adults. Physical activity was assessed using an interview and lung function using a spirometer at baseline (2004-5) and follow-up (2012-13). General linear regression was used to assess associations between activity and lung function. Logistic regression was used to assess the odds of new cases of abnormal lung function. Some 14% of participants were defined as physically inactive at baseline, 50% were classified into the moderate group, and 36% into the vigorous group. In comparison with remaining inactive at follow-up, remaining active was positively associated with forced vital capacity (FVC) (beta=0.09, 95% confidence interval [CI]: 0.01, 0.17; p=0.02) and forced expiratory volume in one second (FEV-1) (beta=0.09, 95% CI: 0.02, 0.15; p=0.01) after adjustment for baseline lung function score and other covariates. Using the fifth centile to define the lower limit of normal (that is, -1.64 z scores), there were lower odds of incident abnormal lung function in participants who remained physically active compared to those who remained inactive (FVC odds ratio=0.31, 95% CI: 0.17, 0.55. FEV-1 odds ratio=0.43, 95% CI: 0.26, 0.72). Similar associations were observed in those who became active. This study suggests that remaining physically active or becoming active in older age is positively associated with lung function and reduced odds of abnormal lung function. PMID- 29111160 TI - Corrigendum to 'CD95-mediated apoptosis in Burkitt's lymphoma B-cells is associated with Pim-1 down-regulation'[Biochimica et Biophysica Acta 1863/1 (2017) 239-252]. PMID- 29111161 TI - Effect of Low-Intensity Pulsed Ultrasound on Joint Injury and Post-Traumatic Osteoarthritis: an Animal Study. AB - This study investigated the therapeutic potential of low-intensity pulsed ultrasound (LIPUS) in post-traumatic osteoarthritis (PTOA). Intra-articular fracture of the medial tibial plateau was surgically created in 30 rats. LIPUS was applied to the operated joints either for the first 2 wk (LIPUS1-2 group) or in weeks 4 and 5 after intra-articular fracture (LIPUS4-5 group). In controls, the operated knees were not treated with LIPUS (LIPUS0 group). The rats were monitored with weekly gait analysis and euthanized at week 8. Among the altered gait parameters, the maximal and average paw print areas in the LIPUS1-2 and LIPUS4-5 groups, but not the LIPUS0 group, had either reached baseline or significantly recovered (70%, p <0.05) by week 8. PTOA pathology in both the LIPUS1-2 and LIPUS4-5 groups was less severe than that in the LIPUS0 group (Mankin score: 5.4 and 4.5 vs. 8.8, p <0.05). In conclusion, LIPUS treatment partially improved the gait of the affected limbs and reduced cartilage degeneration in PTOA. PMID- 29111162 TI - A Comparative Study of Histopathological Changes in the Ascending Aorta and the Risk Factors Related to Histopathological Conditions and Aortic Dilatation in Patients With Tetralogy of Fallot and a Functionally Univentricular Heart. AB - BACKGROUND: The purposes of this study were to prospectively evaluate the histologic characteristics of the aortic wall of patients undergoing univentricular type of repair and compare the same with the findings observed in patients undergoing intracardiac repair of tetralogy of Fallot (TOF). PATIENTS AND METHODS: Operatively excised full-thickness aortic wall tissue from 99 consecutive patients undergoing either intracardiac repair of TOF (group I; n=42) or univentricular repair (group II; n=57) were studied by light microscopy. Age at operation was 13 months to 28 years (mean 99.97+/-73.21months) for group I and 9 months to 25 years (mean 79.52+/-60.09) months for group II patients. RESULTS: Dilatation of the ascending aorta was present in 85.7% patients with TOF and 91.2% patients with a univentricular heart. Seventeen (17.2%) aortic specimens were histologically normal and were used as normal controls (group I, n=5; group II, n=12). A lamellar count of less than 60 was associated with a sensitivity of 97.2% and a specificity of 66.7% in patients undergoing repair of TOF and a sensitivity of 84.6% and a specificity of 80% in patients undergoing univentricular type of repairs respectively. Patients undergoing intracardiac repair of TOF and those undergoing univentricular repair exhibited 23.67 times (15.91-147.40) and 8.48 times (3.62-15.84) increased risk of aortic dilatation respectively. CONCLUSIONS: Our findings indicate the existence of significant elastic fragmentation, muscle disarray, medionecrosis and fibrosis involving the ascending aortic media in patients with a functionally univentricular heart and dilated aorta. These histopathological changes are similar to those encountered in patients with TOF and dilated aorta. PMID- 29111163 TI - Professionalism: A Core Competency, but What Does it Mean? A Survey of Surgery Residents. AB - OBJECTIVE: Professionalism is 1 of the 6 core competencies of the Accreditation Council of Graduate Medical Education. Despite its obvious importance, it is poorly defined in the literature and an understanding of its meaning has not been evaluated on surgical trainees. The American College of Surgeons (ACS) has previously published tenets of surgical professionalism. However, surgery residents may not share similar views on professionalism as those of the ACS. DESIGN: Surgical residents of all levels at 2 surgery residencies located in the same city were interviewed regarding their personal definitions, thoughts, and experiences regarding professionalism during their training. They were then queried regarding 20 points of professionalism as outlined by the ACS tenets of professionalism. SETTING: The study utilized the surgery residencies at William Beaumont Army Medical Center and Texas Tech University Health Science Center in El Paso, Texas. PARTICIPANTS: All general surgery residents at each program were invited to participate in the study. Eighteen residents volunteered to take the survey and be interviewed. RESULTS: The definitions of professionalism centered on clinical competence. Surgery residents conveyed experiences with both professional and unprofessional behavior. Seven of the 20 ACS tenets of professionalism were unanimously agreed upon. There were key differences between resident definitions and those as outlined by the ACS. The least agreed upon ACS tenets of professionalism include professionalism education, public education, and public health. CONCLUSIONS: Surgical trainees express personal experiences in both professional and unprofessional behavior. Their definitions of professionalism are not as expansive as those of the ACS and seem to focus on patient and colleague interaction. Due to the lack of congruency, a tailored curriculum for professionalism based upon ACS tenets appears warranted. PMID- 29111164 TI - Pretreatment of food waste for methane and hydrogen recovery: A review. AB - Food waste (FW) management by biological process is more attractive and eco friendly approach than thermo-chemical conversion or landfilling. However, FW composition and physico-chemical and biological characteristics affect the overall biological process in terms of product yield and degradation rate. To overcome this major bottle-neck, the pretreatment of FW is proposed. Therefore this review aims to provide a comprehensive summary of the importance of pretreatment of FW with respect to FW management by anaerobic digestion (AD) and dark fermentation (DF). It also reviews the existing knowledge gaps and future research perspectives for better integration of FW pretreatments for AD and DF, which should include (i) the preservation of carbon mass through freeze and thaw, or drying; and (ii) improve the carbon accessibility through particle size reduction and thermal pretreatments for high-rate bioenergy recovery. PMID- 29111165 TI - 3-Hydroxy-3-methylglutaryl flavone glycosides from the leaves of Turpinia arguta. AB - Three new 3-hydroxy-3-methylglutaryl (HMG) flavone 7-O-diglycosides, argutosides A-C (1-3); two new flavone 7-O-triglycosides, argutosides D-E (4-5); and one known apigenin 7-O-triglycoside (6), were isolated from the leaves of Turpinia arguta. The structures of these compounds were elucidated by spectroscopic and chemical techniques. The NO inhibitory activities of compounds 1-6 were evaluated using lipopolysaccharide-induced RAW264.7 cells. Only compound 2 showed a moderate inhibitory effect on NO production with an IC50 value of 25.74MUM. Compounds 1-6 were not cytotoxic to RAW264.7 cells at 10MUM. PMID- 29111166 TI - Deregulated expression of miR-107 inhibits metastasis of PDAC through inhibition PI3K/Akt signaling via caveolin-1 and PTEN. AB - Pancreatic ductal adenocarcinoma (PDAC) displays a highly aggressive malignancy and is considered to be an incurable and rapidly lethal disease. MicroRNAs (miRNAs) are small non-coding RNAs of approximately nucleotides that regulate several aspects of tumors pathogenesis, including migration, invasion, metastasis and epithelial-mesenchymal transition. We have found that miR-107 was significantly high expression in PDAC tissues and cells. High miR-107 expression is associated with poor clinicopathological parameters and prognosis in PDAC patients. Deregulated expression of miR-107 in PDAC cells (AsPC-1 and Panc-1) is sufficient to reduce cell migration and invasion, and to induce upregulation of epithelial markers (beta-catenin, ZO-1 and E-cadherin) and a decrease of mesenchymal marker expression (ZEB-1 and vimentin). We also found that the caveolin-1, PTEN and p-Akt expression are modulated by miR-107 in PDAC cells. Moreover, our study clearly demonstrated that deregulated expression of miR-107 inhibited cell migration and invasion and EMT by up-regulation of caveolin-1 and PTEN, and inhibition of PI3K/Akt signaling in PDAC cells. Our study suggested that miR-107 expression might both be a useful indicator of the metastatic potential and provided a new potential therapeutic target in PDAC. PMID- 29111167 TI - Heme oxygenase-1 protects bone marrow mesenchymal stem cells from iron overload through decreasing reactive oxygen species and promoting IL-10 generation. AB - Iron overload (IO) caused by frequent blood transfusion in hematological diseases has become a major concern. In this study, up-regulation of heme oxygenase-1 (HO 1), a protector against oxidative stress, was observed in bone marrow mesenchymal stem cells (BMMSCs) at the early stage of IO and had favorable prognosis in an IO mouse model. Given that the protective role of HO-1 in IO damage of BMMSCs was still unknown, the mechanism was explored in vitro and in vivo. BMMSCs were transfected with HO-1/siHO-1 in vitro, and the mouse model was established to further evaluate the effect of HO-1 on IO in vivo. As a result, HO-1 decreased the apoptotic rate of BMMSCs with IO through reducing intracellular reactive oxygen species (ROS) but increasing IL-10 secretion. In addition, IL-10 was mediated by HO-1 via the ERK pathway. Intracellular iron was down-regulated by hepcidin depending on IL-10. In conclusion, HO-1 protects BMMSCs from ROS by secreting IL-10 upon iron overload. PMID- 29111169 TI - Non-arrhythmic pre-excitation-induced cardiomyopathy. PMID- 29111168 TI - Standardized programming to reduce the burden of inappropriate therapies in implantable cardioverter defibrillators - Single centre follow up results. AB - BACKGROUND: Current algorithms and device morphology templates have been proposed in current Implantable Cardioverter-Defibrillators (ICDs) to minimize inappropriate therapies (ITS), but this has not been completely successful. AIM: Assess the impact of a deliberate strategy of using an atrial lead implant with standardized parameters; based on all current ICD discriminators and technologies, on the burden of ITS. METHOD: A retrospective single-centre analysis of 250 patients with either dual chamber (DR) ICDs or biventricular ICDs (CRTDs) over a (41.9 +/- 27.3) month period was performed. The incidence of ITS on all ICD and CRTD patients was chronicled after the implementation of standardized programming. RESULTS: 39 events of anti-tachycardial pacing (ATP) and/or shocks were identified in 20 patients (8% incidence rate among patients). The total number of individual therapies was 120, of which 34% were inappropriate ATP, and 36% were inappropriate shocks. 11 patients of the 250 patients received ITS (4.4%). Of the 20 patients, four had ICDs for primary prevention and 16 for a secondary prevention. All the episodes in the primary indication group were inappropriate, while seven patients (43%) of the secondary indication group experienced inappropriate therapies. CONCLUSIONS: The burden of ITS in the population of patients receiving ICDs was 4.4% in the presence of atrial leads. The proposed rationalized programming criteria seems an effective strategy to minimize the burden of inappropriate therapies and will require further validation. PMID- 29111170 TI - Moderate-intensity 4mT static magnetic fields prevent bone architectural deterioration and strength reduction by stimulating bone formation in streptozotocin-treated diabetic rats. AB - Type 1 diabetes mellitus (T1DM) has been associated with deterioration of bone microarchitecture and strength, resulting in increased fracture risk. Substantial studies have revealed the capacity of moderate-intensity static magnetic fields (SMF) on promoting osteoblastogenesis in vitro and stimulating bone growth and bone regeneration in vivo, whereas it is unknown whether SMF can resist T1DM associated osteopenia/osteoporosis. We herein investigated the potential effects of whole-body SMF exposure with 4mT on bone loss in streptozotocin-induced T1DM rats. We found that SMF exposure for 16weeks inhibited architectural deterioration of trabecular bone and cortical bone and mechanical strength reduction in T1DM rats, as evidenced by the MicroCT and 3-point bending findings. Our serum biochemical, bone histomorphometric and PCR results revealed that SMF induced higher serum osteocalcin, mineral apposition rate and osteoblast number of trabecular bone, and higher skeletal osteocalcin, BMP2 and Runx2 gene expression in T1DM rats, whereas SMF showed no significant alteration in serum CTX, skeletal osteoclast number, or osteoclastogenesis-related RANKL-RANK signaling gene expression. Together, our findings suggest that moderate SMF prevented bone architectural deterioration and strength reduction by inhibiting the reduction of bone formation in T1DM rats, and indicate that SMF might become a promising biophysical countermeasure for T1DM-related osteopenia/osteoporosis. PMID- 29111171 TI - Hip Symptoms, Physical Performance, and Health Status in Older Adults With Chronic Low Back Pain: A Preliminary Investigation. AB - OBJECTIVES: To determine (1) whether there are differences in the prevalence of clinical hip symptoms between older adults with and without chronic low back pain (CLBP); and (2) whether coexisting hip symptoms are associated with worse physical performance and poorer health-related quality of life (HRQOL). DESIGN: Case-control study. SETTING: Individuals participated in a standardized evaluation in a clinical laboratory. PARTICIPANTS: Clinical hip symptoms, which are proposed predictors of radiographic hip osteoarthritis according to American College of Rheumatology guidelines, were evaluated in a volunteer sample of community-dwelling older adults with CLBP (n=54; aged 60-85y) and in age- and sex matched healthy controls (n=54). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Physical performance was measured by the repeated chair rise test and stair-climbing test. HRQOL was measured by the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: Hip joint pain, morning stiffness, and pain with hip internal rotation were more common among older adults with CLBP (P<.05). Participants with CLBP and coexisting hip symptoms had worse physical performance than individuals without CLBP or hip symptoms (P<.0001). Additionally, the presence of coexisting hip symptoms was associated with worse HRQOL, particularly in the domains of social functioning, mental health, and role limitations attributable to emotional problems as measured by the SF-36 (P<.01). CONCLUSIONS: Given our limited understanding of CLBP among older adults, there is a definitive need to systematically explore coexisting pain conditions that may contribute to worse outcomes. Based on these data, future longitudinal studies should explore whether coexisting hip symptoms are associated with a worse prognosis in older adults with CLBP. PMID- 29111172 TI - Nutritional counseling with or without systematic use of oral nutritional supplements in head and neck cancer patients undergoing radiotherapy. AB - BACKGROUND: To evaluate the benefit of oral nutritional supplements (ONS) in addition to nutritional counseling in head and neck cancer (HNC) patients undergoing radiotherapy (RT). METHODS: In a single-center, randomized, pragmatic, parallel-group controlled trial (ClinicalTrials.gov: NCT02055833; February 2014 August 2016), 159 newly diagnosed HNC patients suitable for to RT regardless of previous surgery and induction chemotherapy were randomly assigned to nutritional counseling in combination with ONS (N = 78) or without ONS (N = 81) from the start of RT and continuing for up to 3 months after its end. Primary endpoint was the change in body weight at the end of RT. Secondary endpoints included changes in protein-calorie intake, muscle strength, phase angle and quality of life and anti-cancer treatment tolerance. RESULTS: In patients with the primary endpoint assessed (modified intention-to-treat population), counseling plus ONS (N = 67) resulted in smaller loss of body weight than nutritional counseling alone (N = 69; mean difference, 1.6 kg [95%CI, 0.5-2.7]; P = 0.006). Imputation of missing outcomes provided consistent findings. In the ONS-supplemented group, higher protein-calorie intake and improvement in quality of life over time were also observed (P < 0.001 for all). The use of ONS reduced the need for changes in scheduled anti-cancer treatments (i.e. for RT and/or systemic treatment dose reduction or complete suspension, HR=0.40 [95%CI, 0.18-0.91], P = 0.029). CONCLUSION: In HNC patients undergoing RT or RT plus systemic treatment, and receiving nutritional counseling, the use of ONS resulted in better weight maintenance, increased protein-calorie intake, improved quality of life and was associated with better anti-cancer treatment tolerance. PMID- 29111173 TI - Epidermal growth factor receptor mutation predicts favorable outcomes in non small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery. AB - PURPOSE: The impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS). METHODS AND MATERIALS: From 2008 to 2015, 147 eligible NSCLC patients with 300 lesions were retrospectively analyzed. Patterns of tyrosine kinase inhibitor (TKI) therapy were recorded. Radiographic response was assessed. Brain progression-free survival (BPFS) and overall survival were calculated and outcome prognostic factors were evaluated. RESULTS: Median follow-up time was 13.5 months. Of the EGFR-genotyped patients, 79 (65%) were EGFR mutants, and 42 (35%) were wild type. Presence of EGFR mutations was associated with higher radiographic complete response rates (CRR). Median time to develop new BM after SRS was significantly longer for mutant-EGFR patients (17 versus 10.5 months, p = 0.02), predominantly for those with adjuvant TKI therapy (26.3 versus 15 months, p = 0.01). EGFR mutations independently predicted better BPFS (HR = 0.55, p = 0.048) in multivariate analysis. CONCLUSIONS: In patients with NSCLC treated with SRS for BM, the presence of EGFR mutations is associated with a higher CRR, longer time for distant brain control, and better BPFS. The combination of SRS and TKI in selective patient group can be an effective treatment choice for BM with favorable brain control and little neurotoxicity. PMID- 29111175 TI - Recognizing Symptom Burden in Advanced Prostate Cancer: A Global Patient and Caregiver Survey. AB - BACKGROUND: Bone metastases in men with prostate cancer are often initially asymptomatic, resulting in delayed identification, diagnosis, and appropriate treatment. To assess how patients with advanced prostate cancer (aPC) communicate symptoms to health care providers, an international patient survey was conducted. METHODS: An online and phone survey was conducted by Harris Poll in 11 countries (Brazil, France, Germany, Japan, Italy, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States) from February 12 to October 27, 2015, in men with aPC (ie, those who reported as having PC beyond the prostate [metastatic]) and their caregivers. Cell weighting was used to ensure equal weight of data across countries. Percentages are based on weighted n values. RESULTS: A total of 927 men with aPC (weighted n = 664) and 400 caregivers completed the survey. Most commonly reported symptoms were fatigue (73%), urinary symptoms (63%), sexual function symptoms (62%), and bone pain (52%). Of 568 patients with bone metastases (weighted n = 421), most (73%) noticed pain before receiving a diagnosis of metastatic PC. Most patients with aPC (56%) were uncertain if their pain was cancer related, 55% felt they had to live with daily pain, 45% sometimes ignored pain, and 39% had difficulty talking about pain. Patients who had a caregiver were more likely than those without to discuss pain at every visit (45% vs. 32%, P < .05). CONCLUSIONS: Disease symptoms in aPC are often underrecognized. Tools encouraging effective communication among patients, caregivers, and health care providers on early symptom reporting may lead to enhanced symptom and disease management. PMID- 29111174 TI - [First treatment strategies in the 2 years following lung cancer diagnosis. ESCAP 2011-CPHG, a real-life study carried out in French general hospitals]. AB - INTRODUCTION: The objective of the ESCAP-2011-CPHG cohort study was to perform a real-life analysis of therapeutic strategies used during the first 2years of follow-up after a diagnosis of primary lung cancer. This paper presents the study and its first results in non-small-cell lung cancer (NSCLC). METHODS: Pulmonologists in the respiratory disease departments of 53 general hospitals consecutively included all patients aged 18years and over with lung cancer newly diagnosed in 2010. RESULTS: Of the 3943 patients included, 3418 (mean age: 65.4 years; male: 76%; never smokers: 12%) had NSCLC (adenocarcinoma: 53%; stages 0 II, IIIA, IIIB and IV: 18, 14, 9 and 59%, respectively). Mean follow-up was 13.2 (SD: 10.1) months; mean number of strategies implemented was 2 (SD: 1.3). Overall, 62% of patients had chemotherapy in the first strategy (74% in the second strategy); the rate of chemotherapy alone increased from 6 to 56% with cancer stage. CONCLUSIONS: ESCAP-2011-CPHG opens the way to many possible analyses of the therapeutic strategies currently implemented in French hospitals, comparing strategies, survival or patient characteristics. PMID- 29111176 TI - Fluorine-18 Prostate-specific Membrane Antigen-1007 Positron Emission Tomography/Computed Tomography and Multiparametric Magnetic Resonance Imaging in Diagnostics of Local Recurrence in a Prostate Cancer Patient After Recent Radical Prostatectomy. PMID- 29111177 TI - Association of Androgen Receptor Expression on Tumor Cells and PD-L1 Expression in Muscle-Invasive and Metastatic Urothelial Carcinoma: Insights for Clinical Research. AB - BACKGROUND: Limited information is available regarding the use of androgen receptor (AR) immunohistochemical expression in muscle-invasive or metastatic urothelial carcinoma. We aimed to evaluate the frequency of AR expression by tumor cells (TC), its prognostic role, and its relationship with programmed cell death ligand 1 (PD-L1) expression in these patients. PATIENTS AND METHODS: From September 2015 to January 2017, we collected tissue from patients who received platinum-based chemotherapy at our center. Immunohistochemistry for AR was performed (1% cutoff of TC). PD-L1 coexpression, by TC or immune cells (1% cutoff), was also analyzed. Molecular analysis of AR gene was performed by sequencing of exons 5 to 8 and by fluorescence in-situ hybridization analysis. Cox models for overall survival (OS), adjusted for stage, visceral metastases, and platinum type, were fitted. RESULTS: A total of 110 patients had tumor samples stained. Overall, 48 (43.6%) had AR-expressing TC: 19 (17.3%) had 1%-5% expression, 15 (13.6%) 5%-25% expression, and 14 (12.7%) > 25% expression. Among the latter, 7 had molecularly evaluated tumor tissue: no AR gene mutations or amplifications were found, but polysomy of Xq chromosome was seen. PD-L1 expression by TC and immunohistochemistry concordantly decreased with increasing levels of AR expression by TC. In Cox analyses, AR expression was not associated with OS, both on univariable (P = .477) and multivariable (P = .505) analyses. CONCLUSION: AR is frequently expressed in patients with muscle-invasive and advanced urothelial carcinoma, and it does not seem to be prognostic for OS. The AR pathway is worthy of clinical studies to assess its synergistic action with anti-PD-L1 therapy. PMID- 29111179 TI - Alternative fluorophores designed for advanced molecular imaging. AB - Fluorescent molecular imaging has advanced drastically over the past decade. With the development of high-resolution microscopy techniques and the ability to visualize intracellular molecular events, there is a growing need for new fluorophores to accompany these fast-developing techniques. Therefore, there has been substantial development of alternative fluorophores for single-molecule detection and molecular imaging. These rationally designed fluorophores have infinite possibilities and novel fluorophores are constantly being produced for different applications. This review focuses on the recent developments in novel fluorophores designed for molecular imaging and single-molecule detection. Here, single-molecule imaging, smart fluorescent probes, two-photon microscopy, Forster resonance energy transfer (FRET) and super-resolution microscopy are discussed in detail. PMID- 29111180 TI - Effects of kestose on gut mucosal immunity in an atopic dermatitis mouse model. AB - BACKGROUND: Atopic dermatitis (AD) is recently increasing among populations, but the underlying mechanisms remain controversial. Interactions between the gut microbiota and mucosal immunity are considered to be a crucial etiology. Fructooligosaccharide (FOS), prebiotics have been reported as activators of the gut microbiota. OBJECTIVE: The aim of this study was to investigate the effects of kestose, the smallest FOS and FOS on atopic dermatitis in mice. METHODS: An AD mouse model was developed by (ovalbumin) epidermal sensitization using BALB/c mice. Kestose (1%, 5%, and 10%) or FOS (5%, positive control) was orally administered throughout the study. RESULTS: In comparison with the values observed for the control AD mice, transepidermal water loss (TEWL), clinical score, and skin inflammation on histopathology were significantly decreased by the oral administration of kestose. Total IgE, thymic stromal lymphopoietin (TSLP) in skin, and IL-4 were also suppressed by this administration. In addition, the population of CD4+Foxp3+ cells in mesenteric lymph nodes (MLNs) and acetate concentrations in feces were significantly increased by kestose treatment. CONCLUSIONS: These findings suggest that kestose activates the gut immune system to induce the tolerance against allergic skin inflammations in AD. PMID- 29111178 TI - Dose-dependent neurocognitive deficits following postnatal day 10 HIV-1 viral protein exposure: Relationship to hippocampal anatomy parameters. AB - Despite the availability of antiretroviral prophylactic treatment, pediatric human immunodeficiency virus type 1 (HIV-1) continues to be a significant risk factor in the post-cART era. The time of infection (i.e., during pregnancy, delivery or breastfeeding) may play a role in the development of neurocognitive deficits in pediatric HIV-1. HIV-1 viral protein exposure on postnatal day (P)1, preceding the postnatal brain growth spurt in rats, had deleterious effects on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2008a,b). In the present study, rats were stereotaxically injected with HIV-1 viral proteins, including Tat1-86 and gp120, on P10 to further examine the role of timing on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2010). The dose-dependent virotoxin effects observed across development following P10 Tat1-86 exposure were specific to spatial learning and absent from prepulse inhibition and locomotor activity. A relationship between alterations in spatial learning and/or memory and hippocampal anatomical parameters was noted. Specifically, the estimated number of neurons and astrocytes in the hilus of the dentate gyrus explained 70% of the variance of search behavior in Morris water maze acquisition training for adolescents and 65% of the variance for adults; a brain-behavior relationship consistent with observations following P1 viral protein exposure. Collectively, late viral protein exposure (P10) results in selective alterations in neurocognitive development without modifying measures of somatic growth, preattentive processing, or locomotor activity, as characterized by early viral protein exposure (P1). Thus, timing may be a critical factor in disease progression, with children infected with HIV earlier in life being more vulnerable to CNS disease. PMID- 29111182 TI - Anacardic acid reduces lipogenesis in human differentiated adipocytes via inhibition of histone acetylation. PMID- 29111181 TI - Secreted immunoregulatory proteins in the skin. AB - The skin, thought initially to protect the body passively from pathogenic organisms and other environmental insults, is now recognised additionally as a sophisticated immune organ that actively regulates local immunity. Studies linking local innate and adaptive immunity to skin health and disease have revealed a complex network of cell communication and cytokine signalling. Here, we review the last 10 years of literature on this topic, and its relevance to skin immunity. PMID- 29111183 TI - Asymptomatic dengue infection in adults of major cities of Pakistan. AB - OBJECTIVE: To determine the asymptomatic dengue infection in adults of Pakistani population. METHODS: This study was conducted in five major cities (Islamabad, Karachi, Lahore, Multan, and Peshawar) of Pakistan. A total of 5 230 adults aged 18 years and above without a history of dengue fever at any point in their life were enrolled from participating laboratories. Those who were confirmed for dengue previously were excluded. Of the total, 62.6% (n = 3 276) were male with an average age of 34.6 years. Participants were briefed about the objectives of the study, and written consent was obtained to perform dengue IgG test using enzyme linked immunosorbent assay. The brief information related to age, gender and area was also taken on proforma. RESULTS: Overall 32.3% (n = 1 691) was having asymptomatic dengue infection which was 67.5% (n = 756) in Karachi followed by 39.1% (n = 391) in Islamabad, 29.9% (n = 316) in Lahore and 21% (n = 228) in Peshawar and none from Multan. More males were affected with asymptomatic dengue infection than females. The asymptomatic dengue infection was significantly higher in different cities; however, there was no significant difference with respect to age groups. CONCLUSIONS: The asymptomatic dengue infection is higher in cities i.e. Karachi, Islamabad and Lahore which are at risk of developing secondary dengue infections. There is a need of awareness among the public about secondary dengue infection. PMID- 29111184 TI - Neuron-protective effect of subanesthestic-dosage ketamine on mice of Parkinson's disease. AB - OBJECTIVE: To discuss the neuron-protective effect and possible mechanism of subanesthestic-dosage ketamine on Parkinson's disease mice induced by 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine. METHODS: A total of 30 mice were divided equally into three groups, model control group (MC group), ketamine treatment group (KT group), and blank control group (BC group), respectively. The Parkinson's disease mice of MC group and KT groups were established by 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (20 mg/kg/d), while mice in KT group were treated by intraperitoneal injection of subanesthestic-dosage ketamine (8 mg/kg). Differences on behaviors and the number of nigra dopaminergic neurons of mice in each group were compared through the behavioral test and tyrosine hydroxylase immunohistochemistry experiments after the treatments. Furthermore, Western blot was used to test the expression of autophagy-related gene LC3-II, Beclin1, Parkin, PINK1, and mTOR. RESULTS: Compared with the BC group, the neuroethology scores were lower and the amount of TH positive cells were less both in MC and MT groups; In KT group, the neuroethology scores were higher and the amount of tyrosine hydroxylase positive cells were significantly more than that in MC group (P < 0.05). Moreover, expression levels of autophagy-related proteins LC3-II, Beclin1, Parkin, and PINK1 were higher, while the mTOR expression level was lower than that in MC group. CONCLUSIONS: The subanesthestic-dosage ketamine has some protective effects on the coordinating ability of movement and cognitive ability of Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. This is probably due to that the autophagy activity of cells is activated by subanesthestic-dosage ketamine and that the neurons are protected. PMID- 29111185 TI - Morphological characteristics associated with rupture risk of multiple intracranial aneurysms. AB - OBJECTIVE: To identify the morphological parameters that are related to intracranial aneurysms (IAs) rupture using a case-control model. METHODS: A total of 107 patients with multiple IAs and aneurysmal subarachnoid hemorrhage between August 2011 and February 2017 were enrolled in this study. Characteristics of IAs location, shape, neck width, perpendicular height, depth, maximum size, flow angle, parent vessel diameter (PVD), aspect ratio (AR) and size ratio (SR) were evaluated using CT angiography. Multiple logistic regression analysis was used to identify the independent risk factors associated with IAs rupture. Receiver operating characteristic curve analysis was performed on the final model, and the optimal thresholds were obtained. RESULTS: IAs located in the internal carotid artery (ICA) was associated with a negative risk of rupture, whereas AR, SR1 (height/PVD) and SR2 (depth/PVD) were associated with increased risk of rupture. When SR was calculated differently, the odds ratio values of these factors were also different. The receiver operating characteristic curve showed that AR, SR1 and SR2 had cut-off values of 1.01, 1.48 and 1.40, respectively. SR3 (maximum size/PVD) was not associated with IAs rupture. CONCLUSIONS: IAs located in the ICA are associated with a negative risk of rupture, while high AR (>1.01), SR1 (>1.48) or SR2 (>1.40) are risk factors for multiple IAs rupture. PMID- 29111186 TI - Plasmodium falciparum found in the bone marrow of a child in Manado City, East Indonesia: A case report. AB - In Indonesia, there are at least 1.3 million cases of malaria each year and Plasmodium falciparum appears to be the most common Plasmodium. The finding of Plasmodium is important for the diagnosis and management of malaria. This is a case of a 4-year-and-9-month-old male who lived in Manado, East Indonesia. He presented with a prolonged fever, was pale in appearance, and was easily fatigued over the last 3 weeks. Hepato-splenomegaly was found on the initial physical examination. Preliminary laboratory findings found pancytopenia and severe anemia. Before he was referred to our hospital, at the primary health center, the initial work-up was negative for Plasmodium with the serial Rapid Diagnostic Test and microscopic peripheral blood smears. Since there were signs and symptoms mimicking malignancy, the patient was referred to our hospital for further malignancy work-up. A bone marrow puncture was done and we incidentally found Plasmodium falciparum in a microscopic bone marrow smear. This was a rare case because Plasmodium was not initially found in the preliminary work-up (Rapid Diagnostic Test and Microscopic) and qPCR is not a routine work-up for Plasmodium suspected patients. Although the mortality rate of malaria is high, this condition can be treated if the clinician was aware of the clinical signs and symptoms in the early onset and prompt medical treatment is administered. In a severe case with an unclear etiology of fever and with signs and symptoms mimicking malignancy, qPCR is recommended. However, a bone marrow puncture can also be considered to exclude the possibility of a malaria infection. PMID- 29111187 TI - A review of five traditionally used anti-diabetic plants of Bangladesh and their pharmacological activities. AB - Plants are used traditionally throughout the globe to treat various diseases. Traditionally used medicinal plants are an essential part of the health sector in Bangladesh due to its abundance of a vast source of ethno-medicine. Rural people from developing country like Bangladesh are greatly dependent on traditional source of medicine. The prevalence of diabetes mellitus is increasing from recent years; therefore various researches are going on to discover better medicine to treat this disease. This study has focused on five plants which are Andrographis paniculata, Ageratum conyzoides, Swertia chirata, Terminalia arjuna, and Azadirachta indica to find out their traditional formulation as anti-diabetic medicine and their pharmacological activity has also been explored through literature search. The available information about traditional anti-diabetic uses of these plants and their pharmacological activities were collected from various electronic sources like Pubmed, SciFinder, Elsevier, Springer, Scopus, Scirus, Science Direct, Google Scholar and Web of Science apart from these locally available books and peer reviewed journal were also used to collect information. This study will help to strengthen the relation between traditional medicine, pharmacology and drug development. A clue may be found from the information provided this review to discover new and better anti-diabetic drugs. PMID- 29111188 TI - Food intake regulation by leptin: Mechanisms mediating gluconeogenesis and energy expenditure. AB - Regulation of blood glucose levels and body fat is critical for survival. Leptin circulates freely in blood and controls body weight and food intake mainly through hypothalamic receptors and regulates glucose metabolism in the liver both directly through leptin receptors and indirectly via the hypothalamic receptors of central nervous system. Leptin affects food intake regulation and eventually glucose metabolism, lipometabolism, endocrine and immune functions, reproductive function, adipose tissue metabolism and energy expenditure. Leptin also exerts peripheral effects directly on glucose metabolism and gluconeogenesis. Most of obese human subjects have elevated plasma levels of leptin associated to the size of their total adipose tissue mass. Hence gluconeogenic function may be an essential factor in the regulation of nutritional intake and weight gain. The aim of this review is therefore to identify and module the possible effects of leptin with special application in gluconeogenesis. In addition, this review includes the study of fat consumption and energy expenditure in the body. Specific modulation of leptin receptors and adipose tissues functioning could have important inference on therapeutic strategies. PMID- 29111189 TI - Clinical and environmental isolates of Burkholderia pseudomallei from Brazil: Genotyping and detection of virulence gene. AB - OBJECTIVE: To evaluate the genetic diversity of clinical and environmental isolates of Burkholderia pseudomallei (B. pseudomallei) recovered in Ceara, Brazil, and screen these isolates for the presence of type three secretion system virulence gene. METHODS: Nineteen B. pseudomallei isolates (9 from clinical cases and 10 from soils) were analyzed. Random amplified polymorphic DNA was performed with primers OPQ-2, OPQ-4 and OPQ-16 to evaluate the genetic diversity, and type three secretion system gene was detected through polymerase chain reaction. RESULTS: Random amplified polymorphic DNA showed a genetic relatedness of approximately 50% among the tested B. pseudomallei isolates, which were grouped into two clades, of which the biggest ones comprised 18/19 isolates for primer OPQ-2, and 17/19 isolates for primer OPQ-16. Primer OPQ-4 grouped the isolates into three clades comprising 1/19, 3/19 and 15/19 isolates. Additionally, type three secretion system gene was detected in all tested isolates. CONCLUSIONS: This is an effort to type B. pseudomallei strains from Ceara, which is important for better understanding this pathogen, contributing for the epidemiological surveillance of melioidosis in this endemic region. PMID- 29111190 TI - Chemical composition, antioxidant and antibacterial activities of essential oil and methanol extract of Artemisia vulgaris and Gaultheria fragrantissima collected from Nepal. AB - OBJECTIVE: To identify the chemical constituents and biological activities of essential oil and crude methanol extract of Artemisia vulgaris (A. vulgaris) and Gaultheria fragrantissima (G. fragrantissima). METHODS: Phytochemical screening, total phenolic and flavonoid content, antibacterial activities, anti-oxidant assay of the crude extract were carried out to identify the biological activities and phytonutrients present in the extract. Furthermore, the chemical constituents present in the essential oil and crude methanol extract were analyzed using gas chromatography mass spectroscopy and high performance liquid chromatography (HPLC) analysis. RESULTS: Gas chromatography mass spectroscopy analysis of essential oil from the aerial part of A. vulgaris revealed 24 different compounds in it. Sabinene (11.29%), beta-thujone (19.19%), chrysanthenone (4.48%), camphor (11.89%), borneol (4.44%) and germacrene D (8.42%) were the major compounds. Similarly, leaves of G. fragrantissima contained methyl salicylate (95%) and asarone (4.64%). Furthermore, methanol extract of leaves of A. vulgaris and G. fragrantissima were found rich in the total flavonoids and phenolic content. HPLC analysis of the methanol extract of leaves A. vulgaris revealed the presence of morin and luteolin, whereas rutin was found as a major flavonoids compound in the leaves of G. fragrantissima. Further, methanol extract of the A. vulgaris and G. fragrantissima showed the highest antioxidant and antibacterial properties compared to the essential oil. CONCLUSIONS: The HPLC analysis of the methanol extract of A. vulgaris shows the presence of luteolin and morin, whereas G. fragrantissima reveals the presence of rutin and a glycosylated flavonoids. Results reveal that A. vulgaris oil is the rich source of monoterpene and sesquiterpene compounds. Furthermore, A. vulgaris and G. fragrantissima are the rich source of the phenolic and flavonoids compounds and show good antioxidant and antibacterial activity. PMID- 29111191 TI - Protective potency of Meristotropis xanthioides against nephrotoxicity in a rat model along with its antioxidant and antibacterial activities. AB - OBJECTIVE: To investigate nephroprotective potential of Meristotropis xanthioides (M. xanthioides) extract against ethanol-induced nephrotoxicity in Wistar rats, and also its total phenolics content, antioxidant and antibacterial activities. METHODS: Total phenol and flavonoid amounts of the leaf and stem extracts were determined by Folin-Ciocalteu and aluminum chloride reagents, respectively. Antioxidant and antibacterial activities of the extracts were investigated by 2,2 diphenyl-1-picrylhydrazyl radical scavenging and disc diffusion methods, respectively. In addition, protective potential of the leaf extract against ethanol-induced nephrotoxicity was studied by histological and biochemical analyses. RESULTS: Obtained results indicated high total phenol [(10.26 +/- 0.46) mg GAE/g of dry extract] and flavonoid [(3.63 +/- 0.62) mg QE/g of dry extract] amounts in the leaf extract. The leaf and stem extracts possessed stronger antioxidant activity [IC50: (0.119 +/- 0.006) mg/mL and IC50: (0.133 +/- 0.009 mg/mL)] than that of ascorbic acid [IC50: (0.142 +/- 0.002) mg/mL]. Also, the extracts showed good antibacterial activity against the most of bacteria taken in this research, especially Gram-positive ones. Histological examinations revealed tissue injury in the kidney of rats treated with ethanol. Results from biochemical assays showed reduction in total protein content and also in superoxide dismutase activity. In addition, remarkable increased levels (P < 0.05) of H2O2 and malondialdehyde were found in ethanol-treated rats in comparison to control group. However, these injuries were significantly improved in rats treated by M. xanthioides leaf extract. CONCLUSIONS: Results from present study demonstrates strong pharmaceutical potential of M. xanthioides extract to apply as a new drug supplement. PMID- 29111192 TI - Antifungal, molluscicidal and larvicidal assessment of anemonin and Clematis flammula L. extracts against mollusc Galba truncatula, intermediate host of Fasciola hepatica in Tunisia. AB - OBJECTIVE: To investigate the potential of anemonin and Clematis flammula (C. flammula) extracts against infective organisms. METHODS: The molluscicidal activities of anemonin and C. flammula extracts against Galba truncatula Mull. (Lymnaeidae) and Fasciola hepatica larval stages contaminating this snail in Tunisia were assessed by testing six groups of snails in 250 mL of extracts and aqueous dechlorinated solutions with different concentrations (ranging from 2.5 to 20.0 mg/L) for 48 h. Besides, the antifungal potential of C. flammula leaves and flowers was evaluated by using the diffusion agar and broth dilution methods against four fungal strains: Aspergillus niger, Pythium catenulatum, Rhizoctonia solani and Fusarium phyllophilum. RESULTS: As a result, hexane and ethyl acetate flower extracts exhibited significant molluscicidal activities with LC50 median lethal concentrations values of 11.87 and 11.65 mg/L, respectively while LC50 value of anemonin was 9.64 mg/L after 48 h exposure. The flower extracts showed a larvicidal effect with a deterioration rate exceeding 35.39% where flower ethyl acetate residue gave a deterioration rate of cercariae close to 97%. Moreover, C. flammula extracts were not noxious to the associated fauna survival. All extracts inhibited the growth of P. catenulatum, the leaves and flowers methanolic extracts had the more important fungicide action with minimum inhibitory concentrations of 1.56 and 3.12 mg/mL together with minimum fungistatic concentrations of 3.12 and 6.25 mg/mL respectively. Only flower extracts were active against Rhizoctonia solani with minimum inhibitory concentrations varying between 0.70 and 1.56 mg/mL and 6.25 mg/mL of minimum fungistatic concentration. Phytochemical tests showed that the antifungal activity may be attributed to the presence of the flavonoids/saponins in the methanolic extracts and the molluscicide effects could be due to the richness of hexane and ethyl acetate extracts on sterols and triterpenoids. CONCLUSIONS: This study emphasizes the important molluscicidal and antiparasitic effects of flower ethyl acetate extracts and anemonin compound as well as the considerable antifungal activities of methanolic extracts. These results improve the therapeutic virtues of C. flammula aerial part extracts. PMID- 29111193 TI - Antioxidant and diuretic activity of co-administration of Capparis spinosa honey and propolis in comparison to furosemide. AB - OBJECTIVE: To study the antioxidant properties of Capparis spinosa (C. spinosa) honey and propolis and the effect of combined honey and propolis administration on urine volume and electrolytes in rats. METHODS: C. spinosa honey [1000 mg/kg body weight (b.wt)], propolis (100 mg/kg b.wt), honey/propolis mixture (C. spinosa honey 1000 mg/kg b.wt/ propolis extract 100 mg/kg b.wt ), distilled water (1 mL/kg b.wt) and furosemide (10 mg/kg b.wt) were orally administered to five groups of rats for 21 d. Urine volume, blood and urine sodium, potassium and chloride were measured. The antioxidant activity of propolis and honey was assessed and their total phenols and flavonoids were determined. RESULTS: Propolis and C. spinosa honey contain polyphenols including flavonoids and propolis demonstrated higher antioxidant activities than honey. Honey significantly increased urine volume and urine electrolyte excretion. Propolis had no significant effect on urine volume, but co-administration of propolis and honey caused significant diuresis. No major changes were observed in plasma electrolytes with the use of honey, propolis or their combination. CONCLUSIONS: Honey and propolis have antioxidant activity and contain polyphenols including flavonoids that are more pronounced in propolis. Honey has a significant diuretic activity alone or in combination with propolis. This is the first study comparing the diuretic effect of co-administration of propolis and C. spinosa honey with furosemide. PMID- 29111194 TI - Synergists action of piperonyl butoxide and S,S,S-tributyl phosphorotrithioate on toxicity of carbamate insecticides against Blattella germanica. AB - OBJECTIVE: To determine the synergists action of piperonyl butoxide (PBO) and S,S,S-tributyl phosphorotrithioate (DEF) on toxicity of carbamate insecticides against Blattella germanica in Tehran city. METHODS: In the current study, German cockroach strains were collected from several hospitals and dormitories in Tehran. At the beginning, different concentrations of bendiocarb and carbaryl (insecticides belong to carbamate group) were determined by surface contact on a susceptible strain. Then, the level of susceptibility and type of resistance mechanisms in the collected strains from contaminated sites to the aforementioned insecticides were studied by using PBO and DEF synergists with different insecticide ratios to synergist (1:0, 1:1, 1:2, 1:3). RESULTS: The DEF synergist along with bendiocarb and carbaryl completely eliminated the resistance in all strains but PBO did not completely eliminate the resistance in the strains of Mofid, Alvand, Valiasr hospitals and Shariati dormitory. Generally, the impact of DEF was observed in the removing resistance more than PBO. CONCLUSIONS: In most of these strains, resistance to bendiocarb and carbaryl is completely eliminated by DEF, showing a very high role of estraze enzymes in resistance to bendiocarb and carbaryl. But in most strains PBO does not remove the resistance because other mechanisms, such as reduced cuticle penetration and insensitivity to the acetylcholine esterase enzyme, may be involved. PMID- 29111195 TI - Giardia duodenalis infection among rural communities in Yemen: A community-based assessment of the prevalence and associated risk factors. AB - OBJECTIVE: To investigate the prevalence and risk factors of Giardia infection among rural communities among rural communities in Yemen. METHODS: In this cross sectional study, a total of 605 stool samples were collected and screened for the presence of Giardia duodenalis (G. duodenalis) cysts and/or trophozoites by using three different diagnostic methods: direct smear, formalin-ether sedimentation, and trichrome staining. A pre-tested questionnaire was used to collect information on the demographic, socioeconomic, behavioural and environmental characteristics of the participants. RESULTS: Overall, 28.1% (170/605) of the participants were infected by G. duodenalis. The prevalence was significantly higher among male participants compared to female (P = 0.034); however, it was not significant among different age groups (P > 0.05). Univariate and multivariate analyses identified four variables as the significant key risk factors of Giardia infection among the sampled communities. These are, in addition to being of the male gender, using unsafe water sources for drinking water, not washing hands after defecation, presence of other family members infected with Giardia, and close contact with domestic animals. CONCLUSIONS: The study reveals that Giardia infection is still prevalent among rural communities in Yemen. The provision of clean and safe drinking water, proper sanitation, and health education regarding personal hygiene practices, particularly handwashing, as well as identifying and treating infected family members is imperative and these interventions should be considered in a strategy to control intestinal parasites among these communities in order to curtail the transmission and morbidity caused by G. duodenalis. PMID- 29111196 TI - Molecular and serological prevalence of Toxoplasma gondii in pregnant women and sheep in Egypt. AB - OBJECTIVE: To investigate molecular and serological prevalence of Toxoplasma gondii (T. gondii) in pregnant women and sheep in Egypt. METHODS: Blood samples collected from healthy 364 pregnant women and 170 sheep were investigated for T. gondii antibodies and parasitemia using highly specific and sensitive surface antigen (TgSAG2) based enzyme linked immunosorbent assay (ELISA) and real time polymerase chain reaction (RT-PCR). RESULTS: Overall prevalence of T. gondii was 51.76%, 17.65% in sheep, 33.79%, 11.81% in pregnant women, using ELISA and RT-PCR respectively. Significant differences in T. gondii prevalence were observed on the basis of contact with cats or soil in pregnant women using either RT-PCR or ELISA. In pregnant women, a significant increase was detected in aged and those eating under-cooked mutton using simultaneous ELISA/RT-PCR. CONCLUSIONS: Consumption of under-cooked infected mutton is an important source of human infection and the combination of the two assays provide accurate and precise data during infection. PMID- 29111197 TI - The critical acromial point: the anatomic location of the lateral acromion in the critical shoulder angle. AB - BACKGROUND: Acromioplasty has been proposed as a means of altering elevated critical shoulder angles (CSAs). We aimed to localize the critical acromion point (CAP) responsible for the acromial contribution of the CSA and determine whether resection of the CAP can alter the CSA to a normal range. METHODS: The CAP and 3 dimensional (3D) CSAs were determined on 3D computed tomography reconstructions of 88 cadaveric shoulders and compared with corresponding CSAs on digitally reconstructed radiographs. The position of the CAP was fluoroscopically isolated in 20 of these specimens and the resulting fluoroscopic CSA compared with the corresponding 3D CAP and 3D CSA. We investigated the CSA before and after a virtual acromioplasty of 2.5 and 5 mm at the CAP in specimens with a CSA greater than 35 degrees . RESULTS: The mean CAP was 21% +/- 10% of the acromial anterior posterior length from the anterolateral corner. There was no difference between the mean 3D CSA and the CSA on digitally reconstructed radiographs (32 degrees vs 32 degrees , P = .096). No difference between the mean fluoroscopic CSA and 3D CSA was found (31 degrees vs 31 degrees , P = .296). A 2.5-mm acromial resection failed to reduce the CSA to 35 degrees or less in 7 of 13 shoulders, whereas a 5 mm resection reduced the CSA to 35 degrees or less in 12 of 13. CONCLUSION: The CAP was localized to the anterolateral acromial edge and was easily identified fluoroscopically. A 5-mm acromial resection was effective in reducing the CSA to 35 degrees or less. These data can guide surgeons in where and how to alter the CSA if future studies demonstrate a clinical benefit to surgically modifying this radiographic parameter. PMID- 29111198 TI - Cumulative Effective Dose and Cancer Risk of Pediatric Population in Repetitive Whole-Body Scan Using Dual-Energy X-Ray Absorptiometry. AB - This study aims to quantitatively evaluate the cumulative effective dose and associated cancer risk of pediatric patients of US and Hong Kong population undergoing repetitive whole-body scans with dual-energy X-ray absorptiometry (DXA) during their diagnosis and follow-up periods. Organ-absorbed doses of pediatric patients undergoing DXA whole-body scan have been computer simulated using patient imaging parameters input to the Monte Carlo software PCXMC. Gender- and age-specific effective doses have been calculated with the simulated organ absorbed doses using the ICRP-103 approach. The associated radiation-induced cancer risk, expressed as lifetime attributable cancer risk (LAR), has been estimated according to the method introduced in the Biological Effects of Ionizing Radiation VII report. Mathematical fitting for effective dose and for LAR, as a function of age at exposure, has been analytically obtained to quantitatively estimate the cumulated effective dose and LAR for pediatric patients of US and Hong Kong population with repetitive DXA whole-body scan during their follow-up period. The effective dose of a single DXA whole-body scan for patients exposed at the age between 5 and 18 years was calculated as 8.47 17.68 uSv. The corresponding LAR for US and Hong Kong population was between the range of 4.57 * 10-7 and 7.14 * 10-7. The cumulative effective dose of DXA whole body scan for patients exposed annually at age between 5 and 18 years was calculated as 180 uSv for girls and 168 uSv for boys. The corresponding cumulative LAR for US and Hong Kong population was calculated as 3.77 * 10-6 to 5.48 * 10-6. Girls would be at a statistically significant higher cumulated cancer risk than boys under the same whole-body DXA protocol (p = 0.03). The probability of cumulative LAR for pediatric populations undergoing annual DXA whole-body scan is regarded as minimal. We demonstrate the use of computer simulation and analytic formulation to quantitatively obtain the cumulated effective dose and cancer risk at any age of exposure, which are useful information for medical personnel to track patient radiation dose and to alleviate patients' parents concern about radiation safety in repetitive whole body scan using DXA. PMID- 29111199 TI - Density dependent re-tuning of autoreactive T cells alleviates their pathogenicity in a lymphopenic environment. AB - Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells. Intriguingly these T cells often retain sufficient effector functions to trigger autoimmune pathology. Here we find that the high population density of the autoreactive T cells that accumulated in such a host limits the progression of the cell-intrinsic tolerance process in T cells. Accordingly, reducing the cell density during a second transfer allowed T cells to further tune down their responsiveness to antigenic stimulation. The retuning of T cells was reflected by a loss of the T cell's abilities to proliferate, produces cytokines or help B cells. We further suggest, based on altering the levels of chronic antigen using miniosmotic pumps, that the effects of cell density on T cell re-tuning may reflect the effective changes in the antigen dose perceived by individual T cells. This could proportionally elicit more negative feedback downstream of the TCR. Consistent with this, the retuned T cells showed signaling defects both proximal and distal to the TCR. Therefore, similar to the immunogenic activation of T cells, cell-intrinsic T cell tolerance may also involve a quantitative and progressive process of tuning down its antigen responsiveness. The progress of such tuning seems to be stabilized at multiple intermediate stages by factors such as cell density, rather than just absolute antigen levels. PMID- 29111200 TI - Quality of Life, Psychological Functioning, and Treatment Satisfaction of Men Who Have Undergone Penile Prosthesis Surgery Following Robot-Assisted Radical Prostatectomy. AB - BACKGROUND: Penile prosthesis surgery is last-line treatment to regaining erectile function after radical prostatectomy (RP) for localized prostate cancer. AIMS: To assess quality of life, psychological functioning, and treatment satisfaction of men who underwent penile implantation after RP; the psychosocial correlates of treatment satisfaction and sexual function after surgery; and the relation between patients' and partners' ratings of treatment satisfaction. METHODS: 98 consecutive patients who underwent penile implantation after RP from 2010 and 2015 and their partners were invited to complete a series of measures at a single time point. Of these, 71 patients and 43 partners completed measures assessing sexual function, psychological functioning, and treatment satisfaction. Proportions of patients who demonstrated good sexual function and satisfaction with treatment and clinical levels of anxiety and depression were calculated. Hierarchical regression analyses were conducted to determine psychosocial factors associated with patient treatment satisfaction and sexual function and patient partner differences in treatment satisfaction. OUTCOMES: Patients completed the Expanded Prostate Cancer Index Composite Short Form (EPIC-26), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), Prostate Cancer-Related Quality of Life Scale, Self-Esteem and Relationship Questionnaire (SEAR), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ 9). Partners completed the GAD-7, PHQ-9, EDITS (partner version), and SEAR. RESULTS: 94% of men reported satisfaction with treatment (EDITS score > 50). 77% of men reported good sexual function (EPIC-26 score > 60). Lower depression scores were associated with higher sexual confidence and sexual intimacy, and these were correlated with better treatment satisfaction and sexual function. Patients experienced higher sexual relationship satisfaction (median score = 90.6) than their partners (median score = 81.2), but there was no difference in treatment satisfaction between groups. Higher patient treatment satisfaction was more likely to be reported for couples whose depression scores were more similar. CLINICAL IMPLICATIONS: It is important to provide preoperative penile implant counseling and encourage patients to seek postoperative counseling if needed. STRENGTHS AND LIMITATIONS: This is one of the first Australian-based studies comprehensively assessing treatment satisfaction and psychosocial health of men after penile prosthesis surgery after RP. This was a retrospective cross sectional study, so there is a possibility of recall bias, and causal associations could not be determined. CONCLUSION: Men in this Australian series who underwent penile prosthesis surgery after RP generally reported good sexual function and treatment satisfaction. Nevertheless, patient and partner mental health influenced their reported experience of the treatment. Pillay B, Moon D, Love C, et al. Quality of Life, Psychological Functioning, and Treatment Satisfaction of Men Who Have Undergone Penile Prosthesis Surgery Following Robot Assisted Radical Prostatectomy. J Sex Med 2017;14:1612-1620. PMID- 29111201 TI - Another reason to favor exclusive breastfeeding: microbiome resilience. PMID- 29111202 TI - Intestinal fructose malabsorption is associated with increased lactulose fermentation in the intestinal lumen. AB - OBJECTIVE: To study fructose malabsorption in children and adolescents with abdominal pain associated with functional gastrointestinal disorders. As an additional objective, the association between intestinal fructose malabsorption and food intake, including the estimated fructose consumption, weight, height, and lactulose fermentability were also studied. METHODS: The study included 31 patients with abdominal pain (11 with functional dyspepsia, 10 with irritable bowel syndrome, and 10 with functional abdominal pain). The hydrogen breath test was used to investigate fructose malabsorption and lactulose fermentation in the intestinal lumen. Food consumption was assessed by food registry. Weight and height were measured. RESULTS: Fructose malabsorption was characterized in 21 (67.7%) patients (nine with irritable bowel syndrome, seven with functional abdominal pain, and five with functional dyspepsia). Intolerance after fructose administration was observed in six (28.6%) of the 21 patients with fructose malabsorption. Fructose malabsorption was associated with higher (p<0.05) hydrogen production after lactulose ingestion, higher (p<0.05) energy and carbohydrate consumption, and higher (p<0.05) body mass index z-score value for age. Median estimates of daily fructose intake by patients with and without fructose malabsorption were, respectively, 16.1 and 10.5g/day (p=0.087). CONCLUSION: Fructose malabsorption is associated with increased lactulose fermentability in the intestinal lumen. Body mass index was higher in patients with fructose malabsorption. PMID- 29111203 TI - The effect of microcracking in the peritubular dentin on the fracture of dentin. AB - Dentin is a biocomposite possessing elegant hierarchical structure, which allows it to resist fracture effectively. Despite the considerable efforts to unravel the peculiar fracture behavior of dentin, the effect of microstructural features on the fracture process is largely unknown. In this study, we explore the interaction between the primary crack with crack tip located in intertubular dentin (ITD) and microcracking of peritubular dentin (PTD) ahead of the primary crack. A micromechanical model accounting for the unique composite structure of dentin is developed, and computational simulations are performed. It is found that the microcracking of PTD located in the crack plane in front of the primary crack tip can promote the propagation of the primary crack, increasing the propensity of coalescence of primary crack and microcracks nucleating in PTD. We show that the two-layer microstructure of dentin enables reduction in driving force of primary crack, potentially enhancing fracture toughness. The high stiffness of PTD plays a critical role in reducing the driving force of primary crack and activating microcracking of PTD. It is further identified that the microcracking of PTD arranged parallel to the crack plane with an offset could contribute to the shielding of primary crack. PMID- 29111204 TI - The impacts of nineteen mutations on the enzymatic activity of USP26. AB - OBJECTIVE: The association between mutations in the USP26 gene and male infertility has been studied intensively. However, the biological function of the mutant proteins remains to be elucidated. To confirm the effects of the reported mutations, we analyse the enzyme activity of USP26 between the wild-type and the variants from a molecular perspective. METHODS: Using pGEX-USP26 as a template, site-directed mutagenesis was conducted to generate nineteen USP26 mutant plasmids. Using Ub-Met-beta-gal and GST-Ub52 as model substrates, a USP cleavage assay was conducted to assess the enzymatic activities of the mutants. RESULTS: The enzyme activity of the Q156H mutant disappeared, but the other 18 mutants had the same activity as the wild type. E174# and E189# were terminal mutants, but they still had the same activity as the wild type. When we constructed the transcription terminal mutants E174#(1-522 bp), E174#(523-2742 bp), E189#(1-567 bp) and E189#(568-2742 bp) artificially, the enzyme activity of these four mutants disappeared. CONCLUSIONS: We have successfully constructed nineteen mutants of USP26. The enzyme activity of the Q156H mutant disappeared, but the enzyme activities of the other 18 mutants were the same as that of the wild type. PMID- 29111205 TI - Hsa-miR-11181 regulates Wnt signaling pathway through targeting of APC2 transcripts in SW480 cell line. AB - Wnt signaling plays important roles in differentiation, morphogenesis and development. This signaling pathway is highly regulated at all levels and microRNAs are small noncoding RNAs regulating Wnt signaling. Here, we intended to investigate hsa-miR-11181 (a novel miRNA located in TrkC gene) effect on Wnt signaling pathway in SW480 cell line. TOP/FOP flash assay indicated up-regulation of Wnt signaling, following the overexpression of hsa-miR-11181, verified through RT-qPCR. Bioinformatics analysis predicted APC1, APC2 and Axin1 might be targeted by hsa-miR-11181. Then, RT-qPCR analysis indicated that APC2 and Axin1 have been significantly down-regulated following the hsa-miR-11181 overexpression. However dual luciferase assay analysis supported only APC2 3'-UTR is directly targeted by this miRNA. Then, treatment of SW480 cells with Wnt-inhibitory small molecules supported the effect of hsa-miR-11181 at the inhibitory complex level containing APC2 protein. Consistently, viability of SW480 cells overexpressing hsa-miR-11181 was significantly elevated, measured through MTT assay. Overall, these results suggest that hsa-miR-11181 may play a crucial role in Wnt signaling regulation and confirmed that APC2 3'-UTR is targeted by hsa-miR-11181 and propose the presence of its recognition sites in the promoter or coding regions of Axin1 gene. PMID- 29111206 TI - Functional mutant GATA4 identification and potential application in preimplantation diagnosis of congenital heart diseases. AB - Congenital heart diseases (CHDs) affect nearly 1% of all neonates and show an increasing tendency. The complex inheritance patterns and multifactorial etiologies make these defects difficult to be identified before complete manifestation. Genetic screening has identified hundreds of specific mutant sites for CHDs based on cardiac transcriptional factors. GATA4 is a master regulator required for ventral morphogenesis and heart tube formation. Its mutation is most widely studied in CHDs. In the past decades, over 100 GATA4 mutant sites have been reported, but only a few functional sites have been identified. Thus, it is important to distinguish deleterious sites from neutral sites. In silico prediction of functional sites using bioinformatics tools can provide the valuable information, but it is not solid enough. Here, the roles of GATA4 in heart development is discussed in detail and its mutation sites in protein coding region are summarized systematically, providing an integrated resource for GATA4 mutations. Furthermore, we discussed the advantage and disadvantage of different methods for functional mutation identification. Especially, the disease model of induced pluripotent stem cell is emerging as a powerful tool to assess GATA4 mutations in human. In the recent years, single-cell based high-throughput sequencing is being applied in preimplantation diagnosis and assisted reproduction progressively, providing a new strategy for the prevention of congenital diseases as we discussed. Based on functional mutant sites identification, preimplantation diagnosis will contribute to CHDs prevention eventually. PMID- 29111207 TI - Variant calling from RNA-seq data of the brain transcriptome of pigs and its application for allele-specific expression and imprinting analysis. AB - Identification of new polymorphic variants from RNA-seq data is difficult mainly because of the errors arising during bioinformatic analysis. Therefore, new experiments in this area are very profitable for improving new statistical methods. In our study of the porcine brain transcriptome, we have identified 10966 polymorphic variants, among which 7277 were single nucleotide polymorphisms (SNPs). Further, we have calculated allelic ratios for the SNPs identified and estimated that 52% of genes in porcine brain are subjected to allele-specific expression (ASE), a phenomenon in which one allele is preferentially expressed. Our investigation presents the first estimates of ASE in porcine brain. In addition, we have used the results of RNA-seq for the identification of SNPs in putatively imprinted genes. Finally, we have used these SNPs for the verification of the imprinted status of the INPP5f variant 2, LRRTM1 and HM13 genes in pigs by Sanger sequencing. We observed that INPP5f variant 2 is paternally expressed, while HM13 and LRRTM1 are biallelically expressed in porcine brain. We have also confirmed maternal expression of the MEG3 gene in pigs. Our results present how RNA-seq data may be used for imprinting studies without sequencing of parental genomes. PMID- 29111208 TI - Recombinant latcripin 11 of Lentinula edodes C91-3 suppresses the proliferation of various cancer cells. AB - Lentinula edodes C91-3 is an edible mushroom that has demonstrated a remarkable anti-tumor effect in various cancer cells both in vitro and in vivo. In the present study, we report the ability of recombinant thioredoxin-like latcripin 11 (LP-11) of Lentinula edodes C91-3 to suppress the proliferation of various cancer cells. The LP-11 gene of Lentinula edodes C91-3 was cloned in the pET-32a(+) expression vector and expressed in a prokaryotic system. The expressed protein was refolded by gradual dialysis and purified by affinity gel filtration chromatography. The antioxidant activity of LP-11 was tested by 1,1-dipheny l-2 picrylhydrazyl (DPPH) assay. The anti-tumor activity of recombinant LP-11 was tested in eight kinds of tumor cell lines by CCK-8 assay. Recombinant LP-11 significantly suppressed the proliferation of various cancer cells, but not normal human umbilical vein endothelial cells. Human lymphoma U937 cells exhibited the most sensitivity to LP-11 protein. U937 cell apoptosis was assessed by Annexin V staining coupled with flow cytometry, and mitochondrial morphology was analyzed by light and electron microscopy. It was revealed that recombinant LP-11 induced apoptosis in human leukemic monocyte lymphoma U937 cells. Our findings suggest that recombinant LP-11 is a promising agent for the treatment of lymphoma. PMID- 29111209 TI - Usefulness of the 2MACE Score to Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation. AB - We investigated the incidence of nonembolic adverse events in 2 cohorts of patients with atrial fibrillation (AF) and validated the 2MACE score ([metabolic syndrome, age >=75] [doubled]; [myocardial infarction or revascularization, congestive heart failure {HF}, and stroke, transient ischemic attack or thromboembolism]) as predictor of major adverse cardiovascular events (MACEs). We recruited 2,630 patients with AF from 2 different cohorts (Murcia AF and FANTASIIA). The 2MACE score was calculated, and during a median of 7.2 years (Murcia AF cohort) and 1.01 years (FANTASIIA) of follow-up, we recorded all nonembolic adverse events and MACEs (composite of nonfatal myocardial infarction or revascularization and cardiovascular death). Receiver operating characteristic curves comparison, reclassification and discriminatory analyses, and decision curve analyses were performed to compare predictive ability and clinical usefulness of the 2MACE score against CHA2DS2-VASc. During follow-up, there were 65 MACEs in the Murcia cohort and 60 in the FANTASIIA cohort. Events rates were higher in the high-risk category (score >=3) (1.94%/year vs 0.81%/year in the Murcia cohort; 6.01%/year vs 1.71%/year, in FANTASIIA, both p <0.001). The predictive performance of 2MACE according to the receiver operating characteristic curve was significantly higher than that of CHA2DS2-VASc (0.662 vs 0.618, p = 0.008 in the Murcia cohort; 0.656 vs 0.565, p = 0.003 in FANTASIIA). Decision curve analyses demonstrated improved clinical usefulness of the 2MACE compared with the CHA2DS2-VASc score. In conclusion, in "real-world" patients with AF, the 2MACE score is a good predictor of MACEs. A score >=3 should be used to categorize patients at "high risk," in identifying patients at risk of MACE. PMID- 29111210 TI - Interaction of Adverse Disease Related Pathways in Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HC) has been characterized as a generally progressive genetic heart disease, creating an ominous perspective for patients and managing cardiologists. We explored the HC disease burden and interaction of adverse clinical pathways to clarify patient expectations over long time periods in the contemporary therapeutic era. We studied 1,000 consecutive HC patients (52 +/- 17 years) at Tufts Medical Center, followed 9.3 +/- 8 years from diagnosis, employing a novel disease pathway model: 46% experienced a benign course free of adverse pathways, but 42% of patients progressed along 1 major pathway, most commonly refractory heart failure to New York Heart Association class III or IV requiring surgical myectomy (or alcohol ablation) or heart transplant; repetitive or permanent atrial fibrillation; and least commonly arrhythmic sudden death events. Eleven percent experienced 2 of these therapeutic end points at different times in their clinical course, most frequently the combination of advanced heart failure and atrial fibrillation, whereas only 1% incurred all 3 pathways. Freedom of progression from 1 to 2 disease pathways, or from 2 to 3 was 80% and 93% at 5 years, respectively. Annual HC-related mortality did not differ according to the number of pathways: 1 (0.8%), 2 (0.8%), or 3 (2.4%) (p = 0.56), and 93% of patients were in New York Heart Association classes I or II at follow-up. In conclusion, it is uncommon for HC patients to experience multiple adverse (but treatable) disease pathways, underscoring the principle that HC is not a uniformly progressive disease. These observations provide a measure of clarity and/or reassurance to patients regarding the true long-term disease burden of HC. PMID- 29111211 TI - Myocardial Infarction in Adults With Congenital Heart Disease. AB - We compared the incidence and 30-day mortality of myocardial infarction (MI) in adults with congenital heart disease (CHD) relative to the general population. This cohort study used nationwide population-based medical databases to identify individuals born before 1982 and diagnosed with CHD in Denmark between 1963 and 2012. Patients were followed for first-time MI using data from the Danish National Registry of Patients. For each subject with CHD, we identified 10 controls from the general population, matched by sex and birth year. A unique personal identifier enabled follow-up for migration, death, or MI. We computed cumulative incidences and hazard ratios (HR) adjusted for birth year and sex for MI and 30-day mortality after MI. We identified 10,501 CHD adults alive at 30 years. By 70 years of age, the cumulative incidence of MI was 10% versus 6.5% for controls. The overall HR of MI in subjects with CHD compared with controls was 2.0 (95% CI 1.7 to 2.3). The 30-day mortality was 18% for the 296 subjects with CHD experiencing an MI during follow-up. The overall HR comparing 30-day mortality after MI between subjects with CHD and controls was 1.4 (95% CI 1.0 to 1.8). The greatest mortality was observed in adults with severe CHD (HR 2.7 [95% CI 1.5 to 5.0]). In conclusion, the incidence of MI and the 30-day mortality after MI for severe CHD were increased in adults with CHD compared with the general population. Underlying mechanisms need to be clarified. PMID- 29111212 TI - Monocyte chemotactic protein-induced protein 1 controls allergic airway inflammation by suppressing IL-5-producing TH2 cells through the Notch/Gata3 pathway. AB - BACKGROUND: Asthmatic and allergic inflammation is mediated by TH2 cytokines (IL 4, IL-5, and IL-13). Although we have learned much about how TH2 cells are differentiated, the TH2 checkpoint mechanisms remain elusive. OBJECTIVES: In this study we investigate how monocyte chemotactic protein-induced protein 1 (MCPIP1; encoded by the Zc3h12a gene) regulates IL-5-producing TH2 cell differentiation and TH2-mediated inflammation. METHODS: The functions of Zc3h12a-/- CD4 T cells were evaluated by checking the expression of TH2 cytokines and transcription factors in vivo and in vitro. Allergic airway inflammation of Zc3h12a-/- mice was examined with murine asthma models. In addition, antigen-specific CD4 T cells deficient in MCPIP1 were transferred to wild-type recipient mice, challenged with ovalbumin (OVA) or house dust mite (HDM), and accessed for TH2 inflammation. RESULTS: Zc3h12a-/- mice have spontaneous severe lung inflammation, with an increase in mainly IL-5- and IL-13-producing but not IL-4-producing TH2 cells in the lung. Mechanistically, differentiation of IL-5-producing Zc3h12a-/- TH2 cells is mediated through Notch signaling and Gata3 independent of IL-4. Gata3 mRNA is stabilized in Zc3h12a-/- TH2 cells. MCPIP1 promotes Gata3 mRNA decay through the RNase domain. Furthermore, deletion of MCPIP1 in OVA- or HDM-specific T cells leads to significantly increased TH2-mediated airway inflammation in OVA or HDM murine models of asthma. CONCLUSIONS: Our study reveals that MCPIP1 regulates the development and function of IL-5-producing TH2 cells through the Notch/Gata3 pathway. MCPIP1 represents a new and promising target for the treatment of asthma and other TH2-mediated diseases. PMID- 29111213 TI - Prenatal and early-life triclosan and paraben exposure and allergic outcomes. AB - BACKGROUND: In cross-sectional studies triclosan and parabens, ubiquitous ingredients in personal care and other products, are associated with allergic disease. OBJECTIVES: We investigated the association between prenatal and early life triclosan and paraben exposure and childhood allergic disease in a prospective longitudinal study. METHODS: Subjects were enrollees in the Vitamin D Antenatal Asthma Reduction Trial. Triclosan, methyl paraben, and propyl paraben concentrations were quantified in maternal plasma samples pooled from the first and third trimesters and urine samples from children at age 3 or 4 years. Outcomes were parental report of physician-diagnosed asthma or recurrent wheezing and allergic sensitization to food or environmental antigens based on serum specific IgE levels at age 3 years in high-risk children. RESULTS: The analysis included 467 mother-child pairs. Overall, there were no statistically significant associations of maternal plasma or child urine triclosan or paraben concentrations with asthma or recurrent wheeze or food or environmental sensitization at age 3 years. A trend toward an inverse association between triclosan and paraben exposure and allergic sensitization was observed. There was evidence of effect measure modification by sex, with higher odds of environmental sensitization associated with increasing paraben concentrations in male compared with female subjects. CONCLUSIONS: We did not identify a consistent association between prenatal and early-life triclosan or paraben concentrations and childhood asthma, recurrent wheeze, or allergic sensitization in the overall study population. The differential effects of triclosan or paraben exposure on allergic sensitization by sex observed in this study warrant further exploration. PMID- 29111215 TI - Methotrexate versus azathioprine in patients with atopic dermatitis: 2-year follow-up data. PMID- 29111214 TI - Association of rhinovirus species with common cold and asthma symptoms and bacterial pathogens. PMID- 29111216 TI - Cat ownership, cat allergen exposure, and trajectories of sensitization and asthma throughout childhood. PMID- 29111218 TI - The Notch pathway inhibitor stapled alpha-helical peptide derived from mastermind like 1 (SAHM1) abrogates the hallmarks of allergic asthma. AB - BACKGROUND: The Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by using the cell-permeable, hydrocarbon-stapled synthetic peptide stapled alpha-helical peptide derived from mastermind-like 1 (SAHM1) resulted in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, the efficacy of SAHM1 in allergic asthma models has remained unexplored. OBJECTIVE: We aimed to investigate the therapeutic efficacy of SAHM1 in a house dust mite (HDM)-driven asthma model. METHODS: Topical therapeutic intervention with SAHM1 or a control peptide was performed during sensitization, challenge, or both with HDM in mice. Airway inflammation was assessed by using multicolor flow cytometry, and bronchial hyperreactivity was studied. Additionally, SAHM1 therapy was investigated in mice with established allergic airway inflammation and in a model in which we neutralized IFN-gamma during HDM challenge to support the TH2 response and exacerbate asthma. RESULTS: SAHM1 treatment during the challenge phase led to a marked reduction of eosinophil and T cell numbers in bronchoalveolar lavage fluid compared with those in diluent treated or control peptide-treated mice. Likewise, T-cell cytokine content and bronchial hyperreactivity were reduced. SAHM1 treatment dampened TH2 inflammation during ongoing HDM challenge and enhanced recovery after established asthma. Additionally, in the presence of anti-IFN-gamma antibodies, SAHM1 downregulated expression of the key TH2 transcription factor GATA3 and intracellular IL-4 in bronchoalveolar lavage fluid T cells, but expression of the TH17 transcription factor retinoic acid-related orphan receptor gammat or intracellular IL-17 was not affected. SAHM1 therapy also reduced serum IgE levels. CONCLUSIONS: Therapeutic intervention of Notch signaling by SAHM1 inhibits allergic airway inflammation in mice and is therefore an interesting new topical treatment opportunity in asthmatic patients. PMID- 29111219 TI - Home freezers kill house dust mites. PMID- 29111217 TI - Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of function mutations. AB - BACKGROUND: Natural killer (NK) cells are critical innate effector cells whose development is dependent on the Janus kinase-signal transducer and activator of transcription (STAT) pathway. NK cell deficiency can result in severe or refractory viral infections. Patients with STAT1 gain-of-function (GOF) mutations have increased viral susceptibility. OBJECTIVE: We sought to investigate NK cell function in patients with STAT1 GOF mutations. METHODS: NK cell phenotype and function were determined in 16 patients with STAT1 GOF mutations. NK cell lines expressing patients' mutations were generated with clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)-mediated gene editing. NK cells from patients with STAT1 GOF mutations were treated in vitro with ruxolitinib. RESULTS: Peripheral blood NK cells from patients with STAT1 GOF mutations had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57, and impaired cytolytic function. STAT1 phosphorylation was increased, but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT1 signaling with the small-molecule Janus kinase 1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function. CONCLUSIONS: Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of increased STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations. PMID- 29111220 TI - PD-1hiCXCR5-CD4+ TFH Cells Play Defense in Cancer and Offense in Arthritis. AB - T follicular helper (TFH) cells are characteristically defined by their CXCR5 positivity and homing to B cell follicles in secondary lymphoid organs (SLO). An expanded subpopulation of functionally comparable and phenotypically similar PD 1hiCXCR5-CD4+ T cells were recently identified in breast cancer (BC) and rheumatoid arthritis (RA) to have beneficial or detrimental roles, respectively, but are they inflammatory tissue effector TFH cells? PMID- 29111222 TI - SSEL-ADE: A semi-supervised ensemble learning framework for extracting adverse drug events from social media. AB - With the development of Web 2.0 technology, social media websites have become lucrative but under-explored data sources for extracting adverse drug events (ADEs), which is a serious health problem. Besides ADE, other semantic relation types (e.g., drug indication and beneficial effect) could hold between the drug and adverse event mentions, making ADE relation extraction - distinguishing ADE relationship from other relation types - necessary. However, conducting ADE relation extraction in social media environment is not a trivial task because of the expertise-dependent, time-consuming and costly annotation process, and the feature space's high-dimensionality attributed to intrinsic characteristics of social media data. This study aims to develop a framework for ADE relation extraction using patient-generated content in social media with better performance than that delivered by previous efforts. To achieve the objective, a general semi-supervised ensemble learning framework, SSEL-ADE, was developed. The framework exploited various lexical, semantic, and syntactic features, and integrated ensemble learning and semi-supervised learning. A series of experiments were conducted to verify the effectiveness of the proposed framework. Empirical results demonstrate the effectiveness of each component of SSEL-ADE and reveal that our proposed framework outperforms most of existing ADE relation extraction methods The SSEL-ADE can facilitate enhanced ADE relation extraction performance, thereby providing more reliable support for pharmacovigilance. Moreover, the proposed semi-supervised ensemble methods have the potential of being applied to effectively deal with other social media-based problems. PMID- 29111221 TI - Portomesentric and splenic vein thrombosis (PMSVT) after bariatric surgery: a systematic review of 110 patients. AB - BACKGROUND: Portomesenteric and splenic vein thrombosis (PMSVT) is a rare but potentially serious complication after bariatric surgery. No study has systematically analyzed its incidence and risk factors. OBJECTIVES: To pool the data regarding PMSVT after bariatric surgery and determine its incidence and risk factors. METHODS: A meta-analysis and systematic review was conducted to retrieve studies on PMSVT after bariatric surgery. RESULTS: A total of 41 eligible studies including 110 patients with postbariatric PMSVT were enrolled; the estimated incidence rate based on 13 studies was .4%. The use of oral contraception was reported in 35.4% of patients, previous surgery in 61.1%, smoking in 37.2%, and history of coagulopathy in 43%. PMSVT mostly occurred after sleeve gastrectomy (78.9%) and within the first postoperative month (88.9%). Pneumoperitoneum pressure was>15 mm Hg in 6% of patients. The portal vein was the most commonly affected vessel (41.5%). Prothrombin 20210 mutation and protein C/S deficiency were the most common thrombophilic conditions. Unfractionated heparin (59.1%), vitamin K antagonists (50.9%), and low molecular weight heparin (39.1%) were the most common treatments for PMSVT. The morbidity and mortality rates for postbariatric PMSVT were 8.2% and 3.6%, respectively. CONCLUSION: PMSVT usually occurs within the first postoperative month and is mostly reported after sleeve gastrectomy. The portal vein is the most commonly involved vessel. A previous hypercoagulable state can be an important risk factor. Most patients can be treated with anticoagulation therapy. Further studies with comprehensive data review of patient information are required. PMID- 29111223 TI - The Origin of Possibility. PMID- 29111225 TI - ANGPTL3 targeting: The power of versatile lipid-lowering. PMID- 29111224 TI - Statin treatment in dialysis patients after acute myocardial infarction improves overall mortality. AB - While statins are widely accepted as a keystone for secondary prevention of cardiovascular disease in the general population, statin treatment in chronic renal failure is still debated. Statins have shown no benefit on cardiovascular outcomes in 4D, AURORA, and SHARP trials conducted in patients on dialysis. However, no study has yet compared statin treatment after acute myocardial infarction in end-stage renal disease (ESRD) patients. Statin treatment significantly decreases overall mortality in ESRD patients with acute myocardial infarction compared to the non-statin group. This is more prominent in the cardiac shock patient subgroup. The results are compatible with other studies, supporting a measurable benefit from statins in ESRD patients. There is no clear consensus on statin treatment in dialysis patients. The study by Chung et al. published in this issue of Atherosclerosis was conducted in a large patients' pool, with a long follow-up period [1]. Authors have reported an important result supporting statin treatment in dialysis patients after acute myocardial infarction. PMID- 29111226 TI - Marketing Food and Beverages to Youth Through Sports. AB - Food and beverage marketing has been identified as a major driver of obesity yet sports sponsorship remains common practice and represents millions of dollars in advertising expenditures. Research shows that food and beverage products associated with sports (e.g., M&M's with National Association for Stock Car Auto Racing logo) generate positive feelings, excitement, and a positive self-image among adults and children. Despite this, self-regulatory pledges made by food companies to limit exposure of unhealthy products to children have not improved the nutritional quality of foods marketed to children. We reviewed the literature about sports-related food marketing, including food and beverage companies' use of sports sponsorships, athlete endorsements, and sports video games. This review demonstrates that sports sponsorships with food and beverage companies often promote energy-dense, nutrient-poor products and while many of these promotions do not explicitly target youth, sports-related marketing affects food perceptions and preferences among youth. Furthermore, endorsement of unhealthy products by professional athletes sends mixed messages; although athletes may promote physical activity, they simultaneously encourage consumption of unhealthy products that can lead to negative health outcomes. We argue that more athletes and sports organizations should stop promoting unhealthy foods and beverages and work with health experts to encourage healthy eating habits among youth. PMID- 29111227 TI - African-American Males in Chicago: Pathways From Early Childhood Intervention to Reduced Violence. AB - PURPOSE: Extreme youth violence is a salient public health crisis in Chicago, particularly among African-American males. This article examines mechanisms through which a preschool intervention program, the Child-Parent Center program, in inner-city Chicago may divert high-risk males from pathways leading to violent criminal behavior. METHODS: We conducted a path analysis from early environmental factors to socioemotional competencies through parent involvement and achievement to violent arrest in emerging adulthood. African-American male participants (N = 677) were followed from age 3 to age 27. RESULTS: Child-Parent Center program attendance initiates a pathway to increased third grade academic achievement and parent involvement, which positively impacts socioemotional competencies and acting out behaviors in adolescence. High parent involvement and low acting out behaviors had direct effects on violent crime in emerging adulthood. CONCLUSIONS: High parent involvement in school, fostered by early childhood intervention, promotes adaptive behaviors in adolescence and reduces arrest for violent crime in emerging adulthood. PMID- 29111228 TI - The effects of truncal adiposity in forced spirometry: Sex differences. AB - The aim of the current paper is to establish the influence of truncal fat accumulation on the spirometric results of a group of healthy individuals. A cross-sectional study of 305 healthy, non-smoking adult subjects (144 males, 161 females) was conducted. Forced spirometry and dual-energy X-ray absorptiometry to quantify body fat were performed. Partial correlation and multiple linear regression analyses were performed. In females, abdominal fat was negatively correlated with forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). In males, thoracic fat was negatively correlated with respiratory variables, as was abdominal fat. In the multiple linear regression, FEV1 was the spirometric parameter that showed higher R2 values in both sexes. Truncal fat had a greater influence on FEV1 than on FVC. In males, no significant differences between the influence of thoracic and abdominal fat on spirometric results were found, and total body fat was shown to have more influence than regional. In females, the influence of abdominal fat was higher. PMID- 29111229 TI - The Academic-Industrial Complexity: Failure to Launch. AB - The pharmaceutical industry has long known that ~80% of the results of academic laboratories cannot be reproduced when repeated in industry laboratories. Yet academic investigators are typically unaware of this problem, which severely impedes the drug development process. This academic-industrial complication is not one of deception, but rather a complex issue related to how scientific research is carried out and translated in strikingly different enterprises. This Opinion describes the reasons for inconsistencies between academic and industrial laboratories and what can be done to repair this failure of translation. PMID- 29111230 TI - High intensity interval training modulates hippocampal oxidative stress, BDNF and inflammatory mediators in rats. AB - Although High Intensity Interval Training (HIIT) are being associated to increase cardiovascular and metabolic adaptation, there is controversy and limited information about the effects of HIIT on hippocampal oxidative stress, pro- and anti-inflammatory cytokines balance and neurotrophic status. Thus, this study evaluated the effects of six weeks of HIIT on hippocampal redox state (oxidative damage and enzymatic and non-enzymatic antioxidant defenses), neuroimmune mediators (TNFalpha, IL-6, IL-1beta and IL-10) and brain-derived neurotrophic (BDNF) levels. After six weeks of HIIT young adults male Wistar rats presented reduced oxidative damage and increased enzymatic (superoxide dismutase) and non enzymatic activity in hippocampus. Moreover HIIT induced a decrease in cytokine content (TNFalpha, IL-6, IL-1beta and IL-10) and enhanced hippocampal BDNF levels. In conclusion, the present study showed for the first time a positive effect of six weeks of HIIT on reducing hippocampal oxidative stress by decreasing lipoperoxidation and inflammatory markers, as well enhancing antioxidant defenses and BDNF content. PMID- 29111231 TI - ROS-AKT-mTOR axis mediates autophagy of human umbilical vein endothelial cells induced by cooking oil fumes-derived fine particulate matters in vitro. AB - Cooking oil fumes-derived PM2.5 (COFs-derived PM2.5) exposure can induce oxidative stress and cytotoxic effects. Here we investigated the role of ROS-AKT mTOR axis in COFs-derived PM2.5-induced autophagy in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with different concentrations of COFs-derived PM2.5, together with or without N-acetyl-L-cysteine (NAC, a radical scavenger) or 3-methyladenine (3-MA, an autophagy inhibitor). Cell viability was assessed with MTT assay, and ROS level was measured with DCFH-DA assay after the treatment. Transmission electron microscopy (TEM) was used to evaluate the formation of autophagosomes, while immunofluorescent assay and western blot were used to assess the expression of LC3-I/II and beclin 1. Proteins involved in the PI3K-AKT-mTOR signaling pathway were measured with western blot. The results showed that the treatment of COFs-derived PM2.5 dose-dependently reduced the viability of HUVECs and increased the ROS levels in the cells. Both immunofluorescent assay and western blot showed that treatment with COFs-derived PM2.5 significantly increased LC3-II and beclin 1 levels, as well as the ratio of LC3-II/LC3-I, which could be rescued by the co-incubation with NAC or 3-MA. TEM also confirmed the increased formation of autophagosomes in the cells treated with COFs-derived PM2.5, while co-treatment with NAC evidently decreased autophagosomes formation. In addition, western blot also showed that the phosphorylation of PI3K, AKT, and mTOR all decreased by the treatment of COFs derived PM2.5, which was effectively rescued by the co-treatment with NAC. These findings demonstrate ROS-AKT-mTOR axis plays a critical role in HUVECs autophagy induced by COFs-derived PM2.5. PMID- 29111232 TI - Antagonism in effectiveness of evofosfamide and doxorubicin through intermolecular electron transfer. AB - Hypoxic cells pose a problem in anticancer chemotherapy, in which often drugs require oxygen as an electron acceptor to bring about the death of actively cycling cells. Bioreductive anticancer drugs, which are selectively activated in the hypoxic regions of tumours through enzymatic one-electron reduction, are being developed for combination with chemotherapy-, radiotherapy- and immunotherapy-containing regimens to kill treatment-resistant hypoxic cells. The most clinically-advanced bioreductive drug, evofosfamide (TH-302), which acts by releasing a DNA-crosslinking mustard, failed to extend overall survival in combination with doxorubicin, a topoisomerase II inhibitor, for advanced soft tissue sarcoma in a pivotal clinical trial. However, the reasons for the lack of additive efficacy with this combination are unknown. Here, we show that the radical anion of evofosfamide undergoes electron transfer to doxorubicin in kinetic competition to fragmentation of the radical anion, thus suppressing the release the cytotoxic mustard. This electron transfer process may account, at least in part, for the lack of overall survival improvement in the recent clinical trial. This study underlines the need to consider both redox and electron transfer chemistry when combining bioreductive prodrugs with other redox active drugs in cancer treatment. PMID- 29111233 TI - Age and immunity: What is "immunosenescence"? AB - As is apparent from the many contributions to this Special Issue of the Journal, the impact of age on immunity is nefarious, with all manner of dysregulated responses attributed to "immunosenescence". These range from poorer responses to vaccination, lower capacity to mediate anti-cancer responses, more inflammation and tissue damage, along with autoimmunity and loss of control of persistent infections. Given the grave clinical implications of altered immune status in aged people, it is of paramount importance to understand the nature of and mechanisms responsible for "immunosenescence". As in any rapidly developing research area, certain paradigms establish themselves early on, by necessity based on earlier and fewer data, and have a disproportionate influence on how investigators think about the subject, especially investigators from other disciplines. It may therefore be appropriate to reconsider our basic knowledge at this juncture, asking exactly what do we mean by the term "immunosenescence"? This is attempted in this contribution to the Special Issue. PMID- 29111234 TI - Exacerbation and Prolongation of Psoriasiform Inflammation in Diabetic Obese Mice: A Synergistic Role of CXCL5 and Endoplasmic Reticulum Stress. AB - Accumulating evidence suggests that psoriasis is frequently accompanied by metabolic disorders, such as obesity and diabetes. However, the mechanisms underlying the association between increased psoriasis severity and concomitant metabolic syndrome have not been fully clarified. Herein, we show that imiquimod induced psoriasiform inflammation was exacerbated and prolonged in diabetic obese mice compared to that in control mice, accompanied by remarkably increased lesional expressions of Cxcl5 and Il-1b. Notably, a large number of CXCL5+ Ly6G+ cells infiltrated the dermis and subcutaneous fat tissue of the diabetic obese mice. Most macrophages in the subcutaneous fat tissues of the diabetic obese mice were positive for expression of IL-1beta and GRP78/Bip, an endoplasmic reticulum stress marker. Depletion of Ly6G+ cells and macrophages diminished the imiquimod induced psoriasiform inflammation. Further, CXCL5 potentiated the secretion of IL 1beta from macrophages and palmitic acid, a fatty acid released from subcutaneous adipocytes, further enhanced IL-1beta secretion via endoplasmic reticulum stress induction. Combined with the fact that the serum levels of both CXCL5 and palmitic acid are significantly elevated in patients with metabolic syndrome, our results suggest a role for CXCL5 and endoplasmic reticulum stress in the increase of psoriasis severity of patients with concomitant metabolic syndrome. PMID- 29111235 TI - Genomic Stability in Syndromic Basal Cell Carcinoma. AB - Basal cell cancers (BCCs) are characterized by upregulation of Hedgehog pathway through loss of PTCH1 or activation of SMO, and SMO inhibitors, such as vismodegib, are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with basal cell nevus syndrome (BCNS) harbor germline defects in PTCH1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS BCCs are more responsive to SMO inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS BCCs have a significantly lower mutational load, lower proportion of UV mutagenesis, increased genomic stability, and harbor fewer functionally resistant SMO mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to SMO inhibitors. BCNS-BCCs appear to have reduced mutator phenotype compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy. PMID- 29111236 TI - Reprint of "Dual blockade of the pro-inflammatory chemokine CCL2 and the homeostatic chemokine CXCL12 is as effective as high dose cyclophosphamide in murine proliferative lupus nephritis". AB - Induction therapy of proliferative lupus nephritis still requires the use of unselective immunosuppressive drugs with significant toxicities. In search of more specific drugs with equal efficacy but fewer side effects we considered blocking pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP 1/CCL2) and homeostatic chemokine stromal cell-derived factor-1 (SDF-1/CXCL12), which both contribute to the onset and progression of proliferative lupus nephritis yet through different mechanisms. We hypothesized that dual antagonism could be as potent on lupus nephritis as the unselective immunosuppressant cyclophosphamide (CYC). We estimated serum levels of CCL2 and CXCL12 in patients with SLE (n=99) and compared the results with healthy individuals (n=21). In order to prove our hypothesis we used l-enantiomeric RNA Spiegelmer(r) chemokine antagonists, i.e. the CCL2-specific mNOX-E36 and the CXCL12-specific NOX-A12 to treat female MRL/lpr mice from week 12 to 20 of age with either anti-CXCL12 or anti-CCL2 alone or both. SLE patients showed elevated serum levels of CCL2 but not of CXCL12. Female MRL/lpr mice treated with dual blockade showed significantly more effective than either monotherapy in preventing proteinuria, immune complex glomerulonephritis, and renal excretory failure and the results are at par with CYC treatment. Dual blockade reduced leukocyte counts and renal IL-6, IL-12p40, CCL-5, CCL-2 and CCR-2 mRNA expression. Dual blockade of CCL2 and CXCL12 can be as potent as CYC to suppress the progression of proliferative lupus nephritis probably because the respective chemokine targets mediate different disease pathomechanisms, i.e. systemic autoimmunity and peripheral tissue inflammation. PMID- 29111237 TI - Imaging findings of primary hepatic angiosarcoma on gadoxetate disodium-enhanced liver MRI: comparison with hepatic haemangiomas of similar size. AB - AIM: To describe imaging characteristics of primary hepatic angiosarcoma on gadoxetate disodium-enhanced dynamic magnetic resonance imaging (MRI) and to determine features that differentiate angiosarcomas from similar-sized haemangiomas. MATERIALS AND METHODS: The study included 15 patients with hepatic angiosarcomas and 35 patients with size-matched hepatic haemangiomas who underwent gadoxetate disodium-enhanced liver MRI. The number, size, growth pattern, signal intensity (SI) characteristics, and SI changes on dynamic scans were evaluated and compared between the two entities. RESULTS: Overall, hepatic angiosarcomas significantly more often showed lesion multiplicity (86.7%), capsular retraction (40%), prominent intratumoural vessels (66.7%), vascular invasion (20%), heterogeneous SI on T2-weighted (100%) and hepatobiliary phase images (80%), and intralesional haemorrhage (60%, all p<0.05). On dynamic scans, angiosarcomas demonstrated enhancing foci of irregular or rim-like nodular/linear or bizarre (86.7%) shapes, with centrifugal or bizarre patterns of progressive enhancement (53.3%). Enhancement of angiosarcomas was less than that of the blood pool on visual grading, but the enhancement curves followed that of the aorta. Regardless of size, angiosarcomas showed heterogeneous T2 SI, intratumoural haemorrhage, and heterogeneity during the hepatobiliary phase, whereas these findings were more common in haemangiomas >6 cm in diameter. CONCLUSION: Gadoxetate disodium-enhanced dynamic liver MRI is capable of depicting vascular hallmarks of hepatic angiosarcomas. Heterogeneous SI on T2-weighted and hepatobiliary phase images, multiplicity, and an enhancement curve following that of the aorta are also distinctive features that differentiate angiosarcomas from haemangiomas. PMID- 29111238 TI - Elastosonography and two-dimensional ultrasonography in diagnosis of axillary lymph node metastasis in breast cancer. AB - AIM: To compare diagnostic value of two-dimensional (2D) ultrasonography and elastosonography for suspected axillary lymph node metastasis of breast cancer. MATERIALS AND METHODS: Elastosonography and 2D ultrasonography were performed on 78 axillary lymph nodes of 78 patients with suspected breast cancer. Scores of shape, long- to short-axis ratio, cortical thickness, and lymph node hilum were summed as the score of each lymph node at 2D ultrasonography, while a four-point scale was adopted for elasticity scoring. The combined score of each lymph node was obtained by summing the score at 2D ultrasonography and that at elasticity scoring. The strain ratio was calculated by comparison of the average strain of the lymph node with that of the subcutaneous tissue. Diagnostic efficacies of 2D ultrasonography, elasticity scoring, and the combined method were compared. RESULTS: There were 78 axillary lymph nodes, including 34 non-metastatic and 44 metastatic nodes. The elasticity scores of non-metastatic and metastatic axillary lymph nodes were 1.44+/-0.82 and 3.11+/-0.75, respectively (p<0.05). The difference in area under the operating characteristic curve (AUC) was statistically significant between 2D ultrasonography and the combined method (p<0.05). The sensitivity, specificity, and accuracy of 2D ultrasonography and elasticity scoring were 77.3% versus 86.4%, 76.5% versus 85.3%, and 76.9% versus 85.9%, respectively (all p>0.05), and those of the combined method were 93.2%, 73.5%, and 84.6%, respectively. There was a significant difference in sensitivity between 2D ultrasonography and the combined method (p<0.05). CONCLUSIONS: Combined application of 2D ultrasonography with elastosonography can improve the diagnostic capability for metastatic axillary lymph node characterisation in breast cancer. PMID- 29111239 TI - CTPA protocol optimisation audit: challenges of dose reduction with maintained image quality. AB - AIM: To assess computed tomography (CT) pulmonary angiography (CTPA) dose and image quality in a large teaching hospital, and subsequently, to optimise the protocol in order to reduce the dose without affecting image quality. MATERIALS AND METHODS: Dose-length product (DLP), patient size, and objective quality parameters (contrast-to-noise ratio and signal-to-noise ratio on standardised levels) were recorded from 31 patients undergoing CTPA, where also a subjective image quality evaluation was carried out independently by three specialist cardiothoracic consultant radiologists. An equivalent objective and subjective quality assessment was carried out on a cohort of the same size in a different tertiary healthcare centre. Moreover, experimental tests using anthropomorphic chest phantoms were performed, using different scan parameters. In light of the above analysis, two of the scanner settings for CTPA were modified, i.e., the SureExposure pre-set was changed to "Standard" noise level, quantified with standard deviation (SD) of 19, and the minimum amperage setting lowered from 80 to 40 mA. A second cohort of patients using this new protocol was audited, following the same methodology. RESULTS: The average DLP of patients undergoing CTPA was initially found to be higher than both local and national dose reference levels (DRLs; 559 versus 300 mGy.cm and 400 mGy.cm, respectively). The new protocol led to a reduction in average DLP (359 mGy.cm) while the image quality, assessed by three cardiothoracic consultant radiologists, was preserved. CONCLUSION: The CTPA protocol was implemented in the Royal Infirmary of Edinburgh resulting in significant dose reduction, and is now compliant with national and local DRLs. The image quality was maintained. PMID- 29111240 TI - Unilateral rhinorrhoea: An atypical aetiology. PMID- 29111241 TI - Trace metal(loid) mobility in waste deposits and soils around Chadak mining area, Uzbekistan. AB - The assessment of potential trace metal(loid) contamination in tailing dumps and soils was characterized in the Chadak mining area (Uzbekistan). Concentrations of trace elements (V, Cr, Co, Ni, Cu, Zn, As, Cd, Sb, Pb) were determined by X-ray fluorescence analysis and compared with background and intervention values (IV). The concentrations of As, Zn, Sb, and Pb were higher in the abandoned than in the active tailing dump, ranging from 42-1689mg/kg for As, 73-332mg/kg for Zn, 14 1507mg/kg for Sb, and 27-386mg/kg for Pb. Selective extractions were applied in order to assess the mobility and availability of trace metal(loid)s in samples. Oxyanion-forming elements such as As and Sb were immobilized by Fe oxides, although to some extent also extractable with acetic acid and soluble-in-water forms were detected, indicating potential bioavailability that can impose a potential toxicity risk for the environment. Selective extractions data also showed that Zn and Pb were relatively immobile, although in higher contamination sites significant amounts of these elements were also extractable with acetic acid. In tailing materials Zn and Pb mobility were negatively correlated by the cation-exchange capacity (CEC) and clay content, indicating the importance of these factors in the reduction of the potential toxicity for these elements. Total concentration of As, Sb, and Pb were also negatively correlated with soil pH, indicating that the oxidation process of sulphide tailings and thus the generation of acidic conditions may lead to release of contaminants over time. However, due to the calcium carbonate content, the acid neutralization capacity of the tailings is not yet exhausted and contaminant concentrations in soil-pore water are still relatively low. The results of our investigation suggest that environmental risk associated with these wastes in semi-arid climate is therefore not a short-term problem but rather requires constant monitoring and additional ecotoxicological studies. PMID- 29111242 TI - Effect of field site hydrogeochemical conditions on the corrosion of milled zerovalent iron particles and their dechlorination efficiency. AB - Milled zerovalent iron (milled ZVI) particles have been recognized as a promising agent for groundwater remediation because of (1) their high reactivity with chlorinated aliphatic hydrocarbons, organochlorine pesticides, organic dyes, and a number of inorganic contaminants, and (2) a possible greater persistance than the more extensively investigated nanoscale zerovalent iron. We have used laboratory-scale batch degradation experiments to investigate the effect that hydrogeochemical conditions have on the corrosion of milled ZVI and on its ability to degrade trichloroethene (TCE). The observed pseudo first-order degradation rate constants indicated that the degradation of TCE by milled ZVI is affected by groundwater chemistry. The apparent corrosion rates of milled ZVI particles were of the same order of magnitude for hydrogeochemical conditions representative for two contaminated field sites (133-140mmolkg-1day-1, indicating a milled ZVI life-time of 128-135days). Sulfate enhances milled ZVI reactivity by removing passivating iron oxides and hydroxides from the Fe0 surface, thus increasing the number of reactive sites available. The organic matter content of 1.69% in the aquifer material tends to suppress the formation of iron corrosion precipitates. Results from scanning electron microscopy, X-ray diffraction, and iron K-edge X-ray adsorption spectroscopy suggest that the corrosion mechanisms involve the partial dissolution of particles followed by the formation and surface precipitation of magnetite and/or maghemite. Numerical corrosion modeling revealed that fitting iron corrosion rates and hydrogen inhibitory terms to hydrogen and pH measurements in batch reactors can reduce the life-time of milled ZVI particles by a factor of 1.2 to 1.7. PMID- 29111243 TI - Spatiotemporal scales of river-groundwater interaction - The role of local interaction processes and regional groundwater regimes. AB - Drinking water production in the vicinity of rivers not only requires the consideration of different spatiotemporal scales and settings of river groundwater interaction processes, but also of local and regional scale groundwater regimes. Selected case studies in combination with field-experiments and the setup of high-resolution groundwater flow models enabled the investigation of the spatiotemporal development of microbial (classical fecal indicator bacteria and total cell counts) and selected organic micropollutants in riverine and regional groundwater for different hydrological settings, including low and high flow conditions. Proxy indicators suitable as surrogates for the diverse contaminations in alluvial aquifers with different settings could be identified. Based on the study results, the basic elements for both groundwater management and river restoration concepts are derived, which include the: (1) compilation and evaluation of the "current state" concerning hydrogeology, microbiology and contamination by organic micropollutants, (2) definition of field-experiments to qualitatively assess variability related to the "current state", and (3) quantitative assessment of groundwater regimes, including variability of groundwater components and inflow areas, by application of high resolution groundwater flow models. The validity and transferability of the concept and inferred controls (specifically drivers and controls of river groundwater interaction) are tested by evaluations derived from hydraulic relationships to river sections with comparable settings and regional groundwater flow regimes in general. The results of our investigations illustrate the influence of dynamic hydrologic boundary conditions on river-groundwater interaction and of regional scale groundwater flow regimes on the water composition of riverine groundwater systems. It is demonstrated how to identify river sections and their variations with intensified river-groundwater exchange processes and how to quantify the transient character of the different groundwater components that constitute the raw water quality of drinking water wells near rivers. PMID- 29111244 TI - Can conservation tillage reduce N2O emissions on cropland transitioning to organic vegetable production? AB - Nitrous oxide (N2O) is an important greenhouse gas and a catalyst of stratospheric ozone decay. Agricultural soils are the source of 75% of anthropogenic N2O emissions globally. Recently, significant attention has been directed at examining effects of conservation tillage on carbon sequestration in agricultural systems. However, limited knowledge is available regarding how these practices impact N2O emissions, especially for organic vegetable production systems. In this context, a three-year study was conducted in a well-drained sandy loam field transitioning to organic vegetable production in the Mid Atlantic coastal plain of USA to investigate impacts of conservation tillage [strip till (ST) and no-till (NT)] and conventional tillage (CT) [with black plastic mulch (CT-BP) and bare-ground (CT-BG)] on N2O emissions. Each year, a winter cover crop mixture (forage radish: Raphanus sativus var. longipinnatus, crimson clover: Trifolium incarnatum L., and rye: Secale cereale L.) was grown and flail-mowed in the spring. Nearly 80% of annual N2O-nitrogen (N) emissions occurred during the vegetable growing season for all treatments. Annual N2O-N emissions were greater in CT-BP than in ST and NT, and greater in CT-BG than in NT, but not different between CT-BG and CT-BP, ST and NT, or CT-BG and ST. Conventional tillage promoted N mineralization and plastic mulch increased soil temperature, which contributed to greater N2O-N fluxes. Though water filled porosity in NT was higher and correlated well with N2O-N fluxes, annual N2O-N emissions were lowest in NT suggesting a lack of substrates for nitrification and denitrification processes. Crop yield was lowest in NT in Year 1 and CT-BP in Year 3 but yield-scaled N2O-N emissions were consistently greatest in CT-BP and lowest in NT each year. Our results suggest that for coarse-textured soils in the coastal plain with winter cover crops, conservation tillage practices may reduce N2O emissions in organic vegetable production systems. PMID- 29111245 TI - Environmental performance of straw-based pulp making: A life cycle perspective. AB - Agricultural straw-based pulp making plays a vital role in pulp and paper industry, especially in forest deficient countries such as China. However, the environmental performance of straw-based pulp has scarcely been studied. A life cycle assessment on wheat straw-based pulp making in China was conducted to fill of the gaps in comprehensive environmental assessments of agricultural straw based pulp making. On average, the global warming potential (GWP), GWP excluding biogenic carbon, acidification potential and eutrophication potential of wheat straw based pulp making are 2299kg CO2-eq, 4550kg CO2-eq, 16.43kg SO2-eq and 2.56kg Phosphate-eq respectively. The dominant factors contributing to environmental impacts are coal consumption, electricity consumption, and chemical (NaOH, ClO2) input. Chemical input decrease and energy recovery increase reduce the total environmental impacts dramatically. Compared with wood-based and recycled pulp making, wheat straw-based pulp making has higher environmental impacts, which are mainly due to higher energy and chemical requirements. However, the environmental impacts of wheat straw-based pulp making are lower than hemp and flax based pulp making from previous studies. It is also noteworthy that biogenic carbon emission is significant in bio industries. If carbon sequestration is taken into account in pulp making industry, wheat straw-based pulp making is a net emitter rather than a net absorber of carbon dioxide. Since wheat straw-based pulp making provides an alternative for agricultural residue management, its evaluation framework should be expanded to further reveal its environmental benefits. PMID- 29111247 TI - Effects of a behavior change campaign on household drinking water disinfection in the Lake Chad basin using the RANAS approach. AB - Worldwide, an estimated 700 million people rely on unimproved drinking water sources; even more consume water that is not safe to drink. Inadequate drinking water quality constitutes a major risk factor for cholera and other diarrheal diseases around the globe, especially for young children in developing countries. Household water treatment and safe storage systems represent an intermediate solution for settings that lack infrastructure supplying safe drinking water. However, the correct and consistent usage of such treatment technologies rely almost exclusively on the consumer's behavior. This study targeted at evaluating effects of a behavior change campaign promoting the uptake of household drinking water chlorination in communities along the Chari and Logone rivers in Chad. The campaign was based on formative research using health psychological theory and targeted several behavioral factors identified as relevant. A total of 220 primary caregivers were interviewed concerning their household water treatment practices and mindset related to water treatment six months after the campaign. The Risks, Attitudes, Norms, Abilities, and Self-regulation (RANAS) model was used to structure the interviews as the RANAS approach had been used for designing the campaign. Results show significantly higher self-reported drinking water chlorination among participants of the intervention. Significant differences from a control group were identified regarding several behavioral factors. Mediation analysis revealed that the intervention positively affected participants' individual risk estimation for diarrheal disease, health knowledge, perceived efforts and benefits of water treatment, social support strategies, knowledge of how to perform chlorination, and perceived ability to do so. The campaign's effect on water treatment was mainly mediated through differences in health knowledge, changes in norms, and self-efficacy convictions. The findings imply that water treatment behavior can be successfully promoted using health psychological theory. However, they also indicate opportunities for improvement in the campaign design and implementation. PMID- 29111246 TI - Successful control of internal phosphorus loading after sediment dredging for 6years: A field assessment using high-resolution sampling techniques. AB - The effectiveness of sediment dredging for the control of internal phosphorus (P) loading, was investigated seasonally in the eutrophic Lake Taihu. The high resolution dialysis (HR-Peeper) and diffusive gradients in thin films (DGT) techniques were used to measure the concentrations of soluble Fe(II) and soluble reactive P (SRP) as well as DGT-labile Fe/P in the non-dredging and post-dredging sediments. The P resupply kinetics from sediment solids were interpreted using DGT Induced Fluxes in Sediments (DIFS) modeling. The results showed no obvious improvement in water and sediment quality after dredging for 6years, due to their geographical proximity (a line distance of approximately 9km). However, dredging significantly decreased the concentrations of soluble Fe(II)/SRP and DGT-labile Fe/P in sediments, with effects varying at different depths below the sediment water interface; More pronounced effects appeared in January and April. The diffusive flux of pore water SRP from sediments decreased from 0.746, 4.08 and 0.353mg/m2/d to 0.174, 1.58 and 0.048mg/m2/d in April, July and January, respectively. DIFS modeling indicated that the P retention capability of sediment solids was improved in April in post-dredging site. Positive correlations between pore water soluble Fe(II) and SRP as well as between DGT-labile Fe and P, reflect the key role of Fe redox cycling in regulating dredging effectiveness. This effect is especially important in winter and spring, while in summer and autumn, the decomposition of algae promoted the release of P from sediments and suppressed dredging effectiveness. Overall, the high-resolution HR-Peeper and DGT measurements indicated a successful control of internal P loading by dredging, and the post-dredging effectiveness was suppressed by algal bloom. PMID- 29111248 TI - Bivariate analysis of floods in climate impact assessments. AB - Climate impact studies regarding floods usually focus on peak discharges and a bivariate assessment of peak discharges and hydrograph volumes is not commonly included. A joint consideration of peak discharges and hydrograph volumes, however, is crucial when assessing flood risks for current and future climate conditions. Here, we present a methodology to develop synthetic design hydrographs for future climate conditions that jointly consider peak discharges and hydrograph volumes. First, change factors are derived based on a regional climate model and are applied to observed precipitation and temperature time series. Second, the modified time series are fed into a calibrated hydrological model to simulate runoff time series for future conditions. Third, these time series are used to construct synthetic design hydrographs. The bivariate flood frequency analysis used in the construction of synthetic design hydrographs takes into account the dependence between peak discharges and hydrograph volumes, and represents the shape of the hydrograph. The latter is modeled using a probability density function while the dependence between the design variables peak discharge and hydrograph volume is modeled using a copula. We applied this approach to a set of eight mountainous catchments in Switzerland to construct catchment specific and season-specific design hydrographs for a control and three scenario climates. Our work demonstrates that projected climate changes have an impact not only on peak discharges but also on hydrograph volumes and on hydrograph shapes both at an annual and at a seasonal scale. These changes are not necessarily proportional which implies that climate impact assessments on future floods should consider more flood characteristics than just flood peaks. PMID- 29111249 TI - Fire severity is more sensitive to low fuel moisture content on Calluna heathlands than on peat bogs. AB - Moorland habitats dominated by the dwarf shrub Calluna vulgaris provide important ecosystem services. Drought is projected to intensify throughout their range, potentially leading to increased fire severity as moisture is a key control on severity. We studied the effect of low fuel moisture content (FMC) on fire severity by using 2*2m rain-out shelters prior to completing 19 experimental fires in two sites in Scotland (UK): a dry heath with thin organic soils and a raised bog with deep, saturated peat, both dominated by Calluna vulgaris. Reduced FMC of the moss and litter (M/L) layer at both sites, and the soil moisture of the dry heath, increased fire-induced consumption of the M/L layer and soil heating at both sites. Increase in fire severity was greater at the dry heath than at the raised bog, e.g. average maximum temperatures at the soil surface increased from 31 degrees C to 189 degrees C at the dry heath, but only from 10 degrees C to 15 degrees C at the raised bog. Substantial M/L layer consumption was observed when its FMC was below 150%. This led to larger seasonal and daily soil temperature fluctuation, particularly at the dry heath during warm months. The results suggest that low FMC following predicted changes in climate are likely to increase wildfire severity and that the impact on vegetation composition and carbon stores may be greater at heathlands than at peatlands. Managed burning aiming to minimise fire severity (e.g. ignition of the M/L layer and exposure to lethal temperatures of ericoid seeds) should be carried out when the FMC of the M/L layer is above 150% and the FMC of the soil is above 200-300%. PMID- 29111250 TI - River sediment quality assessment using sediment quality indices for the Sydney basin, Australia affected by coal and coal seam gas mining. AB - Coal mining activities in the Sydney basin have been historically associated with significant environmental impacts. The region is facing more recent coal seam gas extraction activities and the synergetic environmental impacts of the new mining activities are still largely unknown. The aim of this study was to provide environmental assessment of river sediments comparing upstream to downstream areas relative to industrial-discharge sites associated with coal and coal-seam gas extraction within the Sydney basin. Various contaminants were measured to determine the sediment quality according to the Australian and New Zealand Environment and Conservation Council (ANZECC) guidelines. Arsenic, nickel and zinc were the main sediment contaminants in downstream samples exceeding the ANZECC guidelines. Degree of contamination (Cd), geoaccumulation index (Igeo), enrichment factor (EF), pollution load index (PLI) and sediment environmental toxicity quotients' increment in downstream sediment were estimated for the studied areas. Toxicology indices of metals present in the sediments near industrial discharge sites were used as an additional tool to compare the level of environmental effects with their increment. The study revealed that the sediments from coal mining sites were highly affected by increased concentrations of manganese, zinc, cobalt, nickel and barium. The sediments associated with coal mining activities were found to be substantially more affected than the sediments near coal seam gas production sites, mainly attributed to the different wastewater discharge licencing requirements. The approach applied in this study can be used as an additional model to assess the contribution of industrial and mining activities on aquatic environments. PMID- 29111251 TI - Deep sea habitats in the chemical warfare dumping areas of the Baltic Sea. AB - The Baltic Sea is a severely disturbed marine ecosystem that has previously been used as a dumping ground for Chemical Warfare Agents (CW). The presence of unexploded underwater ordnance is an additional risk factor for offshore activities and an environmental risk for the natural resources of the sea. In this paper, the focus is on descriptions of the marine habitat based on the observations arising from studies linked to the CHEMSEA, MODUM and DAIMON projects. Investigated areas of Bornholm, Gotland and Gdansk Deeps are similarly affected by the Baltic Sea eutrophication, however, at depths greater than 70m several differences in local hydrological regimes and pore-water heavy metal concentrations between those basins were observed. During the lifespan of presented studies, we were able to observe the effects of Major Baltic Inflow, that started in December 2014, on local biota and their habitats, especially in the Bornholm Deep area. Reappearance of several meiofauna taxa and one macrofauna specimen was observed approximately one year after this phenomenon, however it's ecological effects already disappeared in March 2017. According to our findings and to the EUNIS Habitat Classification, the three reviewed areas should be characterized as Deep Sea Muddy Sands, while the presence of suspicious bomb-like objects both beneath and on top of the sediments confirms their CW dumpsite status. PMID- 29111252 TI - Organic matter control on the distribution of arsenic in lake sediments impacted by ~65years of gold ore processing in subarctic Canada. AB - Climate change is profoundly affecting seasonality, biological productivity, and hydrology in high northern latitudes. In sensitive subarctic environments exploitation of mineral resources led to contamination and it is not known how cumulative effects of resource extraction and climate warming will impact ecosystems. Gold mines near Yellowknife, Northwest Territories, subarctic Canada, operated from 1938 to 2004 and released >20,000t of arsenic trioxide (As2O3) to the environment through stack emissions. This release resulted in elevated arsenic concentrations in lake surface waters and sediments relative to Canadian drinking water standards and guidelines for the protection of aquatic life. A meta-analytical approach is used to better understand controls on As distribution in lake sediments within a 30-km radius of historic mineral processing activities. Arsenic concentrations in the near-surface sediments range from 5mg.kg-1 to over 10,000mg.kg-1 (median 81mg.kg-1; n=105). Distance and direction from the historic roaster stack are significantly (p<0.05) related to sedimentary As concentration, with highest As concentrations in sediments within 11km and lakes located downwind. Synchrotron-based MUXRF and MUXRD confirm the persistence of As2O3 in near surface sediments of two lakes. Labile organic matter (S1) is significantly (p<0.05) related to As and S concentrations in sediments and this relationship is greatest in lakes within 11km from the mine. These relations are interpreted to reflect labile organic matter acting as a substrate for microbial growth and mediation of authigenic precipitation of As-sulphides in lakes close to the historic mine where As concentrations are highest. Continued climate warming is expected to lead to increased biological productivity and changes in organic geochemistry of lake sediments that are likely to play an important role in the mobility and fate of As in aquatic ecosystems. PMID- 29111253 TI - Developing strategies to reduce spray drift in pneumatic spraying in vineyards: Assessment of the parameters affecting droplet size in pneumatic spraying. AB - Pneumatic sprayers are widely used in vineyards due to their very fine droplet size, which makes the drift risk to become an important problem to be considered. The aim of this study was to assess the effect of the spout diameter at the release point on the spray droplet size and uniformity achieved for different liquid flow rates (LFR) and air flow rates (AFR). A test bench was developed to simulate a real pneumatic sprayer under laboratory conditions, and it was empirically adjusted to match the air pressure conditions as closely as possible to real working conditions. Two positions of insertion of the liquid hose, the conventional position (CP) and an alternative position (AP), were tested for three LFRs, 1.00, 1.64, and 2.67Lmin-1, and four AFRs, 0.280, 0.312, 0.345, and 0.376m3s-1. The air speed decrease between the two insertion points of the liquid hose was measured. A Malvern SprayTec(r) instrument was used to measure the droplet size, and the D50, D10, and D90 parameter values were obtained. The relative SPAN factor (RSF) was also calculated. A model to predict variations in D50 was fitted using the aforementioned parameters. The results show that variations in the diameter of the spout significantly change the droplet size, producing a mean increase of 59.45% in D50 and similar increases in D10 and D90. The model developed to predict variations in D50 has a very high degree of accuracy (R2=0.945). The relative decrease in the air speed along the spout did not present significant differences for the different airflow rates tested. The results of the study show that the droplet size produced in pneumatic spraying can be modified easily by varying the air spout dimensions. This should be taken into account by manufacturers from a design point of view. PMID- 29111254 TI - Metal pollution investigation of Goldman Park, Middletown Ohio: Evidence for steel and coal pollution in a high child use setting. AB - A geochemical investigation of both ballfield sediment and street sediment in a park adjacent to a major steel manufacturing site in Middletown, Ohio revealed Pb, Cu, Cr and Zn exceeded background levels, but in heterogeneous ways and in varying levels of health concern. Pb, Sn, and Zn had geoaccumulation values>2 (moderate to heavy pollutants) in street sediment samples. Cr had a geoaccumulation value>1, while Ni, W, Fe and Mn had geoaccumulation values between 1 and 0 in street sediment. Street sediment contamination factors for respective elements are Zn (10.41), Sn (5.45), Pb (4.70), Sb (3.45), Cr (3.19), W (2.59), and Mn (2.43). The notable elements with the highest factors for ball fields are Zn (1.72), Pb (1.36), Cr (0.99), V (0.95), and Mn (1.00). High correlation coefficients of known constituents of steel, such as Fe and Mo, Ni and Cr, W and Co, W and V, as well as particulate steel and coal spherule fragments found by SEM suggest probable sourcing of some of the metals from the AK Steel facility directly adjacent to the park. However, overall extensive heterogeneity of metal pollutants in the area points to the difficulties in sourcing pollutant metals, with many outside sources likely contributing as well. This study demonstrates that different sediment media can be impacted by significantly different metal pollutants even when in very close proximity to a single source and points to unrecognized complexity in urban pollution processes in the region. This study pertains to large-scale regional importance, as Middletown, Ohio is indicative of a typical post-industrial Midwestern U.S. city where limited investigation has been conducted regarding urban pollution and sourcing of materials. PMID- 29111255 TI - Comment on "Mortality effects assessment of ambient PM2.5 pollution in the 74 leading cities of China" by Die Fang, Qin'geng Wang, Huiming Li, Yiyong Yu, Yan Lu, Xin Qian. AB - In a recent publication in the journal Science of the Total Environment, Die Fang et al. (2016) reported health effects of current ambient PM2.5 (particulate matters with aerodynamic diameters <2.5MUm) pollution in 74 leading cities in China. It is a meaningful original study using the latest air quality surveillance data. However, we suppose their results may over-estimate the long term exposure-response coefficients for per 10MUg/m3 increase in PM2.5 concentration. Moreover, we have concern about the linear relationship the authors assumed for long-term exposure to PM2.5 and the health outcomes. We also have concern about the sufficiency of confounder adjustment. Our suggestions are mainly based on our previous research experience and previous literature. We believe that the debate is conducive to a more accurate and more reasonable estimation of the health effects of PM2.5. PMID- 29111256 TI - Carbon biogeochemical cycle is enhanced by damming in a karst river. AB - Currently, there is a lack of systematic knowledge concerning carbon (C) biogeochemical cycles in impounded rivers. In this study, we investigated different C species and related environmental factors from July 2007 to June 2008 and from May 2011 to May 2012 in the impounded Wujiang River, SW China to understand the influence of dam construction on the riverine C cycle. The results showed that average concentrations of dissolved CO2, dissolved inorganic C (DIC), dissolved organic C, and particulate organic C (POC) were 81.73MUmol/L, 2283.55MUmol/L, 158.11MUmol/L, and 37.54MUmol/L, respectively. Meanwhile, delta13CDIC ranged from -10.070/00 to -4.920/00 with an average of -8.330/00, while delta13CPOC ranged from -35.300/00 to -22.280/00 with an average of 29.200/00. Thermal and chemical stratifications developed seasonally and exerted a significant influence on the C cycle of the released water. The C species and related delta13C showed remarkable heterogeneity in time and space. Evidence from delta13C demonstrated that the C system in this river was primarily influenced by carbonate weathering, whereas in the reservoir, it was primarily controlled by algal activity. The coefficients of variance for different C species in the reservoir and released water were higher than those in the river. Our study indicated that biological activity became a key controlling factor for the C biogeochemical cycle and accelerated it after damming, especially in the warm seasons. The results of this study have important implications for understanding the C cycle in elongated and deep reservoirs. PMID- 29111257 TI - A catchment-scale model to predict spatial and temporal burden of E. coli on pasture from grazing livestock. AB - Effective management of diffuse microbial water pollution from agriculture requires a fundamental understanding of how spatial patterns of microbial pollutants, e.g. E. coli, vary over time at the landscape scale. The aim of this study was to apply the Visualising Pathogen &Environmental Risk (ViPER) model, developed to predict E. coli burden on agricultural land, in a spatially distributed manner to two contrasting catchments in order to map and understand changes in E. coli burden contributed to land from grazing livestock. The model was applied to the River Ayr and Lunan Water catchments, with significant correlations observed between area of improved grassland and the maximum total E. coli per 1km2 grid cell (Ayr: r=0.57; p<0.001, Lunan: r=0.32; p<0.001). There was a significant difference in the predicted maximum E. coli burden between seasons in both catchments, with summer and autumn predicted to accrue higher E. coli contributions relative to spring and winter (P<0.001), driven largely by livestock presence. The ViPER model thus describes, at the landscape scale, spatial nuances in the vulnerability of E. coli loading to land as driven by stocking density and livestock grazing regimes. Resulting risk maps therefore provide the underpinning evidence to inform spatially-targeted decision-making with respect to managing sources of E. coli in agricultural environments. PMID- 29111258 TI - Effectiveness of mechanical thinning and prescribed burning on fire behavior in Pinus nigra forests in NE Spain. AB - Fuel treatments can mitigate present and future impacts of climate change by reducing fire intensity and severity. In recent years, Pinus nigra forests in the Mediterranean basin have been dramatically affected by the new risk of highly intense and extreme fires and its distribution area has been reduced. New tools are necessary for assessing the management of these forests so they can adapt to the challenges to come. Our main goal was to evaluate the effects of different fuel treatments on Mediterranean Pinus nigra forests. We assessed the forest response, in terms of forest structure and fire behavior, to different intensities of low thinning treatments followed by different slash prescriptions (resulting in: light thinning and lop and scatter; light thinning and burn; heavy thinning and lop and scatter; heavy thinning and burn; and, untreated control). Treatments that used fire to decrease the resulting slash were the most effective for reducing active crown fires decreasing the rate of spread and flame length more than 89%. Low thinning had an effect on torching potential, but there was no difference between intensities of thinning. Only an outcoming crown fire could spread actively if it was sustained by a high-enough constant wind speed and enough surface fuel load. Overall, treatments reduce fire intensity and treated areas have a more homogenous fire behavior response than untreated areas. This provides opportunities to extinguish the fire and reduce the probability of trees dying from the fire. It would be helpful to include ecological principles and fire behavior criteria in silvicultural treatment guidelines in order to perform more efficient management techniques in the future. PMID- 29111259 TI - Cancer incidence and mortality among young adults aged 20-39 years worldwide in 2012: a population-based study. AB - BACKGROUND: To date, the burden of cancer among young adults has rarely been studied in depth. Our aim was to describe the scale and profile of cancer incidence and mortality worldwide among 20-39 year-olds, highlighting major patterns by age, sex, development level, and geographical region. METHODS: We did a population-based study to quantify the burden of young adult cancers worldwide. We defined young adult cancers as those occurring between the ages of 20 and 39 years because these individuals will have passed puberty and adolescence, but not yet experienced the effects of hormonal decline, immune response deterioration, or organ dysfunction associated with chronic health conditions. Global, regional, and country-specific (n=184) data estimates of the number of new cancer cases and cancer-associated deaths that occurred in 2012 among young adults were extracted in four 5-year bands from the International Agency for Research on Cancer's GLOBOCAN 2012 for all cancers combined and for 27 major types as defined by the International Classification of Disease, tenth revision. We report the number of new cancer cases and cancer-associated deaths overall and by sex alongside corresponding age-standardised rates (ASR) per 100 000 people per year. We also present results using four levels of the Human Development Index (HDI; low [least developed], medium, high, and very high [most developed]), which is a composite indicator for socioeconomic development comprising life expectancy, education, and gross national income. FINDINGS: 975 396 new cancer cases and 358 392 cancer associated deaths occurred among young adults worldwide in 2012, which equated to an ASR of 43.3 new cancer cases per 100 000 people per year and 15.9 cancer associated deaths per 100 000 people per year. The burden was disproportionally greater among women and the most common cancer types overall in terms of new cases were female breast cancer, cervical cancer, thyroid cancer, leukaemia, and colorectal cancer; in terms of deaths, female breast cancer, liver cancer, leukaemia, and cervical cancer were the main contributors. When assessed by development level and geographical region, the cancer profile varied substantially; generally, the burden of infection-associated cancers was greater in regions under transition. Cancer incidence was elevated in very high-HDI regions compared with low-HDI regions (ASR 64.5 vs 46.2 cancer cases per 100 000 people per year); however, the mortality burden was 3 times higher in low-HDI regions (ASR 25.4 vs 9.2 cancer-associated deaths per 100 000 people per year), reflecting differences in cancer profiles and inferior outcomes. INTERPRETATION: The global cancer burden among 20-39 year-olds differs from that seen in younger or older ages and varies substantially by age, sex, development level, and geographical region. Although the cancer burden is lower in this age group than that observed in older ages, the societal and economic effects remain great given the major effects of premature morbidity and mortality. Targeted surveillance, prevention, and treatment are needed to reduce the cancer burden in this underserved age group. FUNDING: International Agency for Research on Cancer (IARC) and European Commission's FP-7 Marie Curie Actions-People-COFUND. PMID- 29111260 TI - Reducing the global cancer burden among young adults. PMID- 29111261 TI - Recommendations of the Spanish Society of Rheumatology on treatment and use of systemic biological and non-biological therapies in psoriatic arthritis. AB - OBJECTIVE: The main purpose of this recommendation statement is to provide clinicians with the best available evidence and the best opinion agreed upon by the panelists for a rational use of synthetic disease modifying antirheumatic drugs (DMARDs) and biologicals in psoriatic arthritis (PsA) patients. The present document also focuses on important aspects in the management of PsA, such as early diagnosis, therapeutic objectives, comorbidities and optimization of treatment. METHODS: The recommendations were agreed by consensus by a panel of 8 expert rheumatologists, previously selected by the Spanish Society of Rheumatology (SER) through an open call. The phases of the work were: identification of key areas for updating the previous consensus, analysis and synthesis of scientific evidence (modified Oxford system, Centre for Evidence based Medicine, 2009) and formulation of recommendations based on this evidence and by consensus techniques. RESULTS: Seventeen recommendations were issued for the treatment of PsA patients. Six of them were of general nature, ranging from the early diagnosis and treatment to the importance of assessing comorbidities. The other 11 were focused on the indications for DMARDs and biological therapy in the distinct clinical forms of the disease. Likewise, the situation of failure of the first biological is addressed and treatment algorithms and a table with the different biological therapies are also included. CONCLUSIONS: We present the update of SER recommendations for the treatment of PsA with DMARDs and biologics. PMID- 29111263 TI - A New Perspective of an Old Villain: Revisiting Biomarkers of Caries Development. PMID- 29111264 TI - Management of clinically relevant postpancreatectomy hemorrhage (PPH) over two decades - A comparative study of 1 450 consecutive patients undergoing pancreatic resection. AB - BACKGROUND/OBJECTIVES: PPH is the main cause of mortality (up to 50%) after pancreatic resection. Due to differences in time of onset, localization and clinical impairment, there is no consistent management algorithm. METHODS: Between 1994 and 2014 the occurrence of PPH in 115 out of 1 450 patients from a prospectively collected database was analyzed. The cohort was divided into two time periods: 1994-2009 and 2010-2014. The differences between the two groups were analyzed. RESULTS: The overall incidence of PPH was 7.9%. The main causes of hemorrhage were the pancreatic anastomosis (31.1%) and the splanchnic arteries (23.5%). In the first period, there were more anastomotic hemorrhages (40.0% vs. 20.4%, p = 0.02), while in the second period more hemorrhages from the splanchnic arteries occurred (12.3% vs. 37%, p = 0.002). Bleeding control was achieved by relaparotomy (45.7%), noninterventionally (22.8%), endoscopically (19.7%) and angiographically (13.4%). In the second period, the relevance of interventional angiography significantly increased (24.6% vs. 4.3%, p = 0.001), whereas endoscopy lost importance (7% vs. 30%, p = 0.001). The in-hospital case fatality rate after PPH was 27.4%, with higher case fatality rate following extraluminal hemorrhage (23.9% vs. 3.4%, p < 0.001). CONCLUSIONS: A shift in the management of PPH could be seen over the two periods. Interventional angiography has gained more importance in the treatment of severe extraluminal hemorrhage of the splanchnic arteries. Adequate treatment of PPH is crucial to improve the outcome. PMID- 29111262 TI - Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination. AB - Cell membrane thyroid hormone (TH) transport can be facilitated by the monocarboxylate transporter 8 (MCT8), encoded by the solute carrier family 16 member 2 (SLC16A2) gene. Human mutations of the gene, SLC16A2, result in the X linked-inherited psychomotor retardation and hypomyelination disorder, Allan Herndon-Dudley syndrome (AHDS). We posited that abrogating MCT8-dependent TH transport limits oligodendrogenesis and myelination. We show that human oligodendrocytes (OL), derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, express MCT8. Moreover, treatment of these cultures with DITPA (an MCT8-independent TH analog), up-regulates OL differentiation transcription factors and myelin gene expression. DITPA promotes hESC-derived OL myelination of retinal ganglion axons in co-culture. Pharmacological and genetic blockade of MCT8 induces significant OL apoptosis, impairing myelination. DITPA treatment limits OL apoptosis mediated by SLC16A2 down-regulation primarily signaling through AKT phosphorylation, driving myelination. Our results highlight the potential role of MCT8 in TH transport for human OL development and may implicate DITPA as a promising treatment for developmentally-regulated myelination in AHDS. PMID- 29111265 TI - Functional assignment for essential hypothetical proteins of Staphylococcus aureus N315. AB - Staphylococcus aureus, the causative agent of nosocomial infections worldwide, has acquired resistance to almost all antibiotics stressing the need to develop novel drugs against this pathogen. In S. aureus N315, 302 genes have been identified as essential genes, indispensable for growth and survival of the pathogen. The functions of 40 proteins encoded by S. aureus essential genes were found to be hypothetical and thus referred as essential hypothetical proteins (EHPs). The present study aims to carry out functional characterization of EHPs using bioinformatics tools/databases, whose performance was assessed by Receiver operating characteristic curve analysis. Evaluation of physicochemical parameters, homology search against known proteins, domain analysis, subcellular localization analysis and virulence prediction assisted us to characterize EHPs. Functional assignment for 35 EHPs was made with high confidence. They belong to different functional classes like enzymes, binding proteins, miscellaneous proteins, helicases, transporters and virulence factors. Around 35% of EHPs were from hydrolases family. A group of EHPs (32.5%) were predicted as virulence factors. Of 35, 19 essential pathogen-specific proteins were considered as probable drug targets. Two targets were found to be druggable and others were novel targets. Outcome of the study could aid to identify novel drugs for better treatment of S. aureus infections. PMID- 29111266 TI - Hepatoprotective and inhibiting HBV effects of polysaccharides from roots of Sophora flavescens. AB - Roots of Sophora flavescens is an important herbal medicine for treatment of HBV and hepatic carcinoma in China. Alkaloids in the root were well known for exhibiting good hepato-protective and anti-HBV effects. However, polysaccharides as main components in the root remained unknown. In the studies, we investigated the chemical features and hepatoprotective effects of Sophora flavescens polysaccharides (SFP-100 and its active fractions) with ConA-induced hepatitis mice, human liver LO2 cells and HepG2.2.15 cells. The results showed that SFP-100 was composed of arabinose, glucose, galactose and galacturonic acid, SFP-100-A mainly contained glucose. SFP-100-B and SFP-100-C were acidic polysaccharides. SFP-100 significantly decreased hepatocytes apoptosis, inhibited the infiltration of neutrophils and macrophages into liver, and improved the production of IFN gamma and IL-6 of splenocytes in ConA-induced hepatitis mice. SFP-100 and its two sugar fractions increased LO2 cell proliferation and reduced cell apoptosis induced by ConA. SFP-100, SFP-100-A and SFP-100-C remarkedly inhibited the secretion of HBsAg and HBeAg by HepG2.2.15 cells.These results suggested Sophora flavescens polysaccharides exerts significant hepatoprotective and anti-HBV roles, and further is used for treatment of immune-mediated liver disease in the future. PMID- 29111267 TI - Process optimization and in vivo performance of docetaxel loaded PHBV-TPGS therapeutic vesicles: A synergistic approach. AB - This research was motivated due to substantial requirement of improved treatment for breast cancer which accounts for over 0.52 million deaths annually worldwide. Utilizing nanoparticles carrying active medicaments as targeted delivery carrier is emerging as a promising approach. For a drug to be clinically effective, it needs to be suitably protected in the biological fluid till it is delivered to the targeted site. Keeping above in mind, we prepared and optimized polymeric nanoparticles by polyhydroxybutyrate-co-hydroxyvalerate (PHBV) a biodegradable polymer utilizing modified emulsification solvent evaporation method. The optimized formulation had particle size of 349+/-3.51nm with entrapment efficiency of 69+/-1.28%. Nanoparticle formation and its surface morphology were confirmed by various electron microscopes. The in vitro and pharmacokinetic studies demonstrated a sustained release of drug in a non-biological system and into rat's bloodstream respectively. Also, the in vitro cytotoxicity and in vivo toxicological evaluation at the therapeutic dose demonstrated the safety and antitumor efficacy of the formulation. Due to formulation characteristic properties, it was found to be effective in enveloping and chaperoning the drug to the suitable site of action. The PHBV-TPGS combination causes the drug to be released in controlled and sustained modes, thereby reducing drug dose and toxicity. PMID- 29111268 TI - Selective aminolysis of acetylated lignin: Toward simultaneously improving thermal-oxidative stability and maintaining mechanical properties of polypropylene. AB - Even with outstanding radical capturing ability, the utilization of lignin as a natural antioxidant in polypropylene (PP) still has been pended. Usually, the compatibility of its blends is improved based on the reaction of hydroxyl content, thus leading to the decreasing content of phenolic hydroxyl (Ph-OH) group and inferior thermal-oxidative stability of lignin blends. Here, the selective aminolysis of acetylated Kraft lignin (pyr-KL) was investigated, which structures were characterized using FTIR, 31P-NMR and GPC. The Ph-OH group of acetylated KL could be released by the addition of pyrrolidine; however the aliphatic hydroxyl group is still blocked. With the control of reaction conditions, the highest oxidation induction time of pyr-KL/PP (0.5wt% loading) reaches up to 22.6min, almost 2.6 times than that of pure PP. More importantly, the mechanical properties of PP were also maintained under the loading of pyr-KL, which is much better than that of curde KL/PP. PMID- 29111269 TI - Oxidation of C-reactive protein by hypochlorous acid leads to the formation of potent platelet activator. AB - We examined the structural and functional consequences of oxidative modification of C-reactive protein (CRP) by hypochlorous acid (HOCl), which can be generated in vivo via the myeloperoxidase/H2O2/Cl- system. HOCl exposure resulted in the oxidation and chlorination of CRP amino acid residues, leading to protein unfolding, greater surface hydrophobicity and the formation of aggregates. After treatment of isolated platelets with 50MUg/ml HOCl-CRP, the modified CRP significantly stimulated platelet activation (over 10-fold increase in the fraction of CD62-positive platelets compared to controls, P<0.008), enhanced deposition of platelets onto immobilized fibrinogen (two-fold rise in platelet adhesion compared to controls, P<0.0001), and induced platelet aggregation by up to 79.5%. The ability of HOCl-CRP to interact with several platelet receptors (TLR-4, GPIIbIIIa) and plasma proteins (C1q, IgG) strongly indicates that HOCl modification leads to structural changes of CRP resulting in the formation of new ligand binding sites, which is characteristic of the monomeric form of CRP exerting pro-inflammatory effects on a variety of cells. Overall, the oxidation of native CRP by HOCl seems to represent an alternative mechanism of CRP modification, by which CRP reveals its pro-inflammatory and pro-thrombotic properties, and as such, it might be of causal relevance in the pathogenesis of atherosclerosis. PMID- 29111270 TI - 4- Substituted sampangine derivatives: Novel acetylcholinesterase and beta-myloid aggregation inhibitors. AB - A series of 4- substituted sampangine derivatives (4-aminoalkylaminosampangine Ar NH(CH2)nNR1R2) has been designed, synthesized, and tested for their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-myloid (Abeta) aggregation. The synthetic compounds exhibited high AChE inhibitory activity and a significant in vitro inhibitory potency toward the self-induced Abeta aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human beta-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Abeta42 secretion levels. Moreover, most of the synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. The result encourages us to study this class of compounds thoroughly and systematically. PMID- 29111271 TI - Forensic characteristics and phylogenetic analysis of two Han populations from the southern coastal regions of China using 27 Y-STR loci. AB - Currently, the largest national database within the Y-STR Haplotype Reference Database (YHRD, https://yhrd.org, release 55) is China, which has a very large Y STR haplotype profiles. However, no haplotype data was available for Hainan province, the smallest and southernmost province of China. Herein, 280 unrelated male Chinese Han individuals residing in Hainan province were recruited and genotyped with 27 Y-STR loci. Moreover, 136 Han individuals from Shenzhen, the largest migrant city in China, also investigated. 279 distinct haplotypes were obtained in the Hainan Han individuals with the overall haplotype diversity (HD) and discrimination capacity (DC) were 0.999974 and 0.9964, respectively. 136 unique haplotypes were observed in the Shenzhen individuals, and thus both of the related HD and DC values were 1.0. The two multi-copy loci (DYS385a/b and DYF387S1a/b) and rapidly mutating Y-STRs (RM Y-STRs, DYS449, DYS518, DYS570, DYS576, DYS627) exhibited high genetic diversity (GD) values (GD>0.7) in two Han populations. Furthermore, genetic relationships along Chinese administrative and ethnic divisions were analyzed, and we also combined our data with existing datasets of non-Chinese groups to explore the genetic variance. Genetic differentiations were observed between Northern and Southern Han nationality, and genetic differences existed between the two Han populations and some ethnic groups, most prominently for the Tibetans and Kazakhs, as well as non-Chinese groups, especially African groups. PMID- 29111272 TI - Novel HBV recombinants between genotypes B and C in 3'-terminal reverse transcriptase (RT) sequences are associated with enhanced viral DNA load, higher RT point mutation rates and place of birth among Chinese patients. AB - As one of the major global public health concerns, hepatitis B virus (HBV) can be divided into at least eight genotypes, which may be related to disease severity and treatment response. We previously demonstrated that genotypes B and C HBV, with distinct geographical distribution in China, had divergent genotype dependent amino acid polymorphisms and variations in reverse transcriptase (RT) gene region, a target of antiviral therapy using nucleos(t)ide analogues. Recently recombination between HBV genotypes B and C was reported to occur in the RT region. However, their frequency and clinical significance is poorly understood. Here full-length HBV RT sequences from 201 Chinese chronic hepatitis B (CHB) patients were amplified and sequenced, among which 31.34% (63/201) were genotype B whereas 68.66% (138/201) genotype C. Although no intergenotypic recombination was detected among C-genotype HBV, 38.10% (24/63) of B-genotype HBV had recombination with genotype C in the 3'-terminal RT sequences. The patients with B/C intergenotypic recombinants had significantly (P<0.05) higher serum HBV DNA level than the "pure" B-genotype cohort did. Moreover, the B/C intergenotypic recombinants were prone to more substitutions at several specific residues in the RT region than genotype B or C. Besides, unlike their parental genotypes, the recombinant HBV appeared to display an altered geographic distribution feature in China. Our findings provide novel insight into the virological, clinical and epidemiological features of new HBV B/C intergenotypic recombinants at the 3' end of RT sequences among Chinese CHB patients. The highly complex genetic background of the novel recombinant HBV carrying new mutations affecting RT protein may contribute to an enhanced heterogeneity in treatment response or prognosis among CHB patients. PMID- 29111273 TI - Sex in microbial pathogens. AB - We review the sexual processes common in pathogenic microorganisms and assess the primary adaptive benefit of such processes. The pathogenic microorganisms considered include bacteria, microbial eukaryotes, and viruses. The sexual processes include bacterial transformation, eukaryotic meiotic sex and virus multiplicity reactivation. Recent evidence shows that sexual processes are common in microbial pathogens. A major general challenge to pathogen survival and infectivity is the need to overcome the hostile defenses of their target host. These defenses characteristically involve production of stresses, including oxidative stress, that can damage the pathogen's genome. Pathogens appear generally to possess enzyme systems that are central to sex and are also associated with a particular type of genomic repair process, recombinational repair. For some pathogens, it has been directly demonstrated that infectivity and virulence depend on sex. The evidence reviewed here supports the conclusion that the primary benefit of sex in pathogens is the repair of genomic damages that would otherwise be deleterious or lethal. This conclusion is in agreement with similar conclusions derived from non-pathogenic model species of bacteria, microbial eukaryotes and viruses. In several pathogenic species it has been shown that the two partner genomes that engage in sex are most often clonally related or closely related genetically. Thus, in pathogenic species, sexual interactions likely generate little or no genetic variation among progeny. However, infrequent outcrossing can occur in these sexual species and this may have important long term consequences. PMID- 29111274 TI - Hospital and Community Characteristics Associated With Pediatric Direct Admission to Hospital. AB - OBJECTIVES: One quarter of pediatric hospitalizations begin as direct admissions, defined as hospitalization without receiving care in the hospital's emergency department (ED). Direct admission rates are highly variable across hospitals, yet previous studies have not examined reasons for this variation. We aimed to determine the relationships between hospital and community factors and pediatric direct admission rates, and to evaluate the degree to which these characteristics explain variation in risk-adjusted direct admission rates. METHODS: We conducted a cross-sectional study of the Healthcare Cost and Utilization Project's Kids Inpatient Database, American Hospital Association Database, and Area Health Resource File, including children <18 years of age who were admitted for a medical hospitalization in states contributing data to all data sets. Using hierarchical generalized linear modeling, we generated risk-adjusted direct admission rates and used generalized linear models to assess the association of hospital and community characteristics with these risk-adjusted rates. RESULTS: We included 211,458 children discharged from 933 hospitals and 26 states; 20.2% were admitted directly. One-fifth of the variance in risk-adjusted direct admission rates was attributed to observed hospital and community factors. The greatest proportion of this explained variance was related to ED volume (37%), volume of pediatric hospitalizations (27%), and size of the pediatrician workforce (12%). CONCLUSIONS: Direct admission rates were associated with several hospital and community characteristics, but the majority of variation in hospitals' direct admission rates was not explained by these factors. These findings suggest opportunities for diverse hospital types to develop the infrastructure and communication systems necessary to support pediatric direct admissions. PMID- 29111275 TI - Morphine delays neural stem cells differentiation by facilitating Nestin overexpression. AB - BACKGROUND: Morphine is used as an analgesic although it causes important secondary effects. These effects are triggered by several mechanisms leading to the dysregulation of gene expression. Here we aimed to study these alterations on neural stem cells (NSC) during CNS development. METHODS: AB strain and tg nestin:GFP zebrafish embryos, zebrafish primary neuron culture and mouse embryonic stem cells were used to assess the effect of morphine by qPCR, time lapse microscopy and western blot. ChIP-qPCR and bisulfite conversion assay were performed to determine the changes exerted by morphine in a Nestin candidate enhancer. RESULTS: Morphine increases GFP in nestin:GFP embryos and overexpresses the NSC marker Nestin. Morphine also exerts a hyperacetylation effect on H3K27 and decreases DNA methylation within a region located 18 Kb upstream nestin transcription starting site. Here, a binding site for the transcription factor complex Sox2/Oct4/Nanog was predicted. These factors are also upregulated by morphine. Besides, morphine increases the histone acetyl transferase p300. The inhibition of p300 activity decreases Nestin. CONCLUSIONS: Morphine facilitates Nestin increase by several mechanisms which include hyperacetylation of H3K27, decreased DNA methylation and the overexpression of the transcription factors sox2, oct4 and nanog. It has also been demonstrated that nestin levels depend on p300 activity. The facilitated Nestin expression delays the normal differentiation of neural stem cells. GENERAL SIGNIFICANCE: The present work provides novel evidence of the effects induced by morphine in the normal differentiation of NSCs, altering Nestin through changes on p300, H3K27ac, DNA methylation and Oct4, Sox2, and Nanog. PMID- 29111276 TI - The persistence of fatty liver has a differential impact on the development of diabetes: The Kangbuk Samsung Health Study. AB - AIMS: To evaluate whether variable fatty liver status over time influence the risk of type 2 diabetes differently. METHODS: We analyzed the data from 7849 subjects without type 2 diabetes who underwent comprehensive health check-ups annually for 5 years. All subjects had an abdominal ultrasonography annually. The risk of incident diabetes was assessed in individuals with sustained non alcoholic fatty liver disease (NAFLD), individuals with changed fatty liver status (intermittent NAFLD group), and individuals who did not have NAFLD (never NAFLD group) during the study period. A subgroup analysis was done in subjects of the intermittent NAFLD group. Incident diabetes was compared according to the number of time diagnosed as NAFLD by annual ultrasonography. RESULTS: During the mean follow-up of 4 years, subjects in the sustained NAFLD group had a HR of 1.50 (95% CI 1.13-1.98) for the development of diabetes compared with those in the never NAFLD group, whereas the risk was not higher in the intermittent NAFLD group (HR 0.99, 95% CI 0.76-1.31). When compared with the intermittent NAFLD group, multivariable adjusted HR for incident diabetes was 1.50 (95% CI 1.20 1.89) in the sustained NAFLD group. As the number of times diagnosed as NAFLD increased, the proportion of subjects who developed diabetes also increased (p = .002). CONCLUSIONS: The presence of fatty liver was differentially associated with incident diabetes based on its duration. The persistence of fatty liver status is an important factor for an independent association between NAFLD and incident diabetes. PMID- 29111277 TI - Resolution of ketoacidosis in children with new onset diabetes: Evaluation of various definitions. AB - AIMS: Data are sparse concerning use of serum electrolyte parameters as compared to venous blood gas (VBG) measurements to monitor acid-base status during treatment of diabetic ketoacidosis (DKA). We explored the utility of various parameters to define DKA resolution by investigating the relationship of venous pH (vpH), anion gap (AG), serum bicarbonate (HCO3), and glucose concentration during management of DKA in children with new onset diabetes mellitus (NODM). METHODS: We included all patients with NODM presenting with DKA to Boston Children's Hospital from 10/1/07-7/1/13. DKA was defined as serum glucose >= 200 mg/dL (11.1 mmol/L) and vpH<7.30; severity as mild <7.30, moderate<7.20, severe<7.10; resolution of DKA as vpH>=7.30 and AG<=18 mmol/L. We used Cox regression to determine time to DKA resolution, and logistic regression to evaluate different serum HCO3 cut-off values as predictors of DKA resolution. RESULTS: 263 patients (133F, mean age 9.9+/-4.4 years, 74% White) were included. DKA was mild in 134 (51%), moderate in 75 (28%) and severe in 54 (20%). In mild DKA, AG closed after normalization of vpH; in moderate and severe DKA, AG closed before normalization of vpH. HCO3>15mmol/L correlated with vpH>=7.30, and had 76% sensitivity and 85% specificity to predict DKA resolution. Median times to DKA resolution were similar using two different definitions: vpH and AG (8.4h [IQR 6.3-11.9]) vs. HCO3>15 mmol/L (7.9 h [IQR 5.0-11.8]), p=.42. CONCLUSIONS: During management of pediatric DKA, HCO3 > 15 mmol/L reliably predicts resolution of DKA. In low-resource settings where VBG is unavailable, electrolyte parameters alone may be used to determine DKA resolution. PMID- 29111278 TI - The association of inflammatory markers and periodontal indexes with the risk of coronary heart disease in Chinese patients with type 2 diabetes mellitus. AB - OBJECTIVES: The present study was designed to investigate the association of four inflammatory markers and five periodontal indexes with the risk of coronary heart disease (CHD) in 131 patients with type 2 diabetes mellitus (T2DM). METHODS: All subjects were inpatients, including 63 T2DM patients with comorbid CHD ("cases") and 68 T2DM patients without CHD ("controls"). The diagnosis of CHD is based on coronary angiography. RESULTS: Peripheral blood concentrations of high sensitivity C-reactive protein (hs-CRP) (11.51 vs. 10.39 mg/L), leptin (24.60 vs. 21.22 ng/L) and visfatin (65.92 vs. 57.62 ng/L) were significantly higher in cases than in controls (P = .033, 0.041 and 0.041, respectively). The levels of three periodontal indexes - probing pocket depth, attachment loss (AL) and sulcus bleeding index, were significantly higher in cases than in controls, especially for periodontal AL (3.60 mm vs. 3.29 mm, P = .002). A Forward logistic regression was performed for selection, and specifically hs-CRP, leptin, visfatin and periodontal AL were found to be associated with the significant risk of CHD (odds ratio: 1.16, 1.07, 1.03 and 2.04; P = .025, .022, .022 and .010, respectively). Importantly, the benefits of inflammatory markers and periodontal indexes over basic risk factors were significant (likelihood ratio test) and obvious (decision curve analysis). A nomogram was delineated based on significant variables, and it had good accuracy (C-index: 0.801, P < .001). CONCLUSIONS: Our findings support the significant contribution of inflammatory markers and periodontal indexes to the pathogenesis of CHD in T2DM. Specifically, hs-CRP, leptin, visfatin and periodontal AL were identified as significant contributors. PMID- 29111279 TI - Glycosylated hemoglobin level may predict the severity of gastroparesis in diabetic patients. AB - AIM: To investigate the association between glycemic control represented by glycated hemoglobin (HbA1c) level and the value of 4-h gastric retention on nuclear scan. METHODS: We retrospectively reviewed records of diabetic patients who had 4-h nuclear gastric emptying study, with documented 4-h retention value, between January 1st, 2002 and July 30th, 2014 and had HbA1C level close to the time of the study. We divided our cohort into patients with good glycemic control (HbA1C <7, group A), fair control (7-9, group B), and poor control (>9, group C). The 4-h retention value and symptoms were compared between the 3 groups. RESULTS: Our cohort included 299 patients; mean age was 59 +/- 14. The median interval between performing gastric emptying study and measuring HbA1C was 41 days. There were 94 patients in group A (HbA1C 6.1 +/- 0.4), 131 patients in group B (HbA1C 7.9 +/- 0.5), and 74 patients in group C (HbA1C 10.9 +/- 1.6). The mean gastric retention value was different between the three study groups, 8.3% +/-17, 11.5% +/-19, and 14.4% +/-21, respectively (P = .03). CONCLUSION: This is the first study to show that HbA1C level is significantly associated with the 4-h retention value on nuclear gastric emptying scan. PMID- 29111280 TI - Akt activation: A potential strategy to ameliorate insulin resistance. AB - Insulin resistance is a hallmark of type 2 diabetes and obesity while the mechanism remains unclear. Current therapy to treat type 2 diabetes is metformin, the 5'-monophosphate-activated protein kinase (AMPK) activator, owing to the ability to augment peripheral glucose uptake. However, metformin also displays limitations, as AMPK activation remains intact and regular in most type 2 diabetes and metformin does not seem to facilitate peripheral insulin resistance. Evidence has shown that PI3K-Akt/PKB pathway could be induced via insulin and act as an important effector. Akt/PKB is capable of inducing a great number of downstream molecules, such as translocating glucose transporters GLUTs to the cell membrane thus increase glucose uptake. Hence, any defect in Akt/PKB pathway along with the downstream molecules could lead to insulin resistance. Inositol pyrophosphates, synthesized by inositol hexakisphosphate (IP6) kinase 1 (IP6K1) and competitive with 3,4,5-bisphosphate (PIP3) to bind the PH domain of Akt/PKB, demonstrate the ability to inhibit Akt signaling. In addition, IP6K1 knockout mice present increased insulin sensitivity and obesity resistance, indicating a novel therapeutic target in confronting insulin resistance. Taken together, we conclude that Akt activation is another potential strategy to ameliorate insulin resistance. PMID- 29111281 TI - Association between alcohol consumption and incidence of impaired insulin secretion and insulin resistance in Japanese: The Saku study. AB - AIMS: To investigate the effect of alcohol consumption on impaired insulin secretion and insulin resistance in Japanese. METHODS: The participants in this 5 year cohort study were 2100 Japanese aged 30-74 years without type 2 diabetes mellitus, impaired insulin secretion, or insulin resistance who underwent a medical checkup including 75-g OGTT between April 2008 and March 2009 at Saku Central Hospital. Alcohol consumption was categorized as follows: non-drinker (0 g/week), light drinker (1-139 g/week in men and 1-69 g/week in women), moderate drinker (140-274 g/week in men and 70-139 g/week in women) and heavy drinker (>=275 g/week in men and >=140 g/week in women). The hazard ratios (HRs) and 95% CIs among light to heavy drinkers for incidence of impaired insulin secretion (insulinogenic index <=51.7) and insulin resistance (HOMA-IR >= 2.5), detected by an OGTT at the time of a follow-up medical checkup before the end of March 2014, were estimated by multivariable adjusted Cox proportional hazard models as reference values for non-drinkers. RESULTS: There were 708 cases of impaired insulin secretion and 191 cases of insulin resistance. The HRs (95% CIs) for impaired insulin secretion in light, moderate and heavy drinkers were 1.16 (0.96 1.40), 1.35 (1.07-1.70) and 1.64 (1.24-2.16), respectively (P for trend <0.001). For insulin resistance, the HRs were 1.22 (0.84-1.76), 1.42 (0.91-2.22) and 1.59 (0.96-2.65), respectively (P for trend = 0.044). CONCLUSION: Alcohol consumption was positively associated with the incidence of both impaired insulin secretion and insulin resistance. PMID- 29111282 TI - Modeling of adipose/blood partition coefficient for environmental chemicals. AB - A Quantitative Structure Activity Relationship (QSAR) model was developed in order to predict the adipose/blood partition coefficient of environmental chemical compounds. The first step of QSAR modeling was the collection of inputs. Input data included the experimental values of adipose/blood partition coefficient and two sets of molecular descriptors for 67 organic chemical compounds; a) the descriptors from Linear Free Energy Relationship (LFER) and b) the PaDEL descriptors. The datasets were split to training and prediction set and were analysed using two statistical methods; Genetic Algorithm based Multiple Linear Regression (GA-MLR) and Artificial Neural Networks (ANN). The models with LFER and PaDEL descriptors, coupled with ANN, produced satisfying performance results. The fitting performance (R2) of the models, using LFER and PaDEL descriptors, was 0.94 and 0.96, respectively. The Applicability Domain (AD) of the models was assessed and then the models were applied to a large number of chemical compounds with unknown values of adipose/blood partition coefficient. In conclusion, the proposed models were checked for fitting, validity and applicability. It was demonstrated that they are stable, reliable and capable to predict the values of adipose/blood partition coefficient of "data poor" chemical compounds that fall within the applicability domain. PMID- 29111283 TI - Pancreatic islet-autonomous effect of arsenic on insulin secretion through endoplasmic reticulum stress-autophagy pathway. AB - Inorganic arsenic is a worldwide environmental pollutant. Arsenic's relationship with the incidence of diabetes arouses concerns on its etiological mechanism. In this study, the glucose-stimulated insulin secretion (GSIS) from isolated pancreatic islets of As2O3-treated mice was significantly lower than that of control mice. It indicated that the effect of As2O3-inhibited GSIS was pancreatic islet-autonomous. The level of phospho-PERK (p-PERK), a biomarker of endoplasmic reticulum (ER) stress, in pancreas of As2O3-treated mice was increased significantly. After treatment with NaAsO2, the p-PERK level in INS-1 rat pancreatic beta- cells was increased correspondingly. After treatment with PERK inhibitor, the GSIS from isolated pancreatic islets of As2O3-treated mice was recovered. Arsenic induced autophagy in pancreatic islets, as evidenced by elevated LC3-II level and depressed P62 level in vivo and in vitro. In NaAsO2 treated INS-1 cells, the initiation of ER stress preceded the stimulation of autophagy, which was a key factor controlling pancreatic beta cell function. Furthermore, knockdown of PERK attenuated NaAsO2-induced autophagy in INS-1 cells. These data indicated that arsenic impaired beta cell function through ER stress-autophagy pathway. The present study will provide new mechanistic insights into arsenic-related diabetes. PMID- 29111285 TI - Reference values of two-dimensional and M-mode echocardiographic measurements as a function of body size in various equine breeds and in ponies. AB - INTRODUCTION: The aim of this study was to establish echocardiographic reference values for the equine species using allometric regression equations based on body weight (BW) and thoracic circumference (TC). ANIMALS: A total of 239 horses or ponies were studied, including 65 warmbloods, 33 Standardbreds, 41 Thoroughbreds, 32 Arabian horses, 28 draft horses, and 40 ponies aged from 1 day to 30 years, weighing from 18 to 890 kg, with no evidence of cardiac disease. METHODS: For each horse or pony, a two-dimensional and M-mode echocardiography was performed. Within each breed, the relationships between BW or TC and echocardiographic dimensions were examined using power regression equations. Predictions and their 95% prediction intervals were calculated for the echocardiographic measurements. RESULTS: Within each breed, all echocardiographic measurements showed a significant and positive relationship with a high coefficient of determination for the estimation of the regression equations using BW and TC as the main explanatory variables. Breed-specific power regression equations as well as the 95% prediction intervals were calculated for each echocardiographic measurement as a function of BW and TC. CONCLUSIONS: In the future, the body size-corrected and breed-specific echocardiographic reference values calculated in the present study could be used to discriminate between normal and abnormal values in a given animal. PMID- 29111284 TI - Two-dimensional echocardiographic estimates of left atrial function in healthy dogs and dogs with myxomatous mitral valve disease. AB - OBJECTIVES: To provide reference intervals for 2-dimensional linear and area based estimates of left atrial (LA) function in healthy dogs and to evaluate the ability of estimates of LA function to differentiate dogs with subclinical myxomatous mitral valve disease (MMVD) and similarly affected dogs with congestive heart failure (CHF). ANIMALS: Fifty-two healthy adult dogs, 88 dogs with MMVD of varying severity. METHODS: Linear and area measurements from 2 dimensional echocardiographs in both right parasternal long and short axis views optimized for the left atrium were used to derive estimates of LA active emptying fraction, passive emptying fraction, expansion index, and total fractional emptying. Differences for each estimate were compared between healthy and MMVD dogs (based on ACVIM classification), and between MMVD dogs with subclinical disease and CHF that had similar LA dimensions. Diagnostic utility at identifying CHF was examined for dogs with subclinical MMVD and CHF. Relationships with bodyweight were assessed. RESULTS: All estimates of LA function decreased with increasing ACVIM stage of mitral valve disease (p<0.05) and showed negative relationships with increasing LA size (all r2 values < 0.2), except for LA passive emptying fraction, which did not differ or correlate with LA size (p=0.4). However, no index of LA function identified CHF better than measurements of LA size. Total LA fractional emptying and expansion index showed modest negative correlations with bodyweight. CONCLUSIONS: Estimates of LA function worsen with worsening MMVD but fail to discriminate dogs with CHF from those with subclinical MMVD any better than simple estimates of LA size. PMID- 29111286 TI - Role of computed tomography angiography in the differentiation of feline truncus arteriosus communis from pulmonary atresia with ventricular septal defect. AB - Two domestic shorthair cats, a 6-month-old castrated male and a 7-month-old intact female, were diagnosed with complex congenital heart disease. Transthoracic echocardiography in both cats revealed a dilated arterial trunk overriding the interventricular septum with a large ventricular septal defect. The pulmonary trunk and branch pulmonary arteries were not visible using standard echocardiographic views in either cat. The differential diagnosis for both cats included truncus arteriosus communis vs. pulmonary atresia with ventricular septal defect. Each cat underwent computed tomography angiography to determine the origin and extent of the pulmonary blood supply and to better define extra cardiac anatomy. Computed tomography angiography led to a diagnosis of truncus arteriosus communis with unrestricted pulmonary blood flow in one cat, whereas the other cat was diagnosed with pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals serving as the primary source of pulmonary blood flow. Computed tomography angiography allowed for the ante mortem differentiation of truncus arteriosus communis from pulmonary atresia with ventricular septal defect in these two cats, leading to an accurate diagnosis and providing valuable information to therapeutic decision-making for each case. PMID- 29111287 TI - Transcatheter closure of a small atrial septal defect with an AmplatzerTM patent foramen ovale occluder in a working dog with cyanosis and exercise intolerance at high altitude. AB - A 6.5-year-old male Border Collie presented for transcatheter closure of an atrial septal defect due to exercise intolerance and cyanosis while working and training at altitude. A small, left-to-right shunting secundum atrial septal defect was confirmed with no evidence of significant right-sided volume overload. Pulmonary hypertension with subsequent right-to-left interatrial shunting occurring during exercise at high altitude was suspected and prompted the closure of the defect due to the dog's continued athletic requirements. The anatomy of the defect prompted use of a patent foramen ovale occluder rather than an atrial septal defect occluder, which was deployed using a combination of fluoroscopic and transesophageal echocardiographic guidance. The owner did not report continued exercise intolerance or cyanosis and the dog's lifestyle and residence at altitude was unchanged. PMID- 29111288 TI - [Together we shall overcome]. PMID- 29111289 TI - [Oxygen peak consumption is a better predictor of cardiovascular risk than handgrip strength in older Chilean women]. AB - BACKGROUND: Handgrip strength (HS) and peak oxygen consumption (Vo2peak) are powerful predictors of cardiovascular risk, although it is unknown which of the two variables is the better predictor. AIM: The objective of the following study was to relate HS and Vo2peak to cardiovascular risk markers in older Chilean women. METHODS: Physically active adult women (n=51; age, 69+/-4.7years) participated in this study. The HS and Vo2peak were evaluated and related to the anthropometric variables of body mass, body mass index (BMI), waist circumference (WC), hip circumference (HC), waist ratio (WR), and waist height ratio (WHR), as well as with the cardiovascular variables systolic (SBP) and diastolic (DBP) and cardiac recovery in one minute (RHR1). A multilinear regression model was used for the analysis of the associated variables (P<.05). RESULTS: The cardiovascular risk markers associated (P<.05) with the handgrip strength of the dominant limb (HSDL) were body mass, BMI, WR, and WHR. The handgrip strength of the non dominant limb (HSNDL) was associated with body mass. Vo2peak was associated with body mass, BMI, HC and RHR1. The multilinear regression model showed a value of r=0.43 in HSDL, r=0.39 in HSNDL and r=0.69 in peak Vo2. CONCLUSION: Although HS and Vo2peak were related to cardiovascular risk markers, Vo2peak offers greater associative power with these cardiovascular risk factors. PMID- 29111290 TI - [Transgenerational impact of chemotherapy: Would the father exposure impact the health of future progeny?] AB - The number of cancer survivors is increasing and their quality of life is becoming a major public health issue. Cancer treatments reduce men's reproductive health by targeting spermatogenesis. Ultimately, DNA, chromatin and the epigenome of spermatozoa can be altered in cancer survivors. Knowing whether the history of cancer and the treatments received can have consequences on the health of their offspring is therefore a fundamental question for these patients. This review gathers the experimental and epidemiological evidences of the effects observed on the direct descendants and on several generations, and draws up the state of knowledge on the mechanisms potentially involved. Experimental data describe inter- and transgenerational effects of paternal exposure depending on the type of treatment, dose and time of exposure. In the human population, the analysis of the effects specifically due to chemotherapy is still limited because they are often combined with irradiation treatments. However, it appears that chemotherapy agents affect the birth rate but do not have a significant impact on the health of the children born. Nevertheless, the demonstration of modifications of the sperm epigenome in cancer survivors, even after a period of remission, as well as changes in the sperm of the progeny in animal models, suggests a possible transgenerational transmission that remains to be studied in the human population. PMID- 29111291 TI - [Can we reduce the decision-to-delivery interval in case of emergency cesarean sections by optimizing the premises' architecture?] AB - OBJECTIVE: To study the influence of architectural premises' improvements on decision-to-delivery interval (DDI) in case of emergency cesarean sections. METHODS: A retrospective observational Before-After study conducted in a type III maternity, first from 2004 to 2009 (Period 1, P1) then after moving our unit to new premises from 2009 to 2013 (P2). DDI, maternal and neonatal outcomes of every emergency cesarean section were studied. RESULTS: The mean DDI of extremely urgent cesarean significantly decreased from 21.3+/-10.3minutes during P1 (n=294) to 14.9+/-7.14minutes during P2 (n=165). During P2 there was an increase in the proportion of extreme emergency cesarean sections done in less than 30minutes (85.1% versus 93.5%, P=0.003) as according to the ACOG recommendations, and also an increase of DDI of less than 15minutes (25.8% versus 61.1%, P<0.001). Also during P2 if there was a reduction of umbilical cord pHs, which were correlated to DDI, we observed a reduction of neonatal hospitalizations (42.2% versus 35.7%, P<0.001). Apgar score was correlated to umbilical cord pH and birth weight, but not to DDI. CONCLUSION: The space optimization has allowed our level III maternity to improve the rate of extreme emergency cesarean sections performed with DDI of less than 30 and even 15minutes, according to international recommendations. These results were obtained by reducing the transfer time to the operating room. Despite a positive correlation between DDI and umbilical cord pH, there was an improvement in neonatal outcomes associated with a decrease of neonatal hospitalizations. PMID- 29111292 TI - [Mammary duct papilloma: How I do... a microdochectomy wire guided]. PMID- 29111293 TI - Serum levels of melatonin may contribute to the pathogenesis of heart failure in children with median age of 1 year. AB - OBJECTIVE: Melatonin has a protective role in adults with cardiovascular disease, but the effects of melatonin in children with cardiac dysfunction are not well understood. This study was designed to explore the variations in melatonin, myeloperoxidase, and caspase-3 levels in children suffering from heart failure. METHODS: Seventy-two pediatric patients with heart failure and twelve healthy children were enrolled in this study. A modified Ross scoring system was used to evaluate clinical cardiac function. Patients with a score of >2 points were included in the study and were divided into three groups according to severity of heart failure: mild (score: 3-6), moderate (score: 7-9), and severe (score: 10 12). Echocardiographic parameters, laboratory data, and serum levels of melatonin, myeloperoxidase, and caspase-3 were measured and analyzed in all patients. RESULTS: Compared with patients with mild and moderate heart failure, patients in the severe heart failure group had significantly decreased left ventricular ejection fraction (p<0.001), and significantly increased serum melatonin levels (p=0.013) and myeloperoxidase levels (p<0.001). Serum melatonin levels were positively correlated with serum caspase-3 levels (p<0.001). The optimal cutoff values of serum melatonin levels for the diagnosis of severe heart failure and primary cardiomyopathy in pediatric patients with heart failure were 54.14pg/mL and 32.88pg/mL, respectively. CONCLUSIONS: Serum melatonin and myeloperoxidase levels were increased in children with severe heart failure. It is likely that increasing melatonin levels may act as a compensatory mechanism in pediatric children with heart failure. PMID- 29111294 TI - Oxygen binding isotope effects of triazole-based HIV-1 reverse transcriptase inhibitors indicate the actual binding site. AB - Binding isotope effects (BIEs) associated with binding of four triazole-based ligands to HIV-1 reverse transcriptase have been calculated at the QM/MM MD level of theory. Two main binding sites: allosteric cavity and RNase H active site, as well as three other sites reported in the literature (the Knuckles, the NNRTI Adjacent, and Incoming Nucleotide Binding) have been considered. The interactions between inhibitors and these protein sites have been quantified by binding free energies obtained from free energy perturbation (FEP) calculations, supported by interaction energy analysis. It has been shown that binding in the allosteric cavity can be distinguished from binding to other sites based on BIEs as it is associated with normal 18O-BIEs of the carbonyl oxygen atom while binding to RNase H active site is characterized by inverse binding isotope effect (18O-BIE < 1). For other sites 18O-BIEs close to unity are predicted. This information points to oxygen binding isotope effects of carbonyl group as indicative of the actual binding site of studied inhibitors. PMID- 29111296 TI - A neurosurgeon's view: Laser interstitial thermal therapy of mesial temporal lobe structures. AB - Stereotactic laser ablation of mesial temporal structures is a promising new surgical intervention for patients with mesial temporal lobe epilepsy (MTLE). Since this procedure was first used to treat MTLE in 2010, the literature contains reports of 37 patients that underwent MR-guided stereotactic laser amygdalohippocampotomy (SLAH) using Laser Interstitial Thermal Therapy (LITT) with at least 1year of follow-up. This early body of data suggests that SLAH is a safe and effective treatment for MTLE in properly selected patients. Moreover, SLAH is substantially less invasive when compared with open surgical procedures including standard anterior temporal lobectomy and its more selective variants, results in immediate destruction of tissue in contrast to radiosurgical treatments for MTLE, and can more readily ablate larger volumes of tissue than is possible with techniques employing radiofrequency ablation. Finally, evidence is accruing that SLAH is associated with lower overall risk of neuropsychological deficits compared to open surgery. Thus, LITT constitutes a novel minimally invasive tool in the neurosurgeon's armamentarium for managing medically refractory seizures that may draw eligible patients to consider surgical interventions to manage their seizures. PMID- 29111295 TI - Kinetic and structural characterization of a cis-3-Chloroacrylic acid dehalogenase homologue in Pseudomonas sp. UW4: A potential step between subgroups in the tautomerase superfamily. AB - A Pseudomonas sp. UW4 protein (UniProt K9NIA5) of unknown function was identified as similar to 4-oxalocrotonate tautomerase (4-OT)-like and cis-3-chloroacrylic acid dehalogenase (cis-CaaD)-like subgroups of the tautomerase superfamily (TSF). This protein lacks only Tyr-103 of the amino acids critical for cis-CaaD activity (Pro-1, His-28, Arg-70, Arg-73, Tyr-103, Glu-114). As it may represent an important variant of these enzymes, its kinetic and structural properties have been determined. The protein shows tautomerase activity with phenylenolpyruvate, but lacks native 4-OT activity and dehalogenase activity with the isomers of 3 chloroacrylic acid. It shows mostly low-level hydratase activity at pH 7.0, converting 2-oxo-3-pentynoate to acetopyruvate, consistent with cis-CaaD-like behavior. At pH 9.0, this compound results primarily in covalent modification of Pro-1, which is consistent with 4-OT-like behavior. These observations could reflect a pKa for Pro-1 that is closer to that of cis-CaaD (~9.2) than to 4-OT (~6.4). A structure of the native enzyme, at 2.6 A resolution, highlights differences at the active site from those of 4-OT and cis-CaaD that add to our understanding of how contemporary TSF reactions and mechanisms may have diverged from a common 4-OT-like ancestor. PMID- 29111297 TI - Mid-Term Outcomes of Repair of Coarctation of Aorta With Hypoplastic Arch: Extended End-to-side Anastomosis Technique. AB - The optimal surgical repair technique for coarctation associated with aortic arch hypoplasia (CoA-AAH) in neonates and infants is controversial. This study evaluates our current strategy using extended end-to-side anastomosis under selective cerebral and myocardial perfusion in treating this group of patients. Through a retrospective review, we analyzed the outcome of 87 infants who underwent surgical repair of CoA-AAH from January 2004 to December 2015. Patients with functional single ventricle were excluded. There were no early mortalities, and 4 patients (4.6%) experienced early complications. Eighty-five patients (97.7%) were followed up during a mean duration of 6.1 +/- 3.53 years. There were 2 late mortalities (2.3%) and 3 reintervention (3.5%) of the aortic arch. Ten year overall survival and freedom from reintervention for the entire cohort was 97.7% and 96.3%, respectively. At last follow-up, 4 patients (4.5%) showed a peak velocity greater than 2.5 m/s across the repair site. Seven patients (8.2%) were hypertensive. Our strategy with extended end-to-side anastomosis under selective cerebral and myocardial perfusion is safe and effective for repairing CoA-AAH in neonates and infants. Concomitant repair of associated cardiac anomalies can be done without added risk. Mid-term results are excellent with low rates of mortality, reintervention, and late hypertension. PMID- 29111299 TI - Diagnosis and treatment guideline for myopic choroidal neovascularization due to pathologic myopia. AB - Pathologic myopia is a leading cause of visual impairment. Development of myopic choroidal neovascularization (CNV) is one of the most common complications that leads to central vision loss in patients with pathologic myopia. If left untreated, it can cause scarring with expanding macular atrophy leading to irreversible visual loss in a period as short as 5 years. Advancements in multimodal imaging technology have furthered our understanding of the condition; however, further studies are necessary to extend its utility in the diagnosis of myopic CNV. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has become the standard-of-care and the recommended first-line treatment option for myopic CNV. Long-term studies have demonstrated that early treatment of confirmed myopic CNV cases with an intravitreal anti-VEGF agent is useful to avoid late-stage complications. This strategy has also been shown to achieve visual outcome improvements for up to 4 years and visual stabilization up to 6 years. This review article provides an overview of the current knowledge on myopic CNV and discusses recent updates in the diagnosis and management of the condition. Furthermore, treatment recommendations are provided based on the authors' expert opinions. PMID- 29111298 TI - Improving neonatal care with the help of veteran resource parents: An overview of current practices. AB - Over the past decade, veteran parents who have lived a neonatal intensive care unit (NICU) experience have become increasingly involved as 'resource parents' to provide peer-to-peer support to "new" NICU parents. These parents can provide a unique form of support to new parents. They can also assume other roles in clinical care, research, administration and/or teaching, but those roles are rarely described in the literature. This article reviews many of the activities performed by resource parents in neonatology. These activities were identified/examined and classified according to the location of involvement (hospital or not), the presence/absence of direct interaction with families and providers, and the topic of involvement. We have also identified gaps in knowledge relative to recruitment and training, development and evaluation of programs, structuring of responsibilities, and remuneration of resource parents. Future research is needed to measure the impact of resource parents on neonatal care. PMID- 29111300 TI - Anogenital Findings in 3569 Pediatric Examinations for Sexual Abuse/Assault. AB - STUDY OBJECTIVE: Accurate interpretation of anogenital examination findings in the context of suspected child and adolescent sexual abuse/assault is essential, because misinterpretation has significant child protection and criminal justice implications. A consensus approach to the interpretation of anogenital examination findings is widely used to support accurate diagnosis; however, a large-scale study using this standardized approach is lacking. The objectives of this study were to: (1) determine the proportion of anogenital examinations for sexual abuse concerns with findings diagnostic of trauma and/or sexual contact; (2) determine whether frequency of diagnostic findings varies according to age, gender, and timing of examination; and (3) characterize diagnostic findings. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Retrospective records of children aged 0-18 years evaluated for sexual abuse/assault were reviewed. Case details of 3569 patients were extracted and anogenital examination findings were reinterpreted using a published consensus approach. RESULTS: Anogenital examination findings diagnostic of trauma and/or sexual contact were present in 173 of 3569 patients (4.8%). The prevalence of diagnostic findings was significantly higher in adolescents than in children younger than 12 years of age (13.9%, 114/823 vs 2.2%, 59/2657), in female vs male patients (5.7%, 164/2866 vs 1.5%, 9/614), and in examinations within 72 hours for children younger than 12 years (14.2%, 91/643 vs 4.5%, 45/997). Acute injuries were the most common type of diagnostic finding. CONCLUSION: Diagnostic findings are present in a small proportion of children and adolescents examined for suspected sexual abuse/assault. It is essential that practitioners who interpret examination findings be adequately trained and familiar with the current consensus approach and are aware of case characteristics associated with higher likelihood of findings. PMID- 29111301 TI - Evolution of highly fecund haploid populations. AB - We consider a model of viability selection in a highly fecund haploid population with sweepstakes reproduction. We use simulations to estimate the time until the allelic type with highest fitness has reached high frequency in a finite population. We compare the time between two reproduction modes of high and low fecundity. We also consider the probability that the allelic type with highest fitness is lost from the population before reaching high frequency. Our simulation results indicate that highly fecund populations can evolve faster (in some cases much faster) than populations of low fecundity. However, high fecundity and sweepstakes reproduction also confer much higher risk of losing the allelic type with highest fitness from the population by chance. The impact of selection on driving alleles to high frequency varies depending on the trait value conferring highest fitness; in some cases the effect of selection can hardly be detected. PMID- 29111302 TI - [Cryopyrin-associated periodic syndromes]. AB - Cryopyrin-associated periodic syndromes (CAPS) are linked to one single gene mutations, however they are associated with 3 syndromes, which are, from the mildest to the most severe phenotype familial cold urticaria, Muckle-Wells syndrome and chronic, infantile, neurologic, cutaneous, articular (CINCA) syndrome also called neonatal-onset multisystem inflammatory disease (NOMID). Autosomic dominant inheritance is present in most cases but in CINCA/NOMID syndrome where neomutations are more common. Mutations in the gene encoding cryopyrin, NLRP3, are associated with deregulation of caspase-1 activity, excessive interleukin-1 production and an autoinflammatory syndrome, which in familial cold urticaria and Muckle-Wells syndrome may be triggered or worsened by exposure to coldness. More and more mutations are described and even somatic mutations that can explain some clinical signs beginning in adulthood. Patients disclose a pseudo-urticarial rash, arthralgia, headaches, sometimes fever, biological inflammation but also, in severe forms of the disease, neurologic inflammation with central deafness, ophthalmologic inflammation, chronic meningitis. Some CINCA/NOMID patients also develop growth cartilage pseudo tumoral hypertrophy. Natural disease history is usually benign in familial cold urticarial but severe in the other forms, particularly regarding neuro-sensorial involvement. In addition, secondary AA amyloidosis may develop in all forms in the absence of control of chronic inflammation. Anti-interleukin-1 treatment with anakinra, rilonacept or canakinumab induces in most cases complete remission, however sequelae may be present, particularly if central deafness or cartilage bone hypertrophy have already developed. This treatment is also important to prevent secondary amyloidosis or stabilize and even sometimes allow improvement of amyloidosis lesions. PMID- 29111303 TI - In vitro characteristics of endothelial cells prepared from human cerebral arteriovenous malformation lesions using a novel method. AB - BACKGROUND AND PURPOSE: The cerebral arteriovenous malformation (cAVM) is a usual and continually unaware reason of heamorrhage and seizure. It contains of feeder arteries, drain veins and abnormal vessel nets. However, pathologic mechanisms of the development of cAVM are unknown. The purpose of this study was to explore a novel protocol to isolate, culture and passage endothelial cells (ECs) from human cAVM lesions. METHODS: We developed a protocol for isolating and growing ECs from eight patients with cAVM. The tissues were microsurgically removed from cAVM lesion and were digested by 0.25% Trypsin-EDTA, and cultured in ECM medium. ECs were selected by FACS and confirmed their EC origin by immunocytochemistry of the basic expression patterns of CD31 and CD34. LDL-uptake and capillary tube formation were used to determine their functional features. RESULTS: The isolated cAVM-ECs exhibited contact inhibition of growth and appearance of rounded cobblestone. cAVM-ECs were CD31- and CD34-positive. In functional assays, cAVM ECs were able to uptake LDL and form capillary tubes. cAVM-ECs from younger patients proliferated faster than that from elders, and cAVM-ECs were less stable than normal artery ECs. In addition, cAVM-ECs appeared to more easily transform into mesenchymal cells than normal artery ECs. CONCLUSION: Using the protocol, isolated cAVM-ECs are stably established, and retain their endothelial phenotypes. These cAVM-ECs may provide a biological tool to examine molecular phenotypes and mechanisms responsible for human cAVM. PMID- 29111304 TI - Who are they? Patients with heart failure in American skilled nursing facilities. AB - BACKGROUND: Heart failure (HF) is common among skilled nursing facility (SNF) residents, yet patients with HF in the SNF setting have not been well described. METHODS: Using Minimum Data Set 3.0 cross-linked to Medicare data (2011-2012), we studied 150,959 HF patients admitted to 13,858 SNFs throughout the USA. ICD-9 codes were used to differentiate patients with HF with preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF), or unspecified HF. RESULTS: The median age of the study population was 82 years, 68% were women, 34% had HFpEF, and 27% had HFrEF. HFpEF patients were older than those with HFrEF. Moderate/severe physical limitations (82%) and cognitive impairment (37%) were common, regardless of HF type. The burden and pattern of common comorbidities, with the exception of coronary heart disease, were similar among all groups, with a median of five comorbidities. One half of patients with HF had been prescribed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 39% evidence-based beta-blockers. CONCLUSIONS: SNF residents with HF are old and suffer from significant physical limitations and cognitive impairment and a high degree of comorbidity. These patients differ substantially from HF patients enrolled in randomized clinical trials and that might explain divergence from treatment guidelines. PMID- 29111305 TI - Landmark discoveries in elucidating the origins of the hypothalamic-pituitary system from the perspective of a basal vertebrate, sea lamprey. AB - The hypothalamic-pituitary (HP) system, which is specific to vertebrates, is considered to be an evolutionary innovation that emerged prior to or during the differentiation of the ancestral jawless vertebrates (agnathans) leading to the neuroendocrine control of many complex functions. Along with hagfish, lampreys represent the oldest lineage of vertebrates, agnathans (jawless fish). This review will highlight our discoveries of the major components of the lamprey HP axis. Generally, gnathostomes (jawed vertebrates) have one or two hypothalamic gonadotropin-releasing hormones (GnRH) while lampreys have three hypothalamic GnRHs. GnRH(s) regulate reproduction in all vertebrates via the pituitary. In gnathostomes, there are three classical pituitary glycoprotein hormones (luteinizing hormone, LH; follicle stimulating hormone, FSH; and thyrotropin, TSH) interacting specifically with three receptors, LH-R, FSH-R, and TSH-R, respectively. In general, FSH and LH regulate gonadal activity and TSH regulates thyroidal activity. In contrast to gnathostomes, we propose that lampreys only have two heterodimeric pituitary glycoprotein hormones, lamprey glycoprotein hormone (lGpH) and thyrostimulin, and two lamprey glycoprotein hormone receptors (lGpH-R I and -R II). Our existing data also suggest the existence of a primitive, overlapping yet functional hypothalamic-pituitary-gonadal (HPG) and HP thyroidal (HPT) endocrine systems in lampreys. The study of basal vertebrates provides promising models for understanding the evolution of the hypothalamic pituitary-thyroidal and gonadal axes in vertebrates. We hypothesize that the glycoprotein hormone/glycoprotein hormone receptor systems emerged as a link between the neuroendocrine and peripheral control levels during the early stages of gnathostome divergence. Our discovery of a functional HPG axis in lamprey has provided important clues for understanding the forces that ensured a common organization of the hypothalamus and pituitary as essential regulatory systems in all vertebrates. This paper will provide a brief snapshot of my discoveries, collaborations and latest findings including phylogenomic analyses on the origins, co-evolution and divergence of ligand and receptor protein families from the perspective of the lamprey hypothalamic-pituitary system. PMID- 29111306 TI - Metagenomic analysis identified co-infection with human rhinovirus C and bocavirus 1 in an adult suffering from severe pneumonia. PMID- 29111307 TI - Human parechovirus infection as an undiagnosed cause of adult pericarditis. PMID- 29111308 TI - Inhibition of microRNA-210 suppresses pro-inflammatory response and reduces acute brain injury of ischemic stroke in mice. AB - Stroke is a leading cause of mortality and chronic neurologic disability. Yet, the successful treatment remains limited. In this study, we investigated the efficacy and the mechanism of a novel treatment, microRNA-210 (miR-210) inhibition, in protecting acute ischemic brain injury in adult mice. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male C57BL/6 mice. MiR-210-LNA (miR-210 inhibitor) or the negative control was administered via intracerebroventricular injection 24h prior or 4h after MCAO. Cerebral infarction volume and behavioral deficits were determined 48h after MCAO. The expression of inflammation-related genes and infiltration/activation of various immune cells in the brain were assessed by RT-qPCR, flow cytometry, and immunohistochemistry. Acute ischemic stroke significantly increased miR-210 levels in the brain, which was abolished by miR-210-LNA administered prior to MCAO. Pre- and post-MCAO treatments with miR-210-LNA significantly decreased cerebral infarction and ameliorated behavioral deficits induced by MCAO. Long term behavioral recovery was also improved by miR-210-LNA post-treatment. At the same time, inhibition of miR-210 significantly reduced the expression of pro inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) and chemokines (CCL2 and CCL3), but had no significant effect on anti-inflammatory factors (TGF-beta and IL-10). In addition, MCAO-induced macrophage infiltration and microglial activation in the brain were inhibited by the miR-210-LNA treatment. In summary, inhibition of miR-210 suppresses pro-inflammatory response and reduces brain damage in the acute phase of ischemic stroke, providing new insight in molecular basis of a novel therapeutic strategy of miR-210 inhibition in the treatment of acute ischemic stroke. PMID- 29111309 TI - Functional Tricuspid Regurgitation and the Dynamic Tricuspid Annulus-New Perspectives From 3D TEE Imaging. PMID- 29111310 TI - Everyday couples' communication research: Overcoming methodological barriers with technology. AB - Relationship behaviors contribute to compromised health or resilience. Everyday communication between intimate partners represents the vast majority of their interactions. When intimate partners take on new roles as patients and caregivers, everyday communication takes on a new and important role in managing both the transition and the adaptation to the change in health status. However, everyday communication and its relation to health has been little studied, likely due to barriers in collecting and processing this kind of data. The goal of this paper is to describe deterrents to capturing naturalistic, day-in-the-life communication data and share how technological advances have helped surmount them. We provide examples from a current study and describe how we anticipate technology will further change research capabilities. PMID- 29111312 TI - Perinatal outcomes after stimulated versus natural cycle IVF: a systematic review and meta-analysis. AB - Pregnancies resulting from assisted reproductive techniques are at higher risk of adverse perinatal outcomes compared with spontaneous conceptions. Underlying infertility and IVF procedures have been linked to adverse perinatal outcomes. It is important to know if ovarian stimulation influences perinatal outcomes after IVF. A systematic search for relevant studies was conducted up to November 2016 on the following databases: PubMed, EMBASE, DARE and Cochrane Central Register of Controlled Trials. Perinatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), large for gestational age (LGA) and congenital anomalies. Data from four studies, which included a total of 96,996 and 704 singleton live births after stimulated IVF and natural or modified natural cycle IVF, were included in the meta-analysis. The risk of PTB (RR 1.27, 95% CI 1.03 to 1.58) and LBW (RR 1.95, 95% CI 1.03 to 3.67) were significantly higher after stimulated compared with natural or modified natural cycle IVF. Data from one study were available for SGA, LGA, congenital anomalies and no significant differences were reported between the groups. This study suggests a higher risk of PTB and LBW after stimulated IVF compared with natural or modified natural IVF, although the absolute increase in risk may be low. PMID- 29111311 TI - Establishment and validation of a score to predict ovarian response to stimulation in IVF. AB - This study aimed to integrate clinical and biological parameters in a score able to predict ovarian response to stimulation for IVF in gonadotrophin-releasing hormone (GnRH) antagonist protocols. A progressive discriminant analysis to establish a score including the main clinical and biological parameters predicting ovarian response was performed by retrospectively analysing data from the first ovarian stimulation cycle of 494 patients. The score was validated in a prospectively enrolled, independent set of 257 patients undergoing their first ovarian stimulation cycle. All ovarian stimulations were performed using a combination of GnRH antagonist and recombinant FSH. Ovarian response was assessed through ovarian sensitivity index (OSI). Parameters from the patients' database were classified according to correlation with OSI: the progressive discriminant analysis resulted in the following calculation: score = 0.192 - (0.004 * FSH (IU/l)) + (0.012 * LH:FSH ratio) + (0.002 * AMH (ng/ml)) - (0.002 * BMI (kg/m2)) + (0.001 * AFC) - (0.002 * age (years)). This score was significantly correlated with OSI in the retrospective (r = 0.599; P < 0.0001) and prospective (r = 0.584; P < 0.0001) studies. In conclusion, the score including clinical and biological parameters could explain 60% of the variance in ovarian response to stimulation. PMID- 29111313 TI - Prevalence and confounders of chronic endometritis in premenopausal women with abnormal bleeding or reproductive failure. AB - In this retrospective cohort study, a consecutive series of 1551 premenopausal women underwent hysteroscopy and endometrial biopsy. Chronic endometritis was diagnosed when plasma cell in endometrial tissue was detected by immunohistochemistry using CD138 epitope. The overall prevalence of chronic endometritis in the population studied was 24.4% The prevalence was significantly increased in the following conditions: recurrent implantation failure (40.8%; P < 0.001), abnormal uterine bleeding (40.7 %; P < 0.001), endometrial hyperplasia (50.0%, P < 0.05) and submucosal fibroid (59.1%; P < 0.001) than those without the respective conditions. The prevalence in specimens obtained from the proliferative phase (26.0%) was significantly higher (P < 0.05) than those from the luteal phase (17.5%). Logistic regression analysis showed three significant factors affecting the prevalence, in descending order of importance: clinical presentation, endometrial hyperplasia and stage of the cycle from which the specimen was obtained. The confounding variables identified in this study may account for the wide range of published prevalence of the condition, and should be considered in the analysis of prevalence data relating to chronic endometritis. PMID- 29111314 TI - Perivitelline threads associated with fragments in human cleavage stage embryos observed through time-lapse microscopy. AB - Perivitelline threads (PVT) are defined as thin filaments that extend across the perivitelline space connecting the zona pellucida with the oolemma or, in some cases, blastomere membrane. This is the first report of PVT in human embryos. Time-lapse imagery from 525 blastocysts with either tested ploidy, known implantation status, or both, were reviewed for the presence of PVT, the cell stage when PVT were first observed, association with fragmentation, ploidy or implantation potential; PVT were observed in most embryos (404/525 [77%]). The euploidy rate was similar in embryos with PVT (61/152 [40%]) and without PVT (17/35 [49%]). Implantation rates were also similar in embryos with PVT (64/259 [25%]) and without PVT (25/90 [28%]). In the embryos in which PVT were observed, 98% (396/404) developed at the two-cell stage. In most embryos (384/404 [95%]), PVT were observed to directly pull fragments from the embryo. Fragmentation occurred significantly less frequently in embryos without PVT compared with PVT (81/121 [67%] versus 388/404 [96%]; P < 0.001). These data suggest an association between PVT and fragmentation. This study is limited in that PVT were not characterized so their nature and origin remain unknown and to be determined in future studies. PMID- 29111315 TI - Protective role of peroxisome proliferator-activated receptor alpha agonists in skin barrier and inflammation. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is one of the three isoforms of PPARs, which are ligand-activated nuclear transcription factors. PPARalpha is highly expressed in liver and its agonists are widely used to treat hyperlipidemia. Epidermal keratinocytes express all three isoforms (alpha, beta/delta, and gamma) of PPARs and PPARalpha is particularly important for regulating the epidermal barrier and inflammation. Agonistic ligation of PPARalpha protects the epidermal barrier function and inhibits the inflammatory response in dermatitis. In this review, we summarize recent topics on the role of PPARalpha in skin biology and discuss the potential use of topical PPARalpha agonists for treating atopic dermatitis and other eczemas. PMID- 29111316 TI - Concentrations of SP-A and HSP70 are associated with polarization of macrophages in pleural effusions of non-small cell lung cancer. AB - Damage-associated molecular pattern (DAMP) molecules can initiate an immune response through Toll-like receptors (TLRs). DAMPs are released from cells as a response to the extracellular danger and can be by-products of tissue damage. In cancer microenvironment necrotic cells release debris which has potency to become DAMPs. Non-small cell lung cancer (NSCLC) is often accompanied by pleural effusion (PE), which contains a variety of DAMPs. Surfactant protein A (SP-A) and heat shock protein 70 (Hsp70) are important DAMPs in the respiratory tract. The aim of this study was to determine a correlation between SP-A or Hsp70 and development of PE in the course of NSCLC. Moreover, we aimed to determine relationships between DAMPs and certain humoral factors associated with formation and persistence of PE as well as pleural-residing macrophages. In 34 PE samples, we estimated concentration of SP-A, Hsp70, IL-6, IL-18, G-CSF, M-CSF, SCF, SDF1alpha, VEGF as well as the fraction of macrophages and their pattern of polarization. We have found correlations between the concentration of the SP-A and Hsp70 and the percentage of PE-derived macrophages, also between concentrations of SP-A and Hsp70, and cytokines which participate in inflammation and processes involved in remodeling of extracellular matrix (ECM). Our data indicate an important role of SP-A during the development of PE associated with NSCLC. We suggest that measurement of concentration level of SP-A can be helpful in the course of diagnosis of malignant PE associated with NSCLC. PMID- 29111317 TI - Development of a quantitative immuno-polymerase chain reaction assay to detect and quantify low levels of human thyroid stimulating hormone. AB - In the present study, we developed both a conventional enzyme-linked immunosorbent assay (ELISA) and a highly sensitive immuno-polymerase chain reaction (IPCR) assay specific for detection of human thyroid stimulating hormone (hTSH). Several anti-hTSH monoclonal antibodies (MAbs) were generated using hybridoma technology. Two pairs of MAbs (B-4 and B-9) were rationally selected and the optimal assay conditions of sandwich ELISAs were established. The ELISA prototypes were evaluated with standards calibrated with WHO 2nd International Reference Preparation for hTSH and in comparison with a commercial ELISA Kit. Although the limit of detection (LOD) was 0.1 MUIU/ml in all cases, B-9-ELISA showed an analytical performance similar to commercial ELISA Kit. Therefore, we selected the B-9 ELISA to develop a hTSH-IPCR assay applying an "Universal-IPCR" format in standard PCR tubes without pretreatment. The signal amplification was achieved through the interaction between the biotinylated detection MAb and mono biotinylated DNA probe pre-self-assembled with neutravidin. The hTSH-IPCR assay showed a significant increase in terms of the slope definition of sensitivity in low levels range. Our results support the potential of IPCR technique for being applied in clinical diagnosis of thyroid states. PMID- 29111318 TI - Corrigendum to "Intraoperative Ultrasound in Patients Undergoing Transsphenoidal Surgery for Pituitary Adenoma: Systematic Review" [World Neurosurgery 106 (2017) 680-685]. PMID- 29111319 TI - Micronuclei formation in rainbow trout cells exposed to multiple stressors: Morpholine, heat shock, and ionizing radiation. AB - Discharges from industrial cooling water systems can include low levels of morpholine (a chemical pH regulator and corrosion inhibitor), as well as transiently higher temperature effluent water which present a potential source of environmental impact to aquatic biota. The effects of environmental levels of morpholine or heat shock (HS) treatment alone and in combination with a challenge high-dose of 137Cs ionizing radiation were studied using the cytokinesis block micronucleus assay in a rainbow trout cell line (RTG-2). Morpholine treatment of 10 or 100mgL-1 alone produced no significant effects, and no interaction was observed in combination with 7.75Gy radiation. A 9 degrees C magnitude HS treatment alone significantly increased micronuclei formation. A synergistic response was observed when 9 degrees C HS was combined with 7.75Gy radiation, with 15% more cells containing 3 or more micronuclei than the sum of each individual stressor. A synergistic increase in the average number of micronuclei was observed when morpholine and a 9 degrees C HS were co-treated. These results indicate that morpholine at environmentally-relevant levels does not impact micronuclei formation or cell cycle progression however 9 degrees C HS may be of potential concern both alone and in combination with other stressor treatments. PMID- 29111320 TI - Clinical states of cirrhosis and competing risks. AB - The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis. PMID- 29111321 TI - Inhibition activity of Lactobacilli supernatant against fungal-bacterial multispecies biofilms on silicone. AB - Fungal-bacterial multispecies biofilms play a major role in failure of medical silicone devices, such as voice prostheses in laryngectomiy. In this study, we determined the effect of Lactobacilli supernatant (cell free) on mixed biofilm formation of fungi and bacteria on silicone in vitro. Lactobacilli supernatant inhibited the adhesion (90 min) of mixed fungi and bacteria species with an efficiency of >90%. Mixed biofilm formation and the metabolic activity of the biofilms were inhibited by 72.23% and 58.36% by Lactobacilli supernatant. The examination using confocal laser scanning microscopy and scanning electron microscopy confirmed that Lactobacilli supernatant inhibited the growth of mixed biofilm and damaged the cells. Moreover, Lactobacilli supernatant also inhibited Candida yeast-to-hyphal transition. Therefore, Lactobacilli supernatant may serve as a possible antibiofilm agent to limit biofilm formation on voice prostheses. PMID- 29111322 TI - Phytochemical analysis and antibacterial activity of Gentiana macrophylla extract against bacteria isolated from burn wound infections. AB - The management of burn wound victims is often considered a difficult task due to frequent infections. Moreover, the treatment with conventional antibiotics is associated with the upsurge of drug resistant bacterial strains. Therefore there is pressing need to explore antimicrobials that could overcome these problems. Plant extracts have been used as antimicrobials in different systems of medicine. Gentiana species have been widely used in Chinese system of traditional medicine for the treatment of various ailments including microbial infections. The aim of the present study was therefore to evaluate the antimicrobial activity of methanolic root extract of Gentiana macrophylla against bacterial strains isolated from wound burns. Preliminary phytochemical screening revealed the phenolic and flavonoids content of the extract to be 26.70 +/- 1.5 mg gallic acid equivalent (GAE)/g DW and 10.11 +/- 0.8 mg quercetin equivalent/g DW respectively. The phenolics and flavonoids content of the extract positively correlated with antioxidant activity of the extract. Evaluation of antimicrobial activity against bacterial strains isolated from wound burns revealed that the G. macrophylla extract exhibited significant antibacterial against all the tested bacterial strains. The MIC values ranged between 60 and 240 MUg/ml. The lowest MIC was observed for S. epidermidis and the highest MIC was observed for E. coli. The MBCs also followed the similar trend and ranged between 106 to 300 MUg/ml. To identify the active constituents responsible for the bioactivity of the extract LC/MS analysis was carried out which lead to the putative identification of five compounds including chlorogenic acid, rutin, sweroside, isogentisin, and gentisin. Taken together, these results indicate G. macrophylla can prove to be an important source of antioxidants and antimicrobials and may be used for the management of wound burns. PMID- 29111323 TI - The role of the ptsI gene on AI-2 internalization and pathogenesis of avian pathogenic Escherichia coli. AB - The LuxS/AI-2 quorum sensing mechanism can regulate the physiological functions of avian pathogenic Escherichia coli (APEC) through internalization of the small molecule autoinducer-2 (AI-2). The ptsI gene encodes enzyme I, which participates in the phosphotransferase system (PTS) that regulates the virulence and AI-2 internalization of bacteria. The aim of the present study was to determine the effect of ptsI on AI-2 internalization and other pathogenesis process in APEC using a ptsI mutant of the APEC strain DE17 (serotype O2), namely DE17DeltaptsI. The results showed that deletion of the ptsI gene changed the rdar (red dry and rough) morphotype and decreased motility and biofilm formation in APEC (p < 0.05). Furthermore, scanning electron microscopy showed that the biofilm structure of DE17DeltaptsI became sparse and more extracellular, as compared with the wild-type strain DE17. Moreover, AI-2 assay showed that AI-2 was internalized by DE17DeltaptsI, while the recombinant PtsI protein had no AI-2 binding activity. Furthermore, deletion of the ptsI gene in APEC significantly increased adherence to DF-1 cells (p < 0.05). The 50% lethal dose of DE17DeltaptsI was decreased by 17.8-fold and the bacterial loads of DE17DeltaptsI were decreased by 13600-, 68.5-, 131-, and 3600-fold in the blood, liver, spleen, and kidney, respectively, as compared to the DE17. Moreover, histopathological analysis showed that the mutant DE17DeltaptsI was associated with reduced pathological changes in the heart, liver, spleen, and kidney of ducklings, respectively, as compared to the wild-type strain DE17. The results of this study will benefit further studies on the functions of the ptsI in APEC. PMID- 29111324 TI - Characterization of the zinc-induced Shank3 interactome of mouse synaptosome. AB - Variants of the SHANK3 gene, which encodes a core scaffold protein of the postsynaptic density of excitatory synapses, have been causally associated with numerous brain disorders. Shank3 proteins directly bind zinc ions through their C terminal sterile alpha motif domain, which enhances the multimerization and synaptic localization of Shank3, to regulate excitatory synaptic strength. However, no studies have explored whether zinc affects the protein interactions of Shank3, which might contribute to the synaptic changes observed after zinc application. To examine this, we first purified Shank3 protein complexes from mouse brain synaptosomal lysates that were incubated with different concentrations of ZnCl2, and analyzed them with mass spectrometry. We used strict criteria to identify 71 proteins that specifically interacted with Shank3 when extra ZnCl2 was added to the lysate. To characterize the zinc-induced Shank3 interactome, we performed various bioinformatic analyses that revealed significant associations of the interactome with subcellular compartments, including mitochondria, and brain disorders, such as bipolar disorder and schizophrenia. Together, our results showing that zinc affected the Shank3 protein interactions of in vitro mouse synaptosomes provided an additional link between zinc and core synaptic proteins that have been implicated in multiple brain disorders. PMID- 29111325 TI - Inhibition of tissue factor signaling in breast tumour xenografts induces widespread changes in the microRNA expression profile. AB - Tissue factor (TF) is a transmembrane receptor for coagulation factor VII/VIIa and is frequently overexpressed by cancer cells. The TF/VIIa complex acts as the main initiator of the clotting cascade in blood and a trigger of intracellular signaling that changes gene expression and the cellular phenotype. However, pathways mediating these changes are still poorly characterized and especially the impact of TF signals on regulatory microRNA (miR) networks in cancer remains unknown. We show that the monoclonal antibody that selectively neutralises the signaling (but not coagulant) function of human TF (CNTO 2559) inhibits progression of MDA-MB-231 breast cancer xenografts in mice and prolongs animal survival. CNTO 2559 blocks FVIIa-induced expression of interleukin 8 (IL-8) by cancer cells without impacting factor Xa (FXa) generation. Notably, acute exposure of MDA-MB-231 tumour xenografts to CNTO 2559 systemic injections triggers wide spread changes in the tumour miR profile including alterations in 75 miRs (55 downregulated) and impacting several miR-regulated and cancer-related pathways. These results suggest that TF signaling in the tumour microenvironment may provoke vast changes in the miR profile of cancer cells, affect disease biology, and reflect tumour interaction with the coagulation system, thereby presenting itself as a possible biomarker. PMID- 29111327 TI - Overexpression of exchange protein directly activated by cAMP-1 (EPAC1) attenuates bladder cancer cell migration. AB - Exchange protein directly activated by cAMP (EPAC) is a mediator of a cAMP signaling pathway that is independent of protein kinase A. EPAC has two isoforms (EPAC1 and EPAC2) and is a cAMP-dependent guanine nucleotide exchange factor for the small GTPases, Rap1 and Rap2. Recent studies suggest that EPAC1 has both positive and negative influences on cancer and is involved in cell proliferation, apoptosis, migration and metastasis. We report that EPAC1 and EPAC2 expression levels were significantly lower in bladder cancer tissue than in normal bladder tissue. In addition, bladder cancer cell lines showed reduced EPAC1 mRNA expression. Furthermore, EPAC1 overexpression in bladder cancer cell lines induced morphologic changes and markedly suppressed cell migration without affecting cell viability. The overexpressed EPAC1 preferentially localized at cell-cell interfaces. In conclusion, reduced EPAC1 expression in bladder tumors and poor migration of EPAC1-overexpressing cells implicate EPAC1 as an inhibitor of bladder cancer cell migration. PMID- 29111326 TI - C/EBPbeta contributes to transcriptional activation of long non-coding RNA NEAT1 during APL cell differentiation. AB - Emerging evidences have shown that long non-coding RNAs (lncRNAs) play critical roles in cancer development and cancer therapy. LncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) is indispensable during acute promyelocytic leukemia (APL) cell differentiation induced by all-trans retinoic acid (ATRA). However, the precise mechanism of NEAT1 upregulation has not been fully understood. In this study, we performed chromatin immunoprecipitation and luciferase reporter assays to demonstrate that C/EBP family transcription factor C/EBPbeta bind to and transactivate the promoter of lncRNA NEAT1 through the C/EBPbeta binding sites both around -54 bp and -1453 bp upstream of the transcription start site. Moreover, the expression of C/EBPbeta was increased after ATRA treatment, and the binding of C/EBPbeta in the NEAT1 promoter was also dramatically increased. Finally, knockdown of C/EBPbeta significantly reduced the ATRA-induced upregulation of NEAT1. In conclusion, C/EBPbeta directly activates the expression of NEAT1 through binding to the promoter of NEAT1. Knockdown of C/EBPbeta impairs ATRA-induced transcriptional activation of NEAT1. Our data indicate that C/EBPbeta contributes to ATRA-induced activation of NEAT1 during APL cell differentiation. Our results enrich our knowledge on the regulation of lncRNAs and the regulatory role of C/EBPbeta in APL cell differentiation. PMID- 29111328 TI - 3-(Naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride attenuates NLRP3 inflammasome-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglial cells. AB - The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome is a multiprotein complex with a role in innate immune responses. NLRP3 inflammasome dysfunction is a common feature of chronic inflammatory diseases. Microglia activation is also associated with neuroinflammatory pathologies. We previously reported that 3-(naphthalen-2 yl(propoxy)methyl)azetidine hydrochloride (KHG26792) reduced hypoxia-induced toxicity by modulating inflammation. However, no studies have elucidated the precise mechanisms for the anti-inflammatory action of KHG26792, in particular via inflammasome mediation. This study investigated the effects of KHG26792 on the inflammasome-mediated signaling pathway in lipopolysaccharide (LPS) stimulated BV2 microglial cells. KHG26792 significantly attenuated several inflammatory responses including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, reactive oxygen species, and mitochondrial potential in these cells. KHG26792 also suppressed LPS-induced increase NLRP3, activated caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) levels. Furthermore, KHG26792 successfully blocked LPS-activated adenosine triphosphate (ATP) level, likely through the purinergic receptor P2X ligand-gated ion channel 7 (P2X7) receptor. Our results suggest that the anti inflammatory functions of KHG26792 may be, at least in part, due to regulation of the P2X7R/NLRP3-mediated signaling pathway during microglial activation. PMID- 29111330 TI - Imaging mass spectroscopy delineates the thinned and thickened walls of intracranial aneurysms. AB - OBJECT: The wall thickness of intracranial aneurysms (IAs) is heterogeneous. Although thinning of the IA wall is thought to contribute to IA rupture, the underlying mechanism remains poorly understood. Recently, imaging mass spectroscopy (IMS) has been used to reveal the distribution of phospholipids in vascular diseases. To investigate the feature of phospholipid composition of IA walls, we conducted IMS in a rat model of experimentally induced IA. MATERIAL AND METHODS: IAs were surgically induced in 7-week-old male rats and analyzed by IMS in negative-ion mode. RESULTS: A molecule at m/z 885.5 was more abundant in the thickened wall than in the thinned wall (P = 0.03). Multiple-stage mass spectroscopy revealed the molecule to be phosphatidylinositol containing stearic acid and arachidonic acid (PI 18:0/20:4). Immunohistochemistry indicated that vascular smooth muscle cells (SMCs) in the thickened wall had dedifferentiated phenotypes. To investigate the relationship between accumulation of PI (18:0/20:4) and phenotypic changes in SMCs, we subjected primary mouse aortic SMCs to liquid chromatography-tandem mass spectrometry. Notably, dedifferentiated SMCs had 1.3-fold more PI (18:0/20:4) than partly differentiated SMCs. CONCLUSIONS: Our study demonstrated the heterogeneity in phospholipid composition of the aneurysmal walls using experimentally induced IAs. PI (18:0/20:4) accumulated at high levels in the thickened aneurysmal wall where synthetic dedifferentiated SMCs exist, suggesting that this phospholipid may be involved in the phenotypic switching of medial SMCs in the IA wall. PMID- 29111329 TI - Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. AB - Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of alpha-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor beta1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment. PMID- 29111332 TI - Floating right heart thrombi: A pooled analysis of cases reported over the past 10years. AB - INTRODUCTION: Floating right heart thrombi (FRHTS) are a rare phenomenon associated with high mortality. Immediate treatment is mandatory, but optimal therapy is controversial. OBJECTIVE: To compare the clinical characteristics according to different treatment strategies and to identify predictors of mortality on patients with FRHTS. METHODS: We conducted a systematic search of reported clinical cases of TTRH from 2006 to 2016. RESULTS: 207 patients were analyzed, median age was 60years, 51.7% were men, 31.4% presented with shock. Pulmonary thromboembolism was present in 85% of the cases. The treatments administered were anticoagulation therapy in 44 patients (21.28%), surgical embolectomy in 89 patients (43%), thrombolytic therapy in 66 patients (31.8%), percutaneous thrombectomy in 3 patients (1.93%) and fibrinolytic in situ in 4 (1.45%). The overall mortality rate was 21.3%. The mortality associated with anticoagulation alone was higher than surgical embolectomy or thrombolysis (36.4 vs 18% vs 18.2%, respectively, p=0.03), and in percutaneous thrombectomy and fibrinolytics in situ was 0%. At multivariate analysis, only anticoagulation alone (odds ratio [OR] 2.4, IC 95% 1.07-5.4, p=0.03), and shock (OR 2.87 (IC 95% 1.3-5.9, p=0.005) showed a statistically significant effect on mortality. CONCLUSION: FRHTS represent a serious form of thromboembolism that requires rapid decisions to improve the survival. Anticoagulation as the only strategy does not seem to be sufficient, while thrombolysis and surgical thrombectomy show better and similar results. A proper individualization of the risk and benefits of both techniques is necessary to choose the most appropriate strategy for our patients. PMID- 29111331 TI - Mating and social exposure induces an opioid-dependent conditioned place preference in male but not in female prairie voles (Microtus ochrogaster). AB - In rodents, sexual stimulation induces a positive affective state that is evaluated by the conditioned place preference (CPP) test. Opioids are released during sexual behavior and modulate the rewarding properties of this behavior. Prairie voles (Microtus ochrogaster) are a socially monogamous species, in which copulation with cohabitation for 6h induces a pair bond. However, the mating induced reward state that could contribute to the establishment of the long-term pair bond has not been evaluated in this species. The present study aimed to determine whether one ejaculation or cohabitation with mating for 6h is rewarding for voles. We also evaluated whether this state is opioid dependent. Our results demonstrate that mating with one ejaculation and social cohabitation with mating for 6h induce a CPP in males, while exposure to a sexually receptive female without mating did not induce CPP. In the female vole, mating until one ejaculation, social cohabitation with mating, or exposure to a male without physical interaction for 6h did not induce CPP. To evaluate whether the rewarding state in males is opioid dependent, the antagonist naloxone was injected i.p. The administration of naloxone blocked the rewarding state induced by one ejaculation and by social cohabitation with mating. Our results demonstrate that in the prairie vole, on the basis of the CPP in the testing conditions used here, the stimulation received with one ejaculation and the mating conditions that lead to pair bonding formation may be rewarding for males, and this reward state is opioid dependent. PMID- 29111333 TI - Oxalic acid quantification in mouse urine and primary mouse hepatocyte cell culture samples by ion exclusion chromatography-mass spectrometry. AB - Due to medical relevance and a direct correlation with some diseases, accurate quantification of oxalic acid in different complex matrices is required. Effective chromatographic separation of this strong carboxylic acid was achieved by ion exclusion chromatography (IELC). Sensitive and selective detection was carried out by means of electrospray ionization-tandem mass spectrometry. Furthermore, it was shown that the isobaric interference of lactic acid is chromatographically resolved. Structurally similar compounds like glyoxylic acid and glycolic acid were baseline separated as well. The application of stable isotope dilution analysis with 13C2 oxalic acid facilitated precise quantification. The developed method was validated with a reference oxalate sample of human urine diluted to a range of 10-500MUM. Finally, the applicability of this method was demonstrated on complex matrices, like mouse urine and supernatants of primary mouse hepatocyte cell cultures. PMID- 29111334 TI - Associations between the effort-reward imbalance model of workplace stress and indices of cardiovascular health: A systematic review and meta-analysis. AB - Work stress can increase the risk of cardiovascular disease by 50%, with increasing research focusing on the underlying mechanisms responsible for these associations. Our meta-analysis assessed the associations of the effort-reward imbalance (ERI) workplace stress model with indices of cardiovascular disease. The search term 'effort*reward*imbalance' produced 22 papers (129 associations, N=93,817) meeting inclusion criteria. Greater ERI was most associated with increased hypertension (r=0.26, p<0.001, N=1180), intima media thickness (r=0.23, p<.001, N=828) and fibrinogen (r=0.13, p=0.03, N=4315). Trait over-commitment was most associated with increased hypertension (r=0.24, p=0.02, N=899) and intima media thickness (r=0.19, p=0.02, N=828). Interventions aimed at reducing the impact of ERI and over-commitment on cardiovascular disease should consider concurrently assessing changes in physiological markers of cardiovascular disease. PMID- 29111336 TI - Regenerative Effects of Basic Fibroblast Growth Factor on Restoration of Thyroarytenoid Muscle Atrophy Caused by Recurrent Laryngeal Nerve Transection. AB - OBJECTIVES: Vocal fold atrophy following unilateral vocal fold paralysis is caused by atrophy of the thyroarytenoid (TA) muscle and remains a challenge. Medialization procedures are popular treatment options; however, hoarseness often remains due to the reduction in mass or tension of the TA muscle. Therefore, in addition to medialization procedures, TA muscle reinnervation is desirable. In vivo studies have shown the potential for basic fibroblast growth factor (bFGF) to affect muscular and nerve regeneration. The present study aimed to examine the regenerative effects of bFGF on restoration of TA muscle atrophy caused by recurrent laryngeal nerve transection. STUDY DESIGN: Prospective animal experiments with controls. METHODS: TA muscle atrophy was induced by unilateral transection of the recurrent laryngeal nerve. One month after transection, different doses (200 ng, 100 ng, 10 ng) of bFGF in 50 uL were repeatedly injected into the TA muscle four times with an interval of 1 week between injections. Saline only was injected in the sham group. Larynges were harvested for histologic and immunohistochemical examination 4 weeks after the final injection. RESULTS: The cross-sectional TA muscle area was significantly larger in the bFGF treated groups compared with the sham-treated groups. Immunohistochemistry indicated that bFGF significantly increases the number of neuromuscular junctions and satellite cells in the TA muscle. CONCLUSIONS: These results suggest that local application of bFGF to the TA muscle may improve TA muscle atrophy caused by recurrent laryngeal nerve paralysis. Furthermore, bFGF may have regenerative effects on both nerves and muscles. PMID- 29111335 TI - Estimated Glomerular Filtration Rate, Cardiovascular Events and Mortality Across Age Groups Among Individuals Older Than 60 Years in Southern Europe. AB - INTRODUCTION AND OBJECTIVES: Individuals with a decreased estimated glomerular filtration rate (eGFR) are at increased risk of all-cause (ACM) and cardiovascular mortality; there is ongoing debate about whether older individuals with eGFR 45 to 59mL/min/1.73 m2 are also at increased risk. We evaluated the association between eGFR and ACM and cardiovascular events (CVE) in people aged 60 to 74 and >= 75 years in a population with a low coronary disease incidence. METHODS: We conducted a retrospective cohort study by using primary care and hospital electronic records. We included 130 233 individuals aged >= 60 years with creatinine measurement between January 1, 2010 and December 31, 2011; eGFR was estimated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. The independent association between eGFR and the risk of ACM and hospital admission due to CVE were determined with Cox and Fine-Gray regressions, respectively. RESULTS: The median was age 70 years, and 56.1% were women; 13.5% had eGFR < 60 (69.7% eGFR 45-59). During a median follow-up of 38.2 months, 6474 participants died and 3746 had a CVE. For ACM and CVE, the HR in older individuals became significant at eGFR < 60. Fully adjusted HR for ACM in the eGFR 45 to 59 category were 1.61; 95%CI, 1.37-1.89 and 1.19; 95%CI, 1.10-1.28 in 60- to 74-year-olds and >= 75-year-olds, respectively; for CVE HR were 1.28; 95%CI, 1.08-1.51 and 1.12; 95%CI, 0.99-1.26. CONCLUSIONS: In a region with low coronary disease incidence, the risk of death and CVE increased with decreasing eGFR. In >= 75-year-olds, the eGFR 45 to 59 category, which had borderline risk for CVE, included many individuals without significant additional risk. PMID- 29111337 TI - The Vocal Tract Organ: A New Musical Instrument Using 3-D Printed Vocal Tracts. AB - The advent and now increasingly widespread availability of 3-D printers is transforming our understanding of the natural world by enabling observations to be made in a tangible manner. This paper describes the use of 3-D printed models of the vocal tract for different vowels that are used to create an acoustic output when stimulated with an appropriate sound source in a new musical instrument: the Vocal Tract Organ. The shape of each printed vocal tract is recovered from magnetic resonance imaging. It sits atop a loudspeaker to which is provided an acoustic L-F model larynx input signal that is controlled by the notes played on a musical instrument digital interface device such as a keyboard. The larynx input is subject to vibrato with extent and frequency adjustable as desired within the ranges usually found for human singing. Polyphonic inputs for choral singing textures can be applied via a single loudspeaker and vocal tract, invoking the approximation of linearity in the voice production system, thereby making multiple vowel stops a possibility while keeping the complexity of the instrument in reasonable check. The Vocal Tract Organ offers a much more human and natural sounding result than the traditional Vox Humana stops found in larger pipe organs, offering the possibility of enhancing pipe organs of the future as well as becoming the basis for a "multi-vowel" chamber organ in its own right. PMID- 29111338 TI - Cross-cultural Adaptation and Validation of the Italian Version of the Vocal Tract Discomfort Scale (I-VTD). AB - OBJECTIVE: To evaluate the reliability and validity of the Italian version of the VTD scale (I-VTD scale). STUDY DESIGN: Cross-sectional, nonrandomized, prospective study with controls. METHODS: For the item generation, a cross cultural adaptation and translation process was performed following the back translation process (phase 1). For reproducibility analysis (phase 2), 102 patients with dysphonia were recruited (internal consistency analysis); 57 of them completed the I-VTD scale twice (test-retest reliability analysis). Seventy three vocally healthy participants completed the I-VTD scale for normative data generation (phase 3). For validity analysis (phase 4), the scores obtained by patients with dysphonia and by vocally healthy participants were compared (construct validity analysis); in addition, 45 patients with dysphonia completed both the I-VTD scale and the Italian version of the Voice Handicap Index for criterion validity analysis. Finally, for responsiveness analysis (phase 5), a cohort of 30 patients with muscle tension dysphonia was recruited, and scores of the I-VTD scale before and after voice therapy were compared. RESULTS: Both the internal consistency and the test-retest reliability of the I-VTD scale were satisfactory. The scores obtained by patients with dysphonia and vocally healthy participants were significantly different. Moderate correlations between the Italian version of the Voice Handicap Index and the I-VTD scores were found. Finally, the scores of the I-VTD scale obtained in pretreatment conditions appeared to be significantly higher than those obtained after successful voice therapy. CONCLUSION: The I-VTD scale appears a reliable and valid instrument for the assessment of vocal tract discomfort in Italian-speaking patients. PMID- 29111339 TI - Combined Vocal Exercises for Rehabilitation After Supracricoid Laryngectomy: Evaluation of Different Execution Times. AB - INTRODUCTION: The supracricoid partial laryngectomy allows the preservation of laryngeal functions with good local cancer control. OBJECTIVE: To assess laryngeal configuration and voice analysis data following the performance of a combination of two vocal exercises: the prolonged /b/vocal exercise combined with the vowel /e/ using chest and arm pushing with different durations among individuals who have undergone supracricoid laryngectomy. METHODS: Eleven patients undergoing partial laryngectomy supracricoid with cricohyoidoepiglottopexy (CHEP) were evaluated using voice recording. Four judges performed separately a perceptive-vocal analysis of hearing voices, with random samples. For the analysis of intrajudge reliability, repetitions of 70% of the voices were done. Intraclass correlation coefficient was used to analyze the reliability of the judges. For an analysis of each judge to the comparison between zero time (time point 0), after the first series of exercises (time point 1), after the second series (time point 2), after the third series (time point 3), after the fourth series (time point 4), and after the fifth and final series (time point 5), the Friedman test was used with a significance level of 5%. The data relative to the configuration of the larynx were subjected to a descriptive analysis. RESULTS: In the evaluation, were considered the judge results 1 which have greater reliability. There was an improvement in the general level of vocal, roughness, and breathiness deviations from time point 4 [T4]. CONCLUSION: The prolonged /b/vocal exercise, combined with the vowel /e/ using chest- and arm pushing exercises, was associated with an improvement in the overall grade of vocal deviation, roughness, and breathiness starting at minute 4 among patients who had undergone supracricoid laryngectomy with CHEP reconstruction. PMID- 29111340 TI - Agenesis of the Left Internal Carotid Artery Associated with Dolichoectatic Intracranial Arteries. AB - A 28-year-old man without a significant medical history visited our hospital complaining of a headache. Computed tomography (CT) demonstrated thick, calcified vertebral artery (VA) and basilar artery (BA), despite the patient being young. Magnetic resonance angiography demonstrated the absence of the left internal carotid artery (ICA). The right ICA, the bilateral VA, and the BA were well developed and dolichoectatic. CT revealed the absence of the carotid canal on the left side. The condition was diagnosed as congenital agenesis of the left ICA with dolichoectatic changes in 3 other arteries. In a young patient with thick, calcified intracranial arteries, close examination is necessary, because vascular anomalies such as ICA agenesis may exist. PMID- 29111341 TI - Low-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Intravenous thrombolysis using tissue plasminogen activator (tPA) improves significantly the neurologic function in patients with acute ischemic stroke (AIS). However, it brings financial burden to patients and is associated with symptomatic intracranial hemorrhage (SICH). Whether low-dose tPA can effectively reduce SICH and has the same efficacy as standard-dose tPA is still controversial. METHODS: We searched for English clinical trials published before March, 2017on the comparison of the efficacy and safety between low and standard dose of tPA in the treatment of AIS using MEDLINE, Embase, and Cochrane Library. The modified Rankin scale (mRS) score was used as the primary efficacy outcome. The mRS1 corresponded to 0-1, whereas mRS2 corresponded to 0-2. The SICH and mortality were adopted as primary safety outcomes. RESULTS: Twelve high-quality studies were selected, including 7686 patients (low-dose: 2888, standard-dose: 4798). With no statistical heterogeneity, the fixed effects model was adopted in the analysis. Similarly to standard doses, low-dose tPA improved the mRS scores (mRS1: odds ratio [OR] = .92, 95% confidence interval [CI] .84-1.02; P = .12; mRS2: OR = .97, 95% CI .88-1.08; P = .57). Compared with standard-dose tPA, low dose tPA reduced the incidence of SICH (by National Institute of Neurological Disorders and Stroke [NINDS] definition: OR = .71, 95% CI .57-0.89; P = .003; by Safe Implementation of Thrombolysis in Stroke Monitoring Study [SITS-MOST] definition: OR = .64, 95% CI .42-0.99; P = .04), while both reduced mortality (OR = .87, 95% CI .74-1.02; P = .08). CONCLUSIONS: Low-dose tPA is comparable to standard-dose tPA in improving the neurologic function and reducing mortality in AIS patients. Moreover, low-dose tPA can reduce the incidence of SICH compared with standard-dose tPA. Therefore, low-dose tPA is highly recommended in AIS patients. PMID- 29111342 TI - The Use of Repetitive Transcranial Magnetic Stimulation for Stroke Rehabilitation: A Systematic Review. AB - OBJECTIVES: Stroke is a leading cause of disability. Alternative and more effective techniques for stroke rehabilitation have been sought to overcome limitations of conventional therapies. Repetitive transcranial magnetic stimulation (rTMS) arises as a promising tool in this context. This systematic review aims to provide a state of the art on the application of rTMS in stroke patients and to assess its effectiveness in clinical rehabilitation of motor function. METHODS: Studies included in this review were identified by searching PubMed and ISI Web of Science. The search terms were (rTMS OR "repetitive transcranial magnetic stimulation") AND (stroke OR "cerebrovascular accident" OR CVA) AND (rehab OR rehabilitation OR recover*). The retrieved records were assessed for eligibility and the most relevant features extracted to a summary table. RESULTS: Seventy out of 691 records were deemed eligible, according to the selection criteria. The majority of the articles report rTMS showing potential in improving motor function, although some negative reports, all from randomized controlled trials, contradict this claim. Future studies are needed because there is a possibility that a bias for non-publication of negative results may be present. CONCLUSIONS: rTMS has been shown to be a promising tool for stroke rehabilitation, in spite of the lack of standard operational procedures and harmonization. Efforts should be devoted to provide a greater understanding of the underlying mechanisms and protocol standardization. PMID- 29111343 TI - Kinetic Origin of Substrate Specificity in Post-Transfer Editing by Leucyl-tRNA Synthetase. AB - The intrinsic editing capacities of aminoacyl-tRNA synthetases ensure a high fidelity translation of the amino acids that possess effective non-cognate aminoacylation surrogates. The dominant error-correction pathway comprises deacylation of misaminoacylated tRNA within the aminoacyl-tRNA synthetase editing site. To assess the origin of specificity of Escherichia coli leucyl-tRNA synthetase (LeuRS) against the cognate aminoacylation product in editing, we followed binding and catalysis independently using cognate leucyl- and non cognate norvalyl-tRNALeu and their non-hydrolyzable analogues. We found that the amino acid part (leucine versus norvaline) of (mis)aminoacyl-tRNAs can contribute approximately 10-fold to ground-state discrimination at the editing site. In sharp contrast, the rate of deacylation of leucyl- and norvalyl-tRNALeu differed by about 104-fold. We further established the critical role for the A76 3'-OH group of the tRNALeu in post-transfer editing, which supports the substrate assisted deacylation mechanism. Interestingly, the abrogation of the LeuRS specificity determinant threonine 252 did not improve the affinity of the editing site for the cognate leucine as expected, but instead substantially enhanced the rate of leucyl-tRNALeu hydrolysis. In line with that, molecular dynamics simulations revealed that the wild-type enzyme, but not the T252A mutant, enforced leucine to adopt the side-chain conformation that promotes the steric exclusion of a putative catalytic water. Our data demonstrated that the LeuRS editing site exhibits amino acid specificity of kinetic origin, arguing against the anticipated prominent role of steric exclusion in the rejection of leucine. This feature distinguishes editing from the synthetic site, which relies on ground-state discrimination in amino acid selection. PMID- 29111345 TI - Aminoacyl-tRNA Quality Control Provides a Speedy Solution to Discriminate Right from Wrong. PMID- 29111344 TI - The Crystal Structure and Conformations of an Unbranched Mixed Tri-Ubiquitin Chain Containing K48 and K63 Linkages. AB - The ability of ubiquitin to function in a wide range of cellular processes is ascribed to its capacity to cause a diverse spectrum of modifications. While a target protein can be modified with monoubiquitin, it can also be modified with ubiquitin chains. The latter include seven types of homotypic chains as well as mixed ubiquitin chains. In a mixed chain, not all the isopeptide bonds are restricted to a specific lysine of ubiquitin, resulting in a chain possessing more than one type of linkage. While structural characterization of homotypic chains has been well elucidated, less is known about mixed chains. Here we present the crystal structure of a mixed tri-ubiquitin chain at 3.1-A resolution. In the structure, the proximal ubiquitin is connected to the middle ubiquitin via K48 and these two ubiquitins adopt a compact structure as observed in K48 di ubiquitin. The middle ubiquitin links to the distal ubiquitin via its K63 and these ubiquitins adopt two conformations, suggesting a flexible structure. Using small-angle X-ray scattering, we unexpectedly found differences between the conformational ensembles of the above tri-ubiquitin chains and chains possessing the same linkages but in the reverse order. In addition, cleavage of the K48 linkage by DUB is faster if this linkage is at the distal end. Taken together, our results suggest that in mixed chains, not only the type of the linkages but also their sequence determine the structural and functional properties of the chain. PMID- 29111346 TI - Evidence for M1-Linked Polyubiquitin-Mediated Conformational Change in NEMO. AB - The NF-kappaB essential modulator (NEMO) is the scaffolding subunit of the inhibitor of kappaB kinase (IKK) holocomplex and is required for the activation of the catalytic IKK subunits, IKKalpha and IKKbeta, during the canonical inflammatory response. Although structures of shorter constructs of NEMO have been solved, efforts to elucidate the full-length structure of NEMO have proved difficult due to its apparent high conformational plasticity. To better characterize the gross dimensions of full-length NEMO, we employed in-line size exclusion chromatography-small-angle X-ray scattering. We show that NEMO adopts a more compact conformation (Dmax=320A) than predicted for a fully extended coiled coil structure (>500A). In addition, we map a region of NEMO (residues 112-150) in its coiled-coil 1 domain that impedes the binding of linear (M1-linked) di ubiquitin to its coiled-coil 2-leucine zipper ubiquitin binding domain. This ubiquitin binding inhibition can be overcome by a longer chain of linear, but not K63-linked polyubiquitin. Collectively, these observations suggest that NEMO may be auto-inhibited in the resting state by intramolecular interactions and that during signaling, NEMO may be allosterically activated by binding to long M1 linked polyubiquitin chains. PMID- 29111347 TI - N6L pseudopeptide interferes with nucleophosmin protein-protein interactions and sensitizes leukemic cells to chemotherapy. AB - NPM1 is a multifunctional nucleolar protein implicated in several processes such as ribosome maturation and export, DNA damage response and apoptotic response to stress stimuli. The NPM1 gene is involved in human tumorigenesis and is found mutated in one third of acute myeloid leukemia patients, leading to the aberrant cytoplasmic localization of NPM1. Recent studies indicated that the N6L multivalent pseudopeptide, a synthetic ligand of cell-surface nucleolin, is also able to bind NPM1 with high affinity. N6L inhibits cell growth with different mechanisms and represents a good candidate as a novel anticancer drug for a number of malignancies of different histological origin. In this study we investigated whether N6L treatment could drive antitumor effect in acute myeloid leukemia cell lines. We found that N6L binds NPM1 at the N-terminal domain, co localizes with cytoplasmic, mutated NPM1, and interferes with its protein-protein associations. N6L toxicity appears to be p53 dependent but interestingly, the leukemic cell line harbouring the mutated form of NPM1 is more resistant to treatment, suggesting that NPM1 cytoplasmic delocalization confers protection from p53 activation. Moreover, we show that N6L sensitizes AML cells to doxorubicin and cytarabine treatment. These studies suggest that N6L may be a promising option in combination therapies for acute myeloid leukemia treatment. PMID- 29111348 TI - NRPa-308, a new neuropilin-1 antagonist, exerts in vitro anti-angiogenic and anti proliferative effects and in vivo anti-cancer effects in a mouse xenograft model. AB - Neuropilin-1 (NRP-1) is an extra-cellular receptor for the main Vascular Endothelial Growth Factor over-expressed in tumour tissues, VEGF-A165. Consequently, NRP-1 is involved in angiogenesis and in tumour growth, and its over-expression is related to a clinical poor prognosis. NRP-1 appears as a major target in oncology, which remains poorly exploited. Herein, we report a new series of 18 small-sized fully organic VEGF-A165/NRP-1 antagonists (NRPas). These compounds share an original scaffold, including two linkers (sulphonamide and amide) and three aromatic cores. Among them, 2a (renamed NRPa-308) emerges as a promising "hit". In vitro,2a exerts not only potent anti-angiogenic activity, but also significant effects on cell viability of large panel of human solid and haematological cancer cell lines. Importantly, 2a is less cytotoxic on healthy tissues than the marketed anti-angiogenic drug sunitinib. Lastly, in a mouse xenograft model (human MDA-MB-231 breast cancer cells), 2a improves the median survival and reduces the tumour growth, but does not exert visible acute toxicity. Altogether, these results highlight its huge potential for a further "hit-to-lead" optimization, leading to new anti-cancer drugs. PMID- 29111349 TI - The developmental transcription factor IRF6 attenuates ABCG2 gene expression and distinctively reverses stemness phenotype in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC), which originates from the nasopharynx, is highly prevalent in Southern China and Southeast Asia, and more than 90% of all NPCs are non-keratinizing undifferentiated cells or poorly differentiated squamous cells. Cancer stem cells (CSCs) are capable of self-renewal and have differentiation potential. These properties form the basis of cancer initiation, development, and radiochemoresistance. However, the molecular mechanisms underlying NPC CSC maintenance remain poorly understood. Here, genomic expression profiling using our previously established monoclonal cellular and animal models revealed that interferon regulatory factor 6 (IRF6) was downregulated in highly metastatic NPC cells, cancer stem-like NPC cells and animal models. Functional assays revealed that elevated IRF6 expression suppressed cell proliferation, growth, CSCs properties and enhanced cell chemotherapeutic sensitivity. However, silencing IRF6 resulted in opposing effects. Moreover, we determined that as a tumor suppressor gene and transcription factor, IRF6 directly bound the upstream region of the ATP-binding cassette sub-family G member 2 (ABCG2) DNA element and suppressed target ABCG2 expression in NPC cells. Consistently, an inverse correlation was observed between the mRNA levels of IRF6 and ABCG2 in clinical NPC samples. With these results, we provide the first evidence that IRF6 directly targets the ABCG2 gene and selectively kills CSCs in NPC and that IRF6 may be a valuable tool for developing new CSC-targeted treatment strategies for undifferentiated NPC patients. PMID- 29111350 TI - Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship. AB - In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high proliferation rate, malignant cells undergo metabolic changes that result in an increased production of lactate, nitric oxide, reactive oxygen species, prostaglandins and other byproducts of arachidonic acid metabolism that influence both the composition of the inflammatory microenvironment and the function of the tumor-associated macrophages (TAMs). In response to cues present in the TME, among which products of altered tumor cell metabolism, TAMs are also required to reprogram their metabolism, with activation of glycolysis, fatty acid synthesis and altered nitrogen cycle metabolism. These changes result in functional reprogramming of TAMs which includes changes in the production of cytokines and angiogenetic factors, and contribute to the tumor progression and metastasis. Understanding the metabolic changes governing the intricate relationship between the tumor cells and the TAMs represents an essential step towards developing novel therapeutic approaches targeting the metabolic reprogramming of the immune cells to potentiate their tumoricidal potential and to circumvent therapy resistance. PMID- 29111351 TI - Chemoprevention with isothiocyanates - From bench to bedside. AB - Isothiocyanates (ITCs) are naturally occurring hydrolization products from glucosinolates (GLSs) in brassicaceae and in epidemiological studies their intake has been weakly to moderately inversely correlated with the risk of colorectal cancer, prostate cancer and lung cancer. Numerous preclinical studies demonstrate chemopreventive mode of actions of ITCs, mainly related to a.) detoxification (induction of phase II enzymes), b.) anti-inflammatory properties by down regulation of NFkappaB activity, c.) cyclin-mediated cell cycle arrest and d.) epigenetic modulation by inhibition of histone deacetylase activity. First prospective clinical trials were promising in patients with risk of prostate cancer recurrence. The glutathione-S-transferase gene expression seems to play a major role in the individual susceptibility towards ITCs. Safety issues are widely unclear and should be more addressed in future studies because ITCs can, in low concentrations, compromise the function of human immune cells and might impair genome stability. PMID- 29111352 TI - Use of antibiotics in paediatric long-term care facilities. AB - BACKGROUND: Adult long-term care (LTC) facilities have high rates of antibiotic use, raising concerns about antimicrobial resistance. Few studies have examined antibiotic use in paediatric LTC facilities. AIM: To describe antibiotic use in three paediatric LTC facilities and to describe the factors associated with use. METHODS: A retrospective cohort study was conducted from September 2012 to December 2015 in three paediatric LTC facilities. Medical records were reviewed for demographics, healthcare-associated infections (HAIs), antimicrobial use and diagnostic testing. Logistic regression was used to identify predictors for antibiotic use. The association between susceptibility testing results and appropriate antibiotic coverage was determined using Chi-squared test. FINDINGS: Fifty-eight percent (413/717) of residents had at least one HAI, and 79% (325/413) of these residents were treated with at least one antibiotic course, totalling 2.75 antibiotic courses per 1000 resident-days. Length of enrolment greater than one year, having a neurological disorder, having a tracheostomy, and being hospitalized at least once during the study period were significantly associated with receiving antibiotics when controlling for facility (all P < 0.001). Diagnostic testing was performed for 40% of antibiotic-treated HAIs. Eighty-six percent of antibiotic courses for identified bacterial pathogens (201/233) provided appropriate coverage. Access to susceptibility testing was not associated with appropriate antibiotic choice (P = 0.26). CONCLUSION: Use of antibiotics in paediatric LTC facilities is widespread. There is further need to assess antibiotic use in paediatric LTC facilities. Evaluation of the adverse outcomes associated with inappropriate antibiotic use, including the prevalence of resistant organisms in paediatric LTC facilities, is critical. PMID- 29111353 TI - Clinical factors predicting persistent carriage of Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae among patients with known carriage. AB - BACKGROUND: Information on the natural duration of carbapenem-resistant Enterobacteriaceae (CRE) carriage and factors associated with persistence of carriage is limited. AIM: To evaluate the clinical variables associated with persistent carriage of Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. METHODS: Data for patients admitted between June 2015 and December 2016 who were identified as KPC-producing CRE carriers by either rectal swabs or clinical cultures were reviewed retrospectively. Patients with follow-up culture data for three months after initial acquisition were included. Regression models were used to evaluate the clinical variables associated with persistence of carriage. FINDINGS: Of the 100 eligible patients, 50 patients (50%) experienced spontaneous decolonization within three months. Among the 50 patients (50%) who remained culture positive after three months, 26 patients carried KPC-producing CRE after six months. Multi-variable analysis revealed that re-admission [adjusted odds ratio (aOR) 9.96; 95% confidence interval (CI) 1.13-87.98; P=0.039], duration of hospitalization (aOR 1.03; 95% CI 1.01-1.05; P=0.003), positive clinical culture (aOR 6.26; 95% CI 1.28-30.54; P=0.023) and carbapenem use (OR 9.15; 95% CI 1.85 45.27; P=0.007) were predictive for persistent carriage after six months. CONCLUSION: The results suggest that patients with KPC-producing CRE in clinical specimens who are using carbapenem, particularly those with multiple and prolonged hospitalizations, are more likely to remain carriers after six months of initial acquisition. This information is useful for coordinating strategies for pre-emptive isolation by predicting the CRE carriage status appropriately, and ensuring active surveillance through risk factor stratification. PMID- 29111354 TI - Three GPI-anchored alkaline phosphatases are involved in the intoxication of Cry1Ca toxin to Spodoptera exigua larvae. AB - Glycosylphosphatidylinositol (GPI)-anchored alkaline phosphatase (ALP) isoforms are crucial for the intoxication of crystal proteins (Cry) to several insect species. We cloned five SeALPs from the larval midgut of Spodoptera exigua, a major pest of many crops. All five SeALPs contain a signal peptide at the N terminus, a phosphatase domain, and a GPI-anchor site at the C-terminus. Additionally, the sequences encode two or three potential N-glycosylation sites. The five SeALPs were highly expressed at the larval stage, especially in the larval gut or Malpighian tubules. Ingestion over four consecutive days of double stranded RNAs (dsRNAs) targeting SeALP1, SeALP2, SeALP3, SeALP4, and SeALP5 significantly reduced the corresponding mRNA levels by 60.0%, 40.0%, 65.6%, 48.1%, and 69.1% respectively, compared with the levels in control larvae that fed on non-specific dsRNA (dsEGFP). When larvae that previously ingested phosphate buffered saline (PBS)-, dsEGFP-, or five dsSeALPs-overlaid diets were then exposed to a diet containing Cry1Ca, the larval mortalities after six days were 70.0%, 71.8%, 49.1%, 54.9%, 65.3%, 52.5%, and 77.4%, respectively. ANOVA analysis revealed that the larvae that previously fed on the dsSeALP1-, dsSeALP2 , and dsSeALP4-overlaid diets had significantly lower mortalities than those that previously ingested the PBS-, dsEGFP-, dsSeALP3- and dsSeALP5-overlaid diets. The results suggest that SeALP1, SeALP2 and SeALP4 are involved in the intoxication of Cry1Ca to S. exigua larvae. PMID- 29111356 TI - Effects of antibiotics on biological activity of Cry1Ac in Bt-susceptible and Bt resistant Helicoverpa armigera strains. AB - In this study, the results showed that the population of midgut bacteria and larval mortality due to Cry1Ac are significantly reduced in antibiotic-treated larvae from Bt-susceptible, -resistant and field-collected strains (96S, BtR, FS respectively) of Helicoverpa armigera. The percentage reduction of larval mortality with increasing concentrations of antibiotics was significantly different among strains with the smallest effect observed in FS. It has been suggested that antibiotics could influence the toxicity of Cry1Ac, possibly by eliminating gut bacteria, hence gut bacteria might be playing essential roles in Bt-induced killing of H. armigera. But elimination of midgut microflora with antibiotics had no effect on resistance level. PMID- 29111355 TI - Transstadial transmission of larval hemocoelic infection negatively affects development and adult female longevity in the mosquito Anopheles gambiae. AB - During all life stages, mosquitoes are exposed to pathogens, and employ an immune system to resist or limit infection. Although much attention has been paid to how adult mosquitoes fight infection, little is known about how an infection during the larval stage affects the biology of the resultant adult. In this study, we investigated whether a bacterial infection in the hemocoel of the African malaria mosquito, Anopheles gambiae, is transstadially transmitted from larvae to adults (both females and males), and whether immune stimulation in the hemocoel as a larva alters development or biological traits of the adult. Specifically, larvae were injected in the hemocoel with either fluorescent microspheres or Escherichia coli, and the following traits were examined: transstadial transmission, larval development to adulthood, adult survival, and adult body size. Our results show that transstadial transmission of hemocoel contents occurs from larvae to pupae and from pupae to adults, but that bacterial prevalence and intensity varies with age. Injury, immune stimulation or infection decreases the proportion of larvae that undergo pupation and eclosion, infection decreases the longevity of adult females, and treatment has complex effects on the body size of the resultant adults. The present study adds larval hemocoelic infection to the known non genetic factors that reduce overall fitness by negatively affecting development and adult biological traits that influence mosquito vector competence. PMID- 29111357 TI - Relevance of Dorsolateral and Frontotemporal Cortex on the Phonemic Verbal Fluency - A fNIRS-Study. AB - Non-invasive brain stimulation is widely used to investigate and manipulate specific brain functions to broaden knowledge about healthy people, and also to provide for a potential treatment option for people with various psychopathological disorders that do not adequately benefit from traditional treatments. Nevertheless, the underlying mechanisms have not been fully investigated yet. The aim of the present study was to investigate whether we could alter the brain activity during a test for executive functioning. Therefore, we measured the activity in the prefrontal cortex (PFC) using near infrared spectroscopy (NIRS) while applying bilateral anodal and cathodal transcranial direct current stimulation (tDCS, 1 mA) to the left and right dorsolateral PFC (dlPFC) during the phonemic part of the verbal fluency test (VFT). A total of 61 young and healthy participants were divided into three groups: left anodal/right cathodal, left cathodal/right anodal stimulation or sham. All participants performed the letter-cued part of the VFT and a control task. Brain activation was simultaneously measured using NIRS. We found only the frontotemporal cortex (FTC) but not the dorsolateral prefrontal cortex (DLPFC) to be activated. Furthermore, stimulating the DLPFC bilaterally by tDCS showed no significant differences between the three different groups when performing the VFT, neither in performance nor in cortical activation. Instead, we found a significant increase in deoxygenated hemoglobin [HHb] while performing the control task in the left anodal/right cathodal stimulation group compared to sham. Interestingly, also an influence on the mood of our participants was observed. These results are of importance especially regarding a better understanding of the influence of the dlPFC on the VFT. PMID- 29111358 TI - Are there Sleep-promoting Neurons in the Mouse Parafacial Zone? AB - Although recent studies have reported that gamma-aminobutyric acid (GABA) neurons in the parafacial zone (PZ) of the rostral medulla are needed for the induction of slow-wave sleep (SWS) and that the PZ is a medullary SWS-promoting center, it remains unknown whether the PZ contains SWS-active or sleep-promoting neurons. In the present study, a total of 125 neurons were recorded, for the first time, in non-anesthetized, head-restrained mice during the complete wake-sleep cycle throughout the PZ of the rostral medulla. The vast majority (87.2%) of the neurons displayed increased activity during both wakefulness (W) and paradoxical (or rapid eye movement) sleep (PS) compared to during SWS (W/PS-active neurons) and a few (8.0%) discharged phasically and selectively during PS (PS-active neurons), but none discharged maximally during SWS (SWS-active neurons) or displayed a higher rate of spontaneous discharge during both SWS and PS than during W (SWS/PS-active neurons). These findings do not support the view that the GABAergic PZ is a medullary SWS-promoting center. PMID- 29111359 TI - Role of Spontaneous Brain Activity in Explicit and Implicit Aspects of Cognitive Flexibility under Socially Conflicting Situations: A Resting-state fMRI Study using Fractional Amplitude of Low-frequency Fluctuations. AB - We are constantly exposed to socially conflicting situations in everyday life, and cognitive flexibility is essential for adaptively coping with such difficulties. Flexible goal choice and pursuit are not exclusively conscious, and therefore cognitive flexibility involves both explicit and implicit forms of processing. However, it is unclear how individual differences in explicit and implicit aspects of flexibility are associated with neural activity in a resting state. Here, we measured intrinsic fractional amplitude of low-frequency fluctuations (fALFF) by resting-state functional magnetic resonance imaging (RS fMRI) as an indicator of regional brain spontaneous activity, together with explicit and implicit aspects of cognitive flexibility using the Cognitive Flexibility Scale (CFS) and Implicit Association Test (IAT). Consistent with the dual processing theory, there was a strong association between explicit aspects of flexibility (CFS score) and "rationalism" thinking style and between implicit aspects (IAT effect) and "experientialism." The level of explicit flexibility was also correlated with fALFF values in the left lateral prefrontal cortex, whereas the level of implicit flexibility was correlated with fALFF values in the right cerebellum. Furthermore, the fALFF values in both regions predicted individual preference for flexible decision-making strategy in a vignettes simulation task. These results add to our understanding of the neural mechanisms underlying flexible decision-making for solving social conflicts. More generally, our findings highlight the utility of RS-fMRI combined with both explicit and implicit psychometric measures for better understanding individual differences in social cognition. PMID- 29111361 TI - Cerebral Venous Collagen Remodeling in a Modified White Matter Lesions Animal Model. AB - To mimic the expected pathological changes of white matter lesions (WMLs) and increase the stability, we applied modified two-vessel occlusion (modified 2VO) (1-week interval bilateral carotid artery occlusion) in stroke-prone renovascular hypertensive rats (RHRSP) and established a modified WMLs model (RHRSP/modified 2VO) that compared their phenotypes with RHRSP and sham-operated rats. In addition, we tried to differentiate small veins from small arteries through the presence of smooth muscle to study the pathological changes of small veins detailed in the model. RHRSP/modified 2VO rats showed higher stability and more extensive white matter damage without an obvious increase in mortality rate at 12 weeks after the modified 2VO operation compared to RHRSP rats. RHRSP/modified 2VO rats showed more severe small venous collagen deposition than RHRSP rats, and the majority of the deposition was collagen I and IV rather than collagen III. In addition, RHRSP/modified 2VO rats possessed cognitive impairment, mild wall thickness and blood-brain barrier disruption. Our findings suggest that the modified WMLs model (RHRSP/modified 2VO) mimics cognitive impairment and small vessel pathological changes similar to WMLs in humans. Differentiating small veins from small arteries through smooth muscle is feasible, and marked small venous deposition may play an important role in the hypertensive white matter lesions. PMID- 29111360 TI - Voluntary Binge-like Ethanol Consumption Site-specifically Increases c-Fos Immunoexpression in Male C57BL6/J Mice. AB - The assessment of binge ethanol-induced neuronal activation, using c-Fos immunoreactivity (IR) as a marker of neuronal activity, is typically accomplished via forced ethanol exposure, such as intraperitoneal injection or gavage. Neuronal activity using a voluntary binge-like drinking model, such as "drinking in-the-dark" (DID), has not been thoroughly explored. Additionally, studies assessing ethanol-elicited neuronal activation may or may not involve stereotaxic surgery, which could impact c-Fos IR. The experiments detailed herein aimed to assess the effects of voluntary binge-like ethanol consumption on c-Fos IR in brain regions implicated in ethanol intake in animals with and without surgery experience. Age-matched male C57BL/6J mice underwent either stereotaxic surgery (Study 1) or no surgery (Study 2). Then, mice experienced one 4-day DID cycle, tail blood samples were collected immediately after test conclusion on day 4, and mice were subsequently sacrificed. In each study, mice that drink ethanol were sorted into those that achieved binge-equivalent blood ethanol concentrations (BECs >= 80 mg/dl) versus those that did not. Relative to water-consuming controls, mice with BECs >= 80 mg/dl showed significantly elevated c-Fos IR in several brain regions implicated in neurobiological responses to ethanol. In general, the brain regions exhibiting binge-induced c-Fos IR were the same between studies, though differences were noted, highlighting the need for caution when interpreting ethanol-induced c-Fos IR when subjects have a prior history of surgery. Altogether, these results provide insight into the brain regions that modulate binge-like ethanol intake stemming from DID procedures among animals with and without surgery experience. PMID- 29111363 TI - Absolute Not Relative Interocular Luminance Modulates Sensory Eye Dominance Plasticity in Adults. AB - If one eye is patched for a period of 2.5 h in human adults, transient changes in sensory eye dominance result with the previously patched eye's contribution being strengthened. Similar changes result from opaque and translucent occlusion suggesting that it is the deprivation of contrast not luminance information that drives these transient shift of sensory eye dominance. However, this does not rule out the possibility that luminance deprivation per se cannot produce changes in sensory eye dominance, indeed based on what we know of the physiology, where the contrast gain of visual neurons is luminance dependent, one would expect it should. We show that if the mean luminance of one eye is reduced 1000-fold for a period of 2.5 h, there are subsequent changes in sensory eye dominance. With further control experiments we show that this deprivation effect critically depends on the absolute luminance of each eye rather than the relative interocular luminance imbalance. These results indicate that changes in contrast gain at an early, monocular stage of the pathway can result in the transient shift of sensory eye dominance. PMID- 29111362 TI - The Cortical Mechanisms Underlying Ocular Dominance Plasticity in Adults are Not Orientationally Selective. AB - Recently, it has been shown that short-term monocular deprivation in adult humans can temporally shift the ocular dominance in favor of the deprived eye. It is not clear whether this form of ocular dominance plasticity can be explained by cortical contrast adaptation, which is known to be orientationally selective. Here we show that if only one eye is deprived of a limited band of orientations for a short period of 2.5 h, the deprived eye's contribution to binocular function at all orientations rather than just those corresponding to the previously deprived orientations is strengthened. This isotropic enhancement is quite different from the orientational enhancement previously reported and suggests a separate neuroplastic mechanism specific to binocular function. PMID- 29111364 TI - CD36 Deficiency Suppresses Epileptic Seizures. AB - Cluster of differentiation 36 (CD36) belongs to the class B scavenger receptor family. CD36 is a glycoprotein found on the surface of various cell types and has been implicated in the mechanism of numerous central nervous system (CNS) diseases. However, the relationship between CD36 and epilepsy remains unknown. In this study, we aimed to detect the expression of CD36 in two different chronic epileptic mouse models and determine whether CD36 deficiency leads to suppressive neuronal hyperexcitability and decreased susceptibility of epileptic seizures. Here, we found that CD36 was expressed in the neurons and that CD36 expression was significantly elevated in epileptic mice induced by pentylenetetrazol (PTZ) and kainic acid (KA). Behavioral studies revealed that CD36 deletion in mice (CD36-/- mice) resulted in an attenuated progression of chronic epilepsy compared with wild-type (WT) mice. Whole-cell patch-clamp technique exhibited a decreased frequency of action potentials (APs) in the hippocampal slices of CD36-/- mice. In addition, local field potential (LFP) analysis further indicated that CD36 deletion reduced the frequency and duration of epileptiform-like discharges. These results revealed that CD36 deficiency could produce an antiepileptic effect and could provide new insight into antiepileptic treatment. PMID- 29111366 TI - Corrigendum to "Design and synthesis of bicyclic acetals as Beta Secretase (BACE1) inhibitors" [Bioorg. Med. Chem. 25 (2017) 5077-5083]. PMID- 29111365 TI - Autologous fat tissue grafting improves pulmonary healing after laser metastasectomy. AB - BACKGROUND: Extensive clinical experience has demonstrated the potential usefulness of autologous fat tissue (AFT) graft in tissue reconstruction, repair or regeneration. In the present study, we evaluated the feasibility and safety of AFT in the repair of surgically injured lung surface. METHODS: Eighty consecutive procedures of pulmonary metastasectomy by laser precision resection, were performed in 66 patients between March 2010 and December 2012. In the first 20 procedures, AFT graft was applied on the wounded pulmonary surface without closure of parenchymal surface. The following 40 procedures were carried on without AFT (20 leaving the resection margins open and 20 closing the resection margins with a running suture). In the remaining 20 procedures, AFT was applied and the resection margins closed. The efficacy of this technique was evaluated by comparing the AFT group with the non-AFT group, with respect to prolonged alveolar air leakage (PAAL), time to drain removal, length of hospital stay, and patient survival at four years. RESULTS: The occurrence of PAAL was lower in the AFT group as compared to non-AFT group (17.5% versus 42.5%, p = 0.027), and median time to drain removal shorter (4 versus 6 days respectively, p = 0.016). Overall 4-year survival was 70% for AFT group, and 59% for non-AFT group (p = 0.34). CONCLUSIONS: This prospective cohort observational study demonstrated the feasibility and safety of AFT pulmonary grafting after laser metastasectomy. AFT graft improved pulmonary healing, by reducing the incidence and severity of PAAL. Moreover, there was no evidence of tumor promotion in the metastatic setting, with a similar overall survival at 4 years. PMID- 29111367 TI - Synthesis and biological evaluation of novel radioiodinated benzimidazole derivatives for imaging alpha-synuclein aggregates. AB - alpha-Synuclein (alpha-syn) aggregates are commonly found in the brains of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB), and some other diseases. Therefore, in vivo imaging of alpha-syn aggregates would aid in drug development, early diagnosis, and monitoring of disease status. In order to develop imaging probes targeting alpha-syn aggregates, we synthesized and evaluated three novel radioiodinated benzimidazole (BI) derivatives for selective imaging of alpha-syn aggregates. In binding experiments, BI-2 exhibited the highest selective binding affinity for alpha-syn aggregates among the BI derivatives. In addition, BI-2 clearly stained Lewy bodies in PD brain sections, but did not label senile plaques deposited in AD brain sections. However, in the biodistribution study using normal mice, [125I]BI-2 did not demonstrate high brain uptake (0.56%ID/g at 2-min post-injection). Further structural modifications of the BI derivatives are needed, but the BI scaffold may be an attractive candidate for developing alpha-syn imaging probes. PMID- 29111368 TI - Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely. AB - Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50 = 10.0 uM), PfDHFR (IC50 = 84.1 nM), P. falciparum 3D7 (IC50 = 53.1 nM), clinical isolated strains Fab9 (IC50 = 14.2 nM) and GB4 (IC50 = 23.4 nM). The in vivo inhibition assays against P. berghei in 10 days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria. PMID- 29111369 TI - Personalized neoantigen vaccines: A new approach to cancer immunotherapy. AB - Neoantigens arise from somatic mutations that differ from wild-type antigens and are specific to each individual patient, which provide tumor specific targets for developing personalized cancer vaccines. Decades of work has increasingly shown the potential of targeting neoantigens to generate effective clinical responses. Current clinical trials using neoantigen targeting cancer vaccines, including in combination with checkpoint blockade monoclonal antibodies, have demonstrated potent T-cell responses against those neoantigens accompanied by antitumor effects in patients. Personalized neoantigen vaccines represent a potential new class of cancer immunotherapy. PMID- 29111370 TI - Synthesis and optical properties of pyrrolidinyl peptide nucleic acid bearing a base discriminating fluorescence nucleobase 8-(pyrene-1-yl)-ethynyladenine. AB - A combination of fluorophore and nucleobase through a pi-conjugated rigid linker integrates the base pairing and the fluorescence change into a single event. Such base discriminating fluorophore can change its fluorescence as a direct response to the base pairing event and therefore have advantages over tethered labels or base surrogates lacking the hydrogen-bonding ability. 8-(Pyrene-1-yl)ethynyl adenine (APyE) has been extensively used as fluorescence labels in DNA and LNA, but it showed little discrimination between different nucleobases. Herein we investigated the synthesis, base pairing ability and optical properties of APyE in pyrrolidinyl peptide nucleic acid - a DNA mimic that shows much stronger affinity and specificity towards DNA than natural oligonucleotides. The APyE in PNA pairs specifically with thymine in the DNA strand, and resulted in 1.5-5.2 fold enhanced and blue-shifted fluorescence emission. Fluorescence quenching was observed in the presence of mismatched base or abasic site directly opposite to the APyE. The behavior of APyE in acpcPNA is distinctively different from DNA whereby a fluorescence was increased selectively upon duplex formation with complementary DNA and therefore emphasizing the unique advantages of using PNA as alternative oligonucleotide probes. Applications as color-shifting probe for detection of trinucleotide repeats in DNA were demonstrated, and the performance of the probe was further improved by combination with reduced graphene oxide as an external nanoquencher. PMID- 29111371 TI - Pharmacodynamics in Alzheimer's disease model rats of a bifunctional peptide with the potential to accelerate the degradation and reduce the toxicity of amyloid beta-Cu fibrils. AB - : The accumulation of the extracellular beta-amyloid (Abeta) aggregates with metal ions in conjunction with reactive oxygen species (ROS) is closely related to the pathogenesis of Alzheimer's disease (AD). Accounting on Cu ions chelating of our previously designed bifunctional peptide GGHRYYAAFFARR (GR) as well as Abeta-Cu fibrils (fAbeta-Cu) dissociation potentials, we report herein an efficient route to synthetically minimize ROS toxicity and degrade fAbeta-Cu. It is worth mentioning that GR combines the metal chelating agent GGH and beta-sheet breaker RYYAAFFARR (RR). The in vitro results have showed that GR disassociates fAbeta-Cu into smaller fragments (sAbeta-Cu, 150-200 nm), easily assimilated by PC12 cell and subsequently degraded in the lysosomes; GR can also suppress the ROS generated by fAbeta-Cu. The viability of PC12 cell treated with fAbeta-Cu has increased, from 38% to about 70% after administration of GR, overwhelming the GGH chelator (46%) and single functional peptide RR (48%). The in vivo results indicated that GR has efficiently reduced Abeta deposition, ameliorated neurologic changes and rescued memory loss, thus, enhancing the cognitive and spatial memory in a AD rat model. This study confirms the superior effect of GR and paves the way toward its future employment in large scale AD treatment. STATEMENT OF SIGNIFICANCE: We have focused on accelerating the degradation of fAbeta-Cu as well as synthetically reducing the ROS toxicity by GR, and, consequently, its benefits in vivo. The bifunctional peptide GR can not only disaggregate fAbeta-Cu into smaller fragments to facilitate uptake and degradation by PC12 cell, but also suppresses the ROS generated by fAbeta-Cu. Thus, the viability of PC12 cell treated with fAbeta-Cu has increased from 38% to 70% after GR administration, overwhelming GGH (46%) and RR (48%). The in vivo studies have revealed that GR improves the spatial memory ability and reduce the amount of senile plaques within brain of AD model rats. Thus, we suppose the bifunctional inhibitor GR has good application prospects in the treatment of AD treatment. PMID- 29111372 TI - Transmural capillary ingrowth is essential for confluent vascular graft healing. AB - : Spontaneous endothelialization of synthetic vascular grafts may occur via three independent or concurrent modalities: transanastomotic (TA) outgrowth, transmural (TM) ingrowth or fallout (FO) from the blood. The limited TA and FO endothelialization, which occurs in humans, results in poor long-term patency in the small diameter position, where TM ingrowth may offer a clinically relevant alternative. To achieve sequential analysis of each mode of healing, loop grafts comprising anastomotically isolated angiopermissive polyurethane control grafts were abluminally sealed using either ePTFE wraps or solid polyurethane skins and implanted in the rat infrarenal aortic loop model for twelve weeks. Positive control grafts showed improved endothelialization and patency compared to the abluminally isolated mid-grafts. Furthermore, the mid-graft healing was accelerated with surface heparin and heparin-growth factor (VEGF, PDGF) modification in a three-week sub-study. We are thus able to distinguish between the three vascular graft endothelialization modes, and conclude that fallout plays a secondary role to TM healing. The increased endothelialisation for growth factor presenting grafts indicates the promise of this simple approach but further optimization is required. STATEMENT OF SIGNIFICANCE: In addition to the full elucidation of, and differentiation between, the three healing/endothelialisation modes of vascular grafts, the significance of the work relates to the near-complete lack of endothelialisation of small diameter vascular grafts in humans (1-2 cm transanastomotic outgrowth on a graft that may be 60 cm long) even after decades of implantation. The concomitant retained midgraft thrombogenicity leads, together with anastomotic hyperplastic responses, to poor long-term outcomes. The large impact of successful translation of the current research to the achievement of full endothelialisation of long peripheral grafts in humans via transmural ingrowth (half a millimetre distance; thickness of the graft wall), is evident, and supported by the large improvements in clinical patencies achievable in by pre-seeding of ePTFE grafts with confluent endothelia. PMID- 29111374 TI - Layer by layer coating of NH2-silicate/polycarboxylic acid polymer saturated by Ni2+ onto the super magnetic NiFe2O4 nanoparticles for sensitive and bio-valuable separation of His-tagged proteins. AB - Magnetic nanoparticles NiFe2O4 was synthesized and covered in the silicate lattice of (3-Aminopropyl) triethoxysilane (APS) by the sol-gel process. Subsequently, the EDTA-dianhydride was attached to the amino surface of magnetic nanoparticles (MNPs) during the nucleophilic attack. This polycarboxylic layer trapped the high level of nickel ions for selective bonding to the His-tagged recombinant protein. The surface of MNPs was investigated by TEM, XRD, SEM (EDSA), VSM, BET, FT-IR and zeta potential analysis which characterized the size, chemical lattice, morphology, magnetic strength, specific surface area, functional groups and charge of the surface of nanoparticles. The performance and validity of the nanoparticles were studied by the purification of His-tagged green fluorescence protein (His-GFP). Also, the safety of proposed Ni-MNPs in the purification procedure of His-tagged proteins for pharmaceutical applications was proved by the determination of the nickel leakage level in the purified final protein using atomic absorption spectroscopy. In vitro cytotoxicity of Ni-MNPs and trace metal ions was investigated by the MTS assay technique. In addition, the comparison of biological activity in purified protein (GM-CSF) and commercial sample did not show any toxic effect. PMID- 29111373 TI - Rickettsia spp. among wild mammals and their respective ectoparasites in Pantanal wetland, Brazil. AB - The genus Rickettsia comprises obligatory intracellular bacteria, well known to cause zoonotic diseases around the world. The present work aimed to investigate the occurrence of Rickettsia spp. in wild animals, domestic dogs and their respective ectoparasites in southern Pantanal region, central-western Brazil, by molecular and serological techniques. Between August 2013 and March 2015, serum, whole blood and/or spleen samples were collected from 31 coatis, 78 crab-eating foxes, seven ocelots, 42 dogs, 110 wild rodents, and 30 marsupials. Serum samples from canids, felids, rodents and marsupials were individually tested by indirect fluorescent antibody test (IFAT) in order to detect IgG antibodies to Rickettsia rickettsii, Rickettsia parkeri and Rickettsia amblyommatis. DNA samples from mammals and ectoparasites were submitted to a multiplex qPCR assay in order to detect and quantify spotted fever group (SFG) and typhus group (TG) rickettsiae and Orientia tsutsugamushi. Positive samples in qPCR assays were submitted to conventional PCR assays targeting gltA, ompA, ompB and htrA genes, followed by sequencing and phylogenetic analyses. The ticks collected (1582) from animals belonged to the species Amblyomma sculptum, Amblyomma parvum, Amblyomma ovale, Amblyomma tigrinum, Rhipicephalus (Boophilus) microplus, Rhipicephalus sanguineus sensu lato and Amblyomma auricularium. Overall, 27 (64.2%) dogs, 59 (75.6%) crab eating foxes and six (85.7%) ocelots were seroreactive (titer>=64) to at least one Rickettsia species. For 17 (40.4%) dogs, 33 (42.3%) crab-eating foxes, and two (33.3%) ocelots, homologous reactions to R. amblyommatis or a closely related organism were suggested. One hundred and sixteen (23.5%) tick samples and one (1.2%) crab-eating fox blood sample showed positivity in qPCR assays for SFG Rickettsia spp. Among SFG Rickettsia-positive ticks samples, 93 (80.2%) belonged to A. parvum, 14 (12%) belonged to A. sculptum species, three (2.5%) belonged to A. auricularim, and six (5.2%) were Amblyomma larval pools. Thirty samples out of 117 qPCR positive samples for SFG Rickettsia spp. also showed positivity in cPCR assays based on gltA, htrA and/or ompB genes. The Blast analyses showed 100% identity with 'Candidatus Rickettsia andeanae' in all 30 sequences obtained from gltA, htrA and/or ompB genes. The concatenated phylogenetic analysis based on gltA and 17-kDa htrA genes grouped the Rickettsia sequences obtained from tick samples in the same clade of 'Candidatus Rickettsia andeanae'. The present study revealed that wild and domestic animals in southern Pantanal region, Brazil, are exposed to SFG rickettsiae agents. Future studies regarding the pathogenicity of these agents are necessary in order to prevent human cases of rickettsiosis in Brazilian southern Pantanal. PMID- 29111375 TI - A novel protocol to provide a suitable cardiac model from induced pluripotent stem cells. AB - Cumulative evidence has proven the safety, feasibility and efficacy of stem cell therapy for cardiomyocyte replacement in heart failure treatment. In contrast to embryonic stem cells, induced pluripotent stem cells (iPS cells) provide a route to the production of patient-specific stem cell lines with no ethical concerns. Recent studies have revealed that myogenic transcription factors activated the expression of conserved microRNAs (miRNAs), such as mir-1, that 'fine-tuned' the output of the transcriptional networks. To introduce an efficient and applicable protocol for establishment of autologous cardiac cellular models, herein we introduced a novel protocol for induction of iPS cells into cardiomyocytes using both microRNA-1 transduction and 5'-Azacitidine treatment. Quantitative evaluation of transcription and translation of cardiac markers such as MHC-alpha, GATA4, FLK and troponin, demonstrated that this new direct protocol led to cardiac differentiation of iPS cells. From a clinical point of view, these results raise the possibility that administration of miRNA mimic or miRNA inhibitor therapies could increase allocation of iPS cells into the cardiac lineage. Taking all the results into account, our novel protocol provides further progress in the application of patient's own cells for more effective therapies. Moreover, such cellular models could be used in personalized drug screening. PMID- 29111376 TI - Analysis of the proficiency of single radial immunodiffusion assays for quality control of influenza vaccines in Korea. AB - Influenza vaccine potency, which is determined by quantitatively measuring the content of Hemagglutinin (HA), is an essential index representing the efficacy of the vaccine. Standardization of the single radial immunodiffusion (SRID) assay, a method for measuring HA content, and proficiency of the testing institutions are crucial for influenza vaccine quality control. Herein, we assessed the proficiency of SRID assays at the National Control Laboratory (NCL) of Korea and several vaccine manufacturers. Eight laboratories participated in this study, and the proficiencies of all laboratories yielded satisfactory results in overall SRID assays. In contrast, there were some unsatisfactory results in measuring with different types of agarose gel plates produced by other laboratories. Overall, our findings demonstrated that the proficiency of SRID assay in the tested laboratories is acceptable for quality control of influenza vaccines and that detailed review on the validation reports regarding the test methods will be helpful for better control. PMID- 29111378 TI - Subacute Rehabilitation Does Have Benefits for Patients With Advanced Cancer. PMID- 29111377 TI - Mass spectrometry analyses of normal and polyglutamine expanded ataxin-3 reveal novel interaction partners involved in mitochondrial function. AB - Deubiquitinating enzymes (DUBs) play important roles in a variety of cellular processes, including regulation of protein homeostasis. The DUB ataxin-3 is an enzyme implicated in protein quality control mechanisms. In the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3), ataxin-3 contains an expanded polyglutamine (polyQ) stretch that leads to aggregation of the protein and neuronal dysfunction. Increasing the understanding of ataxin-3 protein interaction partners could help to elucidate disease mechanisms. Hence, we analyzed the repertoire of proteins interacting with normal and polyQ expanded ataxin-3 by mass spectrometry. This showed that both normal and polyQ expanded ataxin-3 interacted with components of the protein quality control system and mitochondria. Five proteins showed increased interaction with polyQ expanded ataxin-3 relative to normal and three of these were mitochondrial proteins. The analyses underline the role of ataxin-3 in ubiquitin biology and point towards a role in mitochondrial biology. PMID- 29111379 TI - A SCN4A mutation causing paramyotonia congenita. AB - Paramyotonia congenita (OMIM 168300) is a non-dystrophic myopathy caused by mutations in the SCN4A gene that sometimes can be confused with myotonia congenita. Another disease also caused by mutations in the gene SCN4A is called myotonia aggravated by potassium (OMIM 170500, 613345). It is estimated that more than 20% of patients with suspected myotonia congenita suffer paramyotonia congenita. The two related SCN4A phenotypes exhibit an autosomal dominant inheritance and are the result of mutations that cause an increase in the function of the protein coded by this gene. In this study we present a case of paramyotonia congenita in a family with several affected members and in which a mutation in the SCN4A gene was identified. Evolutionary conservation data and predictive algorithms of pathogenicity allow us to conclude that this DNA variant is the cause of the disease in this family. PMID- 29111380 TI - Hypoxia-inducible factor 1Alpha may regulate the commitment of mesenchymal stromal cells toward angio-osteogenesis by mirna-675-5P. AB - BACKGROUND AIMS: During bone formation, angiogenesis and osteogenesis are regulated by hypoxia, which is able to induce blood vessel formation, as well as recruit and differentiate human mesenchymal stromal cells (hMSCs). The molecular mechanisms involved in HIF-1alpha response and hMSC differentiation during bone formation are still unclear. This study aimed to investigate the synergistic role of hypoxia and hypoxia-mimetic microRNA miR-675-5p in angiogenesis response and osteo-chondroblast commitment of hMSCs. METHODS: By using a suitable in vitro cell model of hMSCs (maintained in hypoxia or normoxia), the role of HIF-1alpha and miR-675-5p in angiogenesis and osteogenesis coupling was investigated, using fluorescence-activated cell sorting (FACS), gene expression and protein analysis. RESULTS: Hypoxia induced miR-675-5p expression and a hypoxia-angiogenic response, as demonstrated by increase in vascular endothelial growth factor messenger RNA and protein release. MiR-675-5p overexpression in normoxia promoted the down regulation of MSC markers and the up-regulation of osteoblast and chondroblast markers, as demonstrated by FACS and protein analysis. Moreover, miR-675-5p depletion in a low-oxygen condition partially abolished the hypoxic response, including angiogenesis, and in particular restored the MSC phenotype, demonstrated by cytofluorimetric analysis. In addition, current preliminary data suggest that the expression of miR-675-5p during hypoxia plays an additive role in sustaining Wnt/beta-catenin pathways and the related commitment of hMSCs during bone ossification. DISCUSSION: MiR-675-5p may trigger complex molecular mechanisms that promote hMSC osteoblastic differentiation through a dual strategy: increasing HIF-1alpha response and activating Wnt/beta-catenin signaling. PMID- 29111381 TI - Baseline Lower Urinary Tract Symptoms in Patients Enrolled in LURN: A Prospective, Observational Cohort Study. AB - PURPOSE: We described and compared the frequency and type of lower urinary tract symptoms reported by men and women at the time that they were recruited from urology and urogynecology clinics into the Symptoms of Lower Urinary Tract Dysfunction Research Network multicenter, prospective, observational cohort study. MATERIALS AND METHODS: At 6 research sites treatment seeking men and women were enrolled who reported any lower urinary tract symptoms at a frequency more than rarely during the last month on the LUTS (Lower Urinary Tract Symptoms) Tool. At baseline the study participants underwent a standardized clinical evaluation and completed validated questionnaires. Urological tests were performed, including pelvic/rectal examination, post-void residual urine measurement and urinalysis. RESULTS: A total of 545 women and 519 men were enrolled in the study. Mean +/- SD age was 58.8 +/- 14.1 years. At baseline nocturia, frequency and a sensation of incomplete emptying were similar in men and women but men experienced more voiding symptoms (90% vs 85%, p = 0.007) and women reported more urgency (85% vs 66%, p <0.001). Women also reported more of any type of urinary incontinence than men (82% vs 51% p <0.001), which was mixed incontinence in 57%. Only 1% of men reported stress incontinence but they had other urinary incontinence, including post-void dribbling in 44% and urgency incontinence in 46%. Older participants had higher odds of reporting symptoms of nocturia and urgency. CONCLUSIONS: In this large, treatment seeking cohort of men and women lower urinary tract symptoms varied widely by gender and age. Men reported more voiding symptoms and nonstress or urgency urinary incontinence while women reported more incontinence overall and urgency. Older participants had greater odds of urgency and nocturia. PMID- 29111383 TI - Disturbed glutathione antioxidative defense is associated with structural brain changes in neuroleptic-naive first-episode psychosis patients. AB - BACKGROUND: Oxidative stress and impaired antioxidant defense are reported in schizophrenia and are thought to be associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, negative symptomatology, and cognitive impairment. To test some of these assumptions we investigated the glutathione (GSH) antioxidant defense system (AODS) and brain structural abnormalities in drug-naive individuals with first acute episode of psychosis (FEP). METHOD: The study involved 27 drug-naive FEP patients and 31 healthy controls (HC). GSH AODS markers and TBARS (thiobarbituric acid reactive substances) were measured in blood plasma and erythrocytes. High-resolution T1 weighted 3T MRI were acquired from all subjects. To investigate brain structural abnormalities and effects of illness on interactions between GSH metabolites or enzyme activities and local grey matter density, voxel-based morphometry (VBM) with the computational anatomy toolbox (CAT12) was used. Symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Symptom Checklist 1990 revised (SCL-90-R). RESULTS: (i) In FEP patients, glutathione reductase activity (GSR) was lower than in the HC group. GSR activity in plasma was inversely correlated with SCL-90-R scores of depression and PANSS scores of the negative symptom subscale. (ii) A reduction of GM was observed in left inferior frontal, bilateral temporal, as well as parietal cortices of FEP patients. (iii) Interaction analyses revealed an influence of illness on GSR/GM associations in the left orbitofrontal cortex (BA 47). CONCLUSION: Our findings support the notion of altered GSH antioxidative defense in untreated acute psychosis as a potential pathomechanism for localized brain structural abnormalities. This pathology relates to a key brain region of social cognition, affective motivation control and decision making, and is clinically accompanied by depressive and negative symptoms. PMID- 29111384 TI - Intracellular compartments of pathogens: Highways to hell or stairways to heaven? PMID- 29111382 TI - Innovative approach to safely induce controlled lipolysis by superparamagnetic iron oxide nanoparticles-mediated hyperthermic treatment. AB - During last years, evidence has been provided on the involvement of overweight and obesity in the pathogenesis and aggravation of several life-threatening diseases. Here, we demonstrate that, under appropriate administration conditions, polyhedral iron oxide nanoparticles are efficiently and safely taken up by 3T3 cell line-derived adipocytes (3T3 adipocytes) in vitro. Since these nanoparticles proved to effectively produce heat when subjected to alternating magnetic field, 3T3 adipocytes were submitted to superparamagnetic iron oxide nanoparticles mediated hyperthermia treatment (SMHT), with the aim of modulating their lipid content. Notably, the treatment resulted in a significant delipidation persisting for at least 24h, and in the absence of cell death, damage or dedifferentiation. Interestingly, transcript expression of adipose triglyceride lipase (ATGL), a key gene involved in canonical lipolysis, was not modulated upon SMHT, suggesting the involvement of a novel/alternative mechanism in the effective lipolysis observed. By applying the same experimental conditions successfully used for 3T3 adipocytes, SMHT was able to induce delipidation also in primary cultures of human adipose-derived adult stem cells. The success of this pioneering approach in vitro opens promising perspectives for the application of SMHT in vivo as an innovative safe and physiologically mild strategy against obesity, potentially useful in association with balanced diet and healthy lifestyle. PMID- 29111386 TI - Method for determining the half-value layer in computed tomography scans using a real-time dosimeter: Application to dual-source dual-energy acquisition. AB - PURPOSE: We have proposed a method for determining the half-value layers (HVL) in dual-source dual-energy computed tomography (DS-DECT) scans without the need for the X-ray tubes to be fixed. METHODS: A custom-made lead-covered case and an ionizing chamber connected with a multi-function digitizer module (a real-time dosimeter) were used. The chamber was placed in the center of the case, and aluminum or copper filters were placed in front of the aperture. The HVL was measured using aperture widths of 1.0, 2.0, and 3.0 cm for tube potentials of 80, 120, and 150 kV in single-source single-energy CT (SS-SECT) scans and was calculated from the peak air kerma rate (peak method) and the integrated air kerma rate (integrating method); the obtained values were compared with those from a conventional non-rotating method performed using the same procedure. The HVL was then measured using an aperture width of 1.0 cm for tube potential combinations of 70/Sn150 kV and 100/Sn150 kV in DS-DECT scans using the peak method. RESULTS: In the SS-SECT scans, the combination of a 1.0-cm aperture and the peak method was adequate due to the small differences in the HVL values obtained for the conventional non-rotating method. The method was also found to be applicable for the DS-DECT scans. CONCLUSIONS: Our proposed method can determine the HVL in SS-SE and DS-DECT scans to a good level of accuracy without the need for the X-ray tubes to be fixed. The combination of a 1.0-cm aperture and the peak method was adequate. PMID- 29111385 TI - JNK1 inhibition by Licochalcone A leads to neuronal protection against excitotoxic insults derived of kainic acid. AB - The mitogen-activated protein kinase family (MAPK) is an important group of enzymes involved in cellular responses to diverse external stimuli. One of the members of this family is the c-Jun-N-terminal kinase (JNK). The activation of the JNK pathway has been largely associated with the pathogenesis that occurs in epilepsy and neurodegeneration. Kainic acid (KA) administration in rodents is an experimental approach that induces status epilepticus (SE) and replicates many of the phenomenological features of human temporal lobe epilepsy (TLE). Recent studies in our group have evidenced that the absence of the JNK1 gene has neuroprotective effects against the damage induced by KA, as it occurs with the absence of JNK3. The aim of the present study was to analyse whether the pharmacological inhibition of JNK1 by Licochalcone A (Lic-A) had similar effects and if it may be considered as a new molecule for the treatment of SE. In order to achieve this objective, animals were pre-treated with Lic-A and posteriorly administered with KA as a model for TLE. In addition, a comparative study with KA was performed between wild type pre-treated with Lic-A and single knock-out transgenic mice for the Jnk1-/- gene. Our results showed that JNK1 inhibition by Lic-A, previous to KA administration, caused a reduction in the convulsive pattern. Furthermore, it reduced phosphorylation levels of the JNK, as well as its activity. In addition, Lic-A prevented hippocampal neuronal degeneration, increased pro-survival anti-apoptotic mechanisms, reduced pro-apoptotic biomarkers, decreased cellular stress and neuroinflammatory processes. Thus, our results suggest that inhibition of the JNK1 by Lic-A has neuroprotective effects and that; it could be a new potential approach for the treatment of SE and neurodegeneration. PMID- 29111387 TI - Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle. AB - Hepassocin (HPS) has recently been identified as a novel hepatokine that causes hepatic steatosis. However, the role of HPS in the development of insulin resistance in skeletal muscle under obesity remains unclear. The effect of hyperlipidemia on hepatic HPS expression was evaluated in primary hepatocytes and liver of mice. HPS-mediated signal pathways were explored using small interfering (si) RNAs of specific genes or inhibitors. We found that treatment of primary hepatocytes with palmitate could induce HPS expression through C/EBPbeta-mediated transcriptional activation. Furthermore, increased HPS expression was observed in the liver of high fat diet (HFD)-fed or tunicamycin-treated mice. Pretreatment with 4-phenylbutyrate (4-BPA) (an endoplasmic reticulum (ER) stress inhibitor) and suppression of p38 by siRNA abrogated the effect of palmitate on HPS expression in primary hepatocytes. Treatment of differentiated C2C12 cells with recombinant HPS caused c-Jun N-terminal kinase (JNK) phosphorylation and impairment of insulin sensitivity in a dose-dependent manner. siRNA-mediated suppression of JNK reduced the effect of HPS on insulin signaling. Furthermore, the suppression of epidermal growth factor receptor (EGFR) by siRNA mitigated both HPS-induced JNK phosphorylation and insulin resistance. In addition, HPS did not affect inflammation and ER stress in differentiated C2C12 cells. In conclusion, we elucidated that ER stress induced by palmitate could increase the expression of HPS in hepatocytes and further contribute to the development of insulin resistance in skeletal muscle via EGFR/JNK-mediated pathway. Taken together, we suggest that HPS could be a therapeutic target for obesity-linked insulin resistance. PMID- 29111388 TI - Activin over-expression in the testis of mice lacking the inhibin alpha-subunit gene is associated with androgen deficiency and regression of the male reproductive tract. AB - Regionalised interaction of the activins, follistatin and inhibin was investigated in the male reproductive tract of mice lacking the inhibin alpha subunit (Inha-/-). Serum and intratesticular activin B, although not activin A and follistatin, were increased in Inha-/- mice at 25 days of age, but all three proteins were elevated at 56 days. None of these proteins were altered within the epididymis and vas deferens at either age. At 25 days, histology of the epididymis and vas deferens was similar to wild-type. At 56 days, the testis contained extensive somatic cell tumours, leading to Leydig cell regression and testosterone deficiency. The epididymis and vas deferens showed epithelial regression and increased prominence of the interstitial stroma. Immunoregulatory and fibrotic gene expression in the epididymis and vas deferens were unchanged. Thus, absence of the inhibin alpha-subunit has marginal effects on activins in the epididymis and vas deferens, and regression of these tissues is associated with androgen deficiency. PMID- 29111389 TI - Antifungal photosensitive activity of Porophyllum obscurum (Spreng.) DC.: Correlation of the chemical composition of the hexane extract with the bioactivity. AB - We report Porophyllum obscurum as a source of new photosensitizers with potential use in Photodynamic Therapy as an alternative for oropharyngeal candidiasis treatment. The antifungal photosensitive activity of different extracts from P. obscurum was evaluated by using microdilution and bioautographic assays. The Minimum Fungicidal Concentration for hexanic extract under UV-A irradiation was 0.98MUg/mL, but it was inactive in experiments without irradiation. The bioassay guided fractionation of this extract led to the isolation of four thiophenes responsible for the photosensitive activity: 2,2':5'2"terthiophene, 5-(3-buten-1 ynyl)-2,2'-bithiophene, 5-(4-acetoxy-1-butenyl)-2,2'- bithiophene and 5-(4 hydroxy-1-butenyl)-2,2'- bithiophene, with Minimum Fungicidal Concentrations ranging 0.24-7.81MUg/mL under UV-A irradiation. The activity of the hexanic extract was evaluated against 25 clinical strains of Candida spp. isolates as etiological agents of oropharyngeal candidiasis. No differences in susceptibility were observed in strains resistant and susceptible to conventional antifungal drugs. Qualitative and quantitative chemical analyses of seven samples of P. obscurum collected in four different phenological stages were carried out showing that full flowering stage possesses the highest thiophenes content. These data also allowed us to establish a correlation between the thiophene composition of the different extracts and their antifungal photosensitive activity, according to a second order polynomial model with the equation: y=11.2603-0.6831*x+0.0108*x2. The thiophenes isolated were the responsible of antifungal photosensitive activity and can be used for the future standardization of the extract. Results showed that P. obscurum hexanic extract could be potentially developed as an Herbal Medicinal Product to be applied as a photosensitizer in Photodynamic Therapy. PMID- 29111390 TI - Treatment of peritoneal carcinomatosis with photodynamic therapy: Systematic review of current evidence. AB - BACKGROUND: Peritoneal carcinomatosis results when tumour cells implant and grow within the peritoneal cavity. Treatment and prognosis vary based on the primary cancer. Although therapy with intention-to-cure is offered to selective patients using cytoreductive surgery with chemotherapy, the prognosis remains poor for most of the patients. Photodynamic therapy (PDT) is a cancer-therapeutic modality where a photosensitiser is administered to patients and exerts a cytotoxic effect on cancer cells when excited by light of a specific wavelength. It has potential application in the treatment of peritoneal carcinomatosis. METHODS: We systematically reviewed the evidence of using PDT to treat peritoneal carcinomatosis in both animals and humans (Medline/EMBASE searched in June 2017). RESULTS: Three human and 25 animal studies were included. Phase I and II human trials using first-generation photosensitisers showed that applying PDT after surgical debulking in patients with peritoneal carcinomatosis is feasible with some clinical benefits. The low tumour-selectivity of the photosensitisers led to significant toxicities mainly capillary leak syndrome and bowel perforation. In animal studies, PDT improved survival by 15-300%, compared to control groups. PDT led to higher tumour necrosis values (categorical values 0-4 [4=highest]: PDT 3.4+/-1.0 vs. control 0.4+/-0.6, p<0.05) and reduced tumour size (residual tumour size is 10% of untreated controls, p<0.001). CONCLUSION: PDT has potential in treating peritoneal carcinomatosis, but is limited by its narrow therapeutic window and possible serious side effects. Recent improvement in tumour selectivity and light delivery systems is promising, but further development is needed before PDT can be routinely applied for peritoneal carcinomatosis. PMID- 29111391 TI - Short-term effects of adjunctive antimicrobial photodynamic therapy in obese patients with chronic periodontitis: A randomized controlled clinical trial. AB - BACKGROUND: The aim of the present study was to assess the effect of antimicrobial photodynamic therapy (aPDT) as an adjunct to scaling and root planing (SRP) on clinical periodontal and immunological parameters in obese patients with chronic periodontitis (CP). METHODS: Fifty-three obese with CP patients were divided into 2 groups receiving aPDT with SRP and SRP only respectively. Full-mouth plaque index (PI), bleeding on probing (BOP), pocket depth (PD) and clinical attachment level (CAL) were assessed at baseline, 6 and 12 weeks post-therapy. Gingival crevicular fluid (GCF) levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 were evaluated using enzyme linked immunosorbent assay at baseline and 12 weeks. RESULTS: There was a significant improvement in all periodontal variables in both study groups at 6 weeks and 12 weeks with respect to the baseline visit (p<0.001). Significant reduction in PD of 4-6mm and >=7mm was observed for aPDT group as compared to SRP group (p<0.01) at both 6 weeks and 12 weeks of follow-up. At 6 weeks, a significant (p<0.001) gain in CAL was observed in both groups, which remained stable at 12 weeks. IL-6 and TNF-alpha levels decreased significantly (p=0.001) at 12 weeks after therapy in both the groups. Inter-group comparison showed significant difference for TNF-alpha (p=0.024) and IL-6 (p=0.044) levels for aPDT group at 12 week follow-up. CONCLUSION: Within the limits of this clinical trial, adjunctive aPDT showed improvement in clinical and immunological parameters in obese patients with CP. Antimicrobial PDT showed additional benefit in moderate and deep periodontal pockets in obese patients with CP. PMID- 29111392 TI - Post-operative care of VRAM flaps for perineal reconstruction: Results of a UK practice survey and literature review. PMID- 29111393 TI - Cyclin-dependent kinase 5-mediated phosphorylation of CHIP promotes the tAIF dependent death pathway in rotenone-treated cortical neurons. AB - Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase. Its dysregulation has been implicated in various neurodegenerative diseases. We previously reported that phosphorylation of the C-terminus of the Hsc70 interacting protein (CHIP) by Cdk5 promotes truncated apoptosis-inducing factor (tAIF)-mediated neuronal death induced by oxidative stress. Here, we determined whether this Cdk5-dependent cell death signaling pathway is present in experimental models of Parkinson's disease. First, we showed that rotenone activates Cdk5 in primary cultures of cortical neurons and causes tAIF-dependent neuronal cell death. This event was attenuated by negative regulation of endogenous Cdk5 activity by the pharmacological Cdk5 inhibitor, roscovitine, or by lentiviral knockdown of Cdk5. Cdk5 phosphorylates CHIP at Ser20 in rotenone treated neurons. Consequently, overexpression of CHIPS20A, but not CHIPWT, attenuates tAIF-induced cell death in rotenone-treated cortical neurons. Taken together, these results indicate that phosphorylation of CHIP at Ser20 by Cdk5 activation inhibits CHIP-mediated tAIF degradation, thereby contributing to tAIF induced neuronal cell death following rotenone treatment. PMID- 29111394 TI - Non-mammalian Toll-like receptor 18 (Tlr18) recognizes bacterial pathogens in common carp (Cyprinus carpio L.): Indications for a role of participation in the NF-kappaB signaling pathway. AB - Toll-like receptors are important pattern recognition receptors that can recognize pathogen-associated molecular patterns (PAMPs) and play a critical role in innate immunity. In the present study, tlr18 was identified from common carp (Cyprinus carpio L.) (named Cctlr18). The deduced amino acid sequence contained only a signal peptide, eight LRR (leucine-rich repeat) motifs, a transmembrane region and a TIR (Toll/IL-1 receptor) domain. Phylogenetic analysis showed that CcTlr18 was most closely related to Ctenopharyngodon idella Tlr18. Quantitative real-time PCR analysis showed that Cctlr18 was constitutively expressed in all investigated tissues with the highest expression level in the skin and lowest expression in the gonad. After injection with inactivated Aeromonas hydrophila, Cctlr18 expression was significantly up-regulated in the head kidney, foregut, hindgut and skin. Moreover, significant up-regulation of Cctlr8 was observed in the spleen, head kidney, hindgut and skin after immersion with live A. hydrophila. In addition, the expression of Cctlr18 was up-regulated in PGN or flagellin-stimulated HKLs. Luciferase reporter assays showed that Cctlr18 activated NF-kappaB in 293 T cells and that NF-kappaB activity was enhanced in Cctlr18 and Ccmyd88 co-transfected cells. Furthermore, Cctlr18 could induce the expression of cytokines genes, including ifn, il-1beta and il-10, in EPC cells. The results suggested that Cctlr18 plays an important role in the immune response and provides basic information for investigating the mechanisms of fish tlr18. PMID- 29111396 TI - Limitations and pitfalls of the pedicle screw testing monitoring technique: An in vivo and in vitro study. AB - OBJECTIVES: Pedicle screw testing is a widely used technique in the field of neuromonitoring for spinal surgery. It was designed by Calancie et al. (1992) in order to detect pedicle breach, one of the major complications of pedicle screw fixation, which can lead to neurological impairment. However, numerous false negative and equivocal results led to its clinical relevance being questioned. We aimed to clarify these discrepancies and characterize electrical parameters underlying this technique. METHODS: In this setting, our study is divided into two parts: (1) a clinical part assessing the difference between direct pedicle hole via the pedicle perforator stimulation and indirect stimulation via the implanted screw; (2) an in vitro study testing the electrical properties (resistivity and conductivity) on a sample of different commonly used pedicle screws. RESULTS: We showed that there were discrepancies between direct perforator stimulation and pedicle screws, especially at high threshold values. These might be attributed to electrical contact discontinuity. In vitro testing revealed that the previously described resistivity variability and the instability of measures are due to the result of slight changes of position of the recording contacts. CONCLUSION: Electrical continuity is crucial in the pedicle screw test technique. This parameter cannot actually be fully ensured and can lead to discrepancies and potentially false negative results. Therefore, we recommend the use of both direct stimulation of the pedicle hole and control testing of the screw. Further studies and improvement of the technique are required to ensure its reliability. PMID- 29111395 TI - Time-response characteristic and potential biomarker identification of heavy metal induced toxicity in zebrafish. AB - The present work aims to explore the time-response (from 24 h to 96 h) characteristic and identify early potential sensitive biomarkers of copper (Cu) (as copper chloride dihydrate), cadmium (Cd) (as cadmium acetate), lead (Pb) (as lead nitrate) and chromium (Cr) (as potassium dichromate) exposure in adult zebrafish, focusing on reactive oxygen species (ROS), SOD activity, lipid peroxidation and gene expression related to oxidative stress and inflammatory response. Furthermore, the survival rate decreased apparently by a concentration dependent manner after Cu, Cr, Cd and Pb exposure, and we selected non-lethal concentrations 0.05 mg/L for Cu, 15 mg/L for Cr, 3 mg/L for Cd and 93.75MUg/L for Pb to test the effect on the following biological indicators. Under non-lethal concentration, the four heavy metals have no apparent histological change in adult zebrafish gills. Similar trends in ROS production, MDA level and SOD activity were up-regulated by the four heavy metals, while MDA level responded more sensitive to Pb by time-dependent manner than the other three heavy metals. In addition, mRNA levels related to antioxidant system (SOD1, SOD2 and Nrf2) were up-regulated by non-lethal concentration Cu, Cr, Cd and Pb exposure. MDA level and SOD1 gene have a more delayed response to heavy metals. Genes related to immunotoxicity were increased significantly after heavy metals exposure at non lethal concentrations. TNF-alpha and IL-1beta gene have similar sensibility to the four heavy metals, while IL-8 gene was more responsive to Cr, Cd and Pb exposure at 48 h groups and IFN-gamma gene showed more sensitivity to Cu at 48 h groups than the other heavy metals. In conclusion, the present works have suggested that the IFN-gamma gene may applied as early sensitive biomarker to identify Cu-induced toxicity, while MDA content and IL-8 gene may use as early sensitive biomarkers for evaluating the risk of Pb exposure. Moreover, IL-8 and IFN-gamma gene were more responsive to heavy metals, which may become early sensitive and potential biomarkers for evaluating inflammatory response induced by heavy metals. This work reinforces the concept of the usefulness of gene expression assays in the evaluation of chemicals effects and helps to establish a background data as well as contributes to evaluate early environmental risk for chemicals, even predicting toxicity. PMID- 29111398 TI - Multi-slice CT (MSCT) imaging in pretrans-catheter aortic valve implantation (TAVI) screening. How to perform and how to interpret. AB - Aortic valve stenosis (AS) is the most common valvular heart disease among elderly. Trans-catheter aortic valve implantation (TAVI) has become an established and effective alternative therapeutical procedure for inoperable and high-risk patients with symptomatic AS. The procedural success is greatly dependent on a thorough pre-TAVI imaging screening. This requires a comprehensive and multi-modality approach, in which multi-slice computed tomography (MSCT) is the cornerstone in the selection of eligible patients, in choosing the appropriate prosthesis and size, and in mapping the safest access route for the intervention. From our experience of more than 400 TAVI procedures and many more MSCTs for screening purposes, we provide clinical and technical details on the use of MSCT pre-TAVI and brief review of the knowledge so far. PMID- 29111399 TI - Development of a simple and practical method of discrimination between Vibrio furnissii and V. fluvialis based on single-nucleotide polymorphisms of 16S rRNA genes observed in V. furnissii but not in V. fluvialis. AB - Vibrio furnissii and V. fluvialis are closely related, the discrimination of which by conventional biochemical assay remains a challenge. Investigation of the sequence of the 16S rRNA genes in a clinical isolate of V. furnissii by visual inspection of a sequencing electropherogram revealed two sites of single nucleotide polymorphisms (SNPs; positions 460 A/G and 1261 A/G) in these genes. A test of 12 strains each of V. fluvialis and V. furnissii revealed these SNPs to be common in V. furnissii but not in V. fluvialis. Divergence of SNP frequency was observed among the strains of V. furnissii tested. Because the SNPs described in V. furnissii produce a difference in the target sequence of restriction enzymes, a combination of polymerase chain reaction (PCR) of the 16S rRNA genes using conventional primers and restriction fragment length polymorphism analysis using Eco RV and Eae I was shown to discriminate between V. fluvialis and V. furnissii. This method is simple and alleviates the need for expensive equipment or primer sets specific to these bacteria. Therefore, we believe that this method can be useful, alongside specific PCR and mass spectrometry, when there is a need to discriminate between V. fluvialis and V. furnissii. PMID- 29111400 TI - Comparison of biofilm cell quantification methods for drinking water distribution systems. AB - Drinking water quality typically degrades after treatment during conveyance through the distribution system. Potential causes include biofilm growth in distribution pipes which may result in pathogen retention, inhibited disinfectant diffusion, and proliferation of bad tastes and odors. However, there is no standard method for direct measurement of biofilms or quantification of biofilm cells in drinking water distribution systems. Three methods are compared here for quantification of biofilm cells grown in pipe loops samplers: biofilm heterotrophic plate count (HPC), biofilm biovolume by confocal laser scanning microscopy (CLSM) and biofilm total cell count by flow cytometry (FCM) paired with Syto 9. Both biofilm biovolume by CLSM and biofilm total cell count by FCM were evaluated for quantification of the whole biofilms (including non-viable cells and viable but not culturable cells). Signal-to-background ratios and overall performance of biofilm biovolume by CLSM and biofilm total cell count by FCM were found to vary with the pipe material. Biofilm total cell count by FCM had a low signal-to-background ratio on all materials, indicating that further development is recommended before application in drinking water environments. Biofilm biovolume by CLSM showed the highest signal-to-background ratio for cement and cast iron, which suggests promise for wider application in full-scale systems. Biofilm biovolume by CLSM and Syto 9 staining allowed in-situ biofilm cell quantification thus elimination variable associated with cell detachment for quantification but had limitations associated with non-specific staining of cement and, to a lesser degree, auto-fluorescence of both cement and polyvinyl chloride materials. Due to variability in results obtained from each method, multiple methods are recommended to assess biofilm growth in drinking water distribution systems. Of the methods investigated here, HPC and CLSM and recommended for further development towards application in full-scale systems. HPC is a sample and widely applied method that quantifies viable culturable cells. CLSM analysis allows the elimination of experimental variables associated with cell detachment and affords the opportunity to evaluate biofilm components such as extracellular polymeric substances through the addition of specific probes. These two methods can be applied together to assess biofilms known to degrade treated water quality during conveyance in full-scale drinking water treatment systems. The significance of improved biofilm assessment methods for drinking water distribution systems lies in advancing understanding of biofilm growth and control mechanisms that may lead to improved water quality during conveyance and at the tap for greater public health protection. PMID- 29111401 TI - Biofilm production is not associated with poor clinical outcome in 485 patients with Staphylococcus aureus bacteraemia. AB - OBJECTIVES: Staphylococcus aureus biofilm may constitute a major cause of virulence. Our main objective was to analyse whether there was an association between biofilm production and poor outcome in patients with S. aureus bacteraemia. METHODS: We studied 485 S. aureus strains isolated from the blood of patients with bacteraemia from 2012 to 2015. We assessed in vitro biomass production using crystal violet assay and metabolic activity using tetrazolium salt assay. Strains were classified in tertile ranks as follows: low biomass producers, moderate biomass producers, high biomass producers, low metabolic activity, moderate metabolic activity and high metabolic activity. We excluded from analysis strains with moderate crystal violet and tetrazolium salt values. We defined poor outcome as fulfillment of one or more of the following conditions: 30-day attributable mortality, infective endocarditis, persistent bacteraemia and recurrent bacteraemia. RESULTS: Outcome was poor in 199 (41.0%) of 485 S. aureus bacteraemia episodes. The distribution of poor outcome with respect to biomass production and metabolic activity was as follows: low biomass producers, 36.6% vs. high biomass producers, 43.2% (p 0.26); and low metabolic activity, 43.5% vs. high metabolic activity, 36.2% (p 0.91). The presence of methicillin-resistant S. aureus was the only characteristic that was more likely to be present in the high metabolic activity group (17.4% vs. 39.3%, p < 0.001). CONCLUSIONS: Biofilm production, as determined by any of the methods used in the present study, is not associated with poor outcome in patients with S. aureus bacteraemia. PMID- 29111402 TI - Monitoring both procalcitonin and C-reactive protein in the early period after tetralogy of Fallot correction in children promotes rational antibiotic use. AB - PURPOSE: This retrospective cohort study aimed to identify the early postoperative kinetics of C-reactive protein (CRP) and procalcitonin (PCT) in children undergoing tetralogy of Fallot (ToF) correction. The ability of these inflammatory markers to guide rational antibiotic usage was also determined. MATERIALS AND METHODS: All consecutive children who underwent ToF correction in 2009-2016 in our referral pediatric cardiac surgery clinic in Gdansk, Poland and did not exhibit infection signs on early postoperative days (POD) were identified. All patients received 48h antibiotic prophylaxis. Antibiotic treatment was extended or empirical antibiotic therapy was introduced if the clinician considered it necessary. CRP and PCT levels were measured on POD1-4 and 1-3, respectively. RESULTS: Of the 60 eligible children, 44 underwent CRP testing only. The remaining 16 patients underwent both CRP and PCT testing. All patients had abnormally high CRP values after surgery. All patients who also underwent PCT testing also displayed elevated PCT levels. The CRP and PCT levels peaked on POD2 (median=99.8mg/L) and POD1 (median=4.08ng/mL), respectively. In the CRP-alone patients, antibiotic prophylaxis was prolonged or empirical antibiotic therapy was started in 59%; in the CRP and PCT group, this was 25% (p<0.05). CONCLUSIONS: The children had elevated CRP and PCT levels after ToF correction, with peaks observed on POD2 and POD1, respectively. Monitoring both CRP and PCT in the early postoperative period may guide antibiotic therapy, thus reducing unnecessary treatment, additional toxicity, and adverse drug interactions without increasing treatment failure. Rational antibiotic treatment may also reduce antibiotic resistance. PMID- 29111403 TI - The critical role of autophagy in cadmium-induced immunosuppression regulated by endoplasmic reticulum stress-mediated calpain activation in RAW264.7 mouse monocytes. AB - Cadmium (Cd) has toxic and suppressive effects on the immune system, but the underlying mechanisms remain poorly understood. Here, we show that autophagy plays a critical role in regulation of Cd-induced immunosuppression in RAW264.7 cells. Cd decreased cell viability in a dose-dependent manner; cleaved caspase-8, caspase-3, and poly (ADP-ribose) polymerase (PARP)-1; increased DNA laddering; induced CCAAT-enhancer-binding protein homologous protein (CHOP); and reduced tumor necrosis factor (TNF)-alpha expression; indicating that caspase-dependent and endoplasmic reticulum (ER)-mediated apoptosis are involved in Cd-induced immunotoxicity. Furthermore, Cd induced autophagy, as demonstrated by microtubule associated protein 1 light chain 3B (LC3B) plasmid DNA transfection and its conversion from LC3-I to the LC3-II form by autophagy inhibitors, via AMP activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling. Pharmacological and genetic inhibition of autophagy suppressed Cd-induced apoptosis, as evidenced by inhibition of caspase-8, caspase-3, and PARP-1 cleavage, indicating that autophagy promotes apoptosis. The pan-caspase inhibitor zVAD inhibited Cd-induced apoptosis, but increased autophagy and decreased cell viability, indicating that autophagy can compensate for reduced apoptotic cell death. Calpain inhibitors blocked Cd-induced apoptosis and autophagy, indicating that calpain plays a critical role in Cd cytotoxicity. Treatment with Ca2+ chelators completely recovered Cd-induced cell viability and inhibited Cd-induced apoptosis and autophagy. Treatment with N-acetyl-l-cysteine (NAC) suppressed Cd induced antioxidant enzyme levels, apoptosis, and autophagy. Collectively, Cd induced oxidative stress triggers ER stress, leading to Ca2+-dependent calpain activation and subsequent activation of autophagy and apoptosis, resulting in immune suppression. PMID- 29111404 TI - A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials. AB - BACKGROUND: Although several studies indicate that placebo response is large to antidepressant pharmacotherapy in major depressive disorder (MDD), no updated meta-analysis has quantified the magnitude of the placebo (sham) response to repetitive transcranial magnetic stimulation (rTMS) in MDD yet. OBJECTIVE: To conduct a systematic review and meta-analysis on this issue in randomized controlled trials (RCTs) involving participants with MDD; and to explore potential moderators. METHODOLOGY: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science electronic databases were searched from inception up to March 15, 2017 for RCTs that investigated the efficacy of any rTMS modality compared to sham intervention in participants with acute depressive episodes. Cochrane Risk of Bias Tool was used to estimate risks. We estimated the placebo effect size (Hedges's g, random-effects model) response using placebo groups baseline and endpoint depressive symptom scores. Meta-regressions have been employed to explore potential moderators of response. RESULTS: Sixty-one studies met eligibility criteria (N=1328; mean age, 47years; 57% females). Placebo response was large (g=0.8, 95% CI=0.65-0.95, p<0.01) regardless of the modality of intervention. Placebo response was directly associated with publication year and depression improvement of the active group, and inversely associated with higher levels of treatment-resistant depression. Other moderators, including gender, age, and stimulator type, were not associated with the outcome. Overall, 24.6%, 67.2%, and 8.2% of studies had an overall low, unclear, and high bias risk, respectively. CONCLUSION: Placebo response in rTMS depression trials was large and associated with depression improvement of the active treatment group. Such result suggests that excluding placebo responders with a run-in phase may not confer advantage since response to 'active' rTMS may decrease as well. Moreover, placebo response may be a component of therapeutic response to rTMS in MDD. In addition, placebo response increase over time could indicate improvement in rTMS trial designs, including better sham rTMS methods. PMID- 29111407 TI - Application of Reverse Transcriptase-PCR-DGGE as a rapid method for routine determination of Vibrio spp. in foods. AB - The aim of this research was to evaluate the feasibility of PCR-DGGE and Reverse Transcriptase-PCR-DGGE techniques for rapid detection of Vibrio species in foods. Primers GC567F and 680R were initially evaluated for amplifying DNA and cDNA of ten references Vibrio species by PCR method. The GC-clamp PCR amplicons were separated according to their sequences by the DGGE using 10% (w/v) polyacrylamide gel containing 45-70% urea and formamide denaturants. Two pair of Vibrio species, which could not be differentiated on the gel, was Vibrio fluvialis - Vibrio furnissii and Vibrio parahaemolyticus - Vibrio harveyi. To determine the detection limit, in the community of 10 reference strains containing the same viable population, distinct DNA bands of 3 species; Vibrio cholerae, Vibrio mimicus and Vibrio alginolyticus were consistently observed by PCR-DGGE technique. In fact, 5 species; Vibrio cholerae, Vibrio mimicus, Vibrio alginolyticus, Vibrio parahaemolyticus and Vibrio fluvialis consistently observed by Reverse Transcriptase-PCR-DGGE. In the community containing different viable population increasing from 102 to 105CFU/mL, PCR-DGGE analysis only detected the two most prevalent species, while RT-PCR-DGGE detected the five most prevalent species. Therefore, Reverse Transcriptase-PCR-DGGE was also selected for detection of various Vibrio cell conditions, including viable cell (VC), injured cells from frozen cultures (IVC) and injured cells from frozen cultures with pre enrichment (PIVC). It was found that cDNA band of all cell conditions gave the same migratory patterns, except that multiple cDNA bands of Plesiomonas shigelloides under IVC and PIVC conditions were found. When Reverse Transcriptase PCR-DGGE was used for detecting Vibrio parahaemolyticus in the pathogen-spiked food samples, Vibrio parahaemolyticus could be detected in the spiked samples containing at least 102CFU/g of this pathogen. The results obtained also corresponded to standard method (USFDA, 2004). In comparison with the detection of the Vibrio profiles in fourteen food samples using standard method, Reverse Transcriptase-PCR-DGGE resulted in 100%, 75% and 50% similarity in 3, 1 and 6 food samples, respectively. PMID- 29111409 TI - MULAN: Evaluation and ensemble statistical inference for functional connectivity. AB - Many analysis methods exist to extract graphs of functional connectivity from neuronal networks. Confidence in the results is limited because, (i) different methods give different results, (ii) parameter setting directly influences the final result, and (iii) systematic evaluation of the results is not always performed. Here, we introduce MULAN (MULtiple method ANalysis), which assumes an ensemble based approach combining multiple analysis methods and fuzzy logic to extract graphs with the most probable structure. In order to reduce the dependency on parameter settings, we determine the best set of parameters using a genetic algorithm on simulated datasets, whose temporal structure is similar to the experimental one. After a validation step, the selected set of parameters is used to analyze experimental data. The final step cross-validates experimental subsets of data and provides a direct estimate of the most likely graph and our confidence in the proposed connectivity. A systematic evaluation validates our strategy against empirical stereotactic electroencephalography (SEEG) and functional magnetic resonance imaging (fMRI) data. PMID- 29111406 TI - Panic-like escape response elicited in mice by exposure to CO2, but not hypoxia. AB - Exposure to elevated concentrations of CO2 or hypoxia has been widely used in psychiatric research as a panic provoking stimulus. However, the use of these respiratory challenges to model panic-like responses in experimental animals has been less straightforward. Little data is available, from behavioral and endocrine perspectives, to support the conclusion that a marked aversive situation, such as that experienced during panic attacks, was evoked in these animals. We here compared the behavioral responses of male CB57BL/6 mice during exposure to 20% CO2 or 7% O2 and its consequence on plasma levels of corticosterone. We also evaluated whether clinically-effective panicolytic drugs affect the behavioral responses expressed during CO2 exposure. The results showed that whereas hypoxia caused a marked reduction in locomotion, inhalation of CO2 enriched air evoked an active escape response, characterized by bouts of upward leaps directed to the border of the experimental cage, interpreted as escape attempts. Corticosterone levels were increased 30min after either of the respiratory challenges used, but it was higher in the hypoxia group. Chronic (21days), but not acute, treatment with fluoxetine or imipramine (5, 10 or 15mg/kg) or a single injection of alprazolam (0.025, 0.05 or 0.1mg/kg), but not of the anxiolytic diazepam (0.025, 0.05 or 0.1 and 1mg/kg) reduced the number of escape attempts, indicating a panicolytic-like effect. Altogether, the results suggest that whereas hypoxia increased anxiety, exposure to 20% CO2 evoked a panic-like state. The latter condition/test protocol seems to be a simple and validated model for studying in mice pathophysiological mechanisms and the screening of novel drugs for panic disorder. PMID- 29111405 TI - Investigation of superior longitudinal fasciculus fiber complexity in recent onset psychosis. AB - BACKGROUND: Standard diffusion tensor imaging measures (e.g., fractional anisotropy; FA) are difficult to interpret in brain regions with crossing white matter (WM) fibers. Diffusion spectrum imaging (DSI) can be used to resolve fiber crossing, but has been difficult to implement in studies of patients with psychosis given long scan times. METHODS: We used four fold accelerated compressed sensing to accelerate DSI acquisition to investigate the superior longitudinal fasciculus (SLF) in 27 (20M/7F) patients with recent onset psychosis and 23 (11M/12F) healthy volunteers. Dependent measures included the number of crossing fiber directions, multi directional anisotropy (MDA), which is a measure sensitive to the anisotropy of the underlying water diffusion in regions of crossing fibers, generalized FA (GFA) computed from the orientation distribution function, FA and tract volume. RESULTS: Patients demonstrated a greater number of crossing WM fibers, lower MDA, GFA and FA in the left SLF compared to healthy volunteers. Patients also demonstrated a reversal in the normal (R>L) asymmetry of crossing fiber directions in the SLF and a lack of normal (L>R) asymmetry in MDA, GFA and FA compared to healthy volunteers. Lower GFA correlated significantly (p<0.05) with worse overall neuropsychological functioning; posthoc tests revealed significant effects with verbal functioning and processing speed. CONCLUSIONS: Our findings provide the first in vivo evidence for abnormal crossing fibers within the SLF among individuals with psychosis and their functional correlates. A reversal in the normal pattern of WM asymmetry of crossing fibers in patients may be consistent with an aberrant neurodevelopmental process. PMID- 29111411 TI - Overlapping and distinct neural correlates of imitating and opposing facial movements. AB - Previous studies have demonstrated that imitating a face can be relatively automatic and reflexive. In contrast, opposing facial expressions may require engaging flexible, cognitive control. However, few studies have examined the degree to which imitation and opposition of facial movements recruit overlapping and distinct neural regions. Furthermore, little work has examined whether opposition and imitation of facial movements differ between emotional and averted eye gaze facial expressions. This study utilized a novel task with 40 participants to compare passive viewing, imitation and opposition of emotional faces looking forward and neutral faces with averted eye gaze [(3: Look, Imitate, Oppose) x (2: Emotion, Averted Eye)]. Imitation and opposition of both types of facial movements elicited overlapping activation in frontal, premotor, superior temporal and anterior intraparietal regions. These regions are recruited during cognitive control, face processing and mirroring tasks. For both emotional and averted eye gaze photos, opposition engaged the superior frontal gyrus, superior temporal sulcus and the anterior intraparietal sulcus to a greater extent compared to imitation. Finally, stimulus type and instruction interacted, such that for the eye gaze condition only, greater activation was observed in the dorsal anterior cingulate (dACC) during opposition compared to imitation, while no significant dACC differences were observed for the emotional expression conditions, which instead showed significantly greater activation in the middle and frontal pole. Overall these results showed significant overlap between imitation and opposition, as well as increased activation of these regions to generate an opposing facial movement relative to imitating. PMID- 29111413 TI - Introduction of the newly elected IBE Secretary-General Mary Secco. PMID- 29111410 TI - The z-spectrum from human blood at 7T. AB - Chemical Exchange Saturation Transfer (CEST) has been used to assess healthy and pathological tissue in both animals and humans. However, the CEST signal from blood has not been fully assessed. This paper presents the CEST and nuclear Overhauser enhancement (NOE) signals detected in human blood measured via z spectrum analysis. We assessed the effects of blood oxygenation levels, haematocrit, cell structure and pH upon the z-spectrum in ex vivo human blood for different saturation powers at 7T. The data were analysed using Lorentzian difference (LD) model fitting and AREX (to compensate for changes in T1), which have been successfully used to study CEST effects in vivo. Full Bloch-McConnell fitting was also performed to provide an initial estimate of exchange rates and transverse relaxation rates of the various pools. CEST and NOE signals were observed at 3.5 ppm, -1.7 ppm and -3.5 ppm and were found to originate primarily from the red blood cells (RBCs), although the amide proton transfer (APT) CEST effect, and NOEs showed no dependence upon oxygenation levels. Upon lysing, the APT and NOE signals fell significantly. Different pH levels in blood resulted in changes in both the APT and NOE (at -3.5 ppm), which suggests that this NOE signal is in part an exchange relayed process. These results will be important for assessing in vivo z-spectra. PMID- 29111414 TI - Environmental sensing and morphological plasticity in plants. AB - All creatures on earth are affected by their surrounding environment. Animals can move and escape unfavorable environmental changes, whereas plants must respond to environmental stimuli. Plants adapt to changes with cellular-level responses to short-term environmental changes, but may adapt to changes in the environment by regulating their development and growth. In this review, we considered changes in atmospheric CO2 concentrations, dry/wet moisture conditions, flooding, and temperature as examples of environmental stimuli. We mainly focused on leaf morphology and stomatal density as examples of developmental and growth patterns of plants in response to the environment. PMID- 29111412 TI - Serotype distribution and antibiotic susceptibility of Streptococcus pneumoniae strains in the south of Tunisia: A five-year study (2012-2016) of pediatric and adult populations. AB - OBJECTIVES: To analyze the serotype distribution of Streptococcus pneumoniae clinical isolates collected in the south of Tunisia over a 5-year period in different age groups and to assess their antimicrobial susceptibility patterns. METHODS: A total of 305 non-duplicate S. pneumoniae isolates were collected between January 2012 and December 2016 at the university hospital in Sfax, Tunisia. All isolates were serotyped by multiplex PCR. The antibiotic susceptibility of all isolates was determined using the disk diffusion test or Etest assay. RESULTS: Among the 305 pneumococcal isolates, 76 (24.9%) were invasive and 229 (75.1%) were non-invasive. The most common serotypes were 19F (20%), 14 (16.7%), 3 (9.2%), 23F (7.5%), 19A (5.9%), and 6B (5.9%). Potential immunization coverage rates for pneumococcal conjugate vaccines PCV7, PCV10, and PCV13 were 58%, 59.3%, and 78.7%, respectively. Three-quarters (75.3%) of pneumococcal isolates were non-susceptible to penicillin. The resistance rate to erythromycin was 71.4%. Only two isolates were resistant to levofloxacin. CONCLUSIONS: 19F and 14 were the most prevalent serotypes in the south of Tunisia. The inclusion of a PCV in the immunization program could be useful for reducing the burden of pneumococcal diseases. The high resistance rate to penicillin and macrolides is alarming. Prudent use of antibiotics is crucial to prevent the selection of multidrug-resistant pneumococci. PMID- 29111415 TI - The planar cell polarity Vangl2 protein: From genetics to cellular and molecular functions. AB - Planar cell polarity (PCP) refers to the capacity of a tissue, typically, but not exclusively, an epithelium, to transmit directional information across the tissue plane such that its cellular constituents can differentiate, divide or move in a coordinated manner and along a common axis, generally orthogonal to the apical basal axis. PCP relies on a core module of highly conserved proteins originally identified in Drosophila which can act intra- and extracellularly. In this review, we focus on the vertebrate ortholog of one of these core PCP components, namely the Vangl2 protein. After a brief historical perspective, we discuss novel cellular settings for which a cellular Vangl2 requirement has been recently documented, with a particular emphasis on adult tissues that rely on Vangl2 for the maintenance of their regenerative capacity or their physiological functions. Finally we compile the most recent data about Vangl2 interacting proteins. PMID- 29111416 TI - Evidence that a Regional Surgical Collaborative Can Transform Care: Surgical Site Infection Prevention Practices for Colectomy in Michigan. AB - BACKGROUND: Surgical site infections (SSI) after colectomy are associated with increased morbidity and health care use. Since 2012, the Michigan Surgical Quality Collaborative (MSQC) has promoted a "bundle" of care processes associated with lower SSI risk, using an audit-and-feedback system for adherence, face-to face meetings, and support for quality improvement projects at participating hospitals. The purpose of this study was to determine whether practices changed over time. STUDY DESIGN: We previously found 6 processes of care independently associated with SSI in colectomy. From 2012 to 2016, we promoted a bundle of 3 care measures (cefazolin/metronidazole, oral antibiotics after mechanical bowel preparation, and normoglycemia) in 52 hospitals. Primary outcome was change in use of the 3-item SSI bundle. We also used a hierarchical logistic regression model to assess the association between 6-item compliance and SSI rate, morbidity, and health care use. RESULTS: The use of cefazolin/metronidazole increased from 18.6% to 32.3% (p < 0.001), oral antibiotic preparation increased from 42.9% to 62.0% (p < 0.001). The increase in normoglycemia was not significant. Concurrently, the SSI rate fell from 6.7% to 3.9% in the 52 hospitals (p = 0.012). Patients receiving more bundle measures had decreased rates of SSI, sepsis, and pneumonia. Morbidity and health care use significantly decreased with increased bundle compliance. CONCLUSIONS: These data show a significant increase in use of process measures promoted by a regional quality improvement collaborative, and an associated decrease in SSI after elective colectomy. These results highlight the promise of regional collaboratives to accelerate practice change and improve outcomes. PMID- 29111417 TI - Ongoing Evolution of Emergency General Surgery as a Surgical Subspecialty. PMID- 29111418 TI - Quality of caregiver-child play interactions with toddlers born preterm and full term: Antecedents and language outcome. AB - BACKGROUND: Preterm birth may leave long-term effects on the interactions between caregivers and children. Language skills are sensitive to the quality of caregiver-child interactions. AIMS: Compare the quality of caregiver-child play interactions in toddlers born preterm (PT) and full term (FT) at age 22months (corrected for degree of prematurity) and evaluate the degree of association between caregiver-child interactions, antecedent demographic and language factors, and subsequent language skill. STUDY DESIGN: A longitudinal descriptive cohort study. SUBJECTS: 39 PT and 39 FT toddlers individually matched on sex and socioeconomic status (SES). OUTCOME MEASURES: The outcome measures were dimensions of caregiver-child interactions, rated from a videotaped play session at age 22months in relation to receptive language assessments at ages 18 and 36months. RESULTS: Caregiver intrusiveness was greater in the PT than FT group. A composite score of child interactional behaviors was associated with a composite score of caregiver interactional behaviors. The caregiver composite measure was associated with later receptive vocabulary at 36months. PT-FT group membership did not moderate the association between caregiver interactional behavior and later receptive vocabulary. CONCLUSIONS: The quality of caregiver interactional behavior had similar associations with concurrent child interactional behavior and subsequent language outcome in the PT and FT groups. Greater caregiver sensitivity/responsiveness, verbal elaboration, and less intrusiveness support receptive language development in typically developing toddlers and toddlers at risk for language difficulty. PMID- 29111420 TI - Viscoelastic shear lag model to predict the micromechanical behavior of tendon under dynamic tensile loading. AB - Owing to its viscoelastic nature, tendon exhibits stress rate-dependent breaking and stiffness function. A Kelvin-Voigt viscoelastic shear lag model is proposed to illustrate the micromechanical behavior of the tendon under dynamic tensile conditions. Theoretical closed-form expressions are derived to predict the deformation and stress transfer between fibrils and interfibrillar matrix while tendon is dynamically stretched. The results from the analytical solutions demonstrate that how the fibril overlap length and fibril volume fraction affect the stress transfer and mechanical properties of tendon. We find that the viscoelastic property of interfibrillar matrix mainly results in collagen fibril failure under fast loading rate or creep rupture of tendon. However, discontinuous fibril model and hierarchical structure of tendon ensure relative sliding under slow loading rate, helping dissipate energy and protecting fibril from damage, which may be a key reason why regularly staggering alignment microstructure is widely selected in nature. According to the growth, injury, healing and healed process of tendon observed by many researchers, the conclusions presented in this paper agrees well with the experimental findings. Additionally, the emphasis of this paper is on micromechanical behavior of tendon, whereas this analytical viscoelastic shear lag model can be equally applicable to other soft or hard tissues, owning the similar microstructure. PMID- 29111421 TI - Substitution impact of highly conserved arginine residue at position 75 in GJB1 gene in association with X-linked Charcot-Marie-tooth disease: A computational study. AB - X-linked Charcot-Marie-Tooth type 1 X (CMTX1) disease is a subtype of Charcot Marie-Tooth (CMT), which is mainly caused by mutations in the GJB1 gene. It is also known as connexin 32 (Cx32) that leads to Schwann cell abnormalities and peripheral neuropathy. CMTX1 is considered as the second most common form of CMT disease. The aim of this study is to computationally predict the potential impact of different single amino acid substitutions at position 75 of Cx32, from arginine (R) to proline (P), glutamine (Q) and tryptophan (W). This position is known to be highly conserved among the family of connexin. To understand the structural and functional changes due to these single amino acid substitutions, we employed a homology-modeling technique to build the three-dimensional structure models for the native and mutant proteins. The protein structures were further embedded into a POPC lipid bilayer, inserted into a water box, and subjected to molecular dynamics simulation for 50 ns. Our results show that the mutants R75P, R75Q and R75W display variable structural conformation and dynamic behavior compared to the native protein. Our data proves useful in predicting the potential pathogenicity of the mutant proteins and is expected to serve as a platform for drug discovery for patients with CMT. PMID- 29111419 TI - Diagnosis of multiple system atrophy. AB - Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs. PMID- 29111422 TI - Shorter sleep duration and longer sleep onset latency are related to difficulty disengaging attention from negative emotional images in individuals with elevated transdiagnostic repetitive negative thinking. AB - BACKGROUND AND OBJECTIVES: Repetitive negative thinking (RNT) is often associated with disruptions in sleep and circadian rhythms. Disruptions in sleep and circadian rhythms may deal a "second hit" to attentional control deficits. This study evaluated whether sleep and circadian rhythm disruptions are related to the top-down control of attention to negative stimuli in individuals with heightened repetitive negative thinking. METHODS: Fifty-two community adults with high levels of transdiagnostic RNT and varying habitual sleep durations and bedtimes participated in a hybrid free-viewing and directed attention task using pairs of emotionally-evocative and neutral images while eye-tracking data were collected. Self-report and clinician-administered interviews regarding sleep were also collected. RESULTS: Shorter habitual sleep duration was associated with more time looking at emotionally negative compared to neutral images during a free-viewing attention task and more difficulty disengaging attention from negative compared to neutral images during a directed attention task. In addition, longer sleep onset latencies were also associated with difficulty disengaging attention from negative stimuli. The relations between sleep and attention for positive images were not statistically significant. LIMITATIONS: A causal link between sleep and attentional control cannot be inferred from these cross-sectional data. The lack of a healthy control sample means that the relations between sleep disruption, attention, and emotional reactivity may not be unique to individuals with RNT. CONCLUSIONS: These findings suggest that sleep disruption may be associated with a specific impact on cognitive resources that are necessary for the top-down inhibitory control of attention to emotionally negative information. PMID- 29111423 TI - Maternal cardiovascular dysfunction in women with early onset preeclampsia and late onset preeclampsia: A cross-sectional study. AB - OBJECTIVES: To compare the cardiovascular changes associated with early onset (EOPE) and late onset (LOPE) subtypes of preeclampsia. METHODS: A prospective matched cross-sectional study involving 50 women each with early and late onset subtypes of preeclampsia conducted in a tertiary hospital in South India. Cardiac function and remodelling were assessed by conventional 2D, M-mode and doppler echocardiography. RESULTS: Women with EOPE had a significantly more altered left ventricular (LV) geometry, global LV diastolic dysfunction, impairment in myocardial contractility (40% vs. 24%) and a higher total vascular resistance index (863.0 vs 704.0 dynes/s/cm5/m2) compared to LOPE. Stroke volume index (55.3 vs. 62.2 ml/m2) and cardiac work index (520.7 vs. 584.9mmHg*L/min/m2) were higher in women with LOPE. However, the systolic function was found to be preserved in the LV in both the groups. CONCLUSIONS: Women with EOPE have a more severe cardiac impairment than those with LOPE. The difference in the hemodynamic indices may provide a chance to tailor patient-specific treatment strategies to improve the pregnancy outcome as well as in early identification and initiation of preventive measures for those at risk of cardiovascular diseases later in life. KEY MESSAGE: Adaptation of the heart in women with early onset subtype differs with that of late onset subtype of preeclampsia. Total vascular resistance is higher in early onset group compared to late onset group having a higher cardiac output. These differences in the hemodynamic indices may provide a chance to tailor patient-specific treatment strategies to improve the pregnancy outcome as well as in early identification and initiation of preventive measures for those at risk of cardiovascular diseases later in life. PMID- 29111424 TI - Abnormal mid-trimester cardiac strain in women with chronic hypertension predates superimposed preeclampsia. AB - BACKGROUND: Chronic hypertension (cHTN) affects 7% of all pregnancies. We hypothesized that cHTN during pregnancy would be associated with abnormal myocardial strain patterns and adverse perinatal outcomes. METHODS: This was a retrospective cohort study of patients seen in a high-risk obstetrics clinic with cHTN. Parturients with a singleton pregnancy who had undergone an echocardiogram as part of routine clinical care were eligible. Clinical and demographic information was collected from medical records. Global peak longitudinal strain (GLS) was measured using automated software from stored echocardiographic images. RESULTS: 60 patients were included in this analysis, of which 48 (80.0%) were African American. The median BMI was 40.6, age was 34 years, and the gestational age was 20.4 weeks at the time of the echo and 37.9 weeks at delivery. Thirty four patients (56.7%) demonstrated abnormal strain, defined as a GLS <= -19%. Patients with abnormal strain were similar in age and BMI to patients with normal cardiac function. When compared to women with normal strain, those with abnormal strain had lower stroke volume (69.0 ml vs 81.5 ml; p = .001) and ejection fraction (49.6% vs 57.5%; p < .0001). Rates of superimposed preeclampsia were higher (38.2% vs 11.5%, p-value = .02) and a higher proportion of patients in the abnormal strain group delivered before 37 weeks (44.1% vs 19.2%; p = .04). CONCLUSION: In a population of parturients with cHTN, we found that more than one half demonstrated subclinical abnormal cardiac function. The presence of abnormal cardiac strain predates superimposed preeclampsia and preterm delivery. Further studies are needed to validate these findings. PMID- 29111425 TI - Transcranial sonographic findings may predict prognosis of gastroprokinetic drug induced parkinsonism. AB - BACKGROUND: Drug-induced parkinsonism (DIP) is one important cause of parkinsonism and a major cause of misleading diagnosis of Parkinson's disease (PD). DIP is caused by dopamine receptor blocking agents. Its symptoms will improve after withdrawal of offending drugs. However, parkinsonism does not regress in several individuals. It may persist or exacerbate despite drug withdrawal. Transcranial sonography (TCS) of the substantia nigra (SN) has been widely used to diagnose PD and differentiate parkinsonism types. The objective of this study was to investigate the value of early TCS findings for predicting clinical outcome of patients with newly diagnosed gastroprokinetic drug-induced parkinsonism after withdrawal of dopamine receptor blocking agents. METHODS: Fifty PD, 69 DIP, and 74 healthy controls were enrolled in this study. Patients with DIP were categorized into two subgroups: clinically improved after drug withdrawal (pure DIP) and clinically persistent or aggravated parkinsonism after drug withdrawal (unmasked PD). TCS was performed for all individuals to detect echogenicity in the SN. RESULTS: Transcranial sonographic SN echogenicity was significantly increased in PD while DIP and controls had similar SN echogenicity. In subgroup analysis of DIP, transcranial sonographic SN echogenicity was significantly increased in unmasked PD compared to that in pure DIP or healthy controls. CONCLUSIONS: SN echogenicity on TCS could be a useful tool to differentiate PD from DIP in clinical situations. Pure DIP and unmasked PD exhibited different SN echogenicity patterns. Early SN echogenicity findings on TCS could be used a biomarker to predict clinical prognosis of DIP. PMID- 29111426 TI - When movement disorders hurt: Addressing pain in hyperkinetic disorders. AB - Pain is an important nonmotor symptom in movement disorders. Dystonia is a hyperkinetic movement disorder characterized by involuntary, sustained or intermittent muscle contractions causing abnormal movements, postures or both. Contrary to common views the nonmotor symptoms are present in dystonia patients. Pain is a prevailing feature of cervical dystonia (CD), the most common form of focal dystonia. The mechanism of pain in CD remains mostly unknown, but there are growing evidence that it could not be only the consequence of muscle hyperactivity. We have shown that botulinum toxin (BoNT) produced pain relief before muscle relaxation and that effect on pain relief lasted longer than the effect on motor improvement. More and more data suggest that pain relief could be attributed to the direct effect of BoNT type A on central nervous system. Pain, depression, and anxiety have been shown to be significant determinants of QoL in focal dystonia patients. Routine clinical examination in patients with dystonia should include evaluation of motor as well as non-motor symptoms. Selective rating assessment should be used in clinical practice to quantify pain. Specific assessment of pain is important to determine the effect of BoNT as the most effective treatment in focal dystonia. PMID- 29111427 TI - When shaking during standing points to hereditary spastic paraplegias. PMID- 29111428 TI - KDM6 and KDM4 histone lysine demethylases emerge as molecular therapeutic targets in human acute myeloid leukemia. AB - Acute myeloid leukemia (AML) remains an aggressive hematopoietic malignancy that is caused by proliferation of immature myeloid cells and is frequently characterized by perturbations in chromatin-modifying enzymes. Emerging evidence indicates that histone demethylases play a role in tumorigenesis. However, due to the complexity of this enormous family of histone-modifying enzymes, substrate redundancy, and context-specific roles, the contribution of each member remains ambiguous and targeting them remains challenging. Here, we analyzed expression of histone-3-lysine (H3K) demethylases and their cognate substrates in a cohort of de novo AML patients, which demonstrated that the expression of H3K27Me3/2 demethylases and selected members of H3K9Me3/2/1-demethylases are significantly increased in AML. KDM6 upregulation is associated with a global decrease in H3K27Me3 level. Importantly, our data show that pharmacological inhibition of H3K27Me3/2-demethylases or H3K9Me3/2-demethylases, either alone or in combination, could be considered an interesting molecular therapeutic modality in human AML independent of its subtype. PMID- 29111429 TI - Megakaryocyte and polyploidization. AB - In mammals, platelets are produced in the blood by cytoplasmic fragmentation of megakaryocytes (MKs). Platelet production is thus dependent on both the MK number and size. During differentiation, MKs switch from a division by mitosis to polyploidization by endomitosis to increase their size. The endomitotic process includes several successive rounds of DNA replication with an entry in mitosis with a failure in late cytokinesis and a defect in karyokinesis. This leads to a giant cell with a modal ploidy at 16N and one multilobulated nucleus. The entire genome is duplicated several times and all alleles remain functional producing a hypermetabolic cell. A defect in abscission explains the cytokinesis failure and is related to an altered accumulation of actomyosin at the cleavage furrow as a consequence of both a low local RhoA activity and silencing of the MYH10 gene. This mechanism is regulated by transcription factors that govern differentiation explaining the intricacies of both processes. However, the endomitotic cell cycle regulation is still incompletely understood, particularly mitosis entry, escape to the tetraploid checkpoint, and defect in karyokinesis. Polyploidization is regulated during ontogeny, the first embryonic MKs being 2N. The molecular mechanism of this embryo-fetal/adult transition is beginning to be understood. In physiological conditions, MK ploidy is increased by an enhanced platelet demand through the thrombopoietin/myeloproliferative leukemia axis. In numerous hematologic malignancies, MK ploidy decreases, but it is always associated with a defect in MK differentiation. It has been proposed that polyploidization induction could be a treatment for some malignant MK disorders. PMID- 29111430 TI - Progress in transnational scientific and ethics review: Commentary on the proposal for a single North American review board for research on dementia. PMID- 29111431 TI - Fliposomes: trans-2-aminocyclohexanol-based amphiphiles as pH-sensitive conformational switches of liposome membrane - a structure-activity relationship study. AB - Recently developed lipids with the trans-2-aminocyclohexanol (TACH) moiety represent unique pH-sensitive conformational switches ("flipids") that can trigger the membrane of liposome-based drug delivery systems at lowered pH as seen in many pathological scenarios. A library of flipids with various TACH-based headgroups and hydrocarbon tails were designed, prepared, and characterized to systematically elucidate the relationship between their chemical structures and their ability to form and to trigger liposomes. Liposomes (fliposomes) consisting of a flipid, POPC and PEG-ceramide were stable at 4 degrees C, pH 7.4 for up to several months and yet released the encapsulated fluorophore in seconds upon acidification. The colloidal properties and encapsulation efficiencies of the fliposomes depended on the structure features of the flipids such as the polarity of the headgroups and the shape and fluidity of the lipid tails. The pH-triggered release also depended on the flipid structure, where shorter linear tails yielded more efficient release. The release of fliposomes was enhanced at different narrow pH ranges, depending on the basicity of the flipid headgroup, which can be estimated either by calculated pKa or by acid/base titration of the flipids while its conformation is monitored by 1H NMR. The structure-activity relationship of the flipids supports "lipid tail conformational shortening" as the mechanism to disrupt lipid membranes and would provide great flexibility in the design of pH sensitive drug delivery systems. PMID- 29111432 TI - Direct determination of carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa from positive blood cultures using laser scattering technology. AB - Delays in appropriate antimicrobial treatment contribute to increased mortality of septic patients. We aimed to develop a methodology for detection of carbapenem resistance in Gram-negative bacteria directly from positive blood cultures (BCs). Initially, meropenem-resistant Enterobacteriaceae (n = 13) and Pseudomonas aeruginosa (n = 32) isolates as well as the same numbers of meropenem-susceptible isolates were used to establish the detection of carbapenem resistance from agar cultures. Growth-based phenotypic detection of meropenem resistance was performed by a laser scattering (LS) method using a BacterioScanTM216R instrument. A subset of the strain collection consisting of meropenem-susceptible and -resistant isolates (each comprising seven P. aeruginosa and three Klebsiella pneumoniae) was used for determination of carbapenem resistance directly from positive BCs. Lysis/centrifugation and filtration/dilution methods were investigated for processing of positive BCs. Four different statistical approaches to discriminate between susceptible and resistant bacteria in real-time were applied and were compared regarding their sensitivity and specificity. After 3 h and 4 h of incubation, respectively, detection of carbapenem resistance in Enterobacteriaceae (sensitivity, 100%; specificity, 100%) and P. aeruginosa (sensitivity, 100%; specificity, >=90%) agar cultures was attainable. Detection of carbapenem resistance directly from positive BCs was achievable with 100% sensitivity and 100% specificity after 4 h and 5 h, respectively, applying lysis/centrifugation and filtration/dilution methods. In conclusion, LS technology combined with lysis/centrifugation and appropriate statistical real time analyses represents a promising option for rapid detection of carbapenem resistance in Gram-negative rods directly from positive BCs. PMID- 29111433 TI - Longitudinal study on antimicrobial consumption and resistance in rabbit farming. AB - Reliable indicators of antimicrobial consumption (AMC) measured with harmonised data and supported by indicators for antimicrobial resistance (AMR) at herd level are necessary to target antimicrobial misuse in food-producing animals. AMC data in 2010-2015 in 32 Italian industrial rabbit holdings weighted with semester production and standardised with animal daily doses (ADDs) were collected. Herd level AMR against eight antimicrobials was assessed in Escherichia coli, Enterococcus faecalis and Enterococcus hirae collected in 2014-2015. Escherichia coli were assessed for mcr-1 and mcr-2 genes. To produce 1 kg of live rabbit, a mean of 71.8 ADDs was used. Overall AMC reduced over time (P < 0.05) owing to lowering consumption of tetracyclines (P < 0.05) and colistin (P < 0.01), but consumption of quinolones (P < 0.05), bacitracin (P < 0.01) and sulfonamides (P = 0.017) increased. All except one indicator E. coli were wild-type for cefotaxime, whereas 97% displayed reduced susceptibility to tetracyclines, 89% to trimethoprim, 63% to enrofloxacin, 24% to chloramphenicol and 21% to colistin. mcr-1 was detected in 50/320 E. coli isolates from 15/32 holdings; mcr-2 was not detected in 58 isolates with colistin MIC >= 2 mg/L. All 305 enterococci were wild-type for ampicillin, ciprofloxacin and vancomycin and displayed reduced tetracycline susceptibility. The mean antimicrobial resistance index (ARI) was 0.5 for E. coli and 0.3 for enterococci. ARI was significantly correlated with AMC at herd level for enterococci (P = 0.008) but not E. coli where high ARI levels were found in a few holdings with low AMC. PMID- 29111434 TI - Empirical treatment of lower urinary tract infections in the face of spreading multidrug resistance: in vitro study on the effectiveness of nitroxoline. AB - The spread of antimicrobial resistance challenges the empirical treatment of urinary tract infections (UTIs). Among others, nitrofurantoin is recommended for first-line treatment, but acceptance among clinicians is limited due to chronic nitrofurantoin-induced lung toxicity and insufficient coverage of Enterobacteriaceae other than Escherichia coli. Nitroxoline appears to be an alternative to nitrofurantoin owing to its favourable safety profile, however data on its current in vitro susceptibility are sparse. In this study, susceptibility to nitroxoline was tested against 3012 urinary clinical isolates (including multidrug-resistant bacteria and Candida spp.) by disk diffusion test and/or broth microdilution. At least 91% of all Gram-negatives (n = 2000), Gram positives (n = 403) and yeasts (n = 132) had inhibition zone diameters for nitroxoline >=18 mm. Except for Pseudomonas aeruginosa, nitroxoline MIC90 values were <=16 mg/L and were 2- to >16-fold lower compared with nitrofurantoin. In extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and methicillin-resistant Staphylococcus aureus (MRSA), MIC90 values of nitroxoline were two-fold higher compared with non-ESBL-producing enterobacteria and methicillin-susceptible S. aureus (MSSA). The in vitro efficacies of nitroxoline and nitrofurantoin against ATCC strains of E. coli, Enterococcus faecalis and Proteus mirabilis were compared by time-kill curves in Mueller-Hinton broth and artificial urine. Nitroxoline was non-inferior against E. coli, P. mirabilis and E. faecalis in artificial urine. In conclusion, nitroxoline showed a broad antimicrobial spectrum, with inhibition zone diameters and MICs of nitroxoline well below the EUCAST breakpoint for E. coli for most organisms, and thus may also be a target for therapy of uncomplicated UTIs. PMID- 29111435 TI - Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model. AB - Cefiderocol is a siderophore cephalosporin that displays potent in vitro activity against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to describe the pharmacokinetics, pharmacodynamics and 24-h efficacy of cefiderocol using dose-ranging methods in a neutropenic murine thigh infection model. Infection was established in neutropenic mice (administered cyclophosphamide 150 mg/kg and 100 mg/kg at 4 days and 1 day prior to inoculation, respectively) with eight Pseudomonas aeruginosa isolates [minimum inhibitory concentration (MIC) range 0.063-0.5 ug/mL] that displayed variable in vivo activity against previously tested beta-lactams with siderophore moieties. Renal excretion was controlled by administration of 5 mg/kg uranyl nitrate 3 days prior to inoculation. Cefiderocol was administered subcutaneously in eight escalating doses [4.2-166.7 mg/kg every 8 h (q8h)]. In pharmacokinetic studies, cefiderocol manifested similar pharmacokinetics across tested doses (4, 100 and 250 mg/kg) with a mean half-life of 0.86 h. In pharmacodynamic studies, the change in CFU after 24 h from the initial inoculum ranged from +3.4 to -3.1 log10 with doses of 4.2-166.7 mg/kg q8h. Dose-response curves for the eight isolates assumed the characteristic sigmoidal shape, with greater CFU reductions as the dose increased. Focusing on the previously defined efficacy parameter of fT>MIC (time that the free drug concentration exceeds the MIC) for this compound, targets for stasis and 1 log10 and 2 log10 reductions ranged from 44.4-94.7, 50.2-97.5 and 62.1-100, respectively. Cefiderocol displayed sustained antibacterial effects against these MDR P. aeruginosa isolates. These data support the cefiderocol dose selected for clinical trials. PMID- 29111437 TI - A new reliable, transposable and cost-effective assay for absolute quantification of total plasmatic bevacizumab by LC-MS/MS in human plasma comparing two internal standard calibration approaches. AB - The quantification of monoclonal antibodies (mAbs) such as bevacizumab, a recombinant humanized immunoglobulin G1 (hIgG1), in biological fluids, is an essential prerequisite to any pharmacokinetic preclinical and clinical study. To date, reference techniques used to quantify mAbs rely on enzyme-linked immunosorbent assay (ELISA) lacking specificity. Furthermore, the commercially available ELISA kit to quantify bevacizumab in human plasma only assesses the free fraction of the drug. However, the conditions of storage and analysis of plasma samples could alter the physiological equilibrium between the free, bound and partially bound forms of bevacizumab and this could result in over- or underestimation of drug concentration. We developed a new assay for absolute quantification of total fraction of bevacizumab by liquid chromatography tandem mass spectrometry (LC-MS/MS) basing identification and quantification of bevacizumab on two specific peptides. In this report we compare our assay with two internal standard (IS) calibration approaches: one using a different human mAb (Trastuzumab) and the other using a stable isotope labeled specific peptide. After enrichment by affinity chromatography on protein A and concentration by ultrafiltration, human plasma samples were proteolyzed by trypsin. Linearity was established from 12.5 to 500MUg/mL with an interday accuracy ranging from 101.7 to 110.6% and precision from 7.0% to 9.9%. This study demonstrates the importance of the choice of the IS in quantifying bevacizumab in human plasma and highlights the difficulty of reaching a reliable proteolysis with a sufficient recovery. We developed a reliable and cost-effective LC-MS/MS method to quantify total plasmatic fraction of bevacizumab in human plasma. Through our development we proposed a generic methodology easily transposable to quantify all IgG1 subclass very useful for clinical pharmacokinetics studies. PMID- 29111436 TI - Topography of human cytochrome b5/cytochrome b5 reductase interacting domain and redox alterations upon complex formation. AB - Cytochrome b5 is the main electron acceptor of cytochrome b5 reductase. The interacting domain between both human proteins has been unidentified up to date and very little is known about its redox properties modulation upon complex formation. In this article, we characterized the protein/protein interacting interface by solution NMR and molecular docking. In addition, upon complex formation, we measured an increase of cytochrome b5 reductase flavin autofluorescence that was dependent upon the presence of cytochrome b5. Data analysis of these results allowed us to calculate a dissociation constant value between proteins of 0.5+/-0.1MUM and a 1:1 stoichiometry for the complex formation. In addition, a 30mV negative shift of cytochrome b5 reductase redox potential in presence of cytochrome b5 was also measured. These experiments suggest that the FAD group of cytochrome b5 reductase increase its solvent exposition upon complex formation promoting an efficient electron transfer between the proteins. PMID- 29111439 TI - The effect of different brightness conditions on visually and memory guided saccades. AB - It is commonly assumed that saccades in the dark are slower than saccades in a lit room. Early studies that investigated this issue using electrooculography (EOG) often compared memory guided saccades in darkness to visually guided saccades in an illuminated room. However, later studies showed that memory guided saccades are generally slower than visually guided saccades. Research on this topic is further complicated by the fact that the different existing eyetracking methods do not necessarily lead to consistent measurements. In the present study, we independently manipulated task (memory guided/visually guided) and screen brightness (dark, medium and light) in an otherwise completely dark room, and measured the peak velocity and the duration of the participant's saccades using a popular pupil-cornea reflection (p-cr) eyetracker (Eyelink 1000). Based on a critical reading of the literature, including a recent study using cornea reflection (cr) eye tracking, we did not expect any velocity or duration differences between the three brightness conditions. We found that memory guided saccades were generally slower than visually guided saccades. In both tasks, eye movements on a medium and light background were equally fast and had similar durations. However, saccades on the dark background were slower and had shorter durations, even after we corrected for the effect of pupil size changes. This means that this is most likely an artifact of current pupil-based eye tracking. We conclude that the common assumption that saccades in the dark are slower than in the light is probably not true, however pupil-based eyetrackers tend to underestimate the peak velocity of saccades on very dark backgrounds, creating the impression that this might be the case. PMID- 29111438 TI - Engineering photosynthetic production of L-lysine. AB - L-lysine and other amino acids are commonly produced through fermentation using strains of heterotrophic bacteria such as Corynebacterium glutamicum. Given the large amount of sugar this process consumes, direct photosynthetic production is intriguing alternative. In this study, we report the development of a cyanobacterium, Synechococcus sp. strain PCC 7002, capable of producing L-lysine with CO2 as the sole carbon-source. We found that heterologous expression of a lysine transporter was required to excrete lysine and avoid intracellular accumulation that correlated with poor fitness. Simultaneous expression of a feedback inhibition resistant aspartate kinase and lysine transporter were sufficient for high productivities, but this was also met with a decreased chlorophyll content and reduced growth rates. Increasing the reductant supply by using NH4+, a more reduced nitrogen source relative to NO3-, resulted in a two fold increase in productivity directing 18% of fixed carbon to lysine. Given this advantage, we demonstrated lysine production from media formulated with a municipal wastewater treatment sidestream as a nutrient source for increased economic and environmental sustainability. Based on our results, we project that Synechococcus sp. strain PCC 7002 could produce lysine at areal productivities approaching that of sugar cane to lysine via fermentation using non-agricultural lands and low-cost feedstocks. PMID- 29111440 TI - A method for single pair mating in an obligate parasitic nematode. AB - Parasitic nematode species have extremely high levels of genetic diversity, presenting a number of experimental challenges for genomic and genetic work. Consequently, there is a need to develop inbred laboratory strains with reduced levels of polymorphism. The most efficient approach to inbred line development is single pair mating, but this is challenging for obligate parasites where the adult sexual reproductive stages are inside the host, and thus difficult to experimentally manipulate. This paper describes a successful approach to single pair mating of a parasitic nematode, Haemonchus contortus. The method allows for polyandrous mating behaviour and involves the surgical transplantation of a single adult male worm with multiple immature adult females directly into the sheep abomasum. We used a panel of microsatellite markers to monitor and validate the single pair mating crosses and to ensure that the genotypes of progeny and subsequent filial generations were consistent with those expected from a mating between a single female parent of known genotype and a single male parent of unknown genotype. We have established two inbred lines that both show a significant overall reduction in genetic diversity based on microsatellite genotyping and genome-wide single nucleotide polymorphism. There was an approximately 50% reduction in heterozygous SNP sites across the genome in the MHco3.N1 line compared with the MoHco3(ISE) parental strain. The MHco3.N1 inbred line has subsequently been used to provide DNA template for whole genome sequencing of H. contortus. This work provides proof of concept and methodologies for forward genetic analysis of obligate parasitic nematodes. PMID- 29111441 TI - Assessment of sexual behavior in rats: The potentials and pitfalls. AB - In the field of behavioral neuroscience, it is essential to use the appropriate animal models for the topic of investigation. Using the wrong model can result in false interpretation of the results. In this review we will discuss the animal models used to study sexual behavior, with a focus on rats. We will discuss the potentials and pitfalls of the different paradigms and try to make recommendations on how research in this field could be optimized. Both male and female sexual behavior are discussed, in addition to sexual motivation. PMID- 29111442 TI - Erratum to "Conversion of Pregabalin to 4-Isobutylpyrrolidone-2". PMID- 29111443 TI - Derivation of endogenous equivalent values to support risk assessment and risk management decisions for an endogenous carcinogen: Ethylene oxide. AB - An approach is presented for ethylene oxide (EO) to derive endogenous equivalent (EE) values, which are endogenous levels normally found within the body expressed in terms of exogenous exposures. EE values can be used to support risk assessment and risk management decisions for chemicals such as EO that have both endogenous and exogenous exposure pathways. EE values were derived using a meta-analysis of data from the published literature characterizing the distribution for an EO biomarker of exposure, hemoglobin N-(2-hydroxyethyl)-valine (HEV), in unexposed populations. These levels are compared to the those reported in exposed populations (smokers, workers). Correlation between the biomarker of exposure and external exposures of EO were applied to this distribution to determine corresponding EE values, which range from 0.13 to 6.9 ppb for EO in air. These values are orders of magnitude higher than risk-based concentration values derived for EO using default methods, and are provided as a pragmatic, data driven alternative approach to managing the potential risks from exogenous exposures to EO. PMID- 29111444 TI - Toxicity assessment of pesticide triclosan by aquatic organisms and degradation studies. AB - Triclosan is considered as an important contaminant and is widely used in personal care products as an antimicrobial agent. This study demonstrates the biodegradation of triclosan by two freshwater microalgae and the acute toxicity of triclosan and 2,4-dichlorophenol. The effects of culture media and light on biodegradation of triclosan and the changing morphology of microalgae were systematically studied. Geitlerinema sp. and Chlorella sp. degraded 82.10% and 92.83% of 3.99 mg/L of triclosan at 10 days, respectively. The microalgal growth inhibition assay confirmed absence of toxic effects of triclosan on Chlorella sp., even at higher concentration (50 mg/L) after 72 h exposure. HPLC analysis showed that 2,4-dichlorophenol was produced as degradation product of triclosan by Geitlerinema sp. and Chlorella sp. This study proved to be beneficial to understand biodegradation and acute toxicity of triclosan by microalgae in order to provide aquatic environmental protection. PMID- 29111445 TI - Bullying among immigrant and non-immigrant early adolescents: School- and student level effects. AB - We examined the association between school immigrant concentration and bullying among immigrant and non-immigrant early adolescents, and identified potential explanatory factors. First generation immigrant students had reduced odds of victimization and perpetration in schools with high (20-60%), compared to low, levels of immigrant concentration. Second generation immigrant students had reduced odds of ethnic/racial victimization in moderately concentrated schools; while non-immigrants had increased odds in the same schools. Non-white students had increased odds of ethnic/racial victimization compared to White students. While students' sense of school belonging and perceived teacher cultural sensitivity were negatively associated with bullying, they did not account for the differential associations noted above. Results demonstrate the importance of immigrant density as a protective school characteristic for immigrant and ethnic minority youth. Additional social processes operating in schools that may explain bullying behaviors among immigrant and non-immigrant youth should be explored to inform programs for promoting inclusion in schools. PMID- 29111446 TI - High and low use of electronic media during nighttime before going to sleep: A comparative study between adolescents attending a morning or afternoon school shift. AB - This study compared the effects of time spent on electronic media devices during nighttime before going to sleep on the sleep-wake cycle, daytime sleepiness, and chronotype in 568 Mexican students (288 girls, mean age = 14.08) attending a double school shift system (287 from morning shift and 281 from afternoon shift). Students completed anonymous self-report questionnaires. Results suggest that high exposure to an electronic media device may have an impact on their sleep wake cycle, regardless of their school shift. Adolescents from the afternoon shift reported more time spent on devices. Those from the morning shift reported daytime sleepiness with the use of MP3 player, and from the afternoon shift with the use of computer, MP3 player, and television. Both school shifts reported an intermediate chronotype with all electronic media devices, but the afternoon shift with a tendency towards eveningness with the use of the computer, smartphone, and MP3 player. PMID- 29111447 TI - Sexting as the mirror on the wall: Body-esteem attribution, media models, and objectified-body consciousness. AB - Sexting motivations during adolescence are related to developmental dimensions such as sexual identity and body-image development-or harmful intentions-such as aggression among peers and partners. Sociocultural and media models can affect explorations of sexuality and redefinitions of body image, which in turn are related to sexting behaviors and motivations. In this study, we investigated the roles of body-esteem attribution, the internalization of media models, and body objectification as predictors of three sexting motivations: sexual purposes, body image reinforcement, and instrumental/aggravated reasons. The participants were 190 Italian adolescents aged from 13 to 20 years old (Mage = 17.4, SDage = 1.8; 44.7% females). Sexual purposes were predicted by body-esteem attribution and body objectification; body-image reinforcement was predicted by the internalization of media models, and instrumental/aggravated reasons were not predicted by any variable. Thus, only sexual purposes and body-image reinforcement appeared to be affected by body-image concerns due to media models. PMID- 29111448 TI - Next generation sequencing as a follow-up test in an expanded newborn screening programme. AB - OBJECTIVES: Contrary to many western European countries, most south-eastern European countries do not have an expanded newborn screening (NBS) program using tandem mass spectrometry. This study would represent one of the first expanded NBS studies in south-eastern Europe and will enable the estimation of the incidences of IEM in Slovenia. We proposed an expanded NBS approach including next-generation sequencing (NGS) as a confirmational analysis. DESIGN & METHODS: We conducted a pilot study of expanded NBS for selected inborn errors of metabolism (IEM) in Slovenia including 10,048 NBS cards. We used an approach including tandem mass spectrometry followed by second tier tests including NGS. Based on the NBS results, 85 children were evaluated at a metabolic follow-up; 80 of them were analyzed using NGS. RESULTS: Altogether, glutaric acidemia type 1 was confirmed in one patient who was a compound heterozygote for two known causative GCDH variants. A patient with suspected very long-chain acyl-CoA dehydrogenase deficiency had negative metabolic follow-up tests, but had two heterozygous ACADVL variants; one known disease-causing variant and one indel, namely c.205-8_205-7delinsGC, that is predicted to be causative. Nine participants had elevated metabolites characteristic of 3-methylcrotonyl-CoA carboxylase deficiency, 2 of them had known causative homozygous variants in MCCC1. The other seven were heterozygous; two had a novel genetic variant c.149_151dupCCA (p.Thr50dup). Cumulative incidences of IEM in Slovenia were similar to other European countries. CONCLUSIONS: NGS proved to be valuable in explaining the abnormal metabolite concentrations in NBS as it enabled the differentiation between affected patients and mere heterozygotes, and it improved the turnaround time of genetic analysis. The results of this study will be instrumental in the routine implementation of expanded NBS in Slovenia. PMID- 29111449 TI - Editorial on laboratory diagnosis and management of plasma cell dyscrasias special issue. PMID- 29111450 TI - Interpersonal dysfunction in borderline personality: a decision neuroscience perspective. AB - Borderline personality disorder (BPD) is characterized by disadvantageous decisions that are often expressed in close relationships and associated with intense negative emotions. Although functional neuroimaging studies of BPD have described regions associated with altered social cognition and emotion processing, these correlates do not inform an understanding of how brain activity leads to maladaptive choices. Drawing on recent research, we argue that formal models of decision-making are crucial to elaborating theories of BPD that bridge psychological constructs, behavior, and neural systems. We propose that maladaptive interactions between Pavlovian and instrumental influences play a crucial role in the expression of interpersonal problems. Finally, we articulate specific hypotheses about how clinical features of BPD may map onto neural systems that implement separable decision processes. PMID- 29111452 TI - Extraversion and cardiovascular responses to recurrent social stress: Effect of stress intensity. AB - The present study sought to establish whether the effects of extraversion on cardiovascular responses to recurrent social stress are contingent on stress intensity. A 2*5*1 mixed-factorial experiment was conducted, with social stress intensity as a between-subject variable, study phase as a within-subject variable, extraversion as a continuous independent variable, and cardiovascular parameter (HR, SBP, DBP, or RSA) as a dependent variable. Extraversion (NEO-FFI), subjective stress, and physiological stress were measured in 166 undergraduate students randomly assigned to undergo moderate (n=82) or high-intensity (n=84) social stress (a public speaking task with different levels of social evaluation). All participants underwent continuous physiological monitoring while facing two consecutive stress exposures distributed across five laboratory phases: baseline, stress exposure 1, post-stress 1, stress exposure 2, post stress 2. Results indicated that under moderate-intensity social stress, participants higher on extraversion exhibited lesser HR reactivity to stress than participants lower on extraversion, while under high-intensity social stress, they exhibited greater HR, SBP, DBP and RSA reactivity. Under both moderate- and high-intensity social stress, participants higher on extraversion exhibited pronounced SBP and DBP response adaptation to repeated stress, and showed either better degree of HR recovery or greater amount of SBP and DBP recovery after stress. These findings suggest that individuals higher on extraversion exhibit physiological flexibility to cope with social challenges and benefit from adaptive cardiovascular responses. PMID- 29111453 TI - Electrophysiological correlates of near outcome and outcome sequence processing in problem gamblers and controls. AB - The magnification of skill component in gambling as well as the gambler's and hot hand fallacies are gambling-related cognitive distortions. The magnification of skill component refers to the belief that one's ability can be used to win in gambling and that there is a reliable way to do so. The gambler's fallacy refers to the belief that a given outcome is unlikely to follow a preceding run of the same outcome (e.g. a coin coming up heads following a run of heads), while the hot hand fallacy refers to the belief that a streak of wins is going to continue. The biopsychological basis of these cognitive distortions can be analyzed by examining the processing of near outcomes and outcome sequences in gambling. Near outcomes refer to close wins and losses that would have almost resulted in the other outcome. The current study aims to investigate the electrophysiological basis of said cognitive distortions as well as its modulation by gambling problems. In the current study a group of problem gamblers and matched controls gambled on a wheel of fortune and a coin toss paradigm. The processing of near outcomes and outcome sequences was analyzed using event-related potentials (FRN, P300). Near outcomes evoked smaller P300 amplitudes in both groups. Furthermore, previous wins were associated with increased P300 amplitudes. Outcome closeness and previous outcome sequences did not modulate the FRN amplitude. The processing of near outcomes and outcome sequences was not modulated by gambling problems. General differences between problem gamblers and controls were found, with problem gamblers showing reduced peak-to-peak FRN amplitudes. This might point towards a generally more favorable evaluation of gambling outcomes in problem gamblers while the electrophysiological correlates of the analyzed cognitive distortions do not differ from those of healthy controls. PMID- 29111454 TI - The application of reward learning in the real world: Changes in the reward positivity amplitude reflect learning in a medical education context. AB - Evidence ranging from behavioural adaptations to neurocognitive theories has made significant advances into our understanding of feedback-based learning. For instance, over the past twenty years research using electroencephalography has demonstrated that the amplitude of a component of the human event-related brain potential - the reward positivity - appears to change with learning in a manner predicted by reinforcement learning theory (Holroyd and Coles, 2002; Sutton and Barto, 1998). However, while the reward positivity (also known as the feedback related negativity) is well studied, whether the component reflects an underlying learning process or whether it is simply sensitive to feedback evaluation is still unclear. Here, we sought to provide support that the reward positivity is reflective of an underlying learning process and further we hoped to demonstrate this in a real-world medical education context. In the present study, students with no medical training viewed a series of patient cards that contained ten physiological readings relevant for diagnosing liver and biliary disease types, selected the most appropriate diagnostic classification, and received feedback as to whether their decisions were correct or incorrect. Our behavioural results revealed that our participants were able to learn to diagnose liver and biliary disease types. Importantly, we found that the amplitude of the reward positivity diminished in a concomitant manner with the aforementioned behavioural improvements. In sum, our data support theoretical predictions (e.g., Holroyd and Coles, 2002), suggest that the reward positivity is an index of a neural learning system, and further validate that this same system is involved in learning across a wide range of contexts. PMID- 29111455 TI - Meta-transcriptomics and the evolutionary biology of RNA viruses. AB - Metagenomics is transforming the study of virus evolution, allowing the full assemblage of virus genomes within a host sample to be determined rapidly and cheaply. The genomic analysis of complete transcriptomes, so-called meta transcriptomics, is providing a particularly rich source of data on the global diversity of RNA viruses and their evolutionary history. Herein we review some of the insights that meta-transcriptomics has provided on the fundamental patterns and processes of virus evolution, with a focus on the recent discovery of a multitude of novel invertebrate viruses. In particular, meta-transcriptomics shows that the RNA virus world is more fluid than previously realized, with relatively frequent changes in genome length and structure. As well as having a transformative impact on studies of virus evolution, meta-transcriptomics presents major new challenges for virus classification, with the greater sampling of host taxa now filling many of the gaps on virus phylogenies that were previously used to define taxonomic groups. Given that most viruses in the future will likely be characterized using metagenomics approaches, and that we have evidently only sampled a tiny fraction of the total virosphere, we suggest that proposals for virus classification pay careful attention to the wonders unearthed in this new age of virus discovery. PMID- 29111456 TI - Viruses associated with Antarctic wildlife: From serology based detection to identification of genomes using high throughput sequencing. AB - The Antarctic, sub-Antarctic islands and surrounding sea-ice provide a unique environment for the existence of organisms. Nonetheless, birds and seals of a variety of species inhabit them, particularly during their breeding seasons. Early research on Antarctic wildlife health, using serology-based assays, showed exposure to viruses in the families Birnaviridae, Flaviviridae, Herpesviridae, Orthomyxoviridae and Paramyxoviridae circulating in seals (Phocidae), penguins (Spheniscidae), petrels (Procellariidae) and skuas (Stercorariidae). It is only during the last decade or so that polymerase chain reaction-based assays have been used to characterize viruses associated with Antarctic animals. Furthermore, it is only during the last five years that full/whole genomes of viruses (adenoviruses, anelloviruses, orthomyxoviruses, a papillomavirus, paramyoviruses, polyomaviruses and a togavirus) have been sequenced using Sanger sequencing or high throughput sequencing (HTS) approaches. This review summaries the knowledge of animal Antarctic virology and discusses potential future directions with the advent of HTS in virus discovery and ecology. PMID- 29111451 TI - Brain-immune interactions in perinatal hypoxic-ischemic brain injury. AB - Perinatal hypoxia-ischemia remains the primary cause of acute neonatal brain injury, leading to a high mortality rate and long-term neurological deficits, such as behavioral, social, attentional, cognitive and functional motor deficits. An ever-increasing body of evidence shows that the immune response to acute cerebral hypoxia-ischemia is a major contributor to the pathophysiology of neonatal brain injury. Hypoxia-ischemia provokes an intravascular inflammatory cascade that is further augmented by the activation of resident immune cells and the cerebral infiltration of peripheral immune cells response to cellular damages in the brain parenchyma. This prolonged and/or inappropriate neuroinflammation leads to secondary brain tissue injury. Yet, the long-term effects of immune activation, especially the adaptive immune response, on the hypoxic-ischemic brain still remain unclear. The focus of this review is to summarize recent advances in the understanding of post-hypoxic-ischemic neuroinflammation triggered by the innate and adaptive immune responses and to discuss how these mechanisms modulate the brain vulnerability to injury. A greater understanding of the reciprocal interactions between the hypoxic-ischemic brain and the immune system will open new avenues for potential immunomodulatory therapy in the treatment of neonatal brain injury. PMID- 29111457 TI - Graded versus ungraded inferior oblique anterior transposition in patients with asymmetric dissociated vertical deviation. AB - PURPOSE: To report the surgical outcomes of graded versus ungraded inferior oblique anterior transposition (IOAT) in treatment of patients with asymmetric dissociated vertical deviation (DVD) and bilateral inferior oblique overaction (IOOA). METHODS: A total of 74 eyes of 37 patients with asymmetric DVD (interocular difference of >=5Delta) and bilateral IOOA of > +1 were included in this randomized clinical trial. In the ungraded group (n = 18), both inferior oblique muscles were sutured at the inferior rectus level; in the graded group (n = 19), the inferior oblique muscles of eyes with more DVD were sutured at the level of the inferior rectus and inferior oblique muscles of eyes with less DVD were sutured 2 mm posterior to the level of the inferior rectus muscle. RESULTS: DVD was significantly reduced in each group (P < 0.001 for both). Although the postoperative mean difference of asymmetry of DVD was less in the ungraded group compared to the graded group (1.2 +/- 1.9 vs 3.2 +/- 1.2 [P = 0.001]), the absolute amounts of reduction of DVD asymmetry were similar (4.3 +/- 2.3 vs 4.4 +/- 3.1 [P = 0.78]). IOOA and V patterns were also reduced postoperatively. CONCLUSIONS: Each method of IOAT was effective in reducing DVD, asymmetry, IOOA, and V patterns. PMID- 29111458 TI - Low-functional programming of the CREB/BDNF/TrkB pathway mediates cognitive impairment in male offspring after prenatal dexamethasone exposure. AB - Adverse intrauterine environments can increase susceptibility to neuropsychiatric diseases that are related to cognitive impairment. In this study, we observed the cognitive impairment of male offspring rats after prenatal dexamethasone exposure (PDE) and explored the associated intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously injected with 0.2mg/kgd dexamethasone from gestational day 9 (GD9) to GD20. A cohort of the pregnant rat group was sacrificed on GD20, and the male fetal rats were collected. Another group of pregnant rats delivered their offspring naturally, and the male adult offspring rats were subjected to behavioural tests postnatally at 26 weeks and then sacrificed. The adult PDE male offspring rats exhibited cognitive impairment, decreased cell proliferation and increased cell apoptosis in the hippocampus, along with damaged synaptic plasticity and disrupted protein synthesis. Meanwhile, activation of GR and downregulation of the cAMP responsive element binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/tropomyosin receptor tyrosine B (TrkB) signalling pathway were found in the adult PDE offspring rats. Further examinations indicated consistent alterations to the fetal hippocampus by PDE. We concluded that PDE can cause cognitive impairment in adult male offspring rats. The mechanism may be associated with low-functional programming of the hippocampal CREB/BDNF/TrkB signalling pathway. PMID- 29111459 TI - Myeloid differentiation protein 2 induced retinal ischemia reperfusion injury via upregulation of ROS through a TLR4-NOX4 pathway. AB - Retinal ischemia reperfusion (I/R) injury is common in many ophthalmic diseases. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in ischemic retinal injury. Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness. Therefore, inhibiting MD2 may be a novel approach to modulate TLR4 signaling and deleterious downstream effects in ischemic retinal injury. We used human Muller MIO-M1 cells treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro I/R model of oxidative injury and tested the therapeutic effect of inhibiting MD2. Furthermore, we inhibited MD2 in a mouse model of retinal I/R injury and confirmed the results using MD2 knockout mice. Our studies show that pharmacological inhibition of MD2 prevented TBHP-induced reactive oxygen species (ROS) generation, inflammation and subsequent apoptosis in Muller cells. We also show that retinal I/R injury in mice induced functional deficits, increased ROS levels, inflammation and apoptosis. These pathological changes were not observed in MD2 knockout mice and attenuated when MD2 was inhibited in wildtype mice. In addition, we discovered that the mechanism of these therapeutic effects involved regulation of NADPH oxidase 4 (NOX4)-MD2-TLR4 complex formation. This study provides evidence that MD2 plays a key role in the pathogenesis of retinal I/R damage by participating in TLR4-NOX4 complex formation and elaboration of oxidative and inflammatory damage. Hence, inhibition of MD2 may reduce TLR-dependent damage during retinal I/R injury. PMID- 29111461 TI - Sonographic Identification of the Flexor Digitorum Accessorius Longus Tendon. PMID- 29111460 TI - High expression of hippocampal glutamic acid decarboxylase 67 mediates hypersensitivity of the hypothalamic-pituitary-adrenal axis in response to prenatal caffeine exposure in rats. PMID- 29111462 TI - Successful Treatment of Multifactorial Chronic Daily Headaches at an Interdisciplinary Chronic Pain Program: A Case Study. AB - : Chronic daily headaches (CDHs) are common, disabling, and difficult to treat. We report a case of a patient with a complex medical history experiencing multifactorial CDH referred for and eventually enrolled in an interdisciplinary chronic pain program. Focusing on enhancing the patient's function while minimizing the use of medications and invasive procedures, this comprehensive rehabilitation intervention consists of diverse treatment approaches, including cognitive-behavioral therapy, physical and occupational therapy, and medical interventions. Despite the patient's challenges with implementation of strategies learned in the program, positive results were seen, including decreased symptomatology, decreased opioid use, and attainment of employment. Although time intensive, interdisciplinary chronic pain programs may result in a greater likelihood for sustained functional improvements and prevention of disability for patients with CDH, even in the most complex. LEVEL OF EVIDENCE: IV. PMID- 29111463 TI - Diagnostic Validity of Combining History Elements and Physical Examination Tests for Traumatic and Degenerative Symptomatic Meniscal Tears. AB - BACKGROUND: The current approach to the clinical diagnosis of traumatic and degenerative symptomatic meniscal tears (SMTs) proposes combining history elements and physical examination tests without systematic prescription of imaging investigations, yet the evidence to support this diagnostic approach is scarce. OBJECTIVE: To assess the validity of diagnostic clusters combining history elements and physical examination tests to diagnose or exclude traumatic and degenerative SMT compared with other knee disorders. DESIGN: Prospective diagnostic accuracy study. SETTINGS: Patients were recruited from 2 orthopedic clinics, 2 family medicine clinics, and from a university community. PATIENTS: A total of 279 consecutive patients who underwent consultation for a new knee complaint. METHODS: Each patient was assessed independently by 2 evaluators. History elements and standardized physical examination tests performed by a physiotherapist were compared with the reference standard: an expert physicians' composite diagnosis including a clinical examination and confirmatory magnetic resonance imaging. Participating expert physicians were orthopedic surgeons (n = 3) or sport medicine physicians (n = 2). Penalized logistic regression (least absolute shrinkage and selection operator) was used to identify history elements and physical examination tests associated with the diagnosis of SMT and recursive partitioning was used to develop diagnostic clusters. MAIN OUTCOME MEASURES: Diagnostic accuracy measures were calculated including sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios (LR+/-) with associated 95% confidence intervals (CIs). RESULTS: Eighty patients had a diagnosis of SMT (28.7%), including 35 traumatic tears and 45 degenerative tears. The combination a history of trauma during a pivot, medial knee pain location, and a positive medial joint line tenderness test was able to diagnose (LR+ = 8.9; 95% CI 6.1-13.1) or exclude (LR- = 0.10; 95% CI 0.03-0.28) a traumatic SMT. Combining a history of progressive onset of pain, medial knee pain location, pain while pivoting, absence of valgus or varus knee misalignment, or full passive knee flexion was able to moderately diagnose (LR+ = 6.4; 95% CI 4.0 10.4) or exclude (LR- = 0.10; 95% CI 0.03-0.31) a degenerative SMT. Internal validation estimates were slightly lower for all clusters but demonstrated positive LR superior to 5 and negative LR inferior to 0.2 indicating moderate shift in posttest probability. CONCLUSION: Diagnostic clusters combining history elements and physical examination tests can support the differential diagnosis of SMT. These results represent the initial derivation of the clusters and external validation is mandatory. LEVEL OF EVIDENCE: I. PMID- 29111464 TI - Participant-Reported Benefits of Involvement in an Adaptive Sports Program: A Qualitative Study. AB - BACKGROUND: Although participation in adaptive sports offers numerous benefits for persons with disabilities, a substantial number of eligible persons do not take part. Previous studies have identified personal and environmental factors that promote or inhibit adaptive sports participation. However, these studies have considered a relatively narrow range of factors. OBJECTIVE: To use qualitative research techniques to identify novel factors that influence participation in a community-based adaptive sports program. DESIGN: Qualitative focus group study. SETTING: Community-based adaptive sports programs affiliated with a rehabilitation hospital network. PARTICIPANTS: Participants were recruited from among 134 adults who registered for the sports program in 2013-2014. Participants with mobility or sensory impairment, absence of cognitive impairment, and English proficiency were included. The 90 former participants with adequate contact information were contacted, and 17 participated in the focus groups. METHODS: Two moderators led each of 3 audio-recorded focus groups using a moderator's guide. We conducted a thematic analysis of transcript data to identify perceived benefits, barriers, and facilitators of participation. RESULTS: Our analysis identified 5 themes: physical well-being and health/safety; interpersonal and social relationships; intrapersonal and beliefs/attitudes; physical environment; and access. Participants experienced participation both as physically beneficial and as transformative in terms of how they view themselves. However, programs drew on limited personal resources and sometimes presented a perceived risk of injury. Finding information about and transportation to programs was a challenge. Participants formed an informal community that modeled what athletes with disabilities are capable of, helping to overcome initial doubts. CONCLUSIONS: To gain the benefits of participation, athletes overcame significant barriers, several of which may be modifiable, including transportation and difficult-to-find information about program offerings. The importance of community and raising awareness of athletes' own abilities suggests a key role for mentorship. Our study contributes to the understanding of experiential aspects that motivate participation in adaptive sports. LEVEL OF EVIDENCE: IV. PMID- 29111465 TI - Effectiveness of Circuit-Based Exercises on Gait Speed, Balance, and Functional Mobility in People Affected by Stroke: A Meta-Analysis. AB - BACKGROUND: Several interventions have been proposed to rehabilitate patients with neurologic dysfunctions due to stroke. However, the effectiveness of circuit based exercises according to its actual definition, ie, an overall program to improve strength, stamina, balance or functioning, was not provided. OBJECTIVE: To examine the effectiveness of circuit-based exercise in the treatment of people affected by stroke. METHODS: A search through PubMed, Embase, Cochrane Library, and Physiotherapy Evidence Database databases was performed to identify controlled clinical trials without language or date restriction. The overall mean difference with 95% confidence interval was calculated for all outcomes. Two independent reviewers assessed the risk of bias. RESULTS: Eleven studies met the inclusion criteria, and 8 presented suitable data to perform a meta-analysis. Quantitative analysis showed that circuit-based exercise was more effective than conventional intervention on gait speed (mean difference of 0.11 m/s) and circuit based exercise was not significantly more effective than conventional intervention on balance and functional mobility. CONCLUSION: Our results demonstrated that circuit-based exercise presents better effects on gait when compared with conventional intervention and that its effects on balance and functional mobility were not better than conventional interventions. LEVEL OF EVIDENCE: I. PMID- 29111466 TI - Anxiety and Insomnia in Young and Middle-Aged Adult Hip Pain Patients With and Without Femoroacetabular Impingement and Developmental Hip Dysplasia. AB - BACKGROUND: In young and middle-aged adults with and without hip deformity, hip pain receives treatment focused primarily related to hip structure. Because this hip pain may be chronic, these patients develop other coexisting, modifiable disorders related to pain that may go undiagnosed in this young and active population, including insomnia and anxiety. OBJECTIVE: The objective of this study was to compare assessments of insomnia and anxiety in young and middle-aged adults presenting with hip pain with no greater than minimal osteoarthritis (OA) compared to asymptomatic healthy controls. Comparisons between types of hip deformity and no hip deformity in hip pain patients were performed to assess whether patients with specific hip deformities were likely to have insomnia or anxiety as a cofounding disorder to their hip pain. DESIGN: Prospective case series with control comparison. SETTING: Two tertiary university physiatry outpatient clinics. PARTICIPANTS: A total of 50 hip pain patients aged 18-40 years and 50 gender- and age-matched healthy controls. METHODS: Patients were enrolled if 2 provocative hip tests were found on physical examination and hip radiographs had no or minimal OA. Radiographic hip deformity measurements were completed by an independent examiner. Comparisons of insomnia and anxiety were completed between 50 hip pain patients and 50 controls and between patients with different types of hip deformity. MAIN OUTCOME MEASURES: Insomnia Severity Index (ISI) and Pain Anxiety Symptoms Scale (PASS). RESULTS: A total of 50 hip pain patients (11 male and 39 female) with mean age of 31.2 +/- 8.31 years enrolled. Hip pain patients slept significantly less (P = .001) per night than controls. Patients experienced significantly greater insomnia (P = .0001) and anxiety (P = .0001) compared to controls. No differences were found in insomnia and anxiety scores between hip pain patients with and without hip deformity or between different types of hip deformity. CONCLUSION: Hip pain patients with radiographs demonstrating minimal to no hip arthritis with and without hip deformity experience significant cofounding yet modifiable disorders of sleep and anxiety. If recognized early in presentation, treatment of insomnia and anxiety ultimately will improve outcomes for hip patients treated either conservatively or surgically for their hip disorder. LEVEL OF EVIDENCE: II. PMID- 29111467 TI - Reverse Shoulder Arthroplasty in Weight-Bearing Shoulders of Wheelchair-Dependent Patients: Outcomes and Complications at 2 to 5 years. AB - BACKGROUND: Wheelchair-dependent patients rely on their upper extremities for mobility and transfers. This entails the heavy use of upper extremities as weight bearing joints, leading to shoulder overuse with increased prevalence of rotator cuff-related disorders and ultimately to challenging cases for shoulder surgeons when a joint replacement is needed. OBJECTIVE: To report the outcomes of reverse shoulder arthroplasty (RSA) in wheelchair-dependent patients with arthritis and rotator cuff tears. DESIGN: Retrospective case series/cross-sectional study. SETTING: Tertiary university hospital. PATIENT (PARTICIPANTS): All wheelchair dependent patients undergoing RSA between 2004 and 2013. METHODS/INTERVENTIONS: Of the 22 wheelchair-dependent patients undergoing RSA, 18 of them had a minimum follow-up of 2 years. There were 9 men and 9 women, with a mean (standard deviation) age and length of follow-up of 68 (8.5) years and 36 (24-63) months. A retrospective chart review and cross-sectional phone calls were conducted to obtain all data. OUTCOMES: Pain, range of motion, functional scores (Neer scale, simple shoulder test, and American Shoulder and Elbow Society), satisfaction, complications/reoperations, radiographic loosening, and 90-day mortality/morbidity. RESULTS: RSA resulted in a significant improvement in pain (P = .02) and nonsignificant improvements in forward flexion (P = .3) and external rotation (P = .07). There were 3 (16%) excellent, 12 (63%) satisfactory, and 4 (21%) unsatisfactory results. The mean (standard deviation) postoperative American Shoulder and Elbow Society score was 56.5 (16.5). All patients stated that they would undergo RSA again. There were no surgically related complications or reoperations. The 90-day mortality and morbidity rates were 0% and 26%, respectively. CONCLUSIONS: RSA is a safe and effective procedure in wheelchair dependent patients who use their shoulders for weight-bearing purposes. Although functional scores are not optimal and medical complications are not uncommon, 79% of patients had an excellent or satisfactory result. LEVEL OF EVIDENCE: III. PMID- 29111469 TI - An in silico approach to determine challenges in the bioavailability of ciprofloxacin, a poorly soluble weak base with borderline solubility and permeability characteristics. AB - Ciprofloxacin is administered as the hydrochloride salt in immediate release formulations for the treatment of various infectious diseases in different patient populations. Due to its weakly basic properties and poor solubility, the in vivo behaviour of this compound could be influenced by both physicochemical and physiological factors. The first aim of this study was to investigate the behaviour of ciprofloxacin (Ciprobay(r) 500 mg tablets) in the human gastro intestinal tract with in vitro dissolution, transfer and two-stage experiments. Ciprobay(r) IR tablets dissolved completely in FaSSGF-V2, but dissolution was incomplete in FaSSIF-V2 and in an achlorhydric medium (FaSSGF-achlorhydric) and slow precipitation was observed in all three media. Ciprofloxacin did not precipitate in the transfer model but in the two-stage test, a simplified version of the transfer model, some precipitation was detected. In the second part of this study the data obtained in the in vitro transfer experiment were integrated into a Physiologically Based Pharmacokinetic (PBPK) Model. Based on the in vitro results, it was concluded that precipitation of ciprofloxacin would be unlikely in vivo. When precipitation was assumed to be negligible in the PBPK model, good predictions of plasma concentration time profiles provided by Bayer Pharma AG and obtained from the open literature were attained. Parameter Sensitivity Analysis (PSA) was conducted on several parameters which may influence the in vivo behaviour of ciprofloxacin. It was shown that precipitation in the gastro intestinal tract in humans after a dose of 500 mg is not a determinant of the PK profile. PSA further suggested that ciprofloxacin behaves in vivo as a BCS Class I drug according to the Biopharmaceutics Classification System (BCS), even though on the basis of available solubility and permeability data the compound has been categorised as a BCS II/IV drug. These findings illustrate the importance of coupling in vitro results with in silico PBPK models to better understand the in vivo behaviour of weakly basic drugs. The PBPK model of ciprofloxacin, which was set up for healthy volunteers, was also modified to predict the in vivo behaviour of ciprofloxacin in several different patient populations. It was shown on the basis of these simulations that the plasma concentration time profile may be less influenced by disease state than previously expected. PMID- 29111468 TI - The therapeutic value of protein (de)nitrosylation in experimental septic shock. AB - Cardiovascular dysfunction and organ damage are hallmarks of sepsis and septic shock. Protein S-nitrosylation by nitric oxide has been described as an important modifier of protein function. We studied whether protein nitrosylation/denitrosylation would impact positively in hemodynamic parameters of septic rats. Polymicrobial sepsis was induced by cecal ligation and puncture. Female Wistar rats were treated with increasing doses of DTNB [5,5'-dithio-bis-(2 nitrobenzoic acid)] 30min before or 4 or 12h after sepsis induction. Twenty-four hours after surgery the following data was obtained: aorta response to phenylephrine, mean arterial pressure, vascular reactivity to phenylephrine, biochemical markers of organ damage, survival and aorta protein nitrosylation profile. Sepsis substantially decreases blood pressure and the response of aorta rings and of blood pressure to phenylephrine, as well as increased plasma levels of organ damage markers, mortality of 60% and S-nitrosylation of aorta proteins increased during sepsis. Treatment with DTNB 12h after septic shock induction reversed the loss of response of aorta rings and blood pressure to vasoconstrictors, reduced organ damage and protein nitrosylation and increased survival to 80%. Increases in protein S-nitrosylation are related to cardiovascular dysfunction and multiple organ injury during sepsis. Treatment of rats with DTNB reduced the excessive protein S-nitrosylation, including that in calcium-dependent potassium channels (BKCa), reversed the cardiovascular dysfunction, improved markers of organ dysfunction and glycemic profile and substantially reduced mortality. Since all these beneficial consequences were attained even if DTNB was administered after septic shock onset, protein (de)nitrosylation may be a suitable target for sepsis treatment. PMID- 29111470 TI - Cluster-randomized controlled trials evaluating complex interventions in general practices are mostly ineffective: a systematic review. AB - OBJECTIVES: The aim of this study was to evaluate how frequently complex interventions are shown to be superior to routine care in general practice-based cluster-randomized controlled studies (c-RCTs) and to explore whether potential differences explain results that come out in favor of a complex intervention. STUDY DESIGN AND SETTING: We performed an unrestricted search in the Central Register of Controlled Trials, MEDLINE, and EMBASE. Included were all c-RCTs that included a patient-relevant primary outcome in a general practice setting with at least 1-year follow-up. We extracted effect sizes, P-values, intracluster correlation coefficients (ICCs), and 22 quality aspects. RESULTS: We identified 29 trials with 99 patient-relevant primary outcomes. After adjustment for multiple testing on a trial level, four outcomes (4%) in four studies (14%) remained statistically significant. Of the 11 studies that reported ICCs, in 8, the ICC was equal to or smaller than the assumed ICC. In 16 of the 17 studies with available sample size calculation, effect sizes were smaller than anticipated. CONCLUSION: More than 85% of the c-RCTs failed to demonstrate a beneficial effect on a predefined primary endpoint. All but one study were overly optimistic with regard to the expected treatment effect. This highlights the importance of weighing up the potential merit of new treatments and planning prospectively, when designing clinical studies in a general practice setting. PMID- 29111471 TI - Association between prospective registration and overall reporting and methodological quality of systematic reviews: a meta-epidemiological study. AB - OBJECTIVES: The aim of this study was to investigate the differences in main characteristics, reporting and methodological quality between prospectively registered and nonregistered systematic reviews. STUDY DESIGN AND SETTING: PubMed was searched to identify systematic reviews of randomized controlled trials published in 2015 in English. After title and abstract screening, potentially relevant reviews were divided into three groups: registered non-Cochrane reviews, Cochrane reviews, and nonregistered reviews. For each group, random number tables were generated in Microsoft Excel, and the first 50 eligible studies from each group were randomly selected. Data of interest from systematic reviews were extracted. Regression analyses were conducted to explore the association between total Revised Assessment of Multiple Systematic Review (R-AMSTAR) or Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) scores and the selected characteristics of systematic reviews. RESULTS: The conducting and reporting of literature search in registered reviews were superior to nonregistered reviews. Differences in 9 of the 11 R-AMSTAR items were statistically significant between registered and nonregistered reviews. The total R-AMSTAR score of registered reviews was higher than nonregistered reviews [mean difference (MD) = 4.82, 95% confidence interval (CI): 3.70, 5.94]. Sensitivity analysis by excluding the registration-related item presented similar result (MD = 4.34, 95% CI: 3.28, 5.40). Total PRISMA scores of registered reviews were significantly higher than nonregistered reviews (all reviews: MD = 1.47, 95% CI: 0.64-2.30; non-Cochrane reviews: MD = 1.49, 95% CI: 0.56-2.42). However, the difference in the total PRISMA score was no longer statistically significant after excluding the item related to registration (item 5). Regression analyses showed similar results. CONCLUSION: Prospective registration may at least indirectly improve the overall methodological quality of systematic reviews, although its impact on the overall reporting quality was not significant. PMID- 29111472 TI - Assessment of 8-hydroxy-2-deoxyguanosine activity, gene expression and antioxidant enzyme activity on rainbow trout (Oncorhynchus mykiss) tissues exposed to biopesticide. AB - The goal of this study was to determinate toxicity mechanism of biopesticide with antioxidant enzymes parameters such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) and malondialdehyde (MDA) levels, oxidative DNA damage (8-hydroxy-2-deoxyguanosine (8-OHdG)), transcriptional changes of heat shock protein 70 (HSP70), and cytochromes P4501A (CYP1A), sod, cat, and gpx in liver and gill tissues of Oncorhynchus mykiss. For this aim, plant-based (natural pesticides, azadirachtin (AZA)) and synthetic pesticides (deltamethrin (DLM)) were exposed on the fish at different concentrations (0.0005 and 0.00025ppm of DLM; 0.24 and 0.12ppm of AZA) for 21 days. According to the results of the study, the activity of SOD, CAT and GPx decreased, but malondialdehyde (MDA) level and activity of 8-OHdG increased in the gill and liver of rainbow trout (p<0.05). Additionally sod, cat and gpx were down regulated; HSP70 and CYP1A were up regulated for transcriptional observation. The downwards regulation of antioxidant (sod, cat and gpx) and the upregulation of HSP70 and CYP1A was obvious with doses of AZA or DLM (p<0.05). The findings of this study suggest that biopesticide can cause biochemical and physiological effects in the fish gill and liver by causing enzyme inhibition, an increase in 8-OHdG levels and changes in both transcriptional parameters (sod, cat, gpx, HSP70 and CYP1A). We found that excessive doses of plant-based pesticide are nearly as toxic as chemical ones for aquatic organisms. Moreover, 8-OHdG, HSP70 and CYP1A used as a biomarker to determinate toxicity mechanism of biopesticide in aquatic environment. PMID- 29111473 TI - Posterior Communicating Artery Giving Rise to Shared-Origin Anterior Choroidal Artery: Case Illustration. AB - BACKGROUND: The origin point of the anterior choroidal artery (AChA) is variable, typically arising from the supraclinoid internal carotid artery (ICA) distal to the posterior communicating artery (PComA) on either the posterolateral or posterior aspect of the ICA. Variations of AChA origin have important clinical implications, and rare origins reported previously include the ICA bifurcation and middle cerebral artery. We provide illustrations of a case of a shared-origin PComA and AChA. CASE DESCRIPTION: A young girl presented with intracranial hemorrhage and underwent angiography to evaluate for an underlying cause. Ultimately, 3-dimensional rotational angiography incidentally demonstrated a common origin of the AChA with the PComA. CONCLUSIONS: A rare case of a shared origin AChA and PComA is reported for angiographic illustration. The radiologic findings, embryology behind the development of the AChA, and neurosurgical and neurovascular relevance of this variant are discussed. The importance of recognizing the origin of the AChA is emphasized. PMID- 29111474 TI - The Middle Temporal Artery: Surgical Anatomy and Exposure for Cerebral Revascularization. AB - BACKGROUND: The middle temporal artery (MTA) is the proximal medial branch of the superficial temporal artery (STA), supplying the temporalis muscle along with deep temporal arteries. Its use in vascularized flaps for reconstructive and otologic procedures has been described, yet its potential use in neurosurgery has not been studied. We report a novel technique for exposing the MTA and evaluated its characteristics for extracranial-intracranial cerebrovascular bypass. METHODS: After a curvilinear frontotemporal incision in 10 cadaveric specimens, the STA was dissected from distal to proximal. The horizontal portion of MTA was found posterolateral to the posterior end of the zygomatic root and was followed proximally until its origin and distally until its 2 terminal branches. The total length, visible branches, and caliber of MTA were measured. RESULTS: The mean total harvested length of MTA was 31.7 +/- 5.1 mm, with an average proximal caliber of 1.7 +/- 0.4 mm, and distal caliber of 1.3 +/- 0.5 mm. There were 4-6 terminal MTA branches. The caliber of the proximal STA trunk was 2.5 +/- 0.5 mm. The origin of the MTA was visible with a mean distance of 16.9 +/- 4.8 mm inferior to the PEZR. The parotid gland was traversed and a communicating auriculotemporal nerve to the temporal branch of the facial nerve crossed MTA in 2 specimens. CONCLUSIONS: MTA can be safely harvested with an anterolateral approach, following its horizontal portion at the level of the zygomatic root, which is constant. The length and caliber of MTA makes it a potential alternative donor vessel or interposition graft for extracranial-intracranial bypass, especially when other donors are unavailable. PMID- 29111475 TI - A total-evidence phylogeny of the lady fern genus Athyrium Roth (Athyriaceae) with a new infrageneric classification. AB - The lady fern genus Athyrium represents one of the most diversified lineages in Athyriaceae with about 160-220 known species, and is notorious for its taxonomic difficulty. Despite progress in recent phylogenetic studies involving this genus, it still lacks a modern systematic and taxonomic update using integrative analyses of molecular and morphological evidence based on a broad species sampling. Here, we present, to our knowledge, the most comprehensive phylogenetic analysis of the genus to date based on a total-evidence approach, covering all formerly accepted segregates within the athyrioid ferns. We sampled up to eight plastid markers and 20 morphological characters for each species. Our analyses, including maximum parsimony, maximum likelihood and Bayesian inference, yield a robust phylogenetic framework. We find that Athyrium is not monophyletic by recovering Athyrium skinneri and A. alpestre nested with Anisocampium and Cornopteris respectively while Pseudocystopteris is included in Athyrium. Furthermore, eight well-resolved clades and two isolated species within Athyrium are found in the phylogenetic topology, which can be also characterized by morphological synapomorphies from traits of petioles, leaves, sori and spores. In the interest of recognizing monophyletic taxa with morphological synapomorphies, we agree with the inclusion of Pseudocystopteris in Athyrium as proposed in previous studies, but treat Anisocampium and Cornopteris as separate genera. We further propose to resurrect a monotypic Pseudathyrium to accommodate A. alpestre. Based on morphological characters and molecular phylogeny, a new infrageneric classification system of Athyrium is proposed which subdivided it into ten sections, and one New-World species A. skinneri is transferred into Anisocampium. PMID- 29111476 TI - Phylogenomics and evolution of floral traits in the Neotropical tribe Malmeeae (Annonaceae). AB - Androdioecy is the rarest sexual system among plants. The majority of androdioecious species are herbaceous plants that have evolved from dioecious ancestors. Nevertheless, some woody and androdioecious plants have hermaphrodite ancestors, as in the Annonaceae, where androdioecious genera have arisen several times in different lineages. The majority of androdioecious species of Annonaceae belong to the Neotropical tribe Malmeeae. In addition to these species, Pseudoxandra spiritus-sancti was recently confirmed to be androdioecious. Here, we describe the morphology of male and bisexual flowers of Pseudoxandra spiritus sancti, and investigate the evolution of androdioecy in Malmeeae. The phylogeny of tribe Malmeeae was reconstructed using Bayesian inference, maximum parsimony and maximum likelihood of 32 taxa, using DNA sequences of 66 molecular markers of the chloroplast genome, sequenced by next generation sequencing. The reconstruction of ancestral states was performed for characters associated with sexual systems and floral morphology. The phylogenetic analyses reconstructed three main groups in Malmeeae, (Malmea (Cremastosperma, Pseudoxandra)) sister to the rest of the tribe, and (Unonopsis (Bocageopsis, Onychopetalum)) sister to (Mosannona, Ephedranthus, Klarobelia, Oxandra, Pseudephedranthus fragrans, Pseudomalmea, Ruizodendron ovale). Hermaphroditism is plesiomorphic in the tribe, with four independent evolutions of androdieocy, which represents a synapomorphy of two groups, one that includes three genera and 14 species, the other with a single genus of seven species. Male flowers are unisexual from inception and bisexual flowers possess staminodes and functional stamens. Pseudoxandra spiritus sancti is structurally androdioecious. PMID- 29111477 TI - Evaluating methods for phylogenomic analyses, and a new phylogeny for a major frog clade (Hyloidea) based on 2214 loci. AB - Phylogenomic approaches offer a wealth of data, but a bewildering diversity of methodological choices. These choices can strongly affect the resulting topologies. Here, we explore two controversial approaches (binning genes into "supergenes" and inclusion of only rapidly evolving sites), using new data from hyloid frogs. Hyloid frogs encompass ~53% of frog species, including true toads (Bufonidae), glassfrogs (Centrolenidae), poison frogs (Dendrobatidae), and treefrogs (Hylidae). Many hyloid families are well-established, but relationships among these families have remained difficult to resolve. We generated a dataset of ultraconserved elements (UCEs) for 50 ingroup species, including 18 of 19 hyloid families and up to 2214 loci spanning >800,000 aligned base pairs. We evaluated these two general approaches (binning, rapid sites only) based primarily on their ability to recover and strongly support well-established clades. Data were analyzed using concatenated likelihood and coalescent species tree methods (NJst, ASTRAL). Binning strongly affected inferred relationships, whereas use of only rapidly evolving sites did not (indicating ~87% of the data contributed little information). The optimal approaches for maximizing recovery and support of well-established clades were concatenated likelihood analysis and the use of a limited number of naive bins (statistical binning gave more problematic results). These two optimal approaches converged on similar relationships among hyloid families, and resolved them with generally strong support. The relationships found were very different from most previous estimates of hyloid phylogeny, and a new classification is proposed. The new phylogeny also suggests an intriguing biogeographical scenario, in which hyloids originated in southern South America before radiating throughout the world. PMID- 29111479 TI - High-level of resistance to beta-lactam and presence of beta-lactamases encoding genes in Ochrobactrum sp. and Achromobacter sp. isolated from soil. AB - OBJECTIVES: Bacteria belonging to the genera Ochrobactrum and Achromobacter are bacteria considered opportunistic, causing infections mainly in immunocompromised patients. beta-lactamases are the main cause of resistance to beta-lactam antibiotics. This study aimed to investigate the antimicrobial resistance profile and the presence of beta-lactamases encoding genes in Ochrobactrum sp. and Achromobacter sp. isolated from Brazilian soils. METHODS: Soil samples from the five regions of Brazil were collected for the isolation of bacteria, which were identified molecularly and then, the minimum inhibitory concentration and detection of beta-lactamases encoding genes were performed. RESULTS: High-level of resistance to beta-lactam antibiotics and different beta-lactamases encoding genes were found (blaCTX-M-Gp1, blaSHV, blaOXA-1-like and blaKPC), including the first report of the presence of blaKPC in bacteria belonging to the genera Ochrobactrum and Achromobacter. CONCLUSION: The results showed that the bacteria from this study, belonging to genera Ochrobactrum and Achromobacter isolated from soil, harbor different beta-lactamases encoding genes and can act as a reservoir of these genes. PMID- 29111478 TI - Verbal working memory and functional large-scale networks in schizophrenia. AB - The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia. PMID- 29111480 TI - Draft genome sequences of two fluoroquinolone-resistant CTX-M-15-producing Escherichia coli ST90 (ST23 complex) isolated from a calf and a dairy cow in South America. AB - OBJECTIVES: Farm animals have been recognised as important carriers and reservoirs of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. The aim of this study was to report the draft genome sequences of two multidrug resistant (MDR) CTX-M-15-producing E. coli strains (47VL and 13B) isolated from different bovine hosts (a calf and a dairy cow), housed separately in a commercial dairy farm in Brazil. METHODS: Total genomic DNA of the E. coli isolates was sequenced using an Illumina MiSeq paired-end 300-bp sequencing platform. Sequence reads were de novo assembled using the A5-miseq pipeline and polishing assembly in Geneious v.R9. The NCBI Prokaryotic Genome Annotation Pipeline v.3.2 was used for genome annotation, whereas whole-genome sequences were analysed using bioinformatic tools from the Center of Genomic Epidemiology and EnteroBase. RESULTS: E. coli 47VL generated a total of 3238770 and E. coli 13B a total of 1422808 paired-end reads of ca. 190* and ca. 80*, respectively. The resistome revealed that both isolates carried resistance genes to aminoglycosides, beta-lactams, macrolides, sulphonamides, trimethoprim and tetracycline. Comparative analyses revealed clonal relatedness. In fact, both isolates belonged to sequence type ST90 (clonal complex CC23) and phylogroup AxB1. CONCLUSION: To our knowledge, these are the first draft genome sequences of CTX-M-15-producing E. coli ST90 isolated from bovines in South America. These data can be used to elucidate genetic features that contribute to colonisation and adaptation of CTX-M-15-producing E. coli in dairy cattle. PMID- 29111482 TI - Detection of the colistin resistance gene mcr-1 in avian pathogenic Escherichia coli in Pakistan. PMID- 29111481 TI - Draft genome sequence of broad-spectrum antibiotic sparsomycin-producing Streptomyces sparsogenes ATCC 25498 from the American Type Culture Collection. AB - OBJECTIVES: Sparsomycin, which exhibits rare broad-spectrum antibiotic and antitumour activity against bacteria, Archaea, Eucarya and various cancer cell lines, has been widely used as a powerful tool to study protein synthesis. Here we report the draft genome sequence of Streptomyces sparsogenes ATCC 25498 from the American Type Culture Collection (ATCC), which has become an organism of interest owing to its ability to produce sparsomycin. METHODS: The whole-genome sequence of S. sparsogenes ATCC 25498 was determined using a high-throughput Illumina HiSeq 2000 platform and genome assembly was performed using the SOAPdenovo method. RESULTS: Whole-genome sequencing analysis revealed a genome size of 10.0Mb. A total of 41 secondary metabolite biosynthetic gene clusters were identified. The gene cluster for the biosynthesis of sparsomycin was localised on scaffold 9. CONCLUSIONS: The genome sequence of S. sparsogenes ATCC 25498 will not only aid in understanding the regulatory mechanism of sparsomycin biosynthesis but will also reveal the ability of the isolate to produce novel bioactive secondary metabolites. PMID- 29111483 TI - Involvement of topoisomerase mutations and qnr and aac(6')Ib-cr genes in conferring quinolone resistance to clinical isolates of Vibrio and Shigella spp. from Kolkata, India (1998-2009). AB - OBJECTIVES: Quinolone antibiotics have been widely used to treat diarrhoeal diseases caused by bacterial agents such as those belonging to the genera Vibrio and Shigella. As these pathogens are accumulating quinolone resistance, treating infections caused by them has become complicated. METHODS: In this study, Vibrio and Shigella spp. isolates obtained from diarrhoeal patients from Kolkata, India, over a period of 12 years (1998-2009) were analysed for quinolone resistance. A total of 27 Vibrio spp. (9 Vibrio cholerae, 11 Vibrio fluvialis and 7 Vibrio parahaemolyticus) and 10 Shigella spp. isolates (7 Shigella flexneri, 2 Shigella dysenteriae and 1 Shigella sonnei) showing reduced susceptibility to quinolones were studied to unravel the genetic factors responsible for quinolone resistance. RESULTS: Antimicrobial susceptibility testing showed a wide spectrum and varying degree of resistance to different generations of quinolones. Genotypic characterisation revealed the involvement of GyrA(S83I) and ParC(S85L) mutations in V. cholerae and V. fluvialis, whereas Shigella spp. isolates showed the mutations S83L and/or D87N/Y in GyrA and S80I or E84K in ParC. Analysis of plasmid-mediated quinolone resistance genes showed that qnrVC5 was detected in three V. fluvialis isolates, aac(6')-Ib-cr in one V. fluvialis isolate and qnrS1 in a S. flexneri isolate. CONCLUSIONS: These results emphasise that quinolone resistance is widespread and therefore quinolones should be used prudently. To the best of our knowledge, this is the first study where resistance to various generations of quinolones in Vibrio and Shigella spp. has been examined in terms of detailed genotype-phenotype correlation. PMID- 29111484 TI - Self-calibrated fluorescent probe resembled as an indicator of the lysosomal phosphatase pertaining to the cancer cells. AB - A self-calibrated fluorescent probe Lyso-Phos has synthesized followed by a straightforward synthetic pathway. Lyso-Phos acts as an indicator for lysosomal phosphatase. Its photophysical property including cellular imaging was described. Lyso-Phos showed ratiometric UV-Vis- absorption changes from lambdaabs 370nm to lambdaabs 450nm in the presence of alkaline phosphatase (ALP). On the other hand, fluorescence intensity lambdaem 560nm of Lyso-Phos has increased around 45-fold in the presence of ALP. The probe Lyso-Phos was found to be highly chemoselective toward the phosphatase compared with other ubiquitous entities in cellular milieu. The non-toxic nature of the Lyso-phos has accounted by observing higher cell viability in prostate cancer- LnCap, fibrosarcoma HT1080 and normal mouse embryo fibroblast NIH3T3 cells. Further, the probe Lyso-Phos was utilized for tracking of cellular phosphatase in live-cells. Lyso-Phos enabled to track cellular phosphatase by the extent of fluorescence labeling of LnCap cells which showed reasonable uptake efficiency in the presence of Lyso-Phos as indicated by the intracellular fluorescence. The phosphoester bond in the probe was cleaved by intracellular alkaline phosphatase leading to turn on fluorescence of the fluorescent probe Lyso-Phos. Finally, cellular colocalization with Lyso-Tracker empowered our speculation that Lyso-Phos can track endogenous phosphatase in the lysosomes. Altogether these findings suggest that Lyso-Phos would be powerful probe to detect phosphates in cancer cells. PMID- 29111485 TI - Magnetic and photocatalytic studies on Zn1-xMgxFe2O4 nanocolloids synthesized by solvothermal reflux method. AB - Biocompatible magnetic semiconductor Zn1-xMgxFe2O4 (x=0, 0.1, 0.3, 0.5 & 0.7) nanoparticles of around 10nm diameter were synthesized by solvothermal reflux method. The method produces well separated and narrow size distributed nanoparticles. Crystal structure, morphology, particles surface properties, surfactant quantity, colloidal stability, magnetic properties and photocatalytic properties of the synthesized nanoparticles were studied. Different characterizations confirmed that all compounds were single crystals and superparamagnetic at room temperature. Saturation mass magnetization (Ms=57.5emu/g) enhances with substituent Mg2+ concentration due to promotion of mixed spinel (normal and inverse) structure. Photocatalytic activity of all synthesized magnetic semiconductor nanoparticles were studied through methylene blue degradation. The degradation of 98% methylene blue was observed on 60 min irradiation of light. It is observed that photocatalytic activity slightly enhances with substituent Mg2+ concentration. The synthesized biocompatible magnetic semiconductor nanoparticles can be utilized as photocatalysts and could also be recycled and separated by applying an external magnetic field. PMID- 29111486 TI - Gray matter network measures are associated with cognitive decline in mild cognitive impairment. AB - Gray matter networks are disrupted in Alzheimer's disease and related to cognitive impairment. However, it is still unclear whether these disruptions are associated with cognitive decline over time. Here, we studied this question in a large sample of patients with mild cognitive impairment with extensive longitudinal neuropsychological assessments. Gray matter networks were extracted from baseline structural magnetic resonance imaging, and we tested associations of network measures and cognitive decline in Mini-Mental State Examination and 5 cognitive domains (i.e., memory, attention, executive function, visuospatial, and language). Disrupted network properties were cross-sectionally related to worse cognitive impairment. Longitudinally, lower small-world coefficient values were associated with a steeper decline in almost all domains. Lower betweenness centrality values correlated with a faster decline in Mini-Mental State Examination and memory, and at a regional level, these associations were specific for the precuneus, medial frontal, and temporal cortex. Furthermore, network measures showed additive value over established biomarkers in predicting cognitive decline. Our results suggest that gray matter network measures might have use in identifying patients who will show fast disease progression. PMID- 29111488 TI - Small bacterial and phagic proteins: an updated view on a rapidly moving field. AB - Small proteins, that is, polypeptides of 50 amino acids (aa) or less, are increasingly recognized as important regulators in bacteria. Secreted or not, their small size make them versatile proteins, involved in a wide range of processes. They may allow bacteria to sense and to respond to stresses, to send signals and communicate, and to modulate infections. Bacteriophages also produce small proteins to influence lysogeny/lysis decisions. In this review, we update the present view on small proteins functions, and discuss their possible applications. PMID- 29111487 TI - Cortical beta-amyloid burden, gray matter, and memory in adults at varying APOE epsilon4 risk for Alzheimer's disease. AB - Models of preclinical Alzheimer's disease (AD) propose that cerebral amyloidosis leads to neurodegeneration and subsequent cognitive decline. This study investigated whether APOE genotype is related to beta-amyloid (Abeta) burden in brain regions preferentially affected by AD and whether Abeta burden is associated with gray-matter (GM) fraction (as a marker of neurodegeneration) and episodic memory performance in cognitively normal middle-aged individuals at varying genetic risk for AD. Three groups of cognitively normal participants aged 50-65 years with a first-degree family history of AD (APOE genotype epsilon4epsilon4 [n = 15], epsilon3epsilon4 [n = 15], and epsilon3epsilon3 [n = 15]) underwent [11C]PiB positron emission tomography scans to quantify cortical Abeta, brain magnetic resonance imaging, and neuropsychological testing. APOE epsilon4epsilon4 participants demonstrated significantly higher cortical Abeta burden than APOE epsilon3epsilon3 (p < 0.001). Furthermore, cortical Abeta burden was inversely associated with cortical GM fraction (p = 0.017) but not episodic memory performance. In cognitively normal, middle-aged individuals, Abeta burden is significantly associated with GM fraction but not episodic memory performance. These findings are consistent with models of preclinical AD in which neurodegeneration occurs before manifest cognitive decline. PMID- 29111489 TI - Absorption, liver first-pass effect, pharmacokinetics and tissue distribution of calycosin-7-O-beta-d-glucopyranoside (C7G) and its major active metabolite, calycosin, following oral administration of C7G in rats by LC-MS/MS. AB - Previously, we discovered calycosin, an extensively distributed metabolite of Calycosin-7-O-beta-d-glucopyranoside (C7G), elicited stronger anti-virus activity than C7G. However, the pharmacokinetics and tissue distribution of C7G and calycosin remained obscure on C7G treatments. In this study, a liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous determination of C7G and calycosin, and it was applied to the pharmacokinetics and tissue distribution of C7G and calycosin following oral administration of C7G at 120mg/kg in rats. Consequently, the exposure of C7G and calycosin was both similarly low in the systemic plasma, but the levels of calycosin were 53.5 folds higher than that of C7G in the portal vein plasma, corresponding to the liver extraction ratio (ER) of C7G and calycosin at 0.3% and 98.5% respectively. Therefore, our results revealed that liver first-pass effect played the predominant role in the poor circulating levels of calycosin on C7G treatments, whereas the intestinal first-pass effect was predominant for those of C7G. In contrast to no observation of C7G, the calycosin levels were 212.1, 30.5 and 4.7 folds higher in the liver, kidney and heart than its circulating levels, respectively. The high tissue distribution of calycosin provided new hints and evidences to the pharmacological mechanisms of C7G and Astragali Radix. PMID- 29111490 TI - Screening and identification of neuroprotective compounds from Scrophularia buergeriana using cell extraction coupled with LC-MS. AB - In the cell extraction_LC-MS method, when cells are incubated with natural product extracts, bioactive compounds selectively bind to extracellular or intracellular targets. The extracts and major compounds (phenylpropanoids and iridoid glycosides) of Scrophularia buergeriana Miquel have been reported to show neuroprotective effects both in vitro and in vivo. In this study, the cell extraction_LC-MS strategy was applied to screen and identify potential neuroprotective compounds from S. buergeriana by using immortalized mouse hippocampal HT22 cells. The results showed that two known compounds from S. buergeriana selectively bound HT22 cells. Additionally, metabolomics analyses were performed using the Mass Profiler Professional and Limma differential expression package of R to identify significant differences between HT22 cells treated with S. buergeriana and untreated cells. The cell extraction approach more accurately reflects in vivo conditions compared with other methods and can be readily used for screening bioactive components from natural products. PMID- 29111491 TI - UHPLC method for multiproduct pharmaceutical analysis by Quality-by-Design. AB - An innovative Analytical Quality-by-Design (AQbD) methodology was followed to develop a specific and robust UHPLC method for the simultaneous separation of 16 active pharmaceutical ingredients (APIs). In the context of pharmaceutical repositioning, these molecules have been selected as good candidates for buccal per mucous (BPM(r)) administration route. Given the structural and physico chemical diversity of compounds, an innovative development strategy based on QbD was applied. The main advantage of QbD is to ensure the robustness of the method. During a first scouting phase, the C18 chromatographic column was selected. Throughout the study, acetonitrile and ethanol based-mobile phases were investigated and compared. Ethanol was chosen as an alternative to acetonitrile due to its green properties coming from its lower toxicity and sourcing from renewable sources. Screening designs were performed to identify critical process parameters (CPPs). In ethanol media, temperature turned out to be a critical factor on peak retention and separation. Response surface methodology was then carried out to optimize CPPs and define the experimental domain of the method where complete separation between all peaks was obtained. Because changes in the elution order of the compounds occurred when modifying the experimental conditions, time differences between peaks were chosen as critical quality attributes, and an original data treatment was developed. It consisted in a systematic modelling of the time intervals between all possible pairs of peaks over the whole 3D experimental domain. Finally, a desirability analysis based on the smallest predicted time interval between peaks enabled to find optimal conditions only with ethanol based-mobile phases. Optimal conditions using ethanol, a Xbridge BEH Shield RP18 column and a 500 mL starting isocratic step, were determined by maximizing the desirability value and corresponded to a gradient slope of 2.57 %/min, a pH of 4.85, and a temperature of 33.7 degrees C. A baseline separation of the 16 APIs was achieved with resolutions superior to 2.4 and the robustness of the method was experimentally validated. PMID- 29111492 TI - Liquid chromatography-electrospray ionization-tandem mass spectrometry method for quantitative estimation of new imiqualine leads with potent anticancer activities in rat and mouse plasma. Application to a pharmacokinetic study in mice. AB - Imidazoquinoxaline derivatives (imiqualines) are a new series of anticancer compounds. Two lead compounds (EAPB0203 and EAPB0503) with remarkable in vitro and in vivo activity on melanoma and T-cell lymphomas have been previously identified. The modulation of the chemical structure of the most active compound, EAPB0503, has led to the synthesis of two compounds, EAPB02302 and EAPB02303, 7 and 40 times more active than EAPB0503 against A375 human melanoma cancer cell line, respectively. The aim of this study was to develop and validate a sensitive and accurate liquid chromatography-electrospray ionization-tandem mass spectrometry method to simultaneously quantify EAPB02303 and its potential active metabolite, EAPB02302, in rat and mouse plasma. Analytes were detected in multiple reaction monitoring acquisition mode using an electrospray ionization detector in positive ion mode. Following a liquid-liquid extraction with ethyl acetate, analytes and internal standard were separated by HPLC reversed-phase on a C18 RP18 Nucleoshell column (2.7MUm, 4.6*100mm). The method was validated according to FDA and EMA Bioanalytical Method Validation guidelines. The robustness of the method was assessed by introducing small variations in nine nominal analytical parameters. Statistical interpretation was performed by mean of the Student's t-test. Standard curves were generated via unweighted quadratic regression of calibrators (EAPB02303: 1.95-1000ng/mL, EAPB02302: 7.81-1000ng/mL in rat plasma; EAPB02303: 0.98-1000ng/mL, EAPB02302: 1.95-1000ng/mL in mouse plasma). From the analysis of QC samples, intra- and inter-assay precision and accuracy studies demonstrated %R.S.Ds. <12.5% and percent deviation from nominal concentration <7%. Matrix effects (mean matrix factors from 91.8-108.5% in rat plasma; and from 90.4-102.4% in mouse plasma) and stability assays (recoveries >87%) were acceptable and in accordance with the guidelines. No quantifiable carryover effect was observed. The LLOQs were 1.95ng/mL for EAPB02303 and 7.81ng/mL for EAPB02302 in rat plasma, and 0.98ng/mL and 1.95ng/mL for the two compounds in mouse plasma, respectively. This method was successfully implemented to support a mouse pharmacokinetic study following a single intraperitoneal administration of EAPB02303 in male C57Bl/6 mice. The obtained pharmacokinetic parameters of EAPB02303 would be useful to optimize the dosing and the rhythm of administration for subsequent preclinical in vivo activity studies. PMID- 29111493 TI - Lateral Cutaneous Nerve Entrapment Syndrome (LACNES): A previously unrecognized cause of intractable flank pain. AB - BACKGROUND AND AIMS: Chronic abdominal pain may occasionally be due to terminal endings of intercostal nerves (ACNES, abdominal cutaneous nerve entrapment syndrome) that are entrapped in the abdominal wall. Spontaneous neuropathic flank pain may also be caused by involvement of branches of these intercostal nerves. Aim is to describe a series of patients with flank pain due to nerve entrapment and to increase awareness for an unknown condition coined Lateral Cutaneous Nerve Entrapment Syndrome (LACNES). METHODS: Patients possibly having LACNES (constant area of flank tenderness, small point of maximal pain with neuropathic characteristics, locoregional altered skin sensation) presenting between January 2007 and May 2016 received a diagnostic 5-10mL 1% lidocaine injection. Pain levels were recorded using a numerical rating scale (0, no pain to 10, worst possible). A >50% pain reduction was defined as success. Long term effect of injections and alternative therapies were determined using a satisfaction scale (1, very satisfied, no pain - 5, pain worse). RESULTS: 30 patients (21 women, median age 52, range 13-78) were diagnosed with LACNES. Pain following one injection dropped from 6.9+/-1.4 to 2.4+/-1.9 (mean, p<0.001) leading to an 83% immediate success rate. Repeated injection therapy was successful in 16 (pain free n=7, pain acceptable, n=9; median 42 months follow-up). The remaining 14 patients received (minimally invasive) surgery (n=5) or other treatments (medication, manual therapy or pulsed radiofrequency, n=9). Overall treatment satisfaction (scale 1 or 2) was attained in 79%. CONCLUSIONS AND IMPLICATIONS: LACNES should be considered in patients with chronic flank pain. Injection therapy is long term effective in more than half of the population. PMID- 29111495 TI - Dual modal ultra-bright nanodots with aggregation-induced emission and gadolinium chelation for vascular integrity and leakage detection. AB - The study of blood brain barrier (BBB) functions is important for neurological disorder research. However, the lack of suitable tools and methods has hampered the progress of this field. Herein, we present a hybrid nanodot strategy, termed AIE-Gd dots, comprising of a fluorogen with aggregation-induced emission (AIE) characteristics as the core to provide bright and stable fluorescence for optical imaging, and gadolinium (Gd) for accurate quantification of vascular leakage via inductively-coupled plasma mass spectrometry (ICP-MS). In this report, we demonstrate that AIE-Gd dots enable direct visualization of brain vascular networks under resting condition, and that they form localized punctate aggregates and accumulate in the brain tissue during experimental cerebral malaria, indicative of hemorrhage and BBB malfunction. With its superior detection sensitivity and multimodality, we hereby propose that AIE-Gd dots can serve as a better alternative to Evans blue for visualization and quantification of changes in brain barrier functions. PMID- 29111496 TI - Direct experience while eating: Laboratory outcomes among individuals with eating disorders versus healthy controls. AB - OBJECTIVE: To compare individuals with eating disorders (EDs) to healthy controls (HCs) to assess for differences in direct engagement in the eating process. METHOD: Participants (n=58) were asked to eat an orange slice. To assess the degree of direct engagement with the eating process, participants were asked to write down 10 thoughts about the experience of eating the orange slice. Next, the participants were instructed to classify the main focus of each thought as either experiential ("direct experience") or analytical ("thinking about"). A direct experience index (DEI) was computed by dividing the number of times that participants classified an experience as a "direct experience" (the numerator) by the total number of all observations (i.e., direct experience+thinking about). Participants also completed the Five Facet Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ) to assess mindfulness facets and decentering, respectively. RESULTS: Compared to controls, participants in the EDs group presented significantly lower levels of direct experience during the eating task (EDs group: mean=43.54, SD=29.64; HCs group: mean=66.17, SD=22.23, p=0.03). Participants in the EDs group also scored significantly lower on other mindfulness-related variables. DISCUSSION: These findings suggest that engagement with the direct experience of eating is lower in individuals with EDs. Future research should investigate the role of mindfulness-based interventions to address direct experience while eating in individuals with EDs. PMID- 29111494 TI - Macrophages as a potential tumor-microenvironment target for noninvasive imaging of early response to anticancer therapy. AB - As a result of therapy-induced apoptosis, peripheral blood monocytes are recruited to tumors, where they become tumor-associated macrophages (TAMs). To date, few studies have investigated noninvasive molecular imaging for assessment of macrophage infiltration in response to therapy-induced apoptosis. Here, noninvasive assessment of changes in tumor accumulation of TAMs was proposed as a new way to measure early tumor response to anticancer therapy. Three different nanoparticles, QD710-Dendron quantum dots (QD710-D), Ferumoxytol, and PG-Gd NIR813, were used for near-infrared fluorescence imaging, T2-weighted magnetic resonance imaging, and dual optical/T1-weighted MR imaging, respectively, in the MDA-MB-435 tumor model. Treatment with Abraxane induced tumor apoptosis and infiltrating macrophages. In spite of markedly different physicochemical properties among the nanoparticles, in vivo imaging revealed increased uptake of all three nanoparticles in Abraxane-treated tumors compared with untreated tumors. Moreover, imaging visualized increased uptake of QD710-D in MDA-MB-435 tumors but not in drug-resistant MDA-MB-435R tumors grown in the mice treated with Abraxane. Our results suggest that infiltration of macrophages due to chemotherapy-induced apoptosis was partially responsible for increased nanoparticle uptake in treated tumors. Noninvasive imaging techniques in conjunction with systemic administration of imageable nanoparticles that are taken up by macrophages are a potentially useful tool for assessing early treatment response. PMID- 29111499 TI - Illness-related absence among preschool children: Insights from a health intervention in Swedish preschools. AB - We evaluate the effect of a preschool health intervention aimed at reducing infections through improved hygiene practices and training of the staff. The large-scale design enables us to study heterogeneous effects with respect to several child and preschool characteristics that are related to the level of illness-related absence. We find no reduction, on average, in children's illness related absence. This conclusion holds across different age groups of preschool children, and for preschools with varying levels of absence before the intervention. We find some suggestive evidence that the intervention may have induced effects operating in different directions: while improved hygiene practices may have reduced illness, stricter guidelines regarding absence during infections seems to have contributed to an increased absence level, resulting in an overall zero effect. Overall, our results suggest that reducing absence through improved hygiene practices is not easily accomplished in a child care setting. PMID- 29111497 TI - Effects of growth hormone on uncoupling protein 1 in white adipose tissues in obese mice. AB - OBJECTIVE: The transition of white adipocytes to beige cells (a phenomenon referred to as browning or beigeing) during obesity has been previously reported. Our study aimed to examine the mechanisms through which obesity induced by a high fat diet (HFD) affects uncoupling protein 1 (UCP1) expression via signal transduction and activator of transcription 5 (STAT5s). DESIGN: Seven-week-old male C57BL/6J mice were fed a normal or HFD for 11weeks. Body weight, white adipose tissue weight, and blood lipid and glucose levels were measured. To unveil the molecular mechanisms of UCP1 expression in adipose tissue, we performed further studying 3T3-L1 cells using qRT-PCR. We also measured UCP1 promoter activity in the TSA201 cell line using a dual luciferase assay. In addition, we analyzed the predicted consensus sequences for STAT5 binding in the UCP1 promoter region. RESULTS: Mice fed an HFD had higher body weight and intra abdominal adipose tissues weight and a higher expression of UCP1, GH receptor (GHR), STATs, suppressors of cytokine signaling (SOCSs), and cytokine-inducible SH2-containing protein (CISH) compared to control mice. In 3T3-L1 cell studies, GH induced phosphorylation of the STAT5, SOCSs, CISH and UCP1 expressions. UCP1 promoter activity was associated with constitutively active STAT5 in a dose dependent manner. We confirmed functional STAT5 binding sites at -425, -279, and 178bp of the UCP1 promoter. CONCLUSION: We suggest that endogenous GH induces UCP1 expression in adipose tissue via STAT5. PMID- 29111498 TI - Transcriptomic response of Debaryomyces hansenii during mixed culture in a liquid model cheese medium with Yarrowia lipolytica. AB - Yeasts play a crucial role in cheese ripening. They contribute to the curd deacidification, the establishment of acid-sensitive bacterial communities, and flavour compounds production via proteolysis and catabolism of amino acids (AA). Negative yeast-yeast interaction was observed between the yeast Yarrowia lipolytica 1E07 (YL1E07) and the yeast Debaryomyces hansenii 1L25 (DH1L25) in a model cheese but need elucidation. YL1E07 and DH1L25 were cultivated in mono and co-cultures in a liquid synthetic medium (SM) mimicking the cheese environment and the growth inhibition of DH1L25 in the presence of YL1E07 was reproduced. We carried out microbiological, biochemical (lactose, lactate, AA consumption and ammonia production) and transcriptomic analyses by microarray technology to highlight the interaction mechanisms. We showed that the DH1L25 growth inhibition in the presence of YL1E07 was neither due to the ammonia production nor to the nutritional competition for the medium carbon sources between the two yeasts. The transcriptomic study was the key toward the comprehension of yeast-yeast interaction, and revealed that the inhibition of DH1L25 in co-culture is due to a decrease of the mitochondrial respiratory chain functioning. PMID- 29111500 TI - The moral hazard effects of consumer responses to targeted cost-sharing. AB - This paper examines the effects of the reference pricing program implemented by the California Public Employees Retirement System (CalPERS) in 2012. The program uses targeted cost-sharing to incentivize patient price shopping. We find that the program leads to a 10.3% increase in the use of low-price providers and reduces the average cost per procedure by 12.5%. We further estimate that the program reduces medical spending by $218.8 per procedure, which we estimate is approximately 53.7% of the excessive spending that is due to patient choice of higher price providers caused by insurance coverage, at the expense of a $94.3 (or 12.5%) reduction in consumer surplus. The cost savings from the reference pricing program is about two to three times as large as the reduction from implementing a high-deductible health plan, while the accompanying consumer surplus reduction is much smaller under reference pricing. PMID- 29111501 TI - Understanding variability in driving recommendations for patients with seizures. AB - BACKGROUND: There is lack of consensus regarding driving restrictions for patients with epilepsy. Regulations vary by state. New York State (NYS) recommends driving restrictions for one year in a person with an episode of loss of consciousness (LOC), with physician discretion. Often, providers make recommendations to permit their patients to drive after a shorter seizure-free period than proposed guidelines. The prevalence and reasons behind more lenient recommendations have not been elucidated. METHODS: Forty-one neurologists were surveyed anonymously in Nassau County, New York. They were questioned about the length of recommended driving restrictions (<=1, 3, 6, or >=12months) that they typically provide to patients with suspected seizures in different clinical scenarios and overall reasons for doing so. Data about level of training, setting of practice, use of antiepileptic drug (AED) levels, and electroencephalogram (EEG) were also collected. RESULTS: Of the 41 neurologists surveyed, 72% reported recommending driving restrictions <12months for patients who experienced LOC, without a confirmed diagnosis of seizure. The majority also recommended driving restriction of <12months for other scenarios including acute symptomatic seizure, exclusively simple partial seizures, nocturnal seizures, psychogenic nonepileptic seizures (PNES), and seizures occurring with or during AED reduction. The most common rationale was to improve patient autonomy and independence. Less than a third of neurologists estimated that the majority of their patients were noncompliant with driving recommendations. CONCLUSION: We found that many neurologists' recommendations for limiting driving for patients with seizure related episodes are shorter than those recommended by NYS. Furthermore, as there are no specific guidelines for questionable epileptic scenarios and seizures occurring nocturnally or without LOC, this appears to contribute to substantial variability in the duration of recommended driving restrictions. This opens a broad discussion about approaches towards advising driving limitations in order to protect public and patient safety while maintaining patient autonomy. PMID- 29111502 TI - A simple clinical score for prediction of nonepileptic seizures. AB - Psychogenic nonepileptic seizures (PNES), often mistaken for epilepsy in community practice, require inpatient video-EEG (VEEG) monitoring for diagnostic confirmation. We developed a simple score designed for use in an outpatient setting to predict the subsequent VEEG diagnosis of PNES. We retrospectively compared fifty-five consecutive patients with VEEG-proven PNES (N1=55) with a group of randomly selected patients with VEEG-proven epilepsy (N2=55). Patients were divided into two groups: I) a 'truly retrospective' group of 27 patients with PNES and 27 patients with epilepsy whose data served to develop the score, and II) a 'pseudoprospective' group of 28 patients each with PNES and epilepsy to whom the score was applied. Six features in the history of the Group I cohort appeared more prominent in patients with PNES than patients with epilepsy and were assigned escalating numerical values as follows: number of declared drug allergies (0, 0.5, 1), number of declared comorbidities (0, 0.5, 1), number of previous invasive medical interventions of any type (0, 0.5, 1), and a history of significant psychological or physical trauma (0 or 1). In addition, a score was assigned to verbal description of the seizures themselves as being consistent (=0), atypical (=1), or indeterminate (=0.5) for epilepsy. The values were added to yield an omnibus score ranging from 0 to 6. Scoring of Group II subjects in a blinded fashion revealed that in general patients with PNES had higher scores, and the majority obtained a score >2; most patients with epilepsy scored <1.5. Group difference in the mean between the PNES and epilepsy cohort was highly significant (p<0.0001, Wilcoxon rank-sum test). Our score is a simple clinical instrument based on the patient history that may find use in the triage of patients awaiting hospitalization for VEEG and in pre-VEEG counseling. PMID- 29111503 TI - Are the clinical classifications for psychogenic nonepileptic seizures reliable? AB - BACKGROUND: Psychogenic nonepileptic seizures (PNESs) are episodes that resemble epileptic seizures but are of psychological origin. A few studies have attempted to describe different types of PNES as a combination of clinical signs but their validation and robustness have not yet been reached. The aim of this study was to assess the inter-rater reliability (IRR) of five existing clinical PNES classifications. METHODS: A total of 107 PNESs from 54 patients were retrospectively analyzed independently by two trained epileptologists, who were blinded to each other's findings. The recorded events were grouped according to the five chosen classifications systems. The IRR was measured using a kappa (kappa) coefficient for each PNES classification. We also report category specific kappa values. RESULTS: Our study demonstrated a mild to moderate IRR (kappa from 0.44-0.68) for classifying PNES using the 5 proposed classification schemes. Within these classifications, the most reproducible classes are the subjective ones followed by the dialeptic group. Classes based on motor signs are the least reproducible. CONCLUSION: The IRR for current clinical classifications of PNES was only moderate. The difficulty to analyze motor signs could explain this poor reliability. It is necessary to ensure the reliability of clinical classifications of PNES in order for them to be a relevant tool in clinical practice or to explore correlations in clinical research. Future research would benefit from increased precision of diagnostic criteria specific to each class. PMID- 29111505 TI - When adverse effects are seen as desirable: Abuse potential of the newer generation antiepileptic drugs. AB - There has been growing recognition of the possible abuse potential of newer generation antiepileptic drugs, and several of these agents have been categorized as controlled substances in the United States. To properly schedule a new medication, the abuse potential, or the potential for a drug to be used for its nonmedical positive subjective effects, must be determined. Performing a human abuse potential study is one step in the overall abuse potential assessment. These studies analyze the abuse potential of a new drug in a very specific population of known recreational drug users. Studying the test drug in this population enables a more meaningful assessment of abuse, and likely represents the population most probable to abuse. In these double-blind, single-dose, active and placebo controlled studies subjects may report their subjective liking, estimated street value, and rate euphoric or depressive sensations of the test drug compared with placebo and scheduled active comparators with a known abuse potential. In order to provide an enhanced understanding of the abuse potential assessment and how it relates to controlled substance scheduling, this review will examine the human abuse potential studies of perampanel, eslicarbazepine, lacosamide, and brivaracetam. PMID- 29111504 TI - Validation of the Polish version of the Beck Depression Inventory in patients with epilepsy. AB - BACKGROUND: Despite the fact that depressive disorders are the most common comorbidities among patients with epilepsy (PWE), such disorders often go unrecognized and untreated. In addition, the availability of validated screening instruments to detect depression in PWE is limited. The aim of the present study was thus to validate the Polish version of the Beck Depression Inventory (BDI) in adult PWE. METHODS: A group of 118 outpatient PWE were invited to participate in the study. Ninety-six patients meeting the inclusion criteria completed the Polish Version of Beck Depression Inventory-I (BDI-I) and were examined by a trained psychiatrist using the Structured Clinical Interview (SICD-I) for Diagnostic and statistical manual of mental disorders - fourth edition (Text revision) (DSM-IV-TR). Receiver operating characteristic (ROC) curves were used to determine the optimal threshold scores for BDI. RESULTS: Receiver operating characteristic analysis showed the area under the curve to be approximately 84%. For major depressive disorder (MDD) diagnosis, the BDI demonstrated the best psychometric properties for a cut-off score to be 18, with a sensitivity of 90.5%, specificity of 70.7%, positive predictive value (PPV) of 46.3%, and negative predictive value (NPV) of 96.4%. For the 'any depressive disorder' group, the BDI optimum cut-off score was 11, with a sensitivity of 82.5%, specificity of 73.2%, PPV of 68.8%, and NPV of 85.4%. CONCLUSIONS: The BDI score is a valid psychometric indicator for depressive disorders in PWE maintaining adequate sensitivity and specificity, high NPV, and acceptable PPV with an optimum cut-off score of 18 for MDD diagnosis. PMID- 29111506 TI - Increasing the Impact Factor in the Ethical Way. PMID- 29111507 TI - Metastable ultracondensed hydrogenous materials. AB - The primary purpose of this paper is to stimulate theoretical predictions of how to retain metastably hydrogenous materials made at high pressure P on release to ambient. Ultracondensed metallic hydrogen has been made at high pressures in the fluid and reported made probably in the solid. Because the long quest for metallic hydrogen is likely to be concluded in the relatively near future, a logical question is whether another research direction, comparable in scale to the quest for metallic H, will arise in high pressure research. One possibility is retention of metastable solid metallic hydrogen and other hydrogenous materials on release of dynamic and static high pressures P to ambient. If hydrogenous materials could be retained metastably on release, those materials would be a new class of materials for scientific investigations and technological applications. This paper is a review of the current situation with the synthesis of metallic hydrogen, potential technological applications of metastable metallic H and other hydrogenous materials at ambient, and general background of published experimental and theoretical work on what has been accomplished with metastable phases in the past and thus what might be accomplished in the future. PMID- 29111508 TI - HUG and SQUEEZE: using CRYSTALS to incorporate resonant scattering in the SQUEEZE structure-factor contributions to determine absolute structure. AB - The resonant-scattering contributions to single-crystal X-ray diffraction data enable the absolute structure of crystalline materials to be determined. Crystal structures can be determined even if they contain considerably disordered regions because a correction is available via a discrete Fourier transform of the residual electron density to approximate the X-ray scattering from the disordered region. However, the corrected model cannot normally account for resonant scattering from atoms in the disordered region. Straightforward determination of absolute structure from crystals where the strongly resonantly scattering atoms are not resolved has therefore not been possible. Using an approximate resonant scattering correction to the X-ray scattering from the disordered regions, we have developed and tested a procedure (HUG) to recover the absolute structure using conventional Flack x refinement or other post-refinement determination methods. Results show that in favourable cases the HUG method works well and the absolute structure can be correctly determined. It offers no useful improvement in cases where the original correction for the disordered region scattering density is problematic, for example, when a large fraction of the scattering density in the crystal is disordered, or when voids are not occupied equally by the disordered species. Crucially, however, if the approach does not work for a given structure, the statistics for the absolute structure measures are not improved, meaning it is unlikely to lead to misassignment of absolute structure. PMID- 29111509 TI - Structural diversity of polynuclear MgxOy cores in magnesium phenoxide complexes. AB - The binuclear complex bis(2,6-di-tert-butyl-4-methylphenolato)-1kappaO,2kappaO (1,2-dimethoxyethane-1kappa2O,O')bis(MU-phenylmethanolato 1:2kappa2O:O)(tetrahydrofuran-2kappaO)dimagnesium(II), [Mg2(C7H7O)2(C15H23O)2(C4H8O)(C4H10O2)] or [(BHT)(DME)Mg(MU-OBn)2Mg(THF)(BHT)], (I), was obtained from the complex [(BHT)Mg(MU-OBn)(THF)]2 by substitution of one tetrahydrofuran (THF) molecule with 1,2-dimethoxyethane (DME) in toluene (BHT is O-2,6-tBu2-4-MeC6H4 and Bn is benzyl). The trinuclear complex bis(2,6-di-tert butyl-4-methylphenolato)-1kappaO,3kappaO-tetrakis(MU-2-methylphenolato) 1:2kappa4O:O;2:3kappa4O:O-bis(tetrahydrofuran)-1kappaO,3kappaO-trimagnesium(II), [Mg3(C7H7O)4(C15H23O)2(C4H8O)2] or [(BHT)2(MU-O-2-MeC6H4)4(THF)2Mg3], (II), was formed from a mixture of Bu2Mg, [(BHT)Mg(nBu)(THF)2] and 2-methylphenol. An unusual tetranuclear complex, bis(MU3-2-aminoethanolato kappa4O:O:O,N)tetrakis(MU2-2-aminoethanolato-kappa3O:O,N)bis(2,6-di-tert-butyl-4 methylphenolato-kappaO)tetramagnesium(II), [Mg4(C2H6NO)6(C15H23O)2] or Mg4(BHT)2(OCH2CH2NH2)6, (III), resulted from the reaction between (BHT)2Mg(THF)2 and 2-aminoethanol. A polymerization test demonstrated the ability of (III) to catalyse the ring-opening polymerization of E-caprolactone without activation by alcohol. In all three complexes (I)-(III), the BHT ligand demonstrates the terminal kappaO-coordination mode. Complexes (I), (II) and (III) have binuclear rhomboid Mg2O2, trinuclear chain-like Mg3O4 and bicubic Mg4O6 cores, respectively. A survey of the literature on known polynuclear MgxOy core types for ArO-Mg complexes is also presented. PMID- 29111510 TI - Cation tautomerism, twinning and disorder in the triclinic and monoclinic forms of 4-amino-5-chloro-2,6-dimethylpyrimidinium 5-chloro-2-hydroxybenzoate and a new disordered refinement of 2-amino-4,6-dimethoxypyrimidin-1-ium thiophene-2 carboxylate. AB - Pyrimidines are important compounds in biology and medicine, and the aminopyrimidine fragment can be identified in three of the four bases in DNA. The targeted drug action of pharmaceuticals containing this functionality is likely to depend heavily on molecular recognition processes involving hydrogen bonding. Crystallization of an equimolar mixture of 4-amino-5-chloro-2,6 dimethylpyrimidine and 5-chloro-2-hydroxybenzoic acid yielded two forms of the 1:1 salt, C6H9ClN3+.C7H4ClO3-, each containing a different tautomeric form of the cation. 6-Amino-5-chloro-2,4-dimethylpyrimidin-1-ium 5-chloro-2-hydroxybenzoate, (I), crystallizes in the space group P-1, with Z' = 2, and all of the component ions are fully ordered. 4-Amino-5-chloro-2,6-dimethylpyrimidin-1-ium 5-chloro-2 hydroxybenzoate, (II), also crystallizes with Z' = 2, but in the space group P21/c and as a merohedral twin which closely mimics an orthorhombic unit cell. In (II), one of the cations and one of the anions is disordered, each over two sets of atomic sites having occupancies of 0.836 (2) and 0.164 (2), and 0.834 (2) and 0.166 (2). The bond lengths in the cations of (I) and (II) provide evidence for o quinonoid and p-quinonoid bond fixation, respectively. A combination of six N H...O hydrogen bonds links the component ions of (I) into two independent four ion aggregates, but the ions in (II) are linked by a combination of four N-H...O and two N-H...N hydrogen bonds to form a three-dimensional framework structure. The recently reported structure of 2-amino-4,6-dimethoxypyrimidin-1-ium thiophene 2-carboxylate, C6H10N3O2+.C5H3O2S-, (III), has been rerefined, using the original data set, to show that the anion is disordered over two sets of atomic sites, approximately related by a 180 degrees rotation about the exocyclic C-C bond, and having occupancies of 0.8687 (19) and 0.1313 (19). PMID- 29111511 TI - A three-dimensional supramolecular framework based on the interlinkage of an interpenetrating diamondoid coordination network. AB - In the development of coordination-driven crystalline materials, O- and N-atom donors from carboxylate and pyridyl-based ligands are widely used classes of multidentate bridging ligands composed of several terminal coordinating groups linked by either rigid or flexible spacers. The rigidity of the ligands can play a vital role in the determination of the structures formed. A new CdII supramolecular compound, namely poly[MU-adipato-kappa2O1:O4-MU-adipato kappa4O1,O1':O4,O4'-diaquabis[MU-1,4-bis(pyridin-4-yl)-1,3-butadiene kappa2N:N']dicadmium(II)], [Cd2(C6H8O4)2(C14H12N2)2(H2O)2]n, (I), has been synthesized by the self-assembly of Cd(NO3)2.4H2O, adipic acid (hexane-1,6-dioic acid; H2adp) and the dipyridyl ligand 1,4-bis(pyridin-4-yl)buta-1,3-diene (1,4 bpbd) under hydrothermal conditions. Single-crystal X-ray diffraction analysis reveals that each CdII centre is located in a distorted octahedral coordination environment, coordinated by one water O atom, three carboxylate O atoms from two different adp2- ligands and two N atoms from two different 1,4-bpbd ligands. The Cd(H2O) units are interconnected by the MU2,kappa2-adp2-, MU2,kappa4-adp2- and 1,4-bpbd ligands, which lie across centres of inversion, to give a 66-dia network. Large cavities within a single diamondoid network permit the mutual threefold interpenetration of crystallographically equivalent frameworks. Hydrogen-bonding interactions between the coordinated water molecules and adp2- carboxylate O atoms anchor the interpenetrating networks into a unique three dimensional supramolecular structure. Topologically, taking the coordinated water molecules and CdII centres as nodes, the whole architecture can be simplified as a binodal (3,7)-connected supramolecular framework. The identity of (I) was further characterized by IR spectroscopy, elemental analysis, thermogravimetric analysis and powder X-ray diffraction. The solid-state photoluminescence properties of (I) were also investigated. PMID- 29111512 TI - Halogen bonding in a series of Br(CF2)nBr-DABCO adducts (n = 4, 6, 8). AB - Halogen bonding (XB) is a highly-directional class of intermolecular interactions that has been used as a powerful tool to drive the design of crystals in the solid phase. To date, the majority of XB donors have been iodine-containing compounds, with many fewer involving brominated analogues. We report the formation of adducts in the vapour phase from a series of dibromoperfluoroalkyl compounds, BrCF2(CF2)nCF2Br (n = 2, 4, 6), and 1,4-diazabicyclo[2.2.2]octane (DABCO). Single-crystal X-ray diffraction studies of the colourless crystals identified 1,4-diazabicyclo[2.2.2]octane-1,4-dibromoperfluorobutane (1/1), C4Br2F8.C6H12N2, (I), 1,4-diazabicyclo[2.2.2]octane-1,6-dibromoperfluorohexane (1/1), C6Br2F12.C6H12N2, (II), and 1,4-diazabicyclo[2.2.2]octane-1,8 dibromoperfluorooctane (1/1), C8Br2F16.C6H12N2, (III), each of which displays a one-dimensional halogen-bonded network. All three adducts exhibit N...Br distances less than the sum of the van der Waals radii, with butane analogue (I) showing the shortest N...Br halogen-bond distances yet reported between a bromoperfluorocarbon and a nitrogen base [2.809 (3) and 2.818 (3) A], which are 0.58 and 0.59 A shorter than the sum of the van der Waals radii. PMID- 29111513 TI - A hybrid imidazolylidene/imidazolium nickel NHC complex: an isolated intermediate. AB - Macrocyclic ligand systems with a variety of (different) donor sites oftentimes give rise to very exciting and unexpected multinuclear metal complexes. We report herein the structure of a trinuclear mixed imidazolylidene/imidazolium nickel N heterocyclic carbene (NHC) complex, namely di-MU-chlorido-bis{MU calix[2]imidazolium[2]imidazolylidene[2]pyrazolate}trinickel(II) tetrakis(hexafluoridophosphate) acetonitrile tetrasolvate, [Ni3(C24H24N12)2Cl2](PF6)4.4CH3CN or [Ni3(LMe)2Cl2](PF6)4.4CH3CN, that can be understood as a trapped reaction intermediate during the synthesis of the respective [Ni2LMe](PF6)2 product. The structure not only contains protonated next to deprotonated imidazole heterocycles, but also Ni2+ ions with fundamentally different coordination modes within one molecule. Two of the three metal atoms are coordinated in a square-pyramidal fashion by half a ligand molecule and one chloride ligand, whereas the third Ni2+ ion is bound octahedrally by four pyrazolate moieties and two chloride anions. PMID- 29111514 TI - A new two-dimensional polymeric cadmium(II) complex containing dicyanamide bridging ligands. AB - As part of an exploration of new coordination polymers, a cadmium-dicyanamide complex, namely poly[benzyltriethylammonium [tri-MU-dicyanamido-kappa6N1:N5 cadmium(II)]], {(C13H22N)[Cd(C2N3)3]}n, has been synthesized by the reaction of benzyltriethylammonium bromide, cadmium nitrate tetrahydrate and sodium dicyanamide in aqueous solution, and characterized by single-crystal X-ray diffraction at room temperature. In the crystal structure, each CdII cation is coordinated by six nitrile N atoms from six anionic dicyanamide (dca) ligands to furnish a slightly distorted octahedral geometry. Neighbouring CdII cations are linked by dicyanamide bridges to construct a two-dimensional anionic layer coordination polymer. One amide N atom in the bridging dca ligand is disordered over two sites. The cations lie between the anionic frameworks and there are no hydrogen-bond interactions between the cations and anions. The organic cations are not involved in the formation of the supramolecular network. PMID- 29111515 TI - Synthon preference in the cocrystal of 3,4,5-trifluorophenylboronic acid with urea. AB - The comprehensive description of the crystal structure of a novel 1:1 cocrystal of 3,4,5-trifluorophenylboronic acid with urea, C6H4BF3O2.CH4N2O, is presented. Both components are good candidates for crystal engineering as they can create a variety of supramolecular synthons. The preference for the formation of different hetrosynthons is verified based on theoretical calculations. The syn-anti conformation of boronic acid has been found to be the most favourable in the formation of intermolecular interactions with urea. Moreover, the distortions present in the boron coordination sphere have been described quantitatively based on experimental data according to bond-valence vector model calculations. The results revealed that the deformation of the sphere is typical for a syn-anti conformation of boronic acids. The supramolecular structure of the cocrystal is composed of large synthons in the form of layers made up of O-H...O and N-H...O hydrogen bonds. The layers are joined via N-H...F hydrogen bonds which are unusual for urea cocrystal structures. PMID- 29111516 TI - An arsenate with the alpha-CrPO4 structure type, NaCa1-xNi3-2xAl2x(AsO4)3 (x = 0.23): crystal structure, charge-distribution and bond-valence-sum analyses. AB - Since the discovery of electrochemically active LiFePO4, materials with tunnel and layered structures built up of transition metals and polyanions have become the subject of much research. A new quaternary arsenate, sodium calcium trinickel aluminium triarsenate, NaCa1-xNi3-2xAl2x(AsO4)3 (x = 0.23), was synthesized using the flux method in air at 1023 K and its crystal structure was determined from single-crystal X-ray diffraction (XRD) data. This material was also characterized by qualitative energy-dispersive X-ray spectroscopy (EDS) analysis and IR spectroscopy. The crystal structure belongs to the alpha-CrPO4 type with the space group Imma. The structure is described as a three-dimensional framework built up of corner-edge-sharing NiO6, (Ni,Al)O6 and AsO4 polyhedra, with channels running along the [100] and [010] directions, in which the sodium and calcium cations are located. The proposed structural model has been validated by bond valence-sum (BVS) and charge-distribution (CHARDI) tools. The sodium ionic conduction pathways in the anionic framework were investigated by means of the bond-valence site energy (BVSE) model, which predicted that the studied material will probably be a very poor Na+ ion conductor (bond-valence activation energy ~7 eV). PMID- 29111517 TI - Copper(II)- and gold(III)-mediated cyclization of a thiourea to a substituted 2 aminobenzothiazole. AB - Benzothiazole derivatives are a class of privileged molecules due to their biological activity and pharmaceutical applications. One route to these molecules is via intramolecular cyclization of thioureas to form substituted 2 aminobenzothiazoles, but this often requires harsh conditions or employs expensive metal catalysts. Herein, the copper(II)- and gold(III)-mediated cyclizations of thioureas to substituted 2-aminobenzothiazoles are reported. The single-crystal X-ray structures of the thiourea N-(3-methoxyphenyl)-N'-(pyridin-2 yl)thiourea, C13H13N3OS, and the intermediate metal complexes aquabis[5-methoxy-N (pyridin-2-yl-kappaN)-1,3-benzothiazol-2-amine-kappaN3]copper(II) dinitrate, [Cu(C13H11N3OS)2(H2O)](NO3)2, and bis{2-[(5-methoxy-1,3-benzothiazol-2 yl)amino]pyridin-1-ium} dichloridogold(I) chloride monohydrate, (C13H12N3OS)2[AuCl2]Cl.H2O, are reported. The copper complex exhibits a distorted trigonal-bipyramidal geometry, with direct metal-to-benzothiazole-ligand coordination, while the gold complex is a salt containing the protonated uncoordinated benzothiazole, and offers evidence that metal reduction (in this case, AuIII to AuI) is required for the cyclization to proceed. As such, this study provides further mechanistic insight into the role of the metal cations in these transformations. PMID- 29111518 TI - Novel modification of anhydrous transition metal oxalates from powder diffraction. AB - The known metal-C2O4 structures may be divided into two modifications, alpha and beta. The alpha-modification has an order-disorder struxture, revealing one dimensional disordering of the metal-oxalate chains, and the beta-modification is ordered. The crystal structures of orthorhombic gamma-MnC2O4 {poly[MU-oxalato manganese(II)]; space group Pmna, a = 7.1333 (1), b = 5.8787 (1), c = 9.0186 (2) A, V = 378.19 (1) A3, Z = 4 and Dx = 2.511 Mg m-3} and gamma-CdC2O4 {poly[MU oxalato-cadmium(II)]; space group Pmna, a = 7.3218 (1), b = 6.0231 (1), c = 9.2546 (2) A, V = 408.13 (1) A3, Z = 4 and Dx = 3.262 Mg m-3} have been obtained from powder diffraction patterns. The structures are isostructural. Each metal atom in each structure is coordinated by seven O atoms which belong to five oxalate ions. The crystal packing, which contains noticeable cavities in the [101] and [001] directions, is not close packed and essentially differs from the known disordered alpha- and ordered beta-modifications of transition metal oxalates. This modification seems to be metastable. It was found that a spontaneous gamma->beta phase transition takes place for gamma-CdC2O4. PMID- 29111519 TI - Synthesis and coordination chemistry of the PPN ligand 2 [bis(diisopropylphosphanyl)methyl]-6-methylpyridine. AB - The synthesis and crystal structure of the multidentate PPN ligand 2 [bis(diisopropylphosphanyl)methyl]-6-methylpyridine (L), C19H35NP2, are described. In the isostructural tetrahedral Fe and Co complexes of type LMCl2 (M = Fe, Co), namely {2-[bis(diisopropylphosphanyl)methyl]-6-methylpyridine kappa2P,N}dichloridoiron(II), [FeCl2(C19H35NP2)], and {2 [bis(diisopropylphosphanyl)methyl]-6-methylpyridine kappa2P,N}dichloridocobalt(II), [CoCl2(C19H35NP2)], the ligand adopts a bidentate P,N-coordination, whereas in the case of the octahedral Mn complex {2 [bis(diisopropylphosphanyl)methyl]-6-methylpyridine kappa2P,P'}bromidotricarbonylmanganese(I), [MnBr(C19H35NP2)(CO)3], the ligand coordinates via both P atoms to the metal centre. PMID- 29111520 TI - Synthesis and structures of photoactive rhenium carbonyl complexes derived from 2 (pyridin-2-yl)-1,3-benzothiazole, 2-(quinolin-2-yl)-1,3-benzothiazole and 1,10 phenanthroline. AB - Carbon monoxide (CO) has recently been identified as a gaseous signaling molecule that exerts various salutary effects in mammalian pathophysiology. Photoactive metal carbonyl complexes (photoCORMs) are ideal exogenous candidates for more controllable and site-specific CO delivery compared to gaseous CO. Along this line, our group has been engaged for the past few years in developing group-7 based photoCORMs towards the efficient eradication of various malignant cells. Moreover, several such complexes can be tracked within cancerous cells by virtue of their luminescence. The inherent luminecscent nature of some photoCORMs and the change in emission wavelength upon CO release also provide a covenient means to track the entry of the prodrug and, in some cases, both the entry and CO release from the prodrug. In continuation of the research circumscribing the development of trackable photoCORMs and also to graft such molecules covalently to conventional delivery vehicles, we report herein the synthesis and structures of three rhenium carbonyl complexes, namely, fac-tricarbonyl[2-(pyridin-2-yl)-1,3 benzothiazole-kappa2N,N'](4-vinylpyridine-kappaN)rhenium(I) trifluoromethanesulfonate, [Re(C7H7N)(C12H8N2S)(CO)3](CF3SO3), (1), fac tricarbonyl[2-(quinolin-2-yl)-1,3-benzothiazole-kappa2N,N'](4-vinylpyridine kappaN)rhenium(I) trifluoromethanesulfonate, [Re(C7H7N)(C16H10N2S)(CO)3](CF3SO3), (2), and fac-tricarbonyl[1,10-phenanthroline-kappa2N,N'](4-vinylpyridine kappaN)rhenium(I) trifluoromethanesulfonate, [Re(C7H7N)(C12H8N2)(CO)3](CF3SO3), (3). In all three complexes, the ReI center resides in a distorted octahedral coordination environment. These complexes exhibit CO release upon exposure to low power UV light. The apparent CO release rates of the complexes have been measured to assess their comparative CO-donating capacity. The three complexes are highly luminescent and this in turn provides a convenient way to track the entry of the prodrug molecules within biological targets. PMID- 29111521 TI - Side-chain conformations in the isomorphous polyfluorinated {4,4'-bis[(2,2 difluoroethoxy)methyl]-2,2'-bipyridine-kappa2N,N'}dichloridopalladium and platinum complexes. AB - The polyfluorinated title compounds, [MCl2(C16H16F4N2O2)] or [4,4'-(HCF2CH2OCH2)2 2,2'-bpy]MCl2 [M = Pd, (1), and M = Pt, (2)], have -C(Halpha)2OC(Hbeta)2CF2H side chains with H-atom donors at the alpha and beta sites. The structures of (1) and (2) are isomorphous, with the nearly planar (bpy)MCl2 molecules stacked in columns. Within one column, pi-dimer pairs alternate between a pi-dimer pair reinforced with C-H...Cl hydrogen bonds (alpha,alpha) and a pi-dimer pair reinforced with C-Hbeta...F(-C) interactions (abbreviated as C-Hbeta...F-C,C Hbeta...F-C). The compounds [4,4'-(CF3CH2OCH2)2-2,2'-bpy]MCl2 [M = Pd, (3), and M = Pt, (4)] have been reported to be isomorphous [Lu et al. (2012). J. Fluorine Chem. 137, 54-56], yet with disorder in the fluorous regions. The molecules of (3) [or (4)] also form similar stacks, but with alternating pi-dimer pairs between the (alpha,beta; alpha,beta) and (beta,beta) forms. Through (C-)H...Cl hydrogen-bond interactions, one molecule of (1) [or (2)] is expanded into an aggregate of two inversion-related pi-dimer pairs, one pair in the (alpha,alpha) form and the other pair in the (C-Hbeta...F-C,C-Hbeta...F-C) form, with the plane normals making an interplanar angle of 58.24 (3) degrees . Due to the demands of maintaining a high coordination number around the metal-bound Cl atoms in molecule (1) [or (2)], the ponytails of molecule (1) [or (2)] bend outward; in contrast, the ponytails of molecule (3) [or (4)] bend inward. PMID- 29111522 TI - Adiponitrile at 100 K. AB - Adiponitrile, C6H8N2, is a key intermediate in the synthesis of the polyamide Nylon 66 and is produced industrially on a large scale. We have determined the crystal and molecular structure of adiponitrile by single-crystal X-ray analysis at 100 K, a suitable crystal (m.p. 275 K) having been grown from the melt at low temperature. The compound crystallizes in the monoclinic space group P21/c with Z = 2. In the crystal structure, the molecule adopts an exact Ci-symmetric gauche anti-gauche conformation of the C-C-C-C skeleton about an inversion centre. The molecules are densely packed, with short intermolecular contacts between the alpha-H and nitrile N atoms. PMID- 29111523 TI - The synthesis, crystal structure and thermal properties of an energetic compound: the hydrated azanium salt of 3,6-bis[(1H-1,2,3,4-tetrazol-5-yl)amino]-1,2,4,5 tetrazine. AB - The energetic ionic salt bis(1-aminoguanidin-2-ium) 5,5'-[1,2,4,5-tetrazine-3,6 diylbis(azanediyl)]bis(1H-1,2,3,4-tetrazol-1-ide) dihydrate, 2CH7N4+.C4H2N142 .2H2O, (I), with a high nitrogen content, has been synthesized and examined by elemental analysis, Fourier transform IR spectrometry, 1H NMR spectroscopy and single-crystal X-ray crystallography. Compound (I) crystallizes in the monoclinic space group P21/c with two water molecules. However, the water molecules are disordered about an inversion centre and were modelled as half-occupancy molecules in the structure. The crystal structure reveals a three-dimensional network of molecules linked through N-H...N, N-H...O, O-H...N and O-H...O hydrogen bonds. Thermal decomposition was investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The exothermic peak temperature is 509.72 K, which indicates that hydrated salt (I) exhibits good thermal stability. Non-isothermal reaction kinetic parameters were calculated via both the Kissinger and the Ozawa methods to yield activation energies of Ek = 239.07 kJ mol-1, lgAk = 22.79 s-1 and EO = 235.38 kJ mol-1 for (I). Additionally, the thermal safety was evaluated by calculating critical temperatures and thermodynamic values, viz. TSADT, TTIT, Tb, DeltaS?, DeltaH? and DeltaG?. The results reveal that (I) exhibits good thermal safety compared to other ion salts of 3,6-bis[(1H-1,2,3,4-tetrazol-5-yl)amino]-1,2,4,5-tetrazine (BTATz). PMID- 29111524 TI - Cs3LiZn2(WO4)4 and Rb3Li2Ga(MoO4)4: different filled derivatives of the cation deficient Cs6Zn5(MoO4)8 structure. AB - Two new compounds, namely cubic tricaesium lithium dizinc tetrakis(tetraoxotungstate), Cs3LiZn2(WO4)4, and tetragonal trirubidium dilithium gallium tetrakis(tetraoxomolybdate), Rb3Li2Ga(MoO4)4, belong to the structural family of Cs6Zn5(MoO4)8 (space group I-43d, Z = 4), with a partially incomplete (Zn5/6?1/6) position. In Cs3LiZn2(WO4)4, this position is fully statistically occupied by (Zn2/3Li1/3), and in Rb3Li2Ga(MoO4)4, the 2Li + Ga atoms are completely ordered in two distinct sites of the space group I-42d (Z = 4). In the same way, the crystallographically equivalent A+ cations (A = Cs, Rb) in Cs6Zn5(MoO4)8, Cs3LiZn2(WO4)4 and isostructural A3LiZn2(MoO4)4 and Cs3LiCo2(MoO4)4 are divided into two sites in Rb3Li2Ga(MoO4)4, as in other isostructural A3Li2R(MoO4)4 compounds (AR = TlAl, RbAl, CsAl, CsGa, CsFe). In the title structures, the WO4 and (Zn,Li)O4 or LiO4, GaO4 and MoO4 tetrahedra share corners to form open three-dimensional frameworks with the caesium or rubidium ions occupying cuboctahedral cavities. The tetrahedral frameworks are related to that of mayenite 12CaO.7Al2O3 and isotypic compounds. Comparison of isostructural Cs3MZn2(MoO4)4 (M = Li, Na, Ag) and Cs6Zn5(MoO4)8 shows a decrease of the cubic lattice parameter and an increase in thermal stability with the filling of the vacancies by Li+ in the Zn position of the Cs6Zn5(MoO4)8 structure, while filling of the cation vacancies by larger Na+ or Ag+ ions plays a destabilizing role. The series A3Li2R(MoO4)4 shows second harmonic generation effects compatible with that of beta'-Gd2(MoO4)3 and may be considered as nonlinear optical materials with a modest nonlinearity. PMID- 29111525 TI - Crystallographic studies of cinnamamide derivatives as a means of searching for anticonvulsant activity. AB - A cinnamamide (3-phenylprop-2-enamide) core is present in many pharmacologically active compounds. We report three new crystal structures of N-substituted cinnamamide derivatives which were screened for anticonvulsant activity, namely (R,S)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide, C12H15NO2, (1), (R,S)-(2E) N-(1-hydroxybutan-2-yl)-3-phenylprop-2-enamide, C13H17NO2, (2), and (2E)-1-(4 hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one, C14H17NO2, (3). Compounds (1) and (2) crystallize in the Pbca space group with one molecule in the asymmetric unit, whereas compound (3) crystallizes in the P21/c space group with two molecules in the asymmetric unit. All the crystal structures are stabilized by intermolecular O-H...O hydrogen bonds and additionally by N-H...O hydrogen bonds in the structures of (1) and (2). The investigated compounds possess fragments that are considered as beneficial for anticonvulsant activity. The conformations of these compounds were analyzed in comparison with the characteristic features of the proposed pharmacophore model of anticonvulsants active in the maximal electroshock test, i.e. a phenyl ring or other hydrophobic unit, an electron donor atom and a hydrogen-bond acceptor/donor domain. In the reported series, two calculated distances fitted the reference model, while the third did not. Structure-activity analysis suggests that anticonvulsant properties may be related to the N-atom substituent. It is beneficial to combine an electron-donor atom (e.g. an O atom) with an H atom in the substituent to ensure appropriate interactions with the molecular target. We analyzed the intermolecular interactions in order to find an appropriate spatial arrangement of the important features responsible for anticonvulsant activity. PMID- 29111526 TI - Copper(II) bis(4,4,4-trifluoro-1-phenylbutane-1,3-dionate) complexes with pyridin 2-one, 3-hydroxypyridine and 3-hydroxypyridin-2-one ligands: molecular structures and hydrogen-bonded networks. AB - Copper(II) bis(4,4,4-trifluoro-1-phenylbutane-1,3-dionate) complexes with pyridin 2-one (pyon), 3-hydroxypyridine (hpy) and 3-hydroxypyridin-2-one (hpyon) were prepared and the solid-state structures of (pyridin-2-one-kappaO)bis(4,4,4 trifluoro-3-oxo-1-phenylbutan-1-olato-kappa2O,O')copper(II), [Cu(C10H6F3O2)2(C5H5NO)] or [Cu(tfpb-kappa2O,O')2(pyon-kappaO)], (I), bis(pyridin 3-ol-kappaO)bis(4,4,4-trifluoro-3-oxo-1-phenylbutan-1-olato kappa2O,O')copper(II), [Cu(C10H6F3O2)2(C5H5NO)2] or [Cu(tfpb-kappa2O,O')2(hpy kappaO)2], (II), and bis(3-hydroxypyridin-2-one-kappaO)bis(4,4,4-trifluoro-3-oxo 1-phenylbutan-1-olato-kappa2O,O')copper(II), [Cu(C10H6F3O2)2(C5H5NO2)2] or [Cu(tfpb-kappa2O,O')2(hpyon-kappaO)2], (III), were determined by single-crystal X ray analysis. The coordination of the metal centre is square pyramidal and displays a rare example of a mutual cis arrangement of the beta-diketonate ligands in (I) and a trans-octahedral arrangement in (II) and (III). Complex (II) presents the first crystallographic evidence of kappaO-monodentate hpy ligation to the transition metal enabling the pyridine N atom to participate in a two dimensional hydrogen-bonded network through O-H...N interactions, forming a graph set motif R22(7) through a C-H...O interaction. Complex (III) presents the first crystallographic evidence of monodentate coordination of the neutral hpyon ligand to a metal centre and a two-dimensional hydrogen-bonded network is formed through N-H...O interactions facilitated by C-H...O interactions, forming the graph-set motifs R22(8) and R22(7). PMID- 29111527 TI - A novel tetrazolate- and cyanide-bridged three-dimensional heterometallic coordination polymer: crystal structure, thermal stability and magnetic properties. AB - By using environmentally friendly K3[Co(CN)6] as a cyanide source, the solvothermal reaction of CuCl2 and tetrazole (Htta) led to a novel tetrazolate- and cyanide-bridged three-dimensional heterometallic CuII-CoIII complex, namely poly[[hexa-MU2-cyanido-kappa12C:N-pentakis(MU3-tetrazolato kappa3N1:N2:N4)cobalt(III)tetracopper(II)] monohydrate], {[CoIIICuII4(CHN4)5(CN)6].H2O}n, (I). The crystal structure analysis reveals that it is the first example of a (6,8,8)-connected three-dimensional framework with a unique topology, constructed from anionic [Co(CN)6]3- and cationic [(Cu1)2(tta)2]2+ and [(Cu2Cu3)(tta)3]+ units through MU2-cyanide and MU3 tetrazolate linkers. The compound was further characterized by thermal analysis, vibrational spectroscopy (FT-IR), scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM-EDS) and magnetic measurements. The magnetic investigation indicates that the complex exhibits antiferromagnetic coupling between adjacent CuII cations. PMID- 29111528 TI - Asymmetric structure of cis-[N-(9-anthracenylmethyl)-1,2 ethanediamine]dipyridineplatinum(II) dinitrate. AB - Platinum antitumour agents, containing aromatic rings, which are used for targeting DNA in effective therapies for the treatment of cancer. We have synthesized the title metallocomplex with an aromatic ligand and determined its crystal structure. In many cases, complexes of platinum and other metals have a symmetrical structure. In contrast, the platinum(II) complex with pyridine and N (9-anthracenylmethyl)-1,2-ethanediamine as ligands (systematic name: cis-{N [(anthracen-9-yl)methyl]ethane-1,2-diamine-kappa2N,N'}bis(pyridine kappaN)platinum(II) dinitrate), [Pt(C5H5N)2(C17H18N2)](NO3)2, is asymmetric. Of the two pyridine ligands, only one is pi-stacked with anthracene, resulting in an asymmetric structure. Moreover, the angle of orientation of each pyridine ligand is variable. Further examination of the packing motif confirms an intermolecular edge-to-face interaction. PMID- 29111529 TI - Two-dimensional coordination polymeric structures in the sodium, potassium and rubidium complex salts with (4-fluorophenoxy)acetic acid. AB - The structures of the sodium, potassium and rubidium complex salts of (4 fluorophenoxy)acetic acid (PFPA), namely poly[MU-aqua-aqua-MU-[2-(4 fluorophenoxy)acetato]-kappa3O1,O2:O1'-sodium], [Na(C8H6FO3)(H2O)2]n, (I), and isotypic poly[MU5-[2-(4-fluorophenoxy)acetato]-kappa5O1,O2:O1,O1':O1':O1':O1' potassium], [K(C8H6FO3)]n, (II), and poly[MU5-[2-(4-fluorophenoxy)acetato] kappa5O1,O2:O1,O1':O1':O1':O1'-rubidium], [Rb(C8H6FO3)]n, (III), have been determined and their coordination polymeric structures described. In the structure of (I), the very distorted octahedral NaO6 coordination polyhedron comprises two bidentate chelating O-atom donors (carboxylate and phenoxy) of the PFPA ligand and three O-atom donors from water molecules, one monodentate and the other MU2-bridging between inversion-related Na centres in a cyclic manner. A bridging carboxylate donor generates two-dimensional polymer layers lying parallel to (001), in which intralayer water O-H...O hydrogen-bonding associations are also present. Structures (II) and (III) are isotypic, each having an irregular MO7 stereochemistry, with the primary metal-ligand bidentate chelate similar to that in (I) and extended into a two-dimensional polymeric layered structure, lying parallel to (100), through five additional bridging carboxylate O atoms. Two of these bonds are from an O,O'-bidentate chelate interaction and the other three are from MU3-O-atom bridges, generating cyclic links with short M...M separations [3.9064 (17) A for (II) and 4.1001 (8) for (III)], the shortest being a centrosymmetric four-membered cyclic link. In the crystals of (I)-(III), intralayer C-H...F interactions are present, but no pi-pi ring interactions are found. PMID- 29111530 TI - LiBC3: a new borocarbide based on graphene and heterographene networks. AB - Li-B-C alloys have attracted much interest because of their potential use in lithium-ion batteries and superconducting materials. The formation of the new compound LiBC3 [lithium boron tricarbide; own structure type, space group P-6m2, a = 2.5408 (3) A and c = 7.5989 (9) A] has been revealed and belongs to the graphite-like structure family. The crystal structure of LiBC3 presents hexagonal graphene carbon networks, lithium layers and heterographene B/C networks, alternating sequentially along the c axis. According to electronic structure calculations using the tight-binding linear muffin-tin orbital-atomic spheres approximations (TB-LMTO-ASA) method, strong covalent B-C and C-C interactions are established. The coordination polyhedra for the B and C atoms are trigonal prisms and for the Li atoms are hexagonal prisms. PMID- 29111531 TI - A new polymorph of 2,6-diaminopyridine. AB - 2,6-Diaminopyridine (26-DAP, C5H7N3) is a common intermediate in the synthesis of aromatic azo chromophores, which are widespread in the dyes and pigments industry. Sublimation of commercial 26-DAP powder yielded a new polymorph, denoted Form II, which grew as colorless orthorhombic needles. Recrystallization from acetone or toluene also yielded Form II as the major phase. Thermal analysis shows that Form II is a less stable polymorph and it converts upon heating at 335 K to the previously reported Form I. PMID- 29111532 TI - Deciphering composition and connectivity of a natural product with the assistance of MS and 2D NMR. AB - A complementary application of three analytical techniques, viz. multidimensional nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS), and single crystal X-ray diffractometry was required to identify and refine two natural products isolated from Millettia versicolor and solvent of crystallization. The two compounds, namely 3-(2H-1,3-benzodioxol-5-yl)-6-methoxy-8,8-dimethyl-4H,8H pyrano[2,3-h]chromen-4-one, or durmillone, (I), and (2E)-1-(4-{[(2E)-3,7 dimethylocta-2,6-dien-1-yl]oxy}-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1 one, (II), could not be separated by routine column chromatography and cocrystallized in a 2:1 ratio with 0.13 molecules of ethanol solvent. Compound (II) and ethanol could not be initially identified by single-crystal X-ray analysis due to complex disorder in the aliphatic chain region of (II). Mass spectrometry ensured that (II) represented only one species disordered over several positions in the solid state, rather than several species cohabitating on the same crystallographic site. The atomic identification and connectivity in (II) were established by several 2D (two-dimensional) NMR techniques, which in turn relied on a knowledge of its exact mass. The derived connectivity was then used in the single-crystal analysis to model the disorder of the aliphatic chain in (II) over three positions and allowed identification of a partially occupied ethanol solvent molecule that was disordered over an inversion center. The disordered moieties were refined with restraints and constraints. PMID- 29111533 TI - Synthesis, crystal structure and activity evaluation of novel 3,4-dihydro-1 benzoxepin-5(2H)-one derivatives as protein-tyrosine kinase (PTK) inhibitors. AB - Four new 3,4-dihydro-1-benzoxepin-5(2H)-one derivatives, namely (E)-4-(5-bromo-2 hydroxybenzylidene)-6,8-dimethoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, (7), (E)-4 [(E)-3-(5-bromo-2-hydroxyphenyl)allylidene]-6,8-dimethoxy-3,4 dihydrobenzo[b]oxepin-5(2H)-one, (8), (E)-4-(5-bromo-2-hydroxybenzylidene)-6 hydroxy-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, C18H15BrO5, (9), and (E)-4 [(E)-3-(5-bromo-2-hydroxyphenyl)allylidene]-6-hydroxy-8-methoxy-3,4 dihydrobenzo[b]oxepin-5(2H)-one, (10), have been synthesized and characterized by FT-IR, NMR and MS. The structure of (9) was confirmed by single-crystal X-ray diffraction. Crystal structure analysis shows that molecules of (9) are connected into a one-dimensional chain in the [010] direction through classical hydrogen bonds and these chains are further extended into a three-dimensional network via C-H...O interactions. The inhibitory activities of these compounds against protein-tyrosine kinases (PTKs) show that 6-hydroxy-substituted compounds (9) and (10) are more effective for inhibiting ErbB1 and ErbB2 than are 6-methoxy substituted compounds (7) and (8). This may be because (9) and (10) could effectively bind to the active pockets of the protein through intermolecular interactions. PMID- 29111534 TI - Complexes of nickel(II) and copper(II) with 1,2,4-triazole-3-carboxylic acid and of cobalt(III) with 3-amino-1,2,4-triazole-5-carboxylic acid. AB - Because of their versatile coordination modes and strong coordination ability for metals, triazole ligands can provide a wide range of possibilities for the construction of metal-organic frameworks. Three transition-metal complexes, namely bis(MU-1,2,4-triazol-4-ide-3-carboxylato)-kappa3N2,O:N1;kappa3N1:N2,O bis[triamminenickel(II)] tetrahydrate, [Ni2(C3HN3O2)2(NH3)6].4H2O, (I), catena poly[[[diamminediaquacopper(II)]-MU-1,2,4-triazol-4-ide-3-carboxylato kappa3N1:N4,O-[diamminecopper(II)]-MU-1,2,4-triazol-4-ide-3-carboxylato kappa3N4,O:N1] dihydrate], {[Cu2(C3HN3O2)2(NH3)4(H2O)2].2H2O}n, (II), (MU-5-amino 1,2,4-triazol-1-ide-3-carboxylato-kappa2N1:N2)di-MU-hydroxido-kappa4O:O bis[triamminecobalt(III)] nitrate hydroxide trihydrate, [Co2(C3H2N4O2)(OH)2(NH3)6](NO3)(OH).3H2O, (III), with different structural forms have been prepared by the reaction of transition metal salts, i.e. NiCl2, CuCl2 and Co(NO3)2, with 1,2,4-triazole-3-carboxylic acid or 3-amino-1,2,4-triazole-5 carboxylic acid hemihydrate in aqueous ammonia at room temperature. Compound (I) is a dinuclear complex. Extensive O-H...O, O-H...N and N-H...O hydrogen bonds and pi-pi stacking interactions between the centroids of the triazole rings contribute to the formation of the three-dimensional supramolecular structure. Compound (II) exhibits a one-dimensional chain structure, with O-H...O hydrogen bonds and weak O-H...N, N-H...O and C-H...O hydrogen bonds linking anions and lattice water molecules into the three-dimensional supramolecular structure. Compared with compound (I), compound (III) is a structurally different dinuclear complex. Extensive N-H...O, N-H...N, O-H...N and O-H...O hydrogen bonding occurs in the structure, leading to the formation of the three-dimensional supramolecular structure. PMID- 29111535 TI - Construction and photocatalytic properties of two metal-mediated coordination polymers based on benzene-1,3,5-tricarboxylic acid and trans-1-(pyridin-3-yl)-2 (pyridin-4-yl)ethene. AB - With the rapid development of modern industry, water pollution has become an intractable environmental issue facing humans worldwide. In particular, the organic dyes discharged into natural water from dyestuffs, dyeing and the textile industry are the main sources of pollution in wastewater. To eliminate these types of pollutants, degradation of organic contaminants through a photocatalytic technique is an effective methodology. To exploit more crystalline photocatalysts for the degradation of organic dyes, two coordination polymers, namely catena poly[[(3,5-dicarboxybenzene-1-carboxylato-kappaO1)silver(I)]-MU-trans-1-(pyridin 3-yl)-2-(pyridin-4-yl)ethene-kappa2N:N'], [Ag(C9H5O6)(C12H10N2)]n or [Ag(H2BTC)(3,4'-bpe)]n, (I), and poly[[(MU3-5-carboxybenzene-1,3-dicarboxylato kappa4O1,O1':O3:O3)[MU-trans-1-(pyridin-3-yl)-2-(pyridin-4-yl)ethene kappa2N:N']cadmium(II)] monohydrate], {[Cd(C9H4O6)(C12H10N2)].H2O}n or {[Cd(HBTC)(3,4'-bpe)].H2O}n, (II), have been prepared by the hydrothermal reactions of benzene-1,3,5-tricarboxylic acid (H3BTC) and trans-1-(pyridin-3-yl) 2-(pyridin-4-yl)ethene (3,4'-bpe) in the presence of AgNO3 or Cd(NO3)2.4H2O, respectively. These two title compounds have been structurally characterized by IR spectroscopy, elemental analysis, single-crystal X-ray diffraction and powder X-ray diffraction. In (I), the AgI ions and organic ligands form a one dimensional coordination chain, and adjacent coordination chains are connected by Ag...O interactions to give rise to a two-dimensional supramolecular network. Each two-dimensional network is entangled with other equivalent networks to generate an infrequent interlocked 2D->3D (2D and 3D are two- and three dimensional, respectively) supramolecular framework. In (II), the CdII ions are bridged by the HBTC2- and 3,4'-bpe ligands, which lie across centres of inversion, to give a two-dimensional coordination network. The thermal stabilities and photocatalytic properties of the title compounds have also been studied. PMID- 29111536 TI - Mono- and dinuclear CuII complexes of the benzyldipicolylamine (BDPA) ligand: crystal structure, synthesis and characterization. AB - The crystal structures of mono- and dinuclear CuII trifluoromethanesulfonate (triflate) complexes with benzyldipicolylamine (BDPA) are described. From equimolar amounts of Cu(triflate)2 and BDPA, a water-bound CuII mononuclear complex, aqua(benzyldipicolylamine-kappa3N,N',N'')bis(trifluoromethanesulfonato kappaO)copper(II) tetrahydrofuran monosolvate, [Cu(CF3SO3)2(C19H19N3)(H2O)].C4H8O, (I), and a triflate-bridged CuII dinuclear complex, bis(MU-trifluoromethanesulfonato-kappa2O:O')bis[(benzyldipicolylamine kappa3N,N',N'')(trifluoromethanesulfonato-kappaO)copper(II)], [Cu2(CF3SO3)4(C19H19N3)2], were synthesized. The presence of residual moisture in the reaction medium afforded water-bound complex (I), whereas dinuclear complex (II) was synthesized from an anhydrous reaction medium. Single-crystal X-ray structure analysis reveals that the CuII centres adopt slightly distorted octahedral geometries in both complexes. The metal-bound water molecule in (I) is involved in intermolecular O-H...O hydrogen bonds with triflate ligands and tetrahydrofuran solvent molecules. In (II), weak intermolecular C-H...F(triflate) and C-H...O(triflate) hydrogen bonds stabilize the crystal lattice. Complexes (I) and (II) were also characterized fully using FT-IR and UV-Vis spectroscopy, cyclic voltammetry and elemental analysis. PMID- 29111537 TI - Synthesis, structure and in vitro cytotoxicity of platinum(II) complexes containing eugenol and a quinolin-8-ol-derived chelator. AB - The synthesis of potassium (eta2-4-allyl-2 methoxyphenol)trichloridoplatinate(II), K[PtCl3(C10H12O2)], (1), starting from Zeise's salt and Ocimum sanctum L. oil has been optimized. Starting from (1), three new platinum(II) complexes, namely (eta2-4-allyl-2-methoxyphenol)chlorido(2 methylquinolin-8-olato-kappa2N,O)platinum(II), (2), (eta2-4-allyl-2 methoxyphenol)chlorido(5-nitroquinolin-8-olato-kappa2N,O)platinum(II), (3), and (eta2-4-allyl-2-methoxyphenol)chlorido(5,7-dichloroquinolin-8-olato kappa2N,O)platinum(II), [Pt(C9H4Cl2NO)Cl(C10H12O2)], (4), containing eugenol and a quinolin-8-ol derivative (R-OQ), have been synthesized and characterized by elemental analyses, MS, IR, 1H NMR and NOESY spectra. For (1) and (4), single crystal X-ray diffraction studies were also carried out. Complexes (2)-(4) show good inhibiting abilities on three human cancer cell lines, i.e. KB, Hep-G2 and LU, with IC50 values of 1.42-17.8 uM. Complex (3) gives an impressively high activity against KB, Hep-G2, LU and MCF-7, with IC50 values of 1.42-4.91 uM, which are much lower than those of cisplatin and some other platinum(II) complexes. PMID- 29111538 TI - Hormone levels following surgical and medical castration: defining optimal androgen suppression. PMID- 29111539 TI - External validation and newly development of a nomogram to predict overall survival of abiraterone-treated, castration-resistant patients with metastatic prostate cancer. AB - Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC); however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS). We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%), 34 (30.9%), and 17 (15.5%) in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l-1), liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months) as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678-0.836). In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters. PMID- 29111542 TI - A Call to Action to Develop Integrated Curricula in Cardiorenal Medicine. AB - With the adoption of the new definition and classification of cardiorenal syndrome (CRS) and its relevant subtypes, much attention has been placed on elucidating the mechanisms of heart and kidney interactions. The pathophysiologic pathways are of great interest by which acute heart failure may result in acute kidney injury (AKI; type 1), chronic heart failure accelerates the progression of chronic kidney disease (CKD; type 2), AKI provokes cardiac events (type 3), and CKD increases the risk and severity of cardiovascular disease (type 4). A remarkable interest has also been placed on the acute and chronic systemic conditions, such as sepsis and diabetes, that simultaneously affect heart and kidney function (type 5). Furthermore, the physiology of acute and chronic heart kidney crosstalk is drawing attention to hemodynamics (fluids, pressures, flows, resistances, perfusion), physiochemical (electrolytes, pH, toxins) and biologic (inflammation, immune system activation, neurohormonal signals) processes. Common clinical scenarios call for recognition, knowledge, and skill in managing CRS. There is a clear need for medical and surgical specialists who are well versed in the pathophysiology and clinical manifestations that arise in the setting of CRS. With this editorial, we make a call to action to encourage universities, medical schools, and teaching hospitals to create a core curriculum for cardiorenal medicine to better equip the physicians of the future for these common, serious, and frequently fatal syndromes. PMID- 29111541 TI - Lipoxin A4 improves erectile dysfunction in rats with type I diabetes by inhibiting oxidative stress and corporal fibrosis. AB - Previous studies have shown that oxidative stress and corporal fibrosis in penile tissues of rats were key pathological factors of erectile dysfunction induced by diabetic mellitus (DMED). Lipoxin A4 (LXA4) was reported to inhibit oxidative stress and fibrosis diseases, while whether it could exert a protective role on erectile function was not clear. Type I diabetic mellitus (DM) was induced in thirty male 10-week-old Sprague-Dawley rats using streptozotocin. Ten weeks later, twenty-two rats with DMED confirmed by an apomorphine test were divided into two groups: the DMED group (n = 11) and the DMED + LXA4 group (n = 11; LXA4 injection daily for 4 weeks). In addition, another ten age-matched rats formed the Control group. We found that erectile function was significantly impaired in the DMED group compared with the Control group, but was improved in the DMED + LXA4 group. Similarly, the over-activated oxidative stress and impaired endothelial function in the DMED group were both improved in the DMED + LXA4 group. Moreover, the DMED group showed serious corporal fibrosis, which was also inhibited by the treatment of LXA4 in the DMED + LXA4 group. Taken together, LXA4 could exert an inhibition role on oxidative stress and fibrosis to improve DMED effectively. PMID- 29111540 TI - Transcription and regulation of hepatitis B virus genes in host sperm cells. AB - To investigate whether transcription of hepatitis B virus (HBV) gene occurs in human sperm, total RNA was extracted from sperm of patients with chronic HBV infection (test-1), from donor sperm transfected with a plasmid containing the full-length HBV genome (test-2), and from nontransfected donor sperm (control), used as the template for reverse transcription-polymerase chain reaction (RT PCR). Positive bands for HBV DNA were observed in the test groups but not in the control. Next, to identify the role of host genes in regulating viral gene transcription in sperm, total RNA was extracted from 2-cell embryos derived from hamster oocytes fertilized in vitro by HBV-transfected (test) or nontransfected (control) human sperm and successively subjected to SMART-PCR, suppression subtractive hybridization, T/A cloning, bacterial amplification, microarray hybridization, sequencing and the Basic Local Alignment Search Tool (BLAST) search to isolate differentially expressed genes. Twenty-nine sequences showing significant identity to five human gene families were identified, with chorionic somatomammotropin hormone 2 (CSH2), eukaryotic translation initiation factor 4 gamma 2 (EIF4G2), pterin-4 alpha-carbinolamine dehydratase 2 (PCBD2), pregnancy specific beta-1-glycoprotein 4 (PSG4) and titin (TTN) selected to represent target genes. Using real-time quantitative RT-PCR (qRT-PCR), when CSH2 and PCBD2 (or EIF4G2, PSG4 and TTN) were silenced by RNA interference, transcriptional levels of HBV s and x genes significantly decreased (or increased) (P < 0.05). Silencing of a control gene in sperm did not significantly change transcription of HBV s and x genes (P > 0.05). This study provides the first experimental evidence that transcription of HBV genes occurs in human sperm and is regulated by host genes. PMID- 29111543 TI - Syncope in Young Women: Broadening the Differential Diagnosis. AB - Syncope is defined as a sudden transient loss of consciousness (TLOC) with concomitant loss of postural tone followed by spontaneous recovery. It is a subset of a broader class of medical conditions, including postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension, and neurally mediated syncope (NMS), that may result in TLOC. The overlap of these clinical conditions leads to confusion regarding syncope classification that can hinder evaluation strategies, and pose challenges for diagnosis and treatment, particularly in young women. In this article, we review POTS, orthostatic hypotension, and NMS with an emphasis on NMS. These diverse orthostatic clinical entities may be associated with syncope and are frequently observed in young, healthy women. The importance of considering NMS as a diagnosis of exclusion cannot be overstated. We report a series of three young, otherwise healthy women, initially diagnosed with NMS, whose clinical course evolved over time into more sinister diagnoses that were overlooked and associated with devastating clinical outcomes. These cases highlight the importance of maintaining a broad differential diagnosis when considering the diagnosis of NMS. Each case synopsis provides key clinical features that must be considered to avoid overlooking more serious clinical conditions. PMID- 29111544 TI - Atrioesophageal Fistula Following Radiofrequency Catheter Ablation of Atrial Fibrillation. AB - Atrioesophageal fistula (AEF) is a rare but catastrophic complication of catheter ablation of atrial fibrillation (AF), with an incidence of 0.03% to 1.5% per year. We report two cases and review the epidemiology, clinical features, pathogenesis, and management of AEF after AF ablation. The principal clinical features of AEF include fever, hematemesis, and neurologic deficits within 2 months after ablation. The close proximity of the esophagus to the posterior left atrial wall is considered responsible for esophageal injury during ablation and the eventual development of AEF. Prophylactic proton pump inhibitors, esophageal temperature monitoring, visualization of the esophagus during catheter ablation, esophageal protection devices, esophageal cooling, and avoidance of energy delivery in close proximity to the esophagus are some techniques to prevent esophageal injury. Eliminating esophageal injury during AF ablation is of utmost importance in preventing AEF. A high index of suspicion and early intervention are necessary to prevent fatal outcomes. Early surgical repair is the mainstay of treatment. PMID- 29111545 TI - Novel Ba-hexaferrite structural variations stabilized on the nanoscale as building blocks for epitaxial bi-magnetic hard/soft sandwiched maghemite/hexaferrite/maghemite nanoplatelets with out-of-plane easy axis and enhanced magnetization. AB - Atomic-resolution scanning-transmission electron microscopy showed that barium hexaferrite (BHF) nanoplatelets display a distinct structure, which represents a novel structural variation of hexaferrites stabilized on the nanoscale. The structure can be presented in terms of two alternating structural blocks stacked across the nanoplatelet: a hexagonal (BaFe6O11)2- R block and a cubic (Fe6O8)2+ spinel S block. The structure of the BHF nanoplatelets comprises only two, or rarely three, R blocks and always terminates at the basal surfaces with the full S blocks. The structure of a vast majority of the nanoplatelets can be described with a SR*S*RS stacking order, corresponding to a BaFe15O23 composition. The nanoplatelets display a large, uniaxial magnetic anisotropy with the easy axis perpendicular to the platelet, which is a crucial property enabling different novel applications based on aligning the nanoplatelets with applied magnetic fields. However, the BHF nanoplatelets exhibit a modest saturation magnetization, MS, of just over 30 emu g-1. Given the cubic S block termination of the platelets, layers of maghemite, gamma-Fe2O3, (M), with a cubic spinel structure, can be easily grown epitaxially on the surfaces of the platelets, forming a sandwiched M/BHF/M platelet structure. The exchange-coupled composite nanoplatelets exhibit a remarkably uniform structure, with an enhanced MS of more than 50 emu g-1 while essentially maintaining the out-of-plane easy axis. The enhanced MS could pave the way for their use in diverse platelet-based magnetic applications. PMID- 29111548 TI - Recent progress in the assembly of nanodevices and van der Waals heterostructures by deterministic placement of 2D materials. AB - Designer heterostructures can now be assembled layer-by-layer with unmatched precision thanks to the recently developed deterministic placement methods to transfer two-dimensional (2D) materials. This possibility constitutes the birth of a very active research field on the so-called van der Waals heterostructures. Moreover, these deterministic placement methods also open the door to fabricate complex devices, which would be otherwise very difficult to achieve by conventional bottom-up nanofabrication approaches, and to fabricate fully encapsulated devices with exquisite electronic properties. The integration of 2D materials with existing technologies such as photonic and superconducting waveguides and fiber optics is another exciting possibility. Here, we review the state-of-the-art of the deterministic placement methods, describing and comparing the different alternative methods available in the literature, and we illustrate their potential to fabricate van der Waals heterostructures, to integrate 2D materials into complex devices and to fabricate artificial bilayer structures where the layers present a user-defined rotational twisting angle. PMID- 29111549 TI - Dynamic covalent bonding-triggered supramolecular gelation derived from tetrahydroxy-bisurea derivatives. AB - A new class of bisurea derivatives bearing tetrahydroxy groups have been proven to be non-gelators in water and various organic solvents even under long-term sonication or efficient heating treatment. We found that it is possible to trigger physical gelation behaviour by constructing dynamic covalent bonding. The results show that formation of dynamic covalent bonding between the borate anion and ethanediol substituent in these bisurea derivatives brings about rapid physical gelation at ambient temperature in a mixture of DMSO and water. During dynamic covalent bonding-triggered gelation, the stepgrowth polymerization from the B-O bonds would increase the size of the molecules and reduce the entropy of mixing as well as facilitate ion-dipole interactions in the linear polymeric gelators. They would drive a self-assembly transition and boost the construction of gel networks in coordination with alpha-tape urea-urea hydrogen bonding. The gelation mechanism was explored by 1H NMR, FTIR and rheology techniques. Moreover, the resulting gels are transparent and thixotropic, and could be turned into the sol state under CO2 or water-stimulus. Furthermore, they are stable in the presence of HAuCl4 and alkali. Therefore, they would afford another new medium for the growth of Au nanocrystals via in situ reduction and a new sensing medium for detecting Hg2+ ions. PMID- 29111552 TI - Novel core-shell-like nanocomposites xCu@Cu2O/MgAlO-rGO through an in situ self reduction strategy for highly efficient reduction of 4-nitrophenol. AB - A series of novel hierarchical nanocomposite catalysts xCu@Cu2O/MgAlO-rGO were fabricated by calcination of CuxMg3-xAl-LDH/rGO precursors (LDH: layered double hydroxide, rGO: reduced graphene oxide, and x = 0.5, 1.0, and 1.5), obtained by a facile citric acid-assisted coprecipitation route, under a N2 flow upon in situ self-reduction of lattice atomic-dispersed Cu2+ by rGO. Systematic characterization reveals highly dispersed core-shell-like Cu@Cu2O nanoparticles near the border between vertically interconnected mixed oxide MgAlO nanoplates and rGO layers. All the obtained catalysts show extraordinary catalytic performances for the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) at room temperature. The 1.0Cu@Cu2O/MgAlO-rGO shows the highest activity for complete conversion of 4-NP with an apparent rate constant (kapp) of 55.3 * 10-3 s-1, a normalized rate constant (knor) of 14 497 s-1 g-1 on an active Cu content, and an unprecedented recycling stability for 25 successive cycles, which are superior to those of the recently reported Cu- and Co-based metal nanoparticles and even compared favourably with those of the most active noble metal catalysts. The superior activity of 1.0Cu@Cu2O/MgAlO-rGO can be attributed to the highly dispersed core-shell-like Cu@Cu2O nanoparticles and the greatly enhanced four phase synergistic effect among Cu, Cu2O, MgAlO and rGO upon calcination. Moreover, 1.0Cu@Cu2O/MgAlO-rGO shows an excellent efficiency in the fixed bed system for the treatment of simulated industrial effluents containing nitrophenols and organic dyes. The present cost-effective, highly efficient and reusable non-noble metal nanocatalyst would open a new pathway for future water remediation. PMID- 29111553 TI - Ligands for f-element extraction used in the nuclear fuel cycle. AB - Liquid-liquid extraction is the major technique being applied for the partitioning of f-elements from nuclear waste. In this review, the recent developments in ligand design, optimization and extraction properties are summarised for the main classes of extractants (organophosphorus ligands, diamides and N-heterocycles), with a focus on the separation of actinides and lanthanides. Structural modifications, pre-organisation and different solvent systems, as key factors for the fine-tuning of the extraction properties, are discussed. From this review, it appears that small modifications of the structure of the ligand, the pre-organising platform or the solvent can have significant impact on the extraction (and separation) of metal ions. Interest in the combinations of ligands for the extraction processes is growing, since they provide improvements over individual ligands. Similarly, unconventional approaches are being pursued to develop more efficient and greener processes. PMID- 29111555 TI - Structure-dependent SERS activity of plasmonic nanorattles with built-in electromagnetic hotspots. AB - Hollow plasmonic nanostructures with built-in and accessible electromagnetic hotspots such as nanorattles, obtained through a galvanic replacement reaction, have received wide attention in chemical and biological sensing and targeted drug delivery. In this study, we investigate the surface enhanced Raman scattering (SERS) activity of plasmonic nanorattles obtained through different degrees of galvanic replacement of Au@Ag nanocubes. We found that the SERS efficacy of the nanorattles is governed by the plasmon extinction intensity, localized surface plasmon resonance (LSPR) wavelength of the nanostructures with respect to the excitation source and intensity of the electromagnetic field at the hotspot, with the latter playing a determining role. Finite-difference time-domain (FDTD) simulations showed excellent agreement with the experimental findings that an optimal degree of galvanic replacement is critical for maximum SERS enhancement. The rational design and synthesis of the plasmonic nanorattles based on these findings can make these nanostructures highly attractive for SERS-based chemical and biological sensing and bioimaging. PMID- 29111554 TI - Sulforaphane protects MLE-12 lung epithelial cells against oxidative damage caused by ambient air particulate matter. AB - Ambient air particulate matter with aerodynamic diameters <=2.5 MUm (PM2.5) can cause pulmonary injury. Oxidative stress is thought to be an important mechanism of PM2.5-mediated toxicity. Sulforaphane (SFN), a compound derived from cruciferous vegetables, is a well-known potent antioxidant; however, its protective effect on lung epithelial cells exposed to PM2.5 is unclear. The results showed that SFN pre-treatment markedly inhibited PM2.5-induced apoptosis of the type II alveolar epithelial cell line MLE-12 by elevating glutathione S transferase levels and decreasing reactive oxygen species. SFN pre-treatment down regulated the expression of the pro-apoptotic proteins Bax and Bad, and reduced the activity of caspase-3, while it up-regulated the expression of the anti apoptotic protein Bcl-2. Moreover, SFN induced the activation of the Akt and ERK pathways, and up-regulated the expression of Nrf2 and its downstream antioxidant genes NQO-1 and HO-1. This is the first study to demonstrate that SFN could protect MLE-12 cells against PM2.5-induced oxidative damage via activation of the Nrf2 pathway and inhibition of the mitochondrial apoptotic pathway; therefore, SFN may be a promising compound for preventing PM2.5-triggered pulmonary cell damage. PMID- 29111556 TI - Mechano-responsive lateral buckling of miniaturized beams standing on flexible substrates. AB - We fabricate an elastomeric beam standing on a flexible substrate using 3D printing and soft lithography and investigate lateral buckling generated in the part of the wall when this beam is under pure bending. We also observe changes in the morphology of wrinkling along the applied strain and geometry of the wall, and then analyze it with scaling concepts. Furthermore, the degree of lateral buckling is controlled through the tip design in the ratchet structure and it is verified with finite element simulation. Based on this, a millimeter scale device with a visual difference according to the curvature is manufactured. PMID- 29111557 TI - A novel perovskite solar cell design using aligned TiO2 nano-bundles grown on a sputtered Ti layer and a benzothiadiazole-based, dopant-free hole-transporting material. AB - This work highlights the utilization of a novel hole-transporting material (HTM) derived from benzothiadiazole: 4-(3,5-bis(trifluoromethyl)phenyl)-7-(5'-hexyl [2,2'-bithiophen]-5-yl)benzo[c][1,2,5]thiadiazole (CF-BTz-ThR) and aligned TiO2 nano-bundles (TiO2 NBs) as the electron transporting layer (ETL) for perovskite solar cells (PSCs). The aligned TiO2 NBs were grown on titanium (Ti)-coated FTO substrates using a facile hydrothermal method. The newly designed CF-BTz-ThR molecule with suitable highest occupied molecular orbital (HOMO) favored the effective hole injection from perovskite deposited aligned TiO2 NBs thin film. The PSCs demonstrated a power conversion efficiency (PCE) of ~15.4% with a short circuit current density (Jsc) of ~22.42 mA cm-2 and an open circuit voltage (Voc) of ~1.02 V. The efficiency data show the importance of proper molecular engineering whilst highlighting the advantages of dopant-free HTMs in PSCs. PMID- 29111558 TI - The development of phytosterol-lecithin mixed micelles and organogels. AB - We demonstrate that by mixing the phytosterol-ester oryzanol with lecithin in an organic solvent, both components may be dispersed at much higher concentrations than they may be individually. Dynamic light scattering and molecular dynamics simulations show that the mechanism for this is the formation of r ~ 4 nm mixed micelles. Infrared spectroscopy and simulations suggest that these micelles are formed due in part to hydrogen bonding of the phosphate of the lecithin head group, and the phenol group of the oryzanol. Rheology shows that by mixing these materials at an equimolar ratio, highly viscous suspensions are created. Furthermore, by adding water to these samples, a solid-like gel may be formed which offers mechanical properties close to those desired for a margarine type spread, whilst still solubilizing the oryzanol. PMID- 29111559 TI - Tetrazolylpyrene unnatural nucleoside as a human telomeric multimeric G quadruplex selective switch-on fluorescent sensor. AB - We report herein the specific sensing of dimeric H45 G-quadruplex DNA via a fluorescence light-up response using fluorescent tetrazolylpyrene nucleoside (TzPyBDo) as a probe. The strong binding of the probe via an intercalative stacking interaction inside the connecting loop of two G-quadruplex units of H45 and the discrimination to other monomeric and long DNA duplexes are accompanied by a drastic enhancement of the emission intensity without compromising the conformation and stability. PMID- 29111560 TI - Identification of a novel mutation in ARSA gene in three patients of an Iranian family with metachromatic leukodystrophy disorder. AB - Metachromatic leukodystrophy disorder (MLD) is an autosomal recessive and lysosomal storage disease. The disease is caused by the deficiency of the enzyme arylsulfatase A (ARSA) which is encoded by the ARSA gene. Different mutations have been reported in different populations. The present study was aimed to detect the mutation type of the ARSA gene in three relative Iranian patients. We found a novel homozygous missense mutation c.1070 G > T (p.Gly357Val) in exon 6 of these patients. The mutation was found to be reported for the first time in MLD patients. The data can update the mutation profile and contribute toward improved clinical management and counseling of MLD patients. PMID- 29111562 TI - Expression analysis on 14-3-3 proteins in regenerative liver following partial hepatectomy. AB - 14-3-3 proteins play a vital part in the regulation of cell cycle and apoptosis as signaling integration points. During liver regeneration, the quiescent hepatocytes go through hypertrophy and proliferation to restore liver weight. Therefore, we speculated that 14-3-3 proteins regulate the progression of liver regeneration. In this study, we analyzed the expression patterns of 14-3-3 proteins during liver regeneration of rat to provide an insight into the regenerative mechanism using western blotting. Only four isoforms (gamma, epsilon, sigma and tau/theta) of the 14-3-3 proteins were expressed in regenerative liver after partial hepatectomy (PH). The dual effects, the significant down-regulation of 14-3-3epsilon and the significant up-regulation of 14-3-3tau/theta at 2 h after PH, might play particularly important roles in S phase entry. The significant peaks of 14-3-3sigma at 30 h and of epsilon and tau/theta at 24 h might be closely related not only to the G2/M transition but also to the size of hepatocytes. Possibly, the peak of 14-3-3epsilon expression seen at 168 h plays critical roles in the termination of liver regeneration by inhibiting cellular proliferation. PMID- 29111561 TI - GSTT1 and GSTM1 null variants in Mestizo and Amerindian populations from northwestern Mexico and a literature review. AB - The GSTT1 and GSTM1 genes are key molecules in cellular detoxification. Null variants in these genes are associated with increase susceptibility to developing different types of cancers. The aim of this study was to determine the prevalence of GSTT1 and GSTM1 null genotypes in Mestizo and Amerindian individuals from the Northwestern region of Mexico, and to compare them with those reported worldwide. GSTT1 and GSTM1 null variants were genotyped by multiplex PCR in 211 Mestizos and 211 Amerindian individuals. Studies reporting on frequency of GSTT1 and GSTM1 null variants worldwide were identified by a PubMed search and their geographic distribution were analyzed. We found no significant differences in the frequency of the null genotype for GSTT1 and GSM1 genes between Mestizo and Amerindian individuals. Worldwide frequencies of the GSTT1 and GSTM1 null genotypes ranges from 0.10 to 0.51, and from 0.11 to 0.67, respectively. Interestingly, in most countries the frequency of the GSTT1 null genotype is common or frequent (76%), whereas the frequency of the GSMT1 null genotype is very frequent or extremely frequent (86%). Thus, ethnic-dependent differences in the prevalence of GSTT1 and GSTM1 null variants may influence the effect of environmental carcinogens in cancer risk. PMID- 29111563 TI - Multiple genes contribute to anhydrobiosis (tolerance to extreme desiccation) in the nematode Panagrolaimus superbus. AB - The molecular basis of anhydrobiosis, the state of suspended animation entered by some species during extreme desiccation, is still poorly understood despite a number of transcriptome and proteome studies. We therefore conducted functional screening by RNA interference (RNAi) for genes involved in anhydrobiosis in the holo-anhydrobiotic nematode Panagrolaimus superbus. A new method of survival analysis, based on staining, and proof-of-principle RNAi experiments confirmed a role for genes involved in oxidative stress tolerance, while a novel medium-scale RNAi workflow identified a further 40 anhydrobiosis-associated genes, including several involved in proteostasis, DNA repair and signal transduction pathways. This suggests that multiple genes contribute to anhydrobiosis in P. superbus. PMID- 29111564 TI - Relationship between XPD, RAD51, and APEX1 DNA repair genotypes and prostate cancer risk in the male population of Rio de Janeiro, Brazil. AB - Susceptibility to cancer ensues in individuals carrying malfunctioning DNA repair mechanisms. The impact of Single Nucleotide Polymorphisms (SNPs) in key DNA repair mechanisms on risk for prostate cancer was investigated in this case control study. Samples consisted of 110 patients with confirmed prostate cancer and 200 unaffected men, from Rio de Janeiro, Brazil. XPD/Lys751Gln (rs13181), APEX1/Asp148Glu (rs1130409), and RAD51/G135C (rs1801320) SNPs were analyzed by PCR-RFLP. Allelic and genotypic frequencies were calculated and compared by Chi Square test. The association between SNPs and clinical/epidemiological data was considered significant by Odds Ratio analysis, with IC95% and a p-value<=0.05. Only the XPD/Lys751Gln SNP significantly increased susceptibility to disease in southeastern Brazilian men, with p<=0.001 [OR=2.36 (1.46-3.84)], with no association with APEX1 or RAD51 SNPs. Combined XPD+RAD51 SNPs were highly associated with the disease, p<=0.005 [OR=3.40 (1.32-9.20)]. A Chi-Square significant association between XPD/Lys751Gln and Gleason score was also observed (OR=9.31; IC95%=1.19-428.0; p=0.022). Epidemiological inquiries revealed that exposure to pesticides significantly impacted the risk for prostate cancer in this population. DNA repair dysfunctions seem to prevail among workers exposed to chemical byproducts to cancer in this specific tissue. Non-invasive genotyping SNPs may help assessment of prostate cancer risk in environmentally exposed populations. PMID- 29111566 TI - Complete sequence and comparative analysis of the chloroplast genome of Plinia trunciflora. AB - Plinia trunciflora is a Brazilian native fruit tree from the Myrtaceae family, also known as jaboticaba. This species has great potential by its fruit production. Due to the high content of essential oils in their leaves and of anthocyanins in the fruits, there is also an increasing interest by the pharmaceutical industry. Nevertheless, there are few studies focusing on its molecular biology and genetic characterization. We herein report the complete chloroplast (cp) genome of P. trunciflora using high-throughput sequencing and compare it to other previously sequenced Myrtaceae genomes. The cp genome of P. trunciflora is 159,512 bp in size, comprising inverted repeats of 26,414 bp and single-copy regions of 88,097 bp (LSC) and 18,587 bp (SSC). The genome contains 111 single-copy genes (77 protein-coding, 30 tRNA and four rRNA genes). Phylogenetic analysis using 57 cp protein-coding genes demonstrated that P. trunciflora, Eugenia uniflora and Acca sellowiana form a cluster with closer relationship to Syzygium cumini than with Eucalyptus. The complete cp sequence reported here can be used in evolutionary and population genetics studies, contributing to resolve the complex taxonomy of this species and fill the gap in genetic characterization. PMID- 29111565 TI - Transcriptome sequencing analysis of alfalfa reveals CBF genes potentially playing important roles in response to freezing stress. AB - Alfalfa (Medicago sativa L.) is an important perennial forage, with high nutritional value, which is widely grown in the world. Because of low freezing tolerance, its distribution and production are threatened and limited by winter weather. To understand the complex regulation mechanisms of freezing tolerance in alfalfa, we performed transcriptome sequencing analysis under cold (4 degrees C) and freezing (-8 degrees C) stresses. More than 66 million reads were generated, and we identified 5767 transcripts differentially expressed in response to cold and/or freezing stresses. These results showed that these genes were mainly classified as response to stress, transcription regulation, hormone signaling pathway, antioxidant, nodule morphogenesis, etc., implying their important roles in response to cold and freezing stresses. Furthermore, nine CBF transcripts differentially expressed were homologous to CBF genes of Mt-FTQTL6 site, conferring freezing tolerance in M. truncatula, which indicated that a genetic mechanism controlling freezing tolerance was conservative between M. truncatula and M. sativa. In summary, this transcriptome dataset highlighted the gene regulation response to cold and/or freezing stresses in alfalfa, which provides a valuable resource for future identification and functional analysis of candidate genes in determining freezing tolerance. PMID- 29111567 TI - A computer vision for animal ecology. AB - A central goal of animal ecology is to observe species in the natural world. The cost and challenge of data collection often limit the breadth and scope of ecological study. Ecologists often use image capture to bolster data collection in time and space. However, the ability to process these images remains a bottleneck. Computer vision can greatly increase the efficiency, repeatability and accuracy of image review. Computer vision uses image features, such as colour, shape and texture to infer image content. I provide a brief primer on ecological computer vision to outline its goals, tools and applications to animal ecology. I reviewed 187 existing applications of computer vision and divided articles into ecological description, counting and identity tasks. I discuss recommendations for enhancing the collaboration between ecologists and computer scientists and highlight areas for future growth of automated image analysis. PMID- 29111568 TI - The use of single recipient internal mammary vessels for bilateral diep flap breast reconstruction in a recipient-vessel-depleted patient. PMID- 29111569 TI - The influence of immunosuppressants on direct-acting antiviral therapy is dependent on the hepatitis C virus genotype. AB - BACKGROUND: Direct-acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified. METHODS: Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real-time polymerase chain reaction or luciferase assay. RESULTS: Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P <= .01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P <= .01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT. CONCLUSION: For patients with HCV GT2a, GT3a, or GT4a infection, mTOR-based immunosuppressive therapy may be beneficial. CNI-based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection. PMID- 29111570 TI - The killer cell lectin-like receptor B1 (KLRB1) 503T>C polymorphism (rs1135816) and acute rejection after liver transplantation. AB - The killer cell lectin-like receptor B1 (KLRB1) gene encodes for CD161 expressed by different subsets of leukocytes involved in the development of acute liver transplant rejection. The single nucleotide polymorphism (SNP) 503T>C (rs1135816) in the KLRB1 gene represents a missense mutation modifying functional properties of CD161. The aim of our study is to determine whether the SNP 503T>C is associated with acute liver transplant rejection. We genotyped the SNP for 163 liver recipients without acute rejection, 125 recipients with a single acute rejection, and 53 recipients with multiple acute rejections. The genotype frequencies within the groups did not show any significant difference. Our data suggest that the SNP 503T>C has no impact on the susceptibility of acute liver transplant rejection. PMID- 29111571 TI - N4 -aryl substituted thiosemicarbazones derived from 1-indanones as potential anti-tumor agents for breast cancer treatment. AB - Breast cancer is the first cause of cancer death in women. Many patients are resistant to current therapies, and even those were sensitive at first may eventually become resistant later. Thiosemicarbazones (TSCs) are synthetic compounds that exhibit several pharmacological activities. In this study, we investigated the potential anti-tumor activity of a set of N4 -arylsubstituted TSCs (N4 -TSCs) on human breast cancer cell lines. Studies on the effect of N4 TSCs (T1, T2, and T3) were carried on MCF-7, MDA-MB 231, and BT 474 cell lines which differ in their expression of ER, PR, and Her2/neu. Non-transformed MCF-10A breast cell line were used as normal cells. Action of N4 -TSCs were evaluated by proliferation assay, quantification of apoptosis and cell cycle analysis. Modulation of clonogenic efficiency and migratory capacity by N4 -TSCs were also evaluated. We further investigated the effects of N4 -TSCs on ROS level and Ribonucleotide Reductase (RR) activity. We analyzed the action of these compounds on cellular mammosphere-forming capacity. We found that T1 and T2 had specific anti-tumor effect on all breast cancer cell lines based on their pro-apoptotic action and inhibitory effect on clonogenic efficiency and cell migration capacity. We also showed that both compounds increased ROS level and inhibited RR activity. Finally, we found that all N4 -TSCs diminished mammospehere-forming capacity of MCF-7 and BT 474 cells. N4 -TSCs showed specific anti-tumor action on human breast cancer cells independently their biomarkers expression pattern. Our results place these compounds as promising novel anti-tumor drugs with potential therapeutic application against different types of breast cancer. PMID- 29111572 TI - Corrigendum. PMID- 29111575 TI - Can Bilingualism Mitigate Set-Shifting Difficulties in Children With Autism Spectrum Disorders? AB - This study investigated the effects of bilingualism on set-shifting and working memory in children with autism spectrum disorders (ASD). Bilinguals with ASD were predicted to display a specific bilingual advantage in set-shifting, but not working memory, relative to monolinguals with ASD. Forty 6- to 9-year-old children participated (20 ASD, 20 typically-developing). Set-shifting was measured using a computerized dimensional change card sort (DCCS) task, and by parent report of executive functioning in daily life. Results showed an advantage for bilingual relative to monolingual children with ASD on the DCCS task, but not for set-shifting in daily life. Working memory was similar for bilinguals and monolinguals with ASD. These findings suggest that bilingualism may mitigate some set-shifting difficulties in children with ASD. PMID- 29111576 TI - Oxidative stress induces renal failure: A review of possible molecular pathways. AB - It has been reported that oxidative stress has a pivotal role in many disorders such as chronic kidney diseases. Free radicals can directly attack cellular elements, trigger intracellular signaling pathways, or induce systemic responses leading to renal damages. In the current review, we evaluated the literature focusing on the main recognized effects of oxidative stress on the pathophysiology of chronic renal disorders. We searched the PubMed-Medline and Scopus databases by using the following key words: oxidative stress, kidney, chronic kidney diseases, and free radicals and found about 200 related articles. Then, we focused on the molecular mechanisms underlying chronic kidney diseases which can be induced by oxidative stress and explored how free radicals stimulate these mechanisms. By reviewing the literature, we found that there are almost nine important molecular pathways through which free radicals influence the renal function. Based on the retrieved data, oxidative stress has an important role in the pathophysiology of chronic kidney diseases. Understanding these pathophysiologic pathways may lead us to find new approaches for the management of these debilitating disorders. PMID- 29111574 TI - Laccase-Mediated Grafting on Biopolymers and Synthetic Polymers: A Critical Review. AB - Laccase-mediated grafting on lignocelluloses has gained considerable attention as an environmentally benign method to covalently modify wood, paper and cork. In recent decades this technique has also been employed to modify fibres with a polysaccharide backbone, such as cellulose or chitosan, to infer colouration, antimicrobial activity or antioxidant activity to the material. The scope of this approach has been further widened by researchers, who apply mediators or high redox potential laccases and those that modify synthetic polymers and proteins. In all cases, the methodology relies on one- or two-electron oxidation of the surface functional groups or of the graftable molecule in solution. However, similar results can very often be achieved through simple deposition, even after extensive washing. This unintended adsorption of the active substance could have an adverse effect on the durability of the applied coating. Differentiating between actual covalent binding and adsorption is therefore essential, but proves to be challenging. This review not only covers excellent research on the topic of laccase-mediated grafting over the last five to ten years, but also provides a critical comparison to highlight either the lack or presence of compelling evidence for covalent grafting. PMID- 29111578 TI - Anomalous bioaccumulation of lead in the earthworm Eisenoides lonnbergi (Michaelsen). AB - Lead concentrations in soil organisms are usually well below those in the associated soil and tend to decrease with each higher trophic level in a food chain. Earthworms of the species Eisenoides lonnbergi provide an exception to this observation, accumulating very high concentrations of lead from acidic soils. Earthworms belonging to this species were collected from strongly to extremely acidic soils at 16 sites on a wildlife refuge in Maryland, USA. A lead concentration as high as 766 mg/kg, dry weight, was detected in depurated E. lonnbergi collected from soil containing only 17 mg/kg of lead. Concentration factors (ratio of lead concentration in earthworms to lead concentration in soil, dry wt) were highly variable at the sites, from 1.0 to 83. As suggested previously, lead absorption by earthworms is enhanced in low-calcium soils. The anomalously high concentrations of lead found in E. lonnbergi are more closely correlated with the uptake of calcium from acidic soils than with bioaccessibility of soil lead. Environ Toxicol Chem 2018;37:914-919. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 29111577 TI - Applications of Acupuncture Therapy in Modulating Plasticity of Central Nervous System. AB - OBJECTIVE: Acupuncture is widely applied for treatment of various neurological disorders. This manuscript will review the preclinical evidence of acupuncture in mediating neural plasticity, the mechanisms involved. MATERIALS AND METHODS: We searched acupuncture, plasticity, and other potential related words at the following sites: PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and VIP information data base. The following keywords were used: acupuncture, electroacupuncture, plasticity, neural plasticity, neuroplasticity, neurogenesis, neuroblast, stem cell, progenitor cell, BrdU, synapse, synapse structure, synaptogenesis, axon, axon regeneration, synaptic plasticity, LTP, LTD, neurotrophin, neurotrophic factor, BDNF, GDNF, VEGF, bFGF, EGF, NT-3, NT-4, NT-5, p75NTR, neurotransmitter, acetylcholine, norepinephrine, noradrenaline, dopamine, monamine. We assessed the effects of acupuncture on plasticity under pathological conditions in this review. RESULTS: Relevant references were reviewed and presented to reflect the effects of acupuncture on neural plasticity. The acquired literatures mainly focused on neurogenesis, alterations of synapses, neurotrophins (NTs), and neurotranimitters. Acupuncture methods mentioned in this article include manual acupuncture and electroacupuncture. CONCLUSIONS: The cumulative evidences demonstrated that acupuncture could induce neural plasticity in rodents exposed to cerebral ischemia. Neural plasticity mediated by acupuncture in other neural disorders, such as Alzheimer's disease, Parkinson's disease, and depression, were also investigated and there is evidence of positive role of acupuncture induced plasticity in these disorders as well. Mediation of neural plasticity by acupuncture is likely associated with its modulation on NTs and neurotransmitters. The exact mechanisms underlying acupuncture's effects on neural plasticity remain to be elucidated. Neural plasticity may be the potential bridge between acupuncture and the treatment of various neurological diseases. PMID- 29111579 TI - Knowledge and perceptions of Zika virus among reproductive-aged women after public announcement of local mosquito-borne transmission. AB - AIM: This study was conducted to ascertain the knowledge and perceptions of the Zika virus among reproductive-aged women living in the first affected area of the United States with local mosquito-borne transmission. METHODS: Reproductive-aged women were surveyed during the four weeks immediately following the announcement of local Zika virus transmission. The survey evaluated the participant's knowledge of Zika pathogenesis and transmission, sequelae of infection, epidemiology and public health information. RESULTS: Fifty-nine women (age range 18-45) completed the survey. Most patients (n = 53, 89.8%) had received information about the Zika virus from the media rather than clinicians. In 93% of the questions, a high level of knowledge was demonstrated by the participants. Personal concern about becoming infected with the Zika virus was significantly higher in those considering pregnancy (n = 13, 86.7% vs n = 21, 47.7%; P = 0.01). CONCLUSION: In the weeks following recognized local transmission of the Zika virus in the continental United States, reproductive-aged women had a high level of knowledge of the Zika virus, but those considering pregnancy harbored the greatest concern of personal risk of infection. PMID- 29111581 TI - Deactivation and Regeneration of NaTaO3 Photocatalyst in Cooperating Dehydrogenation Coupling of Isopropanol and Hydrogenation Coupling of Acetone Reaction System. AB - Photocatalyst activity is influenced by many factors, such as adsorption of by products, runoff of surface hydroxyl groups and carriers. In this study, a simple and efficient photocatalyst regeneration method was developed. Results indicated that NaTaO3 photocatalyst lost its photoactivity after three cycles of reaction that involves coupling of isopropanol and hydrogenation coupling of acetone reaction system. Runoff of Na on the surface was the main reason for the deactivation of NaTaO3 photocatalyst. After hydrothermal treatment of the deactivated NaTaO3 with 10 m NaOH at 180 degrees C for 12 h, its photocatalytic activity was restored to the original level. The photocatalytic activity remained stable even after 10 cycles. PMID- 29111580 TI - Drug residues in used syringes in Switzerland: A comparative study. AB - Harm reduction services, including needle-exchange programmes, have been implemented in Switzerland for over 20 years. Their main aim is to lessen the negative social and/or physical consequences associated with illicit drug consumption and, therefore, improve prevention messages. To this end, knowledge of illicit drug consumption practices is necessary. Periodic self-report surveys are the primary source of data for monitoring drug users' behaviour. Analysis of residual content of used syringes can bring further and objective knowledge about consumed products through analytically confirmed data. Used syringes were sampled in 2 syringe-exchange facilities in Lausanne. These structures are a bus where the users bring back their syringes (ABS) and an automatic injecting kit dispenser (AIKD). Once syringes were collected, a validated gas chromatography mass spectrometry (GC-MS) method was implemented in order to detect drugs (licit or illicit) contained in the residual content of used syringes. Cocaine was the most common drug detected alone (39% in ABS and 31% in AIKD), followed by the simultaneous detection of heroin and cocaine (12% and 17%) and heroin and midazolam (12% and 17%). The differences between the illicit drugs distribution of used syringes collected in AIKD and ABS were not statistically significant. Analysis of residual content of used syringes as a monitoring tool is an original approach that has already led to a better understanding of the habits of drug injection users. Over the long term, this approach is a powerful tool to track and detect new consumption practices in a quasi-real-time. PMID- 29111582 TI - Utilizing break-even analysis in a competitive laser market. PMID- 29111583 TI - From Peptide Fragments to Whole Protein: Copper(II) Load and Coordination Features of IAPP. AB - The copper-binding features of rat islet amyloid polypeptide (r-IAPP) are herein disclosed through the determination of the stability constants and spectroscopic properties of its copper complex species. To mimic the metal binding sites of the human IAPP (h-IAPP), a soluble, single-point mutated variant of r-IAPP, having a histidine residue in place of Arg18, was synthesized, that is, r-IAPP(1-37; R18H). The peptide IAPP(1-8) was also characterized to have deeper insight into the N-terminus copper(II)-binding features of r-IAPP as well as of its mutated form. A combined experimental (thermodynamic and spectroscopic) and computational approach allowed us to assess the metal loading and the coordination features of the whole IAPP. At physiological pH, the N-terminal amino group is the Cu2+ main binding site both of entire r-IAPP and of its mutated form that mimics h-IAPP. The histidine residue present in this mutated polypeptide accounts for the second Cu2+ binding. We can speculate that the copper driven toxicity of h-IAPP in comparison to that of r-IAPP can be attributed to the different metal loading and the presence of a second metal anchoring site, the His18 , whose role is usually invoked in the process of h-IAPP aggregation. PMID- 29111584 TI - Recent applications of gas chromatography with high-resolution mass spectrometry. AB - Gas chromatography coupled to high-resolution mass spectrometry is a powerful analytical method that combines excellent separation power of gas chromatography with improved identification based on an accurate mass measurement. These features designate gas chromatography with high-resolution mass spectrometry as the first choice for identification and structure elucidation of unknown volatile and semi-volatile organic compounds. Gas chromatography with high-resolution mass spectrometry quantitative analyses was previously focused on the determination of dioxins and related compounds using magnetic sector type analyzers, a standing requirement of many international standards. The introduction of a quadrupole high-resolution time-of-flight mass analyzer broadened interest in this method and novel applications were developed, especially for multi-target screening purposes. This review is focused on the development and the most interesting applications of gas chromatography coupled to high-resolution mass spectrometry towards analysis of environmental matrices, biological fluids, and food safety since 2010. The main attention is paid to various approaches and applications of gas chromatography coupled to high-resolution mass spectrometry for non-target screening to identify contaminants and to characterize the chemical composition of environmental, food, and biological samples. The most interesting quantitative applications, where a significant contribution of gas chromatography with high resolution mass spectrometry over the currently used methods is expected, will be discussed as well. PMID- 29111585 TI - Tear ferning test in healthy dogs. AB - PURPOSE: To evaluate and compare three tear sampling methods using two grading scales for administering the tear ferning test (TFT) to healthy dogs. METHODS: In total, 90 dogs (180 eyes) were subjected to tear sampling using millimetered strips, reused after the Schirmer tear test (STT) (Schirmer group, SG). Then, the dogs were subdivided into three groups according to sampling approach: micropipette (MPG), microcapillary (MCG), and Schirmer sample 2 (S2G). The collected tears were dried on a clean microscope glass slide at room temperature and humidity. The ferning patterns were observed under a polarized light microscope and classified according to the Rolando and Masmali grading scales. RESULTS: Although all three methods were feasible, the STT was easier to perform in clinical settings. Type I and Grade 1 were the most commonly observed (64.17% and 61.7%, respectively) regardless of collection method. There was no significant difference between the STT median values and the TFT classifications. CONCLUSIONS: The TFT is appropriate for dogs and can be performed using the three suggested sampling methods, with a higher frequency of Type I and Grade 1. Thus, it is possible to use both grading scales in the classification of tear ferning in dogs. PMID- 29111586 TI - An unusual case of feline acute corneal hydrops: atypical disease presentation and possible in vivo detection of Descemet's membrane detachment in the cat's unaffected eye. AB - A 1-year-old, female spayed, domestic shorthair cat presented for blepharospasm of the right eye. Slit-lamp biomicroscopic examination showed focal corneal ulceration and presumptive keratomalacia of the right eye. Examination of the left eye was normal apart from a focal endothelial opacity. Within the first 24 h of medical management, the right eye developed marked corneal edema and globular anterior protrusion of the corneal surface consistent with feline acute corneal hydrops (FACH). Surgical management consisted of a bridge conjunctival graft, nictitating membrane flap, and temporary tarsorrhaphy. Resolution of corneal edema and pain occurred in the right eye within 24 days. Spectral domain optical coherence tomography (SD-OCT) of the anterior segment was performed in both eyes. Conjunctival tissue from the bridge graft precluded examination of deeper corneal structures in the right eye. The left eye displayed a focal separation of the corneal endothelium and Descemet's membrane from the overlying stroma. These SD OCT findings are similar to the analogous syndrome found in humans and represent a potential etiology for FACH of the right eye in the case presented here. Unfortunately, the cat was lost to follow-up and the progression of this lesion to FACH in the left eye could not be determined. PMID- 29111587 TI - Multifractal Approaches of the Ring Tensile Rupture Patterns of Dried Laver (Porphyra) as Affected by the Relative Humidity. AB - : The effect of water activity (aw ) or the relative humidity (RH) on the tensile rupture properties of dried laver (DL) associated with structures formed with phycocolloids was investigated. The morphological characteristics of tensile ruptured DL samples at various relative humidities were evaluated by multifractal analysis. The RH of the microclimate was controlled from 10% to 90% at 25 degrees C using supersaturated salt solutions. The sorption isotherm of DL was experimentally obtained and quantitatively analyzed using mathematical models. The monolayer moisture contents from the Guggenheim-Anderson-de Boer (GAB) model was 5.92% (w.b.). An increase in the RH resulted in increasing ring tensile stress and maintaining constant ring tensile strain up to 58% to 75% RH, whereas the ring tensile stress and the ring tensile strain rapidly decreased and increased, respectively, when the RH was higher than 75%. The general fractal dimensions and the multifractal spectra f(alpha) manifested that the patterns of the lowest and the highest moisture content of dried laver showed high irregularity. The different multifractal parameters obtained from the DL at various RHs well-represented the transient moment of the structures from the monolayer moisture to texture changes associated with RH. Overall, the ring tensile test and the multifractal analysis were useful tools to analyze the change of crispness of DL from its structural characteristics. In addition, the results of this study revealed that the integration and disintegration properties of DL occurred through the networks of phycocolloids at various moisture contents. PRACTICAL APPLICATION: Texture properties are the most important quality attributes for commercial dried laver (DL) products. The relative humidity influences the texture properties of DL during production, storage, shipping, and consuming. This study well characterized the effect of the relative humidity on the texture properties of DL using the tensile tests under microclimate conditions. This information is very practical and can be immediately applied to control the relative humidity of the packaging and the storage room for DL. PMID- 29111588 TI - Investigations of Phlebotomus perniciosus sand flies in rural Spain reveal strongly aggregated and gender-specific spatial distributions and advocate use of light-attraction traps. AB - The spatial and temporal distribution of Phlebotomus perniciosus (Diptera: Psychodidae) (Newstead, 1911), the sand fly vector of pathogens of public and animal health importance, was investigated in a high sand fly density rural area in Spain using light-attraction and sticky-interception traps. Traps were placed inside animal buildings and outside at increasing distance from animals. A total of 8506 sand flies were collected, 87% with light traps. Species frequency differed between trap types. The abundance of P. perniciosus decreased exponentially with increasing distance to animals and, while females were most common in the animal enclosure, males predominated in adjoining storage places. Increasing CO2 concentration had an additional positive effect on female abundance only. Both male and female density increased with rising temperature, and there was some indication that females were more active than males at higher relative humidity. The study confirms that P. perniciosus aggregates around animal premises, although male and female distributions differ and should be analysed separately to account for biological and behavioural differences. This provides further evidence that light traps offer an accurate estimation of the relative spatial and temporal abundance of P. perniciosus, conferring an added value for the study of this species and the risk of pathogen transmission. PMID- 29111589 TI - Effect of In Vitro Digestion on the Total Antioxidant Capacity and Phenolic Content of 3 Species of Oregano (Hedeoma patens, Lippia graveolens, Lippia palmeri). AB - : Oregano phenolic compounds have been studied for their anti-inflammatory properties. Nonetheless, after ingestion, the gastrointestinal environment can affect their antioxidant stability and thus their bioactive properties. To evaluate the effect of in vitro gastrointestinal (GI) digestion on the phenolic compounds of 3 species of oregano (Hedeoma patens, Lippia graveolens, and Lippia palmeri), the total reducing capacity, total flavonoid content, and antioxidant capacity were evaluated before and after in vitro GI digestion. In addition, the phenolic compounds of the 3 oregano species were identified and quantified by UPLC-PDA before and after in vitro GI digestion. It was shown that the reducing capacity, flavonoid content and antioxidant capacity were affected by the GI digestion process. Moreover, the phenolic compounds identified were apigenin-7 glucoside, scutellarein, luteolin, luteolin-7-glucoside, phloridzin and chlorogenic acid, and their levels were affected by the in vitro GI process. Our results showed that the phenolic compounds from these 3 species of oregano are affected by the in vitro digestion process, and this effect is largely attributable to pH changes. These changes can modify the bioavailability and further anti-inflammatory activity of oregano phenolics, and thus, further research is needed. PRACTICAL APPLICATION: Oregano is a rich source of polyphenols that have shown bioactive properties like anti-inflammatory potential. However, little is known of the gastrointestinal fate of oregano polyphenols which is imperative to fully understand its bioaccessibility. Our results are important to develop new administration strategies which could help protect the antioxidant and anti-inflammatory potential and bioaccessibility of such compounds. PMID- 29111590 TI - Enhancement of Moisture Protective Properties and Stability of Pectin through Formation of a Composite Film: Effects of Shellac and Plasticizer. AB - : The aim of this investigation was to develop the high moisture protective ability and stable pectin through the design of composite films based on varying shellac concentrations. A film casting method was applied to prepare a free film. The moisture protective properties and mechanical properties were investigated. The findings was the composite films exhibited the reductions in the hydrophilicity, water vapor permeability, and the moisture content compared with pectin films. The single and composite films were then study for their stability at 40 degrees C and 75% RH for 90 d. Among the concentrations of shellac, 50% (w/w) could improve stability in terms of moisture protection after 90 d of storage, whereas lower concentrations of shellac (10% to 40%) could not achieve this. However, the higher shellac content also contributed to weaker mechanical properties. The mechanical improvement and stability of composite films with the incorporation of plasticizers were further investigated. Polyethylene glycol 400 and diethyl phthalate at a concentration of 10% were used. The results indicated that both plasticizers could enhance the mechanical characteristics and had a slight effect on moisture protection. The stability of pectin in terms of moisture protective properties could, therefore, be modified through the fabrication of composite films with hydrophobic polymers, that is, shellac and the addition of proper plasticizers to enhance mechanical properties, which could offer wide applications for edible film in food, agro, and pharmaceutical industries. PRACTICAL APPLICATION: The composite film with 50% shellac could improve moisture protective properties of pectin film. Adding a plasticizer could build up the higher mechanical characteristics of composite film. Stability of pectin could be modified by fabrication of composite films with proper content of shellac and plasticizer. PMID- 29111591 TI - Magnetoencephalographic imaging of ictal high-frequency oscillations (80-200 Hz) in pharmacologically resistant focal epilepsy. AB - OBJECTIVE: Specificity of ictal high-frequency oscillations (HFOs) in identifying epileptogenic abnormality is significant, compared to the spikes and interictal HFOs. The objectives of the study were to detect and to localize ictal HFOs by magnetoencephalography (MEG) for identifying the seizure onset zone (SOZ), evaluate the cortical excitability from preictal to ictal transition, and establish HFO concordance rates with other modalities and postsurgical resection. METHODS: Sixty-seven patients with drug-resistant epilepsy had at least 1 spontaneous seizure each during MEG acquisition, and analysis was carried out on 20 seizures from 20 patients. Ictal MEG data were bandpass filtered (80-200 Hz) to visualize, review, and analyze the HFOs co-occurring with ictal spikes. Source montages were generated on both hemispheres, mean fast Fourier transform was computed on virtual time series for determining the preictal to ictal spectral power transition, and source reconstruction was performed with sLORETA and beamformers. The concordance rates of ictal MEG HFOs (SOZ) was estimated with 4 reference epileptogenic regions. RESULTS: In each subject, transient bursts of high-frequency oscillatory cycles, distinct from the background activity, were observed in the periictal continuum. Time-frequency analysis showed significant spectral power surge (85-160 Hz) during ictal state (P < .05) compared to preictal state, but there was no variation in the peak HFO frequencies (P > .05) for each subgroup and at each source montage. HFO source localization was consistent between algorithms (k = 0.857 +/- 0.138), with presumed epileptogenic zone (EZ) comparable to other modalities. In patients who underwent surgery (n = 6), MEG HFO SOZ was concordant with the presumed EZ and the surgical resection site (100%), and all were seizure-free during follow-up. SIGNIFICANCE: HFOs could be detected in the MEG periictal state, and its sources were accurately localized. During preictal to ictal transition, HFOs exhibited dynamic augmentation in intrinsic epileptogenicity. Spatial overlap of ictal HFO sources was consistent with EZ determinants and the surgical resection area. PMID- 29111592 TI - Inflammatory milieu cultivated Sema3A signaling promotes chondrocyte apoptosis in knee osteoarthritis. AB - Osteoarthritis (OA) is the leading degenerative joint disease and featured by articular cartilage destruction, where chondrocyte apoptosis plays a critical role. Semaphorin-3A (Sema3A) has been implicated in OA chondrocyte physiology. In this study we aimed to uncover how Sema3A signaling is regulated in chondrocytes and investigate its role in OA chondrocyte survival. Here, we report that Sema3A and its receptor neuropilin-1 (Nrp1) are synchronously upregulated in cartilage chondrocytes of knee OA patients. Their expressions in chondrocytes could be induced by the stimulation of proinflammatory cytokines IL-1beta and TNF-alpha and subsequent transcriptional activation orchestrated by C/EBPbeta. The resulting excessive Sema3A signaling promotes chondrocyte apoptosis through impairing PI3K/Akt prosurvival signaling. These findings indicate a regulatory mechanism and a proapoptotic function of aberrant Sema3A signaling in OA chondrocytes, and suggest that targeting Sema3A signaling might interfere OA pathogenesis. PMID- 29111593 TI - Sustainable Chemistry: A Future Guiding Principle. AB - "... Chemistry is currently faced with one of the biggest challenges in its history. The main reaction to this is a search for how new resources can be utilized in the synthesis of (new) compounds. However, much more is needed to meet this challenge: Sustainable chemistry is simultaneously both a path and a goal. It is not a new subdiscipline of chemistry, but a guiding principle. It uses the knowledge of all chemical subdisciplines along the entire lifecycles of chemical products ..." Read more in the Guest Editorial by Klaus Kummerer. PMID- 29111594 TI - Letter to 'Successful treatment of uterine artery pseudoaneurysm with laparoscopic temporary clamping of bilateral uterine arteries, followed by hysteroscopic surgery': Pseudoaneurysm and vascular involution. PMID- 29111595 TI - Prominent alterations of wild barley leaf transcriptome in response to individual and combined drought acclimation and heat shock conditions. AB - Under field conditions, drought and heat stress typically happen simultaneously and their negative impact on the agricultural production is expected to increase worldwide under the climate change scenario. In this study, we performed RNA sequencing analysis on leaves of wild barley (Hordeum spontaneum) originated from the northern coastal region of Egypt following individual drought acclimation (DA) and heat shock (HS) treatments and their combination (CS, combined stresses) to distinguish the unique and shared differentially expressed genes (DEG). Results indicated that the number of unique genes that were differentially expressed following HS treatment exceeded the number of those expressed following DA. In addition, the number of genes that were uniquely differentially expressed in response to CS treatment exceeded the number of those of shared responses to individual DA and HS treatments. These results indicate a better adaptation of the Mediterranean wild barley to drought conditions when compared with heat stress. It also manifests that the wild barley response to CS tends to be unique rather than common. Annotation of DEG showed that metabolic processes were the most influenced biological function in response to the applied stresses. PMID- 29111596 TI - Compliance between clinical and genetic diagnosis of choroidal hypoplasia in 103 Norwegian Border Collie puppies. AB - OBJECTIVE: To describe the frequency of the nonhomologous end-joining factor 1 (NHEJ1) mutation and the compliance between clinical and genetic diagnosis of choroidal hypoplasia (CH) in a group of Norwegian Border Collies. ANIMALS STUDIED: Border collie puppies in the age from 5 to 8 weeks. MATERIAL AND METHODS: Puppies included in the study had a complete ophthalmological examination. All findings were recorded, and an ECVO scheme form was issued for each puppy. DNA samples were achieved from buccal swabs. Genetic typing was performed for the 7.8-kb deletion in the gene encoding NHEJ1. Dogs with none, one, or two copies of the mutated allele were classified as free, carriers, and affected, respectively. RESULTS: 103 Border Collie puppies from 16 litters, 52 females and 51 males, were included in the study. Ages ranged from 5.1 to 8.9 weeks. One puppy had clinical findings consistent with CH and optic nerve coloboma compatible with the diagnosis Collie Eye Anomaly (CEA). Findings on ophthalmological examination of the remaining puppies were within normal limits. On genetic testing, 85 puppies were clear of the mutation in the NHEJ1 gene, 17 puppies were carriers, and one puppy was genetically affected. CONCLUSIONS: A good compliance between the clinical diagnosis and the genetic test results was found in all of the puppies examined. The allele frequency of the mutation was 6.3%. PMID- 29111598 TI - Comparison of corneal thickness measurements using ultrasound pachymetry, ultrasound biomicroscopy, and digital caliper in frozen canine corneas. AB - OBJECTIVE: To evaluate the clinical efficacy among ultrasound pachymetry (UP), ultrasound biomicroscopy (UBM), and manual measurement (MM) with digital caliper by comparing corneal thickness (COT) values obtained from frozen canine corneas ex vivo. PROCEDURES: COT was measured using UP, UBM, and MM in eight enucleated normal canine eyes frozen at -20 degrees C for 4 weeks. After thawing at room temperature for 2 h, the COT values were obtained from five sites on each cornea: central corneal thickness (CCOT), thickness at the 3, 6, 9, and 12 o'clock positions (3COT, 6COT, 9COT, and 12COT, respectively). For each device, measurements were performed three times at each designated site by one operator. Intraclass correlation coefficient, repeated-measures analysis of variance, and Bland-Altman plot were performed for statistical analyses. RESULTS: The mean CCOT was 839.0 +/- 138.2, 857.6 +/- 127.9, and 849.1 +/- 132.8 MUm for UP, UBM, and MM, respectively. There was no statistically significant difference among the measurements by all three devices (P > 0.05). The statistical agreement among these devices was also shown to be good according to Bland-Altman plots. In addition, the values measured on the peripheral sites of the cornea (3COT, 6COT, 9COT, and 12COT) also revealed no significant differences among the three devices. The difference between CCOT and peripheral corneal thickness was also statistically insignificant. CONCLUSIONS: The UP, UBM, and MM measurements showed statistically similar COT values. The UBM and UP provided accurate and reliable measurements comparable to MM and could be used effectively for clinical COT measurements. PMID- 29111599 TI - Experimental investigation of alternative transmission functions: Quantitative evidence for the importance of nonlinear transmission dynamics in host-parasite systems. AB - Understanding pathogen transmission is crucial for predicting and managing disease. Nonetheless, experimental comparisons of alternative functional forms of transmission remain rare, and those experiments that are conducted are often not designed to test the full range of possible forms. To differentiate among 10 candidate transmission functions, we used a novel experimental design in which we independently varied four factors-duration of exposure, numbers of parasites, numbers of hosts and parasite density-in laboratory infection experiments. We used interactions between amphibian hosts and trematode parasites as a model system and all candidate models incorporated parasite depletion. An additional manipulation involving anaesthesia addressed the effects of host behaviour on transmission form. Across all experiments, nonlinear transmission forms involving either a power law or a negative binomial function were the best-fitting models and consistently outperformed the linear density-dependent and density independent functions. By testing previously published data for two other host macroparasite systems, we also found support for the same nonlinear transmission forms. Although manipulations of parasite density are common in transmission studies, the comprehensive set of variables tested in our experiments revealed that variation in density alone was least likely to differentiate among competing transmission functions. Across host-pathogen systems, nonlinear functions may often more accurately represent transmission dynamics and thus provide more realistic predictions for infection. PMID- 29111597 TI - Responses of an adventitious fast-growing plant to photodynamic stress: comparative study of anionic and cationic porphyrin effect on Arabidopsis thaliana. AB - Antimicrobial photodynamic treatment (APDT) based on the use of a photosensitizer to produce reactive oxygen species (ROS) that induce cell death could be envisaged to fight against plant pathogens. For setting this strategy, we want to study how plants themselves respond to photodynamic treatment. In previous work we showed that tomato plantlets were able to resist photoactivated tetra (N methylpyridyl) porphyrin (CP) or the zinc metalated form (CP-Zn). To enlarge our plant expertise related to exogenous porphyrins treatment and to further defend this approach, we studied how a weed like Arabidopsis thaliana responded to exogenous supply of anionic and cationic porphyrins. Both types of photosensitizers had no negative effect on seed germination and did not hamper the development etiolated Arabidopsis plantlet under dark conditions. Thus, post emergence effects of porphyrin photoactivation on the development of 14 day-old in vitro Arabidopsis plantlet under light were observed. CP-Zn was the most efficient photosensitizer to kill Arabidopsis plantlets while anionic tetra (4 sulfonatophenyl) porphyrin only delayed their growth and development. Indeed only 7% of plantlets could be rescued after CP-Zn treatment. Furthermore, non enzymatic and enzymatic defense components involved in detoxification of ROS generated by CP-Zn under illumination were downregulated or stable with the exception of sevenfold increase in proline content. As previously demonstrated in the literature for microbial agents and in the present work for Arabidopsis, CP Zn was efficient enough to eradicate unwanted vegetation and plant pathogens without at the same time killing plants of agronomic interest such as tomato plantlets. PMID- 29111600 TI - Mortality and acute complications in children and young adults diagnosed with Type 1 diabetes in Yorkshire, UK: a cohort study. AB - AIMS: To examine all-cause and cause-specific mortality in a population-based cohort of people with early and late onset of Type 1 diabetes. METHODS: The Yorkshire Register of Diabetes in Children and Young People includes individuals with early (0-14 years) and late (15-29 years) Type 1 diabetes onset, diagnosed between 1978 and 2013. This register was linked to death certification data from the Office for National Statistics to calculate standardized mortality ratios, cumulative mortality curves using Kaplan-Meier survival estimates, and Cox regression modelling. Ethnicity was derived using Onomap. Deprivation status was classified using the Townsend index. The underlying cause of death in each case was clinically verified. RESULTS: There were 229 deaths in 5498 individuals with 100 959 person-years of follow-up. The overall standardized mortality ratio was 4.3 (95% CI 3.8 to 4.9). There were no significant differences in standardized mortality ratios according to age of onset, sex or deprivation status. The standardized mortality ratios were significantly higher for people of white ethnic origin [8.1 (95% CI 6.9 to 9.4)] than for those of South-Asian ethnic origin [3.4 (95% CI 1.7 to 6.4)]. The mortality risk was lower in those diagnosed in later years (2002 to 2013 for the early-onset and 2006 to 2013 for the late onset group) compared with earlier years (1991 to 1997 for the early-onset and 1991 to 1997 for the late-onset group) for both onset groups [hazard ratio 0.13 (95% CI 0.05 to 0.33) vs 0.24 (95% CI 0.07 to 0.81)]. Mortality risk improved over time for chronic complications in the early-onset group only, but there was no improvement in either onset group with regard to acute complications. CONCLUSIONS: An excess of deaths in the population with Type 1 diabetes remains. Although the all-cause mortality risk has fallen over time, no improvement has been found in the mortality risk associated with acute complications. PMID- 29111601 TI - Active migration is associated with specific and consistent changes to gut microbiota in Calidris shorebirds. AB - Gut microbes are increasingly recognised for their role in regulating an animal's metabolism and immunity. However, identifying repeatable associations between host physiological processes and their gut microbiota has proved challenging, in part because microbial communities often respond stochastically to host physiological stress (e.g. fasting, forced exercise or infection). Migratory birds provide a valuable system in which to test host-microbe interactions under physiological extremes because these hosts are adapted to predictable metabolic and immunological challenges as they undergo seasonal migrations, including temporary gut atrophy during long-distance flights. These physiological challenges may either temporarily disrupt gut microbial ecosystems, or, alternatively, promote predictable host-microbe associations during migration. To determine the relationship between migration and gut microbiota, we compared gut microbiota composition between migrating and non-migrating ("resident") conspecific shorebirds sharing a flock. We performed this across two sandpiper species, Calidris ferruginea and Calidris ruficollis, in north-western Australia, and an additional C. ruficollis population 3,000 km away in southern Australia. We found that migrants consistently had higher abundances of the bacterial genus Corynebacterium (average 28% abundance) compared to conspecific residents (average <1% abundance), with this effect holding across both species and sites. However, other than this specific association, community structure and diversity was almost identical between migrants and residents, with migration status accounting for only 1% of gut community variation when excluding Corynebacterium. Our findings suggest a consistent relationship between Corynebacterium and Calidris shorebirds during migration, with further research required to identify causal mechanisms behind the association, and to elucidate functionality to the host. However, outside this specific association, migrating shorebirds broadly maintained gut community structure, which may allow them to quickly recover gut function after a migratory flight. This study provides a rare example of a repeatable and specific response of the gut microbiota to a major physiological challenge across two species and two distant populations. PMID- 29111603 TI - Optimizing outcomes of lymphatic-venous anastomosis (LVA) supermicrosurgery by preoperative identification of reflux-free vein: Choose the vein wisely. PMID- 29111602 TI - Scedosporium apiospermum infection of the urinary system with a review of treatment options and cases in the literature. AB - Infection with Scedosporium species is associated with a significant morbidity and mortality and is becoming increasingly common, especially in immunocompromised patients. We describe the presentation and successful management of an immunocompromised patient with Scedosporium apiospermum infection of the upper urinary tract system, a rare disease manifestation. The current literature on urinary tract scedosporiosis is further reviewed with emphasis on treatment options and limitations of current antifungal therapy. PMID- 29111604 TI - A comparative study with a 755 nm picosecond Alexandrite laser with a diffractive lens array and a 532 nm/1064 nm Nd:YAG with a holographic optic. AB - BACKGROUND AND OBJECTIVES: This study was performed to better understand the cutaneous effects of using a fractional picosecond laser at 755 nm with a diffractive lens array and a picosecond Nd:YAG laser at 532 mn and 1064 nm with a holographic optic. We characterized the injuries created by these devices on skin clinically and histologically over 24 hours. With this information we modeled the effects of these devices on a cutaneous target. METHODS: Eight patients, representing Fitzpatrick skin types I-VI, were treated on their backs with a picosecond Alexandrite laser with a diffractive lens array, as well as a picosecond Nd:YAG laser at 532 nm and 1064 nm with a holographic optic. Photographs were taken 15 minutes and 24 hours after treatments. Punch biopsies were obtained at 24 hours and examined histologically. RESULTS: Treatment with the picosecond Nd:YAG laser at both 532 nm and 1064 nm with the holographic optic revealed erythema and small scatted areas of petechial hemorrhage areas immediately and in many cases at 24 hours after treatment. The 755 nm picosecond Alexandrite laser with diffractive lens array produced erythema immediately after treatment, which largely dissipated 24 hours later. Histologies revealed intra epidermal vacuoles with all three wavelengths. Fractional picosecond Nd:YAG laser at 532 nm and 1064 nm with the holographic optic showed focal areas of dermal and intra-epidermal hemorrhage with areas of vascular damage in some patients. CONCLUSIONS: This study demonstrates that both fractional picosecond devices produce vacuoles in the skin, which are most likely due to areas of laser induced optical breakdown (LIOB). In the patients (skin type II-IV) we observed scatter areas of hemorrhage in the skin, due to vascular damage with the 532 nm and 1064 nm, but not with 755 nm wavelengths. Lasers Surg. Med. 50:37-44, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29111605 TI - Influenza and Pneumocystis jirovecii pneumonia in an allogeneic hematopoietic stem cell transplantation recipient: Coinfection or superinfection? AB - Influenza infection and Pneumocystis jirovecii pneumonia (PJP) in hematopoietic stem cell transplant (HSCT) patients are well characterized; however, no dual infections have been reported in this patient population and little evidence of mechanisms of interaction between the two infections exists. We present a 53-year old male allogeneic HSCT patient on immunosuppressive therapy for the treatment of graft versus host disease initially diagnosed with influenza A H3 and later PJP. Despite the development of acute respiratory distress syndrome, the patient was successfully treated with appropriate antimicrobial therapy and aggressive supportive care. This case demonstrates the necessity of maintaining a high index of suspicion for fungal (including PJP) coinfection or superinfection in the setting of worsening influenza infection. PMID- 29111606 TI - Incubation with Cu(II) and Zn(II) salts enhances MALDI-TOF mass spectra of amyloid-beta and alpha-synuclein toward in vivo analysis. AB - Insoluble senile plaque aggregates are indicative of Alzheimer's disease pathology. A similar phenomenon occurs in Parkinson's disease with the build-up of Lewy bodies. The analysis of senile plaques, and other brain samples, from Alzheimer's disease and Parkinson's disease patients by matrix-assisted laser desorption/ionization mass spectrometry has advantages but also presents obstacles because of the nature of the processes utilized in isolation procedures and storage. Salts, buffers, and detergents necessary in the isolation of biological species may cause adducts and ion suppression that convolute the spectra obtained. We previously determined that amyloid-beta from isolated senile plaque deposits fragment similarly to the synthetic 40 and 42 amino acid peptide when analyzed by matrix-assisted laser desorption/ionization mass spectrometry. In addition, alpha-synuclein also fragments predictably by in-source decay. This provides information that may be applied to the identification and localization of amyloid-beta and alpha-synuclein in senile plaques and intact tissue sections. Ion suppression must still be accounted for when analyzing biological samples, which makes identifying fragments at lower abundance difficult. The addition of certain transition-metal salts (Cu(II), Zn(II)) to the sample prior to analysis serves to "clean" the spectra and allow the peptide fragments produced to be observed with a much higher signal to noise and occasionally, improved resolution. We present a systematic study of incubation with different metal salts and their impact on the quality of the spectra, as well as the role of the binding of the metals to the model biological compounds, obtained for synthetic amyloid-beta, synthetic alpha-synuclein, and isolated senile plaques. The optimized sample preparation methods presented will provide for simpler and more thorough identification of these biologically relevant species in human-derived samples. PMID- 29111607 TI - An Incomplete Spin Transition Associated with a Z'=1->Z'=24 Crystallographic Symmetry Breaking. AB - Crystalline [FeL2 ][BF4 ]2 ?Me2 CO (L=N-[2,6-di{pyrazol-1-yl}pyrid-4 yl]acetamide) is high-spin at room temperature, and undergoes an abrupt, hysteretic spin-crossover at T1/2 =137 K (DeltaT1/2 =14 K) that proceeds to about 50 % completeness. This is associated with a crystallographic phase transition, from phase 1 (P21 /c, Z=4) to phase 2 (P21 , Z=48). The cations associate into chains in the crystal through weak intermolecular pi???pi interactions. Phase 2 contains a mixture of high-spin and low-spin molecules, which are grouped into triads along these chains. The perchlorate salt [FeL2 ][ClO4 ]2 ?Me2 CO also adopts phase 1 at room temperature but undergoes a different phase transition near 135 K to phase 3 (P21 /c, Z=8) without a change in spin state. PMID- 29111608 TI - Approach for gait analysis in persons with limb loss including residuum and prosthesis socket dynamics. AB - Musculoskeletal modeling and marker-based motion capture techniques are commonly used to quantify the motions of body segments, and the forces acting on them during human gait. However, when these techniques are applied to analyze the gait of people with lower limb loss, the clinically relevant interaction between the residual limb and prosthesis socket is typically overlooked. It is known that there is considerable motion and loading at the residuum-socket interface, yet traditional gait analysis techniques do not account for these factors due to the inability to place tracking markers on the residual limb inside of the socket. In the present work, we used a global optimization technique and anatomical constraints to estimate the motion and loading at the residuum-socket interface as part of standard gait analysis procedures. We systematically evaluated a range of parameters related to the residuum-socket interface, such as the number of degrees of freedom, and determined the configuration that yields the best compromise between faithfully tracking experimental marker positions while yielding anatomically realistic residuum-socket kinematics and loads that agree with data from the literature. Application of the present model to gait analysis for people with lower limb loss will deepen our understanding of the biomechanics of walking with a prosthesis, which should facilitate the development of enhanced rehabilitation protocols and improved assistive devices. PMID- 29111609 TI - Enantiospecific sp2 -sp3 Coupling of ortho- and para-Phenols with Secondary and Tertiary Boronic Esters. AB - The coupling of ortho- and para-phenols with secondary and tertiary boronic esters has been explored. In the case of para-substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph3 BiF2 or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (-)-4-(1,5-dimethylhex-4-enyl)-2-methyl phenol. For ortho substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho-lithiation and borylation gave the coupled product, again with complete stereospecificity. PMID- 29111610 TI - The function and mechanism of vocal accommodation in humans and other primates. AB - The study of non-human animals, in particular primates, can provide essential insights into language evolution. A critical element of language is vocal production learning, i.e. learning how to produce calls. In contrast to other lineages such as songbirds, vocal production learning of completely new signals is strikingly rare in non-human primates. An increasing body of research, however, suggests that various species of non-human primates engage in vocal accommodation and adjust the structure of their calls in response to environmental noise or conspecific vocalizations. To date it is unclear what role vocal accommodation may have played in language evolution, in particular because it summarizes a variety of heterogeneous phenomena which are potentially achieved by different mechanisms. In contrast to non-human primates, accommodation research in humans has a long tradition in psychology and linguistics. Based on theoretical models from these research traditions, we provide a new framework which allows comparing instances of accommodation across species, and studying them according to their underlying mechanism and ultimate biological function. We found that at the mechanistic level, many cases of accommodation can be explained with an automatic perception-production link, but some instances arguably require higher levels of vocal control. Functionally, both human and non-human primates use social accommodation to signal social closeness or social distance to a partner or social group. Together, this indicates that not only some vocal control, but also the communicative function of vocal accommodation to signal social closeness and distance must have evolved prior to the emergence of language, rather than being the result of it. Vocal accommodation as found in other primates has thus endowed our ancestors with pre-adaptations that may have paved the way for language evolution. PMID- 29111611 TI - Peptidase inhibitors in tick physiology. AB - Peptidase inhibitors regulate a wide range of physiological processes involved in the interaction between hematophagous parasites and their hosts, including tissue remodeling, the immune response and blood coagulation. In tick physiology, peptidase inhibitors have a crucial role in adaptation to improve parasitism mechanisms, facilitating blood feeding by interfering with defense-related host peptidases. Recently, a larger number of studies on this topic led to the description of several new tick inhibitors displaying interesting novel features, for example a role in pathogen transmission to the host. A comprehensive review discussing these emerging concepts can therefore shed light on peptidase inhibitor functions, their relevance to tick physiology and their potential applications. Here, we summarize and examine the general characteristics, functional diversity and action of tick peptidase inhibitors with known physiological roles in the tick-host-pathogen interaction. PMID- 29111612 TI - Rubrioxytricha guamensis nov. spec. (Ciliophora, Spirotricha), a Novel Hypotrich Ciliate from Guam (United States), Micronesia. AB - The oxytrichid ciliate Rubrioxytricha guamensis nov. spec. isolated from water samples collected from a small freshwater pond near the Hagatna River in Hagatna, Guam (United States territory), Micronesia, was investigated, using live observation and protargol impregnation. The morphology, ontogenesis, and molecular phylogeny inferred from the small-subunit rRNA gene sequences were studied. The new species is mainly characterized by a cell size of about 100 * 35 MUm in vivo, two elongate ellipsoidal macronuclear nodules and two micronuclei, a single contractile vacuole, a colorless cytoplasm, yellowish cortical granules, arranged in short rows and in small groups, an adoral zone occupying about 34% of body length and comprising 27 membranelles on average, about 27 cirri each in the right and left marginal rows, 18 frontoventral transverse cirri, four dorsal kineties including one dorsomarginal row, and one or two caudal cirri at the posterior end of dorsal kinety 3. The ontogenesis of the new species is similar to that of Rubrioxytricha indica Naqvi et al., 2006. Phylogenetic analyses based on SSU rRNA gene sequences consistently place the new species within the family Oxytrichidae Ehrenberg, 1838, where it clustered with other Rubrioxytricha species, viz., R. tsinlingensis, R. ferruginea, and R. haematoplasma. PMID- 29111613 TI - Management of Shiga toxin producing Escherichia coli-infected children: A multi national, multi-specialty survey. AB - AIM: Research has highlighted the potential role that hydration status may play in predicting outcomes in Shiga toxin-producing Escherichia coli (STEC)-infected children. Because little is known about the management of STEC-infected children in the pre-haemolytic uremic syndrome phase, we compared paediatric emergency medicine and nephrologist-stated management approaches to STEC-infected children. METHODS: Members of the Pediatric Emergency Research Canada (PERC; n = 228), the Pediatric Emergency Medicine Collaborative Research Committee (PEM CRC; n = 221) and the Canadian Association of Pediatric Nephrologists (CAPN; n = 66) were surveyed. Five individualised e-mail requests containing a link to a 42-question web-based survey were sent to eligible participants. RESULTS: Of 496 potentially eligible participants, 276 (56%) submitted complete survey responses. In children with classic features of STEC infection, baseline haemoglobin/haematocrit is obtained by 54% of PERC, 41% of PEM CRC and 83% of CAPN members (P < 0.001), and baseline renal function is obtained by 51% of PERC, 38% of PEM CRC and 83% of CAPN members (P < 0.001). Intravenous fluids are more often recommended by nephrologists (28%) compared with PEM physicians (7%), P < 0.001. In children with known E. coli O157:H7 infection, nephrologists more commonly recommend clinical follow-up (P = 0.003), complete blood counts (P < 0.001) and renal function/electrolyte testing (P < 0.001). Intravenous fluid administration and admission are more commonly recommended by nephrologists (P = 0.03 and P < 0.001, respectively). CONCLUSION: Compared with paediatric nephrologists, paediatric emergency medicine physicians are less likely to perform baseline and follow-up blood tests and to administer intravascular volume expansion in children at risk of, and with confirmed, E. coli O157:H7 infection. PMID- 29111614 TI - Has noninvasive prenatal testing impacted termination of pregnancy and live birth rates of infants with Down syndrome? AB - BACKGROUND: Implementation of noninvasive prenatal testing (NIPT) as a highly accurate aneuploidy screening test has raised questions around whether the high uptake may result in more terminations of pregnancies and fewer births of children with Down syndrome (DS). AIM: The aim of the study was to investigate the impact of NIPT on termination and live birth rates for DS. METHODS: Literature reporting pregnancy outcomes following NIPT was reviewed. Termination rates were calculated for women with a high-risk NIPT result for DS. Two audits of pregnancy outcomes where NIPT indicated DS were conducted in the United Kingdom and Singapore. RESULTS: Fourteen studies from the United States, Asia, Europe, and the United Kingdom were included in the review. Live births of children with DS were reported in 8 studies. Termination rates following NIPT were unchanged or decreased when compared to termination rates prior to the introduction of NIPT. Audits found 15 of 43 women in the United Kingdom and 2 of 6 in Singapore continued pregnancies following a high-risk NIPT result. CONCLUSIONS: Termination rates following the detection of DS by NIPT are unchanged or decreased compared to historical termination rates. Impact on live birth rates may be minimal in settings where termination rates fall. Population based studies are required to determine the true impact. PMID- 29111615 TI - Glutathione S-transferase genes and the risk of type 2 diabetes mellitus: Role of sexual dimorphism, gene-gene and gene-smoking interactions in disease susceptibility. AB - BACKGROUND: Compromised defense against reactive oxygen species (ROS) is considered important in the pathogenesis of type 2 diabetes mellitus (T2DM); therefore, genes encoding antioxidant defense enzymes may contribute to disease susceptibility. This study investigated whether polymorphisms in genes encoding glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) jointly contribute to the risk of T2DM. METHODS: In all, 1120 unrelated Russian subjects (600 T2DM patients, 520 age- and sex-matched healthy subjects), were recruited to the study. Genotyping was performed by multiplex polymerase chain reaction (PCR; del/del polymorphisms of GSTM1 and GSTT1) and TaqMan-based PCR (polymorphisms I105V and A114V of GSTP1). Plasma ROS and glutathione levels in study subjects were analyzed by fluorometric and colorimetric assays, respectively. RESULTS: Genotype del/del GSTT1 was significantly associated with the risk of T2DM (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.17-2.21, P = 0.003). Gender stratified analysis showed that the deletion genotypes of GSTM1 (OR 1.99, 95% CI 1.30-3.05; P = 0.0002, Q = 0.016) and GSTT1 (OR 2.23, 95% CI 1.22-4.09; P = 0.008, Q = 0.0216), as well as genotype 114A/V of GSTP1 (OR 2.85, 95% CI 1.44 5.62; P = 0.005, Q = 0.02) were associated with an increased risk of T2DM exclusively in males. Three genotype combinations (i.e. GSTM1+ * GSTT1+, GSTM1+ * GSTP1 114A/A and GSTT1+ * GSTP1 114A/A) showed significant associations with a decreased risk of T2DM in males. CONCLUSIONS: This study demonstrates, for the first time, that genes encoding glutathione S-transferases jointly contribute to the risk of T2DM, and that their effects on disease susceptibility are gender specific. PMID- 29111616 TI - Daclatasvir and asunaprevir treatment in patients infected by genotype 1b of hepatitis C virus with no or subtle resistant associated substitutions (RAS) in NS5A-Y93. AB - In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan, daclatasvir and asunaprevir (DCV+ASV), in chronic hepatitis C patients infected HCV genotype 1b with no or subtle amount of baseline resistant associated substitutions (RAS). Among 924 patients registered in our multicenter study, 750 patients who were proven not to be infected with NS5A-Y93H RAS by direct sequencing and to have no or subtle amount (less than 20%) of NS5A-Y93H RAS by probe assays (Cycleave or PCR invader assay) were included in this study. We investigated the anti-viral effect and factors associated with SVR12. In statistical analysis, P < 0.05 was considered as significant. The SVR12 rate in this population was 92.1% (562/618). Factors associated with SVR12 were male (odds ratio: 2.128; 95%CI: 1.134-4.000, P = 0.019); lower serum gammaGTP (odds ratio: 1.007; 95%CI: 1.002-1.012, P = 0.006); lower HCV-RNA (odds ratio: 1.848; 95%CI: 1.087-3.145, P = 0.023), and RVR (odds ratio: 6.250; 95%CI: 2.445-15.873, P < 0.001). No patients with gammaGTP ? 80 IU/L without RVR showed SVR12 (0/4, 0%) and one patients with gammaGTP ? 20-< 80 IU/L and HCV-RNA ? 6.5 logIU/mL without RVR (5/10, 50%) and two female patients with RVR but gammaGTP ? 80 IU/L and HCV-RNA ? 6.5 logIU/mL (7/13, 53.8%) showed a low SVR12 rate. In the present study, we showed a good viral response with DCV ASV treatment and identified four predictive factors associated with SVR12. These four markers could be a good predictive markers for the viral effect of this treatment regimen in patients with no or subtle amount of RAS in NS5A-Y93. PMID- 29111617 TI - Ocular and periocular hemangiosarcoma in six horses. AB - OBJECTIVE: To determine the characteristics of and prognosis for ocular and periocular hemangiosarcoma in horses. ANIMAL STUDIED: Six horses treated for ocular or periocular hemangiosarcoma. PROCEDURE: A retrospective review of medical records from 2007 to 2015 was performed to identify horses with a histologic diagnosis of ocular or periocular hemangiosarcoma. Signalment (age, sex, breed), duration of clinical signs, prior treatment, tumor size and location, medical and surgical treatment including postoperative chemotherapy, follow-up time, and outcome were obtained from medical records. Histopathology was reviewed by a board-certified pathologist. RESULTS: In six horses diagnosed with ocular or periocular hemangiosarcoma, no breed, age, or sex was overrepresented. Sites included the temporal limbus (3), third eyelid (2), and uvea (1). With the exception of one horse with uveal hemangiosarcoma, 5/6 horses had lightly pigmented periocular haircoat. Histologic features of ocular hemangiosarcoma in 6/6 cases included high cellularity, nuclear pleomorphism, and inflammation with a mitotic index ranging from 0 to 8 mitoses per 10 consecutive 400* fields. Five of six tumors displayed solar elastosis, indicating ultraviolet light-induced damage to sub-epithelial collagen. Treatment included surgical excision in all cases and was not associated with recurrence in 4/6. Three cases that received ancillary treatment with topical mitomycin C had no postoperative recurrence. Two cases with postexcisional recurrence had histologic evidence of incomplete excision. CONCLUSIONS: Complete surgical excision may be associated with resolution of periocular and ocular hemangiosarcoma in horses. Etiopathogenesis may include exposure to ultraviolet light. PMID- 29111619 TI - Incidence and cost of hospitalisation of children with injuries from playground equipment falls in New South Wales, Australia. AB - AIMS: To describe the epidemiological profile and cost of hospitalised injuries caused by playground equipment falls of children aged 0-14 years, in New South Wales, Australia. METHODS: Linked New South Wales hospitalisation data from 1 January 2010 to 30 June 2014 were used to describe the incidence of hospitalisation for playground falls, the age-standardised rate of hospitalisation per year, age group and gender, the characteristics of the injured children and the injury incident. Health outcomes, such as length of stay in hospital, and the hospital costs associated with the injuries were examined by age group. Negative binomial regression assessed the trend in hospitalisation rates over time. RESULTS: There were 7795 hospitalisations of children for playground fall injuries. The highest hospitalisation rate was for the 5-9 year olds (220.7 per 100 000 population) and was higher in males than females (234.2 and 206.3 per 100 000 population, respectively). The majority of these injuries occurred in schools (17.1%) and homes (14.6%), and were as a result of falls from trampolines (34.3%) and climbing apparatuses (28.2%). Over half the playground falls led to fractures of the elbow and wrist (54.7%). The total hospital cost of playground fall-related injuries was $18 million. CONCLUSION: Rates of hospitalisation of children for playground fall injuries remain high despite implementation of national playground safety standards in Australia. This research highlights where interventions should be targeted to reduce the incidence and burden of injuries following falls from playground equipment. PMID- 29111618 TI - Toxic metals in amniotic fluid and altered gene expression in cell-free fetal RNA. AB - Both exposures to toxic metals, as well as deficiencies in essential metals, during pregnancy has been linked to a variety of negative reproductive outcomes. The exact etiologies of such outcomes and the effects of fetal exposure to these metals are largely unknown. Therefore, the ability to assess levels of these elements is critical to determining the underlying causes of such conditions and the effects that both essential and nonessential metals have on fetal development. Thus, using cell-free fetal RNA from amniotic fluid, we set out to measure the association between amniotic fluid levels of toxic and essential metals and fetal gene expression. We find that arsenic was associated with increased expression of 3 genes known to play roles in both birth-related and reproductive effects. The results highlight the potential for detrimental health effects of prenatal metals exposure and the potential to identify biomarkers of environmental exposure during this critical developmental period. PMID- 29111620 TI - Readying Community Water Fluoridation Advocates through Training, Surveillance, and Empowerment. AB - This paper describes the Community Water Fluoridation Advocacy Training Project that was designed to develop networks of community water fluoridation advocates in rural communities. The South Carolina (SC) Department of Health and Environmental Control Division of Oral Health staff and the SC Dental Association were responsible for developing and facilitating the training sessions for key policy influencers, which included medical and dental providers, early childhood educators, and water system operators and managers. Findings from the post training survey indicate that participants increased their knowledge and skills to discuss the impact of water fluoridation on the dental health of community residents. Participants identified a need for online access to water fluoridation education and advocacy materials. Dental public health competencies illustrated: communication and collaboration with groups and individuals, and advocate, implement and evaluate public health policy, legislation and regulations. PMID- 29111621 TI - Medical Devices; Clinical Chemistry and Clinical Toxicology Devices; Classification of the Total 25-Hydroxyvitamin D Mass Spectrometry Test System. Final order. AB - The Food and Drug Administration (FDA, the Agency, or we) is classifying the total 25-hydroxyvitamin D mass spectrometry test system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the total 25 hydroxyvitamin D mass spectrometry test system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29111623 TI - Medical Devices; Exemption From Premarket Notification; Class II Devices; Autosomal Recessive Carrier Screening Gene Mutation Detection System. Final order. AB - The Food and Drug Administration (FDA or Agency) is publishing an order to exempt autosomal recessive carrier screening gene mutation detection systems from the premarket notification requirements, subject to certain limitations. This exemption from 510(k), subject to certain limitations, is immediately in effect for autosomal recessive carrier screening gene mutation detection systems. This exemption will decrease regulatory burdens on the medical device industry and will eliminate private costs and expenditures required to comply with certain Federal regulations. FDA is also amending the codified language for the autosomal recessive carrier screening gene mutation detection system devices classification regulation to reflect this final determination. PMID- 29111622 TI - Medical Devices; Immunology and Microbiology Devices; Classification of the Genetic Health Risk Assessment System. Final order. AB - The Food and Drug Administration (FDA, the Agency, or we) is classifying the genetic health risk assessment system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the genetic health risk assessment system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29111624 TI - Medicare and Medicaid Programs; CY 2018 Home Health Prospective Payment System Rate Update and CY 2019 Case-Mix Adjustment Methodology Refinements; Home Health Value-Based Purchasing Model; and Home Health Quality Reporting Requirements. Final rule. AB - This final rule updates the home health prospective payment system (HH PPS) payment rates, including the national, standardized 60-day episode payment rates, the national per-visit rates, and the non-routine medical supply (NRS) conversion factor, effective for home health episodes of care ending on or after January 1, 2018. This rule also: Updates the HH PPS case-mix weights using the most current, complete data available at the time of rulemaking; implements the third year of a 3-year phase-in of a reduction to the national, standardized 60-day episode payment to account for estimated case-mix growth unrelated to increases in patient acuity (that is, nominal case-mix growth) between calendar year (CY) 2012 and CY 2014; and discusses our efforts to monitor the potential impacts of the rebasing adjustments that were implemented in CY 2014 through CY 2017. In addition, this rule finalizes changes to the Home Health Value-Based Purchasing (HHVBP) Model and to the Home Health Quality Reporting Program (HH QRP). We are not finalizing the implementation of the Home Health Groupings Model (HHGM) in this final rule. PMID- 29111625 TI - Performance and reliability of the Y-Balance TestTM in high school athletes. AB - BACKGROUND: Lower extremity injuries account for 32.9% of the overall injuries in high school athletes. Previous research has suggested that asymmetry greater than 4 cm using the Y-Balance TestTM Lower Quarter (YBT-LQ) in the anterior direction is predictive of non-contact injuries in adults and collegiate athletes. The prevalence of asymmetries or abnormal YBT-LQ performance is not well documented for adolescents. The primary purposes of this study are: 1) to characterize the prevalence of YBT-LQ asymmetries and performance in a cross-sectional sample of adolescents; 2) to examine possible differences in performance on the YBT-LQ between male and female adolescents; and 3) to describe the test-retest reliability of the YBT-LQ in a subsample of adolescents. METHODS: Observational cross-sectional study. High-school athletes completed the YBT-LQ as main outcome measure. RESULTS: A total of 51 male and 59 female high-school athletes participated in this study. Asymmetries greater than 4cm in the posteromedial (PM) reach direction were most prevalent for male (54.9%) and female (50.8%) participants. Females presented with slightly higher composite scores. Good reliability (ICC=0.89) was found for the anterior (ANT) direction, and moderate reliability with 0.76 for posterolateral (PL) and 0.63 for PM directions. The MDC95 for the ANT direction was 6% and 12% for both the PL and PM directions. CONCLUSIONS: The YBT-LQ performance can be beneficial in assessing recovery in an injured extremity compared to the other limb. However, due to the large MDC95, noted in the PM and PL directions, the differences between sequential testing cannot be attributed to true change in balance unless they exceed the MDC95. In this study, 79% of the athletes presented with at least one asymmetry in YBT-LQ reach distances. Moderate reliability in the PL and PM directions warrants reexamination of the definition of asymmetry in these directions. PMID- 29111626 TI - Technical, tactical and movement analysis of men's professional tennis on hard courts. AB - BACKGROUND: There is very little information in tennis relating performance to both the movement of the players and the effectiveness of their shots. This study aimed to identify differences between winners and losers in the volume and intensity of their movements, as well as in the effectiveness of their shots. METHODS: Matches (N = 8) at the 2011 ATP 500 tournament in Valencia (Spain) were recorded and analysed using SAGIT, a computerised vision-tracking system. Data were split into points for movement analysis, and into games for stroke analysis. RESULTS: Players winning points used more offensive strategies and spent more time in the offensive zone than point losers. They also forced point losers to cover more distance at a higher speed. Game winners hit more winning shots, made fewer unforced errors, and were more effective than game losers. CONCLUSIONS: These results suggest that winner players controlled the game by playing more offensively and forcing losers to play in defensive positions, move greater distances at a faster speed, and make more errors. PMID- 29111627 TI - Quantification of bowling workload and changes in cognitive function in elite fast bowlers in training compared with twenty20 cricket. AB - BACKGROUND: Bowling overs are the primary recorded measure for workloads in cricket for youth through to professionals. However, the validity of this measure has never been tested. Additionally, despite the cognitive component of cricket being suggested to be very high, changes in psychomotor processing speed has again not been explored. METHODS: Eight professional English county cricket bowlers participated in the study. Participants wore global positioning systems with a tri-axial accelerometer during a Twenty20 match and training. Bowling overs were expressed relative to external forces. Additionally, cognitive function (as measured by psychomotor speed) was assessed pre and post Twenty20 game and training. RESULTS: When expressed relative to high intensity running distance or external forces from the tri-axial accelerometer, the cost of each over (6 deliveries) was over 100% higher in a Twenty20 game compared to training. Psychomotor speed was unchanged although error within the cognitive task increased post Twenty20 (391 +/- 82 to 547 to 104 ms) and training (414 +/- 110 to 561 to 238 ms). This data suggests that reaction time is unchanged from cricket but the chance of making the correct decision is increased. CONCLUSIONS: Movements in fielding should be quantified or bowling workloads adjusted to account for the high intensity fielding associated with Twenty20 cricket. Cognitive function was impaired following bowling, suggesting practitioners may also monitor psychomotor changes when assessing fatigue and allow appropriate time to mentally recover. PMID- 29111628 TI - Comparison of body fat percentage of male soccer players of different competitive levels, playing positions and age groups: a meta-analysis. AB - BACKGROUND: The aim of the present meta-analysis was to compare the body fat percentage (%) between male soccer players of different competitive levels, playing positions and age groups. EVIDENCE ACQUISITION: The systematic search was conducted using different databases and according to the Population/Intervention or Exposure/Comparison/Outcome(s) [PICO] criteria. EVIDENCE SYNTHESIS: Higher percentage values of body fat in lower-level soccer players than higher-level counterparts (ES=0.18, 95% CI -0.86 to -0.14, P=0.006) were noted. Higher body fat % values in goalkeepers than defenders (ES=0.21, 95% CI -1.17 to -0.34, P<0.001), midfielders (ES=0.26, 95% CI -1.50 to -0.45, P<0.001) and forwards (ES=0.18, 95% CI -1.26 to -0.53, P<0.001) were observed. There was no significant association between % of body fat and age (P=0.86). CONCLUSIONS: In conclusion, body fat percentage clearly distinguished higher- from lower-level soccer players. These findings also imply that body fat percentage differ as a function of positional role in soccer and that sports scientists, coaches, and strength and conditioning professionals need to be aware of the specific positional requirements in soccer in terms of body fat. However, due to some limitations of the present meta-analysis (high statistically significant heterogeneity and evidence of publication bias), further studies are urgently needed in the field. PMID- 29111629 TI - Effects of Muay Thai training frequency on body composition and physical fitness in healthy untrained women. AB - BACKGROUND: The purpose of the study was to compare the effects of different frequencies of Muay Thai training on body composition, and physical fitness in healthy untrained women. METHODS: Twenty women were randomly assigned to one of two training groups: G2X (n = 9) performed Muay Thai twice a week, while G3X (n = 11) performed the same program three times a week, both for 13 weeks. Anthropometric dimensions, fat-free mass, fat mass, resting metabolic rate, VO2 max, upper-body and abdominal muscle endurance, explosive leg power, agility, flexibility, and dietary intake were measured at pre and post-training. Training intensity was estimated every training session by rating of perceived exertion with a Borg 10- point scale. RESULTS: Both groups significantly improved in all measured physical fitness variables, without any significant changes in body composition. G2X was not significantly different from G3X on any variable. Average relative changes for all performance variables in G2X and G3X were 28.5% and 27.5%, respectively. CONCLUSIONS: Thirteen-weeks of Muay Thai practice can improve physical fitness in women, regardless of weekly frequency (two or three times a week). This suggests that instructors and coaches can structure a Muay Thai training program based on a twice or three-times per week protocol in order to promote positive changes in several important outcomes related to health for healthy untrained women. Moreover, practitioners are able to choose their training frequency preference, since both frequencies provided similar adaptations. PMID- 29111630 TI - Anthropometric profile of combat athletes via multivariate analysis. AB - BACKGROUND: Athletic success is a complex phenotype influenced by multiple factors, from sport-specific skills to anthropometric characteristics. Considering the latter, the literature has repeatedly indicated that athletes possess distinct physical characteristics depending on the practiced discipline. The aim of the present study was to apply univariate and multivariate methods to assess a wide range of morphometric and somatotypic characteristics in male combat athletes. METHODS: Biometric data were obtained from 206 male university level practitioners of judo, jiu-jitsu, karate, kickboxing, taekwondo, and wrestling. Measures included height- and length-based variables, breadths, circumferences, and skinfolds. Body proportions and somatotype, using Sheldon's method of somatotopy as modified by Heath and Carter, were then determined. Body fat percentage was assessed by bioelectrical impedance analysis using tetrapolar hand-to-foot electrodes. Data were subjected to a wide array of statistical analysis. RESULTS: The results show between-group differences in the magnitudes of the analyzed characteristics. While mesomorphy was the dominant component of each group somatotype, enhanced ectomorphy was observed in those disciplines that require a high level of agility. Principal component analysis reduced the multivariate dimensionality of the data to three components (characterizing body size, height-based measures, and the anthropometric structure of the upper extremities) that explained the majority of data variance. CONCLUSIONS: The development of a sport-specific anthropometric profile via height- and mass-based and morphometric and somatotypic variables can aid in the design of training protocols and the identification of athlete markers as well as serve as a diagnostic criterion in predicting combat athlete performance. PMID- 29111631 TI - Physical performance characteristics between male and female youth surfing athletes. AB - BACKGRAUND: Despite some knowledge about the fitness levels of elite surfers, there is limited published research examining gender differences, particularly in young athletes. The purpose of this study was to describe and compare the sex differences in physical performance characteristics of elite youth surfers. It was also aimed to study the association between physical performance variables. METHODS: This longitudinal prospective study was based on a total of twenty male and female youth surfers performed a battery of physical performance tests: anthropometrics, weight-bearing dorsiflexion test, Functional Movement Screen, lower extremity dynamic stability, lower limb dynamic strength, paddling and apnea test. The magnitude of differences between male and female surfers was tested and the percentage of difference between performances. RESULTS: When testing the correlation between the anthropometric and physical fitness variables and between performance variables, males and females present specific intra sex results that should be interpreted by surf coaches. CONCLUSIONS: Concerning better performance, working with young surfing athletes body composition have to be managed and the development of lower limb dynamic strength, especially for girls younger surfers. Supplementary it seems that Star Excursion Balance Test when compared bilaterally, can be a time efficiency indicator of the influence of surf training on the magnitude of lower limb asymmetry and postural control. In this way, surf coaches working with young athletes can implement appropriate and adjust training interventions. PMID- 29111632 TI - Rating of perceived capacity: a proposal to predict adequate levels of physical activity in visually impaired individuals. AB - BACKGROUND: There are several instruments that are generally used to analyze levels of physical activity (PA) in people with visual impairment. However, few instruments are validated for this population.The purpose of this study was to compare the subjective and objective variables of PA and to propose the use of the Rating of Perceived Capacity (RPC) to evaluate the level of moderate to vigorous physical activity (MVPA) per day in this population. METHODS: Thirty seven individuals with visual impairment participated in the study (19 blind without light perception and 18 low-vision). For the subjective physical activity evaluation, it was used the International Physical Activity Questionnaire Short Form (IPAQ-SF) and for the objective evaluation, it was used the ActiGraph GT3X+. RESULTS: Among the three analyzed (PA) intensities: moderate physical activity (MPA), vigorous physical activity (VPA) and MVPA, in VPA and MVPA was observed differences between the two methods (p=0.002 and p=0.011 respectively). Furthermore, the concordance between subjective and objective MVPA was not observed (ICC=0.239; p=0.176), and a greater variability of differences in MVPA between the two methods was observed by the Bland Altman scatter plot. However, positive correlation were found between the RPC and MVPA (p=0.470; p=0.003). In addition, in the Receiver Operating Characteristic (ROC) curve analysis, it was verified that values greater than 8 points in the RPC showed a predictive capacity for sufficient levels of objective MVPA (AUC = 0.809, sensitivity = 66.7, specificity = 90.9, p = <0.001). CONCLUSIONS: We concluded that the MVPA per day obtained by IPAQ-SF did not show agreement for the objective MVPA in visually impaired individuals. On the other hand, RPC presented itself as a alternative, practical and accessible tool to predict adequate levels of MVPA per day in this population. PMID- 29111633 TI - Soft Matter Lubrication: Does Solid Viscoelasticity Matter? AB - Classical lubrication theory is unable to explain a variety of phenomena and experimental observations involving soft viscoelastic materials, which are ubiquitous and increasingly used in e.g. engineering and biomedical applications. These include unexpected ruptures of the lubricating film and a friction-speed dependence, which cannot be elucidated by means of conventional models, based on time-independent stress-strain constitutive laws for the lubricated solids. A new modeling framework, corroborated through experimental measurements enabled via an interferometric technique, is proposed to address these issues: Solid/fluid interactions are captured thanks to a coupling strategy that makes it possible to study the effect that solid viscoelasticity has on fluid film lubrication. It is shown that a newly defined visco-elasto-hydrodynamic lubrication (VEHL) regime can be experienced depending on the degree of coupling between the fluid flow and the solid hysteretic response. Pressure distributions show a marked asymmetry with a peak at the flow inlet, and correspondingly, the film thickness reveals a pronounced shrinkage at the flow outlet; friction is heavily influenced by the viscoelastic hysteresis which is experienced in addition to the viscous losses. These features show significant differences with respect to the classical elasto hydrodynamic lubrication (EHL) regime response that would be predicted when solid viscoelasticity is neglected. A simple yet powerful criterion to assess the importance of viscoelastic solid contributions to soft matter lubrication is finally proposed. PMID- 29111634 TI - One-Step Synthesis of CuO-Cu2O Heterojunction by Flame Spray Pyrolysis for Cathodic Photoelectrochemical Sensing of l-Cysteine. AB - CuO-Cu2O heterojunction was synthesized via a one-step flame spray pyrolysis (FSP) process and employed as photoactive material in construction of a photoelectrochemical (PEC) sensing device. The surface analysis showed that CuO Cu2O nanocomposites in the size less than 10 nm were formed and uniformly distributed on the electrode surface. Under visible light irradiation, the CuO Cu2O-coated electrode exhibited admirable cathodic photocurrent response, owing to the favorable property of the CuO-Cu2O heterojunction such as strong absorption in the visible region and effective separation of photogenerated electron-hole pairs. On the basis of the interaction of l-cysteine (l-Cys) with Cu-containing compounds via the formation of Cu-S bond, the CuO-Cu2O was proposed as a PEC sensor for l-Cys detection. A declined photocurrent response of CuO-Cu2O to addition of l-Cys was observed. Influence factors including CuO-Cu2O concentration, coating amount of CuO-Cu2O, and applied bias potential on the PEC response toward l-Cys were optimized. Under optimum conditions, the photocurrent of the proposed sensor was linearly declined with increasing the concentration of l-Cys from 0.2 to 10 MUM, with a detection limit (3S/N) of 0.05 MUM. Moreover, this PEC sensor displayed high selectivity, reproducibility, and stability. The potential applicability of the proposed PEC sensor was assessed in human urine samples. PMID- 29111635 TI - Gravity-Drawn Silicone Filaments: Production, Characterization, and Wormlike Chain Dynamics. AB - We introduce a method to produce continuous polydimethylsiloxane (PDMS) silicone filaments on the order of 0.5 m long and 100 MUm in diameter. The approach overcomes traditional limitations in silicone drawing by partially precuring the polymer and drawing through a tube furnace. We characterize the filaments' mechanical properties, and their ability to switch hydrophobicity by UV-ozone and corona discharge patterning. The flexible filaments' dynamic properties were evaluated by way of athermal acoustic excitation at the air-water interface, revealing conformational reconfigurability consistent with a wormlike chain model. We envision applications in rapid prototyping and as a platform for model foldamer studies. PMID- 29111636 TI - Reaction Mechanism of Area-Selective Atomic Layer Deposition for Al2O3 Nanopatterns. AB - The reaction mechanism of area-selective atomic layer deposition (AS-ALD) of Al2O3 thin films using self-assembled monolayers (SAMs) was systematically investigated by theoretical and experimental studies. Trimethylaluminum (TMA) and H2O were used as the precursor and oxidant, respectively, with octadecylphosphonic acid (ODPA) as an SAM to block Al2O3 film formation. However, Al2O3 layers began to form on the ODPA SAMs after several cycles, despite reports that CH3-terminated SAMs cannot react with TMA. We showed that TMA does not react chemically with the SAM but is physically adsorbed, acting as a nucleation site for Al2O3 film growth. Moreover, the amount of physisorbed TMA was affected by the partial pressure. By controlling it, we developed a new AS-ALD Al2O3 process with high selectivity, which produces films of ~60 nm thickness over 370 cycles. The successful deposition of Al2O3 thin film patterns using this process is a breakthrough technique in the field of nanotechnology. PMID- 29111637 TI - Synthesis of Cellulose-graft-Polypropionic Acid Nanofiber Cation-Exchange Membrane Adsorbers for High-Efficiency Separations. AB - Fabrication of membrane adsorbers with elevated binding capacity and high throughput is highly desired for simplifying and improving purification efficiencies of bioproducts (biotherapeutics, vaccines, etc.) in the biotechnological and biopharmaceutical industries. Here we demonstrate the preparation of a novel class of self-supported, cellulose-graft-polypropionic acid (CL-g-PPA) cation-exchange nanofiber membrane adsorbers under mild reaction conditions for the purification of positively charged therapeutic proteins. In our fabrication method, acrylonitrile was first polymerized and surface grafted onto cellulose nanofibers using cerium ammonium nitrate as a redox initiator to form cellulose-g-polyacrylonitrile (CL-g-PAN). CL-g-PAN was then submitted to a hydrolyzation reaction to form CL-g-PPA cationic membrane adsorbers. Morphology and structural characterization illustrated the formation of CL-g-PPA membranes with uniform coating of polyacid nanolayers along the individual nanofibers without disturbing the nanofiber structure. Benefiting from these numerous cationic polyacid binding sites and inherent large surface area and open porous structure, CL-g-PPA nanofiber membrane adsorbers showed a lysozyme static adsorption capacity of 1664 mg/g of nanofibers. These membranes showed a lysozyme dynamic binding capacity of 508 mg/g of nanofibers at 10% breakthrough (equivalent to 206 g/L capacity), with a residence time of less than 6 s. Moreover, CL-g-PPA self-supported nanofibers displayed excellent structural stability and reversibility after several cycles of protein binding studies. This dynamic binding capacity of the CL-g-PPA nanofiber membranes was 3.2 times higher than that of macroporous cellulose membranes and 8.5 times higher than that of the Sartobind S commercial membrane adsorber. Considering the simple fabrication method employed, excellent protein adsorption capacity, remarkable structural stability, and reusability, CL-g-PPA nanofiber membranes provided a versatile platform for the chromatographic separations of biomolecules (e.g., proteins, nucleic acids, and viral vaccines) as well as water purification and similar ion exchange applications. PMID- 29111638 TI - Synergistic Activity of Co and Fe in Amorphous Cox-Fe-B Catalyst for Efficient Oxygen Evolution Reaction. AB - Water splitting has been greatly limited by the sluggish kinetics of the oxygen evolution reaction (OER). High-oxidation-state metal species are required as the favorable active sites in OER. Here, amorphous Cox-Fe-B (x is the molar ratio of Co/Fe), Co-B, and Fe-B compounds were successfully synthesized as the oxygen evolution electrocatalysts. The calculation of turnover frequency (TOF) indicates that both the Co and Fe sites are active for OER. Cyclic voltammetry, X-ray photoelectron spectroscopy, and long-term stability curves were used to demonstrate that Fe can stabilize Co in a higher oxidation level and meanwhile promote the generation of OOH-like species (the key intermediates for OER). The reduced impedance for Co2-Fe-B (compared with that for Fe-B and Co-B) obtained from the electrochemical impedance spectra confirms the enhanced conductivity for the Co2-Fe-B. This optimal sample on Cu substrate shows a low overpotential of 0.298 V at the current density of 10 mA cm-2 with a decreased overpotential of 42 mV compared to that of Co-B. The Co2-Fe-B catalyst also exhibits a small Tafel slope of 62.6 mV/dec and good stability. The enhanced performance could be attributed to the synergistic effect of the increased population of high oxidation-state metal-OOH species and the promoted conductivity of the catalyst. A solar-to-hydrogen energy conversion efficiency of 4.2% and a Faradaic efficiency of 97.2% can be achieved by connecting the HER and as-prepared OER electrodes to a crystalline silicon solar cell. PMID- 29111639 TI - Synergistic Effect to High-Performance Perovskite Solar Cells with Reduced Hysteresis and Improved Stability by the Introduction of Na-Treated TiO2 and Spraying-Deposited CuI as Transport Layers. AB - For a typical perovskite solar cell (PKSC), both the electron transport layers (ETLs) and hole transport materials (HTMs) play a very important role in improving the device performance and long-term stability. In this paper, we firstly improve the electron transport properties by modification of TiO2 ETLs with Na species, and an enhanced power conversion efficiency (PCE) of 16.91% has been obtained with less hysteresis. Subsequently, an inorganic CuI film prepared by a facile spray deposition method has been employed to replace the conventional spiro-OMeTAD as the HTM in PKSCs. Because of the improved transport properties at the ETL/perovskite and perovskite/HTM interfaces, a maximum photovoltaic efficiency of 17.6% with reduced hysteresis has been achieved in the PKSC with both the Na-modified TiO2 ETL and 60 nm-thick CuI layer HTM. To our knowledge, the PCE achieved in this paper is one of the highest values ever reported for the PKSC devices with inorganic HTMs. More significantly, the PKSCs exhibit an outstanding device stability, their PCE remains constant after storage in the dark for 50 days, and they can retain approximately 92% of their initial efficiency after storage even for 90 days. PMID- 29111640 TI - Importance of Substrate Functionality on the Adhesion and Debonding of a Pressure Sensitive Adhesive under Water. AB - We investigate the effect of an aqueous environment on the adhesion of a model acrylic pressure-sensitive adhesive (PSA) composed of 2-ethylhexyl acrylate-co acrylic acid. We use probe-tack adhesion measurements accompanied by in situ imaging of the contact region during bonding and debonding. Within the probe-tack tests, we use both hydrophilic (piranha and plasma treatment) and hydrophobic (C18-silanization) surface treatments to investigate the contribution of the probe's surface energy on the underwater adhesion. In examining contact formation in air and underwater, we find that the presence of water when contact is made leads to different modes of PSA relaxation and contact formation. For all probes investigated, the adhesive strength between the PSA and the probe decreases when measured underwater. Additionally, we observe that the presence of water during debonding has a more pronounced effect on the adhesive strength of the PSA when probed by a hydrophilic surface as opposed to a hydrophobic surface. Using fingering wavelength analysis, we estimate the surface energy of the PSA in situ and find that when submerged in water, the PSA has a significantly higher surface energy compared to in air. Therefore, combining the observation of different modes of contact formation, the increase in surface energy, and the importance of the surface energy of the probe, we suggest that the decrease in adhesive strength in water can be explained by the hydration of the PSA and by trapped water defects between the PSA and the probe. PMID- 29111641 TI - Temperature-Responsive Hierarchical Polymer Brushes Switching from Bactericidal to Cell Repellency. AB - Unlike conventional poly(N-isopropylacrylamide) (PNIPAM)-based surfaces switching from bactericidal activity to bacterial repellency upon decreasing temperature, we developed a hierarchical polymer architecture, which could maintain bactericidal activities at room temperature while presenting bacterial repellency at physiological temperature. In this architecture, a thermoresponsive bactericidal upper layer consisting of PNIPAM-based copolymer and vancomycin (Van) moieties was built on an antifouling poly(sulfobetaine methacrylate) (PSBMA) bottom layer via sequential surface-initiated photoiniferter-mediated polymerization. At room temperature below the lower critical solution temperature (LCST), the PNIPAM-based upper layer was stretchable, facilitating contact killing of bacteria by Van. At physiological temperature (above the LCST), the PNIPAM-based layer collapsed, thus leading to the burial of Van and exposure of bottom PSBMA brushes, finally displaying notable performances in bacterial inhibition, dead bacteria detachment, and biocompatibility, simultaneously. Our strategy provides a novel pathway in the rational design of temperature-sensitive switchable surfaces, which shows great advantages in the real-world infection resistant applications. PMID- 29111642 TI - A Stretchable and Transparent Nanocomposite Nanogenerator for Self-Powered Physiological Monitoring. AB - Smart sensing electronic devices with good transparency, high stretchability, and self-powered sensing characteristics are essential in wearable health monitoring systems. This paper innovatively proposes a stretchable nanocomposite nanogenerator with good transparency that can be conformally attached to the human body to harvest biomechanical energy and monitor physiological signals. The work reports an innovative device that uses sprayed silver nanowires as transparent electrodes and sandwiches a nanocomposite of piezoelectric BaTiO3 and polydimethylsiloxane as the sensing layer, which exhibits good transparency and mechanical transformability with stretchable, foldable, and twistable properties. The highly flexible nanogenerator affords a good input-output linearity under the vertical force and the sensing ability to detect lateral stretching deformation up to 60% strain under piezoelectric mechanisms. Furthermore, the proposed device can effectively harvest touch energies from the human body as a single-electrode triboelectric nanogenerator. Under periodic contact and separation, a maximum output voltage of 105 V, a current density of 6.5 MUA/cm2, and a power density of 102 MUW/cm2 can be achieved, exhibiting a good power generation performance. Owing to the high conformability and excellent sensitivity of the nanogenerator, it can also act as a self-powered wearable sensor attached to different parts of the human body for real-time monitoring of the human physiological signals such as eye blinking, pronunciation, arm movement, and radial artery pulse. The designed nanocomposite nanogenerator shows great potential for use in self powered e-skins and healthcare monitoring systems. PMID- 29111643 TI - Kiwifruit-like Persistent Luminescent Nanoparticles with High-Performance and in Situ Activable Near-Infrared Persistent Luminescence for Long-Term in Vivo Bioimaging. AB - Persistent luminescence nanoparticles (PLNPs) have great potential for bioimaging because they can eliminate the tissue autofluorescence and improve the signal-to noise ratio significantly. High-temperature calcination is a necessary process for the PLNPs to achieve high luminescence intensity and long afterglow time. However, high-temperature calcination usually results in uncontrollable morphology and poor homogeneity of PLNPs, which greatly limit their applications. Therefore, there is still a high demand to find a suitable method for synthesizing PLNPs with high luminescence intensity and long afterglow time while maintaining their monodispersed morphology. Herein, we report a facile silica template method to synthesize PLNPs with a kiwifruit-like structure that can tolerate high-temperature calcination. The as-prepared kiwifruit-like SiO2@ZnGa2O4:Cr3+@SiO2 PLNPs have enhanced near-infrared persistent luminescence, uniform morphology and size, and good biocompatibility. Moreover, the SiO2@ZnGa2O4:Cr3+@SiO2 PLNPs can be repeatedly activated by soft X-rays in situ and emit near-infrared persistent luminescence with long decay time, holding great potential for deep-tissue and long-term in vivo bioimaging. We believe that this study will open new perspectives for synthesizing high-performance PLNPs for optical imaging and diversified applications. PMID- 29111644 TI - Condensing Vapor Phase Polymerization (CVPP) of Electrochemically Capacitive and Stable Polypyrrole Microtubes. AB - We introduce a novel condensing vapor phase polymerization (CVPP) strategy for depositing microtubes of the conducting polymer polypyrrole; these serve as one dimensional hollow microstructures for storing electrochemical energy. In CVPP, water droplets are structure-directing templates for polypyrrole microtubes. Water vapor condensation and polymerization occur simultaneously-conformal coatings of microtubes deposit on porous substrates such as hard carbon fiber paper or glass fiber filter paper. A mechanistic evolution of the microtubular morphology is proposed and tested based on the mass transport of water and monomer vapors as well as on the reaction stoichiometry. A coating of PPy microtubes is characterized by a high reversible capacitance of 342 F g-1 at 5 mV s-1 throughout 5000 cycles of cyclic voltammetry and a low sheet resistance of 70.2 Omega ?-1. The open tubular structure is controlled in situ during synthesis and leads to electrodes that exhibit electrochemical stability at high scanning rates up to 250 mV s-1 retaining all stored charge, even after extensive cycling at 25 mV s-1. PMID- 29111645 TI - "Cuju"-Structured Iron Diselenide-Derived Oxide: A Highly Efficient Electrocatalyst for Water Oxidation. AB - Electrocatalysts with outstanding performance have been highly desired toward exploration of new energy storage and conversion devices/systems as well as making an efficient and eco-friendly utilization of green energy. In this study, we composed an iron-based binary diselenide-derived oxide (Fe-SDO) with a facile one-step hydrothermal method to utilize the earth-abundant iron and the probably prosperous catalytic performance of metal-selenides compounds. The catalyst exhibits an overpotential of 226 mV at a current density of 10 mA/cm2, a Tafel slope of 41 mV dec-1, and robust durability after catalyzing vigorous OER for 36 h constantly. Through several analytical methods conducted before and after the oxygen evolution reaction activation on FeSe2 it was discovered that such catalyst possessed a morphology as "Cuju"-like balls with porosity inside in which we explored the vacancy defects and lattice distortion that play significant roles in generating the high electrocatalytic performance of our proposed catalyst by inducing remarkable electron conductivity in the porous Cuju balls (a Chinese traditional football). Throughout our work the superb electrocatalyst performance of the iron-based compounds was demonstrated, and subsequently the underlying reason for such electrocatalyst performance was addressed, which may push boundaries for the exploration of iron-based compounds as OER catalyst and large-scale commercial application of such compounds in the future. PMID- 29111646 TI - Structural Analyses of Phase Stability in Amorphous and Partially Crystallized Ge Rich GeTe Films Prepared by Atomic Layer Deposition. AB - The local bonding structures of GexTe1-x (x = 0.5, 0.6, and 0.7) films prepared through atomic layer deposition (ALD) with Ge(N(Si(CH3)3)2)2 and ((CH3)3Si)2Te precursors were investigated using Ge K-edge X-ray absorption spectroscopy (XAS). The results of the X-ray absorption fine structure analyses show that for all of the compositions, the as-grown films were amorphous with a tetrahedral Ge coordination of a mixture of Ge-Te and Ge-Ge bonds but without any signature of Ge-GeTe decomposition. The compositional evolution in the valence band electronic structures probed through X-ray photoelectron spectroscopy suggests a substantial chemical influence of additional Ge on the nonstoichiometric GeTe. This implies that the ALD process can stabilize Ge-abundant bonding networks like -Te-Ge-Ge-Te in amorphous GeTe. Meanwhile, the XAS results on the Ge-rich films that had undergone post-deposition annealing at 350 degrees C show that the parts of the crystalline Ge-rich GeTe became separated into Ge crystallites and rhombohedral GeTe in accordance with the bulk phase diagram, whereas the disordered GeTe domains still remained, consistent with the observations of transmission electron microscopy and Raman spectroscopy. Therefore, amorphousness in GeTe may be essential for the nonsegregated Ge-rich phases and the low growth temperature of the ALD enables the achievement of the structurally metastable phases. PMID- 29111647 TI - Insulator-to-Metal Transition at Oxide Interfaces Induced by WO3 Overlayers. AB - Interfaces between complex oxides constitute a unique playground for two dimensional electron systems (2DESs), where superconductivity and magnetism can arise from combinations of bulk insulators. The 2DES at the LaAlO3/SrTiO3 interface is one of the most studied in this regard, and its origin is determined by the polar field in LaAlO3 as well as by the presence of point defects, like oxygen vacancies and intermixed cations. These defects usually reside in the conduction channel and are responsible for a decrease of the electronic mobility. In this work, we use an amorphous WO3 overlayer to obtain a high-mobility 2DES in WO3/LaAlO3/SrTiO3 heterostructures. The studied system shows a sharp insulator-to metal transition as a function of both LaAlO3 and WO3 layer thickness. Low temperature magnetotransport reveals a strong magnetoresistance reaching 900% at 10 T and 1.5 K, the presence of multiple conduction channels with carrier mobility up to 80 000 cm2 V-1 s-1, and quantum oscillations of conductance. PMID- 29111648 TI - Shape-Uniform, High-Quality Monolayered MoS2 Crystals for Gate-Tunable Photoluminescence. AB - Two-dimensional molybdenum disulfide (MoS2) has recently drawn major attention due to its promising applications in electronics and optoelectronics. Chemical vapor deposition (CVD) is a scalable method to produce large-area MoS2 monolayers, yet it is challenging to achieve shape-uniform, high-quality monolayered MoS2 grains as random, diverse crystallographic orientations and various shapes are produced in the same CVD process. Here, we report the growth of high-quality MoS2 monolayers with uniform triangular shapes dominating (up to 89%) over other shapes on both SiO2/Si and sapphire substrates. The new confined space CVD process prevents contamination and helps regulate the Mo/S ratio during the deposition. The as-grown triangular MoS2 monolayers exhibit grain sizes up to 150 MUm and possess better crystalline properties and lighter n-type doping concentration than those of the monolayers grown by common CVD methods. The corresponding field effect transistor devices show high electron mobilities of 50 60 cm2 V-1 s-1 and positive threshold voltages of 21-35 V. This mild n-type behavior makes it possible to regulate the formation of excitons by back-gate voltage due to the interaction of excitons with free charge carriers in the MoS2 channel. As a result, gate-tunable photoluminescence (PL) effect, which is rarely achievable for MoS2 samples prepared by common CVD or mechanical exfoliation, is demonstrated. This study provides a simple versatile approach to fabricating monolayered crystals of MoS2 and other high-quality transition metal dichalcogenides and could lead to new optoelectronic devices based on gate tunable PL effect. PMID- 29111649 TI - Omnidirectional Deformable Energy Textile for Human Joint Movement Compatible Energy Storage. AB - Omnidirectional deformability is an unavoidable basic requirement for wearable devices to accommodate human daily motion particularly at human joints. We demonstrate omnidirectionally bendable and stretchable textile-based electrochemical capacitor that retains high power performance under complex mechanical deformation. Judicious synergistic hybrid structure of woven elastic polymer yarns with carbon nanotubes and conductive polymers offers reliable electrical and electrochemical activity even under repeated cycles of severe complex deformation modes. The textile-based electrochemical capacitors exhibit omnidirectional stretchability with 93% of capacitance retention under repeated 50% omnidirectional stretching condition while demonstrating excellent specific capacitance (412 mF cm-2) and cycle stability (>2000 stretch). The wearable power source stably powers red LED under omnidirectional stretching that accompanies human elbow joint motion. PMID- 29111650 TI - Surface Engineering of Thin Film Composite Polyamide Membranes with Silver Nanoparticles through Layer-by-Layer Interfacial Polymerization for Antibacterial Properties. AB - We developed a simple and facile approach to covalently immobilize Ag nanoparticles (NPs) onto polyamide surfaces of thin film composite membranes through layer-by-layer interfacial polymerization (LBL-IP) for biofouling mitigation. Stable and uniform bovine serum albumin (BSA) capped Ag NPs with an average diameter of around 20 nm were synthesized using BSA as a template under the assistance of sonication, and Ag NPs incorporated thin film composite (TFC) polyamide membrane was then fabricated by LBL-IP on a nanoporous polysulfone (PSf) substrate upon sequential coating with m-phenylenediamine (MPD) aqueous solution, trimesoyl chloride (TMC)-hexane solution, and finally BSA-capped Ag NPs aqueous solution. The influence of Ag NPs incorporation was investigated on the surface physicochemical properties, water permeability, and salt rejection of TFC polyamide membrane. Our findings show that Ag NPs functionalized membrane exhibited excellent antibacterial properties without sacrificing their permeability and rejection, and Ag NPs incorporation affected very little surface roughness and charge of polyamide layer. Moreover, the incorporated Ag NPs presented a low release rate and excellent stability on polyamide surface in cross-flow conditions. Given the simplicity and versatility of this approach, our study provides a practicable avenue for direct incorporation of various surface tailored nanomaterials on the polyamide surface to develop high-performance TFC membranes with fouling-resistant properties on a large scale. PMID- 29111651 TI - A Series of Lithium Pyridyl Phenolate Complexes with a Pendant Pyridyl Group for Electron-Injection Layers in Organic Light-Emitting Devices. AB - We report a new series of lithium pyridyl phenolate complexes with a pendant pyridyl group, Li2BPP, Li3BPP, and Li4BPP, in which the pendant pyridines are substituted at the 2-, 3-, and 4-positions, respectively. The most important difference between these complexes is their molecular planarity; Li3BPP and Li4BPP adopt twisted bipyridine structures, whereas Li2BPP adopts a planar structure owing to the steric hindrance and chelating effect of bipyridine on the Li core. The planar structure leads to crystallization through pi-pi stacking interactions, and the small differences in the molecular structures of the pendant pyridine rings cause drastic differences in the physical properties of thin solid films of these complexes. We applied these complexes as electron injection layers (EILs) in Ir(ppy)3-based organic light-emitting devices. When thin EILs were used, Li3BPP and Li4BPP afforded lower driving voltages than Li2BPP; the order of the driving voltages followed the order of their electron affinity values. Moreover, the dependence of driving voltage on the EIL thickness was investigated for each complex. Among the three LiBPP derivatives, Li2BPP based devices showed almost negligible EIL thickness dependence, which may be attributable to the high crystallinity of Li2BPP. All LiBPP-based devices also showed higher stability than conventional 8-quinolinolato lithium-based devices. PMID- 29111652 TI - Ionic Liquid Mediated Dispersion and Support of Functional Molecules on Cellulose Fibers for Stimuli-Responsive Chromic Paper Devices. AB - Functional molecules play a significant role in the development of high performance composite materials. Functional molecules should be well dispersed (ideally dissolved) and supported within an easy-to-handle substrate to take full advantage of their functionality and ensure easy handling. However, simultaneously achieving the dissolution and support of functional molecules remains a challenge. Herein, we propose the combination of a nonvolatile ionic liquid and an easy-to-handle cellulose paper substrate for achieving this goal. First, the photochromic molecule, i.e., diarylethene, was dissolved in the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([bmim]NTf2). Then, diarylethene/[bmim]NTf2 was supported on cellulose fibers within the paper, through hydrogen bonding between [bmim] cations of the ionic liquid and the abundant hydroxyl groups of cellulose. The as-prepared paper composites exhibited reversible, rapid, uniform, and vivid coloration and bleaching upon ultraviolet and visible light irradiation. The photochromic performance was superior to that of the paper prepared in the absence of [bmim]NTf2. This concept could be applied to other functional molecules. For example, lithium perchlorate/[bmim] tetrafluoroborate supported within cellulose paper acted as a flexible electrolyte to provide a paper-based electrochromic device. These findings are expected to further the development of composite materials with high functionality and practicality. PMID- 29111653 TI - Surface State Density Determines the Energy Level Alignment at Hybrid Perovskite/Electron Acceptors Interfaces. AB - Substantial variations in the electronic structure and thus possibly conflicting energetics at interfaces between hybrid perovskites and charge transport layers in solar cells have been reported by the research community. In an attempt to unravel the origin of these variations and enable reliable device design, we demonstrate that donor-like surface states stemming from reduced lead (Pb0) directly impact the energy level alignment at perovskite (CH3NH3PbI3-xClx) and molecular electron acceptor layer interfaces using photoelectron spectroscopy. When forming the interfaces, it is found that electron transfer from surface states to acceptor molecules occurs, leading to a strong decrease in the density of ionized surface states. As a consequence, for perovskite samples with low surface state density, the initial band bending at the pristine perovskite surface can be flattened upon interface formation. In contrast, for perovskites with a high surface state density, the Fermi level is strongly pinned at the conduction band edge, and only minor changes in surface band bending are observed upon acceptor deposition. Consequently, depending on the initial perovskite surface state density, very different interface energy level alignment situations (variations over 0.5 eV) are demonstrated and rationalized. Our findings help explain the rather dissimilar reported energy levels at interfaces with perovskites, refining our understanding of the operating principles in devices comprising this material. PMID- 29111654 TI - NiFeCr Hydroxide Holey Nanosheet as Advanced Electrocatalyst for Water Oxidation. AB - By introducing chromium into a nickel-iron layered double hydroxide (LDH), a nickel iron chromium hydroxide nanomesh catalyst has been achieved on nickel foam substrate via electrodeposition followed by partial etching of chromium. The electrodeposited chromium acts as a sacrificial template to introduce holes in the LDH to increase the electrochemically active surface area, and the remaining chromium synergistically modulates the electronic structure of the composite. The obtained electrode shows extraordinary performance for oxygen evolution reaction and excellent electrochemical stability. The onset potential of the as-prepared electrode in 1 M KOH is only 1.43 V vs RHE, and the overpotential to achieve a high current density of 100 mA.cm-2 is only 255 mV, outperforming benchmark nonprecious NiFe hydroxide composite electrode in alkaline media. PMID- 29111655 TI - Graphene Aerogel Templated Fabrication of Phase Change Microspheres as Thermal Buffers in Microelectronic Devices. AB - Phase change materials, changing from solid to liquid and vice versa, are capable of storing and releasing a large amount of thermal energy during the phase change, and thus hold promise for numerous applications including thermal protection of electronic devices. Shaping these materials into microspheres for additional fascinating properties is efficient but challenging. In this regard, a novel phase change microsphere with the design for electrical-regulation and thermal storage/release properties was fabricated via the combination of monodispersed graphene aerogel microsphere (GAM) and phase change paraffin. A programmable method, i.e., coupling ink jetting-liquid marbling-supercritical drying (ILS) techniques, was demonstrated to produce monodispersed graphene aerogel microspheres (GAMs) with precise size-control. The resulting GAMs showed ultralow density, low electrical resistance, and high specific surface area with only ca. 5% diameter variation coefficient, and exhibited promising performance in smart switches. The phase change microspheres were obtained by capillary filling of phase change paraffin inside the GAMs and exhibited excellent properties, such as low electrical resistance, high latent heat, well sphericity, and thermal buffering. Assembling the phase change microsphere into the microcircuit, we found that this tiny device was quite sensitive and could respond to heat as low as 0.027 J. PMID- 29111656 TI - Charge-Gated Ion Transport through Polyelectrolyte Intercalated Amine Reduced Graphene Oxide Membranes. AB - Charge-gated channels are nature's solutions for transport of water molecules and ions through aquaporins in biological membranes while excluding undesired substances. The same mechanism has good potentials to be adopted in pressure or electrically driven membrane separation processes. Herein, we report highly charged nanochannels created in polyelectrolyte (PE) intercalated amine reduced graphene oxide membrane (PE@ArGO membrane). The PE@ArGO membrane, with a rejection layer of ~160 nm in thickness, features a laminate structure and a smooth top surface of a low roughness (typically ~17.2 nm). Further, a modified PE@ArGO membrane (mPE@ArGO membrane) was developed in situ using free chlorine scavenging post-treatment method, which was designed to alter the charge while keeping alteration to the layered structure minimal. The surface charge of the PE@ArGO and mPE@ArGO membrane was +4.37 and -4.28 mC/m2 respectively. In pressure driven processes, the pure water permeability for PE@ArGO and mPE@ArGO was 2.9 and 10.8 L m-2 h-1 bar-1, respectively. Salt rejection is highly dependent on the charge density of the membrane surface, the valence of the co-ions and the size of ions in hydrated form. For example, in the positively charged PE@ArGO membranes, the rejection of the salts follows the order of: R(MgCl2), 93.0% > R(NaCl), 88.2% ~ R(MgSO4), 88.1% > R(Na2SO4), 65.1%; while in the negatively charged mPE@ArGO membranes, the rejection of the salts follows the order of: R(Na2SO4), 90.3% > R(NaCl), 85.4% > R(MgSO4), 68.3% > R(MgCl2), 42.9%. To the best knowledge of the authors, this is the first study to report graphene oxide based membranes (GOBMs) with high density positive/negative charge gated ion transport behavior. What's more, the high rejection rate along with high water permeability of the PE@ArGO and mPE@ArGO membranes has not been achieved by other types of GOBMs. PMID- 29111657 TI - Nanoporous TiNb2O7/C Composite Microspheres with Three-Dimensional Conductive Network for Long-Cycle-Life and High-Rate-Capability Anode Materials for Lithium Ion Batteries. AB - On the basis of the advantages of ideal cycling stability, high discharge voltage (1.65 V), and excellent reversibility, more and more attention has been focused on TiNb2O7 (marked as TNO) as an anode material candidate for lithium-ion batteries. However, the poor electronic conductivity and low ionic diffusion rate intrinsically restrict its practical use. Herein, we first synthesize the TNO/C composite microspheres with three-dimensionally (marked as 3D) electro-conductive carbon network and abundant nanoporous structure by a simple spray-drying method. The microspheres are constructed by irregularly primary cubic nanoparticle units with size of 100-200 nm. The nanopores throughout the microspheres range from 1 to 50 nm. As an anode material, the prepared TNO/C composite microspheres demonstrate a prominent charge/discharge capacity of 323.2/326 mA h g-1 after 300 cycles at 0.25 C (1 C = 388 mA g-1) and 259.9/262.5 mA h g-1 after 1000 long cycles at a high current density of 5 C, revealing the ideal reversible capacity and long cycling life. Meanwhile, the TNO/C composite microspheres present ideal rate performance, showing the discharge capacity of 120 mA h g-1 at 30 C after 10 cycles. The super electrochemical performance could be attributed to the 3D electro-conductive carbon network and nanoporous structure. The nanopores facilitate the permeation of electrolyte into the intercontacting regions of the anode materials. Carbon layers disperse uniformly throughout the 3D microspheres, effectively improving the electrical conductivity of the electrode. Hence, the prepared TNO/C composite microspheres have great potential to be used as an anode material for lithium-ion batteries. PMID- 29111658 TI - Structure-Property Correlation in Luminescent Indolo[3,2-b]indole (IDID) Derivatives: Unraveling the Mechanism of High Efficiency Thermally Activated Delayed Fluorescence (TADF). AB - A series of indolo[3,2-b]indole (IDID) derivatives are designed as a novel structural platform for thermally activated delayed fluorescence (TADF) emitters. Intramolecular charge transfer (ICT)-type molecules consisting of IDID donor (D) and various acceptor (A) moieties are synthesized and characterized in the protocol of the systematical structure-property correlation. IDID derivatives exhibit high efficiency, prompt fluorescence as well as TADF with emission ranges tuned by the chemical structure of the acceptor units. Interestingly, almost all of the IDID derivatives show an identical energy level of the lowest triplet excited state (T1) attributed to the locally excited triplet state of the IDID backbone (3LEID), while that of their lowest singlet excited state (S1) is largely tuned by varying the acceptor units. Thus, we demonstrate the underlying mechanism in terms of the molecular engineering. Among the compounds, Tria-phIDID and BP-phIDID generate efficient delayed fluorescence based on the small energy gap between the lowest singlet and triplet excited states (DeltaEST) and mediation of the 3LEID state. Organic light-emitting diodes with these Tria phIDID and BP-phIDID as a dopant in the emitting layer show highly efficient electroluminescence with maximum external quantum efficiencies of 20.8% and 13.9%, respectively. PMID- 29111659 TI - Collapse of DNA Tetrahedron Nanostructure for "Off-On" Fluorescence Detection of DNA Methyltransferase Activity. AB - As a potential detection technique, highly rigid and versatile functionality of DNA tetrahedron nanostructures is often used in biosensing systems. In this work, a novel multifunctional nanostructure has been developed as an "off-on" fluorescent probe for detection of target methyltransferase by integrating the elements of DNA tetrahedron, target recognition, and dual-labeled reporter. This sensing system is initially in an "OFF" state owing to the close proximity of fluorophores and quenchers. After the substrate is recognized by target methyltransferase, the DNA tetrahedron can be methylated to produce methylated DNA sites. These sites can be recognized and cut by the restriction endonuclease DpnI to bring about the collapse of the DNA tetrahedron, which leads to the separation of the dual-labeled reporters from the quenchers, and thus the recovery of fluorescence signal to produce an "ON" state. The proposed DNA tetrahedron-based sensing method can detect Dam methyltransferase in the range of 0.1-90 U mL-1 with a detection limit of 0.045 U mL-1 and shows good specificity and reproducibility for detection of Dam methyltransferase in a real sample. It has been successfully applied for screening various methylation inhibitors. Thus, this work possesses a promising prospect for detection of DNA methyltransfrase in the field of clinical diagnostics. PMID- 29111660 TI - a-Axis GaN/AlN/AlGaN Core-Shell Heterojunction Microwires as Normally Off High Electron Mobility Transistors. AB - Micro/nanowire-based devices have been envisioned as a promising new route toward improved electronic and optoelectronic applications, which attracts considerable research interests. However, suffering from applicable strategies to synthesize uniform core-shell structures to meet the requirement for the investigations of electrical transport behaviors along the length direction or high electron mobility transistor (HEMT) devices, heterojunction wire-based electronics have been explored limitedly. In the present work, GaN/AlN/AlGaN core-shell heterojunction microwires on patterned Si substrates were synthesized without any catalyst via metalorganic chemical vapor deposition. The as-synthesized microwires had low dislocation, sharp, and uniform heterojunction interfaces. Electrical transport performances were evaluated by fabricating HEMTs on the heterojunction microwire channels. Results demonstrated that a normally off operation was achieved with a threshold voltage of 1.4 V, a high on/off current ratio of 108, a transconductance of 165 mS/mm, and a low subthreshold swing of 81 mV/dec. The normally off operation may attribute to the weak polarization along semipolar facets of the heterojunction, which leads to weak constrain of 2DEG. PMID- 29111661 TI - Using p-type PbS Quantum Dots to Quench Photocurrent of Fullerene-Au NP@MoS2 Composite Structure for Ultrasensitive Photoelectrochemical Detection of ATP. AB - Ultrasensitive and rapid quantification of the universal energy currency adenosine triphosphate (ATP) is an extremely critical mission in clinical applications. In this work, a "signal-off" photoelectrochemical (PEC) biosensor was designed for ultrasensitive ATP detection based on a fullerene (C60) decorated Au nanoparticle@MoS2 (C60-Au NP@MoS2) composite material as a signal indicator and a p-type PbS quantum dot (QD) as an efficient signal quencher. Modification of wide band gap C60 with narrow band gap MoS2 to form an ideal PEC signal indicator was proposed, which could significantly improve photocurrent conversion efficiency, leading to a desirable PEC signal. In the presence of p type PbS QDs, the PEC signal of n-type C60-Au NP@MoS2 was effectively quenched because p-type PbS QDs could compete with C60-Au NP@MoS2 to consume light energy and electron donor. Besides, the conversion of a limited amount of target ATP into an amplified output PbS QD-labeled short DNA sequence (output S1) was achieved via target-mediated aptazyme cycling amplification strategy, facilitating ultrasensitive ATP detection. The proposed signal-off PEC strategy exhibited a wide linear range from 1.00 * 10-2 pM to 100 nM with a low detection limit of 3.30 fM. Importantly, this proposed strategy provides a promising platform to detect ATP at ultralow levels and has potential applications, including diagnosis of ATP-related diseases, monitoring of diseases progression and evaluation of prognosis. PMID- 29111663 TI - Mussel-Inspired Universal Bioconjugation of Polydiacetylene Liposome for Droplet Array Biosensors. AB - Most solid-state biosensor platforms require a specific immobilization chemistry and a bioconjugation strategy separately to tether sensory molecules to a substrate and attach specific receptors to the sensory unit, respectively. We developed a mussel-inspired universal conjugation method that enables both surface immobilization and bioconjugation at the same time. By incorporating dopamine or catechol moiety into self-signaling polydiacetylene (PDA) liposomes, we demonstrated efficient immobilization of the PDA liposomes to a wide range of substrates, without any substrate modification. Moreover, receptor molecules having a specificity toward a target molecule can also be attached to the immobilized PDA liposome layer without any chemical modification. We applied our mussel-inspired conjugation method to a droplet-array biosensor by exploiting the hydrophilic nature of PDA liposomes coated on a hydrophobic polytetrafluoroethylene surface and demonstrated selective and sensitive detection of vascular endothelial growth factor down to 10 nM. PMID- 29111662 TI - Evaluation of Removal Mechanisms in a Graphene Oxide-Coated Ceramic Ultrafiltration Membrane for Retention of Natural Organic Matter, Pharmaceuticals, and Inorganic Salts. AB - Functionalized graphene oxide (GO), derived from pure graphite via the modified Hummer method, was used to modify commercially available ceramic ultrafiltration membranes using the vacuum method. The modified ceramic membrane functionalized with GO (ceramicGO) was characterized using a variety of analysis techniques and exhibited higher hydrophilicity and increased negative charge compared with the pristine ceramic membrane. Although the pure water permeability of the ceramicGO membrane (14.4-58.6 L/m2 h/bar) was slightly lower than that of the pristine membrane (25.1-62.7 L/m2 h/bar), the removal efficiencies associated with hydrophobic attraction and charge effects were improved significantly after GO coating. Additionally, solute transport in the GO nanosheets of the ceramicGO membrane played a vital role in the retention of target compounds: natural organic matter (NOM; humic acid and tannic acid), pharmaceuticals (ibuprofen and sulfamethoxazole), and inorganic salts (NaCl, Na2SO4, CaCl2, and CaSO4). While the retention efficiencies of NOM, pharmaceuticals, and inorganic salts in the pristine membrane were 74.6%, 15.3%, and 2.9%, respectively, these increased to 93.5%, 51.0%, and 31.4% for the ceramicGO membrane. Consequently, the improved removal mechanisms of the membrane modified with functionalized GO nanosheets can provide efficient retention for water treatment under suboptimal environmental conditions of pH and ionic strength. PMID- 29111664 TI - Oxygen Plasma-Treated Graphene Oxide Surface Functionalization for Sensitivity Enhancement of Thin-Film Piezoelectric Acoustic Gas Sensors. AB - In this work, we presented a thin-film piezoelectric acoustic gas sensor with enhanced sensitivity by a surface modification strategy of oxygen plasma treated graphene oxide (GO) functionalization. By exposing to ammonia vapor (NH3) of various concentrations at controlled temperature and humidity, the characteristics of the GO-coated acoustic sensor were investigated, that is, sensitivity, linearity, response, and recovery time. Oxygen plasma treatment of the GO-coated sensor further enhanced the sensitivity compared with the freshly prepared GO-coated sensor. The mechanism of oxygen plasma treatment effect on the GO-coated sensor was discussed based on characterizations of X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, scanning electron microscope (SEM), and precise weighing of the acoustic sensor. It was found that the oxygen plasma treatment introduces numerous defects to GO flakes, which are uniformly distributed across the GO surface, providing more gas molecule binding sites. PMID- 29111665 TI - Operando Raman Spectroscopy and Synchrotron X-ray Diffraction of Lithiation/Delithiation in Silicon Nanoparticle Anodes. AB - Operando Raman spectroscopy and synchrotron X-ray diffraction were combined to probe the evolution of strain in Li-ion battery anodes made of crystalline silicon nanoparticles. The internal structure of the nanoparticles during two discharge/charge cycles was evaluated by analyzing the intensity and position of Si diffraction peaks and Raman TO-LO phonons. Lithiation/delithiation of the silicon under limited capacity conditions triggers the formation of "crystalline core-amorphous shell" particles, which we evidenced as a stepwise decrease in core size, as well as sequences of compressive/tensile strain due to the stress applied by the shell. In particular, we showed that different sequences occur in the first and the second cycle, due to different lithiation processes. We further evidenced critical experimental conditions for accurate operando Raman spectroscopy measurements due to the different heat conductivity of lithiated and delithiated Si. Values of the stress extracted from both operando XRD and Raman are in excellent agreement. Long-term ex situ measurements confirmed the continuous increase of the internal compressive strain, unfavorable to the Si lithiation and contributing to the capacity fading. Finally, a simple mechanical model was used to estimate the sub-nanometer thickness of the interfacial shell applying the stress on the crystalline core. Our complete operando diagnosis of the strain and stress in SiNPs provides both a detailed scenario of the mechanical consequences of lithiation/delithiation in SiNP and also experimental values that are much needed for the benchmarking of theoretical models and for the further rational design of SiNP-based electrodes. PMID- 29111667 TI - Advances in Microchip Liquid Chromatography. PMID- 29111666 TI - Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains. AB - The cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-dependent protein kinases (PKA and PKG) are key effectors of cyclic nucleotide signaling. Both share structural features that include tandem cyclic nucleotide-binding (CNB) domains, CNB-A and CNB-B, yet their functions are separated through preferential activation by either cAMP or cGMP. Based on structural studies and modeling, key CNB contact residues have been identified for both kinases. In this study, we explored the requirements for conversion of PKA activation from cAMP-dependent to cGMP-dependent. The consequences of the residue substitutions T192R/A212T within CNB-A or G316R/A336T within CNB-B of PKA RIalpha on cyclic nucleotide binding and holoenzyme activation were assessed in vitro using purified recombinant proteins, and ex vivo using RIalpha-deficient mouse embryonic fibroblasts genetically reconstituted with wild-type or mutant PKA-RIalpha. In vitro, a loss of binding and activation selectivity was observed when residues in either one of the CNB domains were mutated, while mutations in both CNB domains resulted in a complete switch of selectivity from cAMP to cGMP. The switch in selectivity was also recapitulated ex vivo, confirming their functional roles in cells. Our results highlight the importance of key cyclic nucleotide contacts within each CNB domain and suggest that these domains may have evolved from an ancestral gene product to yield two distinct cyclic nucleotide-dependent protein kinases. PMID- 29111669 TI - Versatile Cutting Method for Producing Fluorescent Ultrasmall MXene Sheets. AB - As a recently created inorganic nanosheet material, MXene has received growing attention and has become a hotspot of intensive research. The efficient morphology control of this class of material could bring enormous possibilities for creating marvelous properties and functions; however, this type of research is very scarce. In this work, we demonstrate a general and mild approach for creating ultrasmall MXenes by simultaneous intralayer cutting and interlayer delamination. Taking the most commonly studied Ti3C2 as an illustrative example, the resulting product possessed monolayer thickness with a lateral dimension of 2 8 nm and exhibited bright and tunable fluorescence. Further, the method could also be employed to synthesize ultrasmall sheets of other MXene phases, for example, Nb2C or Ti2C. Importantly, although the strong covalent M-C bond was to some extent broken, all of the characterizations suggested that the chemical structure was composed of well-maintained host layers without observation of any serious damages, demonstrating the superior reaction efficiencies and safeties of our methods. This work may provide a facile and general approach to modulate various nanoscale materials and could further stimulate the vast applications of MXene materials in many optical-related fields. PMID- 29111668 TI - Ultrasensitive High-Resolution Mass Spectrometric Analysis of a DNA Adduct of the Carcinogen Benzo[a]pyrene in Human Lung. AB - Benzo[a]pyrene (BaP), an archetypical polycyclic aromatic hydrocarbon, is classified as "carcinogenic to humans" and is ubiquitous in the environment, as evident by the measurable levels of BaP metabolites in virtually all human urine samples examined. BaP carcinogenicity is believed to occur mainly through its covalent modification of DNA, resulting in the formation of BPDE-N2-dG, an adduct formed between deoxyguanosine and a diol epoxide metabolite of BaP, with subsequent mutation of critical growth control genes. In spite of the liquid chromatography-mass spectrometry (LC-MS)-based detection of BPDE-N2-dG in BaP treated rodents, and indirectly through high-performance liquid chromatography (HPLC)-fluorescence detection of BaP-7,8,9,10-tetraols released from human DNA upon acid hydrolysis, BPDE-N2-dG adducts have rarely if ever been observed directly in human samples using LC-MS techniques, even though sophisticated methodologies have been employed which should have had sufficient sensitivity. With this in mind, we developed a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) methodology employing high resolution/accurate mass analysis for detecting ultratrace levels of these adducts. These efforts are directly translatable to the development of sensitive detection of other small molecules using trap-based LC-ESI-MS/MS detection. The developed methodology had a limit of detection (LOD) of 1 amol of BPDE-N2-dG on column, corresponding to 1 BPDE-N2-dG adduct per 1011 nucleotides (1 adduct per 10 human lung cells) using 40 MUg of human lung DNA. To our knowledge, this is the most sensitive DNA adduct quantitation method yet reported, exceeding the sensitivity of the 32P-postlabeling assay (~1 adduct per 1010 nucleotides). Twenty-nine human lung DNA samples resulted in 20 positive measurements above the LOD, with smoker and nonsmoker DNA containing 3.1 and 1.3 BPDE-N2-dG adducts per 1011 nucleotides, respectively. PMID- 29111670 TI - Non-Neurotoxic Nanodiamond Probes for Intraneuronal Temperature Mapping. AB - Optical biomarkers have been used extensively for intracellular imaging with high spatial and temporal resolution. Extending the modality of these probes is a key driver in cell biology. In recent years, the nitrogen-vacancy (NV) center in nanodiamond has emerged as a promising candidate for bioimaging and biosensing with low cytotoxicity and stable photoluminescence. Here we study the electrophysiological effects of this quantum probe in primary cortical neurons. Multielectrode array recordings across five replicate studies showed no statistically significant difference in 25 network parameters when nanodiamonds are added at varying concentrations over various time periods, 12-36 h. The physiological validation motivates the second part of the study, which demonstrates how the quantum properties of these biomarkers can be used to report intracellular information beyond their location and movement. Using the optically detected magnetic resonance from the nitrogen-vacancy defects within the nanodiamonds we demonstrate enhanced signal-to-noise imaging and temperature mapping from thousands of nanodiamond probes simultaneously. This work establishes nanodiamonds as viable multifunctional intraneuronal sensors with nanoscale resolution, which may ultimately be used to detect magnetic and electrical activity at the membrane level in excitable cellular systems. PMID- 29111671 TI - Quantitative and Structural Assessment of Histone Methyllysine Analogue Engagement by Cognate Binding Proteins Reveals Affinity Decrements Relative to Those of Native Counterparts. AB - Methyllysine analogues (MLAs), furnished by aminoethylation of engineered cysteine residues, are widely used surrogates of histone methyllysine and are considered to be effective proxies for studying these epigenetic marks in vitro. Here we report the first structure of a trimethyllysine MLA histone in complex with a protein binding partner, quantify the thermodynamic distinctions between MLAs and their native methyllysine counterparts, and demonstrate that these differences can compromise qualitative interpretations of binding at the nucleosome level. Quantitative measurements with two methyllysine binding protein modules reveal substantial affinity losses for the MLA peptides versus the corresponding native methyllysine species in both cases, although the thermodynamic underpinnings are distinct. MLA and methyllysine adopt distinct conformational geometries when in complex with the BPTF PHD finger, a well established H3K4me3 binding partner. In this case, an ~13-fold Kd difference at the peptide level translates to nucleosomal affinities for MLA analogues that fall outside of the detectable range in a pull-down format, whereas the methyllysine species installed by native chemical ligation demonstrates robust binding. Thus, despite their facile production and commercial availability, there is a significant caveat of potentially altered binding affinity when MLAs are used in place of native methyllysine residues. PMID- 29111673 TI - Nano into Micro Formulations of Tobramycin for the Treatment of Pseudomonas aeruginosa Infections in Cystic Fibrosis. AB - Here, nano into micro formulations (NiMs) of tobramycin for the treatment of Pseudomonas aeruginosa airway infections in cystic fibrosis (CF) are described. NiMs were produced by spray drying a solution containing polymers or sugars and a nanometric polyanion-tobramcyin complex (PTC), able to achieve a prolonged antibiotic release. NiMs properties were compared to TOBIPodhaler(Novartis), the only one commercially available dry powder inhalatory formulation based on porous microparticles. Produced NiMs showed adequate characteristics for pulmonary administration, as spherical shape, micrometric size, and high cytocompatibility toward human bronchial epithelial cells. Contrarily to TOBIPodhaler, some of produced NiMs, thanks to their specific chemical composition, are able to facilitate the drug diffusion through the mucus secretion, achieving, at the same time, a sustained tobramycin delivery. Moreover, NiMs showed pronounced antimicrobial activity against P. aeruginosa pathogens and their biofilm, if compared to free tobramycin and TOBIPodhaler, demonstrating the potential of obtained formulations as drug delivery systems for the treatment of pulmonary infections in CF patients. PMID- 29111674 TI - Highly Sensitive Electrochemical Sensor for the Detection of Anions in Water Based on a Redox-Active Monolayer Incorporating an Anion Receptor. AB - In the present work, gold electrodes were modified using a redox-active layer based on dipyrromethene complexes with Cu(II) or Co(II) and a dipodal anion receptor functionalized with dipyrromethene. These modified gold electrodes were then applied for the electrochemical detection of anions (Cl-, SO42-, and Br-) in a highly diluted water solution (in the picomolar range). The results showed that both systems, incorporating Cu(II) as well as Co(II) redox centers, exhibited highest sensitivity toward Cl-. The selectivity sequence found for both systems was Cl- > SO42- > Br-. The high selectivity of Cl- anions can be attributed to the higher binding constant of Cl- with the anion receptor and the stronger electronic effect between the central metal and anion in the complex. The detection limit for the determination of Cl- was found at the 1.0 pM level for both sensing systems. The electrodes based on Co(II) redox centers displayed better selectivity toward Cl- anion detection than those based on Cu(II) centers which can be attributed to the stronger electronic interaction between the receptor-target anion complex and the Co(II)/Co(III) redox centers in comparison to the Cu(II)/Cu(I) system. Applicability of gold electrodes modified with DPM Co(II)-DPM-AR for the electrochemical determination of Cl- anions was demonstrated using the artificial matrix mimicking human serum. PMID- 29111672 TI - Deciphering Conformational Changes Associated with the Maturation of Thrombin Anion Binding Exosite I. AB - Thrombin participates in procoagulation, anticoagulation, and platelet activation. This enzyme contains anion binding exosites, ABE I and ABE II, which attract regulatory biomolecules. As prothrombin is activated to thrombin, pro-ABE I is converted into mature ABE I. Unexpectedly, certain ligands can bind to pro ABE I specifically. Moreover, knowledge of changes in conformation and affinity that occur at the individual residue level as pro-ABE I is converted to ABE I is lacking. Such changes are transient and were not captured by crystallography. Therefore, we employed nuclear magnetic resonance (NMR) titrations to monitor development of ABE I using peptides based on protease-activated receptor 3 (PAR3). Proton line broadening NMR revealed that PAR3 (44-56) and more weakly binding PAR3G (44-56) could already interact with pro-ABE I on prothrombin. 1H 15N heteronuclear single-quantum coherence NMR titrations were then used to probe binding of individual 15N-labeled PAR3G residues (F47, E48, L52, and D54). PAR3G E48 and D54 could interact electrostatically with prothrombin and tightened upon thrombin maturation. The higher affinity for PAR3G D54 suggests the region surrounding thrombin R77a is better oriented to bind D54 than the interaction between PAR3G E48 and thrombin R75. Aromatic PAR3G F47 and aliphatic L52 both reported on significant changes in the chemical environment upon conversion of prothrombin to thrombin. The ABE I region surrounding the 30s loop was more affected than the hydrophobic pocket (F34, L65, and I82). Our NMR titrations demonstrate that PAR3 residues document structural rearrangements occurring during exosite maturation that are missed by reported X-ray crystal structures. PMID- 29111675 TI - Spectrum-Resolved Dual-Color Electrochemiluminescence Immunoassay for Simultaneous Detection of Two Targets with Nanocrystals as Tags. AB - A spectrum-resolved dual-color electrochemiluminescence (ECL) immunoassay was designed and implemented to simultaneously detect carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) with CdTe (lambdamax = 776 nm) and CdSe (lambdamax = 550 nm) nanocrystals (NCs) as ECL tags. The CdTe and CdSe NCs were labeled with respective probe antibodies (Ab2) of CEA and AFP, respectively, and then immobilized onto the working electrode surface via sandwich-type immunoreactions. Both CdTe and CdSe NCs within the NCs immunocomplexes can be electrochemically reduced and simultaneously give off monochromatic ECL emissions in the near infrared and greenish regions, respectively, when (NH4)2S2O8 was used as a cathodic ECL coreactant. The ECL spectra of the two surface-confined NCs were well separated and had no cross energy-transfer interactions, which made the dual color immunoassay highly selective and sensitive toward respective target analytes. With the proposed ECL biosensor, CEA and AFP were simultaneously detected and quantified with an extremely low detection limit of 1 pg/mL for CEA and 10 fg/mL for AFP, respectively. This work demonstrated the probability of performing multianalyte assays via a spectrum-resolved ECL strategy with improved sensitivity and signal-to-noise ratio as compared to NCs-based fluorescent multianalyte assays. PMID- 29111676 TI - Active Gating, Molecular Pumping, and Turnover Determination in Biomimetic Lipidic Cubic Mesophases with Reconstituted Membrane Proteins. AB - Understanding the mechanisms controlling molecular transport in bioinspired materials is a central topic in many branches of nanotechnology. In this work, we show that biomolecules of fundamental importance in biological processes, such as glucose, can be transported in an active, controlled, and selective manner across macroscopic lipidic cubic mesophases, by correctly reconstituting within them their corresponding membrane protein transporters, such as Staphylococcus epidermidis (GlcPSe). Importantly, by duly exploiting the symporter properties of GlcPSe of coupled glucose/H+ transport, the diffusion of glucose can further be tuned by independent physiological stimuli, such as parallel or antiparallel pH gradients, offering an important model to study molecular exchange processes in cellular machinery. We finally show that by measuring the transport properties of the lipidic mesophases with and without the GlcPSe membrane protein reconstituted within, it becomes possible to determine its intrinsic conductance. We generalize these findings to other membrane proteins from the antiporters family, such as the bacterial ClC exchanger from Escherichia coli (EcClC), providing a robust method for evaluating the turnover rate of the membrane proteins in general. PMID- 29111678 TI - Bipolar Electrochemistry on a Nanopore-Supported Platinum Nanoparticle Electrode. AB - In this Technical Note, we describe a method to fabricate nanopore-supported Pt nanoparticle electrodes and their use in bipolar electrochemistry. A Pt nanoparticle is deposited on the orifice of a solid-state nanopore inside a focused-ion beam (FIB) system. Complete blockage of the nanopore with Pt metal forms a closed bipolar nanoparticle electrode whose size and shape can be tunable in one simple step. Nanoparticle electrodes and their arrays can be prepared on different substrates such as the tip of a glass pipet, a double-barrel pipet, and a freestanding silicon nitride membrane. Steady-state voltammetry can be performed on such nanoparticle electrodes via bipolar electrochemistry. Moreover, an array of Pt nanoparticles can be used for fluorescence-enabled electrochemical microscopy. Future use of highly advanced FIB systems may allow nanoparticles of <10 nm to be fabricated which may enable coupled electrochemical reactions of single redox molecules. Pipette-supported single particle electrodes may also find useful applications in high resolution imaging with nanoscale scanning electrochemical microscopy (SECM) and neurochemical analysis inside single cells. PMID- 29111679 TI - Recombinant Protein Polymers for Colloidal Stabilization and Improvement of Cellular Uptake of Diamond Nanosensors. AB - Fluorescent nanodiamonds are gaining increasing attention as fluorescent labels in biology in view of the fact that they are essentially nontoxic, do not bleach, and can be used as nanoscale sensors for various physical and chemical properties. To fully realize the nanosensing potential of nanodiamonds in biological applications, two problems need to be addressed: their limited colloidal stability, especially in the presence of salts, and their limited ability to be taken up by cells. We show that the physical adsorption of a suitably designed recombinant polypeptide can address both the colloidal stability problem and the problem of the limited uptake of nanodiamonds by cells in a very straightforward way, while preserving both their spectroscopic properties and their excellent biocompatibility. PMID- 29111680 TI - Indirect Nanoplasmonic Sensing Platform for Monitoring Temperature-Dependent Protein Adsorption. AB - The development of highly surface-sensitive measurement approaches to monitor protein adsorption across different temperatures would advance understanding of how thermally activated processes contribute to the denaturation of adsorbed proteins. Herein, we established an indirect nanoplasmonic sensing approach to monitor the temperature-dependent adsorption and denaturation of bovine serum albumin (BSA) protein onto a silica-coated array of plasmonic gold nanodisks. A theoretical model was developed to explain how the denaturation of an individual, adsorbed protein molecule influences the localized surface plasmon resonance (LSPR) measurement response and provided an analytical framework to estimate the effect of temperature-dependent protein denaturation on the corresponding adsorption kinetics. The sensing performance of this measurement platform was also characterized across the tested range of temperatures. With increasing temperature (up to 50 degrees C), it was observed that adsorbed proteins undergo greater denaturation. Circular dichroism spectroscopy and dynamic light scattering experiments verified that individual BSA monomers in bulk solution had increasingly lower conformational stability at higher temperatures within this range, which correlated with the extent of denaturation in the adsorbed state. At higher temperatures, distinct kinetic profiles arising from multilayer/aggregate formation on the sensor surface were also detected. Taken together, our findings identify that the high surface sensitivity and temperature stability of LSPR sensors make them broadly useful analytical tools for monitoring thermally activated biomacromolecular interaction processes. PMID- 29111677 TI - Novel Bivalent 5-HT2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo. AB - The 5-HT2A receptor (5-HT2AR) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HT2AR:5-HT2AR homodimer in these disorders are necessary. We chemically modified the selective 5-HT2AR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HT2AR:5-HT2AR homodimer function. We tested these molecules for 5-HT2AR antagonist activity in a cell line stably expressing the functional 5-HT2AR and quantified a downstream signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK1/2), in comparison to in vivo efficacy of altering spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT mediated phosphorylation of ERK1/2 in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length, with the intermediate linker lengths being the most potent. The Ki values for the binding of bivalent ligands to 5-HT2AR were only slightly lower than the values for the parent (+)-M100907 compound, but significant selectivity for 5-HT2AR over 5-HT2BR or 5-HT2CR binding was retained. In addition, the 11-atom-linked bivalent 5-HT2AR antagonist (2 mg/kg, intraperitoneally) demonstrated efficacy on par with that of (+)-M100907 in inhibiting cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HT2AR antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT2AR structure and function. PMID- 29111681 TI - Design of Glycopolymers Carrying Sialyl Oligosaccharides for Controlling the Interaction with the Influenza Virus. AB - We designed glycopolymers carrying sialyl oligosaccharides by "post-click" chemistry and evaluated the interaction with the influenza virus. The glycopolymer structures were synthesized in a well-controlled manner by reversible addition-fragmentation chain transfer polymerization and the Huisgen reaction. Acrylamide-type monomers were copolymerized to give hydrophilicity to the polymer backbones, and the hydrophilicity enabled the successful introduction of the oligosaccharides into the polymer backbones. The glycopolymers with different sugar densities and polymer lengths were designed for the interaction with hemagglutinin on the virus surface. The synthesized glycopolymers showed the specific molecular recognition against different types of influenza viruses depending on the sugar units (6'- or 3'-sialyllactose). The sugar density and the polymer length of the glycopolymers affected the interaction with the influenza virus. Inhibitory activity of the glycopolymer against virus infection was demonstrated. PMID- 29111682 TI - Monitoring Membrane Lipidome Turnover by Metabolic 15N Labeling and Shotgun Ultra High-Resolution Orbitrap Fourier Transform Mass Spectrometry. AB - Lipidomes undergo permanent extensive remodeling, but how the turnover rate differs between lipid classes and molecular species is poorly understood. We employed metabolic 15N labeling and shotgun ultra-high-resolution mass spectrometry (sUHR) to quantify the absolute (molar) abundance and determine the turnover rate of glycerophospholipids and sphingolipids by direct analysis of total lipid extracts. sUHR performed on a commercial Orbitrap Elite instrument at the mass resolution of 1.35 * 106 (m/z 200) baseline resolved peaks of 13C isotopes of unlabeled and monoisotopic peaks of 15N labeled lipids (Deltam = 0.0063 Da). Therefore, the rate of metabolic 15N labeling of individual lipid species could be determined without compromising the scope, accuracy, and dynamic range of full-lipidome quantitative shotgun profiling. As a proof of concept, we employed sUHR to determine the lipidome composition and fluxes of 62 nitrogen containing membrane lipids in human hepatoma HepG2 cells. PMID- 29111683 TI - A Noncanonical Role for Yersiniabactin in Bacterial Copper Acquisition. PMID- 29111684 TI - Correction to A Chemoproteomic Platform To Assess Bioactivation Potential of Drugs. PMID- 29111685 TI - Thermal Shift as an Entropy-Driven Effect. AB - Thermal shift assays (TSAs) are among the most commonly used biophysical approaches in drug discovery in both academic and industrial settings. However, the most common interpretation of the data generated by a TSA is purely qualitative, using only the change in melting temperature (DeltaTm) as a metric. This has left many questions surrounding the interpretation of the data as well as whether the TSA truly correlates with other assays. TSAs also lack theoretical descriptions of the melt behavior of proteins in the presence of multiple ligands. Here we describe a novel simplified analytical framework based on "pseudoisothermal" models as well as exact thermodynamic descriptions of protein ligand melt behavior rooted in changes in the entropy of melting. We show how the models are broad and independently applicable, in that they can describe the behavior of any macromolecule such as a protein or DNA and demonstrate good correlations with other techniques. These models are shown to give good descriptions of assay systems containing single or multiple ligands and can determine the mechanism of interaction. The models are derived from first principles, and the theoretical justification is discussed. PMID- 29111686 TI - Centrifugation-Controlled Thermal Convection and Its Application to Rapid Microfluidic Polymerase Chain Reaction Devices. AB - Here, we report the developed cyclo olefin polymer (COP) microfluidic chip on a fabricated rotating heater stage that utilizes centrifugation-assisted thermal cycle in a ring-structured microchannel for polymerase chain reaction (PCR). The PCR solution could be driven by thermal convection and continuously exchanged high/low temperatures in a ring structured microchannel without the use of typical syringe pump. More importantly, the flow rate was controlled by the relative gravitational acceleration only. The platform enables amplification within 10 min at 5G and has a detection limit of 70.5 pg/channel DNA concentration (beta-actin, 295 bp). The current rotating system is capable of testing four different samples in parallel. The microfluidic chip can be preloaded with the PCR premix solution for on-site utility, and, with all of the features integrated to the system, the test can be conducted without the need for specialized laboratory and trained laboratory staff. In addition, this innovative chemical reaction technique has the potential to be utilized in other micromixing applications. PMID- 29111687 TI - Time-Gated Imaging of Latent Fingerprints and Specific Visualization of Protein Secretions via Molecular Recognition. AB - Persistent nanophosphors can remain luminescent after excitation ceases; thus, they offer a promising way to avoid background fluorescence interference in bioimaging. In this work, Zn2GeO4:Ga,Mn (ZGO:Ga,Mn) persistent luminescence nanoparticles were developed and they were employed for time-gated imaging of latent fingerprints (LFP). The nanoparticles were functionalized with a carboxyl group and utilized to label LFP through reacting with the amino group in the LFP. Results proved the potent ability of ZGO:Ga,Mn in eliminating background fluorescence to afford highly sensitive LFP imaging. Moreover, LFP aged for 60 days were successfully detected due to the presence of highly stable amino acids. After being functionalized with concanavalin A, the nanoparticles achieved visualization of glycoproteins in LFP. This strategy provides great versatility in LFP imaging and good potential in uncovering the chemical information within LFP, making it valuable in forensic investigations and medical diagnostics. PMID- 29111688 TI - Durable Anti-Superbug Polymers: Covalent Bonding of Ionic Liquid onto the Polymer Chains. AB - Here, we fabricated the ionic liquid (IL) grafted poly(vinylidene fluoride) (PVDF) (PVDF-g-IL) via electron-beam irradiation to fight common bacteria and multidrug-resistant "superbugs". Two types of ILs, 1-vinyl-3-butylimmidazolium chloride (IL (Cl)) and 1-vinyl-3-ethylimidazolium tetrafluoroborate (IL (BF4)), were used. It was found that the PVDF-g-IL exhibited superior antibacterial performance, with almost the same mechanical and thermal performance as unmodified PVDF. Nonwovens and films made from PVDF-g-IL materials exhibited broad-spectrum antimicrobial activity against common bacteria and "superbugs" with the strong electrostatic interactions between ILs and microbial cell membranes. With extremely low IL loading (0.05 wt %), the cell reduction of PVDF g-IL (Cl) nonwovens improved from 0.2 to 4.4 against S. aureus. Moreover, the antibacterial activity of PVDF-g-IL nonwovens was permanent for the covalent bonds between ILs and polymer chains. The work provides a simple strategy to immobilize ionic antibacterial agents onto polymer substrates, which may have great potential applications in healthcare and household applications. PMID- 29111689 TI - Functional Characterization of a Condensation Domain That Links Nonribosomal Peptide and Pteridine Biosynthetic Machineries in Photorhabdus luminescens. AB - Nonribosomal peptide synthetases (NRPSs) produce a wide variety of biologically important small molecules. NRPSs can interface with other enzymes to form hybrid biosynthetic systems that expand the structural and functional diversity of their products. The pepteridines are metabolites encoded by an unprecedented pteridine NRPS-type hybrid biosynthetic gene cluster in Photorhabdus luminescens, but how the distinct enzymatic systems interface to produce these molecules has not been examined at the biochemical level. By an unknown mechanism, the genetic locus can also affect the regulation of other enzymes involved in autoinducer and secondary metabolite biosynthesis. Here, through in vitro protein biochemical assays, we demonstrate that an atypical NRPS condensation (C) domain present in the pathway condenses acyl units derived from alpha-keto acids onto a free 5,6,7,8 tetrahydropterin core, producing the tertiary cis-amide-containing pepteridines. Solution studies of the chemically synthesized molecules led to the same amide regiochemistries that were observed in the natural products. The biochemical transformations mediated by the C domain destroy the radical scavenging activity of its redox active tetrahydropterin substrate. Secondary metabolite analyses revealed that the pepteridine locus affects select metabolic pathways associated with quorum sensing, antibiosis, and symbiosis. Taken together, the results suggest that the pathway likely regulates cellular redox and specialized metabolic pathways through engagement with the citric acid cycle. PMID- 29111690 TI - Aerosol Health Effects from Molecular to Global Scales. AB - Poor air quality is globally the largest environmental health risk. Epidemiological studies have uncovered clear relationships of gaseous pollutants and particulate matter (PM) with adverse health outcomes, including mortality by cardiovascular and respiratory diseases. Studies of health impacts by aerosols are highly multidisciplinary with a broad range of scales in space and time. We assess recent advances and future challenges regarding aerosol effects on health from molecular to global scales through epidemiological studies, field measurements, health-related properties of PM, and multiphase interactions of oxidants and PM upon respiratory deposition. Global modeling combined with epidemiological exposure-response functions indicates that ambient air pollution causes more than four million premature deaths per year. Epidemiological studies usually refer to PM mass concentrations, but some health effects may relate to specific constituents such as bioaerosols, polycyclic aromatic compounds, and transition metals. Various analytical techniques and cellular and molecular assays are applied to assess the redox activity of PM and the formation of reactive oxygen species. Multiphase chemical interactions of lung antioxidants with atmospheric pollutants are crucial to the mechanistic and molecular understanding of oxidative stress upon respiratory deposition. The role of distinct PM components in health impacts and mortality needs to be clarified by integrated research on various spatiotemporal scales for better evaluation and mitigation of aerosol effects on public health in the Anthropocene. PMID- 29111691 TI - Optimal Recycling of Steel Scrap and Alloying Elements: Input-Output based Linear Programming Method with Its Application to End-of-Life Vehicles in Japan. AB - Importance of end-of-life vehicles (ELVs) as an urban mine is expected to grow, as more people in developing countries are experiencing increased standards of living, while the automobiles are increasingly made using high-quality materials to meet stricter environmental and safety requirements. While most materials in ELVs, particularly steel, have been recycled at high rates, quality issues have not been adequately addressed due to the complex use of automobile materials, leading to considerable losses of valuable alloying elements. This study highlights the maximal potential of quality-oriented recycling of ELV steel, by exploring the utilization methods of scrap, sorted by parts, to produce electric arc-furnace-based crude alloy steel with minimal losses of alloying elements. Using linear programming on the case of Japanese economy in 2005, we found that adoption of parts-based scrap sorting could result in the recovery of around 94 98% of the alloying elements occurring in parts scrap (manganese, chromium, nickel, and molybdenum), which may replace 10% of the virgin sources in electric arc furnace-based crude alloy steel production. PMID- 29111692 TI - Fingerprints of Modified RNA Bases from Deep Sequencing Profiles. AB - Posttranscriptional modifications of RNA bases are not only found in many noncoding RNAs but have also recently been identified in coding (messenger) RNAs as well. They require complex and laborious methods to locate, and many still lack methods for localized detection. Here we test the ability of next-generation sequencing (NGS) to detect and distinguish between ten modified bases in synthetic RNAs. We compare ultradeep sequencing patterns of modified bases, including miscoding, insertions and deletions (indels), and truncations, to unmodified bases in the same contexts. The data show widely varied responses to modification, ranging from no response, to high levels of mutations, insertions, deletions, and truncations. The patterns are distinct for several of the modifications, and suggest the future use of ultradeep sequencing as a fingerprinting strategy for locating and identifying modifications in cellular RNAs. PMID- 29111693 TI - Electrical Actuation of a DNA Origami Nanolever on an Electrode. AB - Development of electrically powered DNA origami nanomachines requires effective means to actuate moving origami parts by externally applied electric fields. We demonstrate how origami nanolevers on an electrode can be manipulated (switched) at high frequency by alternating voltages. Orientation switching is long-time stable and can be induced by applying low voltages of 200 mV. The mechanical response time of a 100 nm long origami lever to an applied voltage step is less than 100 MUs, allowing dynamic control of the induced motion. Moreover, through voltage assisted capture, origamis can be immobilized from folding solution without purification, even in the presence of excess staple strands. The results establish a way for interfacing and controlling DNA origamis with standard electronics, and enable their use as moving parts in electro-mechanical nanodevices. PMID- 29111694 TI - Promotion of Homogeneous Ice Nucleation by Soluble Molecules. AB - Atmospheric aerosols nucleate ice in clouds, strongly impacting precipitation and climate. The prevailing consensus is that ice nucleation is promoted heterogeneously by the surface of ice nucleating particles in the aerosols. However, recent experiments indicate that water-soluble molecules, such as polysaccharides of pollen and poly(vinyl alcohol) (PVA), increase the ice freezing temperature. This poses the question of how do flexible soluble molecules promote the formation of water crystals, as they do not expose a well defined surface to ice. Here we use molecular simulations to demonstrate that PVA promotes ice nucleation through a homogeneous mechanism: PVA increases the nucleation rate by destabilizing water in the solution. This work demonstrates a novel paradigm for understanding ice nucleation by soluble molecules and provides a new handle to design additives that promote crystallization. PMID- 29111695 TI - Modeling the Concentration of Volatile and Semivolatile Contaminants in Direct Contact Membrane Distillation (DCMD) Product Water. AB - Direct contact membrane distillation (DCMD) is an emerging water treatment technology that has high salt rejection; however, its commercialization potential for applications such as seawater desalination or industrial wastewater reuse may be limited by low rejection of volatile and semivolatile contaminants. In this manuscript, a contaminant concentration (CC) model describing the transport of volatile and semivolatile contaminants for DCMD systems was developed and validated using data from the bench-scale DCMD treatment of synthetic wastewaters. The DCMD tests showed that the more volatile contaminants (methyl tert-butyl ether, acetone, pentanone, butanol, and hexanol) accumulated in the permeate collection stream at greater concentrations than in the feed stream. The validated CC model (average normalized root mean squared error <=11.3%) was then used to evaluate the product water quality from the large-scale DCMD treatment of oil and gas produced waters. The modeled product water contaminant concentrations exceeded the Environmental Protection Agency limits for discharging to publicly owned treatment works. This indicated that DCMD treatment of produced waters may require additional processing to meet discharge requirements. PMID- 29111696 TI - Sequencing the Dermatan Sulfate Chain of Decorin. AB - Glycomics represents one of the last frontiers and most challenging in omic analysis. Glycosylation occurs in the endoplasmic reticulum and the Golgi organelle and its control is neither well-understood nor predictable based on proteomic or genomic analysis. One of the most structurally complex classes of glycoconjugates is the proteoglycans (PGs) and their glycosaminoglycan (GAG) side chains. Previously, our laboratory solved the structure of the chondroitin sulfate chain of the bikunin PG. The current study examines the much more complex structure of the dermatan sulfate GAG chain of decorin PG. By utilizing sophisticated separation methods followed by compositional analysis, domain mapping, and tandem mass spectrometry coupled with analysis by a modified genetic algorithm approach, the structural motif for the decorin dermatan sulfate chain was determined. This represents the second example of a GAG with a prominent structural motif, suggesting that the structural variability of this class of glycoconjugates is somewhat simpler than had been expected. PMID- 29111697 TI - A New Bis(phthalocyaninato) Terbium Single-Ion Magnet with an Overall Excellent Magnetic Performance. AB - Bulky and strong electron-donating dibutylamino groups were incorporated onto the peripheral positions of one of the two phthalocyanine ligands in the bis(phthalocyaninato) terbium complex, resulting in the isolation of heteroleptic double-decker (Pc)Tb{Pc[N(C4H9)2]8} {Pc = phthalocyaninate; Pc[N(C4H9)2]8 = 2,3,9,10,16,17,23,24-octakis(dibutylamino)phthalocyaninate} with the nature of an unsymmetrical molecular structure, a square-antiprismatic coordination geometry, an intensified coordination field strength, and the presence of organic radical-f interaction. As a total result of all these factors, this sandwich-type tetrapyrrole lanthanide single-ion magnet (SIM) exhibits an overall enhanced magnetic performance including a high blocking temperature (TB) of 30 K and large effective spin-reversal energy barrier of Ueff = 939 K, rendering it the best sandwich-type tetrapyrrole lanthanide SIM reported thus far. PMID- 29111698 TI - Assembly of Lyotropic Liquid Crystals with Solid Crystal's Structural Order Translated from the Lipid Rafts in Cell Membranes. AB - Self-assembly offers a powerful way to control the complexity and hierarchy of nanoscale materials, and promises to create a diverse range of emergent properties. Successful syntheses that allow a delicate structural design of building units play an important role. However, as can be learned from many cellular processes and functions, coself-assembly using logically chosen additives should be equally effective in designing self-assembly. Herein I show that, translated from the dynamic nanoscale assemblies in cell membranes known as lipid rafts, coself-assembly of 1-decanol into cetyltrimethylammonium chloride micelles for the assembly of lyotropic liquid crystals generates new structural complexity and hierarchy, and a surprising property that is emerging from it. Designing the intermolecular forces in the way that cholesterol interacts with sphingolipids promotes the synergistic balance between the flexibility and rigidity, and the unique molecular recognition for silicic acid, followed by the micelle coalescence. This very much resembles the assembly process of the lipid rafts in cell membranes and triggers orders of magnitude of sharp increases in X ray diffraction intensity. The analysis of the diffraction patterns shows that the structural order of these liquid crystals matches that of solid crystals, often of single crystals. Furthermore, the assembly of the liquid crystals promotes a substantial increase in the condensation rate of silicic acids by guiding them to form a silicate trimer along the surface of micelles. This very much resembles the role of the lipid rafts that sharply increases the reaction rate of biomolecules by guiding them to form discrete species along the surface of membranes. This finding demonstrates that it is possible to translate the key features of cellular processes and functions into artificial self-assembling systems of our choice using the building units that are readily available, thus creating novel soft materials. PMID- 29111699 TI - Investigation of Trimethyllysine Binding by the HP1 Chromodomain via Unnatural Amino Acid Mutagenesis. AB - Trimethyllysine (Kme3) reader proteins are targets for inhibition due to their role in mediating gene expression. Although all such reader proteins bind Kme3 in an aromatic cage, the driving force for binding may differ; some readers exhibit evidence for cation-pi interactions whereas others do not. We report a general unnatural amino acid mutagenesis approach to quantify the contribution of individual tyrosines to cation binding using the HP1 chromodomain as a model system. We demonstrate that two tyrosines (Y24 and Y48) bind to a Kme3-histone tail peptide via cation-pi interactions, but linear free energy trends suggest they do not contribute equally to binding. X-ray structures and computational analysis suggest that the distance and degree of contact between Tyr residues and Kme3 plays an important role in tuning cation-pi-mediated Kme3 recognition. Although cation-pi interactions have been studied in a number of proteins, this work is the first to utilize direct binding assays, X-ray crystallography, and modeling, to pinpoint factors that influence the magnitude of the individual cation-pi interactions. PMID- 29111700 TI - Proteomic Investigation of Metabolic Changes of Mushroom (Flammulina velutipes) Packaged with Nanocomposite Material during Cold Storage. AB - Metabolic changes of mushroom (Flammulina velutipes) applied with polyethylene (PE) material (Normal-PM) or nanocomposite reinforced PE packaging material (Nano PM) were monitored using tandem mass tags (TMT) labeling combined with two dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) technique. A total of 429 proteins were investigated as differentially expressed proteins (DEPs) among treatments after a cold storage period. A total of 232 DEPs were up-regulated and 65 DEPs were down-regulated in Nano-PM packed F. velutipes compared to that of Normal-PM. The up-regulated DEPs were mainly involved in amino acid synthesis and metabolism, signal transduction, and response to stress while the down-regulated DEPs were largely located in mitochondrion and participated in carbohydrate metabolic, amino acid synthesis and metabolism, and organic acid metabolic. It was also revealed that Nano-PM could inhibit the carbohydrate and energy metabolism bioprocess, promote amino acids biosynthesis, enhance antioxidant system, and improve its resistance to stress, resulting in a further extended shelf life of F. velutipes. PMID- 29111701 TI - Mitochondrial Imaging with Combined Fluorescence and Stimulated Raman Scattering Microscopy Using a Probe of the Aggregation-Induced Emission Characteristic. AB - In vivo quantitative measurement of biodistribution plays a critical role in the drug/probe development and diagnosis/treatment process monitoring. In this work, we report a probe, named AIE-SRS-Mito, for imaging mitochondria in live cells via fluorescence (FL) and stimulated Raman scattering (SRS) imaging. The probe features an aggregation-induced emission (AIE) characteristic and possesses an enhanced alkyne Raman peak at 2223 cm-1. The dual-mode imaging of AIE-SRS-Mito for selective mitochondrion-targeting was examined on a homemade FL-SRS microscope system. The detection limit of the probe in the SRS imaging was estimated to be 8.5 MUM. Due to the linear concentration dependence of SRS and inertness of the alkyne Raman signal to environmental changes, the intracellular distribution of the probe was studied, showing a local concentration of >2.0 mM in the mitochondria matrix, which was >100-fold higher than the incubation concentration. To the best of our knowledge, this is the first time that the local concentration of AIE molecules inside cells has been measured noninvasively and directly. Also, the nonquenching effect of such AIE molecules in cell imaging has been verified by the positive correlation of FL and SRS signals. Our work will encourage the utilization of SRS microscopy for quantitative characterization of FL probes or other nonfluorescent compounds in living biological systems and the development of FL-SRS dual-mode probes for specific biotargets. PMID- 29111702 TI - Identification and Interrogation of the Herbicidin Biosynthetic Gene Cluster: First Insight into the Biosynthesis of a Rare Undecose Nucleoside Antibiotic. AB - Herbicidins are adenosine-based nucleoside antibiotics with an unusual tricyclic undecose core decorated with a (5-hydroxy)tiglyl moiety. Feeding studies are herein reported demonstrating that the tricyclic core is derived from d-glucose and d-ribose, whereas the tiglyl moiety is derived from an intermediate of l isoleucine catabolism. Identification of the gene cluster for herbicidin A biosynthesis in Streptomyces sp. L-9-10 as well as its verification by heterologous expression in a nonproducing host are described, and the results of in vitro characterization of a carboxyl methyltransferase encoded in the cluster, Her8, are presented. Based on these observations, a biosynthetic pathway is proposed for herbicidins. PMID- 29111703 TI - Nicosulfuron Biodegradation by a Novel Cold-Adapted Strain Oceanisphaera psychrotolerans LAM-WHM-ZC. AB - Nicosulfuron is a common environmental pollutant, posing a great threat to aquatic systems and causing significant damage to crops. This study reported a cold-adapted strain Oceanisphaera psychrotolerans LAM-WHM-ZC, which efficiently degrades nicosulfuron over a wide range of temperatures (5 to 40 degrees C). The Box-Behnken design method was used to optimize the degradation conditions. O. psychrotolerans LAM-WHM-ZC can degrade 92.4% and 74.6% of initially supplemented 100 mg/L nicosulfuron under the optimum and low temperature of 18.1 and 5 degrees C, respectively, within 7 days. O. psychrotolerans LAM-WHM-ZC was found to be highly efficient in degrading cinosulfuron, chlorsulfuron, rimsulfuron, bensulfuron methyl, and ethametsulfuron methyl. Metabolites from nicosulfuron degradation were identified by UPLC-MS, and a possible degradation pathway was proposed. Furthermore, O. psychrotolerans LAM-WHM-ZC can also degrade nicosulfuron in soil; 78.6% and 67.4% of the initial nicosulfuron supplemented at 50 mg/kg were removed at 18.1 and 5 degrees C, respectively, within 15 days. PMID- 29111704 TI - New Method To Produce Kokumi Seasoning from Protein Hydrolysates Using Bacterial Enzymes. AB - In the present study, we demonstrate a novel use for a commercially available glutaminase that can be used as a gamma-glutamyltranspeptidase in kokumi seasoning production. Soy protein and gluten were hydrolyzed using a protease isolated from Bacillus licheniformis. The resulting protein hydrolysates were gamma-glutamylated with a gamma-glutamyltranspeptidase, which is sold as a glutaminase from Bacillus amyloliquefaciens, to produce kokumi seasonings. For gamma-glutamylation of soy protein hydrolysate, glutamine was added to the reaction mixture. On the other hand, reaction conditions for enzymatic proteolysis were optimized to liberate glutamine from gluten in large amounts, and the addition of glutamine was not required for gamma-glutamylation of gluten hydrolysate. The soy protein and gluten hydrolysates as well as their gamma glutamylated products were subjected to taste evaluation. Soy protein hydrolysates were bitter. Although gamma-glutamylation significantly reduced bitterness, the taste was still considered unfavorable. gamma-Glutamylated gluten hydrolysate is the most preferable sample and had significantly enhanced thickness, kokumi, and umami tastes, with a moderate increase in saltiness. PMID- 29111705 TI - One-Bead-Two-Compound Thioether Bridged Macrocyclic gamma-AApeptide Screening Library against EphA2. AB - Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics gamma-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected alpha amino acids, which were orthogonal to solid phase synthesis of gamma-AApeptides. Employing the thioether linkage, the desired macrocyclic gamma-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (Kd = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation. PMID- 29111707 TI - Lysine-Derived Protein-Bound Heyns Compounds in Bakery Products. AB - Fructose and dicarbonyl compounds resulting from fructose in heated foods have been linked to pathophysiological pathways of several metabolic disorders. Up to now, very little has been known about the Maillard reaction of fructose in food. Heyns rearrangement compounds (HRCs), the first stable intermediates of the Maillard reaction between amino components and fructose, have not yet been quantitated as protein-bound products in food. Therefore, the HRCs glucosyllysine and mannosyllysine were synthesized and characterized by NMR. Protein-bound HRCs in cookies containing various sugars and in commercial bakery products were quantitated after enzymatic hydrolysis by RP-HPLC-ESI-MS/MS in the multiple reaction monitoring mode through application of the standard addition method. Protein-bound HRCs were quantitated for the first time in model cookies and in commercial bakery products containing honey, banana, and invert sugar syrup. Concentrations of HRCs from 19 to 287 mg/kg were found, which were similar to or exceeded the content of other frequently analyzed Maillard reaction products, such as N-epsilon-carboxymethyllysine (10-76 mg/kg), N-epsilon-carboxyethyllysine (2.5-53 mg/kg), and methylglyoxal-derived hydroimidazolone 1 (10-218 mg/kg) in the analyzed cookies. These results show that substantial amounts of HRCs form during food processing. Analysis of protein-bound HRCs in cookies is therefore useful to evaluate the Maillard reaction of fructose. PMID- 29111706 TI - 17O MAS NMR Correlation Spectroscopy at High Magnetic Fields. AB - The structure of two protected amino acids, FMOC-l-leucine and FMOC-l-valine, and a dipeptide, N-acetyl-l-valyl-l-leucine (N-Ac-VL), were studied via one- and two dimensional solid-state nuclear magnetic resonance (NMR) spectroscopy. Utilizing 17O magic-angle spinning (MAS) NMR at multiple magnetic fields (17.6-35.2 T/750 1500 MHz for 1H) the 17O quadrupolar and chemical shift parameters were determined for the two oxygen sites of each FMOC-protected amino acids and the three distinct oxygen environments of the dipeptide. The one- and two dimensional, 17O, 15N-17O, 13C-17O, and 1H-17O double-resonance correlation experiments performed on the uniformly 13C,15N and 70% 17O-labeled dipeptide prove the attainability of 17O as a probe for structure studies of biological systems. 15N-17O and 13C-17O distances were measured via one-dimensional REAPDOR and ZF-TEDOR experimental buildup curves and determined to be within 15% of previously reported distances, thus demonstrating the use of 17O NMR to quantitate interatomic distances in a fully labeled dipeptide. Through-space hydrogen bonding of N-Ac-VL was investigated by a two-dimensional 1H-detected 17O R3-R-INEPT experiment, furthering the importance of 17O for studies of structure in biomolecular solids. PMID- 29111708 TI - Group Additivity in Ligand Binding Affinity: An Alternative Approach to Ligand Efficiency. AB - Group additivity is a concept that has been successfully applied to a variety of thermochemical and kinetic properties. This includes drug discovery, where functional group additivity is often assumed in ligand binding. Ligand efficiency can be recast as a special case of group additivity where DeltaG/HA is the group equivalent (HA is the number of non-hydrogen atoms in a ligand). Analysis of a large data set of protein-ligand binding affinities (Ki) for diverse targets shows that in general ligand binding is distinctly nonlinear. It is possible to create a group equivalent scheme for ligand binding, but only in the context of closely related proteins, at least with regard to size. This finding has broad implications for drug design from both experimental and computational points of view. It also offers a path forward for a more general scheme to assess the efficiency of ligand binding. PMID- 29111709 TI - Casimir-Polder Size Consistency: A Constraint Violated by Some Dispersion Theories. AB - A key goal in quantum chemistry methods, whether ab initio or otherwise, is to achieve size consistency. In this work we formulate the related idea of "Casimir Polder size consistency" that manifests in long-range dispersion energetics. We show that local approximations in time-dependent density functional theory dispersion energy calculations violate the consistency condition because of incorrect treatment of highly nonlocal "xc kernel" physics, by up to 10% in our tests on closed-shell atoms. PMID- 29111710 TI - Effect of Pachybasin on General Toxicity and Developmental Toxicity in Vivo. AB - To document the safety of pachybasin, a secondary metabolite of Trichoderma harzianum, for use as a bioagricultural agent, it was subjected to general toxicological testing in mice and developmental toxicity in zebrafish. With either 5 or 20 mg kg-1 pachybasin i.p. injection, mice behavioral responses such as motor coordination, spontaneous locomotor activity, or nociceptive pain were not influenced. In long-term effect (daily injection for 14 days), the physiological, hematological, liver, and kidney functions were not altered either. Evidence for the developmental toxicity of pachybasin (10-100 MUM) in 72 h exposure period was shown in zebrafish larvae, based on developmental retardation, impairment of chorion, and increase of mortality. In summary, there are no significant general toxicities presented in the pachybasin-treated adult male mice. However, the embryo-toxicity in aquatic biota should be taken into consideration during bioagricultural agent application. PMID- 29111711 TI - Formal Total Synthesis of (+)-C9-Deoxyomuralide from l-Leucine Using a Double Sacrificial Chirality Transfer Approach. AB - Formal stereocontrolled syntheses of (+/-)- and (+)-C9-deoxyomuralide is reported, constituting one of the shortest routes to the full carbon skeleton reported to date. PMID- 29111712 TI - Adsorption of Water onto SrTiO3 from Periodic Moller-Plesset Second-Order Perturbation Theory. AB - Adsorption of water onto metal oxide surfaces is a long-standing problem motivated by relevance to many promising technological applications. In this work, we compute the adsorption energy of water on SrTiO3 using periodic Moller Plesset second-order perturbation theory (MP2). We compare our MP2 results to density functional and hybrid density functional theory calculations with and without the widely used D3 dispersion correction. The MP2 ground-state adsorption energy of water on SrTiO3 (001) at one monolayer coverage is 0.9 eV on the TiO2 termination in the molecular configuration and 0.6 eV in the dissociative configuration, the corresponding results on the SrO termination being 0.9 eV for both modes of adsorption. These results are reproduced well by the PBE and PBE0 exchange-correlation functionals. Correcting for dispersion effects through the D3 dispersion correction leads to significantly overestimated adsorption energies for both PBE and PBE0 with respect to MP2. The D3 correction also fails to capture the difference in electron correlation between the molecular and dissociative adsorption states, similarly to the optB86b van der Waals density functional. PMID- 29111713 TI - Comprehensive Transcriptome Analysis of Phytohormone Biosynthesis and Signaling Genes in the Flowers of Chinese Chinquapin (Castanea henryi). AB - Chinese chinquapin (Castanea henryi) nut provides a rich source of starch and nutrients as food and feed, but its yield is restricted by a low ratio of female to male flowers. Little is known about the developmental programs underlying sex differentiation of the flowers. To investigate the involvement of phytohormones during sex differentiation, we described the morphology of male and female floral organs and the cytology of flower sex differentiation, analyzed endogenous levels of indole-3-acetic acid (IAA), gibberellins (GAs), cytokinins (CKs), and abscisic acid (ABA) in the flowers, investigated the effects of exogenous hormones on flower development, and evaluated the expression profiles of genes related to biosyntheses and signaling pathways of these four hormones using RNA-Seq combined with qPCR. Morphological results showed that the flowers consisted of unisexual and bisexual catkins, and could be divided into four developmental stages. HPLC results showed that CK accumulated much more in the female flowers than that in the male flowers, GA and ABA showed the opposite results, while IAA did not show a tendency. The effects of exogenous hormones on sex differentiation were consistent with those of endogenous hormones. RNA-Seq combined with qPCR analyses suggest that several genes may play key roles in hormone biosynthesis and sex differentiation. This study presents the first comprehensive report of phytohormone biosynthesis and signaling during sex differentiation of C. henryi, which should provide a foundation for further mechanistic studies of sex differentiation in Castanea Miller species and other nonmodel plants. PMID- 29111714 TI - Quantitation of Nine Lactones in Dairy Cream by Stable Isotope Dilution Assays Based on Novel Syntheses of Carbon-13-Labeled gamma-Lactones and Deuterium Labeled delta-Lactones in Combination with Comprehensive Two-Dimensional Gas Chromatography with Time-of-Flight Mass Spectrometry. AB - Lactones are well-known aroma compounds in, e.g., fruits and fermented foods as well as in dairy products, such as cream or milk powders. The latter are often used in confectionary products, e.g., milk chocolate. Lactones are suggested to contribute to the distinct aroma of dairy products and have also been reported in milk chocolate. However, data on their contribution to the overall aroma of this type of chocolate are scarce. As a result of their pH-dependent instability and their low volatility, a reliable quantitation of lactones is a challenge. Thus, to allow for a quantitation of nine lactones in one single comprehensive two dimensional gas chromatography with time-of-flight mass spectrometry in electron ionization mode run, new synthetic routes were developed for five carbon-13 labeled gamma-lactones and four deuterium-labeled delta-lactones, with the isotope label in the ring to be used in stable isotope dilution assays. The concentrations of the nine lactones were then analyzed in raw and pasteurized cream as well as in a heat-treated raw cream. delta-Dodecalactone and delta decalactone showed the highest concentrations in both the raw and pasteurized cream. In the latter, delta-dodecalactone reached a 2.5-fold higher concentration compared to the raw cream. Subsequent heat treatments in a lab scale showed a further increase by factors of 13 and 19, respectively, suggesting a high potential of lactone precursors in cream. The results serve as a basis for further studies on lactone formation in other thermally processed products, such as milk chocolate. PMID- 29111715 TI - Environmental Growing Conditions in Five Production Systems Induce Stress Response and Affect Chemical Composition of Cocoa (Theobroma cacao L.) Beans. AB - Cocoa beans are produced all across the humid tropics under different environmental conditions provided by the region but also by the season and the type of production system. Agroforestry systems compared to monocultures buffer climate extremes and therefore provide a less stressful environment for the understory cocoa, especially under seasonally varying conditions. We measured the element concentration as well as abiotic stress indicators (polyamines and total phenolic content) in beans derived from five different production systems comparing monocultures and agroforestry systems and from two harvesting seasons. Concentrations of N, Mg, S, Fe, Mn, Na, and Zn were higher in beans produced in agroforestry systems with high stem density and leaf area index. In the dry season, the N, Fe, and Cu concentration of the beans increased. The total phenolic content increased with proceeding of the dry season while other abiotic stress indicators like spermine decreased, implying an effect of the water availability on the chemical composition of the beans. Agroforestry systems did not buffer the variability of stress indicators over the seasons compared to monocultures. The effect of environmental growing conditions on bean chemical composition was not strong but can contribute to variations in cocoa bean quality. PMID- 29111716 TI - Aromatic Extension at 2,6-Positions of Anthracene toward an Elegant Strategy for Organic Semiconductors with Efficient Charge Transport and Strong Solid State Emission. AB - Organic semiconductors integrating excellent charge transport with efficient solid emission are very challenging to be attained in the construction of light emitting transistors and even for realization of electrically pumped organic lasers. Herein, we introduce naphthyl units at 2,6-positions of anthracene to achieve 2,6-di(2-naphthyl)anthracene (dNaAnt), which adopts J-aggregated mode in the solid state as a balanced strategy for excellent charge transporting and efficient solid state emission. Single crystal field-effect transistors show mobility up to 12.3 cm2.V-1.s-1 and a photoluminescence quantum yield of 29.2% was obtained for dNaAnt crystals. Furthermore, organic light-emitting transistors (OLETs) based on dNaAnt single crystals distribute outstanding balanced ambipolar charge transporting property (MUh = 1.10 cm2.V-1.s-1, MUe = 0.87 cm2.V-1.s-1) and spatially controllable emission, which is one of the best performances for OLETs. PMID- 29111718 TI - Linear Conjugated Polymer Backbones Improve Alignment in Nanogroove-Assisted Organic Field-Effect Transistors. AB - Three cyclopentadithiophene-difluorophenylene copolymers (named PhF2,3, PhF2,5, and PhF2,6), which differ by the arrangement of fluorines on the phenylene structural unit, were designed and synthesized for the fabrication of organic field-effect transistors (OFETs). Single crystal structures of model compounds representative of the backbone and density functional theory (DFT) were used to estimate the backbone shape for each copolymer. The different substitution arrangements impact the backbone secondary structure through different nonbonding F...H interactions. PhF2,5 and PhF2,6 assumed more linear backbones relative to PhF2,3, which in turn impacts self-assembly and polymer chain alignment on nanogrooved (NG) substrates. A larger improvement of charge carrier mobility for the more linear backbones was achieved when using NG substrates. Among the three polymers, PhF2,6 achieved the highest average field-effect hole mobility (5.1 cm2 V-1 s-1). As evidenced by grazing incidence wide-angle X-ray scattering (GIWAXS), thin films of PF2,5 and PF2,6 exhibited a higher degree of anisotropic alignment, relative to the more curved PF2,3 counterpart, consistent with the higher hole mobilities. This work gives insight into how nonbonding interactions can influence charge carrier mobility through changes in secondary structure and suggests that polymers with more linear shapes might be preferred for achieving greater levels of alignment within the confines of a NG environment. PMID- 29111717 TI - Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate. AB - Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF 06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h. PMID- 29111719 TI - Theoretical Analysis of Activity Cliffs among Benzofuranone-Class Pim1 Inhibitors Using the Fragment Molecular Orbital Method with Molecular Mechanics Poisson Boltzmann Surface Area (FMO+MM-PBSA) Approach. AB - Significant activity changes due to small structural changes (i.e., activity cliffs) of serine/threonine kinase Pim1 inhibitors were studied theoretically using the fragment molecular orbital method with molecular mechanics Poisson Boltzmann surface area (FMO+MM-PBSA) approach. This methodology enables quantum chemical calculations for large biomolecules with solvation. In the course of drug discovery targeting Pim1, six benzofuranone-class inhibitors were found to differ only in the position of the indole-ring nitrogen atom. By comparing the various qualities of complex structures based on X-ray, classical molecular mechanics (MM)-optimized, and quantum/molecular mechanics (QM/MM)-optimized structures, we found that the QM/MM-optimized structures provided the best correlation (R2 = 0.85) between pIC50 and the calculated FMO+MM-PBSA binding energy. Combining the classical solvation energy with the QM binding energy was important to increase the correlation. In addition, decomposition of the interaction energy into various physicochemical components by pair interaction energy decomposition analysis suggested that CH-pi and electrostatic interactions mainly caused the activity differences. PMID- 29111721 TI - How Well Can the M06 Suite of Functionals Describe the Electron Densities of Ne, Ne6+, and Ne8+? AB - The development of better approximations to the exact exchange-correlation functional is essential to the accuracy of density functionals. A recent study suggested that functionals with few parameters provide more accurate electron densities than recently developed many-parameter functionals for light closed shell atomic systems. In this study, we calculated electron densities, their gradients, and Laplacians of Ne, Ne6+, and Ne8+ using 19 electronic structure methods, and we compared them to the CCSD reference results. Two basis sets, namely, aug-cc-pomegaCV5Z and aug-cc-pV5Z, are utilized in the calculations. We found that the choice of basis set has a significant impact on the errors and rankings of some of the selected methods. The errors of electron densities, their gradients, and Laplacians calculated with the aug-cc-pV5Z basis set are substantially reduced, especially for Minnesota density functionals, as compared to the results using the aug-cc-pomegaCV5Z basis set (a larger basis set utilized in earlier work (Medvedev et al. Science 2017, 355, 49-52)). The rankings of the M06 suite of functionals among the 19 methods are greatly improved with the aug cc-pV5Z basis set. In addition, the performances of the HSE06, BMK, MN12-L, and MN12-SX functionals are also improved with the aug-cc-pV5Z basis set. The M06 suite of functionals is capable of providing accurate electron densities, gradients, and Laplacians using the aug-cc-pV5Z basis set, and thus it is suitable for a wide range of applications in chemistry and physics. PMID- 29111720 TI - Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems. AB - An increasingly important endeavor is to develop computational strategies that enable molecular dynamics (MD) simulations of biomolecular systems with spontaneous changes in protonation states under conditions of constant pH. The present work describes our efforts to implement the powerful constant-pH MD simulation method, based on a hybrid nonequilibrium MD/Monte Carlo (neMD/MC) technique within the highly scalable program NAMD. The constant-pH hybrid neMD/MC method has several appealing features; it samples the correct semigrand canonical ensemble rigorously, the computational cost increases linearly with the number of titratable sites, and it is applicable to explicit solvent simulations. The present implementation of the constant-pH hybrid neMD/MC in NAMD is designed to handle a wide range of biomolecular systems with no constraints on the choice of force field. Furthermore, the sampling efficiency can be adaptively improved on the-fly by adjusting algorithmic parameters during the simulation. Illustrative examples emphasizing medium- and large-scale applications on next-generation supercomputing architectures are provided. PMID- 29111723 TI - Synthetic Method to Form 2,2'-Bis(naphthoquinone) Compounds. AB - We have discovered a transition-metal-free approach to the synthesis of 2,2' bis(naphthoquinones) using a Diels-Alder reaction of conjugated ketene silyl acetals with benzoquinone. Its monomer analogue can also be synthesized by simply increasing the equivalents of benzoquinone. PMID- 29111722 TI - Multistep Conformation Selection in Amyloid Assembly. AB - Defining pathways for amyloid assembly could impact therapeutic strategies for as many as 50 disease states. Here we show that amyloid assembly is subject to different forces regulating nucleation and propagation steps and provide evidence that the more global beta-sheet/beta-sheet facial complementarity is a critical determinant for amyloid nucleation and structural selection. PMID- 29111724 TI - Fermionic Statistics in the Strongly Correlated Limit of Density Functional Theory. AB - Exact pieces of information on the adiabatic connection integrand, Wlambda[rho], which allows evaluation of the exchange-correlation energy of Kohn-Sham density functional theory, can be extracted from the leading terms in the strong coupling limit (lambda -> infinity, where lambda is the strength of the electron-electron interaction). In this work, we first compare the theoretical prediction for the two leading terms in the strong coupling limit with data obtained via numerical implementation of the exact Levy functional in the simple case of two electrons confined in one dimension, confirming the asymptotic exactness of these two terms. We then carry out a first study on the incorporation of the Fermionic statistics at large coupling lambda, both numerical and theoretical, confirming that spin effects enter at orders ~e-?lambda. PMID- 29111725 TI - Model Studies To Access the [6,7,5,5]-Core of Ineleganolide Using Tandem Translactonization-Cope or Cyclopropanation-Cope Rearrangements as Key Steps. AB - Recently, we reported a convergent cyclopropanation-Cope approach to the core of ineleganolide, which was the first disclosed synthesis of the core of the norditerpene natural product ineleganolide. In this complementary work, a model system for the core of ineleganolide has been prepared through a series of tandem cyclopropanation-Cope and translactonization-Cope rearrangements. Work with this model system has enriched our understanding of the cyclopropanation-Cope rearrangement sequence. Additionally, research into this model system has driven the development of tandem translactonization-Cope rearrangements. PMID- 29111726 TI - TDDFT Study of the Optical Excitation of Nucleic Acid Bases-C60 Complexes. AB - The potential of C60 as a nucleic acid base (NAB) optical sensor is theoretically explored. We investigate the adsorption of four NABs, namely, adenine, cytosine, guanine, and thymine, on C60 in the gas phase. For the optimal NAB@C60 adsorption configurations, obtained using a dispersion-corrected density functional, we calculate the vis-near-ultraviolet optical response using time-dependent density functional theory. While the isolated C60 and NAB molecules do not exhibit visible optical excitation, we find that C60/NAB conjugation gives rise to distinct spectral features in the visible range. These results suggest that C60 conjugation can be applied for photodetection of individual NABs. PMID- 29111727 TI - Bioisostere Identification by Determining the Amino Acid Binding Preferences of Common Chemical Fragments. AB - To assist in the structural optimization of hit/lead compounds during drug discovery, various computational approaches to identify potentially useful bioisosteric conversions have been reported. Here, the preference of chemical fragments to hydrogen bonds with specific amino acid residues was used to identify potential bioisosteric conversions. We first compiled a data set of chemical fragments frequently occurring in complex structures contained in the Protein Data Bank. We then used a computational approach to determine the amino acids to which these chemical fragments most frequently hydrogen bonded. The results of the frequency analysis were used to hierarchically cluster chemical fragments according to their amino acid preferences. The Euclid distance between amino acid preferences of chemical fragments for hydrogen bonding was then compared to MMP information in the ChEMBL database. To demonstrate the applicability of the approach for compound optimization, the similarity of amino acid preferences was used to identify known bioisosteric conversions of the epidermal growth factor receptor inhibitor gefitinib. The amino acid preference distance successfully detected bioisosteric fragments corresponding to the morpholine ring in gefitinib with a higher ROC score compared to those based on topological similarity of substituents and frequency of MMP in the ChEMBL database. PMID- 29111729 TI - Retinal Binding to Apo-Gloeobacter Rhodopsin: The Role of pH and Retinal Carotenoid Interaction. AB - Over the past few decades, the structure, functions, properties, and molecular mechanisms of retinal proteins have been studied extensively. The newly studied retinal protein Gloeobacter rhodopsin (gR) acts as a light-driven proton pump, transferring a proton from the cytoplasmic region to the extracellular region of a cell following light absorption. It was previously shown that gR can bind the carotenoid salinixanthin (sal). In the present study, we report the effect of pH on the binding of retinal to the apo-protein of gR, in the presence and absence of sal, to form the gR pigment. We found that binding at different pH levels reflects the titration of two different protein residues, one at the lower pKa 3.5 and another at the higher pKa 8.4, that affect the pigment's formation. The maximum amount of pigment was formed at pH 5, both with and without the presence of sal. The introduction of sal accelerates the rate of pigment formation by a factor of 190. Furthermore, it is suggested that occupation of the binding site by the retinal chromophore induces protein conformational alterations which in turn affect the carotenoid conformation, which precedes the formation of the retinal-protein covalent bond. Our examination of synthetic retinal analogues in which the ring structure was modified revealed that, in the absence of sal, the retinal ring structure affects the rate of pigment formation and that the intact structure is needed for efficient pigment formation. However, the presence of sal abolishes this effect, and all-trans retinal and its modified ring analogues bind at a similar rate. PMID- 29111730 TI - One-Pot Synthesis of alpha-Carbonyl Bicyclic Furans via a Sequential Diels Alder/5-Exo-Dig Cyclization/Oxidation Reaction. AB - A new one-pot approach to construct alpha-carbonyl bicyclic furans from easily accessible diynones is described. This reaction sequence proceeds via a Diels Alder cycloaddition reaction catalyzed by dimethylaluminum chloride followed by a 5-exo-dig cyclization/oxidation reaction catalyzed by copper(II) chloride. This methodology generates alpha-carbonyl-functionalized dihydroisobenzofuran derivatives in good to excellent yields. PMID- 29111728 TI - Nanoparticle-Cell Interactions: Relevance for Public Health. AB - Nanoparticles, especially metal oxide nanoparticles, are used in a wide range of commercial and industrial applications that result in direct human contact, such as titanium dioxide nanoparticles in paints, food colorings, and cosmetics, or indirectly through release of nanoparticle-containing materials into the environment. Workers who process nanoparticles for downstream applications are exposed to especially high concentrations of nanoparticles. For physical chemists, nanoparticles present an interesting area of study as the small size of nanoparticles changes the properties from that of the bulk material, leading to novel properties and reactivity. For the public health community, this reduction in particle size means that exposure limits and outcomes that were determined from bulk material properties are not necessarily valid. Informed determination of exposure limits requires a fundamental understanding of how nanoparticles interact with cells. This Feature Article highlights the areas of intersection between physical chemistry and public health in understanding nanoparticle-cell interactions, with a focus on titanium dioxide nanoparticles. It provides an overview of recent research examining the interaction of titanium dioxide nanoparticles with cells in the absence of UV light and provides recommendations for additional nanoparticle-cell research in which physical chemistry expertise could help to inform the public health community. PMID- 29111731 TI - Self-Avoiding Conformational Sampling Based on Histories of Past Conformational Searches. AB - Self-avoiding conformational sampling (SACS) is proposed as an enhanced conformational sampling method for proteins. In SACS, the following conformational resampling is repeated for a given protein: (1) identification of newly visited states in a subspace and (2) conformational resampling by restarting short-time molecular dynamics (MD) simulations from the newly visited states. To identify the newly visited states, a set of history-dependent histograms projected onto the subspace is used. One is constructed from the trajectories sampled at the current (ith) cycle, and the other is constructed from all of the trajectories accumulated up through the previous ((i - 1)th) cycle. By reference to the history-dependent histograms, the newly visited states appearing at the current (ith) cycle are defined as a difference set between them. By repeating the cycle of conformational resampling, SACS prevents the system from revisiting states that have already been visited for previous cycles, promoting structural transitions via resampling from the newly visited states. To verify the conformational sampling efficiency of SACS, the present method was applied to reveal underlying mechanisms of biologically important domain motions of maltodextrin binding protein in explicit water and successfully reproduced the open-closed transition with a reasonable (nanosecond-order) computational cost. PMID- 29111732 TI - Photoinduced Electron Transfer in Naphthalene Diimide End-Capped Thiophene Oligomers. AB - A series of linear thiophene oligomers containing 4, 6, 8, 10, and 12 thienylene units were synthesized and end-capped with naphthalene diimide (NDI) acceptors with the objective to study the effect of oligomer length on the dynamics of photoinduced electron transfer and charge recombination. The synthetic work afforded a series of nonacceptor-substituted thiophene oligomers, Tn, and corresponding NDI end-capped series, TnNDI2 (where n is the number of thienylene repeat units). This paper reports a complete photophysical characterization study of the Tn and TnNDI2 series by using steady-state absorption, fluorescence, singlet oxygen sensitized emission, two-photon absorption, and nanosecond microsecond transient absorption spectroscopy. The thermodynamics of photoinduced electron transfer and charge recombination in the TnNDI2 oligomers were determined by analysis of photophysical and electrochemical data. Excitation of the Tn oligomers gives rise to efficient fluorescence and intersystem crossing to a triplet excited state that is easily observed by nanosecond transient absorption spectroscopy. Bimolecular photoinduced electron transfer from the triplet states, 3Tn*, to N,N-dimethylviologen (MV2+) occurs, and by using microsecond transient absorption it is possible to assign the visible region absorption spectra for the one electron oxidized (polaron) states, Tn+*. The fluorescence of the TnNDI2 oligomers is quenched nearly quantitatively, and no long-lived transients are observed by nanosecond transient absorption. These findings suggest that rapid photoinduced electron transfer and charge recombination occurs, NDI-1(Tn)*-NDI -> NDI-(Tn)+*-NDI-* -> NDI-Tn-NDI. Preliminary femtosecond-picosecond transient absorption studies on T4NDI2 reveal that both forward electron transfer and charge recombination occur with k > 1011 s-1, consistent with both reactions being nearly activationless. Analysis with semiclassical electron transfer theory suggests that both reactions occur at near the optimum driving force where -DeltaG ~ lambda. PMID- 29111733 TI - A Theoretical and Computational Analysis of the Methyl-Vinyl + O2 Reaction and Its Effects on Propene Combustion. AB - A detailed analysis of the reaction of CH3CCH2 and CH3CHCH with molecular oxygen is presented. The C3H5O2 potential energy surface was characterized using a combination of electronic structure methods. The majority of the stationary points on the PES was determined at the CCSD(T)-F12a/cc-pVTZ-F12//B2PLYPD3/cc pVTZ level of theory, with the remaining transition states computed using multireference methods. Microcanonical rate theory and the master equation are used to determine the temperature- and pressure-dependent rate coefficients for each reaction channel. The main product channels are CH2O + CH3CO for CH3CCH2 and CH3CHO + CHO for CH3CHCH. The rate constants for these two reactions at 1 atm are k = 9.03 * 1022 * T-3.21 * exp-2162/T and 1.50 * 1019 * T-2.10 * exp-1260/T cm-3 mol-1 s-1, respectively. In contrast to C2H3 + O2, the methyl-vinyl + O2 reactions remain chain propagating, even at high temperatures. The new rate coefficients were implemented in a detailed mechanism taken from the literature. These changes have a modest effect on the ignition delay time and laminar flame speeds for propene combustion. PMID- 29111734 TI - Kinetic Limitation to Inorganic Ion Diffusivity and to Coalescence of Inorganic Inclusions in Viscous Liquid-Liquid Phase-Separated Particles. AB - Mixed organic/inorganic aerosols may undergo liquid-liquid phase separation (LLPS) when the relative humidity drops in the atmosphere. Phase-separated particles adopt different morphologies, which will have different consequences for atmospheric chemistry and climate. Recent laboratory studies on submicron particles led to speculation whether LLPS observed for larger drops might actually be suppressed in smaller droplets. Here, we report on micron-sized droplets of a ternary mixture of ammonium sulfate (AS), carminic acid, and water at different temperatures, which were exposed to typical atmospheric drying rates ranging from 0.34 to 5.0% RH min-1. Our results reveal that increasing the drying rate and lowering the temperature results in different morphologies after LLPS and may suppress the growth and coalescence of the inorganic-rich phase inclusions due to kinetic limitations in a viscous matrix. The coalescence time was used to estimate the viscosity of the organic-rich phase within a factor of 20, and based on the Stokes-Einstein relationship, we estimated AS diffusivity. Furthermore, we evaluated the initial growth of inclusions to quantitatively determine the AS diffusivity in the organic-rich phase, which is about 10-8 cm2 s 1 at room temperature. Extrapolation of diffusivity to lower temperatures using estimations for the diffusion activation energy leads us to conclude that the growth of the inorganic phase is not kinetically impeded for tropospheric submicron particles larger than 100 nm. PMID- 29111735 TI - Metal-Free Synthesis of 2-Substituted 3-(2-Hydroxyaryl)quinolines and 4-(2 Hydroxyaryl)acridines via Benzyne Chemistry. AB - A metal-free approach for the synthesis of 3-aryl-2-substituted quinolines and 4 arylacridines has been developed via the 1,3-dipolar cycloaddition reactions of arynes with N-oxides. Reactions of various 2-substitued quinoline N-oxides with ortho-(trimethylsilyl)aryltriflates in the presence of KF gave 3-(2 hydroxyaryl)quinoline derivatives in good yields. Acridine N-oxides also reacted with arynes to furnish 4-(2-hydroxyaryl)acridines, albeit in moderate yields. PMID- 29111737 TI - Intramolecular Diels-Alder Reactions of Tethered Enoate Substituted Furans Induced by Dialkylaluminum Chloride. AB - Gold(I)-catalyzed cycloisomerization of enynols 11 and 17, obtained by Sonogashira coupling, led to the tethered enoate-substituted furans 14 and 19. While attempts at thermal and several Lewis acid induced intramolecular Diels Alder reactions remained fruitless, dialkylaluminum chloride led to the formation of hexahydroindene and octahydronaphthalene derivatives 20-23. Their formation can be explained by Lewis acid induced opening of the epoxy bridge with transfer of one alkyl group to the intermediate cycloadduct. PMID- 29111736 TI - Structure-Affinity Relationships and Structure-Kinetic Relationships of 1,2 Diarylimidazol-4-carboxamide Derivatives as Human Cannabinoid 1 Receptor Antagonists. AB - We report on the synthesis and biological evaluation of a series of 1,2 diarylimidazol-4-carboxamide derivatives developed as CB1 receptor antagonists. These were evaluated in a radioligand displacement binding assay, a [35S]GTPgammaS binding assay, and in a competition association assay that enables the relatively fast kinetic screening of multiple compounds. The compounds show high affinities and a diverse range of kinetic profiles at the CB1 receptor and their structure-kinetic relationships (SKRs) were established. Using the recently resolved hCB1 receptor crystal structures, we also performed a modeling study that sheds light on the crucial interactions for both the affinity and dissociation kinetics of this family of ligands. We provide evidence that, next to affinity, additional knowledge of binding kinetics is useful for selecting new hCB1 receptor antagonists in the early phases of drug discovery. PMID- 29111738 TI - Binary Superlattice Design by Controlling DNA-Mediated Interactions. AB - Most binary superlattices created using DNA functionalization rely on particle size differences to achieve compositional order and structural diversity. Here we study two-dimensional (2D) assembly of DNA-functionalized micron-sized particles (DFPs), and employ a strategy that leverages the tunable disparity in interparticle interactions, and thus enthalpic driving forces, to open new avenues for design of binary superlattices that do not rely on the ability to tune particle size (i.e., entropic driving forces). Our strategy employs tailored blends of complementary strands of ssDNA to control interparticle interactions between micron-sized silica particles in a binary mixture to create compositionally diverse 2D lattices. We show that the particle arrangement can be further controlled by changing the stoichiometry of the binary mixture in certain cases. With this approach, we demonstrate the ability to program the particle assembly into square, pentagonal, and hexagonal lattices. In addition, different particle types can be compositionally ordered in square checkerboard and hexagonal-alternating string, honeycomb, and Kagome arrangements. PMID- 29111739 TI - Competitive Removal of Cu(II) and Cd(II) from Water Using a Biocomposite Hydrogel. AB - With an objective to improve the adsorption properties of a synthetic hydrogel, potato starch (PS) was incorporated in the ter-copolymer (TP) of acrylic acid (AA), acrylamide (AM), and bicarboxylic itaconic acid (IA) during polymerization of the monomers. The resulting TP-PS composite hydrogels were characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), nuclear magnetic resonance (NMR), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDX), and rheological properties. These hydrogels were used for removal of Cu(II) and Cd(II) as single and binary competitive mixtures from water. The effect of PS as well as various physicochemical parameters such as solution pH, adsorbent dosage, contact time of gel with metal ion in water, and concentration of metal ion in water was studied in batch experiments. The adsorption results indicated that the gels could be used as an efficient adsorbent for removal of Cu(II) and Cd(II) from water as single as well as binary mixtures. The TP-PS4 gel containing 4 wt % starch showed a removal % of 85.8 and 77.6 and adsorption capacity (mg/g gel) of 214.5 and 193.9 for Cu(II) and Cd(II), respectively, from water containing 50 mg/L of each of these metal ions in a solution pH of 5.5 and a dose of only 0.2 g/L gel. PMID- 29111740 TI - Impact of Element Doping on Photoexcited Electron Dynamics in CdS Nanocrystals. AB - Element doping plays a key role in achieving desired properties of semiconductor nanocrystals. In the energy-state landscape the doping-induced localized impurity states (LIS) can bring on significant modification of photoelectrochemical effects. It is difficult to retrieve information regarding the doping-induced LIS. Here we report on such information gleaned on a prototypical system of CdS nanocrystals slightly doped with In3+, through joint observations from photoluminescence (PL) and ultrafast transient absorption (TA) spectroscopy. The nonradiative nature of the In-doping induced LIS is revealed by PL. The TA observations, with a set of control experiments, enable us to capture a picture of the photoexcited electron dynamics and unravel the photoexcited electron reservoir (PEER) effect associated with the In-doping induced band gap LIS. This work establishes a fundamental, mechanistic understanding of the significant impact of element doping on the photoexcited electron dynamics in this model system, offering useful inputs for relevant material design and applications. PMID- 29111741 TI - Theoretical Probing of Weak Anion-Cation Interactions in Certain Pyridinium-Based Ionic Liquid Ion Pairs and the Application of Molecular Electrostatic Potential in Their Ionic Crystal Density Determination: A Comparative Study Using Density Functional Approach. AB - A comprehensive study on the structure, nature of interaction, and properties of six ionic pairs of 1-butylpyridinium and 1-butyl-4-methylpyridinium cations in combination with tetrafluoroborate (BF4-), chloride (Cl-), and bromide (Br-) anions have been carried out using density functional theory (DFT). The anion cation interaction energy (DeltaEint), thermochemistry values, theoretical band gap, molecular orbital energy order, DFT-based chemical activity descriptors [chemical potential (MU), chemical hardness (eta), and electrophilicity index (omega)], and distribution of density of states (DOS) of these ion pairs were investigated. The ascendancy of the -CH3 substituent at the fourth position of the 1-butylpyridinium cation ring on the values of DeltaEint, theoretical band gap and chemical activity descriptors was evaluated. The DeltaEint values were negative for all six ion pairs and were highest for Cl- containing ion pairs. The theoretical band gap value after -CH3 substitution increased from 3.78 to 3.96 eV (for Cl-) and from 2.74 to 2.88 eV (for Br-) and decreased from 4.9 to 4.89 eV (for BF4-). Ion pairs of BF4- were more susceptible to charge transfer processes as inferred from their significantly high eta values and comparatively small difference in omega value after -CH3 substitution. The change in eta and MU values due to the -CH3 substituent is negligibly small in all cases except for the ion pairs of Cl-. Critical-point (CP) analyses were carried out to investigate the AIM topological parameters at the interionic bond critical points (BCPs). The RDG isosurface analysis indicated that the anion-cation interaction was dominated by strong Hcat...Xani and Ccat...Xani interactions in ion pairs of Cl- and Br- whereas a weak van der Waal's effect dominated in ion pairs of BF4-. The molecular electrostatic potential (MESP)-based parameter DeltaDeltaVmin measuring the anion-cation interaction strength showed a good linear correlation with DeltaEint for all 1-butylpyridinium ion pairs (R2 = 0.9918). The ionic crystal density values calculated by using DFT-based MESP showed only slight variations from experimentally reported values. PMID- 29111742 TI - Increased Post-Translational Lysine Acetylation of Myelin Basic Protein Is Associated with Peak Neurological Disability in a Mouse Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis. AB - Citrullination of arginine residues is a post-translational modification (PTM) found on myelin basic protein (MBP), which neutralizes MBPs positive charge, and is implicated in myelin damage and multiple sclerosis (MS). Here we identify lysine acetylation as another neutralizing PTM to MBP that may be involved in myelin damage. We quantify changes in lysine and arginine PTMs on MBP derived from mice induced with an experimental autoimmune encephalomyelitis (EAE) model of MS using liquid chromatography tandem mass spectrometry. The changes in PTMs are correlated to changes in neurological disability scoring (NDS), as a marker of myelin damage. We found that lysine acetylation increased by 2-fold on MBP during peak NDS post-EAE induction. We also found that mono- and dimethyl-lysine, as well as asymmetric dimethyl-arginine residues on MBP were elevated at peak EAE disability. These findings suggest that the acetylation and methylation of lysine on MBP are PTMs associated with the neurological disability produced by EAE. Since histone deacetylase (HDAC) inhibitors have been previously shown to improve neurological disability, we also show that treatment with trichostatin A (a HDAC inhibitor) improves the NDS of EAE mice but does not change MBP acetylation. PMID- 29111743 TI - Influence of Capillary Effects on Electric Response of Well-Ordered Carbon Nanotube Film. AB - The interface structure in nanocomposite materials often directly influences the electric, thermal, and mechanical properties of functional architectures and limits their application in many fields, in addition to the characteristics of their nanobuilding blocks. In this work, we report that the electronic transport characteristic of a well-ordered carbon nanotube film is adjusted by the structural evolution of the junction caused by capillary effects. This mechanism can explain the resistance change and recovery throughout the immersion evaporation process and even the anomalous transient decrease in the resistance. Meanwhile, we establish a relationship between the resistance change ratio of the film and the interfacial tension between the film and the immersion liquid. The ability to achieve a sensitive and repeatable resistance change in a carbon nanotube film could have important implications in the measurement of liquid properties, liquid sensors, and solution analysis and provide a new avenue for the development of new multifunctional architectures. PMID- 29111745 TI - Self-Assembled 3D Hierarchical Copper Hydroxyphosphate Modified by the Oxidation of Copper Foil as a Recyclable, Wide Wavelength Photocatalyst. AB - In this work, three-dimensional flower-like and petal-like copper hydroxyphosphate Cu5(OH)4(PO4)2 (CHP) based on the self-assembly of numerous nanosheets has been successfully fabricated on a copper foil by a mild one-pot wet-chemical method without ligand assistance. This research contributes to the development of the method to change the morphology of the CHP active material by varying the degree of substrate oxidation. The two different CHP architectures were used to photocatalytically degrade rhodamine 6G (Rh 6G) under solar light, which can absorb wide-range light wavelength from the UV to the near-infrared region. They all exhibit high photocatalytic activity and good durability, which are potential candidates for high performance and recyclable wide wavelength photocatalysis. PMID- 29111744 TI - CdTe-Based Photoanode for Oxygen Evolution from Water under Simulated Sunlight. AB - This study investigated the properties of a photoanode fabricated by depositing a p-type CdTe thin film on a CdS-coated FTO substrate (CdTe/CdS/FTO) via close space sublimation. This CdTe/CdS/FTO electrode was found to work as a photoanode with a long absorption edge wavelength of 830 nm. In a CdTe-based photoanode such as this, the p-n junction formed at the CdTe/CdS interface promotes charge separation of photoexcited carriers and forces photogenerated holes to move toward the photoanode surface to promote oxidation reactions on the electrode surface. A MoOx buffer layer was also found to play a crucial role in facilitating the transfer of photogenerated holes to surface reaction sites through decreasing the energy barrier at the interface between the CdTe and a surface protective layer. A biphotoelectrode photoelectrochemical cell composed of a CdTe-based photoanode and a CdTe-based photocathode exhibited a solar-to hydrogen conversion efficiency of 0.22% without an external voltage in response to illumination by AM 1.5G light. PMID- 29111746 TI - Voltage Drop in a Ferroelectric Single Layer Capacitor by Retarded Domain Nucleation. AB - Ferroelectric (FE) capacitor is a critical electric component in microelectronic devices. Among many of its intriguing properties, the recent finding of voltage drop (V-drop) across the FE capacitor while the positive charges flow in is especially eye-catching. This finding was claimed to be direct evidence that the FE capacitor is in negative capacitance (NC) state, which must be useful for (infinitely) high capacitance and ultralow voltage operation of field-effect transistors. Nonetheless, the NC state corresponds to the maximum energy state of the FE material, so it has been widely accepted in the community that the material alleviates that state by forming ferroelectric domains. This work reports a similar V-drop effect from the 150 nm thick epitaxial BaTiO3 ferroelectric thin film, but the interpretation was completely disparate; the V drop can be precisely simulated by the reverse domain nucleation and propagation of which charge effect cannot be fully compensated for by the supplied charge from the external charge source. The disappearance of the V-drop effect was also observed by repeated FE switching only up to 10 cycles, which can hardly be explained by the involvement of the NC effect. The retained reverse domain nuclei even after the subsequent poling can explain such behavior. PMID- 29111748 TI - Palladium-Catalyzed Hydroaminocarbonylation of Alkynes with Tertiary Amines via C N Bond Cleavage. AB - An efficient strategy for the cleavage of the C-N bond of tertiary amines was developed with DTBP as an oxidant, in which the cleaved H atom and amine moiety were successfully transferred to the desired products. This strategy has enabled an efficient palladium-catalyzed hydroaminocarbonylation of alkynes with tertiary amines. Notably, the catalyst loading could be lowered from 5 to 0.1 mol %, which represents the lowest catalyst loading among the reported work on carbonylation via C-N bond activation. PMID- 29111747 TI - Constructing Ultrahigh-Capacity Zinc-Nickel-Cobalt Oxide@Ni(OH)2 Core-Shell Nanowire Arrays for High-Performance Coaxial Fiber-Shaped Asymmetric Supercapacitors. AB - Increased efforts have recently been devoted to developing high-energy-density flexible supercapacitors for their practical applications in portable and wearable electronics. Although high operating voltages have been achieved in fiber-shaped asymmetric supercapacitors (FASCs), low specific capacitance still restricts the further enhancement of their energy density. This article specifies a facile and cost-effective method to directly grow three-dimensionally well aligned zinc-nickel-cobalt oxide (ZNCO)@Ni(OH)2 nanowire arrays (NWAs) on a carbon nanotube fiber (CNTF) with an ultrahigh specific capacitance of 2847.5 F/cm3 (10.678 F/cm2) at a current density of 1 mA/cm2, These levels are approximately five times higher than those of ZNCO NWAs/CNTF electrodes (2.10 F/cm2) and four times higher than Ni(OH)2/CNTF electrodes (2.55 F/cm2). Benefiting from their unique features, we successfully fabricated a prototype coaxial FASC (CFASC) with a maximum operating voltage of 1.6 V, which was assembled by adopting ZNCO@Ni(OH)2 NWAs/CNTF as the core electrode and a thin layer of carbon coated vanadium nitride (VN@C) NWAs on a carbon nanotube strip (CNTS) as the outer electrode with KOH poly(vinyl alcohol) (PVA) as the gel electrolyte. A high specific capacitance of 94.67 F/cm3 (573.75 mF/cm2) and an exceptional energy density of 33.66 mWh/cm3 (204.02 MUWh/cm2) were achieved for our CFASC device, which represent the highest levels of fiber-shaped supercapacitors to date. More importantly, the fiber-shaped ZnO-based photodetector is powered by the integrated CFASC, and it demonstrates excellent sensitivity in detecting UV light. Thus, this work paves the way to the construction of ultrahigh-capacity electrode materials for next-generation wearable energy-storage devices. PMID- 29111749 TI - Unraveling the Formation Mechanism of Dendritic Fibrous Nanosilica. AB - We studied the formation mechanism of dendritic fibrous nanosilica (DFNS) that involves several intriguing dynamical steps. Through electron microscopy and real time small-angle X-ray scattering studies, it has been demonstrated that the structural evolution of bicontinuous microemulsion droplets (BMDs) and their subsequent coalescence, yielding nanoreactor template, is responsible for to the formation of complex DFNS morphology. The role of cosurfactant has been found to be quite crucial, which allowed the understanding of this intricate mechanism involving the complex interplay of self-assembly, dynamics of BMDs formation, and coalescence. The role of BMDs in formation of DFNS has not been reported so far and the present work allows a deeper molecular-level understanding of DFNS formation. PMID- 29111750 TI - Self-Catalyzed Vapor-Liquid-Solid Growth of Lead Halide Nanowires and Conversion to Hybrid Perovskites. AB - Lead halide perovskites (LHPs) have shown remarkable promise for use in photovoltaics, photodetectors, light-emitting diodes, and lasers. Although solution-processed polycrystalline films are the most widely studied morphology, LHP nanowires (NWs) grown by vapor-phase processes offer the potential for precise control over crystallinity, phase, composition, and morphology. Here, we report the first demonstration of self-catalyzed vapor-liquid-solid (VLS) growth of lead halide (PbX2; X = Cl, Br, or I) NWs and conversion to LHP. We present a kinetic model of the PbX2 NW growth process in which a liquid Pb catalyst is supersaturated with halogen X through vapor-phase incorporation of both Pb and X, inducing growth of a NW. For PbI2, we show that the NWs are single-crystalline, oriented in the ?1210? direction, and composed of a stoichiometric PbI2 shaft with a spherical Pb tip. Low-temperature vapor-phase intercalation of methylammonium iodide converts the NWs to methylammonium lead iodide (MAPbI3) perovskite while maintaining the NW morphology. Single-NW experiments comparing measured extinction spectra with optical simulations show that the NWs exhibit a strong optical antenna effect, leading to substantially enhanced scattering efficiencies and to absorption efficiencies that can be more than twice that of thin films of the same thickness. Further development of the self-catalyzed VLS mechanism for lead halide and perovskite NWs should enable the rational design of nanostructures for various optoelectronic technologies, including potentially unique applications such as hot-carrier solar cells. PMID- 29111752 TI - Sulfur-Directed Ligand-Free C-H Borylation by Iridium Catalysis. AB - An iridium-catalyzed ortho C-H borylation reaction directed by cyclic dithioacetal moiety is disclosed. A series of borylation products were obtained in moderate to good yields under mild conditions in exclusive mono- and ortho regioselectivity. Thus, the 1,3-dithiane or 1,3-dithiolane group serves as a remarkable effective directing group for C-H borylation without any ligand assistance. The further transformations of the borylation products are also carried out to change boryl group to other functional groups. PMID- 29111751 TI - Extraordinary Long-Term-Stability in Kinetically Stabilized Amorphous Solid Dispersions of Fenofibrate. AB - Inhibition of recrystallization of the drug substance in kinetically stabilized amorphous solid dispersions (ASDs) within and beyond shelf life is still a matter of debate. Generally, these ASD systems are considered to be prone to recrystallization, but examples of their long-term stability are emerging in the literature. Since, in some cases, the formation of crystals may impact bioavailability, recrystallization may present a relevant risk for patients as it potentially lowers the effective dose of the formulation. This study shows that such metastable formulations may indeed remain amorphous even after 15 years of storage under ambient conditions. A formulation of fenofibrate stored for 15 years was compared to a freshly prepared batch. A complete physicochemical characterization regarding content, purity, water content and glass transition was conducted. The emphasis of this physicochemical characterization was on crystallinity as a critical quality attribute: polarized light microscopy (PLM) was used as the standard qualitative method and X-ray powder diffraction (XRPD) as the standard quantitative method. An investigation of the crystal growth kinetics by transmission Raman spectroscopy (TRS) was conducted to build a predictive model. The model was applied successfully to predict the observed physical state of the 15-year-old samples. The observations presented here demonstrate that kinetic stabilization alone is able to prevent crystallization in ASDs over prolonged storage periods, suggesting the need for a reassessment of the risk perception for this kind of ASD formulations. PMID- 29111753 TI - Biogenic Nanostructured Porous Silicon as a Carrier for Stabilization and Delivery of Natural Therapeutic Species. AB - Nanostructured mesoporous silicon (pSi) derived from the silicon-accumulator plant Tabasheer (Bambuseae) is demonstrated to serve as a potential carrier matrix for carrying and stabilizing naturally active, but otherwise metastable, therapeutic agents. Particularly, in this study, garlic oil containing phytochemicals (namely, allicin) that are capable of inhibiting Staphylococcus aureus (S. aureus) bacterial growth were incorporated into Tabasheer-derived porous silicon. Thermogravimetric analysis (TGA) indicated that relatively high amounts of the extract (53.1 +/- 2.2 wt %) loaded into pSi are possible by simple infiltration. Furthermore, by assessing the antibacterial activity of the samples using a combination technique of agar disk diffusion and turbidity assays against S. aureus, we report that biogenic porous silicon can be utilized to stabilize and enhance the therapeutic effects of garlic oil for up to 4 weeks when the samples were stored under refrigerated conditions (4 degrees C) and 1 week at room temperature (25 degrees C). Critically, under ultraviolet (UV) light (365 nm) irradiation for 24 h intervals, plant-derived pSi is shown to have superior performance in protecting garlic extracts over porous silica (pSiO2) derived from the same plant feedstock or extract-only controls. The mechanism for this effect has also been investigated. PMID- 29111755 TI - Directed Self-Assembly of Polarizable Ellipsoids in an External Electric Field. AB - The interplay between shape anisotropy and directed long-range interactions enables the self-assembly of complex colloidal structures. As a recent highlight, ellipsoidal particles polarized in an external electric field were observed to associate into well-defined tubular structures. In this study, we systematically investigate such directed self-assembly using Monte Carlo simulations of a two point-charge model of polarizable prolate ellipsoids. In spite of its simplicity and computational efficiency, we demonstrate that the model is capable of capturing the complex structures observed in experiments on ellipsoidal colloids at low volume fractions. We show that, at sufficiently high electric field strength, the anisotropy in shape and electrostatic interactions causes a transition from three-dimensional crystal structures observed at low aspect ratios to two-dimensional sheets and tubes at higher aspect ratios. Our work thus illustrates the rich self-assembly behavior accessible when exploiting the interplay between competing long- and short-range anisotropic interactions in colloidal systems. PMID- 29111756 TI - Organic CO Prodrugs Activated by Endogenous ROS. AB - CO prodrugs with triggered release mechanisms are highly desirable for targeted delivery. Herein described are organic CO prodrugs that are activated by ROS and thus can be used to selectively deliver CO to cells with elevated ROS levels. Such CO prodrugs can serve as powerful tools for targeted delivery to disease sites with elevated ROS levels and to explore the therapeutic applications of CO. PMID- 29111754 TI - Chemical Modulation of the Human Oligopeptide Transporter 1, hPepT1. AB - In humans, peptides derived from dietary proteins and peptide-like drugs are transported via the proton-dependent oligopeptide transporter hPepT1 (SLC15A1). hPepT1 is located across the apical membranes of the small intestine and kidney, where it serves as a high-capacity low-affinity transporter of a broad range of di- and tripeptides. hPepT1 is also overexpressed in the colon of inflammatory bowel disease (IBD) patients, where it mediates the transport of harmful peptides of bacterial origin. Therefore, hPepT1 is a drug target for prodrug substrates interacting with intracellular proteins or inhibitors blocking the transport of toxic bacterial products. In this study, we construct multiple structural models of hPepT1 representing different conformational states that occur during transport and inhibition. We then identify and characterize five ligands of hPepT1 using computational methods, such as virtual screening and QM-polarized ligand docking (QPLD), and experimental testing with uptake kinetic measurements and electrophysiological assays. Our results improve our understanding of the substrate and inhibitor specificity of hPepT1. Furthermore, the newly discovered ligands exhibit unique chemotypes, providing a framework for developing tool compounds with optimal intestinal absorption as well as future IBD therapeutics against this emerging drug target. PMID- 29111757 TI - Carbene-Catalyzed Formal [5 + 5] Reaction for Coumarin Construction and Total Synthesis of Defucogilvocarcins. AB - An N-heterocyclic carbene-catalyzed formal [5 + 5] reaction between enals and furanones that generates multisubstituted coumarins in a single step is reported. Five atoms in each of the substrates are involved in this catalytic process to form a benzene and a lactone ring. The power of the method is further demonstrated in metal-free total syntheses of several natural products (defucogilvocarcins M, E, and V) bearing coumarin as the key structural motif. PMID- 29111758 TI - Beating Homogeneous Nucleation and Tuning Atomic Ordering in Glass-Forming Metals by Nanocalorimetry. AB - In this paper, the amorphous Ce68Al10Cu20Co2 (atom %) alloy was in situ prepared by nanocalorimetry. The high cooling and heating rates accessible with this technique facilitate the suppression of crystallization on cooling and the identification of homogeneous nucleation. Different from the generally accepted notion that metallic glasses form just by avoiding crystallization, the role of nucleation and growth in the crystallization behavior of amorphous alloys is specified, allowing an access to the ideal metallic glass free of nuclei. Local atomic configurations are fundamentally significant to unravel the glass forming ability (GFA) and phase transitions in metallic glasses. For this reason, isothermal annealing near Tg from 0.001 s to 25,000 s following quenching becomes the strategy to tune local atomic configurations and facilitate an amorphous alloy, a mixed glassy-nanocrystalline state, and a crystalline sample successively. On the basis of the evolution of crystallization enthalpy and overall latent heat on reheating, we quantify the underlying mechanism for the isothermal nucleation and crystallization of amorphous alloys. With Johnson-Mehl Avrami method, it is demonstrated that the coexistence of homogeneous and heterogeneous nucleation contributes to the isothermal crystallization of glass. Heterogeneous rather than homogeneous nucleation dominates the isothermal crystallization of the undercooled liquid. For the mixed glassy-nanocrystalline structure, an extraordinary kinetic stability of the residual glass is validated, which is ascribed to the denser packed interface between amorphous phase and ordered nanocrystals. Tailoring the amorphous structure by nanocalorimetry permits new insights into unraveling GFA and the mechanism that correlates local atomic configurations and phase transitions in metallic glasses. PMID- 29111759 TI - Rhodium-Catalyzed Site-Selective Coupling of Indoles with Diazo Esters: C4 Alkylation versus C2-Annulation. AB - A Rh(III)-catalyzed site-selective C-H activation of C(3)-functionalized indoles in a coupling with diazo esters has been realized with carbonyl as a weakly coordinating group. The coupling selectivity is dictated by the temperature and additives, affording either C4-alkylated indoles or C2-annulated lactones in moderate to excellent efficiency. PMID- 29111760 TI - Selective Induction of Optical Magnetism. AB - An extension of the Maxwell-Faraday law of electromagnetic induction to optical frequencies requires spatially appropriate materials and optical beams to create resonances and excitations with curl. Here we employ cylindrical vector beams with azimuthal polarization to create electric fields that selectively drive magnetic responses in dielectric core-metal nanoparticle "satellite" nanostructures. These optical frequency magnetic resonances are induced in materials that do not possess spin or orbital angular momentum. Multipole expansion analysis of the scattered fields obtained from electrodynamics simulations show that the excitation with azimuthally polarized beams selectively enhances magnetic vs electric dipole resonances by nearly 100-fold in experiments. Multipolar resonances (e.g., quadrupole and octupole) are enhanced 5 fold by focused azimuthally versus linearly polarized beams. We also selectively excite electric multipolar resonances in the same identical nanostructures with radially polarized light. This work opens new opportunities for spectroscopic investigation and control of "dark modes", Fano resonances, and magnetic modes in nanomaterials and engineered metamaterials. PMID- 29111761 TI - Photonic Effects for Magnetic Dipole Transitions. AB - The radiative transition probability is a fundamental property for optical transitions. Extensive research, theoretical and experimental, has been conducted to establish the relation between the photonic environment and electric dipole (ED) transition probabilities. Recent work shows that the nanocrystal (NC)-cavity model accurately describes the influence of the refractive index n on ED transition rates for emitters in NCs. For magnetic dipole (MD) transitions, theory predicts a simple n3 dependence. However, experimental evidence is sparse and difficult to obtain. Here we report Eu3+-(with distinct ED+MD transitions) and Gd3+-(MD transitions) doped beta-NaYF4 NC model systems to probe the influence of n on ED and MD transition probabilities through luminescence lifetime and ED/MD intensity ratio measurements. The results provide strong experimental evidence for an n3 dependence of MD transition probabilities. This insight is important for understanding and controlling the variation of spectral distribution in emission spectra by photonic effects. PMID- 29111762 TI - Metabolomics and Lipidomics Profiling of a Combined Mitochondrial Plus Endoplasmic Reticulum Fraction of Human Fibroblasts: A Robust Tool for Clinical Studies. AB - Mitochondria and endoplasmic reticulum (ER) are physically and functionally connected. This close interaction, via mitochondria-associated membranes, is increasingly explored and supports the importance of studying these two organelles as a whole. Metabolomics and lipidomics are powerful approaches for the exploration of metabolic pathways that may be useful to provide deeper information on these organelles' functions, dysfunctions, and interactions. We developed a quick and simple experimental procedure for the purification of a mitochondria-ER fraction from human fibroblasts. We applied combined metabolomics and lipidomics analyses by mass spectrometry with excellent reproducibility. Seventy-two metabolites and 418 complex lipids were detected with a mean coefficient of variation around 12%, among which many were specific to the mitochondrial metabolism. Thus this strategy based on robust mitochondria-ER extraction and "omics" combination will be useful for investigating the pathophysiology of complex diseases. PMID- 29111763 TI - Exploring Au Droplet Motion in Nanowire Growth: A Simple Route toward Asymmetric GaP Morphologies. AB - Here we show a new nanowire growth procedure, exploring the thermally activated motion of Au droplets on III-V surfaces. We show that by setting a single growth parameter we can activate the crawling motion of Au droplets in vacuum and locally modify surface composition in order to enhance vapor-solid (VS) growth along oxide-free areas on the trail of the metal particle. Asymmetric VS growth rates are comparable in magnitude to the vapor-liquid-solid growth, producing unconventional wurtzite GaP morphologies, which shows negligible defect density as well as optical signal in the green spectral region. Finally, we demonstrate that this effect can also be explored in different substrate compositions and orientations with the final shape finely tuned by group III flow and nanoparticle size. This distinct morphology for wurtzite GaP nanomaterials can be interesting for the design of nanophotonics devices. PMID- 29111764 TI - How Indium Nitride Senses Water. AB - The unique electronic band structure of indium nitride InN, part of the industrially significant III-N class of semiconductors, offers charge transport properties with great application potential due to its robust n-type conductivity. Here, we explore the water sensing mechanism of InN thin films. Using angle-resolved photoemission spectroscopy, core level spectroscopy, and theory, we derive the charge carrier density and electrical potential of a two dimensional electron gas, 2DEG, at the InN surface and monitor its electronic properties upon in situ modulation of adsorbed water. An electric dipole layer formed by water molecules raises the surface potential and accumulates charge in the 2DEG, enhancing surface conductivity. Our intuitive model provides a novel route toward understanding the water sensing mechanism in InN and, more generally, for understanding sensing material systems beyond InN. PMID- 29111765 TI - Nanostructures and Dynamics of Isochorically Confined Amorphous Drug Mediated by Cooling Rate, Interfacial, and Intermolecular Interactions. AB - The production and stabilization of amorphous drugs by the nanoconfinement effect has recently become a research hotspot in pharmaceutical sciences. Herein, two guest/host systems, indomethacin (IMC) and griseofulvin (GSF) confined in anodic aluminum oxide (AAO) templates with different pore diameters (25-250 nm) are investigated by differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). The crystallization of the confined drugs is suppressed, and their glass transition temperatures show an evident pore-size dependency. Moreover, a combination of dielectric and calorimetric results demonstrates that the significant change in the temperature dependence of the structural relaxation time during the cooling process is attributed to the vitrification of the interfacial molecules and the local density heterogeneity under isochoric confinement. Interestingly, compared with the case of IMC/AAO, which can be described by a typical two-layer model, GSF/AAO presents an rare scenario of three glass transition temperatures under fast cooling (40-10 K/min), indicating that there exists a thermodynamic nonequilibrium interlayer between the bulk-like core and interfacial layer. In contrast, the slow cooling process (0.5 K/min) would lead confined GSF into the stable core-shell nanostructure. Using surface modification, the interfacial effect is confirmed to be an important reason for the different phenomena between these two guest/host systems, and intermolecular hydrogen bonding is also suggested to be emphasized considering the long-range effect of interfacial interactions. Our results not only provide insight into the glass transition behavior of geometrically confined supercooled liquids, but also offer a means of adjusting and stabilizing the nanostructure of amorphous drugs under two-dimensional confinement. PMID- 29111766 TI - Gold(I) Catalyzed Dearomative Claisen Rearrangement of Allyl, Allenyl Methyl, and Propargyl Aryl Ethers. AB - Claisen rearrangements of allyl aryl ethers to generate enones bearing all carbon quaternary centers are accelerated by Ph3PAuNTf2 under mild conditions in good yields. Multiple C-C bond containing variants of the allyl fragment are viable, including alkylidenecyclopropanes, allenes, and alkynes, which generate all carbon stereogenic centers substituted with vinyl cyclopropanes, 1,3-butadienyl, and allenyl substituents, respectively, for subsequent synthetic manipulation. With allyl phenyl ethers, the product of the [3,3] rearrangements can be trapped by a tandem [4 + 2] cycloaddition to generate complex molecular scaffolds from readily available, achiral starting materials. PMID- 29111767 TI - Is It Acceptable to Assess Prenatal Smoking Risk to Infants without Considering Socioeconomic Status? PMID- 29111768 TI - Differences in symptoms, first medical contact and pre-hospital delay times between patients with ST- and non-ST-elevation myocardial infarction. AB - AIM: In ST-elevation myocardial infarction, time to reperfusion is crucial for the prognosis. Symptom presentation in myocardial infarction influences pre hospital delay times but studies about differences in symptoms between patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction are sparse and inconclusive. The aim was to compare symptoms, first medical contact and pre-hospital delay times in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction. METHODS AND RESULTS: This multicentre, observational study included 694 myocardial infarction patients from five hospitals. The patients filled in a questionnaire about their pre-hospital experiences within 24 h of hospital admittance. Chest pain was the most common symptom in ST-elevation myocardial infarction and non-ST-elevation myocardial infarction (88.7 vs 87.0%, p=0.56). Patients with cold sweat (odds ratio 3.61, 95% confidence interval 2.29-5.70), jaw pain (odds ratio 2.41, 95% confidence interval 1.04-5.58), and nausea (odds ratio 1.70, 95% confidence interval 1.01-2.87) were more likely to present with ST-elevation myocardial infarction, whereas the opposite was true for symptoms that come and go (odds ratio 0.58, 95% confidence interval 0.38-0.90) or anxiety (odds ratio 0.52, 95% confidence interval 0.29-0.92). Use of emergency medical services was higher among patients admitted with ST-elevation myocardial infarction. The pre-hospital delay time from symptom onset to first medical contact was significantly longer in non-ST-elevation myocardial infarction (2:05 h vs 1:10 h, p=0.001). CONCLUSION: Patients with ST-elevation myocardial infarction differed from those with non-ST-elevation myocardial infarction regarding symptom presentation, ambulance utilisation and pre-hospital delay times. This knowledge is important to be aware of for all healthcare personnel and the general public especially in order to recognise symptoms suggestive of ST-elevation myocardial infarction and when to decide if there is a need for an ambulance. PMID- 29111769 TI - Xeroderma Pigmentosum Group C Deficiency Alters Cigarette Smoke DNA Damage Cell Fate and Accelerates Emphysema Development. AB - Cigarette smoke (CS) exposure is a major risk factor for the development of emphysema, a common disease characterized by loss of cells comprising the lung parenchyma. The mechanisms of cell injury leading to emphysema are not completely understood but are thought to involve persistent cytotoxic or mutagenic DNA damage induced by CS. Using complementary cell culture and mouse models of CS exposure, we investigated the role of the DNA repair protein, xeroderma pigmentosum group C (XPC), on CS-induced DNA damage repair and emphysema. Expression of XPC was decreased in mouse lungs after chronic CS exposure and XPC knockdown in cultured human lung epithelial cells decreased their survival after CS exposure due to activation of the intrinsic apoptosis pathway. Similarly, cell autophagy and apoptosis were increased in XPC-deficient mouse lungs and were further increased by CS exposure. XPC deficiency was associated with structural and functional changes characteristic of emphysema, which were worsened by age, similar to levels observed with chronic CS exposure. Taken together, these findings suggest that repair of DNA damage by XPC plays an important and previously unrecognized role in the maintenance of alveolar structures. These findings support that loss of XPC, possibly due to chronic CS exposure, promotes emphysema development and further supports a link between DNA damage, impaired DNA repair, and development of emphysema. PMID- 29111771 TI - Staphylococcus aureus alpha-Toxin Induces Actin Filament Remodeling in Human Airway Epithelial Model Cells. AB - Exposure of cultured human airway epithelial model cells (16HBE14o-, S9) to Staphylococcus aureus alpha-toxin (hemolysin A, Hla) induces changes in cell morphology and cell layer integrity that are due to the inability of the cells to maintain stable cell-cell or focal contacts and to properly organize their actin cytoskeletons. The aim of this study was to identify Hla-activated signaling pathways involved in regulating the phosphorylation level of the actin depolymerizing factor cofilin. We used recombinant wild-type hemolysin A (rHla) and a variant of Hla (rHla-H35L) that is unable to form functional transmembrane pores to treat immortalized human airway epithelial cells (16HBE14o-, S9) as well as freshly isolated human nasal tissue. Our results indicate that rHla-mediated changes in cofilin phosphorylation require the formation of functional Hla pores in the host cell membrane. Formation of functional transmembrane pores induced hypophosphorylation of cofilin at Ser3, which was mediated by rHla-induced attenuation of p21-activated protein kinase and LIM kinase activities. Because dephosphorylation of pSer3-cofilin results in activation of this actin depolymerizing factor, treatment of cells with rHla resulted in loss of actin stress fibers from the cells and destabilization of cell shape followed by the appearance of paracellular gaps in the cell layers. Activation of protein kinase A or activation of small GTPases (Rho, Rac, Cdc42) do not seem to be involved in this response. PMID- 29111770 TI - Contemporary trends in cardiogenic shock: Incidence, intra-aortic balloon pump utilisation and outcomes from the London Heart Attack Group. AB - BACKGROUND: Cardiogenic shock remains a major cause of morbidity and mortality in patients with ST-segment elevation myocardial infarction. We aimed to assess the current trends in cardiogenic shock management, looking specifically at the incidence, use of intra-aortic balloon pump therapy and outcomes in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. METHODS AND RESULTS: We undertook an observational cohort study of 21,210 ST-segment elevation myocardial infarction patients treated between 2005-2015 at the eight Heart Attack Centres in London, UK. Patients' details were recorded at the time of the procedure into local databases using the British Cardiac Intervention Society percutaneous coronary intervention dataset. There were 1890 patients who presented with cardiogenic shock. The primary outcome was all-cause mortality at a median follow-up of 4.1 years (interquartile range: 2.2-5.8 years). Increasing rates of cardiogenic shock were seen over the course of the study with consistently high mortality rates of 45-70%. A total of 685 patients underwent intra-aortic balloon pump insertion during primary percutaneous coronary intervention for cardiogenic shock with decreasing rates over time. Those patients undergoing intra-aortic balloon pump therapy were younger, more likely to have poor left ventricular function and less likely to have had previous percutaneous coronary intervention compared to the control group. Procedural success rates were similar (86.0% vs 87.1%, p=0.292) although crude, in-hospital major adverse cardiac event rates were higher (43.8% vs 33.7%, p<0.0001) in patients undergoing intra-aortic balloon pump therapy. Kaplan-Meier analysis demonstrated significantly higher mortality rates in patients receiving intra-aortic balloon pump therapy (50.9% intra-aortic balloon pump vs 39.9% control, p<0.0001) during the follow-up period. After multivariate Cox analysis (hazard ratio 1.04, 95% confidence interval 0.62-1.89) and the use of propensity matching (hazard ratio: 1.29, 95% confidence interval: 0.68-1.45) intra-aortic balloon pump therapy was not associated with mortality. CONCLUSION: Cardiogenic shock treated by percutaneous coronary intervention is increasing in incidence and remains a condition associated with high mortality and limited treatment options. Intra-aortic balloon pump therapy was not associated with a long-term survival benefit in this cohort and may be associated with increased early morbidity. PMID- 29111772 TI - Aggregating validity indicators: The salience of domain specificity and the indeterminate range in multivariate models of performance validity assessment. AB - This study was designed to examine the "domain specificity" hypothesis in performance validity tests (PVTs) and the epistemological status of an "indeterminate range" when evaluating the credibility of a neuropsychological profile using a multivariate model of performance validity assessment. While previous research suggests that aggregating PVTs produces superior classification accuracy compared to individual instruments, the effect of the congruence between the criterion and predictor variable on signal detection and the issue of classifying borderline cases remain understudied. Data from a mixed clinical sample of 234 adults referred for cognitive evaluation (MAge = 46.6; MEducation = 13.5) were collected. Two validity composites were created: one based on five verbal PVTs (EI-5VER) and one based on five nonverbal PVTs (EI-5NV) and compared against several other PVTs. Overall, language-based tests of cognitive ability were more sensitive to elevations on the EI-5VER compared to visual-perceptual tests; whereas, the opposite was observed with the EI-5NV. However, the match between predictor and criterion variable had a more complex relationship with classification accuracy, suggesting the confluence of multiple factors (sensory modality, cognitive domain, testing paradigm). An "indeterminate range" of performance validity emerged that was distinctly different from both the Pass and the Fail group. Trichotomized criterion PVTs (Pass-Borderline-Fail) had a negative linear relationship with performance on tests of cognitive ability, providing further support for an "in-between" category separating the unequivocal Pass and unequivocal Fail classification range. The choice of criterion variable can influence classification accuracy in PVT research. Establishing a Borderline range between Pass and Fail more accurately reflected the distribution of scores on multiple PVTs. The traditional binary classification system imposes an artificial dichotomy on PVTs that was not fully supported by the data. Accepting "indeterminate" as a legitimate third outcome of performance validity assessment has the potential to improve the clinical utility of PVTs and defuse debates regarding "near-Passes" and "soft Fails." PMID- 29111773 TI - Factors to consider when reviewing and reconciling research findings: Methodological, statistical and theoretical. AB - Neuroscience is a rapidly evolving interdisciplinary field that is changing the way research is conducted and theories are developed. However, variability between studies and apparently discrepant findings may contribute to difficulties identifying commonalities that can help inform and enhance clinical practice. This article presents a framework to consider when reviewing neuropsychological studies, such that apparent discrepancies in findings may be considered in unison to provide informed theoretical understanding. For illustrative purposes, the article considers the studies of Vargha-Khadem, Salmond, Friston, Gadian, and Mishkin ( 2003 ) and Beauchamp et al. ( 2008 ), which report contrasting memory deficits during development in association with apparently similar bilateral hippocampal damage. The importance of reflecting on participant characteristics, methodological approaches, statistical analysis, and the interpretative value placed on selective test findings are discussed. Factors such as functional brain development, relationships between apparently "typical" functioning and underlying neural structures and networks, the limits of plasticity on the developing cognitive system and clinical implications are also considered. Thus, this article provides a structure that can be applied when reviewing neuropsychological studies and evaluating research inconsistencies, with consideration of the need for greater collaboration between neuroscientists and clinicians to support the development of translational research with real life implications. PMID- 29111774 TI - An Introduction to Network Psychometrics: Relating Ising Network Models to Item Response Theory Models. AB - In recent years, network models have been proposed as an alternative representation of psychometric constructs such as depression. In such models, the covariance between observables (e.g., symptoms like depressed mood, feelings of worthlessness, and guilt) is explained in terms of a pattern of causal interactions between these observables, which contrasts with classical interpretations in which the observables are conceptualized as the effects of a reflective latent variable. However, few investigations have been directed at the question how these different models relate to each other. To shed light on this issue, the current paper explores the relation between one of the most important network models-the Ising model from physics-and one of the most important latent variable models-the Item Response Theory (IRT) model from psychometrics. The Ising model describes the interaction between states of particles that are connected in a network, whereas the IRT model describes the probability distribution associated with item responses in a psychometric test as a function of a latent variable. Despite the divergent backgrounds of the models, we show a broad equivalence between them and also illustrate several opportunities that arise from this connection. PMID- 29111775 TI - Social jetlag and depression status: Results obtained from the Netherlands Study of Depression and Anxiety. AB - Social jetlag, the misalignment between the internal clock and the socially required timing of activities, is highly prevalent, especially in people with an evening chronotype and is hypothesized to be related to the link between the evening chronotype and major depressive disorder. Although social jetlag has been linked to depressive symptoms in non-clinical samples, it has never been studied in patients with major depressive disorder (MDD). This study is aimed to study social jetlag in patients with major depressive disorder and healthy controls, and to further examine the link between social jetlag and depressive symptomatology. Patients with a diagnosis of MDD (n = 1084) and healthy controls (n = 385), assessed in a clinical interview, were selected from the Netherlands Study of Depression and Anxiety. Social jetlag was derived from the Munich Chronotype Questionnaire, by calculating the absolute difference between the midsleep on free days and midsleep on work days. Depression severity was measured with the Inventory of Depressive Symptomatology. It was found that patients with MDD did not show more social jetlag compared to healthy controls, neither in a model without medication use (beta = 0.06, 95% CI: -0.03-0.15, p = 0.17) nor in a model where medication use is accounted for. There was no direct association between the amount of social jetlag and depressive symptoms, neither in the full sample, nor in the patient group or the healthy control group. This first study on social jetlag in a clinical sample showed no differences in social jetlag between patients with MDD and healthy controls. PMID- 29111776 TI - CranioSacral Therapy, Brain Injury, and American Football: Time for a Convergence. PMID- 29111777 TI - Reply to Ong and Schechter: Is It Acceptable to Assess Prenatal Smoking Risk to Infants without Considering Socioeconomic Status? PMID- 29111778 TI - Multi-Carotenoids at Physiological Levels Inhibit VEGF-Induced Tube Formation of Endothelial Cells and the Possible Mechanisms of Action Both In Vitro and Ex Vivo. AB - Carotenoids have been shown to exhibit antiangiogenic activities. Several studies have indicated that carotenoids used in combination were more effective on antioxidation and anticancer actions than carotenoids used singly. However, it is unclear whether multi-carotenoids have antiangiogenic effects. We investigated the effects of multi-carotenoids at physiological plasma levels of Taiwanese (abbreviated as MCT, with a total of 1.4 MUM) and Americans (abbreviated as MCA, with a total of 1.8 MUM), and of post-supplemental plasma levels (abbreviated as HMC with a total of 3.55 MUM) on vascular endothelial growth factor (VEGF) induced tube formation in human umbilical vein endothelial cells (HUVECs) and rat aortic rings. MCT, MCA, and HMC inhibited VEGF-induced migration, invasion, and tube formation of HUVECs as well as new vessels formation in rat aortic rings. MCT, MCA, and HMC inhibited activities o?f matrix metalloproteinase (MMP)-2, urokinase plasminogen activator, and phosphorylation of VEGF receptor 2 induced by VEGF. Moreover, MCT, MCA, and HMC significantly upregulated protein expression of tissue inhibitors of MMP-2 and plasminogen activator inhibitor-1. These results demonstrate the antiangiogenic effect of multi-carotenoids both in vitro and ex vivo with possible mechanistic actions involving attenuation of VEGF receptor 2 phosphorylation and extracellular matrix degradation. PMID- 29111779 TI - Immediate, lag and time window effects of meteorological factors on ST-elevation myocardial infarction incidence. AB - The influence of several meteorological parameters on acute myocardial infarction (AMI) incidences with immediately and/or delayed effects has been widely reported. It remains unknown whether the individual AMI subtypes reveal similar patterns. To date, generally seasonal variation in ST elevation MI (STEMI) has been investigated. However, these approaches couldn't detect the effects of changes in multiple meteorological variables on STEMI incidence within a specific season. Therefore, the aim of our study is to explore immediate, delayed and cumulative effects of average daily temperature, atmospheric pressure and humidity on nation-wide STEMI hospital admissions. We linked daily hospitals' STEMI admission data with meteorological stations' data according to the patient's permanent residence. Subsequently, a multivariate analysis based on a main effect generalised linear model, assuming a log-link function with a Poisson distribution, was conducted. With the help of lags, we were able to analyse delayed effects, while the cumulative effects of specific meteorological variables were analysed utilising time windows. As a result, we confirmed immediate and delayed negative effect of low temperature and low relative humidity for all observed lags as well as cumulative average effects of low temperature and low relative humidity for all observed time windows. However, no delayed, single-day effect for atmospheric pressure was detected. Nevertheless, the cumulative average effect was confirmed in all time windows suggesting that prolonged low pressure influences the incidence of STEMI. A novelty of our approach is the comparative examination of immediate, delayed and cumulative effect of specific meteorological variables on the incidence of STEMI. This approach enables us to gain a new insight into the phenomenon studied. PMID- 29111781 TI - Cognitive disorders in a patient with an arachnoid cyst of the sylvian fissure and improvement after surgical treatment: Case description. AB - Arachnoid cysts cause a wide spectrum of clinical symptoms. Often it is difficult to clearly establish the relation between the presence of an arachnoid cyst and problems reported by the patient, which may, although not necessarily, be due to chronically elevated intracranial pressure. In recent years, increasing attention is paid to cognitive disorders accompanying arachnoid cysts, such as memory disorders, attention disorders, or language function disorders. This article presents a case of an 11-year-old patient, treated at the University Children's Hospital in Cracow for an arachnoid cyst, located in the left middle cranial fossa. This analysis is focused on the description of cognitive and intellectual deficits of the child, as well as the discussion on their connection with the arachnoid cyst. Prior to the neurosurgical procedure, the boy presented significant deficits in cognitive functions, especially mnestic and attention functions and, also, a quite low level of intellectual functioning. Neuropsychological examination performed after the procedure indicated a significant improvement of cognitive functioning for all the functions, as well as a higher level of intellectual functioning. This analysis attempts to answer whether and to what extent the child still suffers from cognitive deficits from the organic lesions. PMID- 29111780 TI - E26 Transformation-Specific Transcription Factor ETS2 as an Oncogene Promotes the Progression of Hypopharyngeal Cancer. AB - The E26 transformation-specific (ETS) family is one of the largest families of transcription factors. Upon activation by MAPK pathway, ETS participates in cell proliferation, differentiation, migration, apoptosis, and metastasis. However, the mechanism by which ETS is deregulated in cancer is unclear. In this study, the authors investigated the role of ETS factor, ETS2, in hypopharyngeal cancer pathogenesis in hypopharyngeal cancer tissues (N = 20) and corresponding non neoplastic tissues (N = 20). The results showed that expression of ETS2 was increased in cancer tissues as compared with the expression in corresponding non neoplastic tissues. Analysis of clinicopathological characteristics showed that increased level of ETS2 is associated with III-IV tumor node metastasis stage and lymph node metastasis. In addition, knockdown of ETS2 by siRNA in pharyngeal cancer cell line, FaDu, significantly decreased cell's vitality and colony forming ability by inducing caspase-3-dependent apoptosis and cell cycle arrest. Furthermore, inhibition of ETS2 could abrogate the migration, invasion, and transforming growth factor-beta-induced epithelial mesenchymal transition through the upregulation of E-cadherin, zona occludens protein-1, together with downregulation of vimentin and alpha-sooth muscle actin. These functions of ETS2 could be associated with the activation of MAPK/p38/ERK/JNK signals. Taken together, the authors opined that ETS2 functions as an oncogene and plays a key role in the progression of hypopharyngeal cancer. PMID- 29111782 TI - Circadian profiles of progesterone, gonadotropins, cortisol and corticotropin in cycling and postmenopausal women. AB - Little is known about the regulation of temporal variations of progesterone over the 24-hr span in young cycling women as well as in postmenopausal women. The purpose of the present study was to investigate the relationships between diurnal variations of progesterone and diurnal variations of hormones of the gonadotropic and corticotropic axes, and to provide further information on the source of progesterone secretion under physiological conditions. Twenty-four-hour hormonal profiles were explored under well-controlled laboratory conditions in 10 healthy women (21-36 yr old) with normal ovulatory cycles during early-mid follicular and late luteal phases, and in 8 healthy postmenopausal women (48-74 yr old). In young cycling women, significant positive relationships were found between progesterone and follicle-stimulating hormone (FSH) - but not luteinizing hormone (LH) - profiles during late luteal phase. Conversely, during follicular phase, significant positive relationships were evidenced between progesterone and cortisol profiles, but not between progesterone and FSH or LH. In postmenopausal women, strong positive correlations were found between progesterone and corticotropin (ACTH) or cortisol profiles. The present results indicate that during late luteal phase, temporal progesterone profiles are associated with FSH rather than with LH profiles. They also provide evidence that adrenal cortex is a major - or possibly the only - source of progesterone production during the follicular phase of the normal ovulatory cycle, and probably the only source after menopause. PMID- 29111783 TI - Would you say "yes" in the evening? Time-of-day effect on response bias in four types of working memory recognition tasks. AB - Across a wide range of tasks, cognitive functioning is affected by circadian fluctuations. In this study, we investigated diurnal variations of working memory performance, taking into account not only hits and errors rates, but also sensitivity (d') and response bias (c) indexes (established by signal detection theory). Fifty-two healthy volunteers performed four experimental tasks twice - in the morning and in the evening (approximately 1 and 10 h after awakening). All tasks were based on Deese-Roediger-McDermott paradigm version dedicated to study working/short-term memory distortions. Participants were to memorize sets of stimuli characterized by either conceptual or perceptual similarity, and to answer if they recognized subsequent stimulus (probe) as an "old" one (i.e. presented in the preceding memory set). The probe was of three types: positive, negative or related lure. In two verbal tasks, memory sets were characterized by semantic or phonological similarity. In two visual tasks, abstract objects were characterized by a number of overlapping similarities or differed in only one detail. The type of experimental material and the participants' diurnal preference were taken into account. The analysis showed significant effect of time of day on false alarms rate (F(1,50) = 5.29, p = 0.03, etap2 = 0.1) and response bias (F(1,50) = 11.16, p = 0.002, etap2 = 0.18). In other words, in the evening participants responded in more liberal way than in the morning (answering "yes" more often). As the link between variations in false alarms rate, response bias and locus coeruleus activity was indicated in literature before, we believe that our data may be interpreted as supporting the hypothesis that diurnal fluctuations in norepinephrine release have effect on cognitive functioning in terms of decision threshold. PMID- 29111784 TI - Short-term effects of wake- and bright light therapy on sleep in depressed youth. AB - Chronotherapeutics are well established for the treatment of depression and associated sleeping problems in adults. However, effects are still understudied in adolescents. Two pilot studies highlighted the crucial role of sleep when it comes to the treatment of depression, by means of chronotherapeutics, in adolescents. The aim of the present study was to investigate the role of adjunctive wake therapy (WT) in addition to bright light therapy (BLT) with respect to sleep behaviors. In the present study, 62 depressed inpatients (aged 13-18 years; diagnosed with Beck Depression Inventory Revision) were randomly assigned to two groups: BLT only (BLT-group) and a combination of BLT and WT (COMB-group). After one night of WT adolescents in the COMB-group revealed longer sleep durations, time in bed, advanced sleep onset, less wakes during night and an improved sleep efficiency. However, one night of WT plus BLT had no additional effect on sleep parameters compared with BLT-group in the long run. Therefore, future studies should assess whether more nights of WT might lead to more sustainable effects. PMID- 29111785 TI - An Explorative Study on the Efficacy and Feasibility of the Use of Motivational Interviewing to Improve Footwear Adherence in Persons with Diabetes at High Risk for Foot Ulceration. AB - BACKGROUND: In this explorative study, we assessed the effect and feasibility of using motivational interviewing to improve footwear adherence in persons with diabetes who are at high risk for foot ulceration and show low adherence to wearing prescribed custom-made footwear. METHODS: Thirteen individuals with diabetes, ulcer history, and low footwear adherence (ie, <80% of steps taken in prescription footwear) were randomly assigned to standard education (ie, verbal and written instructions) or to standard education plus two 45-min sessions of motivational interviewing. Adherence was objectively measured over 7 days using ankle- and shoe-worn sensors and was calculated as the percentage of total steps that prescribed footwear was worn. Adherence was assessed at home and away from home at baseline and 1 week and 3 months after the intervention. Feasibility was assessed for interviewer proficiency to apply motivational interviewing and for protocol executability. RESULTS: Median (range) baseline, 1-week, and 3-month adherence at home was 49% (6%-63%), 84% (5%-98%), and 40% (4%-80%), respectively, in the motivational interviewing group and 35% (13%-64%), 33% (15%-55%), and 31% (3%-66%), respectively, in the standard education group. Baseline, 1-week, and 3 month adherence away from home was 91% (79%-100%), 97% (62%-99%) and 92% (86% 98%), respectively, in the motivational interviewing group and 78% (32%-97%), 91% (28%-98%), and 93% (57%-100%), respectively, in the standard education group. None of the differences were statistically significant. Interviewer proficiency was good, and the protocol could be successfully executed in the given time frame. CONCLUSIONS: Footwear adherence at home increases 1 week after motivational interviewing to clinically relevant but not statistically significant levels (ie, 80%) but then returns over time to baseline levels. Away from home, adherence is already sufficient at baseline and remains so over time. The use of motivational interviewing seems feasible for the given purpose and patient group. These findings provide input to larger trials and provisionally suggest that additional or adjunctive therapy may be needed to better preserve adherence. PMID- 29111786 TI - Active Hexose Correlated Compound (AHCC) Inhibits the Proliferation of Ovarian Cancer Cells by Suppressing Signal Transducer and Activator of Transcription 3 (STAT3) Activation. AB - The purpose of this study was to investigate the antiproliferative effect of active hexose correlated compound (AHCC), derived from basidiomycete mushroom culture, on ovarian cancer cell lines. An in vitro growth inhibition assay was performed using AHCC in ovarian cancer cell lines. Western blotting was performed to investigate the mechanism of the observed antiproliferative effect of AHCC. We identified that ovarian cancer cell viability was significantly reduced through treatment with AHCC compared to that in the control. AHCC inhibited constitutive signal transducer and activator of transcription 3 (STAT3) phosphorylation in ovarian cancer cell lines. In contrast, treatment with pervanadate, a protein tyrosine phosphatase inhibitor, reversed AHCC-induced STAT3 suppression. AHCC treatment induced the expression of SHP-1, a protein tyrosine phosphatase, and suppressed the expression of cyclin D1, Bcl-2, Mcl-1, survivin, and VEGF, which are STAT3-regulated gene products that are associated with cell proliferation or apoptosis. These results suggest that AHCC has an antiproliferative effect on ovarian cancer cell lines, via STAT3 phosphorylation; thus, this compound has the potential to be a complementary and alternative anticancer therapy for the treatment of ovarian cancer. PMID- 29111787 TI - Performance Status, Prognostic Scoring, and Parenteral Nutrition Requirements Predict Survival in Patients with Advanced Cancer Receiving Home Parenteral Nutrition. AB - We describe a cohort of Home Parenteral Nutrition (HPN) patients with advanced cancer in order to identify factors affecting prognosis. Demographic, anthropometric, biochemical and medical factors, Karnofsky Performance Status (KPS), Glasgow Prognostic Score (GPS), and PN requirements were recorded. Univariate and multivariate analyses were performed including Kaplan-Meier curves, Cox Regression, and correlation analyses. In total, 107 HPN patients (68 women, 39 men, mean age 57 yr) with advanced cancer were identified. The main indications for HPN were bowel obstruction (74.3%) and high output ostomies (14.3%). Cancer cachexia was present in 87.1% of patients. The hazard ratio (HR) for upper gastrointestinal and "other" cancers vs. gynaecological malignancy was 1.75 (p = 0.077) and 2.11 (p = 0.05), respectively. KPS score, GPS, PN volume, and PN potassium levels significantly predicted survival (HRKPS >=50 vs <50 = 0.47; HRGPS = 2 vs. GPS = 0 = 3.19). In multivariate analysis, KPS and GPS remained significant predictors (p < 0.05), whilst PN volume reached borderline significance (p = 0.094). Survival was not significantly affected by the presence of metastatic disease, previous or concurrent surgery, chemo-radiotherapy, or indication for HPN (p > 0.05). Most patients passed away in their homes or hospice (77.9%). Performance status, prognostic scoring, and PN requirements may predict survival in patients with advanced cancer receiving HPN. PMID- 29111788 TI - SEM Based CARMA Time Series Modeling for Arbitrary N. AB - This article explains in detail the state space specification and estimation of first and higher-order autoregressive moving-average models in continuous time (CARMA) in an extended structural equation modeling (SEM) context for N = 1 as well as N > 1. To illustrate the approach, simulations will be presented in which a single panel model (T = 41 time points) is estimated for a sample of N = 1,000 individuals as well as for samples of N = 100 and N = 50 individuals, followed by estimating 100 separate models for each of the one-hundred N = 1 cases in the N = 100 sample. Furthermore, we will demonstrate how to test the difference between the full panel model and each N = 1 model by means of a subject-group reproducibility test. Finally, the proposed analyses will be applied in an empirical example, in which the relationships between mood at work and mood at home are studied in a sample of N = 55 women. All analyses are carried out by ctsem, an R-package for continuous time modeling, interfacing to OpenMx. PMID- 29111789 TI - Evening chronotype and sleepiness predict impairment in executive abilities and academic performance of adolescents. AB - The study aim was to better understand sleep and sleep-related factors affecting everyday executive capacities and academic performance among healthy adolescents. A cross-sectional survey on sleep, phase preference, academic performance and executive functions of high-school students was conducted. Female gender, grade status, sleepiness and evening chronotype accounted for approximately 25-30% of the variance in daily executive ability. Sleep duration was a weak predictor of executive skills. Lower school grades were associated with increased sleepiness, evening preference and poorer executive skills. These findings support the need for health education on ways to attenuate sleepiness and delayed phase in this population. PMID- 29111790 TI - Early adopters of perioperative medicine: who are they and what motivates them? AB - Perioperative medicine is an emerging specialty aimed at improving outcomes in the high-risk surgical population. The authors set out to characterize the demographics and determine the motivation of 'early adopters' of this specialty by retrospectively reviewing the application forms of students enrolled on the UCL Perioperative Medicine Masters Programme. A total of 139 applications were reviewed. The median age of applicants was 35 years; 81% were UK based, with the remainder from a worldwide distribution. Seventeen per cent were consultant anaesthetists and 64% anaesthetic trainees, with the remainder including doctors from other specialties (17%) and nurses (2%). Qualitative analysis using grounded theory methodology revealed common motivational themes: the belief that perioperative medicine would lead to better patient care, that it represents the future working practice for anaesthetists, a desire to be able to better lead local developments, and personal fulfilment and benefit. The responses provided insight into the motivation of an international cohort of professionals. Perioperative medicine was perceived as a developing multidisciplinary specialty that will lead to better patient care. Applicants understood the importance of perioperative care extending beyond the operating theatre which may explain the growing demand for training in perioperative medicine. PMID- 29111792 TI - Radiation-induced sigmoid stricture: an important differential. PMID- 29111791 TI - Ventricular bigemini or something less common? PMID- 29111793 TI - Rapid onset intracranial hypertension in a young woman after starting nitrofurantoin. PMID- 29111794 TI - Problem-based learning: a review. PMID- 29111796 TI - Clinical News. PMID- 29111797 TI - Social media for a clinician in training. PMID- 29111795 TI - An unusual right hilar 'mass' with enlarged mediastinal lymph nodes. PMID- 29111798 TI - Perioperative medicine: a new model of care? AB - The discipline of perioperative medicine provides a foundation for the consistent delivery of safe and good quality care to surgical patients. Its goals include the identification and optimal care of the high-risk surgical patient, fostering patient-centred decision making throughout the surgical perioperative pathway, and reducing unwarranted variation in practice. In turn, this should reduce preventable complications and improve patient satisfaction, long-term morbidity and survival. This review concludes a series of articles which have described the epidemiology of surgical disease, the growth in the objective means of risk assessment, and novel outcome measures. It describes shortcomings in current practice, and how perioperative care pathways may overcome these. It discusses the growth of enhanced recovery programmes, which exemplify many of the sub specialty's principles of patient-centred and coordinated care. Reported initiatives to modify local health-care systems, such as the Perioperative Surgical Home, are presented. Consideration is given to how clinicians can use the philosophy and tools of quality improvement methodology, with important current examples. The article concludes by looking at obstacles to change when introducing new frameworks and the future horizons for the discipline. PMID- 29111799 TI - Pretibial lacerations. PMID- 29111800 TI - Perioperative risk. AB - The high-risk surgical patient is a growing challenge to modern health care. This cohort, although comprising only 10-15% of surgical procedures, accounts for approximately 80% of postoperative deaths and suffers a high rate of postoperative morbidity. Developing robust systems to help identify and better manage this patient group should be a priority. Risk stratification has become a valuable clinical tool for shared decision-making and the development of individualized care plans. Methods for stratifying individual risk include assessment tools, measures of functional capacity and plasma biomarker assays. Routine evaluation of perioperative risk is central to the delivery of high quality, appropriate surgical care. PMID- 29111802 TI - Perioperative medicine: an evolutionary process. PMID- 29111801 TI - Quality improvement in perioperative medicine: driving the revolution. AB - Perioperative medicine and quality improvement are both emerging fields with the potential to contribute to safer and more reliable care for surgical patients. One key component has been the evolution of the national audit project programme. This article describes the current state of quality improvement within perioperative medicine, the evolution of the national audit project programme and the effects it has produced on the quality of patient care. The article also highlights opportunities for health-care professionals to engage with this innovative area of medicine. PMID- 29111804 TI - Alexander Wood: inventor of the hypodermic syringe and needle. PMID- 29111803 TI - DRESS syndrome triple whammy: sulfasalazine, amoxicillin and HHV-7. PMID- 29111805 TI - Management of acute pancreatitis: a practical guide. PMID- 29111806 TI - Deep vs awake extubation for craniotomies. PMID- 29111808 TI - The surgical epidemic. AB - This article outlines the growing demand for surgical services globally, both in developing and developed countries. The implications of this increasing demand are explored, with particular attention focused on the enduring burden of perioperative complications. The role of critical care in ensuring the safe delivery of surgical services is also examined. Solutions to the 'surgical epidemic' are proposed including the role of perioperative medicine in reconfiguring services to provide safe surgical care. PMID- 29111809 TI - Informing patients about blood transfusion. PMID- 29111810 TI - New outcome measures in perioperative care. AB - Improvements in outcome measurement are needed to produce quality improvement in perioperative care. However, problems with the collection and use of outcome data persist in research and clinical practice. This is being addressed by several national programmes and initiatives to standardize and integrate outcome measurement. The use of different outcome measures is changing and there has been a transition towards patient-focused measures. Traditional measures of quality in perioperative care include mortality, morbidity and resource utilization measures. Patient-focused measures include patient-reported outcome measures and measures of patient experience. Each of these has advantages and disadvantages in different situations. The routine collection, analysis and dissemination of data relating to perioperative outcome is beneficial to patients, clinicians, hospitals, commissioners, regulators and researchers. PMID- 29111811 TI - Treatment of limb length discrepancy following total hip arthroplasty. AB - Limb length discrepancy is the leading cause of patient dissatisfaction following total hip arthroplasty and the most common reason for litigation in the field of orthopaedics. This article provides a systematic, stepwise approach for identifying the aetiology of limb length discrepancy following total hip arthroplasty and provides guidance on the treatment of this complication to optimize postoperative clinical and functional outcomes. This review discusses postoperative history taking, clinical examination, radiographic assessment, conservative treatment, and surgical intervention for the management of patients with established limb length discrepancy following total hip arthroplasty. A comprehensive understanding of the multifactorial nature and methods of managing postoperative limb length discrepancy is essential for optimizing patient satisfaction, clinical outcomes and long-term function following total hip arthroplasty. PMID- 29111812 TI - Erratum. PMID- 29111813 TI - Reverse thoracoplasty. PMID- 29111814 TI - Sarsaparilla (Smilax Glabra Rhizome) Extract Activates Redox-Dependent ATM/ATR Pathway to Inhibit Cancer Cell Growth by S Phase Arrest, Apoptosis, and Autophagy. AB - Sarsaparilla (Smilax Glabra Rhizome) exerts growth inhibitory effect on multiple cancer cells in vitro and in vivo, and redox-dependent persistent activation of ERK1/2 has been reported to underlie this effect. Here, we report an activation of ATM/ATR-dependent signaling pathway also as a mechanism for the cancer cell growth inhibition induced by the supernatant fraction of the water-soluble extract from sarsaparilla (SW). SW treatment (3.5 MUg/MUL) promoted the phosphorylations of ATM, ATR, and CHK1 in AGS and HT-29 cells. The ATM kinase inhibitor, KU55933, could reverse SW-induced ERK phosphorylation but not the reduced glutathione/oxidized glutathione (GSH/GSSG) imbalance in AGS cells. However, both the redox inhibitor glutathione (GSH) and ERK inhibitor U0126 antagonized SW-induced phosphorylations of ATM, ATR, and CHK1 in AGS cells. We further found KU55933 significantly antagonized SW-induced S phase arrest, apoptosis, autophagy and the resultant cell growth inhibition. Our results provide another molecular basis for the anticancer action of sarsaparilla. PMID- 29111815 TI - Novel treatment regimen of Vogt-Koyanagi-Harada disease with a reduced dose of corticosteroids combined with immunosuppressive agents. AB - PURPOSE: To investigate the effectiveness, visual outcome, and prognostic factors of Vogt-Koyanagi-Harada (VKH) disease treatment with a reduced dose of corticosteroids combined with immunosuppressive agents. METHODS: The clinical characteristics, auxiliary examinations, treatment result, visual outcome, and prognostic factors in VKH patients were analyzed. RESULTS: A total of 998 VKH patients were divided into posterior uveitis group (Group1), anterior uveal involvement group (Group 2), and recurrent granulomatous anterior uveitis group (Group 3). Reduced doses of corticosteroids combined with immunosuppressive agents were used for 1-1.5 years. Uveitis was controlled in 100%, 100%, and 96.8% of these three groups, respectively. Visual improvement and stability was observed in 98.1%, 96.5%, and 88.3%, respectively. Treatment after disease onset, visual acuity at first visit, and 1 month after treatment was positively associated with BCVA at last visit (p < 0.05). CONCLUSION: A reduced dose of corticosteroids combined with immunosuppressive agents effectively controlled the intraocular inflammation and improved visual acuity in most Chinese VKH patients. PMID- 29111816 TI - Comparing the response to acute and chronic exposure to short wavelength lighting emitted from computer screens. AB - The use of electronic devices with light-emitting screens has increased exponentially in the last decade. As a result, humans are continuously exposed to unintentional artificial light. We explored the effects of acute and chronic exposure to artificial light at night (ALAN) via screen illumination on sleep, circadian rhythms, and related functional outcomes. Nineteen participants (11 female and 8 males, mean age 28.1 +/- 7.2 years) underwent a six-night study with three experimental conditions using a repeated-measures design: baseline (first night, no light exposure), acute ALAN exposure (second night), and chronic ALAN exposure (third to sixth nights). Each light exposure lasted for 2 hours (21:00 23:00). Participants underwent an overnight polysomnography at the end of each condition (nights 1, 2, and 6). We collected urine samples (for melatonin metabolite analysis), while body (oral) temperatures were measured before and after exposure. Each morning, the participants filled out questionnaires and conducted a computerized attention test. Both acute and chronic illumination significantly disrupted sleep continuity and architecture and led to greater self reported daytime sleepiness, negative emotions, and attention difficulties. Both exposure types also altered circadian rhythms, subduing the normal nocturnal decline in body temperature and dampening nocturnal melatonin secretion. In sum, ALAN exposure from electronic screens has an immediate, detrimental, yet stable effect on sleep, circadian regulation, and next-day functional outcomes. Given the widespread use of electronic devices today, our findings suggest that even one night of screen light exposure may be sufficient to cause adverse effects on health and performance. PMID- 29111817 TI - Structural, ultrastructural, and morphometric study of the zebrafish ocular surface: a model for human corneal diseases? AB - PURPOSE: A morphological and morphometric study of the adult zebrafish ocular surface was performed to provide a comprehensive description of its parts and to evaluate its similarity to the human. MATERIALS AND METHODS: The eyes of adult zebrafish were processed for light, transmission and scanning electron microscopy, and for immunohistochemical stain of corneal nerves; a morphometric analysis was also performed on several morphological parameters. RESULTS: The corneal epithelium was formed by five layers of cells. No Bowman's layer could be demonstrated. The stroma consisted of lamellae of different thickness with few keratocytes. The Descemet's membrane was absent as the flat and polygonal endothelial cells directly adhered to the deepest corneal lamella. The immunohistochemical stain of neurofilaments failed to demonstrate corneal nerve fibers. The conjunctival epithelium was stratified, overlying the stroma formed by a subepithelial and a deep layer, this latter connected to the scleral cartilage. In the peripheral cornea and in the conjunctiva, many goblet and rodlet cells were observed. The morphometric analysis showed that the peripheral cornea epithelium was thicker when compared to the other parts of the ocular surface, with smaller superficial cells. Desmosomes and hemidesmosomes in the conjunctiva were significantly fewer in number than the other parts of the ocular surface. The stroma was thinner in the conjunctiva than in the cornea, while corneal lamellae were thicker in the intermediate stroma. CONCLUSIONS: The zebrafish ocular surface showed significant differences compared to the human, such as the absence of Bowman's layer, Descemet's membrane and corneal nerve fibers, the reduced stromal thickness, and the presence of rodlet cells. On the basis of these original findings, it is suggested that the use of the zebrafish as a model for studying normal or pathological human corneas should be undertaken with particular caution. PMID- 29111818 TI - Glycemic Control and Quality of Life Following Cataract Surgery in Patients with Type 2 Diabetes and without Maculopathy. AB - OBJECTIVE: To assess whether cataract removal surgery will improve glycemic control and quality of life in patients with diabetes. METHODS: A prospective longitudinal study of 28 patients with type 2 diabetes and without diabetic retinopathy scheduled for cataract removal surgery. During the 4 months of follow up, measurements of glycated hemoglobin (HbA1c) were obtained and assessment of quality of life was performed using two questionnaires: The EuroQoL 5-Dimension (EQ-5D(r)) and the Multidimensional Diabetes Questionnaire (MDQ). RESULTS: HbA1c values decreased by approximately 0.45% following surgery (7.24% to 6.78%, P = 0.009). Younger patients reduced HbA1c significantly more than older patients (0.73% vs. 0.03%, respectively, P = 0.043). Younger age also correlated with better visual acuity improvement (R = -0.44, P = 0.02). Poor glycemic control prior to surgery correlated with better HbA1c reductions, with a 42% chance for reduction of at least 0.5% HbA1c in patients with preoperative HbA1c values of 7.5% and a 72% chance for reduction in patients with preoperative HbA1c values of 8.5%. Quality of life was improved by 14% following surgery, as noted in the MDQ results (33.9-38.7, P = 0.034) only. CONCLUSIONS: Cataract removal surgery may positively influence glycemic control and quality of life in type 2 diabetic patients without maculopathy. Younger patients achieved superior improvement in visual and glycemic outcomes. The results of this study highlight the need for frequent inquiry regarding eyesight deterioration in patients with diabetes. PMID- 29111819 TI - Danshensu Decreases UVB-Induced Corneal Inflammation in an Experimental Mouse Model via Oral Administration. AB - BACKGROUND: Danshensu is a bioactive constituent of Salvia miltiorrhiza, a plant commonly used in traditional Chinese medicine. In this study, we investigated the pharmacological efficacy of sodium danshensu, or named salvianic acid A sodium (SAS) on ultraviolet B (UVB)-mediated corneal inflammatory injury in mice. METHODS: Albino mice were divided into one blank control group, and three UVB radiation groups, i.e. SAS-untreated group, and prophylactic treatment groups with SAS at 1 and 10 mg/kg via oral administration. The structure integrity and inflammatory changes of cornea were assessed by surface evaluation of smoothness, topographic distortion, opacity, lissamine green staining, and histologic tissue staining. The inflammatory cytokines was measured by bead-based ELISA assays. RESULTS: Prophylactic treatment of SAS significantly inhibited pathologic changes, improved tissue structural integrity, and reduced inflammatory injury in the cornea after UVB exposure. Dosing with SAS treatment attenuated the incidence rate of leukocyte influx by inhibit increase of interleukin (IL)-1beta, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. Treatment with 10 mg/kg SAS was more effective in preventing the onset of corneal damage than that with 1 mg/kg SAS. CONCLUSIONS: These results indicate that SAS exhibit the pharmacological efficacy on corneal protection through its inhibition of UVB induced photodamage and subsequently inflammatory injury in vivo. PMID- 29111820 TI - Identification of Feeder Vessels in Ocular Surface Neoplasia Using Indocyanine Green Angiography. AB - PURPOSE: To evaluate indocyanine green angiography (ICGA) for the identification and characterization of afferent (feeding) and efferent (draining) vessels in patients with ocular surface neoplasia. MATERIALS AND METHODS: Consecutive patients with biopsy-proven benign, pre-invasive, or invasive ocular surface tumors of the bulbar conjunctiva were included. Patients underwent anterior segment optical coherence tomography, ICGA, and color photography for the evaluation of the thickness, location, number, and diameter of afferent and efferent vessels of the lesions. RESULTS: Twenty-two eyes of 22 patients with papillomas (n = 4), intra-epithelial neoplasia lesion (n = 2) in situ or invasive carcinomas (n = 6), nevus (n = 5), conjunctival melanocytic intra-epithelial neoplasia lesion (n = 1), and in situ or invasive melanomas (n = 4) were investigated. Afferent (feeder) vessels were identified in all lesions. There were fewer afferent (3.1 +/- 1.6) than efferent (7.5 +/- 3.5) vessels per lesion (p < 0.001) and the mean diameter was smaller for afferent (101 +/- 62 MUm, 28 281) than efferent vessels (137 +/- 51 MUm, 31-652; p = 0.017). The number of afferent and efferent vessels was associated with the thickness of the lesion (p = 0.037, p < 0.01). Lesion filling times differed between benign and invasive or pre-invasive lesions (p = 0.018). CONCLUSIONS: ICGA is a useful adjunctive in vivo imaging method for the assessment of the vasculature in patients with suspected ocular surface neoplasia. PMID- 29111821 TI - Correlations of Corneal Optical Densitometry, Endothelial Hexagonality Percentage, and Epithelium Thickness. AB - PURPOSE: Our aim was to examine the associations between the cornea morphological parameters, endothelial cell density, and anterior chamber measurements. METHODS: This observational study included 50 eyes of 50 healthy volunteers. The thicknesses of corneal epithelium, Bowman's layer, stroma, Descemet's membrane endothelium complex, and pre-ocular tear film were measured by means of anterior segment optical coherence tomography. The keratometry (K), corneal volume (CV), corneal optical densitometry (COD), iridocorneal angle (ICA), anterior chamber depth (ACD), and anterior chamber volume (ACV) measurements were taken by the Scheimpflug anterior segment imaging. The corneal endothelial cell density and percentage of hexagonality were measured by specular microscopy. RESULTS: The COD was only correlated with the thickness of Bowman's layer (r = -0.30, p = 0.035). The hexagonal endothelial cell percentage was correlated with the thickness of the pre-ocular tear film (r = -0.50, p < 0.001), ACD (r = 0.40, p = 0.004), and ACV (r = 0.34, p = 0.015). The corneal epithelium thickness was associated with the ACD (r = 0.30, p = 0.034), ACV (r = 0.34, p = 0.018), K-flat (r = -0.35, p = 0.013), and K-steep (r = -0.29, p = 0.038) readings. CONCLUSIONS: The anterior chamber morphological parameters (i.e., ACV, ACD) were significantly positively correlated with the hexagonal endothelial cell percentage and corneal epithelium thickness in healthy adults. PMID- 29111823 TI - Surgical Results in Ocriplasmin Candidates With Symptomatic Vitreomacular Traction Syndrome. AB - PURPOSE: To report surgical outcomes in a series of cases with symptomatic vitreomacular traction that met MIVI-TRUST (Microplasmin for intravitreous injection-traction release without surgical treatment) criteria for ocriplasmin use who underwent primary 25-gauge vitrectomy. MATERIALS AND METHODS: A single center retrospective chart review study was performed in patients who underwent primary 25-gauge vitrectomy for symptomatic vitreomacular traction (VTM) from January 2013 through January 2016. Pre- and postoperative visual acuity (measured by the early treatment diabetic retinopathy acuity test), and posterior hyaloid focal attachment to the macula (demonstrated by high-definition optical coherence tomography) were analyzed. In addition, intra- and postoperative complications were obtained from medical records. RESULTS: Fifteen consecutive cases of symptomatic VMT traction that underwent primary 25-gauge vitrectomy were included. All met the MIVI-TRUST criteria for ocriplasmin use. In all cases, VMT resolution, macular hole closure, and improvement in best corrected visual acuity (BCVA) were observed. Mean visual acuity improved from 56.53 +/- 16.04 letters at baseline to 73.13 +/- 7.46 letters at 24 weeks of follow-up. The mean BCVA improvement from baseline was 16.60 letters (range 6-44), which was statistically significant (P < 0.0001). Ten of fifteen patients (66.6%) showed significant improvement of their BCVA to 20/40 or better (70 or more in ETDRS visual acuity test). No significant intra- or postoperative complications were documented. CONCLUSIONS: Primary 25-gauge pars plana vitrectomy in eyes with symptomatic vitreomacular traction is able to efficiently resolve VMT and macular holes, improving vision in candidates for intravitreal injection of ocriplasmin. This well-tolerated surgical procedure may be a reliable and predictable alternative for resolving VMT pathology. PMID- 29111824 TI - Binary Complementary Filters for Compressive Raman Spectroscopy. AB - The previously described optimized binary compressive detection (OB-CD) strategy enables fast hyperspectral Raman (and fluorescence) spectroscopic analysis of systems containing two or more chemical components. However, each OB-CD filter collects only a fraction of the scattered photons and the remainder of the photons are lost. Here, we present a refinement of OB-CD, the OB-CD2 strategy, in which all of the collected Raman photons are detected using a pair of complementary binary optical filters that direct photons of different colors to two photon counting detectors. The OB-CD2 filters are generated using a new optimization algorithm described in this work and implemented using a holographic volume diffraction grating and a digital micromirror device (DMD) whose mirrors are programed to selectively direct photons of different colors either to one or the other photon-counting detector. When applied to pairs of pure liquids or two component solid powder mixtures, the resulting OB-CD2 strategy is shown to more accurately estimate Raman scattering rates of each chemical component, when compared to the original OB-CD, thus facilitating chemical classification at speeds as fast as 3 MUs per measurement and the collection of Raman images in under a second. PMID- 29111822 TI - Repercussions of hypo and hyperthyroidism on the heart circadian clock. AB - Myocardial gene expression and metabolism fluctuate over the course of the day in association with changes in energy supply and demand. Time-of-day-dependent oscillations in myocardial processes have been linked to the intrinsic cardiomyocyte circadian clock. Triiodothyronine (T3) is an important modulator of heart metabolism and function. Recently, our group has reported time-of-day dependent rhythms in cardiac T3 sensitivity, as well as, T3-mediated acute alterations on core clock components. Hypo and hyperthyroidism are the second most prevalent endocrine disease worldwide. Considering the importance of the cardiomyocyte circadian clock and T3 to cardiac physiology, the aim of this study was to investigate the consequences of chronic hypo and hyperthyroidism on 24-h rhythms of circadian clock genes in the heart. Hypo and hyperthyroidism was induced in rats by thyroidectomy (Tx) and i.p. injections of supraphysiological dose of T3, respectively. Here we report alterations in mRNA levels of the major core clock components (Bmal1, Per2, Nr1d1, and Rora) for both experimental conditions (with the exception of Per2 during hyperthyroid condition). Oscillations in mRNA levels of key glucose and fatty-acid metabolism genes known to be clock controlled (Pdk4, Ucp3, Acot1, and Cd36) were equally affected by the experimental conditions, especially during the hypothyroid state. These findings suggest that chronic alterations in thyroid status significantly impacts 24-h rhythms in circadian clock and metabolic genes in the heart. Whether these perturbations contribute toward the pathogenesis of cardiac dysfunction associated with hypo and hyperthyroidism requires further elucidation. PMID- 29111825 TI - Healthcare reform in China: challenges and opportunities. PMID- 29111827 TI - Prism under cover test in alternate fixation horizontal strabismus. AB - PURPOSE: To evaluate the applicability of the prism under cover test (PUCT) to quantify manifest deviation in horizontal strabismus with alternate fixation when simultaneous prism and cover test (SPCT) is not feasible. METHODS: Children aged 4-11 years, with alternate fixation horizontal strabismus and alternate prism and cover test (APCT) distance deviation (DD) up to 25 PD were eligible. In group 1 of the study, SPCT was not feasible (n = 18), whereas in group 2, it was feasible (n = 24). Refraction, PUCT, APCT, central/peripheral fusion, and stereoacuity were measured. Repeatability of PUCT, agreement between PUCT and SPCT, and Pearson correlations between variables were studied. RESULTS: In group 1, mean DD was 15.6 and 9.5 PD using APCT and PUCT, respectively (intraclass correlation, ICC: 0.90). Mean stereoacuity was 201.1 arc seconds. PUCT was better correlated with stereoacuity than APCT, but not significantly (p = 0.12). Coefficient of repeatability for PUCT was 3.4 PD. In group 2, mean DD was 17.6, 14.1, and 12.5 PD using APCT, PUCT, and SPCT, respectively. Mean stereoacuity was 285.9 arc seconds. Correlations APCT-PUCT (0.87), APCT-SPCT (0.82), and SPCT-PUCT (0.95) were significant. APCT did not show as good correlation with stereoacuity (0.58) as SPCT and PUCT (0.74 and 0.78, respectively). Concordance correlation coefficient between SPCT and PUCT was 0.91, and Bland Altman agreement between the two variables was also good. CONCLUSIONS: PUCT is a procedure with good repeatability, of interest in children to estimate manifest deviation when SPCT is not feasible, and in support of the diagnosis of monofixation syndrome. PMID- 29111826 TI - Integration of systematic clinical interprofessional training in a student faculty collaborative primary care practice. AB - The changing healthcare environment and movement toward team-based care are contemporary challenges confronting health professional education. The primary care workforce must be prepared with recent national interprofessional competencies to practice and lead in this changing environment. From 2012 to 2014, the weekly Beth Israel Deaconess Crimson Care Collaborative Student-Faculty Practice collaborated with Northeastern University to develop, implement and evaluate an innovative model that incorporated interprofessional education into primary care practice with the goal of improving student understanding of, and ability to deliver quality, team-based care. In the monthly interprofessional clinic, an educational curriculum empowered students with evidence-based, team based care principles. Integration of nursing, pharmacy, medicine, and masters of public health students and faculty into direct patient care, provided the opportunity to practice skills. The TeamSTEPPS(r) Teamwork Attitudes Questionnaire was administered pre- and post-intervention to assess its perceived impact. Seventeen students completed the post-intervention survey. Survey data indicated very positive attitudes towards team-based care at baseline. Significant improvements were reported in attitudes towards situation monitoring, limiting personal conflict, administration support and communication. However, small, but statistically significant declines were seen on one team structure and two communication items. Our program provides further evidence for the use of interprofessional training in primary care. PMID- 29111828 TI - Preparation and Evaluation of Biodegradable Scleral Plug Containing Curcumin in Rabbit Eye. AB - BACKGROUND: To test whether biodegradable curcumin-loaded scleral plug is a promising choice for treating posterior ocular diseases, the study investigated the in vitro release profile of the scleral plug and its safety in vivo. METHODS: Scleral plugs containing 0.5 mg, 1.0 mg and 1.5 mg curcumin were synthesized by a compression-sintering method. These scleral plugs were placed in tubes containing balanced salt solution (BSS) buffer, which was replaced by fresh buffer daily. The curcumin concentration in the removed aliquot was tested daily for 14 days using high-performance liquid chromatography (HPLC). In the study, 44 rabbits were randomly divided into four groups: control, 0.5 mg, 1.0 mg and 1.5 mg curcumin groups. The scleral plug was trans-scleral fixed in the right eye of the rabbits in the three curcumin-treated groups. The control rabbits only received sclerotomy. The treated rabbit eyes were examined by a slit-lamp biomicroscope, an indirect ophthalmoscope and electroretinogram (ERG), and subjected to histological analysis. RESULTS: The concentration of the 1.5 mg curcumin-loaded scleral plug was higher than 15 MUg/ml for consecutive 14 days in vitro. The in vivo experiments revealed intraocular pressure, a-wave and b-wave amplitudes of ERG, and conjunctival reaction degree were not significantly different between the four groups. Retinal structure was normal in the curcumin-treated groups. The sclerotomy wound healed after the plug was completely degraded. Anterior chamber reaction or complications were not observed. CONCLUSION: The study suggests that curcumin-loaded scleral plug could sustain high concentration of curcumin in vitro and is safe in vivo. It might be a promising alternative choice for the treatment of posterior ocular diseases. PMID- 29111829 TI - Effect of Cryopreserved Amniotic Membrane on the Mechanical Properties of Skeletal Muscle after Strabismus Surgery in Rabbits. AB - PURPOSE: To study the functional recovery of the superior rectus muscle (SRM) after its partial resection in a rabbit model with and without cryopreserved amniotic membrane (AM). MATERIAL AND METHODS: Resection of the right and left SRMs of 30 rabbits was performed. On the left eyes, a single sheet of equine cryopreserved AM was placed covering the muscle edge sutured. Active and passive mechanical properties of muscles operated with and without AM were monitored over time at 30 (n = 10), 60 (n = 10), and 90 (n = 10) days after surgery. Muscle samples were extracted and electrically stimulated to register the force exerted by the samples, characterizing its active behavior. They were, then, subjected to stretching test to obtain its resistance to deformation, known as passive behavior. Moreover, right and left eyes of a control group (n = 5) were equally subjected to active and passive tests to characterize the physiological behavior of SRM muscles. RESULTS: On active function examination, statistically significant differences were documented between the following: control vs AM and no AM at 30 days (p = 0.002 and p = 0.04, respectively). All other comparisons were insignificant (p > 0.05). On passive function analysis, significant differences were only found between control vs. no AM at 30 days (p = 0.004) and between AM vs. no AM at 30 days (p = 0.002). Indeed, muscle operated without AM did not recover a normal passive function until 60 days after surgery. CONCLUSION: Cryopreserved AM is effective in accelerating recovery of SRM passive function in rabbits. Nevertheless, AM produced no significant effect on recovery of SRM active function.?. PMID- 29111830 TI - Surgical and non-surgical management of malignant pleural effusions. AB - INTRODUCTION: Optimal management of malignant pleural effusion (MPE) is important in the care of patients with advanced cancer. Surgical (especially video-assisted thoracoscopic surgery (VATS)) and non-surgical strategies are available. Clinicians should be aware of the evidence supporting the use of different modalities to guide treatment choice. Areas covered: This review covers published evidence of the advantages and disadvantages of VATS and non-surgical alternatives for MPE management. Expert commentary: Randomized clinical trials (RCTs) are needed to define the roles and benefits of VATS as existing literature is often flawed by selection bias. Three RCTs have failed to show benefits of VATS talc poudrage over bedside talc pleurodesis. VATS-pleurectomy offered no survival advantage in a RCT of mesothelioma patients. Modification of VATS techniques has reduced the invasiveness and associated risks. Future trials should compare VATS with contemporary, non-surgical approaches (especially combined Indwelling Pleural Catheter (IPC) and chemical pleurodesis therapy). Individualized management for different subgroups of MPE patients should be a long-term research goal. Studies are needed on better patient selection, and adjunct non-invasive, supportive (e.g. nutrition and exercise) therapies. PMID- 29111831 TI - Comparison of Different Cell Culture Media in the Model of the Isolated and Superfused Bovine Retina: Investigating the Limits of More Physiological Perfusion Solutions. AB - PURPOSE: The isolated superfused retina is a standardized tool in ophthalmological research. However, stable electroretinogram (ERG) responses can only be obtained for around eight hours; therefore, limiting its use. The aim of this study was to evaluate the short-term potential of different cell culture media and to promote long-term testing based on the results obtained. MATERIALS AND METHODS: For the experimental procedure bovine retinae were prepared and perfused with the standard Sickel solution and an ERG was performed. After recording stable a- or b-waves, different media (Dulbecco's Modified Eagle's Medium (DMEM), MACS, and Neurobasal) were superfused for 45 minutes. ERG recovery was monitored overall for 75 minutes. Analysis of the mRNA expression of Thy-1, GFAP, Bax/Bcl-2-ratio, Rhodopsin, and Opsin via qRT-PCR was performed directly after ERG recording on the same retina. RESULTS: None of the tested media had a negative effect on a-wave amplitudes, although b-wave amplitudes decreased (DMEM) or increased (MACS and Neurobasal) compared to the standard solution (Sickel) after 45 minutes of exposure. However, after 75 minutes of wash-out, no difference to the standard solution alone could be observed. Exposure to different media either had no effect or decreased the Opsin and Rhodopsin mRNA levels. Thy-1 expression was strongly diminished in DMEM and MACS (by 2-3-fold), whereas incubation in Neurobasal medium led to a slight increase compared to incubation with the standard solution. Furthermore, the Bax/Bcl-2 ratio indicated an anti-apoptotic effect (Bax/Bcl-2 = 0.16; p < 0.05) for Neurobasal. CONCLUSION: Neurobasal medium displayed the best electrophysiological properties in the short term and may be applicable for stable long-term escalation testing. PMID- 29111832 TI - The Use of Antibiotics Before Transanal Endoscopic Microsurgery. PMID- 29111833 TI - Alterations in retinal nerve fiber layer thickness in early stages of diabetic retinopathy and potential risk factors. AB - AIMS: To investigate the loss of retinal nerve fiber layer (RNFL) in type-2 diabetic patients with early-stage diabetic retinopathy (DR) and to identify potential risk factors accounting for these alterations. METHODS: In this cross sectional study, 158 type-2 diabetic patients were divided into three groups based on their DR status. RNFL thickness and other optic disc parameters were obtained by optical coherence tomography (OCT) and then compared among different groups. We investigated the potential association between RNFL loss and systemic risk factors for DR, including diabetes duration, body mass index (BMI), serum lipids, hemoglobin A1c (HbA1c) and albumin-creatinine ratio (ACR). One-way ANOVA was carried out to compare RNFL thickness among different groups, Pearson correlation and multivariate linear regression analysis were performed to determine potential risk factors related to RNFL thickness in these patients. RESULTS: There were significant differences in the average (F = 8.872, P = 0.003), superior (F = 8.769, P = 0.004), and inferior (F = 8.857, P = 0.003) RNFL thickness of both eyes among the groups, but no obvious difference in optic disc parameters was found. Diabetic duration, BMI, TG, High density lipoprotein cholesterol (HDL), HbA1c, and ACR were found negatively related to the RNFL thickness in both or single eye according to Pearson correlation analysis. After controlling for age, gender, and axis length (AL) in multivariate linear regression analysis, the diabetic duration was associated significantly with RNFL thickness of superior in both eye (right eye: p = 0.016, left eye: p = 0.024), BMI was related to the nasal quadrant of the right eye (p = 0.034), and TG was related to the inferior of the right eye (p = 0.037), HbA1c (p = 0.026) was associated significantly with the average RNFL thickness of the right eye. In addition, ACR was found negatively related to average (p = 0.042) and inferior quadrant (p = 0.014) of the left eye, respectively. CONCLUSIONS: RNFL loss might be the earliest structural change of retina in diabetic patients, and associated with diabetic duration, BMI, TG, HbA1c, and ACR. The conclusions of this study need to be proved by other well-matched and large-scale prospective clinical trials in the future, because the correlations discovered in our study were weak. PMID- 29111834 TI - Evolving multidimensional pharmacological approaches to CNV therapy in AMD. AB - PURPOSE: The leading cause of severe visual loss world-wide is age-related macular degeneration. Although anti-Vascular Endothelial Growth Factor agents have significantly led to the initial pharmacologic reversal of vision loss in many cases of exudative macular degeneration, there still has been recurrence of choroidal neovascularization, and/or the onset of chorioretinal atrophy with fibrosis. MATERIALS AND METHODS: In this review we discuss the status of anti- Vascular Endothelial Growth Factor in age-related macular degeneration and describe different studies focused on new potential therapeutic targets beyond anti- Vascular Endothelial Growth Factor. RESULTS: Further investigations have elicited that Vascular Endothelial Growth Factor is only one of many angiogenic, and pro-inflammatory factors that bring about the growth and leakage of active choroidal neovascularization. Various new multifaceted strategies, including inhibitors to down-stream targets of endothelial cell division, such as TNP-470, may lead to a more permanent inactivation of choroidal neovascularization. CONCLUSIONS: Based on the accumulated results in the treatment of age-related macular degeneration, it is hoped that the appropriate combination of anti Vascular Endothelial Growth Factor agents with longer-acting and multidimensional pharmaceuticals, such as Methionine Aminopeptidase-2 inhibitors, will more effectively control choroidal neovascularization, prevent atrophy and fibrosis, and reduce the burden of frequent intraocular injections in age-related macular degeneration. PMID- 29111835 TI - Improving outcomes in adults with diabetes through an interprofessional collaborative practice program. AB - In 2014, the Midwest Interprofessional Practice, Education and Research Center partnered with a Federally Qualified Health Center (FQHC) to implement an interprofessional collaborative practice (IPCP) education program to improve the health of adult patients with diabetes and to improve practice efficiency. This partnership included integrating an interprofessional team of students with the practice team. Twenty-five students and 20 staff engaged in the IPCP program, which included completion of educational modules on IPCP and implementation of daily huddles, focus patient visits, phone calls, team-based case presentations, medication reconciliation, and student-led group diabetes education classes. This study used a sequential mixed methods design. Tools used for collecting data from staff and students included demographic forms, the Interdisciplinary Education Perception Scale (IEPS), the Entry-level Interprofessional Questionnaire, the Collaborative Practice Assessment Tool, and pre/post module knowledge tests completed at baseline and at one-year post implementation. Patient clinical indicators included HgbA1c, glucose, lipid panel laboratory assessments, body mass index, blood pressure, and documentation of annual dental, foot, and eye examinations. Practice efficiency was measured by the average number of patients seen per provider per hour. Both students and staff showed significant knowledge gains in IPCP on Team Dynamics and Tips for Behavioural Changes knowledge tests (p < .05). Patients who had an HgbA1c of >= 7% significantly decreased their HgbA1c (p < .05) and glucose (p < .01). However, BMI and annual dental and eye examinations did not improve. Providers demonstrated an increase in the number of patients seen per hour. This IPCP intervention showed improvement in practice efficiencies and select patient outcomes in a family practice clinic. PMID- 29111836 TI - Long-Term Changes in Backscattered Light Measurements in Keratoconus Corneas Treated with Collagen Cross-Linking. AB - PURPOSE: Our aim was to compare densitometry data between keratoconus and normal corneas and to assess the long-term changes in corneal backscattered light values after corneal collagen cross-linking (CXL) treatment. MATERIAL AND METHODS: Retrospective analysis was performed on 26 eyes of normal patients (age: 32.71 +/ 12.68 years) and 39 eyes of keratoconus patients (28.93 +/- 7.59 years) using the Pentacam HR corneal densitometry module before CXL and during the postoperative period, which lasted a mean of 2.53 years (range: 1-4 years). Corneal backscattered light values in grey scale unit (GSU) were recorded for the anterior 120 um, the center layer, and the posterior 60 um of the cornea in four concentric, central rings. An additional calculation was performed with converting GSU values to GSU/cubic millimeters (mm3) with surface area calculations and using corneal thickness data. RESULTS: Statistically significant differences were observed between normal and keratoconus group densitometry values (in GSU/mm3) in all annuli of the center layer; all, but anterior layer of the 10-12 annuli; all annuli of the total thickness and in all values of the total diameter. In all these cases, the normal cornea showed higher GSU/mm3 values compared to keratoconus corneas (p < 0.05). One month after the CXL treatment, the GSU/mm3 data increased significantly in the anterior, the center, and the posterior zone (p < 0.05), followed by its slow decrease. At the end of the follow-up period, the GSU/mm3 values were significantly higher in all three zones compared to those before the CXL treatment (p < 0.01). CONCLUSION: Densitometry measurements can reflect the changes of optical quality of the cornea. These measurements may play a valuable role in assessing keratoconus and optical changes of the corneas after CXL treatment. PMID- 29111837 TI - Conjunctival Tear Layer Temperature, Evaporation, Hyperosmolarity, Inflammation, Hyperemia, Tissue Damage, and Symptoms: A Review of an Amplifying Cascade. AB - PURPOSE: This review examines the evidence for and significance of pre conjunctival tear temperature being higher than central pre-corneal temperature with associated more rapid evaporation of warmer pre-conjunctival tears in normal eyes but especially in hyperemic dry eye disease. METHODS: PubMed searches using the terms "evaporative dry eye," "conjunctival tear evaporation," "tear evaporation," and "dry eye conjunctival hyperemia" indicated 157, 49, 309, and 96 potentially relevant papers, respectively. Selections from these lists were the basis for examining the significance of the evidence relevant to pre-conjunctival tear layer temperature and evaporation. RESULTS: There is evidence supporting an amplifying inflammatory and para-inflammatory hyperemia dry eye cascade, which increases pre-conjunctival tear temperature and the risk of accelerated pre conjunctival tear evaporation with exacerbated osmolarity elevation and inflammation. Dry eye cascade amplification is consistent with increases in symptoms and inflammatory as well as para-inflammatory hyperemia toward the end of the waking day. Apart from age-related conjunctivochalasis, dry eye-related conjunctival epithelial cell pathology including reduced goblet cell numbers and associated mucin deficiency, squamous metaplasia, and increased separation of cell layers could help to destabilize tears and facilitate evaporation as part of an amplifying cascade. CONCLUSIONS: Greater difficulty in assessing conjunctival tear break up may contribute to an underestimation of a role for faster evaporation of pre-conjunctival tears in dry eye disease and help explain any non correspondence between symptoms and corneal signs of dry eye disease. Success with anti-inflammatory therapies for dry eye disease may be at least partly due to reductions in conjunctival hyperemia and deamplification of evaporative cascades. Conjunctival inflammatory hyperemia in other diseases may contribute to accelerated pre-conjunctival tear evaporation and the risk of tear-deficiency- associated exacerbation of those diseases including impaired responses to therapeutic approaches to them. Similarly, postsurgical conjunctival inflammation and associated acceleration of tear evaporation could contribute to delayed wound healing. PMID- 29111838 TI - Exploring barriers and facilitators to the clinical use of virtual reality for post-stroke unilateral spatial neglect assessment. AB - BACKGROUND: Hemineglect, defined as a failure to attend to the contralesional side of space, is a prevalent and disabling post-stroke deficit. Conventional hemineglect assessments lack sensitivity as they contain mainly non-functional tasks performed in near-extrapersonal space, using static, two-dimensional methods. This is of concern given that hemineglect is a strong predictor for functional deterioration, limited post-stroke recovery, and difficulty in community reintegration. With the emerging field of virtual reality, several virtual tools have been proposed and have reported better sensitivity in neglect related deficits detection than conventional methods. However, these and future virtual reality-based tools are yet to be implemented in clinical practice. OBJECTIVES: The present study aimed to explore the barriers/facilitators perceived by clinicians in the use of virtual reality for hemineglect assessment; and to identify features of an optimal virtual assessment. METHODS: A qualitative descriptive process, in the form of focus groups, self-administered questionnaire and individual interviews was used. RESULTS: Two focus groups (n = 11 clinicians) were conducted and experts in the field (n = 3) were individually interviewed. Several barriers and facilitators, including personal, institutional, client suitability, and equipment factors, were identified. Clinicians and experts in the field reported numerous features for the virtual tool optimization. CONCLUSION: Factors identified through this study lay the foundation for the development of a knowledge translation initiative towards an implementation of a virtual assessment for hemineglect. Addressing the identified barriers/facilitators during implementation and incorporating the optimal features in the design of the virtual assessment could assist and promote its eventual adoption in clinical settings. Implications for rehabilitation A multimodal and active knowledge translation intervention built on the presently identified modifiable factors is suggested to be implemented to support the clinical integration of a virtual reality-based assessment for post-stroke hemineglect. To amplify application and usefulness of a virtual-reality based tool in the assessment of post-stroke hemineglect, optimal features identified in the present study should be incorporated in the design of such technology. PMID- 29111839 TI - The interpretation of physical activity, exercise, and sedentary behaviours by persons with multiple sclerosis. AB - OBJECTIVES: This study adopted a qualitative research design with directed content analysis and examined the interpretations of physical activity, exercise, and sedentary behaviour by persons with multiple sclerosis. METHODS: Fifty three persons with multiple sclerosis who were enrolled in an exercise trial took part in semi-structured interviews regarding personal interpretations of physical activity, exercise, and sedentary behaviours. RESULTS: Forty three percent of participants indicated a consistent understanding of physical activity, 42% of participants indicated a consistent understanding of exercise, and 83% of participants indicated a consistent understanding of sedentary behaviour with the standard definitions. There was evidence of definitional ambiguity (i.e., 57, 58, and 11% of the sample for physical activity, exercise, and sedentary behaviour, respectively); 6% of the sample inconsistently defined sedentary behaviour with standard definitions. Some participants described physical activity in a manner that more closely aligned with exercise and confused sedentary behaviour with exercise or sleeping/napping. CONCLUSIONS: Results highlight the need to provide and utilise consistent definitions for accurate understanding, proper evaluation and communication of physical activity, exercise, and sedentary behaviours among persons with multiple sclerosis. PRACTICE IMPLICATIONS: The application of consistent definitions may minimise ambiguity, alleviate the equivocality of findings in the literature, and translate into improved communication about these behaviours in multiple sclerosis. Implications for Rehabilitation The symptoms of multiple sclerosis can be managed through participation in physical activity and exercise. Persons with multiple sclerosis are not engaging in sufficient levels of physical activity and exercise for health benefits. Rehabilitation professionals should use established definitions of physical activity, exercise, and sedentary behaviours when communicating about these behaviours among persons with multiple sclerosis. PMID- 29111840 TI - ECG beat classification using empirical mode decomposition and mixture of features. AB - Computer-aided analysis is useful in predicting arrhythmia conditions of the heart by analysing the recorded ECG signals. In this work, we proposed a method to detect, extract informative features to classify six types of heartbeat of ECG signals obtained from the MIT-BIH Arrhythmia database. The powerful discrete wavelet transform (DWT) is used to eliminate different sources of noises. Empirical mode decomposition (EMD) with adaptive thresholding has been used to detect precise R-peaks and QRS complex. The significant features consists of temporal, morphological and statistical were extracted from the processed ECG signals and combined to form a set of features. This feature set is classified with probabilistic neural network (PNN) and radial basis function neural network (RBF-NN) to recognise the arrhythmia beats. The process achieved better result with sensitivity of 99.96%, and positive predictivity of 99.81 with error rate of 0.23% in detecting the QRS complex. In class-oriented scheme, the arrhythmia conditions are classified with accuracy of 99.54%, 99.89% using PNN and RBF-NN classifier respectively. The obtained result confirms the superiority of the proposed scheme compared to other published results cited in literature. PMID- 29111841 TI - Strategies and industrial perspectives to improve oral absorption of biological macromolecules. AB - INTRODUCTION: Therapeutic proteins have become a highly attractive drug of choice due to minimal toxicity, high activity and exquisite specificity. Oral delivery of protein drugs is a very interesting area for research, and, naturally, numerous technologies are required to improve the oral bioavailability of therapeutic proteins. Areas covered: This review article systemically generalized the major physiological barriers facing oral macromolecule delivery as well as the current approaches and novel developments in the field, including permeation enhancers, enzyme inhibitors, particulate drug delivery system, ligand delivery system, mucoadhesive delivery system, mucus penetration delivery system and other strategies. Expert opinion: The development of composite formulation methods need to meet regulatory requirements for reproducibility, manufacturing cost, and bioavailability. So far, oral delivery of protein and peptide drugs is still facing immense challenges despite of the fact that some clinical studies are undergoing. The most advanced clinical strategies for therapeutic proteins are co administration of absorption enhancers or protease inhibitors. Besides, rising new technologies in the field also provides a growing opportunity, such as nanotechnology, mucoadhesive and mucus penetration particulate delivery system. PMID- 29111842 TI - Retinal and Choroidal Changes in Patients with Parkinson's Disease Detected by Swept-Source Optical Coherence Tomography. AB - PURPOSE: To evaluate the ability of new Swept source (SS) optical coherence tomography (OCT) technology to detect changes in retinal and choroidal thickness in patients with Parkinson's disease (PD). DESIGN: Observational case-control cross sectional study, developed from January to May 2016. METHODS: In total, 50 eyes from 50 patients diagnosed with PD and 54 eyes of 54 healthy controls underwent retinal and choroidal assessment using SS DRI Triton OCT (Topcon), using the 3D Wide protocol. Total macular thickness and peripapillary data (retinal, ganglion cell layer [GCL+, GCL++] and retinal nerve fiber layer [RNFL] thickness) were analyzed. Macular and peripapillary choroidal thickness was evaluated (Figure 1). RESULTS: Significant peripapillary retinal thinning was observed in PD patients in total average (p = 0.017), in the nasal (p = 0.038) and temporal (p = 0.004) quadrants and in superotemporal (p = 0.004), nasal (p = 0.039), inferotemporal (p = 0.019), and temporal (p = 0.003) sectors. RNFL and GCL ++ thickness showed a significant reduction in the inferotemporal sector (p = 0.026 and 0.009, respectively). No differences were observed in macular retinal thickness between controls and patients. Choroidal thickness was found to have increased in all sectors in PD patients compared with controls, both in the macular (inner nasal, p = 0.015; inner inferior, p = 0.030; outer nasal, p = 0.012; outer inferior, p = 0.049) and the peripapillary area (total thickness, p = 0.011; nasal, p = 0.025; inferior, p = 0.007; temporal, p = 0.003; inferotemporal, p = 0.003; inferonasal, p = 0.016) Conclusion: New SS technology for OCT devices detects retinal thinning in PD patients, providing increased depth analysis of the choroid in these patients. The choroid in PD may present increased thickness compared to healthy individuals; however, more studies and histological analysis are needed to corroborate our findings. PMID- 29111843 TI - Experience of using non-invasive ventilation as an adjunct to airway clearance techniques in adults with cystic fibrosis-A qualitative study. AB - BACKGROUND: Adults with cystic fibrosis (CF) suffer from abnormally thick mucus that is difficult to clear from the airways. Different airway clearance techniques (ACTs) can be used to clear secretions and non-invasive ventilation (NIV) can be used as an adjunct to these techniques. ACTs are ideally introduced at the time of diagnosis and thereafter modified throughout the patient's lifespan and disease progress. PURPOSE: The research aim was to describe adult patients' views and experiences with using NIV as an adjunct to ACT. METHOD: Eighteen adults with CF were interviewed about their experiences with using NIV during ACT. Semi-structured interviews were conducted and analyzed in accordance with qualitative content analysis. RESULTS: The results gave rise to the overall theme 'Becoming Friends with NIV' and six associated categories: 1) getting a sense of control and feedback; 2) getting support; 3) dealing with doubt; 4) finding the rhythm; 5) feeling the effects; and 6) finding their own motivation. The findings represent a learning process for adults during the implementation stages of NIV; the physiotherapist was found to play a key role in this process. CONCLUSION: 'Becoming Friends with NIV' involves a learning process for adults with CF. To facilitate this learning process, different aspects should be taken into account so as to promote independence and self-management, which in turn allows the patient to experience the treatment as meaningful. The findings are relevant to physiotherapists working with adults and NIV, as improved insight into and understanding of the relationship may have a positive influence on the outcome and success of NIV usage. PMID- 29111844 TI - A new perspective on the genetics of keratoconus: why have we not been more successful? AB - Twin studies and family studies suggest an important genetic basis for keratoconus (KC). Involvement and association of several genes with the disease has been reported. Additionally, genes associated with central corneal thickness (CCT) and corneal curvature (CC) via genome-wide association studies (GWAS), also potentially underlie KC. Although a long list of genes has been reported for KC, the evidence for a pathogenic role for most genes remains limited. Furthermore, if the involvement of the reported genes in KC development can be proven, they only account for a limited number of patients. VSX1, ZNF469, SOD1, and miR184 have been most frequently investigated, but only mutations in miR184 indisputably underlie corneal abnormalities. For the three other genes, analysis of the minor allele frequencies (MAF) in public databases argues against a pathogenic role for most reported variants. For the remainder of variants, functional evidence is needed to prove their contribution to the pathogenesis. Despite the large amount of studies, clear results remain rare. A possible explanation for the cumbersome gene-identification is that genetic defects underlying KC are located in regions that are understudied (such as non-coding regions) or that KC is not as monogenic (= one gene with large effect size) as initially considered. Since many of the applied research strategies can only identify large effect mutations, strategies to identify variants with smaller effect sizes might lead to more progress in KC research. PMID- 29111845 TI - Pre-clinical evaluation of the mechanical properties of a low-stiffness cement injectable hip stem. AB - In total hip arthroplasty (THA), the femoral stem can be fixed with or without bone cement. Cementless stem fixation is recommended for young and active patients as it eliminates the risk of loss of fixation at the bone-cement and cement-implant interfaces. Cementless fixation, however, suffers from a relatively high early revision rate. In the current research, a novel low stiffness hip stem was designed, fabricated and tested. The stem design provided the option to inject biodegradable bone cement that could enhance initial stem stability. The stem was made of Ti6Al4V alloy. The proximal portion of the stem was porous, with cubic cells. The stem was fabricated using electron beam melting (EBM) technology and tested in compression and bending. Finite-element analysis was used to evaluate stem performance under a dynamic load representing a stair descending cycle and compare it to the performance of a solid stem with similar geometry. The von Mises stresses and maximum principal strains generated within the bone increased after porous stem insertion compared to solid stem insertion. The low-modulus stem tested in this study has acceptable mechanical properties and generates strain patterns in bone that appear compatible with clinical use. PMID- 29111846 TI - Investigation of CAV1/CAV2 rs4236601 and CDKN2B-AS1 rs2157719 in primary open angle glaucoma patients from Brazil. AB - Large-scale genome-wide association studies have identified several susceptibility variants associated with the risk of primary open-angle glaucoma (POAG), among which rs4236601 (CAV1/CAV2) at chromosome 7q31 and rs2157719 at chromosome 9p21 (CDKN2B-AS1). The purpose of this study was to investigate whether these variants contribute to the incidence of POAG in a sample of the Brazilian Southeastern population and to determine the best-fitted genetic model for these single nucleotide polymorphisms (SNPs). A case-control study with 557 individuals, 310 with POAG, and 247 controls was conducted through PCR and direct sequencing. We observed a significant effect of the heterozygous genotype (G/A) of rs2157719 that occurred more frequently in the control group (p = 0.0004; OR: 0.517, CI 95%: 0.357-0.745). Allele frequencies also differed between cases and controls (p = 0.006; OR: 0.694, CI 95%: 0.522-0.922) with the best-fitted genetic model for rs2157719 being the codominant model. No differences were observed for genotype and allele distributions in relation to rs4236601 in the CAV1/CAV2 region. The association of rs2157719 (CDKN2B-AS1) with the POAG phenotype corroborates previously published results, reinforcing the importance of this variant in POAG etiology. PMID- 29111847 TI - Validation of the manual inclinometer and flexicurve for the measurement of thoracic kyphosis. AB - INTRODUCTION: Physiotherapists commonly use the manual inclinometer and Flexicurve for the clinical measurement of thoracic spinal posture. The aim of this study is to examine the concurrent validity of the Flexicurve and manual inclinometer in relation to the radiographic Cobb angle for the measurement of thoracic kyphosis. METHODS: Eleven subjects (seven males, four females) underwent a sagittal plane spinal radiograph. Immediately following the radiograph, a physiotherapist measured thoracic kyphosis using the Flexicurve and manual inclinometer before the subjects moved from position. Cobb angles were subsequently measured from the radiographs by an independent examiner. RESULTS: A strong correlation was demonstrated between both the Cobb angle and the Flexicurve angle (r = 0.96) and the Cobb angle and the manual inclinometer angle (r = 0.86). On observation of the Bland-Altman plots, the inclinometer showed good agreement with the Cobb angle (mean difference 4.8 degrees +/- 8.9 degrees ). However, the Flexicurve angle was systematically smaller than the Cobb angle (mean difference 20.3 degrees +/- 6.1 degrees ), which reduces its validity. CONCLUSION: The manual inclinometer is recommended as a valid instrument for measuring thoracic kyphosis, with good agreement with the gold standard. While the Flexicurve is highly correlated to the gold standard, they have poor agreement. Therefore, physiotherapists should take caution when interpreting its results. PMID- 29111848 TI - Study on the effect of total dissolved solids (TDS) on the performance of an SBR for COD and nutrients removal. AB - In this study, the effect of total dissolved solids (TDS) on the performance of a sequencing batch reactor (SBR) system to treat synthetic wastewater with microbial inoculum was evaluated. The SBR was operated continuously for eight days on a 6-h cycle with anaerobic/anoxic/aerobic phases in each cycle after entering the steady state, and the influent TDS was tested at five levels, i.e., 750, 1500, 3000, 4500, and 6000 mg L-1. The results showed that only two TDS levels (750 and 1500 mg L-1) could achieve good COD removal efficiencies (94.8 and 92.2%, respectively). For TDS levels equal to, or greater than, 3000 mg L-1, a 20% reduction in COD removal efficiency resulted. Different from COD, removal of NH4+-N appeared not to be affected by the TDS content, and a removal efficiency of higher than 97% was obtained, regardless of the TDS content. However, only the lowest two TDS levels achieved high phosphate removals (>99%), and the removal efficiency dropped to 57.8 and 45.9%, respectively, for TDS levels of 3000 and 4500 mg L-1. More interestingly, a phosphate release, instead of uptake, was observed at the TDS level of 6000 mg L-1. It may be concluded that for effective phosphate removal, the TDS level in the liquid should be controlled under 1500 mg L-1, and higher liquid TDS levels were detrimental to the aerobes and could disrupt the aerobic metabolism, leading to the failure of the SBR treatment system. A tendency that raising TDS content would adversely affect the aerobic oxygen uptake rate was observed, which could also result in SBR upset. A power regression with an R of 0.9844 was established between the influent TDS concentration and the TDS removal efficiency, which may be used to estimate the SBR performance in TDS removal based on the influent TDS content. PMID- 29111850 TI - Chitosan-based coatings in the prevention of intravascular catheter-associated infections. AB - Central venous access devices play an important role in patients with prolonged intravenous administration requirements. In the last years, the coating of these devices with bactericidal compounds has emerged as a potential tool to prevent bacterial colonization. Our study describes the modification of 3D-printed reservoirs and silicone-based catheters, mimicking central venous access devices, through different approaches including their coating with the well known biocompatible and bactericidal polymer chitosan, with the anionic polysaccharide alginate; also, plasma treated surfaces were included in the study to promote polymer adhesion. The evaluation of the antimicrobial action of those surface modifications compared to that exerted by a model antibiotic (ciprofloxacin) adsorbed on the surface of the devices was carried out. Surface characterization was developed by different methodologies and the bactericidal effects of the different coatings were assayed in an in vitro model of Staphylococcus aureus infection. Our results showed a significant reduction in the reservoir roughness (<=73%) after coating though no changes were observed for coated catheters which was also confirmed by scanning electron microscopy, pointing to the importance of the surface device topography for the successful attachment of the coating and for the subsequent development of bactericidal effects. Furthermore, the single presence of chitosan on the reservoirs was enough to fully inhibit bacterial growth exerting the same efficiency as that showed by the model antibiotic. Importantly, chitosan coating showed low cytotoxicity against human keratinocytes, human lung adenocarcinoma epithelial cells, and murine colon carcinoma cells displaying viability percentages in the range of the control samples (>95%). Chitosan-based coatings are proposed as an effective and promising solution in the prevention of microbial infections associated to medical devices. PMID- 29111849 TI - Does taping in addition to physiotherapy improve the outcomes in subacromial impingement syndrome? A systematic review. AB - BACKGROUND: Taping is used with or without other interventions for many purposes, especially to manage pain and improve functional activity in patients with shoulder pain. OBJECTIVES: The aim of this review was to determine whether any taping technique in addition to physiotherapy care is more effective than physiotherapy care alone in patients with shoulder impingement syndrome. METHODS: A systematic search of Cochrane Database of Systematic Review, MEDLINE (EBSCO), Physiotherapy Evidence Database (PEDro), CINAHL (EBSCO), PUBMED, AMED, EMBASE (OVID), The Kinesio Kinesio(r) Taping Method, Kinesio(r) Tex Tape UK and International websites ( www.kinesiotaping.co.uk ; www.kinesiotaping.com ) was conducted to June 2015. The outcome measures were pain, disability, range of motion and muscle strength. As data were not suitable for meta-analysis, narrative synthesis were applied. RESULTS: Three randomized controlled trials and one controlled trial (135 patients) were included. The results were conflicting and weak on the effectiveness of taping as an adjunct therapy for improvement of pain, disability, range of motion and muscle strength. CONCLUSION: Clinical taping in addition to physiotherapy interventions (e.g. exercise, electrotherapy, and manual therapy) might be an optional modality for managing patients with shoulder impingement syndrome, especially for the initial stage of the treatment; however, we need further robust, placebo controlled and consistent studies to prove whether it is more effective than physiotherapy interventions without taping. PMID- 29111851 TI - Websites Related to Volume 31, Issue 4. PMID- 29111852 TI - EMG-triggered stimulation post spinal cord injury: A case report. AB - BACKGROUND: Mechanical injury in patients with spinal cord injury (SCI) rarely transects the cord completely, even when the injury is classified as complete. These patients can show sub-clinical evidence of spared motor connections, which might be amenable to targeted rehabilitation. Neurophysiological evaluations can complement the clinical evaluation by providing objective data about conduction across the SCI site. CASE DESCRIPTION: A twenty-four year old patient with SCI was admitted to a rehabilitation centre 49 days post traumatic SCI. His injury was categorized as motor and sensory complete (AIS A) with a neurological level of C4. The strength of his triceps bilaterally was recorded 0/5 repeatedly by his therapists during the five-month period post-injury. As a result, no training was provided for these muscles during the rehabilitation program. Neurophysiological Assessment: Motor evoked potentials (MEPs) were recorded from his left triceps with transcranial magnetic stimulation (TMS) which confirmed the existence of spared corticospinal connections to this muscle post-injury. INTERVENTION: He completed a series of active-assisted exercises with an EMG-triggered neuromuscular stimulation (NMS) device for his left triceps comprising 20-minutes elbow extension (15 trials), three times per day for 4 weeks. OUTCOME: The strength of his left triceps gradually improved to 2/5. DISCUSSION: Neurophysiological evaluation can be useful in identifying residual function below the level of injury, which can, in turn, be enhanced through appropriate rehabilitation strategies. PMID- 29111853 TI - Metabolism and disposition of 2-ethylhexyl-p-methoxycinnamate following oral gavage and dermal exposure in Harlan Sprague Dawley rats and B6C3F1/N mice and in hepatocytes in vitro. AB - 1. 2-Ethylhexyl-p-methoxycinnamate (EHMC) is commonly used as an ingredient in sunscreens, resulting in potential oral and dermal exposure in humans. 2. Clearance and metabolism of EHMC in hepatocytes and disposition and metabolism of EHMC in rodents following oral (8-800 mg/kg) intravenous (IV) (8 mg/kg) or dermal (0.8-80 mg/kg representing 0.1-10% formulation concentration) exposure to [14C]EHMC were investigated in rats and mice. 3. EHMC was rapidly cleared from rat and mouse hepatocytes (half-life <=3.16 min) and less rapidly (half-life <=48 min) from human hepatocytes. 4. [14C]EHMC was extensively absorbed and excreted primarily in urine by 72 h after oral administration to rats (65-80%) and mice (63-72%). Oral doses to rats were excreted to a lesser extent (3-8%) in feces and as CO2 (1-4%). Radioactive residues in tissues were <1% of the dose. There were no sex or species differences in disposition in rats. 5. Following dermal application, 34-42% of an 8-mg/kg dose was absorbed in rats, and 54-62% in mice in 72-h. 6. Among numerous urinary metabolites associated with hydrolysis of the ester, two potential reproductive and developmental toxicants, 2-ethylhexanol and 2-ethylhexanoic acid were produced by metabolism of EHMC. PMID- 29111855 TI - Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents. AB - PURPOSE: The purpose of the current study was to assess the potential involvement of acid-sensing ion channel 1 (ASIC1) in retinal ganglion cell (RGC) death and investigate the neuroprotective effects of inhibitors of ASICs in promoting RGC survival following optic nerve crush (ONC). RESULTS: ASIC1 protein was significantly increased in optic nerve extracts at day 7 following ONC in rats. Activated calpain-1 increased at 2 and 7 days following ONC as evidenced by increased degradation of alpha-fodrin, known substrate of calpain. Glial fibrillary acidic protein levels increased significantly at 2 and 7 days post injury. By contrast, glutamine synthetase increased at 2 days while decreased at 7 days. The inhibition of ASICs with amiloride and psalmotoxin-1 significantly increased RGC survival in rats following ONC (p < 0.05, one-way ANOVA). The mean number of surviving RGCs in rats (n = 6) treated with amiloride (100 uM) following ONC was 1477 +/- 98 cells/mm2 compared with ONC (1126 +/- 101 cells/mm2), where psalmotoxin-1 (1 MUM) treated rats (n = 6) and subjected to ONC had 1441 +/- 63 RGCs/mm2 compared with ONC (1065 +/- 76 RGCs/mm2). Average number of RGCs in control rats (n = 12) was 2092 +/- 46 cells/mm2. Blocking of ASICs also significantly increased RGC survival from ischemic-like insult from 473 +/- 80 to 842 +/- 49 RGCs/mm2 (for psalmotoxin-1) and from 628 +/- 53 RGCs/mm2 to 890 +/- 55 RGCs/mm2 (for amiloride) with p <= 0.05, using one-way ANOVA. Acidification (a known activator of ASIC1) increased intracellular Ca2+ ([Ca2+]i) in rat primary RGCs, which was statistically blocked by pretreatment with 100 nM psalmotoxin-1. CONCLUSIONS: ASIC1 up-regulation-induced influx of extracellular calcium may be responsible for activation of calcium-sensitive calpain-1 in the retina. Calpain-1 induced degradation of alpha-fodrin and leads to morphological changes and eventually neuronal death. Therefore, blockers of ASIC1 can be used as potential therapeutics in the treatment of optic nerve degeneration. ABBREVIATIONS: 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF); acid-sensing ion channels (ASICs); analysis of variance (ANOVA); bicinchoninic acid (BCA); brain-derived neurotrophic factor (BDNF); central nervous system (CNS); ciliary neurotrophic factor (CNTF); dimethyl sulfoxide (DMSO); endoplasmic reticulum (ER); ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA); ethylenediaminetetraacetic acid (EDTA); Food and Drug Administration (FDA); glial fibrillary acidic protein (GFAP); glutamine synthetase (GS); intraocular pressure (IOP); kilodalton (kDa); Krebs-Ringer Buffer (KRB); optic nerve crush (ONC); phosphate-buffered saline (PBS); plasma membrane (PM); polymerase chain reaction (PCR); retinal ganglion cell (RGC); RNA Binding Protein With Multiple Splicing (RBPMS); room temperature (RT); standard error of the mean (SEM). PMID- 29111854 TI - The effect of morphine upon DNA methylation in ten regions of the rat brain. AB - Morphine is one of the most effective analgesics in medicine. However, its use is associated with the development of tolerance and dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided insight into mechanisms possibly underlying addiction. In this study, we sought to identify epigenetic changes in ten regions of the rat brain following acute and chronic morphine exposure. We analyzed DNA methylation of six nuclear encoded genes implicated in brain function (Bdnf, Comt, Il1b, Il6, Nr3c1, and Tnf) and three mitochondrially-encoded genes (Mtco1, Mtco2, and Mtco3), and measured global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5 hmC) levels. We observed differential methylation of Bdnf and Il6 in the pons, Nr3c1 in the cerebellum, and Il1b in the hippocampus in response to acute morphine exposure (all P value < 0.05). Chronic exposure was associated with differential methylation of Bdnf and Comt in the pons, Nr3c1 in the hippocampus and Il1b in the medulla oblongata (all P value < 0.05). Global 5mC levels significantly decreased in the superior colliculus following both acute and chronic morphine exposure, and increased in the hypothalamus following chronic exposure. Chronic exposure was also associated with significantly increased global 5hmC levels in the cerebral cortex, hippocampus, and hypothalamus, but significantly decreased in the midbrain. Our results demonstrate, for the first time, highly localized epigenetic changes in the rat brain following acute and chronic morphine exposure. Further work is required to elucidate the potential role of these changes in the formation of tolerance and dependence. PMID- 29111857 TI - Intra- and inter-rater reliability of movement and palpation tests in patients with neck pain: A systematic review. AB - Neck pain is common and often becomes chronic. Various clinical tests of the cervical spine are used to direct and evaluate treatment. This systematic review aimed to identify studies examining the intra- and/or interrater reliability of tests used in clinical examination of patients with neck pain. A database search up to April 2016 was conducted in PubMed, CINAHL, and AMED. The Quality Appraisal of Reliability Studies Checklist (QAREL) was used to assess risk of bias. Eleven studies were included, comprising tests of active and passive movement and pain evaluating participants with ongoing neck pain. One study was assessed with a low risk of bias, three with medium risk, while the rest were assessed with high risk of bias. The results showed differing reliabilities for the included tests ranging from poor to almost perfect. In conclusion, active movement and pain for pain or mobility overall presented acceptable to very good reliability (Kappa >0.40); while passive intervertebral tests had lower Kappa values, suggesting poor reliability. It may be a coincidence that the studies indicating very good reliability tended to be of higher quality (low to moderate risk of bias), while studies finding poor reliability tended to be of lower quality (high risk of bias). Regardless, the current recommendation from this review would suggest the clinical use of tests with acceptable reliability and avoiding the use of tests that have been shown to not be reliable. Finally, it is critical that all future reliability studies are of higher quality with low risk of bias. PMID- 29111858 TI - Women's Health Endocrine Update. AB - The clinical update serves as a brief review of recently published, high-impact, and potentially practice changing journal articles summarized for our readers. Topics include menopause, sexual dysfunction, breast health, contraception, osteoporosis, and cardiovascular disease. In this clinical update, we selected four recent high-impact publications related to endocrine issues in women. We have chosen to highlight research on subclinical hypothyroidism during pregnancy and adverse pregnancy outcomes, including cognitive outcomes in offspring; the progression of metabolic syndrome severity during the menopausal transition; and the association of diabetes and metformin use with cancer risk and mortality. PMID- 29111856 TI - Vascular-derived connective tissue growth factor (Ctgf) is critical for pregnancy induced beta cell hyperplasia in adult mice. AB - During pregnancy, maternal beta cells undergo compensatory changes including hypertrophy, hyperplasia, and increased glucose-stimulated insulin secretion (GSIS). Failure of these adaptations to occur can result in gestational diabetes mellitus. The secreted protein, Connective tissue growth factor (Ctgf), is critical for normal beta cell development and promotes regeneration after partial beta cell ablation. During embryogenesis, Ctgf is expressed in pancreatic ducts, vasculature, and beta cells. In the adult pancreas, Ctgf is expressed only in the vasculature. Here, we report that pregnant mice with global Ctgf haploinsufficiency (CtgfLacZ/+) have an impairment in maternal beta cell proliferation, while beta cell proliferation in virgin CtgfLacZ/+ females is unaffected. Additionally, alpha-cell proliferation, beta cell size, and GSIS were unaffected in CtgfLacZ/+ mice, suggesting that vascular-derived Ctgf has a specific role in islet compensation during pregnancy. PMID- 29111859 TI - Effect of physical therapy management of nonspecific low back pain with exercise addiction behaviors: A case series. AB - This case series describes two patients, aged 35 and 45 years, respectively, who presented with chronic nonspecific low back pain (NSLBP) having exercise addiction (EA) behaviors. Diagnosis of EA was based on clinical findings, exercising patterns and withdrawal symptoms along with high scores in the EA inventory. This report is a potential first-time description of the successful physical therapy management of NSLBP associated with EA utilizing pain neuroscience education (with individualized curriculum), mindfulness, breathing, quota-based reduction in exercises and modification of exercises into social participation, pleasure activities and hobbies. Both the patients were seen once a week, for 8 weeks. At discharge, they were pain-free and fully functional, which was maintained at a six-month follow-up. PMID- 29111861 TI - Compound heterozygous variants in IFT140 as a cause of nonsyndromic retinitis pigmentosa. PMID- 29111860 TI - Identification of the Gender-Specific Health Needs of Women Following Lung Transplantation. AB - BACKGROUND: Little is known of the prevalence and severity of menstrual dysfunction, climacteric symptoms, pelvic floor disorders, sexual problems, and psychological wellbeing after lung transplantation in women. MATERIALS AND METHODS: Adult female lung transplant recipients, attending the Alfred Hospital Lung Transplant Service in Melbourne, Australia participated in a women's health, cross-sectional questionnaire-based study. RESULTS: The 123 of 149 potential participants were recruited between September 2014 and July 2015. Their median age was 53.5 years, and 44 were premenopausal, 3 perimenopausal, and 76 postmenopausal. Moderate-severe menstrual and premenstrual symptoms were common, and 43% of partnered premenopausal women were not using contraception. Vasomotor symptoms (VMS) were common in postmenopausal women <55 years (80.0%), and the use of menopausal hormone therapy was low (8.9%). The estimated prevalence of low sexual desire associated with distress was 24.4%. Low wellbeing was significantly and independently associated with being aged 50 <= 60 years, moderate-severe VMS, impaired forced expiratory volume in 1 second, and psychotropic medication use. CONCLUSIONS: Our findings demonstrate that premenopausal lung transplant recipients need to be asked about bothersome menstrual symptoms, and contraceptive compliance needs regular review. Transplant recipients at midlife have substantially lower wellbeing than women of other ages and this needs attention, including assessment and management of menopausal symptoms. PMID- 29111862 TI - Slit Lamp-Based Ocular Scoring Systems in Toxicology and Drug Development: A Literature Survey. AB - PURPOSE: To present a survey of the features of published slit lamp-based scoring systems and their applicability in the context of modern ocular toxicology and drug development. METHODS: References describing original or modified slit lamp based scoring systems for human or veterinary clinical patients or in investigative or toxicologic research were collected following a comprehensive literature review using textbooks and online publication searches. Each system's indications and features were compiled to facilitate comparison. RESULTS: Literature review identified 138 original or modified scoring systems. Most (48%) were published for evaluation of the ocular surface, 34% for the general anterior segment, and 18% for the lens. Most systems were described for assessment of human patients (50%) and small albino laboratory species such as rabbits (19%), rats (12%), and mice (8%). Systems described for pigmented laboratory species and for larger species such as dogs, cats, pigs, and nonhuman primates (NHPs) were comparatively underrepresented. No systems described a lens scoring scheme specific to the dog, cat, pig, or NHP. Scoring schemes for aqueous and vitreous cells were infrequently described for laboratory species. CONCLUSIONS: Many slit lamp-based scoring systems have been published, but the features of each differ and complicate translation of findings between different species. Use and interpretation of any scoring system in toxicology and drug development must be done with awareness of the limitations of the system being used. PMID- 29111863 TI - Multicomponent Exercise Intervention and Metacognition in Obese Preadolescents: A Randomized Controlled Study. AB - This study examines the effect of a 12-week multicomponent exercise intervention on metacognition among preadolescents with obesity. Seventy-five preadolescents were randomly assigned to either a multicomponent exercise group or a reading control group. An exercise intervention consisting of a jumping rope was utilized to develop multifaceted fitness features, with each session lasting for 75 min and three sessions being conducted per week for 12 weeks. Results revealed significant interactions between group and time point for cardiovascular fitness, muscular endurance, flexibility, and power, as well as for Tower of London task measures, including total move score, total executive time, and total planning solving time, with better postintervention performances achieved by the exercise group. Positive correlations between the physical fitness and metacognition measurements were also observed. These findings suggest that the multicomponent exercise benefits metacognition in obese preadolescents, with exercise-associated changes in multifaceted fitness features mediating the relationship between exercise and metacognition. PMID- 29111864 TI - Development of Acyclovir-Loaded Albumin Nanoparticles and Improvement of Acyclovir Permeation Across Human Corneal Epithelial T Cells. AB - PURPOSE: The aim of the present study was to develop acyclovir (ACV) ocular drug delivery systems of bovine serum albumin (BSA) nanoparticles as well as to assess their in vitro transcorneal permeation across human corneal epithelial (HCE-T) cell multilayers. METHODS: The ACV-loaded BSA nanoparticles were prepared by desolvation method along with physicochemical characterization, cytotoxicity, as well as in vitro transcorneal permeation studies across HCE-T cell multilayers. RESULTS: The nanoparticles appeared to be spherical in shape and nearly uniform in size of about 200 nm. The size of nanoparticles became smaller with decreasing BSA concentration, while the ratios of water to ethanol seemed not to affect the size. Increasing the amount of ethanol in desolvation process led to significant reduction of drug entrapment of nanoparticles with smaller size and more uniformity. The ACV-loaded BSA nanoparticles prepared were shown to have no cytotoxic effect on HCE-T cells used in permeation studies. The in vitro transcorneal permeation results revealed that ACV could permeate through the HCE T cell multilayers significantly higher from BSA nanoparticles than from aqueous ACV solutions. CONCLUSION: The ACV-loaded BSA nanoparticles could be prepared by desolvation method without glutaraldehyde in the formulation. ACV could increasingly permeate through the multilayers of HCE-T cells from the ACV-loaded BSA nanoparticles. Therefore, the ACV-loaded BSA nanoparticles could be a highly potential ocular drug delivery system. PMID- 29111865 TI - Determination of pharmaceutical compounds in hospital wastewater and their elimination by advanced oxidation processes. AB - This study investigates the mineralization efficiency, i.e. removal of total organic carbon (TOC) in hospital wastewater by direct ozonation, ozonation with UV radiation (O3/UV), homogeneous catalytic ozonation (O3/Fe2+) and homogeneous photocatalytic ozonation (O3/Fe2+/UV). The influence of pH and reaction time was evaluated. For the best process, toxicity and degradation efficiency of the selected pharmaceutical compounds (PhCs) were determined. The results showed that the PhCs detected in the hospital wastewater were completely degraded when the mineralization efficiency reached 54.7% for O3/UV with 120 minutes of reaction time using a rate of 1.57 g O3 h-1. This process also achieved a higher chemical oxygen demand removal efficiency (64.05%), an increased aromaticity reduction efficiency (81%) and a toxicity reduction. PMID- 29111866 TI - Moral Identity Predicts Doping Likelihood via Moral Disengagement and Anticipated Guilt. AB - In this study, we integrated elements of social cognitive theory of moral thought and action and the social cognitive model of moral identity to better understand doping likelihood in athletes. Participants (N = 398) recruited from a variety of team sports completed measures of moral identity, moral disengagement, anticipated guilt, and doping likelihood. Moral identity predicted doping likelihood indirectly via moral disengagement and anticipated guilt. Anticipated guilt about potential doping mediated the relationship between moral disengagement and doping likelihood. Our findings provide novel evidence to suggest that athletes, who feel that being a moral person is central to their self-concept, are less likely to use banned substances due to their lower tendency to morally disengage and the more intense feelings of guilt they expect to experience for using banned substances. PMID- 29111867 TI - 'Memorcise': implications for patient compliance and medication adherence. PMID- 29111868 TI - Editorial. PMID- 29111869 TI - Biosynthesized colloidal silver and gold nanoparticles as emerging leishmanicidal agents: an insight. AB - Many recent key innovations in nanotechnology have greatly fascinated scientists to explore new avenues in treatment and diagnosis of emerging diseases. Due to extensive utilization of metallic nanoparticles (NPs) in diverse biomedical applications, scientists are looking forward to green synthesis of NPs as safer, simple, fast, and low-cost method over chemical and physical methods. Due to enriched phytochemistry, no need for maintenance and ready availability, plants are preferred for green synthesis of silver (AgNPs) and gold NPs (AuNPs). Recently, several researchers have exploited these biogenic NPs as potential antileishmanial agents. The current article is focused to mechanistically explain the antileishmanial activity of biogenic AuNPs and AgNPs with a futuristic discussion on the faith of these particles as emerging antileishmanial agents. PMID- 29111870 TI - External ophthalmomyiasis caused by Oestrus ovis in east China. AB - External ophthalmomyiasis is a superficial infestation of the eye tissues by the larvae or maggots of flies. External ophthalmomyiasis, caused by Oestrus ovis, is found occasionally in shepherding areas, but is rare in the cities of eastern China. We present a case of a 30-year-old man with complaints of a foreign body sensation, lacrimation and itching in the right eye, with uncorrected visual acuity of 20/20 in each eye. Six larvae were removed from the conjunctival sac and were ultimately authenticated as the first instar larvae of Oestrus ovis. He responded well after prompt appropriate therapy. PMID- 29111871 TI - Temporal trend in the levels of polycyclic aromatic hydrocarbons emitted in a big tire landfill fire in Spain: Risk assessment for human health. AB - In May 2016, a big fire occurred in an illegal landfill placed in Sesena (Toledo, Spain), where between 70,000 and 90,000 tons of tires had been accumulated during years. Just after the fire, and because of the increase of airborne PAHs, we found that cancer risks for the population living in the neighborhood of the landfill were 3-5 times higher than for the rest of inhabitants of Sesena. Some months after our initial (June 2016) study, two sampling campaigns (December 2016 and May 2017) were performed to assess the temporal trends of the environmental levels of PAHs, as well as to reassure that these chemicals did not pose any risk for the human health of Sesena inhabitants. In soils, the total concentrations of the 16 PAHs (December 2016), as well as the sum of the seven carcinogenic PAHs, showed values between 8.5 and 94.7 ng g-1 and between 1.0 and 42.3 ng g-1, respectively. In May 2017, a significant decrease (between 4 and 38 times) in the levels of PAHs in air was observed, with total concentrations ranging between 3.49 and 5.06 ng m-3. One year after the fire, the cancer risk at different zones of Sesena was similar, being lower than that found in June 2016, and negligible according to national and international agencies. PMID- 29111872 TI - Views of clinical trial participants on the readability and their understanding of informed consent documents. AB - BACKGROUND: One of the ethical imperatives for a valid consent process in clinical medication trials is that the process be guided by and recorded in an informed consent document (ICD). Concerns have been expressed, however, about readability and participant understanding of ICDs, which are often 10-20 pages long. Objective measures of readability and understanding have been used to support these concerns in several articles, but surprisingly the voice of trial participants on ICDs has not been heard in previous studies. Hence, this study compares participants' subjective views on readability and their understanding of ICDs with those ICDs' objective readability scores. It also evaluates whether family, friends, and additional aids would foster better understanding of the ICD. METHODS: Sixty current trial participants rated the readability and their understanding of deidentified standard ICDs. These had been sourced from two multicenter international Phase III trials on medication for diabetes mellitus and cancer. RESULTS: Less than 10% of participants considered the ICDs difficult to read or difficult to understand in spite of objective readability scores at levels of about 12th grade education, but about a quarter considered the ICDs to be too technical. Participants gave mixed responses about friends or family members helping or the need for videos, pictures, additional reading material, and frequently answered questions (FAQ) sheets as an aid to their understanding. CONCLUSIONS: These findings suggest individual clinical trial participants should be engaged on their views of an ICD, for doing so is part of informed consent as a process rather than consent being merely focused on written information. Such participant-specific engagement should guide whether family and friends, videos, pictures, additional reading material, and FAQ sheets would be of assistance in improving understanding. PMID- 29111873 TI - Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: Results from a clinical trial cohort. AB - BACKGROUND: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). OBJECTIVE: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. METHODS: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. RESULTS: Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (-0.31 um/year) and GCIPL (-0.29 um/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 um was associated with greater annualized RNFL atrophy (-0.85 um/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. CONCLUSION: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations. PMID- 29111875 TI - Wicked policy issues in regenerative medicine and the need to explore new avenues for public engagement. PMID- 29111874 TI - Volatile emerging contaminants in melon fruits, analysed by HS-SPME-GC-MS. AB - The aim of this research was to develop and validate a headspace-solid phase micro-extraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) method for the determination of volatile emerging contaminants in fruit. The method showed good precision (RSD <= 14%) and satisfactory recoveries (99.1-101.7%) and LOD and LOQ values ranging between 0.011-0.033 MUg kg-1 and 0.037-0.098 MUg kg-1, respectively. The method was applied to investigate the content of volatile emerging contaminants in two varieties of melon fruit (Cucumis melo L.) cultivated adjoining high-risk areas. Glycol ethers, BHT, BHA and BTEX (benzene, toluene, ethylbenzene and xylene) were determined in melon fruit pulps for the first time, with different sensitivities depending on sample and variety. Although the amount of the volatile contaminants in the melon samples were in the order of ug kg-1, the safety of vegetable crops cultivated near risk areas should be more widely considered. The results showed that this accurate and reproducible method can be useful for routine safety control of fruits and vegetables. PMID- 29111876 TI - Impact of Anticipated Bias from Healthcare Professionals on Perceived Successful Aging Among Transgender and Gender Nonconforming Older Adults. AB - PURPOSE: Transgender and gender nonconforming (TGNC) persons have routinely experienced high rates of violence and discrimination. Discrimination in healthcare can affect the ability of TGNC persons to age successfully as it often deters them from seeking care. The purpose of this study was to determine if anticipation of bias from healthcare professionals, as well as other variables, predicted perceived successful aging in a sample of TGNC adults. METHODS: A total of 384 (of the original 1963) participants older than 50 years completed the relevant parts of an 83-item online survey as part of the Trans MetLife Survey on Later-Life Preparedness and Perceptions in Transgender-Identified Individuals. RESULTS: Larger social support networks and higher levels of confidence that a healthcare professional will treat them with dignity and respect as a TGNC person at the end of their life were associated with increased odds of perceiving that they were aging successfully. CONCLUSION: With high rates of discrimination and prejudice toward TGNC persons in various contexts (e.g., healthcare, education, and housing), it is imperative that practitioners, researchers, policymakers, and institutions work together to eradicate healthcare disparities, promote social change, and support an environment that encourages successful aging. This calls for a coordinated, proactive outreach effort to put trust back into a system that has historically let down an entire subset of the population. PMID- 29111877 TI - DNA methylation alterations induced by transient exposure of MCF-7 cells to maghemite nanoparticles. AB - AIM: To evaluate the DNA methylation profile of MCF-7 cells during and after the treatment with maghemite nanoparticles (MNP-CIT). MATERIALS & METHODS: Noncytotoxic MNP-CIT concentrations and cell morphology were evaluated by standard methods. DNA methylation was assessed by whole genome bisulfite sequencing. DNA methyltransferase (DNMT) genes expression was analyzed by qRT PCR. RESULTS: A total of 30 and 60 ugFeml-1 MNP-CIT accumulated in cytoplasm but did not present cytotoxic effects. The overall percentage of DNA methylation was not affected, but 58 gene-associated regions underwent DNA methylation reprogramming, including genes related to cancer onset. DNMT transcript levels were also modulated. CONCLUSION: Transient exposure to MNP-CIT promoted epigenomic changes and altered the DNMT genes regulation in MCF-7 cells. These events should be considered for biomedical applications. PMID- 29111878 TI - May I have the next dance? Chinese gay men exploring selves and practices through the tradition of dance in public spaces. AB - This study explores the way in which some Chinese gay men negotiate dance performances in parks and other public spaces in an attempt to invent and experiment with 'possible selves'. In most circumstances, these same men conceal their sexual orientation for fear of stigma and discrimination, experiencing in the process something of a 'divided self'. Little attention has been given to understanding the way such individuals negotiate and construct same-sex experiences, especially through the negotiation of specific and restricted social interactions and performances. Based on participant observation with a group of dancers practising in a Chinese public park, this paper analyses how these men explore same-sex relations and lifestyles through the circumscribed performance of collective public dance. PMID- 29111879 TI - Worst case prediction of additives migration from polystyrene for food safety purposes: a model update. AB - A reliable prediction of migration levels of plastic additives into food requires a robust estimation of diffusivity. Predictive modelling of diffusivity as recommended by the EU commission is carried out using a semi-empirical equation that relies on two polymer-dependent parameters. These parameters were determined for the polymers most used by packaging industry (LLDPE, HDPE, PP, PET, PS, HIPS) from the diffusivity data available at that time. In the specific case of general purpose polystyrene, the diffusivity data published since then shows that the use of the equation with the original parameters results in systematic underestimation of diffusivity. The goal of this study was therefore, to propose an update of the aforementioned parameters for PS on the basis of up to date diffusivity data, so the equation can be used for a reasoned overestimation of diffusivity. PMID- 29111880 TI - Early marriage and cultural constructions of adulthood in two slums in Dar es Salaam. AB - This study examines under-18 marriage in urban Tanzania from an ethnographic perspective. Due to poverty and high unemployment, some girls aspire to early marriage. Two pathways to early marriage are identified: first, poverty and gendered economic disparities motivate girls to begin transactional sexual activity at an early age, leading parents to favour early marriage as a risk reduction measure. Second, educational opportunities are often closed off to girls before marriage, as a result of which early marriage becomes the only culturally approved pathway that allows girls to present themselves to others as a self-sufficient agent. These pathways are reinforced by cultural and religious concepts surrounding the transition from childhood to adulthood. The study finds that, in urban Tanzania, two important factors associated with early marriage are the prevalence of premarital sex leading to out-of-wedlock pregnancies, and the relatively high cost of secondary schooling, which blocks educational opportunities for girls after the age of 15. PMID- 29111881 TI - Negotiating gay men's relationships: how are monogamy and non-monogamy experienced and practised over time? AB - When viewed over time, many gay men's relationships are not static, or firmly fixed to monogamy or non-monogamy. This paper uses in-depth interviews with 61 Australian gay men to explore how monogamy and non-monogamy are experienced over time, expectations of what constitutes the norms regarding gay men's relationships and how couples experience and practices change. Although some gay men may idealise monogamy, particularly at the beginning of a relationship, it is often experienced as temporary. Non-monogamy is often seen as a likely prospect for gay relationships owing to the social and cultural norms that operate in gay communities. These expected trajectories are reflected in practice - many relationships begin monogamously and then become non-monogamous over time. While the application of 'rules', experimentation and flexibility can facilitate change, couples may struggle to navigate new territory as their relationship structures shift. This is particularly the case when partners value monogamy and non-monogamy differently, or when one partner's values change. These findings shed light on how gay men approach change to the status of 'fidelity' within their relationships, and the tensions and opportunities that change can produce for couples. PMID- 29111882 TI - Depletion of tylosin residues in feathers, muscle and liver from broiler chickens after completion of antimicrobial therapy. AB - Tylosin is one of the most commonly used antimicrobial drugs from the macrolide family and in broiler chickens it is used specially for the treatment of infectious pathologies. The poultry industry produces several by-products, among which feathers account for up to 7% of a chicken's live weight, thus they amount to a substantial mass across the whole industry. Feathers have been repurposed as an animal feed ingredient by making them feather meal. Therefore, the presence of high concentrations of residues from antimicrobial drugs in feathers might pose a risk to global public health, due to re-entry of these residues into the food chain. This work aimed to characterise the depletion behaviour of tylosin in feather samples, while considering its depletion in muscle and liver tissue samples as a reference point. To achieve this goal, we have implemented and validated an analytical methodology suitable for detecting and quantifying tylosin in these matrices. Sixty broiler chickens, raised under controlled conditions, received an oral dose of 32 mg kg-1 of tylosin for 5 days. Tylosin was quantified in muscle, liver and feathers by liquid chromatography coupled with a photodiode array detector (HPLC-DAD). High concentrations of tylosin were detected in feather samples over the whole experimental period after completing both the therapy and the recommended withdrawal time (WDT). On the other hand, tylosin concentrations in muscle and liver tissue samples fell below the limit of detection of this method on the first sampling day. Our results indicate that the WDT for feather samples is 27 days, hence using feather meal for the formulation of animal diets or for other agricultural purposes could contaminate with antimicrobial residues either other livestock species or the environment. In consequence, we recommend monitoring this matrix when birds have been treated with tylosin, within the context of poultry farming. PMID- 29111883 TI - Multiple sclerosis and HLA genotypes: A possible influence on brain atrophy. AB - BACKGROUND: The strongest genetic determinant for multiple sclerosis (MS) is located at the human leukocyte antigen (HLA) class II DRB1 and DQB1 loci. OBJECTIVES: To investigate the possible role of predisposing HLA genotypes in determining brain atrophy. METHODS: HLA genotypes were categorized as high risk (two predisposing haplotypes) or medium/low risk (one or no predisposing haplotypes). Patients underwent a brain magnetic resonance imaging (MRI) study and volumes of white matter (WM), gray matter (GM), and whole brain (WB) were estimated with SIENAX. Longitudinal atrophy was also assessed with SIENA. RESULTS: The study included 240 MS patients. In 51/240 (21%) subjects, a high risk HLA genotype was observed, while medium- and low-risk HLA genotypes were 109/240 (45%) and 80/240 (34%), respectively. Multiple regression analysis found that the high-risk HLA genotype was associated with significant reduction in WB ( p = 0.02) and GM ( p = 0.03) volumes compared with the medium-/low-risk HLA genotypes, independently from MS clinical features. The longitudinal study included 60 patients and showed a brain volume loss of -0.79% in high-risk HLA genotype group versus -0.56% in low-risk HLA genotype. CONCLUSION: Our results suggest an influence of HLA genotype on WB and GM atrophy. Further investigations are necessary to confirm these findings. PMID- 29111885 TI - Retraction Notice. PMID- 29111884 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1-30 June, 2017. PMID- 29111886 TI - Predictive modelling of the exposure to steviol glycosides in Irish patients aged 1-3 years with phenylketonuria and cow's milk protein allergy. AB - Children with Phenylketonuria (PKU) and severe cow's milk protein allergy (CMPA) consume prescribed, specially formulated, foods for special medical purposes (FSMPs) as well as restricted amounts of normal foods. These patients are exposed to artificial sweeteners from the consumption of a combination of free and prescribed foods. Young patients with PKU and CMPA have a higher risk of exceeding acceptable daily intakes (ADI) for additives than age-matched healthy children. A predictive modelling approach has been adapted successfully to assess the additive exposure of young patients with PKU and CMPA to artificial sweeteners. Steviol glycosides (E960) are at various stages of regulatory approval for the various food categories in the EU but are not as yet permitted for use in products intended for young children. The aim of this study was to predict potential steviol glycoside exposure in young children with PKU and CMPA considering the potential for future provisions for the use of this sweetener. The recent introduction of steviol glycosides means that no exposure data are available for children with CMPA and PKU. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010-11). Specially formulated amino acid-based FSMPs are used to replace whole or milk protein foods and were included in the exposure model to replace restricted foods. The recommendations to ensure adequate protein intake in these patients were used to determine FSMP intake. Exposure assessment results indicated that the maximum permitted level (MPL) for FSMPs would warrant careful consideration to avoid exposures above the ADI. These data can be used to inform recommendations for the medical nutrition industry. PMID- 29111887 TI - Use of Short Message Service and Smartphone Applications in the Management of Surgical Patients: A Systematic Review. AB - BACKGROUND: Mobile health and telemedicine are rapidly evolving fields used to provide healthcare remotely to patients. For surgical patients, telemedicine can improve patient education and remote monitoring of postoperative symptoms. We performed a systematic review of studies involving the use of short message service (SMS) and mobile application-based interventions in surgical patients to evaluate the advantages and disadvantages of each system, as well as of mobile interventions as a whole. MATERIALS AND METHODS: Major electronic databases were searched using relevant keywords from inception until November 2016. Studies involving SMS or mobile application-based communication protocols involving at least 25 preoperative or postoperative patients were included. Studies of systems involving communication exclusively between healthcare professionals were excluded. RESULTS: A total of 2,492 unique studies were identified through keyword search. After applying inclusion and exclusion criteria, 15 studies were included in this review. Intervention modalities were SMS (8 studies), mobile application (4), combined SMS and application (1), automated phone call (1), and electronic transmission of pictures to the physician (1). Intervention methods were symptom monitoring (7), patient education (2), protocol adherence reminders (4), and combined symptom monitoring and protocol adherence reminders (2). Both mobile applications and SMS-based interventions increased adherence to medications and protocols and improved clinic attendance. Lower readmission rates and emergency room visits were reported. Satisfaction with automated communication systems was high for both patients and physicians. CONCLUSIONS: Mobile interventions provide a sophisticated yet simple tool to improve perioperative healthcare. Future considerations to address include usage fatigue and Health Insurance Portability and Accountability Act compliance concerns. PMID- 29111888 TI - Stability of DON and DON-3-glucoside during baking as affected by the presence of food additives. AB - The mycotoxin deoxynivalenol (DON) is one of the most common mycotoxins of cereals worldwide, and its occurrence has been widely reported in raw wheat. The free mycotoxin form is not the only route of exposure; modified forms can also be present in cereal products. Deoxynivalenol-3-glucoside (DON-3-glucoside) is a common DON plant conjugate. The mycotoxin concentration could be affected by food processing; here, we studied the stability of DON and DON-3-glucoside during baking of small doughs made from white wheat flour and other ingredients. A range of common food additives and ingredients were added to assess possible interference: ascorbic acid (E300), citric acid (E330), sorbic acid (E200), calcium propionate (E282), lecithin (E322), diacetyltartaric acid esters of fatty acid mono- and diglycerides (E472a), calcium phosphate (E341), disodium diphosphate (E450i), xanthan gum (E415), polydextrose (E1200), sorbitol (E420i), sodium bicarbonate (E500i), wheat gluten and malt flour. The DON content was reduced by 40%, and the DON-3-glucoside concentration increased by >100%, after baking for 20 min at 180 degrees C. This confirmed that DON and DON-3-glucoside concentrations can vary during heating, and DON-3-glucoside could even increase after baking. However, DON and DON-3-glucoside are not affected significantly by the presence of the food additives tested. PMID- 29111889 TI - The Combined Effects of Exercise, Diet, and a Multi-Ingredient Dietary Supplement on Body Composition and Adipokine Changes in Overweight Adults. AB - BACKGROUND: Very few weight and fat loss supplements undergo finished-product research to examine efficacy. The purpose of this study was to determine the effects of an 8-week diet and exercise program on body composition, hip and waist girth, and adipokines and evaluate whether a dietary supplement containing raspberry ketone, capsaicin, caffeine, garlic, and Citrus aurantium enhanced outcomes. METHODS: Overweight men and women completed this randomized, placebo controlled, double-blind study. Participants consumed 4 capsules/d of supplement (EXP; n = 18) or placebo (PLA; n = 18). Participants underwent 8 weeks of daily supplementation, calorie restriction (500 kcal < RMR [resting metabolic rate] * 1.2), and supervised progressive exercise training 3 times a week. Body composition, girth, and adipokines were assessed at baseline and postintervention (T1 and T2). RESULTS: Significant decreases in weight (-2.6 +/- 0.57 kg, p < 0.001), fat mass (-1.8 +/- 0.20 kg; p < 0.001), and percentage body fat (-3.7% +/ 0.29%, p < 0.001) and a significant increase in lean body mass (LBM; 1.5 +/- 0.26 kg; p < 0.001) were seen from T1 to T2 in both groups. For men, only those in the EXP group increased LBM from T1 to T2 (1.3 +/- 0.38 kg; p < 0.05). Hip girth was also reduced, with the women in the EXP group (-10.7 +/- 2.15 cm, p < 0.001) having a greater reduction. There was a time by group interaction, with significant decreases in leptin (p < 0.001) and significant increases in adiponectin (p < 0.05) in the EXP group. CONCLUSIONS: Significant improvements in adipokines and leptin support the utility of exercise, diet, and fat loss for impacting inflammatory biomarkers. The improvement in adiponectin with EXP may suggest a unique health mechanism. PMID- 29111890 TI - Polyethylene glycol-b-poly(lactic acid) polymersomes as vehicles for enzyme replacement therapy. AB - AIM: Polymersomes are created to deliver an enzyme-based therapy to the brain in lysosomal storage disease patients. MATERIALS & METHODS: Polymersomes are formed via the injection method using poly(ethylene glycol)-b-poly(lactic acid) (PEGPLA) and bound to apolipoprotein E, to create a brain-targeted delivery vehicle. RESULTS: Polymersomes have a smallest average diameter of 145 +/- 21 nm and encapsulate beta-galactosidase at 72.0 +/- 12.2% efficiency. PEGPLA polymersomes demonstrate limited release at physiologic pH (7.4), with a burst release at the acidic pH (4.8) of the lysosome. PEGPLA polymersomes facilitate delivery of active beta-galactosidase to an in vitro model of GM1 gangliosidosis. CONCLUSION: The foundation has been laid for testing of PEGPLA polymersomes to deliver enzymatic treatments to the brain in lysosomal storage disorders for the first time. PMID- 29111891 TI - Regenerative medicine in India: trends and challenges in innovation and regulation. AB - The government of India has heavily promoted research and development in regenerative medicine together with domestic innovation and business development initiatives. Together, these promise a revolution in healthcare and public empowerment in India. Several national and transnational linkages have emerged to develop innovative capacity, most prominently in stem cell and cord blood banking, as well as in gene therapy, tissue engineering, biomaterials and 3D printing. However, challenges remain of achieving regulatory oversight, viable outputs and equitable impacts. Governance of private cord blood banking, nanomaterials and 3D bioprinting requires more attention. A robust social contract is also needed in healthcare more generally, so that participation in research and innovation in regenerative medicine is backed up by treatments widely accessible to all. PMID- 29111893 TI - [Psychological Health of Children with Chronic Physical Illness and their Parents - Results from Meta-Analyses]. AB - Psychological Health of Children with Chronic Physical Illness and their Parents Results from Meta-Analyses The present paper summarizes results from meta analyses on psychological well-being of children with chronic physical illnesses and their parents. At the beginning, we discuss potential reasons for psychological effects of a chronic physical illness on children and adolescents as well as their parents. We then summarize results of meta-analyses of studies that compared aspects of mental health of children with a chronic physical illness and their parents with families of healthy children. Depressive symptoms, anxiety, and internalizing symptoms in general were most elevated in children with chronic fatigue syndrome and chronic headache while externalizing symptoms were most elevated in young people with epilepsy, chronic headache, and cerebral palsy. Depression and anxiety was less elevated in the ill children than in their parents. Parents of children with HIV-infection/AIDS and cerebral palsy reported the highest levels of distress, followed by parents of children diagnosed with cancer and spina bifida. Conclusions are drawn for future research and practice. PMID- 29111894 TI - [Healthy Siblings of Children with Autism Spectrum Disorders. A Mixed-methods Pilot Study]. AB - Healthy Siblings of Children with Autism Spectrum Disorders. A Mixed-methods Pilot Study Healthy siblings of chronically ill and/or disabled children may have an increased risk of developing behavioral problems; this is particularly given for siblings of children with Autism Spectrum Disorders (ASD). Quality of life and distress of five siblings (12-15 years) of children with ASD were examined using self- and parent-proxy-reports. Guideline-based interviews were conducted with the siblings and their parents and analyzed according to Mayring. Quality of life described by the children resembled the KINDLR's standardized range of scores, but parents described a decreased quality of life. Both siblings and parents reported low to medium distress. Interviews revealed healthy children are asked by their parents to take responsibility for their siblings with ASD. Parents assumed their healthy children are less affected by the ASD of the sibling. The healthy siblings described being "annoyed" by ASD-associated behavior and partly feeling "treated unfairly". They wished their sibling no longer "suffered" from ASD or behaved "normally". The results of this pilot study, albeit with a small sample, show siblings do experience low to medium burden. This burden is often caused by the sibling relationship or the ASD associated behavior. Suggestions for supporting the healthy siblings are given. PMID- 29111895 TI - [Congress Dates]. PMID- 29111897 TI - [Test Reviews]. PMID- 29111896 TI - [Editorial]. PMID- 29111899 TI - [Authors]. PMID- 29111898 TI - [The Need for Psychosocial Support in Parents of Chronically Ill Children]. AB - The Need for Psychosocial Support in Parents of Chronically Ill Children Chronic illness in childhood and adolescence is associated with special requirements and demands on affected families. In particular, severe chronic diseases and rare diseases with a high level of health care needs or with progressive medical diagnoses permanently challenge the families' resources. The aim of this study was to assess the need for psychological, nursing, legal and organisational support from a parent's perspective. Using qualitative content analysis according to Mayring, data from 96 parents of 68 chronically ill children were evaluated. The findings suggest an increased need for psychosocial support, but, the ideas, needs, and goals of parents are very versatile. However, family-based psychosocial support programs, which are adapted to the specific family situations, are unanimously judged to be useful. Interventions should be flexible as well as tailored to the affected families' individual needs. PMID- 29111900 TI - [Contents]. PMID- 29111901 TI - [Parenting Stress in Mothers of Children with Down Syndrome in Preschool Age]. AB - Parenting Stress in Mothers of Children with Down Syndrome in Preschool Age Research suggests that parenting stress is elevated in parents of children with intellectual disabilities. However, data are inconsistent if this holds true for parents of children with Down syndrome. As part of the Heidelberg Down syndrome study, 52 mothers of children with Down syndrome (mean age: 5 years) completed the German adaptation of the Parenting Stress Index. These results show significantly elevated stress scores in scales measuring demanding and less acceptable behavior of the children (child characteristics). Scores in scales measuring parent characteristics do not differ significantly from the norms. Global stress scores are associated with the degree of behavioral problems (SDQ) and adaptive competence (VABS-II). A regression analysis points to optimism as a dispositional trait of the mother which makes a significant contribution to the prediction of parenting stress scores. The implications for early intervention are discussed. PMID- 29111902 TI - The Effect of Cranberry Juice Consumption on the Recurrence of Urinary Tract Infection: Relationship to Baseline Risk Factors. AB - OBJECTIVE: The objective of this study was to assess relationships between clinical predictors of urinary tract infection (UTI) and effects of cranberry juice consumption on recurrence in a post hoc analysis of a 24-week, randomized, double-blind, placebo-controlled, multicenter clinical trial in women with a recent history of UTI. METHODS: Participants consumed a cranberry (n = 185) or placebo (n = 188) beverage (240 mL) daily. Odds ratios (OR) from 20 candidate predictor variables were evaluated in univariate analyses to assess clinical UTI incidence relationships in the placebo group. A multivariate logistic regression model was developed. The effects of cranberry juice consumption were evaluated in subsets categorized by the likelihood of a UTI event based on the prediction model. RESULTS: In the placebo group, the final multivariate regression model identified four variables associated with the odds for having >= 1 UTI: intercourse frequency >= 1 time during the prior 4 weeks (OR: 2.36; 95% confidence interval [CI]: 0.98, 5.71; p = 0.057), use of vasectomy or hormonal methods for contraception (OR: 2.58; 95% CI: 1.20, 5.58; p = 0.016), most recent UTI < 90 days prior to screening (OR: 2.28; 95% CI; 1.12, 4.67; p = 0.024), and living in France compared with the United States (OR: 0.17; 95% CI: 0.04, 0.79; p = 0.024). Three propensity categories were investigated (24-week probability < 10%, 10%-21%, and > 21%). Incidence rate ratios for the cranberry vs placebo groups were 0.76 (95% CI: 0.22, 2.60; p = 0.663) for those with < 10% probability, 0.73 (95% CI: 0.35, 1.53; p = 0.064) for those with 10% to 21% probability, and 0.58 (95% CI: 0.35, 0.97; p = 0.039) for those with > 21% probability. CONCLUSIONS: Results suggest that clinical predictors identify women with low and high risk of clinical UTI recurrence, which may be useful for design of clinical studies evaluating preventive therapies. PMID- 29111903 TI - Suicide Acceptability and Sexual Orientation: Results from the General Social Survey 2008-2014. AB - Lesbian, gay, and bisexual (LGB) individuals have higher prevalence of lifetime suicide ideation and attempt than their heterosexual peers, but less is known about differences in suicide acceptability (i.e., believing suicide is a viable answer to a problem). The purpose of this study was to examine if LGB adults had greater suicide acceptability than heterosexual adults. A total of 4 items in the General Social Surveys from 2008 to 2014 assessed whether a nationally representative sample of U.S. adult respondents (n = 5,037) thought it acceptable for individuals to kill themselves if one: goes bankrupt, dishonors their family, is tired of living, or has an incurable disease. Multiple logistic regression analyses were used to assess the association of sexual orientation with suicide acceptability items after adjusting for confounding factors. Compared with heterosexuals, lesbians/gays had higher odds of reporting suicide acceptability if one goes bankrupt (OR = 1.92; 95% CI: 1.06, 3.46), dishonors family (OR = 1.83; 95% CI: 1.01, 3.28), or is tired of living (OR = 2.25; 95% CI: 1.30, 3.90). Bisexual and heterosexual groups were largely similar across the 4 suicide acceptability items. No sexual orientation differences were observed for reporting acceptability of suicide in the instance of an incurable disease. Post hoc analyses revealed significant interactions between sex and sexual orientation, such that differences in suicide acceptability seemed to be driven by sexual minority women rather than by sexual minority men. Suicide acceptability differs by sexual orientation, and community-level interventions around changing norms about suicide may be a prevention strategy for sexual minority individuals. PMID- 29111904 TI - Optimization and characterization of the formation of oil-in-water diazinon nanoemulsions: Modeling and influence of the oil phase, surfactant and sonication. AB - Nanoemulsions are particularly suitable as a platform in the development of delivery systems for lipophilic functional agents. Current research describes the formation of oil-in-water (O/W) diazinon nanoemulsions using synthetic and natural additives by adopting a high-energy (ultrasound) emulsification method. The diazinon nanoemulsions were spontaneously formed by adding dropwise a mixture of diazinon, solvent and co-solvent in an aqueous solution containing a surfactant (tween or lecithin) with continuous stirring. The nanoemulsions were then formed by ultra-sonication. The effects of three levels of active ingredient, solvent, co-solvent, surfactant, sonication time and sonication cycle and power were performed by Minitab software to design the experiment. Effects of these factors on droplet size, polydispersity index (PDI), viscosity and pH of nanoemulsions were investigated. The results of the modeling showed that the experimental data could be adequately adapted in a second-order polynomial model with a multiple regression coefficient r2 of 0.821 for the prediction of particle size, PDI and viscosity. The long-term and thermodynamic stability of the prepared nanoemulsions were tested. The droplet size and morphology of the nanoemulsions were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). On this basis, a water-insoluble insecticide diazinon was incorporated into 26 optimized nanoemulsion systems to demonstrate potential applications in pest control. The results of DLS and TEM measurements showed that most of prepared nanoemulsions had an almost monodisperse droplet size distribution (PDI < 200 nm). Incorporation of diazinon had no significant effect on the size and stability of the nanoemulsions and the formulated nanoemulsion remained stable after four months of storage. PMID- 29111905 TI - The Effects of Coenzyme Q10 Supplementation on Glucose Metabolism, Lipid Profiles, Inflammation, and Oxidative Stress in Patients With Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVE: Data on the effects of coenzyme Q10 (CoQ10) supplementation on glucose metabolism, lipid profiles, inflammation, and oxidative stress in subjects with diabetic nephropathy (DN) are scarce. This research was done to determine the effects of CoQ10 supplementation on metabolic status in subjects with DN. METHODS: This randomized double-blind placebo-controlled clinical trial was done in 50 subjects with DN. Participants were randomly assigned into two groups to intake either 100 mg/day CoQ10 supplements (n = 25) or placebo (n = 25) for 12 weeks. Fasting blood samples were obtained at first and after 12-week intervention to quantify metabolic profiles. RESULTS: After 12 weeks of treatment, compared with the placebo, CoQ10 supplementation resulted in significant decreases in serum insulin levels (-3.4 +/- 6.8 vs +0.8 +/- 6.4 uIU/mL, p = 0.02), homeostasis model of assessment-estimated insulin resistance ( 1.0 +/- 2.0 vs +0.2 +/- 1.8, p = 0.03), homeostasis model of assessment-estimated B cell function (-12.3 +/- 26.3 vs +3.5 +/- 23.1, p = 0.02) and HbA1c (-1.1 +/- 1.0 vs -0.1 +/- 0.2%, p < 0.001), and a significant improvement in quantitative insulin sensitivity check index (+0.009 +/- 0.01 vs -0.006 +/- 0.01, p = 0.01). In addition, CoQ10 supplementation significantly decreased plasma malondialdehyde (MDA) (-0.6 +/- 0.5 vs +0.5 +/- 1.0 umol/L, p < 0.001) and advanced glycation end products levels (AGEs) (-316.4 +/- 380.9 vs +318.6 +/- 732.0 AU, p < 0.001) compared with the placebo. Supplementation with CoQ10had no significant impacts on fasting plasma glucose (FPG), lipid profiles, and matrix metalloproteinase-2 (MMP-2) compared with the placebo. CONCLUSIONS: Taken together, our study demonstrated that CoQ10 supplementation for 12 weeks among DN patients had favorable effects on glucose metabolism, MDA, and AGEs levels, but unchanged FPG, lipid profiles, and MMP-2 concentrations. PMID- 29111906 TI - Types of Smokers Who Seek Smoking Cessation Treatment According to Psychopathology. AB - : Psychopathology and psychological distress have been shown to be related to poor smoking cessation outcomes and abstinence maintenance. Thus, it is important to identify individuals with high levels of psychopathology before undergoing smoking cessation treatment in order to increase their likelihood of success. OBJECTIVE: The primary aim of the present study was to analyze whether we could classify smokers by using self-reported measures of psychopathology. In addition, a secondary aim was to examine if there were significant differences among the groups of smokers regarding sociodemographic information, nicotine dependence, and cessation rates at the end of treatment and at 6- and 12-month follow-ups. METHODS: Participants were 281 smokers seeking smoking cessation treatment. Participants were classified into different smoking groups by using a 2-step cluster analysis based on baseline scores on the Restructured Clinical (RC) scales of the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF), Beck Depression Inventory-II (BDI-II), and State-Trait Anxiety Inventory (STAI). RESULTS: Smokers were classified into 3 groups according to levels of psychopathology: Low (n = 158), Intermediate (n = 78), and High (n = 45). Smokers in the High Group were more likely to present higher levels of psychopathology and to continue smoking at the end of treatment when compared with the two other clusters. In addition, smokers classified in this group were more likely to be nicotine dependent and from a low social class. CONCLUSIONS: A subgroup of smokers can be easily identified through self-report measures of psychopathology. Furthermore, these individuals were more likely to continue smoking at the end of treatment. This suggests that this group with high levels of psychopathology might benefit from future interventions that are more intensive or cessation treatments targeted to their specific characteristics. PMID- 29111907 TI - Bioelectrical Impedance Vector Analysis in Healthy Term Infants in the First Three Months of Life in Brazil. AB - OBJECTIVE: Bioelectrical impedance vectorial analysis (BIVA) can be considered a favorable method for evaluation and monitoring of nutritional and hydration status without assumptions regarding body composition or requirement of prediction formulas. The present study aimed to determine bivariate tolerance intervals of the whole-body impedance vector for healthy term infants aged 1 to 3 months. METHODS: This is a descriptive cross-sectional study. Anthropometric and bioelectrical impedance data (800 mA-50 kHz) were obtained. Bivariate vector analysis was conducted with the resistance-reactance (RXc) graph method. BIVA software was used to construct the graphs. RESULTS: A total of 150 appropriate for gestational age infants (48.7% boys) who were exclusively breastfed and were 56.4 (SD = 23.1) days of age were studied. RXc tolerance ellipses (50, 75, and 95%) were constructed for boys and girls, but a general reference graph was defined for all infants considering the overlapping of ellipses between the genders. All graphs differed from those in national and foreign studies. CONCLUSION: New reference tolerance ellipses (95, 75, and 50%) for 1- to 3-month old infants were constructed, pointing out the need for specific reference values of total body impedance vectors in different regions of Brazil. The RXc tolerance ellipses can be used for clinical practice and provide an easy method to evaluate and monitor body composition and hydration status. PMID- 29111908 TI - Misuse of antenatal care and its association with adverse outcomes of pregnancy in a Southern rural area of Vietnam. AB - Researchers in Vietnam reported a high percentage of pregnant women attending ANC at least once, but an insufficient utilization of ANC services remains. The evidence demonstrating how the utilization of these services affect pregnancy outcome is not documented in Vietnam. We investigated the association between the misuse of ANC services and pregnancy outcome, and assessed other determinants associated with ANC services utilization. We conducted a prospective community based study in Trang Bom district, Dong Nai, during 12 consecutive months. Data were collected using a structured questionnaire and medical records. Women were followed up to delivery. Misuse of ANC services, related factors and its association with adverse events were assessed using logistic regression. Out of 3301 pregnant women, 91% initiated an ANC visit within first trimester, 95% attended at least three ANC visits, but a low percentage of pregnant women underwent blood and urine tests at least once (20% and 39%, respectively). Factors significantly associated with a higher risk of adverse outcomes were lack of blood test and urine test, parity >= 3, ANC visits < 3, history of an adverse outcome, and having a clinical condition. Blood and urine tests were less frequently used by young women, women from ethnic minorities, women using only private facilities for ANC attendance, and women with a low number of ANC visits. Despite a high percentage of early entry into ANC and of at least three ANC visits, misuse of ANC services still exists and contributes to adverse outcomes. There is a need to increase the awareness of women on the benefits of ANC services by educating young women as well as women with several children. Health workers should be encouraged to propose suitable ANC services to pregnant women. PMID- 29111909 TI - Women's reproductive decision making and abortion experiences in Cape Town, South Africa: A qualitative study. AB - Unintended pregnancy is a significant public health issue in South Africa. Despite free services including contraception, women face structural and institutional barriers to accessing care. This qualitative study comprised interviews with 16 women aged 18 to 40 years and receiving post-abortion services at a public clinic in Cape Town. Data analysis revealed three main themes: personal journeys in seeking abortion, contraceptive experiences, and contrasting feelings of empowerment (in reproductive decision making) and disempowerment (in the health care system). Women perceived themselves as solely responsible for their reproductive health, but found it difficult to obtain adequate information or services. PMID- 29111911 TI - Trends in long-acting reversible contraceptive (LARC) use, LARC use predictors, and dual-method use among a national sample of college women. AB - OBJECTIVE: Assess long-acting reversible contraceptive (LARC) and other contraceptive use trends, identify LARC use predictors, and examine dual method use. PARTICIPANTS: Women in the American College Health Association-National College Health Assessment (ACHA-NCHA) II, aged 18-24 years, who reported having vaginal sex (N = 37,899). METHODS: Secondary analyses of Fall 2011-2014 ACHA-NCHA II data. RESULTS: Statistically significant increases in LARC usage and, specifically, implant usage, were found. Characteristics associated with LARC use included age, race/ethnicity, relationship status, and school type. Students reporting LARC use had lower odds of condom usage compared with non-LARC hormonal method users. CONCLUSION: This analysis of LARC predictors and dual LARC/condom use has implications for research and health promotion efforts. Findings suggest that college health services are well positioned to meet the sexual and reproductive health needs of diverse populations of students. College health professionals should elicit students' individual and/or relationship priorities to tailor messaging/services offered for pregnancy/STI prevention. PMID- 29111912 TI - Special focus issue on regenerative medicine in society: interdisciplinary perspectives (part II) - Foreword. PMID- 29111913 TI - Mental Health Symptomatology and Exposure to Non-Fatal Suicidal Behavior: Factors That Predict Vulnerability and Resilience Among College Students. AB - Despite efforts to identify risk factors following exposure to completed suicide, research has paid less attention to the associations between exposure to non fatal suicide behavior (NFSB) and mental health symptomatology-factors that may underlie one's susceptibility to future suicidal thoughts and behaviors. This study examined differences in mental health symptomatology among 192 college students exposed to NFSB and 202 exposed to general stressors. Results indicated that students exposed to NFSB had significantly higher levels of depression and anxiety compared to those exposed to a variety of other stressors but not NFSB. Furthermore, among those exposed, a number of risk and protective factors emerged in relation to psychological sequelae, such as emotional stability, social support, and the quality of the relationship between the exposed and suicidal individual. These findings highlight the importance of enhancing provisions of support for those exposed to NFSB. PMID- 29111914 TI - Incidence of osteonecrosis of the jaw (ONJ) in cancer patients with bone metastases treated with bisphosphonates and/or denosumab: some comments and questions. PMID- 29111915 TI - Effects of Egg Consumption on Blood Lipids: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. AB - BACKGROUND: It is widely agreed that egg consumption only modestly influences serum lipid concentrations. However, there is no meta-analysis summarizing existing randomized controlled trials. OBJECTIVE: The purpose of this study was to conduct a meta-analysis of published randomized controlled trials to explore the quantitative effect of egg consumption on serum lipid concentrations. DESIGN: Online databases including MEDLINE, Proquest and Google Scholar were systematically searched. Studies that were published after 2000 and compared serum lipids concentrations in egg-consumers and non egg-consumers were included. The data were obtained from 28 studies. Weighted mean differences were calculated as the ultimate effect using random effects model. RESULTS: Overall, egg consumption increased total cholesterol (TC) by 5.60 mg/dL (95% CI: 3.11, 8.09; P<0.0001), low density lipoprotein-cholesterol (LDL-C) by 5.55 mg/dL (95% CI: 3.14, 7.69; P<0.0001) and high density lipoprotein-cholesterol (HDL-C) by 2.13 mg/dL (95% CI: 1.10, 3.16; P<0.0001) compared with the control group. Heterogeneity found between studies was explained partly by study design and participant response to dietary cholesterol. No effect of increased egg consumption on LDL-C:HDL-C and TC:HDL-C ratios, and triglyceride (TG) concentrations were found. No association was observed between number of eggs consumed per day or study duration and any of the serum lipid markers. CONCLUSION: Consumption of egg increases total cholesterol, LDL-C and HDL-C, but not LDL-C:HDL-C, TC:HDL-C and TG compared with low egg control diets. To assess the risk of coronary events, future studies should focus on the postprandial effect of egg consumption and effects on coronary risk. PMID- 29111917 TI - The Journal of Gerontological Social Work's last issue of 2017. PMID- 29111919 TI - Improving prenatal care in pregnant women in Iranshahr, Iran: Applying Health Belief Model. AB - PURPOSE: To determine the effect of an education-based intervention on receiving adequate prenatal care. METHODS: This randomized, controlled trial was conducted on 90 primiparous pregnant women, referred in Iranshahr, Iran for prenatal care (intervention = 45, control group = 45). The data were collected from February to June 2016 using a questionnaire developed based on the Health Belief Model (HBM). The intervention group received three intervention sessions during the second trimester of pregnancy, and 3 months after intervention, both groups completed a questionnaire. Data were analyzed using independent sample t-tests, chi-squared tests, paired t-test, Pearson and multivariate regression. FINDINGS: Unlike the control group, in the intervention group's mean scores for knowledge, variables from the HBM model and frequency of prenatal care significantly differed from pre to post-intervention (pre-intervention mean = 12.62 +/- 2.63, post-intervention mean = 17.71 +/- 1.56, (p ? 0.05). Self-efficacy was positively correlated with knowledge (r = 0.304, p = 0.02) and adequate prenatal care (r = 0.583, p ? 0.001). The constructs of the HBM explained 75% of the variance in frequency of prenatal care in multivariable models. CONCLUSIONS: Developing an educational program based on the HBM was effective in the adoptation of prenatal care. Additionally, considering social, economic, and educational follow-up while implementing these programs is recommended. PMID- 29111920 TI - Unwanted pregnancy, pregnancy loss, and other risk factors for intimate partner violence in the Democratic Republic of the Congo. AB - The Democratic Republic of the Congo (DRC) has one of the highest rates of violence against women in the world; however, few studies have focused on this issue. In this study, we assessed the interrelationship among intimate partner violence (IPV), unintended pregnancy, pregnancy loss, and other sociodemographic factors in the DRC. Our analyses were based on data from the DRC demographic and health survey, conducted from November 2013 to February 2014. We constructed generalized estimating equation models to analyze the data from a sample of 5,120 married women. Our results showed that having a husband or partner who exhibited controlling behaviors, women who justified wife-beating, having a mother who had experienced IPV, and having a husband or partner who consumed alcohol were positively associated with IPV, whereas decision-making autonomy among women was negatively associated with IPV. In the community, the proportion of women who had experienced IPV and that of those who had completed secondary or higher education were positively and negatively associated with any IPV type, respectively. In addition, emotional IPV and any IPV type were positively associated with pregnancy loss. Our results indicate the necessity of implementing programs targeting gender equality at both individual and community levels. PMID- 29111922 TI - Courses and workshops offered by the Air & Waste Management Association. PMID- 29111921 TI - Charles W. Gruber, 1910-2001. PMID- 29111923 TI - The Rescinding of DACA: What Should Healthcare Professionals and Academics Do? (and Why?). PMID- 29111924 TI - Harm and Parental Permission: A Response to Our Critics. PMID- 29111925 TI - To Whom Do Children Belong? PMID- 29111926 TI - Informed Consent Is Inadequate and Shared Decision Making Is Ineffective: Arguing for the Primacy of Authenticity in Decision-Making Paradigms. PMID- 29111927 TI - Children Are Not the Property of Their Parents: The Need for a Clear Statement of Ethical Obligations and Boundaries. PMID- 29111928 TI - Health Communication: Not Just Autonomy, Also Justice. PMID- 29111929 TI - Autonomy, Information, and Paternalism in Clinical Communication. PMID- 29111930 TI - Expanding Parental Permission in Pediatric Treatment: A Hasty Generalization. PMID- 29111931 TI - Parental Permission in the Context of Family-Centered Care. PMID- 29111932 TI - Extending Ethical Strides: From Tribal IRBs to the Bronx Community Research Review Board. PMID- 29111933 TI - A Dose of Paternalism: How Eliciting Values, Not Amplifying Parental Permission, Can Promote the Interest of Children and Families. PMID- 29111934 TI - Review of J. L. Schwartz and A. L. Caplan, eds., Vaccination Ethics and Policy. PMID- 29111935 TI - Communication Education, Modeling, and Protocols Transform Clinicians to Agents of Empowerment. PMID- 29111937 TI - Minimizing the Child's Interests by Focus on Parental Values and Identities. PMID- 29111936 TI - Empowerment Failure: How Shortcomings in Physician Communication Unwittingly Undermine Patient Autonomy. AB - Many health care decisions depend not only upon medical facts, but also on value judgments-patient goals and preferences. Until recent decades, patients relied on doctors to tell them what to do. Then ethicists and others convinced clinicians to adopt a paradigm shift in medical practice, to recognize patient autonomy, by orienting decision making toward the unique goals of individual patients. Unfortunately, current medical practice often falls short of empowering patients. In this article, we reflect on whether the current state of medical decision making effectively promotes patients' health care goals. We base our reflections, in part, on research in which we observed physicians making earnest efforts to partner with patients in making treatment decisions, but still struggling to empower patients-failing to communicate clearly to patients about decision relevant information, overwhelming patients with irrelevant information, overlooking when patients' emotions made it hard to engage in choices, and making recommendations before discussing patients' goals. PMID- 29111938 TI - Review of Calvin Wai-Loon Ho, Juridification in Bioethics: Governance of Human Pluripotent Cell Research. PMID- 29111939 TI - Sowing the SEED for Patient Empowerment. PMID- 29111940 TI - Medical Culture's Bias to Actively Intervene Can Undermine Patient Empowerment and Welfare. PMID- 29111941 TI - Reasons to Amplify the Role of Parental Permission in Pediatric Treatment. AB - Two new documents from the Committee on Bioethics of the American Academy of Pediatrics (AAP) expand the terrain for parental decision making, suggesting that pediatricians may override only those parental requests that cross a harm threshold. These new documents introduce a broader set of considerations in favor of parental authority in pediatric care than previous AAP documents have embraced. While we find this to be a positive move, we argue that the 2016 AAP positions actually understate the importance of informed and voluntary parental involvement in pediatric decision making. This article provides a more expansive account of the value of parental permission. In particular, we suggest that an expansive role for parental permission may (1) reveal facts and values relevant to their child's treatment, (2) encourage resistance to suboptimal default practices, (3) improve adherence to treatment, (4) nurture children's autonomy, and (5) promote the interests of other family members. PMID- 29111942 TI - Can Families Have Interests? PMID- 29111943 TI - Integrating Informed Nondissent Into Informed Consent Standards. PMID- 29111944 TI - Thwarting Shared Decision Making Is an Egregious Medical Error: Let's Treat It Like One. PMID- 29111945 TI - Permission to Speak? Voices in Pediatric Decision Making. PMID- 29111946 TI - Needed: A More Rigorous Analysis of Models of Decision Making and a Richer Account of Respect for Autonomy. PMID- 29111947 TI - Clearing the air: American Indian tribal college students' exposure to second hand smoke & attitudes towards smoke free campus policies. AB - OBJECTIVE: The purpose of this study was to examine knowledge, awareness, and support for campus smoke-free policies. PARTICIPANTS: 1,256 American Indian tribal college students from three tribal colleges in the Midwest and Northern Plains. METHODS: Data are from an observational cross-sectional study of American Indian tribal college students, collected through a web-based survey. RESULTS: Only 40% of tribal college students reported not being exposed to second hand smoke in the past 7 days. A majority of nonsmokers (66%) agreed or strongly agreed with having a smoke-free campus, while 34.2% of smokers also agreed or strongly agreed. Overall, more than a third (36.6%) of tribal college students were not aware of their campus smoking policies. CONCLUSIONS: Tribal campuses serving American Indian students have been much slower in adopting smoke-free campus policies. Our findings show that tribal college students would support a smoke-free campus policy. PMID- 29111948 TI - Editorial Policy and Manuscript Preparation Guidelines. PMID- 29111949 TI - A&WMA Annual Conference Preview: 2003 Critical Review to Cover Co2 Emissions and Global Warming. PMID- 29111951 TI - Editorial Policies and Submittal Instructions. PMID- 29111950 TI - Methods for coping with premenstrual change: Development and validation of the German Premenstrual Change Coping Inventory. AB - During the premenstrual phase, psychological and physiological changes can occur, which are associated with different levels of disability. When they appear with Premenstrual Dysphoric Disorder (PMDD), different coping strategies may be used by women to deal with premenstrual changes. Currently no German measure exists for assessing premenstrual symptom-related coping strategies. Therefore, we developed the Premenstrual Change Coping Inventory (PMS-Cope). First, the 33-item questionnaire was tested with an exploratory factor analytic approach (EFA) in a sample of 150 women prospectively diagnosed with PMDD or severe Premenstrual Syndrome from August 2013 until March 2016. The EFA resulted in a 12-item scale with a two-factor structure: "seeking positive affect-inducing activities" and "seeking support"; Cronbach's alpha of 0.73 and 0.71, respectively, demonstrated good reliability for both factors. Confirmatory factor analysis based on a second sample of 89 women conducted from May 2016 until June 2016 confirmed the two factor structure. Additionally, a potential third factor "healthcare use behavior" was tested with an EFA. For the three-factor solution, satisfactory Cronbach's alpha values (0.70-0.72) were detected. The PMS-Cope was shown to be a valid, reliable, and economic measure. In future research, cross validations and confirmatory factor analyses with the three-factor solution should be conducted. PMID- 29111952 TI - Introduction: Clinical and Community Practice with Deaf and Hard of Hearing People. PMID- 29111953 TI - Gender and geographic differences in Medicare service utilization during the last six months of life. AB - End-of-life issues are important for senior women, particularly rural women, who are more likely than their urban counterparts to live alone. The role of residence as a factor for health-care utilization among Medicare beneficiaries during the last six months of life has yet to be investigated. The purpose of this study is to examine whether service utilization in the last six months of life differs across gender and rurality. The sample was restricted to fee-for service Medicare beneficiaries who died between July 1, 2013, and December 31, 2013 (n = 39,508). The odds of rural beneficiaries using home health (aOR 0.87; 95% CI 0.81-0.93) and/or hospice (aOR 0.82; 95% CI 0.77-0.87) in the last six months of life were lower than urban beneficiaries. Female beneficiaries were more likely to use support services such as hospice (aOR 1.24; 95% CI 1.18-1.29) and/or home health services (aOR 1.07; 95% CI 1.02-1.13) than male beneficiaries. The odds of female beneficiaries using inpatient (aOR 1.14; 95% CI 1.08-1.20) and/or outpatient (aOR 1.06; 95% CI 1.01-1.12) were higher than male beneficiaries. This research is important as we examine the range of health services used during the last six months of life, by gender and rurality. Future research is needed to understand how access to health services, residential isolation, and age- and disease-related factors relate to women's observed greater use of inpatient, outpatient, hospice, and home health services in the last six months of life. PMID- 29111954 TI - Working with Stories: Street-Level Bureaucrats and Their Work with Individuals with Psychiatric Disability Exposed to Interpersonal Violence. AB - The focus of our attention is the meeting between street-level bureaucrats and individuals with psychiatric disability exposed to interpersonal violence. Based on 11 interviews, we illustrate how stories are understood, used, and made meaningful to the street-level bureaucrat. The contribution of this article is first of all that of being a framework, from a storytelling point of view, for the work and organizational experiences of street-level bureaucrats. Second, by paying attention to the story part of these relationships, we can better understand the situation of individuals with psychiatric disability exposed to interpersonal violence given their interaction with different street-level bureaucrats. PMID- 29111955 TI - Assessment of Integration of Disability Content into Social Work Education. AB - Three hundred members of the Council on Social Work Education (CSWE) responded to a survey regarding the inclusion of disability content in social work courses and supports needed to increase disability content. Although respondents generally agreed that disability content is important in social work education, its inclusion is inconsistent, with most frequent inclusion in courses on diversity and least frequent inclusion in courses on research. Respondents identified barriers to increasing disability content, including lack of resources for teaching, lack of relevant faculty expertise, and an overcrowded curriculum. Strategies and resources for infusing disability content into social work education are discussed. PMID- 29111956 TI - Childhood disadvantages and the timing of the onset of natural menopause in Latin America and the Caribbean. AB - The aim of this study is to investigate the association of early life factors with the timing of the onset of natural menopause in Costa Rica and Puerto Rico. We use Cox proportional hazard models to estimate the risk of the onset of menopause. Our results suggest that socioeconomic disadvantages, as expressed by difficulties attending school due to economic hardships or parents never living together, increase the risk of the onset of natural menopause among Puerto Rican women. Among Costa Rican women, early life nutrition, estimated using anthropometric measures, is related to the timing of the onset of natural menopause. PMID- 29111957 TI - Correlates of Voting Participation of People with Intellectual and Developmental Disabilities. AB - People with intellectual and developmental disabilities (IDD) vote less frequently than nondisabled people and people with other disabilities. This study explores what factors facilitate and hinder people with IDD's voting participation. To do so, 1,341 people with IDD were surveyed using the Personal Outcome Measures(r). Binary logistic regressions revealed significant relationships between voting participation, and support needs, residence types, guardianship statuses, and organizational supports. Along with the right supports, attention to barriers that might exist can ensure people with IDD are able to make use of their civil rights and participate in this crucial form of civic engagement. PMID- 29111958 TI - The effects of a community-based intervention on women's knowledge and attitudes about safe abortion in intervention and comparison towns in Oromia, Ethiopia. AB - The aim of this post-intervention assessment was to measure the effects of community intervention on the knowledge and attitudes of women regarding safe abortion in Ethiopia. In 2014, following implementation of an educational intervention on sexual and reproductive health from December 2012 to December 2013, 800 women were interviewed about their knowledge, attitudes, and practices regarding abortion. Multivariate regression analyses of respondents' demographics, sources of abortion information, knowledge, and attitudes about safe abortion were conducted. More women in the intervention community knew safe abortion was available in the community (76 percent vs. 57 percent; p < 0.001). Women in the intervention community had greater odds of feeling that women should have access to safe abortion services (adjusted odds ratio [aOR]: 1.55, 95 percent confidence interval [CI]: 1.06, 2.28) after adjusting for socio demographic characteristics. They had significantly greater odds of feeling comfortable and confident talking to a healthcare provider (aOR: 2.44, 95 percent CI: 1.55, 3.84) and/or her partner (aOR: 2.47, 95 percent CI: 1.58, 3.85) about abortion. Increased mobilization of community networks in disseminating sexual health and abortion information was followed by increased knowledge of abortion services in the intervention community and improved reproductive choices for women. PMID- 29111960 TI - The aspirin in reducing events in the elderly trial: Statistical analysis plan. AB - Rationale Aspirin has positive and negative effects on a number of age-related chronic conditions and there is uncertainty regarding its role in primary prevention in people aged 70 years and over. Aims To assess whether daily active treatment of 100 mg enteric-coated aspirin will extend the duration of disability free life in healthy older participants. Design A double-blind, randomized, placebo-controlled primary prevention trial undertaken in Australia and the United States with careful adjudication of endpoints including stroke. Study outcome In Australia 16,703 individuals were recruited through general practices across five states and territories, and in the United States, 2411 participants were recruited through 34 clinical sites across the country. Follow-up of participants will finish at the end of 2017 with average follow-up exceeding 4.25 years per person. Discussion The statistical analysis plan for ASPREE, finalized after closure of recruitment but before the end of patient follow-up, outlines the primary analyses and a range of subgroup and sensitivity analyses. (International Standard Randomized Controlled Trial Number Register ISRCTN83772183 and clinicaltrials.gov Number NCT01038583). PMID- 29111961 TI - Factors That May Influence Parent Treatment Decision Making for Young Children with Autism Spectrum Disorder. AB - The number of interventions available for children with autism spectrum disorder (ASD) has expanded greatly in recent years, although relatively little is known about the factors that influence family caregivers as they make treatment decisions for their children. This study involved a statewide survey of parents of young children with ASD to examine the relative weights of the factors that influenced their treatment decisions. Results suggested that caregivers rely on their own intuition for much decision making, although selected professionals are also influential. Implications for professionals working with children with ASD and their families are discussed. PMID- 29111962 TI - Age-specific factors related to institutional delivery in Nigeria: Insights from the 2011 Multiple Indicator Cluster Survey. AB - With 814 maternal deaths per 100,000 live births, maternal mortality remains a significant public health problem in Nigeria. We examined associations between maternal age and institutional delivery among 9,485 women, using data from the 2011 Nigeria Multiple Indicator Cluster Survey. We used multiple logistic regression to identify enabling factors and barriers to institutional delivery. Older maternal age was positively associated with institutional delivery. In age stratified, adjusted analyses, secondary/higher education and living in wealthy households were consistently associated with increased odds of institutional delivery among the youngest (15-19 years) and the oldest (40-49 years) women. Higher parity was associated with significantly reduced odds of institutional delivery among women <40 years, but was not associated among women aged 40-49 years. Among women of 40-49 years, attending at least four antenatal care (ANC) visits was associated with increased odds of institutional delivery; among women of ages 15-19 years, the association was not significant. Similarly, having a skilled ANC provider was not significantly associated with institutional delivery among women aged 15-19 and 40-49 years. These findings suggest that women at the highest risk for maternal death may face barriers to institutional delivery services. Focused policies and programs are needed to address women's reproductive health vulnerabilities. PMID- 29111963 TI - Endophytic fungal production rates of volatile organic compounds are highest under microaerophilic conditions. AB - Volatile organic compound (VOC) production from an endophytic fungus was quantified at four oxygen concentrations (0, 1, 13 and 21 %) throughout culture growth phases. The filamentous fungus, a Nodulisporium sp. (designated TI-13), was grown in a solid-state reactor with an agricultural byproduct, beet pulp, as the solid substrate. The VOCs, with potential applications as biofuels, natural flavour compounds and bioactive mixtures, were measured with a recently introduced platinum catalyst and proton transfer reaction mass spectrometry quantification system. The highest-specific production rates of carbon number four and higher VOCs were observed under microaerophilic conditions, which is the expected environment within the plant host. Specific production rates of two ester compounds increased by at least 19 times under microaerophilic conditions compared with those under any other oxygen concentration studied. Total VOC production, including small molecules such as ethanol and acetaldehyde, increased by 23 times when compared between aerobic and anoxic conditions, predominately due to increased production of ethanol. Additionally, total specific production for all 21 compounds quantified was highest under reduced oxygen conditions. PMID- 29111964 TI - A phylogenetic and evolutionary analysis of antimycin biosynthesis. AB - Streptomyces species and other Actinobacteria are ubiquitous in diverse environments worldwide and are the source of, or inspiration for, the majority of antibiotics. The genomic era has enhanced biosynthetic understanding of these valuable chemical entities and has also provided a window into the diversity and distribution of natural product biosynthetic gene clusters. Antimycin is an inhibitor of mitochondrial cytochrome c reductase and more recently was shown to inhibit Bcl-2/Bcl-XL-related anti-apoptotic proteins commonly overproduced by cancerous cells. Here we identify 73 putative antimycin biosynthetic gene clusters (BGCs) in publicly available genome sequences of Actinobacteria and classify them based on the presence or absence of cluster-situated genes antP and antQ, which encode a kynureninase and a phosphopantetheinyl transferase (PPTase), respectively. The majority of BGCs possess either both antP and antQ (L-form) or neither (S-form), while a minority of them lack either antP or antQ (IQ- or IP form, respectively). We also evaluate the biogeographical distribution and phylogenetic relationships of antimycin producers and BGCs. We show that antimycin BGCs occur on five of the seven continents and are frequently isolated from plants and other higher organisms. We also provide evidence for two distinct phylogenetic clades of antimycin producers and gene clusters, which delineate S form from L- and I-form BGCs. Finally, our findings suggest that the ancestral antimycin producer harboured an L-form gene cluster which was primarily propagated by vertical transmission and subsequently diversified into S-, IQ- and IP-form biosynthetic pathways. PMID- 29111965 TI - Flavobacterium commune sp. nov., isolated from freshwater and emended description of Flavobacterium seoulense. AB - A Gram-stain-negative, yellow, facultatively-anaerobic, short, rod-shaped, non spore-forming bacterium, designated PK15T, was isolated from freshwater. Growth was observed at 4-40 degrees C (optimum, 30 degrees C), pH 6-9 (optimum, 8), and in the presence of 0-0.8 % (w/v) NaCl (optimum, 0.4 %). Strain PK15T exhibited both catalase and oxidase activities and was able to reduce nitrate. On the basis of 16S rRNA gene sequence similarities, strain PK15T was shown to belong to the genus Flavobacterium with close similarities to Flavobacterium palustre S44T (97.9 %) and Flavobacterium seoulense EM1321T (97.7 %). Menaquinone 6 (MK-6) was the major respiratory quinone, while the G+C content of the genomic DNA was 35.5 (+/-0.9) mol%. The major polar lipids were phosphatidylethanolamine, three unidentified aminolipids, one unidentified aminophospholipid and three unidentified polar lipids. The predominant cellular fatty acids (>=10 %) were anteiso-C15 : 0 (17.3 %), a summed feature comprising C16 : 1omega7c and/or C16 : 1omega6c (15.1 %) and iso-C15 : 0 (10.0 %). Chemotaxonomic data supported the affiliation of strain PK15T to the genus Flavobacterium. The results of physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain PK15T from strains of closely related species. It was, therefore, evident that PK15T represents a novel species of the genus Flavobacterium, for which the name Flavobacterium commune sp. nov. is proposed with strain PK15T (=KCTC 52562T=JCM 32115T) as the type strain. Based on the results of the chemotaxonomic characterization in the present study, an emended description of Flavobacterium seoulense is also proposed. PMID- 29111966 TI - Bacillus populi sp. nov. isolated from Populus euphratica rhizosphere soil of the Taklamakan desert. AB - A rod-shaped, endospore-forming, aerobic bacterium, designated FJAT-45347T, was isolated from rhizosphere soil collected from the Taklamakan desert in Xinjiang (PR China). Growth was observed at 15-35 degrees C (optimum 25 degrees C), in 0 % and 20.0 % NaCl (optimum 8.0 %) and at pH 7.5-12.0 (optimum 8.0), respectively. The cell-wall peptidoglycan contained meso-diaminopimelic acid and the isoprenoid quinone was MK-7. The main fatty acids were iso-C15 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Phylogenetic analysis based on 16S rRNA gene sequences affiliated FJAT-45347T to the genus Bacillus, and it showed the highest sequence similarities to Bacillus clarkii DSM 8720T (96.1 %). The average nucleotide identity and in silico DNA-DNA hybridization values between FJAT-45347T and the most closely related species were 68.5 and 26.2 %, respectively, which were lower than the thresholds commonly used to define species (96 and 70 %, respectively), indicating that it represented a member of a different taxon. The DNA G+C content was 40.6 mol%. The phenotypic characters and taxono-genomics study revealed that FJAT-45347T represents a novel species of the genus Bacillus, for which the name Bacilluspopuli sp. nov. is proposed. The type strain is FJAT-45347T (=DSM 104632T=CCTCC AB 2016257T). PMID- 29111968 TI - Melaminivora jejuensis sp. nov., isolated from Swinery waste. AB - A sulfur-oxidizing bacterium, designated strain KBB12T, was isolated from swinery waste collected in Jeju, Republic of Korea. The cells were Gram-stain-negative, flagellated and rod-shaped. Growth occurred at 15-45 degrees C (optimum, 30-37 degrees C), at pH 6-9 (optimum, pH 7.0) and in the presence of 0-1 % (w/v) NaCl. The major cellular fatty acids were summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1 omega7c, C16 : 0 and C18 : 1omega7c. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phospholipid and an unidentified lipid. The major isoprenoid quinone was ubiquinone-8 (Q-8) and the DNA G+C content of the genomic DNA was 69.6 mol%. Phylogenetic analyses, based on 16S rRNA gene sequences, showed that the novel isolate belongs to the genus Melaminivora and was most closely related to Melaminivora alkalimesophila CY1T (97.2 % similarity). The DNA-DNA relatedness values between strain KBB12T and M. alkalimesophila DSM26005T was 43.4+/-2.7 %. On the basis of phylogenetic and phenotypic evidence, it is proposed that strain KBB12T represents a novel species of the genus Melaminivora, for which the name Melaminivora jejuensis sp. nov. is proposed. The type strain is KBB12T (=KCTC 32230T=JCM 18740T). PMID- 29111967 TI - Recombinant expression and characterisation of the oxygen-sensitive 2-enoate reductase from Clostridium sporogenes. AB - 'Ene'-reductases have attracted significant attention for the preparation of chemical intermediates and biologically active products. To date, research has been focussed primarily on Old Yellow Enzyme-like proteins, due to their ease of handling, whereas 2-enoate reductases from clostridia have received much less attention, because of their oxygen sensitivity and a lack of suitable expression systems. A hypothetical 2-enoate reductase gene, fldZ, was identified in Clostridium sporogenes DSM 795. The encoded protein shares a high degree of homology to clostridial FMN- and FAD-dependent 2-enoate reductases, including the cinnamic acid reductase proposed to be involved in amino acid metabolism in proteolytic clostridia. The gene was cloned and overexpressed in Escherichia coli. Successful expression depended on the use of strictly anaerobic conditions for both growth and enzyme preparation, since FldZ was oxygen-sensitive. The enzyme reduced aromatic enoates, such as cinnamic acid or p-coumaric acid, but not short chain unsaturated aliphatic acids. The beta,beta-disubstituted nitroalkene, (E)-1-nitro-2-phenylpropene, was reduced to enantiopure (R)-1-nitro 2-phenylpropane with a yield of 90 %. By contrast, the alpha,beta-disubstituted nitroalkene, (E)-2-nitro-1-phenylpropene, was reduced with a moderate yield of 56 % and poor enantioselectivity (16 % ee for (S)-2-nitro-1-phenylpropane). The availability of an expression system for this recombinant clostridial 2-enoate reductase will facilitate future characterisation of this unusual class of 'ene' reductases, and expand the biocatalytic toolbox available for enantioselective hydrogenation of carbon-carbon double bonds. PMID- 29111969 TI - Resistance mechanisms of linezolid-nonsusceptible enterococci in Korea: low rate of 23S rRNA mutations in Enterococcus faecium. AB - PURPOSE: To investigate linezolid-resistance mechanisms in linezolid nonsusceptible enterococci (LNSE) isolated from a tertiary hospital in Korea. METHODOLOGY: Enterococcal isolates exhibiting linezolid MICs >=4 mg l-1 that were isolated between December 2011 and May 2016 were investigated by PCR and sequencing for mutations in 23S rRNA or ribosomal proteins (L3, L4 and L22) and for the presence of cfr, cfr(B) and optrA genes.Results/Key findings. Among 135 LNSE (87 Enterococcus faecium and 48 Enterococcus faecalis isolates), 39.1 % (34/87) of E. faecium and 18.8 % (9/48) of E. faecalis isolates were linezolid resistant. The optrA carriage was the dominant mechanism in E. faecalis: 13 isolates, including 10 E. faecalis [70 % (7/10) linezolid-resistant and 30 % (3/10) linezolid-intermediate] and three E. faecium [33.3 % (1/3) linezolid resistant and 66.7 % (2/3) linezolid-intermediate], contained the optrA gene. G2576T mutations in the 23S rRNA gene were detected only in E. faecium [14 isolates; 71.4 % (10/14) linezolid-resistant and 28.6 % (4/14) linezolid intermediate]. One linezolid-intermediate E. faecium harboured a L22 protein alteration (Ser77Thr). No isolates contained cfr or cfr(B) genes and any L3 or L4 protein alterations. No genetic mechanism of resistance was identified for 67.6 % (23/34) of linezolid-resistant E. faecium. CONCLUSION: A low rate of 23S rRNA mutations and the absence of known linezolid-resistance mechanisms in the majority of E. faecium isolates suggest regional differences in the mechanisms of linezolid resistance and the possibility of additional mechanisms. PMID- 29111971 TI - Rheinheimera salexigens sp. nov., isolated from a fishing hook, and emended description of the genus Rheinheimera. AB - A Gram-negative, rod-shaped bacterium, designated KH87T, was isolated from a fishing hook that had been baited and suspended in seawater off O'ahu, Hawai'i. Based on a comparison of 1524 nt of the 16S rRNA gene sequence of strain KH87T, its nearest neighbours were the GammaproteobacteriaRheinheimera nanhaiensis E407 8T (96.2 % identity), Rheinheimera chironomi K19414T (96.0 %), Rheinheimera pacifica KMM 1406T (95.8 %), Rheinheimera muenzenbergensis E49T (95.7 %), Alishewanella solinquinati KMK6T (94.9 %) and Arsukibacterium ikkense GCM72T (94.6 %). Cells of KH87T were motile by a single polar flagellum, strictly aerobic, and catalase- and oxidase-positive. Growth occurred between 4 and 39 degrees C, and in a circumneutral pH range. Major fatty acids in whole cells of strain KH87T were cis-9-hexadecenoic acid, hexadecanoic acid and cis-11 octadecenoic acid. The quinone system contained mostly menaquinone MK-7, and a minor amount of ubiquinone Q-8. The polar lipid profile contained the major lipids phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, an unidentified aminolipid, and a lipid not containing phosphate, an amino group or a sugar moiety. Putrescine was the major polyamine. Physiological, biochemical and genomic data, including obligate halophily, absence of amylolytic activity, a quinone system dominated by MK-7 and DNA G+C content (42.0 mol%) distinguished KH87T from extant Rheinheimera species; strain KH87T was also distinguished by a multi-locus sequence analysis of aligned and concatenated 16S rRNA, gyrB, rpoB and rpoD gene sequences. Based on phenotypic and genotypic differences, the species Rheinheimera salexigens sp. nov. is proposed to accommodate KH87T as the type strain (=ATCC BAA-2715T=CIP 111115T). An emended description of the genus Rheinheimera is also proposed. PMID- 29111970 TI - Complementation of a metK-deficient E. coli strain with heterologous AdoMet synthetase genes. AB - S-adenosyl-l-methionine (AdoMet) is an essential metabolite, playing a wide variety of metabolic roles. The enzyme that produces AdoMet from l-methionine and ATP (methionine adenosyltransferase, MAT) is thus an attractive target for anti cancer and antimicrobial agents. It would be very useful to have a system that allows rapid identification of species-specific inhibitors of this essential enzyme. A previously generated E. coli strain, lacking MAT (?metK) but containing a heterologous AdoMet transporter, was successfully complemented with heterologous metK genes from several bacterial pathogens, as well as with MAT genes from a fungal pathogen and Homo sapiens. The nine tested genes, which vary in both sequence and kinetic properties, all complemented strain MOB1490 well in rich medium. When these strains were grown in glucose minimal medium, growth delays or defects were observed with some specific metK genes, defects that were dramatically reduced if l-methionine was added to the medium. PMID- 29111972 TI - Streptomyces capitiformicae sp. nov., a novel actinomycete producing angucyclinone antibiotics isolated from the head of Camponotus japonicus Mayr. AB - A novel actinomycete, designated strain 1H-SSA4T, was isolated from the head of an ant (Camponotus japonicus Mayr) and was found to produce angucyclinone antibiotics. A polyphasic approach was used to determine the taxonomic status of strain 1H-SSA4T. The DNA G+C content of the draft genome sequence, consisting of 11.4 Mbp, was 70.0 mol%. 16S rRNA gene sequence similarity studies showed that strain 1H-SSA4T belongs to the genus Streptomyces with the highest sequence similarity to Streptomyces hygroscopicus subsp. ossamyceticus NBRC 13983T (98.9 %), and phylogenetically clustered with this species, Streptomyces torulosus LMG 20305T (98.8 %), Streptomyces ipomoeae NBRC 13050T (98.5 %) and Streptomyces decoyicus NRRL 2666T (98.4 %). The morphological and chemotaxonomic properties of the strain were also consistent with those members of the genus Streptomyces. A combination of DNA-DNA hybridization experiments and phenotypic tests were carried out between strain 1H-SSA4T and the above-mentioned strains, which further clarified their relatedness and demonstrated that strain 1H-SSA4T could be distinguished from these strains. Therefore, the strain is concluded to represent a novel species of the genus Streptomyces, for which the name Streptomyces capitiformicae sp. nov. is proposed. The type strain is 1H-SSA4T (=CGMCC 4.7403T=DSM 104537T). PMID- 29111973 TI - Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses. AB - Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C2-domain, Ca2+-binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice (OtofAla515,Ala517/Ala515,Ala517) with lower Ca2+-binding affinity of the C2C domain. The IHC ribbon synapse structure, synaptic Ca2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca2+ concentration, by varying Ca2+ influx through voltage-gated Ca2+-channels or Ca2+ uncaging. Otoferlin thus functions as a Ca2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone. PMID- 29111974 TI - Architecture of TAF11/TAF13/TBP complex suggests novel regulation properties of general transcription factor TFIID. AB - General transcription factor TFIID is a key component of RNA polymerase II transcription initiation. Human TFIID is a megadalton-sized complex comprising TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). TBP binds to core promoter DNA, recognizing the TATA-box. We identified a ternary complex formed by TBP and the histone fold (HF) domain-containing TFIID subunits TAF11 and TAF13. We demonstrate that TAF11/TAF13 competes for TBP binding with TATA-box DNA, and also with the N-terminal domain of TAF1 previously implicated in TATA box mimicry. In an integrative approach combining crystal coordinates, biochemical analyses and data from cross-linking mass-spectrometry (CLMS), we determine the architecture of the TAF11/TAF13/TBP complex, revealing TAF11/TAF13 interaction with the DNA binding surface of TBP. We identify a highly conserved C terminal TBP-interaction domain (CTID) in TAF13, which is essential for supporting cell growth. Our results thus have implications for cellular TFIID assembly and suggest a novel regulatory state for TFIID function. PMID- 29111975 TI - Kinesin motility is driven by subdomain dynamics. AB - The microtubule (MT)-associated motor protein kinesin utilizes its conserved ATPase head to achieve diverse motility characteristics. Despite considerable knowledge about how its ATPase activity and MT binding are coupled to the motility cycle, the atomic mechanism of the core events remain to be found. To obtain insights into the mechanism, we performed 38.5 microseconds of all-atom molecular dynamics simulations of kinesin-MT complexes in different nucleotide states. Local subdomain dynamics were found to be essential for nucleotide processing. Catalytic water molecules are dynamically organized by the switch domains of the nucleotide binding pocket while ATP is torsionally strained. Hydrolysis products are 'pulled' by switch-I, and a new ATP is 'captured' by a concerted motion of the alpha0/L5/switch-I trio. The dynamic and wet kinesin-MT interface is tuned for rapid interactions while maintaining specificity. The proposed mechanism provides the flexibility necessary for walking in the crowded cellular environment. PMID- 29111976 TI - CD40 is a major regulator of dendrite growth from developing excitatory and inhibitory neurons. AB - Dendrite size and morphology are key determinants of the functional properties of neurons and neural circuits. Here we show that CD40, a member of the TNF receptor superfamily, is a major regulator of dendrite growth and elaboration in the developing brain. The dendrites of hippocampal excitatory neurons were markedly stunted in Cd40-/- mice, whereas those of striatal inhibitory neurons were much more exuberant. These striking and opposite phenotypic changes were also observed in excitatory and inhibitory neurons cultured from Cd40-/- mice and were rescued by soluble CD40. The changes in excitatory and inhibitory neurons cultured from Cd40-/- mice were mimicked in neurons of Cd40+/+ mice by treatment with soluble CD40L and were dependent on PKC-beta and PKC-gamma, respectively. These results suggest that CD40-activated CD40L reverse signalling has striking and opposite effects on the growth and elaboration of dendrites among major classes of brain neurons by PKC-dependent mechanisms. PMID- 29111979 TI - Machine learning and data science in soft materials engineering. AB - In many branches of materials science it is now routine to generate data sets of such large size and dimensionality that conventional methods of analysis fail. Paradigms and tools from data science and machine learning can provide scalable approaches to identify and extract trends and patterns within voluminous data sets, perform guided traversals of high-dimensional phase spaces, and furnish data-driven strategies for inverse materials design. This topical review provides an accessible introduction to machine learning tools in the context of soft and biological materials by 'de-jargonizing' data science terminology, presenting a taxonomy of machine learning techniques, and surveying the mathematical underpinnings and software implementations of popular tools, including principal component analysis, independent component analysis, diffusion maps, support vector machines, and relative entropy. We present illustrative examples of machine learning applications in soft matter, including inverse design of self assembling materials, nonlinear learning of protein folding landscapes, high throughput antimicrobial peptide design, and data-driven materials design engines. We close with an outlook on the challenges and opportunities for the field. PMID- 29111980 TI - Impact of continuation of metformin prior to elective coronary angiography on acute contrast nephropathy in patients with normal or mildly impaired renal functions. AB - OBJECTIVE: Discontinuation of metformin treatment in patients scheduled for elective coronary angiography (CAG) is controversial because of post-procedural risks including acute contrast-induced nephropathy (CIN) and lactic acidosis (LA). This study aims to discuss the safety of continuing metformin treatment in patients undergoing elective CAG with normal or mildly impaired renal functions. METHODS: Our study was designed as a single-centered, randomized, and observational study including 268 patients undergoing elective CAG with an estimated glomerular filtration rate of >60 mL/min/1.73 m2. Of these patients, 134 continued metformin treatment during angiography, whereas 134 discontinued it 24 h before the procedure. CIN was defined as either a 25% relative increase in serum creatinine levels from the baseline or a 0.5 mg/dL increase in the absolute value that measured 48 h after CAG. Logistic regression analysis was performed to identify independent predictors of CIN and LA after CAG. RESULTS: Both groups were comparable in terms of demographics and laboratory values. CIN at 48 h was 8% (11/134) in the metformin continued group and 6% (8/134) in the metformin discontinued group (p=0.265). Patients in neither of the groups developed metformin-induced LA. Based on multiple regression analysis, the ejection fraction [p=0.029, OR: 0.760; 95% CI (0.590-0.970)] and contrast volume [p=0.016, OR: 0.022 95% CI (0.010-0.490)] were independent predictors of CIN. CONCLUSION: Patients scheduled for elective CAG with normal or mildly impaired renal functions and preserved left ventricular ejection fraction (>40%) may safely continue metformin treatment. PMID- 29111977 TI - Nanos promotes epigenetic reprograming of the germline by down-regulation of the THAP transcription factor LIN-15B. AB - Nanos RNA-binding proteins are required for germline development in metazoans, but the underlying mechanisms remain poorly understood. We have profiled the transcriptome of primordial germ cells (PGCs) lacking the nanos homologs nos-1 and nos-2 in C. elegans. nos-1nos-2 PGCs fail to silence hundreds of transcripts normally expressed in oocytes. We find that this misregulation is due to both delayed turnover of maternal transcripts and inappropriate transcriptional activation. The latter appears to be an indirect consequence of delayed turnover of the maternally-inherited transcription factor LIN-15B, a synMuvB class transcription factor known to antagonize PRC2 activity. PRC2 is required for chromatin reprogramming in the germline, and the transcriptome of PGCs lacking PRC2 resembles that of nos-1nos-2 PGCs. Loss of maternal LIN-15B restores fertility to nos-1nos-2 mutants. These findings suggest that Nanos promotes germ cell fate by downregulating maternal RNAs and proteins that would otherwise interfere with PRC2-dependent reprogramming of PGC chromatin. PMID- 29111981 TI - The detection of interval colorectal cancers following screening by fecal immunochemical test may predict worse outcomes and prompt ethical concerns: a 6 year population-based cohort study in a full district. AB - The rates of colorectal cancer (CRC) interval surveyed in screen-detected patients using a fecal immunochemical test (FIT) are not negligible. The aim of this study was to assess the effect of interval cancer on outcomes compared with a population with cancer diagnosed after a positive test result. All patients between 50 and 71 years of age, who were residents of the Mantua district, affected by CRC and operated on from 2005 to 2010 were reviewed. Other than patient-related, disease-related, and treatment-related factors and tumor location, this population was differentiated as either participating or not to screening and then into populations developing interval cancer after a negative FIT result. Mortality was investigated by univariate analysis and by overall survival rates. The mean age of the 975 patients enrolled was 62 years (61.7% males). Most patients (n=575, 59%) were not screen detected, and 400 (41%) were screen detected. Fifty-six (5.7%) patients in the latter group, representing 14% of the participants, developed interval cancer after a negative FIT result. Their cancer was mostly localized in the right colon (41.1%) instead of the left colon and rectum (P=0.02). They also showed higher stages (P=0.001), a moderate degree of differentiation (P=0.001), and overall higher mortality rates than patients with cancer diagnosed after a positive test result (P=0.001). The effect of interval CRC after screening with FIT resulted in worse outcomes compared with the FIT-positive group. With such findings, patients who had negative results for FIT should be informed of the risk of developing cancer within the rounds of screening to independently gain educational skills in the area of health prevention. PMID- 29111982 TI - Management of Immune-mediated Cytopenias in the Era of Cancer Immunotherapy: A Report of 4 Cases. AB - Recent advancements in immunotherapy have brought promising drugs to fight cancers; a subset of immunotherapy medications are known as checkpoint inhibitors. Their mechanism of action relies on upregulating antitumor response by reversing T-cell suppression; as a consequence the effect can also result in a spectrum of immune related complications. Reported complications to date include: skin, gastrointestinal mucosa, hypophysis, liver, endocrine system, nervous system, kidney, musculoskeletal system and the hematologic system. The management of immune related complications typically includes the use of steroids and other strategies of immunosuppression. The current recommendations are not organ specific and little is known about the response and outcomes related to the hematologic system. Hereby we report four cases evaluated at the hematology service at the University of Texas MD Anderson Cancer Center for cytopenias after check point inhibitor therapies. All cases were responsive to conventional interventions for immune-mediated cytopenias. PMID- 29111984 TI - Asbestos Exposures, Mesothelioma Incidence and Mortality, and Awareness by General Practitioners in the Molise Region, Central Italy. AB - OBJECTIVE: The aim of this study was to evaluate environmental asbestos sources, mesothelioma incidence and mortality, and awareness on asbestos-related diseases (ARDs) by general practitioners (GPs) in Molise Region. METHODS: The contaminated sites in three towns were identified by census; mesothelioma incidence (2000 to 2012) and mortality (2003 to 2013) was achieved from local registries; GPs were interviewed on practiced population's exposures and ARDs diagnosis. RESULTS: About 54.3% of visited sites were contaminated (71.2% by friable asbestos) and 38.8% was extremely damaged. Over above time-periods, 32 mesothelioma cases (62.5% males, 25% in people aged 70 to 75 years) and 27 deaths (90% males, 69 +/- 10 years, 70.4% pleural mesothelioma) have been reported. A total of 122 GPs were interviewed who had diagnosed 40 mesothelioma and 28 asbestosis cases. CONCLUSION: There is the need of remediation/removal interventions for contaminated sites and of strategies to increase GPs awareness on asbestos risks for better patients' management. PMID- 29111978 TI - The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity. AB - The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood. We show that the eukaryotic translation initiation factor eIF4E, an oncoprotein, drives HA biosynthesis. eIF4E stimulates production of enzymes that synthesize the building blocks of HA, UDP-Glucuronic acid and UDP-N Acetyl-Glucosamine, as well as hyaluronic acid synthase which forms the disaccharide chain. Strikingly, eIF4E inhibition alone repressed HA levels as effectively as directly targeting HA with hyaluronidase. Unusually, HA was retained on the surface of high-eIF4E cells, rather than being extruded into the extracellular space. Surface-associated HA was required for eIF4E's oncogenic activities suggesting that eIF4E potentiates an oncogenic HA program. These studies provide unique insights into the mechanisms driving HA production and demonstrate that an oncoprotein can co-opt HA biosynthesis to drive malignancy. PMID- 29111985 TI - Occupational UV-Exposure is a Major Risk Factor for Basal Cell Carcinoma: Results of the Population-Based Case-Control Study FB-181. AB - OBJECTIVE: The aim of this study was to investigate the role of occupational and nonoccupational ultraviolet (UV)-exposure concerning the development of basal cell carcinoma (BCC). METHODS: We undertook a population-based multicenter case control study. Patients with first incident BCC (n = 836) were propensity score matched by age and sex to controls without skin cancer (n = 836). Sociodemographic characteristics, clinical characteristics, and lifetime UV exposure were assessed by trained investigators. The differential estimation of occupational and nonoccupational UV-exposure dosages was based on validated instruments and established reference values. Associations were assessed using multivariable-adjusted conditional logistic regression models. RESULTS: Individuals with high levels of occupational UV-exposure were at significantly increased BCC-risk compared with individuals with low [odds ratio (OR) 1.84; 95% confidence interval (95% CI) 1.19 to 2.83 and moderate (OR 1.97; 95% CI 1.20 to 3.22) occupational UV-exposure. Nonoccupational UV-exposure was not independently associated with BCC. CONCLUSION: Skin cancer prevention strategies should be expanded to the occupational setting. PMID- 29111986 TI - Prevalence of Hearing Loss Among Noise-Exposed Workers Within the Health Care and Social Assistance Sector, 2003 to 2012. AB - OBJECTIVE: The purpose was to estimate the prevalence of hearing loss for noise exposed U.S. workers within the Health Care and Social Assistance (HSA) sector. METHODS: Audiograms for 1.4 million workers (8702 within HSA) from 2003 to 2012 were examined. Prevalences and adjusted risks for hearing loss as compared with a reference industry were estimated for the HSA sector and all industries combined. RESULTS: While the overall HSA sector prevalence for hearing loss was 19%, the prevalences in the Medical Laboratories subsector and the Offices of All Other Miscellaneous Health Practitioners subsector were 31% and 24%, respectively. The Child Day Care Services subsector had a 52% higher risk than the reference industry. CONCLUSION: High-risk industries for hearing loss exist within the HSA sector. Further work is needed to identify the sources of noise exposure and protect worker hearing. PMID- 29111983 TI - Acute Flare of Bullous Pemphigus With Pembrolizumab Used for Treatment of Metastatic Urothelial Cancer. AB - In the past decade, the resurgence of immunotherapy has changed the landscape of cancer therapy. Checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen-4, programmed death-1 on lymphocytes, and programmed death ligand-1 on tumors cells are currently utilized in the management of several cancers. These agents are double-edged sword with the positive effect being robust antitumor response but on the other side they can throttle up the normal immunologic homeostasis in a negative way, leading to adverse autoimmune toxicities. These adverse toxicities are frequent if patients have active autoimmune disorders. Here, we report a rare case of quiescent bullous pemphigoid which flared after initiation of pembrolizumab, a programmed death ligand-1 inhibitor. PMID- 29111987 TI - Does Workplace Bullying Affect Long-Term Sickness Absence Among Coworkers? AB - AIM: To examine if non-bullied employees at work units (WUs) with workplace bullying have more long-term sickness absence (LTSA) than employees in non bullying WUs. METHODS: We included 7229 public health employees from 302 WUs and 3158 responders to a questionnaire on working conditions and health in 2007. WUs were classified into three categories of WUs; (1) no bullying (0% bullied); (2) moderate prevalence of bullying (less than 10% bullied); and (3) high prevalence of bullying (more than or equal to 10% bullied). LTSA (more than or equal to 30 consecutive days of sickness absence) during the following 2 years was obtained by linkage to the Danish register of sickness absence compensation benefits and social transfer payments. RESULTS: Non-bullied coworkers in WUs, where bullying was reported had 15% to 22% more LTSA compared with non-bullying WUs. CONCLUSION: Workplace bullying may be associated with LTSA in the entire WU. PMID- 29111988 TI - Letter on: "Mortality of Talc Miners and Millers From Val Chisone, Northern Italy". PMID- 29111989 TI - Improvements in Psychological Health Following a Residential Yoga-Based Program for Frontline Professionals. AB - OBJECTIVE: The purpose of this pilot study was to examine the effects of a residential yoga-based program on psychological health and health behaviors in frontline professionals. METHODS: Frontline professionals from education, health care, human services, and corrections participated in the RISE (Resilience, Integration, Self-awareness, Engagement) program and completed questionnaires at baseline, post-program, and 2 months following RISE. RESULTS: Paired samples t tests revealed improvements in mindfulness, stress, resilience, affect, and sleep quality from baseline to post-program (all Ps < 0.001, N = 55), which were sustained at the 2-month follow-up (all Ps < 0.01, N = 40). Participants also reported increases in exercise, fruit, and vegetable consumption post-program (all Ps < 0.001), all of which persisted at the 2-month follow-up (all Ps < 0.01) except exercise. CONCLUSION: These findings suggest that RISE improved indices of psychological health and healthy behaviors that remained 2 months following RISE. PMID- 29111990 TI - Cancer Risk Associated With Exposure to Bitumen and Bitumen Fumes: An Updated Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate whether cancer risks are increased among bitumen (asphalt) workers. METHODS: Systematic review and meta-analysis of cancer risks (lung, upper aerodigestive tract (UADT), esophagus, bladder, kidney, stomach, and skin) and bitumen exposure. Certainty in the epidemiological evidence that bitumen exposed workers experience increased cancer risks was rated using Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS: After excluding lower-quality studies, lung cancer risks were not increased among bitumen-exposed workers (meta-relative risk [RR] 0.94, 95% CI 0.74 to 1.20, eight studies). Increased risks of UADT and stomach cancers were observed (meta-RR 1.31, 95% CI 1.03 to 1.67, 10 studies and meta-RR 1.29, 95% CI 1.03 to 1.62, seven studies, respectively). CONCLUSIONS: Except for lung cancer, evidence for increased cancer risks among bitumen-exposed workers was judged to be of low certainty, due to inadequate exposure characterization and unmeasured confounders (coal tar exposure, smoking, and alcohol consumption). PMID- 29111992 TI - Cardiovascular and Cerebral Hemodynamics in Asymptomatic Healthy Subjects With/Without Abnormal Head-up Tilt Test Versus Recurrent Fainters. AB - PURPOSE: The aim of this study was to compare hemodynamic and autonomic responses during head-up tilt test (HUTT) between healthy volunteers and patients with a history of fainting and confirmed vasovagal syncope. We hypothesize that the autonomic and hemodynamic physiologic responses remain intact during orthostatic stress in people without previous fainting and negative HUTT, but deteriorate similarly in patients with recurrent vasovagal syncope and in asymptomatic healthy subjects who develop a vasovagal response during HUTT. METHODS: The study included 57 asymptomatic healthy volunteers (42% women, mean age 23.7 +/- 3.6 years) categorized as negative HUTT (n = 41) and positive HUTT (n = 16). They were compared with 14 patients (50% women, mean age 24.2 +/- 6.1 years) with previous spontaneous recurrent syncope and inducible vasovagal response during HUTT. Cerebral and cardiovascular hemodynamic variables were assessed noninvasively during the HUTT in each participant. RESULTS: In all patients with recurrent syncope, tilt was positive after a mean delay of 15.6 +/- 8.6 minutes and did not differ from the time to syncope observed after 19.6 +/- 6.9 minutes in asymptomatic healthy subjects with a positive test. A significant decrease throughout the tilting was observed in the blood pressure, peripheral resistances, cerebral blood flow, and vascular efferent sympathetic regulation in both groups of subjects with a positive test. CONCLUSIONS: This study shows that there are subjects, without a history of syncope, who have a positive HUTT with hemodynamic and autonomic responses alike to patients with confirmed vasovagal syncope, precluding them to be selected as controls in vasovagal syncope studies. PMID- 29111991 TI - Multiple Chemical Sensitivity: Review of the State of the Art in Epidemiology, Diagnosis, and Future Perspectives. AB - OBJECTIVE: Systematic bibliography analysis of about the last 17 years on multiple chemical sensitivity (MCS) was carried out in order to detect new diagnostic and epidemiological evidence. The MCS is a complex syndrome that manifests as a result of exposure to a low level of various common contaminants. The etiology, diagnosis, and treatment are still debated among researchers. METHOD: Querying PubMed, Web of Science, Scopus, Cochrane library, both using some specific MESH terms combined with MESH subheadings and through free search, even by Google. RESULTS: The studies were analyzed by verifying 1) the typology of study design; 2) criteria for case definition; 3) presence of attendances in the emergency departments and hospital admissions, and 4) analysis of the risk factors. OUTLOOK: With this review, we give some general considerations and hypothesis for possible future research. PMID- 29111993 TI - Enhanced Osteogenic Differentiation Potential of Stem-Cell Spheroids Created From a Coculture of Stem Cells and Endothelial Cells. AB - PURPOSE: This study was performed to fabricate stem-cell spheroids formed with human gingiva-derived stem cells and endothelial cells and to evaluate their viability and osteogenic differentiation potential. MATERIALS AND METHODS: Gingiva-derived stem cells were isolated, and stem cells and endothelial cells with a total of 6 * 10 cells were seeded into concave micromolds with different ratios of 6:0 (group 1), 4:2 (group 2), 3:3 (group 3), and 2:4 (group 4). RESULTS: Gingiva-derived stem cells and/or endothelia cells formed spheroids in concave microwells. There was a decreasing trend in the diameter of spheroids with increasing amounts of endothelial cells, but there were no statistically significant differences between the groups. The secretion of vascular endothelial growth factor from the spheroids was noted. The results of the alkaline phosphatase activity assays showed significantly higher values for groups 2, 3, and 4 when compared with the value of group 1. CONCLUSIONS: Conclusively, stem cell spheroids formed with human gingiva-derived stem cells and endothelial cells using concave microwells enhanced osteogenic differentiation potential, and multicell spheroid-based cell delivery could be a simple and effective strategy for improving stem-cell therapy. PMID- 29111994 TI - Identification of the Infection Source of an Outbreak of Mycobacterium Chelonae Keratitis After Laser in Situ Keratomileusis. AB - PURPOSE: Nontuberculous mycobacteria keratitis is a rare but challenging complication of laser in situ keratomileusis (LASIK). This study was conducted to determine the source(s) of infection in a cluster of cases of keratitis after LASIK and to describe this outbreak and patients' outcomes. METHODS: In this retrospective, case series, single-center study, 86 patients were included who underwent LASIK or photorefractive keratectomy between December 2011 and February 2012. Corneal scrapes from the affected eyes, samples of tap and distilled water, water from the reservoir of the distilling equipment, steamer, and autoclave cassette; antiseptic and anesthetic solutions and surgical instrument imprints were cultivated in liquid and on solid media. Gram-negative bacteria and yeasts were identified using automated systems and mycobacteria by polymerase chain reaction-restriction enzyme analysis of the hsp65 gene (PRA-hsp65) and DNA sequencing. Mycobacterial isolates were typed by pulsed-field gel electrophoresis. The cases and outcomes are described. The main outcome measure was identification of the source(s) of the mycobacterial infections. RESULTS: Eight (15 eyes) of 86 patients (172 eyes) who underwent LASIK developed infections postoperatively; no patients who underwent photorefractive keratectomy developed infections. Mycobacterium chelonae was isolated from 4 eyes. The distilled water collected in the surgical facility contained the same M. chelonae strain isolated from the patients' eyes. Different gram-negative bacteria and yeasts were isolated from samples collected at the clinic but not from the patients' eyes. CONCLUSIONS: Tap water distilled locally in surgical facilities may be a source of infection after ocular surgery and its use should be avoided. PMID- 29111995 TI - Diagnostic Evaluation of Co-Occurrence of Acanthamoeba and Fungi in Keratitis: A Preliminary Report. AB - PURPOSE: To test the hypothesis that the coexistence of Acanthamoeba with other forms of microbial keratitis, especially fungal keratitis (FK), is more prevalent than suspected. METHODS: A prospective diagnostic study whereby patients presenting with stromal keratitis were additionally tested for Acanthamoeba, irrespective of the initial diagnosis. In addition to the routine workup with Gram stain, KOH mount, and cultures on blood agar and potato dextrose agar, nonnutrient agar was included. Confocal microscopy was performed where feasible. Samples for polymerase chain reaction studies were also obtained. We present the preliminary report of the first 100 culture-positive cases. The primary outcome measured was the number of coexistent Acanthamoeba and FK. The secondary outcomes were the total number of Acanthamoeba cases detected and the correlation between clinical diagnosis and microbiological observations. RESULTS: Of the first 100 cases, 22 were culture positive for Acanthamoeba, of which 9 were associated with concurrent FK, 5 with bacterial keratitis, and 8 in isolation. However, only 2 cases were diagnosed clinically as Acanthamoeba, whereas 5 were Acanthamoeba suspects. An additional 4 cases of fungal/Acanthamoeba coexistence in keratitis were revealed purely by confocal microscopy. CONCLUSIONS: Acanthamoeba can coexist with other forms of microbial keratitis. The frequency of infection coexistent or otherwise is higher than reported, and the possibility of coinfection must be considered especially in unresponsive cases. Including nonnutrient agar and confocal microscopy in all cases of keratitis would perhaps translate into better treatment strategies and outcomes. PMID- 29111996 TI - Microbial Keratitis After Accelerated Corneal Collagen Cross-Linking in Keratoconus. AB - PURPOSE: To assess the pattern of microbial keratitis after accelerated corneal collagen cross-linkage (aCXL) in patients with keratoconus. METHOD: The medical records of cases of keratoconus that underwent aCXL from June 2014 to May 2017 were reviewed. Cases that developed microbial keratitis after aCXL were included in the study. The clinical, microbiological profile and the treatment outcomes were evaluated. RESULTS: Of 532 eyes that underwent aCXL, 7 cases developed microbial keratitis during the study period. Median age at presentation was 11 years (range 8-17). Association with vernal keratoconjunctivitis was noted in 57.1% of cases (n = 4/7). The median time at the onset of infection was 3 days after aCXL (range 1-4). Microbiological reports revealed mixed infection in 3 cases [coagulase-negative Staphylococcus (CoNS) + Aspergillus fumigatus, Staphylococcus aureus and Mucor spp., Staph. aureus and Acanthamoeba], Staph. aureus in 2 cases, and CoNS and Alternaria spp. in 1 case each. Resistance to fourth-generation fluoroquinolones was noted in 83.3% of cases of bacterial keratitis (n = 5/6). All cases were initially managed with empirical antibiotic treatment that was later tailored based on microbiological reports. One case eventually required therapeutic penetrating keratoplasty for corneal perforation. At 6 months, the corrected distance visual acuity was >6/60 in 3 cases while 4 cases had corrected distance visual acuity <6/60. CONCLUSIONS: Microbial keratitis after aCXL is rare; however, the infection tends to be severe with high preponderance of mixed infection and resistance to fourth-generation fluoroquinolones. PMID- 29111997 TI - beta-Blocker use is associated with a higher relapse risk of inflammatory bowel disease: a Dutch retrospective case-control study. AB - OBJECTIVE: Inflammatory bowel disease (IBD) is a multifactorial disease and many factors may influence the disease course, like the concomitant use of medication. An example thereof is the use of beta-blockers, antagonizing beta-adrenergic receptors. beta-adrenergic receptor activation has potent anti-inflammatory effects on the immune system. We addressed whether an association exists between the use of beta-blockers and the course of IBD, defined by the risk of a disease relapse in patients with IBD. PATIENTS AND METHODS: In this retrospective case control study, we used a population-based cohort of patients with IBD. We identified colitis relapses using IBD medication prescriptions as a proxy. We calculated the number of relapses per 100 person-years and compared this between patients with IBD using beta-blockers and patients with IBD not using beta blockers. We used Cox proportional hazards models with shared frailty to compare the relative relapse risk between both groups. RESULTS: A total of 250 patients with IBD were included, of which 30 patients used a beta-blocker for at least 3 months. With the Cox proportional hazards model with shared frailty, adjusted for age and sex, we observed a 54% (hazard ratio: 1.54; 95% confidence interval: 1.05 2.25; P=0.03) higher risk of a relapse in the group of patients with IBD using beta-blockers versus the group not using beta-blockers. CONCLUSION: Even in this limited cohort study, we show that patients with IBD using beta-blockers have an increased relapse risk. Indeed, concomitant medication use seems to be a factor that can influence the course of IBD, and this should be acknowledged while making decisions about treatment of IBD and follow-up. PMID- 29111998 TI - Combining the outcomes of endoscopy, laboratory testing, and professional judgement in gastroenterological decision-making. AB - The need to combine the results of multiple separate tests or make decisions based on the judgement by multiple experts permeates the clinical and professional practice of a gastroenterologist. The present analysis is aimed at delineating four different means to combine results of multiple tests and discuss their applicability and limitations. In serial testing, the overall test outcome is rated as being positive if the outcome is positive in all individual tests applied in series. Serial testing increases the overall specificity at the expense of decreasing sensitivity. In parallel testing, the overall test outcome is rated as being positive if the outcome is positive in any of the multiple tests. Parallel testing increases the overall sensitivity at the expense of decreasing specificity. In majority testing, the overall test outcome follows the rating by the majority of testers. Majority testing avoids the trade-off between sensitivity and specificity associated with serial and parallel testing and leads to relatively high overall values for both test characteristics. For majority testing to function well, however, it requires many independent testers, which can render this method costly and impractical in the clinical setting. Sequential testing applies to situations in which the output of a previous test provides the input for a later test. Sequential testing generally results in an overall test with lower sensitivity and specificity values than any of the individual tests and should be avoided if possible. All methods to improve test performance by combining the results of multiple tests have limitations and need to be regarded with skepticism. In the long run, the best solutions are provided by improvements of the individual test or performance by the individual diagnostician/reviewer through training and acquisition of new skills. PMID- 29111999 TI - Terlipressin is superior to midodrine/octreotide for hepatorenal syndrome type 1. PMID- 29112001 TI - A phase II study to evaluate the pharmacokinetics, safety, and tolerability of Risperidone ISM multiple intramuscular injections once every 4 weeks in patients with schizophrenia. AB - This study characterized the pharmacokinetics, safety, and tolerability of Risperidone ISM, a new long-acting intramuscular formulation, for monthly administration without oral supplementation. Patients with schizophrenia received multiple intramuscular injections of 75 mg in the gluteal or deltoid muscle at 28 day intervals. Of the 70 randomized patients, 67 received at least one dose of study medication. The mean Cmax of the active moiety was achieved 24-48 h (tmax) after each administration, regardless of injection site. They ranged over four consecutive doses from 39.6 to 53.2 and 54.1 to 61 ng/ml, when given in gluteal or deltoid muscle, respectively. Active moiety achieved therapeutic levels by 2 h after dose, and the levels were maintained throughout the 4-week dosing period. No significant changes across the study were observed on either Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 (94%) patients experienced at least one treatment-emergent adverse event (TEAE). One serious TEAE (dystonia) was related to study treatment. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%). Risperidone ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-week dosing period over multiple intramuscular injections and was found to be safe and well tolerated. PMID- 29112002 TI - Surveillance of Surgical Meshes in Ventral Hernias and Unpredictability of Their History. AB - : The authors read the article "The importance of registries in the postmarketing surveillance of surgical meshes" by Kockerling et al, and they completely agree on the role of a clinical follow-up of surgical meshes even if they suggest that a surveillance longer than one year is advisable, particularly in IPOM repair, to collect not only late complications but also more serious adverse events. This seems be the only way to properly assess the safety of the mesh. PMID- 29112003 TI - Measuring Processes of Care in Palliative Surgery: A Novel Approach Using Natural Language Processing. AB - : Palliative surgical procedures are often performed for patients with limited survival. Quality measures for processes of care at the end of life are appropriate in palliative surgery, but have not been applied in this patient population. In this paper, the authors propose 4 quality measures for end-of-life care in a palliative surgery, and then demonstrate the utility of natural language processing for implementing these measures. PMID- 29112004 TI - Anastomotic Leak Does Not Impact Oncologic Outcomes After Preoperative Chemoradiotherapy and Resection for Rectal Cancer. AB - OBJECTIVE: The aim of this study was to evaluate the relationship of anastomotic leakage, local recurrence, and overall survival in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and curative resection. BACKGROUND: Little is known about the association between anastomotic leakage and oncologic outcomes after preoperative CRT. METHODS: A total of 698 consecutive primary rectal cancer patients after preoperative CRT between April 19, 2000, and December 27, 2013, were retrospectively reviewed. Forty-seven patients who had anastomotic leakage were compared with 651 patients who had no anastomotic leakage. RESULTS: Of 698 patients, 47 (6.7%) patients had anastomotic leakage. Among these 47 patients, 39 (83.0%) had grade C leak that required urgent operation, while 8 (17.0%) had grade B leak that was managed expectantly or by percutaneous drainage. The median follow-up period was 47.6 months (range, 27.1 to 68.9 months). One hundred twenty (17.2%) recurrences were identified among all patients. The median overall disease-free survival was 43 months (range, 22.4 to 66.7 months). Five-year disease-free survival did not differ significantly between the 2 groups (80.5% vs 80.4%, P = 0.839). Five-year local recurrence-free survival did not differ significantly either between the 2 groups (93.7% vs 94.9%, P = 0.653). Five-year overall survival rates of patients with or without leakage were 90.9% and 86.3%, respectively (P = 0.242). Five-year cancer-specific survival rates of patients with or without leakage were 92.2% and 86.3%, respectively (P = 0.248). CONCLUSION: After preoperative CRT, an anastomotic leak is not associated with a significant increase in local recurrence or long-term survival in rectal cancer. PMID- 29112005 TI - John L. Cameron, MD: Overview of His Career. AB - : Introduction to the John Cameron Festschrift. PMID- 29112006 TI - Modified Lumbosacral Angle and Modified Pelvic Incidence as New Parameters for Management of Pediatric High-grade Spondylolisthesis. AB - STUDY DESIGN: Retrospective clinical study. OBJECTIVE: We aimed to introduce new parameters that can better describe the pelvic morphology and lumbosacral segmental deformity in children with high-grade spondylolisthesis of the L5 vertebra: modified pelvic incidence (mPI) and modified lumbosacral angle (mLSA). Also, we aimed to establish the mLSA as a convenient, reliable measurement method and criteria to evaluate the reduction of L5 vertebral slippage. SUMMARY OF BACKGROUND DATA: Numerous parameters and methods exist to evaluate segmental deformity and reduction of L5 vertebral slippage, but no definitive standard for accurately and conveniently describing lumbosacral kyphosis and degree of reduction exists. METHODS: A total of 24 children with high-grade spondylolisthesis (S group) and 152 children without spondylolisthesis (non-S group) underwent standard lateral radiography of the spine in our hospital between June 2009 and June 2014. We compared mPI and mLSA between the S and non-S groups. The agreement and repeatability of mPI and mLSA were also assessed. Preoperative and postoperative Japanese Orthopaedic Association (JOA) and Scoliosis Research Society (SRS)-22 scores were compared to assess clinical outcomes in the S group. The correlations between modified parameter applications and clinical outcomes were also assessed. RESULTS: While mPI did not differ between groups, mLSA differed significantly. In the non-S group, mLSA was lordotic (25.51+/-6.41 degrees). In the S group, mLSA was kyphotic (25.85+/-5.17 degrees) before surgery and lordotic (20.74+/-7.04 degrees) postoperatively. The agreement and repeatability of mPI and mLSA were good, and clinical outcomes of the S group were satisfactory. Positive correlations were found between modified parameter applications and the improvement rates of JOA scores. CONCLUSIONS: mPI and mLSA can better describe the pelvic morphology and local deformity of pediatric high-grade L5 spondylolisthesis, and mLSA can serve as a useful index for correcting lumbosacral kyphosis, rebalancing the sagittal spinal profile and predicting clinical outcomes. PMID- 29112007 TI - Trajectories and predictors of the long-term course of low back pain: cohort study with 5-year follow-up. AB - Low back pain (LBP) is a major health challenge globally. Research has identified common trajectories of pain over time. We aimed to investigate whether trajectories described in 1 primary care cohort can be confirmed in another, and to determine the prognostic value of factors collected 5 years prior to the identification of the trajectory. The study was conducted on 281 patients who had consulted primary care for LBP, at that point completed a baseline questionnaire, and then returned a questionnaire at 5-year follow-up plus at least 3 (of 6) subsequent monthly questionnaires. Baseline factors were measured using validated tools. Pain intensity scores from the 5-year follow-up and monthly questionnaires were used to assign participants into 4 previously derived pain trajectories (no or occasional mild, persistent mild, fluctuating, and persistent severe), using latent class analysis. Posterior probabilities of belonging to each cluster were estimated for each participant. The posterior probabilities for the assigned clusters were very high (>0.90) for each cluster except for the smallest "fluctuating" cluster (0.74). Lower social class and higher pain intensity were significantly associated with a more severe trajectory 5 years later, as were patients' perceptions of the greater consequences and longer duration of pain, and greater passive behavioural coping. Low back pain trajectories identified previously appear generalizable. These allow better understanding of the long term course of LBP, and effective management tailored to individual trajectories needs to be identified. PMID- 29112008 TI - TLR4 deficiency abrogated widespread tactile allodynia, but not widespread thermal hyperalgesia and trigeminal neuropathic pain after partial infraorbital nerve transection. AB - Pain sensitization after partial infraorbital nerve transection (p-IONX) in mice not only presents in orofacial region, but also spreads to distant body parts. The roles of toll-like receptor 4 (TLR4) in orofacial pain and the spreading process are still unclear. Here, we found that mice with deficient TLR4 because of Tr4 gene point mutation (C3H/HeJ) or spontaneous deletion (C57BL/10ScNJ) developed tactile allodynia and thermal hyperalgesia in the vibrissal pad in a parallel way to their respective wild types (C3HeB/FeJ or C57BL/6J) after p-IONX. However, allodynia in the hind paw was absent in mice with TLR4 deficiency. Pharmacological antagonism of TLR4 with LPS-RS, administered either intracisternally or intrathecally, abrogated allodynia in the hind paw without affecting the hypersensitivity in the vibrissal pad and hyperalgesia in the hind paw. Although TNF-alpha expression was upregulated in both the medulla and lumbar cord, the expression of TLR4 downstream molecule MyD88 increased only in the lumbar cord after p-IONX in wild types. By contrast, hind paw hypersensitivity after partial sciatic nerve ligation was significantly attenuated by TLR4 deletion. The hypersensitivity, which did not spread to the vibrissal pad, was accompanied with upregulation of MyD88 in the lumbar cord rather than in the medulla. These results suggest that TLR4 participates in the spread of allodynia component of orofacial pain to distant body sites, but not trigeminal neuropathic pain or the spread of its hyperalgesia component. This study suggests that TLR4 may serve as a potential target for the management of widespread allodynia associated with orofacial pain. PMID- 29112009 TI - Communication about chronic pain and opioids in primary care: impact on patient and physician visit experience. AB - Patients and physicians report that communication about chronic pain and opioids is often challenging, but there is little empirical research on whether patient physician communication about pain affects patient and physician visit experience. This study video recorded 86 primary care visits involving 49 physicians and 86 patients taking long-term opioids for chronic musculoskeletal pain, systematically coded all pain-related utterances during these visits using a custom-designed coding system, and administered previsit and postvisit questionnaires. Multiple regression was used to identify communication behaviors and patient characteristics associated with patients' ratings of their visit experience, physicians' ratings of visit difficulty, or both. After adjusting for covariates, 2 communication variables-patient-physician disagreement and patient requests for opioid dose increases-were each significantly associated with both worse ratings of patient experience and greater physician-reported visit difficulty. Patient desire for increased pain medicine was also significantly positively associated with both worse ratings of patient experience and greater physician-reported visit difficulty. Greater pain severity and more patient questions were each significantly associated with greater physician-reported visit difficulty, but not with patient experience. The association between patient requests for opioids and patient experience ratings was wholly driven by 2 visits involving intense conflict with patients demanding opioids. Patient physician communication during visits is associated with patient and physician ratings of visit experience. Training programs focused on imparting communication skills that assist physicians in negotiating disagreements about pain management, including responding to patient requests for more opioids, likely have potential to improve visit experience ratings for both patients and physicians. PMID- 29112010 TI - Potential Visualization of Sorafenib-Induced Acidosis Using 11C-Acetate PET/CT in Patients With Hepatocellular Carcinoma. AB - C-acetate uptake could be increased in physiologic or inflammatory conditions without evidence of cancer. We report a hepatocellular carcinoma patient with sorafenib-induced metabolic acidosis, who showed increased hepatic uptake of C acetate. C-acetate PET/CT might be a potentially useful surrogate marker to monitor these adverse effects via the changes in C-acetate uptake patterns from before to after drug withdrawal. PMID- 29112011 TI - Role of Various Metabolic Parameters Derived From Baseline 18F-FDG PET/CT as Prognostic Markers in Non-Small Cell Lung Cancer Patients Undergoing Platinum Based Chemotherapy. AB - PURPOSE: The aim of this study was to prospectively evaluate the role of various quantitative and semiquantitative metabolic parameters derived from dynamic and static baseline F-FDG PET/CT in prediction of overall survival (OS) in non-small cell lung cancer (NSCLC) patients who were planned to undergo platinum-based chemotherapy. METHODS: Sixty patients (51 male and 9 female patients) with biopsy proven NSCLC and mean age 59.55 +/- 10.06 years who were planned to undergo platinum-based chemotherapy were enrolled in the study. Each patient underwent a baseline regional dynamic and a static whole-body F-FDG PET/CT after injecting 0.21 mCi/kg (5.18-7.77 MBq/kg) of F-FDG intravenously. Two dynamic PET/CT parameters, that is, net influx rate constant and glucose metabolic rate at 30 and 60 minutes, were evaluated. In addition, whole-body PET/CT parameters, that is, SUVmax, average SUV, tumor-to-background ratio, metabolic tumor volume (MTV), total lesion glycolysis (TLG) of the primary tumor, and MTV and TLG of whole-body tumor lesions, were evaluated. Best possible cutoffs for all parameters were calculated using receiver operating characteristic curve analysis. Survival analysis was performed using log-rank test, Kaplan-Meier curves, and Cox proportional hazards model to determine the prognostic markers for OS. RESULTS: The median follow-up period was 4.4 months (range, 8 days to 15.9 months). In univariate analysis, the 4 static whole-body PET/CT parameters, that is, MTV, TLG, and MTV and TLG of whole-body tumor lesions, were found to be significantly associated with OS with cutoff values of 120, 800, 160, and 1350 cm and hazard ratios of 3.64 (P = 0.001), 3.35 (P = 0.002), 2.51 (P = 0.019), and 2.69 (P = 0.008), respectively. In multivariate survival analysis, MTV was found to be an independent prognostic marker for OS. CONCLUSIONS: Baseline MTV and TLG evaluated from primary tumor as well as the whole-body tumor lesions are reliable prognostic markers of OS in NSCLC patients undergoing platinum-based chemotherapy. However, other baseline whole-body PET/CT parameters (SUVmax, average SUV, and tumor-to-background ratio) and dynamic PET/CT parameters (net influx rate constant, glucose metabolic rate) have no prognostic value in these patients. PMID- 29112012 TI - Semiquantitative Analysis of Dopamine Transporter Scans in Patients With Parkinson Disease. AB - PURPOSE: Dopamine transporter (DaT) imaging is an adjunct diagnostic tool in parkinsonian disorders. Interpretation of DaT scans is based on visual reads. SBRquant is an automated method that measures the striatal binding ratio (SBR) in DaT scans, but has yet to be optimized. We aimed to (1) optimize SBRquant parameters to distinguish between patients with Parkinson disease (PD) and healthy controls using the Parkinson's Progression Markers Initiative (PPMI) database and (2) test the validity of these parameters in an outpatient cohort. METHODS: For optimization, 336 DaT scans (215 PD patients and 121 healthy controls) from the PPMI database were used. Striatal binding ratio was calculated varying the number of summed transverse slices (N) and positions of the striatal regions of interest (d). The resulting SBRs were evaluated using area under the receiver operating characteristic curve. The optimized parameters were then applied to 77 test patients (35 PD and 42 non-PD patients). Striatal binding ratios were also correlated with clinical measures in the PPMI-PD group. RESULTS: The optimal parameters discriminated the training groups in the PPMI cohort with 95.8% sensitivity and 98.3% specificity (lowest putamen SBR threshold, 1.037). The same parameters discriminated the groups in the test cohort with 97.1% sensitivity and 100% specificity (lowest putamen SBR threshold, 0.875). A significant negative correlation (r = -0.24, P = 0.0004) was found between putamen SBRs and motor severity in the PPMI-PD group. CONCLUSIONS: SBRquant discriminates DaT scans with high sensitivity and specificity. It has a high potential for use as a quantitative diagnostic aid in clinical and research settings. PMID- 29112013 TI - Cancer Therapy-associated Lymphoproliferative Disorders: An Under-recognized Type of Immunodeficiency-associated Lymphoproliferative Disorder. AB - We describe the clinicopathologic features of 17 patients who had a hematologic malignancy of various types, were treated, and subsequently developed a lymphoproliferative disorder (LPD). There were 10 men and 7 women with a median age of 59 years (range, 36 to 83 y). The primary hematologic neoplasms included: 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, 3 plasma cell myeloma, 2 acute monoblastic leukemia, and 1 case each of mixed-phenotype acute leukemia, chronic myeloid leukemia, splenic marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, T-cell prolymphocytic leukemia, and peripheral T-cell lymphoma. All patients were treated with chemotherapy with or without therapeutic antibodies; 3 also underwent autologous stem cell transplantation. The mean interval from initiation of therapy for initial hematologic malignancy to onset of LPD was 66 months (range, 3 to 299 mo). Ten (59%) LPDs were extranodal and 7 (41%) involved nodal tissues. The histologic diagnoses included: 8 diffuse large B-cell lymphoma, 4 classical Hodgkin lymphoma, 3 polymorphic LPD, 1 lymphomatoid granulomatosis, and 1 Epstein-Barr virus (EBV) mucocutaneous ulcer. Fourteen cases were EBV. Following the onset of LPD, chemotherapy was administered to 10 (59%) patients. With a median follow-up of 100 months (range, 5 to 328 mo), 8 (47%) patients are alive and 9 (53%) died. One (6%) patient with lymphomatoid granulomatosis underwent spontaneous remission. On the basis of the clinicopathologic features and high prevalence of EBV infection in this cohort, we believe that these LPDs show similarities with other types of immunodeficiency associated LPDs. We suggest that cancer therapy-associated LPD be included in future classification systems for immunodeficiency-associated LPDs. PMID- 29112014 TI - HPV E6/E7 mRNA In Situ Hybridization in the Diagnosis of Cervical Low-grade Squamous Intraepithelial Lesions (LSIL). AB - Cervical low-grade squamous intraepithelial lesions (LSIL) (aka cervical intraepithelial neoplasia, grade 1 [CIN1]) can present considerable diagnostic challenges and are associated with poor interobserver reproducibility and overdiagnosis. Furthermore, ancillary studies such as p16 immunohistochemistry have shown little utility in resolving the LSIL versus negative/reactive differential. Human papillomavirus (HPV) RNA in situ hybridization (ISH) has shown promise as a diagnostic aid in this setting, but has not been studied in a large case series. We herein investigate high-risk and low-risk HPV RNA ISH in 126 cervical biopsies originally diagnosed as LSIL/CIN1 and compare HPV RNA ISH results to expert-adjudicated morphologic diagnosis to assess whether this assay can help routine cases attain the existing "gold standard" of morphologic consensus diagnosis. We also assess whether this criterion standard can be further improved by integration of HPV RNA ISH results. A consensus diagnosis of intraepithelial lesion (CIN1) was confirmed in 61% of cases, whereas 57% were HPV RNA. HPV-RNA positivity was 84% sensitive and 86% specific for an expert adjudicated diagnosis of CIN1. Conversely, consensus diagnosis was 90% sensitive and 78% specific for the presence of HPV RNA. Integrating RNA ISH into morphologic review led to further reclassification of 10% of cases, resulting in 95% sensitivity and 98% specificity of HPV RNA ISH for a CIN1 diagnosis and 98% sensitivity and 92% specificity of CIN1 for the presence of HPV RNA. These findings suggest that judicious use of HPV RNA ISH can improve the accuracy of LSIL/CIN1 diagnosis for morphologically ambiguous cases. PMID- 29112015 TI - PD-L1 and PD-L2 Are Differentially Expressed by Macrophages or Tumor Cells in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type. AB - As checkpoint molecules' inhibition may represent a therapeutic option in relapsing cases, we assessed programmed death ligands' (PD-L1/PD-L2) expression in a series of 29 primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) cases. Double immunostaining for either PD-L1 or PD-L2 was associated either with PAX5 staining to evaluate tumor cells or with CD68 or CD163 staining for macrophages. The microenvironment of PCDLBCL-LT was characterized by immunostainings for CD3 (tumor-infiltrating lymphocytes), FOXP3 (regulatory T cells), programmed cell death-1, and CD33 (myeloid-derived suppressor cells). The 9p24.1 locus encoding for PD-L1/PD-L2 was evaluated by fluorescence in situ hybridization. A PD-L1 expression was observed in all cases. However, double staining with PD-L1/PAX5 identified only 1 case harboring PD-L1 expression by tumor cells. All cases displayed PD-L1 expression by numerous immune cells, characterized as CD68 CD163 M2 macrophages. A normal fluorescence in situ hybridization pattern was observed in 21 of 26 cases. Three cases (11.5%) harbored a low polysomy status including the case with PD-L1 expression by tumor cells. Interestingly, 2 cases (7.7%) exhibited a PD-L1/PD-L2 locus break-apart pattern, and PD-L2 expression by tumor cells was observed. PD-L2 expression by tumor cells was not observed in the 24 cases without 9p24.1 rearrangement. Treating patients with relapsing PCDLBCL-LT by using immune checkpoint inhibitors may have an indirect effect through immune cells, except in rare cases with 9p24.1 rearrangement leading to PD-L2 expression by tumor cells. Reprogramming tumor-associated macrophages with anticancer therapies is appealing in such lymphoma subtypes wherein M2 macrophages represent the majority of immune cells. PMID- 29112016 TI - B Lymphoblastic Leukemia/Lymphoma With Burkitt-like Morphology and IGH/MYC Rearrangement: Report of 3 Cases in Adult Patients. AB - Isolated MYC rearrangement without other recurrent genetic abnormalities is rare in B lymphoblastic leukemia/lymphoma (B-ALL/LBL), with most cases reported in pediatric patients. We report 3 adult cases with lymphoblasts showing a precursor B cell immunophenotype, and isolated MYC/IGH translocation. All 3 cases occurred in male patients with initial presentation of diffuse lymphadenopathy. Cases 1 and 2 had B-ALL with significantly increased lymphoblasts in peripheral blood and bone marrow. Case 3, a patient with human immunodeficiency virus infection, had the diagnosis of B-LBL made on a retroperitoneal lymph node biopsy and had no peripheral blood or bone marrow involvement. The leukemic and lymphoma cells in all 3 cases demonstrated Burkitt lymphoma-like morphology with deeply basophilic cytoplasm and numerous cytoplasmic vacuoles. However, all 3 had immature immunophenotypes including expression of terminal deoxynucleotidyl transferase (TdT), absence of BCL6, and dim-to-negative CD45. CD20 was largely negative in 2 of 3 cases. All 3 had confirmed MYC/IGH translocation, but lacked rearrangements of BCL2 or BCL6. EBV was negative by Epstein-Barr virus encoded small RNA in situ hybridization. Treatment protocols varied, including both high-risk ALL-type (protocol 8707) and high-grade lymphoma regimens (hyper-CVAD [cyclophosphamide, vincristine, adriamycin, and dexamethasone]), but no patient achieved continuous complete remission. These cases seem to represent a distinct biological phenomenon, in which a MYC translocation may be acquired at an immature stage of differentiation, thus manifesting features of both B-ALL/LBL and Burkitt lymphoma. PMID- 29112017 TI - Neoplastic Lesions of Gastric Adenocarcinoma and Proximal Polyposis Syndrome (GAPPS) Are Gastric Phenotype. AB - : Neoplastic lesions of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) are gastric phenotype. GAPPS was reported in 2011 as a new autosomal dominant gastric polyposis syndrome characterized by involvement of the gastric body/fundus with sparing of the antrum by multiple polyps, reported to be primarily fundic gland polyps (FGPs), with progression to dysplasia and adenocarcinoma of intestinal type. Our series consists of 51 endoscopic biopsies and 5 gastrectomy specimens from 25 patients belonging to a previously defined GAPPS family. Slides were reviewed and further stains performed. Endoscopy was abnormal in 15 of the 25 patients: carpeting polyposis of the gastric body and fundus in 14 and a gastric mass without polyposis in one. The most common polypoid lesion (seen in 12 patients) was a disorganized proliferation of specialized/oxyntic glands high up in the mucosa involving the attenuated foveolar region around the gastric pits, which we have termed "hyperproliferative aberrant pits". Well developed FGP were seen in 10 patients. Established neoplastic lesions seen in 9 patients were: (1) discrete gastric adenomas, (2) multifocal "flat" dysplasia in the setting of hyperproliferative aberrant pits +/ FGPs, (3) adenomatous tissue associated with adenocarcinoma. All cases of dysplasia were of gastric phenotype based on morphology and mucin immunohistochemistry. IN CONCLUSION: (1) the spectrum of gastric pathology associated with GAPPS is wider than previously reported, (2) the earliest microscopic clue is the finding of hyperproliferative aberrant pits, and (3) the dysplasia is gastric phenotype and the subsequent adenocarcinoma may follow the gastric pathway of carcinogenesis. PMID- 29112018 TI - Tumor Budding and PDC Grade Are Stage Independent Predictors of Clinical Outcome in Mismatch Repair Deficient Colorectal Cancer. AB - Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P<0.000). Both budding and PDC grade were associated with WHO grade, perineural invasion, lympho vascular invasion, and extramural vascular invasion, and the presence of LNM in dMMR CRC (P<0.009). Independent predictors of LNM were PDC grade (odds ratio, 4.12; 95% confidence interval [CI], 1.69-10.04; P=0.011) and EMVI (odds ratio, 3.81; 95% CI, 1.56-9.19; P<0.000). Only pTstage (hazard ratio [HR], 4.11; 95% CI, 1.48-11.36; P=0.007) and tumor budding (HR, 2.99; 95% CI, 1.72-5.19; P<0.000) were independently associated with worse disease-free survival (DFS). If tumor budding was excluded from the model, PDC grade became significant for DFS (HR, 2.34; 95% CI, 1.34-4.09; P=0.003). WHO Grade does not independently correlate with clinical outcome in dMMR CRC. PDC grade and extramural vascular invasion are independent predictors of LNM. Tumor budding and pTstage are the best predictors of DFS. If tumor budding cannot be assessed, PDC grade may be used as a prognostic surrogate. PMID- 29112019 TI - Utility of p16 Immunohistochemistry in Evaluating Negative Cervical Biopsies Following High-risk Pap Test Results. AB - The Lower Anogenital Squamous Terminology (LAST) Standardization Project for human papilloma virus (HPV)-associated lesions specifically recommends the use of p16 immunohistochemistry (IHC) as an adjunct to morphologic assessment of cervical biopsies interpreted as negative or low-grade squamous intraepithelial lesion (LSIL) from patients with prior high-risk Pap test results (high-grade squamous intraepithelial lesion [HSIL], atypical squamous cells cannot exclude HSIL, atypical glandular cells [AGC], or HPV16 atypical squamous cells of undetermined significance [ASC-US]). The impetus for this recommendation is to increase detection of missed high-grade disease. However, the quality of evidence supporting this recommendation was lower than that for the other LAST recommendations addressing improved consistency in the diagnosis of HSIL with the use of p16. A database search spanning 10 years identified 341 cases (encompassing 736 discrete biopsy specimens) interpreted as negative for dysplasia from 330 patients with a prior high-risk Pap result (atypical squamous cells cannot exclude HSIL, HSIL, atypical glandular cells, not otherwise specified [AGC-NOS], atypical endocervical cells--NOS [AEC-NOS], and AEC-favor neoplastic). p16 IHC was performed and detected missed abnormalities in 11/341 (3.2%) cases. The abnormalities corresponded to missed foci of HSIL (cervical intraepithelial neoplasia [CIN] 2) (n=1), SIL-indeterminate grade (n=7), atypical squamous metaplasia (n=2), and LSIL [CIN1]) (n=1). Subsequent histologic follow up identified HSIL or greater in 6/8 (75%) p16 cases versus 20/79 (25.3%) p16 cases (P=0.0079). p16 IHC performed on biopsies interpreted as negative from patients with prior high-risk Pap test results increased the detection rate of missed SIL. A p16 result also significantly increased the likelihood of HSIL on subsequent biopsy. Although further studies are required to determine what percentage of missed HSIL justifies the additional cost, improved detection of HSIL in high-risk patients may lead to fewer diagnostic procedures and fewer patients lost to follow-up. PMID- 29112020 TI - Distinguishing Neurofibroma From Desmoplastic Melanoma: The Value of p53. AB - Distinguishing desmoplastic melanomas (DMs) from neurofibromas (NFs) can be histologically challenging in some cases. To date, a reliable marker to differentiate the 2 entities has remained elusive. S100 subtyping and CD34 fingerprinting have been proposed, but controversy remains as to their reliability. Missense mutations in TP53 are often found in DMs, resulting in a dominant negative effect and paradoxical accumulation of the tumor suppressor protein p53. We hypothesized that p53 may be expressed differentially in DMs, making it a valuable tool in differentiating DMs from NFs. Using immunohistochemistry, we compared p53 protein expression in 20 DMs and 20 NFs retrieved from our tissue archives and stained with p53 antibody (Monoclonal, DO 7). Patients with DM included 18 men and 2 women (age, 36 to 95 y; mean, 70.5 y; median, 70 y). Fifteen (15/20) tumors occurred in head and neck area; 2 (2/20) on the trunk; and 3 (3/20) on the extremities. Patients with NF included 12 men and 8 women (age, 47 to 85 y; mean, 65.2 y; median, 69.5 y). Eleven (11/20) tumors occurred on the trunk, 6 (6/20) on the extremities, and 3 (3/20) on the head and neck area. A total of 19/20 (95%) DMs were positive for p53. DM Histo-scores ranged from 0 to 300 (mean, 203; median, 260). Nuclear accumulation of p53 was seen in all 19 positive DMs. None of the 20 NFs were positive for p53 (2-tailed t test P-value <0.0001). Detection of p53 by immunohistochemistry can help to distinguish DMs from NFs. PMID- 29112021 TI - Heartmate III Replacement for Recurring Left Ventricular Assist Device Pump Thrombosis. AB - Left ventricular assist devices (LVADs) are being used widely to support patients with advanced systolic heart failure. Some of these patients will need more than one LVAD replacement due to pump thrombosis. The Heartmate III LVAD (Abbott Inc, Chicago, IL) recently has been shown to have a very low incidence of pump thrombosis. In this article, we describe cases of patients with multiple pump thrombosis events, who were successfully replaced with the Heartmate III. PMID- 29112022 TI - Handover Structure and Quality in the Acute Medical Assessment Unit: A Prospective Observational Study. AB - OBJECTIVES: Inadequate patient handovers are associated with the occurrence of medical errors. The objective of the present study was to explore the structure and quality of handovers in the acute medical assessment unit. METHODS: A prospective observational study was conducted in an academic hospital in the Netherlands. Handover structure was observed by ordering handover information according to the elements of the Situation, Background, Assessment, Recommendation, and Read back (SBAR-R) handover tool. Handover quality was measured by means of a questionnaire, i.e., the rating tool for handover quality, and by assessing situation awareness of the degree to which professionals after a handover agreed on the complexity of the patient's care needs. RESULTS: A total of 71 handovers were observed. In most handovers, different elements of the SBAR R were used frequently (median, 7.5 elements; range, 2.0-15.0). On the quality of handovers, 109 respondents (44.1%) completed the questionnaire. On a 0-to-100 scale, median scores on information transfer were 67.9 (interquartile range [IQR],17.9), 75.0 (IQR, 25.0) on shared understanding, and 75.0 (IQR, 16.7) on working atmosphere. Agreement in situation awareness was 70.0%. CONCLUSIONS: Handovers in the acute medical assessment unit were poorly structured; however, the perceived quality of handovers was substantial. Implementing the SBAR-R may be an effective strategy to improve handover practice and situation awareness, although further study to its applicability in acute medical assessment units is necessary. PMID- 29112023 TI - Behavior of Anesthesiology Residents in a Situation of Intravenous Route Occlusion During Syringe Pump Use in a Simulated Intensive Care Unit. AB - INTRODUCTION: Unintentional catecholamine flush caused by inappropriate release of an intravenous occlusion during use of a syringe pump in the intensive care unit (ICU) can have dangerous consequences in patients receiving critical care. We investigated whether anesthesiology residents understood how to deal with syringe pump occlusion in a simulated ICU setting. METHODS: We set up a mannequin that virtually simulated a sedated patient under mechanical ventilation after cardiac surgery, with epinephrine and dopamine being infused by syringe pumps to maintain blood pressure at 100/50 mm Hg. Prior to a participant entering the simulated ICU, one of the stopcocks for the catecholamine was occluded. Thereafter, the blood pressure of the mannequin dropped to 60/30 mm Hg. If the participant inappropriately released the occlusion, resulting in a catecholamine flush, an operator immediately elevated the blood pressure to 200/100 mm Hg. In the subsequent debriefing session, the simulation facilitator evaluated whether the participant could diagnose that intravenous occlusion was the cause of hypotension in this scenario. RESULTS: Sixteen anesthesiology residents participated in the study. Only 3 of 10 participants who had previous knowledge of how such situations should be handled could appropriately release back pressure. Eleven residents released the occlusion without relieving syringe pressure. After their debriefing sessions, all the participants were of the opinion that the present simulation training was impressive and useful for them. CONCLUSIONS: Anesthesiology residents might inappropriately handle a situation of intravenous occlusion in their clinical practice. It may be necessary for the manufacturers to improve the safety features of syringe pumps. PMID- 29112024 TI - Evaluation of Patient Safety Culture in Community Pharmacies. AB - OBJECTIVE: Medication errors are common in community pharmacies. Safety culture is considered a factor for medication safety but has not been measured in this setting. The objectives of this study were to describe safety culture measured using the Agency for Healthcare Research and Quality (AHRQ) Community Pharmacy Survey on Patient Safety Culture and to assess predictors of overall patient safety. METHODS: This is a cross-sectional survey of community pharmacists practicing in Wisconsin measuring safety culture. Demographic variables collected included pharmacist and pharmacy characteristics. Data were analyzed using descriptive statistics, chi, and multivariate logistic regression analyses. RESULTS: A total of 445 surveys were completed (response rate, 82%). Safety culture was positively associated with the following: an independent pharmacy (adjusted odds ratio [AOR], 1.69; 95% confidence interval [CI], 1.11-2.57), a health maintenance organization or clinic (AOR, 2.25; 95% CI, 1.34-3.78), being somewhat familiar with patients (AOR, 3.35; 95% CI, 1.82-6.19), or very/extremely familiar with patients (AOR, 8.8; 95% CI, 4.68-16.59). Five of the composite scores differed significantly from the results of the AHRQ pilot study (response to mistakes, communication openness, organizational learning-continuous improvement, communication about prescriptions across shifts, and overall patient safety). Consistent with the AHRQ pilot study, the composite describing staffing, work pressure, and pace had the lowest score (37.6%). CONCLUSIONS: Understanding the safety culture of community pharmacies can help identify areas of strength and those that require improvement. Improvement efforts that focus on staffing, work pressure, and pace in community pharmacies may lead to better safety culture. PMID- 29112025 TI - The Impact of Adverse Events on Clinicians: What's in a Name? AB - Unanticipated patient adverse events can also have a serious negative impact on clinicians. The term second victim was coined to highlight the experience of health professionals with these events and the need to effectively support them. However, there is some controversy over use of the term second victim. This article explores terminology used to describe the professionals involved in adverse events and services to support them. There is a concern that use of the term victim may connote passivity or stigmatize involved clinicians. Some patient advocates are also offended by the term, believing that it deemphasizes the experience of patients and families. Despite this, the term is now coming into widespread use by clinicians and health care managers as well as policy makers. As the importance of emotional support for clinicians continues to gain visibility, the terminology surrounding it will undoubtedly change and evolve. At this time, it may be most appropriate to label this important phenomenon in a way that local leaders are comfortable with-in a way that promotes its recognition and adoption of solutions. For example, for policy makers and health care managers, the term second victim may have value because it is memorable and connotes urgency. For support programs that appeal directly to health care workers, different language may attract more users. Debate concerning the benefits and drawbacks to this terminology will enhance and further drive its evolution, while helping retain our industry's focus on the importance of developing and evaluating programs to support clinicians in need. PMID- 29112026 TI - Nursing Home Patient Safety Culture Perceptions Among US and Immigrant Nurses. AB - : Patient safety is a global concern, yet little is known about how and whether perceptions of patient safety culture (PSC) vary by nurses' countries of origin and preparation. This is particularly important in American nursing homes (NHs), which are increasingly hiring non-US born and prepared nurses to fill staffing needs. OBJECTIVES: This study compared the PSC perceptions of foreign and domestic born and trained nurses working in urban NHs in 5 states to analyze how nurses' PSC perceptions corresponded to their personal and professional characteristics. METHODS: We distributed 3539 surveys to registered nurses and licensed practical/vocational nurses employed in 98 urban NHs across 5 states with higher percentages of internationally prepared nurse workers. Respondents' perceptions of their workplace safety culture were measured with the NH Survey on PSC survey from the Agency for Healthcare Research and Quality (AHRQ) and examined 12 dimensions of PSC. A total of 1629 returned surveys indicated a 46% returned rate. RESULTS: Results from 1133 analyzed surveys indicated that nurses born and educated abroad exhibited more favorable PSC perceptions in their workplaces, followed by nurses born abroad and educated in the United States. Nurses born and educated in the United States demonstrated the lowest perceptions of workplace PSC overall (P < 0.001). CONCLUSIONS: Although foreign born and trained nurses report higher PSC perceptions than domestically born and educated nurses, further research is needed to understand why these differences occur. PMID- 29112027 TI - Dentists Survey on Adverse Events During Their Clinical Training. AB - BACKGROUND: Adverse events (AEs) begin challenging the safe practice of dentistry early when students start treating patients at dental school. We assessed the frequency with which dentists caused common AEs during their undergraduate clinical training. METHODS: A convenience sample of dentists, graduated from more than 34 dental schools in Mexico and other Spanish speaking countries, answered a confidential, self-administered questionnaire with closed-format questions on common AEs they caused and their active errors that could have led to AEs in the teaching clinics. RESULTS: Of 207 participants, 80% had graduated recently. As undergraduates, 79% caused AEs; 38% admitted to causing one adverse event, 41% to causing two or more, and 36% committed active errors that could have hurt patients. No significant associations between AEs and sex or type of school were observed. CONCLUSIONS: The results indicate that dental students caused AEs or committed errors that placed patients at risk, during their clinical training. PRACTICAL IMPLICATIONS: Dental schools must identify challenges to patient safety at their teaching clinics and introduce risk reduction strategies to protect their patients and foster a safety culture in dental education. PMID- 29112028 TI - Implementation of an Electronic Checklist to Improve Patient Handover From Ward to Operating Room. AB - OBJECTIVE: Research has identified numerous safety risks in perioperative patient handover. In handover from ward to operating room (OR), patients are often transferred by a third person. This adds to the risk of loss of important information and of caregivers in the OR not identifying possible risk factors. The aim of this study was to describe the implementation process and completion rate of a new preoperative, ward-to-OR checklist. Our goal was a 90% fulfillment. METHOD: This study is a prospective, observational study in a Danish University Hospital including all patients undergoing surgery in 2013. The checklist was a screen page with 27 checkboxes of information relevant for a safe handover. The checklist should be completed in the ward before handover to the OR and should be checked in the OR before receiving the patient. The Plan-Do-Study-Act (PDSA) cycle method was used in the implementation process of the checklist. RESULTS: A total of 17.361 patients were included. In wards with only elective surgery (plastic and breast surgery), the checklist was used in 1.419 of 2.286 patients (62.1%). In wards with both elective and emergency surgery (abdominal, orthopedic, urology, gynecology and obstetrics), the checklist was used in 1.963 of 7.460 elective patients (26.3%) and in 812 of 7.615 emergency patients (10.7 %). CONCLUSION: Our goal of a 90% fulfillment was not reached. The electronic checklist seemed to be used most frequently in wards with only elective surgery. PMID- 29112029 TI - Identifying Risks and Opportunities in Outpatient Surgical Patient Safety: A Qualitative Analysis of Veterans Health Administration Staff Perceptions. AB - OBJECTIVES: Little is known about patient safety risks in outpatient surgery. Inpatient surgical adverse events (AEs) risk factors include patient- (e.g., advanced age), process- (e.g., inadequate preoperative assessment), or structure related characteristics (e.g., low surgical volume); however, these factors may differ from outpatient care where surgeries are often elective and in younger/healthier patients. We undertook an exploratory qualitative research project to identify risk factors for AEs in outpatient surgery. METHODS: We developed a conceptual framework of patient, process, and structure factors associated with surgical AEs on the basis of a literature review. This framework informed our semistructured interview guide with (1) open-ended questions about a specific outpatient AE that the participant experienced and (2) outpatient surgical patient safety risk factors in general. We interviewed nationwide Veterans Health Administration surgical staff. Results were coded on the basis of categories in the conceptual framework, and additional themes were identified using content analysis. RESULTS: Fourteen providers representing diverse surgical roles participated. Ten reported witnessing an AE, and everyone provided input on risk factors in our conceptual framework. We did not find evidence that patient race/age, surgical technique, or surgical volume affected patient safety. Emerging factors included patient compliance, postoperative patient assessments/instruction, operating room equipment needs, and safety culture. CONCLUSIONS: Surgical staff are familiar with AEs and patient safety problems in outpatient surgery. Our results show that processes of care undertaken by surgical providers, as opposed to immutable patient characteristics, may affect the occurrence of AEs. The factors we identified may facilitate more targeted research on outpatient surgical AEs. PMID- 29112030 TI - Nurses' Views Highlight a Need for the Systematic Development of Patient Safety Culture in Forensic Psychiatry Nursing. AB - BACKGROUND: Although forensic nurses work with the most challenging psychiatric patients and manifest a safety culture in their interactions with patients, there have been few studies on patient safety culture in forensic psychiatric nursing. OBJECTIVES: The aim of this qualitative study was to describe nurses' views of patient safety culture in their working unit and daily hospital work in 2 forensic hospitals in Finland. METHODS: Data were collected over a period of 1 month by inviting nurses to answer an open-ended question in an anonymous Web based questionnaire. A qualitative inductive analysis was performed on nurses' (n = 72) written descriptions of patient safety culture in state-owned forensic hospitals where most Finnish forensic patients are treated. RESULTS: Six main themes were identified: "systematization of an open and trusting communication culture," "visible and close interaction between managers and staff," "nonpunitive responses to errors, learning and developing," "balancing staff and patient perspectives on safety culture," "operational safety guidelines," and "adequate human resources to ensure safety." CONCLUSIONS: The findings highlight the influence of the prevailing culture on safety behaviors and outcomes for both healthcare workers and patients. Additionally, they underline the importance of an open culture with open communication and protocols. PMID- 29112031 TI - How Differences Between Manager and Clinician Perceptions of Safety Culture Impact Hospital Processes of Care. AB - OBJECTIVE: Evidenced-based processes of care improve patient outcomes, yet universal compliance is lacking, and perceptions of the quality of care are highly variable. The purpose of this study is to examine how differences in clinician and management perceptions on teamwork and communication relate to adherence to hospital processes of care. METHODS: Hospitals submitted identifiable data for the 2012 Hospital Survey on Patient Safety Culture and the Centers for Medicare and Medicaid Services' Hospital Compare. The dependent variable was a composite, developed from the scores on adherence to acute myocardial infarction, heart failure, and pneumonia process of care measures. The primary independent variables reflected 4 safety culture domains: communication openness, feedback about errors, teamwork within units, and teamwork between units. We assigned each hospital into one of 4 groups based on agreement between managers and clinicians on each domain. Each hospital was categorized as "high" (above the median) or "low" (below) for clinicians and managers in communication and teamwork. RESULTS: We found a positive relationship between perceived teamwork and communication climate and processes of care measures. If managers and clinicians perceived the communication openness as high, the hospital was more likely to adhere with processes of care. Similarly, if clinicians perceived teamwork across units as high, the hospital was more likely to adhere to processes of care. CONCLUSIONS: Manager and staff perceptions about teamwork and communications impact adherence to processes of care. Policies should recognize the importance of perceptions of both clinicians and managers on teamwork and communication and seek to improve organizational climate and practices. Clinician perceptions of teamwork across units are more closely linked to processes of care, so managers should be cognizant and try to improve their perceptions. PMID- 29112033 TI - Barriers to Speaking Up About Patient Safety Concerns. AB - OBJECTIVES: We sought to examine the association between willingness of health care professionals to speak up about patient safety concerns and their perceptions of two types of organizational culture (ie, safety and teamwork) and understand whether nursing professionals and other health-care professionals reported the same barriers to speaking up about patient safety concerns. METHODS: As part of an annual safety culture survey in a large health-care system, we asked health-care professionals to tell us about the main barriers that prevent them from speaking up about patient safety concerns. Approximately 1341 respondents completed the anonymous, electronic survey. RESULTS: A little more than half (55%) of the participants mentioned leadership (fear of no change or retaliation) and personal (ie, fear of negative feedback or being wrong) barriers concerning why they would not speak up about patient safety concerns. The remaining participants (45%) indicated they would always speak up. These findings about barriers were consistent across nurses and other health-care professionals. Safety culture (SC) and teamwork culture (TC) scores were significantly more positive in those indicating they would always speak up (SC = 89%, TC = 89%) than in those who provided reasons for not speaking up (SC = 63%, TC = 64%) (t1205 = 13.99, P < 0.05, and t1217 = 13.61, P < 0.05, respectively). CONCLUSIONS: Health care professionals emphasized leadership and personal barriers as reasons for not speaking up. We also demonstrated an association between not speaking up and lower safety and teamwork culture scores. PMID- 29112032 TI - Room Traffic in Orthopedic Surgery: A Prospective Clinical Observational Study of Time of Day. AB - OBJECTIVE: High rates of operating room (OR) traffic may contribute to surgical air contamination and surgical site infections (SSIs). The purpose of this study was to evaluate room traffic patterns in orthopedic implant procedures to determine the frequency of door openings and if time of day had an effect on room traffic. METHODS: In 2015, OR traffic was assessed in orthopedic implant cases. Room traffic was reported as the number of door openings per minute. Counts of how many people were present in the operating room were noted in 5-minute intervals from the time of sterile case opening to dressing placement. Operative cases were observed and categorized into 3 periods (6:00-9:59, 10:00-13:59, and 14:00-17:59) to assess if time of day affected room traffic. RESULTS: Forty-six cases were observed for the present study. Among all cases, the mean room traffic rate was 35.2 openings per hour (SD, 10; range, 13.2-60.8). One-way analysis of variance revealed no statistically significant difference among groups (6:00-9:59 [n = 29], 10:00-13:59 [n = 10], and 14:00-17:59 [n = 7]) as it relates door openings per minute (room traffic rate) (P = 0.9237) or mean number of people in the OR (P = 0.3560). Pearson correlation revealed no correlation between case start time and room traffic rates (P = 0.6129, r = 0.0059) or between case start time and mean number of people in the OR (P = 0.3435, r = 0.0214). CONCLUSIONS: Room traffic rates and mean number of people in the OR do not correlate with time of day of case in orthopedic implant procedures. PMID- 29112034 TI - Learning From Incident Reporting? Analysis of Incidents Resulting in Patient Injuries in a Web-Based System in Swedish Health Care. AB - OBJECTIVES: Incident reporting (IR) systems have the potential to improve patient safety if they enable learning from the reported risks and incidents. The aim of this study was to investigate incidents registered in an IR system in a Swedish county council. METHODS: The study was conducted in the County Council of Ostergotland, Sweden. Data were retrieved from the IR system, which included 4755 incidents occurring in somatic care that resulted in patient injuries from 2004 to 2012. One hundred correctly classified patient injuries were randomly sampled from 3 injury severity levels: injuries leading to deaths, permanent harm, and temporary harm. Three aspects were analyzed: handling of the incident, causes of the incident, and actions taken to prevent its recurrence. RESULTS: Of the 300 injuries, 79% were handled in the departments where they occurred. The department head decided what actions should be taken to prevent recurrence in response to 95% of the injuries. A total of 448 causes were identified for the injuries; problems associated with procedures, routines, and guidelines were most common. Decisions taken for 80% of the injuries could be classified using the IR system documentation and root cause analysis. The most commonly pursued type of action was change of work routine or guideline. CONCLUSIONS: The handling, causes, and actions taken to prevent recurrence were similar for injuries of different severity levels. Various forms of feedback (information, education, and dialogue) were an integral aspect of the IR system. However, this feedback was primarily intradepartmental and did not yield much organizational learning. PMID- 29112035 TI - How Can Safer Care Be Achieved? Patient Safety Officers' Perceptions of Factors Influencing Patient Safety in Sweden. AB - OBJECTIVE: This study aimed to survey health care professionals in Sweden on the factors that they believe have been most important in reaching the current level of patient safety and achieving safer care in the future as well as the characteristics of the county councils that have been the most successful in achieving safe care. METHODS: The study population consisted of 222 patient safety officers, that is, health care professionals with strategic positions in patient safety work in the county councils. A postal questionnaire was used for data collection. RESULTS: The survey response rate was 70%. The factors that were considered most important for the current level of patient safety were efforts to reduce the use of antibiotics; Swedish patient safety law; and internal discussions with the county council management, heads of health care units, health care providers, and so on. The factors that were considered most important to achieve safer care in the future were improved communication between health care practitioners and patients, improved organizational culture, improved communication, and patient safety knowledge as a compulsory component of basic education for health care practitioners. CONCLUSIONS: Several factors rated highly for achieving the current level of patient safety are part of the government-supported financial incentive plan. Patient safety is attributed to a broad range of factors, and many solutions might contribute to improved patient safety in the future. The most successful county councils are characterized by leadership support for patient safety, well-organized patient safety work, long term commitment to patient safety, and an organizational culture that is conducive to patient safety. PMID- 29112036 TI - Succession Planning in State Health Agencies in the United States: A Brief Report. AB - OBJECTIVE: Approximately 25% of the public health workforce plans to retire by 2020. Succession planning is a core capability of the governmental public health enterprise; however, limited data are available regarding these efforts in state health agencies (SHAs). METHODS: We analyzed 2016 Workforce Gaps Survey data regarding succession planning in SHAs using the US Office of Personnel Management's (OPM's) succession planning model, including 6 domains and 27 activities. Descriptive statistics were calculated for all 41 responding SHAs. RESULTS: On average, SHAs self-reported adequately addressing 11 of 27 succession planning activities, with 93% of SHAs adequately addressing 1 or more activities and 61% adequately addressing 1 or more activities in each domain. CONCLUSIONS: The majority of OPM-recommended succession planning activities are not being addressed, and limited succession planning occurs across SHAs. Greater activity in the OPM-identified succession planning domains may help SHAs contend with significant turnover and better preserve institutional knowledge. PMID- 29112037 TI - The Public Health Workforce Taxonomy: Revisions and Recommendations for Implementation. AB - Public health workforce size and composition have been difficult to accurately determine because of the wide variety of methods used to define job title terms, occupational categories, and worker characteristics. In 2014, a preliminary consensus-based public health workforce taxonomy was published to standardize the manner in which workforce data are collected and analyzed by outlining uniform categories and terms. We summarize development of the taxonomy's 2017 iteration and provide guidelines for its implementation in public health workforce development efforts. To validate its utility, the 2014 taxonomy was pilot tested through quantitative and qualitative methods to determine whether further refinements were necessary. Pilot test findings were synthesized, themed by axis, and presented for review to an 11-member working group drawn from the community of experts in public health workforce development who refined the taxonomy content and structure through a consensus process. The 2017 public health workforce taxonomy consists of 287 specific classifications organized along 12 axes, intended for producing standardized descriptions of the public health workforce. The revised taxonomy provides enhanced clarity and inclusiveness for workforce characterization and will aid public health workforce researchers and workforce planning decision makers in gathering comparable, standardized data to accurately describe the public health workforce. PMID- 29112038 TI - Calculating State-Level Estimates of Upcoming Older Adult Health Needs. AB - OBJECTIVES: Census demographers have provided projections of the increased numbers of older adults in upcoming decades, but it is less clear whether they will also be any more or less healthy than current seniors. This is critical information for state planners, as the majority of older adults will need assistance with activities of daily living to remain in their homes. Previous longitudinal and cohort studies have yielded national estimates, but those more costly sources are generally beyond the resources of state public health agencies. We provide a more practicable model for assessing state-level changes in health-related quality of life (HRQOL) among middle-aged versus older adults as a guide to probable upcoming home- and community-based service needs. METHODS: We used 2 sets of state Behavioral Risk Factor Surveillance System data 15 years apart to calculate and compare adjusted odds ratios of 8 poor HRQOL measures for middle-aged and older adults. RESULTS: Compared with their peers only 15 years earlier, recent middle-aged adults had higher odds of poor outcomes across all HRQOL measures, whereas adults 65-74 years had higher odds of poor outcomes for far fewer of the measures. Among adults 75 years and older, odds were higher compared with 15 years ago for only 1 measure (multiple days of poor mental health). CONCLUSIONS: Compared with older adults, the health profile of middle aged adults in this state appears to have worsened much more rapidly in the past 15 years, indicating that these adults will have many more health-related needs when they become seniors. While this model is less sophisticated than others using longitudinal data, it provides the state-level data that are often more compelling to state policy makers. PMID- 29112040 TI - Using Data Analytics as Evidentiary Support for Financial Outcome Success in Nurse-Led Population-Based Clinics. AB - Achieving the highest quality in health care requires organizations to develop clinical improvements that result in measurable outcomes for success. The purpose of this article is to demonstrate an example of clinical quality improvement through the use of data analytics to generate evidence for financial return on investment in two nurse-led, population-based clinics. PMID- 29112044 TI - Don't fall for predatory conferences either. PMID- 29112041 TI - Alcohol and Mortality: Combining Self-Reported (AUDIT-C) and Biomarker Detected (PEth) Alcohol Measures Among HIV Infected and Uninfected. AB - BACKGROUND: Unhealthy alcohol use may be particularly detrimental among individuals living with HIV and/or hepatitis C virus (HCV), and is often under reported. Direct biomarkers of alcohol exposure may facilitate improved detection of alcohol use. METHODS: We evaluated the association of alcohol exposure determined by both self-report [Alcohol Use Disorders Identification Test Consumption (AUDIT-C)] and a direct biomarker [phosphatidylethanol (PEth)], with mortality among HIV-infected and HIV-uninfected in the Veterans Aging Cohort Study-Biomarker Cohort. We considered PEth <8 ng/mL to represent no alcohol use. Alcohol exposure by AUDIT-C scores [0, 1-3/1-2 (men/women), 4-7/3-7 (men/women), 8-12] and PEth (<8, >=8) was combined into categories to model the relationship of alcohol with mortality. Participants were followed from blood collection date for 5 years or until death within 5 years. RESULTS: The sample included 2344 (1513 HIV+; 831 uninfected) individuals, 95% men. During a median follow-up of 5 years, 13% died. Overall, 36% were infected with HCV (40% HIV+/HCV+, 27% HIV /HCV+). Overall, 43% (1015/2344) had AUDIT-C = 0 (abstinence). Of these, 15% (149/1015) had PEth >=8 suggesting recent alcohol exposure. Among those with AUDIT-C = 0, HCV+ individuals were more likely to have PEth >=8. After controlling for age, sex, race, HIV, HCV, and HIV viral suppression, those with AUDIT-C = 0 but PEth >=8 had the highest risk of mortality (adjusted hazard ratio 2.15, 95% confidence interval: 1.40 to 3.29). CONCLUSIONS: PEth in addition to self-report may improve detection of alcohol use in clinical settings, particularly among those at increased risk of harm from alcohol use. Individuals infected with HCV were more likely to under-report alcohol use. PMID- 29112042 TI - Network Viral Load: A Critical Metric for HIV Elimination. AB - BACKGROUND: Associations have been observed between an aggregate viral load measure, the community viral load, and new HIV diagnoses. The community viral load aggregates viral loads within chosen geographic areas, restricting inferences about HIV acquisition risk to these areas. We develop a more precise metric, the network viral load (NVL), to measure the composite viral load within a risk network of a HIV-negative individual. METHODS: We examined the relationship between NVL and HIV infection among young men who have sex with men in Chicago, United States. Networks were generated using respondent-driven sampling. NVL was defined as the prevalence of viremic individuals in one's risk network, characterized as those with a viral load >=20 k copies per milliliter. Permutation tests were conducted to account for dependency. RESULTS: After controlling for total connections, age, substance use during sex, syphilis diagnosis (previous 12 months), and frequency of condomless anal sex (previous 6 months), we found a positive association between NVL and HIV infection. Compared with a network with all HIV-seronegative members, the odds of HIV infection with an NVL of <10% viremia were 1.85 (95% confidence interval: 1.18 to 2.92) times higher and those with an NVL of >=10% viremia were 2.73 (95% confidence interval: 1.54 to 4.85) times higher. CONCLUSIONS: We found a positive association between NVL and HIV seroprevalence. Although limited in its ability to infer causality, NVL could have substantial public health implications for persons most at risk for HIV infection, given that this novel metric avoids overreliance on individual level behavior or broad community indices. PMID- 29112045 TI - Managing panhypopituitarism in adults. PMID- 29112043 TI - Coercion and HIV Self-Testing in Men Who Have Sex With Men: Implementation Data From a Cross-Sectional Survey in China. PMID- 29112046 TI - Rapid response teams: What's the latest? PMID- 29112047 TI - Memantine, an NMDA Receptor Antagonist, Prevents Thyroxin-induced Hypertension, but Not Cardiac Remodeling. AB - Stimulation of glutamatergic tone has been causally linked to myocardial pathogenesis and amplified systemic blood pressure (BP). Memantine, a noncompetitive N-methyl-D-aspartate glutamatergic receptor (NMDA-R) antagonist, has been proposed to be an active cardioprotective drug. However, the efficacy of memantine and subsequently the possible involvement of the NMDA-R in the thyroxin (T4)-induced cardiovascular complications have never been investigated. We examined the effect of memantine (30 mg.kg.d) on the T4 (500 MUg.kg.d)-provoked increase in mouse BP, cardiac hypertrophy indicated by enlarged overall myocardial mass, and reformed reactions of the contractile myocardium both in vivo and ex vivo after 2 weeks of treatment. Memantine alone did not result in any cardiovascular pathology in mice. Instead, memantine significantly prevented the T4-triggered systemic hypertension. But, it did not reverse cardiac hypertrophy, coupled in vivo left ventricular dysfunction (LV) or ex vivo right ventricular (RV) papillary muscle contractile alterations of the T4-treated mice. Our results openly direct the cardiovascular safety and tolerability of memantine therapy. Yet, extra research is necessary to endorse these prospective advantageous outcomes. Also, we believe that this is the first study to inspect the possible role of NMDA-R in the T4-stimulated cardiovascular disorders and concluded that NMDA-R could play a key role in the T4-induced hypertension. PMID- 29112048 TI - Results of a Community-based, Randomized Study Comparing a Clear Liquid Diet With a Low-residue Diet Using a Magnesium Citrate Preparation for Screening and Surveillance Colonoscopies. AB - BACKGROUND: Current bowel preparations for colonoscopy include a clear liquid diet (CLD) along with consumption of a laxative. This dietary restriction along with large volume bowel preparations are barriers to compliance and willingness among patients in scheduling screening examinations. The aim of our study was to compare the efficacy and tolerability of a low-volume split dose magnesium citrate bowel preparation in patients on a low-residue diet (LRD) with those on a CLD. METHODS: In this single center, single blinded, randomized controlled trial, patients scheduled for outpatient colonoscopies were assigned to either a CLD or a LRD 1 day before the examination. Both groups received a split dose magnesium citrate preparation. The quality of the preparation was rated using the Boston Bowel Preparation Scale (BBPS). Patient satisfaction and side effects were evaluated using a questionnaire. RESULTS: We were unable to detect a significant difference in the BBPS scores between the LRD and CLD groups (P=0.581). A significantly higher percentage of patients in the LRD group rated the diet as easy compared with the CLD group (P<0.001). Satisfaction scores were significantly higher in the LRD group, compared with the CLD group (P<0.001). The side effect profiles of both arms were similar. CONCLUSIONS: There was no significant difference between LRD and CLD in patients using a magnesium citrate bowel preparation for screening and surveillance colonoscopies. Patient satisfaction scores were higher with a LRD compared with a CLD. We believe the LRD should be the recommended diet in patients using a standard bowel preparation for screening and surveillance colonoscopy. PMID- 29112049 TI - Compassion Practices, Nurse Well-Being, and Ambulatory Patient Experience Ratings. AB - BACKGROUND: Compassion practices both recognize and reward compassion in the workplace as well as provide compassionate support to health care employees. However, these practices represent an underexplored organizational tool that may aid clinician well-being and positively impact patient ambulatory care experiences. OBJECTIVE: To examine the relationship between compassion practices and nursing staff well-being and clinic-level patients' experience ratings in the ambulatory clinic setting. RESEARCH DESIGN: Surveys were collected from ambulatory nurses in January and February of 2015 in 30 ambulatory clinics affiliated with an academic medical center. Patient experience ratings were collected April to June of 2015. SUBJECTS: One hundred seventy-seven ambulatory nurses (Registered Nurses, LPNs, medical assistants), as well as 3525 adult patients from the ambulatory clinics. MEASURES: Ambulatory nurses assessed compassion practices, emotional exhaustion, and psychological vitality. Patient experience ratings were patient perceptions of courtesy and caring shown by nurses and patients' ratings of the outpatient services. RESULTS: Compassion practices are significantly and negatively associated with nurse emotional exhaustion and positively associated with nurse psychological vitality. At the clinic-level, compassion practices are significantly and positively associated with patient perceptions of caring shown by nurses and overall patient ratings of the outpatient clinic. Supplemental analyses provide preliminary evidence that nurse well-being mediates the relationship between compassion practices and patient ratings of their care experience. CONCLUSIONS: Our findings illustrate that compassion practices are positively associated with nurse well-being and patient perceptions of the care experience in outpatient clinics. PMID- 29112050 TI - Inference With Difference-in-Differences With a Small Number of Groups: A Review, Simulation Study, and Empirical Application Using SHARE Data. AB - BACKGROUND: Difference-in-differences (DID) estimation has become increasingly popular as an approach to evaluate the effect of a group-level policy on individual-level outcomes. Several statistical methodologies have been proposed to correct for the within-group correlation of model errors resulting from the clustering of data. Little is known about how well these corrections perform with the often small number of groups observed in health research using longitudinal data. METHODS: First, we review the most commonly used modeling solutions in DID estimation for panel data, including generalized estimating equations (GEE), permutation tests, clustered standard errors (CSE), wild cluster bootstrapping, and aggregation. Second, we compare the empirical coverage rates and power of these methods using a Monte Carlo simulation study in scenarios in which we vary the degree of error correlation, the group size balance, and the proportion of treated groups. Third, we provide an empirical example using the Survey of Health, Ageing, and Retirement in Europe. RESULTS: When the number of groups is small, CSE are systematically biased downwards in scenarios when data are unbalanced or when there is a low proportion of treated groups. This can result in over-rejection of the null even when data are composed of up to 50 groups. Aggregation, permutation tests, bias-adjusted GEE, and wild cluster bootstrap produce coverage rates close to the nominal rate for almost all scenarios, though GEE may suffer from low power. CONCLUSIONS: In DID estimation with a small number of groups, analysis using aggregation, permutation tests, wild cluster bootstrap, or bias-adjusted GEE is recommended. PMID- 29112051 TI - A Comparison of the Effects of Short-Term Plyometric and Resistance Training on Lower-Body Muscular Performance. AB - Whitehead, MT, Scheett, TP, McGuigan, MR, and Martin, AV. A comparison of the effects of short-term plyometric and resistance training on lower-body muscular performance. J Strength Cond Res 32(10): 2743-2749, 2018-The purpose of this study was to compare effects of short-term plyometric and resistance training on lower-body muscular performance. A convenience sample of 30 male subjects aged 21.3 +/- 1.8 years (height, 177.3 +/- 9.4 cm; mass, 80.0 +/- 2.6 kg; body fat, 16.1 +/- 1.2%) participated in this investigation. Participants were grouped, and they participated in progressive plyometric (PLT) or resistance training (SRT) twice per week for 8 consecutive weeks or a control (CNT) group that did not participate in any training. Performance tests were administered before and after the training period, and it included measures of high-speed muscular strength (standing long jump, vertical jump), low-speed muscular strength (1-repetition maximal back squat), running speed (20-m sprint), and running agility (505 agility test). Analysis of variance followed by post hoc analyses was performed to determine significant differences between the groups. Significance set at p <= 0.05 for all analyses. Significant improvements were observed in the PLT group for standing long jump, vertical jump, and 1-repetition maximal back squat compared with the CNT group and for vertical jump as compared with the SRT group. Significant improvements were observed in the SRT group 1-repetition maximal back squat compared with the CNT group. There were no differences observed between any of the groups for the 20-m sprint or the 505 agility test after the training. These data indicate that 8 weeks of progressive plyometric training results in improvements in parameters of high-speed and low-speed muscular strength with no appreciable change in speed or agility. Additionally, the improvement in low speed muscular strength observed from 8 weeks of progressive plyometric training was comparable to the results observed from 8 weeks of progressive strength training. PMID- 29112052 TI - Training Load Indices, Perceived Tolerance, and Enjoyment Among Different Models of Resistance Training in Older Adults. AB - Conlon, JA, Haff, GG, Tufano, JJ, and Newton, RU. Training load indices, perceived tolerance, and enjoyment among different models of resistance training in older adults. J Strength Cond Res 32(3): 867-875, 2018-The purpose of this study was to investigate the relationship between volume load (VL), training monotony, and strain, and perceived tolerance and enjoyment, across periodized and nonperiodized (NP) resistance training (RT) in older adults. Forty-one healthy, untrained apparently healthy older adults (women = 21, men = 20; 70.9 +/ 5.1 years; 166.3 +/- 8.2 cm; 72.9 +/- 13.4 kg) were randomly stratified into a NP, block periodized (BP), or daily undulating periodized (DUP) group and completed a 22-week RT intervention at a frequency of 3 d.wk. All training was executed on RT machines and training volume was equalized between training groups based on total repetitions. Despite statistical differences in VL, training monotony, and strain between NP, BP, and DUP RT, perceived tolerance and enjoyment were similar across training models. Therefore, no meaningful relationships between training load indices (VL, monotony, and strain) and perceived tolerance and enjoyment were evident. Based on these results, periodization strategies do not appear to impact perceived tolerance or enjoyment of RT among the elderly, yet are recommended for better management of training load, potentially reducing the risk of illness and injury and promoting long-term adherence. Above all, practitioners should promote a friendly, supportive, and motivating training environment to increase program adherence and consequent training adaptations. PMID- 29112053 TI - Concurrent Validity and Reliability of a Linear Positional Transducer and an Accelerometer to Measure Punch Characteristics. AB - Lambert, C, Beck, BR, and Weeks, BK. Concurrent validity and reliability of a linear positional transducer and an accelerometer to measure punch characteristics. J Strength Cond Res 32(3): 675-680, 2018-Punch speed is an important factor in the sport of boxing, and its measurement has important implications for monitoring training progression and outcomes. The aim of the current study was to establish the concurrent validity and reliability of a linear positional transducer and an accelerometer for the quantification of punch characteristics in untrained adults. Men and women aged 18-30 years with no previous boxing experience and no upper-limb musculoskeletal injuries were recruited. Participants performed 6 straight right punches; 3 at a self determined 50% effort; and 3 at maximum effort. An accelerometer (Crossbow) and a linear positional transducer (GymAware) were used to examine peak velocity and acceleration of each punch. Validity was examined using Pearson's correlation analyses and by calculating mean bias and limits of agreement between measures from each device, whereas reliability was established using intraclass correlation coefficients (ICCs). Forty-four healthy young adults (28M and 16F; age 22.2 +/- 2.9 years) participated. Moderate-to-strong positive associations were observed for both devices at 50% effort for velocity (r = 0.572-0.696) and acceleration (r = 0.867-0.921) and at maximum effort for velocity (r = 0.748 0.781) and acceleration (r = 0.897-0.946). High levels of reliability were observed with maximum punches for both devices (ICC = 0.922-0.981). Overall, moderate-strong measurement validity and reliability for punch speed was observed between the accelerometer and GymAware. Thus, the GymAware linear positional transducer is an acceptable measurement tool for the quantification of punch speed for straight punches in untrained adults. PMID- 29112054 TI - Lower Extremity Stiffness: Considerations for Testing, Performance Enhancement, and Injury Risk. AB - Brazier, J, Maloney, S, Bishop, C, Read, PJ, and Turner, AN. Lower extremity stiffness: considerations for testing, performance enhancement, and injury risk. J Strength Cond Res XX(X): 000-000, 2017-Force-deformation characteristics of the lower limb have been associated with athletic performance and may modulate the risk of injury. Despite these known associations, measurements of lower extremity stiffness are not commonly administered by strength and conditioning coaches. This review provides an overview of the available literature pertaining to the effects of lower extremity stiffness on physical performance and injury risk. Practical methods of monitoring and training stiffness are also discussed. The cumulative body of evidence indicates that increases in lower extremity stiffness are associated with heightened performance in athletic tasks such as hopping, jumping, throwing, endurance running, sprinting, and changing direction. Relationships with injury are less conclusive because both excessive and insufficient limb stiffness have been postulated to increase risk. Thus, the "optimal" level of stiffness seems to be dependent on the anthropometry and physical capabilities of the athlete, in addition to sport-specific activity demands. Training interventions can positively enhance lower extremity stiffness, including isometric, eccentric, and isotonic strength training and plyometrics. Complex training also seems to provide a potent stimulus and may be more effective than the use of singular training modes. For plyometric activities, it is recommended that coaches use a developmental sequence of exercises with increasing eccentric demand to provide an appropriate stimulus based on the training age and technical competency of the athlete. PMID- 29112055 TI - Self-Selected Resistance Exercise Load: Implications for Research and Prescription. AB - Barbosa-Netto, S, d'Acelino-e-Porto, OS, and Almeida, MB. Self-selected resistance exercise load: implications for research and prescription. J Strength Cond Res XX(X): 000-000, 2017-Resistance training has been widely used for maintaining or improving the quality of life and sports performance. It is not clear, however, whether the load commonly used in these exercises is equivalent to the number of repetitions determined for execution, that is, the level of effort applied to the self-selected load. Ergo, the aim of this study was to identify the number of maximum repetitions that strength training practitioners can perform with the load commonly used (self-selected) to perform 10 repetitions in their training routines. The sample consisted of 160 healthy trained men (25.7 +/- 4.5 years, 81.2 +/- 10.4 kg, 177.9 +/- 6.2 cm). Subjects answered the question "What weight do you usually lift for 10 repetitions on free-weight bench press exercise?" The answer was considered the self-selected 10 repetitions load (S10RL). After a brief warm-up, each individual was instructed to perform as many repetitions as possible at S10RL (repetition maximum [RMS10RL]) at a single bout of free-weight bench press. The RMS10RL was analyzed with the single sample t test, adopting the reference value of 10 repetitions. Individuals performed 16 +/ 5RMS10RL (median = 15), which represent a statistical difference for the 10 repetition reference value (p < 0.001). The most prevalent RMS10RL range was from 13 to 15 repetitions (31%), and only 22% performed between 10 and 12 repetitions. It was concluded that most individuals can perform a number of repetitions well above the 10 repetitions predicted for the selected load. Therefore, the training routines are not compatible with maximum effort. PMID- 29112056 TI - Effects of a Resistance Training Intervention on Strength, Power, and Performance in Adolescent Dancers. AB - Dowse, RA, McGuigan, MR, and Harrison, C. Effects of a resistance training intervention on strength, power, and performance in adolescent dancers. J Strength Cond Res XX(X): 000-000, 2017-The aim of this study was to determine whether a 9-week resistance training program could have a significant effect on maximum lower-body strength and power, dynamic balance, and dance performance in adolescent dancers. Twelve competitive adolescent female dancers trained in jazz, ballet, and contemporary were recruited from local dance schools and assigned to a resistance training group (dance experience 9.2 +/- 2.4 years; age 14.2 +/- 1.9 years; height 155.6 +/- 9.1 cm; and mass 48.9 +/- 13.8 kg). Anthropometry (height, seated height, mass, and skinfolds), subjective dancing performance, dynamic balance (eyes open [EO] and eyes closed), maximum lower-body strength (isometric midthigh pull), and power (vertical countermovement jump, squat jump, and single-leg countermovement jump) were assessed before and after the 9-week intervention period. Posttesting identified a significant improvement EO overall stability (p = 0.003; effect size [ES] = 0.88), EO anterior-posterior stability (p = 0.003; ES = 0.92), peak force (p < 0.001; ES = 0.61), peak power (p = 0.021; ES = 0.22), and subjective dancing performance (p = 0.008; ES = 0.76). These results were accompanied by a trivial but significant change in mass (p = 0.023; ES = 0.09) that was attributed to growth and no significant change in body fat or the sum of skinfolds. This study demonstrated that resistance training can have a significant effect on dynamic balance, maximum lower-body strength, and power without adversely affecting artistic or esthetic components. The results suggest that incorporating resistance training may enhance strength and power adaptations and manage growth-related changes in adolescent dancers. PMID- 29112057 TI - Game Responses During Young Padel Match Play: Age and Sex Comparisons. AB - Garcia-Benitez, S, Courel-Ibanez, J, Perez-Bilbao, T, and Felipe, JL. Game responses during young padel match play: age and sex comparisons. J Strength Cond Res 32(4): 1144-1149, 2018-The purpose of this study was to assess match activity profile and temporal structure in U-16 and U-18 male and female padel players from the 2014 Spanish Youth National Championship. A total of 1,670 rallies from 12 matches were recorded through systematic observation. Variables pertaining to game and point duration, rest interval time, number of strokes per rally (SR), and match total duration were registered. Current findings show that significant influences of age and sex on game demands in youth padel players strengthen the importance of knowing specific game characteristics during formative stages for training accordingly. In particular, padel match activity in youth players was characterized by longer rallies, longer resting interval time, and more number of SR compared with other racket sports, resulting in lower effort index. More specifically, results revealed an increment on match requirements in U-18 players compared with U-16. Besides, we found a greater use of lobs in females, particularly in U-16 players. This information may constitute a useful guide for the design of appropriate game strategies and specific-training sessions according to competitive demands in youth padel players. PMID- 29112058 TI - Validation of the Omron HEM-9210T by the ANSI/AAMI/ISO 81060-2 with two novel cuffs: wide range and extra-large. PMID- 29112059 TI - Response to 'Regarding: validation of the Omron HEM-9210T by the ANSI/AAMI/ISO 81060-2 with two novel cuffs: wide-range and extra-large'. PMID- 29112060 TI - Where is the greatest impact of uncontrolled HIV infection on AIDS and non-AIDS events in HIV? AB - OBJECTIVE: The extent to which controlled and uncontrolled HIV interact with ageing, European region of care and calendar year of follow-up is largely unknown. METHOD: EuroSIDA participants were followed after 1 January 2001 and grouped according to current HIV progression risk; high risk (CD4 cell count <=350/MUl, viral load >=10 000 copies/ml), low risk (CD4 cell count >=500 cells/MUl, viral load <50 copies/ml) and intermediate (other combinations). Poisson regression investigated interactions between HIV progression risk, age, European region of care and year of follow-up and incidence of AIDS or non-AIDS events. RESULTS: A total of 16 839 persons were included with 136 688 person years of follow-up. In persons aged 30 years or less, those at high risk had a six-fold increased incidence of non-AIDS compared with those at low risk, compared with a two-to-three-fold increase in older persons (P = 0.0004, interaction). In Eastern Europe, those at highest risk of non-AIDS had a 12-fold increased incidence compared with a two-to-four-fold difference in all other regions (P = 0.0029, interaction). Those at high risk of non-AIDS during 2001 2004 had a two-fold increased incidence compared with those at low risk, increasing to a five-fold increase between 2013 and 2016 (P < 0.0001, interaction). Differences among high, intermediate and low risk of AIDS were similar across age groups, year of follow-up and Europe (P = 0.57, 0.060 and 0.090, respectively, interaction). CONCLUSION: Factors other than optimal control of HIV become increasingly important with ageing for predicting non-AIDS, whereas differences across Europe reflect differences in patient management as well as underlying socioeconomic circumstances. The differences between those at high, intermediate and low risk of non-AIDS between 2013 and 2016 likely reflects better quality of care. PMID- 29112061 TI - Temporal trends of transmitted HIV drug resistance in a multinational seroconversion cohort. AB - BACKGROUND: The rate of transmitted drug resistance (TDR) may increase with wider use of antiretroviral therapy and can contribute to therapeutic failure. We analysed time trends in TDR among HIV seroconverters. METHODS: Using CASCADE data of individuals with well estimated dates of HIV seroconversion, we examined HIV nucleotide sequences collected prior to antiretroviral therapy use from 1996 2012. All samples were taken within 12 months of testing HIV positive. Using logistic regression, we examined the association between TDR and year of seroconversion, adjusting for confounders. RESULTS: Of 4717 individuals seroconverting between 1996 and 2012, median (IQR) age at seroconversion was 33 (27, 39) years. The majority (3839; 92%) were male, mainly exposed through MSM (3767; 80%), and infected with subtype B (3464; 73%). Overall, 515 (11%) individuals had at least one drug resistance-related mutation; 280 individuals with nucleoside reverse transcriptase, 185 with nonnucleoside reverse transcriptase, and 144 with protease inhibitor mutations. Estimated TDR prevalence was 19.4% (8.2, 36.0) in 1996, significantly decreasing to 8.5% (5.9, 11.9) in 2012 [odds ratio (OR; 95% confidence interval (CI)) = 0.92 (0.90, 0.95) per year increase]. Individuals exposed through sex between men and women were significantly less likely to have been infected with a drug-resistant strain [OR (95% CI) = 0.59 (0.41, 0.87) compared with MSM], and there was marginal evidence that sampling during acute infection was associated with higher odds of resistance [OR (95% CI) = 1.20 (0.97, 1.7), P = 0.093] compared with later sampling. CONCLUSION: TDR has decreased over calendar time although a significant proportion of new infections still carry resistance-related mutations. PMID- 29112062 TI - Health-related quality of life of people with HIV: an assessment of patient related factors and comparison with other chronic diseases. AB - OBJECTIVES: The health-related quality of life (HRQOL) of people with HIV is lower than in the general population, but it is unknown how it compares with that of persons with other chronic medical conditions. We compared HRQOL in HIV with HRQOL in diabetes mellitus type 1, diabetes mellitus type 2 and rheumatoid arthritis (RA). In addition, we investigated factors associated with HRQOL in HIV. DESIGN: Cross-sectional study. METHODS: HRQOL was measured with the Medical Outcomes Study Short Form 36-item Health Survey in a nationwide sample of people with HIV in care in the Netherlands and on combination antiretroviral therapy for at least 6 months. We added data from studies in diabetes mellitus types 1 and 2, and RA. Logistic regression analysis was used to examine: the association between disease group and a poor HRQOL, and patient factors associated with poor HRQOL in HIV. RESULTS: The odds of a poor physical HRQOL in the HIV group were comparable with the odds in diabetes mellitus types 1 and 2, but lower than in RA patients. The odds of a poor mental HRQOL in HIV were higher than in the other groups. In HIV, a history of AIDS, longer duration of combination antiretroviral therapy and severe comorbidity were associated with a poor physical HRQOL. Sub-Saharan African descent and CD4 cell count of less than 350 cells/MUl were associated with poor mental HRQOL. CONCLUSION: People with HIV were more likely to have a poor mental HRQOL than patients with other chronic conditions. Addressing mental health should be an integral part of outpatient HIV care. PMID- 29112064 TI - Placental transfer of elvitegravir and cobicistat in an ex-vivo human cotyledon double perfusion model. AB - OBJECTIVE: To determine the transplacental pharmacokinetics of the HIV integrase strand transfer inhibitor elvitegravir and of cobicistat, a cytochrome P450 inhibitor used as a pharmacoenhancer in antiretroviral therapy. DESIGN AND METHODS: Maternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in seven open circuit experiments and 10 closed-circuit (recirculating) experiments. Elvitegravir and cobicistat were added to a maternal perfusate containing 2 g/l of human serum albumin and antipyrine, as a marker to validate the cotyledon's viability. Elvitegravir and cobicistat concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. RESULTS: For elvitegravir, in open-circuit experiments the mean (+/-SD) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 19 +/- 13% and the mean clearance index was 0.46 +/- 0.21; in the closed circuit model, after 3 h of perfusion the FTR was 20 +/- 10% and the mean accumulation index was 12.28 +/- 5.57. For cobicistat, in the open perfusions the FTR was 23 +/- 13% and the mean clearance index was 0.63 +/- 0.34; in the closed perfusions after 3 h the fetal-to-maternal ratio of cobicistat was 21 +/- 11%. The mean accumulation index was 3.46 +/- 2.19 CONCLUSION:: The two models concurred to show moderate placental transfer of elvitegravir and cobicistat across the placenta as well as elvitegravir accumulation in the placenta tissue. Whether this may lead to toxicities and modifications in fetal or placental metabolism requires clinical studies. PMID- 29112063 TI - Sex-based differences in neurocognitive functioning in HIV-infected young adults. AB - INTRODUCTION: Sex differences in cognition of HIV positive (HIV) patients are controversial. We aimed to investigate the relationship between cognition, HIV status, and sex, in a highly homogenous cohort of young Romanians parenterally infected during early childhood. METHODS: In total, 250 HIV participants were compared with age-matched HIV negative (HIV) controls (n = 72) in a cross sectional study. After standardized neurocognitive, psychological testing and medical evaluation, linear regression was used to assess the effect of sex and HIV on neurocognitive outcomes. RESULTS: Study participants were on average 23 years old with balanced sex distribution (% women = 52% vs. 43%). HIV were more educated (12.7 vs. 11.6 years, P = 0.002).HIV status was associated with a lower global performance (beta = -0.22, P < 0.001), after controlling for age and education. HIV women had better previous and current HIV-associated markers. The effect of HIV on global cognition did not differ between sexes in most cognitive domains (beta = 0.07, P = 0.14). An interaction between sex, HIV status, and cognitive functioning was found in the psychomotor domain. HIV women had worse motor skills than HIV women (beta = -0.32, P < 0.001) suggesting a specific effect of HIV on motor functioning in women only. Moreover, current CD4 less than 200 cells/MUl (P = 0.013) and longer time lived with CD4 less than 200 cells/MUl (P = 0.023) were negatively correlated with the motor scaled score in women (beta = -0.22, P = 0.034). CONCLUSION: Despite less advanced disease in women, long term HIV infection has an equally detrimental effect on cognitive performances of both sexes, in all cognitive domains, except the psychomotor domain where women are preferentially affected. PMID- 29112065 TI - The effects of HIV and smoking on aortic and splenic inflammation. AB - OBJECTIVE: To determine the association of smoking and HIV status with tissue specific inflammation measured by flurodeoxyglucose positron emission tomography (PET). DESIGN: A cross-sectional study. METHODS: We prospectively enrolled 55 HIV study participants on stable antiretroviral therapy and 19 age-matched HIV uninfected controls without known cardiovascular disease. We measured aortic target-to-background ratio (TBR) and spleen standardized uptake values (SUV) 3-h post-FDG, and used regression models to examine the independent association of HIV and smoking status with PET variables. RESULTS: Overall, median (interquartile range) age was 50 (42-55) years; 81% were men and 54% were current smokers (median 0.5 packs/day, 25 pack-years]. Median CD4 of HIV study participants was 690 cells/ml and 88% had HIV-1 RNA less than 20 c/ml; 43% were on a protease inhibitor. In fully adjusted models, HIV was associated with 0.16 (95% confidence interval 0.04-0.27; P = 0.009) higher aortic TBR, whereas current smoking was marginally associated with a lower TBR [-0.11 (95% confidence interval -0.23 to 0.01); P = 0.07]. Spleen SUVmean was not associated with HIV or smoking, and there was no evidence for an HIVsmoking interaction for aortic or spleen models (all P > 0.1). Spleen SUVmean was positively associated with biomarkers of inflammation and coronary artery calcium, but adjustment for traditional cardiovascular disease risk factors attenuated these relationships. CONCLUSION: The FDG-PET study of HIV study participants suggests that HIV is associated with increased aortic inflammation independent of traditional risk factors, but smoking is not. Future studies should continue to explore the mechanistic roles of smoking and inflammation at various stages of clinical and subclinical atherosclerotic vascular disease in HIV. PMID- 29112066 TI - Emulating a target trial of antiretroviral therapy regimens started before conception and risk of adverse birth outcomes. AB - OBJECTIVE: To compare the effect of preconception initiation of zidovudine, lamivudine, nevirapine (ZDV/3TC/NVP) versus tenofovir, emtricitabine, efavirenz (TDF/FTC/EFV) on adverse birth outcomes. DESIGN: Emulation of a hypothetical (target) trial using a birth surveillance study in Botswana during an era of CD4 based antiretroviral therapy (ART) initiation. METHODS: In women who initiated ART less than 3 years from HIV diagnosis, conceived 0.5-5 years after ART initiation, and delivered at least 24-week gestation, we estimated risk ratios for stillbirth, preterm delivery (<37 weeks), very preterm delivery (<32 weeks), small-for-gestational-age (SGA) (<10 percentile), very SGA (<3 percentile), and any adverse or severe birth outcome for first-line ZDV/3TC/NVP versus TDF/FTC/EFV. We conducted a historical comparison in women who initiated TDF/FTC/EFV in 2012-2015 and ZDV/3TC/NVP in 2004-2011, and a contemporaneous comparison in an era of overlapping use from 2009 to 2013. RESULTS: In the historical comparison, 1108 women initiated TDF/FTC/EFV and 637 initiated ZDV/3TC/NVP. In the contemporaneous comparison, 1052 initiated TDF/FTC/EFV and 298 initiated ZDV/3TC/NVP. TDF/FTC/EFV initiators were younger and more likely to be nulliparous than ZDV/3TC/NVP initiators in both comparisons. In the historical comparison, the adjusted risk ratios (95% confidence interval) comparing ZDV/3TC/NVP with TDF/FTC/EFV were 2.95 (1.76, 4.96) for stillbirth, 1.40 (1.17, 1.67) for preterm delivery, 2.58 (1.70, 3.91) for very preterm delivery, 1.96 (1.64, 2.34) for SGA, 2.32 (1.73, 3.09) for very SGA, 1.54 (1.38, 1.72) for any adverse birth outcome, and 2.20 (1.76, 2.75) for any severe birth outcome, and were similar in the contemporaneous comparison. CONCLUSION: Preconception initiation of ZDV/3TC/NVP compared with TDF/FTC/EFV may increase the risk of adverse birth outcomes. PMID- 29112067 TI - Memory B cell dysregulation in HIV-1-infected individuals. AB - OBJECTIVE: To characterize the effect of the HIV-1 infection and antiretroviral treatment (ART) in the human memory B (MEB)-cell compartment. DESIGN: A cross sectional study was designed to analyze MEB cells of HIV-1 ART treated and ART naive study participants, and uninfected individuals. METHODS: Frequency and absolute counts of MEB cell subsets in blood were determined by multicolor flow cytometry. Spontaneous cell death and B-cell proliferative capacity was evaluated in vitro by cell culture and flow cytometry. Splenic function was determined by pitted erythrocytes quantification in HIV-1 ART-treated study participants. RESULTS: HIV-1 ART-treated individuals did not show functional hyposplenism despite the lack of recovery IgMIgDCD27 marginal zone-like B cells. Moreover, two germinal center-dependent MEB cells subsets were also dysregulated in HIV-1 individuals: IgMIgDCD27 (IgM only) cells were increased, whereas the switched subset (IgMIgD) was reduced in viremic individuals. Althought ART restored the numbers of these populations; the switched MEB cells were enriched in CD27 cells, which showed the highest susceptibility to spontaneous cell death ex vivo. In addition, B cells from viremic individuals showed a poor response to B-cell receptor and toll-like receptor 9 stimulation that was circumvented when both stimuli were used simultaneously. CONCLUSION: B cells from HIV-1 study participants show a poor stimulation capacity, that may be bypassed by the proper combination of stimuli, and a dysregulated MEB cell pool that suggest an affectation of the germinal center reaction, only partially normalized by ART. Interestingly, hyposplenism does not explain the lack of recovery of the marginal zone-like B cells in ART-treated HIV-1 individuals. PMID- 29112068 TI - Initial treatment response among HIV subtype F infected patients who started antiretroviral therapy based on integrase inhibitors. AB - : HIV-1 subtype B (54.4%) and subtype F (27.2%) are the most prevalent variants in patients who started antiretroviral therapy including an integrase inhibitor in the last 2 years in Northwest Spain. Virological response rates to antiretroviral therapy based on integrase inhibitor were significantly lower among F subtypes compared with B subtypes at weeks 12 (25.0% vs. 75.0%) and 24 (59.1% vs. 95.0%). Subtype F was independently associated with virological response at 24 weeks [odds ratio 11.8 (95% confidence interval 1.1-119.9); P = 0.037]. PMID- 29112069 TI - Neuropsychological performance in African children with HIV enrolled in a multisite antiretroviral clinical trial. AB - OBJECTIVE AND DESIGN: Children with HIV infection (HIV+) are at neuropsychological risk, but few studies have evaluated this at multiple sites in low-income and middle-income countries. We compared neuropsychological outcomes at enrollment (>5 years age) among HIV+, HIV perinatally exposed uninfected (HEU), and HIV unexposed uninfected (HUU) children from four sub-Saharan countries. METHODS: IMPAACT P1060 compared nevirapine versus lopinavir/ritonavir based antiretroviral treatment (ART) in HIV-infected children 6-35 months of age. The present study (P1104s) enrolled P1060 children at 5-11 years of age and evaluated their neuropsychological performance over 2 years using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), Tests of Variables of Attention (TOVA), Bruininks-Oseretsky Test, 2nd edition (BOT-2), and parent reported Behavior Rating Inventory of Executive Function (BRIEF). Cohorts were compared using generalized estimating equations least-squares means adjusted for site, child age and sex, and personal and social characteristics for child and caregiver. RESULTS: Six hundred and eleven (246 HIV+, 183 HEU, 182 HUU) of the 615 enrolled at six sites [South Africa (three), Zimbabwe, Malawi, Uganda] were available for analysis. Mean age was 7.2 years, 48% male, 69% in school. Unadjusted and adjusted comparisons were consistent. HIV+ children performed significantly worse than HEU and HUU cohorts on all KABC-II cognitive performance domains and on BOT-2 total motor proficiency (P < 0.001), but not on the BRIEF Global Executive Indices. HUU and HEU cohorts were comparable on cognitive outcomes. HIV+ children initiated on ART before 1 year of age had significantly better BRIEF evaluations (lower scores - fewer behavior problems), compared with those started after (P = 0.03). CONCLUSION: Significant cognitive deficits were documented among HIV+ children at school age, even when started on ART at an early age. Earlier HIV treatment, neuropsychological monitoring, and rehabilitative interventions are all needed. Subsequent testing for 2 more years will help further evaluate how HIV infection and exposure affect the developmental trajectory. PMID- 29112071 TI - The role of menopause in tenofovir diphosphate and emtricitabine triphosphate concentrations in cervical tissue. AB - OBJECTIVE: Although postmenopausal (post-M) women have behavioral and biological risk factors for HIV infection, the activity of preexposure prophylaxis (PrEP) agents in older adults has not been well studied. DESIGN: We used an ex-vivo approach to compare the tissue concentrations of tenofovir (TFV) diphosphate (TFVdp) and emtricitabine (FTC) triphosphate (FTCtp) in cervical tissues from premenopausal (pre-M) and post-M women. METHOD: Cervical explants from 16 pre-M and 11 post-M women were incubated in 10-300 MUg/ml TFV or FTC for 24 h. Explants were then snap frozen in liquid nitrogen and stored until analysis. TFVdp and FTCtp were quantified using tandem liquid chromatography-mass spectrometry. RESULTS: Active metabolite concentrations of TFVdp were more than nine-fold lower in post-M explants (P < 0.05). The percentage of TFV converted to TFVdp in pre-M explants was 0.0038 [below the limit of quantification (BLQ)-0.5886] compared with 0.0004 (BLQ-0.0706) in post-M explants. The majority of FTCtp concentrations were BLQ. For both TFVdp and FTCtp, there was a trend for more unquantifiable concentrations in post-M vs. pre-M (TFV: 38 vs. 21%, P = 0.2; FTC: 71 vs. 52%, P = 0.2). CONCLUSION: These findings could have implications in the use of nucleotide-based PrEP strategies targeted to older women. If validated in vivo, lower exposures of active nucleoside/tide metabolites could mean post-M women need higher doses of TFV-based PrEP to achieve protective efficacy. PMID- 29112070 TI - Switching from a ritonavir-boosted protease inhibitor to a dolutegravir-based regimen for maintenance of HIV viral suppression in patients with high cardiovascular risk. AB - OBJECTIVE: To compare the efficacy, safety, and impact on lipid fractions of switching from a ritonavir-boosted protease inhibitor (PI/r) to a dolutegravir (DTG) regimen. METHODS: HIV type 1-infected adults more than 50 years or with a Framingham score more than 10% were eligible if plasma HIV RNA less than 50 copies per ml for at least 24 weeks while on a PI/r regimen. Patients were randomized to switch to DTG or to remain on PI/r. Primary endpoints were: proportion maintaining HIV RNA less than 50 copies per ml and percentage change from baseline of total cholesterol at week 48. RESULTS: In total, 415 patients (32 sites in six European countries) were randomized: 205 to DTG and 210 to continue PI/r. About 89% were men, 87% more than 50 years, 74% had a Framingham score more than 10%, with a median CD4 cell count of 617 cells per MUl and suppressed viremia for a median of 5 years. At week 48, in the intent-to-treat analysis, treatment success rate was 93.1% in DTG group and 95.2% in PI/r group (difference -2.1%, 95% confidence interval -6.6 to 2.4, noninferiority demonstrated). There were four virological failures with DTG and one with PI/r with no emergent resistance mutations. There was no significant difference in severe adverse events or grade 3 or 4 adverse events or treatment modifying adverse events. Total cholesterol and other lipid fractions (except high-density lipoprotein cholesterol) improved significantly (P < 0.001) in the DTG group regardless of PI/r at baseline. CONCLUSION: Switching to a DTG regimen in virologically suppressed HIV type 1 patients with high cardiovascular disease risk was noninferior, and significantly improved lipid profiles. PMID- 29112072 TI - An advanced BLT-humanized mouse model for extended HIV-1 cure studies. AB - OBJECTIVE: Although bone marrow, liver, thymus (BLT)-humanized mice provide a robust model for HIV-1 infection and enable evaluation of cure strategies dependent on endogenous immune responses, most mice develop graft versus host disease (GVHD), limiting their utility for extended HIV cure studies. This study aimed to: evaluate the GVHD-resistant C57 black 6 (C57BL/6) recombination activating gene 2 (Rag2)gammacCD47 triple knockout (TKO)-BLT mouse as a model to establish HIV-1 latency. Determine whether TKO-BLT mice could be maintained on antiretroviral therapy (ART) for extended periods of time. Assess the rapidity of viral rebound following therapy interruption. DESIGN: TKO-BLT mice were HIV-1 infected, treated with various ART regimens over extended periods of time and assayed for viral rebound following therapy interruption. METHODS: Daily subcutaneous injection and oral ART-mediated suppression of HIV-1 infection was tested at various doses in TKO-BLT mice. Mice were monitored for suppression of viremia and cellular HIV-1 RNA and DNA prior to and following therapy interruption. RESULTS: Mice remained healthy for 45 weeks posthumanization and could be treated with ART for up to 18 weeks. Viremia was suppressed to less than 200 copies/ml in the majority of mice with significant reductions in cellular HIV 1 RNA and DNA. Treatment interruption resulted in rapid viral recrudescence. CONCLUSION: HIV-1 latency can be maintained in TKO-BLT mice over extended periods on ART and rapid viral rebound occurs following therapy removal. The additional 15-18 weeks of healthy longevity compared with other BLT models provides sufficient time to examine the decay kinetics of the latent reservoir as well as observe delays in recrudescence in HIV-1 cure studies. PMID- 29112073 TI - Benefits and risks of rapid initiation of antiretroviral therapy. AB - BACKGROUND: Recent attention has focused on the question of how quickly antiretroviral therapy (ART) should be started once HIV diagnosis is confirmed. We assessed whether rapid ART initiation improves patient outcomes. METHODS: We searched five databases from inception up to August 2017. Rapid ART initiation was defined as initiation within 14 days of HIV diagnosis. Data were pooled using random effects meta-analysis. RESULTS: Across the randomized trials, ART start on the same day increased viral suppression at 12 months [three trials: relative risk (RR) 1.17, 95% confidence interval (CI) 1.07-1.27], retention in care at 12 months (RR 1.11, 95% CI 0.99-1.26), and the likelihood of starting ART within 90 days (four trials: RR 1.35, 95% CI 1.13-1.62) and 12 months after eligibility was established (three trials: RR 1.17, 95% CI 1.07-1.27). There was a nonsignificant trend toward reduced mortality (three trials: RR 0.53, 95% CI 0.24-1.08), as well as reduced loss to follow-up at 12 months (2 trials: RR 0.66, 95% CI 0.42-1.04). In the observational studies, offering accelerated ART initiation resulted in a greater likelihood of having started ART within 3 months (two studies: RR 1.53, 95% CI 1.11-2.10). There was a trend toward an increased risk of being lost to follow-up at 6 months (three studies: RR 1.85, 95% CI 0.96-3.55). CONCLUSION: Accelerated ART initiation can lead to improved clinical outcomes and is likely to be of particular benefit in those settings where extensive patient preparation prior to starting ART results in long delays. These findings informed a WHO recommendation supporting accelerated ART initiation, including same day ART start. PMID- 29112074 TI - Toll-like receptor 9 polymorphism is associated with increased Epstein-Barr virus and Cytomegalovirus acquisition in HIV-exposed infants. AB - : Polymorphisms in the Toll-like receptor 9 1635 locus have been associated with HIV-1 acquisition and progression. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) acquisition were compared between Kenyan HIV-exposed infants by 1635 genotype. Having one or more copies of the 1635A allele was associated with increased CMV acquisition in HIV-infected infants (42 vs. 11%, P = 0.03) and increased risk of EBV acquisition in HIV-exposed uninfected infants (hazard ratio = 4.2, P = 0.02) compared with 1635GG. In addition, 1635A was associated with 0.4 log10 copies/ml lower median EBV levels in HIV-infected infants (P = 0.03). These data suggest a potentially important role for this locus in primary herpesvirus infection. PMID- 29112075 TI - Consequences of a changing US strategy in the global HIV investment landscape. AB - OBJECTIVE: The global fight against HIV/AIDS in Africa has long been a focus of US foreign policy, but this could change if the federal budget for 2018 proposed by the US Office of Management and Budget is adopted. We aim to inform public and Congressional debate around this issue by evaluating the historical and potential future impact of US investment in the African HIV response. DESIGN/METHODS: We use a previously published mathematical model of HIV transmission to characterize the possible impact of a series of financial scenarios for the historical and future AIDS response across Sub-Saharan Africa. RESULTS: We find that US funding has saved nearly five million adults in Sub-Saharan Africa from AIDS-related deaths. In the coming 15 years, if current numbers on antiretroviral treatment are maintained without further expansion of programs (the proposed US strategy), nearly 26 million new HIV infections and 4.4 million AIDS deaths may occur. A 10% increase in US funding, together with ambitious domestic spending and focused attention on optimizing resources, can avert up to 22 million HIV infections and save 2.3 million lives in Sub-Saharan Africa compared with the proposed strategy. CONCLUSION: Our synthesis of available evidence shows that the United States has played, and could continue to play, a vital role in the global HIV response. Reduced investment could allow more than two million avoidable AIDS deaths by 2032, whereas continued leadership by the United States and other countries could bring UNAIDS targets for ending the epidemic into reach. PMID- 29112076 TI - Virologic suppression and CD4+ cell count recovery after initiation of raltegravir or efavirenz-containing HIV treatment regimens. AB - OBJECTIVE: To explore the effectiveness of raltegravir-based antiretroviral therapy (ART) on treatment response among ART-naive patients seeking routine clinical care. DESIGN: Cohort study of adults enrolled in HIV care in the United States. METHODS: We compared virologic suppression and CD4 cell count recovery over a 2.5 year period after initiation of an ART regimen containing raltegravir or efavirenz using observational data from a US clinical cohort, generalized to the US population of people with diagnosed HIV. We accounted for nonrandom treatment assignment, informative censoring, and nonrandom selection from the US target population using inverse probability weights. RESULTS: Of the 2843 patients included in the study, 2476 initiated the efavirenz-containing regimen and 367 initiated the raltegravir-containing regimen. In the weighted intent-to treat analysis, patients spent an average of 74 (95% confidence interval: 41, 106) additional days alive with a suppressed viral load on the raltegravir regimen than on the efavirenz regimen over the 2.5-year study period. CD4 cell count recovery was also superior under the raltegravir regimen. CONCLUSION: Patients receiving raltegravir spent more time alive and suppressed than patients receiving efavirenz, but the probability of viral suppression by 2.5 years after treatment was similar between groups. Optimizing the amount of time spent in a state of viral suppression is important to improve survival among people living with HIV and to reduce onward transmission. PMID- 29112077 TI - Technological Distractions (Part 2): A Summary of Approaches to Manage Clinical Alarms With Intent to Reduce Alarm Fatigue. AB - OBJECTIVE: Alarm fatigue is a widely recognized safety and quality problem where exposure to high rates of clinical alarms results in desensitization leading to dismissal of or slowed response to alarms. Nonactionable alarms are thought to be especially problematic. Despite these concerns, the number of clinical alarm signals has been increasing as an everincreasing number of medical technologies are added to the clinical care environment. DATA SOURCES: PubMed, SCOPUS, Embase, and CINAHL. STUDY SELECTION: We performed a systematic review of the literature focused on clinical alarms. We asked a primary key question; "what interventions have been attempted and resulted in the success of reducing alarm fatigue?" and 3 secondary key questions; "what are the negative effects on patients/families; what are the balancing outcomes (unintended consequences of interventions); and what human factor approaches apply to making an effective alarm?" DATA EXTRACTION: Articles relevant to the Key Questions were selected through an iterative review process and relevant data was extracted using a standardized tool. DATA SYNTHESIS: We found 62 articles that had relevant and usable data for at least one key question. We found that no study used/developed a clear definition of "alarm fatigue." For our primary key question 1, the relevant studies focused on three main areas: quality improvement/bundled activities; intervention comparisons; and analysis of algorithm-based false and total alarm suppression. All sought to reduce the number of total alarms and/or false alarms to improve the positive predictive value. Most studies were successful to varying degrees. None measured alarm fatigue directly. CONCLUSIONS: There is no agreed upon valid metric(s) for alarm fatigue, and the current methods are mostly indirect. Assuming that reducing the number of alarms and/or improving positive predictive value can reduce alarm fatigue, there are promising avenues to address patient safety and quality problem. Further investment is warranted not only in interventions that may reduce alarm fatigue but also in defining how to best measure it. PMID- 29112078 TI - Survival Outcomes Following the Use of Extracorporeal Membrane Oxygenation as a Rescue Technology in Critically Ill Patients: Results From Pennsylvania 2007 2015. AB - OBJECTIVE: To examine real-world outcomes of survival, length of stay, and discharge destination, among all adult extracorporeal membrane oxygenation admissions in one state over nearly a decade. DESIGN: Retrospective analysis of administrative discharge data. SETTING: State-wide administrative discharge data from Pennsylvania between 2007 and 2015. PATIENTS: All 2,948 consecutive patients billed under a Diagnosis-Related Grouper 3 grouper and in whom a procedural code for extracorporeal membrane oxygenation was present, admitted between the beginning of 2007 and the end of 2015 to hospitals regulated by the state of Pennsylvania. Admitting diagnoses were coded as respiratory, cardiac, cardiac arrest, or uncategorized based on administrative data. MEASUREMENTS AND MAIN RESULTS: Unadjusted in-hospital mortality, length of stay, and discharge destination. Summary statistics and tests of differences by age 65 years or older and by admitting diagnosis were performed. Outcomes by age were plotted using running-mean smoothed graphs. Over the 9-year period, the average observed death rate was 51.7%. Among all survivors, 14.6% went home to self-care and a further 15.2% to home health care. Of all survivors, 43.8% were readmitted within 1 month, and 60.6% within 1 year. Among elderly survivors, readmission rates were 52.3% and 65.5% within 1 month and 1 year, respectively. The likelihood of dying in-hospital increased with age that of being discharged home or to postacute care decreased. CONCLUSIONS: In a "usual clinical practice" setting, short-term outcomes are similar to those observed in clinical trials such as Conventional Ventilation or ECMO for Severe Adult Respiratory Failure, in registries such as extracorporeal life support organization, and in smaller single-site studies. More data on longer term follow-up are needed to allow clinicians to better inform patient selection and care. PMID- 29112080 TI - beta-lactam Therapeutic Drug Management in the PICU. AB - OBJECTIVES: To determine whether contemporary beta-lactam anti-infective dosing recommendations in critically ill children achieve concentrations associated with maximal anti-infective activity. The secondary objective was to describe the microbiological and clinical outcomes associated with beta-lactam therapeutic drug management. DESIGN: Electronic Medical Record Review. SETTING: A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. PATIENTS: Patients admitted to the PICU from September 1, 2014, to May 31, 2017, with sepsis and those receiving extracorporal therapy with either extracorporeal membrane oxygenation or continuous renal replacement therapy that had routine beta-lactam therapeutic drug management. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-two patients were in the total cohort and 23 patients in the infected cohort accounting for 248 samples for therapeutic drug management analysis. The median age was 1 year (range, 4 d to 18 yr) with a mean weight of 19.7 +/- 22.3 kg (range, 2.7-116 kg). Twenty-three patients (28%) had growth of an identified pathogen from a normally sterile site. Seventy-eight of 82 patients (95%) had subtherapeutic anti-infective concentrations and did not attain the primary pharmacodynamic endpoint. All patients in the infected cohort achieved a microbiological response, and 22 of 23 (95.7%) had a positive clinical response. CONCLUSIONS: Overall, 95% of patients had subtherapeutic anti-infective concentrations and did not achieve the requisite pharmacodynamic exposure with current pediatric dosing recommendations. All patients achieved a microbiological response, and 95.7% achieved clinical response with active beta-lactam therapeutic drug management. These data suggest beta-lactam therapeutic drug management is a potentially valuable intervention to optimize anti-infective pharmacokinetics and the pharmacodynamic exposure. Further, these data also suggest the need for additional research in specific pediatric populations and assessing clinical outcomes associated with beta-lactam therapeutic drug management in a larger cohort of pediatric patients. PMID- 29112079 TI - Acute Physiologic Stress and Subsequent Anxiety Among Family Members of ICU Patients. AB - OBJECTIVES: The ICU is a complex and stressful environment and is associated with significant psychologic morbidity for patients and their families. We sought to determine whether salivary cortisol, a physiologic measure of acute stress, was associated with subsequent psychologic distress among family members of ICU patients. DESIGN: This is a prospective, observational study of family members of adult ICU patients. SETTING: Adult medical and surgical ICU in a tertiary care center. SUBJECTS: Family members of ICU patients. INTERVENTIONS: Participants provided five salivary cortisol samples over 24 hours at the time of the patient ICU admission. The primary measure of cortisol was the area under the curve from ground; the secondary measure was the cortisol awakening response. Outcomes were obtained during a 3-month follow-up telephone call. The primary outcome was anxiety, measured by the Hospital Anxiety and Depression Scale-Anxiety. Secondary outcomes included depression and posttraumatic stress disorder. MEASUREMENTS AND MAIN RESULTS: Among 100 participants, 92 completed follow-up. Twenty-nine participants (32%) reported symptoms of anxiety at 3 months, 15 participants (16%) reported depression symptoms, and 14 participants (15%) reported posttraumatic stress symptoms. In our primary analysis, cortisol level as measured by area under the curve from ground was not significantly associated with anxiety (odds ratio, 0.94; p = 0.70). In our secondary analysis, however, cortisol awakening response was significantly associated with anxiety (odds ratio, 1.08; p = 0.02). CONCLUSIONS: Roughly one third of family members experience anxiety after an ICU admission for their loved one, and many family members also experience depression and posttraumatic stress. Cortisol awakening response is associated with anxiety in family members of ICU patients 3 months following the ICU admission. Physiologic measurements of stress among ICU family members may help identify individuals at particular risk of adverse psychologic outcomes. PMID- 29112081 TI - Predictors, Prevalence, and Outcomes of Early Crystalloid Responsiveness Among Initially Hypotensive Patients With Sepsis and Septic Shock. AB - OBJECTIVES: The prevalence of responsiveness to initial fluid challenge among hypotensive sepsis patients is unclear. To avoid fluid overload, and unnecessary treatment, it is important to differentiate these phenotypes. We aimed to 1) determine the proportion of hypotensive sepsis patients sustaining favorable hemodynamic response after initial fluid challenge, 2) determine demographic and clinical risk factors that predicted refractory hypotension, and 3) assess the association between timeliness of fluid resuscitation and refractoriness. DESIGN: Secondary analysis of a prospective, multisite, observational, consecutive-sample cohort. SETTING: Nine tertiary and community hospitals over 1.5 years. PATIENTS: Inclusion criteria 1) suspected or confirmed infection, 2) greater than or equal to two systemic inflammatory response syndrome criteria, 3) systolic blood pressure less than 90 mm Hg, greater than 40% decrease from baseline, or mean arterial pressure less than 65 mm Hg. MEASUREMENTS AND MAIN RESULTS: Sex, age, heart failure, renal failure, immunocompromise, source of infection, initial lactate, coagulopathy, temperature, altered mentation, altered gas exchange, and acute kidney injury were used to generate a risk score. The primary outcome was sustained normotension after fluid challenge without vasopressor titration. Among 3,686 patients, 2,350 (64%) were fluid responsive. Six candidate risk factors significantly predicted refractoriness in multivariable analysis: heart failure (odds ratio, 1.43; CI, 1.20-1.72), hypothermia (odds ratio, 1.37; 1.10-1.69), altered gas exchange (odds ratio, 1.33; 1.12-1.57), initial lactate greater than or equal to 4.0 mmol/L (odds ratio, 1.28; 1.08-1.52), immunocompromise (odds ratio, 1.23; 1.03-1.47), and coagulopathy (odds ratio, 1.23; 1.03-1.48). High risk patients (>= three risk factors) had 70% higher (CI, 48-96%) refractory risk (19% higher absolute risk; CI, 14-25%) versus low-risk (zero risk factors) patients. Initiating fluids in greater than 2 hours also predicted refractoriness (odds ratio, 1.96; CI, 1.49-2.58). Mortality was 15% higher (CI, 10-18%) for refractory patients. CONCLUSIONS: Two in three hypotensive sepsis patients were responsive to initial fluid resuscitation. Heart failure, hypothermia, immunocompromise, hyperlactemia, and coagulopathy were associated with the refractory phenotype. Fluid resuscitation initiated after the initial 2 hours more strongly predicted refractoriness than any patient factor tested. PMID- 29112084 TI - Feed-related Splanchnic Oxygenation in Preterm Infants With Abnormal Antenatal Doppler Developing Gut Complications. AB - Preterm infants with antenatal absent or reversed end diastolic flow (AREDF) in umbilical arteries are at major risk for gastrointestinal (GI) complications, such as necrotizing enterocolitis, intestinal perforation and feeding intolerance. Near-infrared spectroscopy provides continuous monitoring of splanchnic oxygenation (SrSO2) and may represent a useful tool to predict GI outcomes in this high-risk population. This observational, pilot study assessed feed-related SrSO2 patterns at enteral feeding introduction and full enteral feeding (FEF) achievement in twenty AREDF infants with gestational age <=34 weeks. Enrolled infants were divided into 2 groups according to the development versus lack of GI complications. Infants developing GI complications showed significantly lower SrSO2 and increased splanchnic oxygen extraction in response to enteral feeds at both enteral feeding introduction and FEF. The potential role of these findings in predicting GI complications in AREDF preterm infants seems promising and deserves further evaluation. PMID- 29112082 TI - Pilot Study Measuring the Novel Satiety Hormone, Pro-Uroguanylin, in Adolescents With and Without Obesity. AB - OBJECTIVE: Disruption of satiety signaling may lead to increased caloric intake and obesity. Uroguanylin, the intestinal hormone, travels as a precursor to the central nervous system where it activates guanylyl cyclase C and stimulates pro satiety neurons. Rodent studies have demonstrated that guanylyl cyclase C knockout mice overeat and have increased weight gain versus wild-type mice and hyper-caloric obesity diminishes uroguanylin expression. We measured circulating plasma pro-uroguanylin, along with other gastrointestinal peptides and inflammatory markers, in human adolescents with and without obesity, as a pilot study. We hypothesized that adolescents with obesity would have less circulating pro-uroguanylin than adolescents without obesity have. METHODS: We recruited 24 adolescents (age 14-17 years) with and without obesity (body mass index >95% or body mass index <95%) and measured plasma pro-uroguanylin at fasting and successive time points after a meal. We measured 3 other satiety hormones and 2 inflammatory markers to characterize overall satiety signaling and highlight any link between uroguanylin and inflammation. RESULTS: Female adolescents with obesity had lower circulating pro-uroguanylin levels than female adolescents without obesity; we observed no difference in males. Other measured gastrointestinal peptides varied in their differences between cohorts. Inflammatory markers were higher in female participants with obesity. CONCLUSIONS: In adolescents with and without obesity, we can measure circulating pro-uroguanylin levels. In female adolescents without obesity, levels are particularly higher. Pro-uroguanylin secretion patterns differ from other circulating gastrointestinal peptides. In female adolescents with obesity, inflammation correlates with decreased pro-uroguanylin levels. PMID- 29112083 TI - Characteristics of Liver Disease in 100 Individuals With Joubert Syndrome Prospectively Evaluated at a Single Center. AB - BACKGROUND AND AIMS: Joubert Syndrome (JS) is a rare, inherited, ciliopathy defined by cerebellar and brainstem malformations and is variably associated with liver, kidney, and ocular dysfunction. This study characterizes the hepatic findings in JS and identifies factors associated with probable portal hypertension. METHODS: Hundred individuals with JS were prospectively evaluated at the National Institutes of Health Clinical Center. Laboratory tests, imaging, and DNA sequencing were performed. Patients were stratified based on the spleen length/patient height ratio as a marker of splenomegaly, used as a surrogate for probable portal hypertension. RESULTS: Forty-three patients (43%) had liver involvement based on elevated liver enzymes and/or liver hyperechogenicity and/or splenomegaly. None of the patients had macroscopic liver cysts or bile duct dilatation. Based on the spleen length/patient height ratio, 13 patients were stratified into a probable portal hypertension group. We observed significant elevations in alkaline phosphatase (269 vs 169 U/L, P <= 0.001), alanine aminotransferase (92 vs 42 U/L, P = 0.004), aspartate aminotransferase (77 vs 40 U/L, P = 0.002), and gamma-glutamyl transferase (226 vs 51 U/L, P <= 0.001) in the probable portal hypertension group. Platelets were lower in the probable portal hypertension cohort (229 vs 299 * 10 cells/MUL, P = 0.008), whereas synthetic function was intact in both groups. Probable portal hypertension was also more prevalent in patients with kidney disease (P = 0.001) and colobomas (P = 0.02), as well as mutations in the TMEM67 gene (P = 0.001). CONCLUSIONS: In JS, probable portal hypertension is associated with abnormal hepatic enzymes, as well as presence of kidney disease, coloboma, and/or mutation in TMEM67. These findings may allow early identification of JS patients who have or are more likely to develop liver disease. PMID- 29112085 TI - Diagnosis and Management of Paediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. AB - Paediatric autoimmune liver disease is characterised by inflammatory liver histology, circulating autoantibodies and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. Two types of paediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (anti-LKM-1/anti-LC-1; AIH-2).Pertinent issues addressing the diagnosis, treatment and long term follow up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate and Mendeley databases over the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique. PMID- 29112086 TI - Randomized Controlled Clinical Trial on Value of Domperidone in Functional Abdominal Pain in Children. AB - OBJECTIVES: The aim of the study was to evaluate the therapeutic effect of domperidone on children with abdominal pain predominant functional gastrointestinal disorders (AP-FGIDs). METHODS: One hundred children (aged 5-12 years) fulfilling Rome III criteria for AP-FGIDs were randomized into 8 weeks of domperidone or placebo treatment. Primary outcomes defined were cure and patient reported general improvement. Secondary outcomes were reduction in the severity of abdominal pain and increase in gastric motility. Patients were followed up for 6 months. RESULTS: Eighty-nine (42 in placebo group, 47 in domperidone group) completed the trial at 8 weeks. Seventy-nine completed the 6-month follow-up. When primary outcomes were assessed at 8 weeks, 37 (74%) in the domperidone group and 25 (50%) in the placebo group showed patient-reported general improvement (P = 0.013), whereas no significant difference was observed in cure (22 [44%] vs 14 [28%] P = 0.09). At 6-month follow-up 30 (60%) in the domperidone group and 19 (38%) in the placebo group reported cure (P = 0.028), whereas 44 (88%) in the domperidone group and 33 (66%) in the placebo group showed patient-reported general improvement (P = 0.009). When assessing secondary outcomes at 8 weeks, the domperidone group reported significant reduction in the severity of abdominal pain (54.1% vs 24.7%, P = 0.008) and an increase in the antral motility index (27.5% vs 7.2%, P = 0.029). None of the patients reported intervention-related adverse effects. CONCLUSIONS: Domperidone may be a safe and effective therapeutic modality to achieve a lasting remission of symptoms in children with AP-FGIDs. PMID- 29112087 TI - Fecal Amino Acid Analysis Can Discriminate De Novo Treatment-Naive Pediatric Inflammatory Bowel Disease From Controls. AB - OBJECTIVES: Endoscopy remains mandatory in the diagnostic work-up of inflammatory bowel disease (IBD), but is a costly and invasive procedure. Identification of novel, noninvasive, diagnostic biomarkers remains a priority. The aim of the present study was to explore the potential of fecal amino acid composition as diagnostic biomarker for pediatric IBD. METHODS: In this case-control study, treatment-naive, de novo pediatric patients with IBD from two tertiary centers were included. Endoscopic severity of ulcerative colitis (UC) and Crohn's disease (CD) was based on physician global assessment scores, substantiated by levels of fecal calprotectin and C-reactive protein at study inclusion. Patients were instructed to collect a fecal sample prior to bowel cleansing. Healthy controls (HCs) were recruited from primary schools in the same region. Dedicated amino acid analysis was performed on all samples. RESULTS: Significant differences between 30 IBD patients (15 UC, 15 CD) and 15 age and sex-matched HCs were found in six amino acids (histidine, tryptophan, phenylalanine, leucine, tyrosine, and valine; all area under the curve >0.75 and P < 0.005), displaying higher levels in IBD. When distributing the patients according to type of IBD, a similar spectrum of amino acids differed between UC and HC (histidine, tryptophan, phenylalanine, leucine, valine, and serine), whereas three amino acids were different between CD and HC (histidine, tryptophan, and phenylalanine). CONCLUSIONS: Significantly increased levels of six different fecal amino acids were found in patients with IBD compared to controls. Whether these differences reflect decreased absorption or increased loss by inflamed intestines needs to be elucidated. PMID- 29112088 TI - Serum 25 Hydroxy Vitamin D Levels in Very Low Birth Weight Infants Receiving Oral Vitamin D Supplementation. AB - BACKGROUND AND OBJECTIVE: Vitamin D supplementation in preterm infants has been recommended by American Academy of Pediatrics (AAP); however, its efficacy and safety has not been well studied. To study 25-hydroxy vitamin D (25OHD) levels as a marker of vitamin D status of very low birth weight infants while on vitamin D supplementation during neonatal intensive care unit hospitalization. METHODS: Retrospective study of preterm infants with birth weight <1500 g admitted to our unit from January 2013 to December 2015 who were on oral vitamin D3 400 IU supplementation. Serum 25OHD level were checked at 4, 8, and 12 weeks of age or before discharge and the levels were stratified as deficient <20 ng/mL, insufficient 20 to 29 ng/mL, normal 30 to 60 ng/mL, high 61 to 100 ng/mL and very high >100 ng/mL. RESULTS: A total of 301 infants were enrolled, 186 very low birth weight (VLBW; 1000-1499 g) infants and 115 extremely low birth weight (ELBW; <1000 g) infants. Approximately 80% of both VLBWs and ELBWs had deficient or insufficient 25OHD levels at 4 weeks of age. On oral vitamin D supplementation, VLBW infants increased their 25OHD levels significantly by 8 and 12 weeks of age, whereas ELBW infants lagged behind at 8 weeks and increased their 25OHD levels by 12 weeks of age. CONCLUSIONS: Eighty percent of ELBW and VLBW infants have either deficient or insufficient vitamin D status at 4 weeks of age. Vitamin D supplementation helps in improving the vitamin D levels, VLBW infants significantly more than ELBW infants. AAP recommendation appears to be safe; however, if using higher supplement dosing, 25OHD level should be monitored to avoid high and very high vitamin D levels. PMID- 29112089 TI - Assessment of Liver Disease Progression in Cystic Fibrosis Using Transient Elastography. AB - OBJECTIVES: Cystic fibrosis-related liver disease (CFLD) can develop silently in early life and approximately 10% of children with cystic fibrosis (CF) become cirrhotic before adulthood. Clinical, biological, and ultrasound criteria used to define CFLD often reveal liver involvement at an advanced stage. The aim of this retrospective study was to assess the progression of liver stiffness measurement (LSM) in pediatric patients with CF. METHODS: The change of LSM, expressed as kPa/year and %/year, was measured using transient elastography (Fibroscan) in 82 children with CF (median age: 6.8 years, interquartile range [IQR]: 5.8). Mean time interval between the 2 LSM was 3.5 years. RESULTS: Median initial liver stiffness was 3.7 kPa (IQR: 1.3), and then progressed by 0.23 kPa/year, that is, 6%/year. The 7 patients who developed CFLD had a higher initial level of alanine aminotransferase (50 [IQR: 15] vs 30 [IQR: 18], P = 0.0001) and presented a more rapid progression of LSM (0.94 vs 0.23 kPa/year, P = 0.02). CONCLUSIONS: The present study shows that the slope of worsening of liver stiffness is greater in patients who will develop CFLD, suggesting that annual transient elastography may be useful to detect risk of severe liver disease at an earlier stage. PMID- 29112090 TI - Clear Liquid Versus Low-fibre Diet in Bowel Cleansing for Colonoscopy in Children: A Randomized Trial. AB - OBJECTIVES: In light of a paucity of data on the role of diet in colonoscopy preparation in paediatric population, the present study was designed to compare the effectiveness of clear liquid and low-fibre diets for breakfast and lunch on the day preceding colonoscopy in children. METHODS: This prospective, randomised trial was conducted at the Department of Paediatric Gastroenterology and Nutrition in Warsaw, Poland. Eligible patients, referred for colonoscopies, were 6 to 18 years old. Patients were randomly divided into 2 groups: the first received a clear liquid diet and the second a low-fibre diet on the day before colonoscopy. In the afternoon, all participants were asked to drink polyethylene glycol with electrolytes at a dose of 66 mL/kg to a maximum of 4 L. The effectiveness of bowel cleansing was measured using the Boston Bowel Preparation Scale (BBPS). The preparation tolerance was assessed by parents and children using a visual analogue scale. Adverse effects were reported. RESULTS: In total, 184 patients were enrolled. Of those, 96 received the clear liquid diet and 88 the low-fibre diet. The mean age of both groups was 15 years. There were no differences between the 2 study groups in age, weight, and sex, as well as in total BBPS score (BBPS >= 5 96.6% vs 95.1%, P = 0.5). The frequency of adverse effects was similar in both groups; nausea was the most common (P = 0.8). CONCLUSIONS: Clear liquid and low-fibre diets administered to children the day before colonoscopy demonstrated similar bowel cleansing effectiveness. PMID- 29112091 TI - Macro- and Microvascular Parameters After Toxic Shock Syndrome. AB - Whether individuals who had toxic shock syndrome in childhood have differences in macro- and retinal microvascular parameters indicative of increased cardiovascular risk is unknown. We found no evidence of adverse macrovascular changes in 22 toxic shock syndrome participants compared with 60 control participants. Microvascular comparisons showed a reduction in retinal total fractal dimension, which has been associated with cardiovascular risk factors in children. PMID- 29112092 TI - Variation in Visiting and Isolation Policies in Neonatal Units: A U.K. Nationwide Survey. AB - Global pandemics, such as H1N1, are a major risk for neonatal patients. We surveyed U.K. tertiary and district neonatal units about visiting and infection control policies relating to viral respiratory infections. There was marked variation with visiting policies, tertiary units being more restrictive. Isolation, screening, and outbreak management of infected babies was highly variable posing a risk in future pandemics. PMID- 29112093 TI - All animals are equal but some animals are more equal than others: Plasma lactate and succinate in hemorrhagic shock-A comparison in rodents, swine, nonhuman primates, and injured patients. AB - BACKGROUND: Plasma levels of lactate and succinate are predictors of mortality in critically injured patients in military and civilian settings. In relative terms, these metabolic derangements have been recapitulated in rodent, swine, and nonhuman primate models of severe hemorrhage. However, no direct absolute quantitative comparison has been evaluated across these species. METHODS: Ultra high pressure liquid chromatography-mass spectrometry with stable isotope standards was used to determine absolute concentrations of baseline and postshock levels of lactate and succinate in rats, pigs, macaques, and injured patients. RESULTS: Baseline levels of lactate and succinate were most comparable to humans in macaques, followed by pigs and rats. Baseline levels of lactate in pigs and baseline and postshock levels of lactate and succinate in rats were significantly higher than those measured in macaques and humans. Postshock levels of lactate and succinate in pigs and macaques, respectively, were directly comparable to measurements in critically injured patients. CONCLUSION: Acknowledging the caveats associated with the variable degrees of shock in the clinical cohort, our data indicate that larger mammals represent a better model than rodents when investigating metabolic derangements secondary to severe hemorrhage. PMID- 29112094 TI - Thrombelastography early amplitudes in bleeding and coagulopathic trauma patients: Results from a multicenter study. AB - BACKGROUND: Early amplitudes in the viscoelastic hemostatic assays, thrombelastography (TEG) and rotation thromboelastometry (ROTEM), provide fast results, which is critical in the resuscitation of bleeding patients. This study investigated associations between TEG early amplitudes and standard TEG variables in a large multicenter cohort of moderately to severely injured trauma patients admitted at three North European Level I Trauma Centers. METHODS: Prospective observational study of 404 trauma patients with clinical suspicion of severe injury from London, UK, Copenhagen, Denmark and Oslo, Norway. Biochemistry and clinical data including outcome and TEG parameters were recorded upon arrival. Kaolin TEG, Rapid TEG, and TEG functional fibrinogen curves were extracted, and early amplitudes A5 and A10 (amplitude at 5 and 10 minutes) were registered. Patients were stratified according to international normalized ratio of 1.2 or less or greater than 1.2, as well as transfusion requirements (nontransfused, 1-9 red blood cell units and >=10 red blood cell units in 12 hours). RESULTS: In total, 404 patients were included, median Injury Severity Score was 13. There were strong positive correlations between A5/A10 and maximum amplitude in all investigated assays. All TEG values except rTEG maximum amplitude and kTEG maximum amplitude correlated significantly with mortality in transfused patients. Time from initiation of assay to A5 and A10 were lowest for rapid TEG and TEG functional fibrinogen compared with kaolin TEG. Rapid TEG A5 reduced time to result with greater than 50% compared with rapid TEG maximum amplitude. CONCLUSION: We found strong associations between TEG early amplitudes A5/A10 and maximum amplitude in rapid TEG, kaolin TEG, and TEG functional fibrinogen across trauma patients with coagulopathy and massive transfusion requirements. Introducing the use of early amplitudes can reduce time to diagnosis of coagulopathy and may be used in TEG monitoring of trauma patient. Further randomized controlled trials evaluating the role of TEG in guiding hemostatic resuscitation are warranted. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 29112095 TI - Cardiac repair in a patient who had a previous clamshell thoracotomy. PMID- 29112096 TI - Genetic analysis of common variants in the ZNF804A gene with schizophrenia and major depressive disorder. AB - AIM/OBJECTIVES/BACKGROUND: ZNF804A has been investigated widely as a candidate susceptibility gene for mental disorders in individuals of different ethnicities. However, in the Han Chinese population, most studies of this gene have focused on associations of the common single nucleotide polymorphism (SNP) rs1344706. METHODS: To investigate additional common variants within ZNF804A, we carried out a case-control study of 13 SNPs distributed across the whole gene, in 1330 schizophrenic patients, 1045 major depressive disorder patients, and 1235 normal controls. RESULTS AND CONCLUSIONS: We found that rs12476147 (P=0.0078) was associated significantly with schizophrenia, but no SNPs showed statistically significant associations with major depressive disorder after Bonferroni correction. Moreover, we also found that haplotype block 2, which included rs12476147 and rs1344706, was associated significantly with schizophrenia and major depressive disorder. Nevertheless, we could not replicate the association of rs1344706 with schizophrenia. In conclusion, the common variant rs12476147 and the related haplotype block in ZNF804A were associated significantly with schizophrenia in the Han Chinese population. PMID- 29112097 TI - Predictive Factors for Long Operative Duration in Patients Undergoing Laparoscopic Cholecystectomy After Endoscopic Retrograde Cholangiography for Combined Choledochocystolithiasis. AB - PURPOSE: Choledochocystolithiasis and its associated complications such as cholangitis and pancreatitis are managed by endoscopic retrograde cholangiography (ERC), with endoscopic stone extraction followed by laparoscopic cholecystectomy (LC). However, affected patients present with complex conditions linked to operative difficulties in performing LC. The aim of this study was to elucidate the predictive factors for a prolonged LC procedure following ERC for treating patients with choledochocystolithiasis. MATERIALS AND METHODS: The medical records of 109 patients who underwent LC after ERC for choledochocystolithiasis from September 2012 to August 2014 were evaluated retrospectively. The cases were divided into long and short operative duration groups using a cutoff operative time of 90 minutes. We used univariate and multivariate analyses to investigate predictive factors associated with long operative duration according to clinical variables, ERC-related factors, and peak serum levels of laboratory test values between the initial presentation and LC (intervening period). RESULTS: Seventeen patients needed >90 min to complete LC. The presence of acute cholecystitis, placement of percutaneous transhepatic gallbladder drainage, higher peak serum white blood cell count and levels of C-reactive protein (CRP), and lower peak serum levels of lipase during the intervening period were associated with prolonged operative duration. Multivariate analysis showed that the independent predictive factors for long operative duration were the presence of acute cholecystitis (hazard ratio, 5.418; P=0.016) and higher peak levels of CRP (hazard ratio, 1.077; P=0.022). CONCLUSION: When patients with choledochocystolithiasis are scheduled for LC after ERC, the presence of acute cholecystitis and high CRP levels during the intervening period could predict a protracted operation. PMID- 29112098 TI - Article Summaries for November-December 2017 Psychosomatic Medicine, Volume 79, Issue 9. PMID- 29112101 TI - Thoracolumbar Intervertebral Disc Area Morphometry in Elderly Chinese Men and Women: Radiographic Quantifications at Baseline and Changes at Year-4 Follow-up. AB - STUDY DESIGN: A population-based radiographic study with longitudinal follow-up. OBJECTIVE: To develop a quantitative index for lumbar disc space narrowing (DSN) evaluation in elderly subjects; to determine how DSN in the elderly is influenced by osteoporosis and sex. SUMMARY OF BACKGROUND DATA: There is paucity of research on quantitative classification of lumbar DSN based on disc areal morphometry. METHODS: With the database of Osteoporotic Fractures in Men (Hong Kong) and Osteoporotic Fractures in Women (Hong Kong) Studies and those who attended the year-4 follow-up (n = 1519 for men and n = 1546 for women), data of 491 women and 592 men were randomly selected. The anterior, middle, and posterior heights; anteroposterior diameter; and area of intervertebral discs (T4T5 to L4L5) were measured on lateral radiographs. Disc area index for lumbar spine (DAIL, disc area divided by the mean of the sum of square of the adjacent upper and lower vertebrae mid-height anterior-posterior diameter) was developed and compared with semiquantitative DSN expert grading. RESULTS: DAIL correlated with semiquantitative grading, with sensitivity and specificity varying from 87.3% to 96.8% for grade 1 DSN (<30% reduction in disc height), and 92.9% to 100% for grade 3 DSN (>60% reduction in disc height). The thoracolumbar disc area loss among men and women during 4-years' follow-up period varied between 1.32% and 3.56%, and it was greater for women (mean: 2.44%) than for men (mean: 1.90%, P = 0.044). Majority of lumbar DSN progressions during 72 to 76 years old were progression from normal disc space to grade 1 DSN. Osteoporosis was associated with greater disc area decrease, both for thoracic and lumbar discs. CONCLUSION: Lumbar DSN can be quantified using DAIL. In elderly Chinese, intervertebral disc narrowing over a 4-year period was greater in women than men, and associated with the presence of osteoporosis. LEVEL OF EVIDENCE: 3. PMID- 29112103 TI - Vasopressin in Vasodilatory Shock for Both Left and Right Heart Anomalous Pediatric Patients After Cardiac Surgery. AB - Although the use of vasopressin has become commonplace in pediatric patients with vasodilatory shock after cardiac surgery, its efficacy and hemodynamic effects have not been systematically documented. Furthermore, previous studies were mainly limited patients with left heart anomalies. To date, the use of vasopressin in patients with right heart anomalies has not yet been reported. To clarify the hemodynamic effects of vasopressin on pediatric patients with vasodilatory shock after cardiopulmonary bypass, 70 consecutive patients, most of whom with right heart anomalies, were retrospectively analyzed in Fuwai Hospital from October 2013 to September 2015. Vasopressin was administered continuously at a dose of 0.0002 to 0.002 u/kg/min. Hemodynamics, urine output, and catecholamine vasopressor doses were compared before and after vasopressin initiation. Results showed that besides the significant increase in blood pressure at 2 h after vasopressin administration, the systemic vascular resistance index also prominently elevated from 894.3 +/- 190.8 dyn/s to 1138.2 +/- 161.4 dyn/s per cm per m, while the heart rate, right atrial pressure, pulmonary artery pressure had a trend of decline. Subsequently, the fluid requirement, the catecholamine vasopressor requirement both decreased and urine output increased. Lactate concentration showed a later remarkable decline at 12 h since vasopressin administration. All the 70 patients survived to hospital discharge. In conclusion, low dose of vasopressin administration was associated with great and timely hemodynamic improvement for pediatric patients with vasodilatory shock after cardiac surgery without any significant adverse effects. PMID- 29112102 TI - An Assessment of the Academic Impact of Shock Society Members. AB - Professional society membership enhances career development and productivity by offering opportunities for networking and learning about recent advances in the field. The quality and contribution of such societies can be measured in part through the academic productivity, career status, and funding success rates of their members. Here, using Scopus, NIH RePORTER, and departmental websites, we compare characteristics of the Shock Society membership to those of the top 55 NIH-funded American university and hospital-based departments of surgery. Shock Society members' mean number of publications, citations and H-indices were all significantly higher than those of non-members in surgery departments (P < 0.001). A higher percentage of members also have received funding from the NIH (42.5% vs. 18.5%, P < 0.001). Regression analysis indicated that members were more likely to have NIH funding compared with non-members (OR 1.46, 95% CI 1.12 1.916). Trauma surgeons belonging to the Shock Society had a higher number of publications and greater NIH funding than those who did not (130.4 vs. 42.7, P < 0.001; 40.4% vs. 8.5%, P < 0.001). Aggregate academic metrics from the Shock Society were superior to those of the Association for Academic Surgery and generally for the Society of University Surgeons as well. These data indicate that the Shock Society represents a highly academic and productive group of investigators. For surgery faculty, membership is associated with greater academic productivity and career advancement. While it is difficult to ascribe causation, certainly the Shock Society might positively influence careers for its members. PMID- 29112104 TI - Cardiogenic Shock Due to End-Stage Heart Failure and Acute Myocardial Infarction: Characteristics and Outcome of Temporary Mechanical Circulatory Support. AB - BACKGROUND: Mechanical circulatory support (MCS) is increasingly used in cardiogenic shock, but outcomes may differ between patients with acute myocardial infarction (AMI) or end-stage heart failure (ESHF). This study aimed to describe the characteristics of patients with cardiogenic shock due to AMI and ESHF. METHODS: Single-center study of consecutive patients with cardiogenic shock due to AMI (n = 26) and ESHF (n = 42) who underwent MCS (extracorporeal life support, Impella or temporary ventricular assist devices). Arterial and venous O2 content and CO2 tension (PCO2), O2-hemoglobin affinity (P50) were measured. Veno-arterial difference in PCO2/arterio-venous difference in O2 content ratio was derived. Acid-base balance was characterized by the Gilfix method. MCS-related complications that required intervention or surgery were collected. RESULTS: Patients with ESHF had lower ejection fraction, higher right and left-sided filling pressures, pulmonary artery pressure and vascular resistance, lower oxygen delivery (DO2) compared with AMI, which was not fully compensated by the increased hemoglobin P50. As a result, patients with ESHF had higher veno arterial difference in PCO2 relative to arterio-venous difference in O2 content. Despite greater anerobic metabolism, patients with ESHF had less severe metabolic acidosis and base deficit compared with AMI, predominantly due to differences in strong ions. CONCLUSION: The cardiogenic shock phenotype in ESHF was distinct from AMI, characterized by higher filling and pulmonary artery pressures, lower DO2, greater anaerobic metabolism but less severe metabolic acidosis. PMID- 29112105 TI - Secretome Conveys the Protective Effects of ASCs: Therapeutic Potential Following Hemorrhagic Shock? AB - OBJECTIVES: We tested whether resuscitation supplemented with rat adipose-derived stem cells (ASCs) or secretome (conditioned media) of ASCs can ameliorate inflammation, cell/organ injury, and/or improve outcome after hemorrhagic traumatic shock (HTS). INTERVENTIONS: Rats were subjected to HTS and a resuscitation protocol that mimics prehospital restrictive reperfusion followed by an adequate reperfusion phase. Twenty minutes into the restrictive reperfusion, animals received an intravenous bolus of 2 * 10 cells (ASC group) or the secretome produced by 2 * 10 ASCs/24 h (ASC-Secretome group). Controls received the vehicle (Vehicle group). All rats were observed for 28-day survival. MEASUREMENTS AND MAIN RESULTS: HTS-induced inflammation represented by IL-6 was inhibited in the ASC (80%, P < 0.001) and in ASC-Secretome (59%, P < 0.01) group at 48 h compared with Vehicle group. At 24 h, HTS-induced liver injury reflected in plasma alanine aminotransferase was ameliorated by 36% (P < 0.001) in both the ASC and ASC-Secretome groups when compared with the Vehicle. There was no effect on kidney function and/or general cell injury markers. HTS induced a moderate 28 day mortality (18%) that was prevented (P = 0.08) in the ASC but not in the ASC Secretome group (12%). CONCLUSIONS: Our data suggest that the ASC-secretome supplemented resuscitation following HTS, in the absence of the stem cells, exerts anti-inflammatory and liver protective effects. Given its ease of preparation, storage, availability, and application (in contrast to the stem cells) we believe that the cell-free secretome has a better therapeutic potential in the early phase of an acute hemorrhagic shock scenario. PMID- 29112106 TI - Mechanisms of Toxicity and Modulation of Hemoglobin-Based Oxygen Carriers (HBOCs). AB - Several adverse events have been associated with the infusion of hemoglobin-based oxygen carriers (HBOCs) including transient hypertension, gastrointestinal, pancreatic/liver enzyme elevation, and cardiac/renal injury in humans. Although several mechanisms have been suggested, the basis of HBOC toxicity is still poorly understood. Scavenging of vascular endothelial nitric oxide (NO) and heme mediated oxidative side reactions are thought to be the major causes of toxicity. However, based on more recent preclinical studies, oxidative pathways (driven by the heme prosthetic group) appear to play a more prominent role in the overall toxicity of free Hb or HBOCs. HBOCs display a diversity of physicochemical properties including molecular size/crosslinking characteristics leading to differences in oxygen affinity, allosteric, redox properties and even oxidative inactivation by protein/heme clearing mechanisms. These diverse characteristics can therefore be manipulated independently, leaving open the possibility of engineering a safe and effective HBOC. To date, several anti-oxidative strategies have been proposed to counteract the redox side reactions of current generation HBOCs. PMID- 29112107 TI - A Scoping Review of Emergency Department Discharge Instructions for Children and Adolescents With Mental Disorders. AB - BACKGROUND: Although most young people under the age of 25 years with mental health presentations to the emergency department (ED) are discharged home, several studies suggest discharge instructions are inadequate. We conducted a scoping review to characterize and map the literature, identify research gaps, and prioritize targeted areas for future reviews for ED discharge instructions for young people with mental disorders. METHODS: Our review was conducted in an iterative approach with 6 stages including identifying the research question, identifying relevant studies, study selection, data extraction, collaring and summarizing, and stakeholder engagement. We characterized the available information on discharge instruction interventions using the Behavior Change Wheel. RESULTS: Of the 805 potential publications screened, 25 were included for extraction. Nine of the 25 articles focused on suicide or self-harm, 6 were on mental health in general or mixed groups, and 9 focused on alcohol, tobacco, or substance use in general. Five studies included younger children (ie, less than 12 years) but ages ranged significantly among studies. Education and persuasion were intervention functions most commonly reported in publications (n = 13 and n = 12, respectively). From the policy categories, recommendations regarding service provision were most frequently made from four publications. Descriptions of theory were limited in publications. CONCLUSIONS: The available literature regarding discharge instructions in the ED for youth with mental disorders is focused on certain content areas (eg, self injurious behaviors, substance use) with more work required in chronic mental disorders that make up a significant proportion of ED visits. Research that extends beyond education and with theoretical underpinnings to explain how and why various interventions work would be useful for clinicians, policy-makers, and other researchers. PMID- 29112108 TI - Nitrous Oxide 70% for Procedural Analgosedation in a Pediatric Emergency Department With or Without Intranasal Fentanyl?: Analgesic Efficacy and Adverse Events if Combined With Intranasal Fentanyl. AB - OBJECTIVES: Nitrous oxide 70% (N20 70%) is an excellent medication for procedural analgosedation in a pediatric emergency department. However, its analgesic efficacy remains uncertain for painful procedures; therefore, a combination with intranasal fentanyl (INF), an opioid, was suggested. This study aimed at observing and assessing the analgesic efficacy and rate of adverse events using N20 70% with and without INF. METHODS: Children who received N20 70% in a tertiary children's hospital emergency department from January 1, 2014 to June 30, 2015 were included in this observational study with prospective data collection. Physicians decided individually whether INF was administered. Medical staff documented the child's behavior during the procedure, adverse events, and satisfaction rate. RESULTS: A total of 442 children were included; 206 (46.6%) received INF. Group differences regarding patient behavior were not statistically significant; however, N20 70% application time was longer in the INF group (P = .02). Nausea was the most frequent adverse event with 13.1% in the INF group versus 8.1% without INF. Inadequate procedural analgosedation was documented only in the INF group, affecting 1.8% of all patients (P = .002). In contrast, anxiety was exclusively observed in the group without INF, which was presumably misjudged pain (P = .03); the satisfaction rate in the INF group was 95.6% compared with 98.7% without INF. CONCLUSIONS: Because of the study design and limitations, no conclusions about adding INF to N20 70% can be made. Additional research is needed to investigate the effect of combining N20 70% with INF. PMID- 29112109 TI - Pediatric Emergency Department and Primary Care Provider Attitudes on Assessing Childhood Adversity. AB - OBJECTIVE: The purpose of this study was to understand pediatric emergency department (ED) and primary care (PC) health care provider attitudes and beliefs regarding the intersection between childhood adversities and health care. METHODS: We conducted in-depth, semistructured interviews in 2 settings (ED and PC) within an urban health care system. Purposive sampling was used to balance the sample among 3 health care provider roles. Interview questions were based on a modified health beliefs model exploring the "readiness to act" among providers. Interviews were recorded, transcribed, and coded. Interviews continued until theme saturation was reached. RESULTS: Saturation was achieved after 26 ED and 19 PC interviews. Emergency department/primary care providers were similar in their perception of patient susceptibility to childhood adversity. Childhood mental health problems were the most frequently referenced adverse outcome, followed by poor childhood physical health. Adult health outcomes because of childhood adversity were rarely mentioned. Many providers felt that knowing about childhood adversity in the medical setting was important because it relates to provision of tangible resources. There were mixed opinions about whether or not pediatric health care providers should be identifying childhood adversities at all. CONCLUSIONS: Although providers exhibited knowledge about childhood adversity, the perceived effect on health was only immediate and tangible. The effect of childhood adversity on lifelong health and the responsibility and potential accountability health systems have in addressing these important health determinants was not recognized by many respondents in our study. Addressing these provider perspectives will be a critical component of successful transformation toward more accountable health care delivery systems. PMID- 29112111 TI - Pediatric Minoxidil Exposures Reported to Texas Poison Centers. AB - OBJECTIVES: It has been suggested that ingestion of even small amounts of minoxidil by young children may result in serious adverse effects. The intent of this study was to describe pediatric minoxidil exposures reported to a statewide poison center system. METHODS: Cases were minoxidil exposures among patients 5 years or younger reported to Texas poison centers during 2000 to 2014. The distribution by various demographic and clinical factors was determined. RESULTS: Of 125 total cases, 58% were male and 78% aged 1 to 2 years. Ingestion alone was reported in 92% of the exposures. Ninety-eight percent of the exposures were unintentional, and 94% occurred at the patient's own residence. Sixty-two percent of the patients were managed on site. The outcome was not serious (no effect, minor effect, not followed [nontoxic], not followed [minimal effects]) in 88% of the exposures. The most common adverse effect was vomiting, reported in 8% of the exposures. The most common treatments were dilution/irrigation/wash (53%), activated charcoal (18%), food/snack (17%), and intravenous fluids (8%). CONCLUSIONS: Few pediatric minoxidil exposures were reported to Texas poison centers. Of these exposures, most involved ingestion, were unintentional, and involved patients who were male and aged 1 to 2 years. Although it has been suggested that pediatric minoxidil ingestions might result in serious adverse effects, this study suggests that most pediatric minoxidil exposures reported to poison centers are not likely to have serious outcomes and may be managed at home. PMID- 29112110 TI - Methodology and Demographics of a Brief Adolescent Alcohol Screen Validation Study. AB - OBJECTIVE: The aim of this study was to determine the psychometric properties of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) 2-question alcohol screen within 16 Pediatric Emergency Care Applied Research Network pediatric emergency departments. This article describes the study methodology, sample characteristics, and baseline outcomes of the NIAAA 2-question screen. METHODS: Participants included 12- to 17-year-olds treated in one of the participating pediatric emergency departments across the United States. After enrollment, a criterion assessment battery including the NIAAA 2-question screen and other measures of alcohol, drug use, and risk behavior was self-administered by participants on a tablet computer. Two subsamples were derived from the sample. The first subsample was readministered the NIAAA 2-question screen 1 week after their initial visit to assess test-retest reliability. The second subsample is being reassessed at 12 and 24 months to examine predictive validity of the NIAAA 2-question screen. RESULTS: There were 4834 participants enrolled into the study who completed baseline assessments. Participants were equally distributed across sex and age. Forty-six percent of the participants identified as white, and 26% identified as black. Approximately one quarter identified as Hispanic. Using the NIAAA 2-question screen algorithm, approximately 8% were classified as low risk, 12% were classified as moderate risk, and 4% were classified as highest risk. Alcohol use was less likely to be reported by black participants, non-Hispanic participants, and those younger than 16 years. DISCUSSION: This study successfully recruited a large, demographically diverse sample to establish rates of the NIAAA screen risk categories across age, sex, ethnicity, and race within pediatric emergency departments. PMID- 29112112 TI - Sialocele Following Traumatic Dental Procedure: A Case Report and Review of Dental Complications. AB - We present a case of a 17-year-old girl with sialadenitis and sialocele due to trauma sustained from a dental procedure. Our objectives are to review relevant literature and anatomy of the floor of the mouth and salivary glands and discuss potential complications of dental procedures. PMID- 29112113 TI - Erratum: Carrasco-Sanchez, V.; et al. Removal of 4-Ethylphenol and 4 Ethylguaiacol with Polyaniline-Based Compounds in Wine-Like Model Solutions and Red Wine. Molecules 2015, 20(8), 14312-14325. PMID- 29112114 TI - Role of Scaffold Protein Proline-, Glutamic Acid-, and Leucine-Rich Protein 1 (PELP1) in the Modulation of Adrenocortical Cancer Cell Growth. AB - PELP1 acts as an estrogen receptor (ER) coactivator that exerts an essential role in the ER's functions. ER coregulators have a critical role in the progression and response to hormonal treatment of estrogen-dependent tumors. We previously demonstrated that, in adrenocortical carcinoma (ACC), ERalpha is upregulated and that estradiol activates the IGF-II/IGF1R signaling pathways defining the role of this functional cross-talk in H295R ACC cell proliferation. The aim of this study was to determine if PELP1 is expressed in ACC and may play a role in promoting the interaction between ERalpha and IGF1R allowing the activation of pathways important for ACC cell growth. The expression of PELP1 was detected by Western blot analysis in ACC tissues and in H295R cells. H295R cell proliferation decrease was assessed by A3-(4,5-Dimethylthiaoly)-2,5-diphenyltetrazolium bromide (MTT) assay and [3H] thymidine incorporation. PELP1 is expressed in ACC tissues and in H295R cells. Moreover, treatment of H295R with E2 or IGF-II induced a multiprotein complex formation consisting of PELP1, IGF1R, ERalpha, and Src that is involved in ERK1/2 rapid activation. PELP1/ER/IGF1R/c-Src complex identification as part of E2- and IGF-II-dependent signaling in ACC suggests PELP1 is a novel and more efficient potential target to reduce ACC growth. PMID- 29112115 TI - Immunoenhancement Effects of Glycosaminoglycan from Apostichopus japonicus: In Vitro and In Cyclophosphamide-Induced Immunosuppressed Mice Studies. AB - In this study, the immunomodulatory activities of Apostichopus japonicus glycosaminoglycan (AHG) on the nature killer (NK) cells, cytotoxic T lymphocytes (CTLs) and cyclophosphamide (CY)-treated mice were investigated. After stimulation with multiple concentrations of AHG (0-100 MUg/mL), NK cells and CTLs displayed outperformance against YAC-1 and B16 cells, respectively. Furthermore, the mitogen-induced splenic lymphocyte proliferation in CY-induced immunosuppressed mice was significantly promoted by AHG. In addition, the administration of AHG dramatically increased the splenocytes Ca2+ concentration and the delayed-type hypersensitivity (DTH) reaction in a dose-dependent manner. Besides, AHG could strongly increase the total antioxidant capacity (T-AOC), the activities of superoxidase dismutase (SOD), catalase (CAT) as well as glutathione peroxidase (GSH-PX), and could decrease the malondialdehyde (MDA) level in the heart, kidney and liver. These findings indicated that AHG played an important role in the immune enhancement and protection against CY-induced immunosuppression and oxidative damage. Our findings provide experimental evidence for further research and possible immunostimulatory applications of AHG in clinical practice. PMID- 29112117 TI - Optimal Quantization Scheme for Data-Efficient Target Tracking via UWSNs Using Quantized Measurements. AB - Target tracking is one of the broad applications of underwater wireless sensor networks (UWSNs). However, as a result of the temporal and spatial variability of acoustic channels, underwater acoustic communications suffer from an extremely limited bandwidth. In order to reduce network congestion, it is important to shorten the length of the data transmitted from local sensors to the fusion center by quantization. Although quantization can reduce bandwidth cost, it also brings about bad tracking performance as a result of information loss after quantization. To solve this problem, this paper proposes an optimal quantization based target tracking scheme. It improves the tracking performance of low-bit quantized measurements by minimizing the additional covariance caused by quantization. The simulation demonstrates that our scheme performs much better than the conventional uniform quantization-based target tracking scheme and the increment of the data length affects our scheme only a little. Its tracking performance improves by only 4.4% from 2- to 3-bit, which means our scheme weakly depends on the number of data bits. Moreover, our scheme also weakly depends on the number of participate sensors, and it can work well in sparse sensor networks. In a 6 * 6 * 6 sensor network, compared with 4 * 4 * 4 sensor networks, the number of participant sensors increases by 334.92%, while the tracking accuracy using 1-bit quantized measurements improves by only 50.77%. Overall, our optimal quantization-based target tracking scheme can achieve the pursuit of data efficiency, which fits the requirements of low-bandwidth UWSNs. PMID- 29112116 TI - Application of Chitosan, Chitooligosaccharide, and Their Derivatives in the Treatment of Alzheimer's Disease. AB - Classic hypotheses of Alzheimer's disease (AD) include cholinergic neuron death, acetylcholine (ACh) deficiency, metal ion dynamic equilibrium disorder, and deposition of amyloid and tau. Increased evidence suggests neuroinflammation and oxidative stress may cause AD. However, none of these factors induces AD independently, but they are all associated with the formation of Abeta and tau proteins. Current clinical treatments based on ACh deficiency can only temporarily relieve symptoms, accompanied with many side-effects. Hence, searching for natural neuroprotective agents, which can significantly improve the major symptoms and reverse disease progress, have received great attention. Currently, several bioactive marine products have shown neuroprotective activities, immunomodulatory and anti-inflammatory effects with low toxicity and mild side effects in laboratory studies. Recently, chitosan (CTS), chitooligosaccharide (COS) and their derivatives from exoskeletons of crustaceans and cell walls of fungi have shown neuroprotective and antioxidative effects, matrix metalloproteinase inhibition, anti-HIV and anti-inflammatory properties. With regards to the hypotheses of AD, the neuroprotective effect of CTS, COS, and their derivatives on AD-like changes in several models have been reported. CTS and COS exert beneficial effects on cognitive impairments via inhibiting oxidative stress and neuroinflammation. They are also a new type of non-toxic beta-secretase and AChE inhibitor. As neuroprotective agents, they could reduce the cell membrane damage caused by copper ions and decrease the content of reactive oxygen species. This review will focus on their anti-neuroinflammation, antioxidants and their inhibition of beta-amyloid, acetylcholinesterase and copper ions adsorption. Finally, the limitations and future work will be discussed. PMID- 29112118 TI - Nutritional Therapies in Congenital Disorders of Glycosylation (CDG). AB - Congenital disorders of glycosylation (CDG) are a group of more than 130 inborn errors of metabolism affecting N-linked, O-linked protein and lipid-linked glycosylation. The phenotype in CDG patients includes frequent liver involvement, especially the disorders belonging to the N-linked protein glycosylation group. There are only a few treatable CDG. Mannose-Phosphate Isomerase (MPI)-CDG was the first treatable CDG by high dose mannose supplements. Recently, with the successful use of d-galactose in Phosphoglucomutase 1 (PGM1)-CDG, other CDG types have been trialed on galactose and with an increasing number of potential nutritional therapies. Current mini review focuses on therapies in glycosylation disorders affecting liver function and dietary intervention in general in N linked glycosylation disorders. We also emphasize now the importance of early screening for CDG in patients with mild hepatopathy but also in cholestasis. PMID- 29112119 TI - Steroidal Glycosides from Convallaria majalis Whole Plants and Their Cytotoxic Activity. AB - Phytochemical examination of Convallaria majalis (Liliaceae) whole plants yielded 15 steroidal glycosides (1-15), including nine new compounds (4-6, 10-15) with a lycotetrose unit. The structures of the new compounds were determined using two dimensional Nuclear magnetic resonance (NMR) analyses and chemical methods. The isolated compounds were evaluated for cytotoxicity against HL-60 human promyelocytic leukemia cells, A549 human lung adenocarcinoma cells, and HSC-4 and HSC-2 human oral squamous cell carcinoma cell lines. Of these, (25S)-spirost-5-en 3beta-yl O-beta-d-glucopyranosyl-(1->2)-O-[beta-d-xylopyranosyl-(1->3)]-O-beta-d glucopyranosyl-(1->4)-beta-d-galactopyranoside (1) exhibited cytotoxic activity against HL-60, A549, HSC-4, and HSC-2 cells with IC50 values ranging from 0.96 to 3.15 MUM. The corresponding furostanol glycoside of 1, (25S)-26-[(beta-d glucopyranosyl)oxy]-22alpha-hydroxyfurost-5-en-3beta-yl O-beta-d-glucopyranosyl (1->2)-O-[beta-d-xylopyranosyl-(1->3)]-O-beta-d-glucopyranosyl-(1->4)-beta-d galactopyranoside (8), was cytotoxic to the adherent cell lines of A549, HSC-4, and HSC-2 cells with IC50 values of 2.97, 11.04, and 8.25 MUM, respectively. The spirostanol lycotetroside (1) caused necrotic cell death in A549 cells in a dose dependent manner. Alternatively, the furostanol lycotetroside (8) induced apoptotic cell death in A549 cells in a time-dependent manner, as was evident by morphological observations and flow cytometry analyses. PMID- 29112120 TI - BUS TRIPS-A Self-Management Program for People with Cognitive Impairments after Stroke. AB - Stroke is a major cause of disability worldwide and different types of impairments can affect the individual's ability to manage everyday activities such as travel that is essential for participation in society. The purpose of this study was to investigate the feasibility of a new self-management intervention (BUS TRIPS) focusing on travelling by bus, and potential contributions to an improved ability to travel by bus for people with cognitive impairments after stroke. This is a pilot study of five individuals, utilizing a multiple case study design with a mixed methods approach. Assessments (Stroke Impact Scale, General Self-Efficacy Scale and Life Satisfaction Scale-11, Item 1) were performed before, two weeks after, and three months after the program. The data collection also comprised reflection notes from the group leaders (an occupational therapist and a physiotherapist), a semi-structured group interview and an individual phone survey. The feasibility of the intervention was presented in four sub-categories: (1) appreciated group format despite too short sessions; (2) the importance of skilled leaders and motivated participants; (3) session material adequate but needs minor revision to fit the target group; and (4) homework is valuable but reflective group discussions must be supported. The narratives of each case showed that all participants made some progress related to travelling by bus, but the overall positive results could not be verified by all of the quantitative assessments. We conclude that the BUS TRIPS intervention is feasible and can potentially contribute to an improved ability to travel by bus for the target group. Future studies is called for, and should focus on recruitment challenges, to clarify assessments that would be suitable to use in larger scale clinical trials and during subsequent implementation in clinical practice. PMID- 29112121 TI - The Potential of iPSCs for the Treatment of Premature Aging Disorders. AB - Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan of the patients. Importantly, these disorders mimic several features of physiological aging. Despite the interest on the study of these diseases, the underlying biological mechanisms remain unknown and no treatment is available. Recent studies on HGPS (due to mutations of the LMNA gene encoding for the nucleoskeletal proteins lamin A/C) have reported disruptions in cellular and molecular mechanisms modulating genomic stability and stem cell populations, thus giving the nuclear lamina a relevant function in nuclear organization, epigenetic regulation and in the maintenance of the stem cell pool. In this context, modeling premature aging with induced pluripotent stem cells (iPSCs) offers the possibility to study these disorders during self-renewal and differentiation into relevant cell types. iPSCs generated by cellular reprogramming from adult somatic cells allows researchers to understand pathophysiological mechanisms and enables the performance of drug screenings. Moreover, the recent development of precision genome editing offers the possibility to study the complex mechanisms underlying senescence and the possibility to correct disease phenotypes, paving the way for future therapeutic interventions. PMID- 29112124 TI - Gene Regulatory Network Rewiring in the Immune Cells Associated with Cancer. AB - The gene regulatory networks (GRNs) of immune cells not only indicate cell identity but also reveal the dynamic changes of immune cells when comparing their GRNs. Cancer immunotherapy has advanced in the past few years. Immune-checkpoint blockades (i.e., blocking PD-1, PD-L1, or CTLA-4) have shown durable clinical effects on some patients with various advanced cancers. However, major gaps in our knowledge of immunotherapy have been recognized. To fill these gaps, we conducted a systematic analysis of the GRNs of key immune cell subsets (i.e., B cell, CD4, CD8, CD8 naive, CD8 Effector memory, CD8 Central Memory, regulatory T, Thelper1, Thelper2, Thelp17, and NK (Nature killer) and DC (Dendritic cell) cells associated with cancer immunologic therapies. We showed that most of the GRNs of these cells in blood share key important hub regulators, but their subnetworks for controlling cell type-specific receptors are different, suggesting that transformation between these immune cell subsets could be fast so that they can rapidly respond to environmental cues. To understand how cancer cells send molecular signals to immune cells to make them more cancer-cell friendly, we compared the GRNs of the tumor-infiltrating immune T cells and their corresponding immune cells in blood. We showed that the network size of the tumor infiltrating immune T cells' GRNs was reduced when compared to the GRNs of their corresponding immune cells in blood. These results suggest that the shutting down certain cellular activities of the immune cells by cancer cells is one of the key molecular mechanisms for helping cancer cells to escape the defense of the host immune system. These results highlight the possibility of genetic engineering of T cells for turning on the identified subnetworks that have been shut down by cancer cells to combat tumors. PMID- 29112122 TI - Identification and Antimicrobial Susceptibility Testing of Anaerobic Bacteria: Rubik's Cube of Clinical Microbiology? AB - Anaerobic bacteria have pivotal roles in the microbiota of humans and they are significant infectious agents involved in many pathological processes, both in immunocompetent and immunocompromised individuals. Their isolation, cultivation and correct identification differs significantly from the workup of aerobic species, although the use of new technologies (e.g., matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, whole genome sequencing) changed anaerobic diagnostics dramatically. In the past, antimicrobial susceptibility of these microorganisms showed predictable patterns and empirical therapy could be safely administered but recently a steady and clear increase in the resistance for several important drugs (beta-lactams, clindamycin) has been observed worldwide. For this reason, antimicrobial susceptibility testing of anaerobic isolates for surveillance purposes or otherwise is of paramount importance but the availability of these testing methods is usually limited. In this present review, our aim was to give an overview of the methods currently available for the identification (using phenotypic characteristics, biochemical testing, gas-liquid chromatography, MALDI-TOF MS and WGS) and antimicrobial susceptibility testing (agar dilution, broth microdilution, disk diffusion, gradient tests, automated systems, phenotypic and molecular resistance detection techniques) of anaerobes, when should these methods be used and what are the recent developments in resistance patterns of anaerobic bacteria. PMID- 29112125 TI - The Development of an IMU Integrated Clothes for Postural Monitoring Using Conductive Yarn and Interconnecting Technology. AB - Spinal disease is a common yet important condition that occurs because of inappropriate posture. Prevention could be achieved by continuous posture monitoring, but most measurement systems cannot be used in daily life due to factors such as burdensome wires and large sensing modules. To improve upon these weaknesses, we developed comfortable "smart wear" for posture measurement using conductive yarn for circuit patterning and a flexible printed circuit board (FPCB) for interconnections. The conductive yarn was made by twisting polyester yarn and metal filaments, and the resistance per unit length was about 0.05 Omega/cm. An embroidered circuit was made using the conductive yarn, which showed increased yield strength and uniform electrical resistance per unit length. Circuit networks of sensors and FPCBs for interconnection were integrated into clothes using a computer numerical control (CNC) embroidery process. The system was calibrated and verified by comparing the values measured by the smart wear with those measured by a motion capture camera system. Six subjects performed fixed movements and free computer work, and, with this system, we were able to measure the anterior/posterior direction tilt angle with an error of less than 4 degrees . The smart wear does not have excessive wires, and its structure will be optimized for better posture estimation in a later study. PMID- 29112123 TI - Down-Regulation of Transglutaminase 2 Stimulates Redifferentiation of Dedifferentiated Chondrocytes through Enhancing Glucose Metabolism. AB - Expansion of chondrocytes for repair of articular cartilage can lead to dedifferentiation, making it difficult to obtain a sufficient quantity of chondrocytes. Although previous studies have suggested that culture in a three dimensional environment induces redifferentiation of dedifferentiated chondrocytes, its underlying mechanisms are still poorly understood in terms of metabolism compared with a two-dimensional environment. In this study, we demonstrate that attenuation of transglutaminase 2 (TG2), a multifunctional enzyme, stimulates redifferentiation of dedifferentiated chondrocytes. Fibroblast like morphological changes increased as TG2 expression increased in passage dependent manner. When dedifferentiated chondrocytes were cultured in a pellet culture system, TG2 expression was reduced and glycolytic enzyme expression up regulated. Previous studies demonstrated that TG2 influences energy metabolism, and impaired glycolytic metabolism causes chondrocyte dedifferentiation. Interestingly, TG2 knockdown improved chondrogenic gene expression, glycolytic enzyme expression, and lactate production in a monolayer culture system. Taken together, down-regulation of TG2 is involved in redifferentiaton of dedifferentiated chondrocytes through enhancing glucose metabolism. PMID- 29112127 TI - Some Properties of Densified Eastern Redcedar as Function of Heat and Pressure. AB - The objective of this study was to evaluate some of the properties of densified eastern redcedar as function of temperature and pressure. Surface quality, adhesive bondline shear strength, hardness, and color changes of the samples compressed using different temperature levels ranging from 100 degrees C to 180 degrees C were investigated. Based on the findings in this work, surface roughness of compressed specimens decreased with increased temperature. Overall adhesive bondline shear strength of the samples decreased as compared to that of control specimens as a result of compression. It appears that densified samples exposed to a temperature of 180 degrees C had significantly darker surface than those of the others, based on color measurement. Data found in this work provide some basic information for more efficient use of underutilized species such as eastern redcedar. PMID- 29112126 TI - Factors That Influence Linkages to HIV Continuum of Care Services: Implications for Multi-Level Interventions. AB - Worldwide, the human immunodeficiency virus (HIV) continuum of care involves health promotion providers (e.g., social workers and health educators) linking patients to medical personnel who provide HIV testing, primary care, and antiretroviral treatments. Regrettably, these life-saving linkages are not always made consistently and many patients are not retained in care. To design, test and implement effective interventions, we need to first identify key factors that may improve linkage-making. To help close this gap, we used in-depth interviews with 20 providers selected from a sample of 250 participants in a mixed-method longitudinal study conducted in New York City (2012-2017) in order to examine the implementation of HIV services for at-risk populations. Following a sociomedical framework, we identified provider-, interpersonal- and environmental-level factors that influence how providers engage patients in the care continuum by linking them to HIV testing, HIV care, and other support services. These factors occurred in four domains of reference: Providers' Professional Knowledge Base; Providers' Interprofessional Collaboration; Providers' Work-Related Changes; and Best Practices in a Competitive Environment. Of particular importance, our findings show that a competitive environment and a fear of losing patients to other agencies may inhibit providers from engaging in linkage-making. Our results suggest relationships between factors within and across all four domains; we recommend interventions to modify factors in all domains for maximum effect toward improving care continuum linkage-making. Our findings may be applicable in different areas of the globe with high HIV prevalence. PMID- 29112128 TI - An Embedded Wireless Sensor Network with Wireless Power Transmission Capability for the Structural Health Monitoring of Reinforced Concrete Structures. AB - Maintenance strategies based on structural health monitoring can provide effective support in the optimization of scheduled repair of existing structures, thus enabling their lifetime to be extended. With specific regard to reinforced concrete (RC) structures, the state of the art seems to still be lacking an efficient and cost-effective technique capable of monitoring material properties continuously over the lifetime of a structure. Current solutions can typically only measure the required mechanical variables in an indirect, but economic, manner, or directly, but expensively. Moreover, most of the proposed solutions can only be implemented by means of manual activation, making the monitoring very inefficient and then poorly supported. This paper proposes a structural health monitoring system based on a wireless sensor network (WSN) that enables the automatic monitoring of a complete structure. The network includes wireless distributed sensors embedded in the structure itself, and follows the monitoring based maintenance (MBM) approach, with its ABCDE paradigm, namely: accuracy, benefit, compactness, durability, and easiness of operations. The system is structured in a node level and has a network architecture that enables all the node data to converge in a central unit. Human control is completely unnecessary until the periodic evaluation of the collected data. Several tests are conducted in order to characterize the system from a metrological point of view and assess its performance and effectiveness in real RC conditions. PMID- 29112129 TI - Enhanced Agronomic Traits and Medicinal Constituents of Autotetraploids in Anoectochilus formosanus Hayata, a Top-Grade Medicinal Orchid. AB - This study developed an efficient and reliable system for inducing polyploidy in Anoectochilus formosanus Hayata, a top-grade medicinal orchid. The resulting tetraploid gave a significant enhancement on various agronomic traits, including dry weight, fresh weight, shoot length, root length, leaf width, the size of stoma, and number of chloroplasts per stoma. A reduction of the ratio of length to width was observed in stomata and leaves of the tetraploid, and consequently, an alteration of organ shape was found. The major bioactive compounds, total flavonoid and gastrodin, were determined by the aluminum chloride colorimetric method and ultra performance liquid chromatography tandem mass spectrometry (UPLC MS/MS), respectively. The tetraploid produced significantly higher contents of total flavonoid and gastrodin in the leaf, the stem, and the whole plant when compared with the diploid. The resulting tetraploids in this study are proposed to be suitable raw materials in the pharmaceutical industry for enhancing productivity and reducing cost. PMID- 29112130 TI - Role of Immunological Memory Cells as a Therapeutic Target in Multiple Sclerosis. AB - Pharmacological targeting of memory cells is an attractive treatment strategy in various autoimmune diseases, such as psoriasis and rheumatoid arthritis. Multiple sclerosis is the most common inflammatory disorder of the central nervous system, characterized by focal immune cell infiltration, activation of microglia and astrocytes, along with progressive damage to myelin sheaths, axons, and neurons. The current review begins with the identification of memory cell types in the previous literature and a recent description of the modulation of these cell types in T, B, and resident memory cells in the presence of different clinically approved multiple sclerosis drugs. Overall, this review paper tries to determine the potential of memory cells to act as a target for the current or newly developed drugs. PMID- 29112131 TI - Juvenile-Onset Diabetes and Congenital Cataract: "Double-Gene" Mutations Mimicking a Syndromic Diabetes Presentation. AB - Monogenic forms of diabetes may account for 1-5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her consanguineous parents and her four other siblings did not have diabetes or cataract, suggesting a recessive syndrome. Using whole exome sequencing of the affected proband, we identified a heterozygous p.R825Q ABCC8 mutation, located at the exact same amino-acid position as the p.R825W recurring diabetes mutation, hence likely responsible for the diabetes condition, and a homozygous p.G71S mutation in CRYBB1, a gene known to be responsible for congenital cataract. Both mutations were predicted to be damaging and were absent or extremely rare in public databases. Unexpectedly, we found that the mother was also homozygous for the CRYBB1 mutation, and both the mother and one unaffected sibling were heterozygous for the ABCC8 mutation, suggesting incomplete penetrance of both mutations. Incomplete penetrance of ABCC8 mutations is well documented, but this is the first report of an incomplete penetrance of a CRYBB1 mutation, manifesting between susceptible subjects (unaffected mother vs. affected child) and to some extent within the patient herself, who had distinct cataract severities in both eyes. Our finding illustrates the importance of family studies to unmask the role of confounding factors such as double-gene mutations and incomplete penetrance that may mimic monogenic syndromes including in the case of strongly evocative family structure with consanguinity. PMID- 29112133 TI - Characterization of Sheep Wool as a Sustainable Material for Acoustic Applications. AB - In recent years, natural materials are becoming a valid alternative to traditional sound absorbers due to reduced production costs and environmental protection. This paper reports the acoustical characterization of sheep wool. Measurements on normal incidence and diffuse-incidence sound absorption coefficients of different samples are reported. The airflow resistance has also been measured. The results prove that sheep wool has a comparable sound absorption performance to that of mineral wool or recycled polyurethane foam. An empirical model is used to calculate the sound absorption of sheep wool samples. A reasonable agreement on the acoustic absorption of all sheep wool samples is obtained. PMID- 29112134 TI - 1H NMR and Multivariate Analysis for Geographic Characterization of Commercial Extra Virgin Olive Oil: A Possible Correlation with Climate Data. AB - 1H Nuclear Magnetic Resonance (NMR) spectroscopy coupled with multivariate analysis has been applied in order to investigate metabolomic profiles of more than 200 extravirgin olive oils (EVOOs) collected in a period of over four years (2009-2012) from different geographic areas. In particular, commercially blended EVOO samples originating from different Italian regions (Tuscany, Sicily and Apulia), as well as European (Spain and Portugal) and non-European (Tunisia, Turkey, Chile and Australia) countries. Multivariate statistical analysis (Principal Component Analisys (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA)) applied on the NMR data revealed the existence of marked differences between Italian (in particular from Tuscany, Sicily and Apulia regions) and foreign (in particular Tunisian) EVOO samples. A possible correlation with available climate data has been also investigated. These results aim to develop a powerful NMR-based tool able to protect Italian olive oil productions. PMID- 29112132 TI - Autophagy Roles in the Modulation of DNA Repair Pathways. AB - Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including premature aging, neurodegenerative diseases, and cancer. The interchange between these pathways is complex and it may occur in both directions. Autophagy is activated in response to several DNA lesions types and it can regulate different mechanisms and molecules involved in DNA damage response (DDR), such as cell cycle checkpoints, cell death, and DNA repair. Thus, autophagy may modulate DNA repair pathways, the main focus of this review. In addition to the already well-documented autophagy positive effects on homologous recombination (HR), autophagy has also been implicated with other DNA repair mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Given the relevance of these cellular processes, the clinical applications of drugs targeting this autophagy-DNA repair interface emerge as potential therapeutic strategies for many diseases, especially cancer. PMID- 29112135 TI - Rapid Construction of Complex Plant RNA Virus Infectious cDNA Clones for Agroinfection Using a Yeast-E. coli-Agrobacterium Shuttle Vector. AB - The availability of infectious full-length clone is indispensable for reverse genetics studies of virus biology, pathology and construction of viral vectors. However, for RNA viruses with large genome sizes or those exhibiting inherent cloning difficulties, procedure to generate biologically active circular DNA (cDNA) clones can be time-consuming or technically challenging. Here we have constructed a yeast-Escherichia coli-Agrobacterium shuttle vector that enables highly efficient homologous recombination in yeast for assembly of Agrobacterium compatible plant virus clones. Using this vector, we show that infectious cDNA clones of a plant negative-stranded RNA virus, sonchus yellow net rhabdovirus, can be rapidly assembled. In addition, one-step assembly of infectious clones of potato virus Y in yeast, either with or without intron, was readily achieved from as many as eight overlapping DNA fragments. More importantly, the recovered yeast plasmids can be transformed directly into Agrobacterium for inoculation, thereby obviating the E. coli cloning steps and associated toxicity issues. This method is rapid, highly efficient and cost-effective and should be readily applicable to a broad range of plant viruses. PMID- 29112136 TI - Gut Microbiome and Putative Resistome of Inca and Italian Nobility Mummies. AB - Little is still known about the microbiome resulting from the process of mummification of the human gut. In the present study, the gut microbiota, genes associated with metabolism, and putative resistome of Inca and Italian nobility mummies were characterized by using high-throughput sequencing. The Italian nobility mummies exhibited a higher bacterial diversity as compared to the Inca mummies when using 16S ribosomal (rRNA) gene amplicon sequencing, but both groups showed bacterial and fungal taxa when using shotgun metagenomic sequencing that may resemble both the thanatomicrobiome and extant human gut microbiomes. Identification of sequences associated with plants, animals, and carbohydrate active enzymes (CAZymes) may provide further insights into the dietary habits of Inca and Italian nobility mummies. Putative antibiotic-resistance genes in the Inca and Italian nobility mummies support a human gut resistome prior to the antibiotic therapy era. The higher proportion of putative antibiotic-resistance genes in the Inca compared to Italian nobility mummies may support the hypotheses that a greater exposure to the environment may result in a greater acquisition of antibiotic-resistance genes. The present study adds knowledge of the microbiome resulting from the process of mummification of the human gut, insights of ancient dietary habits, and the preserved putative human gut resistome prior the antibiotic therapy era. PMID- 29112137 TI - Subacute Sclerosing Panencephalitis of the Brainstem as a Clinical Entity. AB - Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurological disorder of early adolescence caused by persistent infection of the measles virus, which remains prevalent worldwide despite an effective vaccine. SSPE is a devastating disease with a characteristic clinical course in subcortical white matter; however, atypical presentations of brainstem involvement may be seen in rare cases. This review summarizes reports to date on brainstem involvement in SSPE, including the clinical course of disease, neuroimaging presentations, and guidelines for treatment. A comprehensive literature search was performed for English-language publications with keywords "subacute sclerosing panencephalitis" and "brainstem" using the National Library of Medicine PubMed database (March 1981-September 2017). Eleven articles focusing on SSPE of the brainstem were included. Predominant brainstem involvement remains uncharacteristic of SSPE, which may lead to misdiagnosis and poor outcome. A number of case reports have demonstrated brainstem involvement associated with other intracranial lesions commonly presenting in later SSPE stages (III and IV). However, brainstem lesions can appear in all stages, independent of higher cortical structures. The varied clinical presentations complicate diagnosis from a neuroimaging perspective. SSPE of the brainstem is a rare but important clinical entity. It may present like canonical SSPE or with unique clinical features such as absence seizures and pronounced ataxia. While SSPE generally progresses to the brainstem, it can also begin with a primary focus of infection in the brainstem. Awareness of varied SSPE presentations can aid in early diagnosis as well as guide management and treatment. PMID- 29112139 TI - Ultra Thin Poly-Si Nanosheet Junctionless Field-Effect Transistor with Nickel Silicide Contact. AB - This study demonstrated an ultra thin poly-Si junctionless nanosheet field-effect transistor (JL NS-FET) with nickel silicide contact. For the nickel silicide film, two-step annealing and a Ti capping layer were adopted to form an ultra thin uniform nickel silicide film with low sheet resistance (Rs). The JL NS-FET with nickel silicide contact exhibited favorable electrical properties, including a high driving current (>107A), subthreshold slope (186 mV/dec.), and low parasitic resistance. In addition, this study compared the electrical characteristics of JL NS-FETs with and without nickel silicide contact. PMID- 29112138 TI - Cytotoxic and Antibacterial Compounds from the Coral-Derived Fungus Aspergillus tritici SP2-8-1. AB - Three novel compounds, 4-methyl-candidusin A (1), aspetritone A (2) and aspetritone B (3), were obtained from the culture of a coral-derived fungus Aspergillus tritici SP2-8-1, together with fifteen known compounds (4-18). Their structures, including absolute configurations, were assigned based on NMR, MS, and time-dependent density functional theory (TD-DFT) ECD calculations. Compounds 2 and 5 exhibited better activities against methicillin-resistant strains of S. aureus (MRSA) ATCC 43300 and MRSA CGMCC 1.12409 than the positive control chloramphenicol. Compound 5 displayed stronger anti-MRSA and lower cytotoxic activities than 2, and showed stronger antibacterial activities against strains of Vibrio vulnificus, Vibrio rotiferianus, and Vibrio campbellii than the other compounds. Compounds 2 and 10 exhibited significantly stronger cytotoxic activities against human cancer cell lines HeLa, A549, and Hep G2 than the other compounds. Preliminary structure-activity relationship studies indicated that prenylation of terphenyllin or candidusin and the tetrahydrobenzene moiety in anthraquinone derivatives may influence their bioactivity. PMID- 29112141 TI - Optimizing Low-Concentration Mercury Removal from Aqueous Solutions by Reduced Graphene Oxide-Supported Fe3O4 Composites with the Aid of an Artificial Neural Network and Genetic Algorithm. AB - Reduced graphene oxide-supported Fe3O4 (Fe3O4/rGO) composites were applied in this study to remove low-concentration mercury from aqueous solutions with the aid of an artificial neural network (ANN) modeling and genetic algorithm (GA) optimization. The Fe3O4/rGO composites were prepared by the solvothermal method and characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), atomic force microscopy (AFM), N2-sorption, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR) and superconduction quantum interference device (SQUID). Response surface methodology (RSM) and ANN were employed to model the effects of different operating conditions (temperature, initial pH, initial Hg ion concentration and contact time) on the removal of the low-concentration mercury from aqueous solutions by the Fe3O4/rGO composites. The ANN-GA model results (with a prediction error below 5%) show better agreement with the experimental data than the RSM model results (with a prediction error below 10%). The removal process of the low-concentration mercury obeyed the Freudlich isotherm and the pseudo-second-order kinetic model. In addition, a regeneration experiment of the Fe3O4/rGO composites demonstrated that these composites can be reused for the removal of low-concentration mercury from aqueous solutions. PMID- 29112140 TI - Dual-Located WHIRLY1 Interacting with LHCA1 Alters Photochemical Activities of Photosystem I and Is Involved in Light Adaptation in Arabidopsis. AB - Plastid-nucleus-located WHIRLY1 protein plays a role in regulating leaf senescence and is believed to associate with the increase of reactive oxygen species delivered from redox state of the photosynthetic electron transport chain. In order to make sure whether WHIRLY1 plays a role in photosynthesis, in this study, the performances of photosynthesis were detected in Arabidopsis whirly1 knockout (kowhy1) and plastid localized WHIRLY1 overexpression (oepWHY1) plants. Loss of WHIRLY1 leads to a higher photochemical quantum yield of photosystem I Y(I) and electron transport rate (ETR) and a lower non photochemical quenching (NPQ) involved in the thermal dissipation of excitation energy of chlorophyll fluorescence than the wild type. Further analyses showed that WHIRLY1 interacts with Light-harvesting protein complex I (LHCA1) and affects the expression of genes encoding photosystem I (PSI) and light harvest complexes (LHCI). Moreover, loss of WHIRLY1 decreases chloroplast NAD(P)H dehydrogenase-like complex (NDH) activity and the accumulation of NDH supercomplex. Several genes encoding the PSI-NDH complexes are also up-regulated in kowhy1 and the whirly1whirly3 double mutant (ko1/3) but steady in oepWHY1 plants. However, under high light conditions (800 MUmol m-2 s-1), both kowhy1 and ko1/3 plants show lower ETR than wild-type which are contrary to that under normal light condition. Moreover, the expression of several PSI-NDH encoding genes and ERF109 which is related to jasmonate (JA) response varied in kowhy1 under different light conditions. These results indicate that WHIRLY1 is involved in the alteration of ETR by affecting the activities of PSI and supercomplex formation of PSI with LHCI or NDH and may acting as a communicator between the plastids and the nucleus. PMID- 29112143 TI - Adaptive Monocular Visual-Inertial SLAM for Real-Time Augmented Reality Applications in Mobile Devices. AB - Simultaneous localization and mapping (SLAM) is emerging as a prominent issue in computer vision and next-generation core technology for robots, autonomous navigation and augmented reality. In augmented reality applications, fast camera pose estimation and true scale are important. In this paper, we present an adaptive monocular visual-inertial SLAM method for real-time augmented reality applications in mobile devices. First, the SLAM system is implemented based on the visual-inertial odometry method that combines data from a mobile device camera and inertial measurement unit sensor. Second, we present an optical-flow based fast visual odometry method for real-time camera pose estimation. Finally, an adaptive monocular visual-inertial SLAM is implemented by presenting an adaptive execution module that dynamically selects visual-inertial odometry or optical-flow-based fast visual odometry. Experimental results show that the average translation root-mean-square error of keyframe trajectory is approximately 0.0617 m with the EuRoC dataset. The average tracking time is reduced by 7.8%, 12.9%, and 18.8% when different level-set adaptive policies are applied. Moreover, we conducted experiments with real mobile device sensors, and the results demonstrate the effectiveness of performance improvement using the proposed method. PMID- 29112142 TI - IGFBP-3 Interacts with the Vitamin D Receptor in Insulin Signaling Associated with Obesity in Visceral Adipose Tissue. AB - Adipose tissue has traditionally only been considered as an energy storage organ. Nevertheless, the importance of this tissue in systemic physiology and, especially, in systemic inflammation has been highlighted in recent years. Adipose tissue expresses proteins related to vitamin D (VD) metabolism, and it has been proposed that it can act as a VD storage tissue. The active form of VD, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is able to modify adipocyte and adipose tissue physiology via the VD receptor (VDR), decreasing the expression of pro inflammatory cytokines in adipose tissue. Moreover, VD deficiency and VDR has been reported to be associated with obesity and diabetes. However, the results of the different studies are not conclusive. Insulin growth binding proteins (IGFBPs) have been identified in adipose tissue, but their roles are poorly understood. Therefore, the objective of this study was to analyze the plasma levels of VD and the gene expression of VDR in the adipose tissue of subjects with morbid obesity (MO) and with different degrees of insulin resistance (IR), as well as the functionality of direct interaction between IGFBP-3 and VDR, which could explain its inhibitory role in adipogenesis. Our results show a novel role of the VD system in the regulation and activation of IGFBP-3 in visceral adipose tissue (VAT) of patients with MO, as a new and alternative mechanism proposed in the insulin signaling associated with obesity. PMID- 29112144 TI - Evidence for a Saponin Biosynthesis Pathway in the Body Wall of the Commercially Significant Sea Cucumber Holothuria scabra. AB - The sea cucumber (phylum Echinodermata) body wall is the first line of defense and is well known for its production of secondary metabolites; including vitamins and triterpenoid glycoside saponins that have important ecological functions and potential benefits to human health. The genes involved in the various biosynthetic pathways are unknown. To gain insight into these pathways in an echinoderm, we performed a comparative transcriptome analysis and functional annotation of the body wall and the radial nerve of the sea cucumber Holothuria scabra; to define genes associated with body wall metabolic functioning and secondary metabolite biosynthesis. We show that genes related to signal transduction mechanisms were more highly represented in the H. scabra body wall, including genes encoding enzymes involved in energy production. Eight of the core triterpenoid biosynthesis enzymes were found, however, the identity of the saponin specific biosynthetic pathway enzymes remains unknown. We confirm the body wall release of at least three different triterpenoid saponins using solid phase extraction followed by ultra-high-pressure liquid chromatography-quadrupole time of flight-mass spectrometry. The resource we have established will help to guide future research to explore secondary metabolite biosynthesis in the sea cucumber. PMID- 29112146 TI - Peptide Nucleic Acid Based Molecular Authentication for Identification of Four Medicinal Paeonia Species Using Melting Array Analysis of the Internal Transcribed Spacer 2 Region. AB - Accurate taxonomic identification of plant materials in herbal medicines is important for product quality control. The genus Paeonia (Saxifragales) is the source of the herbal preparations Paeoniae Radix (Paeoniae Radix Alba and Paeoniae Radix Rubra) and Moutan Radicis Cotex. However, confusion has arisen regarding their contents due to linguistic and taxonomic ambiguities, similar morphologies and different definitions of Paeoniae Radix in the Korean and Chinese national pharmacopoeias, leading to the distribution of adulterated products. To develop a method for identifying the four Paeonia species used in these medicines, three fluorescently-labeled peptide nucleic acid (PNA) probes were designed against ITS2 sequences containing single nucleotide polymorphisms (SNPs) and used in a real-time PCR melting curve assay. Each of the four Paeonia species was accurately identified using this analysis. The accuracy and analytical stability of the PNA melting curve assay was confirmed using commercially available samples of the four Paeonia species. This assay is a reliable genetic tool to distinguish between different Paeonia-derived herbal medicines and identify the botanical origins of Paeoniae Radix and Moutan Radicis Cortex. This technique may also contribute to quality control and standardization of herbal medicines by providing a reliable authentication tool and preventing the distribution of inauthentic adulterants. PMID- 29112145 TI - Pattern of Road Traffic Injuries in Rural Bangladesh: Burden Estimates and Risk Factors. AB - Globally, road traffic injury (RTI) causes 1.3 million deaths annually. Almost 90% of all RTI deaths occur in low- and middle-income countries. RTI is one of the leading causes of death in Bangladesh; the World Health Organization estimated that it kills over 21,000 people in the country annually. This study describes the current magnitude and risk factors of RTI for different age groups in rural Bangladesh. A household census was carried out in 51 unions of seven sub districts situated in the north and central part of Bangladesh between June and November 2013, covering 1.2 million individuals. Trained data collectors collected information on fatal and nonfatal RTI events through face-to-face interviews using a set of structured pre-tested questionnaires. The recall periods for fatal and non-fatal RTI were one year and six months, respectively. The mortality and morbidity rates due to RTI were 6.8/100,000 population/year and 889/100,000 populations/six months, respectively. RTI mortality and morbidity rates were significantly higher among males compared to females. Deaths and morbidities due to RTI were highest among those in the 25-64 years age group. A higher proportion of morbidity occurred among vehicle passengers (34%) and pedestrians (18%), and more than one-third of the RTI mortality occurred among pedestrians. Twenty percent of all nonfatal RTIs were classified as severe injuries. RTI is a major public health issue in rural Bangladesh. Immediate attention is needed to reduce preventable deaths and morbidities in rural Bangladesh. PMID- 29112147 TI - Measuring the Effect of Housing Quality Interventions: The Case of the New Zealand "Rental Warrant of Fitness". AB - In New Zealand, as in many other countries, housing in the private-rental sector is in worse condition than in the owner-occupier housing sector. New Zealand residential buildings have no inspection regime after original construction signoff. Laws and regulations mandating standards for existing residential housing are outdated and spread over a range of instruments. Policies to improve standards in existing housing have been notoriously difficult to implement. In this methods paper, we describe the development and implementation of a rental Warrant of Fitness (WoF) intended to address these problems. Dwellings must pass each of 29 criteria for habitability, insulation, heating, ventilation, safety, amenities, and basic structural soundness to reach the WoF minimum standard. The WoF's development was based on two decades of research on the impact of housing quality on health and wellbeing, and strongly influenced by the UK Housing Health and Safety Rating System and US federal government housing standards. Criteria were field-tested across a range of dwelling types and sizes, cities, and climate zones. The implementation stage of our WoF research consists of a non-random controlled quasi-experimental study in which we work with two city-level local government councils to implement the rental WoF, recruiting adjoining council areas as controls, and measuring changes in health, economic, and social outcomes. PMID- 29112148 TI - Effects of Polysaccharides from Platycodon grandiflorum on Immunity-Enhancing Activity In Vitro. AB - The study is aimed at investigating the immunoenhancement activity of polysaccharides from Platycodon grandiflorum polysaccharides (PGPSs) in vitro. In this study, some research on lymphocyte proliferation, cell cycle, and the levels of CD4+ and CD8+ T cells were performed. Four different concentrations of PGPSs (PGPStc, PGPS60c, PGPS80c, and PGPStp) were harvested and added to peripheral blood T lymphocytes. We observed significant increases in T lymphocyte proliferation at PGPStc groups individually or synergistically with phytohemagglutinin (PHA) at most concentrations, and their lymphocyte proliferation rates were the highest. The active sites of PGPStc and PGPS60c were subsequently chosen. Then, we utilized flow cytometry to determine lymphocyte cell cycle distribution and levels of CD4+ and CD8+ T cells. At most time points, PGPStc could facilitate lymphocyte cell cycle progression from the G0/G1 phase to the S and G2/M phases and, simultaneously, increase the levels of CD4+ and CD8+ T cells. These results indicate that PGPStc enhances the immune functions, suggesting that PGPStc could be a potential immunopotentiator for further in vivo and clinical trial experiments. PMID- 29112150 TI - Fabrication of In Vitro Cancer Microtissue Array on Fibroblast-Layered Nanofibrous Membrane by Inkjet Printing. AB - In general, a drug candidate is evaluated using 2D-cultured cancer cells followed by an animal model. Despite successful preclinical testing, however, most drugs that enter human clinical trials fail. The high failure rates are mainly caused by incompatibility between the responses of the current models and humans. Here, we fabricated a cancer microtissue array in a multi-well format that exhibits heterogeneous and batch-to-batch structure by continuous deposition of collagen suspended Hela cells on a fibroblast-layered nanofibrous membrane via inkjet printing. Expression of both Matrix Metalloproteinase 2 (MMP2) and Matrix Metalloproteinase 9 (MMP9) was higher in cancer microtissues than in fibroblast free microtissues. The fabricated microtissues were treated with an anticancer drug, and high drug resistance to doxorubicin occurred in cancer microtissues but not in fibroblast-free microtissues. These results introduce an inkjet printing fabrication method for cancer microtissue arrays, which can be used for various applications such as early drug screening and gradual 3D cancer studies. PMID- 29112151 TI - Generalized Nonlinear Chirp Scaling Algorithm for High-Resolution Highly Squint SAR Imaging. AB - This paper presents a modified approach for high-resolution, highly squint synthetic aperture radar (SAR) data processing. Several nonlinear chirp scaling (NLCS) algorithms have been proposed to solve the azimuth variance of the frequency modulation rates that are caused by the linear range walk correction (LRWC). However, the azimuth depth of focusing (ADOF) is not handled well by these algorithms. The generalized nonlinear chirp scaling (GNLCS) algorithm that is proposed in this paper uses the method of series reverse (MSR) to improve the ADOF and focusing precision. It also introduces a high order processing kernel to avoid the range block processing. Simulation results show that the GNLCS algorithm can enlarge the ADOF and focusing precision for high-resolution highly squint SAR data. PMID- 29112152 TI - Yarrowia lipolytica Extracellular Lipase Lip2 as Biocatalyst for the Ring-Opening Polymerization of epsilon-Caprolactone. AB - Yarrowia lipolytica (YL) is a "non-conventional" yeast that is capable of producing important metabolites. One of the most important products that is secreted by this microorganism is lipase, a ubiquitous enzyme that has considerable industrial potential and can be used as a biocatalyst in the pharmaceutical, food, and environmental industries. In this work, Yarrowia lipolytica lipase (YLL) was immobilized on Lewatit and Amberlite beads and is used in the enzymatic ring-opening polymerization (ROP) of cyclic esters in the presence of different organic solvents. YLL immobilized on Amberlite XAD7HP had the higher protein adsorption (96%) and a lipolytic activity of 35 U/g. Lewatit VPOC K2629 has the higher lipolytic activity (805 U/g) and 92% of protein adsorption. The highest molecular weight (Mn 10,685 Da) was achieved at 90 degrees C using YLL that was immobilized on Lewatit 1026 with decane as solvent after 60 h and 100% of monomer conversion. PMID- 29112149 TI - Polyphenols as Promising Drugs against Main Breast Cancer Signatures. AB - Breast cancer is one of the most common neoplasms worldwide, and in spite of clinical and pharmacological advances, it is still a clinical problem, causing morbidity and mortality. On the one hand, breast cancer shares with other neoplasms some molecular signatures such as an imbalanced redox state, cell cycle alterations, increased proliferation and an inflammatory status. On the other hand, breast cancer shows differential molecular subtypes that determine its prognosis and treatment. These are characterized mainly by hormone receptors especially estrogen receptors (ERs) and epidermal growth factor receptor 2 (HER2). Tumors with none of these receptors are classified as triple negative breast cancer (TNBC) and are associated with a worse prognosis. The success of treatments partially depends on their specificity and the adequate molecular classification of tumors. New advances in anticancer drug discovery using natural compounds have been made in the last few decades, and polyphenols have emerged as promising molecules. They may act on various molecular targets because of their promiscuous behavior, presenting several physiological effects, some of which confer antitumor activity. This review analyzes the accumulated evidence of the antitumor effects of plant polyphenols on breast cancer, with special attention to their activity on ERs and HER2 targets and also covering different aspects such as redox balance, uncontrolled proliferation and chronic inflammation. PMID- 29112153 TI - Chokeberry Pomace as a Determinant of Antioxidant Parameters Assayed in Blood and Liver Tissue of Polish Merino and Wrzosowka Lambs. AB - Despite being a plant by-product, chokeberry pomace is believed to exert some therapeutic effects because it is one of the richest sources of highly bioavailable non-enzymatic antioxidants. The aim of this study was to determine the functionality of bioactive compounds present in the Aronia melanocarpa pomace (chokeberry) based on enzymatic and non-enzymatic parameters related to the active defence of liver and blood against the effects of oxidative stress. The experiment was conducted with 48 lambs of two breeds-Polish Merino and Wrzosowka. Experimental groups were administered the basic feed with the addition of 150 g or 300 g of black chokeberry pomace per each kg of the complete feed. The activities of antioxidative enzymes (superoxide dismutase, glutathione peroxidase), peptides (glutathione, glutathione disulfide), and a lipid peroxidation indicator (malondialdehyde), as well as the capacity of non enzymatic antioxidants were investigated. The results proved a strong effect of bioactive compounds contained in the black chokeberry pomace on the estimated parameters. The inclusion of chokeberry pomace in feed mixtures brought many benefits linked with the antioxidative protection. Parameters responsible for the oxidative status were significantly modified despite the commonly-held view about a limited possibility of transferring phenolic compounds to the organs. PMID- 29112155 TI - Efficacy of Bee Venom Acupuncture for Chronic Low Back Pain: A Randomized, Double Blinded, Sham-Controlled Trial. AB - Bee venom acupuncture (BVA) is an effective treatment for chronic low back pain (CLBP) through the pharmacological effects of bee venom and the simultaneous stimulation of acupoints. However, evidence of its efficacy and safety in humans remains unclear. Using a double-blind, randomized study, 54 patients with non specific CLBP were assigned to the BVA and sham groups. All participants underwent six sessions of real or sham BVA for 3 weeks, in addition to administration of 180 mg of loxonin per day. The primary outcome, that is, "bothersomeness" derived from back pain, was assessed using the visual analog scale. Secondary outcomes included pain intensity, dysfunction related to back pain (Oswestry Disability Index), quality of life (EuroQol 5-Dimension), and depressive mood (Beck's depression inventory). Outcomes were evaluated every week during the treatment period and followed up at weeks 4, 8, and 12. After 3 weeks of the treatment, significant improvements were observed in the bothersomeness, pain intensity, and functional status in the BVA group compared with the sham group. Although minimal adverse events were observed in both groups, subsequent recovery was achieved without treatment. Consequently, our results suggest that it can be used along with conventional pharmacological therapies for the treatment of CLBP. PMID- 29112156 TI - Effects of Lonomia obliqua Venom on Vascular Smooth Muscle Cells: Contribution of NADPH Oxidase-Derived Reactive Oxygen Species. AB - Envenomation caused by human contact with the caterpillar Lonomia is characterized by deleterious effects on coagulation and patency of blood vessels. The cellular effects induced by Lonomia obliqua venom highlights its capacity to activate endothelial cells, leading to a proinflammatory phenotype. Having more knowledge about the mechanisms involved in envenomation may contribute to better treatment. We aimed to evaluate the effects of Lonomia obliqua caterpillar bristle extract (LOCBE) on vascular smooth muscle cells (VSMC). We observed that LOCBE induced VSMC migration, which was preceded by alterations in actin cytoskeleton dynamics and Focal Adhesion Kinase activation. LOCBE also induced Extracellular Signal-Regulated Kinase (ERK) phosphorylation in VSMC, and the inhibition of this pathway impaired cell proliferation. Stimulation of VSMC with LOCBE triggered reactive oxygen species (ROS) production through the activation of NADPH oxidase. The rapid increase in these ROS further induced mitochondrial ROS production, however only NADPH oxidase-derived ROS were involved in ERK activation in VSMC. We that demonstrated the chemotactic and proliferative effects of LOCBE on VSMC were dependent on ROS production, mainly through NADPH oxidase. Together, the data show that Lonomia obliqua venom can interact with and activate VSMC. These effects rely on ROS production, suggesting new potential targets for treatment against vascular damage during envenomation. PMID- 29112154 TI - Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities. AB - Fluoroquinolones are synthetic antibacterial agents that stabilize the ternary complex of prokaryotic topoisomerase II enzymes (gyrase and Topo IV), leading to extensive DNA fragmentation and bacteria death. Despite the similar structural folds within the critical regions of prokaryotic and eukaryotic topoisomerases, clinically relevant fluoroquinolones display a remarkable selectivity for prokaryotic topoisomerase II, with excellent safety records in humans. Typical agents that target human topoisomerases (such as etoposide, doxorubicin and mitoxantrone) are associated with significant toxicities and secondary malignancies, whereas clinically relevant fluoroquinolones are not known to exhibit such propensities. Although many fluoroquinolones have been shown to display topoisomerase-independent antiproliferative effects against various human cancer cells, those that are significantly active against eukaryotic topoisomerase show the same DNA damaging properties as other topoisomerase poisons. Empirical models also show that fluoroquinolones mediate some unique immunomodulatory activities of suppressing pro-inflammatory cytokines and super inducing interleukin-2. This article reviews the extended roles of fluoroquinolones and their prospects as lead for the unmet needs of "small and safe" multimodal-targeting drug scaffolds. PMID- 29112157 TI - Vitamin D Axis in Inflammatory Bowel Diseases: Role, Current Uses and Future Perspectives. AB - Increasing evidence supports the concept that the vitamin D axis possesses immunoregulatory functions, with vitamin D receptor (VDR) status representing the major determinant of vitamin D's pleiotropic effects. Vitamin D promotes the production of anti-microbial peptides, including beta-defensins and cathelicidins, the shift towards Th2 immune responses, and regulates autophagy and epithelial barrier integrity. Impairment of vitamin D-mediated pathways are associated with chronic inflammatory conditions, including inflammatory bowel diseases (IBD). Interestingly, inhibition of vitamin D pathways results in dysbiosis of the gut microbiome, which has mechanistically been implicated in the development of IBD. Herein, we explore the role of the vitamin D axis in immune mediated diseases, with particular emphasis on its interplay with the gut microbiome in the pathogenesis of IBD. The potential clinical implications and therapeutic relevance of this interaction will also be discussed, including optimizing VDR function, both with vitamin D analogues and probiotics, which may represent a complementary approach to current IBD treatments. PMID- 29112158 TI - Carbon Nanotubes as Fluorescent Labels for Surface Plasmon Resonance-Assisted Fluoroimmunoassay. AB - The photoluminescence properties of carbon nanotubes (CNTs), including the large Stokes shift and the absence of fluorescent photobleaching, can be used as a fluorescent label in biological measurements. In this study, the performance of CNTs as a fluorescent label for surface plasmon resonance (SPR)-assisted fluoroimmunoassay is evaluated. The fluorescence of (8, 3) CNTs with an excitation wavelength of 670 nm and an emission wavelength of 970 nm is observed using a sensor chip equipped with a prism-integrated microfluidic channel to excite the SPR. The minimum detectable concentration of a CNT dispersed in water using a visible camera is 0.25 MUg/mL, which is equivalent to 2 * 1010 tubes/mL. The target analyte detection using the CNT fluorescent labels is theoretically investigated by evaluating the detectable number of CNTs in a detection volume. Assuming detection of virus particles which are bound with 100 CNT labels, the minimum number of detectable virus particles is calculated to be 900. The result indicates that CNTs are effective fluorescent labels for SPR-assisted fluoroimmunoassay. PMID- 29112159 TI - miR-1224-5p Mediates Mitochondrial Damage to Affect Silica-Induced Pulmonary Fibrosis by Targeting BECN1. AB - Silicosis is associated with fibroblast proliferation and extracellular matrix deposition in lung tissues. The dysregulation of miR-1224-5p has been implicated in several human cancers; however, the expression and function of miR-1224-5p in silicosis is unknown. The mitochondrial dysfunctions play critical roles in some diseases, but how these processes are regulated in silicosis remains limited. Here, we explored the role of miR-1224-5p in a mouse model of silicosis. We showed that the expression of miR-1224-5p is increased both in lung tissues of silica-induced pulmonary fibrosis and fibroblasts exposed to TGF-beta1. Repression of miR-1224-5p expression attenuated silica-induced fibrotic progression in vivo and TGF-beta1-induced myofibroblast differentiation in vitro. Additionally, we demonstrated that miR-1224-5p facilitated silica-induced pulmonary fibrosis primarily by repressing one of target genes, BECN1, thereby blocking PARK2 translocation to mitochondria and inducing the accumulation of damaged mitochondria. Furthermore, the activation of PDGFR signal mediated by mitochondrial damage and insufficient mitophagy resulted in myofibroblast differentiation. Collectively, these data indicated that miR-1224-5p exerts key functions in silica-induced pulmonary fibrosis and may represent a potential therapeutic target for silicosis. PMID- 29112160 TI - Reclamation of Marine Chitinous Materials for the Production of alpha-Glucosidase Inhibitors via Microbial Conversion. AB - Six kinds of chitinous materials have been used as sole carbon/nitrogen (C/N) sources for producing alpha-glucosidase inhibitors (aGI) by Paenibacillus sp. TKU042. The aGI productivity was found to be highest in the culture supernatants using demineralized crab shell powder (deCSP) and demineralized shrimp shell powder (deSSP) as the C/N source. The half maximal inhibitory concentration (IC50) and maximum aGI activity of fermented deCSP (38 ug/mL, 98%), deSSP (108 ug/mL, 89%), squid pen powder (SPP) (422 ug/mL, 98%), and shrimp head powder (SHP) (455 ug/mL, 92%) were compared with those of fermented nutrient broth (FNB) (81 ug/mL, 93%) and acarbose (1095 ug/mL, 74%), a commercial antidiabetic drug. The result of the protein/chitin ratio on aGI production showed that the optimal ratio was 0.2/1. Fermented deCSP showed lower IC50 and higher maximum inhibitory activity than those of acarbose against rat intestinal alpha-glucosidase. PMID- 29112162 TI - Syntheses of Novel 4-Substituted N-(5-amino-1H-1,2,4-triazol-3-yl)pyridine-3 sulfonamide Derivatives with Potential Antifungal Activity. AB - Candidiasis represent a serious threat for patients with altered immune responses. Therefore, we have undertaken the synthesis of compounds comprising a pyridine-3-sulfonamide scaffold and known antifungally active 1,2,4-triazole substituents. Thus a series of novel 4-substituted N-(5-amino-1H-1,2,4-triazol-3 yl)pyridine-3-sulfonamides have been synthesized by multistep reactions starting from 4-chloropyridine-3-sulfonamide via N'-cyano-N-[(4-substitutedpyridin-3 yl)sulfonyl]carbamimidothioates which were further converted with hydrazine hydrate to the corresponding 1,2,4-triazole derivatives 26-36. The final compounds were evaluated for antifungal activity against strains of the genera Candida, Geotrichum, Rhodotorula, and Saccharomycess isolated from patients with mycosis. Many of them show greater efficacy than fluconazole, mostly towards Candida albicans and Rhodotorula mucilaginosa species, with MIC values <= 25 ug/mL. A docking study of the most active compounds 26, 34 and 35 was performed showing the potential mode of binding to Candida albicans lanosterol 14alpha demethylase. Also in vitro cytotoxicity of selected compounds have been evaluated on the NCI-60 cell line panel. PMID- 29112163 TI - Surface-Enhanced Resonance Raman Scattering of Rhodamine 6G in Dispersions and on Films of Confeito-Like Au Nanoparticles. AB - Surface-enhanced resonance Raman scattering (SERRS) of rhodamine 6G was measured on confeito-like Au nanoparticles (CAuNPs). The large CAuNPs (100 nm in diameter) in aqueous dispersion systems showed stronger enhancing effect (analytical enhancement factor: over 105) of SERRS than the small CAuNPs (50 nm in diameter), while the spherical Au nanoparticles (20 nm in diameter) displayed rather weak intensities. Especially, minor bands in 1400-1600 cm-1 were uniquely enhanced by the resonance effect of CAuNPs. The enhancement factors revealed a concentration dependence of the enhancing effect at low concentration of rhodamine 6G. This dependency was due to a large capacity of hot-spots on CAuNPs, which were formed without agglomeration. The surface-enhancing behaviour in the film systems was similar to that in the dispersions, although the large CAuNPs had lower enhancing effect in the films, and the small CAuNPs and the spherical Au nanoparticles were more effective in their films. These results suggest that the CAuNPs have an advantage in ultrasensitive devices both in dispersions and films, compared to the agglomerate of spherical Au nanoparticles. PMID- 29112164 TI - Effect of Intranasally Delivered rh-VEGF165 on Angiogenesis Following Cerebral Hypoxia-Ischemia in the Cerebral Cortex of Newborn Piglets. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) stimulates vascular genesis and angiogenesis. Cerebral Hypoxia-Ischemia (HI) leads to the reduction of vasculature in the cerebral cortex of newborn piglets. OBJECTIVE: The present study tests the hypothesis that post-hypoxia intranasal administration of recombinant human VEGF165 (rh-VEGF165) for 3 days increases the vascular density in the cerebral cortex of newborn piglets without promoting neovascularization. DESIGN/METHODS: Ventilated newborn piglets were divided into three groups (n = 5/group): normoxic (Nx), hypoxic-ischemic (HI), and HI treated with intranasal rh VEGF165rh-VEGF165 (HI-VEGF). HI piglets were exposed to HI (0.05 FiO2) for 30 min. Recombinant h-VEGF165 (100 ng/kg) was administered 15 min after HI and then once daily for 3 days. The animals were perfused transcardially and coronal brains sections were processed for Isolectin, Hoechst, and ki-67 cell proliferation marker staining. To assess the vascular density, 30-35 fields per animal section were manually counted using image J software. RESULTS: The vascular density (vessels/mm2) was 42.0 +/- 8.0 in the Nx group, 26.4 +/- 4.8 (p < 0.05 vs. Nx) in the HI group, and 46.0 +/- 11.9 (p < 0.05 vs. HI) in the HI VEGF group. When stained for newly formed vessels, via Ki-67 staining, the vascular density was 5.4 +/- 3.6 in the Nx group (p < 0.05 vs. HI), 10.2 +/- 2.1 in the HI group, and 10.9 +/- 2.9 in the HI-VEGF group (p = 0.72 vs. HI). HI resulted in a decrease in vascular density. Intranasal rh-VEGF165rh-VEGF165 resulted in the attenuation of the HI-induced decrease in vascular density. However, rh-VEGF165 did not result in the formation of new vascularity, as evident by ki-67 staining. CONCLUSIONS: Intranasal rh-VEGF165 may prevent the HI induced decrease in the vascular density of the brain and could serve as a promising adjuvant therapy for hypoxic-ischemic encephalopathy (HIE). PMID- 29112166 TI - Unexpected High Diversity of Terrestrial Cyanobacteria from the Campus of the University of the Ryukyus, Okinawa, Japan. AB - Terrestrial cyanobacterial strains were isolated from the Nishihara campus of the University of the Ryukyus, Okinawa, Japan. The 13 sampling sites were distributed in a 200 m radius and appeared as dry, blackened stains. From these small areas, 143 cyanobacterial strains were established. The strains were divided into five morphotypes, including unicells, unicells with baeocytes, non-branching filaments, false-branching filaments, and heterocystous strains. From the strains, 105 partial 16S rRNA gene sequences were obtained and could be classified into 30 generic types. Among them, 22 unique strains and over 1100 bps of data were selected for further phylogenetic analyses. These sequences were positioned into six main clades corresponding to cyanobacterial orders: Nostocales, Chroococidiopsidales, Chroococcales, Oscillatoriales, Pleurocapsales, and Synechococcales. Almost all sequences had no identical matching data in GenBank and many of them had no closely related data. These data suggest that the terrestrial cyanobacteria are very divese even within close sampling areas, such as within the campus of the University of the Ryukyus. The established strains are not only important for classification of terrestrial cyanobacteria but also for possible application studies in the future. PMID- 29112165 TI - Poxvirus Host Range Genes and Virus-Host Spectrum: A Critical Review. AB - The Poxviridae family is comprised of double-stranded DNA viruses belonging to nucleocytoplasmic large DNA viruses (NCLDV). Among the NCLDV, poxviruses exhibit the widest known host range, which is likely observed because this viral family has been more heavily investigated. However, relative to each member of the Poxviridae family, the spectrum of the host is variable, where certain viruses can infect a large range of hosts, while others are restricted to only one host species. It has been suggested that the variability in host spectrum among poxviruses is linked with the presence or absence of some host range genes. Would it be possible to extrapolate the restriction of viral replication in a specific cell lineage to an animal, a far more complex organism? In this study, we compare and discuss the relationship between the host range of poxvirus species and the abundance/diversity of host range genes. We analyzed the sequences of 38 previously identified and putative homologs of poxvirus host range genes, and updated these data with deposited sequences of new poxvirus genomes. Overall, the term host range genes might not be the most appropriate for these genes, since no correlation between them and the viruses' host spectrum was observed, and a change in nomenclature should be considered. Finally, we analyzed the evolutionary history of these genes, and reaffirmed the occurrence of horizontal gene transfer (HGT) for certain elements, as previously suggested. Considering the data presented in this study, it is not possible to associate the diversity of host range factors with the amount of hosts of known poxviruses, and this traditional nomenclature creates misunderstandings. PMID- 29112167 TI - Overexpression of a New Chitinase Gene EuCHIT2 Enhances Resistance to Erysiphe cichoracearum DC in Tobacco Plants. AB - In this study, we cloned a new chitinase gene, EuCHIT2, from Eucommia ulmoides Oliver (E. ulmoides) using rapid amplification of cDNA ends (RACE) technology and constructed an overexpression vector, pSH-35S-EuCHIT2, to introduce it into tobacco (Nicotiana tabacum cv. Xanthi). Resistance to Erysiphe cichoracearum de Candolle (E.cichoracearum DC) and molecular mechanisms in the transgenic tobacco were determined by drop inoculation, spore counting, determination of physicochemical indicators, and analysis of gene expression. The chitinase activity and resistance to E. cichoracearum DC were significantly higher in the transgenic tobacco than in wild-type tobacco (p < 0.05). The activities of peroxidase (POD) and catalase (CAT), after inoculation with E. cichoracearum DC, were higher in the transgenic tobacco than in the wild-type. Conversely, the malondialdehyde (MDA) content was significantly lower in the transgenic tobacco than the wild-type before and after inoculation. In addition, our study also indicated that the resistance to E. cichoracearum DC might involve the salicylic acid (SA) and jasmonic acid (JA) pathways, because the expression levels of pathogenesis-related gene 1 (PR-1a) and coronatine-insensitive 1 (COI1) were significantly increased and decreased, respectively, after inoculation with E. cichoracearum DC. The present study supports the notion that PR-1a and POD participate in resistance to E. cichoracearum DC in the transgenic tobacco plants. PMID- 29112168 TI - Low-Temperature Crystal Structures of the Hard Core Square Shoulder Model. AB - In many cases, the stability of complex structures in colloidal systems is enhanced by a competition between different length scales. Inspired by recent experiments on nanoparticles coated with polymers, we use Monte Carlo simulations to explore the types of crystal structures that can form in a simple hard-core square shoulder model that explicitly incorporates two favored distances between the particles. To this end, we combine Monte Carlo-based crystal structure finding algorithms with free energies obtained using a mean-field cell theory approach, and draw phase diagrams for two different values of the square shoulder width as a function of the density and temperature. Moreover, we map out the zero temperature phase diagram for a broad range of shoulder widths. Our results show the stability of a rich variety of crystal phases, such as body-centered orthogonal (BCO) lattices not previously considered for the square shoulder model. PMID- 29112161 TI - Collateral Damage Intended-Cancer-Associated Fibroblasts and Vasculature Are Potential Targets in Cancer Therapy. AB - After oncogenic transformation, tumor cells rewire their metabolism to obtain sufficient energy and biochemical building blocks for cell proliferation, even under hypoxic conditions. Glucose and glutamine become their major limiting nutritional demands. Instead of being autonomous, tumor cells change their immediate environment not only by their metabolites but also by mediators, such as juxtacrine cell contacts, chemokines and other cytokines. Thus, the tumor cells shape their microenvironment as well as induce resident cells, such as fibroblasts and endothelial cells (ECs), to support them. Fibroblasts differentiate into cancer-associated fibroblasts (CAFs), which produce a qualitatively and quantitatively different extracellular matrix (ECM). By their contractile power, they exert tensile forces onto this ECM, leading to increased intratumoral pressure. Moreover, along with enhanced cross-linkage of the ECM components, CAFs thus stiffen the ECM. Attracted by tumor cell- and CAF-secreted vascular endothelial growth factor (VEGF), ECs sprout from pre-existing blood vessels during tumor-induced angiogenesis. Tumor vessels are distinct from EC lined vessels, because tumor cells integrate into the endothelium or even mimic and replace it in vasculogenic mimicry (VM) vessels. Not only the VM vessels but also the characteristically malformed EC-lined tumor vessels are typical for tumor tissue and may represent promising targets in cancer therapy. PMID- 29112169 TI - Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-Arylthiazole 2-Methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors. AB - Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2 methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 +/- 0.02 MUM) in vitro and showed an acceptable metabolic stability. PMID- 29112170 TI - PSN-PC: A Novel Antimicrobial and Anti-Biofilm Peptide from the Skin Secretion of Phyllomedusa-camba with Cytotoxicity on Human Lung Cancer Cell. AB - Peptides derived from amphibian skin secretion are promising drug prototypes for combating widespread infection. In this study, a novel peptide belonging to the phylloseptin family of antimicrobial peptides was isolated from the skin secretion of the Phyllomedusa camba, namely phylloseptin-PC (PSN-PC). The biosynthetic precursor was obtained by molecular cloning and the mature peptide sequence was confirmed through tandem mass spectrometry (MS/MS) fragmentation sequencing in the skin secretion. The synthetic replicate exhibited a broad spectrum antimicrobial activity against Staphylococcus aureus, methicillin resistant Staphylococcus aureus,Escherichia coli, Pseudomonas aeruginosa, Candida albicans at concentrations of 2, 2, 8, 32 and 2 uM, respectively. It also showed the capability of eliminating S. aureus biofilm with a minimal biofilm eradication concentration of 8 uM. The haemolysis of this peptide was not significant at low concentrations but had a considerable increase at high concentrations. Additionally, this peptide showed an anti-proliferation effect on the non-small cell lung cancer cell line (NCI-H157), with low cytotoxicity on the human microvascular endothelial cell line (HMEC-1). The discovery of the novel peptide may provide useful clues for new drug discoveries. PMID- 29112171 TI - Antimicrobial Abietane-Type Diterpenoids from Plectranthus punctatus. AB - Four new para-benzoquinone containing abietane-type diterpenoids (1-4) along with thirteen known diterpenoids (5-17) were isolated from the roots of Plectranthus punctatus. The structures of the compounds were established by detailed spectroscopic analyses and comparison with literature data. The compounds were tested for their antibacterial and cytotoxic activity and showed significant inhibitory activity against all bacterial strains used, with compounds 6, 8, 10, and 11 showing an inhibition zone for Staphylococcus warneri even greater than the reference drug, gentamycin. PMID- 29112172 TI - A Bibliometric Analysis of Research on Supported Ionic Liquid Membranes during the 1995-2015 Period: Study of the Main Applications and Trending Topics. AB - A bibliometric analysis based on Scopus database was performed to identify the global research trends related to Supported Ionic Liquid Membranes (SILMs) during the time period from 1995 to 2015. This work tries to improve the understanding of the most relevant research topics and applications. The results from the analysis reveal that only after 2005 the research efforts focused on SILMs became significant, since the references found before that year are scarce. The most important research works on the four main application groups for SILMs defined in this work (carbon dioxide separation, other gas phase separations, pervaporation and liquid phase separations) were summarized in this paper. Carbon dioxide separation appeared as the application that has received by far the most attention according to the research trends during the analysed period. Comments about other significant applications that are gaining attention, such as the employment of SILMs in analytical tasks or their consideration for the production of fuel cells, have been included. PMID- 29112173 TI - Chemical Fingerprint and Multicomponent Quantitative Analysis for the Quality Evaluation of Cyclocarya paliurus Leaves by HPLC-Q-TOF-MS. AB - Cyclocarya paliurus is an edible and medicinal plant containing various bioactive components with significant health benefits. A combinative method using high performance liquid chromatography (HPLC) fingerprint and quantitative analysis was developed and successfully applied for characterization and quality evaluation of C. paliurus leaves collected from 18 geographical locations of China. For the fingerprint analysis, 21 common peaks were observed among the 18 samples, and these peaks were identified by high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q TOF-MS), while a simultaneous quantification of 16 markers was conducted to interpret the variations of contents of these bioactive compounds among the C. paliurus leaves from different geographical locations. Quantification results showed that the contents of these sixteen investigated compounds varied greatly among the leaves from different locations. The developed new method would be a valuable reference for further study and development of this bioactive plant. PMID- 29112175 TI - The Virtual Environment for Rapid Prototyping of the Intelligent Environment. AB - Advances in domains such as sensor networks and electronic and ambient intelligence have allowed us to create intelligent environments (IEs). However, research in IE is being held back by the fact that researchers face major difficulties, such as a lack of resources for their experiments. Indeed, they cannot easily build IEs to evaluate their approaches. This is mainly because of economic and logistical issues. In this paper, we propose a simulator to build virtual IEs. Simulators are a good alternative to physical IEs because they are inexpensive, and experiments can be conducted easily. Our simulator is open source and it provides users with a set of virtual sensors that simulates the behavior of real sensors. This simulator gives the user the capacity to build their own environment, providing a model to edit inhabitants' behavior and an interactive mode. In this mode, the user can directly act upon IE objects. This simulator gathers data generated by the interactions in order to produce datasets. These datasets can be used by scientists to evaluate several approaches in IEs. PMID- 29112177 TI - Recognition and Matching of Clustered Mature Litchi Fruits Using Binocular Charge Coupled Device (CCD) Color Cameras. AB - Recognition and matching of litchi fruits are critical steps for litchi harvesting robots to successfully grasp litchi. However, due to the randomness of litchi growth, such as clustered growth with uncertain number of fruits and random occlusion by leaves, branches and other fruits, the recognition and matching of the fruit become a challenge. Therefore, this study firstly defined mature litchi fruit as three clustered categories. Then an approach for recognition and matching of clustered mature litchi fruit was developed based on litchi color images acquired by binocular charge-coupled device (CCD) color cameras. The approach mainly included three steps: (1) calibration of binocular color cameras and litchi image acquisition; (2) segmentation of litchi fruits using four kinds of supervised classifiers, and recognition of the pre-defined categories of clustered litchi fruit using a pixel threshold method; and (3) matching the recognized clustered fruit using a geometric center-based matching method. The experimental results showed that the proposed recognition method could be robust against the influences of varying illumination and occlusion conditions, and precisely recognize clustered litchi fruit. In the tested 432 clustered litchi fruits, the highest and lowest average recognition rates were 94.17% and 92.00% under sunny back-lighting and partial occlusion, and sunny front-lighting and non-occlusion conditions, respectively. From 50 pairs of tested images, the highest and lowest matching success rates were 97.37% and 91.96% under sunny back-lighting and non-occlusion, and sunny front-lighting and partial occlusion conditions, respectively. PMID- 29112176 TI - Characteristics of Multifunctional, Eco-Friendly Lignin-Al2O3 Hybrid Fillers and Their Influence on the Properties of Composites for Abrasive Tools. AB - The main aim of the present study was the preparation and comprehensive characterization of innovative additives to abrasive materials based on functional, pro-ecological lignin-alumina hybrid fillers. The behavior of lignin, alumina and lignin-Al2O3 hybrids in a resin matrix was explained on the basis of their surface and application properties determined by inverse gas chromatography, the degree of adhesion/cohesion between components, thermomechanical and rheological properties. On the basis of the presented results, a hypothetical mechanism of interactions between lignin and Al2O3 as well as between lignin-Al2O3 hybrids and phenolic resins was proposed. It was concluded that lignin compounds can provide new, promising properties for a phenolic binder combining the good properties of this biopolymer as a plasticizer and of alumina as a filler improving mechanical and thermal properties. The use of such materials may be relatively non-complicated and efficient way to improve the performance of bonded abrasive tools. PMID- 29112174 TI - miRNAs, Melanoma and Microenvironment: An Intricate Network. AB - miRNAs are central players in cancer biology and they play a pivotal role in mediating the network communication between tumor cells and their microenvironment. In melanoma, miRNAs can impair or facilitate a wide array of processes, and here we will focus on: the epithelial to mesenchymal transition (EMT), the immune milieu, and metabolism. Multiple miRNAs can affect the EMT process, even at a distance, for example through exosome-mediated mechanisms. miRNAs also strongly act on some components of the immune system, regulating the activity of key elements such as antigen presenting cells, and can facilitate an immune evasive/suppressive phenotype. miRNAs are also involved in the regulation of metabolic processes, specifically in response to hypoxic stimuli where they can mediate the metabolic switch from an oxidative to a glycolytic metabolism. Overall, this review discusses and summarizes recent findings on miRNA regulation in the melanoma tumor microenvironment, analyzing their potential diagnostic and therapeutic applications. PMID- 29112178 TI - Efficacy and Effectiveness of Carnitine Supplementation for Cancer-Related Fatigue: A Systematic Literature Review and Meta-Analysis. AB - BACKGROUND: Carnitine deficiency has been implicated as a potential pathway for cancer-related fatigue that could be treated with carnitine supplementation. The aim of this systematic literature review and meta-analysis was to evaluate the literature regarding the use of supplemental carnitine as a treatment for cancer related fatigue. METHODS: Using the PRISMA guidelines, an electronic search of the Cochrane Library, MEDLINE, Embase, CINAHL and reference lists was conducted. Data were extracted and independently assessed for quality using the Academy of Nutrition and Dietetics evidence analysis by two reviewers. In studies with positive quality ratings, a meta-analysis was performed using the random-effects model on Carnitine and cancer-related fatigue. RESULTS: Twelve studies were included for review with eight reporting improvement in measures of fatigue, while four reported no benefit. However, many studies were non-randomized, open label and/or used inappropriate dose or comparators. Meta-analysis was performed in three studies with sufficient data. Carnitine did not significantly reduce cancer-related fatigue with a standardized mean difference (SMD) of 0.06 points ((95% CI -0.09, 0.21); p = 0.45). CONCLUSION: Results from studies with lower risk of bias do not support the use of carnitine supplementation for cancer related fatigue. PMID- 29112180 TI - Impaired right ventricular function as a predictor of early mortality in patients with light- chain cardiac amyloidosis assessed in a cardiology department. AB - INTRODUCTION Light-chain (AL) amyloidosis is the most common cardiac amyloidosis. Despite progress in treatment, early mortality remains a substantial problem in these patients. OBJECTIVES The aim of this study was to determine a clinical profile of patients diagnosed with AL amyloidosis in a cardiology department, as well as to define the cut-off point for early mortality and identify predictors of early mortality in this population. PATIENTS AND METHODS The study included 30 patients (14 women; median age, 61.5 years) with AL amyloidosis confirmed by echocardiography and biopsy of 2 organs. RESULTS Six patients were diagnosed with stage II amyloidosis according to the Mayo 2004 classification, and 24 patients-with stage III. Early mortality was defined as death during 102 days after diagnosis and was observed in 14 patients. Patients who died earlier were younger and more frequently reported a weight loss of more than 10 kg and orthostatic hypotension than patients who died later. Moreover, they had higher concentrations of high-sensitivity troponin T and N-terminal pro B-type natriuretic peptide (NT-proBNP) and worse left and right ventricular (RV) contractility. In the Cox models, the age of less than 64 years, NT-proBNP levels exceeding 4968 pg/ml, RV end-diastolic diameter of less than 34 mm, and tricuspid annular plane systolic excursion lower than 13 mm were significant predictors of mortality within 102 days after diagnosis. CONCLUSIONS We presented the results of the first Polish prospective noninterventional study on AL amyloidosis diagnosed in the cardiology department. We found that patients have advanced disease at the time of diagnosis. Younger age, impaired RV function, and higher concentrations of cardiac markers are predictors of worse prognosis. PMID- 29112181 TI - Vitamin D supplementation in respiratory diseases: evidence from randomized controlled trials. AB - Pulmonary diseases are one of the most important causes of morbidity and mortality. Although vitamin D is best known for its role in calcium, phosphorus, and bone homeostasis, it has gained attention in the recent years because of a wide range of extraskeletal effects, including its immunomodulatory and antibacterial potential. Vitamin D deficiency is highly prevalent in chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, tuberculosis, and asthma, and several clinical studies have been conducted investigating the effect of vitamin D supplementation on disease outcomes. In this review, we searched for positive evidence on vitamin D supplementation from randomized controlled trials and elaborated on the optimal serum vitamin D levels and dosing regimens for an effective intervention. While vitamin D supplementation seems to be beneficial as an add-on treatment for adult patients with asthma and a potent intervention to reduce exacerbations in patients with COPD, there is little evidence for its therapeutic use in cystic fibrosis, pneumonia, and tuberculosis. PMID- 29112179 TI - Green Ultrasound versus Conventional Synthesis and Characterization of Specific Task Pyridinium Ionic Liquid Hydrazones Tethering Fluorinated Counter Anions: Novel Inhibitors of Fungal Ergosterol Biosynthesis. AB - A series of specific task ionic liquids (ILs) based on a pyridiniumhydrazone scaffold in combination with hexafluorophosphate (PF6-), tetrafluoroboron (BF4-) and/or trifluoroacetate (CF3COO-) counter anion, were designed and characterized by IR, NMR and mass spectrometry. The reactions were conducted under both conventional and green ultrasound procedures. The antifungal potential of the synthesized compounds 2-25 was investigated against 40 strains of Candida (four standard and 36 clinical isolates). Minimum inhibitory concentrations (MIC90) of the synthesized compounds were in the range of 62.5-2000 MUg/mL for both standard and oral Candida isolates. MIC90 results showed that the synthesized 1-(2-(4 chlorophenyl)-2-oxoethyl)-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-pyridin-1 ium hexafluorophosphate (11) was found to be most effective, followed by 4-(2-(4 fluorobenzylidene)hydrazinecarbonyl)-1-(2-(4-nitrophenyl)-2-oxoethyl)-pyridin-1 ium hexafluorophosphate (14) and 1-(2-ethoxy-2-oxoethyl)-4-(2-(4 fluorobenzylidene)hydrazinecarbonyl)pyridin-1-ium hexafluorophosphate (8). All the Candida isolates showed marked sensitivity towards the synthesized compounds. Ergosterol content was drastically reduced by more active synthesized compounds, and agreed well with MIC90 values. Confocal scanning laser microscopy (CLSM) results showed that the red colored fluorescent dye enters the test agent treated cells, which confirms cell wall and cell membrane damage. The microscopy results obtained suggested membrane-located targets for the action of these synthesized compounds. It appears that the test compounds might be interacting with ergosterol in the fungal cell membranes, decreasing the membrane ergosterol content and ultimately leading to membrane disruption as visible in confocal results. The present study indicates that these synthesized compounds show significant antifungal activity against Candida which forms the basis to carry out further in vivo experiments before their clinical use. PMID- 29112182 TI - Differential expression of programmed death 1 (PD-1) on CD4+ and CD8+ T cells in rheumatoid arthritis and psoriatic arthritis. AB - INTRODUCTION Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are characterized by chronic inflammatory processes mediated by proinflammatory cytokines that affect the synovial lining. Programmed death 1 (PD-1) is a critical regulator of T-cell activation by downregulating immune responses. OBJECTIVES The aim of the study was to investigate whether the expression of PD-1 on CD4+ and CD8+ T cells differs between patients with RA and those with PsA. PATIENTS AND METHODS The study included 100 patients with RA, 31 patients with PsA, and 52 healthy controls. The percentages, absolute numbers, and mean fluorescence intensity (MFI) of CD4+PD-1+ and CD8+PD-1+T cells from peripheral blood were analyzed using flow cytometry. RESULTS The percentages and absolute numbers of CD4+ and CD8+ T cells with PD-1 expression were significantly higher in patients with RA than in controls. In patients with PsA, the percentages of CD4+PD-1+ and CD8+PD-1+ T cells were significantly lower than in controls. Because of the high frequency of PD-1-positive T cells in RA and their low frequency in PsA, we analyzed the expression level by analyzing the MFI. The median MFI of PD-1 on CD4+ and CD8+ T cells was significantly higher in patients with RA (median, 421 and 437, respectively) in comparison with patients with PsA (median, 222 and 198, respectively) and controls (median, 205 and 187, respectively). CONCLUSIONS The differential expression of PD-1 in RA and PsA suggests that PD-1 might be involved in autoimmune mechanisms in RA and autoinflammatory mechanisms in PsA in a different manner. PMID- 29112183 TI - Leukotriene biosynthesis in coronary artery disease. Results of the Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) study. AB - INTRODUCTION Leukotrienes (LTs) may be involved in atherosclerosis and may contribute to cardiovascular outcomes in CAD. OBJECTIVES We aimed to compare the baseline LT production in patients with stable CAD (sCAD) and myocardial infarction (MI), and to assess whether an increased LT production is associated with major adverse cardiovascular events (MACEs) at 1 year after MI. PATIENTS AND METHODS LTIMI (Leukotrienes and Thromboxane In Myocardial Infarction) was a single-center, prospective, observational study of patients with stable sCAD and MI. Urinary leukotriene E4 (LTE4) levels were measured on admission, at 1 month, and at 1 year, using high-performance liquid chromatography tandem mass spectrometry. RESULTS Of the 404 patients screened, 289 were enrolled (110 with sCAD and 179 with MI; mean [SD] age, 63.9 [10.9] years). Patients with MI had higher median (interquartile range [IQR]) levels of log-transformed LTE4 (logLTE4) than those with sCAD (4.74 pg/mg creatinine [4-5.45] vs 4.51 pg/mg creatinine [3.99 4.86], respectively; P <0.001). Median (IQR) logLTE4 levels in patients with MI significantly decreased at 1 month to 4.37 pg/mg creatinine (3.81-4.95), and at 1 year to 4.16 pg/mg creatinine (3.55-4.85). The baseline urinary logLTE4 levels were similar in patients with MACEs and those without MACEs (median [IQR], 4.78 pg/mg creatinine [4.01-5.56]) and 4.68 pg/mg creatinine [3.97-5.28], respectively; P >0.05). Multiple regression showed no relation between LTE4 levels and the incidence of MACEs. CONCLUSIONS LT production assessed by urinary LTE4 excretion is higher in patients with MI than in those with sCAD; however, LTE4 levels at baseline do not differ between patients with and without MACEs at 1 year after MI. PMID- 29112184 TI - Insulin-like growth factor system in remission and flare of inflammatory bowel diseases. AB - INTRODUCTION Insulin-like growth factor 1 (IGF-1) is involved in the modulation of immunity and inflammation. It also plays a role in regulating the migration of endothelial cells and production of vasoactive agents. OBJECTIVES This study assessed the concentrations of IGF-1 and insulin-like growth factor binding protein 3 (IGFBP-3) and their relationships to disease activity in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS A total of 129 adult patients with IBD (69 with Crohn disease [CD] and 60 with ulcerative colitis [UC]) were involved in the study. The control group consisted of 31 healthy volunteers. Biochemical serum analyses were performed and the associations of IGF-1 and IGFBP-3 with inflammatory markers and disease activity were assessed. RESULTS IGF-1 levels were decreased in patients with active UC compared with those with nonactive UC (mean [SD], 78.3 [22.7] ng/ml and 96.2 [24.5] ng/ml, respectively; P = 0.02) and controls (94.5 [26.5] ng/ml; P = 0.03). The IGF-1 level was lower in patients with active CD compared with those with nonactive CD (mean [SD], 79.2 [24.9] ng/ml and 110.1 [43.4] ng/ml, respectively; P <0.001). The IGFBP-3 level was lower in patients with active UC compared with those with nonactive UC (P = 0.04) and controls (P = 0.04). IGF-1 correlated negatively with C-reactive protein (CRP) levels (P <0.01), disease activity (P <0.05), and disease duration (P <0.05). IGFBP-3 levels correlated negatively with CRP levels (P <0.05). CONCLUSIONS The IGF system is disrupted in patients with IBD. Systemic levels of the IGF axis components are related to disease activity and duration. PMID- 29112185 TI - Monocyte to large platelet ratio as a diagnostic tool for pulmonary embolism in patients with acute exacerbation of chronic obstructive pulmonary disease. AB - INTRODUCTION A higher prevalence of pulmonary embolism (PE) has been noted among patients with chronic obstructive pulmonary disease (COPD), particularly in those with acute exacerbations of COPD (AECOPD). Due to a similar clinical presentation and the lack of highly specific laboratory tests, there is a common overuse of computed tomography pulmonary angiography (CTPA). The introduction of an additional, simple, and inexpensive diagnostic tool to help in the diagnosis of PE in patients with AECOPD would be of special interest for everyday clinical practice. OBJECTIVES The aim of the study was to assess the usefulness of the monocyte to large platelet ratio (MLPR) as a diagnostic tool for PE in patients with AECOPD. PATIENTS AND METHODS We performed a retrospective evaluation of patients with AECOPD and suspicion of PE who underwent CTPA. The MLPR was investigated as a marker of thrombosis. Receiver operating characteristics (ROC) curve analyses were preformed to measure the accuracy of the MLPR in comparison with CTPA results and to identify the cutoff value for the MLPR. RESULTS A total of 101 patients (56 men and 45 women; median age, 72 years; range, 37-94 years) were included in the study. The MLPR showed an excellent accuracy in comparison with CTPA results: the area under the ROC curve was 0.945 (95% confidence interval [CI], 0.904-0.986). The MLPR was characterized by a good accuracy of qualitative test parameters, with high sensitivity (100%; 95% CI, 79.6-100) and specificity (85.7%; 95% CI, 75.9-92.6). CONCLUSIONS The MLPR measurement appears to be a reliable, simple, inexpensive, and widely available test that may help in the differential diagnosis of PE in patients with AECOPD. PMID- 29112186 TI - Association between bone remodeling and inflammatory markers in obstructive sleep apnea in relation to disease severity. AB - INTRODUCTION There is growing evidence that obstructive sleep apnea (OSA) influences both bone metabolism and structure. Chitinase-3-like protein 1 (YKL 40) is a novel inflammatory and remodeling marker, the levels of which were shown to increase in OSA. YKL-40 can probably alter the bone turnover. OBJECTIVES The aim of the study was to assess a possible interplay between YKL-40 and bone turnover markers in patients with different stages of OSA, and to evaluate the relation between bone mass, severity of OSA, and YKL-40 levels. PATIENTS AND METHODS The study involved 72 male patients with OSA. They were divided into 3 groups according to disease severity, using the apnea-hypopnea index (AHI): group 1 (n = 18; 5<= AHI <15), group 2 (n = 25; 15<= AHI <30), and group 3 (n = 29; AHI >=30). All patients underwent polysomnography and densitometry. Fasting blood samples were collected for YKL-40, C-terminal telopeptide of typeI collagen (CTX), procollagen type 1 N-terminal propeptide (P1NP), and other markers. RESULTS P1NP differed between groups 1 and 2, as well as groups 1 and 3 (P = 0.02). Group 2 had higher CTX levels than group 1 (borderline significance, P = 0.05). A simple linear regression analysis showed that serum YKL-40 levels were associated with the levels of CTX (P <0.0001, beta = 0.9871) and P1NP (P <0.0001, beta = 0.9780). CONCLUSIONS Our study might suggest that YKL-40 is associated with bone turnover in OSA. We may assume that this marker influences both bone formation and destruction; thus, OSA could be characterized by preserved bone mineral density. PMID- 29112187 TI - The absolute number of circulating nonclassical (CD14+CD16++) monocytes negatively correlates with DAS28 and swollen joint count in patients with peripheral spondyloarthritis. AB - INTRODUCTION A different clinical course and pattern of skeletal involvement in peripheral and axial spondyloarthritis (SpA) suggests a distinct pathophysiology of these 2 phenotypic manifestations of SpA. Monocytes, as part of the innate immune system, seem to play an important role in the pathogenesis of SpA, but the exact inflammatory pathways remain to be elucidated. Regulatory T lymphocytes (Treg) and Th17 lymphocytes are also known to influence proinflammatory and anti-inflammatory reactions. OBJECTIVES The aim of our study was to compare the absolute numbers of monocyte subpopulations, Treg, and Th17 lymphocytes with clinical measures of disease activity in patients with peripheral and axial SpA. PATIENTS AND METHODS We enrolled 21 patients with peripheral SpA and 27 patients with axial SpA diagnosed according to the Assessment of SpondyloArthritis International Society classification criteria, as well as 23 healthy controls. Patients were under 45 years, naive to synthetic and biological disease-modifying antirheumatic drugs and without the administration of systemic glucocorticoids. The absolute numbers of classical, intermediate, nonclassical monocytes, Treg, and Th17 in peripheral blood were analyzed. Disease activity was assessed using the Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Disease Activity Score 28 (DAS28). RESULTS In patients with SpA, the number of circulating nonclassical monocytes was decreased in comparison with controls. Only in the peripheral SpA group, a significant negative correlation was found between the concentration of nonclassical monocytes and DAS28 and the number of swollen joints. The 3 groups did not differ in terms of the concentrations of classical or intermediate monocytes and Treg or Th17 lymphocytes. CONCLUSIONS Nonclassical monocytes may play a role in induction and perpetuation of peripheral joint inflammation, at least in peripheral SpA, as cells infiltrating the synovium. PMID- 29112188 TI - Diagnosis and treatment of acquired hemophilia: a single -center experience. PMID- 29112189 TI - Quantification of sensitivity and resistance of breast cancer cell lines to anti cancer drugs using GR metrics. AB - Traditional means for scoring the effects of anti-cancer drugs on the growth and survival of cell lines is based on relative cell number in drug-treated and control samples and is seriously confounded by unequal division rates arising from natural biological variation and differences in culture conditions. This problem can be overcome by computing drug sensitivity on a per-division basis. The normalized growth rate inhibition (GR) approach yields per-division metrics for drug potency (GR50) and efficacy (GRmax) that are analogous to the more familiar IC50 and Emax values. In this work, we report GR-based, proliferation corrected, drug sensitivity metrics for ~4,700 pairs of breast cancer cell lines and perturbagens. Such data are broadly useful in understanding the molecular basis of therapeutic response and resistance. Here, we use them to investigate the relationship between different measures of drug sensitivity and conclude that drug potency and efficacy exhibit high variation that is only weakly correlated. To facilitate further use of these data, computed GR curves and metrics can be browsed interactively at http://www.GRbrowser.org/. PMID- 29112191 TI - Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior. AB - Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects. PMID- 29112190 TI - Jaw biodynamic data for 24 patients with chronic unilateral temporomandibular disorder. AB - This study assessed 24 adult patients, suffering from severe chronic unilateral pain diagnosed as temporomandibular joint (TMJ) disorder (TMD). The full dentate patients had normal occlusion and had never received an occlusal therapy, i.e., were with natural dental evolution/maturation. The following functional and dynamic factors were assessed: (1) chewing function; (2) TMJ remodeling or the condylar path (CP); and (3) lateral jaw motion or lateral guidance (LG). CPs were assessed using conventional axiography, and LG was assessed by K7 jaw tracking. Seventeen (71%) of the 24 (100%) patients consistently showed a habitual chewing side. The mean (standard deviation [SD]) of the CP angles was 47.90 (9.24) degrees. The mean (SD) of the LG angles was 42.95 (11.78) degrees. Data collection emerged from the conception of a new TMD paradigm where the affected side could be the habitual chewing side, the side with flatter lateral jaw motion or the side with an increased CP angle. These data may lead to improved diagnosis, therapy plans and evolution in TMD patients. PMID- 29112192 TI - The perilous path from publication to practice. PMID- 29112193 TI - Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia. AB - Schizophrenia (SZ) is associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction is manifest as cognitive deficits that appear to arise from disturbances in gamma frequency oscillations. These oscillations are generated in DLPFC layer 3 (L3) via reciprocal connections between pyramidal cells (PCs) and parvalbumin (PV)-containing interneurons. The density of cortical PV neurons is not altered in SZ, but expression levels of several transcripts involved in PV cell function, including PV, are lower in the disease. However, the transcriptome of PV cells has not been comprehensively assessed in a large cohort of subjects with SZ. In this study, we combined an immunohistochemical approach, laser microdissection, and microarray profiling to analyze the transcriptome of DLPFC L3 PV cells in 36 matched pairs of SZ and unaffected comparison subjects. Over 800 transcripts in PV neurons were identified as differentially expressed in SZ subjects; most of these alterations have not previously been reported. The altered transcripts were enriched for pathways involved in mitochondrial function and tight junction signaling. Comparison with the transcriptome of L3 PCs from the same subjects revealed both shared and distinct disease-related effects on gene expression between cell types. Furthermore, network structures of gene pathways differed across cell types and subject groups. These findings provide new insights into cell type-specific molecular alterations in SZ which may point toward novel strategies for identifying therapeutic targets. PMID- 29112195 TI - Face and predictive validity of the ClockDelta19 mouse as an animal model for bipolar disorder: a systematic review. AB - Mice carrying the circadian locomotor output cycles Kaput delta 19 N-ethyl-N nitrosoure (ENU) mutation (ClockDelta19) are used as an animal model for bipolar disorder (BD). We aimed to systematically review the face validity (phenotypical and pathophysiological resemblance with BD) and predictive validity (responsiveness to treatments used in BD) of this model in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. We carried out a systematic search of the databases PubMed and Embase, combining search terms covering BD and ClockDelta19. The 22 studies included in the review (from a total of 1281 identified records) show that the behavioral phenotype of the ClockDelta19 mouse is characterized by hyperactivity, decreased anxiety-like behavior, decreased depression-like behavior and increased preference for rewarding stimuli. This is highly consistent with mania in humans. Moreover, the ClockDelta19 mouse exhibits rapid mood cycling (a manic-like phenotype during the day followed by euthymia at night), which is consistent with BD. Chronic administration of lithium, a drug with well established mood stabilizing effect in humans with BD, reverses the majority of the bipolar-like traits and most of the neurobiological abnormalities observed in the ClockDelta19 mouse. In conclusion, the ClockDelta19 mouse has substantial face validity as an animal model for BD. The predictive validity of the ClockDelta19 mouse has primarily been investigated via studies using lithium challenge. Therefore, further studies are needed to determine how the ClockDelta19 mouse responds to other mood-stabilizing treatments of BD such as valproate, lamotrigine, carbamazepine, oxcarbazepine, antipsychotics, electroconvulsive therapy and various light interventions. PMID- 29112194 TI - Genome-wide association study identifies a novel locus for cannabis dependence. AB - Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations. PMID- 29112197 TI - Association of genetic ancestry with striatal dopamine D2/D3 receptor availability. AB - Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [11C]raclopride (P<0.0001), while correcting for age, sex, BMI, education, smoking status, and estimated socioeconomic status (ZIP codes). Effects of ethnicity on D2R were not driven by variation in dopaminergic candidate genes. Instead, candidate gene associations with striatal D2R were diminished when correcting for ancestry. These findings imply that future studies investigating D2 receptor genes should covary for genetic ancestry or study homogeneous populations. Moreover, ancestry studies on human neurobiology should control for socioeconomic differences between ethnic groups. PMID- 29112198 TI - Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study. AB - A previous genetic study has suggested that schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) share common disease-associated genes. However, whether individuals with first-degree relatives (FDRs) with schizophrenia have a higher risk of these major psychiatric disorders requires further investigation. This study used Taiwan's National Health Insurance Research Database and identified 151 650 patients with schizophrenia and 227 967 individuals with FDRs with schizophrenia. The relative risks (RRs) of schizophrenia and other major psychiatric disorders were assessed in individuals with FDRs with schizophrenia. The individuals with FDRs with schizophrenia exhibited higher RRs (95% confidence interval) of major psychiatric disorders, namely schizophrenia (4.76, 4.65-4.88), bipolar disorder (3.23, 3.12-3.35), major depressive disorder (2.05, 2.00-2.10), ASD (2.55, 2.35-2.77) and ADHD (1.31, 1.25-1.37) than were found in the total population. Several sensitivity analyses were conducted to confirm these results. A dose-dependent relationship was observed between the risks of major psychiatric disorders and the numbers of FDRs with schizophrenia. The increased risks of major psychiatric disorders were consistent in different family relationships, namely among parents, offspring, siblings and twins. Our study supports the familial dose-dependent co-aggregation of schizophrenia, bipolar disorder, major depressive disorder, ASD and ADHD, and our results may prompt governmental public health departments and psychiatrists to focus on the mental health of individuals with FDRs with schizophrenia. PMID- 29112199 TI - Research to the N-Power: The Strengths of Networked Clinical Collaboration in Spain. PMID- 29112196 TI - Understanding the roles of mutations in the amyloid precursor protein in Alzheimer disease. AB - Many models of disease progression in Alzheimer's disease (AD) have been proposed to help guide experimental design and aid the interpretation of results. Models focussing on the genetic evidence include the amyloid cascade (ACH) and presenilin (PSH) hypotheses and the amyloid precursor protein (APP) matrix approach (AMA), of which the ACH has held a dominant position for over two decades. However, the ACH has never been fully accepted and has not yet delivered on its therapeutic promise. We review the ACH, PSH and AMA in relation to levels of APP proteolytic fragments reported from AD-associated mutations in APP. Different APP mutations have diverse effects on the levels of APP proteolytic fragments. This evidence is consistent with at least three disease pathways that can differ between familial and sporadic AD and two pathways associated with cerebral amyloid angiopathy. We cannot fully evaluate the ACH, PSH and AMA in relation to the effects of mutations in APP as the APP proteolytic system has not been investigated systematically. The confounding effects of sequence homology, complexity of competing cleavages and antibody cross reactivities all illustrate limitations in our understanding of the roles these fragments and the APP proteolytic system as a whole in normal aging and disease play. Current experimental design should be refined to generate clearer evidence, addressing both aging and complex disorders with standardised reporting formats. A more flexible theoretical framework capable of accommodating the complexity of the APP proteolytic system is required to integrate available evidence. PMID- 29112201 TI - Quality Matters: Improving the Quality of Care for Patients With Complex Colorectal Polyps. PMID- 29112200 TI - Peripheral Eosinophilia in Patients With Inflammatory Bowel Disease Defines an Aggressive Disease Phenotype. AB - OBJECTIVES: Peripheral blood eosinophilia (PBE) in inflammatory bowel disease (IBD) is associated with ulcerative colitis (UC) and active disease. Little data exist on the long-term impact of PBE on disease course. We aimed to investigate the multi-year patterns of PBE and its impact on disease severity in a large IBD cohort. METHODS: We performed a registry analysis of a consented, prospective, natural history IBD cohort at a tertiary center from 2009 to 2014. Demographics, comorbidities, disease activity, healthcare utilization, and time to hospitalization or surgical resection of patients who displayed PBE were compared to patients without PBE. RESULTS: Of the 2,066 IBD patients, 19.2% developed PBE. PBE was significantly associated with UC (P<0.001), extensive colitis (P<0.001), and shorter disease duration (P=0.03). Over six years, PBE patients had more active disease (Harvey-Bradshaw Index P=0.001; ulcerative colitis activity index P<0.001), concurrent C-reactive protein elevation (P<0.001), healthcare utilization (hospitalization P<0.001, IBD surgery P<0.001), and more aggressive medical therapy (prednisone P<0.001, anti-TNF P<0.001). Patients with PBE had a significantly reduced time to hospitalization in both UC (P<0.001) and Crohn's disease (CD) (P<0.001) and reduced time to colectomy in UC (P=0.003). On multivariable modeling, PBE remained significantly associated with hospitalization and surgery in both CD and UC. New diagnosis of UC with PBE was associated with increased steroid (P=0.007) and anti-TNF (P=0.001) requirement. CONCLUSION: This multi-year study of a large IBD cohort suggests that peripheral blood eosinophilia represents a biomarker of a distinct IBD subgroup, with a unique inflammatory signature, and at risk for worse clinical outcomes. PMID- 29112203 TI - A Few Spanish Pearls for the American Journal of Gastroenterology. PMID- 29112202 TI - Adherence to a Healthy Lifestyle is Associated With a Lower Risk of Diverticulitis among Men. AB - OBJECTIVES: Diverticulitis is a common disease with high clinical burden. We evaluated the joint contribution of multiple lifestyle factors to risks of incident diverticulitis. We also estimated the proportion of diverticulitis preventable by lifestyle modifications. METHODS: We prospectively examined the association between lifestyle factors (red meat, dietary fiber intake, vigorous physical activity (activity with metabolic equivalent >=6), body mass index (BMI), and smoking) and risk of diverticulitis among participants in the Health Professionals Follow-Up Study. RESULTS: We documented 907 incident cases of diverticulitis during 757,791 person-years. High intake of red meat, low intake of dietary fiber, low vigorous physical activity, high BMI, and smoking were independently associated with increased risks of diverticulitis (all P<0.05). Low risk lifestyle was defined as average red meat intake <51 g per day, dietary fiber intake in the top 40% of the cohort (about 23 g per day), vigorous physical activity in the highest 50% among participants with non-zero vigorous physical activity (roughly 2 h of exercise weekly), normal BMI between 18.5-24.9 kg m-2, and never-smoker. There was an inverse linear relationship between number of low risk lifestyle factors and diverticulitis incidence (P for trend<0.001). Compared with men with no low-risk lifestyle factors, the multivariable relative risks of diverticulitis were 0.71 (95% confidence interval (CI): 0.59-0.87) for men with 1 low-risk lifestyle factor; 0.66 (95% CI: 0.55-0.81) for 2 low-risk factors; 0.50 (95% CI: 0.40-0.62) for 3 low-risk factors; 0.47 (95% CI: 0.35-0.62) for 4 low risk factors, and 0.27 (95% CI: 0.15-0.48) for 5 low-risk factors. Adherence to a low-risk lifestyle could prevent 50% (95% CI: 20-71%) of incident diverticulitis. CONCLUSIONS: Adherence to a low-risk lifestyle is associated with reduced incidence of diverticulitis. PMID- 29112206 TI - Intratumoral heterogeneity and clonal evolution in blood malignancies and solid tumors. AB - This meeting held at the University of Barcelona in March 2017, brought together scientists and clinicians worldwide to discuss current and future clinico biological implications of intratumoral heterogeneity (ITH) and subclonal evolution in cancer diagnosis, patient stratification, and treatment resistance in diagnosis, treatment and follow-up. There was consensus that both longitudinal and tumor multi-region studies in matched samples are needed to better understand the dynamics of ITH. The contribution of the epigenome and microenvironment to ITH and subclone evolution remains understudied. It was recommended to combine computational, pathology and imaging tools to study the role of the microenvironment in subclone selection/evolution. PMID- 29112207 TI - Palladium-catalyzed direct sulfonylation of C-H bonds with the insertion of sulfur dioxide. AB - A palladium-catalyzed direct sulfonylation of C-H bonds with the insertion of sulfur dioxide under mild conditions is reported. The sulfonylative couplings with the insertion of sulfur dioxide into C-H bonds are effective, and two classes of sulfonylative products are formed in moderate to good yields by the combination of radical chemistry and palladium-catalyzed C-H activation. PMID- 29112208 TI - Calcium carbonate crystallisation at charged graphite surfaces. AB - Calcium carbonate crystallisation on surfaces has been studied extensively due to its prominence in biomineralisation, but the role of surface charge in nucleation and growth is not well understood. We have employed potential-controlled Highly Oriented Pyrolytic Graphite (HOPG) surfaces to demonstrate the significant impact of surface charge on calcium carbonate crystallisation: at negatively charged HOPG surfaces, calcite, aragonite and vaterite all nucleate from high energy positively-charged crystal faces, contrasting with the stable (104) calcite planes nucleated at positively charged surfaces. These observations are explained and rationalised. PMID- 29112210 TI - Magnetic functionalities in MOFs: from the framework to the pore. AB - In this review, we show the different approaches developed so far to prepare metal-organic frameworks (MOFs) presenting electronic functionalities, with particular attention to magnetic properties. We will cover the chemical design of frameworks necessary for the incorporation of different magnetic phenomena, as well as the encapsulation of functional species in their pores leading to hybrid multifunctional MOFs combining an extended lattice with a molecular lattice. PMID- 29112209 TI - Dual-target cancer theranostic for glutathione S-transferase and hypoxia inducible factor-1alpha inhibition. AB - We developed a dual-target theranostic F671, which could exhibit synergetic anticancer effects for inhibiting the activities of glutathione S-transferase and the accumulation of hypoxia inducible factor-1alpha. F671 undergoes self immolative cleavage when exposed to GSTP1-1 in live cancer cells, facilitating the visualization of molecule release and distribution, as well as confirming the autophagy-induced apoptosis. PMID- 29112212 TI - Characterization of the superlattice region of a quantum cascade laser by secondary ion mass spectrometry. AB - Secondary ion mass spectrometry is applied to the depth profiling of the superlattice active region of lattice matched (~9.2 MUm) Al0.48In0.52As/In0.53Ga0.47As/InP quantum cascade lasers. The developed measurement procedure is capable of characterizing the quality of each individual layer in the superlattice region, including layers as thin as 0.7 nm. The oxygen level for AlInAs and InGaAs layers is in the range of 1-3 * 1017 atms per cm3 and below the detection limit (~1 * 1016 atms per cm3), respectively. Oxygen is not uniformly distributed in the AlInAs layers - more oxygen is embedded into the structure during the very first stage of the growth of the AlInAs layer and thus the corresponding interface is 1.83 +/- 0.31 times more contaminated than the other. The procedure can also be operated in 3D imaging mode which proves to be invaluable for failure analysis. PMID- 29112213 TI - Controllable formation of multi-layered SnO2@Fe2O3 sandwich cubes as a high performance anode for Li-ion batteries. AB - The design and controllable synthesis of hollow multi-layered "sandwich" nanostructures offer opportunities for metal oxides to buffer the volume expansion and aggregation due to coalescence into bulk structures, while realizing improved tap density and superior ion transport. We report the intentional construction of Fe2O3 nanorod-assembled layers to cover and fill the surface and interlayer of double-shelled SnO2 hollow nanocubes (HNCs) to form multi-layered SnO2@Fe2O3 sandwich nanocubes (SNCs). The crystallinity and morphological characteristics confirm that the dense well-aligned Fe2O3 nanorods vertically cover all surfaces of the SnO2 layers. When used as the anode active material for lithium-ion batteries (LIBs), these sandwich hetero-nanostructures demonstrate evidently improved Li ion storage performances compared to pure SnO2, with higher specific capacity and cyclability (750.8 mA h g-1 after 200 cycles at a current density of 500 mA g-1) due to the synergistic effect of the hollow multi-layered nanostructure and uniform Fe2O3 hetero-coating. PMID- 29112218 TI - A facile strategy for enzyme immobilization with highly stable hierarchically porous metal-organic frameworks. AB - Metal-organic frameworks (MOFs) have drawn extensive research interest as candidates for enzyme immobilization owing to their tunable porosity, high surface area, and excellent chemical/thermal stability. Herein, we report a facile and universal strategy for enzyme immobilization using highly stable hierarchically porous metal-organic frameworks (HP-MOFs). The HP-MOFs were stable over a wide pH range (pH = 2-11 for HP-DUT-5) and met the catalysis conditions of most enzymes. The as-prepared hierarchical micro/mesoporous MOFs with mesoporous defects showed a superior adsorption capacity towards enzymes. The maximum adsorption capacity of HP-DUT-5 for glucose oxidase (GOx) and uricase was 208 mg g-1 and 225 mg g-1, respectively. Furthermore, we constructed two multi-enzyme biosensors for glucose and uric acid (UA) by immobilizing GOx and uricase with horseradish peroxidase (HRP) on HP-DUT-5, respectively. These sensors were efficiently applied in the colorimetric detection of glucose and UA and showed good sensitivity, selectivity, and recyclability. PMID- 29112221 TI - Cryptorchidism and non-seminomatous testis cancer. AB - An analysis of 107 cases of cryptorchidism and non-seminomatous germ cell cancer treated between 1960 and 1976 is presented. The incidence of cryptorchidism in patients with testicular cancer is 9.8%. Eighty patients presented with ipsilateral inguinal tumours, 12 with contralateral intrascrotal tumours and 15 with abdominal tumours. There were 52 embryonal, 36 teratocarcinoma, 9 teratoma, and 10 choriocarcinoma tumours. The 5 year survival for all patients was 52.3%. The age distribution, pathology and stage of the patients was similar to non seminomatous tumours not associated with cryptorchidism. PMID- 29112223 TI - Discussion. PMID- 29112222 TI - Testis cancer incidence - suggestion of a world pattern. AB - Testis carcinoma may be an indicator of damage to the genome, and the increase in morbidity found in various countries may therefore be of wider interest than immediately apparent. Changes in morbidity from testis cancer, and international differences are largely determined by the incidence among younger men. The author has therefore compared rates for the three consecutive five-year age groups 25 to 39 years from a number of countries with cancer registration. The lowest rates are found for Africans and US negroes, with slightly higher rates found in Asia. Increasing rates are found in Norway, Hamburg, and Denmark where incidence is highest, while Finland shows apparently stable and low rates. It is suggested that rates are increasing in England. Morbidity rates vary in the United States. In Canada, Quebec shows lower rates than other provinces. It is suggested to look for prenatal causative factors. PMID- 29112224 TI - Variants in CIB2 cause DFNB48 and not USH1J. AB - The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH-causing gene. PMID- 29112225 TI - Global and targeted circulating microRNA profiling of colorectal adenoma and colorectal cancer. AB - BACKGROUND: Circulating microRNAs (miRNAs) are emerging as promising biomarkers for cancer. The objective of the current study was to investigate the potential of circulating cell-free miRNAs as biomarkers for colorectal cancer (CRC) and its precursor lesion, colorectal adenoma. METHODS: The serum levels of 800 miRNAs were assessed in a discovery set of 21 patients with CRC, 19 patients with adenoma, and 21 healthy controls using the NanoString miRNA analysis platform. Significantly differentially expressed miRNAs were examined further in a validation cohort of 34 patients with CRC, 33 patients with adenoma, and 35 healthy controls using Fluidigm quantitative polymerase chain reaction assays. RESULTS: The ratios between the expression values of the differentially expressed miRNAs were computed. Three miRNA ratios (miR-17-5p/miR-135b, miR-92a-3p/miR135b, and miR-451a/miR-491-5p) were validated for discriminating patients with adenoma and those with CRC from the healthy control group, and 5 miRNA ratios (let-7b/miR 367-3p, miR-130a-3p/miR-409-3p, miR-148-3p/miR-27b, miR-148a-3p/miR-409-3p, and miR-21-5p/miR-367-3p) were validated for discriminating patients with CRC from those with adenoma and healthy controls. The area under the receiver operating characteristic curve values for the 3 miRNA ratios in discriminating patients with adenoma from healthy controls were 0.831 and 0.735, respectively, in the discovery and validation sets. The area under the receiver operating characteristic curve values for the 5 miRNA ratios in discriminating patients with CRC from those with adenoma were 0.797 and 0.732, respectively, in the discovery and validation sets. Pathway analysis revealed that target genes regulated by the miRNAs from the miRNA ratios were enriched mainly in metabolism related and inflammation-related pathways. CONCLUSIONS: The data from the current study suggest that circulating miRNAs can distinguish patients with CRC and those with adenoma and may represent novel biomarkers for the early, noninvasive detection of CRC. Cancer 2018;124:785-96. (c) 2017 American Cancer Society. PMID- 29112226 TI - New Institutionalization in Long-Term Care After Hospital Discharge to Skilled Nursing Facility. AB - BACKGROUND/OBJECTIVES: Approximately half of individuals newly admitted to long term care (LTC) nursing homes (NHs) experienced a prior hospitalization followed by discharge to a skilled nursing facility (SNF). The objective was to examine characteristics associated with new institutionalizations of older adults on this care trajectory. DESIGN: Retrospective cohort study. SETTING: SNFs and LTC NHs. PATIENTS: Medicare fee-for-service beneficiaries admitted to 7,442 SNFs in 2013 (N = 597,986). MEASUREMENTS: We used demographic and clinical characteristics from Medicare data and the Minimum Data Set. We defined "new institutionalization" as LTC NH residence for longer than 90 non-SNF days, starting within 6 months of hospital discharge. RESULTS: For individuals who survived 6 months after hospital discharge, the overall rate of new LTC institutionalizations was 10.0% (N = 59,736). Older age, white race, being unmarried, Medicaid eligibility, higher income, more comorbidities, cognitive impairment, depression, functional limitations, hallucinations and delusions, aggressive behavior, incontinence, and pressure ulcers were associated with higher adjusted odds of new LTC institutionalization. In analyses stratified according to race and ethnicity, higher income was associated with lower odds of LTC institutionalization for whites (odds ratio (OR) = 0.92, 95% confidence interval (CI) = 0.89-0.96) and greater odds for blacks (OR = 1.40, 95% CI = 1.27 1.55) and Hispanics (OR = 1.44, 95% CI = 1.25-1.66). Moderate or severe depression, functional limitations, hallucinations and delusions, aggressive behavior, and being unmarried were stronger risk factors for LTC for cognitively intact individuals than for those with moderate to severe cognitive impairment. Being unmarried and having more comorbidities were stronger predictors in those aged 66 to 70 than in those aged 81 to 85 and 91 and older. CONCLUSION: Associations between risk factors and new LTC institutionalizations varied according to race and ethnicity, age, and level of cognitive function. Programs that target older adults at greater risk may be an effective strategy for reducing new institutionalizations and fostering aging in place. PMID- 29112227 TI - Trends and variations in postmastectomy radiation therapy for breast cancer in patients with 1 to 3 positive lymph nodes: A National Cancer Data Base analysis. AB - BACKGROUND: High-level evidence is lacking to guide treatment decisions about postmastectomy radiation therapy (PMRT) in patients who have breast cancer with 1 to 3 positive lymph nodes who receive contemporary systemic therapies, leading to potential variations in PMRT delivery. The objective of this study was to examine nationwide trends in PMRT use in this group. METHODS: The National Cancer Data Base (NCDB) was used to identify 93,372 women who had T1-T2N1 breast cancer diagnosed between 2003 and 2012. Patients who received neoadjuvant chemotherapy or radiation therapy (RT) and those who had bilateral breast cancers were excluded. Time trends were evaluated using the Cochrane-Armitage test and correlated the receipt of PMRT with various patient demographic, facility, clinicopathologic, and treatment variables using multivariable logistic regression. A second analysis was performed for patients who were diagnosed during 2010 and included radiation oncologist density as an additional covariate. P values < .0001 were considered statistically significant. RESULTS: Overall, 22.5% of the study population received PMRT, representing an increase from 19.1% in 2003 to 30.3% in 2012. Factors associated with greater PMRT use included younger age, lower Charlson-Deyo comorbidity scores, shorter distance to the treating facility, treatment at a comprehensive cancer program, facility location in the New England Census division, and higher density of radiation oncologists. Increased PMRT use was associated with later year of diagnosis, receipt of chemotherapy, receipt of hormone therapy, higher grade disease, larger tumor size, greater numbers of positive lymph nodes, positive margins, and absence of immediate breast reconstruction (all P < .0001). CONCLUSIONS: The receipt of PMRT by patients with breast cancer who have 1 to 3 positive lymph nodes has increased over time, with wide variability in practice patterns in the United States. Cancer 2018;124:482-90. (c) 2017 American Cancer Society. PMID- 29112228 TI - Discussion. PMID- 29112229 TI - Biobehavioral modulation of the exosome transcriptome in ovarian carcinoma. AB - BACKGROUND: Social factors in the patient macroenvironment have been shown to influence molecular events in the tumor microenvironment and thereby influence cancer progression. However, biomarkers providing a window into the longitudinal effects of biobehavioral factors on tumor biology over time are lacking. Exosome analysis is a novel strategy for in vivo monitoring of dynamic changes in tumor cells. This study examined exosomal profiles from patients with low or high levels of social support for epithelial-mesenchymal transition (EMT) polarization and gene expression related to inflammation and beta-adrenergic signaling. METHODS: Exosomes were isolated from plasma sampled from a series of 40 women before primary surgical resection of advanced-stage, high-grade ovarian carcinoma. Samples were selected for analysis on the basis of extremes of low and high levels of social support. After exosomal isolation and RNA extraction, a microarray analysis of the transcriptome was performed. RESULTS: Primary analyses identified significant upregulation of 67 mesenchymal-characteristic gene transcripts and downregulation of 63 epithelial-characteristic transcripts in patients with low social support; this demonstrated increased EMT polarization (P = .0002). Secondary analyses using promoter sequence bioinformatics supported a priori hypotheses linking low social support to 1) increased activity of cyclic adenosine monophosphate response element binding protein (CREB)/activating transcription factor (ATF) family transcription factors that mediate the beta adrenergic response to catecholamines via the cyclic adenosine monophosphate/protein kinase A signaling pathway (mean fold change for CREB: 2.24 +/- 0.65; P = .0019; mean fold change for ATF: 2.00 +/- 0.55; P = .0049) and 2) increased activity of the proinflammatory nuclear factor kappaB/Rel family of transcription factors (mean fold change: 2.10 +/- 0.70; P = .0109). CONCLUSIONS: These findings suggest the possibility of leveraging exosomes as a noninvasive assessment of biobehavioral factors to help to direct personalized treatment approaches. Cancer 2018;124:580-6. (c) 2017 American Cancer Society. PMID- 29112230 TI - Longitudinal analysis of quality-of-life outcomes in children during treatment for acute lymphoblastic leukemia: A report from the Children's Oncology Group AALL0932 trial. AB - BACKGROUND: Children with average-risk acute lymphoblastic leukemia (AR-ALL) face many challenges that can adversely affect their quality of life (QOL). However, to the authors' knowledge, patterns and predictors of QOL impairment during therapy have not been well characterized to date. METHODS: Patients with AR-ALL who were enrolled on the Children's Oncology Group AALL0932 trial were offered participation in this prospective cohort study if they were aged >=4 years at the time of diagnosis and had an English-speaking parent. At approximately 2 months, 8 months, 17 months, 26 months, and 38 months (boys only) after diagnosis, parents completed the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0 (PedsQL4.0) and McMaster Family Assessment Device instruments for QOL (physical, emotional, and social functioning) and family functioning, respectively. The proportions of individuals scoring in the impaired range (2 standard deviations below the population mean) were calculated at each time point. Longitudinal impairment patterns and predictors were examined. RESULTS: A total of 594 participants with AR-ALL were diagnosed at a mean age of 6.0 years (standard deviation, 1.6 years). At 2 months, a substantial proportion of participants had impaired scores for physical (36.5%; 95% confidence interval [95% CI], 32.3%-40.8%) and emotional (26.2%; 95% CI, 22.5%-30.2%) functioning compared with population norms of 2.3%. These elevations persisted at 26 months. Emotional impairment at 2 months (odds ratio, 3.4; 95% CI, 1.5-7.7) was found to significantly predict emotional impairment at 26 months. In repeated measures analysis with multivariate modeling, unhealthy family functioning (odds ratio, 1.5; 95% CI, 1.1-2.1) significantly predicted emotional impairment controlling for age and sex. QOL outcomes were similar between sexes at the end of therapy (26 months for girls and 38 months for boys). CONCLUSIONS: Many children with AR ALL experience physical and emotional functioning impairment that begins early in treatment and persists. Early screening may identify high-risk patients who might benefit from family-based interventions. Cancer 2018;124:571-9. (c) 2017 American Cancer Society. PMID- 29112231 TI - Individualized outcome prognostication for patients with laryngeal cancer. AB - BACKGROUND: Accurate prognostication is essential to the optimal management of laryngeal cancer. Predictive models have been developed to calculate the risk of oncologic outcomes, but extensive external validation of accuracy and reliability is necessary before implementing them into clinical practice. METHOD: Four published prognostic calculators that predict 5-year overall survival for patients with laryngeal cancer were evaluated using patient information from a prospective epidemiology study cohort (n = 246; median follow-up, 60 months) with previously untreated, stage I through IVb laryngeal squamous cell carcinoma. RESULTS: Different calculators yielded substantially different predictions for individual patients. The observed 5-year overall survival was significantly higher than the averaged predicted 5-year overall survival of the 4 calculators (71.9%; 95% confidence interval [CI], 65%-78%] vs 47.7%). Statistical analyses demonstrated the calculators' limited capacity to discriminate outcomes for risk stratified patients. The area under the receiver operating characteristic curve ranged from 0.68 to 0.72. C-index values were similar for each of the 4 models (range, 0.66-0.68). There was a lower than expected hazard of death for patients who received induction (bioselective) chemotherapy (hazard ratio, 0.46; 95% CI, 0.24-0.88; P = .024) or primary surgical intervention (hazard ratio, 0.43; 95 % CI, 0.21-0.90; P = .024) compared with those who received concurrent chemoradiation. CONCLUSIONS: Suboptimal reliability and accuracy limit the integration of existing individualized prediction tools into routine clinical decision making. The calculators predicted significantly worse than observed survival among patients who received induction chemotherapy and primary surgery, suggesting a need for updated consideration of modern treatment modalities. Further development of individualized prognostic calculators may improve risk prediction, treatment planning, and counseling for patients with laryngeal cancer. Cancer 2018;124:706-16. (c) 2017 American Cancer Society. PMID- 29112232 TI - Estimating global treatment toxicity burden from adverse-event data. AB - BACKGROUND: A summary measure that reflects the global toxicity burden of a treatment is essential for comparing therapies. Current toxicity summaries are ad hoc and do not distinguish among the severities and types of toxicities. Here a clinically feasible method for estimating the toxicity burden, based on a prospective evaluation of the toxicity profile of a randomized clinical trial of 746 prostate cancer patients conducted by SWOG, is proposed. METHODS: For 308 patients who experienced severe toxicities, 2 physicians randomly selected from 14 physicians evaluated each toxicity profile and assigned a visual analogue scale score (0-10) based on their impression of the global burden of toxicities. With mixed-effects models, severity scores and a 10-point toxicity burden score (TBS) were derived from 27 predictors accounting for severe (grade 3) and life threatening (grade 4) toxicities for each organ class of the Common Terminology Criteria for Adverse Events. RESULTS: For most organ classes, grade 3 toxicities had a TBS of 4.14 (95% confidence interval [CI], 3.65-4.63), but infections, cardiovascular events, and pulmonary events had a higher TBS with differences of 0.87 (95% CI, 0.53-1.21), 0.88 (95% CI, 0.51-1.25), and 0.73 (95% CI, 0.22-1.24), respectively. Moreover, most grade 4 events had a higher TBS than grade 3 events, except for hemorrhaging, pain, metabolic events, and musculoskeletal events. The intrarater and interrater correlations were 0.91 and 0.59, respectively. CONCLUSIONS: The burden of toxicity grades differs with toxicity types. A TBS provides a toxicity burden summary that incorporates physicians' perspectives and differentiates between severe and life-threatening toxicities and organ classes. Cancer 2018;124:858-64. (c) 2017 American Cancer Society. PMID- 29112233 TI - Neuroendocrine tumors and fibrosis: An unsolved mystery? AB - Neuroendocrine tumors are a heterogeneous group of slow-growing neoplasms arising mainly from the enterochromaffin cells of the digestive and respiratory tract. Although they are relatively rare, their incidence is rising. It has long been observed that they often are associated with the development of fibrosis, both local and distant. Fibrotic complications, such as carcinoid heart disease and mesenteric desmoplasia, may lead to considerable morbidity or even affect prognosis. The elucidation of the pathophysiology of fibrosis would be of critical importance for the development of targeted therapeutic strategies. In this article, the authors review the available evidence regarding the biological basis of fibrosis in neuroendocrine tumors. They explore the role of the tumor microenvironment and the interplay between tumor cells and fibroblasts as a key factor in fibrogenesis and tumor development/progression. They also review the role of serotonin, growth factors, and other peptides in the development of carcinoid-related fibrotic reactions. Cancer 2017;123:4770-90. (c) 2017 American Cancer Society. PMID- 29112234 TI - Impact of the insurance type of head and neck cancer patients on their hospitalization utilization patterns. AB - BACKGROUND: Head and neck cancer (HNC) patients with Medicaid, Medicare, or no insurance show poor outcomes in comparison with privately insured patients. It was hypothesized that nonprivate insurance coverage biases the selection of the treatment site to favor hospitals that are not associated with optimum treatment outcomes. This study assessed the relation between the insurance type of HNC patients and the hospital type for inpatient care. METHODS: Adult HNC patients were identified from the Nationwide Inpatient Sample (2012 and 2013). The primary exposure was the insurance provider type. The outcome was the hospital type, which was classified by the hospital's ownership and its location and teaching status. Multivariate multinomial logistic regression models were constructed to control for the patient's age, sex, race, income, mortality risk, and geographic location. The analysis was weighted and was adjusted for multiple comparisons. RESULTS: In all, 37,466 HNC patients representing 187,330 patients nationally were identified. After adjustments for age, sex, race, income, and mortality risk, in comparison with privately insured patients, Medicaid, Medicare, and uninsured patients demonstrated 1.14 to 2.29 increased odds of undergoing treatment at rural, urban nonteaching, private investor-owned, or government (nonfederal) hospitals (P < .05). This trend remained apparent even after adjustments for the geographic location. CONCLUSIONS: Uninsured patients or patients insured by government programs predominantly underwent care for HNC at hospital types most often associated with inferior survival outcomes. This finding could explain some proportion of insurance-related disparities in HNC outcomes. Further studies are warranted to determine whether interventions to promote equitable access to optimal hospital settings for patients, regardless of their insurance type, might improve outcomes among nonprivate insurance holders. Cancer 2018;124:760-8. (c) 2017 American Cancer Society. PMID- 29112236 TI - Amelogenesis imperfecta in the dentition of a wild chimpanzee. AB - This report describes a case of amelogenesis imperfecta in the dentition of a female chimpanzee. Amelogenesis imperfecta is a group of rare genetic conditions that create severe enamel defects, which, although well researched in humans, has not yet been investigated in wild non-human primates. PMID- 29112235 TI - Prevalence of anthracycline-related cardiac dysfunction in long-term survivors of adult-onset lymphoma. AB - BACKGROUND: Anthracycline-related heart failure is a leading cause of morbidity in survivors of adult-onset lymphoma. There is a paucity of information on screening for late-occurring preclinical disease, which, in turn, has limited guidelines for early detection and intervention. The objectives of this study were to examine the prevalence and risk of cardiac dysfunction, as measured by echocardiography (abnormal left ventricular systolic/diastolic function or strain), in lymphoma survivors who received treatment with anthracyclines and to evaluate the diagnostic yield of blood biomarkers in the asymptomatic setting. METHODS: Lymphoma survivors who underwent hematopoietic cell transplantation (HCT) (n = 78) or received conventional therapy (non-HCT; n = 77) were compared with each other and with a group of matched controls (n = 51); the study was limited to lymphoma survivors who were >5 years from diagnosis. RESULTS: At a median follow-up of 9.4 years after diagnosis, 1 in 5 (20.6 %) lymphoma survivors had cardiac dysfunction; the odds of having cardiac dysfunction were 6.6-fold greater (odds ratio [OR], 6.6; P = .01) among lymphoma survivors compared with matched controls. There was a dose-dependent risk of cardiac dysfunction according to the cumulative anthracycline dose (controls [referent group], 1-249 mg/m2 [OR, 4.7; P = .05], and >=250 mg/m2 [OR, 7.6; P < .01]), but there was no difference in the prevalence of cardiac dysfunction between conventionally treated and HCT survivors. The diagnostic accuracy of cardiac blood biomarkers in the asymptomatic setting was quite poor. CONCLUSIONS: In these long-term survivors, there was a high rate of cardiac dysfunction that was independent of HCT status. The growing number of lymphoma survivors makes it imperative to identify reliable and cost-effective strategies to decrease the burden of heart failure in this population. Cancer 2018;124:850-7. (c) 2017 American Cancer Society. PMID- 29112237 TI - The effect of patient's delay and doctor's delay in patients with malignant germ cell tumours. AB - In 103 patients with malignant germ cell tumours the initial clinical diagnosis was incorrect in 45 (44%). The correct diagnosis was established within 2 months in only 31% of the patients, and delayed by more than 6 months in 27%. Stage, distribution and survival were correlated with the histology, but not with the duration of symptoms or the patient's/doctor's delay. Rapidly growing tumours often belonged to the non-seminornaious group where advanced tumour stages and low survival rates were more common than in the seminoma group. The overall prognosis of patients with malignant germ cell tumours may be increased by an early diagnosis of testicular tumours in non-symptomatic patients, especially in men with possible risk factors (cryptorchidism, atrophic testis, antecedent contralateral testicular cancer). PMID- 29112238 TI - Discussion. PMID- 29112239 TI - Early detection of testicular cancer: An introduction. PMID- 29112240 TI - Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. AB - BACKGROUND: Acute splenic sequestration crises are a complication of sickle cell disease, with high mortality rates and frequent recurrence in survivors of first attacks. Splenectomy and blood transfusion, with their consequences, are the mainstay of long-term management used in different parts of the world. This is a 2017 update of a Cochrane Review first published in 2002, and previously updated, most recently in 2015. OBJECTIVES: To assess whether splenectomy (total or partial), to prevent acute splenic sequestration crises in people with sickle cell disease, improved survival and decreased morbidity in people with sickle cell disease, as compared with regular blood transfusions. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and handsearching relevant journals and abstract books of conference proceedings. We also searched clinical trial registries. Additional trials were sought from the reference lists of the trials and reviews identified by the search strategy.Date of the most recent search: 14 August 2017. SELECTION CRITERIA: All randomized or quasi-randomized controlled trials comparing splenectomy (total or partial) to prevent recurrence of acute splenic sequestration crises with no treatment or blood transfusions in people with sickle cell disease. DATA COLLECTION AND ANALYSIS: No trials of splenectomy for acute splenic sequestration were found. MAIN RESULTS: No trials of splenectomy for acute splenic sequestration were found. AUTHORS' CONCLUSIONS: Splenectomy, if full, will prevent further sequestration and if partial, may reduce the recurrence of acute splenic sequestration crises. However, there is a lack of evidence from trials showing that splenectomy improves survival and decreases morbidity in people with sickle cell disease. There is a need for a well-designed, adequately-powered, randomized controlled trial to assess the benefits and risks of splenectomy compared to transfusion programmes, as a means of improving survival and decreasing mortality from acute splenic sequestration in people with sickle cell disease.There are no trials included in the review and we have not identified any relevant trials up to August 2017. We will continue to run searches to identify any potentially relevant trials; however, we do not plan to update other sections of the review until new trials are published. PMID- 29112241 TI - Periodontal therapy for the management of cardiovascular disease in patients with chronic periodontitis. AB - BACKGROUND: There is an association between chronic periodontitis and cardiovascular disease (CVD). However, it is not known whether periodontal therapy could prevent or manage CVD in patients with chronic periodontitis. OBJECTIVES: The objective of this systematic review was to investigate the effects of periodontal therapy in preventing the occurrence of, and management or recurrence of, CVD in patients with chronic periodontitis. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 31 August 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 7), MEDLINE Ovid (1946 to 31 August 2017), Embase Ovid (1980 to 31 August 2017) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL EBSCO) (1937 to 31 August 2017) . The US National Institutes of Health Trials Registry (ClinicalTrials.gov), the World Health Organization International Clinical Trials Registry Platform and Open Grey were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases.We also searched the Chinese BioMedical Literature Database (1978 to 27 August 2017), the China National Knowledge Infrastructure (1994 to 27 August 2017), the VIP database (1989 to 27 August 2017) and Sciencepaper Online (2003 to 27 August 2017). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs were considered eligible. Studies were selected if they included patients with a diagnosis of chronic periodontitis and previous CVD (secondary prevention studies) or no CVD (primary prevention studies); patients in the intervention group received active periodontal therapy compared to maintenance therapy, no periodontal treatment or another kind of periodontal treatment in the control group. DATA COLLECTION AND ANALYSIS: Two review authors carried out the study identification, data extraction and risk of bias assessment independently and in duplicate. Any discrepancies between the two authors were resolved by discussion or with a third review author. A formal pilot-tested data extraction form was adopted for the data extraction, and the Cochrane tool for risk of bias assessment was used for the critical appraisal of the literature. MAIN RESULTS: No studies were identified that assessed primary prevention of CVD in people with periodontitis. One study involving 303 participants with >= 50% blockage of one coronary artery or a coronary event within three years, but not the three months prior, was included. The study was at high risk of bias due to deviation from the protocol treatment allocation and lack of follow-up data. The trial compared scaling and root planing (SRP) with community care for a follow-up period of six to 25 months. No data on deaths (all-cause or CVD-related) were reported. There was insufficient evidence to determine the effect of SRP and community care in reducing the risk of CVD recurrence in patients with chronic periodontitis (risk ratio (RR) 0.72; 95% confidence interval (CI) 0.23 to 2.22; very low quality evidence). The effects of SRP compared with community care on high-sensitivity C reactive protein (hs-CRP) (mean difference (MD) 0.62; -1.45 to 2.69), the number of patients with high hs-CRP (RR 0.77; 95% CI 0.32 to 1.85) and adverse events (RR 9.06; 95% CI 0.49 to 166.82) were also not statistically significant. The study did not assess modifiable cardiovascular risk factors, other blood test results, heart function parameters or revascularisation procedures. AUTHORS' CONCLUSIONS: We found very low quality evidence that was insufficient to support or refute whether periodontal therapy can prevent the recurrence of CVD in the long term in patients with chronic periodontitis. No evidence on primary prevention was found. PMID- 29112242 TI - A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long term survival with triple prophylaxis. AB - BACKGROUND: In a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen-identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP-) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP. METHODS: In the current study, the authors performed a long-term follow-up to discover possible late effects of the intensified GVHD prophylaxis. RESULTS: The median follow-up for surviving patients was 24.5 years. In the MP+ group, the overall survival and recurrence-free survival were higher (P = .021 and P = .028, respectively) and the nonrecurrence mortality was lower (P = .003) than in the MP group. There was a trend toward a lower cumulative incidence and a significantly lower prevalence (P = .031) of chronic GVHD in the MP+ group. There was no difference noted with regard to the rate of disease recurrence or in the incidence of secondary malignancies. Eleven patients in the MP- group but none in the MP+ group died >15 years after transplantation. At the end of follow-up, the overall survival rates in the MP+ and MP- groups were 55% and 20%, respectively, and the recurrence-free survival rates were 49% and 15%, respectively. CONCLUSIONS: Long-term survival was found to be higher among the patients given MP in addition to cyclosporine and methotrexate. There was marked late nonrecurrence mortality observed in the group not given MP. No adverse late effects caused by the addition of corticosteroid were observed. Cancer 2018;124:727-33. (c) 2017 American Cancer Society. PMID- 29112244 TI - Discussion. PMID- 29112243 TI - Richieri-Costa-Pereira syndrome: Expanding its phenotypic and genotypic spectrum. AB - Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5' untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16 repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation. PMID- 29112245 TI - Experimental production of testicular teratomas in the mouse. AB - Testicular teratomas are congenital tumours that are extremely rare in mice except for the inbred strain 129 and strains derived from it. A third of the males of strain 129/Sv-ter has spontaneous teratomas. Teratomas may be easily produced experimentally in some inbred strains and hybrids by grafting genital ridges from male foetuses 12 days of gestation to scrotal adult testes. The grafted genital ridges develop into well formed testes and most of them have teratomas composed of many kinds of well differentiated tissues derived from all 3 germ layers. Experimentally induced teratomas may be recognized as early as six days after grafting when they are composed of small clusters of embryonal carcinoma cells. The low temperature of the scrotal testis is a critical factor in experimental teratocarcinogenesis. When genital ridges from genetically sterile (S1/S1) foetuses that lack germ cells are grafted, they develop into testes without teratomas whereas grafts from testes that develop from their normal littermates do have teratomas. This demonstrates that testicular teratomas are derived from primordial germ cells. PMID- 29112246 TI - Microspectrophotometric DNA measurements of carcinoma-in-situ germ cells in the testis. AB - Early detection of premalignant changes of the testis in at-risk groups seems to be of considerable significance. Hitherto the diagnosis of carcinoma-in-situ testis has been based upon conventional histological techniques. A microspec trophotometric study of the DNA content in Feulgen stained carcinoma-in-situ germ cells of eight infertile men revealed an aneuploid DNA distribution pattern. The results support the assumption that these cells are of malignant nature, and furthermore, the findings indicate that DNA measurements may be of value in discriminating between malignant and non-malignant intra-tubular germ cells in testicular biopsies. PMID- 29112248 TI - Discussion. PMID- 29112247 TI - Human teratocarcinoma cell lines. A review. AB - A review is given of studies on human teratocarcinoma cell lines in culture. A human ovarian teratocarcinoma line (PA-1) has been characterized in detail (Zeuthen et al. 1980) and has been shown to exhibit some properties of human teratocarcinoma stem-cells. This line forms embryoid bodies with a distinct outer cell layer analogous to endodermal cells formed by some mouse teratocarcinoma cell lines, and also is capable of a certain limited differentiation in culture as well as upon transplantation to nude mice. A panel of human testicular teratocarcinoma cell lines has been studied by Andrews et al. (1980): While these cells also share some embryonic characteristics, their differentiation in culture is more limited. Studies of various markers suggest that these lines are equivalent to a pre-blastocyst stage derivation. The PA-1 cell line and possibly two other testicular teratocarcinoma lines could possibly be derived at a stage equivalent to a later stage of development. PMID- 29112249 TI - Discussion. PMID- 29112251 TI - Discussion. PMID- 29112250 TI - Discussion. PMID- 29112252 TI - Carcinoma-in-situ of the testis and invasive growth of different types of germ cell tumours. A revised germ cell theory. AB - The hypothesis is proposed that seminomas and non-seminomas are histogenetically closely related and both types of germ cell tumours may originate from a common precursor cell: namely the germ cell showing the carcinoma-in-situ pattern. However, it is suggested that the spermatocytic seminoma is an exception as it may originate from spermatocytes. PMID- 29112253 TI - Recent advances in detection of metastatic testicular cancer. AB - The recent advances in therapy of testicular cancer have made the early diagnosis and localization of metastases desirable and rewarding. The objectives of this presentation are to describe 1) the utilization of selective venous catheterization of venous outflow from the tumour or organ containing tumour producing minute amounts of alpha subunit or intact molecule of hCG; 2) the utilization of a new liposoluble contrast material that is picked up by the reticuloendothelial system of the liver therefore enhancing the computed tomographic (CT) images of liver metastases for earlier detection compared to the conventional CT images; and 3) the utilization of radioimmunodetection of AFP- and hCG-producing tumours by preparing specific and sensitive radioactive antibody labelled with 131 I, the deposition of which may be localized by conventional scintigraphy. PMID- 29112254 TI - Atypical germ cells in testicular biopsy in male sterility. AB - Of 2178 patients who underwent testicular biopsy for the investigation of male sterility between 1950 and 1979 at Zurich University, 10 cases with atypical germ cells (AGC) could be demonstrated (corresponding to 0.46%). Based on the clinical course, the cases are subdivided in three groups: 1) subsequent development of a testicular germ cell tumour within the period of a few months (2 patients), 2) development of germ cell tumour following a tumour-free interval of several years (2 patients) and 3) no tumour development up to the present (6 patients). The presence of AGC, therefore, is of quite varied significance. The possibilities whether they represent a precancerous lesion, a reactive alteration, intratubular spread of frank tumour cells, or stem cells of all kinds of testicular neoplasms, are discussed. PMID- 29112255 TI - Discussion. PMID- 29112256 TI - Distribution of carcinoma-in-situ in testes from infertile men. AB - Quantitative histologial studies on 4 testes removed because of carcinoma-in-situ (CIS) were performed in order to determine the distribution of CIS within the testis and to estimate the likelihood of diagnosing testicular CIS by biopsy. The CIS changes were distributed in all parts of the testes but were less frequent in the parts adjacent to the epididymis. In the 4 testes examined 1.4 to 599 of the entire testicular volume contained seminiferous tubules with CIS. In parts of the testes where more than approximately 10% of the testicular volume consisted of tubules with CIS all simulated biopsies measuring 3 mm contained the lesion. The same was true for simulated biopsies measuring 1.5 mm when more then approximately 30% of the testicular volume consisted of tubules with CIS. If the distribution of CIS generally is similar to that found in the 4 analysed testes there seems to be a high probability of detecting the disease by one or two testicular biopsies. PMID- 29112257 TI - Discussion. PMID- 29112258 TI - Clinical aspects of testicular carcinoma-in-situ. AB - Carcinoma-in-situ germ cells were demonstrated in testicular biopsies from 9 of 826 patients (1.1%) from a selected group of Danish infertile men. A similar observation was noted in testicular biopsies from 9 Swiss patients (representing 0.55% of the total number of infertile patients biopsied in that study). Such changes were also seen in 8 testicular biopsies from the contralateral testis of 180 patients (4.4%) with carcinoma of the teitis. Moreover, carcinoma-in-situ has beer, found in maldecended testes and in gonads of patients with the testicular feminization syndrome although the incidence of carcinoma-in-situ in these two latter groups is unknown. The malignant potential of carcinoma-in-situ of the testis in infertile men has been clearly demonstrated, whereas its clinical significance in other groups of patients remains to be determined. PMID- 29112259 TI - Discussion. PMID- 29112260 TI - Ultrasound in the detection of testicular tumours. AB - Ultrasonic scanning provides high resolution sectional images of the scrotal content. The value of ultrasound in the detection of testicular tumours is discussed based on the ultrasonic findings in the normal testis as well as the findings in two patients with malignant testicular tumours. PMID- 29112261 TI - Serum and tissue markers of testicular tumours. AB - This article reviews the value of the tumour markers alpha-foetoprotein (AFP) and human chorionic gonadotrophin (hCG) in the management of patients with testicular germ-cell tumours, especially non-seminomatous tumours. Recent developments in their use, such as metabolic decay rate analysis, are discussed. Possible new markers for testicular cancer, particularly SP-1 and placental alkaline phosphatase, are reviewed. PMID- 29112262 TI - Immunohistochemical demonstration of tumour associated antigens in carcinoma-in situ of the testis. AB - Atypical germ cells or so-called carcinoma-in-situ of the testis are often found in the tissue adjacent to germ cell tumours. The present study was performed to investigate if tumour associated antigens demonstrated immunohistochemically in the tumours could also be demonstrated in the carcinoma-in-situ. Using indirect immunoperoxidase technique 39 orchidectomy specimens were examined for the presence of a series of antigens: alpha-foetoprotein (AFP), alpha1 -antitrypsin (A1 AT), human chorionic gonadotrophin (hCG). specific pregnancy beta glycoprotein (SP1 ), human placental lactogen (hPL), carcino-embryonic antigen (CEA) and ferritin (FER). FER was demonstrated in the atypical cells in 24/29 cases of carcinoma-in-situ of the testis. HCG was demonstrated in intratubular syncytiotrophoblast-like cells in one case and in atypical germ cells in another specimen. No staining reaction was found for the other antigens investigated Normal germinal epithelium and germinal epithelium in non-malignant pathological changes of the testis were never stained. These findings which indicate that FER may be a possible marker of carcinoma-in-situ of the testis is of utmost interest, however investigation of a larger series is mandatory. PMID- 29112263 TI - Concluding remarks. PMID- 29112264 TI - Discussion. PMID- 29112265 TI - Discussion. PMID- 29112266 TI - Extra embryonic elements in testicular tumours. AB - Extra embryonic elements in germ cell tumours resemble the trophectoderm or yolk sac endoderm which are the extra embryonic membranes of the developing embryo. True chorionic (trophoblastic) differentiation with syncytiotrophoblast and cytotrophoblast, perhaps with a villous pattern, is rare and is associated with a very poor prognosis and with hCG production. Isolated syncytiotrophoblastic cells also produce hCG but are prognostically less sinister. Yolk sac elements occur in two thirds of non seminomatous germ cell tumours, and affect all age groups. Pure forms of yolk sac tumour (YST) occur but are not common except in infants. They are often associated with AFP production but AFP is not a specific marker for YST. Yolk sac tumours have a similar prognosis to malignant teratoma undifferentiated (MTU: embrvonal carcinoma). PMID- 29112267 TI - The applications of xenografts in the study of human germ cell tumours. AB - Human germ cell tumours have been established as transplantable xenografts in immune suppressed and congenitally athymic animals. This review summarises the current and potential uses of this animal model in the study of these tumours, including the generation of 'human' tumour material for histological, immunocytochemical and ultrastructural analysis, for radio- and chemosensitivity testing, and for the development of new techniques of tumour imaging. PMID- 29112269 TI - Origin and classification of germ cell tumours. PMID- 29112268 TI - Signs and symptoms of adult testicular tumours. AB - Seven per cent of the testicular tumour population of 292 men gave a history of undescended testes, an incidence figure not effected by orchidopexy. The main feature of seminomas (140 patients, median age 44.2 years) was testicular swelling whereas local pain and back pain prevailed in patients with non seminomatous tumours (152 men, median age 29.8 years), although they had a shorter history. In about 25 per cent of cases, the examining physician made an erroneous diagnosis, by confusing the lesion with epididymitis, hydrocele or torsion. The first presenting feature in 16 patients was attributed to metastases and in 5 cases the testicular mass was found incidentally during routine physical examination. PMID- 29112270 TI - Discussion. PMID- 29112271 TI - Discussion. PMID- 29112272 TI - Discussion. PMID- 29112273 TI - Discussion. PMID- 29112274 TI - The origin and classification of testicular germ cell tumours. AB - The histological appearances which must be considered in the differential diagnosis of in situ carcinoma and the interpretation of atypical intratubular cells are discussed. The two areas where new techniques are casting doubts on the validity of existing tumour classification are identified and a plea is made for a prospective study and full correlation of clinical laboratory findings. PMID- 29112276 TI - Discussion. PMID- 29112275 TI - Expression, purification, and characterization of a novel laccase from Setosphaeria turcica in Eschericha coli. AB - Laccases are multicopper oxidases (E.C. 1.10.3.2) that catalyze the oxidation of many phenolic compounds. In this study, a novel laccase, Stlac4, from Setosphaeria turcica was cloned and expressed in Escherichia coli by insertion into the pET-30a expression plasmid. The recombinant laccase was purified and visualized on SDS-PAGE as a single band with an apparent molecular weight of 71.5 KDa, and confirmed by Western blot. The maximum activity of the purified laccase was 127.78 U . mg-1 , the optimum temperature and pH value were 60 degrees C and 4.0 respectively, measured by oxidation of 2,2'-Azinobis-(3-ethylbenzthiazoline-6 sulphonate) (ABTS). Purified laccase activity under different metal ions and an inhibitor were tested, revealing that laccase activity increased by approximately 434.8% with Fe3+ , and 217.4% with Cu2+ at 10 mmol . L-1 concentrations, Mn2+ increased the laccase activity only at 5 mmol . L-1 , while Na+ increased activity at 1 mmol . L-1 but inhibited activity at 5 and 10 mmol . L-1 . SDS increased laccase activity at 1 mmol . L-1 , and inhibited activity at 5 and 10 mmol . L-1 . PMID- 29112277 TI - SDS-PAGE procedure: Application for characterization of new entirely uncharged nucleic acids analogs. AB - SDS-PAGE is considered to be a universal method for size-based separation and analysis of proteins. In this study, we applied the principle of SDS-PAGE to the analysis of new entirely uncharged nucleic acid (NA) analogues, - phosphoryl guanidine oligonucleotides (PGOs). The procedure was also shown to be suitable for morpholino oligonucleotides (PMOs) and peptide nucleic acids (PNAs). It was demonstrated that SDS can establish hydrophobic interactions with these types of synthetic NAs, giving them a net negative charge and thus making these molecules mobile in polyacrylamide slab gels under the influence of an electric field. PMID- 29112278 TI - Cytomegalovirus (CMV) DNA quantification in bronchoalveolar lavage fluid of immunocompromised patients with CMV pneumonia. AB - Cytomegalovirus (CMV) pneumonia causes major morbidity and mortality. Its diagnosis requires demonstration of viral cytopathic changes in tissue, entailing risks of lung biopsy. This study aimed to determine CMV viral load (VL) thresholds in bronchoalveolar lavage fluid (BALF) for diagnosis of CMV pneumonia in immunocompromised patients. CMV VL in BALF was studied in 17 patients (83% transplant recipients) and 21 control subjects with and without CMV pneumonia, respectively, using an FDA-approved PCR assay (Cobas(r) AmpliPrep/Cobas TaqMan(r) CMV Test, Roche Molecular Systems, Inc.) calibrated to the WHO International Standard for CMV DNA (NIBSC: 09/162). Receiver operating characteristic curve analysis produced a BALF CMV VL threshold of 34 800, IU/mL with 91.7% sensitivity and 100.0% specificity for diagnosis of possible, probable, and proven CMV pneumonia in transplant patients, while a threshold of 656 000 IU/mL yielded 100% sensitivity and specificity among biopsy-proven cases. For all immunocompromised patients, a VL threshold of 274 IU/mL was selected. VL thresholds also were normalized to BALF cell count yielding a threshold of 0.32 IU/106 cells with 91.7% sensitivity and 90.5% specificity for possible, probable, and proven CMV pneumonia in transplant recipients. Monitoring CMV VL in BALF may be a less invasive method for diagnosing CMV pneumonia in immunocompromised patients. PMID- 29112279 TI - Nutrients intake, and serum calcium and phosphorus levels: An evidence-based study. AB - INTRODUCTION: Dietary calcium and phosphorus appear to be important determinants of dyslipidemia and hypertension. We have investigated (1) the prevalence of hypocalcemia and hypophosphatemia in an Iranian population, and (2) the association between nutrient's intake and serum levels of calcium and phosphorus. METHODS: A total of 908 individuals were enrolled using a stratified-cluster sampling method from the Mashhad stroke and heart atherosclerosis disorder (MASHHAD) study. Dietplan6 software was used for 24-hour recalls and food frequency questionnaire to investigate macro- and micronutrient intakes of our population, followed by univariate analysis for evaluation of the association of dairy consumption with serum calcium and phosphorus. RESULTS: We observed that the mean dietary Ca intake was 862.4 mg/d (672.7-1052) for men and 864.2 mg/d (604.5-1123) for women in our population, which is lower than the dietary reference intake for Ca. Moreover, a significant relationship was detected between serum calcium level and dietary intakes of saturated fatty acids, copper, iodine, sucrose, potato, and juices. Of note, we observed a negative association between copper intake, and serum Ca (P?.01). Also, a significant association was found between serum phosphorus levels and dietary intakes of chicken meat and fresh fruits. Interestingly, we observed an inverse relationship between tea and Ca/P ratio (eg, -r=.098; P=.02). CONCLUSION: We found that the dietary intake of Ca was not sufficient in our population and was associated with the dietary intake of some macro- and micronutrient, supporting further investigation on clinical impact of this condition on calcium/phosphorus deficiency related diseases. PMID- 29112281 TI - Effects of increased apical enlargement on the amount of unprepared areas and coronal dentine removal: a micro-computed tomography study. AB - AIM: To evaluate the effects of progressive apical enlargement on the amount of unprepared root canal surface area and remaining dentine thickness. METHODOLOGY: The root canals of 30 extracted mandibular incisors with Vertucci's type I configuration were instrumented with rotary HyFlex CM instruments (Coltene Whaledent, Altstatten, Switzerland) up to 4 instruments larger than the first one that bound at the working length (WL). Teeth were scanned in a micro-computed tomography (micro-CT) device before canal preparation and after instrumentation with the 2nd, 3rd and 4th larger instruments. The amount of unprepared surface area in the full canal or in the apical 4 mm as well as the remaining dentine thickness at 10 mm from the WL were calculated and compared. The general linear model for repeated measures adjusted by Bonferroni's post hoc test was used for statistic analysis. RESULTS: There was a significant reduction in the amount of unprepared areas after each increase in preparation size (P < 0.01). This was observed for both the full canal length and the 4-mm apical segment. The amount of remaining dentine was also significantly reduced after each file size (P < 0.01). However, dentine thickness always remained greater than 1 mm, even after using the largest instrument. CONCLUSION: Apical preparations up to 4 instruments larger than the first one to bind at the WL caused a significant progressive reduction in the unprepared canal area. PMID- 29112280 TI - Characterization and correlates of exercise among adolescents with anorexia nervosa and bulimia nervosa. AB - OBJECTIVE: To characterize exercise behaviors among adolescents with anorexia nervosa (AN), atypical AN, or bulimia nervosa (BN), and determine associations between exercise and medical risk. STUDY DESIGN: Cross-sectional electronic medical records of all patients evaluated by the Eating Disorder Program at Stanford between January 1997 and February 2011 were retrospectively reviewed. RESULTS: 1,083 subjects (961 females, 122 males; mean age 15.6) met eligibility criteria. Most patients (89.7%) reported exercise (mean 7.0 h per week over mean 5.4 days per week) prior to presentation. Running (49.9%), calisthenics (40.7%), walking (23.4%), soccer (20.9%), and swimming (18.2%) were the most common exercises; a majority (60.6%) reported team sport participation. Males were less likely to report team exercise (p = .005). Bradycardia (heart rate <50) at presentation was associated with team sport participation (adjusted odds ratio [AOR] 1.66, 95% confidence interval [CI] 1.02-2.72) and hours of exercise per week (AOR 1.05, 95% CI 1.02-1.09), controlling for diagnosis, sex, age, duration of illness, rate of weight loss, and percent median body mass index (%mBMI). DISCUSSION: Adolescents with AN, atypical AN, and BN reported high levels of exercise. Females reported more team sport participation. Greater exercise frequency and team sport participation were associated with bradycardia. Further studies assessing the relationship between exercise and bradycardia may help inform the medical management of adolescents with these eating disorders who are more physically active. PMID- 29112282 TI - Antifungals discovery: an insight into new strategies to combat antifungal resistance. AB - : Undeniably, new antifungal treatments are necessary against pathogenic fungi. Fungal infections have significantly increased in recent decades, being highlighted as important causes of morbidity and mortality, particularly in immunocompromised patients. Five main antifungal classes are used: (i) azoles, (ii) echinocandins, (iii) polyenes, (iv) allylamines and (v) pyrimidine analogues. Moreover, the treatment of mycoses has several limitations, such as undesirable side effects, narrow activity spectrum, a small number of targets and fungal resistance, which are still of major concern in clinical practice. The discovery of new antifungals is mostly achieved by the screening of natural or synthetic/semisynthetic chemical compounds. The most recent discoveries in drug resistance mechanism and their avoidance were explored in a review, focusing on different antifungal targets, as well as new agents or strategies, such as combination therapy, that could improve antifungal therapy. SIGNIFICANCE AND IMPACT OF THE STUDY: The failure to respond to antifungal therapy is complex and is associated with microbiological resistance and increased expression of virulence in fungal pathogens. Thus, this review offers an overview of current challenges in the treatment of fungal infections associated with increased antifungal drug resistance and the formation of biofilms in these opportunistic pathogens. Furthermore, the most recent and potential strategies to combat fungal pathogens are explored here, focusing on new agents as well as innovative approaches, such as combination therapy between antifungal drugs or with natural compounds. PMID- 29112283 TI - The pretreatment neutrophil-lymphocyte ratio may predict prognosis of patients with liver cancer: A systematic review and meta-analysis. AB - BACKGROUND: At present, several studies have reported that the pretreatment neutrophil-lymphocyte ratio (NLR) may be associated with the prognosis of liver cancer. Nevertheless, their conclusions remain controversial. Thus, we performed a meta-analysis of 54 studies to evaluate the prognostic value of NLR. METHOD: Databases including PubMed, Embase, Cochrane Library, and Web of Science were searched to July 2017. RESULT: A total of 54 studies including 12 979 patients were included in this meta-analysis. Elevated NLR had a close relationship with the overall survival (OS) (HR 1.52; 95% CI 1.39-1.67), recurrence-free survival (RFS) (HR 1.84; 95% CI 1.48-2.30), and disease-free survival (DFS) (HR 1.71; 95% CI 1.39-2.11) of liver cancer, respectively. In addition, elevated NLR was associated with the presence of tumor vascular invasion (OR 2.35; 95% CI 1.93 2.86), multiple tumors (OR 1.38; 95% CI 1.15-1.66), alpha-fetoprotein >= 400 ng/mL (OR 1.51; 95% CI 1.15-1.98), presence of HbsAg (+) (OR 0.68; 95% CI 0.51 0.90), and cirrhosis (OR: 0.59; 95% CI 0.44-0.80). CONCLUSION: This meta-analysis indicated that elevated NLR may be an effective and noninvasive indicator for prognosis of patients with liver cancer. PMID- 29112284 TI - Morphological and cellular diversity of magnetotactic bacteria: A review. AB - Magnetotactic bacteria (MTB) are getting much attention in the recent years due to the biomineralization in their magnetosomes (MS). MS are unique organelles that are bio-mineralized due to MTB. MS contains nanosized crystal minerals of magnetite or greigite covered by bilayer lipid membrane, which are originated from cytoplasmic membrane (CM). MS are organized as an ordered chain into the cell which acts as a miniature compass needle. Furthermore, the biodiversity of MTB and their distribution is principally linked with the characteristics and growths of the MS. MTB are often considered as a part of the bacterial biomass from all of the aquatic environments. There have been a lot of genes that control the functions of MTB by accumulating as clusters of genomes such as magnetosomes genomic island (MAI). Therefore, in the present review, the function of the genes and proteins has been highlighted, which are mainly associated with the construction and formation of MS. In addition, the biodiversity, morphology and cell biology of MTB is discussed in greater detail to understand the formation of MS crystals by MTB. PMID- 29112286 TI - President's Message: A journey well traveled. PMID- 29112285 TI - Alcohol-Induced Impairment of Balance is Antagonized by Energy Drinks. AB - BACKGROUND: The acute administration of alcohol reliably impairs balance and motor coordination. While it is common for consumers to ingest alcohol with other stimulant drugs (e.g., caffeine, nicotine), little is known whether prototypical alcohol-induced balance impairments are altered by stimulant drugs. The purpose of this study was to examine whether the coadministration of a high-caffeine energy drink with alcohol can antagonize expected alcohol-induced increases in body sway. METHODS: Sixteen social drinkers (of equal gender) participated in 4 separate double-blind dose administration sessions that involved consumption of alcohol and energy drinks, alone and in combination. Following dose administration, participants completed automated assessments of balance stability (both eyes open and eyes closed) measured using the Biosway Portable Balance System. Participants completed several subjective measures including self reported ratings of sedation, stimulation, fatigue, and impairment. Blood pressure and pulse rate were recorded repeatedly. RESULTS: The acute administration of alcohol increased body sway, and the coadministration of energy drinks antagonized this impairment. When participants closed their eyes, alcohol induced body sway was similar whether or not energy drinks were ingested. While alcohol administration increased ratings of sedation and fatigue, energy drink administration increased ratings of stimulation and reduced ratings of fatigue. Modest increases in systolic and diastolic blood pressure following energy drink administration were also observed. CONCLUSIONS: Visual assessment of balance impairment is frequently used to indicate that an individual has consumed too much alcohol (e.g., as part of police-standardized field sobriety testing or by a bartender assessing when someone should no longer be served more alcohol). The current findings suggest that energy drinks can antagonize alcohol-induced increases in body sway, indicating that future work is needed to determine whether this observation regarding neuromotor functioning applies to alcohol in combination with all types of stimulant drugs. PMID- 29112287 TI - Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors. AB - Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore, there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the synthesis and characterization of ten benzyl benzamides 8a-j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a percent inhibition of 82.2% at 10 MUM concentration and an IC50 value of 1.3 MUM. The docking study shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by a hydrophobic lining. Furthermore, the scaffold of 8a-j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities. PMID- 29112290 TI - Discussion. PMID- 29112288 TI - A preliminary study of momentary, naturalistic indicators of binge-eating episodes in adults with obesity. AB - OBJECTIVES: Binge eating is common in adults with obesity. The Diagnostic and Statistical Manual for Psychiatric Disorders describes five indicators of binge eating (eating more rapidly than usual; eating until uncomfortably full; eating large amounts of food when not physically hungry; eating alone because of embarrassment over how much one is eating; and feeling disgusted with oneself, depressed, or very guilty after overeating), but their validity is unclear. METHOD: We examined preliminary associations between the five indicators and binge versus nonbinge episodes among 50 adults with obesity via ecological momentary assessment. RESULTS: Generalized linear models revealed that, relative to nonbinge episodes, self-reported binge episodes were associated with lower pre episode hunger (p = .004), higher postepisode fullness (p < .001), a greater likelihood of reporting moderate to extreme shame prior to eating in conjunction with eating alone (p < .001), and a greater likelihood of reporting moderate to extreme disgust, depression, and/or guilt after eating (p < .001), but not with eating more rapidly than usual (p = .85). DISCUSSION: Results support the validity of most binge-eating indicators, although the utility of the rapid eating criterion is questionable. Future research should examine whether modifying these indicators in binge-eating interventions would reduce the occurrence of loss of control and/or overeating. PMID- 29112289 TI - Pharmacokinetics of intravenous lithium chloride and assessment of agreement between two methods of lithium concentration measurement in the horse. AB - BACKGROUND: Pharmacokinetics of lithium chloride (LiCl) administered as a bolus, once i.v. have not been determined in horses. There is no point-of-care test to measure lithium (Li+ ) concentrations in horses in order to monitor therapeutic levels and avoid toxicity. OBJECTIVES: To determine the pharmacokinetics of LiCl in healthy adult horses and to compare agreement between two methods of plasma Li+ concentration measurement: spectrophotometric enzymatic assay (SEA) and inductively coupled plasma mass spectrometry (ICP-MS). STUDY DESIGN: Nonrandomised, single exposure with repeated measures over time. METHODS: Lithium chloride was administered (0.15 mmol/kg bwt) as an i.v. bolus to eight healthy adult horses. Blood samples were collected pre-administration and at multiple times until 48 h post-administration. Samples were analysed by two methods (SEA and ICP-MS) to determine plasma Li+ concentrations. Pharmacokinetics were determined based on the reference ICP-MS data. RESULTS: Adverse side effects were not observed. The SEA showed linearity, R2 = 0.9752; intraday coefficient of variation, 2.5%; and recovery, 96.3%. Both noncompartmental and compartmental analyses (traditional two-stage and nonlinear mixed-effects [NLME] modelling) were performed. Geometric mean values of noncompartmental parameters were plasma Li+ concentration at time zero, 2.19 mmol/L; terminal elimination half-life, 25.68 h; area under the plasma concentration-time curve from time zero to the limit of quantification, 550 mmol/L min; clearance, 0.273 mL/min/kg; mean residence time, 31.22 h; and volume of distribution at steady state, 511 mL/kg. Results of the traditional two-stage analysis showed good agreement with the NLME modelling approach. Bland-Altman analyses demonstrated poor agreement between the SEA and ICP-MS methods (95% limits of agreement = 0.14 +/- 0.13 mmol/L). MAIN LIMITATIONS: Clinical effects of LiCl have not been investigated. CONCLUSIONS: The LiCl i.v. bolus displayed pharmacokinetics similar to those reported in other species. The SEA displayed acceptable precision but did not agree well with the reference method (ICP-MS). The Summary is available in Spanish - see Supporting Information. PMID- 29112292 TI - A kit ligand, stem cell factor as a possible mediator inducing overactive bladder. AB - OBJECTIVE: To investigate whether c-kit ligand, stem cell factor (SCF) affects the biological behavior of overactive bladder (OAB) and discuss the role of SCF as a possible mediator inducing OAB. MATERIALS AND METHODS: First, we performed an immunohistochemical study to examine the localization of SCF in the guinea pig and human bladder. Next, urinary SCF levels were measured in patients with OAB and in control subjects to evaluate a potential biomarker for the diagnosis of OAB. Third, we examined the effect of SCF administration on the urinary bladder using guinea pigs to obtain additional information about SCF. The animals were administered with mouse SCF, and cystometry was performed. The following urodynamic parameters were analyzed: inter-contraction interval, maximum voiding pressure, pressure threshold, detrusor baseline pressure, and the number of non voiding contractions. RESULTS: Immunohistochemical study showed that the expression of SCF was observed throughout the bladder wall, but especially in the urothelium of guinea pig and human bladder. Medians and IQRs of urinary SCF and SCF/creatinine levels in OAB patients (85.9 pg/mL [42.8, 199.0] and 1.30 [0.56, 2.71], respectively) were significantly higher than in control subjects (18.9 pg/mL [5.0, 43.6] and 0.26 [0.13, 0.43], respectively). SCF administration dose dependently shortened the intercontraction interval and an increased number of non-voiding contractions (P < 0.05). CONCLUSIONS: Our present data suggest that SCF produced in the urinary bladder may act as a possible mediator by binding to c-kit, which is expressed in ICC-like cells in the suburothelial and muscle layers, to control bladder function. PMID- 29112293 TI - Foreword. PMID- 29112294 TI - Internal funding required to improve HIV care. PMID- 29112295 TI - Cell surface molecules of human teratoma cell lines. AB - Conventional antisera, monoclonal antibodies and lectins have been used to investigate the cell surface composition of several human teratoma-derived cell lines. This review summarizes our current knowledge obtained from such investigations and uses the information available on murine teratocarcinoma systems as a framework for discussion to compare and contrast the human and murine systems. The potential application of antibodies directed against cell surface molecules in such techniques as in vivo tumour imaging and drug targeting is also discussed. PMID- 29112296 TI - Live Faecalibacterium prausnitzii induces greater TLR2 and TLR2/6 activation than the dead bacterium in an apical anaerobic co-culture system. AB - Inappropriate activation of intestinal innate immune receptors, such as toll-like receptors (TLRs), by pathogenic bacteria is linked to chronic inflammation. In contrast, a "tonic" level of TLR activation by commensal bacteria is required for intestinal homeostasis. A technical challenge when studying this activation in vitro is the co-culturing of oxygen-requiring mammalian cells with obligate anaerobic commensal bacteria. To overcome this, we used a novel apical anaerobic co-culture system to successfully adapt a TLR activation assay to be conducted in conditions optimised for both cell types. Live Faecalibacterium prausnitzii, an abundant obligate anaerobe of the colonic microbiota, induced higher TLR2 and TLR2/6 activation than the dead bacterium. This enhanced TLR induction by live F. prausnitzii, which until now has not previously been described, may contribute to maintenance of gastrointestinal homeostasis. This highlights the importance of using physiologically relevant co-culture systems to decipher the mechanisms of action of live obligate anaerobes. PMID- 29112298 TI - MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer's disease. AB - AIM: Despite continuing research into Alzheimer's disease (AD), its pathological mechanisms and modulating factors remain unknown. Several genes influence AD pathogenesis by affecting inflammatory pathways. Myocyte-enhancer factor 2C (MEF2C) is one such candidate gene for AD. METHODS: We examined MEF2C mRNA expression levels and methylation rates of CpG on its promoter region in peripheral leukocytes from Japanese AD patients compared with age- and sex matched control subjects. RESULTS: In peripheral leukocytes, MEF2C mRNA expression levels in AD subjects were significantly lower than those in control subjects (0.86 +/- 0.25 vs 0.99 +/- 0.27, respectively, P = 0.007) and were correlated with the Alzheimer's Disease Assessment Scale (r = -0.345, P = 0.049) and the Mini Mental State Examination (r = 0.324, P = 0.02). No significant differences were found in methylation rates between AD and control subjects. CONCLUSION: MEF2C mRNA expression in leukocytes may be a biological marker for cognitive decline in AD. PMID- 29112297 TI - Longitudinal analyses of adoptive parents' expectations and depressive symptoms. AB - Grounded in a theoretical model specific to adoptive parents, we examined the relationship between parental expectations and depressive symptoms across time. Assessments of 129 adoptive parents of 64 children were performed at three time points before and after placement of an adopted child with the family: 4-6 weeks pre-placement and 4-6 weeks and 5-6 months post-placement. Expectations were assessed in four dimensions: expectations of self as parents, of the child, of family and friends, and of society. Depressive symptoms were assessed with the Center for Epidemiologic Studies-Depression scale. Associations between parental expectations and depressive symptoms were analyzed, and longitudinal multilevel modeling was conducted to explore influences on expectations over time. Parental expectations changed from pre- to post-placement. With the exception of expectations of self as parent, adoptive parents' pre-adoption expectations were affirmed in the post-adoption time periods. In each expectation dimension, higher affirmation of expectations was correlated with decreased depressive symptoms before and after placement of a child. While parental expectations are not unique to adoptive parents, the essence and characteristics of certain expectations are unique to these parents. When working with adoptive parents, nurses who care for families should assess expectations both pre- and post-placement with awareness of their relationship to depressive symptoms. PMID- 29112299 TI - Activation of lpxR gene through enterohaemorrhagic Escherichia coli virulence regulators mediates lipid A modification to attenuate innate immune response. AB - During the course of infection, pathogens must overcome a variety of host defence systems. Modulation of lipid A, which is a strong stimulant for host immune systems, is one of the strategies used by microorganisms to evade the host response. The lpxR gene, which encodes a lipid A 3'-O-deacylase, is commonly found in several pathogens and has been shown to reduce the inflammatory response. Here, we demonstrated that the lpxR gene of enterohaemorrhagic Escherichia coli (EHEC) was positively regulated by two virulence regulators, Pch and Ler, and that this regulation was coordinated with the locus of enterocyte effacement genes, which encode major virulence factors for colonisation. The lpxR promoter was repressed by the binding of H-NS, but the competitive binding of both regulators resulted in transcription activation. Next, we showed that lipid A from the lpxR mutant was more stimulatory of the inflammatory response in macrophage-like cells than lipid A from wild-type EHEC. Furthermore, phagocytic activity and phagosome maturation in host cells infected with the lpxR mutant were increased in a p38 mitogen-activated protein kinase-dependent manner in comparison with wild-type EHEC infection. Finally, we demonstrated that the pch mutant, which is deficient in activation of the locus of enterocyte effacement genes, was phagocytised more efficiently than the wild type. Thus, EHEC modulates lipid A to dampen the host immune response when activating virulence genes for colonisation. PMID- 29112300 TI - Enantioselective and Collective Total Syntheses of Xanthanolides. AB - An enantioselective synthesis of (+)-8-epi-xanthatin hinging on a chiral phosphoric acid catalyzed tandem allylboration/lactonization reaction is reported. With (+)-8-epi-xanthatin as the precursor, the collective synthesis of a series of synthetically challenging xanthanolides was also accomplished. Among them, xanthipungolide, one of the most complex xanthanolide monomers, was accessed through a bioinspired tandem double-bond isomerization/6pi electronic cyclization/intramolecular Diels-Alder reaction, and pungiolides A, B, D, E, and L-N, a group of xanthanolide dimers, were assembled through a bioinspired Diels Alder dimerization followed by late-stage diversification. PMID- 29112301 TI - Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin-induced eIF4E activation. AB - Activation of eukaryotic translation initiation factor 4E (eIF4E) is a cellular survival mechanism in response to chemotherapy in cancers. In this work, we demonstrate that targeting eIF4E by ribavirin sensitizes hepatocellular carcinoma (HCC) cell response to doxorubicin. Ribavirin inhibits growth and survival of HCC cells, and to a greater extent than in normal liver cells. Its combination with doxorubicin achieves greater efficacy than single drug in vitro and in vivo. Ribavirin suppresses phosphorylation of molecules involved in Akt/mTOR/eIF4E pathway. Overexpression of the phosphomimetic form (S209D) but not the nonphosphorylatable form (S209A) eIF4E significantly reverses the inhibitory effects of ribavirin. Interestingly, doxorubicin significantly increases p eIF4E(S209) level in a dose- and time-dependent manner, suggesting that doxorubicin induces eIF4E activation in HCC cells. In addition, eIF4E activation induced by doxorubicin in HCC cells is inhibited by ribavirin. Our work demonstrates the greater efficacy of ribavirin and doxorubicin combination and its underlying mechanisms. PMID- 29112302 TI - TMD1 domain and CRAC motif determine the association and disassociation of MxIRT1 with detergent-resistant membranes. AB - Iron is essential for most living organisms. The iron-regulated transporter1 (IRT1) plays a major role in iron uptake in roots, and its trafficking from endoplasmic reticulum (ER) to plasma membrane (PM) is tightly coordinated with changes in iron environment. However, studies on the IRT1 response are limited. Here, we report that Malus xiaojinesis IRT1 (MxIRT1) associates with detergent resistant membranes (DRMs, a biochemical counterpart of PM microdomains), whereas the PM microdomains are known platforms for signal transduction in the PM. Depending on the shift of MxIRT1 from microdomains to homogeneous regions in PM, MxIRT1-mediated iron absorption is activated by the cholesterol recognition/interaction amino acid consensus (CRAC) motif of MxIRT1. MxIRT1 initially associates with DRMs in ER via its transmembrane domain 1 (TMD1), and thus begins DRMs-dependent intracellular trafficking. Subsequently, MxIRT1 is sequestered in COPII vesicles via the ER export signal sequence in MxIRT1. These studies suggest that iron homeostasis is influenced by the CRAC motif and TMD1 domain due to their determination of MxIRT1-DRMs association. PMID- 29112303 TI - Isomerisation of Liquid-Crystalline Tristriazolotriazines. AB - Star-shaped discotic liquid crystals with columnar superstructures constitute a highly interesting class of organic materials. Phenyl-substituted tris[1,2,4]triazolo-[1,3,5]triazine, prepared by a Huisgen reaction of phenyltetrazole and cyanuric chloride, represents an excellent core for discotic liquid crystals (DLCs). The thermal stability is not perfect, at temperatures above the clearing point, a successive threefold isomerization leads to a highly planar, C3 -symmetrical isomer, which mainly differs in the orientation of the aryl substituents to the centre of the molecule. A new class of discotic liquid crystals has been obtained: Equipped with peripheral alkoxy chains both isomers can form broad thermotropic mesophases. The optical, thermal, and physical properties were investigated by polarized optical microscopy, differential scanning calorimetry, wide-angle X-ray scattering, UV/Vis absorption and fluorescence spectroscopic measurements. The thermotropic properties are decisively affected by the molecular structure of the isomers, isomerisation leads to higher melting points but also the loss or even gain of mesomorphism is observed. PMID- 29112304 TI - The benefits of hepatitis C virus cure: Every rose has thorns. AB - To examine mid-term benefits on hepatic complications, extrahepatic clinical syndromes and quality of life associated with HCV cure; to review the few safety issues linked to oral direct-acting antivirals (DAAs); and to discuss the potential population benefits of reducing the burden of HCV infection. DAAs cure HCV infection in more than 95% of patients. The halting of liver inflammation and fibrosis progression translates into both hepatic and extrahepatic benefits and reduces the need for liver transplantation. A reduction in the frequency of extrahepatic manifestations such as mixed cryoglobulinaemia and vasculitis and improvements in quality of life and fatigue have also been described. A few safety issues linked to DAAs such as the potential recurrence of aggressive HCC, the flares of hepatitis B virus in patients with overt or occult HBV infection are been discussed. Curing HCV infection also has a high potential to reduce the burden of HCV infection at the population level. With widespread scaling up of HCV treatment, several modeling studies suggest that major reductions in HCV prevalence and incidence are possible, and that elimination of viral hepatitis is an achievable target by 2030. PMID- 29112305 TI - Diflunisal in the Treatment of the Pain of Osteoarthritis Summary of Clinical Studies. AB - In comprehensive clinical studies, diflunisal - a new nonsteroidal antiinflammatory drug with a long duration of action - was shown to be highly effective and generally well tolerated in the short- and long-term treatment of the pain of osteoarthritis. In double-blind comparison studies, diflunisal was comparable in efficacy to aspirin and better tolerated. In a separate study with ibuprofen, 800 to 1,200 mg daily (manufacturer's present recommended dose, 900 to 2,400 mg daily), diflunisal, 500 to 750 mg daily, was more effective and comparable in tolerability. Diflunisal had a longer duration of action, requiring only twice-a-day dosage. PMID- 29112306 TI - Comparison of Fecal Blood Loss after Use of Aspirin and Diflunisal. AB - Diflunisal 1,000 mg/day, aspirin 4.0 g/day, or placebo were given to 36 healthy volunteers for 14 days to determine fecal blood loss. There was a significant increase in fecal blood loss from baseline in the aspirin group compared to both the diflunisal and placebo groups. A slight but significant increase in fecal blood loss in the diflunisal group at Week 1 was reported; however, there was no significant increase at Week 2. Use of diflunisal was not associated with any consistent blood loss or serious adverse reactions. PMID- 29112307 TI - Effects of Diflunisal on Platelet Function and Fecal Blood Loss. AB - The effects of diflunisal, a nonacetylated difluorinated salicylate, on platelet function were compared with those of aspirin and placebo. In a randomized, double blind trial, normal subjects were given diflunisal, 250, 500, or 1,000 mg twice daily; aspirin, 650 or 1,300 mg twice daily; or placebo for 8-day periods. Diflunisal, 250 mg, had no effect on platelet function, whereas 500 mg induced minimal inhibition of collagen-induced release of platelet serotonin, and 1,000 mg inhibited platelet malondialdehyde production, moderately prolonged template bleeding times (p = NS), and increased fecal blood loss (p < 0.05). In contrast, aspirin, 650 mg, markedly inhibited collagen-induced platelet aggregation and serotonin release, and 1,300 mg prolonged bleeding time (p < 0.01) and increased fecal blood loss (p < 0.01). The effects of aspirin lasted for up to 5 days, whereas changes induced by diflunisal had returned to baseline 24 hours after the drug was discontinued. We conclude that in doses in the same range as those of aspirin diflunisal inhibits platelet function less. PMID- 29112308 TI - A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Acetaminophen, an Acetaminophen-Codeine Combination, and Placebo in Postoperative Pain. AB - The analgesic efficacy of single 500 and 1,000 mg doses of diflunisal, a new nonsteroidal antiinflammatory analgesic, was compared in a double-blind study with acetaminophen 600 mg, the combination of acetaminophen 600 mg with codeine 60 mg, and placebo in 132 inpatients with postoperative pain. Using a self-rating record, patients rated their pain and its relief hourly for up to 12 hours after medication. Diflunisal 500 and 1,000 mg were significantly superior to placebo for every measure of total and peak analgesia, and a significant analgesic effect persisted for 8 hours. Acetaminophen alone and the acetaminophen-codeine combination were significantly superior to placebo for most measures of analgesia, and their effects were significant for 4 and 5 hours respectively. Differences among the active medications were not statistically significant for measures of total or peak analgesia. PMID- 29112309 TI - Chemical and Pharmacological Properties of Diflunisal. AB - Diflunisal, 5-(2',4'-difluorophenyl) salicylic acid, was discovered as a potent antiinflammatory analgesic agent after an extensive investigation of more than 500 salicylic acid analogs. The addition of a difluorophenyl substituent at the C5 position of salicylic acid yielded a new molecule with much improved lipophilicity, a longer duration of action, and a molecular configuration that is optimal for greater antiinflammatory and analgesic activities. The difluorophenyl group is metabolically stable; the acyl and phenolic glucuronides of the intact diflunisal are major urinary metabolites. The absence of an O-acetyl group in this novel salicylate analog circumvents the well-known in vivo acylation potential of aspirin and renders diflunisal a reversible cyclooxygenase inhibitor with a secondary oxygen radical scavenging effect. In a variety of analgesic, acute, and chronic antiinflammatory models, diflunisal is active at 10 mg/kg, approximately 5 to 10 times more potent than aspirin. It has a relatively low potential to cause gastrointestinal irritation as indicated by the lack of acute effect on the integrity of gastric mucosal barrier, no change of intragastric potential, and no disturbance of prostaglandin production by the gastric tissue. Diflunisal holds promise as a new clinically useful analgesic and antiinflammatory drug with good tolerance and a long duration of action. PMID- 29112310 TI - A Method for the 12-Hour Evaluation of Analgesic Efficacy in Outpatients with Postoperative Oral Surgery Pain: Three Studies of Diflunisal. AB - We have developed a method for measuring the efficacy of a single dose of an analgesic for 12 hours after administration to outpatients with postoperative oral surgery pain. Using a self-rating record, patients evaluate their pain and its relief for 12 hours after medication. We have used this method successfully in a series of three studies to compare diflunisal, a new nonsteroidal antiinflammatory analgesic, with placebo and aspirin 650 mg, acetaminophen 600 mg, propoxyphene napsylate 100 mg, or a combination of acetaminophen with either codeine 60 mg or propoxyphene 100 mg. Diflunisal evinced an unusually long duration of analgesic effect. In each study, all doses of diflunisal were significantly superior to placebo through the end of the 12-hour observation period, while the standards were superior for periods ranging from 2 to 7 hours. In terms of peak analgesia, diflunisal 1,000 mg was comparable to the acetaminophen-codeine combination and was significantly superior to all the other analgesic standards. PMID- 29112311 TI - A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Zomepirac Sodium, Aspirin, and Placebo in Postoperative Oral Surgery Pain. AB - One hundred ninety-nine outpatients with pain following oral surgery were randomly assigned, on a double-blind basis, a single oral dose of diflunisal (500 or 1,000 mg), zomepirac sodium 100 mg, aspirin 650 mg, or placebo. Using a self rating record, subjects rated their pain and its relief hourly for 12 hours after medication. Measures of total and peak analgesia were derived from these patients' subjective reports. Diflunisal (500 and 1,000 mg) and zomepirac were significantly superior to aspirin and placebo for every measure of total and peak analgesia. Based upon the first 4 hours of observation, aspirin was superior to placebo for every measure of analgesia. Diflunisal 500 and 1,000 mg were comparable to zomepirac in peak analgesia and significantly superior to zomepirac for all measures of total analgesia. The onset of analgesia was comparable for 1,000 mg diflunisal, zomepirac, and aspirin, but more rapid for these treatments than for 500 mg diflunisal. The duration of analgesia was 12 hours for diflunisal, 9 hours for zomepirac, and 3 hours for aspirin. PMID- 29112312 TI - Review of the Animal and Clinical Pharmacology of Diflunisal. AB - Diflunisal is a new salicylic acid derivative identified after a search for a compound with improved potency, enhanced gastrointestinal tolerance relative to its antiinflammatory activity, and a longer duration of action than that of aspirin. Animal and clinical studies have confirmed these properties. As an inhibitor of cyclooxygenase tested in vitro in a sheep seminal vesicle preparation, diflunisal was less potent than indomethacin but 10 to 20 times more active than aspirin. In addition, it was shown biochemically to act as a moderate free radical scavenger. Diflunisal is well absorbed from the gastrointestinal tract, is subject to dose-dependent pharmacokinetics (like aspirin), and reaches steady-state levels in a predictable fashion in most persons. The drug is excreted by the kidneys, and its apparent half-life is lengthened in the presence of renal failure. A number of drug interactions have been described. Diflunisal produces reversible effects on platelet aggregation when given in high doses, whereas aspirin produces irreversible aggregation at low doses. Measurements of fecal blood loss and endoscopic examinations have confirmed the improved gastrointestinal tolerance of diflunisal compared to aspirin. PMID- 29112313 TI - President's letter November 2017. PMID- 29112314 TI - Interfering with DNA High-Order Structures using Chiral Ruthenium(II) Complexes. AB - In this work, it was found that DNA can undergo B-Z transformational changes and compaction in the presence of DNA intercalators such as ruthenium(II) polypyridyl complexes. The link between B-Z transition and condensation is weak but can be strengthened under certain circumstances with slight alterations to the structures of the ruthenium(II) complexes. Here, following on from previous research, this work reports a series of ruthenium(II) complexes with imidazophenanthroline ligands, which vary in size and planarity. The complexes exhibit distinct effects on DNA structures, ranging from little impact to the transformation of DNA secondary structures to the formation of higher-order DNA structures. Further studies on DNA morphological changes induced by chiral ruthenium(II) complexes are observed by atomic force microscopy and transmission electron microscopy. PMID- 29112315 TI - Reverse double inversion-recovery: Improving motion robustness of cardiac T2 weighted dark-blood turbo spin-echo sequence. AB - BACKGROUND: Cardiac dark-blood turbo spin-echo (TSE) imaging is sensitive to through-plane motion, resulting in myocardial signal reduction. PURPOSE: To propose and validate reverse double inversion-recovery (RDIR)-a dark-blood preparation with improved motion robustness for the cardiac dark-blood TSE sequence. STUDY TYPE: Prospective. POPULATION: Healthy volunteers (n = 10) and patients (n = 20). FIELD STRENGTH: 1.5T (healthy volunteers) and 3T (patients). ASSESSMENT: Compared to double inversion recovery (DIR), RDIR swaps the two inversion pulses in time and places the slice-selective 180 degrees in late diastole of the previous cardiac cycle to minimize slice misregistration. RDIR and DIR were performed in the same left-ventricular basal short-axis slice. Healthy subjects were imaged with two preparation slice thicknesses, 110% and 200%, while patients were imaged using a 200% slice thickness only. Images were assessed quantitatively, by measuring the myocardial signal heterogeneity and the extent of dropout, and also qualitatively on a 5-point scale. STATISTICAL TESTS: Quantitative and qualitative data were assessed with Student's t-test and Wilcoxon signed-rank test, respectively. RESULTS: In healthy subjects, RDIR with 110% slice thickness significantly reduced signal heterogeneity in both the left ventricle (LV) and right ventricle (RV) (LV: P = 0.006, RV: P < 0.0001) and the extent of RV dropout (P < 0.0001), while RDIR with 200% slice thickness significantly reduced RV signal heterogeneity (P = 0.001) and the extent of RV dropout (P = 0.0002). In patients, RDIR significantly reduced RV myocardial signal heterogeneity (0.31 vs. 0.43; P = 0.003) and the extent of RV dropout (24% vs. 46%; P = 0.0005). LV signal heterogeneity exhibited a trend towards improvement with RDIR (0.12 vs. 0.16; P = 0.06). Qualitative evaluation showed a significant improvement of LV and RV visualization in RDIR compared to DIR (LV: P = 0.04, RV: P = 0.0007) and a significantly improved overall image quality (P = 0.03). DATA CONCLUSION: RDIR TSE is less sensitive to through-plane motion, potentiating increased clinical utility for black-blood TSE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1498-1508. PMID- 29112316 TI - A modified dose-response model that describes the relationship between haemagglutination inhibition titre and protection against influenza infection. AB - AIMS: Develop a model for quantifying the risk of an adverse human response to influenza virus infection as a function of exposure dose and pre-exposure antibody titre level. METHODS AND RESULTS: We evaluated the relationship between haemagglutination inhibition (HI) titre (as a measure of specific antibody response) and protection against influenza infection and modelled this relationship by incorporating HI titre as a variable into dose-response models. Using a maximum likelihood estimation approach, the resulting model was capable of providing statistically acceptable fits to most available data. CONCLUSIONS: The incorporated HI titre dependency in the model quantifies the protective effect of antibody titre. The modelling can be used to predict the protection effectiveness associated with elevated HI titre levels post vaccination to different levels of exposures. SIGNIFICANCE AND IMPACT OF THE STUDY: The study incorporates HI titre level as a variable into a dose-response model for influenza infection. The approaches developed in this study could be used to evaluate other factors associated with the predictability of HI titre or other surrogate endpoints for influenza vaccines. PMID- 29112317 TI - "Prostate cancer is far more hidden...": Perceptions of stigma, social isolation and help-seeking among men with prostate cancer. AB - The purpose of this study was to provide in-depth insight into men's experiences of prostate cancer, specifically: perceived stigma and self-blame, social isolation, unmet need and help-seeking. A qualitative descriptive approach was used. Semi-structured interviews were undertaken with 20 men diagnosed with prostate cancer, and thematic analysis was undertaken. Some participants perceived a stigma associated with prostate cancer and cancer in general, which sometimes acted as a barrier to disclosure. Self-blame and internalisation of cause was not a prominent issue. Participants' descriptions of emotional distress, social isolation and anxiety demonstrated the impact of prostate cancer. Social isolation was most commonly reported as a physical consequence of treatment and/or side effects. Participants felt both support and ongoing care were limited at post-treatment. Most did not seek or receive help for emotional or psychosocial problems from a formal source due to anticipated awkwardness, autonomous coping, not burdening others, unwanted sympathy and retaining privacy. Prostate cancer can cause considerable emotional and social burden for some men, and many are unlikely to seek or receive help. Men, and their support networks, require active encouragement throughout diagnosis, treatment and follow-up to overcome barriers and access additional support, particularly for sexual, emotional and psychosocial issues. PMID- 29112319 TI - Fluorescence Commutation and Surface Photopatterning with Porphyrin Tetradithienylethene Switches. AB - Four tetradithienylethene (DTE) substituted porphyrins, the free base 1H2 , and three metal derivatives (1Zn, 1Co, 1Ni), were synthesized and studied. These dyads, for which the DTE units are connected to the porphyrin's meso positions via a meta-phenyl spacer, exhibit reversible photochromic properties in all cases, with conversion to the photostationary state (PSS) up to 88 %, as confirmed by absorption and NMR spectroscopies. Compounds 1H2 and 1Zn are fluorescent in solution and display a red emission. Upon irradiation with UV light to trigger the closing of the DTEs, the fluorescence of both the free base and zinc porphyrin was very efficiently quenched in solution. The reversible, photo-switching of luminescence was retained in a tetra-DTE free-base porphyrin doped polystyrene film, for which photo-patterning was demonstrated by confocal scanning microscopy. The tunable fluorescent properties of this multi-DTE framework render this compound of interest as a photo-rewritable fluorescent ink. PMID- 29112318 TI - Antimicrobial activity of broccoli (Brassica oleracea var. italica) cultivar Avenger against pathogenic bacteria, phytopathogenic filamentous fungi and yeast. AB - AIMS: The objective of this study was to show whether the edible part of broccoli has antibacterial and antifungal activity against micro-organism of importance in human health and vegetable spoilage, and to test if this effect was partially due to antimicrobial peptides (AMPs). METHODS AND RESULTS: Crude extracts were obtained from florets and stems of broccoli cultivar Avenger and the inhibitory effect was demonstrated against pathogenic bacteria (Bacillus cereus, Staphylococcus xylosus, Staphylococcus aureus, Shigella flexneri, Shigella sonnei, Proteus vulgaris), phytopathogenic fungi (Colletotrichum gloeosporioides, Asperigillus niger) and yeasts (Candida albicans and Rhodotorula sp.). It was shown that samples treated with proteolytic enzymes had a reduction of approximately 60% in antibacterial activity against Staph. xylosus, suggesting that proteinaceous compounds might play a role in the inhibitory effect. Antimicrobial components in crude extracts were thermoresistant and the highest activity was observed under acidic conditions. It was shown that antifungal activity of broccoli's crude extracts might not be attributed to chitinases. CONCLUSIONS: Organic broccoli cultivar Avenger has antimicrobial activity against pathogenic bacteria, yeast and phytophatogenic fungi. Data suggest that this effect is partially due to AMPs. SIGNIFICANCE AND IMPACT OF THE STUDY: Broccoli's crude extracts have activity not only against pathogenic bacteria but also against phytophatogenic fungi of importance in agriculture. We suggest for first time that the inhibitory effect is probably due to AMPs. PMID- 29112320 TI - All-Polymer Solar Cells Based on a Conjugated Polymer Containing Siloxane Functionalized Side Chains with Efficiency over 10. AB - A novel wide-bandgap conjugated copolymer based on an imide-functionalized benzotriazole building block containing a siloxane-terminated side-chain is developed. This copolymer is successfully used to fabricate highly efficient all polymer solar cells (all-PSCs) processed at room temperature with the green solvent 2-methyl-tetrahydrofuran. When paired with a naphthalene diimide-based polymer electron-acceptor, the all-PSC exhibits a maximum power conversion efficiency (PCE) of 10.1%, which is the highest value so far reported for an all PSC. Of particular interest is that the PCE remains 9.4% after thermal annealing at 80 degrees C for 24 h. The resulting high efficiency is attributed to a combination of high and balanced bulky charge carrier mobility, favorable face-on orientation, and high crystallinity. These observations indicate that the resulting copolymer can be a promising candidate toward high-performance all-PSCs for practical applications. PMID- 29112321 TI - Metatranscriptomic data reveal the effect of different community properties on multifunctional redundancy. AB - The assessment of functional redundancy (FR) is essential to understand community structure-function relationships because FR buffers the functional performance of communities against changes in community composition. We introduce a novel metatranscriptome-based approach to quantify FR, which permits multifunctional aspects to be addressed. FR among prokaryotes was ranked in water samples after exposure to changing salinity. FR was higher for functional categories with mostly broad functions shared among many taxa than for functional categories containing many narrow functions. Furthermore, community characteristics had a higher impact on FR than environmental conditions. The metric also allows FR to be estimated between selected groups of taxa, and FR was high between more closely related organisms if communities were grown in similar environmental conditions. Overall, our data revealed a pronounced influence of functional diversity on the one hand but also the characteristics of individual community members on FR, which was specifically high in those communities whose members were more sensitive to salinity changes. PMID- 29112322 TI - Ab Initio Ligand Field Molecular Mechanics and the Nature of Metal-Ligand pi Bonding in Fe(II) 2,6-di(pyrazol-1-yl)pyridine Spin Crossover Complexes. AB - A ligand field molecular mechanics (LFMM) force field has been constructed for the spin states of [Fe(bpp)2 ]2+ (bpp=2,6-di(pyrazol-1-yl)pyridine) and related complexes. A new charge scheme is employed which interpolates between partial charges for neutral bpp and protonated [H3 bpp]3+ to achieve a target metal charge. The LFMM angular overlap model (AOM) parameters are fitted to fully ab initio d orbital energies. However, several AOM parameter sets are possible. The ambiguity is resolved by calculating the Jahn-Teller distortion mode for high spin, which indicates that in [Fe(bpp)2 ]2+ pyridine is a pi-acceptor and pyrazole a weak pi-donor. The alternative fit, assumed previously, where both ligands act as pi-donors leads to an inconsistent distortion. LFMM optimisations in the presence of [BF4 ]- or [PF6 ]- anions are in good agreement with experiment and the model also correctly predicts the spin state energetics for 3 pyrazolyl substituents where the interactions are mainly steric. However, for 4 pyridyl or 4-pyrazolyl substituents, LFMM only treats the electrostatic contribution which, for the pyridyl substituents, generates a fair correlation with the spin crossover transition temperatures, T1/2 , but in the reverse sense to the dominant electronic effect. Thus, LFMM generates its smallest spin state energy difference for the substituent with the highest T1/2 . One parameter set for all substituted bpp ligands is insufficient and further LFMM development will be required. PMID- 29112323 TI - Identification of GBF1 as a cellular factor required for hepatitis E virus RNA replication. AB - The hepatitis E virus (HEV) genome is a single-stranded, positive-sense RNA that encodes three proteins including the ORF1 replicase. Mechanisms of HEV replication in host cells are unclear, and only a few cellular factors involved in this step have been identified so far. Here, we used brefeldin A (BFA) that blocks the activity of the cellular Arf guanine nucleotide exchange factors GBF1, BIG1, and BIG2, which play a major role in reshuffling of cellular membranes. We showed that BFA inhibits HEV replication in a dose-dependent manner. The use of siRNA and Golgicide A identified GBF1 as a host factor critically involved in HEV replication. Experiments using cells expressing a mutation in the catalytic domain of GBF1 and overexpression of wild type GBF1 or a BFA-resistant GBF1 mutant rescuing HEV replication in BFA-treated cells, confirmed that GBF1 is the only BFA-sensitive factor required for HEV replication. We demonstrated that GBF1 is likely required for the activity of HEV replication complexes. However, GBF1 does not colocalise with the ORF1 protein, and its subcellular distribution is unmodified upon infection or overexpression of viral proteins, indicating that GBF1 is likely not recruited to replication sites. Together, our results suggest that HEV replication involves GBF1-regulated mechanisms. PMID- 29112325 TI - Reduction of Dioxygen by Radical/B(p-C6 F4 X)3 Pairs to Give Isolable Bis(borane)superoxide Compounds. AB - Triplet dioxygen was reduced by TEMPO or trityl radicals in the presence of two molar equivalents of the strong B(p-C6 F4 X)3 (X: F or H) boron Lewis acids under mild conditions to give the bis(borane)superoxide systems 2. The sensitive radical anion species were isolated and characterized by methods including X-ray crystal structure analysis and EPR spectroscopy. PMID- 29112324 TI - De novo assembly of the zucchini genome reveals a whole-genome duplication associated with the origin of the Cucurbita genus. AB - The Cucurbita genus (squashes, pumpkins and gourds) includes important domesticated species such as C. pepo, C. maxima and C. moschata. In this study, we present a high-quality draft of the zucchini (C. pepo) genome. The assembly has a size of 263 Mb, a scaffold N50 of 1.8 Mb and 34 240 gene models. It includes 92% of the conserved BUSCO core gene set, and it is estimated to cover 93.0% of the genome. The genome is organized in 20 pseudomolecules that represent 81.4% of the assembly, and it is integrated with a genetic map of 7718 SNPs. Despite the small genome size, three independent lines of evidence support that the C. pepo genome is the result of a whole-genome duplication: the topology of the gene family phylogenies, the karyotype organization and the distribution of 4DTv distances. Additionally, 40 transcriptomes of 12 species of the genus were assembled and analysed together with all the other published genomes of the Cucurbitaceae family. The duplication was detected in all the Cucurbita species analysed, including C. maxima and C. moschata, but not in the more distant cucurbits belonging to the Cucumis and Citrullus genera, and it is likely to have occurred 30 +/- 4 Mya in the ancestral species that gave rise to the genus. PMID- 29112326 TI - Real-world challenges and unmet needs in the diagnosis and treatment of suspected invasive pulmonary aspergillosis in patients with haematological diseases: An illustrative case study. AB - Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases. PMID- 29112327 TI - Non-Equilibrium Self-Assembly of Monocomponent and Multicomponent Tubular Structures in Rotating Fluids. AB - When suspended in a denser rotating fluid, lighter particles experience a cylindrically symmetric confining potential that drives their crystallization into either monocomponent or unprecedented binary tubular packing. These assemblies form around the fluid's axis of rotation, can be dynamically interconverted (upon accelerating or decelerating the fluid), can exhibit preferred chirality, and can be made permanent by solidifying the fluid. The assembly can be extended to fluids forming multiple concentric interfaces or to systems of bubbles forming both ordered and "gradient" structures within curable polymers. PMID- 29112328 TI - Low-power laser irradiation decreases lipid droplet accumulation in the parotid glands of diabetic rats. AB - Lipid droplet accumulation has been related to salivary gland hypofunction in diabetes. In this study, the effect of laser irradiation on the parotid glands (PGs) of diabetic rats was analyzed with regard to its effect on lipid droplet accumulation, intracellular calcium concentration and calmodulin expression. The animals were distributed into 6 groups: D0, D5, D20 and C0, C5, C20, for diabetic (D) and control animals (C), respectively. Twenty-nine days following diabetes induction, PGs of groups D5 and C5; D20 and C20 were irradiated with 5 and 20 J/cm2 of a red diode laser at 100 mW, respectively. After 24 hours, PGs were removed for histological, biochemical, and western blotting analysis. The diabetic animals showed lipid droplet accumulation, which was decreased after irradiation. Ultrastructurally, the droplets were nonmembrane bound and appeared irregularly located in the cytoplasm. Moreover, diabetic animals showed an increased intracellular calcium concentration. In contrast, after laser irradiation a progressive decrease in the concentration of this ion was observed, which would be in agreement with the results found in the increased expression of calmodulin in D20. These data are promising for using laser to decrease lipid droplet accumulation in PGs, however, more studies are necessary to better understand its mechanisms. Micrographs showing decreased lipid accumulation after laser irradiation in light micrographs (LM), and morphology of lipid droplet in transmission electron microscopic (TEM). LM: (A) PGs from nondiabetic rats that did not receive Laser irradiation (LI), (B) PGs from nondiabetic rats that received a dose of 20 J/cm2 , (C) lipid accumulation (arrows) in the secretory cells from diabetic rats that did not receive irradiation, (D) reduction of lipid accumulation in the secretory cells from diabetic rats that received a dose of 20 J/cm2 and TEM: (E) scale bar = 5 MUm, (F) scale bar = 1 MUm, and (G) scale bar = 0.5 MUm. PMID- 29112329 TI - In Vitro and In Vivo Investigation of Potential for Complex CYP3A Interaction for PF-00251802 (Dagrocorat), a Novel Dissociated Agonist of the Glucocorticoid Receptor. AB - The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF-04171327 (fosdagrocorat) is a phosphate ester prodrug of PF-00251802 (dagrocorat), a selective high-affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF-04015475. This study evaluated the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of PF-00251802 and PF 04015475 in vitro and used model-based prediction approaches to estimate clinical impact. PF-00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF-00251802 and PF-04015475 are time-dependent inhibitors and inducers of CYP3A in vitro; PF-00251802 is also a time-dependent inhibitor of CYP2D6. Model-based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open-label, multiple-dose study evaluated the effect of PF-04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF-04171327 resulted in equivalent pharmacokinetic profiles (AUCinf , 21.17 vs 20.28 ng.h/mL, respectively), indicating that PF 04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF-00251802 and PF-04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038). PMID- 29112330 TI - Facile and versatile strategy to prepare magnetic molecularly imprinted particles based on the coassembly of magnetic nanoparticles and amphiphilic random copolymers. AB - Magnetic molecularly imprinted polymer nanoparticles for bisphenol A were prepared by coassembling magnetic nanoparticles and amphiphilic random copolymers. Under optimized conditions, bisphenol A as template molecules, magnetic molecularly imprinted polymer particles with regular morphology, small size, good monodispersity, and high content of OA-Fe3 O4 were prepared by the coassembly method using P(MMA-co-MAA) with monomer ratio of 9:1. These magnetic molecularly imprinted polymer particles could be rapidly collected by an external magnet within 1 min. The saturated adsorption capacity of the magnetic molecularly imprinted polymer for bisphenol A was 201.5 mg/g, and the imprinting factor was 2.5. The separation factors for bisphenol A to beta-estradiol, estriol, and diethylstilbestrol was 3.1, 2.9, and 3.7, respectively. Unlike assembling amphiphilic copolymer in the selective solvent, the coassembly process was simple and rapid. Therefore, the present work provided a facile and versatile approach to construct magnetic molecularly imprinted polymer nanoparticles under mild conditions. PMID- 29112332 TI - Unbinding of Kinesin from Microtubule in the Strongly Bound States Enhances under Assisting Forces. AB - The ability to predict the cellular dynamics of intracellular transport has enormous potential to impact human health. A key transporter is kinesin-1, an ATP driven molecular motor that shuttles cellular cargos along microtubules (MTs). The dynamics of kinesins depends critically on their unbinding rate from MT, which varies depending on the force direction applied on the motor, i.e. the force-unbinding rate relation is asymmetric. However, it remains unclear how changing the force direction from resisting (applied against the motion direction) to assisting (applied in the motion direction) alters the kinesin's unbinding and stepping. Here, we propose a theoretical model for the influence of the force direction on the stepping dynamics of a single kinesin. The model shows that the asymmetry of the force-unbinding rate relation is independent of ATP concentration. It also reveals that the synthesis of ATP from backward stepping under assisting forces is less likely than under resisting forces. It then finds that the unbinding of kinesin in the strongly MT-bound kinetic states enhances under assisting forces. PMID- 29112331 TI - Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir-containing regimens. AB - Treatment with the direct-acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of >=95% in hepatitis C virus (HCV) genotypes (GT) 1-6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV-mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo. PMID- 29112333 TI - Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk. AB - ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, beta = 25.9 mU mL-1 per minor allele; FVIIa-AT, beta = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, beta = 7.8 mU mL-1 per minor allele; FVIIa-AT, beta = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk. PMID- 29112335 TI - Heterojunction-Assisted Co3 S4 @Co3 O4 Core-Shell Octahedrons for Supercapacitors and Both Oxygen and Carbon Dioxide Reduction Reactions. AB - Expedition of electron transfer efficiency and optimization of surface reactant adsorption products desorption processes are two main challenges for developing non-noble catalysts in the oxygen reduction reaction (ORR) and CO2 reduction reaction (CRR). A heterojunction prototype on Co3 S4 @Co3 O4 core-shell octahedron structure is established via hydrothermal lattice anion exchange protocol to implement the electroreduction of oxygen and carbon dioxide with high performance. The synergistic bifunctional catalyst consists of p-type Co3 O4 core and n-type Co3 S4 shell, which afford high surface electron density along with high capacitance without sacrificing mechanical robustness. A four electron ORR process, identical to the Pt catalyzed ORR, is validated using the core-shell octahedron catalyst. The synergistic interaction between cobalt sulfide and cobalt oxide bicatalyst reduces the activation energy to convert CO2 into adsorbed intermediates and hereby enables CRR to run at a low overpotential, with formate as the highly selective main product at a high faraday efficiency of 85.3%. The remarkable performance can be ascribed to the synergistic coupling effect of the structured co-catalysts; heterojunction structure expedites the electron transfer efficiency and optimizes surface reactant adsorption product desorption processes, which also provide theoretical and pragmatic guideline for catalyst development and mechanism explorations. PMID- 29112334 TI - WtF-Nano: One-Pot Dewatering and Water-Free Topochemical Modification of Nanocellulose in Ionic Liquids or gamma-Valerolactone. AB - Ionic liquids are used to dewater a suspension of birch Kraft pulp cellulose nanofibrils (CNF) and as a medium for water-free topochemical modification of the nanocellulose (a process denoted as "WtF-Nano"). Acetylation was applied as a model reaction to investigate the degree of modification and scope of effective ionic liquid structures. Little difference in reactivity was observed when water was removed, after introduction of an ionic liquid or molecular co-solvent. However, the viscoelastic properties of the CNF suspended in two ionic liquids show that the more basic, but non-dissolving ionic liquid, allows for better solvation of the CNF. Vibrio fischeri bacterial tests show that all ionic liquids in this study were harmless. Scanning electron microscopy and wide-angle X-ray scattering on regenerated samples show that the acetylated CNF is still in a fibrillar form. 1 D and 2 D NMR analyses, after direct dissolution in a novel ionic liquid electrolyte solution, indicate that both cellulose and residual xylan on the surface of the nanofibrils reacts to give acetate esters. PMID- 29112336 TI - What do the public know about anatomy? Anatomy education to the public and the implications. AB - Public knowledge of the anatomical "self" is lacking and evidence points towards a growing need for anatomy education to the wider public. The public were offered the opportunity to learn human anatomy and complete an anatomical knowledge survey afterwards. Sixty-three participants volunteered to attempt to place 20 anatomical structures on a blank human body template. Responses were scored independently and then collated. A mixed effects logistic model was used to examine any associations with participants' as a random effect and all other factors as fixed effects. Results showed a statistically significant quadratic trend with age. Participants in health-related employment scored significantly higher than those not in health-related employment. There was a significant interaction between gender and organ type with males scoring higher than females in identifying muscles, but not in identifying internal organs. The current study demonstrates the general public's eagerness to learn anatomy despite their limited knowledge of the human body, and the need for widening participation. Furthermore, it raises an awareness of the anatomical literacy needs of the general public, especially in school children and young adults. Furthermore, it emphasizes the value of health literacy as a focus in undergraduate medical education. Anatomy literacy appears to be neglected, and this experience provides an example of a possible mode of public engagement in anatomy. Anat Sci Educ 11: 117-123. (c) 2017 American Association of Anatomists. PMID- 29112337 TI - Intimate Partner Abuse. PMID- 29112338 TI - Palliative care in decompensated cirrhosis: A review. AB - Decompensated cirrhosis is an illness that causes tremendous suffering. The incidence of cirrhosis is increasing and rates of liver transplant, the only cure, remain stagnant. Palliative care is focused on improving quality of life for patients with serious illness by addressing advanced care planning, alleviating physical symptoms and providing emotional support to the patient and family. Palliative care is used infrequently in patients with decompensated cirrhosis. The allure of transplant as a potential treatment option for cirrhosis, misperceptions about the role of palliative care and difficulty predicting prognosis in liver disease are potential contributors to the underutilization of palliative care in this patient population. Studies have demonstrated some benefit of palliative care in patients with decompensated cirrhosis but the literature is limited to small observational studies. There is evidence that palliative care consultation in other patient populations lowers hospital costs and ICU utilization and improves symptom control and patient satisfaction. Prospective randomized control trials are needed to investigate the effects of palliative care on traditional- and patient-reported outcomes as well as cost of care in decompensated cirrhosis for transplant eligible and ineligible patient populations. PMID- 29112339 TI - Oral health survey of five-year-olds 2014/15: Have strategies for increasing the levels of parental consent in Bradford been effective? AB - Public Health England facilitates national epidemiological surveys of five-year olds to monitor oral health, both locally and nationally. Positive consent for participation in surveys such as these was introduced in 2006 following guidance from the Department of Health. Following this change, consent rates have fallen slightly. Bradford, a city in West Yorkshire in the north of England, has actively tried to encourage an increase in consent rates. In the 2014/15 survey several measures were implemented to encourage parents to return their consent forms in order to increase consent levels. Despite these additional measures consent rates have continued to fall. The schools involved in both the current (2014/15) and previous (2011/12) surveys were directly compared and the results showed a 4% decrease in consent returns. Consequently, recommendations have been made to investigate alternative strategies for increasing levels of survey participation. One of the suggested strategies is to gain consent for all health screening including dental examinations at school entry. PMID- 29112340 TI - Finnish Dentists Find Smoking Cessation Important but Seldom Offer Practical Support for Their Patients. AB - OBJECTIVES: To investigate Finnish dentists' smoking cessation related attitudes, consultation practices and familiarity with the local treatment guideline on smoking cessation. BASIC RESEARCH DESIGN: An online questionnaire was sent to 1740 dentists, which corresponds to 39% of dentists in Finland. A total of 456 dentists responded (response rate 26%), of whom 435 (95%) were clinicians. The dentists' smoking cessation practices were also compared to ones reported in a previous study in Finnish physicians. RESULTS: Dentists found smoking cessation important and often discussed and recommended quitting to the patients, but concrete withdrawal actions were seldom provided. The local treatment guideline on smoking cessation was actively utilized by 36% of the dentists. Adherence to the guideline was associated with higher rates of smoking cessation activities and success in them. Smoking cessation activity among dentists was significantly lower than in Finnish physicians. In accordance with the literature, among dentists, the most common barriers for smoking cessation were lack of time (44%) and education (42%). CONCLUSION: Although smoking cessation is discussed with patients, dentists are less active in taking concrete actions to support the patient on withdrawal. Adherence to the local treatment guideline was associated with better capabilities in dealing with tobacco withdrawal and a more active role in smoking cessation. The results suggest that more education on the local smoking cessation treatment guideline and cessation intervention is needed in order to overcome the remaining barriers to promoting effective smoking cessation in dental practice. PMID- 29112341 TI - The interaction effects between race and functional disabilities on the prevalence of self-reported periodontal diseases - National Health and Nutrition Examination Survey 2011-2012. AB - BACKGROUND: Racial minority groups and adults with functional disabilities (FDs) disproportionally experience periodontal diseases. However, little is known about the interactions of these two characteristics in disease prevalence. The purpose of this study was to examine the association between FDs and periodontal experiences, and to identify whether race has a particular influence on this relationship. METHODS: Data were derived from the National Health and Nutrition Examination Survey 2011-2012, in a representative sample of adults aged 30 years and older. FDs were defined as experiencing limitations in activities of daily living. The weighted logistic regression models were performed using SAS software. RESULTS: The incidence of FDs was associated with a poor self-rated perception of teeth and gum health, gum disease, bone loss, and loss of teeth. The racial minority groups with FDs were more likely to report poor teeth and gum health, loose teeth, and a history of gum disease treatment. Mexican Americans with FDs reported poor teeth and gum health, gum disease, and had been previously treated for gum disease. African Americans with FDs were more likely to be diagnosed with bone loss and loose teeth. PRACTICAL IMPLICATIONS: Racial minority groups with FDs were more likely to be associated with periodontal disease and poor oral health. To improve oral health, access to dental care among minority populations is important, particularly for people with FDs in community settings. Dentists should reach out to these underrepresented groups to address their oral health needs. PMID- 29112342 TI - Factors supporting dentist leaders' retention in leadership. AB - OBJECTIVE: The aim was to study factors associated with staying in a dentist leadership position. PARTICIPANTS AND METHODS: We used an electronic questionnaire to gather data from 156 current or former Finnish dentist leaders in 2014. Principal component analysis categorized statements regarding time usage and opportunities in managerial work into five main components. Associations between these main component scores and the tendency to stay as a leader were analyzed with logistic regression. RESULTS: Out of the five main components, two were significantly associated with staying as a leader: 'career intentions', which represented intent to continue or to leave the leadership position; and 'work time control opportunities', which represented how leaders could control their own work time. Other factors that supported staying were leadership education, more work time available for leadership work, and lower age. The main component 'work pressure' decreased, although not significantly, the odds of continuing; it included lack of leadership work time, and pressure from superiors or subordinates. CONCLUSIONS: Leaders have important roles in health care, ensuring everyday operations as well as developing their organizations to meet future challenges. Knowledge of these supporting factors will enable dentist leaders and their organizations to improve working conditions in order to recruit and retain motivated and competent persons. In addition, well-designed education is important to inspire and encourage future leaders. PMID- 29112343 TI - Translating Pasteur to the Maghreb. AB - More than 125 years after its foundation (*), the Pasteur Institute is still oneof the world's largest, best known and most powerful biomedical researchinstitutions. The original motherhouse was founded by Louis Pasteur in1888 thanks to the funds and facilities generously provided by the Parismunicipality and the French state and also to the donations of voluntarycontributors from France and the most disparate corners of the globe.Before the great savant died seven years later, official branches had alreadybeen opened in Saigon, Lille, Tunis, Algiers, Sydney and Nha-Trang, notto speak about many others which had adopted the trademark withouthaving a formal connection to the Parisian headquarters, such as those inRio de Janeiro, New York, Chicago or Istanbul. During the first quarter ofthe 20th century, new official institutes were established in various Frenchcolonies and protectorates as well as in countries with significant economic,political or cultural links with France such as Brazil, Greece, Romania, theSoviet Union, and Iran. Today, the so-called Institut Pasteur InternationalNetwork comprises 32 centers in the five continents . PMID- 29112347 TI - Double trouble: French colonialism in Morocco and the early historyof the Pasteur Institutes of Tangier and Casablanca (1895-1932). AB - Morocco was the last North African country in which a Pasteurinstitute was created, nearly two decades later than in Tunisia and Algeria. Infact, two institutes were opened, the first in Tangier in 1913 and the second inCasablanca in 1932. This duplication, far from being a measure of success, wasthe material expression of the troubles Pastorians had experienced in getting asolid foothold in the country since the late 19th century. These problems partlyderived from the pre-existence of a modest Spanish-Moroccan bacteriologicaltradition, developed since the late 1880s within the framework of the SanitaryCouncil and Hygiene Commission of Tangier, and partly from the uncoordinatednature of the initiatives launched from Paris and Algiers. Although a PasteurInstitute was finally established, with Paul Remlinger as director, the failure ofFrance to impose its colonial rule over the whole country, symbolized by theestablishment of an international regime in Tangier, resulted in the creation ofa second centre in Casablanca. While elucidating many hitherto unclear factsabout the entangled origins of both institutes, the author points to the solidityof the previously independent Moroccan state as a major factor behind thetroubled translation of Pastorianism to Morocco. Systematically dismissed ordownplayed by colonial and postcolonial historiography, this solidity disruptedthe French takeover of the country and therefore Pastorian expectations. PMID- 29112344 TI - The laboratory and the village. The Algiers Pasteur Institute and "colonization physicians" in the fight against malaria (1904-1939). AB - From the late 19th century, some of the physicians settled inAlgeria and teachers at the School of Medicine of Algiers sought to map theextent of malaria in order to propose prophylactic measures against a diseasethat was widespread in the countryside of the colony. When the fight againstmalaria was organized in Algeria at the beginning of the 20th century, underthe joint direction of the General Government and the Pasteur Institute, the Institute researchers needed to gather various types of data for determiningepidemic indexes and preparing action programmes. The so-called "colonizationphysicians", responsible for delivering healthcare to colonials and natives inrural districts since the 1850s, appeared to be appropriate collaborators with theadministration in the campaigns. The organizers of these campaigns also workedwith agents quininisateurs (quinine distributors) and those involved in anti-larvalmeasures, as well as with agencies responsible for roads and bridges and forwater services, among others. However, there were soon repeated calls for themto be trained in the new bacteriology techniques. Advanced courses were alsoproposed to allow these practitioners to act as true and effective agents of theanti-malarial service, such as the 34-day course organized in 1932 by the PasteurInstitute of Algeria. PMID- 29112348 TI - The Pasteur Institutes of Maghreb: divided memories, transversalhistory. AB - The choice of the expression "History of the Maghreb Pasteurinstitutes" is suggestive of a post-colonial approach and raises questions aboutthe shared future of those centres. The author offers a comparative view of thepast of the Institutes in Tunis, Algiers and Casablanca, relying on recent researchin social sciences and the development of oral history. The Institutes werecreated separately at different times but more or less followed a single modellinking research, production, and teaching. Fighting infectious diseases was partof the colonial heritage, but it was above all the promise of modernisation linkedto participation in the Pastorian Revolution that explains why the three Institutesnever discontinued their activities in the three Southern Mediterranean capitalsAt the turn of the 21th century, the Pasteur Institutes of the Maghreb, incommon with the mother Institute in Paris, were faced by new challenges ina changing political and epidemiological context. The International PasteurInstitutes Network was formally established in 2003. What is the future of theMaghreb Institutes? Will they form a separate entity? And what links will theycreate with the rest of the world, especially the Arab World? These questions areboth scientific and political. PMID- 29112349 TI - Experts, chemistry and medicine: Antonio Casares (1812-1888),Jose Salgado (1811 1890) and the controversy around the analysisof Carratraca Spa waters. AB - This article studies a scientific controversy on the chemical analysisof Carratraca Spa water and discusses the shaping of the scientific authorityof two mid-19th century Spanish experts in mineral waters: Antonio Casares,professor of chemistry at the University of Santiago, and Jose Salgado, medicaldirector of the Spa. It considers the resources employed by the two expertsin the dispute and shows that much of the scientific controversy involved notonly technical issues but also numerous economic, social and personal interestsof the participants. Besides addressing the role played by both experts in thecontroversy, the article reports on the participation of other stakeholders withdifferent levels of expertise. Their involvement in the dispute was reflectedin specialized media, medical reports, special issues, chemical treatises, andspecialized articles as well as in the general press. Finally, the article shows thatdiscussions on analytical methods, instrument use or results interpretation alsoinvolved consideration of other issues, such as the training and skills of expertsand their privileges, prerogatives and scientific authority, which affected thedevelopment and ending of the controversy. PMID- 29112350 TI - The professional identity of the practicante: the case of Aragon,1857-1936. AB - The objective of this study was to reconstruct the professionalidentity of the practicante (male assistant in medicine and surgery) by analyzingthree professional journals of this collective in Zaragoza (Aragon). The discourseof practicantes on their profession insists that they were the only assistants forphysicians with technical qualities. This affirmation constituted a key elementin shaping their identity, contributing in turn to establish the moral andsocial legitimization of practicantes and their professional authority. This wasconstructed in counterpoint to the profile, qualifications and gender identity ofthe other professional healthcare assistant, the nurse. Despite achieving a cleardiscourse on their professional identity and developing certain professionalinfrastructures through the work of institutions and key figures, practicanteswere not able to consolidate a collective project of upward social mobility thatwould improve their status and enhance social recognition of the profession.This led to the construction of a group identity that was largely characterizedby apathy, frustration and disunion, elements that eventually weakened theprofession. PMID- 29112352 TI - Rafael Vilar Fiol (1885-1971) and the attempt to found a dentalschool in Valencia before the Civil War. AB - During the first third of the 20th century, the dental profession inSpain was disputed by several groups of healthcare professionals, includingsurgery practitioners and dental technicians. The most intense conflict wasbetween dentists and stomatologists. In the case of Valencia, this strugglebecame apparent in the attempt to create a dental school during the firstSpanish Republican period. This project was supported by the Faculty ofMedicine and by the local authorities but was not implemented due to thespecial interests of practicing dentists and the School of Dentistry in the CentralUniversity of Madrid. The institutionalization of dentistry in Valencia was limitedto the teaching of an isolated subject in the Faculty of Medicine, preventing theadoption of a university model that would have encouraged the consolidationof the dental profession in all its aspects, not solely in terms of improvementsin dental care. Opposition to the project was largely based on a campaign todiscredit its main promoter, Rafael Fiol Vilar (1885-1971). This Valencian doctorand dentist is virtually unknown by historians, but he had an excellent academicbackground and an extraordinary international projection for that time. He mayhave been ignored because of his exile after the Spanish Civil War and the failureof his project for the University of Valencia. PMID- 29112353 TI - Expertise, accidents and hernias in the context of the right tohealth, Colombia 1915-1946. AB - For most physicians, the assessment of disability in cases of workaccident or occupational disease is very relative matter, and clinical judgmentsare subjective and unsatisfactory in legal settings. Work accident legislation givesthem the task of deciding on any causal links between accident and diseaseand indicating any economic compensation that should be awarded. They musttherefore reach beyond their scientific knowledge to understand the multitudeof social factors that underlie these problems in the world of work. In thisarticle, we analyze Colombian sources from the first half of the 20th century onthe physiology of labor, fatigue, professional risk, work accidents, occupationaldiseases, among other issues. The aim is to advance understanding of how thefield of medical knowledge established an ethical approach for experts in casesof occupational accidents, focusing on hernias, typical misfortunes of the worldof work. PMID- 29112361 TI - 1T-Phase Transition Metal Dichalcogenides (MoS2, MoSe2, WS2, and WSe2) with Fast Heterogeneous Electron Transfer: Application on Second-Generation Enzyme-Based Biosensor. AB - Two-dimensional transition metal dichalcogenides (TMDs) have been in the spotlight for their intriguing properties, including a tunable band gap and fast heterogeneous electron-transfer (HET) rate. Understandably, they are especially attractive in the field of electrochemical biosensors. In this article, HET capabilities of various TMDs (MoS2, MoSe2, WS2, and WSe2) within group VI chemically exfoliated via t-BuLi intercalation are studied and these capabilities are used in the second generation electrochemical glucose biosensor. Strikingly, tungsten dichalcogenides (WS2 and WSe2) exhibit superior HET properties compared to that of their molybdenum counterparts (MoS2 and MoSe2). When incorporated into second generation glucose biosensors, WS2 and WSe2 generated a higher electrochemical responses than that of MoS2 and MoSe2, following the same trend as expected. The commendable performance by WX2 is attributed to the dominance of 1T phase, revealed by characterization data. The developed and optimized 1T WX2 based biosensor achieved analytical requirements of selectivity, wide linear ranges, as well as low limits of detection and quantification. The outstanding electrochemical performances of WS2 and WSe2 are to be recognized, adding on to the fact that they are not decorated with any metal nanoparticles. This is imperative to showcase the real potential of two-dimensional TMDs in electrochemical biosensors. PMID- 29112362 TI - Performance and Reliability of Electrowetting-on-Dielectric (EWOD) Systems Based on Tantalum Oxide. AB - The electrowetting-on-dielectric behavior of Cytop/Tantalum oxide (TaOx) bilayers is studied by measuring their response vs applied voltage and under prolonged periodic cycling, below and above the threshold voltage VT corresponding to the breakdown field for the oxide. TaOx exhibits symmetric solid state I-V characteristics, with electronic conduction dominated by Schottky, Poole-Frenkel emission; conduction is attributed to oxygen vacancies (6 * 1016 cm-3), resulting in large currents at low bias. Electrolyte/Metal Oxide/Metal I-V characteristics show oxide degradation at (<5 V) cathodic bias; anodic bias in contrast results in stable characteristics until reaching the anodization voltage, where the oxide thickens, leading eventually to breakdown and oxygen production at the electrode. Electrowetting angle vs applied voltage undergoes three different stages: a parabolic variation of contact angle (CA) with applied voltage, CA saturation, and rebound of the CA to higher values due to degradation of the polymer layer. The contact angle remained stable for several hundred cycles if the applied voltage was less than VT; degradation in contrast is fast when the voltage is above VT. Degradation of the electrowetting response with time is linked to charge accumulation in the polymer, which inhibits the rebound of the CA when voltage is being applied. PMID- 29112363 TI - Green Fabrication of Ultrathin Co3O4 Nanosheets from Metal-Organic Framework for Robust High-Rate Supercapacitors. AB - Two-dimensional cobalt oxide (Co3O4) is a promising candidate for robust electrochemical capacitors with high performance. Herein, we use 2,3,5,6 tetramethyl-1,4-diisophthalate as a recyclable ligand to construct a Co-based metal-organic framework of UPC-9, and subsequently, we obtain ultrathin hierarchical Co3O4 hexagonal nanosheets with a thickness of 3.5 nm through a hydrolysis and calcination process. A remarkable and excellent specific capacitance of 1121 F.g-1 at a current density of 1 A.g-1 and 873 F.g-1 at a current density of 25 A.g-1 were achieved for the as-prepared asymmetric supercapacitor, which can be attributed to the ultrathin 2D morphology and the rich macroporous and mesoporous structures of the ultrathin Co3O4 nanosheets. This synthesis strategy is environmentally benign and economically viable due to the fact that the costly organic ligand molecules are recycled, reducing the materials cost as well as the environmental cost for the synthesis process. PMID- 29112364 TI - Selective Deposition of Multiple Sensing Materials on Si Nanobelt Devices through Plasma-Enhanced Chemical Vapor Deposition and Device-Localized Joule Heating. AB - This paper describes a novel method, using device-localized Joule heating (JH) in a plasma enhanced atomic layer deposition (PEALD) system, for the selective deposition of platinum (Pt) and zinc oxide (ZnO) in the n- regions of n+/n-/n+ polysilicon nanobelts (SNBs). COMSOL simulations were adopted to estimate device temperature distribution. However, during ALD process, the resistance of SNB device decreased gradually and reached to minima after 20 min JH. As a result, thermal decomposition of precursors occurred during PEALD process. Selective deposition in the n- region was dominated by CVD instead of ALD. Selective deposition of Pt and ZnO films has been achieved and characterized using atomic force microscopy, scanning electron microscopy, and transmission electron microscopy. PMID- 29112365 TI - Nanopyroxene Grafting with beta-Cyclodextrin Monomer for Wastewater Applications. AB - Emerging nanoparticle technology provides opportunities for environmentally friendly wastewater treatment applications, including those in the large liquid tailings containments in the Alberta oil sands. In this study, we synthesize beta cyclodextrin grafted nanopyroxenes to offer an ecofriendly platform for the selective removal of organic compounds typically present in these types of applications. We carry out computational modeling at the micro level through molecular mechanics and molecular dynamics simulations and laboratory experiments at the macro level to understand the interactions between the synthesized nanomaterials and two-model naphthenic acid molecules (cyclopentanecarboxylic and trans-4-pentylcyclohexanecarboxylic acids) typically existing in tailing ponds. The proof-of-concept computational modeling and experiments demonstrate that monomer grafted nanopyroxene or nano-AE of the sodium iron-silicate aegirine are found to be promising candidates for the removal of polar organic compounds from wastewater, among other applications. These nano-AE offer new possibilities for treating tailing ponds generated by the oil sands industry. PMID- 29112366 TI - Aptamer-Templated Silver Nanoclusters Embedded in Zirconium Metal-Organic Framework for Bifunctional Electrochemical and SPR Aptasensors toward Carcinoembryonic Antigen. AB - This study reported a novel biosensor based on the nanocomposite of zirconium metal-organic framework (Zr-MOF, UiO-66) embedded with silver nanoclusters (Ag NCs) using the carcinoembryonic antigen (CEA)-targeted aptamer as template (AgNCs@Apt@UiO-66). The synthesized AgNCs@Apt@UiO-66 nanocomposite not only possesses good biocompatibility, active electrochemical performance, and strong bioaffinity, but also can be dispersed to form two-dimensional nanocomposite with nanoscale thickness. As such, the use of the AgNCs@CEA-aptamer enables AgNC@Apt@UiO-66 with sensitive and selective detection capacity of trace CEA, further concurrently being exploited as scaffold for surface plasmon resonance spectroscopy (SPR) and electrochemical biosensors. The results showed that the proposed electrochemical AgNC@Apt@UiO-66-based aptasensor exhibits high sensitivity with a low detection limit (LOD) of 8.88 and 4.93 pg.mL-1 deduced from electrochemical impedance spectroscopy and differential pulse voltammetry, respectively, within a broad linear range of the CEA concentration (0.01-10 ng.mL 1). Meanwhile, the developed SPR biosensor exhibited a slightly high LOD of 0.3 ng.mL-1 within the CEA concentration of 1.0-250 ng.mL-1. Both the electrochemical and SPR aptasensors displayed high selectivity, good reproducibility, stability, acceptable regenerability, and applicability in real human serum samples. These results proved that the proposed aptamer-targeted Zr-MOF nanocomposite can be utilized in multiple-functionally biosensing, further promoting the potential application of Zr-MOF-related nanomaterials in clinical diagnosis. PMID- 29112367 TI - Alkyne Benzannulation Reactions for the Synthesis of Novel Aromatic Architectures. AB - Aromatic compounds and polymers are integrated into organic field effect transistors, light-emitting diodes, photovoltaic devices, and redox-flow batteries. These compounds and materials feature increasingly complex designs, and substituents influence energy levels, bandgaps, solution conformation, and crystal packing, all of which impact performance. However, many polycyclic aromatic hydrocarbons of interest are difficult to prepare because their substitution patterns lie outside the scope of current synthetic methods, as strategies for functionalizing benzene are often unselective when applied to naphthalene or larger systems. For example, cross-coupling and nucleophilic aromatic substitution reactions rely on prefunctionalized arenes, and even directed metalation methods most often modify positions near Lewis basic sites. Similarly, electrophilic aromatic substitutions access single regioisomers under substrate control. Cycloadditions provide a convergent route to densely functionalized aromatic compounds that compliment the above methods. After surveying cycloaddition reactions that might be used to modify the conjugated backbone of poly(phenylene ethynylene)s, we discovered that the Asao-Yamamoto benzannulation reaction is notably efficient. Although this reaction had been reported a decade earlier, its scope and usefulness for synthesizing complex aromatic systems had been under-recognized. This benzannulation reaction combines substituted 2-(phenylethynyl)benzaldehydes and substituted alkynes to form 2,3 substituted naphthalenes. The reaction tolerates a variety of sterically congested alkynes, making it well-suited for accessing poly- and oligo(ortho arylene)s and contorted hexabenzocoronenes. In many cases in which asymmetric benzaldehyde and alkyne cycloaddition partners are used, the reaction is regiospecific based on the electronic character of the alkyne substrate. Recognizing these desirable features, we broadened the substrate scope to include silyl- and halogen-substituted alkynes. Through a combined experimental and computational approach, we have elucidated mechanistic insight and key principles that govern the regioselectivity outcome of the benzannulation of structurally diverse alkynes. We have applied these methods to prepare sterically hindered, shape-persistent aromatic systems, heterocyclic aromatic compounds, functionalized 2-aryne precursors, polyheterohalogenated naphthalenes, ortho arylene foldamers, and graphene nanoribbons. As a result of these new synthetic avenues, aromatic structures with interesting properties were uncovered such as ambipolar charge transport in field effect transistors based on our graphene nanoribbons, conformational aspects of ortho-arylene architectures resulting from intramolecular pi-stacking, and modulation of frontier molecular orbitals via protonation of heteroatom containing aromatic systems. Given the availability of many substituted 2-(phenylethynyl)benzaldehydes and the regioselectivity of the benzannulation reaction, naphthalenes can be prepared with control of the substitution pattern at seven of the eight substitutable positions. Researchers in a range of fields are likely to benefit directly from newly accessible molecular and polymeric systems derived from polyfunctionalized naphthalenes. PMID- 29112368 TI - Biphase-Interface Enhanced Sodium Storage and Accelerated Charge Transfer: Flower Like Anatase/Bronze TiO2/C as an Advanced Anode Material for Na-Ion Batteries. AB - Flower-like assembly of ultrathin nanosheets composed of anatase and bronze TiO2 embedded in carbon is successfully synthesized by a simple solvothermal reaction, followed with a high-temperature annealing. As an anode material in sodium-ion batteries, this composite exhibits outstanding electrochemical performances. It delivers a reversible capacity of 120 mA h g-1 over 6000 cycles at 10 C. Even at 100 C, there is still a capacity of 104 mA h g-1. Besides carbon matrix and hierarchical structure, abundant interfaces between anatase and bronze greatly enhance the performance by offering additional sites for reversible Na+ storage and improving the charge-transfer kinetics. The interface enhancements are confirmed by discharge/charge profiles, rate performances, electrochemical impedance spectra, and first-principle calculations. These results offer a new pathway to upgrade the performances of anode materials in sodium-ion batteries. PMID- 29112370 TI - Z-Scheme NiTiO3/g-C3N4 Heterojunctions with Enhanced Photoelectrochemical and Photocatalytic Performances under Visible LED Light Irradiation. AB - Direct Z-scheme NiTiO3/g-C3N4 heterojunctions were successfully assembled by using simple calcination method and the photoelectrochemical and photocatalytic performance were investigated by light emitting diode (LED). The photoanode composed by the heterojunction with about 50 wt % NiTiO3 content exhibits the best photoelectrochemical activity with photoconversion efficiency up to 0.066%, which is 4.4 and 3.13 times larger than NiTiO3 or g-C3N4. The remarkably enhanced photoelectrochemical and photocatalytic activity of the heterojunction can be due to the efficiently photogenerated electron-hole separation by a Z-scheme mechanism. PMID- 29112369 TI - On the Better Understanding of the Surprisingly High Performance of Metal-Organic Framework-Based Mixed-Matrix Membranes Using the Example of UiO-66 and Matrimid. AB - Metal-organic frameworks feature a certain framework flexibility, mainly due to a linker mobility inside the lattice. The latter is responsible for effects like breathing or gate-opening, thus making predictions of the sorption and diffusion behavior quite difficult. Permeation measurements on supported UiO-66 membranes at low temperatures and on polymer-coated UiO-66 membrane layers as well as 2H NMR line shape studies and nitrogen sorption measurements of UiO-66 with deuterated linkers in Matrimid as mixed-matrix membranes (MMM) indicate that the 2-site 180 degrees flips (pi-flips) of the aromatic ring are hindered by the presence of (i) the surrounding polymer Matrimid and (ii) residual solvent molecules, thus giving profound insights into the molecular understanding of gas transport through metal-organic framework-based MMMs. PMID- 29112371 TI - Selenium Encapsulated into Metal-Organic Frameworks Derived N-Doped Porous Carbon Polyhedrons as Cathode for Na-Se Batteries. AB - The substitution of Se for S as cathode for rechargeable batteries, which confine selenium in porous carbon, attracts much attention as a potential area of research for energy storage systems. To date, there are no reports about metal organic frameworks (MOFs) to use for Na-Se batteries. Herein, MOFs-derived nitrogen-doped porous carbon polyhedrons (NPCPs) have been obtained via facile synthesis and annealing treatment. Se is encapsulated into the mesopores of carbon polyhedrons homogeneously by melt-diffusion process to form Se/NPCPs composite, using as cathode for advanced Na-Se batteries. Se/NPCPs cathode exhibits excellent rate capabilities of 351.6 and 307.8 at 0.5C and 2C, respectively, along with good cycling performance with high Coulombic efficiency of 99.7% and slow decay rate of 0.05% per cycle after 1000 cycles at 2C, which result from the NPCPs having a unique porous structure to accommodate volumetric expansion of Se during discharge-charge processes. Nitrogen doping could enhance the electrical conductivity of carbon matrix and facilitate rapid charge transfer. PMID- 29112372 TI - Tuning the Color Palette of Fluorescent Copper Sensors through Systematic Heteroatom Substitution at Rhodol Cores. AB - Copper is an essential nutrient for sustaining life, and emerging data have expanded the roles of this metal in biology from its canonical functions as a static enzyme cofactor to dynamic functions as a transition metal signal. At the same time, loosely bound, labile copper pools can trigger oxidative stress and damaging events that are detrimental if misregulated. The signal/stress dichotomy of copper motivates the development of new chemical tools to study its spatial and temporal distributions in native biological contexts such as living cells. Here, we report a family of fluorescent copper sensors built upon carbon-, silicon-, and phosphorus-substituted rhodol dyes that enable systematic tuning of excitation/emission colors from orange to near-infrared. These probes can detect changes in labile copper levels in living cells upon copper supplementation and/or depletion. We demonstrate the ability of the carbon-rhodol based congener, Copper Carbo Fluor 1 (CCF1), to identify elevations in labile copper pools in the Atp7a-/- fibroblast cell model of the genetic copper disorder Menkes disease. Moreover, we showcase the utility of the red-emitting phosphorus-rhodol based dye Copper Phosphorus Fluor 1 (CPF1) in dual-color, dual-analyte imaging experiments with the green-emitting calcium indicator Calcium Green-1 to enable simultaneous detection of fluctuations in copper and calcium pools in living cells. The results provide a starting point for advancing tools to study the contributions of copper to health and disease and for exploiting the rapidly growing palette of heteroatom-substituted xanthene dyes to rationally tune the optical properties of fluorescent indicators for other biologically important analytes. PMID- 29112373 TI - Structure-Activity Relationships of the S-Linked Glycocin Sublancin. AB - Sublancin is a 37-amino acid antimicrobial peptide belonging to the glycocin family of natural products. It contains two helices that are held together by two disulfide bonds as well as an unusual S-glucosidic linkage to a Cys in a loop connecting the helices. We report the reconstitution of the biosynthetic pathway to this natural product in Escherichia coli. This technology enabled the evaluation of the structure-activity relationships of the solvent-exposed residues in the helices. The biosynthetic machinery proved tolerant of changes in both helices, and the bioactivity studies of the resulting mutants show that two residues in helix B are important for bioactivity, Asn31 and Arg33. PMID- 29112374 TI - Macroscopic Alignment and Assembly of pi-Conjugated Oligopeptides Using Colloidal Microchannels. AB - One-dimensional (1-D) supramolecular self-assembly offers a powerful strategy to achieve long-range unidirectional ordering of organic semiconducting materials via noncovalent interactions. Using a hierarchical assembly, electronic and optoelectronic materials can be constructed for applications including organic conducting nanowires, organic field-effect transistors (OFETs), and organic light emitting devices (OLEDs). Despite recent progress, it remains challenging to precisely align and assemble 1-D structures over large areas in a rapid and straightforward manner. In this work, we demonstrate a facile strategy to macroscopically align supramolecular fibers using a templating method based on sacrificial colloidal microchannels. Through use of this approach, colloidal microchannels are generated on a solid surface using a simple fabrication method, followed by the spontaneous self-assembly of pi-conjugated oligopeptides inside large arrays of microchannels triggered by solvent evaporation. Following oligopeptide assembly and removal of sacrificial microchannels, the structural properties of oligopeptide fibers were characterized using atomic force microscopy (AFM), atomic force microscope-infrared spectroscopy (AFM-IR), photoinduced force microscopy (PiFM), fluorescence polarization microscopy, and electron microscopy. These results reveal the macroscopic alignment of oligopeptide fibers into ordered structures over millimeter length scales, facilitated by colloidal microchannel templating. In addition, the charge transport properties (I-V curves) of pi-conjugated oligopeptides assembled using this method were determined under a wide range of applied voltages using interdigitated array electrodes and conductive AFM. Overall, this work illustrates a simple yet robust strategy to pattern 1-D supramolecular fibers over large areas, thereby offering new routes for assembling materials for organic electronics. PMID- 29112375 TI - Gold Polar Intermetallics: Structural Versatility through Exclusive Bonding Motifs. AB - The design of new materials with desired chemical and physical characteristics requires thorough understanding of the underlying composition-structure-property relationships and the experimental possibility of their modification through the controlled involvement of new components. From this point of view, intermetallic phases, a class of compounds formed by two or more metals, present an endless field of combinations that produce several chemical compound classes ranging from simple alloys to true ionic compounds. Polar intermetallics (PICs) belong to the class that is electronically situated in the middle, between Hume-Rothery phases and Zintl compounds and possessing e/a (valence electron per atom) values around 2. In contrast to the latter, where logical rules of formation and classification systems were developed decades ago, polar intermetallics remain a dark horse with a huge diversity of crystal structures but unclear mechanisms of their formation. Partial incorporation of structural and bonding features from both nonpolar and Zintl compounds is commonly observed here. A decent number of PICs can be described in terms of complex metallic alloys (CMAs) following the Hume-Rothery electron-counting schemes but exhibit electronic structure changes that cannot be explained by the latter. Our research is aimed at the discovery and synthesis of new polar intermetallic compounds, their structural characterization, and investigation of their properties in line with the analysis of the principles connecting all of these components. Understanding of the basic structural tendencies is one of the most anticipated outcomes of this analysis, and systematization of the available knowledge is the initial and most important step. In this Account, we focus on a well-represented but rather small section of PICs: ternary intermetallic compounds of gold with electropositive and post transition metals of groups 12 to 15. The strong influence of relativistic effects in its chemical bonding results in special, frequently unique structural motifs, while at the same time gold participates in common structure types as an ordinary transition element. Enhanced bonding strength leads to the formation and stabilization of complex homo- and heteroatomic clusters and networks that are compositionally restricted to just a few options throughout the periodic table. Because it has the highest absolute electronegativity among metals, comparable to those of some halogens, gold usually plays the role of an anion, even being able to form true salts with the most electropositive metals. We discuss the occurrence of the structure types and show the place of gold intermetallics in the general picture. Among the structures considered are ones as common as AlB2 or BaAl4 types, in line with the recently discovered diamond-like homoatomic metal networks, formation of local fivefold symmetry, different types of tunneled structures, and more complex intergrown multicomponent structures. PMID- 29112376 TI - Pressure-Induced Melting of Confined Ice. AB - The classic regelation experiment of Thomson in the 1850s deals with cutting an ice cube, followed by refreezing. The cutting was attributed to pressure-induced melting but has been challenged continuously, and only lately consensus emerged by understanding that compression shortens the O:H nonbond and lengthens the H-O bond simultaneously. This H-O elongation leads to energy loss and lowers the melting point. The hot debate survived well over 150 years, mainly due to a poorly defined heat exchange with the environment in the experiment. In our current experiment, we achieved thermal isolation from the environment and studied the fully reversible ice-liquid water transition for water confined between graphene and muscovite mica. We observe a transition from two-dimensional (2D) ice into a quasi-liquid phase by applying a pressure exerted by an atomic force microscopy tip. At room temperature, the critical pressure amounts to about 6 GPa. The transition is completely reversible: refreezing occurs when the applied pressure is lifted. The critical pressure to melt the 2D ice decreases with temperature, and we measured the phase coexistence line between 293 and 333 K. From a Clausius-Clapeyron analysis, we determine the latent heat of fusion of two-dimensional ice at 0.15 eV/molecule, being twice as large as that of bulk ice. PMID- 29112377 TI - Transparent Perovskite Light-Emitting Touch-Responsive Device. AB - A light-emitting touch-responsive device (LETD) for instantaneous visualization of pressure mapping is reported. The LETD integrates an organometal halide perovskite polymer composite emissive layer and a flexible silver nanowire polyurethane composite transparent electrode. The composite emissive layer contains methylammonium lead bromide nanocrystals uniformly dispersed in a poly(ethylene oxide) (PEO) matrix and emits an intense green luminescence that peaks at 529 nm. The PEO matrix promotes the formation of small perovskite grains (~20 nm) and a pinhole-free composite film with surface roughness of only 2.96 nm. The composite transparent electrode is separated from the emissive layer with a 100 MUm thick spacer. When a local pressure is applied, a Schottky contact is formed instantaneously between the metal and the emissive layer, and electroluminescence is produced at voltages as low as 2.5 V and reaches 1030 cd/m2 at 6 V. The transparent LETD has approximately 68% transparency. It can be bent to a 6 mm radius when polyethylene terephthalate is used as the substrate. The perovskite LETD has fast response and can be pixelated to offer potential applications in robotics, motion detection, fingerprint devices, and interactive wallpapers. PMID- 29112378 TI - Nanoscale Control over the Mixing Behavior of Surface-Confined Bicomponent Supramolecular Networks Using an Oriented External Electric Field. AB - Strong electric fields are known to influence the properties of molecules as well as materials. Here we show that by changing the orientation of an externally applied electric field, one can locally control the mixing behavior of two molecules physisorbed on a solid surface. Whether the starting two-component network evolves into an ordered two-dimensional (2D) cocrystal, yields an amorphous network where the two components phase separate, or shows preferential adsorption of only one component depends on the solution stoichiometry. The experiments are carried out by changing the orientation of the strong electric field that exists between the tip of a scanning tunneling microscope and a solid substrate. The structure of the two-component network typically changes from open porous at negative substrate bias to relatively compact when the polarity of the applied bias is reversed. The electric-field-induced mixing behavior is reversible, and the supramolecular system exhibits excellent stability and good response efficiency. When molecular guests are adsorbed in the porous networks, the field-induced switching behavior was found to be completely different. Plausible reasons behind the field-induced mixing behavior are discussed. PMID- 29112379 TI - High-Throughput Chemical Probing of Full-Length Protein-Protein Interactions. AB - Human biology is regulated by a complex network of protein-protein interactions (PPIs), and disruption of this network has been implicated in many diseases. However, the targeting of PPIs remains a challenging area for chemical probe and drug discovery. Although many methodologies have been put forth to facilitate these efforts, new technologies are still needed. Current biochemical assays for PPIs are typically limited to motif-domain and domain-domain interactions, and assays that will enable the screening of full-length protein systems, which are more biologically relevant, are sparse. To overcome this barrier, we have developed a new assay technology, "PPI catalytic enzyme-linked click chemistry assay" or PPI cat-ELCCA, which utilizes click chemistry to afford catalytic signal amplification. To validate this approach, we have applied PPI cat-ELCCA to the eIF4E-4E-BP1 and eIF4E-eIF4G PPIs, key regulators of cap-dependent mRNA translation. Using these examples, we have demonstrated that PPI cat-ELCCA is amenable to full-length proteins, large (>200 kDa) and small (~12 kDa), and is readily adaptable to automated high-throughput screening. Thus, PPI cat-ELCCA represents a powerful new tool in the toolbox of assays available to scientists interested in the targeting of disease-relevant PPIs. PMID- 29112380 TI - On-Chip Sorting of Long Semiconducting Carbon Nanotubes for Multiple Transistors along an Identical Array. AB - Ballistic transport and sub-10 nm channel lengths have been achieved in transistors containing one single-walled carbon nanotube (SWNT). To fill the gap between single-tube transistors and high-performance logic circuits for the replacement of silicon, large-area, high-density, and purely semiconducting (s-) SWNT arrays are highly desired. Here we demonstrate the fabrication of multiple transistors along a purely semiconducting SWNT array via an on-chip purification method. Water- and polymer-assisted burning from site-controlled nanogaps is developed for the reliable full-length removal of metallic SWNTs with the damage to s-SWNTs minimized even in high-density arrays. All the transistors with various channel lengths show large on-state current and excellent switching behavior in the off-state. Since our method potentially provides pure s-SWNT arrays over a large area with negligible damage, numerous transistors with arbitrary dimensions could be fabricated using a conventional semiconductor process, leading to SWNT-based logic, high-speed communication, and other next generation electronic devices. PMID- 29112381 TI - Two Players Make a Formidable Combination: In Situ Generated Poly(acrylic anhydride-2-methyl-acrylic acid-2-oxirane-ethyl ester-methyl methacrylate) Cross Linking Gel Polymer Electrolyte toward 5 V High-Voltage Batteries. AB - Electrochemical performance of high-voltage lithium batteries with high energy density is limited because of the electrolyte instability and the electrode/electrolyte interfacial reactivity. Hence, a cross-linking polymer network of poly(acrylic anhydride-2-methyl-acrylic acid-2-oxirane-ethyl ester methyl methacrylate) (PAMM)-based electrolyte was introduced via in situ polymerization inspired by "shuangjian hebi", which is a statement in a traditional Chinese Kungfu story similar to the synergetic effect of 1 + 1 > 2. A poly(acrylic anhydride) and poly(methyl methacrylate)-based system is very promising as electrolyte materials for lithium-ion batteries, in which the anhydride and acrylate groups can provide high voltage resistance and fast ionic conductivity, respectively. As a result, the cross-linking PAMM-based electrolyte possesses a significant comprehensive enhancement, including electrochemical stability window exceeding 5 V vs Li+/Li, an ionic conductivity of 6.79 * 10-4 S cm-1 at room temperature, high mechanical strength (27.5 MPa), good flame resistance, and excellent interface compatibility with Li metal. It is also demonstrated that this gel polymer electrolyte suppresses the negative effect resulting from dissolution of Mn2+ ions at 25 and 55 degrees C. Thus, the LiNi0.5Mn1.5O4/Li and LiNi0.5Mn1.5O4/Li4Ti5O12 cells using the optimized in situ polymerized cross-linking PAMM-based gel polymer electrolyte deliver stable charging/discharging profiles and excellent rate performance at room temperature and even at 55 degrees C. These findings suggest that the cross-linking PAMM is an intriguing candidate for 5 V class high-voltage gel polymer electrolyte toward high-energy lithium-on batteries. PMID- 29112382 TI - Iron(II) Complexes of a Hemilabile SNS Amido Ligand: Synthesis, Characterization, and Reactivity. AB - We report an easily prepared bis(thioether) amine ligand, SMeNHSMe, along with the synthesis, characterization, and reactivity of the paramagnetic iron(II) bis(amido) complex, [Fe(kappa3-SMeNSMe)2] (1). Binding of the two different thioethers to Fe generates both five- and six-membered rings with Fe-S bonds in the five-membered rings (av 2.54 A) being significantly shorter than those in the six-membered rings (av 2.71 A), suggesting hemilability of the latter thioethers. Consistent with this hypothesis, magnetic circular dichroism (MCD) and computational (TD-DFT) studies indicate that 1 in solution contains a five coordinate component [Fe(kappa3-SMeNSMe)(kappa2-SMeNSMe)] (2). This ligand hemilability was demonstrated further by reactivity studies of 1 with 2,2' bipyridine, 1,2-bis(dimethylphosphino)ethane, and 2,6-dimethylphenyl isonitrile to afford iron(II) complexes [L2Fe(kappa2-SMeNSMe)2] (3-5). Addition of a Bronsted acid, HNTf2, to 1 produces the paramagnetic, iron(II) amine-amido cation, [Fe(kappa3-SMeNSMe)(kappa3-SMeNHSMe)](NTf2) (6; Tf = SO2CF3). Cation 6 readily undergoes amine ligand substitution by triphos, affording the 16e- complex [Fe(kappa2-SMeNSMe)(kappa3-triphos)](NTf2) (7; triphos = bis(2 diphenylphosphinoethyl)phenylphosphine). These complexes are characterized by elemental analysis; 1H NMR, Mossbauer, IR, and UV-vis spectroscopy; and single crystal X-ray diffraction. Preliminary results of amine-borane dehydrogenation catalysis show complex 7 to be a selective and particularly robust precatalyst. PMID- 29112383 TI - Ozone Formation Induced by the Impact of Reactive Bromine and Iodine Species on Photochemistry in a Polluted Marine Environment. AB - Reactive iodine and bromine species (RIS and RBS, respectively) are known for altering atmospheric chemistry and causing sharp tropospheric ozone (O3) depletion in polar regions and significant O3 reduction in the marine boundary layer (MBL). Here we use measurement-based modeling to show that, unexpectedly, both RIS and RBS can lead to enhanced O3 formation in a polluted marine environment under volatile organic compound (VOC)-limited conditions associated with high nitrogen oxide (NOX = [NO] + [NO2]) concentrations. Under these conditions, the daily average O3 mixing ratio increased to ~44 and ~28% for BrO and IO mixing ratios of up to ~6.8 and 4.7 ppt, respectively. The increase in the level of O3 was partially induced by enhanced ClNO3 formation for higher Br2 and I2 emission flux. The increase in the level of O3 was associated with an increased mixing ratio of hydroperoxyl radical to hydroxyl radical ([HO2]/[OH]) and increased [NO2]/[NO] with higher levels of RBS and/or RIS. NOX-rich conditions are typical of the polluted MBL, near coastlines and ship plumes. Considering that O3 is toxic to humans, plants, and animals and is a greenhouse gas, our findings call for adequate updating of local and regional air-quality models with the effects of activities of RBS and RIS on O3 mixing ratios in the polluted MBL. PMID- 29112384 TI - Efficient Capture and Effective Sensing of Cr2O72- from Water Using a Zirconium Metal-Organic Framework. AB - Highly efficient decontamination of heavily toxic Cr2O72- from water remains a serious task for public health and ecosystem protection. An easily regenerative and reused sorbent with suitable porosity may address this task. Herein, a series of water-stable and ecofriendly metal-organic frameworks (MOFs) with large surface areas were assessed for their ability to adsorb and separate Cr2O72- from aqueous solutions. Among these tested MOFs, NU-1000 shows an extraordinary capability to efficiently capture (within 3 min) Cr2O72- with a sorption capacity of up to 76.8 mg/g, which is the largest one for the neutral MOF-based Cr2O72- sorbents. NU-1000 also shows remarkable selectivity for Cr2O72- capture and can effectively reduce the Cr(VI) concentration from 24 ppm to 60 ppb, which is below the acceptable limit for the drinking water standard (100 ppb by the U.S. Environmental Protection Agency). Moreover, this adsorbent can be easily regenerated by Soxhlet extraction with an acidic methanol solution (2.5 M HCl) and can be reused at least three times without a significant loss of it adsorption ability. More intriguingly, NU-1000 can also serve as an efficient photoluminescent probe for the selective detection of Cr2O72- in aqueous media. The Cr2O72- detection limit is as low as 1.8 MUM, and the linear range is from 1.8 to 340 MUM. Our work shows that NU-1000 is a unique material combining both efficient sorption and exceptional fluorescent sensing of Cr2O72- in aqueous media. PMID- 29112385 TI - Models for Unsymmetrical Active Sites in Metalloproteins: Structural, Redox, and Magnetic Properties of Bimetallic Complexes with MII-(MU-OH)-FeIII Cores. AB - Bimetallic complexes are important sites in metalloproteins but are often difficult to prepare synthetically. We have previously introduced an approach to form discrete bimetallic complexes with MII-(MU-OH)-FeIII (MII = Mn, Fe) cores using the tripodal ligand N,N',N"-[2,2',2"-nitrilotris(ethane-2,1 diyl)]tris(2,4,6-trimethylbenzenesulfonamido) ([MST]3-). This series is extended to include the rest of the late 3d transition metal ions (MII = Co, Ni, Cu, Zn). All of the bimetallic complexes have similar spectroscopic and structural properties that reflect little change despite varying the MII centers. Magnetic studies performed on the complexes in solution using electron paramagnetic resonance spectroscopy showed that the observed spin states varied incrementally from S = 0 through S = 5/2; these results are consistent with antiferromagnetic coupling between the high-spin MII and FeIII centers. However, the difference in the MII ion occupancy yielded only slight changes in the magnetic exchange coupling strength, and all complexes had J values ranging from +26(4) to +35(3) cm-1. PMID- 29112386 TI - Responses in Ozone and Its Production Efficiency Attributable to Recent and Future Emissions Changes in the Eastern United States. AB - Ozone production efficiency (OPE), a measure of the number of ozone (O3) molecules produced per emitted NOX (NO + NO2) molecule, helps establish the relationship between NOX emissions and O3 formation. We estimate long-term OPE variability across the eastern United States using two novel approaches: an observation-based empirical method and a chemical transport model (CTM) method. The CTM approach explicitly controls for differing O3 and NOX reaction product (NOZ) deposition rates and separately estimates OPEs from on-road mobile and electricity generating unit sources across a broad spatial scale. We find lower OPEs in urban areas and that average July OPE increased over the eastern United States domain between 2001 and 2011 from 11 to 14. CTM and empirical approaches agree at low NOZ concentrations, but CTM OPEs are greater than empirical OPEs at high NOZ. Our results support that NOX emissions reductions become more effective at reducing O3 at lower NOZ concentrations. Electricity generating unit OPEs are higher than mobile OPEs except near emissions locations, meaning further utility NOX emissions reductions will have greater per unit impacts on O3 regionally. PMID- 29112387 TI - Aggregates of Defined Stereochemical Scaffolds: A Study in Solution of a Zinc(II) Schiff Base Complex Derived from the Enantiopure trans-1,2-Cyclopentanediamine. AB - Molecular aggregation of bis(salicylaldiminato) ZnII Schiff base, ZnL, complexes is a topic of current interest. In this paper, we report a novel complex derived from the enantiopure trans-1,2-cyclopentanediamine, (R)-1, in order to probe the effect of the defined stereochemistry on its coordination geometry and aggregation properties, through detailed 1H NMR, DOSY NMR, UV/vis, and circular dichroism spectroscopic studies and accurate DFT calculations. This complex shows several peculiarities in solution, behaving very differently from ZnL complexes and more importantly from the related trans-1,2-diaminocyclohexane derivative. Unexpectedly, experimental data suggest the existence in DMSO of two species in equilibrium, the classical monomeric adduct and a dimer, indicating that the DMSO is not sufficiently strong Lewis basic to completely deaggregate the complex. Also, in chloroform an unusual behavior is observed with the existence of a single defined dimeric species characterized as a dinuclear double helicate Zn2L2 structure which does not deaggregate even with the addition of pyridine in large stoichiometric excess. The formation of mononuclear adducts occurs only when dissolving the complex in the stronger Lewis base pyridine. All these data indicate the helicate (R)-1-h complex has a higher thermodynamic stability than that of the cyclohexane analogue, leading to its unique aggregation properties. PMID- 29112388 TI - Electrochemical Ammonia Recovery from Source-Separated Urine for Microbial Protein Production. AB - Conventional plant and meat protein production have low nitrogen usage efficiencies and high energy needs. Microbial protein (MP) is an alternative that offers higher nitrogen conversion efficiencies with low energy needs if nitrogen is recovered from a concentrated waste source such as source-separated urine. An electrochemical cell (EC) was optimized for ammonia recovery as NH3/H2 gas mixtures usable for MP production. Undiluted hydrolyzed urine was fed to the caustic-generating cathode compartment for ammonia stripping with redirection to the anode compartment for additional ammonium extraction. Using synthetic urine at 48 A m-2 the nitrogen removal efficiency reached 91.6 +/- 2.1%. Tests with real urine at 20 A m-2, achieved 87.1 +/- 6.0% and 68.4 +/- 14.6% requiring 5.8 and 13.9 kWh kg N-1 recovered, via absorption in acid or MP medium, respectively. Energy savings through accompanying electrolytic H2 and O2 production were accounted for. Subsequently, MP was grown in fed-batch on MP medium with conventional NH4+ or urine-derived NH3 yielding 3.74 +/- 1.79 and 4.44 +/- 1.59 g CDW L-1, respectively. Dissolution of gaseous NH3 in MP medium maintained neutral pH in the MP reactor preventing caustic addition and thus salt accumulation. Urine-nitrogen could thus be valorized as MP via electrochemical ammonia recovery. PMID- 29112389 TI - Electrode-Electrolyte Interfaces in Lithium-Sulfur Batteries with Liquid or Inorganic Solid Electrolytes. AB - Electrode-electrolyte interfacial properties play a vital role in the cycling performance of lithium-sulfur (Li-S) batteries. The issues at an electrode electrolyte interface include electrochemical and chemical reactions occurring at the interface, formation mechanism of interfacial layers, compositional/structural characteristics of the interfacial layers, ionic transport across the interface, and thermodynamic and kinetic behaviors at the interface. Understanding the above critical issues is paramount for the development of strategies to enhance the overall performance of Li-S batteries. Liquid electrolytes commonly used in Li-S batteries bear resemblance to those employed in traditional lithium-ion batteries, which are generally composed of a lithium salt dissolved in a solvent matrix. However, due to a series of unique features associated with sulfur or polysulfides, ether-based solvents are generally employed in Li-S batteries rather than simply adopting the carbonate type solvents that are generally used in the traditional Li+-ion batteries. In addition, the electrolytes of Li-S batteries usually comprise an important additive, LiNO3. The unique electrolyte components of Li-S batteries do not allow us to directly take the interfacial theories of the traditional Li+-ion batteries and apply them to Li-S batteries. On the other hand, during charging/discharging a Li-S battery, the dissolved polysulfide species migrate through the battery separator and react with the Li anode, which magnifies the complexity of the interfacial problems of Li-S batteries. However, current Li-S battery development paths have primarily been energized by advances in sulfur cathodes. Insight into the electrode-electrolyte interfacial behaviors has relatively been overshadowed. In this Account, we first examine the state-of-the-art contributions in understanding the solid-electrolyte interphase (SEI) formed on the Li-metal anode and sulfur cathode in conventional liquid-electrolyte Li-S batteries and how the resulting chemical and physical properties of the SEI affect the overall battery performance. A few strategies recently proposed for improving the stability of SEI are briefly summarized. Solid Li+-ion conductive electrolytes have been attempted for the development of Li-S batteries to eliminate the polysulfide shuttle issues. One approach is based on a concept of "all-solid-state Li-S battery," in which all the cell components are in the solid state. Another approach is based on a "hybrid-electrolyte Li-S battery" concept, in which the solid electrolyte plays roles both as a Li+-ion conductor for the electrochemical reaction and as a separator to prevent polysulfide shuttle. However, these endeavors with the solid electrolyte are not able to provide an overall satisfactory cell performance. In addition to the low ionic conductivity of solid state electrolytes, a critical issue lies in the poor interfacial properties between the electrode and the solid electrolyte. This Account provides a survey of the relevant research progress in understanding and manipulating the interfaces of electrode and solid electrolytes in both the "all-solid-state Li-S batteries" and the "hybrid-electrolyte Li-S batteries". A recently proposed "semi solid-state Li-S battery" concept is also briefly discussed. Finally, future research and development directions in all the above areas are suggested. PMID- 29112390 TI - Aerobic Oxidations of Light Alkanes over Solid Metal Oxide Catalysts. AB - Heterogeneous metal oxide catalysts are widely studied for the aerobic oxidations of C1-C4 alkanes to form olefins and oxygenates. In this review, we outline the properties of supported metal oxides, mixed-metal oxides, and zeolites and detail their most common applications as catalysts for partial oxidations of light alkanes. By doing this we establish similarities between different classes of metal oxides and identify common themes in reaction mechanisms and research strategies for catalyst improvement. For example, almost all partial alkane oxidations, regardless of the metal oxide, follow Mars-van Krevelen reaction kinetics, which utilize lattice oxygen atoms to reoxidize the reduced metal centers while the gaseous O2 reactant replenishes these lattice oxygen vacancies. Many of the most-promising metal oxide catalysts include V5+ surface species as a necessary constituent to convert the alkane. Transformations involving sequential oxidation steps (i.e., propane to acrylic acid) require specific reaction sites for each oxidation step and benefit from site isolation provided by spectator species. These themes, and others, are discussed in the text. PMID- 29112391 TI - Efficient Gas-Sensing for Formaldehyde with 3D Hierarchical Co3O4 Derived from Co5-Based MOF Microcrystals. AB - Detecting formaldehyde at low operating temperature and maintaining long-term stability are of great significance. In this work, a hierarchical Co3O4 nanostructure has been fabricated by calcining Co5-based metal-organic framework (MOF) microcrystals. Co3O4-350 particles were used for efficient gas-sensing for the detecting of formaldehyde vapor at lower working temperature (170 degrees C), low detection limit of 10 ppm, and long-term stability (30 days), which not only is the optimal value among all reported pure Co3O4 sensing materials for the detection of formaldehyde but also is superior to that of majority of Co3O4-based composites. Such extraordinarily efficient properties might be resulted from hierarchically structures, larger surface area and unique pore structure. This strategy is further confirmed that MOFs, especially Co-clusters MOFs, could be used as precursor to synthesize 3D nanostructure metal oxide materials with high performance, which possess high porosity and more active sites and shorter ionic diffusion lengths. PMID- 29112392 TI - Solid Versus Solution Spin Crossover and the Importance of the Fe-N=C(X) Angle. AB - A new family of mononuclear [FeII(Rdpt)2(NCE)2] complexes (E = S, Se, or BH3) is formed by 1:2 reaction of [FeII(pyridine)4(NCE)2] with the monotopic pyridyl triazole ligand 4-(4-methylphenyl)-3-(2-pyridinyl)-5-phenyl-4H-1,2,4-triazole (tolpyph). The three complexes are obtained as six different solvatomorphs: [FeII(tolpyph)2(NCS)2].H2O (1.H2O), 1.1.5CH3OH.0.5H2O, [FeII(tolpyph)2(NCSe)2] (2), 2.1.5H2O, [FeII(tolpyph)2(NCBH3)2] (3), and 3.H2O. Single-crystal X-ray diffraction reveals that 1.1.5CH3OH.0.5H2O and 2 are high-spin (HS) at 100 K, while 3 is low-spin (LS) at 100 K and HS at 373 K. Compound 3 is the first structurally characterized example of an [FeII(Rdpt)2(NCE)2]-type complex with NCBH3 co-ligand: the crystal packing is dominated by aromatic stacking interactions. Solid-state magnetic measurements show that 1.H2O and 2.1.5H2O remain HS down to 50 K, whereas 3.H2O undergoes spin crossover (SCO) with a T1/2 of 309 K, slightly above room temperature. A literature survey of analogous trans [FeII(Rdpt)2(NCX)2]-type complexes (53 distinct crystal structures) shows that for the complexes that are SCO active in the solid state the Fe-N=C(X) angle is usually close to straight, 162-178 degrees , whereas it is usually lower, 142-159 degrees , for the complexes that remain HS. UV-vis studies in CHCl3 solution show that in each case the use of a 6:1 ratio of tolpyph/Fe(II) is required to ensure the iron(II) is present in solution as [FeII(tolpyph)2(NCE)2]. Interestingly, using this ratio, all three compounds are SCO-active in CDCl3 solution-in dramatic contrast to the solid-state findings. Specifically, while compounds 1 and 2 are not SCO-active in the solid state (they remain HS), they undergo gradual SCO in CDCl3 solution, with T1/2 values of 290 and 310 K, respectively. In CDCl3 solution, compound 3 has a T1/2 value of 288 K, which is 21 K lower than in the solid state. These results highlight the differences between solid state (ligand field; crystal packing) and solution (ligand field; solvation) effects on SCO, with the latter studies revealing room-temperature SCO for all three of these complexes. PMID- 29112393 TI - Ring-Fusion of Perylene Diimide Acceptor Enabling Efficient Nonfullerene Organic Solar Cells with a Small Voltage Loss. AB - We report a novel small molecule acceptor (SMA) named FTTB-PDI4 obtained via ring fusion between the thiophene and perylene diimide (PDI) units of a PDI-tetramer with a tetrathienylbezene (TTB) core. A small voltage loss of 0.53 V and a high power conversion efficiency of 10.58% were achieved, which is the highest value reported for PDI-based devices to date. By comparing the fused and nonfused SMAs, we show that the ring-fusion introduces several beneficial effects on the properties and performances of the acceptor material, including more favorable energy levels, enhanced light absorption and stronger intermolecular packing. Interestingly, morphology data reveal that the fused molecule yields higher domain purity and thus can better maintain its molecular packing and electron mobility in the blend. Theoretical calculations also demonstrate that FTTB-PDI4 exhibits a "double-decker" geometry with two pairs of mostly parallel PDI units, which is distinctively different from reported PDI-tetramers with highly twisted geometries and can explain the better performance of the material. This work highlights the promising design of PDI-based acceptors by the ring-fusion strategy. PMID- 29112394 TI - Synthesis and Photoluminescence Properties of a Blue-Emitting La3Si8N11O4:Eu2+ Phosphor. AB - Eu2+-doped La3Si8N11O4 phosphors were synthesized by the high temperature solid state method, and their photoluminescence properties were investigated in this work. La3Si8N11O4:Eu2+ exhibits a strong broad absorption band centered at 320 nm, spanning the spectral range of 300-600 nm due to 4f7 -> 4f65d1 electronic transitions of Eu2+. The emission spectra show a broad and asymmetric band peaking at 481-513 nm depending on the Eu2+ concentration, and the emission color can be tuned in a broad range owing to the energy transfer between Eu2+ ions occupying two independent crystallographic sites. Compared to the Ce3+-doped La3Si8N11O4, the Eu2+-doped one shows a larger thermal quenching, predominantly owing to photoionization. Under 320 nm excitation, the internal and external quantum efficiencies are 44 and 33%, respectively. PMID- 29112395 TI - Deciphering Nature's Intricate Way of N,S-Dimethylating l-Cysteine: Sequential Action of Two Bifunctional Adenylation Domains. AB - Dimethylation of amino acids consists of an interesting and puzzling series of events that could be achieved, during nonribosomal peptide biosynthesis, either by a single adenylation (A) domain interrupted by a methyltransferase (M) domain or by the sequential action of two of such independent enzymes. Herein, to establish the method by which Nature N,S-dimethylates l-Cys, we studied its formation during thiochondrilline A biosynthesis by evaluating TioS(A3aM3SA3bT3) and TioN(AaMNAb). This study not only led to identification of the exact pathway followed in Nature by these two enzymes for N,S-dimethylation of l-Cys, but also revealed that a single interrupted A domain can N,N-dimethylate amino acids, a novel phenomenon in the nonribosomal peptide field. These findings offer important and useful insights for the development and engineering of novel interrupted A domain enzymes to serve, in the future, as tools for combinatorial biosynthesis. PMID- 29112396 TI - Mechanism of Rhodium-Catalyzed C-H Functionalization: Advances in Theoretical Investigation. AB - Transition-metal-catalyzed cross-coupling has emerged as an effective strategy for chemical synthesis. Within this area, direct C-H bond transformation is one of the most efficient and environmentally friendly processes for the construction of new C-C or C-heteroatom bonds. Over the past decades, rhodium-catalyzed C-H functionalization has attracted considerable attention because of the versatility and wide use of rhodium catalysts in chemistry. A series of C-X (X = C, N, or O) bond formation reactions could be realized from corresponding C-H bonds using rhodium catalysts. Various experimental studies on rhodium-catalyzed C-H functionalization reactions have been reported, and in tandem, mechanistic and computational studies have also progressed significantly. Since 2012, our group has performed theoretical studies to reveal the mechanism of rhodium-catalyzed C H functionalization reactions. We have studied the changes in the oxidation state of rhodium and compared the Rh(I)/Rh(III) catalytic cycle to the Rh(III)/Rh(V) catalytic cycle using density functional theory calculation. The development of advanced computational methods and improvements in computing power make theoretical calculation a powerful tool for the mechanistic study of rhodium chemistry. Computational study is able to not only provide mechanistic insights but also explain the origin of regioselectivity, enantioselectivity, and stereoselectivity in rhodium-catalyzed C-H functionalization reactions. This Account summarizes our computational work on rhodium-catalyzed C-H functionalization reactions. The mechanistic study under discussion is divided into three main parts: C-H bond cleavage step, transformation of the C-Rh bond, and regeneration of the active catalyst. In the C-H bond cleavage step, computational results of four possible mechanisms, including concerted metalation deprotonation (CMD), oxidative addition (OA), Friedel-Crafts-type electrophilic aromatic substitution (SEAr), and sigma-complex assisted metathesis (sigma-CAM) are discussed. Subsequent transformation of the C-Rh bond, for example, via insertion of CO, olefin, alkyne, carbene, or nitrene, constructs new C-C or C heteroatom bonds. For the regeneration of the active catalyst, reductive elimination of a high-valent rhodium complex and protonation of the C-Rh bond are emphasized as potential mechanism candidates. In addition to detailing the reaction pathway, the regioselectivity and diastereoselectivity of rhodium catalyzed C-H functionalization reactions are also commented upon in this Account. The origin of the selectivity is clarified through theoretical analysis. Furthermore, we summarize and compare the changes in the oxidation state of rhodium along the complete reaction pathway. The work described in this Account demonstrates that rhodium catalysis might proceed via Rh(I)/Rh(III), Rh(II)/Rh(IV), Rh(III)/Rh(V), or non-redox-Rh(III) catalytic cycles. PMID- 29112398 TI - New ACE-Inhibitory Peptides from Hemp Seed (Cannabis sativa L.) Proteins. AB - A hemp seed protein isolate, prepared from defatted hemp seed meals by alkaline solubilization/acid precipitation, was subjected to extensive chemical hydrolysis under acid conditions (6 M HCl). The resulting hydrolysate was fractionated by semipreparative RP-HPLC, and the purified fractions were tested as inhibitors of angiotensin converting enzyme (ACE). Mono- and bidimensional NMR experiments and LC-MS analyses led to the identification of four potentially bioactive peptides, i.e. GVLY, IEE, LGV, and RVR. They were prepared by solid-phase synthesis, and tested for ACE-inhibitory activity. The IC50 values were GVLY 16 +/- 1.5 MUM, LGV 145 +/- 13 MUM, and RVR 526 +/- 33 MUM, confirming that hemp seed may be a valuable source of hypotensive peptides. PMID- 29112397 TI - ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance. AB - Certain commensal Escherichia coli contain the clb biosynthetic gene cluster that codes for small molecule prodrugs known as precolibactins. Precolibactins are converted to colibactins by N-deacylation; the latter are postulated to be genotoxic and to contribute to colorectal cancer formation. Though advances toward elucidating (pre)colibactin biosynthesis have been made, the functions and mechanisms of several clb gene products remain poorly understood. Here we report the 2.1 A X-ray structure and molecular function of ClbS, a gene product that confers resistance to colibactin toxicity in host bacteria and which has been shown to be important for bacterial viability. The structure harbors a potential colibactin binding site and shares similarity to known hydrolases. In vitro studies using a synthetic colibactin analog and ClbS or an active site residue mutant reveal cyclopropane hydrolase activity that converts the electrophilic cyclopropane of the colibactins into an innocuous hydrolysis product. As the cyclopropane has been shown to be essential for genotoxic effects in vitro, this ClbS-catalyzed ring-opening provides a means for the bacteria to circumvent self induced genotoxicity. Our study provides a molecular-level view of the first reported cyclopropane hydrolase and support for a specific mechanistic role of this enzyme in colibactin resistance. PMID- 29112399 TI - Amber-Compatible Parametrization Procedure for Peptide-like Compounds: Application to 1,4- and 1,5-Substituted Triazole-Based Peptidomimetics. AB - Peptidomimetics are molecules of particular interest in the context of drug design and development. They are proteolytically and metabolically more stable than their natural peptide counterparts but still offer high specificity toward their biological targets. In recent years, 1,4- and 1,5-disubstituted 1,2,3 triazole-based peptidomimetics have emerged as promising lead compounds for the design of various inhibitory and tumor-targeting molecules as well as for the synthesis of peptide analogues. The growing popularity of triazole-based peptidomimetics and a constantly broadening range of their application generated a demand for elaborate theoretical investigations by classical molecular dynamics simulations and molecular docking. Despite this rising interest, accurate and coherent force field parameters for triazole-based peptidomimetics are still lacking. Here, we report the first complete set of parameters dedicated to this group of compounds, named TZLff. This parametrization is compatible with the latest version of the AMBER force field (ff14SB) and can be readily applied for the modeling of pure triazole-based peptidomimetics as well as natural peptide sequences containing one or more triazole-based modifications in their backbone. The parameters were optimized to reproduce HF/6-31G* electrostatic potentials as well as MP2/cc-pVTZ equilibrium Hessian matrices and conformational potential energy surfaces through the use of a genetic algorithm-based search and least squares fitting. Following the standards of AMBER, we introduce residue building units, thus allowing the user to define any given sequence of triazole-based peptidomimetics. Validation of the parameter set against ab initio- and NMR-based reference systems shows that we obtain fairly accurate results, which properly capture the conformational features of triazole-based peptidomimetics. The successful and efficient parametrization strategy developed in this work is general enough to be applied in a straightforward manner for parametrization of other peptidomimetics and, potentially, any polymeric assemblies. PMID- 29112401 TI - Fluorescence Photoswitching of a Diarylethene by Irradiation with Single Wavelength Visible Light. AB - Photoswitchable turn-on mode fluorescent molecules have been so far successfully used in super-resolution fluorescence microscopies. Here, we report on fluorescence photoswitching of 1,2-bis(2-ethyl-6-phenyl-1-benzothiophene-1,1 dioxide-3-yl)perfluorocyclopentene (1) by irradiation with single-wavelength visible (420 nm < lambda < 470 nm) light, the wavelength of which is longer than the 0-0 transition of open-ring isomer 1a, without UV light excitation. By absorbing very weak hot bands or Urbach tails 1a underwent a cyclization reaction to produce fluorescent closed-ring isomer 1b. Both cyclization and cycloreversion reactions of 1 took place with the visible light in the far off-resonance region of the absorption edge. Based on numerical simulations of the formation process of 1b from 1a by irradiation with 450 nm light, weak absorption coefficients at 450 nm in n-hexane and CCl4 were estimated to be 0.084 and 0.19 M-1 cm-1, respectively. The reversible fluorescence photoswitching with the single visible light is advantageously applicable to super-resolution fluorescence imaging in biological systems. PMID- 29112400 TI - Lactoferrin Exerts Antitumor Effects by Inhibiting Angiogenesis in a HT29 Human Colon Tumor Model. AB - To investigate the effect and potential mechanisms of lactoferrin on colon cancer cells and tumors, HT29 and HCT8 cells were exposed to varying concentrations of lactoferrin, and the impacts on cell proliferation, migration, and invasion were observed. Cell proliferation test showed that high dosage of lactoferrin (5-100 mg/mL) inhibited cell viability in a dose-dependent manner, with the 50% concentration of inhibition at 81.3 +/- 16.7 mg/mL and 101 +/- 23.8 mg/mL for HT29 and HCT8 cells, respectively. Interestingly, migration and invasion of the cells were inhibited dramatically by 20 mg/mL lactoferrin, consistent with the significant down regulation of VEGFR2, VEGFA, pPI3K, pAkt, and pErk1/2 proteins. HT29 was chosen as the sensitive cell line to construct a tumor-bearing nude mice model. Notably, HT29 tumor weight was greatly reduced in both the lactoferrin group (26.5 +/- 6.7 mg) and the lactoferrin/5-Fu group (14.5 +/- 5.1 mg), compared with the control one (39.3 +/- 6.5 mg), indicating that lactoferrin functioned as a tumor growth inhibitor. Considering lactoferrin also reduced the growth of blood vessels and the degree of malignancy, we concluded that HT29 tumors were effectively suppressed by lactoferrin, which might be achieved by regulation of phosphorylation from various kinases and activation of the VEGFR2 PI3K/Akt-Erk1/2 pathway. PMID- 29112402 TI - Combined Falling Drop/Open Port Sampling Interface System for Automated Flow Injection Mass Spectrometry. AB - The aim of this work was to demonstrate and to evaluate the analytical performance of a combined falling drop/open port sampling interface (OPSI) system as a simple noncontact, no-carryover, automated system for flow injection analysis with mass spectrometry. The falling sample drops were introduced into the OPSI using a widely available autosampler platform utilizing low cost disposable pipet tips and conventional disposable microtiter well plates. The volume of the drops that fell onto the OPSI was in the 7-15 MUL range with an injected sample volume of several hundred nanoliters. Sample drop height, positioning of the internal capillary on the sampling end of the probe, and carrier solvent flow rate were optimized for maximum signal. Sample throughput, signal reproducibility, matrix effects, and quantitative analysis capability of the system were established using the drug molecule propranolol and its isotope labeled internal standard in water, unprocessed river water and two commercially available buffer matrices. A sample-to-sample throughput of ~45 s with a ~4.5 s base-to-base flow injection peak profile was obtained in these experiments. In addition, quantitation with minimally processed rat plasma samples was demonstrated with three different statin drugs (atorvastatin, rosuvastatin, and fluvastatin). Direct characterization capability of unprocessed samples was demonstrated by the analysis of neat vegetable oils. Employing the autosampler system for spatially resolved liquid extraction surface sampling exemplified by the analysis of propranolol and its hydroxypropranolol glucuronide phase II metabolites from a rat thin tissue section was also illustrated. PMID- 29112403 TI - Selective ortho C-H Activation of Pyridines Directed by Lewis Acidic Boron of PBP Pincer Iridium Complexes. AB - Transition-metal mediated C-H functionalization has emerged as a powerful method in the chemistry relevant to the synthesis of pharmaceuticals, agrochemicals, and advanced materials. Because organic molecules typically contain multiple types of C-H bonds, selective C-H functionalization is a major ongoing challenge. C-H activation of heteroatom-containing organics has often been approached via the use of the directing effect, whereby the coordination to the basic heteroatom directs the reactive metal center to a specific C-H bond. We now report a different approach where the nitrogen donor in pyridine derivatives coordinates to an ancillary Lewis acidic boryl ligand directly attached to the metal (iridium) center, as opposed to the metal itself. This topology directs the iridium center to activate a different C-H bond than in the cases of directing donor coordination to the metal. Using this strategy, we demonstrate ortho regiospecific C-H activation of pyridines and an example of the subsequent functionalization via C-C bond formation. PMID- 29112404 TI - The Relationship of Collagen Structural and Compositional Heterogeneity to Tissue Mechanical Properties: A Chemical Perspective. AB - Collagen is the primary protein component in mammalian connective tissues. Over the last 20 years, evidence has mounted that collagen matrices exhibit substantial heterogeneity in their hierarchical structures and that this heterogeneity plays important roles in both structure and function. Herein, an overview of studies addressing the nanoscale compositional and structural heterogeneity is provided and connected to work exploring the mechanical implications for a number of tissues. PMID- 29112405 TI - Imaging the Pore Structure of Geological Materials with Bifunctional Nanoparticles. AB - Analysis of complex pore structure of geomaterials is a fundamental issue in geoscience. Here bifunctional nanoparticles with magnetic and fluorescent properties are introduced as novel markers for optical imaging of pore structure in geomaterials. Using the paramagnetic property, powder of the nanoparticle is driven into pores under an external magnetic field, avoiding a tedious sample preparation and eliminating artificial damage of sample preparation in conventional methods. Meanwhile, the fluorescent nanoparticle marker offers a sharp contrast imaging between the rock matrix (black) and pores (bright) under microscopy. Furthermore, fluorescent nanoparticles with different sizes and colors are designed to demonstrate the potential of the method for describing pore throat sizes. Combining the merits of the paramagnetic and fluorescent properties of nanoparticles, a convenient and practical sample preparation is proposed to promote optical imaging analysis of the pore structure in geomaterials. PMID- 29112406 TI - Nicrophorusamides A and B, Antibacterial Chlorinated Cyclic Peptides from a Gut Bacterium of the Carrion Beetle Nicrophorus concolor. AB - Nicrophorusamides A and B (1 and 2) were discovered from a rare actinomycete, Microbacterium sp., which was isolated from the gut of the carrion beetle Nicrophorus concolor. The structures of the nicrophorusamides were established as new chlorinated cyclic hexapeptides bearing uncommon amino acid units mainly based on 1D and 2D NMR spectroscopic analysis. The absolute configurations of the amino acid residues 5-chloro-l-tryptophan, d-threo-beta-hydroxyasparagine/d asparagine, l-ornithine, l-allo-isoleucine, d-leucine, and d-valine were determined using Marfey's method and chemical derivatization with 2,3,4,6-tetra-O acetyl-beta-d-glucopyranosyl isothiocyanate followed by LC/MS analysis. Nicrophorusamide A (1) showed antibacterial activity against several Gram positive bacteria. PMID- 29112407 TI - Secondary Metabolites in Allergic Plant Pollen Samples Modulate Afferent Neurons and Murine Tracheal Rings. AB - Plant pollens are strong airborne elicitors of asthma. Their proteinaceous allergens have been studied intensively, but little is known about a possible contribution of pollen secondary metabolites to the nonallergic exacerbation of asthma. Pollen samples originating from 30 plant species were analyzed by HPLC coupled to PDA, ESIMS, and ELSD detectors and off-line NMR spectroscopy. Polyamine conjugates, flavonoids, and sesquiterpene lactones were identified. Polyamine conjugates were characteristic of all Asteraceae species. The presence of sesquiterpene lactones in Asteraceae pollen varied between species and pollen lots. All plant pollen, including those from non-Asteraceae species, contained to some extent electrophiles as determined by their reaction with N-acetyl-l cysteine. Selected pollen extracts and pure compounds were tested in murine afferent neurons and in murine tracheal preparations. Tetrahydrofuran extracts of Ambrosia artemisiifolia and Ambrosia psilostachya pollen and a mixture of sesquiterpene lactones coronopilin/parthenin increased the intracellular Ca2+ concentration in 15%, 32%, and 37% of cinnamaldehyde-responsive neurons, respectively. In organ bath experiments, only the sesquiterpene lactones tested induced a weak dilatation of naive tracheas and strongly lowered the maximal methacholine-induced tracheal constriction. A tetrahydrofuran extract of A. psilostachya and coronopilin/parthenin led to a time-dependent relaxation of the methacholine-preconstricted trachea. These results provide the first evidence for a potential role of pollen secondary metabolites in the modulation of the tracheal tone. PMID- 29112408 TI - Ensemble- and Rigidity Theory-Based Perturbation Approach To Analyze Dynamic Allostery. AB - Allostery describes the functional coupling between sites in biomolecules. Recently, the role of changes in protein dynamics for allosteric communication has been highlighted. A quantitative and predictive description of allostery is fundamental for understanding biological processes. Here, we integrate an ensemble-based perturbation approach with the analysis of biomolecular rigidity and flexibility to construct a model of dynamic allostery. Our model, by definition, excludes the possibility of conformational changes, evaluates static, not dynamic, properties of molecular systems, and describes allosteric effects due to ligand binding in terms of a novel free-energy measure. We validated our model on three distinct biomolecular systems: eglin c, protein tyrosine phosphatase 1B, and the lymphocyte function-associated antigen 1 domain. In all cases, it successfully identified key residues for signal transmission in very good agreement with the experiment. It correctly and quantitatively discriminated between positively or negatively cooperative effects for one of the systems. Our model should be a promising tool for the rational discovery of novel allosteric drugs. PMID- 29112409 TI - Trends in Strong Chemical Bonding in C2, CN, CN-, CO, N2, NO, NO+, and O2. AB - The strong chemical bonds between C, N, and O play a central role in chemistry, and their formation and cleavage are critical steps in very many catalytic processes. The close-lying molecular orbital energies and large correlation effects pose a challenge to electronic structure calculations and have led to different bonding interpretations, most notably for C2. One way to approach this problem is by strict benchmark comparison of related systems. This work reports reference electronic structures and computed bond dissociation enthalpies D0 for C2, CN, CN-, CO, N2, NO, NO+, O2 and related systems C2+ and C2- at chemical accuracy (~1 kcal/mol or 4 kJ/mol) using CCSD(T)/aug-cc-pV5Z, with additional benchmarks of HF, MP2, CCSD, explicitly correlated F12 methods, and four density functionals. Very large correlation and basis set effects are responsible for up to 93% of total D0. The order of the molecular orbitals 1piu and 3sigmag changes, as seen in textbooks, depending on total and effective nuclear charge. Linear trends are observed in 2sigmau-2sigmag orbital splitting (R2 = 0.91) and in D0 of C2, C2-, and C2+ (R2 = 0.99). The correlation component of D0 of C2 is by far the largest (~93%) due to a poor HF description. Importantly, density functional theory fails massively in describing this series consistently in both limits of effective nuclear charge, and Hartree-Fock exchange or meta functionals do not remedy this 100 kJ/mol error, which should thus be addressed in future density functional developments as it affects very many studies involving cleavage or formation of these bonds. PMID- 29112410 TI - Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers. AB - Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 MUg/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models. PMID- 29112412 TI - Correction to "Z-Selective Metathesis Homocoupling of 1,3-Dienes by Molybdenum and Tungsten Monoaryloxide Pyrrolide (MAP) Complexes". PMID- 29112411 TI - Making Changes: N6-Methyladenosine-Mediated Decay Drives the Endothelial-to Hematopoietic Transition. PMID- 29112413 TI - Thermodynamics Far from the Thermodynamic Limit. AB - Understanding how small systems exchange energy with a heat bath is important to describe how their unique properties can be affected by the environment. In this contribution, we apply Landsberg's theory of temperature-dependent energy levels to describe the progressive thermalization of small systems as their spectrum is perturbed by a heat bath. We propose a mechanism whereby the small system undergoes a discrete series of excitations and isentropic spectrum adjustments leading to a final state of thermal equilibrium. This produces standard thermodynamic results without invoking system size. The thermal relaxation of a single harmonic oscillator is analyzed as a model example of a system with a quantized spectrum than can be embedded in a thermal environment. A description of how the thermal environment affects the spectrum of a small system can be the first step in using environmental factors, such as temperature, as parameters in the design and operation of nanosystem properties. PMID- 29112414 TI - Squid Suckerin Biomimetic Peptides Form Amyloid-like Crystals with Robust Mechanical Properties. AB - We present the self-assembly of fibers formed from a peptide sequence (A1H1) derived from suckerin proteins of squid sucker ring teeth (SRT). SRT are protein only biopolymers with an unconventional set of physicochemical and mechanical properties including high elastic modulus coupled with thermoplastic behavior. We have identified a conserved peptide building block from suckerins that possess the ability to assemble into materials with similar mechanical properties as the native SRT. A1H1 displays amphiphilic characteristics and self-assembles from the bottom-up into mm-scale fibers initiated by the addition of a polar aprotic solvent. A1H1 fibers are thermally resistant up to 239 degrees C, coupled with an elastic modulus of ~7.7 GPa, which can be explained by the tight packing of beta-sheet-enriched crystalline building blocks as identified by wide-angle X-ray scattering (WAXS), with intersheet and interstrand distances of 5.37 and 4.38 A, respectively. A compact packing of the peptides at their Ala-rich terminals within the fibers was confirmed from molecular dynamics simulations, and we propose a hierarchical model of fiber assembly of the mature peptide fiber. PMID- 29112415 TI - Photochemistry of 2-Formylphenylnitrene: A Doorway to Heavy-Atom Tunneling of a Benzazirine to a Cyclic Ketenimine. AB - The slippery potential energy surface of aryl nitrenes has revealed unexpected and fascinating reactions. To explore such a challenging surface, one powerful approach is to use a combination of a cryogenic matrix environment and a tunable narrowband radiation source. In this way, we discovered the heavy-atom tunneling reaction involving spontaneous ring expansion of a fused-ring benzazirine into a seven-membered ring cyclic ketenimine. The benzazirine was generated in situ by the photochemistry of protium and deuterated triplet 2-formylphenylnitrene isolated in an argon matrix. The ring-expansion reaction takes place at 10 K with a rate constant of ~7.4 * 10-7 s-1, despite an estimated activation barrier of 7.5 kcal mol-1. Moreover, it shows only a marginal increase in the rate upon increase of the absolute temperature by a factor of 2. Computed rate constants with and without tunneling confirm that the reaction can only occur by a tunneling process from the ground state at cryogenic conditions. It was also found that the ring-expansion reaction rate is more than 1 order of magnitude faster when the sample is exposed to broadband IR radiation. PMID- 29112416 TI - Redox Conditions Affect Dissolved Organic Carbon Quality in Stratified Freshwaters. AB - The quality of dissolved organic carbon (DOC) affects both carbon cycling in surface waters and drinking water production. Not much is known about the influence of environmental conditions on DOC quality. We studied the effect of redox conditions on the chemical composition of DOC in a drinking water reservoir by Fourier transform ion cyclotron resonance mass spectrometry in combination with sediment core incubation experiments under manipulated redox conditions. We observed clear differences in DOC quality among oxic epilimnion, anoxic hypolimnion, and sediment porewater. Sediment porewater showed relatively high intensities of polyphenol-like components with H/C ratios of <1 and O/C ratios of >0.6. Consistent with this, anoxic incubation of a sediment core resulted in an accumulation of these components in the overlying water. The observed pattern of DOC quality change can be explained by redox-dependent adsorption/desorption of DOC on iron minerals. Under oxic conditions, the polyphenol-like components bind on freshly formed iron hydroxides, a process that affects both DOC stability in surface waters and treatability during drinking water production. PMID- 29112417 TI - Water and Temperature Stresses Impact Canola (Brassica napus L.) Fatty Acid, Protein, and Yield over Nitrogen and Sulfur. AB - Interactive effects of weather and soil nutrient status often control crop productivity. An experiment was conducted to determine effects of nitrogen (N) and sulfur (S) fertilizer rate, soil water, and atmospheric temperature on canola (Brassica napus L.) fatty acid (FA), total oil, protein, and grain yield. Nitrogen and sulfur were assessed in a 4-yr study with two locations, five N rates (0, 45, 90, 135, and 180 kg ha-1), and two S rates (0 and 17 kg ha-1). Water and temperature were assessed using variability across 12 site-years of dryland canola production. Effects of N and S were inconsistent. Unsaturated FA, oleic acid, grain oil, protein, and theoretical maximum grain yield were highly related to water and temperature variability across the site-years. A nonlinear model identified water and temperature conditions that enabled production of maximum unsaturated FA content, oleic acid content, total oil, protein, and theoretical maximum grain yield. Water and temperature variability played a larger role than soil nutrient status on canola grain constituents and yield. PMID- 29112418 TI - Harnessing Molecular Vibrations to Probe Triplet Dynamics During Singlet Fission. AB - Ultrafast vibrational spectroscopy in the mid-infrared spectral range provides the opportunity to probe the dynamics of electronic states involved in all stages of the singlet fission reaction through their unique vibrational frequencies. This capability is demonstrated using a model singlet fission chromophore, 6,13 bis(triisopropylsilylethynyl) pentacene (TIPS-Pn). The alkyne groups of the TIPS side chains are coupled to the conjugated framework of the pentacene cores, enabling direct examination of the dynamics of triplet excitons that have successfully separated from correlated triplet pair states in crystalline films of TIPS-Pn. Relaxation processes during the separation of triplet excitons and triplet-triplet annihilation after their separation result in the formation of hot ground state molecules that also exhibit unique vibrational frequencies. Because all organic molecules possess native vibrational modes, ultrafast vibrational spectroscopy offers a new approach to examine the dynamics of electronic intermediates that may inform ongoing efforts to utilize singlet fission to overcome thermalization losses in photovoltaic applications. PMID- 29112420 TI - Selective Double Hydroboration and Dihydroborylsilylation of Organonitriles by an Iron-indium Cooperative Catalytic System. AB - Organonitriles (RC=N) were selectively converted into the corresponding diborylamines (RCH2N(Bpin)2) in reactions with pinacolborane (pinBH) in the presence of a catalytic amount of the iron-indium complex [Fe(CH3CN)6][cis Fe(CO)4(InCl3)2]. The catalytic reaction mechanism was tentatively proposed. In addition, this catalytic system was found to be applicable for the synthesis of borylsilylamine in high yield when organonitrile was treated with hydroborane and hydrosilane simultaneously. PMID- 29112419 TI - Coordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer's Disease. AB - Positron emission tomography (PET) is emerging as one of the most important diagnostic tools for brain imaging, yet the most commonly used radioisotopes in PET imaging, 11C and 18F, have short half-lives, and their usage is thus somewhat limited. By comparison, the 64Cu radionuclide has a half-life of 12.7 h, which is ideal for administering and imaging purposes. In spite of appreciable research efforts, high-affinity copper chelators suitable for brain imaging applications are still lacking. Herein, we present the synthesis and characterization of a series of bifunctional compounds (BFCs) based on macrocyclic 1,4,7 triazacyclononane and 2,11-diaza[3.3](2,6)pyridinophane ligand frameworks that exhibit a high affinity for Cu2+ ions. In addition, these BFCs contain a 2 phenylbenzothiazole fragment that is known to interact tightly with amyloid beta fibrillar aggregates. Determination of the protonation constants (pKa values) and stability constants (log beta values) of these BFCs, as well as characterization of the isolated copper complexes using X-ray crystallography, electron paramagnetic resonance spectroscopy, and electrochemical studies, suggests that these BFCs exhibit desirable properties for the development of novel 64Cu PET imaging agents for Alzheimer's disease. PMID- 29112421 TI - Monometallic and Bimetallic Platinum Complexes with Fluorinated beta-Diketiminate Ligands. AB - Presented here are complexes of two different fluorinated beta-diketiminate (NacNac) ligands with cyclometalated platinum. Reaction of the cyclometalated platinum dimers [Pt(C^N)(MU-X)]2 [C^N = 2-phenylpyridine (ppy), 2-(2,4 difluorophenyl)pyridine (F2ppy); X = Cl, Br] with lithium salts of backbone fluorinated beta-diketiminate ligands produces two structure types, depending on the temperature of the reaction. At milder temperatures (<80 degrees C), the major product is an unusual halide-bridged diplatinum complex, demonstrating a unique NacNac binding mode bridging the two platinum centers. At higher temperatures (>100 degrees C), the major species is a monoplatinum complex of the type Pt(C^N)(NacNac). The complexes display reduction waves in their cyclic voltammograms at mild potentials, as well as intense visible absorption bands (lambda > 500 nm), that depend minimally on the identity of the C^N ligand or, in the case of the bimetallic complexes, the identity of the bridging halide. In addition, the monoplatinum complexes exhibit structured luminescence in the red and near-infrared regions deriving a NacNac-centered triplet state. All of these observations suggest that the NacNac pi system contributes substantially to the frontier orbitals and motivates continued exploration of fluorinated beta diketiminate ligands in the design of complexes with desirable ligand-based redox and optical properties. PMID- 29112422 TI - Surface Modification of a NiS2 Nanoarray with Ni(OH)2 toward Superior Water Reduction Electrocatalysis in Alkaline Media. AB - Interface engineering has been demonstrated to be effective in promoting hydrogen evolution reaction (HER) in an alkaline solution. Herein, we report that the HER activity of a NiS2 nanoarray on a titanium mesh (NiS2/TM) in alkaline media is greatly boosted by the electrodeposition of Ni(OH)2 onto NiS2 [Ni(OH)2-NiS2/TM]. Ni(OH)2-NiS2/TM only needs an overpotential of 90 mV to deliver 10 mA cm-2 in 1.0 M KOH. Density functional theory calculations confirm that Ni(OH)2-NiS2 has a lower water dissociation free energy and a more optimal hydrogen adsorption free energy than NiS2. PMID- 29112423 TI - Enabling Simultaneous Extreme Ultra Low-k in Stiff, Resilient, and Thermally Stable Nano-Architected Materials. AB - Low dielectric constant (low-k) materials have gained increasing popularity because of their critical role in developing faster, smaller, and higher performance devices. Their practical use has been limited by the strong coupling among mechanical, thermal, and electrical properties of materials and their dielectric constant; a low-k is usually attained by materials that are very porous, which results in high compliance, that is, silica aerogels; high dielectric loss, that is, porous polycrystalline alumina; and poor thermal stability, that is, Sr-based metal-organic frameworks. We report the fabrication of 3D nanoarchitected hollow-beam alumina dielectrics which k is 1.06-1.10 at 1 MHz that is stable over the voltage range of -20 to 20 V and a frequency range of 100 kHz to 10 MHz. This dielectric material can be used in capacitors and is mechanically resilient, with a Young's modulus of 30 MPa, a yield strength of 1.07 MPa, a nearly full shape recoverability to its original size after >50% compressions, and outstanding thermal stability with a thermal coefficient of dielectric constant (TCK) of 2.43 * 10-5 K-1 up to 800 degrees C. These results suggest that nanoarchitected materials may serve as viable candidates for ultra low-k materials that are simultaneously mechanically resilient and thermally and electrically stable for microelectronics and devices. PMID- 29112424 TI - A Mechanistic Explanation for the Regioselectivity of Nonenzymatic RNA Primer Extension. AB - A working model of nonenzymatic RNA primer extension could illuminate how prebiotic chemistry transitioned to biology. All currently known experimental reconstructions of nonenzymatic RNA primer extension yield a mixture of 2'-5' and 3'-5' internucleotide linkages. Although long seen as a major problem, the causes of the poor regioselectivity of the reaction are unknown. We used a combination of different leaving groups, nucleobases, and templating sequences to uncover the factors that yield selective formation of 3'-5' internucleotide linkages. We found that fast and high yielding reactions selectively form 3'-5' linkages. Additionally, in all cases with high 3'-5' regioselectivity, Watson-Crick base pairing between the RNA monomers and the template is observed at the extension site and at the adjacent downstream position. Mismatched base-pairs and other factors that would perturb the geometry of the imidazolium bridged intermediate lower both the rate and regioselectivity of the reaction. PMID- 29112425 TI - Asymmetric Total Synthesis of (-)-Clovan-2,9-dione Using Rh(I)-Catalyzed [3 + 2 + 1] Cycloaddition of 1-Yne-vinylcyclopropane and CO. AB - The asymmetric total synthesis of clovan-2,9-dione with a [6.3.1.01,5]dodecane skeleton has been achieved. The synthesis features a Rh(I)-catalyzed [3 + 2 + 1] cycloaddition of 1-yne-vinylcyclopropane (1-yne-VCP) with CO and an intramolecular aldol reaction to obtain the skeleton of the target molecule. PMID- 29112426 TI - Self-Assembly Growth of In-Rich InGaAs Core-Shell Structured Nanowires with Remarkable Near-Infrared Photoresponsivity. AB - Understanding the compositional distribution of ternary nanowires is essential to build the connection between nanowire structures and their potential applications. In this study, we grew epitaxial ternary InGaAs nanowires with high In concentration on GaAs {111}B substrates. Our detailed electron microscopy characterizations suggest that the grown ternary InGaAs nanowires have an extraordinary core-shell structure with In-rich cores and Ga-enriched shells, in which both nanowire cores and shells showed compositional gradient. It was found that In-rich nanowire cores are formed due to the Ga-limited growth environment, caused by the competition with the spontaneous InGaAs planar layer growth on the substrate that consumes more Ga than the nominal Ga concentration during the growth. Moreover, the composition gradient in the nanowires cores and shells is a result of strain relaxation between them. Our optoelectronic property measurements from prototype nanowire devices show a remarkable photoresponsivity under the near-infrared illumination. This study provides a new approach for designing and realizing complex nanowire heterostructures for high-efficiency nanowire-based systems and devices. PMID- 29112427 TI - Infrared Spectroscopic Analysis of the Adsorption of Pyridine Carboxylic Acids on Colloidal Ceria. AB - Surface adsorption of a homologous series of pyridine carboxylic acids on a hydrated colloidal cerium dioxide (ceria) film is characterized using the combination of experimental and computationally determined infrared (IR) spectra. Experimental analyses employ attenuated total reflectance (ATR) IR spectroscopy of deposited colloidal ceria thin films equilibrated with three pyridine carboxylic acids at pH 3.0, 5.5, and 8.5. The corresponding computational IR spectra for the energy-minimized intermediate and base forms of the pyridine carboxylic acids use density functional theory calculations at the B3LYP/6 311++G** level of theory. Solvent effects are modeled using both the COSMO implicit solvation model and the inclusion of explicit water molecules. Experimental IR spectra show that the adsorptive interactions between the pyridine carboxylic acids and ceria surface are due to the outer-sphere coordination of cerium ions in the films. Vibrational assignments based on combined experimental and computational results indicate that both pyridyl ring nitrogen and carboxylate functional groups account for the interaction of pyridine carboxylic acids at ceria surfaces. Experimentally determined Langmuir constants point to the intermediate form of picolinic acid (pyridine-2-carboxylic acid) as having the strongest adsorption to ceria compared to the other pyridine carboxylic acids investigated. The enhanced adsorption of picolinic acid is attributed to the adjacency of the protonated pyridyl nitrogen and the carboxylate group relative to nicotinic acid (pyridine-3-carboxylic acid) and isonicotinic acid (pyridine-4-carboxylic acid). PMID- 29112428 TI - Photoredox Catalysis Induced Bisindolylation of Ethers/Alcohols via Sequential C H and C-O Bond Cleavage. AB - A visible-light-engaged 2-fold site-selective alkylation of indole derivatives with aliphatic ethers or alcohols has been accomplished for easy access to symmetric 3,3'-bisindolylmethane derivatives. The experimental data suggest a sequential photoredox catalysis induced radical addition and proton-mediated Friedel-Crafts alkylation mechanism. PMID- 29112429 TI - 3-Hydroxy-2-(trialkylsilyl)phenyl Triflate: A Benzyne Precursor Triggered via 1,3 C-sp2-to-O Silyl Migration. AB - 3-Hydroxy-2-(trialkylsilyl)phenyl triflates are presented as new versatile hydroxyaryne precursors. These are base-activated aryne precursors induced via a C-sp2-to-O 1,3-Brook rearrangement. The reaction of various arynophiles and 3 trialkylsiloxybenzyne generated from 3-hydroxy-2-(trialkylsilyl)phenyl triflate efficiently afforded highly regioselective phenol derivatives. Furthermore, through crossover experiments, the intramolecular mechanism of silyl migration was demonstrated. PMID- 29112430 TI - Binding Free Energies of Host-Guest Systems by Nonequilibrium Alchemical Simulations with Constrained Dynamics: Illustrative Calculations and Numerical Validation. AB - In the companion article (Giovannelli et al., 10.1021/acs.jctc.7b00594), we presented an alchemical approach, based on nonequilibrium molecular dynamics simulations, to compute absolute binding free energies of a generic host-guest system. Two alternative computational routes, called binded-domain and single point alchemical-path schemes, have been proposed. This study is addressed to furnish numerical validation and illustrative examples of the above-mentioned alchemical schemes. Validation is provided by comparing binding free-energy data relative to two poses of a Zn(II).anion complex with those recovered from an alternative approach, based on steered molecular dynamics simulations. We illustrate important technical and theoretical aspects for a good practice in applying both alchemical schemes, not only through the calculations on the Zn(II).anion complex, but also estimating absolute binding free energies of 1:1 complexes of beta-cyclodextrin with aromatic compounds (benzene and naphthalene). Comparison with experimental data and previous molecular dynamics simulation studies further confirms the validity of the present nonequilibrium-alchemical methodology. PMID- 29112431 TI - Pleiokomenines A and B: Dimeric Aspidofractinine Alkaloids Tethered with a Methylene Group. AB - Pleiokomenines A and B (1 and 2), first examples of dimeric aspidofractinine alkaloids linked by a methylene bridge, were isolated from the stem bark of Pleiocarpa mutica. Their structures were elucidated by a combination of spectroscopic analyses and semisynthetic derivatization of pleiocarpinine (3) and a formaldehyde equivalent mediated by scandium trifluoromethanesulfonate. Pleiokomenines A (1) and B (2) showed moderate antiplasmodial activities in the micromolar range against the FcB1 strain. PMID- 29112432 TI - Force Field Parametrization of Metal Ions from Statistical Learning Techniques. AB - A novel statistical procedure has been developed to optimize the parameters of nonbonded force fields of metal ions in soft matter. The criterion for the optimization is the minimization of the deviations from ab initio forces and energies calculated for model systems. The method exploits the combination of the linear ridge regression and the cross-validation techniques with the differential evolution algorithm. Wide freedom in the choice of the functional form of the force fields is allowed since both linear and nonlinear parameters can be optimized. In order to maximize the information content of the data employed in the fitting procedure, the composition of the training set is entrusted to a combinatorial optimization algorithm which maximizes the dissimilarity of the included instances. The methodology has been validated using the force field parametrization of five metal ions (Zn2+, Ni2+, Mg2+, Ca2+, and Na+) in water as test cases. PMID- 29112433 TI - Construction of 6,10-syn- and -anti-2,5-Dioxabicyclo[2.2.1]heptane Skeletons via Oxonium Ion Formation/Fragmentation: Prediction of Structure of (E)-Ocellenyne by NMR Calculation. AB - A highly efficient and stereoselective route to potential synthetic intermediates for ocellenyne and related C15 acetogenin natural products with 6,10-syn- and 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core structures has been developed by means of an iterative biogenesis-inspired oxonium ion formation/fragmentation sequence. In accordance with chemical transformations, the most likely stereostructure for (E)-ocellenyne on the basis of GIAO 13C NMR calculations possesses a 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core, as predicted from a plausible biosynthetic pathway, instead of the spectroscopically proposed 6,10 syn-2,5-dioxabicyclo[2.2.1]heptane skeleton. PMID- 29112434 TI - N-Butyl-l-deoxynojirimycin (l-NBDNJ): Synthesis of an Allosteric Enhancer of alpha-Glucosidase Activity for the Treatment of Pompe Disease. AB - The highly stereocontrolled de novo synthesis of l-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. l-NBDNJ is able to enhance lysosomal alpha-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when coincubated with the recombinant human alpha-glucosidase. In addition, differently from its d-enantiomer, l-NBDNJ does not act as a glycosidase inhibitor. PMID- 29112435 TI - Vibrational Structure in Magnetic Circular Dichroism Spectra of Polycyclic Aromatic Hydrocarbons. AB - Absorption and magnetic circular dichroism (MCD) spectroscopies are powerful and simple methods to discriminate among various compounds. Polycyclic aromatic hydrocarbons provide particularly strong signal, which, for example, facilitates their detection in the environment. However, interpretation of the spectra is often based on quantum-chemical simulations, providing a limited precision only. In the present work, we use time-dependent density functional theory and complete active space second-order perturbation theories to understand spectral features observed in a series of naphthalene, anthracene, phenanthrene, and three larger compounds. The electronic computations provided reasonable agreement with the experiment for the smaller molecules, while a large error persisted for the bigger ones. However, many discrepancies could be explained by vibrational splitting of the electronic transitions across the entire spectral range. Compared to plain absorption, MCD spectral bands and their vibrational splitting were more specific for each aromatic molecule. The computational tools allowing simulations of detailed vibrational features in the electronic spectra thus promise to open a qualitatively new chapter in the spectroscopy of aromatic compounds. PMID- 29112436 TI - Capturing the Elusive Water Trimer from the Stepwise Growth of Water on the Surface of the Polycyclic Aromatic Hydrocarbon Acenaphthene. AB - Polycyclic aromatic hydrocarbons (PAHs) are key players in reaction chemistry. While it is postulated that they serve as a basis for ice grains, there has been no direct detection of PAHs in astronomical environments. We aim to investigate the hydration of PAHs to set a foundation for the future exploration of potential ice formation pathways. We report results from chirped pulse Fourier transform microwave spectroscopy and quantum-chemical calculations for the PAH acenaphthene and acenaphthene complexed with up to four water molecules. The acenaphthene (H2O)3 complex is of particular interest as the elusive cyclic water trimer was observed. It appears in a slightly distorted configuration when compared with the pure water trimer. This is explained by hydrogen-bond net cooperativity effects. Binding energies for the complexes are presented. Our results provide insight into the onset of complex aggregation that could be occurring in extraterrestrial environments as part of ice grain formation. PMID- 29112437 TI - The Hydrogen Abstraction Reaction H2S + OH -> H2O + SH: Convergent Quantum Mechanical Predictions. AB - The hydrogen abstraction reaction H2S + OH -> H2O + SH has been studied using the "gold standard" CCSD(T) method along with the Dunning's aug-cc-pVXZ (up to 5Z) basis sets. For the reactant (entrance) complex, the CCSD(T) method predicts a HSH...OH hydrogen-bonded structure to be lowest-lying, and the other lower-lying isomers, including the two-center three-electron hemibonded structure H2S...OH, have energies within 2 kcal/mol. The similar situation is for the product (exit) complex. With the aug-cc-pV5Z single point energies at the aug-cc-pVQZ geometry, the dissociation energy for the reactant complex to the reactants (H2S + OH) is predicted to be 3.37 kcal/mol, and that for the product complex to the products (H2O + SH) is 2.92 kcal/mol. At the same level of theory, the classical barrier height is predicted to be only 0.11 kcal/mol. Thus, the OH radical will react promptly with H2S in the atmosphere. We have also tested the performance of 29 density functional theory (DFT) methods for this reaction. Most of them can reasonably predict the reaction energy, but the different functional give quite different energy barriers, ranged from -10.3 to +2.8 kcal/mol, suggesting some caution in choosing density functionals to explore the PES of chemical reactions. PMID- 29112438 TI - (Oligo-)Thiophene Functionalized Tetraazaperopyrenes: Donor-Acceptor Dyes and Ambipolar Organic Semiconductors. AB - Tetraazaperopyrenes (TAPPs) have been functionalized with thiophene and terthiophene units of different architecture resulting in a variety of organic donor-acceptor (D-A) compounds. The influence of the connection of the thiophenes to the TAPP core on their structural, photophysical and electrochemical properties has been studied in detail by a combination of X-ray crystallography, UV-vis and fluorescence spectroscopy as well as cyclic voltammetry, which allowed the establishment of structure-property relationships. The HOMO-LUMO gap is significantly decreased upon substitution of the TAPP core with electron-donating thiophene units, the extent of which is strongly influenced by the orientation of the thiophene units. The latter also crucially directs the molecular packing in the solid. Linkage at the alpha-position allows both inter- and intramolecular N...S interaction, whereas linkage in the beta-position prevents intramolecular N...S interaction, resulting in a less pronounced conjugation of the TAPP core and the thiophene units. The new TAPP derivatives were processed as semiconductors in organic thin-film transistors (TFTs) that show ambipolar behavior. The insight into band gap and structure engineering may open up new possibilities to tailor the electronic properties of TAPP-based materials for certain desired applications. PMID- 29112439 TI - Liquid-Vapor Phase Diagram of RPBE-D3 Water: Electronic Properties along the Coexistence Curve and in the Supercritical Phase. AB - On the basis of ab initio Gibbs ensemble Monte Carlo simulations, we map the liquid-vapor phase diagram of water described by the RPBE density functional supplemented by D3 dispersion corrections and estimate the critical point by density extrapolation. Knowing the approximate location of the critical point, two sets of ab initio molecular dynamics simulations at gas-like and liquid-like densities deep in the supercritical phase of water are carried out where particular attention is payed to ergodic sampling in view of large correlation lengths and long correlation times. Structural, H-bonding, and dipolar properties of RPBE-D3 water are analyzed along the liquid-vapor coexistence curve upon moving toward the critical point and compared to those in the supercritical state. The properties of high-density supercritical water are astonishingly similar to those of the liquid on the coexistence curve under subcritical conditions at comparable density. Upon decomposing the molecular dipole moments into purely configurational and electronic polarization/charge-transfer contributions, it is demonstrated that the latter play a decreasing role in liquid water upon approaching the critical point on the coexistence curve. Moreover, these many-body effects are systematically suppressed in supercritical water due to the significantly reduced H-bonding network. PMID- 29112442 TI - Iridium-Catalyzed Highly Regioselective Azide-Ynamide Cycloaddition to Access 5 Amido Fully Substituted 1,2,3-Triazoles under Mild, Air, Aqueous, and Bioorthogonal Conditions. AB - A highly regioselective method to access 5-amido fully substituted 1,2,3 triazoles by iridium-catalyzed azide-ynamide cycloaddition under mild, air, aqueous, and bioorthogonal conditions is reported. The excellent regioselectivities may derive from the strong coordination between the carbonyl oxygen of ynamide and the pi-acidic iridium. Since the iridium ion is insensitive to oxygen/water and exhibits low cytotoxicity, it could catalyze this reaction in both organic and biological environments efficiently. Preparation in gram-scale and application in carbohydrates highlight this method. PMID- 29112441 TI - Fluorescence Enhancement of a Cationic Fluorene-Phenylene Conjugated Polyelectrolyte Induced by Nonionic n-Alkyl Polyoxyethylene Surfactants. AB - The modulation of conjugated polyelectrolyte fluorescence response by nonionic surfactants is dependent on the structures of the surfactant and polymer, polymer average molecular weight, and polyelectrolyte-surfactant interactions. In this paper, we study the effect of nonionic n-alkyl polyoxyethylene surfactants (CiEj) with different alkyl chain lengths (CiE5 with i = 6, 8, 10, and 12) and number of oxyethylene groups (C12Ej with j = 5, 7, and 9) on the photophysics and ionic conductivity of poly{[9,9-bis(6'-N,N,N-trimethylammonium)-hexyl]-2,7-fluorene-alt 1,4-phenylene}bromide (HTMA-PFP) in dimethyl sulfoxide-water 4% (v/v). Molecular dynamics simulations show that HTMA-PFP chains tend to approach as the simulation evolves. However, the minimum distance between the polymer centers of mass increases upon addition of the surfactant and grows with both the surfactant alkyl chain length and the number of oxyethylene groups, although there are no specific polymer-surfactant interactions. A significant increase in the polymer emission intensity has been observed at surfactant concentrations around their critical micelle concentrations (cmcs), which is attributed to polymer aggregate disruption. However, an increase in the solution conductivity for concentrations above the C12E5 cmc has only been observed for the HTMA-PFP/C12E5 system. The enhancement of fluorescence emission intensity and conductivity upon surfactant addition increases with polymer average molecular weights and seems to be controlled by the polymer-surfactant proximity, which is maximum for C10E5 and C12E5. PMID- 29112443 TI - Real-Time Observation of Nonadiabatic Bifurcation Dynamics at a Conical Intersection. AB - Looking into temporal dynamics of the reactive flux that is precisely located at the well-characterized conical intersection has been one of chemists' longstanding goals. We report here real-time nonadiabatic bifurcation dynamics in the S-CH3 bond predissociation of thioanisole (C6H5SCH3) in the first electronically excited state (S1). It is found that two distinct adiabatic and nonadiabatic reaction pathways are activated simultaneously only when the vibronic state near the first conical intersection is optically accessed. Our time-resolved measurement of the product state distribution could separate two different dynamic channels unambiguously, unraveling the detailed dynamic mechanism of the nonadiabatic reaction taking place in the vicinity of the conical intersection. The nonadiabatic channel, where the reactive flux funnels through two consecutive conical intersections along the reaction coordinate, is found to be significantly faster than the adiabatic channel along the minimum energy reaction pathway. The kinetic energy release ratio and the nonadiabatic transition probability are found to be much higher for the nonadiabatic channel than those of the adiabatic channel, giving insights into the bifurcation dynamics occurring at the conical intersection. PMID- 29112444 TI - Room-Temperature Giant Charge-to-Spin Conversion at the SrTiO3-LaAlO3 Oxide Interface. AB - The two-dimensional electron gas (2DEG) formed at the interface between SrTiO3 (STO) and LaAlO3 (LAO) insulating layer is supposed to possess strong Rashba spin orbit coupling. To date, the inverse Edelstein effect (i.e., spin-to-charge conversion) in the 2DEG layer is reported. However, the direct effect of charge to-spin conversion, an essential ingredient for spintronic devices in a current induced spin-orbit torque scheme, has not been demonstrated yet. Here we show, for the first time, a highly efficient spin generation with the efficiency of ~6.3 in the STO/LAO/CoFeB structure at room temperature by using spin torque ferromagnetic resonance. In addition, we suggest that the spin transmission through the LAO layer at a high temperature range is attributed to the inelastic tunneling via localized states in the LAO band gap. Our findings may lead to potential applications in the oxide insulator based spintronic devices. PMID- 29112445 TI - Isolation of Chamigrene Sesquiterpenes and Absolute Configuration of Isoobtusadiene from the Brittle Star Ophionereis reticulata. AB - The chemical study of the Brazilian brittle star Ophionereis reticulata led to the isolation of three chamigrene sesquiterpenes, including the partially characterized isoobtusadiene (1), its unreported acetyl derivative (2), and the known (+)-elatol (3). The complete elucidation of the structures 1 and 2 was accomplished by 1D and 2D NMR spectroscopy. The first assignment of the absolute configuration of the isoobtusadiene skeleton is suggested as 6S,9R,10S on the basis of the NMR analysis of the Mosher's ester derivatives of 1 and the ECD study of the acetyl derivative 2. Chamigrenes are typical constituents of Laurencia red algae. O. reticulata is a predator with a preference for algae. Thus, the origin of these metabolites can be likely ascribed to diet. PMID- 29112446 TI - Relevance of Half-Life in Drug Design. AB - Drug half-life has important implications for dosing regimen and peak-to-trough ratio at the steady state. A half-life of 12-48 h is generally ideal for once daily dosing of oral drugs. If the half-life is too short, it may require more frequent dosing in order to maintain desired exposures and avoid unnecessarily high peak concentrations. This may pose challenges to achieving optimal efficacy, safety, and patient compliance. If the half-life is too long, the time over which accumulation and subsequent elimination occur may be prolonged. This may pose problems with managing adverse effects and the design of efficient clinical trials. Half-life is a key parameter for optimization in research and development. Structural modification to affect clearance, and to a lesser extent volume of distribution, is the preferred means of modulating half-life. An effective approach to half-life optimization requires an understanding of the many pitfalls associated with its estimation and interpretation. PMID- 29112447 TI - Transition-Metal-Free Stereocomplementary Cross-Coupling of Diols with Boronic Acids as Nucleophiles. AB - The transition-metal-free diastereoselective C(sp2)-C(sp3) cross-coupling between unprotected diols and boronic acids or potassium organotrifluoroborates is reported. Depending on the reaction conditions, the syn or the anti reaction products are obtained in a stereocomplementary fashion. This type of coupling is developed with alkenyl-, heteroaryl- and arylboron compounds as carbon nucleophiles. PMID- 29112448 TI - New Force Field Model for Propylene Glycol: Insight to Local Structure and Dynamics. AB - In this work we developed a new force field model (FFM) for propylene glycol (PG) based on the OPLS all-atom potential. The OPLS potential was refined using quantum chemical calculations, taking into account the densities and self diffusion coefficients. The validation of this new FFM was carried out based on a wide range of physicochemical properties, such as density, enthalpy of vaporization, self-diffusion coefficients, isothermal compressibility, surface tension, and shear viscosity. The molecular dynamics (MD) simulations were performed over a large range of temperatures (293.15-373.15 K). The comparison with other force field models, such as OPLS, CHARMM27, and GAFF, revealed a large improvement of the results, allowing a better agreement with experimental data. Specific structural properties (radial distribution functions, hydrogen bonding and spatial distribution functions) were then analyzed in order to support the adequacy of the proposed FFM. Pure propylene glycol forms a continuous phase, displaying no microstructures. It is shown that the developed FFM gives rise to suitable results not only for pure propylene glycol but also for mixtures by testing its behavior for a 50 mol % aqueous propylene glycol solution. Furthermore, it is demonstrated that the addition of water to the PG phase produces a homogeneous solution and that the hydration interactions prevail over the propylene glycol self-association interactions. PMID- 29112449 TI - An Average Solvent Electrostatic Configuration Protocol for QM/MM Free Energy Optimization: Implementation and Application to Rhodopsin Systems. AB - A novel atomistic methodology to perform free energy geometry optimization of a retinal chromophore covalently bound to any rhodopsin-like protein cavity is presented and benchmarked by computing the absorption maxima wavelengths (lambdamax) of distant rhodopsin systems. The optimization is achieved by computing the Nagaoka's Free Energy Gradient (FEG) within an Average Solvent Electrostatic Configuration (ASEC) atomistic representation of the thermodynamic equilibrium and minimizing such quantity via an iterative procedure based on sequential classical MD and constrained QM/MM geometry optimization steps. The performance of such an ASEC-FEG protocol is assessed at the CASPT2//CASSCF/Amber level by reproducing the lambdamax values observed for 12 mutants of redesigned human cellular retinol binding protein II (hCRBPII) systems; a set of 10 distant wild-type rhodopsins from vertebrates, invertebrates, eubacteria, and archaea organisms; and finally a set of 10 rhodopsin mutants from an eubacterial rhodopsin. The results clearly show that the proposed protocol, which can be easily extended to any protein incorporating a covalently bound ligand, yields correct lambdamax trends with limited absolute errors. PMID- 29112450 TI - The 2016 Lush Prize Awards. PMID- 29112451 TI - 2016 Lush Science Prize. AB - The Lush Prize supports animal-free testing by awarding monetary prizes totalling L250,000 to the most effective projects and individuals who have been working toward the goal of replacing animals in product or ingredient safety testing. Prizes are awarded for developments in five strategic areas: Science; Lobbying; Training; Public Awareness; and Young Researchers. In the event of a major breakthrough leading to the replacement of animal tests in the area of 21st Century Toxicology, a Black Box Prize (equivalent to the entire annual fund of L250,000) is awarded. The Science Prize is awarded to the researchers whose work the judging panel believe has made the most significant contribution to the replacement of animal testing in the preceding year. This Background Paper outlines the research projects that were shortlisted and presented to the judging panel as potential candidates for the 2016 Lush Science Prize. This process involved reviewing recent work of the relevant scientific institutions and projects in this area, such as the OECD, CAAT, The Hamner Institutes, ECVAM, UK NC3Rs, and the US Tox21 Programme. Recent developments in toxicity testing research were also identified by searching for relevant published papers in the literature, and analysing abstracts from conferences focusing on animal replacement in toxicity testing that had been held in the preceding 12 months - for example the EUSAAT-Linz, Society of Toxicology, and SEURAT-1 conferences. PMID- 29112452 TI - High-throughput prediction of nephrotoxicity in humans. AB - The Lush Science Prize 2016 was awarded to Daniele Zink and Lit-Hsin Loo for the interdisciplinary and collaborative work between their research groups in developing alternative methods for the prediction of nephrotoxicity in humans. The collaboration has led to the establishment of a series of pioneering alternative methods for nephrotoxicity prediction, which includes: predictive gene expression markers based on pro-inflammatory responses; predictive in vitro cellular models based on pluripotent stem cell-derived proximal tubular-like cells; and predictive cellular phenotypic markers based on chromatin and cytoskeletal changes. A high-throughput method was established for chemical testing, which is currently being used to predict the potential human nephrotoxicity of ToxCast compounds in collaboration with the US Environmental Protection Agency. Similar high-throughput imaging-based methodologies are currently being developed and adapted by the Zink and Loo groups, to include other human organs and cell types. The ultimate goal is to develop a portfolio of methods accepted for the accurate prediction of human organ-specific toxicity and the consequent replacement of animal experiments. PMID- 29112453 TI - New animal-free concepts and test methods for developmental toxicity and peripheral neurotoxicity. AB - The complex toxicological fields of repeat dose organ toxicity (RDT) and developmental and reproductive toxicity (DART) still require new concepts and approaches to achieve a fully animal-free safety assessment of chemicals. One novel approach is the generation of relevant human cell types from pluripotent stem cells, and the use of such cells for the establishment of phenotypic test methods. Due to their broad endpoints, such tests capture multiple types of toxicants, i.e. they are a readout for the activation of many adverse outcome pathways (AOPs). The 2016 Lush Science Prize was awarded for the development of one such assay, the PeriTox test, which uses human peripheral neurons generated from stem cells. The assay endpoints measure various cell functions, and these give information on the potential neurotoxicity and developmental neurotoxicity hazard of test compounds. The PeriTox test method has a high predictivity and sensitivity for peripheral neurotoxicants, and thus addresses the inherent challenges in pesticide testing and drug development. Data from the test can be obtained quickly and at a relatively high-throughput, and thus, the assay has the potential to replace animal-based safety assessment during early product development or for screening potential environmental toxicants. PMID- 29112454 TI - Training and good science are the foundation stones for animal replacement. AB - Good science, the training of energetic and enthusiastic young researchers, and the experience of industry veterans, will all be needed to drive the implementation and regulatory approval of animal replacement methods in industry. PMID- 29112456 TI - ERRATUM. PMID- 29112455 TI - On the journey toward humane education in Brazil: First request for a total ban of harmful animal use in professional and higher education. AB - The Brazilian Network for Humane Education (RedEH( is an independent and self managed group comprised of academics from ten different Brazilian states and a number of international collaborators. In 2016, in a concerted effort to change the educational field in Brazil and propagate humane education, RedEH sent a request to the Brazilian National Council for the Control of Animal Experimentation (CONCEA(, asking that harmful animal use in education in professional and undergraduate courses be banned. This was the first formal request for a total replacement of harmful animal use in education in Brazil, and represented a major historic landmark in the advancement of Brazilian science education. This paper presents the full text of the request, as well as outlining its national and international repercussions. The request was supported by InterNICHE and representatives of 18 other international organisations. A major national impact of the request was its recognition by the Federal Council of Veterinary Medicine. With this action, academics and researchers took a potentially revolutionary step in the Brazilian education arena, with regard to advancing and supporting a higher quality, ethical and democratic educational system. PMID- 29112457 TI - FOSL1 Promotes Kras-induced Lung Cancer through Amphiregulin and Cell Survival Gene Regulation. AB - The FOSL1/AP-1 transcription factor regulates gene expression, thereby controlling various pathophysiological processes. It is a major effector of RAS ERK1/2 signaling and is activated in human lung epithelia by tumorigenic stimuli. Recent evidence shows an inverse correlation between FOSL1 expression and the survival of patients with lung cancer and adenocarcinomas; however, its role in lung tumorigenesis remains elusive. In this work, we sought to determine the role of FOSL1 in Kras-induced lung adenocarcinoma in vivo and its downstream effector mechanisms. We used mice expressing the Kras oncogene in the lung with concomitant Fosl1 deletion, Kras-activated murine alveolar epithelial cells (mAECs) with Fosl1 deletion, and KRAS mutant human lung adenocarcinoma (HLAC) cells with FOSL1 deficiency, and performed cell proliferation and gene expression analyses. Mutant Kras induced Fosl1 expression in vitro (mAECs) and in vivo (lung tissue), and mice with Fosl1 deletion showed reduced levels of mutant Kras induced lung tumorigenesis and survived longer than Fosl1-sufficient mice. Studies with mutant Kras-activated mAECs and KRAS-mutant HLAC cells revealed that FOSL1 regulates mutant KRAS-induced gene expression, thereby controlling cell proliferation and survival. In contrast, FOSL1 depletion in non-KRAS-mutant HLAC cells and nonmalignant human lung epithelia had no effect. Our data support the notion that FOSL1-mediated expression of amphiregulin and apoptotic and antioxidative genes plays a role in regulating HLAC cell proliferation and survival. FOSL1 is a determinant of lung cancer in vivo and regulates HLAC cell proliferation and survival, largely in the context of KRAS mutations. Activation of FOSL1 in adenocarcinomas may be a prognostic marker and potential target for human lung cancer with KRAS mutations. PMID- 29112458 TI - Detrimental effects of alcohol exposure around conception: putative mechanisms. AB - In western countries, alcohol consumption is widespread in women of reproductive age, and in binge quantities. These countries also continue to have high incidences of unplanned pregnancies, with women often reported to cease drinking after discovering their pregnancy. This suggests the early embryo may be highly exposed to the detrimental effects of alcohol during the periconception period. The periconception and pre-implantation windows, which include maturation of the oocyte, fertilisation, and morphogenesis of the pre-implantation embryo, are particularly sensitive times of development. Within the oviduct and uterus, the embryo is exposed to a unique nutritional environment to facilitate its development and establish de-novo expression of the genome through epigenetic reprogramming. Alcohol has wide-ranging effects on cellular stress, as well as hormonal, and nutrient signalling pathways, which may affect the development and metabolism of the early embryo. In this review, we summarise the adverse developmental outcomes of early exposure to alcohol (prior to implantation in animal models) and discuss the potential mechanisms for these outcomes that may occur within the protected oviductal and uterine environment. One interesting candidate is reduced retinoic acid synthesis, as it is implicated in the control of epigenetic reprogramming and cell lineage commitment, processes that have adverse consequences for the formation of the placenta, and subsequently, fetal programming. PMID- 29112440 TI - Chemical Biology of H2S Signaling through Persulfidation. AB - Signaling by H2S is proposed to occur via persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH). Persulfidation provides a framework for understanding the physiological and pharmacological effects of H2S. Due to the inherent instability of persulfides, their chemistry is understudied. In this review, we discuss the biologically relevant chemistry of H2S and the enzymatic routes for its production and oxidation. We cover the chemical biology of persulfides and the chemical probes for detecting them. We conclude by discussing the roles ascribed to protein persulfidation in cell signaling pathways. PMID- 29112460 TI - Opioid Neurotoxicity Treated with Intrathecal Drug Delivery System Implant. PMID- 29112459 TI - Atomoxetine, Parent Training, and Their Effects on Sleep in Youth with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Sleep disturbance is often a problem for children with either autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD). Psychostimulant medications used to treat ADHD symptoms can exacerbate this problem. For children with ASD and ADHD, atomoxetine (ATX) is a viable alternative to psychostimulants. We investigated the effects of ATX and a manualized parent training (PT) program targeting noncompliance, on the sleep quality of children with ASD and ADHD. METHODS: Participants in a randomized clinical trial were treated with ATX + PT, ATX alone, PT alone, or placebo (PBO) alone, for 10 weeks. Fifty-four of 128 (42%) caregivers completed the Children's Sleep Habits Questionnaire (CSHQ) at baseline and endpoint. Analysis of covariance was used to investigate possible differences between treatment groups. RESULTS: There were no significant differences between treatment groups, including PBO on the CSHQ 33-Item total score, total hours of sleep per day, and total minutes awake after sleep onset at the study endpoint. CONCLUSION: ATX appears sleep neutral. Clinicians who treat ADHD symptoms in children and adolescents with ASD may prefer ATX over psychostimulants when sleep disturbance is an issue. PMID- 29112461 TI - Calcium and Vitamin D Supplementation in Boys with Risperidone-Induced Hyperprolactinemia: A Randomized, Placebo-Controlled Pilot Study. AB - BACKGROUND: The chronic use of antipsychotics has been associated with impaired bone mineralization, partially mediated by hyperprolactinemia. We examined if calcium and vitamin D supplementation promote bone mineral accrual in boys with risperidone-induced hyperprolactinemia. METHODS: Between February 2009 and November 2013, medically healthy, 5- to 17-year-old boys were enrolled in a 36 week double-blind, placebo-controlled study, examining the skeletal effects of supplementation with 1250 mg calcium carbonate and 400 IU of vitamin D3 in risperidone-induced hyperprolactinemia. Anthropometric, dietary, physical activity, and psychiatric assessments were conducted at baseline and week 18 and 36. Plasma prolactin and vitamin D concentrations were measured at baseline and week 36. Total body less head bone mineral content (BMC) and radius trabecular bone mineral density (BMD) were measured at baseline, week 18, and week 36, using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, respectively. Linear mixed-effects regression analysis examined the longitudinal effect of treatment on skeletal outcomes. RESULTS: Forty-seven boys (mean age: 11.0 +/- 2.6 years) were randomized and 38 completed the study. At study entry, the average dietary calcium intake was below the recommended limit, but the average vitamin D concentration was normal. Calcium and vitamin D supplementation failed to significantly increase BMC or trabecular BMD. It also failed to affect several other skeletal and anthropometric outcomes, including plasma vitamin D concentration. CONCLUSIONS: In this 9-month long pilot study, supplementation with a modest dose of calcium and vitamin D did not increase bone mass accrual in risperidone-treated boys with hyperprolactinemia. Alternative approaches should be investigated to optimize bone health in this population to prevent future morbidity and premature mortality. ClinicalTrials.gov Identifier: NCT00799383. PMID- 29112463 TI - Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. AB - Alcohol drinking is an established risk factor for several malignancies, and it is a potentially modifiable risk factor for cancer. The Cancer Prevention Committee of the American Society of Clinical Oncology (ASCO) believes that a proactive stance by the Society to minimize excessive exposure to alcohol has important implications for cancer prevention. In addition, the role of alcohol drinking on outcomes in patients with cancer is in its formative stages, and ASCO can play a key role by generating a research agenda. Also, ASCO could provide needed leadership in the cancer community on this issue. In the issuance of this statement, ASCO joins a growing number of international organizations by establishing a platform to support effective public health strategies in this area. The goals of this statement are to: * Promote public education about the risks between alcohol abuse and certain types of cancer; * Support policy efforts to reduce the risk of cancer through evidence-based strategies that prevent excessive use of alcohol; * Provide education to oncology providers about the influence of excessive alcohol use and cancer risks and treatment complications, including clarification of conflicting evidence; and * Identify areas of needed research regarding the relationship between alcohol use and cancer risk and outcomes. PMID- 29112464 TI - My Cup Runneth Over. PMID- 29112466 TI - The Effect of Inspiratory Resistance on Exercise Performance and Perception in Moderate Normobaric Hypoxia. AB - : Seo, Yongsuk, Jeremiah Vaughan, Tyler D. Quinn, Brittany Followay, Raymond Roberge, Ellen L. Glickman, and Jung-Hyun Kim. The effect of inspiratory resistance on exercise performance and perception in moderate normobaric hypoxia. High Alt Med Biol. 18:417-424, 2017. PURPOSE: Respirators are simple and efficient in protecting workers against toxic airborne substances; however, their use may limit the physical performance of workers. The purpose of this study was to determine the effect of inspiratory resistance on physical performance and breathing perception in normobaric hypoxia. METHOD: Nine healthy men wore a tight fitting respiratory mask outfitted with one of four different inspiratory resistors (R) (0, 1.5, 4.5, 7.5 cm H2O/L/Sec) while exercising at normobaric hypoxia (17% O2) at submaximal exercise workloads of 50, 100, and 150 W on a cycle ergometer for 10 minutes each, followed by a maximal oxygen uptake (VO2max) test to exhaustion. RESULTS: Maximal power output at R7.5 was significantly lower than R0 (p = 0.016) and R1.5 (p = 0.035). Respiration rate was significantly reduced at R4.5 (p = 0.011) and R7.5 (p <= 0.001) compared with R0. Minute ventilation was significantly decreased in R7.5 compared with R0 (p = 0.003), R1.5 (p = 0.010), and R4.5 (p = 0.016), whereas VO2 was not significantly changed. Breathing comfort (BC) and breathing effort (BE) were significantly impaired in R7.5 (BC: p = 0.025, BE: p = 0.001) and R4.5 (BC: p = 0.007, BE: p = 0.001) compared with R0, but rating of perceived exertion (RPE) remained unchanged. CONCLUSIONS: Added inspiratory resistance limited maximal power output and increased perceptions of BC and BE in normobaric hypoxia. However, low-to moderate inspiratory resistance did not have a deleterious effect on VO2 or RPE at submaximal or maximal exercise. Perceptual and physiological characteristics of respirators of varying inspiratory resistances should be considered by manufacturers and end users during design and respirator selection processes. PMID- 29112465 TI - High-Throughput Screening Identifies 1,4,5-Substituted 1,2,3-Triazole Analogs as Potent and Specific Antagonists of Pregnane X Receptor. AB - Human pregnane X receptor (hPXR) is a nuclear receptor that regulates the expression of phase I and phase II drug-metabolism enzymes, as well as that of drug transporters. hPXR is a "xenobiotics sensor" and can be activated by structurally diverse compounds. The activation of hPXR by its agonists increases the clearance of xenobiotics by increasing the expression of drug-metabolism enzymes and drug transporters, possibly leading to drug toxicity, drug resistance, and other adverse drug reactions. Therefore, hPXR antagonists might attenuate agonist-mediated activation of hPXR and reduce the risk of adverse drug reactions. Several hPXR antagonists have been reported, but none of them is specific for hPXR. In this study, we present the first large-scale, unbiased, cell-based high-throughput screen to identify specific hPXR antagonists. Among the 132,975 compounds screened, we identified the 1,4,5-substituted 1,2,3 triazole analogs as potent and specific hPXR antagonists by sequentially performing primary screening, retesting, and dose-response analysis using cell based hPXR gene reporter and receptor binding assays, as well as receptor and promoter specificity assays. The compound SJ000076745-1 is the most potent and specific hPXR antagonist in the 1,4,5-substituted 1,2,3-triazole chemical class, having a cell-based hPXR antagonist 50% inhibitory concentration (IC50) value of 377 +/- 16 nM and an hPXR binding inhibitory IC50 value of 563 +/- 40 nM. PMID- 29112462 TI - Cancer vaccines and immunotherapeutic approaches in hepatobiliary and pancreatic cancers. AB - Hepatobiliary and pancreatic cancers along with other gastrointestinal malignancies remain the leading cause of cancer-related deaths worldwide. Strategies developed in the recent years on immunotherapy and cancer vaccines in the setting of primary liver cancer as well as in pancreatic cancer are the scope of this review. Significance of orthotopic and autochthonous animal models which mimic and/or closely reflect human malignancies allowing for a prompt and trustworthy analysis of new therapeutics is underlined. Combinational approaches that on one hand, specifically target a defined cancer-driving pathway, and on the other hand, restore the functions of immune cells, which effector functions are often suppressed by a tumor milieu, are shown to have the strongest perspectives and future directions. Among combinational immunotherapeutic approaches a personalized- and individual cancer case-based therapy is of special importance. PMID- 29112467 TI - Meniscectomy and Resultant Articular Cartilage Lesions of the Knee Among Prospective National Football League Players: An Imaging and Performance Analysis. AB - BACKGROUND: The effect of prior meniscectomy and the resulting reduction in meniscal tissue on a potential National Football League (NFL) player's articular cartilage status and performance remain poorly elucidated. Purpose/Hypothesis: (1) To determine the epidemiology, imaging characteristics, and associated articular cartilage pathology of the knee among players with a previous meniscectomy who were participating in the NFL Combine and (2) to evaluate the effect of these injuries on performance as compared with matched controls. The hypothesis was that players with less meniscal tissue would have worse cartilage status and inferior performance metrics in their first 2 NFL seasons. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All athletes with a history of a meniscectomy and magnetic resonance imaging scan of the knee who participated in the NFL Combine (2009-2015) were identified. Medical records and imaging were analyzed, and surgical history, games missed in college, position played, and draft position were documented. The conditions of the meniscus and cartilage were graded with modified ISAKOS scores (International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine) and ICRS scores (International Cartilage Repair Society), respectively. Players with a previous meniscectomy of at least 10% of total medial or lateral meniscal volume excised (ISAKOS meniscus grade <=8) and matched controls without a significant pre Combine injury were similarly evaluated and compared by position of play through analysis of draft position, number of games played and started, and how many eligible plays they participated in (snap percentage) within the first 2 NFL seasons. RESULTS: Of the 2285 players who participated in the NFL Combine (2009 2015), 287 players (322 knees) had a prior meniscectomy (206 lateral, 81 medial). Among these players, 247 (85%) had a total of 249 chondral lesions, most commonly on the lateral femoral condyle (111 lesions, 45%). There was a significant inverse correlation found between the ISAKOS medial and lateral meniscus grade and the corresponding compartment chondral lesion grade ( P = .001). A poorer meniscus score was also associated with worse chondral pathology, especially in the lateral compartment. After controlling for position of play, the injury-free control group had a significantly greater number of total games played and games started and higher snap percentage versus those with a prior meniscectomy of at least 10% volume (ISAKOS meniscus grade <=8). Players with severe chondral lesions (ICRS grade 4) in the medial and lateral compartments had significantly worse performance metrics when compared with matched controls. CONCLUSION: Previous meniscectomy of at least 10% of total medial or lateral meniscus volume in prospective NFL players was significantly correlated with larger and more severe chondral lesions. Chondral and meniscal defects of the knee were found to result in a significant decrease in objective performance measures during a player's initial NFL career versus matched controls. Given these findings, players with a prior meniscectomy with evidence of chondral damage should be evaluated carefully for their overall functional levels; however, additional work is needed to fully clarify the effect of prior knee meniscal surgery on overall NFL performance. PMID- 29112468 TI - The Effects of On-Pump and Off-Pump Coronary Artery Bypass Surgery on Respiratory Function in the Early Postoperative Period. AB - BACKGROUND: Respiratory complications are common after cardiac surgery and the use of extracorporeal circulation is one of the main causes of lung injury. We hypothesized a better postoperative respiratory function in off-pump coronary artery bypass grafting (OPCABG) as compared with "on-pump coronary artery bypass grafting" (ONCABG). METHODS: This is a retrospective, single-center study at a cardiothoracic intensive care unit (ICU) in a tertiary university hospital. Consecutive data on 339 patients undergoing elective CABG (n = 215 ONCABG, n = 124 OPCABG) were collected for 1 year from the ICU electronic medical records. We compared respiratory variables (Pao2, Pao2/Fio2 ratio, Sao2, and Paco2) at 7 predefined time points (ICU admission, postoperative hours 1, 3, 6, 12, 18, and 24). We also evaluated time to extubation, rates of reintubation, and use of noninvasive ventilation (NIV). We used mixed-effects linear regression models (with time as random effect for clustering of repeated measures) adjusted for a predetermined set of covariates. RESULTS: The values of Pao2 and Pao2/Fio2 were significantly higher in the OPCABG group only at ICU admission (mean differences: 9.7 mm Hg, 95% confidence interval [CI] 3.1-16.2; and 27, 95% CI 6.1-47.7, respectively). The OPCABG group showed higher Paco2, overall ( P = .02) and at ICU admission (mean difference 1.8 mm Hg, 95% CI: 0.6-3), although mean values were always within normal range in both groups. No differences were seen in Sao2 values, time to extubation, rate of reintubation rate, and use of postoperative NIV. Extubation rate was higher in OPCABG only at postoperative hour 12 (92% vs ONCABG 82%, P = .02). CONCLUSION: The OPCABG showed only marginal improvements of unlikely clinical meaning in oxygenation as compared to ONCABG in elective low risk patients. PMID- 29112469 TI - Risk of Clinically Significant Prostate Cancer Associated With Prostate Imaging Reporting and Data System Category 3 (Equivocal) Lesions Identified on Multiparametric Prostate MRI. AB - OBJECTIVE: The objective of this study is to determine the frequency of clinically significant cancer (CSC) in Prostate Imaging Reporting and Data System (PI-RADS) category 3 (equivocal) lesions prospectively identified on multiparametric prostate MRI and to identify risk factors (RFs) for CSC that may aid in decision making. MATERIALS AND METHODS: Between January 2015 and July 2016, a total of 977 consecutively seen men underwent multiparametric prostate MRI, and 342 underwent MRI-ultrasound (US) fusion targeted biopsy. A total of 474 lesions were retrospectively reviewed, and 111 were scored as PI-RADS category 3 and were visualized using a 3-T MRI scanner. Multiparametric prostate MR images were prospectively interpreted by body subspecialty radiologists trained to use PI-RADS version 2. CSC was defined as a Gleason score of at least 7 on targeted biopsy. A multivariate logistic regression model was constructed to identify the RFs associated with CSC. RESULTS: Of the 111 PI-RADS category 3 lesions, 81 (73.0%) were benign, 11 (9.9%) were clinically insignificant (Gleason score, 6), and 19 (17.1%) were clinically significant. On multivariate analysis, three RFs were identified as significant predictors of CSC: older patient age (odds ratio [OR], 1.13; p = 0.002), smaller prostate volume (OR, 0.94; p = 0.008), and abnormal digital rectal examination (DRE) findings (OR, 3.92; p = 0.03). For PI RADS category 3 lesions associated with zero, one, two, or three RFs, the risk of CSC was 4%, 16%, 62%, and 100%, respectively. PI-RADS category 3 lesions for which two or more RFs were noted (e.g., age >= 70 years, gland size <= 36 mL, or abnormal DRE findings) had a CSC detection rate of 67% with a sensitivity of 53%, a specificity of 95%, a positive predictive value of 67%, and a negative predictive value of 91%. CONCLUSION: Incorporating clinical parameters into risk stratification algorithms may improve the ability to detect clinically significant disease among PI-RADS category 3 lesions and may aid in the decision to perform biopsy. PMID- 29112470 TI - Safety and Efficacy of Catheter-Directed Therapies as a Supplement to Surgical Decompression in Venous Thoracic Outlet Syndrome. AB - OBJECTIVE: The purpose of this study is to evaluate the role of endovascular therapy in the management of venous thoracic outlet syndrome (TOS), with an emphasis on its role after surgical decompression. MATERIALS AND METHODS: This single-center retrospective review identified all patients who underwent conventional contrast-enhanced venography as a component of the imaging evaluation of clinically suspected venous TOS from January 2004 through September 2015. Eighty-one patients were identified, with a mean (+/- SD) age of 33 +/- 12 years, of whom 59% (48/81) were women. After imaging confirmation of venous TOS, a standardized treatment protocol combining surgical and endovascular intervention was used for management. RESULTS: Of the 81 patients included in the study, 73 (90%) had angiographic evidence of venous TOS; 41 of these 73 patients (56%) underwent endovascular venous intervention (e.g., thrombolysis or angioplasty before surgical) decompression. A total of 67 patients (67/73; 92%) with venous TOS underwent surgical decompression, with 56 of these (56/73; 77%) undergoing postoperative venography. Of these 56 patients who underwent postoperative venography, 48 (86%) required venoplasty, four had normal-appearing subclavian veins (7%) and had no intervention, and four of 48 (8%) had chronic total venous occlusions that could not be recanalized. Only four of the 48 of the patients (8%) who underwent postdecompression venoplasty required subsequent repeat venography and intervention for management of persistent or recurrent symptoms, whereas all others (44/48; 92%) remained symptom free on clinical follow-up. No complications were identified that were related to the endovascular interventions. CONCLUSION: Combining venography and endovascular venous intervention with surgical decompression in managing patients with clinically suspected venous TOS is safe and effective. Postdecompression venoplasty appears to be highly effective, with a low rate of symptom recurrence. PMID- 29112471 TI - Screening for Breast Cancer in Women Age 75 Years and Older. AB - OBJECTIVE: Older women undergoing regular mammography experience significant reductions in breast cancer mortality, except in women with severe comorbidities or limited life expectancy. Optimizing screening strategies requires informed discussions of benefits and risks given each woman's health status. CONCLUSION: This article will review the benefits and risks of screening mammography in women older than 75 years within the context of life expectancy and comorbidities and summarize the current recommendations from professional organizations for screening mammography in older women. PMID- 29112472 TI - Clinical Evaluation of Silent T1-Weighted MRI and Silent MR Angiography of the Brain. AB - OBJECTIVE: New MRI sequences based on rapid radial acquisition have reduced gradient noise. The purpose of this study was to compare Silent T1-weighted and unenhanced MR angiography (MRA) against conventional sequences in a clinical population. MATERIALS AND METHODS: The study cohort consisted of 40 patients with suspected brain metastases (median age, 60 years; range, 23-91 years) who underwent T1-weighted contrast-enhanced MRI and 51 patients with suspected vascular lesions or cerebral ischemia (median age, 60 years; range, 16-94 years) who underwent unenhanced intracranial MRA. Three neuroradiologists reviewed the images blindly and rated several measures of image quality on a 5-point Likert scale. Reviewers recorded the number of enhancing lesions and whether Silent images were better than, worse than, or equivalent to conventional images. RESULTS: For T1-weighted MR images, ratings were slightly lower for Silent versus conventional images, except for diagnostic confidence. Although more lesions were detected on conventional images, this difference was not statistically significant; agreement was seen in 88% of cases. In 48% of cases, T1-weighted scans were deemed equivalent, but when a preference existed, it was usually for conventional images (38% vs 14%). Conventional MRA images were rated higher on all image quality metrics and were strongly preferred (reviewers preferred conventional images in 69% of cases, rated the images as equivalent in 27% of cases, and preferred Silent images in 4% of cases). In some cases, artifacts on Silent images caused reduced vessel caliber, vessel irregularities, and even absent vessels. CONCLUSION: Although conventional T1-weighted images were preferred overall, most Silent T1-weighted images were rated as equivalent to or better than conventional images and represent a potential alternative for imaging of noise-averse patients. Silent MRA scored significantly worse and could not be recommended at this time, suggesting that it requires additional refinement before routine clinical use. PMID- 29112473 TI - Percutaneous Thermal Ablation of Spinal Metastases: Recent Advances and Review. AB - OBJECTIVE: The purpose of this study was to review the available armamentarium and most recent advances in minimally invasive, image-guided percutaneous thermal ablation for treatment of spinal metastases. CONCLUSION: Minimally invasive percutaneous spine thermal ablation technologies have proved safe and effective in management of selected patients with spinal metastases. Special attention to procedure techniques including choice of ablation modality, thermoprotection, adequacy of treatment, and postablation imaging is essential for improved patient outcomes. PMID- 29112474 TI - JOURNAL CLUB: MRI Evaluation of Midtarsal (Chopart) Sprain in the Setting of Acute Ankle Injury. AB - OBJECTIVE: This study determined the frequency and MRI appearance of osseous and ligamentous injuries in midtarsal (Chopart) sprains and their association with ankle sprains after acute ankle injuries. Prospective diagnosis of and interobserver agreement regarding midtarsal injury among musculoskeletal radiologists were also assessed. SUBJECTS AND METHODS: Two cohorts with ankle MRI were identified via a digital PACS search: patients who had undergone MRI within 8 weeks after ankle injury and control subjects who had not sustained ankle trauma. Studies were retrospectively reviewed in consensus as well as independently, assessing ligamentous and osseous injury to the Chopart joint (calcaneocuboid and talonavicular joints) and associated lateral collateral and deltoid ligamentous injury. Interobserver agreement was calculated, and prospective radiology reports were reviewed to determine the musculoskeletal radiologist's familiarity with Chopart joint injury. RESULTS: MR images of control subjects (n = 16) and patients with ankle injury (n = 47) were reviewed. The normal dorsal calcaneocuboid and calcaneocuboid component of bifurcate ligaments were variably visualized; the remaining normal ligaments were always seen. Eleven patients (23%) had midtarsal ligamentous and osseous injury consistent with midtarsal sprain (eight acute or subacute, one probable, and two old). Six (75%) of eight acute or subacute cases had coexisting lateral collateral ligament injury. Eighty-nine percent of osseous injuries were reported prospectively, but 83% of ligamentous injuries were missed. Substantial interobserver agreement was achieved regarding diagnosis of midtarsal sprain. CONCLUSION: Midtarsal sprains are commonly associated with acute ankle injury and with ankle sprains. Presently, midtarsal sprains may be underrecognized by radiologists; thus, greater familiarity with the MRI spectrum of ligamentous and osseous injuries at the Chopart joint is important for accurate diagnosis and clinical management. PMID- 29112475 TI - Transjugular Venous Approach for Endovascular Interventions in Hemodialysis Grafts and Fistulas of the Upper Extremities. AB - OBJECTIVE: This article describes the use of a transjugular venous access for interventions in upper extremity hemodialysis arteriovenous fistulas (AVFs) and grafts. This access is used in selected patients in whom direct puncture of the hemodialysis access is considered to be difficult or cumbersome. Technical success was achieved in 96.7% of patients. If an intervention is unsuccessful, the transjugular access offers the possibility of placement of a dialysis catheter for temporary or long-term hemodialysis. CONCLUSION: The transjugular approach for hemodialysis access endovascular interventions is technically successful and safe. Initially described as an intervention to treat malfunctioning arteriovenous grafts, we have used it successfully in AVF interventions. In our opinion, this approach is a safe and effective alternative that may prove useful in selected patients. PMID- 29112476 TI - Cross-Sectional Evaluation of Plasma Vitamin D Levels in a Large Cohort of Italian Patients with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. AB - BACKGROUND: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are immune-mediated diseases characterized by obsessive-compulsive symptoms and/or tics triggered by group A Streptococcus infections. Despite the well-known action of 25-hydroxyvitamin D [25(OH)D] on different conditions driven by systemic inflammation, there are no data about the 25(OH)D status in patients with PANDAS. AIMS: To evaluate plasma 25(OH)D levels in a large cohort of children and adolescents with PANDAS and comparing the results with healthy controls. METHODS: We have evaluated plasma 25(OH)D levels in 179 Italian patients with PANDAS (49 females, 130 males, mean age at diagnosis: 101.4 +/- 30.1 months) and in an age-, gender-, and body mass index matched control group of 224 healthy subjects. RESULTS: Patients with PANDAS have shown more frequently reduced 25(OH)D levels (<30 ng/mL) in comparison with controls (94.6% vs. 82.5%, p = 0.0007). Patients with PANDAS had also lower levels of 25(OH)D than controls (20.4 +/- 6.9 ng/mL vs. 24.8 +/- 7.3 ng/mL, p < 0.0001). This difference was observed during both winter (13.7 +/- 3.25 ng/mL vs. 21.4 +/- 5.9 ng/mL, p < 0.0001) and summer (21.8 +/- 6.5 ng/mL vs. 32.5 +/- 8.7 ng/mL, p < 0.0001). Notably, serum 25(OH)D levels correlated with both number of streptococcal (strep) infections before diagnosis of PANDAS (p < 0.005) and with infection recurrence (p < 0.005). CONCLUSIONS: PANDAS patients have reduced 25(OH)D levels, which appear related to streptococcal infections and the probability of recurrence. Further long-term studies with higher number of patients are needed to investigate and confirm this relationship. PMID- 29112477 TI - The Renaissance of Gene and Cell Therapy: Florence 2016. PMID- 29112479 TI - A New Era in Critical Care Ultrasound: Professionalization. PMID- 29112480 TI - Introduction to special issue: International Society for Vaccines Annual Congress 2016. PMID- 29112481 TI - Diffusion Tensor Imaging of Central Auditory Pathways in Patients with Sensorineural Hearing Loss: A Systematic Review. AB - Objective The radiologic evaluation of patients with hearing loss includes computed tomography and magnetic resonance imaging (MRI) to highlight temporal bone and cochlear nerve anatomy. The central auditory pathways are often not studied for routine clinical evaluation. Diffusion tensor imaging (DTI) is an emerging MRI-based modality that can reveal microstructural changes in white matter. In this systematic review, we summarize the value of DTI in the detection of structural changes of the central auditory pathways in patients with sensorineural hearing loss. Data Sources PubMed, Embase, and Cochrane. Review Methods We used the Preferred Reporting Items for Systematic Reviews and Meta Analysis statement checklist for study design. All studies that included at least 1 sensorineural hearing loss patient with DTI outcome data were included. Results After inclusion and exclusion criteria were met, 20 articles were analyzed. Patients with bilateral hearing loss comprised 60.8% of all subjects. Patients with unilateral or progressive hearing loss and tinnitus made up the remaining studies. The auditory cortex and inferior colliculus (IC) were the most commonly studied regions using DTI, and most cases were found to have changes in diffusion metrics, such as fractional anisotropy, compared to normal hearing controls. Detectable changes in other auditory regions were reported, but there was a higher degree of variability. Conclusion White matter changes based on DTI metrics can be seen in patients with sensorineural hearing loss, but studies are few in number with modest sample sizes. Further standardization of DTI using a prospective study design with larger sample sizes is needed. PMID- 29112483 TI - Clinicopathologic Factors Predictive of Occult Lymph Node Involvement in Cutaneous Head and Neck Melanoma. AB - Objectives Evaluate clinicopathologic factors contributing to regional lymph node (LN) metastases in cutaneous head and neck melanoma (HNM). Study Design Retrospective review of a national cancer database. Setting National Cancer Database (2004-2012). Methods National Cancer Database (NCDB) cases diagnosed between 2004 and 2012 were reviewed. Inclusion criteria were head and neck cutaneous site codes, melanoma histology codes, and clinically node-negative status. Independent, clinicopathologic factors associated with pathologic positive LN status were identified by multivariable logistic regression. Subset analysis was performed on thin melanoma cases of 0.75 to 1 mm tumor depth to determine factors predictive of LN involvement and survival. Results Of 66,495 cases meeting inclusion criteria, 18,882 had nodes examined pathologically with 9.7% presenting with occult positive LN involvement. Mean (SD) age was 62.9 (16.13) years, and primary sites were scalp and neck (42.2%), face (40.2%), and external ear, lip, or eyelid (7.6%). Multivariable analysis found younger age; primary site of cutaneous scalp, neck, or face; increasing thickness; mitoses; ulceration; and vertical growth phase presence were independently associated with LN positivity ( P < .001). Only 2% of 0.75- to 1.0-mm Breslow thickness cases had regional LN involvement, and age >70 was negatively associated with LN involvement ( P = .002) in this subset. Conclusion This is the largest study examining factors predictive of occult LN involvement in patients with clinical node-negative cutaneous HNM who may benefit from sentinel LN biopsy. Primary sites of external ear, lip, or eyelid are less likely to present with occult nodal involvement, and older patients with T1a melanoma >=0.76 mm are unlikely to present with regional node metastasis and may not require sentinel node guided management. PMID- 29112482 TI - Regulating the advertising and promotion of stem cell therapies. AB - There are widespread concerns with the ways in which 'unproven' stem cell therapies are advertised to patients. This article explores the potential and limits of using laws that regulate advertising and promotion as a tool to address these concerns. It examines general consumer protection laws and laws and policies on advertising medical products and services, focusing on the USA, Canada and Australia. The content of existing laws and policies covers most of the marketing practices that cause concern, but several systemic factors are likely to limit enforcement efforts. Potential reforms in Australia that would prevent direct-to-consumer advertising of autologous cell therapies are justified in principle and should be considered by other jurisdictions, but again face important practical limits to their effectiveness. PMID- 29112484 TI - The Effect of Telehealth Interventions on Quality of Life of Cancer Patients: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: In 2016, ~1.7 million new cases of cancer were diagnosed. Cancer patients can have physical, functional, and psychosocial issues when dealing with cancer treatment. Telehealth has been effectively introduced to help deliver treatment to patients suffering from chronic disease; however, there is little consensus on its effectiveness in administering sociobehavioral cancer treatments. Thus, this study determines the benefits of telehealth-based interventions providing emotional and symptom support in improving quality of life (QOL) among cancer patients. METHODS: Two researchers conducted comprehensive searches on PubMed, SCOPUS, Medline, PsycINFO, ERIC, Psychology and Behavioral Collection, and Medline Complete. Key search terms included telehealth or telemedicine and QOL and cancer. Articles were included if they assessed a telehealth-delivered intervention for adult cancer patients and provided a QOL assessment. Data were extracted to calculate mean effect sizes for QOL measures on the effectiveness of telehealth relative to usual care (UC) for cancer treatments. RESULTS: Out of 414 articles identified in our initial search, nine articles fit our inclusion criteria. Both telehealth (Hedges g = 0.211, p = 0.016) and standard of care (Hedges g = 0.217, p < 0.001) cancer treatment delivery methods demonstrated small, but statistically significant improvements in QOL measures. However, there were no statistically significant differences in effectiveness between the telehealth interventions and UC (p = 0.76). CONCLUSIONS: The results indicate that telehealth interventions are as effective at improving QOL scores in patients undergoing cancer treatment as in-person UC. Further studies should be undertaken on different modalities of telehealth to determine its appropriate and effective use in interventions to improve the QOL for cancer patients undergoing treatment. PMID- 29112486 TI - Ten years of experience and progress of electronic immunization registry system in Jiangsu Province, China. AB - The electronic immunization registry system (EIRs) can improve the vaccine coverage monitoring significantly. The EIRs in Jiangsu Province, China was set up since 2006. In this paper, the mechanism and structure of the EIRs were summarized, and then some function of this system were illustrated. The application of the EIRs was believed to be an effective health management and electronic vaccine record quality improvement tool in China. The experience and progress we gained could provide a valuable example for other countries. PMID- 29112487 TI - Pharmacotherapy for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review. AB - Objective Angioedema is a potentially life-threatening complication of angiotensin-converting enzyme inhibitor (ACEI) use, occurring in up to 0.5% of users. Although the pathophysiology of ACEI-induced angioedema is attributable to elevated serum bradykinin, standard management typically includes corticosteroids and antihistamines. We sought to summarize the evidence supporting pharmacotherapy for ACEI-induced angioedema. Data Sources PubMed, MEDLINE, and Embase portals. Methods A systematic literature review was conducted according to the PRISMA guidelines. Databases were queried by 3 independent reviewers for English-language studies published between 1980 and 2017. The initial search screened for all occurrences of "angioedema" and then was further refined to include studies of ACEI-related cases and exclude hereditary angioedema. Results Five articles representing 218 cases were identified, including 3 randomized controlled trials and 2 prospective case series with historical controls. One of 2 studies of icatibant (bradykinin B2 receptor antagonist) found more rapid symptom improvement than that with a control group of corticosteroids and antihistamines. Two studies of ecallantide (plasma kallikrein inhibitor) and 1 study of C1 inhibitor replacement found no significant benefit over control. No studies were identified that compared the efficacy of corticosteroids with antihistamines, of one dose with another, of fresh frozen plasma, or of combination therapy. Conclusion The efficacy of treatment of ACEI-induced angioedema with bradykinin antagonists, kallikrein inhibitor, and C1 inhibitor warrants further study. Although consistent benefit of these medications has not been demonstrated, their use has not caused harm. One study examining off-label use of icatibant has demonstrated efficacy over control. In addition, further study is needed to establish the efficacy and mechanism of action of standard pharmacotherapy such as corticosteroids and antihistamines in treatment of this condition. PMID- 29112488 TI - Immunogenicity and safety of a novel seasonal influenza preservative-free vaccine manufactured in Kazakhstan: Results of a randomized, comparative, phase II clinical trial in adults. AB - BACKGROUND: The study was aimed at comparative evaluation of seasonal influenza vaccine RIBSP versus commercial vaccine VAXIGRIP(r) for immunogenicity and safety in the course of clinical trial phase II on healthy volunteers aged 18-60 years. METHODS: The trial involved 150 subjects in randomized 2:1 groups that received either RIBSP vaccine or comparator vaccine VAXIGRIP(r). One dose (0.5 ml) of either vaccine contained 15 MUg of hemagglutinin of each influenza virus strain recommended by WHO for the Northern hemisphere in 2016-2017 flu season. The observation period lasted 21 day. The trial was registered at ClinicalTrials.gov identifier NCT 03016143. RESULTS: Assessment of immunogenic activity of the vaccine under study showed that in 21 day the portion of participants with 4-fold seroconversions was 87.0% to A/H1N1; 63.0% to A/H3N2 and 59.0% to B virus. Antibody titer increase factor in the group of subjects that received RIBSP vaccine was 23.3 for A/H1N1; 4.4 for A/H3N2 and 4.5 for B virus. The volunteers that received RIBSP vaccine demonstrated 95% seroprotection level against A/H1N1; 84% against A/H3N2 and 80% against B virus. RIBSP vaccine met the CHMP criteria of the Committee for Medicinal Products for Human Use (CPMP/BWP/214/96). In the course of evaluating the vaccine safety no serious undesirable effects were recorded. All changes of laboratory data were slight and single in most cases. All recorded local reactions have been light in character and these have been predicted reactions observed at vaccination against influenza. CONCLUSION: Comparison of the allantoic inactivated split vaccine obtained in vaccines RIBSP and VAXIGRIP(r), showed similar immunogenic activity. Both vaccines were safe for the study participants. PMID- 29112489 TI - [The present and future of Hospital Pharmacy in Latin America]. PMID- 29112490 TI - Implementation of Specialized Pharmaceutical Care Hospital Outpatient Clinics in a Hospital Pharmacy Department. AB - OBJECTIVE: To describe the organization of patient care into Specialized Pharmaceutical Care Hospital Outpatient Clinics in a Hospital Pharmacy Department, to evaluate their healthcare quality, and the quality perceived by outpatients. METHOD: A retrospective observational study in a High-Level Hospital Pharmacy Department during three periods (years 2010, 2013 and 2016); description of the organization at the levels of structure, human resources, material resources and working procedures; evaluation of healthcare quality through the analysis of three variables in terms of procedure: prior appointment compliance, waiting time and documentation of pharmaceutical care; evaluation of quality perceived by outpatients through a satisfaction survey; comparative statistical analysis of means (Student's t) and proportions (Pearson's chi square). RESULTS: Fifteen (15) specialized outpatient clinics were opened and managed by 18 pharmacists; between the initial and final periods of the study (2010 vs. 2016), the compliance with previous appointments was of 61.3% vs. 88.8% (p <0001), waiting time was 27.6+/-12.1 vs. 12.1+/-5.4 minutes (p <0.0001), documentation of pharmaceutical care in the clinical record was of 2.3% vs. 9.81% (p <0.0001), and the overall satisfaction perceived by the patients was 6.63+/-2.36 vs. 9.16+/-1.27 (p <0.01). CONCLUSIONS: The model of Specialized Pharmaceutical Care Hospital Outpatient Clinics exposed, focused on the patient and with continuity of care, has improved the quality of care and the quality perceived by the patients and it's in optimal conditions to investigate its contribution on health outcomes and on the health system through a better quality, safety and efficiency of pharmacotherapy. PMID- 29112491 TI - Predictive factors of hyperglycemia in hospitalized adults receiving total parenteral nutrition. AB - OBJECTIVE: To know those predictive factors of hyperglycemia that could guide us the design of a parenteral nutrition and it could avoid later complications associated with it. Methods: A prospective observational study was designed; adult hospitalized patients who received total parenteral nutrition at least 48 hours were included. Nutritional and pharmacotherapeutic follow-up were performed according to usual practice. Variables collected included demographic, clinical, analytical and nutrition and pharmacotherapy. Results: Fifty-eight patients were included, with 28 patients (48.3%) with glucose restriction. This intervention was statistically associated with elevated glycemia prior to parenteral nutrition (OR: 1.38, 95% CI 1.11-1.73, p = 0.004) and BMI (OR: 1.29, 95% CI 1.05-1.58, p = 0.014), with more frequent intervention was in patients with BMI > 25 (overweight and obese) (OR: 10.00; 95% CI 1.15-86.95, p = 0.037). CONCLUSIONS: Pre-parenteral glycemic values, diabetes and BMI values > 25 are predictors of hyperglycemia, so a early intervention to prevent and correct hyperglycemia may improve clinical outcomes in patients with parenteral nutrition. PMID- 29112492 TI - Failure mode and effects analysis applied to the administration of liquid medication by oral syringes. AB - OBJECTIVE: To carry out a Failure Mode and Effects Analysis (FMEA) to the use of oral syringes. METHODS: A multidisciplinary team was assembled within the Safety Committee. The stages of oral administration process of liquid medication were analysed, identifying the most critical and establishing the potential modes of failure that can cause errors. The impact associated with each mode of failure was calculated using the Risk Priority Number (RPN). Preventive actions were proposed. RESULTS: Five failure modes were identified, all classified as high risk (RPN> 100). Seven of the eight preventive actions were implemented. CONCLUSIONS: The FMEA methodology was a useful tool. It has allowed to know the risks, analyse the causes that cause them, their effects on patient safety and the measures to reduce them. PMID- 29112493 TI - [Cysteamine ophthalmic hydrogel for the treatment of ocular cystinosis]. AB - Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its administration by the topical ocular route. The aim of the present study is to determine the stability of an ophthalmic hydrogel of cysteamine, which can be potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical and chemical parameters were evaluated: osmolality, pH and cysteamine concentration, which has been measured by a method of ultra performance liquid chromatography-tandem mass spectrometer (UPLC MS/MS). Descriptive assays were also performed, such as transparency measurement and microbiological assays in order to verify its sterility. The obtained results allow us to conclude that the cysteamine hydrogel is stable during 30 days, being recommendable its preservation in refrigerated conditions. PMID- 29112494 TI - Proposal for the Creation of a National Strategy for Precision Medicine in Cancer: a position statement of SEOM, SEAP and SEFH. AB - Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Precision medicine is transforming clinical and biomedical research, as well as health care itself from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational and knowledge-related challenges. Without a national strategy, precision medicine, which will be implemented one way or another, could take place without the appropriate planning that can guarantee technical quality, equal access of all citizens to the best practices, violating the rights of patients and professionals and jeopardizing the solvency of the healthcare system. With this paper from the Spanish Societies of Medical Oncology (SEOM), Pathology (SEAP), and Hospital Pharmacy (SEFH) we highlight the need to institute a consensual national strategy for the development of precision medicine in our country, review the national and international context, comment on the opportunities and challenges for implementing precision medicine, and outline the objectives of a national strategy on precision medicine in cancer. PMID- 29112495 TI - [Choriocarcinoma: a case report]. PMID- 29112496 TI - [Bleomycin, when miligrams do not refer to weight]. PMID- 29112497 TI - [Controversies about the mechanism of postcoital levonorgestrel: evidences according to the decrease of pregnancies]. PMID- 29112498 TI - [Deprescribing: guiding its definition]. PMID- 29112499 TI - [Polypharmacy and potential drug-drug interactions in an HIV-infected elderly population]. PMID- 29112501 TI - Triple threat: adiposity, aging, atrial fibrillation. PMID- 29112502 TI - Canine Bracket Guide for Substitution Cases. PMID- 29112503 TI - Effectiveness of Clear Aligners in Treating Patients with Anterior Open Bite: A Retrospective Analysis. PMID- 29112504 TI - Miniscrew-Assisted Treatment of a Transposed and Horizontally Impacted Upper Central Incisor. PMID- 29112505 TI - Effects of Bisphosphonates on Orthodontic Treatment and the TMJ: A Systematic Review. PMID- 29112506 TI - Extraction of Gingivally Retained Deciduous Teeth Using Orthodontic Elastics. PMID- 29112507 TI - Physiological Drifting of Ectopic Canines. PMID- 29112509 TI - Association Between Sensorimotor Impairments and Functional Brain Changes in Patients With Low Back Pain: A Critical Review. AB - Low back pain (LBP) coincides with sensorimotor impairments, for example, reduced lumbosacral tactile and proprioceptive acuity and postural control deficits. Recent functional magnetic resonance imaging studies suggest that sensorimotor impairments in LBP may be associated with brain changes. However, no consensus exists regarding the relationship between functional brain changes and sensorimotor behavior in LBP. Therefore, this review critically discusses the available functional magnetic resonance imaging studies on brain activation related to nonnociceptive somatosensory stimulation and motor performance in individuals with LBP. Four electronic databases were searched, yielding nine relevant studies. Patients with LBP showed reduced sensorimotor-related brain activation and a reorganized lumbar spine representation in higher-order (multi)sensory processing and motor regions, including primary and secondary somatosensory cortices, supplementary motor area, and superior temporal gyrus. These results may support behavioral findings of sensorimotor impairments in LBP. In addition, patients with LBP displayed widespread increased sensorimotor-evoked brain activation in regions often associated with abnormal pain processing. Overactivation in these regions could indicate an overresponsiveness to sensory inputs that signal potential harm to the spine, thereby inducing overgeneralized protective responses. Hence, functional brain changes could contribute to the development and recurrence of LBP. However, future studies investigating the causality between sensorimotor-related brain function and LBP are imperative. PMID- 29112508 TI - Estrogen Modulates Corneal Nociception and Maintains Corneal Homeostasis in Rat Eye. AB - PURPOSE: To evaluate the role of estrogen in corneal nociception, its influence on lacrimal secretion, and development of dry eye. METHODS: Ovariectomy was performed in normal healthy female rats (OVX). Estrogen replacement was performed in a population of these rats (OVX+E). Tests for dry eye and corneal sensitivity were performed and compared with rats in proestrus (PRO) as controls. Gene expression of neuropeptides such as substance P, calcitonin gene receptor-like protein (CGRP), estrogen receptor alpha, TRPV1, and TRPM8 was evaluated in the cornea and trigeminal ganglion. Expression of substance P and CGRP in the cornea was also examined by immunohistochemistry. The response of the cornea to capsaicin and menthol was evaluated to identify the activity of receptors TRPV1 and TRPM8, respectively. RESULTS: There was a significant decrease in tear formation (4.2 +/- 0.6 mm/min vs. 6.6 +/- 0.42 mm/min), corneal sensitivity (2.2 +/- 0.17 cm vs. 6 +/- 0 cm), and increase in fluorescein staining in corneas after ovariectomy compared with controls. There was a significant decrease in gene expression of CGRP, substance P, TRPV1, and TRPM8 in the ovarioectomized cornea. A significant decrease in tear formation (3.17 +/- 0.30 mm/min vs. 7.17 +/- 0.87 mm/min) and eye wipe response (10.5 +/- 1.99 wipes vs. 18.33 +/- 1.05 wipes) after treatment with menthol and capsaicin in OVX rats was observed. Estrogen replacement significantly enhanced tear formation (4.02 +/- 0.6 mm/min vs. 6.7 +/- 0.80 mm/min), corneal sensitivity (2.2 +/- 0.17 cm vs. 3.2 +/- 0.17 cm), and response to capsaicin (10.5 +/- 1.99 eye wipes vs. 24.5 +/- 0.92 wipes) and menthol (3.17 +/- 0.30 mm/min vs. 6.5 +/- 0.22 mm/min) and increased expression of neuropeptides, TRPV1 and TRPM8. CONCLUSIONS: This study demonstrates the role of estrogen in corneal nociception and its deficiency as a cause of dry eye. PMID- 29112510 TI - Prediction of postpercutaneous coronary intervention myocardial infarction: insights from intravascular imaging, coronary flow, and biomarker evaluation. AB - BACKGROUND: Percutaneous coronary intervention-induced myocardial infarction (PMI) has prognostic significance. Identifying patients at high risk for PMI is desirable as it may alter strategy and facilitate early preventative therapy. We therefore sought to establish whether preprocedural demographic, interventional (plaque characteristics and coronary microcirculatory function), and inflammatory, endothelial damage, and platelet-derived biomarker data could predict the risk of PMI. PATIENTS AND METHODS: We performed target vessel pressure wire to assess fractional flow reserve, index of microcirculatory resistance (IMR) and coronary flow reserve, plaque characterization by virtual histology intravascular ultrasound, and assayed peripheral biomarkers before uncomplicated PCI in 88 patients. We then analyzed post-PCI cardiac troponin level to adjudicate PMI based on the third universal definition of myocardial infarction. RESULTS: Overall incidence of PMI was 27%. Women [10/15 (66%) vs. 14/73 (19%), P<0.001] and those with low body mass (27.1+/-3.9 vs. 29.7+/-5.5 kg/m; P=0.02) were at significantly higher risk of PMI. Preprocedural coronary flow reserve was lower in individuals with a subsequent PMI (1.8+/-1.2 vs. 2.1+/ 1.3. P=0.03), and patients with higher pre-PCI IMR were more likely to sustain PMI [IMR>22: 10/23 (44%) vs. <=22: 14/65 (22%), P=0.04], although neither was predictive after multivariate analysis. Plaque characterization by virtual histology intravascular ultrasound did not discriminate those at risk of PMI. However, peripheral venous interleukin (IL)-18 and IL-8 levels were independently negatively and positively associated with PMI, respectively. CONCLUSION: Women and those with low BMI, particularly when associated with high IL-8 and low IL-18 levels, appear to be at increased risk of PMI. PMID- 29112511 TI - An Anesthesiologist's Perspective on the History of Basic Airway Management: The "Progressive" Era, 1904 to 1960. AB - This third installment of the history of basic airway management discusses the transitional-"progressive"-years of anesthesia from 1904 to 1960. During these 56 yr, airway management was provided primarily by basic techniques with or without the use of a face mask. Airway maneuvers were inherited from the artisanal era: head extension and mandibular advancement. The most common maneuver was head extension, also used in bronchoscopy and laryngoscopy. Basic airway management success was essential for traditional inhalation anesthesia (ether, chloroform) and for the use of the new anesthetic agents (cyclopropane, halothane) and intravenous drugs (thiopental, curare, succinylcholine). By the end of the era, the superiority of intermittent positive pressure ventilation to spontaneous ventilation in anesthesia and negative pressure ventilation in resuscitation had been demonstrated and accepted, and the implementation of endotracheal intubation as a routine technique was underway. PMID- 29112512 TI - Causal Analysis of World Health Organization's Surgical Safety Checklist Implementation Quality and Impact on Care Processes and Patient Outcomes: Secondary Analysis From a Large Stepped Wedge Cluster Randomized Controlled Trial in Norway. AB - OBJECTIVE: We hypothesize that high-quality implementation of the World Health Organization's Surgical Safety Checklist (SSC) will lead to improved care processes and subsequently reduction of peri- and postoperative complications. BACKGROUND: Implementation of the SSC was associated with robust reduction in morbidity and length of in-hospital stay in a stepped wedge cluster randomized controlled trial conducted in 2 Norwegian hospitals. Further investigation of precisely how the SSC improves care processes and subsequently patient outcomes is needed to understand the causal mechanisms of improvement. METHODS: Care process metrics are reported from one of our earlier trial hospitals. Primary outcomes were in-hospital complications and care process metrics, e.g., patient warming and antibiotics. Secondary outcome was quality of SSC implementation. Analyses include Pearson's exact chi test and binary logistic regression. RESULTS: A total of 3702 procedures (1398 control vs. 2304 intervention procedures) were analyzed. High-quality SSC implementation (all 3 checklist parts) improved processes and outcomes of care. Use of forced air warming blankets increased from 35.3% to 42.4% (P < 0.001). Antibiotic administration postincision decreased from 12.5% to 9.8%, antibiotic administration preincision increased from 54.5% to 63.1%, and nonadministration of antibiotics decreased from 33.0% to 27.1%. Surgical infections decreased from 7.4% (104/1398) to 3.6% (P < 0.001). Adjusted SSC effect on surgical infections resulted in an odds ratio (OR) of 0.52 (95% confidence interval (CI): 0.38-0.72) for intervention procedures, 0.54 (95% CI: 0.37-0.79) for antibiotics provided before incision, and 0.24 (95% CI: 0.11-0.52) when using forced air warming blankets. Blood transfusion costs were reduced by 40% with the use of the SSC. CONCLUSIONS: When implemented well, the SSC improved operating room care processes; subsequently, high-quality SCC implementation and improved care processes led to better patient outcomes.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 29112513 TI - Endoscopic Sciatic Nerve Decompression After Fracture or Reconstructive Surgery of the Acetabulum in Comparison With Endoscopic Treatments in Idiopathic Deep Gluteal Syndrome. AB - OBJECTIVE: The purpose of this study was to assess the endoscopic findings of the sciatic nerve and clinical outcomes of major traumatic sciatic nerve neuropathies after fracture or reconstructive surgery of the acetabulum with idiopathic deep gluteal syndrome (DGS) groups. DESIGN: Retrospective review of patient reports. SETTING: Level I trauma center of a tertiary university hospital. PARTICIPANTS: The study included 70 patients who consecutively underwent endoscopic sciatic nerve decompression. Patients who had previous fractures or reconstructive surgeries of the acetabulum were categorized as the major trauma group, whereas those without major trauma were categorized as the idiopathic group (45 patients) after a minimum of 24-months of follow-up period. MAIN OUTCOME MEASURES: The results were evaluated using the modified Harris Hip Score (mHHS), Hip outcome, and 12-Item Short Form Health Survey scores, respectively. RESULTS: In the major trauma group, all patients with sensory symptoms showed some degree of relief after the endoscopic sciatic nerve release. None of the patients with complete foot drop demonstrated complete improvement. Three patients with motor weakness without foot drop showed complete improvement in motor function. The mean mHHS increased from 61.5 +/- 13.4 to 84.1 +/- 8.1 (P = 0.031). In the idiopathic DGS group, the mean mHHS increased from 73.8 +/- 10.3 to 94.4 +/- 5.3 (P = 0.003). The Benson outcomes rating in the major trauma group was statistically lower than that in the idiopathic DGS group. CONCLUSION: Endoscopic release of the sciatic nerve after fractures or reconstructive surgeries could provide some improvements without complications. However, more favorable outcomes were observed in the idiopathic DGS group. PMID- 29112514 TI - Effects of Intravenous Cold Saline on Hyperthermic Athletes Representative of Large Football Players and Small Endurance Runners. AB - OBJECTIVE: To evaluate the cooling effects of intravenous (IV) cold normal (0.9%) saline on hyperthermic athletes. DESIGN: Randomized crossover study design. SETTING: Controlled research laboratory. PARTICIPANTS: Twelve male participants who were representative of a collegiate cross-country (6) and American football (6) population. INTERVENTIONS: Participants underwent body composition analysis using a BodPod. They were placed in an environmentally controlled chamber and brought to a Tc of 39.5 degrees C with dynamic exercise. When temperatures were reached, they were treated with either 2 L of cold saline (CS) (4 degrees C) or intravenous room temperature (22 degrees C) saline (RS) over a ~30-minute period. Tre was measured with a rectal temperature probe every minute during the treatment period. MAIN OUTCOME MEASURES: Total DeltaTre (ending Tre - starting Tre) and cooling rate (total change in Tre/time) were measured for each condition, and body composition variables calculated included body surface area (BSA), BSA-to-mass ratio (BSA/mass), lean body mass, and body fat percentage (%BF) (P < 0.05). RESULTS: Statistically significant differences were found in the total DeltaTre and cooling rate between the CS and RS trials. The cooling rate for the CS trials was significantly correlated to mass, BSA, BSA/mass, and %BF. CONCLUSIONS: In hyperthermic athletes, core temperature was reduced more effectively using chilled saline during IV infusion. Body composition had a significant impact on overall cooling revealing that the smaller and leaner participants cooled at a greater rate. When indicated, CS infusion could be considered for cooling hyperthermic individuals when other methods are not available. PMID- 29112515 TI - In Response to: Measles Can Destroy a Dream: The Case of the Settebello. PMID- 29112516 TI - Intravoxel Incoherent Motion Analysis of Abdominal Organs: Application of Simultaneous Multislice Acquisition. AB - PURPOSE: The aim of this study was to systematically evaluate the accuracy of quantitative intravoxel incoherent motion (IVIM) analysis of the upper abdomen applying simultaneous multislice (SMS) diffusion-weighted imaging (DWI) to reduce acquisition time. MATERIALS AND METHODS: Diffusion-weighted imaging of parenchymal abdominal organs was performed in 8 healthy volunteers at 3 T using a standard DWI sequence (acceleration factor 1 [AF1]) and an SMS-accelerated echo planar imaging sequence with acceleration factors 2 and 3 (AF2/AF3). Intravoxel incoherent motion analysis was performed with a multistep algorithm for true diffusion coefficient (Dt), pseudodiffusion coefficient (D*), and fraction of perfusion (Fp) measured for the liver, kidney cortex and medulla, pancreas, spleen, and erector spinae muscle. Qualitative and quantitative parameters were compared using a repeated measurement 1-way analysis of variance test and the Bonferroni post hoc method. RESULTS: Simultaneous multislice DWI provided diagnostic image quality in all volunteers with a reduction of scan time of 50% for AF2 (67% for AF3) compared with the standard sequence. Decent IVIM analysis for Dt, D*, and Fp can be calculated on the images of both the SMS sequences AF2 and AF3 with typical organ characteristics of IVIM; however, systematical deviations from AF1 were observed: Dt values increased and Fp decreased significantly with higher acceleration factor for liver, kidney, pancreas, and muscle (P < 0.05). Fitting curves of higher acceleration factors tend to be more monoexponentially shaped. CONCLUSIONS: Simultaneous multislice acceleration provides considerable scan time reduction for upper abdomen DWI with equivalent quality of IVIM analysis compared with the standard nonaccelerated technique. Systematic discrepancies of the true Dt, D*, and Fp for SMS acquisitions need to be considered when comparing to standard DWI sequences. PMID- 29112518 TI - Guided Growth: Current Perspectives and Future Challenges. PMID- 29112517 TI - Use of antidementia drugs in German patients with Alzheimer's disease. AB - The objective of this study was to evaluate the use of antidementia drugs (ADDs) in patients with Alzheimer's disease (AD) regarding German guideline recommendations and to assess correlations between the use of ADDs and the patients' characteristics. A total of 395 community-dwelling and institutionalized patients with AD across all severity stages of dementia were recruited in this cross-sectional study. Associations between the prescription of ADDs and patients' sociodemographic and clinical parameters (neuropsychiatric symptoms, cognitive capacity, daily activities, and health-related quality of life) were analyzed in multiple logistic regression analyses. ADDs were prescribed in 46.6% of all participants and less often in institutionalized patients (38.2 vs. 50.4%, P=0.025). Patients with mild-to-moderate dementia had a higher chance of receiving ADDs [odds ratio (OR)=3.752, 95% confidence interval (CI): 1.166-12.080 and OR=3.526, 95% CI: 1.431-8.688] as well as those treated by neurologists/psychiatrists (OR=2.467, 95% CI: 1.288-4.726). Overall, 39% of the patients with mild cognitive deficits (Mini-Mental Status Examination 27-30) received ADDs and 21% of the mildly demented patients (Mini-Mental Status Examination 20-26) received memantine. The treatment with ADDs was in part not in line with German guideline recommendations. Particularly, the lower use of ADDs in patients not attending neuropsychiatric specialists should be further evaluated. PMID- 29112519 TI - Methadone Versus Buprenorphine for Opioid Use Dependence and Risk of Neonatal Abstinence Syndrome. AB - BACKGROUND: Our objective was to estimate the association between methadone and neonatal abstinence syndrome compared with buprenorphine using a probabilistic bias analysis to account for unmeasured confounding by severity of addiction. METHODS: We used a cohort of live-born infants exposed in utero to methadone or buprenorphine for maternal opioid maintenance therapy at Magee-Womens Hospital in Pittsburgh, PA, from 2013 to 2015 (n = 716). We determined exposure and outcome status using pharmacy billing claims. We used log-binomial regression models to assess association of treatment with neonatal abstinence syndrome after adjusting for parity, maternal race, age, delivery year, employment, hepatitis c, smoking, marital, and insurance status. We implemented probabilistic bias analysis, informed by an internal validation study, to assess the impact of unmeasured confounding by severity of addiction. RESULTS: Infants exposed to methadone in utero were more likely to experience neonatal abstinence syndrome compared with those exposed to buprenorphine (RR, 1.3; 95% CI, 1.2, 1.5). After adjustment, infants exposed to methadone were more likely (adjusted RR, 1.3; 95% CI, 1.1, 1.5) than infants exposed to buprenorphine to have the syndrome. In the validation cohort (n = 200), severe addiction was more common in methadone- versus buprenorphine-exposed deliveries (77% vs. 32%). However, adjustment for severe addiction in the bias analysis only slightly attenuated the association (RR, 1.2; 95% CI, 1.0, 1.4), supporting conventional analysis. CONCLUSIONS: Methadone is associated with increased risk of neonatal abstinence syndrome compared with buprenorphine in infants exposed in utero. This association is subject to minimal bias due to unmeasured confounding by severity of addiction. PMID- 29112520 TI - Maternal Diabetes Mellitus and Genital Anomalies in Male Offspring: A Nationwide Cohort Study in 2 Nordic Countries. AB - BACKGROUND: Pre-existing diabetes has been associated with an increased risk of congenital malformations overall, but studies on genital anomalies in boys are conflicting and possible causal mechanisms are not well understood. Previous studies have mainly assessed pregestational and gestational diabetes in combination. Yet considering the vulnerable time windows for the genital anomalies, associations could well differ between types of diabetes and between the 2 genital anomalies and we therefore aimed to study this further. METHODS: A population-based cohort study of 2,416,246 singleton live-born boys from Denmark (1978-2012) and Sweden (1987-2012) was carried out using Danish and Swedish register-based data. Using Cox regression models, we estimated hazard ratios for hypospadias and cryptorchidism according to maternal diabetes. We considered type and severity of diabetes, as well as timing of diagnosis in relation to birth. RESULTS: Pregestational type 1 diabetes was associated with a higher risk of both genital anomalies. The highest risks were seen for boys of mothers with diabetic complications (hazard ratio for hypospadias = 2.33 [95% confidence interval, 1.48, 3.66] and hazard ratio for cryptorchidism = 1.92 [95% confidence interval, 1.39, 2.65]). Gestational diabetes was associated with slightly increased risks of both genital anomalies. CONCLUSIONS: These results are consistent with the hypothesis that poor glycemic control may interfere with fetal genital development in the critical early period of organogenesis. Given the widespread and increasing occurrence of diabetes, these results are of public health importance. PMID- 29112521 TI - Toward Open-source Epidemiology. PMID- 29112522 TI - Implementing the National Institute for Health and Clinical Excellence Head Injury 2014 Guidelines in a major children's hospital emergency department. AB - OBJECTIVES AND BACKGROUND: Head injury is a common paediatric emergency department presentation. The National Institute for Health and Clinical Excellence updated its guidance in January 2014 regarding imaging required for adults and children following a head injury (CG176). This study looked at the rates of computed tomography (CT) head scans performed and adherence rates to CG176. PATIENTS AND METHODS: A single-centre audit was carried out, examining imaging practice in children with head injuries. CG176 was implemented formally in August 2014 to the new trainee doctors. The primary outcome was adherence to CG176. As the data were binary, 95% confidence intervals were used for comparison. RESULTS: In all, 1797 patients were identified as having a head injury. Implementation at the Sheffield's Children NHS Foundation Trust resulted in a statistically significant increase in guideline adherence from 79.2% [95% confidence interval (CI): 76.4-81.9%] to 85.1% (95% CI: 82.9-87.4%). The greatest impact in adherence was found in CT head scans, from 95.8% (95% CI: 94.5-97.2%) to 97.7% (95% CI: 96.7-98.6%). CONCLUSION: The implementation at the Sheffield's Children NHS Foundation Trust was successful in satisfying the aim of CG176 by increasing adherence and decreasing CT head scans. This success could be explained by the formal implementation to the new cohort of doctors and better physician agreement with the guidelines. The increase in adherence is contrary to the previous studies. PMID- 29112523 TI - Electrophysiological Study of the Frontal Branch of the Facial Nerve in Normal Subjects. AB - INTRODUCTION: The authors compared the electrophysiological results of the frontal branch over the main trunk stimulation of the facial nerve in normal subjects. METHODS: Nerve conduction studies of the main trunk and frontal branch of the facial nerve were performed on both sides of 31 healthy subjects, recording the compound muscle action potential (CMAP) from the frontalis muscle. RESULTS: A good quality CMAP was obtained in all subjects after stimulation of the frontal branch, but only in 64.5% of nerves after stimulation of the main trunk of the facial nerve. Furthermore, nerve conduction studies of the frontal branch required less intense stimuli and were better tolerated. CONCLUSIONS: The authors suggest that stimulation of the frontal branch is a simple, reliable and well-tolerated technique to evaluate the facial nerve. PMID- 29112524 TI - Dermoscopic Guidance of Talimogene Laherparepvec Injection for Metastatic Melanoma. PMID- 29112525 TI - A Novel Window Technique Using CO2 Laser, and a Review of Methods for Nail Matrix Biopsy of Longitudinal Melanonychia. AB - BACKGROUND: Nail matrix histopathological examination is essential to diagnose longitudinal melanonychia (LM). Several methods for nail matrix biopsy have been introduced but are often difficult to perform because of their invasiveness and technical difficulty. Therefore, a less invasive and novel biopsy technique is needed. OBJECTIVE: To introduce a window technique for nail matrix biopsy. MATERIALS AND METHODS: We retrospectively reviewed the medical records and histopathological specimens of patients with LM who underwent the window technique for nail matrix biopsy at our institution between September 2015 and December 2016. RESULTS: Eleven cases from 10 patients with LM were subjected to our tailored window technique assisted by carbon dioxide (CO2) laser and dermoscopy. We performed nail plate dermoscopy to select the biopsy site and used CO2 laser to create the window in the proximal nail plate. Nail matrix pigmentation was carefully investigated using intraoperative dermoscopy. The technique established appropriate diagnosis in 11 LM cases, without significant complications, as follows: melanoma in situ (4 cases) and nail matrix activation (7 cases). CONCLUSION: The window technique assisted by CO2 laser and dermoscopy can be a minimally invasive and effective method for nail matrix LM biopsy under local anesthesia. PMID- 29112526 TI - Staffing Metrics in Mohs Surgery. PMID- 29112527 TI - Syringocystadenoma Papilliferum in Coexistence With Verrucous Carcinoma on the Face. PMID- 29112528 TI - Commentary on Polyalkylimide. PMID- 29112529 TI - Factors Influencing Squamous Cell Carcinoma In Situ Recurrence and Implications for Treatment Choice. AB - BACKGROUND: Numerous treatment modalities have been reported for squamous cell carcinoma in situ (SCCIS). Risk factors for recurrence have not been systematically reviewed. OBJECTIVE: To systematically review and summarize the data on risk factors that contribute to recurrence of SCCIS. MATERIALS AND METHODS: A PubMed search was completed using the terms "SCCIS," "Bowen's disease," "Bowen's disease and recurrence," and "Bowen's disease and Mohs." These sources were cross-referenced for the terms "treatment," "management," "therapy," "recurrence," and "margins." Studies were selected on the basis of relevance and applicable treatments. RESULTS: Immunosuppression was the only variable with a statistically signficant association with progression or recurrence of SCCIS. Although there were no data directly correlating subclinical lateral extension or invasive squamous cell carcinoma within SCCIS with recurrence, evidence supports both of these as common features of SCCIS. Other potential recurrence risk factors for which there are limited supporting data included tumor size, depth of follicular extension, and location. CONCLUSION: Immunosuppression was the only risk factor associated with increased risk of tumor recurrence. Subclinical tumor extension and occult invasive squamous cell carcinoma are relatively common features that theoretically could increase recurrence risk. These factors should be considered when deciding upon treatment for SCCIS. Further study is required to quantify variables that influence recurrence and to identify optimal treatment options. PMID- 29112530 TI - The Prevalence of Psychiatric Disorders and Mental Health Services Utilization by Parents and Relatives Living With Individuals With Autism Spectrum Disorders in Puerto Rico. AB - Knowledge about prevalence rates of psychiatric disorders and mental health services use among parents and relatives of persons with autism spectrum disorder (ASD) is limited, particularly when referring to epidemiologic samples. The current study is based on an island-wide probabilistic multistage cluster sample of adult individuals (N = 3062) living in Puerto Rico. Results showed a significantly higher rate of attention deficit hyperactivity disorder and serious mental illness in parents (n = 34) or relatives (n = 34) of ASD individuals, as compared with the Puerto Rico adult population as a whole. Although not definitive because of the small sample size, the fact that the rates of mental health utilization were similar to the population sample suggests a need for greater attention by health professionals attending children with ASD to the needs for mental health services of both parents and relatives of individuals with ASD. PMID- 29112531 TI - Core Metrics Pilot Project: A Case Study. PMID- 29112532 TI - Speech in Noise Perception as a Marker of Cognitive Impairment in HIV Infection. AB - OBJECTIVES: Human immunodeficiency virus positive (HIV+) individuals report hearing difficulties, but standard audiological tests show no, or small, changes in peripheral hearing ability. The hearing complaints may reflect central nervous system (CNS) auditory processing deficits, rather than middle or inner ear problems, and may result from CNS damage due to HIV infection or treatment. If central auditory task performance and cognitive deficits in HIV+ individuals are shown to be related, then central auditory tests might serve as a "window" into CNS function in these patients. DESIGN: We measured cognitive performance (Mandarin Montreal Cognitive Assessment [MoCA]) and speech in noise perception (Mandarin hearing-in-noise test [HINT]) in 166 normal-hearing HIV+ individuals (158 men, 8 women, average age 36 years) at the Shanghai Public Health Clinical Center in Shanghai, China. Data collection included audiometry, tympanometry, and the Amsterdam Inventory of Auditory Handicap (AIAH), which assesses the subjective ability to understand speech and localize sound. RESULTS: Subjects had no middle ear disease and met criteria for normal-hearing sensitivity (all thresholds 20 dB HL or less). A significant negative relationship between speech reception thresholds (SRT) and MoCA scores (r = 0.15, F = 28.2, p < 0.001) existed. Stepwise linear regression showed that when the factors of age, MoCA scores, hearing thresholds, and education level were considered, only age and MoCA scores contributed independently to the SRT results (overall model r = 0.30, F = 38.8, p < 0.001). Subjective hearing complaints from the AIAH supported the HINT results. AIAH and MoCA scores were also related (r = 0.05, F = 8.5, p = 0.004), with those with worse MoCA scores having more problems on the AIAH. When the cohort was divided into those with normal and abnormal performance on the MoCA, those with abnormal performance on the MoCA had significantly higher average SRTs (p < 0.001). CONCLUSIONS: Understanding speech in noise measured both objectively with the HINT and subjectively with the AIAH was inversely related to cognitive abilities despite a normal ability to hear soft sounds determined by audiometry. Although age was also an important independent factor affecting speech perception, the age relationship within the speech findings in this study may represent more than just age-related declines in speech in noise understanding. Although reliable data on disease duration are not available, the older members of this cohort likely had HIV longer and probably had more severe symptoms at presentation than the younger members because early detection and treatment of HIV in Shanghai has improved over time. Therefore, the age relationship may also include elements of disease duration and severity. Speech perception, especially in challenging listening conditions, involves cortical and subcortical centers and is a demanding neurological task. The problems interpreting speech in noise HIV+ individuals have may reflect HIV-related or HIV treatment-related, central nervous damage, suggesting that CNS complications in HIV+ individuals could potentially be diagnosed and monitored using central auditory tests. PMID- 29112533 TI - ABO Blood Group and Cochlear Status: Otoacoustic Emission Markers. AB - OBJECTIVES: There are an increasing number of research studies examining the effects of ABO blood group on susceptibility to disease. However, little is known regarding the potential relationship between blood group and hearing. Higher risk of noise-induced hearing loss was linked to blood group O in several occupational health studies. Based on this finding, a recent study of cochlear status was conducted with normal-hearing female participants representing equal numbers of the four blood groups in the ABO blood group system. ABO blood group was associated with cochlear characteristics, including the prevalence of spontaneous otoacoustic emissions (SOAEs) and the amplitudes of transient-evoked otoacoustic emissions (TEOAEs) and distortion-product otoacoustic emissions (DPOAEs). Females with blood group O showed significantly lower amplitudes of DPOAEs at some frequencies and lower prevalence of SOAEs compared with participants with blood group B. There was a general trend of reduced TEOAE and DPOAE amplitudes in blood group O individuals compared with participants with non-O blood groups. Following from this finding, and based on known sex differences in otoacoustic emission characteristics, the present study examined the possible effects of blood group on otoacoustic emission status in males. DESIGN: Sixty clinically normal-hearing males aged between 18 and 26 years, with equal numbers of participants in each of the ABO blood groups, were recruited by purposive sampling. SOAE, DPOAE, and linear and nonlinear TEOAE recordings were collected from all participants, as well as tympanometric data related to external and middle ear characteristics. RESULTS: The male blood group O participants exhibited significantly lower SOAE prevalence and reduced amplitudes of DPOAEs on average, and in the midfrequency range, than participants with blood group B, and lower nonlinear and linear TEOAE amplitudes at a number of frequencies when compared with participants with blood groups A and B. A consistent trend of lower TEOAE and DPOAE response amplitudes was observed in participants with blood group O. No significant difference was noted among blood groups for outer or middle ear characteristics. CONCLUSIONS: These results were consistent with previous findings of reduced otoacoustic emission responses in female blood group O individuals. Results support the hypothesis that blood group O individuals may be at increased risk of cochlear damage from noise exposure. Further investigation on the potential link between ABO blood group and auditory status, including potentially differential effects of noise exposure on cochlear function, is needed. The possible effects of ABO blood group on other aspects of audition, such as hearing sensitivity, speech understanding, and auditory processing, should be evaluated. PMID- 29112535 TI - Tempo-spatial discrimination is lower for noxious stimuli than for innocuous stimuli. AB - The exteroceptive sensory system is responsible for sensing external stimuli in relation to time and space. The aim of this study was to investigate the tempo spatial properties of the exteroceptive system using painful laser heat and nonpainful mechanical touch stimulation. Thirteen healthy subjects were stimulated on the volar forearm using 2 paradigms: a continuous stimulation along a line on the skin and a 2-point stimulation. The line stimulations were delivered in both the distal and proximal direction with lengths of 25, 50, 75, and 100 mm. The 2-point stimulations were assessed by simultaneous stimuli at a point-to-point distance ranging from 10 to 100 mm, in steps of 10 mm. The subjects reported the intensity (0-10 numeric rating scale, 3: pain threshold) and either direction (line stimuli) or number of perceived points (2-point stimuli). All mechanical line stimulations were reported correctly, ie, a directional discrimination threshold of less than 25 mm. For painful laser line stimulation, the directional discrimination threshold was 68.5 and 70.2 mm for distally and proximally directed stimuli, respectively. The 2-point discrimination threshold for painful laser stimulation (67.9 mm) was higher than for the mechanical stimulation (34.5 mm). Numeric rating scale increased both with line length and distance between the 2 points (linear mixed model, P < 0.001). The findings indicate that the tempo-spatial acuity of the exteroceptive system is lower for noxious stimuli than for innocuous stimuli. This is possible due to the larger receptive fields of nociceptive neurons and/or less lateral inhibition. PMID- 29112534 TI - Interleukin 1beta inhibition contributes to the antinociceptive effects of voluntary exercise on ischemia/reperfusion-induced hypersensitivity. AB - Issues of peripheral circulation have been increasingly suggested as an underlying cause of musculoskeletal pain in many conditions, including sickle cell anemia and peripheral vascular disease. We have previously shown in our model of transient ischemia and reperfusion (I/R) injury of the forelimb that individual group III and IV muscle afferents display altered chemosensitivity and mechanical thresholds 1 day after injury. Functional alterations corresponded to increased evoked and spontaneous pain-related behaviors and decreased muscle strength and voluntary activity-all actions that echo clinical symptoms of ischemic myalgia. These behavioral and physiological changes appeared to originate in part from the action of increased interleukin 1beta (IL1beta) in the injured muscles at its upregulated IL1 receptor 1 within the dorsal root ganglion. Here, we describe that two days of voluntary wheel running prior to I/R blocks both injury-induced IL1beta enhancement and the subsequent development of ischemic myalgia-like behaviors. Furthermore, the protective effects of 2 days prior exercise on the I/R-evoked increases in pain-related behaviors were also paralleled with systemic injection of the IL1 receptor antagonist during I/R. Interleukin 1 receptor antagonist treatment additionally prevented the I/R induced changes in mechanical and chemical sensitivity of individual primary muscle afferents. Altogether, these data strengthen the evidence that transient I/R injury sensitizes group III and IV muscle afferents via increased IL1beta in the muscles to stimulate ischemic myalgia development. Targeting IL1beta may, therefore, be an effective treatment strategy for this insidious type of muscle pain. PMID- 29112536 TI - Text Messaging and Teen Sexual Health Behavior: Long-term Follow-up of a Cluster Randomized Trial. PMID- 29112538 TI - Patient-Perceived Facilitators of and Barriers to Electronic Portal Use: A Systematic Review. PMID- 29112539 TI - Correlating Abdominal Wall Thickness and Body Mass Index to Predict Usefulness of Right Lower Quadrant Ultrasound for Evaluation of Pediatric Appendicitis. AB - OBJECTIVES: To inform selective and efficient use of appendix ultrasound (US) beyond adult parameters of body mass index (BMI) of less than 25 kg/m, we correlate abdominal wall thickness (AWT) with age and BMI to generate parameters for male and female children. Information presented in chart format can aid in the decision to utilize US for the evaluation of appendicitis. METHODS: In this observational study, 1600 pediatric computed tomography scans of the abdomen and pelvis were analyzed to obtain measurements of AWT in the right lower quadrant. Measurements were correlated by patient age, BMI, and sex. Results and consensus based recommendations were presented in chart format with color-coded groupings to allow for convenient referencing in the clinical setting. RESULTS: One thousand four hundred eighty-eight computed tomography scans and AWT measurements were included. All age groups with BMI of less than 25 kg/m and all male and female groups younger than 6 years regardless of BMI had median AWT of less than 4 cm resulting in strong recommendation for US. Males older than 6 years and all female age groups with BMI of greater than 30 kg/m and female older than 15 years and BMI of greater than 25 kg/m had AWT of more than 5 cm resulting in low recommendation for US. CONCLUSIONS: While the BMI cutoff standard of less than 25 kg/m for usefulness of appendix US holds in the adult population, our data expand the acceptable range in children younger than 9 years regardless of BMI and male children with BMI up to 30 kg/m. Female children younger than 15 years with a BMI up to 30 kg/m may also be amenable to right lower quadrant US based on AWT. These parameters inform selective and efficient use of US for appendix evaluation. PMID- 29112537 TI - Infusion Pump Interoperability: High Reliability and Safety Concerns Lead to Unintended Consequences. PMID- 29112540 TI - Aeromedical Transport in Children: A Descriptive Analysis of 96 Cases. AB - OBJECTIVE: Pediatric aeromedical transport (AT) is highly challenging. We aim to describe a series of 96 cases of children requiring medical transport in terms of the indication, modalities, and related adverse events. METHODS: In this single center retrospective study, we included air-transported patients less than 18 years old. RESULTS: During the study period, 96 patients, with median age of 120 months (range, 0-204), were air transported. The reason for AT was repatriation to the home country from another hospital in 65 (67.7%), whereas for 31 (32.3%) patients, it was for transport from a hospital to another for a special procedure. The main diagnosis was trauma surgery (n = 38; 39.5%). Fifteen (15.6%) patients were mechanically ventilated. No patient sustained serious adverse events during the flight. Patients were transported by an air ambulance or by a scheduled aircraft in 55.2% and 44.8%, respectively. The median flight distance was 822 km (range, 277-9878), and most of the ATs were intra-European (n = 41; 42.7%). CONCLUSION: This study describes an international experience in providing AT services for pediatric clinical cases. Among pediatric patients, the younger ones constitute a specific population, and most of them require mechanical ventilation. Therefore, the transport of these patients seems to be more appropriate in a dedicated air ambulance. PMID- 29112541 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Cardiovascular and thoracic surgery. AB - : None of the predictive models for venous thromboembolism (VTE) prophylaxis have been designed for and validated in patients undergoing cardiothoracic and vascular surgery. The presence of one or more risk factors [age over 70 years old, transfusion of more than 4 U of red blood cells/fresh frozen plasma/cryoprecipitate, mechanical ventilation lasting more than 24 h, postoperative complication (e.g. acute kidney injury, infection/sepsis, neurological complication)] should place the cardiac population at high risk for VTE. In this context, we suggest the use of pharmacological prophylaxis as soon as satisfactory haemostasis has been achieved, in addition to intermittent pneumatic compression (IPC) (Grade 2C). In patients undergoing abdominal aortic aneurysm repair, particularly when an open surgical approach is used, the risk for VTE is high and the bleeding risk is high. In this context, we suggest the use of pharmacological prophylaxis as soon as satisfactory haemostasis is achieved (Grade 2C). Patients undergoing thoracic surgery in the absence of cancer could be considered at low risk for VTE. Patients undergoing thoracic surgery with a diagnosis of primary or metastatic cancer should be considered at high risk for VTE. In low-risk patients, we suggest the use of mechanical prophylaxis using IPC (Grade 2C). In high-risk patients, we suggest the use of pharmacological prophylaxis in addition to IPC (Grade 2B). PMID- 29112542 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Neurosurgery. AB - : Although there are numerous publications addressing venous thromboembolism and its prevention in neurosurgery, there are relatively few high-quality studies to guide decisions regarding thromboprophylaxis. In patients undergoing craniotomy, we recommend that if intermittent pneumatic compression (IPC) is used, it should be applied before the surgical procedure or on admission (Grade 1C). In craniotomy patients at particularly high risk for venous thromboembolism, we suggest considering the initiation of mechanical thromboprophylaxis with IPC preoperatively with addition of low molecular weight heparin (LMWH) postoperatively when the risk of bleeding is presumed to be decreased (Grade 2C). In patients with non-traumatic intracranial haemorrhage, we suggest thromboprophylaxis with IPC (Grade 2C). For patients who have had non-traumatic intracranial haemorrhage, we suggest giving consideration to commencement of LMWH or low-dose unfractionated heparin when the risk of bleeding is presumed to be low (Grade 2C). We suggest continuing thromboprophylaxis until full mobilisation of the patient (Grade 2C). For patients undergoing spinal surgery with no additional risk factors, we suggest no active thromboprophylaxis intervention apart from early mobilisation (Grade 2C). For patients undergoing spinal surgery with additional risk factors, we recommend starting mechanical thromboprophylaxis with IPC (Grade 1C), and we suggest the addition of LMWH postoperatively when the risk of bleeding is presumed to be decreased (Grade 2C). PMID- 29112543 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Surgery during pregnancy and the immediate postpartum period. AB - : Thromboembolic events in the pregnant and postpartum patient remain rare but potentially fatal complications. The aim of this section was to analyse the few prospective studies addressing the issue of thromboprophylaxis following a surgical procedure during and immediately after pregnancy, as well as national guidelines, and to propose European guidelines on this specific condition. Thromboprophylaxis is broadly recommended due to the combined risks of surgery and pregnancy or the postpartum period, regardless of the mode of delivery. We recommend prophylactic thromboprophylaxis following surgery during pregnancy or the postpartum period when they imply, as a consequence, bed rest, until full mobility is recovered (Grade 1C). Similarly, thromboprophylaxis should be used in cases of perioperative infection during pregnancy or the postpartum period. Concerning thromboprophylaxis following a caesarean section, it seems avoidable only in elective procedures in low-risk patients, after a normal pregnancy, and with an early rehabilitation protocol. The duration of thromboprophylaxis following caesarean section should be at least 6 weeks for high-risk patients, and at least 7 days for the other patients requiring anticoagulation (Grade 1C). PMID- 29112544 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Day surgery and fast-track surgery. AB - : In recent years, day surgery and fast-track surgery have experienced a continuous increase in volume. Many procedures are now performed on an outpatient protocol, including general, orthopaedic, oncological, reconstructive or vascular surgery. The management of these patients is safe, but the incidence of venous thromboembolism in this population remains unknown. Several risk factors can be identified and stratified derived from studies of inpatient surgical management (e.g. Caprini score). Recommendations for thromboprophylaxis should be tailored from the assessment of both personal and procedure-related risk factors, although with a lack of evidence for application in outpatient management. For patients undergoing a low-risk procedure without additional risk factors, we recommend only general measures of thromboprophylaxis (early ambulation, optimal hydration) (Grade 1B). For patients undergoing a low-risk procedure with additional risk factors, or a high-risk procedure without additional risk factors, we recommend general measures of thromboprophylaxis (Grade 1B) and we suggest the administration of pharmacological prophylaxis with low molecular weight heparins (Grade 2B). For patients undergoing a high-risk procedure with additional risk factors we recommend general measures of thromboprophylaxis (Grade 1B) and pharmacological prophylaxis with low molecular weight heparins over other drugs (Grade 1B), or suggest specific mechanical measures in case of increased bleeding risk (Grade 2C). Pharmacological prophylaxis should last a minimum of 7 days (Grade 1B), although in selected cases of fast-track surgery, thromboprophylaxis could be limited to hospitalisation only (Grade 2C) and in specific cases of high risk procedures, thromboprophylaxis could be extended for up to 4 weeks (Grade 2B). PMID- 29112545 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Intensive care. AB - : Venous thromboembolism is a common and potentially life-threatening complication that occurs in 4 to 15% of patients admitted to ICUs despite the routine use of pharmacological prophylaxis. We therefore recommend an institution wide protocol for the prevention of venous thromboembolism (Grade 1B). The routine use of ultrasonographic screening for deep vein thrombosis is not recommended when thromboprophylactic measures are in place (Grade 1B), as the detection of asymptomatic deep vein thrombosis may prompt therapeutic anticoagulation that may increase bleeding risk but has no proven reduction of clinically significant thrombotic events. In critically ill patients, we recommend pharmacological prophylaxis with low molecular weight heparin over low dose heparin (Grade 1B). For critically ill patients with severe renal insufficiency, we suggest the use of low-dose heparin (Grade 2C), dalteparin (Grade 2B) or reduced doses of enoxaparin (Grade 2C). Monitoring of anti-Xa activity may be considered when low molecular weight heparin is used in these patients (Grade 2C). No study has prospectively evaluated the efficacy and safety of deep vein thrombosis prophylaxis in critically ill patients with severe liver dysfunction. Thus, the use of pharmacological prophylaxis in these patients should be carefully balanced against the risk of bleeding. For critically ill patients, we recommend against the routine use of inferior vena cava filters for the primary prevention of venous thromboembolism (Grade 1C). When the diagnosis of heparin-induced thrombocytopaenia is suspected or confirmed, all forms of heparin must be discontinued (Grade 1B). In these patients, immediate anticoagulation with a nonheparin anticoagulant rather than discontinuation of heparin alone is recommended (Grade 1C). PMID- 29112546 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Surgery in the obese patient. AB - : A systematic literature search was performed and patients were selected as obese patients undergoing bariatric surgery or obese patients undergoing nonbariatric surgical procedures. In addition, patients were stratified according to low risk of venous thromboembolism and high risk of venous thromboembolism (age >55 years, BMI >55 kg m, history of venous thromboembolism, venous disease, sleep apnoea, hypercoagulability or pulmonary hypertension). Prophylaxis of venous thromboembolism was analysed depending on the type of modality: compression devices of the lower extremities (including intermittent pneumatic compression and graduated compression stockings), pharmacological prophylaxis or inferior vena cava filters. Two prospective studies compared mechanical devices and pharmacological prophylaxis vs. a mechanical device alone without significant differences. A few randomised controlled studies and most of the prospective nonrandomised studies showed that low-dose low molecular weight heparin (3000 to 4000 anti-Xa IU 12 h subcutaneously) was acceptable for obese patients with a lower risk of venous thromboembolism, but a higher dose of low molecular weight heparin (4000 to 6000 anti-Xa IU 12 h subcutaneously) should be proposed for obese patients with a higher risk of venous thromboembolism. Extended prophylaxis for 10 to 15 days was well tolerated for obese patients with a high risk of venous thromboembolism in the postdischarge period. The safety and efficacy of inferior vena cava filters in bariatric surgical patients is highly heterogeneous. There were no randomised trials that analysed prophylaxis of venous thromboembolism in obese patients undergoing nonbariatric surgery. Higher doses of anticoagulants could be proposed for obese patients with a BMI more than 40 kg m. The lack of good quality randomised trials with a low risk of bias did not allow us to propose strong recommendations. PMID- 29112547 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Chronic treatments with antiplatelet agents. AB - : Antiplatelet agents (APA) are considered first-line therapy in preventing cardiovascular thrombotic events, but they are of limited value in the prophylaxis of venous thromboembolism (VTE) during the perioperative period. Consequently, many patients should receive both an APA and an anticoagulant. This combination can increase the bleeding risk and it is necessary to make some recommendations to minimise that risk. In patients receiving APA chronically, if the risk of VTE outweighs the risk of bleeding, we suggest pharmacological prophylaxis (grade 2C). In patients treated with dual antiplatelet therapy undergoing a procedure associated with a high risk of VTE, resuming both APA shortly after the procedure must be prioritised over pharmacological VTE prevention (grade 2C). If the risk of bleeding from a combination of an APA and an anticoagulant outweighs the risk of VTE, we suggest mechanical thromboprophylaxis over anticoagulant prophylaxis, without discontinuing the APA (grade 2C). Patients in whom neuraxial anaesthesia is planned, a higher rate of complications could occur if pharmacological thromboprophylaxis is administered concurrently and postoperative thromboprophylaxis initiation should be suggested (grade 2C). After surgery, the first dose of aspirin should be given once haemostasis is guaranteed (grade 2B). In the case of clopidogrel, give the drug without a loading dose between 24 and 48 h after surgery (grade 2C). PMID- 29112548 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Aspirin. AB - : There is a good rationale for the use of aspirin in venous thromboembolism prophylaxis in some orthopaedic procedures, as already proposed by the 9th American College of Chest Physicians' guidelines (Grade 1C). We recommend using aspirin, considering that it may be less effective than or as effective as low molecular weight heparin for prevention of deep vein thrombosis and pulmonary embolism after total hip arthroplasty, total knee arthroplasty and hip fracture surgery (Grade 1C). Aspirin may be less effective than or as effective as low molecular weight heparins for prevention of deep vein thrombosis and pulmonary embolism after other orthopaedic procedures (Grade 2C). Aspirin may be associated with a low rate of bleeding after total hip arthroplasty, total knee arthroplasty and hip fracture surgery (Grade 1B). Aspirin may be associated with less bleeding after total hip arthroplasty, total knee arthroplasty and hip fracture surgery than other pharmacological agents (Grade 1B). No data are available for other orthopaedic procedures. We do not recommend aspirin as thromboprophylaxis in general surgery (Grade 1C). However, this type of prophylaxis could be interesting especially in low-income countries (Grade 2C) and adequate large scale trials with proper study designs should be carried out (Grade 1C). PMID- 29112549 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Patients with preexisting coagulation disorders and after severe perioperative bleeding. AB - : In patients with inherited bleeding disorders undergoing surgery, we recommend assessment of individual risk for venous thromboembolism, taking into account the nature of the surgery and anaesthetic, type and severity of bleeding disorder, age, BMI, history of thrombosis, the presence of malignancy and other high-risk comorbidities. Venous thromboembolism risk should be balanced against the increased bleeding risk associated with anticoagulant use in patients with known bleeding disorders (Grade 1C). In these patients undergoing major surgery, we recommend against routine postoperative use of pharmacological thromboprophylaxis, especially for patients with haemophilia A and B (Grade 1B). Glomerular filtration rate should be assessed before initiation of each direct oral anticoagulant, and also at least once a year or more frequently as needed, such as postoperatively before the resumption of therapeutic direct oral anticoagulant administration, when it is suspected that renal function could decline or deteriorate (Grade 1C). Reduced dosages of low molecular weight heparins may be used relatively safely during transient severe (<50 * 10 l) thrombocytopaenia (Grade 2C). Monitoring of anti-Xa levels may be used to adjust the doses of low molecular weight heparin in patients with moderate or severe thrombocytopaenia (Grade 2C). The delay between major gastrointestinal bleeding and resuming warfarin should be at least 7 days (Grade 2C). For patients at a high risk of thromboembolism and with a high bleeding risk after surgery, we consider that administering a reduced dose of direct oral anticoagulant on the evening after surgery and on the following day (first postoperative day) after surgery is a good practice (Grade 2B). PMID- 29112551 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Inferior vena cava filters. AB - : The indications for the use of an inferior vena cava filter (IVCF) in the context of deep venous thrombosis to prevent pulmonary embolism remain controversial. Despite wide use in clinical practice, great variation exists in national and international guidelines in regard to the indications. In addition, clinical practice is based on poor-quality data from trauma and bariatric surgery with a high incidence of complications. It is often difficult to assess their efficacy and lack of filter retrieval appears to be a substantial issue compared with a potential benefit by insertion of these devices. Complications usually refer to increased risk of deep venous thrombosis, filter perforation, filter penetration, filter migration, inferior vena cava occlusion and subsequently failure in pulmonary embolism prevention. Evidence from low-quality studies or registries, with small numbers of patients and conflicting findings, does not allow for a strong recommendation for or against the use of IVCFs. IVCFs should only be considered in cases of very high risk of pulmonary embolism and in perioperative situations at very high risk of bleeding, resulting in a prolonged contra-indication to pharmacological prophylaxis. PMID- 29112550 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Mechanical prophylaxis. AB - : Institutional protocols need to address the indications for pharmacological and mechanical thromboprophylaxis. The use of graduated compression stockings (GCS) and intermittent pneumatic compression (IPC) strongly differs between institutions. As a consequence, no strong recommendations can be made based on the contemporary high-level evidence. Although different clinical practices can be supported, such approaches should be part of an institutional strategy to reduce the burden of venous thromboembolism (VTE). We recommend against the use of GCS alone without pharmacological thromboprophylaxis for prevention of VTE in patients at intermediate and high risk. For patients at high risk of VTE with contraindications for pharmacological thromboprophylaxis, we recommend the use of mechanical prophylaxis and suggest the use of IPC over GCS. However, for those patients receiving pharmacological thromboprophylaxis who are without a very high risk of VTE prophylaxis, we recommend against the routine use of mechanical thromboprophylaxis either with GCS or IPC. We suggest combined mechanical and pharmacological prophylaxis in selected patients at very high risk of VTE prophylaxis and suggest IPC rather than GCS in these selected patients. PMID- 29112552 TI - European guidelines on perioperative venous thromboembolism prophylaxis. PMID- 29112553 TI - European Guidelines on perioperative venous thromboembolism prophylaxis: Executive summary. PMID- 29112554 TI - When Treatment Delay May Be Beneficial in Patients: Further Investigation Needed. PMID- 29112555 TI - Human Papilloma Virus and Anal Squamous Cell Cancer in IBD: Is It Time to Update Our Practice Parameters? PMID- 29112556 TI - What Every Colorectal Surgeon Should Know About the Legislative Response to the Opioid Epidemic. PMID- 29112557 TI - Appendiceal Neoplasms. PMID- 29112558 TI - Expert Commentary on Appendiceal Neoplasms. PMID- 29112559 TI - Do Moderate Surgical Treatment Delays Influence Survival in Colon Cancer? AB - BACKGROUND: Studies examining treatment delay and survival after surgical treatment of colon cancer have varied in quality and outcome, with little evidence available regarding the safety of longer surgical treatment wait times. OBJECTIVE: Our study examined the effect of surgical treatment wait times on survival for patients with stage I to III colon cancer. DESIGN: A subset cohort analysis was performed using data from a prospectively maintained database. SETTINGS: The study was conducted at a tertiary referral center. PATIENTS: Data on all of the patients undergoing elective surgery for stage I to III colon cancer from 2006 to 2015 were collected from a prospectively maintained clinical and administrative database. MAIN OUTCOME MEASURES: We examined the impact of prolonged wait time to surgery on disease-free and overall survival. Patients were divided into 2 groups based on a treatment wait time of <=30 or >30 days and were compared using a Cox proportional hazards model. A subgroup analysis was performed using alternative treatment delay cutoffs of 60 and 90 days. RESULTS: There were 908 patients with stage I to III colon cancer treated over the study period, with a median treatment wait time of 38 days (interquartile range, 21-61 days); 368 patients were treated within 30 days, and 540 were treated beyond 30 days from diagnosis. In adjusted multivariate analysis, a treatment delay of >30 days was not associated with decreased disease-free survival (HR = 0.89 (95% CI, 0.61-1.3); p = 0.52) or overall survival (HR = 0.82 (95% CI, 0.63-1.1); p = 0.16). Likewise, subgroup analysis using alternative treatment delay cutoffs of 60 and 90 days did not demonstrate an adverse effect on survival. LIMITATIONS: This study was limited by retrospective analysis. CONCLUSIONS: Despite longer median treatment wait times from diagnosis to surgery, with the majority of patients exceeding 30 days and many experiencing delays of 2 to 3 months, no adverse impact on survival was observed. Patients who require additional consultations or investigations preoperatively may safely have their surgery moderately delayed to minimize their perioperative risk without any evidence that this will compromise treatment outcomes. See Video Abstract at http://links.lww.com/DCR/A397. PMID- 29112560 TI - Is the Distance Worth It? Patients With Rectal Cancer Traveling to High-Volume Centers Experience Improved Outcomes. AB - BACKGROUND: It is unclear whether traveling long distances to high-volume centers would compensate for travel burden among patients undergoing rectal cancer resection. OBJECTIVE: The purpose of this study was to determine whether operative volume outweighs the advantages of being treated locally by comparing the outcomes of patients with rectal cancer treated at local, low-volume centers versus far, high-volume centers. DESIGN: This was a population-based study. SETTINGS: The National Cancer Database was queried for patients with rectal cancer. PATIENTS: Patients with stage II or III rectal cancer who underwent surgical resection between 2006 and 2012 were included. MAIN OUTCOME MEASURES: The outcomes of interest were margins, lymph node yield, receipt of neoadjuvant chemoradiation, adjuvant chemotherapy, readmission within 30 days, 30-day and 90 day mortality, and 5-year overall survival. RESULTS: A total of 18,605 patients met inclusion criteria; 2067 patients were in the long-distance/high-volume group and 1362 in the short-distance/low-volume group. The median travel distance was 62.6 miles for the long-distance/high-volume group and 2.3 miles for the short distance/low-volume group. Patients who were younger, white, privately insured, and stage III were more likely to have traveled to a high-volume center. When controlled for patient factors, stage, and hospital factors, patients in the short-distance/low-volume group had lower odds of a lymph node yield >=12 (OR = 0.51) and neoadjuvant chemoradiation (OR = 0.67) and higher 30-day (OR = 3.38) and 90-day mortality (OR = 2.07) compared with those in the long-distance/high volume group. The short-distance/low-volume group had a 34% high risk of overall mortality at 5 years compared with the long-distance/high-volume group. LIMITATIONS: We lacked data regarding patient and physician decision making and surgeon-specific factors. CONCLUSIONS: Our results indicate that when controlled for patient, tumor, and hospital factors, patients who traveled a long distance to a high-volume center had improved lymph node yield, neoadjuvant chemoradiation receipt, and 30- and 90-day mortality compared with those who traveled a short distance to a low-volume center. They also had improved 5-year survival. See Video Abstract at http://links.lww.com/DCR/A446. PMID- 29112561 TI - Nodal Disease in Rectal Cancer Patients With Complete Tumor Response After Neoadjuvant Chemoradiation: Danger Below Calm Waters. AB - BACKGROUND: A subset of patients with rectal cancer who undergo neoadjuvant chemoradiation therapy will develop a complete pathologic tumor response. Complete nodal response is not universal in these patients and is difficult to assess clinically. Quantifying the risk of nodal disease would allow for targeted therapy with either radical resection or "watchful waiting." OBJECTIVE: This study aimed to identify risk factors for residual nodal disease in ypT0 rectal adenocarcinoma. DESIGN: This is a retrospective case control study. SETTINGS: The National Cancer Database 2006 to 2014 was used to identify patients for this study. PATIENTS: Patients with stage II/III rectal adenocarcinoma who completed chemoradiation therapy followed by resection and who had ypT0 tumors were included. Patients with metastatic disease and <2 lymph nodes evaluated were excluded. Patients were divided into 2 groups: node positive and node negative. MAIN OUTCOME MEASURES: The main outcome was nodal disease. The secondary outcome was overall survival. RESULTS: A total of 42,257 patients with stage II/III rectal cancer underwent chemoradiation therapy and radical resection; 4170 (9.9%) patients had ypT0 tumors and 395 (9.5%) were node positive. Of patients with clinically node-negative disease (ie, pretreatment imaging), 6.2% were node positive after chemoradiation therapy and resection. In multivariable analysis, factors predictive of nodal disease included increasing (pretreatment) clinical N stage, high tumor grade (3/4), perineural invasion, and lymphovascular invasion. Higher clinical T-stage was inversely associated with residual nodal disease. Overall 5-year survival was significantly different between patients with ypN0, ypN1, and ypN2 disease (87.4%, 82.2%, and 62.5%, p = 0.002). LIMITATIONS: This study was limited by the lack of clinical detail in the database and the inability to assess recurrence. CONCLUSIONS: Ten percent of patients with ypT0 tumors had positive nodes after chemoradiation therapy and resection. Factors associated with residual nodal disease included clinical nodal disease at diagnosis and poor histologic features. Patients with any of these features should consider radical resection regardless of tumor response. Others could be suitable for "watchful waiting" strategies. See Video Abstract at http://links.lww.com/DCR/A458. PMID- 29112562 TI - Initiation of a Transanal Total Mesorectal Excision Program at an Academic Training Program: Evaluating Patient Safety and Quality Outcomes. AB - BACKGROUND: Short-term results have shown that transanal total mesorectal excision is safe and effective for patients with mid to low rectal cancers. Transanal total mesorectal excision is considered technically challenging; thus, adoption has been limited to a few academic centers in the United States. OBJECTIVE: The aim of this study is to describe outcomes after the initiation of a transanal total mesorectal excision program in the setting of an academic colorectal training program. DESIGN: This is a single-center retrospective review of consecutive patients who underwent transanal total mesorectal excision from December 2014 to August 2016. SETTING: This study was conducted at an academic center with a colorectal residency program. PATIENTS: Patients with benign and malignant diseases were selected. INTERVENTION: All transanal total mesorectal excisions were performed with abdominal and perineal teams working simultaneously. OUTCOME MEASURES: The primary outcomes measured were pathologic quality, length of hospital stay, 30-day morbidity, and 30-day mortality. RESULTS: There were 40 patients (24 male). The median age was 55 years (interquartile range, 46.7-63.4) with a median BMI of 29 kg/m (interquartile range, 24.6-32.4). The primary indication was cancer (n = 30), and tumor height from the anal verge ranged from 0.5 to 15 cm. Eighty percent (n = 24) of the patients who had rectal cancer received preoperative chemoradiation. The most common procedures were low anterior resection (67.5%), total proctocolectomy (15%), and abdominoperineal resection (12.5%). Median operative time was 380 minutes (interquartile range, 306-454.4), with no change over time. For patients with malignancy, the mesorectum was complete or nearly complete in 100% of the specimens. A median of 14 lymph nodes (interquartile range, 12-17) were harvested, and 100% of the rectal cancer specimens achieved R0 status. Median length of stay was 4.5 days (interquartile range, 4-7), and there were 6 readmissions (15%). There were no deaths or intraoperative complications. LIMITATIONS: This study's limitations derive from its retrospective nature and single-center location. CONCLUSIONS: A transanal total mesorectal excision program can be safely implemented in a major academic medical center. Quality outcomes and patient safety depend on a comprehensive training program and a coordinated team approach. See Video Abstract at http://links.lww.com/DCR/A448. PMID- 29112563 TI - Naples Prognostic Score, Based on Nutritional and Inflammatory Status, is an Independent Predictor of Long-term Outcome in Patients Undergoing Surgery for Colorectal Cancer. AB - BACKGROUND: The existing scores reflecting the patient's nutritional and inflammatory status do not include all biomarkers and have been poorly studied in colorectal cancers. OBJECTIVE: The purpose of this study was to assess a new prognostic tool, the Naples prognostic score, comparing it with the prognostic nutritional index, controlling nutritional status score, and systemic inflammation score. DESIGN: This was an analysis of patients undergoing surgery for colorectal cancer. SETTINGS: The study was conducted at a university hospital. PATIENTS: A total of 562 patients who underwent surgery for colorectal cancer in July 2004 through June 2014 and 468 patients undergoing potentially curative surgery were included. MaxStat analysis dichotomized neutrophil:lymphocyte ratio, lymphocyte:monocyte ratio, prognostic nutritional index, and the controlling nutritional status score. The Naples prognostic scores were divided into 3 groups (group 0, 1, and 2). The receiver operating characteristic curve for censored survival data compared the prognostic performance of the scoring systems. MAIN OUTCOME MEASURES: Overall survival and complication rates in all patients, as well as recurrence and disease-free survival rates in radically resected patients, were measured. RESULTS: The Naples prognostic score correlated positively with the other scoring systems (p < 0.001) and worsened with advanced tumor stages (p < 0.001). Patients with the worst Naples prognostic score experienced more postoperative complications (all patients, p = 0.010; radically resected patients, p = 0.026). Compared with group 0, patients in groups 1 and 2 had worse overall (group 1, HR = 2.90; group 2, HR = 8.01; p < 0.001) and disease-free survival rates (group 1, HR = 2.57; group 2, HR = 6.95; p < 0.001). Only the Naples prognostic score was an independent significant predictor of overall (HR = 2.0; p = 0.03) and disease-free survival rates (HR = 2.6; p = 0.01). The receiver operating characteristic curve analysis showed that the Naples prognostic score had the best prognostic performance and discriminatory power for overall (p = 0.02) and disease-free survival (p = 0.04). LIMITATIONS: This is a single-center study, and its validity needs additional external validation. CONCLUSIONS: The Naples prognostic score is a simple tool strongly associated with long-term outcome in patients undergoing surgery for colorectal cancer. See Video Abstract at http://links.lww.com/DCR/A469. PMID- 29112564 TI - A Surgical Clostridium-Associated Risk of Death Score Predicts Mortality After Colectomy for Clostridium difficile. AB - BACKGROUND: A Clostridium difficile-associated risk of death score was recently developed and validated by using a national cohort of both nonsurgical and surgical patients admitted with C difficile infection. However, risk scores specifically derived from surgical cohorts and designed for patients with C difficile infection are currently unavailable. OBJECTIVE: The aim of this study was to develop a risk of death score for patients with C difficile infection who are being considered for total abdominal colectomy because of the failure of medical therapy. DESIGN: This is a retrospective cohort study. SETTINGS: This study was conducted with the use of a national database. PATIENTS: All patients undergoing total colectomy for C difficile infection were identified in the National Surgical Quality Improvement Program database from 2005 to 2014. MAIN OUTCOME MEASURES: Variables similar to the original scoring system were used in multivariable analyses to determine the risk of 30-day mortality for patients, and a model was constructed to estimate the predicted probability of mortality after surgery. RESULTS: Of 532 patients who underwent surgery, 32.7% experienced 30-day postoperative mortality. Patient covariates associated with significantly increased mortality included age greater than 80 years (OR 5.5, p = 0.003), need for preoperative mechanical ventilation (OR 3.1, p < 0.001), chronic steroid use (OR 2.9, p < 0.001), underlying cardiopulmonary disease (OR 2.0, p = 0.001), and acute renal failure (OR=1.7, p = 0.03). These and other comorbidities, including hepatic disease, a cancer diagnosis, and both insulin- and noninsulin-dependent diabetes mellitus, were used to construct a model to estimate the predicted probability of mortality, which ranged from 8.0% to 96.1% based on individual comorbidity profiles. These estimates differed substantially when compared with those obtained using the National Surgical Quality Improvement Program risk calculator, which estimated the risk of mortality among surgical patients as being consistently lower. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: Our surgical scoring system allows preoperative risk stratification for patients being evaluated for colectomy for C difficile infection, potentially helping to avoid futile surgery. See Video Abstract at http://links.lww.com/DCR/A434. PMID- 29112566 TI - What Is the Risk of Anastomotic Leak After Repeat Intestinal Resection in Patients With Crohn's Disease? AB - BACKGROUND: Approximately half of Crohn's patients require intestinal resection, and many need repeat resections. OBJECTIVE: The purpose of this study was to evaluate the increased risk of clinical anastomotic leak in patients with a history of previous intestinal resection undergoing repeat resection with anastomosis for Crohn's disease. DESIGN: This was a retrospective analysis of prospectively collected departmental data with 100% capture. SETTINGS: The study was conducted at the department of colorectal surgery in a tertiary care teaching hospital between July 2007 and March 2016. PATIENTS: A cohort of consecutive patients with Crohn's disease who were treated with intestinal resection and anastomosis, excluding patients with proximal fecal diversion, were included. The cohort was divided into 2 groups, those with no previous resection compared with those with previous resection. MAIN OUTCOME MEASURES: Clinical anastomotic leak within 30 days of surgery was measured. RESULTS: Of the 206 patients who met criteria, 83 patients had previous intestinal resection (40%). The 2 groups were similar in terms of patient factors, immune-suppressing medication use, and procedural factors. Overall, 20 clinical anastomotic leaks were identified (10% leak rate). There were 6 leaks (5%) detected in patients with no previous intestinal resection and 14 leaks (17%) detected in patients with a history of previous intestinal resection (p < 0.005). The OR of anastomotic leak in patients with Crohn's disease with previous resection compared with no previous resection was 3.5 (95% CI, 1.3-9.4). Patients with 1 previous resection (n = 53) had a leak rate of 13%, whereas patients with >=2 previous resections (n = 30) had a leak rate of 23%. The number of previous resections correlated with increasing risk for clinical anastomotic leak (correlation coefficient = 0.998). LIMITATIONS: This was a retrospective study with limited data to perform a multivariate analysis. CONCLUSIONS: Repeat intestinal resection in patients with Crohn's disease is associated with an increased rate of anastomotic leakage when compared with initial resection despite similar patient, medication, and procedural factors. See Video Abstract at http://links.lww.com/DCR/A459. PMID- 29112565 TI - A Randomized Control Trial of Preoperative Oral Antibiotics as Adjunct Therapy to Systemic Antibiotics for Preventing Surgical Site Infection in Clean Contaminated, Contaminated, and Dirty Type of Colorectal Surgeries. AB - BACKGROUND: Preoperative bowel preparation with or without oral antibiotics is controversial in terms of postoperative surgical site infections. OBJECTIVE: This study aimed to evaluate the efficacy of oral antibiotics as adjunct therapy to systemic antibiotics with mechanical bowel preparation for preventing surgical site infections in clean contaminated, contaminated, and dirty colorectal procedures. DESIGN: This was a single-center, prospective randomized study. SETTING: This study was conducted at the General Surgery Department at Jinling Hospital, Nanjing University, China, from July 15, 2014 to January 20, 2016. PATIENTS: Patients aged >=18 years scheduled for abdominal surgery with clean contaminated, contaminated, and dirty wounds were selected. INTERVENTIONS: Patients were randomly assigned to receive preoperative mechanical bowel preparation or mechanical bowel preparation with oral antibiotics. MAIN OUTCOMES: The primary outcome was the rate of surgical site infections. The secondary outcomes were extra-abdominal complications, duration of postoperative ileus, and readmission rate. RESULTS: Ninety-five patients were allocated to each group. Eight and 26 surgical site infections (8.42% vs 27.3 %, p = 0.004) occurred in the mechanical bowel preparation with oral antibiotics and mechanical bowel preparation groups. Thirteen extra-abdominal complications were reported: 6 in the mechanical bowel preparation with oral antibiotics group and 7 in the mechanical bowel preparation group (6.3% vs 7.3%, p = 0.77). Postoperative ileus duration did not differ between groups (p = 0.23). There were 4 readmissions in the mechanical bowel preparation group and none in the mechanical bowel preparation with oral antibiotics group (p = 0.04). On multivariable analysis, blood loss >=500 mL (OR, 5.1; 95% CI, 1.27-20.4; p = 0.02), ASA score >=3 (OR, 3.9; 95% CI, 1.2-12.5; p = 0.01), contaminated types (OR, 3.6; 95% CI, 1.5-8.6; p = 0.01), and administration of preoperative oral antibiotics (OR, 0.20; 95% CI, 0.06-0.60; p = 0.005) independently affected the incidence of surgical site infections. LIMITATIONS: This was a single-center study. CONCLUSION: Preoperative oral antibiotics, as adjunct therapy to systemic antibiotics and mechanical bowel preparation, significantly reduced surgical site infections and minimized the readmission rates in clean contaminated, contaminated, and dirty types of colorectal surgery. See Video Abstract at http://links.lww.com/DCR/A437. PMID- 29112567 TI - A Pilot Study of the Prevalence of Anal Human Papillomavirus and Dysplasia in a Cohort of Patients With IBD. AB - BACKGROUND: Defective cell-mediated immunity increases the risk of human papillomavirus-associated anal dysplasia and cancer. There is limited information on anal canal disease in patients with IBD. OBJECTIVE: The purpose of this study was to assess anal/vaginal human papillomavirus and anal dysplasia prevalence in patients with IBD. DESIGN: Patients had an anal examination before routine colonoscopy. SETTINGS: The study was conducted at a tertiary IBD referral center. PATIENTS: We studied a convenience sample of sexually active male and female patients with IBD who were not on biological therapy. INTERVENTION: Anal examination, anal and vaginal human papillomavirus testing, anal cytology, and high-resolution anoscopy/biopsy were carried out. MAIN OUTCOME MEASURES: Anal and vaginal human papillomavirus types, anal cytology, and biopsy grade were measured. RESULTS: Twenty-five male and 21 female evaluable participants, 31 with Crohn's disease, 14 with ulcerative colitis, and 1 with indeterminate colitis, were predominantly white (91.3%), treatment experienced (76.1%), an average age of 38.1 years (range, 22.0-66.0 y), and had an average length of IBD diagnosis of 9.3 years (range, 1.0-33.0 y). Eighteen (39.1%) had an abnormal perianal examination and 3 (6.5%) had an abnormal digital examination. Forty-one (89.1%) had anal human papillomavirus, 16 with a single type and 25 with multiple types (range, 2-5 types). Human papillomavirus type 16 was most common (65.2%), followed by human papillomavirus types 11 and 45 (37.0% each). Nineteen of 21 (90.5%) women had vaginal human papillomavirus. Overall, 21 (45.7%) had abnormal anal cytology. Thirty three (71.7%) had >=1 anal biopsy (9 had multiple), with dysplasia diagnosed in 28 (60.9%) and high-grade and low-grade squamous intraepithelial lesions diagnosed in 4 (8.7%) and 24 (43.5%). LIMITATIONS: No control group was included, and no detailed sexual history was taken. CONCLUSIONS: A high prevalence of anal and vaginal human papillomavirus and anal dysplasia was demonstrated in the study population outcomes. See Video Abstract at http://links.lww.com/DCR/A379. PMID- 29112568 TI - Sacral Nerve Stimulation for Fecal Incontinence: How Long Should the Test Phase Be? AB - BACKGROUND: Decision-making for pulse generator implantation for sacral nerve stimulation in the management of fecal incontinence is based on the results of a test phase. Its duration is still a matter of debate. OBJECTIVE: The purpose of this study was to determine whether an early positive response during the test phase could predict implantation of a permanent sacral nerve pulse generator. DESIGN: This was a short-term observational cohort study. A positive response was defined as a >50% decrease of fecal leaks compared with baseline. A multivariate logistic regression was computed to predict pulse generator implantation after the first week of the test phase. SETTINGS: The study was conducted in 3 national referral centers. PATIENTS: From January 2006 to December 2012, 144 patients with fecal incontinence enrolled in a prospectively maintained database completed a 2- to 3-week bowel diary, at baseline and during test phase. MAIN OUTCOME MEASURES: The primary outcome was the clinical decision to implant a pulse generator. The primary predictor was a calculated score including the number of leak episodes, bowel movements, and urgencies and the time to defer defecation expressed in minutes during the first screening test week. RESULTS: After the first, second and third week of the test phase, 81 (56%) of 144, 96 (67%) of 144, and 93 (70%) of 131 patients had a positive test. A permanent pulse generator was implanted in 114. Time to defer defecation increased during the 3 weeks of screening. Urgencies were unchanged. The computed score was predictive of a permanent pulse generator implantation (Se = 72.6% (95% CI, 59.8-83.1); Sp = 100% (95% CI, 78.2 100); c-index = 0.86 (95% CI, 0.78-0.94)). LIMITATIONS: No cost analysis or projection based on our proposal to reduce the test phase has been made. CONCLUSIONS: Permanent pulse generator implantation can be safely proposed early (1-week screening) to fast responders. Nonetheless, permanent implantation may be decided as well in patients exhibiting a delayed response. Whether a rapid response to sacral nerve stimulation could be predictive of a long-term response remains to be determined. See Video Abstract at http://links.lww.com/DCR/A452. PMID- 29112569 TI - Stromal Cell-Derived Factor 1 Plasmid Regenerates Both Smooth and Skeletal Muscle After Anal Sphincter Injury in the Long Term. AB - BACKGROUND: Regenerating muscle at a time remote from injury requires re expression of cytokines to attract stem cells to start and sustain the process of repair. OBJECTIVE: We aimed to evaluate the sustainability of muscle regeneration after treatment with a nonviral plasmid expressing stromal cell-derived factor 1. DESIGN: This was a randomized study. SETTINGS: The study was conducted with animals in a single research facility. INTERVENTIONS: Fifty-six female age /weight-matched Sprague-Dawley rats underwent excision of the ventral half of the anal sphincter complex. Three weeks later, rats were randomly allocated (n = 8) to one of the following groups: no treatment, 100 MUg of plasmid encoding stromal cell-derived factor 1 injected locally, local injection of plasmid and 8 * 10 bone marrow-derived mesenchymal stem cells, and plasmid encoding stromal cell derived factor 1 injected locally with injection of a gelatin scaffold mixed with bone marrow-derived mesenchymal stem cells. MAIN OUTCOME MEASURES: Anal manometry, histology, immunohistochemistrym and morphometry were performed 8 weeks after treatment. Protein expression of cytokines CXCR4 and Myf5 was investigated 1 week after treatment (n = 6 per group). ANOVA was used, with p < 0.0083 indicating significant differences for anal manometry and p < 0.05 for all other statistical analysis. RESULTS: Eight weeks after treatment, all of the groups receiving the plasmid had significantly higher anal pressures than controls and more organized muscle architecture in the region of the defect. Animals receiving plasmid alone had significantly greater muscle in the defect (p = 0.03) than either animals with injury alone (p = 0.02) or those receiving the plasmid, cells, and scaffold (p = 0.03). Both smooth and skeletal muscles were regenerated significantly more after plasmid treatment. There were no significant differences in the protein levels of CXCR4 or Myf5. LIMITATIONS: The study was limited by its small sample size and because stromal cell-derived factor 1 was not blocked. CONCLUSIONS: A plasmid expressing stromal cell-derived factor 1 may be sufficient to repair an injured anal sphincter even long after the injury and in the absence of mesenchymal stem cell or scaffold treatments. See Video Abstract at http://links.lww.com/DCR/A451. PMID- 29112570 TI - Rectal Eversion Technique: A Method to Achieve Very Low Rectal Transection and Anastomosis With Particular Value in Laparoscopic Cases. AB - INTRODUCTION: Transection of the rectum at the anorectal junction is required for proper resection in ulcerative colitis and restorative proctocolectomy. Achieving stapled transection at the pelvic floor is often challenging, particularly during laparoscopic proctectomy. Transanal mucosectomy and handsewn anastomosis are frequently used to achieve adequate resection. Rectal eversion provides an alternative for low anorectal transection and maintains the ability to perform stapled anastomosis. TECHNIQUE: The purpose of this article is to describe a technique for low anorectal transection. The work was conducted at tertiary care center by 2 colon and rectal surgeons on patients undergoing total proctocolectomy with creation of ileal pouch rectal anastomosis for ulcerative colitis. We measured the ability to achieve low stapled anastomosis. RESULTS: Very low transection was achieved, allowing for creation of IPAA without leaving significant rectal cuff. This study was limited because it is an early experience that was not performed in the setting of a scientific investigation. No sphincter or bowel functional data were obtained or evaluated. CONCLUSIONS: Rectal eversion technique provides an alternative to mucosectomy when low pelvic transection is difficult to achieve. See Video at http://links.lww.com/DCR/A441. PMID- 29112571 TI - Fluorescence-guided Robotic Total Mesorectal Excision with Lateral Pelvic Lymph Node Dissection in Locally Advanced Rectal Cancer: A Video Presentation. PMID- 29112572 TI - Comments on the Article, "Selected Techniques of Anal Fistula Surgery from Antiquity Through the Early 20th Century". PMID- 29112573 TI - Bowel Prep and Oral Antibiotics in Colorectal Surgery. PMID- 29112574 TI - The Authors Reply. PMID- 29112578 TI - A Dedicated Partnership in Safe Medication Practices. PMID- 29112579 TI - The Truth Is, Patients Are Safer Today Than 20 Years Ago. PMID- 29112580 TI - The Role of the Registered Nurse in the Insertion of Nontunneled Central Vascular Access Devices. AB - As the result of requests from several state boards of nursing, the Infusion Nurses Society (INS) convened a task force to determine whether insertion of central vascular access devices by appropriately trained registered nurses (RNs) should be recommended. The task force consisted of RNs and advanced practice registered nurses with infusion therapy experience in various practice settings. The results are presented in INS' newest position paper, adopted by the INS Board of Directors, September 2017. PMID- 29112581 TI - Instituting Vincristine Minibag Administration: An Innovative Strategy Using Simulation to Enhance Chemotherapy Safety. AB - The first fatal incident of wrong-route administration of vinca alkaloids occurred in 1968. Initial recommendations for practice change occurred in 2005. In 2012, 54% of oncology treatment sites had changed their practice. The authors' institution has developed a safe, adaptable, and consistent process to prepare, deliver, and administer vinca alkaloids by means of a minibag delivery. A multidisciplinary team, including representatives from the nursing and pharmacy departments, reviewed the literature and developed all processes, including staff education. Minibag administration began in August 2015, and more than 2063 doses have been administered without any extravasations. To date, the simulation strategy for education is effective, and the delivery system is safe. PMID- 29112582 TI - A Review of Best Practices for Intravenous Push Medication Administration. AB - In 2015, the Institute for Safe Medication Practices (ISMP) released safe practice guidelines for adult intravenous (IV) push medications. ISMP's most recent set of guidelines has added to a growing list of recommendations from professional groups on the safe use of IV medications. These recommendations and guidelines vary with regard to their audience, scope, and terminology. In some ways, these variations may contribute to confusion and delayed adoption of the standards. This report attempts to provide clarity about the rationale and background regarding the need for practice improvement, discussion of various guidelines, and practice mitigation strategies to improve patient safety. PMID- 29112583 TI - Improving Quality of Chest Radiographs After Placement of Peripherally Inserted Central Catheters. AB - The goal of this study was to determine the best method for localizing peripherally inserted central catheters (PICCs) in postplacement portable chest radiographs. A retrospective analysis showed no significant difference in visualization of the PICC tip between different chest radiograph projections. Modifications were made to an institutional PICC protocol to obtain anteroposterior chest views with the guidewire present only. Repeat analysis demonstrated statistically significant increases in the frequency of anteroposterior radiographs performed, the number of chest radiographs with guidewire, and the localization of the catheter. By standardizing the acquisition of PICC placement chest radiographs, fewer variant projection radiographs were performed and the catheter tip was confidently localized in more examinations. PMID- 29112584 TI - Rheumatoid Arthritis: Pathophysiology and Safe Administration of Biologics. AB - Approximately 1 in 5 people in the United States suffers from autoimmune diseases. To explain the pathophysiology of autoimmune disease, a basic understanding of the normal and dysfunctional immune system is necessary. Rheumatoid arthritis is used as a model to explain the basics of autoimmune disease. The infusion nurse plays a key role in patient education and the safe administration of biologics. PMID- 29112585 TI - Evaluation of the Predictive Validity of Thermography in Identifying Extravasation With Intravenous Chemotherapy Infusions. AB - Early detection of extravasation is important, but conventional methods of detection lack objectivity and reliability. This study evaluated the predictive validity of thermography for identifying extravasation during intravenous antineoplastic therapy. Of 257 patients who received chemotherapy through peripheral veins, extravasation was identified in 26. Thermography was performed every 15 to 30 minutes during the infusions. Sensitivity, specificity, positive predictive value, and negative predictive value using thermography were 84.6%, 94.8%, 64.7%, and 98.2%, respectively. This study showed that thermography offers an accurate prediction of extravasation. PMID- 29112586 TI - The Role of Immunoglobulin in the Treatment of Immune-Mediated Peripheral Neuropathies. AB - Immune-mediated neuropathies are a group of peripheral nerve disorders characterized by motor or sensory deficits caused by inflammation leading to demyelination or axonal injury. Intravenous immunoglobulin (IVIg) has been demonstrated to be an effective therapy for the 3 most common immune-mediated neuropathies: Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. This review summarizes current data on the rationale for the use of IVIg in immune-mediated neuropathies, addressing mechanism of action, clinical evidence, and practical considerations for its use. PMID- 29112587 TI - Incidence of Infusion Site Reactions in Peripheral Fosaprepitant Infusions. AB - Fosaprepitant is administered intravenously to treat chemotherapy-induced nausea and vomiting. To verify the incidence of infusion site reactions and the relationship among risk factors, a quantitative retrospective cohort study was undertaken. The study included patients seen between October 2013 and February 2014. Fifty-seven patients were included in the study, and there were 105 infusions among them. Infusion site reactions were identified in 42 (40%) cases. Risk factors identified by the study included age (P < .001), insertion at the back of the hand and wrist (P < .001), and first fosaprepitant administration (P < .001). The study found evidence of a higher incidence of infusion site reactions than was reported in the package insert. PMID- 29112588 TI - Trajectories of Anxiety and Depression After Liver Transplantation as Related to Outcomes During 2-Year Follow-Up: A Prospective Cohort Study. AB - OBJECTIVE: The aims of the study were to examine whether distinct trajectories of anxious and depressive symptoms are present among liver transplant recipients from before transplantation to 2 years afterward, to identify associated demographic, clinical, and individual characteristics, and to examine the influence of distinct trajectories on outcomes. METHODS: A prospective, multicenter cohort study was performed among 153 liver transplant recipients. Data were retrieved using questionnaires administered before transplantation and at 3, 6, 12, and 24 months after transplantation. Clinical data were retrieved by medical record review. Latent class growth analysis was used to identify distinct trajectories. chi test, analyses of variance, and multinomial logistic regression were used to identify associated variables and the impact of the distinct trajectories on outcomes. RESULTS: Three distinct trajectories for symptoms of anxiety (State-Trait Anxiety Inventory-short form) as well as depression (Center for Epidemiological Studies Depression Scale) were identified: "no symptoms," "resolved symptoms," and "persistent symptoms." The trajectories of persistent anxiety and depression comprised, respectively, 23% and 29% of the transplant recipients. Several clinical and individual variables were associated with the trajectories of persistent anxiety and/or depression: experiencing more adverse effects of the immunosuppressive medication, lower level of personal control, more use of emotion-focused coping, less disclosure about the transplant, and more stressful life events. The trajectories of persistent symptoms were associated with worse outcomes regarding medication adherence and health-related quality of life, but not with mortality. CONCLUSIONS: A significant subset of transplant recipients showed persistent symptoms of anxiety and depression from before to 2 years after transplantation. These results emphasize the importance of psychosocial care in the transplant population. PMID- 29112589 TI - Androgens Mediate beta-adrenergic Vasorelaxation Impairment Using Adenylyl Cyclase. AB - Cardiovascular disease development has been associated with sex differences, suggesting that sex hormones are implicated in vascular function and development of hypertension. Vascular tone comparison at different stages of rat growth represents a good model to study testosterone-related vascular response. We explored the role of testosterone in modulation of age-dependent impaired beta adrenergic vasodilation. The 3-week-old male Sprague-Dawley rats were sorted in 3 week-old rats without any manipulation and 3-week-old rats treated with testosterone. The 9-week-old rats were randomly grouped into 9-week-old rats without any manipulation (sham), 9-week-old rats that underwent gonadectomy (9 week-old castrated), and 9-week-old castrated treated with testosterone replacement therapy (9-week-old castrated + testosterone). Vascular relaxation was evaluated in aortic rings. beta-adrenergic receptor protein expression, cyclic adenosine monophosphate production, testosterone levels, and adenylyl cyclase (AC) gene expression were assessed. Testosterone levels were low in 3 week-old and 9-week-old castrated rats compared with 9-week-old sham rats. Testosterone replacement raised these levels in 3-week-old and 9-week-old castrated rats similar to those of 9-week-old sham rats. SQ22536, the AC inhibitor, prevented isoproterenol-induced relaxation in aortic rings from 3-week old and 9-week-old castrated rats. The beta-adrenergic receptor protein expression was similar in all experimental groups. AC mRNA and protein expression and cyclic adenosine monophosphate levels were elevated in 3-week-old and 9-week old castrated rats compared with 3-week-old + testosterone, 9-week-old sham, and 9-week-old castrated + testosterone rats. In conclusion, we demonstrated that age maturation was associated with vascular relaxation impairment. Variations in testosterone levels and reduced AC expression may be responsible for this altered vascular function. PMID- 29112590 TI - Effect of Andrographolide on Gene Expression Profile and Intracellular Calcium in Primary Rat Myocardium Microvascular Endothelial Cells. AB - Andrographolide (ANDRO) is a diterpene lactone compound with extensive biological effects, such as antibacterial, antitumor and treatment of cardiovascular diseases. Until now, studies on the pharmacological functions of ANDRO are still in progress. However, little is known about the gene expression profile and calcium response of endothelial cells to ANDRO. In this study, we used a microarray technology to investigate the gene expression responses in primary rat myocardium microvascular endothelial cells treated with 10 MUg/mL ANDRO. The expression of caveolin-1 and 1-phosphatidylinositol 4, 5-bisphosphate phosphodiesterase delta3 was verified by RT-PCR and western blot. In addition, we investigated the effect of ANDRO on intracellular calcium induced by exogenous adenosine triphosphate and on inflammatory response induced by lipopolysaccharide. Results showed that ANDRO treatment induced an abundance of differential expressed genes, exhibiting a multitarget regulatory effect. ANDRO significantly decreased caveolin-1 and phosphodiesterase delta3 expression, lipopolysaccharide-induced IL-6 and TNF-alpha levels and expression of several chemokine genes, which are associated with reducing inflammation response and decreasing calcium release without affecting normal endothelia cell function, suggesting that ANDRO may be a potential candidate to treat cardiovascular diseases with less toxicity. PMID- 29112591 TI - Pharmacokinetics and Pharmacodynamics of Low-, Intermediate-, and High-Dose Landiolol and Esmolol During Long-Term Infusion in Healthy Whites. AB - The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective beta blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared. Drug blood concentrations and areas under the curve were dose proportional. The half life of landiolol (4.5 minutes) was significantly shorter than that of esmolol (6.9 minutes). Volume of distribution and total clearance were lower for landiolol. Heart rate reduction was faster and more pronounced with landiolol and retained throughout the administration period; effects on blood pressure were not different. Landiolol turned out to be superior to esmolol with respect to pharmacokinetic and pharmacodynamic profile and local tolerability. PMID- 29112592 TI - Antihypertensive Therapy and New On-set of Diabetes Mellitus: The Double-Edge Sword. PMID- 29112593 TI - Age-related changes in luteal dynamics: preliminary associations with antral follicular dynamics and hormone production during the human menstrual cycle. AB - OBJECTIVE: The aim of the study was to test the hypothesis that the development of luteal phase dominant follicles (LPDFs) as women age is associated with abnormal luteal function. METHODS: Luteal and antral follicle diameter were quantified in ovulatory women of midreproductive age (MRA; 18-35 y; n = 9) and advanced reproductive age (ARA; 45-55 y; n = 16) every 1 to 3 days during one complete interovulatory interval. Blood was drawn at each visit and assayed for progesterone, estradiol, inhibin A, follicle-stimulating hormone, and luteinizing hormone. Luteal diameter and hormone profiles were compared within MRA and ARA women with versus without LPDFs. RESULTS: Luteal growth and regression profiles were similar in MRA women with typical versus no LPDFs (13.9, 14.8 mm; P > 0.1); however, luteal phase estradiol and progesterone were greater in MRA women with typical (91.1 ng/L, 8.81 MUg/L) versus no (48.8 ng/L, 7.32 MUg/L) LPDFs, respectively (LPDF effect, P < 0.1). In the ARA group, mean luteal diameter was lowest in women with atypical LPDFs (12.3 mm), greatest in those with typical LPDFs (16.0 mm), and moderate in those with no LPDFs (13.6 mm), (P < 0.1). Reduced luteal growth in ARA women with atypical versus typical and/or no LPDFs occurred simultaneously to greater luteal phase estradiol (199 vs 69.0, 78.4 ng/L) lower progesterone (7.38 vs 10.7, 13.8 ug/L), and lower inhibin A (36.3, 35.6, 51.2) (P < 0.1). CONCLUSIONS: The development of LPDFs as women age was associated with reduced luteal growth, greater estradiol, lower progesterone, and lower inhibin A. These findings provide preliminary evidence that variations in antral folliculogenesis contribute to luteal insufficiency during the menopausal transition. PMID- 29112595 TI - Risk factors associated with intensity of climacteric symptoms in Brazilian middle-aged women: a population-based household survey. AB - OBJECTIVE: To determine the factors associated with the intensity of climacteric somatovegetative, psychological, and urogenital symptoms among middle-aged women in the Metropolitan Region of Campinas, Brazil. METHODS: A cross-sectional population-based household survey was conducted with 749 women aged 45 to 60 years. The dependent variable was the intensity of menopausal symptoms assessed using the Menopause Rating Scale. The independent variables were sociodemographic data, health-related habits and problems, self-perception of health, and gynecological background. RESULTS: The mean age of the women was 52.5 +/- 4.4 years, and the mean age at onset of menopause was 46.5 +/- 5.8 years. The intensity of menopausal symptoms was defined using the subscale scores of the median Menopause Rating Scale. Poisson multiple regression for somatovegetative, psychological, and urogenital symptoms showed several associated factors of each subscale, though some factors were common. Factors associated with moderate to severe climacteric symptoms in all the subscales of the Menopause Rating Scale were self-perception of health as "fair"/"poor"/"very poor" (P < 0.01), depression/anxiety (P < 0.01), and osteoarticular diseases (P < 0.01). CONCLUSIONS: The severity of climacteric symptoms in the different Menopause Rating Scale domains was related to a broad set of factors. Each Menopause Rating Scale subscale had its own set of factors, but some were common. Presence of chronic diseases, depression or anxiety, and worst self-perception of health were highlighted. A better understanding of these factors may help to not only reduce the effect of climacteric symptoms on the quality of life of middle-aged women, but also identify groups of women who need multidisciplinary health care. PMID- 29112594 TI - Sexual activity and vaginal symptoms in the postintervention phase of the Women's Health Initiative Hormone Therapy Trials. AB - OBJECTIVE: To assess the impact of discontinuing oral hormone therapy (HT) on sexual activity, vaginal symptoms, and sexual activity components among participants in the estrogen-progestin therapy (EPT) and estrogen therapy (ET) trial of the Women's Health Initiative. METHODS: Surveys were sent postintervention to those who were still taking study pills and agreed to continue in the study when the trials were stopped. Comparisons between former HT and placebo users were accomplished with chi-square tests for categorical variables and t tests for continuous variables. RESULTS: In all, 13,902 women with mean age at survey 69.9 years (EPT trial, women with intact uterus) and 71.7 years (ET trial, women with history of hysterectomy) responded. Prevalence of sexual activity postintervention was not significantly different between former EPT and placebo users (36.0% vs 34.2%; P = 0.37). Sexual activity of former ET users was 5.6% higher than placebo users (27.6% vs 22.0%; P = 0.001). The majority of sexually active women overall maintained orgasmic capacity and sexual satisfaction. Former EPT users were 10% to 12% more likely than former placebo users to report decreased desire, arousal, intercourse, climax, and satisfaction with sexual activity, and also increased dryness and dyspareunia upon discontinuing study drugs (P < 0.001). Former ET users were more likely than placebo users to report rare to no desire or arousal postintervention (P < 0.001). CONCLUSIONS: Postintervention ET trial participants formerly assigned to ET were significantly more likely to report sexual activity than those formerly assigned to placebo. Women who discontinued EPT were significantly more likely to report negative vaginal and sex-related effects. PMID- 29112596 TI - Increased cardiac and stroke death risk in the first year after discontinuation of postmenopausal hormone therapy. AB - OBJECTIVE: The aim of the study was to evaluate the risk of cardiac and stroke deaths in women who discontinue postmenopausal hormone therapy (HT). METHODS: We analyzed the risk of death due to cardiac (n = 5,204) and cerebrovascular (n = 3,434) causes in Finnish women who discontinued systemic HT during 1994 to 2013 (n = 432,775). The risks were compared with those in the age-matched female background population and with those in age-matched HT users. Women diagnosed with cardiac or cerebrovascular events within 1 year before discontinuation of HT were excluded (n = 8,711). RESULTS: Women younger than 60 years at discontinuation of HT showed a significantly increased risk of cardiac death (after <=5 y of HT exposure, standardized mortality ratio [SMR] 1.52, 95% CI 1.13 2.00; after >5 y of exposure, SMR 2.08, 95% CI 1.44-2.90) and stroke death (after <=5 y of exposure, SMR 2.62, 95% CI 2.07-3.28; after >5 y of exposure, SMR 3.22, 95% CI 2.29-4.40) during the first year after treatment as compared with age matched female background population. When compared with HT users, elevations in risks of cardiac and stroke deaths were even higher. Increased mortality risks were limited to the first post-HT year because increases in risks vanished or markedly decreased when the follow-up time was extended over more than 1 year. CONCLUSIONS: Discontinuation of postmenopausal HT may be associated with increased risk of cardiac and stroke death in the first posttreatment year. Further investigation is required to evaluate causality of the observed associations. PMID- 29112597 TI - Association of age at menarche with obesity and hypertension among southwestern Chinese women: a new finding. AB - OBJECTIVES: The purpose of this study was to assess the association of the age at menarche with obesity and hypertension among southwestern Chinese women. METHODS: Participants in a cross-sectional study were required to recall and complete a standard self-reporting questionnaire, including age at menarche and lifestyle habits. Cardiovascular risk factors were obtained from the questionnaire or a physical examination. The main outcomes were obesity and hypertension. The association was examined by binary logistic regression and birth cohort. Odds ratios for adiposity and hypertension were computed across menarcheal ages. RESULTS: A cohort of 7,119 women with a mean age of 44.7 years was included in the study. After adjustments, odds ratios (and 95% confidence interval) for obesity across menarcheal age categories (<=11, 12-13, 14-15, 16-17, >=18) were 3.75 [1.35-10.41], 1.15 [0.90-1.48], 1 (referent), 0.92 [0.75-1.12], and 0.74 [0.58-0.96], respectively (Ptrend < 0.001). For hypertension, they were 0.38 [0.13-1.08], 1.03 [0.80-1.33], 1 (referent), 1.21 [0.98-1.49], and 1.39 [1.08 1.80], respectively (Ptrend = 0.03). After adjustment by birth cohort, age at menarche was not associated with obesity but was still positively associated with hypertension. CONCLUSIONS: This study is the first to report that, among southwestern Chinese women, a late menarche tends to be associated with a high risk of hypertension, but with a low risk of obesity. The association between menarche and obesity tends to differ among birth cohorts. Knowledge of the menarcheal history could be a preventive marker for cardiovascular disease. PMID- 29112598 TI - Age at natural menopause in Koreans: secular trends and influences thereon. AB - OBJECTIVES: Age at natural menopause (ANM) has become an important health issue in older women. We explored secular trends in ANM in Korea during the past decade, and defined factors predicting ANM. METHODS: A total of 12,761 naturally menopausal women were selected from the 2001 to 2014 data of the Korea National Health and Nutrition Examination Survey, stages II to VI. The participants were divided into four groups based on 5-year ANM categories: <45, 45 to 49, 50 to 54, and >=55 years. To identify factors associated with ANM, the regression analysis was used. RESULTS: Both the mean (SE) and median (SE) ANM were 49.30 (0.07) years. The cumulative proportion of women experiencing menopause before the age of 40, 45, 50, and 55 years was 3.6%, 11.8%, 46.0%, and 90.3%, respectively. The mean (SE) ANM in women born in 1929 or earlier, and between 1930 to 1934, 1935 to 1939, 1940 to 1944, and 1945 to 1949, was 47.9 (0.3), 48.1 (0.2), 48.8 (0.2), 50.1 (0.2), and 50.5 (0.1) years, respectively (P < 0.001). Residence in a rural area (odds ratio [OR] 1.82), low weight status (OR 1.61), a history of or current smoking, a low educational level, being without a partner, and participating in at least moderate physical activity (OR 1.47, 1.33, 1.32, and 1.26, respectively) were more likely to result in an early ANM. Women with prior childbirth were less likely to experience early menopause (OR 0.34). In contrast, late menopause was associated with obesity and being overweight (OR 1.63 and 1.27). CONCLUSIONS: We found that the mean ANM exhibited upward secular trends. Socioeconomic status and lifestyle factors were the principal independent factors affecting ANM. PMID- 29112600 TI - Low bone mineral density in middle-aged women: a red flag for sarcopenia. AB - OBJECTIVE: This study evaluated whether low bone density, a condition related to aging, is associated with low muscle mass, a surrogate for sarcopenia, and whether it could be used as a marker of the condition. METHODS: We studied 483 women aged 35 to 69 years old who appeared healthy and attended a preventive gynecological examination. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) and regional body composition. BMD was assessed using the T-score. Low appendicular lean mass (aLM) adjusted by height (aLM index) was defined according to Baumgartner et al (<5.45 kg/m). The association of low aLM index with bone mass was evaluated with a binary logistic regression using a cutoff point on the receiver operating characteristic curves for the T-score of 1.5. RESULTS: The participants had a mean age of 54.7 +/- 9.1 years, body mass index of 24.6 +/- 3.6 kg/m, aLM index of 5.9 +/- 0.6 kg/m (22.6% showed sarcopenia), abdominal fat percentage of 44.0 +/- 9.1%, and T-score of -0.48 +/- 0.97. In the logistic regression model, we found that low BMD implied a significant risk for sarcopenia (odds ratio [OR] 1.77; 95% CI, 1.02-3.06). In contrast, excess body weight was a protective factor (OR 0.12; 95% CI, 0.06 0.25). Neither age nor abdominal fat percentage, however, influenced the likelihood of sarcopenia in these women. CONCLUSIONS: A BMD T-score below -1.5 suggests low muscle mass in middle-aged women, which is a central element in the diagnosis of sarcopenia. Early diagnosis provides the opportunity to introduce preventive and therapeutic options. PMID- 29112599 TI - Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women. AB - OBJECTIVE: To better understand the relationship between cardiovascular disease risk and age-at-natural menopause using genetic data. METHODS: Early menopause is associated with cardiovascular disease risk. We constructed a genetic risk score comprising 56 age-at-natural menopause decreasing alleles in men and women from the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and the Rotterdam Study. If the genetic predisposition to earlier age-at-natural menopause is associated with increased cardiovascular disease risk, it is reasonable to ask whether the risk is shared by men carrying the alleles, despite not experiencing menopause. We estimated the hazard ratio for the score for time to first cardiovascular event. To investigate the possible genetic pleiotropy between age-at-natural menopause and cardiovascular disease, we performed cross trait linkage disequilibrium score regressions between age-at-natural menopause and cardiovascular disease and risk factors using genome-wide association studies. RESULTS: Twenty-two thousand five hundred and sixty-eight cardiovascular disease-free participants at baseline were analyzed (9,808 men, 12,760 women). Each additional unit of the genetic propensity to earlier age-at-natural menopause increased the hazard of both cardiovascular disease and cardiac death in women (cardiovascular disease: hazard ratio 1.10 [1.04-1.16], P = 9.7 * 10; cardiac death: 1.12 [1.02-1.24], P = 0.03), whereas no effect was observed for either outcome in men (hazard ratio 0.99 [0.95-1.04], P = 0.71; 1.05 [0.94-1.16], P = 0.34). We found significant negative genetic correlations in women, but not men, between age-at-natural menopause and cardiovascular disease and risk factors. CONCLUSION: Genetic variants associated with earlier age-at-natural menopause are associated with increased cardiovascular disease risk in women, but not men, suggesting sex-specific genetic effects on cardiovascular disease risk. PMID- 29112601 TI - Seeing the light: the need for randomized trials of vaginal laser in postmenopausal women. PMID- 29112605 TI - 2017 Founders Award - George Chabot. PMID- 29112606 TI - 2017 Distinguished Scientific Achievement Award - John D. Zimbrick. PMID- 29112602 TI - Occupational Exposures and Metabolic Syndrome Among Hispanics/Latinos: Cross Sectional Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - OBJECTIVE: We assessed the cross-sectional relationships of self-reported current occupational exposures to solvents, metals, and pesticides with metabolic syndrome and its components among 7127 participants in the Hispanic Community Health Study/Study of Latinos. METHODS: Metabolic syndrome was defined as a clustering of abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and/or high fasting glucose. Regression models that incorporated inverse probability of exposure weighting were used to estimate prevalence ratios. RESULTS: Solvent exposure was associated with a 32% higher prevalence of high blood pressure (95% confidence interval: 1.09 to 1.60) than participants not reporting exposure. No associations were observed for occupational exposures with abdominal obesity, high triglycerides, low high density lipoprotein, or metabolic syndrome. CONCLUSION: Our findings suggest that solvent exposure may be an important occupational risk factor for high blood pressure among Hispanics/Latinos in the United States. PMID- 29112607 TI - 2017 Distinguished Public Service Award - Michael T. Ryan. PMID- 29112608 TI - 2017 Elda E. Anderson Award - Jason Davis. PMID- 29112609 TI - 2017 Honor Roll Award - David P. Alberth. PMID- 29112610 TI - 2017 Honor Roll Award - Kenneth Eger. PMID- 29112612 TI - 2017 50-Year Members. PMID- 29112611 TI - 2017 Honor Roll Award - Jeffrey A. Leavey. PMID- 29112613 TI - 2017 Honorees as Fellows of the Health Physics Society. PMID- 29112614 TI - 2017 Homeland Security Section Service Award - Allen Brodsky. PMID- 29112616 TI - 2017 Chapter Volunteer Award. PMID- 29112615 TI - 2017 Military Health Physics Section Awards. PMID- 29112617 TI - 2017 Student Travel Grant Recipients. PMID- 29112618 TI - 2017 Student Fellowships. PMID- 29112619 TI - 2017 American Academy of Health Physics Awards. PMID- 29112620 TI - Evaluation of the Accuracy of Polymer Gels for Determining Electron Dose Distributions in the Presence of Small Heterogeneities. AB - The aim of this study is to evaluate the application and accuracy of polymer gels for determining electron dose distributions in the presence of small heterogeneities made of bone and air. Different cylindrical phantoms containing MAGIC (Methacrylic and Ascorbic acid in Gelatin Initiated by Copper) normoxic polymer gel were used under the slab phantoms during irradiation. MR images of the irradiated gel phantoms were obtained to determine their R2 (spin-spin) relaxation maps for conversion to absorbed dose. One- and 2-dimensional lateral dose profiles were acquired at depths of 1 and 4 cm for 8 and 15 MeV electron beams. The results were compared with the doses measured by a diode detector at the same positions. In addition, the dose distribution in the axial orientation was measured by the gel dosimeter. The slope and intercept for the R2 versus dose curve were 0.509 +/- 0.002 Gy s and 4.581 +/- 0.005 s, respectively. No significant variation in dose-R2 response was seen for the two electron energies within the applied dose ranges. The mean dose difference between the measured gel dose profiles was smaller than 3% compared to those measured by the diode detector. These results provide further demonstration that electron dose distributions are significantly altered in the presence of tissue inhomogeneities such as bone and air cavity and that MAGIC gel is a useful tool for 3-dimensional dose visualization and qualitative assessment of tissue inhomogeneity effects in electron beam dosimetry. PMID- 29112621 TI - The Role Of Extracellular Fluid in Biokinetic Modeling. AB - The pharmacokinetic equations of Pierson et al. describing the behavior of bromide in rat provide a general approach to the modeling of extracellular fluid (ECF). The movement of material into ECF spaces is rapid and is completely characterized by tissue volumes and vascular flow rates to and from a tissue, the volumes of the tissue, and the ECF associated with the tissue. Early-time measurements are needed to characterize ECF. Measurements of DTPA disappearance from plasma by Wedeking et al. are discussed as an example of such measurements. In any biokinetic model, the fastest transfer rates are not determinable with the usual datasets, and if determined empirically, these rates will have very large and highly correlated uncertainties, so particular values of these rates, even though the model fits the available data, are not significant. A pharmacokinetic front-end provides values for these fast rates. An example of such a front-end for a 200-g rat is given. PMID- 29112624 TI - Effect of Early- and Adult-Life Socioeconomic Circumstances on Physical Inactivity. AB - PURPOSE: This study aimed to investigate the associations between early- and adult-life socioeconomic circumstances and physical inactivity (level and evolution) in aging using large-scale longitudinal data. METHODS: This study used the Survey of Health Ageing and Retirement in Europe, a 10-yr population-based cohort study with repeated measurements in five waves, every 2 yr between 2004 and 2013. Self-reported physical inactivity (waves 1, 2, 4, and 5), household income (waves 1, 2, 4, and 5), educational attainment (wave of the first measurement occasion), and early-life socioeconomic circumstance (wave 3) were collected in 22,846 individuals 50 to 95 yr of age. RESULTS: Risk of physical inactivity was increased for women with the most disadvantaged early-life socioeconomic circumstances (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.20-1.86). With aging, the risk of physical inactivity increased for both sexes and was strongest for those with the most disadvantaged early-life socioeconomic circumstances (OR, 1.04 (95% CI, 1.02-1.06) for women; OR, 1.02 (95% CI, 1.00 1.05) for men), with the former effect being more robust than the latter one. The association between early-life socioeconomic circumstances and physical inactivity was mediated by adult-life socioeconomic circumstances, with education being the strongest mediator. CONCLUSIONS: Early-life socioeconomic circumstances predicted high levels of physical inactivity at older ages, but this effect was mediated by socioeconomic indicators in adult life. This finding has implications for public health policies, which should continue to promote education to reduce physical inactivity in people at older ages and to ensure optimal healthy aging trajectories, especially among women with disadvantaged early-life socioeconomic circumstances. PMID- 29112625 TI - Ischemic Preconditioning Improves Time Trial Performance at Moderate Altitude. AB - PURPOSE: Endurance athletes often compete and train at altitude where exercise capacity is reduced. Investigating acclimation strategies is therefore critical. Ischemic preconditioning (IPC) can improve endurance performance at sea level through improved O2 delivery and utilization, which could also prove beneficial at altitude. However, data are scarce, and there is no study at altitudes commonly visited by endurance athletes. METHODS: In a randomized, crossover study, we investigated performance and physiological responses in 13 male endurance cyclists during four 5-km cycling time trials (TT), preceded by either IPC (3 * 5 min ischemia/5-min reperfusion cycles at 220 mm Hg) or SHAM (20 mm Hg) administered to both thighs, at simulated low (FIO2 0.180, ~1200 m) and moderate (FIO2 0.154, ~2400 m) altitudes. Time to completion, power output, cardiac output (Q), arterial O2 saturation (SpO2), quadriceps tissue saturation index (TSI) and RPE were recorded throughout the TT. Differences between IPC and SHAM were analyzed at every altitude using Cohen effect size (ES) and compared with the smallest worthwhile change. RESULTS: At low altitude, IPC possibly improved time to complete the TT (-5.2 s, -1.1%; Cohen ES +/- 90% confidence limits -0.22, 0.44; 0.01), power output (2.7%; ES 0.21, 0.08; 0.51), and Q (5.0%; ES 0.27, 0.00; 0.54), but did not alter SpO2, muscle TSI, and RPE. At moderate altitude, IPC likely enhanced completion time (-7.3 s; -1.5%; ES -0.38, -0.55; -0.20), and power output in the second half of the TT (4.6%; ES 0.28, -0.15; 0.72), increased SpO2 (1.0%; ES 0.38, -0.05; 0.81), and decreased TSI (-6.5%; ES -0.27, -0.73; 0.20) and RPE (-5.4%, ES -0.27, -0.48; -0.06). CONCLUSIONS: Ischemic preconditioning may provide an immediate and effective strategy to defend SpO2 and enhance high-intensity endurance performance at moderate altitude. PMID- 29112626 TI - Effects of Ad libitum Low-Carbohydrate High-Fat Dieting in Middle-Age Male Runners. AB - PURPOSE: This study examined the effects of a 3-wk ad libitum, low-carbohydrate (<50 g.d) high-fat (~70% of calories) (LCHF) diet on markers of endurance performance in middle-age, recreationally competitive male runners. METHODS: All subjects (n = 8) after their normal high-carbohydrate (HC) diet had anthropometric measures assessed and completed five 10-min running bouts at multiple individual race paces in the heat while physiological variables, metabolic variables, and perceptual responses were recorded. After 20 min of rest, participants completed a 5-km time trial on a road course. Subjects then consumed an LCHF diet for 3 wk and returned for repeat testing. RESULTS: Body mass and seven-site skinfold thickness sum decreased by approximately 2.5 kg (P < 0.01) and 13 mm (P < 0.05) after LCHF diet. Rectal temperature was higher after the first 10 min of exercise (37.7 degrees C +/- 0.3 degrees C vs 37.3 degrees C +/- 0.2 degrees C) in the HC diet but did not differ at any other time with LCHF diet. Heart rate and perceptual measures did not display any consistent differences between treatments excluding thirst sensation for LCHF diet. RER and carbohydrate oxidation declined significantly, whereas fat oxidation increased after LCHF diet for every pace (P < 0.01). There was no significant difference (P = 0.25) in a 5-km time trial performance, but LCHF diet (23.45 +/- 2.25 min) displayed a trend of improved performance versus HC (23.92 +/- 2.57 min). CONCLUSION: Improved body composition and fat oxidation from LCHF diet potentially negate expected performance decrement from reduced carbohydrate use late in exercise for nonelite runners. An acute decrease in training capacity is expected; however, if performance improvement is not exhibited after 3 wk, diet cessation is suggested for negative responders. PMID- 29112627 TI - Impact of Blood Flow Restriction Exercise on Muscle Fatigue Development and Recovery. AB - PURPOSE: The present study was designed to provide mechanistic insight into the time course and etiology of muscle fatigue development and recovery during and after low-intensity exercise when it is combined with blood flow restriction (BFR). METHODS: Seventeen resistance-trained males completed four sets of low intensity isotonic resistance exercise under two experimental conditions: knee extension exercise (i) with BFR and (ii) without BFR (CON). Neuromuscular tests were performed before, during (immediately after each set of knee extension exercise), and 1, 2, 4, and 8 min after each experimental condition. Maximal voluntary torque, quadriceps twitch torque in response to paired electrical stimuli at 10 Hz (PS10) and 100 Hz (PS100), PS10.PS100 ratio as an index of low frequency fatigue, and voluntary activation were measured under isometric conditions. Perceptual and EMG data were recorded during each exercise condition. RESULTS: After the first set of exercise, BFR induced significantly greater reductions in maximal voluntary torque, PS100, and PS10.PS100 ratio compared with CON. These parameters progressively declined throughout the BFR protocol but recovered substantially within 2 min postexercise when blood flow was restored. Neither a progressive decline in the course of the exercise protocol nor a substantial recovery of these parameters occurred during and after CON. Only at exercise termination, voluntary activation differed significantly between BFR and CON with greater reductions during BFR. CONCLUSION: At the early stage of exercise, BFR exacerbated the development of muscle fatigue mainly due to a pronounced impairment in contractile function. Despite the high level of muscle fatigue during BFR exercise, the effect of BFR on muscle fatigue was diminished after 2 min of reperfusion, suggesting that BFR has a strong but short-lasting effect on neuromuscular function. PMID- 29112628 TI - Exercise-induced Protein Arginine Methyltransferase Expression in Skeletal Muscle. AB - PURPOSE: This study aimed to determine protein arginine methyltransferase 1 (PRMT1), -4 (also known as coactivator-associated arginine methyltransferase 1 [CARM1]), and -5 expression and function during acute, exercise-induced skeletal muscle remodeling in vivo. METHODS: C57BL/6 mice were assigned to one of three experimental groups: sedentary, acute bout of exercise, or acute exercise followed by 3 h of recovery. Mice in the exercise groups performed a single bout of treadmill running at 15 m.min for 90 min. Hindlimb muscles were collected, and quantitative real-time polymerase chain reaction and Western blotting were used to examine exercise-induced gene expression. RESULTS: The PRMT gene expression and global enzyme activity were muscle-specific, generally being higher (P < 0.05) in slow, oxidative muscle, as compared with faster, more glycolytic tissue. Despite the significant activation of canonical exercise-induced signaling involving AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), PRMT expression and activity at the whole muscle level were unchanged. However, subcellular analyses revealed a significant exercise-evoked myonuclear translocation of PRMT1 before the nuclear accumulation of PGC-1alpha. Acute physical activity also augmented (P < 0.05) the targeted methyltransferase activities of the PRMT in the myonuclear compartment, suggesting that PRMT-mediated histone arginine methylation is part of the early signals that drive muscle plasticity. Finally, basal PGC-1alpha asymmetric dimethylarginine status, as well as constitutive interactions between PGC-1alpha and PRMT1 or CARM1 may contribute to the exercise-induced muscle remodeling process. CONCLUSIONS: The present study provides the first evidence that PRMT activity is selectively augmented during the initial activation of exercise induced skeletal muscle remodeling in vivo. These data support the emergence of PRMTs as important players in the regulation of skeletal muscle plasticity. PMID- 29112629 TI - Maximal Exercise Alters the Inflammatory Phenotype and Response of Mononuclear Cells. AB - PURPOSE: Monocytes express the CD14 receptor that facilitates lipopolysaccharide (LPS) ligation to toll-like receptor 4 (TLR4) to elicit production of interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-alpha). However, proinflammatory conditions, such as strenuous exercise, increase the percentage of monocytes expressing CD16, a receptor that enhances LPS stimulated TNF-alpha production. Therefore, we examined whether maximal treadmill exercise would alter the inflammatory phenotype of classical (CD14/CD16) and proinflammatory monocytes (intermediate [CD14/CD16] and nonclassical [CD14/CD16]), evidenced by changes in TLR4, CD14, and CD16 receptor expression, and their inflammatory response to ex vivo LPS stimulation. METHODS: Human mononuclear cells from 25 male participants (age, 24.2 +/- 4.0 yr) were isolated before and after exercise to assess TLR4, CD14, and CD16 expression by flow cytometry and ex vivo production of LPS stimulated inflammatory cytokines (IL-6, IL-10, and TNF-alpha). RESULTS: Exercise reduced the percentage of classical monocytes and increased the percentage of intermediate and nonclassical monocytes. In addition, TLR4 expression decreased on classical and intermediate monocytes, but not the nonclassical monocyte subset. Furthermore, although CD14 expression decreased on all monocyte subsets, CD16 expression increased on intermediate monocytes only. In parallel with these phenotypic changes, the inflammatory milieu shifted toward a proinflammatory response after LPS stimulation (decreased IL-6 and IL-10 and increased IL-6 to IL 10 ratio and TNF-alpha production). CONCLUSIONS: These findings demonstrate that acute maximal exercise elicits a proinflammatory phenotype of isolated monocytes exposed to LPS and highlight potential mechanisms that will help elucidate the role of acute and chronic exercise on the innate immune response of circulating monocytes. PMID- 29112630 TI - A Measure of Team Resilience: Developing the Resilience at Work Team Scale. AB - OBJECTIVE: This study develops, and initial evaluates, a new measure of team based resilience for use in research and practice. METHODS: We conducted preliminary analyses, based on a cross-sectional sample of 344 employees nested within 31 teams. RESULTS: Seven dimensions were identified through exploratory and confirmatory factor analyses. The measure had high reliability and significant discrimination to indicate the presence of a unique team-based aspect of resilience that contributed to higher work engagement and higher self-rated team performance, over and above the effects of individual resilience. Multilevel analyses showed that team, but not individual, resilience predicted self-rated team performance. CONCLUSION: Practice implications include a need to focus on collective as well as individual behaviors in resilience-building. The measure provides a diagnostic instrument for teams and a scale to evaluate organizational interventions and research the relationship of resilience to other constructs. PMID- 29112631 TI - Economic Evaluation of Occupational Safety and Health Interventions From the Employer Perspective: A Systematic Review. AB - OBJECTIVES: The aim of this systematic review was to evaluate the cost effectiveness of occupational safety and health interventions from the employer perspective. METHODS: A comprehensive literature search (2005 to 2016) in five electronic databases was conducted. Pre-2005 studies were identified from the reference lists of previous studies and systematic reviews, which have similar objective to those of this search. RESULTS: A total of 19 randomized controlled trials and quasi-experimental studies were included, targeting diverse health problems in a number of settings. Few studies included organizational-level interventions. When viewed in relation to the methodological quality and the sufficiency of economic evidence, five of 11 cost-effective occupational safety and health (OSH) interventions appear to be promising. CONCLUSION: The present systematic review highlights the need for high-quality economic evidence to evaluate the cost-effectiveness of OSH interventions, especially at organizational-level, in all areas of worker health. PMID- 29112632 TI - Prediction of 60-Day Case Fatality in Critically Ill Patients Receiving Renal Replacement Therapy: External Validation of a Prediction Model. AB - BACKGROUND: A recent prognostic model, predicting 60-day case fatality in critically ill patients requiring renal replacement therapy (RRT), has been developed (Acute Renal Failure Trial Network [ATN] study). Because many prognostic models are suggested in literature, but just a few have found its way into clinical practice, we aimed to externally validate this prediction model in an independent cohort. METHODS: A total of 1,053 critically ill patients requiring RRT from the MIMIC-III database were analyzed. The models' discrimination was evaluated using c-statistics. Calibration was evaluated by Hosmer-Lemeshow (H-L) test and GiViTi calibration belt. RESULTS: In a case-mix population, including patients with normal or altered serum creatinine (sCr) at intensive care unit admission, discrimination was moderate, with a c-statistic of 0.71 in the nonintegerized risk model. In patients with altered baseline sCr, better discrimination was achieved with the integer risk model (0.76, 95% confidence interval, 0.71-0.81). As for the calibration, although the H-L test was good only in patients with normal/slightly altered sCr at admission, the calibration belt disclosed no significant deviations from the bisector line for any of the models in patients, regardless of admission sCr. Of note, a refitted model had a c-statistics of 0.85, similar to the derivation cohort. CONCLUSIONS: The ATN prognostic model can be useful in a broad cohort of critically ill patients. Although it showed only moderate discrimination capacity when patients with elevated admission sCr were included, using a refitted model improved it, illustrating the need for continuous external validation and updating of prognostic models over time before their implementation in clinical practice. PMID- 29112634 TI - Baroreflex Sensitivity and Blood Pressure Variability can Help in Understanding the Different Response to Therapy During Acute Phase of Septic Shock. AB - BACKGROUND: Mean values of hemodynamic variables are poorly effective in evaluating an actual recovery of the short-term autonomic mechanisms for blood pressure (BP) and heart rate (HR) regulation. The aim of this work is to analyze the response to therapy in the early phase of septic shock to verify possible associations between BP recovery and BP autonomic control. METHODS: This is an ancillary study from the multicenter prospective observational trial Shockomics (NCT02141607). A total of 21 septic shock patients were studied at two time points during the acute phase of shock and were classified according to changes in SOFA score. Time series of BP components and HR were analyzed in time and frequency domain. Baroreflex sensitivity (BRS) was assessed, and a mathematical model for the decomposition of diastolic arterial pressure (DAP) oscillations was used to understand the different contributions of BRS and HR on peripheral vascular resistance control. RESULTS: Only those patients, who significantly improved organ function (responders, R), showed an increase of mean value and low frequency (LF) power in BP time series. Fluid accumulation was higher in the non responders (NR). BRS increased in NR and the model of DAP variability showed that the contribution of HR was highly reduced in NR. CONCLUSIONS: Although patients reached the mean BP target of 65 mmHg, our analyses highlighted important differences in terms of autonomic nervous system control. BP variability, HR variability and baroreflex trends can add information to individual vital sign measure such as mean BP, and can help in understanding the responsiveness to the combination of symphatomimetic drugs and fluid therapy. PMID- 29112633 TI - 2017 Military Supplement: Current Challenges in the Development of Acellular Hemoglobin Oxygen Carriers by Protein Engineering. AB - This article reviews the key biochemical mechanisms that govern O2 transport, NO scavenging, and oxidative degradation of acellular hemoglobin and how these ideas have been used to try to develop strategies to engineer safer and more effective hemoglobin-based oxygen carriers (HBOCs). Significant toxicities due to acellular hemoglobin (Hb) have been observed after the administration of HBOCs or after the lysis of red cells, and include: (a) rapid clearance and kidney damage due to dissociation into dimers, haptoglobin binding, and macrophage activation; (b) early O2 release leading to decreased tissue perfusion in capillary beds; (c) interference with endothelial and smooth muscle signaling due to nitric oxide (NO) scavenging; (d) autooxidization of heme iron followed by production of reactive oxygen species; and (e) iron overload symptoms due to hemin loss, globin denaturation, iron accumulation, and further inflammation. Protein engineering can be used to mitigate some of these side effects but requires an in-depth mechanistic understanding of the biochemical and biophysical features of hemoglobin that regulate quaternary structure, O2 affinity, NO dioxygenation, and resistance to oxidation, hemin loss, and unfolding. PMID- 29112635 TI - Peritoneal Carcinomatosis Presenting as a Sister Mary Joseph Nodule. PMID- 29112636 TI - Disseminated Peritoneal Leiomyomatosis. PMID- 29112637 TI - Improving Ultrasound Detection of Uterine Adenomyosis Through Computational Texture Analysis. AB - The purpose of our study was to determine if a textural analysis metric can be implemented to improve diagnosis of adenomyosis by ultrasound.We retrospectively identified 38 patients with a magnetic resonance imaging (MRI) diagnosis of uterine adenomyosis that also had a pelvic ultrasound within 6 months. We also identified 50 normal pelvic ultrasound examinations confirmed by a normal pelvic MRI within 6 months as a control group. A region of interest (ROI) was subsequently placed on the study population ultrasound image corresponding to the area of adenomyosis on MRI. An ROI was placed in the area of the junctional zone in the normal controls. The abnormal and normal ROIs were then compared against trained normal and abnormal distributions to determine the success rate, sensitivity, specificity, and negative and positive predictive values of our computer metric. The ultrasound reports performed before MRI were also reviewed to determine the radiologist correct/incorrect interpretation rate for comparison with our textural analysis metric.Using a training population of 50 normal ultrasound examinations (confirmed with a normal MRI) and 38 abnormal ultrasound examinations (MRI confirmed adenomyosis), we had an overall 75% (66/88 accurately diagnosed) success rate with a sensitivity, specificity, and negative and positive predictive values of 70%, 79%, 73%, and 76%, respectively (P < .0001). The sensitivity and false-negative rate of the initial ultrasound interpretation were 26% (10/38) and 74% (28/38), respectively. PMID- 29112638 TI - The Role of Real-Time Sonoelastography in the Differentiation of Benign From Malignant Parotid Gland Tumors. AB - OBJECTIVE: The aims of this study are to evaluate the utility of sonoelastography for parotid gland masses and to determine which cutoff strain ratio (SR) would be best for the differentiation between benign and malignant lesions. METHODS: From August 2015 to December 2016, 39 parotid gland masses were examined prospectively by ultrasonography and strain sonoelastography. Elastographic scores were determined by a 4-point scoring method. Interventional procedures were performed on all patients after sonographic examinations. The lesions were divided into groups as benign or malignant according to histopathological findings. The difference in elastographic scores between benign and malignant masses was evaluated. RESULTS: Among the 39 parotid gland masses, 33 (84.6%) were benign and 6 (15.3%) were malignant tumors with 53.8% (n = 21) of the lesions being on the right side. Pleomorphic adenoma (41%) was the most common neoplasm followed by Warthin tumor (28.2%). The median elastographic score was 2 (range, 1-3) for benign tumors, and it was 3 (range, 2-4) (P = 0.003) for malignant tumors. Median SR was 1.11 (range, 0.26-2.15), and it was 2.75 (range, 1.03-3.54) (P = 0.01) for benign and malignant tumors. In the receiver operating characteristic analysis, the cutoff value of the SR was 2.1, sensitivity was 83.3%, specificity was 97%, positive predictive value was 83.3%, negative predictive value was 97%, and accuracy was 94%. CONCLUSIONS: There was a statistically significant difference between benign lesions and malignant lesions in both elastography score and SR. It is possible that elastography can improve the noninvasive diagnostic accuracy for certain pathological conditions. PMID- 29112639 TI - Sonographic Features of Cervical Lymph Nodes in Patients With Hashimoto Thyroiditis and the Impacts From the Levothyroxine With Prednisone Therapy. AB - OBJECTIVE: This study aimed to evaluate the ultrasonographic pattern of cervical lymph nodes (CLNs) and whether levothyroxine with prednisone therapy is effective for lymphadenopathy in patients with Hashimoto thyroiditis (HT). METHODS: This retrospective study was looking at patients with confirmed diagnosis of HT who underwent comprehensive neck ultrasound examination. We reviewed sonographic findings in 127 patients with HT, 234 euthyroid patients with goiter, and 122 healthy subjects. In addition, 30 untreated HT patients with cervical lymphadenopathy were recruited for the levothyroxine with prednisone therapy. We rescanned the patients 9 months after treatment with levothyroxine and prednisone. RESULTS: Patients with HT had a higher rate of CLN detection on ultrasound than euthyroid patients with goiter and healthy subjects at cervical levels III, IV, and VI (P < 0.01). In addition, patients with HT had a higher rate of detection of CLNs with abnormal sonographic features than the other 2 groups, most notably at cervical levels III, IV, and VI (P < 0.01). After the treatment, the mean thyroid volume, thyroid nodule volume, CLN volume, symptom score, and cosmetic grade of 30 HT patients were remarkably decreased (P < 0.01 or P < 0.001). CONCLUSIONS: Hashimoto thyroiditis seems to be associated with an increased rate of detection of CLNs with abnormal sonographic features, particularly at cervical levels III, IV, and VI. Therapy with levothyroxine with prednisone is effective for cervical lymphadenopathy in patients with HT. PMID- 29112640 TI - Distance Between the Distal Rectal Pouch and Perineum in Neonates of Low-Birth Weight With Imperforate Anus. AB - This study was to evaluate the correlation between birth weight and the distance between distal rectal pouch and perineum (P-P distance) and to determine a cutoff value for P-P distance to diagnose low-type imperforate anus in neonates with low birth weight (LBW).We included 15 neonates with LBW (mean weight, 2012 +/- 470 g; range, 906-2452 g) and imperforate anus (surgically confirmed: 11 low type and 3/1 intermediate/high type), who underwent ultrasonography on the day after birth. Type of imperforate anus was defined based on the International Classification of Anorectal Anomalies. The P-P distances on ultrasonograms were measured. Pearson correlation coefficient test and receiver operating characteristic curve were used for statistical analyses.Among all 15 neonates, nonsignificant correlation was observed between the birth weight and P-P distance (r = 0.36; P = 0.18). Mean P-P distance was 9.0 +/- 6.6 mm (range, 1.0-24.0 mm) in all neonates, 5.7 +/- 2.8 mm (range, 1.0-11.0 mm) in the 11 neonates with low type imperforate anus, and 18.3 +/- 9.1 mm (range, 14.0-24.0 mm) in the 4 neonates with intermediate-/high-type imperforate anus. Using cutoff P-P distance of 12.5 mm, sensitivity and specificity for diagnosis of low-type imperforate anus were 100% (11/11) and 100% (4/4), respectively.In conclusion, nonsignificant correlation was observed between P-P distance and birth weight, and cutoff P-P distance to diagnose low-type imperforate anus was 12.5 mm. Despite the very small sample size in our study, and only 4 neonates with intermediate-/high-type imperforate anus, these findings are important because surgical management whether transperineal anoplasty or diverting colostomy is decided based on the type of imperforate anus, and P-P distance to diagnose the type of imperforate anus was feasible even in neonates with LBW. PMID- 29112641 TI - Obstetrics and Gynecology Ultrasound Sara Harvey, MD Ovarian Masses With Papillary Projections Diagnosed and Removed During Pregnancy: Ultrasound Features and Histological Diagnosis. PMID- 29112642 TI - Musculoskeletal Ultrasound and Other. PMID- 29112643 TI - Assessment of Fetal Congenital Heart Diseases by 4-Dimensional Ultrasound Using Spatiotemporal Image Correlation: Pictorial Review. AB - The aim of this pictorial review is to describe the technical advances achieved through the application of 4-dimensional (4D) ultrasound using spatiotemporal image correlation (STIC) over conventional 2-dimensional ultrasound in the prenatal detection of congenital heart disease (CHD). Spatiotemporal image correlation is a volume imaging technique that simplifies fetal heart studies while providing more diagnostic information than is typically available from traditional 2-dimensional studies. Four-dimensional software allows the study of cardiac anatomy and function during a single cardiac cycle and has greatly contributed to diagnostic enhancement of CHD. Color flow and power Doppler can be added to STIC in the study of vessel anatomy and to increase the detection of ventricular septal defects. Anatomical details of the fetus can be displayed in multiple images such as using computed tomography or magnetic resonance imaging. In addition, cardiac anatomy can be sectioned freely and reconstructed using different reformatting applications. Realistic views of the fetal heart, with particular emphasis on myocardium and endocardium cushion, can be reached using novel lightening techniques. Moreover, using 4D ultrasound, echolucent structures can be converted into solid voxels generating "digital casts" of the fetal heart that enhances the understanding of the great vessel relationships in the ventricular inflow and outflow tracts. Recently, sillhouette mode has shown to improve depth perception and resolution compared with conventional 3D power Doppler in the study of inflow and outflow tracts. Here, a gallery of prenatally detected CHD using 4D ultrasound with STIC and different applications is described. PMID- 29112644 TI - Is Lung Ultrasound Useful for Diagnosing Pneumonia in Children?: A Meta-Analysis and Systematic Review. AB - BACKGROUND: Childhood mortality due to pneumonia is high. Chest radiography is the primary imaging modality used for the evaluation of pneumonia in children. Lung ultrasonography (LUS) is a newer, alternative diagnostic method that has been gaining popularity in recent years. We conducted a meta-analysis to summarize the diagnostic usefulness of LUS for childhood pneumonia. METHODS: All studies included in this meta-analysis were retrieved from PubMed, Elsevier's Science Direct, and Springer, and by manual searches including the use of reference lists, through March 31, 2017. Two researchers independently screened the literature, extracted the data, and evaluated risks of bias in accordance with the inclusion and exclusion criteria. For the meta-analysis, we calculated the pooled sensitivity and specificity, pooled positive likelihood ratio, negative likelihood ratio, and the diagnostic odds ratio. Summary receiver operating characteristic curve was used to assess the overall performance of LUS. RESULTS: Our search identified 1038 articles, and we selected 51 of these for detailed review. Eight studies containing 1013 patients met all the inclusion criteria and were included in the final meta-analysis. The pooled sensitivity and specificity for the diagnosis of pneumonia using LUS were 93.0% (95% confidence interval, 88.0%-96.0%) and 96.0% (95% confidence interval, 92.0%-98.0%), respectively. The pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 25.8 (11.0, 60.4), 0.07 (0.05, 0.12), and 344 (104, 1140), respectively. In addition, the summary receiver operating characteristic area under the curve was calculated to be 0.98 (0.97, 0.99). A Fagan plot analysis demonstrated that when pretest probabilities were 25%, 50%, and 75%, the positive posttest probabilities were 90%, 96%, and 99%, respectively, and the negative posttest probabilities were 2%, 7%, and 18%, respectively. Four clinical signs were most frequently observed using LUS in the screening of children with pneumonia: pulmonary consolidation, positive air bronchogram, abnormal pleural line, and pleural effusion. CONCLUSIONS: Current evidence supports LUS as a useful imaging alternative for the diagnosis of childhood pneumonia. That it is easily carried out, readily available, relatively inexpensive, and free from the hazards of radiation make it an attractive alternative to chest radiography and physical examination for the diagnosis and the follow-up of pneumonia in children. PMID- 29112645 TI - Topical 5-Fluorouracil for Women With High-Grade Vaginal Intraepithelial Neoplasia. AB - OBJECTIVE: To examine success rates of 5-fluorouracil, excision, and laser ablation as the initial and secondary management strategies for women with high grade vaginal intraepithelial neoplasia. METHODS: We conducted a retrospective case series of women referred to a single center for management of biopsy-proven, high-grade vaginal intraepithelial neoplasia between April 1994 and May 2016. Data including demographic characteristics, human papillomavirus risk factors, antecedent Pap cytology, concurrent or prior cervical and vulvar dysplasia, and treatment outcome including follow-up Pap cytology were recorded. All women were counseled on options of excision, laser ablation, or 5-fluorouracil, which was administered intravaginally according to a standardized regimen. Recurrence was defined as a biopsy showing any vaginal intraepithelial neoplasia diagnosis after primary treatment. RESULTS: Forty-seven patients were treated initially with 5 fluorouracil, 35 were treated with excision, and 22 were treated with laser ablation. Demographics were similar between groups. No recurrence was noted in 35 women treated with 5-fluorouracil (74%; 95% CI 62-87%), 20 treated with excision (57%; 95% CI 41-74%), and nine treated with laser ablation (41%; 95% CI 20-61%). Among 13 patients treated with 5-fluorouracil for recurrence, eight (62%) did not experience a second recurrence. Nine of 58 (16%) patients ever treated with 5 fluorouracil reported a side effect, most commonly irritation and dyspareunia. CONCLUSION: 5-fluorouracil was associated with a 74% success rate as the initial treatment modality for high-grade vaginal dysplasia. There is also a role for 5 fluorouracil in the management of recurrent or persistent high-grade vaginal intraepithelial neoplasia. PMID- 29112646 TI - Transfusion Preparedness Strategies for Obstetric Hemorrhage: A Cost Effectiveness Analysis. AB - OBJECTIVE: To evaluate the cost-effectiveness of common obstetric transfusion preparedness strategies to prevent emergency-release transfusions. METHODS: A decision analytic model compared five commonly used transfusion preparedness strategies in a general obstetric population. Patients were classified as being at low, moderate, or high risk for transfusion. The most prepared strategy used a policy of universal type and screen plus crossmatch for high-risk patients. Other strategies used universal type and screen only, universal hold clot plus crossmatch for high-risk patients, selective type and screen only in high-risk patients, or no routine admission testing. Strategies were compared using transfusion-related cost and probability estimates derived from patient-level data and from the published literature. The primary outcome was incremental cost per emergency-release transfusion prevented. A strategy was considered cost effective if the cost was less than $1,500 per emergency-release transfusion avoided as determined by expert consensus. Emergency-release transfusion included universal donor or type-specific packed red cells that are not crossmatched to the recipient. Along with the base-case analyses, we also conducted one- and two way sensitivity analyses and probabilistic sensitivity analyses using second order Monte Carlo simulation. Variability in the willingness-to-pay threshold was explored in a cost-effectiveness acceptability analysis. The model was conducted from a hospital perspective. RESULTS: In the base-case analysis, the strategy of universal type and screen with crossmatch for high-risk patients yielded an incremental cost of $115,541 per emergency-release transfusion prevented compared with a strategy of universal hold clot. The universal hold clot strategy yielded a cost of $2,878 per emergency-release transfusion prevented compared with a strategy of no routine admission testing. Strategies using universal type and screen were cost-effective in zero of the 10,000 simulations at a willingness-to pay threshold of $1,500 per emergency-release transfusion prevented. Even at willingness to pay greater than $10,000 to prevent an emergency-release transfusion, universal type and screen strategies were not cost-effective. CONCLUSION: Transfusion preparedness with universal type and screen is not cost effective in a general obstetric population across a wide range of assumptions and variable ranges. PMID- 29112647 TI - Intrauterine Device Use and Cervical Cancer Risk: A Systematic Review and Meta analysis. AB - OBJECTIVE: To estimate the association between use of an intrauterine device (IUD) and risk of cervical cancer by subjecting existing data to critical review, quantitative synthesis, and interpretation. DATA SOURCES: We searched PubMed, Web of Science, ClinicalTrials.gov, and catalogs of scientific meetings and abstracts, theses, and dissertations queried from inception through July 2016. METHODS OF STUDY SELECTION: Examination of abstracts from 225 reports identified 34 studies with individual-level measures of use of an IUD and incident cervical cancer. By critically assessing the full text of these reports, independent reviewers identified 17 studies conducted without recognized sources of systematic error, of which 16 could be harmonized for meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Point and interval estimates of the association between use of an IUD and incident cervical cancer were extracted from original reports into a structured database along with key features of study design and implementation. A random-effects meta-analysis was implemented to quantitatively synthesize extracted estimates and assess likely influence of publication bias, residual confounding, heterogeneity of true effect size, and human papillomavirus prevalence and cervical cancer incidence in source populations. Women who used an IUD experienced less cervical cancer (summary odds ratio 0.64, 95% CI 0.53-0.77). Neither confounding by recognized risk factors nor publication bias seems a plausible explanation for the apparent protective effect, which may be stronger in populations with higher cervical cancer incidence. CONCLUSION: Invasive cervical cancer may be approximately one third less frequent in women who have used an IUD. This possible noncontraceptive benefit could be most beneficial in populations with severely limited access to screening and concomitantly high cervical cancer incidence. PMID- 29112648 TI - Cost of Care for the Initial Management of Ovarian Cancer. AB - OBJECTIVE: To examine the cost of care during the first year after a diagnosis of ovarian cancer, estimate the sources of cost, and explore the out-of-pocket costs. METHODS: We performed a retrospective cohort study of women with ovarian cancer diagnosed from 2009 to 2012 who underwent both surgery and adjuvant chemotherapy using the Truven Health MarketScan database. This database is comprised of patients covered by commercial insurance sponsored by more than 100 employers in the United States. Medical expenditures, including physician reimbursement, for a 12-month period beginning on the date of surgery were estimated. All payments were examined, including out-of-pocket costs for patients. Payments were divided into expenditures for inpatient care, outpatient care (including chemotherapy), and outpatient drug costs. The 12-month treatment period was divided into three phases: surgery to 30 days (operative period), 1-6 months (adjuvant therapy), and 6-12 months after surgery. The primary outcome was the overall cost of care within the first year of diagnosis of ovarian cancer; secondary outcomes included assessment of factors associated with cost. RESULTS: A total of 26,548 women with ovarian cancer who underwent surgery were identified. After exclusion of patients with incomplete insurance enrollment or coverage, those who did not undergo chemotherapy, and those with capitated plans, our cohort consisted of 5,031 women. The median total medical expenditures per patient during the first year after the index procedure were $93,632 (interquartile range $62,319-140,140). Inpatient services accounted for $30,708 (interquartile range $20,102-51,107; 37.8%) in expenditures, outpatient services $52,700 (interquartile range $31,210-83,206; 58.3%), and outpatient drug costs $1,814 (interquartile range $603-4,402; 3.8%). The median out-of-pocket expense was $2,988 (interquartile range $1,649-5,088). This included $1,509 (interquartile range $705-2,878) for outpatient services, $589 (interquartile range $3-1,715) for inpatient services, and $351 (interquartile range $149-656) for outpatient drug costs. CONCLUSION: The average cost of care for women with ovarian cancer in the first year after surgery is approximately $100,000. Patients bear approximately 3% of these costs in the form of out-of-pocket expenses. PMID- 29112650 TI - Maternal Pulse Pressure and the Risk of Postepidural Complications: A Randomized Controlled Trial. AB - OBJECTIVE: To test the hypothesis that increasing the intravenous fluid bolus volume at the time of epidural placement in women with narrow pulse pressure would reduce postepidural fetal heart rate (FHR) abnormalities, hypotension, and resuscitative obstetric interventions. METHODS: We performed a single-center randomized controlled trial. Eligible participants were normotensive with a nonanomalous singleton gestation at or after 35 weeks and with a narrow pulse pressure (less than 45 mm Hg) on admission. Enrolled patients remained eligible for randomization at epidural request if they were within 6 hours of admission and the FHR remained category 1. Patients were allocated to a 500-mL (institutional standard) or 1,500-mL intravenous fluid bolus at epidural placement. A reference group with admission pulse pressure 50 mm Hg or greater was also evaluated. The primary outcome was a category 2 or 3 FHR pattern within 60 minutes after the epidural test dose. Evaluated secondary outcomes included maternal hypotension and composite resuscitative interventions to correct FHR abnormalities or hypotension. We calculated that 276 women (138/group) would provide 80% power to detect a relative 50% reduction in the occurrence of the primary outcome from 27% in the 500-mL group to 13.5% in the 1,500-mL group (two sided alpha=0.05). RESULTS: From October 2015 to November 2016, 276 women were allocated to receive a 500-mL (n=139) or 1,500-mL (n=137) fluid bolus. One hundred thirty-eight women were evaluated in the reference group. Demographic, obstetric, and labor characteristics were similar between groups. The 1,500-mL group had significantly fewer postepidural FHR abnormalities (38.0% compared with 51.8%, relative risk 0.73, 95% CI 0.56-0.96, P=.02). Maternal systolic hypotension (10.2% compared with 34.5%, relative risk 0.30, 95% CI 0.17-0.51, P<.001) and composite postepidural interventions (18.3% compared with 44.2%, relative risk 0.42, 95% CI 0.28-0.62, P<.001) were also less frequent in the 1,500-mL group. Fetal heart rate abnormalities remained significantly less frequent in the reference group than among women with a narrow pulse pressure on admission for delivery. CONCLUSION: A 1,500-mL intravenous fluid bolus in women with a narrow pulse pressure decreases the risk of postepidural FHR abnormalities (number needed to treat=7), results in less frequent postepidural hypotension, and reduces the need for resuscitative interventions. Admission pulse pressure may be used to individualize intrapartum fluid management at the time of initiation of neuraxial labor analgesia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02565485. PMID- 29112649 TI - Racial and Ethnic Differences in Utilization of Labor Management Strategies Intended to Reduce Cesarean Delivery Rates. AB - OBJECTIVE: To examine whether racial and ethnic differences exist in the frequency of and indications for cesarean delivery and to assess whether application of labor management strategies intended to reduce cesarean delivery rates is associated with patient's race and ethnicity. METHODS: This is a secondary analysis of a multicenter observational obstetric cohort. Trained research personnel abstracted maternal and neonatal records of greater than 115,000 pregnant women from 25 hospitals (2008-2011). Women at term with singleton, nonanomalous, vertex, liveborn neonates were included in two cohorts: 1) nulliparous women (n=35,529); and 2) multiparous women with prior vaginal deliveries only (n=39,871). Women were grouped as non-Hispanic black, non Hispanic white, Hispanic, and Asian. Multivariable logistic regression was used to evaluate the following outcomes: overall cesarean delivery frequency, indications for cesarean delivery, and utilization of labor management strategies intended to safely reduce cesarean delivery. RESULTS: A total of 75,400 women were eligible for inclusion, of whom 47% (n=35,529) were in the nulliparous cohort and 53% (n=39,871) were in the multiparous cohort. The frequencies of cesarean delivery were 25.8% among nulliparous women and 6.0% among multiparous women. For nulliparous women, the unadjusted cesarean delivery frequencies were 25.0%, 28.3%, 28.7%, and 24.0% for non-Hispanic white, non-Hispanic black, Asian, and Hispanic women, respectively. Among nulliparous women, the adjusted odds of cesarean delivery were higher in all racial and ethnic groups compared with non Hispanic white women (non-Hispanic black adjusted odds ratio [OR] 1.47, 95% CI 1.36-1.59; Asian adjusted OR 1.26, 95% CI 1.14-1.40; Hispanic adjusted OR 1.17, 95% CI 1.07-1.27) as a result of greater odds of cesarean delivery both for nonreassuring fetal status and labor dystocia. Nonapplication of labor management strategies regarding failed induction, arrest of dilation, arrest of descent, or cervical ripening did not contribute to increased odds of cesarean delivery for non-Hispanic black and Hispanic women. Compared with non-Hispanic white women, Hispanic women were actually less likely to experience elective cesarean delivery (adjusted OR 0.60, 95% CI 0.42-0.87) or cesarean delivery for arrest of dilation before 4 hours (adjusted OR 0.67, 95% CI 0.49-0.92). Additionally, compared with non-Hispanic white women, Asian women were more likely to experience cesarean delivery for nonreassuring fetal status (adjusted OR 1.29, 95% CI 1.09-1.53) and to have had that cesarean delivery be performed in the setting of a 1-minute Apgar score 7 or greater (adjusted OR 1.79, 95% CI 1.07-3.00). A similar trend was seen among multiparous women with prior vaginal deliveries. CONCLUSION: Although racial and ethnic disparities exist in the frequency of cesarean delivery, differential use of labor management strategies intended to reduce the cesarean delivery rate does not appear to be associated with these racial and ethnic disparities. PMID- 29112651 TI - Progesterone for Prevention of Preterm Birth: Shortcomings and Unintended Consequences of the Orphan Drug Act. AB - Preterm birth is a problem of major public health significance that continues to plague our country despite the existence of a therapy, 17alpha hydroxyprogesterone caproate, with known efficacy in reducing the risk of spontaneous preterm birth among high-risk women. Over the past several years, the Louisiana Department of Health has undertaken a robust, multifaceted initiative to improve access to 17alpha-hydroxyprogesterone caproate, which resulted in a 3.5-fold increase in the percentage of eligible high-risk pregnant women in the Medicaid program who received the therapy between 2013 and 2016. Yet despite Louisiana's progress, the vast majority of the eligible population still fails to receive 17alpha-hydroxyprogesterone caproate. In this Current Commentary, we argue that the high price of progesterone since U.S. Food and Drug Administration approval has unnecessarily complicated access, and our nation has potentially suffered nearly 60,000 avoidable premature births as a consequence. We present the history of the orphan drug approval and manufacturer-imposed price increase for injectable progesterone, the interplay between the drug's high price and the persistence of racial and ethnic disparities in preterm birth, which are particularly germane in Louisiana, and Louisiana's broad-reaching efforts to improve progesterone coverage. The story of 17alpha-hydroxyprogesterone caproate highlights the durable barriers that high prices place in the way of access and helps illuminate the shortcomings and unintended consequences of the Orphan Drug Act. This case, however, is not an outlier; it is the far-too-common product of monopoly pricing in the U.S. pharmaceutical market, inadvertently bolstered by existing law, at the expense of affordability and patient access. PMID- 29112652 TI - Effect of Cervical Cancer Screening Programs on Preterm Birth: A Decision and Cost-Effectiveness Analysis. AB - OBJECTIVE: To assess the effect of age at initiation and interval of cervical cancer screening in women of reproductive age on the risk of future preterm birth and subsequent adverse neonatal outcome relative to maternal life-years gained and cost of both screening and preterm birth. METHODS: In this decision and cost effectiveness analysis, we compared eight cytology-based screening programs varying in age of onset (21, 24, 25, 27, or 30 years) and screening interval (3 or 5 years) in a fictive cohort of 100,000 women. We used the microsimulation screening analysis model to estimate number of cervical intraepithelial neoplasia diagnoses, large loop excisions of the transformation zone (LLETZs), life-years gained, cervical cancer cases, deaths, and costs of screening and treatment. We used the number of LLETZs to calculate additional preterm births, subsequent neonatal morbidity, mortality, and associated costs. RESULTS: The number of LLETZs per 100,000 women varied from 9,612 for the most intensive screening (every 3 years from age 21 years) to 4,646 for the least intensive screening (every 5 years from age 30 years). Compared with the least intensive program, the most intensive program increased maternal life-years gained by 9% (10,728 compared with 9,839), decreased cervical cancer cases by 67% (52 compared with 158), and cervical cancer deaths by 75% (four compared with 16) at the expense of 250% (158 compared with 45) more preterm births and 320% (four compared with one) more neonatal deaths while increasing total costs by $55 million ($77 compared with $23 million). The number of maternal life-years gained per additional preterm birth varied from 68 to 258 with subsequent total costs per maternal life years gained of $7,212 and $2,329. CONCLUSION: Cervical cancer screening every 3 years and subsequent treatment in women aged younger than 30 years yield limited life-years but may have substantial perinatal adverse effects. Consequently, women who plan to have children may benefit from a more cautious screening approach, taking into account their risk for both cancer and preterm birth. PMID- 29112653 TI - Long-term Results for Expectant Management of Ultrasonographically Diagnosed Benign Ovarian Teratomas. AB - OBJECTIVE: To assess the natural history of ultrasonographically diagnosed benign ovarian teratomas in asymptomatic women. METHODS: We conducted a retrospective observational cohort study of 408 women (mean age 36.6 years, range 14-81 years) diagnosed as having an ovarian teratoma by transvaginal ultrasonography (except eight who only had a transabdominal study done) between January 2003 and December 2013 at a single tertiary care institution. Six hundred thirteen women were diagnosed with ovarian teratoma of whom 205 were promptly treated surgically, leaving 408 patients followed conservatively with follow-up scans at 3 and 6 months from diagnosis and then yearly. The ultrasonographic diagnosis of a benign ovarian teratoma required at least one of the following features: a cystic mass with mixed echogenicity, thick band-like echoes, a fat-fluid level, or echogenic tubercle with posterior shadowing. Clinical, ultrasonographic, and histologic data (in case of surgery) were retrieved for analysis. RESULTS: During follow-up, 130 of 408 (31.8%) women underwent surgery. The main reason for surgery was the physician's recommendation according to our protocol (n=115). One patient had adnexal torsion. Most surgeries (112/130 [86.2%]) were performed within the first 5 years after diagnosis. The remainder (278/408) is still being followed (median time 45.6 months, range 6-147 months). The vast majority of these lesions had no change and women remain asymptomatic. Histologic diagnosis of tumors removed surgically revealed a benign ovarian teratoma in 103 of 130 (79.2%) of the women. There were two borderline tumors, four endometriomas, three fibromas, seven serous cysts, two mucinous cysts, two stroma ovarii, seven other benign, and no case of malignant tumor. CONCLUSION: Our results demonstrate that expectant management might be a reasonable option for managing asymptomatic women who receive a ultrasonographic diagnosis of a benign ovarian teratoma. The risk of undergoing surgery for this lesion decreases significantly after 5 years to follow-up. With careful observation, the risk of missing a diagnosis of malignancy is low. PMID- 29112655 TI - Multiparous Ewe as a Model for Teaching Vaginal Hysterectomy Techniques. AB - BACKGROUND: Despite being linked to improving patient outcomes and limiting costs, the use of vaginal hysterectomy is on the wane. Although a combination of reasons might explain this trend, one cause is a lack of practical training. An appropriate teaching model must therefore be devised. Currently, only low fidelity simulators exist. Ewes provide an appropriate model for pelvic anatomy and are well-suited for testing vaginal mesh properties. This article sets out a vaginal hysterectomy procedure for use as an education and training model. METHOD: A multiparous ewe was the model. Surgery was performed under general anesthesia. The ewe was in a lithotomy position resembling that assumed by women on the operating table. EXPERIENCE: Two vaginal hysterectomies were performed on two ewes, following every step precisely as if the model were human. Each surgical step of vaginal hysterectomy performed on the ewe and on a woman were compared side by side. We identified that all surgical steps were particularly similar. The main limitations of this model are costs ($500/procedure), logistic problems (housing large animals), and public opposition to animal training models. CONCLUSION: The ewe appears to be an appropriate model for teaching and training of vaginal hysterectomy. PMID- 29112654 TI - Within-Family Analysis of Interpregnancy Interval and Adverse Birth Outcomes. AB - OBJECTIVE: To examine associations among interpregnancy interval, the duration from the preceding birth to the conception of the next-born index child, and adverse birth outcomes using designs that adjust for measured and unmeasured factors. METHODS: In this prospective cohort study, we used population-based Swedish registries from 1973 to 2009 to estimate the associations between interpregnancy interval (referent 18-23 months) and adverse birth outcomes (ie, preterm birth [less than 37 weeks of gestation], low birth weight [LBW; less than 2,500 g], small for gestational age [SGA; greater than 2 SDs below average weight for gestational age]). Analyses included cousin and sibling comparisons and postbirth intervals (ie, the interval between secondborn and thirdborn offspring predicting secondborn outcomes) to address unmeasured familial confounding. RESULTS: Traditional cohort-wide analyses showed higher odds of preterm birth (adjusted odds ratio [OR] 1.51, 99% CI 1.39-1.63, 5.99% preterm births]) and LBW (adjusted OR 1.25, 99% CI 1.13-1.39, 3.32% LBW) after a short interpregnancy interval (0-5 months) compared with offspring born after an interpregnancy interval of 18-23 months (3.21% preterm births, 1.92% LBW). Except for preterm birth (adjusted OR 1.72, 99% CI 1.26-2.35), associations were attenuated in cousin comparisons. A small association between a short interpregnancy interval and preterm birth remained in sibling comparisons (adjusted OR 1.22, 99% CI 1.11 1.35), but associations with LBW (adjusted OR 0.83, 99% CI 0.74-0.94) and SGA (adjusted OR 0.74, 99% CI 0.64-0.85) reversed direction. For pregnancy intervals of 60 months or more, odds of preterm birth (adjusted OR 1.51, 99% CI 1.43-1.60, 5.07% preterm births), LBW (adjusted OR 1.61, 99% CI 1.50-1.73, 3.43% low-birth weight births), and SGA (adjusted OR 1.54, 99% CI 1.42-1.66, 2.49% SGA births) were also higher when compared with the reference interval (1.53% SGA). Associations between long interpregnancy interval and adverse birth outcomes remained through cousin and sibling comparisons. Postbirth interval analyses showed familial confounding is present for short interpregnancy intervals, but supported independent associations for long interpregnancy intervals. CONCLUSION: Familial confounding explains most of the association between a short interpregnancy interval and adverse birth outcomes, whereas associations with long interpregnancy intervals were independent of measured and unmeasured factors. PMID- 29112656 TI - Interpregnancy Interval After Pregnancy Loss and Risk of Repeat Miscarriage. AB - OBJECTIVE: To assess whether interpregnancy interval length after a pregnancy loss is associated with risk of repeat miscarriage. METHODS: This analysis includes pregnant women participating in the Right From the Start (2000-2012) community-based prospective cohort study whose most recent pregnancy before enrollment ended in miscarriage. Interpregnancy interval was defined as the time between a prior miscarriage and the last menstrual period of the study pregnancy. Miscarriage was defined as pregnancy loss before 20 weeks of gestation. Cox proportional hazard models were used to estimate crude and adjusted hazard ratios and 95% CIs for the association between different interpregnancy interval lengths and miscarriage in the study pregnancy. Adjusted models included maternal age, race, parity, body mass index, and education. RESULTS: Among the 514 study participants who reported miscarriage as their most recent pregnancy outcome, 15.7% had a repeat miscarriage in the study pregnancy (n=81). Median maternal age was 30 years (interquartile range 27-34) and 55.6% of participants had at least one previous livebirth (n=286). When compared with women with interpregnancy intervals of 6-18 months (n=136), women with intervals of less than 3 months (n=124) had the lowest risk of repeat miscarriage (7.3% compared with 22.1%; adjusted hazard ratio 0.33, 95% CI 0.16-0.71). Neither maternal race nor parity modified the association. Attempting to conceive immediately was not associated with increased risk of miscarriage in the next pregnancy. CONCLUSION: An interpregnancy interval after pregnancy loss of less than 3 months is associated with the lowest risk of subsequent miscarriage. This implies counseling women to delay conception to reduce risk of miscarriage may not be warranted. PMID- 29112658 TI - Adding Azithromycin to Cephalosporin for Cesarean Delivery Infection Prophylaxis: A Cost-Effectiveness Analysis. AB - OBJECTIVE: To investigate the cost-effectiveness of adding azithromycin to standard cephalosporin regimens of cesarean delivery prophylaxis by considering the maternal outcomes in the current and potential subsequent pregnancies. METHODS: A cost-effectiveness model was created using TreeAge to compare the outcomes of using azithromycin-cephalosporin with cephalosporin alone in a theoretical cohort of 700,000 women, the approximate number of nonelective cesarean deliveries annually in the United States that occur during labor or after membrane rupture. Outcomes examined included endometritis, wound infection, sepsis, venous thromboembolism, and maternal death in the current pregnancy and uterine rupture, cesarean hysterectomy, and maternal death in subsequent pregnancies, including cost and quality-adjusted life-years for both pregnancies. Probabilities, utilities, and costs were derived from the literature, and a cost effectiveness threshold was set at $100,000 per quality-adjusted life-year. Sensitivity analyses were used to determine the robustness of our results. RESULTS: Compared with cephalosporin alone for prophylaxis, our model showed 16,100 fewer cases of endometritis, 17 fewer cases of sepsis, eight fewer cases of venous thromboembolism, and one fewer maternal death with azithromycin cephalosporin. Additionally, this strategy prevented 36 uterine ruptures and four cesarean hysterectomies in the subsequent pregnancy. Overall, the addition of azithromycin led to both lower costs and higher quality-adjusted life-years when compared with standard cephalosporin prophylaxis. In sensitivity analysis, we found that as long as the cost of azithromycin remained below $930 (baseline cost $27), it was cost-effective. CONCLUSION: For women who undergo cesarean delivery in labor or after membrane rupture, compared with cephalosporin alone, the addition of azithromycin to cesarean delivery infection prophylaxis is less costly and leads to better maternal outcomes in the index delivery and subsequent deliveries. These findings support the use of prophylactic azithromycin at the time of cesarean delivery. PMID- 29112657 TI - Placental Complications Associated With Psychostimulant Use in Pregnancy. AB - OBJECTIVE: To evaluate whether psychostimulants used to treat attention deficit/hyperactivity disorder (ADHD) are associated with risk of adverse placental-associated pregnancy outcomes including preeclampsia, placental abruption, growth restriction, and preterm birth. METHODS: We designed a population-based cohort study in which we examined a cohort of pregnant women and their liveborn neonates enrolled in Medicaid from 2000 to 2010. Women who received amphetamine-dextroamphetamine or methylphenidate monotherapy in the first half of pregnancy were compared with unexposed women. We considered atomoxetine, a nonstimulant ADHD medication, as a negative control exposure. To assess whether the risk period extended to the latter half of pregnancy, women who continued stimulant monotherapy after 20 weeks of gestation were compared with those who discontinued. Risk ratios and 95% CIs were estimated with propensity score stratification to control for confounders. RESULTS: Pregnancies exposed to amphetamine-dextroamphetamine (n=3,331), methylphenidate (n=1,515), and atomoxetine (n=453) monotherapy in early pregnancy were compared with 1,461,493 unexposed pregnancies. Among unexposed women, the risks of the outcomes were 3.7% for preeclampsia, 1.4% for placental abruption, 2.9% for small for gestational age, and 11.2% for preterm birth. The adjusted risk ratio for stimulant use was 1.29 for preeclampsia (95% CI 1.11-1.49), 1.13 for placental abruption (0.88-1.44), 0.91 for small for gestational age (0.77-1.07), and 1.06 for preterm birth (0.97-1.16). Compared with discontinuation (n=3,527), the adjusted risk ratio for continuation of stimulant use in the latter half of pregnancy (n=1,319) was 1.26 for preeclampsia (0.94-1.67), 1.08 for placental abruption (0.67-1.74), 1.37 for small for gestational age (0.97-1.93), and 1.30 for preterm birth (1.10-1.55). Atomoxetine was not associated with the outcomes studied. CONCLUSION: Psychostimulant use during pregnancy was associated with a small increased relative risk of preeclampsia and preterm birth. The absolute increases in risks are small and, thus, women with significant ADHD should not be counseled to suspend their ADHD treatment based on these findings. PMID- 29112659 TI - Tissue Extraction Techniques for Leiomyomas and Uteri During Minimally Invasive Surgery. AB - Fragmented tissue extraction (morcellation) of uterine and leiomyoma tissue in gynecologic surgery has been performed for decades, but recent years have seen a vast expansion of techniques to address risks associated with tissue dispersion. Use of power, or electromechanical, morcellation has largely been replaced by manual morcellation with a scalpel. Morcellation can take place through a laparoscopic incision, a minilaparotomy incision, or through a colpotomy. Containment systems are now available for both power and manual morcellation, allowing tissue fragmentation to take place within an enclosed specimen bag. These products require additional training and skill and may add operating time, but have the potential to mitigate risks associated with tissue dissemination. PMID- 29112661 TI - Role of Insurance Coverage in Contraceptive Use After Abortion. AB - OBJECTIVE: To assess postaspiration abortion contraceptive use and the role of insurance coverage for abortion in a state that covers abortion and contraception for low-income women. METHODS: This is a secondary analysis of a previously published prospective study to assess the safety of abortion provision. From 2007 through 2013, women seeking first-trimester aspiration abortion were recruited at 25 clinical facilities within four Planned Parenthood affiliates and Kaiser Permanente of Northern California. Patients' medical charts were reviewed to assess the contraceptive methods received on the day of the abortion. A 4-week follow-up survey assessed contraceptive use and contraceptive-related incidents. Primary outcomes included leaving with any method on the day of the abortion and use of any method at the 4-week assessment. Secondary outcomes included intrauterine device or implant use on the day of the procedure and at 4 weeks and switching to a less effective method at 4 weeks. RESULTS: A total of 19,673 women agreed to participate, and 13,904 (71%) completed the 4-week follow-up survey. Ninety-four percent (18,486/19,673) left their abortion visit with a contraceptive method: 21% (4,111/19,673) with an intrauterine device, implant, or permanent method. By the 4-week survey, 8% (1,135/13,904) switched from a high- or medium-efficacy method to a low-efficacy or no method; 0.4% (60/13,904) experienced a contraceptive incident. In adjusted regression analyses, women who paid for the abortion with Medicaid were significantly more likely to use any method (adjusted odds ratio [OR] 3.70, 95% CI 3.09-4.42) or an intrauterine device or implant (adjusted OR 2.14, 95% CI 1.92-2.38) on the day of the abortion than those who did not pay with insurance. Experiencing a contraceptive-related incident was associated with switching to a low-efficacy or no method by the 4 week survey (adjusted OR 3.98, 95% CI 2.20-7.22). CONCLUSION: Insurance coverage for abortion is associated with postabortion contraceptive provision and use, even in settings that cover abortions and contraception for low-income women. PMID- 29112660 TI - Opioid Prescribing Patterns, Patient Use, and Postoperative Pain After Hysterectomy for Benign Indications. AB - OBJECTIVE: To quantify physician prescribing patterns and patient opioid use in the 2 weeks after hysterectomy at an academic institution and to determine whether patient factors predict postsurgical opioid use and pain recovery. METHODS: We conducted a prospective quality initiative study by recruiting all English-speaking patients undergoing hysterectomy for benign, nonobstetric indications at a university hospital between August 2015 and December 2015, excluding those with major medical morbidities or substance abuse. Before hysterectomy, patients completed the Fibromyalgia Survey, a validated measure of centralized pain. After hysterectomy, opioid use (converted to oral morphine equivalents) and pain scores (0-10 numeric rating scale) were collected by a daily diary and a structured telephone interview 14 days after surgery. Primary outcomes were total opioid prescribed and consumed in the 2 weeks after hysterectomy. Secondary outcomes included daily opioid use and daily pain severity for 14 days after hysterectomy. RESULTS: Of 103 eligible patients, 102 (99%) agreed to participate, including 44 (43.1%) laparoscopic, 42 (41.2%) vaginal, and 16 (15.7%) abdominal hysterectomies. Telephone surveys were completed on 89 (87%) participants; diaries were returned from 60 (59%) participants. Diary nonresponders had different baseline characteristics than nonresponders. Median amount of opioid prescribed was 200 oral morphine equivalents (interquartile range 150-250). Patients reported using approximately half of the opioids prescribed with a median excess of 110 morphine equivalents (interquartile range 40-150). The best fit model of total opioid consumption identified preoperative Fibromyalgia Survey Score, overall body pain, preoperative opioid use, prior endometriosis, abdominal hysterectomy (compared with laparoscopic), and uterine weight as significant predictors. Highest tertile of Fibromyalgia Survey Score was associated with greater daily opioid consumption (13.9 [95% CI 3.0-24.8] greater oral morphine equivalents at baseline, P=.02). CONCLUSION: Gynecologists at a large academic medical center prescribe twice the amount of opioids than the average patient uses after hysterectomy. A personalized approach to prescribing opioids for postoperative pain should be considered. PMID- 29112662 TI - Perioperative Complications of Cesarean Delivery Myomectomy: A Meta-analysis. AB - OBJECTIVE: To assess the association of myomectomy during cesarean delivery with intraoperative and perioperative maternal morbidity. DATA SOURCES: We searched MEDLINE (1966-2017), Scopus (2004-2017), ClinicalTrials.gov (2008-2017), EMBASE (1980-2017), and Cochrane Central Register of Controlled Trials CENTRAL (1999 2017) databases. METHODS OF STUDY SELECTION: We selected all observational studies that reported outcomes on patients undergoing myomectomy at the time of cesarean delivery. Statistical meta-analysis was performed with RevMan 5.3. RESULTS: Nineteen studies were included in our systematic review with a total number of 3,900 women. Among them, 2,301 women had myomectomy during cesarean delivery and 1,599 had cesarean delivery only. Women undergoing concomitant myomectomy had a mild decline in hemoglobin compared with those who had cesarean delivery only (mean difference 0.25 mg/dL, 95% CI 0.06-0.45). Myomectomy at the time of cesarean delivery is associated with longer surgical time compared with cesarean delivery alone (mean difference 13.87 minutes, 95% CI 4.78-22.95). Blood transfusion (odds ratio [OR] 1.41, 95% CI 0.96-2.07) and postoperative fever (OR 1.12, 95% CI 0.80-1.56) rates did not differ between the two groups (myomectomy compared with no myomectomy). A statistically, but not clinically, significant increase in postoperative hospitalization was evident in the myomectomy group (mean difference 0.35 days, 95% CI 0.25-0.46). CONCLUSION: This systematic review and meta-analysis of observational studies demonstrated an association with increased operative time and hemoglobin drop in patients who underwent cesarean myomectomy compared with cesarean delivery alone. No increased rate of major hemorrhage or need for transfusion was identified. Cesarean myomectomy may be considered in cases of isolated myomas, although randomized trials are needed. PMID- 29112663 TI - Training Physicians in Advocacy: Why It Matters. AB - At a time in our country's history when state and federal legislative regulations on medical practice and access to services are at an all-time high, effective physician advocacy in women's health is crucial to the evolution of our profession and the provision of quality and equitable patient care. Inclusion of specific advocacy training programs in residency and beyond should be considered a priority. Ensuring a unified set of goals for advocacy training is important to training the next generation of competent and skilled physician advocates for leadership in academia and professional organizations. Sharing of initiatives and efforts to integrate advocacy into the training continuum across our community may inspire broader acceptance and implementation of such programs. PMID- 29112664 TI - Placental Alpha Microglobulin-1 Compared With Fetal Fibronectin to Predict Preterm Delivery in Symptomatic Women. AB - OBJECTIVE: To compare the rapid bedside test for placental alpha microglobulin-1 with the instrumented fetal fibronectin test for prediction of imminent spontaneous preterm delivery among women with symptoms of preterm labor. METHODS: We conducted a prospective observational study on pregnant women with signs or symptoms suggestive of preterm labor between 24 and 35 weeks of gestation with intact membranes and cervical dilatation less than 3 cm. Participants were prospectively enrolled at 15 U.S. academic and community centers. Placental alpha microglobulin-1 samples did not require a speculum examination. Health care providers were blinded to placental alpha microglobulin-1 results. Fetal fibronectin samples were collected through speculum examination per manufacturer requirements and sent to a certified laboratory for testing using a cutoff of 50 ng/mL. The coprimary endpoints were positive predictive value (PPV) superiority and negative predictive value (NPV) noninferiority of placental alpha microglobulin-1 compared with fetal fibronectin for the prediction of spontaneous preterm birth within 7 days and within 14 days. RESULTS: Of 796 women included in the study cohort, 711 (89.3%) had both placental alpha microglobulin-1 and fetal fibronectin results and valid delivery outcomes available for analysis. The overall rate of preterm birth was 2.4% (17/711) within 7 days of testing and 4.2% (30/711) within 14 days of testing with respective rates of spontaneous preterm birth of 1.3% (9/703) and 2.9% (20/701). Fetal fibronectin was detected in 15.5% (110/711), and placental alpha microglobulin-1 was detected in 2.4% (17/711). The PPVs for spontaneous preterm delivery within 7 days or less among singleton gestations (n=13) for placental alpha microglobulin-1 and fetal fibronectin were 23.1% (3/13) and 4.3% (4/94), respectively (P<.025 for superiority). The NPVs were 99.5% (619/622) and 99.6% (539/541) for placental alpha microglobulin-1 and fetal fibronectin, respectively (P<.001 for noninferiority). CONCLUSION: Although placental alpha microglobulin-1 performed the same as fetal fibronectin in ruling out spontaneous preterm delivery among symptomatic women, it demonstrated statistical superiority in predicting it. PMID- 29112665 TI - Long-term Risk of a Seizure Disorder After Eclampsia. AB - OBJECTIVE: To evaluate the incidence rate and relative risk of a seizure disorder after eclampsia. METHODS: We evaluated 1,565,733 births in a retrospective data linkage cohort study in Ontario, Canada, from April 1, 2002, to March 31, 2014. We included females aged 15-50 years and excluded patients with epilepsy, conditions predisposing to seizure, and those who died within 30 days of the delivery discharge date. The exposure was defined as a hypertensive disorder of pregnancy, namely 1) eclampsia, 2) preeclampsia, or 3) gestational hypertension. The referent was an unaffected pregnancy. The primary outcome was the risk of seizure disorder starting 31 days after a hospital birth discharge. Risk was expressed as an incidence rate and a hazard ratio (HR) with 95% CI. The predefined study hypothesis was that women with eclampsia would have an increased risk of future seizure disorder. RESULTS: There were 1,615 (0.10%) pregnancies exclusively affected by eclampsia, 17,264 (1.1%) with preeclampsia, 60,863 (3.9%) with gestational hypertension, and 1,485,991 (94.9%) unaffected. A future seizure disorder was significantly more likely after a pregnancy with eclampsia (4.58/10,000 person-years) than a pregnancy without a hypertensive disorder of pregnancy (0.72/10,000 person-years; crude HR 6.09, 95% CI 2.73-13.60). The adjusted HR was minimally attenuated from 6.09 to 5.42 (95% CI 2.42-12.12) after multivariable adjustment for confounders at the index birth as well as adjusting for traumatic brain injury, stroke, cerebral tumor, aneurysm or hemorrhage, and multiple sclerosis. The risk of seizure disorder was doubled in pregnancies affected by preeclampsia (adjusted HR 1.96, 95% CI 1.21-3.17), but not by gestational hypertension (adjusted HR 1.01, 95% CI 0.71-1.43). CONCLUSION: Women with eclampsia should be reassured that, although the relative risk of a seizure disorder is higher than unaffected women, the absolute risk is extremely low (approximately one seizure/2,200 person-years). PMID- 29112666 TI - Disparities in Chronic Conditions Among Women Hospitalized for Delivery in the United States, 2005-2014. AB - OBJECTIVE: To estimate trends in the prevalence and socioeconomic distribution of chronic conditions among women hospitalized for obstetric delivery in the United States. METHODS: A retrospective, serial cross-sectional analysis was conducted using 2005-2014 data from the National Inpatient Sample. We estimated the prevalence of eight common, chronic conditions, each associated with obstetric morbidity and mortality, among all childbearing women and then across socioeconomic predictors of obstetric outcomes. Differences over time were measured and compared across rural and urban residence, income, and payer subgroups for each condition. RESULTS: We identified 8,193,707 delivery hospitalizations, representing 39,273,417 delivery hospitalizations occurring nationally between 2005 and 2014. Identification of at least one chronic condition increased significantly between 2005-2006 and 2013-2014 (66.9 per 1,000 delivery hospitalizations in 2005-2006 compared with 91.8 per 1,000 delivery hospitalizations in 2013-2014). The prevalence of multiple chronic conditions also increased during the study period, from 4.7 (95% CI 4.2-5.2) to 8.1 (95% CI 7.8-8.4) per 1,000 delivery hospitalizations between 2005-2006 and 2013-2014. Chronic respiratory disease, chronic hypertension, substance use disorders, and pre-existing diabetes were the disorders with the greatest increases in prevalence over time. Increasing disparities over time were identified across all socioeconomic subgroups analyzed including rural compared with urban residence, income, and payer. Key areas of concern include the rate at which substance use disorders rose among rural women and the disproportionate burden of each condition among women from the lowest income communities and among women with Medicaid as their primary payer. CONCLUSION: Between 2005-2006 and 2013-2014, the prevalence of chronic conditions increased across all segments of the childbearing population. Widening disparities were identified over time with key areas of concern including disproportionate, progressive increases in the burden of chronic conditions among women from rural and low-income communities and those with deliveries funded by Medicaid. PMID- 29112667 TI - Pica in Pregnancy: An Unusual Presentation. AB - BACKGROUND: Pica is common in pregnancy and is often felt to be benign. The following case of severe pica presenting without anemia is unusual in its presentation, laboratory findings, and treatment. CASE: A 31-year-old multiparous woman at 37 0/7 weeks of gestation presented with esophagitis and gastritis secondary to laundry detergent consumption. She had borderline anemia (hemoglobin of 11 g/dL and hematocrit of 37%, mean corpuscular volume 80%) but was severely iron-deficient (serum ferritin 7 micrograms/dL). Parenteral iron infusion was associated with dramatic resolution of her cravings within 36 hours of treatment. CONCLUSION: Pica may be related to deficient iron stores in the absence of anemia and can result in serious morbidity. Parenteral iron may be associated with rapid pica resolution in symptomatic pregnant patients. PMID- 29112668 TI - What Is New in Recurrent Miscarriage?: Best Articles From the Past Year. AB - This month we focus on current research in recurrent miscarriage. Dr. Hansen discusses five recent publications, which are concluded with a "bottom line" that is a take-home message. A complete reference for each can be found on on this page along with direct links to abstracts. PMID- 29112669 TI - Prediction Is Very Difficult, Especially if It Is About the Future. PMID- 29112670 TI - Connect the Dots-December 2017. PMID- 29112671 TI - Travel Characteristics and Pretravel Health Care Among Pregnant or Breastfeeding U.S. Women Preparing for International Travel. AB - OBJECTIVE: To study characteristics and preventive interventions of adult pregnant and breastfeeding travelers seeking pretravel health care in the United States. METHODS: This cross-sectional study analyzed data (2009-2014) of pregnant and breastfeeding travelers seen at U.S. travel clinics participating in Global TravEpiNet. Nonpregnant, nonbreastfeeding adult female travelers of childbearing age were used for comparison. We evaluated the prescription of malaria chemoprophylaxis and antibiotics for this population as well as the administration of three travel-related vaccines: hepatitis A, typhoid, and yellow fever. We also evaluated use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis and influenza vaccines, because these are widely recommended in pregnancy. RESULTS: Of 21,138 female travelers of childbearing age in Global TravEpiNet, 170 (0.8%) were pregnant and 139 (0.7%) were breastfeeding. Many traveled to destinations endemic for mosquito-borne illnesses, including malaria (pregnant: 95%; breastfeeding: 94%), dengue (pregnant: 87%; breastfeeding: 81%), or yellow fever (pregnant: 35%; breastfeeding: 50%). Compared with nonpregnant, nonbreastfeeding adult female travelers, eligible pregnant travelers were less likely to be vaccinated against hepatitis A (28% compared with 51%, P<.001) and typhoid (35% compared with 74%, P<.001). More than 20% of eligible pregnant travelers did not receive influenza vaccination. Yellow fever vaccine was occasionally provided to pregnant and breastfeeding travelers traveling to countries entirely endemic for yellow fever (6 [20%] of 30 pregnant travelers and 18 [46%] of 39 breastfeeding travelers). Half of pregnant travelers and two thirds of breastfeeding travelers preparing to travel to malaria-holoendemic countries received a prescription for malaria prophylaxis. CONCLUSION: Most pregnant and breastfeeding travelers seen for pretravel health consultations traveled to destinations with high risk for vector-borne or other travel-related diseases. Destination-specific preventive interventions were frequently underused. PMID- 29112673 TI - Feedback is the breakfast of champions: the significance of self-controlled formal feedback for autonomous task engagement. AB - With the aim of examining the positive effect of the formal feedback mechanism itself beyond its informational aspect, we engaged participants in the stopwatch task and recorded their electroencephalogram throughout the experiment. This task requires a button press to stop the watch within a given time interval, the completion of which is simultaneously accompanied by adequate information on task performance. In the self-controlled feedback mode, participants could freely choose whether to request formal feedback after completing the task. In another mode, additional feedback was not provided. The 'non-choice' cue was found to elicit a more negative cue-elicited feedback negativity compared with 'choice', suggesting that the opportunity to solicit formal feedback was perceived as more desirable. In addition, a more enhanced stimulus-preceding negativity was observed prior to the task initiation cue in the self-controlled feedback condition, indicating that participants paid more sustained anticipatory attention during task preparation. Taken together, these electrophysiological results suggested an inherent reward within the formal feedback mechanism itself and the significance of self-controlled formal feedback for autonomous task engagement. PMID- 29112672 TI - Diagnosis of Cervical Precancers by Endocervical Curettage at Colposcopy of Women With Abnormal Cervical Cytology. AB - OBJECTIVE: To evaluate the performance of routine endocervical curettage (ECC) for diagnosing high-grade cervical intraepithelial neoplasia (CIN) 2 or worse and additional precancers not otherwise detected by ectocervical biopsies. METHODS: In a secondary analysis of the Biopsy Study, a cross-sectional study conducted between 2009 and 2012 at the University of Oklahoma Health and Sciences Center that found an incremental increase in detection of cervical precancers by multiple biopsies at colposcopy, ECC was performed in most women aged 30 years or older. Cervical intraepithelial neoplasia 2 or worse yield by ECC alone was evaluated in analyses stratified by cervical cytology (atypical squamous cells of undetermined significance [ASC-US] or low-grade squamous intraepithelial lesions [LSIL] compared with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions [ASC-H] or high-grade squamous intraepithelial lesions [HSIL] or worse), colposcopic impression (less than high-grade compared with high grade), human papillomavirus (HPV)-16 infection status, whether the examination was satisfactory, and by ECC indications per the current guidelines for cervical cancer screening. The diagnostic value of ECC for detecting additional disease was evaluated by the number of lesion-directed ectocervical biopsies. RESULTS: Of the 204 women aged 30 years or older, 181 (88.7%) underwent ECC. Overall ECC detected 14.4% CIN 2 or worse (95% CI 10.0-20.2%). Endocervical curettage was more likely to find disease in the endocervix among women with high-grade cytology, positive HPV-16 infection, or high-grade colposcopic impressions (respective P values <.05). Among women with ASC-US or LSIL cytology, those with an unsatisfactory examination had a 13.0% CIN 2 or worse yield on ECC (95% CI 6.1 25.7); when colposcopic examination was normal or satisfactory with visible abnormal lesions, ECC detected less than 5% CIN 2 or worse in the endocervix. An ASC-H or HSIL or worse cytology was associated with a CIN 2 or worse yield of 25.8% by ECC (95% CI 16.6-37.9%). However, ECC found only 3.9% (95% CI 1.9-7.8%) additional CIN 2 or worse beyond the cumulative disease detected by up to four biopsies of visible acetowhite ectocervical lesions. Additional CIN 2 or worse yield by ECC increased when fewer lesion-directed biopsies were taken (P<.05). CONCLUSION: The additional yield of CIN 2 or worse by ECC in a colposcopy with up to four ectocervical biopsies was low. Based on our findings, we recommend routine ECC be performed in women aged 45 years old or older with HPV-16 infection and in any woman aged 30 years or older with HSIL or worse or ASC-H cytology, high-grade colposcopic impression, or ASC-US or LSIL cytology and an unsatisfactory examination. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00339989. PMID- 29112674 TI - Interleukin-10 and PD150606 modulate expression of AMPA receptor GluA1 and GluA2 subunits under hypoxic conditions. AB - The goal of this study was to evaluate the effects of anti-inflammatory cytokine, interleukin-10 (IL-10), and calpain inhibitor, PD150606, on the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits in rat hippocampal slices exposed to repeated brief hypoxic episodes. We studied both individual and combinatory effects of PD150606 and IL-10 on the expression of AMPA receptor subunits under hypoxic conditions for GluA1 and GluA2 as well as their phosphorylated forms - pSer831-GluA1 and pSer880-GluA2. Additionally, we studied whether brief hypoxic episodes and IL-10 may affect mRNA expression of transcriptional factors such as hypoxia-inducible factor-1alpha and nuclear factor kappaB (NF-kappaB). Western blotting analysis of hippocampal slice homogenates revealed that IL-10 and PD150606, both individually and in combination, ameliorate hypoxia-induced decrease in the expression of GluA1 and pSer831-GluA1, with different level of efficiency measured at 10, 50, and 90 min after hypoxia induction. Interestingly, brief hypoxic episodes did not induce any changes in the expression of GluA2 and pSer880-GluA2 subunits, whereas PD150606 showed biphasic effect, decreasing the expression of GluA2 and pSer880-GluA2 at 10 min and potentiating it at 90 min after hypoxia induction. IL-10 alone did not show any effect but was able to reverse PD150606 action on the expression of pSer880-GluA2 at 10 min and further potentiated it for GluA2 at 90 min after hypoxia. Finally, PCR analysis revealed that modulation of GluA1 and GluA2 expressions by hypoxia, and IL-10 was not associated with changes in the expression of hypoxia-inducible factor-1alpha and nuclear factor-kappaB (NF kappaB) transcriptional factors. PMID- 29112675 TI - Potassium channels-mediated electrophysiologic responses are inhibited by cytosolic phospholipase A2alpha ablation. AB - Cytosolic phospholipase A2alpha (cPLA2alpha) is implicated in the progression of excitotoxic neuronal injury and cerebral ischemia. Previous work suggests that cPLA2alpha increases aberrant electrophysiologic events through attenuating K channel functions. Nevertheless, which K channels are affected by cPLA2alpha needs to be determined. Here we examined K channels-mediated electrophysiologic responses in hippocampal CA1 pyramidal neurons from wild-type and cPLA2alpha mice using simultaneous patch-clamp recording and confocal Ca imaging. After the exposure to the blockers of Ca-sensitive and A-type K channels, all CA1 neurons developed spike broadening and increased dendritic Ca transients. These effects were occluded in CA1 neurons from cPLA2alpha mice. Therefore, cPLA2alpha modulates the functions of Ca-sensitive and A-type K channels in neurotoxicity. PMID- 29112676 TI - Semantic relationship shared between words: influence on associative recognition supported by event-related potentials. AB - A number of recent studies have shown that familiarity can contribute to associative recognition, specifically when the to-be-paired items are perceived as a single unit; however, whether semantic relationship between two items can help them form a unitization is still heatedly debated, with largely inconsistent results. The present study uses event-related potentials (ERPs) to investigate whether semantic relation can serve as a unitization approach by manipulating levels of unitization (LOU). Results revealed that semantic-related conditions were supported by both familiarity and recollection, whereas unrelated pairs solely by recollection, indicating that semantic relation can encourage unitization. On a larger frame, though, we proposed that the incompatible results among different groups is because of the position of semantic relation on the LOU continuum - just around the threshold to form familiarity, thus unstable enough to produce FN400 in every experiment setting with any particular materials. We further propose that such a threshold position is because of semantic relations helping unitization by having two items share an overlapped representation, which is weaker than other high LOU but beyond-the-threshold relations (e.g. synonyms) that encourage unitization in a stronger manner. PMID- 29112677 TI - The effect of the high-approach versus low-approach motivational positive affect on the processing stage of cognitive control: an event-related potential study. AB - The present study used the event-related potentials to investigate the effect of task-irrelevant, high-approach versus low-approach motivational positive affect on proactive and reactive control, and their neural mechanisms. A cue stimulus and a probe stimulus were presented successively in each trial. Participants were required to maintain the information of the cue and respond to the probe. The results showed that high-approach positive affect reduced the amplitudes of P3b after the cue of low frequency and enlarged the amplitudes of contingent negative variation before all the probes. Conversely, low-approach motivational positive affect improved the amplitude of P3a after the probe in some trials. These findings demonstrated that high (compared with the low)-approach motivational positive affect improved proactive control and influenced the early stage of the cognitive control process. Low (relative to high)-approach motivational positive affect facilitated reactive control and influenced the late process stage of cognitive control. PMID- 29112678 TI - Perception of time in microgravity and hypergravity during parabolic flight. AB - We explored the effect of gravity on the accuracy for estimating durations of 3.5, 7, and 14 s. Experiments were performed on board an Airbus A310 during parabolic flights eliciting repeated exposures to short periods of 0, 1, and 1.8 g. Two methods for obtaining duration estimates were used, reproduction and production of duration, in two conditions: a control counting condition and a concurrent reading condition. Simple reaction times were also measured to assess attention. The results showed that the temporal accuracies during the reproduction task in the concurrent reading condition were significantly underestimated in 0 g compared with 1 g. Reaction times were also longer in 0 g. However, there was no difference in duration estimates in the production tasks. These results suggest that the temporal underestimation in 0 g is caused by decreased selective attention and impaired retrieval of information in episodic memory. PMID- 29112679 TI - Monetary incentives at retrieval promote recognition of involuntarily learned emotional information. AB - Previous studies have suggested that the effects of reward on memory processes are affected by certain factors, but it remains unclear whether the effects of reward at retrieval on recognition processes are influenced by emotion. The event related potential was used to investigate the combined effect of reward and emotion on memory retrieval and its neural mechanism. The behavioral results indicated that the reward at retrieval improved recognition performance under positive and negative emotional conditions. The event-related potential results indicated that there were significant interactions between the reward and emotion in the average amplitude during recognition, and the significant reward effects from the frontal to parietal brain areas appeared at 130-800 ms for positive pictures and at 190-800 ms for negative pictures, but there were no significant reward effects of neutral pictures; the reward effect of positive items appeared relatively earlier, starting at 130 ms, and that of negative pictures began at 190 ms. These results indicate that monetary incentives at retrieval promote recognition of involuntarily learned emotional information. PMID- 29112680 TI - Diagnostic Dilemmas in Fourth Nerve Palsies. PMID- 29112681 TI - Contiguous Silicone Oil Migration From the Vitreous Cavity to the Optic Tract. PMID- 29112682 TI - Cross-Coupling Effects of Silencing of Cyclooxygenase-2 (COX-2)/Aggrecanase-1 and Over-Expressed Insulin-Like Growth Factor 1 (IGF-1) in an Osteoarthritis Animal Model. AB - BACKGROUND This study aimed to observe the effect of lentivirus-mediated cyclooxygenase-2 and aggrecanase-1 silencing and insulin-like growth factor-1 overexpression in human bone marrow mesenchymal stem cells after injection into model osteoarthritic knees. MATERIAL AND METHODS Using genetic recombination technique, the genes of cyclooxygenase-2, aggrecanase-1, and insulin-like growth factor-1 were recombined into the lentiviral vectors, and we transfected the human bone marrow stem cells in vitro. The BMSC transfected with lentivirus without genes served as a blank-virus group, and saline was used for another control group. One week later, the cytokines PGE2, aggrecanase-1, hIGF-1, and IL 1 were detected and compared between groups. RESULTS Compared with blank-virus group, the expression of COX-2 (85.81+/-5.12 ng/L) and aggrecanase1 (6.256+/ 1.66) were decreased in the virus group (p<0.05), while the expression of hIGF-1 (17.46+/-1.86) was increased (p<0.05). The concentrations of PGE2 (85.81+/-5.12 ng/L), aggrecanase1 (51.34+/-5.463 ng/L), and IL-1 (82.31+/-4.321 ng/L) decreased (p<0.05) within the knee, but the concentration of hIGF-1 (44.33+/-0.7194 ng/L) increased (p<0.05). Compared with the other groups, the results of histological and immunohistochemical examinations demonstrated that the abrasion of articular cartilage was significantly improved and repaired. CONCLUSIONS Lentivirus mediated RNAi can inhibit the expression of COX-2 mRNA and aggrecanase-1mRNA, and enhance the hIGF-1 mRNA expression, thereby influencing the concentration of cytokines in the early osteoarthritic model knee joints. PMID- 29112683 TI - Targeting de novo lipogenesis as a novel approach in anti-cancer therapy. AB - BACKGROUND: Although altered membrane physiology has been discussed within the context of cancer, targeting membrane characteristics by drugs being an attractive therapeutic strategy has received little attention so far. METHODS: Various acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN) inhibitors (like Soraphen A and Cerulenin) as well as genetic knockdown approaches were employed to study the effects of disturbed phospholipid composition on membrane properties and its functional impact on cancer progression. By using state-of-the-art methodologies such as LC-MS/MS, optical tweezers measurements of giant plasma membrane vesicles and fluorescence recovery after photobleaching analysis, membrane characteristics were examined. Confocal laser scanning microscopy, proximity ligation assays, immunoblotting as well as migration, invasion and proliferation experiments unravelled the functional relevance of membrane properties in vitro and in vivo. RESULTS: By disturbing the deformability and lateral fluidity of cellular membranes, the dimerisation, localisation and recycling of cancer-relevant transmembrane receptors is compromised. Consequently, impaired activation of growth factor receptor signalling cascades results in abrogated tumour growth and metastasis in different in vitro and in vivo models. CONCLUSIONS: This study highlights the field of membrane properties as a promising druggable cellular target representing an innovative strategy for development of anti-cancer agents. PMID- 29112684 TI - CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma. AB - BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare and challenging endocrine malignancy. Once spread, the therapeutic options are limited and the outcome poor. For these patients, the identification of new druggable biological markers is of great importance. Here, we investigated the prognostic and biological role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in MTC. METHODS: Eighty six MTC and corresponding non-neoplastic thyroid specimens were immunohistochemically stained for CXCR4/7 using tissue microarray technology and expression levels correlated with clinicopathological variables. Medullary thyroid carcinoma cell line TT was treated with recombinant human SDF1alpha/CXCL12 (rh-SDF1alpha) and CXCR4 antagonists AMD3100 and WZ811. Changes in cell cycle activation, tumour cell invasiveness as well as changes in mRNA expression levels of genes associated with epithelial-mesenchymal transition (EMT) were investigated. RESULTS: High CXCR4 expression was associated with large tumour size and metastatic disease. CXCR4 antagonists significantly reduced tumour cell invasiveness, while the treatment with rh-SDF1alpha stimulated invasive growth, caused cell cycle activation and induced EMT. CONCLUSIONS: The CXCR4/CXCR7/CXCL12 axis plays an important role in MTC. We provide first evidence that the chemokine receptors might serve as potential therapeutic targets in patients with advanced MTC and offer new valuable insight into the underlying molecular machinery of metastatic MTC. PMID- 29112685 TI - Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer. AB - BACKGROUND: Pretreatment serum squamous cell carcinoma antigen (SCCA) is a prognostic biomarker in women with cervical cancer. SCCA has not been evaluated as an early indicator of response to chemoradiation therapy (CRT). The molecular role of the two SCCA isoforms, SCCA1 (SERPINB3) and SCCA2 (SERPINB4), in cervical cancer is unknown. We hypothesised that changes in serum SCCA during definitive CRT predicts treatment response, and that SCCA1 mediates radiation resistance. METHODS: Patients treated with definitive CRT for cervical squamous carcinoma with serum SCCA measured were included. SCCA immunohistochemistry was performed on tumour biopsies. Post-treatment FDG-PET/CT, recurrence, and overall survival were recorded. Radiation response of cervical tumour cell lines after SCCA1 expression or CRISPR/Cas9 knockout was evaluated by clonogenic survival assay. RESULTS: Persistently elevated serum SCCA during definitive CRT was an independent predictor of positive post-therapy FDG-PET/CT (P=0.043), recurrence (P=0.0046) and death (P=0.015). An SCCA1-expressing vector increased radioresistance, while SCCA knock out increased radiosensitivity of cervical tumour cell lines in vitro. CONCLUSIONS: Early response assessment with serum SCCA is a powerful prognostic tool. These findings suggest that escalation of therapy in patients with elevated or sustained serum SCCA and molecular targeting of SCCA1 should be considered. PMID- 29112687 TI - Ribosome origami. PMID- 29112686 TI - Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response. AB - BACKGROUND: Tumour-derived exosomes (TEXs) have a potential for application in cancer vaccines. Whether TEXs after induction by interferon regulatory factor 1 (IRF-1) are capable of enhancing the antitumour response remains to be determined. METHODS: Exosomes released by tumour cells infected with IRF-1 expressing adenovirus (IRF-1-Exo) or treated with interferon-gamma (IFN-Exo) were isolated via ultracentrifugation. The IRF-1 target proteins IL-15Ralpha and MHC class I (MHC-I) were analysed by western blot. Exosomes along with CpG adjuvant were injected into tumour models to assess the antitumour effects. Tumours were harvested for immunofluorescence staining. Splenocytes from tumour-bearing mice were co-cultured with tumour cells. The IFNgamma-positive and granzyme B-positive CD8alpha+ splenocyte cells were quantified by flow cytometry. RESULTS: The IRF-1 Exo or IFN-Exo displayed increased IL-15Ralpha and MHC-I expression. Injection of IRF-1-Exo or IFN-Exo combined with CpG had improved antitumour effects in mice. This effect may be a result of increased infiltration of tumours by CD4+ and CD8alpha+ T cells. Antibody-mediated depletion of CD4+ or CD8+ T cells abrogated the antitumour effects. Splenocytes isolated from CpG+IRF-1-Exo-injected Hepa 1-6 tumour mice had increased IFNgamma-positive and granzyme B-positive CD8+ cells after co-culturing with Hepa 1-6 cells as compared with MC38 cells. CONCLUSIONS: The IRF-1 priming of TEXs enhances antitumour immune response. PMID- 29112688 TI - Measuring success: The challenge of social protection in helping eliminate tuberculosis. AB - In this Perspective on the research article by William Rudgard and colleagues, Priya Shete and coauthor discuss the challenges of measuring the impact of social protection programs such as cash transfers. PMID- 29112689 TI - HIV prevalence and behavioral and psychosocial factors among transgender women and cisgender men who have sex with men in 8 African countries: A cross-sectional analysis. AB - INTRODUCTION: Sub-Saharan Africa bears more than two-thirds of the worldwide burden of HIV; however, data among transgender women from the region are sparse. Transgender women across the world face significant vulnerability to HIV. This analysis aimed to assess HIV prevalence as well as psychosocial and behavioral drivers of HIV infection among transgender women compared with cisgender (non transgender) men who have sex with men (cis-MSM) in 8 sub-Saharan African countries. METHODS AND FINDINGS: Respondent-driven sampling targeted cis-MSM for enrollment. Data collection took place at 14 sites across 8 countries: Burkina Faso (January-August 2013), Cote d'Ivoire (March 2015-February 2016), The Gambia (July-December 2011), Lesotho (February-September 2014), Malawi (July 2011-March 2012), Senegal (February-November 2015), Swaziland (August-December 2011), and Togo (January-June 2013). Surveys gathered information on sexual orientation, gender identity, stigma, mental health, sexual behavior, and HIV testing. Rapid tests for HIV were conducted. Data were merged, and mixed effects logistic regression models were used to estimate relationships between gender identity and HIV infection. Among 4,586 participants assigned male sex at birth, 937 (20%) identified as transgender or female, and 3,649 were cis-MSM. The mean age of study participants was approximately 24 years, with no difference between transgender participants and cis-MSM. Compared to cis-MSM participants, transgender women were more likely to experience family exclusion (odds ratio [OR] 1.75, 95% CI 1.42-2.16, p < 0.001), rape (OR 1.95, 95% CI 1.63-2.36, p < 0.001), and depressive symptoms (OR 1.30, 95% CI 1.12-1.52, p < 0.001). Transgender women were more likely to report condomless receptive anal sex in the prior 12 months (OR 2.44, 95% CI 2.05-2.90, p < 0.001) and to be currently living with HIV (OR 1.81, 95% CI 1.49-2.19, p < 0.001). Overall HIV prevalence was 25% (235/926) in transgender women and 14% (505/3,594) in cis-MSM. When adjusted for age, condomless receptive anal sex, depression, interpersonal stigma, law enforcement stigma, and violence, and the interaction of gender with condomless receptive anal sex, the odds of HIV infection for transgender women were 2.2 times greater than the odds for cis-MSM (95% CI 1.65-2.87, p < 0.001). Limitations of the study included sampling strategies tailored for cis-MSM and merging of datasets with non-identical survey instruments. CONCLUSIONS: In this study in sub-Saharan Africa, we found that HIV burden and stigma differed between transgender women and cis-MSM, indicating a need to address gender diversity within HIV research and programs. PMID- 29112691 TI - Reaching global HIV/AIDS goals: What got us here, won't get us there. AB - In a Perspective, Wafaa El-Sadr and colleagues discuss tailored approaches to treatment and prevention of HIV infection. PMID- 29112690 TI - Disrupted epithelial/macrophage crosstalk via Spinster homologue 2-mediated S1P signaling may drive defective macrophage phagocytic function in COPD. AB - INTRODUCTION: We have previously established a link between impaired phagocytic capacity and deregulated S1P signaling in alveolar macrophages from COPD subjects. We hypothesize that this defect may include a disruption of epithelial macrophage crosstalk via Spns2-mediated intercellular S1P signaling. METHODS: Primary alveolar macrophages and bronchial epithelial cells from COPD subjects and controls, cell lines, and a mouse model of chronic cigarette smoke exposure were studied. Cells were exposed to 10% cigarette smoke extract, or vehicle control. Spns2 expression and subcellular localization was studied by immunofluorescence, confocal microscopy and RT-PCR. Phagocytosis was assessed by flow-cytometry. Levels of intra- and extracellular S1P were measured by S1P [3H] labeling. RESULTS: Spns2 expression was significantly increased (p<0.05) in alveolar macrophages from current-smokers/COPD patients (n = 5) compared to healthy nonsmokers (n = 8) and non-smoker lung transplant patients (n = 4). Consistent with this finding, cigarette smoke induced a significant increase in Spns2 expression in both human alveolar and THP-1 macrophages. In contrast, a remarkable Spns2 down-regulation was noted in response to cigarette smoke in 16HBE14o- cell line (p<0.001 in 3 experiments), primary nasal epithelial cells (p<0.01 in 2 experiments), and in smoke-exposed mice (p<0.001, n = 6 animals per group). Spns2 was localized to cilia in primary bronchial epithelial cells. In both macrophage and epithelial cell types, Spns2 was also found localized to cytoplasm and the nucleus, in line with a predicted bipartile Nuclear Localization Signal at the position aa282 of the human Spns2 sequence. In smoke exposed mice, alveolar macrophage phagocytic function positively correlated with Spns2 protein expression in bronchial epithelial cells. CONCLUSION: Our data suggest that the epithelium may be the major source for extracellular S1P in the airway and that there is a possible disruption of epithelial/macrophage cross talk via Spns2-mediated S1P signaling in COPD and in response to cigarette smoke exposure. PMID- 29112694 TI - Curcumin dietary supplements and everolimus-based cancer treatment. PMID- 29112692 TI - Contemporary disengagement from antiretroviral therapy in Khayelitsha, South Africa: A cohort study. AB - BACKGROUND: Retention in care is an essential component of meeting the UNAIDS "90 90-90" HIV treatment targets. In Khayelitsha township (population ~500,000) in Cape Town, South Africa, more than 50,000 patients have received antiretroviral therapy (ART) since the inception of this public-sector program in 2001. Disengagement from care remains an important challenge. We sought to determine the incidence of and risk factors associated with disengagement from care during 2013-2014 and outcomes for those who disengaged. METHODS AND FINDINGS: We conducted a retrospective cohort study of all patients >=10 years of age who visited 1 of the 13 Khayelitsha ART clinics from 2013-2014 regardless of the date they initiated ART. We described the cumulative incidence of first disengagement (>180 days not attending clinic) between 1 January 2013 and 31 December 2014 using competing risks methods, enabling us to estimate disengagement incidence up to 10 years after ART initiation. We also described risk factors for disengagement based on a Cox proportional hazards model, using multiple imputation for missing data. We ascertained outcomes (death, return to care, hospital admission, other hospital contact, alive but not in care, no information) after disengagement until 30 June 2015 using province-wide health databases and the National Death Registry. Of 39,884 patients meeting our eligibility criteria, the median time on ART to 31 December 2014 was 33.6 months (IQR 12.4-63.2). Of the total study cohort, 592 (1.5%) died in the study period, 1,231 (3.1%) formally transferred out, 987 (2.5%) were silent transfers and visited another Western Cape province clinic within 180 days, 9,005 (22.6%) disengaged, and 28,069 (70.4%) remained in care. Cumulative incidence of disengagement from care was estimated to be 25.1% by 2 years and 50.3% by 5 years on ART. Key factors associated with disengagement (age, male sex, pregnancy at ART start [HR 1.58, 95% CI 1.47-1.69], most recent CD4 count) and retention (ART club membership, baseline CD4) after adjustment were similar to those found in previous studies; however, notably, the higher hazard of disengagement soon after starting ART was no longer present after adjusting for these risk factors. Of the 9,005 who disengaged, the 2 most common initial outcomes were return to ART care after 180 days (33%; n = 2,976) and being alive but not in care in the Western Cape (25%; n = 2,255). After disengagement, a total of 1,459 (16%) patients were hospitalized and 237 (3%) died. The median follow-up from date of disengagement to 30 June 2015 was 16.7 months (IQR 11-22.4). As we included only patient follow up from 2013-2014 by design in order to maximize the generalizability of our findings to current programs, this limited our ability to more fully describe temporal trends in first disengagement. CONCLUSIONS: Twenty-three percent of ART patients in the large cohort of Khayelitsha, one of the oldest public-sector ART programs in South Africa, disengaged from care at least once in a contemporary 2 year period. Fifty-eight percent of these patients either subsequently returned to care (some "silently") or remained alive without hospitalization, suggesting that many who are considered "lost" actually return to care, and that misclassification of "lost" patients is likely common in similar urban populations. A challenge to meeting ART retention targets is developing, testing, and implementing program designs to target mobile populations and retain them in lifelong care. This should be guided by risk factors for disengagement and improving interlinkage of routine information systems to better support patient care across complex care platforms. PMID- 29112693 TI - Comparison of two cash transfer strategies to prevent catastrophic costs for poor tuberculosis-affected households in low- and middle-income countries: An economic modelling study. AB - BACKGROUND: Illness-related costs for patients with tuberculosis (TB) >=20% of pre-illness annual household income predict adverse treatment outcomes and have been termed "catastrophic." Social protection initiatives, including cash transfers, are endorsed to help prevent catastrophic costs. With this aim, cash transfers may either be provided to defray TB-related costs of households with a confirmed TB diagnosis (termed a "TB-specific" approach); or to increase income of households with high TB risk to strengthen their economic resilience (termed a "TB-sensitive" approach). The impact of cash transfers provided with each of these approaches might vary. We undertook an economic modelling study from the patient perspective to compare the potential of these 2 cash transfer approaches to prevent catastrophic costs. METHODS AND FINDINGS: Model inputs for 7 low- and middle-income countries (Brazil, Colombia, Ecuador, Ghana, Mexico, Tanzania, and Yemen) were retrieved by literature review and included countries' mean patient TB-related costs, mean household income, mean cash transfers, and estimated TB specific and TB-sensitive target populations. Analyses were completed for drug susceptible (DS) TB-related costs in all 7 out of 7 countries, and additionally for drug-resistant (DR) TB-related costs in 1 of the 7 countries with available data. All cost data were reported in 2013 international dollars ($). The target population for TB-specific cash transfers was poor households with a confirmed TB diagnosis, and for TB-sensitive cash transfers was poor households already targeted by countries' established poverty-reduction cash transfer programme. Cash transfers offered in countries, unrelated to TB, ranged from $217 to $1,091/year/household. Before cash transfers, DS TB-related costs were catastrophic in 6 out of 7 countries. If cash transfers were provided with a TB specific approach, alone they would be insufficient to prevent DS TB catastrophic costs in 4 out of 6 countries, and when increased enough to prevent DS TB catastrophic costs would require a budget between $3.8 million (95% CI: $3.8 million-$3.8 million) and $75 million (95% CI: $50 million-$100 million) per country. If instead cash transfers were provided with a TB-sensitive approach, alone they would be insufficient to prevent DS TB-related catastrophic costs in any of the 6 countries, and when increased enough to prevent DS TB catastrophic costs would require a budget between $298 million (95% CI: $219 million-$378 million) and $165,367 million (95% CI: $134,085 million-$196,425 million) per country. DR TB-related costs were catastrophic before and after TB-specific or TB sensitive cash transfers in 1 out of 1 countries. Sensitivity analyses showed our findings to be robust to imputation of missing TB-related cost components, and use of 10% or 30% instead of 20% as the threshold for measuring catastrophic costs. Key limitations were using national average data and not considering other health and social benefits of cash transfers. CONCLUSIONS: A TB-sensitive cash transfer approach to increase all poor households' income may have broad benefits by reducing poverty, but is unlikely to be as effective or affordable for preventing TB catastrophic costs as a TB-specific cash transfer approach to defray TB-related costs only in poor households with a confirmed TB diagnosis. Preventing DR TB-related catastrophic costs will require considerable additional investment whether a TB-sensitive or a TB-specific cash transfer approach is used. PMID- 29112695 TI - Recent development of antiSMASH and other computational approaches to mine secondary metabolite biosynthetic gene clusters. AB - Many drugs are derived from small molecules produced by microorganisms and plants, so-called natural products. Natural products have diverse chemical structures, but the biosynthetic pathways producing those compounds are often organized as biosynthetic gene clusters (BGCs) and follow a highly conserved biosynthetic logic. This allows for the identification of core biosynthetic enzymes using genome mining strategies that are based on the sequence similarity of the involved enzymes/genes. However, mining for a variety of BGCs quickly approaches a complexity level where manual analyses are no longer possible and require the use of automated genome mining pipelines, such as the antiSMASH software. In this review, we discuss the principles underlying the predictions of antiSMASH and other tools and provide practical advice for their application. Furthermore, we discuss important caveats such as rule-based BGC detection, sequence and annotation quality and cluster boundary prediction, which all have to be considered while planning for, performing and analyzing the results of genome mining studies. PMID- 29112696 TI - Comprehensive evaluation of non-hybrid genome assembly tools for third-generation PacBio long-read sequence data. AB - Long reads obtained from third-generation sequencing platforms can help overcome the long-standing challenge of the de novo assembly of sequences for the genomic analysis of non-model eukaryotic organisms. Numerous long-read-aided de novo assemblies have been published recently, which exhibited superior quality of the assembled genomes in comparison with those achieved using earlier second generation sequencing technologies. Evaluating assemblies is important in guiding the appropriate choice for specific research needs. In this study, we evaluated 10 long-read assemblers using a variety of metrics on Pacific Biosciences (PacBio) data sets from different taxonomic categories with considerable differences in genome size. The results allowed us to narrow down the list to a few assemblers that can be effectively applied to eukaryotic assembly projects. Moreover, we highlight how best to use limited genomic resources for effectively evaluating the genome assemblies of non-model organisms. PMID- 29112697 TI - Defining a functional network homeostasis after stroke: EEG-based approach is complementary to functional MRI. PMID- 29112698 TI - TabPath: interactive tables for metabolic pathway analysis. AB - Motivation: Information about metabolic pathways in a comparative context is one of the most powerful tool to help the understanding of genome-based differences in phenotypes among organisms. Although several platforms exist that provide a wealth of information on metabolic pathways of diverse organisms, the comparison among organisms using metabolic pathways is still a difficult task. Results: We present TabPath (Tables for Metabolic Pathway), a web-based tool to facilitate comparison of metabolic pathways in genomes based on KEGG. From a selection of pathways and genomes of interest on the menu, TabPath generates user-friendly tables that facilitate analysis of variations in metabolism among the selected organisms. Availability and implementation: TabPath is available at http://200.239.132.160:8686. Contact: lmmorei@gmail.com. PMID- 29112699 TI - Complicated hereditary spastic paraplegia due to ATP13A2 mutations: what's in a name? PMID- 29112700 TI - Reply: Complicated hereditary spastic paraplegia due to ATP13A2 mutations: what's in a name? PMID- 29112701 TI - Effect of docetaxel duration on clinical outcomes: exploratory analysis of CLEOPATRA, a phase III randomized controlled trial. AB - Background: Combination pertuzumab, trastuzumab, and docetaxel (D) is considered standard first-line treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. This post hoc, exploratory analysis of CLEOPATRA study data evaluated the clinical effects of D treatment duration within this regimen. The clinical benefits of pertuzumab and trastuzumab by different durations of D treatment were also evaluated. Patients and methods: Patients with HER2-positive metastatic breast cancer received trastuzumab and D plus pertuzumab or placebo. Clinical outcomes were analyzed by the number of D cycles that patients received (<6D, 6D, or >6D). Progression-free survival (PFS) and overall survival (OS) for each treatment arm within each D cycle group were estimated using the Kaplan-Meier approach. Time-dependent, multivariate Cox regression was applied to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for HER2-targeted therapy and D cycle groups. Results: Overall, 804 patients received <6D (n = 119), 6D (n = 210), or >6D (n = 475) cycles. After adjusting for pertuzumab benefits versus placebo (PFS HR = 0.61, 95% CI 0.51-0.74, P < 0.0001; OS HR = 0.60, 95% CI, 0.49-0.74, P < 0.0001), >6D versus 6D cycles was not associated with statistically significant improvements in PFS (HR = 0.80, 95% CI 0.63-1.01, P = 0.0640) or OS (HR = 0.88, 95% CI 0.69 1.12, P = 0.3073). Consistent improvements in PFS and OS were observed with pertuzumab versus placebo, irrespective of D duration. The HRs for PFS were 0.395, 0.615, and 0.633 for <6D, 6D, and >6D cycles, respectively (P < 0.05 for all D cycle groups). Corresponding HRs for OS were 0.577, 0.700, and 0.612, respectively (P < 0.05 for <6D and >6D). Conclusions: After accounting for pertuzumab benefits, more than six cycles of D treatment was not associated with significant improvements in either PFS or OS compared with six cycles. The addition of pertuzumab to trastuzumab improved clinical outcomes versus trastuzumab plus placebo, regardless of D treatment duration. ClinicalTrials.gov identifier: NCT00567190. PMID- 29112703 TI - Reply: Defining a functional network homeostasis after stroke: EEG-based approach is complementary to functional MRI. PMID- 29112702 TI - CommWalker: correctly evaluating modules in molecular networks in light of annotation bias. AB - Motivation: Detecting novel functional modules in molecular networks is an important step in biological research. In the absence of gold standard functional modules, functional annotations are often used to verify whether detected modules/communities have biological meaning. However, as we show, the uneven distribution of functional annotations means that such evaluation methods favor communities of well-studied proteins. Results: We propose a novel framework for the evaluation of communities as functional modules. Our proposed framework, CommWalker, takes communities as inputs and evaluates them in their local network environment by performing short random walks. We test CommWalker's ability to overcome annotation bias using input communities from four community detection methods on two protein interaction networks. We find that modules accepted by CommWalker are similarly co-expressed as those accepted by current methods. Crucially, CommWalker performs well not only in well-annotated regions, but also in regions otherwise obscured by poor annotation. CommWalker community prioritization both faithfully captures well-validated communities and identifies functional modules that may correspond to more novel biology. Availability and implementation: The CommWalker algorithm is freely available at opig.stats.ox.ac.uk/resources or as a docker image on the Docker Hub at hub.docker.com/r/lueckenmd/commwalker/. Contact: deane@stats.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29112705 TI - Coloured Petri nets for multilevel, multiscale and multidimensional modelling of biological systems. AB - Owing to the availability of data of one biological phenomenon at different levels/scales, modelling of biological systems is moving from single level/scale to multiple levels/scales, which introduces a number of challenges. Coloured Petri nets (ColPNs) have been successfully applied to multilevel, multiscale and multidimensional modelling of some biological systems, addressing many of these challenges. In this article, we first review the basics of ColPNs and some popular extensions, and then their applications for multilevel, multiscale and multidimensional modelling of biological systems. This understanding of how to use ColPNs for modelling biological systems will assist readers in selecting appropriate ColPN classes for specific modelling circumstances. PMID- 29112704 TI - Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma. AB - Background: Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma. Patients and methods: We carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial. Results: Mutant BRAF or NRAS ctDNA was detected (>=1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval [DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79-5.47; P < 0.0001] and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80-5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83-5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88-6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%-55%) versus 65% (95% CI 56%-72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40-4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32-4.74, P = 0.005). Conclusion: ctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy. Clinical trial number: ISRCTN 81261306. PMID- 29112706 TI - NanoStringNormCNV: pre-processing of NanoString CNV data. AB - Summary: The NanoString System is a well-established technology for measuring RNA and DNA abundance. Although it can estimate copy number variation, relatively few tools support analysis of these data. To address this gap, we created NanoStringNormCNV, an R package for pre-processing and copy number variant calling from NanoString data. This package implements algorithms for pre processing, quality-control, normalization and copy number variation detection. A series of reporting and data visualization methods support exploratory analyses. To demonstrate its utility, we apply it to a new dataset of 96 genes profiled on 41 prostate tumour and 24 matched normal samples. Availability and implementation: NanoStringNormCNV is implemented in R and is freely available at http://labs.oicr.on.ca/boutros-lab/software/nanostringnormcnv. Contact: paul.boutros@oicr.on.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29112707 TI - Effect of normalization methods on the performance of supervised learning algorithms applied to HTSeq-FPKM-UQ data sets: 7SK RNA expression as a predictor of survival in patients with colon adenocarcinoma. AB - Motivation: One of the main challenges in machine learning (ML) is choosing an appropriate normalization method. Here, we examine the effect of various normalization methods on analyzing FPKM upper quartile (FPKM-UQ) RNA sequencing data sets. We collect the HTSeq-FPKM-UQ files of patients with colon adenocarcinoma from TCGA-COAD project. We compare three most common normalization methods: scaling, standardizing using z-score and vector normalization by visualizing the normalized data set and evaluating the performance of 12 supervised learning algorithms on the normalized data set. Additionally, for each of these normalization methods, we use two different normalization strategies: normalizing samples (files) or normalizing features (genes). Regardless of normalization methods, a support vector machine (SVM) model with the radial basis function kernel had the maximum accuracy (78%) in predicting the vital status of the patients. However, the fitting time of SVM depended on the normalization methods, and it reached its minimum fitting time when files were normalized to the unit length. Furthermore, among all 12 learning algorithms and 6 different normalization techniques, the Bernoulli naive Bayes model after standardizing files had the best performance in terms of maximizing the accuracy as well as minimizing the fitting time. We also investigated the effect of dimensionality reduction methods on the performance of the supervised ML algorithms. Reducing the dimension of the data set did not increase the maximum accuracy of 78%. However, it leaded to discovery of the 7SK RNA gene expression as a predictor of survival in patients with colon adenocarcinoma with accuracy of 78%. PMID- 29112708 TI - Pulmonary wedge resection for Stage I non-small-cell lung cancer: possible alternative strategy to lobectomy. PMID- 29112709 TI - Re-aligning the ASCO and ESMO clinical benefit frameworks for modern cancer therapies. PMID- 29112711 TI - Pharmacokinetics and Pharmacodynamic Target Attainment of Benzylpenicillin in an Adult Severely Ill Sub-Saharan African Patient Population. AB - Background: In intensive care (ICU) patients, systemic exposure of beta-lactam antibiotics can be altered, and positive clinical outcome is associated with increasing fT > MIC ratios. In sub-Saharan African hospitals, benzylpenicillin (PEN) is frequently used for the empiric treatment of severe pneumococcal infections. Pharmacokinetic data for non-ICU hospitalized populations are lacking. Methods: We performed a population pharmacokinetic (PPK) study in an adult Mozambican hospital population treated intravenously with PEN from October 2014 through November 2015. Four blood samples/patient were collected for total PEN (PENt) and unbound PEN (PENu) concentration measurement. We developed a PPK model through nonlinear mixed-effects analysis and performed simulations for different patient variable, dosing, and pharmacodynamic target scenarios. Results: One hundred twelve participants yielded 387 PENt and 53 PENu concentrations. The median body mass index was 18.3 (range, 10.5-31.3) kg/m2 and the median albumin concentration and creatinine clearance (CrCl) were 29 (range, 12-44) g/L and 80 (range, 3-195) mL/minute, respectively. In a 1-compartment model, CrCl was positively correlated with PENt clearance. For infections with a microorganism with a minimum inhibitory concentration (MIC) of 1 mg/L, simulations demonstrated that with 3 million IU (1.8 g) every 6 hours, 74.1% would have a PENu concentration greater than the MIC during half of the dosing interval (fT > MIC = 50%), whereas this was 24.8% for the fT > MIC = 100% target. For pathogens with an MIC of 0.06 mg/L, these percentages were 98.2% and 72.3%, respectively. Conclusions: Severely ill adult sub-Saharan African patients may be at high risk for underexposure to PENu during routine intermittent bolus dosing, especially when their renal function is intact and when infected with pathogens with intermediate susceptibility. PMID- 29112710 TI - Interventions to Reduce the Incidence of Hospital-Onset Clostridium difficile Infection: An Agent-Based Modeling Approach to Evaluate Clinical Effectiveness in Adult Acute Care Hospitals. AB - Background: Despite intensified efforts to reduce hospital-onset Clostridium difficile infection (HO-CDI), its clinical and economic impacts continue to worsen. Many institutions have adopted bundled interventions that vary considerably in composition, strength of evidence, and effectiveness. Considerable gaps remain in our knowledge of intervention effectiveness and disease transmission, which hinders HO-CDI prevention. Methods: We developed an agent-based model of C. difficile transmission in a 200-bed adult hospital using studies from the literature, supplemented with primary data collection. The model includes an environmental component and 4 distinct agent types: patients, visitors, nurses, and physicians. We used the model to evaluate the comparative clinical effectiveness of 9 single interventions and 8 multiple-intervention bundles at reducing HO-CDI and asymptomatic C. difficile colonization. Results: Daily cleaning with sporicidal disinfectant and C. difficile screening at admission were the most effective single-intervention strategies, reducing HO-CDI by 68.9% and 35.7%, respectively (both P < .001). Combining these interventions into a 2-intervention bundle reduced HO-CDI by 82.3% and asymptomatic hospital onset colonization by 90.6% (both, P < .001). Adding patient hand hygiene to healthcare worker hand hygiene reduced HO-CDI rates an additional 7.9%. Visitor hand hygiene and contact precaution interventions did not reduce HO-CDI, compared with baseline. Excluding those strategies, healthcare worker contact precautions were the least effective intervention at reducing hospital-onset colonization and infection. Conclusions: Identifying and managing the vast hospital reservoir of asymptomatic C. difficile by screening and daily cleaning with sporicidal disinfectant are high-yield strategies. These findings provide much-needed data regarding which interventions to prioritize for optimal C. difficile control. PMID- 29112712 TI - The protective role of melatonin in porcine oocyte meiotic failure caused by the exposure to benzo(a)pyrene. AB - STUDY QUESTION: Does melatonin restore the benzo(a)pyrene (BaP)-induced meiotic failure in porcine oocytes? SUMMARY ANSWER: Melatonin effectively inhibits the increased reactive oxygen species (ROS) level and apoptotic rate in BaP-exposed porcine oocytes to recover the meiotic failure. WHAT IS KNOWN ALREADY: BaP, a widespread environmental carcinogen found in particulate matter, 2.5 um or less (PM2.5), has been shown to have toxicity at the level of the reproductive systems. BaP exposure disrupts the steroid balance, alters the expression of ovarian estrogen receptor and causes premature ovarian failure through the rapid depletion of the primordial follicle pool. In addition, acute exposure to BaP has transient adverse effects on the follicle growth, ovulation and formation of corpora lutea, which results in transient infertility. STUDY DESIGN, SIZE, DURATION: Porcine oocytes were randomly assigned to control, BaP-exposed and melatonin-supplemented groups. BaP was dissolved in dimethylsulphoxide and diluted to a final concentration of 50, 100 or 250 MUM with maturation medium, respectively. Melatonin was dissolved in the absolute ethanol and diluted with maturation medium to a final concentration of 1 nM, 100 nM, 10 MUM and 1 mM, respectively. The in vitro cultured oocytes from each group after treatment were applied to the subsequent analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Acquisition of oocyte meiotic competence was assessed using immunostaining, fluorescent intensity quantification and/or immunoblotting to analyse the cytoskeleton assembly, mitochondrial integrity, cortical granule dynamics, ovastacin distribution, ROS level and apoptotic rate. Fertilization ability of oocytes was examined by sperm binding assay and IVF. MAIN RESULTS AND THE ROLE OF CHANCE: BaP exposure resulted in the oocyte meiotic failure (P = 0.001) via impairing the meiotic apparatus, showing a prominently defective spindle assembly (P = 0.003), actin dynamics (P < 0.001) and mitochondrion integrity (P < 0.001). In addition, BaP exposure caused the abnormal distribution of cortical granules (P < 0.001) and ovastacin (P = 0.003), which were consistent with the observation that fewer sperm bound to the zona pellucida surrounding the unfertilized BaP exposed eggs (P < 0.001), contributing to the fertilization failure (P < 0.001). Conversely, melatonin supplementation recovered, at least partially, all the meiotic defects caused by BaP exposure through inhibiting the rise in ROS level (P = 0.015) and apoptotic rate (P = 0.001). LIMITATIONS, REASONS FOR CAUTION: We investigated the negative impact of BaP on the oocyte meiotic maturation in vitro, but not in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Our findings not only deeply clarify the potential mechanisms of BaP-induced oocyte meiotic failure, but also extend the understanding about how environmental pollutants influence the reproductive systems in humans. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Natural Science Foundation of China (31571545) and the Natural Science Foundation of Jiangsu Province (BK20150677). The authors have no conflict of interest to disclose. PMID- 29112713 TI - ST product characteristics and relationships with perceptions and behaviors among rural adolescent males: a qualitative study. AB - Although smoking declines in the United States, the prevalence of male adolescent smokeless tobacco (ST; moist snuff and chewing tobacco) use remains unchanged. ST product characteristics, such as flavoring, packaging, and branding, could influence adolescents' ST initiation and continued use. This qualitative study examines the potential role of product characteristics in shaping ST-related perceptions and behaviors among rural adolescent males. Semi-structured individual interviews were conducted at three California rural high schools. ST users were asked about their experiences and perceptions related to product characteristics. Interviews were transcribed, coded, and analyzed using a general inductive approach. Participants associated flavored ST with appealing non tobacco products, such as chewing gum and alcohol. Availability of different varieties and flavors stimulated interest and curiosity in sampling or switching between ST products. Time-limited promotional flavors and packaging also enhanced product appeal. Adolescent ST users preferred certain brands based on perceived brand features and perceived nicotine content, associating higher-strength brands as better suited for experienced ST users. Brand preferences frequently reflected perceived ST brand popularity within peer groups. Based on these observations, potential ST regulation and health education campaigns to address misconceptions about ST characteristics could influence adolescents' ST-related perceptions and reduce ST use among this vulnerable population. PMID- 29112714 TI - The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export. AB - mRNA splicing and export plays a key role in the regulation of gene expression, with recent evidence suggesting an additional layer of regulation of gene expression and cellular function through the selective splicing and export of genes within specific pathways. Here we describe a role for the RNA processing factors THRAP3 and BCLAF1 in the regulation of the cellular DNA damage response (DDR) pathway, a key pathway involved in the maintenance of genomic stability and the prevention of oncogenic transformation. We show that loss of THRAP3 and/or BCLAF1 leads to sensitivity to DNA damaging agents, defective DNA repair and genomic instability. Additionally, we demonstrate that this phenotype can be at least partially explained by the role of THRAP3 and BCLAF1 in the selective mRNA splicing and export of transcripts encoding key DDR proteins, including the ATM kinase. Moreover, we show that cancer associated mutations within THRAP3 result in deregulated processing of THRAP3/BCLAF1-regulated transcripts and consequently defective DNA repair. Taken together, these results suggest that THRAP3 and BCLAF1 mutant tumors may be promising targets for DNA damaging chemotherapy. PMID- 29112715 TI - RefSeq: an update on prokaryotic genome annotation and curation. AB - The Reference Sequence (RefSeq) project at the National Center for Biotechnology Information (NCBI) provides annotation for over 95 000 prokaryotic genomes that meet standards for sequence quality, completeness, and freedom from contamination. Genomes are annotated by a single Prokaryotic Genome Annotation Pipeline (PGAP) to provide users with a resource that is as consistent and accurate as possible. Notable recent changes include the development of a hierarchical evidence scheme, a new focus on curating annotation evidence sources, the addition and curation of protein profile hidden Markov models (HMMs), release of an updated pipeline (PGAP-4), and comprehensive re-annotation of RefSeq prokaryotic genomes. Antimicrobial resistance proteins have been reannotated comprehensively, improved structural annotation of insertion sequence transposases and selenoproteins is provided, curated complex domain architectures have given upgraded names to millions of multidomain proteins, and we introduce a new kind of annotation rule-BlastRules. Continual curation of supporting evidence, and propagation of improved names onto RefSeq proteins ensures that the functional annotation of genomes is kept current. An increasing share of our annotation now derives from HMMs and other sets of annotation rules that are portable by nature, and available for download and for reuse by other investigators. RefSeq is found at https://www.ncbi.nlm.nih.gov/refseq/. PMID- 29112716 TI - Gene3D: Extensive prediction of globular domains in proteins. AB - Gene3D (http://gene3d.biochem.ucl.ac.uk) is a database of globular domain annotations for millions of available protein sequences. Gene3D has previously featured in the Database issue of NAR and here we report a significant update to the Gene3D database. The current release, Gene3D v16, has significantly expanded its domain coverage over the previous version and now contains over 95 million domain assignments. We also report a new method for dealing with complex domain architectures that exist in Gene3D, arising from discontinuous domains. Amongst other updates, we have added visualization tools for exploring domain annotations in the context of other sequence features and in gene families. We also provide web-pages to visualize other domain families that co-occur with a given query domain family. PMID- 29112717 TI - Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs. PMID- 29112718 TI - Rfam 13.0: shifting to a genome-centric resource for non-coding RNA families. AB - The Rfam database is a collection of RNA families in which each family is represented by a multiple sequence alignment, a consensus secondary structure, and a covariance model. In this paper we introduce Rfam release 13.0, which switches to a new genome-centric approach that annotates a non-redundant set of reference genomes with RNA families. We describe new web interface features including faceted text search and R-scape secondary structure visualizations. We discuss a new literature curation workflow and a pipeline for building families based on RNAcentral. There are 236 new families in release 13.0, bringing the total number of families to 2687. The Rfam website is http://rfam.org. PMID- 29112720 TI - fusionDB: assessing microbial diversity and environmental preferences via functional similarity networks. AB - Microbial functional diversification is driven by environmental factors, i.e. microorganisms inhabiting the same environmental niche tend to be more functionally similar than those from different environments. In some cases, even closely phylogenetically related microbes differ more across environments than across taxa. While microbial similarities are often reported in terms of taxonomic relationships, no existing databases directly link microbial functions to the environment. We previously developed a method for comparing microbial functional similarities on the basis of proteins translated from their sequenced genomes. Here, we describe fusionDB, a novel database that uses our functional data to represent 1374 taxonomically distinct bacteria annotated with available metadata: habitat/niche, preferred temperature, and oxygen use. Each microbe is encoded as a set of functions represented by its proteome and individual microbes are connected via common functions. Users can search fusionDB via combinations of organism names and metadata. Moreover, the web interface allows mapping new microbial genomes to the functional spectrum of reference bacteria, rendering interactive similarity networks that highlight shared functionality. fusionDB provides a fast means of comparing microbes, identifying potential horizontal gene transfer events, and highlighting key environment-specific functionality. PMID- 29112721 TI - Tailored communications for obesity prevention in pediatric primary care: a feasibility study. AB - Recommendations for the prevention of childhood obesity encourage providers to counsel parents and their children on healthy diet and activity behaviors. This study evaluated the feasibility of a theory-based, tailored communication intervention for obesity prevention (Team Up for Health) delivered during a well child visit. A two-armed randomized controlled trial was used. Parents of children aged 4-10 years were recruited from a list of patients due for a well child visit at a pediatric primary care clinic. Parents were randomized to either the 'immediate' condition (parent and pediatrician received the tailored report at the well-child visit) or the 'delayed' condition (parent received the report at the end of the study). Self-report measures assessed physical activity, fruits, vegetables, television time, sugary drinks, and 100% fruit juice. Parents completed assessments at baseline, <48 h and 4-week follow-up. Providers were interviewed at the end of the study. Independent t-tests were used to examine between group differences. Seven areas of feasibility were evaluated: Recruitment, randomization, measurement, retention, acceptability, implementation and demand. Results showed high rates of measurement (85%) and acceptability (89%) and implementation (80%) of the intervention. In conclusion, Team Up for Health was feasible; however, a larger study is needed to evaluate its efficacy. PMID- 29112722 TI - On the Relative Role of Different Age Groups During Epidemics Associated With Respiratory Syncytial Virus. AB - Background: While circulation of respiratory syncytial virus (RSV) results in high rates of hospitalization, particularly among young children and elderly individuals, little is known about the role of different age groups in propagating annual RSV epidemics. Methods: We evaluate the roles played by individuals in different age groups during RSV epidemics in the United States between 2001 and 2012, using the previously defined relative risk (RR) statistic estimated from the hospitalization data from the Healthcare Cost and Utilization Project. Transmission modeling was used to examine the robustness of our inference method. Results: Children aged 3-4 years and 5-6 years each had the highest RR estimate for 5 of 11 seasons included in this study, with RSV hospitalization rates in infants being generally higher during seasons when children aged 5-6 years had the highest RR estimate. Children aged 2 years had the highest RR estimate during one season. RR estimates in infants and individuals aged >=11 years were mostly lower than in children aged 1-10 years. Highest RR values aligned with groups for which vaccination had the largest impact on epidemic dynamics in most model simulations. Conclusions: Our estimates suggest the prominent relative roles of children aged <=10 years (particularly among those aged 3-6 years) in propagating RSV epidemics. These results, combined with further modeling work, should help inform RSV vaccination policies. PMID- 29112719 TI - A lesion model of envy and Schadenfreude: legal, deservingness and moral dimensions as revealed by neurodegeneration. AB - The study of moral emotions (i.e. Schadenfreude and envy) is critical to understand the ecological complexity of everyday interactions between cognitive, affective, and social cognition processes. Most previous studies in this area have used correlational imaging techniques and framed Schadenfreude and envy as unified and monolithic emotional domains. Here, we profit from a relevant neurodegeneration model to disentangle the brain regions engaged in three dimensions of Schadenfreude and envy: deservingness, morality, and legality. We tested a group of patients with behavioural variant frontotemporal dementia (bvFTD), patients with Alzheimer's disease, as a contrastive neurodegeneration model, and healthy controls on a novel task highlighting each of these dimensions in scenarios eliciting Schadenfreude and envy. Compared with the Alzheimer's disease and control groups, patients with bvFTD obtained significantly higher scores on all dimensions for both emotions. Correlational analyses revealed an association between envy and Schadenfreude scores and greater deficits in social cognition, inhibitory control, and behaviour disturbances in bvFTD patients. Brain anatomy findings (restricted to bvFTD and controls) confirmed the partially dissociable nature of the moral emotions' experiences and highlighted the importance of socio-moral brain areas in processing those emotions. In all subjects, an association emerged between Schadenfreude and the ventral striatum, and between envy and the anterior cingulate cortex. In addition, the results supported an association between scores for moral and legal transgression and the morphology of areas implicated in emotional appraisal, including the amygdala and the parahippocampus. By contrast, bvFTD patients exhibited a negative association between increased Schadenfreude and envy across dimensions and critical regions supporting social-value rewards and social-moral processes (dorsolateral prefrontal cortex, angular gyrus and precuneus). Together, this study provides lesion-based evidence for the multidimensional nature of the emotional experiences of envy and Schadenfreude. Our results offer new insights into the mechanisms subsuming complex emotions and moral cognition in neurodegeneration. Moreover, this study presents the exacerbation of envy and Schadenfreude as a new potential hallmark of bvFTD that could impact in diagnosis and progression. PMID- 29112723 TI - In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. AB - Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology and its protein interactome, as well as the effects of CHCHD10 depletion or expression of disease-associated mutations in wild-type cells. We find that CHCHD10 associates with membranes in the mitochondrial intermembrane space, where it interacts with a closely related protein, CHCHD2. Furthermore, both CHCHD10 and CHCHD2 interact with p32/GC1QR, a protein with various intra and extra-mitochondrial functions. CHCHD10 and CHCHD2 have short half-lives, suggesting regulatory rather than structural functions. Cell lines with CHCHD10 knockdown do not display bioenergetic defects, but, unexpectedly, accumulate excessive intramitochondrial iron. In mice, CHCHD10 is expressed in many tissues, most abundantly in heart, skeletal muscle, liver, and in specific CNS regions, notably the dopaminergic neurons of the substantia nigra and spinal cord neurons, which is consistent with the pathology associated with CHCHD10 mutations. Homozygote CHCHD10 knockout mice are viable, have no gross phenotypes, no bioenergetic defects or ultrastructural mitochondrial abnormalities in brain, heart or skeletal muscle, indicating that functional redundancy or compensatory mechanisms for CHCHD10 loss occur in vivo. Instead, cells expressing S59L or R15L mutant versions of CHCHD10, but not WT, have impaired mitochondrial energy metabolism. Taken together, the evidence obtained from our in vitro and in vivo studies suggest that CHCHD10 mutants cause disease through a gain of toxic function mechanism, rather than a loss of function. PMID- 29112725 TI - Peptide transporter YjiY influences the expression of the virulence gene mgtC to regulate biofilm formation in Salmonella. AB - Formation of a biofilm is one of the coping strategies of Salmonella against antimicrobial environmental stresses including nutrient starvation. However, the channeling of the starvation cue towards biofilm formation is not well understood. Our study shows that a carbon starvation gene, yjiY, coding for a peptide transporter, influences the expression of a virulence-associated gene mgtC in Salmonella to regulate biofilm formation. We demonstrate here that the mutant strain DeltayjiY is unable to form a biofilm due to the increased expression of mgtC. The upregulation of mgtC in the DeltayjiY strain correlates with the downregulation of the biofilm master regulator gene, csgD, and reduced levels of ATP. Our work further indicates that a yjiY-encoded peptide transporter may regulate the expression of mgtC by transporting proline peptides. PMID- 29112724 TI - Severe Influenza Is Characterized by Prolonged Immune Activation: Results From the SHIVERS Cohort Study. AB - Background: The immunologic factors underlying severe influenza are poorly understood. To address this, we compared the immune responses of influenza confirmed hospitalized individuals with severe acute respiratory illness (SARI) to those of nonhospitalized individuals with influenza-like illness (ILI). Methods: Peripheral blood lymphocytes were collected from 27 patients with ILI and 27 with SARI, at time of enrollment and then 2 weeks later. Innate and adaptive cellular immune responses were assessed by flow cytometry, and serum cytokine levels were assessed by a bead-based assay. Results: During the acute phase, SARI was associated with significantly reduced numbers of circulating myeloid dendritic cells, CD192+ monocytes, and influenza virus-specific CD8+ and CD4+ T cells as compared to ILI. By the convalescent phase, however, most SARI cases displayed continued immune activation characterized by increased numbers of CD16+ monocytes and proliferating, and influenza virus-specific, CD8+ T cells as compared to ILI cases. SARI was also associated with reduced amounts of cytokines that regulate T-cell responses (ie, interleukin 4, interleukin 13, interleukin 12, interleukin 10, and tumor necrosis factor beta) and hematopoiesis (interleukin 3 and granulocyte-macrophage colony-stimulating factor) but increased amounts of a proinflammatory cytokine (tumor necrosis factor alpha), chemotactic cytokines (MDC, MCP-1, GRO, and fractalkine), and growth-promoting cytokines (PDGFBB/AA, VEGF, and EGF) as compared to ILI. Conclusions: Severe influenza cases showed a delay in the peripheral immune activation that likely led prolonged inflammation, compared with mild influenza cases. PMID- 29112726 TI - Reconstructed genomes of novel Dehalococcoides mccartyi strains from 1,2,3,4 tetrachlorodibenzo-p-dioxin-dechlorinating enrichment cultures reveal divergent reductive dehalogenase gene profiles. AB - Polychlorinated dibenzo-p-dioxin (PCDD)-contaminated sites are widespread and associated with a variety of anthropogenic sources. PCDDs and other organohalide pollutants can serve as terminal electron acceptors for anaerobic respiration by specialized bacteria containing reductive dehalogenases (RdhA). These microorganisms, therefore, play an important role in the bioremediation of PCDD contaminated sites. Two anaerobic enrichment cultures established using sediments collected from the PCDD-polluted Hackensack (USA) and Kymijoki (Finland) rivers showed robust reductive dechlorination of 1,2,3,4-tetrachlorodibenzo-p-dioxin (1,2,3,4-TeCDD). Here, we report on the draft genome reconstructions of the two predominant Dehalococcoides strains from the metagenomes of these dehalogenating enrichment cultures. Furthermore, we gathered a complete list of RdhA in the two predominant Dehalococcoides strains, and determined which are likely to be responsible for the reductive dechlorination of PCDDs. The divergent rdhA gene profiles of the Dehalococcoides strains likely reflect their exposure to different organohalide compounds in their original habitats. Both draft genomes contained a full length rdhA gene with high sequence similarity to a rdhA gene, i.e. cbrA, found in Dehalococcoides mccartyi CBDB1 known to reductively dechlorinate 1,2,3,4-tetrachlorobenzene. This gene homologue might also be responsible for reductive dechlorination of 1,2,3,4-TeCDD in the enrichments and could be used as a biomarker to determine the potential for the bioremediation of PCDD-contaminated sediments. PMID- 29112727 TI - Application of CRISPR Interference for Metabolic Engineering of the Heterocyst Forming Multicellular Cyanobacterium Anabaena sp. PCC 7120. AB - Anabaena sp. PCC 7120 (A. 7120) is a heterocyst-forming multicellular cyanobacterium that performs nitrogen fixation. This cyanobacterium has been extensively studied as a model for multicellularity in prokaryotic cells. We have been interested in photosynthetic production of nitrogenous compounds using A. 7120. However, the lack of efficient gene repression tools has limited its usefulness. We originally developed an artificial endogenous gene repression method in this cyanobacterium using small antisense RNA. However, the narrow dynamic range of repression of this method needs to be improved. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) interference (CRISPRi) technology was developed and was successfully applied in some unicellular cyanobacteria. The technology requires expression of nuclease deficient CRISPR-associated protein 9 (dCas9) and a single guide RNA (sgRNA) that is complementary to a target sequence, to repress expression of the target gene. In this study, we employed CRISPRi technology for photosynthetic production of ammonium through repression of glnA, the only gene encoding glutamine synthetase that is essential for nitrogen assimilation in A. 7120. By strictly regulating dCas9 expression using the TetR gene induction system, we succeeded in fine tuning the GlnA protein in addition to the level of glnA transcripts. Expression of sgRNA by the heterocyst-specific nifB promoter led to efficient repression of GlnA in heterocysts, as well as in vegetative cells. Finally, we showed that ammonium is excreted into the medium only when inducers of expression of dCas9 were added. In conclusion, CRISPRi enables temporal control of desired products and will be a useful tool for basic science. PMID- 29112728 TI - Onion Thrips (Thysanoptera: Thripidae) Feeding Promotes Infection By Pantoea ananatis in Onion. AB - Onion thrips, Thrips tabaci Lindeman, is a primary insect pest of onions (Allium cepa) worldwide. Onion thrips cause feeding damage by destroying epidermal tissue. They are also vectors of Pantoea ananatis (Serrano) Mergaert, the bacteria that causes center rot. Onions with center rot develop white streaks with water-soaked margins along the onion leaves, which turn necrotic and lead to bulb rot during storage. The role of thrips feeding on the establishment and progression of bacterial infection in onions has not been investigated. Onions infested with thrips and inoculated with P. ananatis had more necrotic tissue and symptoms were more severe with increasing thrips density. We conducted a fluorescence microscopy study that examined how P. ananatis (expressing a fluorescence protein gene) colonized a control group of onions without thrips in comparison to a test group of onions with thrips. We found that P. ananatis colonized some onions in the control group because of naturally existing wounds in the epidermal tissue but more colonization was found in the thrips infested group because of the increased presence of entry points caused by thrips feeding. Overall, our results demonstrate that wounds caused by thrips feeding facilitate center rot development by providing entry sites for the bacteria into leaf tissue. PMID- 29112729 TI - Single freeze per vein strategy with the second-generation cryoballoon for atrial fibrillation: a propensity score-matched study between 180- and 240-s application time in a large cohort of patients. AB - Aims: The single-freeze strategy using the second-generation cryoballoon (CB-A, Arctic Front Advance, Medtronic, Minneapolis, MN, USA) has been reported to be as effective as the recommended double-freeze approach in several single-centre studies. In this retrospective, international, multicentre study, we compare the 3-min single-freeze strategy with the 4-min single-freeze strategy. Methods and results: Four hundred and thirty-two patients having undergone pulmonary vein isolation (PVI) by means of CB-A using a single-freeze strategy were considered for this analysis. A cohort of patients who were treated with a 3-min strategy (Group 1) was compared with a propensity score-matched cohort of patients who underwent a 4-min strategy (Group 2). Pulmonary vein isolation was successfully achieved in all the veins using the 28-mm CB-A. The procedural and fluoroscopy times were lower in Group 1 (67.8 +/- 17 vs. 73.8 +/- 26.3, P < 0.05; 14.9 +/- 7.8 vs. 24.2 +/- 10.6 min, P < 0.05). The most frequent complication was PNP, with no difference between the two groups (P = 0.67). After a mean follow-up of 13 +/- 8 months, taking into consideration a blanking period of 3 months, 85.6% of patients in Group 1 and 87% of patients in Group 2 were free from arrhythmia recurrence at final follow-up (P = 0.67). Conclusion: There is no difference in acute success, rate of complications, and freedom from atrial fibrillation recurrences during the follow-up between 3-min and 4-min per vein freeze strategies. The procedural and fluoroscopy times were significantly shorter in 3 min per vein strategy. PMID- 29112730 TI - Premature mortality due to breast cancer among Canadian women: an analysis of a 30-year period from 1980 through 2010. AB - Background: Breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer deaths for women. In the present study, we examined the trend of premature mortality due to breast cancer among Canadian women from 1980 through 2010 and proposed a new measure of lifespan shortening. Methods: Mortality data for female breast cancer was obtained from the World Health Organization mortality database. Years of life lost (YLL) was estimated using Canadian life tables. Average lifespan shortened (ALSS) that is calculated and expressed by a ratio of YLL relative to expected lifespan. Results: Over this study period, age-standardized rates of breast cancer mortality adjusted to World Standard Population decreased by 40% from 23.2 to 14.2 per 100 000 women. The adjusted YLL rates fell from 5.3 years per 1000 women to 3.3 years. On average women with breast cancer died 20.8 years prior to expected death in 1980 and 18.3 years early in 2010. A novel measure of lifespan shortening, the ALSS decreased from one-fourth of the lifespan in 1980 to one-fifth in 2010. Conclusions: Our study reports that among Canadian women with breast cancer, a smaller proportion of life was lost on average at the end of the study period. The 'life lost' measures presented in this study would be useful tools to monitor the pattern of premature mortality for chronic conditions. These measures gauge the effectiveness of the health system with respect to early detection and treatment. PMID- 29112731 TI - In a Resource-Limited Setting, Is Oral Ibuprofen Effective for Closure of a Patent Ductus Arteriosus in a Preterm Neonate? PMID- 29112733 TI - Goserelin does not preserve ovarian function against chemotherapy-induced damage. PMID- 29112732 TI - Identifying structural variants using linked-read sequencing data. AB - Motivation: Structural variation, including large deletions, duplications, inversions, translocations, and other rearrangements, is common in human and cancer genomes. A number of methods have been developed to identify structural variants from Illumina short-read sequencing data. However, reliable identification of structural variants remains challenging because many variants have breakpoints in repetitive regions of the genome and thus are difficult to identify with short reads. The recently developed linked-read sequencing technology from 10X Genomics combines a novel barcoding strategy with Illumina sequencing. This technology labels all reads that originate from a small number (~5-10) DNA molecules ~50Kbp in length with the same molecular barcode. These barcoded reads contain long-range sequence information that is advantageous for identification of structural variants. Results: We present Novel Adjacency Identification with Barcoded Reads (NAIBR), an algorithm to identify structural variants in linked-read sequencing data. NAIBR predicts novel adjacencies in a individual genome resulting from structural variants using a probabilistic model that combines multiple signals in barcoded reads. We show that NAIBR outperforms several existing methods for structural variant identification - including two recent methods that also analyze linked-reads - on simulated sequencing data and 10X whole-genome sequencing data from the NA12878 human genome and the HCC1954 breast cancer cell line. Several of the novel somatic structural variants identified in HCC1954 overlap known cancer genes. Availability: Software is available at compbio.cs.brown.edu/software. Contact: braphael@princeton.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29112734 TI - Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses. AB - Background: Memantine has shown clinical utility in preventing radiation-induced cognitive impairment, but the mechanisms underlying its protective effects remain unknown. We hypothesized that abnormal glutamate signaling causes radiation induced abnormalities in neuronal structure and that memantine prevents synaptic toxicity. Methods: Hippocampal cultures expressing enhanced green fluorescent protein were irradiated or sham-treated and their dendritic spine morphology assessed at acute (minutes) and later (days) times using high-resolution confocal microscopy. Excitatory synapses, defined by co-localization of the pre- and postsynaptic markers vesicular glutamate transporter 1 and postsynaptic density protein 95, were also analyzed. Neurons were pretreated with vehicle, the N methyl-d-aspartate-type glutamate receptor antagonist memantine, or the glutamate scavenger glutamate pyruvate transaminase to assess glutamate signaling. For animal studies, Thy-1-YFP mice were treated with whole-brain radiotherapy or sham with or without memantine. Results: Unlike previously reported long-term losses of dendritic spines, we found that the acute response to radiation is an initial increase in spines and excitatory synapses followed by a decrease in spine/synapse density with altered spine dynamics. Memantine pre-administration prevented this radiation-induced synaptic remodeling. Conclusion: These results demonstrate that radiation causes rapid, dynamic changes in synaptic structural plasticity, implicate abnormal glutamate signaling in cognitive dysfunction following brain irradiation, and describe a protective mechanism of memantine. PMID- 29112735 TI - Whole-tree distribution and temporal variation of non-structural carbohydrates in broadleaf evergreen trees. AB - Non-structural carbohydrates (NSCs) form a fundamental yet poorly quantified carbon pool in trees. Studies of NSC seasonality in forest trees have seldom measured whole-tree NSC stocks and allocation among organs, and are not representative of all tree functional types. Non-structural carbohydrate research has primarily focussed on broadleaf deciduous and coniferous evergreen trees with distinct growing seasons, while broadleaf evergreen trees remain under-studied despite their different growth phenology. We measured whole-tree NSC allocation and temporal variation in Eucalyptus obliqua L'Her., a broadleaf evergreen tree species typically occurring in mixed-age temperate forests, which has year-round growth and the capacity to resprout after fire. Our overarching objective was to improve the empirical basis for understanding the functional importance of NSC allocation and stock changes at the tree- and organ-level in this tree functional type. Starch was the principal storage carbohydrate and was primarily stored in the stem and roots of young (14-year-old) trees rather than the lignotuber, which did not appear to be a specialized starch storage organ. Whole-tree NSC stocks were depleted during spring and summer due to significant decreases in starch mass in the roots and stem, seemingly to support root and crown growth but potentially exacerbated by water stress in summer. Seasonality of stem NSCs differed between young and mature trees, and was not synchronized with stem basal area increments in mature trees. Our results suggest that the relative magnitude of seasonal NSC stock changes could vary with tree growth stage, and that the main drivers of NSC fluctuations in broadleaf evergreen trees in temperate biomes could be periodic disturbances such as summer drought and fire, rather than growth phenology. These results have implications for understanding post-fire tree recovery via resprouting, and for incorporating NSC pools into carbon models of mixed-age forests. PMID- 29112737 TI - Estimation of Burden of Influenza among under-Five Children in India: A Meta Analysis. AB - Background: We estimated the burden of influenza-related acute respiratory tract infection (ARI) among under-fives in India through meta-analysis. Methodology: We estimated pooled incidence and proportional positivity of laboratory-diagnosed influenza among under-fives using data from observational studies published from 1 January 1961 to 31 December 2016. Death due to influenza was estimated using a multiplier model. Results: Influenza-associated ARI incidence was estimated as 132 per 1000 child-years (115-149). The patients positive for influenza among ARI in outpatients and inpatients were estimated to be 11.2% (8.8-13.6) and 7.1% (5.5 8.8), respectively. We estimated total influenza cases during 2016 as 16 009 207 (13 942 916-18 082 769) in India. Influenza accounted for 10 913 476 (9 504 666 12 362 310) outpatient visits and 109 431 (83 882-134 980) hospitalizations. A total of 27 825 (21 382-34 408) influenza-associated under-five deaths were estimated in India in 2016. Conclusion: Influenza imposes a substantial burden among under-fives in India. Public health approach for its prevention and control needs to be explored. PMID- 29112736 TI - VarCards: an integrated genetic and clinical database for coding variants in the human genome. AB - A growing number of genomic tools and databases were developed to facilitate the interpretation of genomic variants, particularly in coding regions. However, these tools are separately available in different online websites or databases, making it challenging for general clinicians, geneticists and biologists to obtain the first-hand information regarding some particular variants and genes of interest. Starting with coding regions and splice sties, we artificially generated all possible single nucleotide variants (n = 110 154 363) and cataloged all reported insertion and deletions (n = 1 223 370). We then annotated these variants with respect to functional consequences from more than 60 genomic data sources to develop a database, named VarCards (http://varcards.biols.ac.cn/), by which users can conveniently search, browse and annotate the variant- and gene level implications of given variants, including the following information: (i) functional effects; (ii) functional consequences through different in silico algorithms; (iii) allele frequencies in different populations; (iv) disease- and phenotype-related knowledge; (v) general meaningful gene-level information; and (vi) drug-gene interactions. As a case study, we successfully employed VarCards in interpretation of de novo mutations in autism spectrum disorders. In conclusion, VarCards provides an intuitive interface of necessary information for researchers to prioritize candidate variations and genes. PMID- 29112738 TI - Hematologic and cytogenetic biomarkers of leukemia risk from formaldehyde exposure. PMID- 29112739 TI - Organophosphate Flame-Retardants Alter Adult Mouse Homeostasis and Gene Expression in a Sex-Dependent Manner Potentially Through Interactions With ERalpha. AB - Flame retardants (FRs) such as polybrominated diphenyl ethers and organophosphate FR (OPFR) persist in the environment and interact with multiple nuclear receptors involved in homeostasis, including estrogen receptors (ERs). However, little is known about the effects of FR, especially OPFR, on mammalian neuroendocrine functions. Therefore, we investigated if exposure to FR alters hypothalamic gene expression and whole-animal physiology in adult wild-type (WT) and ERalpha KO mice. Intact WT and KO males and ovariectomized WT and KO females were orally dosed daily with vehicle (oil), 17alpha-ethynylestradiol (2.5 MUg/kg), 2,2', 4,4 tetrabromodiphenyl ether (BDE-47, 1 or 10 mg/kg), or an OPFR mixture {1 or 10 mg/kg of tris(1, 3-dichloro-2-propyl)phosphate, triphenyl phosphate, and tricresyl phosphate each} for 28 days. Body weight, food intake, body composition, glucose and insulin tolerance, plasma hormone levels, and hypothalamic and liver gene expression were measured. Expression of neuropeptides, receptors, and cation channels was differentially altered between WT males and females. OPFR suppressed body weight and energy intake in males. FR increased fasting glucose levels in males, and BDE-47 augmented glucose clearance in females. Liver gene expression indicated FXR activation by BDE-47 and PXR and CAR activation by OPFR. In males, OPFR increased ghrelin but decreased leptin and insulin independent of body weight. The loss of ERalpha reduced the effects of both FR on hypothalamic and liver gene expression and plasma hormone levels. The physiological implications are that males are more sensitive than ovariectomized females to OPFR exposure and that these effects are mediated, in part, by ERalpha. PMID- 29112741 TI - Atherosclerosis as a potential pitfall in the diagnosis of giant cell arteritis. AB - Objectives: To explore whether the increase in the intima-media thickness (IMT) in arteriosclerotic disease correlates with the increase in the IMT in temporal arteries (TAs) and if that could mimic the US GCA halo sign. Methods: Consecutive patients ?50 years old with high vascular risk and without signs or symptoms of GCA were included. The carotid US IMT measurements were obtained using a standardized software radiofrequency-tracking technology. Colour Doppler US and grey-scale measurements of the IMT in the branches of both TAs were performed by a second sonographer using a 22 MHz probe. Results: Forty patients were studied (28 men) with a mean age of 70.6 years. The carotid IMT exhibited significant correlation with the TA IMT. A carotid IMT >0.9 mm was associated with a temporal IMT >0.3 mm. Only one patient had an IMT >0.34 mm in two branches. Conclusions: Atherosclerotic disease with a carotid IMT >0.9 mm increases the TA IMT and might mimic the halo sign. As atherosclerosis is common in this age group, we propose a cut-off of TA IMT >0.34 mm in at least two branches to minimize false positives in a GCA diagnosis. PMID- 29112742 TI - Getting to Zero New Tuberculosis Infections: Insights From the National Institutes of Health/US Centers for Disease Control and Prevention/Bill & Melinda Gates Foundation Workshop on Research Needs for Halting Tuberculosis Transmission. PMID- 29112740 TI - Evaluation of damage in giant cell arteritis. AB - Objectives: To evaluate damage and variables associated with damage in GCA. Methods: Patients with GCA enrolled in a prospective, multicentre, longitudinal study were included. Per-protocol assessments were made with the Vasculitis Damage Index and the Large-Vessel Vasculitis Index of Damage. Results: The study included 204 patients: 156 women (76%), mean age at diagnosis 71.3 years (s.d. 8.3), mean follow-up of 3.5 years (s.d. 1.9). One or more damage item was present in 54% at baseline and 79% at the last follow-up on the Vasculitis Damage Index, and 60% at baseline and 82% at the last follow-up on the Large-Vessel Vasculitis Index of Damage. The most frequently observed damage items were large-artery complications (29% cohort) and ocular (22%). Among 117 patients with new damage, most new items were ocular (63 patients), cardiac/vascular (48) and musculoskeletal (34). Of these, treatment-associated items were frequently observed, including cataracts (46 patients), osteoporosis (22) and weight gain (22). Disease-associated new damage included ischaemic optic neuropathy (3 patients), limb claudication (13), arterial occlusions (10) and damage requiring vascular intervention (10). In univariate analysis, the risk of damage increased 22% for every additional year of disease duration [odds ratio (OR) 1.22 (95% CI 1.04, 1.45)]. In 94 patients enrolled within ?90 days of diagnosis of GCA, the risk of new damage at the last follow-up decreased 30% for each additional relapse [OR 0.70 (95% CI 0.51, 0.97)]. Conclusions: Large-artery complications and ocular manifestations are the most commonly occurring items of damage in GCA. Most new damage is associated with treatment. These findings emphasize the cumulative burden of disease in GCA. PMID- 29112743 TI - Designing and Evaluating Interventions to Halt the Transmission of Tuberculosis. AB - To reduce the incidence of tuberculosis, it is insufficient to simply understand the dynamics of tuberculosis transmission. Rather, we must design and rigorously evaluate interventions to halt transmission, prioritizing those interventions most likely to achieve population-level impact. Synergy in reducing tuberculosis transmission may be attainable by combining interventions that shrink the reservoir of latent Mycobacterium tuberculosis infection (preventive therapy), shorten the time between disease onset and treatment initiation (case finding and diagnosis), and prevent transmission in key settings, such as the built environment (infection control). In evaluating efficacy and estimating population level impact, cluster-randomized trials and mechanistic models play particularly prominent roles. Historical and contemporary evidence suggests that effective public health interventions can halt tuberculosis transmission, but an evidence based approach based on knowledge of local epidemiology is necessary for success. We provide a roadmap for designing, evaluating, and modeling interventions to interrupt the process of transmission that fuels a diverse array of tuberculosis epidemics worldwide. PMID- 29112744 TI - Research Roadmap for Tuberculosis Transmission Science: Where Do We Go From Here and How Will We Know When We're There? AB - High rates of tuberculosis transmission are driving the ongoing global tuberculosis epidemic, and there is a pressing need for research focused on understanding and, ultimately, halting transmission. The ongoing tuberculosis human immunodeficiency virus (HIV) coepidemic and rising rates of drug-resistant tuberculosis in parts of the world add further urgency to this work. Success in this research will require a concerted, multidisciplinary effort on the part of tuberculosis scientists, clinicians, programs, and funders and must span the research spectrum from biomedical sciences to the social sciences, public health, epidemiology, cost-effectiveness analyses, and operations research. Heterogeneity of tuberculosis disease, both among individual patients and among communities, poses a substantial challenge to efforts to interrupt transmission. As such, it is likely that effective interventions to stop transmission will require a combination of approaches that will vary across different epidemiologic settings. This research roadmap summarizes key gaps in our current understanding of transmission, as laid out in the preceding articles in this series. We also hope that it will be a call to action for the global tuberculosis community to make a sustained commitment to tuberculosis transmission science. Halting transmission today is an essential step on the path to end tuberculosis tomorrow. PMID- 29112745 TI - Drivers of Tuberculosis Transmission. AB - Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis infection; incident disease can result from either a recent (ie, weeks to months) or a remote (ie, several years to decades) infection event. Although we cannot identify with certainty the timing and location of tuberculosis transmission for individuals, approaches for estimating the individual probability of recent transmission and for estimating the fraction of tuberculosis cases due to recent transmission in populations have been developed. Data used to estimate the probable burden of recent transmission include tuberculosis case notifications in young children and trends in tuberculin skin test and interferon gamma-release assays. More recently, M. tuberculosis whole genome sequencing has been used to estimate population levels of recent transmission, identify the distribution of specific strains within communities, and decipher chains of transmission among culture-positive tuberculosis cases. The factors that drive the transmission of tuberculosis in communities depend on the burden of prevalent tuberculosis; the ways in which individuals live, work, and interact (eg, congregate settings); and the capacity of healthcare and public health systems to identify and effectively treat individuals with infectious forms of tuberculosis. Here we provide an overview of these factors, describe tools for measurement of ongoing transmission, and highlight knowledge gaps that must be addressed. PMID- 29112746 TI - Tuberculosis Infectiousness and Host Susceptibility. AB - The transmission of tuberculosis is complex. Necessary factors include a source case with respiratory disease that has developed sufficiently for Mycobacterium tuberculosis to be present in the airways. Viable bacilli must then be released as an aerosol via the respiratory tract of the source case. This is presumed to occur predominantly by coughing but may also happen by other means. Airborne bacilli must be capable of surviving in the external environment before inhalation into a new potential host-steps influenced by ambient conditions and crowding and by M. tuberculosis itself. Innate and adaptive host defenses will then influence whether new infection results; a process that is difficult to study owing to a paucity of animal models and an inability to measure infection directly. This review offers an overview of these steps and highlights the many gaps in knowledge that remain. PMID- 29112747 TI - What We Know About Tuberculosis Transmission: An Overview. AB - Tuberculosis remains a global health problem with an enormous burden of disease, estimated at 10.4 million new cases in 2015. To stop the tuberculosis epidemic, it is critical that we interrupt tuberculosis transmission. Further, the interventions required to interrupt tuberculosis transmission must be targeted to high-risk groups and settings. A simple cascade for tuberculosis transmission has been proposed in which (1) a source case of tuberculosis (2) generates infectious particles (3) that survive in the air and (4) are inhaled by a susceptible individual (5) who may become infected and (6) then has the potential to develop tuberculosis. Interventions that target these events will interrupt tuberculosis transmission and accelerate the decline in tuberculosis incidence and mortality. The purpose of this article is to provide a high-level overview of what is known about tuberculosis transmission, using the tuberculosis transmission cascade as a framework, and to set the scene for the articles in this series, which address specific aspects of tuberculosis transmission. PMID- 29112748 TI - Intermittent lighting improves resilience of broilers during the peak phase of sub-clinical necrotic enteritis infection. AB - Necrotic enteritis, either in its clinical or sub-clinical form is known to cause massive economic losses in the broiler chicken industry. Currently, the use of in feed antibiotics as growth promoters is discouraged. Therefore, mechanisms to control NE through diet include reduction of digesta viscosity, promotion of lower pH in the gastrointestinal tract (GIT) through acidification of feed, production of short-chain fatty acids and overall stimulation of beneficial bacteria growth. Intermittent lighting programs increase feed retention in the crop and reduce pH in the foregut compartments in comparison with standard commercial lighting programs and therefore may be a valuable, yet underexploited, barrier to prevent the invasion of the GIT by pathogens. In this experiment, a 2 * 2 factorial arrangement of treatments was employed in a randomized design to investigate whether intermittent lighting would increase broiler resilience to sub-clinical necrotic enteritis. A total of 390 Cobb 500 same-hatch, mixed sex, day-old chicks were assigned to 30 floor pens to test the effect of 2 factors, namely, lighting schedule (continuous, 18L:6D vs. intermittent, 1L:3D:1L:3D:1L:3D:1L:3D:2L:6D) and a sub-clinical necrotic enteritis challenge (challenge vs. no challenge). Challenged birds had lower feed intake and weight gain and poorer feed conversion ratio (FCR; P < 0.005). Intermittent lighting reduced feed intake (P < 0.05) without compromising final body weight gain. During the peak phase of Clostridium perfringens Type A infection, the negative impact of the disease challenge on feed efficiency was lower for animals under intermittent lighting than for those under a 18L:6D schedule (2-way interaction, P < 0.005). Thus, in flocks that are raised under antibiotic-free production systems, intermittent lighting programs applied at least during the critical period for necrotic enteritis risks, i.e., d 18-24, may be a practical, non medicated way to increase resilience of broilers to this disease. PMID- 29112749 TI - PGG.Population: a database for understanding the genomic diversity and genetic ancestry of human populations. AB - There are a growing number of studies focusing on delineating genetic variations that are associated with complex human traits and diseases due to recent advances in next-generation sequencing technologies. However, identifying and prioritizing disease-associated causal variants relies on understanding the distribution of genetic variations within and among populations. The PGG.Population database documents 7122 genomes representing 356 global populations from 107 countries and provides essential information for researchers to understand human genomic diversity and genetic ancestry. These data and information can facilitate the design of research studies and the interpretation of results of both evolutionary and medical studies involving human populations. The database is carefully maintained and constantly updated when new data are available. We included miscellaneous functions and a user-friendly graphical interface for visualization of genomic diversity, population relationships (genetic affinity), ancestral makeup, footprints of natural selection, and population history etc. Moreover, PGG.Population provides a useful feature for users to analyze data and visualize results in a dynamic style via online illustration. The long-term ambition of the PGG.Population, together with the joint efforts from other researchers who contribute their data to our database, is to create a comprehensive depository of geographic and ethnic variation of human genome, as well as a platform bringing influence on future practitioners of medicine and clinical investigators. PGG.Population is available at https://www.pggpopulation.org. PMID- 29112750 TI - High stocking density alters bone-related calcium and phosphorus metabolism by changing intestinal absorption in broiler chickens. AB - Live performance, bone health and metabolic responses to the interaction among stocking density and dietary concentrations of total calcium (TCa) and non phytate phosphorus (NPP) were determined on 2,232 Ross 308 female broilers over a 3-wk experimental period. From 22 d of age, birds were randomly divided into 48 groups and provided with different corn-soybean meal-based diets varying in TCa (0.70% or 0.90%) and NPP (0.28% or 0.36%) content at 1 of 2 stocking densities [28.6 (LSD, 13 broilers/m2) and 39.6 (HSD, 18 broilers/m2) kg of predicted final BW/m2 floor space], according to a 2 * 2 * 2 factorial design with 6 replications in each treatment. Regardless of NPP supplementation, a high-TCa (0.90%) diet aggravated the impact of HSD on growth (BW gain and feed efficiency, P < 0.001) and motility (gait score, P < 0.001). This might be explained by deteriorating tibia quality (relative weight, mineral composition and biomechanical property; P < 0.01), due to the involvement of decreasing duodenal absorption (type IIb sodium-phosphate co-transporter mRNA, P < 0.001) in reduced phosphorus retention (P < 0.001). On the contrary, increasing dietary NPP (0.36%), particularly if high in TCa (0.90%), boosted TCa retention (P < 0.05) by improving absorption (calcium-binding protein D28k transcription, P < 0.05) for LSD chickens, hence enhancing bone development (relative tibia weight and tibia breaking strength, P < 0.05) and leg health (walking ability, P < 0.05). Together, HSD and LSD birds show an impaired TCa tolerance and a higher TCa+NPP threshold, respectively, to allow the optimization of bone quality via altered intestinal absorption. PMID- 29112751 TI - Multimorbidity and co-morbidity in atrial fibrillation and effects on survival: findings from UK Biobank cohort. AB - Aims: To examine the number and type of co-morbid long-term health conditions (LTCs) and their associations with all-cause mortality in an atrial fibrillation (AF) population. Methods and results: Community cohort participants (UK Biobank n = 502 637) aged 37-73 years were recruited between 2006 and 2010. Self-reported LTCs (n = 42) identified in people with AF at baseline. All-cause mortality was available for a median follow-up of 7 years (interquartile range 76-93 months). Hazard ratios (HRs) examined associations between number and type of co-morbid LTC and all-cause mortality, adjusting for age, sex, socio-economic status, smoking, and anticoagulation status. Three thousand six hundred fifty-one participants (0.7% of the study population) reported AF; mean age was 61.9 years. The all-cause mortality rate was 6.7% (248 participants) at 7 years. Atrial fibrillation participants with >=4 co-morbidities had a six-fold higher risk of mortality compared to participants without any LTC. Co-morbid heart failure was associated with higher risk of mortality [HR 2.96, 95% confidence interval (CI) 1.83-4.80], whereas the presence of co-morbid stroke did not have a significant association. Among non-cardiometabolic conditions, presence of chronic obstructive pulmonary disease (HR 3.31, 95% CI 2.14-5.11) and osteoporosis (HR 3.13, 95% CI 1.63-6.01) was associated with a higher risk of mortality. Conclusion: Survival in middle-aged to older individuals with self-reported AF is strongly correlated with level of multimorbidity. This group should be targeted for interventions to optimize their management, which in turn may potentially reduce the impact of their co-morbidities on survival. Future AF clinical guidelines need to place greater emphasis on the issue of co-morbidity. PMID- 29112752 TI - Reply to Sawabata. PMID- 29112753 TI - Genome-nutrition divergence: evolving understanding of the malnutrition spectrum. AB - Humans adapted over a period of 2.3 million years to a diet high in quality and diversity. Genome-nutrition divergence describes the misalignment between modern global diets and the genome formed through evolution. A survey of hominin diets over time shows that humans have thrived on a broad range of foods. Earlier diets were highly diverse and nutrient dense, in contrast to modern food systems in which monotonous diets of staple cereals and ultraprocessed foods play a more prominent role. Applying the lens of genome-nutrition divergence to malnutrition reveals shared risk factors for undernutrition and overnutrition at nutrient, food, and environmental levels. Mechanisms for food system shifts, such as crop neutral agricultural policy, agroecology, and social policy, are explored as a means to realign modern diets with the nutritional patterns to which humans may be better adapted to thrive. PMID- 29112754 TI - The association between the nature of the goal committed to and quitting smoking. AB - Commitments to goals are theorized to affect behavior change outcomes, but competing theories argue for hard to achieve goals and strategic sub-goals as optimum strategies for success. This study aimed to explore whether the nature of the goal affects smoking cessation outcomes. A total of 1043 participants in a randomized controlled trial of variations to an automated computer generated cessation advice program, who had made a quit attempt were asked at 1 month post quit about the initial goal they had set at the time of making the attempt. They were also followed up at 6 months post quit. Compared with those reporting 'seeing how it will go', those who reported the goal of 'taking it a cigarette at a time' were less likely to be quit at 1 month, while those with the most ambitious goal, to 'never smoke again', were more likely to be quit, and were more likely to maintain abstinence for 6 months. Indeed, 'taking it a cigarette at a time' was associated with greater short-term relapse. There is likely to be a benefit in encouraging smokers to set ambitious long-term goals rather than setting intermediate or non-specific goals. PMID- 29112756 TI - Global Health Journal Club-Opening Editorial Applying Evidence-based Medicine in Resource-Limited Nations. PMID- 29112757 TI - Apparent metabolizable energy of by-products from the soybean oil industry for broilers: acidulated soapstock, glycerin, lecithin, and their mixture. AB - A study was conducted to determine the AMEn contents of fat by-products from the soybean oil industry for broiler chickens. A total of 390 slow-feathering Cobb * Cobb 500 male broilers were randomly distributed into 13 treatments having 6 replicates of 5 birds each. Birds were fed a common starter diet from placement to 21 d. Experimental corn-soy diets were composed of four fat sources, added at 3 increasing levels each, and were fed from 21 to 28 d. Fat sources utilized were acidulated soybean soapstock (ASS), glycerol (GLY), lecithin (LEC), and a mixture (MIX) containing 85% ASS, 10% GLY and 5% LEC. A 4 * 3 + 1 factorial arrangement was used with 4 by-products (ASS, GLY, LEC, or MIX), 3 inclusion levels and 1 basal diet. Each of the four fat by-product sources was included in the diets as follow: 2% of by-products (98% basal + 2% by-product), 4% (96% basal + 4% by product), or 6% (94% basal + 6% by-product). Birds were submitted to 94, 96, 98, and 100% of ad libitum feed intake; therefore, the differences in AMEn consumption were only due to the added by-product. Total excreta were collected twice daily for 72 h to determine apparent metabolizable energy contents starting at 25 d. The AMEn intake was regressed against feed intake and the slope was used to estimate AMEn values for each fat source. Linear regression equations (P < 0.05) estimated for each by-product were as follow: 7,153X - 451.9 for ASS; 3,916X - 68.2 for GLY; 7,051X - 448.3 for LEC, and 8,515X - 622.3 for MIX. Values of AMEn were 7,153, 3,916, 7,051, and 8,515 kcal/kg DM for ASS, GLY, LEC, and MIX, respectively. The present study generated AMEn for fat by-products data that can be used in poultry feed formulation. It also provides indications that, by adding the 3 by-products in the proportions present in the MIX, considerable economic advantage can be attained. PMID- 29112755 TI - Insilico direct folding of thrombin-binding aptamer G-quadruplex at all-atom level. AB - The reversible folding of the thrombin-binding DNA aptamer G-quadruplexes (GQs) (TBA-15) starting from fully unfolded states was demonstrated using a prolonged time scale (10-12 MUs) parallel tempering metadynamics (PTMetaD) simulation method in conjunction with a modified version of the AMBER bsc1 force field. For unbiased descriptions of the folding free energy landscape of TBA-15, this force field was minimally modified. From this direct folding simulation using the modified bsc1 force field, reasonably converged free energy landscapes were obtained in K+-rich aqueous solution (150 mM), providing detailed atomistic pictures of GQ folding mechanisms for TBA-15. This study found that the TBA folding occurred via multiple folding pathways with two major free energy barriers of 13 and 15 kcal/mol in the presence of several intermediate states of G-triplex variants. The early formation of these intermediates was associated with a single K+ ion capturing. Interestingly, these intermediate states appear to undergo facile transitions among themselves through relatively small energy barriers. PMID- 29112758 TI - The role of arginine metabolic pathway during embryogenesis and germination in maritime pine (Pinus pinaster Ait.). AB - Vegetative propagation through somatic embryogenesis is critical in conifer biotechnology towards multivarietal forestry that uses elite varieties to cope with environmental and socio-economic issues. An important and still sub-optimal process during in vitro maturation of somatic embryos (SE) is the biosynthesis and deposition of storage proteins, which are rich in amino acids with high nitrogen (N) content, such as arginine. Mobilization of these N-rich proteins is essential for the germination and production of vigorous somatic seedlings. Somatic embryos accumulate lower levels of N reserves than zygotic embryos (ZE) at a similar stage of development. To understand the molecular basis for this difference, the arginine metabolic pathway has been characterized in maritime pine (Pinus pinaster Ait.). The genes involved in arginine metabolism have been identified and GFP-fusion constructs were used to locate the enzymes in different cellular compartments and clarify their metabolic roles during embryogenesis and germination. Analysis of gene expression during somatic embryo maturation revealed high levels of transcripts for genes involved in the biosynthesis and metabolic utilization of arginine. By contrast, enhanced expression levels were only observed during the last stages of maturation and germination of ZE, consistent with the adequate accumulation and mobilization of protein reserves. These results suggest that arginine metabolism is unbalanced in SE (simultaneous biosynthesis and degradation of arginine) and could explain the lower accumulation of storage proteins observed during the late stages of somatic embryogenesis. PMID- 29112759 TI - Epigenetics and complex diseases, a new era in the assessment of exposure and risk? PMID- 29112760 TI - Improvement of Bolton broth by supplementation with tazobactam for the isolation of Campylobacter from chicken rinses. AB - Overgrowth of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) on Campylobacter media prevents the latter's selective isolation, thereby making the improvement of Campylobacter-selective media necessary. We evaluated tazobactam (an ESBL inhibitor) to supplement Bolton enrichment broth (Tz-Bolton broth) for the selective isolation of Campylobacter in chicken carcass rinses. First, using 20 strains of ESBL-producing E. coli and 13 Campylobacter strains, we found 4 MUg/mL of tazobactam to be optimal for inhibiting the ESBL producing E. coli while allowing the growth of all tested Campylobacter strains. Next, 80 whole chicken carcasses were rinsed with buffered peptone water (BPW), and 25 mL of BPW rinse was mixed with 2 * blood-free Bolton broth (25 mL) with or without tazobactam followed by incubation at 42 degrees C for 48 h under microaerobic conditions. A loopful of the incubated broth was inoculated on modified charcoal-cefoperazone-deoxycholate agar (mCCDA) and microaerobically incubated at 42 degrees C for 48 h. The tazobactam supplemented Bolton broth showed a higher Campylobacter isolation rate (38.8%, p < 0.05) than normal Bolton broth (15%). Moreover, the number of mCCDA plates with non-Campylobacter was much lower (p < 0.05) after enrichment in Tz-Bolton broth (0%) than in the normal Bolton broth (80%), suggesting that selectivity of the modified broth was superior to normal Bolton broth. PMID- 29112762 TI - Alteration of Bile Acid and Cholesterol Biosynthesis and Transport by Perfluorononanoic Acid (PFNA) in Mice. AB - Perfluorochemicals produce hepatotoxic effects via activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and constitutive androstane receptor (CAR) nuclear receptors in animals. Bile formation is one major liver function. But it remains unknown whether perfluorochemicals alter metabolism of bile acids (BAs) in liver. The present study was designed to determine the impact of perfluorononanoic acid (PFNA) on BA and cholesterol homeostasis in mice. A single dose of PFNA (0.1 mmol/kg) was intraperitoneally administered to adult male wild-type (WT), PPARalpha-null, and CAR-null mice. PFNA caused cholestasis in the WT mice, indicated by increased serum alanine aminotransferase, hyperbilirubinemia, elevated BA concentrations in mouse serum, and appearance of bile plugs in mouse liver. In addition, PFNA decreased total and some individual BAs in mouse liver. PFNA increased the concentrations of total and taurine conjugated, as well as some individual BAs in the serum of WT and CAR-null mice but not in PPARalpha-null mice, indicating a PPARalpha-dependent mechanism. PFNA decreased mRNA expression of most BA-related transporters (sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide [Oatp]1a1, Oatp1b2, and bile salt export pump) and BA biosynthetic enzymes (Cyp7a1, 7b1, 8b1, and 27a1) in mouse liver, but increased mRNA expression of some efflux transporters (breast cancer resistance protein, multidrug resistance transporter 2, multidrug resistance-associated protein [Mrp] 2, Mrp3, and Mrp4), primarily via a PPARalpha-dependent mechanism. Moreover, PFNA increased free and total cholesterol in mouse liver but not in mouse serum. Furthermore, PFNA increased mRNA expression of sterol transporters, namely Abca1, g1, g5/g8, and steroidogenic acute regulatory protein via PPARalpha. In conclusion, PFNA produced cholestasis in mouse liver, and the activation of PPARalpha plays a central role in regulating BA and cholesterol metabolism and transport in mouse serum and liver. PMID- 29112761 TI - Draft genome of the Marco Polo Sheep (Ovis ammon polii). AB - Background: The Marco Polo Sheep (Ovis ammon polii), a subspecies of argali (Ovis ammon) that is distributed mainly in the Pamir Mountains, provides a mammalian model to study high altitude adaptation mechanisms. Due to over-hunting and subsistence poaching, as well as competition with livestock and habitat loss, O. ammon has been categorized as an endangered species on several lists. It can have fertile offspring with sheep. Hence, a high-quality reference genome of the Marco Polo Sheep will be very helpful in conservation genetics and even in exploiting useful genes in sheep breeding. Findings: A total of 1022.43 Gb of raw reads resulting from whole-genome sequencing of a Marco Polo Sheep were generated using an Illumina HiSeq2000 platform. The final genome assembly (2.71 Gb) has an N50 contig size of 30.7 Kb and a scaffold N50 of 5.49 Mb. The repeat sequences identified account for 46.72% of the genome, and 20 336 protein-coding genes were predicted from the masked genome. Phylogenetic analysis indicated a close relationship between Marco Polo Sheep and the domesticated sheep, and the time of their divergence was approximately 2.36 million years ago. We identified 271 expanded gene families and 168 putative positively selected genes in the Marco Polo Sheep lineage. Conclusions: We provide the first genome sequence and gene annotation for the Marco Polo Sheep. The availability of these resources will be of value in the future conservation of this endangered large mammal, for research into high altitude adaptation mechanisms, for reconstructing the evolutionary history of the Caprinae, and for the future conservation of the Marco Polo Sheep. PMID- 29112763 TI - Insight Into Reduction of Wakefulness by Suvorexant in Patients With Insomnia: Analysis of Wake Bouts. AB - Study Objectives: To examine the duration and frequency of wake bouts underlying the wakefulness-after-sleep-onset (WASO) reduction with suvorexant. Methods: We analyzed polysomnogram recordings from clinical trials involving 1518 insomnia patients receiving suvorexant (40/30, 20/15 mg) or placebo to determine the following: (1) the number of, and time spent in, long or short wake bouts and (2) the association between sleep quality and bout characteristics. We also compared wake and sleep bout characteristics of suvorexant in insomnia patients versus zolpidem in healthy subjects undergoing experimentally induced transient insomnia. Results: Relative to placebo, suvorexant decreased the number and time spent in long wake bouts (>2 minutes) and increased the number and time spent in short wake bouts (<=2 minutes). The time spent in long wake bouts during Night-1 decreased by 32-54 minutes, whereas the time spent in short wake bouts increased by 2-6 minutes. On average, a patient returned to sleep from his or her longest awakening more than twice as fast on suvorexant than placebo. The reduced time spent in long wake bouts resulted in odds ratios of self-reported good or excellent sleep quality ranging from 1.59 to 2.19 versus placebo. The small increase in time spent in short wake bouts had no effect on odds ratios. Findings were more pronounced for the higher (40/30 mg) doses of suvorexant. The wake and sleep bout characteristics of suvorexant differed from zolpidem which equally decreased the number of wake and sleep bouts of all durations during the early part of the night. Conclusion: Suvorexant reduces WASO by reducing long wake bouts. This reduction has a positive effect on sleep quality. Clinical Trials: Trial registration at www.clinicaltrials.gov NCT01097616; NCT01097629. PMID- 29112764 TI - Sleep Apnea and Kidney Function Trajectory: Results From a 20-Year Longitudinal Study of Healthy Middle-Aged Adults. AB - Study Objectives: To determine whether sleep apnea, defined by polysomnography, accelerates kidney function decline in generally healthy adults not selected for sleep apnea or kidney disease. Methods: We performed a retrospective cohort study in 855 participants from the Wisconsin Sleep Cohort Study, a large 20-year population-based study of sleep apnea, who had at least one polysomnogram and serial measurements of serum creatinine over time. Sleep apnea was defined as an apnea-hypopnea index >= 15 or positive airway pressure (PAP) use at baseline. We compared the slope of estimated glomerular filtration rate (eGFR) change and odds of rapid eGFR decline (>2.2 mL/minute/1.73 m2/year) for those with and without sleep apnea. Results: The mean follow-up was 13.9 +/- 3.4 years. The cohort was 50.4 +/- 7.6 years, 55% male, and 97% white. The mean eGFR was 89.3 +/- 13.8 mL/minute/1.73 m2 and 11% had sleep apnea. Overall, the mean eGFR change was 0.88 +/- 1.12 mL/minute/1.73 m2/year. Compared with those without sleep apnea, participants with sleep apnea had a 0.2 mL/minute/1.73 m2/year slower eGFR decline though this was not statistically significant (95% CI [-0.06-0.45], p = .134). When we excluded those on PAP therapy (n = 17), eGFR decline was even slower among those with sleep apnea (0.36 mL/minute/1.73 m2/year slower, 95% CI [0.08-063], p = .012). Those with sleep apnea had lower odds of rapid eGFR decline but this was not statistically significant, even after excluding PAP users. Conclusion: Among healthy middle-aged adults, the presence of sleep apnea at baseline did not accelerate kidney function decline compared with those without sleep apnea over time. PMID- 29112765 TI - Epidemiology and risk factors for hepatitis C virus genotypes in a high prevalence region in Italy. AB - Hepatitis C virus (HCV) is globally widespread. Southern Italy is a high prevalence region where the distribution of the HCV genotypes (GTs) is changing. Intravenous drug abuse is the only risk factor associated with a specific HCV GT (GT3). The aim of this study was to evaluate the distribution and the risk factors for specific HCV GTs. A total of 682 patients with measurable serum HCV RNA were enrolled between January and March 2017. We recorded clinical information and the presence of risk factors for HCV. GT1b was the prevalent genotype in our patients (59.8%). HCV GT1a and GT3 infections were more frequent among patients aged <=60 years (14.9% vs 2.2%, p<0.01 and 13.6% vs 0.8%, p<0.01, respectively). At multivariate analysis, intravenous drug abuse and age <=60 years were associated with GT1a infection (OR: 4.79; 95% CI: 2.43-9.47, p <0.001 and OR: 5.07; 95CI: 2.25-11.40, p<0.001, respectively), while age <=60 years was the only risk factor for GT3 (OR: 15.81; 95CI: 4.76-52.54, p <0.001). In the Campania region, we observed an increase in GT1a and GT3 rates compared with those observed in previous years. Age <=60 was an independent risk factor for GT1a and GT3 infection. Intravenous drug use was independently associated with GT1a infection. PMID- 29112766 TI - Persistence of ZIKV-RNA in the cellular fraction of semen is accompanied by a surrogate-marker of viral replication. Diagnostic implications for sexual transmission. AB - As asymptomatic infections represent 80% of ZIKV-infected individuals, sexual transmission is a rising concern. Recent studies highlighted a preferential association of ZIKV with the cellular fraction (CF) of different specimen types. Our aim was to evaluate the presence of ZIKV-RNA in different body fluids, focusing on semen specimens to assess the ZIKV-RNA content in either the unfractionated sample, its CF or seminal plasma (SP). In addition, to establish if the presence of ZIKV genome was associated with active virus replication, we measured the levels of negative-strand ZIKV-RNA. ZIKV total-RNA was detected in blood, urine and unfractionated semen, and neg-RNA in semen CF and SP samples longitudinally collected from two ZIKV-positive men followed at the National Institute for Infectious Diseases "L. Spallanzani", Italy. In both patients, ZIKV total-RNA was detected in CF with ct values always lower than in the corresponding unfractionated samples, and was observed even in the CF from negative unfractionated semen samples. In Patient 2, neg-RNA was also detected in CF, suggesting ongoing viral replication. Our results demonstrate higher clinical sensitivity of CF as compared to whole semen testing, emphasizing the need to extend ZIKV-RNA testing to CF, to rule out virus presence and the possible risk of sexual transmission. PMID- 29112767 TI - Fast and reliable diagnosis of XDR Acinetobacter baumannii meningitis by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Bacterial meningitis is a medical emergency needing quick and timely diagnosis. Even though meningitis caused by Acinetobacter baumannii is relatively rare, it is associated with high mortality rates especially in neurosurgery patients and represents a serious therapeutic problem due to the limited penetration of effective antibiotics into the cerebrospinal fluid. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) has been effectively used as a rapid method for microbial identification. In this case report we identified A. baumanni by MALDI-TOF technique directly from the CSF drawn from the external ventricular drainage of a patient with severe confusional state and signs of meningism. Simultaneously the antibiotic susceptibility test was performed by automated method from the pellet of the broth-enriched sample. The MALDI-TOF technique allowed microbial identification in less than 30 minutes, and the susceptibility test result was available in eight hours, thus allowing a fast diagnosis ready for prompt and targeted antimicrobial therapy. PMID- 29112768 TI - An autochthonous sexually transmitted Zika virus infection in Italy 2016. AB - We describe two cases of Zika virus infection involving an Italian patient returning from the Dominican Republic and his wife, who remained in Italy and had not travelled to Zika virus endemic areas in the previous months. The infection was transmitted through unprotected sexual intercourse after the man's return to Italy. PMID- 29112769 TI - Dynamic changes of the composition of plasma HDL particles in patients with cardiac disease: Spotlight on sphingosine-1-phosphate/serum amyloid A ratio. AB - Several epidemiological studies reported an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease (ASCVD). However, therapeutic interventions targeted at raising HDL-cholesterol failed to improve cardiovascular outcomes, suggesting that HDL components distinct from cholesterol may account for the anti atherothrombotic effects attributed to this lipoprotein. Sphingosine-1-phosphate (S1P) and the acute phase protein serum amyloid A (SAA) have been identified as integral constituents of HDL particles. Evidence suggests that S1P and SAA levels within HDL particles may be affected by inflammation and oxidative stress, which are coexisting processes underlying ASCVD. Because SAA, an inflammation-related marker, and S1P, an anti-atherothrombotic marker, have relatively clear opposite characteristics among the HDL-associated proteins, the approach of assessing the two markers simultaneously may provide new insights in clinical practice (S1P/SAA Index). This review focuses on evidence in support of the concept that the S1P/SAA Index may affect the HDL atheroprotective properties and may, therefore represent a potential target for therapeutic interventions. PMID- 29112770 TI - Interactive effects of morphine and dopamine receptor agonists on spatial recognition memory in mice. AB - Both opiates and dopamine play important roles in learning and memory. Although synergistic action between these two neurotransmitters has been found, their functional roles remain unclear. Here, low dose morphine (2.5 mg/kg) and low dose dopamine receptor agonists (apomorphine 0.05 mg/kg; SKF38393 0.01 mg/kg; bromocriptine 0.05 mg/kg), which have no effects on spatial recognition memory, were injected intraperitoneally into mice 30 minutes before a memory test in a two-trial recognition Y-maze. The Y-maze is based on the innate tendency of rodents to explore novel environments and is therefore suitable for exploring the effects of morphine on learning and memory. Our results showed that both D1-like and D2-like dopamine receptor agonists dose-dependently impaired the retrieval of spatial recognition memory in the Y-maze, and co-administration of memory ineffective doses of apomorphine (0.05 mg/kg), SKF38393 (0.01 mg/kg), or bromocriptine (0.05 mg/kg) and of morphine (2.5 mg/kg) resulted in impaired spatial recognition memory retrieval in mice. These findings suggest the existence of interactions between morphine and dopamine receptor agonists in memory processing and that activation of the dopamine system might contribute to morphine-induced impairment of memory, which could provide insight into human addiction. PMID- 29112771 TI - Role of mitochondria and mitochondria-targeted agents in non-alcoholic fatty liver disease. AB - Mitochondria play a pivotal role in the fatty acid oxidation and have been found to be affected early during the macrovesicular fat accumulation in the hepatocytes. The fatty infiltration is the primary cause of oxidative stress and inflammation in the non-alcoholic fatty liver disease (NAFLD), which can lead to the peroxidation of phospholipids, such as cardiolipin. Oxidative stress-induced damage to mitochondrial DNA can result in the impairment of oxidative phosphorylation and further increases the generation of reactive oxygen species. The mitochondrial damage may eventually lead to apoptotic death of hepatocytes. The apoptosis along with the generated cytokines from the stellate and Kupffer cells further augment the fibrotic changes to advance the disease. Hence, alleviation of the mitochondrial impairment, particularly in the early stages of NAFLD, may prevent the progression of the disease. Among the various experimentally studied mitochondrial-targeted agents, triphenylphosphonium cation ligated ubiquinone Q10 and vitamin E, Szeto-Scheller peptides, and superoxide dismutase mimetic-salen manganese complexes (EUK-8 and EUK-134) have been found to be most promising. In addition to these mitochondrial-targeted agents, a novel area of therapy called mitotherapy have also emerged. However, clinical studies conducted so far are still fragmentary to validate their efficacy. This review article discusses the mitochondria-targeted molecules and their potential role in the treatment of NAFLD. PMID- 29112772 TI - Regulation of thyroid sodium-iodide symporter in different stages of goiter: Possible involvement of reactive oxygen species. AB - Na+ /I- symporter (NIS) transports iodide into thyrocytes, a fundamental step for thyroid hormone biosynthesis. Our aim was to evaluate NIS regulation in different status of goitrogenesis and its underlying mechanisms. Wistar rats were treated with methimazole (MMI) for 5 and 21 days, to achieve different status of goiter. We then evaluated the effect of MMI removal for 1 day (R1d), after 5 (R1d-5d) or 21 (R1d-21d) days of MMI treatment. MMI increased thyroid weight, iodide uptake and in vitro TPO activity in a time-dependent way. Although MMI removal evoked a rapid normalization of TPO activity in R1d-5d, it was still high in R1d-21d. On the other hand, iodide uptake was rapidly down-regulated in R1d-21d, but not in R1d-5d, suggesting that the increased TPO activity in R1d-21d led to increased intraglandular organified iodine (I-X), which is known to inhibit iodide uptake. Since TGFbeta has been shown to mediate some effects of I-X, we evaluated TGFbeta and TGFbeta receptor mRNA levels, which were increased in R1d-21d. Moreover, it has been demonstrated that TGFbeta stimulates NOX4. Accordingly, our data revealed increased NOX4 expression and H2 O2 generation in R1d-21d. Finally, we evaluated the effect of H2 O2 on NIS function and mRNA levels in PCCL3 thyroid cell line, which were reduced. Thus, the present study suggests that there is a relationship between the size of the goiter and NIS regulation and that the mechanism might involve I-X, TGFbeta, NOX4 and increased ROS production. PMID- 29112773 TI - The Profession of Couple, Marital, and Family Therapy (CMFT): Defining Ourselves and Moving Forward. AB - The field of Couple, Marital, and Family Therapy (CMFT) has evolved and strengthened, but we still have work to do when it comes to identity, comprehensive scholarly resources, empirical support, and name brand recognition. We explore the reasons for these challenges and propose ways to address them: embracing the interdisciplinary nature of the field, consistently organizing treatment effectiveness by problem rather than by intervention model, continuing innovation in theory development, and utilizing more diverse and meaningful research methods. This approach provides a more accurate representation of the scope of practice of CMFTs, the range of mental and physical health problems we address, and the depth and extent of the existing research on the effectiveness of relational therapies. PMID- 29112775 TI - Remotely sensed canopy height reveals three pantropical ecosystem states: reply. PMID- 29112774 TI - Neuroactive Steroid (3alpha,5alpha)3-hydroxypregnan-20-one (3alpha,5alpha-THP) and Pro-inflammatory Cytokine MCP-1 Levels in Hippocampus CA1 are Correlated with Voluntary Ethanol Consumption in Cynomolgus Monkey. AB - BACKGROUND: Neuroactive steroids such as (3alpha,5alpha)3-hydroxypregnan-20-one (3alpha,5alpha-THP, allopregnanolone) are potent neuromodulators that enhance GABAergic neurotransmission and produce inhibitory neurobehavioral and anti inflammatory effects. Chronic ethanol (EtOH) consumption reduces 3alpha,5alpha THP levels in human plasma, but has brain region- and species-specific effects on central nervous system levels of 3alpha,5alpha-THP. We explored the relationship between 3alpha,5alpha-THP levels in the hippocampus and voluntary EtOH consumption in the cynomolgus monkey following daily self-administration of EtOH for 12 months and further examined the relationship with hypothalamic-pituitary adrenal (HPA) axis function prior to EtOH exposure. We simultaneously explored hippocampus levels of monocyte chemoattractant protein 1 (MCP-1), a pro inflammatory cytokine that plays an important role in the neuroimmune response to EtOH, following chronic self-administration. METHODS: Monkeys were subjected to scheduled induction of water and EtOH consumption (0 to 1.5 g/kg) over 4 months, followed by free access to EtOH or water for 22 h/d over 12 months. Immunohistochemistry was performed using an anti-3alpha,5alpha-THP or anti-MCP-1 antibody. Prolonged voluntary drinking resulted in individual differences in EtOH consumption that ranged from 1.2 to 4.2 g/kg/d over 12 months. RESULTS: Prolonged EtOH consumption increased cellular 3alpha,5alpha-THP immunoreactivity by 12 +/- 2% (p < 0.05) and reduced MCP-1 immunoreactivity by 23 +/- 9% (p < 0.05) in the hippocampus CA1. In both cases, the effect of EtOH was most pronounced in heavy drinkers that consumed >=3 g/kg for >=20% of days. 3alpha,5alpha-THP immunoreactivity was positively correlated with average daily EtOH intake (Spearman r = 0.76, p < 0.05) and dexamethasone inhibition of HPA axis function (Spearman r = 0.9, p < 0.05). In contrast, MCP-1 immunoreactivity was negatively correlated with average daily EtOH intake (Spearman r = -0.78, p < 0.05) and dexamethasone suppression of HPA axis function (Spearman r = -0.76, p < 0.05). Finally, 3alpha,5alpha-THP and MCP-1 immunoreactivity were inversely correlated with each other (Spearman r = -0.68, p < 0.05). CONCLUSIONS: These data indicate that voluntary, long-term EtOH consumption results in higher levels of 3alpha,5alpha-THP, while decreasing levels of MCP-1 in the CA1 hippocampus, and that both changes may be linked to HPA axis function and the magnitude of voluntary EtOH consumption. PMID- 29112776 TI - A meta-ethnography of the facilitators and barriers to successful implementation of patient complaints processes in health-care settings. AB - OBJECTIVE: To synthesize experiences of the patient complaints process for patients and health-care professionals to identify facilitators and barriers in the successful implementation of patient complaints processes. This will assist the development of cultural change programmes, enabling complaints managers to incorporate stakeholder perspectives into future care. DESIGN: Systematic literature search and meta-ethnography, comprising reciprocal syntheses of "patient" and "professional" qualitative studies, combined to form a "line-of argument" embodying both perspectives. DATA SOURCES: MEDLINE, CINAHL and PsycINFO (database inception to April 2015) were searched to identify international literature in primary and secondary health-care settings, involving qualitative data collection and analysis. Further studies were identified from hand-searching relevant journals, contacting authors, article reference lists and Google Scholar. RESULTS: A total of 13 papers, reporting 9 studies from the United Kingdom, Sweden, Australia and New Zealand, were included in the synthesis. Facilitators and barriers to the successful implementation of patient complaints processes were identified across the perspectives of both patients and health care professionals. Patients sought to individualize the complaints process by targeting specific professionals who engaged in practices that undermined the identity of patients. In contrast, professionals obscured their own individualism through maintaining a collective identity and withholding personal judgement in relation to patient complaints. CONCLUSIONS: Complainants recognized health-care professionals as bearers of individual accountability for unsatisfactory care, in opposition to the stance of collective responsibility endorsed by professionals. Implementation of patient complaints processes must reconcile the need for individualized resolution, whilst striving to improve the future provision of health care through a collaborative approach between patients and professionals. PMID- 29112777 TI - Elucidating the Distribution and Speciation of Boron and Cesium in BCsX Zeolite Catalysts for Styrene Production. AB - An improved understanding of the nature and distribution of boron and cesium species in BCsX zeolites is a prerequisite to guide future developments in the environmentally attractive, yet challenging, production of styrene through the side-chain alkylation of toluene with methanol. Herein, standard characterization and catalytic tests are complemented by integrated visualization through time-of flight secondary-ion mass spectrometry and energy-dispersive X-ray spectroscopy and detailed assessment by 133 Cs and 11 B NMR spectroscopy, to correlate the properties and performance during successive ion-exchange and impregnation steps in the preparation of both powders and millimeter-sized granules. The results highlight a significant impact of catalyst scaleup on the effective introduction of boron species, which originates chemical heterogeneity that is linked to selectivity losses. They also illustrate the complexity of elucidating the role of this promotor, which interacts with cesium cations and exhibits different coordination states and chemical environments, depending on the pretreatment. PMID- 29112778 TI - Clinical application of hysteroscopic hydrotubation for unexplained infertility in the mare. AB - BACKGROUND: Therapeutic techniques for oviductal obstruction in the mare are limited. Nonsurgical and retrograde flushing may be an attractive alternative to current treatment methods for oviductal blockage. OBJECTIVES: To evaluate hysteroscopic selective hydrotubation as a treatment option for presumptive equine oviductal blockage. STUDY DESIGN: Retrospective case series. METHODS: A quantity of 10 mL of saline was flushed through the oviducts in 28 standing sedated mares, which had reproductive histories of unexplained subfertility, by inserting a catheter into the uterotubal junction under endoscopic guidance. All mares in the study had been mated through several cycles (2-20 oestrous cycles) by known fertile stallions prior to treatment, with no evidence of conception. The average number of cycles for each mare prior to treatment was 6.5 +/- 4.5. RESULTS: Saline was successfully infused into a total of 50 oviducts. Of 28 mares, 26 conceived after the treatment. The average number of cycles for each mare to become pregnant after treatment was 1.8 +/- 0.8. MAIN LIMITATIONS: Diagnosis of blocked oviducts was presumptive, and pretreatment infertility was used as the control. CONCLUSIONS: This study revealed that hysteroscopic hydrotubation using saline improved pregnancy rates in mares in which oviductal blockage was suspected as a cause of unexplained subfertility. PMID- 29112779 TI - A Supramolecular Capsule for Reversible Polysulfide Storage/Delivery in Lithium Sulfur Batteries. AB - Supramolecular materials, in which small organic molecules are assembled into regular structures by non-covalent interactions, attract tremendous interests because of their highly tunable functional groups and porous structure. Supramolecular adsorbents are expected to fully expose their abundant adsorptive sites in a dynamic framework. In this contribution, we introduced cucurbit[6]uril as a supramolecular capsule for reversible storage/delivery of mobile polysulfides in lithium-sulfur (Li-S) batteries to control undesirable polysulfide shuttle. The Li-S battery equipped with the supramolecular capsules retains a high Coulombic efficiency and shows a large increase in capacity from 300 to 900 mAh g-1 at a sulfur loading of 4.2 mg cm-2 . The implementation of supramolecular capsules offers insights into intricate multi-electron-conversion reactions and manifests as an effective and efficient strategy to enhance Li-S batteries and analogous applications that involve complex transport phenomena and intermediate manipulation. PMID- 29112780 TI - Associations of lifestyle factors with serum dehydroepiandrosterone sulphate and insulin-like growth factor-1 concentration in prepubertal children. AB - OBJECTIVE: Little is known about the relationships of dietary factors, physical activity and sedentary behaviour to dehydroepiandrosterone sulphate (DHEAS) and insulin-like growth factor-1 (IGF-1) concentrations among prepubertal children. Therefore, we studied the associations of these lifestyle factors with serum DHEAS and IGF-1 in children. DESIGN AND SUBJECTS: Cross-sectional analysis of a population sample of 431 prepubertal children aged 6-9 years. MEASUREMENTS: Assessment of dietary factors by food records and physical activity and sedentary behaviour by a combined heart rate and movement monitor and a questionnaire. Measurement of serum DHEAS and IGF-1. RESULTS: Consumption of low-fibre grain products (standardized regression coefficient beta = .118, P = .017) and intake of vegetable protein (beta = .100, P = .045) was positively and consumption of sugar-sweetened beverages (beta = -.117, P = .018) was inversely associated with DHEAS after adjustment for sex, age and body fat percentage. Energy intake (beta = .160, P = .001) was positively associated with IGF-1 adjusting for sex, age and body fat percentage. Vigorous physical activity was inversely associated with DHEAS after adjustment for sex and age (beta = -.120, P = .027), and total (beta = -.137, P = .007), moderate (beta = -.130, P = .012), vigorous (beta = -.136, P = .011) and moderate to vigorous physical activity (beta = -.160, P = .003) were inversely and total sedentary behaviour (beta = .151, P = .003) was positively associated with IGF-1 adjusting for sex and age. None of physical activity measures was associated with DHEAS or IGF-1 after additional adjustment for body fat percentage. CONCLUSIONS: Lifestyle factors have weak and moderate associations with biochemical markers of adrenarche in prepubertal children. These associations indicate body fat independent and dependent influences of diet and physical activity, respectively. PMID- 29112782 TI - Reporting of Infant Mortality and Birth Outcomes Prior to Viability. PMID- 29112783 TI - Toblerols: Cyclopropanol-Containing Polyketide Modulators of Antibiosis in Methylobacteria. AB - Trans-AT polyketide synthases (PKSs) are a family of biosynthetically versatile modular type I PKSs that generate bioactive polyketides of impressive structural diversity. In this study, we detected, in the genome of several bacteria a cryptic, architecturally unusual trans-AT PKS gene cluster which eluded automated PKS prediction. Genomic mining of one of these strains, the model methylotroph Methylobacterium extorquens AM1, revealed unique epoxide- and cyclopropanol containing polyketides named toblerols. Relative and absolute stereochemistry were determined by NMR experiments, chemical derivatization, and the comparison of CD data between the derivatized natural product and a synthesized model compound. Biosynthetic data suggest that the cyclopropanol moiety is generated by carbon-carbon shortening of a more extended precursor. Surprisingly, a knock-out strain impaired in polyketide production showed strong inhibitory activity against other methylobacteria in contrast to the wild-type producer. The activity was inhibited by complementation with toblerols, thus suggesting that these compounds modulate an as-yet unknown methylobacterial antibiotic. PMID- 29112781 TI - Lags in the response of mountain plant communities to climate change. AB - Rapid climatic changes and increasing human influence at high elevations around the world will have profound impacts on mountain biodiversity. However, forecasts from statistical models (e.g. species distribution models) rarely consider that plant community changes could substantially lag behind climatic changes, hindering our ability to make temporally realistic projections for the coming century. Indeed, the magnitudes of lags, and the relative importance of the different factors giving rise to them, remain poorly understood. We review evidence for three types of lag: "dispersal lags" affecting plant species' spread along elevational gradients, "establishment lags" following their arrival in recipient communities, and "extinction lags" of resident species. Variation in lags is explained by variation among species in physiological and demographic responses, by effects of altered biotic interactions, and by aspects of the physical environment. Of these, altered biotic interactions could contribute substantially to establishment and extinction lags, yet impacts of biotic interactions on range dynamics are poorly understood. We develop a mechanistic community model to illustrate how species turnover in future communities might lag behind simple expectations based on species' range shifts with unlimited dispersal. The model shows a combined contribution of altered biotic interactions and dispersal lags to plant community turnover along an elevational gradient following climate warming. Our review and simulation support the view that accounting for disequilibrium range dynamics will be essential for realistic forecasts of patterns of biodiversity under climate change, with implications for the conservation of mountain species and the ecosystem functions they provide. PMID- 29112784 TI - Clinical and genetic features of patients with facial-sparing facioscapulohumeral muscular dystrophy. AB - BACKGROUND AND PURPOSE: Facial-sparing scapular myopathy (SHD) is the most common atypical form of facioscapulohumeral muscular dystrophy (FSHD), clinically defined as without apparent facial muscle weakness on neurological examination. The clinical profiles and genetic features of SHD are limited. METHODS: A cohort of 21 Chinese patients with SHD were confirmed by molecular genetic analysis based on pulsed-field gel electrophoresis. The clinical assessments and methylation analysis were noted. RESULTS: The patients had FSHD-related EcoRI fragments with 4qA haplotype ranging from 18 kb to 33 kb (mean 26.3 +/- 4.6 kb). The mean onset age was 25.52 +/- 8.3 years. Over half of the patients had scapular winging and asymmetry weakness consistent with FSHD, without facial symptoms during their visit. Their facial electromyogram results were almost normal or mild myogenic damage, as well as the myopathology and serum creatine kinase. A conflict was unexpectedly found in intergenerational DR1 methylation analysis. CONCLUSION: Facial-sparing scapular myopathy is characterized as mild myopathic symptoms and chronic progression of weakness. The diagnosis should be accurately confirmed through FSHD-sized fragment detection and 4qA/B variant determination. Although the next generations of SHD had more severe muscular symptoms, local hypomethylation within D4Z4 was not found as a modifier for clinical heterogeneity. PMID- 29112785 TI - Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. AB - BACKGROUND AND PURPOSE: Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. METHODS: A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. RESULTS: No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. CONCLUSIONS: Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral. PMID- 29112786 TI - Circulating B-type natriuretic peptide in women with and without recent gestational diabetes: The impact of current glucose intolerance. AB - CONTEXT: Circulating B-type natriuretic peptide, as measured by the N-terminal fragment of its prohormone (NT-proBNP), is inversely associated with incident type 2 diabetes (T2DM) but positively related to future cardiovascular disease (CVD). Recognizing that gestational diabetes (GDM) identifies women at future risk for both T2DM and CVD, we sought to determine whether gestational glucose tolerance relates to NT-proBNP in the years after delivery. DESIGN/PATIENTS/MEASUREMENTS: Three hundred and forty women underwent a glucose challenge test (GCT) and an oral glucose tolerance test (OGTT) in pregnancy, yielding 4 gestational glucose tolerance groups: GDM (n = 105); gestational impaired glucose tolerance (n = 59); abnormal GCT with a normal OGTT (n = 98); and normal GCT with normal OGTT (n = 75). At 3-year postpartum, they underwent cardiometabolic characterization (including measurement of estimated glomerular filtration rate (eGFR), adiponectin and NT-proBNP) and repeated the OGTT, revealing 69 women with glucose intolerance (prediabetes/diabetes). RESULTS: At 3 year postpartum, serum NT-proBNP did not differ between the 4 original gestational glucose tolerance groups (P = .44), but instead progressively decreased across current glucose tolerance strata, from normal to prediabetes to diabetes (P = .006). Indeed, on logistic regression analysis, NT-proBNP emerged as a negative predictor of prediabetes/diabetes (OR = 0.903, 95% CI 0.825-0.988, P = .026). On multiple linear regression analyses of NT-proBNP, the significant association with current glucose intolerance was ultimately attenuated in a fully adjusted model, revealing two independent determinants of NT-proBNP: eGFR (t = 2.71, P = .007) and adiponectin (t = 2.44, P = .015). CONCLUSION: Serum NT-proBNP relates to current glucose intolerance, rather than preceding gestational dysglycaemia. Thus, the diabetic (rather than vascular) risk implications of NT proBNP predominate in young women. PMID- 29112787 TI - Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition. AB - Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics, we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS- and KRAS-mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho-CHK1, decreased CDK4 expression, and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS- and KRAS-mutant cancer cells by dabrafenib, but not vemurafenib. Combined silencing of NEK9 and CDK16 was associated with enhanced inhibition of melanoma cell proliferation. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. PMID- 29112788 TI - Nonstrangulating intestinal infarctions associated with Strongylus vulgaris: Clinical presentation and treatment outcomes of 30 horses (2008-2016). AB - BACKGROUND: Strongylus vulgaris is re-emerging in horses kept under surveillance based parasite control regimens. Information on nonstrangulating intestinal infarction associated with S. vulgaris is needed to improve recognition of the condition. OBJECTIVE: To describe the typical clinical presentation, laboratory findings, gross pathology, treatment and outcome of horses with nonstrangulating intestinal infarction. STUDY DESIGN: Retrospective case series. METHODS: Nonstrangluating intestinal infarction was diagnosed in 30 horses with a localised intestinal infarction with concurrent signs of S. vulgaris migration and no signs of intestinal strangulation or enterocolitis. Data were obtained from medical records in the period 2008-2016. Long-term follow-up information was obtained by telephonic interviews. Levels of S. vulgaris-specific antibodies were retrospectively assessed. Associations between nonstrangulating intestinal infarction and selected variables were evaluated using Fisher's exact and Mann Whitney U tests. RESULTS: The most consistent findings at admission were mild colic of >24 h duration without signs of shock or strangulated intestine, increased peritoneal fluid WBC (>5 * 109 /L), increased serum amyloid A (SAA) concentration and a positive S. vulgaris-specific antibody titre. Medical treatment was attempted in nine horses with none surviving. Exploratory laparotomy was performed in 21 horses. Eleven horses were subjected to euthanasia intraoperatively due to the presumed poor prognosis. Of the nine horses, three (33%) undergoing intestinal resection survived to discharge. The surviving horses were alive and returned to athletic function for at least 2 years following discharge. MAIN LIMITATIONS: Only nine of the 30 horses underwent resection of the infarcted intestine, and the prognosis for surgical intervention in nonstrangulating intestinal infarction is, therefore, difficult to estimate. CONCLUSIONS: In areas where S. vulgaris is prevalent, nonstrangulating intestinal infarction should be considered as a differential diagnosis in horses presenting with mild colic and peritonitis. Survival of nonstrangulating intestinal infarction is possible in cases where surgical intervention with resection of the infarcted intestine is feasible. The summary is available in Spanish - see Supporting Information. PMID- 29112790 TI - Crop rotations for increased soil carbon: perenniality as a guiding principle. AB - More diverse crop rotations have been promoted for their potential to remediate the range of ecosystem services compromised by biologically simplified grain based agroecosystems, including increasing soil organic carbon (SOC). We hypothesized that functional diversity offers a more predictive means of characterizing the impact of crop rotations on SOC concentrations than species diversity per se. Furthermore, we hypothesized that functional diversity can either increase or decrease SOC depending on its associated carbon (C) input to soil. We compiled a database of 27 cropping system sites and 169 cropping systems, recorded the species and functional diversity of crop rotations, SOC concentrations (g C kg/soil), nitrogen (N) fertilizer applications (kg N.ha-1 .yr 1 ), and estimated C input to soil (Mg C.ha-1 .yr-1 ). We categorized crop rotations into three broad categories: grain-only rotations, grain rotations with cover crops, and grain rotations with perennial crops. We divided the grain-only rotations into two sub-categories: cereal-only rotations and those that included both cereals and a legume grain. We compared changes in SOC and C input using mean effect sizes and 95% bootstrapped confidence intervals. Cover cropped and perennial cropped rotations, relative to grain-only rotations, increased C input by 42% and 23% and SOC concentrations by 6.3% and 12.5%, respectively. Within grain-only rotations, cereal + legume grain rotations decreased total C input ( 16%), root C input (-12%), and SOC (-5.3%) relative to cereal-only rotations. We found no effect of species diversity on SOC within grain-only rotations. N fertilizer rates mediated the effect of functional diversity on SOC within grain only crop rotations: at low N fertilizer rates (<=75 kg N.ha-1 .yr-1 ), the decrease in SOC with cereal + legume grain rotations was less than at high N fertilizer rates. Our results show that increasing the functional diversity of crop rotations is more likely to increase SOC concentrations if it is accompanied by an increase in C input. Functionally diverse perennial and cover cropped rotations increased both C input and SOC concentrations, potentially by exploiting niches in time that would otherwise be unproductive, that is, increasing the "perenniality" of crop rotations. PMID- 29112789 TI - Kinetic Analysis of PRMT1 Reveals Multifactorial Processivity and a Sequential Ordered Mechanism. AB - Arginine methylation is a prevalent post-translational modification in eukaryotic cells. Two significant debates exist within the field: do these enzymes dimethylate their substrates in a processive or distributive manner, and do these enzymes operate using a random or sequential method of bisubstrate binding? We revealed that human protein arginine N-methyltransferase 1 (PRMT1) enzyme kinetics are dependent on substrate sequence. Further, peptides containing an Neta-hydroxyarginine generally demonstrated substrate inhibition and had improved KM values, which evoked a possible role in inhibitor design. We also revealed that the perceived degree of enzyme processivity is a function of both cofactor and enzyme concentration, suggesting that previous conclusions about PRMT sequential methyl transfer mechanisms require reassessment. Finally, we demonstrated a sequential ordered Bi-Bi kinetic mechanism for PRMT1, based on steady-state kinetic analysis. Together, our data indicate a PRMT1 mechanism of action and processivity that might also extend to other functionally and structurally conserved PRMTs. PMID- 29112791 TI - Outcomes from 10 years of biodiversity offsetting. AB - We quantified net changes to the area and quality of native vegetation after the introduction of biodiversity offsetting in New South Wales, Australia-a policy intended to "prevent broad-scale clearing of native vegetation unless it improves or maintains environmental values." Over 10 years, a total of 21,928 ha of native vegetation was approved for clearing under this policy and 83,459 ha was established as biodiversity offsets. We estimated that no net loss in the area of native vegetation under this policy will not occur for 146 years. This is because 82% of the total area offset was obtained by averting losses to existing native vegetation and the rate that these averted losses accrue was over-estimated in the policy. There were predicted net gains in 10 of the 14 attributes used to assess the quality of habitat. An overall net gain in the quality of habitat was assessed under this policy by substituting habitat attributes that are difficult to restore (e.g. mature trees) with habitat attributes for which restoration is relatively easy (e.g. tree seedlings). Long-term rates of annual deforestation did not significantly change across the study area after biodiversity offsetting was introduced. Overall, the policy examined here provides no net loss of biodiversity: (i) many generations into the future, which is not consistent with intergenerational equity; and (ii) by substituting different habitat attributes, so gains are not equivalent to losses. We recommend a number of changes to biodiversity offsetting policy to overcome these issues. PMID- 29112792 TI - Biochanin A improves fibre fermentation by cellulolytic bacteria. AB - AIMS: The objective was to determine the effect of the isoflavone biochanin A (BCA) on rumen cellulolytic bacteria and consequent fermentative activity. METHODS AND RESULTS: When bovine microbial rumen cell suspensions (n = 3) were incubated (24 h, 39 degrees C) with ground hay, cellulolytic bacteria proliferated, short-chain fatty acids were produced and pH declined. BCA (30 MUg ml-1 ) had no effect on the number of cellulolytic bacteria or pH, but increased acetate, propionate and total SCFA production. Addition of BCA improved total digestibility when cell suspensions (n = 3) were incubated (48 h, 39 degrees C) with ground hay, Avicel, or filter paper. Fibrobacter succinogenes S85, Ruminococcus flavefaciens 8 and Ruminococcus albus 8 were directly inhibited by BCA. Synergistic antimicrobial activity was observed with BCA and heat killed cultures of cellulolytic bacteria, but the effects were species dependent. CONCLUSIONS: These results indicate that BCA improves fibre degradation by influencing cellulolytic bacteria competition and guild composition. SIGNIFICANCE AND IMPACT OF THE STUDY: BCA could serve as a feed additive to improve cellulosis when cattle are consuming high-fibre diets. Future research is needed to evaluate the effect of BCA on fibre degradation and utilization in vivo. PMID- 29112794 TI - Triple-negative breast cancer in the elderly. PMID- 29112793 TI - Effect of partially replacing a barley-based concentrate with flaxseed-based products on the rumen bacterial population of lactating Holstein dairy cows. AB - AIMS: The effects of partial replacement of a barley-based concentrate with flaxseed-based products on the rumen bacterial population of lactating Holstein dairy cows were evaluated. METHODS AND RESULTS: Treatments fed were CONT, a normal diet that included barley silage, alfalfa hay and a barley-based concentrate that contained no flaxseed or faba beans; FLAX, inclusion of a nonextruded flaxseed-based product containing 55.0% flaxseed, 37.8% field peas and 6.9% alfalfa; EXT, similar to FLAX, but the product was extruded and EXTT, similar to FLAX, but product was extruded and field peas were replaced by high tannin faba beans. The rumen bacterial population was evaluated by utilizing 16S rRNA gene sequencing. Most abundant phyla, families and genera were unaffected. However, some taxa were affected; for example, unsaturated fatty acid content was negatively correlated with Clostridiaceae, and tannin content was negatively correlated with BS11 and Paraprevotellaceae. CONCLUSIONS: Predominant rumen bacterial taxa were not affected, but the abundance of some taxa found in lower proportions shifted, possibly due to sensitivity to unsaturated fatty acids or tannins. SIGNIFICANCE AND IMPACT OF THE STUDY: Flaxseed-based products were effective for partially replacing barley-based concentrate in rations of lactating dairy cows. No negative effects of these products were observed on the abundance of predominant rumen bacterial taxa, with only minor shifts in less abundant bacteria. PMID- 29112795 TI - Bio-analytical applications of microbial fuel cell-based biosensors for onsite water quality monitoring. AB - Globally, sustainable provision of high-quality safe water is a major challenge of the 21st century. Various chemical and biological monitoring analytics are presently utilized to guarantee the availability of high-quality water. However, these techniques still face some challenges including high costs, complex design and onsite and online limitations. The recent technology of using microbial fuel cell (MFC)-based biosensors holds outstanding potential for the rapid and real time monitoring of water source quality. MFCs have the advantages of simplicity in design and efficiency for onsite sensing. Even though some sensing applications of MFCs were previously studied, e.g. biochemical oxygen demand sensor, recently numerous research groups around the world have presented new practical applications of this technique, which combine multidisciplinary scientific knowledge in materials science, microbiology and electrochemistry fields. This review presents the most updated research on the utilization of MFCs as potential biosensors for monitoring water quality and considers the range of potentially toxic analytes that have so far been detected using this methodology. The advantages of MFCs over established technology are also considered as well as future work required to establish their routine use. PMID- 29112796 TI - Molybdenum Doping Augments Platinum-Copper Oxygen Reduction Electrocatalyst. AB - Improving the efficiency of Pt-based oxygen reduction reaction (ORR) catalysts while also reducing costs remains an important challenge in energy research. To this end, we synthesized highly stable and active carbon-supported Mo-doped PtCu (Mo-PtCu/C) nanoparticles (NPs) from readily available precursors in a facile one pot reaction. Mo-PtCu/C displays two-to-fourfold-higher ORR half-cell kinetics than reference PtCu/C and Pt/C materials, a trend that was confirmed in proof-of concept experiments by using a H2 /O2 microlaminar fuel cell. This Mo-induced activity increase mirrors observations for Mo-PtNi/C NPs and possibly suggests an emerging trend. Electrochemical-accelerated stability tests revealed that dealloying was greatly reduced in Mo-PtCu/C in contrast to the binary alloys PtCu/C and PtMo/C. Supporting DFT studies suggested that the exceptional stability of Mo-PtCu could be attributed to oxidative resistance of the Mo-doped atoms. Furthermore, our calculations revealed that oxygen could induce segregation of Mo to the catalytic surface, at which it effected beneficial changes to the surface oxygen adsorption energetics in the context of the Sabatier principle. PMID- 29112797 TI - Exploring anatomy and physiology using iPad applications. AB - This study examined the use of iPads with anatomy applications (apps) in the laboratory sections of the largest undergraduate course at the university, Anatomy and Physiology, serving more than 300 students. The majority of these students were nursing, exercise science/physical education and biology majors. With a student survey (student opinion) and student practicum grades as metrics, this study determined whether the introduction of this novel mobile technology improved student grades and aided the students in learning the course material. The results indicated that students' grades improved with the introduction of the iPads, and 78% of the students reported that the iPads facilitated their ability to learn the course material. There was a positive association between frequency of app use and standardized mastery of the course material, as students who used the apps more frequently scored higher and indicated that they felt as though they had learned the material more comprehensively. Owning or having an iPad at home did not have a significant effect on the learning of the material. The general consensus by students was that iPad anatomy apps should be used frequently to better develop student understanding of the course material. Anat Sci Educ 11: 336-345. (c) 2017 American Association of Anatomists. PMID- 29112798 TI - Perceptions of first-year medical students towards learning anatomy using cadaveric specimens through peer teaching. AB - During the last decade, global interest in the multiple benefits of formal peer teaching has increased. This study aimed to explore the perceptions of first-year medical students towards the use of peer teaching to learn anatomy using cadaveric specimens. A descriptive, cross-sectional, retrospective survey was carried out. Data were collected using an online questionnaire which was administered to all medical students who were in their second year of their medical school curriculum and who had participated in sessions taught by their peers during their first year. Peer teaching was perceived as an effective method of learning anatomy by more than half of the participants. Analysis of mean responses revealed that the peer teachers created a positive, non-intimidating learning environment. Overall, participants gave positive feedback on their peer teachers. Six categories emerged from the responses given by participants as to why they would or would not recommend peer teaching. Ways of improvement as suggested by the respondents were also reported. Variables found to be significantly associated with the perceived benefits of the peer teaching program included sex differences, educational level and recommendations for peer teaching. This study brings to light the merits and demerits of peer teaching as viewed through the eyes of the peer learners. Peer teaching provides a sound platform for teaching and learning anatomy. Further discussions at higher levels are encouraged in order to explore the feasibility of introducing formal peer teaching in the medical curriculum. Anat Sci Educ 11: 346-357. (c) 2017 American Association of Anatomists. PMID- 29112799 TI - Design, synthesis, biological evaluation, and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II). AB - A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. The biological evaluation showed that most of the target compounds exhibited potent inhibitory activities against AChE. Among them, compound 1q possessed the strongest anti-AChE activity with an IC50 value of 0.15 nm and high AChE/BuChE selectivity (SI > 5,000). Moreover, compound 1q had low toxicity in normal nerve cells and was relatively stable in rat plasma. Together, the current finding may provide a new approach for the discovery of novel anti-Alzheimer's disease agents. PMID- 29112801 TI - Value of the Routine Assessment of Patient Index Data 3 in Patients With Psoriatic Arthritis: Results From a Tight-Control Clinical Trial and an Observational Cohort. AB - OBJECTIVE: To analyze the Routine Assessment of Patient Index Data 3 (RAPID3), a patient-reported, composite index, designed initially for feasibility in clinical care. RAPID3 was developed in rheumatoid arthritis, but has been found useful in many rheumatic diseases. We analyzed RAPID3 in patients with psoriatic arthritis (PsA). METHODS: Post hoc analyses were performed on 2 independent data sets, the Tight Control of Psoriatic Arthritis (TICOPA) clinical trial, and the Long-Term Outcome in Psoriatic Arthritis Study (LOPAS II), an observational cohort. RAPID3 (range 0-30) is the total of three 0-10 scores for the Health Assessment Questionnaire disability index (recalculated from 0-3), pain visual analog scale (VAS), and global VAS. RAPID3 scores were compared to the Psoriatic Arthritis Disease Activity Score (PASDAS), the Disease Activity in Psoriatic Arthritis (DAPSA), and other available clinical measures, according to Spearman's correlation coefficients, standardized response mean, SEM, smallest detectible difference, minimally important difference (in patients who improved), and receiver operating characteristic curves. RAPID3 remission was compared to criteria for both standard minimal disease activity (MDA) and very low disease activity (VLDA). RESULTS: RAPID3 was correlated significantly with PASDAS in TICOPA (r = 0.79, P < 0.01) and with DAPSA in LOPAS II (rho = 0.59, P < 0.01), and with most other measures in both data sets. RAPID3 discriminated between tight control and standard care in TICOPA at 48 weeks at levels comparable to DAPSA and the PASDAS (P < 0.01). RAPID3 remission discriminated treatment groups in TICOPA intermediate between MDA and VLDA criteria. CONCLUSION: RAPID3 appears comparably informative to PASDAS and DAPSA in PsA, with greater feasibility for routine clinical care. PMID- 29112800 TI - Association of Femoroacetabular Impingement and Delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage: A Population-Based Study. AB - OBJECTIVE: To assess the association of femoroacetabular impingement (FAI) and delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) T1 relaxation values (RVs), and to evaluate whether subtypes of FAI (cam, pincer, and mixed) are associated with region-specific dGEMRIC T1 RVs. METHODS: A population-based sample of white subjects with and without hip pain, ages 20-49 years, was selected through random-digit dialing. A sample of 128 subjects underwent hip-joint 3T dGEMRIC scans. Radiographic cam FAI was defined as an alpha angle >55 degrees , while pincer FAI was defined by a lateral center edge angle >40 degrees , or a positive cross-over sign. Mixed impingement was defined by the presence of both cam and pincer impingement. Overall and region-specific T1 RVs were compared between all FAI subtypes, using weighted linear regression analysis to account for sampling design of the study. RESULTS: Subjects had a mean age of 38 years and 51% were female. We did not find an association of FAI with overall hip T1 RV (mean difference -15.5 [95% confidence interval -77.23, 47.14]). Significant associations of cartilage degeneration in anterior superior and central superior regions were found in subjects with mixed FAI compared to other FAI subtypes and non-FAI subjects. CONCLUSION: Subjects with mixed FAI had reduced T1 RVs compared to other FAI subtypes. No substantial cartilage degeneration was found in pure cam or pincer FAI compared to no-FAI hips. These results indicate that the presence of cam or pincer impingements alone does not suggest the beginning of cartilage degeneration. In contrast, the presence of both FAI subtypes is a risk factor for early cartilage damage. PMID- 29112803 TI - Gas Selectivity Control in Co3O4 Sensor via Concurrent Tuning of Gas Reforming and Gas Filtering using Nanoscale Hetero-Overlayer of Catalytic Oxides. AB - Co3O4 sensors with a nanoscale TiO2 or SnO2 catalytic overlayer were prepared by screen-printing of Co3O4 yolk-shell spheres and subsequent e-beam evaporation of TiO2 and SnO2. The Co3O4 sensors with 5 nm thick TiO2 and SnO2 overlayers showed high responses (resistance ratios) to 5 ppm xylene (14.5 and 28.8) and toluene (11.7 and 16.2) at 250 degrees C with negligible responses to interference gases such as ethanol, HCHO, CO, and benzene. In contrast, the pure Co3O4 sensor did not show remarkable selectivity toward any specific gas. The response and selectivity to methylbenzenes and ethanol could be systematically controlled by selecting the catalytic overlayer material, varying the overlayer thickness, and tuning the sensing temperature. The significant enhancement of the selectivity for xylene and toluene was attributed to the reforming of less reactive methylbenzenes into more reactive and smaller species and oxidative filtering of other interference gases, including ubiquitous ethanol. The concurrent control of the gas reforming and oxidative filtering processes using a nanoscale overlayer of catalytic oxides provides a new, general, and powerful tool for designing highly selective and sensitive oxide semiconductor gas sensors. PMID- 29112804 TI - Scalable Approach to Highly Efficient and Rapid Capacitive Deionization with CNT Thread As Electrodes. AB - A scalable route to highly efficient purification of water through capacitive deionization (CDI) is reported using CNT-thread as electrodes. Electro-sorption capacity (qe) of 139 mg g-1 and average salt-adsorption rate (ASAR) of 2.78 mg g 1min-1 achieved here is the highest among all known electrode materials and nonmembrane techniques, indicating efficient and rapid deionization. Such exceptional performance is achieved with feedstock concentrations (<=1000 ppm) where conventional techniques such as reverse osmosis and electrodialysis prove ineffective. Further, both cations (Na+, K+, Mg2+, and Ca2+) and anions (Cl-, SO42- and NO3-) are removed with equally high efficiency (~80%). Synergism between electrical conductivity (~25 S cm-1), high specific surface area (~900 m2 g-1), porosity (0.7 nm, 3 nm) and hydrophilicity (contact angle ~25 degrees ) in CNT-thread electrode enable superior contact with water, rapid formation of extensive electrical double layer and consequently efficient deionization. The tunable capacitance of the device (0.4-120 mF) and its high specific capacitance (~27.2 F g-1) enable exceptional performance across a wide range of saline concentrations (50-1000 ppm). Facile regeneration of the electrode and reusability of the device is achieved for several cycles. The device demonstrated can desalinate water as it trickles down its surface because of gravity, thereby eliminating the requirement of any water pumping system. Finally, its portable adaptability is demonstrated by operating the device with an AA battery. PMID- 29112802 TI - Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions. AB - OBJECTIVE: To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies. METHODS: Virtual and face-to-face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions. RESULTS: Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response. CONCLUSION: Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO. PMID- 29112805 TI - Mechanistic Insight into Electrocatalytic H2 Production by [Fe2(CN){MU CN(Me)2}(MU-CO)(CO)(Cp)2]: Effects of Dithiolate Replacement in [FeFe] Hydrogenase Models. AB - DFT has been used to investigate viable mechanisms of the hydrogen evolution reaction (HER) electrocatalyzed by [Fe2(CN){MU-CN(Me)2}(MU-CO)(CO)(Cp)2] (1) in AcOH. Molecular details underlying the proposed ECEC electrochemical sequence have been studied, and the key functionalities of CN- and amino-carbyne ligands have been elucidated. After the first reduction, CN- works as a relay for the first proton from AcOH to the carbyne, with this ligand serving as the main electron acceptor for both reduction steps. After the second reduction, a second protonation occurs at CN- that forms a Fe(CNH) moiety: i.e., the acidic source for the H2 generation. The hydride (formally 2e/H+), necessary to the heterocoupling with H+ is thus provided by the MU-CN(Me)2 ligand and not by Fe centers, as occurs in typical L6Fe2S2 derivatives modeling the hydrogenase active site. It is remarkable, in this regard, that CN- plays a role more subtle than that previously expected (increasing electron density at Fe atoms). In addition, the role of AcOH in shuttling protons from CN- to CN(Me)2 is highlighted. The incompetence for the HER of the related species [Fe2{MU-CN(Me)2}(MU CO)(CO)2(Cp)2]+ (2+) has been investigated and attributed to the loss of proton responsiveness caused by CN- replacement with CO. In the context of hydrogenase mimicry, an implication of this study is that the dithiolate strap, normally present in all synthetic models, can be removed from the Fe2 core without loss of HER, but the redox and acid-base processes underlying turnover switch from a metal-based to a ligand-based chemistry. The versatile nature of the carbyne, once incorporated in the Fe2 scaffold, could be exploited to develop more active and robust catalysts for the HER. PMID- 29112806 TI - Water Analysis: Emerging Contaminants and Current Issues. PMID- 29112807 TI - Lithium Self-Discharge and Its Prevention: Direct Visualization through In Situ Electrochemical Scanning Transmission Electron Microscopy. AB - To understand the mechanism that controls low-aspect-ratio lithium deposition morphologies for Li-metal anodes in batteries, we conducted direct visualization of Li-metal deposition and stripping behavior through nanoscale in situ electrochemical scanning transmission electron microscopy (EC-STEM) and macroscale-cell electrochemistry experiments in a recently developed and promising solvate electrolyte, 4 M lithium bis(fluorosulfonyl)imide in 1,2 dimethoxyethane. In contrast to published coin cell studies in the same electrolyte, our experiments revealed low Coulombic efficiencies and inhomogeneous Li morphology during in situ observation. We conclude that this discrepancy in Coulombic efficiency and morphology of the Li deposits was dependent on the presence of a compressed lithium separator interface, as we have confirmed through macroscale (not in the transmission electron microscope) electrochemical experiments. Our data suggests that cell compression changed how the solid-electrolyte interphase formed, which is likely responsible for improved morphology and Coulombic efficiency with compression. Furthermore, during the in situ EC-STEM experiments, we observed direct evidence of nanoscale self-discharge in the solvate electrolyte (in the state of electrical isolation). This self discharge was duplicated in the macroscale, but it was less severe with electrode compression, likely due to a more passivating and corrosion-resistant solid electrolyte interphase formed in the presence of compression. By combining the solvate electrolyte with a protective LiAl0.3S coating, we show that the Li nucleation density increased during deposition, leading to improved morphological uniformity. Furthermore, self-discharge was suppressed during rest periods in the cycling profile with coatings present, as evidenced through EC-STEM and confirmed with coin cell data. PMID- 29112808 TI - Comparative Analysis of Supply Risk-Mitigation Strategies for Critical Byproduct Minerals: A Case Study of Tellurium. AB - Materials criticality assessment is a screening framework increasingly applied to identify materials of importance that face scarcity risks. Although these assessments highlight materials for the implicit purpose of informing future action, the aggregated nature of their findings make them difficult to use for guidance in developing nuanced mitigation strategy and policy response. As a first step in the selection of mitigation strategies, the present work proposes a modeling framework and accompanying set of metrics to directly compare strategies by measuring effectiveness of risk reduction as a function of the features of projected supply demand balance over time. The work focuses on byproduct materials, whose criticality is particularly important to understand because their supplies are inherently less responsive to market balancing forces, i.e., price feedbacks. Tellurium, a byproduct of copper refining, which is critical to solar photovoltaics, is chosen as a case study, and three commonly discussed byproduct-relevant strategies are selected: dematerialization of end-use product, byproduct yield improvement, and end-of-life recycling rate improvement. Results suggest that dematerialization will be nearly twice as effective at reducing supply risk as the next best option, yield improvement. Finally, due to its infrequent use at present and its dependence upon long product lifespans, recycling end-of-life products is expected to be the least effective option despite potentially offering other benefits (e.g., cost savings and environmental impact reduction). PMID- 29112809 TI - Revisiting OPLS Force Field Parameters for Ionic Liquid Simulations. AB - Our OPLS-2009IL force field parameters (J. Chem. Theory Comput. 2009, 5, 1038 1050) were originally developed and tested on 68 unique ionic liquids featuring the 1-alkyl-3-methylimidazolium [RMIM], N-alkylpyridinium [RPyr], and choline cations. Experimental validation was limited to densities and a few, largely conflicting, heat of vaporization (DeltaHvap) values reported in the literature at the time. Owing to the use of Monte Carlo as our sampling technique, it was also not possible to investigate the reproduction of dynamics. The [RMIM] OPLS 2009IL parameters have been revisited in this work and adapted for use in molecular dynamics (MD) simulations. In addition, new OPLS-AA parameters have been developed for multiple anions, i.e., AlCl4-, BF4-, Br-, Cl-, NO3-, PF6-, acetate, benzoate bis(pentafluoroethylsulfonyl)amide, bis(trifluoroethylsulfonyl)amide, dicyanamide, formate, methylsulfate, perchlorate, propanoate, thiocyanate, tricyanomethanide, and trifluoromethanesulfonate. The computed solvent densities, heats of vaporization, viscosities, diffusion coefficients, heat capacities, surface tensions, and other relevant solvent data compared favorably with experiment. A charge scaling of +/ 0.8 e was also investigated as a means to mimic polarization and charge transfer effects. The 0.8-scaling led to significant improvements for DeltaHvap, surface tension, and self-diffusivity; however, a concern when scaling charges is the potential degradation of local intermolecular interactions at short ranges. Radial distribution functions (RDFs) were used to examine cation-anion interactions when employing 0.8*OPLS-2009IL and the scaled force field accurately reproduced RDFs from ab initio MD simulations. PMID- 29112810 TI - Electronic Effects on Room-Temperature, Gas-Phase C-H Bond Activations by Cluster Oxides and Metal Carbides: The Methane Challenge. AB - This Perspective discusses a story of one molecule (methane), a few metal-oxide cationic clusters (MOCCs), dopants, metal-carbide cations, oriented-electric fields (OEFs), and a dizzying mechanistic landscape of methane activation! One mechanism is hydrogen atom transfer (HAT), which occurs whenever the MOCC possesses a localized oxyl radical (M-O*). Whenever the radical is delocalized, e.g., in [MgO]n*+ the HAT barrier increases due to the penalty of radical localization. Adding a dopant (Ga2O3) to [MgO]2*+ localizes the radical and HAT transpires. Whenever the radical is located on the metal centers as in [Al2O2]*+ the mechanism crosses over to proton-coupled electron transfer (PCET), wherein the positive Al center acts as a Lewis acid that coordinates the methane molecule, while one of the bridging oxygen atoms abstracts a proton, and the negatively charged CH3 moiety relocates to the metal fragment. We provide a diagnostic plot of barriers vs reactants' distortion energies, which allows the chemist to distinguish HAT from PCET. Thus, doping of [MgO]2*+ by Al2O3 enables HAT and PCET to compete. Similarly, [ZnO]*+ activates methane by PCET generating many products. Adding a CH3CN ligand to form [(CH3CN)ZnO]*+ leads to a single HAT product. The CH3CN dipole acts as an OEF that switches off PCET. [MC]+ cations (M = Au, Cu) act by different mechanisms, dictated by the M+-C bond covalence. For example, Cu+, which bonds the carbon atom mostly electrostatically, performs coupling of C to methane to yield ethylene, in a single almost barrier-free step, with an unprecedented atomic choreography catalyzed by the OEF of Cu+. PMID- 29112811 TI - Carry-Over Effects Across Metamorphosis of a Pesticide on Female Lifetime Fitness Strongly Depend on Egg Hatching Phenology: A Longitudinal Study under Seminatural Conditions. AB - Current ecological risk assessment of pesticides fails to protect aquatic biodiversity. For the first time, we tested two potential reasons for this failure with regard to carry-over effects across metamorphosis: their dependence on hatching period, and the lack of studies quantifying adult fitness under seminatural conditions. Using the damselfly Coenagrion puella sampled from six populations, we designed an outdoor longitudinal one-year study starting from the egg stage. We exposed the aquatic larvae to the pesticide esfenvalerate (0.11 MUg/L) during the initial microcosm part. Next, we monitored the lifetime fitness of the terrestrial adults in an insectary. Exposure to the pesticide negatively impacted not only larval traits, but also drastically reduced lifetime mating success of adult females. The impact of this postmetamorphic effect of the pesticide on the population level was three times more important than the effects in the larval stage. Importantly, this carry-over effect was only present in females that hatched early in the season, and was not mediated by metamorphic traits (age and mass at emergence). We provide proof-of-principle under seminatural conditions for two potential pitfalls that need to be considered when improving risk assessment: carry-over effects on adult fitness can (i) be much more important than effects during the larval stage and may not be captured by metamorphic traits, and (ii) be strongly modulated by egg hatching dates. PMID- 29112812 TI - Slow Spin Relaxation in Dioxocobaltate(II) Anions Embedded in the Lattice of Calcium Hydroxyapatite. AB - Pure-phase cobalt-doped calcium hydroxyapatite ceramic samples with composition Ca10(PO4)6[(CoO2)x(OH)1-2x]2, where x = 0-0.2, were synthesized by high temperature solid-state reaction, and their crystal structures, vibrational spectra, and magnetic properties were studied. Co atoms are found to enter into the apatite trigonal channel formally substituting H atoms and forming bent dioxocobaltate(II) anions. The anion exhibits single-molecule-magnet (SMM) behavior: slow relaxation of magnetization below 8 K under a nonzero magnetic field with an energy barrier of 63 cm-1. The barrier value does not depend on the concentration of Co ions, virtually coincides with the zero-field-splitting energy as determined from direct-current magnetization, and is very close to the value obtained earlier for cobalt-doped strontium hydroxyapatite. Moreover, the vibration frequencies of the dioxocobaltate(II) anion are found to be the same in calcium and strontium apatite matrixes. The very weak dependence of the SMM parameters on the matrix nature in combination with good chemical and thermal stabilities of the compounds provides wide opportunities to exploit the intrinsic properties of such a SMM-like anion. PMID- 29112813 TI - Lost, but Found with Nile Red: A Novel Method for Detecting and Quantifying Small Microplastics (1 mm to 20 MUm) in Environmental Samples. AB - Marine plastic debris is a global environmental problem. Surveys have shown that <5 mm plastic particles, known as microplastics, are significantly more abundant in surface seawater and on shorelines than larger plastic particles are. Nevertheless, quantification of microplastics in the environment is hampered by a lack of adequate high-throughput methods for distinguishing and quantifying smaller size fractions (<1 mm), and this has probably resulted in an underestimation of actual microplastic concentrations. Here we present a protocol that allows high-throughput detection and automated quantification of small microplastic particles (20-1000 MUm) using the dye Nile red, fluorescence microscopy, and image analysis software. This protocol has proven to be highly effective in the quantification of small polyethylene, polypropylene, polystyrene, and nylon-6 particles, which frequently occur in the water column. Our preliminary results from sea surface tows show a power-law increase in small microplastics (i.e., <1 mm) with a decreasing particle size. Hence, our data help to resolve speculation about the "apparent" loss of this fraction from surface waters. We consider that this method presents a step change in the ability to detect small microplastics by substituting the subjectivity of human visual sorting with a sensitive and semiautomated procedure. PMID- 29112814 TI - Optical Sensors Using Solvatochromic Metal-Organic Frameworks. AB - A series of copper and 1,3-phenylebis(azanetriyl)tetrabenzoate based MOFs were obtained by postsynthetic modification of DUT-71 (DUT = Dresden University of Technology) using various nitrogen containing, neutral ligands to afford the compounds DUT-74, DUT-95, DUT-112, and DUT-114. The structure of the new MOFs DUT 112 and DUT-114 was solved from synchrotron X-ray single-crystal diffraction data. Both structures are tetragonal (P4/mnc) but differ slightly in the lattice parameters. All materials show specific shifts in absorption bands in solid state UV/vis spectra as a response to the exposure to various analytes. Analyzing this shift, it was possible to distinguish between solvents differing in polarity. Moreover, the determination of the polar analyte content in the excess of lower polarity solvent at low concentrations of 0.01 wt % is feasible. PMID- 29112815 TI - Residual Lithium Carbonate Predominantly Accounts for First Cycle CO2 and CO Outgassing of Li-Stoichiometric and Li-Rich Layered Transition-Metal Oxides. AB - The role of residual lithium carbonate in the electrochemistry and outgassing of lithium transition-metal oxides (TMOs) has been largely overlooked. By combining in situ gas analysis, isotopic labeling, and a surface carbonate titration, we show that the presence of residual lithium carbonate (Li2CO3) on the surface of both Ni-rich Li-stoichiometric (specifically LiNi0.6Mn0.2Co0.2O2) and Li-rich (Li1.2Ni0.15Co0.1Mn0.55O2) TMOs has a direct correlation with the amount of CO2 and CO evolved and has a relationship with O2 evolved from the TMO lattice on the first charge. By selectively isotopically labeling the residual surface Li2CO3, which remains in small quantities (~0.1 wt %) after synthesis, and not the carbonate electrolyte, we further show that, up to 4.8 V vs Li/Li+ on the first charge, carbonate electrolyte degradation negligibly contributes to gas evolution. These key conclusions warrant a reassessment of our notion of oxidative decomposition of carbonate electrolytes on TMO surfaces and, more generally, the reactivity of TMO surfaces. For the battery research community, our results highlight the importance of quantification of the surface contaminants and suggest that further research is needed to fully understand the long-term effects of trace surface Li2CO3. PMID- 29112816 TI - Surface Composition and Crystallinity of Coalescing Silver-Gold Nanoparticles. AB - Bimetallic nanoparticles exhibit catalytic, optical, electronic, and magnetic synergy between their constituent metals. Typically, that synergy is traced to the domain structure and surface characteristics of such particles. Here these characteristics of coalescing Ag-Au nanoparticles of various initial sizes and morphologies (segregated or alloys) are investigated by atomistic molecular dynamics (MD) at different temperatures. Silver atoms exhibit increased mobility over Au and occupy gradually the surface of the coalesced (or sintered) bimetallic particle, consistent with scanning electron microscopy and selective O2 chemisorption experiments for heterogeneous catalysis of ethylene oxidation. The characteristic sintering time of equally sized Ag-Au nanoparticles is similar to that of pure Au but shorter than that of Ag nanoparticles. When the latter coalesce with substantially bigger Au ones, a patchy Ag layer is formed at the Au particle surface. However, when Ag nanoparticles are bigger, then Au is rather embedded into Ag, consistent with microscopy data. Most notably, X-ray diffraction (XRD) patterns of Ag-Au nanoparticles are obtained by MD, distinguishing segregated from alloyed ones. The latter exhibit a weaker XRD reflection of the (200) crystalline plane and, most distinctly, form smaller crystal size (highly polycrystalline) than coalescing pure and segregated Ag and Au nanoparticles, quantitatively explaining the structure of flame-made Ag-Au nanoparticles for biomaterial applications. PMID- 29112817 TI - On-Surface Cyclization of ortho-Dihalotetracenes to Four- and Six-Membered Rings. AB - We report on the surface-catalyzed formal [2+2] and [2+2+2] cycloadditions of ortho-activated tetracene species on a Ag(111) substrate under ultrahigh vacuum conditions. Three different products are obtained: tetracene dimers, trimers, and tetramers. The former results from the formation of a four-membered ring while the other two arise from cyclization into six-membered rings. These on-surface reactions have been monitored by scanning tunneling microscopy and rationalized by density functional theory calculations. Our approach, based on the reaction of ortho-dihalo precursor monomers via formal cycloadditions, establishes an additional method for the highly active field of on-surface synthesis and enables the development of novel 1D and 2D covalent carbon nanostructures. PMID- 29112818 TI - Metabolomics Approach To Understand Mechanisms of beta-N-Oxalyl-l-alpha,beta diaminopropionic Acid (beta-ODAP) Biosynthesis in Grass Pea (Lathyrus sativus L.). AB - A study was performed to identify metabolic processes associated with beta-ODAP synthesis in grass pea using a metabolomics approach. GC-MS metabolomics was performed on seedlings at 2, 6, and 25 days after sowing. A total of 141 metabolites were detected among the three time points representing much of grass pea primary metabolism, including amino acids, carbohydrates, purines, and others. Principal component analysis revealed unique metabolite profiles of grass pea tissues among the three time points. Fold change, hierarchical clustering, and orthogonal projections to latent structures-discriminant analyses, and biochemical pathway ontologies were used to characterize covariance of metabolites with beta-ODAP content. The data indicates that alanine and nitrogen metabolism, cysteine and sulfur metabolism, and purine, pyrimidine, and pyridine metabolism were associated with beta-ODAP metabolism. Our results reveal the metabolite profiles in grass pea development and provide insights into mechanisms of beta-ODAP accumulation and degradation. PMID- 29112819 TI - Humidity- and Sunlight-Driven Motion of a Chemically Bonded Polymer Bilayer with Programmable Surface Patterns. AB - We report a bilayer of sodium alginate/polyvinylidene fluoride (SA/PVDF) that is chemically bonded through a series of interfacial coupling reactions. The SA layer is hydrophilic in structure and is capable of strong interaction with water molecules, thus presenting high sensitivity to humidity, whereas the PVDF layer is hydrophobic, inert to humidity. This structural feature results in the bilayer having asymmetric humidity-responsive performances that can thus make its shape change with directionality, which cannot be achieved in an SA single layer. The responsive process to humidity can be adjusted by exposure of the bilayer to sunlight by means of a photothermal effect that accelerates dehydration of the bilayer to cause more rapid shape deformations. When the sunlight is removed, the bilayer adsorbs humidity again and returns to its original shape, indicating good reversibility. To exactly regulate the shape deformations of the bilayer with external stimuli, we employ Ca2+-treated filter paper to customize crosslinking reactions in the SA layer as desired patterns which are capable of causing different mechanical tensors and swellabilities in the bilayer so as to regulate and control the actuations for self-folding, curling, twisting, and coiling in response to sunlight and humidity.On the other hand, the chemically bonded bilayer has stronger interfacial toughness and is capable of reaching 300 J m-2, which is around 12 times the interfacial toughness of the physically combined bilayer; as a result, the chemically bonded bilayer is capable of sustaining continuous shape deformations without interfacial failure. The directionally mechanical actuations can be utilized in designing an indicator to roughly indicate the range of intensity of sunlight by coupling the chemically bonded bilayer into a typical electric circuit, in which the range of intensity of sunlight can be easily estimated by visual observation of the light-emitting diodes. PMID- 29112820 TI - Daedophamide, a Cytotoxic Cyclodepsipeptide from a Daedalopelta sp. Sponge Collected in Indonesia. AB - A new cyclodepsipeptide, daedophamide (1), has been isolated from a Daedalopelta sp. marine sponge collected from Alor Island (Indonesia). The planar structure of 1 was assigned on the basis of extensive 1D and 2D NMR spectroscopy and mass spectrometry. Daedophamide (1) contains 11 amino acid residues and an amide linked 3-hydroxy-2,4,6,8-tetramethylnonanoic acid (Htemna). The amino acid constituents were identified as l-Leu, N-Me-l-Gln, d-Arg, d-Asp, d-allo-Thr, l Pip, d-Ala, d-Ser, 3,4-dimethyl-Gln, O-MeThr, and 4-amino-7-guanidino-2,3 dihydroxyheptanoic acid (Agdha). The absolute configurations of eight of the amino acid residues in 1 were determined by application of the Marfey's method after acid-catalyzed hydrolysis, with the relative configurations of the remaining three amino acid residues and the Htemna unit being assigned by comparison of the NMR data with those reported for other similar peptides. Compound 1 displayed strong cytotoxic activity against a panel of four human tumor cell lines with GI50 values in the submicromolar range. PMID- 29112821 TI - Luminescence of Molecular Nitrogen Nanoclusters Containing Stabilized Atoms. AB - We studied the luminescence of molecular nitrogen nanoclusters containing stabilized nitrogen, oxygen, hydrogen, and deuterium atoms. Optical spectra were observed during the destruction of these ensembles of nanoclusters accompanied by a rapid release of chemical energy stored in the samples. Several interesting features were observed including a broad band near lambda ~ 360 nm, which was identified as emission corresponding to 2Ag->1Ag transition of N4(D2h) polymeric nitrogen. Also the sharp lines at lambda ~ 336 and 473 nm were observed, and their assignments to ND radicals are discussed. PMID- 29112822 TI - Synthesis and Immunological Comparison of Differently Linked Lipoarabinomannan Oligosaccharide-Monophosphoryl Lipid A Conjugates as Antituberculosis Vaccines. AB - A monophosphoryl lipid A (MPLA) derivative having the 6'-OH group substituted with an NH2 group was synthesized and coupled with the upstream terminal tetrasaccharide of mycobacterial lipoarabinomannan (LAM) via an amide bond to create a novel type of MPLA-based fully synthetic glycoconjugate vaccine. The same tetrasaccharide was also coupled with MPLA at the 1-O-position. Immunological activities of the two synthetic conjugates were evaluated in mice and compared. Both afforded robust overall and IgG antibody responses, but intraperitoneal injection elicited responses significantly stronger than those from subcutaneous injection. It was thus speculated that MPLA conjugates might act via stimulating B1 lymphocytes present in the intrapleural and peritoneal cavities. Moreover, the 6'-N-conjugate afforded antibody titers much higher than those of the 1-O-conjugate. These results revealed not only the self-adjuvant property of MPLA conjugates to elicit robust IgG antibody responses but also the impact of MPLA structure on the immunological activity of its conjugates. It was concluded that LAM oligosaccharide-MPLA conjugates, especially 6'-N-linked, are promising candidates as antituberculosis vaccines worthy of further investigation. Additionally, the 6'-amino derivative of MPLA was proved to be a useful carrier for the development of fully synthetic carbohydrate-based conjugate vaccines. PMID- 29112825 TI - Errata. PMID- 29112823 TI - Obstructive Sleep Apnea during REM Sleep and Cardiovascular Disease. AB - RATIONALE: Obstructive sleep apnea (OSA) during REM sleep is a common disorder. Data on whether OSA that occurs predominantly during REM sleep is associated with health outcomes are limited. OBJECTIVES: The present study examined the association between OSA during REM sleep and a composite cardiovascular endpoint in a community sample with and without prevalent cardiovascular disease. METHODS: Full-montage home polysomnography was conducted as part of the Sleep Heart Health Study. The study cohort was followed for an average of 9.5 years, during which time cardiovascular events were assessed. Only participants with a non-REM apnea hypopnea index (AHI) of less than 5 events/h were included. A composite cardiovascular endpoint was determined as the occurrence of nonfatal or fatal events, including myocardial infarction, coronary artery revascularization, congestive heart failure, and stroke. Proportional hazards regression was used to derive the adjusted hazards ratios for the composite cardiovascular endpoint. MEASUREMENTS AND MAIN RESULTS: The sample consisted of 3,265 subjects with a non REM AHI of less than 5.0 events/h. Using a REM AHI of less than 5.0 events/h as the reference group (n = 1,758), the adjusted hazards ratios for the composite cardiovascular endpoint in those with severe REM OSA (>=30 events/h; n = 180) was 1.35 (95% confidence interval, 0.98-1.85). Stratified analyses demonstrated that the association was most notable in those with prevalent cardiovascular disease and severe OSA during REM sleep with an adjusted hazards ratio of 2.56 (95% confidence interval, 1.46-4.47). CONCLUSIONS: Severe OSA that occurs primarily during REM sleep is associated with higher incidence of a composite cardiovascular endpoint, but in only those with prevalent cardiovascular disease. PMID- 29112824 TI - Errata. PMID- 29112826 TI - Immunohistochemical Analysis on Cortex-to-Cortex Healing After Mandibular Vertical Ramus Osteotomy: A Preliminary Study. AB - PURPOSE: The present study analyzed the expression of specific cytokines in the transforming growth factor (TGF)-beta superfamily postoperatively after mandibular vertical ramus osteotomy (VRO). MATERIALS AND METHODS: Four beagle dogs were enrolled and euthanized at 1, 2, 4, and 8 weeks postoperatively for immunohistochemical analysis using 6 specific antibodies (bone morphogenetic protein [BMP]-2/4, BMP-7, TGF-beta2, TGF-beta3, matrix metalloproteinase-3, and vascular endothelial growth factor [VEGF]). The results from the surgical site and control (adjacent area) were compared. RESULTS: Generalized upregulation of BMP-2/4 was observed in all healing periods, and the strongest expression of BMP 7 was observed at 1 week postoperatively. The strongest expression of TGF-beta2 was observed at 8 weeks with increasing pattern. The strong expression of TGF beta3 was observed at 1 and 4 weeks, with the strongest expression of VEGF at 1 week, with a decreasing pattern. No notable uptake was detected with the 6 specific antibodies in the adjacent bone (control). CONCLUSIONS: The absence of internal fixation after VRO led to dynamic healing with a specific expression pattern of BMP-7 and TGF-beta2. The anatomic factors, including sufficient preexisting vascularity, led to the earlier expression pattern of VEGF. PMID- 29112827 TI - Incremental validity of estimated cannabis grams as a predictor of problems and cannabinoid biomarkers: Evidence from a clinical trial. AB - BACKGROUND: Quantifying cannabis use is complex due to a lack of a standardized packaging system that contains specified amounts of constituents. A laboratory procedure has been developed for estimating physical quantity of cannabis use by utilizing a surrogate substance to represent cannabis, and weighing the amount of the surrogate to determine typical use in grams. METHOD: This secondary analysis utilized data from a multi-site, randomized, controlled pharmacological trial for adult cannabis use disorder (N=300), sponsored by the National Drug Abuse Treatment Clinical Trials Network, to test the incremental validity of this procedure. In conjunction with the Timeline Followback, this physical scale-based procedure was used to determine whether average grams per cannabis administration predicted urine cannabinoid levels (11-nor-9-carboxy-Delta9-tetrahydrocannabinol) and problems due to use, after accounting for self-reported number of days used (in the past 30 days) and number of administrations per day in a 12-week clinical trial for cannabis use disorder. RESULTS: Likelihood ratio tests suggest that model fit was significantly improved when grams per administration and relevant interactions were included in the model predicting urine cannabinoid level (X2=98.3; p<0.05) and in the model predicting problems due to cannabis use (X2=6.4; p<0.05), relative to a model that contained only simpler measures of quantity and frequency. CONCLUSIONS: This study provides support for the use of a scale-based method for quantifying cannabis use in grams. This methodology may be useful when precise quantification is necessary (e.g., measuring reduction in use in a clinical trial). PMID- 29112829 TI - A Case of Gastrointestinal Opportunistic Infection. PMID- 29112828 TI - Black Stoma: What Could It Be? PMID- 29112830 TI - A Liver Full of Stars: Hepatostellular! PMID- 29112831 TI - Reply. PMID- 29112832 TI - A Novel Cause of Rectal Hemorrhage in the Intensive Care Unit. PMID- 29112833 TI - Pancreatic Fusion Abnormality Found During a Whipple Procedure. PMID- 29112834 TI - Natural killer cells play an essential role in resolution of antigen-induced inflammation in mice. AB - This study examined whether NK cells are important for resolution of antigen induced inflammation. C57BL/6 mice were immunized twice with methylated BSA (mBSA) and inflammation induced by intraperitoneal injection of mBSA. Mice were injected intravenously with anti-asialo GM1 (alphaASGM1) or a control antibody 24h prior to peritonitis induction and peritoneal exudate collected at different time points. Expression of surface molecules and apoptosis on peritoneal cells was determined by flow cytometry and concentration of chemokines, cytokines, soluble cytokine receptors and lipid mediators by ELISA and LC-MS/MS. Apoptosis in parathymic lymph nodes and spleens was determined by TUNEL staining. Mice administered alphaASGM1 had lower peritoneal NK cell numbers and a higher number of peritoneal neutrophils 12h after induction of inflammation than control mice. The number of neutrophils was still high in the alphaASGM1 treated mice when their number had returned to baseline levels in the control mice, 48h after induction of inflammation. Peritoneal concentrations of the neutrophil regulators G-CSF and IL-12p40 were higher at 12h in the alphaASGM1 treated mice than in the control mice, whereas concentrations of lipid mediators implicated in resolution of inflammation, i.e. LXA4 and PGE2, were lower. Reduced apoptosis was detected in peritoneal neutrophils as well as in draining lymph nodes and spleens from the alphaASGM1 treated mice compared with that in the control mice. In addition, alphaASGM1 treated mice had lower number of peritoneal NK cells expressing NKp46 and NKG2D, receptors implicated in NK cell-induced neutrophil apoptosis. Furthermore, alphaASGM1 treatment completely blocked the increase in CD27+ NK cells that occurred in control mice following induction of inflammation, but CD27+ NK cells have been suggested to have a regulatory role. These results indicate a crucial role for NK cells in resolution of antigen-induced inflammation and suggest their importance in tempering neutrophil recruitment and maintaining neutrophil apoptosis. PMID- 29112835 TI - Biodegradation of di-n-butyl phthalate (DBP) by a novel endophytic Bacillus megaterium strain YJB3. AB - Phthalic acid esters (PAEs) are a group of recalcitrant and hazardous organic compounds that pose a great threat to both ecosystem and human beings. A novel endophytic strain YJB3 that could utilize a wide range of PAEs as the sole carbon and energy sources for cell growth was isolated from Canna indica root tissue. It was identified as Bacillus megaterium based on morphological characteristics and 16S rDNA sequence homology analysis. The degradation capability of the strain YJB3 was investigated by incubation in mineral salt medium containing di-n-butyl phthalate (DBP), one of important PAEs under different environmental conditions, showing 82.5% of the DBP removal in 5days of incubation under the optimum conditions (acetate 1.2g.L-1, inocula 1.8%, and temperature 34.2 degrees C) achieved by two-step sequential optimization technologies. The DBP metabolites including mono-butyl phthalate (MBP), phthalic acid (PA), protocatechuic acid (PCA), etc. were determined by GC-MS. The PCA catabolic genes responsible for the aromatic ring cleavage of PCA in the strain YJB3 were excavated by whole-genome sequencing. Thus, a degradation pathway of DBP by the strain YJB3 was proposed that MBP was formed, followed by PA, and then the intermediates were further utilized till complete degradation. To our knowledge, this is the first study to show the biodegradation of PAEs using endophyte. The results in the present study suggest that the strain YJB3 is greatly promising to act as a competent inoculum in removal of PAEs in both soils and crops. PMID- 29112836 TI - Developing ionic liquid forms of picloram with reduced negative effects on the aquatic environment. AB - As a widely used herbicide, picloram has been frequently detected in the aquatic environment due to its high leaching potential and low adsorption by soil. To reduce aquatic environmental risk of this herbicide caused by leaching and runoff, five herbicidal ionic liquids (HILs) based on picloram were prepared by pairing isopropylamine, octylamine, octadecylamine, 1-methylimidazole, 4 methylmorpholine respectively. Their physicochemical properties including water solubility, octanol-water partition coefficient, surface activity, leaching, as well as soil adsorption were compared. The results showed that these properties could be adjusted by appropriate selection of counter cations. The HILs with long alkyl chains in cations had low water solubility and leaching characteristics, good surface tension and lipophilicity, as well as high soil adsorption. Compared with currently used picloram in the forms of potassium salts, HIL3 had more excellent herbicidal activity against broadleaf weeds and may offer a lower use dosage. The HILs based on picloram can reduce its negative effects on the aquatic environment and can be used as a desirable alternative to commercial herbicidal formulations of picloram in future. PMID- 29112837 TI - Vertical observation and analysis on rapid formation and evolutionary mechanisms of a prolonged haze episode over central-eastern China. AB - To clarify the rapid formation and evolutionary mechanisms of an extremely severe and persistent haze and fog (HF) episode that occurred in central-eastern China from Dec 20 to 25, 2015, a novel campaign was conducted and vertical profiles of wind, temperature, light extinction coefficient (LEC) and PM2.5 concentration were used to analyze the rapid formation and evolutionary mechanisms of this HF episode. The substantial downward transportation of regional pollution from high layers and stagnant weather conditions favorable for the local pollution accumulation were the two main causes of the rapid increase in pollutant concentration. Southwest wind speeds of 4m/s between 300 and 600m and obvious downward flows were observed, whereas the southwest wind speeds were low below 300m, and strong temperature inversion with intensity of 4.5 degrees C/100m expanded vertically to a height of 600m. Two peaks of PM2.5 concentration were observed at 200 and 700m, corresponding to 235 and 215MUg/m3, respectively. The frequent change in wind direction and wind speeds resulted in the fluctuation of PM2.5 concentration. The turbulence within lower layers of the troposphere was enhanced by easterly and northerly winds which decreased the pollution level; however, the strength and stretching height of the winds were insufficient to fully clear the air of pollutants. The PM2.5 concentration revealed 2-high concentration layers in the vertical direction. The maximum concentration layer was below 100m, while the second high-concentration layer was at 400m. PMID- 29112838 TI - Arsenic in agricultural soils across China: Distribution pattern, accumulation trend, influencing factors, and risk assessment. AB - Arsenic (As) in the environment is of concern due to its strong toxicity and high risks to the ecosystems and humans. In this study, soil samples across China collected in 2011 and 2016 were used to determine the concentrations of arsenic in arable soils. The median concentration of arsenic in surface soils was 9.7mg/kg. The inventory of arsenic in the Chinese agricultural surface soils was estimated to be 3.7*106tons. In general, arsenic contamination was found higher in South and Northeast China than in other regions, with means of 18.7 and 15.8mg/kg, respectively. Vertically, arsenic concentrations were higher in top layer (0-15cm) soils (median of 9.8mg/kg) and decreased with soil depth (medians of 8.9mg/kg at 15-30cm and 8.0mg/kg at 30-45cm). By comparing with published data, an increasing accumulation trend over the past decades was found and this enhancement was positively related with the long-term application of fertilizers in agricultural practice, especially phosphate fertilizers. Soil pH was found to affect the movement of arsenic in soil, and high-pH conditions enhanced the pool of arsenic. The ecological risk assessment revealed that arsenic in Chinese agricultural soil posed a low risk to the ecosystem. Regarding human health, the mean hazard indices (HIs) of arsenic were below 1, suggesting an absence of non carcinogenic risks. In addition, the cancer risks of arsenic in all soil samples were within the acceptable range (below 1*10-4), indicating low to very low risks to the exposed population. Findings from this study are valuable to provide effective management options for risk avoidance and to control the persistent accumulation of arsenic in the agriculture sector across the world. PMID- 29112839 TI - Environmental fate of amine oxide: Using measured and predicted values to determine aquatic exposure. AB - Amine oxide (AO) surfactants are used widely in North American household detergents resulting in >44,000mtons disposed down the drain annually. Due to AOs substantial down the drain disposal volume, wide dispersive use, and high aquatic toxicity, there is a need to evaluate ecological exposure and corresponding risk. This study refined the current knowledge regarding the fate of AO disposed down the drain through laboratory simulation studies to evaluate biodegradation in the sewer and during activated sludge wastewater treatment. A monitoring program which measured effluent AO concentrations for the dominant carbon chain lengths, C12 and C14, at 44 wastewater treatment plants (WWTP) across the continental US was also conducted. The study results were then used as input into probabilistic exposure models to predict US receiving stream concentrations. In three separate OECD 314A Sewer Water Die-Away studies AO was rapidly biodegraded with >76% mineralized by study completion and the geometric mean of the primary biodegradation rates being 0.184h-1. Two OECD 303A Activated Sludge WWTP Simulation studies showed rapid and complete biodegradation of AO with <=0.09% of parent AO remaining in the effluent, <=0.03% of parent AO sorbed to sludge solids, and >97% complete mineralization of AO. Monitoring at US WWPTs confirmed low levels of AO in effluents with mean C12 and C14AO concentrations of 52.8 and 20.1ng/L respectively. Based on the monitoring data, the 90th percentile concentrations of C12 and C14AO for 7Q10 low flow stream conditions were >2 orders of magnitude lower than the predicted no effect concentrations indicating negligible aquatic risk from AO in US receiving streams. This study verifies that AO is safe for the aquatic environment even at the currently high usage volumes due to rapid biodegradation during transit through the sewer and wastewater treatment. PMID- 29112840 TI - Antibiotics and common antibacterial biocides stimulate horizontal transfer of resistance at low concentrations. AB - There is a rising concern that antibiotics, and possibly other antimicrobial agents, can promote horizontal transfer of antibiotic resistance genes. For most types of antimicrobials their ability to induce conjugation below minimal inhibitory concentrations (MICs) is still unknown. Our aim was therefore to explore the potential of commonly used antibiotics and antibacterial biocides to induce horizontal transfer of antibiotic resistance. Effects of a wide range of sub-MIC concentrations of the antibiotics cefotaxime, ciprofloxacin, gentamicin, erythromycin, sulfamethoxazole, trimethoprim and the antibacterial biocides chlorhexidine digluconate, hexadecyltrimethylammoniumchloride and triclosan were investigated using a previously optimized culture-based assay with a complex bacterial community as a donor of mobile resistance elements and a traceable Escherichia coli strain as a recipient. Chlorhexidine (24.4MUg/L), triclosan (0.1mg/L), gentamicin (0.1mg/L) and sulfamethoxazole (1mg/L) significantly increased the frequencies of transfer of antibiotic resistance whereas similar effects were not observed for any other tested antimicrobial compounds. This corresponds to 200 times below the MIC of the recipient for chlorhexidine, 1/20 of the MIC for triclosan, 1/16 of the MIC for sulfamethoxazole and right below the MIC for gentamicin. To our best knowledge, this is the first study showing that triclosan and chlorhexidine could stimulate the horizontal transfer of antibiotic resistance. Together with recent research showing that tetracycline is a potent inducer of conjugation, our results indicate that several antimicrobials including both common antibiotics and antibacterial biocides at low concentrations could contribute to antibiotic resistance development by facilitating the spread of antibiotic resistance between bacteria. PMID- 29112841 TI - Extraction and quantification of chlorophenolate molecules in soils spiked with 2,4-dichlorophenol and 2,4,5-trichlorophenol. AB - The compounds 2,4-dichlorophenol (2,4-DCP) and 2,4,5-trichlorophenol (2,4,5-TCP) are classified as priority pollutants, with potentially hazardous impacts on the environment. In soil, dissociation of the phenol group occurs, resulting in the simultaneous presence of neutral phenol and anionic phenolate. Although the toxicity of 2,4-DCP and 2,4,5-TCP to soil microbiota has been suggested to be mainly due to the phenolate anion, this hypothesis cannot be tested due to the lack of appropriate methods of extracting and quantifying the anionic form of these compounds (unlike the neutral form, which can be easily quantified). In this study, we developed a method that enables extraction and quantification of phenolate ions. The method could therefore be used to elucidate the processes that regulate the behaviour of chlorophenolic molecules in soil and to clarify the distribution and toxicity of these compounds in the edaphic environment. The proposed method uses saline solutions (CaCl2, KCl and K2SO4) of low ionic strength to extract the chlorophenolate anion from soil, followed by sequential transformation of the anion from the aqueous solution to an organic solvent that enables subsequent identification and quantification of the molecule by gas chromatography. Two soils of contrasting pH were used to test whether the proposed method was practicable. The method enabled analysis of the distribution of the neutral and anionic forms of the chlorophenols in both types of soil considered and revealed the influence of soil pH in this distribution. PMID- 29112842 TI - Occurrence and geodatabase mapping of three contaminants of emerging concern in receiving water and at effluent from waste water treatment plants - A first overview of the situation in the Republic of Ireland. AB - This constitutes the first study to address occurrence and geodatabase mapping of the anti-inflammatory drug diclofenac (DCL) and the natural (17-beta-estradiol or E2) and synthetic (17-alpha-ethynylestradiol or EE2) estrogenic hormones in Republic of Ireland receiving waters over the period 1999 to 2015. Among these data, 317 samples came from concentration studies, while 205 were from effect based studies. Monitoring data came from 16 waste water treatment plants (WWTPs), 23 water bodies (including rivers, lakes, marine and transitional waters) and 7 from domestic locations. Out of approximately 1000 WWPTs in the Republic of Ireland, only 16 have been monitored for at least one of these compounds of emerging concern (CECs). Diclofenac is found in treated effluents from 5 WWTPs at levels at least as high as other European WWPTs, and sometime higher. Measurements of E2 and EE2 in WWPT effluents were rare and effluents were more often evaluated for total estrogens; these CECs were generally not detected using conventional analytical methods because of limits of detection being too high compared to environmental concentrations and WFD environmental quality standards. There was good agreement between occurrence of these CEC and regional drug dispensing data in Ireland. Mapping the aforementioned data onto appropriate river basin catchment management tools will inform predictive and simulated risk determinations to inform investment in infrastructure that is necessary to protect rivers and beaches and economic activities that rely on clean water. There is a pressing commensurate need to refine/develop new analytical methods with low levels of detection for future CEC intervention. PMID- 29112843 TI - Modeling future water footprint of barley production in Alberta, Canada: Implications for water use and yields to 2064. AB - Despite the perception of being one of the most agriculturally productive regions globally, crop production in Alberta, a western province of Canada, is strongly dependent on highly variable climate and water resources. We developed agro hydrological models to assess the water footprint (WF) of barley by simulating future crop yield (Y) and consumptive water use (CWU) within the agricultural region of Alberta. The Soil and Water Assessment Tool (SWAT) was used to develop rainfed and irrigated barley Y simulation models adapted to sixty-seven and eleven counties, respectively through extensive calibration, validation, sensitivity, and uncertainty analysis. Eighteen downscaled climate projections from nine General Circulation Models (GCMs) under the Representative Concentration Pathways 2.6 and 8.5 for the 2040-2064 period were incorporated into the calibrated SWAT model. Based on the ensemble of GCMs, rainfed barley yield is projected to increase while irrigated barley is projected to remain unchanged in Alberta. Results revealed a considerable decrease (maximum 60%) in WF to 2064 relative to the simulated baseline 1985-2009 WF. Less water will also be required to produce barley in northern Alberta (rainfed barley) than southern Alberta (irrigated barley) due to reduced water consumption. The modeled WF data adjusted for water stress conditions and found a remarkable change (increase/decrease) in the irrigated counties. Overall, the research framework and the locally adapted regional model results will facilitate the development of future water policies in support of better climate adaptation strategies by providing improved WF projections. PMID- 29112844 TI - Polycyclic aromatic hydrocarbons in house dust and surface soil in major urban regions of Nepal: Implication on source apportionment and toxicological effect. AB - Urban centers have turned to be the provincial store for resource consumptions and source releases of different types of semi-volatile organic compounds (SVOCs) including polycyclic aromatic hydrocarbons (PAHs), bringing about boundless environmental pollutions, among different issues. Human prosperity inside urban communities is unambiguously dependent on the status of urban soils and house dusts. However, environmental occurrence and sources of release of these SVOCs are challenging in Nepalese cities, as exceptionally very limited data are accessible. This motivated us to explore the environmental fate, their source/sink susceptibilities and health risk associated with PAHs. In this study, we investigated the contamination level, environmental fate and sources/sink of 16 EPA's priority pollutants in surface soil and house dusts from four major cities of Nepal. Additionally, the toxicological effect of individual PAH was studied to assess the health risk of PAHs. Generally, the concentrations of ?16PAHs in surface soil were 1.5 times higher than house dust, and ranged 767 6770ng/g dry weight (dw) (median 1810ng/g dw), and 747-4910 dw (median 1320ng/g dw), respectively. High molecular weight-PAHs both in soil and dust were more abundant than low molecular weight-PAHs, suggesting the dominance of pyrogenic source. Moderate to weak correlation of TOC and BC with PAHs in soil and dust suggested little or no role of soil organic carbon in sorption of PAHs. Source diagnostic ratio and principal component analysis indicated fossil fuel combustion, traffic/vehicular emissions and combustion of biomass are the principal sources of PAHs contamination in Nepalese urban environment. The high average TEQ value of PAHs in soil than dust suggested high risk of soil carcinogenicity compared to dust. PMID- 29112845 TI - Small RNAs Turn Over a New Leaf as Morphogens. AB - In this issue of Developmental Cell, Skopelitis et al. (2017) demonstrate that sharp boundaries of gene expression can be created by threshold-based readout of mobile small RNA gradients. Support for this hypothesis comes from manipulation of small RNAs involved in top-bottom leaf patterning and from a novel synthetic biology approach. PMID- 29112846 TI - Adding a Piece to the Leaf Epidermal Cell Shape Puzzle. AB - The jigsaw puzzle-shaped pavement cells in the leaf epidermis collectively function as a load-bearing tissue that controls organ growth. In this issue of Developmental Cell, Majda et al. (2017) shed light on how the jigsaw shape can arise from localized variations in wall stiffness between adjacent epidermal cells. PMID- 29112847 TI - Evidence for Converging DNA Methylation Pathways in Placenta and Cancer. AB - CpG island promoters are generally devoid of DNA methylation in somatic cells but are frequently methylated during tumorigenesis. Reporting recently in Nature, Smith et al. (2017) show that the signaling-induced methylome in early extraembryonic tissues resembles that of many cancers, suggesting that placental nuclear programming might be co-opted in tumorigenesis. PMID- 29112848 TI - Vms1 Relieves a Mitochondrial Import Chokehold. AB - Ribosome stalling results in the production of truncated proteins that can cause proteotoxic stress if not efficiently degraded. A recent paper by Izawa et al. (2017) identifies Vms1 as a key player in the regulation of ribosome quality control specifically on mitochondria-localized ribosomes, ultimately preventing protein aggregate accumulation within mitochondria. PMID- 29112849 TI - Astrocytes Supply Presynaptic Terminals with a Sweet Incentive to Make Connections. AB - Glial cells shape neural circuits by secreting cues that contribute to the spatiotemporal control of connectivity. A new study in Neuron from Farhy Tselnicker et al. (2017) shows that the astrocyte-secreted heparan sulfate proteoglycan GPC4 acts on presynaptic terminals to indirectly regulate AMPA receptor clustering and active synapse formation. PMID- 29112850 TI - Mechanochemical Polarization of Contiguous Cell Walls Shapes Plant Pavement Cells. AB - The epidermis of aerial plant organs is thought to be limiting for growth, because it acts as a continuous load-bearing layer, resisting tension. Leaf epidermis contains jigsaw puzzle piece-shaped pavement cells whose shape has been proposed to be a result of subcellular variations in expansion rate that induce local buckling events. Paradoxically, such local compressive buckling should not occur given the tensile stresses across the epidermis. Using computational modeling, we show that the simplest scenario to explain pavement cell shapes within an epidermis under tension must involve mechanical wall heterogeneities across and along the anticlinal pavement cell walls between adjacent cells. Combining genetics, atomic force microscopy, and immunolabeling, we demonstrate that contiguous cell walls indeed exhibit hybrid mechanochemical properties. Such biochemical wall heterogeneities precede wall bending. Altogether, this provides a possible mechanism for the generation of complex plant cell shapes. PMID- 29112851 TI - Propagating Wave of ERK Activation Orients Collective Cell Migration. AB - The biophysical framework of collective cell migration has been extensively investigated in recent years; however, it remains elusive how chemical inputs from neighboring cells are integrated to coordinate the collective movement. Here, we provide evidence that propagation waves of extracellular signal-related kinase (ERK) mitogen-activated protein kinase activation determine the direction of the collective cell migration. A wound-healing assay of Mardin-Darby canine kidney (MDCK) epithelial cells revealed two distinct types of ERK activation wave, a "tidal wave" from the wound, and a self-organized "spontaneous wave" in regions distant from the wound. In both cases, MDCK cells collectively migrated against the direction of the ERK activation wave. The inhibition of ERK activation propagation suppressed collective cell migration. An ERK activation wave spatiotemporally controlled actomyosin contraction and cell density. Furthermore, an optogenetic ERK activation wave reproduced the collective cell migration. These data provide new mechanistic insight into how cells sense the direction of collective cell migration. PMID- 29112852 TI - Neural Lineage Progression Controlled by a Temporal Proliferation Program. AB - Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I->0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems. PMID- 29112854 TI - HBL1 Is a Human Long Noncoding RNA that Modulates Cardiomyocyte Development from Pluripotent Stem Cells by Counteracting MIR1. PMID- 29112853 TI - The Zygotic Transition Is Initiated in Unicellular Plant Zygotes with Asymmetric Activation of Parental Genomes. AB - The zygotic transition, from a fertilized egg to an embryo, is central to animal and plant reproduction. Animal embryos depend upon maternally provided factors until zygotic genome activation (ZGA). In plants, the timing and parental genome contributions to ZGA are unresolved. Here, we use the flowering plant Oryza sativa (rice) to characterize transcriptomes of time-staged isogenic and hybrid zygotes following fertilization. Large-scale transcriptomic changes were observed in unicellular zygotes, including upregulation of S-phase genes, a characteristic of ZGA. The parental contributions to ZGA were highly asymmetric. Zygotic transcription was primarily from the maternal genome and included genes for basic cellular processes. Transcription of the paternal genome was highly restricted but unexpectedly included genes encoding putative pluripotency factors expressed at the onset of ZGA. Thus, distinct transcriptional activities are exhibited by the parental genomes during the initiation of embryogenesis, which presumptively derive from divergent pre-zygotic transcriptional states established in the gametes. PMID- 29112855 TI - Teachers' stress intensifies violent disciplining in Tanzanian secondary schools. AB - Violent forms of discipline in schools continue to be widespread across the globe despite their damaging effects. Since little is known about factors influencing the extent of violence applied by teachers, this study aimed to investigate the influence of teachers' stress, work satisfaction, and personal characteristics on their disciplining style. Using structural equation modeling, associations between violent discipline, burnout symptoms, and job perceptions (pressure and difficulties in class) reported by 222 teachers from 11 secondary schools in Tanzania in 2015 were analyzed. Results indicated a direct association between perceived stress and emotional violent discipline (beta=.18, p<.05) as well as physical violent discipline (beta=.37, p<.001). Perceived stress also mediated the association between job perceptions and both forms of violent disciplining. The model showed good model fit (chi2 [44, n=222]=67.47 (p=.013), CFI=.94, TLI=.91, IFI=.94, RMSEA=.049 [90%-CI=.02-.07, PCLOSE=.50], SRMR=.06). Our findings suggest that teachers' personal perceptions of their work as well as their stress burden play a role in their disciplining styles. Our findings underline the importance of integrating topics, such as stress and coping as well as positive, nonviolent discipline measures into the regular teacher's training and in addition to develop and evaluate school-based preventative interventions for teachers. PMID- 29112856 TI - The experience of violence against children in domestic servitude in Haiti: Results from the Violence Against Children Survey, Haiti 2012. AB - BACKGROUND: There have been estimates that over 150,000 Haitian children are living in servitude. Child domestic servants who perform unpaid labor are referred to as "restaveks." Restaveks are often stigmatized, prohibited from attending school, and isolated from family placing them at higher risk for experiencing violence. In the absence of national data on the experiences of restaveks in Haiti, the study objective was to describe the sociodemographic characteristics of restaveks in Haiti and to assess their experiences of violence in childhood. METHODS: The Violence Against Children Survey was a nationally representative, cross-sectional household survey of 13-24year olds (n=2916) conducted May-June 2012 in Haiti. A stratified three-stage cluster design was used to sample households and camps containing persons displaced by the 2010 earthquake. Respondents were interviewed to assess lifetime prevalence of physical, emotional, and sexual violence occurring before age 18. Chi-squared tests were used to assess the association between having been a restavek and experiencing violence in childhood. FINDINGS: In this study 17.4% of females and 12.2% of males reported having been restaveks before age 18. Restaveks were more likely to have worked in childhood, have never attended school, and to have come from a household that did not have enough money for food in childhood. Females who had been restaveks in childhood had higher odds of reporting childhood physical (OR 2.04 [1.40-2.97]); emotional (OR 2.41 [1.80-3.23]); and sexual violence (OR 1.86 [95% CI 1.34-2.58]) compared to females who had never been restaveks. Similarly, males who had ever been restaveks in childhood had significantly increased odds of emotional violence (OR 3.06 [1.99-4.70]) and sexual violence (OR 1.85 [1.12-3.07]) compared to males who had never been restaveks, but there was no difference in childhood physical violence. INTERPRETATION: This study demonstrates that child domestic servants in Haiti experience higher rates of childhood violence and have less access to education and financial resources than other Haitian children. These findings highlight the importance of addressing both the lack of human rights law enforcement and the poor economic circumstances that allow the practice of restavek to continue in Haiti. PMID- 29112857 TI - Tongue development in stillborns autopsied at different gestational ages. AB - OBJECTIVES: This study aimed to analyze, through the morphometric method, the perimeter and length of the tongue, the collagen fibers, and the perimeter of blood vessels at different gestational ages and fetal weights. MATERIAL AND METHODS: Tongues (n=55) of stillborns autopsied at 23-40 weeks of gestational age were macroscopically analyzed, and their length and perimeter were measured. Fifty-five tongue fragments were collected through a longitudinal section in the region that accompanies the median lingual sulcus and histologically processed. Slides were stained with picrosirius and immunolabeled with CD31 antibody. Quantification was performed on collagen fibers under polarized light, and on the perimeter of vessels with the CD31. RESULTS: A positive and significant correlation of gestational age with tongue perimeter and length was found. There was a positive and significant correlation between collagen fibers and gestational age, as well as between gestational age and the perimeter of blood vessels. Between collagen fibers and fetal weight, a positive and significant increase was observed. Regarding the correlation between the perimeter of blood vessels and the fetal weight, an increase was observed. CONCLUSION: As gestational age advances, there is an increase in tongue perimeter and length, in the percentage of collagen fibers, and in vascular perimeter, demonstrating that tongue formation is directly related to tongue growth and development. PMID- 29112858 TI - Sensory abnormalities in children with autism spectrum disorder. AB - OBJECTIVE: The clinical picture of children with autism spectrum disorder is characterized by deficits of social interaction and communication, as well as by repetitive interests and activities. Sensory abnormalities are a very frequent feature that often go unnoticed due to the communication difficulties of these patients. This narrative review summarizes the main features of sensory abnormalities and the respective implications for the interpretation of several signs and symptoms of autism spectrum disorder, and therefore for its management. SOURCES: A search was performed in PubMed (United States National Library of Medicine) about the sensory abnormalities in subjects (particularly children) with autism spectrum disorder. SUMMARY OF THE FINDINGS: Sensory symptoms are common and often disabling in children with autism spectrum disorder, but are not specific for autism, being a feature frequently described also in subjects with intellectual disability. Three main sensory patterns have been described in autism spectrum disorder: hypo-responsiveness, hyper-responsiveness, and sensory seeking; to these, some authors have added a fourth pattern: enhanced perception. Sensory abnormalities may negatively impact the life of these individuals and their families. An impairment not only of unisensory modalities but also of multisensory integration is hypothesized. CONCLUSIONS: Atypical sensory reactivity of subjects with autism spectrum disorder may be the key to understand many of their abnormal behaviors, and thus it is a relevant aspect to be taken into account in their daily management in all the contexts in which they live. A formal evaluation of sensory function should be always performed in these children. PMID- 29112859 TI - Translation and cultural adaptation of the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS v2.0). AB - OBJECTIVES: To translate and culturally adapt the Pediatric Eosinophilic Esophagitis Symptom Score (version 2.0), a tool used to assess pediatric eosinophilic esophagitis symptoms reported by patients and/or their parents/caregivers. METHODS: The Pediatric Eosinophilic Esophagitis Symptom Score was translated through the following stages: initial translation, back translation, and consensus of independent reviewers through the Delphi technique. The pre-final version of the Pediatric Eosinophilic Esophagitis Symptom Score was applied to five 8-to-18-year-old patients and to ten parents of two-to-18-year old patients from an outpatient pediatric gastroenterology service (pre-test). RESULTS: During the translation process, no translations presenting with difficult consensus in the review process or grammar inconsistencies were observed. During the pre-test, difficulties in comprehension of some unconventional terms, e.g., "nausea", were observed. Adverbs of frequency, such as "quase nunca" were also identified as being of difficult understanding by patients and parents, and the substitution by the term "raramente" was suggested. Such difficulties may be inherent to the pediatric age group. Age 8 years or above should be considered adequate for the self-reporting of symptoms. CONCLUSIONS: The study presents the Brazilian version of the Pediatric Eosinophilic Esophagitis Symptom Score, which is adapted to the Brazilian culture. This version may be introduced as a clinical and research tool for the assessment of patients with esophagic disease symptoms. The Pediatric Eosinophilic Esophagitis Symptom Score is a breakthrough in the evaluation of symptoms of pediatric eosinophilic esophagitis, since it reinforces the importance of self-reporting by patients who experience this disease. PMID- 29112860 TI - Parental competence programs to promote positive parenting and healthy lifestyles in children: a systematic review. AB - OBJECTIVE: To analyze the available evidence regarding the efficacy of interventions on parents whose children were aged 2-5 years to promote parental competence and skills for children's healthy lifestyles. SOURCE: Articles published in English and Spanish, available at PubMed, Psycinfo, CINAHL, Web of Science, Eric, and Cochrane Library were reviewed. SUMMARY OF THE FINDINGS: The literature search yielded 2282 articles. Forty-one full texts were retrieved and assessed for inclusion using the PRISMA flow diagram. Twenty-six articles were excluded, as they did not meet the inclusion criteria. In the end, 15 studies were included. The studies were conducted between 2003 and 2016, nine in North America, four in Europe, and two in Asia. Extracted data were synthesized in a tabular format. CASPe guide was used to assess the quality of studies that was moderate overall. Parental self-efficacy was the main construct assessed in most studies. Four studies reported an increase in parental self-efficacy, although most of them were studies without control groups. CONCLUSIONS: Outcomes of interventions to improve parental competence in order to promote children's lifestyles are promising, but inconsistent. Additional studies with higher methodological and conceptual quality are needed. PMID- 29112862 TI - Oilbirds. AB - A Quick guide to oilbirds: nocturnal birds found only in Neotropical rainforests that, rather like many bat species, live in caves where they use echolocation for orientation. PMID- 29112861 TI - Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf). AB - Mesothelioma is a fatal tumor of the pleura and is strongly associated with asbestos exposure. The molecular mechanisms underlying the long latency period of mesothelioma and driving carcinogenesis are unknown. Moreover, late diagnosis means that mesothelioma research is commonly focused on end-stage disease. Although disruption of the CDKN2A (INK4A/ARF) locus has been reported in end stage disease, information is lacking on the status of this key tumor suppressor gene in pleural lesions preceding mesothelioma. Manufactured carbon nanotubes (CNTs) are similar to asbestos in terms of their fibrous shape and biopersistent properties and thus may pose an asbestos-like inhalation hazard. Here we show that instillation of either long CNTs or long asbestos fibers into the pleural cavity of mice induces mesothelioma that exhibits common key pro-oncogenic molecular events throughout the latency period of disease progression. Sustained activation of pro-oncogenic signaling pathways, increased proliferation, and oxidative DNA damage form a common molecular signature of long-CNT- and long asbestos-fiber-induced pathology. We show that hypermethylation of p16/Ink4a and p19/Arf in CNT- and asbestos-induced inflammatory lesions precedes mesothelioma; this results in silencing of Cdkn2a (Ink4a/Arf) and loss of p16 and p19 protein, consistent with epigenetic alterations playing a gatekeeper role in cancer. In end-stage mesothelioma, silencing of p16/Ink4a is sustained and deletion of p19/Arf is detected, recapitulating human disease. This study addresses the long standing question of which early molecular changes drive carcinogenesis during the long latency period of mesothelioma development and shows that CNT and asbestos pose a similar health hazard. PMID- 29112863 TI - The liver. AB - The liver is a critical hub for numerous physiological processes. These include macronutrient metabolism, blood volume regulation, immune system support, endocrine control of growth signaling pathways, lipid and cholesterol homeostasis, and the breakdown of xenobiotic compounds, including many current drugs. Processing, partitioning, and metabolism of macronutrients provide the energy needed to drive the aforementioned processes and are therefore among the liver's most critical functions. Moreover, the liver's capacities to store glucose in the form of glycogen, with feeding, and assemble glucose via the gluconeogenic pathway, in response to fasting, are critical. The liver oxidizes lipids, but can also package excess lipid for secretion to and storage in other tissues, such as adipose. Finally, the liver is a major handler of protein and amino acid metabolism as it is responsible for the majority of proteins secreted in the blood (whether based on mass or range of unique proteins), the processing of amino acids for energy, and disposal of nitrogenous waste from protein degradation in the form of urea metabolism. Over the course of evolution this array of hepatic functions has been consolidated in a single organ, the liver, which is conserved in all vertebrates. Developmentally, this organ arises as a result of a complex differentiation program that is initiated by exogenous signal gradients, cellular localization cues, and an intricate hierarchy of transcription factors. These processes that are fully developed in the mature liver are imperative for life. Liver failure from any number of sources (e.g. viral infection, overnutrition, or oncologic burden) is a global health problem. The goal of this primer is to concisely summarize hepatic functions with respect to macronutrient metabolism. Introducing concepts critical to liver development, organization, and physiology sets the stage for these functions and serves to orient the reader. It is important to emphasize that insight into hepatic pathologies and potential therapeutic avenues to treat these conditions requires an understanding of the development and physiology of specialized hepatic functions. PMID- 29112864 TI - Compass orientation drives naive pelagic seabirds to cross mountain ranges. AB - Wildlife migration is a spectacular phenomenon [1]. Studies using telemetry - tracking devices attached on free-living animals - have shown that large topographic barriers and obstacles, such as oceans and deserts, elicit extreme feats of migration [2]. Overcoming the challenges of these obstacles might require experience and skill that young individuals lack [2-5]. Further, younger, inexperienced animals might determine their migration routes using navigation strategies different from those of older animals [6-9], but our knowledge of how orientation mechanisms and experience drive migration strategy is limited. We have studied how experienced (adults) and inexperienced (first-time migrating fledglings) streaked shearwaters (Calonectris leucomelas) approach the challenge of migration using animal-borne tracking devices. The study birds migrate from a colony on the north of a large topographic barrier, Honshu Island, Japan. Shearwaters use a wind- and wave-based flight pattern-dynamic soaring-to extract energy for highly efficient travel over oceans [10]. We therefore expected that shearwaters migrating southward from the colony would make substantial detours to avoid any landmasses. We found that migrating adults followed one of two paths that detour around landmasses that hinder direct southerly migration. In contrast, inexperienced fledglings followed a straight course in a south-oriented direction that forced them to complete a trans-mountain journey, suggesting that the birds rely on an innate compass. Thus, we suggest that fledglings would eventually override the simple compass navigation, which appears to be the primary driver for their extreme migration, before being able to interact appropriately with the marine environment. PMID- 29112866 TI - Insect Neurobiology: An Eye to Forward Motion. AB - For many animals, visual motion provides essential information for navigating through the environment. A new study in flies reveals novel neurons capable of multiplexing information of a visual scene and encoding relative depth perception from motion disparity. PMID- 29112865 TI - Tread-water feeding of Bryde's whales. AB - Many previous studies have shown that rorqual whales (Balaenopteridae), including the blue whale (Balaenoptera musculus), fin whale (B. physalus), sei whale (B. borealis), Bryde's whale (B. edeni), minke whale (B. acutorostrata), and humpback whale (Megaptera novaeangliae), employ a strategy called lunge feeding to capture a large amount of krill and/or fish for nourishment [1]. Lunge feeding entails a high energetic cost due to the drag created by an open mouth at high speeds [1,2]. In the upper Gulf of Thailand, Bryde's whales, which feed on small fish species [3], predominantly anchovies, demonstrated a range of feeding behaviors such as oblique, vertical, and lateral lunging. Moreover, they displayed a novel head-lifting feeding behavior characterized by holding the vertical posture for several seconds with an open mouth at the water surface. This study describes the head-lifting feeding by Bryde's whales, which is distinct from the typical lunge feeding of rorqual whales. Whales showing this behavior were observed on 58 occasions, involving 31 whales and including eight adult-calf pairs. Whales caught their prey using a series of coordinated movements: (i) lifting the head above the water with a closed mouth, (ii) opening the mouth until the lower jaw contacted the sea surface, which created a current of water flowing into the mouth, (iii) holding their position for several seconds, (iv) waiting for the prey to enter the mouth, and (v) closing the mouth and engulfing the prey underwater (Figure 1A-F, Movie S1 in Supplemental Information published with this article online). When a whale kept its upper jaw above the sea surface, many anchovies in the targeted shoal appeared to lose orientation and flowed passively into the mouth of the whale by the current created by the lower mandible breaking the surface of the water. We measured the duration of feeding events when the whales had a wide-open mouth mostly above the sea surface. The mean and maximum feeding durations were 14.5 +/- 5.4 (SD; n = 58 events) and 32 s, respectively. Deployment of animal-borne data loggers yielded approximately 44 minutes of recordings from a single whale. The acceleration data showed that stroke rates, including tail beat and whole-body movements during feeding, were faster (approximately 0.7 s cycle) than during a cruising swim (approximately 3 s cycle) (Figure 1G). The swimming speed was lower than that in the stall speed (0.2 m s 1) of the device during the feeding phase, suggesting that thrust force was used to hold the head up and to stabilize body posture (Figure 1G). Stable positioning using the fluke and flipper was confirmed by video data for both the downward and upward direction of the whale (Figure S1). According to the visual and behavioral data, we named the head-lifting feeding as 'tread-water feeding'. Generally, all species of baleen whale, including rorqual whales, show active chasing and feeding, i.e., skimming, suction, and engulfing with lunging [1]. Tread-water feeding is considered passive feeding as compared with other feeding behaviors because the whales do not swim forward in pursuit of prey during the period from mouth opening to closing, and although they need thrust force to stabilize their posture, the head does not actively move. To the best of our knowledge, this discovery of tread-water feeding in Bryde's whales represents the first report of passive feeding in baleen whales, which indicates their flexible capacity to modify their foraging strategy in relation to variable environments. PMID- 29112867 TI - Mechanosensation: A Catch Bond That Only Hooks One Way. AB - Single-molecule force spectroscopy and modeling have revealed that the adhesion molecule vinculin and F-actin form a catch bond that is dependent on the direction of forces along the actin filament. This may underlie the mechanisms by which cells sense directional physical cues. PMID- 29112868 TI - Drosophila Connectomics: Mapping the Larval Eye's Mind. AB - A new study has mapped the connectome - the shapes and connections of all the neurons- of the visual system of a Drosophila larva, providing a structural basis for understanding the neural circuitry of larval vision. PMID- 29112869 TI - Hearing: The Future of Sensory Rehabilitation? AB - A new randomized, double-blind controlled study has found that playing a video game modeled from sensory foraging behavior can improve the aging brain's ability to hear complex signals hidden in background noise. PMID- 29112870 TI - Ancient DNA: Saber-Toothed Cats Are the Same Beasts After All. AB - Ancient DNA from the saber-toothed cat Homotherium reveals that the late Pleistocene species from Europe and North America were the same. Homotherium turns out to be only distantly related to the well-known saber-toothed Smilodon. PMID- 29112871 TI - Chromosome Segregation: Is the Spindle All About Microtubules? AB - The spindle segregates chromosomes in cell division and it has long been discussed whether it is microtubules alone that build this fundamental molecular machine. Recent work in mouse oocytes now shows that actin filaments co-assemble with microtubules to promote faithful chromosome segregation. PMID- 29112872 TI - Microbiology: And Amoebophilus Invented the Machine Gun! AB - Bacterial contractile injection systems are fascinating particles that use a spring-like mechanism to inject an effector-loaded needle into target cells. A recent study shows that the intracellular bacterium Amoebophilus asiaticus uses arrays of contractile structures to escape from the amoeba phagosome. PMID- 29112873 TI - Mesothelioma: Identical Routes to Malignancy from Asbestos and Carbon Nanotubes. AB - Exposure of laboratory mice to carbon nanotubes mimics exposure to asbestos, from initial and chronic inflammation, through loss of the same tumour-suppressor pathways and eventual sporadic development of malignant mesothelioma. Fibres of a similar nature may pose significant health risks to humans. PMID- 29112874 TI - The Origin and Diversification of Mitochondria. AB - Mitochondria are best known for their role in the generation of ATP by aerobic respiration. Yet, research in the past half century has shown that they perform a much larger suite of functions and that these functions can vary substantially among diverse eukaryotic lineages. Despite this diversity, all mitochondria derive from a common ancestral organelle that originated from the integration of an endosymbiotic alphaproteobacterium into a host cell related to Asgard Archaea. The transition from endosymbiotic bacterium to permanent organelle entailed a massive number of evolutionary changes including the origins of hundreds of new genes and a protein import system, insertion of membrane transporters, integration of metabolism and reproduction, genome reduction, endosymbiotic gene transfer, lateral gene transfer and the retargeting of proteins. These changes occurred incrementally as the endosymbiont and the host became integrated. Although many insights into this transition have been gained, controversy persists regarding the nature of the original endosymbiont, its initial interactions with the host and the timing of its integration relative to the origin of other features of eukaryote cells. Since the establishment of the organelle, proteins have been gained, lost, transferred and retargeted as mitochondria have specialized into the spectrum of functional types seen across the eukaryotic tree of life. PMID- 29112875 TI - Utilizing Geographic Information Systems (GIS) to analyze geographic and demographic patterns related to forensic case recovery locations in Florida. AB - This paper highlights how Geographic Information Systems (GIS) can be utilized to analyze biases and patterns related to physical and cultural geography in Florida. Using case recovery locations from the C. Addison Pound Human Identification Laboratory (CAPHIL), results indicate that the majority of CAPHIL cases are recovered from urban areas with medium to low population density and low rates of crime. The results also suggest that more accurate record keeping methods would enhance the data. PMID- 29112876 TI - Factors influencing attitudes toward advance directives in Korean older adults. AB - AIM: We aimed to determine the factors influencing attitudes toward advance directives in Korean older adults with consideration of an Asian cultural background. METHODS: We recruited community-dwelling older adults aged 60 years or older at a regional senior welfare center in Korea. Demographic factors and mental and physical health status were examined using questionnaires and a physical examination. The questionnaire also assessed perceived necessity of advance directives and related experiences. RESULTS: Most participants (79.32%) agreed that advance directives were necessary. Older adults with high education levels (odds ratio [OR] 2.31, 95% confidence interval [CI] 0.84-6.34), low economic status (OR 2.09, 95% C.I. 0.60-7.27), and poor cognitive function (adjusted odds ratio [aOR] 2.10, 95% CI 0.89-4.97) had a greater odds of agreeing that advance directives are necessary. All participants with self-care problems (9/9) and most participants with at risk status of physical functioning (13/14) reported agreement. Death-related experiences were also associated. Notably, individuals who had discussions on end-of-life care with family members showed a greater odds of agreeing that advance directives are necessary (aOR 2.12, 95% CI 0.88-5.11). CONCLUSIONS: The factors associated with increased agreement that advance directives are necessary were high education level, low economic status, poor cognitive function, problems in self-care, poor physical functioning, death related experiences. Especially, discussions of end-of-life care with family members increased the agreement. Thus, discussion on end-of-life care should be encouraged and the factors influencing older adults' attitudes toward advance directives should be considered in developing policies for such discussion. PMID- 29112877 TI - Weakness: The most frequent criterion among pre-frail and frail older Portuguese. AB - AIM: In Portugal, the burden of pre-frailty and frailty in community-dwelling older adults is still unknown. The purpose of this study is to estimate the frequency of frailty in a Portuguese sample with >= 65years and to evaluate its associated factors. We also intend to identify which criterion has more impact on the diagnosis of frailty. METHODS: 1457 older adults with >= 65years from the Nutrition UP 65 study were evaluated in a cross-sectional analysis. Frailty was identified according to Fried et al. by the presence of three or more of the following factors: unintentional weight loss, self-reported exhaustion, slowness, weakness and low physical activity. Pre-frailty was defined as the presence of one or two of these criteria. The association between individuals' characteristics and frailty status was analysed through logistic regression analysis. RESULTS: The frequency of pre-frailty and frailty is 54.3% and 21.5%, respectively. In older adults classified as pre-frail or frail, 76.7% presented weakness and 48.6% exhaustion. In multivariate analyses, frailty was associated with age >75, lower education level, being single, divorced or widower, being professionally inactive, poor self-perception of health status, not drinking alcohol, being obese and undernourished or at undernutrition risk. CONCLUSION: This condition is very prevalent in Portuguese older adults, one fifth are frail whereas half are pre-frail. Weakness identified by low handgrip strength is the most prevalent criterion in pre-frail and frail Portuguese older adults. PMID- 29112878 TI - Reproductive and endocrine-disrupting toxicity of Microcystis aeruginosa in female zebrafish. AB - Microcystis aeruginosa, a primary species in cyanobacterial blooms, is ubiquitously distributed in water. Microcystins (MCs) purified from M. aeruginosa can exert reproductive toxicity in fish. However, the effects of M. aeruginosa at environmentally relevant levels on the reproductive and endocrine systems of zebrafish are still unknown. The present study investigated the reproductive and endocrine-disrupting toxicity of M. aeruginosa on female zebrafish (Danio rerio) by short-term exposure (96 h). After exposure, marked histological lesions in the liver or gonads, such as nuclear pyknosis and deformation, were observed, and the fertilization rate and hatchability of eggs spawned from treated females were both significantly lower than they were in females in the control group, suggesting the possibility of transgenerational effects of M. aeruginosa exposure. Moreover, M. aeruginosa exposure decreased the concentration of 17beta estradiol (E2) and testosterone (T) in female zebrafish. Interestingly, the vtg1 transcriptional level significantly decreased in the liver, whereas plasma vitellogenin (VTG) protein levels increased. The present findings indicate that M. aeruginosa could modulate endocrine function by disrupting transcription of hypothalamic-pituitary-gonadal-liver (HPGL) axis-related genes, and impair the reproductive capacity of female zebrafish, suggesting that M. aeruginosa causes potential adverse effects on fish reproduction in Microcystis bloom-contaminated aquatic environments. PMID- 29112879 TI - Myocardial strain computed at multiple spatial scales from tagged magnetic resonance imaging: Estimating cardiac biomarkers for CRT patients. AB - Abnormal cardiac motion can indicate different forms of disease, which can manifest at different spatial scales in the myocardium. Many studies have sought to characterise particular motion abnormalities associated with specific diseases, and to utilise motion information to improve diagnoses. However, the importance of spatial scale in the analysis of cardiac deformation has not been extensively investigated. We build on recent work on the analysis of myocardial strains at different spatial scales using a cardiac motion atlas to find the optimal scales for estimating different cardiac biomarkers. We apply a multi scale strain analysis to a 43 patient cohort of cardiac resynchronisation therapy (CRT) patients using tagged magnetic resonance imaging data for (1) predicting response to CRT, (2) identifying septal flash, (3) estimating QRS duration, and (4) identifying the presence of ischaemia. A repeated, stratified cross validation is used to demonstrate the importance of spatial scale in our analysis, revealing different optimal spatial scales for the estimation of different biomarkers. PMID- 29112881 TI - Safe Driving Climate among Friends (SDCaF): A new scale. AB - Reckless driving among young people, especially young men, is a major cause of injury and fatalities the world over. Like other aspects of this age group, young drivers' driving behaviors and norms are influenced by the accepted social discourse of their peers. Yet despite extensive existing knowledge on young drivers, very few studies have dealt specifically with their characteristic friendship relations. This lacuna in the literature may reflect the absence of specific research tools for examining driving with friends. To fill this gap, we conducted a series of studies with 706 young drivers (aged 17-24) of both sexes aimed at developing and validating a multidimensional scale designed to examine the effect of the social relations of adolescents and young adults on their driving. Entitled Safe Driving Climate among Friends (SDCaF), the final scale consists of 19 items, which tap four dimensions of driving with friends: friends' pressure; social costs of driving with friends; communication with friends about driving; and shared commitment to safe driving. The validity of the scale was established by examining associations between its four dimensions and various variables of personality, friendship, and driving. The findings indicate good reliability and validity, with the three variables of resistance to peer influence, self-disclosure, and personal responsibility for safe driving yielding positive associations with the SDCaF dimensions communication and shared commitment to safe driving, and negative associations with the dimensions friends' pressure and social costs. General tendency to respond to social pressure was positively associated with the dimensions of friends' pressure and social costs, and negatively associated with shared commitment to safe driving. Gender differences were also found, with men scoring higher than women on friends' pressure, and lower than women on shared commitment to safe driving. The SDCaF can serve as a research tool, as well as a diagnostic instrument for detecting susceptibility to reckless driving among young drivers, thereby aiding in the design of targeted educational and intervention programs. PMID- 29112880 TI - The joint effects of family risk of obesity and neighborhood environment on obesity among women. AB - Obesity is a significant health problem in the United States that has encouraged a search for modifiable risk factors, such as walkable neighborhood designs. Prior research has shown linkages between a family history of obesity (i.e., due to either genetic or non-genetic factors) and an individual's risk of elevated body mass index (BMI). Yet, we know little about the possible interactions between neighborhood walkability and family susceptibility to unhealthy BMI in predicting individual BMI. This paper addresses this important research gap using a sample of 9918 women, derived from vital and administrative data in the Utah Population Database. We use a novel indicator of familial risk (a summary measure of siblings' BMI) and a neighborhood walkability score to capture familial susceptibility and environmental exposures, respectively. The analysis focuses on distinct risk combinations of familial susceptibility and neighborhood walkability. Compared with the "best" combination of lean family BMI history and more walkable neighborhoods, women in all of the other three family weight history/neighborhood categories show greater risks of obesity. Our results also indicate that the neighborhood environment has a strong association with individual obesity among women with higher family risk of obesity but that the association between neighborhood environment and individual obesity is even stronger for women with a lower family risk of obesity. PMID- 29112882 TI - Age-related patterns in work-related injury claims from older New Zealanders, 2009-2013: Implications of injury for an aging workforce. AB - OBJECTIVES: This study describes the incidence, nature and cause of work-related injuries in older New Zealand workers to understand the risks of work-related injury in this rapidly aging population. METHODS: Data for the period 2009-2013 from 25,455 injured workers aged 55-79 years, extracted from national work related injury entitlement claims, were stratified by age group and analysed by sex, industry, injury type and cause. Age-specific claims rates were calculated by year, sex and ethnicity. RESULTS: Patterns of injury differed by age: 70-79 year olds had the highest injury rates and proportion of claims due to falls (45%), for the self-employed (32%), for the agriculture sector (24%), and for fatal injuries (5%). DISCUSSION: The burden of work-related injuries in older workers, particularly in those aged over 70, will increase with their increasing participation in work. Workplace injury prevention strategies and interventions need to consider the specific characteristics and vulnerabilities of older workers. PMID- 29112883 TI - A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2alpha: a potential role for targeting HIF-2alpha to prevent and treat reflux esophagitis. AB - Traditionally, reflux esophagitis was assumed to develop as a caustic, chemical injury inflicted by refluxed acid. Recently, however, studies in rats and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury, with hypoxia inducible factor (HIF)-2alpha playing a major role. In response to the reflux of acid and bile, HIF-2alpha in esophageal epithelial cells becomes stabilized, thereby increasing production of pro-inflammatory cytokines that attract T lymphocytes and other inflammatory cells to damage the esophagus. Recent studies have identified small molecule inhibitors of HIF-2alpha that demonstrate exquisite isoform selectivity, and clinical trials for treatment of HIF-2alpha-driven kidney cancers are ongoing. It is conceivable that a HIF 2alpha-directed therapy might be a novel approach to prevention and treatment of reflux esophagitis. PMID- 29112884 TI - Appearance-based rejection sensitivity as a mediator of the relationship between symptoms of social anxiety and disordered eating cognitions and behaviors. AB - Previous research has established a robust relationship between symptoms of social anxiety and disordered eating. However, the mechanisms that may underpin this relationship are unclear. Appearance-based rejection sensitivity (ABRS)-the tendency to anxiously expect and overreact to signs of appearance-based rejection may be a crucial explanatory mechanism, as ABRS has been shown to maintain social anxiety symptoms and predict disordered eating. We therefore tested whether ABRS mediated the relationship between social anxiety symptoms and various indices of disordered eating (over-evaluation of weight/shape, restraint, binge eating, compulsive exercise, and vomiting). Data from community-based females (n=299) and males (n=87) were analyzed. ABRS was shown to mediate the relationship between social anxiety and the over-evaluation, restraint, binge eating, and compulsive exercise frequency, but not vomiting. These effects also occurred for both females and males separately. Findings demonstrated that ABRS may be an important mechanism explaining why socially anxious individuals report elevated symptoms of disordered eating. Future research testing all proposed mediating variables of the social anxiety-disordered eating link in a single, integrative model is required to identify the most influential mechanisms driving this relationship. PMID- 29112885 TI - Commensal Koch's postulates: establishing causation in human microbiota research. AB - Advances in high-throughput sequencing technologies and the development of sophisticated bioinformatics analysis methods, algorithms, and pipelines to handle the large amounts of data generated have driven the field of human microbiome research forward. This specialist knowledge has been crucial to thoroughly mine the human gut microbiota, particularly in the absence of methods for the routine cultivation of most enteric microorganisms. In recent years, however, significant efforts have been made to address the 'great plate count anomaly' and to overcome the barriers to cultivation of the fastidious and mostly strictly anaerobic bacteria that reside in the human gut. As a result, many new species have been discovered, characterised, genome sequenced, and deposited in culture collections. These continually expanding resources enable experimental investigation of the human gut microbiota, validation of hypotheses made with sequence-based analyses, and phenotypic characterisation of its constituent microbes. Herein we propose a variant of Koch's postulates, aimed at providing a framework to establish causation in microbiome studies, with a particular focus on demonstrating the health-promoting role of the commensal gut microbiota. PMID- 29112886 TI - Uncontrolled manifold analysis of joint angle variability during table tennis forehand. AB - This study was conducted with the objective of evaluating the variance structure of the trunk and racket arm joint angles in table tennis topspin forehand using the uncontrolled manifold (UCM) approach, regarding racket orientation as the task variable. Nine advanced and eight intermediate male collegiate table tennis players performed the topspin strokes against backspin balls. The trunk, upper limb, and racket were modeled as six rigid-link segments with a total of 16 rotation degrees of freedom. The UCM analysis was conducted using 30 trial datasets per participant to quantify the degree of redundancy exploitation needed to stabilize the vertical and horizontal angles of the racket. Irrespective of the performance level, the variance of the joint angle vector increased towards ball impact. The degree of redundancy exploitation increased towards ball impact. As a result, the variability of the racket angles was minimal at impact. Both groups of players used the relative movement between the racket and the hand to stabilize the racket angles at ball impact. The variance of the joint angle vector that affected the vertical racket face angle at ball impact was significantly smaller for advanced players than for intermediate players, and the degree of redundancy exploitation to stabilize that angle at impact tended to be larger for the advanced players. The ability to use the redundancy of the joint configuration to stabilize the vertical racket face angle at impact may be a critical factor that affects performance level. PMID- 29112888 TI - Age of pubertal onset and 2nd to 4th digit ratios: Preliminary findings. AB - BACKGROUND: The second to fourth digit ratio (2D:4D) is used as a marker of prenatal sex hormone exposure. The aim of this study was to evaluate the possible relation between digit ratio and age of pubertal onset. METHODS: Participants were 321 men and 202 women aged between 18 and 28 at the time of assessment who self-reported their onset of puberty (i.e., age at first conscious ejaculation or menarche). Participants' right and left digit lengths were measured from hand scans. RESULTS: All groups of males, i.e., early, average, and late pubertal onset, had lower mean 2D:4D than the comparable female groups, regardless of the relative timing of their pubertal onset. Among the males, there was a significant difference in digit ratios between individuals who experienced early, average, and late onset of puberty. In the males, we observed a positive relationship between 2D:4D and age of pubertal onset for both right and left hands. There were no significant differences in 2D:4D among the three groups of female maturers. We observed no significant association between digit ratios and age at menarche. CONCLUSIONS: These data lend further support for using 2D:4D as a measure of prenatal androgen exposure. PMID- 29112887 TI - Comparative performance analysis of human iPSC-derived and primary neural progenitor cells (NPC) grown as neurospheres in vitro. AB - Developmental neurotoxicity (DNT) testing performed in rats is resource-intensive (costs, time, animals) and bears the issue of species extrapolation. Thus, reliable alternative human-based approaches are needed for predicting neurodevelopmental toxicity. Human induced pluripotent stem cells (hiPSCs) represent a basis for an alternative method possibly being part of an alternative DNT testing strategy. Here, we compared two hiPSC neural induction protocols resulting in 3D neurospheres: one using noggin and one cultivating cells in neural induction medium (NIM protocol). Performance of Nestin+/SOX2+ hiPSC derived neural progenitor cells (NPCs) was compared to primary human NPCs. Generally, primary hNPCs first differentiate into Nestin+ and/or GFAP+ radial glia-like cells, while the hiPSC-derived NPCs (hiPSC-NPC) first differentiate into betaIII-Tubulin+ neurons suggesting an earlier developmental stage of hiPSC NPC. In the 'Neurosphere Assay', NIM generated hiPSC-NPC produced neurons with higher performance than with the noggin protocol. After long-term differentiation, hiPSC-NPC form neuronal networks, which become electrically active on microelectrode arrays after 85days. Finally, methylmercury chloride inhibits hiPSC-NPC and hNPC migration with similar potencies. hiPSC-NPCs-derived neurospheres seem to be useful for DNT evaluation representing early neural development in vitro. More system characterization by compound testing is needed to gain higher confidence in this method. PMID- 29112889 TI - Challenges in the automated synthesis of [18F]-1-fluoroethyl tryptophan: Formation of both O- and N-alkylated products. AB - [18F]Fluoroethyl tosylate was synthesized using an automated "Synthra" module using ethylene di-tosylate and [18F]fluoride/K222/K2CO3 in acetonitrile. [18F]Fluoroethyl tosylate was purified by semi-preparative HPLC followed by reformulation using a C18 Sep-Pak cartridge and eluted with DMF. Using this [18F]fluoroethyl tosylate, we attempted to alkylate protected tryptophan aiming to obtain the N-[18F]fluoroethyl-t-Boc-tryptophan methyl ester. Initial attempts resulted in the formation of the O-alkylated, rather than N-alkylated product. Manual removal of the cartridge from the automated module, followed by an extended drying of the cartridge under high flow nitrogen, was required to form the desired N-alkylated product. This demonstrates that the drying process in automated modules requires modification for sensitive N-alkylation of compounds and may be essential for compounds like tryptophan methyl ester that have multiple potential sites of alkylation in their chemical structure. PMID- 29112890 TI - Evaluation of 4T's scoring system in the identification of heparin-induced thrombocytopenia in patients with mechanical circulatory support. PMID- 29112891 TI - A novel research model for evaluating sunscreen protection in the UV-A1. AB - The use of a broad spectrum sunscreen is considered one of the main and most popular measures for preventing the damaging effects of ultraviolet radiation (UVR) on the skin. In this study we have developed a novel in vitro method to assess sunscreens efficacy to protect calcineurin enzyme activity, a skin cell marker. The photoprotective efficacy of sunscreen products was assessed by measuring the UV-A1 radiation-induced depletion of calcineurin (Cn) enzyme activity in primary neonatal human dermal fibroblast (HDFn) cell lysates. After exposure to 24J/cm2 UV-A1 radiation, the sunscreens containing larger amounts of UV-A1 filters (brand B), the astaxanthin (UV-A1 absorber) and the Tinosorb(r) M (UV-A1 absorber) were capable of preventing loss of Cn activity when compared to the sunscreens formulations of brand A (low concentration of UV-A1 filters), with the Garcinia brasiliensis extract (UV-B absorber) and with the unprotected cell lysate and exposed to irradiation (Irradiated Control - IC). The Cn activity assay is a reproducible, accurate and selective technique for evaluating the effectiveness of sunscreens against the effects of UV-A1 radiation. The developed method showed that calcineurin activity have the potential to act as a biological indicator of UV-A1 radiation-induced damages in skin and the assay might be used to assess the efficacy of sunscreens agents and plant extracts prior to in vivo tests. PMID- 29112892 TI - BLIPPED (BLIpped Pure Phase EncoDing) high resolution MRI with low amplitude gradients. AB - MRI image resolution is proportional to the maximum k-space value, i.e. the temporal integral of the magnetic field gradient. High resolution imaging usually requires high gradient amplitudes and/or long spatial encoding times. Special gradient hardware is often required for high amplitudes and fast switching. We propose a high resolution imaging sequence that employs low amplitude gradients. This method was inspired by the previously proposed PEPI (pi Echo Planar Imaging) sequence, which replaced EPI gradient reversals with multiple RF refocusing pulses. It has been shown that when the refocusing RF pulse is of high quality, i.e. sufficiently close to 180 degrees , the magnetization phase introduced by the spatial encoding magnetic field gradient can be preserved and transferred to the following echo signal without phase rewinding. This phase encoding scheme requires blipped gradients that are identical for each echo, with low and constant amplitude, providing opportunities for high resolution imaging. We now extend the sequence to 3D pure phase encoding with low amplitude gradients. The method is compared with the Hybrid-SESPI (Spin Echo Single Point Imaging) technique to demonstrate the advantages in terms of low gradient duty cycle, compensation of concomitant magnetic field effects and minimal echo spacing, which lead to superior image quality and high resolution. The 3D imaging method was then applied with a parallel plate resonator RF probe, achieving a nominal spatial resolution of 17 MUm in one dimension in the 3D image, requiring a maximum gradient amplitude of only 5.8 Gauss/cm. PMID- 29112894 TI - Study the effects of mesenchymal stem cell conditioned medium injection in mouse model of acute colitis. AB - BACKGROUND AND AIM: Inflammatory bowel disease (IBD) is an autoimmune inflammatory disorder that results in inflammatory responses in individuals who are genetically susceptible. Uncontrolled inflammation in Crohn's disease (CD) or Ulcerative colitis (UC) affects the patient quality of life. Current therapies are not completely effective while cell therapy, especially the treatment with mesenchymal stem cells (MSCs) absorb lots of attention due to its immunomodulatory properties. So, we examined the effects of mesenchymal stem cells-conditioned medium (MSC-CM) in the experimental model of acute colitis. MATERIAL AND METHOD: MSC-CM was isolated from C57Bl/6 male mice and stored. The acute colitis induction in C57BL/6 mice was performed by dissolving dextran sulfate sodium (DSS) in drinking water and then CM injected intraperitoneally. During the study body weight changes, bleeding, stool consistency, disease activity index (DAI), mortality rate, weight and length of the colon and histopathological analysis were recorded as well as changes in the percentage of Treg cells. The level of IL-17, IL-10, and TGF-beta were measured, too. Data were reported as mean+/-SD and analyzed by One-Way ANOVA test. RESULTS: Based on the results it is recognized CM inhibited the weight loss and bleeding and improved fecal consistency and DAI. Macroscopic examination of the colon showed that after infusion, colon inflammation was reduced and histopathological analysis showed a decrease in mucosal degeneration. The percentage of Treg cells, secretion of IL 10 and TGF-beta was increased while the IL-17 level was reduced. CONCLUSION: This study showed that mesenchymal stem cell secretion with immunomodulatory properties has the potential to reduce inflammatory responses. PMID- 29112893 TI - Natural product beta-thujaplicin inhibits homologous recombination repair and sensitizes cancer cells to radiation therapy. AB - Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR) mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients' responses to radiation therapy, a mainstay of treatment for many human cancers. In this study, in order to systematically identify natural products with an inhibitory effect on HR repair, we developed a high-throughput image-based HR repair screening assay and screened a chemical library containing natural products. Among the most interesting of the candidate compounds identified from the screen was beta-thujaplicin, a bioactive compound isolated from the heart wood of plants in the Cupressaceae family, can significantly inhibit HR repair. We further demonstrated that beta-thujaplicin inhibits HR repair by reducing the recruitment of a key HR repair protein, Rad51, to DNA double-strand breaks. More importantly, our results showed that beta thujaplicin can radiosensitize cancer cells. Additionally, beta-thujaplicin sensitizes cancer cells to PARP inhibitor in different cancer cell lines. Collectively, our findings for the first time identify natural compound beta thujaplicin, which has a good biosafety profile, as a novel HR repair inhibitor with great potential to be translated into clinical applications as a sensitizer to DNA-damage-inducing treatment such as radiation and PARP inhibitor. In addition, our study provides proof of the principle that our robust high throughput functional HR repair assay can be used for a large-scale screening system to identify novel natural products that regulate DNA repair and cellular responses to DNA damage-inducing treatments such as radiation therapy. PMID- 29112895 TI - Polyactin A is a novel and potent immunological adjuvant for peptide-based cancer vaccine. AB - Synthetic peptide cancer vaccines are poorly immunogenic sub-unit vaccines and thus essentially need adjuvants in their formulations to increase the efficacy by enhancing the peptide-specific immune response. However, aluminum-based compounds are almost dependent for clinical use at present. Therefore, the increasing use of peptide-based vaccines makes the need for novel and potent adjuvants. Polyactin A (PAA) has been used for the clinical treatment of impaired immunity in China for over 30years. To figure out the adjuvant effects of PAA for E75 peptide breast cancer vaccine (Her2 p369-p377), the generation of mature dendritic cells (DCs) from peripheral blood monocytes (PBMCs) cultured with PAA, IL-4 and TNF-alpha was assessed by morphologic features and the expressions of special surface markers using flow cytometry. Then the functional features of PBMCs-derived DCs cultured with PAA, IL-4 and TNF-alpha were investigated by inducing E75-specific cytotoxicity. Finally, C57BL/6-Tg(HLA-A2.1)1Enge/J transgenic mice were immunized with E75 and various amounts of PAA, and splenic lymphocyte proliferation and the IFN-gamma level were determined. The results showed that PAA, just like granulocyte-macrophage colony stimulating factor, with IL-4 and TNF-alpha efficiently induced mature DCs from PBMCs, and these DCs could trigger a potent E75 peptide-specific CD8+ T-cell response in vitro. Immunization with E75 and PAA significantly increased positive rates of CD4+ and CD8+ T lymphocytes, and enhanced splenocytes proliferation and levels of IFN-gamma in splenocytes when induced by E75. Our results indicated that PAA could efficiently induce E75-specific immunologic responses in vitro and in vivo. Therefore, PAA possesses potent adjuvant effect on peptide-based cancer vaccine. Our study provides a safe, effective and novel adjuvant for clinical use. PMID- 29112896 TI - Staphylococcal food poisoning caused by Staphylococcus argenteus harboring staphylococcal enterotoxin genes. AB - Staphylococcal food poisoning (SFP) is caused by staphylococcal enterotoxins (SEs) preformed in food materials. SE genes are encoded on mobile genetic elements and are widely found across Staphylococcus species including S. argenteus, although most SFP cases are caused by S. aureus. S. argenteus, recently discriminated from S. aureus as a novel species, are non-pigmented staphylococci phenotypically related to S. aureus. In 2014 and 2015, two independent food poisoning cases occurred in Osaka, Japan, in which non-pigmented staphylococci were predominantly isolated. Several enterotoxin genes (seb, seg, sei, sem, sen, seo, and selu2) were found in their genome and the production of SEB was confirmed by reverse passive agglutination tests. The non-pigmented isolates from patients, food handlers, food, and cooking utensils all produced the same pulsed-field gel electrophoresis pattern. These non-pigmented isolates were coagulase-positive and biochemically identical to S. aureus. We performed further genetic analysis using nucA sequencing and multi-locus sequence typing, and identified these isolates as S. argenteus. We also found that seb was encoded on the Staphylococcus aureus pathogenicity island, while seg, sei, sem, sen, seo, and selu2 were encoded on the enterotoxin gene cluster. From these results, we concluded that the two food poisoning outbreaks were SFP cases caused by S. argenteus harboring SE genes. PMID- 29112897 TI - Integrity in nursing students: A concept analysis. AB - OBJECTIVE: The purpose of this review was to clarify the concept of nursing student integrity. Unlike published reviews that highlight the absence of integrity, the author sought to identify the positive defining characteristics of integrity. DESIGN: Concept analysis. DATA SOURCES: A literature review was conducted using the Cumulative Index for Nursing and Allied Health, Social Science Index, Psyc Info and Medline. Inclusion criteria included peer reviewed articles, written in English, with no limitation on publication date. The search also revealed that a concept analysis of integrity had not been performed. REVIEW METHODS: Walker and Avant's (2005) eight step modification of Wilson's (1963) classic concept analysis procedure was used as the organizing framework to explore how the concept of integrity is defined in the current literature. RESULTS: Nursing student integrity was analyzed using Walker and Avant's method of concept analysis: concept definition, defining attribute, model, borderline, related and contrary cases, antecedents, consequences and empirical referents (Walker and Avant 2005). Defining attributes to nursing student integrity were honesty, ethical behavior and professionalism. Antecedents to integrity included an academic culture of respect, characterized by student-faculty relationships derived from mutual respect, trust and a shared learning goal. CONCLUSIONS: This review identified honesty, ethical behavior and professionalism as the defining attributes of integrity. The importance of faculty as role models of integrity was paramount in building a culture of honesty. Future research should explore faculty perceptions of their professional role as models of integrity, and faculty perceptions of behaviors that promote a culture of respect. PMID- 29112898 TI - Development and validation of an analytical method using UPLC-MS/MS to quantify everolimus in dried blood spots in the oncology setting. AB - While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated. An 7.5mm disk from the central part of the DBS was punched, followed by the extraction of everolimus from the DBS by methanol/acetonitrile (80/20%) spiked with deuterium-labelled everolimus as internal standard. Subsequently, everolimus was separated and analyzed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The UPLC-MS/MS method was validated according to the European Medicine Agency (EMA) guideline. Everolimus concentrations could be quantified over the range of 3-75MUg/L. The intra- and inter-assay precision and accuracy of the method were shown to be acceptable (coefficient of variation <=10.7% and relative error <=4.4%, respectively). The matrix effects appeared to be influenced by the hematocrit effect. The hematocrit effect was tested in a range of 0.20-0.50L/L, at which hematocrit accuracy and precision were satisfactory at values >=0.25L/L. However, at 0.20L/L hematocrit in combination with high everolimus concentrations of 20 and 40MUg/L, the precision was adequate (<=7.4%), but the accuracy was >15% of the nominal concentration. Everolimus was stable in DBS for at least 80days at 2-8 degrees C. Given these results, the everolimus DBS method has been successfully developed and validated. Special attention is necessary for cancer patients with both a 0.20L/L hematocrit in combination with everolimus concentrations >=20MUg/L. A clinical validation for the use of everolimus DBS in cancer patients is currently being undertaken. PMID- 29112899 TI - Authentication of animal origin of heparin and low molecular weight heparin including ovine, porcine and bovine species using 1D NMR spectroscopy and chemometric tools. AB - High resolution (600MHz) nuclear magnetic resonance (NMR) spectroscopy is used to distinguish heparin and low-molecular weight heparins (LMWHs) produced from porcine, bovine and ovine mucosal tissues as well as their blends. For multivariate analysis several statistical methods such as principal component analysis (PCA), factor discriminant analysis (FDA), partial least squares - discriminant analysis (PLS-DA), linear discriminant analysis (LDA) were utilized for the modeling of NMR data of more than 100 authentic samples. Heparin and LMWH samples from the independent test set (n=15) were 100% correctly classified according to its animal origin. Moreover, by using 1H NMR coupled with chemometrics and several batches of bovine heparins from two producers were differentiated. Thus, NMR spectroscopy combined with chemometrics is an efficient tool for simultaneous identification of animal origin and process based manufacturing difference in heparin products. PMID- 29112900 TI - Serum metabonomics study of the hepatoprotective effect of amarogentin on CCl4 induced liver fibrosis in mice by GC-TOF-MS analysis. AB - Amarogentin (AG) is a secoiridoid glycoside that is mainly extracted from the traditional Chinese medicine Swertia and Gentiana, which have been widely used in clinical practice to treat liver disease. However, the exact hepatoprotective mechanism of AG was still looking forward to further elucidation by far. In this study, C57BL/6 mice were divided into the following three groups: control, model and AG. Fibrosis was induced by CCl4. Mice were orally treated with 100mg/kg AG or with normal saline as a control. At the end of the experiment, the validity of the model and the hepatoprotective effects of AG were examined by histopathology and biochemical indicators. Metabonomics technology was further performed to systematically evaluate the endogenous metabolite profiles. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) technology with pattern recognition analysis, including principal component analysis (PCA) and orthogonal partial least square discriminant analysis (OPLS-DA), showed a clear separation of the model group and the control group, with the AG treatment group located much closer to the control group than the model group, which was consistent with the results of biochemical and histopathological assays. Moreover, nine potential biomarkers were identified to elucidate the drug mechanism of AG, which may be related to pathways of amino acid and fatty acid metabolism. PMID- 29112901 TI - Novel method for the determination of average molecular weight of natural polymers based on 2D DOSY NMR and chemometrics: Example of heparin. AB - Apart from the characterization of impurities, the full characterization of heparin and low molecular weight heparin (LMWH) also requires the determination of average molecular weight, which is closely related to the pharmaceutical properties of anticoagulant drugs. To determine average molecular weight of these animal-derived polymer products, partial least squares regression (PLS) was utilized for modelling of diffused-ordered spectroscopy NMR data (DOSY) of a representative set of heparin (n=32) and LMWH (n=30) samples. The same sets of samples were measured by gel permeation chromatography (GPC) to obtain reference data. The application of PLS to the data led to calibration models with root mean square error of prediction of 498Da and 179Da for heparin and LMWH, respectively. The average coefficients of variation (CVs) did not exceed 2.1% excluding sample preparation (by successive measuring one solution, n=5) and 2.5% including sample preparation (by preparing and analyzing separate samples, n=5). An advantage of the method is that the sample after standard 1D NMR characterization can be used for the molecular weight determination without further manipulation. The accuracy of multivariate models is better than the previous results for other matrices employing internal standards. Therefore, DOSY experiment is recommended to be employed for the calculation of molecular weight of heparin products as a complementary measurement to standard 1D NMR quality control. The method can be easily transferred to other matrices as well. PMID- 29112902 TI - Development of a stability- indicating HPLC method for simultaneous determination of ten related substances in vonoprazan fumarate drug substance. AB - Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C18 (250mm*4.6mm, 5.0MUm) column. The mobile phase consisted of (A) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - methanol - acetonitrile (72:25:3, v/v/v) and (B) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia. PMID- 29112903 TI - Characterization of systems with amino-acids and oligosaccharides as modifiers of biopharmaceutical properties of furosemide. AB - Furosemide is the most commonly prescribed diuretic drug in spite of its suboptimal biopharmaceutical properties. In this work, the addition of different amino-acids was studied with the aim of selecting an enhancer of the furosemide solubility. The best results were obtained with arginine. Also, binary (furosemide:arginine) and ternary (furosemide:arginine:beta-cyclodextrin and furosemide:arginine:maltodextrin) systems were prepared by the kneading method and they were compared with their corresponding physical mixtures. These new systems were characterized by Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. In addition, dissolution studies were performed in simulated gastric fluid. The best results in relation to improving biopharmaceutical properties were obtained with a binary combination of furosemide and arginine, demonstrating that this system could result in a suitable candidate for the development of a promising pharmaceutical formulation of the drug. PMID- 29112904 TI - Procalcitonin accurately predicts lung transplant adults with low risk of pulmonary graft dysfunction and intensive care mortality. AB - PURPOSE: We evaluated the association of procalcitonin (PCT), IL-6-8-10 plasma levels during the first 72h after lung transplantation (LT) with ICU-mortality, oxygenation, primary graft dysfunction (PGD), and one-year graft function after LT. MATERIAL AND METHODS: Prospective, observational study. PCT and IL-6-8-10 plasma levels were measured at 24h, 48h and 72h after LT from 100 lung transplant recipients (LTr). Patients were followed until one year after LT. End-points were ICU survival, grade 3 PGD at 72h and one-year graft function. RESULTS: Higher PCT at 24h was associated with lower PaO2/FIO2 ratio and Grade 3 PGD over the first 72h after LT (p<0.05). PCT at 24h was higher in the 9 patients who died (2.90 vs 1.47ng/mL, p<0.05), with AUC=0.74 for predicting ICU-mortality. All patients with PCT<2ng/mL at 24h following LT, survived in the ICU (p<0.05). PCT and IL-10 at 48h were correlated with FEV1 (rho=-0.35) and FVC (rho=-0.29) one year after LT. (p<0.05). CONCLUSIONS: A breakpoint of PCT<2ng/mL within 24h has a high predictive value to exclude grade 3 PGD at 72h and for ICU survival. Moreover, both PCT and IL-10 within 48h were associated with significantly better graft function one year after surgery. PMID- 29112905 TI - Determinants of hair cortisol concentration in children: A systematic review. AB - BACKGROUND: Several factors are known contribute to hair cortisol concentration (HCC) in adults. However, there is less research on determinants of HCC in children and adolescents. HCC is a valuable tool for medical research pertaining to the hypothalamic-pituitary-adrenal (HPA) axis. This review aims to assess the extent to which established determinants of HCC in adults have been consistently reported in children (birth - 18 years) and to identify determinants of HCC specific to this age group. METHODS: Eligible studies were identified, selected and appraised as per PRISMA-P guidelines and as detailed in our systematic review protocol, registered on PROSPERO (registration number CRD42017056220). In view of contrasting methods and measures, a meta-analysis could not be done but a qualitative synthesis was performed. RESULTS: Thirty-six studies were included in the analysis. Higher HCC is associated with male sex and anthropometry, particularly increased body mass index and waist circumference. There is preliminary evidence to suggest that socio-economic status is inversely related to child HCC, particularly with reference to caregiver education and income. Of note, most of the studies analysing socio-economic variables were performed in relatively equal societies. Hair wash frequency and use of hair products and treatments do not affect HCC when proximal segments of hair are used. There is conflicting evidence regarding the relationship between HCC and age in children and adolescents. Further investigation is required to better delineate if and how the following are associated with HCC in children: hair colour, hair type, exposure to trauma and stressors, psychiatric illness, atopic illness, steroid use (including topical and inhaled steroids) and perinatal variables. CONCLUSIONS: Sex and anthropometry are potential confounders and should be considered for adjustment in hair cortisol research. Hair wash frequency and use of hair products and treatments are not important confounders when proximal hair segments are used. A better understanding of HCC in children in relation to exposure to trauma and stressors is required before it can be used as a biomarker, particularly in terms of vulnerable developmental stages, definition and measurement of stress, and temporal relationship to stressors. Age, SES and other correlates also warrant further investigation. PMID- 29112906 TI - Factors affecting knowledge transfer from continuing professional education to clinical practice: Development and psychometric properties of a new instrument. AB - Despite the emphasis placed on the implementation of continuing professional education programs in Iran, researchers or practitioners have not developed an instrument for assessing the factors that affect the knowledge transfer from such programs to clinical practice. The aim of this study was to design and validate such instrument for the Iranian context. The research used a three-stage mix method. In the first stage, in-depth interviews with nurses and content analysis were conducted, after which themes were extracted from the data. In the second stage, the findings of the content analysis and literature review were examined, and preliminary instrument options were developed. In the third stage, qualitative content validity, face validity, content validity ratio, content validity index, and construct validity using exploratory factor analysis was conducted. The reliability of the instrument was measured before and after the determination of construct validity. Primary tool instrument initially comprised 53 items, and its content validity index was 0.86. In the multi-stage factor analysis, eight questions were excluded, thereby reducing 11 factors to five and finally, to four. The final instrument with 43 items consists of the following dimensions: structure and organizational climate, personal characteristics, nature and status of professionals, and nature of educational programs. Managers can use the Iranian instrument to identify factors affecting knowledge transfer of continuing professional education to clinical practice. PMID- 29112907 TI - Impact of annual bone loss and different bone quality on dental implant success - A finite element study. AB - BACKGROUND: For dental implant success, experimentally established thresholds should limit bone stresses and strains. From these metrics, the ultimate functional load, which determines the implant load-carrying capacity, can be calculated. Obviously, its decrease due to bone loss shortens implant service life. A comparison of how bone loss affects the ultimate functional loads of various implants can provide the clinician with meaningful feedback concerning the suitability and longevity of implants. The aim of this study is to evaluate the lifetime of different dental implants placed in I-IV bone types on the basis of a comparison of their ultimate functional loads with consideration of the bone loss factor. METHOD: Von Mises stress and first principal strain distributions in bone-implant interface were studied and ultimate functional loads were calculated. Models of I-IV bone types were designed. 3.3 * 8.0 mm (A), 4.1 * 12.0 mm (B) and 4.8 * 14.0 mm (C) implants were analyzed at 10 levels of bone loss. Ultimate functional loads, which generated the ultimate von Mises stress and first principal strain in bone, were computed. RESULTS: For the implants A, B, and C placed in type I bone, ultimate functional load values were above 120.92 N experimental functional load, which corresponded to 10+, 10+, and 10 + years of service with 0.2 mm annual bone loss. For type II bone, the lifetime was 4, 10+, and 10 + years. For type III bone, the lifetime was 4, 5, and 5 years. For type IV bone, first principal strains were initially deleterious for all implants. CONCLUSIONS: In oral implantology, bone loss is an essential factor for implant longevity prognosis. While evaluating implant load-carrying capacity, clinicians should take into account the factor of implant longevity decrease. PMID- 29112908 TI - Reproductive decision-making in women living with human immunodeficiency virus: A systematic review. AB - OBJECTIVES: Analyze and synthesize the research evidence to understand the reproductive decisions made by women living with HIV from the beginning of the epidemic to the present. Evaluate the barriers and the facilitators for reproductive decision-making. Identify areas of strength, improvement, and those requiring further research. DESIGN AND DATA SOURCES: Systematic review following the PRISMA guideline. PubMed, CINAHL, PsycINFO, Cochrane Library, SocINDEX, Embase, and Scopus databases were searched from 1985 to 2016 using the following Keywords: HIV, AIDS, pregnancy, reproduction, and decision-making. STUDY SELECTION: A total of 42 research papers were included in this review. Initially, 1563 papers were identified for the review by database (n=1544) and hand (n=19) searches. With three review levels, 1521 papers were excluded (title review, n=1272; abstract review, n=136; and full paper review, n=113). Studies published in English in peer-reviewed journals using both quantitative and qualitative methods and addressing reproductive decisions in women living with HIV were included. Thirdly, inclusion eligibility was assessed by title, abstract, and full text. REVIEW METHODS: Random allocation conducted by the primary researcher assigned an equal number of papers to each researcher for review, including detailed instructions with an abstraction form. Discrepancies were resolved by two researchers. Research quality was assessed using the NCHBL Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, the Critical Appraisal Skills Programme for the qualitative studies and its version for systematic reviews RESULTS: The review included 42 papers, both quantitative (n=24) and qualitative methods (n=14). Most studies were completed by physicians (n=16) or nurses (n=15). More than two-thirds of the studies were performed in urban settings with predominantly African-American women (n=27). Eight factors were identified as influencing the reproductive decision-making process in women living with HIV: 'Socio-demographic, Health status and Pregnancy', 'Religion and spirituality', 'Beliefs and Attitudes about Antiretroviral Therapy', 'Healthcare providers', 'Significant others', 'Motherhood and fulfillment', 'Fear of perinatal infection and infection of partner(s)', 'Birth control and pregnancy management'. CONCLUSIONS: Health care providers are not providing patient centered care by applying scientific evidence to their practice when advising women with HIV in making reproductive decisions. Despite the strong evidence indicating pregnancy for women with HIV results in a safe birthing trajectory, one not likely to jeopardize the health of the either the mother or fetus, providers continue to recommend the women with HIV avoid pregnancy and neglect to invite partners to participate in the discussion. PMID- 29112909 TI - Potential diagnostic value of 131I-MIBG myocardial scintigraphy in discrimination between Alzheimer disease and dementia with Lewy bodies. AB - OBJECTIVES: Clinical difficulty to discriminate between the Alzheimer disease (AD) and dementia with Lewy bodies (DLB) has led researchers to focus on highly sensitive functional imaging modalities. The aim of the present study was to assess 131I-MIBG cardiac imaging to distinguish between AD and DLB. PATIENTS AND METHODS: Seventeen patients who were known cases of dementia underwent 131I-MIBG myocardial scintigraphy to differentiate AD from DLB. Planar and 131I-MIBG SPECT were obtained 2h after the injection of 1mCi 131I-MIBG on a dual head gamma camera. The visual assessment of the heart uptake compared with lungs and the quantification based on the heart to mediastinal ratio (HMR) were done. The cardiac receiver operating characteristic (ROC) curve was designed for the optimal HMR cut-off values to predict the diagnoses of the patients. The diagnoses were clinically confirmed during the follow up of 14+/-8.2 months. RESULTS: Out of 17 patients (13 males; 76.5%), 10 patients had AD (7 males; 70%) and 7 patients had DLB (6 males; 85%). The pooled HMR was 1.74+/-0.33 in the study population; with 1.95+/-0.22 in the AD group and 1.43+/-0.20 in the DLB group to demonstrate significantly different HMR scores between patients with AD and DLB (p value=0.001). The visual interpretation was positive in 10 patients (accuracy of 88.2%). The shortest distance on the ROC curve to the optimal value corresponding to HMR=1.57 identified 10 patients with a high HMR (positive cardiac uptake) and 7 patients with a low HMR (negative cardiac uptake), the accuracy calculated at 88.2%. CONCLUSION: 131I-MIBG myocardial scintigraphy is a potential alternative diagnostic modality for discrimination between AD and DLB when 123I is not available. PMID- 29112910 TI - Biomechanical characterization of ex vivo human brain using ultrasound shear wave spectroscopy. AB - The characterization of brain tissue is crucial to better understand neurological disorders. Mechanical characterization is an emerging tool in that field. The purpose of this work was to validate a transient ultrasound technique aimed at measuring dispersion of mechanical parameters of the brain tissue. The first part of this work was dedicated to the validation of that technique by comparing it with two proven rheology methods: a rotating plate rheometer, and a viscoelastic spectroscopy apparatus. Experiments were done on tissue mimicking gels. Results were compared on storage and loss modulus in the 20-100 Hz band. Our method was validated for the measurement of storage modulus dispersion, with some reserves on the measurement of loss modulus. The second part of this work was the measurement of the mechanical characteristics of ex vivo human white matter. We were able to measure the dispersion of the storage and loss modulus in the 20-100 Hz band, fitting the data with a custom power law model. PMID- 29112911 TI - Interactome evolution: insights from genome-wide analyses of protein-protein interactions. AB - We highlight new evolutionary insights enabled by recent genome-wide studies on protein-protein interaction (PPI) networks ('interactomes'). While most PPIs are mediated by a single sequence region promoting or inhibiting interactions, many PPIs are mediated by multiple sequence regions acting cooperatively. Most PPIs perform important functions maintained by negative selection: we estimate that less than ~10% of the human interactome is effectively neutral upon perturbation (i.e. 'junk' PPIs), and the rest are deleterious upon perturbation; interfacial sites evolve more slowly than other sites; many conserved PPIs show signatures of co-evolution at the interface; PPIs evolve more slowly than protein sequence. At the same time, many PPIs undergo rewiring during evolution for lineage-specific adaptation. Finally, chaperone-protein and host-pathogen interactomes are governed by distinct evolutionary principles. PMID- 29112912 TI - Investigation of high pressure effect on the structure and adsorption of beta lactoglobulin. AB - beta-Lactoglobulin, being one of the principal whey protein, is of huge importance to the food industry. Temperature/pressure effects on this small protein has been extensively studied by industry. To characterize biochemical properties of beta-lactoglobulin after or during pressurization, a wide range of methods have been used thus far. In this study, for the first time, the pressure induced conformation of beta-lactoglobulin in the crystal state was determined, at pressure 430 MPa. Changes observed in the high pressure structure correlate with the physico-chemical properties of pressure-treated beta-lactoglobulin obtained from dynamic light scattering, electrophoretic mobility and quartz crystal microbalance with dissipation monitoring measurements. A comparison between the beta-lactoglobulin structures determined at both high and ambient pressure contrasts the stable nature of the protein core and adjacent loop fragments. At high pressure the beta-lactoglobulin structure presents early signs of dimer dissociation, charge and conformational changes characteristic for initial unfolded intermediate as well as a significant modification of the binding pocket volume. Those observations are supported by changes in zeta potential values and results in increase affinity of the beta-lactoglobulin adsorption onto gold surface. Observed pressure-induced structural modifications were previously suggested as an important factor contributing to beta lactoglobulin denaturation process. Presented studies provide detailed analysis of pressure-associated structural changes influencing beta-lactoglobulin conformation and consequently its adsorption. PMID- 29112913 TI - Multifunctional nanocomplex for surface-enhanced Raman scattering imaging and near-infrared photodynamic antimicrobial therapy of vancomycin-resistant bacteria. AB - Since vancomycin (Van)-resistant enterococci (VRE) strains first emerged as a serious threat to public health, extensive studies focused on optical imaging and antimicrobial therapy have been performed for monitoring and microbiological control. In this study, we developed silicon 2,3-naphthalocyanine dihydroxide (Nc) and Van functionalized silica-encapsulated, silver-coated gold nanoparticles (Au@AgNP@SiO2@Nc-Van) as a novel theranostic system for surface-enhanced Raman scattering (SERS) detection and antimicrobial photodynamic therapy (aPDT) of VRE strains. The silver-coated gold nanoparticle, as the SERS-active core, exhibited excellent Raman enhancement efficacy. Results of in vitro bacterial SERS imaging revealed Van-enhanced specific binding affinity toward VRE. Meanwhile, Si(IV) naphthalocyanine, serving as a near-infrared (NIR) photosensitizer, was axially linked to the nanoparticle surface, yielding nanostructured hybrid materials that could photoinactivate VRE. Almost 4-5 logs of bacterial reduction were obtained upon in vitro photodynamic therapy of VRE treated with a nanomolar concentration of the nanocomplex. Mouse infection assays were applied for an in vivo evaluation of VRE lethality. Upon near-infrared light irradiation, this hybrid nanomaterial caused obvious infection regression and even complete eradication compared to the findings in the non-treated groups. Therefore, this novel nanosystem integrating SERS imaging and noninvasive aPDT has huge potential for applications in theranostics with regard to VRE management. PMID- 29112914 TI - Motor imagery development and proprioceptive integration: Which sensory reweighting during childhood? AB - It is widely accepted that motor imagery development during childhood may be due to refinement of internal models of action. At the same time, gradual improvement of predictive motor control in children may reflect an increasing ability to integrate the proprioceptive afferences with other sources of sensory information (especially vision). The current study investigated the extent to which motor imagery refinement observed between 5 and 9 years of age was related to the increasing ability to integrate proprioceptive afferences with vision and audition signals. To attain this goal, we compared motor imagery performances of 96 children (32 5-year-olds, 32 7-year-olds, and 32 9-year-olds) who received either visual and auditory inputs (VA condition) or visual, auditory, and proprioceptive inputs (VAP condition) during the imagery task. Motor imagery capacity was evaluated by means of mental chronometry paradigm based on a walking task. Our results revealed that correlations between overt and covert movements gradually increased across age in either the VA or VAP condition. Most important, in 5- and 7-year-olds, covert walking times were significantly longer than overt walking times in the VAP condition, whereas covert walking times were not different from actual walking times in the VA condition. In 9-year-olds, covert walking times were not different from overt walking times in either the VAP or VA condition. We suggest that motor imagery refinement during childhood can be partially related to the ability to integrate proprioceptive inputs with other sources of sensory information. Furthermore, our results shed light on the sensory content of motor images in children. PMID- 29112915 TI - Acute Abdomen Secondary to a Spontaneous Perforation of the Biliary Tract, a Rare Complication of Choledocholithiasis. AB - INTRODUCTION: The spontaneous perforation of the biliary tract (SPBT) is an extremely rare cause of peritonitis, which was first described by Freeland in 1982, to date only around 70 cases have been reported. Here we present a case of spontaneous perforation of the biliary tract, in a patient with choledocholithiasis, which was treated with ultrasound-guided drainage and ERCP. CASE REPORT: A 51-year-old male was admitted to the emergency room for 15-day evolution jaundice, localized pain in the right flank and hypochondrium of 3days. He had a history of cholecystectomy 15 years ago and 4 episodes of cholangitis, the last one in 2015. A magnetic resonance imaging (MRI) was performed, that showed evidence of choledocholithiasis, in addition to a possible biliary leakage. The patient was treated with ultrasound-guided drainage and ERCP successfully. DISCUSSION: Spontaneous perforation of the biliary tract is a disease entity in which wall of the extrahepatic or intrahepatic duct is perforated without any traumatic or iatrogenic injury. The clinical presentation varies from nonspecific abdominal pain to biliary peritonitis, in most of the cases forming bilomas. Universal management involves decompression of the biliary tree and repair of the leak site. CONCLUSION: The spontaneous perforation of the biliary tract is a disease that represents a diagnostic challenge. The treatment in the patients with SPBT is not well established and has to be individualized for each case, depending on the history of the patient, the site of perforation, the time of evolution, the suspicion of infection, and the patient status. PMID- 29112916 TI - Morphology and ultrastructure of Dufour's and venom glands in the ant Camponotus japonicus Mayr (Hymenoptera: Formicidae). AB - The Dufour's and venom glands are two important exocrine glands in ants. In this study, the morphology and fine structure of these two glands are described in the ant Camponotus japonicus Mayr. The Dufour glands have a characteristic bilobed shape and show a difference in size and color between the female castes (minor and major workers, alate and dealate queens). The external surface of Dufour's gland shows different features among the female castes. It appears more hypertrophied in major workers than in the other castes, indicating for a more pronounced function. The cells of the glandular epithelium in Dufour's gland are characterized by abundant mitochondria, basal invaginations and developed muscle fibres. The venom gland is morphologically similar in the different female castes, and consists of a venom reservoir, a convoluted gland and a bifurcated free secretory filament, with the convoluted gland appearing as a large cap lying on top of the reservoir. Cells of the convoluted gland and the free secretory filaments contain numerous mitochondria and a prominent end apparatus. The results will contribute to understanding the functional morphology of these glands among the different castes in Camponotus ants. PMID- 29112917 TI - Influence of minor combined addition of Cr and Pr on microstructure, mechanical properties and corrosion behaviors of an ultrahigh strength Al-Zn-Mg-Cu-Zr alloy. AB - This work focuses on controlling grain boundary structure in an ultra-high strength Al-8.6Zn-2.5Mg-2.2Cu-0.16Zr (wt.%) alloy by the combined addition of trace Cr (0.1wt.%) and Pr (0.14wt.%), and evaluating mechanical properties and localized corrosion behaviors of the alloy in the peak aged condition. The introduction of trace Cr and Pr leads to the formation of nanoscale Cr, Pr containing Al3Zr and Zr-containing PrCr2Al20 dispersoids which can obviously inhibit the recrystallization and sub-grain growth of the super-high strength Al Zn-Mg-Cu alloys, and retain the deformation-recovery microstructure dominated by low-angle grain boundaries. The nearly ellipsoidal dispersoids with a size of 10 35nm are discretely distributed and precipitate free zones are hardly formed in low-angle grain boundaries. This new alloy composition exhibits better combined properties, higher resistance to stress corrosion, exfoliation corrosion and inter-granular corrosion with the undamaged strength, ductility and fracture toughness. PMID- 29112918 TI - Toxicity of weathered Deepwater Horizon oil to bay anchovy (Anchoa mitchilli) embryos. AB - The BP-contracted Deepwater Horizon Macondo well blowout occurred on 20 April 2010 and lasted nearly three months. The well released millions of barrels of crude oil into the northern Gulf of Mexico, causing extensive impacts on pelagic, benthic, and estuarine fish species. The bay anchovy (Anchoa mitchilli) is an important zooplanktivore in the Gulf, serving as an ecological link between lower trophic levels and pelagic predatory fish species. Bay anchovy spawn from May through November in shallow inshore and estuarine waters throughout the Gulf. Because their buoyant embryos are a dominant part of the inshore ichthyoplankton throughout the summer, it is likely bay anchovy embryos encountered oil in coastal estuaries during the summer and fall of 2010. Bay anchovy embryos were exposed to a range of concentrations of two field-collected Deepwater Horizon oils as high-energy and low-energy water accommodated fractions (HEWAFs and LEWAFs, respectively) for 48h. The median lethal concentrations (LC50) were lower in exposures with the more weathered oil (HEWAF, 1.48ug/L TPAH50; LEWAF, 1.58ug/L TPAH50) compared to the less weathered oil (HEWAF, 3.87ug/L TPAH50; LEWAF, 4.28ug/L TPAH50). To measure delayed mortality and life stage sensitivity between embryos and larvae, an additional 24h acute HEWAF exposure using the more weathered oil was run followed by a 24h grow-out period. Here the LC50 was 9.71ug/L TPAH50 after the grow-out phase, suggesting a toxic effect of oil at the embryonic or hatching stage. We also found that exposures prepared with the more weathered Slick B oil produced lower LC50 values compared to the exposures prepared with Slick A oil. Our results demonstrate that even relatively acute environmental exposure times can have a detrimental effect on bay anchovy embryos. PMID- 29112919 TI - A novel method of utilization of hot dip galvanizing slag using the heat waste from itself for protection from radiation. AB - A novel, unconventional, low cost, eco-friendly and effective shielding materials have been made utilizing the hot dip galvanizing slag using the heat waste from itself, thereby saving the natural resources and preventing the environmental pollution. SEM-EDS of shielding materials indicates that the other elements are distributed in Zn element. The mass attenuation properties of shielding materials were measured using a narrow beam geometrical setup at 0.662MeV, 1.17MeV and 1.33MeV. The half value thickness layer, effective atomic number, and electron density were used to analyze the shielding performance of the materials. The EBFs and EABFs for the prepared shielding materials were also studied with incident photon energy for penetration depths upto 40mfp. The shielding effectiveness has been compared with lead, iron, zinc, some standard shielding concretes, different glasses and some alloys. The shielding effectiveness of the prepared samples is almost found comparable to iron, zinc, selected alloys and glasses while better than some standard shielding concretes. In addition, it is also found that the bending strength of all shielding materials is more than 110MPa. PMID- 29112920 TI - Performance evaluation of a biodiesel fuelled transportation engine retrofitted with a non-noble metal catalysed diesel oxidation catalyst for controlling unregulated emissions. AB - In present study, engine exhaust was sampled for measurement and analysis of unregulated emissions from a four cylinder transportation diesel engine using a state-of-the-art FTIR (Fourier transform infrared spectroscopy) emission analyzer. Test fuels used were Karanja biodiesel blend (B20) and baseline mineral diesel. Real-time emission measurements were performed for raw exhaust as well as exhaust sampled downstream of the two in-house prepared non-noble metal based diesel oxidation catalysts (DOCs) and a baseline commercial DOC based on noble metals. Two prepared non-noble metal based DOCs were based on Co-Ce mixed oxide and Lanthanum based perovskite catalysts. Perovskite based DOC performed superior compared to Co-Ce mixed oxide catalyst based DOC. Commercial noble metal based DOC was found to be the most effective in reducing unregulated hydrocarbon emissions in the engine exhaust, followed by the two in-house prepared non-noble metal based DOCs. PMID- 29112921 TI - A novel fungal arsenic methyltransferase, WaarsM reduces grain arsenic accumulation in transgenic rice (Oryza sativa L.). AB - Rice (Oryza sativa L.) grown on arsenic-containing soil and water become a primary dietary source of arsenic and pose a significant health risk. Gene modification is an important and practical approach to reduce arsenic accumulation in rice grains. Here, we reported a WaarsM gene of soil fungus Westerdykella aurantiaca, expressed in rice able to convert toxic inorganic arsenicals to methylated arsenic species, therefore, reduce arsenic accumulation in rice grains. In response to arsenic treatment in hydroponics, WaarsM expressing transgenic lines showed a marked increase in arsenic resistance and reduces its accumulation compared to NT. Also, WaarsM expressing transgenic Line 1 evolved ca. 157ng and ca. 43ng volatile arsenicals (mg-1 fresh weight) after 72h of exposure to 25MUM AsIII and 250MUM AsV, respectively. Transgenic Line 1, grown in soil irrigated with arsenic-containing water accumulates about 50% and 52% lower arsenic than NT in shoot and root, respectively; while arsenic concentration in polished seeds and husk of the transgenic line was reduced by 52% compared to NT. Thus, the present study demonstrates that the expression of WaarsM in rice induces arsenic methylation and volatilization, provides a potential strategy to reduce arsenic accumulation in rice grain. PMID- 29112922 TI - Statistical comparison of leaching behavior of incineration bottom ash using seawater and deionized water: Significant findings based on several leaching methods. AB - Bottom ashes generated from municipal solid waste incineration have gained increasing popularity as alternative construction materials, however, they contains elevated heavy metals posing a challenge for its free usage. Different leaching methods are developed to quantify leaching potential of incineration bottom ashes meanwhile guide its environmentally friendly application. Yet, there are diverse IBA applications while the in situ environment is always complicated, challenging its legislation. In this study, leaching tests were conveyed using batch and column leaching methods with seawater as opposed to deionized water, to unveil the metal leaching potential of IBA subjected to salty environment, which is commonly encountered when using IBA in land reclamation yet not well understood. Statistical analysis for different leaching methods suggested disparate performance between seawater and deionized water primarily ascribed to ionic strength. Impacts of leachant are metal-specific dependent on leaching methods and have a function of intrinsic characteristics of incineration bottom ashes. Leaching performances were further compared on additional perspectives, e.g. leaching approach and liquid to solid ratio, indicating sophisticated leaching potentials dominated by combined geochemistry. It is necessary to develop application-oriented leaching methods with corresponding leaching criteria to preclude discriminations between different applications, e.g., terrestrial applications vs. land reclamation. PMID- 29112924 TI - Raman spectrum of methane in nitrogen, carbon dioxide, hydrogen, ethane, and propane environments. AB - Using binary CH4 - mixtures with varied concentrations of H2, N2, CO2, C2H6 and C3H8 and a fixed ambient pressure of 25bar, the influence of the environment on spectral characteristics (Raman shift, half-width, peak intensity) of Q-branches of the nu1, nu2, nu3, and 2nu4 methane Raman bands are investigated. It is found that depending on the environment these bands demonstrate different changes in their Raman shifts and half-widths. It is shown that the ratios of peak intensities I(nu2)/I(nu1), I(nu3)/I(nu1) and I(2nu4)/I(nu1) are very sensitive to the environment. The Raman shifts and half-widths of CH4 bands are assumed to depend on the absolute concentration of molecules in the analyzed medium. The data obtained would be useful in Raman diagnostics of natural gas. PMID- 29112923 TI - Novel rhodamine Schiff base type naked-eye fluorescent probe for sensing Fe3+ and the application in cell. AB - Three rhodamine schiff-base type fluorescent sensors R1-R3 for detecting iron ion (Fe3+), 2-furanacrolein rhodamine hydrazone (R1), furfural rhodamine hydrazone (R2) and 2-furanacrolein rhodamine ethylenediamine (R3) have been synthesized by using rhodamine B derivatives and furan derivatives as staring materials. And their recognition abilities for Fe3+ were studied by fluorescence spectroscopy. The result showed that R1 is a best selective probe for Fe3+ over other metal ions in EtOH/H2O (1:1, v/v) due to having 2-furanacrolein for unique space coordination structural. The recognition of Fe3+ and mechanism of the sensor were characterized and determined by fluorescence spectra and Fukui function. And the fluorescence intensity of the probe R1 for Fe3+ was proportional to its concentration with the linear correlation coefficient of 0.9965 and the binding constant of 7.66*104M-1. And the cell imaging experiment indicated a successful application of the probe R1 for Fe3+ in living cell. PMID- 29112925 TI - Effective dispersion of multi-walled carbon nanotubes in aqueous solution using an ionic-gemini dispersant. AB - A promising ionic-gemini molecule, 4, 4'-di (n-tetradecyl) diphenylmethane disulfate salt (DSDM), is reported for effective dispersion of multi-walled carbon nanotubes (MWCNTs) in aqueous medium in the present investigation. The dispersibility and stability of the DSDM-modified MWCNTs were characterized by UV vis spectrophotometer, Raman spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy and zeta potential measurements. The hydrophobic interaction between alky chains and carbon nanotubes as well as the pi-pi-stacking interaction between benzene rings and carboatomic rings in MWCNTs enables a successful modification of DSDM onto the MWCNT surface. The dispersed MWCNTs individually existed in dispersion with no structural damage, indicating a much better performance than the MWCNTs dispersed by the sodium dodecylbenzene sulfonate (SDBS), a frequently reported single-chain ionic dispersant. Surface potential measurements showed that the DSDM-modified MWCNTs were negatively charged, giving rise to electrostatic repulsion between the MWCNTs in aqueous solution. A better MWCNT dispersion effect was observed with the increase in MWCNT surface potential, and the dispersion with high MWCNT surface potential presents high dispersion stability with no agglomeration appeared for more than 5 months. The magnesium (Mg) matrix composite fabricated based on the DSDM-dispersed MWCNTs demonstrated excellent mechanical properties compared to pure Mg. Our research may provide an alternative way to improve the mechanical properties of composites. PMID- 29112926 TI - Fabrication of Mn3O4-carbon nanotube composites with high areal capacitance using cationic and anionic dispersants. AB - Mn3O4-multiwalled carbon nanotube (MWCNT) electrodes for supercapacitors with high active mass loadings have been fabricated with the goal of achieving a high area normalized capacitance (CS) and enhanced capacitance retention at high charge-discharge rates. Poly(4-styrenesulfonic acid-co-maleic acid) sodium salt P(SSA-MA) was used as a charging and dispersing agent for the fabrication of Mn3O4. The unique bonding properties of the MA monomers allowed efficient P(SSA MA) adsorption on Mn3O4, whereas SSA monomers imparted a negative charge. Cationic ethyl violet (EV) and pyronin Y (PY) dyes were used for dispersion and charging of MWCNT. Good dispersion of the individual components and their electrostatic heterocoagulation facilitated efficient mixing, which allowed enhanced capacitive behavior at mass loadings of 28.4 mg cm-2, which meet requirements for practical applications. The highest capacitance of 2.8 F cm-2 was obtained at a scan rate of 2 mV s-1 for the composites, prepared using PY. However, the composites, prepared using EV showed better capacitance retention of 88% in the scan rate range of 2-100 mV s-1 and the capacitance of 2.1 F cm-2 was obtained at a scan rate of 100 mV s-1. The composites showed activation behavior during cycling, which resulted in a capacitance increase and electrical resistance reduction. The results of this investigation showed that Mn3O4-MWCNT composites, prepared by new colloidal methods are promising materials for practical applications in electrochemical supercapacitors. PMID- 29112927 TI - Digital to analog resistive switching transition induced by graphene buffer layer in strontium titanate based devices. AB - Resistive switching behaviour can be classified into digital and analog switching based on its abrupt and gradual resistance change characteristics. Realizing the transition from digital to analog switching in the same device is essential for understanding and controlling the performance of the devices with various switching mechanisms. Here, we investigate the resistive switching in a device made with strontium titanate (SrTiO3) nanoparticles using X-ray diffractometry, scanning electron microscopy, Raman spectroscopy, and direct electrical measurements. It is found that the well-known rupture/formation of Ag filaments is responsible for the digital switching in the device with Ag as the top electrode. To modulate the switching performance, we insert a reduced graphene oxide layer between SrTiO3 and the bottom FTO electrode owing to its good barrier property for the diffusion of Ag ions and high out-of-plane resistance. In this case, resistive switching is changed from digital to analog as determined by the modulation of interfacial resistance under applied voltage. Based on that controllable resistance, potentiation and depression behaviours are implemented as well. This study opens up new ways for the design of multifunctional devices which are promising for memory and neuromorphic computing applications. PMID- 29112928 TI - A new insight into the theoretical design of highly dispersed and stable ceria supported metal nanoparticles. AB - How to design and develop ceria supported metal nanoparticles (M/CeO2) catalysts with high performance and sintering resistance is a great challenge in heterogeneous catalysis and surface science. In the present work, we propose two ways to improve the anti-sintering capability of M/CeO2 catalysts. One is to introduce Ti atom on CeO2 (1 1 1) to form monatomically dispersed Ti, TiOx or TiO2-like species on ceria. Density functional theory calculations show that the much stronger interactions between Au and Ti modified CeO2 (1 1 1) occur compared with that on CeO2 (1 1 1). According to the electronic analysis, the strong interactions are attributed to the electron transfer from the Ti modified ceria substrate to Au. The other is to dope Ti into CeO2 (1 1 1) to form TixCe1-xO2. This also leads to the interaction enhancement between Au and TixCe1-xO2 (1 1 1). Electronic analysis indicates that the charge protuberance of surface O atoms near Ti atom results in the strong interactions between metal and ceria. This work provides new ideas for preparing M/CeO2 catalysts with high dispersity and stability, and sheds light into the theoretical design of catalysts. PMID- 29112929 TI - In-situ ion-exchange synthesis Ag2S modified SnS2 nanosheets toward highly photocurrent response and photocatalytic activity. AB - Heterojunction photocatalyst systems are deemed to be an excellent option to improve the photocatalytic behavior of a material. In this paper, Ag2S/SnS2 heterojunction photocatalysts were prepared by a simple in-situ ion exchange method from SnS2 nanosheets. The Ag2S/SnS2 composite photoanode exhibits 13.99 MUA/cm2 photocurrent density at 0.7 V (vs. Ag/AgCl) in 0.5 M Na2SO4 solution and a significant increase in photocatalytic activity compared to SnS2 nanosheets. Ag2S (8 wt%)/SnS2 composite shows the highest activity (0.0440 mg/min) in the degradation of MO and good stability. The reactive species trapping experiments confirmed hole (h+) and hydroxyl radical (OH) are active groups and play key roles in the photocatalytic degradation reaction. The highly effective photoelectrochemical and phocatalytic activities of Ag2S/SnS2 heterojunctions are attributed to the efficient separation of photogenerated hole-electron pairs. This work may provide a novel concept for the rational design of high performance SnS2-based photocatalysts. PMID- 29112930 TI - How the interaction of PVP-stabilized Ag nanoparticles with models of cellular membranes at the air-water interface is modulated by the monolayer composition. AB - The antimicrobial property of silver nanoparticles (AgNPs) is believed to be associated to their interaction with biointerfaces such as microbial cell membranes, encouraging research on the identification of membrane sites capable of AgNPs binding. Although significant progress has been made in that regard, the exact molecular mechanism of action is yet to be fully understood. In this study, AgNPs dispersed in aqueous media and stabilized with polyvinylpyrrolidone were incorporated in Langmuir monolayers of selected lipids that served as cell membrane models. Results from pressure-area isotherms, vibrational spectroscopy and Brewster angle microscopy revealed condensation of glycoside-free lipid monolayers, evidencing that the AgNPs interact mostly with the lipid hydrophilic head groups. In contrast, the monolayers of systems containing glycoside derivatives were found to expand upon AgNPs incorporation, indicating that the glycosidic compounds might facilitate the incorporation of these nanoparticles in cellular membranes. These data can be therefore correlated with the possible toxicity and microbicide effect of AgNPs in lipidic surfaces of mammalian and microbial membranes. PMID- 29112931 TI - Comparison of fusion protein and DC vaccine in inhibition of mouse B16F10 melanoma tumor. AB - Dendritic cell (DC) vaccine and fusion protein vaccine have been put into clinical use in cancer immunotherapy. This study compared DC vaccine and fusion protein vaccine directly in their capability of inducing specific immune response. We used mouse Granulocyte Macrophage-Colony Stimulating Factor (mGM CSF) fused with gastrin-releasing peptide (GRP) and Gonadotrophin Releasing Hormone (GnRH) respectively to obtain mGM-CSF/GRP6 (mG6) and mGM-CSF/mGGn (mGGn) fusion proteins. We prepared fusion protein vaccine and DC vaccine including mG6 protein vaccine (6P), mGGn protein vaccine (nP), mG6 DC vaccine (6D) and mGGn DC vaccine (nD), then the two proteins were mixed to prepare combination proteins vaccine (6nP) and DC vaccine (6nD). After that, C57BL/6 mice were injected with B16F10 cell line to build melanoma tumor model, and were immunized with vaccines to produce antibodies to inhibit and destruct melanoma tumor cells. The discoveries showed that anti- mGM-CSF-GRP6 and anti- mGM-CSF-mGGn antibody vaccines were successfully created as expected; this was deduced from significant inhibition of melanoma tumor in vivo and significant reduction of tumor weight and volume. The effects of DC groups were better than that of the protein groups and the combination of vaccines were more effective than vaccine given separately. Our results indicate that using combination vaccine provides a new strategy to inhibit melanoma tumor growth but a complete cure of melanoma needs further investigations. PMID- 29112932 TI - Anti-atherosclerotic effect of Longxuetongluo Capsule in high cholesterol diet induced atherosclerosis model rats. AB - Chinese dragon's blood, the red resin of Dracaena cochinchinensis, one of the famous traditional medicines, has been used to promote blood circulation, disperse blood stasis, stop bleeding, relieve pain and muscle regeneration for thousands of years. The aims of this study were to evaluate the anti atherosclerotic effect of Longxuetongluo Capsule (LTC), which made by total phenolic compounds of Chinese dragon's blood, in high cholesterol diet (HCD) induced atherosclerosis model rats and explore the possible mechanism. Atherosclerosis rats were induced by administration of HCD for 4 weeks and treated with atorvastatin (2.08mg/kg/d) or various concentrations of LTC (81, 162 and 324mg/kg/d) for additional 4 weeks. Body weight (BW), lipid profiles, serum VCAM-1, ICAM-1, MCP-1, AST and ALT were then tested. Histopathological evaluation of aorta and liver were determined by hematoxylin and eosin staining. NF-kappaB expression in aorta was detected by Immunohistochemical staining. Meanwhile, the inhibition effects of LTC on the migration and proliferation and Intracellular Ca2+ levels induced by PDGF-BB were also evaluated in rat aortic smooth muscle cells (A7r5). The results demonstrated that LTC produced a significant anti atherosclerotic activity in terms of reduction in serum lipids and lipoprotein profile, VCAM-1, ICAM-1, MCP-1, AST, ALT levels, and increase in HDL-c level compared to atherosclerotic group. Rats treated with LTC not only attenuated the pathological region and atheroma formation, but also reduced hepatic steatosis and inflammatory cell infiltration. Immunohistochemical analysis showed LTC reduced NF-kappaB expression in aorta. Furthermore, PDGF-BB induced proliferation and migration of A7r5 and intracellular calcium rise were also abrogated by LTC. The results indicate that LTC prevents atherosclerosis and fatty liver by controlling lipid metabolism, the underlying mechanism may attributed to its anti inflammation activity, regulation of the vascular smooth muscle function and intracellular calcium signaling. PMID- 29112933 TI - Hyperinsulinemia-induced PAX6 expression promotes endometrial epithelial cell proliferation via negatively modulating p27 signaling. AB - Polycystic ovarian syndrome (PCOS) is thought to involve hyperinsulinism (insulin resistance, IR) and high prevalence of endometrial epithelial hyperplasia, but how these two pathologies are synergistically regulated in endometrial epithelial cells remains largely unknown. Here, we report a key role for the transcription factor PAX6 in the modulation of PCOS-induced endometrial epithelial proliferation. PAX6 was significantly induced in the endometrial tissues from PCOS patients, and this induction, regulated upstream by high levels of insulin, was closely correlated to the pathogenesis of IR in endometrial epithelial cells. Overexpression of the exogenous PAX6 potentiated the insulin-elicited accumulation of S phase in endometrial epithelial cells and thereby promoted endometrial epithelial proliferation. In parallel, by using luciferase reporter and ChIP assay, we found that PAX6 directly bound to the promoter of CDKN1B gene (the gene encoding p27 protein, a negative regulator of cell cycle) and inhibited CDKN1B transcription in the insulin-stimulated endometrial epithelial cells. We conclude that excessive PAX6 expression in insulin-challenged endometrial epithelial cells may contribute to the uncontrollable endometrial epithelial proliferation. Our results also provide a mechanistic explanation for the functional link between hyperinsulinemia and p27 loss in the pathogenesis of endometrial epithelial hyperplasia in PCOS patients. PMID- 29112934 TI - Long non-coding RNA GAS5 antagonizes the chemoresistance of pancreatic cancer cells through down-regulation of miR-181c-5p. AB - OBJECTIVE: To explore the core mechanism of long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) in the regulation of multidrug resistance of pancreatic cancer cells. METHODS: mRNA levels of GAS5, miR-181c-5p and Hippo pathway related genes were detected by quantitative real-time PCR (qRT-PCR). Protein levels of MDR-1, MST1, YAP and TAZ were measured by western blot. Cell viability was detected by MTT assay. The combination between GAS5 and miR-181c-5p was confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assay. We also established pancreatic cancer-bearing mice model and analyzed tumor volumes. RESULTS: Our data showed GAS5 expression was significantly down-regulated, miR 181c-5p expression was significantly up-regulated in pancreatic cancer cells. Besides, Overexpresson of GAS5 obviously inhibited cell viability, while GAS5 knockdown showed the opposite outcome. Additionally, we also found that GAS5 negatively regulated miR-181c-5p, and miR-181c-5p dramatically promoted pancreatic cancer cell chemoresistance through inactivating the Hippo signaling. GAS5 regulated chemoresistance and Hippo pathway of pancreatic cancer cells via miR-181c-5p/Hippo. Finally, we confirmed that overexpression of GAS5 inhibited tumor growth in pancreatic cancer-bearing mice model. CONCLUSION: GAS5 regualtes Hippo signaling pathway via miR-181c-5p to antagonize the development of multidrug resistance in pancreatic cancer cells. PMID- 29112935 TI - Histone deacetylase 6 inhibitor ACY-1215 protects against experimental acute liver failure by regulating the TLR4-MAPK/NF-kappaB pathway. AB - Histone deacetylase 6 (HDAC6) is considered a new target for anticancer, anti inflammatory, and neurodegenerative treatment. ACY-1215 is a selective histone deacetylase 6 inhibitor, and it has been recognized as a potential anticancer and anti-inflammation drug. The aim of our study was to investigate whether ACY-1215 has protective effects on acute liver failure (ALF) in mice and explore its potential mechanism. Male C57/BL6 mice were divided into normal, model, and ACY 1215 groups. ACY-1215 (25mg/kg) and same amounts of saline were given to mice. After 2h, the ALF models were induced by lipopolysaccharide (LPS, 100MUg/kg) combined with D-galactosamine (D-gal, 400mg/kg). All animals were killed after 24h. The expressions of HDAC6 were determined by western blotting and RT-PCR assay. The expression levels of inflammatory cytokines were detected by ELISA and RT-PCR. The protein expression of Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor kappaB (NF-kappaB) species were determined by western blot. The mortality of mice with ALF induced by LPS and D gal was significantly decreased by ACY-1215 pretreatment. Procedures to manage ALF caused adversely affected liver histology and function; this damage was repaired by pretreatment of ACY-1215. ACY-1215 treatment also attenuated the serum and messenger RNA levels of the proinflammatory cytokines. Pretreatment of ACY-1215 significantly decreased the protein expression of TLR4 and the activation of MAPK and NF-kappaB signalling pathways. ACY-1215 has potential therapeutic value in mice with ALF by directly inhibiting inflammatory response via regulation of the TLR4-MAPK/NF-kB pathway. PMID- 29112937 TI - A ligand-based comparative molecular field analysis (CoMFA) and homology model based molecular docking studies on 3', 4'-dihydroxyflavones as rat 5-lipoxygenase inhibitors: Design of new inhibitors. AB - In this study, ligand based comparative molecular field analysis (CoMFA) with five principal components was performed on class of 3', 4'-dihydroxyflavone derivatives for potent rat 5-LOX inhibitors. The percentage contributions in building of CoMFA model were 91.36% for steric field and 8.6% for electrostatic field. R2 values for training and test sets were found to be 0.9320 and 0.8259, respectively. In case of LOO, LTO and LMO cross validation test, q2 values were 0.6587, 0.6479 and 0.5547, respectively. These results indicate that the model has high statistical reliability and good predictive power. The extracted contour maps were used to identify the important regions where the modification was necessary to design a new molecule with improved activity. The study has developed a homology model for rat 5-LOX and recognized the key residues at the binding site. Docking of most active molecule to the binding site of 5-LOX confirmed the stability and rationality of CoMFA model. Based on molecular docking results and CoMFA contour plots, new inhibitors with higher activity with respect to the most active compound in data set were designed. PMID- 29112936 TI - Designing anti-Zika virus peptides derived from predicted human-Zika virus protein-protein interactions. AB - The production of anti-Zika virus (ZIKV) therapeutics has become increasingly important as the propagation of the devastating virus continues largely unchecked. Notably, a causal relationship between ZIKV infection and neurodevelopmental abnormalities has been widely reported, yet a specific mechanism underlying impaired neurological development has not been identified. Here, we report on the design of several synthetic competitive inhibitory peptides against key pathogenic ZIKV proteins through the prediction of protein protein interactions (PPIs). Often, PPIs between host and viral proteins are crucial for infection and pathogenesis, making them attractive targets for therapeutics. Using two complementary sequence-based PPI prediction tools, we first produced a comprehensive map of predicted human-ZIKV PPIs (involving 209 human protein candidates). We then designed several peptides intended to disrupt the corresponding host-pathogen interactions thereby acting as anti-ZIKV therapeutics. The data generated in this study constitute a foundational resource to aid in the multi-disciplinary effort to combat ZIKV infection, including the design of additional synthetic proteins. PMID- 29112938 TI - Impact of baseline cytogenetic findings and cytogenetic response on outcome of high-risk myelodysplastic syndromes and low blast count AML treated with azacitidine. AB - Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p<10-4) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS. PMID- 29112940 TI - Vaginal Candidiasis Infection Treated Using Apple Cider Vinegar: A Case Report. AB - A 32-y-old married woman was admitted with intense vaginal discharge with foul odor, itching, groin pain, and infertility for the past 5 y. Candida albicans was isolated from the culture of vaginal swab. The patient was diagnosed with chronic vaginal candida infection. She failed to respond to integrative medicine methods prescribed. Recovery was achieved with the application of apple cider vinegar. Alternative treatment methods can be employed in patients unresponsive to medical therapies. As being one of these methods, application of apple cider vinegar can cure vaginal candida infection. PMID- 29112939 TI - Serious games for arm rehabilitation of persons with multiple sclerosis. A randomized controlled pilot study. AB - OBJECTIVES: The feasibility and preliminary evidence for efficacy of a serious games platform compared to exergame using the Wii for arm rehabilitation in persons with multiple sclerosis (MS) was investigated. METHODS: A pilot single blind randomized (2:1) controlled in clinic trial was carried out. Sixteen persons with MS participated (age years 56.8 (SD 12.3), MS-onset years 19.4 (SD 12.3), EDSS 6.5). Ten participants used a serious games platform (Rehab@Home) while 6 participants played with the commercial Wii platform, for four weeks (40min, 12 sessions/4 weeks). Feasibility and user experience measures were collected. Primary outcomes were the 9 Hole Peg Test (9HPT) and the Box and Block test (BBT). Secondary outcomes were the EQ-5D visual analogue scale (EQ-VAS) and the SF-12. Nonparametric analysis was used to verify changes from pre to post rehabilitation within group and treatment effect was verified with Mann-Whitney U test. P value was set at 0.10 and clinical improvement was set at 20% improvement from baseline. RESULTS: Serious games were perceived positively in terms of user experience and motivation. There were clinically significant improvements in arm function in the serious games group as measured by 9HPT (38-29.5s, P = 0.046, > 20%) and BBT 32-42 cubes, P = 0.19, > 20%) following the 12 gaming sessions while the exergame group did not improve on either test (9HPT 34.5-41.5s, P = 0.34; BBT 38,5 to 42 cubes, P = 0.34). Only the exergame group perceived themselves as having improved their health. There was a significant between groups treatment effect only in perception of health (EQ-VAS) (Z = 1.93, P = 0.06) favouring the exergame group. CONCLUSIONS: Virtual reality in a serious gaming approach was feasible and beneficial to arm function of persons with MS but motivational aspects of the approach may need further attention. PMID- 29112941 TI - Yoga Can Improve Assisted Reproduction Technology Outcomes in Couples With Infertility. AB - Context * Depending on the cause of the infertility, nonsurgical or surgical treatments may be used to treat men and women with infertility. Despite improved outcomes due to medical advances, assisted reproductive technology (ART) for couples with infertility is sometimes unsuccessful. Success may be affected by the patient's social, psychological, and physical status. Objective * The study examined the effects of yoga-including asanas (yoga poses), pranayama (proper breathing), shavasana, and meditation-on male and female fertility and ART outcomes. Design * The research team performed a literature review, electronically searching for articles published between January 1978 and January 2016 in the PubMed, Scopus, ScienceDirect, and Google Scholar databases. Setting * The study took place at the Reproductive Biotechnology Research Center at the Avicenna Research Institute at the Academic Center for Education, Culture, and Research (Tehran, Iran). Participants * Participants were couples with infertility taking part in 87 reviewed studies. Intervention * Yoga was the intervention. Outcome Measures * The outcome measures comprised fertility factors in males and females, fertility rate, and ART success rate. Results * The reviewed studies showed that yoga can provide stress management for patients with infertility, with beneficial effects on fertility, helping couples give birth. They found that yoga also could reduce pain; decrease depression, anxiety, and stress; reduce the rate of assisted vaginal delivery; and improve fetal outcomes. Conclusions * Yoga can help couples overcome infertility and increase the ART success rate by improving the physiological and psychological states of both men and women. PMID- 29112942 TI - Acupuncture for Primary Dysmenorrhea: A Meta-analysis of Randomized Controlled Trials. AB - Context * Primary dysmenorrhea (PD) is one of the most common complaints among young women. Acupuncture has been widely applied as a therapeutic modality in China and abroad for PD; however, the evidence for its benefits is still not convincing. Objective * The study intended to conduct a systematic review of randomized, controlled trials (RCTs) to evaluate the evidence regarding the use of acupuncture in treating PD. Design * The research team retrieved reports for RCTs published in 7 databases from their inception to March 2016, with no language restrictions: PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials, the Chinese National Knowledge Infrastructure database, the Chinese Biomedical database, and the Wanfang database. Setting * The study was conducted at the Beijing University of Traditional Chinese Medicine (Beijing, China). Participants * Participants in the reviewed studies were women aged 14 to 49 y who had received a diagnosis of PD in the absence of any visible pelvic pathology. Interventions * The types of acupuncture included traditional acupuncture, electroacupuncture, ear acupuncture, scalp acupuncture, superficial acupuncture, electrosuperficial acupuncture, wrist-ankle acupuncture, and abdominal acupuncture. Outcome Measures * The primary outcome was pain relief measured using a visual analogue scale (VAS), a verbal rating scale (VRS), or a numerical rating scale (NRS). The secondary outcomes included (1) overall improvement as measured by the short-form McGill pain questionnaire or symptom scale based on the Clinical Study Guideline for New Developed Chinese Medicine, (2) menstrual distress as measured by the Menstrual Distress Questionnaire, (3) quality of life as measured by a validated scale (eg, the short-form 36), and (4) adverse effects. Results * Twenty-three trials enrolling a total of 2770 patients were included in the review. Overall, most trials were of poor quality. Among the trials, only 6 were evaluated as having a low risk of bias, 3 of which indicated that acupuncture was statistically more effective than sham acupuncture-mean difference (MD), -3.51; 95% confidence interval (CI), -5.27 to -1.75; P < .0001; I2, 0%-or no treatment-MD, -21.95; 95% CI, -25.45 to -18.45; P < .00001; I2, 0% on the VAS (0 to 100 mm). Acupuncture also showed superiority to the control arms on the VRS, the NRS, and the McGill pain questionnaire, but those findings had been influenced by methodological flaws. Conclusions * The available evidence suggests that acupuncture may be effective for PD and justifies future high quality studies. PMID- 29112943 TI - Electrocardiogram reading: a randomized study comparing 2 e-learning methods for medical students. AB - INTRODUCTION Interpretation of the electrocardiogram (ECG) is an essential skill in most medical specialties; however, the best method of teaching how to read ECGs has not been determined. OBJECTIVES The aim of the study was to compare the effectiveness of collaborative (C-eL) and self (S-eL) e-learning of ECG reading among medical students. PATIENTS AND METHODS A total of 60 fifth year medical students were randomly assigned to the C-eL and S-eL groups. S-eL students received 15 ECG recordings with a comprehensive description by email (one every 48 hours), while C-eL students received the same ECG recordings without description. C-eL students were expected to analyze each ECG together within the subgroups using an internet platform and to submit the interpretation within 48 hours. Afterwards, they received a description of each ECG. C-eL students' activity was assessed based on the number of words written on the internet platform during discussion. A final test consisted of 10 theoretical questions and 10 ECG recordings. The final score was a sum of points obtained for the interpretation of ECG recordings. The main endpoint of the study was the number of students whose final score was 56% or higher. RESULTS The final test was completed by 53 students (88.3%). The main endpoint was achieved in 20 C-eL students (77%) and in 13 S-eL students (48.1%), P = 0.03. The final score was 6.4 (interquartile range [IQR], 5.8-7.6) in the C-eL group and 5.6 (IQR, 4.2-7.2) in the S-eL group, P = 0.04. It correlated with the results of the theoretical test and students' activity during C-eL (r = 0.42, P = 0.002 and r = 0.4, P = 0.04, respectively). CONCLUSIONS C-eL of ECG reading among fifth-year medical students is superior to S-eL. PMID- 29112944 TI - Chronic obstructive pulmonary disease affects the angiographic presentation and outcomes of patients with coronary artery disease treated with percutaneous coronary interventions. AB - INTRODUCTION The incidence of chronic obstructive pulmonary disease (COPD) in patients treated with percutaneous coronary intervention (PCI) is underestimated, and the effect of COPD on atherosclerosis and the outcomes of PCI is not fully understood. OBJECTIVES The aim of this study was to assess the impact of COPD on periprocedural outcomes of PCI, as well as its relationship with clinical presentation and the type of coronary artery lesions. PATIENTS AND METHODS Data were prospectively collected using a national electronic registry of PCI procedures performed in Poland between January 2015 and December 2016. Out of the 221 187 PCIs, 5594 patients had been diagnosed with COPD before the intervention. RESULTS Patients with COPD were older than those without COPD (mean [SD] age, 70.3 [9.9] years vs 67 [10.8] years; P <0.001) and more often were males (72.3% vs 67.8%; P <0.001). Non-ST-segment elevation myocardial infarction (NSTEMI) was a more common clinical presentation of coronary artery disease (CAD) in the COPD group, while ST-segment elevation myocardial infarction (STEMI) occurred more frequently in the non-COPD group. Multivessel disease (MVD) with or without left main coronary artery (LMCA) involvement and separate LMCA was diagnosed more often in the COPD group. At baseline, the culprit lesion was more often restenosis and in-stent thrombosis in the COPD group, whereas de-novo lesion-in the non-COPD group. The rates of periprocedural mortality and myocardial infarction did not differ between the groups with and without COPD (0.13% vs 0.12%, P = 0.88 and 0.53% vs 0.45%, P = 0.39, respectively). COPD was found to be an independent predictor of restenosis assessed before PCI in patients with a history of PCI (P = 0.006). CONCLUSIONS Patients with COPD diagnosed before PCI are at an increased risk of MVD with or without LMCA involvement and NSTEMI. Restenosis and in-stent thrombosis occur more often in patients with COPD before PCI. PMID- 29112945 TI - Biomechanical changes during abdominal aortic aneurysm growth. AB - The biomechanics-based Abdominal Aortic Aneurysm (AAA) rupture risk assessment has gained considerable scientific and clinical momentum. However, such studies have mainly focused on information at a single time point, and little is known about how AAA properties change over time. Consequently, the present study explored how geometry, wall stress-related and blood flow-related biomechanical properties change during AAA expansion. Four patients with a total of 23 Computed Tomography-Angiography (CT-A) scans at different time points were analyzed. At each time point, patient-specific properties were extracted from (i) the reconstructed geometry, (ii) the computed wall stress at Mean Arterial Pressure (MAP), and (iii) the computed blood flow velocity at standardized inflow and outflow conditions. Testing correlations between these parameters identified several nonintuitive dependencies. Most interestingly, the Peak Wall Rupture Index (PWRI) and the maximum Wall Shear Stress (WSS) independently predicted AAA volume growth. Similarly, Intra-luminal Thrombus (ILT) volume growth depended on both the maximum WSS and the ILT volume itself. In addition, ILT volume, ILT volume growth, and maximum ILT layer thickness correlated with PWRI as well as AAA volume growth. Consequently, a large ILT volume as well as fast increase of ILT volume over time may be a risk factor for AAA rupture. However, tailored clinical studies would be required to test this hypothesis and to clarify whether monitoring ILT development has any clinical benefit. PMID- 29112946 TI - Targeting of cadherin-11 decreases skin fibrosis in the tight skin-1 mouse model. AB - OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Cadherin-11 (CDH11) expression is increased in fibrotic skin and lung tissue. Targeting CDH11 may be an effective approach to treating fibrosis. We hypothesize that targeting CDH11 will decrease fibrosis in the tight skin-1 (Tsk-1) mouse model. METHODS: CDH11 expression was determined in the Tsk-1 mouse model using quantitative real time PCR and immunofluorescence (IF). Inhibitory anti- CDH11 monoclonal antibodies were tested in Tsk-1 mice for their ability to decrease hypodermal fibrosis. RESULTS: Expression of CDH11 was increased in fibrotic skin from Tsk-1 mice compared to pallid controls. IF staining demonstrated that CDH11 expression localized to fibroblasts within the hypodermis of fibrotic skin. Treatment with inhibitory anti-CDH11 monoclonal antibodies decreased hypodermal thickness and fibrotic mediators in Tsk-1 mice compared to control antibodies. CONCLUSIONS: These data demonstrate an important role for CDH11 in the development of skin fibrosis in Tsk-1 mice. These data add to the growing evidence for the important role of CDH11 in tissue fibrosis and fibrotic disease such as systemic sclerosis. PMID- 29112947 TI - Sugar analog synthesis by in vitro biocatalytic cascade: A comparison of alternative enzyme complements for dihydroxyacetone phosphate production as a precursor to rare chiral sugar synthesis. AB - Carbon-carbon bond formation is one of the most challenging reactions in synthetic organic chemistry, and aldol reactions catalysed by dihydroxyacetone phosphate-dependent aldolases provide a powerful biocatalytic tool for combining C-C bond formation with the generation of two new stereo-centres, with access to all four possible stereoisomers of a compound. Dihydroxyacetone phosphate (DHAP) is unstable so the provision of DHAP for DHAP-dependent aldolases in biocatalytic processes remains complicated. Our research has investigated the efficiency of several different enzymatic cascades for the conversion of glycerol to DHAP, including characterising new candidate enzymes for some of the reaction steps. The most efficient cascade for DHAP production, comprising a one-pot four-enzyme reaction with glycerol kinase, acetate kinase, glycerophosphate oxidase and catalase, was coupled with a DHAP-dependent fructose-1,6-biphosphate aldolase enzyme to demonstrate the production of several rare chiral sugars. The limitation of batch biocatalysis for these reactions and the potential for improvement using kinetic modelling and flow biocatalysis systems is discussed. PMID- 29112948 TI - Using quantitative features extracted from T2-weighted MRI to improve breast MRI computer-aided diagnosis (CAD). AB - Computer-aided diagnosis (CAD) has been proposed for breast MRI as a tool to standardize evaluation, to automate time-consuming analysis, and to aid the diagnostic decision process by radiologists. T2w MRI findings are diagnostically complementary to T1w DCE-MRI findings in the breast and prior research showed that measuring the T2w intensity of a lesion relative to a tissue of reference improves diagnostic accuracy. The diagnostic value of this information in CAD has not been yet quantified. This study proposes an automatic method of assessing relative T2w lesion intensity without the need to select a reference region. We also evaluate the effect of adding this feature to other T2w and T1w image features in the predictive performance of a breast lesion classifier for differential diagnosis of benign and malignant lesions. An automated feature of relative T2w lesion intensity was developed using a quantitative regression model. The diagnostic performance of the proposed feature in addition to T2w texture was compared to the performance of a conventional breast MRI CAD system based on T1w DCE-MRI features alone. The added contribution of T2w features to more conventional T1w-based features was investigated using classification rules extracted from the lesion classifier. After institutional review board approval that waived informed consent, we identified 627 breast lesions (245 malignant, 382 benign) diagnosed after undergoing breast MRI at our institution between 2007 and 2014. An increase in diagnostic performance in terms of area under the curve (AUC) from the receiver operating characteristic (ROC) analysis was observed with the additional T2w features and the proposed quantitative feature of relative T2w lesion intensity. AUC increased from 0.80 to 0.83 and this difference was statistically significant (adjusted p-value = 0.020). PMID- 29112949 TI - Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) represents a genomically unstable cancer type with extensive copy number aberrations. The relationship of gene copy number alterations and subsequent mRNA levels has only fragmentarily been described. The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190) and their association with survival. While more than half of all analyzed gene copy number-gene expression pairs showed statistically significant correlations (10,296 of 18,756 genes), high correlations, with a correlation coefficient >0.7, were obtained only in a subset of 301 genes (1.6%), including KRAS, EGFR and MDM2. Higher correlation coefficients were associated with higher copy number and expression levels. Strong correlations were frequently based on few tumors with high copy number gains and correspondingly increased mRNA expression. Among the highly correlating genes, GO groups associated with posttranslational protein modifications were particularly frequent, including ubiquitination and neddylation. In a meta-analysis including 1,779 patients we found that survival associated genes were overrepresented among highly correlating genes (61 of the 301 highly correlating genes, FDR adjusted p<0.05). Among them are the chaperone CCT2, the core complex protein NUP107 and the ubiquitination and neddylation associated protein CAND1. In conclusion, in a comprehensive analysis we described a distinct set of highly correlating genes. These genes were found to be overrepresented among survival-associated genes based on gene expression in a large collection of publicly available datasets. PMID- 29112950 TI - Single primer isothermal amplification (SPIA) combined with next generation sequencing provides complete bovine coronavirus genome coverage and higher sequence depth compared to sequence-independent single primer amplification (SISPA). AB - Coronaviruses are of major importance for both animal and human health. With the emergence of novel coronaviruses such as SARS and MERS, the need for fast genome characterisation is ever so important. Further, in order to understand the influence of quasispecies of these viruses in relation to biology, techniques for deep-sequence and full-length viral genome analysis are needed. In the present study, we compared the efficiency of two sequence-independent approaches [sequence-independent single primer amplification (SISPA) and single primer isothermal amplification (SPIA, represented by the Ovation kit)] coupled with high-throughput sequencing to generate the full-length genome of bovine coronavirus (BCoV) from a nasal swab. Both methods achieved high genome coverage (100% for SPIA and 99% for SISPA), however, there was a clear difference in the percentage of reads that mapped to BCoV. While approximately 45% of the Ovation reads mapped to BCoV (sequence depth of 169-284 944), only 0.07% of the SISPA reads (sequence depth of 0-249) mapped to the reference genome. Although BCoV was the focus of the study we also identified a bovine rhinitis B virus (BRBV) in the data sets. The trend for this virus was similar to that observed for BCoV regarding Ovation vs. SISPA, but with fewer sequences mapping to BRBV due to a lower amount of this virus. In summary, the SPIA approach used in this study produced coverage of the entire BCoV (high copy number) and BRBV (low copy number) and a high sequence/genome depth compared to SISPA. Although this is a limited study, the results indicate that the Ovation method could be a preferred approach for full genome sequencing if a low copy number of viral RNA is expected and if high sequence depth is desired. PMID- 29112951 TI - Phenotype and specificity of T cells in primary human cytomegalovirus infection during pregnancy: IL-7Rpos long-term memory phenotype is associated with protection from vertical transmission. AB - Congenital human cytomegalovirus (HCMV) infection is the major cause of birth defects and a precise definition of the HCMV-specific T-cell response in primary infection may help define reliable correlates of immune protection during pregnancy. In this study, a high throughput method was used to define the frequency of CD4+ and CD8+ T cells specific for four HCMV proteins in the naive compartment of seronegative subjects and the effector/memory compartments of subjects with primary/remote HCMV infection. The naive repertoire displayed comparable frequencies of T cells that were reactive with HCMV structural (pp65, gB and the pentamer gHgLpUL128L) and non-structural (IE-1) proteins. Whereas, following natural infection, the majority of effector/memory CD4+ and CD8+ T cells recognized either gB or IE-1, respectively, and pp65. The pattern of T cell reactivity was comparable at early and late stages of infection and in pregnant women with primary HCMV infection transmitting or not transmitting the virus to the fetus. At an early stage of primary infection, about 50% of HCMV-reactive CD4+ T cells were long-term IL-7Rpos memory cells, while 6-12 months later, the frequency of these cells increased to 70%, approaching 100% in remote infections. In contrast, only 10-20% of HCMV-specific CD8+ T cells were long-term memory cells up to 12 months after infection onset, thereafter increasing to 70% in remote infections. Interestingly, a significantly higher frequency of HCMV specific CD4+ T cells with a long-term IL-7Rpos memory phenotype was observed in non-transmitting compared to transmitting women. These findings indicate that immunodominance in HCMV infection is not predetermined in the naive compartment, but is the result of virus-host interactions and suggest that prompt control of HCMV infection in pregnancy is associated with the rapid development of long-term IL-7Rpos memory HCMV-specific CD4+ T cells and a low risk of virus transmission to the fetus. PMID- 29112952 TI - Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection. AB - Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating K. pneumoniae clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with K. pneumoniae by launching bacterial growth controlling interactions between alveolar macrophages and natural killer (NK) cells. Type I IFNs are important but disparate and incompletely understood regulators of defense against bacterial infections. Type I IFN receptor 1 (Ifnar1)-deficient mice infected with K. pneumoniae failed to activate NK cell derived IFN-gamma production. IFN-gamma was required for bactericidal action and the production of the NK cell response-amplifying IL-12 and CXCL10 by alveolar macrophages. Bacterial clearance and NK cell IFN-gamma were rescued in Ifnar1 deficient hosts by Ifnar1-proficient NK cells. Consistently, type I IFN signaling in myeloid cells including alveolar macrophages, monocytes and neutrophils was dispensable for host defense and IFN-gamma activation. The failure of Ifnar1 deficient hosts to initiate a defense-promoting crosstalk between alveolar macrophages and NK cell was circumvented by administration of exogenous IFN-gamma which restored endogenous IFN-gamma production and restricted bacterial growth. These data identify NK cell-intrinsic type I IFN signaling as essential driver of K. pneumoniae clearance, and reveal specific targets for future therapeutic exploitations. PMID- 29112953 TI - Aldehyde dehydrogenase 1 isoenzyme expression as a marker of cancer stem cells correlates to histopathological features in head and neck cancer: A meta analysis. AB - There is a lack of predictive biomarkers that can identify patients with head and neck squamous cell carcinoma (HNSCC) who will experience treatment failure and develop drug resistance, recurrence, and metastases. Cancer stem-like cells (CSC) were identified as a subset of cells within the tumor in a variety of solid tumors including HNSCC. CSC are considered the tumor-initiating population responsible for recurrence or metastasis and are associated with therapy resistance. This meta-analysis including fourteen studies with altogether 1258 patients updates and summarizes all relevant data on the impact of ALDH1+ CSC on the prognosis of HNSCC and its association with clinicopathological parameters. ALDH1 expression is highly correlated with tumor differentiation (G3 vs. G1+G2; odds ratio = 2.85. 95% CI: 1.72-4.73, P<0.0001) and decreased overall survival (relative risk = 1.77. 95% CI: 1.41-2.22, P<0.0001) if one out of seven studies was excluded because of heterogeneity. These findings provide insights into the understanding of more aggressive tumor phenotypes and also suggest that the prognostic value provided by HNSCC-subtyping by CSC frequency warrant further clinical investigation. PMID- 29112954 TI - Metabolic dynamics restricted by conserved carriers: Jamming and feedback. AB - To uncover the processes and mechanisms of cellular physiology, it first necessary to gain an understanding of the underlying metabolic dynamics. Recent studies using a constraint-based approach succeeded in predicting the steady states of cellular metabolic systems by utilizing conserved quantities in the metabolic networks such as carriers such as ATP/ADP as an energy carrier or NADH/NAD+ as a hydrogen carrier. Although such conservation quantities restrict not only the steady state but also the dynamics themselves, the latter aspect has not yet been completely understood. Here, to study the dynamics of metabolic systems, we propose adopting a carrier cycling cascade (CCC), which includes the dynamics of both substrates and carriers, a commonly observed motif in metabolic systems such as the glycolytic and fermentation pathways. We demonstrate that the conservation laws lead to the jamming of the flux and feedback. The CCC can show slow relaxation, with a longer timescale than that of elementary reactions, and is accompanied by both robustness against small environmental fluctuations and responsiveness against large environmental changes. Moreover, the CCC demonstrates robustness against internal fluctuations due to the feedback based on the moiety conservation. We identified the key parameters underlying the robustness of this model against external and internal fluctuations and estimated it in several metabolic systems. PMID- 29112955 TI - Salmonella Typhimurium DT193 and DT99 are present in great and blue tits in Flanders, Belgium. AB - Endemic infections with the common avian pathogen Salmonella enterica subspecies enterica serovar Typhimurium (Salmonella Typhimurium) may incur a significant cost on the host population. In this study, we determined the potential of endemic Salmonella infections to reduce the reproductive success of blue (Cyanistes caeruleus) and great (Parus major) tits by correlating eggshell infection with reproductive parameters. The fifth egg of each clutch was collected from nest boxes in 19 deciduous forest fragments. Out of the 101 sampled eggs, 7 Salmonella Typhimurium isolates were recovered. The low bacterial prevalence was reflected by a similarly low serological prevalence in the fledglings. In this study with a relatively small sample size, presence of Salmonella did not affect reproductive parameters (egg volume, clutch size, number of nestlings and number of fledglings), nor the health status of the fledglings. However, in order to clarify the impact on health and reproduction a larger number of samples have to be analyzed. Phage typing showed that the isolates belonged to the definitive phage types (DT) 193 and 99, and multi-locus variable number tandem repeat analysis (MLVA) demonstrated a high similarity among the tit isolates, but distinction to human isolates. These findings suggest the presence of passerine-adapted Salmonella strains in free-ranging tit populations with host pathogen co-existence. PMID- 29112957 TI - Laccase SilA from Streptomyces ipomoeae CECT 3341, a key enzyme for the degradation of lignin from agricultural residues? AB - The role of laccase SilA produced by Streptomyces ipomoeae CECT 3341 in lignocellulose degradation was investigated. A comparison of the properties and activities of a laccase-negative mutant strain (SilA-) with that of the wild-type was studied in terms of their ability to degrade lignin from grass lignocellulose. The yields of solubilized lignin (acid precipitable polymeric lignin, APPL) obtained from wheat straw by both strains in Solid State Fermentation (SSF) conditions demonstrated the importance of SilA laccase in lignin degradation with the wild-type showing 5-fold more APPL produced compared with the mutant strain (SilA-). Analytical pyrolysis and FT-IR (Fourier Transform Infrared Spectroscopy) confirmed that the APPL obtained from the substrate fermented by wild-type strain was dominated by lignin derived methoxyphenols whereas those from SilA- and control APPLs were composed mainly of polysaccharides. This is the first report highlighting the role of this laccase in lignin degradation. PMID- 29112956 TI - HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study. AB - BACKGROUND: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. METHODS AND FINDINGS: Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. CONCLUSIONS: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission. PMID- 29112958 TI - Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV positive persons at high predicted CVD and CKD risk: A prospective analysis of the D:A:D observational study. AB - BACKGROUND: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has developed predictive risk scores for cardiovascular disease (CVD) and chronic kidney disease (CKD, defined as confirmed estimated glomerular filtration rate [eGFR] <= 60 ml/min/1.73 m2) events in HIV-positive people. We hypothesized that participants in D:A:D at high (>5%) predicted risk for both CVD and CKD would be at even greater risk for CVD and CKD events. METHODS AND FINDINGS: We included all participants with complete risk factor (covariate) data, baseline eGFR > 60 ml/min/1.73 m2, and a confirmed (>3 months apart) eGFR < 60 ml/min/1.73 m2 thereafter to calculate CVD and CKD risk scores. We calculated CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (<=1%, >1%-5%, >5%) and fitted Poisson models to assess whether CVD and CKD risk group effects were multiplicative. A total of 27,215 participants contributed 202,034 person-years of follow-up: 74% male, median (IQR) age 42 (36, 49) years, median (IQR) baseline year of follow-up 2005 (2004, 2008). D:A:D risk equations predicted 3,560 (13.1%) participants at high CVD risk, 4,996 (18.4%) participants at high CKD risk, and 1,585 (5.8%) participants at both high CKD and high CVD risk. CVD and CKD event rates by predicted risk group were multiplicative. Participants at high CVD risk had a 5.63-fold (95% CI 4.47, 7.09, p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (95% CI 1.09, 1.56, p = 0.005) increase in CVD events compared to those at low risk. Participants' CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction (p = 0.329 and p = 0.291 for CKD and CVD, respectively). The main study limitation is the difference in the ascertainment of the clinically defined CVD endpoints and the laboratory-defined CKD endpoints. CONCLUSIONS: We found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD events compared with those at low predicted risk for both outcomes, and compared to those at high predicted risk for only CVD or CKD events. This suggests that CVD and CKD risk in HIV positive persons should be assessed together. The results further encourage clinicians to prioritise addressing modifiable risks for CVD and CKD in HIV positive people. PMID- 29112959 TI - A prospective cohort study of safety and patient satisfaction of voluntary medical male circumcision in Botswana. AB - Randomized trials have shown that voluntary medical male circumcision (VMMC) significantly reduces the risk of HIV acquisition in men. However, the rate of complications associated with the surgical procedure varies from 0.7% to 37.4% in real-world settings. We assessed the frequency, type and severity of adverse events following VMMC among 427 adult men surgically circumcised in southeastern Botswana; 97% completed >=1 follow-up visit within seven days post-circumcision. Thirty moderate AEs were observed in 28 men resulting in an overall AE rate of 6.7%. Patient satisfaction was high: >95% were very or somewhat satisfied with the procedure and subsequent follow-up care. PMID- 29112960 TI - Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma. AB - BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. MATERIALS AND METHODS: Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). RESULTS: All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. CONCLUSION: In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients. PMID- 29112961 TI - Optimization of non-denaturing protein extraction conditions for plant PPR proteins. AB - Pentatricopeptide repeat proteins are one of the major protein families in flowering plants, containing around 450 members. They participate in RNA editing and are related to plant growth, development and reproduction, as well as to responses to ABA and abiotic stresses. Their characteristics have been described in silico; however, relatively little is known about their biochemical properties. Different types of PPR proteins, with different tasks in RNA editing, have been suggested to interact in an editosome to complete RNA editing. Other non-PPR editing factors, such as the multiple organellar RNA editing factors and the organelle RNA recognition motif-containing protein family, for example, have also been described in plants. However, while evidence on protein interactions between non-PPR RNA editing proteins is accumulating, very few PPR protein interactions have been reported; possibly due to their high instability. In this manuscript, we aimed to optimize the conditions for non-denaturing protein extraction of PPR proteins allowing in vivo protein analyses, such as interaction assays by co-immunoprecipitation. The unusually high protein degradation rate, the aggregation properties and the high pI, as well as the ATP-dependence of some PPR proteins, are key aspects to be considered when extracting PPR proteins in a non-denatured state. During extraction of PPR proteins, the use of proteasome and phosphatase inhibitors is critical. The use of the ATP-cofactor reduces considerably the degradation of PPR proteins. A short centrifugation step to discard cell debris is essential to avoid PPR precipitation; while in some cases, addition of a reductant is needed, probably caused by the pI/pH context. This work provides an easy and rapid optimized non-denaturing total protein extraction protocol from plant tissue, suitable for polypeptides of the PPR family. PMID- 29112962 TI - Increasing prevalence of diabetes mellitus in a developing country and its related factors. AB - BACKGROUND: All countries, irrespective of their developmental stage, face an increasing burden of non-communicable diseases including diabetes mellitus. There is substantial evidence of the existence of the gap in the level of diabetes mellitus and its complications prevention and control measures in developing countries. This study aimed to assess the prevalence of diabetes mellitus in urban and rural dwellers in a low-income country from both younger and older population and to identify factors related. METHODS: This is a community based comparative cross-sectional study conducted in a low-income country, Ethiopia. The sample size was determined by EPI-Info for two populations; the WHO's STEP wise approach for non-communicable diseases surveillance in developing countries was employed for sampling, study variable selection and data collection procedures. Fasting blood glucose levels were measured by finger pricking after overnight fasting. Data entry was done by EPI-data computer program version 3.1 and then processed by SPSS version 20. Bivariate and multivariate logistic regression tests were used to assess the associations between diabetes status of individuals and its potential predictor variables. P-value < 0.05 was considered as statistically significant level. RESULT: The study was conducted on 1405 individuals with age range of 18-97 years old. The mean fasting blood glucose level for study participants was 91.16mg/dl; while it was 94.73mg/dl for urban and 87.71mg/dl for rural dwellers. The prevalence of diabetes mellitus was 3.3%; while it was 2.0% for rural and (4.6%) for urban dwellers. Both the mean blood glucose level and the prevalence of diabetes mellitus were significantly higher for urban residents than rural. More than three-fourths of diabetic cases were newly diagnosed by this study. Urban dwellers, centrally obese, overweight, and hypertensive individuals have higher odds of getting diabetes mellitus. CONCLUSIONS AND RECOMMENDATIONS: High prevalence of diabetes mellitus involving both old and young population was documented. Most diabetic cases were suddenly diagnosed during this survey. The problem is noticeably alarming, attention should be given to the control and prevention of diabetes mellitus and related complications. PMID- 29112963 TI - Effectiveness of a combination strategy for linkage and retention in adult HIV care in Swaziland: The Link4Health cluster randomized trial. AB - BACKGROUND: Gaps in the HIV care continuum contribute to poor health outcomes and increase HIV transmission. A combination of interventions targeting multiple steps in the continuum is needed to achieve the full beneficial impact of HIV treatment. METHODS AND FINDINGS: Link4Health, a cluster-randomized controlled trial, evaluated the effectiveness of a combination intervention strategy (CIS) versus the standard of care (SOC) on the primary outcome of linkage to care within 1 month plus retention in care at 12 months after HIV-positive testing. Ten clusters of HIV clinics in Swaziland were randomized 1:1 to CIS versus SOC. The CIS included point-of-care CD4+ testing at the time of an HIV-positive test, accelerated antiretroviral therapy (ART) initiation for treatment-eligible participants, mobile phone appointment reminders, health educational packages, and noncash financial incentives. Secondary outcomes included each component of the primary outcome, mean time to linkage, assessment for ART eligibility, ART initiation and time to ART initiation, viral suppression defined as HIV-1 RNA < 1,000 copies/mL at 12 months after HIV testing among patients on ART >=6 months, and loss to follow-up and death at 12 months after HIV testing. A total of 2,197 adults aged >=18 years, newly tested HIV positive, were enrolled from 19 August 2013 to 21 November 2014 (1,096 CIS arm; 1,101 SOC arm) and followed for 12 months. The median participant age was 31 years (IQR 26-39), and 59% were women. In an intention-to-treat analysis, 64% (705/1,096) of participants at the CIS sites achieved the primary outcome versus 43% (477/1,101) at the SOC sites (adjusted relative risk [RR] 1.52, 95% CI 1.19-1.96, p = 0.002). Participants in the CIS arm versus the SOC arm had the following secondary outcomes: linkage to care regardless of retention at 12 months (RR 1.08, 95% CI 0.97-1.21, p = 0.13), mean time to linkage (2.5 days versus 7.5 days, p = 0.189), retention in care at 12 months regardless of time to linkage (RR 1.48, 95% CI 1.18-1.86, p = 0.002), assessment for ART eligibility (RR 1.20, 95% CI 1.07-1.34, p = 0.004), ART initiation (RR 1.16, 95% CI 0.96-1.40, p = 0.12), mean time to ART initiation from time of HIV testing (7 days versus 14 days, p < 0.001), viral suppression among those on ART for >=6 months (RR 0.97, 95% CI 0.88-1.07, p = 0.55), loss to follow-up at 12 months after HIV testing (RR 0.56, 95% CI 0.40-0.79, p = 0.002), and death (N = 78) within 12 months of HIV testing (RR 0.80, 95% CI 0.46-1.35, p = 0.41). Limitations of this study include a small number of clusters and the inability to evaluate the incremental effectiveness of individual components of the combination strategy. CONCLUSIONS: A combination strategy inclusive of 5 evidence-based interventions aimed at multiple steps in the HIV care continuum was associated with significant increase in linkage to care plus 12-month retention. This strategy offers promise of enhanced outcomes for HIV-positive patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01904994. PMID- 29112964 TI - Environment-dependence of behavioural consistency in adult male European green lizards (Lacerta viridis). AB - Understanding the background mechanisms affecting the emergence and maintenance of consistent between-individual variation within population in single (animal personality) or across multiple (behavioural syndrome) behaviours has key importance. State-dependence theory suggests that behaviour is 'anchored' to individual state (e.g. body condition, gender, age) and behavioural consistency emerges through behavioural-state feedbacks. A number of relevant state variables are labile (e.g. body condition, physiological performance) and expected to be affected by short-term environmental change. Yet, whether short-term environmental shifts affect behavioural consistency during adulthood remains questionable. Here, by employing a full-factorial laboratory experiment, we explored if quantity of food (low vs. high) and time available for thermoregulation (3h vs. 10h per day) had an effect on activity and risk-taking of reproductive adult male European green lizards (Lacerta viridis). We focussed on different components of behavioural variation: (i) strength of behavioural consistency (repeatability for animal personality; between-individual correlation for behavioural syndrome), (ii) behavioural type (individual mean behaviour) and (iii) behavioural predictability (within-individual behavioural variation). Activity was repeatable in all treatments. Risk-taking was repeatable only in the low basking treatments. We found significant between-individual correlation only in the low food * long basking time group. The treatments did not affect behavioural type, but affected behavioural predictability. Activity predictability was higher in the short basking treatment, where it also decreased with size (~ age). Risk-taking predictability in the short basking treatment increased with size under food limitation, but decreased when food supply was high. We conclude that short-term environmental change can alter various components of behavioural consistency. The effect could be detected in the presence/absence patterns of animal personality and behavioural syndrome and the level of individual behavioural predictability, but not in behavioural type. PMID- 29112965 TI - Overlapping RdDM and non-RdDM mechanisms work together to maintain somatic repression of a paramutagenic epiallele of maize pericarp color1. AB - Allelic variation at the Zea mays (maize) pericarp color1 (p1) gene has been attributed to epigenetic gene regulation. A p1 distal enhancer, 5.2 kb upstream of the transcriptional start site, has demonstrated variation in DNA methylation in different p1 alleles/epialleles. In addition, DNA methylation of sequences within the 3' end of intron 2 also plays a role in tissue-specific expression of p1 alleles. We show here a direct evidence for small RNAs' involvement in regulating p1 that has not been demonstrated previously. The role of mediator of paramutation1 (mop1) was tested in the maintenance of somatic silencing at distinct p1 alleles: the non-paramutagenic P1-wr allele and paramutagenic P1-rr' epiallele. The mop1-1 mutation gradually relieves the silenced phenotype after multiple generations of exposure; P1-wr;mop1-1 plants display a loss of 24-nt small RNAs and DNA methylation in the 3' end of the intron 2, a region close to a Stowaway transposon. In addition, a MULE sequence within the proximal promoter of P1-wr shows depletion of 24nt siRNAs in mop1-1 plants. Release of silencing was not correlated with small RNAs at the distal enhancer region of the P1-wr allele. We found that the somatic silencing of the paramutagenic P1-rr' is correlated with significantly reduced H3K9me2 in the distal enhancer of P1-rr'; mop1-1 plants, while symmetric DNA methylation is not significantly different. This study highlights that the epigenetic regulation of p1 alleles is controlled both via RdDM as well as non-RdDM mechanisms. PMID- 29112966 TI - Lengthening of knee flexor muscles by percutaneous needle tenotomy: Description of the technique and preliminary results. AB - BACKGROUND: Knee flexion contractures occur frequently in non-ambulatory, aged persons and persons with central nervous system lesions, rendering positioning and nursing care difficult. There are often risks associated with surgical interventions. OBJECTIVE: To evaluate the effectiveness of percutaneous needle tenotomy to lengthen the knee flexor muscles and improve passive function. METHODS: This was a retrospective study of all patients who underwent percutaneous needle tenotomy between 2012 and 2014. Tenotomy was carried out in the semi-tendinosus, biceps femoris and gracillis muscles under local anesthesia. The procedure took no more than 40 minutes. Range of motion (ROM) was evaluated immediately post-operatively and 3 months later. RESULTS: Thirty-four needle tenotomies were carried out. Mean lack of knee extension was 94.2 degrees (range 35-120 degrees ) pre-op, (range 15-90 degrees ; p<0.05) immediately post-op and 50.1 degrees (range 10-90 degrees ; p<0.05) three months later, thus a mean increase of 44.1 degrees knee extension (range 0-90 degrees ). All care and positioning objectives were achieved. There were no complications and procedure related pain was rated as 3-4/ 10. CONCLUSIONS: Needle tenotomy was well tolerated and yielded a significant increase in ROM with no unwanted effects. All objectives were achieved. This technique could be used in an ambulatory care setting or within institutions for severely disabled individuals. PMID- 29112967 TI - Expression patterns of conjunctival mucin 5AC and aquaporin 5 in response to acute dry eye stress. AB - The relationship between aquaporin (AQP) 5 and mucin (MUC) 5AC in the conjunctiva was investigated in response to acute dry eye (DE) stress. A mixed-mechanism rabbit DE model, in which the main lacrimal gland, Harderian gland, and nictitating membrane were resected, was further explored in this study. Conjunctival impression cytology specimens were harvested before excision (BE) and up to 3 months after excision (AE) in 8 (16 eyes) male New Zealand White rabbits, and immunoblotting was employed to assess the expression of AQP5 and MUC5AC. It was observed that AQP5 and MUC5AC showed a positive, synchronous expression pattern with progressive upregulation at protein level up to 2 months AE. At 3 months, the expression of both proteins decreased, but was still higher than that of BE. Such a synchronous relationship was further observed in mouse conjunctiva epithelium primary cells under hyperosmotic condition. Moreover, the co-immunoprecipitation of AQP5 and MUC5AC suggested a possible physical interaction between the two molecules. Our data indicates that conjunctival AQP5 and MUC5AC act synchronously in response to acute DE stress. PMID- 29112968 TI - Fitness cost of reassortment in human influenza. AB - Reassortment, which is the exchange of genome sequence between viruses co infecting a host cell, plays an important role in the evolution of segmented viruses. In the human influenza virus, reassortment happens most frequently between co-existing variants within the same lineage. This process breaks genetic linkage and fitness correlations between viral genome segments, but the resulting net effect on viral fitness has remained unclear. In this paper, we determine rate and average selective effect of reassortment processes in the human influenza lineage A/H3N2. For the surface proteins hemagglutinin and neuraminidase, reassortant variants with a mean distance of at least 3 nucleotides to their parent strains get established at a rate of about 10-2 in units of the neutral point mutation rate. Our inference is based on a new method to map reassortment events from joint genealogies of multiple genome segments, which is tested by extensive simulations. We show that intra-lineage reassortment processes are, on average, under substantial negative selection that increases in strength with increasing sequence distance between the parent strains. The deleterious effects of reassortment manifest themselves in two ways: there are fewer reassortment events than expected from a null model of neutral reassortment, and reassortant strains have fewer descendants than their non reassortant counterparts. Our results suggest that influenza evolves under ubiquitous epistasis across proteins, which produces fitness barriers against reassortment even between co-circulating strains within one lineage. PMID- 29112969 TI - Monumental olive trees of Cyprus contributed to the establishment of the contemporary olive germplasm. AB - Even though Cyprus was an important crossing point for the westward spread of olive, and one of the primary regions of domestication, its genetic recourses remain uncharted at a great extent. Throughout the centuries, a number of ancient olive trees remain in the same orchards, contributing to Cypriot oleiculture and society. In an attempt to explore this monumental genetic pool, a survey was conducted to identify centennial olive trees in rural provinces of Cyprus. Microsatellites were employed in order to study their genetic composition (including rootstocks when feasible) and to establish possible associations among genotypes. High numbers of specific alleles, suggestive of the distinctiveness of this germplasm, were detected, and both grafting and rootstock propagation was verified. Moreover, it was determined by Bayesian structural and network reticulate analysis that centennial olives can be divided in two discrete genetic clusters having intermediate admixed accessions. Furthermore, it was determined that all contemporary Cypriot cultivars, that were included in the present study, were highly affiliated exclusively to one genetic group, a strong evidence of selection among elite clones. The information acquired from the current study reveals the genetic rareness of this material and its contribution to the current olive germplasm. PMID- 29112970 TI - Karyotype relationships among selected deer species and cattle revealed by bovine FISH probes. AB - The Cervidae family comprises more than fifty species divided into three subfamilies: Capreolinae, Cervinae and Hydropotinae. A characteristic attribute for the species included in this family is the great karyotype diversity, with the chromosomal numbers ranging from 2n = 6 observed in female Muntiacus muntjak vaginalis to 2n = 70 found in Mazama gouazoubira as a result of numerous Robertsonian and tandem fusions. This work reports chromosomal homologies between cattle (Bos taurus, 2n = 60) and nine cervid species using a combination of whole chromosome and region-specific paints and BAC clones derived from cattle. We show that despite the great diversity of karyotypes in the studied species, the number of conserved chromosomal segments detected by 29 cattle whole chromosome painting probes was 35 for all Cervidae samples. The detailed analysis of the X chromosomes revealed two different morphological types within Cervidae. The first one, present in the Capreolinae is a sub/metacentric X with the structure more similar to the bovine X. The second type found in Cervini and Muntiacini is an acrocentric X which shows rearrangements in the proximal part that have not yet been identified within Ruminantia. Moreover, we characterised four repetitive sequences organized in heterochromatic blocks on sex chromosomes of the reindeer (Rangifer tarandus). We show that these repeats gave no hybridization signals to the chromosomes of the closely related moose (Alces alces) and are therefore specific to the reindeer. PMID- 29112971 TI - Effects of positive end-expiratory pressure and recruitment maneuvers in a ventilator-induced injury mouse model. AB - BACKGROUND: Positive-pressure mechanical ventilation is an essential therapeutic intervention, yet it causes the clinical syndrome known as ventilator-induced lung injury. Various lung protective mechanical ventilation strategies have attempted to reduce or prevent ventilator-induced lung injury but few modalities have proven effective. A model that isolates the contribution of mechanical ventilation on the development of acute lung injury is needed to better understand biologic mechanisms that lead to ventilator-induced lung injury. OBJECTIVES: To evaluate the effects of positive end-expiratory pressure and recruitment maneuvers in reducing lung injury in a ventilator-induced lung injury murine model in short- and longer-term ventilation. METHODS: 5-12 week-old female BALB/c mice (n = 85) were anesthetized, placed on mechanical ventilation for either 2 hrs or 4 hrs with either low tidal volume (8 ml/kg) or high tidal volume (15 ml/kg) with or without positive end-expiratory pressure and recruitment maneuvers. RESULTS: Alteration of the alveolar-capillary barrier was noted at 2 hrs of high tidal volume ventilation. Standardized histology scores, influx of bronchoalveolar lavage albumin, proinflammatory cytokines, and absolute neutrophils were significantly higher in the high-tidal volume ventilation group at 4 hours of ventilation. Application of positive end-expiratory pressure resulted in significantly decreased standardized histology scores and bronchoalveolar absolute neutrophil counts at low- and high-tidal volume ventilation, respectively. Recruitment maneuvers were essential to maintain pulmonary compliance at both 2 and 4 hrs of ventilation. CONCLUSIONS: Signs of ventilator-induced lung injury are evident soon after high tidal volume ventilation (as early as 2 hours) and lung injury worsens with longer-term ventilation (4 hrs). Application of positive end-expiratory pressure and recruitment maneuvers are protective against worsening VILI across all time points. Dynamic compliance can be used guide the frequency of recruitment maneuvers to help ameloriate ventilator-induced lung injury. PMID- 29112972 TI - How accurately can other people infer your thoughts-And does culture matter? AB - This research investigated how accurately people infer what others are thinking after observing a brief sample of their behaviour and whether culture/similarity is a relevant factor. Target participants (14 British and 14 Mediterraneans) were cued to think about either positive or negative events they had experienced. Subsequently, perceiver participants (16 British and 16 Mediterraneans) watched videos of the targets thinking about these things. Perceivers (both groups) were significantly accurate in judging when targets had been cued to think of something positive versus something negative, indicating notable inferential ability. Additionally, Mediterranean perceivers were better than British perceivers in making such inferences, irrespective of nationality of the targets, something that was statistically accounted for by corresponding group differences in levels of independently measured collectivism. The results point to the need for further research to investigate the possibility that being reared in a collectivist culture fosters ability in interpreting others' behaviour. PMID- 29112973 TI - Reading wild minds: A computational assay of Theory of Mind sophistication across seven primate species. AB - Theory of Mind (ToM), i.e. the ability to understand others' mental states, endows humans with highly adaptive social skills such as teaching or deceiving. Candidate evolutionary explanations have been proposed for the unique sophistication of human ToM among primates. For example, the Machiavellian intelligence hypothesis states that the increasing complexity of social networks may have induced a demand for sophisticated ToM. This type of scenario ignores neurocognitive constraints that may eventually be crucial limiting factors for ToM evolution. In contradistinction, the cognitive scaffolding hypothesis asserts that a species' opportunity to develop sophisticated ToM is mostly determined by its general cognitive capacity (on which ToM is scaffolded). However, the actual relationships between ToM sophistication and either brain volume (a proxy for general cognitive capacity) or social group size (a proxy for social network complexity) are unclear. Here, we let 39 individuals sampled from seven non-human primate species (lemurs, macaques, mangabeys, orangutans, gorillas and chimpanzees) engage in simple dyadic games against artificial ToM players (via a familiar human caregiver). Using computational analyses of primates' choice sequences, we found that the probability of exhibiting a ToM-compatible learning style is mainly driven by species' brain volume (rather than by social group size). Moreover, primates' social cognitive sophistication culminates in a precursor form of ToM, which still falls short of human fully-developed ToM abilities. PMID- 29112974 TI - Impact of extensive antibiotic treatment on faecal carriage of antibiotic resistant enterobacteria in children in a low resistance prevalence setting. AB - We prospectively studied the consequences of extensive antibiotic treatment on faecal carriage of antibiotic-resistant enterobacteria in a cohort of children with cystic fibrosis (CF) and a cohort of children with cancer compared to healthy children with no or low antibiotic exposure. The study was conducted in Norway in a low resistance prevalence setting. Sixty longitudinally collected faecal samples from children with CF (n = 32), 88 samples from children with cancer (n = 45) and 127 samples from healthy children (n = 70) were examined. A direct MIC-gradient strip method was used to detect resistant Enterobacteriaceae by applying Etest strips directly onto agar-plates swabbed with faecal samples. Whole genome sequencing (WGS) data were analysed to identify resistance mechanisms in 28 multidrug-resistant Escherichia coli isolates. The prevalence of resistance to third-generation cephalosporins, gentamicin and ciprofloxacin was low in all the study groups. At inclusion the prevalence of ampicillin-resistant E. coli and trimethoprim-sulfamethoxazole-resistant E. coli in the CF group compared to healthy controls was 58.6% vs. 28.4% (p = 0.005) and 48.3% vs. 14.9% (p = 0.001), respectively, with a similar prevalence at the end of the study. The prevalence of resistant enterobacteria was not significantly different in the children with cancer compared to the healthy children, not even at the end of the study when the children with cancer had been treated with repeated courses of broad-spectrum antibiotics. Children with cancer were mainly treated with intravenous antibiotics, while the CF group mainly received peroral treatment. Our observations indicate that the mode of administration of antibiotics and the general level of antimicrobial resistance in the community may have an impact on emergence of resistance in intestinal enterobacteria during antibiotic treatment. The WGS analyses detected acquired resistance genes and/or chromosomal mutations that explained the observed phenotypic resistance in all 28 multidrug-resistant E. coli isolates examined. PMID- 29112975 TI - Referral determinants in Swiss primary care with a special focus on managed care. AB - Studies have shown large variation of referral probabilities in different countries, and many influencing factors have been described. This variation is most likely explained by different healthcare systems, particularly to which extent primary care physicians (PCPs) act as gatekeepers. In Switzerland no mandatory gatekeeping system exists, however insurance companies offer voluntary managed care plans with reduced insurance premiums. We aimed at investigating the role of managed care plans as a potential referral determinant in a non gatekeeping healthcare system. We conducted a cross-sectional study with 90 PCPs collecting data on consultations and referrals in 2012/2013. During each consultation up to six reasons for encounters (RFE) were documented. For each RFE PCPs indicated whether a referral was initiated. Determinants for referrals were analyzed by hierarchical logistic regression, taking the potential cluster effect of the PCP into account. To further investigate the independent association of the managed care plan with the referral probability, a hierarchical multivariate logistic regression model was applied, taking into account all available data potentially affecting the referring decision. PCPs collected data on 24'774 patients with 42'890 RFE, of which 2427 led to a referral. 37.5% of patients were insured in managed health care plans. Univariate analysis showed significant higher referral rates of patients with managed care plans (10.7% vs. 8.5%). The difference in referral probability remained significant after controlling for other confounders in the hierarchical multivariate regression model (OR 1.355). Patients in managed care plans were more likely to be referred than patients without such a model. These data contradict the argument that patients in managed care plans have limited healthcare access, but underline the central role of PCPs as coordinator of care. PMID- 29112976 TI - Calcein+/PI- as an early apoptotic feature in Leishmania. AB - Although leishmaniases are responsible for high morbidity and mortality all over the world, no really satisfying treatment exists. Furthermore, the corresponding parasite Leishmania undergoes a very characteristic form of programmed cell death. Indeed, different stimuli can induce morphological and biochemical apoptotic-like features. However, the key proteins involved in mammal apoptosis, such as caspases and death receptors, are not encoded in the genome of this parasite. Currently, little is known about Leishmania apoptosis, notably owing to the lack of specific tools for programmed cell death analysis in these parasites. Furthermore, there is a need for a better understanding of Leishmania programmed cell death in order (i) to better understand the role of apoptosis in unicellular organisms, (ii) to better understand apoptosis in general through the study of an ancestral eukaryote, and (iii) to identify new therapeutic targets against leishmaniases. To advance understanding of apoptosis in Leishmania, in this study we developed a new tool based on the quantification of calcein and propidium iodide by flow cytometry. This double labeling can be employed to distinguish early apoptosis, late apoptosis and necrosis in Leishmania live cells with a very simple and rapid assay. This paper should, therefore, be of interest for people working on Leishmania and related parasites. PMID- 29112977 TI - Initial clinical experience with dual-layer detector spectral CT in patients with acute intracerebral haemorrhage: A single-centre pilot study. AB - PURPOSE: The purpose of this study was to investigate the clinical feasibility of spectral analyses using dual-layer detector spectral computed tomography (CT) in acute intracerebral haemorrhage (ICH). MATERIAL AND METHODS: We retrospectively reviewed patients with acute ICH who underwent CT angiography on a dual-layer detector spectral CT scanner. A spectral data analysis was performed to detect contrast enhancement in or adjacent to acute ICH by using spectral image reconstructions including monoenergetic (MonoE), virtual noncontrast (VNC), and iodine overlay fusion images. We also acquired a spectral plot to assess material differentiation within lesions. RESULTS: Among the 30 patients, the most common cause of acute ICH was chronic hypertension (18/30, 60%) followed by trauma (5/30, 16.7%), brain tumour (3/30, 10%), Moyamoya disease (2/30, 6.7%), and haemorrhagic diathesis from anticoagulation therapy (2/30, 6.7%). Of 30 patients, 13 showed suboptimal iodine suppression in the subcalvarial spaces on VNC images compared with true noncontrast images. The CT angiographic spot sign within the acute ICH was detected in four patients (4/30, 13.3%). All three tumours were metastatic and included lung cancer (n = 2) and hepatocellular carcinoma (n = 1) which showed conspicuous delineation of an enhancing tumour portion in the spectral analysis. Spectral analyses allowed the discrimination of acute haemorrhage and iodine with enhanced lesion visualization on the MonoE images obtained at lower keVs (less than 70 keV) and spectral plot. CONCLUSIONS: Even though the image quality of VNC is perceived to be inferior, it is feasible to evaluate acute ICH in clinical settings using dual-layer detector spectral CT. The MonoE images taken at lower keVs were useful for depicting contrast enhancing lesion, and spectral plot might be helpful for material differentiation in patients with acute ICH. PMID- 29112978 TI - Personalized blood glucose prediction: A hybrid approach using grammatical evolution and physiological models. AB - The large patient variability in human physiology and the effects of variables such as exercise or meals challenge current prediction modeling techniques. Physiological models are very precise but they are typically complex and specific physiological knowledge is required. In contrast, data-based models allow the incorporation of additional inputs and accurately capture the relationship between these inputs and the outcome, but at the cost of losing the physiological meaning of the model. In this work, we designed a hybrid approach comprising physiological models for insulin and grammatical evolution, taking into account the clinical harm caused by deviations from the target blood glucose by using a penalizing fitness function based on the Clarke error grid. The prediction models were built using data obtained over 14 days for 100 virtual patients generated by the UVA/Padova T1D simulator. Midterm blood glucose was predicted for the 100 virtual patients using personalized models and different scenarios. The results obtained were promising; an average of 98.31% of the predictions fell in zones A and B of the Clarke error grid. Midterm predictions using personalized models are feasible when the configuration of grammatical evolution explored in this study is used. The study of new alternative models is important to move forward in the development of alarm-and-control applications for the management of type 1 diabetes and the customization of the patient's treatments. The hybrid approach can be adapted to predict short-term blood glucose values to detect continuous glucose-monitoring sensor errors and to estimate blood glucose values when the continuous glucose-monitoring system fails to provide them. PMID- 29112979 TI - Examining the accuracy of students' self-reported academic grades from a correlational and a discrepancy perspective: Evidence from a longitudinal study. AB - The present longitudinal study examined the reliability of self-reported academic grades across three phases in four subject domains for a sample of 916 high school students. Self-reported grades were found to be highly positively correlated with actual grades in all academic subjects and across grades 9 to 11 underscoring the reliability of self-reported grades as an achievement indicator. Reliability of self-reported grades was found to differ across subject areas (e.g., mathematics self-reports more reliable than language studies), with a slight yet consistent tendency to over-report achievement levels also observed across grade levels and academic subjects. Overall, the absolute value of over- and underreporting was low and these patterns were not found to differ between mathematics and verbal subjects. In sum, study findings demonstrate the consistent predictive utility of students' self-reported achievement across grade levels and subject areas with the observed tendency to over-report academic grades and slight differences between domains nonetheless warranting consideration in future education research. PMID- 29112980 TI - Recurrence quantification analysis to characterize cyclical components of environmental elemental exposures during fetal and postnatal development. AB - Environmental exposures to essential and toxic elements may alter health trajectories, depending on the timing, intensity, and mixture of exposures. In epidemiologic studies, these factors are typically analyzed as a function of elemental concentrations in biological matrices measured at one or more points in time. Such an approach, however, fails to account for the temporal cyclicity in the metabolism of environmental chemicals, which if perturbed may lead to adverse health outcomes. Here, we conceptualize and apply a non-linear method-recurrence quantification analysis (RQA)-to quantify cyclical components of prenatal and early postnatal exposure profiles for elements essential to normal development, including Zn, Mn, Mg, and Ca, and elements associated with deleterious health effects or narrow tolerance ranges, including Pb, As, and Cr. We found robust evidence of cyclical patterns in the metabolic profiles of nutrient elements, which we validated against randomized twin-surrogate time-series, and further found that nutrient dynamical properties differ from those of Cr, As, and Pb. Furthermore, we extended this approach to provide a novel method of quantifying dynamic interactions between two environmental exposures. To achieve this, we used cross-recurrence quantification analysis (CRQA), and found that elemental nutrient-nutrient interactions differed from those involving toxicants. These rhythmic regulatory interactions, which we characterize in two geographically distinct cohorts, have not previously been uncovered using traditional regression based approaches, and may provide a critical unit of analysis for environmental and dietary exposures in epidemiological studies. PMID- 29112981 TI - Adjustment of the dynamic weight distribution as a sensitive parameter for diagnosis of postural alteration in a rodent model of vestibular deficit. AB - Vestibular disorders, by inducing significant posturo-locomotor and cognitive disorders, can significantly impair the most basic tasks of everyday life. Their precise diagnosis is essential to implement appropriate therapeutic countermeasures. Monitoring their evolution is also very important to validate or, on the contrary, to adapt the undertaken therapeutic actions. To date, the diagnosis methods of posturo-locomotor impairments are restricted to examinations that most often lack sensitivity and precision. In the present work we studied the alterations of the dynamic weight distribution in a rodent model of sudden and complete unilateral vestibular loss. We used a system of force sensors connected to a data analysis system to quantify in real time and in an automated way the weight bearing of the animal on the ground. We show here that sudden, unilateral, complete and permanent loss of the vestibular inputs causes a severe alteration of the dynamic ground weight distribution of vestibulo lesioned rodents. Characteristics of alterations in the dynamic weight distribution vary over time and follow the sequence of appearance and disappearance of the various symptoms that compose the vestibular syndrome. This study reveals for the first time that dynamic weight bearing is a very sensitive parameter for evaluating posturo-locomotor function impairment. Associated with more classical vestibular examinations, this paradigm can considerably enrich the methods for assessing and monitoring vestibular disorders. Systematic application of this type of evaluation to the dizzy or unstable patient could improve the detection of vestibular deficits and allow predicting better their impact on posture and walk. Thus it could also allow a better follow-up of the therapeutic approaches for rehabilitating gait and balance. PMID- 29112982 TI - Empirical and model-based estimates of spatial and temporal variations in net primary productivity in semi-arid grasslands of Northern China. AB - Spatiotemporal variations in net primary productivity (NPP) reflect the dynamics of water and carbon in the biosphere, and are often closely related to temperature and precipitation. We used the ecosystem model known as the Carnegie Ames-Stanford Approach (CASA) to estimate NPP of semiarid grassland in northern China counties between 2001 and 2013. Model estimates were strongly linearly correlated with observed values from different counties (slope = 0.76 (p < 0.001), intercept = 34.7 (p < 0.01), R2 = 0.67, RMSE = 35 g C.m-2.year-1, bias = 0.11 g C.m-2.year-1). We also quantified inter-annual changes in NPP over the 13 year study period. NPP varied between 141 and 313 g C.m-2.year-1, with a mean of 240 g C.m-2.year-1. NPP increased from west to east each year, and mean precipitation in each county was significantly positively correlated with NPP annually, and in summer and autumn. Mean precipitation was positively related to NPP in spring, but not significantly so. Annual and summer temperatures were mostly negatively correlated with NPP, but temperature was positively correlated with spring and autumn NPP. Spatial correlation and partial correlation analyses at the pixel scale confirmed precipitation is a major driver of NPP. Temperature was negatively correlated with NPP in 99% of the regions at the annual scale, but after removing the effect of precipitation, temperature was positively correlated with the NPP in 77% of the regions. Our data show that temperature effects on production depend heavily on recent precipitation. Results reported here have significant and far-reaching implications for natural resource management, given the enormous size of these grasslands and the numbers of people dependent on them. PMID- 29112983 TI - Identification of Viscum album L. miRNAs and prediction of their medicinal values. AB - MicroRNAs (miRNAs) are a class of approximately 22 nucleotides single-stranded non-coding RNA molecules that play crucial roles in gene expression. It has been reported that the plant miRNAs might enter mammalian bloodstream and have a functional role in human metabolism, indicating that miRNAs might be one of the hidden bioactive ingredients in medicinal plants. Viscum album L. (Loranthaceae, European mistletoe) has been widely used for the treatment of cancer and cardiovascular diseases, but its functional compounds have not been well characterized. We considered that miRNAs might be involved in the pharmacological activities of V. album. High-throughput Illumina sequencing was performed to identify the novel and conserved miRNAs of V. album. The putative human targets were predicted. In total, 699 conserved miRNAs and 1373 novel miRNAs have been identified from V. album. Based on the combined use of TargetScan, miRanda, PITA, and RNAhybrid methods, the intersection of 30697 potential human genes have been predicted as putative targets of 29 novel miRNAs, while 14559 putative targets were highly enriched in 33 KEGG pathways. Interestingly, these highly enriched KEGG pathways were associated with some human diseases, especially cancer, cardiovascular diseases and neurological disorders, which might explain the clinical use as well as folk medicine use of mistletoe. However, further experimental validation is necessary to confirm these human targets of mistletoe miRNAs. Additionally, target genes involved in bioactive components synthesis in V. album were predicted as well. A total of 68 miRNAs were predicted to be involved in terpenoid biosynthesis, while two miRNAs including val-miR152 and miR9738 were predicted to target viscotoxins and lectins, respectively, which increased the knowledge regarding miRNA-based regulation of terpenoid biosynthesis, lectin and viscotoxin expressions in V. album. PMID- 29112984 TI - Olfactory signaling of aggressive intent in male-male contests of cave crickets (Troglophilus neglectus; Orthoptera: Rhaphidophoridae). AB - In animal contests, communicating aggressive motivation is most often mediated by visual or acoustic signals, while chemical signals are not expected to serve such a function since they are less able to be modulated by the sender during the changing behavioral context. We describe a rare example of ephemeral olfactory signals in terrestrial animals, signals that are emitted via protrusive scent glands in male cave crickets Troglophilus neglectus (Orthoptera, Rhaphidophoridae) to reflect the state of the signaler's aggression. We correlate the intensity of behaviorally expressed aggression of the individuals in dyadic contests with the frequency and extent of their gland tissue protrusion, the latter serving as an indication of the amount of released odor. We detected large amounts of odor release during brief gland protrusions, and the absence of its release during gland retraction. Males protruded the glands during and after encountering a rival, with the degree of protrusion increasing with the intensity of the signalers' aggression. During the encounters, the degree of gland protrusion increased most strongly with the occurrence of the elevated body posture, directly preceding the attack. This degree was significantly higher in encounter winners than in losers displaying such posture, suggesting the highly important role of the released odor for contest resolution. After the encounters, glands were protruded almost exclusively by winners, apparently announcing victory. We tested for the function of the olfactory signals also directly, by preventing gland tissue protrusion in symmetric and asymmetric treatments of the contestants. Treating only the dominant individuals decreased the percentage of encounters they won by over 60%, while treating both contestants elicited a significant increase in the frequency and duration of fights. During contests, the olfactory signals of T. neglectus apparently function as a highly effective threat, which prevents maximal contest escalation and decreases the conflict related costs. PMID- 29112987 TI - Democratizing science with the aid of parametric design and additive manufacturing: Design and fabrication of a versatile and low-cost optical instrument for scattering measurement. AB - This paper focuses on the application of rapid prototyping techniques using additive manufacturing in combination with parametric design to create low-cost, yet accurate and reliable instruments. The methodology followed makes it possible to make instruments with a degree of customization until now available only to a narrow audience, helping democratize science. The proposal discusses a holistic design-for-manufacturing approach that comprises advanced modeling techniques, open-source design strategies, and an optimization algorithm using free parametric software for both professional and educational purposes. The design and fabrication of an instrument for scattering measurement is used as a case of study to present the previous concepts. PMID- 29112986 TI - Simultaneous genome-wide gene expression and transcript isoform profiling in the human malaria parasite. AB - Gene expression DNA microarrays have been vital for characterizing whole-genome transcriptional profiles. Nevertheless, their effectiveness relies heavily on the accuracy of genome sequences, the annotation of gene structures, and the sequence dependent performance of individual probes. Currently available gene expression arrays for the malaria parasite Plasmodium falciparum rely on an average of 2 probes per gene, usually positioned near the 3' end of genes; consequently, existing designs are prone to measurement bias and cannot capture complexities such as the occurrence of transcript isoforms arising from alternative splicing or alternative start/ stop sites. Here, we describe two novel gene expression arrays with exon-focused probes designed with an average of 12 and 20 probes spanning each gene. This high probe density minimizes signal noise inherent in probe-to-probe sequence-dependent hybridization intensity. We demonstrate that these exon arrays accurately profile genome-wide expression, comparing favorably to currently available arrays and RNA-seq profiling, and can detect alternatively spliced transcript isoforms as well as non-coding RNAs (ncRNAs). Of the 964 candidate alternate splicing events from published RNA-seq studies, 162 are confirmed using the exon array. Furthermore, the exon array predicted 330 previously unidentified alternate splicing events. Gene expression microarrays continue to offer a cost-effective alternative to RNA-seq for the simultaneous monitoring of gene expression and alternative splicing events. Microarrays may even be preferred in some cases due to their affordability and the rapid turn around of results when hundreds of samples are required for fine-scale systems biology investigations, including the monitoring of the networks of gene co expression in the emergence of drug resistance. PMID- 29112985 TI - The relation between, metabolic syndrome and quality of life in patients with Systemic Lupus Erythematosus. AB - INTRODUCTION: Systemic Lupus Erythematosus (SLE) is associated to an increased prevalence of Metabolic Syndrome (MeS) and to a reduction of Quality of Life (QoL). The aim of this study is to evaluate the association between MeS and QoL in SLE. METHODS: SLE patients were consecutively enrolled in a cross sectional study. MeS was defined according to IFD definition. Therapy with glucocorticoids (GC) and antimalarial was analyzed as cumulative years of exposure. We used a cut off of 7.5 mg of prednisone to define high daily dose of GC. QoL was quantified using SF-36. We used BDI and HAM-H to assess symptoms of mood disorders. Fatigue was evaluated using Facit-Fatigue, physical activity using IPAQ, sleep quality using PSQI and alexithymia using TAS-20. RESULTS: We enrolled 100 SLE patients. MeS prevalence was 34%. Patients with MeS presented reduced scores in SF-36 MCS and PCS compared to patients without MeS (p 0.03 and p 0.004). BDI and HAM-H score were significantly higher in patients meeting MeS criteria compared to subjects without MeS (p 0.004, p 0.02). These results were confirmed after adjustment for confounders. Compared to patients without MeS, those with MeS presented higher age, lower education level, higher recent SELENA-SLEDAI, higher number of flares, increased SDI, longer cumulative exposure to high dose GC and shorter duration of antimalarial therapy. In the multiple logistic regression model, the variable associated to the Odds Ratio of having MeS were: the average of recent SELENA-SLEDAI (OR 1.15 p 0.04), the years of exposure to high dose of GC (OR 1.18 p 0.004), the years of exposure to antimalarials (OR 0.82 p 0.03) and the BDI score (OR 1.1 p 0.005). CONCLUSION: A modern management of SLE should not miss to take all the possible measures to ensure an adequate QoL to SLE patients, with particular attention to those affected by MeS. PMID- 29112988 TI - Relationship between spending on electronic cigarettes, 30-day use, and disease symptoms among current adult cigarette smokers in the U.S. AB - OBJECTIVE: To examine the relationship between spending on electronic cigarettes (e-cigarettes) and disease symptoms compared with the relationship between 30-day e-cigarette use and disease symptoms among adult cigarette smokers in the U.S. METHODS: We analyzed data from the Tobacco and Attitudes Beliefs Survey which included 533 respondents aged 24+ who were current cigarette smokers and e cigarette ever users. Fifteen self-reported disease symptoms were included as outcome variables. Separate multivariable logistic regression models were estimated for each disease symptom with total spending on e-cigarettes in the past 30 days and with reported 30-day e-cigarette use. All models controlled for cigarettes smoked per day (CPD) and sociodemographic characteristics. RESULTS: We found that those who spent more on e-cigarettes were more likely to report chest pain (AOR = 1.25, 95% CI 1.02-1.52), to notice blood when brushing their teeth (AOR = 1.23, 95% CI 1.02-1.49), to have sores or ulcers in their mouth (AOR = 1.36, 95% CI 1.08-1.72), and to have more than one cold (AOR = 1.36, 95% CI 1.05 1.78) than those with no spending on e-cigarettes in the past 30 days in an adjusted analysis. After controlling for CPD and other covariates, there were no significant relationships between 30-day e-cigarette use and symptoms. Even after controlling for CPD, e-cigarette expenditures or use was associated with greater odds of wheezing and shortness of breath. CONCLUSIONS: E-cigarette expenditures might be a more useful measure of intensity of e-cigarette use. The additional health effect of e-cigarette use or expenditures among smokers independent of the effect of CPD suggests that e-cigarette use adds adverse health effects even among cigarette smokers. PMID- 29112989 TI - Distribution, maturity and population structure of Meganyctiphanes norvegica and Thysanoessa inermis around Iceland in spring. AB - This study aims to explain the distribution, maturity and population structure of Meganyctiphanes norvegica and Thysanoessa inermis in springtime in relation to main hydrographic regions around Iceland: Atlantic in the southwest, Atlantic Arctic mixture in the north and Arctic in the east. Krill were collected 14-29 May 2013 using a macrozooplankton trawl. Biomass of both species combined was significantly higher in the southwest than in north and east. M. norvegica clearly dominated in Atlantic waters, whereas T. inermis was more evenly distributed around the island, while the highest values were also observed in the southwest for this species. Simple linear regressions showed that the abundance of M. norvegica was positively related to temperature, salinity and phytoplankton concentration, while the abundance of T. inermis was negatively related to bathymetry. Multiple linear regression analyses did not add to this information of a positive relationship between abundance and temperature for M. norvegica, while T. inermis was shown to be negatively related to both temperature and bathymetry. During the latter half of May, the main spawning of both species was confined to the regions off the southwest coast. Sex ratio (males/females) of M. norvegica was higher in the southwest than in the north and east, whereas T. inermis showed a similar sex ratio all around the island. In all regions, M. norvegica appears to have a lifespan of 2 years while T. inermis of 1 year in the southwest and possibly 2 years in north and east. PMID- 29112990 TI - Correction: Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006551.]. PMID- 29112992 TI - Risk Factors for Dystonia after Selective Dorsal Rhizotomy in Nonwalking Children and Adolescents with Bilateral Spasticity. AB - We recently showed a beneficial effect of selective dorsal rhizotomy (SDR) on daily care and comfort in nonwalking children with severe bilateral spasticity. However, despite careful selection, some patients showed dystonia after the intervention, in which cases caregivers tended to be less satisfied with the result.The aim of this study is to identify risk factors for dystonia after SDR in children and adolescents with severe bilateral spasticity (GMFCS levels IV/V).Clinical and MRI risk factors for dystonia after SDR were studied in our cohort of 24 patients. Patients with clinical evidence of dystonia and brain MRI showing basal ganglia abnormalities were excluded for SDR.Nine of 24 patients (38%) showed some degree of dystonia after SDR. There was a significant association between the cause of spasticity and dystonia after SDR; in six (67%) patients with a congenital disorder, dystonia was present versus three (20%) with an acquired disorder (Chi-squared test: C(1) = 5.23, p = 0.02).This study allows more optimal selection of patients that may benefit from SDR. Patients with an acquired cause of spasticity, when selected carefully on clinical examination and MRI, rarely show dystonia after SDR. However, patients with an underlying congenital disorder have a considerable risk of dystonia after SDR. PMID- 29112991 TI - Immuno-virological response and associated factors amongst HIV-1 vertically infected adolescents in Yaounde-Cameroon. AB - INTRODUCTION: Limited studies have reported the outcomes of lifelong antiretroviral therapy (ART) amongst adolescents living with HIV (ALWHIV) in resource-limited settings (RLS), thus classifying this population as underserved. We therefore aimed to ascertain the immunological and virological responses, and associated factors amongst Cameroonian ALWHIV. METHOD: A cross-sectional and observational study was conducted from January through May 2016 at the National Social Insurance Fund Health Centre in Yaounde-Cameroon. Immunological and virological responses were evaluated using CD4 cell count and viral load respectively, with viral suppression (VS) defined as <50 copies/ml. Adherence was evaluated using self-reported missing doses during the past 14 days. Data were analyzed using R v.3.3.0, with p<0.05 considered statistically significant. RESULTS: Of the 145 ALWHIV on ART enrolled in the study, 52% were female, median age [interquartile (IQR)] was 13 [11-16] years, median [IQR] time-on-ART was 7 [5 10] years, 48% were orphans, 92% were on first-line ART and 36% were adherent to ART. Following ART response, 79% (114/145) had CD4 >=500/mm3, 71.0% (103/145) were on VS of whom 52.4% (76/145) had a sustained VS. Duration of ART was associated with immune restoration (Odd Ratio 3.73 [1.26-12.21]) but not with virological response. Risks of poor adherence were greater in orphans of both parents (p = 0.078). CONCLUSION: In this urban setting of Cameroon, ALWHIV receiving ART show favorable immunological and virological response in a medium run. For long-term ART success, implementing a close monitoring of adherence and risks of viral rebound would be highly relevant, especially for orphans of both parents. PMID- 29112993 TI - Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know. AB - Autophagy is a fundamental and conserved intracellular pathway that mediates the degradation of macromolecules and organelles in lysosomes. Proper autophagy function is important for central nervous system development and neuronal function. Over the last 5 years, several single gene disorders of the autophagy pathway have emerged: EPG5-associated Vici syndrome, WDR45-associated beta propeller protein-associated neurodegeneration, SNX14-associated autosomal recessive spinocerebellar ataxia 20, ATG5-associated autosomal-recessive ataxia syndrome, SQSTM1/p62-associated childhood-onset neurodegeneration, and several forms of the hereditary spastic paraplegias. This novel and evolving group of disorders is characterized by prominent central nervous system involvement leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration. Predominant involvement of the long white matter tracts and the cerebellum are anatomic and imaging hallmarks, with common findings that include a thinning of the corpus callosum and cerebellar hypoplasia or atrophy. A storage disease phenotype by clinical or imaging criteria is present in some diseases. Most congenital disorders of autophagy are progressive and over time involve pathology in multiple brain regions. This review provides a detailed clinical, imaging and genetic characterization of congenital disorders of autophagy and highlights the importance of this pathway for childhood-onset neurological diseases. PMID- 29112994 TI - Risk of recurrence after endoscopic resection of early colorectal cancer with positive margins. AB - BACKGROUND AND STUDY AIM: Additional surgery is recommended if an endoscopically resected T1 colorectal cancer (CRC) specimen shows a positive resection margin. We aimed to investigate the significance of a positive resection margin in endoscopically resected T1 CRC. PATIENTS AND METHODS: We enrolled 265 patients with T1 CRC who underwent endoscopic resection between January 2001 and December 2016. The inclusion criteria were: 1) complete resection by endoscopy, and 2) pathology of a positive margin. Among the 265 patients, 213 underwent additional surgery and 52 did not. In the additional surgery group, various clinicopathological factors were evaluated with respect to the presence or absence of residual tumor. The follow-up results were assessed in the group that did not undergo additional surgery. RESULTS: In the 213 patients who underwent additional surgery, residual tumor was detected in 13 patients (6.1 %), and none of the clinicopathological factors was significantly associated with the presence of residual tumor. Among the 52 patients who did not undergo additional surgery, recurrence was detected in 4 (7.7 %), and all 4 underwent salvage surgery. Among these four patients, three had no risk factors for lymph node metastasis and recurrence was at the previous resection site; pathology was high grade dysplasia, rpT3N0M0, and rpT1N0M0, respectively. CONCLUSIONS: A positive resection margin in endoscopically resected T1 CRC is related to a relatively low incidence of residual tumor (6.1 %). Although current guidelines recommend additional surgery for such cases, surveillance and timely salvage surgery could be another option in selected cases. PMID- 29112995 TI - Prenatal and Postnatal Follow-up in Trisomies 13 and 18: A 20-Year Experience in a Tertiary Center. AB - OBJECTIVE: Trisomies 13 and 18 are among the most common autosomal aneuploidies associated with high mortality rates. Conventional management strategies offer to limit interventional support; however, some of the recent studies suggest that intervention does make a difference in terms of survival. STUDY DESIGN: A retrospective cohort study was performed between January 1996 and January 2016, covering all cases with such trisomies. A total of 69 cases were reviewed for clinical aspects, outcome, and management strategies. RESULTS: In almost all pregnancies with follow-up, at least one indication present for invasive testing (54/55). Invasive testing was not performed in 18.5% of such cases. All parents opted for termination in cases with prenatal diagnosis. None of the liveborns had prenatal diagnoses, thus, neonatal resuscitation and intensive care unit admission were not withheld in such infants. Major intervention was done in only one patient with full trisomy 13. Median survival for infants with full trisomies 13 and 18 was 36 and 60 days, respectively. Almost half the patients died within 1 month. CONCLUSION: To which extent the major interventions should be withheld is an issue of debate in managing such infants; however, current approaches are subject to change, given the technological advances. PMID- 29112996 TI - Angle of Progression on Ultrasound in the Second Stage of Labor and Spontaneous Vaginal Delivery. AB - OBJECTIVE: The objective of this study was to assess the association between the angle of progression (AoP) measured by transperineal ultrasound and mode of delivery and duration of the second stage. STUDY DESIGN: This is a prospective observational study of nulliparous women with a singleton gestation at term in which serial transperineal ultrasound examinations were obtained during the second stage of labor. Multivariable logistic regression and adjusted survival models were used for the analysis. RESULTS: A total of 137 patients were included in the analysis and median AoP for the study group was 153 degrees. The adjusted odds ratio (aOR) of requiring an operative delivery was 2.6 times higher for those patients who had an AoP < 153 degrees and the aOR of requiring a cesarean delivery was almost six times higher when compared with those patients who had an AoP >= 153 degrees (95% confidence interval [CI]: 1.0, 6.2; p = 0.04; aOR: 5.8, 95% CI: 1.2-28.3; p = 0.03, respectively). Those patients with an AoP < 153 degrees were at a higher hazard of staying pregnant longer (adjusted hazard ratio: 1.8, 95% CI: 1.2-2.8, p = 0.005). CONCLUSION: The AoP has the potential to predict spontaneous vaginal delivery and the duration of the second stage of labor which may be useful in counseling patients and managing their labor. PMID- 29112997 TI - Comparison of Neonatal Abstinence Syndrome Treatment with Sublingual Buprenorphine versus Conventional Opioids. AB - OBJECTIVE: The objective of this study was to compare duration of opioid treatment and length of stay outcomes for neonatal abstinence syndrome (NAS) using sublingual buprenorphine versus traditional weaning with methadone or morphine. STUDY DESIGN: This retrospective cohort analysis evaluated infants treated for NAS at a single community hospital from July 2013 through June 2017. A standardized weaning protocol was introduced in June 2015, allowing for treatment with sublingual buprenorphine regardless of type of intrauterine opioid exposure. General linear models were used to calculate adjusted mean duration of opioid treatment and length of hospitalization with 95% confidence intervals for infants treated with buprenorphine compared with traditional weaning with either methadone or morphine. RESULTS: A total of 360 infants were treated with either buprenorphine (n = 174) or a traditional opioid (n = 186). Infants treated with buprenorphine experienced a 3.0-day reduction in opioid treatment duration of 7.4 (6.3-8.5) versus 10.4 (9.3-11.5) days (p < 0.001) and a 2.8-day reduction in length of stay of 12.4 (11.3-13.6) versus 15.2 (14.1-16.4) days (p < 0.001). CONCLUSION: Our study provides an independent confirmation that among infants experiencing NAS following a wide array of intrauterine opioid exposures, buprenorphine weaning supports a shortened treatment duration compared with conventional weaning agents. PMID- 29112998 TI - ? PMID- 29112999 TI - Use of Incisional Negative Pressure Wound Therapy in Skin-Containing Free Tissue Transfer. AB - BACKGROUND: Negative pressure wound therapy (NPWT) was initially introduced for wound management, but its benefits have stimulated the investigation of its use in new clinical scenarios. Most recently, incisional NPWT has been shown to be a benefit. Incisional NPWT applied to skin-containing free tissue transfer has not been well defined. This may originate from concerns of dressing material obscuring frequent examination of the newly transferred tissue or risk of pedicle compression and potential for increased risk of tissue loss. We aim to describe incisional NPWT in cutaneous free tissue transfer. METHODS: An institutional review board-approved retrospective review of consecutive free tissue transfer patients was completed over a 3-year period. Free tissue transfer procedures were performed in standard manner. After fixation of the flap to the donor site with interrupted sutures, one or two drainage tubes were inserted in the subflap position. The surface of the flap was protected with Vaseline gauze followed by a 1 cm thick layer of sterile cotton. The vacuum-assisted closure (VAC) sponge (KCI, TX) was then placed in the standard fashion and negative pressure at -125 mm Hg was initiated in a continuous mode. A window was routinely made over the flap's distal region to allow for serial flap examination. For extremity procedures, no splints were utilized, and patients were limited to motion in the hospital bed. NPWT was employed continuously for 7 days and subsequently removed along with operative drains. RESULTS: A total of 24 consecutive patients underwent free tissue transfer. The average patient age was 39.8 years with a mean body mass index of 23. Tobacco use was noted in 58% of patients in the series. The indication for the free tissue transfer included trauma (N = 21), malignancy (N = 2), and burn reconstruction (N = 1). The areas of reconstruction included scalp (N = 5), lower extremity (N = 11), and upper extremity (N = 8). Skin-containing free flaps employed consisted of the latissimus dorsi myocutaneous free flap (N = 16), anterolateral thigh free flap (N = 6), thoracodorsal artery perforator free flap (N = 1), and radial forearm free flap (N = 1). The average defect size reconstructed was 238.3 cm2 with a mean operative time of 501 minutes. Postoperatively, patients remained in the hospital an average of 15.5 days (range: 9-32 days) with a mean follow-up of 8.1 months. No hematomas, seromas, surgical-site infections, or deep vein thrombosis/pulmonary embolism occurred in the series. None of the flaps required return to the operating room. There were no documented cases of partial or complete flap loss. CONCLUSIONS: NPWT may be employed in a fashion similar to the standard incisional application. With this technique, serial flap examination remains possible and is not associated with pedicle compression or increased rates of flap loss. Interestingly, no splints were utilized with the VAC device which itself may serve as a relative immobilizer of an extremity. PMID- 29113001 TI - The impact of high-end ultrasound in the management of a patient with neuroendocrine tumor of the ileum. AB - Diagnostic imaging of jejuno-ileal neuroendocrine tumors (NETs) has been described as challenging. Follow-up requires the detection of metastatic spread as well as screening for local recurrence. Multimodal imaging concepts must often be applied.We report the case of a 45-year-old man with a history of ileal NET. At 2 points in follow-up of our patient, information provided by high-end ultrasound changed prognosis and treatment considerably: when positron emission tomography/computed tomography newly detected suspected hepatic metastases, contrast-enhanced ultrasound correctly identified the lesions as intrahepatic vascular shunts. Moreover, profound B-mode ultrasound solely detected ileal recurrence, leading to early removal of the tumor. PMID- 29113000 TI - Outcomes of Subfascial, Suprafascial, and Super-Thin Anterolateral Thigh Flaps: Tailoring Thickness without Added Morbidity. AB - BACKGROUND: Subfascial anterolateral thigh (ALT) flap thickness can be problematic with regards to bulk, oral competence, shoe-fit, or as a potential source of recurrent wound breakdown. We have utilized distinct upper thigh fascial planes to fashion thin (suprafascial) or super-thin (periscarpal) ALT flaps to improve surface topography. We compared outcomes based on ALT flap thickness to determine any significant differences in extremity coverage and reconstruction. METHODS: Analysis was completed on patients who consecutively underwent ALT free tissue transfer at a single institution from May 2012 to January 2017. Patient's operative, and postoperative characteristics were evaluated. Univariate analysis determined differences among matching as well as functional outcomes. A multivariable regression identified independent risk factors associated with patient, donor site, and flap complications. RESULTS: Fifty-one patients met inclusion criteria. Of these, 16 (31.4%) underwent traditional subfascial ALT flaps, and 35 (68.6%) underwent suprafascial (N = 23) or super-thin (N = 12) flaps. Thin flap patients were more likely to use tobacco (42.9% versus 6.3%; p < 0.01), have fewer perforators (1.20 +/- 0.41 versus 1.64 +/- 0.63; p < 0.009), and shorter mean operative times (425.9 +/- 87.8 versus 511.9 +/- 79.9; p < 0.002), but nearly identical flap sizes (163 cm2 versus 168 cm2). There were no significant differences in flap complications (18% versus 22%) or donor-site complications (6.3% versus 5.7%) between the thick and thin cohorts, respectively (p > 0.05). In subgroup analysis, diabetes mellitus was an independent risk factor for donor site morbidity (odds ratio [OR] = 1.23; p = 0.027) for all groups, whereas tobacco use and obesity (body mass index [BMI] > 30) failed to significantly alter outcomes independently. CONCLUSIONS: Tailoring ALT thickness can be performed safely without compromising flap outcomes or patient morbidity. Suprafascial and super-thin ALTs allowed for safe, precise solutions for tissue coverage. PMID- 29113002 TI - [Acute liver failure as a rare case of a frequent disease]. AB - Here we report the case of a 63-year-old female patient who was admitted with acute liver failure. The etiology turned out to be an acute fulminant hepatitis caused by hepatitis C virus (HCV) infection of unknown origin. Fulminant hepatitis due to acute hepatitis C is very rare and hardly reported but a potential cause of acute liver failure due to massive hepatic necrosis, which may lead to encephalitis and multi-organ-failure. During follow-up spontaneous virological clearance was observed. The case illustrates that acute HCV infection, which is confirmed by the detection of HCV-RNA, has to be considered in the differential diagnosis of acute liver failure. PMID- 29113003 TI - [Comparison of safety insertion techniques of percutaneous endoscopic gastrostomy in nurses and physicians - a non-randomized interventional pilot study on a simulation model]. AB - Percutaneous endoscopic gastrostomy (PEG) insertion represents a standardized procedure for enteral nutrition in patients with long-term eating difficulties for various reasons. In a clinical setting, delegation of stomach puncture and placement of a PEG tube, within the context of percutaneous endoscopic gastrostomy amongst nurses, occurs. In Germany, there are no studies yet showing the differences between physicians and nurses regarding the safety of percutaneous stomach puncture.In a non-randomized quasi-experimental interventional study on a simulation model, the safety of stomach puncture within the context of percutaneous endoscopic gastrostomy between physicians and nurses with special training was compared. Technical skills were recorded with video cameras and provided the basis for the following analysis. The study contained: (1) a theoretical preparation phase, (2) training on simulation model and a repeated practice of the skills, and (3) stomach puncture on the simulation model. The actions were recorded with a multichannel video technique. As part of the concept, nurses and physicians were trained together in theory and practice. The analysis was conducted with the newly designed Assessment Instrument Percutaneous Endoscopic Gastrostomy (AS-PEG). Seven physicians and 17 nurses took part in the pilot study. On average, the physicians reached a score of 36.4 +/- 2.2 (33 - 39) and nurses 37.4 +/- 2 (32 - 40), while the maximum score was 42. The evaluation of technical skills on the recorded videos by means of Assessment Instrument Percutaneous Endoscopic Gastrostomy (AS-PEG) showed no tendency to significant differences between physicians and nurses after theoretical and practical training. The study contributes a first objective evaluation of technical skills on stomach puncture within the context of percutaneous endoscopic gastrostomy with the newly designed AS-PEG. PMID- 29113004 TI - Direct-acting antiviral agents in the treatment of chronic Hepatitis C - "Real life" experience from an academic centre and two specialized clinical practices. AB - The introduction of the new direct antiviral agents has revolutionized the therapy of chronic hepatitis C. Today we are able to cure the vast majority of our patients with an 8- to 12-week therapy course of an antiviral combination therapy with an excellent safety profile. Real-life data are very important to further develop our experience with the new therapeutics and help us to improve the care of our patients in our everyday clinical practice.In our study, we present the retrospective analysis of a representative German cohort of 344 patients with chronic hepatitis C treated with the new direct antiviral agents. The patients were recruited in an academic center of southern Germany (University Clinic of Ulm, Clinic of Internal Medicine I) and in 2 highly specialized clinical practices in the city center and the near region of Ulm. Within this in detail characterized study cohort, we analyzed the efficacy and safety of antiviral therapy under real-life conditions.In 322 patients, we could document SVR12 data and found an excellent overall SVR12 rate of 97.8 % across all genotypes. In more detail, we could show comparable SVR12 results of 99 % and 99.2 % in patients with the hepatitis C virus subtypes 1a and 1b of and an excellent SVR12 rate of 93.1 % in genotype 3 patients without liver cirrhosis. Nevertheless, SVR12 rates tend to be lower in patients with the presence of liver cirrhosis, especially in genotype 3 patients with the lowest SVR12 rate in the whole study group of only 80 %. In general, there were no major safety issues except of 1 patient treated with a protease-inhibitor-based regimen who developed a generalized skin reaction and needed hospitalization and premature end of antiviral therapy.In summary, our analysis of this well characterized representative cohort of 344 patients adds more information in the field of real life experience with the new antiviral therapeutics and could therefore contribute to improve the care of our patients. Together with the existing real life data, we now can proceed in achieving the aim of viral eradication of hepatitis C virus within our population. PMID- 29113005 TI - Is integrated relaxation pressure a promising predictor of effectiveness of peroral endoscopic myotomy for achalasia? AB - BACKGROUND: Peroral endoscopic myotomy (POEM), first introduced in 2010, appears to be an effective therapy with few complications. This study aimed to find an optimal predictor of POEM outcome in achalasia. METHODS: We retrospectively assessed 89 patients diagnosed with achalasia who underwent POEM in General Hospital of Tianjin Medical University, from September 2012 to March 2015. Associations of Eckardt score with symptom duration, lower esophageal resting pressure, 4-second integrated relaxation pressure (4s-IRP), and maximum esophageal diameter were assessed before POEM. The most relevant data were progressively grouped to compare symptom improvement after POEM in 85 patients at 1 year follow-up. RESULTS: The most significant correlation was found between 4s IRP and Eckardt score (p < 0.01). The 85 achalasia patients (1-year follow-up after POEM) were divided into 3 groups according to 4s-IRP values; patients with mean 4s-IRP of 25 - 34 mmHg exhibited significantly greater improvement of clinical symptoms compared with the remaining 2 groups (p < 0.05). No significant postoperative difference was noted between types I and II in all patients according to Chicago classification criteria. The 40 patients with 4s-IRP of 25 - 34 mmHg were further divided into 2 subgroups; the 28 patients with type II achalasia responded better to POEM than the 12 with type I disease (p < 0.05). CONCLUSIONS: 4s-IRP, together with achalasia subtypes, may predict treatment outcome after POEM. Patients with type II achalasia and 4s-IRP of 25 - 34 mmHg may experience more satisfactory remission after POEM. PMID- 29113006 TI - Transjugular portal vein recanalization with creation of intrahepatic portosystemic shunt (PVR-TIPS) in patients with chronic non-cirrhotic, non malignant portal vein thrombosis. AB - PURPOSE: To determine safety and efficacy of transjugular portal vein recanalization with creation of intrahepatic portosystemic shunt (PVR-TIPS) in patients with chronic non-cirrhotic, non-malignant portal vein thrombosis (PVT). METHODS: This retrospective study includes 17 consecutive patients with chronic non-cirrhotic PVT (cavernous transformation n = 15). PVR-TIPS was indicated because of variceal bleeding (n = 13), refractory ascites (n = 2), portal biliopathy with recurrent cholangitis (n = 1), or abdominal pain (n = 1). Treatment consisted of a combination of transjugular balloon angioplasty, mechanical thrombectomy, and-depending on extent of residual thrombosis transjugular intrahepatic portosystemic shunt and additional stenting of the portal venous system. RESULTS: Recanalization was successful in 76.5 % of patients despite cavernous transformation in 88.2 %. Both 1- and 2-year secondary PV and TIPS patency rates were 69.5 %. Procedure-related bleeding complications occurred in 2 patients (intraperitoneal bleeding due to capsule perforation, n = 1; liver hematoma, n = 1) and resolved spontaneously. However, 1 patient died due to subsequent nosocomial pneumonia. During follow-up, 3 patients with TIPS occlusion and PVT recurrence experienced portal hypertensive complications. CONCLUSIONS: PVR-TIPS is safe and effective in selected patients with chronic non cirrhotic PVT. Due to technical complexity and possible complications, it should be performed only in specialized centers with high experience in TIPS procedures. PMID- 29113007 TI - [Gluten-free diet - Update 2017]. AB - Since sixty years, the gluten-free diet (GFD) is the only therapeutic option for patients with celiac disease or dermatitis herpetitormis to normalize symptoms and prevent complications. In recent years, the use of a gluten-free diet is rapidly growing because of presumed effects on well-being and control of body weight. GFD is becoming a popular health choice for everybody.In the present review, evidence-based indications for a gluten-free diet are stressed, the need for profound dietary counselling and education of the patient is underlined, problems and pitfalls of the implementation of a gluten-free diet in daily practice and possible side effects of long-term gluten-free diets are mentioned. New methods to control adherence to a gluten-free diet and aspects of nutritional quality of commercial gluten-free products are discussed in detail. PMID- 29113008 TI - [Drug therapy in coeliac disease - "from bench to bedside"]. AB - Coeliac disease is one of the most common diseases worldwide, with an estimated global prevalence of 0.5 - 1 %. The disease is triggered by a combination of environmental (gluten proteins from wheat, rye or barley) and genetic factors (mainly the human leucocyte antigens HLA-DQ2 or -DQ8). At present, a strict gluten-free diet (GFD) represents the only treatment option. However, strict adherence to a GFD is challenging, since even highly motivated patients may be subject to inadvertent or background exposure to gluten. Thus, rigorous avoidance of gluten necessitates extensive constraint of patients' food choices and social interactions. Moreover, even in fully adherent patients, a GFD may fail to induce clinical or histological normalisation. New (adjunctive) non-dietary therapeutic strategies for patients with coeliac disease are therefore of great interest. In this review, on the basis of the current understanding of its pathophysiology, we examine and discuss novel pharmacological approaches for the treatment of coeliac disease. PMID- 29113009 TI - ? PMID- 29113010 TI - Comparison of four methods of endotracheal tube passage in simulated airways: There is room for improved techniques. AB - OBJECTIVE: Endotracheal intubation requires laryngoscopy followed by passage of the endotracheal tube (ETT). Tube passage can be difficult, but there is little evidence to support which adjunct for tube passage is most effective. METHODS: The four tube passage adjuncts tested were the naked ETT, stylet ETT, railroaded bougie and preloaded bougie. Participants completed pre- and post-test surveys identifying demographics, experience and method preference. After instruction, participants completed eight intubations on manikins with 'easy' and 'difficult' airways. RESULTS: One hundred and seventeen practitioners who were experienced emergency medicine physicians, anaesthesiologists and out-of-hospital providers completed 936 total ETT attempts. For the 'difficult' airway, the percentage first pass success (95% confidence interval [CI]) for the naked ETT was 30.8% (23.1-39.7%). This was significantly lower than the stylet ETT (95.7% [86.6 100%]), the railroaded bougie (75.2% [63.8-86.6%]), or the preloaded bougie (89.7% [79.7-99.7%]). On difficult airways, the median (interquartile range [IQR]) time-to-intubation was fastest in the stylet ETT (25.0 s [20.9-32.2 s]) with the railroaded bougie being the slowest (43.2 s [36.5-56.2 s]). Seventy-nine per cent of participants stated that they would change their practice based on participating in this study. Participants increased their preference for the preloaded bougie from 30.6% to 69.4%. CONCLUSION: The data show that tube passage with a stylet ETT or a preloaded bougie is superior in terms of higher first pass success, faster time-to-intubation and higher post-test preference. The naked ETT is clearly inferior to other methods. This research supports the recommendation to use a stylet ETT or bougie for every predicted difficult intubation. PMID- 29113011 TI - Aspergillus fumigatus adhesion factors in dormant conidia revealed through comparative phenotypic and transcriptomic analyses. AB - Aspergillus fumigatus is an important fungal pathogen of humans. Inhaled conidia of A. fumigatus adhere to pulmonary epithelial cells, causing opportunistic infection. However, little is known about the molecular mechanism of the adherence of resting conidia. Fungal molecules adhesive to host cells are presumed to be displayed on the conidial surface during conidial formation as a result of changes in gene expression. Therefore, we exhaustively searched for adhesion molecules by comparing the phenotypes and the gene expression profiles of A. fumigatus strains that have conidia showing either high or low adherence to human pulmonary A549 cells. Morphological observation suggested that strains that produce conidia of reduced size, hydrophobicity, or number show decreased adherence to A549 cells. K-means cluster analyses of gene expression revealed 31 genes that were differentially expressed in the high-adherence strains during conidial formation. We knocked out three of these genes and showed that the conidia of AFUA_4G01030 (encoding a hypothetical protein) and AFUA_4G08805 (encoding a haemolysin-like protein) knockout strains had significantly reduced adherence to host cells. Furthermore, the conidia of these knockout strains had lower hydrophobicity and fewer surface spikes compared to the control strain. We suggest that the selectively expressed gene products, including those we identified experimentally, have composite synergistic roles in the adhesion of conidia to pulmonary epithelial cells. PMID- 29113012 TI - The suprachiasmatic nucleus drives day-night variations in postprandial triglyceride uptake into skeletal muscle and brown adipose tissue. AB - NEW FINDINGS: What is the central question of this study? What are the factors influencing day-night variations in postprandial triglycerides? What is the main finding and its importance? Rats show low postprandial plasma triglyceride concentrations early in the active period that are attributable to a higher uptake by skeletal muscle and brown adipose tissue. We show that these day-night variations in uptake are driven by the suprachiasmatic nucleus, probably via a Rev-erbalpha-mediated mechanism and independent of locomotor activity. These findings highlight that the suprachiasmatic nucleus has a major role in day-night variations in plasma triglycerides and that disturbances in our biological clock might be an important risk factor contributing to development of postprandial hyperlipidaemia. Energy metabolism follows a diurnal pattern, mainly driven by the suprachiasmatic nucleus (SCN), and disruption of circadian regulation has been linked to metabolic abnormalities. Indeed, epidemiological evidence shows that night work is a risk factor for cardiovascular disease, and postprandial hyperlipidaemia is an important contributor. Therefore, the aim of this work was to investigate the factors that drive day-night variations in postprandial triglycerides (TGs). Intact and SCN-lesioned male Wistar rats were subjected to an oral fat challenge during the beginning of the rest phase (day) or the beginning of the active phase (night). The plasma TG profile was evaluated and tissue TG uptake assayed. After the fat challenge, intact rats showed lower postprandial plasma TG concentrations early in the night when compared with the day. However, no differences were observed in the rate of intestinal TG secretion between day and night. Instead, there was a higher uptake of TG by skeletal muscle and brown adipose tissue early in the active phase (night) when compared with the rest phase (day), and these variations were abolished in rats bearing bilateral SCN lesions. Rev-erbalpha gene expression suggests this as a possible mediator of the mechanism linking the SCN and day-night variations in TG uptake. These findings show that the SCN has a major role in day-night variations in plasma TGs by promoting TG uptake into skeletal muscle and brown adipose tissue. Consequently, disturbance of the biological clock might be an important risk factor contributing to the development of hyperlipidaemia. PMID- 29113013 TI - Deciphering the demographic history of allochronic differentiation in the pine processionary moth Thaumetopoea pityocampa. AB - Understanding the processes of adaptive divergence, which may ultimately lead to speciation, is a major question in evolutionary biology. Allochronic differentiation refers to a particular situation where gene flow is primarily impeded by temporal isolation between early and late reproducers. This process has been suggested to occur in a large array of organisms, even though it is still overlooked in the literature. We here focused on a well-documented case of incipient allochronic speciation in the winter pine processionary moth Thaumetopoea pityocampa. This species typically reproduces in summer and larval development occurs throughout autumn and winter. A unique, phenologically shifted population (SP) was discovered in 1997 in Portugal. It was proved to be strongly differentiated from the sympatric "winter population" (WP), but its evolutionary history could only now be explored. We took advantage of the recent assembly of a draft genome and of the development of pan-genomic RAD-seq markers to decipher the demographic history of the differentiating populations and develop genome scans of adaptive differentiation. We showed that the SP diverged relatively recently, that is, few hundred years ago, and went through two successive bottlenecks followed by population size expansions, while the sympatric WP is currently experiencing a population decline. We identified outlier SNPs that were mapped onto the genome, but none were associated with the phenological shift or with subsequent adaptations. The strong genetic drift that occurred along the SP lineage certainly challenged our capacity to reveal functionally important loci. PMID- 29113014 TI - Environmental filtering by pH and soil nutrients drives community assembly in fungi at fine spatial scales. AB - Whether niche processes, like environmental filtering, or neutral processes, like dispersal limitation, are the primary forces driving community assembly is a central question in ecology. Here, we use a natural experimental system of isolated tree "islands" to test whether environment or geography primarily structures fungal community composition at fine spatial scales. This system consists of isolated pairs of two distantly related, congeneric pine trees established at varying distances from each other and the forest edge, allowing us to disentangle the effects of geographic distance vs. host and edaphic environment on associated fungal communities. We identified fungal community composition with Illumina sequencing of ITS amplicons, measured all relevant environmental parameters for each tree-including tree age, size and soil chemistry-and calculated geographic distances from each tree to all others and to the nearest forest edge. We applied generalized dissimilarity modelling to test whether total and ectomycorrhizal fungal (EMF) communities were primarily structured by geographic or environmental filtering. Our results provide strong evidence that as in many other organisms, niche and neutral processes both contribute significantly to turnover in community composition in fungi, but environmental filtering plays the dominant role in structuring both free-living and symbiotic fungal communities at fine spatial scales. In our study system, we found pH and organic matter primarily drive environmental filtering in total soil fungal communities and that pH and cation exchange capacity-and, surprisingly, not host species-were the largest factors affecting EMF community composition. These findings support an emerging paradigm that pH may play a central role in the assembly of all soil-mediated systems. PMID- 29113015 TI - Subfamily-dependent alternative reproductive strategies in worker honeybees. AB - Functional worker sterility is the defining feature of insect societies. Yet, workers are sometimes found reproducing in their own or foreign colonies. The proximate mechanisms underlying these alternative reproductive phenotypes are keys to understanding how reproductive altruism and selfishness are balanced in eusocial insects. In this study, we show that in honeybee (Apis mellifera) colonies, the social environment of a worker, that is, the presence and relatedness of the queens in a worker's natal colony and in surrounding colonies, significantly influences her fertility and drifting behaviour. Furthermore, subfamilies vary in the frequency of worker ovarian activation, propensity to drift and the kind of host colony that is targeted for reproductive parasitism. Our results show that there is an interplay between a worker's subfamily, reproductive state and social environment that substantially affects her reproductive phenotype. Our study further indicates that honeybee populations show substantial genetic variance for worker reproductive strategies, suggesting that no one strategy is optimal under all the circumstances that a typical worker may encounter. PMID- 29113016 TI - Cryptococcal dissemination to the central nervous system requires the vacuolar calcium transporter Pmc1. AB - Cryptococcus neoformans is a basidiomycetous yeast and the cause of cryptococcosis in immunocompromised individuals. The most severe form of the disease is meningoencephalitis, which is one of the leading causes of death in HIV/AIDS patients. In order to access the central nervous system, C. neoformans relies on the activity of certain virulence factors such as urease, which allows transmigration through the blood-brain barrier. In this study, we demonstrate that the calcium transporter Pmc1 enables C. neoformans to penetrate the central nervous system, because the pmc1 null mutant failed to infect and to survive within the brain parenchyma in a murine systemic infection model. To investigate potential alterations in transmigration pathways in these mutants, global expression profiling of the pmc1 mutant strain was undertaken, and genes associated with urease, the Ca2+ -calcineurin pathway, and capsule assembly were identified as being differentially expressed. Also, a decrease in urease activity was observed in the calcium transporter null mutants. Finally, we demonstrate that the transcription factor Crz1 regulates urease activity and that the Ca2+ calcineurin signalling pathway positively controls the transcription of calcium transporter genes and factors related to transmigration. PMID- 29113017 TI - Cumulative and partially recoverable impacts of nitrogen addition on a temperate steppe. AB - Atmospheric nitrogen (N) deposition has been shown to decrease biodiversity and change nutrient cycles in terrestrial ecosystems. However, our understanding of ecological responses to chronic N addition and ecological recovery of grassland from N enrichment is limited. Here we present evidence from an 11-year grassland experiment with a range of N addition rates (0, 30, 60, 120, 240, and 480 kg N.ha 1 .yr-1 ) in Inner Mongolia, China. Chronic N addition led to a reduction in species richness, Shannon diversity index, and soil pH and an increase in aboveground biomass, foliar N, and soil mineral N. High N addition rates (240 and 480 kg N.ha-1 .yr-1 ) showed significant effects in the first and second years, which stabilized over time. Nitrogen addition at low rates (30 and 60 kg N.ha-1 .yr-1 ) took longer (e.g., three years or more) to achieve significant effects. The negative impacts of high N addition (480 kg N.ha-1 .yr-1 ) were reduced and species richness, Shannon diversity index, and soil pH showed a limited but rapid recovery with the cessation of N addition. Our findings suggest serious and cumulative impacts of N addition on plant and soil communities but the potential for partial system recovery over time if N inputs decline or cease. PMID- 29113018 TI - Fast and robust detection of ancestral selective sweeps. AB - There are few methods tailored for detecting signals of positive selection in populations directly ancestral to multiple descendent populations. We introduce the ancestral branch statistic (ABS), a four-population summary statistic for identifying selective sweeps occurring in the direct ancestor of a pair of populations. Simulations show that ABS performs at least as well as, and often better under model violations, than the complementary likelihood approach of 3P CLR across diverse selection scenarios and parameter values. We first applied ABS to contemporary human genomic data to identify genes that may have been adaptive in ancestral East Asian populations, uncovering the well-established candidate EDAR, as well as a novel candidate SLC35F3, which encodes a putative thiamine transporter that may have been involved in adaptation to eating polished grains. Next, we performed scans with ancient European genomic data to reexamine evidence of recent positive selection in ancestral Europeans. The MCM6/LCT cluster and the SLC45A2 and HERC2 genes are strong outliers, agreeing with previous studies. Novel candidates, such as SLC30A9 and CYP1A2, may have been involved in adaptation to local nutrient sufficiency and lifestyle changes. Finally, we provide open-source software, CalcABS, which can perform genomic scans of ancestral sweeps with ABS from population allele frequency data. PMID- 29113019 TI - Diving into research: A practical guide for emergency medicine trainees. PMID- 29113020 TI - The genetics of obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is a common chronic disease and is associated with high social and economic costs. OSA is heritable, and there is evidence of both direct genetic contributions to OSA susceptibility and indirect contributions via 'intermediate' phenotypes such as obesity, craniofacial structure, neurological control of upper airway muscles and of sleep and circadian rhythm. Investigation of the genetics of OSA is an important research area and may lead to improved understanding of disease aetiology, pathogenesis, adverse health consequences and new preventive strategies and treatments. Genetic studies of OSA have lagged behind other chronic diseases; however recent gene discovery efforts have been successful in finding genetic loci contributing to OSA-associated intermediate phenotypes. Nevertheless, many of the seminal questions relating to the genetic epidemiology of OSA and associated factors remain unanswered. This paper reviews the current state of knowledge of the genetics of OSA, with a focus on genomic approaches to understanding sleep apnoea. PMID- 29113021 TI - Trauma case review: A quality and safety feature of the Victorian State Trauma System. AB - The aim of the present study was to describe the trauma case review process and its role in a regionalised trauma system. Victoria has a population of 5.9 million people, accounting for 26% of Australia's population. Victoria has been serviced by an inclusive, organised trauma system since 2000 comprising 138 health services with trauma designations and three major trauma services. Pre- and interhospital guidelines prescribe the timely transport of patients to the appropriate level of trauma service. A review of the role and contribution of 10 years of operation of the trauma case review group (CRG) was undertaken to describe the aims, processes and governance surrounding the implementation of an individual case review for specified major trauma patients. Specified patients were those identified by the Victorian State Trauma Registry as being managed outside of established Victorian State Trauma System prehospital and interhospital guidelines. A state-wide trauma case review process was implemented across the trauma system using data-informed detection flags and screening criteria. Using data from the Victorian State Trauma Registry, detection flags were correlated with patients at risk of a poorer outcome, thereby ensuring that all patients managed outside of the requirements of established trauma triage and transfer guidelines were subject to review. The CRG provides an individual review process as a technique for assessing and monitoring major trauma patient care and compliance with trauma system triage and transfer guidelines. The process has been effective as a quality and safety strategy by improving clinician knowledge of major trauma triage and transfer guidelines and facilitating improved compliance, particularly with interhospital transfers. Strong compliance has been achieved from health services with the requirement to internally review and respond to CRG concerns regarding 'high-risk' trauma cases. Anecdotal feedback from health services regarding participation in the CRG process has been positive. The trauma case review process is an embedded feature of the Victorian State Trauma System that aims to improve compliance with major trauma guidelines by reviewing major trauma cases that have been managed outside of established triage and transfer guidelines. All trauma-designated Victorian health services, Ambulance Victoria and Victorian adult and paediatric patient retrieval services might receive trauma cases for review. The process is also an integral component of trauma system clinical governance, which enables the identification of system level issues for escalation to the State Trauma Committee and the Victorian Department of Health and Human Services. PMID- 29113022 TI - Mitochondrial helicase Irc3 translocates along double-stranded DNA. AB - Irc3 is a superfamily II helicase required for mitochondrial DNA stability in Saccharomyces cerevisiae. Irc3 remodels branched DNA structures, including substrates without extensive single-stranded regions. Therefore, it is unlikely that Irc3 uses the conventional single-stranded DNA translocase mechanism utilized by most helicases. Here, we demonstrate that Irc3 disrupts partially triple-stranded DNA structures in an ATP-dependent manner. Our kinetic experiments indicate that the rate of ATP hydrolysis by Irc3 is dependent on the length of the double-stranded DNA cosubstrate. Furthermore, the previously uncharacterized C-terminal region of Irc3 is essential for these two characteristic features and forms a high affinity complex with branched DNA. Together, our experiments demonstrate that Irc3 has double-stranded DNA translocase activity. PMID- 29113023 TI - Metabarcoding of freshwater invertebrates to detect the effects of a pesticide spill. AB - Biomonitoring underpins the environmental assessment of freshwater ecosystems and guides management and conservation. Current methodology for surveys of (macro)invertebrates uses coarse taxonomic identification where species-level resolution is difficult to obtain. Next-generation sequencing of entire assemblages (metabarcoding) provides a new approach for species detection, but requires further validation. We used metabarcoding of invertebrate assemblages with two fragments of the cox1 "barcode" and partial nuclear ribosomal (SSU) genes, to assess the effects of a pesticide spill in the River Kennet (southern England). Operational taxonomic unit (OTU) recovery was tested under 72 parameters (read denoising, filtering, pair merging and clustering). Similar taxonomic profiles were obtained under a broad range of parameters. The SSU marker recovered Platyhelminthes and Nematoda, missed by cox1, while Rotifera were only amplified with cox1. A reference set was created from all available barcode entries for Arthropoda in the BOLD database and clustered into OTUs. The River Kennet metabarcoding produced matches to 207 of these reference OTUs, five times the number of species recognized with morphological monitoring. The increase was due to the following: greater taxonomic resolution (e.g., splitting a single morphotaxon "Chironomidae" into 55 named OTUs); splitting of Linnaean binomials into multiple molecular OTUs; and the use of a filtration-flotation protocol for extraction of minute specimens (meiofauna). Community analyses revealed strong differences between "impacted" vs. "control" samples, detectable with each gene marker, for each major taxonomic group, and for meio- and macrofaunal samples separately. Thus, highly resolved taxonomic data can be extracted at a fraction of the time and cost of traditional nonmolecular methods, opening new avenues for freshwater invertebrate biodiversity monitoring and molecular ecology. PMID- 29113024 TI - Neuroprotective Effects of Butanol Fraction of Cordyceps cicadae on Glutamate Induced Damage in PC12 Cells Involving Oxidative Toxicity. AB - The current study was aimed at investigating the neuroprotective effects of the butanol fraction from Cordyceps cicadae (CBU ), which was responsible for the anti-aging effect of this medicine. Glutamate-induced PC12 cells were used as a model to determine the neuroprotective effect against oxidative cell death. Cell viability, cytotoxicity, flow cytometry, mitochondrial transmembrane potential (MMP), reactive oxygen species (ROS), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) levels were analyzed to assess neuronal cell survival or death. The results obtained from the above evaluations showed that CBU was the most effective fraction and even better than pure compounds present in C. cicadae in terms of suppressing glutamate-induced damage in PC12 cells, increasing cell viability, decreasing lactase dehydrogenase (LDH) release, and reduction of apoptosis induced by exposure to glutamate. Furthermore, CBU protected cells against mitochondrial dysfunction and oxidative stress as indicated by the suppression of ROS accumulation and up regulation of the levels of GSH-Px and SOD. In summary, the above results showed that CBU exerted neuroprotective effect against oxidative damage, and this activity could be partly due to the action of nucleosides present in the CBU . PMID- 29113025 TI - The consideration of heart rate complexity as a co-morbidity factor for liver transplantation selection procedures. PMID- 29113026 TI - How gut transcriptional function of Drosophila melanogaster varies with the presence and composition of the gut microbiota. AB - Despite evidence from laboratory experiments that perturbation of the gut microbiota affects many traits of the animal host, our understanding of the effect of variation in microbiota composition on animals in natural populations is very limited. The core purpose of this study on the fruit fly Drosophila melanogaster was to identify the impact of natural variation in the taxonomic composition of gut bacterial communities on host traits, with the gut transcriptome as a molecular index of microbiota-responsive host traits. Use of the gut transcriptome was validated by demonstrating significant transcriptional differences between the guts of laboratory flies colonized with bacteria and maintained under axenic conditions. Wild Drosophila from six field collections made over two years had gut bacterial communities of diverse composition, dominated to varying extents by Acetobacteraceae and Enterobacteriaceae. The gut transcriptomes also varied among collections and differed markedly from those of laboratory flies. However, no overall relationship between variation in the wild fly transcriptome and taxonomic composition of the gut microbiota was evident at all taxonomic scales of bacteria tested for both individual fly genes and functional categories in Gene Ontology. We conclude that the interaction between microbiota composition and host functional traits may be confounded by uncontrolled variation in both ecological circumstance and host traits (e.g., genotype, age physiological condition) under natural conditions, and that microbiota effects on host traits identified in the laboratory should, therefore, be extrapolated to field population with great caution. PMID- 29113027 TI - Detect, correct, retract: How to manage incorrect structural models. AB - The massive technical and computational progress of biomolecular crystallography has generated some adverse side effects. Most crystal structure models, produced by crystallographers or well-trained structural biologists, constitute useful sources of information, but occasional extreme outliers remind us that the process of structure determination is not fail-safe. The occurrence of severe errors or gross misinterpretations raises fundamental questions: Why do such aberrations emerge in the first place? How did they evade the sophisticated validation procedures which often produce clear and dire warnings, and why were severe errors not noticed by the depositors themselves, their supervisors, referees and editors? Once detected, what can be done to either correct, improve or eliminate such models? How do incorrect models affect the underlying claims or biomedical hypotheses they were intended, but failed, to support? What is the long-range effect of the propagation of such errors? And finally, what mechanisms can be envisioned to restore the validity of the scientific record and, if necessary, retract publications that are clearly invalidated by the lack of experimental evidence? We suggest that cognitive bias and flawed epistemology are likely at the root of the problem. By using examples from the published literature and from public repositories such as the Protein Data Bank, we provide case summaries to guide correction or improvement of structural models. When strong claims are unsustainable because of a deficient crystallographic model, removal of such a model and even retraction of the affected publication are necessary to restore the integrity of the scientific record. PMID- 29113028 TI - Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis. AB - : Portal hypertension (PH) drives most of the clinical complications in chronic liver diseases. However, its progression in nonalcoholic steatohepatitis (NASH) and its association with the intestinal microbiota (IM) have been scarcely studied. Our aim was to investigate the role of the IM in the mechanisms leading to PH in early NASH. The experimental design was divided in two stages. In stage 1, Sprague-Dawley rats were fed for 8 weeks a high-fat, high-glucose/fructose diet (HFGFD) or a control diet/water (CD). Representative rats were selected as IM donors for stage 2. In stage 2, additional HFGFD and CD rats underwent intestinal decontamination, followed by IM transplantation with feces from opposite-diet donors (heterologous transplant) or autologous fecal transplant (as controls), generating four groups: CD-autotransplanted, CD-transplanted, HFGFD autotransplanted, HFGFD-transplanted. After IM transplantation, the original diet was maintained for 12-14 days until death. HFGFD rats developed obesity, insulin resistance, NASH without fibrosis but with PH, intrahepatic endothelial dysfunction, and IM dysbiosis. In HFGFD rats, transplantation with feces from CD donors caused a significant reduction of PH to levels comparable to CD without significant changes in NASH histology. The reduction in PH was due to a 31% decrease of intrahepatic vascular resistance compared to the HFGFD autotransplanted group (P < 0.05). This effect occurs through restoration of the sensitivity to insulin of the hepatic protein kinase B-dependent endothelial nitric oxide synthase signaling pathway. CONCLUSION: The IM exerts a direct influence in the development of PH in rats with diet-induced NASH and dysbiosis; PH, insulin resistance, and endothelial dysfunction revert when a healthy IM is restored. (Hepatology 2018;67:1485-1498). PMID- 29113029 TI - Differential requirement for ATG2A domains for localization to autophagic membranes and lipid droplets. AB - ATG2 is one of the autophagy-related (ATG) proteins essential for autophagosome formation and localizes to isolation membranes and lipid droplets in mammalian cells. Here, we investigated the requirement of regions in ATG2A for its organellar localization and function. The N-terminal amino acids 1-198 and the C terminal amino acids 1830-1938 are required for the localization to isolation membranes and lipid droplets, respectively. The C-terminal region is not required for the localization to isolation membranes and for autophagy. We also identified an amphipathic helix in ATG2A that is required for both its localization to organelles and autophagosome formation. These data suggest that the dual localization of ATG2A is regulated by different regions. PMID- 29113030 TI - Recent advances in transarterial embolotherapies in the treatment of hepatocellular carcinoma. AB - Management of hepatocellular carcinoma (HCC) can be maximized with the utilization of multiple treatment modalities including transplant, surgical resection and locoregional therapies including ablative therapies and transarterial embolotherapies. Although transplant and surgical resection offer the best clinical outcomes, a limited number of patients are amenable to these surgical treatment options due to the advanced disease at presentation. Transarterial embolotherapies including conventional transarterial chemoembolization (cTACE), bland transarterial embolization (TAE), drug-eluting beads transarterial chemoembolization (DEB-TACE) and selective internal radiation therapy (SIRT) with Yttrium 90 (90Y) have played an increasingly important role for these patients with unresectable HCC. With a better understanding of different transarterial embolotherapies, more personalized and precise treatment should be implemented for these patients with unresectable HCC. In this review, the updated evidence on the current role of each embolotherapy in the treatment of HCC is summarized. PMID- 29113031 TI - Role of core needle biopsy as a first-line diagnostic tool for thyroid nodules: a retrospective cohort study. AB - PURPOSE: The purpose of this study was to evaluate the diagnostic efficacy of fine-needle aspiration (FNA), core needle biopsy (CNB), and combined FNA/CNB for the first-line diagnosis of thyroid nodules. METHODS: A total of 782 consecutive nodules that underwent simultaneous FNA and CNB were analyzed in this study. We compared the rate of inconclusive results and the diagnostic values for malignancy among FNA, CNB, and combined FNA/CNB. RESULTS: CNB showed a lower rate (10.2%) of inconclusive results than FNA (23.7%) (P<0.001). Combined FNA/CNB showed a lower rate (6.5%) of inconclusive results than FNA (all nodules, P<0.001; macronodules, P<0.001; and micronodules, P<0.001, respectively) or CNB (all nodules, P<0.001; macronodules, P<0.001; and micronodules, P=0.003, respectively). Combined FNA/ CNB and CNB showed significantly higher sensitivity, accuracy, and diagnostic performance for malignancy as defined by criterion 1 (Bethesda category VI) or criterion 2 (Bethesda categories IV/V/VI) than FNA (P<0.001). However, there was no significant difference in the sensitivity, accuracy, or diagnostic performance between combined FNA/CNB and CNB (with criterion 1, P=0.063, P=0.063, and P=0.412, respectively; with criterion 2, P=0.500, P=0.500, and P=0.348, respectively). CONCLUSION: CNB was found to be more effective than FNA for the diagnosis of thyroid nodules, and its sensitivity and diagnostic performance for malignancy were similar to those of combined FNA/CNB. CNB has the potential to be an effective alternative first-line diagnostic tool for thyroid nodules when performed by an experienced operator. PMID- 29113033 TI - Association between Lameness and Indicators of Dairy Cow Welfare Based on Locomotion Scoring, Body and Hock Condition, Leg Hygiene and Lying Behavior. AB - Dairy cow welfare is an important consideration for optimal production in the dairy industry. Lameness affects the welfare of dairy herds by limiting productivity. Whilst the application of LS systems helps in identifying lame cows, the technique meets with certain constraints, ranging from the detection of mild gait changes to on-farm practical applications. Recent studies have shown that certain animal-based measures considered in welfare assessment, such as body condition, hock condition and leg hygiene, are associated with lameness in dairy cows. Furthermore, behavioural changes inherent in lame cows, especially the comfort in resting and lying down, have been shown to be vital indicators of cow welfare. Highlighting the relationship between lameness and these welfare indicators could assist in better understanding their role, either as risk factors or as consequences of lameness. Nevertheless, since the conditions predisposing a cow to lameness are multifaceted, it is vital to cite the factors that could influence the on-farm practical application of such welfare indicators in lameness studies. This review begins with the welfare consequences of lameness by comparing normal and abnormal gait as well as the use of LS system in detecting lame cows. Animal-based measures related to cow welfare and links with changes in locomotion as employed in lameness research are discussed. Finally, alterations in lying behaviour are also presented as indicators of lameness with the corresponding welfare implication in lame cows. PMID- 29113034 TI - Directed Evolution of Recombinant C-Terminal Truncated Staphylococcus epidermidis Lipase AT2 for the Enhancement of Thermostability. AB - In the industrial processes, lipases are expected to operate at temperatures above 45 degrees C and could retain activity in organic solvents. Hence, a C terminal truncated lipase from Staphylococcus epidermis AT2 (rT-M386) was engineered by directed evolution. A mutant with glycine-to-cysteine substitution (G210C) demonstrated a remarkable improvement of thermostability, whereby the mutation enhanced the activity five-fold when compared to the rT-M386 at 50 degrees C. The rT-M386 and G210C lipases were purified concurrently using GST affinity chromatography. The biochemical and biophysical properties of both enzymes were investigated. The G210C lipase showed a higher optimum temperature (45 degrees C) and displayed a more prolonged half-life in the range of 40-60 degrees C as compared to rT-M386. Both lipases exhibited optimal activity and stability at pH 8. The G210C showed the highest stability in the presence of polar organic solvents at 50 degrees C compared to the rT-M386. Denatured protein analysis presented a significant change in the molecular ellipticity value above 60 degrees C, which verified the experimental result on the temperature and thermostability profile of G210C. PMID- 29113035 TI - Room-Temperature Pressure-Induced Optically-Actuated Fabry-Perot Nanomechanical Resonator with Multilayer Graphene Diaphragm in Air. AB - We demonstrated a miniature and in situ ~13-layer graphene nanomechanical resonator by utilizing a simple optical fiber Fabry-Perot (F-P) interferometric excitation and detection scheme. The graphene film was transferred onto the endface of a ferrule with a 125-MUm inner diameter. In contrast to the pre tension induced in membrane that increased quality (Q) factor to ~18.5 from ~3.23 at room temperature and normal pressure, the limited effects of air damping on resonance behaviors at 10-2 and 105 Pa were demonstrated by characterizing graphene F-P resonators with open and micro-air-gap cavities. Then in terms of optomechanical behaviors of the resonator with an air micro-cavity configuration using a polished ferrule substrate, measured resonance frequencies were increased to the range of 509-542 kHz from several kHz with a maximum Q factor of 16.6 despite the lower Knudsen number ranging from 0.0002 to 0.0006 in damping air over a relative pressure range of 0-199 kPa. However, there was the little dependence of Q on resonance frequency. Note that compared with the inferior F-P cavity length response to applied pressures due to interfacial air leakage, the developed F-P resonator exhibited a consistent fitted pressure sensitivity of 1.18 * 105 kHz3/kPa with a good linearity error of 5.16% in the tested range. These measurements shed light on the pre-stress-dominated pressure-sensitive mechanisms behind air damping in in situ F-P resonant sensors using graphene or other 2D nanomaterials. PMID- 29113036 TI - In-Class Cycling to Augment College Student Academic Performance and Reduce Physical Inactivity: Results from an RCT. AB - Most college students sit 14 hours per week on average, excluding sedentary study time. Researchers observing workplace and elementary school settings with active workstations to combat sedentary behavior have shown enhanced cognition without distraction. Until now, incorporating active workstations in college classroom settings remained relatively unexplored. This study's purpose was to assess academic performance using in-class stationary cycle desks during a semester-long lecture course. Twenty-one college students (19-24 years) enrolled in a lecture course volunteered and were split into traditional sit (SIT) and stationary cycle (CYC) groups randomly, matched on a calculated factor equal to a physical activity (PA) score (0-680) multiplied by grade point average (GPA; 4.0 scale). CYC pedaled a prescribed rate of perceived exertion (RPE) of less than 2 out of 10 during a 50-min lecture, 3 * week for 12 weeks. CYC averaged 42 min, 7.9 miles, and 1.7 RPE during class throughout the semester. No significant differences (p > 0.05) were observed between CYC and SIT on in-class test scores or overall course grades. Although statistically insignificant, CYC had higher mean test scores and overall course grades vs. SIT (i.e., B+ vs. B, respectively). Low intensity cycling during a college lecture course maintained student academic performance and possibly reduced weekly sedentary behavior time. PMID- 29113037 TI - Vitamin D and VDR in Gynecological Cancers-A Systematic Review. AB - In recent years, a vast amount of studies have centered on the role of vitamin D in the pathogenesis of certain types of cancers such as breast, colorectal and lung cancer. Increasing evidence suggests that vitamin D and its receptor play a crucial role in the development of gynecological cancers. In this review, we systematically analyzed the effect of vitamin D and the vitamin D receptor on endometrial, ovarian, cervical, vulvar and vaginal cancer. Our literature research shows that vitamin D levels and vitamin-D-related pathways affect the risk of gynecological cancers. Numerous ecological studies give evidence on the inverse relationship between UVB exposure and gynecological cancer risk. However, epidemiologic research is still inconclusive for endometrial and ovarian cancer and insufficient for rarer types of gynecological cancers. The vitamin D receptor (VDR) is upregulated in all gynecological cancers, indicating its influence on cancer etiology. The VDR polymorphism FokI (rs2228570) seems to increase the risk of ovarian cancer. Other nuclear receptors, such as the RXR, also influence gynecological cancers. Although there is limited knowledge on the role of the VDR/RXR on the survival of endometrial, cervical, vulvar or vaginal cancer patients, some studies showed that both receptors influence survival. Therefore, we suggest that further studies should focus on the vitamin D- and its hetero dimer receptor RXR in gynecological cancers. PMID- 29113038 TI - Micronutrient Dietary Intake in Latina Pregnant Adolescents and Its Association with Level of Depression, Stress, and Social Support. AB - Adolescent pregnant women are at greater risk for nutritional deficits, stress, and depression than their adult counterparts, and these risk factors for adverse pregnancy outcomes are likely interrelated. This study evaluated the prevalence of nutritional deficits in pregnant teenagers and assessed the associations among micronutrient dietary intake, stress, and depression. One hundred and eight pregnant Latina adolescents completed an Automated Self-Administered 24-hour dietary recall (ASA24) in the 2nd trimester. Stress was measured using the Perceived Stress Scale and the Prenatal Distress Questionnaire. Depressive symptoms were evaluated with the Reynolds Adolescent Depression Scale. Social support satisfaction was measured using the Social Support Questionnaire. More than 50% of pregnant teenagers had an inadequate intake (excluding dietary supplement) of folate, vitamin A, vitamin E, iron, zinc, calcium, magnesium, and phosphorous. Additionally, >20% of participants had an inadequate intake of thiamin, riboflavin, niacin, vitamin B6, vitamin B12, vitamin C, copper, and selenium. Prenatal supplement inclusion improved dietary intake for most micronutrients except for calcium, magnesium, and phosphorous, (>50% below the Estimated Average Requirement (EAR)) and for copper and selenium (>20% below the EAR). Higher depressive symptoms were associated with higher energy, carbohydrates, and fats, and lower magnesium intake. Higher social support satisfaction was positively associated with dietary intake of thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, vitamin C, vitamin E, iron, and zinc. The findings suggest that mood and dietary factors are associated and should be considered together for health interventions during adolescent pregnancy for the young woman and her future child. PMID- 29113041 TI - Perceptions of Hunting and Hunters by U.S. Respondents. AB - Public acceptance of hunting and hunting practices is an important human dimension of wildlife management in the United States. Researchers surveyed 825 U.S. residents in an online questionnaire about their views of hunting, hunters, and hunting practices. Eighty-seven percent of respondents from the national survey agreed that it was acceptable to hunt for food whereas 37% agreed that it was acceptable to hunt for a trophy. Over one-quarter of respondents did not know enough about hunting over bait, trapping, and captive hunts to form an opinion about whether the practice reduced animal welfare. Chi-square tests were used to explore relationships between perceptions of hunters and hunting practices and demographics. Those who knew hunters, participated in hunting-related activities, visited fairs or livestock operations, or were males who had more favorable opinions on hunting. A logistic regression model showed that not knowing a hunter was a statistically significant negative predictor of finding it acceptable to hunt; owning a pet was statistically significant and negative for approving of hunting for a trophy. PMID- 29113040 TI - beta-Cyclodextrin Attenuates Perfluorooctanoic Acid Toxicity in the Zebrafish Embryo Model. AB - Perfluorooctanoic acid (PFOA) has been linked to negative health outcomes including cancer, thyroid disease, infertility, and developmental delays. beta Cyclodextrin (beta-CD), a cyclic sugar, has been previously shown to form strong host-guest complexes with PFOA, and is proposed as a means of environmental remediation with respect to this widespread contaminant. In the present study, beta-CD was directly examined with regards to possible attenuation of the toxicity of PFOA specifically employing the zebrafish (Danio rerio) embryo model. Zebrafish embryos were exposed to various concentrations of PFOA without beta-CD, and with equimolar (1:1) and excess (2:1) molar ratios of beta-CD to PFOA, and assessed for lethality and developmental toxicity through seven days post fertilization (dpf). Rapid onset of lethality with limited morphological abnormalities was observed at relatively low concentrations of PFOA (LC50 ~ 50 ppm), along with effects on morphometric and neurobehavioral parameters in surviving embryos. A highly significant difference (p < 0.0001) was observed between the 2:1 treatment, and both 1:1 and PFOA only treatments, with respect to lethal concentration and apparent neurobehavioral effects, suggesting an effectively reduced toxicity of the fully complexed PFOA. In contrast, however, neither beta-CD treatment reduced developmental toxicity with respect to the morphometric endpoint (i.e., interocular distance). Whereas LC50 of PFOA alone did not change over 7 dpf, the 1:1 and 2:1 values decreased slightly over time, suggesting either delayed or alternative toxic effects on later developmental stages at presumptively lowered levels. This study, therefore, indicates beta-CD may be an effective agent to reduce toxicity of and mitigate environmental health concerns associated with PFOA, but that further study is required to elucidate the mechanism of complexation as it relates to the attenuation of toxicity. PMID- 29113039 TI - Surviving a Dry Future: Abscisic Acid (ABA)-Mediated Plant Mechanisms for Conserving Water under Low Humidity. AB - Angiosperms are able to respond rapidly to the first sign of dry conditions, a decrease in air humidity, more accurately described as an increase in the vapor pressure deficit between the leaf and the atmosphere (VPD), by abscisic acid (ABA)-mediated stomatal closure. The genes underlying this response offer valuable candidates for targeted selection of crop varieties with improved drought tolerance, a critical goal for current plant breeding programs, to maximize crop production in drier and increasingly marginalized environments, and meet the demands of a growing population in the face of a changing climate. Here, we review current understanding of the genetic mechanisms underpinning ABA mediated stomatal closure, a key means for conserving water under dry conditions, examine how these mechanisms evolved, and discuss what remains to be investigated. PMID- 29113042 TI - pH-Responsive Micelle-Based Cytoplasmic Delivery System for Induction of Cellular Immunity. AB - (1) Background: Cytoplasmic delivery of antigens is crucial for the induction of cellular immunity, which is an important immune response for the treatment of cancer and infectious diseases. To date, fusogenic protein-incorporated liposomes and pH-responsive polymer-modified liposomes have been used to achieve cytoplasmic delivery of antigen via membrane rupture or fusion with endosomes. However, a more versatile cytoplasmic delivery system is desired for practical use. For this study, we developed pH-responsive micelles composed of dilauroyl phosphatidylcholine (DLPC) and deoxycholic acid and investigated their cytoplasmic delivery performance and immunity-inducing capability. (2) Methods: Interaction of micelles with fluorescence dye-loaded liposomes, intracellular distribution of micelles, and antigenic proteins were observed. Finally, antigen specific cellular immune response was evaluated in vivo using ELIspot assay. (3) Results: Micelles induced leakage of contents from liposomes via lipid mixing at low pH. Micelles were taken up by dendritic cells mainly via macropinocytosis and delivered ovalbumin (OVA) into the cytosol. After intradermal injection of micelles and OVA, OVA-specific cellular immunity was induced in the spleen. (4) Conclusions: pH-responsive micelles composed of DLPC and deoxycholic acid are promising as enhancers of cytosol delivery of antigens and the induction capability of cellular immunity for the treatment of cancer immunotherapy and infectious diseases. PMID- 29113043 TI - An FBG Optical Approach to Thermal Expansion Measurements under Hydrostatic Pressure. AB - We report on an optical technique for measuring thermal expansion and magnetostriction at cryogenic temperatures and under applied hydrostatic pressures of 2.0 GPa. Optical fiber Bragg gratings inside a clamp-type pressure chamber are used to measure the strain in a millimeter-sized sample of CeRhIn5. We describe the simultaneous measurement of two Bragg gratings in a single optical fiber using an optical sensing instrument capable of resolving changes in length [dL/L = (L- L0)/L0] on the order of 10-7. Our results demonstrate the possibility of performing high-resolution thermal expansion measurements under hydrostatic pressure, a capability previously hindered by the small working volumes typical of pressure cells. PMID- 29113044 TI - Inter-Rater Reliability of Provider Interpretations of Irritable Bowel Syndrome Food and Symptom Journals. AB - There are currently no standardized methods for identifying trigger food(s) from irritable bowel syndrome (IBS) food and symptom journals. The primary aim of this study was to assess the inter-rater reliability of providers' interpretations of IBS journals. A second aim was to describe whether these interpretations varied for each patient. Eight providers reviewed 17 IBS journals and rated how likely key food groups (fermentable oligo-di-monosaccharides and polyols, high-calorie, gluten, caffeine, high-fiber) were to trigger IBS symptoms for each patient. Agreement of trigger food ratings was calculated using Krippendorff's alpha reliability estimate. Providers were also asked to write down recommendations they would give to each patient. Estimates of agreement of trigger food likelihood ratings were poor (average alpha = 0.07). Most providers gave similar trigger food likelihood ratings for over half the food groups. Four providers gave the exact same written recommendation(s) (range 3-7) to over half the patients. Inter-rater reliability of provider interpretations of IBS food and symptom journals was poor. Providers favored certain trigger food likelihood ratings and written recommendations. This supports the need for a more standardized method for interpreting these journals and/or more rigorous techniques to accurately identify personalized IBS food triggers. PMID- 29113045 TI - Pilot Study: Comparison of Sourdough Wheat Bread and Yeast-Fermented Wheat Bread in Individuals with Wheat Sensitivity and Irritable Bowel Syndrome. AB - Many patients suspect wheat as being a major trigger of their irritable bowel syndrome (IBS) symptoms. Our aim was to evaluate whether sourdough wheat bread baked without baking improvers and using a long dough fermentation time (>12 h), would result in lower quantities of alpha-amylase/trypsin inhibitors (ATIs) and Fermentable, Oligo-, Di-, Mono-saccharides and Polyols (FODMAPs), and would be better tolerated than yeast-fermented wheat bread for subjects with IBS who have a poor subjective tolerance to wheat. The study was conducted as a randomised double-blind controlled 7-day study (n = 26). Tetrameric ATI structures were unravelled in both breads vs. baking flour, but the overall reduction in ATIs to their monomeric form was higher in the sourdough bread group. Sourdough bread was also lower in FODMAPs. However, no significant differences in gastrointestinal symptoms and markers of low-grade inflammation were found between the study breads. There were significantly more feelings of tiredness, joint symptoms, and decreased alertness when the participants ate the sourdough bread (p <= 0.03), but these results should be interpreted with caution. Our novel finding was that sourdough baking reduces the quantities of both ATIs and FODMAPs found in wheat. Nonetheless, the sourdough bread was not tolerated better than the yeast fermented bread. PMID- 29113046 TI - Additivity vs Synergism: Investigation of the Additive Interaction of Cinnamon Bark Oil and Meropenem in Combinatory Therapy. AB - Combinatory therapies have been commonly applied in the clinical setting to tackle multi-drug resistant bacterial infections and these have frequently proven to be effective. Specifically, combinatory therapies resulting in synergistic interactions between antibiotics and adjuvant have been the main focus due to their effectiveness, sidelining the effects of additivity, which also lowers the minimal effective dosage of either antimicrobial agent. Thus, this study was undertaken to look at the effects of additivity between essential oils and antibiotic, via the use of cinnamon bark essential oil (CBO) and meropenem as a model for additivity. Comparisons between synergistic and additive interaction of CBO were performed in terms of the ability of CBO to disrupt bacterial membrane, via zeta potential measurement, outer membrane permeability assay and scanning electron microscopy. It has been found that the additivity interaction between CBO and meropenem showed similar membrane disruption ability when compared to those synergistic combinations which was previously reported. Hence, results based on our studies strongly suggest that additive interaction acts on a par with synergistic interaction. Therefore, further investigation in additive interaction between antibiotics and adjuvant should be performed for a more in depth understanding of the mechanism and the impacts of such interaction. PMID- 29113047 TI - Improved Durability and Sensitivity of Bitterness-Sensing Membrane for Medicines. AB - This paper reports the improvement of a bitterness sensor based on a lipid polymer membrane consisting of phosphoric acid di-n-decyl ester (PADE) as a lipid and bis(1-butylpentyl) adipate (BBPA) and tributyl o-acetylcitrate (TBAC) as plasticizers. Although the commercialized bitterness sensor (BT0) has high sensitivity and selectivity to the bitterness of medicines, the sensor response gradually decreases to almost zero after two years at room temperature and humidity in a laboratory. To reveal the reason for the deterioration of the response, we investigated sensor membranes by measuring the membrane potential, contact angle, and adsorption amount, as well as by performing gas chromatography mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC MS/MS). We found that the change in the surface charge density caused by the hydrolysis of TBAC led to the deterioration of the response. The acidic environment generated by PADE promoted TBAC hydrolysis. Finally, we succeeded in fabricating a new membrane for sensing the bitterness of medicines with higher durability and sensitivity by adjusting the proportions of the lipid and plasticizers. PMID- 29113048 TI - The Application of EM38: Determination of Soil Parameters, Selection of Soil Sampling Points and Use in Agriculture and Archaeology. AB - Fast and accurate assessment of within-field variation is essential for detecting field-wide heterogeneity and contributing to improvements in the management of agricultural lands. The goal of this paper is to provide an overview of field scale characterization by electromagnetic induction, firstly with a focus on the applications of EM38 to salinity, soil texture, water content and soil water turnover, soil types and boundaries, nutrients and N-turnover and soil sampling designs. Furthermore, results concerning special applications in agriculture, horticulture and archaeology are included. In addition to these investigations, this survey also presents a wide range of practical methods for use. Secondly, the effectiveness of conductivity readings for a specific target in a specific locality is determined by the intensity at which soil factors influence these values in relationship to the desired information. The interpretation and utility of apparent electrical conductivity (ECa) readings are highly location- and soil specific, so soil properties influencing the measurement of ECa must be clearly understood. From the various calibration results, it appears that regression constants for the relationships between ECa, electrical conductivity of aqueous soil extracts (ECe), texture, yield, etc., are not necessarily transferable from one region to another. The modelling of ECa, soil properties, climate and yield are important for identifying the location to which specific utilizations of ECa technology (e.g., ECa-texture relationships) can be appropriately applied. In general, the determination of absolute levels of ECa is frequently not possible, but it appears to be quite a robust method to detect relative differences, both spatially and temporally. Often, the use of ECa is restricted to its application as a covariate or the use of the readings in a relative sense rather than as absolute terms. PMID- 29113049 TI - Synthesis and Antibacterial Activity of Benzo[4,5]isothiazolo[2,3-a]pyrazine-6,6 dioxide Derivatives. AB - Using a routine procedure, a number of derivatives of the benzo[4,5]isothiazolo[2,3-a]pyrazine-6,6-dioxide ring system have been synthesized from readily available starting materials. A series of chalcones were synthesized, which were subsequently reacted with chlorosulfonic acid to generate chalcone sulfonyl chlorides. The chalcone sulfonyl chlorides were then treated with bromine to generate dibromo chalcone sulfonyl chlorides. These were subsequently reacted with 1,2-diaminopropane and 2-methyl-1,2-diaminopropane in boiling ethanol resulting in compounds 2-10 and 11-19 respectively, in 12-80% yields. The products were characterized by spectral analysis and the definitive structure of compound 11 was determined by X-ray crystallography. The synthesized compounds were screened for potential antibacterial properties against Bacillus subtilis, Escherichia coli, Proteus vulgaris and Staphylococcus aureus. PMID- 29113050 TI - Resistive Switching of Sub-10 nm TiO2 Nanoparticle Self-Assembled Monolayers. AB - Resistively switching devices are promising candidates for the next generation of non-volatile data memories. Such devices are up to now fabricated mainly by means of top-down approaches that apply thin films sandwiched between electrodes. Recent works have demonstrated that resistive switching (RS) is also feasible on chemically synthesized nanoparticles (NPs) in the 50 nm range. Following this concept, we developed this approach further to the sub-10 nm range. In this work, we report RS of sub-10 nm TiO2 NPs that were self-assembled into monolayers and transferred onto metallic substrates. We electrically characterized these monolayers in regard to their RS properties by means of a nanorobotics system in a scanning electron microscope, and found features typical of bipolar resistive switching. PMID- 29113051 TI - Antibacterial Activity of the Non-Cytotoxic Peptide (p-BthTX-I)2 and Its Serum Degradation Product against Multidrug-Resistant Bacteria. AB - Antimicrobial peptides can be used systemically, however, their susceptibility to proteases is a major obstacle in peptide-based therapeutic development. In the present study, the serum stability of p-BthTX-I (KKYRYHLKPFCKK) and (p-BthTX-I)2, a p-BthTX-I disulfide-linked dimer, were analyzed by mass spectrometry and analytical high-performance liquid chromatography (HPLC). Antimicrobial activities were assessed by determining their minimum inhibitory concentrations (MIC) using cation-adjusted Mueller-Hinton broth. Furthermore, biofilm eradication and time-kill kinetics were performed. Our results showed that p BthTX-I and (p-BthTX-I)2 were completely degraded after 25 min. Mass spectrometry showed that the primary degradation product was a peptide that had lost four lysine residues on its C-terminus region (des-Lys12/Lys13-(p-BthTX-I)2), which was stable after 24 h of incubation. The antibacterial activities of the peptides p-BthTX-I, (p-BthTX-I)2, and des-Lys12/Lys13-(p-BthTX-I)2 were evaluated against a variety of bacteria, including multidrug-resistant strains. Des-Lys12/Lys13-(p BthTX-I)2 and (p-BthTX-I)2 degraded Staphylococcus epidermidis biofilms. Additionally, both the peptides exhibited bactericidal activities against planktonic S. epidermidis in time-kill assays. The emergence of bacterial resistance to a variety of antibiotics used in clinics is the ultimate challenge for microbial infection control. Therefore, our results demonstrated that both peptides analyzed and the product of proteolysis obtained from (p-BthTX-I)2 are promising prototypes as novel drugs to treat multidrug-resistant bacterial infections. PMID- 29113053 TI - HPLC Analysis and Biochemical Characterization of LOX from Eschscholtzia californica Cham. AB - BACKGROUND: Plant lipoxygenases (LOXs, EC 1.13.11.12) are involved in lipid degradation, regulation of growth and development, senescence, and defence reactions. LOX represents the starting enzyme of the octadecanoid pathway. The aim of the work was to purify LOX from California poppy (Eschscholtzia californica Cham.), to determine its biochemical properties and to identify and quantify the products of LOX reaction with unsaturated fatty acids. METHODS: LOX from California poppy seedlings was purified by hydrophobic chromatography (Phenyl-Sepharose CL-4B) and by ion-exchange chromatography (Q-Sepharose). The isolated LOX was incubated with linoleic acid used as a substrate. The HPLC experiments were performed with the Agilent Technologies 1050 series HPLC system. For the preparative separation of a mixture of hydroxy fatty acids from the sample matrix, the RP-HPLC method was used (column 120-5 Nucleosil C18). Then, the NP-HPLC analysis (separation, identification, and determination) of hydroxy fatty acid isomers was carried out on a Zorbax Rx-SIL column. RESULTS: The purified LOX indicates the presence of a nontraditional plant enzyme with dual positional specificity (a ratio of 9- and 13-hydroperoxide products 1:1), a relative molecular mass of 85 kDa, a pH optimum of 6.5, an increasing activity stimulation by CaCl2 till 2 mM, and a high substrate reactivity to linoleic acid with kinetic values of KM 2.6 mM and Vmax 3.14 MUM/min/mg. CONCLUSIONS: For the first time, the LOX from California poppy seedlings was partially purified and the biochemical properties of the enzyme were analyzed. A dual positional specificity of the LOX found from California poppy seedlings is in agreement with the results obtained for LOXs isolated from other Papaveraceaes. A 1:1 ratio of 9 /13-HODE is attractive for the simultaneous investigation of both biotic stress responses (indicated by the 9-HODE marker) and the biosynthesis of jasmonic acid and jasmonates (indicated by the 13-HODE marker). PMID- 29113052 TI - Multifaceted Biomedical Applications of Functional Graphene Nanomaterials to Coated Substrates, Patterned Arrays and Hybrid Scaffolds. AB - Because of recent research advances in nanoscience and nanotechnology, there has been a growing interest in functional nanomaterials for biomedical applications, such as tissue engineering scaffolds, biosensors, bioimaging agents and drug delivery carriers. Among a great number of promising candidates, graphene and its derivatives-including graphene oxide and reduced graphene oxide-have particularly attracted plenty of attention from researchers as novel nanobiomaterials. Graphene and its derivatives, two-dimensional nanomaterials, have been found to have outstanding biocompatibility and biofunctionality as well as exceptional mechanical strength, electrical conductivity and thermal stability. Therefore, tremendous studies have been devoted to employ functional graphene nanomaterials in biomedical applications. Herein, we focus on the biological potentials of functional graphene nanomaterials and summarize some of major literature concerning the multifaceted biomedical applications of functional graphene nanomaterials to coated substrates, patterned arrays and hybrid scaffolds that have been reported in recent years. PMID- 29113054 TI - AS1041, a Novel Synthesized Derivative of Marine Natural Compound Aspergiolide A, Arrests Cell Cycle, Induces Apoptosis, and Inhibits ERK Activation in K562 Cells. AB - AS1041 is a novel synthesized anthraquinone lactone derivative of marine natural compound aspergiolide A (ASP-A) with new structure skeleton and marked cytotoxicity in cancer cells. To study its cytotoxicity in detail, we evaluated its activity on human K562 chronic myelogenous leukemia cells and investigated the related molecule mechanisms. AS1041 significantly inhibited the proliferation and colony formation of K562 cells. Moreover, AS1041 arrested cell cycle progression at G2/M phase in a concentration-dependent manner, and also caused concentration- and time-dependent induction of apoptosis. In addition, the molecular mechanisms investigation showed that AS1041 did not localize in the cellular nucleus and did not affect topoisomerases I or II. However, AS1041 could inactivate extracellular signal-regulated kinase (ERK) and contribute to AS1041 induced apoptosis. We concluded that AS1041 was cytotoxic to K562 leukemia cells and the cytotoxicity related to the cell cycle arrest, apoptosis induction, and ERK inhibition. These results implied that AS1041 was a novel derivative of ASP-A with significant cytotoxicity to chronic myelogenous leukemia cells and may have therapeutic potential for the treatment of cancer and leukemia. PMID- 29113055 TI - Total Synthesis and Metabolic Stability of Hispidulin and Its d-Labelled Derivative. AB - Hispidulin is a naturally occurring flavone known to have various Central nervous system (CNS) activities. Proposed synthetic approaches to synthesizing hispidulin have proven unsatisfactory due to their low feasibility and poor overall yields. To solve these problems, this study developed a novel scheme for synthesizing hispidulin, which had an improved overall yield as well as more concise reaction steps compared to previous methods reported. Additionally, using the same synthetic strategy, d-labelled hispidulin was synthesized to investigate its metabolic stability against human liver microsome. This work may produce new chemical entities for enriching the library of hispidulin-derived compounds. PMID- 29113056 TI - Ultrafast Spectroscopy of Fano-Like Resonance between Optical Phonon and Excitons in CdSe Quantum Dots: Dependence of Coherent Vibrational Wave-Packet Dynamics on Pump Fluence. AB - The main goal of the present work is to study the coherent phonon in strongly confined CdSe quantum dots (QDs) under varied pump fluences. The main characteristics of coherent phonons (amplitude, frequency, phase, spectrogram) of CdSe QDs under the red-edge pump of the excitonic band [1S(e)-1S3/2(h)] are reported. We demonstrate for the first time that the amplitude of the coherent optical longitudinal-optical (LO) phonon at 6.16 THz excited in CdSe nanoparticles by a femtosecond unchirped pulse shows a non-monotone dependence on the pump fluence. This dependence exhibits the maximum at pump fluence ~0.8 mJ/cm2. At the same time, the amplitudes of the longitudinal acoustic (LA) phonon mode at 0.55 THz and of the coherent wave packet of toluene at 15.6, 23.6 THz show a monotonic rise with the increase of pump fluence. The time frequency representation of an oscillating signal corresponding to LO phonons revealed by continuous wavelet transform (CWT) shows a profound destructive quantum interference close to the origin of distinct (optical phonon) and continuum-like (exciton) quasiparticles. The CWT spectrogram demonstrates a nonlinear chirp at short time delays, where the chirp sign depends on the pump pulse fluence. The CWT spectrogram reveals an anharmonic coupling between optical and acoustic phonons. PMID- 29113057 TI - 9,10-Dihydrophenanthrene with Two Spiro(dibenzocycloheptatriene) Units: A Highly Strained Caged Hydrocarbon Exhibiting Reversible Electrochromic Behavior. AB - The title dispiro hydrocarbon 1 was designed as a new electrochromic material. This multiply clamped hexaphenylethane-type electron donor was prepared from 2,2' diiodobiphenyl via biphenyl-2,2'-diylbis(dibenzotropylium) 22+ salt. X-ray analysis of 1 revealed a highly strained structure as reflected by an elongated "ethane" bond [bond length: 1.6665(17) A] and nearly eclipsed conformation. The weakened bond was cleaved upon two-electron oxidation to regenerate the deeply colored dication 22+. The reversible interconversion between 1 and 22+ is accompanied not only by a drastic color change but also by C-C bond formation/cleavage. Thus, the voltammogram showed a pair of well-separated redox waves, which is characteristic of "dynamic redox (dyrex)" behavior. The tetrahydro derivative of 1 with two units of spiro(dibenzocycloheptadiene), which suffers from more severe steric congestion, was also prepared. The crystallographically determined bond length for the central C-C bond [1.705(4) A] is greatest among the values reported for 9,9,10,10-tetraaryl-9,10 dihydrophenanthrene derivatives. PMID- 29113058 TI - Structural Health Monitoring of Above-Ground Storage Tank Floors by Ultrasonic Guided Wave Excitation on the Tank Wall. AB - There is an increasing interest in using ultrasonic guided waves to assess the structural degradation of above-ground storage tank floors. This is a non invasive and economically viable means of assessing structural degradation. Above ground storage tank floors are ageing assets which need to be inspected periodically to avoid structural failure. At present, normal-stress type transducers are bonded to the tank annular chime to generate a force field in the thickness direction of the floor and excite fundamental symmetric and asymmetric Lamb modes. However, the majority of above-ground storage tanks in use have no annular chime due to a simplified design and/or have a degraded chime due to corrosion. This means that transducers cannot be mounted on the chime to assess structural health according to the present technology, and the market share of structural health monitoring of above-ground storage tank floors using ultrasonic guided wave is thus limited. Therefore, the present study investigates the potential of using the tank wall to bond the transducer instead of the tank annular chime. Both normal and shear type transducers were investigated numerically, and results were validated using a 4.1 m diameter above-ground storage tank. The study results show shear mode type transducers bonded to the tank wall can be used to assess the structural health of the above-ground tank floors using an ultrasonic guided wave. It is also shown that for the cases studied there is a 7.4 dB signal-to-noise ratio improvement at 45 kHz for the guided wave excitation on the tank wall using shear mode transducers. PMID- 29113059 TI - First-Row Late Transition Metals for Catalytic Alkene Hydrofunctionalisation: Recent Advances in C-N, C-O and C-P Bond Formation. AB - This review provides an outline of the most noteworthy achievements in the area of C-N, C-O and C-P bond formation by hydroamination, hydroalkoxylation, hydrophosphination, hydrophosphonylation or hydrophosphinylation reaction on unactivated alkenes (including 1,2- and 1,3-dienes) promoted by first-row late transition metal catalytic systems based on manganese, iron, cobalt, nickel, copper and zinc. The relevant literature from 2009 until mid-2017 has been covered. PMID- 29113060 TI - Amidoxime Polymers for Uranium Adsorption: Influence of Comonomers and Temperature. AB - Recovering uranium from seawater has been the subject of many studies for decades, and has recently seen significant progress in materials development since the U.S. Department of Energy (DOE) has become involved. With DOE direction, the uranium uptake for amidoxime-based polymer adsorbents has more than tripled in capacity. In an effort to better understand how these new adsorbent materials behave under different environmental stimuli, several experimental and modeling based studies have been employed to investigate impacts of competing ions, salinity, pH, and other factors on uranium uptake. For this study, the effect of temperature and type of comonomer on uranium adsorption by three different amidoxime adsorbents (AF1, 38H, AI8) was examined. Experimental measurements of uranium uptake were taken in 1-L batch reactors from 10 to 40 degrees C. A chemisorption model was developed and applied in order to estimate unknown system parameters through optimization. Experimental results demonstrated that the overall uranium chemisorption process for all three materials is endothermic, which was also mirrored in the model results. Model simulations show very good agreement with the data and were able to predict the temperature effect on uranium adsorption as experimental conditions changed. This model may be used for predicting uranium uptake by other amidoxime materials. PMID- 29113061 TI - Effects of Marine Oils, Digested with Human Fluids, on Cellular Viability and Stress Protein Expression in Human Intestinal Caco-2 Cells. AB - In vitro digestion of marine oils has been reported to promote lipid oxidation, including the formation of reactive aldehydes (e.g., malondialdehyde (MDA) and 4 hydroxy-2-hexenal (HHE)). We aimed to investigate if human in vitro digestion of supplemental levels of oils from algae, cod liver, and krill, in addition to pure MDA and HHE, affect intestinal Caco-2 cell survival and oxidative stress. Cell viability was not significantly affected by the digests of marine oils or by pure MDA and HHE (0-90 MUM). Cellular levels of HSP-70, a chaperone involved in the prevention of stress-induced protein unfolding was significantly decreased (14%, 28%, and 14% of control for algae, cod and krill oil, respectively; p <= 0.05). The oxidoreductase thioredoxin-1 (Trx-1) involved in reducing oxidative stress was also lower after incubation with the digested oils (26%, 53%, and 22% of control for algae, cod, and krill oil, respectively; p <= 0.001). The aldehydes MDA and HHE did not affect HSP-70 or Trx-1 at low levels (8.3 and 1.4 MUM, respectively), whilst a mixture of MDA and HHE lowered Trx-1 at high levels (45 MUM), indicating less exposure to oxidative stress. We conclude that human digests of the investigated marine oils and their content of MDA and HHE did not cause a stress response in human intestinal Caco-2 cells. PMID- 29113062 TI - Effects of Chitooligosaccharide Coating Combined with Selected Ionic Polymers on the Stimulation of Ornithogalum saundersiae Growth. AB - Recently, agricultural and horticultural sectors have shown an increased interest in the use of biopolymers and their derivatives as growth biostimulators. So far, coating is a little known method of applying the biostimulators. Our three-year study investigated coating the bulbs of Ornithogalum saundersiae with chitooligosaccharide (COS), sodium alginate, carrageenan, gellan gum and xanthan gum. The coating method was based on the formation of polyelectrolyte complexes. The COS with 48,000 g mol-1 molecular weight was contained by means of controlled free-radical degradation. Biopolymer coatings stimulated plant growth and flowering, total chlorophyll content, total polyphenol content and the levels of nitrogen, phosphorus, potassium and boron. The plants grown from the bulbs coated with COS + gellan gum exhibited the most vigorous growth, were first to flower, showed the highest antioxidant activity (DPPH), and the greatest content of pigments, polyphenols, l-ascorbic acid, potassium, phosphorus, zinc and manganese. These results suggest COS formulated with gellan gum shows promise as a potential biostimulator of plant growth. PMID- 29113063 TI - Inhibitory Effect of Arachis hypogaea (Peanut) and Its Phenolics against Methylglyoxal-Derived Advanced Glycation End Product Toxicity. AB - Methylglyoxal (MGO) is a highly reactive dicarbonyl compound that causes endothelial dysfunction and plays important roles in the development of diabetic complications. Peanuts are rich in energy, minerals, and antioxidants. Here, we report the potential beneficial effects of peanuts, and particularly the phenolic contents, against MGO-mediated cytotoxicity. Firstly, we optimized the extraction conditions for maximum yield of phenolics from peanuts by examining different processing methods and extraction solvents. To estimate the phenolic contents of peanut extracts, a simultaneous analysis method was developed and validated by ultra-high-performance liquid chromatography-tandem mass spectrometry. We found that roasted peanuts and their 80% methanol extracts showed the highest amount of total phenolics. Secondly, we evaluated the inhibitory effects of phenolics and peanut extracts against MGO-mediated cytotoxicity. Phenolics and peanut extracts were observed to inhibit advanced glycation end product (AGE) formation as well as to break preformed AGEs. Furthermore, pretreatment with peanut extracts significantly inhibited MGO-induced cell death and reactive oxygen species production in human umbilical vein endothelial cells. Peanut extracts prevented MGO-induced apoptosis by increasing Bcl-2 expression and decreasing Bax expression, and MGO-mediated activation of mitogen-activated protein kinases (MAPKs). In conclusion, the constituents of peanuts may prevent endothelial dysfunction and diabetic complications. PMID- 29113064 TI - Inhibition of Cyclic Adenosine Monophosphate-Specific Phosphodiesterase by Various Food Plant-Derived Phytotherapeutic Agents. AB - Background: Phosphodiesterases (PDEs) play a major role in the regulation of cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP) mediated pathways. Their inhibitors exhibit anti-inflammatory, vasodilatory and antithrombotic effects. Therefore, consumption of foods with PDE-inhibiting potential may possess beneficial influence on the risk of cardiovascular diseases. Methods: Four plant extracts (Arbutus unedo, Camellia sinensis, Cynara scolymus, Zingiber officinale) with promising ingredient profiles and physiological effects were tested for their ability to inhibit cAMP-specific PDE in vitro in a radioactive assay. Results: Strawberry tree fruit (Arbutus unedo) and tea (Camellia sinensis) extracts did not inhibit PDE markedly. Alternatively, artichoke (Cynara scolymus) extract had a significant inhibitory influence on PDE activity (IC50 = 0.9 +/- 0.1 mg/mL) as well as its flavone luteolin (IC50 = 41 +/ 10 MUM) and 3,4-dicaffeoylquinic acid (IC50 > 1.0 mM). Additionally, the ginger (Zingiber officinale) extract and one of its constituents, [6]-gingerol, significantly inhibited PDE (IC50 = 1.7 +/- 0.2 mg/mL and IC50 > 1.7 mM, respectively). Crude fractionation of ginger extract showed that substances responsible for PDE inhibition were in the lipoid fraction (IC50 = 455 +/- 19 MUg/mL). Conclusions: A PDE-inhibitory effect was shown for artichoke and ginger extract. Whether PDE inhibition in vivo can be achieved through ingestion of artichoke or ginger extracts leading to physiological effects concerning cardiovascular health should be addressed in future research. PMID- 29113065 TI - Lanthanide Photoluminescence in Heterometallic Polycyanidometallate-Based Coordination Networks. AB - Solid-state functional luminescent materials arouse an enormous scientific interest due to their diverse applications in lighting, display devices, photonics, optical communication, low energy scintillation, optical storage, light conversion, or photovoltaics. Among all types of solid luminophors, the emissive coordination polymers, especially those based on luminescent trivalent lanthanide ions, exhibit a particularly large scope of light-emitting functionalities, fruitfully investigated in the aspects of chemical sensing, display devices, and bioimaging. Here, we present the complete overview of one of the promising families of photoluminescent coordination compounds, that are heterometallic d-f cyanido-bridged networks composed of lanthanide(3+) ions connected through cyanide bridges with polycyanidometallates of d-block metal ions. We are showing that the combination of cationic lanthanide complexes of selected inorganic and organic ligands with anionic homoligand [M(CN)x]n- (x = 2, 4, 6 and 8) or heteroligand [M(L)(CN)4]2- (L = bidentate organic ligand, M = transition metal ions) anions is the efficient route towards the emissive coordination networks revealing important optical properties, including 4f-metal centred visible and near-infrared emission sensitized through metal-to-metal and/or ligand-to-metal energy transfer processes, and multi-coloured photoluminescence switchable by external stimuli such as excitation wavelength, temperature, or pressure. PMID- 29113066 TI - Polyphenol-Rich Dry Common Beans (Phaseolus vulgaris L.) and Their Health Benefits. AB - Polyphenols are plant metabolites with potent anti-oxidant properties, which help to reduce the effects of oxidative stress-induced dreaded diseases. The evidence demonstrated that dietary polyphenols are of emerging increasing scientific interest due to their role in the prevention of degenerative diseases in humans. Possible health beneficial effects of polyphenols are based on the human consumption and their bioavailability. Common beans (Phaseolus vulgaris L.) are a greater source of polyphenolic compounds with numerous health promoting properties. Polyphenol-rich dry common beans have potential effects on human health, and possess anti-oxidant, anti-diabetic, anti-obesity, anti-inflammatory and anti-mutagenic and anti-carcinogenic properties. Based on the studies, the current comprehensive review aims to provide up-to-date information on the nutritional compositions and health-promoting effect of polyphenol-rich common beans, which help to explore their therapeutic values for future clinical studies. Investigation of common beans and their impacts on human health were obtained from various library databases and electronic searches (Science Direct PubMed, and Google Scholar). PMID- 29113067 TI - Omics Approaches for Identifying Physiological Adaptations to Genome Instability in Aging. AB - DNA damage causally contributes to aging and age-related diseases. The declining functioning of tissues and organs during aging can lead to the increased risk of succumbing to aging-associated diseases. Congenital syndromes that are caused by heritable mutations in DNA repair pathways lead to cancer susceptibility and accelerated aging, thus underlining the importance of genome maintenance for withstanding aging. High-throughput mass-spectrometry-based approaches have recently contributed to identifying signalling response networks and gaining a more comprehensive understanding of the physiological adaptations occurring upon unrepaired DNA damage. The insulin-like signalling pathway has been implicated in a DNA damage response (DDR) network that includes epidermal growth factor (EGF)-, AMP-activated protein kinases (AMPK)- and the target of rapamycin (TOR)-like signalling pathways, which are known regulators of growth, metabolism, and stress responses. The same pathways, together with the autophagy-mediated proteostatic response and the decline in energy metabolism have also been found to be similarly regulated during natural aging, suggesting striking parallels in the physiological adaptation upon persistent DNA damage due to DNA repair defects and long-term low-level DNA damage accumulation occurring during natural aging. These insights will be an important starting point to study the interplay between signalling networks involved in progeroid syndromes that are caused by DNA repair deficiencies and to gain new understanding of the consequences of DNA damage in the aging process. PMID- 29113069 TI - Characterization and Differentiation of Petroleum-Derived Products by E-Nose Fingerprints. AB - Characterization of petroleum-derived products is an area of continuing importance in environmental science, mainly related to fuel spills. In this study, a non-separative analytical method based on E-Nose (Electronic Nose) is presented as a rapid alternative for the characterization of several different petroleum-derived products including gasoline, diesel, aromatic solvents, and ethanol samples, which were poured onto different surfaces (wood, cork, and cotton). The working conditions about the headspace generation were 145 degrees C and 10 min. Mass spectroscopic data (45-200 m/z) combined with chemometric tools such as hierarchical cluster analysis (HCA), later principal component analysis (PCA), and finally linear discriminant analysis (LDA) allowed for a full discrimination of the samples. A characteristic fingerprint for each product can be used for discrimination or identification. The E-Nose can be considered as a green technique, and it is rapid and easy to use in routine analysis, thus providing a good alternative to currently used methods. PMID- 29113068 TI - UVA, UVB Light, and Methyl Jasmonate, Alone or Combined, Redirect the Biosynthesis of Glucosinolates, Phenolics, Carotenoids, and Chlorophylls in Broccoli Sprouts. AB - Broccoli sprouts contain health-promoting phytochemicals that can be enhanced by applying ultraviolet light (UV) or phytohormones. The separate and combined effects of methyl jasmonate (MJ), UVA, or UVB lights on glucosinolate, phenolic, carotenoid, and chlorophyll profiles were assessed in broccoli sprouts. Seven-day old broccoli sprouts were exposed to UVA (9.47 W/m2) or UVB (7.16 W/m2) radiation for 120 min alone or in combination with a 25 uM MJ solution, also applied to sprouts without UV supplementation. UVA + MJ and UVB + MJ treatments increased the total glucosinolate content by ~154% and ~148%, respectively. MJ induced the biosynthesis of indole glucosinolates, especially neoglucobrassicin (~538%), showing a synergistic effect with UVA stress. UVB increased the content of aliphatic and indole glucosinolates, such as glucoraphanin (~78%) and 4-methoxy glucobrassicin (~177%). UVA increased several phenolics such as gallic acid (~57%) and a kaempferol glucoside (~25.4%). MJ treatment decreased most phenolic levels but greatly induced accumulation of 5-sinapoylquinic acid (~239%). MJ treatments also reduced carotenoid and chlorophyll content, while UVA increased lutein (~23%), chlorophyll b (~31%), neoxanthin (~34%), and chlorophyll a (~67%). Results indicated that UV- and/or MJ-treated broccoli sprouts redirect the carbon flux to the biosynthesis of specific glucosinolates, phenolics, carotenoids, and chlorophylls depending on the type of stress applied. PMID- 29113070 TI - Electronic Cigarette Use in Students and Its Relation with Tobacco-Smoking: A Cross-Sectional Analysis of the i-Share Study. AB - While young adults often try e-cigarettes, little is known about its use and the reasons for experimentation, particularly in relation with tobacco-smoking. In 2016, data were collected from 2720 French-speaking students participating in a web-based study on students' health: the internet-based Students Health Research Enterprise (i-Share) project. Univariate analyses and multivariable logistic regressions were performed to study the relationship between e-cigarette use and smoking status. Two out of five students declared having tried e-cigarettes and 3.6% were current users. Former smokers were more likely than current smokers to use e-cigarettes currently. Among those who had never smoked, 13.5% had tried e cigarettes. Very few (0.3%) were current users, alternating e-liquids with and without nicotine. The three main reasons for trying e-cigarettes were curiosity, offer to try by someone, and attractiveness of e-liquid flavors. Among current smokers, previous attempts to quit smoking and a strong desire to stop tobacco were reported more in e-cigarette current users than in former users. In this large sample of French students, findings were consistent with the possibility that e-cigarettes might be used as smoking cessation or reduction aids by some young adults whereas other young never-smokers could be exposed to nicotine. PMID- 29113071 TI - Development of 1,2,3-Triazole-Based Sphingosine Kinase Inhibitors and Their Evaluation as Antiproliferative Agents. AB - Two series of N-(aryl)-1-(hydroxyalkyl)pyrrolidine-2-carboxamides (2a-2g and 3a 3g) and 1,4-disubstituted 1,2,3-triazoles (5a-5h and 8a-8h) were synthesized. All the compounds, containing a lipophilic tail and a polar headgroup, were evaluated as sphingosine kinase (SphK) inhibitors by assessing their ability to interfere with the acetylcholine (Ach) induced relaxation of aortic rings pre-contracted with phenylephrine. Moreover, their antiproliferative activity was tested on several cell lines expressing both SphK1 and SphK2. Compounds 5h and 8f, identified as the most efficient antiproliferative agents, showed a different selectivity profile, with 8f being selective for SphK1. PMID- 29113073 TI - An Ontology-Based Reasoning Framework for Querying Satellite Images for Disaster Monitoring. AB - This paper presents a framework in which satellite images are classified and augmented with additional semantic information to enable queries about what can be found on the map at a particular location, but also about paths that can be taken. This is achieved by a reasoning framework based on qualitative spatial reasoning that is able to find answers to high level queries that may vary on the current situation. This framework called SemCityMap, provides the full pipeline from enriching the raw image data with rudimentary labels to the integration of a knowledge representation and reasoning methods to user interfaces for high level querying. To illustrate the utility of SemCityMap in a disaster scenario, we use an urban environment-central Stockholm-in combination with a flood simulation. We show that the system provides useful answers to high-level queries also with respect to the current flood status. Examples of such queries concern path planning for vehicles or retrieval of safe regions such as "find all regions close to schools and far from the flooded area". The particular advantage of our approach lies in the fact that ontological information and reasoning is explicitly integrated so that queries can be formulated in a natural way using concepts on appropriate level of abstraction, including additional constraints. PMID- 29113072 TI - Effects of 1.8 GHz Radiofrequency Fields on the Emotional Behavior and Spatial Memory of Adolescent Mice. AB - The increasing use of mobile phones by teenagers has raised concern about the cognitive effects of radiofrequency (RF) fields. In this study, we investigated the effects of 4-week exposure to a 1.8 GHz RF field on the emotional behavior and spatial memory of adolescent male mice. Anxiety-like behavior was evaluated by open field test (OFT) and elevated plus maze (EPM) test, while depression-like behavior was evaluated by sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST). The spatial learning and memory ability were evaluated by Morris water maze (MWM) experiments. The levels of amino acid neurotransmitters were determined by liquid chromatography-mass spectrometry (LC MS). The histology of the brain was examined by hematoxylin-eosin (HE) staining. It was found that the depression-like behavior, spatial memory ability and histology of the brain did not change obviously after RF exposure. However, the anxiety-like behavior increased in mice, while, the levels of gamma-aminobutyric acid (GABA) and aspartic acid (Asp) in cortex and hippocampus significantly decreased after RF exposure. These data suggested that RF exposure under these conditions do not affect the depression-like behavior, spatial memory and brain histology in adolescent male mice, but it may however increase the level of anxiety, and GABA and Asp were probably involved in this effect. PMID- 29113074 TI - Simultaneous Determination and Investigation of Nine Fungicides in Fruits Using Diethylenetriamine-Functional Magnetic Core-Shell Polymer Modified Graphene Oxide as an Efficient Adsorbent Coupled to UPLC-HRMS. AB - In this study, diethylenetriamine-functional magnetic core-shell polymer modified graphene oxide (DETA-MPs-GO) was prepared via precipitation polymerization and amidation reaction, and it was characterized by transmission electron microscopy (TEM), Fourier-transformed infrared spectroscopy (FTIR), and X-ray diffractometer (XRD). Subsequently, a magnetic solid-phase extraction (MSPE) procedure was applied to the as-synthesized DETA-MPs-GO for the detection of nine fungicides in fruit samples, prior to ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). The homogenized fruit samples, spiked with D labelled internal standards, were firstly extracted by 5 mL of acetonitrile twice and then purified by DETA-MPs-GO adsorbents. The optimization of the adsorption and elution conditions of DETA-MPs-GO toward fungicides was carried out to attain a satisfactory adsorption performance and desorption efficiency. The adsorption mechanism was carefully investigated, and the results revealed that a synergistic adsorption mechanism, including hydrogen bond and a pi-pi stacking interaction, was confirmed. Moreover, the limits of quantitation (LOQs) of the proposed approach were in the range of 0.01 to 0.30 MUg/kg under the optimum conditions. The average recoveries at three spiking levels were 84.9% to 105.2%, with relative standard deviations (RSDs) varying from 0.8% to 8.2% (n = 6). The developed method was successfully utilized for the screening and detection of fungicides in 81 fruit samples purchased from markets. A detailed survey was carried out about the concentration distribution, types of fungicides, and combined use of fungicides in different fruits. PMID- 29113075 TI - Dietary Zinc Acts as a Sleep Modulator. AB - While zinc is known to be important for many biological processes in animals at a molecular and physiological level, new evidence indicates that it may also be involved in the regulation of sleep. Recent research has concluded that zinc serum concentration varies with the amount of sleep, while orally administered zinc increases the amount and the quality of sleep in mice and humans. In this review, we provide an exhaustive study of the literature connecting zinc and sleep, and try to evaluate which molecular mechanism is likely to be involved in this phenomenon. A better understanding should provide critical information not only about the way zinc is related to sleep but also about how sleep itself works and what its real function is. PMID- 29113076 TI - Gene Expression Analysis of the Effect of Ischemic Infarction in Whole Blood. AB - Given the abundance of stroke patients and deaths from stroke worldwide, many studies concerning the aftermath of stroke are being carried out. To reveal the precise effect of ischemic infarction, we conducted a comprehensive gene expression analysis. Alongside a middle cerebral artery occlusion (MCAO) Sprague Dawley rat model, we used a group undergoing sham surgery for comparison, which was the same as MCAO surgery but without blood vessel occlusion. Subsequently, infarction of the brains of MCAO-treated rats occurred, but did not occur in the sham-treated rats. Using whole blood, we carried out DNA microarray analysis, revealing the gene expression alterations caused by stroke. Downregulation of immune pathways and cluster of differentiation (CD) molecules indicated immunodepression. By conducting miRNA microarray analysis, we extracted seven miRNAs as significantly regulated: miR-107-5p, miR-383-5p, miR-24-1-5p, mir-191b, miR-196b-5p, and miR-3552 were upregulated, and mir-194-1 was downregulated. Among these seven miRNAs, three had one target mRNA each that was extracted as differentially expressed, and the expression levels of all pairs were inversely correlated. This indicates the occurrence of miRNA-mRNA regulatory systems in blood: between miR-107-5p and H2A histone family member Z (H2afz), miR-196b-5p and protein tyrosine phosphatase receptor type C (Ptprc), and miR-3552 and serine/arginine-rich splicing factor 2 (Srsf2). Moreover, six miRNAs had matching human miRNAs with similar sequences, which are potential human stroke biomarkers. PMID- 29113078 TI - Integrated Evaluation of Reliability and Power Consumption of Wireless Sensor Networks. AB - Power consumption is a primary interest in Wireless Sensor Networks (WSNs), and a large number of strategies have been proposed to evaluate it. However, those approaches usually neither consider reliability issues nor the power consumption of applications executing in the network. A central concern is the lack of consolidated solutions that enable us to evaluate the power consumption of applications and the network stack also considering their reliabilities. To solve this problem, we introduce a fully automatic solution to design power consumption aware WSN applications and communication protocols. The solution presented in this paper comprises a methodology to evaluate the power consumption based on the integration of formal models, a set of power consumption and reliability models, a sensitivity analysis strategy to select WSN configurations and a toolbox named EDEN to fully support the proposed methodology. This solution allows accurately estimating the power consumption of WSN applications and the network stack in an automated way. PMID- 29113077 TI - The Oligomeric Form of the Escherichia coli Dps Protein Depends on the Availability of Iron Ions. AB - The Dps protein of Escherichia coli, which combines ferroxidase activity and the ability to bind DNA, is effectively used by bacteria to protect their genomes from damage. Both activities depend on the integrity of this multi-subunit protein, which has an inner cavity for iron oxides; however, the diversity of its oligomeric forms has only been studied fragmentarily. Here, we show that iron ions stabilize the dodecameric form of Dps. This was found by electrophoretic fractionation and size exclusion chromatography, which revealed several oligomers in highly purified protein samples and demonstrated their conversion to dodecamers in the presence of 1 mM Mohr's salt. The transmission electron microscopy data contradicted the assumption that the stabilizing effect is given by the optimal core size formed in the inner cavity of Dps. The charge state of iron ions was evaluated using Mossbauer spectroscopy, which showed the presence of Fe3O4, rather than the expected Fe2O3, in the sample. Assuming that Fe2+ can form additional inter-subunit contacts, we modeled the interaction of FeO and Fe2O3 with Dps, but the binding sites with putative functionality were predicted only for Fe2O3. The question of how the dodecameric form can be stabilized by ferric oxides is discussed. PMID- 29113079 TI - Synthesis of Ferrofluids Made of Iron Oxide Nanoflowers: Interplay between Carrier Fluid and Magnetic Properties. AB - Ferrofluids are nanomaterials consisting of magnetic nanoparticles that are dispersed in a carrier fluid. Their physical properties, and hence their field of application are determined by intertwined compositional, structural, and magnetic characteristics, including interparticle magnetic interactions. Magnetic nanoparticles were prepared by thermal decomposition of iron(III) chloride hexahydrate (FeCl3.6H2O) in 2-pyrrolidone, and were then dispersed in two different fluids, water and polyethylene glycol 400 (PEG). A number of experimental techniques (especially, transmission electron microscopy, Mossbauer spectroscopy and superconducting quantum interference device (SQUID) magnetometry) were employed to study both the as-prepared nanoparticles and the ferrofluids. We show that, with the adopted synthesis parameters of temperature and FeCl3 relative concentration, nanoparticles are obtained that mainly consist of maghemite and present a high degree of structural disorder and strong spin canting, resulting in a low saturation magnetization (~45 emu/g). A remarkable feature is that the nanoparticles, ultimately due to the presence of 2 pyrrolidone at their surface, are arranged in nanoflower-shape structures, which are substantially stable in water and tend to disaggregate in PEG. The different arrangement of the nanoparticles in the two fluids implies a different strength of dipolar magnetic interactions, as revealed by the analysis of their magnetothermal behavior. The comparison between the magnetic heating capacities of the two ferrofluids demonstrates the possibility of tailoring the performances of the produced nanoparticles by exploiting the interplay with the carrier fluid. PMID- 29113081 TI - Coverage Probability and Area Spectral Efficiency of Clustered Linear Unmanned Vehicle Sensor Networks. AB - In this paper, we consider clustered unmanned vehicle (UV) sensor networks for swarm sensing applications in a linear structure such as highway, tunnel, underwater pipelines, power lines, and international border. We assume that the linear UV sensor networks follow Thomas cluster process (TCP), in which the cluster locations are modelled by Poisson point process (PPP), while the cluster members (UVs) are normally distributed around their cluster centers. We focus on communications between UVs within a cluster such as local sensing data transfer or swarm coordination, where multiple UV pairs can share the same frequency band simultaneously. Thus, in the presence of co-channel interference both from the same cluster and the other clusters, we study the coverage and area spectral efficiency of the clustered UV sensor networks in a linear topology. PMID- 29113080 TI - Biophysical and In Silico Studies of the Interaction between the Anti-Viral Agents Acyclovir and Penciclovir, and Human Serum Albumin. AB - Acyclovir (ACV) and penciclovir (PNV) have been commonly used during the last few decades as potent antiviral agents, especially for the treatment of herpes virus infections. In the present research their binding properties with human serum albumin (HSA) were studied using different advanced spectroscopic and in-silico methods. The interactions between ACV/PNV and HSA at the three investigated temperatures revealed a static type of binding. Extraction of the thermodynamic parameters of the ACV-HSA and PNV-HSA systems from the measured spectrofluorimetric data demonstrated spontaneous interactions with an enthalpy change (?H0) of -1.79 +/- 0.29 and -4.47 +/- 0.51 kJ.mol-1 for ACV and PNV, respectively. The entropy change (?S0) of 79.40 +/- 0.95 and 69.95 +/- 1.69 J.mol 1.K-1 for ACV and PNV, respectively, hence supported a potential contribution of electrostatic binding forces to the ACV-HSA and PNV-HSA systems. Putative binding of ACV/PNV to HSA, using previously reported site markers, showed that ACV/PNV were bound to HSA within subdomains IIA and IIIA (Sudlow sites I and II). Further confirmation was obtained through molecular docking studies of ACV-HSA and PNV HSA binding, which confirmed the binding site of ACV/PNV with the most stable configurations of ACV/PNV within the HSA. These ACV/PNV conformers were shown to have free energies of -25.61 and -22.01 kJ.mol-1 for ACV within the HSA sites I and II and -22.97 and -26.53 kJ.mol-1 for PNV in HSA sites I and II, with hydrogen bonding and electrostatic forces being the main binding forces in such conformers. PMID- 29113083 TI - Dimension-Factorized Range Migration Algorithm for Regularly Distributed Array Imaging. AB - The two-dimensional planar MIMO array is a popular approach for millimeter wave imaging applications. As a promising practical alternative, sparse MIMO arrays have been devised to reduce the number of antenna elements and transmitting/receiving channels with predictable and acceptable loss in image quality. In this paper, a high precision three-dimensional imaging algorithm is proposed for MIMO arrays of the regularly distributed type, especially the sparse varieties. Termed the Dimension-Factorized Range Migration Algorithm, the new imaging approach factorizes the conventional MIMO Range Migration Algorithm into multiple operations across the sparse dimensions. The thinner the sparse dimensions of the array, the more efficient the new algorithm will be. Advantages of the proposed approach are demonstrated by comparison with the conventional MIMO Range Migration Algorithm and its non-uniform fast Fourier transform based variant in terms of all the important characteristics of the approaches, especially the anti-noise capability. The computation cost is analyzed as well to evaluate the efficiency quantitatively. PMID- 29113082 TI - TGF-beta1/Smad3 Signaling Pathway Mediates T-2 Toxin-Induced Decrease of Type II Collagen in Cultured Rat Chondrocytes. AB - T-2 toxin can cause damage to the articular cartilage, but the molecular mechanism remains unclear. By employing the culture of rat chondrocytes, we investigated the effect of the TGF-beta1/Smad3 signaling pathway on the damage to chondrocytes induced by T-2 toxin. It was found that T-2 toxin could reduce cell viability and increased the number of apoptotic cells when compared with the control group. After the addition of the T-2 toxin, the production of type II collagen was reduced at mRNA and protein levels, while the levels of TGF-beta1, Smad3, ALK5, and MMP13 were upregulated. The production of the P-Smad3 protein was also increased. Inhibitors of TGF-beta1 and Smad3 were able to reverse the effect of the T-2 toxin on the protein level of above-mentioned signaling molecules. The T-2 toxin could promote the level of MMP13 via the stimulation of TGF-beta1 signaling in chondrocytes, resulting in the downregulation of type II collagen and chondrocyte damage. Smad3 may be involved in the degradation of type II collagen, but the Smad3 has no connection with the regulation of MMP13 level. This study provides a new clue to elucidate the mechanism of T-2 toxin-induced chondrocyte damage. PMID- 29113084 TI - Synergy Effect of Combining Fluorescence and Mid Infrared Fiber Spectroscopy for Kidney Tumor Diagnostics. AB - Matching pairs of tumor and non-tumor kidney tissue samples of four patients were investigated ex vivo using a combination of two methods, attenuated total reflection mid infrared spectroscopy and fluorescence spectroscopy, through respectively prepared and adjusted fiber probes. In order to increase the data information content, the measurements on tissue samples in both methods were performed in the same 31 preselected positions. Multivariate data analysis revealed a synergic effect of combining the two methods for the diagnostics of kidney tumor compared to individual techniques. PMID- 29113085 TI - Centralized Multi-Sensor Square Root Cubature Joint Probabilistic Data Association. AB - This paper focuses on the tracking problem of multiple targets with multiple sensors in a nonlinear cluttered environment. To avoid Jacobian matrix computation and scaling parameter adjustment, improve numerical stability, and acquire more accurate estimated results for centralized nonlinear tracking, a novel centralized multi-sensor square root cubature joint probabilistic data association algorithm (CMSCJPDA) is proposed. Firstly, the multi-sensor tracking problem is decomposed into several single-sensor multi-target tracking problems, which are sequentially processed during the estimation. Then, in each sensor, the assignment of its measurements to target tracks is accomplished on the basis of joint probabilistic data association (JPDA), and a weighted probability fusion method with square root version of a cubature Kalman filter (SRCKF) is utilized to estimate the targets' state. With the measurements in all sensors processed CMSCJPDA is derived and the global estimated state is achieved. Experimental results show that CMSCJPDA is superior to the state-of-the-art algorithms in the aspects of tracking accuracy, numerical stability, and computational cost, which provides a new idea to solve multi-sensor tracking problems. PMID- 29113087 TI - An Energy Efficient Adaptive Sampling Algorithm in a Sensor Network for Automated Water Quality Monitoring. AB - Power management is crucial in the monitoring of a remote environment, especially when long-term monitoring is needed. Renewable energy sources such as solar and wind may be harvested to sustain a monitoring system. However, without proper power management, equipment within the monitoring system may become nonfunctional and, as a consequence, the data or events captured during the monitoring process will become inaccurate as well. This paper develops and applies a novel adaptive sampling algorithm for power management in the automated monitoring of the quality of water in an extensive and remote aquatic environment. Based on the data collected on line using sensor nodes, a data-driven adaptive sampling algorithm (DDASA) is developed for improving the power efficiency while ensuring the accuracy of sampled data. The developed algorithm is evaluated using two distinct key parameters, which are dissolved oxygen (DO) and turbidity. It is found that by dynamically changing the sampling frequency, the battery lifetime can be effectively prolonged while maintaining a required level of sampling accuracy. According to the simulation results, compared to a fixed sampling rate, approximately 30.66% of the battery energy can be saved for three months of continuous water quality monitoring. Using the same dataset to compare with a traditional adaptive sampling algorithm (ASA), while achieving around the same Normalized Mean Error (NME), DDASA is superior in saving 5.31% more battery energy. PMID- 29113086 TI - Iron Deficiency Anemia, Not Iron Deficiency, Is Associated with Reduced Attention in Healthy Young Women. AB - Women of reproductive age are at increased risk for iron deficiency (ID) and iron deficiency anemia (IDA), with both implicated in decreased cognitive function (CF). Obesity may complicate this association via inflammatory-mediated ferritin elevation. This cross-sectional study examined the association between hematological iron status (iron replete (IR), ID or IDA) and CF in healthy, young (18-35 years) women of normal-weight (NW: BMI 18.5-24.9 kg/m2) or obese-weight (OB: BMI >30 kg/m2). Participants completed a validated, computer-based cognition assessment evaluating impulsivity, attention, information processing, memory and executive function; CF reported as z-scores (mean +/- SD). Iron status and CF were compared between groups via ANOVA, with adjustment for potential confounders (BMI, physical activity, C-reactive protein) via ANCOVA. A total of 157 NW and 142 OB women (25.8 +/- 5.1 years) participated. Prevalence of ID and IDA were 14% and 6% respectively, with no significant difference between NW and OB groups. Women with IDA scored significantly lower on attention (although within normal range; +/-1 z-score), compared to ID (IDA: -0.75 +/- 1.89; ID: 0.53 +/- 1.37; p = 0.004) but not IR (0.03 +/- 1.33, p = 0.21) groups; there were no significant differences between ID and IR groups (p = 0.34). Adjustment for confounders did not significantly alter these results. In conclusion, women with IDA showed significantly reduced attention compared to women with ID. PMID- 29113088 TI - Oxidative Stress in Cardiovascular Diseases: Involvement of Nrf2 Antioxidant Redox Signaling in Macrophage Foam Cells Formation. AB - Oxidative stress is an important risk factor contributing to the pathogenesis of cardiovascular diseases. Oxidative stress that results from excessive reactive oxygen species (ROS) production accounts for impaired endothelial function, a process which promotes atherosclerotic lesion or fatty streaks formation (foam cells). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in cellular redox homeostasis. Upon exposure to oxidative stress, Nrf2 is dissociated from its inhibitor Keap-1 and translocated into the nucleus, where it results in the transcriptional activation of cell defense genes. Nrf2 has been demonstrated to be involved in the protection against foam cells formation by regulating the expression of antioxidant proteins (HO-1, Prxs, and GPx1), ATP-binding cassette (ABC) efflux transporters (ABCA1 and ABCG1) and scavenger receptors (scavenger receptor class B (CD36), scavenger receptor class A (SR-A) and lectin-type oxidized LDL receptor (LOX-1)). However, Nrf2 has also been reported to exhibit pro-atherogenic effects. A better understanding on the mechanism of Nrf2 in oxidative stress-induced cardiac injury, as well as the regulation of cholesterol uptake and efflux, are required before it can serve as a novel therapeutic target for cardiovascular diseases prevention and treatment. PMID- 29113089 TI - Predicting Physical Activity and Healthy Nutrition Behaviors Using Social Cognitive Theory: Cross-Sectional Survey among Undergraduate Students in Chongqing, China. AB - (1) Background: Generally suggested public health measures to reduce obesity were to limit television (TV) viewing, enhance daily physical activities, enable the consumption of fruit and vegetables, and reduce sugar-sweetened beverage intake. This study analyzed the extent to which selected social cognitive theory constructs can predict these behaviors among Chinese undergraduate students. (2) Methods: This cross-sectional study included 1976 undergraduate students from six universities in Chongqing, China. A self-administered five-point Likert common physical activity and nutrition behavior scale based on social cognitive theory was utilized. (3) Results: This study included 687 (34.77%) males and 1289 (65.23%) females. A total of 60.14% of the students engaged in exercise for less than 30 min per day. Approximately 16.5%of the participants spent at least 4 h watching TV and sitting in front of a computer daily. Approximately 79% of the participants consumed less than five cups of fruit and vegetables daily. Undergraduate students who had high self-efficacy scores had more leisure time physical activities. Those who have high expectation scores had considerable time watching TV and sitting in front of a computer. Undergraduate students who had high expectation and self-efficacy scores had substantially low consumption of sugar-sweetened beverages. Those who had high self-efficacy scores consumed considerable amounts of fruit and vegetables. Furthermore, the type of university, BMI group, gender, age, lack of siblings, and grade level were associated with the aforementioned four behaviors. (4) Conclusion: Physical inactivity and unhealthy nutrition behaviors are common among undergraduate students. This study used social cognitive theory to provide several implications for limiting the TV viewing, enhancing daily physical activities, consuming fruit and vegetables, and reducing sugar-sweetened beverage intake among undergraduate students. PMID- 29113090 TI - The Advent of Indium Selenide: Synthesis, Electronic Properties, Ambient Stability and Applications. AB - Among the various two-dimensional semiconductors, indium selenide has recently triggered the interest of scientific community, due to its band gap matching the visible region of the electromagnetic spectrum, with subsequent potential applications in optoelectronics and especially in photodetection. In this feature article, we discuss the main issues in the synthesis, the ambient stability and the application capabilities of this novel class of two-dimensional semiconductors, by evidencing open challenges and pitfalls. In particular, we evidence how the growth of single crystals with reduced amount of Se vacancies is crucial in the road map for the exploitation of indium selenide in technology through ambient-stable nanodevices with outstanding values of both mobility of charge carriers and ON/OFF ratio. The surface chemical reactivity of the InSe surface, as well as applications in the fields of broadband photodetection, flexible electronics and solar energy conversion are also discussed. PMID- 29113091 TI - Linking Compositional and Functional Predictions to Decipher the Biogeochemical Significance in DFAA Turnover of Abundant Bacterioplankton Lineages in the North Sea. AB - Deciphering the ecological traits of abundant marine bacteria is a major challenge in marine microbial ecology. In the current study, we linked compositional and functional predictions to elucidate such traits for abundant bacterioplankton lineages in the North Sea. For this purpose, we investigated entire and active bacterioplankton composition along a transect ranging from the German Bight to the northern North Sea by pyrotag sequencing of bacterial 16S rRNA genes and transcripts. Functional profiles were inferred from 16S rRNA data using Tax4Fun. Bacterioplankton communities were dominated by well-known marine lineages including clusters/genera that are affiliated with the Roseobacter group and the Flavobacteria. Variations in community composition and function were significantly explained by measured environmental and microbial properties. Turnover of dissolved free amino acids (DFAA) showed the strongest correlation to community composition and function. We applied multinomial models, which enabled us to identify bacterial lineages involved in DFAA turnover. For instance, the genus Planktomarina was more abundant at higher DFAA turnover rates, suggesting its vital role in amino acid degradation. Functional predictions further indicated that Planktomarina is involved in leucine and isoleucine degradation. Overall, our results provide novel insights into the biogeochemical significance of abundant bacterioplankton lineages in the North Sea. PMID- 29113092 TI - Recipient HLA-G +3142 CC Genotype and Concentrations of Soluble HLA-G Impact on Occurrence of CMV Infection after Living-Donor Kidney Transplantation. AB - The expression modulation of the immunosuppressive non-classical Human leukocyte antigen-G (HLA-G) molecule and its soluble isoforms is an immune evasion strategy being deployed by cytomegalovirus (CMV). The +3142 C>G single nucleotide polymorphism (SNP) located within the 3' untranslated region (3'UTR) is of crucial importance for the regulation of HLA-G expression. Therefore, we analyzed the influence of the +3142 C>G HLA-G SNP on the occurrence of CMV infection in a cohort of 178 living-donor kidney recipients and their 178 corresponding donors. In addition, soluble HLA-G (sHLA-G) levels were quantified before and after transplantation. The presence of the HLA-G +3142 CC genotype in recipients, but not donors of our cohort as along with elevated sHLA-G levels (>= 6.1 ng/mL) were associated with higher susceptibility to CMV infection after transplantation. Our results provided evidence that i) HLA-G is implicated in the establishment of CMV after living-donor kidney transplantation and ii) recipient HLA-G +3142 CC genotype and sHLA-G concentration levels could represent important predictive risk markers for CMV infection. PMID- 29113093 TI - View Point: Semaphorin-3E: An Emerging Modulator of Natural Killer Cell Functions? AB - Semaphorin-3E (Sema-3E) is a member of a large family of proteins originally identified as axon guidance cues in neural development. It is expressed in different cell types, such as immune cells, cancer cells, neural cells, and epithelial cells. Subsequently, dys-regulation of Sema-3E expression has been reported in various biological processes that range from cancers to autoimmune and allergic diseases. Recent work in our laboratories revealed a critical immunoregulatory role of Sema-3E in experimental allergic asthma. We further speculate possible immune modulatory function(s) of Sema-3E on natural killer (NK) cells. PMID- 29113095 TI - Dynamic Fracture Behavior of Steel Fiber Reinforced Self-Compacting Concretes (SFRSCCs). AB - Three-point bending tests on notched beams of three types of steel fiber reinforced self-compacting concrete (SFRSCC) have been performed by using both a servo-hydraulic machine and a drop-weight impact instrument. The lo ading rates had a range of six orders of magnitude from 2.20 * 10-3 mm/s (quasi-static) to 2.66 * 103 mm/s. These SFRSCCs had the same matrix, but various types of steel fiber (straight and hooked-end) and contents (volume ratios), 0.51%, 0.77% and 1.23%, respectively. The results demonstrate that the fracture energy and the flexural strength increase as the loading rate increases. Moreover, such tendency is relatively moderate at low rates. However, at high rates it is accentuated. For the 0.51% fiber content, the dynamic increase factors of the flexural strength and the fracture energy are approximately 6 and 3, while for the 1.23% fiber content, they are around 4 and 2, respectively. Thus, the higher the fiber content the less rate sensitivity there is. PMID- 29113094 TI - Pediatric Chronic Intestinal Failure in Italy: Report from the 2016 Survey on Behalf of Italian Society for Gastroenterology, Hepatology and Nutrition (SIGENP). AB - BACKGROUND: Intestinal failure (IF) is the reduction in functioning gut mass below the minimal level necessary for adequate digestion and absorption of nutrients and fluids for weight maintenance in adults or for growth in children. There is a paucity of epidemiologic data on pediatric IF. The purpose of this study was to determine the prevalence, incidence, regional distribution and underlying diagnosis of pediatric chronic IF (CIF) requiring home parenteral nutrition (HPN) in Italy. METHODS: Local investigators were selected in 19 Italian centers either of reference for pediatric HPN or having pediatric gastroenterologists or surgeons on staff and already collaborating with the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition with regard to IF. Data requested in this survey for children at home on Parenteral Nutrition (PN) on 1 December 2016 included patient initials, year of birth, gender, family's place of residence and underlying diagnosis determining IF. RESULTS: We recorded 145 CIF patients on HPN aged <=19 years. The overall prevalence was 14.12/million inhabitants (95% CI: 9.20-18.93); the overall incidence was 1.41/million inhabitant years (95% CI: 0.53-2.20). CONCLUSION: Our survey provides new epidemiological data on pediatric CIF in Italy; these data may be quantitatively useful in developing IF care strategy plans in all developed countries. PMID- 29113096 TI - Structure and Mechanical Properties of Al-Cu-Fe-X Alloys with Excellent Thermal Stability. AB - In this work, the structure and mechanical properties of innovative Al-Cu-Fe based alloys were studied. We focused on preparation and characterization of rapidly solidified and hot extruded Al-Cu-Fe, Al-Cu-Fe-Ni and Al-Cu-Fe-Cr alloys. The content of transition metals affects mechanical properties and structure. For this reason, microstructure, phase composition, hardness and thermal stability have been investigated in this study. The results showed exceptional thermal stability of these alloys and very good values of mechanical properties. Alloying by chromium ensured the highest thermal stability, while nickel addition refined the structure of the consolidated alloy. High thermal stability of all tested alloys was described in context with the transformation of the quasicrystalline phases to other types of intermetallics. PMID- 29113098 TI - Detonation Velocity Measurement with Chirped Fiber Bragg Grating. AB - Detonation velocity is an important parameter for explosive, and it is crucial for many fields such as dynamic chemistry burn models, detonation propagation prediction, explosive performance estimation, and so on. Dual-channel detonation velocity measurement method and system are described. The CFBG sensors are pasted both on the surface and in the center of the explosive cylinder. The length of CFBG sensors is measured via the hot-tip probe method. The light intensity reflected from the CFBG sensors attached to the explosive is transformed to voltage, and the voltage-time is then measured with the oscilloscope. According to the five experiments results, the relative standard uncertainty of detonation velocity is below 1%. PMID- 29113097 TI - Structure and Function of Caliciviral RNA Polymerases. AB - Caliciviruses are a leading agent of human and animal gastroenteritis and respiratory tract infections, which are growing concerns in immunocompromised individuals. However, no vaccines or therapeutics are yet available. Since the rapid rate of genetic evolution of caliciviruses is mainly due to the error-prone nature of RNA-dependent RNA polymerase (RdRp), this article focuses on recent studies of the structures and functions of RdRp from caliciviruses. It also provides recent advances in the interactions of RdRp with virion protein genome linked (VPg) and RNA and the structural and functional features of its precursor. PMID- 29113099 TI - A Blood Meal Enhances Innexin mRNA Expression in the Midgut, Malpighian Tubules, and Ovaries of the Yellow Fever Mosquito Aedes aegypti. AB - Mosquitoes are vectors of pathogens that cause diseases of medical and veterinary importance. Female mosquitoes transmit these pathogens while taking a blood meal, which most species require to produce eggs. The period after a blood meal is a time of extreme physiological change that requires rapid coordination of specific tissues. Gap junctions (GJ) are intercellular channels that aid in the coordination of cells within tissues via the direct transfer of certain small molecules and ions between cells. Evolutionarily distinct groups of proteins form the gap junctions of vertebrate and invertebrate animals (connexins and innexins, respectively). Aedes aegypti mosquitoes possess six genes encoding innexins: inx1, inx2, inx3, inx4, inx7, and inx8. The goal of this study was to identify potential roles of innexins in the physiology of mosquitoes after a blood meal by using qPCR to quantify their mRNA expression in adult females at 3 h and 24 h post-blood meal (PBM) relative to non-blood-fed controls. We found that at 24 h PBM, expression levels of inx2, inx3, and inx4 mRNAs increased; inx2 was the most highly upregulated innexin in key tissues associated with blood-meal digestion and egg production (i.e., the midgut and ovaries, respectively). However, knocking down inx2 mRNA levels by over 75% via RNA interference had no significant effect on fecundity. Altogether, our results suggest that a blood meal influences the molecular expression of innexins in mosquitoes, but their specific physiological roles remain to be elucidated. PMID- 29113100 TI - Spatiotemporal Association of Real-Time Concentrations of Black Carbon (BC) with Fine Particulate Matters (PM2.5) in Urban Hotspots of South Korea. AB - We evaluated the spatiotemporal distributions of black carbon (BC) and particulate matters with aerodynamic diameters of less than 2.5 m (PM2.5) concentrations at urban diesel engine emission (DEE) hotspots of South Korea. Concentrations of BC and PM2.5 were measured at the entrance gate of two diesel bus terminals and a train station, in 2014. Measurements were conducted simultaneously at the hotspot (Site 1) and at its adjacent, randomly selected, residential areas, apartment complex near major roadways, located with the same direction of 300 m (Site 2) and 500 m (Site 3) away from Site 1 on 4 different days over the season, thrice per day; morning (n = 120 measurements for each day and site), evening (n = 120), and noon (n = 120). The median (interquartile range) PM2.5 ranged from 12.6 (11.3-14.3) to 60.1 (47.0-76.0) MUg/m3 while those of BC concentrations ranged from 2.6 (1.9-3.7) to 6.3 (4.2-10.3) MUg/m3. We observed a strong relationship of PM2.5 concentrations between sites (slopes 0.89 0.9, the coefficient of determination 0.89-0.96) while the relationship for BC concentrations between sites was relatively weak (slopes 0.76-0.85, the coefficient of determination 0.54-0.72). PM2.5 concentrations were changed from 4% to 140% by unit increase of BC concentration, depending on site and time while likely supporting the necessity of monitoring of BC as well as PM2.5, especially at urban DEE related hotspot areas. PMID- 29113101 TI - Effects of Airborne Particulate Matter on Respiratory Health in a Community near a Cement Factory in Chilanga, Zambia: Results from a Panel Study. AB - We conducted a panel study to investigate seasonal variations in concentrations of airborne PM2.5 and PM10 and the effects on respiratory health in a community near a cement factory; in Chilanga; Zambia. A panel of 63 and 55 participants aged 21 to 59 years from a community located at the edge of the factory within 1 km and a control community located 18 km from the factory respectively; were followed up for three climatic seasons July 2015 to February 2016. Symptom diary questionnaires were completed and lung function measurements taken daily for 14 days in each of the three climatic seasons. Simultaneously, PM2.5 and PM10 concentrations in ambient air were monitored at a fixed site for each community. Mean seasonal concentrations of PM2.5 and PM10 ranged from 2.39-24.93 MUg/m3 and 7.03-68.28 MUg/m3 respectively in the exposed compared to the control community 1.69-6.03 MUg/m3 and 2.26-8.86 MUg/m3. The incident rates of reported respiratory symptoms were higher in the exposed compared to the control community: 46.3 vs. 13.8 for cough; 41.2 vs. 9.6 for phlegm; 49.0 vs.12.5 for nose; and 13.9 vs. 3.9 for wheeze per 100 person-days. There was a lower performance on all lung indices in the exposed community compared to the control; overall the mean FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity) predicted percentage for the exposed was six and four percentage points lower than the control. Restriction of industrial emissions coupled with on-going monitoring and regulatory enforcement are needed to ensure that PM (airborne particulate matter) levels in the ambient air are kept within recommended levels to safeguard the respiratory health of nearby community residents. PMID- 29113103 TI - Deep Recurrent Neural Networks for Human Activity Recognition. AB - Adopting deep learning methods for human activity recognition has been effective in extracting discriminative features from raw input sequences acquired from body worn sensors. Although human movements are encoded in a sequence of successive samples in time, typical machine learning methods perform recognition tasks without exploiting the temporal correlations between input data samples. Convolutional neural networks (CNNs) address this issue by using convolutions across a one-dimensional temporal sequence to capture dependencies among input data. However, the size of convolutional kernels restricts the captured range of dependencies between data samples. As a result, typical models are unadaptable to a wide range of activity-recognition configurations and require fixed-length input windows. In this paper, we propose the use of deep recurrent neural networks (DRNNs) for building recognition models that are capable of capturing long-range dependencies in variable-length input sequences. We present unidirectional, bidirectional, and cascaded architectures based on long short term memory (LSTM) DRNNs and evaluate their effectiveness on miscellaneous benchmark datasets. Experimental results show that our proposed models outperform methods employing conventional machine learning, such as support vector machine (SVM) and k-nearest neighbors (KNN). Additionally, the proposed models yield better performance than other deep learning techniques, such as deep believe networks (DBNs) and CNNs. PMID- 29113102 TI - Midkine and NANOG Have Similar Immunohistochemical Expression Patterns and Contribute Equally to an Adverse Prognosis of Oral Squamous Cell Carcinoma. AB - To increase the overall survival rate and obtain a better prognosis for oral squamous cell carcinoma (OSCC) patients, the detection of more effective and reliable tumor prognostic markers is needed. This study is focused on the analysis of correlation between the clinicopathological features of OSCCs and the immunohistochemical (IHC) expression patterns of MIDKINE (MK) and NANOG. Sixty two primary OSCC patients were selected and their pretreatment biopsy specimens were immunohistochemically analyzed for the MK and NANOG proteins. The IHC expression patterns, clinicopathological features, and overall survival rates were assessed to identify any correlations. MK and NANOG showed significantly similar IHC expression patterns: both demonstrated enhanced expression in histologically high-grade and clinically late-stage OSCCs. Weak or negative expression of MK and NANOG was correlated with negative neck node metastasis. Clinicopathologically, late tumor stage, neck node metastasis, high-grade tumor, and palliative treatment groups showed significantly lower overall survival rates. The enhanced expression of MK and NANOG was associated with lower overall survival rates. In particular, enhanced co-detection of MK and NANOG showed significant correlation with poor prognosis. In conclusion, enhanced IHC expression patterns of MK and NANOG in OSCC patients was significantly associated with lower overall survival rates and unfavorable clinicopathological features. These results demonstrate that analysis of IHC expression patterns of MK and NANOG in pretreatment biopsy specimens during the work-up period can provide a more definitive prognosis prediction for each OSCC patient that can help clinicians to develop a more precise individual treatment modality. PMID- 29113104 TI - Super-Resolution of Plant Disease Images for the Acceleration of Image-based Phenotyping and Vigor Diagnosis in Agriculture. AB - Unmanned aerial vehicles (UAVs or drones) are a very promising branch of technology, and they have been utilized in agriculture-in cooperation with image processing technologies-for phenotyping and vigor diagnosis. One of the problems in the utilization of UAVs for agricultural purposes is the limitation in flight time. It is necessary to fly at a high altitude to capture the maximum number of plants in the limited time available, but this reduces the spatial resolution of the captured images. In this study, we applied a super-resolution method to the low-resolution images of tomato diseases to recover detailed appearances, such as lesions on plant organs. We also conducted disease classification using high resolution, low-resolution, and super-resolution images to evaluate the effectiveness of super-resolution methods in disease classification. Our results indicated that the super-resolution method outperformed conventional image scaling methods in spatial resolution enhancement of tomato disease images. The results of disease classification showed that the accuracy attained was also better by a large margin with super-resolution images than with low-resolution images. These results indicated that our approach not only recovered the information lost in low-resolution images, but also exerted a beneficial influence on further image analysis. The proposed approach will accelerate image based phenotyping and vigor diagnosis in the field, because it not only saves time to capture images of a crop in a cultivation field but also secures the accuracy of these images for further analysis. PMID- 29113105 TI - The Molecular and Phenotypic Basis of the Glioma Invasive Perivascular Niche. AB - Gliomas are devastating brain cancers that have poor prognostic outcomes for their patients. Short overall patient survival is due to a lack of durable, efficacious treatment options. Such therapeutic difficulties exist, in part, due to several glioma survival adaptations and mechanisms, which allow glioma cells to repurpose paracrine signalling pathways and ion channels within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space or promote evasion from anti-cancer defence mechanisms. Ultimately, this culminates in glioma repopulation and migration at distances beyond the original tumour site, which is a considerable obstacle for effective treatment. After an era of failed phase II trials targeting individual signalling pathways, coupled to our increasing knowledge of glioma sub-clonal divergence, combinatorial therapeutic approaches which target multiple molecular pathways and mechanisms will be necessary for better treatment outcomes in treating malignant gliomas. Furthermore, next-generation therapy which focuses on infiltrative tumour phenotypes and disruption of the vascular and perivascular microenvironments harbouring residual disease cells offers optimism for the localised control of malignant gliomas. PMID- 29113106 TI - Headspace Solid-Phase Microextraction and Ultrasonic Extraction with the Solvent Sequences in Chemical Profiling of Allium ursinum L. Honey. AB - A volatile profile of ramson (wild garlic, Allium ursinum L.) honey was investigated by headspace solid-phase microextraction (HS-SPME) and ultrasonic solvent extraction (USE) followed by gas chromatography and mass spectrometry (GC FID/GC-MS) analyses. The headspace was dominated by linalool derivatives: cis- and trans-linalool oxides (25.3%; 9.2%), hotrienol (12.7%), and linalool (5.8%). Besides direct extraction with dichloromethane and pentane/diethyl ether mixture (1:2, v/v), two solvent sequences (I: pentane -> diethyl ether; II: pentane -> pentane/diethyl ether (1:2, v/v) -> dichloromethane) were applied. Striking differences were noted among the obtained chemical profiles. The extracts with diethyl ether contained hydroquinone (25.8-36.8%) and 4-hydroxybenzoic acid (11.6 16.6%) as the major compounds, while (E)-4-(r-1',t-2',c-4'-trihydroxy-2',6',6' trimethylcyclohexyl)but-3-en-2-one predominated in dichloromethane extracts (18.3 49.1%). Therefore, combination of different solvents was crucial for the comprehensive investigation of volatile organic compounds in this honey type. This particular magastigmane was previously reported only in thymus honey and hydroquinone in vipers bugloss honey, while a combination of the mentioned predominant compounds is unique for A. ursinum honey. PMID- 29113107 TI - Redesigning Journal Clubs to Staying Current with the Literature. AB - Staying current with the literature is of paramount importance to the pharmacist engaged in an evidence-based clinical practice. Given the expanding roles and responsibilities of today's pharmacists combined with exponential growth in new medical and health sciences literature, staying current has become an extremely daunting task. Traditional journal clubs have focused upon their role as a training vehicle for teaching critical reading skills to residents. However, schools of pharmacy are now required to provide instruction in biostatistics, research design, and interpretation. We present a paradigm shift in the traditional journal club model whereby a collection of periodicals is screened and a short synopsis of the pertinent articles is provided. The associated tasks for screening and presenting of the primary literature are shared among a group of clinicians and trainees with similar practice interests resulting in a more reasonable workload for the individual. This journal club method was effective in identifying a significant majority of articles judged to be pertinent by independent groups of clinicians in the same practice arenas. Details regarding the shared core practice and knowledge base elements, journal club format, identification of journals, and evaluation of the success of the journal club technique are provided. PMID- 29113108 TI - Polymorphisms in FFAR4 (GPR120) Gene Modulate Insulin Levels and Sensitivity after Fish Oil Supplementation. AB - The objective was to test whether FFAR4 single nucleotide polymorphisms (SNPs) are associated with glycemic control-related traits in humans following fish oil supplementation. A total of 210 participants were given 3 g/day of omega-3 (n-3) fatty acids (FA) (1.9-2.2 g of eicosapentaenoic acid (EPA) and 1.1 g of docosahexaenoic acid (DHA)) during six weeks. Biochemical parameters were taken before and after the supplementation. Using the HapMap database and the tagger procedure in Haploview, 12 tagging SNPs in FFAR4 were selected and then genotyped using TaqMan technology. Transcript expression levels were measured for 30 participants in peripheral mononuclear blood cells. DNA methylation levels were measured for 35 participants in leukocytes. In silico analyses were also performed. Four gene-diet interactions on fasting insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) index values were found. rs17108973 explained a significant proportion of the variance of insulin levels (3.0%) and HOMA-IR (2.03%) index values. Splice site prediction was different depending on the allele for rs11187527. rs17108973 and rs17484310 had different affinity for transcription factors depending on the allele. n-3 FAs effectively improve insulin-related traits for major allele homozygotes of four FFAR4 SNPs as opposed to carriers of the minor alleles. PMID- 29113109 TI - Efficient Graph-Based Resource Allocation Scheme Using Maximal Independent Set for Randomly- Deployed Small Star Networks. AB - In future scenarios of heterogeneous and dense networks, randomly-deployed small star networks (SSNs) become a key paradigm, whose system performance is restricted to inter-SSN interference and requires an efficient resource allocation scheme for interference coordination. Traditional resource allocation schemes do not specifically focus on this paradigm and are usually too time consuming in dense networks. In this article, a very efficient graph-based scheme is proposed, which applies the maximal independent set (MIS) concept in graph theory to help divide SSNs into almost interference-free groups. We first construct an interference graph for the system based on a derived distance threshold indicating for any pair of SSNs whether there is intolerable inter-SSN interference or not. Then, SSNs are divided into MISs, and the same resource can be repetitively used by all the SSNs in each MIS. Empirical parameters and equations are set in the scheme to guarantee high performance. Finally, extensive scenarios both dense and nondense are randomly generated and simulated to demonstrate the performance of our scheme, indicating that it outperforms the classical max K-cut-based scheme in terms of system capacity, utility and especially time cost. Its achieved system capacity, utility and fairness can be close to the near-optimal strategy obtained by a time-consuming simulated annealing search. PMID- 29113110 TI - Two Paralogous Genes Encoding Auxin Efflux Carrier Differentially Expressed in Bitter Gourd (Momordica charantia). AB - The phytohormone auxin regulates various developmental programs in plants, including cell growth, cell division and cell differentiation. The auxin efflux carriers are essential for the auxin transport. To show an involvement of auxin transporters in the coordination of fruit development in bitter gourd, a juicy fruit, we isolated novel cDNAs (referred as McPIN) encoding putative auxin efflux carriers, including McPIN1, McPIN2 (allele of McPIN1) and McPIN3, from developing fruits of bitter gourd. Both McPIN1 and McPIN3 genes possess six exons and five introns. Hydropathy analysis revealed that both polypeptides have two hydrophobic regions with five transmembrane segments and a predominantly hydrophilic core. Phylogenetic analyses revealed that McPIN1 shared the highest homology to the group of Arabidopsis, cucumber and tomato PIN1, while McPIN3 belonged to another group, including Arabidopsis and tomato PIN3 as well as PIN4. This suggests different roles for McPIN1 and McPIN3 in auxin transport involved in the fruit development of bitter gourd. Maximum mRNA levels for both genes were detected in staminate and pistillate flowers. McPIN1 is expressed in a particular period of early fruit development but McPIN3 continues to be expressed until the last stage of fruit ripening. Moreover, these two genes are auxin-inducible and qualified as early auxin-response genes. Their expression patterns suggest that these two auxin transporter genes play a pivotal role in fruit setting and development. PMID- 29113111 TI - The MXL-3/SBP-1 Axis Is Responsible for Glucose-Dependent Fat Accumulation in C. elegans. AB - Chronic exposure to elevated glucose levels leads to fatty acid accumulation, which promotes the development of metabolic diseases such as obesity and type 2 diabetes. MXL-3 is a conserved transcriptional factor that modulates the inhibition of lipolysis in Caenorhabditis elegans. However, the role of MXL-3 in lipid metabolism during nutrient excess remains unknown. We hypothesized that inhibition of MXL-3 prevents glucose-dependent fat accumulation. Nematodes from wild-type N2, MXL-3::GFP and sbp-1 or mxl-3 null strains were grown on standard, high glucose or high glucose plus metformin plates for 24 h. Using laser-scanning confocal microscopy, we monitored the glucose-induced activation of MXL-3 labeled with GFP (MXL-3::GFP). Lipid levels were determined by Oil Red O (ORO) staining and gas chromatography/mass spectrometry, and gene expression was assessed by qRT PCR. We found that high glucose activated MXL-3 by increasing its rate of nuclear entry, which in turn increased lipid levels via sterol regulatory element-binding protein (SBP-1). This activated critical genes that synthesize long chain unsaturated fatty acids (MUFAs and PUFAs) and repress lipolytic genes. Interestingly, the anti-diabetic drug metformin inhibited MXL-3 activation and subsequently prevented glucose-dependent fat accumulation. These findings highlight the importance of the MXL-3/SBP-1 axis in the regulation of lipid metabolism during nutritional excess and provide new insight into the mechanism by which metformin prevents lipid accumulation. This study also suggests that inhibition of MXL-3 may serve as a potential target for the treatment of chronic metabolic diseases, including obesity, type 2 diabetes, and cardiovascular disease. PMID- 29113113 TI - Dietary Pattern during 1991-2011 and Its Association with Cardio Metabolic Risks in Chinese Adults: The China Health and Nutrition Survey. AB - Increased prevalence of overweight and obesity, diabetes, hypertension, and other cardio metabolic risks has become a public health concern in China, a country undergoing nutrition transition. We investigated the dietary pattern during 1991 2011 and its association with these risks in a longitudinal study among adults; Adults in The China Health and Nutrition Survey were included. Three-day food consumption was collected by 24 h recall method. Anthropometric measures, blood pressure, fasting blood glucose and lipids was collected in 2009. Dietary pattern was generated using principal components analysis. The associations between dietary pattern and cardio metabolic risk were assessed with generalized linear regression adjusted for age, sex, and social economic status (SES). "Traditional" pattern loaded with rice, meat, and vegetables, and "Modern" pattern had high loadings of fast food, milk, and deep-fried food. "Traditional" pattern was inversely associated with cardio metabolic risks, with linear slopes ranging from -0.15 (95% confidence interval (CI): -0.18, -0.12) for hypertension to -0.67 (95% CI: -0.73, -0.60) for impaired glucose control. "Modern" pattern was associated positively with those factors, with slopes ranging 0.10 (95% CI: 0.04, 0.17) for high cholesterol to 0.42 (95% CI: 0.35, 0.49) for impaired glucose control. Dietary patterns were associated with cardio metabolic risk in Chinese adults. PMID- 29113114 TI - A Novel Experimental and Modelling Strategy for Nanoparticle Toxicity Testing Enabling the Use of Small Quantities. AB - Metallic nanoparticles (NPs) differ from other metal forms with respect to their large surface to volume ratio and subsequent inherent reactivity. Each new modification to a nanoparticle alters the surface to volume ratio, fate and subsequently the toxicity of the particle. Newly-engineered NPs are commonly available only in low quantities whereas, in general, rather large amounts are needed for fate characterizations and effect studies. This challenge is especially relevant for those NPs that have low inherent toxicity combined with low bioavailability. Therefore, within our study, we developed new testing strategies that enable working with low quantities of NPs. The experimental testing method was tailor-made for NPs, whereas we also developed translational models based on different dose-metrics allowing to determine dose-response predictions for NPs. Both the experimental method and the predictive models were verified on the basis of experimental effect data collected using zebrafish embryos exposed to metallic NPs in a range of different chemical compositions and shapes. It was found that the variance in the effect data in the dose-response predictions was best explained by the minimal diameter of the NPs, whereas the data confirmed that the predictive model is widely applicable to soluble metallic NPs. The experimental and model approach developed in our study support the development of (eco)toxicity assays tailored to nano-specific features. PMID- 29113112 TI - G2/M-Phase Checkpoint Adaptation and Micronuclei Formation as Mechanisms That Contribute to Genomic Instability in Human Cells. AB - One of the most common characteristics of cancer cells is genomic instability. Recent research has revealed that G2/M-phase checkpoint adaptation-entering mitosis with damaged DNA-contributes to genomic changes in experimental models. When cancer cells are treated with pharmacological concentrations of genotoxic agents, they undergo checkpoint adaptation; however, a small number of cells are able to survive and accumulate micronuclei. These micronuclei harbour damaged DNA, and are able to replicate and reincorporate their DNA into the main nucleus. Micronuclei are susceptible to chromothripsis, which is a phenomenon characterised by extensively rearranged chromosomes that reassemble from pulverized chromosomes in one cellular event. These processes contribute to genomic instability in cancer cells that survive a genotoxic anti-cancer treatment. This review provides insight into checkpoint adaptation and its connection to micronuclei and possibly chromothripsis. Knowledge about these mechanisms is needed to improve the poor cancer treatment outcomes that result from genomic instability. PMID- 29113116 TI - Statistical Analysis on the Mechanical Properties of Magnesium Alloys. AB - Knowledge of statistical characteristics of mechanical properties is very important for the practical application of structural materials. Unfortunately, the scatter characteristics of magnesium alloys for mechanical performance remain poorly understood until now. In this study, the mechanical reliability of magnesium alloys is systematically estimated using Weibull statistical analysis. Interestingly, the Weibull modulus, m, of strength for magnesium alloys is as high as that for aluminum and steels, confirming the very high reliability of magnesium alloys. The high predictability in the tensile strength of magnesium alloys represents the capability of preventing catastrophic premature failure during service, which is essential for safety and reliability assessment. PMID- 29113115 TI - Ferulaldehyde Improves the Effect of Methotrexate in Experimental Arthritis. AB - Methotrexate (MTX) is still the gold standard for treatment of rheumatoid arthritis (RA). The therapeutic efficacy of low-dose of MTX can be increased by its combination with a natural substance, ferulaldehyde (FRA). The aim of this study was to evaluate the effect FRA and MTX administered alone or in combination in adjuvant arthritis. The disease was induced to Lewis male rats by intradermal injection, which contains a suspension of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experiment of 28 days included: healthy animals, arthritic animals, arthritic animals with administration of FRA at the oral daily dose of 15 mg/kg, arthritic animals with administration of MTX at the oral dose of 0.3 mg/kg twice a week, and arthritic animals administered with FRA and MTX. FRA in monotherapy decreased significantly only the level of interleukin-1beta (IL-1beta) and matrix metalloproteinase-9 in plasma. Combination of FRA and low-dose MTX was more effective than MTX alone when comparing body weight, hind paw volume, arthritic score, plasmatic levels of IL 1beta, activity of gamma-glutamyl transferase, and relative mRNA expression of IL 1beta in the spleen. Therefore, the combination treatment was the most effective. The obtained results are interesting for future possible innovative therapy of patients with RA. PMID- 29113117 TI - Discrimination Increases Suicidal Ideation in Black Adolescents Regardless of Ethnicity and Gender. AB - BACKGROUND: Discrimination is a common experience for Blacks across various developmental periods. Although much is known about the effect of discrimination on suicidal ideation of adults, less is known about the same association in Black youth. AIM: We examined the association between discrimination and suicidal ideation in a national sample of Black youth. We also explored gender and ethnic differences in this association. METHODS: We used data from the National Survey of American Life-Adolescents (NSAL-A), 2003-2004. In total, 1170 Black adolescents entered the study. This number was composed of 810 African American and 360 Caribbean Black youth (aged 13 to 17 years). Demographic and socioeconomic factors were controls, perceived discrimination was the predictor, and lifetime suicidal ideation was the outcome. Logistic regression was used to test the association between perceived discrimination and suicidal ideation in the pooled sample, as well as based on ethnicity and gender. RESULTS: In the pooled sample of Black youth, higher perceived discrimination was associated with higher odds of suicidal ideation (Odds Ratio (OR) = 1.09; 95% Confidence Interval (CI) = 1.02-1.17). This association was significant net of age, ethnicity, gender, and socioeconomic status. We did not find interactions between perceived discrimination and ethnicity or gender on suicidal ideation. Perceived discrimination was associated with suicidal ideation in African Americans (CI = 1.09; 95% CI = 1.01-1.17) and Caribbean Blacks (CI = 1.16; 95% CI = 1.03-1.32), males (CI = 1.11; 95% CI = 1.00-1.25), and females (CI = 1.08; 95% CI = 1.00 1.16). CONCLUSION: Discrimination jeopardizes the mental health of Black youth. In a universal pattern, discrimination is associated with suicidal ideation in Black youth. More research is needed on this topic. PMID- 29113118 TI - Sleep, Health and Wellness at Work: A Scoping Review. AB - Many occupational factors may interfere with sleep. Sleep disturbances can, in turn, endanger the health and safety of workers. This rapid review of the literature identifies the main factors that alter the quantity and quality of sleep, indicates the effects these alterations have on the wellbeing of workers and suggests some health promotion measures. PMID- 29113119 TI - Prescribing Physical Activity for the Prevention and Treatment of Osteoporosis in Older Adults. AB - Osteoporosis is an age-related disease, characterised by low bone mineral density (BMD) and compromised bone geometry and microarchitecture, leading to reduced bone strength. Physical activity (PA) has potential as a therapy for osteoporosis, yet different modalities of PA have varying influences on bone health. This review explores current evidence for the benefits of PA, and targeted exercise regimes for the prevention and treatment of osteoporosis in older adults. In particular, the outcomes of interventions involving resistance training, low- and high-impact weight bearing activities, and whole-body vibration therapy are discussed. Finally, we present recommendations for future research that may maximise the potential of exercise in primary and secondary prevention of osteoporosis in the ageing population. PMID- 29113120 TI - The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues. AB - Pelvic radiation for cancer therapy can damage a variety of normal tissues. In this study, we demonstrate that radiation causes acute changes to pelvic fibroblasts such as the transformation to myofibroblasts and the induction of senescence, which persist months after radiation. The addition of the manganese porphyrin, MnTE-2-PyP, resulted in protection of these acute changes in fibroblasts and this protection persisted months following radiation exposure. Specifically, at two months post-radiation, MnTE-2-PyP inhibited the number of alpha-smooth muscle actin positive fibroblasts induced by radiation and at six months post-radiation, MnTE-2-PyP significantly reduced collagen deposition (fibrosis) in the skin and bladder tissues of irradiated mice. Radiation also resulted in changes to T cells. At two months post-radiation, there was a reduction of Th1-producing splenocytes, which resulted in reduced Th1:Th2 ratios. MnTE-2-PyP maintained Th1:Th2 ratios similar to unirradiated mice. At six months post-radiation, increased T cells were observed in the adipose tissues. MnTE-2 PyP treatment inhibited this increase. Thus, MnTE-2-PyP treatment maintains normal fibroblast function and T cell immunity months after radiation exposure. We believe that one of the reasons MnTE-2-PyP is a potent radioprotector is due to its protection of multiple cell types from radiation damage. PMID- 29113121 TI - Benefits of Multidimensional Measures of Child Well Being in China. AB - In recent decades, measures of child well-being have evolved from single dimension to multidimensional measures. Multi-dimensional measures deepen and broaden our understanding of child well-being and inform us of areas of neglect. Child well-being in China today is measured through proxy measures of household need. This paper discusses the evolution of child well-being measures more generally, explores the benefits of positive indicators and multiple dimensions in formulating policy, and then reviews efforts to date by the Chinese government, researchers, and non-governmental and intergovernmental organizations to develop comprehensive multidimensional measures of child well-being in China. The domains and their potential interactions, as well as data sources and availability, are presented. The authors believe that child well-being in China would benefit from the development of a multidimensional index and that there is sufficient data to develop such an index. PMID- 29113122 TI - Investigation of Interaction between Dislocation Loop and Coherent Twin Boundary in BCC Ta Film during Nanoindentation. AB - In this work, the interaction between dislocation loop (DL) and coherent twin boundary (CTB) in a body-centered cubic (BCC) tantalum (Ta) film during nanoindentation was investigated with molecular dynamics (MD) simulation. The formation and propagation of <111> full DLs in the nanotwinned (nt) Ta film during the indentation was observed, and it was found that CTB can strongly affect the stress distribution in the Ta film, and thus change the motion and type of dislocations. There are three kinds of mechanisms for the interaction between DL and CTB in a twinned BCC Ta film: (i) dislocation absorption, (ii) dislocation desorption, and (iii) direct slip transmission. The nucleation of twin boundary dislocations and the formation of the steps in CTB were also observed during the indentation. The mechanisms presented in this work can provide atomic images for understanding the plastic deformation of BCC metals with mirror-symmetry grain boundary structures, and provide available information for the evaluation and design of high-performance nt BCC metallic thin film coatings. PMID- 29113123 TI - High Neonatal Blood Iron Content Is Associated with the Risk of Childhood Type 1 Diabetes Mellitus. AB - (1) Background: Iron requirement increases during pregnancy and iron supplementation is therefore recommended in many countries. However, excessive iron intake may lead to destruction of pancreatic beta-cells. Therefore, we aim to test if higher neonatal iron content in blood is associated with the risk of developing type 1 diabetes mellitus (T1D) in childhood; (2) Methods: A case control study was conducted, including 199 children diagnosed with T1D before the age of 16 years from 1991 to 2005 and 199 controls matched on date of birth. Information on confounders was available in 181 cases and 154 controls. Iron was measured on a neonatal single dried blood spot sample and was analyzed by laser ablation inductively coupled plasma mass spectrometry. Multivariate logistic regression was used to evaluate if iron content in whole blood was associated with the risk of T1D; (3) Results: A doubling of iron content increased the odds of developing T1D more than two-fold (odds ratio (95% CI), 2.55 (1.04; 6.24)). Iron content increased with maternal age (p = 0.04) and girls had higher content than boys (p = 0.01); (4) Conclusions: Higher neonatal iron content associates to an increased risk of developing T1D before the age of 16 years. Iron supplementation during early childhood needs further investigation, including the causes of high iron in neonates. PMID- 29113125 TI - Single-Shot Dense Depth Sensing with Color Sequence Coded Fringe Pattern. AB - A single-shot structured light method is widely used to acquire dense and accurate depth maps for dynamic scenes. In this paper, we propose a color sequence coded fringe depth sensing method. To overcome the phase unwrapping problem encountered in phase-based methods, the color-coded sequence information is embedded into the phase information. We adopt the color-encoded De Bruijn sequence to denote the period of the phase information and assign the sequence into two channels of the pattern, while the third channel is used to code the phase information. Benefiting from this coding strategy, the phase information distributed in multiple channels can improve the quality of the phase intensity by channel overlay, which results in precise phase estimation. Meanwhile, the wrapped phase period assists the sequence decoding to obtain a precise period order. To evaluate the performance of the proposed method, an experimental platform is established. Quantitative and qualitative experiments demonstrate that the proposed method generates a higher precision depth, as compared to a Kinect and larger resolution ToF (Time of Flight) camera. PMID- 29113126 TI - A Robust High-Accuracy Ultrasound Indoor Positioning System Based on a Wireless Sensor Network. AB - This paper describes the development and implementation of a robust high-accuracy ultrasonic indoor positioning system (UIPS). The UIPS consists of several wireless ultrasonic beacons in the indoor environment. Each of them has a fixed and known position coordinate and can collect all the transmissions from the target node or emit ultrasonic signals. Every wireless sensor network (WSN) node has two communication modules: one is WiFi, that transmits the data to the server, and the other is the radio frequency (RF) module, which is only used for time synchronization between different nodes, with accuracy up to 1 MU s. The distance between the beacon and the target node is calculated by measuring the time-of-flight (TOF) for the ultrasonic signal, and then the position of the target is computed by some distances and the coordinate of the beacons. TOF estimation is the most important technique in the UIPS. A new time domain method to extract the envelope of the ultrasonic signals is presented in order to estimate the TOF. This method, with the envelope detection filter, estimates the value with the sampled values on both sides based on the least squares method (LSM). The simulation results show that the method can achieve envelope detection with a good filtering effect by means of the LSM. The highest precision and variance can reach 0.61 mm and 0.23 mm, respectively, in pseudo-range measurements with UIPS. A maximum location error of 10.2 mm is achieved in the positioning experiments for a moving robot, when UIPS works on the line-of-sight (LOS) signal. PMID- 29113127 TI - Label-Free Detection of Cancer Biomarkers Using an In-Line Taper Fiber-Optic Interferometer and a Fiber Bragg Grating. AB - A compact and label-free optical fiber sensor based on a taper interferometer cascaded with a fiber Bragg grating (FBG) is proposed and experimentally demonstrated for detection of a breast cancer biomarker (HER2). The tapered fiber optic interferometer is extremely sensitive to the ambient refractive index (RI). In addition, being insensitive to the RI variation, the FBG can be applied as a temperature thermometer due to its independent response to the temperature. Surface functionalization to the sensor is carried out to achieve specific targeting of the unlabeled biomarkers. The result shows that the proposed sensor presents a low limit-of-detection (LOD) of 2 ng/mL, enabling its potentials of application in early diagnosis on the breast cancer. PMID- 29113124 TI - Role of Placental VDR Expression and Function in Common Late Pregnancy Disorders. AB - Vitamin D, besides its classical role in bone metabolism, plays a distinct role in multiple pathways of the feto-maternal unit. Calcitriol is the major active ligand of the nuclear vitamin D receptor (VDR). The vitamin D receptor (VDR) is expressed in different uteroplacental parts and exerts a variety of functions in physiologic pregnancy. It regulates decidualisation and implantation, influences hormone secretion and placental immune modulations. This review highlights the role of the vitamin D receptor in physiologic and disturbed pregnancy, as preeclampsia, fetal growth restriction, gestational diabetes and preterm birth. We discuss the existing literature regarding common VDR polymorphisms in these pregnancy disorders. PMID- 29113128 TI - Surface Modification of Li(Ni0.6Co0.2Mn0.2)O2 Cathode Materials by Nano-Al2O3 to Improve Electrochemical Performance in Lithium-Ion Batteries. AB - Al2O3-coated Li(Ni0.6Co0.2Mn0.2)O2 cathode materials were prepared by simple surface modification in water media through a sol-gel process with a dispersant. The crystallinity and surface morphology of the samples were characterized through X-ray diffraction analysis and scanning electron microscopy observation. The Li(Ni0.6Co0.2Mn0.2)O2 cathode material was of a polycrystalline hexagonal structure and agglomerated with particles of approximately 0.3 to 0.8 MUm in diameter. The nanosized Al2O3 particles of low concentration (0.06-0.12 wt %) were uniformly coated on the surface of Li(Ni0.6Co0.2Mn0.2)O2. Measurement of electrochemical properties showed that Li(Ni0.6Co0.2Mn0.2)O2 coated with Al2O3 of 0.08 wt % had a high initial discharge capacity of 206.9 mAh/g at a rate of 0.05 C over 3.0-4.5 V and high capacity retention of 94.5% at 0.5 C after 30 cycles (cf. uncoated sample: 206.1 mAh/g and 90.8%, respectively). The rate capability of this material was also improved, i.e., it showed a high discharge capacity of 166.3 mAh/g after 5 cycles at a rate of 2 C, whereas the uncoated sample showed 155.8 mAh/g under the same experimental conditions. PMID- 29113129 TI - Atmospheric Pressure Plasma Polymerization Synthesis and Characterization of Polyaniline Films Doped with and without Iodine. AB - Although polymerized aniline (polyaniline, PANI) with and without iodine (I2) doping has already been extensively studied, little work has been done on the synthesis of PANI films using atmospheric pressure plasma (APP) deposition. Therefore, this study characterized pure and I2-doped PANI films synthesized using an advanced APP polymerization system. The I2 doping was conducted ex-situ and using an I2 chamber method following the APP deposition. The pure and I2 doped PANI films were structurally analyzed using field emission scanning electron microscope (FE-SEM), atomic force microscope (AFM), X-ray Diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and time of flight secondary ion mass spectrometry (ToF-SIMS) studies. When increasing the I2 doping time, the plane and cross-sectional SEM images showed a decrease in the width and thickness of the PANI nanofibers, while the AFM results showed an increase in the roughness and grain size of the PANI films. Moreover, the FT-IR, XPS, and ToF-SIMS results showed an increase in the content of oxygen-containing functional groups and C=C double bonds, yet decrease in the C-N and C-H bonds when increasing the I2 doping time due to the reduction of hydrogen in the PANI films via the I2. To check the suitability of the conductive layer for polymer display applications, the resistance variations of the PANI films grown on the interdigitated electrode substrates were also examined according to the I2 doping time. PMID- 29113130 TI - Mechanistic Study of Copper-Catalyzed C-H Hydroxylation/C-S Coupling by ESI-HR MS and DFT Calculations. AB - The reaction mechanism of Cu-catalyzed C-H hydroxylation/C-S coupling was studied using electrospray ionization high resolution mass spectrometry (ESI-HR MS) and density functional theory calculations (DFT). Notably, a series of CuI and CuIII complexes were observed as key intermediates and identified using ESI-HR MS. Furthermore, a catalyst cycle involving proton abstraction/oxidative addition/reductive elimination was proposed. This study is important and valuable with respect to C-H functionalization. PMID- 29113131 TI - Interaction of alpha- and beta-zearalenols with beta-cyclodextrins. AB - Zearalenone (ZEN) is a mycotoxin produced by Fusarium fungi. ZEN primarily contaminates different cereals, and exerts a strong xenoestrogenic effect in animals and humans. ZEN is a fluorescent mycotoxin, although molecular interactions and microenvironmental changes significantly modify its spectral properties. During biotransformation, ZEN is converted into alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL), the toxic metabolites of ZEN, which mimick the effect of estrogen. Cyclodextrins (CDs) are host molecules, and have been studied extensively; they can form stable complexes with several mycotoxins, including ZEN. However, information is limited regarding the interactions of CDs with ZOLs. Therefore, we studied the interactions of alpha- and beta-ZOLs with native and six chemically modified beta-CDs by fluorescence spectroscopy. Fluorescence enhancement during complex formation, as well as binding constants, were determined. To understand ZOL-CD interactions better, molecular modeling studies were also carried out. Both mycotoxin derivatives formed the most stable complexes with methylated and sulfobutylated CD-derivatives; however, the CD complexes of alpha-ZOL were significantly stronger than those of beta-ZOL. The data presented here indicate which of the chemically modified beta-CDs appear more suitable as fluorescence enhancers or as potential mycotoxin binders. PMID- 29113132 TI - Chitin and Cellulose Processing in Low-Temperature Electron Beam Plasma. AB - Polysaccharide processing by means of low-temperature Electron Beam Plasma (EBP) is a promising alternative to the time-consuming and environmentally hazardous chemical hydrolysis in oligosaccharide production. The present paper considers mechanisms of the EBP-stimulated destruction of crab shell chitin, cellulose sulfate, and microcrystalline cellulose, as well as characterization of the produced oligosaccharides. The polysaccharide powders were treated in oxygen EBP for 1-20 min at 40 degrees C in a mixing reactor placed in the zone of the EBP generation. The chemical structure and molecular mass of the oligosaccharides were analyzed by size exclusion and the reversed phase chromatography, FTIR spectroscopy, XRD-, and NMR-techniques. The EBP action on original polysaccharides reduces their crystallinity index and polymerization degree. Water-soluble products with lower molecular weight chitooligosaccharides (weight average molecular mass, Mw = 1000-2000 Da and polydispersity index 2.2) and cellulose oligosaccharides with polymerization degrees 3-10 were obtained. The 1H NMR analysis revealed 25-40% deacetylation of the EBP-treated chitin and FTIR spectroscopy detected an increase of carbonyl- and carboxyl-groups in the oligosaccharides produced. Possible reactions of beta-1,4-glycosidic bonds' destruction due to active oxygen species and high-energy electrons are given. PMID- 29113133 TI - ZnO Nanostructures for Tissue Engineering Applications. AB - This review focuses on the most recent applications of zinc oxide (ZnO) nanostructures for tissue engineering. ZnO is one of the most investigated metal oxides, thanks to its multifunctional properties coupled with the ease of preparing various morphologies, such as nanowires, nanorods, and nanoparticles. Most ZnO applications are based on its semiconducting, catalytic and piezoelectric properties. However, several works have highlighted that ZnO nanostructures may successfully promote the growth, proliferation and differentiation of several cell lines, in combination with the rise of promising antibacterial activities. In particular, osteogenesis and angiogenesis have been effectively demonstrated in numerous cases. Such peculiarities have been observed both for pure nanostructured ZnO scaffolds as well as for three-dimensional ZnO based hybrid composite scaffolds, fabricated by additive manufacturing technologies. Therefore, all these findings suggest that ZnO nanostructures represent a powerful tool in promoting the acceleration of diverse biological processes, finally leading to the formation of new living tissue useful for organ repair. PMID- 29113134 TI - Non-Covalent Loading of Anti-Cancer Doxorubicin by Modularizable Peptide Self Assemblies for a Nanoscale Drug Carrier. AB - We prepared nanoscale, modularizable, self-assembled peptide nanoarchitectures with diameters less of than 20 nm by combining beta-sheet-forming peptides tethering a cell-penetrating peptide or a nuclear localization signal sequence. We also found that doxorubicin (Dox), an anti-cancer drug, was non-covalently accommodated by the assemblies at a ratio of one Dox molecule per ten peptides. The Dox-loaded peptide assemblies facilitated cellular uptake and subsequent nuclear localization in HeLa cells, and induced cell death even at low Dox concentrations. This peptide nanocarrier motif is a promising platform for a biocompatible drug delivery system by altering the targeting head groups of the carrier peptides. PMID- 29113135 TI - Nonalcoholic Fatty Liver Disease Is Exacerbated in High-Fat Diet-Fed Gnotobiotic Mice by Colonization with the Gut Microbiota from Patients with Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is a serious liver disorder associated with the accumulation of fat and inflammation. The objective of this study was to determine the gut microbiota composition that might influence the progression of NAFLD. Germ-free mice were inoculated with feces from patients with nonalcoholic steatohepatitis (NASH) or from healthy persons (HL) and then fed a standard diet (STD) or high-fat diet (HFD). We found that the epididymal fat weight, hepatic steatosis, multifocal necrosis, and inflammatory cell infiltration significantly increased in the NASH-HFD group. These findings were consistent with markedly elevated serum levels of alanine transaminase, aspartate transaminase, endotoxin, interleukin 6 (IL-6), monocyte chemotactic protein 1 (Mcp1), and hepatic triglycerides. In addition, the mRNA expression levels of Toll-like receptor 2 (Tlr2), Toll-like receptor 4 (Tlr4), tumor necrosis factor alpha (Tnf-alpha), Mcp1, and peroxisome proliferator-activated receptor gamma (Ppar-gamma) significantly increased. Only abundant lipid accumulation and a few inflammatory reactions were observed in group HL-HFD. Relative abundance of Bacteroidetes and Firmicutes shifted in the HFD-fed mice. Furthermore, the relative abundance of Streptococcaceae was the highest in group NASH-HFD. Nevertheless, obesity-related Lactobacillaceae were significantly upregulated in HL-HFD mice. Our results revealed that the gut microbiota from NASH Patients aggravated hepatic steatosis and inflammation. These findings might partially explain the NAFLD progress distinctly was related to different compositions of gut microbiota. PMID- 29113136 TI - Discovering the Deregulated Molecular Functions Involved in Malignant Transformation of Endometriosis to Endometriosis-Associated Ovarian Carcinoma Using a Data-Driven, Function-Based Analysis. AB - The clinical characteristics of clear cell carcinoma (CCC) and endometrioid carcinoma EC) are concomitant with endometriosis (ES), which leads to the postulation of malignant transformation of ES to endometriosis-associated ovarian carcinoma (EAOC). Different deregulated functional areas were proposed accounting for the pathogenesis of EAOC transformation, and there is still a lack of a data driven analysis with the accumulated experimental data in publicly-available databases to incorporate the deregulated functions involved in the malignant transformation of EOAC. We used the microarray gene expression datasets of ES, CCC and EC downloaded from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database. Then, we investigated the pathogenesis of EAOC by a data-driven, function-based analytic model with the quantified molecular functions defined by 1454 Gene Ontology (GO) term gene sets. This model converts the gene expression profiles to the functionome consisting of 1454 quantified GO functions, and then, the key functions involving the malignant transformation of EOAC can be extracted by a series of filters. Our results demonstrate that the deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response and cell-cell signaling play the key roles in the malignant transformation of EAOC. These results provide the evidence supporting the specific molecular pathways involved in the malignant transformation of EAOC. PMID- 29113137 TI - Multimodal Counseling Interventions: Effect on Human Papilloma Virus Vaccination Acceptance. AB - Human papilloma virus (HPV) vaccine was developed to reduce HPV-attributable cancers, external genital warts (EGW), and recurrent respiratory papillomatosis. Adolescent HPV vaccination series completion rates are less than 40% in the United States of America, but up to 80% in Australia and the United Kingdom. Population-based herd immunity requires 80% or greater vaccination series completion rates. Pro-vaccination counseling facilitates increased vaccination rates. Multimodal counseling interventions may increase HPV vaccination series non-completers' HPV-attributable disease knowledge and HPV-attributable disease prophylaxis (vaccination) acceptance over a brief 14-sentence counseling intervention. An online, 4-group, randomized controlled trial, with 260 or more participants per group, found that parents were more likely to accept HPV vaccination offers for their children than were childless young adults for themselves (68.2% and 52.9%). A combined audiovisual and patient health education handout (PHEH) intervention raised knowledge of HPV vaccination purpose, p = 0.02, and HPV vaccination acceptance for seven items, p < 0.001 to p = 0.023. The audiovisual intervention increased HPV vaccination acceptance for five items, p < 0.001 to p = 0.006. That HPV causes EGW, and that HPV vaccination prevents HPV attributable diseases were better conveyed by the combined audiovisual and PHEH than the control 14-sentence counseling intervention alone. PMID- 29113138 TI - Evaluating the Potential Value of Natural Product Cuminic Acid against Plant Pathogenic Fungi in Cucumber. AB - Fusarium wilt and anthracnose are two major diseases which limit the yield and quality of cucumber worldwide. Cuminic acid was extracted from the seed of Cuminum cyminum L. The mean EC50 values of cuminic acid for inhibiting mycelial growth and zoospore germination of five Fusarium oxysporum f. sp. cucumerinum strains were 25.66 +/- 3.02 MUg/mL and 15.99 +/- 2.19 MUg/mL, and of four Colletotrichum lagenarium (Pass.) Ellis and Halsted strains were 29.53 +/- 3.18 MUg/mL and 18.41 +/- 2.78 MUg/mL, respectively. In greenhouse experiments, cuminic acid at 2000 MUg/mL exhibited 70.77% protective and 62.63% curative efficacies against F. oxysporum, and 65.43% protective and 55.46% curative efficacies against C. lagenarium. Moreover, the translocation behavior of cuminic acid, determined by high performance liquid chromatography (HPLC), showed that it could be readily absorbed and transported upward and downward in cucumber. Importantly, superoxide dismutase (SOD) and pyphenol oxidase (PPO) activities of cucumber leaves treated with cuminic acid increased significantly. All results indicated that cuminic acid showed antifungal activity, and could be used as a botanical fungicide in disease management. This study encourages further investigation on the mechanism of action of cuminic acid and the development of alternative antifungal drugs. PMID- 29113140 TI - ZnO Interactions with Biomatrices: Effect of Particle Size on ZnO-Protein Corona. AB - Zinc oxide (ZnO) nanoparticles (NPs) have been widely used for food fortification, because zinc is essential for many enzyme and hormone activities and cellular functions, but public concern about their potential toxicity is increasing. Interactions between ZnO and biomatrices might affect the oral absorption, distribution, and toxicity of ZnO, which may be influenced by particle size. In this study, ZnO interactions with biomatrices were investigated by examining the physicochemical properties, solubility, protein fluorescence quenching, particle-protein corona, and intestinal transport with respect to the particle size (bulk vs. nano) in simulated gastrointestinal (GI) and plasma fluids and in rat-extracted fluids. The results demonstrate that the hydrodynamic radii and zeta potentials of bulk ZnO and nano ZnO in biofluids changed in different ways, and that nano ZnO induced higher protein fluorescence quenching than bulk ZnO. However, ZnO solubility and its intestinal transport mechanism were unaffected by particle size. Proteomic analysis revealed that albumin, fibrinogen, and fibronectin play roles in particle-plasma protein corona, regardless of particle size. Furthermore, nano ZnO was found to interact more strongly with plasma proteins. These observations show that bulk ZnO and nano ZnO interact with biomatrices in different ways and highlight the need for further study of their long-term toxicity. PMID- 29113141 TI - In Vitro Degradation of Borosilicate Bioactive Glass and Poly(l-lactide-co epsilon-caprolactone) Composite Scaffolds. AB - Composite scaffolds were obtained by mixing various amounts (10, 30 and 50 weight % [wt %]) of borosilicate bioactive glass and poly(l-lactide-co-epsilon caprolactone) (PLCL) copolymer. The composites were foamed using supercritical CO2. An increase in the glass content led to a decrease in the pore size and density. In vitro dissolution/reaction test was performed in simulated body fluid. As a function of immersion time, the solution pH increased due to the glass dissolution. This was further supported by the increasing amount of Ca in the immersing solution with increasing immersion time and glass content. Furthermore, the change in scaffold mass was significantly greater with increasing the glass content in the scaffold. However, only the scaffolds containing 30 and 50 wt % of glasses exhibited significant hydroxyapatite (HA) formation at 72 h of immersion. The compression strength of the samples was also measured. The Young's modulus was similar for the 10 and 30 wt % glass-containing scaffolds whereas it increased to 90 MPa for the 50 wt % glass containing scaffold. Upon immersion up to 72 h, the Young's modulus increased and then remained constant for longer immersion times. The scaffold prepared could have great potential for bone and cartilage regeneration. PMID- 29113139 TI - Anti-HIV Activity of Ocimum labiatum Extract and Isolated Pheophytin-a. AB - Ocimum plants are traditionally used to manage HIV/AIDS in various African countries. The effects of Ocimum labiatum extract on HIV-1 protease (PR) and reverse transcriptase (RT) is presented here along with characterization of an identified bioactive compound, achieved through 1H- and 13C-NMR. The extract's effect on HIV-1 replication was assessed by HIV-1 p24 antigen capture. Cytotoxicity of samples was evaluated using tetrazolium dyes and real-time cell electronic sensing (RT-CES). Ocimum labiatum inhibited HIV-1 PR with an IC50 value of 49.8 +/- 0.4 MUg/mL and presented weak inhibition (21%) against HIV-1 RT. The extract also reduced HIV-1 replication in U1 cells at a non-cytotoxic concentration (25 MUg/mL). The CC50 value of the extract in U1 cells was 42.0 +/- 0.13 MUg/mL. The HIV-1 PR inhibiting fraction was purified using prep-HPLC and yielded a chlorophyll derivative, pheophytin-a (phy-a). Phy-a inhibited HIV-1 PR with an IC50 value of 44.4 +/- 1.5 MUg/mL (51 +/- 1.7 MUM). The low cytotoxicity of phy-a in TZM-bl cells was detected by RT-CES and the CC50 value in U1 cells was 51.3 +/- 1.0 MUg/mL (58.9 +/- 1.2 MUM). This study provides the first in vitro evidence of anti-HIV activity of O. labiatum and isolated phy-a, supporting further investigation of O. labiatum for lead compounds against HIV-1. PMID- 29113142 TI - A Real-Time Smooth Weighted Data Fusion Algorithm for Greenhouse Sensing Based on Wireless Sensor Networks. AB - Wireless sensor networks are widely used to acquire environmental parameters to support agricultural production. However, data variation and noise caused by actuators often produce complex measurement conditions. These factors can lead to nonconformity in reporting samples from different nodes and cause errors when making a final decision. Data fusion is well suited to reduce the influence of actuator-based noise and improve automation accuracy. A key step is to identify the sensor nodes disturbed by actuator noise and reduce their degree of participation in the data fusion results. A smoothing value is introduced and a searching method based on Prim's algorithm is designed to help obtain stable sensing data. A voting mechanism with dynamic weights is then proposed to obtain the data fusion result. The dynamic weighting process can sharply reduce the influence of actuator noise in data fusion and gradually condition the data to normal levels over time. To shorten the data fusion time in large networks, an acceleration method with prediction is also presented to reduce the data collection time. A real-time system is implemented on STMicroelectronics STM32F103 and NORDIC nRF24L01 platforms and the experimental results verify the improvement provided by these new algorithms. PMID- 29113143 TI - Sevoflurane Postconditioning-Induced Anti-Inflammation via Inhibition of the Toll Like Receptor-4/Nuclear Factor Kappa B Pathway Contributes to Neuroprotection against Transient Global Cerebral Ischemia in Rats. AB - The anti-inflammatory actions of sevoflurane postconditioning are suggested as an important mechanism of sevoflurane postconditioning-induced neuroprotection against cerebral ischemia. Here, we determined whether the anti-inflammatory effects of sevoflurane postconditioning were mediated via inhibition of the toll like receptor (TLR)-4/nuclear factor kappa B (NF-kappaB) pathway after global transient cerebral ischemia in rats. Forty-five rats were randomly assigned to five groups as follows: (1) control (10 min of ischemia, n = 10); (2) sevoflurane postconditioning (two periods of sevoflurane inhalation after ischemia for 10 min with a wash period of 10 min, n = 10); (3) resatorvid (intraperitoneal injection of a selective TLR-4 antagonist (3 mg/kg) 30 min before ischemia, n = 10); (4) sevoflurane postconditioning plus resatorvid (n = 10), and sham (n = 5). The numbers of necrotic and apoptotic cells in the hippocampal CA1 region, the expression levels of TLR-4, NF-kappaB, cleaved caspase-3, and tumor necrosis factor alpha (TNF-alpha) in the anterior part of each brain, and the serum levels of TNF-alpha, interleukin 6 (IL-6), and interleukin 1 beta (IL-1beta) were assessed 1 day after ischemia. The necrotic cell counts and expression levels of TLR-4, NF-kappaB, caspase-3, and TNF-alpha in brain tissue as well as serum levels of pro-inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) were significantly higher in the control group than in the other groups. Our findings suggest that the anti-inflammatory actions of sevoflurane postconditioning via inactivation of the TLR-4/NF-kappaB pathway and subsequent reduction in pro inflammatory cytokine production, in part, contribute to sevoflurane postconditioning-induced neuroprotection after global transient cerebral ischemia in rats. PMID- 29113144 TI - Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells. AB - The hepatitis C virus (HCV) causes chronic liver disease leading to fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection triggers various types of cell death which contribute to hepatitis C pathogenesis. However, much is still unknown about the impact of viral proteins on them. Here we present the results of simultaneous immunocytochemical analysis of markers of apoptosis, autophagy, and necrosis in Huh7.5 cells expressing individual HCV proteins or their combinations, or harboring the virus replicon. Stable replication of the full length HCV genome or transient expression of its core, E1/E2, NS3 and NS5B led to the death of 20-47% cells, 72 h posttransfection, whereas the expression of the NS4A/B, NS5A or NS3-NS5B polyprotein did not affect cell viability. HCV proteins caused different impacts on the activation of caspases-3, -8 and -9 and on DNA fragmentation. The structural core and E1/E2 proteins promoted apoptosis, whereas non-structural NS4A/B, NS5A, NS5B suppressed apoptosis by blocking various members of the caspase cascade. The majority of HCV proteins also enhanced autophagy, while NS5A also induced necrosis. As a result, the death of Huh7.5 cells expressing the HCV core was induced via apoptosis, the cells expressing NS3 and NS5B via autophagy-associated death, and the cells expressing E1/E2 glycoproteins or harboring HCV the replicon via both apoptosis and autophagy. PMID- 29113145 TI - Associations between Nut Consumption and Health Vary between Omnivores, Vegetarians, and Vegans. AB - Regular nut consumption is associated with reduced risk factors for chronic disease; however, most population-based studies lack consideration of effect modification by dietary pattern. The UK Women's Cohort Study (UKWCS) provides an ideal opportunity to examine relationships between nut consumption and chronic disease risk factors in a large sample with diverse dietary patterns. Nut and nutrient intake from 34,831 women was estimated using a food frequency questionnaire among self-identified omnivores, vegetarians and vegans. In this cross-sectional analysis, higher nut consumption was associated with lower body weight (difference between highest and lowest consumption categories from adjusted model: 6.1 kg; 95% CI: 4.7, 7.6) body mass index (BMI, 2.4 units difference; 95% CI: 1.9, 2.9), and waist circumference (2.6 cm difference; 95% CI: 1.4, 3.8) (all p for linear trend < 0.001). Higher nut consumption was also associated with reduced prevalence of high cholesterol and high blood pressure; having a history of heart attack, diabetes and gallstones; and markers of diet quality (all adjusted p for linear trend <= 0.011). Higher nut consumption appeared overall to be associated with greater benefits amongst omnivores compared to vegetarians and vegans. Findings support existing literature around beneficial effects of nut consumption and suggest that benefits may be larger among omnivores. Nut promotion strategies may have the highest population impact by specifically targeting this group. PMID- 29113146 TI - A Simple Method to Decode the Complete 18-5.8-28S rRNA Repeated Units of Green Algae by Genome Skimming. AB - Green algae, Chlorella ellipsoidea, Haematococcus pluvialis and Aegagropila linnaei (Phylum Chlorophyta) were simultaneously decoded by a genomic skimming approach within 18-5.8-28S rRNA region. Whole genomic DNAs were isolated from green algae and directly subjected to low coverage genome skimming sequencing. After de novo assembly and mapping, the size of complete 18-5.8-28S rRNA repeated units for three green algae were ranged from 5785 to 6028 bp, which showed high nucleotide diversity (pi is around 0.5-0.6) within ITS1 and ITS2 (Internal Transcribed Spacer) regions. Previously, the evolutional diversity of algae has been difficult to decode due to the inability design universal primers that amplify specific marker genes across diverse algal species. In this study, our method provided a rapid and universal approach to decode the 18-5.8-28S rRNA repeat unit in three green algal species. In addition, the completely sequenced 18-5.8-28S rRNA repeated units provided a solid nuclear marker for phylogenetic and evolutionary analysis for green algae for the first time. PMID- 29113147 TI - Antibacterial Activity of Polyphenols: Structure-Activity Relationship and Influence of Hyperglycemic Condition. AB - Polyphenols are plant-derived natural products with well-documented health benefits to human beings, such as antibacterial activities. However, the antibacterial activities of polyphenols under hyperglycemic conditions have been rarely studied, which could be relevant to their antibacterial efficacy in disease conditions, such as in diabetic patients. Herein, the antibacterial activities of 38 polyphenols under mimicked hyperglycemic conditions were evaluated. The structure-antibacterial activity relationships of polyphenols were also tested and analyzed. The presence of glucose apparently promoted the growth of the bacterial strains tested in this study. The OD600 values of tested bacteria strains increased from 1.09-fold to 1.49-fold by adding 800 mg/dL glucose. The polyphenols showed structurally dependent antibacterial activities, which were significantly impaired under the hyperglycemic conditions. The results from this study indicated that high blood glucose might promote bacterial infection, and the hyperglycemic conditions resulting from diabetes were likely to suppress the antibacterial benefits of polyphenols. PMID- 29113148 TI - Role of galectins in lung cancer. AB - Lung cancer is the leading cause of cancer-associated mortality worldwide and is also associated with a poor prognosis. As in numerous other types of cancer, galectins have been demonstrated to be involved in the progression of lung cancer. Galectins belong to a superfamily of lectins, which are carbohydrate binding proteins. There are at least 15 members in the galectin family, however, only galectin-1, -2, -3, -4, -7, -8, -9, -10, -12, and -13 are found in humans. Galectins are able to mediate interactions between cells, including homotypic and heterotypic interactions; they also facilitate the bindings between cells and extracellular matrix components. These cell-cell and cell-matrix interactions, as well as the galectin signaling on the cell surface, are able to modulate signaling pathways and thereby influence cellular functions and behaviors. Galectin-1, -3, -4, -7, -8 and -9 are associated with lung cancer. These galectins are associated with tumor invasion, migration, metastasis and progression, and may serve important roles in the tumor microenvironment of lung cancer. The majority of galectins are associated with the progression of lung cancer, with the exception of galectin-9, which is associated with enhanced anticancer immunity. Therefore, galectins may be potential targets for developing novel lung cancer therapies. PMID- 29113149 TI - Research progress on circadian clock genes in common abdominal malignant tumors. AB - The circadian clock refers to the inherent biological rhythm of an organism, which, is accurately regulated by numerous clock genes. Studies in recent years have reported that the abnormal expression of clock genes is ubiquitous in common abdominal malignant tumors, including liver, colorectal, gastric and pancreatic cancer. In addition, the abnormal expression of certain clock genes is closely associated with clinical tumor parameters or patient prognosis. Studies in clock genes may expand the knowledge about the mechanism of occurrence and development of tumors, and may provide a new approach for tumor therapy. The present study summarizes the research progress in this field. PMID- 29113150 TI - Aberrant chromatin remodeling in gynecological cancer. AB - Epigenetic regulatory mechanisms are a current focus in studies investigating cancer. Chromatin remodeling alters chromatin structure and regulates gene expression, and aberrant chromatin remodeling is involved in carcinogenesis. AT rich interactive domain-containing protein 1A (ARID1A) and SWItch/sucrose non fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 are remodeling factors that are mutated in numerous types of cancer. In gynecological cancer, ARID1A mutations have been identified in 46 57% of clear cell carcinoma and 30% of endometrioid carcinoma. Mutations of chromodomain helicase, DNA-binding protein 4 have been detected in 17-21% of endometrial serous cancer, and mutations of ARID1A and mixed-lineage leukemia 3 occur in 36 and 27% of uterine carcinosarcoma, respectively. These data suggest that aberrant chromatin remodeling is a potential cause of cancer, and have led to the development of novel proteins targeting these processes. Additional accumulation of information on the mechanisms of chromatin remodeling and markers for these events may promote personalized anticancer therapies. PMID- 29113151 TI - Alternative splicing regulation in tumor necrosis factor-mediated inflammation. AB - It is generally accepted that alternative splicing has an effect on disease when it leads to conspicuous changes in relevant proteins, but that the combinatorial effect of several small modifications can have marked outcomes as well. Inflammation is a complex process involving numerous signaling pathways, among which the tumor necrosis factor (TNF) pathway is one of the most studied. Signaling pathways are commonly represented as intricate cascades of molecular interactions that eventually lead to the activation of one or several genes. Alternative splicing is a common means of controlling protein expression in time and space; therefore, it can modulate the outcome of signaling pathways through small changes in their elements. Notably, the overall process is tightly regulated, which is easily overlooked when analyzing the pathway as a whole. The present review summarizes recent studies of the alternative splicing of key players of the TNF pathway leading to inflammation, and hypothesizes on the cumulative results of those modifications and the impact on cancer development. PMID- 29113152 TI - Effect of surgical margins on prognosis in aggressive fibromatosis: A single institutional analysis of 90 patients. AB - The treatment of aggressive fibromatosis poses a therapeutic challenge in an interdisciplinary setting. The extent of surgical resection is still discussed controversially. The present retrospective analysis aimed to determine prognostic factors leading to recurrence. Between 2000 and 2014, 114 patients with aggressive fibromatosis were treated surgically at BG-University Hospital Bergmannsheil (Bochum, Germany). Univariate and multivariate analyses were restricted to 90 participants with information available on surgical margins at the initial procedure. The median follow-up time was 7.7 years. A total of 45 patients (50%) developed recurrence during follow-up. Primary tumors were resected with negative margins (R0) in 50 patients (68%) and with microscopically positive margins (R1) in 28 patients (25%). In addition, tumors in 12 patients (7%) were resected with macroscopically positive margins at the initial surgical procedure. The rates of recurrence-free survival (RFS) after 5 years were 68.8% [95% confidence interval (CI), 53.5-79.9%] in patients with R0-resected primary tumors and 34.1% (95% CI, 19.9-48.9%) in patients with R1/R2-status (P=0.001). Narrow and wide clear margins within the R0-group were not associated with significantly different outcomes. Adjuvant radiation, tumor site and patient age were not associated with a significant alteration of RFS. The current results suggest that the attainment of microscopically negative surgical margins at the initial surgical treatment is associated with a significantly improved prognosis. A conservative surgical approach involving the attainment of narrow negative margins while preserving function should be sought in patients in whom tumor resection is indicated. The decision for resection should be made interdisciplinary in each case based on tumor progression, available treatment alternatives and the decision of the informed patient. PMID- 29113153 TI - The role of LASS2 in regulating bladder cancer cell tumorigenicity in a nude mouse model. AB - Previous in vitro studies have demonstrated that LAG1 longevity assurance homolog 2 (LASS2) is a novel tumor suppressor gene that is significantly associated with the proliferation and invasion ability of tumor cells. However, the role LASS2 serves in regulating bladder cancer cell tumorigenicity and tumor growth in vivo has not yet been elucidated in animal or clinical studies. In the present study, LASS2 knockdown in human bladder cancer EJ-M3 cells significantly promoted the growth of xenografts in nude mice compared with the control group, while overexpression of LASS2 suppressed tumor growth; however, this was not statistically significant. Furthermore, LASS2 knockdown resulted in more apparent heteromorphism and a higher activity of matrix metalloproteinase (MMP)-2 and MMP 9 in xenograft tumors. The data from the present study demonstrated that LASS2 knockdown significantly promoted the tumorigenicity and growth of EJ-M3 xenograft tumors in nude mice, and that LASS2 overexpression has a tendency to inhibit the growth of xenografts, suggesting that it may be a potential therapeutic target for bladder cancer. PMID- 29113154 TI - Synergistic inhibitory effects of an engineered antibody-like molecule ATF-Fc and trastuzumab on tumor growth and invasion in a human breast cancer xenograft mouse model. AB - The overexpression of the oncogene human epidermal growth factor receptor 2 (HER 2) has been associated with decreased disease-free survival and is a marker of poor prognosis of invasive breast cancer. Although the high efficacy of trastuzumab, a drug that targets the HER-2 oncogene, has been widely recognized, the efficiency of the treatment remains at ~30%. Therefore, novel effective treatments are required for patients with recurrent metastatic breast cancer. The present study aimed to investigate the effects of an engineered antibody-like molecule administered alone or in combination with trastuzumab on the tumor growth and metastasis of HER-2-positive breast cancer. Another aim was to investigate novel cancer therapies for HER-2-positive breast cancer. The engineered antibody-like molecule consists of the amino-terminal fragment (ATF) of human urokinase-type plasminogen (uPA) and is conjugated with the Fc fragment of human immunoglobulin G1 (ATF-Fc). The anti-cancer effect of ATF-Fc (alone and in combination with trastuzumab) on tumor cells and in a nude mouse tumor model was evaluated by detecting the expression of uPA, urokinase plasminogen activator receptor (uPAR) and HER-2. In vitro experiments demonstrated that specifically blocking the uPA-uPAR and HER-2 signaling pathways may effectively promote the apoptosis of breast cancer cells. Additionally, ATF-Fc-induced cell death in HER 2-positive breast cancer cells was observed in vivo. When ATF-Fc was administered in combination with trastuzumab, cell death was increased and breast cancer metastasis was reduced. The novel engineered antibody-like molecule ATF-Fc was able to inhibit HER-2-positive breast cancer cell growth and metastasis by interfering with uPA and its receptor (uPA-uPAR) system. Additionally, the antibody-like molecule exhibits a synergistic inhibitory effect when administered in combination with trastuzumab. PMID- 29113155 TI - POEMS syndrome presentation with progressive weakness in upper and lower limbs: A case report. AB - Polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes (POEMS) syndrome is a rare variant of plasma cell disorders with multiple systemic manifestations. A 50-year-old female patient presented with progressive weakness in her upper and lower limbs; tingling, numbness and burning in her feet; polyneuropathy (demyelinating in the majority of cases of POEMS syndrome); monoclonal plasma cell disorder (typicallylambda-restricted in cases of POEMS syndrome); sclerotic lesions on the spine and pelvis; organomegaly, including hepatomegaly, splenomegaly and lymphadenopathy; edema; pleural effusion; adrenal, thyroidal, pituitary, gonadal and pancreatic endocrinopathy; skin changes, including hyperpigmentation, dry skin and hypertrichosis; thrombocytosis; pulmonary hypertension; low vitamin B12 and weight loss. Following the diagnosis of POEMS syndrome, the patient was treated only with pain-alleviating corticosteroids. Respiratory failure-induced mortality occurred 24 months after the patient first experienced difficulty walking and numbness in her lower extremities. The present study suggests that abnormal symptoms in cases of POEMS syndrome should be further evaluated during the diagnosis and treatment. PMID- 29113156 TI - Identification of potential therapeutic targets for gliomas by bioinformatics analysis. AB - Gliomas are primary tumors that originate in the brain or spinal cord and develop from supportive glial cells. The present study aimed to identify potential candidate molecular markers for the treatment of gliomas, and to explore the underlying mechanisms of this disease. The gene expression profile data GSE50021, which consisted of 10 specimens of normal brain tissues and 35 specimens of glioma tissues, was downloaded from Gene Expression Omnibus (GEO). The methylation microarray data GSE50022, consisting of 28 glioma specimens, was also downloaded from GEO. Differentially expressed genes (DEGs) between patients with glioma and normal individuals were identified, and key methylation sites were screened. Transcriptional regulatory networks were constructed, and target genes were selected. Survival analysis of key methylation sites and risk analysis of sub-pathways were performed, from which key genes and pathways were selected. A total of 79 DEGs and 179 key methylation sites were identified, of which 20 target genes and 36 transcription factors were included in the transcriptional regulatory network. Glutamate metabotropic receptor 2 (GRM2) was regulated by 8 transcription factors. Inositol-trisphosphate 3-kinase A (ITPKA) was a significantly enriched DEG, associated with the inositol phosphate metabolism pathway, Survival analysis revealed that the survival time of patients with lower methylation levels in cg00157228 was longer than patients with higher methylation levels. ITPKA was the closest located gene to cg00157228. In conclusion, GRM2 and enriched ITPKA, associated with the inositol phosphate metabolism pathway, may be key mechanisms in the development and progression of gliomas. Furthermore, the present study provided evidence for an additional mechanism of methylation induced gliomas, in which methylation results in the dysregulation of specific transcripts. The results of the present study may provide a research direction for studying the mechanisms underlying the development and progression of gliomas. PMID- 29113157 TI - Lack of microsatellite instability in gastrointestinal stromal tumors. AB - The microsatellite instability (MSI) phenotype may constitute an important biomarker for patient response to immunotherapy, particularly to anti-programmed death-1 inhibitors. MSI is a type of genomic instability caused by a defect in DNA mismatch repair (MMR) proteins, which is present mainly in colorectal cancer and its hereditary form, hereditary nonpolyposis colorectal cancer. Gastrointestinal stromal tumor (GIST) development is associated with activating mutations of KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet derived growth factor receptor alpha (PDGFRA), which are oncogenes that predict the response to imatinib mesylate. In addition to KIT/PDGFRA mutations, other molecular alterations are important in GIST development. In GISTs, the characterization of the MSI phenotype is scarce and the results are not consensual. The present study aimed to assess MSI in a series of 79 GISTs. The evaluation of MSI was performed by pentaplex polymerase chain reaction comprising five markers, followed by capillary electrophoresis. The expression of MMR proteins was evaluated by immunohistochemistry. Regarding the KIT/PDGFRA/B-Raf proto-oncogene, serine/threonine kinase molecular profile of the 79 GISTs, 83.6% of the tumors possessed KIT mutations, 10.1% had PDGFRA mutations and 6.3% were triple wild-type. The mutated-PDGFRA cases were associated with gastric location and a lower mitotic index compared with KIT-mutated and wild-types, and these patients were more likely to be alive and without cancer. MSI analysis identified 4 cases with instability in one marker, however, additional evaluation of normal tissue and immunohistochemical staining of MMR proteins confirmed their microsatellite-stable nature. The results of the present study indicated that MSI is not involved in GIST tumorigenesis and, therefore, cannot serve as a biomarker to immunotherapy response in GIST. PMID- 29113158 TI - Lysosome-associated protein transmembrane4beta is involved in multidrug resistance processes of colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common reasons for cancer-associated mortality worldwide. The present study aimed to investigate the drug resistance mechanism of the oxaliplatin (OXA)-resistant HT-29 cell line (HT-29/L-OHP) and examine the expression of lysosome-associated protein transmembrane 4beta (LAPTM4beta), a drug resistance-associated gene. In the present study, a drug concentration gradient method was used to establish the drug-resistant HT-29/L OHP cell line. Cell apoptosis was analyzed by flow cytometry. LAPTM4beta mRNA expression was examined by reverse transcription-quantitative polymerase chain reaction analysis and LAPTM4beta-35 expression was examined by western blot analysis. Cell morphology of the HT-29/L-OHP drug-resistant cell line was examined. The results indicated that the intercellular space among HT-29 cells was small, with aggregative growth while the intercellular space among HT-29/L OHP cells was large, with scattered growth. The apoptotic rate in HT-29/L-OHP cells (11.7%) was significantly lower compared with that in HT-29 cells (17.7%) (P<0.05). LAPTM4beta mRNA expression in HT-29/L-OHP cells was significantly increased compared with that in HT-29 cells (P<0.05). The relative expression of LAPTM4beta-35 protein in HT-29/L-OHP cells was significantly higher compared with that inHT-29 cells (P<0.05). In conclusion, LAPTM4beta may be involved in the multidrug resistance processes of CRC. Therefore, LAPTM4beta may serve as a novel biomarker for drug resistance of CRC. PMID- 29113159 TI - Treatment of osteosarcoma around the knee in skeletally immature patients. AB - Limb sparing surgery in growing young patients with malignant tumors is difficult as invasion of the physis by the tumor or surgical resection through the metaphysis may cause significant limb discrepancy following surgery. At present, hinged tumor prosthesis or biological reconstructions are the main methods following tumor resection in these patients. The aim of the present study was to assess different procedures for the treatment of osteosarcoma around knee joints in immature patients. A retrospective study of 56 patients (<15 years old, open physis) who had been treated for osteosarcoma around the knee joint between January 2007 and December 2015 was performed. Clinical data collected included patient demographics (age at diagnosis, sex and date of diagnosis), tumor characteristics [location, Enneking stage and subtype on magnetic resonance imaging (MRI)], treatment (response to neoadjuvant chemotherapy and type of primary surgery) and clinical outcomes (limb function, discrepancy and overall survival). The median age at the time of diagnosis was 12.14 years (range, 3-15 years). There were 32 male patients (57.1%). A total of 41 (82%) tumors were located at the distal femur, and 15 (18%) at the proximal tibia. A total of 49 (87.5%) patients were diagnosed with stage IIB tumors, and 7 (12.5%) had stage III, according to the Enneking stage classification. Different surgical methods, including amputation, rotation-plasty, endoprosthesis and biological instructions (e.g., allograft) were performed according to MRI type classification. During follow-up, 21 patients (37.5%) succumbed to disease. The Musculoskeletal Tumor Society score ranged from excellent to fair functional result. Recurrence (2 cases, 16.67%) and infection (2, cases, 16.67%) were the main complications following endoprosthesis replacement, while delayed union (12 cases, 57.14%) and fracture (3 cases, 14.29%) were the main causes for biological reconstructions. Limb-length discrepancy ranged from 0-10 cm in limb-saving surgery. The overall survival rate was 57.66% with different cohorts in Enneking stages IIB and III, with or without involvement of the physis and different cycles of chemotherapy. Results of the present study indicated that different limb saving surgeries, including epiphysis/physis preservation with biological construction in patients with MRI types I to III and endoprosthetic/osteoarticular reconstruction in patients with MRI types IV and V, are useful in the management of osteosarcoma in growing young patients with proper surgery indications, and knee joint function was maintained with acceptable complications including limb discrepancy, delayed union, infection, recurrence and fracture. PMID- 29113160 TI - Germline cytotoxic lymphocytes defective mutations in Chinese patients with lymphoma. AB - Certain patients with lymphoma may harbor mutations in perforin 1 (PRF1), unc-13 homolog D (UNC13D), syntaxin 11 (STX11), STXBP2 (syntaxin binding protein 2) or SH2 domain containing 1A (SH2D1A), which causes functional defects of cytotoxic lymphocytes. Data regarding the association between genetic defects and the development of lymphoma in Chinese patients are limited to date. In the present study, 90 patients with lymphoma were analyzed for UNC13D, PRF1, STXBP2, STX11, SH2D1A and X-linked inhibitor of apoptosis. Mutations were observed in 24 (26.67%) patients; 16 patients exhibited mutations in UNC13D, 7 exhibited PRF1 mutations, and 1 exhibited monoallelic mutation in STX11. UNC13D c.2588G>A/p.G863D mutation was detected in 9 patients (10.00%) and in 4/210 controls (1.90%). This mutation was predicted to be pathogenic and it predominantly existed in the Chinese population. These findings suggest that impaired cytotoxic machinery may represent a predisposing factor for the development of lymphoma. Furthermore, these data describe a distinct mutation spectrum in Chinese patients with lymphoma, whereby UNC13D is the most frequently mutated gene. In addition, these findings suggest UNC13D c.2588G>A mutation is a founder mutation in Chinese patients. PMID- 29113161 TI - Methylation of 14-3-3sigma gene and prognostic significance of 14-3-3sigma expression in non-small cell lung cancer. AB - Loss of 14-3-3sigma expression through DNA methylation has been associated with carcinogenesis and the prognosis for various cancer types. Detection of methylation of the gene in serum may be useful for diagnostic utility. The present study aimed to investigate the correlation between 14-3-3sigma methylation level in 36 paired tumor tissues of non-small cell lung cancer (NSCLC) and matched serum using methylation-specific polymerase chain reaction. The prognostic significance of 14-3-3sigma expression in 167 NSCLC was also evaluated using immunohistochemistry. Methylation of the 14-3-3sigma gene was identified in all samples. The methylation level in the serum (mean 87.7%, range 64.6-100%) was higher compared with tumor (mean 46.7%, range 25.3-56.3%). However, no significant correlation between methylation levels in tissues and serums was observed (Spearman's correlation, -0.036; P=0.837). In the 167 tumor tissues, the majority of the cases (83.8%) exhibited negative expression. Adenocarcinoma is more likely to exhibit negative expression (91.4%) compared with squamous cell carcinoma (70.2%). No significant difference was identified in the overall survival according to 14-3-3sigma expression status and 14-3-3sigma expression did not demonstrated independent prognostic significance. In conclusion, NSCLC harbors certain levels of 14-3-3sigma methylation in the tumor and the sera of patients. The clinical value of serum 14-3-3sigma methylation should be further elucidated. Immunohistochemical expression 14-3-3sigma protein has limited value on prognostic significance. PMID- 29113162 TI - Retrospective analysis of the association between human epidermal growth factor receptor 2 amplification and chromosome enumeration probe 17 status in patients with breast cancer. AB - The aim of the present study was to identify potential human epidermal growth factor receptor 2 (HER2) amplification, according to American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) 2013 HER2 testing guidelines, in patients previously determined not to possess HER2 amplification, in accordance with previous 2007 guidelines. Potential discrepancies may arise from chromosome enumeration probe 17 (CEP17) amplification, deletion, polysomyor monosomy. HER2, CEP17, tumor protein p53 (TP53) and retinoic acid receptor alpha (RARA) genes from 67 patient specimens with suspected amplification, polysomy or monosomy of CEP17 were analyzed using fluorescence in situ hybridization. HER2 status was interpreted using 2007 and 2013 ASCO HER2 test guidelines as well as the reference genes TP53 and RARA. According to ASCO/CAP2007 HER2 guidelines, 20 patients exhibited HER2 amplification (29.85%), 41 were without HER2 amplification (including 25 with polysomy, 15 with monosomy and 1 with suspected monosomy plus co-amplification of HER2 and CEP17) and the remaining 6 patients were equivocal. Using ASCO/CAP 2013 HER2 guidelines, 49 patients exhibited HER2 gene amplification (73.1%). The 29-patient increase included 6 originally at equivocal levels but now demonstrating amplification, 22 originally with polysomy but now revealing co-amplification, and 1 with suspected monosomy plus co amplification of HER2 and CEP17. According to TP53 and RARA, HER2 was amplified in 43 patients (64.1%). Using the revised guidelines, HER2, originally identified as amplified in 6 patients, was not amplified following the introduction of TP53 and RARA control genes. Among these 6, 4 possessed normal TP53 and RARA. The incidence of co-amplification of HER2 and CEP17 was 1.4% (21/1,518). RARA and TP53 are suitable control genes to evaluate HER2 status. PMID- 29113163 TI - Knockdown of MSI1 inhibited the cell proliferation of human osteosarcoma cells by targeting p21 and p27. AB - Osteosarcoma is the most common type of primary bone cancer in children and adolescents, but its mechanism remains unclear. Musashi RNA-binding protein 1 (MSI1) is highly expressed in certain cancer types and functions as a putative progenitor/stem cell marker. In the present study, it was demonstrated that MSI1 expression in osteosarcoma tissue was higher compared with in the paraneoplastic tissue samples. Knockdown of MSI1 using shRNA in MG-63 and HOS cells inhibited cell proliferation in vitro and tumor formation in vivo, suggesting that MSI1 serves an essential role in osteosarcomagenesis. Further investigations demonstrated that the knockdown of MSI1 leads to the cell cycle arrest at G0/G1 phase, and the upregulation of p21 and p27 protein expression in osteosarcoma cells. Additionally, luciferase assays demonstrated that MSI1 can bind to the 3' untranslated regions of p21 and p27 mRNA. In conclusion, the results of the present study suggest that the knockdown of MSI11 can suppress cell proliferation of osteosarcoma by targeting p21 and p27 and subsequently inhibiting cell cycle progression. PMID- 29113164 TI - Methylation and expression of RECK, P53 and RUNX genes in patients with esophageal cancer. AB - The methylation and expression of RECK, P53 and RUNX genes in patients with esophageal cancer was investigated. In order to achieve this aim, a sample of 58 patients with esophageal cancer, treated between February 2013 and February 2014, were considered as the observation group. Additionally, a sample of 42 healthy individuals was selected as the control group. Methylation status of RECK, P53 and RUNX genes from the observation and control groups were detected by MSP. Reverse transcriptase-quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), western blot and immunohistochemistry were used to detect the mRNA and protein levels of RECK, P53 and RUNX in both the observation and the control groups. Results showed that the methylation rates of RECK, P53 and RUNX genes in patients with esophageal cancer were 72.4% (42/58), 1.7% (1/58) and 3.4% (2/58), respectively, which were significantly different from those in the control group [7.1% (3/42), 90.5 (38/42), and 83.3% (35/42), respectively]. The mRNA expression level of RECK is only equal to the 2.3% of that in the control group, while the mRNA expression levels of P53 and RUNX were 65.1 and 47.2 times higher than those in the control group, respectively (p<0.05). ELISA showed that RECK protein level in the observation group (0.12+/-0.05) ug/l, was significantly lower than the control group (3.46+/-0.08) ug/l (p<0.05), while, P53 and RUNX protein levels in observation group were significantly higher than that in healthy people (6.43+/ 0.12 ug/l vs. 0.64+/-0.06 ug/l and 4.32+/-0.14 ug/l vs. 0.53+/-0.09 ug/l, respectively), and the results were similar to western blot. The data of immunohistochemistry showed that the proportion of RECK protein positive cells in the observation group was significantly lower than that in the control group (9.5 vs. 82.3%, P<0.05), while the proportions of P53 and RUNX protein positive cell in the observation group were significantly higher than those in the control group (78.4 vs. 11.1% and 87.3 vs. 9.06%), respectively, (P<0.05). This study concluded that, in patients with esophageal cancer, the methylation of RECK gene is increased and the expression of RECK gene is inhibited, while methylation of RUNX gene decreased and their expression was increased. This change in methylation of these genes may promote the occurrence and development of esophageal cancer. PMID- 29113165 TI - The prognostic significance of tumor lymphangiogenesis and lymphatic vessel density in endometrioid carcinoma of the uterine corpus. AB - The present study aimed to assess the prognostic significance of tumor lymphangiogenesis and lymphatic vessel density (LVD) in endometrioid carcinoma of the uterine corpus. The association between LVD and various factors, including lymphatic vessel invasion (LVI), and nodal metastases, were investigated. Among 202 surgically treated cases, 19 cases with nodal metastases with the infiltration reaching the outer-half myometrium (N+ group) were selected. The LVDs of hotspots in each case were examined at 100* magnification on D2-40 stained slides of the inner- and outer-half myometrium of the peritumoral, and control compartments. Furthermore, for the peritumoral compartment, the LVDs in two types of areas, LVI-present and LVI-absent, were examined for each location of myometrium, which amounted to 6 spots/case. They were statistically compared. Second, to determine whether the existing myometrium influenced LVD, LVDs in the intratumoral compartment were investigated, which were defined as a region where residual muscular tissue was unrecognizable with desmin-immnostaining. As a negative control group, LVDs of the inner- and outer-half myometrium of the peritumoral, and control compartments of 29 cases without nodal metastases in stage IB (N- group) were examined. No significant association was identified between the LVD and frequency of LVI. However, the LVDs in the peritumoral compartment and inner-half myometrium were higher compared those in the control compartment, and outer-half myometrium in N+ and N- groups, respectively. No significant differences were identified in LVD of the peritumoral compartment between groups. The lymphatic vessels were absent where the existing muscular tissue was absent in 16/19 cases. Although higher LVDs in the peritumoral compartment suggested tumor lymphangiogenesis, it was not associated with LVI and nodal metastases. Other factors that influenced LVD were the location in the myometrium and the existing myometrium. PMID- 29113166 TI - Expression of circadian clock genes in human colorectal adenoma and carcinoma. AB - Circadian rhythms are fundamental biological systems in most organisms. Epidemiological and animal studies have demonstrated that disruption of circadian rhythms is linked to tumor progression and mammalian tumorigenesis. However, the clinical significance of in situ clock gene expression in precancerous and cancerous colorectal lesions remains unknown. The present study aimed to investigate mRNA transcript levels of circadian clock genes within human colorectal cancer and adenoma tissue sections. Using in situ hybridization, the expression of key clock genes, including period circadian protein homolog (Per) 1 and 2, cryptochrome 1 (Cry1), circadian locomoter output cycles protein kaput (Clock), brain and muscle ARNT-like protein 1 (Bmal1) and casein kinase 1epsilon (CK1epsilon) were retrospectively examined in 51 cases of colorectal carcinoma and 10 cases of adenoma. The expression of clock genes was almost undetectable in the majority of adenomas, whereas positive expression of clock genes was observed in 27-47% of carcinomas. Notably, positive Per1, Per2 and Clock staining in colorectal carcinomas were each significantly associated with a larger tumor size (P=0.012, P=0.011 and P=0.009, respectively). Tumors with positive Per2 and Clock expression tended to exhibit deeper depth of invasion and were generally more advanced than tumors that did not express these genes (P=0.052 and P=0.064, respectively). However, no statistically significant association was observed between clock gene expression and clinicopathological variables, including histopathological differentiation, lymph node metastasis, depth of invasion or disease stage, although Per2-positive tumors tended to be associated with poorer overall survival (P=0.060). The results of the current study suggest that dysregulated expression of clock genes may be important in human colorectal tumorigenesis. PMID- 29113167 TI - Endocan silencing induces programmed cell death in hepatocarcinoma. AB - Hepatocarcinoma is a type of high-grade malignant carcinoma identified worldwide. Its rapid development and late diagnosis prevents effective tumor resection in the majority of patients, and therefore recent studies have targeted metabolic signaling pathways and the tumor microenvironment for potential treatments. To investigate whether endocan may be a gene target for hepatocarcinoma treatment, the present study employed the following measures: MTT and Transwell assays, flow cytometry, western blotting and an mRFP-GFP-LC3 double fluorescence system. Following endocan gene silencing, cell proliferation was significantly inhibited and the number of invasive cells in the endocan siRNA-treated group was reduced compared with the control-siRNA treated-group. Furthermore, the apoptosis rate was 15% and autophagy was detected in the endocan short interfering (si)RNA treated group compared with the control-siRNA treated-group. Using western blotting to detect NF-kappaB expression in the nucleus, the NF-kappaB expression was identified to be significantly reduced in the siRNA-treated group compared with the control groups. Endocan gene silencing inhibited hepatocarcinoma cell viability and invasion, whilst inducing apoptosis and autophagy. The results of the present study suggest that the effect of endocan gene silencing on cell survival was mediated via the NF-kappaB signaling pathway. PMID- 29113168 TI - Negative correlation between X-linked inhibitors of apoptosis and second mitochondria-derived activator of caspase expression levels in cervical carcinoma and cervical intraepithelial neoplasia. AB - X-linked inhibitors of apoptosis (XIAP) and second mitochondria-derived activator of caspase (Smac) have been widely reported to serve roles in the development of cervical carcinoma. The present study analyzed the associations between the expression levels of XIAP and Smac in normal cervical epithelium, cervical intraepithelial neoplasia (CIN) and cervical carcinoma. Immunohistochemistry staining of formalin-fixed, paraffin-embedded tissue sections was performed in order to analyze the expression levels of XIAP and Smac in 15 cases of normal cervical tissues, 69 cases of CIN and 76 cases of cervical carcinoma. All the tissue samples were confirmed by pathological diagnosis. The association of XIAP and Smac expression levels was analyzed using one-way analysis of variance, chi2 tests and Spearman's rho for the nonparametric bi-variant correlation analysis. Overall survival was determined using the log-rank test and Kaplan-Meier survival curves. The expression level of XIAP was increased in CIN and cervical carcinoma tissues compared with normal cervical tissues, whereas Smac demonstrated a converse expression pattern to XIAP in these tissues. The positive staining level of XIAP protein was increased in grade 3 CIN compared with that in grade 1-2 CIN, and was significantly higher in the less-differentiated tissue of cervical carcinoma compared with the well- or medium-differentiated tissues (P<0.05). The staining level was also significantly increased in cervical carcinoma with stage 2b-3 compared with tissues from stage 1-2a carcinoma (P<0.05). The expression levels of Smac were in opposition to these results. XIAP was associated with pelvic lymph node metastasis, whereas no association was identified with Smac expression. The expression level of XIAP was significantly and negatively associated with cell survival time in cervical carcinoma, whereas the expression level of Smac was significantly and positively associated with cell survival time in cervical carcinoma. Therefore, XIAP and Smac may participate in the development of cervical cancer. The expression levels of XIAP and Smac were significantly and inversely associated. This may be useful in early diagnosis, evaluation of surgery and chemotherapy and the prognosis of cervical carcinoma. PMID- 29113169 TI - Lentivirus-mediated RNA interference inhibits the tumorigenicity of cluster of differentiation 44+ tumor cells in hypopharyngeal cancer. AB - The present study aimed to investigate whether the inhibition of cluster of differentiation (CD)44 expression reduces the tumorigenicity of CD44+ cancer stem cells in hypopharyngeal cancer. To assess this, effective recombinant CD44 short hairpin RNA-expressing lentiviruses were produced. Lentivirus-mediated RNA interference (RNAi) was then used to knockdown CD44 gene expression in the hypopharyngeal cancer FaDu cell line. The viability of FaDu cells in the two control groups and the RNAi group (RNAi-CD44 lentiviral vector) was detected using an MTT assay in vitro. Cells from each group were injected into non-obese diabetic/severe combined immunodeficiency mice and their tumorigenicity determined in vivo. Following lentivirus-mediated RNAi, an MTT assay indicated that cells from the RNAi group exhibited lower viability than the control group. The in vivo tumorigenicity study further revealed a significant difference in tumorigenic rates between the RNAi group and the control group (Fisher's exact test, P<0.05). In addition, tumors in the RNAi group of animals had a longer incubation period than those in the control groups, and the mean tumor volume was also significantly smaller (t=3.47, P<0.05). Pathological study confirmed that all tumors were poorly differentiated squamous cell carcinomas with cellular heterogeneity. The viability of the hypopharyngeal cancer FaDu cells in vitro and their tumorigenicity in vivo were markedly inhibited once CD44 was knocked down. The results of the present study therefore suggest that CD44 may confer tumorigenic characteristics upon CD44+ cancer stem cells in hypopharyngeal cancer. PMID- 29113170 TI - Screening of potential therapy targets for prostate cancer using integrated analysis of two gene expression profiles. AB - The aim of the present study was to analyze potential therapy targets for prostate cancer using integrated analysis of two gene expression profiles. First, gene expression profiles GSE38241 and GSE3933 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between prostate cancer and normal control samples were identified using the Linear Models for Microarray Data package. Pathway enrichment analysis of DEGs was performed using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Furthermore, protein-protein interaction (PPI) networks of DEGs were constructed, on the basis of the Search Tool for the Retrieval of Interacting Genes/Proteins database. The Molecular Complex Detection was utilized to perform module analysis of the PPI networks. In addition, transcriptional regulatory networks were constructed on the basis of the associations between transcription factors (TFs) and target genes. A total of 529 DEGs were identified, including 129 upregulated genes that were primarily associated with to the cell cycle. Additionally, 400 downregulated genes were identified, which were principally enriched in the pathways associated with vascular smooth muscle contraction and focal adhesion. Cell Division Cycle Associated 8, Cell Division Cycle 45, Ubiquitin Conjugating Enzyme E2 C and Thymidine Kinase 1 were identified as hub genes in the upregulated sub-network. Furthermore, the upregulated TF E2F, and the downregulated TF Early Growth Response 1, were identified to be critical in the transcriptional regulatory networks. The identified DEGs and TFs may have critical roles in the progression of prostate cancer, and may be used as target molecules for treating prostate cancer. PMID- 29113171 TI - Clinicopathological features and prognostic factors in angiosarcoma: A retrospective analysis of 200 patients from a single Chinese medical institute. AB - Angiosarcoma is a rare soft tissue sarcoma, and the data about its clinicopathological features and prognostic factors are limited. The purpose of the present study was to report a large series of angiosarcoma at a single institution. Clinical data from 200 cases of angiosarcoma from the Shanghai Cancer Center (Shanghai, China) between March 2006 and March 2014 were retrospectively analyzed. The study population included 97 males and 103 females with ages between 4 and 91 years (median, 53 years). According to the tumor location, 200 cases were divided into 4 groups: i) Tumors involving the head and neck; ii) breast; iii) viscera (including internal organs and bone); and iv) soft tissue (including trunk and extremities). Of the 113 patients with follow-up data, 46 patients succumbed to the disease with a median interval of 10 months. Tumor recurrence/metastasis was identified in 66 patients with a median interval of 4 months. The disease-free survival (DFS) rate at 5-years was 19.3% and the overall survival (OS) rate at 5-years was 40.8%. Site of tumor origin, size (>=5 cm) and histological differentiation influenced DFS (P=0.032, 0.038 and <0.001, respectively), and OS (P<0.001, 0.008 and <0.001, respectively) rates. Age (<65 years) and multimodal treatment correlated with improved OS (P=0.003 and <0.001, respectively). Tumor differentiation and treatment modality were identified to be independent determinants of OS (P<0.001 and 0.038, respectively). Tumor recurrence/metastasis was an independent predictor of DFS (P<0.001). The prognosis of angiosarcoma is poor and the mortality rate is high. The site of tumor origin, size, histological differentiation, age, treatment modality and tumor recurrence/metastasis are all significant prognostic factors. In the present study, multimodal treatment may improve the clinical outcome of patients with angiosarcoma. PMID- 29113172 TI - Elevated FKBP52 expression indicates a poor outcome in patients with breast cancer. AB - The 52-kDa FK506-binding protein (FKBP52), a regulator of steroid hormone receptor signaling, is potentially involved in a variety of hormone-dependent cancer types. The present study investigated the expression and clinical implications of FKBP52 in breast cancer. Immunohistochemistry was performed on samples from 145 breast cancer patients and on 66 unmatched breast non-cancerous tissues (as controls) to determine the expression level of FKBP52. Publicly available microarray and RNA-seq datasets used in the present study were downloaded from the European Bioinformatics Institute ArrayExpress. Kaplan-Meier survival analysis was also performed. FKBP52 expression was moderately higher in the tumors than that in the non-cancerous tissues, but this difference was not statistically significant (P=0.176). However, available microarray datasets exhibited a significant difference in FKBP52 mRNA levels between breast tumors and controls. In the 145 breast cancer patients, elevated FKBP52 expression was significantly associated with advanced Tumor-Node-Metastasis (TNM) stage (P=0.015), lymph node metastasis (P=0.015) and tumors with poor histological differentiation (P=0.047). FKBP52 expression was negatively associated with estrogen receptor expression (P=0.033), but positively associated with human epidermal growth factor receptor 2 expression (P=0.033). However, there was no association between FKBP52 and progesterone receptor expression. Survival analyses demonstrated that FKBP52 was indicative of a poor overall survival rate (P=0.026), which was consistent with the result of Kaplan-Meier analysis, exhibiting a negative association between the mRNA of FKBP52 and overall survival (OS) (P=0.044). Other than for FKBP52 [hazard ratio (HR), 2.315; 95% confidence interval (CI), 1.077-4.975; P=0.032], univariate analysis revealed that clinical stage exhibited a significant influence on the prognosis of the breast cancer patients (HR, 2.148; 95% CI, 1.011-4.566; P=0.047). However, multivariate analysis revealed that only clinical stage, not FKBP52, was an independent prognostic factor (HR, 2.721; 95% CI, 1.169-6.335; P=0.020). Patients were further classified according to their OS. Compared with the controls (3.94+/ 2.992), FKBP52 expression in breast cancer patients with OS of <=3 years (5.39+/ 3.409; P=0.042) or OS of <=5 years (5.88+/-3.473; P=0.005) was significantly increased, respectively. However, no significant difference in FKBP52 expression was observed between controls and individuals with an OS time of >3 years (4.84+/ 3.769; P=0.109) or >5 years (5.32+/-3.372; P=0.090). Elevated FKBP52 expression may be involved in tumor progression and invasion, given its positive association with TNM stage and lymph node metastasis. Although it is not an independent predictor, FKBP52 has promise as a biological marker for estimating the progression of breast cancer. PMID- 29113173 TI - Bioinformatics analysis of SRSF1-controlled gene networks in colorectal cancer. AB - Colorectal cancer is the third most common type of cancer and the fourth leading cause of cancer-associated mortality worldwide. Serine/arginine-rich splicing factor 1 (SRSF1) is a well-characterized oncogenic factor that promotes tumorigenesis by controlling a number of alternative splicing events. However, there is limited network analysis, from a global aspect, to study the effect of SRSF1 on colorectal cancer. In the present study, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of available gene regulation data from The Cancer Genome Atlas database revealed the enriched functions and signaling pathways of SRSF1. Subsequently, Oncomine analysis was performed, which demonstrated that SRSF1 was upregulated in a number of types of colon cancer. From overlapping the analysis of 2,678 SRSF1-related genes and 3,625 colorectal cancer genes in GeneCards, 468 genes were identified as SRSF1-related colorectal cancer genes. The GO results revealed that these overlapped genes were primarily enriched in metabolic processes, response to DNA damage, regulation of the cell cycle and a number of additional biological processes. KEGG pathway analysis revealed that SRSF1-related colorectal cancer genes were associated with the cell cycle, deregulated signaling pathways associated with cancer progression and colorectal cancer signaling pathways. In addition, the Search Tool for the Retrieval of Interacting Genes/Proteins database and Cytoscape analysis demonstrated that 468 SRSF1-related colorectal cancer genes exhibit potential interaction networks in which these genes were enriched in DNA metabolic processes, cell cycle regulation and regulation of apoptosis. The results of the present study suggested that SRSF1 exhibited an increased degree of interaction with key molecules, including NUF2 NDC80 kinetochore complex component, kinesin family member 2C, structural maintenance of chromosomes 3, ATM serine/threonine kinase, BRCA1 DNA repair associated, protein kinase DNA-activated catalytic polypeptide, heat shock protein 90 alpha family class A member 1, ras homolog family member A, and phosphatase and tensin homolog. Collectively, the bioinformatics analysis of the present study indicated that SRSF1 may have key functions in the progression and development of colorectal cancer. PMID- 29113175 TI - Correlation of MMP-9 and p53 protein expression with prognosis in metastatic spinal tumor of lung cancer. AB - The aim of the study was to compare the protein expression of MMP-9 and p53 and examine their correlation with prognosis in lung cancer metastatic spinal tumor. Tissue samples were obtained from 30 cases of para-cancerous tissue (group I), 75 cases of non-metastatic lung cancer tissue (group II) and 100 cases of metastatic spinal tumor tissue of lung cancer (group III). The protein expression of MMP-9 and p53 was detected by immunohistochemistry and was present in all three groups. The positive rate for MMP-9 was 20, 67 and 83%, respectively. There was a significant difference among the three groups (p<0.05). The positive rate for p53 was 16.7, 78.7 and 92%, respectively. There was a highly significant difference among the three groups (p<0.01). There was a positive correlation between the protein expressions of MMP-9 and p53 (Spearman's correlation coefficient r=0.351, p<0.05). The positive or negative expression of the two proteins was statistically significant (p<0.05) for 5-year survival. The expression of MMP-9 and p53 proteins in metastatic spinal tumors of lung cancer showed increasing trends, and the expression of MMP-9 and p53 proteins was significantly higher compared to non-metastatic lung cancer tissue and para-cancerous tissue samples. This likely was associated with the invasion and metastasis of lung cancer to the spine. Survival analysis suggested that the overexpression of p53 and MMP-9 were correlated with poor prognosis. PMID- 29113174 TI - Quantitative analysis of permeability for glioma grading using dynamic contrast enhanced magnetic resonance imaging. AB - The objective of the present study was to quantitatively analyze the permeability of tumor entity and peritumor edema in glioma grading, using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). In the present retrospective study, 80 patients underwent T1-weighted DCE-MRI examination at 3.0 T and the pathological results (including astrocytoma and oligodendroglioma) were obtained between January 2012 and June 2015. All cases were surgically validated as grade I-IV gliomas. The original DCE-MRI data were analyzed using dual compartment modified Tofts model. The forward volume transfer constant (Ktrans), backflux rate (kep) and fractional volume (ve) were calculated with the region of interest selected on the highest permeability area of the tumor entity and peritumor edema. Analysis of variance with the Bonferroni correction was used to compare the values of Ktrans, kep, and ve of the tumor entity and peritumor edema in different glioma grades. The results of the present study revealed that the Ktrans, kep, and ve values in each stage were associated with the pathological grading (r=0.951, 0.804 and 0.766, respectively). There were significant differences identified between different tumor grades in Ktrans, kep, with the exception being between grades II and III in kep. In addition, there was a significant difference revealed between grade I/II and grade III/IV in ve. Receiver operator characteristics curve analysis was used to evaluate the diagnosis accuracies of permeability parameters. Ktrans was demonstrated to exhibit the highest sensitivity and specificity for evaluating the tumor grade. With the threshold values of 0.160, 0.420 and 0.935 in Ktrans on tumor, glioma grades I vs. II, II vs III and III vs. IV may be differentiated with sensitivities of 0.900, 0.950 and 0.950, and specificities of 0.950, 0.950 and 0.850, respectively. Furthermore, associations were observed between the Ktrans, kep and ve values of peritumor edema and the pathological grading in glioma (Ktrans r=0.438, P<0.001; Kep r=0.385, P<0.001; Ve r=0.397, P<0.001, respectively). Ktrans values in peritumoral edema revealed significant differences between low-grade and high-grade glioma. The sensitivity and specificity for Ktrans of peritumor edema were 0.975 and 0.950, with a threshold value of 0.007. Therefore, the DCE-MRI parameters of Ktrans of tumor entity and peritumor edema in gliomas may be used to accurately differentiate glioma grades. PMID- 29113176 TI - Stereolithographic model-assisted reconstruction of the mandibular condyle with a vascularized fibular flap following hemimandibulectomy: Evaluation of morphological and functional outcomes. AB - The vascularized fibular flap is one of the standard treatment choices for the reconstruction of the mandible; however, the consequences of condylar restoration have not previously been reported. The use of three-dimensional models allows for a more predictable reconstruction. The purpose of the present study was to assess the outcome of stereolithographic model-assisted reconstruction of the mandibular condyle with a vascularized fibular flap. A total of 5 patients underwent mandibular resection including the condyle and immediate reconstruction with a vascularized fibular flap. A stereolithographic model was used to determine the length and angle of the bony reconstruction. In all patients, the temporomandibular joint (TMJ) disc was preserved, and the contoured fibular end was placed directly into the glenoid fossa under the TMJ disc. To investigate the morphological and functional outcomes, radiographic and clinical examinations were performed, and a food scale questionnaire was administered. The mean period of follow-up was 23 months, and all the flaps were viable. Cosmetic results were generally satisfactory. Radiographic assessment revealed that the end of the fibular graft became round-shaped. None of the patients had abnormal bone resorption, dislocation or ankylosis. The mean value of maximum mouth opening was 31 mm. No patients exhibited difficulties with occlusion. All patients recovered their ability to ingest nearly the same foods that were ingested prior to surgery. The stereolithographic model-assisted reconstruction of mandibular condyle with a vascularized fibular flap is therefore useful for morphological and functional reconstructions of the hemimandible, including condylar defects. PMID- 29113177 TI - Potential role of indoleamine 2,3-dioxygenase in primary biliary cirrhosis. AB - Indoleamine 2,3-dioxygenase (IDO)-induced immunosuppression can be clinically beneficial for autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by autoimmune lesions of intrahepatic bile duct epithelial cells that may lead to irreversible cirrhosis or hepatocellular carcinoma. The present study assessed the expression and function of IDO in a cell culture model and in PBC patients. IDO expression was monitored in a human immortalized but non malignant biliary epithelial cell (iBEC) line. Increased expression of IDO1/2 was observed in the iBECs following stimulation with interferon-gamma (IFN-gamma). The induction of IDO was IFN-gamma-dependent, but was independent of the transforming growth factor-beta (TGF-beta) pathway. IDO enzymatic activity was observed in the supernatant of iBECs following stimulation with IFN-gamma using colorimetric assays. A total of 47 serum samples from PBC patients were used to examine IDO activity by high-performance liquid chromatography, with samples from 24 healthy volunteers used as controls. Patients with PBC exhibited an increased rate of tryptophan to kynurenine conversion (P>0.01). Liver sections from patients with PBC (n=5) and those of healthy controls (n=5) were used for immunohistochemical studies. IDO expression was observed in biliary epithelial cells and in hepatocytes of PBC patients. Finally, the effect of tryptophan metabolites on human cluster of differentiation (CD) 4+ T cells in inducing polarization towards a regulatory T cell phenotype was examined. 3 Hydroxykynurenine significantly upregulated the fraction of CD4+ cells expressing forkhead box p3 (Foxp3). The results of the present study suggest a therapeutic opportunity for the management of PBC and indicate that tryptophan catabolism could serve as a potential biomarker to monitor disease progression. PMID- 29113179 TI - Blocking integrin beta1 decreases adhesion in chemoresistant urothelial cancer cell lines. AB - Treatment failure in metastatic bladder cancer is commonly caused by acquisition of resistance to chemotherapy in association with tumor progression. Since alterations of integrins can influence the adhesive and invasive behaviors of urothelial bladder cancer cell lines, the present study aimed to evaluate the role of integrins in bladder cancer cells with acquired resistance to standard first-line chemotherapy with gemcitabine, and cisplatin. Therefore, four gemcitabine- and four cisplatin-resistant sublines out of a panel of four parental urothelial bladder cancer cell lines (TCC-SUP, HT1376, T24, and 5637) were used. Expression of integrin subunits alpha3, alpha5, alpha6, beta1, beta3, and beta4 was detected using flow cytometry. Adhesion and chemotaxis were analyzed. For functional assays, integrin beta1 was attenuated with a blocking antibody. In untreated cells, chemotaxis was upregulated in 3/4 gemcitabine resistant sublines. In cisplatin-resistant cells, chemotaxis was enhanced in 2/4 cell lines. Acquired chemoresistance induced the upregulation of integrin beta1 in all four tested gemcitabine-resistant sublines, as well as an upregulation in 3/4 cisplatin-resistant sublines compared with parental cell lines. Following the inhibition of integrin beta1, adhesion to extracellular matrix components was downregulated in 3/4 gemcitabine-resistant sublines and in all four tested cisplatin-resistant sublines. Since integrin beta1 is frequently upregulated in chemoresistant urothelial cancer cell lines and inhibition of integrin beta1 may influence adhesion, further studies are warranted to evaluate integrin beta1 as a potential therapeutic target for bladder cancer in vivo. PMID- 29113178 TI - Immunohistochemical profile and prognostic significance in primary central nervous system lymphoma: Analysis of 89 cases. AB - The majority of primary central nervous system lymphomas (PCNSLs) are diffuse large B cell lymphoma, characterized by poor prognosis. In the present study, the expression of cluster of differentiation (CD)10, B cell lymphoma (BCL)-6, multiple myeloma-1 (MUM-1), BCL-2, CD138 and Ki-67 was analyzed by immunohistochemistry in 89 Chinese PCNSL cases, and the potential prognostic significance was evaluated. CD10, BCL-6, MUM-1, BCL-2 and CD138 were positive in 16.9 (15/89), 51.7 (46/89), 92.1 (82/89), 73.3 (63/86) and 0% (0/65) of all cases, respectively. According to the Hans algorithm, 71 patients (79.8%) were classified into the non-germinal center B cell-like (non-GCB) group, indicating a post-germinal center origin of PCNSL. The median follow-up time of 73 patients was 13 months [95% confidence interval (CI), 10.93-15.08]. The median overall survival (OS) time was 45.3 months (95% CI, 25.01-65.59) and the median progression-free survival (PFS) time was 30.0 months (95% CI, 13.43-46.57). Age (>60 years) was associated with a shorter OS time (P=0.009). Ki-67 (cutoff point 90%) was associated with shorter OS (P=0.037) and shorter PFS (P=0.039) times. No other immunohistochemical markers were associated with prognosis. On multivariate analysis, age (>60 years) was associated with shorter OS time (P=0.038), but immunophenotype and expression status of Ki-67, CD10, BCL-6 and BCL-2 did not predict prognosis. In conclusion, high Ki-67 expression may predict poor prognosis in PCNSL. The present study was limited by its sample size and short follow-up time. This requires more evidence to further clinical study. PMID- 29113180 TI - Helicobacter pylori modulates cyclooxygenase-2 and 15-hydroxy prostaglandin dehydrogenase in gastric cancer. AB - Persistent infection with Helicobacter pylori may contribute to the carcinogenesis of gastric cancer through modulating local prostaglandin E2 (PGE2) levels. Cyclooxygenase-2 (COX-2) and 15-hydroxy prostaglandin dehydrogenase (15 PGDH) are two key enzymes that regulate PGE2 synthesis and inactivation, respectively. The present study was designed to investigate the expression of COX 2 and 15-PGDH in gastric cancer specimens (n=66) in comparison to that of control specimens (n=70) and, furthermore, to semi-quantitatively assess the level of COX 2 and 15-PGDH mRNA and protein in tissues with or without H. pylori infection by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. It was revealed that COX-2 was expressed in almost all gastric cancer specimens infected with H. pylori (32 out of 33 specimens), but it was also expressed in 2/3 gastric cancers without H. pylori infection (22 out of 33 specimens). By contrast, COX-2 was expressed in <1/6 control subjects regardless of H. pylori infection. Furthermore, 15-PGDH was expressed in control samples but significantly downregulated in gastric cancer specimens. H. pylori infection resulted in slight inhibition of 15-PGDH in control subjects, but significant inhibition of 15-PGDH mRNA expression and protein synthesis in the gastric cancer specimens. These findings indicated that COX-2 and 15-PGDH, the two enzymes that regulate PGE2 levels, were significantly altered in gastric cancer, and that H. pylori may contribute to gastric carcinogenesis through modulating COX-2 and 15 PGDH mRNA expression and protein synthesis. PMID- 29113181 TI - MicroRNA profiling and bioinformatics analyses reveal the potential roles of microRNAs in chordoma. AB - Chordoma is a rare aggressive bone tumor arising from remnants of the notochord, and patients with chordoma have a poor prognosis. However, the unique expression profiles of microRNAs (miRNAs/miRs) and their downstream signaling pathways in chordoma remain incompletely characterized. The aim of the present study was to delineate the global miRNA expression profile and associated signaling networks in chordoma. miRNA profiling was performed on chordoma and fetal notochord tissues. Differentially expressed miRNAs in chordoma were analyzed using microarrays with hierarchical clustering analysis. The target genes of the differentially expressed miRNAs were predicted, and Gene Ontology (GO) and pathway analyses were performed for the intersecting genes. A total of 42 miRNAs were significantly dysregulated in chordoma compared with that in fetal nucleus pulposus tissues. The expression of hsa-miR-21-3p, hsa-miR-150-5p, hsa-miR-1290 and hsa-miR-623 were validated using the reverse transcription-quantitative polymerase chain reaction. On the basis of the intersection predicted by three databases (Targetscan, microRNA.org and PITA), 10,292 potential miRNA targets were identified. Bioinformatic analyses suggested that these dysregulated miRNAs and their predicted targets were functions of signaling pathways in cancer, the mitogen-activated protein kinase signaling pathway, regulation of actin cytoskeleton, focal adhesion and endocytosis. In particular, human (hsa-)miR-185 5p was identified as a crucial miRNA in chordoma development via the Wnt signaling pathway. The results of the present study provide a comprehensive expression and functional profile of differentially expressed miRNAs associated with chordoma. This profile may serve as a potential tool for biomarker and therapeutic target identification in patients with chordoma. PMID- 29113182 TI - Pteisolic acid G, a novel ent-kaurane diterpenoid, inhibits viability and induces apoptosis in human colorectal carcinoma cells. AB - Human colorectal cancer (CRC) is a major cause of cancer morbidity and mortality, and its incidence rates are increasing in economical transitioning areas globally. To develop efficient chemotherapy drugs for CRC, the present study isolated and identified a novel ent-kaurane diterpenoid from Pteris semipinnata, termed pterisolic acid G (PAG). This ent-kaurane diterpenoid was demonstrated to significantly inhibit the growth of human CRC HCT116 cells in a time- and dose dependent manner, determined using the Cell Counting Kit-8 assay. Additionally, western blot analysis, Hoechst 33342 staining and cytometry analysis revealed that PAG not only inhibited the viability of HCT116 cells by suppressing the dishevelled segment polarity protein 2/glycogen synthase kinase 3 beta/beta catenin pathway, but also induced the apoptosis of HCT116 cells by downregulating nuclear factor-kappaB p65 activity, stimulating p53 expression and promoting the generation of intracellular reactive oxygen species. These results suggest that PAG, a novel inhibitor of the Wnt/beta-catenin pathway and inducer of apoptosis, should be investigated in more detail using in vivo experiments and comprehensive mechanistic studies in order to examine the potential use of PAG as a novel therapeutic agent for the treatment of CRC. PMID- 29113183 TI - Function of the macrophage-capping protein in colorectal carcinoma. AB - To investigate the role of macrophage-capping protein (CapG) in the development and progression of colorectal carcinoma (CRC), immunohistochemistry (IHC), Kaplan Meier survival analysis, wound healing and Transwell migration assays were performed. The IHC results demonstrated that CapG was relatively highly expressed in CRC tissue compared with non-tumor tissue (P<0.001), and that the expression of CapG was significantly associated with the tumor site, differentiation, lymph node metastasis and clinical stage (P=0.021, P=0.036, P=0.012 and P=0.009, respectively). Wound healing and Transwell migration assays demonstrated that the reduction of CapG expression in a CRC cell line by RNA interference was associated with significantly impaired motility (P<0.001). Kaplan-Meier survival analysis revealed that the expression of CapG in tumor samples was not significantly associated with disease-free survival time. In conclusion, CapG was overexpressed in CRC and was associated with tumor progression; therefore, it may be a useful prognostic biomarker and therapeutic target in CRC. PMID- 29113184 TI - LncRNA UCA1 promotes the invasion and EMT of bladder cancer cells by regulating the miR-143/HMGB1 pathway. AB - The long non-coding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) is an oncogenic lncRNA in bladder cancer, and its upregulation is associated with enhanced cell invasion. However, the underlying mechanism remains to be elucidated. The present study demonstrated that UCA1 was positively associated with cell invasion ability and promoted epithelial-mesenchymal transition (EMT) of bladder cancer cells by inducing high mobility group box 1 (HMGB1). Furthermore, bioinformatics and luciferase reporter assays demonstrated binding sites of the tumor suppressive miR-143 within UCA1 and the 3'untranslated region of HMGB1. UCA1 negatively regulated miR-143 expression in a dose-dependent manner in bladder cancer cells. In addition, UCA1 and HMGB1 were upregulated and miR-143 was downregulated in bladder cancer specimens. Overall, the data suggested that UCA1 may promote the invasion and EMT of bladder cancer cells by regulating the miR-143/HMGB1 pathway, which exhibits an important regulatory role in the pathology of bladder cancer. PMID- 29113185 TI - Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling. AB - AMP-activated protein kinase (AMPK) is known as a pivotal regulator of cellular metabolism. Mounting evidences have demonstrated that AMPK activation exerts tumor suppressive activity on leukemia cells. The present study reported that adenine, an AMPK activator, triggers cell cycle arrest and autophagy of human chronic myelogenous leukemia K562 cells consequently suppressing cell viability. The present findings revealed that adenine treatment (4.0-8.0 mM) significantly inhibited the viability of K562 cells to 69.3+/-2.5% (24 h) and 53.4+/-2.1% (48 h) of the control. Flow cytometric analysis revealed that there was a significant accumulation in G2/M phase, but not sub-G1 phase K562 cells following exposure to adenine. Additional investigation demonstrated that adenine treatments significantly increased the number of acidic vesicular organelles and the level of autophagosomal microtubule associated protein 1 light chain 3 alpha (LC3) marker. By contrast, cleavage of caspase-9, caspase-3 and poly-ADP-ribose polymerase was insignificantly affected in K562 cells following adenine treatment. In K562 cells, adenine was able to markedly promote the phosphorylation of AMPKalpha and suppress the phosphorylation of mammalian target of rapamycin (mTOR), a downstream target of AMPK. In addition, inhibiting AMPK phosphorylation using dorsomorphin restored mTOR phosphorylation, inhibited the accumulation of LC3 and significantly recovered the suppressed cell viability in response to adenine. Taken together, the present results demonstrated that adenine induced G2/M phase arrest and autophagic cell death, consequently suppressing the viability of K562 cells, which may attribute to the AMPK activation triggered by adenine. These findings provide evidence that adenine may be beneficial to chronic myelogenous leukemia therapy by suppressing excessive cell proliferation. PMID- 29113186 TI - Puerarin induces cell apoptosis in human chondrosarcoma cell line SW1353 via inhibition of the PI3K/Akt signaling pathway. AB - Chondrosarcoma is a malignant soft tissue sarcoma with poor prognosis. Puerarin has been demonstrated to possess anticancer properties; however, the effects of puerarin in human chondrosarcoma cells remain unknown. The present study aimed to investigate the anticancer effects of puerarin in SW1353 human chondrosarcoma cells. SW1353 cells were treated with increasing concentrations of puerarin for different durations. Cell viability was evaluated using MTT assays. Cell apoptosis rates were determined by flow cytometry. The activities of caspase-3 and caspase-9 were measured by enzymatic assay. The expression of RAC-alpha serine/threonine-protein kinase (Akt), phosphorylated-Akt, caspase-3 and apoptosis-associated proteins, including B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) were detected by western blotting. Puerarin significantly decreased cell viability and significantly induced apoptosis of SW1353 cells. In addition, puerarin significantly increased the enzymatic activities of caspase-3 and caspase-9. Puerarin treatment suppressed the expression of p-Akt and Bcl-2 but promoted the expression of Bax and cleaved caspase-3 in SW1353 cells. Notably, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 abrogated the decreased phosphorylation of Akt, suggesting that the PI3K/Akt signaling pathway is involved in mediating the anticancer effects of puerarin. The data from the present study indicated that puerarin exhibits anticancer effects in SW1353 cells and may be a potential therapeutic drug for patients with chondrosarcoma. PMID- 29113187 TI - Overexpression of tumor suppressor gene ZNF750 inhibits oral squamous cell carcinoma metastasis. AB - Zinc-finger protein 750 (ZNF750) encodes a putative C2H2 zinc finger protein and is typically mutated or deleted in squamous cell carcinoma. The role of ZNF750 in oral squamous cell carcinoma (OSCC) remains unknown. The aim of the present study was to investigate the effects of ZNF750 overexpression in CAL-27 cells. Cell viability, and the expression of genes associated with proliferation, differentiation and the epithelial-mesenchymal transition were investigated in CAL-27 cells following ZNF750 overexpression, using Cell Counting kit-8, reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. In addition, scratch wound, invasion and migration assays were performed. Cell viability, matrix metalloproteinase 28 expression, cyclin B1 expression and mesenchymal marker neural cadherin expression were decreased following ZNF750 overexpression compared with the control groups. ZNF750 overexpression induced the differentiation-associated genes late cornified envelope 3A and small proline-rich protein 1A and upregulated the expression of late epidermal differentiation factor Kruppel-like factor 4. Overexpression of ZNF750 in CAL-27 cells resulted in inhibition of cell invasion and migration. Taken together, these data suggest that ZNF750 may inhibit the metastasis of OSCC. PMID- 29113188 TI - Zoledronic acid sensitizes rhabdomyosarcoma cells to cytolysis mediated by human gammadelta T cells. AB - Rhabdomyosarcoma (RMS) is the most common type of soft-tissue sarcoma in children. Immunotherapy has been proposed as a treatment for this deadly tumor. In the present study, the cytotoxicity of ex vivo expanded gammadelta T cells on RMS cell lines was evaluated and the molecular interactions involved were investigated. gammadelta T cells were expanded in vitro using peripheral blood mononuclear cells from 5 healthy donors and were stimulated with zoledronic acid (Zol) and interleukin 2. RMS cell lines RD and A-673 were used as target cells. The cytotoxicity of the gammadelta T cells against RMS was assessed in vitro and in vivo. gammadelta T cells were cytotoxic to RMS cells. Importantly, Zol markedly increased their cytotoxic potential. RMS cells treated with Zol stimulated gammadelta T cells to produce interferon gamma. gammadelta T cell mediated cytotoxicity was primarily through the T cell receptor-dependent signaling pathway in blocking studies. Transfer of gammadelta T cells together with Zol into nude mice induced the regression of RD tumor xenotransplants. The results of the present study provide the rationale for the clinical evaluation of gammadelta T cells in RMS. PMID- 29113189 TI - The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells. AB - The oncogene ETS-related gene (ERG) encodes a transcription factor with roles in the regulation of haematopoiesis, angiogenesis, vasculogenesis, inflammation, migration and invasion. The ERG oncogene is activated in >50% of prostate cancer cases, generally through a gene fusion with the androgen-responsive promoter of transmembrane protease serine 2. Phosphatase and tensin homologue (PTEN) is an important tumour suppressor gene that is often inactivated in cancer. ERG overexpression combined with PTEN inactivation or loss is often associated with aggressive prostate cancer. The present study aimed to determine whether or not ERG regulates PTEN transcription directly. ERG was demonstrated to bind to the PTEN promoter and repress its transcription. ERG overexpression reduced endogenous PTEN expression, whereas ERG knockdown increased PTEN expression. The ability of ERG to repress PTEN may contribute to a more cancer-permissive environment. PMID- 29113190 TI - Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland. AB - Targeted therapy of non-small cell lung cancer (NSCLC) patients with mutations in the epidermal growth factor receptor (EGFR) gene has been associated with improved prognosis. However, there is a shortage on data from real-world clinical practice in management of EGFR-positive NSCLC patients in Poland. The present study retrospectively analyzed data from the INSIGHT study to evaluate the incidence and clinical management of EGFR-positive NSCLC in Poland. The authors additionally aimed to identify predictors of the EGFR mutation and factors associated with clinical stage of the tumor at diagnosis. Incidence of EGFR mutations was 11.8% and the most common mutations were a deletion on exon 19 and an L858R substitution on exon 21. Mutations were strongly associated with female gender [male vs. female odds ratio (OR): 0.51; P=0.004] and never having smoked (current/past smoker vs. never smoked OR: 0.16; P<0.001), and advanced clinical stage (stage IV vs. stage I/II OR: 2.89; P=0.029). Patients with EGFR mutation were also observed to have a greater propensity to develop bone metastasis (OR: 11.62; P=0.008). Multivariate regression analysis demonstrated that patients with past or current smoking history or a poor performance on the Eastern Cooperative Oncology Group (ECOG) scale were less likely to have the EGFR mutation. Furthermore, EGFR-positive patients with greater ECOG scores and a tumor other than adenocarcinoma or squamous cell carcinoma were more likely to present advanced tumors. Early screening for EGFR mutation and the use of EGFR-targeting therapies as first-line agents may lead to better prognosis and successful clinical management of EGFR-positive NSCLC patients. PMID- 29113191 TI - How to detect the rare BCR-ABL (e14a3) transcript: A case report and literature review. AB - The Philadelphia (Ph; BCR-ABL) chromosome originates from a translocation event between chromosomes 9 and 22, and results in the BCR-ABL fusion gene. In chronic myelogenous leukemia (CML), the BCR-ABL gene is mainly coded for by a major breakpoint cluster region (M-bcr, e13a2 and e14a2). However, in some patients, BCR-ABL genes are encoded by a minor (m)-bcr, e1a2, and a micro (u)-bcr region, e19a2. These transcripts revealed a different clinical course. The present study described a CML patient whose cytogenetics and FISH analyses of bone marrow revealed a karyotype of 46, XY t(9,22) (q34;q11), while the commercial kits of quantitative PCR (qPCR) failed to detect the BCR-ABL fusion gene. Further multiplex Reverse transcription-PCR (RT-PCR) and sequencing analyses identified a rare e14a3 (b3a3) fusion transcript. PMID- 29113192 TI - miR-514a-3p functions as a tumor suppressor in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common type of kidney cancer, and the prognosis of metastatic RCC remains poor with a high rate of recurrence and mortality. A previous study has revealed that microRNA (miRNA), which negatively regulates protein expression, serves a role of oncogene or tumor suppressor. The aim of the present study was to investigate the expression and function of miR 514a-3p in RCC. To detect the expression of miR-514a-3p in 32 paired RCC tissues, quantitative polymerase chain reaction (qPCR) was performed. The function of miR 514a-3p in the proliferation, mobility and apoptosis of RCC cells (786-O and ACHN) was assessed by MTT, CCK-8, cell scratch, Transwell, Hoechst 33342 staining and flow cytometry assay. The results of qPCR revealed that miR-514a-3p was significantly downregulated in RCC tissues compared with adjacent normal tissues. Upregulation of miR-514a-3p by transfection of mimics suppressed RCC cell proliferation, migration and invasion, and induced cell apoptosis. The results revealed that miR-514a-3p was significantly downregulated in RCC and may serve a role as tumor suppressor in RCC. Further studies are required, focusing on the possibility of using miR-514a-3p as a biomarker for RCC as well as the pathway of miR-514a-3p in RCC. PMID- 29113193 TI - Value of endorectal ultrasonography in measuring the extent of mesorectal invasion and substaging of T3 stage rectal cancer. AB - The present study aimed to determine the value of endorectal ultrasound (ERUS) and magnetic resonance imaging (MRI) for T3 rectal cancer, and substaging of T3 rectal cancer by measuring the extent of mesorectal invasion (EMI). The clinical data of patients with rectal cancer who were admitted to the general surgical department of Peking Union Medical College Hospital (Beijing, China) were reviewed and analyzed. Two ultrasound practitioners independently measured the EMI on ERUS, and a radiologist measured the EMI on MRI. The consistency of ERUS measurements between the two doctors was assessed using intraclass consistency (ICC) analysis. T3 stages were subdivided into T3a (EMI <=5 mm) and uT3b (EMI >5 mm). The accuracy of MRI and ERUS in T3 rectal cancer, and T3 substaging of rectal cancer was assessed and compared according to the pathological results. The Bland-Altman scatter plot demonstrated good consistency between the ERUS measurement and pathology measurement. Furthermore, the consistency of the ERUS measurement between the two doctors was good (ICC, 0.9344; 95% confidence interval, 0.8789-0.9645). The diagnostic accuracies for T3 rectal cancer, for the two ultrasound doctors and for MRI were 86.9% (53/61), 85.2% (52/61), and 90.2% (55/61), respectively. The accuracy, sensitivity and specificity for the two individual ultrasound doctors in the substaging of T3 tumors were 79.1% (34/43), 66.7% (10/15), and 85.7% (24/28), compared with 67.4% (31/43), 60% (9/15), and 82.1% (23/28), respectively. The accuracy of MRI in the substaging of T3 tumors was 86.0% (37/43), which was not statistically higher compared with those of ERUS (P>0.05). In conclusion, ERUS is a valuable tool for measuring the EMI and substaging T3 rectal cancer, and thus, can be complementary to MRI in selecting the appropriate treatment for rectal cancer. PMID- 29113194 TI - Immune-related adverse events during anticancer immunotherapy: Pathogenesis and management. AB - Immunotherapy is one of the most recent systemic treatments to emerge for use in oncology, and is based on the blocking of inhibitory immune checkpoints to potentiate the immune response to cancer. The anti-cytotoxic T lymphocyte associated antigen-4 antibody ipilimumab and anti-programmed cell death protein 1 antibodies, including nivolumab and pembrolizumab, are currently available and widely used, and other immune-inhibiting antibodies are now under intensive investigation. These antibodies have shown efficacy in a growing number of tumor types, following initial observations of their notable effects in melanoma treatment. Despite the efficacy of these antibodies, their novel mechanisms of action are also associated with a new class of side effects called immune-related adverse events (IRAEs). These side effects do not share a common pathophysiology with other anticancer treatments and, therefore, they often require specific therapies. When detected early and correctly treated, IRAEs are reversible; however, they can become severe and life-threatening if underestimated or inappropriately treated. This review aims to revisit the pathogenesis of IRAEs, with attention to gastrointestinal manifestations, since these are common and potentially dangerous complications of immunotherapy and represent a major cause of treatment discontinuation. Recommendations and guidelines for the management of IRAEs are also presented, in order to provide a clear and applicable algorithm for use by clinicians. PMID- 29113195 TI - Advances in targeting the transforming growth factor beta1 signaling pathway in lung cancer radiotherapy. AB - Lung cancer was demonstrated to be the most lethal type of malignant tumor amongst humans in the global cancer statistics of 2012. As one of the primary treatments, radiotherapy has been reported to induce remission in, and even cure, patients with lung cancer. However, the side effects of radiotherapy may prove lethal in certain patients. In past decades, the transforming growth factor beta1 (TGFB1) signaling pathway has been revealed to serve multiple functions in the control of lung cancer progression and the radiotherapy response. In mammals, this signaling pathway is initiated through activation of the TGFB1 receptor complex, which signals via cytoplasmic SMAD proteins or other downstream signaling pathways. Multiple studies have demonstrated that TGFB1 serves important functions in lung cancer radiotherapy. The present study summarized and reviewed recent progress in elucidating the function of the TGFB1 signaling pathway in predicting radiation pneumonitis, as well as current strategies for targeting the TGFB1 signaling pathway in lung cancer radiotherapy, which may provide potential targets for lung cancer therapy. PMID- 29113196 TI - Inhibition of DMH-DSS-induced colorectal cancer by liposomal bovine lactoferrin in rats. AB - Bovine lactoferrin (bLF) is a multifunctional protein with anti-inflammatory, antibacterial, antiviral, anti-tumour and immunoregulatory effects. The present study was conducted to evaluate the anti-inflammatory and anti-tumour effects of liposomal bLF (LbLF) in a 1,2-dimethylhydrazine (DMH)/dextran sulphate sodium (DSS)-induced model of carcinogenesis in F344 rats. F344 rats were randomly divided into three groups: Control (water), 500 or 1,000 mg/kg/day LbLF; additionally, the rats were injected with DMH (20 mg/kg) once per week for 8 consecutive weeks, after one week of drinking water containing 1% DSS. All rats were sacrificed at 25 weeks. The tissues were examined for the presence of aberrant crypt foci (ACF) and subjected to histopathological analysis. Additionally, human colon cancer cells were utilised to investigate the effect of LbLF on proliferation and inflammation. Rats from the 500 and 1,000 mg/kg/day LbLF groups harboured significantly fewer colon ACF, adenomas and adenocarcinomas than the rats from the control group. Lastly, it was demonstrated that LbLF inhibits cell growth and TNF-alpha mRNA expression. These data support the hypothesis that LbLF affects colorectal carcinogenesis by suppressing inflammation and cell proliferation in rats. PMID- 29113197 TI - Acidic stress induces apoptosis and inhibits angiogenesis in human bone marrow derived endothelial progenitor cells. AB - Bone marrow-derived endothelial progenitor cells (BM-EPCs) are exposed to acidotic environments in a variety of physiological and pathological conditions, including in tumors. However, the effect of acidosis on the function of BM-EPCs is still not fully understood. In the present study, BM-EPCs were isolated and cultured at an extracellular pH (pHe) of 6.5 or pHe 7.4 in vitro prior to various experiments being performed. Cellular proliferation, migration and tube formation ability were detected by DNA content quantification, Transwell assay and Matrigel based angiogenesis assay. ELISA and western blot analysis measured protein secretion and expression, respectively. The results demonstrated that BM-EPCs cultured at pHe 6.5 compared with at pHe 7.4 demonstrated: Induced apoptosis; inhibited cellular proliferation, migration and adhesion; markedly reduced vascular endothelial growth factor (VEGF) expression; and the capacity to incorporate into vascular networks. Acidic pHe 6.5 induced ratio expression of B cell lymphoma 2 (Bcl2)/Bcl2 associated X-protein (Bax), which in turn induced apoptosis, and inhibited cellular proliferation and other functional activities, with involvement of activation of VEGF receptor 2, protein kinase B and p38 mitogen activated protein kinase. These observations raise the possibility that the acidic extracellular environment may perform an important role in the vasculogenesis of BM-EPCs in tumor microenvironments. Therefore, culturing cancer cells at a lower pH that simulates endogenous tumor conditions may improve retention of the cellular heterogeneity identified in tumors. PMID- 29113198 TI - Downregulation of miR-186 is associated with metastatic recurrence of gastrointestinal stromal tumors. AB - Although dysregulation of microRNAs (miRNAs/miRs) is a common feature of human malignancies, its involvement in gastrointestinal stromal tumors (GISTs) is not fully understood. The present study aimed to identify the miRNAs that perform a role in GIST metastasis. miRNA expression profiles from a series of 32 primary GISTs were analyzed using microarrays, and miR-186 was observed to be downregulated in tumors exhibiting metastatic recurrence. Reverse transcription quantitative polymerase chain reaction analysis of an independent cohort of 100 primary GISTs revealed that low miR-186 expression is associated with metastatic recurrence and a poor prognosis. Inhibition of miR-186 in GIST-T1 cells promoted cell migration. Gene expression microarray analysis demonstrated that miR-186 inhibition upregulated a set of genes implicated in cancer metastasis, including insulin-like growth factor-binding protein 3, AKT serine/threonine kinase 2, hepatocyte growth factor receptor, CXC chemokine receptor 4 and epidermal growth factor-containing fibulin-like extracellular matrix protein 1. These results suggest that the downregulation of miR-186 is involved in the metastatic recurrence of GISTs, and that miR-186 levels could potentially be a predictive biomarker for clinical outcome. PMID- 29113199 TI - miR-214 targets the PTEN-mediated PI3K/Akt signaling pathway and regulates cell proliferation and apoptosis in ovarian cancer. AB - The present study aimed to investigate the potential role of microRNA (miR)-214 in targeting the phosphatase and tensin homolog (PTEN)-mediated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in ovarian cancer (OC). The target gene of miR-214 was determined by luciferase reporter gene assay and was indicated to be PTEN. Human SK-OV-3 cells were transfected with a miR-214 inhibitor and a miR-214 mimic, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect relative expression of miR-214. The MTT assay was performed to detect cell viability following transfection. Cell cycle and apoptosis were assessed by staining with propidium iodide (PI) and double staining with Annexin V/PI, respectively. The expression levels of PTEN and PI3K/Akt signaling pathway associated proteins were detected by western blot analysis. The expression of miR 214 in tumor tissues and normal tissues was detected by RT-qPCR, and PTEN expression was detected by immunohistochemistry. SK-OV-3 cells transfected with a miR-214 inhibitor showed significantly inhibited cell viability and proliferation, and markedly increased apoptotic rate. SK-OV-3 cells transfected with miR-214 mimic showed significantly increased viability and proliferation, and markedly decreased apoptotic rate. The cells transfected with a miR-214 inhibitor exhibited significantly upregulated PTEN expression and significantly downregulated phosphatidylinositol (3,4,5)-trisphosphate (PIP3), phosphorylated (p)-Akt and p-glycogen synthase kinase (GSK)-3beta expression. The cells transfected with miR-214 mimic exhibited significantly downregulated PTEN expression and significantly upregulated PIP3, p-Akt and p-GSK-3beta expressions. The OC tissues exhibited an increased expression of miR-214 and a reduced positive rate of PTEN expression compared with adjacent normal tissues. miR-214 may activate the PI3K/Akt signaling pathway by downregulating the targeted PTEN, which may promote OC cell proliferation and inhibit apoptosis. PMID- 29113200 TI - Role of high mobility group A1 and body mass index in the prognosis of patients with breast cancer. AB - The high mobility group A1 (HMGA1) protein is associated with poor prognosis in patients with a wide range of cancers. However, the affect of HMGA1 on the risk of mortality from breast cancer (BC) has not been fully characterized. In the present retrospective multiple center study, the HMGA1 expression level was determined by performing immunohistochemistry on surgical tissue samples of 273 BC specimens from the Second Affiliated Hospital of Zhejiang University (Zhejiang, China) and 310 BCs from the National Engineering Center for Biochip (Shanghai, China). Kaplan-Meier analysis and Cox proportional hazard model were employed to analyze the survivability. HMGA1 expression was significantly associated with tumor histological degree and body mass index (BMI). However, HMGA1 expression showed no prognostic value in patients with BC. Combined evaluation of HMGA1 expression and high BMI (>=24 kg/m2) predicted worse overall survival of BC. Therefore, HMGA1 and BMI were considered to serve synergistic roles in the development and progression of BC, and combined evaluation of HMGA1 expression and high BMI may be an effective marker in predicting poor prognosis of BC patients. PMID- 29113201 TI - High expression of monocarboxylate transporter 4 predicts poor prognosis in patients with lung adenocarcinoma. AB - Monocarboxylate transporter 4 (MCT-4) serves a key function in transporting lactate across the plasma membrane in various types of human cancer. Evidence indicates that MCT-4 expression is associated with non-small cell lung cancer; however, the distribution and clinical significance of MCT-4 in the lung adenocarcinoma (AC) subtype remain unknown. Thus, the aim of the present study was to explore the clinicopathological significance and prognostic values of MCT 4 expression in lung AC. Quantum dots-based immunofluorescence histochemistry was performed to observe the expression of MCT-4 in 146 specimens of lung AC and corresponding normal lung tissues. MCT-4 protein and mRNA were detected by western blotting and reverse transcription-quantitative polymerase chain reaction from 30 fresh samples of lung AC and corresponding normal lung tissues. Of the 146 samples, 25 (17.1%) exhibited high and 121 (82.9%) exhibited low MCT-4 expression. MCT-4, at the protein and mRNA level, was significantly increased in tumor specimens compared with corresponding normal lung tissue (P<0.05). MCT-4 protein expression was significantly associated with depth of invasion (P=0.034). A survival curve analysis indicated that high MCT-4 expression in lung AC was associated with a decreased overall survival rate (P=0.001). Multivariate analysis demonstrated that high MCT-4 level was an independent prognostic factor (hazard ratio, 3.192; 95% confidence interval, 1.804-5.646; P=0.001) for patients with lung AC. The results have demonstrated that high MCT-4 expression is significantly associated with the poor prognosis and disease progression of patients with lung AC. Therefore, MCT-4 may be a candidate therapeutic target in lung AC. PMID- 29113202 TI - EZH2 and histone deacetylase inhibitors induce apoptosis in triple negative breast cancer cells by differentially increasing H3 Lys27 acetylation in the BIM gene promoter and enhancers. AB - Enhancer of zeste homolog 2 (EZH2), a subunit of polycomb repressive complex 2, is a histone methyl-transferase and is considered to work cooperatively with histone deacetylases (HDACs) in the same protein complex to mediate gene transcription repression by increasing histone H3 Lys27 trimethylation (H3K27me3), in particular in the nucleosome (s). EZH2 is overexpressed in numerous types of cancer, including triple negative breast cancer (TNBC), a subtype of breast cancer, which there are no effective treatment options for. Thus, inhibition of EZH2 may be harnessed for targeted therapy of this disease. The present study demonstrated that co-treatment with an EZH2 inhibitor and a HDAC inhibitor additively induced apoptosis in two TNBC cell lines, namely MDA-MB 231 and MDA-MB-436. The increased rate of cell death was associated with an elevation of B cell lymphoma-2 like 11 (BIM) expression level, a pro-apoptotic protein at the protein and mRNA expression levels in these two cell lines. The expression of forkhead box O1 (FOXO1), a known upstream transcriptional activator of BIM, was upregulated in both cell lines by the HDAC inhibitor, and the effect was more pronounced in MDA-MB-436 cells with higher phosphorylation levels of protein kinase B, a negative regulator of FOXO1, compared with MDA-MB-231 cells. Conversely, FOXO1 expression was inhibited following treatment with the EZH2 inhibitor, suggesting that EZH2 and HDAC inhibitors induced BIM expression via a FOXO1-independent mechanism. The present study further revealed that the EZH2 inhibitor, but not the HDAC inhibitor, induced high levels of H3K27 acetylation (H3K27ac) in the BIM promoter. By contrast, compared with the effect of the EZH2 inhibitor, HDAC inhibitor treatment resulted in an increase in H3K27ac at two BIM enhancers. Collectively, the results of the present study indicated that EZH2 and HDACs act differentially on H3K27ac levels in the nucleosome at the promoter and enhancer regions of the BIM gene. Through the upregulation of BIM, co-treatment with EZH2 and HDAC inhibitors had a pronounced therapeutic effect on TNBC cells, suggesting that co-targeting EZH2 and HDAC proteins represents a viable therapeutic option for the treatment of TNBC. PMID- 29113203 TI - Distribution of uridine diphosphate glucuronosyltransferase 1A polymorphisms and their role in irinotecan-induced toxicity in patients with cancer. AB - Uridine diphosphate glucuronosyltransferase 1A (UGT1A1), which affects irinotecan metabolism, has been associated with severe adverse reactions in patients with cancer treated with irinotecan. However, neither large-scale analysis of the distribution of UGT1A1 polymorphisms, nor standardized assessment of how UGT1A1 polymorphisms affect irinotecan treatment has been performed in China. The aim of the present study was to investigate the distribution of UGT1A1 polymorphisms (*28 and *6) in 2,093 Chinese patients with cancer who were treated with irinotecan from more than 15 hospitals in Shandong, to examine how the coexistence of UGT1A1*6 and UGT1A1*28 alleles may be able to predict toxicities induced by irinotecan in 105 of the patients, and to search for other relevant risk factors. The distribution of the genotypes was as follows: TA6/TA6 (1,601, 76.5%), TA6/TA7 (463, 22.1%) and TA7/TA7 (29, 1.4%) for UGT1A1*28 (n=2,093); and G/G (286, 66.4%), G/A (124, 28.8%) and A/A (21, 4.9%) for UGT1A1*6 (n=431). The most frequent severe hematological toxicity was neutropenia, and the predominant non-hematological toxicities were diarrhea and cholinergic syndrome. In toxicity comparisons, grade 3-4 leukopenia and neutropenia were significantly higher in TA6/TA7 compared with TA6/TA6 (P<0.05). The UGT1A1*6 polymorphism was associated with a higher risk of severe diarrhea and total adverse drug reactions (P<0.05). Logistic regression showed that the UGT1A1*6 genotype was an independent predictor of severe diarrhea. These findings suggested that the UGT1A1*28 and UGT1A1*6 genotypes may be associated with irinotecan-induced severe toxicity, and clarified the clinical importance of UGT1A1 polymorphisms, particularly UGT1A1*6, regarding irinotecan therapy in Chinese patients. PMID- 29113204 TI - Application of dual-source CT perfusion imaging and MRI for the diagnosis of primary liver cancer. AB - The objective of the present study was to evaluate the application of dual-source CT perfusion imaging and MRI for the diagnosis of primary liver cancer. Sixty three patients with primary liver cancer were selected between February 2015 and May 2016. All patients underwent examinations by dual-source CT perfusion imaging and MRI. The perfusion parameters of the focus center and normal liver parenchyma by CT examination and the hemodynamic parameters of the focus center and normal liver parenchyma by MRI examination were analyzed. The accuracy rates of the three detection methods (CT perfusion imaging, MRI, and combined examination) were analyzed and compared by ROC curves. Dual-source CT perfusion imaging revealed that blood flow and blood volume of the focus center were significantly higher than those of normal liver parenchyma (P<0.05). MRI examination showed that hepatic arterial perfusion and hepatic perfusion index of the focus center were significantly higher than those of normal liver parenchyma; portal venous perfusion of the focus center was significantly lower than that of normal liver parenchyma (P<0.05); the difference in total liver perfusion between the focus center and normal liver parenchyma was not significant (P>0.05); the accuracy rates of CT perfusion imaging, MRI, and combined examination were 76.19, 85.71, and 95.24% respectively; the area under the curve of CT perfusion imaging was 0.753 (P<0.05), the sensitivity was 79.2% and the specificity was 74.7%; the area under the curve of MRI was 0.846 (P<0.05), the sensitivity was 84.6%, and the specificity was 80.5%; the area under the curve of CT combined with MRI was 0.947 (P<0.05), the sensitivity was 94.6%, and the specificity was 86.5%. In conclusion, the effect of dual-source CT perfusion imaging combined with MRI for examination of primary liver cancer is superior to that of single use of CT or MRI, and has high clinical application and popularization value. PMID- 29113205 TI - A novel method to identify differential pathways in uterine leiomyomata based on network strategy. AB - The aim of the present study was to identify differential pathways in uterine leiomyomata (UL) using a novel method based on protein-protein interaction networks and pathway analysis. The pathway networks were constructed by examining the intersections of the Reactome database and the Search Tool for the Retrieval of Interacting Genes/proteins (STRING) protein-protein interaction (PPI) networks. The Objective network was defined as the differential expressed genes (DEGs) associated with the interactions identified by STRING. Topological centrality (degree) analysis was performed for the Objective network to explore the hub genes and hub networks. Subsequent to isolating the intersections between the Pathway and Objective networks, randomization tests were conducted to identify the differential pathways. There were 559,598 interactions in the Pathway networks. A total of 657 genes with 3,835 interactions were mapped in the Objective network, which included 20 hub genes. It was identified that 358 pathways demonstrated interaction with the Objective network, such as Signal Transduction, Immune System and Signaling by G-protein-coupled receptor (GPCR). By accessing the randomization tests, P-values of these pathways were close to 0, which indicated that they were significantly different. The present study successfully identified differential pathways (such as signal transduction, immune system and signaling by GPCR) in UL, which may be potential biomarkers in the detection and treatment of UL. PMID- 29113206 TI - Nuclear paraspeckle assembly transcript 1 promotes the metastasis and epithelial mesenchymal transition of hepatoblastoma cells by inhibiting miR-129-5p. AB - The abnormal expression of nuclear paraspeckle assembly transcript 1 (NEAT1) may serve critical functions for the development and progression of various types of human tumor. However, the expression and biological function of NEAT1 in hepatoblastoma (HB) and the underlying mechanisms for the function of NEAT1 in HB remain largely uncharacterized. In the present study, the results of reverse transcription-quantitative polymerase chain reaction revealed that the expression of NEAT1 was significantly elevated in HB tissues. HB tissues with metastasis also exhibited significantly increased levels of NEAT1 compared with tissues without metastasis. The biological functions of NEAT1 were then assessed using gain-/loss-of-function studies. The results of in vitro assays revealed that inhibiting NEAT1 expression reduced the migration and invasion of HepG2 cells. By contrast, the induced expression of NEAT1 exhibited the opposite effect. The present study also demonstrated that the inhibition of NEAT1 expression prevented the epithelial-mesenchymal transition of HepG2 cells, whereas forced expression of NEAT1 exhibited the opposite effect. In addition, it was confirmed that NEAT1 could modulate the expression of microRNA (miR)-129-5p in HepG2 cells, and that NEAT1 may exert its effect on the metastatic behaviors and epithelial-mesenchymal transition of HepG2 cells by inhibiting miR-129-5p. In conclusion, the present study indicated that NEAT1 expression was aberrantly increased in HB and that it may promote the metastasis of HB cells by inhibiting miR-129-5p. Targeting NEAT1 may potentially be a novel therapeutic option for treating patients with HB. PMID- 29113207 TI - Brain metastatic alveolar soft-part sarcoma: Clinicopathological profiles, management and outcomes. AB - Alveolar soft-part sarcoma (ASPS) is a rare sarcoma that presents in the buttocks or thigh of young adults and often metastasizes to the brain. The present study examined the clinical features and morphology of brain metastatic ASPS. The case records of eight patients with brain metastatic ASPS admitted between November 2008 and March 2015 were reviewed. The relevant clinical data (including patient age and sex, neuroimaging studies, histopathological and immunohistochemical features, surgical records and follow-up reports) were collected through a review of patient records. The sex distribution was 3:1 male to female and the age ranged between 15 and 33 years at the time of surgery. In total, five patients with brain metastases had concurrent pulmonary metastases. The lesions were hypointense on T1-weighted images in every patient, hyperintense on T2-weighted images in six patients and contrast enhancement was present in all patients. The most notable immunohistochemical feature was strong immunohistochemical staining for TFE3 in each patient. Gross total resection was performed in all eight patients, with two patients undergoing adjuvant radiotherapy and one undergoing adjuvant chemotherapy. Four recurrent cases were observed during the follow-up. TFE3 staining and knowledge of its microscopic characteristics would facilitate earlier diagnosis: Early diagnosis with a multidisciplinary, multimodal approach to treatment is required to achieve extended disease-free survival in patients with brain metastatic ASPS. PMID- 29113208 TI - Calcifying cystic odontogenic tumor accompanied by a dentigerous cyst: A case report. AB - A calcifying cystic odontogenic tumor (CCOT) is a proliferation of odontogenic epithelium and scattered nests of ghost cells and calcifications that may form the lining of a cyst, or present as a solid mass. It was previously described by Gorlin et al in 1962 as a calcifying odontogenic cyst. Dentigerous cysts are developmental odontogenic jaw cysts, commonly manifesting in the second and third decades of life. The present study reports an asymptomatic case in a 13-year-old boy who was referred to the outpatient clinic of the Osaka Dental University Hospital (Osaka, Japan) for additional investigation of an area of radiolucency in the lower right jaw. X-ray demonstrated a unilocular, well-circumscribed, radiolucent lesion in the mandible, which measured 30*20 mm, with radiopaque structures within it. Enucleation of the lesion with tooth extraction was performed, which histopathologically revealed features of a CCOT and a cyst. To the best of our knowledge, the occurrence of such a lesion has not been previously identified. The present study examined the significance of the case with a brief review of the literature. PMID- 29113209 TI - Prognostic value of copper transporter 1 expression in patients with clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) features a Von Hippel-Lindau mutation, associated with a hypoxia-inducible factor (HIF) imbalance. Copper transporter 1 (CTR1) may also promote tumor progression through the modulation of the HIF pathway by copper. Therefore, the present study explored the prognostic effect of tumor CTR1 expression in patients with ccRCC. A total of 293 patients with ccRCC that underwent nephrectomy were retrospectively enrolled. CTR1 expression was assessed by immunohistochemistry, and its association with clinicopathological features and prognosis were evaluated. The present data indicated that high tumor CTR1 expression was independently associated with poor overall survival (OS) [hazard ratio, 2.291; 95% confidence interval (CI), 1.389-3.777; P<0.001] and disease-free survival (DFS) (hazard ratio, 2.210; 95% CI, 1.299-3.759; P=0.003) rates in patients with ccRCC. Furthermore, CTR1 expression was significantly higher for Mayo Clinic stage, size, grade and necrosis score risk groups, and could be incorporated into several existing prognostic models to improve performance. Nomograms incorporating tumor CTR1 expression with other parameters performed well in the 5- and 8-year OS and DFS rate predictions of patients (concordance index 0.805 and 0.787, respectively). In conclusion, the present study demonstrated that CTR1 expression is a potential independent biomarker for poor prognosis for the recurrence and survival prediction of patients with ccRCC following nephrectomy. PMID- 29113210 TI - Analysis of imaging characteristics of primary malignant bone tumors in children. AB - The present study aimed to investigate the imaging characteristics of primary malignant bone tumors in children. The imaging results of 34 children with primary malignant bone tumors confirmed by histopathological diagnosis between March 2008 and January 2014 were retrospectively analyzed. In total, 25 patients had osteosarcoma, with radiography and computed tomography (CT) showing osteolytic bone destruction or/and osteoblastic bone sclerosis, an aggressive periosteal reaction, a soft-tissue mass and cancerous bone. The tumors appeared as mixed magnetic resonance imaging (MRI) signals that were inhomogeneously enhanced. A total of 5 patients presented with Ewing sarcoma, with radiography and CT showing invasive bone destruction and a soft-tissue mass. Of the 5 cases, 2 showed a laminar periosteal reaction. The tumors were shown to have mixed low signal on T1-weighted images (T1WI) and high signal on T2-weighted images (T2WI); 1 case showed marked inhomogeneous enhancement. Another 3 patients exhibited chondrosarcoma. Of these cases, 1 was adjacent to the cortex of the proximal tibia, and presented with local cortical bone destruction and a soft-tissue mass containing scattered punctate and amorphous calcifications. MRI revealed mixed low T1 signal and high T2 signals. Another case was located in the medullary cavity of the distal femur, with radiography revealing a localized periosteal reaction. The tumor appeared with mixed MRI signals, and with involvement of the epiphysis and epiphyseal plates. Radiography and CT of the third case showed bone destruction in the right pubic ramus, with patchy punctate, cambered calcifications in the soft-tissue mass. MRI of the soft-tissue mass revealed isointensity on T1WI and heterogeneous hyperintensity on T2WI. Ossifications and the septum appeared as low T1WI and T2WI. Of the 34 patients, 1 patient presented with lymphoma involving the T12, L1 and L2 vertebrae. CT showed vertebral bone destruction, a soft-tissue mass and a compression fracture of L1. MRI showed a soft-tissue mass with low T1 signal and high T2 signal and marked inhomogeneous enhancement. Overall, osteosarcoma was the most common primary malignant bone tumor, followed by Ewing sarcoma, chondrosarcoma and lymphoma. Osteoblastic or osteolytic bone destruction, an invasive periosteal reaction, soft-tissue masses, a tumor matrix and inhomogeneous enhancement were important imaging features of malignant bone tumors. PMID- 29113211 TI - Aberrant expression of CD133 and CD82 in patients with pediatric acute lymphoblastic leukemia and the clinical significance. AB - Cluster of differentiation (CD)133 is considered to be a marker of leukemia stem cells (LSCs), which are one of the primary causes of occurrence, drug resistance and relapse of acute lymphoblastic leukemia (ALL). CD82, an adhesion molecule, performs an important role in the interaction between LSCs and their niche. The purpose of the present study was to assess CD133 and CD82 expression in patients with pediatric ALL, and to evaluate the association with the clinical data. Using flow cytometric assessment and reverse transcription-polymerase chain reaction, CD133 and CD82 expression levels were measured in the bone marrow (BM) of 37 patients with newly diagnosed (ND) pediatric ALL [ALL-ND; 30 B-cell-ALL (B-ALL) and 7 T-cell-ALL (T-ALL)], in 22 patients with complete remission pediatric ALL (ALL-CR) and in 16 age-matched children without BM disease. BM plasma CD82 concentrations were measured by ELISA. The CD82 mRNA expression level in the patients with ALL-ND was significantly higher compared with that in the controls. CD82 mRNA expression levels in pediatric patients with B cell-ALL (B-ALL) were higher than those in ALL-CR patients and controls. For T-ALL, CD82 expression in ND patients was higher than in controls. CD133 mRNA expression levels in patients with pediatric B-ALL-ND were higher than that of controls and patients with ALL CR. The frequency of CD34+ cells in pediatric ALL was significantly higher than that in controls. Frequencies of CD34+CD133+ or CD34+CD82+ cells in pediatric ALL were higher than those in controls. A positive association was observed between CD133 and CD82 mRNA expression in patients with B-ALL. A significant association was observed between CD133 mRNA expression and the hyperdiploid karyotype. Therefore, it was considered that CD133 and CD82 may serve an important role in the evolution of pediatric ALL. CD133 and CD82 should be considered as potential markers for the prognosis of patients with ALL. PMID- 29113212 TI - Knockdown of FUSE binding protein 1 enhances the sensitivity of epithelial ovarian cancer cells to carboplatin. AB - Epithelial ovarian cancer (EOC) affects almost 25,000 women annually and is the fifth most common malignancy in women in North America. A combination of surgery and cytotoxic chemotherapy may produce a favorable clinical response. The platinum-paclitaxel combination regimen is the chemotherapy gold-standard for advanced ovarian cancer, and carboplatin is one of the agents in this combination therapy. However, the majority of patients eventually experience a relapse due to the development of platinum resistance. FUSE binding protein 1 (FBP1) has been identified as an anti-apoptotic and pro-proliferative oncoprotein that is overexpressed in hepatocellular carcinoma. Its high expression is also associated with carboplatin resistance. In the present study, it was identified that the expression of FBP1 was significantly higher in EOC tissues than in normal epithelial ovarian or in epithelial ovarian adenoma tissue. FBP1 expression was significantly correlated with the grade of epithelial ovarian cancer. Carboplatin inhibited the expression of FBP1 in epithelial ovarian cancer cells and the knockdown of FBP1 enhanced the inhibition of cell viability and migration by carboplatin. In addition to FBP1, carboplatin also inhibited the expression of beta-catenin and matrix metalloproteinase (MMP)-9. Furthermore, the expression of beta-catenin and MMP-9 were lower in FBP1 knockdown cells compared with control EOC cells. FBP1 may thus serve a role in the regulation of the expression of beta catenin and MMP-9; the inhibition of beta-catenin and MMP-9 by carboplatin may be mediated through the inhibition of FBP1. The inhibition of FBP1 expression by carboplatin may be a mechanism in the treatment of EOC by carboplatin. PMID- 29113213 TI - Correlation between the presence of circulating tumor cells and the pathologic type and staging of non-small cell lung cancer during the early postoperative period. AB - This study investigated possible correlations between the presence of circulating tumor cells (CTCs) and the pathologic types and staging of non-small cell lung cancer (NSCLC) during the early postoperative period. Sixty-nine patients with NSCLC were enrolled in the study. Clinical staging was performed by postoperative pathological examination and imaging. Multiple mRNA in situ analyses targeting specifically expressed genes were carried out to identify the presence of CTCs. Correlations between age, sex, TNM stage and pathological types with the detection rate of CTCs were also established. The results showed the positivity rate of CTCs in patients >55 years was significantly higher than that of patients <55 years (94.74 vs. 70.97%, P<0.05). There was no significant difference in the positivity rate of CTCs between male and female patients (85.71 vs. 85.29%, P>0.05). The correlations between the detection rate of epithelial type or mixed type CTCs with tumor size, lymph node metastasis and distant metastasis TNM in patients with NSCLC were not significant (P>0.05). However, higher TNM stages correlated with higher detection rates of mesenchymal CTCs (P<0.05). There were also significant differences in the detection rates of CTCs amongst the three different pathologic types (adenocarcinoma, squamous cell and large cell carcinomas) (P<0.05). Based on our results, the detection of mesenchymal CTCs during the early postoperative period can help prognosticate the recurrence and metastasis of NSCLC, which is beneficial to the development of individualized treatment strategies. PMID- 29113214 TI - Ginkgolic acid inhibits the invasiveness of colon cancer cells through AMPK activation. AB - Tumor cell invasion and metastasis are important processes in colorectal cancer that exert negative effects on patient outcomes; consequently, a prominent topic in the field of colorectal cancer study is the identification of safe and affordable anticancer drugs against cell invasion and metastasis, with limited side effects. Ginkgolic acid is a phenolic acid extracted from ginkgo fruit, ginkgo exotesta and ginkgo leaves. Previous studies have indicated that ginkgolic acid inhibits tumor growth and invasion in a number of types of cancer; however, limited studies have considered the effects of ginkgolic acid on colon cancer. In the present study, SW480 colon cancer cells were treated with a range of concentrations of ginkgolic acid; tetrazolium dye-based MTT, wound-scratch and transwell migration assays were performed to investigate the effects on the proliferation, migration and invasion of colon cancer cells, and potential mechanisms for the effects were explored. The results indicated that ginkgolic acid reduced the proliferation and significantly inhibited the migration and invasion of SW480 cells in a concentration-dependent manner. Additional experiments indicated that ginkgolic acid significantly decreased the expression of invasion-associated proteins, including matrix metalloproteinase (MMP)-2, MMP 9, urinary-type plasminogen activator and C-X-C chemokine receptor type 4, and activated adenosine monophosphate activated protein kinase (AMPK) in SW480 cells. Small interfering RNA silencing of AMPK expression reversed the effect of ginkgolic acid on the expression of invasion-associated proteins. This result suggested that ginkgolic acid inhibited the proliferation, migration and invasion of SW480 colon cancer cells by inducing AMPK activation and inhibiting the expression of invasion-associated proteins. PMID- 29113215 TI - Functional analysis of BRCT missense mutations in BRCA1-mutated Chinese Han familial breast cancer. AB - Breast cancer 1 (BRCA1) is one of the most common tumor suppressor genes in breast cancer. The BRCT domain of BRCA1 has been shown to have a critical role in tumor suppression. In a previous study, two de novo BRCT missense mutations of BRCA1, G1763V and L1786P were identified from Chinese females with familial breast cancer. In the present study, the function of these two novel mutations were assessed by bioinformatics analysis and a series of experiments investigating cell proliferation, cell cycle and chemotherapy combination. Although bioinformatics analysis indicated that the mutants may be deleterious, a series of experiments revealed that the two mutants significantly reduced the growth and increased cell apoptosis similar to the function of BRCA1 wild type. Furthermore, no synergistic effect between the Olaparib and BRCA1 mutation was noted on cell apoptosis. These results demonstrated that these two mutations did not affect the tumor suppressor function of BRCA1. It was concluded that not all BRCA1 missense mutations are pathogenic and that any new BRCA1 mutation should be assessed for its effect on the tumor suppressor function of BRCA1. PMID- 29113216 TI - MicroRNA-10b expression in node-negative breast cancer-correlation with metastasis and angiogenesis. AB - Metastasis accounts for the majority of cases of mortality in patients with axillary lymph node-negative (ANN) breast cancer. Angiogenesis is an essential component of the metastatic pathway. Studies regarding microRNA (miR)-10b expression in patients with ANN breast cancer and the function of angiogenesis in breast cancer remain scarce. The present study was performed in order to determine the biological significance of miR-10b, and investigate the association between miR-10b and microvessel density (MVD) measured in ANN breast cancer. miR 10b expression and immunohistochemical analysis for MVD were assessed in 195 patients with ANN of invasive ductal carcinoma, including 65 cases with distant metastasis 'poor group', and 130 cases without any recurrence 'good group'. miR 10b expression was higher in the 'poor group' (73.8%) compared with that in the 'good group' (51.5%; P=0.003). Multivariate logistic regression demonstrated that miR-10b retained independent prognostic significance for distant metastasis along with MVD and vascular invasion. Among 195 patients, miR-10b expression was significantly associated with tumor grade, tumor size and molecular subtypes (P<0.05). In addition, miR-10b expression was positively associated with the MVD count (r=0.370; P<0.001), tumor grade (r=0.168; P=0.019) and tumor size (r=0.175; P=0.014). The results of the current study suggest that miR-10b is a useful marker for predicting metastasis and angiogenesis in ANN breast cancer. PMID- 29113217 TI - Grape seed proanthocyanidins induce mitochondrial pathway-mediated apoptosis in human colorectal carcinoma cells. AB - Grape seed proanthocyanidins (GSPs) have been reported to possess a wide array of pharmacological and biochemical properties. Recently, GSPs have been reported to inhibit various types of colorectal cancer; however, the mechanism(s) involved remain unclear. The present study investigated the effects of GSPs on HCT-116 human colorectal carcinoma cell line. Exposure of these cells to GSPs for 48 h resulted in a significant concentration-dependent inhibition of cell viability. Further investigation indicated that GSPs induced apoptosis of these cells. Analyses of mRNA expression levels using reverse transcription-quantitative polymerase chain reaction and protein expression levels by western blotting revealed that this was associated with increased expression levels of p53 tumor suppressor protein, cytochrome c, and pro-apoptotic proteins, apoptosis regulator Bax (Bax) and Bcl-2 homologous antagonist/killer. Furthermore, decreased expression levels of the anti-apoptotic protein, B cell lymphoma-2 and activation of caspase-2, caspase-3 and caspase-9 were demonstrated. GSP-induced loss of mitochondrial membrane potential was also detected by JC-1 assay. These findings suggested that GSPs induced colon cancer cell apoptosis via the mitochondrial signaling pathway. This provided evidence indicating that GSPs may provide potential chemotherapeutic agents for colorectal cancer. PMID- 29113218 TI - Chest wall-parallel vs. conventional subclavian venous catheterization in cancer chemotherapy: A comparison of complication rates. AB - The incidence of complications such as pneumothorax and hematoma between the chest wall-parallel and conventional subclavian venous catheterization in cancer chemotherapy was compared. From December 2011 to March 2016, a total of 314 patients undergoing chemotherapy for cancer in the Guizhou Provincial People's Hospital were assigned to either the Chest Wall-parallel (n=155) or the conventional subclavian venous catheterization group (n=159) in order to observe the primary success rate for catheterization and to assess the incidence of complications such as pneumothorax, hemothorax, hematoma, and internal jugular venous injury. The primary success rates for catheterization were not significantly different between the conventional and chest wall-parallel subclavian venous catheterization groups (94.3% vs. 96.8%, P>0.05), with a total catheterization success rate of 100% in both groups. However, the incidence of pneumothorax was significantly different between the groups (6.29% in conventional vs. 0% in chest wall-parallel subclavian venous catheterization group, P<0.05). Therefore, compared to conventional subclavian venous catheterization, the chest wall-parallel approach could reduce the risk of or even totally prevent pneumothorax and other venipunctures and is, thus, a relatively safe and effective technique that could have wide applications in clinical settings. PMID- 29113219 TI - The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis. AB - The relationship between the expression levels of matrix metalloproteinase-2 (MMP 2) and MMP-9 and breast cancer prognosis was studied. Two breast cancer cell lines (MDA-MB-231 and MCF-7) and one human normal breast cell line (HS578Bst) were investigated. Fluorescence real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect cellular mRNA and protein MMP-2 and MMP-9 expression levels. Breast cancer tissue samples from 80 patients and tumor-adjacent normal tissue samples from 40 patients were collected, and MMP-2 and MMP-9 expression in these samples were examined using immunohistochemistry (IHC). The relationship of MMP-2 and MMP-9 expression levels with breast cancer patient clinicopathological parameters and prognosis was analyzed. RT-PCR and western blot results showed that MMP-2 and MMP-9 mRNA and protein expression levels were significantly higher in MDA-MB-231 and MCF-7 cells than in HS578Bst cells. A high expression of MMP-2 and MMP-9 was found in 83.75% (67/80) and 78.75% (63/80) of breast cancer tissue samples, respectively. MMP-2 and MMP-9 expression in breast cancer tissues were significantly different from that in tumor-adjacent normal tissues (p<0.01). MMP-2 and MMP-9 expression levels in breast cancer tissues were correlated with lymph node metastasis and tumor staging. Single factor survival analysis showed that MMP-2 and MMP-9 were factors influencing breast cancer prognosis. MMP-2 and MMP-9 are highly expressed in breast cancer tissues and are closely related to lymph node metastasis and tumor staging. MMP-2 and MMP-9 can be used as reference indices for guiding breast cancer prognosis and treatment. PMID- 29113220 TI - PAX8 is a potential marker for the diagnosis of primary epithelial ovarian cancer. AB - The present study aimed to investigate the clinical significance of paired-box 8 (PAX8) in primary epithelial ovarian cancer (PEOC). Using immunohistochemical (IHC) staining, the expression of PAX8 in 60 patients with PEOC, 20 patients with ovarian benign lesions and 10 patients with metastatic ovarian cancer (MOC), was examined based on the clinicopathological profiles of the patients. The correlation between PAX8 expression and the clinicopathological parameters or prognosis of patients was statistically analyzed. PAX8 was revealed to be highly expressed in PEOC, but not in MOC, as indicated by IHC staining. The rate of positivity of PAX8 in PEOC was 92% (57/60) with no significant difference of PAX8 expression found between the various pathological types of PEOC (P=0.871). The rate of positivity of PAX8 in ovarian benign tumors was 85%, demonstrating no significant difference in comparison with that of PEOC (P=0.761). PAX8 staining and statistical analysis revealed that the higher the grade of PEOC, the less the cancer cell had differentiated (P=0.033) and the more the cancer had advanced according to International Federation of Gynaecological Oncologists (FIGO) staging (P=0.003). Survival rate statistics showed that PEOC patients with higher PAX8 expression exhibited a shorter postoperative survival rate (P=0.009). PAX8 was specifically expressed in PEOC, and its expression level was associated with the degree of cancer cell differentiation, FIGO stage, and survival rate, indicating that PAX8 is a potential marker for the diagnosis of PEOC. PMID- 29113221 TI - SPARC inhibits breast cancer bone metastasis and may be a clinical therapeutic target. AB - Breast cancer is one of the most common types of cancer in females worldwide, and metastasis to bone is an important characteristic of malignancy. The present study aimed to investigate the molecular mechanism of breast cancer to bone metastasis of secreted protein acidic and rich in cysteine (SPARC). Immunohistochemistry was performed to examine the expression of SPARC in primary breast tumors and bone metastatic foci. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression level of SPARC in several types of breast cancer cell. A Transwell filter assay was used to assess the effect of SPARC on breast cancer cell invasion ability, and an osteoblast differentiation assay was employed to analyze the effect of SPARC on the differentiation ability of mesenchymal stem cells. Clinical data revealed that decreased stromal SPARC expression is associated with breast cancer to bone metastasis. Gain- and loss-of-function studies reveal that SPARC inhibits the migration and invasion of breast cancer cells, and suppresses osteoclast activation in the breast cancer microenvironment. SPARC serves an important role in breast cancer bone metastasis and may be a promising therapeutic target for the treatment of breast cancer bone metastasis. PMID- 29113222 TI - High level of homeobox A9 and PBX homeobox 3 expression in gastric cancer correlates with poor prognosis. AB - The homeobox protein homeobox (HOXA9) is a transcriptional factor that regulates patterning during embryogenesis and controls cell differentiation. HOXA9 dysfunction has been implicated in certain cancers. However, the role of HOXA9 in gastric cancer is poorly understood. The present study investigated HOXA9 and its cofactor PBX homeobox 3 (PBX3) expression in patients with gastric cancer. Paired tissue samples from 24 patients and paraffin embedded tissues of gastric cancer patients (104 males and 24 females) were included. HOXA9 and PBX3 expression levels were determined by reverse transcription quantitative polymerase chain reaction in fresh tissues, and by immunohistochemical staining in paraffin embedded tissues. The association between HOXA9/PBX3 expression and clinicopathological features was established. The results demonstrated that HOXA9 and PBX3 mRNA levels were significantly upregulated (P=0.032 for HOXA9 and P=0.031 for PBX3) in gastric cancer tissue. Immunohistochemical staining revealed that HOXA9 expression was associated with differentiation, lymph node metastasis and tumor-node-metastasis (TNM) stage, and PBX3 expression was associated with lymph node metastasis and TNM stage. Correlation analysis revealed a high coincidental expression of HOXA9 and PBX3 levels in gastric cancer (r=0.391; P<0.001). Survival analysis showed that high expression of HOXA9 or PBX3 was associated with poor survival of gastric cancer, and multivariate analysis using Cox's regression model showed that PBX3 expression was an independent prognostic factor in gastric cancer. There was elevated expression of HOXA9 and PBX3 in gastric cancer patients, and high-level expression of those proteins was associated with poor prognosis of gastric cancer. The present study underlines the significance of HOXA9/PBX3 in the development of gastric cancer. PMID- 29113223 TI - CD44+/CD24- phenotype predicts a poor prognosis in triple-negative breast cancer. AB - Cancer stem cells are enriched in triple-negative breast cancer (TNBC) tumor tissues, which present strong capacities of proliferation and tumorigenicity. The present study detected the distribution of cancer stem cell markers cluster of differentiation (CD)44/CD24 and analyzed the clinical outcomes of different CD44/CD24 phenotypes in patients with TNBC. Multivariate Cox regression analyses were performed with regard to the prognostic value of cancer stem cell markers CD44/CD24, aldehyde dehydrogenase 1 and other baseline clinical characteristics, including tumor size, lymph node involved, adjuvant chemotherapy, Ki-67, breast cancer susceptibility gene 1, cellular tumor antigen p53, vimentin and basal-like status. The multivariate analyses showed that three of these factors, CD44/CD24 phenotype, basal-like status and number of lymph nodes involved, had an impact on overall survival. Furthermore, patients with CD44+/CD24- phenotype, basal-like tumors and >=4 lymph nodes involved had a significantly worse prognosis. The expression of CD44 and CD24 was detected by double-staining immunohistochemistry, which can locate cancer stem cells individually. Overall, the present results indicated that CD44/CD24 status evaluated by double-staining immunohistochemistry constitutes an independent prognostic factor for TNBC. PMID- 29113224 TI - T-cell immunoglobulin mucin-3 as a potential inducer of the epithelial mesenchymal transition in hepatocellular carcinoma. AB - T-cell immunoglobulin mucin (TIM)-3 is an important member of the TIM gene family, which was thought to contribute to the progression of numerous types of cancer, including hepatocellular carcinoma (HCC); however, the mechanism underlying TIM-3 functions in HCC progression has not yet been extensively investigated. The present study aimed to investigate the function of TIM-3 in the metastasis of HCC and to determine whether the alteration of TIM-3 expression levels regulated the epithelial-mesenchymal transition (EMT) occurrence of HCC, using epithelial (E)-cadherin, neuronal (N)-cadherin, matrix metallopeptidase-9 (MMP-9), Twist 1, Slug, Snail, and Smad as EMT biomarkers. The results demonstrated that upregulation of TIM-3 using TIM-3 lentiviral activation particles (5 ul) increased cell migration and invasion, which was decreased in TIM-3 short interfering RNA-infected cells (10 uM, 3 ul) correspondingly. SMMC 7721 HCC cells were used as the control. EMT was aggravated in TIM-3 upregulated SMMC-7721 cells, which was attenuated in the TIM-3 interference group, accompanied by an alteration of E-cadherin, N-cadherin, MMP-9, Twist 1, Slug, Snail and Smad expression levels. The data presented suggests that TIM-3 serves an essential role in the metastasis of HCC, the mechanism of which was associated with EMT occurrence. Interference of TIM-3 is expected to be an effective means to prevent and control EMT, and further the metastasis of HCC. PMID- 29113225 TI - Effect of siRNA-mediated gene silencing of transketolase on A549 lung cancer cells. AB - The aim of the present study was to investigate the effects of transketolase (TKT) on cell proliferation, cell migration and interaction with other metabolism associated genes in A549 lung cancer cells. A549 cells were transfected with three TKT-specific small interfering (si)RNAs, screened for the optimal transfection concentration, and sequenced with flow cytometry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell viability was evaluated using Cell Counting Kit-8 (CCK-8), cell cycle was assessed by flow cytometric analysis. Cell migration was determined by scratch-wound and Transwell chamber assays. The changes in mRNA expression levels of glucose-6-phosphate dehydrogenase (G6PDH), transaldolase (TAL), sorbitol dehydrogenase (SORD), phosphoribosyl pyrophosphate synthetase 1 (PRPS1) and hexokinase 1 (HK1) were detected by RT-qPCR. siRNA-C at 50 nmol/l was selected for the subsequent experiments. Compared with the negative control, cell proliferation of the TKT siRNA-C group was inhibited dramatically (CCK-8 24 h, 0.2984+/-0.0371 vs. 0.0952+/-0.0063; P<0.0001), the cell cycle was arrested at the G1/G0 cell cycle phase (58+/-2.0% vs. 70+/-2.5%; P=0.002), and cell migration ability was decreased [wound size, 254.71+/-34.96 vs. 349.12+/-37.43 um (P=0.0001); Transwell migration, 250+/-47.8/field vs. 150+/-49.0/field (P<0.0001)]. The mRNA expression levels of G6PDH, TAL, SORD, PRPS1 and HK1 were downregulated in the TKT-siRNA-C group compared with the negative control. The present study revealed that synthetic TKT-siRNA can inhibit A549 cell viability and migration, which may be due to arrest of the cell cycle and downregulation of relevant metabolic enzymes. PMID- 29113226 TI - Silencing of semaphorin 3C suppresses cell proliferation and migration in MCF-7 breast cancer cells. AB - Previous studies have suggested that semaphorin 3C (SEMA3C) is involved in the tumorigenesis and metastasis of a number of types of cancer. The aim of the present study was to investigate the role of SEMA3C in the proliferation and migration of MCF-7 breast cancer cells. Small interfering (si)RNA sequences targeting SEMA3C were constructed and transfected into MCF-7 cells in order to silence the expression of SEMA3C. Cell proliferation and migration were measured using CCK-8 and Transwell assays, respectively. Transfection with SEMA3C siRNA significantly downregulated the expression of SEMA3C in MCF-7 cells, and significantly suppressed cell proliferation and migration. Therefore, SEMA3C targeted siRNA may be of potential use for the early diagnosis and treatment of breast cancer. PMID- 29113227 TI - Low-dose valproic acid with low-dose gemcitabine augments MHC class I-related chain A/B expression without inducing the release of soluble MHC class I-related chain A/B. AB - To improve natural killer group 2 member D (NKG2D)-dependent cytotoxicity, the inhibition of cleavage and release of major histocompatibility complex class 1 related chain (MIC) molecules from the tumor surface are required. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is able to induce cell-surface MICA/B on tumor cells. In the present study, the ability of VPA and gemcitabine (GEM) to upregulate MICA/B in pancreatic cancer cells was investigated, resulting in the inhibition of cleavage and release of MIC molecules from the tumor surface. Flow cytometry was used to quantify MICA/B expression in six human pancreatic cancer lines. Functional cytotoxic activity of gammadeltaT cells against pancreatic cancer cells treated with VPA and GEM was determined using cytotoxicity assays. At low doses of VPA (0.7 mM) and GEM (0.001 uM), which did not induce tumor growth alterations, the agents individually increased cell surface MICA/B expression in MICA/B-positive cell lines, but not in the MICA/B negative cell line. Furthermore, the combination of VPA and GEM synergistically induced cell-surface MICA/B expression. In MICA/B-positive cell lines, the increase in MICA/B expression was dependent on VPA concentration. The combination of low-dose VPA and GEM enhanced the susceptibility of the PANC-1 cell line to gammadeltaT cell-mediated tumor cell lysis. It was observed that soluble MIC was released from PANC-1 in the culture supernatant following treatment with GEM. However, the combination of low-dose VPA with low-dose GEM increased MICA/B expression without inducing soluble MIC, resulting in enhanced tumor cell lysis. The results of the present study suggest that the combined administration of low dose VPA with low-dose GEM has the potential to enhance the therapeutic effects of immunotherapy in pancreatic cancer. Furthermore, it is proposed that the combination acts, in part, by upregulating MICA/B and prevents soluble MIC from being released. PMID- 29113228 TI - Intron-specific shRNA-mediated downregulation of survivin and promotion of apoptosis in HeLa cells. AB - Overexpression of the survivin gene contributes to tumorigenesis; it has been recognized as an important target for cancer therapy. In the present study, survivin expression was suppressed using recombinant plasmid mediated short hairpin RNAs (shRNAs) that were constructed to target exonic or intronic sequences of the survivin gene. In addition, a negative control shRNA was constructed. HeLa cells were transfected with specific shRNA constructs and the blocking efficiency of each shRNA was assessed at the mRNA and protein levels; and the five shRNA constructs with higher blocking efficiency were selected. Cell apoptosis was assessed by flow cytometry (FCM) following Annexin V-fluorescein isothiocyanate/propidium iodide double staining. Hoechst staining was used to detect the morphological diversity of the nuclei in apoptotic cells. The results demonstrated that survivin expression was effectively reduced by the transfection of shRNAs in HeLa cells. In addition, the apoptotic rates of the shRNA-treated groups were significantly increased compared with the negative control group according to the FCM results. The nuclei of HeLa cells exhibited apoptotic characteristics in the shRNA-treated groups as identified by Hoechst staining. Survivin-targeting shRNAs effectively downregulated the expression of the gene and markedly increased the apoptotic rate of HeLa cells. Data from the present study also indicated that the intron-specific shRNA demonstrate a high efficiency of inhibition of survivin expression and were able to induce cell apoptosis of HeLa cells through RNAi, potentially providing novel target sites for tumor therapy. In conclusion, the present study suggests that intron-specific blocking of survivin by RNAi may provide a tool for anticancer therapy. PMID- 29113229 TI - Fatty acid synthase affects expression of ErbB receptors in epithelial to mesenchymal transition of breast cancer cells and invasive ductal carcinoma. AB - The aim of the present study was to investigate changes in the expression of ErbBs during epithelial-mesenchymal transition (EMT) of breast cancer cells and its association with the expression of fatty acid synthase (FASN). MCF-7-MEK5 cells were used as the experimental model, while MCF-7 cells were used as a control. Tumor cells were implanted into nude mice for in vivo analysis. Cerulenin was used as a FASN inhibitor. Reverse transcription-polymerase chain reaction and western blot analysis were used to detect expression levels of FASN and ErbB1-4. Immunohistochemistry was used to detect the expression of FASN and ErbB1-4 in 58 invasive ductal carcinomas (IDC), as well as their association with clinicopathological characteristics. The expression of FASN and ErbB1-4 in MCF-7 MEK5 cells and tumor tissues increased significantly compared with controls (P<0.001). Inhibition of FASN by cerulenin resulted in a significant decrease in expression of ErbB1, 2 and 4 (P<0.001), whereas there was no evident change in ErbB3. In IDC samples, the expression of FASN and ErbB1-4 increased considerably in lymph node metastases compared with non-lymph node metastases (P<0.05). ErbB2 expression increased in advanced clinical stages (II, III and IV) of IDC and in tumors with larger diameters (P<0.05). The expression of ErbB3 increased in ER positive tumors (P<0.05). Additionally, a positive association between the expression of FASN and ErbB1, 2 and 4 was observed (P<0.05). FASN activates ErbB1, 2 and 4, and their dimers, which are polymerized via the microstructural domain of the cell membrane. This may initiate EMT and consequentlyincrease the invasion and migration of cancer cells. However, ErbB3 may also affect tumor progression via a FASN-independent pathway. PMID- 29113230 TI - Squamous cell transformation and EGFR T790M mutation as acquired resistance mechanisms in a patient with lung adenocarcinoma treated with a tyrosine kinase inhibitor: A case report. AB - The present case report describes the infrequent coexistence of squamous cell transformation and the epidermal growth factor receptor (EGFR) T790M mutation as resistance mechanisms to first line treatment with tyrosine kinase inhibitors. The patient was a 44-year-old female, diagnosed with a primitive advanced lung adenocarcinoma with bone metastases. The tumor was positive for the EGFR exon 19 deletion, therefore the patient was treated with afatinib (40 mg/day, orally) and radiotherapy for bone lesions. After 16 months, the patient developed resistance. Cytological examination of the pleural effusion confirmed an adenocarcinoma positive for the EGFR exon 19 deletion and the T790M mutation within exon 20, while a biopsy from the upper left bronchus revealed a keratinizing squamous cell carcinoma positive for the EGFR exon 19 deletion. In addition, the EGFR mutations were concomitantly detected in circulating cell-free tumour DNA. Due to the presence of the T790M mutation, the patient underwent osimertinib therapy (80 mg/day, orally), which resulted in a partial tumour regression at the 2-month follow-up, whereas the squamous lesions were treated with radiotherapy. The adenocarcinoma and squamous carcinoma components may share the same origin, according to the presence of the EGFR exon 19 deletion in both lesions. More accurate characterization of resistance mechanisms may lead to the development of improved treatment regimens. PMID- 29113231 TI - Reduced miR-125a levels associated with poor survival of patients with hepatocellular cancer. AB - MicroRNAs (miRNAs) serve an important role in tumorigenesis and development. Although a low expression of miR-125a in hepatocellular carcinoma (HCC) has been reported, the clinical significance remains unknown. In the current study, the data of Gene Expression Omnibus datasets was analyzed and significantly low expression of miR-125a in HCC was verified. Furthermore, the expression and clinical significance of miR-125a was investigated in 27 normal liver and 98 HCC tissue samples using reverse transcription-quantitative polymerase chain reaction analysis. The results demonstrated that the level of miR-125a expression was lower in HCC biopsies compared with that in normal liver tissues. Survival analysis established that miR-125a expression was negatively associated with the prognosis of HCC. Multivariate survival analysis demonstrated that patients with HCC with lowmiR-125a and Ki67-positive expression have shorter overall, and disease-free survival times. Altogether, the results of the current study provide the first evidence that reducedmiR-125a expression is associated with HCC progression and poor prognosis in patients, suggesting that miR-125a may have potential prognostic value as a tumor biomarker for patients with HCC. PMID- 29113232 TI - Inhibition of cyclooxygenase-2 sensitizes lung cancer cells to radiation-induced apoptosis. AB - Radiotherapy resistance is an enduring major setback in lung cancer therapy, and is responsible for a large proportion of treatment failures. In previous years, cyclooxygenase-2 (COX-2) has frequently been reported to promote tumor occurrence and development, suggesting a potential role in radiotherapy resistance. To investigate whether COX-2 inhibitors can be applied in radiosensitization, an MTT assay was performed to examine cell viability after X-ray radiation in the presence or absence of the specific COX-2 inhibitor Celecoxib. Cell apoptosis and cell cycle changes were also detected through laser confocal scanning microcopy and flow cytometry. X-ray treatment only caused mild cell death in lung cancer A549 cells. However, combination treatment using celecoxib and X-ray radiation exhibited improved inhibitory effects and significantly suppressed cell proliferation. Therefore, COX-2 inhibitors combined with radiotherapy can counteract radiation-induced high COX-2 expression, demonstrating that celecoxib can function as a radiosensitizer of lung cancer cells. It is therefore reasonable to predict COX-2 inhibitors to be potential clinical radiotherapy synergists. PMID- 29113233 TI - Higher expression level of tyrosine kinase-like orphan receptor 2 and Wnt member 5a in papillary thyroid carcinoma is associated with poor prognosis. AB - The tyrosine kinase-like orphan receptor 2 (ROR2) has a wnt-mediated, pro tumorigenic role in certain types of cancer. The present study was designed to assess the protein expression level of ROR2 and its putative ligand Wnt member 5a (Wnt5a), as well as the association with clinicopathological features in papillary thyroid carcinoma (PTC). A total of 58 patients were recruited, resulting in 58 human PTC tissue samples and their paired adjacent noncancerous tissue samples being obtained. The protein expression levels of ROR2 and Wnt5a were evaluated by immunohistochemistry and western blotting, and messenger RNA expression levels were determined by reverse transcription-quantitative polymerase chain reaction. ROR2 and Wnt5a protein and mRNA expression were significantly overexpressed in PTC tissues (P<0.05). The present study also revealed that ROR2 and Wnt5a were significantly associated with tumor stage and lymph node metastasis (P<0.05). There was a positive association between ROR2 and Wnt5a expression levels (r=0.857; P=0.007). In conclusion, ROR2 and Wnt5a may act as tumor suppressor genes in the development of PTC; overexpression of ROR2 and Wnt5a in PTC may be important for tumorigenesis and tumor development. PMID- 29113234 TI - Upregulation of TCTP is associated with cholangiocarcinoma progression and metastasis. AB - In order to investigate the role of translationally-controlled tumor protein (TCTP) in cholangiocarcinoma (CCA) progression and metastasis, TCTP protein staining in paraffin-embedded sections of human CCA tissue samples was examined using immunohistochemistry, and its expression was subsequently compared with clinicopathological parameters. Small interfering RNA (siRNA) targeting TCTP (siTCTP) were transfected into CCA cell lines to evaluate its effects on cellular functions. The proliferation, tumorigenicity and migration abilities of the transfected cells were measured using sulforhodamine B, clonogenic and would healing assays, respectively. The protein levels of TCTP and its associated molecules were evaluated by western blot analysis. Of the 119 individual cases of CCA tissues analyzed, high TCTP scores were significantly correlated with overall metastasis (P=0.044) and a shorter survival time (P<0.001). Multivariate proportional hazards analysis revealed that TCTP is an independent indicator of poor prognosis in CCA (hazard ratio =2.864; P<0.001). siTCTP transfection suppressed CCA cell growth and migration abilities, compared with the control cells (P<0.01). The siTCTP reduced the protein levels of focal adhesion kinase (FAK), phospho-FAK, nuclear factor kappa-light-chain-enhancer of activated B cells and matrix metalloproteinase 9, suggesting potential roles of TCTP in regulating CCA progression and metastasis. In conclusion, the upregulation of TCTP is clinically significant in patients with CCA, serving roles in CCA progression, particularly in cell survival and metastasis. Suppression of TCTP may serve as a potential target in CCA prevention and treatment. PMID- 29113236 TI - Biochanin A induces anticancer effects in SK-Mel-28 human malignant melanoma cells via induction of apoptosis, inhibition of cell invasion and modulation of NF-kappaB and MAPK signaling pathways. AB - The present study aimed to investigate the antitumor activity of Biochanin A in SK-Mel-28 human malignant melanoma cells. An MTT assay was used to study the cytotoxic effects of Biochanin A. In vitro wound healing and invasion assays were used to investigate the effects on cell migration and invasion. Fluorescence microscopy using acridine orange/propidium iodide was used to study effects on cell morphology and apoptosis. Nuclear factor (NF)-kappaB and mitogen-activated protein kinase (MAPK) protein expression levels were determined by western blot analysis. The results indicated that Biochanin A significantly inhibited the growth of SK-Mel-28 cells in a dose and time dependent manner. Treatment of the cells with Biochanin A induced apoptosis in a dose dependent manner. Additionally, Biochanin A led to inhibition of cell migration and invasion in a dose-dependent manner and upregulated the expression of key proteins in the NF kappaB and MAPK signaling pathways. PMID- 29113235 TI - Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome. AB - Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, and no targeted therapy is currently available. The aim of the present study was to investigate the prognostic significance of the expression of V-Ki-ras2 Kappairsten rat sarcoma viral oncogene homolog (KRAS), downstream signaling pathway genes and the association with clinical characteristics in PDAC patients undergoing radical surgery. Tumors and adjacent non-neoplastic pancreatic tissues were examined in 45 patients with histologically verified PDAC. KRAS and B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene mutation analysis was performed using the KRAS/BRAF/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha array. The transcript profile of 52 KRAS downstream signaling pathway genes was assessed using quantitative-polymerase chain reaction. KRAS mutation was detected in 80% of cases. The genes of four signaling pathways downstream of KRAS, including the phosphoinositide 3-kinase/3 phosphoinositide-dependent protein kinase 1/V-akt murine thymoma viral oncogene homolog 1, RAL guanine nucleotide exchange factor, Ras and Rab interactor 1/ABL proto-oncogene-1, non-receptor tyrosine kinase, and RAF proto-oncogene serine/threonine-protein kinase/mitogen-activated protein kinase pathways, exhibited differential expression in PDAC compared with that in the adjacent normal tissues. However, no significant differences in expression were evident between patients with KRAS-mutated and wild-type tumors. The expression of KRAS downstream signaling pathways genes did not correlate with angioinvasion, perineural invasion, grade or presence of lymph node metastasis. Additionally, the presence of KRAS mutations was not associated with overall survival. Among the KRAS downstream effective signaling pathways molecules investigated, only v raf-1 murine leukemia viral oncogene homolog 1 expression was predictive of prognosis. Overall, KRAS mutation is present in the majority of cases of PDAC, but is not associated with changes in the expression of KRAS downstream signaling pathways and the clinical outcome. This may partly explain the failure of KRAS targeted therapies in PDAC. PMID- 29113237 TI - MicroRNA-10a suppresses breast cancer progression via PI3K/Akt/mTOR pathway. AB - Previous studies have demonstrated that microRNA-10a (miR-10a) regulates various opposing biological functions in breast cancer. The aim of the present study was to investigate the exact functions of miR-10a in the pathogenesis of breast cancer. miR-10a expression was initially detected in two human breast cancer cell lines, MCF-7 and MDA-MB-231 and a normal human mammary epithelial cell line MCF 10A. The proliferation, migration and apoptosis of breast cancer cells were analyzed using MTT assays, Transwell assays and flow cytometry, respectively, following transfection of MCF-7 and MDA-MB-231 cells with an miR-10a mimic or anti-miR-10a. The expression of phosphorylated (p-)protein kinase B (Akt), p mammalian target of rapamycin (p-mTOR), p-ribosomal protein S6 kinase beta-1 (p p70S6K), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Cytochrome C (Cyt C), B-cell lymphoma 2 (Bcl-2), BCL-2 associated X, apoptosis regulator (Bax), and cleaved caspase-3 were analyzed by western blotting. The migration of MCF-7 cells pretreated with an mTOR inhibitor CCI-779, was detected using a Transwell assay. Relative miR-10a expression was significantly elevated in MDA-MB-231 breast cancer cells and was at its highest levels in MCF-7 cells. Transfection with the miR-10a mimic significantly inhibited proliferation and migration, and promoted the apoptosis of breast cancer cells. Furthermore, upregulation of miR-10a markedly suppressed the levels of p-Akt, p-mTOR, p-p70S6K, and PIK3CA, and increased the expression of Cyt C, cleaved caspase-3, and the ratio of Bax/Bcl-2. Anti-miR-10a had the opposite effects. In addition, CCI-779 reversed the effect of anti-miR-10a on the migration of MCF-7 cells in a dose-dependent manner. In conclusion, miR-10a is downregulated in high aggressive breast cancer cells. miR-10a inhibited the proliferation and migration, and promoted apoptosis of breast cancer cells via phosphoinositide/Akt/mTOR signaling, and the mitochondrial apoptotic pathway. PMID- 29113238 TI - Selection of reference genes for gene expression studies in human bladder cancer using SYBR-Green quantitative polymerase chain reaction. AB - Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is a rapid, reliable and widely used method of studying gene expression profiles that requires appropriate normalization for accurate and reliable results. Reference genes are usually used to normalize mRNA levels; however, the expression levels of these reference genes may vary between cell types, developmental stages, species and experimental conditions. Therefore, a normalization strategy is an important precondition for reliable conclusions, with endogenous controls requiring determination for every experimental system. In the present study, 18 reference genes used in various prior studies were analyzed to determine their applicability in bladder cancer. A total of 35 matched malignant and non malignant bladder cancer (specifically transitional cell carcinoma) tissue specimens were examined. RNA and cDNA quality was stringently controlled. Candidate reference genes were assessed using SYBR-Green RT-qPCR. mRNA abundance was compared and reference genes with distinct ranges of expression to possible target genes were excluded. Genes that were differentially expressed in matched non-cancerous and cancerous samples were also excluded, using quantification cycle analysis. Subsequently, the stability of the selected reference genes was analyzed using three different methods: geNorm, NormFinder and BestKeeper. The rarely used ribosomal protein S23 (RPS23) was the most stable single reference gene, with RPS23, tumor protein, translationally controlled 1 and RPS13 comprising the optimal reference gene set for all the bladder samples. These stable reference genes should be employed in normalization and quantification of transcript levels in future expression studies of bladder cancer-associated genes. PMID- 29113239 TI - CD109 expression is upregulated in penile squamous cell carcinoma. AB - Cluster of differentiation (CD) 109 is a glycosylphosphatidylinositol-anchored cell surface glycoprotein and a co-receptor for transforming growth factor beta. The expression of CD109 has been detected in squamous cell carcinoma of the lung, esophagus, skin and gallbladder. The aim of the present study was to evaluate CD109 expression in penile squamous cell carcinoma (PSCC). CD109 expression in PSCC tumor and adjacent tissues from 45 specimens in tissue microarrays was examined by immunohistochemical analyses. In addition, 3 fresh surgical samples of PSCC were collected and examined for their CD109 mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence staining. CD109 transcription and expression were significantly higher in the PSCC tissues compared with adjacent normal penile tissues, and its expression was restricted to squamous cells. However, CD109 expression level was not associated with the PSCC differentiation grade. These results suggest that CD109 may be associated with the pathogenesis of PSCC, and may therefore be a potential therapeutic target. PMID- 29113240 TI - Downregulation of microRNA-301a inhibited proliferation, migration and invasion of non-small cell lung cancer by directly targeting DLC1. AB - Increasing evidence has indicated that the abnormal expression of microRNAs contributes to tumorigenesis and tumor development. Understanding the roles of microRNAs in non-small cell lung cancer (NSCLC) might provide valuable information for therapeutic strategies in the therapy for patients with NSCLC. In the present study, significant upregulation of microRNA (miR)-301a was observed in NSCLC tissues and cell lines compared with normal adjacent tissues and a normal human bronchial epithelial cell line. The inhibition of miR-301a suppressed proliferation, migration and invasion of NSCLC cells. Functional analyses indicated that DLC1 was a direct target of miR-301a in NSCLC. Inhibiting miR-301a expression decreased DLC1 expression at mRNA and protein levels. Moreover, DLC1 knockdown partially reversed the inhibition of proliferation, migration and invasion induced by miR-301a knockdown in NSCLC cells. Therefore, these findings may provide novel insights into the molecular mechanisms of miR 301a in proliferation, migration and invasion of NSCLC cells. The findings also indicated that miR-301a may act as a novel potential therapeutic target for patients with NSCLC. PMID- 29113241 TI - Expression of the cytoskeleton regulatory protein Mena in human gastric carcinoma and its prognostic significance. AB - The cytoskeleton regulatory protein Mena is reportedly overexpressed in breast cancer; however, data regarding its expression level and clinical significance in gastric carcinoma (GC) is limited. The aim of the present study was to investigate Mena expression levels and prognostic significance in GC. Mena mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction in 10 paired GC and adjacent normal tissues. The Mena protein expression level was analyzed in paraffin-embedded GC samples and adjacent normal tissues by immunohistochemistry. Statistical analyses were also performed to evaluate the clinicopathological significance of Mena. The results revealed that the mRNA expression level of Mena was significantly higher in G Ct issues compared with in adjacent normal tissues from10 paired samples. In the paraffin embedded tissue samples, the protein expression level of Mena was higher in G Ct issues compared with in adjacent normal tissues. Compared with adjacent normal tissues, Mena overexpression was observed in 52.83% (56/106) of patients. The overexpression of Mena was significantly associated with the T stage (P=0.033), tumor-node-metastasis (TNM) stage (P<0.001) and decreased overall survival (P<0.001). Based on a multivariate analysis, Mena expression level was an independent prognostic factor for overall survival time. In conclusion, Mena wasoverexpressed in G C tissues and significantly associated with the T stage, TNM stage and overall survival time. Mena may therefore be suitable as a prognostic indicator for patients with GC. PMID- 29113242 TI - Eupatolide inhibits the TGF-beta1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5. AB - The epithelial-mesenchymal transition (EMT) is a hallmark of cancer metastasis, and the associated molecular signaling pathways are regarded as therapeutic targets for cancer treatment. Thus, suppressing EMT with a natural chemical compound may be of therapeutic benefit. Eupatolide is a natural chemical compound extracted from the medicinal plant Inula britannica, which is used in Eastern Asia to treat bronchitis, disorders of the digestive system and inflammation. Besides the anti-inflammatory function of eupatolide, the present study found that eupatolide suppressed the migration and invasion of breast cancer cells, which was associated with the downregulation of vimentin in MDA-MB-231 cells and the upregulation of E-cadherin in MCF-7 cells. Treatment with eupatolide also significantly inhibited the migration and invasion of breast cancer cells that had been stimulated with transforming growth factor-beta1 (TGF-beta1). Eupatolide also suppressed TGF-beta1-induced EMT via downregulation of mothers against decapentaplegic homolog 3 (SMAD3) phosphorylation and transcriptional repression of TGF-beta receptor 1 (ALK5). In addition to this canonical pathway, the non canonical protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways were also inhibited by eupatolide treatment. In summary, the results suggest that eupatolide suppresses the migration and invasion of breast cancer cells by blocking the canonical ALK5-SMAD3 signaling pathway and the non canonical ERK and AKT signaling pathways. PMID- 29113243 TI - Differential gene expression analysis in glioblastoma cells and normal human brain cells based on GEO database. AB - The differentially expressed genes between glioblastoma (GBM) cells and normal human brain cells were investigated to performed pathway analysis and protein interaction network analysis for the differentially expressed genes. GSE12657 and GSE42656 gene chips, which contain gene expression profile of GBM were obtained from Gene Expression Omniub (GEO) database of National Center for Biotechnology Information (NCBI). The 'limma' data packet in 'R' software was used to analyze the differentially expressed genes in the two gene chips, and gene integration was performed using 'RobustRankAggreg' package. Finally, pheatmap software was used for heatmap analysis and Cytoscape, DAVID, STRING and KOBAS were used for protein-protein interaction, Gene Ontology (GO) and KEGG analyses. As results: i) 702 differentially expressed genes were identified in GSE12657, among those genes, 548 were significantly upregulated and 154 were significantly downregulated (p<0.01, fold-change >1), and 1,854 differentially expressed genes were identified in GSE42656, among the genes, 1,068 were significantly upregulated and 786 were significantly downregulated (p<0.01, fold-change >1). A total of 167 differentially expressed genes including 100 upregulated genes and 67 downregulated genes were identified after gene integration, and the genes showed significantly different expression levels in GBM compared with normal human brain cells (p<0.05). ii) Interactions between the protein products of 101 differentially expressed genes were identified using STRING and expression network was established. A key gene, called CALM3, was identified by Cytoscape software. iii) GO enrichment analysis showed that differentially expressed genes were mainly enriched in 'neurotransmitter:sodium symporter activity' and 'neurotransmitter transporter activity', which can affect the activity of neurotransmitter transportation. KEGG pathway analysis showed that the differentially expressed genes were mainly enriched in 'protein processing in endoplasmic reticulum', which can affect protein processing in endoplasmic reticulum. The results showed that: i) 167 differentially expressed genes were identified from two gene chips after integration; and ii) protein interaction network was established, and GO and KEGG pathway analyses were successfully performed to identify and annotate the key gene, which provide new insights for the studies on GBN at gene level. PMID- 29113244 TI - Impact of the individualization of the first-line chemotherapy for advanced colorectal cancer based on collagen gel droplet-embedded drug sensitivity test. AB - Leucovorin (FOL) and fluorouracil (5-FU) plus oxaliplatin (l-OHP; FOLFOX) or FOL and 5-FU plus irinotecan (SN-38; FOLFIRI) are widely used as first-line chemotherapy regimens in the treatment of advanced colorectal cancer (CRC). However, second-line chemotherapy must be abandoned in certain cases due to disease progression, adverse effects or high medical cost. Therefore, the most effective regimen should be selected as first-line chemotherapy. We reported that individualization of first-line treatment (FOLFOX/FOLFIRI/Dual/Poor responder) was possible using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) and that individualized first-line chemotherapy with CD-DST may improve the prognosis of patients with unresectable CRC. The aim of the present prospective cohort study was to evaluate the individualization of first-line chemotherapy using CD-DST, with a focus on prognosis. Between March 2008 and December 2015, tumor specimens were obtained from 120 patients with CRC who had not received preoperative chemotherapy. CD-DST was performed and the growth inhibition rate (IR) was determined by exposure for 24 h with 5-FU and l-OHP (6.0 and 3.0 ug/ml, respectively) and 5-FU and SN-38 (6.0 and 0.2 ug/ml, respectively). The cumulative distribution of IR values under each condition was evaluated on the basis that the clinical response to FOLFOX and FOLFIRI is equivalent (~50%). The prognosis of dual responder was improved compared with that of poor responders, however this difference was identified to be significant. There was no different prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first line regimen in dual responders. However, in poor responders, there were significant differences of prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first-line regimen (P=0.036). In conclusion, the results from the present study suggest that administration of the recommended first-line regimen using CD-DST for patients with unresectable CRC is important for the improvement of prognosis, particularly in poor responders. PMID- 29113245 TI - Temporomandibular dislocation caused by pancreatic cancer metastasis: A case report. AB - Metastasis-induced dislocation of the temporomandibular joint (TMJ) is rare. The present study describes a case of TMJ dislocation caused by metastasis from pancreatic cancer, and discusses this in the context of literature on occlusal abnormality and/or dislocation due to metastasis. In the present case, unilateral TMJ dislocation was suspected when the patient first presented; destructive bone changes were not observed on conventional radiographs, and magnetic resonance imaging (MRI) revealed a tumorous lesion. The present case suggests that healthcare professionals should consider whether a malignant disease is present in cases of occlusal abnormality and/or dislocation of the TMJ, and that, in patients with TMJ dislocation that cannot easily be repositioned, additional imaging examinations, including MRI, should be performed as soon as possible, regardless of whether destructive bone changes are present. Metastasis to the TMJ is typically associated with generalized skeletal metastasis in the final stage of malignancy. Therefore, it is crucial to consider the possibility of cervical spine metastasis in order to decrease the risk of cervical fracture when attempting reduction of a TMJ dislocation, particularly in patients with a history of cancer. PMID- 29113246 TI - Effect of pretreatment psoas muscle mass on survival for patients with unresectable pancreatic cancer undergoing systemic chemotherapy. AB - To the best of our knowledge, there are few previous studies that have investigated the effect of decreased skeletal muscle mass (DSMM) on survival in patients with unresectable advanced pancreatic cancer (APC) who are undergoing systemic chemotherapy. Thus, the present study aimed to investigate the impact of DSMM, as determined by the psoas muscle index (PMI) following computed tomography and prior to systemic chemotherapy, on the outcomes of patients with unresectable APC (n=61). The primary endpoint used was the overall survival (OS) rate. The OS rates in the PMI-High group (exceeds the median PMI value in each gender) were retrospectively compared with those in the PMI-Low group (below the median PMI value in each gender), and factors associated with OS were investigated using univariate and multivariate analyses. The study cohort included 31 male and 30 female patients with a median age of 72 years, 13 of whom were stage IVA, and 48 were stage IVB. The median PMI in males was 4.3 cm2/m2 (range, 1.6-8.2 cm2/m2), while that in females was 2.3 cm2/m2 (range, 0.7-6.1 cm2/m2). The proportion of patients with performance status 0 in the PMI-High group was significantly high, compared with that in the PMI-Low group [83.3% (25/30) vs. 58.1% (18/31); P=0.0486]. Body mass index in the PMI-High group was significantly higher compared with that in the PMI-Low group (P=0.0154). The 1-year cumulative survival rate was 43.3% in the PMI-High group and 12.9% in the PMI-Low group (P=0.0027). Following multivariate analysis, PMI (P=0.0036), prothrombin time (P=0.0044) and carbohydrate antigen 19-9 (P=0.0451) were identified to be significant predictors of OS. In conclusion, DSMM, as determined by the PMI, could be a significant predictor of prognosis in patients with unresectable APC who are receiving systemic chemotherapy. PMID- 29113247 TI - Induction of oxidative stress by anticancer drugs in the presence and absence of cells. AB - Reactive oxygen species (ROS) are generated in the cell through multiple mechanisms. Intracellular ROS are rapidly detoxified by various enzymatic and non enzymatic mechanisms; however, disruption of the oxidant-antioxidant balance causes oxidative stress and elicits cell damage. The oxidative stress induced by chemotherapy is known to cause side effects in patients with cancer. However, few studies have examined whether anticancer drugs induce oxidative stress in cancer cells. Furthermore, the precise mechanism by which anticancer drugs induce the generation of ROS remains unclear. In the present study, to investigate whether anticancer drugs induce oxidative stress, DLD-1 human colorectal cancer cells were treated with 20 different anticancer drugs and then stained with CellROX(r) ROS detection reagent. Furthermore, an oxygen radical absorbance capacity assay in the presence of copper was performed to estimate the oxidative activities of the anticancer drugs in the absence of cells. The data of the present study using assay methods in the presence and absence of cells suggest that nimustine, actinomycin D, doxorubicin, mitomycin C, mitoxantrone, carmofur, gemcitabine, mercaptopurine, camptothecin, paclitaxel, vinblastine, and vinorelbine are able to induce oxidative stress. PMID- 29113248 TI - Gene expression profile comparison between colorectal cancer and adjacent normal tissues. AB - The present study aimed to compare gene expression profiles between colorectal cancer and adjacent normal tissues, and to perform a preliminarily analysis of the key genes and underlying molecular mechanisms implicated in colorectal cancer development. Gene expression microarray chips were used to screen genes that were differently expressed between colorectal cancer and adjacent normal tissues. Approximately 1,183 genes were differentially expressed in cancer tissues compared with adjacent normal tissues (P<=0.05; fold difference, >2.0), of which 570 genes were upregulated and 613 genes were downregulated. In total, 6 upregulated genes, including keratin 23, collagen type X alpha1, collagen type XI alpha1, cell migration-inducing hyaluronan-binding protein, transforming growth factor-beta1 and V-Myc avian myelocytomatosis viral oncogene homolog, and 2 downregulated genes, including channel alpha subunit 7 and EPH receptor A7, were selected and validated using reverse transcription-quantitative polymerase chain reaction, which exhibited results that were consistent with the microarray analysis. These 1,183 differentially expressed genes were further classified into 71 groups based on their functions using gene ontology and pathway analyses. Kyoto Encyclopedia of Genes and Genomes analysis of these upregulated or downregulated genes suggested that 23 signaling pathways were involved. The present study preliminarily screened for and identified key genes and signaling pathways that may be closely associated with colorectal cancer development. However, subsequent gene function studies are required to verify these findings. PMID- 29113249 TI - Transcriptome analysis reveals dysregulated long non-coding RNAs and mRNAs associated with extrahepatic cholangiocarcinoma progression. AB - The incidence of extrahepatic cholangiocarcinoma (ECC) is the highest of all the cholangiocarcinoma cases. However, the molecular mechanism of ECC genesis and progression remains unclear. Long non-coding RNAs (lncRNAs) have been revealed to perform critical regulatory roles in cancer biology. In order to understand lncRNA expression patterns and their potential function in ECC, a transcriptome analysis of lncRNA and mRNA expression was performed in ECC and paired adjacent non-cancerous tissues using Agilent human lncRNA + mRNA arrayV4.0 (4*180 K format). It was identified that 268 lncRNAs and 459 mRNAs were differentially expressed in ECC. Among these, 78 lncRNAs and 66 mRNAs were upregulated >2-fold compared with adjacent non-cancerous tissues, and 190 lncRNAs and 393 mRNAs were downregulated in the ECC samples. Differences in lncRNA expression between ECC and paired adjacent non-cancerous tissues were confirmed using reverse transcription-quantitative polymerase chain reactionas proof of principle. Functional analysis of co-expressed mRNAs with lncRNAs indicated that these dysregulated lncRNAsmay be involved in known ECC-associated biological processes and pathways. The present findings indicated that mRNAs and lncRNAs perform important roles in the development and progression of ECC. The present findings may lay the foundation for future efforts to understand the role of lncRNAs and develop novel biomarkers in ECC. PMID- 29113250 TI - Comparison of miRNA and gene expression profiles between metastatic and primary prostate cancer. AB - The present study aimed to identify the regulatory mechanisms associated with the metastasis of prostate cancer (PC). The microRNA (miRNA/miR) microarray dataset GSE21036 and gene transcript dataset GSE21034 were downloaded from the Gene Expression Omnibus database. Following pre-processing, differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) between samples from patients with primary prostate cancer (PPC) and metastatic prostate cancer (MPC) with |log2 fold change (FC)| >1 and a false discovery rate <0.05 were selected using the Linear Models for Microarray and RNA-seq Data 4 package of R. Next, a DEM-DEG regulatory network was constructed by downloading miRNA-DEG pairs from the miRNA.org database. Finally, functional annotation of each DEM-DEG module was performed using the Database for Annotation, Visualization and Integrated Discovery based on the Gene Ontology database. The upregulated miRNAs, including miR-144, miR-494 and miR-181a, exhibited a higher degree of connections compared with other nodes, including in the DEM-DEG regulatory network, and regulated a number of downregulated DEGs. According to the functional annotation of the DEM DEG modules, miR-144 and its targeted DEGs enriched the highest number of biological process terms (36 terms), followed by miR-494 (24 terms), miR-30d (18 terms), miR-181a (15 terms), hsa-miR-196a (8 terms), miR-708 (7 terms) and miR 486-5p (2 terms). Therefore, these miRNAs may serve roles in the metastasis of PC cells via downregulation of their corresponding target DEGs. PMID- 29113251 TI - Structural MRI research in patients with nasopharyngeal carcinoma following radiotherapy: A DTI and VBM study. AB - The aim of the present study was to investigate the microstructural characteristics of the brain lobes following radiotherapy (RT) for patients with nasopharyngeal carcinoma (NPC) at distinct times. Diffusion tensor imaging (DTI) and 3D-T1-weighted imaging was performed in 70 age- and sex-matched subjects, 24 of whom were pre-treatment patients. The patients were divided into three groups, according to the time following completion of RT. Fractional anisotropy (FA) and gray matter (GM) volume were determined. The DTI data were analyzed using tract based spatial statistics and the GM volume was analyzed using voxel-based morphometry (VBM). Compared with the pre-RT group, the mean FA values in the left parietal lobe white matter (WM) and right cerebellum decreased significantly in the post-RT 0-6 month group (P<0.05). In addition, the mean FA values in the right parietal lobe WM decreased significantly in the post-RT 6-12 month group (P<0.05), compared with the pre-RT group. The FA level in the right temporal lobe remained significantly decreased, compared with that in the pre-RT group (P<0.05) for 1 year after RT. Furthermore, compared with pre-RT group, the GM volume in the bilateral frontal lobe, right occipital lobe, left parietal lobe, right temporal lobe and left cerebellum decreased significantly in the post-RT 0-6 month group (P<0.05), and in the bilateral temporal lobe, parietal lobe, right frontal lobe and left cerebellum, the GM volume decreased significantly in the post-RT 6-12 month group (P<0.05). The GM volume in the right temporal lobe, bilateral frontal lobe and bilateral cerebellum remained significantly decreased compared with that in the pre-RT group (P<0.05) for 1 year after RT. A combination of DTI and VBM may be used to determine radiation-induced brain injury in patients treated for NPC. PMID- 29113252 TI - MicroRNA-25 contributes to cisplatin resistance in gastric cancer cells by inhibiting forkhead box O3a. AB - Gastric cancer (GC) is a common type of malignancy worldwide, and chemotherapeutic resistance accounts for the majority of the failures in clinical treatment. MicroRNAs (miRs) are a class of small non-coding RNAs, which serve essential roles in GC. The present study aimed to investigate the potential role of miR-25 in the cisplatin sensitivity of GC cells. The expression level of miR 25 was significantly upregulated in the cisplatin-resistant GC cell line SGC 7901/DDP compared with the SGC-7901 parental cell line. Overexpression of miR-25 significantly enhanced cell cycle progression and decreased the sensitivity of SGC-7901 cells to cisplatin, whereas inhibition of miR-25 in the SGC-7901/DDP cisplatin-resistant cells resulted in cell cycle arrest at the G0/G1 phase and significantly increased drug sensitivity. Furthermore, the tumor suppressor forkhead box O3a (FOXO3a) was identified as a direct target gene of miR-25 by luciferase assay and western blot analysis, and was shown to mediate the drug resistance phenotype of GC cells. These findings suggest that upregulation of miR 25 is important for GC cells to establish a cisplatin-resistant phenotype via a FOXO3a-dependent mechanism. Therefore, targeting miR-25 may be a promising therapeutic approach to treat patients with cisplatin-resistant GC. PMID- 29113253 TI - Overexpression of CD164 in oral cavity squamous cell carcinoma predicts a favourable prognosis. AB - The aim of the present study was to investigate the association between cluster of differentiation (CD) 164 expression with clinicopathological parameters and prognosis among patients with oral cavity squamous cell carcinoma (OSCC). The present study retrospectively reviewed 70 patients with OSCC who underwent curative primary surgery. A number of patients subsequently received postoperative chemoradiotherapy although the specimens were not exposed to radiation or chemotherapy prior to anti-CD164 antibody immunohistochemical staining. CD164 overexpression was arbitrarily defined as exhibiting an H-score of >=120. Univariate and multivariate analyses were performed for sex, age, American Joint Committee on Cancer stage, tumour location, histological grade, surgical margin and H-score. The 5-year overall survival rate was 54.4% and the median follow-up time was 46 months for surviving patients. Univariate analyses revealed that a low overall survival rate was associated with advanced-stage disease (P<0.001), buccogingival tumour location (P=0.038) and a CD164 H-score of <120 (P=0.016). Multivariate Cox's regression analyses revealed that poor overall survival rate was associated with advanced-stage disease (P=0.001) and a CD164 H score of <120 (P=0.04). CD164 overexpression in OSCC was associated with favourable survival rate. Thus, CD164 expression may be a clinically useful predictor of prognosis in patients with OSCC. PMID- 29113254 TI - Epigenetic analysis of FHL1 tumor suppressor gene in human liver cancer. AB - Liver cancer is one of the most common types of cancer among human malignancies. Four and a half LIM domains 1 (FHL1), as a tumor suppressor gene, is frequently downregulated in multiple types of human cancer. However, the role and specific mechanisms of FHL1 as a tumor suppressor in liver cancer are poorly understood. The present study aimed to investigate the role and associated mechanisms of FHL1 in human liver cancer. The level of FHL1 mRNA in hepatocellular carcinoma (HCC) tissue specimens and cell lines derived from the human liver was determined using reverse transcription polymerase chain reaction and western blot analysis. The association between FHL1 expression and clinicopathological characteristics of patients with liver cancer was analyzed. Western blotting, small interfering RNA (siRNA) and chromatin immunoprecipitation were used to study the expression association of FHL1 and enhancer of zeste homolog 2 (EZH2) in human liver cancer and to explore the regulatory mechanism of FHL1 downregulation. Colony formation and migration assays were performed while FHL1 was overexpressed in Hep3B cells. The results showed that the expression of FHL1 mRNA in tumor tissue decreased, exhibiting a significant difference compared with the adjacent non-cancerous tissue (P<0.05). However, the downregulation of FHL1 was not significantly associated with the sex, age, hepatitis B virus infection status, tumor size, distant metastasis status or level of tumor differentiation of the patients. FHL1 was synergistically silenced by DNA methylation and histone modification, and 3 deanzaneplanocin A (DZNep), an inhibitor of EZH2, which is a histone methyltransferase of the polycomb repressive complex 2, which catalyzes histone H3 lysine 27 tri-methylation (H3K27me3). A significant association between FHL1 and EZH2 expression was identified in the female hepatocellular carcinoma (HCC) samples, but was not in the male HCC samples. FHL1 overexpression and DZNep treatment significantly suppressed the growth and migration of Hep3B cells by restoring FHL1 expression. H3K27me3 was significantly enriched at the FHL1 promoter region, as indicated by a chromatin immunoprecipitation assay, and associated with the epigenetic repression of the FHL1 tumor suppressor gene in HCC cell lines. In conclusion, the present study provides an insight into DNA methylation and EZH2-H3K27me3 epigenetic repression of FHL1 in human liver cancer. PMID- 29113255 TI - Acute renal failure due to small cell neuroendocrine carcinoma of the left kidney: A case report. AB - The majority of small cell carcinoma (SCC) cases originate from the lungs. SCC of the kidneys is rare. Among genitourinary tumors, renal cell carcinoma is the most common type of tumor to be associated with paraneoplastic syndromes. The majority of paraneoplastic syndromes disappear following nephrectomy in renal cell carcinoma cases. The present case involved the assessment of a female patient with SCC of the left kidney. The patient was diagnosed with acute renal failure and underwent a laparoscopic left radical nephrectomy. Surgical intervention removed the need for dialysis; the patient was under follow-up observation every week without any requirement for dialysis for 8 months and received adjuvant carboplatin-etoposide chemotherapy. Surgery is an option for dialysis-dependent patients with a renal tumor. The removal of the tumor burden may restore renal function and eliminate paraneoplastic syndromes. PMID- 29113256 TI - NUDT expression is predictive of prognosis in patients with clear cell renal cell carcinoma. AB - The nudix hydroxylase (NUDT) family of genes may have notable roles in cancer growth and metastasis. The present study aimed to determine the prognostic ability of NUDT genes in clear cell renal cell carcinoma (ccRCC). Data from 509 patients with ccRCC was obtained from The Cancer Genome Atlas (TCGA) database and 192 patient samples from Fudan University Shanghai Cancer Center (FUSCC) were analyzed in the present study. The expression profile of NUDT gene family members in the TCGA cohort was obtained from the TCGA RNA sequencing database. Pathological characteristics, including age, sex, tumor size, tumor grade, stage, laterality and overall survival were collected. Cox proportional hazards regression model and Kaplan-Meier survival analysis were performed to assess the associations between pathological characteristics and expression levels of NUDT family genes. NUDT family genes that exhibited associations with overall survival (OS) were further validated in the FUSCC cohort. In the TCGA cohort, Cox proportional hazards analysis found that NUDT5 [hazards ratio (HR)=1.676; 95% confidence interval (CI), 1.097-2.559] and NUDT17 (HR=1.375; 95% CI, 1.092-1.732) were predictive of ccRCC prognosis. Further analysis revealed that low NUDT5 (P<0.0001) and NUDT17 (P<0.0001) expression were associated with poorer OS rates in the TCGA cohort. In the FUSCC cohort, low NUDT5 expression was also associated with poor OS rates (P=0.0116), and tumor grade was a factor that influenced the expression level of NUDT5 (P=0.016). PMID- 29113257 TI - Potato freeze-thaw solution enhances immune function and antitumor activity in vivo. AB - Although potato extract, derived from various methods, exhibits anticancer, antiviral and anti-parasite activities in vitro and in vivo, the bioactivity of potato solution remains unclear using the freeze-thaw extraction method granted by the State Intellectual Property Office of China. In the present study, a potato freeze-thaw solution (PFTS) was fed to mice with ascites tumor that were pre-treated with cyclophosphamide. The numbers of peripheral white blood cells (WBCs), macrophage phagocytosis, lymphocyte transformation and survival of mice were measured. While mice injected with cyclophosphamide exhibited decreased counts of peripheral WBCs, treatment of the cyclophosphamide-injected mice with PFTS for 10 days significantly increased the number of peripheral WBCs and reversed WBC counts to the normal level, a comparable effect to that of Ganoderma lucidum. In addition, treatment with PFTS for 20 days significantly enhanced peritoneal macrophage phagocytosis and lymphocyte transformation. Lastly, PFTS was noticed to prolong the survival of tumor-bearing mice when compared with that of control mice. Collectively, these data suggested that PFTS, at least in part, enhances immune function and possesses antitumor activity. PMID- 29113258 TI - Combination of calcineurin B subunit (CnB) and 5-fluorouracil reverses 5 fluorouracil-induced immunosuppressive effect and enhances the antitumor activity in hepatocellular carcinoma. AB - Five-fluorouracil (5-FU) is a widely used chemotherapeutic agent for digestive system tumors; however, continuous use of 5-FU may cause severe side effects, including myelosuppression and immunosuppression. Our previous study revealed that calcineurin B subunit (CnB), an innovative genetic engineering antitumor protein, possesses tumor-suppressive effects with low toxicity. CnB can bind to and activate integrin alphaM on macrophages, subsequently promoting the expression, and secretion of TNF-related apoptosis-inducing ligand, a specific proapoptotic cytokine. In the present study, whether the combined use of CnB and 5-FU can reverse the myelosuppression, and immunosuppressive effects of 5-FU by reactivating the immune system thus increasing antitumor efficacy, was investigated. It was demonstrated that combined treatment of 5-FU and CnB led to increased tumor-suppressive effects, as indicated by reduced tumor volume and weight when compared with 5-FU or CnB treatment alone in a hepatoma xenograph model. In addition, it was demonstrated that combined treatment inhibited the proliferation of hepatoma cells. Notably, the addition of CnB to 5-FU-based therapy completely reversed the immunosuppressive effect of 5-FU. The spleen index and total number of white blood cells in the combination group were higher compared with that of the 5-FU alone group. Furthermore, pathological examinations indicated that CnB attenuated 5-FU-induced organ damage. Based on these findings, it is proposed that CnB may serve as a novel and promising drug candidate for the improvement of 5-FU-based chemotherapy. PMID- 29113259 TI - Downregulated long non-coding RNA TCONS_00068220 upregulates apoptosis in gastric cancer cells. AB - Long non-coding RNAs (lncRNAs) are emerging as a fundamental class of biological effect or molecules that perform pivotal functions in the regulation of the genome. With advances in bioinformatics and genomics, extensive identification and characterization of lncRNAs is now possible. They regulate cellular growth, differentiation and apoptosis. Dysregulation of lncRNAs has been associated with numerous types of human cancer. In the present study, the expression profile of differentially expressed genes (DEGs) and lncRNAs in gastric cancer (GC) samples and normal tissue samples was evaluated with bioinformatics. The biological functions of the predicted lncRNA TCONS_00068220 were focused on; the DEGs co expressed with TCONS_00068220 were enriched in cancer-associated pathways. TCONS_00068220 was demonstrated to be upregulated in GC tissues and cell lines compared with normal controls. In addition, an increased rate of apoptosis was observed in NCI-N87 cells following transfection with small interfering RNA against TCONS_00068220. These data suggest that TCONS_00068220 may be associated with the pathogenesis of GC, and it may serve as a potential therapeutic target. PMID- 29113260 TI - Expression of c-Met and hepatocyte growth factor in various gastric pathologies and its association with Helicobacter pylori infection. AB - Activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway was identified to be associated with malignant tumors. The present study aimed at determining the expression of HGF and c-Met in gastric carcinogenesis and its association with Helicobacter pylori infection. Gastric biopsies were obtained from 160 H. pylori-negative and -positive patients, including those with chronic gastritis, intestinal metaplasia, dysplasia and gastric cancer (GC). Proteins were extracted from GES-1, gastric epithelial, and AGS, gastric adenocarcinoma, cells following co-culture with H. pylori in vitro. The expression of HGF and c Met in gastric tissues or cells was determined using immunohistochemistry and western blot analysis. The expression of c-Met increased in GC tissues (72.5%) compared with that in pre-cancerous lesions (17.5, 17.5 and 30%). Additional analysis identified that the expression of HGF and c-Met was significantly increased in the presence of H. pylori infection in dysplasia and gastric cancer samples. Furthermore, H. pylori may activate the HGF/c-Met signaling pathway in vitro, which may contribute to gastric carcinogenesis. PMID- 29113261 TI - Rs1008805 polymorphism of CYP19A1 gene is associated with the efficacy of hormone therapy in stage I-II and operable stage III breast cancer. AB - It has been hypothesized that single nucleotide polymorphisms in CYP19A1 gene may alter aromatase activity and circulating steroid hormone levels in females. Therefore, it is biologically reasonable that CYP19A1 rs1008805 (A/G) polymorphism may be associated with the clinical outcome of hormone therapy. Genotyping for the CYP19A1 rs1008805 polymorphism was performed for 287 females with hormone receptor (HR)-positive early breast cancer, and potential associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS). Based on the analysis of the whole cohort, no significant differences were observed between rs1008805 genotypes and DFS. However, in postmenopausal females, rs1008805 variants were significantly associated with DFS (AA vs. AG vs. GG, 89.2 vs. 58.2 vs. 32.7 months; P=0.019). In addition, when the population was divided into two cohorts, females with the GG variant exhibited a significantly poorer DFS [GG vs. AA or AG, 32.7 vs. 70.6 months; hazard ratio (HR), 3.613; 95% confidence interval (CI), 1.380-9.457; P=0.005]. Furthermore, when adjusted for other patient features in multivariate analyses, GG genotype remained an independent prognostic marker for DFS (HR, 3.439; 95% CI, 1.251 9.456; P=0.017). However, there were no significant differences in DFS between patients harboring the minor allele and those with the homozygous common allele (AG or GG vs. AA, 52.4 vs. 89.2 months; HR, 1.288; 95% CI, 0.705-2.353; P=0.408). There were also no associations between rs1008805 polymorphism and DFS for premenopausal females. In conclusion, the homozygous minor allele (GG) of CYP19A1 rs1008805 was identified to be significantly associated with an inferior clinical outcome of hormone therapy in postmenopausal hormone receptor-positive patients with early breast cancer. If confirmed by further study, genotyping for CYP19A1 rs1008805 polymorphism may provide predictive information to improve the selection of endocrine treatment. PMID- 29113262 TI - Preparation, pharmacokinetics, tissue distribution and antitumor effect of sorafenib-incorporating nanoparticles in vivo. AB - Sorafenib is a molecularly targeted drug used for treating hepatocellular carcinoma. However, sorafenib may affect the function of normal hepatocytes, and the clinical application of sorafenib is limited due to its adverse effects. The aim of the current study was to improve the effectiveness of sorafenib by preparing it as a nanoparticle formulation using nanoprecipitation technology. Sorafenib was combined with a polyethylene glycol monomethyl ether-racemic polylactic acid copolymer. The properties of the nanoparticles, including particle size, xi potential and release efficiency, were measured. The pharmacokinetic profile, tissue distribution and tumor-inhibiting effects of the nanoparticles were determined in vitro and in vivo. Compared with sorafenib, the nanoparticle formulation exhibited a significant increase in in vivo retention time. The concentration of sorafenib in tumor tissues was significantly higher than that in normal tissues following treatment with sorafenib nanoparticles. Sorafenib nanoparticles were more efficacious in inhibiting tumor growth compared with sorafenib alone. The results, provided they can be extended to humans, suggest that sorafenib nanoparticles may specifically target hepatocellular carcinoma. PMID- 29113263 TI - Artesunate inhibits proliferation and invasion of mouse hemangioendothelioma cells in vitro and of tumor growth in vivo. AB - Artesunate has been demonstrated to be a novel potential antitumor agent in numerous studies. However, its efficacy in infantile hemangioma is unknown. The aim of the present study was to investigate the role of artesunate in the control of vascular tumor biological behavior and molecular mechanism using mouse hemangioendothelioma endothelial (EOMA) cells and a nude mouse model. Cell viability, apoptosis and invasion were determined by an MTT assay, flow cytometric analysis and Transwell invasion assay, respectively. Reverse transcription-quantitative polymerase chain reaction and western blotting were utilized to examine the expression of genes and proteins. Inoculated EOMA cells were injected into the subcutaneous tissues of nude mice to observe the effect of artesunate therapy on the vascular tumor, an effect that was similar to that of pingyangmycin (PYM). It was identified that artesunate treatment (0-600 ug/ml) inhibited cell growth in a time- and dose-dependent manner. Artesunate at 300 ug/ml significantly reduced the proliferation and invasion of EOMA cells, and significantly decreased the expression of vascular endothelial growth factor (VEGF)-A, VEGFR-1, VEGFR-2 and hypoxia inducible factor-1alpha over time; caspase 3 was simultaneously upregulated in vitro. Artesunate significantly inhibited tumor growth, and the curative effect was similar to that observed with PYM in vivo. It was concluded that artesunate could effectively inhibit the growth of vascular tumors, and thus could be a novel drug candidate for the treatment of infantile hemangioma. PMID- 29113264 TI - Cancer cell-expressed B7-H3 regulates the differentiation of tumor-associated macrophages in human colorectal carcinoma. AB - Co-stimulatory molecule B7 homolog 3 protein (B7-H3) has been described as an important tumor antigen in various human tumors. The exact role of B7-H3 in tumor progression and its receptor are still ambiguous. The phenotype and the function of tumor-associated macrophages (TAMs) in human solid tumors are complicated and could contribute to the shaping of the tumor microenvironment. In the present study, B7-H3 expression and lymphocyte infiltration were investigated by immunohistochemistry in 117 colorectal carcinoma (CRC) patients. B7-H3 expression was positively associated with the infiltrating density of macrophage in CRC tissues, and B7-H3 expression and the infiltrating density of macrophages were negatively associated with the overall survival rate of patients. The putative B7 H3 receptor was found on activated monocytes and macrophages, indicating the direct function of B7-H3 signal on macrophages. Additional results revealed that during the differentiation of TAMs, B7-H3 promoted the polarization of type 2 macrophages (M2s) and switch of the M1 phenotype to the M2 phenotype. Thus, B7-H3 signaling promotes M2 differentiation via the putative receptor on monocytes and macrophages. Targeting the manipulation of TAMs through the B7-H3 pathway may be valuable for the development of novel immunotherapeutic strategies against human CRC. PMID- 29113265 TI - CDX2 is involved in microRNA-associated inflammatory carcinogenesis in gastric cancer. AB - The development of gastric cancer is significantly associated with chronic inflammation, such as caused by Helicobacter pylori (H. pylori) infection. Caudal type homeobox 2 (CDX2) is a homeobox protein involved in intestinal differentiation in normal and in aberrant locations, and is associated with inflammation. The authors of the present study have previously reported that CDX2 may have a suppressive role in the progression and carcinogenesis of gastric carcinoma. In the present study, the authors initially confirmed that a decreased expression of CDX2, as detected by immunohistochemistry, is associated with poor cancer-specific survival in 210 gastric cancer cases, which is consistent with several previously published studies. To elucidate the potential mechanisms underlying this association, the authors investigated the mechanism of CDX2 suppression, which included interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) and p53 signaling pathways. The present study confirmed that CDX2 was suppressed by activation of the IL-6/STAT3 signaling pathway via miR-181b in vitro. It was further revealed that gastric cancer with negative CDX2 expression is associated with negative p53 staining, and this association was particularly significant in undifferentiated gastric cancer. The activation of the IL-6/STAT3 signaling pathway suppressed miR-34a, which is induced by p53. This suggests that the activation of the IL-6/STAT3 signaling pathway inflammation signaling pathway suppresses the p53 signaling pathway in tumors without TP53 mutation, which results in poor prognostic outcomes. In conclusion, CDX2 may be a useful prognostic biomarker for gastric cancer and is associated with p53 inactivation. PMID- 29113266 TI - Overexpression of HS6ST2 is associated with poor prognosis in patients with gastric cancer. AB - The purpose of the present study was to investigate the clinical significance of the expression of heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) in gastric cancer (GC). The Affymetrix GeneChip(r) Human Genome U133 Plus 2.0 Array (Affymetrix; Thermo Fisher Scientific, Inc., Waltham, MA, USA) was used to identify differentially expressed genes in GC tissues vs. adjacent non-tumor gastric tissues. Candidate genes were further verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). In addition, an independent dataset was obtained from the Gene Expression Omnibus, and a survival analysis was performed. Microarray analysis demonstrated that HS6ST2 was upregulated (>12-fold) in GC tissues compared with that in adjacent non-tumor tissues. RT-qPCR and IHC analysis of HS6ST2 in GC tissues and adjacent non-tumor tissues confirmed the microarray data. Furthermore, a positive association was demonstrated between HS6ST2 overexpression with the depth of tumor invasion, distant metastasis, and tumor-node metastasis stage. Survival analysis revealed an association between patients with increased expression of HS6ST2 and a poor prognosis of gastric cancer. Cox regression analysis indicated that the expression of HS6ST2 was an independent negative prognostic factor for GC. The expression of HS6ST2 in GC was significantly associated with specific clinicopathological parameters and prognosis of disease, thus we propose that HS6ST2 may represent a novel biomarker for GC. PMID- 29113267 TI - Overexpression of Rictor protein in colorectal cancer is correlated with tumor progression and prognosis. AB - In order to understand the clinical significance of rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) in colorectal cancer (CRC), 62 CRC tissue samples excised during operations were evaluated by immunohistochemistry. Analysis of the association between the expression level of Rictor protein and clinicopathological parameters demonstrated that the expression level of Rictor in CRC tissues was significantly higher than that in paracarcinoma tissues (P<0.0001). In cellular experiments, this result was further confirmed by comparing differences in Rictor expression between the CRC cell lines HCT116, SW480 and LoVo, and the human normal liver cell line HL-7702. It was also noticed that the expression of Rictor was associated with Dukes stage, lymphatic metastasis and prognosis, as determined by chi2 test, Kaplan Meier analysis and log-rank test. These results suggest that Rictor may be a novel target for the treatment and prognostic assessment of CRC patients in the future. PMID- 29113268 TI - JAB1-STAT3 activation loop is associated with recurrence following 5-fluorouracil based adjuvant chemotherapy in human colorectal cancer. AB - Jun activation domain-binding protein 1 (JAB1) has been shown to have multiple roles in tumorigenesis, including the degradation of tumor suppressor proteins such as p53, Smad7, Runx3 and the cyclin-dependent kinase inhibitor p27Kip1, and the activation of oncogenic transcription factors, such as c-Jun and hypoxia inducible factor-1alpha. In addition, our previous study revealed that JAB1 positively regulates signal transducer and activator of transcription 3 (STAT3) DNA-binding activity in human colon cancer cells. In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop. Furthermore, high JAB1 expression is associated with a poor prognosis in numerous malignant carcinomas. However, the association between JAB1 expression and prognosis in colorectal cancer remains unclear. The aim of the present study was to elucidate the association between JAB1 and STAT3 expression and recurrence in colorectal cancer. In the present study, it was found that high JAB1 expression in primary colorectal cancer tissues is an independent predictor of recurrence following 5-fluorouracil (5-FU)-based adjuvant chemotherapy in colorectal cancer patients, and that high expression of both JAB1 and STAT3 in primary colorectal cancer tissues is associated with a lower recurrence-free survival rate following 5-FU-based adjuvant chemotherapy compared to high expression of only JAB1 or STAT3. Overall, these results suggest that JAB1 is a novel predictive marker of recurrence following 5-FU-based adjuvant chemotherapy in colorectal cancer patients, and that the JAB1-STAT3 activation loop may be a potential therapeutic target in recurrent colorectal cancer following 5-FU-based adjuvant chemotherapy. PMID- 29113269 TI - The expression and significance of histone lysine methylation in endometrial cancer. AB - Histone modifications of lysine residues have been implicated as having diagnostic and/or prognostic significance in numerous types of cancer. In the present study, the significance of the histone H3 methylation of lysine 4 (H3K4) and lysine 27 (H3K27) were investigated in endometrial cancer. Specifically, immunohistochemical analysis was used to detect the cellular expression levels of H3K27 trimethylation (H3K27me3), H3K4 trimethylation (H3K4me3) and H3K4 dimethylation (H3K4me2) in glandular epithelial tissues and stromal tissues. The association between the methylation levels of histone markers and clinicopathological parameters were analyzed. The results demonstrated that in epithelial cells, H3K4me2 and H3K4me3 exhibited the highest levels in endometrial cancer, followed by precancerous lesions and a normal endometrium. Low expression levels of H3K4me2 in glandular epithelium of endometrial cancer were significantly associated with a clinical early International Federation of Gynecology and Obstetrics stage (P=0.006). For stromal tissues, the expression level of H3K27me3 in Type 1 endometrial cancer was significantly lower compared with that in the normal endometrium (P=0.043) and precancerous lesions (P<0.001). The expression level of H3K4me2 was significantly lower in the stroma of Type 1 and 2 cancer compared within the normal endometrium (P=0.005). A low H3K4me3 expression level in the stroma of endometrial cancer tissues was associated with P53-negativity (P=0.032). In conclusion, the cellular expression levels of histone H3 methylation were differentially presented in glandular epithelial and stromal elements in endometrial tissues. A low expression level of activation marker H3K4me2 in glandular epithelium defined a subset of patients with early stage endometrial adenocarcinoma and may have potential prognostic value. PMID- 29113270 TI - Cleistanthin A inhibits the invasion and metastasis of human melanoma cells by inhibiting the expression of matrix metallopeptidase-2 and -9. AB - It has been demonstrated that numerous types of metastatic cancer overexpress vacuolar-type H+ (V)-ATPases. It may be possible to inhibit the growth and metastasis of human cancer cells by inhibiting V-ATPases. It was previously reported that diphyllin, a novel V-ATPase inhibitor, can inhibit the migration and invasion of SGC7901 human gastric cancer cells; however, the effects of cleistanthin A (CA), a diphyllin glycoside, on melanoma cells has not been demonstrated. The present study aimed to investigate the effect of CA as a V ATPase inhibitor and its effects on the invasion and metastasis of A375 cells. The results of an MTT assay in the present study indicated that the growth inhibition of A375 cells by CA was induced in a dose- and time-dependent manner; however, A375 cell viability was not significantly affected by low concentrations (0.03, 0.1 and 0.3 uM) after 24 h. Similar results were obtained by viable cell counting with trypan blue. Therefore, these concentrations of CA were selected for the treatment of A375 cells in further experiments. It was demonstrated that CA inhibited the expression of V-ATPases in a dose-dependent manner and decreased the internal pH level of A375 cells. Alterations to the lysosomal pH were associated with the CA concentration. Furthermore, CA treatment induced a significant decrease in cell migration and invasion, as demonstrated with wound healing and Transwell assays. Gelatin zymography and western blot analysis demonstrated that the expression levels of matrix metallopeptidase (MMP)-2 and -9 decreased following CA treatment. Therefore, CA can be characterized as a novel V ATPase inhibitor for the treatment of melanoma that may inhibit invasion and metastasis by downregulating the expression of MMP-2 and -9. PMID- 29113271 TI - Significance of imaging and clinical features in the differentiation between primary and secondary pulmonary lymphoma. AB - The aim of the present study was to analyze the differences in imaging and clinical features between primary pulmonary lymphoma (PPL) and secondary pulmonary lymphoma (SPL) to provide insight into pulmonary lymphoma for an improved clinical diagnosis. A retrospective study of 38 patients with pulmonary lymphoma (19 PPL and 19 SPL) treated between September 1, 2006, and December 31, 2015, was performed. The clinical manifestations, and computed tomography (CT) and positron emission tomography-CT images of each case were collected. chi2 and Fisher's exact tests were applied to assess statistically significant differences between PPL and SPL in terms of clinical and imaging features. The significant variables were further applied to canonical discriminate analysis. The CT results revealed that the occurrence of a >3-cm mass (P=0.007), peripheral location (lower than the segmental bronchi) (P=0.027), cavitation (P=0.008) and consolidation (P=0.027) were associated with PPL, while peripheral and hilar location (P=0.003) or mediastinal and hilar lymph node engagement (P=0.044) were predominantly observed in SPL. However, no significant differences between clinical manifestations and the maximum standard uptake value of pulmonary lesions in PPL and SPL were identified (all P>0.05). A function derived from discriminate analysis was generated that may predict the affiliation to PPL or SPL radiographically, with an overall accuracy of <=92.1%. The results of the present study revealed that PPL and SPL exhibit distinctive features on CT images due to distinct molecular mechanisms and growth patterns. Careful observation of CT features may be useful in the diagnosis of PPL and SPL regarding the tumor morphology, location and lymph node involvement. PMID- 29113272 TI - Overexpression of calcyphosine is associated with poor prognosis in esophageal squamous cell carcinoma. AB - Calcyphosine (CAPS), a calcium-binding protein, has been identified as a potential diagnostic and prognostic biomarker in several human carcinomas. However, little is known about CAPS in esophageal squamous cell carcinoma (ESCC). The present study aimed to investigate the expression levels of CAPS in ESCC tissues and evaluate its clinicopathological significance. Reverse transcription quantitative polymerase chain reaction and immunohistochemical staining were conducted to detect the expression of CAPS in ESCC tissues and adjacent non cancerous tissues. ESCC samples exhibited higher levels of CAPS mRNA than paired non-cancerous samples (P=0.0015), and the mRNA level of CAPS was positively associated with histological grade (P=0.0013) and tumor invasion depth (P=0.0206). In addition, Kaplan-Meier survival analysis revealed that patients with high CAPS expression experienced significantly shorter 5-year overall survival times than those with low CAPS expression (P=0.0112). Multivariate analysis demonstrated that CAPS protein expression was an independent prognostic biomarker for patients with ESCC. In conclusion, the findings of the present study demonstrated that CAPS may represent a novel diagnostic indicator and an independent prognostic biomarker in ESCC. PMID- 29113273 TI - Yolk sac tumor of upper lip: A case report. AB - Yolk sac tumors (YSTs) are a type of malignant germ cell tumor that usually grow in the gonads. They are difficult to recognize at other sites outside the gonads, and no case has been reported involving the upper lip. The present study reported the case of a 13-month-old girl exhibiting an isolated YST occurring in the upper lip. The histology and elevation of alpha-fetoprotein were typical for a YST. The patient was cured following effective chemotherapy and surgery resection. After 36 months of follow-up, there was no sign of recurrence or metastasis. A total of 20 cases of primary YSTs of the head and neck extracranial region since 1997 were reviewed. The present study aims to inform the scientific community of the clinical and pathologic features of this patient. PMID- 29113274 TI - Simvastatin potentiates doxorubicin activity against MCF-7 breast cancer cells. AB - Simvastatin is a low density lipoprotein-lowering drug that is widely used to prevent and treat cardiovascular disease by inhibiting the mevalonate pathway. Simvastatin also exhibits inhibitory effects on a number of types of cancer. In the present study, the effects of simvastatin on the activity of doxorubicin in the breast cancer MCF-7 cell line, and the mechanisms by which this interaction occurs were investigated. The effect of simvastatin and doxorubicin treatment, alone and in combination, on the growth of MCF-7 cells was evaluated by a sulforhodamine B and colony formation assay. To delineate the mechanisms of cell death, the following parameters were measured: Reactive oxygen species (ROS) production using the fluorescence probe dihydroethidium; caspase 3 activity by the fluorometry method; gene expression by quantitative polymerase chain reaction; and apoptotic- and proliferative-related protein levels by western blotting. MCF-7 cell proliferation was significantly suppressed by 24-48 h treatment with simvastatin alone. Doses of 10-50 uM simvastatin also enhanced the cytotoxicity of doxorubicin against MCF-7 cells in a dose-dependent manner, and decreased the colony-forming ability of MCF-7 cells. Simvastatin alone or in combination with doxorubicin significantly increased ROS levels. Combination treatment significantly decreased expression of the cell cycle regulatory protein Ras-related C3 botulinum toxin substrate 1 and numerous downstream proteins including cyclin-dependent kinase (Cdk) 2, Cdk4 and Cdk6. Additionally, simvastatin in combination with doxorubicin significantly induced expression of the cyclin-dependent kinase inhibitor p21, increased cytochrome c and caspase 3 expression and reduced cyclin D1 expression. In conclusion, simvastatin acts synergistically with the anticancer drug doxorubicin against MCF-7 cells, possibly through a downregulation of the cell cycle or induction of apoptosis. Although additional studies are required, simvastatin and doxorubicin combination may be a reasonable regimen for the treatment of breast cancer. PMID- 29113275 TI - E6/E7 proteins are potential markers for the screening and diagnosis of cervical pre-cancerous lesions and cervical cancer in a Chinese population. AB - The present prospective study aimed to evaluate the effects of E6/E7 protein detection by western blotting on cervical cancer (CC) early screening compared with detection by Hybrid Capture 2 (HC2) test and ThinPrep cytological test (TCT) in a Chinese population. A total of 450 cases of cervical intraepithelial neoplasia (CIN) suspected samples (positive in >=1 indicator of TCT and HC2 test) were recruited from women who were treated at the International Peace Maternity and Child Health Hospital (Shanghai, China) from March 2014 to February 2015. Each sample was analyzed by cytological test. In addition, human papillomavirus (HPV) DNA examination by Hybrid Capture Tube test and E6/E7 protein expression detection by western blotting were performed in all samples, as well as histologic diagnosis to determine the stage of CIN. The results revealed that, for the diagnosis of CIN2+, although the sensitivity of E6/E7 protein detection was lower than that of HC2 test (71.3 vs. 96.6%, respectively), the specificity was markedly improved (67.6 vs. 5.9%, respectively). Compared with that of TCT, the sensitivity of E6/E7 protein detection was much higher (36.2 vs. 71.3%, respectively), but the specificity was lower (88.2 vs. 67.6%, respectively). In the present study, HPV E6/E7 protein expression was evaluated as a potential new biomarker for CC, with satisfactory diagnostic values for HPV types 16 and 18. The relative diagnostic value may be further improved by combination of E6/E7 messenger RNA detection. PMID- 29113276 TI - Regulatory network involving miRNAs and genes in serous ovarian carcinoma. AB - Serous ovarian carcinoma (SOC) is one of the most life-threatening types of gynecological malignancy, but the pathogenesis of SOC remains unknown. Previous studies have indicated that differentially expressed genes and microRNAs (miRNAs) serve important functions in SOC. However, genes and miRNAs are identified in a disperse form, and limited information is known about the regulatory association between miRNAs and genes in SOC. In the present study, three regulatory networks were hierarchically constructed, including a differentially-expressed network, a related network and a global network to reveal associations between each factor. In each network, there were three types of factors, which were genes, miRNAs and transcription factors that interact with each other. Focus was placed on the differentially-expressed network, in which all genes and miRNAs were differentially expressed and therefore may have affected the development of SOC. Following the comparison and analysis between the three networks, a number of signaling pathways which demonstrated differentially expressed elements were highlighted. Subsequently, the upstream and downstream elements of differentially expressed miRNAs and genes were listed, and a number of key elements (differentially expressed miRNAs, genes and TFs predicted using the P-match method) were analyzed. The differentially expressed network partially illuminated the pathogenesis of SOC. It was hypothesized that if there was no differential expression of miRNAs and genes, SOC may be prevented and treatment may be identified. The present study provided a theoretical foundation for gene therapy for SOC. PMID- 29113277 TI - Sequence variations of mitochondrial DNA D-loop region in patients with acute myeloid leukemia. AB - The aim of the present study was to explore variations of the displacement (D) loop region in patients with acute myeloid leukemia (AML) and their possible associations with AML pathogenesis. Blood or bone marrow samples from 216 patients with AML (158 AML patients in the first stage, and 58 more patients with AML-M3 for further verification), and 146 healthy controls were collected. Sanger sequencing was performed for the D-loop region ranging between nucleotide (nt)15811 and nt 775. With the exception of mitochondrial microsatellite instability (mtMSI) variations, a total of 2,630 variations in 232 loci were identified with similar variation rates/person in patients with AML and controls when compared with the revised Cambridge reference sequence (8.54+/-2.14 vs. 8.77+/-2.15; P=0.366). A positive association between AML and variation-T152C was identified, which occurred more frequently in patients with AML compared with in controls [26.6 vs. 17.1%; P=0.048; odds ratio (OR), 1.752; 95% confidence interval (CI), 1.004-3.058]. Furthermore, T152C was identified to be associated with promyelocytic leukemia-retinoic acid receptor alpha(PML-RARalpha) and French American-British AML subtypes, with a tendency to occur in patients with AML-M3. The AML-M3 sample size was extended by 58 cases, and it was identified that the T152C variation rate was significantly higher in patients with AML-M3 compared with that of controls (41.0 vs. 17.1%; P<0.001; OR, 3.228; 95% CI, 1.714-6.079). However, no association was identified between the T152C variation and clinical characteristics, or chemotherapy response in patients with AML-M3. In addition, the mtMSIs, including D310, mt514-523 (CA)n and T16189C, demonstrated no association with AML risk. Together, the results of the present study suggest that the mitochondrial DNA D-loop region is high variable, and that T152C is associated with AML risk, particularly regarding the M3 subtype. T152C mayparticipate in AML pathogenesis and may be a diagnostic biomarker; however further studies with larger sample sizes are required in order to verify its value. PMID- 29113278 TI - Serum Golgi protein 73 is a prognostic rather than diagnostic marker in hepatocellular carcinoma. AB - Serum Golgi protein 73 (sGP73) is a candidate diagnostic biomarker for hepatocellular carcinoma (HCC). However, current evidence of its diagnostic value is conflicting, primarily due to the small sample sizes of previous studies, and its prognostic role in HCC also remains unclear. In the present study, sGP73 levels in 462 patients with HCC, 186 patients with liver cirrhosis, and 83 healthy controls were evaluated using ELISA, and it was identified that the median sGP73 levels were significantly higher in the HCC (18.7 ng/ml) and liver cirrhosis (18.5 ng/ml) patients than in the healthy controls (0 ng/ml; both P<0.001); however, the levels did not significantly differ between the HCC and liver cirrhosis groups (P=0.632). sGP73 had an inferior sensitivity and specificity for HCC diagnosis (27.79 and 77.96%, respectively) compared with alpha-fetoprotein (57.36 and 90.96%, respectively; P<0.001). In the HCC group, a high level of sGP73 was associated with aggressive clinicopathological features and independently predicted poor overall survival (OS) time (P<0.001). Additionally, in patients with resectable HCC, a high level of sGP73 was associated with significantly decreased disease-free survival (P<0.001) and OS (P=0.039) times compared with a low level of sGP73. This study demonstrated that sGP73 is unsuitable as a diagnostic marker for the early detection of HCC; however, it is an independent negative prognostic marker, providing a novel risk stratification factor and a potential therapeutic molecular target for HCC. PMID- 29113279 TI - HMGB1-mediated autophagy confers resistance to gemcitabine in hormone-independent prostate cancer cells. AB - As a main treatment of prostate cancer, castration therapy has been widely applied in the clinic. However, the therapeutic strategy for hormone-independent prostate cancer (HIPC) was not satisfied. Gemcitabine is an important chemotherapeutic agent that has been approved for the treatment of numerous human solid tumors, including HIPC, whereas the gemcitabine resistance has become a serious problem in clinical chemotherapy. In the present study, the mechanisms of resistance to gemcitabine were investigated in HIPC cell lines. The results demonstrated that the autophagy markers were induced significantly in HIPC cells subsequent to gemcitabine treatment. Meanwhile, administration of gemcitabine to HIPC cells increased the expression of high mobility group box1 (HMGB1). Furthermore, the gemcitabine-induced autophagy response was attenuated in stable HIPC cells harboring HMGB1 shRNA. Notably, the HIPC cells stably transfected with HMGB1 shRNA or treated with autophagy inhibitors were more sensitive to gemcitabine compared with the control group. These data suggested that inhibition of HMGB1 increased the sensitivity to gemcitabine by decreasing autophagy response in HIPC cells. Overall, the present findings demonstrate a new mechanism for the resistance to gemcitabine in HIPC cell lines. PMID- 29113280 TI - Association between CBR1 polymorphisms and NSCLC in the Chinese population. AB - Carbonyl reductase 1 (CBR1) is theorized to participate in various cellular processes, such as signal transduction, apoptosis, carcinogenesis and drug resistance, and is highly expressed in certain malignancies, including lung tumors. Several studies have provided evidence that gene polymorphisms may affect susceptibility to non-small cell lung cancer (NSCLC). The present study aimed to investigate the association between the CBR1 single-nucleotide polymorphisms (SNPs) rs3787728 and rs2835267, and NSCLC in a Chinese population. The data indicated that the allele frequency in CBR1 rs3787728 was significantly different between patients with NSCLC and the controls [odds ratio (OR)=1.209; 95% confidence interval (CI)=1.013-1.442; P=0.0349], and was significantly different between male patients with NSCLC and the corresponding controls (OR=1.278; 95% CI=1.016-1.607; P=0.0358). The CBR1 rs3787728 thymine (T)/T allele homozygote was associated with an increased risk of NSCLC in all patients (OR=1.382; 95% CI=1.019-1.875; P=0.037), and patients possessing the rs3787728 T/T major allele homozygote exhibited a 1.537-fold greater risk with respect to developing lung squamous-cell carcinoma (SCC) in all patients (95% CI=1.019-2.318; P=0.0395). The CBR1 rs3787728 cytosine (C)/C allele homozygote was associated with a decreased risk of adenocarcinoma (ADC) in male patients (OR=0.633; 95% CI=0.413-0.969; P=0.0348); however, no significant association was observed in CBR1 rs2835267 between SNPs and SCC or ADC-type NSCLC. In conclusion, the results revealed that genetic polymorphisms of CBR1 rs3787728 were associated with susceptibility to NSCLC. Additional studies are required to identify the functional impact of CBR1 expression and activity in NSCLC. PMID- 29113281 TI - Direct effects of phenformin on metabolism/bioenergetics and viability of SH-SY5Y neuroblastoma cells. AB - Phenformin, a member of the biguanides class of drugs, has been reported to be efficacious in cancer treatment. The focus of the current study was to establish whether there were direct effects of phenformin on the metabolism and bioenergetics of neuroblastoma SH-SY5Y cancer cells. Cell viability was assessed using the alamar blue assay, flow cytometry analysis using propidium iodide and annexin V stain and poly (ADP-ribose) polymerase analysis. Cellular and mitochondrial oxygen consumption was determined using a Seahorse Bioscience Flux analyser and an Oroboros Oxygraph respirometer. Cells were transfected using electroporation and permeabilized for in situ mitochondrial functional analysis using digitonin. Standard protocols were used for immunoblotting and proteins were separated on denaturing gels. Phenformin was effective in reducing the viability of SH-SY5Y cells, causing G1 cell cycle arrest and inducing apoptosis. Bioenergetic analysis demonstrated that phenformin significantly decreased oxygen consumption in a dose- and time-dependent manner. The sensitivity of oxygen consumption in SH-SY5Y cells to phenformin was circumvented by the expression of NADH-quinone oxidoreductase 1, a ubiquinone oxidoreductase, suggesting that complex I may be a target of phenformin. As a result of this inhibition, adenosine monophosphate protein kinase is activated and acetyl-coenzyme A carboxylase is inhibited. To the best of our knowledge, the current study is the first to demonstrate the efficacy and underlying mechanism by which phenformin directly effects the survival of neuroblastoma cancer cells. PMID- 29113282 TI - Common mechanism of pathogenesis in various types of metastatic osteosarcoma. AB - The present study aimed to investigate the common metastatic mechanism in various types of metastatic osteosarcoma (OS). Gene expression profiles generated from the metastatic OS KHOS and KRIB cell lines and the non-metastatic OS HOS cell line were compared. Two groups of differentially expressed genes (DEGs) between KHOS or KRIB and HOS were screened (P<0.01 and |fold change| >=2) and then underwent Gene Ontology (GO) and pathway enrichment analyses. Subsequently, the protein-protein interaction (PPI) network was constructed and the subnetwork was mined. Furthermore, overlapping DEGs of these two groups were identified and pathway enrichment and regulatory network analyses were performed. A total of 1,552 and 1,330 DEGs from KHOS vs. HOS and KRIB vs. HOS were obtained, respectively. GO and pathway enrichment analyses of DEGs between KRIB and HOS, including anatomical structure morphogenesis and focal adhesion, were similar to those between KHOS and HOS. Vascular endothelial growth factor A and epidermal growth factor receptor were hub nodes in the PPI network for KHOS and KRIB. Subnetworks of these two groups were similar. In addition, 421 upregulated and 595 downregulated overlapping genes were enriched in the mitogen-activated protein kinase and transforming growth factor-beta signaling pathways. Furthermore, seven vital transcription factors, including hes-related family bHLH transcription factor with YRPW motif 1 (HEY1), were obtained. Overall, different types of metastatic OS were shown to exhibit a similar mechanism of pathogenesis. With the exception of cell adhesion and angiogenesis, recapitulation of the morphogenetic processes facilitates OS tumor formation and metastasis. Genes such as HEY1 are important for metastatic OS. Further studies are required in order to confirm these results. PMID- 29113283 TI - Epigallocatechin-3-gallate induces apoptosis in acute promyelocytic leukemia cells via a SHP-1-p38alpha MAPK-Bax cascade. AB - Acute promyelocytic leukemia (APL) is characterized by a specific chromosomal translation, resulting in a fusion gene that affects the differentiation, proliferation and apoptosis of APL cells. Epigallocatechin-3-gallate (EGCG), a catechin, exhibits numerous biological functions, including antitumor activities. Previous studies have reported that EGCG induces apoptosis in NB4 cells. However, the molecular mechanism underlying EGCG-induced apoptosis remains unclear. The present study aimed to determine the molecular basis of EGCG-induced apoptosis in NB4 cells. EGCG treatment significantly inhibited the viability of NB4 cells in a dose-dependent manner. In addition, EGCG treatment induced apoptosis and increased the levels of (Bcl-2-like protein 4) Bax protein expression. Moreover, EGCG treatment was able to increase phosphorylated (p)-p38alpha mitogen-activated protein kinase (MAPK) and Src homology 1 domain-containing protein tyrosine phosphatase (SHP-1) expression. Pretreatment with PD169316 (a p38 MAPK inhibitor) partially blocked EGCG-induced apoptosis and inhibited EGCG-mediated Bax expression. Similarly, pretreatment with NSC87877, an inhibitor of SHP-1, partially blocked EGCG-induced apoptosis and inhibited EGCG-mediated increases in p-p38alpha MAPK and Bax expression. Therefore, the results of the present study indicate that EGCG is able to induce apoptosis in NB4 cells via the SHP-1 p38alphaMAPK-Bax cascade. PMID- 29113284 TI - Proteasome inhibitors in glioblastoma. AB - [This retracts the article DOI: 10.3892/ol.2017.5585.]. PMID- 29113285 TI - Risk stratification in therapy-related myelodysplastic syndromes. PMID- 29113286 TI - Molecular response prediction in CML: novel ideas? PMID- 29113287 TI - Cohesin mutations: contributors to myeloid malignancies. PMID- 29113288 TI - HDAC6 inhibitor WT161 downregulates growth factor receptors in breast cancer. AB - We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERalpha and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition. Moreover WT161 analog MAZ1793, which lacks HDAC inhibitory effect, similarly triggers cell line growth inhibition and downregulation of these receptors. We also confirm that WT161 significantly inhibits in vivo MCF7 cell growth, associated with downregulation of ERalpha, in a murine xenograft model. Finally, WT161 synergistically enhances bortezomib-induced cytotoxicity, even in bortezomib-resistant breast cancer cells. Our results therefore provide the rationale to develop a novel class of therapeutic agents targeting growth pathways central to the pathogenesis of breast cancer. PMID- 29113289 TI - Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients. AB - Purpose: Glioblastoma is a deadly brain cancer with a median survival time of ~15 months. Ionizing radiation plus the DNA alkylator temozolomide (TMZ) is the current standard therapy. PAC-1, a procaspase-3 activating small molecule, is blood-brain barrier penetrant and has previously demonstrated ability to synergize with diverse pro-apoptotic chemotherapeutics. We studied if PAC-1 could enhance the activity of TMZ, and whether addition of PAC-1 to standard treatment would be feasible in spontaneous canine malignant gliomas. Experimental Design: Using cell lines and online gene expression data, we identified procaspase-3 as a potential molecular target for most glioblastomas. We investigated PAC-1 as a single agent and in combination with TMZ against glioma cells in culture and in orthotopic rodent models of glioma. Three dogs with spontaneous gliomas were treated with an analogous human glioblastoma treatment protocol, with concurrent PAC-1. Results: Procaspase-3 is expressed in gliomas, with higher gene expression correlating with increased tumor grade and decreased prognosis. PAC-1 is cytotoxic to glioma cells in culture and active in orthotopic rodent glioma models. PAC-1 added to TMZ treatments in cell culture increases apoptotic death, and the combination significantly increases survival in orthotopic glioma models. Addition of PAC-1 to TMZ and radiation was well-tolerated in 3 out of 3 pet dogs with spontaneous glioma, and partial to complete tumor reductions were observed. Conclusions: Procaspase-3 is a clinically relevant target for treatment of glioblastoma. Synergistic activity of PAC-1/TMZ in rodent models and the demonstration of feasibility of the combined regime in canine patients suggest potential for PAC-1 in the treatment of glioblastoma. PMID- 29113290 TI - Telomere DNA damage signaling regulates cancer stem cell evolution, epithelial mesenchymal transition, and metastasis. AB - Chromosome ends are protected by telomeres that prevent DNA damage response and degradation. When telomeres become critically short, the DNA damage response is activated at chromosome ends which induces cellular senescence or apoptosis. Telomeres are protected by the double stranded DNA binding protein TRF2 and maintained by telomerase or a recombination based mechanism known as alternative lengthening of telomeres (ALT). Telomerase is expressed in the basal layer of the epidermis, and stem cells in epidermis have longer telomeres than proliferating populations. Stem cell expansion has been associated with epithelial-mesenchymal transition (EMT) in cancer. EMT is a critical process in cancer progression in which cells acquire spindle morphology, migrate from the primary tumor, and spread to distant anatomic sites. Our previous study demonstrated that loss of TRF2 expression observed in human squamous cell carcinomas expanded metastatic cancer stem cells during mouse skin carcinogenesis. To determine if telomerase inhibition could block the TRF2-null mediated expansion of metastatic clones, we characterized skin carcinogenesis in a conditional TRF2/Terc double null mutant mouse. Loss of TRF2 and Terc expression resulted in telomere DNA damage, severely depleted CD34 + and Lgr6+ cancer stem cells, and induced terminal differentiation of metastatic cancer cells. However a novel cancer stem cell population evolved in primary tumors exhibiting genomic instability, ALT, and EMT. Surprisingly we discovered that metastatic clones evolved prior to histopathologic onset of primary tumors. These results have important implications for understanding the evolution and treatment of metastatic cancer. PMID- 29113291 TI - Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells - TREAT-ME-1 - a phase I, first in human, first in class trial. AB - Purpose: This phase I, first in human, first in class clinical study aimed at evaluating the safety, tolerability and efficacy of treatment with genetically modified mesenchymal stromal cells (MSC) in combination with ganciclovir (GCV). MSC_apceth_101 are genetically modified autologous MSCs used as vehicles for a cell-based gene therapy in patients with advanced gastrointestinal adenocarcinoma. Experimental design: The study design consisted of a dose escalation 3 + 3 design. All patients (n = 6) were treated with up to three applications of MSC_apceth_101, followed by GCV infusions given on three consecutive days starting 48 hours after injection of MSC_apceth_101. Three of six patients received a total dose of 1.5 * 106 cells/kg. Two patients received three doses of 1 * 106 cells/kg, while one patient received only two doses of 1 * 106 cells/kg due to a SADR. Results: Six patients received MSC_apceth_101. No IMP related serious adverse events occurred. Adverse-events related to IMP-injection were increased creatinine, cough, fever, and night sweat. TNF, IL-6, IL-8, IL-10 and sE-Selectin, showed that repeated application is immunologically safe, but induces a switch of the functional properties of monocytes to an inflammatory phenotype. Treatment induced stable disease in 4/6 patients, and progressive disease in 2/6 patients. Conclusion: Treatment with MSC_apceth_101 in combination with GCV demonstrated acceptable safety and tolerability in patients with advanced gastrointestinal adenocarcinoma. PMID- 29113292 TI - NOD mice, susceptible to pancreatic autoimmunity, demonstrate delayed growth of pancreatic cancer. AB - Pancreatic cancer is a high mortality form of cancer, with a median survival only six months. There are multiple associated risk factors associated, most importantly type 2 diabetes, obesity, pancreatitis and smoking. The relative rarity of the disease, however, has made it difficult to dissect causative risk factors, especially with related risk factors. A major unanswered question with important therapeutic implications is the effect of immunological responses on pancreatic cancer formation, with data from other cancers suggesting the potential for local immunological responses to either increase cancer development or increase cancer elimination. Due to the rarity and late diagnosis of pancreatic cancer direct epidemiological evidence is lacking, thus necessitating a reliance on animal models. Here we investigated the relationship between pancreatic autoimmunity and cancer by backcrossing the well characterised Ela1 Tag transgenic model of pancreatic cancer onto the pancreatic autoimmune susceptible NOD mouse strain. Through longitudinal magnetic resonance imaging we found that the NOD genetic background delayed the onset of pancreatic tumours and substantially slowed the growth rate of tumours after development. These results suggest that elevated autoimmune surveillance of the pancreas limits tumour formation and growth, identifying pancreatic cancer as a promising target for immune checkpoint blockade therapies that unleash latent autoimmunity. PMID- 29113293 TI - Telomere attrition, kidney function, and prevalent chronic kidney disease in the United States. AB - Background: Telomere length is an emerging novel biomarker of biologic age, cardiovascular risk and chronic medical conditions. Few studies have focused on the association between telomere length (TL) and kidney function. Objective: We investigated the association between TL and kidney function/prevalent chronic kidney disease (CKD) in US adults. Methods: The National Health and Nutrition Examination Survey (NHANES) participants with measured data on kidney function and TL from 1999 to 2002 were included. Estimated glomerular filtration rate (eGFR) was based on CKD Epidemiology Collaboration (CKD-EPI) equation. Urinary albumin excretion was assessed using urinary albumin-creatinine ratio (ACR). We used multivariable adjusted linear and logistic regression models, accounting for the survey design and sample weights. Results: Of the 10568 eligible participants, 48.0% (n=5020) were men. Their mean age was 44.1 years. eGFR significantly decreased and ACR significantly increased across increasing quarters of TL (all p<0.001). The association between TL and kidney function remained robust even after adjusting for potential confounding factors, but the association between TL and ACR was only borderline significant (beta-coefficient= -0.012, p=0.056). Conclusion: The association of kidney function with a marker of cellular senescence suggests an underlying mechanism influencing the progression of nephropathy. PMID- 29113294 TI - Therapeutic management and one-year outcomes in elderly patients with acute coronary syndrome. AB - Background: Elderly represents a subgroup of high-risk ACS patients due to their advanced age and other comorbidities. Unfortunately, they are also often under represented in many studies and clinical trials. Furthermore, cardiologists commonly find difficulties in the choice of the antiplatelet treatment and even on whether invasive revascularization should be used. In this study, the management of elderly ACS patients regarding antiplatelet therapy and revascularization procedures will be analyzed. Methods: 1717 ACS patients were consecutively included in this study from 3 tertiary Hospitals in the Southeast of Spain. Of them, 529 (30.8%) were >= 75 years. They were mainly male (60.7%) with a mean age of 81.4+/-4.7 years. Clinical characteristics, treatment received (antiaplatelet therapy, revascularization) and outcome were analyzed. Results: Regression analysis showed that being >= 75 years is independently associated with neither performing catheterization (79.6% vs 97.1%), nor revascularization (51.8% vs 72.5%), being the medical conservative treatment the election in these elderly patients (40.6% vs 18.9%) (p < 0.001 for all). Furthermore, ticagrelor prescription were significantly decreased in older patients (11.5% vs 19.6%; p < 0.001). Regarding patients outcome after one-year of follow-up, being >= 75 years was associated with death, major adverse cardiac events (MACE) and major bleeding (all of them p < 0.001). Importantly, nor performing catheterization was independently associated with MACE and death in Cox multivariate analysis in elderly patients. Conclusions: Elderly patients with ACS are undertreated both invasively and pharmacologically, and this fact might be associated with the observed worse outcomes. PMID- 29113295 TI - Sodium fluoride induces renal inflammatory responses by activating NF-kappaB signaling pathway and reducing anti-inflammatory cytokine expression in mice. AB - Fluoride is widely distributed in the environment and often results in adverse health effects on animals and human beings. It has been proved that fluoride can induce inflammatory responses in vitro. However, very limited reports are focused on fluoride-induced inflammatory responses in vivo. In this study, mice were used to investigate sodium fluoride (NaF) induced renal inflammatory responses and the potential mechanism by using the methods of pathology, biochemistry, enzyme linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. A total of 240 ICR mice were randomly divided into four equal groups: the control group and three experimental groups (NaF was given orally at the dose of 0, 12, 24 and 48 mg/kg body weight for 42 days, respectively). The results showed that NaF in excess of 12 mg/kg induced the renal histopathological lesions, and inflammatory responses via the activation of nuclear factor-kappa B (NF-kappaB) signaling pathway and the reduction of anti-inflammatory cytokines expression. The activation of NF-kappaB signaling pathway was characterized by increasing the nitric oxide (NO) and prostaglandin E2 (PGE2) contents, inducible nitric oxide synthase (iNOS) activities and mRNA expression levels, and the mRNA and protein expression levels of cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin-6 (IL-6) and interleukin-8 (IL-8) in three NaF treated groups. Concurrently, the mRNA and protein expression levels of the anti inflammatory cytokines including interleukin-4 (IL-4) and interleukin-10 (IL-10) were decreased in three experimental groups when compared with those in the control group. PMID- 29113296 TI - Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma. AB - Glioblastoma multiforme (GBM) presents the most malignant form of glioma, with a 5-year survival rate below 3% despite standard therapy. Novel immune-based therapies in improving treatment outcomes in GBM are therefore warranted. Several molecularly defined targets have been identified mediating anti-GBM cellular immune responses. Mesothelin is a tumor-associated antigen (TAA) which is expressed in several solid tumors with different histology. Here, we report the immunological significance of mesothelin in human malignant glioma. Expression of mature, surface-bound mesothelin protein was found to bein human GBM defined by immunofluorescence microscopy, and on freshly isolated, single cell suspension of GBM tumor cells and GBM tumor cell lines, determined by based on flow cytometric analysis. Peripheral blood (PB) from patients with GBM, stimulated with mesothelin peptides and IL-2, IL-15 and IL-21, exhibited increased antigen specific IFN-gamma and TNF-alpha production. Anti-mesothelin directed T-cell responses could also be detected in tumor - infiltrating lymphocytes (TIL) isolated from GBM speciments. Furthermore, T cells cultured in the presence of IL 2, IL-15 and IL-21 displayed enhanced mesothelin-specific CD4+ and CD8+ subset proliferation, based on ELISA and flow cytometric readouts. Mesothelin-specific IgG antibodies as well as (shed) mature mesothelin protein were detected in plasma samples from patients with GBM by indirect ELISA. Finally yet importantly, we identified distinct immune recognition hotspots within the mature mesothelin component, defined by peptide-specific IFN-gamma responses from peripheral T cells from patients with GBM. Mesothelin may therefore qualify as a viable target for immunotherapeutic approaches for patients with GBM. PMID- 29113297 TI - Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex. AB - Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. The needs for new therapeutic strategies for MCL patients call for further understanding on the molecular mechanisms of pathogenesis of MCL. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators of gene expression and disease development, however, the role of lncRNAs in non-Hodgkin lymphoma and specifically in MCL is still unknown. Next generation RNA-sequencing was carried out on MCL patient samples along with normal controls and data was analyzed. As a result, several novel lncRNAs were found significantly overexpressed in the MCL samples with lncRNA ROR1-AS1 the most significant one. We cloned the ROR1-AS1 lncRNA in expression vector and ectopically transfected in MCL cell lines. Results showed that overexpression of ROR1-AS1 lncRNA promoted growth of MCL cells while decreased sensitivity to the treatment with drugs ibrutinib and dexamethasone. ROR-AS1 overexpression also decreased the mRNA expression of P16 (P = 0.21), and SOX11 (p = 0.017), without much effect on P53, ATM and P14 mRNA. RNA-immunoprecipitation assays demonstrated high affinity binding of lncRNA ROR1-AS1 with EZH2 and SUZ12 proteins of the polycomb repressive complex-2 (PRC2). Suppressing EZH2 activity with pharmacological inhibitor GSK343 abolished binding of ROR1-AS1 with EZH2. Taken together, this study identified a functional lncRNA ROR-AS1 involved with regulation of gene transcription via associating with PRC2 complex, and may serve as a novel biomarker in MCL patients. PMID- 29113298 TI - IL-8, GRO and MCP-1 produced by hepatocellular carcinoma microenvironment determine the migratory capacity of human bone marrow-derived mesenchymal stromal cells without affecting tumor aggressiveness. AB - New therapies are needed for advanced hepatocellular carcinoma (HCC) and the use of mesenchymal stromal cells (MSCs) carrying therapeutic genes is a promising strategy. HCC produce cytokines recruiting MSCs to the tumor milieu and modifying its biological properties. Our aim was to study changes generated on human MSCs exposed to conditioned media (CM) derived from human HCC fresh samples and xenografts. All CM shared similar cytokines expression pattern including CXCL1-2 3/GRO, CCL2/MCP-1 and CXCL8/IL-8 being the latter with the highest concentration. Neutralizing and knockdown experiments of CCL2/MCP-1, CXCL8/IL-8, CXCR1 and CXCR2 reduced in vitro MSC migration of >=20%. Simultaneous CXCR1 and CXCR2 neutralization resulted in 50% of MSC migration inhibition. MSC stimulated with CM (sMSC) from HuH7 or HC-PT-5 showed a 2-fold increase of migration towards the CM compared with unstimulated MSC (usMSC). Gene expression profile of sMSC showed ~500 genes differentially expressed compared with usMSC, being 46 genes related with cell migration and invasion. sMSC increased fibroblasts and endothelial cells chemotaxis. Finally, sMSC with HuH7 CM and then inoculated in HCC tumor bearing-mice did not modify tumor growth. In this work we characterized factors produced by HCC responsible for the changes in MSC chemotactic capacity with would have an impact on therapeutic use of MSCs for human HCC. PMID- 29113299 TI - MicroRNA-210 suppresses glucocorticoid receptor expression in response to hypoxia in fetal rat cardiomyocytes. AB - Hypoxia is a common intrauterine stressor, often resulting in intrauterine growth restriction and increased risk for cardiovascular disease later in life. The aim of this work was to test the hypothesis that microRNA-210 (miR-210) mediates the detrimental suppression of glucocorticoid receptor (GR) in response to hypoxia in fetal rat cardiomyocytes. Cardiomyocytes isolated from gestational day 21 Sprague Dawley fetal rats showed increased miR-210 levels and reduced GR abundance after exposure to ex vivo hypoxia (1% O2). In regard to mechanisms, the different contributions of hypoxia response elements (HREs) motifs in the regulation of miR 210 promoter activity and the miR-210-mediated repression of GR expression were determined in rat embryonic heart-derived myogenic cell line H9c2. Moreover, using a cell culture-based model of hypoxia-reoxygenation injury, we assessed the cytotoxic effects of GR suppression under hypoxic conditions. The results showed that hypoxia induced HIF-1alpha-dependent miR-210 production, as well as miR-210 mediated GR suppression, in cardiomyocytes. Furthermore, inhibition or knockdown of GR exacerbated cell death in response to hypoxia-reoxygenation injury. Altogether, the present study demonstrates that the HIF-1alpha-dependent miR-210 mediated suppression of GR in fetal rat cardiomyocytes increases cell death in response to hypoxia, providing novel evidence for a possible mechanistic link between fetal hypoxia and programming of ischemic-sensitive phenotype in the developing heart. PMID- 29113300 TI - Deletion of tumor suppressors adenomatous polyposis coli and Smad4 in murine luminal epithelial cells causes invasive prostate cancer and loss of androgen receptor expression. AB - Prostate cancer is the most diagnosed non-skin cancer in the US and kills approximately 27,000 men per year in the US. Additional genetic mouse models are needed that recapitulate the heterogeneous nature of human prostate cancer. The Wnt/beta-catenin signaling pathway is important for human prostate tumorigenesis and metastasis, and also drives tumorigenesis in mouse models. Loss of Smad4 has also been found in human prostate cancer and drives tumorigenesis and metastasis when coupled with other genetic aberrations in mouse models. In this work, we concurrently deleted Smad4 and the tumor suppressor and endogenous Wnt/beta catenin inhibitor adenomatous polyposis coli (Apc) in luminal prostate cells in mice. This double conditional knockout model produced invasive castration resistant prostate carcinoma with no evidence of metastasis. We observed mixed differentiation phenotypes, including basaloid and squamous differentiation. Interestingly, tumor cells in this model commonly lose androgen receptor expression. In addition, tumors disappear in these mice during androgen cycling (castration followed by testosterone reintroduction). These mice model non metastatic castration resistant prostate cancer and should provide novel information for tumors that have genetic aberrations in the Wnt pathway or Smad4. PMID- 29113301 TI - UCP2 and PRMT1 are key prognostic markers for lung carcinoma patients. AB - Cancer cells have developed unique strategies to meet their high energy demand. Therefore, they have established a setting of Ca2+-triggered high mitochondrial activity. But mitochondrial Ca2+ uptake has to be strictly controlled to avoid mitochondrial Ca2+ overload that would cause apoptotic cell death. Methylation by protein arginine methyl transferase 1 (PRMT1) desensitizes the mitochondrial Ca2+ uptake machinery and reduces mitochondrial Ca2+ accumulation in cancer cells. In case of PRMT1-driven methylation, proper mitochondrial Ca2+ uptake is reestablished by increased activity of uncoupling protein 2 (UCP2), pointing to an importance of these proteins for cancer cell survival and activity. Accordingly, in this study we investigated the impact of UCP2 and PRMT1 on the fate of human lung cancer cells (A549, Calu-3 and H1299) as well as on patients suffering from lung carcinoma. We show that combined overexpression of UCP2 and PRMT1 significantly enhances viability, proliferation as well as mitochondrial respiration. In line with these findings, the overall survival probability of lung carcinoma patients with high mRNA expression levels of UCP2 and PRMT1 is strongly reduced. Furthermore, analysis via The Cancer Genome Atlas (TCGA) reveals upregulation of both proteins, UCP2 and PRMT1, as common feature of various cancer types. These findings suggest that proper mitochondrial Ca2+ uptake is essential for devastating tumor growth, and highlight the importance of a tightly controlled mitochondrial Ca2+ uptake to ensure proper ATP biosynthesis while avoiding dangerous mitochondrial Ca2+ overload. By that, the study unveils proteins of the mitochondrial Ca2+ uptake as potential targets for cancer treatment. PMID- 29113302 TI - Clinical evaluation of palliative chemoradiotherapy for metastatic esophageal cancer. AB - Platinum-based chemotherapy is considered a standard treatment option for patients with metastatic esophageal carcinoma. However, the overall survival of patients receiving such treatment is <1 year. A common presenting symptom of esophageal cancer is dysphagia, which has a substantial impact on quality of life. We have now retrospectively evaluated the efficacy and safety of palliative chemoradiotherapy for patients with stage IV esophageal cancer, most of whom are unfit for curative chemoradiotherapy. Fifty consecutive patients diagnosed with stage IV esophageal cancer were treated with concurrent chemoradiotherapy at Kindai University Hospital between April 2008 and December 2014. Most (90%) patients received a total radiation dose of at least 50 Gy, and the median number of treatment cycles per patient was four for the combination of 5-fluorouracil and cisplatin. The response of the primary tumor and the overall response were 80% and 44%, respectively. The dysphagia score was improved after chemoradiotherapy in 36 (72%) patients and did not change between before and after treatment in 14 (28%) patients. With a median follow-up time of 9.4 months from the start of chemoradiotherapy, the median progression-free survival and overall survival were 4.7 and 12.3 months, respectively. Three patients (T4b in two, T3 in one) developed esophagobronchial fistula after completion of chemoradiotherapy (n = 2) or after disease progression (n = 1), resulting in death in each case. Our results suggest that palliative chemoradioiotherapy was safe and contributed the improvement of dysphagia in patients with stage IV esophageal cancer. PMID- 29113303 TI - Mitochondrion-associated protein peroxiredoxin 3 promotes benign prostatic hyperplasia through autophagy suppression and pyroptosis activation. AB - Benign prostatic hyperplasia (BPH) is one of the most common diseases in the senior men and age plays an important role in the initiation and development of BPH. Mammalian cells primarily use the autophagy-lysosome system to degrade misfolded/aggregated proteins and dysfunctional organelles such as mitochondria and suppress pyroptosis, a type of cell death that stimulates inflammatory responses and growth of other cells around. Peroxiredoxin 3 (PRDX3) is the only mitochondrion-associated member of peroxiredoxin family enzymes that exert their protective antioxidant role in cells through their peroxidase activity. We hypothesized that PRDX3 may inhibit autophagy to activate pyroptosis to induce growth of prostatic epithelial cells. Here we show that PRDX3 maintained the integrity of mitochondria and its depletion led to an enhancement of oxidative stresses. PRDX3-associated and PRDX3-free mitochondria co-existed in the same cells. PRDX3 expressed at higher levels in prostatic epithelial cells in prostate tissues from BPH patients and BPH-representative cell line than in prostate tissues from healthy donors and a cell line representing normal epithelial cells. PRDX3 suppressed autophagy flux and activated pyroptosis to induce inflammatory responses and stimulate the over-growth of prostate tissues. Therefore, higher levels of PDRX3 in prostatic epithelial cells may promote the initiation and development of BPH through autophagy inhibition and pyroptosis activation. PMID- 29113304 TI - Significant association of YAP1 and HSPC111 proteins with poor prognosis in Chinese gastric cancer patients. AB - Hippo-YAP1 is a tumor-suppressor signaling pathway that inhibits cell proliferation and accelerates apoptosis. However, the role of YAP1 in gastric cancer (GC) is still in dispute. Ribosomal biogenesis is closely correlated with human malignancies. HBV pre-S2 trans-regulated protein 3 (HSPC111) is a portion of an RNA-dependent complex and plays a crucial role in ribosome biosynthesis. Nevertheless, little is known about the expression and function of this factor in GC. In the present study, we evaluated the significance of YAP1 together with HSPC111 in gastric cancer. According to The Cancer Genome Atlas database, high YAP1 mRNA expression was significantly associated with poor prognosis of GC patients, and dramatically increased mRNA levels of HSPC111 are observed in GC tissues. Consistent with these findings, we detected increased expression of both YAP1 and HSPC111 in GC cell lines and clinical samples. Notably, nuclear expression of YAP1 was positively correlated with clinical stage (P = 0.041), tumor size (P = 0.023), and lymph node metastasis (P = 0.007), while HSPC111 expression was correlated with lymph node metastasis (P = 0.014). Our analyses also detected a correlation between HSPC111 expression and nuclear and cytoplasmic YAP1 in clinical samples (nuclear: r = 0.2615, P = 0.004; cytoplasm: r = -0.3721, P < 0.001) and cell lines. Finally, we showed that patients who were HSPC111- and nuclear YAP1-positive were associated with the worst prognosis (34.5 +/- 4.8 months, p = 0.001), and that nuclear expression of YAP1 might act as an independent prognostic factor for GC patients. PMID- 29113305 TI - Vinpocetine alleviate cerebral ischemia/reperfusion injury by down-regulating TLR4/MyD88/NF-kappaB signaling. AB - Inflammatory responses play crucial roles in cerebral ischemia/reperfusion injury. Toll-like receptor 4 (TLR4) is an important mediator of the neuroinflammatory response to cerebral ischemia/reperfusion injury. Vinpocetine is a derivative of the alkaloid vincamine and exerts an anti-inflammatory effect by inhibiting NF-kappaB activation. However, the effects of vinpocetine on pathways upstream of NF-kappaB signaling, such as TLR4, have not been fully elucidated. Here, we used mouse middle cerebral artery occlusion (MCAO) and cell based oxygen-glucose deprivation (OGD) models to evaluate the therapeutic effects and mechanisms of vinpocetine treatment. The vinpocetine treatment significantly reduced mice cerebral infarct volumes and neurological scores. Moreover, the numbers of TUNEL+ and Fluoro-Jade B+ cells were significantly decreased in the ischemic brain tissues after vinpocetine treatment. In the OGD model, the vinpocetine treatment also increased the viability of cultured cortical neurons. Interestingly, vinpocetine exerted a neuroprotective effect on the mouse MCAO model and cell-based OGD model by inhibiting TLR4-mediated inflammatory responses and decreasing proinflammatory cytokine release through the MyD88-dependent signaling pathway, independent of TRIF signaling pathway. In conclusion, vinpocetine exerts anti-inflammatory effects to ameliorate cerebral ischemia/reperfusion injury in vitro and in vivo. Vinpocetine may inhibit inflammatory responses through the TLR4/MyD88/NF-kappaB signaling pathway, independent of TRIF-mediated inflammatory responses. Thus, vinpocetine may be an attractive therapeutic candidate for the treatment of ischemic cerebral injury or other inflammatory diseases. PMID- 29113306 TI - Role of LOXL2 in the epithelial-mesenchymal transition and colorectal cancer metastasis. AB - Colorectal cancer (CRC) is one of the most dangerous types of malignant tumors, and cancer metastasis is a major factor in the failure of CRC therapy. Recently, LOXL2 (lysyl oxidase-like 2) has been shown to represent a regulator of epithelial-mesenchymal transition (EMT) in different cancer types. However, LOXL2 has not been reported to be involved in CRC metastasis. In this study, we demonstrated that LOXL2 expression is strongly correlated with the rate of CRC metastasis, it participates in the regulation of EMT-related molecule expression in CRC cells in vitro, and it is involved in migratory potential alterations. Additionally, tissue microarray analysis of CRC patients showed an increase in the probability of developing CRC distant metastasis and a decrease in the survival rate of patients with high LOXL2 expression. The results obtained in this study indicate that LOXL2 is involved in the development and progression of CRC metastasis, and therefore, its expression levels may represent a useful prognostic marker. PMID- 29113307 TI - Prediction of clinical outcome and survival in soft-tissue sarcoma using a ten lncRNA signature. AB - The prognostic value of long non-coding RNAs (lncRNAs) in patients with soft tissue sarcoma has rarely been unraveled. The aim of the study was to find a lncRNA signature to predict the clinical outcome and survival in soft-tissue sarcoma based on the high-throughput RNA-seq data from The Cancer Genome Atlas (TCGA) database. The lncRNAs which closely correlated with overall survival in 258 soft-tissue sarcoma patients were identified with Cox proportional regression model. Ten lncRNAs, including RP11-560J1.2, AP001432.14, RP4-665J23.1, LINC00680, AC006129.2, RP11-230G5.2, BACH1-IT2, RP11-274B21.9, RP11-504A18.1 and RP11 713P17.3, were selected to calculate a risk score. The risk score could effectively predict patients' outcome, such as the status of mitotic count of tumor cells, person neoplasm cancer and residual tumor. More inspiringly, the risk score generated from the 10-lncRNA signature was an independent prognostic indicator for soft-tissue sarcoma patients. Overall, this 10-lncRNA signature gains the potential as an effective prognostic tool for soft-tissue sarcoma as part of the integrated clinical RNA-seq program. PMID- 29113308 TI - KDM4A as a prognostic marker of oral squamous cell carcinoma: Evidence from tissue microarray studies in a multicenter cohort. AB - Purpose: Previous studies have identified histone demethylase KDM4A to be a key epigenetic priming factor for the invasive squamous cell carcinoma growth and metastasis. The purpose of this study was to examine KDM4A as an independent prognostic marker in oral squamous cell carcinoma, using multicenter tissue microarrays. Results: The expression of KDM4A was significantly correlated with lymph node metastasis and TNM stage. KDM4A overexpression was associated with poor overall survival, and it was found to be a statistically significant independent predictor of all-cause mortality. These findings are validated by external TCGA HNSCC data. Addition of KDM4A expression improved the discriminatory accuracy of standard clinicopathologic features for prediction of cancer-specific survival (Model 4, area under the curve = 0.740, 95% confidence interval = 0.685 to 0.795, and Model 3, AUC = 0.695, 95% CI = 0.637 to 0.753, respectively). Materials and Methods: KDM4A expression was measured by immunohistochemistry, using tissue microarrays of OSCC samples collected from 313 patients. Kruskal-Wallis and chi-square tests were applied to investigate the correlation between KDM4A expression and clinicopathological factors. Overall survival analysis was performed using the Kaplan-Meier and multivariable logistic regression models, and the predictive ability of KDM4A in combination with known OSCC risk factors was evaluated. Receiver operating characteristic curves were used to assess discriminatory accuracy of these models. Additionally, disease free survival was analyzed in patients with head and neck SCC reported on The Cancer Genome Atlas database. Conclusions: KDM4A expression is an independent predictor for the survival time of patients with OSCC and may be a valuable consideration to postoperative treatment options. PMID- 29113309 TI - Macrophage migration inhibitory factor promotes vasculogenic mimicry formation induced by hypoxia via CXCR4/AKT/EMT pathway in human glioblastoma cells. AB - Macrophage migration inhibitory factor (MIF) is over-expressed and secreted in various cancer cells in particular in response to hypoxia. Recent studies have shown that, under hypoxic conditions, glioblastoma (GBM) cells display the ability to drive blood-perfused vasculogenic mimicry (VM). The aim of this study was to investigate the underlying mechanism of MIF in the regulation of hypoxia induced VM in GBM cells. By analyzing clinical specimens, we observed the co localization of MIF, C-X-C motif chemokine receptor 4 (CXCR4) and VM in hypoxic regions of gliomas. In vitro, the exposure of GBM cells (U87 and U251) to hypoxia increased the expression of MIF and CXCR4 and induced VMs. Other data demonstrated that ectogenic rhMIF promoted VMs in GBM cells and knock-down endogenous MIF attenuated hypoxia-induced VMs. In addition, we demonstrated that MIF augmented VM formation ability by enhancing the epithelial mesenchymal transition (EMT) through the CXCR4-AKT pathway. Moreover, in vivo, the subcutaneous injection of rhMIF resulted in the progression of EMT and VMs formation. On the contrary, CXCR4-AKT pathway inhibitors blocked the effects of rhMIF on EMT and VMs formation. Collectively, our results support a critical role for the MIF-CXCR4 signaling axis in regulating hypoxia-induced VMs formation, indicating the potential usefulness of MIF as a notable target for the anti vascularization treatment of GBM. PMID- 29113310 TI - Inference of time-delayed gene regulatory networks based on dynamic Bayesian network hybrid learning method. AB - Gene regulatory networks (GRNs) research reveals complex life phenomena from the perspective of gene interaction, which is an important research field in systems biology. Traditional Bayesian networks have a high computational complexity, and the network structure scoring model has a single feature. Information-based approaches cannot identify the direction of regulation. In order to make up for the shortcomings of the above methods, this paper presents a novel hybrid learning method (DBNCS) based on dynamic Bayesian network (DBN) to construct the multiple time-delayed GRNs for the first time, combining the comprehensive score (CS) with the DBN model. DBNCS algorithm first uses CMI2NI (conditional mutual inclusive information-based network inference) algorithm for network structure profiles learning, namely the construction of search space. Then the redundant regulations are removed by using the recursive optimization algorithm (RO), thereby reduce the false positive rate. Secondly, the network structure profiles are decomposed into a set of cliques without loss, which can significantly reduce the computational complexity. Finally, DBN model is used to identify the direction of gene regulation within the cliques and search for the optimal network structure. The performance of DBNCS algorithm is evaluated by the benchmark GRN datasets from DREAM challenge as well as the SOS DNA repair network in Escherichia coli, and compared with other state-of-the-art methods. The experimental results show the rationality of the algorithm design and the outstanding performance of the GRNs. PMID- 29113311 TI - The anti-apoptotic BAG3 protein is involved in BRAF inhibitor resistance in melanoma cells. AB - BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumour types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumour cells and can sustain IKK-gamma levels, allowing a sustained activation of NF-kappaB. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas. BRAFV600E is the most frequent mutation detected in malignant melanomas and is targeted by Vemurafenib, a specific inhibitor found to be effective in the treatment of advanced melanoma. However, patients with BRAF mutated melanoma may result insensitive ab initio or, mostly, develop acquired resistance to the treatment with this molecule. Here we show that BAG3 down modulation interferes with BRAF levels in melanoma cells and sensitizes them to Vemurafenib treatment. Furthermore, the down-modulation of BAG3 protein in an in vitro model of acquired resistance to Vemurafenib can induce sensitization to the BRAFV600E specific inhibition by interfering with BRAF pathway through reduction of ERK phosphorylation, but also on parallel survival pathways. Future studies on BAG3 molecular interactions with key proteins responsible of acquired BRAF inhibitor resistance may represent a promising field for novel multi-drugs treatment design. PMID- 29113312 TI - FKBP51 decreases cell proliferation and increases progestin sensitivity of human endometrial adenocarcinomas by inhibiting Akt. AB - In this study, we investigated the role of FK506 binding protein 51 (FKBP51) in human endometrial adenocarcinoma progression. Immunohistochemical analysis showed decreased FKBP51 expression in endometrial adenocarcinoma tissues. Moreover, higher FKBP51 expression was observed in the normal secretory phase than in proliferative-phase endometrial tissues. FKBP51-shRNA transfected KLE cells showed high Ser473-phospho Akt with decreased p21 and p27 levels, which promoted S-G2/M phase cell cycle progression and proliferation. Conversely, FKBP51 overexpressing Ishikawa cells showed low Ser473-phospho Akt, which led to increased p21 and p27 levels and, in turn, G0/G1 cell cycle arrest and decreased cell proliferation. FKBP51 overexpression in progesterone receptor-positive Ishikawa cells sensitized them to medroxyprogesterone acetate (MPA; progestin) treatment by repressing Akt signaling. Conversely, FKBP51-shRNA knockdown in RL95 2 cells attenuated progestin sensitivity. These findings indicate FKBP51 inhibits cell proliferation and promotes progestin sensitivity in endometrial adenocarcinoma by decreasing Akt signaling. PMID- 29113313 TI - Whole-exome analysis in osteosarcoma to identify a personalized therapy. AB - Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy. We identified 18,275 somatic variations in 8,247 genes and we found three mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the highest number of variations; it is an important component of a histone H3 lysine 4 methyltransferase complex and it is one of the histone modifiers previously implicated in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15 genes that showed variations only in patients that did not respond to therapy and developed metastasis and some of these genes are involved in carcinogenesis and tumor progression in other tumors. These data could offer the opportunity to get a key molecular target to identify possible new strategies for early diagnosis and new therapeutic approaches for osteosarcoma and to provide a tailored treatment for each patient based on their genetic profile. PMID- 29113315 TI - Tumor PD-L1 status and CD8+ tumor-infiltrating T cells: markers of improved prognosis in oropharyngeal cancer. AB - Introduction: The aim of this study was to evaluate the expression of PD-L1 in oropharyngeal squamous cell carcinoma. Its relation with clinicopathological variables, tumor infiltrating lymphocytes and survival was also determined. Results: Positive PD-L1 status for the SP142 clone related with improved overall survival in oropharyngeal squamous cell carcinoma. Tumors heavily infiltrated by tumor infiltrating lymphocytes were also linked with better outcome, and this as well for the total number of tumor infiltrating lymphocytes as for the CD3+ and CD8+ T cell count. A Cox proportional hazard model proved that solely infiltrating CD8+ T cells exhibit a positive effect on overall survival (hazard ratio = 0.31 [0.14-0.70]; P = 0.0050). Materials and Methods: Formalin-fixed, paraffin-embedded tissue from oropharyngeal tumors of 99 patients was immunohistochemically stained for PD-L1 (SP142 and 22C3 clones), CD3, CD8 and FoxP3. Expression of PD-L1, CD3, CD8, FoxP3 and HPV status were correlated with clinicopathological variables. Overall survival was determined by a log-rank (Mantel-Cox) test whereas the Cox proportional hazard model was used for multivariate analysis. Conclusions: Our results demonstrate that CD8+ T lymphocytes constitute an independent prognostic marker in patients diagnosed with oropharyngeal squamous cell carcinoma. PD-L1 positivity for SP142, but not for 22C3, also tends to have a positive effect on survival in oropharyngeal squamous cell carcinoma. PMID- 29113314 TI - Glypican-3 induces oncogenicity by preventing IGF-1R degradation, a process that can be blocked by Grb10. AB - Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide. Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R). In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF 1R signaling. We demonstrated that GPC3 decreased IGF-1-induced IGF-1R ubiquitination and degradation and increased c-Myc protein levels. GPC3 bound to Grb10, a mediator of ligand-induced receptor ubiquitination, and the overexpression of Grb10 blocked GPC3-enhanced IGF-1-induced ERK phosphorylation. GPC3 promoted the growth of NIH3T3 and PLC-PRF-5 cells in serum-free medium but did not promote the growth of IGF-1R negative R- cells. Grb10 overexpression decreased GPC3-promoted cell growth. Therefore, the present study elucidates the mechanisms of GPC3-induced oncogenicity, which may highlight new strategies for the treatment of HCC. PMID- 29113316 TI - Efficacy of sub-threshold focused ultrasound irradiation against pancreatic cancer xenografts evaluated using magnetic resonance imaging. AB - We investigated the efficacy and optimal period for using magnetic resonance imaging (MRI) to detect effects of sub-threshold focused ultrasound (FUS) irradiation. Nude mice bearing pancreatic cancer xenografts were subjected to MRI and pathology examnation before, and 24 h, 48 h, 2 weeks after irradiation, which were used to evaluate therapeutic effects of FUS. Tumor volumes were lower post treatment than control group (P < 0.05). The T1WI turbo spin echo (T1WI-TSE) sequence was similar signal before and after treatment. On T1 enhanced scanning sequence (T1WI-SPIR) imaging, ablation lesions appeared as patchy areas of low signal after 24 h and 48 h. After 2 weeks, the ablation lesions contained low signal areas with clear borders. Hematoxylin and eosin (HE) staining revealed small vessels at ablation lesions with no obvious boundary between cell injury areas and normal tumor cells areas in early-stage, while revealed obvious boundaries 2 weeks post-treatment. Terminal deoxynucleotidyl transferase modified, dUTP nick-end labeling (TUNEL) staining showed cell apoptosis in early stage, and revealed reduced apoptotic cells and increased necrotic cell areas 2 weeks later. These findings indicate sub-threshold FUS induces pancreatic cancer cell apoptosis and inhibits tumor growth. Contrast-enhanced MRI delineated the ablation lesions better 2 weeks post-treatment than early stage. PMID- 29113317 TI - Hydroxychloroquine and risk of cancer in patients with primary Sjogren syndrome: propensity score matched landmark analysis. AB - Hydroxychloroquine inhibits systemic inflammation and autophagy and may thus have antineoplastic effects [1]. We investigated the effect of hydroxychloroquine on cancer risk in patients with primary Sjogren syndrome(pSS). We used the Taiwan National Health Insurance Database to compare cancer incidence between incident pSS patients with or without at least 6-month hydroxychloroquine use within a 1- or 3-year period. Propensity score matched landmark analysis was used. We included 4194 alive patients without cancer 1 year after pSS diagnosis from 2000 through 2005. The propensity score matched 1148 patients with at least 6-month hydroxychloroquine exposure at 1 year after diagnosis and 1148 patients without. Median follow-up after the 1-year landmark was 6 years. During follow up 62 hydroxychloroquine users and 56 non-hydroxychloroquine users developed cancer. Kaplan-Meier estimates showed no difference in overall survival between hydroxychloroquine users and non-users in the 1-year. Hydroxychloroquine was associated with a hazard ratio (HR) of 1.11 (95% CI, 0.78-1.60) in 1-year landmark analysis. In 3-year landmark analysis, hydroxychloroquine was associated with a HR for cancer of 1.37 (95% CI, 0.97-1.94). This propensity score matched landmark analysis of Taiwanese patients with incident pSS found that hydroxychloroquine was not associated with cancer risk nor protection. PMID- 29113318 TI - Follicular metabolic changes and effects on oocyte quality in polycystic ovary syndrome patients. AB - Polycystic ovary syndrome (PCOS) is a common complex and heterogeneous disorder, affecting up to 10% women at reproductive age. It causes three fourth of the ovulatory infertility and PCOS patients often give poor IVF quality. Although some metabolic profiles have been investigated in PCOS patient sera and urine, the follicular fluid, providing fruitful biochemical information about oocyte environment during development has been ignored. In this work, based on NMR metabolomics approach, metabolic profile of follicular fluid of PCOS patients has been explored and compared with healthy controls. Significant increases of glycoprotein, acetate, cholesterol, significant decreases of lactic acid, glutamine, pyruvate, and alanine, have been discovered in PCOS follicular fluids. Furthermore, the Pearson correlations analysis indicated significant relationship existed between ART results and NMR detected follicular metabolites. All these results indicated that PCOS may induce dyslipidemia, low-grade inflammation, and disorder of glycolysis, pyruvate and amino acid metabolism in follicular fluids. PMID- 29113319 TI - Comparative proteomic analysis of virulent and avirulent strains of Toxoplasma gondii reveals strain-specific patterns. AB - Research exploring the proteome of Toxoplasma gondii oocysts has gained momentum over the past few years. However, little is known about the oocyst's protein repertoires that contribute to differential virulence among T. gondii strains. Here, we used isobaric tag for relative and absolute quantitation-based proteomic analysis of oocysts of two T. gondii strains exhibiting the virulent PYS (ToxoDB#9) phenotype versus the less virulent PRU (Type II, ToxoDB#1) phenotype. Our aim was to determine protein expression patterns that contribute to the virulence of a particular phenotype. A total of 2,551 proteins were identified, of which 374 were differentially expressed proteins (DEPs) (|log2 fold change| >= 0.58 and P < 0.05). DEPs included 192 increased and 182 decreased proteins. Gene Ontology and KEGG pathway analyses revealed a large number of DEPs enriched in various metabolic processes. Protein interaction network analysis using STRING identified inosine monophosphate dehydrogenase (IMPDH), Bifunctional GMP synthase/glutamine amidotransferase protein, Glucose-6-phosphate 1-dehydrogenase, and Citrate synthase as the top four hubs. Of the 22 virulence proteins commonly expressed in the oocysts of the two strains, 13 and 2 proteins were increased in PYS strain and PRU strain, respectively. Also, 10 and 3 of the 22 identified oocyst wall proteins showed higher expression in oocysts of PRU strain and PYS strain, respectively. These findings revealed new proteomic differences in the oocysts of T. gondii strains of different genotypic backgrounds. PMID- 29113320 TI - Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies. AB - We performed exome-wide association studies to identify single nucleotide polymorphisms that either influence fasting plasma glucose level or blood hemoglobin A1c content or confer susceptibility to type 2 diabetes mellitus in Japanese. Exome-wide association studies were performed with the use of Illumina Human Exome-12 DNA Analysis or Infinium Exome-24 BeadChip arrays and with 11,729 or 8635 subjects for fasting plasma glucose level or blood hemoglobin A1c content, respectively, or with 14,023 subjects for type 2 diabetes mellitus (3573 cases, 10,450 controls). The relation of genotypes of 41,265 polymorphisms to fasting plasma glucose level or blood hemoglobin A1c content was examined by linear regression analysis. After Bonferroni's correction, 41 and 17 polymorphisms were significantly (P < 1.21 * 10-6) associated with fasting plasma glucose level or blood hemoglobin A1c content, respectively, with two polymorphisms (rs139421991, rs189305583) being associated with both. Examination of the relation of allele frequencies to type 2 diabetes mellitus with Fisher's exact test revealed that 87 polymorphisms were significantly (P < 1.21 * 10-6) associated with type 2 diabetes mellitus. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that four polymorphisms (rs138313632, rs76974938, rs139012426, rs147317864) were significantly (P < 1.44 * 10-4) associated with type 2 diabetes mellitus, with rs138313632 and rs139012426 also being associated with fasting plasma glucose and rs76974938 with blood hemoglobin A1c. Five polymorphisms-rs139421991 of CAT, rs189305583 of PDCL2, rs138313632 of RUFY1, rs139012426 of LOC100505549, and rs76974938 of C21orf59-may be novel determinants of type 2 diabetes mellitus. PMID- 29113321 TI - Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway. AB - We investigated whether radiation influences the susceptibility of non-small cell lung cancer (NSCLC) cells to NK cell mediated cytotoxicity. We found radiation treatment increased expression of programmed cell death ligand 1 (PD-L1), but decreased NK group 2, member D (NKG2D) ligand expressions in A549 and H157 NSCLC cells. Both types of changes would have protected tumor cells from the cytotoxic action of NK cells. Consistently, we detected similar alteration in these molecules in radioresistant A549R26-1 and H157R24-1 subline cells. Higher PD-L1 level was also observed in tumors of A549R26-1 cell-derived xenografts than tumors of parental A549 (A549P) cell-derived xenografts. Accordingly, we found radioresistant cells were more resistant to the cytotoxic action of NK cells than parental cells, and such resistance was decreased when neutralizing antibody (Ab) of PD-L1 was added to the radioresistant cell/NK cell co-cultures. In mechanism studies, we found that IL-6-MEK/Erk signaling contributed most significantly to the up-regulation of PD-L1/down-regulation of NKG2D ligands in radioresistant cells. The addition of the MEK/Erk inhibitor increased the susceptibility of A549R26-1 and H157R24-1 cells to NK-cell cytotoxicity while no significant effect was observed in parental cells. Moreover, we detected enhanced NK-cell cytotoxicity to radioresistant cells when PD-L1 Ab and MEK/Erk inhibitor were added together to co-cultures of tumor/NK cells compared to when PD-L1 Ab was used alone. We suggest that combined use of PD-L1 Ab and MEK/Erk inhibitor may offer better therapeutic benefits than PD-L1 Ab alone to treat NSCLC patients who are receiving radiotherapy or who are at the radioresistant stage. PMID- 29113322 TI - Artificial neural network models for early diagnosis of hepatocellular carcinoma using serum levels of alpha-fetoprotein, alpha-fetoprotein-L3, des-gamma-carboxy prothrombin, and Golgi protein 73. AB - More than 70% of hepatocellular carcinoma (HCC) cases develop as a consequence of liver cirrhosis (LC). Here we have evaluated the diagnostic potential of four serum biomarkers, and developed models for HCC diagnosis and differentiation from LC patients. Serum levels of alpha-fetoprotein (AFP), AFP-L3, des-gamma-carboxy prothrombin (DCP), and Golgi protein 73 (GP73) were analyzed in 114 advanced HCC patients, 81 early stage HCC patients, and 152 LC patients. Multilayer perceptron (MLP) and radial basis function (RBF) neural networks were used to construct the diagnostic models. Using all stages, HCC diagnostic models had a higher sensitivity (>70%) than the individual serum biomarkers, whereas only early stage HCC diagnostic models had a higher specificity (>80%). The early stage HCC diagnostic models could not be used as HCC screening tools due to their low sensitivity (about 40%). These results suggest that a combination of the two models might be used as a screening tool to distinguish early stage HCC patients from LC patients, thus improving prevention and treatment of HCC. PMID- 29113323 TI - Reduced expression of BMP3 contributes to the development of pulmonary fibrosis and predicts the unfavorable prognosis in IIP patients. AB - Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two related diseases involving varying degrees of pulmonary fibrosis with no effective cure. Bone morphogenetic protein 3 (BMP3) is a member of the transforming growth factor-beta (TGF-beta) super-family, which has not been implicated in pulmonary fibrosis previously. In this study, we aimed to investigate the potential role of BMP3 playing in pulmonary fibrosis from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of BMP3 was evaluated in 83 cases of IPF and INSIP by immunohistochemistry. The function of BMP3 was investigated in both fibroblast cells and a bleomycin induced murine pulmonary fibrosis model. The clinical relevance of BMP3 expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that BMP3 was significantly down-regulated in lung tissues of patients with IPF and INSIP. Consistently, lower expression of BMP3 also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of BMP3 prevented pulmonary fibrosis processing through inhibiting cellular proliferation of fibroblasts as well as TGF-beta1 signal transduction. Finally, the relatively higher expression of BMP3 in IPF patients was associated with less/worse mortality. Intravenous injection of recombinant BMP3. Taken together, our results suggested that the low expression level of BMP3 may indicate the unfavorable prognosis of IPF patients, targeting BMP3 may represent a novel potential therapeutic method for pulmonary fibrosis management. PMID- 29113324 TI - Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness. AB - The unfolded protein response (UPR) is a stress pathway controlled by GRP78 to mediate IRE1, PERK, and ATF6 signaling. We show that targeting GRP78, IRE1, and PERK differentially regulates macrophage polarization. Specifically, PERK targeting enhanced macrophage proliferation and macrophage-mediated killing but not GRP78 or IRE1. Targeting UPR in cancer cells also differentially affected macrophage cytolytic capacity. Tumoral IRE1 or GRP78 inhibition enhanced macrophage-mediated cancer cell clearance. Conditioned media from GRP78-silenced cancer cells caused reciprocal regulation of CD80 and CD206, suggesting control of plasticity by secreted factors. GRP78 targeting in mice resulted in a cytokine shift and increased tumoral CD80+/CD68+ cells, suggesting an M1-like profile. Targeting UPR in both macrophage and cancer cells indicates that PERK or GRP78 reduction enhances macrophage clearance of cancer cells. Recent evidence suggests that macrophage polarization influences immune checkpoint therapy resistance. To determine whether UPR effects immunotherapy resistance, analysis of matched melanoma patient PBMC before/after developing ipilimumab resistance demonstrated increased UPR signaling and an M2-like macrophage population, supporting a novel role of UPR signaling and innate immune regulation in anti-CTLA-4 therapy resistance. These data suggest that targeting GRP78 or PERK promotes an anti tumor immune response by either directly promoting macrophage cytolytic activity or indirectly by shifting tumoral cytokine secretion. PMID- 29113325 TI - Elevated expression of MMP-2 and TIMP-2 cooperatively correlates with risk of lung cancer. AB - Lung cancer is one of the most common form of malignant diseases and the leading cause of cancer-related mortality worldwide. It is reported that approximately two-thirds of lung cancer patients is the presence of advance disease at the time of diagnosis. Hence novel lung cancer diagnostic tests, which can be used to screen individuals at high risk, are required. In the derivation cohort, a total of 88 patients admitted into hospital with suspected lung cancer were included. Bronchial alveolar lavage fluid (BALF) and lung tissue samples were collected from included patients, and were analyzed for MMP-2 and TIMP-2 expression. The results showed a higher level of MMP-2 and TIMP-2 expression and secretion in airways of lung cancer patients than that of benign diseases. A statistically significant correlation was observed between MMP-2 and TIMP-2. In addition, a validation cohort involving 107 patients was conducted to confirm these results. Interesting, BALF MMP-2 and TIMP-2 showed a high sensitivity and specificity in predicting the malignant nature of pulmonary disease in both derivation cohort and validation cohort. The findings in this study suggested that elevated expression of MMP-2 and TIMP-2 cooperatively correlates with risk of lung cancer. Measurement of MMP-2 and TIMP-2 in BALF might be helpful for differential diagnosis of primary lung cancer. PMID- 29113326 TI - Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways. AB - Inflammation is implicated in triple negative breast cancer (TNBC) progression. TNBC carries a worse prognosis than other breast cancer subtypes, and with the clinical and molecular heterogeneity of TNBC, there is a lack of effective therapeutic targets available. Identification of molecular targets for TNBC subtypes is crucial towards personalized patient stratification. Inducible nitric oxide synthase (iNOS) has been shown to induce p53 mutation accumulation, basal like gene signature enrichment and transactivation of the epidermal growth factor receptor (EGFR) via s-nitrosylation. Herein we report that iNOS is associated with disease recurrence, distant metastasis and decreased breast cancer specific survival in 209 cases of TNBC. Employing TNBC cell lines representing normal basal breast, and basal-like 1 and basal-like 2 tumors, we demonstrate that nitric oxide (NO) induces EGFR-dependent ERK phosphorylation in basal-like TNBC cell lines. Moreover NO mediated cell migration and cell invasion was found to be dependent on EGFR and ERK activation particularly in basal-like 2 TBNC cells. This occurred in conjunction with NF-kappaB activation and increased secretion of pro-inflammatory cytokines IL-8, IL-1beta and TNF-alpha. This provides substantial evidence for EGFR as a therapeutic target to be taken into consideration in the treatment of a specific subset of basal-like TNBC overexpressing iNOS. PMID- 29113327 TI - The prevalence of malignant and borderline ovarian cancer in pre- and post menopausal Chinese women. AB - The incidence of ovarian cancer depends on the ethnicity and geographical area. Menopausal status is a well-known risk factor for ovarian cancer and most cases occur after menopause in Caucasians. However, it is less clear how the status of menopause or age at diagnosis is associated with ovarian cancer including its subtypes in Chinese women. Data on 1,283 women with primary malignant or borderline ovarian cancer including age at diagnosis, age at menopause and histology from the largest women's hospital in China was analysed. The median age at diagnosis was 53, 44 and 23 years for epithelial ovarian cancer or sex-cord tumors or germ cell tumors respectively. 58% of epithelial ovarian cancers were diagnosed after menopause, while 58% and 95% of sex-cord tumors and germ cell tumors were diagnosed before menopause. Around 60% of serous, endometrioid and clear-cell carcinoma of epithelial ovarian cancer were diagnosed after menopause, while 23% of mucinous carcinoma was diagnosed after menopause. The median age at diagnosis was 35 years for borderline ovarian cancer and 80% of patients were diagnosed before menopause. Our data demonstrates that the median age at diagnosis of ovarian cancer is younger in our study population than Caucasians reported in the literature regardless of malignant or borderline ovarian cancers, and regardless of subtypes of epithelial ovarian cancer. The prevalence of ovarian cancer is proportionately higher in our study population before menopause than Caucasians. Our results suggest clinicians to be more aware of the symptoms of ovarian cancer in premenopausal Chinese women. PMID- 29113328 TI - Diabetes and risk of Kaposi's sarcoma: effects of high glucose on reactivation and infection of Kaposi's sarcoma-associated herpesvirus. AB - Patients with diabetes are generally prone to pathogen infection and tumor progression. Here, we investigated the potential association between diabetes and Kaposi's sarcoma (KS), a tumor linked to infection with Kaposi's sarcoma associated herpesvirus (KSHV). By using Taiwan's National Health Insurance Research Database, we found that diabetes is statistically associated with increased risk of KS in a case-control study. Since a high level of blood sugar is the hallmark of diabetes, we determined whether high glucose promotes both KSHV reactivation and infection, which are crucial for KS pathogenesis. Our results showed that high glucose significantly increases lytic reactivation of KSHV but not Epstein-Barr virus, another related human oncogenic gammaherpesvirus, in latently infected cells. Activation of the transcription factor AP1 by high glucose is critically required for the onset of KSHV lytic reactivation. We also demonstrated that high glucose enhances susceptibility of various target cells to KSHV infection. Particularly, in endothelial and epithelial cells, levels of specific cellular receptors for KSHV entry, including integrin alpha3beta1 and xCT/CD98, are elevated under high glucose conditions, which correlate with the enhanced cell susceptibility to infection. Taken together, our studies implicate that the high-glucose microenvironment may be an important predisposing factor for KS development. PMID- 29113329 TI - The clock gene, brain and muscle Arnt-like 1, regulates autophagy in high glucose induced cardiomyocyte injury. AB - High-glucose-induced cardiomyocyte injury is the major cause of diabetic cardiomyopathy, but its regulatory mechanisms are not fully understood. Here, we report that a circadian clock gene, brain and muscle Arnt-like 1 (Bmal1), increases autophagy in high-glucose-induced cardiomyocyte injury. We constructed a hyperglycemia model with cultured cardiomyocytes from neonatal rats. High glucose-induced inhibition of autophagy and cardiomyocyte injury were attenuated by Bmal1 overexpression and aggravated by its knockdown. Furthermore, autophagy stabilization by 3-methyladenine or rapamycin partially suppressed the effects of altered Bmal1 expression on cardiomyocyte survival. Mechanistically, Bmal1 mediated resistance to high-glucose-induced inhibition of autophagy at least partly by inhibiting mTOR signaling activity. Collectively, our findings suggest that the clock gene Bmal1 is a positive regulator of autophagy through the mTOR signaling pathway and protects cardiomyocytes against high-glucose toxicity. PMID- 29113330 TI - Flow cytometric analysis of CD64 expression pattern and density in the diagnosis of acute promyelocytic leukemia: a multi-center study in Shanghai, China. AB - No unified immunophenotypic profiles and corresponding analytic strategies have been established for the rapid diagnosis of acute promyelocytic leukemia (APL) using flow cytometry (FCM). Here we describe a characteristic immunophenotypic panel that can rapidly and accurately distinguish APL from other types of adult acute myeloid leukemia (AML) using only FCM. By comparing APL cells and non-APL AML cells that share APL common immunophenotypes (CD34-CD117+HLA-DR-) we found that CD64 was a significant factor that differentiated APL from other AMLs. Further retrospective analyses of 205 APL and 629 non-APL AML patients from different hematology centers showed that either the CD64dim and homoCD13+homo CD33+homoMPO+ (myeloperoxidase) CD11c- panel or the CD64dim and homoCD13+homo CD33+homoMPO+ CD11c+CD10-CD117+ SSChigh (high side scatter signal) panel could distinguish APL from non-APL AML patients with nearly 100% sensitivity, specificity and accuracy. Moreover, relative quantification of CD64 expression enhanced the applicability of our APL diagnostic immunophenotypic panels (ADI panels) in different hematology centers. Application of the ADI-panels will decrease diagnosis time and improve personalized treatment for APL, a life threatening disease with very rapid progression. PMID- 29113332 TI - LncRNAs downregulated in childhood acute lymphoblastic leukemia modulate apoptosis, cell migration, and DNA damage response. AB - Childhood acute lymphoblastic leukemia (cALL) accounts for 25% of pediatric cancers and is one of the leading causes of disease-related death in children. Although long non-coding RNAs (lncRNAs) have been implicated in cALL etiology, progression, and treatment response, little is known about their exact functional role. We had previously sequenced the whole transcriptome of 56 cALL patients and identified lncRNA transcripts specifically silenced in tumoral cells. Here we investigated the impact of restoring the expression of three of these (RP11 624C23.1, RP11-203E8, and RP11-446E9) in leukemic cell lines had dramatic impact on cancer hallmark cellular phenotypes such as apoptosis, cell proliferation and migration, and DNA damage response. Interestingly, both RP11-624C23.1 and RP11 203E8 had very similar impacts on DNA damage response, specifically displaying lower gamma-H2A.X and higher apoptosis levels than control cells in response to genotoxic stress. These results indicate that silencing RP11-624C23.1 or RP11 203E8 could provide a selective advantage to leukemic cells by increasing resistance to genotoxic stress, possibly by modulating the DDR pathway. Since genotoxic agents are fundamental parts of antineoplastic treatment, further investigation of the mechanisms these lncRNAs impact would provide novel and interesting avenues for overcoming treatment resistance. PMID- 29113331 TI - Cross-sectional associations between genetic polymorphisms in metabolic enzymes and longer leukocyte telomere length induced by omethoate. AB - Purpose: This study aimed to explore the effects of genetic polymorphisms in metabolic enzymes on relative telomere length changes and explore the mechanism of canceration induced by omethoate. Materials and Methods: 180 long-term omethoate-exposed workers and 115 healthy controls were recruited. Real-time PCR method was applied to determine the relative telomere length in peripheral blood leukocytes DNA, and Six polymorphic loci of GSTT1(+/-), GSTM1(+/-), GSTP1 rs1695, CYP2E1 rs6413432, CYP2E1 rs3813867 and PON2 rs12026 were detected by polymerase chain reaction and restriction fragment length polymorphism method; Multiple linear regression was conducted to explore the effects of omethoate exposure and genetic polymorphisms on the telomere length. Results: The relative telomere lengths in the control group (0.94 [0.76, 1.32]) were significantly shorter than that in the exposure group (1.50 [1.11, 2.57]) (Z = 7.910, P < 0.001). Univariate analysis showed that the relative telomere lengths of the GSTM1-deletion individuals were significantly longer than that of the non - deletion genotype in the control group (Z = 2.911, P = 0.004), and the relative telomere lengths of GSTP1 rs1695 polymorphism locus (GG+AG) genotype individuals were longer than that of AA genotype in the exposure group. The difference was statistically significant (Z = 2.262, P = 0.024). Multivariate analysis found that pesticide exposure (b = 0.524, P < 0.001) and GSTM1 polymorphism (b = -0.136, P = 0.029) had an impact on telomere length. Conclusions: The relative telomere lengths of omethoate-exposure workers were longer than that in the control population. Also GSTM1 genetic polymorphism may influence the changes of the telomere length induced by omethoate. PMID- 29113333 TI - Simultaneous silencing of TGF-beta1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis. AB - Excessive skin scars due to elective operations or trauma represent a challenging clinical problem. Pathophysiology of hypertrophic scars entails a prolonged inflammatory and proliferative phase of wound healing. Over expression of TGF beta1 and COX-2 play key regulatory roles of the aberrant fibrogenic responses and proinflammatory mediators. When we silenced TGF-beta1 and COX-2 expression simultaneously in primary human fibroblasts, a marked increase in the apoptotic cell population occurred in contrast to those only treated with either TGF-beta1 or COX-2 siRNA alone. Furthermore, using human hypertrophic scar and skin graft implant models in mice, we observed significant size reductions of the implanted tissues following intra-scar administration of TGF-beta1/COX-2 specific siRNA combination packaged with Histidine Lysine Polymer (HKP). Gene expression analyses of those treated tissues revealed silencing of the target gene along with down regulations of pro-fibrotic factors such as alpha-SMA, hydroxyproline acid, Collagen 1 and Collagen 3. Using TUNEL assay detection, we found that the human fibroblasts in the implanted tissues treated with the TGF-beta1/COX-2siRNAs combination exhibited significant apoptotic activity. Therefore we conclude that a synergistic effect of the TGF-beta1/COX-2siRNAs combination contributed to the size reductions of the hypertrophic scar implants, through activation of fibroblast apoptosis and re-balancing between scar tissue deposition and degradation. PMID- 29113334 TI - Exosomal miR-665 as a novel minimally invasive biomarker for hepatocellular carcinoma diagnosis and prognosis. AB - Recent studies have shown that circulating microRNAs are potential biomarkers for various types of malignancies. The aim of this study was to investigate the feasibility of using serum exosomal microRNAs (miRNAs) as novel serological biomarkers for hepatocellular carcinoma (HCC) diagnosis and prognosis. Exosomes are small membranous vesicles (30-100 nm). Exosomal miR-665 levels in HCC patients were significantly higher than those in healthy subjects (P < 0.05), and exosomal miR-665 levels were significantly upregulated in tumours larger in size (> 5 cm), in tumours with local invasion and in those at an advanced clinical stage (stage III/IV) of HCC (P = 0.0042, 0.0197, and 0.0276, respectively). The survival time of the exosomal miR-665 high-expression group (n = 17) was significantly shorter than that of the low-expression group (n = 13) (P = 0.036). In addition, we found that HCC cell-derived exosomes promoted hepatoma cell proliferation and upregulated the expression level of proteins in the MAPK/ERK pathway in vitro and in vivo. This study suggests that serum exosomal miR-665 may be a novel minimally invasive biomarker for HCC diagnosis and prognosis. PMID- 29113335 TI - Maternal and fetal outcomes of pregnant women with type 1 diabetes, a national population study. AB - Pregnancy in women with type 1 diabetes is associated with poor maternal and neonatal outcomes. However, the risk of these outcomes has never been evaluated in an Asian national population. In this work, we report the maternal and fetal outcomes of pregnant women with type 1 diabetes in Taiwan. A total of 2,350,339 pregnancy records created between 2001 and 2012 were obtained from the National Health Insurance database and analyzed. Here, 630 pregnancy records were identified in women having type 1 diabetes. Compared with pregnant women without type 1 diabetes, pregnant women with the disease showed increased risk of multiple adverse outcomes, including preeclampsia, eclampsia, cesarean delivery, adult respiratory distress syndrome, pulmonary edema, sepsis, chorioamnionitis, pregnancy-related hypertension, puerperal cerebrovascular disorders, acute renal failure, and shock. Fetuses of type 1 diabetic mothers were at increased risk of stillbirth, premature birth, large for gestational age, low birth weight, and low Apgar score. Of the studied endpoints, only preeclampsia showed an improvement in the late period (2011-2012) when compared with the early period (2001-2010). These findings reveal that pregnant women with type 1 diabetes are at significantly increased risk of developing many adverse maternal and fetal outcomes. Therefore, pregnancy outcomes in women with type 1 diabetes should be improved. PMID- 29113336 TI - Asymptomatic hyperuricemia and coronary artery disease in elderly patients without comorbidities. AB - Because many subjects with hyperuricemia have comorbidities, it can be difficult to differentiate the role of hyperuricemia from that of other comorbidities of coronary artery disease (CAD). Subjects aged >= 65 years were enrolled in the study and were available at enrollment and at 5-year follow-up. Subjects were excluded if they were overweight or obese, hypertensive, diabetic, hyperlipidemic, had a pre-existing cardiovascular disease, a history of gout or hyperuricemia on medications, or chronic kidney disease as estimated by a glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2. We used Poisson regression to estimate the hazard ratio (HR) for incident CAD events between hyperuricemic (> 7 mg/dL in men and >= 6 mg/dL in women) and normouricemic subjects. A total of 2,142 subjects without comorbidities (mean age of 70.7 +/- 5.9 years, 1,194 men) were followed for 57.4 +/- 8.9 months. Hyperuricemia was associated with an increased cumulative incidence of incident CAD events (15.0% versus 8.8%, P < 0.001). After adjusting for confounding factors, hyperuricemia independently predicted the risk of incident CAD events (HR=1.71, 95% CI 1.26 2.34). In conclusion, asymptomatic hyperuricemia is a valuable biomarker for predicting the development of incident CAD events. PMID- 29113337 TI - Long noncoding RNA SNHG20 promotes gastric cancer progression by inhibiting p21 expression and regulating the GSK-3beta/ beta-catenin signaling pathway. AB - Recent studies have indicated that long non-coding RNAs (lncRNAs) play important regulatory roles in tumor development and progression. However, the contribution of small nucleolar RNA host gene 20 (SNHG20) to gastric cancer development remains largely unknown. The aim of the study is to investigate the functional significance of SNHG20 involved in gastric cancer (GC) progression. In the study, our results demonstrated that the expression levels of SNHG20 were remarkably up regulated in GC cells. Functionally, SNHG20 promoted the GC MKN45 and BGC-823 cells proliferation and invasion. Furthermore, knockdown of SNHG20 significantly inhibited the epithelial-mesenchymal transition (EMT) in MKN45 and BGC-823 cells, whereas, the overexpression of SNHG20 had the promoting effects. Moreover, we found that overexpression of SNHG20 in MKN45 and BGC-823 cells significantly inhibited the expression of E-cadherin and p21 via binding to EZH2 and regulated the GSK-3beta/beta-catenin signaling pathway. Thus, the results showed that SNHG20 acted as an oncogene in GC and targeting SNHG20 may serve as a therapeutic target for GC. PMID- 29113339 TI - A new model to predict intravenous immunoglobin-resistant Kawasaki disease. AB - Objectives: To clarify the independent risk factors and construct predictive model for intravenous immunoglobin (IVIG)-resistant KD (IVIGRKD). Results: The ratio of male to female in the overall samples was 1.62:1 and the incidence of IVIGR was 17.9%. Multivariate regression analysis showed that the OR (95% CI) values of fever duration >= 7 days, delayed diagnosis, gamma-glutamyl transferase >= 25 U/L, serum sodium <= 135 mmol/L, neutrophil-to-lymphocyte ratio >= 2.8 and platelets <= 350 * 109/L were 2.94 (2.17-4.00), 1.64 (1.07-2.53), 1.38 (1.07 1.79), 1.68 (1.30-2.19), 1.58 (1.22-2.06) and 1.39 (1.08-1.80), respectively. Based on these OR values, a new predictive model was established with an AUC of 0.685, a sensitivity of 60.7% and a specificity of 66.5%, and showed superiority to formerly reported models. Further analysis of patients <= 6 months old gave rise to improved predictions for IVIGRKD with an AUC of 0.746 relative the new model for the total samples. Materials and Methods: A total of 2,126 KD cases were enrolled in this study. Clinical indicators showing significant differences were screened using univariate analysis, and the independent risk factors were further elucidated using multivariate regression analysis. A new model was constructed, and the predictive ability was evaluated with the area under the curve (AUC) value and the sensitivity and specificity by using the receiver operating characteristic (ROC) curve. Conclusions: The new model for predicting IVIGRKD in this study is superior to those reported previously, and further analysis of patients with IVIGRKD younger than 6 months old allowed optimization of the predictive model. PMID- 29113338 TI - MiR-23a modulates X-linked inhibitor of apoptosis-mediated autophagy in human luminal breast cancer cell lines. AB - Autophagy is a conserved multi-step lysosomal process that is induced by diverse stimuli including cellular nutrient deficiency. X-linked inhibitor of apoptosis (XIAP) promotes cell survival and recently has been demonstrated to suppress autophagy. Herein, we examined regulation of XIAP-mediated autophagy in breast cancer cells and determined the underlying molecular mechanism. To investigate this process, autophagy of breast cancer cells was induced by Earle's balanced salt solution (EBSS). We observed discordant expression of XIAP mRNA and protein in the autophagic process induced by EBSS, suggesting XIAP may be regulated at a post-transcriptional level. By scanning several miRNAs potentially targeting XIAP, we observed that forced expression of miR-23a significantly decreased the expression of XIAP and promoted autophagy, wherever down-regulation of miR-23a increased XIAPexpression and suppressed autophagy in breast cancer cells. XIAP was confirmed as a direct target of miR-23a by reporter assay utilizing the 3'UTR of XIAP. In vitro, forced expression of miR-23a promoted autophagy, colony formation, migration and invasion of breast cancer cell by down-regulation of XIAP expression. However, miR-23a inhibited apoptosis of breast cancer cells independent of XIAP. Xenograft models confirmed the effect of miR-23a on expression of XIAP and LC3 and that miR-23a promoted breast cancer cell invasiveness. Therefore, our study demonstrates that miR-23a modulates XIAP mediated autophagy and promotes survival and migration in breast cancer cells and hence provides important new insights into the understanding of the development and progression of breast cancer. PMID- 29113340 TI - Analgecine enhances the anti-tumor response of radiotherapy by increasing apoptosis and cell cycle arrest in non-small cell lung cancer. AB - We investigated whether Analgecine treatment enhanced the antitumor response of radiotherapy in non-small cell lung cancer (NSCLC) cells. Lewis lung carcinoma (LLC) xenograft mice treated with Analgecine plus irradiation showed reduced tumor growth and increased survival. Tumor cell apoptosis was enhanced by Analgecine, based on TUNEL assays. It also increased plasma levels of pro inflammatory cytokines (IL-6, IL-12, and IFN-gamma) and decreased anti inflammatory cytokines (TGFbeta and IL-10), suggesting an enhanced immune response. Analgecine plus irradiation reduced cell viability and colony formation by A549 NSCLC cells. Analgecine treatments also activated apoptotic signaling with increased levels of pro-apoptotic proteins, including cytochrome c, caspase 3, cleaved caspase-3, caspase-9, p53 and Bax, and decreased Bcl2. Analgecine enhanced G2/M phase arrest in A549 cells by decreasing cyclinB1 and CDK1. These observations demonstrate that Analgecine combined with radiotherapy enhances anti tumor responses by inducing apoptosis and cell cycle arrest. Moreover, they suggest possible future clinical application of Analgecine for the treatment of NSCLC. PMID- 29113341 TI - Knockout of toll-like receptor impairs nerve regeneration after a crush injury. AB - Background: Toll-like receptors (TLRs) are involved in the initiation of Schwann cell activation and subsequent recruitment of macrophages for clearance of degenerated myelin and neuronal debris after nerve injury. The present study was designed to investigate the regenerative outcome and expression of myelination related factors in Tlr-knockout mice following a sciatic nerve crush injury. Materials and methods: A standard sciatic nerve crush injury, induced by applying constant pressure to the nerve with a No. 5 jeweler's forceps for 30 s, was performed in C57BL/6, Tlr2-/- , Tlr3-/- , Tlr4-/- , Tlr5-/- , and Tlr7-/- mice. Quantitative histomorphometric analysis of toluidine blue-stained nerve specimens and walking track analysis were performed to evaluate nerve regeneration outcomes. PCR Arrays were used to detect the expression of neurogenesis-related genes of dorsal root ganglia as well as of myelination-related genes of the distal nerve segments. Results: Worse nerve regeneration after nerve crush injury was found in all Tlr-knockout mice than in C57BL/6 mice. Delayed expression of myelin genes and a different expression pattern of myelination-related neurotrophin genes and transcription factors were found in Tlr-knockout mice in comparison to C57BL/6 mice. In these TLR-mediated pathways, insulin-like growth factor 2 and brain-derived neurotrophic factor, as well as early growth response 2 and N-myc downstream-regulated gene 1, were significantly decreased in the early and late stages, respectively, of nerve regeneration after a crush injury. Conclusions: Knockout of Tlr genes decreases the expression of myelination related factors and impairs nerve regeneration after a sciatic nerve crush injury. PMID- 29113342 TI - Overexpression of microRNA-132 enhances the radiosensitivity of cervical cancer cells by down-regulating Bmi-1. AB - We examined the effects of microRNA-132 (miR-132) on Bmi-1 expression and radiosensitivity in HeLa, SiHa, and C33A cervical cancer (CC) cells and 104 CC patients. MiR-132 expression was decreased and Bmi-1 expression was increased in tumor tissues compared to adjacent normal tissues and in radiotherapy-resistant patients compared to radiotherapy-sensitive patients. MiR-132 expression and Bmi 1 mRNA expression were also negatively correlated in tumor tissues. HeLa, SiHa, and C33A cells were divided into blank, miR-132 negative control (NC), miR-132 inhibitor, miR-132 mimics, siBmi-1, and miR-132 inhibitor + siBmi-1 groups, after which expression of miR-132 and Bmi-1, and the interaction between them and cell survival, proliferation, and apoptosis were examined. Bmi-1 was confirmed as a target of miRNA-132. Survival was higher and apoptosis lower in the miR-132 inhibitor group than the blank group after various doses of radiation. By contrast, survival was lower and apoptosis higher in the miRNA-132 mimics and siBmi-1 groups than in the blank group. Moreover, miR-132 expression increased and Bmi-1 mRNA expression decreased in each group at radiation doses of 6 and 8 Gy. Finally, co-administration of radiotherapy and exogenous miR-132 inhibited the growth of HeLa cell transplant-induced tumors in nude mice more effectively than radiotherapy alone. These results suggest overexpression of miR-132 enhances the radiosensitivity of CC cells by down-regulating Bmi-1 and that miR-132 may be a useful new target for the treatment of CC. PMID- 29113343 TI - PP2A mediates apoptosis or autophagic cell death in multiple myeloma cell lines. AB - The crosstalk between apoptosis and autophagy contributes to tumorigenesis and cancer therapy. The process by which BetA (betulinic acid), a naturally occurring triterpenoid, regulates apoptosis and autophagy as a cancer therapy is unclear. In this study, we show for the first time that protein phosphatase 2A (PP2A) acts as a switch to regulate apoptosis and autophagic cell death mediated by BetA. Under normal conditions, caspase-3 is activated by the mitochondrial pathway upon BetA treatment. Activated caspase-3 cleaves the A subunit of PP2A (PP2A/A), resulting in the association of PP2A and Akt. This association inactivates Akt to initiate apoptosis. Overexpression of Bcl-2 attenuates the mitochondrial apoptosis pathway, resulting in caspase-3 inactivation and the dissociation of PP2A and Akt. PP2A isolated from Akt binds with DAPK to induce autophagic cell death. Meanwhile, in vivo tumor experiments have demonstrated that BetA initiates different types of cell death in a myeloma xenograft model. Thus, PP2A can shift myeloma cells from apoptosis to autophagic cell death. These findings have important implications for the therapeutic application of BetA, particularly against apoptosis-resistant cancers. PMID- 29113344 TI - Polysaccharides from Chrysanthemum morifolium Ramat ameliorate colitis rats by modulating the intestinal microbiota community. AB - The gut microflora dysbiosis has been closely related with the inflammatory bowel disease (IBD). In this study, the effect of polysaccharides from Chrysanthemum morifolium Ramat on the gut microbiota was evaluated by ulcerative colitis (UC) rat model. Physiological and pathological analyses suggested that Chrysanthemum polysaccharides possessed notably protective effects on UC in vivo. Based on the Illumina MiSeq platform, 16S rRNA sequencing of the rat colonic contents indicated that the intestinal flora structure remarkably changed in the model rats and the tendency was alleviated to a certain degree by treatment with different dosages of Chrysanthemum polysaccharides. In normal groups, there were more Firmicutes than Bacteroidetes, but this change lost at the pathological state. Following Chrysanthemum polysaccharides, rising Firmicutes/Bacteroidetes ratio was validated. Besides the microbial diversity and the community richness of the UC rats were improved by Chrysanthemum polysaccharides, the composition of intestinal microflora in the model group were also restored after oral administration of Chrysanthemum polysaccharides. The abundance of opportunistic pathogens was decreased (Escherichia, Enterococcus and Prevotella), while the levels of protective bacteria such as Butyricicoccus and Clostridium (butyrate producing bacteria), Lactobacillus and Bifidobacterium (probiotics), Lachnospiraceae and Rikenellaceae elevated in various degrees. Correlation analysis between intestinal flora and biochemical factors suggested that the relative abundance of protective bacteria was positively correlated with the levels of anti-inflammatory cytokines such as IL-4, IL-10 and IL-11, while aggressive bacteria were positively correlated with proinflammatory cytokine such as IL-23,IL-6, IF-17,TNF-alpha,IL-1beta and IFN-gamma. The above results showed that the intestinal flora were closely related to the secretion and expression of cytokines in the body, and they interacted with each other to regulate immune function. Thus, Chrysanthemum polysaccharides could ameliorate ulcerative colitis by fostering beneficial intestinal flora growth, modulating the balance of intestinal microecology and restoring the immune system. PMID- 29113345 TI - Combined targeting of Raf and Mek synergistically inhibits tumorigenesis in triple negative breast cancer model systems. AB - Aberrant Ras-MAPK signaling from receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), is a hallmark of triple negative breast cancer (TNBC); thus providing rationale for targeting the Ras-MAPK pathway. Components of this EGFR/HER2-Ras-Raf-Mek-Erk pathway were co-targeted in the MDA-MB-231 and MDA-MB 468 human TNBC cell lines, and in vitro effects on signaling and cytotoxicity, as well as in vivo effects on xenograft tumor growth and metastasis were assessed. The dual EGFR/HER2 inhibitor lapatinib (LPN) displayed greater cytotoxic potency and MAPK signaling inhibition than the EGFR inhibitor erlotinib, suggesting both EGFR and HER2 contribute to MAPK signaling in this TNBC model. The Raf inhibitor sorafenib (SFN) or the Mek inhibitor U0126 suppressed MAPK signaling to a greater extent than LPN; which correlated with greater cytotoxic potency of SFN, but not U0126. However, U0126 potentiated the cytotoxic efficacy of LPN and SFN in an additive and synergistic manner, respectively. This in-series Raf-Mek co targeting synergy was recapitulated in orthotopic mouse xenografts, where SFN and the Mek inhibitor selumitinib (AZD6244) inhibited primary tumor growth and pulmonary metastasis. Raf and Mek co-inhibition exhibits synergy in TNBC models and represent a promising combination therapy for this aggressive breast cancer type. PMID- 29113346 TI - Study on the status of thyroid function and thyroid nodules in chinese breast cancer patients. AB - We performed a study to investigate the status of thyroid nodules and thyroid functions in Chinese breast cancer women. The clinical data of female patients with breast cancer or benign breast diseases and normal populace were evaluated. The thyroxine(T4) level in initially diagnosed breast cancer patients were significantly higher than those in benign breast diseases patients (7.68+/-1.51 vs 7.29+/-1.52ug/dl, p<0.001), while the TSH levels were slightly lower than in benign breast diseases patients(3.23+/-4.59 vs 3.60+/-6.74uIU/ml, p=0.302). The overall incidence of hypothyroidism in initially diagnosed breast cancer and benign breast diseases patients were 28.65% and 32.74%(p=0.195). During chemotherapy, the T4(7.08+/-1.69ug/dl), fT3(2.87+/-0.48pg/ml) and fT4(0.83+/ 0.15ng/dl) levels were significantly lower than in initially diagnosed breast cancer patients(7.68+/-1.51ug/dl, 3.07+/-0.50pg/ml, 0.88+/-0.20ng/dl, p<0.05). The incidence of thyroid nodules in initially diagnosed breast cancer patients, benign breast diseases patients and healthy population were 56.17%, 43.64%, 34.49%(p<0.001). The incidence of TI-RADS>=4 TN in initially diagnosed breast cancer patients and benign breast diseases patients were significantly higher than in normal population(7.27% vs 9.45% vs 2.87%, p<0.001). The incidence of TI RADS>=4 thyroid nodules in breast cancer patients receiving chemotherapy was significantly higher than in initially diagnosed breast cancer patients(11.71% vs 7.27%, p<0.05). These data indicate that the incidence of thyroid disease in breast disease patients is higher than in normal population in China, and the breast diseases, especially breast cancer, might be related to the high incidence of thyroid nodules. PMID- 29113347 TI - Lunasin functionally enhances LDL uptake via inhibiting PCSK9 and enhancing LDLR expression in vitro and in vivo. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease which regulates serum low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of the hepatic low-density lipoprotein receptor (LDLR), and has become an attractive therapeutic target for cholesterol lowering intervention. Lunasin, a 43-amino acid polypeptide initially isolated from soybean, has been previously proven to possess cholesterol lowering activity. Here we identified the down-regulation of PCSK9 expression by lunasin as one new mechanism that increased cell-surface LDLR level and enhanced LDL uptake in vitro and in vivo. Treatment of HepG2 cells with lunasin inhibited the expression of PCSK9 at mRNA and protein levels in a dose-and-time dependent manner via down-regulating hepatocyte nuclear factor-1alpha (HNF-1alpha), thereby contributing to increasing LDLR level and functionally enhancing LDL uptake. ApoE-/- mice receiving lunasin administration by intraperitoneal injection at doses of 0.125~0.5 MUmol/kg.day for 4 weeks had significantly lower PCSK9 and higher LDLR levels in hepatic tissue, as well as remarkably reduced total-cholesterol (T-CHO) and LDL-C in blood as compared to mice in vehicle control group. Furthermore, we identified that LDLR expression was up-regulated by lunasin via PI3K/Akt-mediated activation of SREBP-2 in HepG2 cells. Taken together, our findings suggest that lunasin inhibits PCSK9 expression by down-regulating HNF-1alpha and enhances LDLR expression via PI3K/Akt-mediated activation of SREBP-2 pathway, thereby functionally enhances LDL uptake in HepG2 cells and in ApoE-/- mice. PMID- 29113348 TI - Sustained-releasing hollow microparticles with dual-anticancer drugs elicit greater shrinkage of tumor spheroids. AB - Polymeric particulate delivery systems are vastly explored for the delivery of chemotherapeutic agents. However, the preparation of polymeric particulate systems with the capability of providing sustained release of two or more drugs is still a challenge. Herein, poly (D, L-lactic-co-glycolic acid, 50:50) hollow microparticles co-loaded with doxorubicin and paclitaxel were developed through double-emulsion solvent evaporation technique. Hollow microparticles were formed through the addition of an osmolyte into the fabrication process. The benefits of hollow over solid microparticles were found to be higher encapsulation efficiency and a more rapid drug release rate. Further modification of the hollow microparticles was accomplished through the introduction of methyl-beta cyclodextrin. With this, a higher encapsulation efficiency of both drugs and an enhanced cumulative release were achieved. Spheroid study further demonstrated that the controlled release of the drugs from the methyl-beta-cyclodextrin loaded hollow microparticles exhibited enhanced tumor regressions of MCF-7 tumor spheroids. Such hollow dual-drug-loaded hollow microparticles with sustained releasing capabilities may have a potential for future applications in cancer therapy. PMID- 29113349 TI - The role of EGFR double minutes in modulating the response of malignant gliomas to radiotherapy. AB - EGFR amplification in cells having double minute chromosomes (DM) is commonly found in glioblastoma multiforme (GBM); however, how much it contributes to the current failure to treat GBM successfully is unknown. We studied two syngeneic primary cultures derived from a GBM with and without cells carrying DM, for their differential molecular and metabolic profiles, in vivo growth patterns, and responses to irradiation (IR). Each cell line has a distinct molecular profile consistent with an invasive "go" (with DM) or angiogenic "grow" phenotype (without DM) demonstrated in vitro and in intracranial xenograft models. Cells with DM were relatively radio-resistant and used higher glycolytic respiration and lower oxidative phosphorylation in comparison to cells without them. The DM containing cell was able to restore tumor heterogeneity by mis-segregation of the DM-chromosomes, giving rise to cell subpopulations without them. As a response to IR, DM-containing cells switched their respiration from glycolic metabolism to oxidative phosphorylation and shifted molecular profiles towards that of cells without DM. Irradiated cells with DM showed the capacity to alter their extracellular microenvironment to not only promote invasiveness of the surrounding cells, regardless of DM status, but also to create a pro-angiogenic tumor microenvironment. IR of cells without DM was found primarily to increase extracellular MMP2 activity. Overall, our data suggest that the DM-containing cells of GBM are responsible for tumor recurrence due to their high invasiveness and radio-resistance and the mis-segregation of their DM chromosomes, to give rise to fast-growing cells lacking DM chromosomes. PMID- 29113350 TI - BRCA1 and STMN1 as prognostic markers in NSCLCs who received cisplatin-based adjuvant chemotherapy. AB - Objective: In this study, we aimed to investigate the predictive effect of BRCA1, STMN1, MAPT and TUBB3 on the prognosis of patients with non-small cell lung cancer (NSCLC). Methods: Seventy NSCLC patients who received platinum-based chemotherapy from June 2009 to July 2011 were enrolled. The protein and mRNA levels of BRCA1, STMN1, MAPT and TUBB3 were determined. Survival time of the patients with NSCLC was also calculated. Results: High expression of BRCA1 or low expression of STMN1 was associated with a better prognosis in NSCLC patients (p<0.01). In contrast, the expression of MAPT and TUBB3 were not closely related with the prognosis of NSCLC patients(p>0.05). Furthermore, patients with high expression of BRCA1 and low expression of STMN1 have lived longer (p<0.01). Conclusion: BRCA1 and STMN1 were independently predictors for prognosis of NSCLCs which received cisplatin-based adjuvant chemotherapy. PMID- 29113351 TI - B7-H4 overexpression is essential for early hepatocellular carcinoma progression and recurrence. AB - B7-H4, another member of costimulatory molecule, has been shown to be overexpressed in multiple types of tumors, including hepatocellular carcinoma (HCC). However, the specific biological role of B7-H4 in HCC still needs to be further explored. In this study, we observed that B7-H4 was highly overexpressed in HCC tissues and cells, and its overexpression strongly correlated with patient's TNM stage, overall survival and early recurrence. Downregulation of B7 H4 significantly suppressed cell growth, invasion, and stemness of HCC by inducing apoptosis in the in vitro experiment. In addition, depletion of B7-H4 could help restore CD8+ T anti-tumor immunity by elevating the expression and secretion levels of CD107a, granzyme A, granzyme B, perforin and IFN-gamma. In a xenografted mouse model of HCC, stable depletion of B7-H4 resulted in significantly smaller mean tumor volume and less mean tumor weight after 30 days of growth, compared to the control group. Together, our results provide insights into the diverse functions of B7-H4 involved in the pathogenesis, recurrence and anti-tumor immunity of HCC, indicating B7-H4 as a novel and effective approach for future treatment strategies that benefits anticancer therapy. PMID- 29113352 TI - Genetic polymorphisms in cyclin D1 are associated with risk of renal cell cancer in the Chinese population. AB - Recently, the functional polymorphisms in Cyclin D1 (CCND1) have been shown the potential influence to risk of renal cell cancer (RCC). Therefore, the present study was performed to investigate whether these polymorphisms could influence the susceptibility of RCC. Four potentially functional polymorphisms in CCND1 (rs1944129, rs7177, rs9344 and rs678653) were genotyped in this hospital-based case-control study, comprising of 1,488 RCC patients and 1,677 cancer-free controls in a Chinese population by the TaqMan assay. The logistic regression was used to assess the associations between CCND1 polymorphisms and the risk of RCC. We found the genotype and allele frequency distribution of rs1944129 and rs7177 were significantly associated with risk of RCC (P = 0.015 and P = 0.018, respectively). The analysis of combined risk alleles revealed that patients with 2-4 risk alleles showed an elevated risk of RCC compared to those with 0-1 risk alleles (OR = 1.35, 95% CI = 1.15 - 1.58, P < 0.001). Furthermore, compared with the genotypes containing G allele (AG and GG), the patients carrying the AA genotype in CCND1 rs1944129 polymorphism had a significantly greater prevalence of high clinical stage disease (OR = 0.56, 95% CI = 0.33 - 0.94, P = 0.029). These results suggested that these CCND1 polymorphisms rs1944129 and rs7177 might contribute to the susceptibility of RCC in the Chinese population. PMID- 29113353 TI - Berberine-targeted miR-21 chemosensitizes oral carcinomas stem cells. AB - Cancer recurrence and chemoresistance are two major obstacles to the treatment of oral squamous cell carcinomas (OSCC). And cancer stem cells (CSCs) have been found to possess tumor initiating, self-renewal and metastasis abilities, resulting in the relapse and chemoresistance of OSCC. In the present study, we investigated the anti-CSCs effect of berberine, a phenanthrene alkaloid isolated from the Berberis genus. Our results demonstrated that berberine dose dependently downregulated the oncogenicity in vitro, including ALDH1 activity, self-renewal property, and colony formation and invasion abilities as well as potentiated chemosensitivity of OSCC-CSCs. In addition, tumor growth in mice was attenuated after oral gavage treatment of berberine. We showed that the expression of miR-21 was suppressed following administration of berberine in OSCC-CSCs. And inhibition of endogenous miR-21 reduced the characteristics of CSCs, including self-renewal, migration, invasion capabilities and ALDH1 activity. Taken together, we demonstrated the anti-CSC effect of berberine in oral cancer and its potential to serve as adjuvant to traditional chemotherapy to improve treatment effect. PMID- 29113355 TI - Association between body mass index (BMI) and vital capacity of college students of Zhuang nationality in China: a cross-section study. AB - Objective: Our study is to evaluate the association between body mass index (BMI) and vital capacity of college students of Zhuang Nationality in China. Methods: 463 college students of Zhuang Nationality from Guangxi Medical University were selected. Basic information, body composition and vital capacity of college students were measured. According to the level of BMI, college students were divided into four groups (BMI<18.5, 18.5<=BMI<23.9, 23.9<=BMI<27.9 and BMI>=27.9). Multivariate logistic regression analysis was performed to assess the association between BMI and vital capacity. Results: In male college students, there was no significant difference in vital capacity between the four groups (3029.54+/-869.25, 3347.06+/-784.54, 3540.00+/-805.35 and 3966.50+/-350.2, P=0.0727, respectively). Multivariate regression analysis showed that after adjusting for confounding factors, no significant association was observed between BMI and vital capacity (OR=115.02, 95% CI: -555.58~785.63; OR=-166.58, 95% CI: -1684.56~1351.41; OR=-484.01, 95% CI:-3504.53, 2536.51, respectively. BMI<18.5 group served as reference group). In female college students, there was also no significant difference in vital capacity between the four groups (2455.15+/-574.4, 2555.06+/-637.03, 2750.33+/-1224.05 and 2473.00+/-159.06, P=0.4011, respectively). Multivariate regression analysis showed that after adjusting for confounding factors, no significant association was observed between BMI and vital capacity (OR=-88.88, 95% CI: -333.59~155.84; OR=20.00, 95% CI: -694.39~734.39; OR=2.86, 95% CI: -1830.58, 1836.3, respectively. BMI<18.5 group served as reference group). Conclusion: There was no evidence that BMI is associated with vital capacity in college students of Zhuang Nationality. PMID- 29113354 TI - 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 spatially mediates autophagy through the AMPK signaling pathway. AB - 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), is a critical enzyme for glycolysis and highly expressed in cancer cells. It plays an essential role in regulating metabolism, angiogenesis, and inflammation. Although PFKFB3 is involved in modulating autophagy, its regulatory role appears to be either positive or negative, which remains to be clarified. Unlike other PFK 2/FBPase isoforms, PFKFB3 can localize in both nucleus and cytoplasm, leading to the speculation that subcellular localization of PFKFB3 may play a regulatory role in autophagy. Here, we found that either a PFKFB3 inhibitor or PFKFB3 silencing by siRNA, suppressed the basal and the H2O2-induced autophagy concomitantly with the inhibition of AMPK activity. While overexpression of the wild type PFKFB3 promoted the H2O2-induced autophagy, the K472/473A mutated PFKFB3, which lost nuclear localizing property, inhibited the autophagic process. Although the K472/473A mutated PFKFB3 stimulated more lactate production, it decreased the activity of AMPK compared to the wild type PFKFB3. Moreover, PFKFB3 similarly regulates the autophagy induced by rasfonin, a fungal secondary metabolite that downregulates the activity of AMPK. Compound C, a widely used AMPK inhibitor, induced the autophagic process but reduced the H2O2-dependent autophagy. Collectively, the data demonstrated that PFKFB3 localizing in nucleus is essential for its regulatory role in autophagy, and PFKFB3 at least positively regulated the H2O2-induced autophagy through the AMPK signaling pathway, which likely played dual roles in the process. PMID- 29113356 TI - Prediction of thyroidal 131I effective half-life in patients with Graves' disease. AB - Purpose: Calculation of effective thyroidal half-life (Teff) of iodine-131(131I) is cumbersome and tedious. The aim of this study was to investigate factors that could be used to predict Teff and to develop a Teff prediction model in Graves' disease patients. Methods: A total of 256 patients with GD were involved in this study. We investigated the influences of age, gender, disease duration, thyroid weight, antithyroid drugs, antithyroid drugs discontinuation period (ADP), thyroid function indexes, thyroid autoantibodies, thyroid-stimulating hormone receptor antibody (TRAb) level and radioactive iodine uptake (RAIU) values before 131I therapy on Teff, applying univariate and multivariate analyses. Results: Teff correlated negatively with thyroid peroxidase antibody, TRAb and thyroid weight, as well as positively with 24-hour, 48-hour, and 72-hour RAIU. Additionally, a longer ADP (especially>= 14d) or without antithyroid drugs before 131I therapy led to a longer Teff. Stepwise multiple linear regression analysis showed that 24-hour and 72-hour RAIU were statistically significant predictors of Teff (P<0.001). The relationship was: predictive Teff=5.277+0.295*72-hour RAIU 0.217*24-hour RAIU (r =0.865, P < 0.001). Conclusion: The present results indicate that prediction of Teff from 24-hour and 72-hour RAIU is feasible in patients with Graves' disease, with high prediction accuracy. PMID- 29113357 TI - Brain gray matter abnormalities in progressive supranuclear palsy revisited. AB - Whole-brain voxel-based morphometry (VBM) studies of progressive supranuclear palsy (PSP) have demonstrated heterogeneous findings regarding gray matter (GM) abnormalities. Here, we used Seed-based d Mapping, a coordinate-based meta analytic approach to identify consistent regions of GM anomalies across studies of PSP. Totally, 18 original VBM studies, comprising 284 patients with PSP and 367 healthy controls were included. As compared to healthy controls, patients with PSP demonstrated significant GM reductions in both cortical and subcortical regions, including the frontal motor cortices, medial (including anterior cingulate cortex) and lateral frontal cortices, insula, superior temporal gyrus, striatum (putamen and caudate nucleus), thalamus, midbrain, and anterior cerebellum. Our study further suggests that many confounding factors, such as age, male ratio, motor severity, cognitive impairment severity, and illness duration of PSP patients, and scanner field-strength, could contribute to the heterogeneity of GM alterations in PSP across studies. Our comprehensive meta analysis demonstrates a specific neuroanatomical pattern of GM atrophy in PSP with the involvement of the cortical-subcortical circuitries that mediate vertical supranuclear gaze palsy, motor disabilities (postural instability with falls and parkinsonism), and cognitive-behavioral disturbances. Confounding factors merit attention in future studies. PMID- 29113358 TI - Down-regulation of CHERP inhibits neuroblastoma cell proliferation and induces apoptosis through ER stress induction. AB - Neuroblastoma is a childhood tumor that is derived from the sympathetic nervous system. In recent years, great progress has been made in our understanding of neuroblastoma. However, applying theories to improve disease outcomes remains challenging. In this study, we observed that calcium homeostasis endoplasmic reticulum protein (CHERP) was involved in the maintenance of neuroblastoma cell proliferation and tumorigenicity. Moreover, elevated CHERP expression was positively correlated with poor patient survival, whereas low CHERP expression was predictive of better outcomes. Additional functional studies showed that CHERP knockdown inhibited neuroblastoma cell proliferation in vitro and resulted in defective tumorigenicity in vivo. Moreover, CHERP depletion suppressed neuroblastoma cell proliferation by inducing endoplasmic reticulum stress and cell apoptosis. Considering the functional roles of CHERP in neuroblastoma development and maintenance, CHERP might function as a novel therapeutic target for neuroblastoma patients. PMID- 29113359 TI - Hepatointestinal complications in polycystic kidney disease. AB - Background: The objective of this study was to determine the incidence of major hepatointestinal complications in patients with polycystic kidney disease (PKD). Methods: We analyzed the Taiwan National Health Insurance claims data (2000-2010) of 6031 patients with PKD and 23,976 non-PKD hospitalized controls. The control cohort was propensity score matched with the PKD cohort at a 1:4 ratio. All patients were followed up from the index date to the first inpatient diagnosis of hepatointestinal complications, death, or 31 December, 2011. Cox proportional hazard regression models were used to identify the risk of outcome after adjustment for potential confounders. Results: The incidence rates of acute pancreatitis, cholangitis, peptic ulcer bleeding, and cirrhosis were 5.72, 4.01, 19.9, and 5.46 per 1000 person-years, respectively, in the PKD cohort. Compared with the non-PKD controls, patients with PKD exhibited an increased risk of hospitalization for acute pancreatitis, cholangitis, peptic ulcer bleeding, and cirrhosis (adjusted subhazard ratio [aSHR]: 2.36, 95% confidence interval [95% CI], 1.95-2.84]; 2.36, [95% CI, 1.95-2.84]; 2.41, [95% CI, 1.93-3.01]; 2.41, [95% CI, 2.17-2.67]; and 1.39, [95% CI, 1.16-1.66], respectively; all p < 0.001). PKD, chronic kidney disease, and alcoholism were independent predictors of all these hepatointestinal complications. Kaplan-Meier analysis revealed an increased overall mortality in patients with PKD who developed acute pancreatitis and peptic ulcer bleeding (log-rank p < 0.05). Conclusion: PKD is associated with clinically significant extrarenal complications including acute pancreatitis, cholangitis, peptic ulcer bleeding, and cirrhosis. PMID- 29113360 TI - microRNA-488 inhibits chemoresistance of ovarian cancer cells by targeting Six1 and mitochondrial function. AB - Dysregulation of miR-488 has been implicated in several human cancers. In this study, we aim to explore its expression and biological function in ovarian cancers. We found miR-488 expression was downregulated in ovarian cancer tissues. Using CCK8 and colony formation assay showed that miR-488 inhibited SKOV3 cell proliferation and colony formation, with downregulation of cyclin D1 and cyclin E protein. While miR-488 inhibitor promoted OVCAR3 cell growth and colony formation. Cell viability and Annexin V/PI staining showed that miR-488 downregulated cell survival and increased apoptosis rate when treated with cisplatin and paclitaxel. Further experiments using MitoTracker and JC-1 staining indicated that miR-488 regulated mitochondrial fission/fusion balance and inhibited mitochondrial membrane potential, with p-Drp1, Drp1 and Fis1 downregulation. Luciferase reporter assay showed that Six1 is a target of miR 488. We also found a negative association between Six1 and miR-488 in ovarian cancer tissues. In addition, Six1 overexpression induced mitochondrial fission and increased mitochondrial potential, with upregulation of Drp1 signaling. Six1 depletion showed the opposite effects. Restoration of Six1 in SKOV3 cells rescued decreased p-Drp1 and Drp1 expression induced by miR-488 mimic. Six1 plasmid also reversed the effects of miR-488 on chemoresistance and apoptosis. Taken together, the present study showed that, by targeting Six1, miR-488 inhibits chemoresistance of ovarian cancer cells through regulation of mitochondrial function. PMID- 29113361 TI - A case-control study on association of nucleotide excision repair polymorphisms and its interaction with environment factors with the susceptibility to non melanoma skin cancer. AB - Aims: To investigate the association of several single nucleotide polymorphisms (SNPs) within nucleotide excision repair (NER) gene and additional gene- gene and gene- smoking interaction with non-melanoma skin cancer (NMSC) risk in a Chinese population. Methods: A total of 1322 participants (939 males, 383 females) were selected, including 660 NMSC patients and 662 control participants. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Logistic regression was performed to investigate association between 4 SNPs within NER gene, additional gene- gene and gene- smoking interaction on NMSC risk. Results: NMSC risk was significantly higher in carriers with G allele of rs2228527 than those with AA genotype (AG + GG versus AA), adjusted OR (95%CI) =1.76 (1.24-2.37), and higher in carriers with the G allele of rs2228529 than those with AA genotype (AG + GG versus AA), adjusted OR (95%CI) = 1.66 (1.24-2.13). However, we did not find any direct association of the rs4134822 and rs1799793 with NMSC risk after covariates adjustment. GMDR model indicated a significant interaction combination (p=0.0010), including rs2228529 and current smoking. Overall, the cross validation consistency of this model was 9/ 10, and the testing accuracy was 60.72%. Current smokers with rs2228529- GA or GG genotype have the highest NMSC risk, compared to never- smokers with rs2228529- AA genotype, OR (95%CI) = 2.92 (1.61-4.29). Conclusions: We found that the G allele of rs2228527 and the G allele of rs2228529 within NER gene, interaction between rs2228529 and current smoking were all associated with increased NMSC risk. PMID- 29113362 TI - PLGA nanoparticles modified with a BBB-penetrating peptide co-delivering Abeta generation inhibitor and curcumin attenuate memory deficits and neuropathology in Alzheimer's disease mice. AB - Alzheimer's disease (AD) is the most common form of dementia, characterized by the formation of extracellular senile plaques and neuronal loss caused by amyloid beta (Abeta) aggregates in the brains of AD patients. Conventional strategies failed to treat AD in clinical trials, partly due to the poor solubility, low bioavailability and ineffectiveness of the tested drugs to cross the blood-brain barrier (BBB). Moreover, AD is a complex, multifactorial neurodegenerative disease; one-target strategies may be insufficient to prevent the processes of AD. Here, we designed novel kind of poly(lactide-co-glycolic acid) (PLGA) nanoparticles by loading with Abeta generation inhibitor S1 (PQVGHL peptide) and curcumin to target the detrimental factors in AD development and by conjugating with brain targeting peptide CRT (cyclic CRTIGPSVC peptide), an iron-mimic peptide that targets transferrin receptor (TfR), to improve BBB penetration. The average particle size of drug-loaded PLGA nanoparticles and CRT-conjugated PLGA nanoparticles were 128.6 nm and 139.8 nm, respectively. The results of Y-maze and new object recognition test demonstrated that our PLGA nanoparticles significantly improved the spatial memory and recognition in transgenic AD mice. Moreover, PLGA nanoparticles remarkably decreased the level of Abeta, reactive oxygen species (ROS), TNF-alpha and IL-6, and enhanced the activities of super oxide dismutase (SOD) and synapse numbers in the AD mouse brains. Compared with other PLGA nanoparticles, CRT peptide modified-PLGA nanoparticles co-delivering S1 and curcumin exhibited most beneficial effect on the treatment of AD mice, suggesting that conjugated CRT peptide, and encapsulated S1 and curcumin exerted their corresponding functions for the treatment. PMID- 29113363 TI - Involvement of inducible nitric oxide synthase and mitochondrial dysfunction in the pathogenesis of enterovirus 71 infection. AB - Enterovirus71 (EV71) is recognized as the main causative agent of severe hand, foot and mouth disease (HFMD). However, the pathogenesis of EV71 infection has not been well characterized. Clinical evidence indicated that inducible nitric oxide synthase (iNOS) induction in the lung of HFMD patients contributes to the severe symptoms of pulmonary edema. In the present study, we recruited 142 subjects including HFMD patients and controls, and serum level of nitric oxide (NO) was determined. Next, cellular and animal model were used to further investigate the roles of iNOS and mitochondria damage during EV71 infection. Serum NO level in HFMD patients with mild or severe symptoms was higher than that in controls, and there was a trend towards an increase in the serum NO level of severe cases relative to mild cases. EV71 infection caused apoptosis and increased levels of NO, iNOS, superoxide dismutase (SOD) activity and malondialdehyde (MDA), and degraded mitochondrial membrane potential (DeltaPsim) in vitro. Pathological alterations of mitochondrial morphology were observed in vitro and in vivo. Furthermore, the expression of iNOS levels in target organs including brain, spinal cord, skeletal muscle, lung and heart were increased with the progression of the pathogenesis of EV71 infection in mice. Taken together, iNOS and mitochondrial damage participate in the pathogenesis of EV71 infection. PMID- 29113364 TI - Alpha-glucosidase inhibitors and risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis. AB - Several studies have shown that anti-diabetic medications may modify the risk of cancer. We performed a systematic review and meta-analysis to evaluate the effect of alpha-glucosidase inhibitors (AGIs) on the risk of cancer in patients with diabetes mellitus. We conducted a systematic search of Medline, EMBASE, and Web of Science databases, up to September 30, 2016. Random-effects model was used to estimate the summary odds ratios (ORs) with 95% CI. Twenty-five studies (14 cohort, 7 case-control, and 4 randomized controlled trials) involving 1,285,433 patients with diabetes were included. Meta-analysis of observational studies showed that the use of AGIs was associated with a lower risk of developing cancer (OR = 0.86, 95% CI 0.78-0.96), especially gastrointestinal cancer (OR = 0.83, 95% CI 0.71-0.97). There was considerable heterogeneity across the studies introduced partly by the quality of included studies and adjustment for potential confounders. Meta-analysis of randomized controlled trials did not reveal any significant association between AGIs and cancer risk. Meta-analysis of observational studies indicated that AGIs may decrease the risk of cancer in individuals with diabetes. PMID- 29113365 TI - Meta-analysis of the correlation between vitamin D and lung cancer risk and outcomes. AB - In this meta-analysis, we analyzed the association between vitamin D levels and lung carcinoma risk and outcomes. Two authors independently searched the Web of Science, Pubmed, EBSCO and Ovid MEDLINE resources with the key words "vitamin D, lung cancer, solar and latitude" and enrolled 22 studies that satisfied the inclusion criteria. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the random (or fixed)-effects model. Potential confounders were carefully adjusted. High vitamin D (or calcium) intake and serum 25(OH)D levels each correlated inversely with lung cancer risk [OR = 0.72 (95% CI: 0.61-0.85, p < 0.001) and OR = 0.89 (95% CI: 0.83-0.97, p < 0.05)]. High circulating 25(OH)D levels also reduced lung cancer mortality with the pooled OR reached 0.39 (95% CI: 0.28-0.54, p < 0.001)]. A positive trend was presented in the relationship between serum 25(OH) D and survival (OR = 1.01, 95% CI: 0.87 1.18, p = 0.87). Subgroup analysis revealed that nonsmokers had higher vitamin D levels, which correlated negatively with lung cancer risk (OR = 0.76, 95% CI: 0.65-0.88, p < 0.01). Moreover, lower sun exposure and high latitude associated with lower vitamin D levels. This meta-analysis shows that high vitamin D (or calcium) intake and serum 25(OH)D levels correlate with lower lung cancer risk and better prognosis. UVB and latitude may play a vital role in lung cancer occurrence and progression, although a direct evidence hasn't been obtained. PMID- 29113366 TI - E-cadherin expression as a prognostic factor in patients with ovarian cancer: a meta-analysis. AB - The prognostic role of epithelial cadherin (E-cadherin) downregulation in ovarian cancer has been assessed for years while the results remain inconclusive. The aim of our study was to assess this issue. Eligible studies were identified through searches of PubMed, EMBASE and Cochrane Database. In total, 1562 patients from 17 studies were included to assess the association between E-cadherin expression and overall survival/progression-free survival and clinicopathological characteristics of ovarian cancer patients. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the effect. The quality of 17 studies was evaluated using the Newcastle Ottawa Quality Assessment Scale. We also performed subgroup analysis, publication bias and sensitivity analysis in this meta-analysis. The results showed that negative E-cadherin expression significantly predicted poor overall survival of ovarian cancer patients (HR = 1.90, 95% CI = 1.50-2.40). However, negative E-cadherin was not associated with poor progression-free survival (HR = 1.19, 95% CI = 0.86 1.64). Moreover, Negative E-cadherin expression was distinctly associated with FIGO stage (OR = 0.42, 95% CI = 0.31-0.57), tumor grade (OR = 0.48, 95% CI = 0.34 0.67), metastasis (OR = 0.13, 95% CI = 0.07-0.26) and recurrence (OR = 0.48, 95% CI = 0.29-0.79). This meta-analysis revealed that negative E-cadherin expression might be a predicative factor of poor prognosis in ovarian cancer patients. PMID- 29113367 TI - MicroRNAs with prognostic significance in osteosarcoma: a systemic review and meta-analysis. AB - Introduction: This study aimed to elucidate the prognostic value of microRNAs (miRNAs) in patients with osteosarcoma. Materials and Methods: Studies were recruited by searching PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang data-bases (final search update conducted January 2017). Eligible studies were identified and the quality was assessed using multiple search strategies. Results: A total of 55 articles that investigated the correlation between miRNA expression and either patient survival or disease recurrence in osteosarcoma was initially identified. Among these, 30 studies were included in the meta-analysis. The results of our meta-analysis revealed that elevated levels of miR-21, miR-214, miR-29, miR-9 and miR-148a were associated with poor prognosis in osteosarcoma. Additionally, downregulated miR 382, miR26a, miR-126, miR-195 and miR-124 expression indicated poor prognosis in osteosarcoma. Conclusions: miRNAs may act as independent prognostic factors in patients with osteosarcoma and are useful in stratifying risk. PMID- 29113368 TI - Antibiotic prophylaxis for infections in patients with acute stroke: a systematic review and meta-analysis of randomized controlled trials. AB - Objective: Infections are frequent after stroke and lead to increased mortality and neurological disability. Antibiotic prophylaxis has potential of decreasing the risk of infections and mortality and improving poor functional outcome. Several studies evaluated antibiotic prophylaxis for infections in acute stroke patients have generated conflicting results. The systematic review of randomized clinical trials (RCTs) aimed at comprehensively assessing the evidence of antibiotic prophylaxis for the treatment of acute stroke patients. Materials and Methods: PubMed, EMBASE, the Cochrane library and the reference lists of eligible articles were searched to identify all potential studies. We included the studies that investigated the efficacy and safety of antibiotic prophylaxis for the treatment of acute stroke patients. The primary outcome included mortality and infection rate. The secondary outcomes included poor functional outcome and adverse events. Results: Seven trials randomizing 4,261 patients were included. Pooled analyses showed that antibiotic prophylaxis did not improve the mortality (risk ratio (RR) = 1.03, 95% confidence interval (CI) 0.84 to 1.26, p = 0.78, I2 = 25%) and poor functional outcome (RR = 0.93, 95% CI 0.80 to 1.08, p = 0.32, I2 = 80%), but reduced the incidence of infection (RR = 0.67, 95% CI 0.53 to 0.84, p = 0.0007, I2 = 49%). No major side effects were reported. Sensitivity analyses confirmed the results of infection rate and poor functional outcome. Conclusions: Antibiotic prophylaxis can be used to treat the infectious events of acute stroke patients although it has no potential of decreased mortality and improved functional outcome. PMID- 29113369 TI - Prognostic role of Gli1 expression in breast cancer: a meta-analysis. AB - Glioma-associated oncogene 1 (Gli1) is a critical transcriptional factor of Sonic hedgehog pathway which has been proved to participate in the initiation and progression of tumor in mammalians. However, its clinical value in breast cancer remains unknown. Thus, a meta-analysis was performed to clarify the association of Gli1 over-expression, clinic-pathological characteristics, molecular subtypes and prognosis in breast cancer. According to included criteria, 13 eligible studies containing 2816 patients all around the world were selected in this study. Our results indicated no significant association of Gli1 expression and histological grade (RR = 1.20, 95% CI: [0.98, 1.47]), T stage (RR = 1.05, 95% CI: [0.87, 1.27]), clinical stage (RR = 1.04, 95% CI: [0.93, 1.18]) and lymph node metastasis (RR = 1.12, 95% CI: [0.92, 1.37]). In addition, pooled RR showed no correlation of Gli1 expression and progesterone receptor (PR) (RR = 0.92, 95% CI: [0.70, 1.21]), estrogen receptor (ER) (RR = 1.03, 95% CI: [0.74, 1.42]), human epidermal growth factor receptor 2 (HER-2) (RR = 1.12, 95% CI: [0.90, 1.39]). Nonetheless, up-regulated Gli1 expression predicts shorter disease-free survival (DFS) (HR = 1.38, 95% CI: [1.05, 1.81]), 3-year survival (HR = 1.74, 95% CI: [1.28, 2.36]), 5-year survival (HR = 2.04, 95% CI: [1.62, 2.57]) and overall survival (OS) (HR = 2.05, 95% CI: [1.60, 2.64]). In conclusion, over-expression of Gli1 tends to progressive stages and is related to unfavorable prognosis of breast cancer, which may become a potential prognosis indicator and therapy target in breast cancer. PMID- 29113370 TI - Serum insulin-like growth factor-1 and its binding protein 3 as prognostic factors for the incidence, progression, and outcome of hepatocellular carcinoma: a systematic review and meta-analysis. AB - Purpose: Previous studies have supported an association between serum insulin like growth factor-1 (IGF1) and IGF-binding protein 3 (IGFBP3) levels and hepatocellular carcinoma (HCC), but the results were inaccurate. It has recently been proposed that IGF1 and IGFBP3 play roles in the time-to-progression (TTP) and overall survival (OS) of HCC patients. Our results revealed that serum IGF1 level is predictive of the progression and survival of HCC patients. Results: HCC was associated with a significant reduction in serum IGF-1 and IGFBP-3 levels compared to cirrhosis (p = 0.037). Low serum IGF1 levels were predictive of a shorter TTP (OR, 2.74; 95% confidence interval [CI], 1.92-3.90) and poorer OS (odds ratio [OR], 2.20; 95% CI, 1.81-2.68) in HCC patients. The IGF1/IGFBP3 molar ratio was not significantly associated with the risk of HCC (OR, 1.311; 95% CI, 0.761-2.260). Materials and Methods: We conducted a comprehensive literature search in PubMed, EMBASE, and the Cochrane Library. Twenty studies met the inclusion criteria and were subjected to statistical analysis. The geometric mean and standard deviation (SD) of serum IGF1 and IGFBP3 levels in the healthy, cirrhosis, and HCC groups were calculated. Pooled odds ratios (ORs) were calculated using a fixed-effects model to analyse the association of serum IGF1 level with the progression and survival of HCC patients. Conclusions: Serum IGF1 and IGFBP3 levels were positively associated with the incidence of HCC. Serum IGF1 level is an independent prognostic factor for the progression and survival of HCC patients. PMID- 29113371 TI - Change in risk of breast cancer after receiving hormone replacement therapy by considering effect-modifiers: a systematic review and dose-response meta-analysis of prospective studies. AB - We synthesize the current literatures and use the power of meta-analysis to examine trends on association between hormone replacement therapy (HRT) and the risk of breast cancer (BC). We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science from their inception until Jan 2017. Prospective studies that provided adjusted risk estimates of HRT and BC risk were eligible. Categorical and dose-response meta-analyses followed the PRISMA were conducted using random effects model and restricted cubic spline model, respectively. Forty-seven publications from thirty-five unique studies were included, involving 3,898,376 of participants and 87,845 of BC cases. Compared with non-users, RR for current estrogen-only therapy (ET) users was 1.14 (95% confidence interval (CI) = 1.05-1.22), and for per year increases was 1.02 (95% CI = 1.02-1.02). Moreover, RR for current estrogen plus progestin therapy (EPT) users was 1.76, (95% CI = 1.56-1.96), and for per year increases was 1.08 (95% CI = 1.08-1.08). Dose-response analyses revealed 8-10 years' onset peaks, and indicated residual increased BC risk remained after stopping use of ET regimen rather than for EPT. Effect-modifiers like BMI, duration of use, race/ethnicity, routes of administration were recognized. In Conclusions, current use of EP or EPT and ever use of tibolone are associated with an elevated risk of BC. Compared with slim HRT users and non-users, lower BC risks were found among overweight/obese HRT users and former EPT users, respectively. Both ET and EPT users are associated with higher risk of lobular BC than ductal BC, and more ER positive than negative BC cases were detected among EPT users. PMID- 29113372 TI - Efficacy and safety of intraperitoneal chemotherapy in patients with advanced gastric cancer: a cumulative meta-analysis of randomized controlled trials. AB - Even when a curative gastrectomy is conducted, the majority of advanced gastric cancer patients with invasion die due to peritoneal recurrence. We performed electronic searches to identify randomized controlled trials published through April 2017 evaluating the effect of intraperitoneal chemotherapy (IPC) on survival rates. We included 23 trials reporting data on 2,767 patients with advanced gastric cancer. Overall, we noted that patients who received IPC had a significantly increased 1-year survival rate, and the treatment effect of IPC on 1-year survival was most prominent in studies conducted in Japan or those with a mean age of less than 60 years. IPC was also associated with an increased incidence of 2-year survival rate, but it was not seen to have this effect in studies conducted in China or Australia or with a mean age greater than 60 years. Similarly, IPC associated with a significantly increased 3-year survival rate, but this difference was not detected in studies conducted in Austria or with a mean age greater than 60 years. IPC has no significant effect on the 5-year survival rate. Finally, IPC was associated with a lower risk of recurrence in patients with advanced gastric cancer. The findings of this study suggest that gastric cancer patients who receive IPC associate with increased 1-year, 2-year, and 3-year survival rates, but this does not extend out to a 5-year survival rate. IPC is also shown to play a protective role against the risk of recurrence in patients with advanced gastric cancer. PMID- 29113373 TI - Left ventricular ejection fraction and left atrium diameter related to new-onset atrial fibrillation following acute myocardial infarction: a systematic review and meta-analysis. AB - Background: New-onset atrial fibrillation (NOAF) occurs frequently in patients with acute myocardial infarction (AMI), and is associated with increased subsequent cardiovascular mortality. However, only a few studies directly evaluated the relationship of left ventricular ejection fraction (LVEF) or left atrium diameter (LAD) and NOAF following AMI. Materials and Methods: MEDLINE(r), EMBASE(r) and the Cochrane Library were carried out to find studies until January 2017. Pooled mean difference (MD) and 95% confidence interval (CI) were calculated to evaluate the value of LVEF and LAD in the prediction of NOAF after AMI. We performed sensitivity analyses to explore the potential sources of heterogeneity. Statistical analyses were carried out using the Revman 5.3. Result: We included 10 qualifying studies comprising a total of 708 patients with NOAF and 6785 controls. Overall, decreased LVEF and increased LAD levels had a significant positive association with NOAF in patients with AMI. The MD in the LVEF levels between the patients with and those without NOAF was -4.91 units (95% Cl: -5.70 to -4.12), test for overall effect z-score = 12.18 (p < 0.00001, I2 = 35%). Moreover, in a subgroup analysis, the MD for LAD and NOAF was 2.55 units (95% Cl: 1.91 to 3.19), test for overall effect z-score = 7.80 (p < 0.00001, I2 = 57%). Conclusions: Our meta-analysis demonstrated that both decreased LVEF and increased LAD levels were associated with greater risk of NOAF following AMI. PMID- 29113374 TI - Meta-analysis of the association between SCARB1 polymorphism and fasting blood lipid levels. AB - Studies have shown that the scavenger receptor class B type 1 (SCARB1) rs5888 polymorphism impacts fasting blood lipid levels differently in men and women. A meta-analysis and statistical tests was therefore performed to determine the relationship between the rs5888 polymorphism and lipid levels in men and women. Twelve studies with 12,147 subjects were selected for this study. In a dominant model, the CT+TT genotype group had lower triglyceride levels than the CC group in men (standardized mean difference (SMD): -0.11; 95% confidence interval (CI): 0.21 to -0.02; P = 0.016; I2 = 51.5%). No statistical differences were detected in women. Subgroup analysis of different racial groups revealed significant correlation between the SCARB1 rs5888 polymorphism and higher high-density lipoprotein cholesterol (HDL-C) levels (SMD: 0.15; 95% CI: 0.08 to 0.21; P <= 0.001; I2 = 0%) and lower triglyceride levels (SMD: -0.16; 95% CI: -0.26 to 0.04; P = 0.013; I2 = 60.6%) in non-Asian men. No evidence of heterogeneity was observed when eliminating outlier studies, and no publication bias was detected. This meta-analysis suggests the SCARB1 rs5888 polymorphism is associated with higher HDL-C and lower triglyceride levels in non-Asian men. PMID- 29113375 TI - Efficacy and safety of triple versus dual antithrombotic therapy in atrial fibrillation and ischemic heart disease: a systematic review and meta-analysis. AB - The optimal antithrombotic regimen for patients with atrial fibrillation and ischemic heart disease remains unclear. Therefore, we aimed to compare the efficacy and safety of triple therapy (TT [an anticoagulant and 2 antiplatelet drugs]) with dual therapy (DAPT [2 antiplatelet drugs] or DT [an anticoagulant and a single antiplatelet drug]) in patients with atrial fibrillation and ischemic heart disease. We systematically searched the Cochrane Library, PubMed and Embase databases for all relevant studies up to August 2017. The overall risk estimates were calculated using the random-effects model. A total of 17 observational studies were included. Regarding the efficacy outcomes, no differences were observed between the triple therapy and the dual therapy for all cause death, cardiovascular death, or thrombotic complications (i.e., acute coronary syndrome, stent thrombosis, thromboembolism/stroke, and major adverse cardiac and cerebrovascular events). Regarding the safety outcomes, compared with DAPT, TT was associated with increased risks of major bleeding (a relative risk of 1.96 [1.40-2.74]), minor bleeding (1.69 [1.06-2.71]) and overall bleeding (1.80 [1.23-2.64]). Compared wtih DT, TT was associated with a greater risk of major bleeding (1.65 [1.23-2.21]), but rates of minor bleeding (0.99 [0.56-1.77]) and overall bleeding (1.14 [0.76-1.71]) were similar. Overall, TT confers an increased hazard of major bleeding with no thromboembolic protection compared with dual therapy in patients with atrial fibrillation and ischemic heart disease. PMID- 29113376 TI - Efficacy of glucocorticoids, vitamin A and caffeine therapies for neonatal mortality in preterm infants: a network meta-analysis. AB - Introduction: The paper aimed to evaluate the efficacy of different therapies in improving survival among preterm infants. Materials and Methods: PubMed and Embase were searched from inception to 2017. We assessed studies for eligibility and extracted data. A Bayesian random-effects model was used to evaluate different therapies combined direct comparisons with indirect evidence. Consistency analysis was achieved using node-splitting plots. Surface under the cumulative ranking curve (SUCRA) was calculated to rank different therapies. Rankings of the competing therapies were also performed. Results: A total of 42 randomized controlled trials (RCTs) were included for the network meta-analysis. Forest plots demonstrated that dexamethasone (OR = 10.13, 95% CrI: 5.11 to 17.89) and vitamin A (OR = 28.44, 95% CrI: 14.66 to 42.11) is superior to placebo in duration of oxygen supplementation while vitamin A (OR = -29.76, 95% CrI: -57.66 to -1.75) is inferior to placebo with regard to duration of hospitalization. Also, dexamethasone (OR = 0.42, 95% CrI: 0.24 to 0.68) showed lower incidence rate of BPD.SUCRA results showed the superiority of Budesonide based on primary efficacy outcomes. In addition, dexamethasone also showed high efficacy ranking in duration of ventilation, duration of oxygen supplementation, and occurrence of BPD. Hydrocortisone was effective in reducing neonatal mortality. No significant difference was found among these drugs. Conclusions: No significant heterogeneity was found among these drugs. In general, budesonide might have the potential to be the optimal drug for its efficacy in reducing neonatal mortality and BPD, the two most essential outcome measures. Dexamethasone might be the suboptimal drug. PMID- 29113377 TI - An updated meta-analysis of the prognostic value of decreased E-cadherin expression in ovarian cancer. AB - Decreased epithelial cadherin (E-cadherin) expression is hypothesized to be related to poor prognosis of ovarian cancer, but the predictive value is still inconsistent. We conducted an updated meta-analysis with a total of 16 studies enrolling 1720 patients to estimate the prognostic value of decreased E-cadherin expression in ovarian cancer. Reduced expression of E-cadherin was significantly associated to poor overall survival (HR = 1.74, 95% CI: 1.40-2.17) and progression-free survival (HR = 1.45, 95% CI: 1.12-1.86) with a large heterogeneity for overall survival. In addition, we found that decreased expression of E-cadherin was significantly correlated with International Federation of Gynecology and Obstetrics grade (HR = 3.74, 95% CI: 2.24-6.23), E cadherin membranous (HR = 1.47, 95% CI: 1.01-2.14), pathologic grade (HR = 1.41, 95% CI: 1.01-1.97), residual tumor size (HR = 2.72, 95% CI: 1.99-3.72), and surgery (HR = 3.21, 95% CI: 1.19-8.67). Our finding suggests that decreased E cadherin expression may be a predictor of poor ovarian cancer prognosis. PMID- 29113379 TI - Clinical characteristics and prognosis of acute myocardial infarction in young smokers and non-smokers (<= 45 years): a systematic review and meta-analysis. AB - The effect of smoking on the prognosis of young patients with acute myocardial infarction (AMI) is inconclusive. We enrolled 2188 young AMI patients (<= 45 years) from the cardiac center of the Chinese PLA General Hospital and Anzhen Hospital and analyzed their clinical characteristics and prognosis. We also searched the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases for January 2001 to March 2017 and considered for inclusion in a meta-analysis those clinical trials that compared prognoses of young smokers and non-smokers with AMI. The proportion of males and alcohol users was higher in young AMI smokers than in non-smokers; the proportion of hypertension was slightly lower. There was no difference in medical treatment between smokers and non-smokers. No differences were evident between smokers and non-smokers regarding in-hospital cardiac events and major adverse cardiovascular events on follow-up, including incidence of stroke. For young AMI patients, smoking did not lead to poorer prognosisin comparison with not smoking. This "smoker's paradox" needs to be confirmed by more randomized controlled multicenter prospective clinical trials. PMID- 29113378 TI - High pretreatment plasma D-dimer predicts poor survival of colorectal cancer: insight from a meta-analysis of observational studies. AB - D-dimer, one of the canonical markers of hypercoagulability, was reported to be a potential prognostic marker of colorectal cancer. However, an inconsistent conclusion existed in several published studies. Thus, we performed this meta analysis to provide a comprehensive insight into the prognostic role for pretreatment D-dimer in colorectal cancer. Six databases (English: Pubmed, Embase and Web of Science; Chinese: CNKI, Wangfang and VIP) were utilized for the literature retrieval. Hazard ratio (HR) was pooled by Stata 12.0. A total of fifteen studies (2283 cases) corresponded to this meta-analysis and provided available data to evaluate the prognostic role of D-dimer for colorectal cancer. The pooled HR reached 2.167 (95%. CI (confidence interval): 1.672-2.809, P < 0.001) utilizing random effect model due to obvious heterogeneity among the included studies (I2: 73.3%; P < 0.001). To explore the heterogeneity among the studies, we conducted a sensitivity analysis and found a heterogeneous study. After removing it, the heterogeneity reduced substantially (I2: 0%; P = 0.549) and we obtained a more convincing result by fixed effect model (HR = 2.143, 95% CI = 1.922-2.390, P < 0.001, 14 studies with 2179 cases). In summary, high pretreatment plasma D-dimer predicts poor survival of colorectal cancer based on the current evidence. Further prospective researches are necessary to confirm the role of D-dimer in colorectal cancer. PMID- 29113380 TI - Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and network meta-analysis of randomized clinical trials. AB - Although adjuvant chemotherapy (ACH) is widely used in clinical practice for the management of muscle-invasive bladder cancer (MIBC), a consensus has yet to be established on which ACH regimen is the most effective for improving postoperative survival. In this study, we aimed to systematically assess the optimal ACH regimen for improving survival outcomes in patients treated with radical cystectomy (RC) for MIBC. A comprehensive literature search was conducted in the PubMed, Embase, and the Cochrane Library databases for all articles published until December 2016 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The study end points were progression-free survival (PFS) and overall survival (OS). A direct pairwise meta-analysis was conducted by pooling the studies that compared RC with ACH and RC alone, and the results are presented as a pooled hazard ratio (HR) with a 95% confidence interval (CI). A Bayesian network meta-analysis was adopted for indirect comparisons among various ACH regimens, and the outcomes are presented as HRs with 95% credible intervals (CrI). The eleven randomized controlled trials ultimately selected for the current analysis comprised of 1,546 patients with 49 to 327 subjects per study. Based on the pairwise meta-analysis, the use of ACH showed significantly better PFS (HR, 0.64; 95% CI, 0.49-0.85) and OS (HR, 0.79; 95% CI, 0.68-0.92) than RC alone. In the network meta-analysis, the gemcitabine/cisplatin/paclitaxel (GCP) combination was the only ACH regimen associated with significant improvement in both the PFS (HR, 0.38; 95% CrI, 0.25 0.58) and OS (HR, 0.38; 95% CrI 0.22-0.65). ACH following RC for MIBC may therefore contribute to improved PFS and OS. In particular, the GCP combination may be the optimal ACH regimen for improving postoperative survival outcomes. Additional well-designed, large scale, prospective, randomized trials are still required to establish the optimal ACH regimen in MIBC patients. PMID- 29113381 TI - The roles of ncRNAs in the diagnosis, prognosis and clinicopathological features of breast cancer: a systematic review and meta-analysis. AB - Background: A number of studies have shown that noncoding RNAs (ncRNAs) are abnormally expressed in breast cancers. However, the roles of ncRNAs remain unclear in breast cancer. Here, we aim to investigate the potential diagnostic and prognostic roles of ncRNAs in breast cancer. Methods: Comprehensive literature search in Medline and Web of Science and a meta-analysis were performed to identify the association between ncRNAs and diagnosis, prognosis, and clinicopathological features of breast cancer. Results: A total of 103 eligible studies, involving16, 828 independent participants, were included in the meta-analysis. In total, there were 98 individual and 11 grouped ncRNAs. 51 studies were eligible for survival analysis, 27 studies were eligible for diagnostic analysis, and 46 studies were eligible for clinicopathological features analysis. The abnormal expression of ncRNAs is associated with OS, RFS and PFS in breast cancer patients. For the diagnosis value of ncRNAs, the pooled OR and 95% CI for sensitivity, specificity, DOR and AUC on all ncRNAs were 0.83 [95% CI: 0.82- 0.84], 0.80 [95% CI: 0.79- 0.82], 24.77 [95% CI: 17.44- 35.16] and 0.9037, respectively. The analysis showed that downregulation of ncRNAs in breast cancer was associated with decreased risk of LNM, increased tumor size and PR expression, whereas, upregulation of ncRNAs was associated with increased HER2 expression. Conclusions: High expression of ncRNAs was associated with poor OS, RFS, and PFS, while low expression of ncRNAs was related to favorable OS and RFS. Meanwhile, ncRNAs have potential diagnostic value for breast cancer. PMID- 29113382 TI - Case-control study of the efficacy of retrogastric Roux-en-Y choledochojejunostomy. AB - The traditional, retrocolic/antegastric Roux-en-Y choledochojejunostomy is technically complicated, and the incidence of postoperative complications remains high. Here we report the outcome of 59 consecutively treated patients (study group, SG) that underwent a new choledochojejunostomy method in which the jejunal loop is passed behind the antrum pyloricum (retrogastric route). A retrospective comparison was made between this group of patients and 187 patients (control group, CG) that underwent conventional Roux-en-Y choledochojejunostomy (antegastric route). Baseline clinicopathological characteristics were similar in both groups, except for the BMI, which was significantly higher in the SG. The time spent on constructing the anastomosis, as well as overall postoperative complications, did not differ between groups. Compared with the CG, the incidence of postoperative delayed gastric emptying was decreased in the SG, and the time elapsed before the patients' first postoperative liquid food consumption was shorter. We ascribe these beneficial effects to the superiority of the modified, retropyloric choledochojejunostomy approach, and propose that this surgical technique is particularly suitable for obese patients, especially those with a short ascending bowel loop. PMID- 29113383 TI - Diagnostic and prognostic potential of serum microRNA-4651 for patients with hepatocellular carcinoma related to aflatoxin B1. AB - Background: The serum microRNAs have been reported as potential biomarkers for hepatitis virus-related hepatocellular carcinoma (HCC); however, their role in aflatoxin B1 (AFB1)-related HCC to has not yet been evaluated. Materials and Methods: We conducted a case-control study, including 366 HCC cases and 662 controls without any evidence of tumors, to identify and assess diagnostic and prognostic potential of serum microRNAs for AFB1-related HCC. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to elucidate diagnostic performance, and to compare the microRNAs with alpha-fetoprotein (AFP) at a cutoff of 20 ng/mL (AFP20) and 400 ng/mL (AFP400). Results: We found 8 differentially expressed microRNAs via the microRNA array analysis; however, only microRNA-4651 was further identified to detect AFB1 positive HCC but not AFB1-negative HCC. For AFB1-positive HCC, microRNA-4651 showed higher accuracy and sensitivity than AFP400 (AUC, 0.85 vs. 0.72; Sensitivity, 78.1% vs. 43.0%). Compared to AFP20, microRNA-4651 exhibited higher potential in identifying small-size (0.68 vs. 0.84 for AUC and 36.7% vs. 75.5% for sensitivity, respectively) and early-stage HCC (0.69 vs. 0.84 for AUC and 38.7% vs. 75.7% for sensitivity, respectively). Additionally, miR-4651 was also associated with HCC prognosis (hazard risk value, 2.67 for overall survival and 3.62 for tumor recurrence analysis). Conclusions: These data suggest that serum microRNA-4651 may be a useful marker for HCC diagnosis and prognosis, especially AFB1-positive cases. PMID- 29113385 TI - Association between body mass index and presence of carotid plaque among low income adults aged 45 years and older: a population-based cross-sectional study in rural China. AB - Carotid plaque is a good surrogate endpoint for assessing arterial atherosclerosis, and atherosclerosis is a reliable predictor of cardiovascular diseases. However, the effect of body mass index on carotid plaque is unknown. Therefore, we aimed to explore the association between body mass index and carotid plaque in a low-income Chinese population. Residents aged >=45 years and free of stroke and cardiovascular diseases were enrolled and divided into four groups based on body mass index. B-mode ultrasonography was performed to measure carotid plaque. The mean age of participants was 59.92 years overall. Significant correlations were observed between the presence of carotid plaque and male sex, older age, systolic blood pressure, fasting plasma glucose, and low-density lipoprotein cholesterol among the different BMI subgroups. Male sex increased the risk of carotid plaque in the overweight and obese groups. Older age and high level of low-density lipoprotein cholesterol were the independent risk factor for carotid plaque in four groups. Increased systolic blood pressure was an independent risk factor in the normal-weight, overweight, and obese groups; however, fasting plasma glucose was only significant in the normal-weight group. Thus, controlling the levels of low-density lipoprotein cholesterol, systolic blood pressure, and fasting plasma glucose is required to reduce carotid plaque risk. PMID- 29113384 TI - Subclinical involvement of the liver is associated with prognosis in treatment naive cancer patients. AB - Background: Routinely tested liver biomarkers as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), butyryl cholinesterase (BChE), albumin and bilirubin are altered in distinct malignancies and hepatic metastases. This study aimed to investigate whether all liver parameters have the ability to predict long-term mortality in treatment naive cancer patients but without a malignant hepatic involvement. Methods: We prospectively enrolled 555 consecutive patients with primary diagnosis of cancer without prior anticancer therapy. BChE, albumin, AST, ALT, GGT and bilirubin as well as the inflammatory makers C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were determined. All-cause mortality was defined as primary endpoint. Results: During a median follow-up of 25 (IQR16-31) months 186 (34%) patients died. All liver parameters were significantly associated with all cause mortality (p < 0.001 for all). However, for patients without a malignant primary or secondary hepatic involvement (82%) only the functional parameters BChE and albumin remained significantly associated with the primary endpoint (crude HR per 1-IQR increase 0.61, 95%CI:0.49-0.77; p < 0.001 for BChE and 0.58, 95%CI:0.47-0.70; p < 0.001 for albumin). This e ect was persistent after multivariate adjustment (adj.HR per 1-IQR increase 0.65, 95%CI:0.50-0.86; p = 0.002 for BChE and 0.63, 95%CI:0.50-0.79; p < 0.001 for albumin). BChE and albumin correlated inversely with CRP (r = -0.21, p < 0.001 and r = -0.36, p < 0.001), SAA (r = -0.19, p < 0.001 and r = -0.33, p < 0.001) and IL-6 (r = -0.13, p = 0.009 and r = -0.17, p = 0.001). Conclusions: Decreased serum BChE and albumin levels are associated with increased all-cause mortality in treatment naive cancer patients without a manifest malignant hepatic involvement irrespective of tumor entity or stage. This association may reflect progressing systemic inflammation and metabolic derangement with subclinical involvement of the liver. PMID- 29113386 TI - Chemotherapy-induced changes of cerebral activity in resting-state functional magnetic resonance imaging and cerebral white matter in diffusion tensor imaging. AB - While chemotherapy related cognitive disorder has been described in many studies, but we still lack relatively reliable and objective diagnostic tools, and there are few similar studies in Asian patients. We recruited Asian breast cancer patients to perform a cohort study to uncover chemotherapy related cognitive disorder by using resting-state functioning magnetic resonance imaging (RS-fMRI) and magnetic resonance diffusion tensor imaging (DTI) combined with neuropsychologic assessments. This is the first prospective study which combines RS-fMRI and DTI to detect chemotherapy related cognitive disorder. The neuropsychologic tests and MRI were performed before and after the chemotherapy. The healthy controls were tested at matched times. The chemotherapy-treated group performed worse on memory and we found significant changes in the cerebellum, right orbitofrontal area, right middle and superior temporal gyrus, right subcentral area, left dorsolateral prefrontal cortex, and precentral gyrus in RS fMRI after chemotherapy. We found changes in the fornix and superior fronto occipital fasciculus with DTI. There was a correlation between some cognitive function and MRI measurements in the correlation analysis, but it was not significant after false discovery rate (FDR) multiple testing corrections. The results indicate that RS-fMRI and DTI may be a prospective application for assessing chemotherapy related cognitive disorder. PMID- 29113388 TI - Association of miR-146a, miR-149, miR-196a2, miR-499 gene polymorphisms with ischemic stroke in a Chinese people. AB - This study aimed to investigate genetic polymorphisms of miR-146a, miR-149, miR 196a2, and miR-499 and genetic susceptibility of ischemic stroke in the population of Guangxi in China. A case-control study was used to investigate miRNAs genetic polymorphisms in 298 patients with ischemic stroke and 303 healthy controls. Single-base extension polymerase chain reaction genotyping principle was used to detect genetic polymorphisms of miRNAs,and the relationship of genotype in each group and blood lipid was compared and analyzed. The genetic polymorphism of miR-499A>G (rs3746444) was associated with ischemic stroke (P < 0.05), and the risk of ischemic stroke was high in patients with G allele (OR = 1.455; 95% CI = 0.531-2.381; P = 0.039) and AG (OR = 1.339; 95% CI = 1.126-1.967; P = 0.037) genotype. The levels of low-density lipoprotein cholesterol, very-low density lipoprotein cholesterol, homocysteine, and lipoprotein in the ischemic stroke group were higher than those in the control group (P < 0.05). The genetic polymorphism of miR-499A>G (rs3746444) was related to ischemic stroke, and G allele and AG genotype may increase the risk of ischemic stroke in the population of Guangxi in China. PMID- 29113389 TI - Psychiatric morbidity and its impact on surgical outcomes for esophageal and gastric cancer patients: A nationwide cohort study. AB - Background: Due to the lack of detailed clinical information, existed evidence regarding a link between psychiatric factors and adverse cancer prognosis was inclusive. Results: We identified 1,340 patients (48.8%) with perioperative psychiatric morbidity. Preoperative psychiatric morbidity was significantly associated with both general and surgical complications within 30 days (RR = 1.3, 95% confidence interval [CI] 1.1-1.5), and the risk of death within 90 days (RR = 1.6; 95% CI 1.1-2.2) after surgery. The hazards for mortality beyond 90 days was approximately 2-fold increased among patients with perioperative psychiatric morbidity (HR = 2.0, 95% CI 1.7-2.3 for overall mortality). Materials and Methods: Based on the Swedish National Registry for Esophageal and Gastric cancer (NREV), we constructed a nationwide prospective cohort containing 2,745 surgically treated patients in 2006-2012. Perioperative psychiatric morbidity was defined as a clinical diagnosis of psychiatric disorder, from two years before to two years after surgery. Using propensity scores, we applied inverse probability of treatment weights (IPTW)-weighted Poisson regression model to evaluate relative risk (RR) of short-term surgical outcomes in relation to perioperative psychiatric morbidity. Further, IPTW-weighted Cox proportional hazards model was used to estimate hazard ratios (HRs) for mortality that occurred after 90 days of surgery. Conclusions: Perioperative psychiatric morbidity could worsen both short term and long-term surgical outcomes among patients with gastric or esophageal cancer. PMID- 29113387 TI - Tacrolimus dose requirement based on the CYP3A5 genotype in renal transplant patients. AB - Tacrolimus (FK506) and cyclosporine A (CsA) are widely used to protect graft function after renal transplantation. The aim of the present study is to determine whether the single nucleotide polymorphism of CYP3A5 is a predictive index of FK506 dose requirement, and also the selection yardstick of FK506 or CsA treatment.We tested archival peripheral blood of 218 kidney recipients for CYP3A5 genotyping with PCR-SSP. Meanwhile, the dose of FK506 and CsA was recorded, blood concentration of the drugs was measured, and graft outcome was monitored.These results indicate that CYP3A5*AA/AG carriers need higher FK506 dose than CYP3A5*GG homozygote to achieve the target blood concentration. For CYP3A5*GG carriers, taking FK506 or CsA are both advisable. CYP3A5*AA/AG carriers preferred to CsA treatment depending on the graft outcomes and drug costs. CYP3A5 genotyping is a new approach to detecting FK506 dose requirement and a predictive index for the FK506 or CsA treatment selection in kidney recipients. PMID- 29113390 TI - Associations between serum bilirubin levels and essential trace elements status in an adult population. AB - Objective: This paper aims to evaluate the relations between serum bilirubin and essential trace elements in an adult population. Results: Demographic and clinical data were stratified according to the median of serum bilirubin concentrations (50th percentiles). There were statistical differences in regarding with age, body mass index, white blood count, hemoglobin, mean corpuscular hemoglobin, alanine aminotransferase, creatinine, high-sensitivity C reactive protein, iron, zinc and copper. Studying the correlation of serum bilirubin levels with iron, zinc, copper and high-sensitivity C-reactive protein, we found positive correlations for iron and zinc, and negative correlations for high-sensitivity C-reactive protein and copper in whole participants. Similar results of correlation analysis were repeated when the further analyses were performed separately for subjects with high and low serum bilirubin concentrations. Similar results were also observed in gender-based stratified analysis. Multiple linear regression analysis revealed that serum bilirubin levels were independently correlated with serum iron, zinc and copper. Materials and Methods: The cross-sectional study involved 264 healthy subjects. Conclusions: The current study demonstrated that serum bilirubin within the reference range is correlated with iron, zinc and copper in an adult population, regardless of potential confounders. PMID- 29113391 TI - Association of type 2 diabetes with liver cirrhosis: a nationwide cohort study. AB - Background: The link between the subcategories of liver cirrhosis and type 2 diabetes is not well known. We investigated the association of type 2 diabetes mellitus with alcoholic cirrhosis and cirrhosis without alcohol. Methods: This nationwide cohort study used the Taiwan National Health Insurance Research Database. Cirrhotic individuals and their matched controls were identified from 2001-2008. In all, 9 313 cirrhotic patients aged 20 years or older were matched by age, sex, and index date with the non-cirrhotic individuals (n = 37 252). Cirrhosis was categorized into alcoholic cirrhosis and cirrhosis without alcohol. Type 2 diabetes mellitus was identified from January 2001- December 2011. Results: The incidence densities (per 1 000 person-months) of type 2 diabetes were as follows: 1.14 (95% CI: 1.09-1.20) in the non-cirrhotic group, 1.88 (CI 1.76-2.01) in patients with cirrhosis, 1.62 (CI 1.48-1.78) in patients with cirrhosis without alcohol, and 2.92 (CI 2.64-3.23) in patients with alcoholic cirrhosis. The adjusted hazards ratio (aHR) for type 2 diabetes mellitus among cirrhotic individuals was 0.774 (CI: 0.715-0.8934). Alcoholic cirrhotic men had a significantly higher risk of type 2 diabetes (aHR 1.182, CI: 1.046-1.335) compared with non-cirrhotic individuals. Increased risks were seen in men (aHR 1.690; CI: 1.455-1.963) and women (aHR 1.715; CI: 1.113-2.645) with alcoholic cirrhosis compared to those with cirrhosis without alcohol. Conclusions: This study indicates that alcoholic cirrhosis is a significant risk factor for type 2 diabetes mellitus compared with cirrhosis without alcohol. PMID- 29113392 TI - Chemotherapy alone is an alternative treatment in treating localized primary ocular adnexal lymphomas. AB - This study investigated the treatment efficacy and long-term adverse effects of various treatment modalities for primary ocular adnexal lymphomas (POALs). We retrospectively reviewed 107 patients who received first-line chemotherapy, radiotherapy, and other treatment modalities from 1990 to 2015. Nighty-three (87%) patients were diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma, with the orbit being the most common site (49 patients, 46%). Among 91 patients with stage I-IIE1 disease, 26 underwent chemotherapy, 34 underwent radiotherapy, and 31 received other treatment modalities. For chemotherapy, radiotherapy, and other treatment modalities, the 5-year event-free survival (EFS) rates were 90.0%, 89.7%, and 85.8% and the 5-year overall survival (OS) rates were 100%, 90.4%, and 87.5%, respectively. Moreover, among 80 patients with stage I-IIE1 MALT lymphoma, the complete remission, 5-year EFS and OS rates were not significantly different between patients receiving chemotherapy and those receiving radiotherapy. Among 16 patients with stage IIE2-IVE disease, the 5-year EFS rates for chemotherapy alone (n = 11) and combined radiotherapy and chemotherapy (n = 5) were 61.7% and 80%, respectively, whereas the 5-year OS rate for both groups was 80.0%. Neutropenia (15.2%) was the most common side effect in patients who received chemotherapy, whereas cataract (16.3%) was the most common late sequela in patients who received radiotherapy. Multivariate analysis revealed that old age (> 60 y) and an advanced stage (stage III/IV) were prognostic factors for poor OS. Our results indicate that chemotherapy yields satisfactory disease control and fewer side effects, and acts as an alternative therapy for patients with localized POALs. PMID- 29113393 TI - Resource utilization and cost saving analysis of subcutaneous versus intravenous trastuzumab in early breast cancer patients. AB - We conducted an economic evaluation of intravenous (IV) vs subcutaneous (SC) trastuzumab for the treatment of patients with early breast cancer (EBC). Data of patients receiving adjuvant IV trastuzumab at our institute in 2014 were used to study three different treatment scenarios: 1) IV trastuzumab, 2) SC trastuzumab, and 3) IV trastuzumab during chemotherapy followed by SC trastuzumab. Our cohort included 114 patients with a median weight of 63.75 kg. Scenario 2 was the most time-saving treatment, with 71.7% reduction in preparation time and 89.3% reduction in chair time compared to scenario 1. Considering full costs, the mean costs per patient/year were ? 14,233 +/- 8,698 for scenario 1, ? 14,272 +/- 8,312 for scenario 2, and ? 14,535 +/- 8,646 for scenario 3 (p = 0.959). When mean body weight was > 65.2 kg, the mean cost was lower in scenario 2 than in scenario 1. Scenario 2 proved a valuable time-saving and cost-saving option. A shift from IV to SC trastuzumab should be considered, especially in capacity-constrained oncology departments. PMID- 29113394 TI - IL-18 polymorphisms contribute to hepatitis B virus-related cirrhosis and hepatocellular carcinoma susceptibility in Chinese population: a case-control study. AB - IL-18 polymorphisms influence the transcriptional activity of the IL-18 gene and associated with various diseases. However, their relationships with hepatitis B virus-related liver diseases had not reached a consensus. So we conducted this case-control study with a view to clarifying the association. We included four groups: healthy controls, chronic hepatitis B virus (CHB) carriers, liver cirrhosis (LC) and hepatocellular carcinoma (HCC) groups with each group of 250 persons. Odd ratios (ORs) and 95% confidence intervals (95%CIs) with or without adjustment were calculated. Haplotype analysis was also performed. The results showed people carrying rs187238 CG genotype had a lower risk of LC (CG vs. CC: OR = 0.59, 95%CI = 0.38-0.91, P = 0.02), while GG genotype carriers had a higher risk of HCC (GG vs. CC+CG: OR = 4.73, 95%CI = 1.01-22.1, P = 0.03) than those with CC and CG genotypes in healthy group. Rs187238 GG genotype increased the risk from CHB to LC status (GG vs. CC: OR = 4.81, 95%CI = 1.03-22.6; GG vs. CC+CG: OR = 4.73, 95%CI = 1.01-22.1), meanwhile the trend also existed by controlling confounding factors (GG vs. CC: OR = 6.25, 95%CI = 1.09-35.8; GG vs. CC+CG: OR = 5.91, 95%CI = 1.04-33.7). Haplotype Crs187238Trs1946518 moderately decreased the risk of CHB carriers developing into HCC (OR = 0.69, 95%CI = 0.50 0.96, P = 0.03) after adjustment. In conclusion, IL-18 rs187238 GG genotype may increase the risk of HCC in healthy population and the risk of LC in CHB carriers. PMID- 29113395 TI - Association between fibrinogen level and the severity of coronary stenosis in 418 male patients with myocardial infarction younger than 35 years old. AB - Fibrinogen (Fib) is a useful marker for predicting the severity of coronary artery disease (CAD) in adult population. However, whether Fib can be a predictor for the presence and severity of CAD in very young MI patients (<=35 years old) remains to be determined. A total of 418 males from 61,863 patients with MI who were under 35 years old were sequentially recruited in our study. The patients were divided into two main groups and three subgroups according to coronary angiograph and Gensini score (GS) system: no coronary artery stenosis (group A), the results of the coronary artery stenosis (group B); low GS, intermediate GS and high GS. Data indicated that Fib, body mass index, current smoking, white blood cell count (WBCC) and GS were significantly higher in group B than those in group A (all P < 0.01). Moreover, there were significant differences in Fib, mean age, diabetes mellitus, family history of CAD, WBCC, left ventricular ejection fraction, and GS between high GS and low GS subgroups (all P < 0.01). A positive correlation between Fib levels and GS was found (r = 0.242, p < 0.001). Receiver operating characteristics curve analysis demonstrated that the best cut-off level of Fib predicting the severity of coronary stenosis was 3.475g/L (sensitivity 64%; specificity 70%) and the area under the curve was 0.656. Fib was also independently associated with high GS (OR=2.173, 95%CI 1.011-4.670, P = 0.047) after adjusting for potential confounders. In conclusion, Fib is significantly related to the presence and severity of coronary stenosis in male patients with MI under 35 years old. PMID- 29113396 TI - Epidermal growth factor receptor is associated with the onset of skeletal related events in non-small cell lung cancer. AB - Background: Bone metastasis and skeletal related events (SREs) are common in non small cell lung cancer (NSCLC). Patients with mutant epidermal growth factor receptor (EGFR) could benefit from tyrosine kinase inhibitors (TKIs). However, it is unclear whether SRE is influenced by EGFR status. We aimed to evaluate the correlation of EGFR status and TKIs with the incidence of SREs. Methods: We conducted a retrospective study of stage IV NSCLC patients with bone metastasis. Incidence rate of SREs was collected and was compared using chi-square test. Logistic-regression analysis was used to identify the risk factors predicting the incidence of SREs. Results: 410 eligible patients were enrolled in the study. 49.0% were detected with EGFR mutation. 49.8% of patients received EGFR-TKIs therapy prior to the onset of SREs. 42.7% experienced at least one SRE. Patients who were treated with TKIs held lower incidence of SREs than patients who were not treated with TKIs (23.5% vs 61.7%, p<0.001). Multivariate analysis showed that poor performance status (OR 5.550, 95%CI 2.290-13.450; p<0.001) and mutant EGFR (OR 3.050, 95%CI 1.608-5.787, p=0.001) were independent risk factors predicting the onset of SREs, while the usage of TKIs (OR 0.102, 95%CI 0.054 0.193, p<0.001) was a protective factor of SREs in NSCLC patients with bone metastasis. Conclusions: This study indicates that the incidence of SREs is common in both patients with and without EGFR mutation. Poor performance ability and mutant EGFR imply higher risks of SREs, while the usage of TKIs may be a protective factor of SREs. PMID- 29113397 TI - Altered putamen functional connectivity is associated with anxiety disorder in Parkinson's disease. AB - In this study, we used resting state-functional magnetic resonance imaging (rs fMRI) to explore altered putamen functional connectivity (FC) in Parkinson's disease patients with anxiety disorder. We divided 65 Parkinson's disease patients into anxiety (PD-A; n=18) and non-anxiety (PD-NA; n=45) groups based on a Hamilton Anxiety Rating Scale cutoff score of 12. The PD-A patients exhibited altered putamen FC with cortical and subcortical regions. The PD-A patients showed enhanced putamen FC with the caudatum, which correlated with increased emotional processing during anxiety. Decreased putamen FC with the orbitofrontal gyrus and cerebellum also correlated with increased anxiety in Parkinson's disease. Our findings demonstrate that anxiety disorder in Parkinson's disease is associated with abnormal putamen FC networks, especially with caudatum, orbitofrontal gyrus and cerebellum. PMID- 29113398 TI - Combing NLR, V20 and mean lung dose to predict radiation induced lung injury in patients with lung cancer treated with intensity modulated radiation therapy and chemotherapy. AB - The purpose was to evaluate the predictive value of baseline neutrophil to lymphocyte ratio (NLR) level in the incidence of grade 3 or higher radiation induced lung injury (RILI) for lung cancer patients. A retrospectively analysis with 166 lung cancer patients was performed. All of the enrolled patients received chemoradiotherapy at our hospital between April 2014 and May 2016. The Cox proportional hazard model was used to identify the potential risk factors for RILI. In this cohort, the incidence of grade 3 or higher RILI was 23.8%. Univariate analysis showed that radiation dose, volume at least received 20Gy (V20), mean lung dose and NLR were significantly associated with the incidence of grade 3 or higher RILI (P = 0.012, 0.008, 0.012, and 0.039, respectively). Multivariate analysis revealed that total dose >= 60 Gy, V20 >= 20%, mean lung dose >= 12 Gy, and NLR >= 2.2 were still independent predictive factors for RILI (P = 0.010, 0.043, 0.028, and 0.015, respectively). A predictive model of RILI based on the identified risk factors was established using receiver operator characteristic curves. The results demonstrated that the combination analysis of V20, mean lung dose and NLR was superior to either of the variables alone. Additionally, we found that the constraint of V20 and mean lung dose were meaningful for patients with higher baseline NLR level. If the value of V20 and mean lung dose lower than the threshold value, the incidence of grade 3 or higher RILI for the high NLR level patients could be decreased from 63.3% to 8.7%. Our study showed that radiation dose, V20, mean lung dose and NLR were independent predictors for RILI. Combination analysis of V20, mean lung dose and NLR may provide a more accurate model for RILI prediction. PMID- 29113399 TI - DCK expression, a potential predictive biomarker in the adjuvant gemcitabine chemotherapy for biliary tract cancer after surgical resection: results from a phase II study. AB - The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. This clinical phase II trial was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patients were started on intravenous infusions of gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of every 28-day cycle. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry. This study enrolled 72 patients with BTC (26 with gallbladder cancer, 33 with extrahepatic cholangiocarcinoma, and 13 with intrahepatic cholangiocarcinoma). The 2-year recurrence-free survival (RFS) rate was 43% (95% CI, 33-57%). Multivariable analysis showed that DCK expression, vascular invasion, and lymph node metastasis were significantly associated with RFS. Twenty-one (31.8%) were positive for DCK immunoreactivity. The median RFS was 34.95 months for DCK-positive patients, compared with 11.41 months for DCK negative patients. Although the primary hypothesis of this study, defined as a 2 year RFS of 60%, was not met, intratumoral DCK expression was significantly associated with RFS in patients with resected BTC treated with postoperative gemcitabine chemotherapy. Future randomized controlled trials are warranted. PMID- 29113400 TI - Evaluation of factors associated with platinum-sensitivity status and survival in limited-stage small cell lung cancer patients treated with chemoradiotherapy. AB - In this retrospective study, we analyzed the association of clinicopathological factors and therapeutic plans with platinum-sensitivity status and survival of limited-stage small cell lung cancer (LS-SCLC) patients. We enrolled 452 LS-SCLC patients with 279 platinum sensitive and 173 platinum refractory patients. The low serum neuro-specific enolase levels (NSE; p = 0.011), neutrophil-to lymphocyte ratios (NLR; p = 0.013) and higher objective response rates (p = 0.003) were associated with sensitive group but not the refractory group. Multivariate analysis showed that treatment modality (HR = 0.267, p < 0.001), serum lactate dehydrogenase (LDH; HR = 1.894, p = 0.016), NLR (HR = 2.043, p = 0.043) and platinum-sensitivity status (HR = 0.561, p = 0.036) were independent prognostic factors for survival. We further showed that the numbers of chemotherapy cycles and response to first-line therapy were independent prognostic factors for refractory patients only. Our study demonstrates that platinum-sensitivity status is of prognostic importance, as it is strongly associated with survival in LS-SCLC patients. PMID- 29113401 TI - Optimal adjuvant chemotherapy for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. AB - Adjuvant chemotherapy improves survival in patients with resected pancreatic cancer but the optimal regimen remains unclear. We aim to compare all possible adjuvant chemotherapy in terms of overall survival and toxic effects. Pubmed, Trial registries and Cochrane library databases for randomized controlled trials were searched until November 2016. Thirteen trials were included for network analysis and the hazard ratios (HRs) for survival and odds ratios for toxic effects were assessed via Aggregate Data Drug Information System software. Only S 1 chemotherapy improved 1-year, 3-year and 5-year survival compared with observation (HR (95% CI): 3.94 (1.18-12.34); 4.08 (1.58-8.24) and 5.09 (1.16 29.83) respectively). Although not significant, gemcitabine plus uracil/tegafur was associated with poorer 1-year and 3-year survival compared with observation (HR (95% CI): 0.85 (0.16-4.03) and 0.86 (0.23-2.95)). Adding radiation to chemotherapy has no significant improvement in survival. S-1 and gemcitabine plus capecitabine are currently the most effective adjuvant therapies for pancreatic cancer. While S1 has only been validated in Asian people, higher toxicity is an issue for gemcitabine plus capecitabine. PMID- 29113403 TI - A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients. AB - Background: Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients. Methods: This study used a Simon 2-stage design requiring >=3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse. Results: Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was >=100 in two subjects whose respective durations of disease control were 151 and 256 days. Conclusions: The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of >=3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression. PMID- 29113402 TI - Patterns of relapse in patients with localized gastric adenocarcinoma who had surgery with or without adjunctive therapy: costs and effectiveness of surveillance. AB - Purpose: After therapy of localized gastric adenocarcinoma (GAC) patients, the costs of surveillance, relapse patterns, and possibility of salvage are unknown. Materials and Methods: We identified 246 patients, who after having a negative peritoneal staging, received therapy (any therapy which included surgery) and were surveyed (every 3-6 months in the first 3 years, then yearly; ~10 CTs and ~7 endoscopies per patient). We used the 2016 Medicare dollars reimbursed as the "costs" for surveillance. Results: Common features were: Caucasians (57%), men (60%), poorly differentiated histology (76%), preoperative chemotherapy (74%), preoperative chemoradiation (59%), and had surgery (100%). At a median follow-up of 3.7 years (range, 0.1 to 18.3), the median overall survival (OS) was 9.2 years (95% CI, 6.0 to 11.2). Tumor grade (p = 0.02), p/yp stage (p < 0.001), % residual GAC (p = 0.05), the R status (p = 0.01), total gastrectomy (p = 0.001), and relapse type (p = 0.02) were associated with OS. Relapse occurred in 79 (32%) patients (only 8% were local-regional) and 90% occurred within 36 months of surgery. P/yp stage (p < 0.001) and total gastrectomy (p = 0.01) were independent prognosticators for OS in the multivariate analysis. Only 1 relapsed patient had successful salvage therapy. The estimated reimbursement for imaging studies and endoscopies was $1,761,221.91 (marked underestimation of actual costs). Conclusions: The median OS of localized GAC patients was excellent with infrequent local-regional relapses. Rigorous surveillance had a low yield and high "costs". Our data suggest that less frequent surveillance intervals and limiting expensive investigations to symptomatic patients may be warranted. PMID- 29113404 TI - Persistence of type-specific human papillomavirus infection among Daqing City women in China with normal cytology: a pilot prospective study. AB - Persistence of high-risk human papillomavirus (HPV) represents the necessary cause of cervical cancer. Researching natural history of HPV infection is important to identify high-risk population of cervical cancer. Since HPV infection is population-specific, the findings in western populations could not be simply extended to Chinese and Asian females. This study investigated the type specific persistence of HPV and related factors among Daqing City women in China. A total of 1759 women aged 18-80 years were enrolled at baseline. Cervical cell specimens were collected for cytological examination and HPV detection. HPV positive individuals with normal cytology were followed up after 12 months. The results showed that HPV prevalence was 8.64% at baseline, of which 85 HPV positive cases with normal cytology were followed up. The one-year type-specific persistence of HPV and high-risk types were 34.12% (29/85) and 34.25% (25/73), respectively. The top three high-risk types were HPV16 (7/17, 41.18%), HPV18 (5/8, 62.50%) and HPV58 (7/15, 46.67%). Age > 50 years was significantly associated with a higher risk of HPV persistence compared to <= 50 (OR = 2.73; 95% CI: 1.07, 6.93). In conclusion, approximately one-third of Daqing City women with HPV infection had at least one-year viral persistence, most of which were high-risk types. Older age represents a risk factor of HPV persistence. PMID- 29113405 TI - Breast cancer is associated to impaired glucose/insulin homeostasis in premenopausal obese/overweight patients. AB - The association between breast cancer (BCa) presence and altered glucose/insulin metabolism is controversial likely due to an inaccurate insulin resistance (IR) assessment and inappropriate stratification of patients by body-mass index (BMI) and menopausal state. 148 women with suspect of sporadic BCa were stratified by BMI and menopause. Fasting levels of glucose, insulin, glycohemoglobin and selected IR-related and tumor-derived markers were measured. Glucose/insulin levels during OGTT were used to calculate insulin resistance/sensitivity indexes. Analysis of 77 BCa-bearing patients and 71 controls showed an association between BCa and IR as demonstrated by impaired glucose/insulin homeostasis (increased fasting- and OGTT-induced glucose levels) and deteriorated IR indexes, which was especially patent in premenopausal women. The association between BCa presence and IR was markedly influenced by BMI, being obese BCa patients significantly more insulin resistant than controls. BCa presence was associated to elevated levels of IR (glucose, triglycerides) and tumor-derived (VEGF) markers, especially in overweight/obese patients. BCa presence is associated to IR in overweight/obese premenopausal but not in premenopausal normal weight or postmenopausal women. Our data support a bidirectional relationship between dysregulated/imbalanced glucose/insulin metabolism and BCa, as tumor- and IR markers are correlated with the impairment of glucose/insulin metabolism in overweight/obese premenopausal BCa patients. PMID- 29113406 TI - Altered DMN functional connectivity and regional homogeneity in partial epilepsy patients: a seventy cases study. AB - Purpose: Clinically diagnosed partial epilepsy is hard to be functionally diagnosed by regular electroencephalograph (EEG) and conventional magnetic resonance imaging (MRI). By collecting transient brain regional signals, blood oxygenation level-dependent (BOLD) function MRI (BOLD-fMRI) can provide brain function change information with high accuracy. By using resting state BOLD-fMRI technique, we aim to investigate the changes of brain function in partial epilepsy patients. Methods: BOLD-fMRI scanning was performed in 70 partial epilepsy and 70 healthy people. BOLD-fMRI data was analyzed by using the Regional Homogeneity (ReHo) method and functional connectivity of Default Mode Network (DMN) methods. The abnormal brain functional connectivity in partial epilepsy patients was detected by Statistical Parametric Mapping 8 (SPM8) analysis. Results: Compared to healthy group, epilepsy patients showed significant decreased ReHo in left inferior parietal lobule/pre- and post-central gyrus, right thalamus/paracentral lobule/Cerebellum anterior and posterior Lobe, bilateral insula. The DMN functional connectivity regions decreased significantly in right uncus, left Inferior parietal lobule, left supramarginal gyrus, left uncus, left parahippocampa gyrus, and left superior temporal gyrus, in epilepsy patients, compared to healthy controls. Significance: This study clarified that both ReHo and functional connectivity of DMN decreased in partial epilepsy patients compared to healthy controls. While left inferior parietal lobule was detected in both ReHo and DMN, many other identified regions were different by using these two BOLD-fMRI techniques. We propose that both ReHo and DMN patterns in BOLD-fMRI may suggest networks responsible for partial epilepsy genesis or progression. PMID- 29113407 TI - Healing touch in radiation therapy: is the benefit tangible? AB - Background: Cancer patients tend to use more and more complementary or alternative medicine concomitantly to radiotherapy. A large part of these patients have recourse to Mind and Body practice, mainly with biofield healers or magnetizers, without any level of evidence. The aim of the present study was to report epidemiologic data on biofield healers in radiation therapy patients, and to assess the possible objective and subjective benefits. Materials and Methods: A retrospective study was conducted in a French cancer institute. All consecutive breast or prostate cancer patients undergoing a curative radiotherapy during 2015 were screened (n = 806). Healer consultation procedure, frequency, and remuneration were collected. Patient's self-evaluation of healer's impact on treatment tolerance was reported. Tolerance (fatigue, pain) was assessed through visual analogic scale (0 to 10). Analgesic consumption was evaluated. Toxicities were described according to NTCAEv4.0. Results: 500 patients were included (350 women and 150 men). A total of 256 patients (51.2%) consulted a healer during their radiation treatment, with a majority of women (58%, p < 0.01). Most of patients had weekly (n = 209, 41.8%) or daily (n = 84, 16.8%) appointments with their healer. Regarding the self-reported tolerance, > 80% of the patients described a "good" or "very good" impact of the healer on their treatment. Healers were mainly voluntary (75.8%). Regarding the clinical efficacy, no difference was observed in prostate and in breast cancer patients (toxicity, antalgic consumption, pain). Conclusions: This study reveals that the majority of patients treated by radiotherapy consults a healer and reports a benefit on subjective tolerance, without objective tolerance amelioration. PMID- 29113408 TI - Liver resection versus transplantation for multiple hepatocellular carcinoma: a propensity score analysis. AB - The aim of this study was to compare the outcomes of patients with multiple hepatocellular carcinoma (HCCs) after liver resection (LR) versus liver transplantation (LT). Patients who had multiple HCCs without macrovascular invasion and who underwent LT or LR between 2007 and 2013 were reviewed. A propensity score matching model was used to adjust baseline differences between the two groups. A total of 204 patients were selected for the current study, including 137 LR patients and 67 LT patients. During follow-up, 100 patients experienced recurrence, and 78 patients died. The 5-year recurrence-free survival rate was 71.1% for the LT group and 31.1% for the LR group (P<0.001). The 5-year overall survival rate was 73.4% for the LT group and 39.8% for the LR group (P<0.001). Moreover, the LT group had better recurrence-free survival and overall survival rates than the LR group regardless of whether the patients met or exceeded the Milan criteria. The multivariate analysis showed that microvascular invasion and LR were independent risk factors for postoperative recurrence, whereas only LR was associated with an increased incidence of mortality. After applying one-to-one propensity score matching, similar results were observed in the propensity score matching model. Our study suggested that LT provided a better prognosis for patients with multiple HCCs than LR regardless of whether the patients met the Milan criteria. PMID- 29113409 TI - Phase I clinical trial of AXL1717 for treatment of relapsed malignant astrocytomas: analysis of dose and response. AB - Purpose: Early phase I study of safety of AXL1717 in patients with recurrent or progressive malignant astrocytomas and evaluation of preliminary anti-tumor efficacy. Patients and methods: Nine patients fulfilling the set criteria were enrolled. Eight had recurrent glioblastoma and one gliosarcoma. Patients were treated with an oral suspension of AXL1717 (215-400 mg bid) cycle-by-cycle in 35 day cycles (28 days bid and 7 days off). Patients with progressive disease and/or toxicity-related dose delay of more than 14 days were withdrawn. Results: Four patients had tumor responses (44%) to AXL1717 treatment. Two of these had stable disease for 12 months (10 cycles at 215-300 mg bid). Due to MRI-detected progression they were then taken off the study. They died 8 and 12 months later, respectively. One patient was treated 8 months (6 cycles with 215 mg bid). He was withdrawn because of disease progression but died after another 25 months. The fourth patient having stable disease died of sepsis due to pancytopenia in the end of cycle 2 on 400 mg bid. A fifth patient underwent surgery after two cycles with 300 mg bid. Pathological analysis demonstrated abundant necrosis and small areas of viable tumor. After one more cycle with 300 mg bid he was withdrawn due to clinical and radiographic worsening and died 11 months later. The other 4 patients did not have any detectable responses and died within 3-13 months after trial entry. Neutropenia was the main adverse effect, which was easily detected and reversible in all but one patient. Conclusion: This clinical phase I study indicates that AXL1717 as a single agent is capable of producing prolonged stable disease and survival of patients with relapsed malignant astrocytomas. The drug was well tolerated. A new formulation of the drug will be used in further investigations in order to better define the optimal dose. PMID- 29113410 TI - A risk prediction system of postoperative hemorrhage following laparoscopy assisted radical gastrectomy with D2 lymphadenectomy for primary gastric cancer. AB - Objectives: To investigate risk factors of postoperative hemorrhage (PH) following laparoscopy-assisted radical gastrectomy (LARG) with D2 lymphadenectomy for primary gastric cancer (PGC) and to use those risk factors to develop a scoring system for risk assessment. Materials and Methods: A total of 1789 PGC patients were enrolled in our study. We analyzed the risk factors of PH and constructed a scoring system using 75% of the cases as the experimental group and 25% of the cases as a verification group to demonstrate the effectiveness. Results: Among these 1789 patients, 46 (2.6%) developed PH. Univariate and multivariate analysis in the experimental group indicated that having more than 41 lymph node excisions, combined organ resection, stage III tumor and postoperative digestive fistula were independent risk factors of PH. According to the independent risk factors, we constructed a scoring system to separate patients into low-risk (0-2 points) and high-risk (>= 3 points) groups. The area under the ROC curve for this scoring system was 0.748. In the verification group, the risk of PH predicted by the scoring system was not significantly different from the actual incidence observed. Conclusions: This scoring system could simply and effectively predict the occurrence of PH following LARG with D2 lymphadenectomy for PGC. The predictive system will help surgeons evaluate risk and select risk-adapted interventions to improve surgical safety. PMID- 29113411 TI - Pancreatoduodenectomy combined with portal-superior mesenteric vein resection and reconstruction with interposition grafts for cancer: a meta-analysis. AB - The use of interposition grafts for portal-superior mesenteric vein (PV-SMV) reconstruction during pancreatoduodenectomy (PD) with venous resection (VR) for localized periampullary tumors is a controversial topic. The present meta analysis aimed to evaluate the perioperative and long-term outcomes in patients who received interposition grafts for PV-SMV reconstruction after PD with VR. The correlative databases were systematically searched to identify relevant trials comparing vein grafts versus no vein grafts during PD with VR. 14 studies including 257 patients with vein grafts and 570 patients without vein grafts were extracted. The meta-analysis indicated no difference in perioperative morbidity, mortality, or thrombosis between the two groups, but the vein graft group was associated with a significantly increased venous thrombosis rate (>= 6 months) (odds ratio [OR] = 2.75; 95% confidence interval [CI], 1.32-5.73; P = .007). The autologous vein group subgroup analysis also revealed a significantly increased vein thrombosis rate (OR = 3.13; 95% CI, 1.45-6.76; P = .004) between the two groups. Meanwhile, the prosthetic vein group subgroup analysis indicated no difference. Additionally, the oncological value of vein grafts during PD for pancreatic cancer survival was analyzed and revealed no difference in 1-year, 3 year, or 5-year survival between the two groups. Using interposition grafts for PV-SMV reconstruction is safe and effective, and has perioperative outcomes and long-term survival rates compared to those with no vein grafts during PD with VR. However, the lower long-term vein patency rate in patients with vein grafts indicate that interposition grafts may be more likely to lose function. PMID- 29113412 TI - Collateral vessels on magnetic resonance angiography in endovascular-treated acute ischemic stroke patients associated with clinical outcomes. AB - Purpose: Collateral vessels were considered to be related with outcome in endovascular-treated acute ischemic stroke patients. This study aimed to evaluate whether the collateral vessels on magnetic resonance angiography (MRA) could predict the clinical outcome. Materials and Methods: Acute stroke patients with internal carotid artery or middle cerebral artery occlusion within 6 hours of symptom onset were included. All patients underwent MRI and received endovascular treatment. The collateral circulations at the Sylvian fissure and the leptomeningeal convexity were evaluated. The preoperative and postoperative infarct volume was measured. The clinical outcome was evaluated by mRS score at 3 months after stroke. Results: Of 55 patients, Cases with insufficient collateral circulation at the Sylvian fissure and leptomeningeal convexity showed that the NIHSS score at arrival and preoperative infarct volume were significantly lower in mRS score of 0-2 (both P < 0.05) than mRS score of 3-6. Multivariate testing revealed age and collateral status at the leptomeningeal convexity were independent of the clinical outcome at 3 months after stroke (odds ratio (95% confidence interval): 1.094 (1.025-1.168); 9.542 (1.812-50.245) respectively). The change of infarct volume in the group with mRS score of 0-2 was smaller than that with mRS score of 3-6. While multivariate logistic models showed that postoperative infarct volume was non-significant in predicting the clinical outcome after stroke. Conclusions: The extent of collateral circulation at the leptomeningeal convexity may be useful for predicting the functional recovery while the relationship between postoperative infarct volume and clinical outcome still requires for further study. PMID- 29113413 TI - Intersecting transcriptomic profiling technologies and long non-coding RNA function in lung adenocarcinoma: discovery, mechanisms, and therapeutic applications. AB - Previously thought of as junk transcripts and pseudogene remnants, long non coding RNAs (lncRNAs) have come into their own over the last decade as an essential component of cellular activity, regulating a plethora of functions within multicellular organisms. lncRNAs are now known to participate in development, cellular homeostasis, immunological processes, and the development of disease. With the advent of next generation sequencing technology, hundreds of thousands of lncRNAs have been identified. However, movement beyond mere discovery to the understanding of molecular processes has been stymied by the complicated genomic structure, tissue-restricted expression, and diverse regulatory roles lncRNAs play. In this review, we will focus on lncRNAs involved in lung cancer, the most common cause of cancer-related death in the United States and worldwide. We will summarize their various methods of discovery, provide consensus rankings of deregulated lncRNAs in lung cancer, and describe in detail the limited functional analysis that has been undertaken so far. PMID- 29113415 TI - The role of miRNA and lncRNA in gastric cancer. AB - Gastric cancer is one of the most common cancers and has the highest mortality rate worldwide. It is worthwhile to explore the mechanism of gastric cancer progression. An increasing number of studies have found that non-coding RNAs including miRNA and lncRNA play important roles in gastric cancer progression. This review summarized the role of ectopic miRNA in gastric cancer proliferation, growth, migration, invasion and apoptosis. Meantime, aberrantly expressed miRNA also received a great deal of attention as potential biomarker for gastric cancer diagnosis and therapy. Over the last decade, lncRNA was considered to regulate gastric cancer progression at the transcript and post-transcript level. At the transcript level, lncRNA induced gastric cancer progression by changing chromatin modification and mRNA stabilization to regulate mRNA and miRNA expression. Furthermore, lncRNA regulated gastric cancer progression by completely combining with miRNA to produce ceRNA or promote protein stabilization at the post transcript level. Greater attention of miRNA and lncRNA in gastric cancer can provide new insight of mechanism of cancer development and may be acted as a new anticancer target. PMID- 29113414 TI - Epithelial-to-mesenchymal transition, circulating tumor cells and cancer metastasis: Mechanisms and clinical applications. AB - Epithelial-to-mesenchymal transition (EMT) endows epithelial cells with enhanced motility and invasiveness, allowing them to participate in many physiological and pathological processes. Epithelial-to-mesenchymal transition contributes to the generation of circulating tumor cells (CTCs) in epithelial cancers because it increases tumor cell invasiveness, promotes tumor cell intravasation and ensures tumor cell survival in the peripheral system. Although the contribution of epithelial-to-mesenchymal transition to tumor cell invasiveness has been confirmed, the role epithelial-to-mesenchymal transition plays in metastasis remains debated. As a favorable material for a "liquid biopsy", circulating tumor cells have been shown to have promising values in the clinical management of tumors. Furthermore, an increasing number of studies have begun to explore the value of CTC-related biomarkers, and some studies have found that the expression of EMT and stemness markers in circulating tumor cells, in addition to CTC detection, can provide more information on tumor diagnosis, treatment, prognosis and research. PMID- 29113416 TI - Internal mammary lymph nodes radiotherapy of breast cancer in the era of individualized medicine. AB - Inclusion internal mammary lymph nodes as a part of regional nodal irradiation have a potential to reduce local recurrence, distant recurrence, and improve survival in breast cancer. However, the increased risk of cardiac toxicity and lungs injure associated with internal mammary lymph nodes irradiation has drew more and more attention. Estimating risk of metastasis in internal mammary lymph nodes based on axillary lymph nodes metastasis status is not always reliable: low risk do not always mean negative in internal mammary lymph nodes and high-risk do not always indicate positive in internal mammary lymph nodes. Inaccurate prediction of in internal mammary lymph nodes metastasis might lead to over- or under-treatment of in internal mammary lymph node. Internal mammary sentinel lymph node biopsy is a minimally invasive technique which has a high potential to accurately evaluate the metastasis status in in internal mammary lymph nodes and improve accuracy of nodal staging. This technique might be a useful tool to guide individualized internal mammary lymph nodes irradiation. PMID- 29113417 TI - Porphyrin photosensitizers in photodynamic therapy and its applications. AB - In 1841, the extraction of hematoporphyrin from dried blood by removing iron marked the birth of the photosensitizer. The last twenty years has witnessed extensive research in the application of photodynamic therapy (PDT) in tumor bearing (or other diseases) animal models and patients. The period has seen development of photosensitizers from the first to the third generation, and their evolution from simple to more complex entities. This review focuses on porphyrin photosensitizers and their effect on tumors, mediated via several pathways involved in cell necrosis, apoptosis or autophagic cell death, and the preventive and therapeutic application of PDT against atherosclerosis. PMID- 29113418 TI - Role of growth differentiation factor 11 in development, physiology and disease. AB - Growth differentiation factor (GDF11) is a member of TGF-beta/BMP superfamily that activates Smad and non-Smad signaling pathways and regulates expression of its target nuclear genes. Since its discovery in 1999, studies have shown the involvement of GDF11 in normal physiological processes, such as embryonic development and erythropoiesis, as well as in the pathophysiology of aging, cardiovascular disease, diabetes mellitus, and cancer. In addition, there are contradictory reports regarding the role of GDF11 in aging, cardiovascular disease, diabetes mellitus, osteogenesis, skeletal muscle development, and neurogenesis. In this review, we describe the GDF11 signaling pathway and its potential role in development, physiology and disease. PMID- 29113420 TI - Evaluating the benefits and adverse effects of an enthracycline-taxane capecitabine combined regimen in patients with early breast cancer. AB - Capecitabine in addition to anthracycline-taxane based regimens for patients with early breast cancer (EBC) has been reported in previous clinical trials, but the reported efficacy of this regimen remained inconsistent. In order to clarify the survival benefit of this regimen, a meta-analysis was performed. The systematic literature search was conducted in PubMed, the Cochrane library and Google scholar. The hazard ratios (HRs) were used to evaluate the efficacy and adverse events. The result indicated that capecitabine combine with an anthracycline taxane based regimen would significantly improve DFS (HR = 0.87, 95% CI 0.77 0.97) and OS (HR = 0.78, 95% CI 0.66-0.91) compared with the controls. In subgroup analysis, we found that capecitabine improved the DFS in hormone receptor negative (HR = 0.72, 95% CI 0.53-0.92) and triple negative (HR = 0.67, 95% CI 0.49-0.86) EBC patients. However, adding capecitabine might also increase the occurrence of some side-effects, such as hand-foot syndrome, stomatitis and diarrhea. Capecitabine combined with an anthracycline-taxane based regimen maybe effective and well-tolerated by patients with EBC, especially for triple negative breast cancer, and might be a good clinical choice. PMID- 29113419 TI - Microenvironmental regulation of the progression of oral potentially malignant disorders towards malignancy. AB - Oral potentially malignant disorders (OPMD) develop in a complex tissue microenvironment where they grow sustainably, acquiring oral squamous cell carcinoma (OSCC) characteristics. The malignant tumor depends on interactions with the surrounding microenvironment to achieve loco-regional invasion and distant metastases. Unlike abnormal cells, the multiple cell types in the tissue microenvironment are relatively stable at the genomic level and, thus, become therapeutic targets with lower risk of resistance, decreasing the risk of OPMD acquiring cancer characteristics and carcinoma recurrence. However, deciding how to disrupt the OPMD and OSCC microenvironments is itself a daunting challenge, since their microenvironments present opposite capacities, resulting in diverse consequences. Furthermore, recent studies revealed that tumor-associated immune cells also participate in the process of differentiation from OPMD to OSCC, suggesting that reeducating stromal cells may be a new strategy to prevent OPMD from acquiring OSCC characteristics and to treat OSCC. In this review, we discuss the characteristics of the microenvironment of OPMD and OSCC as well as new therapeutic strategies. PMID- 29113421 TI - Oxidative stress-induced diseases and tea polyphenols. AB - Reactive oxide species are the middle products of normal metabolism, and play a crucial role in cell signaling transduction. On the contrary, accumulation of excess reactive oxide species results in oxidative stress that often brings multifarious impairment to cells, including decrease of ATP level in cells, elevation of cytosolic Ca2+, DNA damage, dysfunction of biological function in lipid bilayer and so on. These effects will finally lead to all kinds of diseases. Tea polyphenols are widely considered as a kind of excellent antioxidant agents. It can be antioxidants by directly scavenging reactive oxide species or chelating transition metals, and indirectly upregulating the activity of antioxidant enzymes. In addition, tea polyphenols have also been observed a potent pro-oxidant capacity, which directly leads to the generation of reactive oxide species, and indirectly induces apoptosis and death of cancer cells. The underlying characters of its pro-oxidant activity in some diseases is not well understood. The present review we will discuss the dual character of tea polyphenols, both antioxidant and pro-oxidant properties, in some human diseases induced by oxidative stress. PMID- 29113423 TI - MicroRNAs in lung cancer. AB - Lung cancer (LC) is a serious public health problem responsible for the majority of cancer deaths and comorbidities in developed countries. Tobacco smoking is considered the main risk factor for LC; however, only a few smokers will be affected by this cancer. Current screening methods are focused on identifying the early stages of this malignancy. Thus, new data concerning the roles of microRNA alterations in inflammation, epithelial-mesenchymal transition and lung disease have increased hope about LC pathogenesis, diagnosis, treatment and prognosis. MicroRNA mechanisms include angiogenesis promotion, cell cycle regulation by modulating cellular proliferation and apoptosis, and migration and invasion inhibition. In this context, this manuscript reviews the current information about many important microRNAs as they relate to the initiation and progression of LC. PMID- 29113422 TI - Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers. AB - Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and despite advances in treatment over the last years, there is still a relapse rate of 50%. New therapeutic agents are awaited to increase the survival of patients. DNA repair targeted agents in combination with standard DNA damaging therapies are a recent evolution in cancer treatment. These agents focus on the DNA damage repair pathways in cancer cells, which are often involved in therapeutic resistance. Interesting targets to overcome these cancer defense mechanisms are: PARP, DNA-PK, PI3K, ATM, ATR, CHK1/2, and WEE1 inhibitors. The application of DNA targeted agents in head and neck squamous cell cancer showed promising preclinical results which are translated to multiple ongoing clinical trials, although no FDA approval has emerged yet. Biomarkers are necessary to select the patients that can benefit the most from this treatment, although adequate biomarkers are limited and validation is needed to predict therapeutic response. PMID- 29113424 TI - Update on the therapeutic significance of estrogen receptor beta in malignant gliomas. AB - Malignant glioma is the most fatal of the astrocytic lineage tumors despite therapeutic advances. Men have a higher glioma incidence than women, indicating that estrogen level differences between men and women may influence glioma pathogenesis. However, the mechanism underlying the anticancer effects of estrogen has not been fully clarified and is complicated by the presence of several distinct estrogen receptor types and the identification of a growing number of estrogen receptor splice variants. Specifically, it is generally accepted that estrogen receptor alpha (ERalpha) functions as a tumor promoter, while estrogen receptor beta (ERbeta) functions as a tumor suppressor, and the role and therapeutic significance of ERbeta signaling in gliomas remains elusive. Thus, a deeper analysis of ERbeta could elucidate the role of estrogens in gender related cancer incidence. ERbeta has been found to be involved in complex interactions with malignant gliomas. In addition, the prognostic value of ERbeta expression in glioma patients should not be ignored when considering translating experimental findings to clinical practice. More importantly, several potential drugs consisting of selective ERbeta agonists have exhibited anti-glioma activities and could further extend the therapeutic potential of ERbeta-selective agonists. Here, we review the literature to clarify the anti-glioma effect of ERbeta. To clarify ERbeta-mediated treatment effects in malignant gliomas, this review focuses on the potential mechanisms mediated by ERbeta in the intracellular signaling events in glioma cells, the prognostic value of ERbeta expression in glioma patients, and various ERbeta agonists that could be potential drugs with anti-glioma activities. PMID- 29113425 TI - Large granular lymphocytosis after transplantation. AB - Post-transplant lymphoproliferative disorders (PTLD) represent a heterogeneous group of diseases that occur following transplantation. Large granular lymphocytic (LGL) lymphocytosis is one type of PTLD, ranging from reactive polyclonal self-limited expansion to oligo/monoclonal lymphocytosis or even to overt leukaemia. LGL lymphocytosis in transplant recipients may present as a relatively indolent version of the condition and may be more common than reported, but its natural history and clinical course have not been well described, and the lack of a reliable classification system has limited studies on this disease. Patients with unexplained cytopenias, autoimmune manifestations, or unexpected remissions may be mislabelled. The purpose of this review was to evaluate the clinical features, immunophenotypes, etiopathogenesis, diagnosis, outcomes and treatment of post-transplantation LGL lymphocytosis. In conclusion, LGL lymphocytosis is a frequent occurrence after transplantation that correlates with certain procedural variables and post-transplant events. LGL lymphocytosis should be considered in patients with unexplained lymphocytosis or when pancytopenia develops after transplantation. The diagnosis of LGL lymphocytosis requires a demonstration of monoclonality, but clonality does not indicate malignancy. Additional studies are necessary to further delineate the potential effects of large granular lymphocytes in the long-term prognosis of post transplant patients. PMID- 29113426 TI - Activating mutation of PDGFRB gene in a rare cardiac undifferentiated intimal sarcoma of the left atrium: a case report. AB - Cardiac sarcoma is a rare malignant tumor with undefined genetic mutations and no targeted therapy. Here in one rare case of undifferentiated cardiac intimal sarcoma (IS), a next-generation sequencing based assay, MSK-IMPACT (Memorial Sloan Kettering - Integrated Mutation Profiling of Actionable Cancer Targets), identified a somatic, activating mutation in PDGFRB, along with amplification of PDGFRA. This E472D mutation of PDGFRB was discovered for the first time in IS. These findings suggest that concurrent aberrant PDGFRA and PDGFRB signaling may be a diagnostic biomarker and molecular therapeutic target of IS of the heart. PMID- 29113427 TI - [Clinical application of mesenchymal stem cells in treatment of acute-on-chronic liver failure and related research advances]. AB - Acute-on-chronic liver failure is a syndrome characterized by acute exacerbation of chronic hepatitis, organ failure, and high mortality. Clinical treatment of acute-on-chronic liver failure included comprehensive medical treatment, artificial liver support system, and liver transplantation, but such methods have their own shortcomings and patients tend to have a poor prognosis. Mesenchymal stem cells (MSCs), as a new type of cell therapy, have wide sources and are easy to extract and culture. Many studies have shown that MSC treatment not only helps to achieve a high survival rate, but also has good tolerability and safety; therefore, the clinical value of MSCs has become a hot research topic. This article reviews the clinical studies on acute-on-chronic liver failure, related mechanisms, and research advances, in order to provide a reference for future clinical trials and application. PMID- 29113428 TI - Visualization of Multicolored in vivo Organelle Markers for Co-Localization Studies in Oryza sativa. AB - Eukaryotic cells consist of a complex network of thousands of proteins present in different organelles where organelle-specific cellular processes occur. Identification of the subcellular localization of a protein is important for understanding its potential biochemical functions. In the post-genomic era, localization of unknown proteins is achieved using multiple tools including a fluorescent-tagged protein approach. Several fluorescent-tagged protein organelle markers have been introduced into dicot plants, but its use is still limited in monocot plants. Here, we generated a set of multicolored organelle markers (fluorescent-tagged proteins) based on well-established targeting sequences. We used a series of pGWBs binary vectors to ameliorate localization and co localization experiments using monocot plants. We constructed different fluorescent-tagged markers to visualize rice cell organelles, i.e., nucleus, plastids, mitochondria, peroxisomes, golgi body, endoplasmic reticulum, plasma membrane, and tonoplast, with four different fluorescent proteins (FPs) (G3GFP, mRFP, YFP, and CFP). Visualization of FP-tagged markers in their respective compartments has been reported for dicot and monocot plants. The comparative localization of the nucleus marker with a nucleus localizing sequence, and the similar, characteristic morphology of mCherry-tagged Arabidopsis organelle markers and our generated organelle markers in onion cells, provide further evidence for the correct subcellular localization of the Oryza sativa (rice) organelle marker. The set of eight different rice organelle markers with four different FPs provides a valuable resource for determining the sub-cellular localization of newly identified proteins, conducting co-localization assays, and generating stable transgenic localization in monocot plants. PMID- 29113430 TI - ChIMES: A Force Matched Potential with Explicit Three-Body Interactions for Molten Carbon. AB - We present a new force field and development scheme for atomistic simulations of materials under extreme conditions. These models, which explicitly include two- and three-body interactions, are generated by fitting linear combinations of Chebyshev polynomials through force matching to trajectories from Kohn-Sham density functional theory (DFT). We apply our method to liquid carbon near the diamond/graphite/liquid triple point and at higher densities and temperatures, where metallization and many-body effects may be substantial. We show that explicit inclusion of three-body interaction terms allows our model to yield improved descriptions of both dynamic and structural properties over previous empirical potential efforts, while exhibiting transferability to nearby state points. The simplicity of our functional form and subsequent efficiency of parameter determination allow for extension of DFT to experimental time and length scales while retaining most of its accuracy. PMID- 29113429 TI - Endophilin A2: A Potential Link to Adiposity and Beyond. AB - Adipose tissue plays a central role in regulating dynamic crosstalk between tissues and organs. A detailed description of molecules that are differentially expressed upon changes in adipose tissue mass is expected to increase our understanding of the molecular mechanisms that underlie obesity and related metabolic co-morbidities. Our previous studies suggest a possible link between endophilins (SH3Grb2 proteins) and changes in body weight. To explore this further, we sought to assess the distribution of endophilin A2 (EA2) in human adipose tissue and experimental animals. Human paired adipose tissue samples (subcutaneous and visceral) were collected from subjects undergoing elective abdominal surgery and abdominal liposuction. We observed elevated EA2 gene expression in the subcutaneous compared to that in the visceral human adipose tissue. EA2 gene expression negatively correlated with adiponectin and chemerin in visceral adipose tissue, and positively correlated with TNF-alpha in subcutaneous adipose tissue. EA2 gene expression was significantly downregulated during differentiation of preadipocytes in vitro. In conclusion, this study provides a description of EA2 distribution and emphasizes a need to study the roles of this protein during the progression of obesity. PMID- 29113431 TI - Effects of 60-Week Feeding Diet Containing Bt Rice Expressing the Cry1Ab Protein on the Offspring of Inbred Wuzhishan Pigs Fed the Same Diet. AB - We evaluated the chronic effects of Bt rice carrying the Cry1Ab protein (1.64 mg/kg) on offspring of highly inbred WZSP, fed with Bt rice for 360 days, in a 60 week feeding study. The WZSP offspring (n = 27) were assigned to two groups (Minghui86 group, female n = 6, male n = 5; Bt group, female n = 11, male n = 5). The average obtained Cry1Ab protein dosage for female and male pigs was 1.003 and 1.234 mg/kg body weight after 10 weeks of feeding, respectively. The experimental feed in the study was nutritionally matched in both groups. The average daily gain and feed conversion ratio of the females in week 3 and males from weeks 1 to 10 were different between the Bt and Minghui86 groups (P < 0.05), and the body weight of the male pigs in week 2 was greater in the Minghui86 group than that of the Bt group (P < 0.05). No other differences were observed, and there were no significant differences in the serum sex steroid level, hematology parameters, relative organ weights, or histopathology. Although differences in some serum chemistry parameters (alanine aminotransferase of female pigs and alkaline phosphatase of male pigs) were observed, they were not considered treatment related. On the basis of these results, long-term intake of transgenic rice carrying Cry1Ab protein exerts no unintended adverse effects on WZSP offspring. PMID- 29113432 TI - Graphene Oxide Filled Lignin/Starch Polymer Bionanocomposite: Structural, Physical, and Mechanical Studies. AB - In this study, graphene oxide (GO) was investigated as a potential nanoreinforcing agent in starch/lignin (ST/L) biopolymer matrix. Bionanocomposite films based on ST/L blend matrix and GO were prepared by solution-casting technique of the corresponding film-forming solution. The structures, morphologies, and properties of bionanocomposite films were characterized by Fourier transform infrared (FTIR), thermal gravimetric analysis (TGA), ultraviolet-visible (UV-vis), SEM, and tensile tests. The experimental results showed that content of GO have a significant influence on the mechanical properties of the produced films. The results revealed that the interfacial interaction formed in the bionanocomposite films improved the compatibility between GO fillers and ST/L matrix. The addition of GO also reduced moisture uptake (Mu) and water vapor permeability of ST/L blend film. In addition, TGA showed that the thermal stability of bionanocomposite films was better than that of neat starch film. These findings confirmed the effectiveness of the proposed approach to produce biodegradable films with enhanced properties, which may be used in packaging applications. PMID- 29113433 TI - Reconfigurable Analog Signal Processing by Living Cells. AB - Living cells are known for their capacity for versatile signal processing, particularly the ability to respond differently to the same stimuli using biochemical networks that integrate environmental signals and reconfigure their dynamic responses. However, the complexity of natural biological networks confounds the discovery of fundamental mechanisms behind versatile signaling. Here, we study one specific aspect of reconfigurable signal processing in which a minimal biological network integrates two signals, using one to reconfigure the network's transfer function with respect to the other, producing an emergent switch between induction and repression. In contrast to known mechanisms, the new mechanism reconfigures transfer functions through genetic networks without extensive protein-protein interactions. These results provide a novel explanation for the versatility of genetic programs, and suggest a new mechanism of signal integration that may govern flexibility and plasticity of gene expression. PMID- 29113436 TI - Silver-, calcium-, and copper molybdate compounds: Preparation, antibacterial activity, and mechanisms. AB - Developing novel compounds with antimicrobial properties can be an effective approach to decreasing the number of healthcare-associated infections, particularly in the context of medical devices and touch surfaces. A variety of molybdate powders (Ag2MoO4, CaMoO4, CuMoO4 and Cu3Mo2O9) were synthesized and characterized, and Escherichia coli was used as a model gram-negative bacterium to demonstrate their antimicrobial properties. Optical density measurements, bacterial colony growth, and stained gel images for protein expression clearly showed that silver- and copper molybdates inhibit bacterial growth, whereas CaMoO4 exhibited no bactericidal effect. All tests were performed in both daylight and darkness to assess the possible contribution of a photocatalytic effect on the activity observed. The main mechanism responsible for the antibacterial effect observed for Ag2MoO4 is related to Ag+ release in combination with medium acidification, whereas for compounds containing copper, leaching of Cu2+ ions is proposed. All these effects are known to cause damage at the cellular level. A photocatalytic contribution to the antibacterial activity was not clearly observable. Based on the pH and solubility measurements performed for powders in contact with various media (ultrapure water and bacterial growth medium), silver molybdate (Ag2MoO4) was identified as the best antibacterial candidate. This compound has great potential for further use in hybrid powder polymer/varnish systems for touch surfaces in healthcare settings. PMID- 29113434 TI - Similar Active Sites and Mechanisms Do Not Lead to Cross-Promiscuity in Organophosphate Hydrolysis: Implications for Biotherapeutic Engineering. AB - Organophosphate hydrolases are proficient catalysts of the breakdown of neurotoxic organophosphates and have great potential as both biotherapeutics for treating acute organophosphate toxicity and as bioremediation agents. However, proficient organophosphatases such as serum paraoxonase 1 (PON1) and the organophosphate-hydrolyzing lactonase SsoPox are unable to hydrolyze bulkyorganophosphates with challenging leaving groups such as diisopropyl fluorophosphate (DFP) or venomous agent X, creating a major challenge for enzyme design. Curiously, despite their mutually exclusive substrate specificities, PON1 and diisopropyl fluorophosphatase (DFPase) have essentially identical active sites and tertiary structures. In the present work, we use empirical valence bond simulations to probe the catalytic mechanism of DFPase as well as temperature, pH, and mutational effects, demonstrating that DFPase and PON1 also likely utilize identical catalytic mechanisms to hydrolyze their respective substrates. However, detailed examination of both static structures and dynamical simulations demonstrates subtle but significant differences in the electrostatic properties and solvent penetration of the two active sites and, most critically, the role of residues that make no direct contact with either substrate in acting as "specificity switches" between the two enzymes. Specifically, we demonstrate that key residues that are structurally and functionally critical for the paraoxonase activity of PON1 prevent it from being able to hydrolyze DFP with its fluoride leaving group. These insights expand our understanding of the drivers of the evolution of divergent substrate specificity in enzymes with identical active sites and guide the future design of organophosphate hydrolases that hydrolyze compounds with challenging leaving groups. PMID- 29113437 TI - Men's reproductive health knowledge in Mankweng District, Limpopo Province. AB - BACKGROUND: Gender roles influence men's attitudes towards reproductive health, and society might assume that reproductive health issues, fertility and family planning are women's responsibilities. Moreover, literature shows that men have insufficient knowledge about reproductive health matters and some misconceptions about modern contraceptive practices. OBJECTIVES: The aim of the study was to describe reproductive health knowledge of men in Mankweng District and was conducted in 2015. METHODS: A descriptive research study was conducted by using quantitative approach. Data were collected by means of questionnaires. Cluster random multistage sampling was used to select villages in Mankweng District and convenient sampling was used to identify participants who met the inclusion criteria to participate on the study. RESULTS: A total of 200 questionnaires were distributed and returned; 197 (98.5%) of the returned questionnaires were eligible for analysis. The findings indicated that the majority of participants, 74% (n = 145), considered their partners to be unclean during menstruation, and 84.77% (n = 167) of participants did not know how to perform self-testicular examination. More than half of the participants, 55.83% (n = 67), were not in favour of vasectomy and had strong opinions about it; some of those who reportedly knew what a vasectomy involves had some misconceptions. CONCLUSION: The findings showed that despite participants' reported knowledge about some reproductive health matters their perceptions were unfavourable towards them. Despite men's sufficient knowledge about sexually transmitted infections (STIs) and ways to protect themselves against STIs men had limited knowledge about other male and female reproductive health matters. PMID- 29113438 TI - Performance in grade 12 mathematics and science predicts student nurses' performance in first year science modules at a university in the Western Cape. AB - BACKGROUND: The demand for highly qualified and skilled nurses is increasing in South Africa as well as around the world. Having a background in science can create a significant advantage for students wishing to enrol for an undergraduate nursing qualification because nursing as profession is grounded in scientific evidence. AIM: The aim of this study was to investigate the predictive validity of grade 12 mathematics and science on the academic performance of first year student nurses in science modules. METHOD: A quantitative research method using a cross-sectional predictive design was employed in this study. The participants included first year Bachelor of Nursing students enrolled at a university in the Western Cape, South Africa. Descriptive and inferential statistics were performed to analyse the data by using the IBM Statistical Package for Social Sciences versions 24. Descriptive analysis of all variables was performed as well as the Spearman's rank correlation test to describe the relationship among the study variables. Standard multiple linear regressions analysis was performed to determine the predictive validity of grade 12 mathematics and science on the academic performance of first year student nurses in science modules. RESULTS: The results of this study showed that grade 12 physical science is not a significant predictor (p > 0.062) of performance in first year science modules. The multiple linear regression revealed that grade 12 mathematics and life science grades explained 37.1% to 38.1% (R2 = 0.381 and adj R2 = 0.371) of the variation in the first year science grade distributions. CONCLUSION: Based on the results of the study it is evident that performance in grade 12 mathematics (beta = 2.997) and life science (beta = 3.175) subjects is a significant predictor (p < 0.001) of the performance in first year science modules for student nurses at the university identified for this study. PMID- 29113439 TI - Nurses' knowledge and attitudes regarding malnutrition in children and its management in Ghana. AB - BACKGROUND: Malnutrition contributes significantly to child morbidity and mortality. Nurses require appropriate knowledge, skills and attitudes to prevent and treat malnutrition in children using appropriate guidelines or protocols. OBJECTIVES: The aim of this article was to assess nurses' knowledge, attitudes towards malnutrition and its management using the World Health Organization (WHO) or United Nations International Children's Fund guidelines for the treatment of severely malnourished children and to evaluate factors associated with their knowledge and attitudes. METHODS: Participants included 104 nurses working in the outpatient and paediatric units or departments of four hospitals in Tamale metropolis. An 88-item questionnaire was used to measure nurses' socio demographic characteristics as well as their knowledge and attitudes towards malnutrition in children and its management using the WHO guidelines for the inpatient treatment of severely malnourished children. RESULTS: Nurses' knowledge in malnutrition and its management was slightly above average (54.0%), but their attitudes were highly positive. Factors that were associated with nurses' knowledge were number of nutrition courses undertaken in nursing school, number of years working as a nurse, receipt of a refresher course on nutrition after school and receipt of training on the guidelines. Nurses' attitudes were associated with report of having awareness on the guidelines, number of years a nurse has been involved in the treatment of a severely malnourished child. CONCLUSION: Nurses' knowledge levels in the inpatient treatment of severely malnourished children were not desirable. However, their attitudes were generally positive. Receipt of previous training, awareness of the WHO guidelines, practice experience and number of years as a nurse significantly affected knowledge and attitude scores in the positive direction. PMID- 29113440 TI - Geigerin-induced cytotoxicity in a murine myoblast cell line (C2C12). AB - Geigeria poisoning in sheep, locally known as 'vermeersiekte', is an economically important plant poisoning in southern Africa. The toxic principles contained by the toxic plants are believed to be several sesquiterpene lactones, such as geigerin, vermeeric acid and vermeerin, which cause striated muscle lesions in small stock. Because of ethical issues surrounding the use of live animals in toxicity studies, there is currently a dire need to establish an in vitro model that can be used to replace traditional animal experimentation. The objective of this study was to determine the cytotoxicity of geigerin in a murine myoblast cell line (C2C12) using methyl-thiazol-tetrazolium (MTT) and lactate dehydrogenase (LDH) assays, annexin V and propidium iodide (PI) flow cytometry and transmission electron microscopy (TEM). Mouse myoblasts were exposed to 2.0 mM, 2.5 mM and 5.0 mM geigerin for 24, 48 and 72 h. A concentration-dependent cytotoxic response was observed. Apoptosis was detected by means of annexin V flow cytometry during the first 24 h and apoptotic bodies were also visible on TEM. According to the LDH and PI flow cytometry results, myoblast cell membranes were not injured. We concluded that the murine myoblast cell line (C2C12) is a suitable model for future studies planned to evaluate the cytotoxicity of other and combinations of sesquiterpene lactones, with and without metabolic activation, implicated in 'vermeersiekte' and to elucidate the subcellular effects of these myotoxins on cultured myoblasts. PMID- 29113441 TI - Obesity and kidney disease: Hidden consequences of the epidemic. AB - No Abstract Available. PMID- 29113442 TI - Barriers and facilitators to adherence to anti-diabetic medications: Ethiopian patients' perspectives. AB - BACKGROUND: Little is known about the experiences of Ethiopian patients with type 2 diabetes related to adherence to their anti-diabetic medications. This may limit attempts to develop and implement patient-centred approaches that consider Ethiopian contexts. OBJECTIVES: To conduct an exploratory study with a focus on identifying barriers and facilitators to anti-diabetic medications adherence in Ethiopian patients with type 2 diabetes. METHODS: Qualitative methods were used to conduct semi-structured interviews with 39 purposively selected participants attending clinic in three public hospitals in central Ethiopia. Open coding was used to analyse the data to identify key themes. RESULTS: A number of factors were identified as barriers and facilitators to participants' adherence to their anti-diabetic medications. The most common factors were perceptions related to their illness including symptoms, consequences and curability; perceptions of medications including safety concerns, convenience and their necessity; religious healing practices and beliefs; perceptions about and experiences with their healthcare providers and the healthcare system including the availability of medications and diabetes education; and finally perceived self-efficacy and social support. CONCLUSIONS: The findings of this study provide guidance to strengthen diabetes education programmes so that they reflect local patient contexts focusing among other things on the illness itself and the anti-diabetic medications. PMID- 29113443 TI - Knowledge, adherence and control among patients with hypertension attending a peri-urban primary health care clinic, KwaZulu-Natal. AB - BACKGROUND: Despite hypertension being a common condition among patients attending primary health care (PHC) clinics, blood pressure (BP) control is often poor. Greater insight into patient-related factors that influence the control of hypertension will assist in the development of an intervention to address the issues identified. AIM: The aim of the study was to assess patient-related variables associated with hypertension control among patients attending a peri urban PHC clinic. SETTING: The setting for this study was a peri-urban PHC clinic in KwaZulu-Natal. METHOD: This was an observational, descriptive and cross sectional study with 348 patients selected over a 1-month period. A validated questionnaire was used to collect data on patients' hypertension knowledge and self-reported adherence, and BP recordings from their medical record were recorded to ascertain control. RESULTS: Of the 348 participants, only 49% had good BP control and 44% (152/348) had concurrent diabetes mellitus. The majority of patients had moderate levels of knowledge on hypertension and exhibited moderate adherence. There was a significant relationship between knowledge and reported adherence, between reported adherence and control, but not between reported knowledge and control. CONCLUSION: Despite over 90% of the study population having moderate knowledge, and 62% with moderate reported adherence, BP was well controlled in only less than 50% of the study population. These findings suggest a need to emphasise adherence and explore new ways of approaching adherence. PMID- 29113444 TI - Perceptions of health care professionals on the safety and security at Odi District Hospital, Gauteng, South Africa. AB - BACKGROUND: For optimum delivery of service, an establishment needs to ensure a safe and secure environment. In 2011, the South African government promulgated the National Core Standards for Health Establishments for safety and security for all employees in all establishments. Little is known about whether these standards are being complied to.Aim and setting: To assess the perceptions of health care professionals (HCPs) on safety and security at Odi District Hospital. METHODOLOGY: A sample of 181 out of a total of 341 HCPs was drawn through a systematic sampling method from each HCP category. Data were collected through a self-administered questionnaire. The SPSS(r) statistical software version 22 was used for data analysis. The level of statistical significance was set at < 0.05. RESULTS: There were more female respondents than male respondents (136; 75.10%). The dominant age group was 28-47 years (114; 57.46%). Perceptions on security personnel, their efficiency and the security system were significantly affirmed (p = 0.0001). The hospital infrastructure, surroundings and plan in emergencies were perceived to be safe (p < 0.0001). The hospital lighting system was perceived as inadequate (p = 0.0041). Only 36 (20.2%) HCPs perceived that hospital authorities were concerned about employees' safety (p < 0.0001). CONCLUSION: HCPs had positive perceptions regarding the hospital's security system. Except for the negative perceptions of the lighting system and the perceived lack of hospital authorities' concern for staff safety, perceptions of the HCPs on the hospital working environment were positive. The hospital authorities need to establish the basis of negative perceptions and enforce remedial measures to redress them. PMID- 29113445 TI - The noncommunicable disease outcomes of primary healthcare screening in two rural subdistricts of the Eastern Cape Province, South Africa. AB - BACKGROUND: Middle and lower income countries are challenged with a double burden of disease: while still coping with the onslaught of Human Immunodeficiency Virus (HIV) and increasing levels of tuberculosis (TB), there is a considerable increase in the level of noncommunicable diseases (NCDs). The poor are especially disadvantaged and are at an increased risk for NCDs. Adequate healthcare resources for this environment can only be allocated once the extent and exact nature of the problem is determined.Aim and setting: The aim of this study was to collect demographic and NCD-related data in the poorest community of the poorest province of South Africa in order to determine the extent of the problem and advise on allocation of resources accordingly. METHODS: Data were collected via a household primary health screening process, which included taking anthropometric measurements, blood pressure and blood glucose and referring to clinics for further testing and treatment where necessary. RESULTS: It was found that the population screened was generally older, consisted of women, and had a high incidence of obesity and hypertension. Of note was the fact that in those without known hypertension, close to 40% of individuals had possible newly diagnosed hypertension. This increased with increase in age and body mass index (BMI). The total prevalence of diabetes was close to 5%, but possible new diabetes was considerably lower at approximately 1%. CONCLUSION: In this rural area of the Eastern Cape, South Africa, undiagnosed hypertension is a major concern and renewed efforts at detection and control are warranted. PMID- 29113446 TI - The relationship between primary healthcare providers and their external supervisors in Rwanda. AB - BACKGROUND: External supervision of Rwandan primary healthcare facilities unfolds as an interaction between supervisors and healthcare providers. Their relationship has not been thoroughly studied in Rwanda, and rarely in Africa. AIM: To explore perceived characteristics and effects of the relationship between providers in public primary healthcare facilities and their external supervisors in Rwanda. SETTING: We conducted three focus group discussions with primary healthcare providers (n = 16), three with external supervisors (n = 15) and one mixed (n = 5). METHODS: Focus groups were facilitated under low-moderator involvement. Findings were extracted thematically and discussed with participating and non-participating providers and supervisors. RESULTS: While external supervision is intended as a source of motivation and professional development in addition to its managerial purpose, it appeared linked to excessive evaluation anxiety among Rwandan primary healthcare providers. Supervisors related this mainly to inescapable evaluations within performance based financing, whereas providers additionally related it to communication problems. CONCLUSION: External supervision appeared driven by systematic performance evaluations, which may prompt a strongly asymmetric supervisory power relation and challenge intentions to explore providers' experienced work problems. There is a risk that this may harm provider motivation, calling for careful attention to factors that influence the supervisory relationship. It is a dilemma that providers most in need of supervision to improve performance may be most unlikely to benefit from it. This study reveals a need for provider-oriented supportive supervision including constructive attention on providers who have performance difficulties, effective relationship building and communication, objective and diligent evaluation and two-way feedback channels. PMID- 29113447 TI - Patient- or person-centred practice in medicine? - A review of concepts. AB - BACKGROUND: Person-centred practice in medicine may provide solutions to several pressing problems in health care, including the cost of services, poor outcomes in chronic care and the rise in litigation. It is also an ethical imperative in itself. However, patient- or person-centred care is not well researched partly because of a lack of conceptual and definitional clarity. AIM: The aim of this review was to analyse essential elements, ethical principles, logic and the practical application of person-centred practice described in clinician- and researcher-defined conceptual frameworks, terms and practices. METHODS: A search of review articles on patient- and person-centred care or medicine was conducted using Medline and Google Scholar. Secondary searches were conducted using references and citations from selected articles. RESULTS: Five conceptual frameworks were identified in terms of their practical application of the ethical principles of beneficence, autonomy and justice. They converge around a few central ideas such as having a holistic perspective of patients and their illness experience, a therapeutic alliance between the patient and clinician as well as respectful, enabling collaboration with the patient. CONCLUSIONS: Terminological differences appear to owe more to disciplinary origins than to substantive meaning. Beneficence needs to be balanced by and practised through respect for patient autonomy. Core ideas in existing conceptual frameworks of patient or person centredness can guide teaching and research. Considering the value and ethical imperative of person-centred practice, training institutions should train health care students and practitioners in its precepts. PMID- 29113448 TI - Can Oxidation-Reduction Potential of Cerebrospinal Fluid Be a Monitoring Biomarker in Amyotrophic Lateral Sclerosis? AB - The monitoring of progression in amyotrophic lateral sclerosis (ALS) relies on clinical outcome measures that take months to interpret, such as revised ALS functional rating scale (ALSFRS-R) score, with no approved biomarkers. A number of clinical studies have documented the involvement of oxidative stress in ALS pathology. Pertinent to this, we propose to evaluate oxidation-reduction potential (ORP) of cerebrospinal fluid (CSF) as a potential indicator of ALS progression. The case-control study included 24 patients with neurological non neurodegenerative disorders (controls) and 82 ALS patients with different degrees of disease (ALSFRS-R score: 21-47). ORP was significantly higher in ALS patients than controls. It was not dependent on age or gender. A strong negative correlation was found between ORP and ALSFRS-R score for all patients and patients with spinal onset. In other words, ORP increased with ALS progression. No correlation was found for the subset of patients with bulbar onset, most likely because of the physical distance between neurodegenerative loci and the site of CSF collection. These results lead to the hypothesis that ORP of CSF has a potential as monitoring biomarker in ALS, particularly in the cohort of patients with spinal onset. Antioxid. Redox Signal. 28, 1570-1575. PMID- 29113450 TI - Physiological Significance of Plant Peroxiredoxins and the Structure-Related and Multifunctional Biochemistry of Peroxiredoxin 1. AB - SIGNIFICANCE: Sessile plants respond to oxidative stress caused by internal and external stimuli by producing diverse forms of enzymatic and nonenzymatic antioxidant molecules. Peroxiredoxins (Prxs) in plants, including the Prx1, Prx5, Prx6, and PrxQ isoforms, constitute a family of antioxidant enzymes and play important functions in cells. Each Prx localizes to a specific subcellular compartment and has a distinct function in the control of plant growth, development, cellular metabolism, and various aspects of defense signaling. Recent Advances: Prx1, a typical Prx in plant chloroplasts, has redox-dependent multiple functions. It acts as a hydrogen peroxide (H2O2)-catalyzing peroxidase, a molecular chaperone, and a biological circadian marker. Prx1 undergoes a functional switching from a peroxidase to a molecular chaperone in response to oxidative stress, concomitant with the structural changes from a low-molecular weight species to high-molecular-weight complexes mediated by the post translational modification of its active site Cys residues. The redox status of the protein oscillates diurnally between hyperoxidation and reduction, showing a circadian rhythmic output. These dynamic structural and functional transformations mediate the effect of plant Prx1 on protecting plants from a myriad of harsh environmental stresses. CRITICAL ISSUES: The multifunctional diversity of plant Prxs and their roles in cellular defense signaling depends on their specific interaction partners, which remain largely unidentified. Therefore, the identification of Prx-interacting proteins is necessary to clarify their physiological significance. FUTURE DIRECTIONS: Since the functional specificity of the four plant Prx isoforms remains unclear, future studies should focus on investigating the physiological importance of each Prx isotype. Antioxid. Redox Signal. 28, 625-639. PMID- 29113451 TI - Nicotine Adenine Dinucleotides: The Redox Currency of the Cell. AB - There has been tremendous and rapidly growing interest in understanding intermediary metabolism as a key aspect of both normal cellular function and as a participant in the molecular pathogenesis of many different complex diseases. This area of research naturally intersects at virtually every level with the substantial and expanding body of knowledge regarding mechanisms of cellular redox balance. In this Forum, the contributing authors address specifically the union of intermediary metabolism and redox biology through detailed consideration of the biochemistry and biology of nicotine adenine dinucleotides, the cell's "redox currency." From technical considerations of how to measure nicotine adenine dinucleotides all the way to detailed treatments of their potential roles in specific disease states, this Forum provides a thorough introduction to a topic that is positioned to be at the heart of the next wave of research in metabolism and redox biology. Antioxid. Redox Signal. 28, 165-166. PMID- 29113449 TI - Where Hematopoietic Stem Cells Live: The Bone Marrow Niche. AB - SIGNIFICANCE: Hematopoietic stem cells (HSCs) can sustain the production of blood throughout one's lifetime. However, for proper self-renewal of its own population and differentiation to blood, the HSC requires a specialized microenvironment called the "niche." Recent Advances: Recent studies using novel mouse models have shed new light on the cellular architecture and function of the HSC niche. Here, we review the different cells that constitute the HSC niche and the molecular mechanisms that underlie HSC and niche interaction. We discuss the evidence and potential features that distinguish the HSC niche from other microenvironments in the bone marrow. The relevance of the niche in malignant transformation of the HSCs and harboring cancer metastasis to the bone is also outlined. In addition, we address how the niche may regulate reactive oxygen species levels surrounding the HSCs. Critical Issues and Future Directions: We propose future directions and remaining challenges in investigating the niche of HSCs. We discuss how a better understanding of the HSC niche may help in restoring an aged hematopoietic system, fighting against malignancies, and transplanting purified HSCs safely and effectively into patients. Antioxid. Redox Signal. 00, 000-000. PMID- 29113452 TI - Raised Fibrinogen Levels and Outcome in Outpatients With Peripheral Artery Disease. AB - The influence of raised fibrinogen levels on outcome in stable outpatients with peripheral arterial disease (PAD) has not been consistently investigated. We used data from the Factores de Riesgo y ENfermedad Arterial (FRENA) registry to compare ischemic events, major bleeding, and mortality in stable outpatients with PAD, according to their baseline plasma fibrinogen levels. Of 1363 outpatients with PAD recruited in FRENA, 558 (41%) had fibrinogen levels >450 mg/100 mL. Over 18 months, 43 patients presented with acute myocardial infarction, 37 had an ischemic stroke, 51 underwent limb amputation, 19 had major bleeding, and 90 died. Compared to patients with normal levels, those with raised fibrinogen levels had an over 2-fold higher rate of ischemic stroke (rate ratio [RR]: 2.30; 95% confidence interval [CI]: 1.19-4.59), limb amputation (RR: 2.58; 95% CI: 1.46 4.67), or death (RR: 2.27; 95% CI: 1.49-3.51) and an over 3-fold higher rate of major bleeding (RR: 3.90; 95% CI: 1.45-12.1). On multivariate analysis, patients with raised fibrinogen levels had an increased risk of developing subsequent ischemic events (hazard ratio [HR]: 1.61; 95% CI: 1.11-2.32) and major bleeding (HR: 3.42; 95% CI: 1.22-9.61). Stable outpatients with PAD and raised plasma fibrinogen levels had increased rates of subsequent ischemic events and major bleeding. PMID- 29113453 TI - The association between socioeconomic status and autism diagnosis in the United Kingdom for children aged 5-8 years of age: Findings from the Born in Bradford cohort. AB - There has been recent interest in the relationship between socioeconomic status and the diagnosis of autism in children. Studies in the United States have found lower rates of autism diagnosis associated with lower socioeconomic status, while studies in other countries report no association, or the opposite. This article aims to contribute to the understanding of this relationship in the United Kingdom. Using data from the Born in Bradford cohort, comprising 13,857 children born between 2007 and 2011, it was found that children of mothers educated to A level or above had twice the rate of autism diagnosis, 1.5% of children (95% confidence interval: 1.1%, 1.9%) compared to children of mothers with lower levels of education status 0.7% (95% confidence interval: 0.5%, 0.9%). No statistically significant relationship between income status or neighbourhood material deprivation was found after controlling for mothers education status. The results suggest a substantial level of underdiagnosis for children of lower education status mothers, though further research is required to determine the extent to which this is replicated across the United Kingdom. Tackling inequalities in autism diagnosis will require action, which could include increased education, awareness, further exploration of the usefulness of screening programmes and the provision of more accessible support services. PMID- 29113455 TI - HDAC1 Governs Iron Homeostasis Independent of Histone Deacetylation in Iron Overload Murine Models. AB - AIMS: Iron-overload disorders are common and could lead to significant morbidity and mortality worldwide. Due to limited treatment options, there is a great need to develop novel strategies to remove the excess body iron. To discover potential epigenetic modulator in hepcidin upregulation and subsequently decreasing iron burden, we performed an epigenetic screen. The in vivo effects of the identified compounds were further tested in iron-overload mouse models, including Hfe-/-, Hjv-/-, and hepatocyte-specific Smad4 knockout (Smad4fl/fl;Alb-Cre+) mice. RESULTS: Entinostat (MS-275), the clinical used histone deacetylase 1 (HDAC1) inhibitor, was identified the most potent hepcidin agonist. Consistently, Hdac1 deficient mice also presented higher hepcidin levels than wild-type controls. Notably, the long-term treatment with entinostat in Hfe-/- mice significantly alleviated iron overload through upregulating hepcidin transcription. In contrast, entinostat showed no effect on hepcidin expression and iron levels in Smad4fl/fl;Alb-Cre+ mice. Further mechanistic studies revealed that HDAC1 suppressed expression of hepcidin through interacting with SMAD4 rather than deacetylation of SMAD4 or histone-H3 on the hepcidin promoter. INNOVATION: The findings uncovered HDAC1 as a novel hepcidin suppressor through complexing with SMAD4 but not deacetylation of either histone 3 or SMAD4. In addition, our study suggested a novel implication of entinostat in treating iron-overload disorders. CONCLUSIONS: Based on our results, we conclude that entinostat strongly activated hepcidin in vivo and in vitro. HDAC1 could serve as a novel hepcidin suppressor by binding to SMAD4, effect of which is independent of BMP/SMAD1/5/8 signaling. Antioxid. Redox Signal. 28, 1224-1237. PMID- 29113456 TI - A systematic review of cost-effectiveness studies of prevention and treatment for eating disorders. AB - BACKGROUND: Eating disorders are serious mental disorders and are associated with substantial economic and social burden. The aim of this study is to undertake a systematic review of the cost-effectiveness studies of both preventive and treatment interventions for eating disorder. METHOD: Electronic databases (including the Cochrane Controlled Trial Register, MEDLINE, PsycINFO, Academic Search Complete, Global Health, CINAHL complete, Health Business Elite, Econlit, Health Policy Reference Center and ERIC) were searched for published cost effectiveness studies of eating disorder prevention and treatment including papers published up to January 2017. The quality of studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: In all, 13 studies met the review inclusion criteria as full cost-effectiveness studies and 8 were published since 2011. The studies included three modelled and one trial-based study focused on prevention, two trial-based and one modelled study for anorexia nervosa treatment and three trial-based studies for bulimia nervosa treatment. The remaining studies targeted binge eating disorder or non-specific eating disorder treatment. The average percent of CHEERS checklist items reported was 71% (standard deviation 21%). Eating disorder interventions were mainly cost-saving or more effective and more costly compared to comparators; however, some results did not reach statistical significance. In the two studies that achieved 100% CHEERS checklist, one study reported that a cognitive dissonance intervention might be cost-effective for prevention of anorexia nervosa and bulimia nervosa with a 90% participation rate and the second study supported lisdexamfetamine to be cost-effective in the treatment of binge eating disorder. Insufficient evidence for long-term cost-effectiveness (e.g. over 2 years) was found. CONCLUSION: Cost-effectiveness studies in eating disorder appear to be increasing in number over the last 6 years. Findings were inconsistent and no firm conclusion can be drawn with regard to comparative value for-money conclusions. However, some promising interventions were identified. Further research with improved methodology is required. PMID- 29113457 TI - The occurrence of deep pectoral myopathy in broilers and associated changes in breast meat quality. AB - 1. Two experiments were conducted to determine the effect of slaughter weight on the incidence and intensity of deep pectoral myopathy (DPM) of M. pectoralis minor (p. minor muscle) in commercial conditions in Turkey and to evaluate the impact of DPM on meat quality traits of pectoralis major (p. major) muscle in broilers. 2. In Experiment 1, a total of 116 250 carcasses from 59 Ross-308 broiler flocks, classified according to slaughter weight as 2.0-2.2, 2.2-2.4, 2.4 2.6 and >2.6 kg, were evaluated for occurrence of DPM. In Experiment 2, p. major samples from unaffected broilers and each DPM stage were evaluated for meat quality, oxidant and antioxidant properties, nutritional value and fatty acid profile. DPM was characterised as 1: muscles with coagulative necrosis, 2: muscles with fibrous tissue texture and pink to plumb and 3: muscles with green necrotic area. 3. The average incidence of DPM was found to be 0.73% in Experiment 1 and independent of slaughter weight. 4. In Experiment 2, p. major muscle of broilers with DPM 1 and 2 had higher pH values with higher redness and drip loss. All DPM stages resulted in an increase in lipid content and malondialdehyde activity and lowered ash content of p. major muscle compared with unaffected birds. DPM 2 increased superoxide dismutase and glutathione peroxidase activities in M. p. major. The p. major of broilers with DPM had lower content of C18:2 conjugated linoleic and C20:3n-6 fatty acids than those of unaffected broilers. Lower Delta6 desaturase and thiosterase activities and 18:2n-6 to 18:3n 3 ratio were observed for all DPM stages compared to unaffected. 5. It was concluded that these changes obtained in p. major muscle of broilers with DPM might indicate biochemical characteristics of muscle degenerations. PMID- 29113458 TI - Biological Production, Detection, and Fate of Hydrogen Peroxide. AB - SIGNIFICANCE: Hydrogen peroxide (H2O2) is generated in numerous biological processes. It transmits cellular signals, contributes to oxidative folding of exported proteins, and, in excess, can be damaging to cells and tissues. Although a strong oxidant, high activation energy barriers make it unreactive with most biological molecules. Its main reactions are with transition metal centers, selenoproteins and selected thiol proteins, with glutathione peroxidases (GPxs) and peroxiredoxins (Prxs) being major targets. It reacts slowly with most thiol proteins, and how they become oxidized during redox signal transmission is not well understood. Recent Advances: Kinetic analysis indicates that Prxs and GPxs are overwhelmingly favored as targets for H2O2 in cells. Studies with localized probes indicate that H2O2 can be produced in cellular microdomains and be consumed by highly reactive targets before it can diffuse to other parts of the cell. Inactivation of these targets alone will not confine it to its site of production. Kinetic data indicate that oxidation of regulatory thiol proteins by H2O2 requires a facilitated mechanism such as directed transfer from source to target or a relay mediated through a highly reactive sensor. Critical Issues and Future Directions: Absolute rates of H2O2 production and steady-state concentrations in cells still need to be characterized. More information on cellular sites of production and action is required, and specific mechanisms of oxidation of regulatory proteins during redox signaling require further characterization. Antioxid. Redox Signal. 29, 541-551. PMID- 29113459 TI - The combined effect of vitamin D and parathyroid hormone concentrations on glucose homeostasis in older patients with prediabetes: A cross-sectional study. AB - BACKGROUND: The combined effect of vitamin D and parathyroid hormone on glucose homeostasis has not been adequately investigated. The aim of this study was to examine the role of parathyroid hormone/vitamin D axis on glucose homeostasis in elderly persons with prediabetes. METHODS: Patients with prediabetes ( n = 144) and healthy age-matched controls ( n = 81) were included in this cross-sectional study. Study parameters included anthropometric characteristics, morning fasting glucose (fasting plasma glucose), insulin (fasting plasma insulin), parathyroid hormone, 25-hydroxyvitamin D, homeostasis model assessment of insulin resistance and homeostasis model assessment of beta-cell function. Both groups were stratified into subgroups according to vitamin D status and tertiles of parathyroid hormone. RESULTS: Both groups were comparable in terms of body mass index, 25-hydroxyvitamin D and parathyroid hormone status. In the prediabetes group, fasting plasma glucose differed significantly across parathyroid hormone tertiles, increasing from the first to the third tertile ( p = 0.011). There were higher fasting plasma glucose values in participants with vitamin D deficiency/parathyroid hormone third tertile compared to all other groups ( p = 0.031, 0.027 and 0.039, respectively). CONCLUSION: Parathyroid hormone status is associated with impaired glucose homeostasis; hypovitaminosis D combined with high parathyroid hormone concentrations are associated with glycaemic dysregulation in elderly patients with prediabetes. PMID- 29113454 TI - Modulators of Redox Metabolism in Head and Neck Cancer. AB - SIGNIFICANCE: Head and neck squamous cell cancer (HNSCC) is a complex disease characterized by high genetic and metabolic heterogeneity. Radiation therapy (RT) alone or combined with systemic chemotherapy is widely used for treatment of HNSCC as definitive treatment or as adjuvant treatment after surgery. Antibodies against epidermal growth factor receptor are used in definitive or palliative treatment. Recent Advances: Emerging targeted therapies against other proteins of interest as well as programmed cell death protein 1 and programmed death-ligand 1 immunotherapies are being explored in clinical trials. CRITICAL ISSUES: The disease heterogeneity, invasiveness, and resistance to standard of care RT or chemoradiation therapy continue to constitute significant roadblocks for treatment and patients' quality of life (QOL) despite improvements in treatment modality and the emergence of new therapies over the past two decades. FUTURE DIRECTIONS: As reviewed here, alterations in redox metabolism occur at all stages of HNSCC management, providing opportunities for improved prevention, early detection, response to therapies, and QOL. Bioinformatics and computational systems biology approaches are key to integrate redox effects with multiomics data from cells and clinical specimens and to identify redox modifiers or modifiable target proteins to achieve improved clinical outcomes. Antioxid. Redox Signal. PMID- 29113460 TI - Impact of Age on Human Adipose Stem Cells for Bone Tissue Engineering. AB - Bone nonunion is a pathological condition in which all bone healing processes have stopped, resulting in abnormal mobility between 2 bone segments. The incidence of bone-related injuries will increase in an aging population, leading to such injuries reaching epidemic proportions. Tissue engineering and cell therapy using mesenchymal stem cells (MSCs) have raised the possibility of implanting living tissue for bone reconstruction. Bone marrow was first proposed as the source of stem cells for bone regeneration. However, as the quantity of MSCs in the bone marrow decreases, the capacity of osteogenic differentiation of bone marrow stem cells is also impaired by the donor's age in terms of reduced MSC replicative capacity; an increased number of apoptotic cells; formation of colonies positive for alkaline phosphatase; and decreases in the availability, growth potential, and temporal mobilization of MSCs for bone formation in case of fracture. Adipose-derived stem cells (ASCs) demonstrate several advantages over those from bone marrow, including a less invasive harvesting procedure, a higher number of stem cell progenitors from an equivalent amount of tissue harvested, increased proliferation and differentiation capacities, and better angiogenic and osteogenic properties in vivo. Subcutaneous native adipose tissue was not affected by the donor's age in terms of cellular senescence and yield of ASC isolation. In addition, a constant mRNA level of osteocalcin and alkaline phosphatase with a similar level of matrix mineralization of ASCs remained unaffected by donor age after osteogenic differentiation. The secretome of ASCs was also unaffected by age when aiming to promote angiogenesis by vascular endothelial growth factor (VEGF) release in hypoxic conditions. Therefore, the use of adipose cells for bone tissue engineering is not limited by the donor's age from the isolation of stem cells up to the manufacturing of a complex osteogenic graft. PMID- 29113462 TI - Simultaneous Transplantation of Fetal Ventral Mesencephalic Tissue and Encapsulated Genetically Modified Cells Releasing GDNF in a Hemi-Parkinsonian Rat Model of Parkinson's Disease. AB - Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-hydroxydopamine rat model of PD, we investigated the feasibility of simultaneous transplantation of rat fetal VM tissue and polymer-encapsulated C2C12 myoblasts genetically modified to produce glial cell line-derived neurotrophic factor (GDNF) or mock-transfected myoblasts on graft function. Amphetamine-induced rotations were assessed prior to transplantation and 2, 4, 6 and 9 wk posttransplantation. We found that rats grafted with VM transplants and GDNF capsules showed a significant functional recovery 4 wk after implantation. In contrast, rats from the VM transplant and mock-capsule group did not improve at any time point analyzed. Moreover, we detected a significantly higher number of tyrosine hydroxylase immunoreactive (TH ir) cells per graft (2-fold), a tendency for a larger graft volume and an overall higher TH-ir fiber outgrowth into the host brain (1.7-fold) in the group with VM transplants and GDNF capsules as compared to the VM transplant and mock-capsule group. Most prominent was the TH-ir fiber outgrowth toward the capsule (9-fold). Grafting of GDNF-pretreated VM transplants in combination with the implantation of GDNF capsules resulted in a tendency for a higher TH-ir fiber outgrowth into the host brain (1.7-fold) as compared to the group transplanted with untreated VM transplants and GDNF capsules. No differences between groups were observed for the number of surviving TH-ir neurons or graft volume. In conclusion, our findings demonstrate that simultaneous transplantation of fetal VM tissue and encapsulated GDNF-releasing cells is feasible and support the graft survival and function. Pretreatment of donor tissue with GDNF may offer a way to further improve cell transplantation approaches for PD. PMID- 29113461 TI - Regenerative Medicine: Shedding Light on the Link between Aging and Cancer. AB - The evidence linking aging and cancer is overwhelming. Findings emerging from the field of regenerative medicine reinforce the notion that aging and cancer are profoundly interrelated in their pathogenetic pathways. We discuss evidence to indicate that age-associated alterations in the tissue microenvironment contribute to the emergence of a neoplastic-prone tissue landscape, which is able to support the selective growth of preneoplastic cell populations. Interestingly, tissue contexts that are able to select for the growth of preneoplastic cells, including the aged liver microenvironment, are also supportive for the clonal expansion of normal, homotypic, transplanted cells. This suggests that the growth of normal and preneoplastic cells is possibly driven by similar mechanisms, implying that strategies based on principles of regenerative medicine might be applicable to modulate neoplastic disease. PMID- 29113463 TI - Age-related Changes in Bone Marrow Mesenchymal Stromal Cells: A Potential Impact on Osteoporosis and Osteoarthritis Development. AB - Aging at the cellular level is a complex process resulting from accumulation of various damages leading to functional impairment and a reduced quality of life at the level of the organism. With a rise in the elderly population, the worldwide incidence of osteoporosis (OP) and osteoarthritis (OA) has increased in the past few decades. A decline in the number and "fitness" of mesenchymal stromal cells (MSCs) in the bone marrow (BM) niche has been suggested as one of the factors contributing to bone abnormalities in OP and OA. It is well recognized that MSCs in vitro acquire culture-induced aging features such as gradual telomere shortening, increased numbers of senescent cells, and reduced resistance to oxidative stress as a result of serial population doublings. In contrast, there is only limited evidence that human BM-MSCs "age" similarly in vivo. This review compares the various aspects of in vitro and in vivo MSC aging and suggests how our current knowledge on rejuvenating cultured MSCs could be applied to develop future strategies to target altered bone formation processes in OP and OA. PMID- 29113465 TI - Porcine Neural Progenitor Cells Derived from Tissue at Different Gestational Ages Can Be Distinguished by Global Transcriptome. AB - The impact of gestational age on mammalian neural progenitor cells is potentially important for both an understanding of neural development and the selection of donor cells for novel cell-based treatment strategies. In terms of the latter, it can be problematic to rely entirely on rodent models in which the gestational period is significantly shorter and the brain much smaller than is the case in humans. Here, we analyzed pig brain progenitor cells (pBPCs) harvested at 2 different gestational ages (E45 and E60) using gene expression profiles, obtained by microarray analysis and quantitative polymerase chain reaction (qPCR), across time in culture. Comparison of the global transcriptome of pBPCs from age-matched transgenic green flourescent protein (GFP)-expressing fetuses versus non- GFP expressing fetuses did not reveal significant differences between the 2 cell types, whereas comparison between E45 and E60 pBPCs did show separation between the data sets by principle component analysis. Further examination by qPCR showed evidence of relative downregulation of proliferation markers and upregulation of glial markers in the gestationally older (E60) cells. Additional comparisons were made. This study provides evidence of age-related changes in the gene expression of cultured fetal porcine neural progenitors that are potentially relevant to the role of these cells during development and as donor cells for transplantation studies. PMID- 29113466 TI - Perspectives of Stem Cell-Based Therapy for Age-Related Retinal Degenerative Diseases. AB - Retinal degenerative diseases, which include age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and glaucoma, mostly affect the elderly population and are the most common cause of decreased quality of vision or even blindness. So far, there is no satisfactory treatment protocol to prevent, stop, or cure these disorders. A great hope and promise for patients suffering from retinal diseases is represented by stem cell-based therapy that could replace diseased or missing retinal cells and support regeneration. In this respect, mesenchymal stem cells (MSCs) that can be obtained from the particular patient and used as autologous cells have turned out to be a promising stem cell type for treatment. Here we show that MSCs can differentiate into cells expressing markers of retinal cells, inhibit production of pro-inflammatory cytokines by retinal tissue, and produce a number of growth and neuroprotective factors for retinal regeneration. All of these properties make MSCs a prospective cell type for cell-based therapy of age-related retinal degenerative diseases. PMID- 29113464 TI - A New Treatment Strategy for Parkinson's Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway. AB - Molecular communications in the gut-brain axis, between the central nervous system and the gastrointestinal tract, are critical for maintaining healthy brain function, particularly in aging. Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's diseases (PD) for which aging shows a major correlative association. Common pathophysiological features exist between T2DM, AD, and PD, including oxidative stress, inflammation, insulin resistance, abnormal protein processing, and cognitive decline, and suggest that effective drugs for T2DM that positively impact the gut-brain axis could provide an effective treatment option for neurodegenerative diseases. Glucagon-like peptide-1 (GLP-1)-based antidiabetic drugs have drawn particular attention as an effectual new strategy to not only regulate blood glucose but also decrease body weight by reducing appetite, which implies that GLP-1 could affect the gut-brain axis in normal and pathological conditions. The neurotrophic and neuroprotective effects of GLP-1 receptor (R) stimulation have been characterized in numerous in vitro and in vivo preclinical studies using GLP-1R agonists and dipeptidyl peptidase-4 inhibitors. Recently, the first open label clinical study of exenatide, a long-acting GLP-1 agonist, in the treatment of PD showed long lasting improvements in motor and cognitive function. Several double-blind clinical trials of GLP-1R agonists including exenatide in PD and other neurodegenerative diseases are already underway or are about to be initiated. Herein, we review the physiological role of the GLP-1R pathway in the gut-brain axis and the therapeutic strategy of GLP-1R stimulation for the treatment of neurodegenerative diseases focused on PD, for which age is the major risk factor. PMID- 29113467 TI - Adipose-Derived Mesenchymal Stem Cells from the Elderly Exhibit Decreased Migration and Differentiation Abilities with Senescent Properties. AB - Adipose-derived stem cells (ASCs) can be applied extensively in the clinic because they can be easily isolated and cause less donor-site morbidity; however, their application can be complicated by patient-specific factors, such as age and harvest site. In this study, we systematically evaluated the effects of age on the quantity and quality of human adipose-derived mesenchymal stem cells (hASCs) isolated from excised chest subcutaneous adipose tissue and investigated the underlying molecular mechanism. hASCs were isolated from donors of 3 different age-groups (i.e., child, young adult, and elderly). hASCs are available from individuals across all age-groups and maintain mesenchymal stem cell (MSC) characteristics. However, the increased age of the donors was found to have a significant negative effect on hASCs frequency base on colony-forming unit fibroblasts assay. Moreover, there is a decline in both stromal vascular fraction (SVF) cell yield and the proliferation rate of hASCs with increasing age, although this relationship is not significant. Aging increases cellular senescence, which is manifested as an increase in SA-beta-gal-positive cells, increased mitochondrial-specific reactive oxygen species (ROS) production, and the expression of p21 in the elderly. Further, advancing age was found to have a significant negative effect on the adipogenic and osteogenic differentiation potentials of hASCs, particularly at the early and mid-stages of induction, suggesting a slower response to the inducing factors of hASCs from elderly donors. Finally, impaired migration ability was also observed in the elderly group and was determined to be associated with decreased expression of chemokine receptors, such as CXCR4 and CXCR7. Taken together, these results suggest that, while hASCs from different age populations are phenotypically similar, they present major differences at the functional level. When considering potential applications of hASCs in cell-based therapeutic strategies, the negative influence of age on hASC differentiation potential and migration abilities should be taken seriously. PMID- 29113468 TI - Hippocampal Cholinergic Neurostimulating Peptide as a Possible Modulating Factor against Glutamatergic Neuronal Disability by Amyloid Oligomers. AB - Despite having pathological changes in the brain associated with Alzheimer's disease (AD), some patients have preserved cognitive function. A recent epidemiological study has shown that diet, exercise, cognitive training, and vascular risk monitoring interventions may reduce cognitive decline in at-risk elderly people in the general population. However, the details of molecular mechanisms underlying this cognitive function preservation are still unknown. Previous reports have demonstrated that enriched environments prevent the impairment of hippocampal long-term potentiation (LTP) through beta2-adrenergic signals, when LTP is incompletely suppressed by synthetic amyloid-beta (Abeta) oligomers. The cholinergic network from the medial septal nucleus (MSN) is also a main modulating system for hippocampal glutamatergic neural activation through nicotinergic and/or muscarinergic acetylcholine receptors. Previously, we reported the importance of a cholinergic regulator gene in the MSN, hippocampal cholinergic neurostimulating peptide (HCNP). By using hippocampal sections from mice, we here demonstrated that the cholinergic neural activation from the MSN enhanced the glutamatergic neuronal activity during unsaturated LTP but not during saturated LTP. Synthetic Abeta oligomers suppressed the hippocampal glutamatergic activity in a concentration-dependent manner. Furthermore, HCNP, as well as a cholinergic agonist acting through the muscarinic M1 receptor, prevented the suppression of hippocampal glutamatergic neuronal activity induced by synthetic Abeta oligomers. This result suggests that the persisting cholinergic activation might be a potential explanation for the individual differences in cognitive effects of AD pathological changes. PMID- 29113469 TI - Improving Neurorepair in Stroke Brain Through Endogenous Neurogenesis-Enhancing Drugs. AB - Stroke induces not only cell death but also neurorepair. De novo neurogenesis has been found in the subventricular zone of the adult mammalian brain days after stroke. Most of these newly generated cells die shortly after the insult. Recent studies have shown that pharmacological manipulation can improve the survival of endogenous neuroprogenitor cells and neural regeneration in stroke rats. As these drugs target the endogenous reparative processes that occur days after stroke, they may provide a prolonged window for stroke therapy. Here, we discuss endogenous neurogenesis-enhancing drugs and review the general status of stroke therapeutics in evaluating the field of pharmacotherapy for stroke. PMID- 29113470 TI - Posttransplant Immune Activation: Innocent Bystander or Insidious Culprit of Posttransplant Accelerated Atherosclerosis. AB - Cardiovascular disease is a major cause of morbidity, disability, and mortality in kidney transplant patients. Cumulative reports indicate that the excessive risk of cardiovascular events is not entirely explained by the increased prevalence of traditional cardiovascular risk factors. Atherosclerosis is a chronic inflammatory disease, and it has been postulated that posttransplant immune disturbances may explain the gap between the predicted and observed risks of cardiovascular events. Although concordant data suggest that innate immunity contributes to the posttransplant accelerated atherosclerosis, only few arguments plead for a role of adaptive immunity. We report and discuss here consistent data demonstrating that CD8+ T cell activation is a frequent posttransplant immune feature that may have pro-atherogenic effects. Expansion of exhausted/activated CD8+ T cells in kidney transplant recipients is stimulated by several factors including cytomegalovirus infections, lymphodepletive therapy (e.g., antithymocyte globulins), chronic allogeneic stimulation, and a past history of renal insufficiency. This is observed in the setting of decreased thymic activity, a process also found in elderly individuals and reflecting accelerated immune senescence. PMID- 29113474 TI - Theme 9 Clinical trials. PMID- 29113471 TI - Oxidative Stress in Stem Cell Aging. AB - Stem cell aging is a process in which stem cells progressively lose their ability to self-renew or differentiate, succumb to senescence or apoptosis, and eventually become functionally depleted. Unresolved oxidative stress and concomitant oxidative damages of cellular macromolecules including nucleic acids, proteins, lipids, and carbohydrates have been recognized to contribute to stem cell aging. Excessive production of reactive oxygen species and insufficient cellular antioxidant reserves compromise cell repair and metabolic homeostasis, which serves as a mechanistic switch for a variety of aging-related pathways. Understanding the molecular trigger, regulation, and outcomes of those signaling networks is critical for developing novel therapies for aging-related diseases by targeting stem cell aging. Here we explore the key features of stem cell aging biology, with an emphasis on the roles of oxidative stress in the aging process at the molecular level. As a concept of cytoprotection of stem cells in transplantation, we also discuss how systematic enhancement of endogenous antioxidant capacity before or during graft into tissues can potentially raise the efficacy of clinical therapy. Finally, future directions for elucidating the control of oxidative stress and developing preventive/curative strategies against stem cell aging are discussed. PMID- 29113476 TI - Theme 2 In vitro experimental models. PMID- 29113477 TI - Theme 3 In vivo experimental models. PMID- 29113472 TI - Cell Therapy for Parkinson's Disease. AB - Cell therapy for Parkinson's disease (PD) began in 1979 with the transplantation of fetal rat dopamine-containing neurons that improved motor abnormalities in the PD rat model with good survival of grafts and axonal outgrowth. Thirty years have passed since the 2 clinical trials using cell transplantation for PD patients were first reported. Recently, cell therapy is expected to develop as a realistic treatment option for PD patients owing to the advancement of biotechnology represented by pluripotent stem cells. Medication using levodopa, surgery including deep brain stimulation, and rehabilitation have all been established as current therapeutic strategies. Strong therapeutic effects have been demonstrated by these treatment methods, but they have been unable to stop the progression of the disease. Fortunately, cell therapy might be a key for true neurorestoration. This review article describes the historical development of cell therapy for PD, the current status of cell therapy, and the future direction of this treatment method. PMID- 29113478 TI - Sessions 1 - 11. PMID- 29113479 TI - Theme 6 Biomarkers. PMID- 29113480 TI - Theme 12 Cognitive and psychological assessment and support. PMID- 29113481 TI - Theme 8 Imaging. PMID- 29113482 TI - Theme 1 Genetics and genomics. PMID- 29113483 TI - Theme 4 Human cell biology and pathology. PMID- 29113484 TI - Theme 11: Improving diagnosis, prognosis and disease progression. PMID- 29113487 TI - Theme 10 Therapeutic strategies. PMID- 29113485 TI - Theme 5 Epidemiology. PMID- 29113490 TI - Theme 13 Respiratory and nutritional management. PMID- 29113489 TI - Theme 14 Multidisciplinary care and improving quality of life. PMID- 29113492 TI - Theme 7 Electrophysiology. PMID- 29113493 TI - Re: Comparison of Surgical Outcomes Between Resection and Enucleation in Robot Assisted Laparoscopic Partial Nephrectomy for Renal Tumors According to the Surface-Intermediate-Base Margin Score: A Propensity Score-Matched Study (From: Takagi T, Kondo T, Tachibana H, et al. J Endourol 2017;31:756-761). PMID- 29113494 TI - Ecologies of power: countermapping the logistical landscapes & military geographies of the U.S. department of defense. PMID- 29113495 TI - Pharmacophore modelling, virtual screening and molecular docking studies on PLD1 inhibitors. AB - Lipid metabolism plays a significant role in influenza virus replication and subsequent infection. The regulatory mechanism governing lipid metabolism and viral replication is not properly understood to date, but both Phospholipase D (PLD1 and PLD2) activities are stimulated in viral infection. In vitro studies indicate that chemical inhibition of PLD1 delays viral entry and reduction of viral loads. The current study reports a three-dimensional pharmacophore model based on 35 known PLD1 inhibitors. A sub-set of 25 compounds was selected as the training set and the remaining 10 compounds were kept in the test set. One hundred and twelve pharmacophore models were generated; a six-featured pharmacophore model (AADDHR.57) with survival score (2.69) produced a statistically significant three-dimensional quantitative structure-activity relationship model with r2 = 0.97 (internal training set), r2 = 0.71 (internal test set) and Q2 = 0.64. The predictive power of the pharmacophore model was validated with an external test set (r2 = 0.73) and a systematic virtual screening work-flow was employed showing an enrichment factor of 23.68 at the top 2% of the dataset (active and decoys). Finally, the model was used for screening of the filtered PubChem database to fetch molecules which can be proposed as potential PLD1 inhibitors for blocking influenza infection. PMID- 29113496 TI - Both youth and long-term vitamin D status is associated with risk of type 2 diabetes mellitus in adulthood: a cohort study. AB - OBJECTIVES: To determine whether vitamin D status in childhood and adolescence (herein collectively referred to as youth) and the long-term status from youth to adulthood is associated with risk of developing type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) in adulthood. MATERIALS AND METHODS: This was a 31-year follow-up study of 2300 participants aged 3-18 years. Multinomial logistic regression was used to assess the association of both (a) baseline 25 hydroxyvitamin D (25OHD) levels and (b) the mean of baseline and the latest follow-up 25OHD levels (continuous variable and quartiles) with incident T2DM and IFG (cut-off = 5.6 mmol/L) in adult life. RESULTS: High serum 25OHD levels in youth and also mean values from youth to adulthood were associated with reduced risk of developing T2DM in adulthood (odds ratio, 95% confidence interval= 0.73, 0.57-0.95 and 0.65, 0.51-0.84, respectively, for each SD increment in 25OHD). Compared to Q1, a dose-dependent negative association was observed across other quartiles of youth 25OHD, while the strongest association was found in the Q3 for the mean 25OHD levels. Neither youth nor the mean 25OHD was associated with IFG. CONCLUSIONS: High serum 25OHD levels in youth, and from child to adult life, were associated with a reduced risk of developing T2DM in adulthood. Key Messages High serum 25OHD levels in youth, and between youth and adulthood, were associated with a lower risk of T2DM in adulthood. Each SD (15.2 nmol/L) increment in youth serum 25OHD levels was associated with a 26% reduction in odds for T2DM, which was independent of a number of confounding variables and other risk factors for T2DM. A similar magnitude of association was observed for the long-term 25OHD levels between youth and adulthood. These findings suggest a potentially simple and cost-effective strategy for reducing adulthood risk of T2DM starting in an earlier stage of life - improving and maintaining vitamin D status throughout youth and early adulthood. PMID- 29113497 TI - Modelling height in adolescence: a comparison of methods for estimating the age at peak height velocity. AB - BACKGROUND: Controlling for maturational status and timing is crucial in lifecourse epidemiology. One popular non-invasive measure of maturity is the age at peak height velocity (PHV). There are several ways to estimate age at PHV, but it is unclear which of these to use in practice. AIM: To find the optimal approach for estimating age at PHV. SUBJECTS AND METHODS: Methods included the Preece & Baines non-linear growth model, multi-level models with fractional polynomials, SuperImposition by Translation And Rotation (SITAR) and functional data analysis. These were compared through a simulation study and using data from a large cohort of adolescent boys from the Christ's Hospital School. RESULTS: The SITAR model gave close to unbiased estimates of age at PHV, but convergence issues arose when measurement error was large. Preece & Baines achieved close to unbiased estimates, but shares similarity with the data generation model for our simulation study and was also computationally inefficient, taking 24 hours to fit the data from Christ's Hospital School. Functional data analysis consistently converged, but had higher mean bias than SITAR. Almost all methods demonstrated strong correlations (r > 0.9) between true and estimated age at PHV. CONCLUSIONS: Both SITAR or the PBGM are useful models for adolescent growth and provide unbiased estimates of age at peak height velocity. Care should be taken as substantial bias and variance can occur with large measurement error. PMID- 29113498 TI - Decreased serum microRNA-21 level is associated with obesity in healthy and type 2 diabetic subjects. AB - BACKGROUND: Recently, much attention has been paid to the role of circulating microRNAs (miRNAs) as novel biomarkers for various diseases. The aim of this study was to investigate the level of a subset of miRNAs in serum samples of the diabetic and healthy subjects. METHODS: Forty two healthy and 45 T2D subjects participated in this study. Serum miR-21, miR-126, and miR-146a levels were measured using real-time PCR. RESULTS: There was no significant difference in the serum level of miR-21, miR-126, and miR-146a between the diabetic and non diabetic groups. The level of miR-21 in obese non-diabetic and diabetic subjects was significantly lower than lean subjects. Correlation analyses in non-diabetic and diabetic groups revealed a significant negative correlation between the amount of miR-21 and body mass index, waist circumference, insulin, and HOMA-IR levels. CONCLUSIONS: A reduced level of miR-21 might associate with obesity and its related metabolic traits such as hyperinsulinaemia. PMID- 29113499 TI - Certainty of Decisions: A Process-Based Model for Decision Making for Children With Severe Neurological Impairment. PMID- 29113500 TI - Fibrotic and apoptotic markers alteration in ovariectomised rats: addition of swimming training preserves lung architecture. AB - CONTEXT: The important role of exercise in pulmonary function during menopause is not well known. Oestrogen deficiency in ageing female mice is accompanied by increase in apoptotic markers such as caspase3 in the lung. OBJECTIVE: The present study was designed to investigate whether swimming training will ameliorate fibrosis and apoptosis resolution in the ovariectomy-induced lung injury rats. MATERIAL AND METHOD: Thirty female rats were assigned to three groups (n = 10 in each group): sham; rats underwent bilateral laparotomy without ovariectomy, OVX; rats underwent bilateral ovariectomy, OVX.Exe; ovariectomised rats that underwent swimming training for eight weeks. At the end of eight weeks, the lungs were harvested and protein expressions in whole lung tissues were analysed by western blotting technique. RESULT: Analysis of proteins expression in the lung showed significant differences between exercise and ovariectomised group (p < .05). CONCLUSION: The present study indicates strong potential of exercise in experimental oestrogen deficiency-induced lung damage. PMID- 29113501 TI - Fabrication of Niclosamide loaded solid lipid nanoparticles: in vitro characterization and comparative in vivo evaluation. AB - Niclosamide (NCS) is an oral anthelminthic drug having low solubility and hence low bioavailability. Current investigation shows an approach to fabricate solid lipid nanoparticles (SLNs) of NCS and evaluated for pharmaceutical, in vitro and in vivo characterization. NFM-3 showed particle size 204.2 +/- 2.2 nm, polydispersity index 0.328 +/- 0.02 and zeta potential -33.16 +/- 2 mV. Entrapment efficiency and drug loading capacity were 84.4 +/- 0.02% and 5.27 +/- 0.03%, respectively. Scanning electron microscopy image indicated that particles were nanoranged. DSC and P-XRD results showed change in physicochemical properties of NCS. FT-IR spectra confirmed compatibility between NCS and excipients. The drug release profile showed sustained release (93.21%) of NCS in 12 h. Different kinetic models showed zero-order kinetics and Case-II transport mechanism. Study showed maximum stability at refrigerated temperature. In vivo pharmacokinetic study showed 2.15-fold increase in NCS peak plasma concentration as solid lipid nanoparticle formulation (NFM-3) compared to commercial product while relative bioavailability was 11.08. Results including in vitro and in vivo release studies of NCS confirmed that SLNs system is suitable to improve oral delivery of NCS with increased aqueous solubility, permeability and finally bioavailability. PMID- 29113502 TI - Osteogenic and antibacterial properties of vancomycin-laden mesoporous bioglass/PLGA composite scaffolds for bone regeneration in infected bone defects. AB - Chronic osteomyelitis and infected bone defects are substantial challenges faced by orthopaedic surgeons. In this study, vancomycin was loaded into mesoporous bioactive glass (MBG) to form a local antibiotic delivery system and then a bone tissue-engineering scaffold combining MBG and poly-(L-lactic-co-glycolic acid) (PLGA) was prepared by freeze-drying fabrication. In vitro degradation and water contact angle analysis suggested that the MBG-incorporated PLGA scaffold exhibited controlled degradability, stabilizing the pH of the surrounding environment and improved the hydrophilicity. Moreover, the presence of MBG provides a well-interconnected pore structure, to which human bone marrow-derived mesenchymal stem cells can attach, spread and proliferate, promoting upregulation of the expression of osteogenic markers. Thus, MBG/PLGA scaffolds exhibit better cytocompatibility and osteoblastic difierentiation properties compared with pure PLGA scaffolds. Vancomycin-loaded scaffolds have been found to yield sustained release that lasts for more than eight weeks in vitro. We tested the antibacterial performance of vancomycin-loaded scaffolds against Staphylococcus aureus, the most common bacteria isolated from infected bone. In vitro experiments demonstrated that loading vancomycin onto the scaffold promoted antibacterial activity and inhibited biofilm formation without deleterious effect on cytocompatibility. In conclusion, the novel inorganic-organic composites are considered potential materials for the treatment of infected bone defects. PMID- 29113504 TI - Enhancement of chemosensitivity by simultaneously silencing of Mcl-1 and Survivin genes using small interfering RNA in human myelomonocytic leukaemia. AB - Acute myeloid leukaemia (AML) is a genetically heterogeneous, severe and rapidly progressing disease triggered by blocking granulocyte or monocyte differentiation and maturation. Overexpression of myeloid cell leukaemia-1 (Mcl-1) and Survivin is associated with drug resistance, tumour progression and inhibition of apoptotic mechanisms in leukaemia and several cancers. In the present study, we examined the combined effect of etoposide and dual siRNA-mediated silencing of Mcl-1 and Survivin on U-937 AML cells. The AML cells were co-transfected with Mcl 1 and Survivin-specific siRNAs and genes silencing were confirmed by quantitative real-time PCR and Western blotting. Subsequently, MTT assay was used for the evaluation of cytotoxic effects by dual siRNA and etoposide on their own and in combination. For the studying of apoptosis, DNA-histone ELISA and annexin-V/FITC assays were performed. Co-transfection of Mcl-1 and Survivin siRNA significantly blocked their expression at the mRNA and protein levels, leading to the induction of apoptosis and strong inhibition of growth (p < .05). Besides, combined treatment of etoposide with Mcl-1 and Survivin siRNAs co-transfection leads to synergistically enhance etoposide-induced cytotoxic and apoptotic effects (p < .05). The results showed that Mcl-1 and Survivin play a major role in the U937 cells survival and their resistance relative to etoposide. Thus, Mcl-1 and Survivin can be considered as promising molecular targets for the treatment of AML. The combination treatment with etoposide, and siRNA-mediated silencing of corresponding genes may be a novel strategy in chemoresistance AML treatment. PMID- 29113503 TI - Effects of crystalline state and self-nanoemulsifying drug delivery system (SNEDDS) on oral bioavailability of the novel anti-HIV compound 6-benzyl-1 benzyloxymethyl-5-iodouracil in rats. AB - The objective of this study was to investigate the effect of crystalline state and a formulation of self-nanoemulsifying drug delivery system (SNEDDS) on oral bioavailability of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non nucleoside reverse transcriptase inhibitor, in rats. The crystalline states of W 1 were characterized by scanning electron microscope (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The SNEDDS was formulated by medium-chain lipids, characterized by droplet particle size. The plasma concentrations of W-1 were measured by high performance liquid chromatography (HPLC). The results indicated that W-1 compound were presented as crystalline forms, A and B, the degree of crystallization in form B was higher than that in form A. The SNEDDS of W-1 displayed a significant increase in the dissolution rate than W-1 powder. Furthermore, after oral administration of W-1 (100 mg/kg), the pharmacokinetic parameters of form A, form B, and W-1 SNEDDS were as follows: AUC0-t 526.4 +/- 123.5, 305.1 +/- 58.5 and 2297 +/- 451 ng h/mL (p < .05, when W 1 SNEDDS were compared with either form A or form B), respectively. With SNEDDS formulation, the relative bioavailabilities were enhanced by 4.36-fold and 7.53 fold over the form A and form B of W-1, respectively. In conclusion, the present results suggested that the crystalline states of W-1 might lead to the lower oral bioavailability, and SNEDDS formulation is a promising strategy of improving bioavailability, in spite of that crystalline states usually carry small lot-to lot variability. PMID- 29113505 TI - Fever, Confusion, and a Severe Headache. PMID- 29113506 TI - Latent Classes and Cumulative Impacts of Adverse Childhood Experiences. AB - Studies of adverse childhood experiences (ACEs) have gauged severity using a cumulative risk (CR) index. Few studies have focused on the nature of the context of adversity and their association with psychosocial outcomes. The objective of this study was to examine the patterning of ACEs and to explore the resultant patterns' association with HIV risk-taking, problem drinking, and depressive symptoms in adulthood. Latent class analysis (LCA) was used to identify homogeneous, mutually exclusive "classes" of 11 of the most commonly used ACEs. The LCA resulted in four high-risk profiles and one low-risk profile, which were labeled: (1) highly abusive and dysfunctional (3.3%; n = 1,983), (2) emotionally abusive alcoholic with parental conflict (6%, n = 3,303), (3) sexual abuse only (4.3%, n = 2,260), (4) emotionally abusive and alcoholic (30.3%, n = 17,460), and (5) normative, low risk (56.3%, n = 32,950). Compared to the low-risk class, each high-risk profile was differentially associated with adult psychosocial outcomes even when the conditional CR within that class was similar. The results further our understanding about the pattern of ACEs and the unique pathways to poor health. Implications for child welfare systems when dealing with individuals who have experienced multiple forms of early childhood maltreatment and/or household dysfunction are discussed. PMID- 29113507 TI - Corrigendum. PMID- 29113508 TI - Outcomes of Children With Critical Bronchiolitis Living in Poor Communities. AB - There are established associations between adverse health outcomes and poverty, but little is known regarding these associations in critically ill children. We hypothesized that living in poorer communities would be associated with unfavorable outcomes in children with critical bronchiolitis. This retrospective study included children with bronchiolitis admitted to a pediatric intensive care unit (PICU) over a 2-year period. Median household income was estimated from patient ZIP codes and 2014 US Census Bureau data. The 2014 Federal Poverty Threshold (FPT) for a family of 4 was $24 008. Patients were classified as living in ZIP codes below or above the 150% FPT (150FPT). Living <150FPT was associated with longer PICU length of stay (LOS), longer hospital LOS, higher odds of needing mechanical ventilation, and increased hospital charges. In this cohort of critically ill children with bronchiolitis, living in a poorer community was associated with more unfavorable clinical outcomes. PMID- 29113509 TI - The microbial metabolite indole-3-propionic acid improves glucose metabolism in rats, but does not affect behaviour. AB - CONTEXT: We have previously shown that an antidepressant-like effect of probiotics in rats was associated with a higher plasma level of the microbial tryptophan metabolite indole-3-propionic acid (IPA). OBJECTIVE: We therefore wanted to study the isolated effect of IPA on behaviour and glucose metabolism in rats. METHODS: Male Sprague-Dawley rats were fed control or IPA-enriched diet for six weeks (n = 12 per group) and assessed in the elevated plus maze, open field and forced swim test. Blood glucose, metabolic hormones and the white blood cell (WBC) composition were analysed. RESULTS: IPA (mean intake 27.3 mg/kg/day) significantly lowered fasting blood glucose level by 0.42 mM (95% CI 0.11-0.73). Similarly, fasting plasma insulin levels and the homeostatic model assessment (HOMA) index of insulin resistance were reduced, whereas plasma metabolic hormones, behaviour and WBC composition remained unaffected by IPA. CONCLUSIONS: Our findings highlight IPA as a promising candidate for treatment of metabolic disorders associated with insulin resistance. PMID- 29113511 TI - Analysis of the clinical outcomes of fetal bowel dilatation combined with other abnormal ultrasonographic features. AB - OBJECTIVES: To explore the significance of fetal bowel dilatation combined with other abnormal ultrasound features in the diagnosis of gastrointestinal malformation. METHODS: A retrospective study of fetuses with bowel dilatation was performed, from August 2012 to October 2015. All the cases were identified from the ultrasound database and all observations of the relationship of prenatal abnormal abdominal ultrasound features and intestinal malformation were performed through the infancy stage. RESULTS: We found 52 fetuses with prenatal suspicion of bowel dilatation. Of these, 20 cases were surgically confirmed to have intestinal malformation, 13 cases had no abnormal bowel loops after birth, 8 cases had abnormal intestinal features while no surgical intervention was performed after birth, 10 cases were lost to follow-up and 1 fetus died in utero at 34 weeks of gestation. Forty cases with full data were divided into three groups, including Group A (Small bowel dilatation combined with other features vs. Isolated small bowel dilatation), Group B (Colonic bowel dilatation combined with other features vs. Isolated colonic bowel dilatation) and Group C (Bowel dilatation combined with other features vs. Isolated bowel dilatation). The intestinal malformation occurrence rates were 73.33% vs. 31.25% in Group A, 50% vs. 25% in Group B, and 70% vs. 30% in Group C. These results suggest that malformation occurs at a lesser frequency in simple bowel dilatation versus bowel dilatation in combination with other abnormal ultrasound features (p = .026), similarly in simple small bowel dilatation versus small bowel dilatation in combination with other abnormal ultrasound features (p = .032). CONCLUSIONS: Prenatal bowel dilatation in combination with other abnormal ultrasound features, especially small bowel dilatation in combination with other abnormal ultrasound features, detected in the second and third trimesters, tended to indicate intestinal malformation, which contributes to enhance the accuracy of prenatal diagnosis of intestinal malformation. PMID- 29113510 TI - Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases. AB - Chronic diseases account for approximately 45% of all deaths in developed countries and are particularly prevalent in countries with the most sophisticated and robust public health systems. Chronic metabolic diseases, specifically lifestyle-related diseases pertaining to diet and exercise, continue to be difficult to treat clinically. The most prevalent of these chronic metabolic diseases include obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiovascular disease and will be the focus of this review. Wnt proteins are highly conserved glycoproteins best known for their role in development and homeostasis of tissues. Given the importance of Wnt signalling in homeostasis, aberrant Wnt signalling likely regulates metabolic processes and may contribute to the development of chronic metabolic diseases. Expression of Wnt proteins and dysfunctional Wnt signalling has been reported in multiple chronic diseases. It is interesting to speculate about an interrelationship between the Wnt signalling pathways as a potential pathological mechanism in chronic metabolic diseases. The aim of this review is to summarize reported findings on the contrasting roles of Wnt signalling in lifestyle-related chronic metabolic diseases; specifically, the contribution of Wnt signalling to lipid accumulation, fibrosis and chronic low-grade inflammation. PMID- 29113512 TI - Diabetes based on 2-h plasma glucose among those classified as having prediabetes based on fasting plasma glucose or A1c. AB - OBJECTIVE: Determine the prevalence of diabetes using 2-h plasma glucose among people who otherwise would be categorized as having prediabetes based on A1c and fasting glucose, and to determine whether those people were more likely to have cardiometabolic risk factors. METHODS: Among 3644 adults with prediabetes based on A1c and fasting glucose in the 2005-2014 National Health and Nutrition Examination Survey, a cross-sectional survey of the US general population, we estimated the percentage who would be categorized as having diabetes based on having a 2-h plasma glucose ?200 mg/dL. We calculated odds ratios of cardiometabolic risk factors associated with having 2-h plasma glucose ?200 mg/dL. RESULTS: A total of 6.9% would be categorized as having diabetes based on 2-h plasma glucose. The adjusted odds ratios (95% confidence interval) associated with having 2-h plasma glucose ?200 mg/dL were significant for total hypertension (2.06, 1.35-3.14), high triglycerides (1.64, 1.10-2.44), low high-density lipoprotein cholesterol (1.55, 1.01-2.39), albuminuria (2.05, 1.33-3.14) and elevated alanine aminotransferase (1.78, 1.09-2.91), but not for other cardiometabolic risk factors. CONCLUSION: A total of 6.9% of people categorized as having prediabetes based on A1c and fasting glucose would be categorized as having diabetes based on 2-h plasma glucose. They were more likely to have hypertension, high triglycerides, low high-density lipoprotein cholesterol, albuminuria and elevated alanine aminotransferase. PMID- 29113514 TI - Microballoon-related interventions in various endovascular treatments of body trunk lesions. AB - Occlusion balloon catheters of 5.2- or 6-French have been used for a few decades in various endovascular treatments of body trunk vascular lesions. However, these catheters may be difficult to place in cases of excessive vessel tortuosity, small vessels, and anatomic complexity. Recently, the introduction of the double lumen microballoon catheters for body trunk vascular lesions has allowed operators to advance them into more distal, smaller, and more tortuous vessels. Since the launch of the first generation microballoon catheters onto the market in Japan in 2011, the microballoon catheters have evolved and are now generally available for clinical use. The purpose of this article is to review the evolution and current clinical applications of the microballoon catheters in the field of interventional radiology. PMID- 29113513 TI - Quantifying HDL proteins by mass spectrometry: how many proteins are there and what are their functions? AB - INTRODUCTION: Many lines of evidence indicate that low levels of HDL cholesterol increase the risk of cardiovascular disease (CVD). However, recent clinical studies of statin-treated subjects with established atherosclerosis cast doubt on the hypothesis that elevating HDL cholesterol levels reduces CVD risk. Areas covered: It is critical to identify new HDL metrics that capture HDL's proposed cardioprotective effects. One promising approach is quantitative MS/MS-based HDL proteomics. This article focuses on recent studies of the feasibility and challenges of using this strategy in translational studies. It also discusses how lipid-lowering therapy and renal disease alter HDL's functions and proteome, and how HDL might serve as a platform for binding proteins with specific functional properties. Expert commentary: It is clear that HDL has a diverse protein cargo and that its functions extend well beyond its classic role in lipid transport and reverse cholesterol transport. MS/MS analysis has demonstrated that HDL might contain >80 different proteins. Key challenges are demonstrating that these proteins truly associate with HDL, are functionally important, and that MS-based HDL proteomics can reproducibly detect biomarkers in translational studies of disease risk. PMID- 29113515 TI - Incentives for recruiting trainee participants in medical education research. AB - INTRODUCTION: In the growing field of medical education research, participant recruitment can be challenging. Incentives, either tangible or intangible, may be offered to encourage participation. This study aimed to understand these incentives and explore the relationship between study quality and incentives in medical education research. METHODS: We reviewed research studies examining medical trainees published in five major journals in 2008. Tangible and intangible incentives used in recruitment were extracted by two researchers. For each quantitative article, medical education research quality instrument (MERSQI) score was calculated and citation counts for all articles were compiled. RESULTS: Of 215 included articles, 8% explicitly reported incentives. Tangible incentives (value range $15-$60 USD) were offered in 7.9% of studies. Intangible incentives were identified in 30% of studies but only one specifically discussed their use. Tangible incentives correlated with a higher MERSQI score (p < 0.001) and with citations (p < 0.001). CONCLUSION: Most studies in medical education did not describe incentives for participation. Information regarding incentives should be reported in all studies to help inform future recruitment efforts and also to understand the study context including factors that may influence participants motivation. PMID- 29113516 TI - Medical genetics and genomics training in obstetrics and gynecology residencies: are we ready for the future? AB - OBJECTIVE: The primary objective of this study is to evaluate the availability and duration of formal medical genetics and genomics (MGG) education during obstetrics and gynecology (OB/GYN) residency training in the United States compared to other noncore OB/GYN rotations. METHODS: We performed a review of rotation schedules published in all American Council for Graduate Medical Education (ACGME)-accredited OB/GYN residency programs' websites during the month of December 2016. Information regarding availability and duration of MGG rotation and other noncore OB/GYN rotations (ultrasound, breast health, and family planning) were collected. RESULTS: Among 256 ACGME-accredited OB/GYN residency programs, rotation schedule was available for 238 (93%). Only 34 programs (14.3%) had some form of MGG rotations. In the GLM, when compared to other noncore OB/GYN rotations, the mean duration of MGG rotation was significantly less than ultrasound (0.07 versus 0.57 months, p < .05) and family planning (0.07 versus 0.42 months, p < .05). The number of residents was the only variable significantly correlated with the availability of an MGG rotation (OR 1.07, 95%CI 1.02-1.13). CONCLUSIONS: Despite the growing importance of MGG in day-to-day OB/GYN practice, only a limited number of ACGME-accredited OB/GYN residency programs offer an MGG rotation. When compared to other noncore OB/GYN rotations, such as, ultrasound and family planning, any MGG rotation was significantly shorter. With clear evidence that MGG will continue to radically change practice of OB/GYN in the future, it is imperative that steps need to be taken to address this deficiency in training. PMID- 29113517 TI - Shock index and delta-shock index are superior to existing maternal early warning criteria to identify postpartum hemorrhage and need for intervention. AB - OBJECTIVE: To determine whether shock index (SI) is superior to traditional vital signs in predicting postpartum hemorrhage and need for intervention. METHODS: Retrospective case-control study in an academic tertiary-care county hospital. Forty-one consecutive postpartum hemorrhage (PPH) cases and 41 controls were frequency-matched by mode of delivery and maternal weight. We measured four criteria: heart rate, systolic blood pressure (SBP), SI (HR/SBP), and delta-SI (peak SI - baseline SI). Using received operating characteristic curves, we compared the discrimination performance of each criterion to predict PPH, transfusion, and surgical intervention, and identified thresholds with the strongest classification. RESULTS: SI <=1.1 can be normal in peripartum. Peak SI and delta-SI were generally superior to heart rate (HR) and SBP in predicting PPH, transfusion, and surgical intervention. SI >=1.143 and SI >=1.412 were strong initial and "critical" thresholds. Delta-SI was the strongest classifier overall; both SI and delta-SI remain sensitive and specific when adjusted for potential confounders. CONCLUSIONS: SI and delta-SI appear to be superior to HR and SBP in predicting PPH and need for intervention. Utility of delta-SI should be prospectively explored. PMID- 29113518 TI - Functional Semi-Blind Source Separation Identifies Primary Motor Area Without Active Motor Execution. AB - High time resolution techniques are crucial for investigating the brain in action. Here, we propose a method to identify a section of the upper-limb motor area representation (FS_M1) by means of electroencephalographic (EEG) signals recorded during a completely passive condition (FS_M1bySS). We delivered a galvanic stimulation to the median nerve and we applied to EEG the semi-Blind Source Separation (s-BSS) algorithm named Functional Source Separation (FSS). In order to prove that FS_M1bySS is part of FS_M1, we also collected EEG in a motor condition, i.e. during a voluntary movement task (isometric handgrip) and in a rest condition, i.e. at rest with eyes open and closed. In motor condition, we show that the cortico-muscular coherence (CMC) of FS_M1bySS does not differ from FS_ M1 CMC (0.04 for both sources). Moreover, we show that the FS_M1bySS's ongoing whole band activity during Motor and both rest conditions displays high mutual information and time correlation with FS_M1 (above 0.900 and 0.800, respectively) whereas much smaller ones with the primary somatosensory cortex [Formula: see text] (about 0.300 and 0.500, [Formula: see text]). FS_M1bySS as a marker of the upper-limb FS_M1 representation obtainable without the execution of an active motor task is a great achievement of the FSS algorithm, relevant in most experimental, neurological and psychiatric protocols. PMID- 29113519 TI - Does the low FODMAP diet improve symptoms of radiation-induced enteropathy? A pilot study. AB - RATIONALE: Patients with radiation-induced enteropathy (RE) after cancer treatment show similar symptoms as patients with irritable bowel syndrome (IBS). The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet (LFD) is a widespread management strategy for IBS. We aimed to investigate if there may be a positive effect of LFD on symptoms and health related quality of life (HRQOL) in patients with RE. METHODS: In an open non controlled pilot study, 11 patients (all female) with RE-related IBS symptoms were recruited largely based on own initiative. All followed LFD for four weeks. IBS Severity Scoring System (IBS-SSS) and IBS Symptom Questionnaire (IBS-SQ) were used to assess symptoms. Short Form Nepean Dyspepsia Index (SF-NDI) and 12-item Short Form Health Survey (SF-12) evaluated HRQOL. A three day food record was used to estimate baseline intake of FODMAPs and to reveal dietary changes. RESULTS: FODMAP intake was successfully reduced, although LFD was found a burdensome intervention. IBS symptoms improved significantly based on mean total score of IBS-SSS and IBS-SQ, which changed from 310.2 +/- 60.7 to 171.4 +/- 107.2 (p = .001) and 27.4 +/- 4.1 to 15.7 +/- 10.1 (p = .002). HRQOL improved based on SF-NDI total score (30.5 +/- 9.4 to 18.3 +/- 8.2, p = .001) and based on mental (p = .047) and physical (p = .134) score of SF-12. Main additional dietary changes were reduced intake of energy, carbohydrates, and fiber. CONCLUSION: Our findings from this small-scaled pilot study indicate that the LFD may alleviate symptoms and improve HRQOL in patients with RE. Further controlled studies with larger sample size should be conducted to verify our results and hopefully enable implementation of LFD as a future part of the management strategy for RE. PMID- 29113520 TI - Preparing teachers for competency-based medical education: Fundamental teaching activities. AB - INTRODUCTION: The move to competency-based medical education has created new challenges for medical teachers, including the need to reflect on and further develop their own competencies as teachers. Guidance is needed to ensure comprehensive and coherent programs of faculty development to meet the needs of teachers. METHODS: The Working Group on Faculty Development of the College of Family Physicians of Canada developed a new concept, Fundamental Teaching Activities (FTAs), to describe the day-to-day work of teachers. These activities are intended to guide teacher professional development. Using task analysis and iterative reviews with teachers and educational leaders, these FTAs were organized into a framework for teachers to identify the actions involved in various teaching tasks, and to reflect on their teaching performance and next steps in personal development. RESULTS: In addition to use by teachers for personal development, the framework is being employed to guide the development of comprehensive faculty development offerings and curriculum, and to organize the beginnings of a national repository of teaching tools. CONCLUSIONS: Designed to support and aid teachers and those charged with faculty development, the Fundamental Teaching Activities Framework holds promise for all teachers in health sciences education. PMID- 29113521 TI - Efficacy and safety of vortioxetine for the treatment of major depressive disorder: a randomised double-blind placebo-controlled study. AB - OBJECTIVE: This study aimed to evaluate the efficacy and adverse events of vortioxetine for Chinese patients with major depressive disorder (MDD) over 10 weeks. METHODS: A total of 120 patients with MDD were randomly assigned to two groups that received vortioxetine 20 mg or placebo for 10 weeks. The outcomes were the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impressions Improvement (CGI-I) scale, Sheehan Disability Scale (SDS) at Week 10, and the presence of adverse events. RESULTS: A total of 113 patients completed the study. Vortioxetine showed greater efficacy than the placebo in improving MADRS, HAM-A, CGI-I, and SDS scores at Week 10. However, no significant differences were found between the groups for any treatment-emergent adverse events. No suicide related to vortioxetine treatment was recorded. CONCLUSIONS: In summary, the results of this study showed that 10 weeks of vortioxetine treatment was efficacious and well-tolerated in patients with MDD. PMID- 29113522 TI - Who uses apps in health promotion? A target group analysis of leaders. AB - User characteristics should be considered when designing features for e-health or m-health applications, as the developed solution should aim to support this specific target group. This study explores the effect of user characteristics (personality, health state, stress/recovery state, leadership behavior) on the interest and likelihood of using an app for health promotion activities at the workplace. Leaders are a key factor for the success of workplace health promotion; therefore, the target group of this study are leaders. The data of 412 leaders were collected in an online study. Hierarchical multiple linear regression analyses were conducted for four outcome criteria ("personal health," "contacting," "leadership feedback" and "corporate key figures"). The findings showed that neuroticism, physical health and health-promoting leadership were important predictors for using an app for monitoring personal health and getting in social contact about health issues. The stress/recovery state was significantly related to the feature of getting in social contact. PMID- 29113523 TI - Monoclonal antibodies for treating osteoporosis. AB - INTRODUCTION: Osteoporosis is the most widespread skeletal disease requiring innovative therapeutic strategies for its management. The understanding of receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin's role in bone cell biology is completely changing the therapeutic landscape. RANKL supports osteoclast formation and activity and is mainly produced by cells of osteoblastic lineage. Sclerostin, an antagonist of the Wnt pathway, has a key role in bone formation and is mainly secreted by osteocytes. High levels of RANKL and sclerostin have been detected in osteoporosis, leading to the production of antibodies able to neutralize their activity. Areas covered: In this review, the authors give an overview and discuss the literature and data on denosumab and romosozumab to treat osteoporosis. Clinical studies indicate that long-term treatment with denosumab causes a continuous increase in bone mineral density with low incidence of adverse effects. Romosozumab treatment gives increases bone formation and improves bone mineral density (BMD) though further studies are needed to better evaluate the adverse effects. Expert opinion: Denosumab and romosozumab show promise in the treatment of osteoporosis. Furthermore, their different mechanisms of action compared to existing anti-osteoporotic drugs may permit alternative strategies for osteoporosis treatment down the line. PMID- 29113524 TI - How does preeclampsia affect neonates? Highlights in the disease's immunity. AB - INTRODUCTION: Preeclampsia (PE) is the primary obstetrical cause in one of the four perinatal deaths. Although the etiology and pathogenesis of preeclampsia is not fully known, a proinflammatory immune state prevails and can disrupt fetal hematopoiesis. Some of the effects on the newborn include neonatal thrombocytopenia, neutropenia, a reduction in T regulatory cells, and an increased cytotoxic natural killer cell profile. METHODS: Electronic databases were searched, and defined criteria were applied to select articles for review. The review covered literature on the effects on neonatal due to maternal preeclampsia, fetal outcomes, and new treatments in research aimed at reducing morbidity and mortality of the disease. DISCUSSION: The cytotoxic environment present in PE affects the development of fetal cell lineages. Neutropenia is observed in 50% of neonates and is correlated with mortality, although its treatment is not well-established. The enhancement in erythropoietin and the hypoxic setting present in the disease can also lead to thrombocytopenia. Per partum management includes platelet transfusion in order to avoid severe complications such as intraventricular hemorrhage. Regarding other cell lines, a cytotoxic profile is observed to be reflecting the milieu present in the mothers' bloodstream. This disruption alters the immune system response into a proinflammatory profile and can be correlated to neonatal necrotizing enterocolitis. An antiangiogenic environment is also part of the preeclampsia presentation and can be responsible for the enhancement of bronchopulmonary dysplasia observed in this population. Meanwhile, the reduction in angiogenic factors, such as vascular endothelial growth factor (VEGF), can be a protective mechanism for retinopathy of prematurity. Studies of the long-term effects of these observations are lacking, but lower neurodevelopmental scores and a higher cardiovascular risk are noted. New treatments in research propose a prevention of the disease during gestation in order to reduce the effects more efficiently in the fetus. Phosphodiesterase inhibitors, endothelin 1 receptor antagonists and manipulation of heme oxygenase-1 enzyme pathway are possible therapeutic alternatives. This review summarizes the current understanding of how preeclampsia affects neonates. As a conclusion, further studies are needed to build up a guideline to manage those effects. A research agenda is proposed. PMID- 29113525 TI - Biological mechanisms underlying the clinical effects of allergen-specific immunotherapy in asthmatic children. AB - INTRODUCTION: Allergen-specific immunotherapy (AIT) is indicated for patients with allergic asthma and/or allergic rhinitis, and can be implemented by either subcutaneous injection (SCIT) or sublingual administration (SLIT). AIT reduces asthma symptoms, lowers the use of pharmacologic controller therapy, and decreases the need for rescue medications. SLIT appears to be safer than SCIT, but SCIT seems to be more efficacious and acts earlier in allergic asthmatic children. Areas covered: This review looks at the pathobiology of allergic asthma as well as the role of regulatory T and B cells in allergen tolerance. It also reviews the immunological mechanisms underlying the clinical effects induced by AIT in allergic asthmatic children. Expert opinion: AIT is very effective in allergic asthmatic children, who can significantly benefit from this particular type of immunotherapy in order to achieve a better control of their disease. AIT is also capable of modifying the natural history of allergic asthma. Furthermore, AIT can potentially represent a valuable therapeutic tool within the context of precision medicine, as recombinant allergen technology might allow the creation of targeted extracts able to be effective against specific proteins to which individual asthmatic children are allergic, thus helping to implement a personalized approach to treatment. PMID- 29113526 TI - Mindfulness interventions in medical education: A systematic review of their impact on medical student stress, depression, fatigue and burnout. AB - INTRODUCTION: Mindfulness-based interventions (MBIs) have gained popularity in medical education. A systematic review was conducted to determine the effectiveness of MBIs for reducing psychological distress in undergraduate medical students. METHODS: A search protocol was conducted using online databases Embase, PubMed, PsycINFO, and MEDLINE. Articles were required to meet the following criteria to be included: (1) describe a MBI or use of mindfulness exercises as part of an intervention, (2) include at least one of: stress, burnout, fatigue, or depression, as an outcome, (3) include quantitative outcomes, and (4) published in English in a peer-reviewed journal. RESULTS: Twelve articles were reviewed. Seven studies reported improvements in at least one targeted outcome. Four of seven studies exploring the impact on stress reported improvements. Five articles studying depression reported reductions. One study exploring burnout reported a decrease on a single subscale. Only one study measured the impact on fatigue (no change reported). Half of studies reviewed included predominantly female samples. CONCLUSIONS: Mixed evidence was found for the use of MBIs for reducing psychological distress in undergraduate medical students. Future work should aim to clarify the impact of mindfulness on burnout and fatigue, and explore the replicability of improvements in male medical students alone. PMID- 29113527 TI - The relationship between spatial ability, cerebral blood flow and learning with dynamic images: A transcranial Doppler ultrasonography study. AB - Determining the effect of dynamic images on learning is often limited to performance measures. This study explores the impact from the perspective of cerebral blood flow in the brain during learning. Performance and neurophysiological response in high and low spatial ability were compared during learning with dynamic images. Individuals with high spatial ability appear to be better suited to learn with complex images such as dynamic images that move in time and space. The results presented here suggest that spatial ability can help to determine the effectiveness of the media we use for teaching. PMID- 29113528 TI - Capturing health literacy assessment in the electronic health record through evidence-based concept creation: A review of the literature and recommendations for action. AB - Health literacy is the capacity to understand and act upon health-related information and navigate the healthcare system. Published evidence demonstrates a relationship between health literacy and health status. Because of this, there are increasingly calls for a health literacy assessment to be collected and stored in the electronic health record for use by the healthcare team. This article describes the results of a literature review of health literacy assessment instruments with the goal of formulating semantically interoperable concepts that may be used to store the interpretation of the health literacy assessment in the electronic health record. The majority of health literacy instruments could be stored in the electronic health record using a three-concept solution of inadequate, marginal and adequate health literacy. This three-concept solution fully supports semantic interoperability needs across the patient care spectrum. PMID- 29113529 TI - Pleuroparenchymal Fibroelastosis With Long History of Asbestos and Silicon Exposure. AB - Pleuroparenchymal fibroelastosis (PPFE) is an uncommon interstitial lung disease. PPFE is characterized by fibroelastosis involving the pleura and subjacent parenchyma with a predominantly upper lobe distribution. While different possible environmental and familial etiologies have been postulated in the literature, the etiology of this disease remains essentially unclear and most cases are considered as idiopathic. In this report, we describe a rare case of PPFE with multiple lung lobe involvements and prolonged asbestos and silica exposure. Our goal is to investigate the exposure of asbestos and silica and try to identify their possible association with PPFE. PMID- 29113530 TI - Time course of compromised urea synthesis in patients with alcoholic hepatitis. AB - OBJECTIVES: Alcoholic hepatitis (AH) markedly decreases the urea synthesis capacity. We aimed to investigate the time course of this compromised essential liver function in patients with AH and its relation to treatment and survival. MATERIALS AND METHODS: Thirty patients with AH were included in a prospective cohort study. We measured the substrate-independent urea synthesis capacity, i.e., the functional hepatic nitrogen clearance (FHNC), in the patients at study entry and again at three months (survivors/available: n = 17). Patients with severe disease (Glasgow Alcoholic Hepatitis Score >=9, n = 17) were randomized to receive either prednisolone or pentoxifylline and were in addition examined after 14 days (n = 9). RESULTS: FHNC (normal range = 25-45 L/h) was markedly decreased at study entry (median = 5.6 (IQR = 3.0-9.6) L/h) and increased by three-fold in survivors at three months (15.1 (12.0-22.9) L/h; p < .001). In patients with severe AH, FHNC was also increased after 14 days of pharmacologic treatment and showed the greatest increase in the patients taking prednisolone (prednisolone 25.4 (20.6-26.2) L/h vs. pentoxifylline 12.3 (8.0-15.3) L/h; p = .05). FHNC at study entry was lower in 90-day non-survivors than in survivors (p = .04). CONCLUSIONS: The decrease in the urea synthesis capacity in patients with AH was the most marked in short-term non-survivors and partly recovered in survivors at three months. In patients on pharmacologic treatment, recovery was observed already after 14 days, and it was nearly complete in those on prednisolone. Thus, metabolic liver failure in AH seems to be prognostically important, is potentially reversible, and may recover more rapidly following treatment with prednisolone. PMID- 29113531 TI - Detection of cytomegalovirus, herpes virus simplex, and parvovirus b19 in spontaneous abortion placentas. AB - OBJECTIVE: This study aims to investigate the presence of Cytomegalovirus (CMV), herpes virus simplex (HSV), and parvovirus B19 (PVB19) in the placental tissue of patients who underwent abortions without an otherwise-defined aetiology. STUDY DESIGN: This cross-sectional study was conducted in a high-risk obstetric maternity facility at a University Hospital in Belo Horizonte, Brazil, from January 2013 to December 2015. We included placenta samples obtained from spontaneous abortions of unknown aetiology. Seventy placenta samples were identified and were classified according to histopathological characteristics. All samples were analysed using immunohistochemistry and polymerase chain reaction for CMV, PVB19, and HSV. The clinical variables were collected from the medical records of patients to verify the association of infection with villitis. The patients were divided into the following groups: I) with villitis (n = 28) and II) without villitis (n = 42). METHODS: Immunohistochemistry used monoclonal anti-CMV antibody (NCL-CMVpp65, Leica Biosystems, Wetzlar, Germany), anti-PVB19 antibody (NCL-PARVO, Leica Biosystems, Wetzlar, Germany), and anti-HSV1/HSV2 antibodies (NCL-HSV-1 and HSV2, Leica Biosystems, Wetzlar, Germany). The data were analysed using the Statistical Package for Social Sciences (SPSS Inc, Chicago, IL) 19.0. RESULTS: Viral agents were detected in five patients (7.14%) in the villitis group. Three patients were positive for CMV, one for PVB19, and one for HSV type 2. Foetal and maternal complications were significantly higher in the group with villitis compared with those in the group without villitis (p = .002). CONCLUSIONS: The prevalence of transplacental viral infections as a cause of spontaneous abortion should be considered high in the placenta with villitis. Thus, this study highlights the need for developing diagnostic tests to clarify the aetiology of abortion and foetal loss. PMID- 29113532 TI - The grounded theory of "trust building". AB - BACKGROUND: Despite the growing importance of spiritual care, the delivery of spiritual care is still an area of disagreement among healthcare providers. OBJECTIVE: To develop a grounded theory about spiritual care delivery based on Iranian nurses' perceptions and experiences. A grounded theory approach: A qualitative study using the grounded theory approach. Participants and research context: Data were collected through holding 27 interviews with 25 participants (17 staff nurses, 3 physicians, 3 patients, 1 family member, and 1 nurse assistant). The study setting was the Imam Khomeini Hospital Complex. Sampling was started purposively and continued theoretically. Data analysis was performed by the method proposed by Strauss and Corbin. Ethical consideration: The study was approved by the Ethics Committee of Tarbiat Modares University and the agreement of the administrators of the study setting was got before starting the study. RESULTS: The core category of the study was "Trust building" which reflected the nature of spiritual care delivery by nurses. Trust building was the result of eight main categories or strategies including creating a positive mentality at hospital admission, understanding patients in care circumstances, having a caring presence, adhering to care ethics, developing meaningful relationships, promoting positive thinking and energy, establishing effective communication with patients, and attempting to create a safe therapeutic environment. Poor interprofessional coordination negatively affected this process while living toward developing greater cognizance of divinity and adhering to the principles of professional ethics facilitated it. The outcome of the process was to gain a sense of partial psychological security. CONCLUSION: The "Trust building" theory can be used as a guide for describing and expanding nurses' roles in spiritual care delivery, developing care documentation systems and clinical guidelines, and planning educational programs for nursing students and staff nurses. PMID- 29113533 TI - Measurement properties and usability of non-contact scanners for measuring transtibial residual limb volume. AB - BACKGROUND: Non-contact scanners may have potential for measurement of residual limb volume. Different non-contact scanners have been introduced during the last decades. Reliability and usability (practicality and user friendliness) should be assessed before introducing these systems in clinical practice. OBJECTIVES: The aim of this study was to analyze the measurement properties and usability of four non-contact scanners (TT Design, Omega Scanner, BioSculptor Bioscanner, and Rodin4D Scanner). STUDY DESIGN: Quasi experimental. METHODS: Nine (geometric and residual limb) models were measured on two occasions, each consisting of two sessions, thus in total 4 sessions. In each session, four observers used the four systems for volume measurement. Mean for each model, repeatability coefficients for each system, variance components, and their two-way interactions of measurement conditions were calculated. User satisfaction was evaluated with the Post-Study System Usability Questionnaire. RESULTS: Systematic differences between the systems were found in volume measurements. Most of the variances were explained by the model (97%), while error variance was 3%. Measurement system and the interaction between system and model explained 44% of the error variance. Repeatability coefficient of the systems ranged from 0.101 (Omega Scanner) to 0.131 L (Rodin4D). Differences in Post-Study System Usability Questionnaire scores between the systems were small and not significant. CONCLUSION: The systems were reliable in determining residual limb volume. Measurement systems and the interaction between system and residual limb model explained most of the error variances. The differences in repeatability coefficient and usability between the four CAD/CAM systems were small. Clinical relevance If accurate measurements of residual limb volume are required (in case of research), modern non-contact scanners should be taken in consideration nowadays. PMID- 29113534 TI - The relationship between neuropsychological tests of visuospatial function and lobar cortical thickness. AB - INTRODUCTION: Tests of visuospatial function are often administered in comprehensive neuropsychological evaluations. These tests are generally considered assays of parietal lobe function; however, the neural correlates of these tests, using modern imaging techniques, are not well understood. In the current study we investigated the relationship between three commonly used tests of visuospatial function and lobar cortical thickness in each hemisphere. METHOD: Data from 374 patients who underwent a neuropsychological evaluation and MRI scans in an outpatient dementia clinic were included in the analysis. We examined the relationships between cortical thickness, as assessed with Freesurfer, and performance on three tests: Judgment of Line Orientation (JoLO), Block Design (BD) from the Fourth edition of the Wechsler Adult Intelligence Scale, and Brief Visuospatial Memory Test-Revised Copy Trial (BVMT-R-C) in patients who showed overall average performance on these tasks. Using a series of multiple regression models, we assessed which lobe's overall cortical thickness best predicted test performance. RESULTS: Among the individual lobes, JoLO performance was best predicted by cortical thickness in the right temporal lobe. BD performance was best predicted by cortical thickness in the right parietal lobe, and BVMT-R-C performance was best predicted by cortical thickness in the left parietal lobe. CONCLUSIONS: Performance on constructional tests of visuospatial function appears to correspond best with underlying cortical thickness of the parietal lobes, while performance on visuospatial judgment tests appears to correspond best to temporal lobe thickness. Future research using voxel-wise and connectivity techniques and including more diverse samples will help further understanding of the regions and networks involved in visuospatial tests. PMID- 29113535 TI - Effects of erythropoietin abuse on exercise performance. AB - The present review provides a comprehensive overview on the erythropoietic and non-erythropoietic effects of rHuEpo on human sport performance, paying attention to quantifying numerically how rHuEpo affects exercise performance and describing physiological changes regarding the most important exercise variables. Much attention has been paid to treatment schedules, in particular, to assess the effects of microdoses of rHuEpo and the prolonged effects on sport performance following withdrawal. Moreover, the review takes into account non-erythropoietic ergogenic effects of rHuEpo, including cognitive benefits of rHuEpo. A significant increase in both Vo2max and maximal cycling power was evidenced in studies taken into account for this review. rHuEpo, administered at clinical dosage, may have significant effects on haematological values, maximal and submaximal physiological variables, whereas few reports show positive effects on exercise perfomance. However, the influence of micro-dose rHuEpo on endurance performance in athletes is still unclear and further studies are warranted. PMID- 29113536 TI - The pigmented epithelium, a bright partner against photoreceptor degeneration. AB - Sight depends on the intimate association between photoreceptors and pigment epithelial cells. The evolutionary origin of this cellular tandem can be traced back to the emergence of bilateral animals, at least 450 million years ago, as they define the minimal unit of the ancestral prototypic eye. Phototransduction is a demanding process from the energetic and homeostatic points of view, and not surprisingly photoreceptive cells are particularly susceptible to damage and degeneration. Here, we will examine the different ancillary roles that the pigmented cells play in the physiology and homeostasis of photoreceptors, linking each one of these processes to the most common hereditary retinal diseases. We will discuss the challenges and opportunities of recent therapeutic advances based on cell and gene replacement. The transition from animal models to clinical trials will be addressed for each one of the different therapeutic strategies with a special focus on those depending on retinal-pigmented epithelial cells. Finally, we will discuss the potential impact of combining CRISPR technologies with gene and cell therapy approaches, which - in the frame of the personalized medicine revolution - may constitute a leap forward in the treatment of retinal dystrophies. PMID- 29113538 TI - Acquired von Willebrand Syndrome in an Infant With Coarctation of the Aorta and Williams Syndrome. AB - An infant with coarctation of the aorta and Williams syndrome was noted to have petechiae in cardiology clinic prior to planned surgical intervention. Workup revealed acquired von Willebrand syndrome secondary to the high shear force generated by the aortic coarctation. He was treated with intra- and postoperative Humate P; there were no postoperative bleeding complications. His acquired von Willebrand syndrome resolved postoperatively. PMID- 29113537 TI - Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma. AB - Treatment and outcome of systemic lupus erythematosus (SLE) in C1q deficient patients are rarely reported. The aim of this report is to share our experience about the course of management of three cases diagnosed as SLE with C1q deficiency, in light of present literature. Initial and dominant complaints of three cases from two different families were cutaneous manifestations. One patient was also diagnosed with arthritis and thrombocytopenia. Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity. C1QA gene of two patients had homozygous nonsense mutation (c.622 > T/p.Gln208Ter). Previously, all of them had been treated with steroids, hydroxychloroquine and methotrexate or azathioprine. It was learned that they had responded only to high dosage prednisolone and their symptoms flared up during dosage reduction even under methotrexate or azathioprine. All symptoms of all three cases improved by daily fresh frozen plasma (FFP) infusions, and once cutaneous lesions subsided, the infusions were reduced to a frequency that would prevent the flare up of the symptoms. Literature search revealed seven reports on fresh frozen plasma treatment in SLE with C1q deficient patients. In this report, it is concluded that severe cutaneous lesions, as seen in these C1q deficient SLE patients, cannot be controlled with conventional immunosuppressive treatment. Instead, regular fresh frozen plasma infusions are proposed as a more reasonable method of treatment. PMID- 29113539 TI - Dietary fish oil, and to a lesser extent the fat-1 transgene, increases astrocyte activation in response to intracerebroventricular amyloid-beta 1-40 in mice. AB - OBJECTIVES: Increases in astrocytes and one of their markers, glial fibrillary acidic protein (GFAP) have been reported in the brains of patients with Alzheimer's disease (AD). N-3 polyunsaturated fatty acids (PUFA) modulate neuroinflammation in animal models; however, their effect on astrocytes is unclear. METHODS: Fat-1 mice and their wildtype littermates were fed either a fish oil diet or a safflower oil diet deprived of n-3 PUFA. At 12 weeks, mice underwent intracerebroventricular infusion of amyloid-beta 1-40. Astrocyte phenotype in the hippocampus was assessed at baseline and 10 days post-surgery using immunohistochemistry with various microscopy and image analysis techniques. RESULTS: GFAP increased in all groups in response to amyloid-beta, with a greater increase in fish oil-fed mice than either fat-1 or wildtype safflower oil-fed mice. Astrocytes in this group were also more hypertrophic, suggesting increased activation. Both fat-1- and fish oil-fed mice had greater increases in branch number and length in response to amyloid-beta infusion than wildtype safflower animals. CONCLUSION: Fish oil feeding, and to a lesser extent the fat-1 transgene, enhances the astrocyte activation phenotype in response to amyloid beta 1-40. Astrocytes in mice fed fish oil were more activated in response to amyloid-beta than in fat-1 mice despite similar levels of hippocampal n-3 PUFA, which suggests that other fatty acids or dietary factors contribute to this effect. PMID- 29113540 TI - Distinct toxic interactions of TiO2 nanoparticles with four coexisting organochlorine contaminants on algae. AB - Engineered nanoparticles are increasingly discharged into the environment. After discharge, these nanoparticles can interact with co-existing organic contaminants, resulting in a phenomena referred to as 'joint toxicity'. This study evaluated joint toxicities of TiO2 nanoparticles (TiO2NPs) with four different (atrazine, hexachlorobenzene, pentachlorobenzene, and 3,3',4,4' tetrachlorobiphenyl) organochlorine contaminants (OCs) toward algae (Chlorella pyrenoidosa). The potential mechanisms underlying the joint toxicity were discussed, including TiO2NPs-OC interactions, effects of TiO2NPs and OCs on biophysicochemical properties of algae and effects of TiO2NPs and OCs on each other's bioaccumulation in algae. The results indicate that coexposure led to a synergistic effect on the joint toxicity for TiO2NPs-atrazine, antagonistic effect for TiO2NPs-hexachlorobenzene and TiO2NPs-3,3',4,4'-tetrachlorobiphenyl, and an additive effect for TiO2NPs-pentachlorobenzene. There was nearly no adsorption of OCs by TiO2NPs, and the physicochemical properties of TiO2NPs were largely unaltered by the presence of OCs. However, both OCs and NPs affected the biophysicochemical properties of algal cells and thereby influenced the cell surface binding and/or internalization. TiO2NPs significantly increased the bioaccumulation of each OC. However, with the exception of atrazine, the bioaccumulation of TiO2NPs decreased when used with each OC. The distinct joint toxicity outcomes were a result of the balance between the increased toxicities of OCs (increased bioaccumulations) and the altered toxicity of TiO2NPs (bioaccumulation can either increase or decrease). These results can significantly improve our understanding of the potential environmental risks associated with NPs. PMID- 29113541 TI - Stent extension into a single inflow vessel is a valuable option after endophlebectomy. AB - Background Venous stenting with an endophlebectomy and arteriovenous fistula can be performed in patients with extensive post-thrombotic changes. However, these hybrid procedures can induce restenosis, sometimes requiring stent extension, into a single inflow vessel. This study investigates the effectiveness of stenting into a single inflow vessel. Methods All evaluated patients had temporary balloon occlusion of the arteriovenous fistula to evaluate venous flow into the stents. When stent inflow was deemed insufficient, AVF closure was postponed and additional stenting was performed. Patency rates and clinical outcomes were evaluated. Results Twenty-four (38%) of 64 patients had additional stenting. The primary, assisted primary and secondary patency were 60 %, 70% and 70% respectively. Villalta score reduced by 6.1 points ( p < 0.001), and venous clinical severity score by 2.7 points ( p = 0.034). Conclusion Stenting through the femoral confluence into a single inflow vessel is a feasible bailout option if primary hybrid intervention fails with relative high patency rates and clinical improvement. PMID- 29113542 TI - Using Facebook and LinkedIn to Recruit Nurses for an Online Survey. AB - Social media is an emerging tool used by researchers; however, limited information is available on its use for participant recruitment specifically. The purpose of this article is to describe the use of Facebook and LinkedIn social media sites in the recruitment of nurses for an online survey, using a 5-week modified online Dillman approach. Within 3 weeks, we exceeded our target sample size ( n = 170) and within 5 weeks recruited 267 English-speaking nurses ( n = 172, Facebook; n = 95, LinkedIn). Advantages included speed of recruitment, cost efficiency, snowballing effects, and accessibility of the researcher to potential participants. However, an analysis of the recruited participants revealed significant differences when comparing the sociodemographics of participants recruited through Facebook and LinkedIn, specifically relating to the characteristics of sex, age, and level of education. Differences between Facebook and LinkedIn as recruitment platforms should be considered when incorporating these strategies. PMID- 29113547 TI - Self-reference in suicidal behaviour. AB - INTRODUCTION: Several lines of evidence suggest a perturbed sense of self in people who attempt suicide, but it has rarely been experimentally studied. Here, we aimed to explore in this population the narrative self through explicit self perception and the self-reference effect in memory. METHODS: Forty-seven patients with a mood disorder, including 20 with a personal history of suicide attempt, completed a self-referential task. During the encoding phase, they were presented with personality traits and had to successively judge whether each trait described themselves ("self condition") or was a desirable trait, in general ("general condition"). Then, they were unexpectedly asked to retrieve as many previously presented traits as possible (free recall phase). RESULTS: Suicide attempters did not differ from non-attempter patients in any self-reference measures. Moreover, none of these measures correlated with current suicidal ideas. During the encoding phase, patients in both groups attributed negative traits to themselves more often than they considered them to be desirable, in general, with an opposite pattern for positive traits. The number of negative traits during the self but not the general condition was correlated with depression, anxiety, and mental pain levels, whereas depression and mental pain levels were correlated with suicidal ideas. No self-reference effect in memory was found. CONCLUSIONS: Overall, measures of the narrative self were not directly associated with suicidality. However, biased self-perception was related to painful and depressive feelings, which were in turn related to suicidal ideas. More research on self-related processing during the suicidal process is warranted. PMID- 29113548 TI - Cognitive functions and health-related quality of life in men with benign prostatic hyperplasia and symptoms of overactive bladder when treated with a combination of tamsulosin and solifenacin in a higher dosage. AB - AIM: To study the cognitive functions and health-related quality of life (HRQoL) in individuals taking a combination of tamsulosin and solifenacin in a higher dosage. METHODS: All patients (n = 262) were assigned to group A (N = 93, tamsulosin 0.4 mg + solifenacin 10 mg per day), group B (N = 83, tamsulosin 0.4 mg + solifenacin 20 mg), and control group C (N = 86; tamsulosin 0.4 mg + placebo). The lower urinary tract (LUT) condition was assessed on the scales International Prostate Symptom Score, Over Active Bladder Awareness Tool and uroflowmetry. The state of cognitive status was assessed on the scales Mini mental State Examination, Controlled Oral Word Association Test, Wechsler Adult Intelligence Scale-Revised, Wechsler III, Color Trails Test, California Verbal Learning Test. RESULTS: The values of cognitive function indicators in the individuals from all groups after treatment did not significantly differ from the respective values at the baseline (p > .05). The values of most HRQoL parameters of the functional state of the LUT significantly improved in groups A and B. A significant correlation between the state of cognitive status and HRQoL, as well as LUT was absent (r <0.3). CONCLUSION: The combination of solifenacin in a double dosage along with tamsulosin can be recommended for elderly benign prostatic hyperplasia patients with overactive bladder symptoms. PMID- 29113549 TI - The Final 30 Days of Life: A Study of Patients With Gastrointestinal Cancer in Ontario, Canada. AB - BACKGROUND: Studies have reported overly aggressive end-of-life care (EOLC) in many cancers. We investigate trends in, and factors associated with, aggressive EOLC among patients who died of gastrointestinal (GI) cancers in Ontario, Canada. METHODS: All patients with primary cause of death from esophageal, gastric, colon, and anorectal cancer from January 2003 to December 2013 were identified through the Ontario Cancer Registry, and information was collected from linked databases. Outcomes representing aggressive EOLC were assessed: administration of chemotherapy, any emergency department (ED) visits, hospital admissions, intensive care unit (ICU) admissions (all within 30 days of death), death in hospital and in ICU, and a composite outcome representing any aggressive EOLC. Temporal trends were analyzed using the Cochran-Armitage test. RESULTS: There were 34 630 patients in the cohort: 43% colon, 26% anorectal, 19% gastric, and 12% esophageal cancers. Aggressive EOLC was delivered to 65%, with a significantly decreasing trend from 64.8% in 2003 to 62.5% in 2013 ( P = .001). Utilization of specific elements of aggressive EOLC included 8% chemotherapy, 46% ED visits, 49% hospital admissions, 6% ICU admissions, 45% death in hospital, and 5% death in ICU. Trends over the study period showed that ED visits (from 43% to 46.9%; P = .0001) and death in ICU (from 3.7% to 4.9%; P = .04) significantly increased; hospital admissions (from 48.9% to 47.8%; P = .02) and death in hospital (from 46.6% to 38.9%; P < .0001) significantly decreased. CONCLUSIONS: Two-thirds of patients with GI cancer had aggressive EOLC in the last 30 days of life. PMID- 29113551 TI - Technology 2.0: A Commentary on Progress, Challenges, and Next Steps. AB - This commentary highlights the importance and promise of the innovative strategies described in the Child Maltreatment special issue on "Technology 2.0: A Focus on the Newest Technological Advances in Child Maltreatment Research." The commentary first highlights the collective advancements reflected in the articles in the special issue, with a primary focus on how the authors' work addresses a general challenge in services research that is perhaps nowhere more problematic than in the field of maltreatment. Next, the commentary extends the discussion of these articles to raise remaining gaps in our knowledge, theory, and methodology, which must be the focus of ongoing research if the true potential of technology as a service delivery vehicle is to be realized. Finally, the commentary concludes with a call for subsequent research which will be inspired by the articles in this special issue. PMID- 29113552 TI - Introduction to the Special Issue on Technology 2.0: A Focus on the Newest Technological Advances in Child Maltreatment Research. PMID- 29113553 TI - Individualizing Surgery in Papillary Thyroid Carcinoma Based on a Detailed Sonographic Assessment of Extrathyroidal Extension. AB - BACKGROUND: Lobectomy may be sufficient for patients with intrathyroidal papillary thyroid carcinomas (PTC) <4 cm without nodal metastasis. Based on the 2015 American Thyroid Association guidelines, a strategy using ultrasound to identify appropriate candidates for lobectomy was implemented. METHODS: Patients with Bethesda V or VI cytology who underwent surgery for PTC (January 2016 to May 2017) were retrospectively reviewed. Eligibility for lobectomy was based on both tumor (unilateral, intrathyroidal tumors <=3 cm in size) and non-tumor (history of hypothyroidism, radiation exposure, etc.) characteristics. A detailed sonographic assessment of extrathyroidal extension (ETE) included surgeon performed evaluation of thyroid capsular distortion, a long interface between tumor and thyroid capsule, irregular or indistinct tumor margins abutting the thyroid capsule, or a tracheal footprint. RESULTS: Of 141 patients with PTC, 35 (25%) patients were candidates for lobectomy, and 105 (75%) patients were not candidates for lobectomy because of non-tumor (n = 46) or tumor (n = 59) characteristics. Of the 35 patients who were candidates for lobectomy, 27 had sonographic ETE on detailed assessment. Total thyroidectomy was performed in 23 patients, while thyroid lobectomy was performed in 12 patients. Total thyroidectomy was indicated based on final histopathology in 15 patients (ETE, aggressive histology, vascular invasion, or cervical metastasis). Histopathologic ETE was present in 13 of these 15 patients and was the only indication for total thyroidectomy in the remaining eight patients. Positive and negative predictive values for the prediction of ETE based on detailed sonographic assessment were 52% and 100%, respectively. In comparison to a strategy of routine total thyroidectomy, a detailed sonographic assessment of ETE reduced the rate of potentially avoidable total thyroidectomy from 57% to 31%. CONCLUSIONS: Patients with PTC who are potential candidates for lobectomy often require total thyroidectomy based on microscopic ETE detected on surgical pathology. A detailed sonographic assessment of ETE can reliably rule out microscopic ETE, reducing the rate of potentially avoidable total thyroidectomy. PMID- 29113554 TI - Laboratory services for managing thyroid disease: different and common viewpoints of ATA and AACC members. AB - We surveyed American Thyroid Association members and members of the Endocrine Division of the American Association of Clinical Chemistry as to what they perceived as priorities for thyroid laboratory services. The response rates were 16% and 25%, respectively. While there was agreement between the groups with regards to a number of items, there were also some differences, in particular with regards to diagnostic algorithms, optimization of result reporting, interest in the role of mass spectrometry and importance of accuracy and reproducibility of results. The survey thus provided insights beyond what might have been achieved by surveying the two groups in isolation. Collaborative surveys should be considered whenever the topic involves more than one professional group. PMID- 29113555 TI - Linear synthesis of the Chol-1 ganglioside core tetrasaccharide and disialyl T antigen glycan using a 5-ureido-sialyl donor. AB - Herein we describe the linear synthesis of a tetrasaccharyl sialoglycan found in both the Chol-1 ganglioside core and disialyl T antigen. The synthesis featured sialylation with a C5-ureido-modified sialyl donor followed by selective isolation of the desired alpha-sialoside via 1,5-lactamization. This methodology enables the linear synthesis of sialoglycans and provides practical access to biologically important carbohydrate molecules. PMID- 29113556 TI - Phospholipase D Family Member 6 Is a Surface Marker for Enrichment of Undifferentiated Spermatogonia in Prepubertal Boars. AB - Spermatogonial stem cells (SSCs) have a functional ability to maintain self renewal and sustain production of spermatozoa throughout the reproductive lifespan of a male. Studies on SSCs can thus better the understandings of spermatogenesis and unravel the mechanisms for self-renewal and differentiation of male germline stem cells. However, the rarity of SSCs in the testis and the lack of reliable surface markers obstruct the related study and further application of SSCs. This is especially the case in livestock animals. In this study, we identified that phospholipase D family member 6 (PLD6) is a surface marker for undifferentiated spermatogonia in boar testes. By magnetic-activated cell sorting, PLD6+ cell fraction comprises 84.45% +/- 0.35% of undifferentiated spermatogonia (marked by PLZF). Xenotransplantation of PLD6+ cells into the recipient mouse testis revealed a ninefold increase of donor cell-derived colony formation compared with that in the unselected cell group, indicating the significant enrichment of SSCs. Furthermore, based on the sorted PLD6+ cells with a high SSC content, we established a feeder-free culture system that could maintain porcine undifferentiated spermatogonia for 4 weeks in vitro with the expression of typical markers throughout the culture period. In conclusion, this study demonstrates that PLD6 is a surface marker of undifferentiated spermatogonia in testes of prepubertal boars and could be utilized to unprecedentedly enrich porcine undifferentiated spermatogonia. These data provide the basis for future studies on the refinement of germ cell culture and manipulation of porcine undifferentiated spermatogonia. PMID- 29113557 TI - Correlation of Lactic Acid and Base Deficit Values Obtained From Arterial and Peripheral Venous Samples in a Pediatric Population During Intraoperative Care. AB - Lactic acid and base deficit (BD) values are frequently monitored in the intensive care unit and operating room setting to evaluate oxygenation, ventilation, cardiac output, and peripheral perfusion. Although generally obtained from an arterial cannula, such access may not always be available. The current study prospectively investigates the correlation of arterial and peripheral venous values of BD and lactic acid. The study cohort included 48 patients. Arterial BD values ranged from -8 to 4 mEq/L and peripheral venous BD values ranged from -8 to 4 mEq/L. Arterial lactic acid values ranged from 0.36 to 2.45 MUmol/L and peripheral venous lactic acid values ranged from 0.38 to 4 MUmol/L. The arterial BD (-0.4 +/- 2.2 mEq/L) was not significantly different from the peripheral venous BD (-0.6 +/- 2.2 mEq/L). The arterial lactic acid (1.0 +/- 0.5 MUmol/L) was not significantly different from the peripheral venous lactic acid (1.1 +/- 0.6 MUmol/L). Pearson correlation coefficients demonstrated a very high correlation between arterial and peripheral venous BD ( r = .88, P < .001) and between arterial and peripheral venous lactic acid ( r = .67, P < .001). Bland-Altman plots of both pairs of measures showed that the majority of observations fell within the 95% limits of agreement. Least-squares regression indicated that a 1-unit increase in arterial BD corresponded to a 0.9-unit increase in peripheral venous BD (95% confidence interval [CI]: 0.7-1.0; P < .001) and a 1-unit increase in arterial lactic acid corresponded to a 0.9-unit increase in peripheral venous lactic acid (95% CI: 0.6-1.2; P < .001). These data demonstrate that there is a clinically useful correlation between arterial and peripheral venous lactic acid and BD values. PMID- 29113558 TI - Neuronal Control of Bone Remodeling. AB - Although the brain is well established as a master regulator of homeostasis in peripheral tissues, central regulation of bone mass represents a novel and rapidly expanding field of study. This review examines the current understanding of central regulation of the skeleton, exploring several of the key pathways connecting brain to bone and their implications both in mice and the clinical setting. Our understanding of central bone regulation has largely progressed through examination of skeletal responses downstream of nutrient regulatory pathways in the hypothalamus. Mutations and modulation of these pathways, in cases such as leptin deficiency, induce marked bone phenotypes, which have provided vital insights into central bone regulation. These studies have identified several central neuropeptide pathways that stimulate well-defined changes in bone cell activity in response to changes in energy homeostasis. In addition, this work has highlighted the endocrine nature of the skeleton, revealing a complex cross talk that directly regulates other organ systems. Our laboratory has studied bone-active neuropeptide pathways and defined osteoblast based actions that recapitulate central pathways linking bone, fat, and glucose homeostasis. Studies of neural control of bone have produced paradigm-shifting changes in our understanding of the skeleton and its relationship with the wider array of organ systems. PMID- 29113560 TI - Efficient RNA structure comparison algorithms. AB - Recently proposed relative addressing-based ([Formula: see text]) RNA secondary structure representation has important features by which an RNA structure database can be stored into a suffix array. A fast substructure search algorithm has been proposed based on binary search on this suffix array. Using this substructure search algorithm, we present a fast algorithm that finds the largest common substructure of given multiple RNA structures in [Formula: see text] format. The multiple RNA structure comparison problem is NP-hard in its general formulation. We introduced a new problem for comparing multiple RNA structures. This problem has more strict similarity definition and objective, and we propose an algorithm that solves this problem efficiently. We also develop another comparison algorithm that iteratively calls this algorithm to locate nonoverlapping large common substructures in compared RNAs. With the new resulting tools, we improved the RNASSAC website (linked from http://faculty.tamuc.edu/aarslan ). This website now also includes two drawing tools: one specialized for preparing RNA substructures that can be used as input by the search tool, and another one for automatically drawing the entire RNA structure from a given structure sequence. PMID- 29113559 TI - Proceedings of the 2017 National Toxicology Program Satellite Symposium. AB - The 2017 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Montreal, Quebec, Canada at the Society of Toxicologic Pathology's 36th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and other topics covered during the symposium included renal papillary degeneration in perinatally exposed animals, an atriocaval mesothelioma, an unusual presentation of an alveolar-bronchiolar carcinoma, a paraganglioma of the organ of Zuckerkandl (also called an extra-adrenal pheochromocytoma), the use of human muscle samples to illustrate the challenges of manual scoring of fluorescent staining, intertubular spermatocytic seminomas, medical device pathology assessment and discussion of the approval process, collagen-induced arthritis, incisor denticles, ameloblast degeneration and poorly mineralized enamel matrix, connective tissue paragangliomas, microcystin-LR toxicity, perivascular mast cells in the forebrain thalamus unrelated to treatment, and 2 cases that provided a review of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) bone nomenclature and recommended application of the terminology in routine nonclinical toxicity studies. PMID- 29113561 TI - Metagenome sequence clustering with hash-based canopies. AB - Metagenomics is the collective sequencing of co-existing microbial communities which are ubiquitous across various clinical and ecological environments. Due to the large volume and random short sequences (reads) obtained from community sequences, analysis of diversity, abundance and functions of different organisms within these communities are challenging tasks. We present a fast and scalable clustering algorithm for analyzing large-scale metagenome sequence data. Our approach achieves efficiency by partitioning the large number of sequence reads into groups (called canopies) using hashing. These canopies are then refined by using state-of-the-art sequence clustering algorithms. This canopy-clustering (CC) algorithm can be used as a pre-processing phase for computationally expensive clustering algorithms. We use and compare three hashing schemes for canopy construction with five popular and state-of-the-art sequence clustering methods. We evaluate our clustering algorithm on synthetic and real-world 16S and whole metagenome benchmarks. We demonstrate the ability of our proposed approach to determine meaningful Operational Taxonomic Units (OTU) and observe significant speedup with regards to run time when compared to different clustering algorithms. We also make our source code publicly available on Github. a. PMID- 29113563 TI - Multidimensional knowledge-based framework is an essential step in the categorization of gene sets in complex disorders. AB - In complex disorders, collaborative role of several genes accounts for the multitude of symptoms and the discovery of molecular mechanisms requires proper understanding of pertinent genes. Majority of the recent techniques utilize either single information or consolidate the independent outlook from multiple knowledge sources for assisting the discovery of candidate genes. In any case, given that various sorts of heterogeneous sources are possibly significant for quality gene prioritization, every source bearing data not conveyed by another, we assert that a perfect strategy ought to give approaches to observe among them in a genuine integrative style that catches the degree of each, instead of utilizing a straightforward mix of sources. We propose a flexible approach that empowers multi-source information reconciliation for quality gene prioritization that augments the complementary nature of various learning sources so as to utilize the maximum information of aggregated data. To illustrate the proposed approach, we took Autism Spectrum Disorder (ASD) as a case study and validated the framework on benchmark studies. We observed that the combined ranking based on integrated knowledge reduces the false positive observations and boosts the performance when compared with individual rankings. The clinical phenotype validation for ASD shows that there is a significant linkage between top positioned genes and endophenotypes of ASD. Categorization of genes based on endophenotype associations by this method will be useful for further hypothesis generation leading to clinical and translational analysis. This approach may also be useful in other complex neurological and psychiatric disorders with a strong genetic component. PMID- 29113562 TI - Utilizing networks for differential analysis of chromatin interactions. AB - Chromatin conformation capture with high-throughput sequencing (Hi-C) is a powerful technique to detect genome-wide chromatin interactions. In this paper, we introduce two novel approaches to detect differentially interacting genomic regions between two Hi-C experiments using a network model. To make input data from multiple experiments comparable, we propose a normalization strategy guided by network topological properties. We then devise two measurements, using local and global connectivity information from the chromatin interaction networks, respectively, to assess the interaction differences between two experiments. When multiple replicates are present in experiments, our approaches provide the flexibility for users to either pool all replicates together to therefore increase the network coverage, or to use the replicates in parallel to increase the signal to noise ratio. We show that while the local method works better in detecting changes from simulated networks, the global method performs better on real Hi-C data. The local and global methods, regardless of pooling, are always superior to two existing methods. Furthermore, our methods work well on both unweighted and weighted networks and our normalization strategy significantly improves the performance compared with raw networks without normalization. Therefore, we believe our methods will be useful for identifying differentially interacting genomic regions. PMID- 29113564 TI - Evaluating the quality of SHAPE data simulated by k-mers for RNA structure prediction. AB - Finding an effective measure to predict a more accurate RNA secondary structure is a challenging problem. In the last decade, an experimental method, known as selective [Formula: see text]-hydroxyl acylation analyzed by primer extension (SHAPE), was proposed to measure the tendency of forming a base pair for almost all nucleotides in an RNA sequence. These SHAPE reactivities are then utilized to improve the accuracy of RNA structure prediction. Due to a significant impact of SHAPE reactivity and in order to reduce the experimental costs, we propose a new model called HL-k-mer. This model simulates the SHAPE reactivity for each nucleotide in an RNA sequence. This is done by fetching the SHAPE reactivities for all sub-sequences of length k (k-mers) appearing in helix and loop regions. For evaluating the quality of simulated SHAPE data, ESD-Fold method is used based on the SHAPE data simulated by the HL-k-mer model ([Formula: see text]). Also, for further evaluation of simulated SHAPE data, three different methods are employed. We also extend this model to simulate the SHAPE data for the RNA pseudoknotted structure. The results indicate that the average accuracies of prediction using the SHAPE data simulated by our models (for [Formula: see text]) are higher compared to the experimental SHAPE data. PMID- 29113565 TI - Using learning analytics to evaluate a video-based lecture series. AB - BACKGROUND: The video-based lecture (VBL), an important component of the flipped classroom (FC) and massive open online course (MOOC) approaches to medical education, has primarily been evaluated through direct learner feedback. Evaluation may be enhanced through learner analytics (LA) - analysis of quantitative audience usage data generated by video-sharing platforms. METHODS AND RESULTS: We applied LA to an experimental series of ten VBLs on electroencephalography (EEG) interpretation, uploaded to YouTube in the model of a publicly accessible MOOC. Trends in view count; total percentage of video viewed and audience retention (AR) (percentage of viewers watching at a time point compared to the initial total) were examined. The pattern of average AR decline was characterized using regression analysis, revealing a uniform linear decline in viewership for each video, with no evidence of an optimal VBL length. Segments with transient increases in AR corresponded to those focused on core concepts, indicative of content requiring more detailed evaluation. We propose a model for applying LA at four levels: global, series, video, and feedback. DISCUSSION AND CONCLUSIONS: LA may be a useful tool in evaluating a VBL series. Our proposed model combines analytics data and learner self-report for comprehensive evaluation. PMID- 29113566 TI - Enhanced cytocompatibility and osteoinductive properties of sol-gel-derived silica/zirconium dioxide coatings by metformin functionalization. AB - The aim of this study was to evaluate the pro-osteogenic properties of sol-gel derived silica/zirconium dioxide coatings functionalized with 1 mM of metformin. The matrices were applied on 316L stainless steel using dip-coating technique. First of all, physicochemical properties of biomaterials were evaluated. Surface morphology and topography was determined using energy-dispersive X-ray spectroscopy and atomic force microscopy. The chemical composition was evaluated using Fourier transform infrared spectroscopy. Further, wettability and surface free energy were characterized. Cytocompatibility of biomaterials was tested in vitro using model of human multipotent mesenchymal stromal cells isolated from adipose tissue. The influence of biomaterials on cells morphology and proliferation was determined. Osteogenic effect of obtained biomaterials was evaluated in terms of their influence on secretory activity of human multipotent mesenchymal stromal cells isolated from adipose tissue and matrix mineralization. Analysis was performed in relation to the control cultures i.e. maintained on pure SS316L substrate and SS316L covered with silica/zirconium dioxide. Obtained results indicate that silica/zirconium dioxide_metformin coatings ameliorated metabolic and proliferative activity of human multipotent mesenchymal stromal cells isolated from adipose tissue, as well as promoted their proper growth and adhesion. The human multipotent mesenchymal stromal cells isolated from adipose tissue cultured on biomaterials were characterized by typical fibroblast-like morphology. The addition of metformin to the silica/zirconium dioxide coatings improved functional differentiation of human multipotent mesenchymal stromal cells isolated from adipose tissue. Osteogenic cultures on silica/zirconium dioxide_metformin were characterized by formation of well-developed osteonodules rich in calcium and phosphorous. Moreover, human multipotent mesenchymal stromal cells isolated from adipose tissue cultured on silica/zirconium dioxide_metformin synthesized increased amount of alkaline phosphatase, bone morphogenetic protein 2 and osteopontin, both on messenger RNA and protein level. Obtained biomaterials modulate cellular plasticity of human multipotent mesenchymal stromal cells isolated from adipose tissue promoting their osteogenic differentiation, thus may find application in broadly defined tissue engineering. PMID- 29113567 TI - Rapid in situ cross-linking of hydrogel adhesives based on thiol-grafted bio inspired catechol-conjugated chitosan. AB - In this paper, a novel chitosan derivative, thiol-grafting bio-inspired catechol conjugated chitosan was synthesized. The chemical structure of the synthesized catechol-conjugated chitosan was verified by 1H NMR, and its contents of thiol group and catechol group were determined by UV-vis spectrum. Four percent of catechol-conjugated chitosan aqueous solution could form hydrogels rapidly in situ in 1 min or less with the addition of sodium periodate. Rheological studies showed that the mechanical properties depend on the concentrations of catechol conjugated chitosan and the molar ratio of sodium periodate to catechol groups. Additionally, the adhesive properties of the resulting adhesives were evaluated, and the adhesion strength of obtained adhesives was as high as 50 kPa because of the complex and multiple interactions, especially the anti-oxidation mechanism of thiol group. The in vitro cytotoxicity assays demonstrated an excellent biocompatibility of the catechol-conjugated chitosan hydrogels. Benefiting from the in situ fast cured, desired mechanical strength, biocompatibility and relatively high adhesion performance, these properties suggested that catechol conjugated chitosan hydrogel adhesives have potential applications as tissue adhesive for soft tissues. PMID- 29113569 TI - Physical Therapy Rehabilitation of an Adolescent Preprofessional Dancer Following Os Trigonum Excision: A Case Report. AB - Study Design Case report. Background An os trigonum can be a source of pain for dancers due to impingement during repetitive ankle plantar flexion movements. Following excision of an os trigonum, it is important to have a gradual, progressive return-to-dance program for optimal recovery. The purpose of this case report is to describe the postoperative management and return-to-dance progression of an adolescent dancer post os trigonum excision. Case Description An adolescent preprofessional female dancer had an extensive history of left posterior heel pain, beginning at age 8, that led to surgical removal of an os trigonum at age 15. Post surgery, the patient was seen for a total of 22 visits over the course of 20 weeks. Treatment included therapeutic exercises, neuromuscular re-education, and manual therapy. Return-to-dance tests and guidelines were used to safely progress to full, unrestricted dance participation. Outcomes The dancer had a full return of ankle range of motion, strength, and balance, improved patient-reported outcome scores, and was able to fully return to dance participation. Discussion Treating a dancer following os trigonum excision should involve a screen for hypermobility, clear communication with the dance instructor, awareness of dance-specific biomechanics, and proper reintegration into dance participation. Level of Evidence Therapy, level 5. J Orthop Sports Phys Ther 2018;48(3):194-203. Epub 7 Nov 2017. doi:10.2519/jospt.2018.7508. PMID- 29113568 TI - Combined delivery of bone morphogenetic protein-2 and insulin-like growth factor 1 from nano-poly (gamma-glutamic acid)/beta-tricalcium phosphate-based calcium phosphate cement and its effect on bone regeneration in vitro. AB - In this study, nano-doped calcium phosphate cement delivery systems (poly (gamma glutamic acid)/beta-tricalcium phosphate/calcium phosphate ceramics and nano (gamma-glutamic acid)/beta-tricalcium phosphate/calcium phosphate ceramic) were fabricated, and low doses (10 ug/g) of two growth factors, insulin-like growth factor-1 and bone morphogenetic protein-2, were encapsulated then sequentially released. We characterized the delivery systems using Fourier transform infrared spectroscopy and X-ray diffraction and measured washout resistance and compressive strength, and thus optimized the most appropriate proportioning of delivery systems for the two growth factors. One of the growth factors was absorbed by the nano-poly (gamma-glutamic acid)/beta-tricalcium phosphate, which was then mixed into the calcium phosphate ceramic solid phase to create a new solid phase calcium phosphate ceramic. Nano-poly (gamma-glutamic acid)/beta tricalcium phosphate/calcium phosphate ceramic carriers were then prepared by blending the new calcium phosphate ceramic solid phase powder with a solution of the remaining growth factor. The effects of different release patterns (studying sequential behavior) of insulin-like growth factor-1 and bone morphogenetic protein-2 on osteogenic proliferation and differentiation of the MC3t3-E1 mouse osteoblast cell were investigated. This combinational delivery system provided a controlled release of the two growth factors, in which nano-doping significantly affected their release kinetics. The incorporation of dual growth factors could potentially stimulate bone healing and promoting bone ingrowth processes at a low dose. PMID- 29113570 TI - A Novel Downhill Gait-Training Program Following a Total Knee Arthroplasty: A Case Report Highlighting the Impacts of Self-selected Speed on Gait Symmetry. AB - Study Design Case report. Background Walking plays an essential role in activities of daily living and has varied health benefits. Studies report that gait speed and symmetry are impacted in individuals following total knee arthroplasty (TKA). Unfortunately, abnormal gait patterns persist in individuals after TKA. Downhill walking may provide a simple and feasible exercise regimen to improve gait patterns. The purpose of this case report was to describe the application of a downhill treadmill training program and the subsequent changes in gait patterns in an individual following a unilateral TKA. Case Description The participant was a 59-year-old woman following a right TKA. Downhill gait training was initiated 1 month post TKA and completed for 5 weeks. Outcomes were assessed using questionnaires, mobility tests, strength of quadriceps, and gait patterns. The treadmill speed was determined by the participant's self-selected gait speed on a level surface. Outcomes The participant's eccentric quadriceps strength in the operated limb significantly increased after the gait training. Her physical function recovered to a level similar to that of previous reports. Postintervention gait analysis was conducted at 2 self-selected speeds, due to an increase in the participant's self-selected gait speed between sessions. The participant demonstrated a more symmetrical gait pattern when walking slower and a more asymmetrical gait pattern at the faster speed. Discussion After completion of downhill gait training in conjunction with therapeutic exercises, the participant showed an increase in quadriceps strength and improved physical function. This case report describes the utilization and potential feasibility of downhill gait training in conjunction with outpatient physical therapy for an individual following unilateral TKA. Level of Evidence Therapy, level 5. J Orthop Sports Phys Ther 2018;48(2):104-110. Epub 7 Nov 2017. doi:10.2519/jospt.2018.7374. PMID- 29113571 TI - Dual-Task Assessment Protocols in Concussion Assessment: A Systematic Literature Review. AB - Study Design Systematic review. Background When assessed in isolation, balance and neurocognitive testing may not be sufficiently responsive to capture changes that occur with concussion. Normal daily activities require simultaneous cognitive and physical demands. Therefore, a dual-task assessment paradigm should be considered to identify performance deficits. Objectives To evaluate the literature and to identify dual-task testing protocols associated with changes in gait after concussion. Methods A systematic review of articles of individuals with concussion who underwent dual-task testing with a combination of motor and cognitive tasks was conducted. The AMED, CINAHL, Embase, PsycINFO, PubMed, Scopus, SPORTDiscus, and Web of Science databases and gray literature were searched from inception to January 29, 2017. Title and abstract, full-text, and quality review and data abstraction were performed by 2 independent reviewers. Results Twenty-four articles met the inclusion criteria. Eleven articles reported decreased gait velocity and increased medial-lateral displacement for individuals with concussion during dual-task conditions. Overall, included articles were of poor to moderate methodological quality. Fifteen articles used the same participants and data sets, creating a threat to validity and limiting the ability to make conclusions. Conclusion A deterioration in gait performance during dual-task testing is present among people with concussion. Specific recommendations for the use of a dual-task protocol to assess individuals with suspected concussion injury in a clinical setting have yet to be determined. J Orthop Sports Phys Ther 2018;48(2):87-103. Epub 7 Nov 2017. doi:10.2519/jospt.2018.7432. PMID- 29113572 TI - Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis. AB - BACKGROUND: Exercise therapy studies in persons with multiple sclerosis (pwMS) primarily focused on motor outcomes in mid disease stage, while cognitive function and neural correlates were only limitedly addressed. OBJECTIVES: This pragmatic randomized controlled study investigated the effects of a remotely supervised community-located "start-to-run" program on physical and cognitive function, fatigue, quality of life, brain volume, and connectivity. METHOD: In all, 42 pwMS were randomized to either experimental (EXP) or waiting list control (WLC) group. The EXP group received individualized training instructions during 12 weeks (3*/week), to be performed in their community aiming to participate in a running event. Measures were physical (VO2max, sit-to-stand test, Six-Minute Walk Test (6MWT), Multiple Sclerosis Walking Scale-12 (MSWS-12)) and cognitive function (Rao's Brief Repeatable Battery (BRB), Paced Auditory Serial Attention Test (PASAT)), fatigue (Fatigue Scale for Motor and Cognitive Function (FSMC)), quality of life (Multiple Sclerosis Impact Scale-29 (MSIS-29)), and imaging. Brain volumes and diffusion tensor imaging (DTI) were quantified using FSL SIENA/FIRST and FSL-TBSS. RESULTS: In all, 35 pwMS completed the trial. Interaction effects in favor of the EXP group were found for VO2max, sit-to-stand test, MSWS-12, Spatial Recall Test, FSMC, MSIS-29, and pallidum volume. VO2max improved by 1.5 mL/kg/min, MSWS-12 by 4, FSMC by 11, and MSIS-29 by 14 points. The Spatial Recall Test improved by more than 10%. CONCLUSION: Community-located run training improved aerobic capacity, functional mobility, visuospatial memory, fatigue, and quality of life and pallidum volume in pwMS. PMID- 29113573 TI - Peculiarities of interaction of synthetic polyribonucleotide poly(rA)-poly(rU) with some intercalators. PMID- 29113574 TI - A novel sexual health referral pathway for patients presenting to the emergency department with gamma-hydroxybutyrate or gamma-butyrolactone overdose. PMID- 29113575 TI - Making sense of mental health service changes. PMID- 29113576 TI - Binding affinity of pyrano[3, 2-f]quinoline and DNA: spectroscopic and docking approach. AB - The interaction between pyrano[3, 2-f]quinoline (PQ) and calf thymus DNA (CTDNA) using spectroscopic and molecular modeling approach has been presented here. Apparent association constant (1.05*105 L/mol) calculated from UV-vis specta, indicates a moderate complex formation between CTDNA and PQ. The quenching phenomena as obtained from emission spectra of ethidium bromide (EB)-CTDNA by PQ was found to be a dynamic one and the binding constants found to be 8.64, 9.25, 11.17, 12.03 * 104 L/mol at 293, 300, 308, and 315 K. Thermodynamic parameter enthalpy change (DeltaH) and entropy change (DeltaS), indicates weak force like van der Walls force and hydrogen bonds having the key role in this binding process. The results of circular dichroism (CD) demonstrate that PQ has not induced characteristic changed in CTDNA. Results achieved from UV absorption and fluorescence spectroscopy indicating the binding mode of PQ with DNA seems to be a nonintercalative binding. The theoretical results as originating from molecular modeling showed that PQ possibly will bind into the hydrophobic region of DNA having docking binding energy = -10.03 kcal/mol and the obtained results are in consonance with the inferences obtained from experimental data. This result is important for the better understanding of pharmaceutical aspects of binding affinity of PQ and CTDNA. PMID- 29113577 TI - A novel kinetic modeling method for the stabilization phase of the composting process for biodegradation of solid wastes. AB - Biomass degradation kinetics of the composting process for kitchen waste, pruned elm tree branches and sheep manure were studied to model changes in volatile solids (VS) over time. Three experimental reactors containing raw mixtures with a carbon to nitrogen (C/N) ratio of 27:1 and a moisture content of 65% were prepared. During the composting process two of the reactors used forced air and the third used natural aeration. The composting stabilization phases in all reactors were completed in 30 days. During this period, composting indexes such as temperature, moisture content and VS changes were recorded. Elementary reactions were used for kinetics modeling of the degradation process. Results showed that the numerical values of rate constant ( k) for zero-order ranged from 0.86 to 1.03 VS*day-1, for first-order models it ranged from 0.01 to 0.02 day-1, for second-order the range was from 1.36*10-5 to 1.78*10-5 VS-1*day-1 and for n order the rate constant ranged from 0.031 to 0.095 VS(1-n)*day-1. The resulting models were validated by comparing statistical parameters. Evaluation of the models showed that, in the aerated reactors, the n-order models (less than 1) successfully estimated the VS changes. In the non-aeration reactor, for the second-order model good agreement was achieved between the simulated and actual quantities of VS. Also, half-life time provided a useful criterion for the estimation of expected time for completion of different phases of composting. PMID- 29113578 TI - Periodic solution of a stochastic SIRS epidemic model with seasonal variation. AB - In this paper, we consider a stochastic SIRS epidemic model with seasonal variation and saturated incidence. Firstly, we obtain the threshold of stochastic system which determines whether the epidemic occurs or not. Secondly, we prove that there is a non-trivial positive periodic solution if [Formula: see text]. PMID- 29113579 TI - Use of Research Interfaces for Psychophysical Studies With Cochlear-Implant Users. AB - A growing number of laboratories are using research interfaces to conduct experiments with cochlear-implant (CI) users. Because these interfaces bypass a subject's clinical sound processor, several concerns exist regarding safety and stimulation levels. Here we suggest best-practice approaches for how to safely and ethically perform this type of research and highlight areas of limited knowledge where further research is needed to help clarify safety limits. The article is designed to provide an introductory level of technical detail about the devices and the effects of electrical stimulation on perception and neurophysiology. From this, we summarize what should be the best practices in the field, based on the literature and our experience. Findings from the review of the literature suggest that there are three main safety concerns: (a) to prevent biological or neural damage, (b) to avoid presentation of uncomfortably loud sounds, and (c) to ensure that subjects have control over stimulus presentation. Researchers must pay close attention to the software-hardware interface to ensure that the three main safety concerns are closely monitored. An important area for future research will be the determination of the amount of biological damage that can occur from electrical stimulation from a CI placed in the cochlea, not in direct contact with neural tissue. As technology used in research with CIs evolve, some of these approaches may change. However, the three main safety principles outlined here are not anticipated to undergo change with technological advances. PMID- 29113580 TI - Prominin-2 Prevents the Formation of Caveolae in Normal and Ovarian Hyperstimulated Pregnancy. AB - During early pregnancy, uterine epithelial cells (UECs) become less adherent to the underlying basal lamina and are subsequently removed so the blastocyst can invade the underlying stroma. This process involves the removal of focal adhesions from the basal plasma membrane of UECs. These focal adhesions are thought to be internalized by caveolae, which significantly increase in abundance at the time of blastocyst implantation. A recent in vitro study indicated that prominin-2 prevents the formation of caveolae by sequestering membrane cholesterol. The present study examines whether prominin-2 affects the formation of caveolae and loss of focal adhesions in UECs during normal and ovarian hyperstimulation (OH) pregnancy in the rat. At the time of fertilization during normal pregnancy, prominin-2 is distributed throughout the basolateral plasma membrane. However, at the time of implantation and coincident with an increase in caveolae, prominin-2 is lost from the basal plasma membrane. In contrast, prominin-2 remains in the basolateral plasma membrane throughout OH pregnancy. Transmission electron microscopy showed that this membrane contained few caveolae throughout OH pregnancy. Our results indicate that prominin-2 prevents the formation of caveolae. We suggest the retention of prominin-2 in the basal plasma membrane during OH pregnancy prevents the formation of caveolae and is responsible for the retention of focal adhesions in this membrane, thereby contributing to the reduced implantation rate observed after such treatments. PMID- 29113581 TI - Comparison of Follicle Isolation Methods for Mouse Ovarian Follicle Culture In Vitro. AB - Ovarian follicle in vitro culture is a promising fertility preservation option to avoid risk of reintroduction of malignant cells. The objective of this study is to compare 4 different follicle isolation methods from ovarian tissue and evaluate the effect of follicle isolation on further in vitro follicle culture and oocyte competency. Mouse ovaries were dissected and randomly divided into 4 groups according to follicle isolation method: mechanical (MCH) isolation, mincing (MNC) isolation, enzymatically digestion using collagenase (COL), and enzymatically digestion using liberase (LIB). The isolated early secondary follicles were cultured for day 10, and ovulation induction was conducted. Follicular diameter and concentrations of steroid hormone in spent media were measured. Also, follicular survival rate and pseudo-antrum formation rate were examined. After ovulation induction, the cumulus oocyte complexes rate and the number of mature oocyte, normal spindle rate, and mitochondrial activity in ovulated oocyte were counted. After in vitro culture, follicular diameter was significantly greater in MNC and MCH group than other groups. Also, follicle survival rate was significantly higher in MNC and MCH groups than other groups. The MNC group had made a result that significantly improved the mature oocyte rate than other groups. The normal meiotic spindle and chromosome rate is significantly higher in MNC and MCH groups than other groups. The MNC method showed significantly improved rate of follicle diameter, survival, pseudo-antrum formation, a mature oocyte, and normal spindle in ovulated oocyte after in vitro culture. Based on the results, MNC method can be an alternative for MCH method that is laborious and time-consuming. PMID- 29113582 TI - The Effects of Magnesium Sulfate on the Inflammatory Response of Placentas Perfused With Lipopolysaccharide: Using the Ex Vivo Dual-Perfused Human Single Cotyledon Model. AB - OBJECTIVES: Multiple mechanisms have been proposed for the neuroprotective effects of magnesium sulfate (MgSO4). We aimed to examine the effects of lipopolysaccharide (LPS) and MgSO4 on the placental expression of nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB), interleukin (IL) 6, adrenocorticotropic hormone (ACTH), and nitric oxide synthase (NOS); all known to participate in the inflammatory cascade. METHODS: Placentas were obtained and selected cotyledons cannulated and dually perfused ex vivo. Placentas were perfused with 4 perfusion protocols: culture medium (M-199; controls), LPS (1 MUg/mL), MgSO4 (6 g/dL), and LPS + MgSO4. Each perfusion experiment continued for 3 hours. Sixteen perfusion experiments were analyzed, 4 separate placentas were studied for each protocol. The protein levels in the perfused cotyledons were studied by Western blot analysis and compared between the groups. Interleukin 6 levels were studied in the maternal and fetal perfusate. RESULTS: The expression of NF-kappaB p65, IL-6, ACTH, and NOS proteins levels were significantly increased in placentas perfused with LPS as compared to placentas perfused with M 199, MgSO4 ( P < .01 for all). Placentas perfused with LPS+ MgSO4 had similar proteins levels as in the controls and MgSO4 groups. Lipopolysaccharide significantly increased IL-6 levels in maternal perfusate. CONCLUSIONS: In the human placenta, MgSO4 blocks the increase in the proteins levels of NF-kappaB, IL 6, ACTH, and NOS in response to inflammatory stimuli. Magnesium sulfate attenuates excessive placental inflammatory response. The decrease in placental ACTH levels following perfusion with MgSO4 may point to an additional non-anti inflammatory mechanism of MgSO4. PMID- 29113585 TI - Medical Teacher in Ten Minutes. PMID- 29113586 TI - Top-rated AMEE MedEdPublish Papers - August 2017. PMID- 29113583 TI - Aberrant Akt Activation During Implantation Window in Infertile Women With Intramural Uterine Fibroids. AB - The objective of the study was to examine the expression and cellular distribution of key signaling components of the phosphatidylinositol-3-kinase (PI3K)/Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)/Protein Kinase B (PKB/Akt) pathway during the window of implantation in infertile women with noncavity-distorting intramural uterine fibroids (n = 21) as compared to fertile controls (n = 15). Relative gene expression analysis of PIK3CA, PTEN, Akt1, and Akt2 genes in midluteal endometrial biopsies was performed by real-time polymerase chain reaction. Immunohistochemistry was used to evaluate the expression of PIK3CA, PTEN, phospho-PTEN, Akt1, Akt2, phospho-Akt1 (serine 473), phospho-Akt1 (threonine 308), and Ki67 proteins. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay was performed for apoptosis detection. In comparison to fertile controls, significant upregulation of Akt1 messenger RNA levels (2.16-fold; P < .05); cell-specific upregulation of the proteins phospho-PTEN ( P < .05), Akt1 ( P < .05), Akt2 ( P < .05), and p-Akt (S473; P < .001); and downregulation of PTEN ( P < .01) were observed in endometrium of infertile women with intramural fibroids. The ratio of p-PTEN/PTEN and p-Akt1 (S473)/Akt1 was also significantly higher in infertile women. Increased Ki67 labeling index in the glandular epithelium and significantly lower apoptotic index in glandular epithelium and stroma were seen in infertile women during the window of implantation. Aberrant Akt activation and the associated imbalance in endometrial proliferation and apoptosis observed in infertile women with intramural fibroids during the midsecretory phase might contribute to impaired endometrial receptivity leading to infertility in these patients. PMID- 29113587 TI - Streptococcus pneumoniae burden and nasopharyngeal inflammation during acute otitis media. AB - Streptococcus pneumoniae (Spn) is a common respiratory pathogen and a frequent cause of acute otitis media (AOM) in children. The first step in bacterial pathogenesis of AOM is the establishment of asymptomatic colonization in the nasopharynx. We studied Spn bacterial burden in conjunction with neutrophil recruitment and inflammatory gene transcription and cytokine secretion in samples of nasal wash collected from normal and otitis-prone children during health, viral upper respiratory infection without middle ear involvement (URI) and AOM. We found no significant associations between otitis-prone status and any of the measured parameters. However, Spn bacterial burden was significantly correlated with neutrophil recruitment, transcription of IL-8, TNF-alpha and SOD2, and secretion of TNF-alpha. We also found that transcription of IL-8 and TNF-alpha mRNA by neutrophils was significantly correlated with the secretion of these cytokines into the nasopharynx. We conclude that Spn bacterial burden in the NP is a major determinant of neutrophil recruitment to the NP and activity during URI and AOM, and that neutrophils are contributors to the secretion of IL-8 and TNF-alpha in the NP when the Spn burden is high. PMID- 29113588 TI - Silica nanoparticles induce NLRP3 inflammasome activation in human primary immune cells. AB - In recent years, the potential use of silica nanoparticles (SiNPs) among different biomedical fields has grown. A deep understanding of the physicochemical properties of nanoparticles (NPs) and their regulation of specific biological responses is crucial for the successful application of NPs. Exposure to NP physicochemical properties (size, shape, porosity, etc.) could result in deleterious effects on cellular functions, including a pro-inflammatory response mediated via activation of the NLRP3 inflammasome. The aim of this study was to evaluate the potential in vitro immunomodulatory effect of 12-nm and 200 nm SiNPs on the expression of pro-inflammatory cytokines and NLRP3 inflammasome components in human primary neutrophils and PBMCs. This study demonstrates that regardless of the size of the nanoparticles, SiNPs induce the production of pro inflammatory cytokines in a dose-dependent manner. Induced IL-1beta production after exposure to SiNPs suggests the involvement of NLRP3 inflammasome components participation in this process. In conclusion, SiNPs induce the production of pro inflammatory cytokines in a dose-dependent manner. Furthermore, our data suggest that the production and release of IL-1beta possibly occurs through the formation of the NLRP3 inflammasome. PMID- 29113590 TI - On the Basis of Preterm Labor. PMID- 29113589 TI - Erratum. PMID- 29113591 TI - Editorial: Emerging Biomarkers in Genitourinary Tumors. PMID- 29113592 TI - Editorial: Multi-target Drug Discovery - Part I. PMID- 29113593 TI - Molecular identification of parasitic nematodes (Nematoda: Strongylida) in feces of wild ruminants from Tunisia. AB - In Tunisia and other North African countries, there is a lack of knowledge about parasite biodiversity within threatened wild ruminants and there are not any studies on their gastrointestinal nematodes. Thus the aim of this study was to identify gastrointestinal fauna in the faecal samples of Tunisian wild ruminants. A total of 262 faecal samples were collected from domestic sheep and goat, and wild ruminants (Addax, Barbary sheep, Barbary red deer, Dorcas gazelle, Slender horned gazelle and Scimitar-horned Oryx) living in protected areas. Samples were examined with floatation (saturated sodium chloride solution), polymerase chain reaction and sequencing of the second internal transcribed spacer region of the rDNA. Microscopic analysis allowed the identification of only Nematodirus genus or molecular tools allowed a first identification of five gastrointestinal nematode species in North African wild ruminants: Chabertia ovina (1.6%), Camelostrongylus mentulatus (1.6%), Marshallagia marshalli (4.7%), Nematodirus helvetianus (62.5%) and Nematodirus spathiger (29.7%). This study reported the first records of C. mentulatus and M. marshalli in Addax and of M. marshalli in Dorcas gazelle and it was the first reported record of N. helvetianus and M. marshalli in Tunisia. PMID- 29113594 TI - Molecular and morphological characterization of the cercariae of Lecithodendrium linstowi (Dollfus, 1931), a trematode of bats, and incrimination of the first intermediate snail host, Radix balthica. AB - Lecithodendrium linstowi is one of the most prevalent and abundant trematodes of bats, but the larval stages and intermediate hosts have not been identified. We present the first molecular and morphological characterization of the cercariae of L. linstowi based on a phylogenetic analysis of partial fragments of LSU and ITS2 rDNA. The first intermediate host was incriminated as Radix balthica by DNA barcoding using cox1 and ITS2 sequences, although the snail morphologically resembled Radix peregra, emphasizing the requirement for molecular identification of lymnaeids as important intermediate hosts of medical and veterinary impact. The application of molecular data in this study has enabled linkage of life cycle stages and accurate incrimination of the first intermediate host. PMID- 29113596 TI - Differences between populations in host manipulation by the tapeworm Schistocephalus solidus - is there local adaptation? AB - Host manipulation whereby a parasite increases its transmission to a subsequent host by altering the behaviour of its current host is very far spread. It also occurs in host-parasite systems that are widely distributed. This offers the potential for local adaptation. The tapeworm Schistocephalus solidus modifies its first intermediate copepod host's predation susceptibility to suit its own needs by reducing its activity before it becomes infective and increasing it thereafter. To investigate potential differences in host manipulation between different populations and test for potential local adaptation with regard to host manipulation, I experimentally infected hosts from two distinct populations with parasites from either population in a fully crossed design. Host manipulation differed between populations mostly once the parasite had reached infectivity. These differences in infective parasites were mostly due to differences between different parasite populations. In not yet infective parasites, however, host population also had a significant effect on host manipulation. There was no evidence of local adaptation; parasites were able to manipulate foreign and local hosts equally well. Likewise, hosts were equally poor at resisting host manipulation by local and foreign parasites. PMID- 29113595 TI - The helminth community of a population of Rattus norvegicus from an urban Brazilian slum and the threat of zoonotic diseases. AB - Urban slums provide suitable conditions for infestation by rats, which harbour and shed a wide diversity of zoonotic pathogens including helminths. We aimed to identify risk factors associated with the probability and intensity of infection of helminths of the digestive tract in an urban slum population of Rattus norvegicus. Among 299 rats, eleven species/groups of helminths were identified, of which Strongyloides sp., Nippostrongylus brasiliensis and, the human pathogen, Angiostrongylus cantonensis were the most frequent (97, 41 and 39%, respectively). Sex interactions highlighted behavioural differences between males and females, as eg males were more likely to be infected with N. brasiliensis where rat signs were present, and males presented more intense infections of Strongyloides sp. Moreover, rats in poor body condition had higher intensities of N. brasiliensis. We describe a high global richness of parasites in R. norvegicus, including five species known to cause disease in humans. Among these, A. cantonensis was found in high prevalence and it was ubiquitous in the study area - knowledge which is of public health importance. A variety of environmental, demographic and body condition variables were associated with helminth species infection of rats, suggesting a comparable variety of risk factors for humans. PMID- 29113597 TI - Antigenicity, immunogenicity and protective efficacy of a conserved Leishmania hypothetical protein against visceral leishmaniasis. AB - In this study, a Leishmania hypothetical protein, LiHyS, was evaluated regarding its antigenicity, immunogenicity and protective efficacy against visceral leishmaniasis (VL). Regarding antigenicity, immunoblottings and an enzyme-linked immunosorbent assay using human and canine sera showed high sensitivity and specificity values for the recombinant protein (rLiHyS) in the diagnosis of VL. When evaluating the immunogenicity of LiHyS, which is possibly located in the parasite's flagellar pocket, proliferative assays using peripheral blood mononuclear cells from healthy subjects or VL patients showed a high proliferative index in both individuals, when compared to the results obtained using rA2 or unstimulated cultures. Later, rLiHyS/saponin was inoculated in BALB/c mice, which were then challenged with Leishmania infantum promastigotes. The vaccine induced an interferon-gamma, interleukin (IL)-12 and granulocyte macrophage colony-stimulating factor production, which was maintained after infection and which was associated with high nitrite and IgG2a antibody levels, as well as low IL-4 and IL-10 production. Significant reductions in the parasite load in liver, spleen, bone marrow and draining lymph nodes were found in these animals. In this context, the present study shows that the rLiHyS has the capacity to be evaluated as a diagnostic marker or vaccine candidate against VL. PMID- 29113598 TI - Service user and caregiver involvement in mental health system strengthening in low- and middle-income countries: a cross-country qualitative study. AB - AIMS: The aims of this paper are to: (i) explore the experiences of involvement of mental health service users, their caregivers, mental health centre heads and policy makers in mental health system strengthening in three low- and middle income countries (LMICs) (Ethiopia, Nepal and Nigeria); (ii) analyse the potential benefits and barriers of such involvement; and (iii) identify strategies required to achieve greater service user and caregiver participation. METHODS: A cross-country qualitative study was conducted, interviewing 83 stakeholders of mental health services. RESULTS: Our analysis showed that service user and caregiver involvement in the health system strengthening process was an alien concept for most participants. They reported very limited access to direct participation. Stigma and poverty were described as the main barriers for involvement. Several strategies were identified by participants to overcome existing hurdles to facilitate service user and caregiver involvement in the mental health system strengthening process, such as support to access treatment, mental health promotion and empowerment of service users. This study suggests that capacity building for service users, and strengthening of user groups would equip them to contribute meaningfully to policy development from informed perspectives. CONCLUSION: Involvement of service users and their caregivers in mental health decision-making is still in its infancy in LMICs. Effective strategies are required to overcome existing barriers, for example making funding more widely available for Ph.D. studies in participatory research with service users and caregivers to develop, implement and evaluate approaches to involvement that are locally and culturally acceptable in LMICs. PMID- 29113599 TI - Haemoparasites of the pied flycatcher: inter-population variation in the prevalence and community composition. AB - The prevalence and community composition of haemoparasites can substantially differ among avian host populations, which may lead to different selection pressures. Therefore, information about these parameters is crucial for understanding, e.g. the inter-population variation in host life history traits. Here, we molecularly screened a population of a long-distance migrant, the pied flycatcher Ficedula hypoleuca, from central Poland for the presence of three genera of blood parasites: Haemoproteus, Plasmodium and Trypanosoma. The infection rate in this population was the highest for haemosporidians (86.8%) and one of the highest for trypanosomes (39.7%) among the thus far screened breeding populations of this species. The haemosporidian community was composed of six Haemoproteus/Plasmodium lineages, and the trypanosome community - 4 species and a parasite assigned to genus level. Trypanosomes were dominated by T. culicavium, a recently described species, corroborating the prediction that insectivorous songbirds are vertebrate hosts of this parasite. Host sex and age did not explain variation in infection incidence except for the higher trypanosome infection rates in males. A comparison of the study population with three other breeding populations previously screened molecularly for haemosporidians showed some geographic differences. This study confirms the importance of examining local parasite communities across a host distribution range. PMID- 29113600 TI - MALDI-TOF MS protein profiling for the rapid identification of Chagas disease triatomine vectors and application to the triatomine fauna of French Guiana - CORRIGENDUM. PMID- 29113601 TI - Incidence of paragonimiasis in Chongqing China: a 6-year retrospective case review. AB - Paragonimiasis is an important infectious disease in Chongqing, China. However, no epidemiological surveys of paragonimiasis have been carried out in Chongqing since it became a municipality in 1997. We conducted a retrospective case review of 683 patients who were referred to our laboratory and diagnosed as having paragonimiasis during 2010-2015. Patients were diagnosed with paragonimiasis based on immunodiagnostic tests in addition to clinical and laboratory findings. Patient data extracted from the epidemiologic form were analysed. The majority of patients were distributed on the east side of the Wujiang River, which belongs to the Three Gorges Reservoir region. Consumption of raw or undercooked freshwater crab or crayfish in the family Cambaridae was the main reason for infection. Notably, more than 50.0% of patients were diagnosed between March and July, indicating that serious clinical symptoms only appear approximately 6 months post infection. Paragonimiasis remains a public health issue in Chongqing, and an epidemiological study of Paragonimus in the Three Gorges region is strongly recommended. PMID- 29113602 TI - Cattle and rainfall affect tick abundance in central Kenya. AB - East Africa is a global hot spot for the diversity of ixodid ticks. As ectoparasites and as vectors of pathogens, ticks negatively affect the well-being of humans, livestock and wildlife. To prevent tick infestations, livestock owners and managers typically treat livestock with acaricides that kill ticks when they attempt to feed on livestock hosts. Because of the costs of preventing and mitigating tick parasitism, predicting where and when ticks will be abundant is an important challenge in this region. We used a 7-year monthly record of tick abundance on large experimental plots to assess the effects of rainfall, wildlife and cattle on larvae, nymphs and adults of two common tick species, Rhipicephalus pulchellus and Rhipicephalus praetextatus. Nymphal and adult ticks were more abundant when there had been high cumulative rainfall in the prior months. They were less abundant when cattle were present than when only large wild mammals were. Larval abundance was not affected by the presence of cattle, and larvae did not appear to be sensitive to rainfall in prior months, though they were less abundant in our surveys when rainfall was high in the sampling month. The challenges of managing ticks in this region are being exacerbated rapidly by changes in rainfall patterns wrought by climate change, and by overall increases in livestock, making efforts to predict the impacts of these drivers all the more pressing. PMID- 29113604 TI - Tau accumulation in two patients with frontotemporal lobe degeneration showing different types of aphasia using 18F-THK-5351 positron emission tomography: a case report. AB - ABSTRACTTau deposits in Alzheimer's disease and corticobasal syndrome have been reported using 18F-THK-5351 positron emission tomography (PET). To our knowledge, our study is the first to demonstrate tau deposits in patients with frontotemporal lobe degeneration (FTLD), using 18F-THK-5351 PET. This case report presents two patients, both of whom showed positive Tau deposition using 18F-THK 5351 PET. One patient was diagnosed with semantic variant primary progressive aphasia (PPA) and the other diagnosed with logopenic variant PPA. Our results suggest an association in the pathology of Alzheimer's disease, corticobasal syndrome, and FTLD, and could plan more effective clinical care in advance. PMID- 29113603 TI - Identification of a novel PYP-1 gene in Sarcoptes scabiei and its potential as a serodiagnostic candidate by indirect-ELISA. AB - Scabies is a parasitic disease caused by the ectoparasite Sarcoptes scabiei, affecting different mammalian species, including rabbits, worldwide. In the present study, we cloned and expressed a novel inorganic pyrophosphatase, Ssc-PYP 1, from S. scabiei var. cuniculi. Immunofluorescence staining showed that native Ssc-PYP-1 was localized in the tegument around the mouthparts and the entire legs, as well as in the cuticle of the mites. Interestingly, obvious staining was also observed on the fecal pellets of mites and in the integument of the mites. Based on its good immunoreactivity, an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant Ssc-PYP-1 (rSsc-PYP-1) as the capture antigen was developed to diagnose sarcoptic mange in naturally infected rabbits; the assay had a sensitivity of 92.0% and specificity of 93.6%. Finally, using the rSsc-PYP 1-ELISA, the Ssc-PYP-1 antibody from 10 experimentally infected rabbits could be detected from 1 week post-infection. This is the first report of S. scabiei inorganic pyrophosphatase and the protein could serve as a potential serodiagnostic candidate for sarcoptic mange in rabbits. PMID- 29113605 TI - Rapid review of cognitive screening instruments in MCI: proposal for a process based approach modification of overlapping tasks in select widely used instruments. AB - : ABSTRACTBackground:A detailed neuropsychological assessment plays an important role in the diagnostic process of Mild Cognitive Impairment (MCI). However, available brief cognitive screening tests for this clinical population are administered and interpreted based mainly, or exclusively, on total achievement scores. This score-based approach can lead to erroneous clinical interpretations unless we also pay attention to the test taking behavior or to the type of errors committed during test performance. METHODS: The goal of the current study is to perform a rapid review of the literature regarding cognitive screening tools for dementia in primary and secondary care; this will include revisiting previously published systematic reviews on screening tools for dementia, extensive database search, and analysis of individual references cited in selected studies. RESULTS: A subset of representative screening tools for dementia was identified that covers as many cognitive functions as possible. How these screening tools overlap with each other (in terms of the cognitive domains being measured and the method used to assess them) was examined and a series of process-based approach (PBA) modifications for these overlapping features was proposed, so that the changes recommended in relation to one particular cognitive task could be extrapolated to other screening tools. CONCLUSION: It is expected that future versions of cognitive screening tests, modified using a PBA, will highlight the benefits of attending to qualitative features of test performance when trying to identify subtle features suggestive of MCI and/or dementia. PMID- 29113606 TI - Nonmotor Symptoms of Parkinson's Disease as Predictors of Dementia. AB - Some nonmotor symptoms (NMS) of Parkinson's disease (PD) have been shown to increase the risk of developing dementia. A total of 52 PD patients without dementia at baseline were examined for NMS over 36 months. Mini-Mental State Examination, Dementia Rating Scale-2, and caregiver-derived (Clinical Dementia Rating) scores were employed to rate patients as having either clear progression or not. Some 20 of 48 participants (41.7%) had clear cognitive decline. Univariate binary regression analysis was statistically significant for age (odds ratio [OR] (CI 95%)=1.24, 1.07-1.45, p=0.006) and orthostatic hypotension (OH) (OR (CI 95%)=4.91, 1.24-19.5, p=0.024). Multivariate analysis showed that only age (OR (CI 95%)=1.19, 1.0-1.41, p=0.05) and OH (OR (CI 95%)=5.57, 1.0-30.97, p=0.05) were correlated with an increased risk of cognitive decline. The presence of OH at baseline may be a significant predictor of progression to dementia in PD. PMID- 29113607 TI - Directional associations between memory impairment and depressive symptoms: data from a longitudinal sample and meta-analysis. AB - BACKGROUND: Previous cross-lagged studies on depression and memory impairment among the elderly have revealed conflicting findings relating to the direction of influence between depression and memory impairment. The current study aims to clarify this direction of influence by examining the cross-lagged relationships between memory impairment and depression in an Asian sample of elderly community dwellers, as well as synthesizing previous relevant cross-lagged findings via a meta-analysis. METHODS: A total of 160 participants (Mage = 68.14, s.d. = 5.34) were assessed across two time points (average of 1.9 years apart) on measures of memory and depressive symptoms. The data were then fitted to a structural equation model to examine two cross-lagged effects (i.e. depressive symptoms >memory; memory->depressive symptoms). A total of 14 effect-sizes for each of the two cross-lagged directions were extracted from six studies (including the present; total N = 8324). These effects were then meta-analyzed using a three level mixed effects model. RESULTS: In the current sample, lower memory ability at baseline was associated with worse depressive symptoms levels at follow-up, after controlling for baseline depressive symptoms. However, the reverse effect was not significant; baseline depressive symptoms did not predict subsequent memory ability after controlling for baseline memory. The results of the meta analysis revealed the same pattern of relationship between memory and depressive symptoms. CONCLUSIONS: These results provide robust evidence that the relationship between memory impairment and depressive symptoms is unidirectional; memory impairment predicts subsequent depressive symptoms but not vice-versa. The implications of these findings are discussed. PMID- 29113608 TI - The Brazilian Family Health Strategy and the management of intestinal parasitic infections. AB - : AimThis study analyzed the management of intestinal parasitic infections in the Family Health Strategy covering Brazilian urban slums. BACKGROUND: The Family Health Strategy is the preferred strategy for providing public, community-based primary health care in the Brazilian Unified Health System (SUS). Through this strategy, Family Health teams are responsible for the health of residents of a defined territory, including health promotion, health education and control of neglected tropical diseases such as intestinal parasitic infections. METHODS: Knowledge, attitudes and practices surveys were applied with Family Health team members (n=58) and patients (n=571) of an agglomeration of Brazilian urban slums in Rio de Janeiro.FindingsThe management of intestinal parasitic infections and health promotion were limited. Health education was not considered an essential aspect of team members' work and did not include environmental or social determinants of health. Community health workers and urban slum residents presented similar knowledge, attitudes and practices regarding intestinal parasitic infections. CONCLUSIONS: Multiple, competing demands promote prioritization of the aspects of care where curative, biomedical activities predominate over prevention and an integral approach to health. However, the complex processes involving the cycle of poverty and disease go beyond the biomedical, limiting the potential for health in urban slums. Implications include a need to better prepare health professionals for primary health care services through reflection on local concerns and the social determinants of health, highlighting the importance of territorialized care and permanent education. PMID- 29113610 TI - The impact of a visual arts program on quality of life, communication, and well being of people living with dementia: a mixed-methods longitudinal investigation. AB - : ABSTRACTBackground:Research reviews highlight methodological limitations and gaps in the evidence base for the arts in dementia care. In response, we developed a 12-week visual art program and evaluated the impact on people living with dementia through a mixed-methods longitudinal investigation. METHODS: One hundred and twenty-five people living with mild to severe dementia were recruited across three research settings in England and Wales (residential care homes, a county hospital, and community venues). Quantitative and qualitative data on quality of life (QoL), communication and perceptions of the program were obtained through interviews and self-reports with participants and their carers. Eight domains of well-being were measured using a standardized observation tool, and data compared to an alternative activity with no art. RESULTS: Across all sites, scores for the well-being domains of interest, attention, pleasure, self-esteem, negative affect, and sadness were significantly better in the art program than the alternative condition. Proxy-reported QoL significantly improved between baseline and 3-month follow-up, but no improvements in QoL were reported by the participants with dementia. This was contrasted by their qualitative accounts, which described a stimulating experience important for social connectedness, well being, and inner-strength. Communication deteriorated between baseline and follow up in the hospital setting, but improved in the residential care setting. CONCLUSIONS: The findings highlight the potential for creative aging within dementia care, the benefits of art activities and the influence of the environment. We encourage dementia care providers and arts and cultural services to work toward embedding art activities within routine care provision. PMID- 29113609 TI - Dermotropic Leishmania donovani in Sri Lanka: visceralizing potential in clinical and preclinical studies. AB - The visceralizing potential of apparently dermotropic Leishmania donovani in Sri Lanka (L. donovani-SL) was investigated through long-term follow-up of cutaneous leishmaniasis (CL) patients and in vivo and in vitro experimental infection models. CL patients (n = 250) treated effectively with intra-lesional antimony therapy were followed-up six monthly for 4 years. There was no clinical evidence of visceralization of infection (VL) during this period. Infection of BALB/c mice with L. donovani-SL (test) through intra-dermal route led to the development of cutaneous lesions at the site of inoculation with no signs of systemic dissemination, in contrast to the observations made in animals similarly infected with a visceralizing strain of L. donovani-1S (control). Cytokine (IL-10, IFN gamma) release patterns of splenocytes and lymph node cell cultures derived from mice primed with experimental infections (with either test or control parasites) revealed significantly high IFN-gamma response associated with test mice with CL, while prominent IL-10 levels were observed in association with control mice with VL. Furthermore, diminished infection efficiency, intracellular growth and survival of L. donovani-SL parasites compared with L. donovani-1S were evident through in vitro macrophage infection experiments. These studies confirm, for the first time, the essential dermotropic nature of L. donovani-SL suggesting natural attenuation of virulence of local parasite strains. PMID- 29113611 TI - THE ADDED VALUE OF INTEGRATE-HTA GUIDANCE IN THE WORK PROCESSES OF HEALTH TECHNOLOGY ASSESSMENT AGENCIES. AB - A central idea underlying the INTEGRATE-HTA project is that many of the interventions that are being used in health care are quite complex. By this, we mean that the relation between the delivery of the intervention on the one hand, and the onset of (desired and undesired) changes may be less straightforward than hoped for. There may be all sorts of reasons for this, varying from a lack of resources, lack of skills, perverse incentives, organizational problems, etc. Not identifying such factors and their potential impact may seriously compromise the policy relevance of a health technology assessment (HTA) (1). However, current approaches and methods in HTA do not seem to be adequately geared to deal with this complexity. PMID- 29113613 TI - DNA barcoding of Cryptosporidium. AB - Cryptosporidium spp. (Apicomplexa) causing cryptosporidiosis are of medical and veterinary significance. The genus Cryptosporidium has benefited from the application of what is considered a DNA-barcoding approach, even before the term 'DNA barcoding' was formally coined. Here, the objective to define the DNA barcode diversity of Cryptosporidium infecting mammals is reviewed and considered to be accomplished. Within the Cryptosporidium literature, the distinction between DNA barcoding and DNA taxonomy is indistinct. DNA barcoding and DNA taxonomy are examined using the latest additions to the growing spectrum of named Cryptosporidium species and within-species and between-species identity is revisited. Ease and availability of whole-genome DNA sequencing of the relatively small Cryptosporidium genome offer an initial perspective on the intra-host diversity. The opportunity emerges to apply a metagenomic approach to purified field/clinical Cryptosporidum isolates. The outstanding question remains a reliable definition of Cryptosporidium phenotype. The complementary experimental infections and metagenome approach will need to be applied simultaneously to address Cryptosporidium phenotype with carefully chosen clinical evaluations enabling identification of virulence factors. PMID- 29113612 TI - Socioeconomic inequalities in resilience and vulnerability among older adults: a population-based birth cohort analysis. AB - : ABSTRACTBackground:Aging is associated with declines in physical capability; however, some individuals demonstrate high well-being despite this decline, i.e. they are "resilient." We examined socioeconomic position (SEP) and resilience and the influence of potentially modifiable behavioral resources, i.e. social support and leisure time physical activity (LTPA), on these relationships. METHODS: Data came from the Medical Research Council National Survey of Health and Development, a nationally-representative birth cohort study. Resilience-vulnerability at age 60-64 years (n = 1,756) was operationalized as the difference between observed and expected levels of well-being, captured by the Warwick-Edinburgh Mental Well being Scale (WEMWBS), given the level of performance-based physical capability. SEP was assessed by father's and own social class, parental education, and intergenerational social mobility. PA and structural/functional social support were reported at ages 53 years and 60-64 years. Path analysis was used to examine mediation of SEP and resilience-vulnerability through LTPA and social support. RESULTS: Participants in the highest social class had scores on the resilience to vulnerability continuum that were an average of 2.3 units (beta = 0.46, 95% CI 0.17, 0.75) higher than those in the lowest social class. Greater LTPA (beta = 0.58, 95% CI 0.31, 0.85) and social support (beta = 3.27, 95% CI 2.90, 3.63) were associated with greater resilience; LTPA partly mediated participant social class and resilience (23.4% of variance). CONCLUSIONS: Adult socioeconomic advantage was associated with greater resilience. Initiatives to increase LTPA may contribute to reducing socioeconomic inequalities in this form of resilience in later life. PMID- 29113614 TI - Validation of family conflict scales for family caregivers of persons with dementia in long-term care facilities and exploration of family conflicts and support. AB - : ABSTRACTBackground:The aim of the study was to develop a family conflict scale for family caregivers of persons with dementia in long-term care facilities and to explore the relationship between family conflicts and family support. METHODS: The scale was developed through forward- and back-translations, interviews with 12 staff members in long-term care facilities, and cognitive interviews with 12 family caregivers who met operational definitions in this study. The test was conducted with 334 family caregivers and a retest was conducted with 318 family caregivers who had indicated willingness to participate further. RESULTS: The internal consistency was relatively high for all subscales (Cronbach's alpha >0.87); sufficient retest reliability was demonstrated for all subscales (intraclass correlation coefficient >0.69). Confirmatory factor analysis supported a three-factor model. Convergent and discriminant validity for each of the family conflict scale subscales, family APGAR, and the Symptom Check List-90 Items-Revised were acceptable. Family caregivers who received no family assistance for caregiving perceived more conflict in their family than those receiving family assistance. CONCLUSIONS: The Japanese version of the family conflict scale for family caregivers of persons with dementia in long-term care facilities was developed. The reliability and validity of the scale were verified. When providing support to family caregivers in long-term care facilities, it is necessary to consider the family from multiple viewpoints, including family conflicts and support conditions from other family members. PMID- 29113615 TI - Falls self-efficacy and falls incidence in community-dwelling older people: the mediating role of coping. AB - : ABSTRACTBackground:A cognitive behavioral model predicts that coping responses mediate the relationship between falls related psychological concerns and falls incidence, in community-dwelling older people. If empirical support could be found for this pathway then interventions could be developed to reduce falls risk by targeting coping strategies. Therefore, this study aimed to begin the process of testing whether coping responses mediate the association between falls self efficacy (a principal element of falls related psychological concerns) and falls incidence, in community-dwelling older people. METHOD: In a cross-sectional design, 160 community-dwelling older people (31 male, 129 female; mean age 83.47 years) completed the Falls Efficacy Scale-International, the Revised-Ways of Coping Questionnaire, the Turning to Religion subscale of the COPE, and a falls questionnaire. Data were analyzed via mediation analysis using a bootstrapping approach. RESULTS: Lower falls self-efficacy was associated with higher falls incidence, and more self-controlling coping was found to be a partial mediator of this association, with a confidence interval for the indirect effect of (0.003, 0.021) and an effect size of kappa2 = 0.035. The association was not mediated by the other measured coping responses; namely, turning to religion, distancing, seeking social support, accepting responsibility, escape-avoidance, planful problem-solving, and positive reappraisal. CONCLUSIONS: Self-controlling coping may mediate the association between falls self-efficacy and falling. If longitudinal studies confirm this finding then coping could be targeted in interventions to reduce falls. PMID- 29113616 TI - Correlates of physical activity among community-dwelling individuals aged 65 years or older with anxiety in six low- and middle-income countries. AB - : ABSTRACTBackground:Given the important health benefits of physical activity (PA) and the higher risk for physical inactivity in people with anxiety, and the high prevalence of anxiety and low PA among the elderly, there is a need for research to investigate what factors influence PA participation among anxious older individuals. We investigated PA correlates among community-dwelling adults aged >= 65 years with anxiety symptoms in six low- and middle-income countries. METHODS: Cross-sectional data from the World Health Organization's Study on Global Ageing and Adult Health were analyzed. PA level was assessed by the Global Physical Activity Questionnaire. 980 participants with anxiety (mean age 73.3 years; 62.4% females) were grouped into those who do and do not (low PA) meet the 150 minutes of moderate-to-vigorous PA per week recommendation. Associations between PA and the correlates were examined using multivariable logistic regressions. RESULTS: The prevalence of low PA was 44.9% (95% CI = 39.2-50.7%). Older age, male gender, less consumption of alcohol, mild cognitive impairment, pain, a wide range of somatic co-morbidities, slow gait, weak grip strength, poor self-rated health, and lower levels of social cohesion were identified as significant positive correlates of low PA. CONCLUSIONS: Our data illustrate that a number of sociodemographic and health factors are associated with PA levels among older people with symptoms of anxiety. The promotion of social cohesion may increase the efficacy of public health initiatives, while from a clinical perspective, somatic co-morbidities, cognitive impairment, pain, muscle strength, and slow gait need to be considered. PMID- 29113617 TI - Molecular detection of Cyclospora cayetanensis in human stool specimens using UNEX-based DNA extraction and real-time PCR. AB - Cyclospora cayetanensis is a coccidian parasite associated with diarrheal illness. In the USA, foodborne outbreaks of cyclosporiasis have been documented almost every year since the mid-1990s. The typical approach used to identify this parasite in human stools is an examination of acid-fast-stained smears under bright-field microscopy. UV fluorescence microscopy of wet mounts is more sensitive and specific than acid-fast staining but requires a fluorescence microscope with a special filter not commonly available in diagnostic laboratories. In this study, we evaluated a new DNA extraction method based on the Universal Nucleic Acid Extraction (UNEX) buffer and compared the performances of four published real-time polymerase chain reaction (PCR) assays for the specific detection of C. cayetanensis in stool. The UNEX-based method had an improved capability to recover DNA from oocysts compared with the FastDNA stool extraction method. The best-performing real-time PCR assay was a C. cayetanensis specific TaqMan PCR that targets the 18S ribosomal RNA gene. This new testing algorithm should be useful for detection of C. cayetanensis in human stool samples. PMID- 29113618 TI - Milk products in the dietary management of childhood undernutrition - a historical review. AB - The present narrative review outlines the use of milk products in infant and young child feeding from early history until today and illustrates how research findings and technical innovations contributed to the evolution of milk-based strategies to combat undernutrition in children below the age of 5 years. From the onset of social welfare initiatives, dairy products were provided by maternal and child health services to improve nutrition. During the last century, a number of aetiological theories on oedematous forms of undernutrition were developed and until the 1970s the dogma of protein deficiency was dominant. Thereafter, a multifactorial concept gained acceptance and protein quality was emphasised. During the last decades, research findings demonstrated that the inclusion of dairy products in the management of severe acute malnutrition is most effective. For children suffering from moderate acute malnutrition the evidence for the superiority of milk-based diets is less clear. There is an unmet need for evaluating locally produced milk-free alternatives at lower cost, especially in countries that rely on imported dairy products. New strategies for the dietary management of childhood undernutrition need to be developed on the basis of research findings, current child feeding practices, socio-cultural conditions and local resources. Exclusive and continued breast-feeding supported by community based nutrition programmes using optimal combinations of locally available complementary foods should be compared with milk product-based interventions. PMID- 29113619 TI - Parasite-mediated host behavioural modifications: Gyrodactylus turnbulli infected Trinidadian guppies increase contact rates with uninfected conspecifics. AB - While group formation provides antipredatory defences, increases foraging efficiency and mating opportunities, it can be counterintuitive by promoting disease transmission amongst social hosts. Upon introduction of a pathogen, uninfected individuals often modify their social preferences to reduce infection risk. Infected hosts also exhibit behavioural changes, for example, removing themselves from a group to prevent an epidemic. Conversely, here we show how Trinidadian guppies infected with a directly transmitted ectoparasite, Gyrodactylus turnbulli, significantly increase their contact rates with uninfected conspecifics. As uninfected fish never perform this behaviour, this is suggestive of a parasite-mediated behavioural response of infected hosts, presumably to offload their parasites. In the early stages of infection, however, such behavioural modifications are ineffective in alleviating parasite burdens. Additionally, we show that fish exposed to G. turnbulli infections for a second time, spent less time associating than those exposed to parasites for the first time. We speculate that individuals build and retain an infection cue repertoire, enabling them to rapidly recognize and avoid infectious conspecifics. This study highlights the importance of considering host behavioural modifications when investigating disease transmission dynamics. PMID- 29113620 TI - Mathematical models of microbial growth and metabolism: a whole-organism perspective. AB - We review the principles underpinning the development of mathematical models of the metabolic activities of micro-organisms. Such models are important to understand and chart the substantial contributions made by micro-organisms to geochemical cycles, and also to optimise the performance of bioreactors that exploit the biochemical capabilities of these organisms. We advocate an approach based on the principle of dynamic allocation. We survey the biological background that motivates this approach, including nutrient assimilation, the regulation of gene expression, and the principles of microbial growth. In addition, we discuss the classic models of microbial growth as well as contemporary approaches. The dynamic allocation theory generalises these classic models in a natural manner and is readily amenable to the additional information provided by transcriptomics and proteomics approaches. Finally, we touch upon these organising principles in the context of the transition from the free-living unicellular mode of life to multicellularity. PMID- 29113622 TI - Surveillance of tuberculosis in the WHO European region in 1995 : results of the feasibility study. AB - Efforts to assess the changing epidemiology of tuberculosis (TB) in Europe have been limited by differences in definitions and in the quality of tuberculosis surveillance systems between countries. In order to standardise the surveillance of TB among Euro. PMID- 29113621 TI - Assessment of Water Physicochemical Parameters in the Strimtori-Firiza Reservoir in Northwest Romania. AB - This article assesses the surface water quality of the Strimtori-Firiza reservoir by analyzing 14 physicochemical parameters among 9 metals in 18 sampling points. A series of possible reservoir pollutants were identified, depending on the nature of the pollutants and their loading. The novelty of the paper consists in the broad spectrum of investigations that includes spatial distribution cluster analysis and mathematical modeling. This article presents an innovative method of assessing the distributions of the metal loads as maps of metal distribution that are in accordance with the developed mathematical models that aim to present the pollutant distribution and the degree of correlation between the physicochemical indicators. The clusters were generated using Ward's and Nearest Neighbor methods that are less used in the studies concerning the analysis of water quality. Measures for maintaining the quality of the water reservoir are proposed considering the importance of the reservoir as source for drinking/industrial water. PMID- 29113623 TI - Establishing a European network for the diagnosis of "imported" viral diseases (ENIVD). AB - The epidemics in recent years of Ebola haemorrhagic fever in Zaire and Gabon acted as a reminder that dangerous infections can be imported very quickly into Europe. Meetings on emerging and re-emerging pathogens organised by the World Health Organization. PMID- 29113624 TI - Outbreak of trichinellosis in the Midi-Pyrenees region of France January - March 1998. AB - Two outbreaks of trichinellosis in the Tarn et Garonne, departement, France were reported by the departmental health autorities on 2 March 1998, to the Reseau National de Sante Publique (RNSP). An epidemiological investigation began on 3 March in order to. PMID- 29113625 TI - An outbreak of mumps in the Province of Leon Spain 1995-1996. AB - In Spain mumps vaccine is given at the age of 15 months together with measles and rubella vaccines since 1982. Increased numbers of cases and outbreaks of mumps appeared in several autonomous communities in 1995. An outbreak of mumps in the province of. PMID- 29113626 TI - Moonlighting proteins - nature's Swiss army knives. AB - The human body is a complex biological machine with billions of cells and vast numbers of biochemical processes - but our genome only contains 22,000 protein encoding genes. Moonlighting proteins provide one way to increase the number of cellular activities. Moonlighting proteins exhibit more than one physiologically relevant biochemical or biophysical function within one polypeptide chain. Already more than 300 moonlighting proteins have been identified, and they include a diverse set of proteins with a large variety of functions. This article discusses examples of moonlighting proteins, how one protein structure can perform two different functions, and how the multiple functions can be regulated. In addition to learning more about what our proteins do and how they work together in complex multilayered interaction networks and processes in our bodies, the study of moonlighting proteins can inform future synthetic biology projects in making proteins that perform new functions and new combinations of functions, for example, for synthesising new materials, delivering drugs into cells, and in bioremediation. PMID- 29113627 TI - The proportion of asymptomatic infections and spectrum of disease among pregnant women infected by Zika virus: systematic monitoring in French Guiana, 2016. AB - Zika virus (ZIKV) infection has been associated with complications during pregnancy. Although the presence of symptoms might be a risk factor for complication, the proportion of ZIKV-infected pregnant women with symptoms remains unknown. Following the emergence of ZIKV in French Guiana, all pregnancies in the territory were monitored by RT-PCR and/or detection of ZIKV antibodies. Follow-up data collected during pregnancy monitoring interviews were analysed from 1 February to 1 June 2016. We enrolled 3,050 pregnant women aged 14 48 years and 573 (19%) had laboratory-confirmed ZIKV infection. Rash, arthralgia, myalgia and conjunctival hyperaemia were more frequently observed in ZIKV positive women; 23% of them (95% confidence interval (CI): 20-27) had at least one symptom compatible with ZIKV infection. Women 30 years and older were significantly more likely to have symptoms than younger women (28% vs 20%). The proportion of symptomatic infections varied from 17% in the remote interior to 35% in the urbanised population near the coast (adjusted risk ratio: 1.6; 95% CI: 1.4-1.9.). These estimates put findings on cohorts of symptomatic ZIKV-positive pregnant women into the wider context of an epidemic with mainly asymptomatic infections. The proportion of symptomatic ZIKV infections appears to vary substantially between populations. PMID- 29113629 TI - Transmission dynamics of the ongoing chikungunya outbreak in Central Italy: from coastal areas to the metropolitan city of Rome, summer 2017. AB - A large chikungunya outbreak is ongoing in Italy, with a main cluster in the Anzio coastal municipality. With preliminary epidemiological data, and a transmission model using mosquito abundance and biting rates, we estimated the basic reproduction number R0 at 2.07 (95% credible interval: 1.47-2.59) and the first case importation between 21 May and 18 June 2017. Outbreak risk was higher in coastal/rural sites than urban ones. Novel transmission foci could occur up to mid-November. PMID- 29113628 TI - Livestock-associated meticillin-resistant Staphylococcus aureus (MRSA) among human MRSA isolates, European Union/European Economic Area countries, 2013. AB - Currently, surveillance of livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA) in humans in Europe is not systematic but mainly event-based. In September 2014, the European Centre for Disease Prevention and Control (ECDC) initiated a questionnaire to collect data on the number of LA-MRSA from human samples (one isolate per patient) from national/regional reference laboratories in European Union/European Economic Area (EU/EEA) countries in 2013. Identification of LA-MRSA as clonal complex (CC) 398 by multilocus sequence typing (MLST) was preferred, although surrogate methods such as spa-typing were also accepted. The questionnaire was returned by 28 laboratories in 27 EU/EEA countries. Overall, LA-MRSA represented 3.9% of 13,756 typed MRSA human isolates, but it represented >= 10% in five countries (Belgium, Denmark, Spain, the Netherlands and Slovenia). Seven of the reference laboratories did not type MRSA isolates in 2013. To monitor the dispersion of LA-MRSA and facilitate targeted control measures, we advocate periodic systematic surveys or integrated multi sectorial surveillance. PMID- 29113631 TI - Providing Value Through Practice Innovation. PMID- 29113630 TI - End-of-season influenza vaccine effectiveness in adults and children, United Kingdom, 2016/17. AB - IntroductionThe United Kingdom is in the fourth season of introducing a universal childhood influenza vaccine programme. The 2016/17 season saw early influenza A(H3N2) virus circulation with care home outbreaks and increased excess mortality particularly in those 65 years or older. Virus characterisation data indicated emergence of genetic clusters within the A(H3N2) 3C.2a group which the 2016/17 vaccine strain belonged to. Methods: The test-negative case-control (TNCC) design was used to estimate vaccine effectiveness (VE) against laboratory confirmed influenza in primary care. Results: Adjusted end-of-season vaccine effectiveness (aVE) estimates were 39.8% (95% confidence interval (CI): 23.1 to 52.8) against all influenza and 40.6% (95% CI: 19.0 to 56.3) in 18-64-year-olds, but no significant aVE in >= 65-year-olds. aVE was 65.8% (95% CI: 30.3 to 83.2) for 2-17 year-olds receiving quadrivalent live attenuated influenza vaccine. Discussion: The findings continue to provide support for the ongoing roll-out of the paediatric vaccine programme, with a need for ongoing evaluation. The importance of effective interventions to protect the >= 65-year-olds remains. PMID- 29113632 TI - Technology Moves Senior Care Pharmacy into the Future. AB - Technology continues to evolve, and pharmacists need to be part of this evolution where goals are reducing readmissions and related costs, improving outcomes, and enabling elders to stay in their homes longer. Increasingly, it's not enough to know about computerized prescription order-entry and electronic medical records. It's important to understand technologies that connect organizations and individuals, as well as those that patients and families are using to enhance safety and quality of life. This requires using effective technology for capturing and sharing information with clinicians and others as well as understanding what consumer-oriented technology can help improve medication adherence and keep people out of the hospital and in their homes. PMID- 29113633 TI - Chad R. Worz 2017-2018 ASCP President. PMID- 29113634 TI - Pharmacy Diabetes Management of a Veteran Population in a Long-Term Care Setting: A Program Evaluation. AB - BACKGROUND: The benefits of an outpatient pharmacy diabetes clinic has been established, with improved patient outcomes and reduced total costs of care. We describe the benefits of an inpatient clinical pharmacy diabetes service within a Department of Veterans Affairs long-term care facility. METHODS: Patients were referred to the pharmacy diabetes monitoring program between February 2016 and August 2016. During this time, clinical pharmacy specialists managed all pharmacotherapy relating to diabetes care as well as all fingerstick monitoring frequencies and laboratory monitoring to achieve a prespecified, patient-specific A1C goal. The primary endpoints were optimization of blood glucose fingerstick monitoring frequency and cessation of sliding-scale insulin. Secondary end points were achievement of A1C goal, reduction of hypoglycemic/hyperglycemic events, and reduction of total insulin injections per day. RESULTS: At the time of discharge or end of the observation period, fingerstick frequency had been reduced by a mean of 7.7 fingersticks/patient/week (35.6% total reduction, median 17.5; interquartile range [IQR] 5.5-21; P = 0.002). All eight patients initially prescribed sliding-scale insulin upon referral had their sliding scale stopped by the end of observation. Total injections per day had been reduced from baseline with a mean reduction of 0.55 injections/patient/day (16.5% total reduction; P < 0.05). A1C also showed improvement from baseline, though this was not statistically significant (median 7.75%, IQR 6.8-8.3; P = 0.1). Total hyperglycemic events were reduced from 36 prior to enrollment to 23 post observation period, while hypoglycemic events decreased from 8 before enrollment to 4 post-observation period. CONCLUSION: Type 2 diabetes mellitus patients managed by clinical pharmacy specialists at a Veterans Affairs long-term care facility significantly decreased weekly fingerstick blood monitoring frequency, number of insulin injections per day, and ceased sliding-scale insulin use. A1C and hypoglycemic and hyperglycemic events remained stable. Our results are limited because of a small sample size. PMID- 29113635 TI - Proton-Pump Inhibitors and Risk of Dementia. AB - Chronic use of a proton-pump inhibitor (PPI) has been associated with a number of unexpected negative outcomes. The most recent revision of the American Geriatrics Society Beers criteria recommends avoiding using longer than eight weeks unless the patient is at high risk. However, this recommendation is often overlooked in the long-term care setting. Recent literature suggests a link between chronic PPI use and increased risk of dementia. A hypothesized mechanism for the relationship between PPI use and dementia has been supported by cellular and animal models. Because of lack of disease-modifying medications for dementia, prevention strategies are essential. The purpose of this article is to compile and summarize information from published research and clinical trials, allowing readers to draw individual conclusions that could potentially lead to a change in recommendations for acid-lowering therapies in an older population. PMID- 29113636 TI - Evaluation of Interventions in Clinical Pharmacist-Led Annual Medicare Wellness Visits Compared with Usual Care. AB - OBJECTIVE: Evaluate and compare the number and types of medication and non medication-related interventions by clinical pharmacists and nonpharmacists conducting an Annual Medicare Wellness Visit (MWV). DESIGN: Multi-center, retrospective case-control study. SETTING: Two community primary care internal medicine clinics in urban Maryland. PARTICIPANTS: Patients who had a MWV performed January 2014 through October 2015. INTERVENTION: Pharmacists conducted required components of a MWV and addressed medication or non-medication-related concerns identified while completing the patient health risk assessment. MAIN OUTCOME MEASURE: Number and types of medication-related interventions identified by clinical pharmacists compared with nonpharmacists completing the MWV. RESULTS: Patients in the pharmacist-led MWV group more often had medication-related interventions than those in the nonpharmacist group (median 2 vs. 0, respectively; P < 0.00001). Pharmacists tended to identify at least 1 to 2 medication interventions for each patient (30.4% and 34.8%, respectively), and nonpharmacists often did not intervene on medications (62.79% of the time). There were 37 medication-related interventions made by the pharmacist group in a cohort of 23 patients, and 20 medication-related interventions by the nonpharmacist group in a cohort of 43 patients. The pharmacist group most often addressed medication without indication (17 occurrences) followed by nonadherence (6 occurrences). Providers in the nonpharmacist group most often recognized subtherapeutic dosage (7 occurrences) and indication without medication (5 occurrences). CONCLUSIONS: Pharmacists completing the MWV had a higher rate of medication-related and non-medication-related interventions than the nonpharmacist group. Pharmacist-led MWVs may lead to more appropriate medication use in elderly patients and serve as a financially sustainable care model to provide clinical pharmacy services in the outpatient setting. PMID- 29113638 TI - Following Failed ACA Repeal Attempts, Trump Takes Administrative Action. PMID- 29113637 TI - Nurses' Knowledge, Perception, and Self-Confidence Regarding Evidence-Based Antibiotic Use in the Long-Term Care Setting. AB - OBJECTIVE: Describe knowledge, perceptions, and self-confidence of nurses in the long-term care setting before and after online antibiotic stewardship education, and assess effectiveness and satisfaction with the education. DESIGN: Pre /postsurvey. SETTING: Three long-term care facilities, Topeka, Kansas. PARTICIPANTS: Convenience sample of 140 licensed practical and registered nurses. INTERVENTIONS: Nurses viewed a 12-minute online module developed by long-term care consultant pharmacists. The module discussed risks of antibiotic use and the Loeb minimum criteria for initiation of antibiotics in long-term care residents for urinary and respiratory tract infections and explored other conditions contributing to suspicion of these infections. MAIN OUTCOME MEASURES: Knowledge, perceptions, and self-confidence were measured using a 5-point Likert-scale survey modified from the Minnesota Department of Health taken before and after the module. RESULTS: Response rate was 45% (63/140) pre-education and 41% (57/140) post-education. Nurses had high baseline self-confidence (mean 4.2 to 4.5/5.0) and pre/post scores did not change significantly. Statistically significant improvements in knowledge and perceptions were seen in 15 of the 33 indices related to assumptions regarding antibiotic use, risks, and indicators of urinary and respiratory bacterial infections. Nurses rated the education as high quality (95%), applicable to practice (95%), and felt very likely to change practice (91%). CONCLUSIONS: Although baseline self-confidence was high, key misperceptions were identified, indicating that nurses may not be aware of their knowledge deficits or misperceptions. This low-cost, 12-minute, online education was highly valued and effectively improved nurses' knowledge and perceptions. PMID- 29113639 TI - European surveillance of travel associated legionnaires' disease 1996. AB - The European Surveillance Scheme for Travel Associated Legionnaires' Disease was established in 1987 to identify clusters and outbreaks of cases of the disease. Twenty-nine collaborating centres in 25 countries contribute case reports in a standard format. PMID- 29113640 TI - General practice utilisation of Medicare Benefits Schedule items to support the care of older patients: findings from the REDIRECT study. AB - Medicare Benefits Schedule (MBS) items designed to support the wellbeing of older people may reduce unnecessary emergency department utilisation, however it is unclear to what extent such items are used. This study examined general practitioner (GP) utilisation of these MBS items through an analysis of the Melbourne East Monash General Practice Database (MAGNET), which contains information collected from GP clinics within the inner east Melbourne region. Sociodemographic and MBS claim data were extracted for patients aged >=75 years attending a GP between 2005 and 2012. Utilisation of 75+ Health Assessments, General Practitioner Management Plans (GPMP), Team Care Arrangements (TCAs) or reviews, or Medication Management Reviews (MMRs) was assessed. There were 12962 (60.6%) patients assigned at least one of the MBS items. The highest level of claiming was for GPMPs (n=4754; 35.8%) and TCAs (n=4476; 33.7%), with MMRs having the lowest use (n=1023; 6.8%). Examination of GP and patient barriers to the uptake of these items is needed, along with a greater understanding as to whether those most at risk of hospitalisation are receiving these services. Strategies that support capacity to implement these items are also required. PMID- 29113641 TI - A simple independent prognostic electrocardiography parameter in first acute anterior myocardial infarction; Precordial total Q wave/precordial total R wave. AB - BACKGROUND: We investigated the prognostic value of precordial total Q wave amplitude/precordial total R wave amplitude ratio (Q/R) in patients with first acute anterior MI treated with primary percutaneous coronary intervention (PPCI). METHODS: We evaluated the in-hospital prognostic impact of Q/R on 354 patients with first acute anterior MI. Patients were stratified by tertiles of admission Q/R, clinical outcomes were compared between those groups. RESULTS: In-hospital univariate analysis revealed notably higher rates of in-hospital death for patients in tertile 3, as compared to patients in tertile 1 (OR 9.7, 95% CI 2.8 33.5, p. CONCLUSION: Q/R in admission ECG in patients with first acute anterior MI provide an independent prognostic marker of in-hospital outcomes. PMID- 29113643 TI - The clinical value of an exaggerated hypertensive response to exercise. PMID- 29113642 TI - Prefrontal-Thalamic Anatomical Connectivity and Executive Cognitive Function in Schizophrenia. AB - BACKGROUND: Executive cognitive functions, including working memory, cognitive flexibility, and inhibition, are impaired in schizophrenia. Executive functions rely on coordinated information processing between the prefrontal cortex (PFC) and thalamus, particularly the mediodorsal nucleus. This raises the possibility that anatomical connectivity between the PFC and mediodorsal thalamus may be 1) reduced in schizophrenia and 2) related to deficits in executive function. The current investigation tested these hypotheses. METHODS: Forty-five healthy subjects and 62 patients with a schizophrenia spectrum disorder completed a battery of tests of executive function and underwent diffusion-weighted imaging. Probabilistic tractography was used to quantify anatomical connectivity between six cortical regions, including PFC, and the thalamus. Thalamocortical anatomical connectivity was compared between healthy subjects and patients with schizophrenia using region-of-interest and voxelwise approaches, and the association between PFC-thalamic anatomical connectivity and severity of executive function impairment was examined in patients. RESULTS: Anatomical connectivity between the thalamus and PFC was reduced in schizophrenia. Voxelwise analysis localized the reduction to areas of the mediodorsal thalamus connected to lateral PFC. Reduced PFC-thalamic connectivity in schizophrenia correlated with impaired working memory but not cognitive flexibility and inhibition. In contrast to reduced PFC-thalamic connectivity, thalamic connectivity with somatosensory and occipital cortices was increased in schizophrenia. CONCLUSIONS: The results are consistent with models implicating disrupted PFC-thalamic connectivity in the pathophysiology of schizophrenia and mechanisms of cognitive impairment. PFC-thalamic anatomical connectivity may be an important target for procognitive interventions. Further work is needed to determine the implications of increased thalamic connectivity with sensory cortex. PMID- 29113644 TI - Poststernotomy mediastinitis: Early risk factors identified but hard to modify. PMID- 29113646 TI - Effects of recombinant canine interferon-gamma injected before general anesthesia with propofol and isoflurane on natural killer cytotoxic activity during anesthesia in dogs. AB - We aimed to determine whether subcutaneous injection of recombinant canine interferon-gamma (rCaIFN-gamma) 1h before general anesthesia with a combination of propofol and isoflurane (P-I) changes the cytotoxic activity of natural killer (NK) cells during anesthesia in dogs. Nine clinically healthy beagles were assigned to one of two groups: rCaIFN-gamma-treated group (n=5) and control group (no treatment, n=4). One hour before P-I anesthesia, rCaIFN-gamma was subcutaneously injected at a dose of 1*104U/kg body weight for the test group and physiologic saline was subcutaneously injected for the control group. Blood samples were collected 1h before P-I anesthesia (immediately before rCaIFN-gamma injection) and 1 and 3h after anesthesia induction. NK cytotoxic activity was measured using the Rose Bengal assay, using canine thyroid adenocarcinoma cells as target cells. In the control group, NK cytotoxic activity decreased significantly over time (P<0.05). On the other hand, in the rCaIFN-gamma group, the activity increased for the first hour after anesthesia induction without a significant difference from the level before anesthesia; furthermore, the activity at 3h after anesthesia induction was comparable with that before anesthesia. NK cytotoxic activity at 1 and 3h after anesthesia induction was significantly higher in the rCaIFNgamma group than in the control group (P<0.05). Subcutaneous injection of rCaIFN-gamma 1h before P-I general anesthesia not only maintained but also enhanced NK cytotoxic activity up to 3h after anesthesia induction in dogs. In conclusion, subcutaneous injection of rCaIFN-gamma before cancer resection in cancer-bearing dogs might be effective for preventing intraoperative dissemination of cancer cells and postoperative cancer recurrence and metastasis. PMID- 29113645 TI - Discrepancies between feline coronavirus antibody and nucleic acid detection in effusions of cats with suspected feline infectious peritonitis. AB - Intra-vitam diagnosis of feline infectious peritonitis (FIP) is a challenge for veterinary diagnosticians, since there are no highly specific and sensitive assays currently available. With the aim to contribute to fill this diagnostic gap, a total of 61 effusions from cats with suspected effusive FIP were collected intra-vitam for detection of feline coronavirus (FCoV) antibodies and RNA by means of indirect immunofluorescence (IIF) assay and real-time RT-PCR (qRT-PCR), respectively. In 5 effusions there was no evidence for either FCoV RNA or antibodies, 51 and 52 specimens tested positive by IIF and qRT-PCR, respectively, although antibody titres>=1:1600, which are considered highly suggestive of FIP, were detected only in 37 effusions. Three samples with high antibody levels tested negative by qRT-PCR, whereas 18 qRT-PCR positive effusions contained no or low-titre antibodies. qRT-PCR positive samples with low antibody titres mostly contained low FCoV RNA loads, although the highest antibody titres were detected in effusions with CT values>30. In conclusion, combining the two methods, i.e., antibody and RNA detection would help improving the intra-vitam diagnosis of effusive FIP. PMID- 29113647 TI - Super-radical hysterectomy for recurrent cervical cancer. AB - BACKGROUND: Recurrent cervical cancer with the pelvic side wall invasion has a deleterious effect on prognosis if there is no alternative method to achieve local tumor control [1, 2]. For the surgical treatment, super-radical hysterectomy has been introduced by Ryukichi Mibayashi in 1941 [3, 4]. However, its feasibility and safety is still on debate because of a lack of reproducibility and high level of surgical techniques. Thus, we showed the surgical procedure of super-radical hysterectomy for recurrent cervical cancer. VIDEO: A 40 year-old woman visited after diagnosis of the pelvic recurrence, who received concurrent chemoradiation before 13 months due to stage IIB cervical cancer. Preoperative examination showed tumor invasion to upper third of the vagina, the right distal ureter and urethra, the posterior bladder wall and the right pelvic wall. Thus, we performed anterior pelvic exenteration with super radical hysterectomy for removing the right pelvic side wall tumors. First, we ligated the right superior gluteal vessels, and then ligated the right internal iliac vessels. Second, we ligated the right inferior gluteal vessels, and subsequently the right internal pudendal vessels. Third, we resected her genitourinary tract with the right internal iliac vessels around the pelvic floor completely. RESULTS: The procedure time was 160 minutes, and she underwent subsequent procedures including ileal conduit and omental J flap. She was discharged after 2 weeks without complications. CONCLUSION: Super-radical hysterectomy can be considered to be feasible and safe through the step-wise ligation of the internal iliac vessels for recurrent cervical cancer with the pelvic side wall invasion. PMID- 29113648 TI - Beta-elemene treatment is associated with improved outcomes of patients with esophageal squamous cell carcinoma. AB - PURPOSE: To investigate the therapeutic effects of concurrent preoperative beta elemene treatment in patients with esophageal squamous cell carcinoma who received concurrent chemoradiotherpay followed by surgery. METHOD: The clinicopathological parameters and outcomes of 102 patients with esophageal squamous cell carcinoma were studied and compared between patients treated with and without beta-elemene. RESULTS: beta-elemene treatment could prolong the overall survival and progression-free survival. The 3-year overall survival rate was also increased by beta-elemene treatment. beta-elemene treatment was an independent prognostic factor for both overall survival and progression-free survival. Occurrence of toxicities associated with chemoradiotherapy was decreased by beta-elemene treatment. CONCLUSIONS: Findings in this study suggested that beta-elemene treatment provided survival benefits and reduced chemoradiotherapy-associated toxicities in patients with esophageal squamous cell carcinoma. PMID- 29113649 TI - Endoscopic sentinel lymph node biopsy and endoscopic axillary lymphadenectomy without liposuction in patients with early stage breast cancer. AB - BACKGROUND: Our purpose was to present a new method of endoscopic sentinel lymph node biopsy (ESLNB) and endoscopic axillary lymphadenectomy (EALND) without liposuction for treating early-stage breast cancer, and compare results with traditional open dissection. METHODS: The medical records of patients with early stage breast cancer who underwent EALND/ESLNB without liposuction or traditional open dissection between March 2015 and September 2016 were retrospectively reviewed. Outcomes between the 2 groups were compared. RESULTS: A total 65 patients with a mean age of 41.2 +/- 9.3 years (range, 23-60 years) were included. Thirty-three patients underwent traditional open lymph node dissection and 32 patients underwent endoscopic treatment. The 2 groups were similar with respect to age, body mass index (BMI), menopausal status, tumor location, and tumor disease stage (all, p > 0.05). The mean operating time was significantly higher in the endoscopic group (91.2 vs. 75.2 min, p = 0.022), while the mean blood loss was significantly lower (28.7 vs. 37.0 ml, p = 0.034). The mean number of SLNs harvested in the open (2.4 +/- 1.6) and the endoscopic (2.3 +/- 1.4) groups were not different (p = 0.829), with a sentinel lymph node retrieval rate of 80%. The mean number of axillary lymph nodes harvested in the open (13.8 +/- 3.3) and the endoscopic (13.3 +/- 3.1) groups were not different (p = 0.457). Scars were minimal in the endoscopic group. CONCLUSION: ESLNB and EALND without liposuction for early-stage breast cancer is feasible, has a low complication rate, a lymph node harvest rate similar to that of open dissection, and has good cosmetic results. Future studies, however, are required to evaluate oncological outcomes. PMID- 29113650 TI - Laparoscopic parenchymal preserving liver resections for colorectal liver metastases in the era of highly effective systemic therapy and selective internal radiation therapy can often prevent a hemihepatectomy. (With video). AB - BACKGROUND: Preservation of hepatic parenchyma is important in liver surgery to prevent postoperative liver failure and according to some reports it could offer a prolonged survival and lower recurrence rates compared to major hepatectomies in patients with colorectal liver metastases. However, laparoscopic parenchyma preserving liver resections can be technically challenging. The aim of this video is to illustrate the concept of laparoscopic parenchymal-preserving liver resections after conversion chemotherapy with targeted therapy. MATERIALS AND METHODS: In this video we present three cases in which a laparoscopic parenchymal preserving liver resection was performed after neo-adjuvant therapy: the first patient had a giant solitary colorectal metastasis in segment V and VIII. Neoadjuvant chemotherapy was given, resulting in a 30% volume reduction of the lesion after which a laparoscopic anterior sectionectomy was successfully performed. The second patient had five colorectal liver metastases. After conversion chemotherapy, four remaining metastases were resected by laparoscopic surgery. The last patient had 7 colorectal liver metastases. After 18 cycles of neo-adjuvant chemotherapy and a good response to selective internal radiation therapy, a laparoscopic liver resection of six metastases and radiofrequency ablation of 1 central lesion were performed. RESULTS: The video of these three cases shows that laparoscopic parenchymal-preserving liver surgery is feasible after neo-adjuvant systemic therapy and selective internal radiation therapy. CONCLUSIONS: The emergence of more effective systemic chemotherapies with biologicals and SIRT for the treatment of colorectal liver metastases often creates a possibility for parenchymal-preserving liver resections to achieve an R0 resection. PMID- 29113651 TI - The role of F18-FDG PET/CT in predicting secondary optimal de-bulking in patients with recurrent ovarian cancer. AB - BACKGROUND AND OBJECTIVES: The decision to perform secondary cytoreductive surgery for recurrent ovarian cancer is generally determined by clinical criteria. The aim of this study was to assess the predictive capability of FDG PET/CT in identifying patients for whom secondary optimal debulking can be obtained. METHODS: We reviewed the records of all women with suspected recurrent ovarian cancer (CA-125 levels >35 U/ml and/or clinical symptoms), at two medical centers, between January 2004 and December 2013. Patients in whom CT scans were negative, indeterminate or indicative of localized disease, were referred for preoperative FDG-PET/CT study. We analyzed the outcomes of those who subsequently underwent cytoreductive surgery. RESULTS: Of 282 women with suspected recurrent ovarian cancer, 48 underwent FDG-PET/CT. The 24 for whom localized disease was detected on PET/CT, subsequently underwent secondary debulking surgery. Patients with PET/CT evidence of multifocal recurrent sites were referred for chemotherapy. Tumor debulking was optimal in 20 patients, and suboptimal in 4. The positive predictive value of PET/CT for optimal debulking was 83.3%. CONCLUSIONS: The findings extend prior reports on the role of FDG-PET/CT in the management of recurrent ovarian cancer, to the prediction of secondary optimal debulking. Future studies should aim to investigate the impact on survival. PMID- 29113652 TI - Examination of cancer cells exposed to gastric serosa by serosal stamp cytology plus RT-PCR is useful for the identification of gastric cancer patients at high risk of peritoneal recurrence. AB - BACKGROUND: We sought to clarify the clinical value of the examination of cancer cells exposed to gastric serosa by our novel method of serosal stamp cytology and a real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. METHOD: A total of 70 patients who underwent gastrectomy were enrolled. Stamp cytology specimens were obtained by stamping the gastric serosa at the primary gastric tumor lesion, followed by Papanicolaou's staining. Samples obtained by brushing the serosa at the primary gastric tumor were analyzed by our RT-PCR of carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20). RESULTS: Among the 70 patients, 11 patients were diagnosed as stamp cytology-positive. Eight and five patients were found to be CEA-positive and CK20-positive, respectively. Since 21 of the 70 patients were either stamp cytology-positive or RT-PCR analysis-positive, these 21 patients were considered to be positive for cancer cells exposed to serosa of primary gastric tumor. The 3-year recurrence free survival rate of the patients with a single positive result by our method (41.7%) was significantly (log rank p = 0.0002) worse than that of the patients with both negative results (81.0%). Our method showed 58.8% sensitivity and 79.2% specificity. A multivariate analysis revealed that a stamp cytology and/or RT-PCR result was an independent prognostic factor for recurrence. CONCLUSION: The examination of cancer cells exposed to gastric serosa by our serosal stamp cytology and RT-PCR system will be useful for the identification of patients at high risk for peritoneal recurrence after curative surgery for gastric cancer. PMID- 29113653 TI - Trends in adherence to NCCN guidelines for breast conserving therapy in women with Stage I and II breast cancer: Analysis of the 1998-2008 National Cancer Data Base. AB - OBJECTIVE: To examine temporal trends in guideline adherence for breast cancer local therapy, by race/ethnicity, socioeconomic and insurance status. BACKGROUND: Treatment guidelines recommend breast conserving therapy (BCT) for women with small cancers, but have been unevenly applied. A better understanding of time trends in guideline adherence may point to interventions for correction. METHODS: Patients with tumors <=2 cm (n = 1,081,075) were identified from 1123 NCDB hospitals, dividing the interval 1998-2011 into 5 segments. Significant differences in rates of guideline adherence over time for race/ethnicity, quartiles of income, education, and insurance status were identified using Chi square tests. Random effects logistic regression was used to compute odds ratios (OR) for the likelihood of guideline adherence controlling for sociodemographic and clinical characteristics, hospital type and region. RESULTS: Multivariate models revealed disparities in use of BCT for women <=39 years (OR 0.49, 95% CI 0.48-0.50); for Asians (OR 0.67, 95% CI 0.65-0.69); for women in the lowest education quartile (OR 0.89, 95% CI 0.87-0.91); and for women in rural regions, (OR 0.79 95% CI 0.76-0.81). The largest radiotherapy disparity was for the oldest women (OR 0.37, 95%CI 0.37-0.38), and in rural regions OR 0.67, 95% CI 0.63-0.71. Over time, differences persisted in BCT use (for race, income, education, insurance type); and for endocrine therapy (by race and education). CONCLUSION: There was mixed progress in reducing disparities in guideline adherence. These results are conservative, since the most favorable tumor stages were analyzed in the NCDB, which reflects higher quality of care than non-participating hospitals. PMID- 29113656 TI - Introduction of the resection severity index as independent risk factor limiting survival after resection of colorectal liver metastases. AB - BACKGROUND: The purpose of this study is to evaluate the influence of the recently introduced resection severity index (RSI) in patients with liver resection for hepatocellular carcinoma on survival after resection of colorectal liver metastases. The RSI quantifies pre-operatively the liver cellular damage, liver synthetic function and loss of organ parenchyma. METHODS: All consecutive patients who underwent liver resection for metastases of colorectal cancer (CLM) between 2000 and 2015 were included in this study. Risk factors limiting survival were analyzed using univariable and multivariable Cox regression analyses. RESULTS: The median survival after liver resection for CLM was 3.0 years. Significant independent risk factors for mortality were the RSI (p = 0.029; hazard ratio (HR): 1.088, 95%-confidence interval (95%-CI): 1.009-1.174), age at resection in years (p = 0.001; HR: 1.017, 95%-CI: 1.007-1.027), pre-operative hemoglobin level (p = 0.041; HR: 0.932, 95%-CI: 0.891-0.997), the cecum as location of primary CRC (p < 0.001; HR: 2.023, 95%-CI: 1.403-2.833), adjuvant chemotherapy (p < 0.001; HR: 1.506, 95%-CI: 1.212-1.878), local relapse of the primary tumor (p = 0.027; HR: 1.591, 95%-CI: 1.057-2.297), the units of intra operatively transfused packed red blood cells (p < 0.001; HR: 1.068, 95%-CI: 1.033-1.104), the size of the largest metastasis (p = 0.002; HR: 1.005, 95%-CI: 1.002-1.008) and the metastasis' distance to the resection margin (p = 0.014; HR: 0.984, 95%-CI: 0.972-0.997). CONCLUSION: The RSI is an independent prognostic factor for survival after liver resection for CLM. Besides the extent of liver resection certain primary tumor characteristics have to be taken into account to ensure long-term survival. PMID- 29113655 TI - Laparoscopic partial nephrectomy following tumor embolization in a hybrid room. Feasibility and clinical outcomes. AB - PURPOSE: In order to limit ischemia and operative bleeding during and after partial nephrectomy we developed a clampless laparoscopic technique, in a hybrid operating room, immediately after super-selective arterial embolization of the renal tumor. We evaluated feasibility and morbidity of this new approach of zero ischemia in partial nephrectomy. METHODS: We included prospectively 50 consecutive patients treated in a hybrid operating room by this new technique for a localized renal tumor in a university hospital between May 2015 and January 2017. We evaluated perioperative data, postoperative complications, surgical margin and modification of renal function one month after surgery. Renal tumor complexity was evaluated by the R.E.N.A.L. score. RESULTS: We included 30 (60%) men and 20 (40%) women with a median age of 61 years (32-84) and a median BMI of 26.85 kg/m2 (20.1-46.4). Tumors were at low, median and high complexity in respectively 11 (22%), 32 (64%) and 7 (14%) cases. Median endovascular and surgical procedures durations were 43 min (16-120) and 80 min (32-150). Median blood loss was 100 mL (10-850). Two Clavien II complications occurred. Median length of hospital stay was 3 days (2-7). Renal function was not modified one month after partial nephrectomy. Median tumor size was 3 cm (1.2-8). Forty tumors (80%) were malignant and surgical margins were positive in one (2%). CONCLUSIONS: Clampless laparoscopic partial nephrectomy in a hybrid operating room without pedicular dissection after previous tumoral embolization is a technically safe and carcinologically efficient mini-invasive alternative for the management of localized renal tumors. PMID- 29113657 TI - Huang's three-step maneuver shortens the learning curve of laparoscopic spleen preserving splenic hilar lymphadenectomy. AB - BACKGROUND: The goal of this study was to investigate the difference between the learning curves of different maneuvers in laparoscopic spleen-preserving splenic hilar lymphadenectomy for advanced upper gastric cancer. METHODS: From January 2010 to April 2014, 53 consecutive patients who underwent laparoscopic spleen preserving splenic hilar lymphadenectomy via the traditional-step maneuver (group A) and 53 consecutive patients via Huang's three-step maneuver (group B) were retrospectively analyzed. RESULTS: No significant difference in patient characteristics were found between the two groups. The learning curves of groups A and B were divided into phase 1 (1-43 cases and 1-30 cases, respectively) and phase 2 (44-53 cases and 31-53 cases, respectively). Compared with group A, the dissection time, bleeding loss and vascular injury were significantly decreased in group B. No significant differences in short-term outcomes were found between the two maneuvers. The multivariate analysis indicated that the body mass index, short gastric vessels, splenic artery type and maneuver were significantly associated with the dissection time in group B. No significant difference in the survival curve was found between the maneuvers. CONCLUSIONS: The learning curve of Huang's three-step maneuver was shorter than that of the traditional-step maneuver, and the former represents an ideal maneuver for laparoscopic spleen preserving splenic hilar lymphadenectomy.To shorten the learning curve at the beginning of laparoscopic spleen-preserving splenic hilar lymphadenectomy, beginners should beneficially use Huang's three-step maneuver and select patients with advanced upper gastric cancer with a body mass index of less than 25 kg/m2 and the concentrated type of splenic artery. PMID- 29113654 TI - The role of intestinal bacteria in the development and progression of gastrointestinal tract neoplasms. AB - More than 100 trillion microorganisms inhabit the human intestinal tract and play important roles in health conditions and diseases, including cancer. Accumulating evidence demonstrates that specific bacteria and bacterial dysbiosis in the gastrointestinal tract can potentiate the development and progression of gastrointestinal tract neoplasms by damaging DNA, activating oncogenic signaling pathways, producing tumor-promoting metabolites such as secondary bile acids, and suppressing antitumor immunity. Other bacterial species have been shown to produce short-chain fatty acids such as butyrate, which can suppress inflammation and carcinogenesis in the gastrointestinal tract. Consistent with these lines of evidence, clinical studies using metagenomic analyses have shown associations of specific bacteria and bacterial dysbiosis with gastrointestinal tract cancers, including esophageal, gastric, and colorectal cancers. Emerging data demonstrate that intestinal bacteria can modulate the efficacy of cancer chemotherapies and novel targeted immunotherapies such as anti-CTLA4 and anti-CD274 therapies, the process of absorption, and the occurrence of complications after gastrointestinal surgery. A better understanding of the mechanisms by which the gut microbiota influence tumor development and progression in the intestine would provide opportunities to develop new prevention and treatment strategies for patients with gastrointestinal tract cancers by targeting the intestinal microflora. PMID- 29113658 TI - Circulating cell-free DNA in plasma of colorectal cancer patients - A potential biomarker for tumor burden. AB - BACKGROUND: Measurement of cell-free DNA (cfDNA) in plasma - the so called liquid biopsy - is a novel method for early detection of cancer. Necrotic cancer cells release various DNA fragments that can be detected in plasma or serum. The aim of our study was to investigate the concentration of circulating ALU115, LINE79 and LINE297 fragments in plasma from venous and arterial blood of colorectal cancer (CRC) patients before, during and 5 days after surgical intervention. PATIENTS AND METHODS: Thirty patients (16 female, 14 male, median age 56 years), undergoing surgery for colorectal and appendix cancer, and 17 healthy volunteers were included in this study. Plasma samples were collected from patients and healthy individuals. Qualitative polymerase chain reaction (PCR) and quantitative real-time PCR analyses were conducted using specific primers for ALU115, LINE79 and LINE297. RESULTS: The concentration of ALU115 was significantly increased in plasma of CRC patients compared to the control group (p = 0.002). Interestingly, the concentration of LINE297 was significantly higher in healthy individuals than patients (p = 0.031). We did not find any difference regarding LINE79 between the two groups (p = 0.893). The total cfDNA concentration was slightly increased in plasma after the surgery (p < 0.056), however, the difference was not significant. Interestingly, no correlation was detected between the peritoneal carcinosis index (PCI) and conventional tumor markers. CONCLUSION: According to our results, the concentration of ALU115 in cfDNA could be a potential biomarker for diagnosis of CRC. LINE79 or the conventional tumor markers CEA or CA19-9 do not seem useful for the detection of malignant tumors. Whether the amount of LINE297 in cfDNA represents a reliable biomarker for early diagnosis has yet to be confirmed. PMID- 29113660 TI - Functional hepatic imaging as a biomarker of primary and secondary tumor response to loco-regional therapies. AB - Objective criteria to measure tumor response are a key tenet for assessment of treatment efficacy when evaluating a therapeutic modality. Several response criteria have been proposed including the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), RECIST 1-1, and European Association for the Study of the Liver (EASL) guidelines. Response following loco-regional therapies (LRT) can be particularly difficult to assess as post-treatment changes may not always relate to changes in lesion size. As imaging modalities and solid tumor therapies continue to advance, there has been growing recognition that measurement of actual tumoricidal activity may not always be related to tumor size, and accurate assessment of treatment response may vary by therapeutic modality. As such, the objective change in the physical size characteristics of a tumor may not accurately reflect biological response to treatment. Functional imaging encompasses methods that are capable of detecting or measuring changes in tissue metabolism, blood flow, or composition. Conventional imaging modalities such as magnetic resonance imaging (MRI) and computed topography (CT) now include techniques such as diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) maps, dynamic contrast enhancement (DCE-MRI), and perfusion CT (pCT). Use of functional cross-sectional imaging is particularly relevant to assess primary and secondary hepatic malignancies treated with LRT, such as trans arterial chemoembolization (TACE), radiofrequency ablation (RFA), yttrium-90 (Y 90), and hepatic arterial infusion (HAI) chemotherapy. We herein review the imaging techniques, as well as the methodologies for measuring tumor response and survival, among patients treated with LRT for primary and secondary hepatic malignancies. PMID- 29113659 TI - A comparative study of neoadjuvant treatment with gemcitabine plus nab-paclitaxel versus surgery first for pancreatic adenocarcinoma. AB - INTRODUCTION: Neoadjuvant treatment has been reported to prolong survival in patients with potentially resectable pancreatic adenocarcinoma (PA). However, there are currently limited clinical results available using nab-paclitaxel and gemcitabine in PA. This paper compares the oncological results of patients affected by potentially resectable PA who underwent surgery first (SF) versus surgery following neoadjuvant treatment (NAT). METHODS: This is an observational, comparative study whereby data were abstracted from a prospective database of patients affected by PA from 2007 to 2016. RESULTS: We included a total of 81 patients (36 SF and 45 NAT) which resulted in being preoperatively similar. Among the NAT patients, treatment was well tolerated and the resection rate was 68.8% (31/45 patients). There was a trend towards a higher R1 resection rate in the SF group compared with the NAT (13.8% vs 3.2%; p = 0.1). Median overall survival in the resected NAT group was higher (30.6 vs 22.1 months; p = 0.04). In the borderline resectable group, overall survival was found to be four times higher compared with SF (43.6 versus 13.5 months; p = 0.001). CONCLUSIONS: These data suggest that neoadjuvant treatment with gemcitabine/nab-paclitaxel is a safe and effective option for potentially resectable PA compared with the SF approach. PMID- 29113661 TI - Program death-1 immune checkpoint and tumor microenvironment in malignant liver tumors. AB - Hepatic malignancies are one of the leading causes of cancer death globally. Considering the limited efficacy of current standard treatments in management of patients with advanced liver cancers, there has been a growing interest in identifying novel therapies. Despite achieving promising results in initial clinical trials, the therapeutic benefit of immunotherapy is limited due to strong immune-tolerogenic characteristics of liver tumors. Therapeutic regimens that impede tumor immunosuppressive mechanisms or elaborate tumor-specific immunity may improve clinical outcomes of patients with liver malignancies. Programmed cell death 1 (PD-1), an inhibitory checkpoint molecule, and its ligands (PD-L1 and -L2) are the main mediators of immunosuppression within the tumor microenvironment. The expression level of PD-1/PD-L1 may act as a biomarker to predict disease progression, as well as long-term survival. Furthermore, early trials have demonstrated the efficacy and safety of targeting PD-1/PD-L1 as an emerging field in the management of patients with advanced hepatocellular carcinoma. We herein review the role of PD-1/PD-L1 in the pathogenesis of liver malignancies, as well as its potential diagnostic and therapeutic implications. PMID- 29113662 TI - Practice variation in Sentinel Lymph Node Biopsy for melanoma patients in different geographical regions in the Netherlands. AB - BACKGROUND: Due to the lack of solid evidence for treatment benefit of Sentinel Lymph Node Biopsy (SLNB) as part of loco-regional surgical treatment of non distant metastatic melanoma, there might be variation in surgical treatment strategies in the Netherlands. The objective of the current study was to assess differences in the performance of SLNB, in geographical regions in the Netherlands, of non-distant metastatic melanoma patients (American Joint Committee on Cancer (AJCC) stage I-III). MATERIALS AND METHODS: A total of 28 550 melanoma patients, diagnosed between 2005 and 2013, were included in this population based retrospective study. Data were retrieved from the Netherlands Cancer Registry (NCR). Treatment strategies in 8 regions of the Netherlands were compared according to stage, excluding patients with distant metastasis (AJCC stage IV). RESULTS: Throughout the Netherlands, there was substantial practice variation across the regions. The performance of SLNB in patients with clinically unsuspected lymph nodes and Breslow thickness >1.0 mm was significantly different between the regions. In a post hoc analysis, we observed that patients aged over 60 years, female patients and patients with a melanoma located in head and neck have lower odds to receive a SLNB. CONCLUSION: There is considerable loco regional practice variation which cannot completely be explained by the patient and tumor characteristics, in the surgical treatment of non-distant metastatic melanoma patients in the Netherlands. Although national guidelines recommend considering SLNB in all patients with a melanoma thicker than 1 mm, only half of the patients received a SLNB. Future research should assess whether this practice variation leads to unwanted variations in clinical outcome. PMID- 29113663 TI - Krukenberg tumors: Seed, route and soil. AB - The aim of this narrative review was to summarize the current evidence on Krukenberg tumors (KTs), addressing what is known on their natural history and their impact on the clinical prognosis and which are the most appropriate management strategies to treat this condition. A literature search was conducted on Pubmed up to December 2016, selecting the most relevant studies on the basis of the scope of the review. KTs are ovarian metastases from primary signet-ring cell carcinomas., characterized by the presence of a sarcoma-like stroma. They have three possible routes of diffusion (lymphatic, peritoneal and hematogenous), but the preferential one is still unclear. Prognosis is dismal. When KTs are encountered in the clinical practice, it is reasonable to offer surgical resection to young, fit patients with limited disease. Palliative surgery should be considered for all patients with symptomatic disease. Further studies should clarify the clinicopathologic characteristics of KTs, their main routes of diffusion, and the possible role of prophylactic oophorectomy, lymphadenectomy and intraperitoneal chemotherapy. Molecular and transitional research should parallel the clinical one to help understanding the natural history of signet ring cell carcinomas. PMID- 29113664 TI - Risk prediction model for major complication after hepatectomy for malignant tumour - A validated scoring system from a university center. AB - OBJECTIVE: To derive and validate a scoring system for major complication after hepatectomy. BACKGROUND: Complications after hepatectomy significantly compromise survival outcomes, method to predict such risk is lacking. A reliable scoring system is therefore awaited. METHODS: Consecutive adult patients receiving hepatectomy for primary or secondary liver malignancy from 1995 to 2014 were recruited. After randomization, patients were allocated to derivation and validation group respectively. A scoring system predicting occurrence of major complication was developed. RESULTS: There were 2613 patients eligible for the study. The overall complication rate for the series was 10%. Impaired performance status (p = 0.014), presence of pre-existing medical illness (p = 0.008), elevated ALP (p = 0.005), urea (p < 0.001), and hypoalbuminemia (p = 0.008), and major hepatectomy (p < 0.001) were found to be independently associated major complications. A score was assigned to each of these factors according to their respective odd ratio. A total score of 0-17 was calculated for all patients. This score was shown to discriminate well with complication rate in both derivation and validation group (c-statistic: 0.71, p < 0.001 and 0.74, p < 0.001 respectively). The complication rate for low (score 0-5), moderate (score 6-10) and high (score 10 or above) risk group were respectively 5%, 16% and 28%. This risk stratification model was tested and confirmed in the validation group using Chi-square goodness-of-fit test (p = 0.864). CONCLUSION: A validated risk stratification model provides an accurate and easy-to-use reference tool for patients and clinicians during the informed consent process. PMID- 29113665 TI - Endoscopic assessment of tumor regression after preoperative chemoradiotherapy as a prognostic marker in locally advanced rectal cancer. AB - PURPOSE: This study was designed to evaluate tumor regression endoscopic criteria for predicting the post-chemoradiotherapy (CRT) prognosis of patients with locally advanced rectal cancer. MATERIAL AND METHODS: A total of 425 patients with rectal cancer who received radical surgery after CRT were included in this study. All patients were divided into two groups according to post-CRT preoperative endoscopic findings: 1) good response (E-GR): scar, telangiectasia, or erythema; 2) minimal or no response (E-MR): nodules, ulcers, strictures, or remnant tumor. Cox proportional hazard models were used to analyze the effect of preoperative clinicopathological variables on disease-free survival (DFS) and overall survival (OS). RESULTS: The independent prognostic factors for DFS were tumor location less than 5 cm from anal verge (hazard ratio [HR] 1.92, 95% confidence interval [CI] 1.27 to 2.88), pre-CRT carcinoembryonic antigen (CEA) > 5 ng/mL (HR 2.10, 95% CI 1.41 to 3.14), histologic high grade (HR 2.96, 95% CI 1.51 to 5.81), and E-GR (HR 0.26, 95% CI 0.08 to 0.83). The independent prognostic factors for OS were age over 65 years, tumor location, pre-CRT CEA, histologic grade, and E-GR (HR 0.13, 95% CI 0.02 to 0.99). CONCLUSIONS: Post-CRT endoscopic findings were predictors of prognosis in patients with rectal cancer. If endoscopic findings are simultaneously used with certain preoperative prognostic factors, rectal cancer patients will potentially have more treatment options. PMID- 29113666 TI - Predictive biomarkers for response of esophageal cancer to chemo(radio)therapy: A systematic review and meta-analysis. AB - BACKGROUND: Esophageal cancer remains a major public health issue worldwide. In clinical practice, chemo(radio)therapy is an important approach to patients with esophageal cancer. Only the part of patients who respond to chemo(radio)therapy achieve better long-term outcome. In this case, predictive biomarkers for response of esophageal cancer patients treated with chemo(radio)therapy are of importance. Meta-analysis of P53 for predicting esophageal cancer response has been reported before and is not included in our study. We performed a systematic review and meta-analysis to summarize and evaluate the biomarkers for predicting response to chemo(radio)therapy. METHOD: PubMed, Web of Science and the Ovid databases were searched to identify eligible studies published in English before March 2017. The risk ratio (or relative risk, RR) was retrieved in articles regarding biomarkers for predicting response of esophageal cancer patients treated with neoadjuvant therapy or chemo(radio)therapy. Fixed and random effects models were used to undertake the meta-analysis as appropriate. RESULT: Forty-six articles reporting 56 biomarkers correlated with the response were finally included. Meta-analyses were carried out when there was more than one study related to the reported biomarker. Results indicated that low expression of (or IHC-negative) COX2, miR-200c, ERCC1 and TS was individually associated with prediction of response. The RR was 1.64 (n = 202, 95% CI 1.22-2.19, P < 0.001), 1.96 (n = 162, 95% CI 1.36-2.83, P < 0.001), 2.55 (n = 206, 95% CI 1.80-3.62, P < 0.001) and 1.69 (n = 144, 95% CI 1.10-2.61, P = 0.02), respectively. High expression of (or IHC-positive) CDC25B and p16 was individually related to prediction of response. The RR was 0.62 (n = 159, 95% CI 0.43-0.89, P = 0.01) and 0.62 (n = 142, 95% CI 0.43-0.91, P = 0.01), respectively. CONCLUSION: Low expression of (or IHC-negative) COX2, miR-200c, ERCC1 and TS, or high expression of (or IHC-positive) CDC25B and p16 are potential biomarkers for predicting the response of esophageal cancer patients treated with chemo(radio)therapy. PMID- 29113667 TI - ABCB1 gene polymorphisms and response to chemotherapy in breast cancer patients: A meta-analysis. AB - The ABCB1 gene encodes the P-glycoprotein, an efflux pump for some antineoplastic agents which acts as a resistance mechanism to chemotherapy. Three SNPs (C3435T, C1236T and G2677T/A), are the most widely studied in ABCB1. The inconsistent conclusions about the association of these polymorphisms and the response to chemotherapy in breast cancer (BC) patients prompted us to conduct a meta analysis. A total of nine (770 patients), five (566 patients) and three studies (367 patients) relating the ABCB1 C3435T, C1236T and G2677T/A polymorphisms respectively, were included. The main analysis revealed a lack of association between ABCB1 polymorphisms and response to chemotherapy in every genetic model: C3435T (dominant OR: 0.888; 95%CI: 0.558-1.413), C1236T (dominant OR: 1.968; 95%CI: 0.609-6.362) and G2677T/A (GG vs GT + GA + TT + TA + AA OR: 0.854; 95%CI: 0.418-1.744). Stratification by ethnicity, cancer type and response criteria did not change the pattern of results. The available evidence indicates that three polymorphisms within ABCB1; C3435T, C1236T and G2677T/A, cannot be considered a reliable predictor of response to chemotherapy in BC patients. PMID- 29113668 TI - Preoperative Geriatric Nutritional Risk Index: A predictive and prognostic factor in patients with pathological stage I non-small cell lung cancer. AB - BACKGROUND: Surgical outcomes of early-stage non-small cell lung cancer (NSCLC) are poor. The Geriatric Nutritional Risk Index (GNRI) is a useful parameter for evaluating nutritional status. We aimed to investigate if preoperative GNRI could be a predictive factor for pathological stage I NSCLC patients. PATIENTS AND METHODS: We retrospectively selected 141 consecutive pathological stage I NSCLC patients treated from August 2005 to August 2010. We analyzed their preoperative GNRI in univariate and multivariate Cox regression analyses for postoperative recurrence-free survival (RFS). RESULTS: A preoperative abnormal GNRI was significantly associated with postoperative recurrence (P = 0.0107). Univariate analyses showed that serum carcinoembryonic antigen (CEA) levels (P = 0.0013), preoperative serum albumin level (P < 0.0001), preoperative GNRI (P = 0.0009), pleural invasion (P < 0.0001) and blood vessel invasion (P = 0.0137) significantly affected RFS. In multivariate analysis, preoperative GNRI (P = 0.0084), CEA level (P = 0.0031), preoperative serum albumin level (P = 0.0041) and pleural invasion (P = 0.0018) were independent prognostic factors. In Kaplan Meier analysis of RFS, cancer-specific survival (CS), and overall survival (OS) by preoperative GNRI, the abnormal GNRI group had significantly shorter RFS, CS, and OS (5-year RFS, CS, and OS: 52.81% vs. 89.15%; P < 0.0001, 81.73% vs. 94.73%; P = 0.0014 and 50.84% vs. 89.57%; P < 0.0001, log-rank test, respectively). CONCLUSIONS: Preoperative GNRI is a novel prognostic factor for pathological stage I NSCLC patients, which can identify high-risk patients for postoperative recurrence and cancer-related death. PMID- 29113669 TI - Target Registration Error minimization involving deformable organs using elastic body splines and Particle Swarm Optimization approach. AB - In minimally invasive surgery one of the main challenges is the precise location of the target during the intervention. The aim of the study is to present usability of elastic body splines (EBS) to minimize TRE error. The method to find the desired EBS parameters values is presented with usage of Particle Swarm optimization approach. This ability of TRE minimization has been achieved for the respiratory phases corresponding to minimum FRE for abdominal (especially liver) surgery. The proposed methodology was verified during experiments conducted on 21 patients diagnosed with liver tumors. This method has been developed to perform operations in real-time on a standard workstation. PMID- 29113670 TI - Primary arthroplasty in healed osteoarticular allograft in patients with history of primary femoral bone tumors. AB - BACKGROUND: Roughly 25-35% of patients who are treated with osteoarticular allograft for primary bone sarcomas or aggressive benign bone tumors require surgery in the long-term due to degenerative changes of the articular surface of the allograft. There are three established methods of reconstruction for this complication; a total hip arthroplasty (THA) or total knee arthroplasty (TKA) in the retained osteoarticular allograft, a proximal or distal endoprosthesis after removal of the allograft, and an allograft-prosthesis composite (APC). The aims of this study are 1) to determine the rate of complication and failure of THA/TKA in healed femoral allograft; 2) to compare the methods of revision for allograft degeneration; and 3) to compare the use of arthroplasty in healed allograft to that of arthroplasty in native bone. METHODS: We included all patients with primary bone sarcomas and locally aggressive primary benign bone tumors treated between 1984 and 2014 with an osteoarticular allograft followed by any subsequent arthroplasty technique as described above. Complications and reasons for failure are described following the classification of Henderson et al. Failure was defined as any complication leading to removal of the initial treatment construct. Failure rates of these groups were compared to primary arthroplasty in a live host bone (Control Group). RESULTS: Complications happened in 25 (61.0%) of the patients with a THA/TKA in the retained allograft, of these, 24 (58.5%) experienced failure, the most common being structural failure/type III (14, 58.3%). Thirteen patients (81.3%) with an endoprosthesis after removal of the allograft experienced complications, all of whom failed. The most common failure modes were aseptic loosening/type II (4, 30.8%) and infection/type IV (5, 38.5%). Complications in patients with an APC were experienced by 12 (85.7%) patients, 11 (78.6%) of whom failed. The most common failure mode was infection/type IV (4, 36.4%). Significantly (p < 0.001) fewer failures were observed in the control group compared to patients with an arthroplasty in a healed allograft. CONCLUSIONS: We found no significant difference in the outcome of treating patients with allograft and subsequent degenerative bone disease with a THA/TKA in a retained allograft, an endoprosthesis after removal of the allograft, or a primary APC, although infection is a significantly greater cause of failure in the latter two. Primary arthroplasty in healed allografts is a less extensive surgery than removing the allograft and shows comparable complication and failure rates. LEVEL OF EVIDENCE: Level III, Therapeutic Study. PMID- 29113671 TI - Predictors of venous thromboembolism in patients with primary sarcoma of bone. AB - : Venous thromboembolism (VTE) is known to be independently associated with both orthopaedic surgery and malignancy. Patients undergoing surgery for musculoskeletal malignancies are at an increased risk for thromboembolic events. Although VTE can lead to serious morbidity and mortality, the potential complications of prophylactic anticoagulation call for a greater understanding of a patient's risk factors, as well as more rigorous guidelines for prophylactic anticoagulation regimens. The aims of this study were to 1) Analyze the rate of VTE in patients surgically treated for primary bone sarcoma; 2) Identify risk factors for VTE in patients with primary bone sarcoma; 3) Discuss the complications associated with prophylactic anticoagulation in patients with primary bone sarcoma. METHODS: This retrospective study identified all patients 18 years and older treated surgically at our institution for a primary bone sarcoma between 1990 and 2015. All patients with at least 90 days of post operative follow-up from the index surgery were analyzed for occurrence of VTE. Those with an event were compared to those without to identify predictors of VTE. RESULTS: 21 patients (5.5%) had a clinically symptomatic, radiographically confirmed VTE within 90 days of index surgery (12 DVT, 9 PE). Higher preoperative white blood cell count (OR 1.15, 95% CI 1.01-1.29) and post-operative wound complications (OR 5.01, 95% CI 1.93-13.55) were found to be independent risk factors for VTE. No differences in terms of efficacy were found among medications. The risk of wound complications increased significantly in patients who received chemical prophylaxis (OR 2.21, 95% CI 1.00-4.87). CONCLUSIONS: Our patient population had a relatively low rate of VTE as compared to the literature. Preoperative white blood cell count (WBC) and post-operative wound complications were both found to be independently associated predictors for VTE in patients with primary bone sarcoma. An elevated WBC may reflect hemoconcentration which per se is prothrombotic in nature. Aggressive DVT prophylaxis may, counter intuitively, increase the risk of thromboembolic events due to prolonged immobilization and additional surgeries that usually occur when addressing postoperative wound complications such as postoperative hematoma and wound dehiscence that may relate to overanticoagulation. Prospective randomized trials comparing different medications in combination with compressive devices are needed to assess efficacy with the lowest complication profile. Simpler protocols may increase patient compliance to prophylactic treatment. PMID- 29113672 TI - Vulvo-vaginal reconstruction after radical excision for treatment of vulvar cancer: Evaluation of feasibility and morbidity of different surgical techniques. AB - BACKGROUND: Vulvar cancer is a rare disease accounting for approximately 5% of female genital tract tumors worldwide. Currently surgery represents the mainstay alone or sometimes, in combination with chemo-radiotherapy, for locally advanced tumors and recurrent disease. However, significant physical and sexual impairment mostly due to anatomical distortion of external genitalia are a consequence of radical surgical treatment. Postoperative reconstruction after demolitive surgeries improves aesthetic and functional results, guarantees an adequate coverage of large tumors and assures safe surgical margin. The present study aimed to analyze feasibility and complication rates of fascio-cutaneous flap after excision for vulvovaginal malignancies. METHODS: PubMed (MEDLINE), Web of Science, and CINAHL were searched for records of validated vulvovaginal reconstructive techniques after demolitive surgery for vulvar cancer. All cohorts were rated for quality using a scoring method taking into account the design of the study, the sample size and quality of report of surgical data and complications. RESULTS: A total of 24 studies met all eligibility criteria for this systematic review. All the studies were realized between 1996 and 2015. The overall sample size was 443 patients. Two major group of flap according to type of movement were identified: Advancement Flap (V-Y Gluteal Fold Flap; Medial Thigh Flap) and Transpositional Flap (Lotus Petal Flap; Gluteal Thigh Flap; Gluteal Fold Flap and Anterolateral Thigh Flap). The overall complications rates reported for advancement (26.7% among 165 patients on 11 series) and transposition flaps (22.3% among 278 patients on 13 series) were comparable. CONCLUSIONS: A tailored procedure, based on patients' characteristics, size and location of the defect is still the goal of a successful reconstructive surgery. Proper planning of the surgical procedures, knowledge of the different surgical options and technical skills are required in order to obtain reliable and satisfying results. PMID- 29113673 TI - Esophageal adenocarcinoma stage III: Survival based on pathological response to neoadjuvant treatment. AB - BACKGROUND: Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced esophageal adenocarcinomas (EAC). Pathological response is thought to be a major prognostic factor. Aims of this study were to determine the frequency of complete response and to compare the survival of complete and incomplete responders in stage III EAC. METHODS: A retrospective review was performed of all stage III patients that underwent neoadjuvant therapy followed by esophagectomy between 1999 and 2015. Patients were classified into complete (pCR) versus incomplete responders (pIR). RESULTS: 110 patients were included. Neoadjuvant chemotherapy was applied in 25 (23%) and chemoradiotherapy in 85 (77%) patients. Pathologic response was complete in 25% (n = 27) and was more common after chemoradiotherapy. Mean F/U interval was 36 months (0.3-173). There was a significant difference in the overall survival between complete and incomplete responders (p = 0.036). Median survival in the pIR group was 24.4 months and the median survival was not reached during the observation time in pCR. The 3-year survival-rate was 70% in pCR and 40% in pIR (p = 0.01). Positive lymph nodes (ypN+) were present in 56 patients (51%). The 3-year-survival-rate was 59% in pIR with ypN0 and 29% in pIR with ypN+ (p = 0.005). CONCLUSIONS: Complete response to neoadjuvant therapy has a significantly better overall and 3-year-survival after esophagectomy than incomplete response. In incomplete responders, residual lymph node disease was associated with a significantly worse survival. These findings suggest that the degree of pathologic response and lymph node status are major prognostic factors for survival in EAC patients with stage III disease. PMID- 29113674 TI - LncRNA ZEB1-AS1 predicts unfavorable prognosis in gastric cancer. AB - OBJECTIVES: LncRNA ZEB1 Antisense 1 (ZEB1-AS1) has been suggested to be an oncogenic role in human hepatocellular carcinoma, osteosarcoma, glioma and esophageal carcinoma progression. However, the clinical significance and biological function of ZEB1-AS1 in gastric cancer is poorly understood. METHODS: Levels of ZEB1-AS1 expression in gastric cancer tissues and cell lines were detected by qRT-PCR. Loss-of-function and gain-of-function studies were conducted to explore the biological function of ZEB1-AS1 in gastric cancer cells migration, invasion and EMT process. Rescued-function studies were performed to explore the association between ZEB1-AS1 and ZEB1 in gastric cancer cells migration, invasion and EMT process. RESULTS: ZEB1-AS1 was overexpressed in gastric cancer tissues and cell lines, and correlated with malignant status and prognosis in gastric cancer patients. ZEB1-AS1 regulated gastric cancer cells migration, invasion and EMT process. ZEB1-AS1 positively regulated ZEB1 expression in gastric cancer cells, and had a strongly positive correlation with ZEB1 expression in gastric cancer tissues. Rescued-function studies showed ZEB1 was critical for ZEB1-AS1 induced gastric cancer cells migration, invasion and EMT process. CONCLUSIONS: ZEB1-AS1 served as oncogenic roles in the regulation of gastric cancer cells migration, invasion and EMT process through modulating ZEB1. PMID- 29113675 TI - Surgery-induced tumor growth in (metastatic) colorectal cancer. AB - Metastatic colorectal cancer (mCRC) is a devastating disease causing 700.000 deaths annually worldwide. Metastases most frequently develop in the liver. Partial hepatectomy has dramatically improved clinical outcome and is the only curative treatment option for eligible patients with mCRC. Pre-clinical studies have shown that surgical procedures can have tumor-promoting local 'side-effects' such as hypoxia and inflammation, thereby altering the behaviour of residual tumor cells. In addition, systemically released factors following (colon or liver) surgery can act as a wakeup-call for dormant tumor cells in distant organs and/or help establish a pre-metastatic niche. Tumor handling during resection may also increase the number of circulating tumor cells. Despite the overwhelming amount of pre-clinical data demonstrating the pro-tumorigenic side effects of surgery, clinical evidence is scarce. Indications for hepatic surgery are rapidly increasing due to a rise in the incidence of mCRC and a trend towards more aggressive surgical treatment. Therefore, it is increasingly important to understand the principles of surgery-induced tumor growth, in order to devise perioperative or adjuvant strategies to further enhance long-term tumor control. In the current study we review the evidence for surgery-stimulated tumor growth and suggest strategies to assess the clinical relevance of such findings. PMID- 29113677 TI - Stapled intestinal anastomoses with endoscopic staplers in premature infants. AB - PURPOSE: The safety and effectiveness of a stapled intestinal anastomosis in adults, children, and infants is well documented. However, in neonates it is not well validated. We hypothesized that premature infants who received a stapled bowel anastomosis utilizing endoscopic staplers had similar outcomes compared to patients with a handsewn anastomosis. METHODS: A retrospective study was performed reviewing premature infants who underwent an intestinal anastomosis over a 4-year period. Patients greater than 36weeks gestational age at birth or a weight greater than 5kg at surgery were excluded. Patient demographics, type of intestinal anastomosis, and anastomotic related complications within 3months were collected and analyzed. RESULTS: Sixty-five patients underwent 71 operations involving an intestinal anastomosis: 33 cases were handsewn, and 38 cases were stapled. Groups were noted to have differences in age, weight, and diagnosis. Complications including leak and anastomotic stricture did not differ between groups. Reports of blood per rectum after surgery were more common in the stapled group (24% versus 6%, p=0.0522), but this did not reach statistical significance. CONCLUSION: There were no significant differences in anastomotic complications when comparing the handsewn and stapled intestinal anastomosis techniques in premature infants weighting less than 5kg. TYPE OF STUDY: Treatment Study. LEVEL OF EVIDENCE: III. PMID- 29113678 TI - A large single-institution review of tracheoesophageal fistulae with evaluation of the use of transanastomotic feeding tubes. AB - INTRODUCTION: Transanastomatic feeding tube (TAT) use in the repair of tracheoesophageal fistulas (TEF) with or without esophageal atresia (EA) and EA with or without TEF allows for earlier enteral feedings, however, may predispose to esophageal stricture. METHODS: We review our institutional experience with esophageal atresia repair over a 15-year period from 2000 to 2015 and report on our observed complication rate with emphasis on the surgical approach and use of TATs. RESULTS: We identified 110 TEF repairs. Ninety-six were Type C, 7 were Type A, 4 were Type D, and 3 were Type E (H-Type). TATs were used in 74% of patients. The stricture rate with the TAT approached 56% versus 17% without a TAT (p<0.0005). There was no difference in leak rate (p=0.27). Ninety-four TEF repairs were performed via open thoracotomy, and 16 were initially approached thoracoscopically. Six out of 16 that were started thoracoscopically were completed with the minimally invasive approach. Whether the case was started thoracoscopically, completed thoracoscopically, or performed open made no difference in the rate of stricture or anastomotic leak, but we did observe an increase in musculoskeletal complications in the open thoracotomy group (28% vs. 0). CONCLUSION: Our data suggests that the use of TATs does not protect against anastomotic leak, but may increase stricture rate. Further, the thoracoscopic group showed no difference in the leak or stricture rate and demonstrated less musculoskeletal complications. Confirmation of these findings will require a prospective study. LEVEL OF EVIDENCE: III. PMID- 29113676 TI - Computational Lipidomics of the Neuronal Plasma Membrane. AB - Membrane lipid composition varies greatly within submembrane compartments, different organelle membranes, and also between cells of different cell stage, cell and tissue types, and organisms. Environmental factors (such as diet) also influence membrane composition. The membrane lipid composition is tightly regulated by the cell, maintaining a homeostasis that, if disrupted, can impair cell function and lead to disease. This is especially pronounced in the brain, where defects in lipid regulation are linked to various neurological diseases. The tightly regulated diversity raises questions on how complex changes in composition affect overall bilayer properties, dynamics, and lipid organization of cellular membranes. Here, we utilize recent advances in computational power and molecular dynamics force fields to develop and test a realistically complex human brain plasma membrane (PM) lipid model and extend previous work on an idealized, "average" mammalian PM. The PMs showed both striking similarities, despite significantly different lipid composition, and interesting differences. The main differences in composition (higher cholesterol concentration and increased tail unsaturation in brain PM) appear to have opposite, yet complementary, influences on many bilayer properties. Both mixtures exhibit a range of dynamic lipid lateral inhomogeneities ("domains"). The domains can be small and transient or larger and more persistent and can correlate between the leaflets depending on lipid mixture, Brain or Average, as well as on the extent of bilayer undulations. PMID- 29113679 TI - Wound complications after chemo-port placement in children: Does closure technique matter? AB - PURPOSE: Wound dehiscence after chemo-port placement is a rare but potentially significant complication. We hypothesize that by using a simple running skin closure technique during chemo-port placement the rate of wound dehiscence and overall wound complications can be significantly decreased. METHODS: IRB approval was obtained and patients <18years that received a tunneled central line with port from June 2012 to April 2016 were analyzed. Data collected on patients included patient demographics, skin closure type, and wound complications within 30days. Chi-square was performed to examine the univariate association with skin closure technique and wound dehiscence. Logistic regression was performed to examine the multivariable association between skin closure type and wound dehiscence and to compute odds ratios. RESULTS: There were 259 ports placed in this cohort: 125 used simple running skin closure technique, and 134 used the subcuticular skin closure. Patients were found to not have any difference in rate of dehiscence or overall wound complications based on gender, age, location of port, or use of steroids or chemotherapy within 1week of port placement. When compared, only 1 case (0.80%) in the simple running group vs 10 cases (7.46%) in the subcuticular group experienced a wound dehiscence [unadjusted OR=14.07 (1.69, 116.99) p=0.0144]. When comparing overall wound complications the simple running group had 3 (2.4%) versus 12 (8.96%) in the subcuticular group [unadjusted OR=4.78 (1.27, 17.94) p=0.0203]. When adjusting for port-number both dehiscence and overall wound complications remained statistically significant. CONCLUSION: We conclude that the simple running skin closure for chemo-port placement in children has superior outcomes in regards to prevention of dehiscence and overall wound related complications when compared to the subcuticular technique. PMID- 29113680 TI - ? PMID- 29113681 TI - Corrigendum to "Environmental monitoring of complex hydrocarbon mixtures in water and soil samples after solid phase microextraction using PVC/MWCNTs nanocomposite fiber" [Chemosphere 93 (9) (November 2013) 1920-1926]. PMID- 29113682 TI - Editorial for special pediatric hemostasis issue BCMD. PMID- 29113683 TI - Technological Advances in Sickle Cell Disease. PMID- 29113684 TI - Blood mercury concentration, fish consumption and anthropometry in Chinese children: A national study. AB - OBJECTIVE: This study sought to obtain national cross-sectional data for blood mercury levels and risk factors for mercury exposure in Chinese children aged 0 to 6years to provide evidence to support preventive measures for reducing childhood blood mercury levels. METHODS: A multi-stage, stratified, clustered random sampling survey was conducted May 2013-Mar 2015. Shanghai, Jilin, Shanxi, Guangdong, Qinghai, Yunnan and Hubei, which are located in seven different geographical regions in China, were selected as the study field. A total of 14,202 children aged 0-6years participated in the study. Whole-blood venous samples (3ml) were collected from the subjects for mercury exposure assessment. The DMA-80 was applied for mercury detection, and a health questionnaire gathering information on related confounders was completed by the subjects' parents of the subjects after they received guidance from the investigators. A general linear model was used for the primary descriptive statistical analysis. Odds ratios (ORs) and 95%CIs for the risk factors were estimated using unconditional logistic regression. RESULTS: A total of 14,202 eligible samples were collected. The mean mercury level was 1.39MUg/L. Other results were as follows: median 1.23MUg/L, p25 0.86MUg/L, p75 1.73MUg/L, and GM 1.10MUg/L. Of the seven geographical regions, Qinghai, in northwestern China, had a median mercury level of 0.37MUg/L, which was significantly lower than the mercury level in Guangdong, in southeastern China (2.01MUg/L). The median blood mercury level of children in suburban areas was 1.34MUg/L, which was remarkably higher than that of children in rural areas (1.09MUg/L). Dichotomous subgroups were generated using the median mercury concentration. Unconditional logistic regression analysis revealed that fish consumption may contribute to increased blood mercury levels (p<0.05). Additionally, we observed significantly positive associations between mercury concentrations and the children's anthropometric characteristics (BMI; p<0.05). CONCLUSIONS: Blood mercury concentrations among Chinese children aged 0-6years were considered low, and children who consumed more marine fish, freshwater fish and shellfish tended to have higher mercury concentrations. Our study suggests that children's growth is likely affected by the positive effects of mercury, which may have implications concerning the positive effects of fish consumption. PMID- 29113685 TI - Expression of beta1integrin in normal epithelium, oral submucous fibrosis and oral squamous cell carcinoma. AB - INTRODUCTION AND AIMS: The possible reason suggested for epithelial atrophy in oral submucous fibrosis (OSMF) is ischemia. Dysregulation in the epithelial proliferation and maturation is also thought to be a cause. The beta1 integrin identifies the oral epithelial stem cells. The changes induced by the arecanut on these cells may result in epithelial alterations. The aim of this study is to evaluate the stem cells distribution and percentage by assessing the beta1 integrin expression. MATERIALS AND METHODS: The study included normal oral mucosa (15 cases) and disease group (97 cases). The disease group was further subdivided into early (29 cases), moderate (34 cases), advanced OSMF (18 cases) and oral squamous cell carcinoma(OSCC) associated with OSMF (16 cases). The tissues were stained for beta1 integrin antibodies. The positive cells and staining intensities were analysed to determine the staining index, and statistically evaluated using KW test statistics. RESULTS: beta1 integrin was observed in retepegs region and the percentage of positive cells was 14%- 30% in the control. In OSMF, the beta1 integrin positivity was observed in basal and suprabasal layers, and the percentage was ranged from 2%-71%. beta1 integrin expression in OSCC was observed both in central and peripheral cells and ranged from 17%-85%. On comparison, the difference in staining index among normal, OSMF and carcinomas was significant at p<0.01. The stem cells percentage was increased both in OSMF and carcinomas. The non-dysplastic epithelium of OSMF with severe atrophy showed lowest percentage. It is inferred that absence of stem cells and proliferation may attribute for the atrophy. PMID- 29113686 TI - Down-regulation of miR-26a-5p in hepatocellular carcinoma: A qRT-PCR and bioinformatics study. AB - BACKGROUND: To practically verify the clinical value of miR-26a-5p and thoroughly explore its target genes as well as its potential functions in hepatocellular carcinoma (HCC). METHODS: HCC and adjacent non-cancerous hepatic tissues of 95 HCC patients were collected for analysis using reverse transcription quantitative real-time PCR (qRT-PCR). For the bioinformatics analysis, we identified potential target genes for miR-26a-5p from differentially expressed genes (DEGs) in Gene Expression Omnibus (GEO) data sets and miRWalk predicted database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) analyses were applied to analyze the prospective mechanisms of the predicted target genes. RESULTS: MiR-26a-5p showed a significantly lower expression level in HCC tissues (1.56+/-1.07) than adjacent benign liver tissues (2.28+/-1.06, P<0.001). The area under the curve (AUC) of the receiver operating characteristic (ROC) was 0.665 (95% CI: 0.588-0.743, P<0.001). Significant correlations between miR-26a-5p expression and clinicopathological features such as gender (r=0.275, P<0.01), clinical TNM stage (r=-0.306, P<0.01), and metastasis (r=-0.321, P<0.01) were observed. To examine potential target genes, we obtained 175 genes for further function analysis, by attaining the intersection of 2062 up-regulated DEGs and 1390 online-predicted target genes. The GO and KEGG pathway annotation indicated focal adhesion, regulation of actin cytoskeleton and the PI3K-Akt signaling pathway as significant prospective mechanisms. The PPI network indicated that NRAS was the most essential hub gene in the whole network. CONCLUSION: Down-regulated miR-26a-5p was closely correlated with the status of metastasis and the progression of HCC. MiR-26a-5p might play protective roles by targeting diverse genes and pathways. PMID- 29113687 TI - Social epidemiology for the 21st century. AB - Social epidemiology, as defined by the textbook of the same name (Berkman et al., 2014) is "that branch of epidemiology concerned with the way that social structures, institutions, and relationships influence health" (p. 2). As our Special Issue commemorates the 50th anniversary of Social Science & Medicine, it is worth noting that the Social Epidemiology office within the journal has existed only for a fraction of that time (fifteen years). So what has been learned in the fifteen years since the establishment of the new office? In this commentary, we spotlight some of the achievements, substantive topics, and future trends in the research papers that we have featured in our Section of the journal. PMID- 29113688 TI - Corrigendum to "Soybeans inoculated with root zone soils of Canadian native legumes harbour diverse and novel Bradyrhizobium spp. that possess agricultural potential" [Syst. Appl. Microbiol. 40 (October (7)) (2017) 440-447]. PMID- 29113689 TI - Assessing the impact of rumen microbial communities on methane emissions and production traits in Holstein cows in a tropical climate. AB - The evaluation of how the gut microbiota affects both methane emissions and animal production is necessary in order to achieve methane mitigation without production losses. Toward this goal, the aim of this study was to correlate the rumen microbial communities (bacteria, archaea, and fungi) of high (HP), medium (MP), and low milk producing (LP), as well as dry (DC), Holstein dairy cows in an actual tropical production system with methane emissions and animal production traits. Overall, DC cows emitted more methane, followed by MP, HP and LP cows, although HP and LP cow emissions were similar. Using next-generation sequencing, it was found that bacteria affiliated with Christensenellaceae, Mogibacteriaceae, S24-7, Butyrivibrio, Schwartzia, and Treponema were negatively correlated with methane emissions and showed positive correlations with digestible dry matter intake (dDMI) and digestible organic matter intake (dOMI). Similar findings were observed for archaea in the genus Methanosphaera. The bacterial groups Coriobacteriaceae, RFP12, and Clostridium were negatively correlated with methane, but did not correlate with dDMI and dOMI. For anaerobic fungal communities, no significant correlations with methane or animal production traits were found. Based on these findings, it is suggested that manipulation of the abundances of these microbial taxa may be useful for modulating methane emissions without negatively affecting animal production. PMID- 29113690 TI - Mesoderm/mesenchyme homeobox gene l promotes vascular smooth muscle cell phenotypic modulation and vascular remodeling. AB - AIMS: To investigate the role of mesoderm/mesenchyme homeobox gene l (Meox1) in vascular smooth muscle cells (SMCs) phenotypic modulation during vascular remodeling. METHODS AND RESULTS: By using immunostaining, Western blot, and histological analyses, we found that Meox1 was up-regulated in PDGF-BB-treated SMCs in vitro and balloon injury-induced arterial SMCs in vivo. Meox1 knockdown by shRNA restored the expression of contractile SMCs phenotype markers including smooth muscle alpha-actin (alpha-SMA) and calponin. In contrast, overexpression of Moex1 inhibited alpha-SMA and calponin expressions while inducing the expressions of synthetic SMCs phenotype markers such as matrix gla protein, osteopontin, and proliferating cell nuclear antigen. Mechanistically, Meox1 mediated the SMCs phenotypic modulation through FAK-ERK1/2 signaling, which appears to induce autophagy in SMCs. In vivo, knockdown of Meox1 attenuated injury-induced neointima formation and promoted SMCs contractile proteins expressions. Meox1 knockdown also reduced the number of proliferating SMCs, suggesting that Meox1 was important for SMCs proliferation in vivo. Moreover, knockdown of Meox1 attenuated ERK1/2 signaling and autophagy markers expressions, suggesting that Meox1 may promote SMCs phenotypic modulation via ERK1/2 signaling autophagy in vivo. CONCLUSION: Our data indicated that Meox1 promotes SMCs phenotypic modulation and injury-induced vascular remodeling by regulating the FAK-ERK1/2-autophagy signaling cascade. Thus, targeting Meox1 may be an attractive approach for treating proliferating vascular diseases. PMID- 29113691 TI - General practitioners and vaccination of children presenting with a benign infection. AB - PURPOSE: To assess the self-reported vaccination behavior of general practitioners (GPs) when asked whether they would recommend the vaccination of a child presenting with a febrile uncomplicated common cold. METHODS: We performed a cross-sectional survey in 2014 on a national sample of GPs. GPs were randomly assigned to one of eight clinical vignettes, all describing a child presenting with an uncomplicated febrile common cold, but differing by age (4 or 11 months), temperature (38 degrees C or 39 degrees C), and the mother's emotional state (calm or worried). GPs were asked whether they would recommend immediate vaccination of the child with a hexavalent vaccine (diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, and hepatitis B), or postpone it. We investigated the relation between the GPs' recommendation to vaccinate, the clinical vignette's variables, and the GPs' perceptions, attitudes, and practices toward vaccination in a multivariate model. RESULTS: Among the 1582 participating GPs, 6% recommended immediate vaccination. This behavior was more frequent with a temperature of 38 degrees C rather than 39 degrees C (10% vs. 3%, P<0.001). GPs who felt comfortable giving explanations about vaccine safety were more likely to recommend immediate vaccination of the febrile child (P=0.045), but none of the other GPs' characteristics were associated with their vaccination behavior. CONCLUSIONS: Almost all GPs postponed the hexavalent vaccination of the febrile child presenting with an uncomplicated viral disease; fever being the major factor affecting their decision. More research is needed on vaccination responses in sick children, as well as clearer guidelines. PMID- 29113692 TI - Sources of inflow and nature of redistribution of 90Sr in the salt lakes of the Crimea. AB - At the first time for the period after the Chernobyl NPP accident the nature of the redistribution of the 90Sr concentrations in components of the ecosystems of the salt lakes of the Crimea were identified and described. Concentration of 90Sr in water of the salt lakes depends on the sources of the inflow this radionuclide into aquatic ecosystems and salinity level of lakes water. Until April 2014 the flow of the Dnieper river water through the Northern-Crimean canal was more important factor of contamination of salt lakes of the Crimea by 90Sr, than atmospheric fallout of this radionuclide after the Chernobyl NPP accident. Concentrations of 90Sr in water of the salt lakes of the Crimea exceeded 2.4 156.5 times its concentrations in their bottom sediments. The 90Sr dose commitments to hydrophytes, which were sampled from the salt lakes of the Crimea have not reached values which could impact them during entire the after-accident period. PMID- 29113693 TI - The value of lactate clearance in admission decisions of patients with acute exacerbation of COPD. AB - BACKGROUND: Lactate and lactate clearance are being used as biomarkers in several critical conditions. The aim of this study was to examine the value of sixth hour lactate clearance in patients who were hospitalized with chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: This single-center, cross sectional study was conducted in a tertiary emergency department (ED) on patients who presented with acute exacerbation of COPD. Discharge or admission decisions were specified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and the clinician's decision. In the study, lactate clearance was defined as the percent decrease in lactate from the time of presentation to the ED to the sixth hour. RESULTS: A total of 495 patients were evaluated and 397 patients were excluded. Among included patients, 53 (54.1%) were admitted to the hospital and 45 (45.9%) were discharged. The median lactate clearance was found to be -11.8% (95% CI: -50.0 to 34.5) in the admitted group and 14.7% (95% CI: -11.3 to 42.3) in the discharged group. Between the two groups, the median difference of lactate clearance was found to be 26.5% (95% CI: 0.6 to 52.4). Multivariate logistic regression analysis revealed that the delta lactate value can determine the hospitalization need of patients (OR: 0.91, 95% CI: 0.85 to 0.97). CONCLUSION: Lactate clearance can be evaluated as a useful marker in patients with COPD exacerbations. This study suggests that lactate monitoring in the ED has clinical benefits in addition to GOLD guidelines when deciding whether to discharge or hospitalize a patient. PMID- 29113694 TI - [Lupus erythematosus treatment with belimumab in daily practice: Retrospective study of 15 patients]. AB - BACKGROUND: Belimumab (an anti-BLyS monoclonal antibody) was recently approved for the treatment of systemic lupus erythematosus (SLE). The aim of the study was to describe efficacy and safety of the drug as well as its impact on serologic parameters and the role of long-term systemic sparing of treatment in clinical practice in LE. PATIENTS AND METHODS: We conducted a retrospective study at Reims University Hospital between 2012 and 2016 including consecutive patients with LE treated with belimumab. Efficacy was evaluated in terms of clinical progression, and normalisation of laboratory factors (anti-DNA antibody and C3 serum levels) and sparing of associated long-term systemic therapies for LE. RESULTS: Among the 15 patients included, a therapeutic response was obtained in 9 patients (60%), with partial remission in 8 of 9 cases. The median titre of anti-DNA antibody was 50IU/mL (range: 4-50) and the median C3 level was 0.82g/L (range: 0.36-1.23) before initiation of belimumab, vs. 25.5IU/mL (range: 2-50) and 0.89g/L (range: 0.34-1.22) at the last evaluation, respectively, without significant modification (P=0.12 and P=0.45). The median dose of prednisone at the time of the first belimumab infusion was reduced from 9.5mg/day (range: 0-18) to 6mg/day (range: 0 20) at the last clinical evaluation. Eight patients (53%) experienced adverse events, and these were very slight or moderate in all cases. CONCLUSION: Belimumab appears to be an effective and well-tolerated treatment for moderately severe systemic LE, allowing sparing of maintenance corticosteroid therapy in order to decrease its frequent adverse events. PMID- 29113695 TI - Re: Long-term Psychological and Quality-of-life Effects of Active Surveillance and Watchful Waiting After Diagnosis of Low-risk Localised Prostate Cancer. PMID- 29113696 TI - Embracing Colonizations: A New Paradigm for Species Association Dynamics. AB - Parasite-host and insect-plant research have divergent traditions despite the fact that most phytophagous insects live parasitically on their host plants. In parasitology it is a traditional assumption that parasites are typically highly specialized; cospeciation between parasites and hosts is a frequently expressed default expectation. Insect-plant theory has been more concerned with host shifts than with cospeciation, and more with hierarchies among hosts than with extreme specialization. We suggest that the divergent assumptions in the respective fields have hidden a fundamental similarity with an important role for potential as well as actual hosts, and hence for host colonizations via ecological fitting. A common research program is proposed which better prepares us for the challenges from introduced species and global change. PMID- 29113697 TI - Sensitivity of a prompt-gamma slit-camera to detect range shifts for proton treatment verification. AB - BACKGROUND AND PURPOSE: A prompt-gamma imaging (PGI) slit-camera was recently applied successfully in clinical proton treatments using pencil beam scanning (PBS) and double scattering (DS). However, its full capability under clinical conditions has still to be systematically evaluated. Here, the performance of the slit-camera is systematically assessed in well-defined error scenarios using realistic treatment deliveries to an anthropomorphic head phantom. MATERIALS AND METHODS: The sensitivity and accuracy to detect introduced global and local range shifts with the slit-camera was investigated in PBS and DS irradiations. For PBS, measured PGI information of shifted geometries were compared spot-wise with un shifted PGI information derived from either a reference measurement or a treatment-plan-based simulation. Furthermore, for DS and PBS the integral PGI signal of the whole field was evaluated. RESULTS: Deviations from the treatment plan were detected with an accuracy better than 2 mm in PBS. The PGI simulation accuracy was well below 1 mm. Interfractional comparisons are more affected by measurement noise. The field-integral PGI sum signal allows the detection of global shifts in DS. CONCLUSIONS: Detection of global and local range shifts under close-to-clinical conditions is possible with the PGI slit-camera. Especially for PBS, high sensitivity and high accuracy in shift detection were found. PMID- 29113698 TI - The control of oligodendrocyte bioenergetics by interferon-gamma (IFN-gamma) and Src homology region 2 domain-containing phosphatase-1 (SHP-1). AB - Glycolysis and mitochondrial respiration are essential for oligodendrocyte metabolism in both the developing and adult CNS. Based on recent reports on the effects of the proinflammatory cytokine IFN-gamma on metabolism and on oligodendrocytes, we addressed whether IFN-gamma may affect oligodendrocyte bioenergetics in ways relevant to CNS disease. Oligodendrocytes of mice treated with IFN-gamma showed significant reductions in aerobic glycolysis and mitochondrial respiration. As expected, IFN-gamma treatment led to the induction of STAT1 in oligodendrocytes indicating active signaling into these cells. To determine the direct effects of IFN-gamma on oligodendrocyte metabolism, cultured oligodendrocytes were treated with IFN-gamma in vitro, which resulted in suppression of glycolysis similar to oligodendrocytes of animals treated with IFN gamma in vivo. Mice lacking SHP-1, a key regulator of IFN-gamma and STAT1 signaling in CNS glia, had high constitutive levels of STAT1 and decreased aerobic glycolysis and mitochondrial respiration rates relative to wild type mouse oligodendrocytes. Together, these data show that IFN-gamma and SHP-1 control oligodendrocyte bioenergetics in ways that may relate to the role of this cytokine in CNS disease. PMID- 29113699 TI - Involvement of caspase-4 in IL-1 beta production and pyroptosis in human macrophages during dengue virus infection. AB - Caspase-4 physically interacts with caspase-1 and is believed to be a proinflammatory caspase that can induce the inflammatory form of programmed cell death (pyroptosis) and the release of mature interleukin (IL)-1beta. However, the function of caspase-4 in dengue virus infection is not yet fully understood. We examined the function of caspase-4 in IL-1beta production and pyroptosis during dengue virus serotype-2 (DENV-2) infection in human macrophages. In this study, DENV-2 infection increased IL-1beta protein level with activated caspase-4 activity. Using primary macrophages, we observed that caspase-4 induces activation of caspase-1 and secretion of IL-1beta in response to DENV-2 infection, without the need for secondary signals to stimulate the assembly of the inflammasome. These findings indicate that the regulation of caspase-1 activity by capsase-4 could represent a unique mechanism. Our data suggest that caspase-4 is upstream of caspase-1 in the pathway that regulates pyroptosis and IL-1beta synthesis in macrophages during DENV-2 infection. PMID- 29113700 TI - High performance dental resin composites with hydrolytically stable monomers. AB - OBJECTIVE: The objectives of this project were to: 1) develop strong and durable dental resin composites by employing new monomers that are hydrolytically stable, and 2) demonstrate that resin composites based on these monomers perform superiorly to the traditional bisphenol A glycidyl dimethacrylate/triethylene glycol dimethacrylate (Bis-GMA/TEGDMA) composites under testing conditions relevant to clinical applications. METHODS: New resins comprising hydrolytically stable, ether-based monomer, i.e., triethylene glycol divinylbenzyl ether (TEG DVBE), and urethane dimethacrylate (UDMA) were produced via composition controlled photo-polymerization. Their composites contained 67.5wt% of micro and 7.5wt% of nano-sized filler. The performances of both copolymers and composites were evaluated by a battery of clinically-relevant assessments: degree of vinyl conversion (DC: FTIR and NIR spectroscopy); refractive index (n: optical microscopy); elastic modulus (E), flexural strength (F) and fracture toughness (KIC) (universal mechanical testing); Knoop hardness (HK; indentation); water sorption (Wsp) and solubility (Wsu) (gravimetry); polymerization shrinkage (Sv; mercury dilatometry) and polymerization stress (tensometer). The experimental UDMA/TEG-DVBE composites were compared with the Bis-GMA/TEGDMA composites containing the identical filler contents, and with the commercial micro hybrid flowable composite. RESULTS: UDMA/TEG-DBVE composites exhibited n, E, Wsp, Wsu and Sv equivalent to the controls. They outperformed the controls with respect to F (up to 26.8% increase), KIC (up to 27.7% increase), modulus recovery upon water sorption (full recovery vs. 91.9% recovery), and stress formation (up to 52.7% reduction). In addition, new composites showed up to 27.7% increase in attainable DC compared to the traditional composites. Bis-GMA/TEGDMA controls exceeded the experimental composites with respect to only one property, the composite hardness. Significantly, up to 18.1% lower HK values in the experimental series (0.458GPa) were still above the clinically required threshold of approx. 0.4GPa. SIGNIFICANCE: Hydrolytic stability, composition-controlled polymerization and the overall enhancement in clinically-relevant properties of the new resin composites make them viable candidates to replace traditional resin composites as a new generation of strong and durable dental restoratives. PMID- 29113701 TI - Electrocardiographic patterns in biventricular pacing delivered by second generation cardiac resynchronization devices. AB - BACKGROUND: With increasing use of cardiac resynchronization therapy (CRT), treating physicians should be familiar with different electrocardiographic (ECG) patterns of left ventricular (LV) lead and biventricular (BiV) pacing. However, there are a few publications on ECG patterns during BiV pacing. PURPOSE: This study was sought to determine different ECG patterns in patients with BiV pacing. METHODS: Twelve-lead ECGs during BiV pacing (right ventricular leads at apex and LV leads in one of the lateral coronary veins) were analyzed in 181 consecutive patients (121 male; mean age, 62.0 +/- 13.5 years) with advanced heart failure and baseline left bundle branch block pattern after at least 6-month of uncomplicated CRT. RESULTS: During BiV pacing, 65% of the patients showed a dominant R wave in V1. There was a right axis deviation in 57% in frontal plane. However, a left superior axis emerged in 34% and normal frontal plane axis in 9%. Sequential BiV pacing (73% vs. 58%, P = 0.04) and pacing from posterolateral coronary vein (80% vs. 60%, p = 0.045) were more likely to present with a dominant R wave in V1. In sequential pacing, AV interval was significantly longer in patients with negative complex in V1 than in those with positive complex (124 +/- 21 vs. 116 +/- 8.0, p = 0.005). A Q/q wave was detected in 85% of patients in lead I and 78% in lead aVL. CONCLUSIONS: BiV pacing from lateral coronary venous branches and right ventricular apex characteristically presented with dominant R wave in V1, Q/q wave in leads I and aVL, and right or left superior axis. However, a negative complex in V1, QRS axis in other quadrants, and lack of Q/q wave in leads I and aVL did not necessarily indicate a problem. PMID- 29113702 TI - Mandibular advancement for adult obstructive sleep apnea: A systematic review and meta-analysis. AB - OBJECTIVES: Patients with mandibular insufficiency can be predisposed to obstructive sleep apnea (OSA). The objective of this study was to systematically review the international literature for mandibular advancement surgeries (MAS) as treatment for adult OSA, and then to perform a meta-analysis. METHODS: Four authors searched five databases from the inception of each database through April 5, 2017. The PRISMA statement was followed. RESULTS: 972 studies were screened, 84 were downloaded, and 11 (57 patients) met criteria. In patients with mandibular insufficiency, MAS reduced apnea-hypopnea index (AHI) (50 patients) from 45.9 +/- 24.7 to 6.2 +/- 10.4 events/h (87% decrease). The lowest oxygen saturation (LSAT) (55 patients) increased from 71.9 +/- 14.6% to 89.0 +/- 11.0%. The AHI mean difference was -34.8 events/h [95% CI -43.9, -25.8]. The AHI standardized mean difference was -1.8 [95% CI -2.5, -1.2] (indicating a large magnitude of effect). Surgical cure was seen in 75% of those with >16 mm of mandibular advancement vs. 35% of those with <16 mm of advancement [Odds Ratio 5.5; 95% CI 1.06-28.4; Chi Square p = 0.035]. CONCLUSIONS: The current literature supports isolated mandibular advancement as an efficacious treatment modality for adult OSA in select patients with mandibular insufficiency. PMID- 29113703 TI - Similar 2-point discrimination and stereognosia but better locognosia at long term with an independent home-based sensory reeducation program vs no reeducation after low-median nerve transection and repair. AB - STUDY DESIGN: Prospective controlled study. INTRODUCTION: Previous studies evaluated the effectiveness of sensory reeducation (SR) after peripheral nerve injury and repair. However, evidence for long-term clinical usefulness of SR is inconclusive. PURPOSE OF THE STUDY: The purpose of this study is to compare the sensory results of patients with low-median nerve complete transection and microsurgical repair, with and without SR at long term. METHODS: We prospectively studied 52 consecutive patients (mean age, 36 years; range, 20-47 years) with low median nerve complete transection and microsurgical repair. When reinnervation was considered complete with perception of vibration with a 256-cycles per second tuning fork (mean, 3.5 months after nerve injury and repair), the patients were sequentially allocated (into 2 groups [group SR, 26 patients, SR; group R, 26 patients, reassured on recovery without SR). SR was conducted in a standardized fashion, in 2 stages, as an independent home-based program: the first stage was initiated when reinnervation was considered complete, and included instruction in home exercises to identify familiar objects and papers of different roughness, and localization of light touch (eyes open and closed); the second stage was initiated when the patients experienced normal static and moving 2-point discrimination (2PD) at the index fingertip of injured hand, and included instruction in home exercises for stereognosia, supplementary exercises for localization of light touch, and identification of small objects (eyes open and closed). Exercises were prescribed for 5-10 minutes, 4 times per day. At 1.5, 3, and 6 years after nerve injury and repair, we evaluated the static and moving 2PD, stereognosia with the Moberg's pick-up test, and locognosia with the modified Marsh test. Comparison between groups and time points was done with the nonparametric analysis of variance (Kruskal-Wallis analysis of variance). RESULTS: Static and moving 2PD and stereognosia were not significantly different between groups at any study period. Locognosia was significantly better at 1.5 and 3 years in group SR; locognosia was excellent in 17 patients of group SR vs 5 patients of group R at 1.5-year follow-up and in 14 patients of group SR vs 5 patients of group R at 3-year follow-up. Locognosia was not different between the study groups at 6-year follow-up. CONCLUSION: A 2-stage home program of SR improved locognosia at 1.5 and 3 years after low-median nerve complete transection and repair without significant differences in other modalities or the 6-year follow-up of a small subsample. PMID- 29113705 TI - Recent advances in diagnosis and treatment of cardiac amyloidosis. AB - Cardiac amyloidosis (CA) has been believed to be a rare disease for a long time, but recent sophisticated diagnostic modalities demonstrate that a considerable number of CA patients are hidden among those diagnosed with heart failure. Prognosis of CA was poor, but recent developments in therapeutic interventions have improved survival in these patients. Therefore, early detection and precise diagnosis is clinically important. In this review article, we overview recent progress in diagnosis and treatment for CA. PMID- 29113704 TI - Antiretroviral Treatment Uptake and Adherence Among Men Who Have Sex With Men and Transgender Women With HIV in Mumbai, India: A Cross-Sectional Study. PMID- 29113706 TI - Calcaneal Avulsion of an Ochronotic Achilles Tendon: A Case Report. AB - Alkaptonuria is a hereditary disorder of phenylalanine and tyrosine, with an incidence of approximately 1/200,000 to 1/1,000,000. Ochronosis is the accumulation of homogentisic acid and its metabolites in connective tissues such as the tendons, cartilage, and skin. In the present case study, a 50-year-old male presented with a nontraumatic calcaneal avulsion without a previous diagnosis of ochronosis. To the best of our knowledge, little information has been reported of this pathology in the Achilles tendon and the surgical management. PMID- 29113707 TI - Helicobacter pylori and proton pump inhibitor therapy: One diagnostic method is enough? PMID- 29113709 TI - Bias in the measurement of radon gas using ionization chambers: Application to SIR. AB - Two main non-destructive techniques can be used to measure standard 222Rn gas ampoules: well-type ionization chambers and gamma-ray spectrometry, the former being used in the Systeme International de Reference (SIR) for international comparison purposes. The reliability of these techniques requires that the variability of the flame-sealed gas glass ampoules used have a negligible influence on the detector response. This variability is studied in this work by considering three parameters: the volume of the ampoule, the position of the sealing point and the thickness of the glass. Results showed that variability of the gas ampoules induced measurement bias larger than the uncertainty of the standard sources. PMID- 29113708 TI - Efficacy and safety of glucagon-like peptide-1 agonists on macrovascular and microvascular events in type 2 diabetes mellitus: A meta-analysis. AB - AIMS: Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events. DATA SYNTHESIS: MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804-0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757-0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830-1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759-1.023; p = 0.097), HF (RR: 0.967; CI: 0.803-1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807 1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625-1.199; p = 0.385). CONCLUSIONS: Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality. PMID- 29113710 TI - Lower Gastrointestinal Tumour Virtual Special Issue. PMID- 29113711 TI - The Lives and Times of Brown Adipokines. AB - Brown adipose tissue (BAT) is responsible for adaptive non-shivering thermogenesis. Moreover, brown fat secretes regulatory factors, so-called brown adipokines, that have autocrine, paracrine, and endocrine actions. Brown adipokines are either polypeptides or nonpeptidic molecules including lipid molecules and microRNAs. The secretory properties of brown fat are essential for tissue remodeling adaptations to thermogenic necessities. The endocrine properties of brown adipokines are thought to contribute to the association between BAT activity and a healthy metabolic profile in relation to glucose and lipid homeostasis. The identification and characterization of brown adipokines may allow the discovery of circulating biomarkers of BAT activity in humans, and will lead to the development of candidate tools for therapeutic interventions in metabolic diseases. PMID- 29113712 TI - Prior antimicrobial therapy duration influences causative pathogens identification in ventilator-associated pneumonia. AB - OBJECTIVE: To determine whether prior antimicrobial therapy, divided in recent or current antibiotic treatment, influences the identification rate and/or the type of causative pathogens in patients with suspected episodes of ventilator-acquired pneumonia. DESIGN: Monocentric retrospective study. SETTING: Intensive car unit in a universitary hospital. PATIENTS: 230 episodes of ventilator-associated pneumonia with a Clinical Pulmonary Infection Score>=6 were retrospectively evaluated. Based on the antimicrobial treatment regimen, we defined 3 groups: the no antimicrobial treatment group (VAP is suspected in patients that has never received antibiotics during the last 90days), group 2: the current antimicrobial therapy (VAP is suspected under antimicrobial therapy) and group 3: the recent antimicrobial therapy (VAP is suspected whereas an antimicrobial treatment has been used during the last 90days but discontinued for >24h). INTERVENTION: Bacteriologic analysis using a protected distal sampling with microscopic examination, culture and microbial identification using MALDI-TOF. MEASUREMENTS AND MAIN RESULTS: Suspected episodes of VAP were sorted as follow: 70 suspected episodes in the no antimicrobial therapy group, 106 suspected episodes in the current antimicrobial therapy group and 54 suspected episodes in the recent antimicrobial therapy group. The rate of positive culture was significantly lower in the current antimicrobial treatment group (group 2) when compared to the recent (group 3) and to the no antimicrobial treatment groups (group 1) (42%, 68% and 86%, respectively). When compared to the recent antibiotherapy group, we observed that current antibiotherapy was significantly associated with a higher rate of MDR positive culture, mainly due to higher rate of MDR Pseudomonas aeruginosa. CONCLUSION: In patients with a high probability of VAP, current but not recent antibiotic use is associated with a lower rate of positive culture with a higher proportion of MDR pathogens, mostly MDR Pseudomonas aeruginosa. PMID- 29113713 TI - Update: Role of surgery in acute necrotizing pancreatitis. AB - Acute necrotizing pancreatitis is a prevalent disease with high morbidity and mortality. The development of radiologic and endoscopic techniques to manage pancreatic necrosis commands a multidisciplinary approach, which has considerably decreased the need for laparotomy. The objective of this update is to define the role of surgery in the multidisciplinary approach to management of necrotizing acute pancreatitis. PMID- 29113714 TI - Laparoscopic versus open colectomy for obstructing right colon cancer: A systematic review and meta-analysis. AB - BACKGROUND: Hemicolectomy is the treatment of choice for intestinal obstruction from right colon cancer. This review compares the laparoscopic vs open access in hemicolectomy for patients with right colon cancer. METHODS: A systematic review and meta-analysis of clinical studies published after January 2017 was performed according to the Prisma guidelines. The study has been recorded on the Prospero register (CRD42016044108). RESULTS: Five studies were included for review. Only one anastomotic leak was reported in conventional open anastomosis group (1.9%) and none of the studies included in the meta-analysis reported re-operations during the first 30 postoperative days. The 30-day postoperative mortality did not differ between the two groups. The length of incision, blood loss, early mobilization after surgery, the 30-day postoperative overall complication rate and hospital length of stay were significantly shorter in the laparoscopic group. The difference in the duration of procedure was statistically significant in favor of the open group. The number of dissected lymph nodes, the overall survival at 5 years and time to flatus were described only in one study, without any significant difference. Finally, none of the trials reported any information concerning differences in the costs between the two techniques. CONCLUSIONS: The better outcomes described in this study achieved with laparoscopy, must be interpreted with caution because of the small number of patients involved, the selection and publication bias and the low level of evidence of the analysed trials. Indeed, the advantages of a minimally invasive approach, which have been demonstrated by the present meta-analysis, should encourage the use of laparoscopy also in emergency setting. PMID- 29113715 TI - Abdominal foreign body textiloma: Imaging and operative appearance. PMID- 29113716 TI - Plethysmography variability index for prediction of fluid responsiveness during graded haemorrhage and transfusion in sevoflurane-anaesthetized mechanically ventilated dogs. AB - OBJECTIVE: To examine the accuracy of plethysmography variability index (PVI) as a noninvasive indicator of fluid responsiveness in hypovolaemic dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: Six adult healthy sevoflurane anaesthetized Beagle dogs. METHODS: Dogs were anaesthetized with 1.3-fold their individual minimum alveolar concentration of sevoflurane. The lungs were mechanically ventilated after neuromuscular blockade with vecuronium bromide. Cardiopulmonary variables including mean arterial blood pressure (MAP), central venous pressure (CVP), transpulmonary thermodilution cardiac output (TPTDCO), stroke volume (SV), perfusion index (PI), pulse pressure variation (PPV), stroke volume variation (SVV) and PVI were determined during six stages of graded venous blood withdrawal (5 mL kg-1 increments) and six stages of graded blood infusion (5 mL kg-1 increments). The cardiopulmonary variables were analysed using paired t test or Wilcoxon signed rank test. Correlations between PPV and SVV or PVI were analysed by linear regression. The accuracy of PPV, SVV and PVI for predicting fluid responsiveness was examined by using receiver operating characteristic curve analysis. A value of p < 0.05 was considered statistically significant. RESULTS: Blood withdrawal resulted in significant increases in PPV and PVI and decreases in MAP, CVP, TPTDCO, SV and PI. Blood infusion resulted in significant increases in MAP, CVP, TPTDCO, SV and PI and decreases in PPV and PVI. PPV and PVI showed a relevant correlation (p < 0.001, r2 = 0.62) and threshold values of PPV >= 16% (sensitivity 71%, specificity 82%) and PVI >= 12% (sensitivity 78%, specificity 72%) for identifying fluid responsiveness. SVV did not change. CONCLUSIONS AND CLINICAL RELEVANCE: Noninvasive measurement of PVI predicted fluid responsiveness with moderate accuracy equal to PPV in sevoflurane anaesthetized mechanically ventilated dogs. Provisional threshold values for identification of fluid responsiveness were PPV >= 16% and PVI >= 12%. Clinical trials are needed to confirm these threshold values in dogs. PMID- 29113717 TI - Risk factors for perinatal cardiac complications in pregnancy with pulmonary hypertension. AB - OBJECTIVE: To analyze the risk factors for complications in pregnancy associated with pulmonary hypertension (PH) and to develop a logistic regression model to predict cardiac outcomes. METHODS: A retrospective analysis was performed on 249 women with PH, who were followed at the Beijing Anzhen Hospital, Affiliated to the Capital Medical University, from January 2012 to March 2015. All pregnancies were recorded. Overall, 214 cases of pulmonary arterial hypertension were identified. Univariate analysis and multivariate analysis were performed to determine the risk factors occurring during or after pregnancy in women with PH. Ultimately, six independent risk factors for cardiac events were determined. RESULTS: There were 70 cases of cardiac complications (28.1%) with PH, including 7 cases of maternal death (2.81%). Independent risk factors were rapid progression of symptoms [OR=3.044, 95%CI (1.042-8.895), P<0.05], brain natriuretic peptide (BNP) plasma levels >=300pg/mL [OR=5.543, 95%CI (1.403 21.896), P<0.05], severe pulmonary hypertension (PAP>=80mmHg, 1mmHg=0.133kPa) [OR=6.769, 95%CI (2.748-16.677), P<0.05], World Health Organization functional class (WHO-FC) III-IV [OR=6.053, 95%CI (2.638-13.886), P<0.05], PH pre-pregnancy [OR=5.434, 95%CI (1.298-22.738), P<0.05], and delivery >=28weeks gestation [OR=10.876, 95%CI (3.957-29.893), P<0.05]. CONCLUSIONS: Early advice on contraception for patients with PH, and the need for patients to undergo a comprehensive assessment of cardiac function pre-pregnancy are suggested from the results of the present study. PMID- 29113718 TI - Pregnancy outcomes in women with previous gestational hypertension: A cohort study to guide counselling and management. AB - OBJECTIVES: In pregnant women with previous gestational hypertension: to compare the prevalence of preeclampsia as defined by the 2001 versus the 2014 International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria, to determine the rates of fetal growth restriction (FGR) as defined, not only by birthweight centile, but in combination with fetal ultrasound studies and, finally, to determine rates of other related outcomes such as gestational diabetes (GDM) and obstetric cholestasis (OC). STUDY DESIGN: This was a retrospective observational study based at the Antenatal Hypertension Clinic, Kings College Hospital, London. Routinely collected data of 773 women booked between 2011 and 2016 with a history of gestational hypertension was analysed. All women were normotensive at booking and those with chronic hypertension were excluded. MAIN OUTCOMES MEASURES: Hypertensive disorders of pregnancy (ISSHP 2014), FGR, GDM. RESULTS: Forty-nine percent developed one or more pregnancy complications, of which 72% were hypertensive disorders of pregnancy, 25.8% preeclampsia, 25% GDM and 19% FGR. Overall recurrence rate of preeclampsia was 12.5% (ISSHP-2014). Higher blood pressure and body mass index at booking were associated with higher risk of preeclampsia and GDM. Earlier gestation of previous hypertension was associated with higher risk of preeclampsia and FGR. The ISSHP-2014 compared to the 2001 guidelines classified 56% more women as having preeclampsia. CONCLUSION: Pregnant women with a history of gestational hypertension have a 49% chance of developing a complication related to a hypertensive disorder, GDM and OC. The rate of preeclampsia was more than doubled if the updated ISSHP-2014 definition was used. PMID- 29113719 TI - Utilization of independent component analysis for accurate pathological ripple detection in intracranial EEG recordings recorded extra- and intra-operatively. AB - OBJECTIVE: To develop and validate a detector that identifies ripple (80-200 Hz) events in intracranial EEG (iEEG) recordings in a referential montage and utilizes independent component analysis (ICA) to eliminate or reduce high frequency artifact contamination. Also, investigate the correspondence of detected ripples and the seizure onset zone (SOZ). METHODS: iEEG recordings from 16 patients were first band-pass filtered (80-600 Hz) and Infomax ICA was next applied to derive the first independent component (IC1). IC1 was subsequently pruned, and an artifact index was derived to reduce the identification of high frequency events introduced by the reference electrode signal. A Hilbert detector identified ripple events in the processed iEEG recordings using amplitude and duration criteria. The identified ripple events were further classified and characterized as true or false ripple on spikes, or ripples on oscillations by utilizing a topographical analysis to their time-frequency plot, and confirmed by visual inspection. RESULTS: The signal to noise ratio was improved by pruning IC1. The precision of the detector for ripple events was 91.27 +/- 4.3%, and the sensitivity of the detector was 79.4 +/- 3.0% (N = 16 patients, 5842 ripple events). The sensitivity and precision of the detector was equivalent in iEEG recordings obtained during sleep or intra-operatively. Across all the patients, true ripple on spike rates and also the rates of false ripple on spikes, that were generated due to filter ringing, classified the seizure onset zone (SOZ) with an area under the receiver operating curve (AUROC) of >76%. The magnitude and spectral content of true ripple on spikes generated in the SOZ was distinct as compared with the ripples generated in the NSOZ (p < .001). CONCLUSIONS: Utilizing ICA to analyze iEEG recordings in referential montage provides many benefits to the study of high-frequency oscillations. The ripple rates and properties defined using this approach may accurately delineate the seizure onset zone. SIGNIFICANCE: Strategies to improve the spatial resolution of intracranial EEG and reduce artifact can help improve the clinical utility of HFO biomarkers. PMID- 29113720 TI - Spanish Cardiac Catheterization and Coronary Intervention Registry. 26th Official Report of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology (1990-2016). AB - INTRODUCTION AND OBJECTIVES: The Working Group on Cardiac Catheterization and Interventional Cardiology presents its annual report on the activity data for 2016. METHODS: All Spanish hospitals with catheterization laboratories were invited to voluntarily contribute their activity data. The information was collected online and was analyzed mainly by an independent company. RESULTS: In 2016, 106 centers participated in the national registry; 80 of these centers are public. A total of 154 362 diagnostic studies were carried out, of which 135 332 were coronary angiograms. These figures are 14% higher than in previous years. The Spanish average of total diagnostic procedures per million population was 3322 (3.127 in 2015). The number of coronary interventional procedures was 7% higher than in the previous year: 68 695 (67 671 in 2015) and, although multivessel treatment decreased by 3%, unprotected left main trunk treatment increased by 9.4%. A total of 104 628 stents were implanted, of which 88 344 (84.4%) were drug-eluting stents (10% higher than in 2015) and 1610 were bioresorbable scaffolds. A total of 20 588 interventional procedures were performed in the acute myocardial infarction setting (10% increase), of which 83.7% were primary angioplasties. The radial approach was used in 74.2% of the diagnostic procedures, similar to the previous year, and in 82.6% of interventional procedures (7% increase). The number of transcatheter aortic valve implantations continued to increase (28% increase, n = 2026), as did the number of percutaneous mitral valve repair procedures (MitraClip) (45% increase, n = 232) and left atrial appendage closures (48.5% increase, n = 496). CONCLUSIONS: The number of diagnostic and therapeutic procedures in acute myocardial infarction increased in 2016. The use of the radial approach and drug-eluting stents also increased in therapeutic procedures. The growing trend observed in previous years continued for the use of transcatheter aortic prosthesis, the MitraClip device, and left atrial appendage closure. PMID- 29113721 TI - Prognostic factors and optimal therapy for stages I-II neuroendocrine carcinomas of the uterine cervix: A multi-center retrospective study. AB - PURPOSE: We aimed to determine appropriate treatment guidelines for patients with stages I-II high-grade neuroendocrine carcinomas (HGNEC) of the uterine cervix in a multicenter retrospective study. PATIENTS AND METHODS: We reviewed the clinicopathological features and prognoses of 93 patients with HGNEC of International Federation of Gynecology and Obstetrics (FIGO) stages I and II. All patients were diagnosed with HGNEC by central pathological review. RESULTS: The median overall survival (OS) and disease-free survival (DFS) were 111.3months and 47.4months, respectively. Eighty-eight patients underwent radical surgery, and five had definitive radiotherapy. The hazard ratio (HR) for death after definitive radiotherapy to death after radical surgery was 4.74 (95% confidence interval [CI], 1.01-15.90). Of the surgery group, 18 received neoadjuvant chemotherapy. Pathological prognostic factors and optimal adjuvant therapies were evaluated for the 70 patients. Forty-one patients received adjuvant chemotherapy with etoposide-platinum (EP) or irinotecan-platinum (CPT-P). Multivariate analyses identified the invasion of lymphovascular spaces as a significant prognostic factor for both OS and DFS. Pelvic lymph node metastasis was also a prognostic factor for DFS. Adjuvant chemotherapy with an EP or CPT-P regimen appeared to improve DFS (HR=0.27, 95% CI, 0.10-0.69). A trend toward improved OS was also observed, but was not statistically significant (HR=0.39, 95% CI, 0.15 1.01). CONCLUSION: Radical surgery followed by adjuvant chemotherapy with an EP or CPT-P regimen was optimal treatment for stages I and II HGNEC of the uterine cervix. PMID- 29113723 TI - Association between Fruit and Vegetable Consumption and Risk of Hypertension in Middle-Aged and Older Korean Adults. AB - BACKGROUND: High fruit and vegetable (F/V) intake may be beneficial for hypertension prevention. However, a prospective association has not been investigated in a Korean population, and differences exist between typical diets in Korea and those of Western populations. OBJECTIVE: The aim of this prospective study was to investigate the association between F/V intake and risk of incident hypertension in middle-aged and older Korean adults using the data from the Korean Genome and Epidemiology Study (KoGES). DESIGN: The KoGES is a large community-based cohort study of Korean adults aged 40 to 69 years, which began in May 2001. Questionnaires on demographic information and lifestyle factors were completed at baseline. Anthropometrics and biochemical measurements were conducted biennially. Fruit and vegetable consumption was assessed with a semiquantitative food frequency questionnaire. Hypertension was defined as a systolic blood pressure>=140 mm Hg or diastolic blood pressure >=90 mm Hg. PARTICIPANTS AND SETTING: A total of 4,257 participants (2,085 men, 2,172 women) without hypertension at baseline were evaluated. MAIN OUTCOME MEASURES: The primary outcome was incident hypertension. STATISTICAL ANALYSIS PERFORMED: Multivariate Cox proportional hazard models were used to examine hazard ratios (HRs) and 95% CIs for incident hypertension according to F/V consumption. RESULTS: During the 8-year follow-up, 1,158 participants (606 men and 552 women) developed hypertension. Among men, frequent fruit consumers (>=4 servings/day) had a 56% lower risk of incident hypertension than did infrequent consumers (<1 serving/day) (HR=0.44, 95% CI=0.32 to 0.60, P for trend <0.0001). Among women, frequent fruit consumers had a 67% lower risk of incident hypertension than did infrequent consumers (HR=0.33, 95% CI=0.24 to 0.45, P for trend <0.0001), after adjustment for potential confounders. However, there was no association between vegetable consumption and risk of incident hypertension in either men or women. CONCLUSION: A higher intake of fruit was prospectively associated with a lower risk of incident hypertension in middle-aged and older Korean adults, regardless of sex. PMID- 29113722 TI - The landscape of somatic mutations in Indonesian cervical cancer is predominated by the PI3K pathway. AB - OBJECTIVE: To investigate the prevalence of somatic mutations in Indonesian cervical carcinoma patients in the context of histology and human papillomavirus (HPV) type. METHODS: In total 174 somatic hot-spot mutations in 13 genes were analyzed by mass spectrometry in 137 Indonesian cervical carcinomas. RESULTS: In 66/137 tumors (48%) 95 mutations were identified. PIK3CA was most frequently mutated (24%), followed by FBXW7 (7%), CTNNB1 (6%), and PTEN (6%). In squamous cell carcinomas more often multiple mutations per sample (p=0.040), and more PIK3CA (p=0.039) and CTNNB1 (p=0.038) mutations were detected compared to adenocarcinomas. PIK3CA mutations were associated with HPV 16 positivity, CDKN2A mutations with HPV 52 positivity, and, interestingly, PTEN mutations with HPV negativity. Balinese tumor samples more often carried multiple mutations (p=0.019), and more CTNNB1, CDKN2A, and NRAS mutations compared to Javanese tumor samples. CONCLUSIONS: Potentially targetable somatic mutations occurred in 48% of Indonesian cervical carcinomas. The landscape of mutations is predominated by mutations concerning the PI3K pathway, and we prompt for more research on developing therapies targeting this pathway, explicitly for the more advanced stage cervical carcinoma patients. PMID- 29113724 TI - Imaging with ultra-small-angle X-ray scattering using a Laue-case analyzer and its application to human breast tumors. AB - PURPOSE: In this study, we demonstrate a novel imaging technique, based on ultra small-angle X-ray scattering (USAXS) that uses a Laue-case Si wafer as the angle analyzer. METHODS: We utilized the (1 1 1) diffraction plane of a 356 MUm thick, symmetrically cut Si wafer as the angle analyzer, denoted by A[L]. With this device, we performed USAXS imaging experiments using 19.8 keV synchrotron X-rays. The objects we imaged were formalin-fixed, paraffin-embedded breast tumors (an invasive carcinoma and an intraductal papilloma). During image acquisition by a charge-coupled device (CCD) camera, we varied the rotation angle of the analyzer in 0.02" steps from -2.40" to +2.40" around the Bragg angle. The exposure time for each image was 2 s. We determined the amount of ultra-small-angle X-ray scattering from the width of the intensity curve obtained for each local pixel during the rotation of the analyzer. RESULTS: We acquired USAXS images of malignant and benign breast tumor specimens using the A[L] analyzer; regions with larger USAXS form brighter areas in the image. We varied the sensitivity of the USAXS image by changing the threshold level of the object rocking curve. CONCLUSIONS: The USAXS images can provide information about the internal distribution of closely packed scattering bodies in a sample with reasonable sensitivity. This information differs from that obtainable through refraction contrast imaging. Although further validation studies will be necessary, we conclude that USAXS imaging using a Laue-case analyzer may have significant potential as a new diagnosis technique. PMID- 29113725 TI - Hormonal induction of ovulation using OvaprimTM [(D-Arg6, Pro9NEt) sGnRH+domperidone] and its impact on embryonic development of wild-caught Longspine scraper, Capoeta trutta (Heckel, 1843). AB - Knowledge of gamete quality is a prerequisite for developing techniques to fertilize eggs and rear offspring for hatchery production. Our objective was to develop assisted reproductive techniques, via hormonal induction of final oocyte maturation (FOM), for Longspine scraper, Capoeta trutta. Fish were administered injections of salmon gonadotropin-releasing hormone analogue containing anti dopaminergic drug (OvaprimTM) or saline (control). Effects of Ovaprim on induction of ovulation, gamete quality, embryonic development, and larval survival were later examined with serum steroid hormone levels and ovarian histology. The saline group failed to spawn, whereas Ovaprim accelerated FOM and induced spawning. Fish treated with Ovaprim showed an increase in gonadosomatic index, egg diameter, and wet weight relative to controls. Average absolute fecundity, relative fecundity, fertilization, and hatching rates were 8823 eggs/spawn, 53 eggs/g body weight, 95%, and 91%, respectively. Serum 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) levels were significantly enhanced by ~4-fold in Ovaprim-treated fish compared to the saline-injected fish, while 17beta-estradiol levels declined upon FOM in hormone treated fish. Embryonic development closely resembled the teleost scheme, despite variations in timing. Larval survival at 6 and 12days post-hatch were 98% and 95%, respectively. Results suggest that Ovaprim is efficient for inducing spawning in C. trutta for stock enhancement or hatchery purposes. PMID- 29113726 TI - Expression of tissue-specific imprinted gene tumor Suppressing Subtransferable Candidate 4 (TSSC4) is altered in placentae produced by nuclear transfer in cattle. AB - Embryonic and placental development is highly orchestrated by epigenetic processes. Disruptions in normal placental development, commonly observed in pregnancies produced by nuclear transfer, are associated with abnormal gene expression and altered epigenetic regulation of imprinted and vital placental genes. The objective of this study was to evaluate expression and epigenetic regulation of the imprinted gene TSSC4 in cotyledonary and intercotyledonary tissues from day 60 pregnancies produced by embryo transfer (ET), in vitro fertilization (IVF) and nuclear transfer (NT) in cattle. TSSC4 expression was reduced by 30% in cotyledons at 60days of gestation in the NT group. The proximal promoter region of TSSC4 showed an increase in the permissive histone mark (H3K4me2) and a reduction in the inhibitory histone mark (H3K9me2) in the cotyledons produced by NT, in relation to cotyledons produced by embryo transfer. Interestingly, H3K9me2 was also significantly reduced in cotyledons produced by IVF, compared to the ET controls. DNA methylation, in CpG-rich regions located at the proximal promoter region and the coding region of TSSC4 did not differ. These results suggest that the reduction in TSSC4 expression, observed following NT, can not be explained by the histone changes investigated in the proximal promoter region of the gene, or by changes in methylation in three regions evaluated. Also, a decrease in the levels of H3K9 dimethylation in IVF samples, indicate that in vitro culturing could corroborate with the alterations seen in the NT group. PMID- 29113727 TI - Effect of Single Layer Centrifugation Porcicoll (70%, 80% and 90%) or supplementation with reduced glutathione, seminal plasma and bovine serum albumin on frozen-thawed boar sperm. AB - Selecting the optimal sperm population is essential for success with reproductive techniques. Porcicoll (formerly Androcoll-P) is a colloid formulation for selection of high-quality boar spermatozoa by single layer centrifugation (SLC). To date, most studies have been carried out with fresh semen and large volumes. We carried out 2 experiments to test the use of Porcicoll for thawed boar semen in small volumes. In Experiment 1, cryopreserved semen doses were thawed, split in 200-MUL aliquots and layered on 1mL of Porcicoll 70%, 80% or 90%, or buffer without colloid. We assessed sperm recovery (the proportion of the loading dose that appeared in the pellet, %), and the physiology of the selected spermatozoa (flow cytometry: Viability, apoptotic changes, capacitation, mitochondrial activity, intracellular reactive oxygen species). The most suitable proportion was Porcicoll 80%, allowing acceptable sperm recovery (16.9+/-4.2%, compared to 70% (35.4%+/-3.0, p<0.001) and 90% (8.2%+/-3.0, P=0.001), and improved quality (mitochondrial activity: Porcicoll 80%: 77.7+/-1% vs Control: 60.3+/-0.7%, P<0.05). In Experiment 2, we compared 3 supplements to Porcicoll 80%: 500mM reduced glutathione (GSH), 20% seminal plasma (SP) and 0.5% bovine serum albumin (BSA). Supplementation with GSH or BSA did not cause relevant changes relative to Control. In contrast, SP induced membrane and acrosomal changes resembling capacitation, which might preclude its use in some applications, and decreased recovery (5.5%+/-1.9 vs. 24.3%+/-1.2 Control; P<0.001). However, it could be useful prior to other applications such as in vitro fertilisation. Overall, Porcicoll is an effective colloid for isolating a high-quality population from thawed boar sperm, 80% being a balanced option for good recovery and high quality. Supplements could be useful depending on the proposed use of the spermatozoa. PMID- 29113728 TI - Expanding the clinical role of community pharmacy: A qualitative ethnographic study of medication reviews in Ontario, Canada. AB - Medication reviews by community pharmacists are an increasingly common strategy to improve medication management for chronic conditions, and are part of wider efforts to make more effective use of community-based health professionals. To identify opportunities to optimize the medication review program in Ontario, Canada, we explored how providers and clients interpret and operationalize medication reviews within everyday community pharmacy practice. We conducted a qualitative ethnographic study at four pharmacies in Ontario, Canada, including non-participant observation of provider and client activities and interactions with specific attention to medication reviews, as well as brief ethnographic interviews with providers and clients, and in-depth, semi-structured interviews with providers. We report on 72h of field research, observation of 178 routine pharmacist-client interactions and 29 medication reviews, 62 brief ethnographic interviews with providers and clients, and 7 in-depth, semi-structured interviews with providers. We found that medication reviews were variably conducted across the dimensions of duration, provider type, location, and interaction style, and that local contexts and system-wide developments influence their meaning and practice. Medication reviews are exemplary of policy efforts to enhance the role of community pharmacies within health systems and the scope of practice of pharmacists as healthcare professionals. Our study highlights the importance of the local structure of community pharmacy practice and the clinical aspirations of pharmacists in the delivery of medication reviews. PMID- 29113729 TI - Intensified Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer in Elderly Patients: Toxicity, Disease Control, and Survival Outcomes. AB - INTRODUCTION: We report the treatment compliance, toxicity rates, and long-term clinical outcomes of elderly patients who received intensified neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). PATIENTS AND METHODS: We identified a retrospective cohort of patients aged >= 70 years with LARC who received intensified neoadjuvant CRT, followed by surgery and adjuvant chemotherapy, from 2007 to 2014. Intensified neoadjuvant CRT consisted of radiotherapy (total dose, 50.4/54 Gy) with concomitant oxaliplatin (50 mg/m2/wk) and 5-fluorouracil (200 mg/m2 in 5 daily continuous infusion). RESULTS: A total of 26 patients were included. All patients completed the programmed CRT. Severe acute toxicity was recorded in 19.2% of cases. Conservative surgery was performed in 16 patients, and a pathologic complete response was achieved in 19.2%. Overall, 26.9% of the patients died. The 5-year overall survival and disease-free survival rates were 70.6% and 65.5%, respectively. CONCLUSIONS: Intensified neoadjuvant CRT is an efficacious and safe treatment option for LARC in elderly patients. PMID- 29113730 TI - Conversion to Resection in Patients Receiving Systemic Chemotherapy for Unresectable and/or Metastatic Colorectal Cancer-Predictive Factors and Prognosis. AB - BACKGROUND: Systemic chemotherapy increases the possibility of resection in patients with initially unresectable colorectal cancer (CRC), especially patients with hepatic metastasis. However, the predictive factors and prognosis of conversion to resection after chemotherapy in patients with various organ metastases remain largely unknown. PATIENTS AND METHODS: We reviewed the data from metastatic CRC (mCRC) patients who had received oxaliplatin- or irinotecan based systemic chemotherapy from 2005 to 2016. The predictors for conversion to surgery were assessed by multivariate analyses. Cancer-free survival and overall survival after the initiation of treatment were compared between patients who had undergone successful conversion therapy and those who had undergone surgery first for resectable stage IV CRC. RESULTS: Of 99 mCRC patients receiving first-line chemotherapy, 23 underwent secondary surgical resection. Single organ metastasis, the presence of liver metastases, and the use of biologic agents were independent predictors of successful conversion therapy. The long-term survival of patients who underwent successful secondary surgery did not differ significantly from that of the 112 patients with resectable stage IV CRC who had undergone surgery first. CONCLUSION: Liver metastases and single organ metastasis were more likely to be resected after chemotherapy than were other metastatic lesions in mCRC. The use of biologic agents contributed to the increased conversion rate. Successful conversion resulted in outcomes similar to those of resectable stage IV CRC. PMID- 29113732 TI - Oxidative stress in ageing and disease development studied by FT-IR spectroscopy. AB - FT-IR spectroscopy was used to investigate the effect of oxidative stress and to approach the mechanism on cancer bone demineralization, aortic valve mineralization and heterotopic ossification on disease development. The FT-IR spectra obtained from paediatric, adult bone and ex vivo irradiated adult healthy bone with a dose of 20Gy were compared with those of healthy bone. The increase of band intensity changes of vasCH2,vsCH2 in the region 3000-2850cm-1 depended on aging, the disease progression and the dose of irradiation. The bands at 3080cm-1 and 1744cm-1, which originate from olefinic terminal bond (v=CH) and ester carbonyl group (vROCO), respectively, indicate the influence of oxidative stress on lipid degradation and peroxidation, respectively. The new bands at about 1690cm-1 and 1516cm-1 denote the presence of beta-sheet conformation of the proteins due to the diseases, confirming the increasing amount of lipophilic environment and fibril formation. Comparison of the FT-IR spectra of calcified aortic valve and hip heterotopic ossification with that of normal bones showed that in the bone-like formation the peroxide anion free radicals play an important role in the disease. PMID- 29113731 TI - Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. AB - BACKGROUND: Few therapeutic options are available to treat the late-stage of human African trypanosomiasis, a neglected tropical disease, caused by Trypanosoma brucei gambiense (g-HAT). The firstline treatment is a combination therapy of oral nifurtimox and intravenous eflornithine that needs to be administered in a hospital setting by trained personnel, which is not optimal given that patients often live in remote areas with few health resources. Therefore, we aimed to assess the safety and efficacy of an oral regimen of fexinidazole (a 2-substituted 5-nitroimidazole with proven trypanocidal activity) versus nifurtimox eflornithine combination therapy in patients with late-stage g HAT. METHODS: In this randomised, phase 2/3, open-label, non-inferiority trial, we recruited patients aged 15 years and older with late-stage g-HAT from g-HAT treatment centres in the Democratic Republic of the Congo (n=9) and the Central African Republic (n=1). Patients were randomly assigned (2:1) to receive either fexinidazole or nifurtimox eflornithine combination therapy according to a predefined randomisation list (block size six). The funder, data management personnel, and study statisticians were masked to treatment. Oral fexinidazole was given once a day (days 1-4: 1800 mg, days 5-10: 1200 mg). Oral nifurtimox was given three times a day (days 1-10: 15 mg/kg per day) with eflornithine twice a day as 2 h infusions (days 1-7: 400 mg/kg per day). The primary endpoint was success at 18 months (ie, deemed as patients being alive, having no evidence of trypanosomes in any body fluid, not requiring rescue medication, and having a cerebrospinal fluid white blood cell count <=20 cells per MUL). Safety was assessed through routine monitoring. Primary efficacy analysis was done in the modified intention-to-treat population and safety analyses in the intention-to treat population. The acceptable margin for the difference in success rates was defined as 13%. This study has been completed and is registered with ClinicalTrials.gov, number NCT01685827. FINDINGS: Between October, 2012, and November, 2016, 419 patients were pre-screened. Of the 409 eligible patients, 14 were not included because they did not meet all inclusion criteria (n=12) or for another reason (n=2). Therefore, 394 patients were randomly assigned, 264 to receive fexinidazole and 130 to receive nifurtimox eflornithine combination therapy. Success at 18 months was recorded in 239 (91%) patients given fexinidazole and 124 (98%) patients given nifurtimox eflornithine combination therapy, within the margin of acceptable difference of -6.4% (97.06% CI -11.2 to 1.6; p=0.0029). We noted no difference in the proportion of patients who experienced treatment-related adverse events (215 [81%] in the fexinidazole group vs 102 [79%] in the nifurtimox eflornithine combination therapy group). Treatment discontinuations were unrelated to treatment (n=2 [1%] in the fexinidazole group). Temporary nifurtimox eflornithine combination therapy interruption occurred in three (2%) patients. 11 patients died during the study (nine [3%] in the fexinidazole group vs two [2%] in the nifurtimox eflornithine combination therapy group). INTERPRETATION: Our findings show that oral fexinidazole is effective and safe for the treatment of T b gambiense infection compared with nifurtimox eflornithine combination therapy in late-stage HAT patients. Fexinidazole could be a key asset in the elimination of this fatal neglected disease. FUNDING: Drugs for Neglected Diseases initiative. PMID- 29113733 TI - Development and evaluation of a novel real-time RT-PCR to detect foot-and-mouth disease viruses from the emerging A/ASIA/G-VII lineage. AB - A new lineage of foot-and-mouth disease virus (FMDV), called A/ASIA/G-VII, emerged from the Indian subcontinent in 2015 and continues to spread in Western Asia. Currently, the distribution of viruses belonging to this lineage is defined using sequencing approaches, but other cheaper and faster diagnostic methods are urgently needed. Thus, this study describes the development and validation of a novel A/ASIA/G-VII lineage-specific real-time RT-PCR (rRT-PCR). Diagnostic sensitivity and specificity were evaluated using representative field specimens and isolates from the A/ASIA/G-VII lineage, as well as samples comprising other FMDV lineages that co-circulate in Asia (n=54). This lineage-specific assay accurately detected all A/ASIA/G-VII samples tested (n=29), and no detection was observed for samples belonging to other FMDV lineages (n=25), namely A/ASIA/Sea 97, A/ASIA/Iran-05SIS-10, A/ASIA/Iran-05FAR-11, Asia1/ASIA/Sindh-08, O/CATHAY, O/ME-SA/PanAsia-2ANT-10, O/ME-SA/Ind-2001d, O/SEA/Mya-98. Additionally, the limit of detection was found to be at least equivalent to a pan-serotypic rRT-PCR assay. Therefore, these data indicate that this newly developed rRT-PCR assay can be applied to characterise field isolates in countries where the A/ASIA/G-VII lineage is endemic, as well as to monitor new incursions and outbreaks due to this lineage. PMID- 29113734 TI - Cellular responses of human astrocytoma cells to dust from the Acheson process: An in vitro study. AB - Silicon carbide (SiC) is largely used in various products such as diesel particulate filters and solar panels. It is produced through the Acheson process where aerosolized fractions of SiC and other by-products are generated in the work environment and may potentially affect the workers' health. In this study, dust was collected directly on a filter in a furnace hall over a time period of 24h. The collected dust was characterized by scanning electron microscopy and found to contain a high content of graphite particles, and carbon and silicon containing particles. Only 6% was classified as SiC, whereof only 10% had a fibrous structure. To study effects of exposure beyond the respiratory system, neurotoxic effects on human astrocytic cells, were investigated. Both low, occupationally relevant, and high doses from 9E-6MUg/cm2 up to 4.5MUg/cm2 were used, respectively. Cytotoxicity assay indicated no effects of low doses but an effect of the higher doses after 24h. Furthermore, investigation of intracellular reactive oxygen species (ROS) indicated no effects with low doses, whereas a higher dose of 0.9MUg/cm2 induced a significant increase in ROS and DNA damage. In summary, low doses of dust from the Acheson process may exert no or little toxic effects, at least experimentally in the laboratory on human astrocytes. However, higher doses have implications and are likely a result of the complex composition of the dust. PMID- 29113735 TI - C-reactive protein concentration as a prognostic factor for inflammation in the management of odontogenic infections. AB - Our aim was to find out if it is possible to correlate the duration of stay in hospital, the severity of infection, involvement of particular anatomical spaces, white cell count, efficacy of surgical treatment, and fever with C-reactive protein (CRP) concentrations on admission. One hundred patients met our inclusion criteria. After their notes had been examined they were subdivided according to whether the infection of the main facial space involved was less severe, moderately severe, or very severe. The relations between degree of severity and CRP concentration on admission (<100mg/L compared with 100+), age (years), sex, and duration of hospital stay (days) were examined using Poisson regression (because the distribution of characteristics, and particularly the duration of stay, were skewed). The overall model was significant (p=0.003). Pearson and deviance chi square tests did not indicate overdispersion (p=0.97 in both cases), which suggested that the assumptions about the Poisson distribution were valid. Log-rank chi square tests indicated that only severity had a significant effect (p=0.0001), and C-reactive protein concentration was not significantly associated with group on admission, age, or sex. The moderately and very severe groups had longer median (range) durations of stay than the less severe group (5 (2-8) compared with 3 (1-8) days, respectively). CRP concentration was not a prognostic factor for the extent of odontogenic infections or presumed duration of stay, but severity scoring was a significant factor in the prediction of duration of stay in hospital. PMID- 29113736 TI - Erratum to "Descendens vagohypoglossi: rare variant of the superior root of ansa cervicalis" [Br J Oral Maxillofac Surg 55 (2017) 834-5]. PMID- 29113738 TI - Quantitative PCR assessment of Lotmaria passim in Apis mellifera colonies co infected naturally with Nosema ceranae. AB - A recently described trypanosomatid species Lotmaria passim and the microsporidium Nosema ceranae infect the honey bee (Apis mellifera), but the interspecific dynamic of these two common gut parasites is unknown. In this study, a real-time qPCR assay was developed to enable the specific detection and quantification of L. passim. The annual dynamics of N. ceranae and L. passim infections were evaluated in ten A. mellifera colonies naturally infected with both parasites at one apiary in Serbia from March 2016 to March 2017. Ten samples (60 bees abdomens) were taken from each colony on 8 sampling occasions. L. passim infection level was evaluated with qPCR, while N. ceranae infection was measured by spore counts. N. ceranae infection level was significantly higher in comparison with that of L. passim (spore or cell equivalents/bee, respectively). Significant positive correlation between infection levels of the parasite species indicates their similar annual dynamics, whilst the differences in the levels of infection between particular months point to a seasonal pattern in the incidence of both parasites. The assay which has been developed and validated creates opportunity for detailed study of L. passim infection kinetics and the improvement in the management practices in beekeeping related to these two parasites. PMID- 29113737 TI - Voluntary alcohol intake after noise exposure in adolescent rats: Hippocampal related behavioral alterations. AB - Different physical or chemical agents, such as noise or alcohol, can induce diverse behavioral and biochemical alterations. Considering the high probability of young people to undergo consecutive or simultaneous exposures, the aim of the present work was to investigate in an animal model if noise exposure at early adolescence could induce hippocampal-related behavioral changes that might be modified after alcohol intake. Male Wistar rats (28-days-old) were exposed to noise (95-97 dB, 2 h). Afterwards, animals were allowed to voluntarily drink alcohol (10% ethanol in tap water) for three consecutive days, using the two bottle free choice paradigm. After that, hippocampal-related memory and anxiety like behavior tests were performed. Results show that whereas noise-exposed rats presented deficits in habituation memory, those who drank alcohol exhibited impairments in associative memory and anxiety-like behaviors. In contrast, exposure to noise followed by alcohol intake showed increases in exploratory and locomotor activities as well as in anxiety-like behaviors, unlike what was observed using each agent separately. Finally, lower levels of alcohol intake were measured in these animals when compared with those that drank alcohol and were not exposed to noise. Present findings demonstrate that exposure to physical and chemical challenges during early adolescence might induce behavioral alterations that could differ depending on the schedule used, suggesting a high vulnerability of rat developing brain to these socially relevant agents. PMID- 29113739 TI - Structural insights into the interaction of a monoclonal antibody and Nodal peptides by STD-NMR spectroscopy. AB - Nodal is a growth factor expressed during early embryonic development, but reactivated in several advanced-stage cancers. Targeting of Nodal signaling, which occurs via the binding to Cripto-1 co-receptor, results in inhibition of cell aggressiveness and reduced tumor growth. The Nodal binding region to Cripto 1 was identified and targeted with a high affinity monoclonal antibody (3D1). By STD-NMR technique, we investigated the interaction of Nodal fragments with 3D1 with the aim to elucidate at atomic level the interaction surface. Data indicate with high accuracy the antibody-antigen contact atoms and confirm the information previously obtained by immune-enzymatic methods. Main residues contacted by 3D1 are P46, V47, E49 and E50, which belong to the Nodal loop involved in the interaction with the co-receptor. PMID- 29113740 TI - Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis. AB - Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination. Dosages of pritelivir from 0.3 to 30 mg/kg reduced mortality (P < 0.001) against HSV-1, E-377. With an acyclovir resistant HSV-1, 11360, pritelivir at 1 and 3 mg/kg increased survival (P < 0.005). With HSV-2, MS infected mice, all dosages higher than the 0.3 mg/kg dose of pritelivir were effective (P < 0.005). For acyclovir resistant HSV-2, strain 12247, pritelivir dosages of 1-3 mg/kg significantly improved survival (P < 0.0001). Combination therapies of pritelivir at 0.1 or 0.3 mg/kg/dose with acyclovir (10 mg/kg/dose) were protective (P < 0.0001) when compared to the vehicle treated group against HSV-2, strain MS (in line with previous data using HSV-1). An increased mean days to death (P < 0.05) was also observed and was indicative of a potential synergy. Pharmacokinetic studies were performed to determine pritelivir concentrations and a dose dependent relationship was found in both plasma and brain samples regardless of infection status or time of initiation of dosing. In summary, pritelivir was shown to be active when treatment was delayed to 72 h post viral inoculation and appeared to synergistically inhibit mortality in this model in combination with acyclovir. We conclude pritelivir has potent and resistance-breaking antiviral efficacy with potential for the treatment of potentially life-threatening HSV type 1 and 2 infections, including herpes simplex encephalitis. PMID- 29113741 TI - Low serum CTRP3 levels are associated with nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. AB - Nonalcoholic fatty liver disease (NAFLD) commonly occurs in patients with type 2 diabetes mellitus (T2DM). C1q/TNF-related protein-3 (CTRP3) levels are decreased in type 2 diabetic patients. However, to date, it is unknown whether low CTRP3 level are correlated with the incidence of NAFLD. The aim of this study was to observe this association in Chinese patients with T2DM. Overall, 175 newly diagnosed T2DM were recruited in this study. The subjects were divided into NAFLD group (n=93) and control group (n=82). Anthropometric parameters, blood pressure, and several biochemical parameters were measured. The body composition was assessed with the bioelectrical impedance analysis (BIA) method. Insulin level was evaluated by radioimmunoassay. Levels of serum CTRP3 and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay. Our findings demonstrated that type 2 diabetic patients with NAFLD had lower levels of serum CTRP3 than did those without NAFLD (P=.002). Serum CTRP3 level was negatively correlated with body mass index (r=-0.271, P=.001), visceral fat area (r=-0.285, P<.001), glycosylated hemoglobin A1c (r=-0.270, P<.001), triglycerides (r=-0.267, P<.001), CRP (r=-0.222, P=.010), IL-6 (r=-0.212, P=.008), and HOMA-IR indices (r=-0.334, P<.001). When compared with the highest CTRP3 tertile, the odds ratio of the middle tertile for NAFLD incidence was 4.54 (95% CI, 1.53-13.47) and 5.80 (95% CI, 1.60-21.02) for the lowest tertile after adjustment for confounding factors. In summary, low serum CTRP3 is a strong predictor for the prevalence of NAFLD in Chinese patients with newly diagnosed T2DM. PMID- 29113742 TI - Change in choroidal thickness after intravitreal injection for treatment of neovascular age-related macular degeneration: Ranibizumab versus aflibercept. AB - PURPOSE: To compare the changes in subfoveal choroidal thickness after intravitreal ranibizumab or aflibercept injections for neovascular age-related macular degeneration (nAMD). METHODS: In this retrospective study, 28 eyes with nAMD treated with 3 consecutive monthly injections of ranibizumab (IVR) and 24 eyes with nAMD treated with 3 consecutive monthly injections of aflibercept (IVA) between September 2012 and June 2016 were reviewed. The follow-up time was 6 months. Changes in two groups' best-corrected visual acuity (BCVA) and subfoveal choroidal thickness by using enhanced depth imaging optical coherence tomography at 1st, 3rd and 6th months were recorded and compared. RESULTS: Choroidal thickness decreased significantly in eyes treated with IVR (P=0.015, 0.01 and 0.01, respectively) or IVA (P=0.001, 0.001 and ?0.001, respectively) at 1, 3 and 6 months examination but IVA treated eyes presented a significantly further reduction in choroidal thickness when compared with ranibizumab (P=0.03, 0,04 and 0.03, respectively). There was no significant difference between aflibercept and ranibizumab group when change in BCVA from baseline compared at 1, 3 and 6th months (P=0.54, 0.06 and 0.37, respectively). There was no correlation between change in choroidal thickness and the BCVA outcomes in either group. CONCLUSIONS: Subfoveal choroidal thickness decreased significantly after both of IVR and IVA injections in patients with nAMD. In conclusion, intravitreal injections of ranibizumab or aflibercept affect not only neovascular lesion but also the underlying choroid. PMID- 29113743 TI - [Retinal sequellae of Behcet disease on ultra wide field photography]. PMID- 29113744 TI - Corrigendum to "Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity" [Eur. J. Med. Chem. 55 (2012) 220-227]. PMID- 29113745 TI - Synthesis and preliminary antiproliferative activity of new pteridin-7(8H)-one derivatives. AB - Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8H)-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC50 values of 4.32 and 7.01 MUM, respectively. Besides, compound 12 induced morphological changes and apoptosis of MKN-45 cells, increased expression of Bax, down regulated expression of Bcl-2 and caused cleavage of caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7H-purine-8 carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established. PMID- 29113746 TI - Quinoline derivatives bearing pyrazole moiety: Synthesis and biological evaluation as possible antibacterial and antifungal agents. AB - In an attempt for development of new antimicrobial agents, three series of quinoline derivatives bearing pyrazole moiety have been synthesized. The first series was synthesized through the synthesis of 4-(quinolin-2-yloxy)benzaldehyde and 4-(quinolin-2-yloxy)acetophenone and then treatment with ketone or aldehyde derivatives to afford the corresponding chalcones. Cyclization of the latter chalcones with hydrazine derivatives led to the formation of new pyrazoline derivatives. The second series was synthesized via the synthesis of 2 hydrazinylquinoline and then treatment with formylpyrazoles to afford the corresponding hydrazonyl pyrazole derivatives. The third series was synthesized through the treatment of 2-hydrazinylquinoline with ethoxyethylidene, dithioacetal and arylidene derivatives to afford the corresponding pyrazole derivatives. The synthesized compounds were evaluated for their expected antibacterial and antifungal activities; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Pyrazole derivative 13b showed better results when compared with the reference drugs as revealed from their MIC values (0.12-0.98 MUg/mL). The pyrazole derivative 13b showed fourfold potency of gentamycin in inhibiting the growth of S. flexneri (MIC 0.12 MUg/mL). Also, compound 13b showed fourfold potency of amphotericin B in inhibiting the growth of A. clavatus (MIC 0.49 MUg/mL) and C. albicans (MIC 0.12 MUg/mL), respectively. The same compound showed twofold potency of gentamycin in inhibiting the growth of P. vulgaris (MIC 0.98 MUg/mL), equipotent to the ampicillin and amphotericin B in inhibiting the growth of S. epidermidis (MIC 0.49 MUg/mL), A. fumigatus (MIC 0.98 MUg/mL), respectively. Thus, these studies suggest that quinoline derivatives bearing pyrazole moiety are interesting scaffolds for the development of novel antibacterial and antifungal agents. PMID- 29113747 TI - Differential effects of EPA, DPA and DHA on cardio-metabolic risk factors in high fat diet fed mice. AB - The aim of the present study was to assess and compare the effects of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) supplementation on lipid metabolism in 4 month-old male C57BL/6J mice fed a high-fat diet. The high-fat fed mice showed evidence of fatty liver, obesity and insulin resistance after being on the high-fat diet for 6 weeks compared with the control low-fat diet fed mice. Supplementation of the high-fat diet with either EPA, DPA or DHA prevented the fatty liver, prevented high serum cholesterol and serum glucose and prevented high liver cholesterol levels. DPA (but not EPA or DHA) was associated with a significantly improved homeostasis model assessment of insulin resistance (HOMA-IR) compared with the high-fat fed mice. Supplementation with DPA and DHA both prevented the decreased serum adiponectin levels, compared with EPA and the high-fat diet. In addition, supplementation with DPA and DHA both prevented the increased serum alanine aminotransferase (ALT) levels compared with EPA and the high-fat group, which can be attributed to down-regulation of TLR-4/NF-kappaB signaling pathway and decreasing lipogenesis in the liver. Therefore, DPA and DHA seem to exert similar effects in cardio-metabolic protection against the high-fat diet and these effects seem to be different to those of EPA. PMID- 29113748 TI - Roles for Xenopus aquaporin-3b (aqp3.L) during gastrulation: Fibrillar fibronectin and tissue boundary establishment in the dorsal margin. AB - Aquaporins and aquaglyceroporins are a large family of membrane channel proteins that allow rapid movement of water and small, uncharged solutes into and out of cells along concentration gradients. Recently, aquaporins have been gaining recognition for more complex biological roles than the regulation of cellular osmotic homeostasis. We have identified a specific expression pattern for Xenopus aqp3b (also called aqp3.L) during gastrulation, where it is localized to the sensorial (deep) layer of the blastocoel roof and dorsal margin. Interference with aqp3b expression resulted in loss of fibrillar fibronectin matrix in Brachet's cleft at the dorsal marginal zone, but not on the free surface of the blastocoel. Detailed observation showed that the absence of fibronectin matrix correlated with compromised border integrities between involuted mesendoderm and noninvoluted ectoderm in the marginal zone. Knockdown of aqp3b also led to delayed closure of the blastopore, suggesting defects in gastrulation movements. Radial intercalation was not affected in aqp3b morphants, while the data presented are consistent with impeded convergent extension movements of the dorsal mesoderm in response to loss of aqp3b. Our emerging model suggests that aqp3b is part of a mechanism that promotes proper interaction between cells and the extracellular matrix, thereby playing a critical role in gastrulation. PMID- 29113749 TI - Long non-coding RNA-ATB promotes EMT during silica-induced pulmonary fibrosis by competitively binding miR-200c. AB - Long non-coding RNAs (lncRNAs) are important signal transduction regulators that act by various patterns. However, little is known about the molecular mechanisms of lncRNA related pathways in occupational lung fibrosis. Our previous study found that epithelial-mesenchymal transition (EMT) was one of the key events in silica-induced pulmonary fibrosis. This study showed that the lncRNA-ATB promoted EMT by acting as a miR-200c sponge. miR-200c was identified by miRNA array as a potential target of lncRNA-ATB and verified by dual luciferase reporter gene together with RNA pull-down assays. Moreover, our findings demonstrated that lncRNA-ATB is abundantly expressed during EMT of lung epithelial cells, which contributes to decreased levels of miR-200c. miR-200c targeted ZEB1 to relief silicosis by blocking EMT in vivo and in vitro. The results also suggested M2 macrophages secreted transforming growth factor-beta1 (TGF-beta1) to induce EMT process by activating lncRNA-ATB in epithelial cells. Collectively, silica stimulated macrophages secreted TGF-beta1 to induce lncRNA-ATB in epithelia cells, promoting EMT by binding with miR-200c and releasing ZEB1. These observations provide further understanding of the regulatory network of silica induced pulmonary fibrosis and identify new therapeutic targets hopefully. PMID- 29113751 TI - Cardiomyopathy induced by incessant ventricular tachycardia originating in the vicinity of the His bundle. AB - A 04-year-old boy was referred to our institution with severe, progressive heart failure of 4-months duration associated with a persistent wide QRS tachycardia with left bundle branch block and severe left ventricular dysfunction. Because of incessant wide QRS tachycardia refractory to antiarrhythmic drugs, he was referred for electrophysiological study. The ECG was suggestive of VT arising from the right ventricle near the His area. Electrophysiological study revealed that origin of tachycardia was septum of the right ventricle, near His bundle, however the procedure was not successful and an inadvertent complete atrioventricular conduction block occurred. The same ventricular tachycardia recurred. A second procedure was performed with a retrograd aortic approach to map the left side of the interventricular septum. The earliest endocardial site for ablation was localized in the anterobasal region of left ventricle near His bundle. In this location, one radiofrequency pulse interrupted VT and rendered it not inducible. The echocardiographic evaluation showed partial reversal of left ventricular function in the first 3 months. The diagnosis was idiopathic parahisian left ventricular tachycardia leading to a tachycardia mediated cardiomyopathy, an extremely rare clinical picture in children. PMID- 29113752 TI - Region-specific glial hyperplasia and neuronal stability of rat lateral geniculate nucleus during aging. AB - The normal aging process is accompanied by functional declines in image-forming and non-image forming visual systems. Among the components of these systems, the thalamic lateral geniculate nucleus (LGN) offers a good model for aging studies since its three anatomical subdivisions, namely dorsal lateral geniculate nucleus (dLGN), intergeniculate leaflet (IGL) and ventral lateral geniculate nucleus (vLGN), receives light information from retina and projects to different brain areas involved in visual-related functions. Nevertheless, there is very little data available about quantitative morphological aspects in LGN across lifespan. In this study, we used design-based stereology to estimate the number of neurons, glial cells, the glia/neuron ratio and the volume of the LGN of Wistar rats from 3, 13 or 23months of age. We examined each LGN subdivision processed by immunohistochemistry for NeuN and Nissl counterstain. We observed no significant age-related neuronal loss in any nuclei and a 21% and 33% significant increase in dLGN and IGL glial cells of 23month-old rats. We also observed the glia/neuron relation increases in dLGN of 13month-old rats and in dLGN, IGL and vLGN internal portion of 23month-old ones. Moreover, we report an age-related increase in IGL volume. These results show region-specific glial hyperplasia during aging within LGN nuclei, perhaps due to compensatory responses to inflammation. In addition, we observed the glia/neuron ratio as a more sensitive parameter to quantify age related alterations. Hence, we provide an updated and expanded quantitative characterization of these visual-related thalamic nuclei and its variability across lifespan. PMID- 29113753 TI - Best practices for online Canadian prenatal health promotion: A public health approach. AB - BACKGROUND: Prenatal health promotion provides information regarding pregnancy risks, protective behaviours and clinical and community resources. Typically, women obtain prenatal health information from health care providers, prenatal classes, peers/family, media and increasingly, Internet sites and mobile apps. Barriers to prenatal health promotion and related services include language, rural/remote location, citizenship and disability. Online public health platforms represent the capacity to reach underserved women and can be customised to address the needs of a heterogeneous population of pregnant women. AIM: Canadian government-hosted websites and online prenatal e-classes were evaluated to determine if accessible, inclusive, comprehensive and evidence-based prenatal health promotion was provided. METHODS: Using a multijurisdictional approach, federal, provincial/territorial, municipal and public health region-hosted websites, along with affiliated prenatal e-classes, were evaluated based on four criteria: comprehensiveness, evidence-based information, accessibility and inclusivity. FINDINGS: Online prenatal e-classes, federal, provincial/territorial and public health-hosted websites generally provided comprehensive and evidence based promotion of essential prenatal topics, in contrast to municipal-hosted websites which provided very limited prenatal health information. Gaps in online prenatal health promotion were identified as lack of French and multilingual content, targeted information and representations of Indigenous peoples, immigrants and women with disabilities. CONCLUSION: Canadian online prenatal health promotion is broadly comprehensive and evidence-based, but fails to address the needs of non-Anglophones and represent the diverse population of Canadian pregnant women. It is recommended that agencies enhance the organisation of website pregnancy portals/pages and collaborate with other jurisdictions and community groups to ensure linguistically accessible, culturally-competent and inclusive prenatal online resources. PMID- 29113754 TI - Nuclear receptor HR3 controls locust molt by regulating chitin synthesis and degradation genes of Locusta migratoria. AB - During growth and development of insects, the steroid hormone 20-Hydroxyecdysone (20E) regulates the molting process through activation of a series of genes including E74, E75 and HR3 by the 20E receptor EcR. Here, we analyzed the function of LmHR3 in the migratory locust Locusta migratoria. By sequence comparison, we first identified and characterized the putative nuclear receptor protein (LmHR3) based on L. migratoria transcriptome data. The full length cDNA is 2272 bp long encoding a protein of 455 amino acids that contains a DNA binding domain (zinc finger) and a ligand binding domain. Phylogenetic analyses showed that LmHR3 has a high homology with the ortholog from Blattaria. RT-qPCR results revealed that LmHR3 has a low level expression in the early days of 5th instar nymphs, and then increases and peaks at day 6, followed by a decrease to low levels before ecdysis. The LmHR3, hence, coincides with the profile of circulating 20E levels. Indeed, we show that transcription of LmHR3 is induced by 20E in vivo, and significantly suppressed by successfully knocking down expression of LmEcR. After injection of dsRNA for LmHR3 (dsLmHR3) at day 2 of earlier instar nymphs (3rd and 4th instar) and final instar nymphs (5th instar), none of the nymphs were able to molt normally, and eventually died. Chitin staining and ultra-structural analysis showed that both the synthesis of the new cuticle and the degradation of the old cuticle were blocked in the dsLmHR3 treated nymphs. Especially, chitin synthesis genes (LmUAP1 and LmCHS1) and chitinase genes (LmCHT5 and LmCHT10) were significantly down-regulated in the dsLmHR3 treatment group. Together, our results suggest that LmHR3 is involved in the control of chitin synthesis and degradation during L. migratoria molting. PMID- 29113750 TI - Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration. AB - Epigenetic mechanisms control various functions throughout the body, from cell fate determination in development to immune responses and inflammation. Neuroinflammation is one of the prime contributors to the initiation and progression of neurodegeneration in a variety of diseases, including Alzheimer's and Parkinson's diseases. Because astrocytes are the largest population of glial cells, they represent an important regulator of CNS function, both in health and disease. Only recently have studies begun to identify the epigenetic mechanisms regulating astrocyte responses in neurodegenerative diseases. These epigenetic mechanisms, along with the epigenetic marks involved in astrocyte development, could elucidate novel pathways to potentially modulate astrocyte-mediated neuroinflammation and neurotoxicity. This review examines the known epigenetic mechanisms involved in regulation of astrocyte function, from development to neurodegeneration, and links these mechanisms to potential astrocyte-specific roles in neurodegenerative disease with a focus on potential opportunities for therapeutic intervention. PMID- 29113755 TI - Early developmental trajectories of preterm infants. AB - BACKGROUND AND OBJECTIVES: Preterm infants are at risk for neuro-developmental impairments and atypical developmental trajectories. The aims of this study were to delineate early developmental trajectories of preterm and full-term infants. METHODS: The cognitive, language, and motor development of 149 infants - 19 extremely preterm (EPT), 34 very preterm (VPT), 57 moderately preterm (MPT), and 39 full-term (FT) - was evaluated using Mullen Scales at 1, 4, 8, 12, and 18 months. Mixed models were applied to examine group differences. Gender, maternal education, and neurobehavior were included as predictors of developmental trajectories. RESULTS: The EPT and VPT infants achieved significantly lower scores than the FT infants in all domains, with a significantly increasing gap over time. The MPT infants' trajectories were more favorable than those of the EPT and VPT infants yet lower than the FT infants on the Visual Reception, Gross, and Fine Motor subscales. Male gender and lower maternal education were associated with lower scores that declined over time. Abnormal neonatal neurobehavior was associated lower Mullen scores and with less stability in scores over time. CONCLUSIONS: The EPT and VPT infants were found to have disadvantages across all domains. The MPT infants revealed more favorable developmental trajectories yet displayed vulnerability compared to the FT infants. Gender, maternal education, and neonatal neurobehavior are important in predicting the developmental outcomes of preterm infants. PMID- 29113756 TI - Fretting and Corrosion Damage in Retrieved Metal-on-Polyethylene Modular Total Hip Arthroplasty Systems: What Is the Importance of Femoral Head Size? AB - BACKGROUND: Fretting and corrosion at the modular femoral head-femoral neck (taper) interface have been reported in retrieved total hip arthroplasty (THA) prostheses. This study investigated associations among implant design, radiographic factors, and patient factors with corrosion and fretting at the taper interface in retrieved metal-on-polyethylene modular THA prostheses. METHODS: Ninety-two retrieved primary metal-on-polyethylene THA implants were evaluated and graded for fretting, corrosion, and damage at the taper interface, including the femoral stem trunnion and femoral head. Preoperative radiographs were assessed for osteolysis and femoral stem alignment; and medical records were reviewed for demographic data. RESULTS: Male patients had greater head corrosion (P = .037), patient age at revision had a weak, negative correlation with trunnion corrosion (rho = -0.20, P = .04), and both body mass index and duration of implantation had weak, positive correlations with head fretting (rho = 0.26, P = .01 and rho = 0.33, P = .001, respectively). A weak, negative correlation was found between femoral head size and both head fretting and head corrosion (rho = 0.26, P = .007 and rho = -0.21, P = .028, respectively), and a weak, positive correlation was found between head offset and trunnion fretting (rho = 0.23, P = .030). Varus femoral stem alignment was associated with greater head fretting (P = .038). CONCLUSION: Larger femoral head sizes were correlated with less severe head corrosion and head fretting, with 28-mm heads exhibiting more moderate-to severe damage. Other factors, such as head-taper engagement and geometry, rather than head size, may affect rates of corrosion and fretting damage at the taper interface. PMID- 29113757 TI - Eight Hundred Twenty-Five Medial Mobile-Bearing Unicompartmental Knee Arthroplaties: The First 10-Year US Multi-Center Survival Analysis. AB - BACKGROUND: FDA approval for the Oxford phase III device was approved for use in the United States in 2004. This study seeks to provide the first long-term, large patient sample size, Oxford phase III multi-site survivorship study in the United States, investigating patient reported outcomes of pain and function, while also providing an in-depth analysis of causes for revision, and finally addressing recent advancements that can help aid the unicompartmental knee arthroplasty (UKA) process and further improve partial knee survivorship. METHODS: Between July 2004 and December 2006, 5 surgeons from around the United States performed medial UKA through the minimally invasive surgical approach, on 825 knees in 695 patients. This was a consecutive series of primary UKAs using the phase III mobile bearing; cemented Oxford Knee (Zimmer Biomet, Warsaw, IN), implanted utilizing phase III instrumentation. UKA survivorship considered all revisions as the end point. Implant survivorship eliminated revisions at which the original Oxford implant was determined to be well fixated and functional intra operatively. RESULTS: A total of 93 knees were revised in this study. Mean follow up was 9.7 years (6-12). Implant survivorship at year 10 was 90% (confidence interval 2.7%). UKA survivorship at year 10 was 85% (confidence interval 3.8%). Average preoperative American Knee Society Score (knee score) was 49 and rose to 90 postoperatively (standard deviations 16 and 18, respectively). Average preoperative American Knee Society Score (function score) was 55 and rose to 77 postoperatively (standard deviations 15 and 28, respectively). CONCLUSION: This was the first large-scale, 10-year, multi-site follow-up of the Oxford mobile bearing medial UKA undertaken in the United States, displaying good survivorship and excellent patient outcomes. PMID- 29113759 TI - Pharmacological and transcriptional inhibition of the G9a histone methyltransferase suppresses proliferation and modulates redox homeostasis in human microvascular endothelial cells. AB - Epigenetic mechanisms, including histone post-translational modifications, are central regulators of cell cycle control. The euchromatic G9a histone methyltransferase (G9a HMT) is a key enzyme catalyzing histone H3 methylation on lysines 9 and 27, and its dysregulation has been linked to uncontrolled proliferation of tumor cells. Here, we have investigated the effect of G9a HMT silencing on cell proliferation of microvascular endothelial cells, a process necessary to sustain tumor growth through the formation of the vascular capillary network. Inhibition of G9a HMT activity in human microvascular endothelial cells (HMEC-1) was performed either pharmacologically, by treatment of cells with BIX 01294 or chaetocin, or transcriptionally, using shRNA. Cell viability and proliferation were examined using the resazurin reduction assay, flow cytometry and immunostaining of phosphorylated checkpoint kinase 1 (pSer317Chk1). Expression of cell cycle- and redox homeostasis-related genes was determined by quantitative PCR. Reactive oxygen species production was measured by oxidation of the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate and the cell's total antioxidant capacity by using the ABTS assay. Inhibition of G9a HMT activity by BIX-01294 treatment or by shRNA attenuated the proliferation of HMEC 1, nuclear localization of phosphorylated Chk1, and induced cell cycle arrest in G1 phase. Transcriptional analysis demonstrated increased gene expression of the cyclin-dependent kinase (CDK) inhibitor p21, and also of Rb1, in BIX-01294 treated cells. Decreased proliferation rate was accompanied by enhanced antioxidant potential of HMEC-1 cells, as demonstrated by reduced production of reactive oxygen species, increased total antioxidant capacity and expression of the antioxidant enzymes catalase and superoxide dismutase 1. Collectively, our results demonstrate of the central role of G9a HMT in the promotion of endothelial cells proliferation, and suggest that endothelial G9a HMT may be a target in the treatment of vascular proliferative disorders and tumor neovascularization. PMID- 29113760 TI - Strengths, weaknesses and future challenges of biosimilars' development. An opinion on how to improve the knowledge and use of biosimilars in clinical practice. AB - Biosimilars started receiving the marketing authorization by European Medicine Agency since 2006. The development of biosimilars follows a well-defined step wise approach, the so-called comparability exercise, which aims to compare non clinical (mainly quality features and biological activity) and clinical (efficacy and safety profiles) features of new biosimilars with their respective reference products. Despite the undeniable advantages of such procedure, some concerns (such as the absence of switching studies or the evaluation of efficacy and safety in all therapeutic indications) still exist about its. In particular, the European regulatory framework on biosimilars approval does not include the conduction of switching studies demonstrating the interchangeability to be carried out before marketing authorization. This is one of the main aspects that negatively affects healthcare professionals' clinical decisions on switch. In order to achieve a better knowledge on safety and efficacy of biosimilar drugs, real world data should be collected and post-marketing efficacy and safety clinical studies (including those evaluating specific endpoints, therapeutic regimens and patients population), should be planned. also the conduction of well designed switching studies is highly advisable, especially in the case of biosimilar drugs used in oncology settings. Lastly, considering the critical role of antidrug antibodies on efficacy/safety profile of biologic drugs, studies based on therapeutic drug monitoring would be useful in order to achieve treatment optimization. Implementing the above strategies could be helpful to fill the gap in knowledge observed in the present European biosimilar regulatory framework. PMID- 29113761 TI - Design, synthesis and in vitro anti-tuberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives. AB - A series of novel benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole hybrids (7a j &8a-j) have been designed and synthesized in excellent yields by Huisgen's [3+2] cyclo addition reaction of 3-(azidomethyl)-2-methyl-6,7-dihydro-5H benzo[6,7]cyclohepta[1,2-b]pyridine (5) with various alkynes 6 in presence of copper sulphate and sodium ascorbate and their structures were confirmed by IR, 1H NMR, 13C NMR and HRMS. The newly synthesized compounds 7a-j &8a-j were evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Among the compounds tested, the compounds 7i and 8g displayed most potent activity with MIC value of 1.56 ug/mL with low cytotoxicity. PMID- 29113758 TI - Demographic, physical and mental health assessments in the adolescent brain and cognitive development study: Rationale and description. AB - The Adolescent Brain and Cognitive Development (ABCD) Study incorporates a comprehensive range of measures assessing predictors and outcomes related to both mental and physical health across childhood and adolescence. The workgroup developed a battery that would assess a comprehensive range of domains that address study aims while minimizing participant and family burden. We review the major considerations that went into deciding what constructs to cover in the demographics, physical health and mental health domains, as well as the process of selecting measures, piloting and refining the originally proposed battery. We present a description of the baseline battery, as well as the six-month interim assessments and the one-year follow-up assessments. This battery includes assessments from the perspectives of both the parent and the target youth, as well as teacher reports. This battery will provide a foundational baseline assessment of the youth's current function so as to permit characterization of stability and change in key domains over time. The findings from this battery will also be utilized to identify both resilience markers that predict healthy development and risk factors for later adverse outcomes in physical health, mental health, and substance use and abuse. PMID- 29113762 TI - The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design. AB - We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Ki = 22.4 MUM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties. PMID- 29113763 TI - Phenoxypropanolamine derivatives as selective inhibitors of the 20S proteasome beta1 and beta5 subunits. AB - New series of thiophene-containing phenoxypropanolamines were synthesized and evaluated for their potency to inhibit the three proteolytic activities of the mammalian 20S proteasome. Noticeable inhibition of both ChT-L and PA activities was obtained with three compounds: one with unsubstituted phenoxypropanolamine group (7) and the two others with a p-Cl-substituted group (4 and 9). For three other compounds (3, 8 and 10), ChT-L activity alone was significantly inhibited. In silico docking performed on the beta5 and beta1 subunits bearing the respective ChT-L and PA catalytic sites showed features common to poses associated with active compounds. These features may constitute a selectivity criterion for structure-guided inhibitor design. PMID- 29113764 TI - Effect of two-level pedicle-screw fixation with different rod materials on lumbar spine: A finite element study. AB - BACKGROUND: Pedicle-screw-rod fixation system is very popular surgical remedy for degenerative disc disease. It is important to observe load vs. spinal motion characteristic for better understanding of clinical problems and treatment of spinal instability associated with low-back pain. OBJECTIVE: The objective of this study is to understand the effect [range of motion (ROM) and intervertebral foramen height] of pedicle-screw fixation with three rod materials on lumbar spine under three physiological loading conditions. METHOD: A three-dimensional finite element (FE) model of lumbar to sacrum (L1-S) vertebrae with pedicle-screw rod fixation at L3-L5 level is developed. Three rod materials [titanium alloy (Ti6Al4V), ultra-high molecular weight poly ethylene (UHMWPE) and poly-ether ether-ketone (PEEK)] are used for two-level fixation and the FE models are simulated for axial rotation, lateral bending and flexion-extension under +/-10 Nm moment and 500 N compressive load and compared with the intact (natural) model. RESULT & DISCUSSION: For axial rotation, lateral bending and flexion, ROM increased 2.8, 4.5 and 1.83 times respectively for UHMWPE, and 3.7, 7.2 and 2.15 times respectively for PEEK in comparison to Ti6Al4V. As ROM is 49, 29 and 31% of the intact model during axial rotation, lateral bending and flexion respectively, PEEK rod produced better motion flexibility than Ti6Al4V and UHMWPE rod. Foramen height increased insignificantly by 2.21% for the PEEK rod with respect to the intact spine during flexion. For the PEEK rod, maximum stress of 40 MPa during axial rotation is much below the yield stress of 98 MPa. CONCLUSION: Ti6Al4V pedicle-screw-rod fixation system highly restricted the ROM of the spine, which is improved by using UHMWPE and PEEK, having lower stiffness. The foramen height did not vary significantly for any implant materials. In terms of ROM and maximum stress, PEEK rod may be considered for a better implant design to get better ROM and thus mobility. PMID- 29113765 TI - Ossification and development of vertebrae in the Balkan crested newt Triturus ivanbureschi (Salamandridae, Caudata). AB - Vertebral morphology, development, and evolution have been investigated for many decades, especially in the recent evo-devo era. Nevertheless, comparative data on development and ossification modes within the major tetrapod groups are scarce and frequently suffer from the use of a simplistic approach, resulting in simplistic generalizations about the formation of tetrapod vertebrae. Here, we describe the development and ossification of trunk vertebrae in Triturus ivanbureschi (Salamandridae, Caudata) and compare the results with published data on other related taxa. In so doing, we focus on the modes of ossification and development of the centrum and neural arches by analysing three developmental stages defined by the degree of limb development: stages 47, 52, and 62 according to Glucksohn (1932). Our examination of histological sections through trunk vertebrae enabled us to identify three modes of ossification within single trunk vertebrae: (i) perichordal (direct ossification of the connective tissue surrounding the notochord); (ii) perichondrial (direct ossification of the perichondrium, consisting of cartilage-covering connective tissue), and (iii) endochondral (ossification within the preformed cartilage template). We also noted the presence of intravertebral or notochordal cartilage. Although our results indicate that this cartilage develops within the notochord surrounded by the continuous notochordal sheath, more detailed further studies could shed light on its origin and development. PMID- 29113766 TI - Institutionalisation of the case management nurse in Spain. Comparative analysis of health systems of the Spanish autonomous communities. AB - Care of chronicity is a pressing issue for health systems because of its high prevalence and the organisational challenges that it generates. Different countries solve the complexity of the care of chronicity through case management by the nursing profession, obtaining good results. This paper analyses the status of institutionalisation of the case management nurse in Spain through the design of a reference standard to compare between the autonomous communities in their approach to chronicity. Thus, we sought to monitor the degree of progress of the institutional structure of the policies for the care of chronicity in our country through this healthcare professional. Our results showed that no autonomous community has reached the maximum standard of implementation and that the situation is very heterogeneous, confirming a weak and erratic degree of institutionalisation of the case management nurse in Spain despite the formal recognition of their role in patient care. PMID- 29113767 TI - Renal Functional Outcome of Partial Nephrectomy for Complex R.E.N.A.L. Score Tumors With or Without Neoadjuvant Sunitinib: A Multicenter Analysis. AB - BACKGROUND: Sunitinib might optimize the feasibility of partial nephrectomy (PN) for complex renal tumors with imperative indications. We compared the renal functional outcomes of patients with complex renal masses who had undergone sunitinib before PN with those of patients who had not required neoadjuvant sunitinib before PN. PATIENTS AND METHODS: We performed a multicenter retrospective analysis of patients with renal cell carcinoma who had undergone PN for a complex renal mass (R.E.N.A.L. nephrometry score, 10-12) and imperative indications from January 2012 to July 2014. Neoadjuvant sunitinib was used in cases for which PN was not considered feasible. The cohort was divided into those patients who had undergone PN without neoadjuvant sunitinib and those who had undergone PN after sunitinib (no-neoadjuvant vs. neoadjuvant). The change in tumor size and R.E.N.A.L. score were assessed. The primary outcome was the change in the estimated glomerular filtration rate (DeltaeGFR) from preoperatively to the last postoperative follow-up visit. RESULTS: The data from 125 consecutive patients were analyzed (47 neoadjuvant and 78 no-neoadjuvant; median follow-up, 21 months). The neoadjuvant plus PN patients had had a greater median tumor size preoperatively (7.2 vs. 6 cm; P = .045). Sunitinib caused a significant decrease in the median tumor size (from 7.2 to 5.8 cm [19.4%]; P = .012) and R.E.N.A.L. score (from 11 to 9; P = .001). No significant differences were found between the neoadjuvant and no-neoadjuvant groups in the ischemia time (P = .413) or incidence of complications (P = .728). The median DeltaeGFR was similar (neoadjuvant, 6.4; no-neoadjuvant, 6.1; P = .534). Linear regression analysis for factors associated with an increasing DeltaeGFR demonstrated increasing age (estimate, -0.074; P = .009) increasing body mass index (estimate, -0.087; P = .043), and decreasing baseline eGFR (estimate, -0.104; P = .02) as significant factors. CONCLUSION: The use of neoadjuvant sunitinib might facilitate complex PN and result in renal functional outcomes similar to those of patients with a complex renal mass who had not required neoadjuvant sunitinib. PMID- 29113768 TI - Female Urethra Adenocarcinoma. AB - Female urethra adenocarcinoma (FUA) is a rare aggressive tumor that occurs in Skene ducts and glands. It is associated with a relatively poor prognosis. The aim of this review was to evaluate FUA in terms of epidemiology, risk factors, diagnosis, natural history of disease, modalities of treatment, and outcomes. These tumors are usually large masses, which typically spread through the lymphatic system. Patients present with vague symptoms similar to urinary tract infections. Cystourethroscopy permits visualization of the urethral tumor and allows biopsies to be performed to remove samples for histologic examination. Magnetic resonance imaging is recommended for tumor staging. Local, superficial, and distal urethral tumors may be treated by partial resection with preservation of the urethra. Radical urethrectomy with wide, comprehensive resection of the paraurethral tissues and anterior vaginal wall may offer superior local control for this disease. Advanced FUA and lymph node positivity are associated with poor prognosis for all survival outcomes (recurrence-free, cancer-specific, and overall survival). Multimodal therapy including surgery, chemotherapy, and radiotherapy is required in the modern management of FUA, although the specific role and combination of each treatment is less clearly determined. Wide resection after chemotherapy and/or radiotherapy is associated with the best local control, but it reduces quality of life. PMID- 29113769 TI - Advanced Scrotal Extramammary Paget's Disease Treated With Apatinib: A Case Report. PMID- 29113770 TI - Pathologic Predictors of Survival During Lymph Node Dissection for Metastatic Renal-Cell Carcinoma: Results From a Multicenter Collaboration. AB - PURPOSE: To determine the therapeutic value of lymph node dissection (LND) during cytoreductive nephrectomy (CN) and assess predictors of cancer-specific survival (CSS) in metastatic renal-cell carcinoma. PATIENTS AND METHODS: We identified 293 consecutive patients treated with CN at 4 academic institutions from March 2000 to May 2015. LND was performed in 187 patients (63.8%). CSS was estimated by the Kaplan-Meier method for the entire cohort and for a propensity score-matched cohort. Cox proportional hazards regression was used to evaluate CSS in a multivariate model and in an inverse probability weighting-adjusted model for patients who underwent dissection. RESULTS: Median follow-up was 12.6 months (interquartile range, 4.47, 30.3), and median survival was 15.9 months. Of the 293 patients, 187 (63.8%) underwent LND. One hundred six patients had nodal involvement (pN+) with a median CSS of 11.3 months (95% confidence interval [CI], 6.6, 15.9) versus 24.2 months (95% confidence interval, 14.1, 34.3) for pN- patients (log-rank P = .002). The hazard ratio for LND was 1.325 (95% CI, 1.002, 1.75) for the whole cohort and 1.024 (95% CI, 0.682, 1.537) in the propensity score-matched cohort. Multivariate analysis revealed that number of positive lymph nodes (P < .001) was a significant predictor of worse CSS. CONCLUSION: For patients with metastatic renal-cell carcinoma undergoing CN with lymphadenectomy, the number of nodes positive was predictive of survival at short-term follow-up. However, nonstandardized lymphadenectomy only provided prognostic information without therapeutic benefit. Prospective studies with standardized templates are required to further ascertain the therapeutic value of LND. PMID- 29113771 TI - Rate and Extent of Pelvic Lymph Node Dissection in the US Prostate Cancer Patients Treated With Radical Prostatectomy. AB - PURPOSE: To evaluate the utilization of pelvic lymph node dissection (PLND) and its extent in contemporary US patients, and to correlate it to the detection of pN1 disease. PATIENTS AND METHODS: A total of 328,710 individuals who received radical prostatectomy between the years 2004 and 2013 were identified within the National Cancer Data Base. The Cochran-Armitage test was used to assess the statistical significance of temporal trends. Logistic regression analysis tested the relationship between the number of lymph nodes removed (LNR) and pN1 rate. RESULTS: Most patients had T2 disease (76.7%) and a Gleason score of 7 (55.9%). Overall, 63.5% of the patients received PLND; this ranged between 58.9% and 72.1% over the study period (P = .8). In patients receiving PLND, mean LNR increased from 6.1 nodes in 2004 to 7.2 nodes in 2013 (P < .001). When stratified by tumor risk, utilization and extent of PLND increased in intermediate- and high-risk tumors, while it decreased in low-risk tumors. Overall pN1 rate was 3.73%, and it increased from 2.9% to 5.3% between 2004 and 2013 (P < .001). In multivariable analysis, LNR was an independent predictor of pN1 (P < .001). CONCLUSION: The utilization patterns of PLND in the United States have improved, with an increased focus on patients with intermediate- and high-risk disease. Likewise, the extent of PLND has improved to include more lymph nodes. This seems to translate into more accurate tumor, node, metastasis classification system staging, as more patients are being appropriately diagnosed with pN1 disease. PMID- 29113772 TI - Oncologic Outcomes of Definitive Treatments for Low- and Intermediate-Risk Prostate Cancer After a Period of Active Surveillance. AB - BACKGROUND: To compare oncologic outcomes of different definitive treatment (DT) modalities in a cohort of patients with prostate cancer (PCa) after active surveillance (AS). METHODS: We identified 237 patients with National Comprehensive Cancer Network (NCCN) low- and intermediate-risk prostate cancer diagnosed from 1990 to 2012 who did not undergo immediate DT within 12 months of diagnosis (ie, AS patients as well as watchful waiting and those refusing DT). Charts were examined for clinical/pathologic data and type of DT: surgery (RP), radiation including brachytherapy (XRT), cryotherapy, and androgen deprivation therapy monotherapy (ADT). The impact of DT on oncologic outcomes of biochemical recurrence (BCR), metastasis, disease-specific (DSS), and overall survival (OS) was examined with the Cox proportional hazards model, along with the Kaplan-Meier method and log-rank test. RESULTS: After median time on AS of 63.4 months, 40% of patients underwent DT: 47% XRT, 28% RP, 14% ADT, and 11% cryotherapy. On multivariable analysis, the use of XRT predicted higher BCR (hazard ratio [HR] 6.1, P = .001) and worse overall mortality (HR 2.1, P = .03) compared with other treatments, controlling for age, Charlson Comorbidity Index (CCI), stage, Gleason score, and NCCN risk category. Median follow-up was 71.7 months. On Kaplan-Meier analysis, 10-year OS was superior for RP versus XRT among patients with prostatic specific antigen (PSA) velocity >2.0 ng/mL/y. CONCLUSIONS: Low- and intermediate risk patients with PCa who progress to DT after AS may be inadequately treated with radiation therapy compared with other DT modalities, especially when pretreatment PSA velocity is > 2 ng/mL/y. PMID- 29113773 TI - Pairing Cancer Biomarkers to Biomedicine. PMID- 29113774 TI - Restricted Presence of POU6F2 in Human Corneal Endothelial Cells Uncovered by Extension of the Promoter-level Expression Atlas. AB - Corneal endothelial cells (CECs) are essential for maintaining the clarity of the cornea. Because CECs have limited proliferative ability, interest is growing in their potentially therapeutic regeneration from pluripotent stem cells. However, the molecular mechanisms of human CEC differentiation remain largely unknown. To determine the key regulators of CEC characteristics, here we generated a comprehensive promoter-level expression profile of human CECs, using cap analysis of gene expression (CAGE) with a single molecule sequencer. Integration with the FANTOM5 promoter-level expression atlas, which includes transcriptome profiles of various human tissues and cells, enabled us to identify 45 promoters at 28 gene loci that are specifically expressed in CECs. We further discovered that the expression of transcription factor POU class 6 homeobox 2 (POU6F2) is restricted to CECs, and upregulated during human CEC differentiation, suggesting that POU6F2 is pivotal to terminal differentiation of CECs. These CEC-specific promoters would be useful for the assessment of fully differentiated CECs derived from pluripotent stem cells. These findings promote the development of corneal regenerative medicine. PMID- 29113775 TI - Spread of predominant neuraminidase and hemagglutinin co-mutations in the influenza A/H3N2 virus genome. AB - Genetic variation of influenza neuraminidase (NA), unlike for hemagglutinin (HA), has not been fully characterized. Therefore, we determined the relation between mutations in the NA and HA genome segments of 205 influenza A/H3N2 viruses isolated from patients in Japan during the five seasons from 2010 to 2015. The amino acid (AA) sequences of the NA and HA proteins in these isolates were then determined. In the 2011-2012 season, there was the emergence of isolates with NA and HA sequences containing AA93G (NA93G) and AA278K (HA278K), respectively (24/48 isolates, 50.0%). This was in contrast to NA93D-HA278N being detected exclusively in the previous 2010-2011 season (24/24 isolates, 100.0%). The isolates with the NA93G-HA278K substitutions became predominant in the following 2012-2013 season (95.8%, 46/48 isolates). The NA and HA phylogenetic trees of the 2011-2012 and 2012-2013 seasons were segregated by clades with NA93D-HA278N or NA93G-HA278K. In the subsequent 2013-2014 and 2014-2015 seasons, the strong relationship between NA93D-HA278N and NA93G-HA278K observed in the previous seasons, was no longer present and NA93G-HA278N (33/52 isolates, 63.5% in the 2014-2015 season) became predominant. In addition, the clades within the NA and HA trees could no longer be segregated based on NA AA93 and HA AA278. These findings suggest that the co-mutation of NA and HA AA sequences is present and may contribute to the formation of an epidemic lineage. PMID- 29113776 TI - Brief assessment of schizotypal traits: A multinational study. AB - The Schizotypal Personality Questionnaire-Brief (SPQ-B) was developed with the aim of examining variations in healthy trait schizotypy, as well as latent vulnerability to psychotic-spectrum disorders. No previous study has studied the cross-cultural validity of the SPQ-B in a large cross-national sample. The main goal of the present study was to analyze the reliability and the internal structure of SPQ-B scores in a multinational sample of 28,426 participants recruited from 14 countries. The mean age was 22.63years (SD=7.08; range 16 68years), 37.7% (n=10,711) were men. The omega coefficients were high, ranging from 0.86 to 0.92 for the total sample. Confirmatory factor analysis revealed that SPQ-B items were grouped either in a theoretical structure of three first order factors (Cognitive-Perceptual, Interpersonal, and Disorganized) or in a bifactor model (three first-order factors plus a general factor of schizotypal personality). In addition, the results supported configural but not strong measurement invariance of SPQ-B scores across samples. These findings provide new information about the factor structure of schizotypal personality, and support the validity and utility of the SPQ-B, a brief and easy tool for assessing self reported schizotypal traits, in cross-national research. Theoretical and clinical implications for diagnostic systems, psychosis models, and cross-national mental health strategies are derived from these results. PMID- 29113777 TI - Further angles to this story: Time consumption in mind-reading, psychosis risk and phenomenology of social cognition. PMID- 29113778 TI - Quantitative polymerase chain reaction based quantification of Brucella DNA in serum of pre- and post-therapeutic occupationally exposed infected human population. AB - BACKGROUND: Brucellosis is one of the neglected zoonotic diseases in humans. The serological methods based on antibody detections are unable to detect the effectiveness of treatment in humans as antibodies persist for long time in humans even after therapy. Therefore, we developed qPCR technique to overcome such discrepancy and device a rapid and efficient test for both diagnosis and follow up of the brucellosis affected individuals. METHODS: High risk suspected individuals with positive serology (RBPT, STAT and iELISA) and PCR were mainly analyzed for DNA quantification by qPCR assay. The bcsp-31 gene, a shared gene of Brucella species was amplified by genus specific primers and cloned to pGEMTTM easy vector and the cloned plasmid were used to construct a standard curve (R2=0.99, efficiency=1.98) over 7 orders of magnitude with sensitivity of ~10 copy number. The assay was found 100% specific. RESULTS: Overall 85 individuals were found positive out of 188. Out of them, 23 serological, PCR and qPCR positive individuals were recommended for 45days therapy according to WHO regimen (Doxycycline and Rifampin) and each case was further followed by qPCR. The mean threshold cycle (Cq) before treatment was 26.05+/-0.347 (3940.5copies/MUl), which increased significantly to 32.7+/-0.66 (259.13copies/MUl) on 4th week during treatment, 35.12+/-3.12 (38.52copies/MUl) at 6th week on day of treatment completion, 35.6+/-0.66 (34.21copies/MUl) on 21st day after treatment depicting a significant reduction in DNA load over the course of treatment. Serological follow up showed that only 3 individuals had decreased STAT titre but no change in RBPT results. Out of 17 symptomatic individuals under therapy, 10 improved clinically, 5 improved clinically with persistent weakness and 2 had no effect of therapy. CONCLUSION: The study suggests that qPCR is more useful and rapid test to follow treated individuals than serology. PMID- 29113780 TI - Dietary antioxidants, food deprivation and growth affect differently oxidative status of blood and brain in juvenile European seabass (Dicentrarchus labrax). AB - Compensatory growth may increase molecular oxidative damage, which may be mitigated through the intake of dietary antioxidants. However, dietary antioxidants may also reduce concentration of antioxidant enzymes, which have a key role in regulating the oxidative status. Here we investigated whether feeding on a diet rich in antioxidants (vitamin E) enables juvenile European seabass (Dicentrarchus labrax) to catch up after a period of food deprivation with negligible effects on the oxidative stress to blood and brain as compared to fish feeding on a normal diet (i.e., not enriched in antioxidants). The results show that a higher intake in antioxidants favoured compensatory growth, but this came at a cost in terms of increased oxidative damage. Increased intake of antioxidants also resulted in changes in the activity of enzymatic antioxidant defences and increased protein oxidative damage in both brain and blood. In addition, food deprivation caused increased protein oxidative damage in brain. Our findings show that the beneficial effects of dietary antioxidants on growth may be offset by hidden detrimental effects and that different early life events affect different components of oxidative status of a given tissue. PMID- 29113781 TI - The effect of reinfection and mixed Trypanosoma cruzi infections on disease progression in mice. AB - The progression of Chagas disease (CD) varies significantly from host to host and is affected by multiple factors. In particular, mixed strain infections and reinfections have the potential to exacerbate disease progression subsequently affecting clinical management of patients with CD. Consequently, an associated reduction in therapeutic intervention and poor prognosis may occur due to this exacerbated disease state. This study investigated the effects of mixed strain infections and reinfection with Trypanosoma cruzi in mice, using two isolates from different discrete typing units, TcI (C8 clone 1) and TcIV (10R26). There were no significant differences in mortality rate, body weight or body condition among mice infected with either C8 clone 1, 10R26, or a mixture of both isolates. However, the parasite was found in a significantly greater number of host organs in mice infected with a mixture of isolates, and the histopathological response to infection was significantly greater in mice infected with C8 clone 1 alone, and C8 clone 1+10R26 mixed infections than in mice infected with 10R26 alone. To investigate the effects of reinfection, mice received either a double exposure to C8 clone 1; a double exposure to 10R26; exposure to C8 clone 1 followed by 10R26; or exposure to 10R26 followed by C8 clone 1. Compared to single infection groups, mortality was significantly increased, while survival time, body weight and body condition were all significantly decreased across all reinfection groups, with no significant differences among these groups. The mortality rate over all reinfection groups was 63.6%, compared to 0% in single infection groups, however there was no evidence of a greater histopathological response to infection. These results suggest firstly, that the C8 clone 1 isolate is more virulent than the 10R26 isolate, and secondly, that a more disseminated infection may occur with a mixture of isolates than with single isolates, although there is no evidence that mixed infections have a greater pathological effect. By contrast, reinfections do have major effects on host survivability and thus disease outcome. This confirms previous research demonstrating spontaneous deaths following reinfection, a phenomenon that to our knowledge has only been reported once before. PMID- 29113779 TI - Hospital-acquired lower respiratory tract infections among high risk hospitalized patients in a tertiary care teaching hospital in China: An economic burden analysis. AB - BACKGROUND: Data on the economic burden of hospital-acquired lower respiratory tract infection (LRTI) among high risk hospitalized patients are lacking in China. This study aims to fill this knowledge gap. METHODS: We used a prospective matched cohort design, comparing patients with LRTIs and 1:1 matched patients without LRTIs. Study period was from January 2013 to December 2015 analyzing inpatients from high risk wards - intensive care unit (ICU), dialysis, hematology, etc. - in a tertiary hospital. Hospital information system and hospital infection surveillance system were applied to extract necessary information. The primary outcome was incidence of hospital-acquired LRTIs, and the secondary was economic burden outcomes, including incremental medical costs and prolonged length of stay (LOS). Wilcoxon's signed rank test was used to explore the differences in the economic burden. RESULTS: Among 5990 hospital visitors over the period of time, 895 (14.94%) had hospital-acquired LRTIs. We analyzed 340 patients with LRTIs and 340 respective controls without infections. The median hospital costs for patients with ICU-acquired LRTIs were significantly higher than those without LRTIs in other wards ($12,301.17 vs. $4674.64, P<0.01). The average attributable cost per patient was $2853.93 ($6916.48 vs. $4062.55, P<0.01). Patients from hematology department had the longest LOS, at 15days (25days vs. 10 days, P<0.01). An LRTI led to an attributable increase in LOS by 8days on average (P<0.01). Western medicine, treatment and laboratory test were the dominant contributors to the growth in overall medical costs in hospital acquired LRTIs. CONCLUSIONS: Hospital-acquired LRTI imposed considerable economic burden on patients hospitalized in high risk wards in China. This study provides the first data for economic evaluation of LRTI, highlighting the urgent need to establish targeted preventive strategies to minimize the occurrence of this complication to reduce economic burden. PMID- 29113782 TI - Interobserver variability in rectum contouring in high-dose-rate brachytherapy for prostate cancer: A multi-institutional prospective analysis. AB - PURPOSE: The aim of this study was to evaluate the interobserver variability (IOV) of rectum contouring, and its dosimetric consequences, for high-dose-rate brachytherapy in patients with prostate cancer across multiple institutions. METHODS AND MATERIALS: Five radiation oncologists contoured rectums in 10 patients on transperineal ultrasound image sets after establishing a delineation consensus. The D0.1cc, D1cc, and D2cc rectum volume parameters were determined. The mean, standard deviation, and range of each dose-volume histogram parameter were evaluated for each patient. The IOV was determined using the coefficient of variation, and the dosimetric impacts on the total dose were analyzed by estimating the biologically equivalent dose (EQD2alpha/beta = 3). RESULTS: The interobserver coefficients of variation (+/-standard deviation) for the reported D0.1cc, D1cc, and D2cc were 5 +/- 1.84%, 4 +/- 1.26%, and 4 +/- 1.33%, respectively. As for the impact on the total dose, the mean dose differences for D0.1cc, D1cc, and D2cc were 10 Gy, 7.3 Gy, and 6.6 Gy, respectively. CONCLUSIONS: The D2cc is robust as evident by the low IOV (<5%). However, some variability ranges almost overlap with the clinical threshold level, which may present dosimetric and clinical complications. General rectal contouring guidelines for prostate high-dose-rate brachytherapy are desirable to reduce discrepancies in delineation. PMID- 29113783 TI - Multiple legumain isoenzymes in ticks. AB - By searching nucleotide databases for the North American Lyme disease vector, Ixodes scapularis, we have complemented the previously characterized European Ixodes ricinus legumain IrAE1 with a full set of nine analogous genes (isae1-9). Six of these were PCR confirmed as genes present in all tick genomes tested. The absolute mRNA copy number examined by quantitative (q)PCR enabled expression profiling and an absolute comparison of mRNA levels for individual I. scapularis (Is)AEs in tick tissues. Four IsAEs (1, 2, 4, 9) were expressed solely in the gut and thus are proposed to be involved in host blood digestion. Expression qPCR profiling over developmental stages confirmed IsAE1, the direct analogue of previously characterized I. ricinus IrAE1, as the principle legumain transcript in partially engorged females, and demonstrated its strong regulation by on-host feeding in larvae, nymphs and females. In contrast, IsAE2 was the predominant gut legumain in unfed nymphs, unfed females and males. In-silico, IsAE1 and IsAE2 protein three-dimensional structural models displayed minimal differences in overall proenzyme structures, even in comparison with recently resolved crystal structures of mammalian prolegumain. Three functional studies were performed in I. ricinus with IsAE1/IsAE2 analogues: double IrAE1/IrAE2 RNA interference silencing, feeding of ticks on IrAE1+IrAE2 immunized hosts and in vitro membrane tick feeding on blood containing a legumain-specific inhibitor. The latter experiment led to reduced weights of fully engorged ticks and limited oviposition, and indicated the potential of legumain inhibitors for novel anti tick interventions. PMID- 29113784 TI - Sex-specific 99th percentiles derived from the AACC Universal Sample Bank for the Roche Gen 5 cTnT assay: Comorbidities and statistical methods influence derivation of reference limits. PMID- 29113785 TI - Label-free electrochemical immunoassay for neuron specific enolase based on 3D macroporous reduced graphene oxide/polyaniline film. AB - The content of neuron specific enolase (NSE) in serum is considered to be an essential indicator of small cell lung cancer (SCLC). Here, a novel label-free electrochemical immunoassay for the detection of NSE based on the three dimensionally macroporous reduced graphene oxide/polyaniline (3DM rGO/PANI) film has been proposed. The 3DM rGO/PANI film was constructed by electrochemical co deposition of GO and aniline into the interspaces of a sacrificial silica opal template modified Au slice. During the co-deposition, GO was successfully reduced by aniline and PANI could be deposited on the surfaces of rGO sheets. The ratio of rGO and PANI in the composite was also optimized to achieve the maximum electrochemical performance. The 3DM rGO/PANI composite provided larger specific surface area for the antibody immobilization, exhibited enhanced conductivity for electron transfer, and more important was that PANI acted as the electroactive probe for indicating the NSE concentration. Under the optimal conditions, a linear current response of PANI to NSE concentration was obtained over 0.5 pg mL 1-10.0 ng mL-1 with a detection limit of 0.1 pg mL-1. Moreover, the immunosensor showed excellent selectivity, good stability, satisfactory reproducibility and regeneration, and was employed to detect NSE in clinical serum specimens. PMID- 29113786 TI - Pulmonary dysfunction and development of different cardiovascular outcomes in the general population. AB - BACKGROUND: Pulmonary dysfunction and cardiovascular disease are major causes of impaired health status in later life, and co-development of these diseases has been reported. AIM: To better understand the pathobiology involved in the co development of these diseases. METHODS: We investigated the impact of pulmonary dysfunction on the development of cardiovascular disease among people aged>=50 years in the English longitudinal study of ageing (ELSA). Hazard ratios were estimated by Cox proportional hazards regression models, with and without a time dependent update of exposure and confounders. Pulmonary function was divided into three categories, with the least affected category as the reference. RESULTS: People with pulmonary dysfunction were at higher risk of developing cardiovascular disease than those with normal pulmonary function: the hazard ratio for pulmonary dysfunction versus healthy in the time-dependent crude analysis of model 1, adjusted for age, body mass index, sex, angina pectoris and heart arrhythmia, was 1.49 (95% confidence interval 1.2-1.9). The effect varied with the precise definition of pulmonary dysfunction and the subtype of the cardiovascular disease, and decreased after correction for some additional confounders but not after correction for inflammatory biomarkers. CONCLUSIONS: A history of pulmonary disease increased the risk of developing cardiovascular disease, but inflammation did not seem to alter the effect of pulmonary dysfunction on cardiovascular disease development. This insight may lead to better understanding and treatment of cardiovascular comorbidities in pulmonary disease; it also indicates that the potentially beneficial effect of targeted anti-inflammatory drugs for pulmonary disease, in terms of reducing cardiovascular risk in these patients, may be limited. PMID- 29113788 TI - Angela Mousley: Developing Tools to Probe Parasite Neurobiology. PMID- 29113787 TI - Nox4 genetic inhibition in experimental hypertension and metabolic syndrome. AB - BACKGROUND: Metabolic syndrome is a combination of symptoms including obesity, dyslipidaemia, glucose intolerance and hypertension. Oxidative stress appears to be a pathophysiological factor that links these signs and encourages progression towards heart failure and diabetes. Nox4 is a hydrogen peroxide nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform - found in various cardiovascular cells and tissues, but also in tissues such as the liver - which is involved in glucose and lipid homeostasis. AIMS: To test whether inhibition of the Nox4 enzyme could improve blood pressure and metabolic parameters in mice receiving either angiotensin II or a high-fat diet. METHODS: Systolic and diastolic arterial pressures, pulse rate and heart rate were obtained in 24 male mice (12 wild-type [WT] and 12 Nox4-/-) before and during 14 days of angiotensin II infusion. After angiotensin II infusion, cardiac histological remodeling was assessed. Weight and biochemical parameters were measured in 18 male and 18 female mice (nine WT and nine Nox4-/- per gender) after 10 weeks on a standard chow diet, then 15 weeks on a high-fat diet. Glucose tolerance and insulin sensitivity were tested at age 25 weeks. RESULTS: Knock-out animals did not demonstrate a baseline blood pressure phenotype, but blocking Nox4 protected against angiotensin II-mediated arterial and pulse pressure increases. No protection against angiotensin II-induced cardiac fibrosis was observed. From a metabolic point of view, Nox4 inhibition reduced plasma triglycerides in male and female mice under a chow diet. However, Nox4 deletion did not affect the metabolic profile under a high-fat diet in males or females, but increased glucose intolerance in females. CONCLUSION: Our data identify Nox4 as a key source of radical oxygen species involved in hypertension and some metabolic problems. PMID- 29113789 TI - A case of lymphangioma-like mesenteric cysts diagnosed as adenocarcinoma of possible pancreatic origin on EUS-FNA. PMID- 29113790 TI - The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase 4: Studies with HK-2 cells in vitro and normal rats in vivo. AB - Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4. PMID- 29113791 TI - PD149163 induces hypothermia to protect against brain injury in acute cerebral ischemic rats. AB - Therapeutic hypothermia is a promising strategy for acute cerebral ischemia via physical or pharmacological methods. In this study, we pharmacologically induced hypothermia on Sprague Dawley rats by intraperitoneally injecting PD149163. We found that mild hypothermia was induced by PD149163 treatment without local cerebral blood flow (LCBF) alteration. To evaluate the neuroprotective effects of PD149163, TTC staining, HE staining and Nissl's staining were performed in our study. We found that PD149163 could prevent neuronal damage, and inhibit proliferation and activation of glial cells induced by ischemia. Simultaneously, we observed PD149163 ameliorated apoptosis characterized by down-regulated caspase-3 and Bax, but elevated Bcl-2. Moreover, PD149163 dramatically reduced JNK and AMPK/mTOR signaling pathway activation, and thereby inhibited autophagy by increased P62 expression, decreased the ratio of LC3-II to LC3-I and the expression of Beclin. Taken together, the present findings reveal the therapeutic effects of PD149163-induced hypothermia in brain ischemia, and provide a new strategy for stroke treatment. PMID- 29113792 TI - Transcription factors: Time to deliver. AB - Transcription factors (TFs) are at the center of the broad regulatory network orchestrating gene expression programs that elicit different biological responses. For a long time, TFs have been considered as potent drug targets due to their implications in the pathogenesis of a variety of diseases. At the same time, TFs, located at convergence points of cellular regulatory pathways, are powerful tools providing opportunities both for cell type change and for managing the state of cells. This task formulation requires the TF modulation problem to come to the fore. We review several ways to manage TF activity (small molecules, transfection, nanocarriers, protein-based approaches), analyzing their limitations and the possibilities to overcome them. Delivery of TFs could revolutionize the biomedical field. Whether this forecast comes true will depend on the ability to develop convenient technologies for targeted delivery of TFs. PMID- 29113793 TI - Doxorubicin encapsulated clicked gold nanoparticle clusters exhibiting tumor specific disassembly for enhanced tumor localization and computerized tomographic imaging. PMID- 29113794 TI - A new rat-compatible robotic framework for spatial navigation behavioral experiments. AB - BACKGROUND: Understanding the neural substrate of information encoding and processing requires a precise control of the animal's behavior. Most of what has been learned from the rodent navigational system results from relatively simple tasks in which the movements of the animal is controlled by corridors or walkways, passive movements, treadmills or virtual reality environments. While a lot has been and continues to be learned from these types of experiments, recent evidence has shown that such artificial constraints may have significant consequences on the functioning of the neural circuits of spatial navigation. NEW METHODS: We present a novel and alternative approach for effectively controlling the precise direction and speed of movement of the animal in an ethologically realistic environment, using a small robot (Sphero). RESULTS: We describe the robotic framework and demonstrate its use in replicating pre-programmed or rat recorded paths. We show that the robot can control the movement of a rat in order to produce specific trajectories and speeds. We demonstrate that the robot can be used to aid the rat in learning a spatial memory task in a large and complex environment. We show that dorsal hippocampal CA1 place cells do not remap when the rat is following the robot. Comparison with existing method(s): Our framework only involves positive motivation and has been tested together with wireless electrophysiology in large and complex environments. CONCLUSIONS: Our robotic framework can be used to design novel tasks and experiments in which electrophysiological recordings would be largely devoid of maze or task-dependent artifacts. PMID- 29113795 TI - A novel rat model of brachial plexus injury with nerve root stumps. AB - BACKGROUND: The C5-C6 nerve roots are usually spared from avulsion after brachial plexus injury (BPI) and thus can be used as donors for nerve grafting. To date, there are no appropriate animal models to evaluate spared nerve root stumps. Hence, the aim of this study was to establish and evaluate a rat model with spared nerve root stumps in BPI. NEW METHOD: In rupture group, the proximal parts of C5-T1 nerve roots were held with the surrounding muscles and the distal parts were pulled by a sudden force after the brachial plexus was fully exposed, and the results were compared with those of sham group. To validate the model, the lengths of C5-T1 spared nerve root stumps were measured and the histologies of the shortest one and the corresponding spinal cord were evaluated. RESULTS: C5 nerve root stump was found to be the shortest. Histology findings demonstrated that the nerve fibers became more irregular and the continuity decreased; numbers and diameters of myelinated axons and thickness of myelin sheaths significantly decreased over time. The survival of motoneurons was reduced, and the death of motoneurons may be related to the apoptotic process. COMPARISON WITH EXISTING METHOD(S): Our model could successfully create BPI model with nerve root stumps by traction, which could simulate injury mechanisms. While other models involve root avulsion or rupturing by distal nerve transection. CONCLUSIONS: This model would be suitable for evaluating nerve root stumps and testing new therapeutic strategies for neuroprotection through nerve root stumps in the future. PMID- 29113796 TI - The BET/BRD inhibitor JQ1 attenuates diabetes-induced cognitive impairment in rats by targeting Nox4-Nrf2 redox imbalance. AB - Diabetes-induced oxidative damage is believed to play an important role in the development of cognitive dysfunction. In this study, the involvement of the Nox4 Nrf2 redox imbalance was investigated. STZ-induced diabetic rats exhibited obvious oxidative stress and apoptosis in the hippocampus assessed by augmentation of lipid peroxidation, positive TUNEL staining, elevated ratio of Bax/Bcl-2 and increased caspase 3 activity. Furthermore, hyperglycemia markedly increased Nox4 activity and reduced the activation of Nrf2 by suppressing its up stream regulatory Akt as well as down-stream target HO-1. Significant improvement of cognitive performance was observed after treatment with the BET/BRD inhibitor JQ1, accompanied by decreased oxidative stress, neuroinflammation and apoptosis in the hippocampus. JQ1 treatment also improved changes in the neuronal cell morphology as well as increased the expression of p-AKT, Nrf2 and HO-1. Our results provide evidence indicating that JQ1 treatment could modulate Nox4-Nrf2 redox imbalance in the hippocampus and may be a promising agent for diabetes associated cognitive dysfunction. PMID- 29113797 TI - Caveolin-1, a binding protein of CD26, is essential for the anti-inflammatory effects of dipeptidyl peptidase-4 inhibitors on human and mouse macrophages. AB - We previously reported that inhibition of dipeptidyl peptidase (DPP)-4, the catalytic site of CD26, prevents atherosclerosis in animal models through suppression of inflammation; however, the underlying molecular mechanisms have not been fully elucidated. Caveolin-1 (Cav-1), a major structural protein of caveolae located on the surface of the cellular membrane, has been reported to modulate inflammatory responses by binding to CD26 in T cells. In this study, we investigated the role of Cav-1 in the suppression of inflammation mediated by the DPP-4 inhibitor, teneligliptin, using mouse and human macrophages. Mouse peritoneal macrophages were isolated from Cav-1+/+ and Cav-1-/- mice after stimulation with 3% thioglycolate. Inflammation was induced by the toll-like receptor (TLR)4 agonist, lipopolysaccharide (LPS), isolated from Escherichia coli. The expression of pro-inflammatory cytokines was determined using reverse transcription-polymerase chain reaction. Co-expression of Cav-1 and CD26 was detected using immunohistochemistry in both mouse and human macrophages. Teneligliptin treatment (10 nmol/L) suppressed the LPS-induced expression of interleukin (IL)-6 (70%) and tumor necrosis factor-alpha (37%) in peritoneal macrophages isolated from Cav-1+/+ mice. However, teneligliptin did not have any effect on the macrophages from Cav-1-/- mice. In human monocyte/macrophage U937 cells, teneligliptin treatment suppressed LPS-induced expression of pro inflammatory cytokines in a dose-dependent manner (1-10 nmol/L). These anti inflammatory effects of teneligliptin were mimicked by gene knockdown of Cav-1 or CD26 using small interfering RNA transfection. Furthermore, neutralization of these molecules using an antibody against CD26 or Cav-1 also showed similar suppression. Teneligliptin treatment specifically inhibited TLR4 and TLR5 agonist mediated inflammatory responses, and suppressed LPS-induced phosphorylation of IL 1 receptor-associated kinase 4, a downstream molecule of TLR4. Next, we determined whether teneligliptin could directly inhibit the physical interaction between Cav-1 and CD26 using the Biacore system. Binding of CD26 to Cav-1 protein was detected. Unexpectedly, teneligliptin also bound to Cav-1, but did not interfere with CD26-Cav-1 binding, suggesting that teneligliptin competes with CD26 for binding to Cav-1. In conclusion, we demonstrated that Cav-1 is a target molecule for DPP-4 inhibitors in the suppression of TLR4-mediated inflammation in mouse and human macrophages. PMID- 29113798 TI - Fucoxanthin attenuates fatty acid-induced lipid accumulation in FL83B hepatocytes through regulated Sirt1/AMPK signaling pathway. AB - The fucoxanthin, isolated from brown algae, was reported to have multiple biological functions to anti-inflammation, anti-tumor, and ameliorated obesity in mice. In this study we investigated whether fucoxanthin could inhibit lipids accumulation in FL83B hepatocytes. FL83B cells were induced as fatty liver cell model by 0.5 mM oleic acid for 48 h, and treated with various concentration of fucoxanthin for 24 h. The results demonstrated that fucoxanthin significantly suppressed lipid accumulation and decreased lipid peroxidation in hepatocytes. Fucoxanthin could decrease lipogenesis-related transcription factor expression, including sterol regulatory element-binding proteins 1c and peroxisome proliferator-activated receptor gamma. It also reduced fatty acid synthase expression and increased adipose triglyceride lipase and the phosphorylation of hormone-sensitive lipase production for lipolysis. Furthermore, fucoxanthin significantly increased phosphorylation of AMP-activated protein kinase (AMPK), and decreased activity of acetyl-CoA carboxylase for regulating fatty acid synthesis. The results suggest that fucoxanthin is an effective marine nature compound for increasing lipolysis and inhibiting lipogenesis in oleic acid induced fatty liver cells through promoted Sirt1/AMPK pathway. PMID- 29113799 TI - Protein S-glutathionylation induced by hypoxia increases hypoxia-inducible factor 1alpha in human colon cancer cells. AB - Hypoxia is a common characteristic of many types of solid tumors. Intratumoral hypoxia selects for tumor cells that survive in a low oxygen environment, undergo epithelial-mesenchymal transition, are more motile and invasive, and show gene expression changes driven by hypoxia-inducible factor-1alpha (HIF-1alpha) activation. Therefore, targeting HIF-1alpha is an attractive strategy for disrupting multiple pathways crucial for tumor growth. In the present study, we demonstrated that hypoxia increases the S-glutathionylation of HIF-1alpha and its protein levels in colon cancer cells. This effect is significantly prevented by decreasing oxidized glutathione as well as glutathione depletion, indicating that S-glutathionylation and the formation of protein-glutathione mixed disulfides is related to HIF-1alpha protein levels. Moreover, colon cancer cells expressing glutaredoxin 1 are resistant to inducing HIF-1alpha and expressing hypoxia responsive genes under hypoxic conditions. Therefore, S-glutathionylation of HIF 1alpha induced by tumor hypoxia may be a novel therapeutic target for the development of new drugs. PMID- 29113800 TI - A Prdm8 target gene Ebf3 regulates multipolar-to-bipolar transition in migrating neocortical cells. AB - Precise control of neuronal migration is essential for the development of the neocortex. However, the molecular mechanisms underlying neuronal migration remain largely unknown. Here we identified helix-loop-helix transcription factor Ebf3 as a Prdm8 target gene, and found that Ebf3 is a key regulator of neuronal migration via multipolar-to-bipolar transition. Ebf3 knockdown cells exhibited severe defects in the formation of leading processes and an inhibited shift to the locomotion mode. Moreover, we found that Ebf3 knockdown represses NeuroD1 transcription, and NeuroD1 overexpression partially rescued migration defects in Ebf3 knockdown cells. Our findings highlight the critical role of Ebf3 in multipolar-to-bipolar transition via positive feedback regulation of NeuroD1 in the developing neocortex. PMID- 29113801 TI - Producing a glycosylating Escherichia coli cell factory: The placement of the bacterial oligosaccharyl transferase pglB onto the genome. AB - Although Escherichia coli has been engineered to perform N-glycosylation of recombinant proteins, an optimal glycosylating strain has not been created. By inserting a codon optimised Campylobacter oligosaccharyltransferase onto the E. coli chromosome, we created a glycoprotein platform strain, where the target glycoprotein, sugar synthesis and glycosyltransferase enzymes, can be inserted using expression vectors to produce the desired homogenous glycoform. To assess the functionality and glycoprotein producing capacity of the chromosomally based OST, a combined Western blot and parallel reaction monitoring mass spectrometry approach was applied, with absolute quantification of glycoprotein. We demonstrated that chromosomal oligosaccharyltransferase remained functional and facilitated N-glycosylation. Although the engineered strain produced less total recombinant protein, the glycosylation efficiency increased by 85%, and total glycoprotein production was enhanced by 17%. PMID- 29113802 TI - Desflurane inhibits endothelium-dependent vasodilation more than sevoflurane with inhibition of endothelial nitric oxide synthase by different mechanisms. AB - The effects of desflurane on endothelium-dependent vasodilation remain uncertain, whereas sevoflurane is known to inhibit it. Endothelium-dependent vasodilation is mainly mediated by endothelial nitric oxide synthase. The effects of desflurane on endothelium-dependent vasodilation were compared with those of sevoflurane, and inhibition mechanisms, including phosphorylation of endothelial nitric oxide synthase and the calcium pathway, were evaluated for the two anesthetics. We hypothesized that desflurane would inhibit endothelium-dependent vasodilation in a concentration-dependent manner more than sevoflurane, with inhibition of a calcium pathway. Isolated rat aortic rings were randomly assigned to treatment with desflurane or sevoflurane for measurements of the vasodilation ratio. To determine NO production with desflurane and sevoflurane, an in vitro assay was performed with cultured bovine aortic endothelial cells. These cells were also used for measurement of intracellular calcium or Western blotting. For endothelium-dependent vasodilation, the ratio of vasodilation was more significantly inhibited by 11.4% desflurane than by 4.8% sevoflurane. Inhibition did not between 5.7% desflurane and 2.4% sevoflurane. No inhibitory effect of desflurane or sevoflurane was observed in endothelium-denuded aorta. Desflurane inhibited nitric oxide production caused by stimulation of bradykinin significantly more than sevoflurane. Desflurane had a greater suppressive effect on the bradykinin-induced increase in intracellular calcium concentration than did sevoflurane. Sevoflurane, but not desflurane, inhibited phosphorylation of the serine 1177 residue by bradykinin stimulation. Desflurane inhibited endothelium-dependent vasodilation more than sevoflurane through inhibition of a calcium pathway. Sevoflurane inhibited endothelium-dependent vasodilation by inhibition of phosphorylation of the serine 1177 residue of endothelial nitric oxide synthase. PMID- 29113803 TI - Demonstration of pharmaceutical tablet coating process by injection molding technology. AB - We demonstrate the coating of tablets using an injection molding (IM) process that has advantage of being solvent free and can provide precision coat features. The selected core tablets comprising 10% w/w griseofulvin were prepared by an integrated hot melt extrusion-injection molding (HME-IM) process. Coating trials were conducted on a vertical injection mold machine. Polyethylene glycol and polyethylene oxide based hot melt extruded coat compositions were used. Tablet coating process feasibility was successfully demonstrated using different coating mold designs (with both overlapping and non-overlapping coatings at the weld) and coat thicknesses of 150 and 300 MUm. The resultant coated tablets had acceptable appearance, seal at the weld, and immediate drug release profile (with an acceptable lag time). Since IM is a continuous process, this study opens opportunities to develop HME-IM continuous processes for transforming powder to coated tablets. PMID- 29113804 TI - Mechanisms of drug release in pH-sensitive micelles for tumour targeted drug delivery system: A review. AB - During the past decades, chemotherapy has been regarded as the most effective method for tumor therapy, but still faces significant challenges, such as poor tumor selectivity and multidrug resistance. The development of targeted drug delivery systems brings certain dramatic advantages for reducing the side effects and improving the therapeutic efficacy. Coupling a specific stimuli-triggered drug release mechanism with these delivery systems is one of the most prevalent approaches for targeted therapy. Among these approaches, pH-sensitive micelles are regarded as the most general strategy with advantages of increasing solubility of water-insoluble drugs, pH-sensitive release, high drug loading, etc. This review will focus on the potential of pH-sensitive micelles in tumor therapy, analyze four types of drug-loaded micelles and mechanisms of drug release and give an exhaustive collection of recent investigations. Sufficient understanding of these mechanisms will help us to design more efficient pH sensitive drug delivery system to address the challenges encountered in targeted drug delivery systems for tumor therapy. PMID- 29113805 TI - Octenylsuccinate hydroxypropyl phytoglycogen enhances the solubility and in-vitro antitumor efficacy of niclosamide. AB - Niclosamide is a promising antitumor agent, but its low aqueous solubility places limit on its antitumor efficacy. The aim of this study was to improve the solubility and dissolution of niclosamide through using octenylsuccinate hydroxypropyl phytoglycogen (OHPP), an amphiphilic dendrimer-like biopolymer. The niclosamide-OHPP solid dispersion (niclo-OHPP SD) was prepared and characterized in terms of crystallinity, molecular interactions, solubility and dissolution profile, in-vitro antitumor efficacy, and in-vitro transdermal amount. X-ray powder diffraction analysis showed the amorphous state of niclosamide in niclo OHPP SD. FTIR showed the formation of hydrogen bonding between niclosamide and OHPP. Solubility of niclosamide with niclo-OHPP SD was about 11,914 times that of niclosamide alone, and 61% of niclosamide with niclo-OHPP SD dissolved in 3 h upon dissolution. Against three cancer cell lines, cytotoxicity assays indicated greater inhibition by using niclo-OHPP SD than by using DMSO-assisted niclosamide solution. The cumulative transdermal amount of niclosamide with niclo-OHPP SD was 5.3 times that with niclosamide alone. This study showed that the use of OHPP could provide strong support for the development of niclosamide-based drug formulations. PMID- 29113806 TI - Cynatratoside-C from Cynanchum atratum displays anti-inflammatory effect via suppressing TLR4 mediated NF-kappaB and MAPK signaling pathways in LPS-induced mastitis in mice. AB - The present study was conducted to isolate anti-inflammatory compound from Cynanchum atratum and investigate the molecular mechanisms of active compound against lipopolysaccharide (LPS)-induced mastitis in mice. Bioassay-guided fractionations and isolation (via ex vivo tests) of compounds with anti inflammatory activity were performed on roots of C. atratum yielding a pure bioactive compound: Cynatratoside-C, identified by comparing spectral data (EI MS, 1H NMR and 13C NMR) with literature values. Ex vivo tests showed that Cynatratoside-C inhibited the expression of TLR4 and pro-inflammatory cytokine (TNF-alpha, IL-6 and IL-1beta) production in LPS-stimulated primary mouse mammary epithelial cells. In vivo results indicated that Cynatratoside-C markedly attenuated LPS-induced mammary histopathologic changes and mammary oxidative stress (MDA, SOD, GPx) activity. Besides, Cynatratoside-C blocked the expression of Toll-like receptor 4 (TLR4) and then suppressed the phosphorylation of nuclear transcription factor-kappa B (NF-kappaB) p65 and degradation inhibitor of NF kappaBalpha (IkappaBalpha). Further study showed that Cynatratoside-C could suppress the phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in mitogen-activated protein kinase (MAPK) signal pathway. In conclusion, our results suggest that Cynatratoside-C played an anti-inflammatory role in LPS-induced mastitis by regulating TLR4 and the NF kappaB and MAPK signaling pathways in mammary gland tissues. Cynatratoside-C may be a promising potential therapeutic reagent for the treatment of mastitis. PMID- 29113807 TI - Cyanate improves insulin sensitivity and hepatic steatosis in normal and high fat fed mice: Anorexic and antioxidative effects. AB - Obesity is an important contributing factor to progression of chronic kidney disease. Cyanate, known as uremic toxin, is an electrophile produced spontaneously from urea or by myeloperoxidase-catalyzed oxidation of thiocyanate. Herein, we explored metabolic effects of cyanate in normal chow diet (NCD)- and high fat diet (HFD)-fed mice. Mice were treated with cyanate (1 mg/mL in drinking water) and fed NCD or HFD. Peritoneal glucose tolerance test (PGTT) and insulin tolerance test (ITT) were performed. Blood urea nitrogen (BUN) and creatinine concentrations were determined. Kidney and liver tissues were analyzed for reactive oxygen species (ROS) and lipid accumulations. Human albumin was carbamylated and evaluated for ROS scavenging activities. Contrary to our expectations, we found that cyanate treatment improved increased insulin sensitivity and alleviated hepatic steatosis in NCD- and HFD-fed mice. PGTT and ITT revealed faster and immediate glucose clearance in cyanate-treated NCD- and HFD-fed mice. Histological analysis of kidney and serum levels of BUN and creatinine showed no significant differences between cyanate-treated and control mice groups. Cyanate treatment reduced appetite and body weight in both NCD- and HFD-fed mice groups. Cyanate also decreased lipid peroxidation levels in the sera and the kidney, attenuated ROS levels in the kidney, which lead us to the findings that cAlb significantly reduced ROS levels compared to Alb in Caki-1 kidney and human umbilical vein endothelial cells. The results in this study may indicate that cyanate improves insulin sensitivity and hepatic steatosis possibly via exerting anorexic and antioxidative effects. PMID- 29113808 TI - Galangin induces cell death by modulating the expression of glyoxalase-1 and Nrf 2 in HeLa cells. AB - The present study was designed to understand the anticancer property and molecular mechanisms associated with chemo preventive effects of galangin. The anticancer effect was evaluated in vitro using human cervical cancer cell line (HeLa). Galangin was found to be effective in inducing cell death and inhibiting proliferation & migration significantly. The inhibitory effect of galangin could be correlated with the increase in ROS production & induction of apoptosis. Besides this the activity of glyoxalase-1, an enzyme important for the detoxification of cytotoxic metabolite methy glyoxal and Nrf-2 (a trascription factor), involved in redox signalling were found to be decreased. We concluded that galangin exerts its chemo preventive effect via redox signalling by inhibiting glyoxalase-1 & increasing oxidative & carbonyl stress. PMID- 29113810 TI - The search image as link between sensation, perception and action. AB - In this paper, it is argued that Jakob von Uexkull's "search image" notion, the original version of this notion within ethology, is still of use. A search image, in Uexkull's sense, is an imagined object that an organism has in mind when it searches for something. Uexkull's conception of the search image is useful both for understanding the theoretical context of contemporary notions of search images, and with an eye to envisioning possible future developments of the idea. Uexkull's classical notion differs from contemporary versions in that it has a wider application, and is therefore of greater relevance to theoretical biology and cognitive science. It constituted an integral part of his ground-breaking Umwelt theory, stressing the fundamental plasticity of the Umwelt, the subjective lifeworld of an animal or human subject. In a contemporary development of Umwelt theory, expressed by the tripartite Umwelt model, the search image notion represents a key connection between the directly experienced core Umwelt and the mediated Umwelt. However, the key function that schemata have in cognitive processes is also the starting point for mistakes in perception. This article details both the constructive function search images have in animal and human perception, and the mismatches in perception they can lead to. It also explains how the existence of search images can help explain puzzles concerning subjective and neural time in contemporary cognitive science. PMID- 29113811 TI - Incorporating gene ontology into fuzzy relational clustering of microarray gene expression data. AB - The product of gene expression works together in the cell for each living organism in order to achieve different biological processes. Many proteins are involved in different roles depending on the environment of the organism for the functioning of the cell. In this paper, we propose gene ontology (GO) annotations based semi-supervised clustering algorithm called GO fuzzy relational clustering (GO-FRC) where one gene is allowed to be assigned to multiple clusters which are the most biologically relevant behavior of genes. In the clustering process, GO FRC utilizes useful biological knowledge which is available in the form of a gene ontology, as a prior knowledge along with the gene expression data. The prior knowledge helps to improve the coherence of the groups concerning the knowledge field. The proposed GO-FRC has been tested on the two yeast (Saccharomyces cerevisiae) expression profiles datasets (Eisen and Dream5 yeast datasets) and compared with other state-of-the-art clustering algorithms. Experimental results imply that GO-FRC is able to produce more biologically relevant clusters with the use of the small amount of GO annotations. PMID- 29113809 TI - MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. AB - BACKGROUND & AIMS: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. METHODS: We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. RESULTS: Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. CONCLUSIONS: miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents. PMID- 29113812 TI - Differential associations of lower cardiac vagal tone with insulin resistance and insulin secretion in recently diagnosed type 1 and type 2 diabetes. AB - OBJECTIVE: It is unclear to which extent altered insulin sensitivity/secretion contribute to the development of diabetic cardiovascular autonomic neuropathy (CAN) characterized by diminished heart rate variability (HRV). We hypothesised that lower HRV is differentially associated with measures of insulin resistance and insulin secretion in recent-onset type 1 and type 2 diabetes. MATERIALS/METHODS: This cross-sectional study included participants from the German Diabetes Study with type 1 (n=275) or type 2 diabetes (n=450) with known diabetes duration <=1year and glucose-tolerant controls (n=81). Four time domain and frequency domain HRV measures each, reflecting vagal and/or sympathetic modulation were determined over 3h during a hyperinsulinaemic-euglycaemic clamp. Insulin sensitivity was calculated as the M-value, while insulin secretion was determined by glucagon-stimulated incremental C-peptide (DeltaC-peptide). RESULTS: After adjustment for sex, age, BMI, smoking, and HbA1c, both M-value and DeltaC-peptide were lower in the diabetes groups compared to controls (P<0.05). In multiple linear regression analyses after Bonferroni correction, vagus mediated HRV indices were positively associated with M-value in both diabetes types (P<0.05) and inversely associated with DeltaC-peptide only in participants with type 1 diabetes (P<0.05). In type 2 diabetes, the low-frequency/high frequency (LF/HF) power as an indicator of sympathovagal balance was weakly inversely associated with M-value. CONCLUSIONS: Insulin resistance may contribute to the development of early cardiovagal suppression rather than sympathetic predominance in both diabetes types, while in type 1 diabetes a lower glucagon stimulated insulin secretion is linked to a possibly compensatory higher parasympathetic tone. Whether interventions aimed at reducing insulin resistance could also reduce the risk of CAN remains to be established. PMID- 29113813 TI - Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it? AB - Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1). Meal-induced GLP-1 secretion is as much as tenfold higher in patients after GB compared to non surgical individuals and inhibition of GLP-1 action during meals reduces postprandial hyperinsulinemia after GB two to three times more than that in persons without surgery. Moreover, in a subgroup of patients with the late complication of postprandial hyperinsulinemic hypoglycemia after GB, GLP1R blockade reverses hypoglycemia by reducing meal stimulated insulin secretion. The role of enteroinsular axis activity after SG, an increasingly popular alternative to GB, is less understood but, similar to GB, SG accelerates nutrient delivery to the intestine, improves glucose tolerance, and increases postprandial GLP-1 secretion. This review will focus on the current evidence for and against the role of GLP-1 on glycemic effects of GB and will also highlight differences between GB and SG. PMID- 29113814 TI - Plasma cell-free DNA level and its integrity as biomarkers to distinguish non small cell lung cancer from tuberculosis. AB - AIMS: The aim of this study was to evaluate the potential clinical value of the plasma cell-free DNA (cfDNA) concentrations and strand integrity as an auxiliary tool for Non-small cell lung cancer (NSCLC) differential diagnosis from tuberculosis in patients with solitary pulmonary nodules detected by computed tomography (CT). METHODS: This research was divided into 3 groups: NSCLC (n=106), tuberculosis (n=105) and healthy controls (n=107). The quantization of plasma DNA fragments was performed by quantitative real-time PCR. Amplifying and quantifying shorter (115bp) and longer (247bp) fragments from abundant genomic ALU repeats. RESULTS: The level of cfDNA (ALU115) in patients with NSCLC [95.67 (51.28, 238.85) ng/MUl] was significantly higher than that in patients with tuberculosis [59.60 (34.25, 102.53) ng/MUl, P=0.001] and that in healthy controls [44.66 (24.56, 66.54) ng/MUl, P=0.001]. The integrity of cfDNA in patients with NSCLC [5.91(4.14, 7.45)] was also significantly higher than that in patients with tuberculosis [3.85 (2.91, 5.06), P=0.000] and that in healthy controls [2.78(2.18, 4.82), P=0.000]. Receiver-operating characteristic (ROC) curve analysis showed that cfDNA(ALU115) and its integrity could be used as biomarkers to distinguish NSCLC from tuberculosis (AUC=0.628, P=0.001, cut-off values=91.48, sensitivity=57.50%, specificity=64.80%; AUC=0.722, P=0.000, cut-off values=5.54, sensitivity=55.70%, specificity=82.90%, respectively). In addition, the effect of integrity of cfDNA(AUC=0.722) to distinguish NSCLC from tuberculosis was higher than traditional tumor marker Carbohydrate antigen 125(CA125) (AUC=0.626), Neuron specific enolase(NSE) (AUC=0.716) and Carcino-embryonic antigen(CEA) (AUC=0.589). CONCLUSIONS: cfDNA and its integrity could be used as indicators for identification of NSCLC from tuberculosis. Moreover, the effect of integrity of cfDNA to distinguish NSCLC from tuberculosis was higher than traditional tumor marker CA125, NSE and CEA. PMID- 29113815 TI - Evaluation of Left Ventricular Diastolic Function by the Intensivist. AB - The assessment of left ventricular diastolic function is an important element of advanced critical care echocardiography. Standard methods of evaluating diastolic function that are routinely performed on an elective basis in the cardiology echocardiography laboratory may be difficult to apply in the critical care unit. In this article, we review methods of measuring diastolic function with echocardiography that are of relevance to the intensivist and present two options for measurement: the standard cardiology method and a simplified approach. PMID- 29113816 TI - HDAC2 Suppresses IL17A-Mediated Airway Remodeling in Human and Experimental Modeling of COPD. AB - BACKGROUND: Although airway remodeling is a central feature of COPD, the mechanisms underlying its development have not been fully elucidated. The goal of this study was to determine whether histone deacetylase (HDAC) 2 protects against cigarette smoke (CS)-induced airway remodeling through IL-17A-dependent mechanisms. METHODS: Sputum samples and lung tissue specimens were obtained from control subjects and patients with COPD. The relationships between HDAC2, IL-17A, and airway remodeling were investigated. The effect of HDAC2 on IL-17A-mediated airway remodeling was assessed by using in vivo models of COPD induced by CS and in vitro culture of human bronchial epithelial cells and primary human fibroblasts exposed to CS extract, IL-17A, or both. RESULTS: HDAC2 and IL-17A expression in the sputum cells and lung tissue samples of patients with COPD were associated with bronchial wall thickening and collagen deposition. Il-17a deficiency (Il-17a-/-) resulted in attenuation of, whereas Hdac2 deficiency (Hdac2+/-) exacerbated, CS-induced airway remodeling in mice. IL-17A deletion also attenuated airway remodeling in CS-exposed Hdac2+/- mice. HDAC2 regulated IL 17A production partially through modulation of CD4+ T cells during T helper 17 cell differentiation and retinoid-related orphan nuclear receptor gammat in airway epithelial cells. In vitro, IL-17A deficiency attenuated CS-induced mouse fibroblast activation from Hdac2+/- mice. IL-17A-induced primary human fibroblast activation was at least partially mediated by autocrine production of transforming growth factor beta 1. CONCLUSIONS: These findings suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of airway remodeling by suppressing airway inflammation and modulating fibroblast activation in COPD. PMID- 29113817 TI - Membrane channels formed by gap junction proteins. PMID- 29113818 TI - Cytochrome-c-assisted escape of cardiolipin from a model mitochondrial membrane. AB - Binding of cytochrome c (Cytc) to cardiolipin (CL) in the inner mitochondrial membrane is involved with the onset of apoptosis. In this study, we used CL containing phospholipid monolayers to mimic the inner mitochondrial membrane. Constant pressure insertion assay was employed to monitor the Cytc-induced expansion of membrane area. Simultaneous epifluorescence microscopy imaging afforded the in-situ visualization of phospholipid demixing and sorting in the membrane. The formation of a CL-rich Ld phase has been observed to prelude the insertion of Cytc. Based on the relative expansion of membrane area, a cluster of a few amino acid residues of Cytc with an area of 117+/-7A2 has been found to insert into the membrane. The insertion of Cytc disrupted the membrane in a way facilitating the escape of CL. When the exclusion of Cytc was induced by compression, CL molecules appeared to escape the membrane together with the protein, which resulted in a loss of more than a half of CL content from the membrane. These findings may aid in understanding the early events leading to the remodeling of inner mitochondrial membrane and loss of its function during apoptosis. PMID- 29113819 TI - Conformational landscapes of membrane proteins delineated by enhanced sampling molecular dynamics simulations. AB - The expansion of computational power, better parameterization of force fields, and the development of novel algorithms to enhance the sampling of the free energy landscapes of proteins have allowed molecular dynamics (MD) simulations to become an indispensable tool to understand the function of biomolecules. The temporal and spatial resolution of MD simulations allows for the study of a vast number of processes of interest. Here, we review the computational efforts to uncover the conformational free energy landscapes of a subset of membrane proteins: ion channels, transporters and G-protein coupled receptors. We focus on the various enhanced sampling techniques used to study these questions, how the conclusions come together to build a coherent picture, and the relationship between simulation outcomes and experimental observables. PMID- 29113820 TI - Biorefinery production of poly-3-hydroxybutyrate using waste office paper hydrolysate as feedstock for microbial fermentation. AB - Waste paper, a major fraction of municipal solid waste, has a potential to serve as renewable feedstock for the biorefineries of fuels, chemicals and materials due to rich in cellulose and abundant at low cost. This study evaluates the possibility of waste office paper (WOP) to serve as a potential feedstock for the biorefinery production of poly (3-hydroxybutyrate). In this study, the WOP was pretreated, enzymatically saccharified and the hydrolysate was used for PHB production. The hydrolysate mainly consists of glucose (22.70g/L) and xylose (1.78g/L) and the corresponding sugar yield was about 816mg/g. Ammonium sulphate and C/N ratio 20 were identified as most favorable for high yield of PHB. The batch fermentation of Cupriavidus necator using the pretreated WOP hydrolysate resulted in cell biomass, PHB production and PHB content of 7.74g/L, 4.45g/L and 57.52%, respectively. The volumetric productivity and yield achieved were 0.061g/L/h and 0.210g/g sugar, respectively. The results suggested that WOP could be a potential alternative feedstock for the biorefinery production of bioplastics. PMID- 29113821 TI - Multiple adaptive amino acid substitutions increase the virulence of a wild waterfowl-origin reassortant H5N8 avian influenza virus in mice. AB - A novel H5N8 highly pathogenic avian influenza virus (HPAIV) caused poultry outbreaks in the Republic of Korea in 2014. The novel H5N8 HPAIV has spread to Asia, Europe, and North America and caused great public concern from then on. Here, we generated mouse-adapted variants of a wild waterfowl-origin H5N8 HPAIV to identify adaptive mutants that confer enhanced pathogenicity in mammals. The mouse lethal doses (MLD50) of the mouse-adapted variants were reduced 31623-fold compared to the wild-type (WT) virus. Mouse-adapted variants displayed enhanced replication in vitro and in vivo, and expanded tissue tropism in mice. Sequence analysis revealed four amino acid substitutions in the PB2 (E627K), PA (F35S), HA (R227H), and NA (I462V) proteins. These data suggest that multiple amino acid substitutions collaboratively increase the virulence of a wild bird-origin reassortant H5N8 HPAIV and cause severe disease in mice. PMID- 29113822 TI - Lack of TNF-alpha signaling through p55 makes the mice more susceptible to acute infection but does not alter state of latency and reactivation of HSV-1. AB - TNF-alpha has been shown to play an important role in pathogenesis and latency of HSV-1 infections. TNF-alpha signals through TNFR1 (p55) and TNFR2 (p75), and signaling through p55 generally results in gene activation leading to induction of inflammatory responses. Here, we studied the role of TNF-alpha signaling in latent virus reactivation in p55-knock out (KO) mouse model of ocular HSV-1 infection. We found that KO mice are more susceptible to HSV-1 infection compared to wild type C57Bl/6 mice. While the absence of TNFRI signaling enhanced the ganglion latent DNA content by two folds, there was no difference in the maintenance and reactivation of latent HSV-1. Strikingly, interfering with inflammatory responses through PGE2 synthesis by treating latently infected wild type mice with indomethacin (COX inhibitor) prior to UV-exposure prevented HSV-1 reactivation. These results suggest that reactivation of latent HSV-1 might result from the cumulative effects of a cascade of inflammatory cytokines including TNF-alpha. PMID- 29113823 TI - Genomic comparison of bovine papillomavirus 1 isolates from bovine, equine and asinine lesional tissue samples. AB - Several attempts have been made to categorize equid- and bovid-specific bovine papillomavirus 1 (BPV1) isolates based on sequence tags. This study includes newly determined sequence information from 33 BPV1 isolates of equine, asinine and bovine origin and investigates sequence bias due to host species. Twenty of the viral genomes were sequenced over their entire length and a further thirteen were sequenced, including flanking sequences, at two specific sites, the LCR and the E5 ORF. Alignment and analyses of the sequences did not reveal statistically significant site differences between the sequences of bovine and equid origin. None of the proposed sites of divergence noted by other authors demonstrated significant species-specific characteristics. Our results suggest that BPV1 is shared between equine, asinine and bovine host species, and that viral transfer between bovines and equids is a repeated and ongoing phenomenon. PMID- 29113824 TI - Comparative analysis of different cell systems for Zika virus (ZIKV) propagation and evaluation of anti-ZIKV compounds in vitro. AB - A strong correlation between Zika virus (ZIKV) infection and severe neurological disease in newborns and occasionally adults has emerged in the Brazilian outbreak. Efficient human cell-based assays are required to test candidate inhibitors of ZIKV replication. The aim of this work was to investigate ZIKV propagation and quantification in different cell lines. The human (U87, A549, Huh7), mosquito (C6/36) and monkey (VERO E6) cell lines tested were all permissive to ZIKV infection. When assessed by plaque forming units (PFU) in three different target cell lines, the maximal production of ZIKV was achieved in Huh7 at day 3 post-infection (6.38+/-0.44 log10PFU/ml). The C6/36 cell line showed a low and slow production of virus when compared with other cell lines. A549 readout cells generated a larger number of plaques compared to Huh7 but not to VERO E6 cells. ZIKV PFU and RNA titers showed the highest correlation when Huh7 and A549 were used as the producer and readout cells, respectively. Also, U87 cells produced ZIKV RNA titers which were highly correlated with PFU independently from the readout cell line. Using the best virus-cell system, sofosbuvir and ribavirin EC50 were 1.2MUM and 1.1MUM when measured through plaque assay, and 4.2MUM and 5.2MUM when measured by quantitative real time PCR (qRT PCR), respectively. In summary, ZIKV can efficiently infect different human cell lines and rapidly reach peak viral titers. Overall, A549 cells appear to be as efficient as the VERO E6 gold standard for plaque assay allowing the use of human, rather than simian, cells for evaluating candidate anti-ZIKV compounds by the reference assay. The possibility to replace the labor-intensive plaque assay with the more rapid and easy-to-perform qRT-PCR is appealing and warrants further investigation. PMID- 29113825 TI - Isolation and genetic characterization of encephalomyocarditis virus 1 from a deceased captive hamadryas baboon. AB - In 2007, numerous hamadryas baboons (Papio hamadryas) died suddenly in an aviary of a primate institute in Sochi, Russia, in the absence of prior clinical signs. Necropsies were suggestive of encephalomyocarditis virus infection, but RT-PCR assays with commonly used primers were negative. Here we report the histopathological results obtained during necropsies and the isolation and genomic characterization of a divergent strain of encephalomyocarditis virus 1 (EMCV-1) from heart tissue of one of the succumbed hamadryas baboons. Phylogenetic analysis indicates that the isolated virus belongs to the newly proposed EMCV-1 lineage G, which clusters alongside lineage C ("Mengo virus"). This study is the first report describing a lineage G strain of EMCV-1 as the etiological agent of a lethal disease outbreak among captive nonhuman primates in Europe. PMID- 29113826 TI - Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance. AB - Ghrelin, a growth hormone-releasing peptide, potentially improves cardiac function, but the mechanisms remain unclear. In the study, the rat heart failure (HF) model was established by ligating the left anterior descending coronary artery (LAD) and treated with ghrelin (100MUg/kg, subcutaneous injection, bid); neonatal rat cardiomyocytes were cultured and stimulated with Ang II (0.1MUM) and ghrelin(0.1MUM) to explore the underlying mechanism of ghrelin in myocardial remodeling. Hemodynamic changes and serum brain natriuretic peptide (BNP) concentrations were measured to assess cardiac function. Left ventricular mass index (LVMI), hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were performed to evaluate myocardial fibrosis. Interestingly, ghrelin significantly improved cardiac function by inhibiting fibrous tissue proliferation. To further explore the mechanisms by which ghrelin interferes with myocardial fibrosis, the levels of activin A (Act A) and its blocker-follistatin (FS) were examined by immunohistochemistry; Act A levels were significantly increased in the myocardial infarction (MI), and ghrelin administeration downregulated Act A expression. In contrast, FS expression showed no significant change in all experimental groups. Furthermore, ghrelin decreased Ang II-induced Act A expression with no effect on FS expression in primary rat cardiomyocytes in vitro (real-time quantitative PCR and ELISA). Thus, ghrelin corrected the Act A/FS imbalance. Finally, Act A treated cultured primary rat cardiac fibroblasts (CFs) showed increased proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay] and enhanced expressions of type I and type III collagen (Col I and Col III) (real-time quantitative PCR). These data suggest that ghrelin inhibits myocardial fibrosis, attenuates left ventricular remodeling, and eventually improves cardiac function by adjusting Act A/FS imbalance. PMID- 29113827 TI - WITHDRAWN: Toxins in Neurobiology: new tools from old molecules. PMID- 29113828 TI - Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4+ T cells of systemic lupus erythematosus. AB - DNA hypomethylation plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus CD4+ T cells. Our results showed that BDH2 expression was decreased, intracellular iron was increased, global DNA hydroxymethylation level was elevated, while methylation level was reduced in lupus CD4+ T cells compared with healthy controls. The decreased BDH2 contributed to DNA hyper-hydroxymethylation and hypomethylation via increasing intracellular iron in CD4+ T cells, which led to overexpression of immune related genes. Moreover, we showed that BDH2 was the target gene of miR-21. miR-21 promoted DNA demethylation in CD4+ T cells through inhibiting BDH2 expression. Our data demonstrated that the dysregulation of iron homeostasis in CD4+ T cells induced by BDH2 deficiency contributes to DNA demethylation and self-reactive T cells in SLE. PMID- 29113829 TI - Increased motor neuron resilience by small molecule compounds that regulate IGF II expression. AB - The selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) is evident by sparing of a few subpopulations during this fast progressing and debilitating degenerative disease. By studying the gene expression profile of resilient vs. vulnerable motor neuron populations we can gain insight in what biomolecules and pathways may contribute to the resilience and vulnerability. Several genes have been found to be differentially expressed in the vulnerable motor neurons of the cervical spinal cord as compared to the spared motor neurons in CNIII/IV. One gene that is differentially expressed and present at higher levels in less vulnerable motor neurons is insulin-like growth factor II (IGF II). The motor neuron protective effect of IGF-II has been demonstrated both in vitro and in SOD1 transgenic mice. Here, we have screened a library of small molecule compounds and identified inducers of IGF-II mRNA and protein expression. Several identified compounds significantly protected motor neurons from glutamate excitotoxicity in vitro. One of the compounds, vardenafil, resulted in a complete motor neuron protection, an effect that was reversed by blocking receptors of IGF II. When administered to naive rats vardenafil was present in the cerebrospinal fluid and increased IGF-II mRNA expression in the spinal cord. When administered to SOD1 transgenic mice, there was a significant delay in motor symptom onset and prolonged survival. Vardenafil also increased IGF-II mRNA and protein levels in motor neurons derived from healthy subject and ALS patient iPSCs, activated a human IGF-II promoter and improved survival of ALS-patient derived motor neurons in culture. Our findings suggest that modulation of genes differentially expressed in vulnerable and resilient motor neurons may be a useful therapeutic approach for motor neuron disease. PMID- 29113830 TI - Sex- and age-associated differences in episodic-like memory and transcriptional regulation of hippocampal steroidogenic enzymes in rats. AB - The aim of this study was to evaluate the episodic-like memory (ELM) and the transcriptional regulation of the enzymes involved in hippocampal allopregnanolone synthesis in young adult and middle-aged male and female rats. Young adult males, but not middle-aged ones, showed a good performance in the ELM task. In contrast, neither young nor middle-aged females were able to discriminate the spatial order in which the objects were presented. In females, aging decreased the transcription of steroidogenic-related genes. In addition, the mRNA levels of 5alpha-reductase-1 were higher and the methylation of its promoter was lower in young adult females than in males, suggesting an epigenetic control. Further studies are needed to establish correlations between ELM and the transcriptional regulation of hippocampal steroidogenic enzymes. Our results contribute to the knowledge of sex differences in gene expression, methylation and memory during aging. PMID- 29113831 TI - The effect of ovarian reserve and receptor signalling on granulosa cell apoptosis during human follicle development. AB - The poor oocyte quality in older women has previously been linked to the depletion of the ovarian reserve of primordial follicles and an increase in granulosal apoptosis. Granulosa cells were collected from 198 follicles and individually analysed by flow cytometry. In the young IVF patients, the level of apoptosis was inversely proportional to the expression of bone morphogenetic protein (BMPR1B) and follicle stimulating hormone (FSH) receptors. Conversely, in the older patients this relationship became dysregulated. In the older patients, at the time of preovulatory maturation, the reduced apoptosis reflects the poor mitogenic growth turnover rate of healthy follicles rather than the death rate in an atretic follicle. Restoring an optimum receptor density and down-regulation of receptors may improve oocyte quality and the pregnancy rate in older women. PMID- 29113832 TI - Connecting chaperone-mediated autophagy dysfunction to cellular senescence. AB - Chaperone-mediated autophagy (CMA) is one of the main pathways of the lysosome autophagy proteolytic system. It regulates different cellular process through the selective degradation of cytosolic proteins. In ageing, the function of CMA is impaired causing an inefficient stress response and the accumulation of damaged, oxidized or misfolded proteins, which is associated with numerous age-related diseases. Deficient protein degradation alters cellular proteostasis and activates signaling pathways that culminate in the induction of cellular senescence, whose accumulation is a typical feature of ageing. However, the relationship between CMA activity and cellular senescence has been poorly studied. Here, we review and integrate evidence showing that CMA dysfunction correlates with the acquisition of many hallmarks of cellular senescence and propose that loss of CMA function during aging promotes cellular senescence. PMID- 29113833 TI - The role of genetic background in susceptibility to chemical warfare nerve agents across rodent and non-human primate models. AB - Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies. Here, we discuss the available literature on strain and selected line differences in cholinesterase activity levels and response to nerve agent-induced toxicity and seizures. We also discuss the available cholinesterase and toxicity literature across different non-human primate species. The available data suggest that robust genetic differences exist in cholinesterase activity, nerve agent-induced toxicity, and chemical-induced seizures. Available cholinesterase data suggest that acetylcholinesterase activity differs across strains, but are limited by the paucity of carboxylesterase data in strains and selected lines. Toxicity and seizures, two outcomes of nerve agent exposure, have not been fully evaluated for genetic differences, and thus further studies are required to understand baseline strain and selected line differences. PMID- 29113834 TI - Aflatoxin B1 impairs sperm quality and fertilization competence. AB - Aflatoxins are poisonous byproducts of the soilborne fungus Aspergillus, involved in the decomposition of plant materials. Aflatoxins can be found in various food products, such as maize, sorghum, millet, rice and wheat. AFB1 is the most toxic of these, classified as a carcinogen and mutagen for both humans and animals. AFB1 has been detected in human cord blood and placenta; however, its toxic effect on sperm is less known. The current study examines sperm responses associated with AFB1 exposure. These included acrosome integrity and function, mitochondrial polarity, DNA fragmentation, fertilization competence and early embryonic development. Spermatozoa were obtained from bull ejaculate and epididymis and capacitated in vitro for 4h with 0, 0.1, 1, 10 and 100MUM AFB1. Following capacitation, acrosome reaction (AR) was induced by Ca2+ ionophore. The integrity and functionality of sperm were examined simultaneously by florescent staining. A Halosperm DNA fragmentation kit was used to evaluate DNA integrity. An in-vitro culture system was used to evaluate fertilization competence and blastocyst formation rate, using bovine oocytes. Findings indicate dose responsive variation among compartments to AFB1 exposure. Sperm viability, expressed by integrity of the plasma membrane, was lower in sperm isolated from ejaculate or epididymis after culturing with AFB1. Exposure to AFB1 reduced the proportion of sperm from the epididymis tail undergoing acrosome reaction induced by Ca2+ ionophore. AFB1 impaired mitochondrial membrane potential (DeltaYm) in sperm isolated from ejaculate and the epididymis tail. Exposing ejaculated sperm to AFB1 increased the proportion of sperm with fragmented DNA and reduced the proportion of embryos that cleaved to the 2- to 4-cell stage, 42h postfertilization, however, the proportion of embryos that developed to blastocysts, 7days postfertilization, did not differ among groups. The findings explore the harmful effects of AFB1 on sperm viability, DeltaPsim and DNA integrity associated with fertility competence. We postulate that AFB1-induced fragmentation in paternal DNA might have a carryover effect on the quality of developing embryos. Further evaluation for the quality of blastocysts derived from sperm exposed to AFB1 is warranted. PMID- 29113835 TI - A novel approach of solid waste management via aromatization using multiphase catalytic pyrolysis of waste polyethylene. AB - A new and innovative approach was adopted to increase the yield of aromatics like, benzene, toluene and xylene (BTX) in the catalytic pyrolysis of waste polyethylene (PE). The BTX content was significantly increased due to effective interaction between catalystZSM-5 and target molecules i.e., lower paraffins within the reactor. The thermal and catalytic pyrolysis both were performed in a specially designed semi-batch reactor at the temperature range of 500 degrees C 800 degrees C. Catalytic pyrolysis were performed in three different phases within the reactor batch by batch systematically, keeping the catalyst in A type- vapor phase, B type- liquid phase and C type- vapor and liquid phase (multiphase), respectively. Total aromatics (BTX) of 6.54 wt% was obtained for thermal pyrolysis at a temperature of 700 degrees C. In contrary, for the catalytic pyrolysis A, B and C types reactor arrangement, the aromatic (BTX) contents were progressively increased, nearly 6 times from 6.54 wt% (thermal pyrolysis) to 35.06 wt% for C-type/multiphase (liquid and vapor phase). The pyrolysis oil were characterized using GC-FID, FT-IR, ASTM distillation and carbon residue test to evaluate its end use and aromatic content. PMID- 29113836 TI - A case for closed-loop recycling of post-consumer PET for automotive foams. AB - Striving to utilize sustainable material sources, polyester polyols made via glycolysis and esterification of recycled polyethylene terephthalate (rPET) scrap were used to synthesize flexible polyurethane (PU) foams typically found in automotive interior applications. The objective of this endeavor was to ascertain if a closed-loop model could be established with the discarded PET feedstock. In five separate formulations, up to 50% of the total polyol content (traditionally derived from petroleum-based feedstock) was replaced with the afore-mentioned sustainable recycled polyols. These foams underwent mechanical, thermal, morphological, and physical characterization testing to determine feasibility for use in an automotive interior. Young's modulus, tensile stress at maximum load, tear resistance, and compression modulus all increased by combined averages of 121%, 67%, 32%, and 150% over the control petroleum-based formulation, respectively, in foams possessing 50% rPET polyol content. Thermal stability also increased with sustainable polyol content; thermogravimetric analysis showed that 50% mass loss temperature increased by an average of 20 degrees C in foams containing 30% recycled polyol. Properties of density and SAG factor remained within 5% of the control petroleum-based reference foams. After comparing these findings to traditional polyols, a compelling argument can be made for the use of post-consumer automotive and industrial feedstocks in developing high-performing interior automotive PU foams. PMID- 29113837 TI - Closed cycle of recycling of waste activated sludge. AB - The recycling of waste activated sludge (WAS) formed in the process of biological purification of sewage is an urgent ecological problem. In the present work, two ways of recycling of WAS containing from 8 to 30% free water, namely, the synthesis of a carbon-containing component and synthesis of porous building ceramics (bricks) with the use of WAS and waste carbonizate, have been considered. For the preparation of a carbon adsorbent, the carbonization of WAS has been carried out in an argon atmosphere. For the synthesis of ceramics, clay cullet-tezontle-WAS mixtures with different contents of the components have been used. Sintering has been performed in air. It has been established that, in treatment of WAS at 600 degrees C for 30 min, better adsorption properties are obtained due to the presence of free carbon bonds. The efficiency of water purification from dyes (methylene blue) depends on the standard conditions: the methylene blue concentration, cabonizate-to-solution ratio, and exposure time of the carbonizate in solution. The use of wet WAS makes it possible to exclude the addition of water from the traditional scheme of preparation of a plastic semiproduct, i.e., realize a water-saving technology. The introduction of low melting cullet, basalt, and WAS powders into red clay makes enables us to reduce substantially the sintering time of porous bricks (down to 8 h) and vary their strength properties. PMID- 29113838 TI - Anaerobic co-digestion of pig manure and food waste; effects on digestate biosafety, dewaterability, and microbial community dynamics. AB - This study assessed the effect of varying pig manure (PM)/food waste (FW) mixing ratio and hydraulic retention time (HRT) on methane yields, digestate dewaterability, enteric indicator bacteria and microbial communities during anaerobic co-digestion. Three 10 L digesters were operated at 39 degrees C, each with a PM/FW feedstock composition of 85%/15%, 63%/37% and 40%/60% (volatile solids basis). While the PM/FW ratio was different among reactors, the organic loading rate applied was equal, and increased stepwise with reducing HRT. The effects of three different HRTs were studied: 41, 29, and 21 days. Increasing the proportion of FW in the feedstock significantly increased methane yields, but had no significant effect on counts of enteric indicator bacteria in the digestate or specific resistance to filtration, suggesting that varying the PM/FW feedstock composition at the mixing ratios studied should not have major consequences for digestate disposal. Decreasing HRT significantly increased volumetric methane yields, increased digestate volatile solids concentrations and increased the proportion of particles >500 um in the digestate, indicating that decreasing HRT to 21 days reduced methane conversion efficiency High throughput 16S rRNA sequencing data revealed that microbial communities were just slightly affected by changes in digester operating conditions. These results would provide information useful when optimizing the start-up and operation of biogas plants treating these substrates. PMID- 29113839 TI - Addressing Financial Toxicity: The Role of the Urologist. PMID- 29113840 TI - Extended Venous Thromboembolism Prophylaxis after Radical Cystectomy: A Call for Adherence to Current Guidelines. AB - PURPOSE: Radical cystectomy is inherently associated with morbidity. We assess the timing and incidence of venous thromboembolism, review current guideline recommendations and provide evidence for considering extended venous thromboembolism prophylaxis in all patients undergoing radical cystectomy. MATERIALS AND METHODS: We searched PubMed(r) for available literature on radical cystectomy and venous thromboembolism, focusing on incidence and timing, evidence supporting extended venous thromboembolism prophylaxis in patients undergoing radical cystectomy or abdominal oncologic surgery, current guideline recommendations, safety considerations and direct oral anticoagulants. Search terms included "radical cystectomy," "venous thromboembolism," "prophylaxis," and "extended oral anticoagulants" and "direct oral anticoagulants" alone and in combination. Relevant articles were reviewed, including original research, reviews and clinical guidelines. References from review articles and guidelines were also assessed to develop a narrative review. RESULTS: The incidence of symptomatic venous thromboembolism in short-term followup after radical cystectomy is 3% to 11.6%, of which more than 50% of cases will occur after hospital discharge. Meta-analyses of clinical trials in patients undergoing major abdominal oncologic operations suggest a decreased risk of venous thromboembolisms for patients receiving extended (4 weeks) venous thromboembolism prophylaxis. Extended prophylaxis should be considered in all radical cystectomy cases. Although the relative risk of bleeding also increases, the overall net benefit of extended prophylaxis clearly favors use for at least 28 days postoperatively. Extrarenal eliminated prophylaxis agents are preferred given the risk of renal insufficiency in radical cystectomy cases, with newer oral anticoagulants providing an alternative route of administration. CONCLUSIONS: Patients undergoing radical cystectomy are at high risk for venous thromboembolism after hospital discharge. There is strong evidence that extended prophylaxis significantly decreases the risk of venous thromboembolism in oncologic surgery cases. Use of extended prophylaxis after radical cystectomy has been poorly adopted, emphasizing the need for better adherence to current urology procedure specific guidelines as extended prophylaxis for radical cystectomy is the standard of care. Specific and rare circumstances may require case by case assessment. PMID- 29113841 TI - Immunotherapy with Checkpoint Blockade in the Treatment of Urothelial Carcinoma. AB - PURPOSE: Although immunotherapy has a long history in the treatment of urothelial carcinoma, its use was limited to intravesical therapy for nonmuscle invasive disease. The development of immune checkpoint blockers for systemic delivery has expanded the application of immunotherapy to advanced metastatic urothelial cancers. MATERIALS AND METHODS: The PubMed(r) database was searched for publications regarding immune checkpoint blockers for the treatment of patients with urothelial carcinoma. Relevant congress abstracts were identified through searches of individual congress websites. RESULTS: A summary of the biology and immunology of urothelial carcinoma provides context to aid in discussing key data pertaining to immune checkpoint blockers that are approved and in development. We address immune mediated adverse events that are unique to immunotherapies and review diagnostic tools that may be useful to identify patients who would most benefit from immunotherapy. CONCLUSIONS: Immunotherapies for urothelial carcinoma have shown clinical efficacy in select patients as well as a manageable safety profile. Studies are ongoing with the aim of expanding the proof of efficacy in metastatic disease and providing additional treatment options for patients with earlier stages of urothelial carcinoma. PMID- 29113842 TI - Ambulatory Care Use among Patients with Spina Bifida: Change in Care from Childhood to Adulthood. AB - PURPOSE: We examined the ambulatory health care visit use of children with spina bifida, adults who transitioned to adult care and adults who continued to seek care in a pediatric setting. MATERIALS AND METHODS: We evaluated use during a 1 year period of patients with spina bifida who visited any outpatient medical clinic within an integrated health care system. Patients were categorized as pediatric (younger than 18 years) or adult (age 18 or older). Adults were divided into those who did not fully transition to adult care and patients who fully transitioned (adult). Frequency and type of health care use were compared. Subanalysis was performed for patients 18 to 25 years old to examine variables associated with successful complete transition to adult care. RESULTS: During 1 year 382 children, 88 patients who did not transition and 293 adult patients with spina bifida had 4,931 clinic visits. Children had greater ambulatory care use (7.25 visits per year) compared to fully transitioned adults (5.33 visits per year, p=0.046). Children more commonly visited surgical clinics (52.3% of visits) and adults more commonly visited medical clinics (48.9%) (p <0.005). Adult transitioned patients were more likely to be female (p=0.004). Of the patients 18 to 25 years old, those who did not transition to adult care had similar outpatient visit types but greater use of inpatient and emergency care than those who transitioned. CONCLUSIONS: Children with spina bifida used more ambulatory care than adults and were more likely to visit a surgical specialist. Adult patients with spina bifida who successfully transitioned to adult care were more likely to be female, and patients who failed to transition were more likely to receive more inpatient and emergency care. PMID- 29113843 TI - Negative eating attitudes and behaviors among adolescents: The role of parental control and perceived peer support. AB - In the present study, we examined from a longitudinal perspective the relationship between parental (both maternal and paternal) psychological control, perceived peer support, and negative eating attitudes and behaviors, focusing on the moderating role that perceived peer support may play in the relationship between parental psychological control in early adolescence and negative eating attitudes and behaviors in late adolescence. In Wave 1, participants were 507 adolescents (249 boys and 258 girls) aged from 14 to 15 years (M = 14.76; SD = 0.63). Three years later (Wave 2), the same adolescents participated again in the study (M = 17.88 years; SD = 0.57). Regression analyses displayed that paternal, but not maternal, achievement-oriented psychological control during early adolescence positively predicted negative eating attitudes and behaviors in late adolescence, whereas perceived peer support negatively predicted negative eating attitudes and behaviors. Results also showed a moderator effect of perceived peer support in the relationship between father's psychological control and negative eating attitudes and behaviors, such that at higher levels of paternal achievement-oriented psychological control, negative eating attitudes and behaviors tended to be higher when perceived peer support was low and to be lower when perceived peer support was high. PMID- 29113844 TI - Quantitative CBCT evaluation of maxillary and mandibular cortical bone thickness and density variability for orthodontic miniplate placement. AB - OBJECTIVE: To assess whether cortical bone thickness and density vary in relation to age, sex and skeletal pattern at the maxillary and mandibular areas suitable for miniplates placement for orthodontic purposes. MATERIALS AND METHODS: CBCT of 92 subjects (42 males and 50 females) with skeletal class I, II or III malocclusion, divided between adolescents and adults, were examined. InVivoDental(r) software (Anatomage Inc, USA) was used to measure 34 maxillary areas and 40 mandibular areas per side. Values obtained were then compared between the groups of subjects. Statistical analysis was performed using the non parametric Wilcoxon-Mann-Whitney rank-sum test for independent samples. RESULTS: No significant differences were found in the cortical bone thickness values between the three skeletal patterns, and according to sex and age. Both maxilla and mandible showed an increase in cortical bone thickness from the anterior towards the posterior regions, and from the alveolar boneto the basal bone. Cortical bone density significantly varied in relation to the subject's age, with adults always showing higher values. Slight clinically significant differences were found between the three skeletal patterns and sex. CONCLUSION: In terms of cortical bone thickness, age, sex and skeletal pattern do not represent valid decision criteria for the evaluation of the best insertion areas for miniplates, while in terms of cortical bone density, only age is useful as a decision criterion. PMID- 29113845 TI - ? PMID- 29113846 TI - Maxillary and mandibular contribution to the establishment of class II malocclusion in an adult Lebanese population. AB - INTRODUCTION: The main aim of this study was to describe the contribution of the maxilla and the mandible to the establishment of a Class II skeletal malocclusion in an adult Lebanese population. Secondary aims were to detect the presence of sex-based dimorphism and to study the influence of the vertical dimension on the Class II skeletal pattern. MATERIAL AND METHOD: A sample of 90 adults in skeletal Class II was recruited and equally distributed according to sex and vertical typology. The study describes the skeletal and dentoalveolar cephalometric characteristics of the Class II sample, essentially according to Coben's cephalometric analysis. RESULTS: The total effective depth of the cranial base and the anterior cranial base angle (SN-BaH) were both greater in the Class II sample. In females, the effective depth of the maxilla (Ptm-A) was larger than normal while SNB was smaller. The parameters describing the size and shape of the body of the mandible were significantly different from those of normal subjects. The upper incisors were in a retrusive position, while the axis of the lower incisors was located normally. The mandibular molars had a more distal sagittal position. Hyperdivergent subjects had more significant posterior alveolar growth, a more retrusive mandibular position and smaller mandibular dimensions than the other two vertical sub-groups. CONCLUSION: The cranial base contributes to the establishment of a Class II malocclusion, and mandibular retrusion cannot be considered as a characteristic shared by all skeletal Class II subjects. Lessening of the absolute length of the mandibular body is the second most frequent etiological factor noted in the Class II sample studied. Most individuals in skeletal Class II have an associated dental Class II malocclusion, and the vertical dimension has an influence on the Class II skeletal pattern. PMID- 29113847 TI - ? PMID- 29113848 TI - High-vacuum optical platform for cryo-CLEM (HOPE): A new solution for non integrated multiscale correlative light and electron microscopy. AB - Cryo-correlative light and electron microscopy (cryo-CLEM) offers a unique way to analyze the high-resolution structural information of cryo-vitrified specimen by cryo-electron microscopy (cryo-EM) with the guide of the search for unique events by cryo-fluorescence microscopy (cryo-FM). To achieve cryo-FM, a trade-off must be made between the temperature and performance of objective lens. The temperature of specimen should be kept below devitrification while the distance between the objective lens and specimen should be short enough for high resolution imaging. Although special objective lens was designed in many current cryo-FM approaches, the unavoided frosting and ice contamination are still affecting the efficiency of cryo-CLEM. In addition, the correlation accuracy between cryo-FM and cryo-EM would be reduced during the current specimen transfer procedure. Here, we report an improved cryo-CLEM technique (high-vacuum optical platform for cryo-CLEM, HOPE) based on a high-vacuum optical stage and a commercial cryo-EM holder. The HOPE stage comprises of a special adapter to suit the cryo-EM holder and a high-vacuum chamber with an anti-contamination system. It provides a clean and enduring environment for cryo specimen, while the normal dry objective lens in room temperature can be used via the optical windows. The 'touch-free' specimen transfer via cryo-EM holder allows least specimen deformation and thus maximizes the correlation accuracy between cryo-FM and cryo EM. Besides, we developed a software to perform semi-automatic cryo-EM acquisition of the target region localized by cryo-FM. Our work provides a new solution for cryo-CLEM and can be adapted for different commercial fluorescence microscope and electron microscope. PMID- 29113849 TI - Marker-free method for accurate alignment between correlated light, cryo-light, and electron cryo-microscopy data using sample support features. AB - Combining fluorescence microscopy with electron cryo-tomography allows, in principle, spatial localization of tagged macromolecular assemblies and structural features within the cellular environment. To allow precise localization and scale integration between the two disparate imaging modalities, accurate alignment procedures are needed. Here, we describe a marker-free method for aligning images from light or cryo-light fluorescence microscopy and from electron cryo-microscopy that takes advantage of sample support features, namely the holes in the carbon film. We find that the accuracy of this method, as judged by prediction errors of the hole center coordinates, is better than 100 nm. PMID- 29113850 TI - Colloid cyst and multiple meningiomata in Gorlin syndrome. AB - A middle-aged man presented with syncope and confusion. Neuroimaging revealed a third ventricular mass with obstructive hydrocephalus and bilateral convexity meningiomata. The masses were excised and pathology showed a colloid cyst and WHO grade 1 meningiomata respectively. Multisystem workup confirmed Gorlin syndrome. To our knowledge, this is the fourth reported case of Gorlin syndrome associated with colloid cyst, and the first case where multiple meningiomata are also present. PMID- 29113851 TI - Impact of academic facility type and volume on post-surgical outcomes following diagnosis of glioblastoma. AB - OBJECTIVE: To identify if facility type and/or facility volume impact overall survival (OS) following diagnosis of glioblastoma (GBM). We also sought to compare early post-surgical outcomes based on these factors. METHODS: The National Cancer Database was queried for patients with GBM diagnosed from 2004 to 2013 with known survival. Patients were grouped based on facility type and facility volume. Multivariable analyses were performed to investigate factors associated OS following diagnosis and Chi-square tests were used to compare early post-surgical outcomes. RESULTS: 89,839 patients met inclusion criteria. Factors associated with improved OS on multivariable analysis included younger patient age, female gender, race, lower comorbidity score, higher performance score, smaller tumor size, unifocal tumors, MGMT hypermethylation, fully resected tumors, radiotherapy, and chemotherapy (each p < .001). Also, OS was improved among patients treated at centers averaging at least 30.2 cases per year (HR 0.948, compared to <7.4 cases/year, p < .001), and patients treated at Academic/Research programs had improved survival compared to those treated at Comprehensive Community Cancer programs (HR 1.069, p < .001) and Integrated Network Cancer programs (HR 1.126, p < .001). Similarly, Academic/Research programs and high volume centers demonstrated improved 30- and 90-day morality as well as 30-day readmission rates (p < .001). CONCLUSIONS: This study suggests that patients treated in Academic/Research programs and high patient-volume centers have increased survival and more favorable early-postsurgical outcomes. The extent to which differences in patient populations, socioeconomic factors, and/or provider expertise play into this cause will be areas of future research. PMID- 29113852 TI - Tumour stem cells in meningioma: A review. AB - Meningioma is a common intracranial and intraspinal neoplasm accounting for 25 30% of all primary neurological tumours. It is associated with high rates of recurrence especially in higher-grade tumours and lesions located at the skull base. Cancer stem cells are increasingly recognised as the origin of cancer and are attributed to loco-regional recurrence, metastasis and treatment resistance. This review presents the accumulating evidence of the presence of tumour stem cells within meningioma and the stem cell markers being used to characterise this putative primitive population within this common tumour. PMID- 29113853 TI - Hyperkinetic transient ischemic attacks preceding deep ganglionic infarction in a patient with a treated parasellar chondrosarcoma. AB - A 44-year-old right-handed female with a past medical history of parasellar chondrosarcoma status post-surgical debulking and proton beam therapy (70 Gy) three years prior to presentation experienced several hours of brief, repetitive episodes of transient hemiballism and dystonia; this was followed by abrupt onset of fixed hemiparesis and dysarthria weeks later, ipsilateral to her prior hyperkinetic movements. She was found to have total occlusion of the right middle cerebral artery with focal stenosis of the proximal right A-1 segment of the anterior cerebral artery adjacent to the remnants of the chondrosarcoma. These focal areas of narrowing were attributed to accelerated atherosclerotic disease, an adverse effect of the radiotherapy used to treat her chondrosarcoma. As treatments improve and mean survival increases for intracranial malignancy, radiation-induced atherosclerotic disease with protean manifestations such as those presented in this case may be encountered more frequently. PMID- 29113854 TI - Incidence of poststroke seizures: A meta-analysis. AB - BACKGROUND: Late-onset poststroke seizure is highly associated with epilepsy but the incidence of it is variable due to different definition and follow-up time. We conducted a meta-analysis to determine the incidence of poststroke seizure and analyze the discrepancies among published studies. METHODS: We searched the literature for relevant articles published in English between January 1, 1990, and December 31, 2014, by using the following search terms: "seizures after stroke," "poststroke seizures," "epilepsy after stroke," "poststroke epilepsy," "incidence," and "follow-up." Reference lists of the relevant articles were reviewed to identify eligible studies not captured by these terms. RESULTS: Seven relevant cohort studies were identified and analyzed. Incidence density was defined as the number of episodes per 100 person-years. Using the definition of late-onset poststroke seizure as seizure occurring 14 days after a stroke, the incidence density was 1.12 (0.95-1.32) per 100 person-years. For poststroke seizures occurring 7 days after the stroke, the incidence density increased to 3.22 (2.94-3.52) per 100 person-years. CONCLUSION: Our results are relevant to the epidemiology of late-onset poststroke seizure, with 14 days being the ideal cutoff time point. The pooled incidence density of late-onset poststroke seizure was 1.12 per 100 person-years in 4 cohort studies. PMID- 29113855 TI - Holospinal epidural abscesses - Institutional experience. AB - PURPOSE: The authors present a holospinal epidural abscesses (HEA) case series and a single institution's experience with varied surgical approaches and outcomes. METHODS: Medical records were queried and reviewed (6 years) for patients with a spinal abscess diagnosis; HEA were selected. Medical history, comorbidities, blood and epidural pathogens, presentation symptoms, abscess location, presence of mass effect, surgical procedures, treatment regimens, and neurological outcomes were collected. RESULTS: Eight patients with HEA were treated; all underwent surgery. In the index procedure, one (12.5%) underwent laminectomy of the entire spinal column, four (50%) focal laminectomies at the area of mass effect, and three (37.5%) skip laminectomies. Of the four patients who initially had focal laminectomies, three (75%) required additional operations for abscess evacuation in other spine regions. Average number of laminectomies per patient was 8.6. Neurologically, 50% of patients improved, 37.5% remained stable, and 12.5% worsened. There was no difference in outcome between patients who underwent skip versus panspinal laminectomies. No differences in outcomes were noted in timing from presentation to surgery (median 5.3 h), location of mass effect, dorsal versus ventral abscesses, or initial symptoms. Of the four patients who had cervical laminectomy without fusion, two developed post laminectomy kyphosis requiring fusion. CONCLUSION: Cervical instability occurred in half the patients who underwent cervical laminectomies without fusion, and there were no adverse outcomes in the patients who were fused in the setting of infection. For lower cervical abscess, upper thoracic laminectomy with catheter irrigation may be sufficient for decompression, minimizing risk of future instability. PMID- 29113856 TI - Has acromegaly been diagnosed earlier? AB - PURPOSE: We investigated whether acromegaly has been diagnosed earlier at the Niigata Medical and Dental University Hospital. METHODS: Patients with acromegaly (n = 81) who underwent their first transsphenoidal surgery from 2006 to 2015 were reviewed. Two groups were compared: those who underwent surgery between 2006 and 2010 (n = 35) and those who underwent surgery between 2011 and 2015 (n = 46). We compared clinical features and serum levels of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1), hypertension (HT) and diabetes mellitus (DM) prevalence between the two groups. RESULTS: Compared with the early group, microadenomas (<10 mm) were more prevalent in the late group (0% vs. 15.2%, p < .05). Serum IGF-1 standard deviation score (SDS) was significantly lower in the late group (8.57 +/- 2.50 vs. 6.44 +/- 2.30, p < .001). In both groups, mean IGF 1 SDS was significantly lower in patients without DM than in those with DM (6.9 +/- 2.6 vs. 8.3 +/- 2.4, p = .02). Logistic regression analysis showed that serum GH and IGF-1 levels were significantly higher in patients with DM than in those without DM. CONCLUSION: Regarding operated cases of GH-producing pituitary adenoma, acromegaly clinical manifestations tended to be milder at diagnosis in later years of the decade, and acromegaly was diagnosed at lower IGF-1 levels and in smaller lesions. Further study is mandatory for the generalization of this trend. PMID- 29113857 TI - A rare neurological complication of Waldenstrom's Macroglobulinemia. AB - Bilateral and simultaneous facial nerve palsy (FNP) is a rare clinical condition occurring in 0.3-2.0% of facial palsy cases and is typically a manifestation of an underlying systemic disease. We here describe a case of a 67-year-old Hispanic man with a known history of Waldenstrom's Macroglobulinemia (WM) who presented to the clinic with a sub-acute onset of bilateral facial weakness. No alternate etiology for the facial weakness was identified after a thorough diagnostic approach. WM is a rare hematological condition due to low-grade B cell lymphoma, where lymphoplasmacytoid cells infiltrate different tissues and secrete monoclonal IgM. Peripheral neuropathy develops in 15-30% of the cases, being usually a chronic, progressive, symmetric, predominantly distal polyneuropathy. Facial nerve impairment is unusual; however, it could be caused by anoxic damage as a result of an increased blood viscosity from IgM monoclonal gammopathy, direct nerve infiltration of tumorous cells and an antibody (anti-MAG) mediated demyelinating process. Treatment is directed to the established mechanism for neural injury. This report highlights a rare condition (WM) with a rare complication (bilateral facial nerve palsy) and illustrates the broad differential comprised by this presenting complaint. PMID- 29113858 TI - Differences in blood pressure by measurement technique in neurocritically ill patients: A technological assessment. AB - Blood pressure data may vary by measurement technique. We performed a technological assessment of differences in blood pressure measurement between non invasive blood pressure (NIBP) and invasive arterial blood pressure (ABP) in neurocritically ill patients. After IRB approval, a prospective observational study was performed to study differences in systolic blood pressure (SBP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) values measured by NIBP arm, ABP at level of the phlebostatic axis (ABP heart) and ABP at level of the external auditory meatus (ABP brain) at 30 and 45-degree head of bed elevation (HOB) using repeated measure analysis of covariance and correlation coefficients. Overall, 168 patients were studied with median age of 57 +/- 15 years, were mostly female (57%), with body mass index <=30 (66%). Twenty-three percent (n = 39) had indwelling intracranial pressure monitors, and 19.7% (n = 33) received vasoactive agents. ABP heart overestimated ABP brain for SBP (11.5 +/- 2.7 mmHg, p < .001), MAP (mean difference 13.3 +/- 0.5 mmHg, p < .001) and CPP (13.4 +/- 3.2 mmHg, p < .001). ABP heart overestimated NIBP arm for SBP (8 +/ 1.5 mmHg, p < .001), MAP (mean difference 8.6 +/- 0.8 mmHg, p < .001), and CPP (mean difference 9.8 +/- 3.2 mmHg, p < .001). Regardless of HOB elevation, ABP heart overestimates MAP compared to ABP brain and NIBP arm. Using ABP heart data overestimates CPP and may be responsible for not achieving SBP, MAP or CPP targets aimed at the brain. PMID- 29113859 TI - Treatment decision for occipital arteriovenous malformations (AVMs) to achieve hemorrhagic control while maximizing visual preservation: Our experience and review of literature. AB - Despite concern of hemorrhagic risk, patients with occipital AVMs are at significant risk for visual disturbances after treatment. We aim to characterize the hemorrhage risk and visual disturbance in occipital AVMs patients from our experience and literature review. We performed retrospective review of occipital AVM patients seen at our institution from 1990 to 2015. Patient characteristics were compared using multivariable logistic regression with follow-up visual disturbance as the outcome. We also systematically reviewed the PubMed database for English literature describing occipital AVMs (with exclusion of case reports). Ninety-seven patients satisfied inclusion criteria for our study. Mean age was 34.9 +/- 16.4 years, with 50.5% male. Thirty-one (32.0%) presented with hemorrhage, and 32 (33.0%) presented with visual disturbance. Average AVM size was 4.0 +/- 2.5 cm. Twenty-five (25.8%) were conservatively managed, 13 (13.4%) underwent surgery, and the rest were managed by radiosurgery (52.6%) or embolization (8.2%), with an obliteration rate of 38.9% in treated patients. During average follow-up of 5.4 years, 6 patients (6.7%) hemorrhaged yielding an annual hemorrhage rate of 1.2% for all patients, and 0.0% for surgically-treated patients. Thirty-seven (38.3%) patients experienced visual disturbance in some capacity, nineteen (21.1%) had de novo visual disturbance, fourteen of which were surgically treated patients (19.4%). Multivariable analysis reveals visual disturbance at presentation (p = .012) and microsurgery (p = .047) are significantly predictors of follow-up visual disturbance. While hemorrhage control remains the primary goal of AVM treatment, visual preservation in occipital AVMs is also a major concern. Recommending patients for microsurgery should be weighed carefully and individualized as it bears the highest risk of visual field disturbance despite most optimal hemorrhage control. PMID- 29113860 TI - Dramatic psychiatric and behavioral symptoms following a subthalamic lesion. AB - Neuropsychiatric symptoms have been well documented after subthalamic nucleus deep brain stimulation (STN-DBS), but those following a subthalamic lesion have been rarely reported. Herein, we present a 43-year-old woman with sudden-onset dramatic psychiatric and behavioral symptoms with hemiballism. Brain magnetic resonance imaging (MRI) with fluid attenuated inversion recovery (FLAIR) sequence during the acute phase demonstrated extensive hyperintensity in the left STN and adjacent regions. Contrast-enhanced MRI showed no abnormal areas of enhancement. Magnetic resonance venography (MRV) was normal. Routine blood and cerebrospinal fluid (CSF) tests were not remarkable. Autoimmune antibodies showed no significant results. A gradual recovery of both psychiatric and behavioral symptoms and hemiballism was observed with steroid and symptomatic treatment. Our case is unique in dramatic neuropsychiatric symptoms following a subthalamic lesion. We would like to point out that severe neuropsychiatric symptoms can occur in the patients with subthalamic lesions, and can be a troubling feature in their management. PMID- 29113861 TI - Identification and characterization of myeloperoxidase in orange-spotted grouper (Epinephelus coioides). AB - Cryptocaryon irritans is an important protozoan ciliate, which has led to heavy economic losses in marine aquaculture. Previous studies have indicated that C. irritans infection could induce the migration of neutrophils to infection sites. Myeloperoxidase (MPO) mainly exists in the cytoplasmic granules of the neutrophil and performs its function by a unique enzymatic capacity to produce hypohalous acid and other toxic oxidants. To determine the involvement of MPO and neutrophils against C. irritans infection in the host, we amplified MPO cDNA (EcMPO) from orange-spotted grouper (Epinephelus coioides). The open reading frame (ORF) of EcMPO encodes a putative polypeptide of 770 amino acids and has typical structural characteristics of mammalian MPO, including a signal peptide, a propeptide, a light chain, a heavy chain, and a peroxidase domain. Bioinformatics analysis has demonstrated that the most important functional sites in mammalian MPO were also conserved in grouper and other piscine MPO, implying the functional conservation of this protein during evolution. A rabbit anti-MPO recombinant protein polyclonal antibody was produced, which could recognize the native MPO protein. The expression of EcMPO was higher in the lympho hematopoietic organs, such as head kidney, trunk kidney, spleen, but lower in muscle, heart, and brain. After infection with C. irritans, the EcMPO transcript was significantly up-regulated at specific time points in the infection sites (skin and gill) and systemic immune organs (head kidney and spleen); The number of EcMPO positive cells first increased and then decreased in the gill, but was still higher than the control after 7 days. These results demonstrated that EcMPO and its positive cells may be involved in anti-C. irritans infection in the grouper, which is attributed to the innate immune mechanisms of the host against parasite infection. PMID- 29113862 TI - Comparative expression analysis of immune-related factors in the sea cucumber Apostichopus japonicus. AB - In order to preliminarily explore the joint involvement of different immune related factors during the same immune process in Apostichopus japonicus, the transcriptional expression of Cu/Zn superoxide dismutase (Cu/Zn-SOD), catalase (CAT), c-type lysozyme (c-LYZ), i-type lysozyme (i-LYZ), cathepsin D, melanotransferrin (MTF), Toll, c-type lectin (c-LCT) and complement 3 (C3) during the development from fertilized eggs to juveniles and after challenging the juveniles with Vibrio splendidus, Pseudoalteromonas nigrifaciens, Shewanella baltica and Bacillus cereus, respectively, was measured using the method of quantitative real-time PCR (qRT-PCR), and then the correlations among different immune-related factors were analyzed. The results showed that the selected immune related factors were expressed at all of the determined developmental stages and significantly up-regulated at doliolaria stage, suggesting the selected factors are indispensable immune components and the immune system might be broadly activated at doliolaria stage in A. japonicus. After challenged with four pathogenic bacteria, Cu/Zn-SOD, CAT, i-LYZ, cathepsin D, MTF, Toll, C3 were all significantly down-regulated at 4 h, indicating that some components of A. japonicus immune system might be inhibited at the beginning of pathogenic bacteria invasion. The immune-responsive analysis also showed that the significant regulation in Toll after challenged with four tested bacteria, that in MTF after challenged with S. baltica and that in C3 after challenged with P. nigrifaciens were all minus, suggesting Toll, MTF and C3 are probably the primary targets of pathogenic bacteria attack. Furthermore, the correlation analysis indicated that, all of the selected immune-related factors except cathepsin D might be in the same immune regulatory network during A. japonicus development, while all of the selected immune-related factors except c-LYZ might be in the same responsive regulatory network after challenged with four pathogenic bacteria. Altogether, A. japonicus immune system exhibited high complexity in regulation during organism development and after bacterial challenges. PMID- 29113863 TI - Long-term outcomes after carotid artery stenting of patients with prior neck irradiation or surgery. AB - BACKGROUND: Carotid artery stenting (CAS) is often performed in patients with carotid artery stenosis who have relative contraindications to carotid endarterectomy (CEA), including hostile neck anatomy (e.g., history of neck irradiation or prior surgery). We examined the impact of hostile neck anatomy on long-term outcomes after CAS. METHODS: All carotid artery stent procedures performed at two institutions from 2006 to 2016 were reviewed. Routine duplex carotid ultrasound was used to assess target lesion restenosis at regular intervals. The primary endpoint was rates of target lesion revascularization (TLR). Secondary endpoints included peri-procedural outcomes, restenosis, stroke, major adverse cardiovascular and cerebrovascular events (MACCE), and mortality during long-term follow up. A Cox proportional hazard model was developed to determine the association between hostile neck anatomy and outcome after CAS. RESULTS: 304 CAS procedures were performed in 268 patients (hostile neck=53, non hostile neck=215). Patients with hostile neck anatomy were more likely to have a history of smoking and history of prior carotid artery revascularization. There were no differences in peri-procedural outcomes including stroke. During follow up to five years there were no significant differences in rates of TLR (1.4% vs. 3.8%, P=0.25), restenosis (1.9% vs. 5.1%, P=0.31), MACCE (26% vs. 18%, P=0.15), ipsilateral stroke (7.5% vs. 2.8%, P=0.101), or mortality (13% vs. 14%, P=0.89). Hostile neck anatomy was not associated with significantly increased 5-year TLR rates in the Cox regression analysis (HR=2.64; 95% CI: 0.44-15.83; P=0.289). CONCLUSIONS: Despite greater comorbidities, patients with hostile neck anatomy and carotid artery stenosis have favorable outcomes after carotid artery stenting. PMID- 29113864 TI - Observations from a real-time, iFR-FFR "hybrid approach" in patients with severe aortic stenosis and coronary artery disease undergoing TAVI. AB - BACKGROUND: The complexity of coronary physiology in presence of severe aortic stenosis (AS) raises concerns about the reliability of pressure-derived indexes in this clinical setting. Furthermore, neither fractional flow reserve (FFR) nor instantaneous wave-free period (iFR) has been validated in AS. Combining iFR and FFR in a tailored decision-making strategy may help to increase simplicity, accuracy and safety of physiology-guided revascularization in AS. METHODS: In this prospective observational study iFR and FFR were measured before and after TAVI during the same procedure in patients with severe AS and concomitant coronary artery disease (CAD). All decisions about revascularization were based on post-TAVI FFR assessment. The best iFR "defer" and "treatment" values were identified according to their baseline negative (NPV) and positive predictive values (PPV) respectively. A post-hoc analysis was then performed to compare the hybrid iFR-FFR approach with the FFR-only strategy. RESULTS: Sixty-two patients underwent pre- and post-TAVI pressure-wire assessment and were included in the analysis. A "defer iFR value" >0.93 yielded a NPV of 98.4% (91.7%-99.9%) to exclude FFR non-significant stenosis (>0.80), and a "treatment iFR value" <0.83 had a PPV of 91.3% (72%-98.9%) to identify FFR-significant stenosis (<=0.80). A hybrid decision-making strategy based on iFR and FFR spared 63% of patients from adenosine, while maintaining 97% overall agreement with FFR lesions classification. CONCLUSION: A hybrid iFR-FFR diagnostic strategy is feasible and safe in patients with severe AS undergoing TAVI and allows to spare the majority of patients from adenosine, while maintaining a high agreement with FFR classification of coronary lesions. PMID- 29113865 TI - Identifying a better strategy for ad hoc percutaneous coronary intervention in patients with anticipated unfavorable radial access: the Little Women study. AB - BACKGROUND: Transradial percutaneous coronary intervention (PCI) offers important advantages over transfemoral PCI, including better outcomes. However, when there is indication to ad hoc PCI, a 6 French workflow is a common default strategy, hence potentially influencing vascular access selection in patients with anticipated small size radial artery. METHODS: A multidimensional evaluation was performed to compare two ad hoc interventional strategies in women <160cm: a full 6 French workflow (namely 6 French introducer sheath, diagnostic catheters and guiding catheter) with a modified workflow consisting in the use of 5 French diagnostic catheters preceded by the placement of a 6 French sheath introducer and followed by a 6 French guiding catheter use for PCI. RESULTS: Overall 120 women (68+/-11years) were enrolled in the study. Coronary angiography has been performed using 5 French or 6 French diagnostic catheters in 57 (47.5%) and 63 (52.5%) cases, respectively. Radial spasm and switch to another access occurred more frequently among women who underwent coronary angiography with 6 French rather than 5 French diagnostic catheters (43% vs. 25%, p=0.03 and 2% vs. 11%, p=0.04, respectively). Total time to guidewire lesion crossing was also significantly higher when PCI has been preceded by 6 French rather than 5 French coronary angiography (23+/-11min vs 16+/-7min, p=0.013). CONCLUSIONS: In patients with anticipated unfavorable radial access, a workflow consisting in 6 French introducer sheath placement, 5 French coronary angiography, and 6 French coronary intervention is on multiple parameters the most straightforward and effective strategy. PMID- 29113866 TI - Intravascular ultrasound enhances the safety of rotational atherectomy. AB - Intravascular ultrasound (IVUS) is mainly used in PCI to treat complex lesions, such as left main bifurcation, chronic total occlusion and calcified lesions. Although IVUS yields useful information such as the presence of napkin-ring calcification, the role of IVUS in rotational atherectomy (RA) is not fully appreciated. Recently, since the deliverability and crossability of IVUS catheters have improved, IVUS should be attempted before RA. Even if the IVUS catheter cannot cross the lesion, IVUS provides information just proximal to the target lesion, which would be useful in the selection of the appropriate guidewire and burr size. IVUS can be repeated following RA, which may influence the decision to continue RA with larger burrs. Circumferential calcification is a good indication for RA, since RA can create a calcium crack that facilitates balloon dilatation. However, if the distribution of calcification is not circumferential, the indication for RA can more safely be determined based on IVUS images than angiographic information alone. Because RA burrs usually follow the route taken by the IVUS catheter, the positional relationship between the IVUS imaging core and calcification would be similar to that between the RA burrs and calcification. The relationship between the RA burrs and distribution of calcification is discussed in this review. PMID- 29113867 TI - Clinical significance of intracoronary thrombus aspirated during primary percutaneous intervention: An immunohistopathological study. AB - BACKGROUND: Manual thrombus aspiration during primary percutaneous intervention provides us with aspirated thrombus sample, that may contain material from the disrupted plaque. Immunohistopathological analysis of thrombus can yield valuable information about the clinical and cardiovascular outcomes and possible mechanisms of myocardial infarction. MATERIAL AND METHODS: We studied and analysed the immunohistopathological features of coronary thrombus aspirated from patients undergoing primary percutaneous coronary angioplasty. Immunohistological staining included markers namely CD68, SMA and CD34 for macrophages, smooth muscle actin and endothelium, respectively. Major adverse cardiac events, angiographic outcome and infarct size were also noted. RESULTS: Fifty-three patients (Mean age - 51.3+/-13years; males-47) who underwent primary percutaneous coronary intervention with aspiration thrombectomy were enrolled. Thrombus was successfully aspirated in 40 of 53 patients (75.4%). Patients with successful thrombus aspiration had higher ST-segment resolution (>=50%) as compared to patients with failed thrombus aspiration. Presence of RBC-rich thrombus on microscopy was more commonly associated with post-procedure TIMI flow of <2 as compared to patients with fibrin-rich thrombus and a trend towards lower myocardial blush grade<2 (P=0.10), and a significantly higher final infarct size (37.5+/-5% vs 25+/-15%; P=0.04 of myocardium) on nuclear scan. Immunohistology revealed presence of plaque material in 72% (26/36) of the samples. CONCLUSIONS: Immunohistopathological evaluation of intracoronary thrombus may be of prognostic importance. High prevalence of plaque material in the aspirated intracoronary thrombus suggests plaque rupture as a possible etiology for vessel occlusion in these patients. SHORT SUMMARY: Immunohistopathological evaluation of intracoronary thrombus reveals high prevalence of plaque material in the aspirated intracoronary thrombus suggesting plaque rupture as a possible etiology for vessel occlusion in Indian STEMI patients. PMID- 29113868 TI - A case of influenza type a myocarditis that presents with ST elevation MI, cardiogenic shock, acute renal failure, and rhabdomyolysis and with rapid recovery after treatment with oseltamivir and intra-aortic balloon pump support. AB - We present a 59-year-old black male with history of type-1 diabetes and alcohol abuse. Patient became critically ill after a 5-day period of burning throat discomfort. On arrival patient was lethargic, in cardiogenic shock with a blood pressure of 81/47mmHg. Immediate diagnoses included diabetic ketoacidosis, acute renal failure, and possible septic shock. He was intubated, resuscitated with intravenous fluids, maintained on three inotropic agents, and given empiric wide spectrum antibiotics. An ECG showed a new ST elevation MI and an echocardiogram showed severe LV dysfunction. Cardiac catheterization showed clean coronaries. With appropriate treatment patient recovered 10days later. PMID- 29113869 TI - The ESCRT machinery: When function follows form. PMID- 29113870 TI - Molecular features of lipid-based antigen presentation by group 1 CD1 molecules. AB - Lipids are now widely considered to play a variety of important roles in T-cell mediated immunity, including serving as antigens. Lipid-based antigens are presented by a specialised group of glycoproteins termed CD1. In humans, three classes of CD1 molecules exist: group 1 (CD1a, CD1b, CD1c), group 2 (CD1d), and group 3 (CD1e). While CD1d-mediated T-cell immunity has been extensively investigated, we have only recently gained insights into the structure and function of group 1 CD1 molecules. Structural studies have revealed how lipid based antigens are presented by group 1 CD1 molecules, as well as shedding light on the molecular requirements for T-cell recognition. Here, we provide an overview of our current understanding of lipid presentation by group 1 CD1 molecules in humans and their recognition by T-cells, as well as examining the potential differences in lipid presentation that may occur across different species. PMID- 29113871 TI - Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. AB - Several epidemiological observations have shown an inverse relation between consumption of plant-based foods, rich in phytochemicals, and incidence of cancer. Phytochemicals, secondary plant metabolites, via their antioxidant property play a key role in cancer chemoprevention by suppressing oxidative stress-induced DNA damage. In addition, they modulate several oxidative stress mediated signaling pathways through their anti-oxidant effects, and ultimately protect cells from undergoing molecular changes that trigger carcinogenesis. In several instances, however, the pro-oxidant property of these phytochemicals has been observed with respect to cancer treatment. Further, in vitro and in vivo studies show that several phytochemicals potentiate the efficacy of chemotherapeutic agents by exacerbating oxidative stress in cancer cells. Therefore, we reviewed multiple studies investigating the role of dietary phytochemicals such as, curcumin (turmeric), epigallocatechin gallate (EGCG; green tea), resveratrol (grapes), phenethyl isothiocyanate (PEITC), sulforaphane (cruciferous vegetables), hesperidin, quercetin and 2'-hydroxyflavanone (2HF; citrus fruits) in regulating oxidative stress and associated signaling pathways in the context of cancer chemoprevention and treatment. PMID- 29113872 TI - Neuroanatomical correlates of time perspective: A voxel-based morphometry study. AB - Previous studies indicated that time perspective can affect many behaviors, such as decisions, risk taking, substance abuse and health behaviors. However, very little is known about the neural substrates of time perspective (TP). To address this question, we characterized different dimensions of TP (including the Past, Present, and Future TP) using standardized Zimbardo Time Perspective Inventory (ZTPI), and quantified the gray matter volume using voxel-based morphometry (VBM) method across two independent samples. Our whole-brain analysis (sample 1, N=150) revealed Past-Negative TP was positively correlated with the GMV of a cluster in LPFC whereas Past-Positive was negatively correlated with the GMV in OFC, and Future TP was negatively correlated with GMV in mPFC. Moreover, two present scales (Present-Hedonistic and Present-Fatalistic TPs) were positively correlated with the GMV of regions in MTG and precuneus, respectively. We further examined the reliability of these correlations between multidimensional TPs and neuroanatomical structures in another independent sample (sample 2, N=58). Results verified our findings that GMV in LPFC could predict Past-Negative TP while GMV in OFC could predict Past-Positive TP, and the GMV in MTG could predict Present-Hedonistic while the GMV in presuneus could predict Present-Fatalistic, as well as the GMV in mPFC could predict Future TP. Thus, our findings suggest that the existence of selective neural basis underlying TPs, and further provide the stable biomarkers for multidimensional TPs. PMID- 29113873 TI - Glucose metabolic alterations in hippocampus of diabetes mellitus rats and the regulation of aerobic exercise. AB - Diabetes could negatively affect the structures and functions of the brain, especially could cause the hippocampal dysfunction, however, the potential metabolic mechanism is unclear. The aim of this study was to investigate the changes of glucose metabolism in hippocampus of diabetes mellitus rats and the regulation of aerobic exercise, and to analyze the possible mechanisms. A rat model of type 2 diabetes mellitus was established by high-fat diet feeding in combination with STZ intraperitoneal injection, then 4 weeks of aerobic exercise was conducted. The glucose metabolites and key enzymes involved in glucose metabolism in hippocampus were respectively detected by GC/MS based metabolomics and western blot. Metabolomics results showed that compared with control rats, the level of citric acid was significantly decreased, while the levels of lactic acid, ribose 5-phosphate, xylulose 5-phosphate and glucitol were significantly increased in the diabetic rat. Compared with diabetic rats, the level of citric acid was significantly increased, while the lactic acid, ribose 5-phosphate and xylulose 5-phosphate were significantly decreased in the diabetic exercise rats. Western blot results showed that lower level of citrate synthase and oxoglutarate dehydrogenase, higher level of aldose reductase and glucose 6 phosphatedehydrogenase were found in the diabetic rats when compared to control rats. After 4 weeks of aerobic exercise, citrate synthase was upregulated and glucose 6-phosphatedehydrogenase was downregulated in the diabetic rats. These results suggest that diabetes could cause abnormal glucose metabolism, and aerobic exercise plays an important role in regulating diabetes-induced disorder of glucose metabolism in the hippocampus. PMID- 29113874 TI - Effect of single doses of pindolol and d-fenfluramine on flumazenil-induced anxiety in panic disorder patients. AB - The effects of the 5-HT1A receptor blocker pindolol and the 5-HT releasing and uptake blocking agent d-fenfluramine, both used as indirect serotonin agonists, on flumazenil-induced acute anxiety reactions were studied in panic disorder patients to test the hypothesis that serotonin (5-HT) inhibits neural systems mediating panic attacks. Thirty never treated or drug free PD patients (16 females) aged 22-49 y (mean+/-SD, 32.9+/-8) received single doses of d fenfluramine (n=10; 30mg, p.o.), pindolol (n=10; 5mg, p.o.), or placebo (n=10) 90 and 45min before a challenge test with flumazenil (1.5mg, i.v., in 10min), under double-blind conditions. Panic attacks occurred in 5 control subjects (placebo flumazenil group), 5 subjects in the pindolol group and in 7 in the d-fenluramine pre-treated patients. Patients experiencing anxiety attacks following flumazenil reported higher increases in anxiety scores. Respiratory rate increases were not different between patients experiencing or not a panic attack. Despite sample size limitation, this study suggests that flumazenil induced anxiety reaction is not a good pharmacological model of panic attacks, considering the absence of serotonergic modulation of its effects. PMID- 29113875 TI - [22 key messages from the CNEMM]. PMID- 29113876 TI - [Indirect causes of maternal deaths (except stroke, cardiovascular diseases and infections): Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Maternal deaths of indirect causes result of a preexisting disease or an affection appeared during the pregnancy without any relationship with obstetrical causes, but worsened by the physiological effects of pregnancy. Among the 23 deaths of indirect cause related to a preexisiting pathology, 22 (96 %) have been analyzed by the expert comity. A known or preexisting chronic disease was documented in 16 patients (sick-cell disorder, n=3, treated epilepsy, n=3, intracerebral carvenomas, n=1, multifocal glial tumor, n=1, breast cancer, n=1, systemic lupus, n=1, diabetes mellitus, n=3, antiphospholipid syndrome, n=1). For 6 women, the pathology was unknown before the pregnancy (glioblastoma, n=2, epilepsy, n=1, Ehlers-Danlos syndrome, n=1, sick-cell disorder, n=1, breast cancer, n=1). While 6 of these deaths has been evaluated as not avoidable, 13 deaths has been considered as possibly (n=12) or certainly (n=1) preventable. The main factor of avoidability was the patient's interaction with the health system (medically non advised pregnancy, lack of adherence to treatment, for example). A pre-pregnancy medical consultation with a specialist should be recommended to all patients with preexisting chronic disease, to allow a complete information about the risks of a pregnancy, treatment adaptation if needed, better adherence and multidisciplinary follow up. PMID- 29113877 TI - [Maternal deaths due to gestational trophoblastic diseases, results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Gestational trophoblastic diseases (GTD) correspond to several entities which all have a common pattern: hypersecretion of human chorionic gondotrophin by trophoblastic hyperplasia. Between 2010 and 2012, there were 4 maternal deaths due to GTD (choriocarcinoma). The ratio of maternal death caused by GTD was 0,16/100,000 living births which was similar to the rate from the 2007-2009 period. These deaths represented 1.6% from the whole maternal mortality and 3.3% of the direct maternal mortality. These four deaths occurred after delivery and the diagnosis of GTD was made between 60 and 180 days in the postpartum period. Two cases seemed to be potentially avoidable. The main causes of suboptimal management were linked to delay either in diagnosis of GTD or in initiating the appropriate treatment. The analysis of these maternal deaths gave the opportunity to stress some major lessons to optimize medical management of GTD. Therefore, a patient presenting with persistent bleedings more than six weeks after delivery needs some specific exams such as plasma human chorionic gondotrophin measurement and histopathologic examination to affirm GTD and start early specific treatments generally leading to complete recovery. PMID- 29113878 TI - [Maternal deaths related to social vulnerabilities. Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - The theme of deprivation is new for the ENCMM. In view of the perceived increase in the number of maternal deaths that may be related to a deprivation situation, we sought to understand the main dimensions that could contribute to maternal death in this context, in order to propose a definition. The selection of cases made a posteriori is mainly based on a qualitative judgment. Between 2010 and 2012, among the deaths evaluated by the CNEMM, one or more elements related to social vulnerability were identified in 8.6% of the cases (18 deaths). The direct criteria used were the concepts of "deprivation" or "social difficulties", difficulties of housing, language barriers and isolation. The absence of prenatal care was retained as an indirect marker. We excluded cases where psychiatric pathology and/or addiction were predominant. Of the 18 cases identified with deprivation factors, death was considered "unavoidable" in 2 cases (11%), "certainly avoidable" or "possibly avoidable" in 13 cases (72%). In 3 cases (17%), avoidability could not be determined. Avoidability was related to the content and adequacy of care in 11 cases out of 13 (85%) and the patient's interaction with the health care system in 10 of 18 cases (56%). The analysis of maternal deaths among women in precarious situations points out that the link between socio-economic deprivation and poor maternal health outcomes potentially includes a specific risk of maternal death. PMID- 29113879 TI - [Epidemiology of maternal mortality in France, 2010-2012]. AB - OBJECTIVE: To describe, for the period 2010-2012, the frequency, the causes, the risk factors, the adequacy of care and the avoidability of maternal deaths in France. METHOD: Data from the National Confidential Enquiry into Maternal Deaths for 2010-2012. RESULTS: For the period 2010-2012, 256 maternal deaths occurred in France, a maternal mortality ratio of 10.3 per 100,000 live births (95% CI: 9.1 11.7), stable compared to 2007-2009. Compared to women aged 25-29, the risk is multiplied by 2.4 for women aged 35-39, and by 3 for women over 40 years. There are territorial disparities: 1 out of 7 maternal deaths occurs in the French overseas departments, and the maternal mortality ratio in those departments is 4 times that of metropolitan, France; and social disparities: the mortality of migrant women remains 2.5 times higher than that of women born in France, particularly for women born in sub-Saharan Africa whose RMM is 3.5 times that native women. A major finding is the 1/3 decrease in direct maternal mortality over the last 10 years, mainly due to for the first time the statistically significant decrease in mortality from obstetric hemorrhage, the frequency of which was divided by 2 in 10 years. However, almost all of the remaining deaths from hemorrhage are considered preventable and this is still the leading cause of maternal mortality in France (11% of deaths). Overall, 56% of these maternal deaths are considered "avoidable" or "possibly avoidable" and in 59% of cases the care provided was not optimal. CONCLUSION: Direct maternal mortality and in particular maternal mortality from hemorrhage has decreased significantly over the past 10 years, indicating improved obstetric care. However, territorial and social inequalities persist, and the majority of deaths remain preventable, which shows that the identification of opportunities for improvement must continue. To go even further in understanding the mechanisms involved, and to identify precise avenues of prevention, it is necessary to analyze in detail the stories of each maternal death in order to identify the repetitive elements in the series of deaths. This is what the following articles in this issue propose, with an analysis by cause of death, according to the idea that the same cause produces the same effects. PMID- 29113880 TI - [Enhanced system for maternal mortality surveillance in France, context and methods]. AB - Maternal mortality, despite its rarity in rich countries, remains a fundamental indicator of maternal health. It is considered as a "sentinel event", consequence of dysfunctions of the health care system, often cumulative. In addition to the classical epidemiological surveillance outcomes-number of deaths, maternal mortality ratio and identification of the subgroups of women at risk-its study allows an accurate analysis of each deceased woman's trajectory to identify opportunities for improvements in the content or organization of care; the correction of which will make it possible to prevent deaths but also upstream morbid events affected by the same dysfunctions. To achieve this dual epidemiological and clinical audit objective, an ad hoc enhanced system is needed. France has had such a system since 1996, the National Confidential enquiry into maternal deaths (ENCMM), coordinated by the Inserm Epope team. The first step is the multi-source identification (direct declaration, death certificate, birth certificates, hospital discharge data) of women who died during pregnancy or within one year of its end. The second step is the collection of detailed information for each death by a pair of clinical assessors. The third stage is the review of these anonymized documents by the National Committee of Experts on Maternal Mortality, which judges whether the death is maternal (causal link) and makes a judgment on the adequacy of care and avoidability of death. The synthesis of the information thus collected for maternal deaths in the period 2010-2012 is the subject of the last report. PMID- 29113881 TI - Reply to the Editor- On the deformation and interpolation of phase maps and concerns in multi-electrode and phase mapping of AF. PMID- 29113882 TI - To the Editor- On the deformation and interpolation of phase maps. PMID- 29113883 TI - To the Editor- Concerns in multi-electrode and phase mapping of AF. PMID- 29113884 TI - Orbital infantile hemangioma and rhabdomyosarcoma in children: differentiation using diffusion-weighted magnetic resonance imaging. AB - PURPOSE: To evaluate differences in magnetic resonance imaging (MRI) appearance between infantile hemangiomas and rhabdomyosarcomas of the orbit in pediatric patients using diffusion-weighted imaging. METHODS: A multicenter retrospective review of MRIs of pediatric patients with infantile hemangiomas and rhabdomyosarcomas of the orbit was performed. MRI examinations from a total of 21 patients with infantile hemangiomas and 12 patients with rhabdomyosarcomas of the orbit were independently reviewed by two subspecialty board-certified neuroradiologists masked to the diagnosis. A freehand region of interest was placed in the mass to obtain the mean apparent diffusion coefficient (ADC) value of the mass as well as within the medulla to obtain a ratio of the ADC mass to the medulla. A t test was used to compare mean ADC and ADC ratios between the two groups. Receiver operating characteristic analysis was performed to determine ADC value and ADC ratio thresholds for differentiation of infantile hemangioma and rhabdomyosarcoma. RESULTS: There was a statistically significant difference in the mean ADC value of infantile hemangiomas compared to rhabdomyosarcomas (1527 * 10-6 mm2/s vs 782 * 10-6 mm2/s; P = 0.0001) and the ADC ratio of the lesion to the medulla (1.77 vs 0.92; P = 0.0001). An ADC threshold of <1159 * 10-6 mm2/sec and an ADC ratio of <1.38 differentiated rhabdomyosarcoma from infantile hemangioma (sensitivity 100% and 100%; specificity 100% and 100%) with area under the curve of 1.0 and 1.0, respectively. CONCLUSIONS: In conjunction with conventional MRI sequences, ADC values obtained from diffusion-weighted MRI are useful to differentiate orbital infantile hemangiomas from rhabdomyosarcomas in pediatric patients. PMID- 29113885 TI - Improvement thermostability of Pseudoalteromonas carrageenovora arylsulfatase by rational design. AB - This study aimed to improve the thermostability of arylsulfatase from Pseudoalteromonas carrageenovora. A total of 10 single-site mutants were chosen using the PoPMuSiC program, and two mutants of K253N and P314T showed enhanced thermal stability. By saturation mutagenesis and thermostability analysis, K253H and P314T were the best mutants at the two sites. Combinational mutations of K253H, P314T and H260L were subsequently introduced, and the best mutant of K253H/H260L was selected. Thermal inactivation analysis showed the half-life (t1/2) value at 55 degrees C for K253H/H260L was 7.7-fold that of the wild-type enzyme (WT), meanwhile this mutant maintained the specific enzyme activity. Structure modeling demonstrated that the additional hydrogen bonds, optimization of surface charge-charge interactions, and increasing of hydrophobic interaction could account for the improved thermostability imparted by K253H/H260L. PMID- 29113886 TI - Physico-mechanical properties of gelatin films modified with Lysine, Arginine and Histidine. AB - The aim of this work was to evaluate the plasticizing effect of Lysine (Lys), Arginine (Arg) and Histidine (His) on gelatin films. Gelatin films incorporated with Lys, Arg and His at different levels (0, 0.5 and 1.0%) were prepared. The films without amino acids were prepared as controls. The addition of Lys increased the elongation at break (EAB) but decreased the tensile strength (TS) compared to the control, especially at 1.0% incorporated level. Arg had cross linking effect on gelatin films through hydrogen bonds demonstrated by FTIR Analysis, which increased TS of the films. His films showed worse EAB, transmission and transparence compared to the control. Furthermore, the addition of Lys and His reduced L* value and a* value with the coincidentally increased b* and DeltaE* values compared with the control. Thermal stability (DSC) and UV light barrier of gelatin films were improved by the addition of three kinds of amino acids. Thus, Lys and Arg had potential to improve the properties of gelatin films as natural plasticizer and cross-linker, respectively. PMID- 29113887 TI - Injectable silk fibroin hydrogels functionalized with microspheres as adult stem cells-carrier systems. AB - Hydrogels are good candidate materials for cell delivery scaffolds because they can mimic the physical, chemical, electrical and biological properties of most of the native tissues. In this study, composite biosynthetic hydrogels were produced by combining the bio-functionality of silk fibroin (SF) with the structural versatility of polyethylene-glycol-diacrylated (PEGDa). The formation of a photopolymerizable PEGDa-SF hydrogel (PSFHy) was optimized for 3D-cell culture. Functionalization of the 3D-PSFHy with protein microspheres (MS) was required to increase the porosity and cell-adhesive properties of the material. Cardiac mesenchymal stem cells, which were cultured within the MS-embedding PSFHy, exhibited good viability and expression of proteins that are characteristic of the initial phases of the cardiac muscle differentiation process. Further, the addition of chondroitin sulfate into the scaffolds improved the cell viability. A cell-preconditioning of the scaffold was also performed, suggesting a potential application of these sponge-like scaffolds for analysing the effects of several extracellular microenvironments, produced by different kinds of cells, on the stem cells fate. The results presented herein highlight on the possibility to use the PSFHys functionalized with MS as stem cell-carrier systems with sponge-like properties, potential ultrasound-imaging contrast agents and controlled biochemical factor delivery. PMID- 29113889 TI - Production optimization, purification and characterization of a heat-tolerant acidic pectinase from Bacillus sp. ZJ1407. AB - Medium compositions for a heat-tolerant acidic pectinase production from Bacillus sp. ZJ1407 were optimized via response surface methodology (RSM) and its enzymatic properties were investigated. A 2-level factorial design was used to estimate the main effect of factors, and to screen the significant factors. A central composite design was used to find out the optimal concentrations of screened key factors. Lactose, tryptone and (NH4)2SO4 were found to have a significant influence on the pectinase activity (p <0.05). The optimal medium compositions were as follows: lactose 44.8g/l, tyrptone 30.9g/l, (NH4)2SO4 1.35g/l, MnSO4.H2O 0.2g/l, MgSO4 0.4g/l and NaCl 3.5g/l. Pectinase was purified to homogeneity by ammonium sulphate precipitation, DEAE-cellulose ion-exchange chromatography and Sephadex G-100 size-exclusion chromatography. The molecular weight of the purified pectinase determined by SDS-PAGE was about 23kDa, and its final specific activity was 110.47U/mg. Its optimal temperature and pH were 37 degrees C and 5.0, respectively. Pectinase was very stable within a pH range of 3.0-5.0, and showed a high thermo-stability at 80 and 90 degrees C. Ba2+ could significantly promote the activity of pectinase, and Mn2+ heavily inhibited its activity. This study provides new insight into the future development and use of pectinase from Bacillus sp. ZJ1407. PMID- 29113888 TI - Ultrasensitive electrochemical immunosensing of tumor suppressor protein p53 in unprocessed human plasma and cell lysates using a novel nanocomposite based on poly-cysteine/graphene quantum dots/gold nanoparticle. AB - An ultrasensitive electrochemical immunosensor for quantitation of tumor suppressor protein p53 based on ternary signal amplification strategy was fabricated. In this work, p53-antibody was immobilized onto a green and biocompatible nanocomposite containing poly l-cysteine (P-Cys) as conductive matrix and graphene quantum dots (GQDs)/gold nanoparticles (GNPs) as dual amplification elements. Therefore, a novel multilayer film based on P-Cys, GQDs, and GNPs was exploited to develop a highly sensitive immunosensor for detection of p53. Fully electrochemical methodology was used to prepare a new transducer on a gold surface which provided a high surface area to immobilize a high amount of the anti-p53. Under optimized condition the calibration curve for p53 concentration was linear up to 0.000197-0.016 pM (by SWV technique) and 0.195-50 pM (by DPV technique) with lower limit of quantification of 0.065 fM. Also, linear range and lower limit of quantification of p53 in unprocessed human plasma were 0.000592-1.296 pM and 0.065 fM, respectively. The method was applied to the assay of p53 in human plasma sample and normal and malignant cell line lysates such as normal cell Line from mouse C3H (L929), colon cancer cell-HCT, prostate cancer cell line PC-3, and human breast adenocarcinoma cell line-MCF7. PMID- 29113890 TI - Analysis of Aspergillus sp. lipase immobilization for the application in organic synthesis. AB - Nowadays, for the industrial implementations, especially in the area of organic synthesis, immobilized enzymes are preferred over their soluble forms. Present study aimed to find fast, cost-efficient, and effective way of lipase immobilization for the use in organic media. Lipase from Aspergillus sp. (Resinase A 2X) was immobilized utilizing cross-linking of enzyme aggregates, covalent immobilization on magnetite particles and adsorption-immobilization using pyrolyzed sugar industry waste product as a novel type of carrier. Covalently- and adsorption-immobilized preparations exhibited greater specific activities (5.61+/-0.18U/mg and 14.2+/-0.63U/mg, respectively) in organic reaction media than the soluble form of the enzyme (0.06+/-0.01U/mg). Enzyme immobilized on the sugar industry waste pyrolyis product was determined as a best way to hyperactivate Resinase A 2X and was chosen for the synthesis of flavor and fragrance compound 2-phenylethyl butanoate. Furthermore, in order to optimize 2 phenylethyl butanoate synthesis conditions, central compositional experimental plan was designed using RSM. It showed that in optimal reaction conditions (4.5h at 40.7 degrees C, with 0.1M of substrate) conversion higher than 90% can be achieved. Studies of the operational stability showed enhanced reusability of adsorption-immobilized lipase (with each cycle, efficiency of the 2-PB synthesis diminished by 20-30%). The use of the sugar industry waste pyrolysis product as a carrier provides a novel, cheap, fast, cost-efficient and eco-friendly way of immobilization with some crucial points to be noted for the best productivity. PMID- 29113891 TI - The rearrangement of motif F in the flavivirus RNA-directed RNA polymerase. AB - In the flavivirus genus, the non-structural protein NS5 plays a central role in RNA viral replication and constitutes a major target for drug discovery. One of the prime challenges in the study of NS5 protein is to investigate the interplay between the two protein domains, namely, the RNA-dependent RNA polymerase (RdRp) domain and the methyltransferase (MTase) domain. These investigations could clarify the multiple roles of NS5 protein in the virus life cycle. Here we present the results of sequence analyses and structural bioinformatics studies of NS5 protein, which suggest that the conserved motif F in the NS5 protein could act as a lock which controls the rearrangement of the domains and as a switch in the protein enzymatic activity. PMID- 29113892 TI - Screening behaviorally active compounds based on fluorescence quenching in combination with binding mechanism analyses of SspOBP7, an odorant binding protein from Sclerodermus sp. AB - Reverse chemical ecology approaches based on the recognition and transport function of odorant binding proteins (OBPs) have been used to screen behaviorally active compounds of insects. In the first place, behaviorally active compounds from Sclerodermus sp., an important ectoparasite of Monochamus alternatus Hope, were screened by SspOBP7. The Fluorescence quenching assays revealed that only six of 19 ligands that had binding affinities in fluorescence competition-binding assays formed complexes with SspOBP7. Pursuing this further, two non-polar ligands, terpinolene and (+)-alpha-longipinene showed strong attractant activities for Sclerodermus sp. The pH change could lead to conformational transition of SspOBP7 from one state to another, which results in low binding affinities at low pH. Finally, a mutational analysis of the SspOBP7 binding cavity proved that changing the cavity had a greater effect on non-polar ligands, and the specific recognition of ligands by SspOBP7 might depend mainly on the appropriate shapes of the cavity and ligands. The most obvious finding to emerge from this work is that the use of fluorescence quenching to study the binding mechanism of OBPs could aid reverse chemical ecology approaches by narrowing the scope of candidate behaviorally active compounds. PMID- 29113893 TI - Saccharide binding by intelectins. AB - This communication probes ligand binding by human Intelectin-1 with several saccharides. Human Intelectin-1 was previously reported to bind to microbial glycans via ribofuranoside or galactofuranoside residues, whereas subsequently, a crystal structure of ligand bound hITLN1 indicated that hITLN1 does not bind to ribofuranoside but distinguishes between microbial and human glycans through a glycan motif - a terminal, acyclic 1,2-diol, which is present on galactofuranose and other microbial saccharides. Here, we demonstrate that besides glycerol and glycerol derivatives (which have an acyclic 1,2-diol), and 2-deoxy-d-galactose, d ribose and 2-deoxy-d-ribose, which have been previously reported as human Intelectin-1 ligands, 2-C-hydroxymethyl-d-ribose, d-talose, d-idose, d-altrose and sorbitol also elute human Intelectin-1 from Sepharose CL-6B. Interestingly, Sepharose, 2-deoxy-d-galactose (in its pyranose form), 2-C-hydroxymethyl-d ribose, d-ribose and 2-deoxy d-ribose lack a terminal, acyclic 1,2-diol. We discuss the implications of these observations and rationalize the discrepancies in the apparent affinity of saccharide ligands for hITLN1 with different assay formats. We also report the distinct saccharide binding profiles of the hITLN1 homologues, HaloITLN and XL35ITLN, and demonstrate that hITLN1 binding to a saccharide ligand may modulate binding to its protein ligand, lactoferrin and vice versa. PMID- 29113894 TI - Combined effect of gene dosage and process optimization strategies on high-level production of recombinant human interleukin-3 (hIL-3) in Pichia pastoris fed batch culture. AB - In this work, the combined effects of gene dosage and process optimization strategies were studied to achieve higher hIL-3 expression in Pichia system. The in-vitro multimerization method was used to generate various Pichia X-33 transformants having multi-copy expression cassettes. The quantitative polymerase chain reaction (qPCR) strategy was used to further confirm the genome integration of hIL-3 expression cassette. From shake flask expression studies, the recombinant hIL-3 concentration in culture supernatant increased upto 8 copies to a level of 310mg/L, thereafter a considerably lower expression was observed. The small scale optimization experiments at shake flask level resulted in an improved product concentration of 350mg/L. The batch and fed-batch fermentation runs in complex medium showed a product concentration of 1.81 and 1.49g/L, respectively. To further enhance the production level, the fermentation runs were conducted in modified minimal media where a maximum hIL-3 protein level of 2.23g/L was obtained in batch fermentation. The specific product yield (YP/X) was at a level of 25.65mg/g DCW, whereas the overall volumetric productivity of the process was 27.31mg/L/h. The biological activity of the partially purified hIL-3 protein was confirmed via the proliferation of human erythroleukemia TF-1 cells using MTT assay. PMID- 29113896 TI - Neuroinflammation produced by heavy alcohol intake is due to loops of interactions between Toll-like 4 and TNF receptors, peroxisome proliferator activated receptors and the central melanocortin system: A novel hypothesis and new therapeutic avenues. AB - Excessive alcohol intake induces an inflammatory response in the brain, via TNFalpha, TLR4 and NF-kappaB signaling pathways. It has been proposed that neuroinflammation would play a very important role in the development of alcohol addiction. In addition to stimulating the synthesis of inflammatory mediators such as IL-6, IL-1beta and TNFalpha, NF-kappaB is capable of reducing the anti inflammatory activity of PPARalpha and PPARgamma. Reciprocally, PPARalpha, PPARgamma and melanocortin 4 receptor (MC4R) can decrease the proinflammatory activity of NF-kappaB, establishing an interplay of inactivations between such nuclear factors and receptors. In this review, we hypothesize that one of the mechanisms by which alcohol produces neuroinflammation is through NF-kappaB mediated decrease in PPARalpha and PPARgamma anti-inflammatory activities; in addition, ethanol negatively affects MC4R activity, decreasing the ability of this receptor to activate PPARgamma. PPARalpha, PPARgamma and MC4R can be pharmacologically activated by synthetic ligands (fibrates, thiazolidinediones and synthetic peptides, respectively); in this context, we propose that the administration of such ligands would decrease neuroinflammation produced by alcohol intake. The advantage of this approach is that fibrates and thiazolidinediones are FDA-approved drugs that have been used for years in other clinical conditions, and now may offer a new perspective for the treatment of alcoholism. PMID- 29113895 TI - Isolation, Structural characterization, and antiproliferative activity of phycocolloids from the red seaweed Laurencia papillosa on MCF-7 human breast cancer cells. AB - Hydrocolloids from seaweeds (phycocolloids) have interesting functional properties like antiproliferative activity. Marine algae consumptions are linked to law cancer incidences in countries that traditionally consume marine products. In this study, we have investigated water-soluble sulfated polysaccharides isolated from the red seaweed Laurencia papillosa and determined their chemical characteristics and biological activities on the human breast cancer cell line MCF-7. Total polysaccharides were extracted and fractionated from L. papillosa and characterized using FTIR-ATR and NMR spectrometry. In addition, their approximate molar mass was determined by GPC method. The chemical characterization of purified polysaccharides reveals the presence of sulfated polysaccharides differentially dispersed in the algal cell wall. They are the three types of carrageenan, kappa, iota and lambda carrageenans, named LP-W1, -W2 and -W3 respectively. Biological effects and cytotoxicity of the identified of the three sulfated polysaccharide fractions were evaluated in MCF-7 cell line. Our results showed a significant inhibition of MCF-7 cell viability by dose dependent manner for cells exposed to LP-W2 and LP-W3 polysaccharides for 24h. The mechanistic of LP fractions-mediated apoptosis in MCF-7 cells was demonstrated. The biological effects of L. papillosa SPs indicate that it may be a promising candidate for breast cancer prevention and therapy. PMID- 29113897 TI - Long lasting effects of chronic WIN55,212-2 treatment on mesostriatal dopaminergic and cannabinoid systems in the rat brain. AB - Cannabinoid administration modulates dopamine transmission via an indirect, multisynaptic mechanism that includes the activation of cannabinoid type-1 receptor (CB1R). The present study evaluated in rodents, the effects of acute and chronic (20 days) WIN55,212-2 administration, a non-selective CB1R agonist, on dopamine uptake and synthesis in the mesolimbic and nigrostriatal dopaminergic pathways and associate them to its effects on the endocannabinoid system. The effect of spontaneous withdrawal, after different abstinence periods (7 days, 20 days), was also assessed. Acute and chronic administration of WIN55,212-2 decreased dopamine transporter (DAT) binding and mRNA levels, as well as tyrosine hydroxylase (TH) mRNA expression in the substantia nigra (SN) and ventral tegmental area (VTA). In the striatum, chronic WIN55,212-2 administration led to decreased protein expression of DAT and TH, whereas no alterations were observed after acute administration, suggesting a diminished dopamine uptake and synthesis after chronic agonist treatment. Furthermore, after chronic agonist treatment, we observed reduced CB1R binding and mRNA levels in SN and striatum, providing evidence for a possible regulatory role of the endocannabinoid system on dopaminergic function. Seven days after WIN55,212-2 cessation, we observed a rebound increase in mRNA, binding and total protein levels of DAT and TH in VTA, SN and striatum proposing the existence of a biphasic expression pattern, which was also observed in CB1R binding levels. Within the 20-day period of abstinence, TH mRNA and protein levels and CB1R binding levels remain increased. The above results indicate that chronic CB1R agonist treatment induces long-lasting control of the mesostriatal dopaminergic activity. PMID- 29113899 TI - Neurosurgery in Octogenarians: A Prospective Study of Perioperative Morbidity, Mortality, and Complications in Elderly Patients. AB - OBJECTIVE: The aging population in industrialized countries shifts the age limit for neurosurgical interventions toward increasingly older patients. This study investigates whether octogenarians (>=80 years) stand out in outcome and incidence of perioperative complications. METHODS: Consecutive patients >=80 years operated on between January 2013 and August 2016 were compared against a control group of patients aged 55-75 years matched by indication for surgery. Status at admission, perioperative complications, functional outcome, and mortality were assessed in a prospective patient registry. Complications were classified in the therapy-oriented Clavien-Dindo grading (CDG) system. RESULTS: We compared 266 octogenarians (median age, 83 years; interquartile range, 81-86 years; 154 men) with 232 controls (median age, 67 years; interquartile range, 60 71 years; 151 men). At follow-up (median, 53 vs. 49 days), median modified Ranking Scale scores were 2 versus 1 and median Karnofsky Performance Status was 80 versus 90; both improved significantly compared to baseline (P < 0.0001). Only admission Karnofsky Performance Status was significantly associated with clinical outcome at follow-up (odds ratio, 1.05; P < 0.0001). Pharmacologic treatment (CDG 2) was sufficient in 56% of all complications in octogenarians (controls, 43%). Octogenarians were more prone to complications as an inpatient (36% vs. 28%; P = 0.04) because of a higher incidence of CDG 2 complications (20% vs. 12%; P = 0.02). The rate of complications that required more extensive therapy did not differ significantly between cohorts. CONCLUSIONS: Neurosurgery in octogenarians had a similar rate of severe complications, morbidity, and mortality as in matched controls. Therefore, age alone should not serve as a contraindication for neurosurgery. PMID- 29113898 TI - Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists. AB - Diversion of synthetic cannabinoids from the lab to drugs of abuse has become increasingly prevalent in recent years. Moreover, as earlier synthetic cannabinoids were banned, manufacturers introduced a new supply of novel compounds to serve as replacements. Hence, the chemical diversity of synthetic cannabinoid analogs has also rapidly increased. The present study examined 8 new synthetic cannabinoids: AM-1220, AM-2232, AM-2233, AM-679, EAM-2201, JWH-210, JHW 251, and MAM-2201. Each compound was assessed for binding affinity and functional activation of CB1 and CB2 receptors, and pharmacological equivalence with Delta9 tetrahydrocannabinol (THC) in THC drug discrimination. All compounds bound to and activated CB1 and CB2 receptors, although efficacy at the CB2 receptor was reduced compared to that for the CB1 receptor. Similarly, all compounds stimulated [35S]GTPgammaS binding through the CB1 receptor, and all compounds except AM-1220 and AM-2233 stimulated [35S]GTPgammaS binding through the CB2 receptor. Furthermore, these compounds, along with CP55,940, substituted for THC in THC drug discrimination. Rank order of potency in drug discrimination was correlated with CB1 receptor binding affinity. Together, these results suggest that all test compounds share the THC-like subjective effects of marijuana. Interestingly, the most potent compounds in CB1 binding in the present study were also the compounds that have been found recently in the U.S., MAM-2201, EAM-2201, JWH-210, AM-2233, and AM-1220. These results indicate that the evolution of the synthetic cannabinoid drug market may be focused toward compounds with increased potency. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 29113900 TI - Dwell Time of Stentriever Influences Complete Revascularization and First-Pass TICI 3 Revascularization in Acute Large Vessel Occlusive Stroke. AB - OBJECTIVE: In acute ischemic stroke with large vessel occlusion, the interaction between the clot retriever and the stent is critical for achieving successful recanalization. The ideal time of stent deployment (dwell time [DT]) to improve revascularization is currently unknown. We systematically analyzed the effect of different DT on final angiographic and clinical outcomes of patients who underwent mechanical thrombectomy. METHODS: The DT was progressively increased from 3 minutes to 5 minutes and then 8 minutes during the study period. The effect of DT on recanalization attempts, successful angiographic outcome (thrombolysis in cerebral ischemia [TICI] 2b or TICI 3), total revascularization time, and immediate and 3-month clinical outcomes were evaluated. The DT of 3 minutes and 5 minutes (DT3-5) was compared against DT of 8 minutes (DT8). RESULTS: Forty patients were included in the analysis. Good angiographic outcome was observed in 94.1% of patients in the DT8 cohort with an average attempt of 1.2 compared with 78.3% with average attempts of 2.0 in other group. Single-pass good recanalization (TICI 2b or 3) and single-pass complete revascularization (TICI3) was significantly higher in the DT group compared with the DT3-5 group (82.4% vs. 43.5% [P = 0.013] and 42.9% vs. 8.7% [P = 0.003], respectively). A favorable trend toward a reduced overall procedural time (34.59 vs. 55.59 minutes) was observed, but was not statistically significant (P = 0.15). CONCLUSIONS: Mild prolongation of DT to 8 minutes improves revascularization outcome with fewer attempts, possibly because of better clot-stent interaction. PMID- 29113901 TI - Efficacy of Using Intermediate Screws in Short-Segment Fixation for Thoracolumbar Fractures: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Some studies have reported that the conventional intersegmental pedicle screws (4-screw fixation [4S]) device for thoracolumbar fractures was associated with inadequate reduction of fractured vertebrae, insufficient correction of kyphosis, and implant failure. Recently, a series of biomechanical studies has confirmed that the addition of intermediate fixation screws (6-screw fixation [6S]) could provide stronger fixation and better reduction of fractured vertebrae. Nevertheless, the clinical and radiologic efficacy of the additional intermediate screws remains unclear. METHODS: A meta-analysis of randomized controlled trials was used to compare clinical and radiologic outcomes and complications of posterior pedicle screws combined with intermediate screws fixation versus conventional intersegmental pedicle screw fixation. We comprehensively searched MEDLINE, OVID, and Springer according to a search strategy, selecting articles based on inclusion criteria, and extracted data from these reports. Risk of bias in included studies was assessed. Pooled estimates and corresponding 95% confidence intervals were calculated. RESULTS: Six randomized controlled trials involving 310 patients were evaluated in this meta analysis. Pooled estimates showed statistically similar baseline characteristics, hospital stays, postoperative visual analog scale scores, and infection rates between the 4S group and the 6S group. The 6S group had significantly less correction loss of segmental angle and of anterior vertebral height compression, and lower implant failure rate. The 6S group also showed a slightly longer operative time and more blood loss than did the 4S group. CONCLUSIONS: Based on our analysis, the combined intermediate screws fixation technique was associated with significantly improved radiologic outcomes but did not seem to compromise other perioperative outcomes. PMID- 29113902 TI - Evaluation of the Use of Calcium Phosphate Cement for Aesthetic Neurosurgical Cranial Reconstruction. AB - OBJECTIVE: The objective of this article is to evaluate whether newly developed calcium phosphate cement (CPC), mounted around the titanium plates, is useful for aesthetic cranial reconstruction by using 2 methods. METHODS: The morphologic changes of CPC were observed in videos of 6 patients who had undergone cranial reconstruction with CPC during the first surgery and required second surgery. The facial aesthetic outcomes of 74 consecutive patients, more than 12 months after frontotemporal or bifrontal craniotomy and reconstruction with or without CPC, were evaluated. RESULTS: Observations of CPC changes were available 1 day, 2 weeks, 2 months, 5 months, 10 months, and 26 months after the first surgeries. CPC, applied superficially on the cranial surface, had not set sufficiently. CPCs, mounted thickly around the titanium plates and forming hydroxyapatite, were residual during the latter period. Comparison between the aesthetic reconstruction group (with CPC) and the simple reconstruction group (without CPC) showed that the objective bump detected by the investigator, and the subjective bump noticed by the patients themselves, were significantly more frequent in the simple reconstruction group. Comparison between the patients without an objective bump and the patients with an objective bump during the follow-up period showed that the proportion of patients after aesthetic cranial reconstruction with CPC was significantly higher in patients without an objective bump. Patients' characteristics, craniotomy procedure, use of a vascularized pericranial flap, and craniotomy-associated complications did not influence the objective bump significantly. CONCLUSIONS: Use of CPC was expected to bring better aesthetic outcomes after neurosurgical cranial reconstructions. PMID- 29113903 TI - Long-Term Follow-Up of Patients with Metastatic Epidural Spinal Cord Compression from Breast Cancer Treated with Surgery Followed by Radiotherapy. AB - OBJECTIVE: To evaluate role of surgery plus radiotherapy (RT) in patients with metastatic epidural spinal cord compression from breast cancer with a follow-up >10 years. METHODS: The study included 23 patients treated between 2004 and 2008. Surgical treatment was performed in patients with good performance status, limited metastatic disease, and progressive neurologic deficit and/or intractable pain. RT was performed delivering a median total dose of 30 Gy in 10 fractions. Clinical outcome was evaluated using the modified visual analog scale for pain, Frankel grade for neurologic deficit, and magnetic resonance imaging before and after treatments and every 3 months thereafter. RESULTS: Minimal resection was performed in 17.4% of patients, curettage in 47.8%, and total tumorectomy in 34.8%, followed by RT in 78.3%. Pain remission was obtained in 98% of patients, and recovery of neurologic function was obtained in 92.9%. Median follow-up time was 153 months (range, 128-209 months). No relapse at site of treatments occurred. Median overall survival time was 47 months (95% confidence interval 33 114 months), and 2-, 5-, and 10-year overall survival rates were 81% (+/-8.6%), 42.9% (+/-10.8%), and 28.6% (+/-9.9%). On univariate analysis, performance status, type of surgical resection, breast cancer phenotype, and presence of other bone metastases were recorded as influencing survival; the last-mentioned was also confirmed in multivariate analysis. CONCLUSIONS: Surgery plus RT is a safe and feasible treatment with limited morbidity. In selected patients with good performance status, positive hormonal receptors, and limited metastatic disease, surgical intervention should be strongly considered early on. PMID- 29113905 TI - Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases. AB - BACKGROUND: Tripartite motif-containing (TRIM) 21 has been implicated in the pathogenesis of several types of autoimmune diseases. OBJECTIVE: We sought to elucidate TRIM21 expression in patients with inflammatory bowel diseases (IBDs) and its role in regulating intestinal mucosal inflammation. METHODS: TRIM21 expression was analyzed in the inflamed mucosa of patients with IBDs by means of quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4+ T cells were transfected with lentivirus-expressing TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by using quantitative RT-PCR and ELISA. TRIM21 /- mice were generated, and trinitrobenzene sulfonic acid- and CD45RBhighCD4+ T cell-induced colitis models were established to determine its role in induction of intestinal inflammation. RESULTS: TRIM21 was expressed predominantly in CD4+ T cells and decreased markedly in the inflamed mucosa of patients with IBDs compared with healthy control subjects. Ectopic expression of TRIM21 inhibited IBD CD4+ T cells to differentiate into TH1 and TH17 cells, whereas downregulation of TRIM21 had the opposite effects. TRIM21-/- mice had more severe colitis after administration of trinitrobenzene sulfonic acid compared with wild-type mice, which was characterized by increased expression of IFN-gamma, TNF-alpha, and IL 17A in the colon. TRIM21-/-CD45RBhighCD4+ T cells reconstituted into recombination-activating gene (Rag1)-/- mice induced more severe colitis than in wild-type control mice. Mechanistically, interferon regulatory factor 3 was identified as a functional downstream target of TRIM21 in that silencing of interferon regulatory factor 3 suppressed TRIM21-/-CD4+ T-cell differentiation into TH1 and TH17 cells. CONCLUSIONS: TRIM21 plays a protective role in mucosal inflammation through inhibiting TH1 and TH17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs. PMID- 29113904 TI - Site-Specific Disulfide Crosslinked Nucleosomes with Enhanced Stability. AB - We engineered nucleosome core particles (NCPs) with two site-specific cysteine crosslinks that increase the stability of the particle. The first disulfide was introduced between the two copies of H2A via an H2A-N38C point mutation, effectively crosslinking the two H2A/H2B heterodimers together to stabilize the histone octamer against H2A/H2B dimer dissociation. The second crosslink was engineered between an R40C point mutation on the N-terminal tail of H3 and the NCP DNA ends by the introduction of a convertible nucleotide. This crosslink maintains the nucleosome DNA in a fixed translational setting relative to the histone octamer and prevents dilution-driven dissociation. The X-ray crystal structures of NCPs containing the disulfides in isolation and in combination were determined. Both disulfides stabilize the structure of the NCP without disturbing the overall structure. Nucleosomes containing these modifications will be advantageous for biochemical and structural studies as a consequence of their greater resistance to dissociation during high dilution in purification, elevated salt for crystallization and vitrification for cryogenic electron microscopy. PMID- 29113906 TI - Human plasma C3 is essential for the development of memory B, but not T, lymphocytes. PMID- 29113907 TI - Assessing the prevalence of protein-energy wasting in haemodialysis patients: A cross-sectional monocentric study. AB - INTRODUCTION: Protein-energy wasting (PEW) is a strong predictive factor for morbidity and mortality in haemodialysis (HD) patients. However, there is no consensus for its assessment. The present study aimed to assess the nutritional status of patients on chronic HD by use of different nutritional assessment parameters, and at verifying which can identify the greatest number of HD patients with PEW. Also, to investigate predictors of nutritional status in a haemodialysis center in Morocco. PATIENTS AND METHODS: This is a cross-sectional analysis performed on 126 patients aged 44.82+/-14.01 years, undergoing maintenance HD in the Department of nephrology of the university hospital centre of Casablanca, Morocco. Energy and nutrients intake assessment was obtained by a three-day period food recall. Biochemical parameters, bioelectric impedance analysis, and subjective global assessment (SGA), have been performed to assess nutritional status. RESULTS: According to SGA the prevalence of PEW was 74.62%. However, when using the ISRMN malnutrition criteria only 36.50% of the patients were diagnosed with PEW. Pearson correlation showed a negative association between the degree of malnutrition evaluated by SGA and serum prealbumin (r= 0.54; P=0.0001), serum albumin (r=-0.50; P=0.001), energy (r=-0.34; P=0.002), protein intake (r=-0.41; P=0.0001), and a significant positive correlation with CRP (r=0.65; P=0.0001) was determined, but not with anthropometric measurements nor lipids profile. The areas under the receiver operating characteristic curve were 0.841 (95% CI: 0.751-0.932) for serum prealbumin, and 0.737 (95% CI: 0.634 0.840) for serum albumin. CONCLUSION: Our results showed a high prevalence of PEW among Haemodialysis patients. Also, our findings suggest that SGA, serum albumin and prealbumin may be relative appropriate and practical markers for assessing nutritional status in HD patients. PMID- 29113909 TI - The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) has a DNA genome but replicates within the nucleus by reverse transcription of an RNA pregenome, which is converted to DNA in cytoplasmic capsids. Capsids in this compartment are correlated with inflammation and epitopes of the capsid protein core (Cp) are a major target for T cell-mediated immune responses. We investigated the mechanism of cytoplasmic capsid transport, which is important for infection but also for cytosolic capsid removal. METHODS: We used virion-derived capsids containing mature rcDNA (matC) and empty capsids (empC). RNA-containing capsids (rnaC) were used as a control. The investigations comprised pull-down assays for identification of cellular interaction partners, immune fluorescence microscopy for their colocalization and electron microscopy after microinjection to determine their biological significance. RESULTS: matC and empC underwent active transport through the cytoplasm towards the nucleus, while rnaC was poorly transported. We identified the dynein light chain LL1 as a functional interaction partner linking capsids to the dynein motor complex and showed that there is no compensatory transport pathway. Using capsid and dynein LL1 mutants we characterized the required domains on the capsid and LL1. CONCLUSIONS: This is the first investigation on the detailed molecular mechanism of how matC pass the cytoplasm upon infection and how empC can be actively removed from the cytoplasm into the nucleus. Considering that hepatocytes with cytoplasmic capsids are better recognized by the T cells, we hypothesize that targeting capsid DynLL1-interaction will not only block HBV infection but also stimulate elimination of infected cells. LAY SUMMARY: In this study, we identified the molecular details of HBV translocation through the cytoplasm. Our evidence offers a new drug target which could not only inhibit infection but also stimulate immune clearance of HBV infected cells. PMID- 29113910 TI - The bidirectional impacts of alcohol consumption and the metabolic syndrome: Cofactors for progressive fatty liver disease. AB - Current medical practice artificially dichotomises a diagnosis of fatty liver disease into one of two common forms: alcoholic liver disease (ALD) and non alcoholic fatty liver disease (NAFLD). Together, these account for the majority of chronic liver diseases worldwide. In recent years, there has been a dramatic increase in the prevalence of obesity and metabolic syndrome within the general population. These factors now coexist with alcohol consumption in a substantial proportion of the population. Each exposure sensitises the liver to the injurious effects of the other; an interaction that drives and potentially accelerates the genesis of liver disease. We review the epidemiological evidence and scientific literature that considers how alcohol consumption interacts with components of the metabolic syndrome to exert synergistic or supra-additive effects on the development and progression of liver disease, before discussing how these interactions may be addressed in clinical practice. PMID- 29113911 TI - Access to care in rare liver diseases: New challenges and new opportunities. AB - Patients with rare diseases are often disadvantaged, particularly those with rare liver diseases. Reasons for disadvantage include delayed or overlooked diagnosis, lack of local expertise and high-quality care, poor scientific understanding of the disease process and limited therapeutic options. In adult liver disease this can be compounded by prejudices towards patients with liver disease in general, because of a perception (incorrect for all rare liver diseases) that liver disease is lifestyle related and thus "self-inflicted". In paediatric rare liver diseases, such as biliary atresia, optimising outcomes requires a particularly timely diagnosis. Irrespective of patient age, the scientific and medical community must rise to the challenge of advancing our understanding of rare liver disease, searching for more effective and specific therapies, and providing the infrastructure to provide the best care for all patients, infants, children, young and older adults. The European Reference Network for Rare Liver Diseases is an important step in this direction. PMID- 29113913 TI - Reply to: "HBV RNA virion-like particles produced under nucleos(t)ide analogues treatment are mainly replication-deficient". PMID- 29113912 TI - Arid1a regulates response to anti-angiogenic therapy in advanced hepatocellular carcinoma. AB - BACKGROUND & AIMS: AT-rich interaction domain 1a (Arid1a), a component of the chromatin remodeling complex, has emerged as a tumor suppressor gene. It is frequently mutated in hepatocellular carcinoma (HCC). However, it remains unknown how Arid1a suppresses HCC development and whether Arid1a deficiency could be exploited for therapy, we aimed to explore these questions. METHODS: The expression of Arid1a in human and mouse HCCs was determined by immunohistochemical (IHC) staining. Gene expression was determined by quantitative PCR, ELISA or western blotting. Arid1a knockdown HCC cell lines were established by lentiviral-based shRNA. Tumor angiogenesis was quantified based on vessel density. The regulation of angiopoietin (Ang2) expression by Arid1a was identified by chromatin immunoprecipitation (ChIP) assay. The tumor promoting function of Arid1a loss was studied with a xenograft model in nude mice and diethylnitrosamine (DEN)-induced HCC in Arid1a conditional knockout mice. The therapeutic values of Ang2 antibody and sorafenib treatment were evaluated both in vitro and in vivo. RESULTS: We demonstrate that Arid1a deficiency, occurring in advanced human HCCs, is associated with increased vessel density. Mechanistically, loss of Arid1a causes aberrant histone H3K27ac deposition at the angiopoietin-2 (Ang2) enhancer and promoter, which eventually leads to ectopic expression of Ang2 and promotes HCC development. Ang2 blockade in Arid1a deficient HCCs significantly reduces vessel density and tumor progression. Importantly, sorafenib treatment, which suppresses H3K27 acetylation and Ang2 expression, profoundly halts the progression of Arid1a-deficient HCCs. CONCLUSIONS: Arid1a-deficiency activates Ang2-dependent angiogenesis and promotes HCC progression. Loss of Arid1a in HCCs confers sensitivity to Ang2 blockade and sorafenib treatment. LAY SUMMARY: AT-rich interaction domain 1a (Arid1a), is a tumor suppressor gene. Arid1a-deficiency promotes Ang2-dependent angiogenesis leading to hepatocellular carcinoma progression. Arid1a-deficiency also sensitizes tumors to Ang2 blockade by sorafenib treatment. PMID- 29113914 TI - HBV RNA virion-like particles produced under nucleos(t)ide analogues treatment are mainly replication-deficient. PMID- 29113915 TI - Bisphenol A accelerates meiotic progression in embryonic chickens via the estrogen receptor beta signaling pathway. AB - Bisphenol A (BPA) as an endocrine-disrupting chemical with weak estrogenic activity affects formation of primordial follicles. This study aimed to identify the potential effects and molecular mechanisms of BPA on meiosis and primordial follicle formation in chickens. The results suggest that the cortical layer was thickened and the number of germ cells that entered into meiosis was increased in BPA-treated ovaries. The percentage of gammaH2AX-positive cells increased significantly. In addition, up-regulated mRNA expression of meiotic genes, including stimulated by retinoic acid gene 8 (Stra8), disrupted meiotic cDNA 1 homologue (Dmc1) and synaptonemal complex protein 3 (Scp3) were observed in BPA treated ovaries. Therefore, progression to meiosis prophase I was accelerated by exposure to BPA. Furthermore, the results demonstrated that injection of BPA resulted in hypomethylation of Dazl (Deleted in A Zoospermia-Like gene) and Stra8 and up-regulation mRNA expression of Dazl and Stra8 during meiotic onset. Finally, the relationship between estrogen receptor (ER) expression and BPA induced meiosis was revealed using an in vitro ovarian culture system. BPA enhanced ERbeta expression at the levels of mRNA and protein, while BPA exerted no significant effect on ERalpha and membrane-bound estrogen receptor (GPR30) expression. The inducing effects of BPA on meiosis were blocked by ER inhibitor. Collectively, these results demonstrate the dynamic ovarian response to BPA exposure, which indicate that BPA affects the formation of primordial follicles by promoting meiotic progression of oocytes via hypomethylation of Dazl and Stra8 and ERbeta signaling pathways. PMID- 29113916 TI - Temperature induced variation in gene expression of thyroid hormone receptors and deiodinases of European eel (Anguilla anguilla) larvae. AB - Thyroid hormones (THs) are key regulators of growth, development, and metabolism in vertebrates and influence early life development of fish. TH is produced in the thyroid gland (or thyroid follicles) mainly as T4 (thyroxine), which is metabolized to T3 (3,5,3'-triiodothyronine) and T2 (3,5-diiodothyronine) by deiodinase (DIO) enzymes in peripheral tissues. The action of these hormones is mostly exerted by binding to a specific nuclear thyroid hormone receptor (THR). In this study, we i) cloned and characterized thr sequences, ii) investigated the expression pattern of the different subtypes of thrs and dios, and iii) studied how temperature affects the expression of those genes in artificially produced early life history stages of European eel (Anguilla anguilla), reared in different thermal regimes (16, 18, 20 and 22 degrees C) from hatch until first feeding. We identified 2 subtypes of thr (thralpha and thrbeta) with 2 isoforms each (thralphaA, thralphaB, thrbetaA, thrbetaB) and 3 subtypes of deiodinases (dio1, dio2, dio3). All thr genes identified showed high similarity to the closely related Japanese eel (Anguilla japonica). We found that all genes investigated in this study were affected by larval age (in real time or at specific developmental stages), temperature, and/or their interaction. More specifically, the warmer the temperature the earlier the expression response of a specific target gene. In real time, the expression profiles appeared very similar and only shifted with temperature. In developmental time, gene expression of all genes differed across selected developmental stages, such as at hatch, during teeth formation or at first-feeding. Thus, we demonstrate that thrs and dios show sensitivity to temperature and are involved in and during early life development of European eel. PMID- 29113918 TI - The impact of diabetes on corneal nerve morphology and ocular surface integrity. AB - Diabetes mellitus is a chronic disease that results from inadequate insulin production or ineffective insulin utilization. It is one of the most common systemic diseases worldwide with increasing prevalence. Diabetes mellitus is associated with premature mortality, macrovascular complications such as cardiovascular disease, and microvascular complications, including nephropathy leading to kidney failure, potentially blinding diabetic retinopathy, and diabetic neuropathy. While the retinal complications of diabetes are well recognized by eye care professionals, the effects on the ocular surface are poorly understood. Recent studies have reported on the association between peripheral neuropathy and corneal neuropathy, showing the latter to be of predictive value for the systemic disease. Corneal neuropathy can lead to loss of corneal sensation and can ultimately result in neurotrophic ulcers and significant visual morbidity. The epithelial fragility and poor wound healing that result from reduced epithelial adhesion to the underlying basement membrane in diabetes, together with corneal neuropathy, are thought to increase the susceptibility to persistent corneal erosions and infection, as well as to increase the risk of post-surgical complications. The aim of this article is to review the impact of diabetes on corneal nerve morphology and ocular surface integrity. Changes in the tear film and ocular surface microbiome are highlighted in discussion of the mechanisms that underpin ocular surface changes that increase the susceptibility to corneal erosion and infection. PMID- 29113919 TI - Lighting up my life: a LOV-based fluorescent reporter for Campylobacter jejuni. AB - In this study, a LOV-based fluorescent reporter (light, oxygen, or voltage sensing domains of phototropin), termed iLOV, was adapted for Campylobacter jejuni and used to investigate promoter activity via monitoring fluorescence intensity and to study the localisation of two chemotaxis proteins. The pC46 complementation vector contains coding sequence from cj0046, a C. jejuni NCTC11168 pseudo-gene and is used to integrate cloned genes onto the C. jejuni chromosome. The pC46 vector was used to construct plasmids containing iLOV, driven by three different C. jejuni constitutive promoters and plasmids containing transcriptional fusions of the iLOV reporter and two chemoreceptors, tlp5 and tlp8. Expression from the porA promoter, pporA, produced the highest fluorescence signals compared to pfdxA (intermediate level) and pmetK (lowest level). The cellular localisation pattern of transducer-like protein (Tlp) clusters, containing Tlp5 and Tlp8, was predominately polar, with Tlp5 positioned only at one and Tlp8 at both poles. Here, we demonstrate that a iLOV fluorescent reporter can be used as a promoter probe or as a gene fusion reporter in Campylobacter spp. This is a new system uniquely placed for studying Campylobacter spp., as it combines resistance to photobleaching and functionality under microaerobic conditions. PMID- 29113917 TI - The diagnosis of limbal stem cell deficiency. AB - Limbal stem cells (LSCs) maintain the normal homeostasis and wound healing of corneal epithelium. Limbal stem cell deficiency (LSCD) is a pathologic condition that results from the dysfunction and/or an insufficient quantity of LSCs. The diagnosis of LSCD has been made mainly based on medical history and clinical signs, which often are not specific to LSCD. Methods to stage the severity of LSCD have been lacking. With the application of newly developed ocular imaging modalities and molecular methods as diagnostic tools, standardized quantitative criteria for the staging of LSCD can be established. Because of these recent advancements, effective patient-specific therapy for different stages of LSCD may be feasible. PMID- 29113921 TI - Antihypertensive responses of vasoactive androgens in an in vivo experimental model of preeclampsia. AB - Dehydroepiandrosterone (DHEA), testosterone (TES) and its 5-reduced metabolites induce a nongenomic vasorelaxation in several vascular beds of mammals; similarly these hormones produce systemic hypotensive and antihypertensive responses in normotensive and hypertensive male rats. Thus, it was hypothesized that the antihypertensive response of androgens, whose levels are elevated during gestation, protect against gestational hypertension. An animal model of preeclampsia was induced in female Wistar rats using DOCA-salt-treated pregnant (PT) and normal pregnant (NP) rats. In vivo experiments in conscious rats revealed that bolus intravenous injections of DHEA, TES, 5alpha- or 5beta dihydrotestosterone (-DHT) log -1.0 to 2.0MUmolk-1min-1, produced substantial transient reductions in arterial blood pressure (BP), without significant changes in heart rate (HR). Mean arterial blood pressure (MAP) was reduced significantly in both groups. PT rats were more sensitive to the antihypertensive responses of androgens than NP. DHEA and 5beta-DHT were the most potent to reduce MAP: 66+/-07 and 69+/-2.0mmHg in PT but only 33+/-0.5 and 35+/-1.2mmHg in NP rats, respectively. In isolated aortas of PT and NP, the concentration-response curves to each androgen (0.1-100MUM) indicated that KCl-induced pre-contraction is more sensitive to all androgens than phenylephrine (Phe) pre-contractions. Notably, 5beta-DHT is the greatest vasorelaxant with KCl-induced contraction than with Phe contraction of both groups, suggesting a preferential blockade on L-VOCCs. TES exhibited minor vasorelaxing effect of aortas pre-contracted with KCl, compared to its precursor DHEA and its 5-reduced metabolites. These data show that these androgens exert acute vasorelaxing effects in vitro and remarkably, reduce the BP in vivo in PT and NP at term pregnancy. Moreover, a deficit in feto-placental androgen production during pregnancy may trigger the development of preeclampsia or gestational hypertension. PMID- 29113920 TI - Intracellular trafficking of a dynein-based nanoparticle designed for gene delivery. AB - The success of viruses in the delivery of the viral genome to target cells relies on the evolutionary selection of protein-based domains able to hijack the intermolecular interactions through which cells respond to intra- and extracellular stimuli. In an effort to mimic viral infection capabilities during non-viral gene delivery, a modular recombinant protein named T-Rp3 was recently developed, containing a DNA binding domain, a dynein molecular motor interacting domain, and a TAT-derived transduction domain. Here, we analyzed at the microscopic level the mechanisms behind the cell internalization and intracellular trafficking of this highly efficient modular protein vector. We found that the protein has the ability to self-assemble in discrete protein nanoparticles resembling viral capsids, to bind and condense plasmid DNA (pDNA), and to interact with eukaryotic cell membranes. Confocal and single particle tracking assays performed on living HeLa cells revealed that the T-Rp3 nanoparticles promoted an impressive speed of cellular uptake and perinuclear accumulation. Finally, the protein demonstrated to be a versatile vector, delivering siRNA at efficiencies comparable to LipofectamineTM. These results demonstrate the high potential of recombinant modular proteins with merging biological functions to fulfill several requirements needed to obtain cost effective non-viral vectors for gene-based therapies. PMID- 29113922 TI - Current Japanese Regulatory Systems for Generics and Biosimilars. AB - Currently, biosimilar products are being actively developed around the world. One reason for this is the expiry of patents of original biopharmaceutical products with an extremely large market share because the biosimilar companies need to avoid infringing patents. A representative example of this is biosimilar versions of monoclonal antibodies. In Japan, the Ministry of Health, Labour and Welfare is promoting the use of biosimilar products because the market share of such products is currently extremely low compared with that of generic products. The Pharmaceuticals and Medical Devices Agency is responsible for reviewing generic and biosimilar products in Japan. However, no comparison of review systems for generics and biosimilars in Japan has been published. A more detailed understanding of review systems is important for using generic and biosimilar products. This article presents the current Japanese review systems for generic and biosimilar products and also the future challenges to facilitate the better regulation of both types of product. PMID- 29113924 TI - Why are there so many sedges? Sumatroscirpeae, a missing piece in the evolutionary puzzle of the giant genus Carex (Cyperaceae). AB - For over a century, the origins and mechanisms underlying the diversification of the enormous temperate genus Carex (>2100 species; Cariceae, Cyperaceae) have remained largely speculative. Characteristics such as its diverse ecology, varied biogeography, and intriguing cytology have made Carex a powerful model for studying plant evolution, but its uncertain sister-group relationships hinder its use in studies that depend on accurate ancestral state estimates and biogeographic inferences. To identify the sister to Carex, we estimated the phylogeny of all genera in the Cariceae-Dulichieae-Scirpeae clade (CDS) using three plastid and two nuclear ribosomal markers. Ancestral state reconstructions of key characters were made, and a time-calibrated tree estimated. Carex is strongly supported as sister to the rare East Asian Sumatroscirpus, sole genus of a new tribe, Sumatroscirpeae trib. nov. Believed to be unique to Carex, the perigynium (prophyllar bract enclosing a flower) is in fact a synapomorphy shared with this small tribe (~4 species) that appeared 36 Mya. We thus suggest the initial key innovation in the remarkable diversification of Carex is not the perigynium, but could be the release of mechanical constraints on perigynia through spikelet truncation, resulting in novel adaptive morphologies. Monoecy, chromosomal change, and rapid inflorescence development enabling phenological isolation may also be involved. The tiny tribe Sumatroscirpeae will provide unprecedented insights into the inflorescence homology, evolution, diversification, and biogeographic history of its sister-group Carex, one of the world's most diverse plant lineages. PMID- 29113925 TI - The 24/7 approach to promoting optimal welfare for captive wild animals. AB - We have an ethical responsibility to provide captive animals with environments that allow them to experience good welfare. Husbandry activities are often scheduled for the convenience of care staff working within the constraints of the facility, rather than considering the biological and psychological requirements of the animals themselves. The animal welfare 24/7 across the lifespan concept provides a holistic framework to map features of the animal's life cycle, taking into account their natural history, in relation to variations in the captive environment, across day and night, weekdays, weekends, and seasons. In order for animals to have the opportunity to thrive, we argue the need to consider their lifetime experience, integrated into the environments we provide, and with their perspective in mind. Here, we propose a welfare assessment tool based upon 14 criteria, to allow care staff to determine if their animals' welfare needs are met. We conclude that animal habitat management will be enhanced with the use of integrated technologies that provide the animals with more opportunities to engineer their own environments, providing them with complexity, choice and control. PMID- 29113923 TI - Effects of spinal non-viral interleukin-10 gene therapy formulated with d-mannose in neuropathic interleukin-10 deficient mice: Behavioral characterization, mRNA and protein analysis in pain relevant tissues. AB - Studies show that spinal (intrathecal; i.t.) interleukin-10 (IL-10) gene therapy reverses neuropathic pain in animal models, and co-administration with the mannose receptor (MR; CD206) ligand d-mannose (DM) greatly improves therapeutic efficacy. However, the actions of endogenous IL-10 may be required for enduring pain control observed following i.t. IL-10 gene therapy, potentially narrowing the application of this non-viral transgene delivery approach. Here, we show that i.t. application of naked plasmid DNA expressing the IL-10 transgene co-injected with DM (DM/pDNA-IL-10) for the treatment of peripheral neuropathic pain in IL-10 deficient (IL-10 KO) mice results in a profound and prolonged bilateral pain suppression. Neuropathic pain is induced by unilateral sciatic chronic constriction injury (CCI), and while enduring relief of light touch sensitivity (mechanical allodynia) in both wild type (WT) and IL-10 KO mice was observed following DM/pDNA-IL-10 co-therapy, transient reversal from allodynia was observed following i.t. DM alone. In stably pain-relieved IL-10 KO mice given DM/pDNA-IL-10, mRNA for the IL-10 transgene is detected in the cauda equina and ipsilateral dorsal root ganglia (DRG), but not the lumbar spinal cord. Further, DM/pDNA-IL-10 application increases anti-inflammatory TGF-beta1 and decreases pro inflammatory TNF mRNA in the ipsilateral DRG compared to allodynic controls. Additionally, DM/pDNA-IL-10 treated mice exhibit decreased spinal pro inflammatory mRNA expression for TNF, CCL2 (MCP-1), and for the microglial specific marker TMEM119. Similarly, DM/pDNA-IL-10 treatment decreases immunoreactivity for the astrocyte activation marker GFAP in lumbar spinal cord dorsal horn. Despite transient reversal and early return to allodynia in DM treated mice, lumbar spinal cord revealed elevated TNF, CCL2 and TMEM119 mRNA levels. Both MR (CD206) and IL-10 receptor mRNAs are increased in the DRG following CCI manipulation independent of injection treatment, suggesting that pathological conditions stimulate upregulation and availability of relevant receptors in critical anatomical regions required for the therapeutic actions of the DM/pDNA-IL-10 co-therapy. Taken together, the current report demonstrates that non-viral DM/pDNA-IL-10 gene therapy does not require endogenous IL-10 for enduring relief of peripheral neuropathic pain and does not require direct contact with the spinal cord dorsal horn for robust and enduring relief of neuropathic pain. Spinal non-viral DM/pDNA-IL-10 co-therapy may offer a framework for the development of non-viral gene therapeutic approaches for other diseases of the central nervous system. PMID- 29113926 TI - The Role of MicroRNA in Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a public health problem that causes high mortality and disability worldwide. Secondary brain damage from this type of injury may cause brain edema, blood-brain barrier destruction, and neurological dysfunction. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level and play vital roles in maintaining and regulating physiological function. Notably, studies suggest that miRNA levels are altered in the cerebral cortex and hippocampus of rats and mice after TBI. These miRNAs exhibit promoting or inhibiting effects on the formation of secondary brain damage, such as promotion of neuron regeneration and apoptosis, alleviation of leakage across the blood-brain barrier (BBB), disruption of intracellular transport, and decreasing the inflammatory response. miRNA levels are also altered in the blood and cerebral spinal fluid (CSF) of humans with TBI. Some special miRNAs in blood were used in clinical trials for TBI diagnosis and prognosis prediction. Treatment with miRNA agomirs or antagomirs alleviated the lesion volume and improved neurological deficits post injury. We review the current progress of miRNA studies in TBI patients and animal models and identify the prospects and difficulties involved in the clinical applications of miRNAs. PMID- 29113927 TI - Editorial on the Special Issue: Molecules and Cognition. PMID- 29113928 TI - Cerebral Malaria Causes Enduring Behavioral and Molecular Changes in Mice Brain Without Causing Gross Histopathological Damage. AB - Malaria, parasitic disease considered a major health public problem, is caused by Plasmodium protozoan genus and transmitted by the bite of infected female Anopheles mosquito genus. Cerebral malaria (CM) is the most severe presentation of malaria, caused by P. falciparum and responsible for high mortality and enduring development of cognitive deficits which may persist even after cure and cessation of therapy. In the present study we evaluated selected behavioral, neurochemical and neuropathologic parameters after rescue from experimental cerebral malaria caused by P. berghei ANKA in C57BL/6 mice. Behavioral tests showed impaired nest building activity as well as increased marble burying, indicating that natural behavior of mice remains altered even after cure of infection. Regarding the neurochemical data, we found decreased alpha2/alpha3 Na+,K+-ATPase activity and increased immunoreactivity of phosphorylated Na+,K+ ATPase at Ser943 in cerebral cortex after CM. In addition, [3H]-Flunitrazepam binding assays revealed a decrease of benzodiazepine/GABAA receptor binding sites in infected animals. Moreover, in hippocampus, dot blot analysis revealed increased levels of protein carbonyls, suggesting occurrence of oxidative damage to proteins. Interestingly, no changes in the neuropathological markers Fluoro Jade C, Timm staining or IBA-1 were detected. Altogether, present data indicate that behavioral and neurochemical alterations persist even after parasitemia clearance and CM recovery, which agrees with available clinical findings. Some of the molecular mechanisms reported in the present study may underlie the behavioral changes and increased seizure susceptibility that persist after recovery from CM and may help in the future development of therapeutic strategies for CM sequelae. PMID- 29113929 TI - Interaction of the Left Dorsolateral Prefrontal Cortex (l-DLPFC) and Right Orbitofrontal Cortex (OFC) in Hot and Cold Executive Functions: Evidence from Transcranial Direct Current Stimulation (tDCS). AB - An organizing principle which has recently emerged proposes that executive functions (EF) can be divided into cognitive (cold) and affective/reward-related (hot) processes related to the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) respectively. A controversial question is whether cold and hot EF are functionally and structurally independent or not. This study investigated how the left DLPFC (l-DLPFC) and right OFC (r-OFC) interact in hot and cold EF using transcranial direct current stimulation (tDCS). Twenty-four healthy male subjects received anodal, cathodal and sham tDCS (20 min, 1.5 mA) over the l-DLPFC (F3) and r-OFC (Fp2) with a 72-h interval between each stimulation condition. After five minutes of stimulation, participants underwent a series of cold and hot EF tasks including the Go/No-Go and Tower of Hanoi (TOH) as measures of cold EF and the BART and temporal discounting tasks as measures of hot EF. Inhibitory control mostly benefited from anodal l-DLPFC/cathodal r-OFC tDCS. Planning and problem solving were more prominently affected by anodal l DLPFC/cathodal r-OFC stimulation, although the reversed electrode position with the anode positioned over the r-OFC also affected some aspects of task performance. Risk-taking behavior and risky decision-making decreased under both anodal l-DLPFC/cathodal r-OFC and anodal r-OFC/cathodal l-DLPFC tDCS. Cold EF rely on DLPFC activation while hot EF rely on both, DLPFC and OFC activation. Results suggest that EF are placed on continuum with lateral and mesial prefrontal areas contributing to cold and hot aspects respectively. PMID- 29113930 TI - Bitter Taste Responses of Gustducin-positive Taste Cells in Mouse Fungiform and Circumvallate Papillae. AB - Bitter taste serves as an important signal for potentially poisonous compounds in foods to avoid their ingestion. Thousands of compounds are estimated to taste bitter and presumed to activate taste receptor cells expressing bitter taste receptors (Tas2rs) and coupled transduction components including gustducin, phospholipase Cbeta2 (PLCbeta2) and transient receptor potential channel M5 (TRPM5). Indeed, some gustducin-positive taste cells have been shown to respond to bitter compounds. However, there has been no systematic characterization of their response properties to multiple bitter compounds and the role of transduction molecules in these cells. In this study, we investigated bitter taste responses of gustducin-positive taste cells in situ in mouse fungiform (anterior tongue) and circumvallate (posterior tongue) papillae using transgenic mice expressing green fluorescent protein in gustducin-positive cells. The overall response profile of gustducin-positive taste cells to multiple bitter compounds (quinine, denatonium, cyclohexamide, caffeine, sucrose octaacetate, tetraethylammonium, phenylthiourea, L-phenylalanine, MgSO4, and high concentration of saccharin) was not significantly different between fungiform and circumvallate papillae. These bitter-sensitive taste cells were classified into several groups according to their responsiveness to multiple bitter compounds. Bitter responses of gustducin-positive taste cells were significantly suppressed by inhibitors of TRPM5 or PLCbeta2. In contrast, several bitter inhibitors did not show any effect on bitter responses of taste cells. These results indicate that bitter-sensitive taste cells display heterogeneous responses and that TRPM5 and PLCbeta2 are indispensable for eliciting bitter taste responses of gustducin positive taste cells. PMID- 29113931 TI - Neurobiological Mechanisms of Chemotherapy-induced Cognitive Impairment in a Transgenic Model of Breast Cancer. AB - Animal studies have reinforced clinical reports of cognitive impairment in cancer survivors following chemotherapy but, until now, all pre-clinical research in this area has been conducted on normal rodents. The present study investigated the effects of chemotherapy on cognition and underlying biological mechanisms in the FVB/N-Tg (MMTV-neu) 202 Mul/J mouse, a well-characterized transgenic model of breast cancer that has similarities to the tumorigenesis which occurs in humans. Tumor-bearing and control mice received three weekly injections of a combination of methotrexate + 5-fluorouracil, or an equal volume of saline. Different aspects of learning and memory were measured before and after treatment. The effects of tumor and chemotherapy on neurogenesis, neuro-inflammatory cytokine activity, and brain volume, as they relate to corresponding cognitive changes, were also measured. The toxic effects of chemotherapy extended to the cancerous model in which substantial cognitive impairment was also associated with the disease. Cognitive deficits were greatest in tumorigenic mice that received the anti cancer drugs. Both tumor growth and chemotherapy caused significant changes in brain volume, including the hippocampus and frontal lobes, two structures that are directly implicated in cognitive tasks that were shown to be vulnerable. The level of hippocampal neurogenesis in adulthood was suppressed in chemotherapy treated mice and associated with loss of hippocampus-controlled cognitive function. Dysregulation of cytokine activity was found in tumorigenic mice and associated with impaired cognitive performance. The results show that chemotherapy and tumor development independently contribute to cognitive deficits through different biological mechanisms. PMID- 29113932 TI - Rapid identification of Bacillus anthracis by real-time PCR with dual hybridization probes in environmental swabs. AB - In the present study, we report the development of a real-time PCR assay for the identification of Bacillus anthracis, based on the amplification of a unique chromosomal marker, the E4 sequence, with dual hybridization probes. The assay was evaluated using a panel of ten B. anthracis strains, two B. anthracis isolates from human clinical samples, 12 B. anthracis environmental swabs and 40 non- B. anthracis strains. All 12 B. anthracis strains and clinical isolates were correctly detected, and the method did not show cross-reactions with other micro organisms. Likewise, the E4 sequence was not found in those strains of B. thuringiensis and B. cereus closely related (homology > 90%) to B. anthracis by computer analysis. On the other hand, this molecular assay showed a high analytical sensitivity, 3.5 genome equivalents per reaction at 95% probability. Furthermore, the real-time PCR assay allowed sequence-specific detection of the amplicon (melting peak with a Tm of 63.5 degrees C +/- 0.5 degrees C) without post-amplification procedures, which offers an additional advantage over other qPCR assays for B. anthracis detection. Finally, the performance of the method was successfully evaluated in 12 environmental samples. In summary, we have developed a rapid and specific method for the molecular identification of Bacillus anthracis in environmental samples. PMID- 29113933 TI - Spread of Klebsiella pneumoniae ST395 non-susceptible to carbapenems and resistant to fluoroquinolones in North-Eastern France. AB - OBJECTIVES: Fluoroquinolones (FQs) are a potential treatment for infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae that are susceptible to these agents. METHODS: Owing to increasing non susceptibility to carbapenems among Enterobacteriaceae, in this study FQ resistance mechanisms were characterised in 36 ertapenem-non-susceptible Klebsiella pneumoniae isolated from North-Eastern France in 2012. The population structure was described by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: Among the 36 isolates, 13 (36%) carried a carbapenemase encoding-gene. Decreased expression of the OmpK35-encoding gene might be considered a major resistance determinant that could explain the non susceptibility to carbapenems. The carbapenemase-producing isolates carried the well-known IncL pOXA-48a plasmid. All 36 K. pneumoniae isolates also harboured a FQ resistance determinant. The aac(6')-Ib-cr gene was the major plasmid-mediated quinolone resistance (PMQR) determinant found in K. pneumoniae (89%; 32/36). MLST identified five sequence types (STs), with the most common being ST395 (69%; 25/36), followed by ST147 (17%; 6/36). ST395 strains showed ertapenem minimum inhibitory concentrations (MICs) ranging from 0.75-32MUg/mL. Klebsiella pneumoniae ST395 isolates did not show enhanced biofilm formation or environmental survival but showed higher chlorhexidine MICs compared with ST147 isolates. CONCLUSIONS: These findings showed that (i) K. pneumoniae ST395 carrying pOXA-48a has spread in North-Eastern France, (ii) aac(6')-Ib-cr is predominant in carbapenem-non-susceptible K. pneumoniae, (iii) K. pneumoniae ST395 is resistant to chlorhexidine and (iv) FQs as an alternative to beta lactams to treat ertapenem-non-susceptible K. pneumoniae are compromised. PMID- 29113934 TI - Validating EHR clinical models using ontology patterns. AB - Clinical models are artefacts that specify how information is structured in electronic health records (EHRs). However, the makeup of clinical models is not guided by any formal constraint beyond a semantically vague information model. We address this gap by advocating ontology design patterns as a mechanism that makes the semantics of clinical models explicit. This paper demonstrates how ontology design patterns can validate existing clinical models using SHACL. Based on the Clinical Information Modelling Initiative (CIMI), we show how ontology patterns detect both modeling and terminology binding errors in CIMI models. SHACL, a W3C constraint language for the validation of RDF graphs, builds on the concept of "Shape", a description of data in terms of expected cardinalities, datatypes and other restrictions. SHACL, as opposed to OWL, subscribes to the Closed World Assumption (CWA) and is therefore more suitable for the validation of clinical models. We have demonstrated the feasibility of the approach by manually describing the correspondences between six CIMI clinical models represented in RDF and two SHACL ontology design patterns. Using a Java-based SHACL implementation, we found at least eleven modeling and binding errors within these CIMI models. This demonstrates the usefulness of ontology design patterns not only as a modeling tool but also as a tool for validation. PMID- 29113936 TI - Reproducible research practices are underused in systematic reviews of biomedical interventions. AB - OBJECTIVES: To evaluate how often reproducible research practices, which allow others to recreate the findings of studies, given the original data, are used in systematic reviews (SRs) of biomedical research. STUDY DESIGN AND SETTING: We evaluated a random sample of SRs indexed in MEDLINE during February 2014, which focused on a therapeutic intervention and reported at least one meta-analysis. Data on reproducible research practices in each SR were extracted using a 26-item form by one author, with a 20% random sample extracted in duplicate. We explored whether the use of reproducible research practices was associated with an SR being a Cochrane review, as well as with the reported use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: We evaluated 110 SRs of therapeutic interventions, 78 (71%) of which were non Cochrane SRs. Across the SRs, there were 2,139 meta-analytic effects (including subgroup meta-analytic effects and sensitivity analyses), 1,551 (73%) of which were reported in sufficient detail to recreate them. Systematic reviewers reported the data needed to recreate all meta-analytic effects in 72 (65%) SRs only. This percentage was higher in Cochrane than in non-Cochrane SRs (30/32 [94%] vs. 42/78 [54%]; risk ratio 1.74, 95% confidence interval 1.39-2.18). Systematic reviewers who reported imputing, algebraically manipulating, or obtaining some data from the study author/sponsor infrequently stated which specific data were handled in this way. Only 33 (30%) SRs mentioned access to data sets and statistical code used to perform analyses. CONCLUSION: Reproducible research practices are underused in SRs of biomedical interventions. Adoption of such practices facilitates identification of errors and allows the SR data to be reanalyzed. PMID- 29113935 TI - Predicting age by mining electronic medical records with deep learning characterizes differences between chronological and physiological age. AB - Determining the discrepancy between chronological and physiological age of patients is central to preventative and personalized care. Electronic medical records (EMR) provide rich information about the patient physiological state, but it is unclear whether such information can be predictive of chronological age. Here we present a deep learning model that uses vital signs and lab tests contained within the EMR of Mount Sinai Health System (MSHS) to predict chronological age. The model is trained on 377,686 EMR from patients of ages 18 85 years old. The discrepancy between the predicted and real chronological age is then used as a proxy to estimate physiological age. Overall, the model can predict the chronological age of patients with a standard deviation error of ~7 years. The ages of the youngest and oldest patients were more accurately predicted, while patients of ages ranging between 40 and 60 years were the least accurately predicted. Patients with the largest discrepancy between their physiological and chronological age were further inspected. The patients predicted to be significantly older than their chronological age have higher systolic blood pressure, higher cholesterol, damaged liver, and anemia. In contrast, patients predicted to be younger than their chronological age have lower blood pressure and shorter stature among other indicators; both groups display lower weight than the population average. Using information from ~10,000 patients from the entire cohort who have been also profiled with SNP arrays, genome-wide association study (GWAS) uncovers several novel genetic variants associated with aging. In particular, significant variants were mapped to genes known to be associated with inflammation, hypertension, lipid metabolism, height, and increased lifespan in mice. Several genes with missense mutations were identified as novel candidate aging genes. In conclusion, we demonstrate how EMR data can be used to assess overall health via a scale that is based on deviation from the patient's predicted chronological age. PMID- 29113937 TI - Characterization of gastrointestinal adverse effects reported in clinical studies of corticosteroid therapy. AB - OBJECTIVES: To examine whether 159 studies included in a previous meta-analysis reported on gastrointestinal bleeding or perforation in accordance with the CONSORT extension for reporting harms outcomes (CONSORT Harms recommendations checklist); whether differences were associated with funding source, journal, or publication year; and whether the CONSORT Harms checklist is a suitable tool for evaluation of adverse effects reporting. STUDY DESIGN AND SETTING: Articles were assessed for fulfillment of the CONSORT Harms recommendations, funding source, publication type, and year. Agreement between reviewers was assessed by comparing scores for each study. RESULTS: The mean CONSORT Harms score was 5.25 out of 10 (standard deviation +/- 2.09). Most studies included information on participant withdrawals (133 studies, 83.6%), absolute risk of gastrointestinal bleeding or perforation (130 studies, 81.8%), and how harms-related information was collected (118 studies, 74.2%). Reporting of gastrointestinal bleeding or perforation increased with higher scores (odds ratio 1.173, P = 0.042). There was no significant association between CONSORT Harms score achieved and publication year or funding source, but there was a trend toward higher scores in studies published in the major medical journals (score difference 0.78, P = 0.052). Definitions of gastrointestinal bleeding differed between studies. Reviewer agreement was fair to moderate with large variations. CONCLUSION: Few studies in the systematic review received high scores using the CONSORT Harms criteria. Most studies reported on the most important criteria regarding risk of gastrointestinal bleeding or perforation. Reviewer agreement showed large variations due to imprecise texts and ambiguous criteria. Routine scoring according to fulfillment of the CONSORT Harms recommendations would be inadvisable without qualified judgment. PMID- 29113938 TI - The split-plot design was useful for evaluating complex, multilevel interventions, but there is need for improvement in its design and report. AB - OBJECTIVES: To describe the sample size calculation, analysis and reporting of split-plot (S-P) randomized controlled trials in health care (trials that use two units of randomization: one at a cluster-level and one at a level lower than the cluster). STUDY DESIGN AND SETTING: We carried out a comprehensive search in the EMBASE database from 1946 to 2016. Health care trials with a S-P design in human subjects were included. Three authors screened and assessed the studies, and the data were extracted on methodology and reporting standards based on CONSORT. RESULTS: Eighteen S-P studies were included, with authors using nine different designations to describe them. Units of randomization were unclear in nine abstracts. Explicit rationale for choosing the design was not given. Ten studies presented a sample size calculation accounting for clustering; the analyses were coherent with that. Flow of participant diagrams was presented but was incomplete in 14 articles. CONCLUSION: S-P designs can be useful complex designs but challenging to report. Researchers need to clearly describe the rationale, sample size calculation, and participant flow. We provide a suggested CONSORT style participant flow diagram to aid reporting. There is need for more research regarding sample size calculation for S-P. PMID- 29113939 TI - A generic Transcriptomics Reporting Framework (TRF) for 'omics data processing and analysis. AB - A generic Transcriptomics Reporting Framework (TRF) is presented that lists parameters that should be reported in 'omics studies used in a regulatory context. The TRF encompasses the processes from transcriptome profiling from data generation to a processed list of differentially expressed genes (DEGs) ready for interpretation. Included within the TRF is a reference baseline analysis (RBA) that encompasses raw data selection; data normalisation; recognition of outliers; and statistical analysis. The TRF itself does not dictate the methodology for data processing, but deals with what should be reported. Its principles are also applicable to sequencing data and other 'omics. In contrast, the RBA specifies a simple data processing and analysis methodology that is designed to provide a comparison point for other approaches and is exemplified here by a case study. By providing transparency on the steps applied during 'omics data processing and analysis, the TRF will increase confidence processing of 'omics data, and regulatory use. Applicability of the TRF is ensured by its simplicity and generality. The TRF can be applied to all types of regulatory 'omics studies, and it can be executed using different commonly available software tools. PMID- 29113940 TI - Screening-level Biomonitoring Equivalents for tiered interpretation of urinary 3 phenoxybenzoic acid (3-PBA) in a risk assessment context. AB - 3-Phenoxybenzoic acid (3-PBA) is a common metabolite of several pyrethroid pesticides of differing potency and also occurs as a residue in foods resulting from environmental degradation of parent pyrethroid compounds. Thus, 3-PBA in urine is not a specific biomarker of exposure to a particular pyrethroid. However, an approach derived from the use of Biomonitoring Equivalents (BEs) can be used to estimate a conservative initial screening value for a tiered assessment of population data on 3-PBA in urine. A conservative generic urinary excretion fraction for 3-PBA was estimated from data for five pyrethroid compounds with human data. Estimated steady-state urinary 3-PBA concentrations associated with reference doses and acceptable daily intakes for each of the nine compounds ranged from 1.7 MUg/L for cyhalothrin and deltamethrin to 520 MUg/L for permethrin. The lower value can be used as a highly conservative Tier 1 screening value for assessment of population urinary 3-PBA data. A second tier screening value of 87 MUg/L was derived based on weighting by relative exposure estimates for the different pyrethroid compounds, to be applied as part of the data evaluation process if biomonitoring data exceed the Tier 1 value. These BE values are most appropriately used to evaluate the central tendency of population biomarker concentration data in a risk assessment context. The provisional BEs were compared to available national biomonitoring data from the US and Canada. PMID- 29113941 TI - Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action. AB - The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor-alpha (PPARalpha), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities. Implications for quantitative risk assessment approaches were discussed, as were implications of not considering MOA and dose in hazard characterization and labeling schemes. Most, but not all, participants considered the CAR and PPARalpha MOAs as not relevant to humans based on quantitative and qualitative differences. In contrast, cytotoxicity is clearly relevant to humans, but a threshold applies. Questions remain for all three MOAs concerning what data are necessary to determine the MOA and to what extent it is necessary to exclude other MOAs. PMID- 29113942 TI - A direct comparison between ERP and fMRI measurements of food-related inhibitory control: Implications for BMI status and dietary intake. AB - Obesity and maintaining a healthy diet have important implications for physical and mental health. One factor that may influence diet and obesity is inhibitory control. We tested how N2 and P3 amplitude, event-related potential (ERP) components that reflect inhibitory control, and functional magnetic resonance imaging (fMRI) activity in brain regions associated with inhibitory control differed toward high- and low-calorie food stimuli across BMI status. We also assessed the relationship between neural indices of food-related inhibitory control and laboratory and daily food intake. Fifty-four individuals (17 normal weight; 18 overweight; 19 individuals with obesity) completed two food-based go/no-go tasks (one with high- and one with low-calorie foods as no-go stimuli), once during ERP data acquisition and once during fMRI data acquisition. After testing, participants were presented with an ad libitum weighed food buffet. Participants also recorded their food intake using the Automated Self Administered 24-hour Dietary Recall (ASA24) system across four days. Individuals recruited more inhibitory control when withholding responses towards high compared to low-calorie foods, although this effect was more consistent for N2 than P3 or fMRI assessments. BMI status did not influence food-related inhibitory control. A larger inhibitory response as measured by N2 amplitude was related to increased ASA24 food intake; P3 amplitude and fMRI region of interest activity did not predict ASA24 intake; neither method predicted food intake from the buffet. ERP and fMRI measurements show similar neural responses to food, although N2 amplitude may be somewhat more sensitive in detecting differences between food types and predicting self-reports of food intake. PMID- 29113943 TI - Effect of aerobic exercise on hippocampal volume in humans: A systematic review and meta-analysis. AB - Hippocampal volume increase in response to aerobic exercise has been consistently observed in animal models. However, the evidence from human studies is equivocal. We undertook a systematic review to identify all controlled trials examining the effect of aerobic exercise on the hippocampal volumes in humans, and applied meta analytic techniques to determine if aerobic exercise resulted in volumetric increases. We also sought to establish how volume changes differed in relation to unilateral measures of left/right hippocampal volume, and across the lifespan. A systematic search identified 4398 articles, of which 14 were eligible for inclusion in the primary analysis. A random-effects meta-analysis showed no significant effect of aerobic exercise on total hippocampal volume across the 737 participants. However, aerobic exercise had significant positive effects on left hippocampal volume in comparison to control conditions. Post-hoc analyses indicated effects were driven through exercise preventing the volumetric decreases which occur over time. These results provide meta-analytic evidence for exercise-induced volumetric retention in the left hippocampus. Aerobic exercise interventions may be useful for preventing age-related hippocampal deterioration and maintaining neuronal health. PMID- 29113944 TI - Reliability of functional magnetic resonance imaging activation during working memory in a multisite study: Clarification and implications for statistical power. AB - In this technical note, we clarify the meaning of the generalizability-theory based coefficients reported in our multisite reliability study of fMRI measures of regional brain activation during working memory processing (Forsyth et al., Neuroimage 2014;97:51-52). While the original paper reported generalizability and dependability coefficients based on the design of our traveling subjects study (in which each subject was scanned twice at each of eight sites), those coefficients are of limited applicability outside of the reliability study context. Here we report generalizability and dependability coefficients that represent the reliability one can expect for a multisite study in which a given subject is scanned once on a scanner drawn randomly from the pool of available scanners (i.e., analogous to the more typical multisite study design). We also characterize the implications of a multisite versus single site study design for statistical power, including a figure that shows sample size requirements to detect activation in two key nodes of the working memory circuitry given observed differences in reliability of measurement between single and multisite designs. PMID- 29113945 TI - Changes in the expression and localization of signaling molecules in mouse facial motor neurons during regeneration of facial nerves. AB - After injury, peripheral axons usually re-extend toward their target, and neuronal functions recover. Previous studies have reported that expression of various molecules are transiently altered in motor neurons after nerve injury, but the time course of these changes and their relationship with functional recovery have not been clearly demonstrated. We used the mouse facial nerve transection and suturing model, and examined the changes in expression of five molecules, choline acetyl transferase (ChAT), galanin, calcitonin gene-related protein (CGRP), gephyrin, and potassium chloride co-transporter 2 (KCC2) in the facial motor neurons after surgery until recovery. Number of ChAT-positive neurons was markedly decreased at days 3 and 7, and recovered to the normal level by day 60, when facial motor functions recovered. Localization of two neuropeptides, CGRP and galanin, was increased in the perikarya and axons during regeneration, and returned to the normal levels by days 60 and 28, respectively. Expression of two postsynaptic elements of gamma-amino butyric acid synapses, gephyrin and KCC2, was decreased at days 3 and 7, and recovered by day 60. These results suggest that ChAT, CGRP, and KCC2 may be objective indicators of regeneration, and altering their expression may be related to the functional recovery and axonal re-extension. PMID- 29113946 TI - Numerical and length densities of microvessels in the human brain: Correlation with preferential orientation of microvessels in the cerebral cortex, subcortical grey matter and white matter, pons and cerebellum. AB - To provide basic data on the local differences in density of microvessels between various parts of the human brain, including representative grey and white matter structures of the cerebral hemispheres, the brain stem and the cerebellum, we quantified the numerical density NV and the length density LV of microvessels in two human brains. We aimed to correlate the density of microvessels with previously published data on their preferential orientation (anisotropy). Microvessels were identified using immunohistochemistry for laminin in 32 samples harvested from the following brain regions of two adult individuals: the cortex of the telencephalon supplied by the anterior, middle, and posterior cerebral artery; the basal ganglia (putamen and globus pallidus); the thalamus; the subcortical white matter of the telencephalon; the internal capsule; the pons; the cerebellar cortex; and the cerebellar white matter. NV was calculated from the number of vascular branching points and their valence, which were assessed using the optical disector in 20-MUm-thick sections. LV was estimated using counting frames applied to routine sections with randomized cutting planes. After correction for shrinkage, NV in the cerebral cortex was 1311+/-326mm-3 (mean+/ SD) and LV was 255+/-119mm-2. Similarly, in subcortical grey matter (which included the basal ganglia and thalamus), NV was 1350+/-445mm-3 and LV was 328+/ 117mm-2. The vascular networks of cortical and subcortical grey matter were comparable. Their densities were greater than in the white matter, with NV=222+/ 147mm-3 and LV=160+/-96mm-2. NV was moderately correlated with LV. In parts of brain with greater NV, blood vessels lacked a preferential orientation. Our data were in agreement with other studies on microvessel density focused on specific brain regions, but showed a greater variability, thus mapping the basic differences among various parts of brain. To facilitate the planning of other studies on brain vascularity and to support the development of computational models of human brain circulation based on real microvascular morphology; stereological data in form of continuous variables are made available as supplements. PMID- 29113947 TI - Diffusion tensor and volumetric magnetic resonance imaging findings in the brains of professional musicians. AB - Professional musicians represent an ideal model to study the training-induced brain plasticity. The current study aimed to investigate the brain volume and diffusion characteristics of musicians using structural magnetic resonance and diffusion tensor imaging (DTI). The combined use of volumetric and diffusion methods in studying musician brain has not been done in literature. Our study group consisted of seven male musicians playing an instrument and seven age- and gender-matched non-musicians. We evaluated the volumes of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) and calculated total intracranial volume (TIV) and measured the fractional anisotropy (FA) of pre-selected WM bundles: corpus callosum (CC), corticospinal tract (CST), superior longitudinal fasciculus (SLF), forceps major (ForMaj), forceps minor (ForMin), and arcuate fasciculus (AF). The mean WM/TIV volume in musicians was higher compared to non musicians. The mean FA was lower in CC, SLF, ForMaj, ForMin, and right AF but higher in right CST in the musicians. The mean value of the total number of fibers was larger in the CST, SLF, left AF, and ForMaj in the musicians. The observed differences were not statistically significant between the groups (p>0.05). However, increased GM volume was found in the musicians compared to the non-musicians in the right and left cerebellum and supramarginal and angular gyrus, left superior and inferior parietal lobule and as well as left middle temporal gyrus. Our findings suggest differing brain structure in musicians and the confirmation of the results on a larger population. PMID- 29113948 TI - Non-steroidal anti-inflammatory drugs and nervous system development. PMID- 29113949 TI - Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM. METHODS: Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, and growth, colony formation, migration and invasion assays were conducted. RESULTS: MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference-mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion. CONCLUSIONS: MiR-137 can exhibit a tumor suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies. PMID- 29113950 TI - Reviewing RECIST in the Era of Prolonged and Targeted Therapy. AB - Accurate assessment of disease response is the foundation of therapeutic trails, which is why the Response Evaluation Criteria in Solid Tumors (RECIST) serve as an international standard that investigators can utilize when examining patient outcomes. Nine years after the initial RECIST criteria were released, an update, RECIST 1.1, was published to improve on the initial criteria and address technologic advancements in imaging. Since then, advancements in both standard clinical and trial practices, combined with improvements in our understanding of cancer biology, have resulted in the identification of a number of limitations of the current RECIST 1.1, either in lack of clear guidance with regard to its best application or in potential benefit of capturing imaging-related data beyond standard categorical response details. As several of these situations reflect the consequences of prolonged control of metastatic disease by using targeted therapies, thoracic oncology has generated many of the key scenarios requiring elucidation and/or improvements. This article specifically examines current controversies in the interpretation and/or optimal utilization of RECIST 1.1, focusing on examples from thoracic oncology, and makes proposals, where possible, on how best to address these issues. These situations include addressing central nervous system versus extra-central nervous system response and progression, depth of response, oligoprogression versus polyprogression, continuation of systemic therapy after use of a local ablative therapy, and the impact of fluctuations in measurements bridging partial response and stable disease categories during prolonged therapy. PMID- 29113951 TI - Editorial-Special issue of the 6th European Workshop on Lipid Mediators. PMID- 29113952 TI - Do all roads lead to the Rome? The glycation perspective! AB - Oxidative, carbonyl, and glycative stress have gained substantial attention recently for their alleged influence on cancer progression. Oxidative stress can trigger variable transcription factors, such as nuclear factor erythroid-2 related factor (Nrf2), nuclear factor kappa B (NF-kappaB), protein-53 (p-53), activating protein-1 (AP-1), hypoxia-inducible factor-1alpha (HIF-1alpha), beta catenin/Wnt and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activated transcription factors can lead to approximately 500 different alterations in gene expression, and can alter expression patterns of inflammatory cytokines, growth factors, regulatory cell cycle molecules, and anti-inflammatory molecules. These alterations of gene expression can induce a normal cell to become a tumor cell. Glycative stress resulting from advanced glycation end products (AGEs) and reactive dicarbonyls can significantly affect cancer progression. AGEs are fashioned from the multifaceted chemical reaction of reducing sugars with a compound containing an amino group. AGEs bind to and trigger the receptor for AGEs (RAGE) through AGE-RAGE interaction, which is a major modulator of inflammation allied tumors. Dicarbonyls like, GO (glyoxal), MG (methylglyoxal) and 3-DG (3-deoxyglucosone) fashioned throughout lipid peroxidation, glycolysis, and protein degradation are viewed as key precursors of AGEs. These dicarbonyls lead to the carbonyl stress in living organisms, possibly resulting in carbonyl impairment of proteins, carbohydrates, DNA, and lipoproteins. The damage caused by carbonyls results in numerous lesions, some of which are involved in cancer pathogenesis. In this review, the effects of oxidative, carbonyl and glycative stress on cancer initiation and progression are thoroughly discussed, including probable signaling pathways and the effects on tumorigenesis. PMID- 29113953 TI - A longitudinal examination of event-related potentials sensitive to monetary reward and loss feedback from late childhood to middle adolescence. AB - Brain regions involved in reward processing undergo developmental changes from childhood to adolescence, and alterations in reward-related brain function are thought to contribute to the development of psychopathology. Event-related potentials (ERPs), such as the reward positivity (RewP) component, are valid measures of reward responsiveness that are easily assessed across development and provide insight into temporal dynamics of reward processing. Little work has systematically examined developmental changes in ERPs sensitive to reward. In this longitudinal study of 75 youth assessed 3 times across 6years, we used principal components analyses (PCA) to differentiate ERPs sensitive to monetary reward and loss feedback in late childhood, early adolescence, and middle adolescence. We then tested reliability of, and developmental changes in, ERPs. A greater number of ERP components differentiated reward and loss feedback in late childhood compared to adolescence, but components in childhood accounted for only a small proportion of variance. A component consistent with RewP was the only one to consistently emerge at each of the 3 assessments. RewP demonstrated acceptable reliability, particularly from early to middle adolescence, though reliability estimates varied depending on scoring approach and developmental period. The magnitude of the RewP component did not significantly change across time. Results provide insight into developmental changes in the structure of ERPs sensitive to reward, and indicate that RewP is a consistently observed and relatively stable measure of reward responsiveness, particularly across adolescence. PMID- 29113955 TI - Treatment of fatigue with methylphenidate, modafinil and amantadine in multiple sclerosis (TRIUMPHANT-MS): Study design for a pragmatic, randomized, double blind, crossover clinical trial. AB - BACKGROUND: Fatigue is the most common symptom of multiple sclerosis (MS). Amantadine, modafinil and amphetamine-like stimulants are commonly used in clinical practice for treatment of fatigue; however, the evidence supporting their effectiveness is sparse and conflicting. OBJECTIVE: To describe the design of a trial study funded by Patient-Centered Outcome Research Institute (PCORI) that will compare the efficacy of commonly used fatigue medications in patients with MS. DESIGN/METHODS: The study is a randomized, placebo-controlled, crossover, four-sequence, four-period, double-blind, multicenter trial of three commonly used medications for the treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) versus placebo in fatigued subjects with MS. Adult patients with MS, with an Expanded Disability Status Scale of <7.0 are eligible to participate. Participants will be randomized to one of four predefined sequences of medication administration. Each sequence comprises four 6-week periods of treatment with one of the 3 study drugs or placebo, and three 2-week washout periods between medication periods. RESULTS: 136 participants will be randomized over two years in two academic centers in the United States starting in the Summer 2017. Complete enrollment is expected by early 2019. The primary outcome of the study is the modified fatigue impact scale (MFIS) score while participants receive the maximally tolerated dose of each study medication (or placebo). Safety and tolerability of the medications and heterogeneity of treatment effect will also be assessed. CONCLUSIONS: Results of the proposed study will provide evidence-based and personalized treatment options for patients affected by MS-related fatigue. Clinicaltrials.gov registration number: NCT03185065. PMID- 29113954 TI - An improved method to quantify human NK cell-mediated antibody-dependent cell mediated cytotoxicity (ADCC) per IgG FcR-positive NK cell without purification of NK cells. AB - Natural killer (NK) lymphocyte ADCC supports anti-viral protection and monoclonal antibody (mAb) anti-tumor therapies. To predict in vivo ADCC therapeutic responses of different individuals, measurement of both ADCC cellular lytic capacity and their NK cellular receptor recognition of antibodies on 'target' cells are needed, using clinically available amounts of blood. Twenty ml of blood provides sufficient peripheral blood mononuclear cells (PBMCs) for the new assay for lytic capacity described here and for an antibody EC50 assay for Fc-receptor recognition. For the lytic capacity assay, we employed flow cytometry to quantify the CD16A IgG Fc-receptor positive NK effector cells from PBMCs to avoid loss of NKs during isolation. Targets were 51Cr-labeled Daudi B cells pretreated with excess obinutuzumab type 2 anti-CD20 mAb and washed; remaining free mAb was insufficient to convert B cells in the PBMCs into 'targets'. We calculated: the percentage Daudis killed at a 1:1 ratio of CD16A-positive NK cells to Daudis (CX1:1); lytic slopes; and ADCC50 lytic units. Among 27 donors, we detected wide ranges in CX1:1 (16-73% targets killed) and in lytic slopes. Slope variations prevented application of lytic units. We recommend CX1:1 to compare individuals' ADCC capacity. CX1:1 was similar for purified NK cells vs. PBMCs and independent of CD16A V & F genotypes and antibody EC50s. With high mAb bound onto targets and the high affinity of obinutuzumab Fc for CD16A, CX1:1 measurements discern ADCC lytic capacity rather than antibody recognition. This assay allows ADCC to be quantified without NK cell isolation and avoids distortion associated with lytic units. PMID- 29113956 TI - Rationale and design of the HOME trial: A pragmatic randomized controlled trial of home-based human papillomavirus (HPV) self-sampling for increasing cervical cancer screening uptake and effectiveness in a U.S. healthcare system. AB - Women who delay or do not attend Papanicolaou (Pap) screening are at increased risk for cervical cancer. Trials in countries with organized screening programs have demonstrated that mailing high-risk (hr) human papillomavirus (HPV) self sampling kits to under-screened women increases participation, but U.S. data are lacking. HOME is a pragmatic randomized controlled trial set within a U.S. integrated healthcare delivery system to compare two programmatic approaches for increasing cervical cancer screening uptake and effectiveness in under-screened women (>=3.4years since last Pap) aged 30-64years: 1) usual care (annual patient reminders and ad hoc outreach by clinics) and 2) usual care plus mailed hrHPV self-screening kits. Over 2.5years, eligible women were identified through electronic medical record (EMR) data and randomized 1:1 to the intervention or control arm. Women in the intervention arm were mailed kits with pre-paid envelopes to return samples to the central clinical laboratory for hrHPV testing. Results were documented in the EMR to notify women's primary care providers of appropriate follow-up. Primary outcomes are detection and treatment of cervical neoplasia. Secondary outcomes are cervical cancer screening uptake, abnormal screening results, and women's experiences and attitudes towards hrHPV self sampling and follow-up of hrHPV-positive results (measured through surveys and interviews). The trial was designed to evaluate whether a programmatic strategy incorporating hrHPV self-sampling is effective in promoting adherence to the complete screening process (including follow-up of abnormal screening results and treatment). The objective of this report is to describe the rationale and design of this pragmatic trial. PMID- 29113957 TI - Population change of Trillium govanianum (Melanthiaceae) amid altered indigenous harvesting practices in the Indian Himalayas. AB - ETHNOBOTANICAL RELEVANCE: Trillium govanianum Wall. ex D. Don (Melanthiaceae) is valued as a traditional medicinal herb in the Himalayan region. Applications include treatment of cancer, hypertension, neurasthenia, giddiness, arthritis, dysentery, inflammation, sepsis and reproductive disorders. Its range is highly specific, and limited to cold, shaded and moist habitats at 2400-3500 m a.s.l. Rhizomes are gathered from wild populations for trade, and this has recently emerged as a significant source of income among indigenous people of the Indian Himalayan region. AIM: To assess the impact of changing rhizome prices on T. govanianum in the Indian Himalayan region by observing the status of existing populations and assessing the typical methods used for gathering and trade of rhizomes. MATERIAL AND METHODS: Ecological attributes were assessed in 17 sites from Tirthan Valley (Himachal Pradesh), Munsiyari and Tunghnath (Uttarakhand). Socio-economic attributes assessed through communal focus groups and interviews with 579 medicinal plants gatherers and 19 traders, using semi-structured open ended questionnaires. RESULTS: Population decline was highest in Munsiyari, followed by Tirthan Valley and Tunghnath, indicating that the species may become locally extinct in some areas. Methods used for gathering did not consider regeneration. CONCLUSION: Gathering of T. govanianum from wild populations is unselective and unmanaged, raising the potential threat of local extinctions. Sustainable utilization and effective conservation is needed to protect the species and maintain community incomes. A status of 'threatened' is justified for the species in the Indian Himalayan region, due to its slow life cycle, specific habitat requirement, low population density, and commercial value. PMID- 29113958 TI - Comparison of two Jatropha species (Euphorbiaceae) used popularly to treat snakebites in Northeastern Brazil: Chemical profile, inhibitory activity against Bothrops erythromelas venom and antibacterial activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jatropha species (Euphorbiaceae) are largely used in traditional medicine to treat different pathologies in Africa, Asia and Latin America. In Northeastern Brazilian folk medicine, several Jatropha species, such as Jatropha gossypiifolia L. and Jatropha mollissima (Pohl) Baill., are indistinctly used to treat snakebites. AIM OF THE STUDY: To compare two of the Brazilian most used Jatropha species for snakebites (J. gossypiifolia and J. mollissima), in relation to their ability to inhibit local edematogenic activity of Bothrops erythromelas snake venom in mice, their in vitro antibacterial activity and phytochemical profile. MATERIAL AND METHODS: Aqueous leaf extracts of J. gossypiifolia (AEJg) and J. mollissima (AEJm) were prepared by decoction. AEJg and AEJm were compared chemically, by thin layer chromatography (TLC) and high-performance liquid chromatography with diode array detection (HPLC-DAD) analysis. They were also pharmacologically compared, using the mouse model of paw edema induced by Bothrops erythromelas snake venom (BeV), and in vitro by broth microdilution and agar dilution antimicrobial tests. RESULTS: Flavonoids were detected as the major compounds in both extracts. However, AEJg and AEJm showed quantitatively different chemical profiles by HPLC-DAD. AEJg presented fewer peaks of flavonoids than AEJm, however, when the intensity of peaks were analyzed, these compounds were at high concentration in AEJg, even using the same concentration of both extracts. Differences were also observed in the biological activity of the two extracts. While no difference was observed when the extracts were administered by oral route (P > 0.05), by the intraperitoneal route AEJg presented anti-edematogenic activity significantly (P < 0.001) higher than AEJm. In antimicrobial assays, only AEJg presented antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus and Bacillus cereus. CONCLUSIONS: Although used indistinctly by folk medicine, our results suggested that AEJg is more active than AEJm in relation to its antiedematogenic and antibacterial activities. Significant differences were observed in their phytochemical profiles, especially a higher content of C-glycosylated flavonoids in the most active species, which could justify the different biological effects observed. These findings strengthen the potentiality of J. gossypiifolia species for use as complementary treatment for local effects induced by Bothrops venoms and could be helpful for distinction of the species and control quality assessment of future herbal medicines based on Jatropha plants. PMID- 29113959 TI - Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease. AB - Both aging and Alzheimer's disease (AD) are associated with widespread epigenetic changes, with most evidence suggesting global hypomethylation in AD. It is, however, unclear how these age-related epigenetic changes are linked to molecular aberrations as expressed in animal models of AD. Here, we investigated age related changes of epigenetic markers of DNA methylation and hydroxymethylation in a range of animal models of AD, and their correlations with amyloid plaque load. Three transgenic mouse models, including the J20, APP/PS1dE9 and 3xTg-AD models, as well as Caribbean vervets (a non-transgenic non-human primate model of AD) were investigated. In the J20 mouse model, an age-related decrease in DNA methylation was found in the dentate gyrus (DG) and a decrease in the ratio between DNA methylation and hydroxymethylation was found in the DG and cornu ammonis (CA) 3. In the 3xTg-AD mice, an age-related increase in DNA methylation was found in the DG and CA1-2. No significant age-related alterations were found in the APP/PS1dE9 mice and non-human primate model. In the J20 model, hippocampal plaque load showed a significant negative correlation with DNA methylation in the DG, and with the ratio a negative correlation in the DG and CA3. For the APP/PS1dE9 model a negative correlation between the ratio and plaque load was observed in the CA3, as well as a negative correlation between DNA methyltransferase 3A (DNMT3A) levels and plaque load in the DG and CA3. Thus, only the J20 model showed an age-related reduction in global DNA methylation, while DNA hypermethylation was observed in the 3xTg-AD model. Given these differences between animal models, future studies are needed to further elucidate the contribution of different AD-related genetic variation to age-related epigenetic changes. PMID- 29113962 TI - Woman in minimally conscious state should be allowed to die, says judge after hearing evidence from family. PMID- 29113960 TI - Lesion oxygenation associates with clinical outcomes in premalignant and early stage head and neck tumors treated on a phase 1 trial of photodynamic therapy. AB - BACKGROUND: We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (StO2) and blood volume (tHb) were studied for associations with patient outcomes. METHODS: PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion StO2 and tHb was measured. RESULTS: Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but StO2 was higher in patients with CR. In tongue/FOM lesions, baseline StO2 [mean(SE)] was 54(4)% in patients (n=12) with CR versus 23(8)% in patients (n=6) with local recurrence/persistence (p=0.01). Similarly, for intact disease, baseline StO2 was 54(3)% in patients (n=10) with CR versus 28(8)% in patients (n=5) without CR (p=0.03). In patients with intact disease, higher baseline StO2 associated with 24-month local control (p=0.02). CONCLUSIONS: Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT. PMID- 29113961 TI - Mobile Phone Multilevel and Multimedia Messaging Intervention for Breast Cancer Screening: Pilot Randomized Controlled Trial. AB - BACKGROUND: Despite the increasing breast cancer incidence and mortality rates, Korean American immigrant women have one of the lowest rates of breast cancer screening across racial groups in the United States. Mobile health (mHealth), defined as the delivery of health care information or services through mobile communication devices, has been utilized to successfully improve a variety of health outcomes. OBJECTIVE: This study adapted the principles of mHealth to advance breast cancer prevention efforts among Korean American immigrant women, an underserved community. METHODS: Using a randomized controlled trial design, 120 Korean American women aged 40 to 77 years were recruited and randomly assigned to either the mMammogram intervention group (n=60) to receive culturally and personally tailored multilevel and multimedia messages through a mobile phone app along with health navigator services or the usual care control group (n=60) to receive a printed brochure. Outcome measures included knowledge, attitudes, and beliefs about breast cancer screening, readiness for mammography, and mammogram receipt. The feasibility and acceptability of the mMammogram intervention was also assessed. RESULTS: The intervention group showed significantly greater change on scores of knowledge of breast cancer and screening guidelines (P=.01). The intervention group also showed significantly greater readiness for mammography use after the intervention compared with the control group. A significantly higher proportion of women who received the mMammogram intervention (75%, 45/60) completed mammograms by the 6-month follow up compared with the control group (30%, 18/60; P<.001). In addition, the intervention group rated satisfaction with the intervention (P=.003), effectiveness of the intervention (P<.001), and increase of knowledge on breast cancer and screenings (P=.001) significantly higher than the control group. CONCLUSIONS: A mobile phone app-based intervention combined with health navigator service was a feasible, acceptable, and effective intervention mechanism to promote breast cancer screening in Korean American immigrant women. A flexible, easily tailored approach that relies on recent technological advancements can reach underserved and hard-to-recruit populations that bear disproportionate cancer burdens. TRIAL REGISTRATION: Clinicaltrials.gov NCT01972048; https://clinicaltrials.gov/show/NCT01972048 (Archived by WebCite at https://clinicaltrials.gov/archive/NCT01972048/2013_10_29). PMID- 29113964 TI - UK's first emergency department for patients over 80 to open in Norwich. PMID- 29113963 TI - Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. AB - Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1Y588X transgenic mouse model, Asxl1Y588X Tg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588X Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit+ cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self renewal and differentiation. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588X Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies. PMID- 29113965 TI - Mitochondrial Oxidative Stress Reduces the Immunopotency of Mesenchymal Stromal Cells in Adults With Coronary Artery Disease. AB - RATIONALE: Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease; however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with coronary artery disease have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis remain elusive. OBJECTIVE: The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from patients with atherosclerosis. METHODS AND RESULTS: Adipose tissue-derived MSCs were isolated from atherosclerotic (n=38) and nonatherosclerotic (n=42) donors. MSCs:CD4+T-cell suppression was assessed in allogeneic coculture systems. Compared with nonatherosclerotic-MSCs, atherosclerotic-MSCs displayed higher levels of both intracellular (P=0.006) and mitochondrial (P=0.03) reactive oxygen species reflecting altered mitochondrial function. The increased mitochondrial reactive oxygen species levels of atherosclerotic-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 P<0.0001, interleukin-8/C-X-C motif chemokine ligand 8 P=0.04, and monocyte chemoattractant protein-1/chemokine ligand 2 P=0.01). Furthermore, treatment of atherosclerotic-MSCs with the reactive oxygen species scavenger N acetyl-l-cysteine reduced the levels of interleukin-6, interleukin-8/C-X-C motif chemokine ligand 8, and monocyte chemoattractant protein-1/chemokine ligand 2 in the MSC secretome and improved MSCs immunosuppressive capacity (P=0.03). CONCLUSIONS: An impaired mitochondrial function of atherosclerotic-MSCs underlies their altered secretome and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of atherosclerotic-MSCs improve their in vitro immunosuppressive ability and may translate into enhanced therapeutic efficiency. PMID- 29113966 TI - Cystic fibrosis newborn screening: outcome of infants with normal sweat tests. AB - Newborn babies positively screened for cystic fibrosis (CF) (high serum immunoreactive trypsin (IRT) with DNA analysis) are referred for a diagnostic sweat test, which may be normal (sweat chloride <30 mmol/L). Unless two gene mutations are identified during Newborn screening (NBS), the babies are discharged from follow-up. We wished to check that none had subsequently developed symptoms suggestive of CF. We retrospectively reviewed patient notes and contacted general practitioners of all babies with a negative sweat test, conducted in one of the four paediatric specialist CF centres in London, over the first 6 years of screening in South East England.Of 511 babies referred, 95 (19%) had a normal sweat test. Five (5%) had CF diagnosed genetically, two of them on extended genome sequencing after clinical suspicion. Eleven (12%) were designated as CF screen positive inconclusive diagnosis (CFSPID); one of the five CF children was originally designated as CFSPID. Seventy-nine (83%) were assumed to be false-positive cases and discharged; follow-up data were available for 51/79 (65%); 32/51 (63%) had no health issues, 19/51 (37%) had other significant non-CF pathology.These results are reassuring in that within the limitations of those lost to follow-up, CF symptoms have not emerged in the discharged children. The high non-CF morbidity in these children may relate to known causes of high IRT at birth. Clinicians need to be aware that a child can have CF despite a normal sweat test following NBS, and if symptoms suggest the diagnosis, further testing, including extended genome sequencing, is required. PMID- 29113967 TI - Clinical characteristics of children presenting with a suspicion or allegation of historic sexual abuse. AB - INTRODUCTION: Police-recorded sexual offences against children and young people (CYP) increased 85% in the UK between 2010/2011 and 2014/2015. Many children delay disclosure, but little data are available regarding characteristics of CYP presenting with historic child sexual abuse (CSA). AIM: To identify the clinical and CSA-related characteristics of CYP presenting with a suspicion or allegation of historic CSA. METHOD: Data were collected on all CYP<17 years presenting with suspected or alleged historic CSA (ie, >3 days since last sexual assault in prepubertal children, >7 days pubertal girls) between October 2009 and November 2014. DATA COLLECTED: source and indication for referral, alleged perpetrator, physical findings. Findings supportive of CSA were peer reviewed for consensus agreement. ANALYSIS: chi2 test, Fisher's exact test and logistic regression. RESULTS: Among 249 CYP, presentation with physical/behavioural symptoms was associated with age <13 years (p<0.01), and alleged penetration with ages 13-17 years (p<0.01). Where known, time since alleged CSA ranged from 1 week to 13 months. Anogenital findings supportive of CSA were present in 7% of examined children (16/233), significantly associated with alleged penetration (p<0.01) and more likely with increasing age (OR 1.46, 95% CI 1.23 to 1.72). Additionally, where tested, sexually transmitted infections (STI) were detected in 2.6% CYP (3/116). Alleged perpetrators were intrafamilial in 66% (126/190). No associations were identified between perpetrator type and gender (p=1.0), age (p=0.7) or indication for referral (p=0.35). CONCLUSIONS: Despite significant time delay since the alleged CSA, this study highlights the persistence of anogenital findings supportive of CSA in 7% and STIs in 2.6% of CYP. PMID- 29113969 TI - Cannabinoids offer alternatives to opioids for pain relief, experts say. PMID- 29113971 TI - Correction to: 2017 ACC/AAP/AHA Health Policy Statement on Opportunities and Challenges in Pediatric Drug Development: Learning From Sildenafil. PMID- 29113968 TI - Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. AB - Objective To investigate whether symptomatic treatment with non-steroidal anti inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care.Design Randomised, double blind, non-inferiority trial.Setting 17 general practices in Switzerland.Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers.Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat.Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03).Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI.Trial registration ClinicalTrials.gov NCT01039545. PMID- 29113973 TI - Maximising the impact of your work using infographics. PMID- 29113972 TI - Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses. AB - The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFbeta1, and TGFbeta2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. Cancer Res; 77(22); 6389-99. (c)2017 AACR. PMID- 29113974 TI - Infographic: Managing non-traumatic back pain in sport. PMID- 29113977 TI - FDA Approves Second CAR T-cell Therapy. AB - The FDA approved the chimeric antigen receptor T-cell therapy axicabtagene ciloleucel, making it the second such treatment for blood cancers in the United States. The therapy is indicated for adults with certain non-Hodgkin lymphomas who have tried at least two other treatments. PMID- 29113975 TI - G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. AB - Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA We investigated their effect in C9orf72 patient iPSC-derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat-expressing Drosophila Therefore, small molecules that target GGGGCC repeat G-quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential. PMID- 29113976 TI - Co-infection with Chikungunya virus alters trafficking of pathogenic CD8+ T cells into the brain and prevents Plasmodium-induced neuropathology. AB - Arboviral diseases have risen significantly over the last 40 years, increasing the risk of co-infection with other endemic disease such as malaria. However, nothing is known about the impact arboviruses have on the host response toward heterologous pathogens during co-infection. Here, we investigate the effects of Chikungunya virus (CHIKV) co-infection on the susceptibility and severity of malaria infection. Using the Plasmodium berghei ANKA (PbA) experimental cerebral malaria (ECM) model, we show that concurrent co-infection induced the most prominent changes in ECM manifestation. Concurrent co-infection protected mice from ECM mortality without affecting parasite development in the blood. This protection was mediated by the alteration of parasite-specific CD8+ T-cell trafficking through an IFNgamma-mediated mechanism. Co-infection with CHIKV induced higher splenic IFNgamma levels that lead to high local levels of CXCL9 and CXCL10. This induced retention of CXCR3-expressing pathogenic CD8+ T cells in the spleen and prevented their migration to the brain. This then averts all downstream pathogenic events such as parasite sequestration in the brain and disruption of blood-brain barrier that prevents ECM-induced mortality in co infected mice. PMID- 29113978 TI - Additive Phenotypes Underlie Epistasis of Fitness Effects. AB - Gene interactions, or epistasis, play a large role in determining evolutionary outcomes. The ruggedness of fitness landscapes, and thus the predictability of evolution and the accessibility of high-fitness genotypes, is determined largely by the pervasiveness of epistasis and the degree of correlation between similar genotypes. We created all possible pairings of three sets of five beneficial first-step mutations fixed during adaptive walks under three different regimes: selection on growth rate alone, on growth rate and thermal stability, and on growth rate and pH stability. All 30 double-mutants displayed negative, antagonistic epistasis with regard to growth rate and fitness, but positive epistasis and additivity were common for the stability phenotypes. This suggested that biophysically simple phenotypes, such as capsid stability, may on average behave more additively than complex phenotypes like viral growth rate. Growth rate epistasis was also smaller in magnitude when the individual effects of single mutations were smaller. Significant sign epistasis, such that the effect of a mutation that is beneficial in the wild-type background is deleterious in combination with a second mutation, emerged more frequently in intragenic mutational pairings than in intergenic pairs, and was evident in nearly half of the double-mutants, indicating that the fitness landscape is moderately uncorrelated and of intermediate ruggedness. Together, our results indicated that mutations may interact additively with regard to phenotype when considered at a basic, biophysical level, but that epistasis arises as a result of pleiotropic interactions between the individual components of complex phenotypes and diminishing returns arising from intermediate phenotypic optima. PMID- 29113979 TI - More than One Way in: Three Gln3 Sequences Required To Relieve Negative Ure2 Regulation and Support Nuclear Gln3 Import in Saccharomyces cerevisiae. AB - Gln3 is responsible for Nitrogen Catabolite Repression-sensitive transcriptional activation in the yeast Saccharomyces cerevisiae In nitrogen-replete medium, Gln3 is cytoplasmic and NCR-sensitive transcription is repressed. In nitrogen-limiting medium, in cells treated with TorC1 inhibitor, rapamycin, or the glutamine synthetase inhibitor, methionine sulfoximine (Msx), Gln3 becomes highly nuclear and NCR-sensitive transcription derepressed. Previously, nuclear Gln3 localization was concluded to be mediated by a single nuclear localization sequence, NLS1. Here, we show that nuclear Gln3-Myc13 localization is significantly more complex than previously appreciated. We identify three Gln3 sequences, other than NLS1, that are highly required for nuclear Gln3-Myc13 localization. Two of these sequences exhibit characteristics of monopartite (K/R Rich NLS) and bipartite (S/R NLS) NLSs, respectively. Mutations altering these sequences are partially epistatic to a ure2Delta. The third sequence, the Ure2 relief sequence, exhibits no predicted NLS homology and is only necessary when Ure2 is present. Substitution of the basic amino acid repeats in the Ure2 relief sequence or phosphomimetic aspartate substitutions for the serine residues between them abolishes nuclear Gln3-Myc13 localization in response to both limiting nitrogen and rapamycin treatment. In contrast, Gln3-Myc13 responses are normal in parallel serine-to-alanine substitution mutants. These observations suggest that Gln3 responses to specific nitrogen environments likely occur in multiple steps that can be genetically separated. At least one general step that is associated with the Ure2 relief sequence may be prerequisite for responses to the specific stimuli of growth in poor nitrogen sources and rapamycin inhibition of TorC1. PMID- 29113981 TI - Acupressure for respiratory allergic diseases: a systematic review of randomised controlled trials. AB - OBJECTIVE: To evaluate the effects and safety of acupressure for the management of respiratory allergic diseases by systematically reviewing randomised controlled trials (RCTs). METHODS: A total of 13 electronic English and Chinese databases were searched until July 2017. Two authors extracted data and evaluated risk of bias independently. Review Manager V.5.3 was employed for data analysis. RESULTS: The literature search identified 186 papers, of which only four of met the inclusion criteria: two for allergic rhinitis (AR) and two for asthma. High and unclear risk of bias existed across all the included studies. The findings demonstrated that acupressure greater effects on the relief of nasal symptoms of AR compared with 1% ephedrine nasal drop plus thermal therapy. With either Western medicine or Chinese herbal medicine as a cointervention, one study indicated that acupressure plus salbutamol was led to a significantly greater improvement of pulmonary function for patients with asthma compared with salbutamol only. However, the remaining two studies indentified no significant differences in any outcome measures between the two groups. CONCLUSIONS: No reliable conclusions regarding the effects of acupressure on AR and asthma could be drawn by this review due to the small number of available trials with significant heterogeneity of study design and high/unclear risk of bias. Further, more rigorously designed RCTs are needed. Acupressure seems safe for symptomatic relief of AR and asthma, although larger studies are required to be able to robustly confirm its safety. TRIAL REGISTRATION NUMBER: ACTRN12617001106325; Pre results. PMID- 29113980 TI - MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis. AB - Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors. Sclerostin is a Wnt antagonist that binds to Wnt co-receptors and prevents Wnt signal activation. Teriparatide, a 1-34 amino terminal fragment of parathyroid hormone (PTH), and abaloparatide, a modified 1-34 amino terminal fragment of PTH related peptide (PTHrp), induce IGF-I, increase bone mineral density (BMD), reduce the incidence of vertebral and non-vertebral fractures and are approved for the treatment of postmenopausal osteoporosis. Romosozumab, a humanized anti sclerostin antibody, increases bone formation, decreases bone resorption, increases BMD and reduces the incidence of vertebral fractures. An increased incidence of cardiovascular events has been associated with romosozumab, which is yet to be approved for the treatment of osteoporosis. In conclusion, cell and molecular studies have formed the foundation for the development of new anabolic therapies for osteoporosis with proven efficacy on the incidence of new fractures. PMID- 29113982 TI - Nanopore sequencing of complex genomic rearrangements in yeast reveals mechanisms of repeat-mediated double-strand break repair. AB - Improper DNA double-strand break (DSB) repair results in complex genomic rearrangements (CGRs) in many cancers and various congenital disorders in humans. Trinucleotide repeat sequences, such as (GAA)n repeats in Friedreich's ataxia, (CTG)n repeats in myotonic dystrophy, and (CGG)n repeats in fragile X syndrome, are also subject to double-strand breaks within the repetitive tract followed by DNA repair. Mapping the outcomes of CGRs is important for understanding their causes and potential phenotypic effects. However, high-resolution mapping of CGRs has traditionally been a laborious and highly skilled process. Recent advances in long-read DNA sequencing technologies, specifically Nanopore sequencing, have made possible the rapid identification of CGRs with single base pair resolution. Here, we have used whole-genome Nanopore sequencing to characterize several CGRs that originated from naturally occurring DSBs at (GAA)n microsatellites in Saccharomyces cerevisiae These data gave us important insights into the mechanisms of DSB repair leading to CGRs. PMID- 29113985 TI - The unofficial vaccine educators: are CDC funded non-profits sufficiently independent? PMID- 29113983 TI - FGF23 Concentration and APOL1 Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes. AB - OBJECTIVE: Cardiovascular and renal complications contribute to higher mortality in patients with diabetes. We assessed novel and conventional predictors of mortality in African American-Diabetes Heart Study (AA-DHS) participants. RESEARCH DESIGN AND METHODS: Associations between mortality and subclinical atherosclerosis, urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), plasma fibroblast growth factor 23 (FGF23) concentration, African ancestry proportion, and apolipoprotein L1 genotypes (APOL1) were assessed in 513 African Americans with type 2 diabetes; analyses were performed using Cox proportional hazards models. RESULTS: At baseline, participants were 55.6% female with median (25th, 75th percentile) age 55 years (49.0, 62.0), diabetes duration 8 years (5.0, 13.0), glycosylated hemoglobin 60.7 mmol/mol (48.6, 76.0), eGFR 91.3 mL/min/1.73 m2 (76.4, 111.3), UACR 12.5 mg/mmol (4.2, 51.2), and coronary artery calcium 28.5 mg Ca2+ (1.0, 348.6); 11.5% had two APOL1 renal-risk variants. After 6.6-year follow-up (5.8, 7.5), 54 deaths were recorded. Higher levels of coronary artery calcified plaque, carotid artery calcified plaque, albuminuria, and FGF23 were associated with higher mortality after adjustment for age, sex, and African ancestry proportion. A penalized Cox regression that included all covariates and predictors associated with mortality identified male sex (hazard ratio [HR] 4.17 [95% CI 1.96-9.09]), higher FGF23 (HR 2.10 [95% CI 1.59-2.78]), and absence of APOL1 renal-risk genotypes (HR 0.07 [95% CI 0.01-0.69]) as the strongest predictors of mortality. CONCLUSIONS: Accounting for conventional risk factors, higher FGF23 concentrations and APOL1 non-renal risk genotypes associated with higher mortality in African Americans with diabetes. These data add to growing evidence supporting FGF23 association with mortality; mechanisms whereby these novel predictors impact survival remain to be determined. PMID- 29113984 TI - Cardiovascular Complications Over 5 Years and Their Association With Survival in the GERODIAB Cohort of Elderly French Patients With Type 2 Diabetes. AB - OBJECTIVE: The GERODIAB study is a multicenter prospective observational study performed over 5 years in French patients aged 70 years or above with type 2 diabetes. This report deals with their cardiovascular complications and their relationship with survival. RESEARCH DESIGN AND METHODS: Consecutive patients (n = 987, median age = 77 years) were included from 56 diabetes centers over 1 year. Individual characteristics, history and complications of diabetes, geriatric factors, and clinical and biological parameters were recorded. Survival was analyzed using the Kaplan-Meier method and proportional hazards regression models. RESULTS: The frequency of cardiovascular complications increased from 47% at inclusion to 67% at 5 years. The most frequent complications were coronary heart disease (increasing from 30% to 41%) and vascular disease of the lower limbs (25% to 35%) and of the cerebral vessels (15% to 26%). Heart failure was less common, but its frequency doubled during the follow-up (9% to 20%). It was strongly associated with poor survival (P < 0.0001), as was vascular disease of the lower limbs (P = 0.0004), whereas coronary heart disease (P = 0.0056) and vascular disease of cerebral vessels (P = 0.026) had mild associations. Amputation (P < 0.0001) and foot wounds (P < 0.0001) were strongly associated with survival. In multivariate models, heart failure was the strongest predictor of poor survival (hazard ratio [HR] 1.96 [95% CI 1.45-2.64]; P < 0.0001). It remained significant when other factors were considered simultaneously (HR 1.92 [95% CI 1.43-2.58]; P < 0.0001). CONCLUSIONS: Cardiovascular complications are associated with poor survival in elderly patients with type 2 diabetes, especially heart failure. PMID- 29113987 TI - BAP1 Is a Novel Target in HPV-Negative Head and Neck Cancer. AB - Purpose: This study examined the potential role of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) in radioresistance in head and neck squamous cell cancer (HNSCC).Experimental Design: We overexpressed, knocked down, and rescued BAP1 expression in six HNSCC cell lines, three human papillomavirus (HPV)-negative and three HPV-positive, and examined the effects on radiosensitivity in vitro and in an HNSCC mouse xenograft model. Radiosensitivity was assessed by clonogenic cell survival and tumor growth delay assays; changes in protein expression were analyzed by immunofluorescence staining and Western blotting. We also analyzed The Cancer Genome Atlas HNSCC database to test for associations between BAP1 expression and outcome in patients.Results: Overexpression of BAP1 induced radioresistance in both cell lines and xenograft models; conversely, BAP1 knockdown led to increased ubiquitination of histone H2A, which has been implicated in DNA repair. We further found that BAP1 depletion suppressed the assembly of constitutive BRCA1 foci, which are associated with homologous recombination (HR), but had minimal effect on gamma H2AX foci and did not affect proteins associated with nonhomologous end joining, suggesting that BAP1 affects radiosensitivity in HNSCC by modifying HR. Finally, in patients with HNSCC, overexpression of BAP1 was associated with higher failure rates after radiotherapy.Conclusions: BAP1 can induce radioresistance in HNSCC cells, possibly via deubiquitination of H2Aub and modulation of HR, and was associated with poor outcomes in patients with HNSCC. BAP1 may be a potential therapeutic target in HNSCC. Clin Cancer Res; 24(3); 600-7. (c)2017 AACR. PMID- 29113988 TI - Seasonal variation in the thermal responses to changing environmental temperature in the world's northernmost land bird. AB - Arctic homeotherms counter challenges at high latitudes using a combination of seasonal adjustments in pelage/plumage, fat deposition and intricate thermoregulatory adaptations. However, there are still gaps in our understanding of their thermal responses to cold, particularly in Arctic birds. Here, we have studied the potential use of local heterothermy (i.e. tissue cooling that can contribute to significantly lower heat loss rate) in Svalbard ptarmigan (Lagopus muta hyperborea) - the world's northernmost land bird. We exposed birds kept under simulated Svalbard photoperiod to low ambient temperatures (Ta; between 0 and -30 degrees C) during three seasons (early winter, late winter, summer), whilst recording resting metabolic rate (RMR), core temperature (Tc) and several cutaneous temperatures. Leg skin temperature varied the most, but still only by up to ~15 degrees C, whereas body trunk skin temperature changed <1 degrees C when Ta decreased from 0 to -30 degrees C. At the same time, Tc increased by 0.9 degrees C, concomitant with increased RMR. This was probably driven by the triggering of cerebral thermosensors in response to cooling of the poorly insulated head, the skin of which was 5.4 degrees C colder at -30 degrees C than at 0 degrees C. Thermal conductance in winter was higher in yearlings, probably because they were time/resource constrained from acquiring a high-quality plumage and sufficient fat reserves as a result of concomitant body growth. In conclusion, Svalbard ptarmigan do not employ extensive local heterothermy for cold protection but instead rely on efficient thermogenesis combined with excellent body insulation. Hence, cold defence in the world's northernmost land bird is not mechanistically much different from that of its lower latitude relatives. PMID- 29113986 TI - Muscadine Grape Skin Extract (MPX) in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial. AB - Purpose: MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer wishing to defer androgen deprivation therapy.Experimental Design: This was a 12-month, multicenter, placebo controlled, two-dose, double-blinded trial of MPX in 125 men with BCR prostate cancer, powered to detect a PSA doubling time (PSADT) difference of 6 months (low dose) and 12 months (high dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500 mg MPX (low), or 4,000 mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation, and polyphenol pharmacokinetics.Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (P = 0.81): control 0.9 months (n = 20; range, 6.7-83.1), low dose 1.5 months (n = 52; range, 10.3-87.2), high dose 0.9 months (n = 40; range, 27.3-88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms; 6.4 months, P = 0.02), but not in control (1.8 months, P = 0.25).Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study. Clin Cancer Res; 24(2); 306 15. (c)2017 AACR. PMID- 29113989 TI - Cold-hearted bats: uncoupling of heart rate and metabolism during torpor at sub zero temperatures. AB - Many hibernating animals thermoregulate during torpor and defend their body temperature (Tb) near 0 degrees C by an increase in metabolic rate. Above a critical temperature (Tcrit), animals usually thermoconform. We investigated the physiological responses above and below Tcrit for a small tree-dwelling bat (Chalinolobus gouldii, ~14 g) that is often exposed to sub-zero temperatures during winter. Through simultaneous measurement of heart rate (fH) and oxygen consumption (VO2 ), we show that the relationship between oxygen transport and cardiac function is substantially altered in thermoregulating torpid bats between 1 and -2 degrees C, compared with thermoconforming torpid bats at mild ambient temperatures (Ta 5-20 degrees C). Tcrit for this species was at a Ta of 0.7+/-0.4 degrees C, with a corresponding Tb of 1.8+/-1.2 degrees C. Below Tcrit, animals began to thermoregulate, as indicated by a considerable but disproportionate increase in both fH and VO2 The maximum increase in fH was only 4-fold greater than the average thermoconforming minimum, compared with a 46-fold increase in VO2 The differential response of fH and VO2 to low Ta was reflected in a 15-fold increase in oxygen delivery per heart beat (cardiac oxygen pulse). During torpor at low Ta, thermoregulating bats maintained a relatively slow fH and compensated for increased metabolic demands by significantly increasing stroke volume and tissue oxygen extraction. Our study provides new information on the relationship between metabolism and fH in an unstudied physiological state that may occur frequently in the wild and can be extremely costly for heterothermic animals. PMID- 29113990 TI - Notch is required for the formation of all nephron segments and primes nephron progenitors for differentiation. AB - Notch signaling plays important roles during mammalian nephrogenesis. To investigate whether Notch regulates nephron segmentation, we performed Notch loss of-function and gain-of-function studies in developing nephrons in mice. Contrary to the previous notion that Notch signaling promotes the formation of proximal tubules and represses the formation of distal tubules in the mammalian nephron, we show that inhibition of Notch blocks the formation of all nephron segments and that constitutive activation of Notch in developing nephrons does not promote or repress the formation of a specific segment. Cells lacking Notch fail to form the S-shaped body and show reduced expression of Lhx1 and Hnf1b Consistent with this, we find that constitutive activation of Notch in mesenchymal nephron progenitors causes ectopic expression of Lhx1 and Hnf1b and that these cells eventually form a heterogeneous population that includes proximal tubules and other types of cells. Our data suggest that Notch signaling is required for the formation of all nephron segments and that it primes nephron progenitors for differentiation rather than directing their cell fates into a specific nephron segment. PMID- 29113991 TI - Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2. AB - The Arp2/3 complex assembles branched actin filaments, which are key to many cellular processes, but its organismal roles remain poorly understood. Here, we employed conditional Arpc4 knockout mice to study the function of the Arp2/3 complex in the epidermis. We found that depletion of the Arp2/3 complex by knockout of Arpc4 results in skin abnormalities at birth that evolve into a severe psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2. Knockout of Arpc4 in cultured keratinocytes was sufficient to induce nuclear accumulation of Nrf2, upregulation of Nrf2 target genes and decreased filamentous actin levels. Furthermore, pharmacological inhibition of the Arp2/3 complex unmasked the role of branched actin filaments in Nrf2 regulation. Consistent with this, we revealed that Nrf2 associates with the actin cytoskeleton in cells and binds to filamentous actin in vitro Finally, we discovered that Arpc4 is downregulated in both human and mouse psoriatic epidermis. Thus, the Arp2/3 complex affects keratinocyte shape and transcriptome through an actin-based cell-autonomous mechanism that influences epidermal morphogenesis and homeostasis. PMID- 29113992 TI - Axonemal dynein assembly requires the R2TP complex component Pontin. AB - Pontin (Ruvbl1) and Reptin (Ruvbl2) are closely related AAA ATPases. They are components of the Ruvbl1-Ruvbl2-Tah1-Pih1 (R2TP) complexes that function as co chaperones for the assembly of multiple macromolecular protein complexes. Here, we show that Pontin is essential for cilia motility in both zebrafish and mouse and that Pontin and Reptin function cooperatively in this process. Zebrafish pontin mutants display phenotypes tightly associated with cilia defects, and cilia motility is lost in a number of ciliated tissues along with a reduction in the number of outer and inner dynein arms. Pontin protein is enriched in cytosolic puncta in ciliated cells in zebrafish embryos. In mouse testis, Pontin is essential for the stabilization of axonemal dynein intermediate chain 1 (DNAI1) and DNAI2, the first appreciated step in axonemal dynein arm assembly. Strikingly, multiple dynein arm assembly factors show structural similarities to either Tah1 or Pih1, the other two components of the R2TP complex. Based on these results, we propose that Pontin and Reptin function to facilitate dynein arm assembly in cytosolic foci enriched with R2TP-like complexes. PMID- 29113993 TI - PXR: More Than Just a Master Xenobiotic Receptor. AB - Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied, and the role of PXR as a xenobiotic sensor has been well established. It is now clear, however, that PXR plays many other roles in addition to its xenobiotic-sensing function. For instance, recent studies have discovered previously unidentified roles of PXR in inflammatory response, cell proliferation, and cell migration. PXR also contributes to the dysregulation of these processes in diseases states. These recent discoveries of the role of PXR in the physiologic and pathophysiologic conditions of other cellular processes provides the possibility of novel targets for drug discovery. This review highlights areas of PXR regulation that require further clarification and summarizes the recent progress in our understanding of the nonxenobiotic functions of PXR that can be explored for relevant therapeutic applications. PMID- 29113994 TI - Hepatocyte-specific deletion of BAP31 promotes SREBP1C activation, promotes hepatic lipid accumulation, and worsens IR in mice. AB - Conditional knockout mice with targeted disruption of B-cell associated protein (BAP)31 in adult mouse liver were generated and challenged with a high-fat diet (HFD) for 36 or 96 days and markers of obesity, diabetes, and hepatic steatosis were determined. Mutant mice were indistinguishable from WT littermates, but exhibited increased HFD-induced obesity. BAP31-deletion in hepatocytes increased the expression of SREBP1C and the target genes, including acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase-1, and increased hepatic lipid accumulation and HFD induced liver steatosis. Immunoprecipitation assay showed that BAP31 interacts with SREBP1C and insulin-induced gene 1 (INSIG1), and BAP31-deletion reduces INSIG1 expression, suggesting that BAP31 may regulate SREBP1C activity by modulating INSIG1 protein levels. Additionally, BAP31-deletion induced glucose and insulin intolerance, decreased Akt and glycogen synthase kinase 3beta phosphorylation, and enhanced hepatic glucose production in mice. Expression of endoplasmic reticulum (ER) stress markers was significantly induced in BAP31 mutant mice. HFD-induced inflammation was aggravated in mutant mice, along with increased c-Jun N-terminal kinase and nuclear factor-kappaB activation. These findings demonstrate that BAP31-deletion induces SREBP activation and promotes hepatic lipid accumulation, reduces insulin signaling, impairs glucose/insulin tolerance, and increases ER stress and hepatic inflammation, explaining the protective roles of BAP31 in the development of liver steatosis and insulin resistance in HFD-induced obesity in animal models. PMID- 29113995 TI - Time for change: a new training programme for morpho-molecular pathologists? AB - The evolution of cellular pathology as a specialty has always been driven by technological developments and the clinical relevance of incorporating novel investigations into diagnostic practice. In recent years, the molecular characterisation of cancer has become of crucial relevance in patient treatment both for predictive testing and subclassification of certain tumours. Much of this has become possible due to the availability of next-generation sequencing technologies and the whole-genome sequencing of tumours is now being rolled out into clinical practice in England via the 100 000 Genome Project. The effective integration of cellular pathology reporting and genomic characterisation is crucial to ensure the morphological and genomic data are interpreted in the relevant context, though despite this, in many UK centres molecular testing is entirely detached from cellular pathology departments. The CM-Path initiative recognises there is a genomics knowledge and skills gap within cellular pathology that needs to be bridged through an upskilling of the current workforce and a redesign of pathology training. Bridging this gap will allow the development of an integrated 'morphomolecular pathology' specialty, which can maintain the relevance of cellular pathology at the centre of cancer patient management and allow the pathology community to continue to be a major influence in cancer discovery as well as playing a driving role in the delivery of precision medicine approaches. Here, several alternative models of pathology training, designed to address this challenge, are presented and appraised. PMID- 29113997 TI - ImaEdge - a platform for quantitative analysis of the spatiotemporal dynamics of cortical proteins during cell polarization. AB - Cell polarity involves the compartmentalization of the cell cortex. The establishment of cortical compartments arises from the spatial bias in the activity and concentration of cortical proteins. The mechanistic dissection of cell polarity requires the accurate detection of dynamic changes in cortical proteins, but the fluctuations of cell shape and the inhomogeneous distributions of cortical proteins greatly complicate the quantitative extraction of their global and local changes during cell polarization. To address these problems, we introduce an open-source software package, ImaEdge, which automates the segmentation of the cortex from time-lapse movies, and enables quantitative extraction of cortical protein intensities. We demonstrate that ImaEdge enables efficient and rigorous analysis of the dynamic evolution of cortical PAR proteins during Caenorhabditis elegans embryogenesis. It is also capable of accurate tracking of varying levels of transgene expression and discontinuous signals of the actomyosin cytoskeleton during multiple rounds of cell division. ImaEdge provides a unique resource for quantitative studies of cortical polarization, with the potential for application to many types of polarized cells.This article has an associated First Person interview with the first authors of the paper. PMID- 29113996 TI - Characterization of the Molecular Mechanisms Underlying Glucose Stimulated Insulin Secretion from Isolated Pancreatic beta-cells Using Post-translational Modification Specific Proteomics (PTMomics). AB - Normal pancreatic islet beta-cells (PBCs) abundantly secrete insulin in response to elevated blood glucose levels, in order to maintain an adequate control of energy balance and glucose homeostasis. However, the molecular mechanisms underlying the insulin secretion are unclear. Improving our understanding of glucose-stimulated insulin secretion (GSIS) mechanisms under normal conditions is a prerequisite for developing better interventions against diabetes. Here, we aimed at identifying novel signaling pathways involved in the initial release of insulin from PBCs after glucose stimulation using quantitative strategies for the assessment of phosphorylated proteins and sialylated N-linked (SA) glycoproteins.Islets of Langerhans derived from newborn rats with a subsequent 9 10 days of maturation in vitro were stimulated with 20 mm glucose for 0 min (control), 5 min, 10 min, and 15 min. The isolated islets were subjected to time resolved quantitative phosphoproteomics and sialiomics using iTRAQ-labeling combined with enrichment of phosphorylated peptides and formerly SA glycopeptides and high-accuracy LC-MS/MS. Using bioinformatics we analyzed the functional signaling pathways during GSIS, including well-known insulin secretion pathways. Furthermore, we identified six novel activated signaling pathways (e.g. agrin interactions and prolactin signaling) at 15 min GSIS, which may increase our understanding of the molecular mechanism underlying GSIS. Moreover, we validated some of the regulated phosphosites by parallel reaction monitoring, which resulted in the validation of eleven new phosphosites significantly regulated on GSIS. Besides protein phosphorylation, alteration in SA glycosylation was observed on several surface proteins on brief GSIS. Interestingly, proteins important for cell-cell interaction, cell movement, cell-ECM interaction and Focal Adhesion (e.g. integrins, semaphorins, and plexins) were found regulated at the level of sialylation, but not in protein expression. Collectively, we believe that this comprehensive Proteomics and PTMomics survey of signaling pathways taking place during brief GSIS of primary PBCs is contributing to understanding the complex signaling underlying GSIS. PMID- 29113998 TI - RhoC regulates the actin remodeling required for phagosome formation during FcgammaR-mediated phagocytosis. AB - Phagosome formation is a complicated process that requires spatiotemporally regulated actin reorganization. We found that RhoC GTPase is a critical regulator of FcgammaR-mediated phagocytosis in macrophages. Our live-cell imaging revealed that RhoC, but not RhoA, is recruited to phagocytic cups engulfing IgG-opsonized erythrocytes (IgG-Es). RhoC silencing through RNAi, CRISPR/Cas-mediated RhoC knockout, and the expression of dominant-negative or constitutively active RhoC mutants suppressed the phagocytosis of IgG-Es. Moreover, RhoC-GTP pulldown experiments showed that endogenous RhoC is transiently activated during phagosome formation. Notably, actin-driven pseudopod extension, which is required for the formation of phagocytic cups, was severely impaired in cells expressing the constitutively active mutant RhoC-G14V, which induced abnormal F-actin accumulation underneath the plasma membrane. mDia1 (encoded by DIAPH1), a Rho dependent actin nucleation factor, and RhoC were colocalized at the phagocytic cups. Similar to what was seen for RhoC, mDia1 silencing through RNAi inhibited phagosome formation. Additionally, the coexpression of mDia1 with constitutively active mutant RhoC-G14V or expression of active mutant mDia1-DeltaN3 drastically inhibited the uptake of IgG-Es. These data suggest that RhoC modulates phagosome formation be modifying actin cytoskeletal remodeling via mDia1. PMID- 29113999 TI - Index of Microcirculatory Resistance at the Time of Primary Percutaneous Coronary Intervention Predicts Early Cardiac Complications: Insights From the OxAMI (Oxford Study in Acute Myocardial Infarction) Cohort. AB - BACKGROUND: Early risk stratification after primary percutaneous coronary intervention (PPCI) for ST-segment-elevation myocardial infarction is currently challenging. Identification of a low-risk group may improve triage of patients to alternative clinical pathways and support early hospital discharge. Our aim was to assess whether the index of microcirculatory resistance (IMR) at the time of PPCI can identify patients at low risk of early major cardiac complications and to compare its performance against guideline-recommended risk scores. METHODS AND RESULTS: IMR was measured using a pressure-temperature sensor wire. Cardiac complications were defined as the composite of cardiac death, cardiogenic shock, pulmonary edema, malignant arrhythmias, cardiac rupture, and presence of left ventricular thrombus either before hospital discharge or within 30-day follow-up. In total, 261 patients undergoing PPCI who were eligible for coronary physiology assessment were prospectively enrolled. Twenty-two major cardiac complications were reported. Receiver operating characteristic curve analysis confirmed the utility of IMR in predicting complications and showed significantly better performance than coronary flow reserve, the Primary Angioplasty in Myocardial Infarction II (PAMI-II), and Zwolle score (P<=0.006). Low microvascular resistance (IMR <=40) was measured in 159 patients (61%) of the study population and identified all patients who were free of major cardiac complications (sensitivity: 100%; 95% CI, 80.5-100%). CONCLUSIONS: IMR immediately at the end of PPCI for ST-segment-elevation myocardial infarction reliably predicts early major cardiac complications and performed significantly better than recommended risk scores. These novel data have implications for early risk stratification after PPCI. PMID- 29114000 TI - MicroRNA-130a, a Potential Antifibrotic Target in Cardiac Fibrosis. AB - BACKGROUND: Cardiac fibrosis occurs because of disruption of the extracellular matrix network leading to myocardial dysfunction. Angiotensin II has been implicated in the development of cardiac fibrosis. Recently, microRNAs have been identified as an attractive target for therapeutic intervention in cardiac pathologies; however, the underlying mechanism of microRNAs in cardiac fibrosis remains unclear. MicroRNA-130a (miR-130a) has been shown to participate in angiogenesis and cardiac arrhythmia; however, its role in cardiac fibrosis is unknown. METHODS AND RESULTS: In this study, we found that miR-130a was significantly upregulated in angiotensin II-infused mice. The in vivo inhibition of miR-130a by locked nucleic acid- based anti-miR-130a in mice significantly reduced angiotensin II-induced cardiac fibrosis. Upregulation of miR-130a was confirmed in failing human hearts. Overexpressing miR-130a in cardiac fibroblasts promoted profibrotic gene expression and myofibroblasts differentiation, and the inhibition of miR-130a reversed the processes. Using the constitutive and dominant negative constructs of peroxisome proliferator-activated receptor gamma 3-'untranslated region (UTR), data revealed that the protective mechanism was associated with restoration of peroxisome proliferator-activated receptor gamma level leading to the inhibition of angiotensin II-induced cardiac fibrosis. CONCLUSIONS: Our findings provide evidence that miR-130a plays a critical role in cardiac fibrosis by directly targeting peroxisome proliferator-activated receptor gamma. We conclude that inhibition of miR-130a would be a promising strategy for the treatment of cardiac fibrosis. PMID- 29114003 TI - Pediatric Patient-Centered Transitions From Hospital to Home: Improving the Discharge Medication Process. AB - OBJECTIVES: Medications prescribed at hospital discharge can lead to patient harm if there are access barriers or misunderstanding of instructions. Filling prescriptions before discharge can decrease these risks. We aimed to increase the percentage of patients leaving the hospital with new discharge medications in hand to 70% by 18 months. METHODS: We used sequential plan-do-study-act cycles from January 2015 to September 2016. We used statistical process control charts to track process measures, new medications filled before discharge, and rates of bedside delivery with pharmacist teaching to the inpatient pediatric unit. Outcome measures included national patient survey data, collected and displayed quarterly, as well as caregiver understanding, comparing inaccuracy of medication teach-back with and without medications in hand before discharge. RESULTS: Rates of patients leaving the hospital with medications in hand increased from a baseline of 2% to 85% over the study period. Bedside delivery reached 71%. Inaccuracy of caregiver report during a postdischarge phone call decreased from 3.3% to 0.7% (P < .05) when medications were in hand before discharge. Patient satisfaction with education of new medication side effects increased from 50% to 88%. CONCLUSIONS: By using an engaged interprofessional team, we optimized use of our on-site outpatient pharmacy and increased the percentage of pediatric patients leaving the hospital with new discharge medications in hand to >80%. This, accompanied by increased rates of bedside medication delivery and pharmacist teaching, was associated with improvements in caregiver discharge medication related experience and understanding. PMID- 29114001 TI - Impaired Central Pulsatile Hemodynamics in Children and Adolescents With Marfan Syndrome. AB - BACKGROUND: Marfan syndrome is characterized by aortic root dilation, beginning in childhood. Data about aortic pulsatile hemodynamics and stiffness in pediatric age are currently lacking. METHODS AND RESULTS: In 51 young patients with Marfan syndrome (12.0+/-3.3 years), carotid tonometry was performed for the measurement of central pulse pressure, pulse pressure amplification, and aortic stiffness (carotid-femoral pulse wave velocity). Patients underwent an echocardiogram at baseline and at 1 year follow-up and a genetic evaluation. Pathogenetic fibrillin 1 mutations were classified between "dominant negative" and "haploinsufficient." The hemodynamic parameters of patients were compared with those of 80 sex, age, blood pressure, and heart-rate matched controls. Central pulse pressure was significantly higher (38.3+/-12.3 versus 33.6+/-7.8 mm Hg; P=0.009), and pulse pressure amplification was significantly reduced in Marfan than controls (17.9+/ 15.3% versus 32.3+/-17.4%; P<0.0001). Pulse wave velocity was not significantly different between Marfan and controls (4.98+/-1.00 versus 4.75+/-0.67 m/s). In the Marfan group, central pulse pressure and pulse pressure amplification were independently associated with aortic diameter at the sinuses of Valsalva (respectively, beta=0.371, P=0.010; beta=-0.271, P=0.026). No significant difference in hemodynamic parameters was found according to fibrillin-1 genotype. Patients who increased aortic Z-scores at 1-year follow-up presented a higher central pulse pressure than the remaining (42.7+/-14.2 versus 32.3+/-5.9 mm Hg; P=0.004). CONCLUSIONS: Central pulse pressure and pulse pressure amplification were impaired in pediatric Marfan syndrome, and associated with aortic root diameters, whereas aortic pulse wave velocity was similar to that of a general pediatric population. An increased central pulse pressure was present among patients whose aortic dilatation worsened at 1-year follow-up. PMID- 29114002 TI - SDF-1alpha (Stromal Cell-Derived Factor 1alpha) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen. AB - BACKGROUND: Activated cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs) proliferate, cause hypertrophy, and produce collagen; in this way, activated CFs contribute to cardiac fibrosis, and activated PGVSMCs and GMCs promote renal fibrosis. In heart and kidney diseases, SDF-1alpha (stromal cell-derived factor 1alpha; endogenous CXCR4 [C-X-C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF-1alpha/CXCR4 axis activates CFs, PGVSMCs, or GMCs. METHODS AND RESULTS: Here we investigated whether SDF-1alpha activates CFs, PGVSMCs, and GMCs to proliferate, hypertrophy, or produce collagen. DPP4 (dipeptidyl peptidase 4) inactivates SDF-1alpha and previous experiments show that growth-promoting peptides have greater effects in cells from genetically-hypertensive animals. Therefore, we performed experiments in the absence and presence of sitagliptin (DPP4 inhibitor) and in cells from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. Our studies show (1) that spontaneously hypertensive and Wistar-Kyoto rat CFs, PGVSMCs, and GMCs express CXCR4 receptors and DPP4 activity; (2) that chronic treatment with physiologically relevant concentrations of SDF-1alpha causes concentration dependent increases in the proliferation (cell number) and hypertrophy (3H leucine incorporation) of and collagen production (3H-proline incorporation) by CFs, PGVSMCs, and GMCs; (3) that sitagliptin augments these effects of SDF 1alpha; (4) that interactions between SDF-1alpha and sitagliptin are greater in spontaneously hypertensive rat cells; (5) that CXCR4 antagonism (AMD3100) blocks all effects of SDF-1alpha; and (6) that SDF-1alpha/CXCR4 signal transduction likely involves the RACK1 (receptor for activated C kinase 1)/Gbetagamma/PLC (phospholipase C)/PKC (protein kinase C) signaling complex. CONCLUSIONS: The SDF 1alpha/CXCR4 axis drives proliferation and hypertrophy of and collagen production by CFs, PGVSMCs, and GMCs, particularly in cells from genetically hypertensive animals and when DPP4 is inhibited. PMID- 29114004 TI - Dysproteinemias and Glomerular Disease. AB - Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage. The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomerulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Ig deposition include the activation of the complement system, which causes complement deposition in C3 glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be produced by clones from any of the B cell lineages and that a malignant state is not required for the development of kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal significance, preservation of renal function requires substantial reduction of the monoclonal protein. With better understanding of the pathogenesis, clone directed strategies, such as rituximab against CD20 expressing B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These clone-directed therapies been found to be more effective than immunosuppressive regimens used in nonmonoclonal protein-related kidney diseases. PMID- 29114006 TI - Hyperkalemia across the Continuum of Kidney Function. PMID- 29114005 TI - Residual Kidney Function and Peritoneal Dialysis-Associated Peritonitis Treatment Outcomes. AB - BACKGROUND AND OBJECTIVES: Residual kidney function contributes to the clearance of antibiotics excreted by the kidneys, lowering the antibiotic concentration, which may adversely affect the treatment of peritoneal dialysis-associated peritonitis. The objective of our study was to examine the relationship between residual kidneyfunction and peritonitis treatment outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study included 181 participants who experienced 339 episodes of Gram-positive, Gram-negative, and culture-negative peritoneal dialysis-associated peritonitis at a single centerfrom 2003 to 2010. Episodes were categorized according to participants' urinary creatinine clearance (0, >0 5, and >5 ml/min). The data were analyzed using generalized estimating equation models to determine the covariate-adjusted association between urinary creatinine clearance and treatment failure (defined as relapse or recurrent peritonitis episodes, peritoneal catheter removal, or death from any cause during peritonitis treatment). RESULTS: Among episodes of peritonitis due to Gram-positive organisms or culture-negative infections, those experienced by participants with urinary creatinine clearance >5 ml/min had significantly higher odds of treatment failure than episodes experienced by anuric participants (27 of 80 versus 20 of 119 episodes resulting in treatment failure for creatinine clearance >5 versus 0 ml/min; odds ratio, 6.80; 95% confidence interval, 2.37 to 19.6). Episodes experienced by participants with creatinine clearance >0-5 ml/min also had significantly higher odds of treatment failure than episodes experienced by anuric participants (14 of 64 episodes resulting in treatment failure for creatinine clearance >0-5 ml/min; odds ratio, 2.87; 95% confidence interval, 1.12 to 7.35). The odds of relapse and recurrent peritonitis among participants with creatinine clearance >5 ml/min was also significantly higher compared with in anuric participants (17 of 80 versus 12 of 119 episodes resulting in relapse and recurrence for creatinine clearance >5 versus 0 ml/min; odds ratio, 6.76; 95% confidence interval, 1.90 to 23.8). Among participants with Gram-negative peritonitis, creatinine clearance was significantly associated with neither treatment failure nor relapse and recurrent peritonitis. CONCLUSIONS: Residual kidney function as measured by greater urinary creatinine clearance was associated with treatment failure among participants with Gram-positive and culture-negative peritonitis. PMID- 29114007 TI - Effective Treatment of PD Peritonitis. PMID- 29114008 TI - 2017 American Heart Association Focused Update on Adult Basic Life Support and Cardiopulmonary Resuscitation Quality: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - Cardiopulmonary resuscitation is a lifesaving technique for victims of sudden cardiac arrest. Despite advances in resuscitation science, basic life support remains a critical factor in determining outcomes. The American Heart Association recommendations for adult basic life support incorporate the most recently published evidence and serve as the basis for education and training for laypeople and healthcare providers who perform cardiopulmonary resuscitation. PMID- 29114009 TI - 2017 American Heart Association Focused Update on Pediatric Basic Life Support and Cardiopulmonary Resuscitation Quality: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. AB - This focused update to the American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care follows the Pediatric Task Force of the International Liaison Committee on Resuscitation evidence review. It aligns with the International Liaison Committee on Resuscitation's continuous evidence review process, and updates are published when the International Liaison Committee on Resuscitation completes a literature review based on new science. This update provides the evidence review and treatment recommendation for chest compression-only CPR versus CPR using chest compressions with rescue breaths for children <18 years of age. Four large database studies were available for review, including 2 published after the "2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care." Two demonstrated worse 30-day outcomes with chest compression-only CPR for children 1 through 18 years of age, whereas 2 studies documented no difference between chest compression-only CPR and CPR using chest compressions with rescue breaths. When the results were analyzed for infants <1 year of age, CPR using chest compressions with rescue breaths was better than no CPR but was no different from chest compression-only CPR in 1 study, whereas another study observed no differences among chest compression-only CPR, CPR using chest compressions with rescue breaths, and no CPR. CPR using chest compressions with rescue breaths should be provided for infants and children in cardiac arrest. If bystanders are unwilling or unable to deliver rescue breaths, we recommend that rescuers provide chest compressions for infants and children. PMID- 29114010 TI - 2017 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary. AB - The International Liaison Committee on Resuscitation has initiated a near continuous review of cardiopulmonary resuscitation science that replaces the previous 5-year cyclic batch-and-queue approach process. This is the first of an annual series of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations summary articles that will include the cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation in the previous year. The review this year includes 5 basic life support and 1 pediatric Consensuses on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Each of these includes a summary of the science and its quality based on Grading of Recommendations, Assessment, Development, and Evaluation criteria and treatment recommendations. Insights into the deliberations of the International Liaison Committee on Resuscitation task force members are provided in Values and Preferences sections. Finally, the task force members have prioritized and listed the top 3 knowledge gaps for each population, intervention, comparator, and outcome question. PMID- 29114011 TI - Albuterol Delivery Efficiency in a Pediatric Model of Noninvasive Ventilation With Double-Limb Circuit. AB - BACKGROUND: Noninvasive ventilation (NIV) is used to treat respiratory failure in patients with concomitant need for aerosol delivery. Limited pediatric data are available on aerosol delivery efficiency, and none at all regarding aerosol delivery efficiency with a double-limb circuit. We compared the effect of position in the double-limb ventilator circuit, types of nebulizer, and ventilator settings on aerosol delivery efficiency in a pediatric model of NIV. We hypothesized that placing a vibrating mesh nebulizer at the ventilator and using the highest inspiratory pressures would increase aerosol delivery efficiency. METHODS: A breathing simulator was connected in series to a low dead space filter holder (lung dose) and to an anatomically correct head/airway model of a 5-year-old child. A non-vented mask connected the model to a ventilator operated on noninvasive bi-level mode and assembled with a double-limb, heated wired adult circuit. Inspiratory pressures of either 15 or 20 cm H2O and an expiratory pressure of 5 cm H2O were used. Two different vibrating mesh nebulizers and 2 different jet nebulizers loaded with albuterol solution were studied. Albuterol was measured with spectrophotometry. Aerosol delivery efficiency was calculated as lung dose expressed as a percentage of the nominal dose. RESULTS: A vibrating mesh nebulizer before the mask or Y-piece provided the highest delivery efficiency and outperformed a vibrating mesh nebulizer integrated into the mask. Vibrating mesh nebulizers delivered more drug than jet nebulizers, regardless of their position in the circuit. Increasing the inspiratory pressure only improved aerosol delivery efficiency with a jet nebulizer placed at the ventilator. CONCLUSIONS: In a pediatric model of NIV, the effect of nebulizer position on aerosol delivery efficiency depends on the type of device and its placement in the ventilator circuit. A vibrating mesh nebulizer placed at the mask or before the Y-piece of the double-limb circuit provided the highest aerosol drug delivery during NIV. Data generated with invasive ventilation models should not be generalized to NIV models. PMID- 29114013 TI - Nanopore Sequencing Comes to Plant Genomes. PMID- 29114012 TI - Cbl downregulation increases RBP4 expression in adipocytes of female mice. AB - Obesity leads to adipose tissue dysfunction, insulin resistance and diabetes. Adipose tissue produces adipokines that contribute to regulate insulin sensitivity. In turn, insulin stimulates the production and release of some adipokines. Casitas-b-lymphoma proteins (c-Cbl, Cbl-b and Cbl3) are intracellular adaptor signalling proteins that are rapidly phosphorylated by activation of tyrosine kinase receptors. c-Cbl is rapidly phosphorylated by insulin in adipocytes. Here, we tested the hypothesis that Cbl signalling regulates adipokine expression in adipose tissue. We determined the adipokine profile of WAT of Cbl-/- and Cbl+/+ mice in the C57BL6 background. Female Cbl-/- mice exhibited altered expression of adiponectin, leptin and RBP4 in visceral adipose tissue, while no significant changes were seen in male mice. TNFalpha and IL6 levels were unaffected by Cbl depletion. RBP4 expression was unchanged in liver. Adipose tissue of Cbl-/- animals showed increased basal activation of extracellular regulated kinases (ERK1/2) compared to Cbl+/+. c-Cbl knockdown in 3T3L1 adipocytes also increased basal ERK phosphorylation and RBP4 expression. Inhibition of ERK1/2 phosphorylation in Cbl-depleted 3T3L1 adipocytes or in adipose tissue explants of Cbl-/- mice reduced RBP4 mRNA. 17beta-Estradiol increased RBP4 mRNA in adipocytes. Cbl depletion did not change ER expression but increased phosphorylation of ERalpha at S118, a target site for ERK1/2. ERK1/2 inhibition reduced phosphoER and RBP4 levels. These findings suggest that Cbl contributes to regulate RBP4 expression in adipose of female mice through ERK1/2 mediated activation of ERalpha. Since Cbl signalling is compromised in diabetes, these data highlight a novel mechanism that upregulates RBP4 locally. PMID- 29114014 TI - Arabidopsis Pollen Fertility Requires the Transcription Factors CITF1 and SPL7 That Regulate Copper Delivery to Anthers and Jasmonic Acid Synthesis. AB - A deficiency of the micronutrient copper (Cu) leads to infertility and grain/seed yield reduction in plants. How Cu affects fertility, which reproductive structures require Cu, and which transcriptional networks coordinate Cu delivery to reproductive organs is poorly understood. Using RNA-seq analysis, we showed that the expression of a gene encoding a novel transcription factor, CITF1 (Cu DEFICIENCY INDUCED TRANSCRIPTION FACTOR1), was strongly upregulated in Arabidopsis thaliana flowers subjected to Cu deficiency. We demonstrated that CITF1 regulates Cu uptake into roots and delivery to flowers and is required for normal plant growth under Cu deficiency. CITF1 acts together with a master regulator of copper homeostasis, SPL7 (SQUAMOSA PROMOTER BINDING PROTEIN LIKE7), and the function of both is required for Cu delivery to anthers and pollen fertility. We also found that Cu deficiency upregulates the expression of jasmonic acid (JA) biosynthetic genes in flowers and increases endogenous JA accumulation in leaves. These effects are controlled in part by CITF1 and SPL7. Finally, we show that JA regulates CITF1 expression and that the JA biosynthetic mutant lacking the CITF1- and SPL7-regulated genes, LOX3 and LOX4, is sensitive to Cu deficiency. Together, our data show that CITF1 and SPL7 regulate Cu uptake and delivery to anthers, thereby influencing fertility, and highlight the relationship between Cu homeostasis, CITF1, SPL7, and the JA metabolic pathway. PMID- 29114015 TI - Genetic Components of Root Architecture Remodeling in Response to Salt Stress. AB - Salinity of the soil is highly detrimental to plant growth. Plants respond by a redistribution of root mass between main and lateral roots, yet the genetic machinery underlying this process is still largely unknown. Here, we describe the natural variation among 347 Arabidopsis thaliana accessions in root system architecture (RSA) and identify the traits with highest natural variation in their response to salt. Salt-induced changes in RSA were associated with 100 genetic loci using genome-wide association studies. Two candidate loci associated with lateral root development were validated and further investigated. Changes in CYP79B2 expression in salt stress positively correlated with lateral root development in accessions, and cyp79b2 cyp79b3 double mutants developed fewer and shorter lateral roots under salt stress, but not in control conditions. By contrast, high HKT1 expression in the root repressed lateral root development, which could be partially rescued by addition of potassium. The collected data and multivariate analysis of multiple RSA traits, available through the Salt_NV_Root App, capture root responses to salinity. Together, our results provide a better understanding of effective RSA remodeling responses, and the genetic components involved, for plant performance in stress conditions. PMID- 29114016 TI - EIN3 and PIF3 Form an Interdependent Module That Represses Chloroplast Development in Buried Seedlings. AB - In buried seedlings, chloroplasts are arrested at the etioplast stage, but they rapidly mature upon emergence of the seedling. Etioplast-chloroplast differentiation is halted through the integration of soil-induced signals, including pressure and the absence of light, although the details on how this information converges to regulate cellular decisions remain unclear. Here, we identify an interdependent transcription module that integrates the mechanical pressure and darkness signals to control chloroplast development in Arabidopsis thaliana Mutations of ETHYLENE-INSENSITIVE3 (EIN3), the primary transcription factor in the ethylene signaling pathway that is activated in response to mechanical pressure, cause early development of etioplasts in the dark and severe photobleaching upon light exposure. Genetic studies demonstrate that repression of etioplast differentiation by EIN3 requires PHYTOCHROME INTERACTING FACTOR3 (PIF3), a darkness-stabilized bHLH transcription factor. EIN3 and PIF3 directly interact and form an interdependent module to repress the expression of most LIGHT HARVESTING COMPLEX (LHC) genes; overexpressing even one LHC could cause premature development of etioplasts. The EIN3-PIF3 transcription module synergistically halts chloroplast development by interdependently co-occupying the promoters of LHC genes. Thus, our results define a transcriptional regulatory module and provide mechanistic insight on the concerted regulation of chloroplast development by multiple soil-induced signals. PMID- 29114018 TI - Accurate detection of chemical modifications in RNA by mutational profiling (MaP) with ShapeMapper 2. AB - Mutational profiling (MaP) enables detection of sites of chemical modification in RNA as sequence changes during reverse transcription (RT), subsequently read out by massively parallel sequencing. We introduce ShapeMapper 2, which integrates careful handling of all classes of adduct-induced sequence changes, sequence variant correction, basecall quality filters, and quality-control warnings to now identify RNA adduct sites as accurately as achieved by careful manual analysis of electrophoresis data, the prior highest-accuracy standard. MaP and ShapeMapper 2 provide a robust, experimentally concise, and accurate approach for reading out nucleic acid chemical probing experiments. PMID- 29114017 TI - A microRNA feedback loop regulates global microRNA abundance during aging. AB - Expression levels of many microRNAs (miRNAs) change during aging, notably declining globally in a number of organisms and tissues across taxa. However, little is known about the mechanisms or the biological relevance for this change. We investigated the network of genes that controls miRNA transcription and processing during C. elegans aging. We found that miRNA biogenesis genes are highly networked with transcription factors and aging-associated miRNAs. In particular, miR-71, known to influence life span and itself up-regulated during aging, represses alg-1/Argonaute expression post-transcriptionally during aging. Increased ALG-1 abundance in mir-71 loss-of-function mutants led to globally increased miRNA expression. Interestingly, these mutants demonstrated widespread mRNA expression dysregulation and diminished levels of variability both in gene expression and in overall life span. Thus, the progressive molecular decline often thought to be the result of accumulated damage over an organism's life may be partially explained by a miRNA-directed mechanism of age-associated decline. PMID- 29114019 TI - Native elongating transcript sequencing reveals global anti-correlation between sense and antisense nascent transcription in fission yeast. AB - Antisense transcription can regulate sense gene expression. However, previous annotations of antisense transcription units have been based on detection of mature antisense long noncoding (aslnc)RNAs by RNA-seq and/or microarrays, only giving a partial view of the antisense transcription landscape and incomplete molecular bases for antisense-mediated regulation. Here, we used native elongating transcript sequencing to map genome-wide nascent antisense transcription in fission yeast. Strikingly, antisense transcription was detected for most protein-coding genes, correlating with low sense transcription, especially when overlapping the mRNA start site. RNA profiling revealed that the resulting aslncRNAs mainly correspond to cryptic Xrn1/Exo2-sensitive transcripts (XUTs). ChIP-seq analyses showed that antisense (as)XUT's expression is associated with specific histone modification patterns. Finally, we showed that asXUTs are controlled by the histone chaperone Spt6 and respond to meiosis induction, in both cases anti-correlating with levels of the paired-sense mRNAs, supporting physiological significance to antisense-mediated gene attenuation. Our work highlights that antisense transcription is much more extended than anticipated and might constitute an additional nonpromoter determinant of gene regulation complexity. PMID- 29114020 TI - Identification of Novel Alleles Conferring Superior Production of Rose Flavor Phenylethyl Acetate Using Polygenic Analysis in Yeast. AB - Flavor compound metabolism is one of the last areas in metabolism where multiple genes encoding biosynthetic enzymes are still unknown. A major challenge is the involvement of side activities of enzymes having their main function in other areas of metabolism. We have applied pooled-segregant whole-genome sequence analysis to identify novel Saccharomyces cerevisiae genes affecting production of phenylethyl acetate (2-PEAc). This is a desirable flavor compound of major importance in alcoholic beverages imparting rose- and honey-like aromas, with production of high 2-PEAc levels considered a superior trait. Four quantitative trait loci (QTLs) responsible for high 2-PEAc production were identified, with two loci each showing linkage to the genomes of the BTC.1D and ER18 parents. The first two loci were investigated further. The causative genes were identified by reciprocal allele swapping into both parents using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9. The superior allele of the first major causative gene, FAS2, was dominant and contained two unique single nucleotide polymorphisms (SNPs) responsible for high 2-PEAc production that were not present in other sequenced yeast strains. FAS2 encodes the alpha subunit of the fatty acid synthetase complex. Surprisingly, the second causative gene was a mutant allele of TOR1, a gene involved in nitrogen regulation. Exchange of both superior alleles in the ER18 parent strain increased 2-PEAc production 70%, nearly to the same level as in the best superior segregant. Our results show that polygenic analysis combined with CRISPR/Cas9-mediated allele exchange is a powerful tool for identification of genes encoding missing metabolic enzymes and for development of industrial yeast strains generating novel flavor profiles in alcoholic beverages.IMPORTANCE Multiple reactions in flavor metabolism appear to be catalyzed by side activities of other enzymes that have been difficult to identify. We have applied genetic mapping of quantitative trait loci in the yeast Saccharomyces cerevisiae to identify mutant alleles of genes determining the production of phenylethyl acetate, an important flavor compound imparting rose- and honey-like aromas to alcoholic beverages. We identified a unique, dominant allele of FAS2 that supports high production of phenylethyl acetate. FAS2 encodes a subunit of the fatty acid synthetase complex and apparently exerts an important side activity on one or more alternative substrates in flavor compound synthesis. The second mutant allele contained a nonsense mutation in TOR1, a gene involved in nitrogen regulation of growth. Together the two alleles strongly increased the level of phenylethyl acetate. Our work highlights the potential of genetic mapping of quantitative phenotypic traits to identify novel enzymes and regulatory components in yeast metabolism, including regular metabolic enzymes with unknown side activities responsible for biosynthesis of specific flavor compounds. The superior alleles identified can be used to develop industrial yeast strains generating novel flavor profiles in alcoholic beverages. PMID- 29114021 TI - Imaging of Cellular Oxidoreductase Activity Suggests Mixotrophic Metabolisms in Thiomargarita spp. AB - The largest known bacteria, Thiomargarita spp., have yet to be isolated in pure culture, but their large size allows for individual cells to be monitored in time course experiments or to be individually sorted for omics-based investigations. Here we investigated the metabolism of individual cells of Thiomargarita spp. by using a novel application of a tetrazolium-based dye that measures oxidoreductase activity. When coupled with microscopy, staining of the cells with a tetrazolium formazan dye allows metabolic responses in Thiomargarita spp. to be to be tracked in the absence of observable cell division. Additionally, the metabolic activity of Thiomargarita sp. cells can be differentiated from the metabolism of other microbes in specimens that contain adherent bacteria. The results of our redox dye-based assay suggest that Thiomargarita is the most metabolically versatile under anoxic conditions, where it appears to express cellular oxidoreductase activity in response to the electron donors succinate, acetate, citrate, formate, thiosulfate, H2, and H2S. Under hypoxic conditions, formazan staining results suggest the metabolism of succinate and likely acetate, citrate, and H2S. Cells incubated under oxic conditions showed the weakest formazan staining response, and then only to H2S, citrate, and perhaps succinate. These results provide experimental validation of recent genomic studies of Candidatus Thiomargarita nelsonii that suggest metabolic plasticity and mixotrophic metabolism. The cellular oxidoreductase response of bacteria attached to the exterior of Thiomargarita also supports the possibility of trophic interactions between these largest of known bacteria and attached epibionts.IMPORTANCE The metabolic potential of many microorganisms that cannot be grown in the laboratory is known only from genomic data. Genomes of Thiomargarita spp. suggest that these largest of known bacteria are mixotrophs, combining lithotrophic metabolism with organic carbon degradation. Our use of a redox-sensitive tetrazolium dye to query the metabolism of these bacteria provides an independent line of evidence that corroborates the apparent metabolic plasticity of Thiomargarita observed in recently produced genomes. Finding new cultivation-independent means of testing genomic results is critical to testing genome-derived hypotheses on the metabolic potentials of uncultivated microorganisms. PMID- 29114023 TI - MCR-1 Inhibition with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Sensitivity to Polymyxin in Escherichia coli. AB - In late 2015, the first example of a transferrable polymyxin resistance mechanism in Gram-negative pathogens, MCR-1, was reported. Since that report, MCR-1 has been described to occur in many Gram-negative pathogens, and the mechanism of MCR 1-mediated resistance was rapidly determined: an ethanolamine is attached to lipid A phosphate groups, rendering the membrane more electropositive and repelling positively charged polymyxins. Acquisition of MCR-1 is clinically significant because polymyxins are frequently last-line antibiotics used to treat extensively resistant organisms, so acquisition of this mechanism might lead to pan-resistant strains. Therefore, the ability to inhibit MCR-1 and restore polymyxin sensitivity would be an important scientific advancement. Peptide conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense molecules that were designed to target mRNA, preventing translation. Peptide conjugation enhances cellular entry, but they are positively charged, so we tested our lead antibacterial PPMOs by targeting an essential Escherichia coli gene, acpP, and demonstrated that they were still effective in mcr-1-positive E. coli strains. We then designed and synthesized two PPMOs targeted to mcr-1 mRNA. Five clinical mcr-1-positive E. coli strains were resensitized to polymyxins by MCR-1 inhibition, reducing MICs 2- to 16-fold. Finally, therapeutic dosing of BALB/c mice with MCR-1 PPMO combined with colistin in a sepsis model reduced morbidity and bacterial burden in the spleen at 24 h and offered a survival advantage out to 5 days. This is the first example of a way to modulate colistin resistance with an antisense approach and may be a viable strategy to combat this globally emerging antibiotic resistance threat.IMPORTANCE Polymyxin use has been increasing as a last line of defense against Gram-negative pathogens with high level resistance mechanisms, such as carbapenemases. The recently described MCR-1 is a plasmid-mediated mechanism of resistance to polymyxins. MCR-1 is currently found in Gram-negative organisms already possessing high-level resistance mechanisms, leaving clinicians few or no antibacterial options for infections caused by these strains. This study utilizes antisense molecules that target mRNA, preventing protein translation. Herein we describe antisense molecules that can be directly antibacterial because they target genes essential to bacterial growth or blockade of MCR-1, restoring polymyxin sensitivity. We also demonstrate that MCR-1 antisense molecules restore the efficacies of polymyxins in mouse models of E. coli septicemia. Considering all things together, we demonstrate that antisense molecules may be effective therapeutics either alone when they target an essential gene or combined with antibiotics when they target specific resistance mechanisms, such as those seen with MCR-1. PMID- 29114022 TI - HupB Is a Bacterial Nucleoid-Associated Protein with an Indispensable Eukaryotic Like Tail. AB - In bacteria, chromosomal DNA must be efficiently compacted to fit inside the small cell compartment while remaining available for the proteins involved in replication, segregation, and transcription. Among the nucleoid-associated proteins (NAPs) responsible for maintaining this highly organized and yet dynamic chromosome structure, the HU protein is one of the most conserved and highly abundant. HupB, a homologue of HU, was recently identified in mycobacteria. This intriguing mycobacterial NAP is composed of two domains: an N-terminal domain that resembles bacterial HU, and a long and distinctive C-terminal domain that contains several PAKK/KAAK motifs, which are characteristic of the H1/H5 family of eukaryotic histones. In this study, we analyzed the in vivo binding of HupB on the chromosome scale. By using PALM (photoactivated localization microscopy) and ChIP-Seq (chromatin immunoprecipitation followed by deep sequencing), we observed that the C-terminal domain is indispensable for the association of HupB with the nucleoid. Strikingly, the in vivo binding of HupB displayed a bias from the origin (oriC) to the terminus (ter) of the mycobacterial chromosome (numbers of binding sites decreased toward ter). We hypothesized that this binding mode reflects a role for HupB in organizing newly replicated oriC regions. Thus, HupB may be involved in coordinating replication with chromosome segregation.IMPORTANCE We currently know little about the organization of the mycobacterial chromosome and its dynamics during the cell cycle. Among the mycobacterial nucleoid-associated proteins (NAPs) responsible for chromosome organization and dynamics, HupB is one of the most intriguing. It contains a long and distinctive C-terminal domain that harbors several PAKK/KAAK motifs, which are characteristic of the eukaryotic histone H1/H5 proteins. The HupB protein is also known to be crucial for the survival of tubercle bacilli during infection. Here, we provide in vivo experimental evidence showing that the C-terminal domain of HupB is crucial for its DNA binding. Our results suggest that HupB may be involved in organizing newly replicated regions and could help coordinate chromosome replication with segregation. Given that tuberculosis (TB) remains a serious worldwide health problem (10.4 million new TB cases were diagnosed in 2015, according to WHO) and new multidrug-resistant Mycobacterium tuberculosis strains are continually emerging, further studies of the biological function of HupB are needed to determine if this protein could be a prospect for novel antimicrobial drug development. PMID- 29114024 TI - Mechanisms of Surface Antigenic Variation in the Human Pathogenic Fungus Pneumocystis jirovecii. AB - Microbial pathogens commonly escape the human immune system by varying surface proteins. We investigated the mechanisms used for that purpose by Pneumocystis jirovecii This uncultivable fungus is an obligate pulmonary pathogen that in immunocompromised individuals causes pneumonia, a major life-threatening infection. Long-read PacBio sequencing was used to assemble a core of subtelomeres of a single P. jirovecii strain from a bronchoalveolar lavage fluid specimen from a single patient. A total of 113 genes encoding surface proteins were identified, including 28 pseudogenes. These genes formed a subtelomeric gene superfamily, which included five families encoding adhesive glycosylphosphatidylinositol (GPI)-anchored glycoproteins and one family encoding excreted glycoproteins. Numerical analyses suggested that diversification of the glycoproteins relies on mosaic genes created by ectopic recombination and occurs only within each family. DNA motifs suggested that all genes are expressed independently, except those of the family encoding the most abundant surface glycoproteins, which are subject to mutually exclusive expression. PCR analyses showed that exchange of the expressed gene of the latter family occurs frequently, possibly favored by the location of the genes proximal to the telomere because this allows concomitant telomere exchange. Our observations suggest that (i) the P. jirovecii cell surface is made of a complex mixture of different surface proteins, with a majority of a single isoform of the most abundant glycoprotein, (ii) genetic mosaicism within each family ensures variation of the glycoproteins, and (iii) the strategy of the fungus consists of the continuous production of new subpopulations composed of cells that are antigenically different.IMPORTANCEPneumocystis jirovecii is a fungus causing severe pneumonia in immunocompromised individuals. It is the second most frequent life-threatening invasive fungal infection. We have studied the mechanisms of antigenic variation used by this pathogen to escape the human immune system, a strategy commonly used by pathogenic microorganisms. Using a new DNA sequencing technology generating long reads, we could characterize the highly repetitive gene families encoding the proteins that are present on the cellular surface of this pest. These gene families are localized in the regions close to the ends of all chromosomes, the subtelomeres. Such chromosomal localization was found to favor genetic recombinations between members of each gene family and to allow diversification of these proteins continuously over time. This pathogen seems to use a strategy of antigenic variation consisting of the continuous production of new subpopulations composed of cells that are antigenically different. Such a strategy is unique among human pathogens. PMID- 29114025 TI - The NOX Family of Proteins Is Also Present in Bacteria. AB - Transmembrane NADPH oxidase (NOX) enzymes have been so far only characterized in eukaryotes. In most of these organisms, they reduce molecular oxygen to superoxide and, depending on the presence of additional domains, are called NOX or dual oxidases (DUOX). Reactive oxygen species (ROS), including superoxide, have been traditionally considered accidental toxic by-products of aerobic metabolism. However, during the last decade it has become evident that both O2*- and H2O2 are key players in complex signaling networks and defense. A well studied example is the production of O2*- during the bactericidal respiratory burst of phagocytes; this production is catalyzed by NOX2. Here, we devised and applied a novel algorithm to search for additional NOX genes in genomic databases. This procedure allowed us to discover approximately 23% new sequences from bacteria (in relation to the number of NOX-related sequences identified by the authors) that we have added to the existing eukaryotic NOX family and have used to build an expanded phylogenetic tree. We cloned and overexpressed the identified nox gene from Streptococcus pneumoniae and confirmed that it codes for an NADPH oxidase. The membrane of the S. pneumoniae NOX protein (SpNOX) shares many properties with its eukaryotic counterparts, such as affinity for NADPH and flavin adenine dinucleotide, superoxide dismutase and diphenylene iodonium inhibition, cyanide resistance, oxygen consumption, and superoxide production. Traditionally, NOX enzymes in eukaryotes are related to functions linked to multicellularity. Thus, the discovery of a large family of NOX-related enzymes in the bacterial world brings up fascinating questions regarding their role in this new biological context.IMPORTANCE NADPH oxidase (NOX) enzymes have not yet been reported in bacteria. Here, we carried out computational and experimental studies to provide the first characterization of a prokaryotic NOX. Out of 996 prokaryotic proteins showing NOX signatures, we initially selected, cloned, and overexpressed four of them. Subsequently, and based on preliminary testing, we concentrated our efforts on Streptococcus SpNOX, which shares many biochemical characteristics with NOX2, the referent model of NOX enzymes. Our work makes possible, for the first time, the study of pure forms of this important family of enzymes, allowing for biophysical and molecular characterization in an unprecedented way. Similar advances regarding other membrane protein families have led to new structures, further mechanistic studies, and the improvement of inhibitors. In addition, biological functions of these newly described bacterial enzymes will be certainly discovered in the near future. PMID- 29114026 TI - Proofreading-Deficient Coronaviruses Adapt for Increased Fitness over Long-Term Passage without Reversion of Exoribonuclease-Inactivating Mutations. AB - The coronavirus (CoV) RNA genome is the largest among the single-stranded positive-sense RNA viruses. CoVs encode a proofreading 3'-to-5' exoribonuclease within nonstructural protein 14 (nsp14-ExoN) that is responsible for CoV high fidelity replication. Alanine substitution of ExoN catalytic residues [ExoN(-)] in severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and murine hepatitis virus (MHV) disrupts ExoN activity, yielding viable mutant viruses with defective replication, up to 20-fold-decreased fidelity, and increased susceptibility to nucleoside analogues. To test the stability of the ExoN(-) genotype and phenotype, we passaged MHV-ExoN(-) 250 times in cultured cells (P250), in parallel with wild-type MHV (WT-MHV). Compared to MHV-ExoN(-) P3, MHV ExoN(-) P250 demonstrated enhanced replication and increased competitive fitness without reversion at the ExoN(-) active site. Furthermore, MHV-ExoN(-) P250 was less susceptible than MHV-ExoN(-) P3 to multiple nucleoside analogues, suggesting that MHV-ExoN(-) was under selection for increased replication fidelity. We subsequently identified novel amino acid changes within the RNA-dependent RNA polymerase and nsp14 of MHV-ExoN(-) P250 that partially accounted for the reduced susceptibility to nucleoside analogues. Our results suggest that increased replication fidelity is selected in ExoN(-) CoVs and that there may be a significant barrier to ExoN(-) reversion. These results also support the hypothesis that high-fidelity replication is linked to CoV fitness and indicate that multiple replicase proteins could compensate for ExoN functions during replication.IMPORTANCE Uniquely among RNA viruses, CoVs encode a proofreading exoribonuclease (ExoN) in nsp14 that mediates high-fidelity RNA genome replication. Proofreading-deficient CoVs with disrupted ExoN activity [ExoN(-)] either are nonviable or have significant defects in replication, RNA synthesis, fidelity, fitness, and virulence. In this study, we showed that ExoN(-) murine hepatitis virus can adapt during long-term passage for increased replication and fitness without reverting the ExoN-inactivating mutations. Passage-adapted ExoN( ) mutants also demonstrate increasing resistance to nucleoside analogues that is explained only partially by secondary mutations in nsp12 and nsp14. These data suggest that enhanced resistance to nucleoside analogues is mediated by the interplay of multiple replicase proteins and support the proposed link between CoV fidelity and fitness. PMID- 29114027 TI - An Alphavirus E2 Membrane-Proximal Domain Promotes Envelope Protein Lateral Interactions and Virus Budding. AB - Alphaviruses are members of a group of small enveloped RNA viruses that includes important human pathogens such as Chikungunya virus and the equine encephalitis viruses. The virus membrane is covered by a lattice composed of 80 spikes, each a trimer of heterodimers of the E2 and E1 transmembrane proteins. During virus endocytic entry, the E1 glycoprotein mediates the low-pH-dependent fusion of the virus membrane with the endosome membrane, thus initiating virus infection. While much is known about E1 structural rearrangements during membrane fusion, it is unclear how the E1/E2 dimer dissociates, a step required for the fusion reaction. A recent Alphavirus cryo-electron microscopy reconstruction revealed a previously unidentified D subdomain in the E2 ectodomain, close to the virus membrane. A loop within this region, here referred to as the D-loop, contains two highly conserved histidines, H348 and H352, which were hypothesized to play a role in dimer dissociation. We generated Semliki Forest virus mutants containing the single and double alanine substitutions H348A, H352A, and H348/352A. The three D loop mutations caused a reduction in virus growth ranging from 1.6 to 2 log but did not significantly affect structural protein biosynthesis or transport, dimer stability, virus fusion, or specific infectivity. Instead, growth reduction was due to inhibition of a late stage of virus assembly at the plasma membrane. The virus particles that are produced show reduced thermostability compared to the wild type. We propose the E2 D-loop as a key region in establishing the E1-E2 contacts that drive glycoprotein lattice formation and promote Alphavirus budding from the plasma membrane.IMPORTANCEAlphavirus infection causes severe and debilitating human diseases for which there are no effective antiviral therapies or vaccines. In order to develop targeted therapeutics, detailed molecular understanding of the viral entry and exit mechanisms is required. In this report, we define the role of the E2 protein juxtamembrane D-loop, which contains highly conserved histidine residues at positions 348 and 352. These histidines do not play an important role in virus fusion and infection. However, mutation of the D loop histidines causes significant decreases in the assembly and thermostability of Alphavirus particles. Our results suggest that the E2 D-loop interacts with the E1 protein to promote Alphavirus budding. PMID- 29114030 TI - Near-Cognate Codons Contribute Complexity to Translation Regulation. AB - The interplay between translation initiation, modification of translation initiation factors, and selection of start sites on mRNA for protein synthesis can play a regulatory role in the cellular response to stress, development, and cell fate in eukaryotic species by shaping the proteome. As shown by Ivanov et al. (mBio 8:e00844-17, 2017, https://doi.org/10.1128/mBio.00844-17), in the filamentous fungus Neurospora crassa, both upstream open reading frames (uORFs) and near-cognate start codons negatively or positively regulate the translation of the transcription factor CPC1 and production of CPC1 isoforms, which mediate the cellular response to amino acid starvation. Dissecting the physiological roles that differentiate cellular choice of translation initiation is an important parameter to understanding mechanisms that determine cell fate via gene regulation and protein synthesis. PMID- 29114028 TI - Dynamic Proteomics of Herpes Simplex Virus Infection. AB - The cellular response to viral infection is usually studied at the level of cell populations. Currently, it remains an open question whether and to what extent cell-to-cell variability impacts the course of infection. Here we address this by dynamic proteomics-imaging and tracking 400 yellow fluorescent protein (YFP) tagged host proteins in individual cells infected by herpes simplex virus 1. By quantifying time-lapse fluorescence imaging, we analyze how cell-to-cell variability impacts gene expression from the viral genome. We identify two proteins, RFX7 and geminin, whose levels at the time of infection correlate with successful initiation of gene expression. These proteins are cell cycle markers, and we find that the position in the cell cycle at the time of infection (along with the cell motility and local cell density) can reasonably predict in which individual cells gene expression from the viral genome will commence. We find that the onset of cell division dramatically impacts the progress of infection, with 70% of dividing cells showing no additional gene expression after mitosis. Last, we identify four host proteins that are specifically modulated in infected cells, of which only one has been previously recognized. SUMO2 and RPAP3 levels are rapidly reduced, while SLTM and YTHDC1 are redistributed to form nuclear foci. These modulations are dependent on the expression of ICP0, as shown by infection with two mutant viruses that lack ICP0. Taken together, our results provide experimental validation for the long-held notion that the success of infection is dependent on the state of the host cell at the time of infection.IMPORTANCE High-throughput assays have revolutionized many fields in biology, both by allowing a more global understanding of biological processes and by deciphering rare events in subpopulations. Here we use such an assay, dynamic proteomics, to study viral infection at the single-cell level. We follow tens of thousands of individual cells infected by herpes simplex virus using fluorescence live imaging. Our results link the state of a cell at the time of virus infection with its probability to successfully initiate gene expression from the viral genome. Further, we identified three cellular proteins that were previously unknown to respond to viral infection. We conclude that dynamic proteomics provides a powerful tool to study single-cell differences during viral infection. PMID- 29114029 TI - Rapid, Selection-Free, High-Efficiency Genome Editing in Protozoan Parasites Using CRISPR-Cas9 Ribonucleoproteins. AB - Trypanosomatids (order Kinetoplastida), including the human pathogens Trypanosoma cruzi (agent of Chagas disease), Trypanosoma brucei, (African sleeping sickness), and Leishmania (leishmaniasis), affect millions of people and animals globally. T. cruzi is considered one of the least studied and most poorly understood tropical disease-causing parasites, in part because of the relative lack of facile genetic engineering tools. This situation has improved recently through the application of clustered regularly interspaced short palindromic repeats CRISPR-associated protein 9 (CRISPR-Cas9) technology, but a number of limitations remain, including the toxicity of continuous Cas9 expression and the long drug marker selection times. In this study, we show that the delivery of ribonucleoprotein (RNP) complexes composed of recombinant Cas9 from Staphylococcus aureus (SaCas9), but not from the more routinely used Streptococcus pyogenes Cas9 (SpCas9), and in vitro-transcribed single guide RNAs (sgRNAs) results in rapid gene edits in T. cruzi and other kinetoplastids at frequencies approaching 100%. The highly efficient genome editing via SaCas9/sgRNA RNPs was obtained for both reporter and endogenous genes and observed in multiple parasite life cycle stages in various strains of T. cruzi, as well as in T. brucei and Leishmania major RNP complex delivery was also used to successfully tag proteins at endogenous loci and to assess the biological functions of essential genes. Thus, the use of SaCas9 RNP complexes for gene editing in kinetoplastids provides a simple, rapid, and cloning- and selection free method to assess gene function in these important human pathogens.IMPORTANCE Protozoan parasites remain some of the highest-impact human and animal pathogens, with very limited treatment and prevention options. The development of improved therapeutics and vaccines depends on a better understanding of the unique biology of these organisms, and understanding their biology, in turn, requires the ability to track and manipulate the products of genes. In this work, we describe new methods that are available to essentially any laboratory and applicable to any parasite isolate for easily and rapidly editing the genomes of kinetoplastid parasites. We demonstrate that these methods provide the means to quickly assess function, including that of the products of essential genes and potential targets of drugs, and to tag gene products at their endogenous loci. This is all achieved without gene cloning or drug selection. We expect this advance to enable investigations, especially in Trypanosoma cruzi and Leishmania spp., that have eluded investigators for decades. PMID- 29114031 TI - Different Substrate Preferences Help Closely Related Bacteria To Coexist in the Gut. AB - Many factors shape the ability of different microbes to coexist in microbial communities. In the human gut, dietary and host-derived nutrients largely drive microbial community structure. How gut microbes with very similar nutrient profiles are able to coexist over time within the same host is not fully understood. Tuncil et al. (mBio 8:e01068-17, 2017, https://doi.org/10.1128/mBio.01068-17) explored glycan prioritization in two closely related human gut bacteria, Bacteroides ovatus and Bacteroides thetaiotaomicron, on complex glycan mixtures that both organisms can degrade. Determining depletion of the individual glycans over time in pure cultures and cocultures revealed that the bacteria seem to have hardwired differences in their preferences for different glycans which likely contribute to their stable coexistence. The researchers also established that gene expression changes of the corresponding polysaccharide utilization loci did not always mirror glycan depletion, which highlights that additional regulatory mechanisms must be present. PMID- 29114032 TI - Alcohol consumption, smoking and development of visible age-related signs: a prospective cohort study. AB - BACKGROUND: Visible age-related signs indicate biological age, as individuals that appear old for their age are more likely to be at poor health, compared with people that appear their actual age. The aim of this study was to investigate whether alcohol and smoking are associated with four visible age-related signs (arcus corneae, xanthelasmata, earlobe crease and male pattern baldness). METHODS: We used information from 11 613 individuals in the Copenhagen City Heart Study (1976-2003). Alcohol intake, smoking habits and other lifestyle factors were assessed prospectively and visible age-related signs were inspected during subsequent examinations. RESULTS: The risk of developing arcus corneae, earlobe crease and xanthelasmata increased stepwise with increased smoking as measured by pack-years. For alcohol consumption, a high intake was associated with the risk of developing arcus corneae and earlobe crease, but not xanthelasmata. CONCLUSIONS: High alcohol consumption and smoking predict development of visible age-related signs. This is the first prospective study to show that heavy alcohol use and smoking are associated with generally looking older than one's actual age. PMID- 29114033 TI - Na leak with gating pore properties in hypokalemic periodic paralysis V876E mutant muscle Ca channel. AB - Type 1 hypokalemic periodic paralysis (HypoPP1) is a poorly understood genetic neuromuscular disease characterized by episodic attacks of paralysis associated with low blood K+ The vast majority of HypoPP1 mutations involve the replacement of an arginine by a neutral residue in one of the S4 segments of the alpha1 subunit of the skeletal muscle voltage-gated Ca2+ channel, which is thought to generate a pathogenic gating pore current. The V876E HypoPP1 mutation has the peculiarity of being located in the S3 segment of domain III, rather than an S4 segment, raising the question of whether such a mutation induces a gating pore current. Here we successfully transfer cDNAs encoding GFP-tagged human wild-type (WT) and V876E HypoPP1 mutant alpha1 subunits into mouse muscles by electroporation. The expression profile of these WT and V876E channels shows a regular striated pattern, indicative of their localization in the t-tubule membrane. In addition, L-type Ca2+ current properties are the same in V876E and WT fibers. However, in the presence of an external solution containing low-Cl- and lacking Na+ and K+, V876E fibers display an elevated leak current at negative voltages that is increased by external acidification to a higher extent in V876E fibers, suggesting that the leak current is carried by H+ ions. However, in the presence of Tyrode's solution, the rate of change in intracellular pH produced by external acidification was not significantly different in V876E and WT fibers. Simultaneous measurement of intracellular Na+ and current in response to Na+ readmission in the external solution reveals a rate of Na+ influx associated with an inward current, which are both significantly larger in V876E fibers. These data suggest that the V876E mutation generates a gating pore current that carries strong resting Na+ inward currents in physiological conditions that are likely responsible for the severe HypoPP1 symptoms associated with this mutation. PMID- 29114034 TI - Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding. AB - Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In such structures, the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A and B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed by segmental flexibility in the native state as probed by heteronuclear NMR spectroscopy and multiple conformer simulations of crystallographic protomers as described in the companion article. We propose a model of the SCI's IR-bound state based on molecular dynamics simulations of a micro-receptor complex. In this model, a loop defined by the SCI's B and C domains encircles the C-terminal segment of the IR alpha subunit. This binding mode predicts a conformational transition between an ultra stable closed state (in the free hormone) and an active open state (on receptor binding). Optimization of this switch within an ultra-stable SCI promises to circumvent insulin's complex global cold chain. The analog's biphasic activity, which serendipitously resembles current premixed formulations of soluble insulin and microcrystalline suspension, may be of particular utility in the developing world. PMID- 29114035 TI - An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein. AB - Thermal degradation of insulin complicates its delivery and use. Previous efforts to engineer ultra-stable analogs were confounded by prolonged cellular signaling in vivo, of unclear safety and complicating mealtime therapy. We therefore sought an ultra-stable analog whose potency and duration of action on intravenous bolus injection in diabetic rats are indistinguishable from wild-type (WT) insulin. Here, we describe the structure, function, and stability of such an analog, a 57 residue single-chain insulin (SCI) with multiple acidic substitutions. Cell-based studies revealed native-like signaling properties with negligible mitogenic activity. Its crystal structure, determined as a novel zinc-free hexamer at 2.8 A, revealed a native insulin fold with incomplete or absent electron density in the C domain; complementary NMR studies are described in the accompanying article. The stability of the analog (DeltaGU 5.0(+/-0.1) kcal/mol at 25 degrees C) was greater than that of WT insulin (3.3(+/-0.1) kcal/mol). On gentle agitation, the SCI retained full activity for >140 days at 45 degrees C and >48 h at 75 degrees C. These findings indicate that marked resistance to thermal inactivation in vitro is compatible with native duration of activity in vivo Further, whereas WT insulin forms large and heterogeneous aggregates above the standard 0.6 mm pharmaceutical strength, perturbing the pharmacokinetic properties of concentrated formulations, dynamic light scattering, and size exclusion chromatography revealed only limited SCI self-assembly and aggregation in the concentration range 1-7 mm Such a combination of favorable biophysical and biological properties suggests that SCIs could provide a global therapeutic platform without a cold chain. PMID- 29114036 TI - Zinc transporter 2 interacts with vacuolar ATPase and is required for polarization, vesicle acidification, and secretion in mammary epithelial cells. AB - An important feature of the mammary gland is its ability to undergo profound morphological, physiological, and intracellular changes to establish and maintain secretory function. During this process, key polarity proteins and receptors are recruited to the surface of mammary epithelial cells (MECs), and the vesicle transport system develops and matures. However, the intracellular mechanisms responsible for the development of secretory function in these cells are unclear. The vesicular zinc (Zn2+) transporter ZnT2 is critical for appropriate mammary gland architecture, and ZnT2 deletion is associated with cytoplasmic Zn2+ accumulation, loss of secretory function and lactation failure. The underlying mechanisms are important to understand as numerous mutations and non-synonymous genetic variation in ZnT2 have been detected in women that result in severe Zn2+ deficiency in exclusively breastfed infants. Here we found that ZnT2 deletion in lactating mice and cultured MECs resulted in Zn2+-mediated degradation of phosphatase and tensin homolog (PTEN), which impaired intercellular junction formation, prolactin receptor trafficking, and alveolar lumen development. Moreover, ZnT2 directly interacted with vacuolar H+-ATPase (V-ATPase), and ZnT2 deletion impaired vesicle biogenesis, acidification, trafficking, and secretion. In summary, our findings indicate that ZnT2 and V-ATPase interact and that this interaction critically mediates polarity establishment, alveolar development, and secretory function in the lactating mammary gland. Our observations implicate disruption in ZnT2 function as a modifier of secretory capacity and lactation performance. PMID- 29114038 TI - Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome. AB - Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene FMR1 on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition. We showed that aberrantly increased activity of the Rho GTPase Rac1 inhibited the actin-depolymerizing factor cofilin, a major determinant of dendritic spine structure, and caused disease-associated spine abnormalities in the somatosensory cortex of FXS model mice. Increased cofilin phosphorylation and actin polymerization coincided with abnormal dendritic spines and impaired synaptic maturation. Viral delivery of a constitutively active cofilin mutant (cofilinS3A) into the somatosensory cortex of Fmr1-deficient mice rescued the immature dendritic spine phenotype and increased spine density. Inhibition of the Rac1 effector PAK1 with a small molecule inhibitor rescued cofilin signaling in FXS mice, indicating a causal relationship between PAK1 and cofilin signaling. PAK1 inhibition rescued synaptic signaling (specifically the synaptic ratio of NMDA/AMPA in layer V pyramidal neurons) and improved sensory processing in FXS mice. These findings suggest a causal relationship between increased Rac1-cofilin signaling, synaptic defects, and impaired sensory processing in FXS and uncover a previously unappreciated role for impaired Rac1-cofilin signaling in the aberrant spine morphology and spine density associated with FXS. PMID- 29114037 TI - Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice. AB - Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP interacting protein 1 (CYFIP1), which subsequently sequesters and inhibits eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP-eIF4E complex and the Rac1-Wave regulatory complex, thereby connecting translational regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP. Treating FXS mice with 4EGI-1, which blocks interactions between eIF4E and eIF4G, a critical interaction partner for translational initiation, reversed defects in hippocampus-dependent memory and spine morphology. We also found that 4EGI-1 normalized the phenotypes of enhanced metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), enhanced Rac1-p21-activated kinase (PAK)-cofilin signaling, altered actin dynamics, and dysregulated CYFIP1/eIF4E and CYFIP1/Rac1 interactions in FXS mice. Our findings are consistent with the idea that an imbalance in protein synthesis and actin dynamics contributes to pathophysiology in FXS mice, and suggest that targeting eIF4E may be a strategy for treating FXS. PMID- 29114040 TI - Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function. AB - Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the in vivo expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the Srf gene was conditionally inactivated with NPHS2-Cre exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the Srf null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function. PMID- 29114039 TI - Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis. AB - Matrix metalloproteinase (MMP) functions modulate synapse formation and activity dependent plasticity. Aberrant MMP activity is implicated in fragile X syndrome (FXS), a disease caused by the loss of the RNA-binding protein FMRP and characterized by neurological dysfunction and intellectual disability. Gene expression studies in Drosophila suggest that Mmps cooperate with the heparan sulfate proteoglycan (HSPG) glypican co-receptor Dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling and that synaptogenic defects in the fly model of FXS are alleviated by either inhibition of Mmp or genetic reduction of Dlp. We used the Drosophila neuromuscular junction (NMJ) glutamatergic synapse to test activity-dependent Dlp and Mmp intersections in the context of FXS. We found that rapid, activity-dependent synaptic bouton formation depended on secreted Mmp1. Acute neuronal stimulation reduced the abundance of Mmp2 but increased that of both Mmp1 and Dlp, as well as enhanced the colocalization of Dlp and Mmp1 at the synapse. Dlp function promoted Mmp1 abundance, localization, and proteolytic activity around synapses. Dlp glycosaminoglycan (GAG) chains mediated this functional interaction with Mmp1. In the FXS fly model, activity-dependent increases in Mmp1 abundance and activity were lost but were restored by reducing the amount of synaptic Dlp. The data suggest that neuronal activity-induced, HSPG dependent Mmp regulation drives activity-dependent synaptogenesis and that this is impaired in FXS. Thus, exploring this mechanism further may reveal therapeutic targets that have the potential to restore synaptogenesis in FXS patients. PMID- 29114041 TI - Phospholipase A2 Receptor 1 Epitope Spreading at Baseline Predicts Reduced Likelihood of Remission of Membranous Nephropathy. AB - The phospholipase A2 receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab (n=29) or antiproteinuric therapy alone (n=29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer (P<0.001). Ten (58.8%) of the 17 patients who had epitope spreading at baseline and were treated with rituximab showed reversal of epitope spreading at month 6. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.72; P=0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P=0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy. PMID- 29114042 TI - Deletion Variants of CFHR1 and CFHR3 Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy. AB - Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H-related genes 1 and 3 (CFHR3,1Delta) is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their CFHR3,1Delta genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of CFHR3 and CFHR1 gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients' medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for CFHR3,1Delta We did not detect an association between CFHR3,1Delta and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, CFHR3,1Delta did not associate with progression to stage 3 CKD or renal death. In conclusion, the CFHR3,1Delta genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits. PMID- 29114043 TI - Subplate neurons are the first cortical neurons to respond to sensory stimuli. AB - In utero experience, such as maternal speech in humans, can shape later perception, although the underlying cortical substrate is unknown. In adult mammals, ascending thalamocortical projections target layer 4, and the onset of sensory responses in the cortex is thought to be dependent on the onset of thalamocortical transmission to layer 4 as well as the ear and eye opening. In developing animals, thalamic fibers do not target layer 4 but instead target subplate neurons deep in the developing white matter. We investigated if subplate neurons respond to sensory stimuli. Using electrophysiological recordings in young ferrets, we show that auditory cortex neurons respond to sound at very young ages, even before the opening of the ears. Single unit recordings showed that auditory responses emerged first in cortical subplate neurons. Subsequently, responses appeared in the future thalamocortical input layer 4, and sound-evoked spike latencies were longer in layer 4 than in subplate, consistent with the known relay of thalamic information to layer 4 by subplate neurons. Electrode array recordings show that early auditory responses demonstrate a nascent topographic organization, suggesting that topographic maps emerge before the onset of spiking responses in layer 4. Together our results show that sound evoked activity and topographic organization of the cortex emerge earlier and in a different layer than previously thought. Thus, early sound experience can activate and potentially sculpt subplate circuits before permanent thalamocortical circuits to layer 4 are present, and disruption of this early sensory activity could be utilized for early diagnosis of developmental disorders. PMID- 29114044 TI - Epigenetic switch turns on genetic behavioral variations. PMID- 29114045 TI - Haplotype resolution at the single-cell level. PMID- 29114046 TI - Pulsed evolution shaped modern vertebrate body sizes. AB - The relative importance of different modes of evolution in shaping phenotypic diversity remains a hotly debated question. Fossil data suggest that stasis may be a common mode of evolution, while modern data suggest some lineages experience very fast rates of evolution. One way to reconcile these observations is to imagine that evolution proceeds in pulses, rather than in increments, on geological timescales. To test this hypothesis, we developed a maximum-likelihood framework for fitting Levy processes to comparative morphological data. This class of stochastic processes includes both an incremental and a pulsed component. We found that a plurality of modern vertebrate clades examined are best fitted by pulsed processes over models of incremental change, stationarity, and adaptive radiation. When we compare our results to theoretical expectations of the rate and speed of regime shifts for models that detail fitness landscape dynamics, we find that our quantitative results are broadly compatible with both microevolutionary models and observations from the fossil record. PMID- 29114047 TI - Prebiotic phosphorylation enabled by microdroplets. PMID- 29114048 TI - New free-exchange model of EmrE transport. AB - EmrE is a small multidrug resistance transporter found in Escherichia coli that confers resistance to toxic polyaromatic cations due to its proton-coupled antiport of these substrates. Here we show that EmrE breaks the rules generally deemed essential for coupled antiport. NMR spectra reveal that EmrE can simultaneously bind and cotransport proton and drug. The functional consequence of this finding is an exceptionally promiscuous transporter: not only can EmrE export diverse drug substrates, it can couple antiport of a drug to either one or two protons, performing both electrogenic and electroneutral transport of a single substrate. We present a free-exchange model for EmrE antiport that is consistent with these results and recapitulates ?pH-driven concentrative drug uptake. Kinetic modeling suggests that free exchange by EmrE sacrifices coupling efficiency but boosts initial transport speed and drug release rate, which may facilitate efficient multidrug efflux. PMID- 29114049 TI - High-temperature charge density wave correlations in La1.875Ba0.125CuO4 without spin-charge locking. AB - Although all superconducting cuprates display charge-ordering tendencies, their low-temperature properties are distinct, impeding efforts to understand the phenomena within a single conceptual framework. While some systems exhibit stripes of charge and spin, with a locked periodicity, others host charge density waves (CDWs) without any obviously related spin order. Here we use resonant inelastic X-ray scattering to follow the evolution of charge correlations in the canonical stripe-ordered cuprate La1.875Ba0.125CuO4 across its ordering transition. We find that high-temperature charge correlations are unlocked from the wavevector of the spin correlations, signaling analogies to CDW phases in various other cuprates. This indicates that stripe order at low temperatures is stabilized by the coupling of otherwise independent charge and spin density waves, with important implications for the relation between charge and spin correlations in the cuprates. PMID- 29114050 TI - Structure and function of yeast Atg20, a sorting nexin that facilitates autophagy induction. AB - The Atg20 and Snx4/Atg24 proteins have been identified in a screen for mutants defective in a type of selective macroautophagy/autophagy. Both proteins are connected to the Atg1 kinase complex, which is involved in autophagy initiation, and bind phosphatidylinositol-3-phosphate. Atg20 and Snx4 contain putative BAR domains, suggesting a possible role in membrane deformation, but they have been relatively uncharacterized. Here we demonstrate that, in addition to its function in selective autophagy, Atg20 plays a critical role in the efficient induction of nonselective autophagy. Atg20 is a dynamic posttranslationally modified protein that engages both structurally stable (PX and BAR) and intrinsically disordered domains for its function. In addition to its PX and BAR domains, Atg20 uses a third membrane-binding module, a membrane-inducible amphipathic helix present in a previously undescribed location in Atg20 within the putative BAR domain. Taken together, these findings yield insights into the molecular mechanism of the autophagy machinery. PMID- 29114051 TI - DSCAM-mediated control of dendritic and axonal arbor outgrowth enforces tiling and inhibits synaptic plasticity. AB - Mature mammalian neurons have a limited ability to extend neurites and make new synaptic connections, but the mechanisms that inhibit such plasticity remain poorly understood. Here, we report that OFF-type retinal bipolar cells in mice are an exception to this rule, as they form new anatomical connections within their tiled dendritic fields well after retinal maturity. The Down syndrome cell adhesion molecule (Dscam) confines these anatomical rearrangements within the normal tiled fields, as conditional deletion of the gene permits extension of dendrite and axon arbors beyond these borders. Dscam deletion in the mature retina results in expanded dendritic fields and increased cone photoreceptor contacts, demonstrating that DSCAM actively inhibits circuit-level plasticity. Electrophysiological recordings from Dscam-/- OFF bipolar cells showed enlarged visual receptive fields, demonstrating that expanded dendritic territories comprise functional synapses. Our results identify cell-adhesion molecule mediated inhibition as a regulator of circuit-level neuronal plasticity in the adult retina. PMID- 29114053 TI - Cell-to-cell variation sets a tissue-rheology-dependent bound on collective gradient sensing. AB - When a single cell senses a chemical gradient and chemotaxes, stochastic receptor ligand binding can be a fundamental limit to the cell's accuracy. For clusters of cells responding to gradients, however, there is a critical difference: Even genetically identical cells have differing responses to chemical signals. With theory and simulation, we show collective chemotaxis is limited by cell-to-cell variation in signaling. We find that when different cells cooperate, the resulting bias can be much larger than the effects of ligand-receptor binding. Specifically, when a strongly responding cell is at one end of a cell cluster, cluster motion is biased toward that cell. These errors are mitigated if clusters average measurements over times long enough for cells to rearrange. In consequence, fluid clusters are better able to sense gradients: We derive a link between cluster accuracy, cell-to-cell variation, and the cluster rheology. Because of this connection, increasing the noisiness of individual cell motion can actually increase the collective accuracy of a cluster by improving fluidity. PMID- 29114052 TI - DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line. AB - Meiotic synapsis and recombination between homologs permits the formation of cross-overs that are essential for generating chromosomally balanced sperm and eggs. In mammals, surveillance mechanisms eliminate meiotic cells with defective synapsis, thereby minimizing transmission of aneuploidy. One such surveillance mechanism is meiotic silencing, the inactivation of genes located on asynapsed chromosomes, via ATR-dependent serine-139 phosphorylation of histone H2AFX (gammaH2AFX). Stimulation of ATR activity requires direct interaction with an ATR activation domain (AAD)-containing partner. However, which partner facilitates the meiotic silencing properties of ATR is unknown. Focusing on the best characterized example of meiotic silencing, meiotic sex chromosome inactivation, we reveal this AAD-containing partner to be the DNA damage and checkpoint protein TOPBP1. Conditional TOPBP1 deletion during pachynema causes germ cell elimination associated with defective X chromosome gene silencing and sex chromosome condensation. TOPBP1 is essential for localization to the X chromosome of silencing "sensors," including BRCA1, and effectors, including ATR, gammaH2AFX, and canonical repressive histone marks. We present evidence that persistent DNA double-strand breaks act as silencing initiation sites. Our study identifies TOPBP1 as a critical factor in meiotic sex chromosome silencing. PMID- 29114054 TI - Three-dimensional visualization and a deep-learning model reveal complex fungal parasite networks in behaviorally manipulated ants. AB - Some microbes possess the ability to adaptively manipulate host behavior. To better understand how such microbial parasites control animal behavior, we examine the cell-level interactions between the species-specific fungal parasite Ophiocordyceps unilateralis sensu lato and its carpenter ant host (Camponotus castaneus) at a crucial moment in the parasite's lifecycle: when the manipulated host fixes itself permanently to a substrate by its mandibles. The fungus is known to secrete tissue-specific metabolites and cause changes in host gene expression as well as atrophy in the mandible muscles of its ant host, but it is unknown how the fungus coordinates these effects to manipulate its host's behavior. In this study, we combine techniques in serial block-face scanning electron microscopy and deep-learning-based image segmentation algorithms to visualize the distribution, abundance, and interactions of this fungus inside the body of its manipulated host. Fungal cells were found throughout the host body but not in the brain, implying that behavioral control of the animal body by this microbe occurs peripherally. Additionally, fungal cells invaded host muscle fibers and joined together to form networks that encircled the muscles. These networks may represent a collective foraging behavior of this parasite, which may in turn facilitate host manipulation. PMID- 29114056 TI - Incremental heating of Bishop Tuff sanidine reveals preeruptive radiogenic Ar and rapid remobilization from cold storage. AB - Accurate and precise ages of large silicic eruptions are critical to calibrating the geologic timescale and gauging the tempo of changes in climate, biologic evolution, and magmatic processes throughout Earth history. The conventional approach to dating these eruptive products using the 40Ar/39Ar method is to fuse dozens of individual feldspar crystals. However, dispersion of fusion dates is common and interpretation is complicated by increasingly precise data obtained via multicollector mass spectrometry. Incremental heating of 49 individual Bishop Tuff (BT) sanidine crystals produces 40Ar/39Ar dates with reduced dispersion, yet we find a 16-ky range of plateau dates that is not attributable to excess Ar. We interpret this dispersion to reflect cooling of the magma reservoir margins below ~475 degrees C, accumulation of radiogenic Ar, and rapid preeruption remobilization. Accordingly, these data elucidate the recycling of subsolidus material into voluminous rhyolite magma reservoirs and the effect of preeruptive magmatic processes on the 40Ar/39Ar system. The youngest sanidine dates, likely the most representative of the BT eruption age, yield a weighted mean of 764.8 +/ 0.3/0.6 ka (2sigma analytical/full uncertainty) indicating eruption only ~7 ky following the Matuyama-Brunhes magnetic polarity reversal. Single-crystal incremental heating provides leverage with which to interpret complex populations of 40Ar/39Ar sanidine and U-Pb zircon dates and a substantially improved capability to resolve the timing and causal relationship of events in the geologic record. PMID- 29114055 TI - Immature HIV-1 lattice assembly dynamics are regulated by scaffolding from nucleic acid and the plasma membrane. AB - The packaging and budding of Gag polyprotein and viral RNA is a critical step in the HIV-1 life cycle. High-resolution structures of the Gag polyprotein have revealed that the capsid (CA) and spacer peptide 1 (SP1) domains contain important interfaces for Gag self-assembly. However, the molecular details of the multimerization process, especially in the presence of RNA and the cell membrane, have remained unclear. In this work, we investigate the mechanisms that work in concert between the polyproteins, RNA, and membrane to promote immature lattice growth. We develop a coarse-grained (CG) computational model that is derived from subnanometer resolution structural data. Our simulations recapitulate contiguous and hexameric lattice assembly driven only by weak anisotropic attractions at the helical CA-SP1 junction. Importantly, analysis from CG and single-particle tracking photoactivated localization (spt-PALM) trajectories indicates that viral RNA and the membrane are critical constituents that actively promote Gag multimerization through scaffolding, while overexpression of short competitor RNA can suppress assembly. We also find that the CA amino-terminal domain imparts intrinsic curvature to the Gag lattice. As a consequence, immature lattice growth appears to be coupled to the dynamics of spontaneous membrane deformation. Our findings elucidate a simple network of interactions that regulate the early stages of HIV-1 assembly and budding. PMID- 29114057 TI - Directed evolution of SecB chaperones toward toxin-antitoxin systems. AB - SecB chaperones assist protein export in bacteria. However, certain SecB family members have diverged to become specialized toward the control of toxin-antitoxin (TA) systems known to promote bacterial adaptation to stress and persistence. In such tripartite TA-chaperone (TAC) systems, the chaperone was shown to assist folding and to prevent degradation of its cognate antitoxin, thus facilitating inhibition of the toxin. Here, we used both the export chaperone SecB of Escherichia coli and the tripartite TAC system of Mycobacterium tuberculosis as a model to investigate how generic chaperones can specialize toward the control of TA systems. Through directed evolution of SecB, we have identified and characterized mutations that specifically improve the ability of SecB to control our model TA system without affecting its function in protein export. Such a remarkable plasticity of SecB chaperone function suggests that its substrate binding surface can be readily remodeled to accommodate specific clients. PMID- 29114058 TI - Filament rigidity and connectivity tune the deformation modes of active biopolymer networks. AB - Molecular motors embedded within collections of actin and microtubule filaments underlie the dynamics of cytoskeletal assemblies. Understanding the physics of such motor-filament materials is critical to developing a physical model of the cytoskeleton and designing biomimetic active materials. Here, we demonstrate through experiments and simulations that the rigidity and connectivity of filaments in active biopolymer networks regulates the anisotropy and the length scale of the underlying deformations, yielding materials with variable contractility. We find that semiflexible filaments can be compressed and bent by motor stresses, yielding materials that undergo predominantly biaxial deformations. By contrast, rigid filament bundles slide without bending under motor stress, yielding materials that undergo predominantly uniaxial deformations. Networks dominated by biaxial deformations are robustly contractile over a wide range of connectivities, while networks dominated by uniaxial deformations can be tuned from extensile to contractile through cross-linking. These results identify physical parameters that control the forces generated within motor-filament arrays and provide insight into the self-organization and mechanics of cytoskeletal assemblies. PMID- 29114060 TI - Ethics Rounds: Death After Pediatric Dental Anesthesia: An Avoidable Tragedy? AB - Early childhood caries (ECC) is the single most common chronic childhood disease. In the treatment of ECC, children are often given moderate sedation or general anesthesia. An estimated 100 000 to 250 000 pediatric dental sedations are performed annually in the United States. The most common medications are benzodiazepines, opioids, local anesthetics, and nitrous oxide. All are associated with serious adverse events, including hypoxemia, respiratory depression, airway obstruction, and death. There is no mandated reporting of adverse events or deaths, so we don't know how often these occur. In this article, we present a case of a death after dental anesthesia and ask experts to speculate on how to improve the quality and safety of both the prevention and treatment of ECC. PMID- 29114059 TI - Effect of naturally occurring Wolbachia in Anopheles gambiae s.l. mosquitoes from Mali on Plasmodium falciparum malaria transmission. AB - A naturally occurring Wolbachia strain (wAnga-Mali) was identified in mosquitoes of the Anopheles gambiae complex collected in the Malian villages of Dangassa and Kenieroba. Phylogenetic analysis of the nucleotide sequence of two 16S rRNA regions showed that wAnga-Mali clusters with Wolbachia strains from supergroup A and has the highest homology to a Wolbachia strain isolated from cat fleas (Ctenocephalides). wAnga-Mali is different from two Wolbachia strains previously reported in A. gambiae from Burkina Faso (wAnga_VK5_STP and wAnga_VK5_3.1a). Quantitative analysis of Wolbachia and Plasmodium sporozoite infection in field collected mosquitoes indicates that the prevalence and intensity of Plasmodium falciparum sporozoite infection is significantly lower in Wolbachia-infected females. The presence of Wolbachia in females from a laboratory Anopheles coluzzii (A. gambiae, M form) colony experimentally infected with P. falciparum (NF54 strain) gametocyte cultures slightly enhanced oocyst infection. However, Wolbachia infection significantly reduced the prevalence and intensity of sporozoite infection, as observed in the field. This indicates that wAnga-Mali infection does not limit early stages of Plasmodium infection in the mosquito, but it has a strong deleterious effect on sporozoites and reduces malaria transmission. PMID- 29114061 TI - Mental Health Screening Quality Improvement Learning Collaborative in Pediatric Primary Care. AB - BACKGROUND: In the United States, up to 20% of children experience a mental health (MH) disorder in a given year, many of whom remain untreated. Routine screening during annual well visits is 1 strategy providers can use to identify concerns early and facilitate appropriate intervention. However, many barriers exist to the effective implementation of such screening. METHODS: A 15-month quality improvement learning collaborative was designed and implemented to improve screening practices in primary care. Participating practices completed a survey at 3 time points to assess preparedness and ability to promote and support MH issues. Monthly chart reviews were performed to assess the rates of screening at well visits, documentation of screening results, and appropriate coding practices. RESULTS: Ten practices (including 107 providers) were active participants for the duration of the project. Screening rates increased from 1% at baseline to 74% by the end of the project. For the 1 practice for which more comprehensive data were available, these screening rates were sustained over time. Documentation of results and appropriate billing for reimbursement mirrored the improvement seen in screening rates. CONCLUSIONS: The learning collaborative model can improve MH screening practices in pediatric primary care, an important first step toward early identification of children with concerns. More information is needed about the burden placed on practices and providers to implement these changes. Future research will be needed to determine if improved identification leads to improved access to care and outcomes. PMID- 29114062 TI - An Interdisciplinary Approach to Toxic Stress: Learning the Lingo. PMID- 29114063 TI - Growth Tracking in Severely Obese or Underweight Children. AB - OBJECTIVES: To illustrate the difficulties in optimal growth monitoring of children with severe obesity or underweight by using the Centers for Disease Control and Prevention (CDC) 2000 age- and sex-specific BMI percentile growth charts. We also aimed to examine the utility of a new modified CDC BMI z score chart to monitor growth in children with normal and extreme BMI percentiles by using real-life clinical scenarios. METHODS: Modified BMI z score charts were created by using the 2000 CDC algorithm. Three cases of children with extreme BMI values and abnormal growth patterns were plotted by using the standard CDC 2000 clinical growth chart, the modified BMI z score chart, and the CDC BMI percentile chart, modified to include the percentage of the 95th percentile (%BMIp95) curves. RESULTS: Children with severe obesity could not be plotted on the standard CDC BMI percentile chart because their BMI points lay above the chart cutoff. Children with a low BMI (<3%) were also difficult to track on the standard BMI percentile chart. The addition of the %BMIp95 scale to the standard BMI percentile chart allowed tracking of severely obese children; however, it did not address severely underweight children and required a change of units within the chart when transitioning from normal to obese BMIs. The modified BMI z score chart allowed uniform tracking. CONCLUSIONS: The modified CDC z score chart is suitable for growth tracking of children with normal and extreme growth patterns; the measures correlate well with the %BMIp95, and the chart can be incorporated easily into existing electronic health record systems for clinical use. PMID- 29114064 TI - SORLA attenuates EphA4 signaling and amyloid beta-induced neurodegeneration. AB - Sortilin-related receptor with LDLR class A repeats (SORLA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer's disease (AD). Although SORLA is known to regulate trafficking of the amyloid beta (Abeta) precursor protein to decrease levels of proteotoxic Abeta oligomers, whether SORLA can counteract synaptic dysfunction induced by Abeta oligomers remains unclear. Here, we show that SORLA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand-induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons. Consistent with these findings, SORLA transgenic mice, compared with WT mice, exhibit decreased EphA4 activation and redistribution to postsynaptic densities, with milder deficits in long-term potentiation and memory induced by Abeta oligomers. Importantly, we detected elevated levels of active EphA4 in human AD brains, where EphA4 activation is inversely correlated with SORLA/EphA4 association. These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with Abeta-induced neurodegeneration in AD. PMID- 29114065 TI - Bim suppresses the development of SLE by limiting myeloid inflammatory responses. AB - The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)-like disease that mirrors aged Bim-/- mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-beta) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE. PMID- 29114066 TI - Senescence and aging: Causes, consequences, and therapeutic avenues. AB - Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression. However, senescence has also been implicated as a major cause of age-related disease. In this regard, recent experimental evidence has shown that the genetic or pharmacological ablation of senescent cells extends life span and improves health span. Here, we review the cellular and molecular links between cellular senescence and aging and discuss the novel therapeutic avenues that this connection opens. PMID- 29114068 TI - Receptor tyrosine kinase activation of RhoA is mediated by AKT phosphorylation of DLC1. AB - We report several receptor tyrosine kinase (RTK) ligands increase RhoA-guanosine triphosphate (GTP) in untransformed and transformed cell lines and determine this phenomenon depends on the RTKs activating the AKT serine/threonine kinase. The increased RhoA-GTP results from AKT phosphorylating three serines (S298, S329, and S567) in the DLC1 tumor suppressor, a Rho GTPase-activating protein (RhoGAP) associated with focal adhesions. Phosphorylation of the serines, located N terminal to the DLC1 RhoGAP domain, induces strong binding of that N-terminal region to the RhoGAP domain, converting DLC1 from an open, active dimer to a closed, inactive monomer. That binding, which interferes with the interaction of RhoA-GTP with the RhoGAP domain, reduces the hydrolysis of RhoA-GTP, the binding of other DLC1 ligands, and the colocalization of DLC1 with focal adhesions and attenuates tumor suppressor activity. DLC1 is a critical AKT target in DLC1 positive cancer because AKT inhibition has potent antitumor activity in the DLC1 positive transgenic cancer model and in a DLC1-positive cancer cell line but not in an isogenic DLC1-negative cell line. PMID- 29114067 TI - Regulation and dysregulation of axon infrastructure by myelinating glia. AB - Axon loss and neurodegeneration constitute clinically debilitating sequelae in demyelinating diseases such as multiple sclerosis, but the underlying mechanisms of secondary degeneration are not well understood. Myelinating glia play a fundamental role in promoting the maturation of the axon cytoskeleton, regulating axon trafficking parameters, and imposing architectural rearrangements such as the nodes of Ranvier and their associated molecular domains. In the setting of demyelination, these changes may be reversed or persist as maladaptive features, leading to axon degeneration. In this review, we consider recent insights into axon-glial interactions during development and disease to propose that disruption of the cytoskeleton, nodal architecture, and other components of axon infrastructure is a potential mediator of pathophysiological damage after demyelination. PMID- 29114069 TI - BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells. AB - Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents. PMID- 29114070 TI - SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer. AB - OBJECTIVE: To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6. DESIGN: We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA approved drugs and its antitumour effects were evaluated in vitroand in vivo. RESULTS: SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a beta2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity. CONCLUSIONS: SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6. ACCESSION NUMBERS: The accession numbers for sequencing data are SRP111763 and SRP111797. PMID- 29114071 TI - Working Memory and Decision-Making in a Frontoparietal Circuit Model. AB - Working memory (WM) and decision-making (DM) are fundamental cognitive functions involving a distributed interacting network of brain areas, with the posterior parietal cortex (PPC) and prefrontal cortex (PFC) at the core. However, the shared and distinct roles of these areas and the nature of their coordination in cognitive function remain poorly understood. Biophysically based computational models of cortical circuits have provided insights into the mechanisms supporting these functions, yet they have primarily focused on the local microcircuit level, raising questions about the principles for distributed cognitive computation in multiregional networks. To examine these issues, we developed a distributed circuit model of two reciprocally interacting modules representing PPC and PFC circuits. The circuit architecture includes hierarchical differences in local recurrent structure and implements reciprocal long-range projections. This parsimonious model captures a range of behavioral and neuronal features of frontoparietal circuits across multiple WM and DM paradigms. In the context of WM, both areas exhibit persistent activity, but, in response to intervening distractors, PPC transiently encodes distractors while PFC filters distractors and supports WM robustness. With regard to DM, the PPC module generates graded representations of accumulated evidence supporting target selection, while the PFC module generates more categorical responses related to action or choice. These findings suggest computational principles for distributed, hierarchical processing in cortex during cognitive function and provide a framework for extension to multiregional models.SIGNIFICANCE STATEMENT Working memory and decision-making are fundamental "building blocks" of cognition, and deficits in these functions are associated with neuropsychiatric disorders such as schizophrenia. These cognitive functions engage distributed networks with prefrontal cortex (PFC) and posterior parietal cortex (PPC) at the core. It is not clear, however, what the contributions of PPC and PFC are in light of the computations that subserve working memory and decision-making. We constructed a biophysical model of a reciprocally connected frontoparietal circuit that revealed shared and distinct functions for the PFC and PPC across working memory and decision-making tasks. Our parsimonious model connects circuit-level properties to cognitive functions and suggests novel design principles beyond those of local circuits for cognitive processing in multiregional brain networks. PMID- 29114072 TI - Neural Representations of Hierarchical Rule Sets: The Human Control System Represents Rules Irrespective of the Hierarchical Level to Which They Belong. AB - Humans use rules to organize their actions to achieve specific goals. Although simple rules that link a sensory stimulus to one response may suffice in some situations, often, the application of multiple, hierarchically organized rules is required. Recent theories suggest that progressively higher level rules are encoded along an anterior-to-posterior gradient within PFC. Although some evidence supports the existence of such a functional gradient, other studies argue for a lesser degree of specialization within PFC. We used fMRI to investigate whether rules at different hierarchical levels are represented at distinct locations in the brain or encoded by a single system. Thirty-seven male and female participants represented and applied hierarchical rule sets containing one lower-level stimulus-response rule and one higher-level selection rule. We used multivariate pattern analysis to investigate directly the representation of rules at each hierarchical level in absence of information about rules from other levels or other task-related information, thus providing a clear identification of low- and high-level rule representations. We could decode low- and high-level rules from local patterns of brain activity within a wide frontoparietal network. However, no significant difference existed between regions encoding representations of rules from both levels except for precentral gyrus, which represented only low-level rule information. Our findings show that the brain represents conditional rules regardless of their level in the explored hierarchy, so the human control system did not organize task representation according to this dimension. Our paradigm represents a promising approach to identifying critical principles that shape this control system.SIGNIFICANCE STATEMENT Several recent studies investigating the organization of the human control system propose that rules at different control levels are organized along an anterior-to posterior gradient within PFC. In this study, we used multivariate pattern analysis to explore independently the representation of formally identical conditional rules belonging to different levels of a cognitive hierarchy and provide for the first time a clear identification of low- and high-level rule representations. We found no major spatial differences between regions encoding rules from different hierarchical levels. This suggests that the human brain does not use levels in the investigated hierarchy as a topographical organization principle to represent rules controlling our behavior. Our paradigm represents a promising approach to identifying which principles are critical. PMID- 29114073 TI - Cellular and Molecular Analysis of Dendritic Morphogenesis in a Retinal Cell Type That Senses Color Contrast and Ventral Motion. AB - As neuronal dendrites develop, they acquire cell-type-specific features including characteristic size, shape, arborization, location and synaptic patterns. These features, in turn, are major determinants of type-specific neuronal function. Because neuronal diversity complicates the task of relating developmental programs to adult structure and function, we analyzed dendritic morphogenesis in a single retinal ganglion cell (RGC) type in mouse called J-RGC. We documented the emergence of five dendritic features that underlie J-RGC physiology: (1) dendritic field size, which approximate receptive field size; (2) dendritic complexity, which affects how J-RGCs sample space; (3) asymmetry, which contributes to direction-selectivity; (4) restricted lamination within the inner plexiform layer (IPL), which renders J-RGCs responsive to light decrements; and (5) distribution of synaptic inputs, which generate a color-opponent receptive field. We found dendritic growth in J-RGCs is accompanied by a refinement in dendritic self-crossing. Asymmetry arises by a combination of selective pruning and elaboration, whereas laminar restriction results from biased outgrowth toward the outermost IPL. Interestingly, asymmetry develops in a protracted dorsoventral wave, whereas lamination does so in a rapid centrifugal wave. As arbors mature, they acquire excitatory and inhibitory synapses, with the latter forming first and being concentrated in proximal dendrites. Thus, distinct mechanisms operate in different spatiotemporal dimensions of J-RGC dendritic patterning to generate the substrate for specific patterns of synaptogenesis. Finally, we asked whether the defining molecular signature of J-RGCs, the adhesion molecule JAM-B, regulates morphogenesis, and showed that it promotes dendro-dendritic interactions. Our results reveal multiple mechanisms that shape a dendritic arbor.SIGNIFICANCE STATEMENT Visual perception begins in the retina, where distinct types of retinal ganglion cells (RGCs) are tuned to specific visual features such as direction of motion. The features to which each RGC type responds are determined largely by the number and type of synaptic inputs it receives, and these, in turn, are greatly influenced by the size, shape, arborization pattern, and location of its dendrites. We analyzed dendritic morphogenesis in a functionally characterized RGC type, the J-RGC, demonstrating distinct mechanisms that operate in different dimensions to generate the dendritic scaffold and synaptic patterns for feature detection. Our work elucidates cellular and molecular mechanisms that shape dendritic arbors and synaptic distribution, enabling J-RGC connectivity and thus, function. PMID- 29114075 TI - Interlayer Repulsion of Retinal Ganglion Cell Mosaics Regulates Spatial Organization of Functional Maps in the Visual Cortex. AB - In higher mammals, orientation tuning of neurons is organized into a quasi periodic pattern in the primary visual cortex. Our previous model studies suggested that the topography of cortical orientation maps may originate from moire interference of ON and OFF retinal ganglion cell (RGC) mosaics, but did not account for how the consistent spatial period of maps could be achieved. Here we address this issue with two crucial findings on the development of RGC mosaics: first, homotypic local repulsion between RGCs can develop a long-range hexagonal periodicity. Second, heterotypic interaction restrains the alignment of ON and OFF mosaics, and generates a periodic interference pattern map with consistent spatial frequency. To validate our model, we quantitatively analyzed the RGC mosaics in cat data, and confirmed that the observed retinal mosaics showed evidence of heterotypic interactions, contrary to the previous view that ON and OFF mosaics are developed independently.SIGNIFICANCE STATEMENT Orientation map is one of the most studied functional maps in the brain, but it has remained unanswered how the consistent spatial periodicity of maps could be developed. In the current study, we address this issue with our developmental model for the retinal origin of orientation map. We showed that local repulsive interactions between retinal ganglion cells (RGCs) can develop a hexagonal periodicity in the RGC mosaics and restrict the alignment between ON and OFF mosaics, so that they generate a periodic pattern with consistent spatial frequency for both the RGC mosaics and the cortical orientation maps. Our results demonstrate that the organization of functional maps in visual cortex, including its structural consistency, may be constrained by a retinal blueprint. PMID- 29114074 TI - Glutamatergic Transmission to Hypothalamic Kisspeptin Neurons Is Differentially Regulated by Estradiol through Estrogen Receptor alpha in Adult Female Mice. AB - Estradiol feedback regulates gonadotropin-releasing hormone (GnRH) neurons and subsequent luteinizing hormone (LH) release. Estradiol acts via estrogen receptor alpha (ERalpha)-expressing afferents of GnRH neurons, including kisspeptin neurons in the anteroventral periventricular (AVPV) and arcuate nuclei, providing homeostatic feedback on episodic GnRH/LH release as well as positive feedback to control ovulation. Ionotropic glutamate receptors are important for estradiol feedback, but it is not known where they fit in the circuitry. Estradiol-negative feedback decreased glutamatergic transmission to AVPV and increased it to arcuate kisspeptin neurons; positive feedback had the opposite effect. Deletion of ERalpha in kisspeptin cells decreased glutamate transmission to AVPV neurons and markedly increased it to arcuate kisspeptin neurons, which also exhibited increased spontaneous firing rate. KERKO mice had increased LH pulse frequency, indicating loss of negative feedback. These observations indicate that ERalpha in kisspeptin cells is required for appropriate differential regulation of these neurons and neuroendocrine output by estradiol.SIGNIFICANCE STATEMENT The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates the pattern of GnRH (negative feedback) and initiates a surge of release that triggers ovulation (positive feedback). GnRH neurons do not express the estrogen receptor needed for feedback (estrogen receptor alpha [ERalpha]); kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to mediate negative and positive feedback, respectively. Here we extend the network through which feedback is mediated by demonstrating that glutamatergic transmission to these kisspeptin populations is differentially regulated during the reproductive cycle and by estradiol. Electrophysiological and in vivo hormone profile experiments on kisspeptin-specific ERalpha knock-out mice demonstrate that ERalpha in kisspeptin cells is required for appropriate differential regulation of these neurons and for neuroendocrine output. PMID- 29114076 TI - Circular RNA DLGAP4 Ameliorates Ischemic Stroke Outcomes by Targeting miR-143 to Regulate Endothelial-Mesenchymal Transition Associated with Blood-Brain Barrier Integrity. AB - Circular RNAs (circRNAs) are highly expressed in the CNS and regulate physiological and pathophysiological processes. However, the potential role of circRNAs in stroke remains largely unknown. Here, we show that the circRNA DLGAP4 (circDLGAP4) functions as an endogenous microRNA-143 (miR-143) sponge to inhibit miR-143 activity, resulting in the inhibition of homologous to the E6-AP C terminal domain E3 ubiquitin protein ligase 1 expression. circDLGAP4 levels were significantly decreased in the plasma of acute ischemic stroke patients (13 females and 13 males) and in a mouse stroke model. Upregulation of circDLGAP4 expression significantly attenuated neurological deficits and decreased infarct areas and blood-brain barrier damage in the transient middle cerebral artery occlusion mouse stroke model. Endothelial-mesenchymal transition contributes to blood-brain barrier disruption and circDLGAP4 overexpression significantly inhibited endothelial-mesenchymal transition by regulating tight junction protein and mesenchymal cell marker expression. Together, the results of our study are illustrative of the involvement of circDLGAP4 and its coupling mechanism in cerebral ischemia, providing translational evidence that circDLGAP4 serves as a novel therapeutic target for acute cerebrovascular protection.SIGNIFICANCE STATEMENT Circular RNAs (circRNAs) are involved in the regulation of physiological and pathophysiological processes. However, whether circRNAs are involved in ischemic injury, particularly cerebrovascular disorders, remains largely unknown. Here, we demonstrate a critical role for circular RNA DLGAP4 (circDLGAP4), a novel circular RNA originally identified as a sponge for microRNA 143 (miR-143), in ischemic stroke outcomes. Overexpression of circDLGAP4 significantly attenuated neurological deficits and decreased infarct areas and blood-brain barrier damage in the transient middle cerebral artery occlusion mouse stroke model. To our knowledge, this is the first report describing the efficacy of circRNA injection in an ischemic stroke model. Our investigation suggests that circDLGAP4 may serve as a novel therapeutic target for acute ischemic injury. PMID- 29114077 TI - The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1. AB - Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury.SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting the TRAF6-Rac1 axis may provide a novel therapeutic strategy for stroke recovery. PMID- 29114078 TI - Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study. AB - Objective To evaluate how selection of patients for high sensitivity cardiac troponin testing affects the diagnosis of myocardial infarction across different healthcare settings.Design Prospective study of three independent consecutive patient populations presenting to emergency departments.Setting Secondary and tertiary care hospitals in the United Kingdom and United States.Participants High sensitivity cardiac troponin I concentrations were measured in 8500 consecutive patients presenting to emergency departments: unselected patients in the UK (n=1054) and two selected populations of patients in whom troponin testing was requested by the attending clinician in the UK (n=5815) and the US (n=1631). The final diagnosis of type 1 or type 2 myocardial infarction or myocardial injury was independently adjudicated.Main outcome measures Positive predictive value of an elevated cardiac troponin concentration for a diagnosis of type 1 myocardial infarction.Results Cardiac troponin concentrations were elevated in 13.7% (144/1054) of unselected patients, with a prevalence of 1.6% (17/1054) for type 1 myocardial infarction and a positive predictive value of 11.8% (95% confidence interval 7.0% to 18.2%). In selected patients, in whom troponin testing was guided by the attending clinician, the prevalence and positive predictive value were 14.5% (843/5815) and 59.7% (57.0% to 62.2%) in the UK and 4.2% (68/1631) and 16.4% (13.0% to 20.3%) in the US. Across both selected patient populations, the positive predictive value was highest in patients with chest pain, with ischaemia on the electrocardiogram, and with a history of ischaemic heart disease.Conclusions When high sensitivity cardiac troponin testing is performed widely or without previous clinical assessment, elevated troponin concentrations are common and predominantly reflect myocardial injury rather than myocardial infarction. These observations highlight how selection of patients for cardiac troponin testing varies across healthcare settings and markedly influences the positive predictive value for a diagnosis of myocardial infarction. PMID- 29114079 TI - GROWTH-REGULATING FACTOR and GRF-INTERACTING FACTOR Specify Meristematic Cells of Gynoecia and Anthers. AB - We investigated the biological roles of the Arabidopsis (Arabidopsis thaliana) GROWTH-REGULATING FACTOR (GRF) and GRF-INTERACTING FACTOR (GIF) transcriptional complex in the development of gynoecia and anthers. There are nine GRFs and three GIFs in Arabidopsis, and seven GRFs are posttranscriptionally silenced by microRNA396 (miR396). We found that overexpression of MIR396 in the gif1 gif2 double mutant background (gif1 gif2 35S:MIR396) resulted in neither ovary nor pollen. Histological and molecular marker-based analyses revealed that the mutant gynoecial primordia failed to develop carpel margin meristems and mature flowers lacked the ovary, consisting only of the stigma, style, and replum-like tissues. The mutant anther primordia were not able to form the pluripotent archesporial cells that produce pollen mother cells and microsporangia. Multiple combinations of GRF mutations also displayed the same phenotypes, indicating that the GRF-GIF duo is required for the formation of those meristematic and pluripotent cells. Most GRF proteins are localized and abundant in those cells. We also found that the weak gynoecial defects of pinoid-3 (pid-3) mutants were remarkably exacerbated by gif1 gif2 double mutations and 35S:MIR396, so that none of the gynoecia produced by gif1 gif2 pid-3 and 35S:MIR396 pid-3 developed ovaries at all. Moreover, gif1 gif2 double mutations and 35S:MIR396 also acted synergistically with 1-N-naphthylphthalamic acid in forming aberrant gynoecia. The results altogether suggest that the GRF-GIF duo regulates the meristematic and pluripotent competence of carpel margin meristems and the archesporial cell lineage and that this regulation is implemented in association with auxin action, ultimately conferring reproductive competence on Arabidopsis. PMID- 29114080 TI - A Role for the F-Box Protein HAWAIIAN SKIRT in Plant microRNA Function. AB - As regulators of gene expression in multicellular organisms, microRNAs (miRNAs) are crucial for growth and development. Although a plethora of factors involved in their biogenesis and action in Arabidopsis (Arabidopsis thaliana) has been described, these processes and their fine-tuning are not fully understood. Here, we used plants expressing an artificial miRNA target mimic (MIM) to screen for negative regulators of miR156. We identified a new mutant allele of the F-box gene HAWAIIAN SKIRT (HWS; At3G61590), hws-5, as a suppressor of the MIM156 induced developmental and molecular phenotypes. In hws plants, levels of some endogenous miRNAs are increased and their mRNA targets decreased. Plants constitutively expressing full-length HWS-but not a truncated version lacking the F-box domain-display morphological and molecular phenotypes resembling those of mutants defective in miRNA biogenesis and activity. In combination with such mutants, hws loses its delayed floral organ abscission ("skirt") phenotype, suggesting epistasis. Also, the hws transcriptome profile partially resembles those of well-known miRNA mutants hyl1-2, se-3, and ago1-27, pointing to a role in a common pathway. We thus propose HWS as a novel, F-box dependent factor involved in miRNA function. PMID- 29114082 TI - Correction to "Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis". PMID- 29114083 TI - Correction to "G-Protein-Coupled Receptor Kinase 2 as a Potential Modulator of the Hallmarks of Cancer". PMID- 29114081 TI - The Energy-Signaling Hub SnRK1 Is Important for Sucrose-Induced Hypocotyl Elongation. AB - Emerging seedlings respond to environmental conditions such as light and temperature to optimize their establishment. Seedlings grow initially through elongation of the hypocotyl, which is regulated by signaling pathways that integrate environmental information to regulate seedling development. The hypocotyls of Arabidopsis (Arabidopsis thaliana) also elongate in response to sucrose. Here, we investigated the role of cellular sugar-sensing mechanisms in the elongation of hypocotyls in response to Suc. We focused upon the role of SnRK1, which is a sugar-signaling hub that regulates metabolism and transcription in response to cellular energy status. We also investigated the role of TPS1, which synthesizes the signaling sugar trehalose-6-P that is proposed to regulate SnRK1 activity. Under light/dark cycles, we found that Suc-induced hypocotyl elongation did not occur in tps1 mutants and overexpressors of KIN10 (AKIN10/SnRK1.1), a catalytic subunit of SnRK1. We demonstrate that the magnitude of Suc-induced hypocotyl elongation depends on the day length and light intensity. We identified roles for auxin and gibberellin signaling in Suc-induced hypocotyl elongation under short photoperiods. We found that Suc-induced hypocotyl elongation under light/dark cycles does not involve another proposed sugar sensor, HEXOKINASE1, or the circadian oscillator. Our study identifies novel roles for KIN10 and TPS1 in mediating a signal that underlies Suc-induced hypocotyl elongation in light/dark cycles. PMID- 29114084 TI - Correction to "The Emerging Role of Cable1 in Cancer and Other Diseases". PMID- 29114085 TI - Opinion: The Next Generation Researchers Initiative at NIH. PMID- 29114087 TI - The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response. AB - The synthetic supercooling drug, icilin, and its primary receptor target, the cation channel transient receptor potential (TRP) melastatin-8 (TRPM8), have been described as potent negative regulators of inflammation in the colon. The aim of this study was to determine whether the anti-inflammatory action of icilin could potentially be used to treat autoimmune neuroinflammatory disorders, such as multiple sclerosis (MS). During experimental autoimmune encephalomyelitis (EAE)-a CD4+ T cell-driven murine model of MS-we found that both wild-type (WT) and TRPM8 deficient EAE mice were protected from disease progression during icilin treatment, as evidenced by delays in clinical onset and reductions in neuroinflammation. In vitro, icilin potently inhibited the proliferation of murine and human CD4+ T cells, with the peripheral expansion of autoantigen restricted T cells similarly diminished by the administration of icilin in mice. Attenuation of both TRPM8-/- and TRP ankyrin-1-/- T-cell proliferation by icilin was consistent with the WT phenotype, which suggests a mechanism that is independent of these channels. In addition, icilin treatment altered the expressional profile of activated CD4+ T cells to one that was indicative of restricted effector function and limited neuroinflammatory potential. These findings identify a potent anti-inflammatory role for icilin in lymphocyte mediated neuroinflammation and highlight clear pleiotropic effects of the compound beyond classic TRP channel activation.-Ewanchuk, B. W., Allan, E. R. O., Warren, A. L., Ramachandran, R., Yates, R. M. The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response. PMID- 29114088 TI - Unruptured Brain Arteriovenous Malformations: Primary ONYX Embolization in ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-Eligible Patients. AB - BACKGROUND AND PURPOSE: In light of evidence from ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations), neurovascular specialists had to reconsider deliberate treatment of unruptured brain arteriovenous malformations (uBAVMs). Our objective was to determine the outcomes of uBAVM treated with primary embolization using ethylene vinyl alcohol (ONYX). METHODS: Patients with uBAVM who met the inclusion criteria of ARUBA and were treated with primary Onyx embolization were assigned to this retrospective study. The primary outcome was the modified Rankin Scale score. Secondary outcomes were stroke or death because of uBAVM or intervention and uBAVM obliteration. RESULTS: Sixty-one patients (mean age, 38 years) were included. The median observation period was 60 months. Patients were treated by embolization alone (41.0%), embolization and radiosurgery (57.4%), or embolization and excision (1.6%). Occlusion was achieved in 44 of 57 patients with completed treatment (77.2%). Forty-seven patients (77.1%) had no clinical impairment at the end of observation (modified Rankin Scale score of <2). Twelve patients (19.7%) reached the outcome of stroke or death because of uBAVM or intervention. Treatment-related mortality was 6.6% (4 patients). CONCLUSIONS: In uBAVM, Onyx embolization alone or combined with stereotactic radiosurgery achieves a high occlusion rate. Morbidity remains a challenge, even if it seems lower than in the ARUBA trial. PMID- 29114090 TI - Sleep, Preconditioning and Stroke. PMID- 29114089 TI - Angiographic and Clinical Characteristics of Thoracolumbar Spinal Epidural and Dural Arteriovenous Fistulas. AB - BACKGROUND AND PURPOSE: The purpose of this study is to compare the angiographic and clinical characteristics of spinal epidural arteriovenous fistulas (SEAVFs) and spinal dural arteriovenous fistulas (SDAVFs) of the thoracolumbar spine. METHODS: A total of 168 cases diagnosed as spinal dural or extradural arteriovenous fistulas of the thoracolumbar spine were collected from 31 centers. Angiography and clinical findings, including symptoms, sex, and history of spinal surgery/trauma, were retrospectively reviewed. Angiographic images were evaluated, with a special interest in spinal levels, feeders, shunt points, a shunted epidural pouch and its location, and drainage pattern, by 6 readers to reach a consensus. RESULTS: The consensus diagnoses by the 6 readers were SDAVFs in 108 cases, SEAVFs in 59 cases, and paravertebral arteriovenous fistulas in 1 case. Twenty-nine of 59 cases (49%) of SEAVFs were incorrectly diagnosed as SDAVFs at the individual centers. The thoracic spine was involved in SDAVFs (87%) more often than SEAVFs (17%). Both types of arteriovenous fistulas were predominant in men (82% and 73%) and frequently showed progressive myelopathy (97% and 92%). A history of spinal injury/surgery was more frequently found in SEAVFs (36%) than in SDAVFs (12%; P=0.001). The shunt points of SDAVFs were medial to the medial interpedicle line in 77%, suggesting that SDAVFs commonly shunt to the bridging vein. All SEAVFs formed an epidural shunted pouch, which was frequently located in the ventral epidural space (88%) and drained into the perimedullary vein (75%), the paravertebral veins (10%), or both (15%). CONCLUSIONS: SDAVFs and SEAVFs showed similar symptoms and male predominance. SDAVFs frequently involve the thoracic spine and shunt into the bridging vein. SEAVFs frequently involve the lumbar spine and form a shunted pouch in the ventral epidural space draining into the perimedullary vein. PMID- 29114091 TI - Circulating Endothelial Markers in Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations. AB - BACKGROUND AND PURPOSE: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a monogenic small vessel disease, caused by C-terminal truncating TREX1 mutations, that can be considered a model for stroke and vascular dementia. The pathophysiology of RVCL-S is largely unknown, but systemic endothelial involvement has been suggested, leading to pathology in the brain and other highly vascularized organs. Here, we investigated circulating endothelial markers to confirm endothelial involvement and identify biomarkers for disease activity. METHODS: We measured circulating levels of von Willebrand factor (VWF) antigen, VWF propeptide, and angiopoietin-2 in members of 3 Dutch RVCL-S families and matched unrelated healthy controls. Stratified analyses based on symptomatology and age were performed. RESULTS: We found elevated levels of VWF antigen, VWF propeptide, and angiopoietin-2 in TREX1 mutation carriers (n=31) compared with family members without a TREX1 mutation (n=33) and unrelated healthy controls (n=31; Kruskal-Wallis test P<0.001 for all comparisons). Effects were most pronounced in mutation carriers with clinical manifestations aged >=40 years (Mann-Whitney U test P<0.001 for all comparisons). Compared with healthy controls, levels of VWF antigen (P=0.02) and angiopoietin-2 (P=0.04) were also elevated in mutation carriers aged <40 years. All 3 markers showed moderate correlations with markers of kidney and liver disease and inflammation (ie, systemic symptoms of RVCL-S). CONCLUSIONS: Our results confirm an important role of the endothelium in RVCL-S pathophysiology. VWF antigen, VWF propeptide, and angiopoietin-2 might serve as early biomarkers of disease activity. Our findings might also help to understand the pathophysiology of common neurovascular disorders, such as stroke. PMID- 29114092 TI - Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation. AB - BACKGROUND AND PURPOSE: Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. METHODS: Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function-blocking antibody (alphaCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. RESULTS: CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood-brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduced thrombosis and increased cerebral perfusion, and (3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced NF-kappaB (nuclear factor kappaB) activation, MMP-9 (matrix metalloproteinase-9) activity, and PAI-1 (plasminogen activator inhibitor-1) expression in brain microvascular endothelial cells. CONCLUSIONS: Inhibition of CD147 ameliorates acute ischemic stroke by reducing thromboinflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thromboinflammatory disorders. PMID- 29114093 TI - Genetics of Spontaneous Intracerebral Hemorrhage. PMID- 29114094 TI - Association of Osteopontin, Neopterin, and Myeloperoxidase With Stroke Risk in Patients With Prior Stroke or Transient Ischemic Attacks: Results of an Analysis of 13 Biomarkers From the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trial. AB - BACKGROUND AND PURPOSE: Established risk factors do not fully identify patients at risk for recurrent stroke. The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) evaluated the effect of atorvastatin on stroke risk in patients with a recent stroke or transient ischemic attack and no known coronary heart disease. This analysis explored the relationships between 13 plasma biomarkers assessed at trial enrollment and the occurrence of outcome strokes. METHODS: We conducted a case-cohort study of 2176 participants; 562 had outcome strokes and 1614 were selected randomly from those without outcome strokes. Time to stroke was evaluated by Cox proportional hazards models. RESULTS: There was no association between time to stroke and lipoprotein associated phospholipase A2, monocyte chemoattractant protein-1, resistin, matrix metalloproteinase-9, N-terminal fragment of pro-B-type natriuretic peptide, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, or soluble CD40 ligand. In adjusted analyses, osteopontin (hazard ratio per SD change, 1.362; P<0.0001), neopterin (hazard ratio, 1.137; P=0.0107), myeloperoxidase (hazard ratio, 1.177; P=0.0022), and adiponectin (hazard ratio, 1.207; P=0.0013) were independently associated with outcome strokes. After adjustment for the Stroke Prognostic Instrument-II and treatment, osteopontin, neopterin, and myeloperoxidase remained independently associated with outcome strokes. The addition of these 3 biomarkers to Stroke Prognostic Instrument-II increased the area under the receiver operating characteristic curve by 0.023 (P=0.015) and yielded a continuous net reclassification improvement (29.1%; P<0.0001) and an integrated discrimination improvement (42.3%; P<0.0001). CONCLUSIONS: Osteopontin, neopterin, and myeloperoxidase were independently associated with the risk of recurrent stroke and improved risk classification when added to a clinical risk algorithm. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00147602. PMID- 29114096 TI - Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway. AB - BACKGROUND AND PURPOSE: White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model. METHODS: Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis. RESULTS: Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1 month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling. CONCLUSIONS: Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion. PMID- 29114095 TI - Direct Mechanical Intervention Versus Bridging Therapy in Stroke Patients Eligible for Intravenous Thrombolysis: A Pooled Analysis of 2 Registries. AB - BACKGROUND AND PURPOSE: Randomized controlled trials have shown that mechanical thrombectomy (MT) plus best medical treatment improves outcome in stroke patients with large-vessel occlusion in the anterior circulation. Whether direct MT is equally effective as bridging thrombolysis (intravenous thrombolysis plus MT) in intravenous thrombolysis eligible patients remains unclear. METHODS: We compared clinical and radiological outcomes at 3 months in 249 bridging patients with 111 patients receiving direct MT for large-vessel occlusion anterior circulation stroke from 2 prospective registries (study period Essen: June 2012 to August 2013, Bern February 2009 to August 2014). We matched all patients from the direct MT group who would have qualified for intravenous thrombolysis with controls from the bridging group, using multivariate and propensity score methods. Subgroup analyses for internal carotid artery occlusions were performed. RESULTS: Baseline characteristics did not differ between the direct MT group and bridging cohort, except for higher rates of coronary heart disease (P=0.029) and shorter intervals from onset to endovascular therapy (P<0.001) in the MT group. Functional outcome, mortality, and intracerebral hemorrhage did not differ, neither in univariate nor after multivariate and propensity score matching. However, in patients with internal carotid artery occlusion, mortality in the direct cohort was significantly lower. CONCLUSIONS: In this matched-pair analysis, there was no difference in outcome in patients with large-vessel occlusion anterior circulation stroke treated with direct MT compared with those treated with bridging thrombolysis; however, mortality in patients with internal carotid artery occlusion treated with direct MT was significantly lower than after bridging thrombolysis. Randomized trials comparing direct MT with bridging therapy are needed. PMID- 29114097 TI - Should Patients With Ischemic Stroke or Transient Ischemic Attack With Atrial Fibrillation and Microbleeds Be Anticoagulated? PMID- 29114098 TI - Production of Composite Scaffold Containing Silk Fibroin, Chitosan, and Gelatin for 3D Cell Culture and Bone Tissue Regeneration. AB - BACKGROUND Bone tissue engineering, a powerful tool to treat bone defects, is highly dependent on use of scaffolds. Both silk fibroin (SF) and chitosan (Cs) are biocompatible and actively studied for reconstruction of tissue engineering. Gelatin (Gel) is also widely applied in the biomedical field due to its low antigenicity and physicochemical stability. MATERIAL AND METHODS In this study, 4 different types of scaffolds were constructed - SF, SF/Cs, SF/Gel, and SF/Cs/Gel and we compared their physical and chemical properties as well as biological characterization of these scaffolds to determine the most suitable scaffold for use in bone regeneration. First, these scaffolds were produced via chemical cross linking method and freeze-drying technique. Next, the characterization of internal structure was studied using scanning electron microscopy and the porosity was evaluated by liquid displacement method. Then, we compared physicochemical properties such as water absorption rate and degradation property. Finally, MC3T3-E1 cells were inoculated on the scaffolds to study the biocompatibility and osteogenesis of the three-dimensional (3D) scaffolds in vitro. RESULTS The composite scaffold formed by all 3 components was the best for use in bone regeneration. CONCLUSIONS We conclude that the best scaffold among the 4 studied for MC3T3-E1 cells is our SF/Cs/Gel scaffold, suggesting a new choice for bone regeneration that can be used to treat bone defects or fractures in clinical practice. PMID- 29114099 TI - Risk Factors and Management for Biliary Complications Following Adult Living Donor Liver Transplantation. AB - BACKGROUND Biliary complications (BCs) following liver transplantation are very serious. Nevertheless, it is still uncertain which components influence the incidence of BCs the most. MATERIAL AND METHODS A consecutive sample of 74 adult recipients who underwent living-donor liver transplantation were enrolled in this study. BCs that were Clavien-Dindo classification grade II or higher were determined as BCs. RESULTS There were 11 out of the 74 recipients who experienced BCs. There were no differences in preoperative background factors between the BCs+ and BCs- group. Unexpectedly, the number of bile duct orifices did not contribute to the BCs (p=0.722). In comparison with the BCs- group, the frequency of post-operative bleeding requiring re-operation was relatively higher (27.3% vs. 7.9%, p=0.0913) and this complication was the only independent risk factor (p=0.0238) for the onset of BCs. Many of the BCs+ recipients were completely treated by endoscopic or radiological intervention (81.8%). However, surgical revision was required for 2 recipients (18.2%). CONCLUSIONS Given these results, it is reasonable to believe that definite hemostasis is required to prevent future BCs. In addition, bile duct multiplicity was not associated with BCs. PMID- 29114101 TI - Gut microbiota: Oral bacteria: a cause of IBD? PMID- 29114100 TI - Successful Treatment of Severe Tardive Dyskinesia with Valbenazine, Including a Patient's Perspective. AB - BACKGROUND Tardive dyskinesia (TD) is a chronic involuntary movement disorder frequently induced by dopamine receptor blockers, particularly first-generation antipsychotics. Until recently, management of TD was restricted to lowering the dose of the current medication, switching to another medication, or using off label treatments with insufficient evidence of efficacy. Valbenazine, a vesicular monoamine transporter-2 (VMAT2) inhibitor, became the first drug to be approved by the FDA specifically for the treatment of TD. CASE REPORT We describe the case of a 49-year-old African-American woman who was diagnosed with bipolar disorder at the age of 34 and treated with lithium carbonate (900 mg daily) and citalopram (10 mg daily). She also received low doses of second-generation antipsychotics for weeks at a time, but these were always discontinued due to severe sedation. Over a decade later, at the age of 45, she experienced rapid onset of severe TD symptoms. She enrolled in a phase III double-blind clinical trial and received valbenazine 80 mg, with encouraging results. CONCLUSIONS Once-daily dosing of valbenazine (80 mg) was effective and safe over a long period, even in this atypical case of severe and rapid-onset TD. PMID- 29114102 TI - Surgery: Robotic assistance confers no benefit in rectal cancer surgery. PMID- 29114103 TI - Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5-HTTLPR/rs25531 Polymorphism, and Stress. AB - DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional face-matching task. Individual SLC6A4 AluJb methylation profiles were ascertained and associated with MDD, amygdala reactivity, 5 HTTLPR/rs25531, and stress. SLC6A4 AluJb methylation was significantly lower in MDD compared to HC and in stressed compared to less stressed participants. Lower AluJb methylation was particularly found in 5-HTTLPR/rs25531 risk allele carriers under stress and correlated with less depressive episodes. fMRI analysis revealed a significant interaction of AluJb methylation and diagnosis in the amygdala, with MDD patients showing lower AluJb methylation associated with decreased amygdala reactivity. While no joint effect of AluJb methylation and 5 HTTLPR/rs25531 existed, risk allele carriers showed significantly increased bilateral amygdala activation. These findings suggest a role of SLC6A4 AluJb methylation in MDD, amygdala reactivity, and stress reaction, partly interwoven with 5-HTTLPR/rs25531 effects. Patients with low methylation in conjunction with a shorter MDD history and decreased amygdala reactivity might feature a more stress-adaptive epigenetic process, maybe via theoretically possible endogenous antidepressant-like effects. In contrast, patients with higher methylation might possibly suffer from impaired epigenetic adaption to chronic stress. Further, the 5-HTTLPR/rs25531 association with amygdala activation was confirmed in our large sample. PMID- 29114104 TI - Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors. AB - Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the alpha7 nicotinic acetylcholine receptor (nAChR), and manifest a variable neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti aggressive, or 'serenic,' an effect which requires alpha7 nAChRs and is recapitulated by GTS-21, an alpha7 nAChR partial agonist. Pharmacotherapies potentiating alpha7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the alpha7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which alpha7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where alpha7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS 21 on attack latency. These data further implicate alpha7 nAChRs in regulation of aggression, and demonstrate that hippocampal alpha7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease. PMID- 29114106 TI - Designing and Implementation of a Heart Failure Telemonitoring System. AB - Introduction: The aim of this study was to identify patients at-risk, enhancing self-care management of HF patients at home and reduce the disease exacerbations and readmissions. Method: In this research according to standard heart failure guidelines and Semi-structured interviews with 10 heart failure Specialists, a draft heart failure rule set for alerts and patient instructions was developed. Eventually, the clinical champion of the project vetted the rule set. Also we designed a transactional system to enhance monitoring and follow up of CHF patients. With this system, CHF patients are required to measure their physiological measurements (vital signs and body weight) every day and to submit their symptoms using the app. additionally, based on their data, they will receive customized notifications and motivation messages to classify risk of disease exacerbation. The architecture of system comprised of six major components: 1) a patient data collection suite including a mobile app and website; 2) Data Receiver; 3) Database; 4) a Specialists expert Panel; 5) Rule engine classifier; 6) Notifier engine. Results: This system has implemented in Iran for the first time and we are currently in the testing phase with 10 patients to evaluate the technical performance of our system. The developed expert system generates alerts and instructions based on the patient's data and the notify engine notifies responsible nurses and physicians and sometimes patients. Detailed analysis of those results will be reported in a future report. Conclusion: This study is based on the design of a telemonitoring system for heart failure self-care that intents to overcome the gap that occurs when patients discharge from the hospital and tries to accurate requirement of readmission. A rule set for classifying and resulting automated alerts and patient instructions for heart failure telemonitoring was developed. It also facilitates daily communication among patients and heart failure clinicians so any deterioration in health could be identified immediately. PMID- 29114107 TI - Clinical and Para Clinical Information Needs of Infertility Electronic Health Records in Iran: A Delphi Study. AB - Background: infertility is referred to the person's inability to conceive pregnancy after one year of intercourse without using protection. This study paves the ground for creating a complete, united, and coherent source of patients' medical information. Materials and Methods: this is an applied research of descriptive-cross sectional type which has been carried out through qualitative - quantitative methods. The sample of the present study was 50 specialists in the field of infertility which has been chosen based on purposive sampling method. Designing the questionnaire was done based on library studies and Gathering experts' views was done based on Delphi technique. Results: 261 items from clinical and Para clinical information of infertile patients' electronic health records were subjected to an opinion poll by experts. During this process 223 items were accepted and 38 items have been rejected after two sessions of surveys by infertility experts. Para clinical information section consisted of 57 items that all of them have been accepted by the experts. Also, clinical information section consisted of 242 items from which 204 items were accepted and 38 items were rejected by the experts. Conclusion: existence of a structured electronic record system of infertile patients' information leads to the integration of patients' information, improvement of health care services and a decrease in treatment costs: all working to increase information safety. Furthermore, only essential and relevant information would be provided for the specialists and it will facilitate and direct the future infertility related studies due to the coherence, unity and relevance of the information. PMID- 29114105 TI - Neuregulin 3 Signaling Mediates Nicotine-Dependent Synaptic Plasticity in the Orbitofrontal Cortex and Cognition. AB - Neuregulin 3 (NRG3) and ErbB4 have been linked to nicotine addiction; however, the neuronal mechanisms and behavioral consequences of NRG3-ErbB4 sensitivity to nicotine remain elusive. Recent literature suggests that relapse to smoking is due to a lack of impulsive control, which is thought to be due to altered functioning within the orbitofrontal cortex (OFC). Therefore, we examined circuitry changes within this structure following nicotine application. We report that nicotine controls synaptic plasticity in the OFC through NRG3/ErbB4 dependent regulation of GABAergic inhibition. We observed that both nicotine and NRG3 facilitated the conversion of long-term potentiation into long-term depression at cortical layer 3/5 synapses. Induction of long-term depression by nicotine relied on nicotinic receptor activation and key regulators of NRG3 signaling: (1) release of intracellular calcium, (2) activation of the BACE1 beta secretase, and (3) ErbB4 receptor activation. Nicotine-induced synaptic plasticity was also associated with accumulation of intracellular GABA and was completely blocked by GABAA/GABAB antagonists. To test whether these mechanisms underlie OFC-dependent behavior, we evaluated the effects of nicotine in the go/no-go task. Nicotine-impaired stimulus discrimination in this task was rescued by pharmacologic disruption of the NRG3 receptor, ErbB4. Altogether, our data indicate that nicotine-induced synaptic plasticity in the OFC and cognitive changes depend on NRG3-ErbB4 signaling. We propose that nicotine activation of this pathway may contribute to nicotine addiction, particularly in individuals with genetic variation in NRG3. PMID- 29114108 TI - Therapeutic Effects of Curcumin on Ultrasonic Morphological Characteristics of Liver in Patients with Metabolic Syndrome. AB - Introduction: Metabolic syndrome (METS) represent a simultaneous presence of multiple metabolic disorders in one person. Prevalence is increasing worldwide, which is probably related to increased obesity and sedentary lifestyle. Non alcoholic steatosis or "fatty liver" is a metabolic disease caused by fat dysfunction. It can be a sign of some other disease, and can often be found in patients with metabolic disorders. Ultrasound is an acceptable method for the identification of fatty steatosis. There is evidence that when turmeric is used as a herbal diet, with its active metabolite of curcumin, can repair fatty acidosis and thus prevent progression of fatty steatosis complications such as cirrhosis and liver cancer. Goal. The aim of the study was to determine the effects of 400 mg curcuminaddition to the nutrition on ultrasound morphological characteristics of the liver in METS patients. Methodology: A prospective cohort study was conducted on 100 subjects with METS, treated in the family medicine practice of the Tuzla Canton, aged 35-70 years. The therapeutic effects of 400 mg curcumin on ultrasound-morphological characteristics of the liver were followed, validated by ultrasound in 50 respondents of experimental groups with METS. The data were processed by the IBM SPSS Statistics 21 statistical analysis program using parametric techniques andStudent's t-test for paired samples. Results: There were 65% of women in the study. There were no statistically significant differences in the age of respondents within the analyzed groups. The use of 400 mg curcumin per day was statistically significantly improved ultrasound morphological characteristics of the liver in subjects with METS. Conclusion: All respondents with METS who used curcumin had beneficial effects on the morphological characteristics of the liver. Curcumin had stronger effects on subjects with METS and DM type 2 than others. PMID- 29114109 TI - Frequency of Acccessory Renal Arteries Diagnosed by Computerized Tomography. AB - Introduction: Accessory renal arteries play a significant role in kidney and abdominal aorta surgery, and renovascular hypertension. In the published literature, the frequency varies considerably, depending on the size of the sample, the method of examination and the ethnic group. Materials and Methods: The aim of this study is to determine the general frequency of accessory renal arteries, their frequency in relation to gender, the origin and the vascularization area, and to determine the differences in left-right and bilateral distribution. Results and Discussion: CT scans of 1357 patients were retrospectively analyzed. Accessory renal arteries were recorded in 35.5% of patients, with a statistically significant difference in male and female incidence (p<0.05) with a ratio of 1.4 : 1. Accessory arteries occur more commonly unilaterally (p<0.05) than bilaterally with a ratio of 4 : 1. Unilateral accessory renal arteries occur at approximately the same frequency at right and left side 1.1 : 1, without statistically significant differences in frequencies (p>0.05). Of the total number of noticed accessory renal arteries 76.7% was originated from abdominal aorta (AA), 23% from renal artery and 0.3% from CIA, with a ratio of 3.3: 1 : 0.0005. Conclusions: The study showed a relatively high frequency of accessory arteries and described their anatomy in detail, which can be of great importance in surgical interventions on abdominal aorta, kidneys, and in case of kidney transplantation. PMID- 29114110 TI - The Diagnosis of Obstructive Hydronephrosis with Color Doppler Ultrasound. AB - Background: The obstructive hydronephrosis is a term that implicates the structural and functional changes of the kidneys as a result of difficulties in the flow of urine. Hydronephrosis specifically describes dilation and swelling of the kidney. Hydronephrosis is a condition that typically occurs when the kidney swells due to the failure of normal drainage of urine from the kidney to the bladder. Our aim was to evaluate the degree of hydronephrosis, causes and diagnostic method. Material and. Methods: This is a study of 136 patients that have been treated at the Department of Urology, University Clinical Centre of Kosovo, Prishtina. For diagnosis of hydronephrosis in our patient, we used as equipment the Color Doppler ultrasound, with resolution of 3.5 MHz-8 MHz. Results: Out of 136 participants in the study, 91 (66.9%) were males and 45 (33.1%) females, with significant difference (P=0.000). The average age for males was 49 years old, whereas for females was 33. This study included patients with a diagnosis of symptomatic hydronephrosis with various causes and degrees. All patients were presented with hydronephrosis. The hydronephrosis grade varied from the stage I up to the IV. In our study we have difference grade of hydronephrosis, X2 test, P= 0.114. The most common causes of hydronephrosis in our study were; kidney stone, ureteral stones, neck stenosis PU, pregnancy, infiltrating bladder cancer, bladder neck contracture, prostate adenoma, infiltrating prostatic carcinoma etc. In this study we have indentified different causes, of which stones dominate as the most usual causes of hydronephrosis P= 0.0001. Conclusion: The Ultrasound is an easy method to be applied, non invasive, and a fast one to help and diagnose the obstructive hydronephrosis. The ultrasound has a high sensitivity and should be used as a screening method followed by other methods, as necessary. Hydronphrosis is most commonly presented to men with an average age about fifties. We came to the conclusion that the main causes of hydronephrosis are kidney stone, followed by ureteral stones, in which, in a larger percentage, they appear with the II degree of hydronephrosis. PMID- 29114111 TI - Intelligent Diagnostic Assistant for Complicated Skin Diseases through C5's Algorithm. AB - Introduction: Intelligent Diagnostic Assistant can be used for complicated diagnosis of skin diseases, which are among the most common causes of disability. The aim of this study was to design and implement a computerized intelligent diagnostic assistant for complicated skin diseases through C5's Algorithm. Method: An applied-developmental study was done in 2015. Knowledge base was developed based on interviews with dermatologists through questionnaires and checklists. Knowledge representation was obtained from the train data in the database using Excel Microsoft Office. Clementine Software and C5's Algorithms were applied to draw the decision tree. Analysis of test accuracy was performed based on rules extracted using inference chains. The rules extracted from the decision tree were entered into the CLIPS programming environment and the intelligent diagnostic assistant was designed then. Results: The rules were defined using forward chaining inference technique and were entered into Clips programming environment as RULE. The accuracy and error rates obtained in the training phase from the decision tree were 99.56% and 0.44%, respectively. The accuracy of the decision tree was 98% and the error was 2% in the test phase. Conclusion: Intelligent diagnostic assistant can be used as a reliable system with high accuracy, sensitivity, specificity, and agreement. PMID- 29114112 TI - Making Use of H-index: the Shape of Science at the University of Sarajevo. AB - Introduction: Quantifying science and scientific contribution has become one of the main tasks in evaluating researchers and their impact. How do we value research and science in Bosnia and Herzegovina (BIH)? Scientific community has mostly agreed upon that one of the best ways to value researchers is through their h-index value. However, there are many databases and services from which h index can be retrieved. Aim: To describe different databases and services such as Google Scholar, Web of Science, Scopus and Researchgate in evaluating the researcher. An additional aim of this paper is to present "the shape" of science at the University of Sarajevo and to examine what are the best predictors of h index. Materials and methods: We analyzed the data from 100 Google Scholar Profiles of researchers from University of Sarajevo. Results: The study showed some benefits and shortcomings of mentioned databases and services. Most researchers in the sample were from natural sciences, in particular from the field of medicine. The mean value of h-index in relation to the researcher's gender was not statistically significant. We conclude the article with some ideas on how to improve the visibility of researchers from BIH. PMID- 29114113 TI - Managing information in Health Informatics. AB - Only once we agree upon our understanding of what words really mean can we debate whether a concept, represented by those words, is or not well represented significantly in specific application. Conceptual clarity and predicative/impredicative competence are the fundamental components for managing information more effectively in Health Informatics, Healthcare and Medicine applications, while promoting innovation and creativity. Medicine was always the art and science of healing. The science became more and more a mechanistic technology in Healthcare; the art was dropped altogether. But uncertainty-as problem in the past is slowly morphing into the evaluative concept of uncertainty as-resource. The key change performance factor is education, distinguishing building on sand from building on rock for Health Informatics! Conceptual clarity, more than instrumental obsession is necessary. In this paper, we present the main concepts of fundamental biomedical enhanced knowledge formalization for Health Informatics and Wellbeing of the future. PMID- 29114115 TI - Data Requirements and the Basis for Designing Health Information Kiosks. AB - Introduction: Health kiosks are an innovative and cost-effective solution that organizations can easily implement to help educate people. Aim: To determine the data requirements and basis for designing health information kiosks as a new technology to maintain the health of society. Methods: By reviewing the literature, a list of information requirements was provided in 4 sections (demographic information, general information, diagnostic information and medical history), and questions related to the objectives, data elements, stakeholders, requirements, infrastructures and the applications of health information kiosks were provided. In order to determine the content validity of the designed set, the opinions of 2 physicians and 2 specialists in medical informatics were obtained. The test-retest method was used to measure its reliability. Data were analyzed using SPSS software. Results: In the proposed model for Iran, 170 data elements in 6 sections were presented for experts' opinion, which ultimately, on 106 elements, a collective agreement was reached. Conclusion: To provide a model of health information kiosk, creating a standard data set is a critical point. According to a survey conducted on the various literature review studies related to the health information kiosk, the most important components of a health information kiosk include six categories; information needs, data elements, applications, stakeholders, requirements and infrastructure of health information kiosks that need to be considered when designing a health information kiosk. PMID- 29114114 TI - Health Professionals Information for Diagnostics Related Groups (DRGs) with the Use of a Website. AB - Introduction: The aim of this research is to inform the health professionals about the ways of introducing and operating the the Diagnosis Related Groups (DRG's) system in the Hellenic National Health System, through the use of the development technologies. An effort is also made to explore the main dimensions of the implementation of the DRG's system, in specific European-Countries that have both adopted the public coverage schemes and the Bismarck health insurance institutions for countries with extensive experience in their implementation. Material and methods: A review of the literature was attempted to investigate the ways of financing of the health services, and of the identification and functionality of the DRG's as well as of the methods used by European countries to investigate this prospective compensation system. Results: The efficient application of DRGs gives the possibility to improve the economic management of Greek hospitals by retaining the costs and consequently contributing to the wise and effective management of hospital expenses. A short training of health professionals on the importance of DRGs in the effective running of Greek hospitals, led to the development of a website. This website will give information on this new method of pricing of hospital health services provided, and will contribute to the overall improvement of health services. Conclusion: Introduction of DRGs, in Greek hospitals will establish a positive condition to solve many emerging health issues and to improve the overall functionality of the health system. Additionally, with the proper implementation of the DRG;s, the financial management of the Greek hospitals, can be improved by keeping the costs down through the proper utilization of the available resources. PMID- 29114116 TI - Benefits of Outsourcing Strategy and IT Technology in Clinical Trials. AB - Introduction: Aim of this paper is to describe some of models of outsourcing (numerous and response to different types of risks and increment of quality is based on individual problem and situation). Defining whether to outsource or not and whether to build or buy new information technology (IT) is question for contract research organization (CRO) and Pharma companies dealing with clinical trials, so the aim of this paper is to show business model that could make process of decision making less time consuming, less segmented and more efficient. Material and methods: This paper has a descriptive character, and represents a review of the literature that deals with the described issues. Results: Outsourcing should enable optimal capacity flexibility (technology that is outsourced should be done only optimally not entirely). The goal with CRO partners is to establish equivalent levels of global quality, as extensions of other research and development activities (by unification of standards of performance of alliance partners with best standards of industry). IT is gaining greater significance at each stage of clinical study and represent an inevitable element of the quality of a clinical study (for the purpose of monitoring of clinical site activities, data collection and management, medical monitoring, statistical programming, statistical analysis, clinical study reporting). Conclusion: CROs are able to maximize work within the CRO global development, to support the notion of a fully integrated outsourced company; facilitate the use of similar business processes and norms, reusing established CRO standards and improve CRO operational decision making within outsourced studies by providing consistent and current information across outsourced and in-house activities. PMID- 29114117 TI - The Most Influential Scientists in the Development of Medical Informatics (18): Isaacs Sedick. PMID- 29114118 TI - 15th International Conference on Informatics, Management and Technology in Health Care, Athens, Greece, 7-9 July, 2017. PMID- 29114119 TI - An overall estimation of losses caused by diseases in the Brazilian fish farms. AB - Parasitic and infectious diseases are common in finfish, but are difficult to accurately estimate the economic impacts on the production in a country with large dimensions like Brazil. The aim of this study was to estimate the costs caused by economic losses of finfish due to mortality by diseases in Brazil. A model for estimating the costs related to parasitic and bacterial diseases in farmed fish and an estimative of these economic impacts are presented. We used official data of production and mortality of finfish for rough estimation of economic losses. The losses herein presented are related to direct and indirect economic costs for freshwater farmed fish, which were estimated in US$ 84 million per year. Finally, it was possible to establish by the first time an estimative of overall losses in finfish production in Brazil using data available from production. Therefore, this current estimative must help researchers and policy makers to approximate the economic costs of diseases for fish farming industry, as well as for developing of public policies on the control measures of diseases and priority research lines. PMID- 29114121 TI - Pathological studies on helminth parasitic infection in mithun (Bos frontalis). AB - A pathological study was carried out in different helminth parasite infection organs in 110 animals during the period from 2010 to 2016. Histopathological examination of hydatid cysts in the liver, showed extensive fibrous connective tissue proliferation with eosinophilic and lymphocytic infiltration, in lung, parenchyma showed severe emphysema with infiltration of alveolar macrophages and lymphocytes infiltration. In Toxocara infection, polymorphonuclear infiltration in the sub-mucosa with hyper activity of goblet cells leading to occlusion of the gland was noted in the tissue sections. In amphistomiasis, intestinal mucosa showed diffuse hyperemia, thickening and ulceration. Petechiae were observed in the anterior part of the duodenum and jejunum. Presence of parasites in the abomasum revealed petechial haemorrhages on the mucousa. In Trichuris infection, the rectum showed hypertrophy, hyperplasia and hyperactivity of the goblet cells. In some places there is focal aggregation of mononuclear cells. PMID- 29114120 TI - Free-living amoebae in the water resources of Iran: a systematic review. AB - Free-living amoebae (FLA) are a group of protozoa with the capabilities of growth in the environment and invasion to the human body which have been isolated from different water sources. Acanthamoeba, Naegleria, and Balamuthia are the most important FLA. These cause a variety of severe complications of eye and central nervous system. Despite the fact that various studies have demonstrated the prevalence of FLA in different parts of Iran, there is no comprehensive evaluation and conclusion regarding the pollution of various water sources in Iran. This review was carried out to achieve the prevalence pattern of FLA in water resources across Iran to design appropriate health strategies. For this purpose, 8 online databases in English and Persian and also graduate thesis and national parasitology congresses were studied. The key words such as "free living amoebae", "Acanthamoeba", "Naegleria", "Hartmannella", "Balamuthia", "Sappinia", "Vermamoebae", "Valkampfia", "water resources", "water" and "Iran" were used to search articles between 1990 to 2017. From a total of 236 articles found, 38 reliable articles were included in the study. From the total number of investigated studies, the estimated prevalence was obtained as 36% among 2430 samples. Although Acanthamoeba prevalence has been considered as a priority, most kinds of free-living amoebae were found in all kinds of water resources. Due to the lack of free-living amoebae prevalence in more than a quarter of the Iranian provinces, more studies are recommended to achieve a better perspective to make comprehensive decisions to improve the hygiene of water resources. PMID- 29114123 TI - Occurrence of two new species of the genus Dipartiella (Raabe, 1959) Stein 1961 (Ciliophora: Trichodinidae) isolated for the first time from ornamental fish. AB - During the parasitological survey of ornamental fish in India the authors identified two trichodinid ciliophorans for the first time in India, during the year 2014-16 and also revealed that goldfish, Carassius auratus, was the most susceptible species for trichodinid infection. Two ciliophorans have been isolated and identified on the basis of wet silver nitrate impregnation technique followed by taxonomic description, morphometric variability and comparative data with its closely related species. Considering all the important features including diameter, structure of denticles, rays and ciliatures the authors are of the opinion that the identified species are new to science. Hence, the name Dipartiella indiana n. sp. and Dipartiella carassii n. sp. are being proposed here. Till date, only two species of the genus have been described from the edible fish, but no attention has been paid to ornamental fish. Moreover, The present study confirms the first report of this genus from ornamental fish species and added two more species under the genus Dipartiella (Raabe, 1959) Stein 1961 along with new host, locality and prevalence rates. PMID- 29114122 TI - Dot enzyme-linked immunosorbent assay (ELISA) for the detection of Toxocara infection using a rat model. AB - Toxocariasis is a zoonotic disease usually caused by dog and cat roundworms, Toxocara canis and T. cati. Detection and diagnosis is difficult in paratenic and accidental hosts, including humans, as they cannot be detected through conventional methods such as fecal examination. Diagnosis therefore relies on immunological methods and molecular methods such as enzyme-linked immunosorbent assay (ELISA) and Western Blot, which are both time-consuming and requires sophisticated equipment. In the Philippines, only a few studies are available on Toxocara seroprevalence. Therefore, there is a need to adapt methods for serodiagnosis of Toxocara infection in humans for the Philippine setting. A dot enzyme linked immunosorbent assay (dot-ELISA) was standardized using T. canis excretory-secretory antigens. Test sera were collected from laboratory rats (Sprague-Dawley strain) experimentally infected with embryonated eggs of T. canis and Ascaris suum as well as rice field rats naturally infected with Taenia taeniaeformis and Nippostrongylus sp. Optimum conditions used were 20 ug/ml antigen concentration and 1:10 serum dilution. The sensitivity, specificity, positive, and negative predictive values were 90% (95% CI 55.5-99.7%), 100% (95% CI 69.2-100.0%), 100% (95% CI 66.4-100%), and 90.9% (95% CI 58.7-99.8%), respectively. Dot-ELISA has the potential to be developed as a cheaper, simpler, and more practical method for detection of anti-Toxocara antibodies on accidental hosts. This is a preliminary study conducted on experimental animals before optimization and standardization for human serum samples. PMID- 29114124 TI - Seroprevalence and molecular evaluation of toxoplasmosis in children with cancer in Khuzestan province, Southwest of Iran. AB - Toxoplasma gondii is an intracellular parasite with global distribution. Toxoplasmosis in individuals with normal immune system is usually asymptomatic, but in immunocompromised patients may lead to death if not cured. In this study, the prevalence rate of acute and chronic toxoplasmosis in children with cancer was investigated using serological and molecular methods. Blood samples were taken from 372 children with cancer in Shafa hospital in Ahvaz, southwest of Iran. Anti-T. gondii IgG and IgM antibodies were investigated by ELISA. The presence of Toxoplasma in the blood samples was evaluated by Nested PCR. Among 372 children with cancer, 155 (41.7%) were positive for anti-T. gondii IgG antibodies and 24 (6.4%) were positive for anti-T. gondii IgM antibodies, as well. In IgG avidity test, 34 (22%) had antibodies indicating acute phase and 121 (78%) had antibodies indicating chronic phase. The Nested PCR results were showed T. gondii parasite in 34 (100%) patients among 34 IgG antibody-positive patients with acute infection, among 16 IgG antibody-positive patients with chronic infection, 10 patients were indicative of T. gondii and 6 patients were not indicative of T. gondii. A total of 50 cases, 44 (88%) were T. gondii-positive and 6 (12%) were T. gondii-negative in Nested PCR. This study showed high prevalence of toxoplasmosis in children with cancer. Results of serological techniques (ELISA and IgG avidity) had a higher overlap with Nested PCR in identifying T. gondii of seropositive patients. PMID- 29114125 TI - Prevalence of Amblyomma gervaisi ticks on captive snakes in Tamil Nadu. AB - Ticks are the important ectoparasites that occur on snakes and transmit rickettsiosis, anaplasmosis and ehrlichiosis. A total of 62 snakes (Reticulated python, Indian Rock Python, Rat snakes and Spectacled cobra) were examined for tick infestation at Chennai Snake Park Trust (Guindy), Arignar Anna Zoological Park (Vandalur) and Rescue centre (Velachery) in Tamil Nadu from September, 2015 to June, 2016. Ticks from infested snakes were collected and were identified as Amblyomma gervaisi (previously known as Aponomma gervaisi). Overall occurrence of tick infestation on snakes was 66.13%. Highest prevalence of tick infestation was observed more on Reticulated Python (Python reticulatus, 90.91%) followed by Indian Rock Python (Python molurus, 88.89%), Spectacled cobra (Naja naja, 33.33%) and Rat snake (Ptyas mucosa, 21.05%). Highest prevalence of ticks were observed on snakes reared at Chennai Snake Park Trust, Guindy (83.33%), followed by Arignar Anna Zoological Park, Vandalur (60.00%) and low level prevalence of 37.50% on snakes at Rescue centre, Velachery. Among the system of management, the prevalence of ticks were more on captive snakes (70.37%) than the free ranging snakes (37.5%). The presences of ticks were more on the first quarter when compared to other three quarters and were highly significant (P <= 0.01). PMID- 29114126 TI - Contracaecum rudolphii Hartwich, 1964 (Nematoda: Anisakidae) in a wild spot billed pelican (Pelecanus philippensis): a case report. AB - Post mortem examination of a spot-billed pelican (Pelecanus philippensis) revealed the presence of numerous anisakid nematodes in the proventriculus. The nematodes were processed in lactophenol as temporary mounts and were identified as Contracaecum rudolphii Hartwich, 1964 based on micrometry and morphological description of the anterior end, the sinuous uterus with sub globular thick shelled eggs in female parasite and the tips of the spicules in male parasite. This is the first record of C. rudolphii in a wild spot-billed pelican from Andhra Pradesh, India. PMID- 29114127 TI - Incidence of gastrointestinal nematodes in goats in and around Mhow, Madhya Pradesh. AB - Gastrointestinal (GI) parasitism in animals is considered as one of the major problems in India causing recurring economic losses to livestock production system owing to morbidity and mortality. But data pertaining to epidemiology of GI nematodes in goats is meager from Malwa region of Madhya Pradesh. Therefore, the present investigation was carried out to study the incidence of GI nematodes in goats in and around Mhow and accordingly a total of 900 faecal samples of goats were collected from Mhow and its adjoining areas and faecal sample examination revealed the incidence of strongyle, Strongyloides papillosus, Trichuris spp. and mixed infection from the study area. Significantly higher infection of GI nematodes was evidenced in the monsoon season (50.67%) when compared with summer (41.33%) and winter (38.33%) seasons. Significantly higher infection rate was documented in >1 year-old-goats (50.43%) than <1 year-old goats (19.31%). Non-significantly higher infection was noted in females (46.04%) than their male counterparts (39.50%). PMID- 29114128 TI - Efficacy of glutathione-S-transferase purified antigen of the gastro-intestinal nematode Haemonchus contortus in diagnosis of sheep haemonchosis. AB - Haemonchus contortus is one of the most pathogenic and economically important parasites of sheep. Different H. contortus antigens; crude somatic antigen (CSA), excretory/secretory antigen (ESA), crude larval antigen (CLA), glutathione-S transferase antigen (GST) and recombinant protein (rhcp 26/23) were prepared and characterized using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. The antigens were immunologically evaluated through indirect enzyme linked immunosorbent assay (ELISA) for diagnosis of haemonchosis in experimentally and naturally infected sheep. Analysis of the resultant bands of SDS-PAGE demonstrated that 13, 6, 11, 2 and 1 protein bands from CSA, ESA, CLA, GST and rhcp 26/23, respectively and analysis of the resultant bands of western blot showed that 13, 6, 4 and 1 reactive bands detected from CSA, ESA, CLA and GST, respectively. The results of ELISA of different antigens revealed that sero-prevelance of CSA, ESA, CLA, GST and rhcp 26/23 were 78.51, 82.34, 85.319, 45.319 and 90.8% respectively, sensitivity were 100, 90, 100, 96.66 and 90%, respectively and specificity were 0, 70, 10, 70 and 6.66%, respectively with diagnostic potency were 50, 80, 55, 83.33 and 48.33%, respectively. Statistical analysis using Chi square test found that GST is the best one that can be used. The cross reactivity of GST antigen, crude Fasciola antigen and crude Moniezia antigen tested versus their homologous hyper immune sera at different dilutions using ELISA. The current study reported that GST antigen could be considered as a promising antigen for diagnosis of haemonchosis. PMID- 29114129 TI - Case report: Severe and progressive bronchopneumonia by Aelurostrongylus abstrusus in an adopted stray cat from Portugal. AB - The cat lungworm Aelurostrongylus abstrusus is the most common respiratory parasite of cats. This nematode has a worldwide distribution and is considered an emerging pathogen. Respiratory signs overlap with those of other pathologies, and some agents which co-exist in the same animal may concur in the clinical scenario. Nonetheless, feline verminous bronchopneumonia is underestimated by practitioners and is not commonly included in differential diagnosis in routine practice. The present report describes the clinical presentation of a 6-month old stray cat from central Portugal, which developed respiratory distress. A clinical improvement of lower respiratory signs was achieved after a course of doxycycline and prednisolone course. However, a relapse with a progressive decline in the respiratory functions occurred two weeks later. A further investigation led to the identification of an A. abstrusus infection that was treated with fenbendazole. Ten days after the treatment the cat became negative for A. abstrusus and further analyses performed in the followings 2 months showed improvement of the animal's pulmonary condition and negative results at the faecal examinations. These findings indicate that veterinarians should include aelurostrongylosis in the differential diagnosis of feline respiratory distress even in non-endemic regions and should perform appropriate diagnostics procedures in the presence of compatible signs. PMID- 29114130 TI - Phylogenetic study based on 28S rRNA gene sequencing of Wuchereria bancrofti isolated from the filaria endemic areas of Bankura district, West Bengal, India. AB - Lymphatic filariasis is one of the major public health concern in India, and Bankura district of West Bengal is one of the main filaria prone area of the country. Wuchereria bancrofti is the causative organism and Culex quinquefasciatus is the main vector of lymphatic filariasis in India. In the present study, infection and infectivity rate of filarial vector C. quinquefasciatus were determined. The molecular characterization, DNA fingerprinting and phylogenetic analysis of W. bancrofti was done. In the study area, overall vector infection and infectivity rates were 4.83 and 0.97%, respectively. The infection and infectivity rate were found to be higher in rainy season and lower in summer season. The AT and GC content of W. bancrofti SNC Bankura (Accession No. JF930705) were 55.59 and 44.41%, respectively. The phylogenetic tree was prepared following neighbour joining, maximum parsimony, minimum evolutionary and UPGMA methods. The study revealed that W. bancrofti SNC Bankura (JF930705) showed 100% similarity with W. bancrofti (Accession No. EU370161). The cluster containing, W. bancrofti SNC Bankura (JF930705) and W. bancrofti (EU370161) branched with Brugia pahangi (M15309) with 62% bootstrap value. W. bancrofti SNC Bankura (JF930705), W. bancrofti (EU370161) and B. pahangi (M15309) branched with Dirofilaria immitis (AF188120) with 78% bootstrap value. PMID- 29114131 TI - A report on two new myxozoan parasites infecting gills of fingerlings of Indian major carps cultured in nursery ponds in Punjab (India). AB - This paper presents the morphological characteristics of two new species belonging to the genus Myxobolus viz M. knobii n. sp. and M. majraiensis n. sp., parasites infecting gill lamellae and gill filaments of fingerlings of Cirrhinus mrigala (Ham.) and Catla catla (Ham.) respectively collected from nursery ponds located in the village Fagan Majra, District Fatehgarh Sahib, Punjab (India). A total of 90 fingerlings were examined (40 Catla catla and 50 Cirrhinus mrigala). Out of which, 32 C. mrigala and 19 C. catla fishes were found infected. The total prevalence rate was recorded as 56.66%. The age of the fish was recorded as 2-3 months and length of the fish ranged 4-4.5 cm. The plasmodia of M. knobii n. sp. were round to irregular, 0.6-1.0 mm in diameter. Myxospores oval to spherical, pot-shaped in frontal view with a prominent knob at anterior end, measured 5.83 * 4.29 um in size. Polar capsules were equal, broadly pyriform, 1.95 * 1.70 um in size having 3-4 polar filament coils. The plasmodia of M. majraiensis n. sp. were round to oval, 0.8-1.5 um in diameter. Myxospores egg-shaped in frontal view also having prominent knob at the anterior end, measured 8.58 * 5.2 um in size. Polar capsules were equal, pyriform, 3.47 * 1.80 um in size having 5-6 polar filament coils. Gill plasmodium index showed heavy infection in both of the species. This is the first report of myxobolid infection in the fingerlings of Indian major carps in nursery ponds in Punjab (India). PMID- 29114132 TI - Variation in faecal worm egg counts of experimentally infected goats and mice with time of day and its implications in diagnosis of helminthosis. AB - Faecal worm egg counts (FEC) are very important indicators in assessing the intensity of helminth infections in animal hosts and inform decisions taken in parasite control programmes. FEC are however affected by many factors which include the dose level of larval challenge, species composition of the worms, worm burden, female worm fecundity and concurrent infections to name but these few. The relevance of time of collection of faecal sample for FEC is not fully known and in most cases faeces for analysis is collected whenever feasible for the researcher on sample collection days. The significance of the time of collection of faeces on FEC was therefore investigated at two different periods of the day, morning and afternoon. Faecal samples were collected at 7-8 a.m. (morning) and at 2-3 p.m. (afternoon) on same sampling days from 6 mice and 10 West African Dwarf goat kids experimentally infected with Heligmosomoides bakeri and Haemonchus contortus respectively. FEC were conducted using the flotation and modified McMaster techniques. Overall, the 2-3 p.m. FEC tended to be higher than the 7-8 a.m. FEC in both animal species but the difference was not significant (P > 0.05). The time of collection of faecal samples for faecal worm egg counts is therefore not a crucial factor that may significantly affect FEC in H. bakeri and H. contortus infected mice and goats respectively although it would be advisable to maintain particular periods for collection of faeces in particular experiments for best results of FEC to be obtained. PMID- 29114133 TI - Molecular identification of Sarcocystis species in raw hamburgers using PCR-RFLP method in Kashan, central Iran. AB - The prevalence of bovine Sarcocystosis is high in the most regions of the world. It can be a human health problem due to consumption of raw or under cooked hamburgers or other bovine meat products. This study was carried out to investigate the prevalence and species identification of Sarcocystis among of hamburgers, using PCR-RFLP methods in Kashan, central Iran. Overall 200 raw industrial hamburgers samples with at least 60% meat were randomly collected from nine different brands in Kashan, central Iran. The genomic DNA was extracted and a PCR-RFLP method was used to amplify an approximately 900 bp fragment at the 18S rRNA(SSU) gene, restriction enzyme BclI was used for species identification. The results showed that 58 (29%) of 200 tested hamburger samples were infected to Sarcocystis spp. The prevalence rate was 31.25 and 26.9% in the hamburgers with 90 and 60-75% meat, respectively. According to PCR-RFLP analysis, 43 (74.1%) of the 58 isolates were Sarcocystis cruzi, 12 (20.7%) showed co-infection to S. cruzi and Sarcocystis hirsuta, 2 (3.5%) was mixed infected to S. cruzi and Sarcocystis hominis, 1 (1.7%) showed the pattern of mix infection to three species. This study revealed one-third of industrial hamburger were infected to S. cruzi or mixed infection of S. cruzi with other bovine sarcocytosis. To prevent cattle infection, the possible ingestion of the disposal sporocyst stage from dogs must be eliminated. Although in this study, the prevalence of S. hominis was low and cannot be considered as a major zoonosis, it should be recommended avoiding eating under cooked hamburger and other bovine meat products to prevent human infection. PMID- 29114134 TI - Epidemiological investigation of gastrointestinal parasites in dog populations in Basra province, Southern Iraq. AB - The understanding of the epidemiology of canine parasitic infections is necessary for an efficient control program to minimize the risk of zoonotic transmission. The objectives of this study were (1) to determine the prevalence of canine gastrointestinal helminths and protozoa in Basra province, Southern Iraq, and (2) to identify the association of epidemiological characteristics (age, breed, gender, and feed type) of dogs with the parasitic infections. A total of 93 fecal samples, collected in the period from December 2014 to June 2015, were examined macroscopically and microscopically for the presence of worm eggs and protozoal oocysts, using centrifugal flotation method. The overall prevalence of infected dogs was 77.4% (72/93). About 54.8% (51/93) dogs were infected with more than one genus of parasites. The prevalence of multiple infections with two, three, and four parasites was 30.1% (28/93), 22.6% (21/93), and 2.2% (2/93), respectively. The most frequently detected parasites were Toxocara canis (62.4%, 58/93), Physaloptera spp. (28%, 26/93), Alaria spp. (26.9%, 25/93), Trichuris vulpis (9.7%, 9/93), and Ancylostoma caninum (7.5%, 7/93). Isospora canis (6.5%, 6/93) and Giardia spp. (4.3%, 4/93) were the only protozoan parasites identified in this study. Toxocara canis infection was significantly associated with sex and age of the dogs (P < 0.05). Feeding type was significantly associated with the occurrence of T. canis (P < 0.0001), A. caninum (P < 0.03) and Alaria spp. (P < 0.02). The high prevalence of intestinal helminths in dog's population suggesting the need for more efficient control measures. The high prevalence of T. canis, T. vulpis, A. caninum and Giardia spp. suggested that dogs could play an active role in the transmission of zoonotic parasites in this area of Iraq. Educating the dog owners and increasing their health awareness should be considered in the control program. The results of the present study provide relevant "base-line" data for assessing the effectiveness of future control strategies against canine parasitic infections. PMID- 29114135 TI - Prevalence of Eimeria species in domestic chickens in Anhui province, China. AB - Prevalence studies can adequately assist in the design of prophylaxis strategies for disease control. Here, the prevalence of Eimeria species in chickens was investigated in Anhui province, China, from July to September 2016. A total of 171 samples were tested by microscopic examination and molecular methods. The prevalence of coccidiosis in Anhui province was found to be 87.75% (150/171). Eimeria tenella was the most prevalent species (80.67%, 121/150), and Eimeria necatrix, Eimeria mitis, Eimeria maxima, Eimeria brunetti and Eimeria acervulina were 68% (102/150), 55.33% (83/150), 54.67% (82/150), 44.67% (67/150) and 2.67% (4/150), respectively. Eimeria praecox was not detected at all. The most common combinations are E. tenella, E. maxima, E. necatrix, E. brunetti and E. mitis (26.67%, 40/150), followed by E. tenella, E. maxima and E. necatrix (19.33%, 29/150). Eimeria necatrix exhibited the highest participation in multiple infections. The results of the present study suggested that Eimeria infection is mixed, severe and widespread in chickens, Therefore, integrated strategies should be performed to prevent and control coccidial infection in chickens in Anhui province. PMID- 29114136 TI - Efficacy of Zingiber officinale ethanol extract on the viability, embryogenesis and infectivity of Toxocara canis eggs. AB - This study evaluated the effect of Zingiber officinale (Z. officinale) ethanol extract on the viability, embryogenesis and infectivity Toxocara canis (T. canis) eggs. It was carried out both in vitro and in vivo. In the in vitro experiment, unembryonated T. canis eggs were incubated with 25, 50 and 100 mg/mL Z. officinale extract at 25 degrees C for 6, 12, and 24 h to assess the effect of Z. officinale on their viability and for two weeks to assess the effect of Z. officinale on their embryogenesis. In vivo experiment was performed to assess the effect of Z. officinale on infectivity of T. canis eggs. Treated embryonated eggs by Z. officinale extract at concentrations of 25, 50 and 100 mg/mL for 24 h were inoculated into mice and their livers were examined for the presence of T. canis larvae on the 7th day after infection and for histopathological evaluation at 14th day post-infection. Z. officinale showed a significant ovicidal activity on T. canis eggs. The best effect was observed with 100 mg/mL concentration after 24 h with an efficacy of 98.2%. However, the treated eggs by 25, 50 mg/mL of Z. officinale extract after 24 h showed ovicidal activity by 59.22 and 82.5% respectively. Moreover, this extract effectively inhibited T. canis eggs embryogenesis by 99.64% and caused their degeneration at the concentration of 100 mg/mL after 2 weeks of treatment. However, the lower concentrations, 25 and 50 mg/mL inhibited embryogenesis by 51.19 and 78.57% respectively. The effect of Z. officinale on the infectivity T. canis eggs was proven by the reduction of larvae recovery in the livers by 35.9, 62.8 and 89.5% in mice groups inoculated by Z. officinale treated eggs at concentrations of 25, 50 and 100 mg/mL respectively. Histopathologically, the liver tissues of mice infected with Z. officinale treated eggs at the concentration of 100 mg/mL appeared healthy with slight degenerative changes of hepatocytes, opposite to that recorded in the infected mice with treated eggs by the lower concentrations. In conclusion; Z. officinale extract possessed dose-dependent anti-T. canis activity on the viability, embryogenesis and infectivity of T. canis eggs. PMID- 29114137 TI - Gross and histopathological alterations associated with cystic echinococcosis in small ruminants. AB - Hydatidosis, an important parasitic zoonoses is a major public health as well as economic concern throughout the world. A total of 2100, sheep (2052) and goats (48), slaughtered or spontaneously dead, from various areas of Kashmir valley were screened for the presence of hydatidosis. Out of 2100 cases, 85 were positive for hydatidosis. The frequently infected organs were lungs and liver. The liver was observed to be the most frequently infected organ with relative prevalence of 61.17% followed by lungs (38.82%). The pulmonary cysts were more fertile (55%) compared to hepatic cysts (45%). Histopathologicallly, the cyst wall consisted of the inner germinal, middle lamellated/laminated, and outer fibrous layer. Inflammatory reaction around the cyst was variable and was characterized by an inner zone of loosely arranged fibroblasts infiltrated with mononuclear cells, followed by densely arranged fibroblasts along with mononuclear cells; and an outer layer of fibrous connective tissue. Fibroplasia and calcification were noted at places. In liver besides the cellular reaction against the expanding cyst, hepatocellular degeneration and cirrhosis were observed, the severity of which was inversely related to the distance from the cyst. The structural details of the protoscolices were clearly discernable. PMID- 29114138 TI - Anti-Trichomonas vaginalis activity of nano Micana cordifolia and Metronidazole: an in vitro study. AB - Trichomonas vaginalis is a flagellate parasite living in the genital tract and it is accounted as a sexually transmitted disease. The clinical symptoms vary from the asymptomatic to the severe form which is usually associated with the irritation, itching and infertility in some severe cases. Many drugs have been applied to treat this disease and Metronidazole is the gold standard for treatment; however, it has also detected that this medicine has many side-effects which it has been motivated the researchers to find an appropriate alternative for this medicine. One of the treatment options is the use of the herbal medicines and natural compounds. Thus, the aim of this study was to compare the in vitro anti-T. vaginalis activity of nano-emulsion of Micana cordifolia and Metronidazole. In this study, T. vaginalis was isolated from the clinical samples and were cultured on a modified Dorsate medium. The nano-emulsion of M. cordifolia was prepared by heating technique. The effect of nano-emulsion of M. cordifolia was separately investigated on the T. vaginalis at the times of 12, 24 and 72 h and the obtained data were analyzed by the Spss 20 using the ANOVA test. The results indicated that the concentration of 100 ppm of nano-emulsion of M. cordifolia at the times of 12, 24 and 72 h has the anti-T. vaginalis activity of 44 +/- 1.66, 37 +/- 1 and 25 +/- 2, respectively. It is also observed that the concentration of 500 ppm of the extract has the best effect and was able to eliminate the 85% of T. vaginalis. Furthermore, the anti-T. vaginalis activity of nano M. cordifolia was observed to be 100% in the concentrations of 1000 ppm. It can be concluded, based on the results, that the nano M. cordifolia has acceptable efficacy on the elimination of T. vaginalis and it can be a suitable alternative for Metronidazole after implementation of complementary tests on laboratory animals and human cells. PMID- 29114139 TI - Epidemiology of pathogenic parasite Histomonas meleagridis in poultry in Lorestan province, western Iran. AB - Histomonas meleagridis is a flagellate protozoan parasite living in the cecum of birds digestive system and is the causative agent of histomoniasis. In this study 110 poultry fresh stool samples were assessed in order to detect H. meleagridis, and egg or adult worm of Heterakis gallinarum in Lorestan province, Iran. The results showed that the prevalence of H. meleagridis was 31%. Also, 19.5% of infected poultry had a watery stool. The eggs or adult worms of H. gallinarum were not seen in any of the samples. The results showed the high prevalence of this parasite, and the factors such as temporary hosts, susceptible hosts, and cloacal transmission with the involvement of water containing the parasite are the effective risk factors in prevalence. It is better to considered H. meleagridis as waterborne parasites, so further epidemiological studies on other birds are suggested to determine the parasite pathogenic strains using molecular methods. PMID- 29114140 TI - Analysis of hospital records of children with hydatid cyst in south of Iran. AB - The clinical manifestations of hydatidosis are various and related to anatomic location. Defining frequent symptoms and signs of the disease is imperative for early management of it. The aim of this report was to analyse the clinical features of infected children with hydatid cysts located in different organs. In this study, medical charts of 57 children between 3 and 16 years of age with hydatid cyst admitted to Pediatric Wards of Nemazee Hospital were evaluated over a 12 year period (from 2003 to 2014, prospectively). All the epidemiologic, clinical, paraclinical and therapeutic data were collected. The frequencies of hydatidosis in males and females were 42.1 and 56.1%, respectively. Hydatid cysts were found in the liver and lungs in 59.6 and 33.3% patients respectively and 2 patients had an asymptomatic cyst in the heart with concomitant liver and lung cysts. The right upper quadrant pain (100%) was the most common symptom in the liver cysts. Phlegm (78.9%), Dyspnea (57.9%), acute (47.4%) and chronic cough (47.4%) were mostly seen in lung hydatid cysts. Some symptoms such as fever (68.4%) and weakness (59.6%) were the most common presenting symptoms in both groups. All children were treated through surgical approaches plus medical treatment. In the present report, liver was the most common site of involvement in children. Liver hydatidosis should be considered in children with upper quadrant pain and pulmonary hydatidosis in children complaining of phlegm and dyspnoea. PMID- 29114141 TI - Effect of phenyl vinyl sulphone cysteine protease inhibitor on Schistosoma mansoni: in vitro and in vivo experimental studies. AB - The present work aimed to study the effect of phenyl vinyl sulphone (PVS), a CPI, on different stages of Schistosoma (S.) mansoni in an in vitro culture study and in experimentally infected mice, compared to PZQ. As regards the in vitro study, different concentrations of PVS (1, 2, 4, 6, 8 and 10 ug/ml) and PZQ (1 ug/ml) were assessed by % worm mortality for schistosomula and adults, and hemoglobin degradation by schistosomula. In vivo study included 8 groups of mice. Intraperitoneal PVS, subgroup (a), and oral PZQ, subgroup (b), were assessed at different durations post infection (pi); at 1, 3, 5 and 7 weeks pi (groups I, II, III and IV, respectively). Infection, PVS, PZQ, and normal control groups (groups V-VIII) were included. The anti-schistosomal effects of PVS were assessed by parasitological, histopathological and haematological parameters. In in vitro study, PVS had a schistosomicidal effect in a concentration and time dependent manner, PVS showed 100% schistosomula mortality at day 2 and 92% adult worm mortality at day 5. Furthermore, PVS decreased hemoglobin degradation by schistosomula. In in vivo study, PVS showed a decrease in total worm burden and tissue egg load in intestine and liver with an increase in number of dead ova in intestine of mice. Furthermore, PVS resulted in a decrease in number, size and cellularity of hepatic granulomas and an increase in hemoglobin concentration.PVS was better than PZQ in reducing each of tissue egg count in intestine at 5 and 7 weeks pi, and hepatic granuloma size at 3, 5 and 7 weeks pi. These results suggest that PVS can be a promising chemotherapeutic agent in Schistosoma mansoni infection. PMID- 29114142 TI - Gastrointestinal parasitic infections in Indian Gaddi (goat) breed bucks: clinical, hemato-biochemical, parasitological and chemotherapeutic studies. AB - The present study was envisaged with an aim to evaluate gastrointestinal parasitic infections in a herd of conserved Gaddi (goat) breed bucks (6-9 months of age) kept on semi-intensive feeding management. The individuals (n = 20) representing the herd were selected and divided into two groups; group I (n = 10), clinically ill and group II (n = 10), sub clinically infected individuals. The clinical examination revealed anemia, emaciation and rise in body temperature of the individuals of group I as compared to group II. The detailed copro parasitological examination and copro-culture revealed the presence of eggs of Moniezia expansa and larvae of Haemonchus species, respectively in the fecal samples of both clinically and sub clinically infected individuals. The hemato biochemical parameters proved vital indicators of the health of group I individuals and exhibited decline in the values of hemoglobin, packed cell volume and total erythrocyte count as compared to group II. Significant (P < 0.05) hypoproteinemia, hypoalbuminemia, hypoglycemia and increased levels of alanine aminotransferase and aspartate aminotransferase were observed in infected individuals as compared to treated ones. The detailed parasitological, hemato biochemical observations and clinical findings elucidated and supported the presence of concurrent gastrointestinal parasitism in the herd. The significant improvement was observed in the health status of the herd after 1 month of the therapeutic management, which was carried out using a combination of fenbendazole and praziquantel in both clinically and sub clinically infected individuals. PMID- 29114143 TI - Assessment of Achyranthes aspera induced toxicity and molecular analysis of RAPD PCR profiles of larval genomic DNA of Aedes aegypti L. (Diptera: Culicidae). AB - Current studies investigated the anti-mosquito potential of Achyranthes aspera against the dengue vector, Aedes aegypti. The stems and leaves of A. aspera were extracted in hexane and evaluated for their toxicity against early fourth instars of A. aegypti. The larvicidal efficacy of the extract was validated as per WHO protocol. The mortality counts were made after 24 h and LC values were calculated at different levels. The adverse impact of extracts was also explored on the larval genomic DNA. The larvae were exposed to extracts at LC50 levels and the alterations in g-DNA was evaluated through RAPD-PCR technique using three random primers; MA-09, MA-12 and MA-26. Our investigations ascertained the larvicidal efficacy of both the leaf and stem extracts of A. aspera resulting in respective LC50 values of 0.068 and 0.082 mg/mL. The extracts also caused variable genotoxic effects with significant changes in the RAPD profiles. The results showed appreciable modifications in larval g-DNA with loss of certain bands and gain of unique bands with 82.35% DNA polymorphism. These alterations suggest the probable DNA damage and mutations in the larval g-DNA caused by certain phytocomponents which could be the possible reason of larval mortality. Our studies evidenced the anti-mosquito potential of A. aspera extracts against A. aegypti causing appreciable larval mortality and significant changes in g-DNA. The A. aspera extracts are suggested as efficient and eco-friendly control agent against A. aegypti, yet further investigations are needed to identify the bioactive constituent and ascertain its effectiveness in the field conditions. PMID- 29114144 TI - Impact of epidemiological factors on the prevalence, intensity and distribution of ectoparasites in pigeons. AB - This study was carried out on domestic pigeons (Columba livia domestica) from September (2014) to June (2015) to determine the prevalence, intensity and species of ectoparasites in Sargodha region, east of Pakistan. A total of 200 domestic pigeons were inspected from the study area. Parasites were collected by forceps and stored in 70% ethanol. The epidemiological information e.g. health condition, color of plumage, mode of living, breed, intensity etc. were recorded in the form of questionnaire. The overall prevalence of ectoparasites in pigeon was 90.5% (181/200). Of the total of 200 (83 males and 117 females) domestic pigeons inspected, 73 (87.95%) and 108 (92.30%) were infected, respectively. The ectoparasites spp. were identified as Columbicola columbae (Linnaeus, 1758) and Colpocephalum turbinatum (Denny, 1842). The Qasid breed showed highest infestation rate (91.25%) as compared to other two observed breeds. Pigeon of white color were more infested (91%) as compared to other colors. Thus color and breed factors showing the random differences. In medicated birds the rate of infestation of ectoparasites was 87% reflecting that drugs are unable to control or might be due to resistance. There was significant difference between the number of parasites on tail, neck, chest and wings within different breeds, as well as in the months. The mean intensity of parasites was in urban areas (28.5), rural areas (14.98), and sub-rural areas (23.55). In conclusion the prevalence of ectoparasites in pigeons is very high in north-east region of Pakistan. PMID- 29114145 TI - Studies on theileriosis in goats from Karnataka, South India. AB - A study was conducted to determine the prevalence of theileriosis in goats from southern districts of Karnataka. Out of 47 goat blood samples examined by microscopy, 68.08% (32/47) were positive for Theileria spp. The parasitemia ranged from 1.0 to 1.8 and 0.1-0.9% in clinical and carrier animals respectively. Out of 325 ticks collected from goats, 92.6 (301) and 7.38 (24)% of the ticks were found to be Haemaphysalis and Rhipicephalus respectively. Hemaphysalis kutchensis (90.15%) was found to be the predominant species followed by R. haemaphysaloides (6.7%), H. intermedia (1.84%), H. bispinosa (0.61%) and R. sanguineus (0.61%). The present study indicated that caprine theileriosis is an endemic disease in Karnataka and suggested that Haemaphysalis and Rhipicephalus ticks may play a role in transmission of the disease. PMID- 29114146 TI - Immunological evaluation of some antigens of Lucilia sericata larvae. AB - The present study aimed to select an antigen of Lucilia sericata larvae showing both high antigenicity and cross-reactive binding abilities with other related antigens of L. sericata larvae for obtaining a promising candidate vaccine antigen. The ELISA results primary concluded that among the excretory secretory (ES) and midgut (MG) antigens of the different larval instars of L. sericata, MGL2 could be characterized as antigen which was able to reflect the highest level of antigenicity and cross-reactivity with the other tested L. sericata antigens. The results were extended to spot the light on the relation between different protein bands in MGL2 and rabbit hyper- immune sera (HIS) raised against the other tested antigens using SDS-PAGE and Western blot technique. Analysis by SDS-PAGE of ES and MG antigens of the different larval instars of L. sericata revealed common protein bands at molecular weights of about 10, 12, 16, 20, 28, 33 and 46 kDa. Western blotting of MGL2 antigen transferred to nitrocellulose sheet revealed reaction by MGL2 HIS to five polypeptide bands; 20, 28, 33, 46 and 63 kDa. Three bands of 28, 33 and 63 kDa were the most prominent bands detected whereas; there was a weak reaction with bands of 20 and 46 kDa. But what was apparent in Western blot was a strong reaction of all tested HIS with a polypeptide band of 63 kDa. This band might be considered to be the main cause of cross reactive binding ability of MGL2 antigen that had been recorded previously in ELISA technique. PMID- 29114148 TI - The enzymes and electrolytes profiles in hydatid cyst fluid of naturally infected Iranian domestic ruminants. AB - Cystic echinoccoccosis is a zoonotic and prevalent disease which causes health problems and economic looses worldwide. The biochemical components of hydatid cyst fluid (HCF) have important role in metabolism and growth of unilocular hydatid cyst. The aim of the current study was to determine HCF level of enzymes and electrolytes profiles in naturally infected Iranian domestic ruminants. The livers and lungs infected with hydatid cysts were collected and HCF was aspirated from a total of 100 cysts obtained from livers (50 cysts) and lungs (50 cysts) of slaughtered domestic ruminants. Biochemical measurement of HCF was undertaken using colorimetric technique, refractometer, flame photometer, and biuret method. The enzyme levels of HCF were also measured by using appropriate kits. The average HCF level of calcium (Ca) was found to be significant higher in cattle (7.49 +/- 1.28 mg/dl) and goats (13.98 +/- 5.11 mg/dl) lungs. The average HCF level of phosphorous (P) was significantly higher in cattle livers (0.82 +/- 0.02 mg/dl) than other examined animals. Measurement of the average HCF level of magnesium (Mg) was significantly lower in camel lungs (11.8 +/- 1.05 mg/dl) than that in cattle livers (10.56 +/- 1.73 mg/dl). The highest average HCF levels of Natrium (Na, 122.8 +/- 11.91 mEq/l) and Kalium (Ka, 7.18 +/- 1.37 mEq/l) were measured in sheep livers. The average HCF level of albumin (Alb) in infected lungs was significantly lower in cattle (0.48 +/- 0.01 mg/ml) than camels (0.95 +/- 0.05 mg/ml). The average HCF level of total protein (TP) in infected lungs was also lower in sheep (0.51 +/- 0.06 mg/dl) than goats (3.21 +/- 0.51 mg/dl). The highest average HCF level of creatine phosphokinase (CPK, 1229.25 +/- 13.21 U/ml) and lactate dehydrogenase (LDH, 363.62 +/- 10.44 U/ml) were measured in infected lungs of camels. It was concluded that HCF level of enzymes and electrolytes had differences in examined Iranian domestic ruminants which may be used to screen and help in characterization and identification of strains of Echinococcus granulosus. PMID- 29114147 TI - Malaria-induced anaemia and serum micronutrients in asymptomatic Plasmodium falciparum infected patients. AB - Interaction between malaria, anaemia and malnutrition is poorly understood in asymptomatic malaria patients. This information is important in the management of malaria infection in many endemic regions in sub-Saharan Africa. Malaria parasitaemia, full blood counts and serum levels of essential micronutrients particularly iron (Fe), zinc (Zn) and copper (Cu) of the patients attending Health Centres in Ilorin, Kwara state were investigated using microscope, auto haemanalyzer and atomic absorption spectrophotometer respectively. A total of 123 (55.2%) of our study population were positive of Plasmodium falciparum. Infection was age-specific (p < 0.0001), and a significant proportion (88.6%) of malaria infected patients were 28.5% mild, 45.5% moderate and 14.6% severely anaemic. The severity of anaemia increases as parasite density increases. Analysis of serum micronutrients revealed a significant low level of iron (3.72 mg/l), copper (2.05 mg/l) and zinc (3.67 mg/l) in infected patients (p < 0.0001); which further increased their anaemic condition. This study confirmed a significant relationship between severity of anaemia and nutritional deficiency in the pathogenesis of malaria infection. We therefore, recommend that immunomodulation potential of micronutrients may be essential in the management of malaria infection. PMID- 29114149 TI - Cat fur mite Lynxacarus radovskyi in India. AB - A Persian cat with the complaint of lustreless dry coat, salt and pepper appearance was brought to the dermatology unit of Madras Veterinary College, Chennai. Microscopical examination of the tape impression and hair coat brushings revealed Lynxacarus radovskyi mites with eggs adhering to the hair shaft. The cat was treated with Ivermectin @ 300 ug/kg body weight subcutaneously once a week for 5 weeks after getting owner's consent. The cat was free from the parasites 5 weeks post treatment. Fomite and close contact might aid the spread of infestation. Isolation coupled with full course of treatment favours complete recovery from the infestation. PMID- 29114150 TI - Response of outbred albino mice to concomitant Heligmosomoides bakeri, Plasmodium berghei and Trypanosoma brucei infections. AB - To investigate the response of mice to concomitant infections with Trypanosoma brucei (Tb), Plasmodium berghei (Pb) and Heligmosomoides bakeri (Hb) infections. Each group of 6 mice was either infected with Pb + Tb + Hb, Pb + Tb, Pb + Hb, Tb + Hb, Pb, Tb, Hb or remained as uninfected controls. Hb infected mice each received 200 infective larvae (L3) of Hb orally, Tb infected mice each received 2 * 10-6 organisms through the intraperitoneal route while Pb infected mice received 1 * 10-5 parasitized red blood cells through the intraperitoneal route. PCV, body weights (BW), faecal egg counts (FEC), Tb parasitaemia, Pb parasitaemia, clinical signs and worm burdens (WB) were determined. FEC were highest in Pb + Tb + Hb and least in Hb group and the difference was significant (P < 0.05). WB was significantly higher in mice with concurrent infections. PCV of infected mice was lower than that of uninfected controls and the difference was significant between Pb + Tb + Hb infected and uninfected controls. The difference in weight loss was significant between Pb + Tb + Hb infected and controls. Mortalities occurred in Pb + Tb + Hb, Tb + Hb and Pb + Hb infected mice. Mortalities and low PCV and low BW were indications that concomitant infections were more pathogenic to the mice than single infections, pathogenicity increasing with increasing number of parasite species involved. PMID- 29114151 TI - Spatio-temporal analysis of cutaneous leishmaniasis using geographic information system among Iranian Army Units and its comparison with the general population of Iran during 2005-2014. AB - To investigate the time trend and distribution of cutaneous leishmaniasis in Iranian Army Units (IAUs) and general population (GP). with using census, Data on CL incidence in IAUs (from AJA University of Medical Sciences) and GP (from Ministry of Health) during 2005-2014 were extracted and entered into the GIS software. Cochran-Armitage test, choropleth map, hot-spot analysis and high/low clustering analysis were used to determine time trend, distribution of disease, hot-spots, and possible abnormal clustering, respectively. The number of infected individuals in IAUs and GP were 6533 and 153,499 respectively (with incidence rates of 143.68 per 100,000 and 25.86 per 100,000, respectively). Time trend analysis revealed the departure from linear trend for the incidence in IAUs (p < 0.001), but no such time trend was found in GP. According to choropleth maps; in IAUs, Khozestan from southwest, Esfahan from central and Kermanshah from west parts of Iran and among GP; Fars, Yazd, and Kerman in southern-east of Iran showed a high incidence rates. In IAUs, Esfahan and Khuzestan provinces was hot spots of CL (p < 0.05), but in GP, provinces like Fars and Khorasan-shomali was hot-spots (p < 0.05). No clustering pattern of disease was observed in either study populations. Observed spatiotemporal variability in CL among IAUs and GP warrants proper health programs particularly to Khozestan and Esfahan in IAUs and Fars and Khorasan-shomali in GP are highly recommended. PMID- 29114152 TI - Characterization of a new isolate of entomopathogenic nematode, Steinernema sangi (Rhabditida, Steinernematidae), and its symbiotic bacteria Xenorhabdus vietnamensis (gamma-Proteobacteria) from Mizoram, northeastern India. AB - A survey was conducted to isolate indigenous EPN, specifically from the northeastern part of India, a biodiversity hotspot region, to record the occurrence and their further use as biological control agent. The morphological and molecular analysis (ITS rDNA for Steinernema and 16S rRNA for Xenorhabdus) revealed that the entomopathogenic nematodes isolated from four different habitats and its symbiotic bacteria are conspecific with Steinernema sangi and Xenorhabdus vietnamensis respectively. The phylogenetic analysis based on maximum parsimony (MP) revealed that Steinernema sangi belongs to feltiae-kraussei oregonense group. The study constitutes the first report of Steinernema sangi and its symbiotic bacteria Xenorhabdus vietnamensis outside the type locality, Vietnam, and in particular from India. PMID- 29114153 TI - Genetic polymorphism of Plasmodium vivax Duffy Binding Protein in malarious areas in southeastern of Iran. AB - Plasmodium vivax parasite causes the largest number of malaria infection in some malarious areas of the world including Iran. Considering transfer and genetic dynamics of the parasite population in a specific area can help us to predict the spread of the infection either emergence of new cases or drug resistance in the context of elimination program in the malarious areas. Study on the genetic diversity of common alleles in a given geographical area, for vaccine and immune level studies can be important. The purpose of this study was to know the status of P. vivax Duffy Binding Protein (PvDBP) polymorphism in patients infected with the parasite in malaria endemic southeastern Iran. The fragment of gene corresponding to PvDBP of thirty P. vivax malaria infected individuals was amplified. A 1176 bp band related to this fragment was purified and PCR-RFLP method was employed using enzymatic digestion with PstI and RsaI restriction enzymes. Ten percent of samples were sent for sequencing. PCR-RFLP showed that 99.7% of the samples were cut as the same together, either the PstI enzyme or the enzyme of RsaI. In each case, only 2 isolates were unlike others. Findings revealed that there is at least 96% identity among isolates in the nucleotide level. Amino acid pattern of PvDBP in Iranian isolates showed little discrepancies with those PvDBP genes that have been recorded in GenBank. Sequencing of PvDBP isolates of Iranian P. vivax infected patients showed low level of genetic polymorphism among them. Results of this study can prepare valuable information for malaria policy makers to intend them in their malaria control program. PMID- 29114154 TI - Comparative efficacy of commercial preparation of deltamethrin and cypermethrin against Ornithodoros spp. of North Gujarat. AB - Ticks have massive capacity of acting as vectors of numerous pathogens that affect human, livestock and pets, which owes to their medical and veterinary importance. In animals, tick infestations are much more severe than in humans. Animals can be parasitized by hundreds or even thousands of ticks, which then proliferates the effect on the host. In almost all tropical and subtropical countries like India not only the hard ticks (Ixodidae) but also the soft ticks (Agrasidae) are responsible for economic losses either by direct injuries or disease transmission. Presently used control measure for ticks is only the use of commercially available acaricide compounds which are not much satisfactory and therefore a check on efficacy of these compounds is necessary for effective control. Commercially available preparations of deltamethrin (Butox, 1.25% E.C.) and cypermethrin (Ectomin, 10% E.C.) were compared for the acaricidal activity against soft ticks, Ornithodoros moubata by using Larval Packet Test. Larval mortality was higher with Butox as compared to Ectomin. Butox elicits 70% larval mortality, at the manufacturer's recommended dosage (25 ppm) while for Ectomin, larval mortality was 38.46% at the manufacturer's recommended dosage (200 ppm). This illustrates that deltamethrin (Butox) is more effective then cypermethrin (Ectomin). PMID- 29114155 TI - In-vitro trials to ascertain sustained release efficacy of assembly pheromone micro particles for the control of brown dog tick, Rhipicephalus sanguineus. AB - Sustained release micro particles were prepared incorporating assembly pheromone and deltamethrin. Two natural polymers, namely, chitosan and calcium alginate and a synthetic polymer, poly-epsilon-caprolactone were used for encapsulating the assembly pheromone-acaricide combination. The micro particles were subjected to in vitro evaluation freshly after preparation and then at monthly intervals to assess their sustained release efficacy. The response of the unfed stages of dog tick, Rhipicephalus sanguineus to fresh and aged micro particles was assessed and results were recorded. The micro particles were found to release assembly pheromone in a sustained manner up to 2 months of study period. PMID- 29114156 TI - Two new species of furcocercous cercariae infecting the fresh water snail, Thiara tuberculata (Muller) in Kozhikode and Malappuram districts of Kerala. AB - Two new species of furcocercous cercariae, Cercaria sp. XVI Malabar n. sp. and Cercaria sp. XVII Malabar n. sp. were recovered from the freshwater snail, Thiara tuberculata in the Malabar region of Kerala. Cercaria sp. XVI Malabar n. sp., a pharyngeate, longifurcate furcocercous cercaria with two pairs of penetration glands and 10 pairs of flame cells was recovered from T. tuberculata collected from Kundayithode in Kozhikode district and Nilambur in Malappuram district of Kerala. Cercaria sp. XVII Malabar n. sp., another pharyngeate, longifurcate cercaria with a rudimentary ventral sucker was recovered from the same snail host collected from Nilambur in Malappuram district. Sporocysts of Cercaria sp. XVI Malabar n. sp. developed in the hepatopancreas, while that of Cercaria sp. XVII Malabar n. sp. were found developing in both hepatopancreas and stomach wall. The present paper describes the new species of cercariae in detail and compares them with related species to establish their systematic position. PMID- 29114157 TI - A study on the occurrence of pinworms in the hindgut of Periplaneta americana. AB - American cockroach, Periplaneta americana harbours pinworms in their gut. In the present study, 88 host cockroaches were dissected and the number of adult females of each pinworm species was recorded from Barasat, North 24 Parganas, West Bengal. Three species of Oxyurid nematodes were found: Hammerschmidtiella diesingi (Hammerschmidt, Helminthologische Beitrage. Isis (oken), Leipz 5:351 358, 1838), Leidynema appendiculatum (Leidy in Proc Acad Natl Sci Phila 5:100 102, 1850) and Thelastoma sp. (Leidy in Proc Nat Acad Sci Phila 4:30, 1849). At a time two nematode infections (double infection) were also found. H. diesingi and L. appendiculatum mixed infection being more common than H. diesingi and Thelastoma sp. infection. Ed the H. diesingi shown highest prevalence (40.90%) and abundance pattern (1.227). It was the dominant species in most cases. Lowest prevalence (7.95%) and abundance pattern (0.272) was found in Thelastoma sp. Thelastoma sp. has the highest mean density (3.428) followed by Hammerschmidtiella diesingi (3) and Leidynema appendiculatum (2.368). Three species were never found in the same host. This study suggests that host sex had no noticeable impact on the occurrence of pinworms. PMID- 29114158 TI - Seroprevalence of toxoplasmosis in voluntary blood donors of Puducherry and surrounding districts of Tamil Nadu. AB - Our objective is to study the seroprevalence of toxoplasmosis in the voluntary blood donors of Puducherry and surrounding districts of Tamil Nadu. A total of 275 healthy blood donors were screened for the presence of IgM and IgG antibodies to Toxoplasma gondii by ELISA test. Donor samples positive for IgM and/or IgG antibodies to T. gondii were subjected to IgG avidity ELISA. While, 54 out of 275 donors had IgG antibodies (19.66%), only one donor had IgM (0.36%) along with IgG. Among 54 IgG positive donors, only two had low avidity (3.7%), indicating recent exposure to the protozoa. Feasibility and cost effectiveness studies should be conducted throughout India to decide regarding screening of blood donors for toxoplasmosis. PMID- 29114159 TI - Therapeutic management of trypanosomosis with ophthalmic involvement in a dog. AB - The present report communicates a case of canine trypanosomosis with ophthalmic involvement, its diagnosis, hemato-biochemistry and therapeutic management in a 2 year old dog. The dog had history of bilateral corneal opacity and impaired vision since last 4 weeks. On the basis of history and clinical signs, a presumptive diagnosis of canine trypanosomosis was made followed by confirmation with Giemsa stained buffy coat smear examination. Therapeutic regimen was comprised of Diminazine aceturate @ 3.5 mg/kg deep IM for two occasions 24 h apart along with parenteral fluids, hematinics, NSAID and multivitamins which yielded favourable response by third day post-therapy. Haemato-biochemical parameters took nearly 14 days of time to return to near normal levels. Improvement with respect to corneal opacity took 6 weeks of time and the animal was followed up to 3 months without any recurrence. PMID- 29114160 TI - Clinical Characteristics of Troublesome Pediatric Tinnitus. AB - Objectives: The frequency of tinnitus in children and adults is practically the same. However, although adults reveal their symptoms and seek for medical aid, the suffering often remains unrecognized in the young. This is due to both the inability of children to properly describe their symptoms and the lack of recognition. Materials and methods: Among 5768 patients entering our department with complaints of tinnitus between 2010 and 2015, there were only 112 children. A full clinical history and medical status had been determined at the time of presentation and were analyzed retrospectively. Results: The average duration from first complain to clinical presentation was approximately 12 months. A normal hearing capability of less than 25 dB was measured in 80% of the cases. Only 23 patients presented with a hearing impairment. The causes ranged from hearing loss, previous orthodontic treatment, noise trauma, middle ear aeration, muscular neck tension, and skull base fracture. Typical co-morbidities such as sleeping disorders, concentration disorders, and hyperacusis were observed. Conclusions: This retrospective study shows that recognition of tinnitus in the childhood is generally delayed. A better characterization of complaints and triggers, however, is a prerequisite to sensitize medical personnel and caretakers for the suffering and to avoid developmental impairments. PMID- 29114161 TI - A new species of Ophryotrocha (Annelida, Eunicida, Dorvilleidae) from hydrothermal vents on the Southwest Indian Ridge. AB - Dorvilleids were collected from hydrothermal vents on the Southwest Indian Ridge by manned submersible Jiaolong. These represent a new species of Ophryotrocha that is here described as Ophryotrocha jiaolongisp. n. This is the first dorvilleid described from vents on the Southwest Indian Ridge. It most closely resembles another vent species, Ophryotrocha akessoni Blake, 1985 from the Galapagos Rift, but can be distinguished by its antennae, palps, jaw structure. The new species has particularly distinctive mandibles, which allow it to be easily identified. PMID- 29114162 TI - A new cave centipede from Croatia, Eupolybothrus liburnicus sp. n., with notes on the subgenus Schizopolybothrus Verhoeff, 1934 (Chilopoda, Lithobiomorpha, Lithobiidae). AB - A new species of Eupolybothrus Verhoeff, 1907 discovered in caves of Velebit Mountain in Croatia is described. E. liburnicussp. n. exhibits a few morphological differences from its most similar congeners, all of which are attributed to the subgenus Schizopolybothrus Verhoeff, 1934, and two approaches to species delimitation using the COI barcode region identify it as distinct from the closely allied E. cavernicolus Stoev & Komericki, 2013. E. spiniger (Latzel, 1888) is redescribed and a lectotype is designated for it as well as E. caesar (Verhoeff, 1899) to stabilize their respective taxonomic status. The subspecies E. acherontis wardaranus Verhoeff, 1937, previously suspected to be a synonym of E. caesar (Verhoeff, 1899), is redescribed and its taxonomy revised after the study of type material whereas the identity of E. acherontis (Verhoeff, 1900) described from a female from southwest Trebinje (Bosnia and Herzegovina) remains unknown. Type material of E. stygis (Folkmanova, 1940) is confirmed to be lost and future designation of neotypes from topotypic specimens is necessary to stabilize its taxonomy. The importance of setal arrangement on the intermediate and 14th tergites and the sexual modifications on the male 15th prefemur for species identification is discussed in the light of present findings, and a review of the species of E. (Schizopolybothrus) that display these traits is also provided. PMID- 29114163 TI - A new and unusual species of Amastigogonus Brolemann, 1913 from Tasmania, Australia (Diplopoda, Spirostreptida, Iulomorphidae). AB - Amastigogonus insularissp. n. is described from Schouten and Tasman Islands off the east coast of Tasmania, and a key is presented for the identification of males of Tasmanian Amastigogonus species. The new species differs from the 10 previously described species of Amastigogonus in having a reduced coxite process on the anterior gonopod. PMID- 29114164 TI - Two new species of Centrodora (Hymenoptera, Aphelinidae) from China, with a key to Chinese species. AB - Two new species of Centrodora Forster, C. crassiscapasp. n. and C. pellucidasp. n., are described from China. A key to species from China based on females is given. PMID- 29114165 TI - A second locality for the Namib darkling beetle Onymacris brainei (Tenebrionidae, Coleoptera) and first report on its molecular phylogenetic placement. AB - Onymacris brainei Penrith, 1984 - the most recent species of Onymacris to be described - is known only from its type locality in the Namib Desert, adjacent to the Cunene River in northern Namibia. No additional specimens are known to have been collected beyond the type series. Herein, we report on eight specimens discovered at a second site near the original locality. DNA from four beetles was used to determine the phylogenetic placement of O. brainei among congeners, based on sequence data from one nuclear (histone III) and two mitochondrial (cox1, cox2) genes. Maximum likelihood analysis identifies O. brainei as a member of the 'white' Onymacris clade, in which it forms a strongly supported subclade with O. bicolor and O. marginipennis. More broadly, its phylogenetic placement augments previous molecular results that revealed a sister taxon relationship between the 'white' Onymacris and a second genus, Physadesmia. The paraphyly of Onymacris with respect to Physadesmia highlights a need for nomenclatural change, but revision should await acquisition of genetic data for the few species outstanding in both genera. PMID- 29114166 TI - Three new species and one new record of the genus Siphunculina from China (Diptera, Chloropidae). AB - Three new species of the genus Siphunculina Rondani from China, S. bulbiferasp. n., S. scalpriformissp. n., and S. shangyongensissp. n., are described and illustrated. One species, S. funicola (de Meijere), is reported from China for the first time. A key to the species of genus Siphunculina from China is given. PMID- 29114167 TI - Data from the ichthyological collection of the Museu Paraense Emilio Goeldi. AB - This dataset contains information on the occurrence of Neotropical fishes (Actinopterygii, Chondrichthyes, Sarcopterygii) collected in South America, mostly from the Brazilian Amazon. The ichthyology collections of the Museu Paraense Emilio Goeldi (MPEG: http://www.museu-goeldi.br/) include specimens collected between 1900 and 2014. The dataset is now available for public consultation on the Global Biodiversity Information Facility portal (http://www.gbif.org/dataset/b0059a3a-5cab-4a08-8d14-d92c23378e43), and through Sistema de Informacao sobre a Biodiversidade Brasileira (http://gbif.sibbr.gov.br/explorador/pt/recurso/62). PMID- 29114168 TI - A new species of Pristimantis from eastern Brazilian Amazonia (Anura, Craugastoridae). AB - In this study a new species of Pristimantis (Anura: Craugastoridae) of the P. conspicillatus species group is described. Pristimantis latrosp. n. is known only from the municipalities of Altamira, Anapu, Brasil Novo, Medicilandia, Uruara and Aveiro (Flona Tapajos, right bank of Tapajos river), in Para state, Brazil. Morphologically, the new species distinguishes from known congeners in the group mainly by the presence of dorsal tubercles and absence of discoidal folds, smooth belly skin, as well as the presence of supernumerary tubercles on hands. The call of the new species consists of seven ascending notes, the first of which has a dominant frequency of 2635 Hz and the last 3272 Hz. Molecular analysis of the 16S mtDNA indicates a genetic distance of 8% to P. chiastonotus, its closet relative, and between 9% and 11% to populations of P. fenestratus. PMID- 29114170 TI - A new species of Pnigalio (Hymenoptera, Eulophidae) parasitizing Eriocrania semipurpurella alpina (Lepidoptera, Eriocraniidae) in China, with its biology and a key to Chinese known species. AB - A new species of Eulophinae, Pnigalio eriocraniae Li & Yang, sp. n., is described and illustrated. This new species is a larval ectoparasitoid of Eriocrania semipurpurella alpina Xu (Lepidoptera, Eriocraniidae), a leaf miner in birch trees, Betula spp. (Betulaceae), in Qinghai Province, northwest China. The biology of the new species and a key to the known species from China are provided. PMID- 29114169 TI - Taxonomic reassessment of two subspecies of Chinese skink in Taiwan based on morphological and molecular investigations (Squamata, Scincidae). AB - The Chinese skink, Plestiodon chinensis (Gray, 1838), is widely distributed across continental China, Taiwan, the Korean Peninsula, and offshore islets, and consists of several subspecies. Here morphological and molecular methods have been used to reassess the taxonomic status and distributions of P. c. formosensis (Van Denburgh, 1912) and P. c. leucostictus (Hikida, 1988), which are endemic to Taiwan and Green Island (an islet off the east coast of Taiwan), respectively. It can be confirmed that the eastern Taiwanese populations of P. c. formosensis exhibit similar juvenile color patterning and genetic composition to the islet subspecies P. c. leucostictus, and are distinct from consubspecific populations in western Taiwan. Therefore, the eastern Taiwanese populations are assigned to P. c. leucostictus, and this subspecies is recognized as a distinct species, Plestiodon leucostictus (Hikida, 1988), based on their unique juvenile coloration and highly divergent DNA sequences. Our results also revealed that P. c. formosensis in western Taiwan is close to nominotypical subspecies from the continent, suggesting the necessity of a comprehensive taxonomic analysis in the future. PMID- 29114172 TI - Theranostic Probes for Cancer Imaging. PMID- 29114171 TI - Molecular phylogenetics of cool-season grasses in the subtribes Agrostidinae, Anthoxanthinae, Aveninae, Brizinae, Calothecinae, Koeleriinae and Phalaridinae (Poaceae, Pooideae, Poeae, Poeae chloroplast group 1). AB - Circumscriptions of and relationships among many genera and suprageneric taxa of the diverse grass tribe Poeae remain controversial. In an attempt to clarify these, we conducted phylogenetic analyses of >2400 new DNA sequences from two nuclear ribosomal regions (ITS, including internal transcribed spacers 1 and 2 and the 5.8S gene, and the 3'-end of the external transcribed spacer (ETS)) and five plastid regions (matK, trnL-trnF, atpF-atpH, psbK-psbI, psbA-rps19-trnH), and of more than 1000 new and previously published ITS sequences, focused particularly on Poeae chloroplast group 1 and including broad and increased species sampling compared to previous studies. Deep branches in the combined plastid and combined ITS+ETS trees are generally well resolved, the trees are congruent in most aspects, branch support across the trees is stronger than in trees based on only ITS and fewer plastid regions, and there is evidence of conflict between data partitions in some taxa. In plastid trees, a strongly supported clade corresponds to Poeae chloroplast group 1 and includes Agrostidinae p.p., Anthoxanthinae, Aveninae s.str., Brizinae, Koeleriinae (sometimes included in Aveninae s.l.), Phalaridinae and Torreyochloinae. In the ITS+ETS tree, a supported clade includes these same tribes as well as Sesleriinae and Scolochloinae. Aveninae s.str. and Sesleriinae are sister taxa and form a clade with Koeleriinae in the ITS+ETS tree whereas Aveninae s.str. and Koeleriinae form a clade and Sesleriinae is part of Poeae chloroplast group 2 in the plastid tree. All species of Trisetum are part of Koeleriinae, but the genus is polyphyletic. Koeleriinae is divided into two major subclades: one comprises Avellinia, Gaudinia, Koeleria, Rostraria, Trisetaria and Trisetum subg. Trisetum, and the other Calamagrostis/Deyeuxia p.p. (multiple species from Mexico to South America), Peyritschia, Leptophyllochloa, Sphenopholis, Trisetopsis and Trisetum subg. Deschampsioidea. Graphephorum, Trisetum cernuum, T. irazuense and T. macbridei fall in different clades of Koeleriinae in plastid vs. nuclear ribosomal trees, and are likely of hybrid origin. ITS and matK trees identify a third lineage of Koeleriinae corresponding to Trisetum subsect. Sibirica, and affinities of Lagurus ovatus with respect to Aveninae s.str. and Koeleriinae are incongruent in nuclear ribosomal and plastid trees, supporting recognition of Lagurus in its own subtribe. A large clade comprises taxa of Agrostidinae, Brizinae and Calothecinae, but neither Agrostidinae nor Calothecinae are monophyletic as currently circumscribed and affinities of Brizinae differ in plastid and nuclear ribosomal trees. Within this clade, one newly identified lineage comprises Calamagrostis coarctata, Dichelachne, Echinopogon (Agrostidinae p.p.) and Relchela (Calothecinae p.p.), and another comprises Chascolytrum (Calothecinae p.p.) and Deyeuxia effusa (Agrostidinae p.p.). Within Agrostidinae p.p., the type species of Deyeuxia and Calamagrostis s.str. are closely related, supporting classification of Deyeuxia as a synonym of Calamagrostis s.str. Furthermore, the two species of Ammophila are not sister taxa and are nested among different groups of Calamagrostis s.str., supporting their classification in Calamagrostis. Agrostis, Lachnagrostis and Polypogon form a clade and species of each are variously intermixed in plastid and nuclear ribosomal trees. Additionally, all but one species from South America classified in Deyeuxia sect. Stylagrostis resolve in Holcinae p.p. (Deschampsia). The current phylogenetic results support recognition of the latter species in Deschampsia, and we also demonstrate Scribneria is part of this clade. Moreover, Holcinae is not monophyletic in its current circumscription because Deschampsia does not form a clade with Holcus and Vahlodea, which are sister taxa. The results support recognition of Deschampsia in its own subtribe Aristaveninae. Substantial further changes to the classification of these grasses will be needed to produce generic circumscriptions consistent with phylogenetic evidence. The following 15 new combinations are made: Calamagrostis * calammophila, C. breviligulata, C. breviligulata subsp. champlainensis, C. * don-hensonii, Deschampsia aurea, D. bolanderi, D. chrysantha, D. chrysantha var. phalaroides, D. eminens, D. eminens var. fulva, D. eminens var. inclusa, D. hackelii, D. ovata, and D. ovata var. nivalis. D. podophora; the new name Deschampsia parodiana is proposed; the new subtribe Lagurinae is described; and a second-step lectotype is designated for the name Deyeuxia phalaroides. PMID- 29114173 TI - In Vivo Quantification of Myocardial Infarction in Mice Using Micro-CT and a Novel Blood Pool Agent. AB - We herein developed a micro-CT method using the innovative contrast agent ExiTronTM MyoC 8000 to longitudinally monitor cardiac processes in vivo in small animals. Experiments were performed on healthy mice and mice with myocardial infarction inflicted by ligation of the left anterior descending artery. Time dependent signal enhancement in different tissues of healthy mice was measured and various contrast agent doses were investigated so as to determine the minimum required dose for imaging of the myocardium. Due to its ability to be taken up by healthy myocardium but not by infarct tissue, ExiTron MyoC 8000 enables detection of myocardial infarction even at a very low dose. The signal enhancement in the myocardium of infarcted mice after contrast agent injection was exploited for quantification of infarct size. The values of infarct size obtained from the imaging method were compared with those obtained from histology and showed a significant correlation (R2 = 0.98). Thus, the developed micro-CT method allows for monitoring of a variety of processes such as cardiac remodeling in longitudinal studies. PMID- 29114174 TI - MR Assessment of Acute Pathologic Process after Myocardial Infarction in a Permanent Ligation Mouse Model: Role of Magnetic Nanoparticle-Contrasted MRI. AB - We evaluated the relationship between myocardial infarct size and inflammatory response using cardiac magnetic resonance imaging (CMR) in an acute myocardial infarction (AMI) mouse model. Myocardial infarction (MI) was induced in 14 mice by permanent ligation of the left anterior descending artery. Late gadolinium enhancement (LGE), manganese-enhanced MRI (MEMRI), and magnetofluorescent nanoparticle MRI (MNP-MRI) were performed 1, 2, and 3 days after MI, respectively. The size of the enhanced lesion was quantitatively determined using Otsu's thresholding method in area-based and sector-based approaches and was compared statistically. Linear correlation between the enhanced lesion sizes was evaluated by Pearson's correlation coefficients. Differences were compared using Bland-Altman analysis. The size of the inflammatory area determined by MNP-MRI (57.1 +/- 10.1%) was significantly larger than that of the infarct area measured by LGE (40.8 +/- 11.7%, P < 0.0001) and MEMRI (44.1 +/- 14.9%, P < 0.0001). There were significant correlations between the sizes of the infarct and inflammatory lesions (MNP-MRI versus LGE: r = 0.3418, P = 0.0099; MNP-MRI versus MEMRI: r = 0.4764, P = 0.0002). MNP-MRI provides information about inflammatory responses in a mouse model of AMI. Thus, MNP-MRI associated with LGE and MEMRI may play an important role in monitoring the disease progression in MI. PMID- 29114175 TI - Head-to-Head Comparison of 68Ga-Citrate and 18F-FDG PET/CT for Detection of Infectious Foci in Patients with Staphylococcus aureus Bacteraemia. AB - Purpose: This study evaluated the potential of 68Ga-citrate positron emission tomography/computed tomography (PET/CT) for the detection of infectious foci in patients with Staphylococcus aureus bacteraemia by comparing it with 2 [18F]fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT. Methods: Four patients admitted to hospital due to S. aureus bacteraemia underwent both 18F-FDG and 68Ga-citrate whole-body PET/CT scans to detect infectious foci. Results: The time from hospital admission and the initiation of antibiotic treatment to the first PET/CT was 4-10 days. The time interval between 18F-FDG and 68Ga-citrate PET/CT was 1-4 days. Three patients had vertebral osteomyelitis (spondylodiscitis) and one had osteomyelitis in the toe; these were detected by both 18F-FDG (maximum standardised uptake value [SUVmax] 6.0 +/- 1.0) and 68Ga-citrate (SUVmax 6.8 +/- 3.5, P = 0.61). Three patients had soft tissue infectious foci, with more intense 18F-FDG uptake (SUVmax 6.5 +/- 2.5) than 68Ga-citrate uptake (SUVmax 3.9 +/- 1.2, P = 0.0033). Conclusions: Our small cohort of patients with S. aureus bacteraemia revealed that 68Ga-citrate PET/CT is comparable to 18F-FDG PET/CT for detection of osteomyelitis, whereas 18F-FDG resulted in a higher signal for the detection of soft tissue infectious foci. PMID- 29114176 TI - Detecting Triple-Vessel Disease with Cadmium Zinc Telluride-Based Single-Photon Emission Computed Tomography Using the Intensity Signal-to-Noise Ratio between Rest and Stress Studies. AB - The purpose of this study was to investigate if a novel parameter, the stress-to rest ratio of the signal-to-noise ratio (RSNR) obtained with a cadmium zinc telluride (CZT) SPECT scanner, could be used to distinguish triple-vessel disease (TVD) patients. Methods. One hundred and two patients with suspected coronary artery disease were retrospectively involved. Each subject underwent a Tl-201 SPECT scan and subsequent coronary angiography. Subjects were separated into TVD (n = 41) and control (n = 61) groups based on coronary angiography results using 50% as the stenosis cutoff. The RSNR was calculated by dividing the stress signal to-noise ratio (SNR) by the rest SNR. Summed scores were calculated using quantitative perfusion SPECT (QPS) for all subjects. Results. The RSNR in the TVD group was found to be significantly lower than that in the control group (0.83 +/ 0.15 and 1.06 +/- 0.17, resp.; P < 0.01). Receiver-operating characteristic (ROC) analysis showed that RSNR can detect TVD more accurately than the summed difference score with higher sensitivity (85% versus 68%), higher specificity (90% versus 72%), and higher accuracy (88% versus 71%). Conclusion. The RSNR may serve as a useful index to assist the diagnosis of TVD when a fully automatic quantification method is used in CZT-based SPECT studies. PMID- 29114177 TI - Associations between 18F-FDG-PET, DWI, and DCE Parameters in Patients with Head and Neck Squamous Cell Carcinoma Depend on Tumor Grading. AB - Our purpose was to analyze associations between positron emission tomography (PET), diffusion weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging in patients with head and neck squamous cell carcinoma (HNSCC). The study involved 34 patients (9 women, 25 men, mean age: 56.7 +/- 10.2 years). In all patients a simultaneous 18F-FDG-PET/MR was performed. DWI was obtained by using of an axial EPI sequence. Minimal ADC values (ADCmin), mean ADC values (ADCmean), and maximal ADC values (ADCmax) were estimated. DCE MRI was performed by using dynamic T1w DCE sequence. The following parameters were estimated: Ktrans, Ve , and Kep. Spearman's correlation coefficient was used to analyze associations between investigated parameters. In overall sample, ADCmean correlated significantly with Ve and Ktrans, ADCmin correlated with Ve , and ADCmax correlated with Ktrans and Ve . SUVmean tended to correlate slightly with Ktrans. In G1/2 tumors, only Ktrans correlated well with ADCmax and SUVmean. In G3 tumors, Ktrans correlated well with Kep and Ve . Ve showed significant correlations with ADCmean and ADCmax. Ktrans correlated with ADCmax. Kep was higher in cancers with N2/3 stages. Tumor metabolism, water diffusion, and tumor perfusion have complex relationships in HNSCC. Furthermore, these associations depend on tumor grading. Kep may predict lymphonodal metastasizing. PMID- 29114178 TI - Cancer Metabolism and Tumor Heterogeneity: Imaging Perspectives Using MR Imaging and Spectroscopy. AB - Cancer cells reprogram their metabolism to maintain viability via genetic mutations and epigenetic alterations, expressing overall dynamic heterogeneity. The complex relaxation mechanisms of nuclear spins provide unique and convertible tissue contrasts, making magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) pertinent imaging tools in both clinics and research. In this review, we summarized MR methods that visualize tumor characteristics and its metabolic phenotypes on an anatomical, microvascular, microstructural, microenvironmental, and metabolomics scale. The review will progress from the utilities of basic spin-relaxation contrasts in cancer imaging to more advanced imaging methods that measure tumor-distinctive parameters such as perfusion, water diffusion, magnetic susceptibility, oxygenation, acidosis, redox state, and cell death. Analytical methods to assess tumor heterogeneity are also reviewed in brief. Although the clinical utility of tumor heterogeneity from imaging is debatable, the quantification of tumor heterogeneity using functional and metabolic MR images with development of robust analytical methods and improved MR methods may offer more critical roles of tumor heterogeneity data in clinics. MRI/MRS can also provide insightful information on pharmacometabolomics, biomarker discovery, disease diagnosis and prognosis, and treatment response. With these future directions in mind, we anticipate the widespread utilization of these MR-based techniques in studying in vivo cancer biology to better address significant clinical needs. PMID- 29114180 TI - Head and Neck Cancer Tumor Segmentation Using Support Vector Machine in Dynamic Contrast-Enhanced MRI. AB - Objective: We aimed to propose an automatic method based on Support Vector Machine (SVM) and Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) to segment the tumor lesions of head and neck cancer (HNC). Materials and Methods: 120 DCE-MRI samples were collected. Five curve features and two principal components of the normalized time-intensity curve (TIC) in 80 samples were calculated as the dataset in training three SVM classifiers. The other 40 samples were used as the testing dataset. The area overlap measure (AOM) and the corresponding ratio (CR) and percent match (PM) were calculated to evaluate the segmentation performance. The training and testing procedure was repeated for 10 times, and the average performance was calculated and compared with similar studies. Results: Our method has achieved higher accuracy compared to the previous results in literature in HNC segmentation. The average AOM with the testing dataset was 0.76 +/- 0.08, and the mean CR and PM were 79 +/- 9% and 86 +/- 8%, respectively. Conclusion: With improved segmentation performance, our proposed method is of potential in clinical practice for HNC. PMID- 29114179 TI - TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases? AB - Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatory foci are crucial for an adequate care for patients. In brain diseases, in vivo positron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the field of TSPO PET imaging in PSIDs. Promising preliminary results have been reported in bowel, cardiovascular, and rheumatic inflammatory diseases, consolidated by preclinical studies. Limitations of TSPO PET imaging in PSIDs, regarding both its large expression in healthy peripheral tissues, unlike in central nervous system, and the production of peripheral radiolabeled metabolites, are also discussed, regarding their possible consequences on TSPO PET signal's quantification. PMID- 29114181 TI - Kinetic Modelling of Infection Tracers [18F]FDG, [68Ga]Ga-Citrate, [11C]Methionine, and [11C]Donepezil in a Porcine Osteomyelitis Model. AB - Introduction: Positron emission tomography (PET) is increasingly applied for infection imaging using [18F]FDG as tracer, but uptake is unspecific. The present study compares the kinetics of [18F]FDG and three other PET tracers with relevance for infection imaging. Methods: A juvenile porcine osteomyelitis model was used. Eleven pigs underwent PET/CT with 60-minute dynamic PET imaging of [18F]FDG, [68Ga]Ga-citrate, [11C]methionine, and/or [11C]donepezil, along with blood sampling. For infectious lesions, kinetic modelling with one- and two tissue-compartment models was conducted for each tracer. Results: Irreversible uptake was found for [18F]FDG and [68Ga]Ga-citrate; reversible uptake was found for [11C]methionine (two-tissue model) and [11C]donepezil (one-tissue model). The uptake rate for [68Ga]Ga-citrate was slow and diffusion-limited. For the other tracers, the uptake rate was primarily determined by perfusion (flow-limited uptake). Net uptake rate for [18F]FDG and distribution volume for [11C]methionine were significantly higher for infectious lesions than for correspondingly noninfected tissue. For [11C]donepezil in pigs, labelled metabolite products appeared to be important for the analysis. Conclusions: The kinetics of the four studied tracers in infection was characterized. For clinical applications, [18F]FDG remains the first-choice PET tracer. [11C]methionine may have a potential for detecting soft tissue infections. [68Ga]Ga-citrate and [11C]donepezil were not found useful for imaging of osteomyelitis. PMID- 29114182 TI - Application of Deep Learning in Automated Analysis of Molecular Images in Cancer: A Survey. AB - Molecular imaging enables the visualization and quantitative analysis of the alterations of biological procedures at molecular and/or cellular level, which is of great significance for early detection of cancer. In recent years, deep leaning has been widely used in medical imaging analysis, as it overcomes the limitations of visual assessment and traditional machine learning techniques by extracting hierarchical features with powerful representation capability. Research on cancer molecular images using deep learning techniques is also increasing dynamically. Hence, in this paper, we review the applications of deep learning in molecular imaging in terms of tumor lesion segmentation, tumor classification, and survival prediction. We also outline some future directions in which researchers may develop more powerful deep learning models for better performance in the applications in cancer molecular imaging. PMID- 29114183 TI - Intensity of 18F-FDG PET Uptake in Culture-Negative and Culture-Positive Cases of Chronic Osteomyelitis. AB - Microbiologic cultures are not infrequently negative in patients with a histopathologic diagnosis of chronic osteomyelitis. Culture-negative cases may represent low-grade infections with a lower metabolic activity than culture positive cases. 18F-FDG PET could potentially detect such a difference. We determined whether the level of 18F-FDG PET uptake differs in patients with culture-negative and culture-positive osteomyelitis. We reviewed the clinical charts of 40 consecutive patients, who had diagnostic 18F-FDG PET for a suspected bone infection. Twenty-six patients were eligible with a confirmed diagnosis based on microbiologic cultures and/or histopathologic examination. Sixteen of 26 patients had chronic osteomyelitis. Eight of them had positive cultures, seven had negative cultures, and one patient had no cultures of the biopsy specimen. The patients with histologically and/or microbiologically proven osteomyelitis were correctly interpreted as true positive in the routine clinical reading of 18F-FDG PET images. There was no relationship between the level of 18F-FDG PET uptake and the presence of positive or negative bacterial cultures. The result favors the concept that that culture-negative cases of osteomyelitis are false negative infections due to nonculturable microbes. 18F-FDG PET may help to confirm the presence of metabolically active infection in these patients and guide their appropriate treatment. PMID- 29114184 TI - Relationships between Caregiving Stress, Depression, and Self-Esteem in Family Caregivers of Adults with a Disability. AB - This study aimed to examine the relationships between caregiving stress, depression, and self-esteem of family caregivers of an adult person with a disability and to identify their effects on their caregiving burden. The study was performed with 108 care providers of adult people with a disability who visited hospital rehabilitation centers. Caregiving stress showed a significant positive correlation with depression and with economic and psychological stress, and it showed a significant negative correlation with self-esteem. When the care provider was aged, female, and without a job and the caregiving cost and time were higher, the caregiving stress was high. When the care provider was female and had a lower income, the depression index was high. When the person with a disability was male and in the forties and the level of disability was higher, the caregiving stress was high. When the disability was related to spinal cord damage, the care provider's depression index was the highest. To reduce caregiving stress and depression in the family caregivers and to improve their self-esteem, continuous support and help from specialists are necessary. Additionally, a variety of intervention programs need to be designed to motivate them to participate regularly at the community level. PMID- 29114185 TI - Medicinal values of bioactive constituents of camel milk: A concise report. PMID- 29114186 TI - Clinical utility of anti-C1q antibody in primary and secondary vasculitic conditions. AB - Objective: Anti-C1q antibodies (Anti-C1q Ab) are seen in hypocomplementemic urticarial vasculitis syndrome (HUVS), infection-associated vasculitis such as hepatitis C virus-related vasculitis and in autoimmune diseases such as rheumatoid vasculitis, polyarteritis nodosa, giant cell arteritis, vascular Behcet's disease, and cryoglobulin associated vasculitis. Aim of this study is to evaluate the presence of Anti-C1q Ab in vasculitis and to determine if any difference exists between primary and secondary vasculitis in relation to this antibody. Patients and Methods: Consecutive patients with diagnosis of either a primary or secondary vasculitis were recruited. Primary vasculitis were diagnosed by the American College of Rheumatology 1990 criteria. Clinical features and serological markers were noted. Anti-C1q Ab was assayed by commercially available ELISA kit (Demeditec Diagnostics GmbH, Germany). Results: Sixty-four patients were recruited for the study comprising of 41 primary vasculitis and 23 secondary vasculitis cases. No difference in Anti-C1q Ab levels between primary and secondary vasculitis was noted. Four patients were positive for Anti-C1q Ab out of the 64 patients. Of the four, one patient was diagnosed as HUVS, 2 patients as systemic lupus erythermatosus with vasculitis (16.7%) and another patient was diagnosed as rheumatoid arthritis with vasculitis (14.28%). Anti-C1q Ab negatively correlated with age and C3, but it correlated positively with erythrocyte sedimentation rate (ESR) in vascultic patients. Conclusion: Presence of anti-C1q Ab did not differ between the patients with primary and secondary vasculitis. Anti-C1q Ab titers correlated with younger age, high ESR, and low C3 in patients with vasculitis in our study. PMID- 29114187 TI - Use of fibular bone graft and cancellous screw fixation in the management of neglected femur neck fractures in young patients. AB - Objective: To present the clinical outcome of patients with neglected femur neck fracture treated with fibular bone graft. Methods: During May 2010-February 2013, 15 patients younger than 35 years of age with neglected fracture neck of femur were managed with non-vascularized fibular graft and cannulated screws. Fractures were classified according to Sandhu Classification. Hip function was assessed using Harris hip score. Results: Fifteen patients with mean age of 28.67 years were managed. Mean period of delay from injury to presentation was 3.07 months. Mean follow-up was 18.5 months. Union was achieved in 13 cases. 2 patients developed nonunion with progression of avascular necrosis (AVN). Patients with healed fracture did not show radiological signs of AVN till the past follow-up. Functional status was evaluated at 6 months according to Harris hip score and was poor in 2 patients, fair in 2 patients, good in 6 patients, and excellent in 5 patients. Conclusion: Fibular graft along with two cancellous screws proved to be an effective technique in our cases with neglected femur neck fractures. PMID- 29114188 TI - Chronic disease prevalence among elderly Saudi men. AB - Objective: Saudi demographic composition has changed because of increased life expectancy and decreased fertility rates. Little data are available about health conditions among older adults in Saudi Arabia, who are expected to represent 20% of the population by 2050. The study aim was to assess the prevalence and risk factors for chronic conditions among older Saudi men. Methods: The sample pertained to 400 men (age >=55 years) from Buraidah, Al-Qassim. Research assistants recruited participants in all the mosques from the randomly selected neighborhoods (16 of 95). They administered a structured questionnaire that assessed self-reported disease history (heart disease, hypertension, diabetes, asthma, gastric/peptic ulcer, and cancer), and medication use; participants' height, weight, blood pressure, and random blood glucose (glucometer) were measured. Multinomial logistic regressions were employed to assess correlates of number of chronic diseases. Results: The mean and standard deviation for age and body mass index (BMI) were 63.0 +/- 7.5 years and 28.9 +/- 4.8 (kg/m2), respectively. 78% (77.8%) were overweight or obese, 35.0% were employed, 54.5% walked daily, 9.3% were current smokers, and 85.0% belonged to the middle class. The prevalence of hypertension, diabetes, heart disease, asthma, ulcer, and cancer were: 71.3% 27.3%, 16.4%, 9.7%, 8.9%, and 2.0%, respectively. Of the participants, 31.0% had one, 34.5% had two or more, and 34.5% did not have any chronic diseases. The likelihood of chronic diseases increased with increased age, higher BMI, and current smoking. Conclusion: The chronic disease prevalence among the Saudi elderly men is substantial. PMID- 29114189 TI - Computer vision syndrome prevalence, knowledge and associated factors among Saudi Arabia University Students: Is it a serious problem? AB - Objectives: Computers and other visual display devices are now an essential part of our daily life. With the increased use, a very large population is experiencing sundry ocular symptoms globally such as dry eyes, eye strain, irritation, and redness of the eyes to name a few. Collectively, all such computer related symptoms are usually referred to as computer vision syndrome (CVS). The current study aims to define the prevalence, knowledge in community, pathophysiology, factors associated, and prevention of CVS. Methods: This is a cross-sectional study conducted in Qassim University College of Medicine during a period of 1 year from January 2015 to January 2016 using a questionnaire to collect relevant data including demographics and various variables to be studied. 634 students were inducted from a public sector University of Qassim, Saudi Arabia, regardless of their age and gender. The data were then statistically analyzed on SPSS version 22, and the descriptive data were expressed as percentages, mode, and median using graphs where needed. Results: A total of 634 students with a mean age of 21. 40, Std 1.997 and Range 7 (18-25) were included as study subjects with a male predominance (77.28%). Of the total patients, majority (459, 72%) presented with acute symptoms while remaining had chronic problems. A clear-cut majority was carrying the symptoms for <5 days and >1 month. The statistical analysis revealed serious symptoms in the majority of study subjects especially those who are permanent users of a computer for long hours. Conclusion: Continuous use of computers for long hours is found to have severe problems of vision especially in those who are using computers and similar devices for a long duration. PMID- 29114190 TI - Knowledge and awareness of Middle East respiratory syndrome coronavirus among Saudi and Non-Saudi Arabian pilgrims. AB - Objective: The current study was intended to evaluate the knowledge and awareness toward Middle East respiratory syndrome coronavirus (MERS-CoV) of pilgrims from Saudi Arabia and from different Arabian countries. Methods: A prospective study was conducted among pilgrims from Saudi Arabia and those from other Arab nations. A total number of 2120 participants including 736 Saudi pilgrims (436 males and 300 females) and 1384 non-Saudi Arabian pilgrims (1384; 909 males and 475 females) were included in the study. The responses of the participants were descriptively analyzed. Pearson correlation coefficient was used to screen the possible correlations among different variables. The differences in the responses between the two groups were evaluated using Mann-Whitney analysis. Results: The responses of the Saudi pilgrims showed statistically significant results in comparison to non-Saudi pilgrims in answering all questions except those related to the presence of efficient vaccination or treatment and the source of information. It was clear that the Saudi pilgrims were more oriented about different aspects of MERS-CoV including the nature of the causative agent, the signs, the severity of the disease, the animals that can transmit the infection to humans, the risk groups, and when one need to be screened for infection. In both Saudi and non-Saudi pilgrims, the official websites of health organizations constitute the main source of their information. Conclusion: It was concluded that Saudi pilgrims possess good knowledge about the MERS-CoV although more orientation is still required. PMID- 29114191 TI - Cardiac autonomic neuropathy in type 2 diabetes mellitus using Bellavere's score system. AB - Objective: Determine the frequency of cardiac autonomic neuropathy (CAN) in type 2 diabetics using Bellavere's score system. Subjects and Methods: The present cross-sectional study was conducted at the Department of Medicine, Isra University Hospital Hyderabad from March to November 2011. Sixty voluntary participants of type 2 diabetes mellitus (DM) were selected through non probability purposive sampling. Cardiac autonomic nerve function was assessed using Bellavere's score system. The data were analyzed on the Statistix version 10.0 (USA) using Student's t-test, Chi-square test, one-way ANOVA, and Tukey Cramer test (P <= 0.05). Results: Of 60 diabetics, CAN was observed in 29 (41.4%). Abnormal heart rate variability (HRV), valsalva ratio, 30-15th ratio, blood pressure (BP) response to standing, and handgrip was noted in 43 (61.4%), 27 (38.5%), 17 (24.2%), 5 (7.14%), and 18 (25.7%), respectively. The hemoglobin A1c was negative correlated with HRV, valsalva ratio, 30-15th ratio, and BP response to sustained handgrip; and positively correlated with BP response to standing, systolic BP, and diastolic BP. Duration of DM was not correlated with cardiac autonomic nerve function tests. Conclusion: The CAN was observed in 29 (41.4%) using Bellavere's score system. The CAN score may be used as feasible and reproducible bedside clinical test in diabetic patients. PMID- 29114192 TI - Optic neuritis: Observation and experience at a tertiary care hospital in Qassim region, Saudi Arabia. AB - Objectives: Optic neuritis (ON) can occur in isolation or association with multiple sclerosis (MS) or neuromyelitis optica. ON, is seen more commonly in Caucasians and interaction is found to exist between ethnic origin and the latitude at which the patient grows up. At present limited information is available about the profile of ON in Saudi patients. We aimed to analyze the records of ON patients, in regard to their presentation, natural history, treatment outcome, and risk and association with MS. Whether, ON in Saudi patients behaves differently from the Western and Asian patients? Methods: In this retrospective observational study; we retrieved the data from the medical records of the patients with ON, who attended the ophthalmology and neurology services of King Fahad Specialist Hospital Buraidah, Al Qassim, Saudi Arabia, from period 2006 to 2012. Results: We recorded data of 60 patients of ON; 38 females (63.3%) and 22 males (36.7%). Color vision was affected in 66.7% of cases. Vision in the affected eye was 20/200 or worse in 74.97 % of our cases. Magnetic resonance imaging (MRI) brain revealed multiple lesions in 55% of cases; most of them developed MS on follow-up. Only 48.3% of patients had received systemic steroids. Vision improved in 85% of our cases. Conclusion: Most of our patients had idiopathic ON, and almost 85% had good visual recovery, in this regard our study is comparable with such studies done in other Asian countries. On the other hand, 55% of our patients had multiple MRI brain lesions, a high risk and association of MS, almost similar to the Western Europe and North American ON patients. PMID- 29114193 TI - Undernutrition and associated factors among adults human immunodeficiency virus positive on antiretroviral therapy in hospitals, East Hararge Zone, Oromia, Ethiopia: A cross-sectional study. AB - Objective: The aim of the study was to assess undernutrition and factors associated with, among people living with human immunodeficiency virus (HIV) and on antiretroviral therapy (ART). Methods: Facility-based cross-sectional study design was implemented. Data were collected using pretested structured questionnaire at ART service site. Basic descriptive statistics were computed. Bivariate and multivariate logistic regression analyses were used to assess the association between outcome variable and explanatory variables. Results: The prevalence of undernutrition (body mass index [BMI] <=18.5 kg/m2) among patients on ART was 30%. The mean BMI was 20.3 with standard deviation +/- 2.9 kg/m2. Undernutrition was significantly associated with CD4 (200-500) (adjusted odds ratio [AOR] = 0.576, 95% confidence interval [CI]: 0.338, 0.979) and CD4 >500 (AOR = 0.431, 95% CI: 0.239-0.778), duration on ART >12 months (AOR = 0.466, 95% CI: 0.224, 0.966), unable to get nutritional care and support (AOR = 2.188, 95% CI: 1.349, 3.549), diarrhea (AOR = 1.641, 95% CI: 1.036, 2.6), khat chewing (AOR = 0.589, 95% CI: 0.377, 0.92), and severe food insecurity (AOR = 1.594, 95% CI: 1.008, 2.521). Conclusions: Our study provides a unique insight into prevalence and associated factors of undernutrition which greatly affect ART outcomes. The study revealed that the undernutrition was found to be high and its problem in HIV-positive patients are interworsen. Diarrhea, severe food insecurity, nutritional care and support, khat chewing, CD4 >200/ul, and duration on ART >12 months were independently associated with undernutrition. Comprehensive nutritional assessment during follow-up and routine nutritional supplement therapy for undernutrition in conjunction with early start on ART need to be initiated. PMID- 29114194 TI - Audiology and speech-language pathology practice in Saudi Arabia. AB - Objectives: Audiology and speech-language pathology (SLP) are relatively new professions in Saudi Arabia. The idea of establishing new audiology and SLP programs in some education facilities has become popular across Saudi Arabia; yet, only four undergraduate and graduate programs are currently available. This study aimed to explore the fields of audiology and SLP in Saudi Arabia, obtain demography of audiologists and Speech-language pathologists (SLPs), understand their current practices, and identify their perspective on what both professions need to improve. Methods: A cross-sectional mixed methods study design was used to address the aim of this study. Two online surveys were prepared and distributed to reach a large number of audiologists and SLPs. Both surveys consisted of close- and open-ended questions and primarily focused on three categories demography, audiology or SLP practices, and audiologists' or SLPs' perspective on their professions in Saudi Arabia. Results: A total of 23 audiologists and 37 SLPs completed the surveys (age range = 21-50 years). The majority of respondents were from Riyadh with different academic qualifications and working experiences. Various practices were noticed among audiologists and SLPs who mainly worked in hospitals. Several suggestions regarding the development of audiology and SLP education and practice in Saudi Arabia are discussed. Conclusion: This study provides useful information about audiology and SLP education and practices in Saudi Arabia. Collaborative work between stakeholders to achieve high-quality educational and practical standards is critical. National database, clinical guidelines and policies should be developed, employed, and supervised. Further research is needed to improve education and practice of both professions in Saudi Arabia. PMID- 29114195 TI - Comparison and prevalence of smoking among Saudi females from different Departments of the College of Applied Medical Sciences in Dammam. AB - Objectives: The aim of this study is to estimate the prevalence of smoking and factors associated with smoking habits among female students in all departments of College of Applied Medical Science (CAMS) at the University of Dammam. Methods: A cross-sectional study was conducted at CAMSs, University of Dammam. Only female students were included from all the departments of CAMS. The modified structured Global Youth Tobacco Survey was used to collect detailed information about smoking habits and factors associated with smoking. Results: A total of 332 out of 408 female students responded to the questionnaire with a response rate of 81%. The overall prevalence of those who tried smoking was 13.3%. Of those, 0.9% were active smokers. Among departments, Respiratory Care Department has the highest prevalence of smoking (25%; n = 11 out of 63) compared to clinical nutrition department where only 11.4% (n = 5 out of 54) either tried smoking or active smokers. The associated factors for smoking were high grade point average (P = 0.01). Interestingly, 61.3% of the sample reported that their first smoking trail was because of their experience to see someone they know is smoking (P = 0.01). Conclusion: The study results suggest that the prevalence of the current smoking is not significantly high. However, our data of this study suggests that some students tried to smoke in the past which may be considered as a risk factor of becoming regular smokers in the future. The study also reveals that the most common trigger to start smoking is their experience of seeing someone they know is smoking. PMID- 29114196 TI - Phenylketonuria: A new look at an old topic, advances in laboratory diagnosis, and therapeutic strategies. AB - Disorders of protein metabolism are the most common diseases among discovered inherited metabolic disorders. Phenylketonuria (PKU), a relatively common disorder that is responsive to treatment, is an inherited autosomal recessive disorder caused by a deficiency in phenylalanine hydroxylase (PAH) or one of several enzymes mediating biosynthesis or regeneration of the PAH cofactor tetrahydrobiopterin. The objective of this review is to discuss therapeutic strategies that have recently emerged for curing patients with PKU, which have demonstrated promising improvements in managing these patients. Data sourcing included a systematic literature review of PubMed with a focus on emerging knowledge pertaining to this well-studied disease. Recent advances in laboratory diagnosis and therapeutic strategies were described. Collectively, promising and rapid enhancements in neonatal diagnostic technologies and recently emerged therapeutic strategies are paving the way for early diagnosis and treating many inborn errors of metabolism, such as PKU. PMID- 29114198 TI - Depression led pitting edema: A rarest case presentation. AB - Pitting edema is the clinical manifestation generally presented due to long standing, especially during summer in the sun, heavy weight bearing, vasodilatation, or cardio-hepatorenal disease or in rare hypothyroidism, but in atypical case may demonstrates depression with progressive stress, that also shows indication of mild pitting edema. We present a case of a non-alcoholic 42 years divorced male under anti-anxiety medication for 10 years who complained of weight gain almost 10 kg in 30 days duration, less attentive to his work, and always feel sleepiness during day (once get to sleep, slept more than 5 h during day) and also late up to morning if not called to wake-up, also with diminished memory, more specific event was before 60 days of these symptoms he unexpectedly suffered family tragedy suggesting depression led progressive stress pitting edema that got managed after appropriate counseling along with changes in his life style. PMID- 29114197 TI - Low levels of Vitamin D an emerging risk for cardiovascular diseases: A review. AB - Sunlight is regarded among greatest gifts that are presented in abundance to the human beings from the God. Sunlight is also a rich source of Vitamin D (Vit D) that prevents us from numerous ailments such as autoimmune disorders, various types of cancer, and the above all cardiovascular diseases (CVD). Evident from recent research that Vit D deficiency may be the cause for hypertension, cardiac autonomic imbalance, vascular endothelial dysfunction, metabolic syndrome, and even diabetes. Concurrently, many studies present research outcomes that are contradictory to earlier results and also raised a concern not for general public but also among their treating physicians. The sole focus of this review is to systematically present the available research data and critically evaluate the link between Vit D deficiency and development of risk factors for CVD. PMID- 29114199 TI - Brain Implants to Erase Memories. PMID- 29114200 TI - Neuroprotective Potential of Cell-Based Therapies in ALS: From Bench to Bedside. AB - Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular. PMID- 29114201 TI - The Influence of Auditory Information on Visual Size Adaptation. AB - Size perception can be influenced by several visual cues, such as spatial (e.g., depth or vergence) and temporal contextual cues (e.g., adaptation to steady visual stimulation). Nevertheless, perception is generally multisensory and other sensory modalities, such as auditory, can contribute to the functional estimation of the size of objects. In this study, we investigate whether auditory stimuli at different sound pitches can influence visual size perception after visual adaptation. To this aim, we used an adaptation paradigm (Pooresmaeili et al., 2013) in three experimental conditions: visual-only, visual-sound at 100 Hz and visual-sound at 9,000 Hz. We asked participants to judge the size of a test stimulus in a size discrimination task. First, we obtained a baseline for all conditions. In the visual-sound conditions, the auditory stimulus was concurrent to the test stimulus. Secondly, we repeated the task by presenting an adapter (twice as big as the reference stimulus) before the test stimulus. We replicated the size aftereffect in the visual-only condition: the test stimulus was perceived smaller than its physical size. The new finding is that we found the auditory stimuli have an effect on the perceived size of the test stimulus after visual adaptation: low frequency sound decreased the effect of visual adaptation, making the stimulus perceived bigger compared to the visual-only condition, and contrarily, the high frequency sound had the opposite effect, making the test size perceived even smaller. PMID- 29114202 TI - Estradiol Uses Different Mechanisms in Astrocytes from the Hippocampus of Male and Female Rats to Protect against Damage Induced by Palmitic Acid. AB - An excess of saturated fatty acids can be toxic for tissues, including the brain, and this has been associated with the progression of neurodegenerative diseases. Since palmitic acid (PA) is a free fatty acid that is abundant in the diet and circulation and can be harmful, we have investigated the effects of this fatty acid on lipotoxicity in hippocampal astrocytes and the mechanism involved. Moreover, as males and females have different susceptibilities to some neurodegenerative diseases, we accessed the responses of astrocytes from both sexes, as well as the possible involvement of estrogens in the protection against fatty acid toxicity. PA increased endoplasmic reticulum stress leading to cell death in astrocytes from both males and females. Estradiol (E2) increased the levels of protective factors, such as Hsp70 and the anti-inflammatory cytokine interleukin-10, in astrocytes from both sexes. In male astrocytes, E2 decreased pJNK, TNFalpha, and caspase-3 activation. In contrast, in female astrocytes E2 did not affect the activation of JNK or TNFalpha levels, but decreased apoptotic cell death. Hence, although E2 exerted protective effects against the detrimental effects of PA, the mechanisms involved appear to be different between male and female astrocytes. This sexually dimorphic difference in the protective mechanisms induced by E2 could be involved in the different susceptibilities of males and females to some neurodegenerative processes. PMID- 29114203 TI - Collagen VI Null Mice as a Model for Early Onset Muscle Decline in Aging. AB - Collagen VI is an extracellular matrix (ECM) protein playing a key role in skeletal muscles and whose deficiency leads to connective tissue diseases in humans and in animal models. However, most studies have been focused on skeletal muscle features. We performed an extensive proteomic profiling in two skeletal muscles (diaphragm and gastrocnemius) of wild-type and collagen VI null (Col6a1-/ ) mice at different ages, from 6- (adult) to 12- (aged) month-old to 24 (old) month-old. While in wild-type animals the number of proteins and the level of modification occurring during aging were comparable in the two analyzed muscles, Col6a1-/- mice displayed a number of muscle-type specific variations. In particular, gastrocnemius displayed a limited number of dysregulated proteins in adult mice, while in aged muscles the modifications were more pronounced in terms of number and level. In diaphragm, the differences displayed by 6-month-old Col6a1-/- mice were more pronounced compared to wild-type mice and persisted at 12 months of age. In adult Col6a1-/- mice, the major variations were found in the enzymes belonging to the glycolytic pathway and the tricarboxylic acid (TCA) cycle, as well as in autophagy-related proteins. When compared to wild-type animals Col6a1-/- mice displayed a general metabolic rewiring which was particularly prominent the diaphragm at 6 months of age. Comparison of the proteomic features and the molecular analysis of metabolic and autophagic pathways in adult and aged Col6a1-/- diaphragm indicated that the effects of aging, culminating in lipotoxicity and autophagic impairment, were already present at 6 months of age. Conversely, the effects of aging in Col6a1-/- gastrocnemius were similar but delayed becoming apparent at 12 months of age. A similar metabolic rewiring and autophagic impairment was found in the diaphragm of 24-month-old wild-type mice, confirming that fatty acid synthase (FASN) increment and decreased microtubule-associated proteins 1A/1B light chain 3B (LC3B) lipidation are hallmarks of the aging process. Altogether these data indicate that the diaphragm of Col6a1-/- animal model can be considered as a model of early skeletal muscle aging. PMID- 29114204 TI - Acute Ethanol Administration Upregulates Synaptic alpha4-Subunit of Neuronal Nicotinic Acetylcholine Receptors within the Nucleus Accumbens and Amygdala. AB - Alcohol and nicotine are two of the most frequently abused drugs, with their comorbidity well described. Previous data show that chronic exposure to nicotine upregulates high-affinity nicotinic acetylcholine receptors (nAChRs) in several brain areas. Effects of ethanol on specific brain nAChR subtypes within the mesolimbic dopaminergic (DA) pathway may be a key element in the comorbidity of ethanol and nicotine. However, it is unknown how alcohol affects the abundance of these receptor proteins. In the present study, we measured the effect of acute binge ethanol on nAChR alpha4 subunit levels in the prefrontal cortex (PFC), nucleus accumbens (NAc), ventral tegmental area (VTA), and amygdala (Amg) by western blot analysis using a knock-in mouse line, generated with a normally functioning alpha4 nAChR subunit tagged with yellow fluorescent protein (YFP). We observed a robust increase in alpha4-YFP subunit levels in the NAc and the Amg following acute ethanol, with no changes in the PFC and VTA. To further investigate whether this upregulation was mediated by increased local mRNA transcription, we quantified mRNA levels of the Chrna4 gene using qRT-PCR. We found no effect of ethanol on alpha4 mRNA expression, suggesting that the upregulation of alpha4 protein rather occurs post-translationally. The quantitative counting of YFP immunoreactive puncta further revealed that alpha4 YFP protein is upregulated in presynaptic boutons of the dopaminergic axons projecting to the shell and the core regions of the NAc as well as to the basolateral amygdala (BLA), but not to the central or lateral Amg. Together, our results demonstrate that a single exposure to binge ethanol upregulates level of synaptic alpha4* nAChRs in dopaminergic inputs to the NAc and BLA. This upregulation could be linked to the functional dysregulation of dopaminergic signalling observed during the development of alcohol dependence. PMID- 29114206 TI - Controversial Effects of D-Amino Acid Oxidase Activator (DAOA)/G72 on D-Amino Acid Oxidase (DAO) Activity in Human Neuronal, Astrocyte and Kidney Cell Lines: The N-methyl D-aspartate (NMDA) Receptor Hypofunction Point of View. AB - Dysfunction of D-amino acid oxidase (DAO) and DAO activator (DAOA)/G72 genes have been linked to neuropsychiatric disorders. The glutamate hypothesis of schizophrenia has proposed that increased DAO activity leads to decreased D serine, which subsequently may lead to N-methyl-D-aspartate (NMDA) receptor hypofunction. It has been shown that DAOA binds to DAO and increases its activity. However, there are also studies showing DAOA decreases DAO activity. Thus, the effect of DAOA on DAO is controversial. We aimed to understand the effect of DAOA on DAO activity in neuron-like (SH-SY5Y), astrocyte-like (1321N1) and kidney-like (HEK293) human cell lines. DAO activity was measured based on the release of hydrogen peroxide and its interaction with Amplex Red reagent. We found that DAOA increases DAO activity only in HEK293 cells, but has no effect on DAO activity in SH-SY5Y and 1321N1 cells. This might be because of different signaling pathways, or due to lower DAO and DAOA expression in SH-SY5Y and 1321N1 cells compared to HEK293 cells, but also due to different compartmentalization of the proteins. The lower DAO and DAOA expression in neuron-like SH-SY5Y and astrocyte-like 1321N1 cells might be due to tightly regulated expression, as previously reported in the human post-mortem brain. Our simulation experiments to demonstrate the interaction between DAOA and human DAO (hDAO) showed that hDAO holoenzyme [hDAO with flavine adenine dinucleotide (FAD)] becomes more flexible and misfolded in the presence of DAOA, whereas DAOA had no effect on hDAO apoprotein (hDAO without FAD), which indicate that DAOA inactivates hDAO holoenzyme. Furthermore, patch-clamp analysis demonstrated no effect of DAOA on NMDA receptor activity in NR1/NR2A HEK293 cells. In summary, the interaction between DAO and DAOA seems to be cell type and its biochemical characteristics dependent which still needs to be elucidated. PMID- 29114207 TI - Histone Deacetylase Inhibitors Are Protective in Acute but Not in Chronic Models of Ototoxicity. AB - Previous studies have reported that modification of histones alters aminoglycoside-induced hair cell death and hearing loss. In this study, we investigated three FDA-approved histone deacetylase (HDAC) inhibitors (vorinostat/SAHA, belinostat, and panobinostat) as protectants against aminoglycoside-induced ototoxicity in murine cochlear explants and in vivo in both guinea pigs and CBA/J mice. Individually, all three HDAC inhibitors reduced gentamicin (GM)-induced hair cell loss in a dose-dependent fashion in explants. In vivo, however, treatment with SAHA attenuated neither GM-induced hearing loss and hair cell loss in guinea pigs nor kanamycin (KM)-induced hearing loss and hair cell loss in mice under chronic models of ototoxicity. These findings suggest that treatment with the HDAC inhibitor SAHA attenuates aminoglycoside induced ototoxicity in an acute model, but not in chronic models, cautioning that one cannot rely solely on in vitro experiments to test the efficacy of otoprotectant compounds. PMID- 29114208 TI - Classification of Mouse Retinal Bipolar Cells: Type-Specific Connectivity with Special Reference to Rod-Driven AII Amacrine Pathways. AB - We confirmed the classification of 15 morphological types of mouse bipolar cells by serial section transmission electron microscopy and characterized each type by identifying chemical synapses and gap junctions at axon terminals. Although whether the previous type 5 cells consist of two or three types was uncertain, they are here clustered into three types based on the vertical distribution of axonal ribbons. Next, while two groups of rod bipolar (RB) cells, RB1, and RB2, were previously proposed, we clarify that a half of RB1 cells have the intermediate characteristics, suggesting that these two groups comprise a single RB type. After validation of bipolar cell types, we examined their relationship with amacrine cells then particularly with AII amacrine cells. We found a strong correlation between the number of amacrine cell synaptic contacts and the number of bipolar cell axonal ribbons. Formation of bipolar cell output at each ribbon synapse may be effectively regulated by a few nearby inhibitory inputs of amacrine cells which are chosen from among many amacrine cell types. We also found that almost all types of ON cone bipolar cells frequently have a minor group of midway ribbons along the axon passing through the OFF sublamina as well as a major group of terminal ribbons in the ON sublamina. AII amacrine cells are connected to five of six OFF bipolar cell types via conventional chemical synapses and seven of eight ON (cone) bipolar cell types via electrical synapses (gap junctions). However, the number of synapses is dependent on bipolar cell types. Type 2 cells have 69% of the total number of OFF bipolar chemical synaptic contacts with AII amacrine cells and type 6 cells have 46% of the total area of ON bipolar gap junctions with AII amacrine cells. Both type 2 and 6 cells gain the greatest access to AII amacrine cell signals also share those signals with other types of bipolar cells via networked gap junctions. These findings imply that the most sensitive scotopic signal may be conveyed to the center by ganglion cells that have the most numerous synapses with type 2 and 6 cells. PMID- 29114205 TI - Biometal Dyshomeostasis and Toxic Metal Accumulations in the Development of Alzheimer's Disease. AB - Biometal dyshomeostasis and toxic metal accumulation are common features in many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. The neurotoxic effects of metal imbalance are generally associated with reduced enzymatic activities, elevated protein aggregation and oxidative stress in the central nervous system, in which a cascade of events lead to cell death and neurodegeneration. Although the links between biometal imbalance and neurodegenerative disorders remain elusive, a major class of endogenous proteins involved in metal transport has been receiving increasing attention over recent decades. The abnormal expression of these proteins has been linked to biometal imbalance and to the pathogenesis of AD. Here, we present a brief overview of the physiological roles of biometals including iron, zinc, copper, manganese, magnesium and calcium, and provide a detailed description of their transporters and their synergistic involvement in the development of AD. In addition, we also review the published data relating to neurotoxic metals in AD, including aluminum, lead, cadmium, and mercury. PMID- 29114209 TI - The Biogenic Amine Tyramine and its Receptor (AmTyr1) in Olfactory Neuropils in the Honey Bee (Apis mellifera) Brain. AB - This article describes the cellular sources for tyramine and the cellular targets of tyramine via the Tyramine Receptor 1 (AmTyr1) in the olfactory learning and memory neuropils of the honey bee brain. Clusters of approximately 160 tyramine immunoreactive neurons are the source of tyraminergic fibers with small varicosities in the optic lobes, antennal lobes, lateral protocerebrum, mushroom body (calyces and gamma lobes), tritocerebrum and subesophageal ganglion (SEG). Our tyramine mapping study shows that the primary sources of tyramine in the antennal lobe and calyx of the mushroom body are from at least two Ventral Unpaired Median neurons (VUMmd and VUMmx) with cell bodies in the SEG. To reveal AmTyr1 receptors in the brain, we used newly characterized anti-AmTyr1 antibodies. Immunolocalization studies in the antennal lobe with anti-AmTyr1 antibodies showed that the AmTyr1 expression pattern is mostly in the presynaptic sites of olfactory receptor neurons (ORNs). In the mushroom body calyx, anti AmTyr1 mapped the presynaptic sites of uniglomerular Projection Neurons (PNs) located primarily in the microglomeruli of the lip and basal ring calyx area. Release of tyramine/octopamine from VUM (md and mx) neurons in the antennal lobe and mushroom body calyx would target AmTyr1 expressed on ORN and uniglomerular PN presynaptic terminals. The presynaptic location of AmTyr1, its structural similarity with vertebrate alpha-2 adrenergic receptors, and previous pharmacological evidence suggests that it has an important role in the presynaptic inhibitory control of neurotransmitter release. PMID- 29114210 TI - Human Novelty Response to Emotional Animal Vocalizations: Effects of Phylogeny and Familiarity. AB - Darwin (1872) postulated that emotional expressions contain universals that are retained across species. We recently showed that human rating responses were strongly affected by a listener's familiarity with vocalization types, whereas evidence for universal cross-taxa emotion recognition was limited. To disentangle the impact of evolutionarily retained mechanisms (phylogeny) and experience driven cognitive processes (familiarity), we compared the temporal unfolding of event-related potentials (ERPs) in response to agonistic and affiliative vocalizations expressed by humans and three animal species. Using an auditory oddball novelty paradigm, ERPs were recorded in response to task-irrelevant novel sounds, comprising vocalizations varying in their degree of phylogenetic relationship and familiarity to humans. Vocalizations were recorded in affiliative and agonistic contexts. Offline, participants rated the vocalizations for valence, arousal, and familiarity. Correlation analyses revealed a significant correlation between a posteriorly distributed early negativity and arousal ratings. More specifically, a contextual category effect of this negativity was observed for human infant and chimpanzee vocalizations but absent for other species vocalizations. Further, a significant correlation between the later and more posteriorly P3a and P3b responses and familiarity ratings indicates a link between familiarity and attentional processing. A contextual category effect of the P3b was observed for the less familiar chimpanzee and tree shrew vocalizations. Taken together, these findings suggest that early negative ERP responses to agonistic and affiliative vocalizations may be influenced by evolutionary retained mechanisms, whereas the later orienting of attention (positive ERPs) may mainly be modulated by the prior experience. PMID- 29114211 TI - Microglial Over-Activation by Social Defeat Stress Contributes to Anxiety- and Depressive-Like Behaviors. AB - Hyper activation of the neuroimmune system is strongly related to the development of neuropsychiatric disorders. Psychosocial stress has been postulated to play an important role in triggering anxiety and major depression. In preclinical models, there is mounting evidence that social defeat stress activates microglial cells in the central nervous system. This type of stress could be one of the major factors in the development of these psychopathologies. Here, we reviewed the most recent literature on social defeat and the associated immunological reactions. We focused our attention on microglial cells and kept the effect of social defeat over microglia separate from the effect of this stressor on other immune cells and the influence of peripheral immune components in priming central immune reactions. Furthermore, we considered how social defeat stress affects microglial cells and the consequent development of anxiety- and depressive-like states in preclinical studies. We highlighted evidence for the negative impact of the over activation of the neuroimmune system, especially by the overproduction of pro inflammatory mediators and cytotoxins. Overproduction of these molecules may cause cellular damage and loss or decreased function of neuronal activity by excessively pruning synaptic connections that ultimately contribute to the development of anxiety- and depressive-like states. PMID- 29114212 TI - Tablet-Based Functional MRI of the Trail Making Test: Effect of Tablet Interaction Mode. AB - The Trail Making Test (TMT) is widely used for assessing executive function, frontal lobe abilities, and visual motor skills. Part A of this pen-and-paper test (TMT-A) involves linking numbers randomly distributed in space, in ascending order. Part B (TMT-B) alternates between linking numbers and letters. TMT-B is more demanding than TMT-A, but the mental processing that supports the performance of this test remains incompletely understood. Functional MRI (fMRI) may help to clarify the relationship between TMT performance and brain activity, but providing an environment that supports real-world pen-and-paper interactions during fMRI is challenging. Previously, an fMRI-compatible tablet system was developed for writing and drawing with two modes of interaction: the original cursor-based, proprioceptive approach, and a new mode involving augmented reality to provide visual feedback of hand position (VFHP) for enhanced user interaction. This study characterizes the use of the tablet during fMRI of young healthy adults (n = 22), with half of the subjects performing TMT with VFHP and the other half performing TMT without VFHP. Activation maps for both TMT-A and TMT-B performance showed considerable overlap between the two tablet modes, and no statistically differences in brain activity were detected when contrasting TMT-B vs. TMT-A for the two tablet modes. Behavioral results also showed no statistically different interaction effects for TMT-B vs. TMT-A for the two tablet modes. Tablet-based TMT scores showed reasonable convergent validity with those obtained by administering the standard pen-and-paper TMT to the same subjects. Overall, the results suggest that despite the slightly different mechanisms involved for the two modes of tablet interaction, both are suitable for use in fMRI studies involving TMT performance. This study provides information for using tablet-based TMT methods appropriately in future fMRI studies involving patients and healthy individuals. PMID- 29114213 TI - Visually Evoked Visual-Auditory Changes Associated with Auditory Performance in Children with Cochlear Implants. AB - Activation of the auditory cortex by visual stimuli has been reported in deaf children. In cochlear implant (CI) patients, a residual, more intense cortical activation in the frontotemporal areas in response to photo stimuli was found to be positively associated with poor auditory performance. Our study aimed to investigate the mechanism by which visual processing in CI users activates the auditory-associated cortex during the period after cochlear implantation as well as its relation to CI outcomes. Twenty prelingually deaf children with CI were recruited. Ten children were good CI performers (GCP) and ten were poor (PCP). Ten age- and sex- matched normal-hearing children were recruited as controls, and visual evoked potentials (VEPs) were recorded. The characteristics of the right frontotemporal N1 component were analyzed. In the prelingually deaf children, higher N1 amplitude was observed compared to normal controls. While the GCP group showed significant decreases in N1 amplitude, and source analysis showed the most significant decrease in brain activity was observed in the primary visual cortex (PVC), with a downward trend in the primary auditory cortex (PAC) activity, but these did not occur in the PCP group. Meanwhile, higher PVC activation (comparing to controls) before CI use (0M) and a significant decrease in source energy after CI use were found to be related to good CI outcomes. In the GCP group, source energy decreased in the visual-auditory cortex with CI use. However, no significant cerebral hemispheric dominance was found. We supposed that intra- or cross-modal reorganization and higher PVC activation in prelingually deaf children may reflect a stronger potential ability of cortical plasticity. Brain activity evolution appears to be related to CI auditory outcomes. PMID- 29114214 TI - Commentary: The Emerging Neuroscience of Third-Party Punishment. PMID- 29114215 TI - Feasibility of 3D Reconstruction of Neural Morphology Using Expansion Microscopy and Barcode-Guided Agglomeration. AB - We here introduce and study the properties, via computer simulation, of a candidate automated approach to algorithmic reconstruction of dense neural morphology, based on simulated data of the kind that would be obtained via two emerging molecular technologies-expansion microscopy (ExM) and in-situ molecular barcoding. We utilize a convolutional neural network to detect neuronal boundaries from protein-tagged plasma membrane images obtained via ExM, as well as a subsequent supervoxel-merging pipeline guided by optical readout of information-rich, cell-specific nucleic acid barcodes. We attempt to use conservative imaging and labeling parameters, with the goal of establishing a baseline case that points to the potential feasibility of optical circuit reconstruction, leaving open the possibility of higher-performance labeling technologies and algorithms. We find that, even with these conservative assumptions, an all-optical approach to dense neural morphology reconstruction may be possible via the proposed algorithmic framework. Future work should explore both the design-space of chemical labels and barcodes, as well as algorithms, to ultimately enable routine, high-performance optical circuit reconstruction. PMID- 29114216 TI - Editorial: Peripheral Nervous System-Machine Interfaces (PNS-MI). PMID- 29114217 TI - Bio-Inspired Genetic Algorithms with Formalized Crossover Operators for Robotic Applications. AB - Genetic algorithms are widely adopted to solve optimization problems in robotic applications. In such safety-critical systems, it is vitally important to formally prove the correctness when genetic algorithms are applied. This paper focuses on formal modeling of crossover operations that are one of most important operations in genetic algorithms. Specially, we for the first time formalize crossover operations with higher-order logic based on HOL4 that is easy to be deployed with its user-friendly programing environment. With correctness guaranteed formalized crossover operations, we can safely apply them in robotic applications. We implement our technique to solve a path planning problem using a genetic algorithm with our formalized crossover operations, and the results show the effectiveness of our technique. PMID- 29114218 TI - Periodontitis, Microbiomes and their Role in Alzheimer's Disease. AB - As far back as the eighteenth and early nineteenth centuries, microbial infections were responsible for vast numbers of deaths. The trend reversed with the introduction of antibiotics coinciding with longer life. Increased life expectancy however, accompanied the emergence of age related chronic inflammatory states including the sporadic form of Alzheimer's disease (AD). Taken together, the true challenge of retaining health into later years of life now appears to lie in delaying and/or preventing the progression of chronic inflammatory diseases, through identifying and influencing modifiable risk factors. Diverse pathogens, including periodontal bacteria have been associated with AD brains. Amyloid-beta (Abeta) hallmark protein of AD may be a consequence of infection, called upon due to its antimicrobial properties. Up to this moment in time, a lack of understanding and knowledge of a microbiome associated with AD brain has ensured that the role pathogens may play in this neurodegenerative disease remains unresolved. The oral microbiome embraces a range of diverse bacterial phylotypes, which especially in vulnerable individuals, will excite and perpetuate a range of inflammatory conditions, to a wide range of extra-oral body tissues and organs specific to their developing pathophysiology, including the brain. This offers the tantalizing opportunity that by controlling the oral specific microbiome; clinicians may treat or prevent a range of chronic inflammatory diseases orally. Evolution has equipped the human host to combat infection/disease by providing an immune system, but Porphyromonas gingivalis and selective spirochetes, have developed immune avoidance strategies threatening the host-microbe homeostasis. It is clear from longitudinal monitoring of patients that chronic periodontitis contributes to declining cognition. The aim here is to discuss the contribution from opportunistic pathogens of the periodontal microbiome, and highlight the challenges, the host faces, when dealing with unresolvable oral infections that may lead to clinical manifestations that are characteristic for AD. PMID- 29114219 TI - Entanglement of UPRER in Aging Driven Neurodegenerative Diseases. AB - The endoplasmic reticulum (ER) is an indispensable cellular organelle that remains highly active in neuronal cells. The ER bears the load of maintaining protein homeostasis in the cellular network by managing the folding of incoming nascent peptides; however, the stress imposed by physiological/environmental factors can cause ER dysfunctions that lead to the activation of ER unfolded protein response (UPRER). Aging leads to deterioration of several cellular pathways and therefore weakening of the UPRER. The decline in functioning of the UPRER during aging results in accumulation of misfolded proteins that becomes intracellular inclusions in neuronal cells, resulting in toxicity manifested as neurodegenerative diseases. With ascension in cases of neurodegenerative diseases, understanding the enigma behind aging driven UPRER dysfunction may lead to possible treatments. PMID- 29114220 TI - Endothelin-1 Regulation of Exercise-Induced Changes in Flow: Dynamic Regulation of Vascular Tone. AB - Although endothelin (ET)-1 is a highly potent vasoconstrictor with considerable efficacy in numerous vascular beds, the role of endogenous ET-1 in the regulation of vascular tone remains unclear. The perspective that ET-1 plays little role in the on-going regulation of vascular tone at least under physiologic conditions is supported by findings that potential ET-1 constriction is minimized by the release of the vasodilator and ET-1 synthesis inhibitor, nitric oxide (NO). Indeed, ET-1 release and constriction is self-limited by ET-1-induced, endothelial ETB receptor-mediated release of NO. Moreover, even if the balance between ET-1 and NO were reversed as the result of lowered NO activity, as occurs in a number of pathophysiologies associated with endothelial dysfunction, the well-known resistance of ET-1 constriction to reversal (as determined with exogenous ET-1) precludes ET-1 in the dynamic, i.e., moment-to-moment, regulation of vascular tone. On the other hand, and as presently reviewed, findings of ET-1 dependent modulation of organ blood flow with exercise under physiologic conditions demonstrate the dynamic regulation of vascular tone by ET-1. We speculate that this regulation is mediated at least in part through changes in ET 1 synthesis/release caused by pulsatile flow-induced shear stress and NO. PMID- 29114221 TI - Phenotypic Screen Identifies a Small Molecule Modulating ERK2 and Promoting Stem Cell Proliferation. AB - Stem cells display a fundamentally different mechanism of proliferation control when compared to somatic cells. Uncovering these mechanisms would maximize the impact in drug discovery with a higher translational applicability. The unbiased approach used in phenotype-based drug discovery (PDD) programs can offer a unique opportunity to identify such novel biological phenomenon. Here, we describe an integrated phenotypic screening approach, employing a combination of in vitro and in vivo PDD models to identify a small molecule increasing stem cell proliferation. We demonstrate that a combination of both in vitro and in vivo screening models improves hit identification and reproducibility of effects across various PDD models. Using cell viability and colony size phenotype measurement we characterize the structure activity relationship of the lead molecule, and identify that the small molecule inhibits phosphorylation of ERK2 and promotes stem cell proliferation. This study demonstrates a PDD approach that employs combinatorial models to identify compounds promoting stem cell proliferation. PMID- 29114222 TI - Ginsenoside Rb1 Enhances Atherosclerotic Plaque Stability by Improving Autophagy and Lipid Metabolism in Macrophage Foam Cells. AB - Atherosclerosis (AS) is a lipid-driven disease in which macrophage foam cells play a critical role by increasing vascular lipid accumulation and contributing to plaque instability. Ginsenoside Rb1 (Rb1), the most abundant active component of ginseng, has been found potently to promote lipid metabolism and attenuate lipid accumulation. However, the underlying mechanisms remain unclear. In this study, the effects of Rb1 on lipid accumulation and plaque stability were investigated both in vitro and in vivo by using primary peritoneal macrophages isolated from C57BL/6 mice and an AS model in ApoE-/- mice. The results showed that Rb1 reduced lipid accumulation both in macrophage foam cells and atherosclerotic plaques. Rb1 treatment promoted plaque stability by modifying plaque composition via the activation of autophagy both in vitro and in vivo. Transmission electron microscopy further showed an increased accumulation of autophagolysosomes in Rb1-treated macrophage foam cells. However, the modulation of lipid accumulation by Rb1 was attenuated by autophagy blockage using autophagy related gene 5 (Atg5) small interfering RNA (siRNA) in vitro. In addition, Rb1 notably increased AMPK phosphorylation both in vitro and in vivo, and the AMPK inhibitor compound C abolished the Rb1-induced autophagy in macrophage foam cells. In conclusion, ginsenoside Rb1 reduced lipid accumulation in macrophage foam cells and enhanced atherosclerotic plaque stability by the induction of macrophage autophagy. Our study provides new evidence for the possible use of Rb1 in the prevention and treatment of AS. PMID- 29114224 TI - Chlorpheniramine Potentiates the Analgesic Effect in Migraine of Usual Caffeine, Acetaminophen, and Acetylsalicylic Acid Combination. AB - Previous studies indicated that addition of the antihistaminic chlorpheniramine to the usual combination of acetylsalicylic acid, acetaminophen, and caffeine further increases their synergism both in terms of anti-inflammatory and analgesic effect. The present non-interventional study tested the superiority of two Algopirin(r) tablets, containing a total of 250 mg acetylsalicylic acid (ASA), 150 mg acetaminophen (paracetamol, PAR), 30 mg caffeine (CAF) and 4 mg chlorpheniramine (CLF) vs. a combination containing 250 mg ASA, 250 mg PAR, and 65 mg CAF recognized as "safe and effective" by FDA in treating migraine. Patients evaluated their pain intensity on the Visual Analog Scale-VAS(PI) before and 30, 60, 120, 180, and 240 min after drug intake. Interpretation of the pain curves as "survival pain curves" was considered as a method for direct comparison of the pain curves. This interpretation permitted the application of the log rank test for comparison of pain hazards. The results of the applied parametric and non-parametric statistical tests indicated significant differences between the main endpoints: both Areas Under Pain Curves and time to decrease of the pain intensity to less than 50% of the initial value comparisons highlighted that Algopirin(r) was more efficient in spite of smaller doses of PAR and CAF. Comparison of "survival of pain" led to the same conclusion concerning the superiority of Algopririn. Consequently, the addition of CLF permitted decreasing of ASA, PAR, and CAF doses as well as their potential side effects, without a loss of analgesic effect. PMID- 29114225 TI - Application of Activated Carbon Derived from Seed Shells of Jatropha curcas for Decontamination of Zearalenone Mycotoxin. AB - In the present study, activated carbon (AC) was derived from seed shells of Jatropha curcas and applied to decontaminate the zearalenone (ZEA) mycotoxin. The AC of J. curcas (ACJC) was prepared by ZnCl2 chemical activation method and its crystalline structure was determined by X-ray diffraction analysis. The crystalline graphitic nature of ACJC was confirmed from the Raman spectroscopy. Scanning electron microscope showed the porous surface morphology of the ACJC surface with high pore density and presence of elemental carbon was identified from the energy dispersive X-ray analysis. From Brunauer-Emmett-Teller (BET) analysis, SBET, micropore area, and average pore diameter of ACJC were calculated as 822.78 (m2/g), 255.36 (m2/g), and 8.5980 (A), respectively. The adsorption of ZEA by ACJC was accomplished with varying contact time, concentration of ZEA and ACJC, and pH of media. The ACJC has adsorbed the ZEA over a short period of time and adsorption of ZEA was dependent on the dose of ACJC. The effect of different pH on adsorption of ZEA by ACJC was not much effective. Desorption studies confirmed that adsorption of ZEA by ACJC was stable. The adsorption isotherm of ZEA by ACJC was well fitted with Langmuir model rather than Freundlich and concluded the homogeneous process of sorption. The maximum adsorption of ZEA by ACJC was detected as 23.14 MUg/mg. Finally, adsorption property of ACJC was utilized to establish ACJC as an antidote against ZEA-induced toxicity under in vitro in neuro-2a cells. The percentage of live cells was high in cells treated together with a combination of ZEA and ACJC compared to ZEA treated cells. In a similar way, DeltaPsiM was not dropped in cells exposed to combination of ACJC and ZEA compared to ZEA treated cells. Furthermore, cells treated with a combination of ZEA and ACJC exhibited lower level of intracellular reactive oxygen species and caspase-3 compared to ZEA treated cells. These in vitro studies concluded that ACJC has successfully protected the cells from ZEA-induced toxicity by lowering the availability of ZEA in media as a result of adsorption of ZEA. The study concluded that ACJC was a potent decontaminating agent for ZEA and could be used as an antidote against ZEA-induced toxicity. PMID- 29114223 TI - The Human Amnion Epithelial Cell Secretome Decreases Hepatic Fibrosis in Mice with Chronic Liver Fibrosis. AB - Background: Hepatic stellate cells (HSCs) are the primary collagen-secreting cells in the liver. While HSCs are the major cell type involved in the pathogenesis of liver fibrosis, hepatic macrophages also play an important role in mediating fibrogenesis and fibrosis resolution. Previously, we observed a reduction in HSC activation, proliferation, and collagen synthesis following exposure to human amnion epithelial cells (hAEC) and hAEC-conditioned media (hAEC CM). This suggested that specific factors secreted by hAEC might be effective in ameliorating liver fibrosis. hAEC-derived extracellular vesicles (hAEC-EVs), which are nanosized (40-100 nm) membrane bound vesicles, may act as novel cell cell communicators. Accordingly, we evaluated the efficacy of hAEC-EV in modulating liver fibrosis in a mouse model of chronic liver fibrosis and in human HSC. Methods: The hAEC-EVs were isolated and characterized. C57BL/6 mice with CCl4-induced liver fibrosis were administered hAEC-EV, hAEC-CM, or hAEC-EV depleted medium (hAEC-EVDM). LX2 cells, a human HSC line, and bone marrow-derived mouse macrophages were exposed to hAEC-EV, hAEC-CM, and hAEC-EVDM. Mass spectrometry was used to examine the proteome profile of each preparation. Results: The extent of liver fibrosis and number of activated HSCs were reduced significantly in CCl4-treated mice given hAEC-EVs, hAEC-CM, and hAEC EVDM compared to untreated controls. Hepatic macrophages were significantly decreased in all treatment groups, where a predominant M2 phenotype was observed. Human HSCs cultured with hAEC-EV and hAEC-CM displayed a significant reduction in collagen synthesis and hAEC-EV, hAEC-CM, and hAEC-EVDM altered macrophage polarization in bone marrow-derived mouse macrophages. Proteome analysis showed that 164 proteins were unique to hAEC-EV in comparison to hAEC-CM and hAEC-EVDM, and 51 proteins were co-identified components with the hAEC-EV fraction. Conclusion: This study provides novel data showing that hAEC-derived EVs significantly reduced liver fibrosis and macrophage infiltration to an extent similar to hAEC-EVDM and hAEC-CM. hAEC-EV-based therapy may be a potential therapeutic option for liver fibrosis. PMID- 29114226 TI - Metformin Use Correlates with Reduced Risk of Gallstones in Diabetic Patients: A 12-Year Follow-up Study. AB - Objective: Few studies are available on the association between gallstones and metformin use. The objective of the study was to determine whether metformin use is associated with gallstones. Methods: A population-based retrospective cohort study was conducted using the database of the Taiwan National Health Insurance Program. Subjects of newly diagnosed diabetes mellitus were included from 2002 to 2013. The metformin-exposure group was defined as >=29 cumulative defined daily dose (DDD) of metformin use. The un-exposure group was defined as <29 cumulative DDD of metformin use. The major endpoint was a new diagnosis of gallstones during the follow-up period. A multivariable Cox proportional hazards regression model was used to evaluate the hazard ratio (HR) and 95% confidence interval (CI) of gallstones associated with metformin use. Results: After controlling for potential confounders, the adjusted HRs of gallstones were 1.11 (95%CI: 0.84 1.46) for subjects with metformin dosage of 29-180 cumulative DDD, and 0.57 (95%CI: 0.42-0.78) for subjects with metformin dosage >180 cumulative DDD, compared with the un-exposure group. Conclusion: Long-term use of metformin is associated with reduced risk of gallstones. PMID- 29114227 TI - Non-linear Heart Rate and Blood Pressure Interaction in Response to Lower-Body Negative Pressure. AB - Early detection of hemorrhage remains an open problem. In this regard, blood pressure has been an ineffective measure of blood loss due to numerous compensatory mechanisms sustaining arterial blood pressure homeostasis. Here, we investigate the feasibility of causality detection in the heart rate and blood pressure interaction, a closed-loop control system, for early detection of hemorrhage. The hemorrhage was simulated via graded lower-body negative pressure (LBNP) from 0 to -40 mmHg. The research hypothesis was that a significant elevation of causal control in the direction of blood pressure to heart rate (i.e., baroreflex response) is an early indicator of central hypovolemia. Five minutes of continuous blood pressure and electrocardiogram (ECG) signals were acquired simultaneously from young, healthy participants (27 +/- 1 years, N = 27) during each LBNP stage, from which heart rate (represented by RR interval), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were derived. The heart rate and blood pressure causal interaction (RR<->SBP and RR<->MAP) was studied during the last 3 min of each LBNP stage. At supine rest, the non-baroreflex arm (RR->SBP and RR->MAP) showed a significantly (p < 0.001) higher causal drive toward blood pressure regulation compared to the baroreflex arm (SBP->RR and MAP->RR). In response to moderate category hemorrhage (-30 mmHg LBNP), no change was observed in the traditional marker of blood loss i.e., pulse pressure (p = 0.10) along with the RR->SBP (p = 0.76), RR->MAP (p = 0.60), and SBP->RR (p = 0.07) causality compared to the resting stage. Contrarily, a significant elevation in the MAP->RR (p = 0.004) causality was observed. In accordance with our hypothesis, the outcomes of the research underscored the potential of compensatory baroreflex arm (MAP->RR) of the heart rate and blood pressure interaction toward differentiating a simulated moderate category hemorrhage from the resting stage. Therefore, monitoring baroreflex causality can have a clinical utility in making triage decisions to impede hemorrhage progression. PMID- 29114228 TI - Integrative Temporo-Spatial, Mineralogic, Spectroscopic, and Proteomic Analysis of Postnatal Enamel Development in Teeth with Limited Growth. AB - Tooth amelogenesis is a complex process beginning with enamel organ cell differentiation and enamel matrix secretion, transitioning through changes in ameloblast polarity, cytoskeletal, and matrix organization, that affects crucial biomineralization events such as mineral nucleation, enamel crystal growth, and enamel prism organization. Here we have harvested the enamel organ including the pliable enamel matrix of postnatal first mandibular mouse molars during the first 8 days of tooth enamel development to conduct a step-wise cross-sectional analysis of the changes in the mineral and protein phase. Mineral phase diffraction pattern analysis using single-crystal, powder sample X-ray diffraction analysis indicated conversion of calcium phosphate precursors to partially fluoride substituted hydroxyapatite from postnatal day 4 (4 dpn) onwards. Attenuated total reflectance spectra (ATR) revealed a substantial elevation in phosphate and carbonate incorporation as well as structural reconfiguration between postnatal days 6 and 8. Nanoscale liquid chromatography coupled with tandem mass spectrometry (nanoLC-MS/MS) demonstrated highest protein counts for ECM/cell surface proteins, stress/heat shock proteins, and alkaline phosphatase on postnatal day 2, high counts for ameloblast cytoskeletal proteins such as tubulin beta5, tropomyosin, beta-actin, and vimentin on postnatal day 4, and elevated levels of cofilin-1, calmodulin, and peptidyl-prolyl cis-trans isomerase on day 6. Western blot analysis of hydrophobic enamel proteins illustrated continuously increasing amelogenin levels from 1 dpn until 8 dpn, while enamelin peaked on days 1 and 2 dpn, and ameloblastin on days 1-5 dpn. In summary, these data document the substantial changes in the enamel matrix protein and mineral phase that take place during postnatal mouse molar amelogenesis from a systems biological perspective, including (i) relatively high levels of matrix protein expression during the early secretory stage on postnatal day 2, (ii) conversion of calcium phosphates to apatite, peak protein folding and stress protein counts, and increased cytoskeletal protein levels such as actin and tubulin on day 4, as well as (iii) secondary structure changes, isomerase activity, highest amelogenin levels, and peak phosphate/carbonate incorporation between postnatal days 6 and 8. Together, this study provides a baseline for a comprehensive understanding of the mineralogic and proteomic events that contribute to the complexity of mammalian tooth enamel development. PMID- 29114229 TI - Structural Control of Microvessel Diameters: Origins of Metabolic Signals. AB - Diameters of microvessels undergo continuous structural adaptation in response to hemodynamic and metabolic stimuli. To ensure adequate flow distribution, metabolic responses are needed to increase diameters of vessels feeding poorly perfused regions. Possible modes of metabolic control include release of signaling substances from vessel walls, from the supplied tissue and from red blood cells (RBC). Here, a theoretical model was used to compare the abilities of these metabolic control modes to provide adequate tissue oxygenation, and to generate blood flow velocities in agreement with experimental observations. Structural adaptation of vessel diameters was simulated for an observed mesenteric network structure in the rat with 576 vessel segments. For each mode of metabolic control, resulting distributions of oxygen and deviations between simulated and experimentally observed flow velocities were analyzed. It was found that wall-derived and tissue-derived growth signals released in response to low oxygen levels could ensure adequate oxygen supply, but RBC-derived signals caused inefficient oxygenation. Closest agreement between predicted and observed flow velocities was obtained with wall-derived growth signals proportional to vessel length. Adaptation in response to oxygen-independent release of a metabolic signal substance from vessel walls or the supplied tissue was also shown to be effective for ensuring tissue oxygenation due to a dilution effect if growth signal substances are released into the blood. The present results suggest that metabolic signals responsible for structural adaptation of microvessel diameters are derived from vessel walls or from perivascular tissue. PMID- 29114230 TI - The Effects of Simulated Wildland Firefighting Tasks on Core Temperature and Cognitive Function under Very Hot Conditions. AB - Background: The severity of wildland fires is increasing due to continually hotter and drier summers. Firefighters are required to make life altering decisions on the fireground, which requires analytical thinking, problem solving, and situational awareness. This study aimed to determine the effects of very hot (45 degrees C; HOT) conditions on cognitive function following periods of simulated wildfire suppression work when compared to a temperate environment (18 degrees C; CON). Methods: Ten male volunteer firefighters intermittently performed a simulated fireground task for 3 h in both the CON and HOT environments, with cognitive function tests (paired associates learning and spatial span) assessed at baseline (cog 1) and during the final 20-min of each hour (cog 2, 3, and 4). Reaction time was also assessed at cog 1 and cog 4. Pre- and post- body mass were recorded, and core and skin temperature were measured continuously throughout the protocol. Results: There were no differences between the CON and HOT trials for any of the cognitive assessments, regardless of complexity. While core temperature reached 38.7 degrees C in the HOT (compared to only 37.5 degrees C in the CON; p < 0.01), core temperature declined during the cognitive assessments in both conditions (at a rate of -0.15 +/- 0.20 degrees C.hr-1 and -0.63 +/- 0.12 degrees C.hr-1 in the HOT and CON trial respectively). Firefighters also maintained their pre-exercise body mass in both conditions, indicating euhydration. Conclusions: It is likely that this maintenance of euhydration and the relative drop in core temperature experienced between physical work bouts was responsible for the preservation of firefighters' cognitive function in the present study. PMID- 29114231 TI - Co-option of Hair Follicle Keratins into Amelogenesis Is Associated with the Evolution of Prismatic Enamel: A Hypothesis. AB - Recent discovery of hair follicle keratin 75 (KRT75) in enamel raises questions about the function of this protein in enamel and the mechanisms of its secretion. It is also not clear how this protein with a very specific and narrow expression pattern, limited to the inner root sheath of the hair follicle, became associated with enamel. We propose a hypothesis that KRT75 was co-opted by ameloblasts during the evolution of Tomes' process and the prismatic enamel in synapsids. PMID- 29114232 TI - Re-Evaluation of Imaging Methods of Reactive Oxygen and Nitrogen Species in Plants and Fungi: Influence of Cell Wall Composition. AB - Developmental transitions and stress reactions in both eukaryotes and prokaryotes are tightly linked with fast and localized modifications in concentrations of reactive oxygen and nitrogen species (ROS and RNS). Fluorescent microscopic analyses are widely applied to detect localized production of ROS and RNS in vivo. In this mini-review we discuss the biological characteristics of studied material (cell wall, extracellular matrix, and tissue complexity) and its handling (concentration of probes, effect of pressure, and higher temperature) which influence results of histochemical staining with "classical" fluorochromes. Future perspectives of ROS and RNS imaging with newly designed probes are briefly outlined. PMID- 29114234 TI - Gender-Specific Covariations between Competencies, Interest and Effort during Science Learning in Virtual Environments. AB - Women are still underrepresented in engineering courses although some German universities offer separate women's engineering courses which include virtual STEM learning environments. To outline information about fundamental aspects relevant for virtual STEM learning, one has to reveal which similarities both genders in virtual learning show. Moreover, the question arises as to whether there are in fact differences in the virtual science learning of female and male learners. Working with virtual STEM learning environments requires strategic and arithmetic-operative competences. Even if we assume that female and male learners have similar competences levels, their correlational pattern of competences, motivational variables, and invested effort during virtual STEM learning might differ. If such gender differences in the correlations between cognitive and motivational variables and learning behavior were revealed, it would be possible to finetune study conditions for female students in a separate engineering course and shape virtual STEM learning in a more gender-appropriate manner. That might support an increase in the number of women in engineering courses. To reveal the differences and similarities between female and male learners, a field study was conducted with 56 students (female = 27, male = 29) as part of the Open MINT Labs project (the German term for Open STEM Labs, OML). The participants had to complete a virtual STEM learning environment during their regular science lessons. The data were collected with questionnaires. The results revealed that the strategic competences of both genders were positively correlated with situational interest in the virtual learning environment. This result shows the big impact strategic competences have for both genders regarding their situational interest. In contrast, the correlations between mental effort and competences differed between female and male participants. Especially female learners' mental effort decreased if they had more strategic competences. On the other hand, female learners' mental effort increased if they had more arithmetic operative competences. All in all, female learners seem to be more sensitive to differences in their strategic and arithmetic-operative competences regarding their mental effort. These results imply that the implementation of separate women's engineering courses could be an interesting approach. PMID- 29114233 TI - The JNK Signaling Pathway in Renal Fibrosis. AB - Fibrosis of the glomerular and tubulointerstitial compartments is a common feature of chronic kidney disease leading to end-stage renal failure. This fibrotic process involves a number of pathologic mechanisms, including cell death and inflammation. This review focuses on the role of the c-Jun amino terminal kinase (JNK) signaling pathway in the development of renal fibrosis. The JNK pathway is activated in response to various cellular stresses and plays an important role in cell death and inflammation. Activation of JNK signaling is a common feature in most forms of human kidney injury, evident in both intrinsic glomerular and tubular cells as well as in infiltrating leukocytes. Similar patterns of JNK activation are evident in animal models of acute and chronic renal injury. Administration of JNK inhibitors can protect against acute kidney injury and suppress the development of glomerulosclerosis and tubulointerstitial fibrosis. In particular, JNK activation in tubular epithelial cells may be a pivotal mechanism in determining the outcome of both acute kidney injury and progression of chronic kidney disease. JNK signaling promotes tubular epithelial cell production of pro-inflammatory and pro-fibrotic molecules as well as tubular cell de-differentiation toward a mesenchymal phenotype. However, the role of JNK within renal fibroblasts is less well-characterized. The JNK pathway interacts with other pro-fibrotic pathways, most notable with the TGF-beta/SMAD pathway. JNK activation can augment TGF-beta gene transcription, induce expression of enzymes that activate the latent form of TGF-beta, and JNK directly phosphorylates SMAD3 to enhance transcription of pro-fibrotic molecules. In conclusion, JNK signaling plays an integral role in several key mechanisms operating in renal fibrosis. Targeting of JNK enzymes has therapeutic potential for the treatment of fibrotic kidney diseases. PMID- 29114235 TI - Biofunctional Understanding and Conceptual Control: Searching for Systematic Consensus in Systemic Cohesion. AB - For first generation scientists after the cognitive revolution, knowers were in active control over all (stages of) information processing. Then, following a decade of transition shaped by intense controversy, embodied cognition emerged and suggested sources of control other than those implied by metaphysical information processing. With a thematic focus on embodiment science and an eye toward systematic consensus in systemic cohesion, the present study explores the roles of biofunctional and conceptual control processes in the wholetheme spiral of biofunctional understanding (see Iran-Nejad and Irannejad, 2017b, Figure 1). According to this spiral, each of the two kinds of understanding has its own unique set of knower control processes. For conceptual understanding (CU), knowers have deliberate attention-allocation control over their first-person "knowthat" and "knowhow" content combined as mutually coherent corequisites. For biofunctional understanding (BU), knowers have attention-allocation control only over their knowthat content but knowhow control content is ordinarily conspicuously absent. To test the hypothesis of differences in the manner of control between CU and BU, participants in two experiments read identical-format statements for internal consistency, as response time was recorded. The results of Experiment 1 supported the hypothesis of differences in the manner of control between the two types of control processes; and Experiment 2 confirmed the results of Experiment 1. These findings are discussed in terms of the predicted differences between BU and CU control processes, their roles in regulating the physically unobservable flow of systemic cohesion in the wholetheme spiral, and a proposal for systematic consensus in systemic cohesion to serve as the second guiding principle in biofunctional embodiment science next to physical science's first guiding principle of systematic observation. PMID- 29114236 TI - Patterns of Joint Improvisation in Adults with Autism Spectrum Disorder. AB - Recent research on autism spectrum disorders (ASDs) suggests that individuals with autism may have a basic deficit in synchronizing with others, and that this difficulty may lead to more complex social and communicative deficits. Here, we examined synchronization during an open-ended joint improvisation (JI) paradigm, called the mirror game (MG). In the MG, two players take turns leading, following, and jointly improvising motion using two handles set on parallel tracks, while their motion tracks are recorded with high temporal and spatial resolution. A series of previous studies have shown that players in the MG attain moments of highly synchronized co-confident (CC) motion, in which there is no typical kinematic pattern of leader and reactive follower. It has been suggested that during these moments players act as a coupled unit and feel high levels of connectedness. Here, we aimed to assess whether participants with ASD are capable of attaining CC, and whether their MG performance relates to broader motor and social skills. We found that participants with ASD (n = 34) can indeed attain CC moments when playing with an expert improviser, though their performance was attenuated in several ways, compared to typically developing (TD) participants (n = 35). Specifically, ASD participants had lower rates of CC, compared with TD participants, which was most pronounced during the following rounds. In addition, the duration of their CC segments was shorter, across all rounds. When controlling for participants' motor skills (both on the MG console, and more broadly) some of the variability in MG performance was explained, but group differences remained. ASD participants' alexithymia further correlated with their difficulty following another's lead; though other social skills did not relate to MG performance. Participants' subjective reports of the game suggest that other cognitive and emotional factors, such as attention, motivation, and reward processing, which were not directly measured in the experiment, may impact their performance. Together, these results show that ASD participants can attain moments of high motor synchronization with an expert improviser, even during an open-ended task. Future studies should examine the ways in which these skills may be further harnessed in clinical settings. PMID- 29114237 TI - Advances in Measurement Invariance and Mean Comparison of Latent Variables: Equivalence Testing and A Projection-Based Approach. AB - Measurement invariance (MI) entails that measurements in different groups are comparable, and is a logical prerequisite when studying difference or change across groups. MI is commonly evaluated using multi-group structural equation modeling through a sequence of chi-square and chi-square-difference tests. However, under the conventional null hypothesis testing (NHT) one can never be confident enough to claim MI even when all test statistics are not significant. Equivalence testing (ET) has been recently proposed to replace NHT for studying MI. ET informs researchers a size of possible misspecification and allows them to claim that measurements are practically equivalent across groups if the size of misspecification is smaller than a tolerable value. Another recent advancement in studying MI is a projection-based method under which testing the cross-group equality of means of latent traits does not require the intercepts equal across groups. The purpose of this article is to introduce the key ideas of the two advancements in MI and present a newly developed R package equaltestMI for researchers to easily apply the two methods. A real data example is provided to illustrate the use of the package. It is advocated that researchers should always consider using the two methods whenever MI needs to be examined. PMID- 29114238 TI - Long-term Monitoring Gait Analysis Using a Wearable Device in Daily Lives of Patients with Parkinson's Disease: The Efficacy of Selegiline Hydrochloride for Gait Disturbance. AB - Objective: The aim of this study was to assess quantitatively the gait disorders in the daily lives of patients with Parkinson's disease (PD) using with a newly developed portable gait rhythmogram (PGR), which has a trunk-mounted acceleration sensor and automatic gait-detection algorithm. Methods: Using the PGR, we recorded the daily walking profiles of 14 PD patients before and after the addition or increase in dose of an MAO-B inhibitor (selegiline, average dose: 4.0 mg/day) as part of their medicine regimen, and evaluated their gait using the unified Parkinson's disease rating scale (UPDRS) and scores from a freezing of gait (FOG) questionnaire. Results: Before treatment with selegiline, the overall movements per 24 h was decreased below 0.41 m/s2 (mean - 1.5 SD) in eight patients. The mean gait acceleration was decreased below 1.94 m/s2 (mean - 2 SD) in 10 patients. The slope of the linear regression line was increased to 1.6 (mean + 1.5 SD) in eight patients. The cadence was increased to 124 steps/min (mean + 1.5 SD) in four patients. Based on continuous PGR recordings in the daily lives of the patients for 24 h, the addition or increase in dose of selegiline increased the amplitudes of gait accelerations in 4 of 10 patients (40.0%), widened the range of gait accelerations in 5 of 8 patients (62.5%), diminished the cadence in 4 of 4 patients (100%), and diminished the fluctuations in gait throughout the day in 12 of 14 patients (85.7%). The UPDRS III and FOG scores significantly improved after the addition or increase in dose of selegiline (p < 0.005, p < 0.01, respectively). However, changes in gait-related scores of UPDRS were not detected in six patients. Conclusion: Improvements in the gait fluctuations of PD patients after the addition or increase in dose of selegiline were detected using the PGR in the daily lives of the patients for 24 h. The PGR had a higher sensitivity for detecting the improvements than UPDRS scores. PMID- 29114239 TI - Botulinumtoxin Improves both Generic and Disease-Specific Quality of Life in Cervical Dystonia. AB - Botulinumtoxin injection (BoNT) into affected muscles is effective to improve motor symptoms of cervical dystonia (CD) by reducing muscle contraction and involuntary dystonic movement and posturing. However, the understanding of the effect on health-related quality of life (HR-QoL) and patient referral under HR QoL aspects is incomplete. In this open-label clinical prospective observational study, we characterized the outcomes in CD (n = 159) from botulinumtoxin on both generic HR-QoL (EuroQol; EQ-5D-5L) and disease-specific HR-QoL [craniocervical dystonia questionnaire (CDQ-24)]. Additionally, we characterized motor and non motor signs of dystonia including motor symptom improvement, depressive symptoms, pain, and sleep quality. We assessed patients at the end of a regular 3-month period from last injection (Timepoint1) and 4 weeks after the re-injection of BoNT (Timepoint2). We aimed to define outcomes on both generic and disease specific HR-QoL and to evaluate predictors of therapeutic outcome in terms of stepwise multiple regression models. Patients with CD showed a robust improvement of both generic and disease-specific HR-QoL. Furthermore, motor and non-motor signs improved. Multiple regression analyses revealed that EQ-5D-5L and "satisfaction with health" (Fragen zur Lebenszufriedenheit-G) at Timepoint1 predicted treatment response on generic HR-QoL outcome (R2 = 0.284; P = 0.019). Similarly, CDQ-24 and Beck's Depression inventory at Timepoint1 predicted the treatment response on disease-specific HR-QoL (R2 = 0.253; P = 0.026). Our study underscores both generic and disease-specific HR-QoL improvements in CD, and provides useful predictors on HR-QoL outcomes. PMID- 29114240 TI - Deficiency in Lipoteichoic Acid Synthesis Causes a Failure in Executing the Colony Developmental Program in Bacillus subtilis. AB - Colonies are an abundant form of bacterial multicellularity; however, relatively little is known about the initial stages of their construction. We have previously described that colony development of the soil bacterium Bacillus subtilis is a highly ordered process, typically initiating with the formation of extending cell chains arranged in a Y shape structure. Furthermore, we demonstrated that Y arm extension is a key for defining the size of the future colony. Here we conducted a genetic screen surveying for mutants deficient in these early developmental stages, and revealed LtaS, the major lipoteichoic acid (LTA) synthase, to be crucial for execution of these events. We found that the ltaS mutant fails to produce proper Y shape structures, forming extremely elongated chains of cells with no evidence of chain breakage, necessary for Y shape formation. Furthermore, we show that frequent cell death at the tips of the cell chains is a major cause in limiting arm extension. Collectively, these perturbations lead to the production of a small sized colony by the mutant. Thus, deficiency in LTA synthesis causes a mechanical failure in executing the colony developmental program. PMID- 29114242 TI - Bacillus sp. Acting as Dual Role for Corrosion Induction and Corrosion Inhibition with Carbon Steel (CS). AB - Present work investigated the role of five different bacteria species as a corrosion inducer as well as corrosion inhibitor with carbon steel (CS). We observed the ability of different bacteria species on the metal surface attachment, biofilm formation, and determined Peroxidase, Catalase enzyme activity in the detached biofilm from the CS surface. We found that each strain has diverse conduct for surface attachment like DS1 3.3, DS2 2.5, DS3 4.3, DS4 4.0, and DS5 4.71 log cfu/cm2 and for biofilm 8.3 log cfu/cm2. The enzyme Peroxidase, Catalase was found in huge concentration inside the biofilm Peroxidase was maximum for DS4 36.0 U/ml and least for DS3 19.54 U/ml. Whereas, Catalase was highest for DS4, DS5 70.14 U/ml and least 57.2 U/ml for DS2. Scanning electron microscopy (SEM) was conducted to examine the biofilm and electrochemical impedance spectroscopy (EIS) were utilized to observe corrosion in the presence of bacteria. The electrochemical results confirmed that DS1, DS3, DS4, and DS5 strains have statistically significant MIC-factors (Microbially Influenced Corrosion) of 5.46, 8.51, 2.36, and 1.04, while DS2 protective effect factor of 0.89. Weight reduction results with carbon steel likewise supports that corrosion was initiated by DS1 and DS3, while DS2 and DS5 have no any impact though with DS4 we watched less weight reduction however assumed no role in the corrosion. We established the relation of Peroxidase enzyme activity of the isolates. DS1, DS3 and having Peroxidase in the range 22.18, 19.54 U/ml which induce the corrosion whereas DS2 and DS5 having 28.57 and 27.0 U/ml has no any effect and DS4 36 U/ml has inhibitory effect, increasing concentration inhibiting the corrosion. For Catalase DS1, DS3 have 67.28, 61.57 U/ml which induce corrosion while DS2 and DS5 57.71 and 59.14 U/ml also has no effect whereas DS4 70.14 U/ml can inhibit corrosion. Results clearly express that in a specific range both enzymes can induce the corrosion. Our goals are to pursuit and locate the potential role of the enzyme in corrosion induction and inhibition. There is still further work is proceeded for the more profound perception. PMID- 29114241 TI - A Nanoscale Study of Carbon and Nitrogen Fluxes in Mats of Purple Sulfur Bacteria: Implications for Carbon Cycling at the Surface of Coastal Sediments. AB - Mass blooms of purple sulfur bacteria growing seasonally on green stranded macroalgae have a major impact on the microbial composition and functionality of intertidal mats. To explore the active anoxygenic phototrophic community in purple bacterial mats from the Roscoff Aber Bay (Brittany, France), we conducted a combined approach including molecular and high-resolution secondary ion mass spectrometry (NanoSIMS) analyses. To investigate the dynamics of carbon and nitrogen assimilation activities, NanoSIMS was coupled with a stable isotope probing (SIP) experiment and a compound specific isotope analysis (CSIA) of fatty acid methyl ester (FAME). Sediment samples were incubated with 13C- and/or 15N labeled acetate, pyruvate, bicarbonate and ammonium. NanoSIMS analysis of 13C - and 15N -incubated samples showed elevated incorporations of 13C - and 15N in the light and of 13C -acetate in the dark into dense populations of spherical cells that unambiguously dominated the mats. These results confirmed CSIA data that ranked vaccenic acid, an unambiguous marker of purple sulfur bacteria, as the most strongly enriched in the light after 13C -acetate amendment and indicated that acetate uptake, the most active in the mat, was not light-dependent. Analysis of DNA- and cDNA-derived pufM gene sequences revealed that Thiohalocapsa related clones dominated both libraries and were the most photosynthetically active members of the mat samples. This study provides novel insights into the contribution of purple sulfur bacteria to the carbon cycle during their seasonal developments at the sediment surface in the intertidal zone. PMID- 29114243 TI - The Identification of Cable Bacteria Attached to the Anode of a Benthic Microbial Fuel Cell: Evidence of Long Distance Extracellular Electron Transport to Electrodes. AB - Multicellular, filamentous, sulfur-oxidizing bacteria, known as cable bacteria, were discovered attached to fibers of a carbon brush electrode serving as an anode of a benthic microbial fuel cell (BMFC). The BMFC had been operated in a temperate estuarine environment for over a year before collecting anode samples for scanning electron microscopy and phylogenetic analyses. Individual filaments were attached by single terminus cells with networks of pilus-like nano-filaments radiating out from these cells, across the anode fiber surface, and between adjacent attachment locations. Current harvesting by the BMFC poised the anode at potentials of ~170-250 mV vs. SHE, and these surface potentials appear to have allowed the cable bacteria to use the anode as an electron acceptor in a completely anaerobic environment. A combination of catalyzed reporter deposition fluorescent in situ hybridization (CARD-FISH) and 16S rRNA gene sequence analysis confirmed the phylogeny of the cable bacteria and showed that filaments often occurred in bundles and in close association with members of the genera Desulfuromonas. However, the Desulfobulbaceae Operational Taxonomic Units (OTUs) from the 16S sequencing did not cluster closely with other putative cable bacteria sequences suggesting that the taxonomic delineation of cable bacteria is far from complete. PMID- 29114244 TI - Phage and Nucleocytoplasmic Large Viral Sequences Dominate Coral Viromes from the Arabian Gulf. AB - Corals that naturally thrive under extreme conditions are gaining increasing attention due to their importance as living models to understand the impact of global warming on world corals. Here, we present the first metagenomic study of viral communities in corals thriving in a thermally variable water body in which the temperature fluctuates between 11 and 39 degrees C in different seasons. The viral assemblages of two of the most abundant massive (Porites harrisoni) and branching (Acropora downingi) corals in offshore and inshore reef systems in the northern Arabian Gulf were investigated. Samples were collected from five reef systems during summer, autumn and winter of 2011/2012. The two coral viromes contain 12 viral families, including 10 dsDNA viral families [Siphoviridae, Podoviridae, Myoviridae, Phycodnaviridae, Baculoviridae, Herpesviridae, Adenoviridae, Alloherpesviridae, Mimiviridae and one unclassified family], one ssDNA viral family (Microviridae) and one RNA viral family (Retroviridae). Overall, sequences significantly similar to Podoviridae were the most abundant in the P. harrisoni and A. downingi viromes. Various morphological types of virus like particles (VLPs) were confirmed in the healthy coral tissue by transmission electron microscopy, including large tailless VLPs and electron-dense core VLPs. Tailed bacteriophages were isolated from coral tissue using a plaque assay. Higher functional gene diversity was recorded in A. downingi than in P. harrisoni, and comparative metagenomics revealed that the Gulf viral assemblages are functionally distinct from Pacific Ocean coral viral communities. PMID- 29114245 TI - The Selective Interaction of Pistacia lentiscus Oil vs. Human Streptococci, an Old Functional Food Revisited with New Tools. AB - Pistacia lentiscus berry oil (LBO) represents a typical vegetal product of the Mediterranean basin that has been formally used in traditional cuisine for 100s of years. In addition to its interesting alimentary properties, this product could represent an interesting candidate in the field of research on the study of new anti-infective agents. In fact, in Mediterranean countries, lentisk oil still continues to be widely used in folk medicine for oral and skin affections, in particular, acute gingivitis, pediatric skin infections such as impetigo and foot plaques, and biofilm related infections often associated with Streptococcus spp. Following these observations, we have hypothesized a "lentisk oil-bacteria" interaction, placing particular emphasis on the different Streptococcal species involved in these oral and skin diseases. In accordance with this hypothesis, the use of standard antimicrobial-antibiofilm methods (MIC, MBC, MBIC) allowed the interesting behavior of these bacteria to be observed and, in this context, the response to lentisk oil appears to be correlated with the pathogenic profile of the considered microorganism. Two probiotic strains of S. salivarius K12/M18 appeared to be non-sensitive to this product, while a set of five different pathogenic strains (S. agalactiae, S. intermedius, S. mitis, S. mutans, S. pyogenes) showed a response that was correlated to the fatty acid metabolic pathway of the considered species. In fact, at different times of bacteria development, selective High Performance Liquid Chromatography analysis of the growth medium containing LBO detected a significant increase in free unsaturated fatty acids (UFAs) in particular oleic, palmitic and linoleic acids, which are already known for their antibacterial activity. In this context, we have hypothesized that LBO could be able to modulate the pathogen/probiotic rate in a Streptococcal population using the fatty acid metabolic pathway to help the probiotic strain. This hypothesis was strengthened by performing antibacterial testing with oleic acid and an in silico evaluation of the Streptococcal MCRA protein, an enzyme involved in the production of saturated fatty acids from UFA. These results show that LBO may have been used in ancient times as a "natural microbial modulating extract" in the prevention of biofilm- associated diseases. PMID- 29114246 TI - Variation of Carbohydrate-Active Enzyme Patterns in the Gut Microbiota of Italian Healthy Subjects and Type 2 Diabetes Patients. AB - The human gut microbiota (GM) has been associated, to date, with various complex functions, essentials for the host health. Among these, it is certainly worth noting the degradation of the so-called microbiota-accessible carbohydrates (MACs), which the GM breaks down through specific enzymes, referred to as carbohydrate-active enzymes (CAZymes). This degradation constitutes the first step in the production of short-chain fatty acids (SCFAs), key microbial small molecules having multiple health-promoting effects for the host organism. The decline in MAC dietary intake in urban Western populations forced the shrinkage of CAZyme repertoire in the GM, as shown by the literature comparing the microbiome layout between Western urban citizens and traditional rural populations. Even if this reduction in GM functional complexity has been associated with the onset of the so-called "diseases of civilization," only few information regarding the CAZyme variation within Western populations has been provided to date, and its connections with diet and health are still unexplored. In this scenario, here we explore the GM-encoded CAZyme repertoire across two Italian adult cohorts, including healthy lean subjects consuming a Mediterranean diet and obese patients affected by type 2 diabetes, consuming a high-fat diet. In order to impute the CAZyme panel, a pipeline consisting of publicly available software - QIIME, FragGeneScan and HMMER - was specifically implemented. Our study highlighted the existence of robust clusters of bacterial species sharing a common MAC degradation profile in the Italian GM, allowing the stratification of the individual GM into different steady states according to the carbohydrate degradation profile, with possible connections with diet and health. PMID- 29114247 TI - Elusive Role of the CD94/NKG2C NK Cell Receptor in the Response to Cytomegalovirus: Novel Experimental Observations in a Reporter Cell System. AB - Human cytomegalovirus (HCMV) infection promotes the differentiation and persistent expansion of a mature NK cell subset, which displays high surface levels of the activating CD94/NKG2C NK cell receptor, together with additional distinctive phenotypic and functional features. The mechanisms underlying the development of adaptive NK cells remain uncertain but some observations support the involvement of a cognate interaction of CD94/NKG2C with ligand(s) displayed by HCMV-infected cells. To approach this issue, the heterodimer and its adaptor (DAP12) were expressed in the human Jurkat leukemia T cell line; signaling was detected by transfection of a reporter plasmid encoding for Luciferase (Luc) under NFAT/AP1-dependent control. Engagement of the receptor by solid-phase bound CD94- or NKG2C-specific monoclonal antibodies (mAbs) triggered Luc expression. Moreover, reporter activation was detectable upon interaction with HLA-E+ 721.221 (.221-AEH) cells, as well as with 721.221 cells incubated with synthetic peptides, which stabilized surface expression of endogenous HLA-E; the response was specifically antagonized by soluble NKG2C- and HLA-E-specific mAbs. By contrast, activation of Jurkat-NKG2C+ was undetectable upon interaction with Human Fetal Foreskin Fibroblasts (HFFF) infected with HCMV laboratory strains (i.e., AD169, Towne), regardless of their differential ability to preserve surface HLA-E expression. On the other hand, infection with two clinical isolates or with the endotheliotropic TB40/E strain triggered Jurkat-NKG2C+ activation; yet, this response was not inhibited by blocking mAbs and was independent of CD94/NKG2C expression. The results are discussed in the framework of previous observations supporting the hypothetical existence of specific ligand(s) for CD94/NKG2C in HCMV-infected cells. PMID- 29114248 TI - Intramuscular DNA Vaccination of Juvenile Carp against Spring Viremia of Carp Virus Induces Full Protection and Establishes a Virus-Specific B and T Cell Response. AB - Although spring viremia of carp virus (SVCV) can cause high mortalities in common carp, a commercial vaccine is not available for worldwide use. Here, we report a DNA vaccine based on the expression of the SVCV glycoprotein (G) which, when injected in the muscle even at a single low dose of 0.1 ug DNA/g of fish, confers up to 100% protection against a subsequent bath challenge with SVCV. Importantly, to best validate vaccine efficacy, we also optimized a reliable bath challenge model closely mimicking a natural infection, based on a prolonged exposure of carp to SVCV at 15 degrees C. Using this optimized bath challenge, we showed a strong age-dependent susceptibility of carp to SVCV, with high susceptibility at young age (3 months) and a full resistance at 9 months. We visualized local expression of the G protein and associated early inflammatory response by immunohistochemistry and described changes in the gene expression of pro inflammatory cytokines, chemokines, and antiviral genes in the muscle of vaccinated fish. Adaptive immune responses were investigated by analyzing neutralizing titers against SVCV in the serum of vaccinated fish and the in vitro proliferation capacity of peripheral SVCV-specific T cells. We show significantly higher serum neutralizing titers and the presence of SVCV-specific T cells in the blood of vaccinated fish, which proliferated upon stimulation with SVCV. Altogether, this is the first study reporting on a protective DNA vaccine against SVCV in carp and the first to provide a detailed characterization of local innate as well as systemic adaptive immune responses elicited upon DNA vaccination that suggest a role not only of B cells but also of T cells in the protection conferred by the SVCV-G DNA vaccine. PMID- 29114251 TI - A Role for the Transcription Factor Arid3a in Mouse B2 Lymphocyte Expansion and Peritoneal B1a Generation. AB - The initiation, commitment, and terminal differentiation of the B cell lineage is stringently controlled by the coordinated action of various transcription factors. Among these, Arid3a has previously been implicated in regulating early B lymphopoiesis, humoral immune responses to phosphocholine, and furthermore to promote the B1 over the B2 cell lineage. We have now interrogated the function of Arid3a in the adult mouse using conditional mutagenesis. We demonstrate that loss of Arid3a does not affect early B cell development or lineage commitment but rather loss of this transcription factor results in a broad expansion of bone marrow B lymphopoiesis in a manner that reflects its developmental expression pattern. Furthermore, loss of Arid3a resulted in expanded splenic B cell numbers with the exception of the B1 lineage that was maintained at normal numbers. However, B1a lymphoyctes were reduced in the peritoneal cavity. In addition, antibody responses to phosphocholine were attenuated in the absence of Arid3a. Hence, functional Arid3a is required in mature B cells for specific immune responses and for generating normal numbers of B cells in a subset dependent manner. PMID- 29114250 TI - A Sensitive Method for Detecting Peptide-specific CD4+ T Cell Responses in Peripheral Blood from Patients with Myasthenia Gravis. AB - Myasthenia gravis (MG) is an autoimmune neurological disorder typified by skeletal muscle fatigue and most often production of autoantibodies against the nicotinic acetylcholine receptor (AChR). The present study was undertaken to assess the extent of AChR-peptide recognition in MG patients using co-culturing (DC:TC) of autologous monocyte-derived dendritic cells (moDCs) and highly enriched CD4+ T cells from the blood as compared to the traditional whole peripheral blood mononuclear cell (PBMC) cultures. We found that the DC:TC cultures were highly superior to the PBMC cultures for detection of reactivity toward HLA-DQ/DR-restricted AChR-peptides. In fact, whereas DC:TC cultures identified recognition in all MG patients the PBMC cultures failed to detect responsiveness in around 40% of the patients. Furthermore, reactivity to multiple peptides was evident in DC:TC cultures, while PBMC cultures mostly exhibited reactivity to a single peptide. No healthy control (HC) CD4+ T cells responded to the peptides in either culture system. Interestingly, whereas spontaneous production of IFNgamma and IL-17 was observed in the DC:TC cultures from MG patients, recall responses to peptides enhanced IL-10 production in 9/13 MG patients, while little increase in IFNgamma and IL-17 was seen. HCs did not produce cytokines to peptide stimulations. We conclude that the DC: TC culture system is significantly more sensitive and better identifies the extent of responsiveness in MG patients to AChR-peptides than traditional PBMC cultures. PMID- 29114252 TI - CD335 (NKp46)+ T-Cell Recruitment to the Bovine Upper Respiratory Tract during a Primary Bovine Herpesvirus-1 Infection. AB - Bovine natural killer (NK) cells were originally defined by the NK activation receptor CD335 [natural killer cell p46-related protein (NKp46)], but following the discovery of NKp46 expression on human T-cells, the definition of conventional bovine NK cells was modified to CD335+CD3- cells. Recently, a bovine T-cell population co-expressing CD335 was identified and these non-conventional T cells were shown to produce interferon (IFN)-gamma and share functional properties with both conventional NK cells and T-cells. It is not known, however, if CD335+ bovine T-cells are recruited to mucosal surfaces and what chemokines play a role in recruiting this unique T-cell subpopulation. In this study, bovine herpesvirus-1 (BHV-1), which is closely related to herpes simplex virus-1, was used to investigate bovine lymphocyte cell populations recruited to the upper respiratory tract following a primary respiratory infection. Immunohistochemical staining with individual monoclonal antibodies revealed significant (P < 0.05) recruitment of CD335+, CD3+, and CD8+ lymphocyte populations to the nasal turbinates on day 5 following primary BHV-1 infection. Dual-color immunofluorescence revealed that cells recruited to nasal turbinates were primarily T-cells that co-expressed both CD335 and CD8. This non-conventional T cell population represented 77.5% of CD355+ cells and 89.5% of CD8+ cells recruited to nasal turbinates on day 5 post-BHV-1 infection. However, due to diffuse IFN-gamma staining of nasal turbinate tissue, it was not possible to directly link increased IFN-gamma production following BHV-1 infection with the recruitment of non-conventional T-cells. Transcriptional analysis revealed CCL4, CCL5, and CXCL9 gene expression was significantly (P < 0.05) upregulated in nasal turbinate tissue following BHV-1 infection. Therefore, no single chemokine was associated with recruitment of non-conventional T-cells. In conclusion, the specific recruitment of CD335+ and CD8+ non-conventional T-cells to viral infected tissue suggests that these cells may play an important role in either the clearance of a primary BHV-1 infection or regulating host responses during viral infection. The early recruitment of non-conventional T-cells following a primary viral infection may enable the host to recognize viral-infected cells through NKp46 while retaining the possibility of establishing T-cell immune memory. PMID- 29114253 TI - Overexpression of OsRRK1 Changes Leaf Morphology and Defense to Insect in Rice. AB - It has been reported that the receptor-like cytoplasmic kinases (RLCKs) regulate many biological processes in plants, but only a few members have been functionally characterized. Here, we isolated a rice gene encoding AtRRK1 homology protein kinase, OsRRK1, which belongs to the RLCK VI subfamily. OsRRK1 transcript accumulated in many tissues at low to moderate levels and at high levels in leaves. Overexpression of OsRRK1 (OE-OsRRK1) caused adaxial rolling and erect morphology of rice leaves. In the rolled leaves of OE-OsRRK1 plants, both the number and the size of the bulliform cells are decreased compared to the wild type (WT) plants. Moreover, the height, tiller number, and seed setting rate were reduced in OE-OsRRK1 plants. In addition, the brown planthopper (BPH), a devastating pest of rice, preferred to settle on WT plants than on the OE-OsRRK1 plants in a two-host choice test, indicating that OE-OsRRK1 conferred an antixenosis resistance to BPH. The analysis of transcriptome sequencing demonstrated that several receptor kinases and transcription factors were differentially expressed in OE-OsRRK1 plants and WT plants. These results indicated that OsRRK1 may play multiple roles in the development and defense of rice, which may facilitate the breeding of novel rice varieties. PMID- 29114249 TI - Control of Phagocytosis by Microbial Pathogens. AB - Phagocytosis is a fundamental process of cells to capture and ingest foreign particles. Small unicellular organisms such as free-living amoeba use this process to acquire food. In pluricellular organisms, phagocytosis is a universal phenomenon that all cells are able to perform (including epithelial, endothelial, fibroblasts, etc.), but some specialized cells (such as neutrophils and macrophages) perform this very efficiently and were therefore named professional phagocytes by Rabinovitch. Cells use phagocytosis to capture and clear all particles larger than 0.5 um, including pathogenic microorganisms and cellular debris. Phagocytosis involves a series of steps from recognition of the target particle, ingestion of it in a phagosome (phagocytic vacuole), maturation of this phagosome into a phagolysosome, to the final destruction of the ingested particle in the robust antimicrobial environment of the phagolysosome. For the most part, phagocytosis is an efficient process that eliminates invading pathogens and helps maintaining homeostasis. However, several pathogens have also evolved different strategies to prevent phagocytosis from proceeding in a normal way. These pathogens have a clear advantage to perpetuate the infection and continue their replication. Here, we present an overview of the phagocytic process with emphasis on the antimicrobial elements professional phagocytes use. We also summarize the current knowledge on the microbial strategies different pathogens use to prevent phagocytosis either at the level of ingestion, phagosome formation, and maturation, and even complete escape from phagosomes. PMID- 29114254 TI - Accelerated Generation of Selfed Pure Line Plants for Gene Identification and Crop Breeding. AB - Production of pure lines is an important step in biological studies and breeding of many crop plants. The major types of pure lines for biological studies and breeding include doubled haploid (DH) lines, recombinant inbred lines (RILs), and near isogenic lines (NILs). DH lines can be produced through microspore and megaspore culture followed by chromosome doubling while RILs and NILs can be produced through introgressions or repeated selfing of hybrids. DH approach was developed as a quicker method than conventional method to produce pure lines. However, its drawbacks of genotype-dependency and only a single chance of recombination limited its wider application. A recently developed fast generation cycling system (FGCS) achieved similar times to those of DH for the production of selfed pure lines but is more versatile as it is much less genotype-dependent than DH technology and does not restrict recombination to a single event. The advantages and disadvantages of the technologies and their produced pure line populations for different purposes of biological research and breeding are discussed. The development of a concept of complete in vitro meiosis and mitosis system is also proposed. This could integrate with the recently developed technologies of single cell genomic sequencing and genome wide selection, leading to a complete laboratory based pre-breeding scheme. PMID- 29114255 TI - Editorial: Salinity Tolerance in Plants: Mechanisms and Regulation of Ion Transport. PMID- 29114256 TI - Involvement of PACLOBUTRAZOL RESISTANCE6/KIDARI, an Atypical bHLH Transcription Factor, in Auxin Responses in Arabidopsis. AB - Auxin regulates nearly all aspects of plant growth and development including cell division, cell elongation and cell differentiation, which are achieved largely by rapid regulation of auxin response genes. However, the functions of a large number of auxin response genes remain uncharacterized. Paclobutrazol Resistance (PRE) proteins are non-DNA binding basic helix-loop-helix transcription factors that have been shown to be involved in gibberellin and brassinosteroid signaling, and light responses in Arabidopsis. Here, we provide molecular and genetic evidence that PRE6, one of the six PRE genes in Arabidopsis, is an auxin response gene, and that PRE6 is involved in the regulation of auxin signaling. By using quantitative RT-PCR, we showed that the expression level of PRE6 was increased in response to exogenously applied IAA. GUS staining results also showed that the expression of GUS reporter gene in the PRE6p:GUS transgenic seedlings was elevated in response to auxin. Phenotypic analysis showed that overexpression of PRE6 in Arabidopsis resulted in auxin-related phenotypes including elongated hypocotyl and primary roots, and reduced number of lateral roots when compared with the Col wild type seedlings, whereas opposite phenotypes were observed in the pre6 mutants. Further analysis showed that PRE6 overexpression plants were hyposensitive, whereas pre6 mutants were hypersensitive to auxin in root and hypocotyl elongation and lateral root formation assays. By using protoplasts transfection, we showed that PRE6 functions as a transcriptional repressor. Consistent with this, the expression of the auxin response reporter DR5:GUS was decreased in PRE6 overexpression lines, but increased in pre6 mutants. When co transfected into protoplasts, ARF5 and ARF8 activated the expression of the PRE6p:GUS reporter. Chromatin immunoprecipitation assays showed that ARF5 and ARF8 can be recruited to the promoter regions of PRE6. Taken together, these results suggest that PRE6 is an auxin response gene whose expression is directly regulated by ARF5 and ARF8, and that PRE6 is a transcriptional repressor that negatively regulates auxin responses in Arabidopsis. PMID- 29114258 TI - Ethylene Mediates Alkaline-Induced Rice Growth Inhibition by Negatively Regulating Plasma Membrane H+-ATPase Activity in Roots. AB - pH is an important factor regulating plant growth. Here, we found that rice was better adapted to low pH than alkaline conditions, as its growth was severely inhibited at high pH, with shorter root length and an extreme biomass reduction. Under alkaline stress, the expression of genes for ethylene biosynthesis enzymes in rice roots was strongly induced by high pH and exogenous ethylene precursor ACC and ethylene overproduction in etol1-1 mutant aggravated the alkaline stress mediated inhibition of rice growth, especially for the root elongation with decreased cell length in root apical regions. Conversely, the ethylene perception antagonist silver (Ag+) and ein2-1 mutants could partly alleviate the alkaline induced root elongation inhibition. The H+-ATPase activity was extremely inhibited by alkaline stress and exogenous ACC. However, the H+-ATPase-mediated rhizosphere acidification was enhanced by exogenous Ag+, while H+ efflux on the root surface was extremely inhibited by exogenous ACC, suggesting that ethylene negatively regulated H+-ATPase activity under high-pH stress. Our results demonstrate that H+-ATPase is involved in ethylene-mediated inhibition of rice growth under alkaline stress. PMID- 29114257 TI - The Rice High-Affinity K+ Transporter OsHKT2;4 Mediates Mg2+ Homeostasis under High-Mg2+ Conditions in Transgenic Arabidopsis. AB - Rice (Oryza sativa; background Nipponbare) contains nine HKT (high-affinity K+ transport)-like genes encoding membrane proteins belonging to the superfamily of Ktr/TRK/HKT. OsHKTs have been proposed to include four selectivity filter-pore forming domains homologous to the bacterial K+ channel KcsA, and are separated into OsHKT1s with Na+-selective activity and OsHKT2s with Na+-K+ symport activity. As a member of the OsHKT2 subfamily, OsHKT2;4 renders Mg2+ and Ca2+ permeability for yeast cells and Xenopus laevis oocytes, besides K+ and Na+. However, physiological functions related to Mg2+in planta have not yet been identified. Here we report that OsHKT2;4 from rice (O. sativa; background Nipponbare) functions as a low-affinity Mg2+ transporter to mediate Mg2+ homeostasis in plants under high-Mg2+ environments. Using the functional complementation assay in Mg2+-uptake deficient Salmonella typhimurium strains MM281 and electrophysiological analysis in X. laevis oocytes, we found that OsHKT2;4 could rescue the growth of MM281 in Mg2+-deficient conditions and induced the Mg2+ currents in oocytes at millimolar range of Mg2+. Additionally, overexpression of OsHKT2;4 to Arabidopsis mutant lines with a knockout of AtMGT6, a gene encoding the transporter protein necessary for Mg2+ adaptation in Arabidopsis, caused the Mg2+ toxicity to the leaves under the high-Mg2+ stress, but not under low-Mg2+ environments. Moreover, this Mg2+ toxicity symptom resulted from the excessive Mg2+ translocation from roots to shoots, and was relieved by the increase in supplemental Ca2+. Together, our results demonstrated that OsHKT2;4 is a low-affinity Mg2+ transporter responsible for Mg2+ transport to aerials in plants under high-Mg2+ conditions. PMID- 29114259 TI - Identification of Splicing Quantitative Trait Loci (sQTL) in Drosophila melanogaster with Developmental Lead (Pb2+) Exposure. AB - Lead (Pb) poisoning has been a major public health issue globally and the recent Flint water crisis has drawn nation-wide attention to its effects. To better understand how lead plays a role as a neurotoxin, we utilized the Drosophila melanogaster model to study the genetic effects of lead exposure during development and identified lead-responsive genes. In our previous studies, we have successfully identified hundreds of lead-responsive expression QTLs (eQTLs) by using RNA-seq analysis on heads collected from the Drosophila Synthetic Population Resource. Cis-eQTLs, also known as allele-specific expression (ASE) polymorphisms, are generally single-nucleotide polymorphisms in the promoter regions of genes that affect expression of the gene, such as by inhibiting the binding of transcription factors. Trans-eQTLs are genes that regulate mRNA levels for many genes, and are generally thought to be SNPs in trans-acting transcription or translation factors. In this study, we focused our attention on alternative splicing events that are affected by lead exposure. Splicing QTLs (sQTLs), which can be caused by SNPs that alter splicing or alternative splicing (AS), such as by changing the sequence-specific binding affinity of splicing factors to the pre-mRNA. We applied two methods in search for sQTLs by using RNA seq data from control and lead-exposed w1118Drosophila heads. First, we used the fraction of reads in a gene that falls in each exon as the phenotype. Second, we directly compared the transcript counts among the various splicing isoforms as the phenotype. Among the 1,236 potential Pb-responsive sQTLs (p < 0.0001, FDR < 0.39), mostly cis-sQTLs, one of the most distinct genes is Dscam1 (Down Syndrome Cell Adhesion Molecule), which has over 30,000 potential alternative splicing isoforms. We have also identified a candidate Pb-responsive trans-sQTL hotspot that appears to regulate 129 genes that are enriched in the "cation channel" gene ontology category, suggesting a model in which alternative splicing of these channels might lead to an increase in the elimination of Pb2+ from the neurons encoding these channels. To our knowledge, this is the first paper that uses sQTL analyses to understand the neurotoxicology of an environmental toxin in any organism, and the first reported discovery of a candidate trans-sQTL hotspot. PMID- 29114260 TI - Crosstalk between Receptor and Non-receptor Mediated Chemical Modes of Action in Rat Livers Converges through a Dysregulated Gene Expression Network at Tumor Suppressor Tp53. AB - Chemicals, toxicants, and environmental stressors mediate their biologic effect through specific modes of action (MOAs). These encompass key molecular events that lead to changes in the expression of genes within regulatory pathways. Elucidating shared biologic processes and overlapping gene networks will help to better understand the toxicologic effects on biological systems. In this study we used a weighted network analysis of gene expression data from the livers of male Sprague-Dawley rats exposed to chemicals that elicit their effects through receptor-mediated MOAs (aryl hydrocarbon receptor, orphan nuclear hormone receptor, or peroxisome proliferator-activated receptor-alpha) or non-receptor mediated MOAs (cytotoxicity or DNA damage). Four gene networks were highly preserved and statistically significant in each of the two MOA classes. Three of the four networks contain genes that enrich for immunity and defense. However, many canonical pathways related to an immune response were activated from exposure to the non-receptor-mediated MOA chemicals and deactivated from exposure to the receptor-mediated MOA chemicals. The top gene network contains a module with 33 genes including tumor suppressor TP53 as the central hub which was slightly up-regulated in gene expression compared to control. Although, there is crosstalk between the two MOA classes of chemicals at the TP53 gene network, more than half of the genes are dysregulated in opposite directions. For example, Thromboxane A Synthase 1 (Tbxas1), a cytochrome P450 protein coding gene regulated by Tp53, is down-regulated by exposure to the receptor-mediated chemicals but up-regulated by the non-receptor-mediated chemicals. The regulation of gene expression by the chemicals within MOA classes was consistent despite varying alanine transaminase and aspartate aminotransferase liver enzyme measurements. These results suggest that overlap in toxicologic pathways by chemicals with different MOAs provides common mechanisms for discordant regulation of gene expression within molecular networks. PMID- 29114261 TI - Low Genetic Diversity and Structuring of the Arapaima (Osteoglossiformes, Arapaimidae) Population of the Araguaia-Tocantins Basin. AB - The arapaima, Arapaima gigas, is a fish whose populations are threatened by both overfishing and the ongoing destruction of its natural habitats. In the Amazon basin, varying levels of population structure have been found in A. gigas, although no data are available on the genetic diversity or structure of the populations found in the Araguaia-Tocantins basin, which has a topographic profile, hydrological regime, and history of fishing quite distinct from those of the Amazon. In this context, microsatellite markers were used to assess the genetic diversity and connectivity of five wild A. gigas populations in the Araguaia-Tocantins basin. The results of the analysis indicated low levels of genetic diversity in comparison with other A. gigas populations, studied in the Amazon basin. The AMOVA revealed that the Arapaima populations of the Araguaia Tocantins basin are structured significantly. No correlation was found between pairwise FST values and the geographical distance among populations. The low level of genetic variability and the evidence of restricted gene flow may both be accounted for by overfishing, as well as the other human impacts that these populations have been exposed to over the years. The genetic fragility of these populations demands attention, given that future environmental changes (natural or otherwise) may further reduce these indices and eventually endanger these populations. The results of this study emphasize the need to take the genetic differences among the study populations into account when planning management measures and conservation strategies for the arapaima stocks of the Araguaia Tocantins basin. PMID- 29114262 TI - In Depth Analysis of the Leading Causes of Maternal Mortality Due to Cesarean Section in Iran. AB - Objective: Despite the declining trend of maternal mortality (MMR) in Iran between 1990 and 2013, direct causes are still the major reasons for maternal death. One of these direct causes is complications of cesarean section (CS). Since the rate of CS in Iran is quite high (47.9%) and the trend continues to rise, there is an alarming threat of the possibility of increasing MMR in the country as a result of cesarean section complications, especially in repeated cases. In this study, we attempted to determine the indications of CS in reported maternal mortality, with special attention to risk factors predisposing to CS and/or to maternal mortality. Materials and methods: A retrospective study was implemented for the period between March 2009 and March 2012. All nationally reported data regarding maternal death during pregnancy, labor and 42 days after parturition during these 3 years was collected and input to software specially designed for this project. Subsequently, cases of maternal death related to pregnancy termination by cesarean section were selected for analysis. Results: There were 393 cases of maternal death with cesarean section as the termination method. Indications of CS were mostly emergency and repeat and the leading causes of death were postpartum hemorrhage and hypertensive disorders. Most of these deaths occurred in academic hospitals and the most common type of delay was brought about by hospital management, specifically personnel issues. Conclusion: Based on this study, acknowledging CS as a serious health threat endangering every achievement in the maternal health program is the most important policy and efforts should be focused on provision of guidelines for realistic CS indications, standardized CS procedures, and post CS care as well as propagation of training courses in risk management and high risk case-finding protocols. PMID- 29114263 TI - The Current Status and Factors Associated With Implanon Service Provision by the Health Extension Workers at the Health Post Level, Wolaita Zone, Southern Ethiopia: A Cross-Sectional Study. AB - Objective: Family Planning is often taken as one of the "Magic Bullet" interventions owing to its high impact and wide reaching nature in achieving multiple goals. This study aimed to assess the current status and the factors associated with health post level Implanon service provision through trained health extension workers in Wolaita zone, southern Ethiopia. Materials and methods: A cross sectional study was conducted among trained health extension workers in Wolaita zone in February 2013. A simple random sampling technique was used to identify a total of 285 trained HEWs. First bivariate, then multivariate logistic regression model along with 95% confidence interval was used to see the independent effect of factors associated with current Implanon service provision by the health extension workers. Results: Currently, the number of Implaon providing trained health extension workers in Wolaita was 264(45.8%). Distance of health post from district health offices and health center, turnover of trained health extension workers in the health post, interest of trained health extension workers in providing Implanon and their job satisfaction to serve as a health extension workers and availability of service delivery guidelines and teaching aids were associated with the current provision of Implanon by health extension workers. Conclusion: Implanon provision among trained health extension workers was affected by different factors. Hence, improving the working conditions of trained health extension workers, regular and periodic facilitative supervision, availing service delivery guidelines and improvement of health management information system are recommended. PMID- 29114264 TI - Knowledge, Attitude and Practice Regarding Cervical Cancer Screening Among Women Attending a Teaching Hospital, Bharatpur, Chitwan. AB - Objective: To find out the knowledge, attitude and practice regarding cervical cancer screening among women. Materials and methods: A descriptive cross sectional study design was used to collect data from 96 women. Each woman was selected alternately from Gynae Out-Patient Department of Teaching Hospital. Data was collected by using semi-structured interview schedule to find out knowledge and practice and Likert scale to find out the attitude regarding cervical cancer screening. Data was analyzed by using SPSS version 20.0 and interpreted in terms of descriptive and inferential statistics. Results: Out of 96 women, mean age was 38.83 +/- 6.57 and 90.6% respondents followed Hinduism. More than three fourth (85.4%) were literate and 59.4% were housewife. Only 9.4% were involved in cervical cancer prevention and screening awareness programme and 2.1% had family history of cervical cancer. As per the findings, only 34.4% and 27.8% had adequate knowledge and practice respectively whereas cent percent women had favorable attitude. Only education level of women was statistically significant with level of knowledge regarding cervical cancer screening (p = 0.041). There was strong negative correlation between knowledge score and practice score regarding cervical cancer screening among women (r = -0.194). Conclusion: Considerable proportions of women have inadequate knowledge and practice regarding cervical cancer screening. Therefore cervical cancer screening health camps and awareness program should be conducted at community level for women to increase the level of knowledge and practice regarding cervical cancer screening. PMID- 29114265 TI - Dehydroepiandrosterone-Sulfate, Insulin Resistance and Ovarian Volume Estimation in Patients With Polycystic Ovarian Syndrome. AB - Objective: To investigate the potential association of DHEA-S with metabolic and hormonal alterations and with disorders of ovarian morphology. Materials and methods: The present study was based on women with PCOS that attended the Gynaecological Endocrinology - Paediatric and Adolescence Endocrinology Department of our clinic. Overall, 321 patients who met the Rotterdam ESHRE/ ASRM - Sponsored criteria for the definition of PCOS were included. Women's personal medical history was recorded, anthropometric parameters were assessed and blood was drawn for analysis of metabolic and hormonal parameters. A gynaecological ultrasound was also performed to evaluate ovarian morphology. Results: Correlation analysis revealed a significant negative correlation of DHEA-S with the mean volume of the right and left ovary and with the maximum volume of the largest ovary. This finding remained significant after adjusting for age and BMI (beta +/- SE = -0.39 +/- 0.17, p = 0.023 in the case of mean ovarian volume and beta +/- SE = -0.36 +/- 0.17, p = 0.032 in the case of the maximum volume of the maximum ovarian volume). Conclusion: The findings of our study reveal a clear negative association of DHEA-S with ovarian volume. To date, however, current evidence in this field are restricted to experimental animal models. Future clinical studies are needed in this field to corroborate our findings. PMID- 29114266 TI - Android Application Model of "Suami Siaga Plus" as an Innovation in Birth Preparedness and Complication Readiness (BP/CR) Intervention. AB - Objective: WHO recommends Mobile health, a practice of medicine and public health supported by mobile devices, to improve community health status and change people's behavior for the health purposes. The present study sought to examine the effectiveness of the android application program of Suami Siaga Plus in increasing husband's scores in birth preparedness and complication readiness (BP/CR) intervention. Materials and methods: It was a randomized controlled trial with pretest-posttest design. A total of 38 couples of husbands and pregnant women from three health centers at three sub districts in Semarang was selected by proportional systematic random sampling technique and equally distributed into control and intervention group. A questionnaire related to BP/CR published by JHPIEGO was employed in data collection. Statistical analysis was performed to obtain the frequency distribution and percentage of the variables, and also to assess the mean difference of BP/CR score of husbands. Results: Husbands' knowledge of key danger signs and five standard elements in BP/CR practices in both intervention and control group increased after counseling. Moreover, the proportion of husbands who understand the key danger signs during pregnancy was higher among those who were exposed by Suami Siaga Plus application delivered via mobile phone. Counseling only increased husbands' score from 61.5 to 62.6 (2%), whilst the combination of counseling and the application boosted 20% of husbands' score from 60.4 to 72.9 (p-value 0.000). Conclusion: A combination of counseling and Suami Siaga Plus application significantly improves husbands and wives' score on BP/CR compared to those who received counseling only. The data suggests the application would be able to suppress the three delays, which in turn can reduce the maternal mortality rate. The study results could be important information for the Department of Health and health professionals to use android application program, in particular to the husband whose wife is in pregnancy, childbirth and postpartum periods. PMID- 29114267 TI - The Best Cut-Off Value for HbA1c as a Screening Tool in Iranian Women With Gestational Diabetes Mellitus. AB - Objective: Gestational diabetes mellitus (GDM) is a prevalent disorder which increases maternal and fetal complications. The oral glucose tolerance test (OGTT) is a traditional, time -consuming and intensive test which is poorly tolerated by pregnant women. To date, increasing evidence considered HbA1c as a screening tool and reported various cut-off values in different populations. In alignment with existing literature, we determined for the first time, the optimal cut-off value for HbA1c in Iranian women with GDM. Materials and methods: This case-control study was conducted in Valie-Asr hospital between June 2015 and March 2016. A total of 200 pregnant women who were diagnosed with GDM were selected as study cases. For the control group, 200 healthy women were randomly selected. Fasting blood samples were taken for biochemical analysis, and OGTT was done in all participants. Demographic and anthropometric indexes were measured. Performance of the HbA1c test was analyzed by the Receiver Operating Characteristic (ROC) curve, and the sensitivity and specificity for different HbA1c cut-off points were calculated subsequently. Results: Analysis showed that the mean age (p < 0.001) and BMI (p < 0.001) were significantly higher in the GDM group compared to those in non-GDM pregnant women. GDM participants reported positive family- and previous history of GDM more than healthy pregnant women (p = 0.04 and p < 0.001, respectively). All the markers for Lipid profile were significantly different between the two groups (p = <0.001) except for total cholesterol. The rate of Caesarean section and neonate's Apgar score were not significantly different between the two groups. The best equilibrium between sensitivity (80%) and specificity (76%) for HbA1c was 5.05%. Conclusion: Our results suggest that pregnant women with HbA1c of >= 5.05% should proceed with an OGTT. Further investigations with larger sample size are needed to provide more robust evidence for the diagnostic and screening value of HbA1c in identifying pregnant women with GDM. PMID- 29114268 TI - Vaginal Fluid Urea and Creatinine in the Diagnosis of Premature Rupture of Membranes in Resource Limited Community Settings. AB - Objective: Diagnosis of premature rupture of membranes (PROM) is difficult in equivocal cases with traditional methods. This study aimed to evaluate the reliability of vaginal washing fluid urea and creatinine for diagnosis of PROM and to determine the cut off value. Materials and methods: The current study was a prospective case control. Women having gestational age of 28 to 42 weeks were divided into two equal groups: Fifty with history of leaking per vagina (study group) and an equal number with gestation matched none leaking (control group) were recruited. Data analysis was done by Student's t-test, receiver operator curve and chi square test. Results: The demographic data of both groups were comparable at the time of sampling (p > 0.05).Vaginal fluid urea and creatinine was significantly higher in study group (p < 0.001). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of vaginal fluid urea with a cut off value > 6mg/dl and creatinine with a cut off value of > 0.3 mg/dl to diagnose PROM were all more than 90%. The sensitivity, specificity, PPV, NPV and accuracy of amniotic fluid index (AFI) to diagnose PROM were 30%, 91.8%, 83.33%, 57.32% and 62 % respectively, with a cut off value of <= 7 cm. The areas under the curves are 0.952 for creatinine, 0.999 for urea and 0.635 for AFI. Conclusion: Detection of vaginal fluid urea and creatinine to diagnose PROM is a simple, reliable and rapid test. Introduction of this method into routine use even in low resource community setting is feasible, practical and cost effective. PMID- 29114269 TI - To Tell, or Not to Tell; Confidentiality in an Iranian HIV Positive Patient: A Viewpoint. AB - Confidentiality is a basic concept in medical ethics and protecting confidentiality is considered as physicians' duty. In some occasions, this protection is in conflict with the right of the patient's sexual partner, who should be informed about the possibility of being infected. The sexual partner being pregnant, the situation is going to be more complicated. In this paper, we present a case discussion with special ethical, legal, social, cultural, and religious aspects. According to this informing sexual partner with the patient's assent, opt-out Human immunodeficiency virus (HIV) screening in pregnant women and enhancing psychosocial and family support are highly recommended. Strategic changes in health system policies and regulations seem to be necessary as well. PMID- 29114271 TI - Organized Chronic Subdural Hematomas Treated by Large Craniotomy with Extended Membranectomy as the Initial Treatment. AB - Objective: The aim of this retrospective study is to evaluate the efficacy and incidence of complications of craniotomy and membranectomy in elderly patients for the treatment of organized chronic subdural hematoma (OCSH). Materials and Methods: We retrospectively reviewed a series of 28 consecutive patients suffering from OCSH, diagnosed by magnetic resonance imaging (MRI) or computer tomography (CT) to establish the degree of organization and determine the intrahematomal architecture including inner membrane ossification. The indication to perform a primary enlarged craniotomy as initial treatment for nonliquefied OCSH with multilayer loculations was based on the hematoma MRI appearance - mostly hyperintense in both T1- and T2-weighted images with a hypointense web- or net-like structure within the hematoma cavity or inner membrane calcification CT appearance - hyperdense. These cases have been treated by a large craniotomy with extended membranectomy as the initial treatment. However, the technique of a burr hole with closed system drainage for 24-72 h was chosen for cases of nonseptated and mostly liquefied Chronic Subdural Hematoma (CSDH). Results: Between 1998 and 2015, 148 consecutive patients were surgically treated for CSDH at our institution. Of these, 28 patients which have OSDH underwent a large craniotomy with extended membranectomy as the initial treatment. The average age of the patients was 69 (69.4 +/- 12.1). Tension pneumocephalus (TP) has occurred in 22.8% of these patients (n = 28). Recurring subdural hemorrhage (RSH) in the operation area has occurred in 11.9% of these patients in the first 24 h. TP with RSH was seen in 4 of 8 TP patients (50%). Large epidural air was seen in one case. Postoperative seizures requiring medical therapy occurred in 25% of our patients. The average stay in the department of neurosurgery was 11 days, ranging from 7 to 28 days. Four patients died within 28 days after surgery; mortality rate was 14.28%. Conclusion: Large craniotomy and extended membrane excision for OSDH still carry a high rate of mortality and morbidity in elderly patients. TP, RSH, and postoperative seizures are frequently seen complications in elderly patients. PMID- 29114273 TI - Formulation and Characterization of Nanomedicine (Solid Lipid Nanoparticle) Associate with the Extract of Pterospermum acerifolium for the Screening of Neurochemicals and Neuroendocrine Effects. AB - Background: Nanotechnology has given the likelihood of conveying medications to particular cells utilizing nanoparticles. Nanosystems can convey the dynamic constituent at an adequate fixation amid the whole treatment time frame, guiding it to the fancied site of activity. Traditional medications do not meet these necessities. The fundamental motivation behind creating elective medication conveyance advancements is to expand effectiveness of medication conveyance and security during the time spent medication conveyance and give more accommodation to the patient. Objectives: Pterospermum acerifolium, basic plant in India, is viewed as carminative, stimulant, and emmenagogue. The improvement of control discharge conveyance systems could prompt huge preferences in the clinical employments of these medications to diminish the toxicities. The point of this study was to figure another conveyance framework for impacts of neurochemicals by the joining of concentrate of P. acerifolium into strong lipid nanoparticles (SLNs). Methods: SLN formulations were prepared by Ethanolic extract, lipid layer was liquefied by warming at 5 degrees C above liquefying purpose of the lipid. After that, SLNs were separated and dried. Shape and surface morphology of the SLNs were pictured by checking scanning electron microscopy. Particle size and size distribution were dictated by photon connection spectroscopy. Results and Discussion: The change of molecule charge was contemplated by zeta potential estimations. Treatment with SLN with concentrate was found to altogether diminish the serum levels of adrenocorticotropic hormone (ACTH), corticosterone and endorphin and in addition the cerebrum and serum level of norepinephrine. Moreover, SLN with concentrate could essentially turn around the constant anxiety by diminishing the cerebrum and serum levels of the monoamine neurotransmitters dopamine, 5-hydroxytryptamine. Conclusion: The outcomes got from this study recommended that the memory-improving impact of SLN with concentrate was interceded through directions of neurochemical and neuroendocrine frameworks. PMID- 29114272 TI - Endoscopic Third Ventriculostomy in Normal Pressure Hydrocephalus and Symptomatic Long-standing Overt Ventriculomegaly. AB - Objectives: The aim of this study is to define the role and effectiveness for an endoscopic third ventriculostomy (ETV) in patients with seconder normal pressure hydrocephalus(SNPH), idiopathic normal pressure hydrocephalus (INPH) and symptomatic longstanding overt ventriculomegaly (SLOVA). Materials and Methods: 3 patients with SLOVA, 3 patients with INPH and 3 patients with SNPH underwent ETV were studied retrospectively. The patients had a follow-up of 1-6 years. Preoperative CT or/and MRI of the brain was done in all cases. Tap test was done in all cases. Clinical examination finding were classified according to the by Japanese Committee for Scientific Research (JCSS) on intractable Hydrocephalus. Patients were studied to evaluate of the patency of ventriculosthomy and aqueduclus slyvius by a Cine PC MR and CSF_DRIVE T2 Sequence MRI after 1-6 years. Results: Headache, gait disturbance and pollakiuria improved in three patients with SNPH underwent ETV, but dementia didn't improve in one patient. Pollakiuria and headache improved in three patients with INPH underwent ETV but preoperative gait disturbance grade three remained unchanged in one patient. Headache improved in three patients with SLOVA underwent ETV. Preoperative gait disturbance grade 3 remained unchanged in one patient, but improved pollakiuria. We confirmed the patency of a third ventriculostomy and decreasing degrees of CSF flow into the aquaductus sylvius. Conclusions: In properly selected patients with SNPH, SLOVA and INPH who had headache, slight gait disturbance and pollakiuria, mainly those with a short duration of symptoms, ETV may provide good results. PMID- 29114270 TI - Trigeminal Neuralgia. AB - Trigeminal neuralgia (TN) is a sudden, severe, brief, stabbing, and recurrent pain within one or more branches of the trigeminal nerve. Type 1 as intermittent and Type 2 as constant pain represent distinct clinical, pathological, and prognostic entities. Although multiple mechanism involving peripheral pathologies at root (compression or traction), and dysfunctions of brain stem, basal ganglion, and cortical pain modulatory mechanisms could have role, neurovascular conflict is the most accepted theory. Diagnosis is essentially clinically; magnetic resonance imaging is useful to rule out secondary causes, detect pathological changes in affected root and neurovascular compression (NVC). Carbamazepine is the drug of choice; oxcarbazepine, baclofen, lamotrigine, phenytoin, and topiramate are also useful. Multidrug regimens and multidisciplinary approaches are useful in selected patients. Microvascular decompression is surgical treatment of choice in TN resistant to medical management. Patients with significant medical comorbidities, without NVC and multiple sclerosis are generally recommended to undergo gamma knife radiosurgery, percutaneous balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation procedures. Partial sensory root sectioning is indicated in negative vessel explorations during surgery and large intraneural vein. Endoscopic technique can be used alone for vascular decompression or as an adjuvant to microscope. It allows better visualization of vascular conflict and entire root from pons to ganglion including ventral aspect. The effectiveness and completeness of decompression can be assessed and new vascular conflicts that may be missed by microscope can be identified. It requires less brain retraction. PMID- 29114274 TI - Outcomes of Minimally Invasive Surgery Compared to Open Posterior Lumbar Instrumentation and Fusion. AB - Introduction: Degenerative spine disease is increasingly common. There are many spinal fusion techniques used to treat degenerative spine disease. This study aims to compare the functional outcome of open versus minimally invasive surgery (MIS) technique in posterior lumbar instrumentation and fusion in degenerative spine disease and to evaluate the perioperative outcome and complications between MIS and open surgery. Materials and Methods: This is an observational cross sectional study conducted on all degenerative spine disease patients who underwent both methods of posterior lumbar instrumentation and fusion from 2010 to 2014 by the Orthopedic and Neurosurgery Department, Sarawak General Hospital. The analyzed variables were method of surgery and the levels involved, demographic data, estimated blood loss, duration of operation, length of hospitalization, visual analog scale of back pain and radicular pain preoperative, postoperative 1 month, 3 months, 6 months, 1 year, and functional outcome. Results: One hundred and twenty-two patients underwent posterior lumbar instrumentation and fusion from 2010 to 2014. Seventy patients were subjected to MIS transforaminal lumbar interbody fusion (TLIF) and 52 open TLIF. Total 89 patients underwent single level of lumbar fusion with sixty patients in MIS group and 29 in open surgeries. MIS TLIF has less estimated blood loss and shorter hospitalization and longer operation time compared to open TLIF, which were statistically significance. MIS TLIF has statistically significance better functional outcome based on Oswestry disability index, Modified NASS score, and RAND 36-item Health Survey 1.0 score. Complications such as infection, new onsets of neurological, and dural tear are equal in both methods of surgery. Conclusion: This study concluded that MIS has better functional outcome compared to open TLIF with shorter hospitalization, faster return to work, and less estimated blood loss. PMID- 29114275 TI - Intraoperative Anatomical and Hemodynamic Analysis of Intracerebral Arteriovenous Malformations by Semi-quantitative Color-coded Indocyanine Green Videoangiography. AB - Objective and Background: To evaluate possible roles for indocyanine green (ICG) based FLOW 800 software in surgical treatment of cerebral arteriovenous malformations (AVMs). Methods: We perform ICG videoangiography several times for each step of AVM resection to elucidate feeders, drainers, and cerebral perfusion. Results: Since 2010, 22 AVM surgeries in our department have been conducted using FLOW 800 intraoperatively. We demonstrated ICG angiograms, color coded images, and semi-quantitative curves for AVMs. By reviewing all these modalities, we would define vascular structure of the AVM, proceed with resection, and finally recheck for any remnant. Conclusions: ICG FLOW 800 software helps the surgeon to recognize feeding and draining vessels of an AVM intraoperatively. Further studies to evaluate semi-quantitative acquired data regarding blood flow and tissue perfusion are warranted. PMID- 29114276 TI - Predictive Value of Motor Evoked Potential Monitoring during Surgery of Unruptured Anterior Circulation Cerebral Aneurysms. AB - Objective and Background: Surgery of unruptured aneurysms is always a great challenge to neurovascular surgeons because no postoperative neurological deficits should be expected postoperatively as the patients are fully asymptomatic before the surgery. Here, we present our experience with selective motor evoked potential (MEP) monitoring of our patients in a 2-year time window. Patients and Methods: From 2012 to 2014, 27 patients with unruptured intracranial aneurysms were operated in our institute with the help of MEP monitoring. All patients underwent endoscope-assisted microsurgery with pre- and post-clipping indocyanine green angiography. Results: In this period, no mortality was observed, but 18.5% of the patients developed postoperative deficits which showed good recovery in all cases. Overall, MEP showed about 90% accuracy in predicting postoperative deficits. Conclusions: MEP as a part of multimodality monitoring of aneurysm surgeries is a valuable tool to improve the outcome. However, we should know its limitations as its results are not always consistent with the outcome. PMID- 29114277 TI - Contributing Factors for Coagulopathy in Traumatic Brain Injury. AB - Context: In traumatic brain injury patients, coagulation disorder causes secondary brain injury, thereby increasing mortality and morbidity. Aims: The aim of this study is to identify the factors responsible for coagulopathy in traumatic brain injury. Settings and Design: This prospective longitudinal study from June 2012 included 100 patients with moderate and severe head injury presenting to National Institute of Neurological and Allied Sciences, Kathmandu, over 1-year period. Subjects and Methods: Patients were evaluated for the development of coagulopathy, defined as collectively three abnormal hemostatic parameters, and associated risk factors for coagulopathy. They were then analyzed for correlation with coagulopathy. Statistical Analysis Used: SPSS version 16 was used for the analysis of data. For identification of contributing factors, a stepwise logistic regression analysis was performed, including the factors with P < 0.05 from the analysis. Results: Among the 100 patients, coagulopathy was present in 63% of cohort. Forty-three patients had severe head injury, and 76.7% (n = 33) of them had coagulopathy compared to 52.7% (n = 30) in 57 patients with moderate head injury (P = 0.013). Statistically significant correlation with coagulopathy was present with polytrauma, severity of head injury, blood transfusion, surgical intervention, and Marshall's classification of CT of the head; however, stepwise logistic regression analysis showed that blood transfusion, surgical intervention, polytrauma, and severity of head injury were significant independent variables responsible for the development of coagulopathy. Conclusions: Traumatic brain injury is complicated with coagulopathy in up to 63% of patients. Blood transfusion, surgical intervention, polytrauma, and severity of head injury are significant independent variables responsible for coagulopathy. PMID- 29114278 TI - Profiling Cognitive Deficits in Intra-Axial and Extra-Axial Tumors Using Addenbrooke's Cognitive Examination as a Screening Tool: An Indian Experience. AB - Background: Tumors of the brain, whether intra- or extra-axial, results in cognitive deficits. The aim of the present study was to profile cognitive deficits using Addenbrooke's Cognitive Examination-Malayalam (ACE-M) as a screen and to determine the sensitivity and specificity of the same. Methods: Seventy four drug naive patients diagnosed to have brain tumors were assessed for cognitive functioning using ACE-M before surgery. Results: Patients with high grade intra-axial tumors showed a significant association on the cognitive domains of registration (0.04), recall (0.01), and visuospatial functioning (0.02). Gender showed an association between registration (0.02) and verbal fluency (0.02) with females performing better while education was significantly associated with retrograde or remote memory (0.00) with college-educated sample performing better. Significance was assumed at P < 0.05. In extra-axial tumors, laterality had a single association with recall (0.02). Males showed a significant cognitive decline on the cognitive domains of attention (0.02), recall (0.05), naming (0.02), and language functions (0.01). College educated group performed better on registration (0.01), recall (0.09), naming (0.00), and visuospatial functioning (0.00). The area under the receiver operating characteristic curve was estimated as 0.75, which indicates fairly good discriminative ability with a cut off of 71/100; sensitivity at 77.3 and specificity fixed at 67. Conclusions: ACE-M is capable of bringing out cognitive deficits along with a number of cognitive domains in patients with intra- and extra-axial tumors in the capacity of a screen, with fairly good levels of sensitivity and specificity. PMID- 29114279 TI - Comparison between Ventriculosubgaleal Shunt and Extraventricular Drainage to Treat Acute Hydrocephalus in Adults. AB - Context: Hydrocephalus, due to subarachnoid or intraventricular hemorrhage (IVH), meningitis, or tumor compression, is usually transient and may resolve after treatment. There are several temporary methods of cerebrospinal fluid (CSF) diversion, none of it is superior to the other, and the decision is based on its various etiologies and factors. Ventriculosubgaleal shunt (VSGS) is one of those temporary measures, which is a simple and rapid CSF decompression method without causing electrolyte and nutritional losses. Aims: The aim is to study the efficacy of VSGS for temporary CSF diversion, compared to extraventricular drainage (EVD) in adult hydrocephalus patients; to evaluate the outcome in terms of avoiding a permanent shunt, and to look for incidences of their complications. Settings and Design: This was a retrospective observational study. Subjects and Methods: The data were acquired from case notes of fifty patients with acute hydrocephalus: 26 secondary to IVH, 10 from aneurysm rupture, 8 posttrauma, and 6 from infection. All these patients had undergone CSF diversion in Hospital Queen Elizabeth II, Sabah, Malaysia, between 2013 and 2015. The patients were followed up from the date of treatment until the resolution of hydrocephalus, where parameters such as shunt dependency and complications were documented. Statistical Analysis Used: All analyses were carried out using Statistical Packages for the Social Sciences Version 22.0. Chi-squared test or Fisher's exact test is used for univariate analysis of categorical variables. Results: A total of 21 (42%) patients underwent EVD insertion and 29 (58%) underwent VSGS insertion. Thirty-seven (74%) patients did not require a permanent shunt; 24 (64.8%) of them were from the VSGS group (P = 0.097). EVD had more intracranial complications (44.1%) compared with VSGS (23.5%), with a statistically significant P = 0.026. Conclusions: VSGS is a safe and viable option for adult hydrocephalus patients, with the possibility of continuation of the treatment for such patients in nonneurosurgical centers, as opposed to patients with EVDs. Furthermore, even though this method had no statistical difference in avoiding a permanent ventriculoperitoneal shunt, VSGS has statistically significant less intracranial complications compared with EVD. PMID- 29114280 TI - Comparison of Stereotactic and Ultrasound-guided Biopsy of Solid Supratentorial Tumor: A Preliminary Report. AB - Introduction: The computed tomography (CT) guided stereotactic biopsy (STB) is considered as method of choice for biopsy of intracranial mass lesions. However, it's disadvantages are frame fixation, time requirement for transportation between CT scan suit to the operation theater with added much higher equipment cost in the relatively resource scarred developing country. Ultrasound-guided biopsy (USGB) is relatively simpler, economical, less time consuming, and real time procedure. Clinical Materials and Methods: Thirty-seven consecutively admitted patients with supratentorial brain tumors, who underwent biopsy of the lesion using CT compatible stereotactic and ultrasound-guided (USGB) procedure formed cohort of the study. Based on location and size of the lesions, the cases were divided into two groups, superficial and deep. Twenty-two patients underwent ultrasound-guided biopsy and 15 with STB. Results: The diagnostic yield of STB was 93% and 91% for ultrasound-guided biopsy. The mean operation time of STB group was 149.00 min and 94 min for USGB, which was statistically significant. Two cases in each group developed hematoma; however, one case in USGB group needed surgical evacuation. The real-time monitoring detected two hematoma intraoperatively, which were further also confirmed on postoperative CT scan head. Conclusions: The ultrasound-guided biopsy procedure (USGB) was simple, relatively shorter time-consuming procedure and equally efficacious and utilizing economical equipment and can act as a safer alternative to CT STB process for biopsy of the intracranial mass lesion. Furthermore, USGB also provided intra operative real-time monitoring, which provided clue for close monitoring in the postoperative period after completion of biopsy to look for development of fresh hematoma development not only at the biopsy site but also along the biopsy track and adjoining area. Perhaps, a longer period of ultrasonic monitoring following the procedure would be of greater help to detect hematoma formation, which is one of the most common complications of the biopsy procedure. PMID- 29114281 TI - Factors Correlated with Unfavorable Outcome after Carpal Tunnel Release Surgery. AB - Objectives: Carpal tunnel release surgery has excellent results. The aim of this study was to identify which baseline clinical and demographic factors could predict a good outcome from surgery. Understanding the impact of prognostic factors will enable surgeons to indicate surgical intervention better, provide appropriate preoperative counseling, and manage expectations postoperatively. Materials and Methods: A prospective, observational study included 620 carpal tunnel syndrome patients (age 42.38 +/- 11.18 years; mean +/- standard deviation). After the diagnosis had been confirmed by electrodiagnostic studies, patients underwent open carpal tunnel release surgery. Patients were evaluated initially after 2 weeks and eventually after 6 months. Surgical outcome was compared with presurgical findings. Results: Response to surgery was good in 89.4% and 94.2% after 2 weeks and 6 months, respectively. Factors correlated significantly with unfavorable outcome of surgery included old age, longer duration of symptoms, negative Phalen's test, abnormal two-point discrimination test, and weakness of abductor pollicis brevis muscle. Gender, retrograde radiation, and nocturnal symptoms did not correlate with surgical outcome. Conclusion: Elderly patients with longstanding disease, neurological deficits, and negative Phalen's test may not respond to surgery as others. This should be kept in mind in preoperative counseling and postoperative expectations. PMID- 29114282 TI - Multicompartmental Primary Spinal Extramedullary Tumors: Value of an Interdisciplinary Approach. AB - Background: Primary extramedullary tumors involving multiple compartments around the spine are a technically demanding group of tumors whose extent traverses beyond the normal confines of those anatomical regions which fall in the common domain of neurosurgeons. In the following series, we present 12 patients who were diagnosed with primary spinal extramedullary tumors with multicompartmental extension, and whose surgical management was facilitated by a combined multidisciplinary approach involving surgeons of other superspecialties. This multidisciplinary assistance from the inception to the culmination of surgical management helped in achieving a better surgical removal, thereby resulting in better surgical outcomes. Materials and Methods: Twelve consecutive patients who fulfilled the inclusion criteria in the 5-year period (January 2010 to January 2015) were included in the series based on the radiological and pathological characteristics of the tumor. Depending on the site of the spine involved by the lesion, radiologists and surgeons were involved from the planning phase of the surgical management, and their assistance in procedures such as preoperative embolization/ureteric stenting was sought whenever was deemed necessary. The extent of resection and total blood loss was recorded meticulously. Regular follow-up (3, 6, and 12 months and 2 and 5 years) of the patients was done after the initial follow-up at 6 weeks and their disability scores were recorded. Results: Of the 12 cases (6 males and 6 females), sacrum was the most common location of the tumors (6). Histopathologically, giant-cell tumors, schwannomas, and chondrosarcomas (3 each) were most common followed by Ewing's sarcoma (2) and malignant peripheral nerve sheath tumor (1). Eight patients had functional status of McCormick scale 1 and two patients had a functional status of 2. One patient was lost to follow-up and one patient died during surgery. Conclusion: Judicious involvement of access surgeons and adjunct therapies along with careful preoperative planning can help in improving surgical outcome in multicompartmental spinal tumors. PMID- 29114284 TI - Intraoperative Magnetic Resonance Imaging for Cranial and Spinal Cases Using Preexisting "C" Shaped Three Side Open 0.2 Tesla Magnetic Resonance Imaging. AB - Background: The existing Intraoperative MRI (IMRI) of developed countries is too costly to be affordable in any developing country and out of the reach of common and poor people of developing country at remote areas. We have used the pre existing (refurbished) 3 side open "C" shaped 0.2 Tesla MRI for IMRI in a very remote area. Materials and Methods: In this technique the 0.2 Tesla MRI and the operating theatre were merged. MRI table was used as an operation table. We have operated 36 cases via IMRI from November 2005 to till date. First case operated was on 13th nov 2005. Results: Low (0.2) Tesla open setup costs very low (around Rs 40 lakhs) so highly affordable to management and thus to patients, used for diagnostic and therapeutic purposes both, the equipments like Nitrous, oxygen and suction is outside the MRI room so no noise inside operative room, positioning the patient didn't take much time due to manual adjustments, no special training to nurses and technicians required because of low (0.2) Tesla power of magnet and same instruments and techniques, sequencing took only 1.31 mints per sequence and re registration is not required since we always note down the two orthogonal axis in x and y axis in preoperative imaging and we were able to operate on posterior fossa tumors as well because of no head fixation except with leucoplast strap. Moreover the images we got intraoperative are highly acceptable. Conclusion: Three side open 0.2 Tesla MRI system, if used for intraoperative guidance, is highly affordable and overcomes the limitations of western setup of IMRI. Postoperative MRI images were highly acceptable and also highly affordable too. PMID- 29114283 TI - A Method for Reconstruction of Severely Damaged Spinal Cord using Autologous Hematopoietic Stem Cells and Platelet-rich Protein as a Biological Scaffold. AB - Introduction: There have been attempts to alter the prognosis of severe spinal cord injury in different centers, but none of which have reliably altered the outcome. Some trials use stem cells (SCs) that produced widely differing results. We hereby add our experience in our center of a surgical reconstruction of the damaged spinal cord using a mixture of SCs and Platelet-Rich Protein (PRP) with fibrin coated as a biological scaffold. Materials and Methods: Four cases of severely damaged spinal cord have been operated for neurolysis and reconstruction of the spinal cord using SCs and platelet-rich protein (PRP) with fibrin coated harvested from the peripheral circulation of the patient. PRP serves to maintain the position of the SCs. One milliliter suspension contains an average of 2.8 * 106 of autologous hematopoietic SCs. Patients were intraoperatively monitored by somatosensory evoked potential, motor evoked potentials, and delta wave. They are clinically followed postoperatively and electromyogram was repeated every 2 weeks. Magnetic resonance imaging (MRI) was repeated regularly. The patients are followed up for a period between 2 and 3 years. Results: One patient demonstrated motor and objective sensory improvement (P = 0.05), two other patients reported subjective sensory improvement, and the fourth one remained without any improvement (P = 0.1). None of these patients demonstrated any sign of deterioration or complication either on the surgery or on implanting of the SCs. MRI clearly proved that the inserted biological scaffold remained in place of reconstruction. Conclusion: SCs may play a role in restoring spinal cord functions. However, the unsolved problems of the use of SCs and related ethical issues should be addressed. PMID- 29114285 TI - Pneumocephalus Presenting as Sudden Thunderclap Headache. AB - Pneumocephalus is a rare condition characterized by the presence of gas within the cranial cavity. This gas arises either from a trauma, tumor, surgical procedure, or occasionally from infection. Pneumocephalus secondary to chronic otitis media is an extremely rare phenomenon. We describe here a 70-year-old male, a known case of chronic suppurative otitis media who presented with sudden onset severe thunderclap headache and was eventually diagnosed as pneumocephalus. PMID- 29114286 TI - Intradural Eosinophilic Granuloma Invading Skull: Case Report and Review of the Literature. AB - Eosinophilic granuloma is a localized form of Langerhans cell histiocytosis, most commonly involving the skeletal system. Their origin from the dura is rare with only a handful of cases on record. We present one such rare case of an eosinophilic granuloma originating from the dura mater with secondary osseous invasion in an 11-year-old female child who presented with a swelling in the right parietal region. Magnetic resonance imaging demonstrated an enhancing mass with a wide dural attachment with a lytic lesion in the overlying skull. Right parietal extended craniotomy was done with the excision of mass from the dura. Histopathological features of mass were characteristic of eosinophilic granuloma which was confirmed by positive immunohistochemical staining for CD1a. PMID- 29114287 TI - Unruptured Internal Carotid Artery Aneurysm Associated with Functional Pituitary Adenoma: A True Association. AB - Detection of incidental intracranial aneurysm on neuroimaging can be associated with pituitary adenoma; however, such association is extremely rare. However, aneurysm with extension into the sella is extremely rare, and increases the risk of inadvertent intraoperative rupture, if trans-sphenoidal decompression is attempted either using endoscopic or microscopic surgical approach. Hanak et al. in a literature review of intrasellar noniatrogenic aneurysms over PubMed search in 2012 could only collect 31 studies, of which only eight cases had pituitary adenoma associated with aneurysm extending into sella. Authors report an interesting case of 52-year-old male diagnosed as case of acromegaly, was put on dopamine agonist, bromocriptine and responding well to therapy, however the magnetic resonance imaging raised suspicion of vascular pathology, and underwent digital subtraction angiography at our center revealed presence of right supracliniod internal carotid aneurysm, which was coiled using endovascular technique with resultant good outcome. PMID- 29114288 TI - Lhermitte-Duclos Disease: A Rare Cause of Cerebellar Ataxia. AB - The aim of this study is to describe a case of Lhermitte-Duclos disease (LDD), which is an extremely rare cause of cerebellar ataxia. LDD is an extremely rare type of benign cerebellar mass and usually manifest as features of raised intracranial pressure and cerebellar dysfunction. Patients may remain asymptomatic for many years, and detection of tumor may be by chance on routine magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). A 29 year-old female presented to the outdoor patient department with 18 months history of a headache, which was moderate to severe in intensity, throbbing in nature, localized to the right side of the head, and associated with nausea and photophobia. On examination, she had mild cerebellar dysfunction, and MRI/MRS finding was consistent with LDD. LDD is a rare cause of headache and cerebellar dysfunction in younger age group. Treatment may be individualized, and conservative management with regular follow-up may be a better approach if symptoms are mild and nonprogressive in nature. PMID- 29114289 TI - Conus Medullaris Arachnoid Cyst Presenting as Cauda Equina Syndrome. AB - Intradural arachnoid cysts are a rare cause of spinal cord and nerve root compression. Primarily, they are present in the thoracic region posteriorly. We report a 25-year-old man who had an intradural arachnoid cyst at the level of conus medullaris presenting with cauda equina syndrome, which is very rare. PMID- 29114291 TI - A Rare Case of Isolated Conus Medullaris Neurenteric Cyst. AB - Spinal neurenteric cysts are very rare congenital anomalies and are commonly associated with other spinal malformations. They are usually located in intradural, extramedullary location. We report a rare case of intramedullary conus medullaris neurenteric cyst without any associated spinal malformation diagnosed preoperatively by magnetic resonance imaging. PMID- 29114290 TI - Open C2 Vertebroplasty: Case Report, Technique, and Review of Literature. AB - : Osteolytic lesions of C2 are challenging pathologies to manage. Vertebroplasty, a minimally invasive technique has been widely used in lytic lesions of thoracic and lumbar spine. However, there has been limited experience with percutaneous vertebroplasty at C2, and the procedure is technically difficult. We describe a safer alternative technique of open vertebroplasty for lytic lesions involving the axis. METHODS: The procedure was performed in a 49-year-old male with a metastatic lytic lesion involving the body and dens of C2 using an anterior cervical approach. The patient had an immediate reduction in pain with complete pain relief at 2 weeks and good stability at 3-month follow-up. The patient did not have any perioperative or postoperative complications. The anterior cervical approach open C2 vertebroplasty is a safe and effective option in the management of C2 osteolytic lesions. PMID- 29114292 TI - Vertex Extradural Hematoma: A Diagnostic Dilemma. AB - Extradural hematomas (EDHs) of vertex are rarely seen and form a small percentage of all EDH. Usual cause of an EDH located at the vertex is tearing of the superior sagittal sinus. A 35-year-old male patient was admitted to our department, with history of fall and lucid interval. Imaging studies showed contusion in the right frontal region with midline shift and bilateral EDH located at vertex which was misinterpreted as artifact or subdural hematoma. We present this rare case and briefly review the literature regarding its etiopathology and associated clinico-radiological findings. The principles of management of this rare entity are also discussed. PMID- 29114293 TI - Solitary Giant Extradural Plasmacytoma. AB - Solitary plasmacytoma of the skull is very rare, and only a few cases have been reported in the literature. It remains controversial whether solitary plasmacytoma of the skull is essentially identical with solitary plasmacytoma of bone or not. Solitary plasmacytoma of bone including solitary plasmacytoma of the skull is characterized by a radiologically solitary bone lesion, neoplastic plasma cells in the biopsy specimen, fewer than 5% plasma cells in bone marrow, <2.0 g/dl monoclonal protein in the serum when present and negative urine test for Bence Jones protein (monoclonal light chain). We report one case of a 70-year old woman who referred to our hospital because of a progressive left parietal swelling. On clinical examination, a painless large soft mass in the right parietal region was observed. Computed tomography revealed an extra-axial mass in the in the left frontoparietal region. The lesion was totally excised despite the bleeding tendency. Histology disclosed the presence of a plasmacytoma. On follow up examination, 7 months later no tumor recurrence or evidence of multiple myeloma was detected. PMID- 29114294 TI - Evisceration of Brain: An Unusual Case Report of Bear Mauling from Eastern India. AB - Even if human beings are the most intelligent among all living beings, they are still not immune to attack from wild animals. Human contact with bears has become more frequent as their habitat is being endangered by frequent deforestation. The sloth bear is one of the few bear species found in India, especially in the hilly areas of Southern Odisha. Bears are highly intelligent and omnivorous animals with long claws coupled with powerful shoulder. Here, we describe the tale of a poor tribal male's encounter with a sloth bear resulting in critical injuries to face, scalp, skull bone, with brain matter fungating-out of the skull. We immediately went for debridement of the, bulged-out contused brain matter and opted for delayed repair of scalp defect with antero-lateral thigh free-flap to save him from fatality along with an acceptable cosmetic repair of the defect. PMID- 29114295 TI - Tumor Recurrence in a Glioblastoma Patient after Discontinuation of Prolonged Temozolomide Treatment. AB - There is no consensus regarding the duration of temozolomide (TMZ) treatment for glioblastoma multiforme (GBM). We report a 53-year-old woman who had a left frontal GBM. The tumor showed good response to TMZ treatment, which was discontinued after 5.5 years with recurrence of tumor at the posterior fossa 6 months later, although there was no definite tumor recurrence in the left frontal region. The tumor failed to respond to the reinstitution of TMZ therapy. Continuous TMZ treatment may be necessary in GBM patients on prolonged TMZ treatment despite improved neurological condition and imaging studies revealing marked tumor regression. PMID- 29114296 TI - Occipital Intraparenchymal Myxopapillary Ependymoma: Case Report and Literature Review. AB - Myxopapillary ependymoma (MPE) is a histological variant of ependymoma found in the conus medullaris or filum terminale region. Intracranial occurrence of the tumor is a rarity. The most characteristic histological feature of myxopapillary tumors is the abundance of intercellular and perivascular mucin and the arborizing vasculature, which tends to form papillae. We are reporting a 14-year old patient presented with seizures caused by the right occipital region intraparenchymal lesion. Histopathology confirmed it to be MPE. Lesion was excised completely. Literature reviews on the topic are discussed regarding the histological findings, natural history, and outcome of surgically treated MPE. This is the fifth reported case of cerebral intraparenchymal primary MPE. PMID- 29114297 TI - Redo Microvascular Decompression in a Patient of Resistant Cochleovestibular Nerve Compression Syndrome. AB - Cochlea-vestibular nerve compression syndrome (CVCS) may present as recurrent attacks of vertigo, dizziness, imbalance, etc. Those patients who do not respond to medical management, are usually managed by "microvascular decompression (MVD) of cochlea-vestibular nerve." The success rate of MVD is not 100% and few patients present with the recurrence of symptoms. We are reporting management of one such resistant case of CVCS. A 40-year-old female patient who was a known case of CVCS, was managed by medical and surgical (MVD) management. She had no relief of symptoms. We did redo MVD of cochlea-vestibular nerve after full evaluation of symptomatology. Patient had complete relief in her symptoms. In failed MVD cases, redo MVD can be performed if patient is still having e/o nerve compression, adhesions on magnetic resonance imaging. PMID- 29114298 TI - Scrotal Migration of Tubing: An Unusual Complication after Ventriculo-peritoneal Shunt. AB - Scrotal migration of peritoneal end of ventriculo-peritoneal (VP) shunt into the patent processus vaginalis (PPV) is a rare complication. Its exact incidence is not mentioned in the literature till date. This may be because of the rarity of this complication, and also because all previous articles related to the complication were case reports. We, in our series, had an incidence of 0.9%. This prospective study has been conducted on 437 patients in the age group of 1 month 3 years who underwent VP shunt for hydrocephalus over a period of 5 years from 2007 to 2011. The incidence of a hernia manifesting after shunt insertion has been reported to be around 16.8%. The average age of patients at the time of insertion of the shunt was 27.25 months (3-48 months). All our patients presented with swollen right sided scrotum after an average of 4 months (3-5 months) after shunt insertion. Shunt migration was more common on the right which is consistent with the incidence of hernias in children. The proper management of such cases includes repositioning of the catheter with the proper closure of the PPV. Usually, shunt revision is not required. We discuss the etiology, treatment and preventive measures of this rare entity. PMID- 29114299 TI - Tree-in-bud Appearance in the Brain: Fungal Granuloma on Contrast Magnetic Resonance Imaging. AB - We describe a case of dural-based homogenously enhancing fungal granuloma in a 29 year-old male who presented with 3 months history of headache. The peculiarity of the case was that there were streaky areas of enhancement around the lesion in the brain parenchyma which resembled tree-in-bud like appearance. The patient underwent surgery and histopathological analysis revealed numerous Aspergillus hyphae. To the best of our knowledge, this is the first case report of a fungal granuloma with atypical parenchymal enhancement pattern. PMID- 29114300 TI - An Adult with Atrial Septal Defect Presenting with a Brain Abscess. AB - The common heart diseases resulting in a brain abscess are associated with a right to left shunt and include tetralogy of Fallot and transposition of great vessels. Atrial septal defect (ASD) is almost always associated with the left to right shunt and therefore is not a commonly considered risk factor for brain abscess. We report the case of a 29-year-old male, with no symptoms of cardiac disease, who presented with the left posterior frontal pyogenic abscess which led to the detection of a silent ASD. Our case emphasizes the need for a careful evaluation of the source of infection in patients with a brain abscess. PMID- 29114301 TI - Subependymal Giant Cell Astrocytoma: Associated Hyperproteinorrhachia Causing Shunt Failures and Nonobstructive Hydrocephalus - Report of Successful Treatment with Long-term Follow-up. AB - Subependymal giant cell astrocytomas (SEGAs) are histologically benign tumors most frequently associated with tuberous sclerosis complex (TSC). Despite their benign histopathological appearance, they may cause unfavorable outcomes due to their intraventricular location. Rarely, SEGA may be associated with hyperproteinorrhachia (high levels of proteins in the cerebrospinal fluid [CSF]), which causes malresorptive, communicating hydrocephalus; certainly, this scenario makes shunt obstruction likely in this patient population. In this report, we illustrate the case of hyperproteinorrhachia in an SEGA patient with known TSC, who presented repeatedly with shunt failure from proteinaceous shunt obstruction. Subsequent surgical resection of the main intraventricular lesion resulted in a dramatic drop in the CSF protein levels and has since prevented further shunt failures. Different treatment concepts and possible pathophysiology are discussed and the pertinent literature is reviewed. PMID- 29114302 TI - Contrecoup Extradural Hematoma with Coronal Suture Diastasis. AB - Extradural hematoma (EDH) generally occurs in the site of impact, that is, coup injury site. EDH is associated with fracture of skull in many a times due to direct impact. However, EDH in counter coup site is a rare occurrence. Hardly, yet, 12 cases have been reported including this case. Here, we reported a case of a 22-year-old male of contrecoup acute EDH who had sustained head injury due to fall from bike. Physical examination revealed direct impact at the left occipito parietal region with laceration of scalp and bruise with transient loss of consciousness at the time of injury. There was no evidence of impact on the right side of his head. Computed tomography scan revealed an EDH in the right fronto temporal region without any bone fracture on bone windows. On intraoperative exploration, it is found that there was coronal suture diastasis with small subgaleal hematoma and right fronto-temporal extradural hematoma. The evacuation of EDH was done. The patient discharged on 3rd postoperative day. It can be concluded that direct impact on head causes exactly opposite hit of brain, and compensatory rebound causes a negative pressure in between the layers causing disruption of vessels and potential accumulation of blood. This mechanism mostly favors for acute subdural hematoma due to compact attachment of dura with cranium. However, in this case, diastasis of coronal suture due to transmitted force is the cause of accumulation of blood extradurally in relatively loosely adhered dura in fronto-temporal region where a potential negative pressure space is created by contrecoup injury. PMID- 29114303 TI - A Case of Occipital Rudimentary Cephalocoele. AB - We report a case of a 1-month-old boy with a cystic swelling in the occipital region without intracranial communication, called atretic cephalocoele. We discuss clues to the diagnosis of atretic cephalocoeles. We also discuss common clinical findings and a possible mechanism by which these lesions develop. PMID- 29114304 TI - Thrombosed Giant "True" Posterior Communicating Artery Aneurysm Treated by Trapping and Thrombectomy. AB - Giant "true" posterior communicating artery (PCOM) aneurysms are rare and the best surgical treatment for them is unclear. We present a case of 85-year-old woman with this type of lesion, 35 mm in diameter, successfully treated by trapping and thrombectomy via pterional approach without complications. There were no perforating arteries originating from the aneurysmal wall. The patient had an uneventful postoperative course. The key for successful treatment for such lesions is preservation of perforators, as trapping may result in ischemic complications. However, our case indicates that trapping and thrombectomy might have relatively low risks for development of such complications, supposing that the thrombosis within the giant "true" PCOM aneurysm induced spontaneous obliteration of perforators, arising from the aneurysmal dome, and that collateral flow from the posterior cerebral artery already compensated the corresponding territories. PMID- 29114305 TI - Frontal Mucocele Mimicking a Frontal Subcutaneous Tumor. AB - Mucoceles are chronic, expanding, mucosa lined pathology of the paranasal sinuses. Frontal mucocele usually presents with the visual complaints such as diplopia, diminution of vision, visual field defect, ptosis, orbital swelling, retro-orbital pain, displacement of eye globe, and proptosis. Very rarely, it can be present as a subcutaneous swelling. This article presents a 58-year-old male patient presenting with an asymptomatic periorbital swelling and a painless forehead mass of 3 years duration. There was a partial ptosis, and an elongated, soft, subcutaneous mass over the forehead. Surgical excision of the mass confirmed the diagnosis of a mucocele. Postoperatively, the patient was asymptomatic. A subcutaneous soft-tissue mass may be the presenting complaint of a frontal mucocele. Careful examination of the surrounding skin may suggest the diagnosis of sinus-related disease and thus direct appropriate investigations. PMID- 29114307 TI - A Rare Case of Aggressive, Huge Primary Orbital Lymphoma with Intracranial Extension and Bone Invasion. AB - Primary orbital lymphoma is a rare entity with only 1% of extranodal lymphomas. They usually present to ophthalmologist and surgical reserved for biopsy or tissue diagnosis. We present a patient who was referred to neurosurgery for a rapid growing orbital lymphoma. It grows from a small nodule in the eyelid to a huge, aggressive, disfiguring lesion invading bone and dura with intracranial extension within 3 months. The patient was treated with total surgical excision followed by systemic chemotherapy. PMID- 29114306 TI - Combined Use of Intraoperative Indocyanine Green and Dynamic Angiography in Rotational Vertebral Artery Occlusion. AB - Rotational vertebral artery occlusion (RVAO) is a well-documented surgically amenable cause of vertebrobasilar insufficiency. Traditionally, patients have been imaged using dynamic rotational angiography. We report a case of RVAO in which intraoperative indocyanine green angiography (ICGA) was used to confirm adequate surgical decompression of the VA. A 57-year-old female who presented with multiple episodes of syncope provoked by turning her head to the right. Rotational dynamic angiography revealed a dominant right VA that became occluded at the level of C5/6 with head rotation to the right. The patient underwent successful surgical decompression of the VA via an anterior cervical approach. ICGA demonstrated VA patency with head rotation. This was further confirmed by intraoperative dynamic catheter angiography. To the best of our knowledge, we present the first use of ICG combined with intra-operative dynamic rotational angiography to document the adequacy surgical decompression of the VA in a patient with RVAO. PMID- 29114308 TI - Calvarial-orbital Metastasis of Prostate Carcinoma which was Diagnosed with Sixth Cranial Nerve Palsy. AB - Sixth nerve palsy is frequently due to infectious orbital lesions, trauma, elevated intracranial pressure, brainstem lesions, and vasculopathies. Here, we describe a rare cause of sixth cranial nerve (CN) palsy secondary to calvarial and orbital metastasis of prostate carcinoma. The diagnosis of the prostate carcinoma with sixth CN palsy is a very rare condition. A 66-year-old male patient presented with complaints of blurred vision, double vision, and inability to move outward in the right eye for 3 weeks. Magnetic resonance imaging revealed a right orbitocalvarial mass and the mass surgically removed completely. Pathologic findings were compatible with prostate adenocarcinoma metastasis. After surgical removal, significant improvement in sixth CN palsy was observed. PMID- 29114309 TI - Pneumocephalus following Dorsal Laminectomy: An Unusual Complication. AB - A 16-year-old male presented at Bangur Institute of Neurosciences Neurosurgery Outpatient Department with history of gradually progressive paraparesis for 5 months associated with stiffness, urinary hesitancy, and urge incontinence for last 2 months. Magnetic resonance imaging spine was done which showed cystic intradural extramedullary space occupying lesion at D4/D5 to D9. Patient had 2 episodes of generalized tonic-clonic seizure on the day 4. Computed tomography scan showed pneumocephalus. Histopathological examination report was that of nonspecific inflammatory cyst. PMID- 29114310 TI - Concurrent Multilevel Spinal Intra-medullary with Extensive Intracranial Tuberculomas: A Rare Case Report. AB - Disseminated tuberculomas in the brain and spinal cord are rare. To the best of our knowledge, only nine cases of spinal intra-medullary tuberculomas with cranial involvement have been reported till date. However, involvement of all levels in the spinal cord, brain stem with pan lobar involvement of the cerebrum and cerebellum has not been reported so far. We present such a case of a 12-year old boy with history of pulmonary tuberculosis, who presented with gradual onset of quadriparesis and generalized seizures. We have discussed the unusual clinical presentation and the temporal changes in magnetic resonance imaging features along with clinical response to treatment. In cases reported so far, the plan of surgical versus medical management has been opted for variably, in cases of spinal intra-medullary involvement with acute neurological deficit. The decision is even more difficult in multilevel spinal intra-medullary tuberculomas. Our patient showed good clinico-radiological improvement with medical management. PMID- 29114311 TI - Giant Cell Glioblastoma in a Child with Clinical and Family History of Neurofibromatosis. AB - We report a case of giant cell glioblastoma (GCG) in a 13-year-old child with clinical features and family history of neurofibromatosis type 1 (NF1). To the best of our knowledge, only two cases of GCG have been reported in a scenario of NF1, and only one of that was in a pediatric age group. A report on our case is presented here along with a review of literature. PMID- 29114312 TI - A Case of High-dose Adenosine Usage for Anterior Communicating Artery Aneurysm Clip Ligation: What is the Dose Limit for a Resistant Response? AB - Intraoperative adenosine is used to induce asystole to facilitate clip ligation of intracranial aneurysms. Typically, 5-10 mg doses are used per administration and approximately 30 mg is used for a given case. An obvious concern with using adenosine is that the patient can remain in asystole or that prolonged hypotension can result in cerebral or cardiovascular ischemia. The upper limit of adenosine administration remains unclear. We present a case of a patient with a large anterior communicating artery aneurysm requiring large doses of adenosine, far exceeding previously reported cases. The patient received a 90 mg dose of adenosine to achieve 5 s of asystole as well as 30 s of hypotension that facilitated vessel dissection and clip application. Moreover, in order to successfully clip his aneurysm, he received a total of 744 mg of adenosine. After each administration of adenosine, his heart rate and blood pressure returned to baseline without the need for chest compressions or other interventions. He tolerated the procedure and had a good neurological outcome. This case is the first report of using such a high dose of adenosine in intracranial aneurysm surgery and suggests that more aggressive administration of adenosine during aneurysm clipping is feasible. Transient hypotension, as seen in this report, can provide surgeons the crucial moments they need to safely secure an aneurysm from circulation. PMID- 29114313 TI - Axillary Nerve Schwannoma: A Rare Case Report. AB - Primary tumors of the brachial plexus are a rare cause of an axillary swelling. Schwannomas are benign tumors arising from Schwann cells. Most of the schwannomas occur in the head and neck region and in the flexor aspect of the limbs. We present a case of a 60-year-old female who presented with pain in the left axilla radiating to the left upper limb since 2 years and a painful swelling in her left axilla for 3 months. The diagnosis is made by fine needle aspiration cytology and magnetic resonance imaging, and confirmed by histopathological examination as schwannoma. PMID- 29114314 TI - Endoscopic Three-surgeon Six-handed Transorbital Transnasal Technique for Excision of Juvenile Nasopharygeal Angiofibroma: New Frontier Explored. AB - Endoscopic endonasal transorbital approach has been described for the removal of orbital lesions located anteromedially in temporal fossa. The same has been observed to be a versatile approach to the anterior and middle cranial fossa only in laboratory studies. This is the first clinical report of combined transorbital transnasal endoscopic approach to the cavernous sinus, superior orbital fissure, and middle cranial fossa in a case of recurrent nasopharyngeal angiofibroma using the three-surgeon six-handed technique. PMID- 29114316 TI - Pure Intra-optic Canal Schwannoma: Report of Two Cases. AB - We report two cases of "pure intra-optic-canal schwannoma." The first patient was a 67-year-old female who presented with a visual field defect and visual impairment in the right eye, and the second patient was a 17-year-old female with progressive visual impairment. Both patients underwent tumor resection through frontotemporal craniotomy combined with extradural anterior clinoidectomy and unroofing of the optic canal. The tumors were not attached to the optic nerve (ON) and were located exclusively inside the optic canal. In both cases, the histological diagnosis was schwannoma. Although the origin of pure intra-optic canal schwannoma is controversial, intra-operative findings suggested that in these cases, the tumors arose from the sympathetic nerve around the ON. PMID- 29114315 TI - Intracranial Hypotension-associated Cerebral Swelling following Cranioplasty: Report of Two Cases. AB - Cranioplasty is a comparatively simple neurosurgical procedure, and fatal complications are rare. This report describes two cases of critical brain swelling after otherwise uneventful cranioplasty. Both cases had subarachnoid hemorrhage and extremely similar clinical courses. They underwent decompressive craniotomy and clipping in the acute phase and had cranioplasty in the chronic phase, resulting in serious cerebral swelling and death. Deep venous sinus thrombosis was revealed in the autopsy for one case. Although no venous occlusion was identified in the other case, radiological findings suggested venous congestion. In both cases, intraoperative cerebrospinal fluid leakage was massive and was prolonged by a drain; therefore, we hypothesized that intracranial hypotension (IH) caused stagnation of venous flow. Neurosurgeons should be aware that fatal venous congestion induced by IH may occur after cranioplasty. To avoid this, tight dural closure should be obtained, and avoidance of the use of subcutaneous drains should be considered. PMID- 29114317 TI - Agenesis of the Internal Carotid Artery with Transcavernous Anastomosis Associated with Anterior Communicating Artery Aneurysms. AB - Agenesis of the internal carotid artery (ICA) is a rare congenital anomaly. Recently, several cases of ICA agenesis have been associated with cerebral aneurysms. We present the seventh case of ICA agenesis with transcavernous anastomosis associated with cerebral aneurysms. A 47-year-old man presented with transient numbness of his left hand. Magnetic resonance angiography indicated the presence of anterior communicating artery (ACoA) aneurysms. Digital subtraction angiography revealed two ACoA aneurysms, absence of the left ICA, and an anomalous collateral vessel connecting the cavernous portions of both internal carotid arteries, which was considered to be a transcavernous anastomosis. Head bone window computed tomography with contrast medium revealed the absence of the petrous carotid canal on the left suggesting the diagnosis of left ICA agenesis. The ACoA aneurysms were clipped successfully, and the postoperative course was uneventful. PMID- 29114318 TI - Intracranial Hemorrhage in Dengue: Where Is It? PMID- 29114319 TI - Carotid Endarterectomy: A Video Demonstration. PMID- 29114320 TI - An efficient synthesis of a C12-higher sugar aminoalditol. AB - The C12-aminoalditol H2NCH2-(CHOBn)10-CH2OH was prepared from two simple monosaccharide building blocks. The synthesis was realized by a regioselective introduction of the azide group and subsequent protection-deprotection transformations. The chemical reactivity of the aminoalditol was tested in the reductive amination reaction with a selectively protected sucrose monoaldehyde. PMID- 29114321 TI - Synthesis of 2-aminosuberic acid derivatives as components of some histone deacetylase inhibiting cyclic tetrapeptides. AB - A new synthesis of the important amino acid 2-aminosuberic acid from aspartic acid is reported. The methodology involves the alternate preparation of (S)-2 aminohept-6-enoate ester as a building block and its diversification through a cross-metathesis reaction to prepare the title compounds. The utility of the protocol is demonstrated through the preparation of three suberic acid derivatives of relevance to the design and the synthesis of peptides of biological relevance. PMID- 29114322 TI - Superstructures with cyclodextrins: Chemistry and applications IV. PMID- 29114324 TI - A mechanochemical approach to access the proline-proline diketopiperazine framework. AB - Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline-proline dipeptides under solvent-free conditions. A deprotection-cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted Pro-Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill. PMID- 29114323 TI - The effect of milling frequency on a mechanochemical organic reaction monitored by in situ Raman spectroscopy. AB - We provide the first in situ and real-time study of the effect of milling frequency on the course of a mechanochemical organic reaction conducted using a vibratory shaker (mixer) ball mill. The use of in situ Raman spectroscopy for real-time monitoring of the mechanochemical synthesis of a 2,3 diphenylquinoxaline derivative revealed a pronounced dependence of chemical reactivity on small variations in milling frequency. In particular, in situ measurements revealed the establishment of two different regimes of reaction kinetics at different frequencies, providing tentative insight into processes of mechanical activation in organic mechanochemical synthesis. PMID- 29114325 TI - Regiodivergent condensation of 5-alkoxycarbonyl-1H-pyrrol-2,3-diones with cyclic ketazinones en route to spirocyclic scaffolds. AB - The condensation of 5-alkoxycarbonyl-1H-pyrrolediones with cyclic ketazinones was systematically investigated. It was discovered that the regioselectivity of this reaction can be easily swapped between two alternative directions affording derivatives of partially hydrogenated indole or benzofurane. The control of this regioselectivity is efficiently governed by steric effects at the hydrazone moiety of the ketazinone reagent. PMID- 29114327 TI - Conjugated nitrosoalkenes as Michael acceptors in carbon-carbon bond forming reactions: a review and perspective. AB - Despite of their chemical instability and high reactivity, conjugated nitrosoalkenes are useful intermediates in target-oriented organic synthesis. The present review deals with carbon-carbon bond forming reactions involving Michael addition to alpha-nitrosoalkenes with a particular focus on recent developments in this methodology and its use in total synthesis. PMID- 29114328 TI - Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies. AB - The scope of applications of dialkyl dicyanofumarates and maleates as highly functionalized electron-deficient dipolarophiles, dienophiles and Michael acceptors is summarized. The importance for the studies on reaction mechanisms of cycloadditions is demonstrated. Multistep reactions with 1,2-diamines and beta aminoalcohols leading to diverse five- and six-membered heterocycles are discussed. Applications of dialkyl dicyanofumarates as oxidizing agents in the syntheses of disulfides and diselenides are described. The reactions with metallocenes leading to charge-transfer complexes with magnetic properties are also presented. PMID- 29114326 TI - Phosphonic acid: preparation and applications. AB - The phosphonic acid functional group, which is characterized by a phosphorus atom bonded to three oxygen atoms (two hydroxy groups and one P=O double bond) and one carbon atom, is employed for many applications due to its structural analogy with the phosphate moiety or to its coordination or supramolecular properties. Phosphonic acids were used for their bioactive properties (drug, pro-drug), for bone targeting, for the design of supramolecular or hybrid materials, for the functionalization of surfaces, for analytical purposes, for medical imaging or as phosphoantigen. These applications are covering a large panel of research fields including chemistry, biology and physics thus making the synthesis of phosphonic acids a determinant question for numerous research projects. This review gives, first, an overview of the different fields of application of phosphonic acids that are illustrated with studies mainly selected over the last 20 years. Further, this review reports the different methods that can be used for the synthesis of phosphonic acids from dialkyl or diaryl phosphonate, from dichlorophosphine or dichlorophosphine oxide, from phosphonodiamide, or by oxidation of phosphinic acid. Direct methods that make use of phosphorous acid (H3PO3) and that produce a phosphonic acid functional group simultaneously to the formation of the P-C bond, are also surveyed. Among all these methods, the dealkylation of dialkyl phosphonates under either acidic conditions (HCl) or using the McKenna procedure (a two-step reaction that makes use of bromotrimethylsilane followed by methanolysis) constitute the best methods to prepare phosphonic acids. PMID- 29114329 TI - Structural diversity in the host-guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies. AB - The complexation of the antifolate pemetrexed (PTX) with native cyclodextrins was studied. This process, along with the findings gathered for the structurally related folic acid was treated as a model for exploiting host-guest interactions of this class of guest molecules in the gas phase, in solution and in the solid state. Mass spectrometry was employed for the investigation of the architecture and relative gas-phase stabilities of these supramolecular complexes. The mode of complexation was further tracked by 1D and 2D NMR proving the formation of the exclusion-type complex with alpha-CD and pseudorotaxane inclusion-type complexes with beta-, and gamma-CDs. UV-vis titrations at pH 7.4 gave association constants for the obtained complexes. The stability of the complexes increases in the series: alpha-CD/PTX < gamma-CD/PTX << beta-CD/PTX. The association of PTX with a monomer cyclodextrin equivalent - methyl alpha-D-glucopyranoside - was investigated for a deeper understanding of the type of host-guest interactions. Solid state studies of PTX/CDs were performed using FTIR-ATR and Raman spectroscopy techniques. PMID- 29114330 TI - Curcuminoid-BF2 complexes: Synthesis, fluorescence and optimization of BF2 group cleavage. AB - Eight difluoroboron complexes of curcumin derivatives carrying alkyne groups containing substituents have been synthesized following an optimised reaction pathway. The complexes were received in yields up to 98% and high purities. Their properties as fluorescent dyes have been investigated. Furthermore, a strategy for the hydrolysis of the BF2 group has been established using aqueous methanol and sodium hydroxide or triethylamine. PMID- 29114332 TI - Molar Uprighting: A Considerable and Safe Decision to Avoid Prosthetic Treatment. AB - Background: Tipped lower molar over edentulous space is very common in orthodontics practice when adults seek treatment. The segmented arch technique features a predictable force system that provides a controlled release of force that can produce light and continuous tooth movement. Case Description: A female adult patient, who lost a permanent lower first molar, needed correction of the position of her permanent first molar place. Instead of making space for rehabilitation, it was closed after second molar uprighting and a balanced interdigitation was created without prosthetics. The patient was successfully treated with segmented arch technique using root correction spring activated with geometry VI to promote uprighting of a tipped molar and Niti spring coil to promote space closure. Practical Implications: Segmented arch technique is known to provide predictable light and continuous forces, which is very much indicated in adult treatment. There are several things to consider when orthodontically treating adult patients. Their periodontal conditions might not be ideal, less bone apposition may occur, and side effects of orthodontic tooth movement are expected. Thus, a predictable and controlled orthodontic treatment is needed. PMID- 29114331 TI - Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines. AB - Phthalocyanines and subphthalocyanines are attracting attention as functional dyes that are applicable to organic solar cells, photodynamic therapy, organic electronic devices, and other applications. However, phthalocyanines are generally difficult to handle due to their strong ability to aggregate, so this property must be controlled for further applications of phthalocyanines. On the other hand, trifluoroethoxy-substituted phthalocyanines are known to suppress aggregation due to repulsion of the trifluoroethoxy group. Furthermore, the electronic characteristics of phthalocyanines are significantly changed by the strong electronegativity of fluorine. Therefore, it is expected that trifluoroethoxy-substituted phthalocyanines can be applied to new industrial fields. This review summarizes the synthesis and application of trifluoroethoxy substituted phthalocyanine and subphthalocyanine derivatives. PMID- 29114333 TI - Comparing the Quality of Life of Patients Requesting Dental Implants Before and After Implant. AB - Background and Objectives: Tooth loss is a serious life event that impairs two important functions, namely, eating and speaking, and has significant side effects on different aspects of quality of life. These effects are internalized by the individual. The present study aimed to compare the quality of life (QOL) of patients requesting dental implants before and after implant. Materials and Methods: This analytical cross-sectional study was conducted on patients referred to the Mashhad faculty of Dentistry and private clinics with dental implants in 2015. Patient Quality Of Life (QOL) was assessed using the Oral Impact on Daily Practice (OIDP) questionnaire. Data were analyzed using SPSS software. Results: In this study, the most common problems reported by patients were eating (78%), smiling, laughing, and embarrassment (53%) before surgery. The quality of life associated with eating; speaking clearly; clean teeth or dentures; light physical activities, such as working at home, going out to work or meeting others; smiling; laughing; showing teeth without discomfort and embarrassment; emotional conditions, such as becoming upset quicker than usual, enjoying communication with others (i.e., friends, relatives and neighbors); and job-related activities significantly increased after surgery, but QOL associated with the amount of sleep and resting did not improve. No significant association was noted between quality of life after implantation and place of residence, education and gender. Conclusion: In this study, implants had a favorable impact on a patient's quality of life. PMID- 29114334 TI - Anesthesia and Analgesia in the Patient with an Unstable Shoulder. AB - Introduction: The patient with an unstable shoulder represents a challenge for the anesthesiologist. Most patients will be young individuals in good health but both shoulder dislocation reduction, a procedure that is usually performed under specific analgesia in an urgent setting, and instability surgery anesthesia and postoperative management present certain peculiarities. Material and Methods: For the purpose of the article, 78 references including clinical trials and reviews were included. The review was organized considering the patient that presents an acute shoulder dislocation and the patient with chronic shoulder instability that requires surgery. In both cases the aspects like general or regional anesthesia, surgical positions and postoperative pain management were analyzed. Conclusion: The patient with an acutely dislocated shoulder is usually managed in the emergency room. Although reduction without analgesia is often performed in non medical settings, an appropriate level of analgesia will ease the reduction procedure avoiding further complications. Intravenous analgesia and sedation is considered the gold standard but requires appropriate monitorization and airway control. Intraarticular local analgesic injection is considered also a safe and effective procedure. General anesthesia or nerve blocks can also be considered. The surgical management of the patient with shoulder instability requires a proper anesthetic management. This should start with an exhaustive preoperative evaluation that should be focused in identifying potential respiratory problems that might be complicated by local nerve blocks. Intraoperative management can be challenging, especially for patients operated in beach chair position, for the relationship with problems related to cerebral hypoperfusion, a situation related to hypotension events directly linked to patient positioning. Different nerve blocks will help attaining excellent analgesia both during and after the surgical procedure. An interescalene nerve block should be considered the best technique, but in certain cases, other blocks can be considered. PMID- 29114335 TI - Imaging of the Unstable Shoulder. AB - Background: Unstable shoulder can occur in different clinical scenarios with a broad spectrum of symptoms and presentations: first-time (or recurrent) traumatic acute shoulder anterior dislocation or chronic anterior instability after repeated dislocations.Imaging in unstable shoulder is fundamental for choosing the right treatment preventing recurrence.The goal of imaging depends on clinical scenario and patient characteristics. Method: Careful selection and evaluation of the imaging procedures is therefore essential to identify, characterize and quantify the lesions. Proper imaging in unstable shoulder cases is critical to the choice of treatment to prevent recurrence, and to plan surgical intervention. Results: In acute setting, radiographs have to roughly detect and characterize the bone defects present. At about 7 days, it is recommended to perform a MR to demonstrate lesions to labrum and/or ligaments and bone defects: in acute setting, the MRA is not necessary, because of effusion and hemarthrosis that behave as the contrast medium.In recurrence, it is fundamental not only to detect lesions but characterize them for planning the treatment. The first study to do is the MRI (with a magnetic field of at least 1.5 Tesla), and if possible MRA, above all in younger patients. Then, on the basis of the pathologic findings as bipolar lesion or severity of bone defects, CT can be performed. PICO method on 2D or 3D CT is helpful if you need to study a glenoid bone loss, with the "en face view" of glenoid, while a 3D CT reconstruction with the humeral head "en face view" is the gold standard to assess an Hill-Sachs lesion. Conclusion: The clinical diagnoses of anterior shoulder instability can be different and acknowledgement of imaging findings is essential to guide the treatment choice.Imaging features are quite different in chronic than in acute scenario. This requires appropriate indications of many different imaging techniques. PMID- 29114336 TI - Physical Exam and Evaluation of the Unstable Shoulder. AB - Background: The clinical evaluation of the patient with shoulder instability can be challenging. The pathological spectrum ranges from the straightforward "recurrent anterior dislocation" patient to the overhead athlete with a painful shoulder but not clear instability episodes. Advances in shoulder arthroscopy and imaging have helped in understanding the anatomy and physiopathology of the symptoms. The aim of this general article is to summarize the main examination manoeuvres that could be included in an overall approach to a patient with a suspicion of instability. Material and Methods: In order to achieve the above mentioned objective, a thorough review of the literature has been performed. Data regarding sensibility and specificity of each test have been included as well as a detailed description of the indications to perform them. Also, the most frequent and recent variations of these diagnostic tests are included. Results: Laxity and instability should be considered separately. For anterior instability, a combination of apprehension, relocation and release tests provide great specificity. On the other hand, multidirectional or posterior instability can be difficult to diagnose especially when the main complain is pain. Conclusion: A detailed interview and clinical examination of the patient are mandatory in order to identify a shoulder instability problem. Range of motion of both shoulders, clicking of catching sensations as well as pain, should be considered together with dislocation and subluxation episodes. Specific instability and hyperlaxity tests should be also performed to obtain an accurate diagnosis. PMID- 29114337 TI - Arthroscopic Soft Tissue Procedures for Anterior Shoulder Instability. AB - Background: Arthroscopy has rapidly transformed the treatment of anterior shoulder instability over the past 30 years. Development of arthroscopic equipment has permitted the investigation and diagnosis of the unstable shoulder, and fixation methods have evolved to promote arthroscopy from an experimental procedure to one of first-line mainstream treatment. Methods: Key research papers were reviewed to identify the fundamental principles in patient diagnosis and appropriate selection for arthroscopic treatment. The evolution of arthroscopy is described in this article to facilitate the understanding of current treatment. Results: Accurate diagnosis of the shoulder instability subtype is essential prior to selection for surgery. Different surgical techniques are described to address different pathology within the glenohumeral joint related to instability and the appropriate method should be selected accordingly to optimise outcome. Conclusion: Anterior shoulder instability can be treated successfully using arthroscopic surgery, but the surgeon must treat each patient as an individual case and recognise the different subtypes of instability, the associated pathological lesions and the limitations of arthroscopy. The article concludes with a suggested algorithm for the treatment of anterior shoulder instability. PMID- 29114338 TI - Rationale of Cruciate Retaining Design in Rheumatoid Arthritis: A Review of Clinical Analysis and its Role in Rheumatoid Arthritis. AB - Background: Over the years, proponents of total knee designs (cruciate retaining and posterior stabilised) have conducted several long-term studies to claim the potential of these designs in several subsets of patients. Total knee arthroplasty (TKA) in patients with rheumatoid arthritis has also been one such domain where numerous studies were conducted in the past. A general perception among majority of arthroplasty surgeons is that, posterior stabilised (PS) is the implanted design of choice among patients with Rheumatoid arthritis (RA). However, with the available literature there is a significant disparity related to the selection of implants in patients with rheumatoid RA. In this review of literature, an attempt is made to identify the clinical performance and role of one such implant design, the cruciate retaining (CR) prosthesis in rheumatoid arthritis. Method: The review was conducted after a series of advanced search in the following medical databases; Pub med, Biomed central, Cochrane and Google scholar for articles related to long term follow up studies of cruciate retaining total knee arthroplasty in rheumatoid arthritis using the keywords cruciate retaining prosthesis, total knee arthroplasty, rheumatoid arthritis. Results: The available data demonstrate that the CR design is attributed with an excellent long term survivorship and functional outcome even in follow up studies up to twenty-five years. Conclusion: The advantages of using a CR design are long term survivorship, controlled femoral roll back and preservation of bone stock. Thus, the data gathered in this review lead to a consideration that the CR design is an implant design on par with PS design in patients with RA. PMID- 29114340 TI - From reflexivity to collectivity: Challenging the benevolence narrative in global health. PMID- 29114339 TI - Lateral Antebrachial Cutaneous Nerve as a Donor Source for Digital Nerve Grafting: A Concept Revisited. AB - Objective: The main objective of this study is to evaluate the availability of lateral antebrachial cutaneous nerve (LACN) autograft for acute or delayed repair of segmented digital nerve injuries. Patients and Methods: 13 digital nerve defects of 11 patients; treated with interposition of LACN graft that harvested from ipsilateral extremity were included in the study. Mean follow up period was 35, 7 months. The mean time from injury to grafting is 53, 3 days. The results of the mean 2PDT and SWMT values of injured /uninjured finger at the end of follow up period were evaluated with Paired T test. The correlation between the defect length and the difference of 2PDT, SWMT values between the uninjured and injured finger at the end of follow up period; were evaluated with Pearson - correlation analysis. Results: The mean value of our 2PDT and SWMT results are ~5,923, ~3, 52, respectively in which can be interpreted between the normal and diminished light touch. The defect length and difference percentage of SWMT values is positively and significantly correlated statistically. Mean length of interposed nerve grafts was 18.5 mm. The age of the patient and the mean values of 2PDT and SWMT with the difference % of 2PDT and % of SWMT are not statistically correlated. Conclusion: Based on results regarding sensory regaining at recipient side and negligible sensory deficit at harvesting side, we suggest that lateral antebrachial cutaneous nerve might be a valuable graft option for digital nerve defects. PMID- 29114341 TI - Tackling challenges of global health electives: Resident experiences of a structured and supervised medicine elective within an existing global health partnership. AB - Background: The Toronto-Addis Ababa Academic Collaboration in Emergency Medicine (TAAAC-EM) deploys teaching teams of Canadian EM faculty to Addis Ababa to deliver a longitudinal residency curriculum. Canadian trainees participate in these teams as a formally structured and supervised elective in global health (GH) and EM, which has been designed to enhance the strength of GH electives and address key challenges highlighted in the literature. Methods: The purpose of this qualitative study was to identify, describe, and evaluate strengths and weaknesses of this elective in relation to its purposeful structure. Residents who completed the elective were invited to participate in face-to-face interviews to discuss their experiences. Results: The findings show that the residents both chose this elective because of its purposefully designed features, and that these same features increased their enjoyment and the educational benefit of the elective. Supervised bedside teaching, relationships shared with Ethiopian residents, and the positive impact the experience had on their clinical practice in Canada were identified as the primary strengths. Conclusion: Purposeful and thoughtful design of global health electives can enhance the resident learning experience and mitigate challenges for trainees seeking global health training opportunities. PMID- 29114342 TI - Guyana's paediatric training program: a global health partnership for medical education. AB - Guyana is a low-middle income country on the northern coast of South America between Venezuela and Suriname. Guyana has relatively high child mortality and a notable gap in health care provision. As of 2011, there were no paediatricians in the public sector where approximately 90% of the population seek care. In response to this unmet need, Guyanese diaspora living in Canada, in partnership with Canadian paediatricians and the main teaching hospital, Georgetown Public Hospital Corporation (GPHC), developed a Master's program in paediatrics. The postgraduate program was designed with adapted training objectives from the Royal College of Physicians and Surgeons of Canada and the American Board of Paediatrics. Innovative strategies to overcome the lack of qualified paediatric faculty in Guyana included web-conferencing and a volunteer North American paediatric faculty presence at GPHC with a goal of 1-2 weeks every month. By November 2016, 10 graduates will have passed through a rigorous program of assessment including a two-day final examination with an objective structured clinical examination (OSCE) component. PMID- 29114343 TI - The Canada-Guyana medical education partnership: using videoconferencing to supplement post-graduate medical education among internal medicine trainees. AB - Background: A Guyana-based, internal medicine (IM) post-graduate medical education program was established in 2013. However, lack of formal teaching sessions are barriers to the program's success. Objective: To describe the partnership between the University of Calgary and the University of Guyana's internal medicine residency programs (IMRP). This partnership was created to support the Guyana's IM academic half-day and is characterized by mutually beneficial, resident-led videoconference teaching sessions. Methods: Calgary medical residents volunteered to create and present weekly teaching presentations to Guyanese residents via videoconference. Questionnaires were completed by Guyanese residents and provided to Calgary residents as feedback on their teaching and presentation skills. A similar survey was completed by Calgary residents. Lessons learned: Twenty-four videoconference teaching sessions were conducted over eight months with a total of 191 and 16 surveys completed by Guyana and Calgary residents, respectively. Over 92% of both Guyana and Calgary residents agreed that the sessions enhanced their learning and over 93% reported increased interest in becoming more involved in international collaborations. 88% of Calgary residents felt the sessions improved their teaching skills. Conclusion: The formation of a resident-led, videoconference teaching series is a mutually beneficial partnership for Canadian and Guyanese medical residents and fosters international collaboration in medical education. PMID- 29114344 TI - An examination of Eyal & Hurst's (2008) framework for promoting retention in resource-poor settings through locally-relevant training: A case study for the University of Guyana Surgical Training Program. AB - Background: Eyal and Hurst proposed that locally relevant medical education can offset the prevalence of physician "brain drain" in resource-poor regions of the world, and presented a framework of the ethical and pragmatic benefits and concerns posed by these initiatives. The present study explored the framework's utility through a case study of the University of Guyana Diploma in Surgery (UGDS) program. Methods: The framework's utility was evaluated using a case study design that included review and analysis of documents and semi-structured interviews with graduates, trainees, faculty members, and policy makers associated with the UGDS program. Data were analyzed from constructivist and interpretivist perspectives, and compared against the benefits and concerns described by Eyal and Hurst. Results: The framework is a useful template for capturing the breadth of experience of locally relevant training in the Guyanese setting. However, the results suggest that delineating the framework factors as either beneficial or concerning may constrict its applicability. The case study design also provided specific insights about the UGDS program, which indicate that the Program has promoted the retention of graduates and a sustainable culture of postgraduate medical education in Guyana. Conclusion: It is suggested that the framework be modified so as to represent the benefits and concerns of locally relevant training along a continuum of advantage. These approaches may help us understand retention within a resource-poor country, but also within particularly remote areas and public health care systems generally. PMID- 29114345 TI - Attitudes towards sub-domains of professionalism in medical education: defining social accountability in the globalizing world. AB - Background: Unmet health needs of populations around the world are a major contributor to lagging health outcomes globally. Medical professionals have a duty to address the health needs of their communities. In a globalizing world, the needs may seem limitless. Yet, most training involves immersion in one health system and its resources. How do practitioners reconcile this potentially limitless demand with their focused training and in understanding their duty to the populations they serve? Methods: A mixed-method design was used. We distributing a pre-validated survey examining all facets of professionalism to the Department of Family Medicine at the University of Ottawa. This was followed by interviewing a purposive sample of residents and faculty with different levels of interest in working with underserved populations, to examine attitudes towards social accountability. Results: Quantitative results did not replicate the factor structure of the pre-validated survey in our cohort. This and other gaps in individual responses were used to construct an interview guide. Interviews revealed differences between residents and faculty. Residents were likely to see social accountability as flowing from personal interest as opposed to a professional duty; and residents' sense of duty can be met through good care of individual patients under their sphere of care. Faculty were more likely to discuss facets of care that they could influence at the health system level nationally and beyond. Conclusion: More usable and succinct instruments are needed to capture individual attitudes on social accountability. Our results identify how new physicians in family medicine in Ottawa, Canada wish to apply learning in global health to local needs, responding to the call to "think global, act local." PMID- 29114346 TI - Enhanced skills in global health and health equity: Guidelines for curriculum development. AB - Introduction: Global health addresses health inequities in the care of underserved populations, both domestic and international. Given that health systems with a strong primary care foundation are the most equitable, effective and efficient, family medicine is uniquely positioned to engage in global health. However, there are no nationally recognized standards in Canada for postgraduate family medicine training in global health. Objective: To generate consensus on the essential components of a Global Health/Health Equity Enhanced Skills Program in family medicine. Methods: A panel comprised of 34 experts in global health education and practice completed three rounds of a Delphi small group process. Results: Consensus (defined as >= 75% agreement) was achieved on program length (12 months), inclusion of both domestic and international components, importance of mentorship, methods of learner assessment (in-training evaluation report, portfolio), four program objectives (advocacy, sustainability, social justice, and an inclusive view of global health), importance of core content, and six specific core topics (social determinants of health, principles and ethics of health equity/global health, cultural humility and competency, pre and post departure training, health systems, policy, and advocacy for change, and community engagement). Conclusion: Panellists agreed on a number of program components forming the initial foundation for an evidence-informed, competency based Global Health/Health Equity Enhanced Skills Program in family medicine. PMID- 29114348 TI - Enriching health-professional programs in global health: Development and implementation of an interdisciplinary and integrated approach. AB - Background: Globalization results in a rapidly diversifying population, increased inequities, and more complex health problems affecting populations. This forces medical schools to integrate global health (GH) into the training of health-care professionals from curriculum development to practical learning activities, here and abroad. Approach: The approach aims at enriching existing programs in GH competencies in an interdisciplinary context. The goal is to ensure that all health-science students develop a certain level of GH competency. The main actions are the mobilization of key stakeholders, the development of a competency framework (CF) to perform gap analysis, tool formalization, and monitoring and evaluation activities. Subsequent to scoping review and stakeholder consultations, ten principles are identified and used to guide the enrichment process. Results: Actual outputs cover a broad scope, from key decision-makers' support and endorsement to the formalization of tools and the consolidation and creation of activities such as service-learning activities, rotations among underserved populations, and training for international rotations. Conclusion: While this unique approach is proving to be a major challenge, the preliminary results are well worth the effort. The project's tangible impacts on health sciences teaching, the GH competence of graduates, and care delivery are topics of interest for future investigation. PMID- 29114347 TI - Examining critical factors affecting graduate retention from an emergency training program in Addis Ababa, Ethiopia: a qualitative study of stakeholder perspectives. AB - Background: In Ethiopia, improvement and innovation of the emergency care system is hindered by lack of specialist doctors trained in emergency medicine, underdeveloped emergency care infrastructure, and resource limitations. Our aim was to examine the critical factors affecting retention of graduates from the Addis Ababa University (AAU) post-graduate emergency medicine (EM) training program within the Ethiopian health care system. Methods: One post-graduate trainee and one program manager from the AAU and the University of Toronto (UT) partnership conducted qualitative interviews with current AAU EM residents and stakeholders in Ethiopian EM. Qualitative inductive thematic analysis was performed. Results: Resident and stakeholder participants identified critical factors in three domains: the individual condition, the occupational environment, and the national context. Within each domain, priority themes emerged from the responses, including the importance of career satisfaction over the career continuum (individual condition), the opportunity to be involved in the developing EM program and challenges associated with resource, economic, and employment constraints (occupational environment), and perceptions regarding the state of awareness of EM and the capacity for change at the societal level (national context). Conclusion: This work underscores the need to continue to address multiple systemic and cultural issues within the Ethiopian health care landscape in order to address EM graduate retention. It also highlights the potential success of a retention strategy focused on the career ambitions of keen EM doctors. PMID- 29114349 TI - Living the questions: reflections of a learner in global mental health. PMID- 29114350 TI - Indira's story. AB - Indira is an independent woman who does not live a traditional Nepali life. She rescues abandoned and abused young women from sexual exploitation and provides them with love, support, and education. Her story highlights the key role of the social determinants of health in caring for marginalized populations. Challenges and benefits of attempting to learn from another's personal narrative are also considered. PMID- 29114351 TI - The personal calculus of moral reasoning and identity in global health professions work. AB - In this personal essay, the author reflects on experiences in global health professions education projects, and the moral reasoning that might be required to define explicitly what constitutes ethical participation. Three interrelated notions are explored: The decision to engage or not through a discussion of the concepts of safety, understanding power dynamics, and analysis of personal and institutional motivations for the projectThe ultimate goals to promote human flourishing and improve equity, through attention to local inequities potentially experienced by either participants or colleagues from home.Attention to the personal transformative potential of participation in global health professions projects. A framework for exploring moral reasoning in global health professions education work using these three concepts is presented as one that the author has found helpful in his own work in global health professions education. PMID- 29114352 TI - Bone Allograft: An Option for Total Mandibular Reconstruction. AB - Total mandibular reconstruction is one of the most challenging modalities in maxillofacial surgery. In this article, we try to introduce a method of total mandible reconstruction. We report a 25-year-old male patient with complete involvement of the mandible by Langerhans cell tumor. The patient underwent total mandibulectomy and reconstruction with bone allograft harvested from a donor who had died the day before. The patient has good functional and aesthetic results in a long time. It seems that bone allograft can be a good alternative to other methods in total mandibular reconstruction. PMID- 29114353 TI - A chromosomal analysis of Nepa cinerea Linnaeus, 1758 and Ranatra linearis (Linnaeus, 1758) (Heteroptera, Nepidae). AB - An account is given of the karyotypes and male meiosis of the Water Scorpion Nepa cinerea Linnaeus, 1758 and the Water Stick Insect Ranatra linearis (Linnaeus, 1758) (Heteroptera, Nepomorpha, Nepidae). A number of different approaches and techniques were tried: the employment of both male and female gonads and mid-guts as the sources of chromosomes, squash and air-drying methods for chromosome preparations, C-banding and fluorescence in situ hybridization (FISH) for chromosome study. We found that N. cinerea had a karyotype comprising 14 pairs of autosomes and a multiple sex chromosome system, which is X1X2X3X4Y (?) / X1X1X2X2X3X3X4X4 (?), whereas R. linearis had a karyotype comprising 19 pairs of autosomes and a multiple sex chromosome system X1X2X3X4Y (?) / X1X1X2X2X3X3X4X4 (?). In both N. cinerea and R. linearis, the autosomes formed chiasmate bivalents in spermatogenesis, and the sex chromosome univalents divided during the first meiotic division and segregated during the second one suggesting thus a post reductional type of behaviour. These results confirm and amplify those of Steopoe (1925, 1927, 1931, 1932) but are inconsistent with those of other researchers. C banding appeared helpful in pairing up the autosomes for karyotype assembly; however in R. linearis the chromosomes were much more uniform in size and general appearance than in N. cinerea. FISH for 18S ribosomal DNA (major rDNA) revealed hybridization signals on two of the five sex chromosomes in N. cinerea. In R. linearis, rDNA location was less obvious than in N. cinerea; however it is suggested to be similar. We have detected the presence of the canonical "insect" (TTAGG) n telomeric repeat in chromosomes of these species. This is the first application of C-banding and FISH in the family Nepidae. PMID- 29114354 TI - Cytogeography of Callisia section Cuthbertia (Commelinaceae). AB - Determining the distribution of cytotypes across the geographic distribution of polyploid complexes can provide valuable information about the evolution of biodiversity. Here, the phytogeography of cytotypes in section Cuthbertia (Small, 1903) Hunt, 1986 is investigated. A total of 436 voucher specimens was georeferenced; 133 new specimens were collected. Based on flow cytometry data, DNA content of all cytotypes in section Cuthbertia was estimated. Utilizing chromosome counts and flow cytometric analysis, cytotype distribution maps were generated. Two disjunct groups of populations of diploid Callisia graminea (Small, 1903) Tucker, 1989 were discovered; tetraploid C. graminea ranges broadly from the coastal plain of North Carolina through central Florida. One hexaploid C. graminea individual was recorded in South Carolina, and numerous individuals of hexaploid C. graminea were found in central Florida. Diploid C. ornata (Small, 1933) Tucker, 1989 occurs in eastern Florida; previously unknown tetraploid and hexaploid populations of C. ornata were discovered in western and central Florida, respectively. Diploid C. rosea (Ventenat, 1800) Hunt, 1986 occurs in Georgia and the Carolinas, with populations occurring on both sides of the Fall Line. The cytotype and species distributions in Callisia are complex, and these results provide hypotheses, to be tested with morphological and molecular data, about the origins of the polyploid cytotypes. PMID- 29114355 TI - Molecular cytogenetic characterization and comparison of the two cultivated Canavalia species (Fabaceae). AB - The two cultivated Canavalia (Adanson, 1763) species, Canavalia gladiata (N. J. von Jacquin, 1788) A. P. de Candolle, 1825 and Canavalia ensiformis (Linnaeus, 1753) A. P. de Candolle, 1825 are closely related based on morphological and molecular phylogenetic data. However, the similarities and differences in genome organization between them have not been evaluated at molecular cytogenetic level. Here, detailed karyotypes of both species were constructed using combined PI and DAPI (CPD) staining, rDNA-FISH and self-genomic in situ hybridization (sGISH). For further comparison, comparative genomic in situ hybridization (cGISH) and sequence analysis of 5S rDNA were applied. Their chromosomes were accurately identified by sGISH and rDNA-FISH signals. Both species had the karyotype formula 2n = 22 = 18m + 4m-SAT, but the karyotype of C. ensiformis was shorter and more asymmetric than that of C. gladiata. They displayed similar CPD bands at all 45S rDNA sites and centromeres. C. gladiata had ten centromeric 5S rDNA loci and two SC (secondary constriction)-associated 45S rDNA loci. C. ensiformis had nine centromeric and one interstitial 5S loci, two SC-associated and one proximal 45S loci. Their sGISH signal patterns displayed both basic similarities and distinct differences. Reciprocal cGISH generated prominent signals in all pericentromeric regions and 45S sites. There was lower level of sequence identity of the non transcribed spacer between their 5S rDNA repeats. These data confirmed the evolutionary closeness between C. gladiata and C. ensiformis and demonstrated obvious differentiation between their genomes, and supported the opinion that C. ensiformis is more advanced in evolution than C. gladiata. PMID- 29114356 TI - Comparative analysis of chromosomal localization of ribosomal and telomeric DNA markers in three species of Pyrgomorphidae grasshoppers. AB - The karyotypes of three species of Pyrgomorphidae grasshoppers were studied: Zonocerus elegans (Thunberg, 1815), Pyrgomorpha guentheri (Burr, 1899) and Atractomorpha lata (Mochulsky, 1866). Data on karyotypes of P. guentheri and Z. elegans are reported here for the first time. All species have karyotypes consisting of 19 acrocentric chromosomes in males and 20 acrocentric chromosomes in females (2n?=19, NF=19; 2n?=20, NF=20) and X0/XX sex determination system. A comparative analysis of the localization of C-heterochromatin, clusters of ribosomal DNA, and telomere repeats revealed inter-species diversity in these cytogenetic markers. These differences indicate that the karyotype divergence in the species studied is not associated with structural chromosome rearrangements, but with the evolution of repeated DNA sequences. PMID- 29114357 TI - Heterochromatin variation and LINE-1 distribution in Artibeus (Chiroptera, Phyllostomidae) from Central Amazon, Brazil. AB - Species in the subgenus Artibeus Leach, 1821 are widely distributed in Brazil. Conserved karyotypes characterize the group with identical diploid number and chromosome morphology. Recent studies suggested that the heterochromatin distribution and accumulation patterns can vary among species. In order to assess whether variation can also occur within species, we have analyzed the chromosomal distribution of constitutive heterochromatin in A. planirostris (Spix, 1823) and A. lituratus (Olfers, 1818) from Central Amazon (North Brazil) and contrasted our findings with those reported for other localities in Brazil. In addition, Ag-NOR staining and FISH with 18S rDNA, telomeric, and LINE-1 probes were performed to assess the potential role that these different repetitive markers had in shaping the current architecture of heterochromatic regions. Both species presented interindividual variation of constitutive heterochromatin. In addition, in A. planirostris the centromeres of most chromosomes are enriched with LINE-1, colocated with pericentromeric heterochromatin blocks. Overall, our data indicate that amplification and differential distribution of the investigated repetitive DNAs might have played a significant role in shaping the chromosome architecture of the subgenus Artibeus. PMID- 29114358 TI - Cytogenetic analysis of five Ctenidae species (Araneae): detection of heterochromatin and 18S rDNA sites. AB - The present study aimed to cytogenetically analyse five Ctenidae species Ctenus ornatus (Keyserling, 1877), Ctenus medius (Keyserling, 1891), Phoneutria nigriventer (Keyserling, 1891), Viracucha andicola (Simon, 1906), and Enoploctenus cyclothorax (Philip Bertkau, 1880), from Brazil. All species presented a 2n? = 28 except for V. andicola, which showed 2n? = 29. Analysis of segregation and behavior of sex chromosomes during male meiosis showed a sex chromosome system of the type X1X20 in species with 28 chromosomes and X1X2X30 in V. andicola. C banding stained with fluorochromes CMA3 and DAPI revealed two distributions patterns of GC-rich heterochromatin: (i) in terminal regions of most chromosomes, as presented in C. medius, P. nigriventer, E. cyclothorax and V. andicola and (ii) in interstitial regions of most chromosomes, in addition to terminal regions, as observed for C. ornatus. The population of Ubatuba (Sao Paulo State) of this same species displayed an additional accumulation of GC-rich heterochromatin in one bivalent. Fluorescent in situ hybridization revealed that this bivalent corresponded to the NOR-bearing chromosome pair. All analyzed species have one bivalent with 18S rDNA site, except P. nigriventer, which has three bivalents with 18S rDNA site. Karyotypes of two species, C. medius and E. cyclothorax, are described for the first time. The latter species is the first karyotyped representative of the subfamily Acantheinae. Finally, 18S rDNA probe is used for the first time in Ctenidae at the present study. PMID- 29114359 TI - Contribution to the cytogenetics of Kuwaniini scale insects (Homoptera, Coccinea, Margarodidae s.l.). AB - Jansenus burgeri Foldi, 1997 (Margarodidae s.l., Xylococcinae, Kuwaniini) was studied cytogenetically for the first time. It was shown that the species reproduces bisexually, displays XX/X(0) sex chromosome system and 2n=6/5 (female/male) including two pairs of long autosomes and a pair of shorter X chromosomes in female. The chromosome complement, adult female morphology and the life cycle of J. burgeri are illustrated. The cytogenetic data are in fact the first ones for Kuwaniini scale insects, because Kuwania oligostigma De Lotto, 1959 briefly cytogenetically studied by Hughes-Schrader (1963), in my opinion, may be excluded from the genus Kuwania Cockerell, 1903 and the tribe Kuwaniini, since this species shows aberrant morphological characters, specifically the total absence of abdominal spiracles and the presence of tubular ducts. PMID- 29114360 TI - Contributions to the cytogenetics of the Neotropical fish fauna. AB - Brazilian fish cytogenetics started as early as the seventies in three pioneering research groups, located at the Universidade Estadual Paulista (UNESP, Botucatu, SP), Universidade Federal de Sao Carlos (UFSCar, Sao Carlos, SP) and Universidade de Sao Paulo (USP, Sao Paulo, SP). Investigations that have been conducted in these groups led to the discovery of a huge chromosomal and genomic biodiversity among Neotropical fishes. Besides, they also provided the expansion of this research area, with the genesis of several other South American research groups, in view of a number of dissertations and doctoral theses developed over years. The current authors were encouraged to make their thesis catalog accessible from a public source, in order to share informations on the taxa and subject matter analyzed. Some of the key contributions to evolutionary fish cytogenetics are also being highligthed. PMID- 29114361 TI - Meiotic behaviour and its implication on species inter-relationship in the genus Curcuma (Linnaeus, 1753) (Zingiberaceae). AB - In this paper, detailed meiotic analysis was investigated in seven species of Curcuma (Linnaeus, 1753) which can contribute significantly to our understanding about species inter-relationship, speciation and evolution. The species were divided into two groups viz., Group I having 2n = 42 (C. comosa Roxburgh, 1810, C. haritha Mangaly & M.Sabu, 1993, C. mangga Valeton & Zijp, 1917, and C. motana Roxburgh, 1800) and Group II with 2n = 63 (C. caesia Roxburgh, 1810, C. longa Linnaeus, 1753 and C. sylvatica Valeton, 1918). Both groups display varying degree of chromosome associations. Group I species showed the prevalence of bivalents, however occasional quadrivalents besides univalents were also encountered. About 48% of the PMCs analyzed in C. mangga showed 21 bivalents (II) meiotic configurations, 32% in C. comosa and 16% in C. haritha. Group II species as expected showed the presence of trivalents besides bivalents, univalents and quadrivalents. About 32% of the PMCs analyzed at MI in C. sylvatica showed 21 trivalents (III) meiotic configurations, 24% in C. longa and 8% in C. caesia. Overall, low frequency of multivalent associations as compared to bivalents indicates that Curcuma is an allopolyploid complex. Moreover, x = 21 is too high a basic number, therefore, we suggest that the genus Curcuma has evolved by hybridization of species with different chromosome numbers of 2n = 24 and 18, resulting in a dibasic amphidiploid species. PMID- 29114362 TI - Comparative cytogenetics of some marsupial species (Didelphimorphia, Didelphidae) from the Amazon basin. AB - We investigated the karyotype of 18 didelphid species captured at 13 localities in the Brazilian Amazon, after conventional staining, C-banding, Ag-NOR and fluorescent in situ hybridization (FISH) using the 18S rDNA probe. Variations were found in the X chromosome, heterochromatin distribution and the 18S rDNA sequence. The main variation observed was in the position of the centromere in the X chromosome of Caluromys philander Linnaeus, 1758 and Marmosa murina Linnaeus, 1758. For both species, the X chromosome showed a geographical segregation in the pattern of variation between eastern and western Brazil, with a possible contact area in the central Amazon. C-banding on the X chromosome revealed two patterns for the species of Marmosops Matschie, 1916, apparently without geographic or specific relationships. The nucleolus organizer region (NOR) of all species was confirmed with the 18S rDNA probe, except on the Y chromosome of Monodelphis touan Shaw, 1800. The distribution of this marker varied only in the genus Marmosa Gray, 1821 [M. murina Thomas, 1905 and M. demerarae Thomas, 1905]. Considering that simple NORs are seen as a plesiomorphic character, we conclude that the species Marmosa spp. and Didelphis marsupialis Linnaeus, 1758 evolved independently to the multiple condition. By increasing the sample, using chromosomal banding, and FISH, we verified that marsupials present intra- and interspecific chromosomal variations, which suggests the occurrence of frequent chromosomal rearrangements in the evolution of this group. This observation contrasts with the chromosomal conservatism expected for didelphids. PMID- 29114363 TI - Dual mechanism of chromatin remodeling in the common shrew sex trivalent (XY 1Y 2). AB - Here we focus on the XY1Y2 condition in male common shrew Sorex araneus Linnaeus, 1758, applying electron microscopy and immunocytochemistry for a comprehensive analysis of structure, synapsis and behaviour of the sex trivalent in pachytene spermatocytes. The pachytene sex trivalent consists of three distinct parts: short and long synaptic SC fragments (between the X and Y1 and between the X and Y2, respectively) and a long asynaptic region of the X in-between. Chromatin inactivation was revealed in the XY1 synaptic region, the asynaptic region of the X and a very small asynaptic part of the Y2. This inactive part of the sex trivalent, that we named the 'head', forms a typical sex body and is located at the periphery of the meiotic nucleus at mid pachytene. The second part or 'tail', a long region of synapsis between the X and Y2 chromosomes, is directed from the periphery into the nucleus. Based on the distribution patterns of four proteins involved in chromatin inactivation, we propose a model of meiotic silencing in shrew sex chromosomes. Thus, we conclude that pachytene sex chromosomes are structurally and functionally two different chromatin domains with specific nuclear topology: the peripheral inactivated 'true' sex chromosome regions (part of the X and the Y1) and more centrally located transcriptionally active autosomal segments (part of the X and the Y2). PMID- 29114364 TI - Outcome of subthalamic nucleus deep brain stimulation on long-term motor function of patients with advanced Parkinson disease. AB - Background: The objective of our study was to assess Unified Parkinson Disease Rating Scale (UPDRS) score in Parkinson disease (PD) patients who underwent subthalamic nucleus (STN) deep brain stimulation (DBS) 6 years after their surgery and to compare their UPDRS score 6 years after DBS with their score before surgery and 6 months after their operation. Methods: In this cross sectional study which was carried out at Neurology Department of Rasool-e Akram Hospital, Tehran, Iran, affiliated to Iran University of Medical Sciences between 2008 and 2014, 37 patients with advanced PD were enrolled using non-randomized sampling method. All of the patients underwent STN DBS surgery and one patient died before being discharged, therefore; we started our study with 36 patients. The UPDRS III total score at preoperative state, 6-month follow-up and 6-year follow-up state were compared using repeated-measure analysis of variance. Results: Thirty-seven patients (26 men and 10 women) with mean age of 50 +/- 3 ranging from 32 to 72 years underwent STN DBS surgery. All patients were suffering from advanced PD with mean period of 11.3 +/- 1.9 years. All patients except one were followed up for six months. And 14 patients (8 men and 6 women) were included in a six-year follow-up. The UPDRS score measurements before surgery, at 6-month follow-up and 6-year follow-up were 18.22 +/- 2.88, 12.80 +/- 3.14, 25.0 +/- 11.8, respectively. Significant increase in UPDRS score was observed between the preoperative and six-year follow-up period (P < 0.001). Conclusion: In conclusion, this study suggests that total UPDRS score will increase at 5 years following STN DBS and also showed that resting tremor, one of UPDRS sub-scores, will improve over time and the benefit of DBS will be persistent even after 6 years. PMID- 29114365 TI - Stroke subtypes, risk factors and mortality rate in northwest of Iran. AB - Background: Stroke is the second most common cause of death and first cause of disability in adults in the world. About 80% of all stroke deaths occur in developing countries. So far, the data on stroke epidemiology have been limited in Iran. Therefore, this study was focused on stroke demographic data, risk factors, types and mortality. Methods: A retrospective study was done in two university tertiary referral hospitals in Tabriz, northwest of Iran, from March 2008 to April 2013. Patients diagnosed with stroke were enrolled in the study. Demographic data, stroke subtypes, duration of hospitalization, stroke risk factors and hospital mortality rate were recorded for all the patients. Results: A total number of 5355 patients were evaluated in the present study. Mean age of the patients was 67.5 +/- 13.8 years, and 50.6% were men. Final diagnosis of ischemic stroke was made in 76.5% of the patients, intra-cerebral hemorrhage (ICH) with or without intra-ventricular hemorrhage (IVH) in 14.3% and subarachnoid hemorrhage (SAH) in 9.2%. Stroke risk factors among the patients were hypertension in 68.8% of the patients, diabetes mellitus (DM) in 23.9%, smoking in 12.6% and ischemic heart diseases (IHD) in 17.1%. Mean hospital stay was 17.3 days. Overall, the in-hospital mortality was 20.5%. Conclusion: Compared to other studies, duration of hospital stay was longer and mortality rate was higher in this study. Hypertension was the most common risk factor and cardiac risk factors and DM had relatively lower rate in comparison to other studies. Because of insufficient data on the epidemiology, patterns, and risk factors of stroke in Iran, there is a necessity to develop and implement a national registry system. PMID- 29114366 TI - Evaluation of non-motor symptoms and their impact on quality of life in patients with Parkinson's disease, Isfahan, Iran. AB - Background: Parkinson's disease (PD) is diagnosed on the basis of motor symptoms, but non-motor symptoms (NMS) have high prevalence in PD and often antecede motor symptoms for years and cause severe disability. This study was conducted to determine the prevalence of NMS in patients with PD. Methods: This cross sectional study was performed in Isfahan, Iran, on patients with PD. The prevalence of NMS was evaluated by the NMS questionnaire, the NMS scale, and Parkinson's disease questionnaire-39 (PDQ-39). The Mini-Mental Status Examination (MMSE) was used for assessing cognition. Results: A total of 81 patients, including 60 men and 21 women, were recruited for this study. The prevalence of NMS was 100%, and the most commonly reported symptom was fatigue (87.7%); there was a strong correlation between NMS and the quality of life (QOL) of patients with PD (P < 0.001). Conclusion: This study showed that NMS are highly prevalent in the PD population and adversely affect QOL in these patients. Early diagnosis and treatment can improve QOL and can help in disability management of patients with PD. PMID- 29114367 TI - The comparison of anti-seizure and tocolytic effects of phenytoin and magnesium sulphate in the treatment of eclampsia and preeclampsia: A randomised clinical trial. AB - Background: To date, magnesium sulphate (MgSO4) is the treatment of choice for prevention of seizure in eclampsia and preeclampsia. However, there are some limitations in the administration of MgSO4 due to its tocolytic effects. The aim of this study was to compare the anticonvulsant and tocolytic effects of MgSO4 and another drug, phenytoin, in patients with eclampsia and preeclampsia. Methods: This clinical trial was conducted on pregnant women hospitalised with eclampsia or preeclampsia, during 2014-2016. The subjects were randomly assigned to two treatment groups using blocking method based on disease (eclampsia or mild and severe preeclampsia). One group received MgSO4 (group M) and another group received phenytoin (group P) as treatment. Each group consisted of 110 and 65 women with mild and severe preeclampsia, respectively (subgroup A), and 25 women with eclampsia (subgroup B). Duration of labor, the number of cesarean sections, convulsions and Apgar scores of infants were compared between the two groups and were considered as treatment outcomes. Results: Convulsion rate was significantly lower with MgSO4 than phenytoin (P = 0.001). No seizure occurred in patients with mild preeclampsia in group P. Duration of stage one of labor (P < 0.001) and the number of cesarean sections (P = 0.040) were significantly higher in group M. However, one-minute Apgar scores for newborns were higher in women treated with MgSO4 compared to that of phenytoin (P = 0.001). Five-minute Apgar was not significantly different. Conclusion: Although MgSO4 is more effective than phenytoin for prevention of convulsion in eclampsia and severe preeclampsia, phenytoin may be considered for treatment of special conditions such as mild preeclampsia. Due to the tocolytic effects of MgSO4 on increasing the duration of labor, the increased risk of cesarean section and the potential for toxicity, physicians should critically consider the best drug according to the condition of the patient. PMID- 29114368 TI - Recurrent isolated optic neuritis: A study on 22 patients. AB - Background: Isolated relapsing optic neuropathy is a recurrent painful optic nerve inflammation without any sign of other demyelinating diseases such as multiple sclerosis (MS) or neuromyelitis optica (NMO) spectrum disorders, and the attacks are purely responsive to steroid therapy. Methods: Recurrent isolated optic neuritis (RION) was diagnosed in patients who presented with at least two disseminating episodes of optic neuritis, and negative clinical, para-clinical, and radiological features of the demyelinating, infiltrative and vasculitis disorders involving optic nerve. The patients were assigned into two groups, chronic recurrent isolated optic neuritis (CRION) entailing patients with steroid dependent attack of optic neuritis and RION patients without steroid dependent attack of optic neuritis. They were monitored over a median of 4.0 +/- 2.5 years. Results: There were 16 women and six men with CRION and RION; with the median age of 31.7 +/- 9.8 (29.3 +/- 9.7 for women and 37.7 +/- 7.7 for men). The women to men ratio was 2.6:1. The mean optic neuritis attack was 2.95 +/- 1.32 in total. Eight patients were RION while 14 patients fulfilled CRION criteria and took long term immuno-suppressive drugs. In their follow-up, 4 out of 14 CRION cases (28.5%) showed clinical and concordant para-clinical features of NMO spectrum disorder. The analysis of demographic data showed that the average number of ON attacks in CRION patients (3.79 +/- 2.32) was significantly more than the average in patients with RION (2.25 +/- 0.46, P = 0.02). Conclusion: CRION is a disease which requires aggressive glucocorticoid and long-term immunosuppressive therapy to restore visual acuity. PMID- 29114369 TI - Bimelic symmetric Hirayama disease: Spectrum of magnetic resonance imaging findings and comparative evaluation with classical monomelic amyotrophy and other motor neuron disease. AB - Background: The aim of the study was to evaluate the magnetic resonance imaging (MRI) findings in bilateral symmetrical Hirayama disease and find out MRI features which are probably more indicative of symmetrical Hirayama disease, thereby help in differentiating this entity from other motor neuron disease (MND). Methods: This prospective as well as retrospective study was carried out from December 2010 to September 2016 in a tertiary care center of northeast India on 92 patients with Hirayama disease. Only 19 patients having bilateral symmetric upper limb involvement at the time of presentation were included in this study sample. Results: Nineteen patients, who constituted 20.6% of 92 patients of clinical and flexion MRI confirmed Hirayama disease were found to have bilateral symmetrical wasting and weakness of distal upper limb muscles at the time of presentation. Mean +/- standard deviation (SD) age of onset of the disease process was 21.7 +/- 3.8 years with mean +/- SD duration of illness of 3.6 +/- 1.3 years. MRI revealed lower cervical cord flattening in 13 (68.4%) patients which was symmetrical in 6 (31.6%) patients and asymmetrical in 7 (36.8%) patients. In the majority of these patients, T2-weighted images (T2WI) cervical cord hyperintensities were found extending from C5 to C6 vertebral level. Seven (36.8%) patients in our study showed bilateral symmetric T2WI hyperintensities in anterior horn cells (AHC). Conclusion: Bilateral symmetrical involvement of Hirayama disease is an uncommon presentation. Symmetrical cervical cord flattening, T2WI cord and/or bilateral AHC hyperintensities were the major MRI findings detected. Flexion MRI demonstrated similar findings in both bimelic amyotrophy and classical unilateral amyotrophy. However, flexion MRI produced some distinguishing features more typical for bilateral symmetrical Hirayama disease which help to differentiate it from other MNDs. PMID- 29114371 TI - Sarcoidosis limbic encephalitis: A case report. PMID- 29114370 TI - Taming Alzheimer's disease: New perspectives, newer horizons. AB - Alzheimer's disease (AD) is the leading cause of dementia. However, current therapies do not prevent progression of the disease. New research into the pathogenesis of the disease has brought about a greater understanding of the "amyloid cascade" and associated receptor abnormalities, the role of genetic factors, and revealed that the disease process commences 10 to 20 years prior to the appearance of clinical signs. This greater understanding of the disease has prompted development of novel disease-modifying therapies (DMTs) which may prevent onset or delay progression of the disease. Using genetic biomarkers like apolipoprotein E (ApoE) epsilon4, biochemical biomarkers like cerebrospinal fluid (CSF) amyloid and tau proteins, and imaging biomarkers like magnetic resonance imaging (MRI) and positron emission tomography (PET), it is now possible to detect preclinical AD and also monitor its progression in asymptomatic people. These biomarkers can be used in the selection of high-risk populations for clinical trials and also to monitor the efficacy and side-effects of DMT. To validate and standardize these biomarkers and select the most reliable, repeatable, easily available, cost-effective and complementary options is the challenge ahead. PMID- 29114372 TI - Churg-Straus syndrome: A case report. PMID- 29114373 TI - Coiled distal internal carotid artery (ICA) aneurysm in transcranial sonography. PMID- 29114375 TI - Base Transceiver Station Antennae Exposure and Human Health. PMID- 29114374 TI - Prevention of Chemotherapy-Induced Nephrotoxicity in Children with Cancer. AB - Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment in children are cisplatin (CPL), ifosfamide (IFO), carboplatin, and methotrexate (MTX). Mechanisms of anticancer drug-induced renal disorders are different and include acute kidney injury (AKI), tubulointerstitial disease, vascular damage, hemolytic uremic syndrome (HUS), and intrarenal obstruction. CPL nephrotoxicity is dose-related and is often demonstrated with hypomagnesemia, hypokalemia, and impaired renal function with rising serum creatinine and blood urea nitrogen levels. CPL, mitomycin C, and gemcitabine treatment cause vascular injury and HUS. High-dose IFO, streptozocin, and azacitidine cause renal tubular dysfunction manifested by Fanconi syndrome, rickets, and osteomalacia. AKI is a common adverse effect of MTX, interferon-alpha, and nitrosourea compound treatment. These strategies to reduce the cytotoxic drug-induced nephrotoxicity should include adequate hydration, forced diuresis, and urinary alkalization. Amifostine, sodium thiosulfate, and diethyldithiocarbamate provide protection against CPL-induced renal toxicity. PMID- 29114376 TI - Dihydroartemisinin Induces Apoptosis in Human Bladder Cancer Cell Lines Through Reactive Oxygen Species, Mitochondrial Membrane Potential, and Cytochrome C Pathway. AB - Background: Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin and has antiproliferative effect. However, such effects of DHA have not yet been revealed for bladder cancer cells. Methods: We used as bladder cancer cell lines to examine the effect of DHA on the cell viability, cell apoptosis, and monitoring of mitochondrial membrane potential (DeltaPsim) changes. Furthermore, the effect of DHA on the reactive oxygen species (ROS) production and cytochrome c release were also detected. We employed MTT assay to investigate the cell proliferation effect of DHA on the EJ-138 and HTB-9 human bladder cancer cells. Annexin/PI staining, caspase-3 activity assay, Bcl-2/Bax protein expression, mitochondrial membrane potential assay, cytochrome c release, and ROS analysis were used for apoptosis detection. Results: DHA significantly reduced cell viability in a dose-dependent manner. Cytotoxicity of DHA was suppressed by N acetylcysteine. The growth inhibition effect of DHA was related to the induction of cell apoptosis, which were manifested by annexin V-FITC staining, activation of caspase-3. DHA also increased ROS generation, cytochrome c release, and loss of mitochondrial transmembrane potential (DeltaPsim) in cells. In addition, the downregulation of regulatory protein Bcl-2 and upregulation of Bax protein by DHA were also observed. Conclusions: These findings demonstrated that DHA induces apoptosis through mitochondrial signaling pathway. These suggest that DHA may be a potential agent for induction of apoptosis in human bladder cancer cells. PMID- 29114377 TI - Nonalcoholic Fatty Liver Disease in a Sample of Iranian Women with Polycystic Ovary Syndrome. AB - Introduction: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women in reproductive age that is associated with insulin resistance (IR) and metabolic abnormalities which are also a part of metabolic syndrome (Met S). This study was aimed to determine the prevalence of nonalcoholic fatty liver disease (NAFLD) women diagnosed with PCOS based on the Rotterdam criteria from January 2013 to June 2014. Methods: In this cross-sectional study, 75 women with PCOS and 75 healthy controls were enrolled. Anthropometric parameters, biochemical and hormonal investigation, were measured in all women. IR was calculated by homeostasis model assessment. Abdominal ultrasonography and biochemical tests were used to determine the NAFLD. Results: The level of triglyceride, cholesterol, low-density lipoprotein, aspartate aminotransferase, alkalin phosphatase, fasting insulin, and homeostatic model assessment index in women with PCOS were significantly higher than women without PCOS. High-density lipoprotein and alanine aminotransferase (ALT) in women with PCOS were significantly lower. The frequency of IR women with or without PCOS was 53.3% and 29.3%, respectively (P = 0.003). The frequency of Met S in women with PCOS was 33.3% and in other was 10.7% (P = 0.001). The prevalence of fatty liver in women with or without PCOS was 38.7% and 18.7%, respectively (0.008). In women with PCOS, body mass index (BMI) (odds ratio [OR] = 4.25; P = 0.046), ALT (OR = 1.62; P = 0.005), fasting insulin (OR = 1.32; P = 0.032), and IR (OR = 58.17; P = 0.025) were associated with a higher fatty liver. Conclusions: NAFLD is frequent in patients with PCOS with combination with other metabolic derangements. BMI, ALT, fasting insulin, and IR are the risk factors for high prevalence of NAFLD in women with PCOS. PMID- 29114378 TI - Imminent Angiotensin-converting Enzyme Inhibitor from Microbial Source for Cancer Therapy. AB - Background: Drugs targeting Angiotensin I-converting enzyme (ACE) have been used broadly in cancer chemotherapy. The recent past coupled with our results demonstrates the effective use of ACE inhibitors (ACEi) as anticancer agents, and they are potentially relevant in deriving new inhibitors. Methods: Bacterial strains were isolated from cow milk collected in Coimbatore, Tamil Nadu, India and plated on nutrient agar medium. The identity of the strain was ascertained by 16s rRNA gene sequencing method and was submitted to the NCBI GenBank nucleotide database. Various substrates were screened for ACEi production by the fermentation with the isolated strain. ACEi was purified by sequential steps of ethanol precipitation, ion exchange column chromatography and gel filtration column chromatography. The apparent molecular mass was determined by SDS-PAGE. The anticancer property was analyzed by studying the cytotoxicity effects of ACEi using Breast cancer MCF-7 cell lines. Results: The isolate coded as BUCTL09 was selected and identified as Micrococcus luteus. Among the seven substrates, only beef extract fermented broth showed an inhibition of 79% and was reported as the best substrate. The peptide was purified and molecular mass was determined. The IC50 value of peptide was found to be 59.5 MUg/ml. The purified peptide has demonstrated to induce apoptosis of cancer cell. Conclusions: The results of this study revealed that Peptide has been determined as an active compound that inhibited the activity of ACE. These properties indicate the possibilities of the use of purified protein as a potent anticancer agent. PMID- 29114379 TI - Mosquito Net and Snakebite. PMID- 29114380 TI - Rubella Seromarkers among Children and Adolescent. PMID- 29114381 TI - Peruvian Scientific Production on Abortion in Scopus. PMID- 29114382 TI - The inhibitory effects of polysaccharide peptides (PsP) of Ganoderma lucidum against atherosclerosis in rats with dyslipidemia. AB - Background: Atherosclerosis occurs as a result of low-density lipoprotein (LDL) deposits oxidation. Endothelial dysfunction is an early process of atherosclerosis. Restoring endothelial lining back to normal by endothelial progenitor cells (EPCs) is critical for slowing or reversing vascular disease progression. Oxidative stress from hydrogen peroxide (H2O2) is increased in dyslipidemia so that antioxidant agent is required to prevent destruction of blood vessels. Objectives: This study aims to report Ganoderma lucidum polysaccharide peptide (PsP) effects in atherogenic process by measuring H2O2 level, IL-10 level, and EPC number in blood serum, and also intima-media thickness of aorta in dyslipidemia Wistar rat model by giving them a hypercholesterol diet (HCD). Materials and methods: The study was an experimental in vivo post-test with control group design. Thirty-five Wistar rats (Rattus norwegicus) were divided into five groups (normal diet group, HCD group, and hypercholesterol groups that received 50 mg/kg, 150 mg/kg, and 300 mg/kg bodyweight PsP). Results: Each treatment group showed significant results for the administration of PsP using the one-way analysis of variance test (p<0.050) for the reduction of H2O2 (p = 0.003), levels of IL-10 (p = 0.027), number of EPC in the blood serum (p = 0.011), and the intima-media thickness of the aorta (p = 0.000). PsP from G. lucidum is a potent antioxidant and may prevent atherogenesis process in patients with dyslipidemia. Conclusions: The optimum doses of PsP in this study is 300 mg/kg bodyweight. Further studies are required to determine the antioxidant effects of PsP G. lucidum and its benefits in the management of dyslipidemia. PMID- 29114383 TI - Placement Of Cardiac PacemaKEr Trial (POCKET) - rationale and design: a randomized controlled trial. AB - Background: A pacemaker system consists of one or two leads connected to a device that is implanted into a pocket formed just below the collarbone. This pocket is typically subcutaneous, that is, located just above the pectoral fascia. Even though the size of pacemakers has decreased markedly, complications due to superficial implants do occur. An alternative technique would be intramuscular placement of the pacemaker device, but there are no randomized controlled trials (RCTs) to support this approach, which is the rationale for the Placement Of Cardiac PacemaKEr Trial (POCKET). The aim is to study if intramuscular is superior to subcutaneous placement of a pacemaker pocket. Methods: In October 2016, we started to enroll 200 consecutive patients with an indication for bradycardia pacemaker implantation. Patients are randomized to random block sizes, stratified by age group (cut-off: 65 years) and sex, and then randomized to either subcutaneous or intramuscular implant. A concealed allocation procedure is employed, using sequentially numbered, sealed envelopes. Pocket site is blinded to the patient and in all subsequent care. The primary endpoint is patient overall satisfaction with the pocket location at 24 months as measured using a visual analog scale (VAS) 0-10. Secondary endpoints are: complications, patient-reported satisfaction at 1, 12, and 24 months (overall satisfaction, pain, discomfort, degree of unsightly appearance, movement problems, and sleep problems due to device). Conclusions: POCKET is a prospective interventional RCT designed to evaluate if intramuscular is superior to subcutaneous placement of a bradycardia pacemaker during a two-year follow-up. PMID- 29114384 TI - Treatment with insulin analogs and prevalence of cardiovascular complications in patients with type 1 diabetes. AB - Background: A lower incidence of cardiovascular events has been reported in type 2 diabetes patients treated with insulin analogs (IAs). Corresponding data on people affected by type 1 diabetes are not available yet. Methodology: We investigated demographic and clinical data from 509 type 1 diabetics, who were treated in an outpatient clinic from 2006 to 2012. Multiple logistic regression was used to investigate the relationship between the type of insulin treatment and the prevalence of cardiovascular (CV) complications, that is, presence of coronary heart, cerebrovascular and peripheral arterial diseases, adjusting for potential confounders. Results: Results from multiple logistic regression revealed that patients with impaired renal function [estimated glomerular filtration rate (eGFR) < 90 ml/min] show lower CV complication rates when treated with IAs (25%) compared with patients treated with human insulin (HI; 28%) and HI/IA (38%, p = 0.06). CV complication rates in the complete patient collective amounted to 17% (IA), 21% (HI) and 21% (HI/IA, p = 0.08). Examination of CV complications according to the type of IA revealed the lowest complication rates in type 1 diabetics treated with insulin lispro (5.9%) and glargine (16%). However, complication rate differences among insulin treatments did not reach statistical significance. Conclusion: The present cross-sectional study shows a borderline significantly lower CV morbidity in people with type 1 diabetes and impaired renal function when treated with IA compared with HI treatment after adjustment for multiple potential confounders [odds ratio (OR) = 0.78, which translates into a 22% lower complication rate]. Validation of these preliminary findings in confirmatory, prospective studies may have important clinical implications. PMID- 29034081 TI - Renal impairment in stroke patients: A comparison between the haemorrhagic and ischemic variants. AB - Background: Renal impairment is regularly seen in hospitalized stroke patients, affecting the outcome of patients, as well as causing difficulties in their management. A prospective cohort study was conducted to assess the trend of renal function in hospitalized ischemic and haemorrhagic stroke patients. The incidence of renal impairment in these subgroups, the contributing factors and the need for renal replacement in renal impaired patients was evaluated. Methods: Alternate day renal function testing was performed in hospitalized stroke patients. Estimated glomerular filtration rate (e-GFR) was calculated and the trend of renal function in the two stroke subgroups (haemorrhagic and ischemic) was assessed, with renal impairment defined as e-GFR < 60mL/ minute per 1.73m 2. Results: Among 52 patients, 25 had haemorrhagic stroke (mean age 59.81 +/- 14.67) and 27 had ischemic stroke (mean age 56.12 +/- 13.08). The mean e-GFR (mL/minute per 1.732m 2) at admission in the haemorrhagic stroke subgroup was 64.79 +/- 25.85 compared to 86.04 +/- 26.09 in the ischemic stroke subgroup (p=0.005). Sixteen out of 25 (64%) patients in the haemorrhagic stroke subgroup and 9 out of 27 (33.3%) patients in the ischemic subgroup developed renal impairment (p=0.027). The location of the bleed (p=0.8), volume of hematoma (p=0.966) and surgical intervention (p=0.4) did not predispose the patients to renal impairment. One out of 16 patients with haemorrhagic stroke (who eventually died), and 2 out of 9 patients with ischemic stroke required renal replacement. Conclusion: Renal impairment is commonly seen in stroke patients, more so in patients who suffered haemorrhagic strokes. The impairment, however, is transient and rarely requires renal replacement therapy. PMID- 29114387 TI - Repeat pneumococcal polysaccharide vaccination does not impair functional immune responses among Indigenous Australians. AB - Indigenous Australians experience one of the highest rates of pneumococcal disease globally. In the Northern Territory of Australia, a unique government funded vaccination schedule for Indigenous Australian adults comprising multiple lifetime doses of the pneumococcal polysaccharide vaccine is currently implemented. Despite this programme, rates of pneumococcal disease do not appear to be declining, with concerns raised over the potential for immune hyporesponse associated with the use of this vaccine. We undertook a study to examine the immunogenicity and immune function of a single and repeat pneumococcal polysaccharide vaccination among Indigenous adults compared to non-Indigenous adults. Our results found that immune function, as measured by opsonophagocytic and memory B-cell responses, were similar between the Indigenous groups but lower for some serotypes in comparison with the non-Indigenous group. This is the first study to document the immunogenicity following repeat 23-valent pneumococcal polysaccharide vaccine administration among Indigenous Australian adults, and reinforces the continued need for optimal pneumococcal vaccination programmes among high-risk populations. PMID- 29114386 TI - Suppression of inflammation and tissue damage by a hookworm recombinant protein in experimental colitis. AB - Gastrointestinal parasites, hookworms in particular, have evolved to cause minimal harm to their hosts when present in small numbers, allowing them to establish chronic infections for decades. They do so by creating an immunoregulatory environment that promotes their own survival, but paradoxically also benefits the host by protecting against the onset of many inflammatory diseases. To harness the therapeutic value of hookworms without using live parasites, we have examined the protective properties of the recombinant protein anti-inflammatory protein (AIP)-1, secreted in abundance by hookworms within the intestinal mucosa, in experimental colitis. Colitic inflammation assessed by weight loss, colon atrophy, oedema, ulceration and necrosis, as well as abdominal adhesion was significantly suppressed in mice treated with a single intraperitoneal dose of AIP-1 at 1 mg kg-1. Local infiltration of inflammatory cells was also significantly reduced, with minimal goblet cell loss and preserved mucosal architecture. Treatment with AIP-1 promoted the production of colon interleukin (IL)-10, transforming growth factor (TGF)-beta and thymic stromal lymphopoietin (TSLP), resulting in the suppression of tumour necrosis factor (TNF)-alpha, IL-13 and IL-17 A cytokines and granulocyte macrophage colony stimulating factor (GM-CSF), CX motif chemokine (CXCL)-11 and cyclooxygenase synthase (COX)-2 mRNA transcripts. AIP-1 promoted the accumulation of regulatory T cells in the colon likely allowing rapid healing of the colon mucosa. Hookworm recombinant AIP-1 is a novel therapeutic candidate for the treatment of inflammatory bowel diseases that can be explored for the prevention of acute inflammatory relapses, an important cause of colorectal cancer. PMID- 29114388 TI - Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus. AB - Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell independent signalling, while mutations of TCF3 impair both T-cell-dependent and independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband. PMID- 29114390 TI - Phospholipase D inhibition by hexanal is associated with calcium signal transduction events in raspberry. AB - Raspberry (Rubus spp.) is an economically important crop with a restricted growing season and very limited fruit shelf-life due to its extreme tenderness. In order to prolong its shelf life, an aqueous composition containing hexanal as the key active ingredient (HC) was applied as a preharvest spray during fruit development. The effects of HC were assessed using physiological, biochemical and anatomical parameters on the treated fruits and compared with the effects of mock inoculation which lacked hexanal. Sugars and acidity did not show a significant change in response to HC treatment, while the pulling force (the tension required to detach the berry from the receptacle) significantly improved in the HC-treated fruits, compared to control. Scanning electron microscope (SEM) analysis revealed a high correlation between the presence of rigid epidermal hairs and a stronger degree of attachment between berries and their receptacle in the HC treated fruits. Further, electron micrographs also showed abnormal crystalline depositions on the epidermal drupelets of the treated berries. Energy Dispersive X-ray Spectroscopy (EDS) analysis showed those crystals to be largely composed of calcium. HC treatment also resulted in the reduction of transcript level of three phospholipase D genes, as well as altered expression pattern of five members of the annexin gene family, and four calmodulin-binding transcription activators. Quantification of PLD activity showed that hexanal inhibited PLD activity in treated berries. The potential crosstalk between hexanal, phospholipase D activity and calcium and this crosstalk's role in delaying fruit softening and in prolonging storage life of fruits shelf life is discussed. PMID- 29114391 TI - Erratum: The bZIP transcription factor MdHY5 regulates anthocyanin accumulation and nitrate assimilation in apple. AB - [This corrects the article DOI: 10.1038/hortres.2017.23.]. PMID- 29114389 TI - Adoptive cell therapy with CD4+ T helper 1 cells and CD8+ cytotoxic T cells enhances complete rejection of an established tumour, leading to generation of endogenous memory responses to non-targeted tumour epitopes. AB - The results of adoptive T-cell therapies (ACTs) are very encouraging and show clinical evidence that ACT can provide a cure for patients with metastatic disease. However, various response rates and long-term cancer remission have been observed in different ACT trials. The types of T cells, prior treatment with chemotherapy and co-administration of other immune-target therapies have been found to influence the efficacy of ACT. In this study, we investigate the ability of ACT using CD4+ T helper 1 (Th1) cells and CD8+ cytotoxic T lymphocytes (CTLs) to reject the growth of established B16-ovalbumin (OVA) melanoma. CD8+ CTLs were found to be the main effector T cells that mediated tumour regression. However, low tumour-free survival rates were observed in ACT with CD8+ CTLs only. Co transferring CD4+ Th1 cells and CD8+ CTLs has been observed to induce a synergistic antitumour response, resulting in complete regression in 80% of the tumour-bearing mice. We also examined a prior Dacarbazine (DTIC) and after virus like particle (VLP)-OVA vaccine treatment to enhance ACT, but no therapeutic benefit was observed during primary B16-OVA tumour growth. Nevertheless, the ACT mediated antitumour response was able to generate memory responses to both B16 OVA and B16-gp33 tumours. VLP-OVA vaccination following ACT enhances the memory responses to tumours that express a heterogenic population of both B16-OVA and B16-gp33 cells; however, it abolished the memory response to tumours consisting of only gp33-expressing cells. These findings provide important information for designing therapeutic treatments for patients with metastatic disease and cancer relapse to achieve durable cancer remission. PMID- 29114392 TI - A common pathogen in an uncommon site: coronary artery stent meticillin-resistant Staphylococcus aureus infection. AB - Introduction. Coronary artery stents are an uncommon site for infection. Only a handful of case reports describe this condition, and Staphylococcus aureus is the most frequent pathogen. Although rare, coronary stent infections are associated with a high mortality rate. Case presentation. We describe the case of a 50-year old man with a past medical history of seven prior meticillin-resistant S. aureus (MRSA) infections over the previous 12 months, who presented with fever and was found to have persistent MRSA bacteraemia. During his hospital course, he developed chest pain and underwent coronary angiography, which revealed a left circumflex coronary to left atrium fistula, presumably due to endarteritis/sent infection. He was treated with combination parenteral antibiotics that were succeeded by oral suppressive therapy. Six months after his diagnosis of coronary stent infection, he suffered a fatal cardiac arrest. Conclusion. Coronary artery stents are an infrequent source of infection; when they occur, they are typically due to S. aureus, have a high mortality and ideally are treated with surgical intervention. PMID- 29114393 TI - Vibrio furnissii, an emerging pathogen causing acute gastroenteritis: a Case Report. AB - Introduction.Vibrio furnissii is a motile, Gram-negative, oxidase-positive, halophilic bacteria first defined in 1977. It is ubiquitously present in marine environments and is one of the 11 non-cholera Vibrio species pathogenic in humans, which can lead to human gastroenteritis and extra-intestinal manifestations. Case presentation. A 73-year-old female patient was admitted to the hospital with acute gastroenteritis after consumption of seafood, which later by microbiological investigations was confirmed as Vibrio furnissii, a member of the family Vibrionaceae. The patient was treated with oral doxycycline and ciprofloxacin. Conclusion.V. furnissii, an emerging pathogen known for quite some time as an aetiological agent responsible, for acute gastroenteritis cases yet to get more clinical attention. Descriptions of putative virulence factors of this pathogen are limited, and in-depth studies on the pathogenesis of V. furnissii need to be established. PMID- 29114394 TI - Staphylococcus caprae bacteraemia and native bone infection complicated by therapeutic failure and elevated MIC: a case report. AB - Introduction.Staphylococcus caprae is a coagulase-negative staphylococcus that has been reported in several cases as a human pathogen. However, it has rarely been reported as pathogen in native bone. Furthermore, the reported MIC levels noted in the literature for vancomycin were <2 ug ml-1making vancomycin a first line choice for infected patients. Case presentation. We report a case of Staphylococcus caprae causing osteomyelitis of the lumbar spine and bacteraemia and resulting in sepsis and ultimately the demise of a patient despite appropriate prolonged antibiotic therapy. Conclusion.Staphylococcus caprae has been reported as a human pathogen since 1983 when it was discovered. We report a case involving native bone infection which is rare in the absence of mechanical hardware. Furthermore, this strain had an elevated MIC for vancomycin which has not been reported in the literature. PMID- 29114395 TI - Gordonia sternal wound infection treated with ceftaroline: case report and literature review. AB - Introduction. Case reports have emerged with identification of Gordonia bronchialis infections including sternal wound infections and foreign bodies such as central lines and shunts. Case presentation. We present a case that demonstrates the need to consider Gordonia infection as a cause of sternal wound infection and highlights the utility of novel diagnostics to aid in the identification of unusual pathogens that can cause post-operative infections. We report here the first successful use of ceftaroline for treatment of a G. bronchialis sternal wound infection. Conclusion. There are only case reports and in vitro assays to date to guide treatment of this infection, and we now add ceftaroline as a new drug to consider, though adequate surgical debridement is paramount. PMID- 29114396 TI - Molecular evidence of Listeria monocytogenes infection relapse in a severe case of endocarditis. AB - Introduction. Endocarditis is a rare complication of bacteraemia due to Listeria monocytogenes and is characterized by a high fatality rate (37-50 %). Recurrent infection by Listeria monocytogenes occurs even more rarely. Case presentation. We report a case of recurrent Listeria monocytogenes infection that resulted in severe endocarditis in a 66-year-old patient with an aortic valve prosthesis. Relapse was confirmed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Conclusion. Our case highlights that the molecular subtyping approach is an important tool for the detection of microbial reinfections and for the support of clinical diagnosis. PMID- 29114397 TI - False-positive galactomannan assay in broncho-alveolar lavage after enteral nutrition solution inhalation: a case report. AB - Introduction. Diagnosis of invasive aspergillosis is challenging and the gold standard for definite diagnosis remains histopathological tissue examination. However, invasive procedures such as lung biopsy are often not feasible in critically ill patients. The detection of fungal cell wall components like Aspergillus galactomannan in broncho-alveolar lavage remains a key component of the diagnostic procedure. False-positive of the Aspergillus galactomannan assay is not frequent. Case presentation. We report a case of positive galactomannan in broncho-alveolar lavage fluid after enteral nutrition aspiration without signs of invasive aspergillosis. Galactomannan was positive in the enteral nutrition solution. Conclusion. Physicians should be aware of this previously unrecognized cause of false-positive galactomannan in broncho-alveolar fluid which can result in unnecessary treatments. PMID- 29114398 TI - Multi-system manifestations of Mycoplasma pneumoniae infection in a young patient. AB - Introduction.Mycoplasma pneumoniae is a small cell-wall-lacking bacterium that belongs to the mycoplasma (Mollicutes) prokaryote micro-organisms. It is a common cause of both upper and lower respiratory tract infections in all age groups. Respiratory illness is the most common manifestation of M. pneumoniae infection; however, extrapulmonary involvement may be present or predominant. The skin, mucus membranes, central nervous system, cardiovascular system, haematopoietic system, kidneys and musculoskeletal system are the most commonly involved extrapulmonary sites. Immune thrombocytopenia purpura has been reported as a rare haematological manifestation of mycoplasma infection. Here, we report, with a literature review, the case of a young adult with M. pneumoniae infection, presenting with acute febrile illness, myringitis, erythema multiforme, mild Raynaud's phenomenon symptoms and severe thrombocytopenia. Case presentation. Our patient was a 24-year-old healthy man who presented to an emergency department with acute febrile illness, upper respiratory tract infection symptoms, myringitis, erythema multiforme skin lesions, severe thrombocytopenia, and pale and cold hands. Mycoplasma serology suggested acute M. pneumoniae infection. The patient had a complete resolution of symptoms and gradual recovery from the thrombocytopenia after a course of anti-Mycoplasma therapy with azithromycin. Our case illustrates the multi-system involvement of M. pneumoniae infection. Conclusion.M. pneumoniae is a frequent cause of upper and lower respiratory tract infections in children and young adults. Multi-system involvement including the skin, vascular and haematological systems in young adults with upper or lower respiratory tract infection, as in our patient, should raise the suspicion of Mycoplasma infection. Our case also illustrates an excellent clinical response and recovery from thrombocytopenia shortly after anti-Mycoplasma antimicrobial therapy. PMID- 29114399 TI - Erratum: Author Correction: Identification of donor microbe species that colonize and persist long term in the recipient after fecal transplant for recurrent Clostridium difficile. AB - [This corrects the article DOI: 10.1038/s41522-017-0020-7.]. PMID- 29114400 TI - An untypeable enterotoxigenic Escherichia coli represents one of the dominant types causing human disease. AB - Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhoea in children below 5 years of age in endemic areas, and is a primary cause of diarrhoea in travellers visiting developing countries. Epidemiological analysis of E. coli pathovars is traditionally carried out based on the results of serotyping. However, genomic analysis of a global ETEC collection of 362 isolates taken from patients revealed nine novel O-antigen biosynthesis gene clusters that were previously unrecognized, and have collectively been called unclassified. When put in the context of all isolates sequenced, one of the novel O-genotypes, OgN5, was found to be the second most common ETEC O-genotype causing disease, after O6, in a globally representative ETEC collection. It's also clear that ETEC OgN5 isolates have spread globally. These novel O-genotypes have now been included in our comprehensive O-genotyping scheme, and can be detected using a PCR-based and an in silico typing method. This will assist in epidemiological studies, as well as in ETEC vaccine development. PMID- 29114401 TI - Aligner optimization increases accuracy and decreases compute times in multi species sequence data. AB - As sequencing technologies have evolved, the tools to analyze these sequences have made similar advances. However, for multi-species samples, we observed important and adverse differences in alignment specificity and computation time for bwa- mem (Burrows-Wheeler aligner-maximum exact matches) relative to bwa-aln. Therefore, we sought to optimize bwa-mem for alignment of data from multi-species samples in order to reduce alignment time and increase the specificity of alignments. In the multi-species cases examined, there was one majority member (i.e. Plasmodium falciparum or Brugia malayi) and one minority member (i.e. human or the Wolbachia endosymbiont wBm) of the sequence data. Increasing bwa-mem seed length from the default value reduced the number of read pairs from the majority sequence member that incorrectly aligned to the reference genome of the minority sequence member. Combining both source genomes into a single reference genome increased the specificity of mapping, while also reducing the central processing unit (CPU) time. In Plasmodium, at a seed length of 18 nt, 24.1 % of reads mapped to the human genome using 1.7+/-0.1 CPU hours, while 83.6 % of reads mapped to the Plasmodium genome using 0.2+/-0.0 CPU hours (total: 107.7 % reads mapping; in 1.9+/-0.1 CPU hours). In contrast, 97.1 % of the reads mapped to a combined Plasmodium-human reference in only 0.7+/-0.0 CPU hours. Overall, the results suggest that combining all references into a single reference database and using a 23 nt seed length reduces the computational time, while maximizing specificity. Similar results were found for simulated sequence reads from a mock metagenomic data set. We found similar improvements to computation time in a publicly available human-only data set. PMID- 29114402 TI - Comparative scaffolding and gap filling of ancient bacterial genomes applied to two ancient Yersinia pestis genomes. AB - Yersinia pestis is the causative agent of the bubonic plague, a disease responsible for several dramatic historical pandemics. Progress in ancient DNA (aDNA) sequencing rendered possible the sequencing of whole genomes of important human pathogens, including the ancient Y. pestis strains responsible for outbreaks of the bubonic plague in London in the 14th century and in Marseille in the 18th century, among others. However, aDNA sequencing data are still characterized by short reads and non-uniform coverage, so assembling ancient pathogen genomes remains challenging and often prevents a detailed study of genome rearrangements. It has recently been shown that comparative scaffolding approaches can improve the assembly of ancient Y. pestis genomes at a chromosome level. In the present work, we address the last step of genome assembly, the gap filling stage. We describe an optimization-based method AGapEs (ancestral gap estimation) to fill in inter-contig gaps using a combination of a template obtained from related extant genomes and aDNA reads. We show how this approach can be used to refine comparative scaffolding by selecting contig adjacencies supported by a mix of unassembled aDNA reads and comparative signal. We applied our method to two Y. pestis data sets from the London and Marseilles outbreaks, for which we obtained highly improved genome assemblies for both genomes, comprised of, respectively, five and six scaffolds with 95 % of the assemblies supported by ancient reads. We analysed the genome evolution between both ancient genomes in terms of genome rearrangements, and observed a high level of synteny conservation between these strains. PMID- 29114403 TI - Transcriptomic analysis of aerobic respiratory and anaerobic photosynthetic states in Rhodobacter capsulatus and their modulation by global redox regulators RegA, FnrL and CrtJ. AB - Anoxygenicphotosynthetic prokaryotes have simplified photosystems that represent ancient lineages that predate the more complex oxygen evolving photosystems present in cyanobacteria and chloroplasts. These organisms thrive under illuminated anaerobic photosynthetic conditions, but also have the ability to grow under dark aerobic respiratory conditions. This study provides a detailed snapshot of transcription ground states of both dark aerobic and anaerobic photosynthetic growth modes in the purple photosynthetic bacterium Rhodobactercapsulatus. Using 18 biological replicates for aerobic and photosynthetic states, we observed that 1834 genes (53 % of the genome) exhibited altered expression between aerobic and anaerobic growth. In comparison with aerobically grown cells, photosynthetically grown anaerobic cells showed decreased transcription of genes for cobalamin biosynthesis (-45 %), iron transport and homeostasis (-42 %), motility (-32 %), and glycolysis (-34 %). Conversely and more intuitively, the expression of genes involved in carbon fixation (547 %), bacteriochlorophyll biosynthesis (162 %) and carotenogenesis (114 %) were induced. We also analysed the relative contributions of known global redox transcription factors RegA, FnrL and CrtJ in regulating aerobic and anaerobic growth. Approximately 50 % of differentially expressed genes (913 of 1834) were affected by a deletion of RegA, while 33 % (598 out of 1834) were affected by FnrL, and just 7 % (136 out of 1834) by CrtJ. Numerous genes were also shown to be controlled by more than one redox responding regulator. PMID- 29114405 TI - Intensive Care Medicine: Enterprise and Journey. PMID- 29114404 TI - A long and abundant non-coding RNA in Lactobacillus salivarius. AB - Lactobacillus salivarius, found in the intestinal microbiota of humans and animals, is studied as an example of the sub-dominant intestinal commensals that may impart benefits upon their host. Strains typically harbour at least one megaplasmid that encodes functions contributing to contingency metabolism and environmental adaptation. RNA sequencing (RNA-seq)transcriptomic analysis of L. salivarius strain UCC118 identified the presence of a novel unusually abundant long non-coding RNA (lncRNA) encoded by the megaplasmid, and which represented more than 75 % of the total RNA-seq reads after depletion of rRNA species. The expression level of this 520 nt lncRNA in L. salivarius UCC118 exceeded that of the 16S rRNA, it accumulated during growth, was very stable over time and was also expressed during intestinal transit in a mouse. This lncRNA sequence is specific to the L. salivarius species; however, among 45 L. salivarius genomes analysed, not all (only 34) harboured the sequence for the lncRNA. This lncRNA was produced in 27 tested L. salivarius strains, but at strain-specific expression levels. High-level lncRNA expression correlated with high megaplasmid copy number. Transcriptome analysis of a deletion mutant lacking this lncRNA identified altered expression levels of genes in a number of pathways, but a definitive function of this new lncRNA was not identified. This lncRNA presents distinctive and unique properties, and suggests potential basic and applied scientific developments of this phenomenon. PMID- 29114406 TI - Educational and Training Programs in Intensive Care Medicine are the Right Way. PMID- 29114407 TI - Should We Use Dexmedetomidine for Sedation in Parturients Undergoing Caesarean Section Under Spinal Anaesthesia? PMID- 29114408 TI - A Different Approach to the Nutritional Therapy in Intensive Care Units: Nutrition Software (ICNUS). AB - Critically ill patients receive nutritional support in addition to extensive organ support therapies in the intensive care units. The transcription of the data obtained by multiple devices from a wide spectrum of usage areas is a challenging process and is prone to errors. Software specifically designed for usage in intensive care units do offer numerous advantages. Primarily, it facilitates to improve the management of time and workflow for the benefit of patients. Therefore, we believed that a different approach was needed for the nutritional regime of our critically ill patients. Following nearly 2 years of research, we developed and implemented the Intensive Care Nutrition Software (ICNUS), which is explained in this article. PMID- 29114409 TI - Effective Loading Dose of Dexmedetomidine to Induce Adequate Sedation in Parturients Undergoing Caesarean Section Under Spinal Anaesthesia. AB - Objective: To calculate the effective dose (ED) of dexmedetomidine for caesarean section under spinal anaesthesia. Methods: Consecutive parturients scheduled for caesarean section under spinal anaesthesia were included. The loading dose of dexmedetomidine was evaluated using the up-and-down method, starting at 1.0 MUg kg-1 and a step size of 0.1 MUg kg-1. The loading dexmedetomidine was administrated by the venous route for 10 min, and afterwards a maintenance dose began at a rate of 0.3 MUg kg-1 h-1 in all parturients. Adequate sedation was defined as a Ramsay sedation score >=3. The ED50 and ED95 of loading dexmedetomidine were calculated using probit regression. Results: The ED50 and ED95 of loading dexmedetomidine for adequate sedation were 0.82 MUg kg-1 (95% confidence intervals [CI] 0.73-0.89 MUg kg-1) and 0.96 MUg kg-1 (95% CI 0.90-1.39 MUg kg-1), respectively. Conclusion: The ED50 and ED95 of loading dexmedetomidine to achieve adequate sedation were 0.82 MUg kg-1 and 0.96 MUg kg-1 for caesarean section under spinal anaesthesia. PMID- 29114410 TI - Can Sevoflurane Induce Micronuclei Formation in Nasal Epithelial Cells of Adult Patients? AB - Objective: Volatile anaesthetics can inhibit the bronchociliary clearence in a dose- and time-dependend way. Moreover, they can have potential mutagenic/carcinogenic effects under chronic exposure. A genotoxicity test micronuclei assay- was carried out in nasal epithelial cells to analyze the genotoxic effect of sevoflurane in adult patients undergoing general anesthesia. Methods: In this study, micronucleus (MN) assay was conducted using nasal epithelial cells of 37 adult patients (age, 18-65 years) who underwent elective, minor, short surgical procedures under general anaesthesia with sevoflurane. Anaesthesia was induced and maintained using 8% sevoflurane (in 6 L min-1 of oxygen) and an inspired concentration of 2% in O2-air mixture, respectively. Nasal epithelial samples were collected at three time points: before anaesthesia induction (T1), after recovery from anaesthesia in the postanaesthesia care unit (T2) and on postoperative day 21 (T3). Results: Sevoflurane significantly increased mean MN (0/00) frequencies in nasal epithelial cells at T2 (6.97+/ 2.33) and T3 (6.22+/-2.47) compared with those at T1 (3.84+/-1.89) (p<0.001). Similar result were observed for MN frequencies if the patients were analysed with regard to age (>40 or <40 years) or sex. Conclusion: Short-term administration of sevoflurane anaesthesia induces MN formation in nasal epithelial cells of this patient population. Further studies are required for evaluation of the results. The prolonged administration of volatile anaesthetics in various risk groups and surgical protocols should be conducted for evaluating their safety. PMID- 29114411 TI - Clinical Comparison of I-Gel Supraglottic Airway Device and Cuffed Endotracheal Tube for Pressure-Controlled Ventilation During Routine Surgical Procedures. AB - Objective: Recently, there has been a trend favouring the use of supraglottic airway devices over endotracheal tubes (ETT) during short surgical procedures. In this study, we are going to assess the suitability of one such supraglottic airway device, i-gel, for pressure-controlled ventilation (PCV) during routine surgical procedures. Methods: The airway management for 60 patients was done with either i-gel (Group I) or cuffed tracheal tube (Group E) for this prospective, randomised, double-blinded study. Insertion time, number of attempts, ease of insertion and haemodynamic monitoring were recorded before, during and after insertion of these devices. Airway leak tests, leak volume and leak fraction were measured at 15, 20 and 25 cm H2O PCV, and pharyngolaryngeal morbidity was evaluated postoperatively. Results: I-gel is easier to insert than a tracheal tube (p=0.0056). The increase in heart rate and MAP was higher following insertion of tracheal tube in the first few minutes (p<0.001) and subsequently became comparable between the two groups. The leak volume and leak fraction between the two groups were comparable at 15 cm H2O PCV, but significant difference was seen at 20 and 25 H2O PCV between the two groups (p=0.232, p<0.001, p<0.001). Thirty minutes later, the leak volume and leak fraction between groups were comparable at 15 cm H2O PCV (p=0.495, p=0.104) but not at 20 and 25 H2O PCV (p<0.001, p<0.001). Pharyngolaryngeal morbidity was significantly lesser in the i-gel group. Conclusion: I-gel provides a reasonable alternative to cuffed ETT for pressure-controlled ventilation provided the pressures can be limited to 15 to 20 cm H2O. PMID- 29114413 TI - Perioperative Factors Affecting Ambulatory Outcomes Following Laparoscopic Adjustable Gastric Banding. AB - Objective: Morbidly obese patients are traditionally hospitalised following bariatric surgery. However, laparoscopic-adjustable gastric banding (LAGB) is amenable for ambulatory care. We hypothesised that the majority of patients can receive an ambulatory LAGB and that both surgical and anaesthetic perioperative factors will significantly affect non-ambulatory LAGB outcomes. Methods: Medical records of 201 consecutive LAGB patients performed at the University of Kansas Medical Centre during a 3-y period were reviewed. Demographic, medical, laboratory, anaesthetic, intraoperative and postoperative data were collected. Factors associated with non-ambulatory outcomes were identified and analysed using logistic regression, and a classification tree analysis was used to rank the descriptive model factor to the non-ambulatory outcome. Results: Average patient age was 43.4+/-11.4 years, and average body mass index was 48.2+/-10.3 kg m2-1. A total of 155 patients (77.1%; 95% confidence interval, 71%-83%; p<0.0001) were discharged home within 2-3 hours of surgery, whereas 36 stayed for 23 hours and 10 required hospital admission for 1-2 days. Increased surgical port numbers (p=0.007), >=50% of total intraoperative fentanyl administered in the recovery room (post-anaesthesia care unit) for the treatment of postoperative pain (p=0.007) and a lack of prophylactic beta-blockade (p=0.001) were three factors associated with non-ambulatory outcomes. Obstructive sleep apnoea was not associated with a non-ambulatory outcome (p=0.83). Conclusion: The majority of patients received an ambulatory LAGB. Meticulous laparoscopic surgical technique with the least feasible number of access ports and multimodal analgesic technique aimed at reduction of postoperative opioid consumption are the most important factors for a successful ambulatory LAGB outcome. PMID- 29114412 TI - Methylene Tetrahydrofolate Reductase Deficiency: the Hidden Risk in Paediatric Anaesthesia. AB - Objective: Methylene tetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive disorder that results in increased homocysteine levels in the body. Hyperhomocysteinemia causes a predisposition to venous and arterial thrombosis and ischaemic insults. The incidence of the deficiency is around 40% in some countries. In this study, we aimed to evaluate the effects of anaesthetic agents in children with MTHFR deficiency. Methods: Twelve paediatric patients with an MTHFR enzyme deficiency who underwent surgery in a ten-month period in a single centre were retrospectively evaluated. Demographic data, homocysteine levels before and after surgery, anaesthesia management and postoperative complications were recorded. Results: In four patients, propofol was used both for anaesthesia induction and total intravenous anaesthesia (TIVA). Eight patients received sevoflurane for both induction and maintenance of anaesthesia. Nitrous oxide (N2O) was not used in any patients. There was not a significant difference between the preoperative and postoperative homocysteine levels (p>0.05). Twenty-four hours after the surgery, the homocysteine levels were within normal limits. No complications were observed. Conclusion: Sevoflurane and propofol have no deleterious effects on homocysteine levels in patients with MTHFR deficiency. Avoidance of N2O is the key point for anaesthetic consideration regarding these patients. PMID- 29114414 TI - Comparison Between the Two-Injection Technique and the Four-Injection Technique in Axillary Brachial Plexus Block with Articaine. AB - Objective: In this study, we aimed to compare axillary brachial plexus block using the two-injection and four-injection techniques assisted with ultrasonography (USG) and nerve stimulator in patients operated for carpal tunnel syndrome with articaine. To evaluate which technique is more effective, we compared the onset time, effectiveness, and duration of block procedures, patient satisfaction, adverse effect of the drug, and complication rates of the motor and sensory blocks. Methods: Sixty patients were randomly divided into two groups. A mixture of physiologic serum added to articain with NaHCO3 (30 mL) was injected into the patients' axilla in both the groups. After the blockage of the musculocutaneous nerve in both the groups, the median nerve in the two-injection group and the median nerve, ulnar nerve, and radial nerve in the four-injection group were blocked. In brachial plexus nerves, sensorial blockage was evaluated with pinprick test, and motor block was evaluated by contraction of the muscles innervated by each nerve. The adverse effects and complications, visual analog scale (VAS) values during the operation, and post-operative patient satisfaction were recorded. Results: Sufficient analgesia and anaesthesia were achieved with no need for an additional local anaesthetics in both the groups. Furthermore, additional sedation requirements were found to be similar in both the groups. A faster rate and a more effective complete block were achieved in more patients from the four-injection group. In the two-injection group, the block could not be achieved for N. radialis in one patient. All other nerves were successfully blocked. Whereas the blockage procedure lasted longer in the four-injection group, the VAS values recorded during the blockage procedure were higher in the four-injection group. No statistical difference was found with regard to patient satisfaction, and no adverse effects and complications were observed in any group. Conclusion: Although the multi-injection method takes more time, it provides faster anaesthesia and more complete blockage than the two-injection method used with articain. The two-injection method can also be used in specific surgery such as for carpal tunnel syndrome, as an alternative to multi-injection method. PMID- 29114415 TI - Effect of Low Dose Remifentanil on Postoperative Pain Relief and Heart Rate Variability in Post-Anaesthesia Care Unit. AB - Objective: Several reports have shown the negligible adverse effects of low-dose remifentanil on the autonomic nervous system. We propose that the administration of low-dose remifentanil would be beneficial without adverse respiratory and hemodynamic effects. This study aimed to examine the effects of low-dose remifentanil on postoperative pain relief and heart rate variability (HRV) after surgery. Methods: In total, 20 patients, who underwent breast cancer surgery, were analysed for HRV in the post-anaesthesia care unit (PACU). A sedative dose of remifentanil was continuously infused if patients experienced pain while in PACU. The remifentanil infusion dose was determined by achieving analgesia with no adverse effects on hemodynamics and/or respiration. Variables of low-frequency power, high-frequency power and low-frequency power/high-frequency power ratio were measured before and after the administration of remifentanil. Pain score was expressed as the numeric rating scale (NRS) from 0 to 10. Results: The mean dosage of remifentanil administered as a continuous infusion was 0.029+/-0.0042 MUg kg-1 min-1. After remifentanil administration, the value of the NRS decreased from 4.2+/-2.9 to 2.7+/-2.6. In addition, the value of high-frequency power increased from 35.6+/-14.3 to 49.4+/-3.0. Conclusion: The continuous infusion of low-dose remifentanil may reduce post-operative pain scores and trigger the relative activation of the parasympathetic nervous system in post-surgical patients. This indicates that continuous infusion of low-dose remifentanil may be a useful option for postoperative pain relief in cases where postoperative pain control proves inadequate even with the application of regional block technique. PMID- 29114416 TI - Outcomes of Antepartum and Postpartum Obstetric Admissions to the Intensive Care Unit of A Tertiary University Hospital: An 8-Year Review. AB - Objective: Although their rates are decreasing, pregnancy-related mortality and morbidity are problems worldwide. In this study, we aimed to review the characteristics, diagnoses, required interventions and outcomes of obstetric patients admitted between 2006 and 2014 to the Intensive Care Unit (ICU) of a tertiary university hospital to provide an indicator for improving the management of critically ill obstetric patients. Methods: A retrospective study of hospital records of obstetric admissions to the ICU was conducted. Results: The pregnancy related ICU admission rate was 0.21% among all deliveries during the study period. Nine antepartum (mean gestational age: 23 weeks) and 48 postpartum (mean gestational age: 34 weeks) obstetric ICU admissions were included. Most obstetric patients admitted antepartum were primiparous (88.8%), whereas those admitted postpartum were multiparous (64.6%). The mean ICU stay was 7 days among the patients admitted antepartum and 6 days among those admitted postpartum. Common medical reasons for ICU admission were respiratory failure and HELLP syndrome in both groups; DIC and eclampsia were also medical reasons causing ICU admission among the postpartum patients. Mechanical ventilation and blood derivative transfusion were the most common interventions required during the ICU stay of the obstetric patients. Maternal death was unique to the patients admitted postpartum (6 patients, 12.5%). Conclusion: We reviewed obstetric admissions to our institution over an 8-year period. We believe that a nationwide study in Turkey that provides an indicator of the frequency, reasons of ICU admission and outcome of obstetric patients is required to improve the quality of intensive care. PMID- 29114417 TI - An Alternative Lung Isolation Technique in Paediatric Pulmonary Alveolar Proteinosis. AB - Lung isolation during the lung lavage of children with pulmonary alveolar proteinosis (PAP) poses challenges to anaesthesiologists. There is no established technique in the management of lung lavage in children; each described technique has its own advantages and disadvantages. We described a patient (2.5-year-old) with PAP, who has undergone left lung lavage. While his lung was isolated by a Fogarty catheter, lavage was performed via a feeding tube, and the right lung was ventilated with a rigid bronchoscope. We suggested that the technique we used was safe and effective because it enabled direct visualisation of both bronchi entrances, allowing early recognition of any possible catheter dislocations at the bronchus of the lavaged lung, completely eliminating the risk of contralateral lung contamination. This case reports an alternative unilateral lung isolation and lavage technique that may be applicable to other paediatric patients with PAP. PMID- 29114418 TI - Stop Being So Sensitive: An Exceptionally Rare Report of Ustekinumab-Induced Sub acute Hypersensitivity Pneumonitis. AB - Hypersensitivity pneumonitis (HSP) is a rare syndrome characterised by granulomatous inflammatory lung disease due to repeated sensitisation from a specific antigen. We present the case of a 61-year old male veteran with a history of nodular eczema who presented with 2 weeks of progressive dyspnoea on exertion and pleuritic chest pain. The patient was started on ustekinumab 5 weeks prior to presentation. Initial workup revealed ground-glass opacities on computed tomography (CT) scan of the chest. Cardiac workup was unrevealing with a normal myocardial perfusion stress test. The patient was started on inhaled corticosteroids and albuterol for reactive airway disease. Due to the persistence of symptoms despite treatment, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL), transbronchial biopsy and endobronchial ultrasound guided biopsy (EBUS). Bronchoscopy showed normal appearing airways of both right and left lungs. The BAL was remarkable for chronic inflammation and pulmonary macrophages. The BAL cell count differential was 1% granulocytes, 50% lymphocytes, 17% eosinophils and 32 mononuclear cells. The pathology from the mediastinal lymph nodes showed reactive inflammatory cells and no malignancy. The pathology from the transbronchial biopsy of the anterior basilar segment of the right lower lobe showed organising pneumonia with occasional ill-defined granulomas that stained negative for Acid Fast Bacilli (AFB) and Grocott's methenamine (GMS) appeared to be consistent with hypersensitivity pneumonitis. Based on the pathological diagnosis of HSP, the patient was managed with discontinuation of ustekinumab, with subsequent improvement of his symptoms. To our knowledge, this is the first report suggesting ustekinumab, like other biological therapies, has the potential to cause HSP. PMID- 29114419 TI - Unanticipated Difficult Airway in a Neonate: Are we Prepared for this CHAOS? AB - Unanticipated difficult airway in a neonate is a challenging situation with many difficulties because of inherent anatomical variations. To complicate the situation there is a lack of appropriate equipment, expertise and established guidelines on the management of difficult airway in neonates and infants. There are few published reports regarding the use of available devices for emergency front-of-neck access. We report the case of airway management of a neonate with an unanticipated finding of subglottic stenosis. Subglottic stenosis is one of the aetiologies of congenital high airway obstruction syndrome, which may be diagnosed antenatally based on ultrasonography findings. PMID- 29114420 TI - Hypocapnia Caused by a Cracked Water Trap. PMID- 29114421 TI - Vocal Cord Paralysis Following Endotracheal Intubation. PMID- 29114422 TI - Diuretics for All? PMID- 29114423 TI - Erratum. AB - [This corrects the article on p. 239 in vol. 45, PMID: 28868174.]. PMID- 29114424 TI - The effects of maxillary expansion on the soft tissue facial profile. AB - Purpose: The aims of this retrospective study were to evaluate the possible changes in soft tissue facial profile induced by orthopedic rapid maxillary expansion (RME) and surgically assisted rapid maxillary expansion (SARME), and to correlate them with the underlying hard tissue alterations. Materials and Methods: 16 patients who received bone borne SARME and 25 patients who were subjected to RME using metal cast splint hyrax appliance were analyzed retrospectively. This research was conducted on lateral cephalometric radiographs taken on 2 occasions: before expansion (T1) and at the beginning of any further orthodontic treatment (T2). Investigated lateral cephalometric parameters consisted of Holdaway soft tissue measurements with some supplementary soft tissue, skeletal and dental assessments. Results: The acquisition of T2 cephalograms which conforms to the initiation of further orthodontic treatment corresponded to 83.25+/-3.51 days for SARME and 85.68+/-4.37 days for RME after the expansion was completed. The only significant change in soft tissue profile of the SARME group was a decrease in upper lip thickness (p<0.05), whereas in the RME group, decrease in soft tissue facial profile angle and increase in H angle were found to be statistically significant (p<0.05 for each). For the RME group, the changes in soft tissue facial profile angle and H angle correlated only with the changes in SNB angle (p<0.05). Conclusion: While bone-borne SARME did not seem to possess the potential to alter soft tissue profile, tooth-borne RME caused a more convex soft tissue profile related to a reduction in SNB. PMID- 29114425 TI - Relationships between initial probing depth and changes in the clinical parameters following non-surgical periodontal treatment in chronic periodontitis. AB - Purpose: The aim of this study was to evaluate the relationship between initial probing depth (IPD) and changes in clinical parameters following non-surgical periodontal treatment (NPT) in chronic periodontitis patients. Subjects and Methods: A total of 1672 periodontal pockets having 3mm<=IPD<=9mm of depth in 15 chronic periodontitis patients were included. NPT consisting of oral hygiene instructions, scaling and root planing was applied in two sessions. Probing depth (PD), clinical attachment level, gingival recessions (GR) were measured before and eight weeks after treatment. Pocket sites were grouped according to their IPD and root number as single- or multi-rooted teeth. Results: Other than the sites having 3 mm IPD, PD reduction and GR increase were significant in all groups (p<0.001). Attachment gains (AG) were significant in all single-rooted teeth (p<0.001) again except those having IPD=3mm. However, AG was significant in multi rooted teeth having only 7mm<=IPD<=9mm (p<0.05). Positive correlations were observed between IPD and PD reduction, GR increase and AG in single-rooted teeth (p<0.001). Furthermore, positive correlations were found between IPD and PD reduction and GR increase in multi-rooted teeth (p<0.001), but there was no correlation between IPD and AG. Conclusion: NPT may lead to positive association between IPD and PD reduction as well as GR increase, which is independent from tooth root anatomy. PMID- 29114426 TI - Investigation of impacted supernumerary teeth: a cone beam computed tomograph (cbct) study. AB - Purpose: The purpose of this study was to investigate the impacted supernumerary teeth which were initially detected on panoramic radiographs by using cone beam computed tomography (CBCT). Materials and Methods: In this retrospective study, supernumerary teeth diagnosed on panoramic radiographs taken from patients who had admitted for routine dental treatment were evaluated using CBCT. Patients' age, gender, systemic conditions as well as number of supernumerary teeth, unilateral-bilateral presence, anatomical localization (maxilla, mandible, anterior-premolar-molar, mesiodens-lateral-canine, parapremolar-paramolar distomolar) shape (rudimentary, supplemental, tuberculate, odontoma), position (palatal-lingual-buccal-labial-central), shortest distance between the tooth and adjacent cortical plate, complications and treatment were assessed. Results: A total of 47 impacted supernumerary teeth in 34 patients were investigated in this study. Of these, 33 (70.2%) were unilateral and 14 (29.8%) were bilateral. Only 1 supernumerary tooth was found in 27 patients (79.4%) whereas 7 patients (20.6%) had 2 or more supernumerary teeth. Most of the teeth located in the anterior region (74.4%) of the jaws and maxilla (74.4%). Twenty teeth (42.5%) were mesiodens, 11 (23.4%) were lateral or canine, 14 (29.7%) were parapremolar and 2(4.4%) were distomolar. Twenty-seven teeth (57.4%) were rudimentary, 15 (31.9%) were supplemental and 5 (10.7%) were odontoma in shape. The shortest distance between the supernumerary tooth and adjacent cortical plate varied between 0 to 2.5 mm with a mean of 0.66 mm. The most common clinical complaint was the non eruption of permanent teeth (42.5%). All supernumerary teeth were removed under local anesthesia. Orthodontic traction was performed for those impacted permanent teeth if necessary. Conclusion: Impacted supernumerary teeth are usually in close proximity to cortical bone. Although this may facilitate surgical access, there is a risk of damaging surrounding anatomical structures. Therefore, CBCT evaluation of impacted supernumerary teeth for accurate planning is recommended. PMID- 29114427 TI - Adhesive system affects repair bond strength of resin composite. AB - Purpose: This study evaluated the effects of different adhesive systems on repair bond strength of aged resin composites. Materials and Methods: Ninety composite discs were built and half of them were subjected to thermal aging. Aged and non aged specimens were repaired with resin composite using three different adhesive systems; a two-step self-etch adhesive, a two-step total-etch adhesive and a one step self-etch adhesive; then they were subjected to shear forces. Data were analyzed statistically. Results: Adhesive type and aging significantly affected the repair bond strengths (p<0.0001). No statistical difference was found in aged composite groups repaired with two-step self- etch or two-step total-etch adhesive. One-step self-etch adhesive showed lower bond strength values in aged composite repair (p<0.0001). Conclusion: In the repair of aged resin composite, two-step self-etch and two-step total-etch adhesives exhibited higher shear bond strength values than that of one-step self-etch adhesive. PMID- 29114428 TI - Does intravenous tranexamic acid reduce blood loss during surgically assisted rapid palatal expansion? AB - Purpose: The purpose of this study was to evaluate the efficacy of tranexamic acid (TXA) in reducing blood loss during surgically assisted rapid palatal expansion (SARPE) procedure. Subjects and Methods: A total of 34 patients (12 male, 22 female) who had been treated surgically under general anesthesia with SARPE including pterygoid disjunction for transverse maxillary deficiency (TMD) were included in this study. The study group (n=17) received intravenous (IV) TXA 10 mg/kg as a preoperative bolus; the control group (n=17) received normal saline solution. Preoperative and postoperative haemoglobin and haematocrit values, intraoperative blood loss, and any blood product transfusion were recorded. Results: Blood loss during SARPE was statistically significantly less in the study group than the control group (p=0.0001). Conclusion: Preoperative IV administration of TXA can effectively control blood loss during when SARPE with pterygoid disjunction is performed. PMID- 29114429 TI - Sectional mandibular complete denture for a total maxillectomy patient with trismus: a clinical report. AB - This report presents the case of a 60-year-old male patient with trismus induced by radiotherapy and fabrication of a sectional mandibular complete denture to allow the insertion of the denture into the mouth. A mandibular sectional denture was designed in two pieces with a locking mechanism by using mini anchor and ball abutment housing with cap. Patients who have undergone maxillectomy often have constricted mouth openings, as a result of surgical intervention and radiotherapy, and complain of an inability to insert or remove dentures. A new approach is vital for sectional dentures because existing sectional denture fabrication techniques cannot meet the ongoing needs of trismus patients. The mini anchor system with ball abutment housing has better mechanical retention in acrylic resin and can provide favorable stabilization during masticatory function; thus, additional framework is not required for assisting in stabilization and retention. PMID- 29114430 TI - Clinical and radiographic features of parry-romberg syndrome. AB - Parry-Romberg syndrome or progressive hemifacial atrophy is a craniofacial disorder characterized by slow and progressive atrophy, generally unilateral, of facial tissues including muscles, bones and skin. The coup de sabre is a clear line of demarcation seen between the normal and abnormal structures. The severity of the facial deformity is dependent on the age of onset of the disease. Cosmetic management is the only available treatment and has to be delayed until facial growth is completed. The present case report deals with a 43-year-old woman with progressive hemifacial atrophy which started from the age of 10 months. Despite almost complete involvement of the right paramedian area and the early age of onset, she had neither eye changes nor any dental malformations. PMID- 29114431 TI - Maxillary first premolars with three root canals: two case reports. AB - It is very important that the dentists have sufficient information about possible variations in the expected root canal configurations in order to achieve success in endodontic treatment. In addition to having adequate knowledge on the variations of the root canal anatomy, periapical radiographs from different angles, careful examination of the pulp chamber floor, and use of dental operation microscope during the procedure are also important factors that contribute to the diagnosis of the additional roots and canals. The aims of this article are to present the diagnostic approach and root canal treatments of two maxillary first premolar teeth with three canals in two patients. PMID- 29114432 TI - Eye-related trauma and infection in dentistry. AB - Despite numerous technological and medical developments achieved in recent years, a significant amount of occupational health problems still exist in modern dentistry. The risk of eye injury is mostly attributed to the use of high-speed hand pieces and ultrasonic devices. A dental clinic may be the source of eye related infection and injury because of mechanical, chemical, microbiological and electromagnetic irritants. Accidents may cause facial injuries that involve eyes of the clinicians, patients as well as dental assistants. Eye injuries can vary from mild irritation to blindness. The use of eye protection tools, such as protective goggles and visors, reduces the risk of eye damage or complete loss of vision while working with dangerous and floating materials. Therefore, all precautions should be taken, even when performing common procedures for which the risk expectancy is relatively low. Clinicians should be aware that they are also responsible for providing adequate protection for their assistants and patients, as well as themselves. PMID- 29114433 TI - Scientific basis of dentistry. AB - Technological and scientific innovations have increased exponentially over the past years in the dentistry profession. In this article, these developments are evaluated both in terms of clinical practice and their place in the educational program. The effect of the biologic and digital revolutions on dental education and daily clinical practice are also reviewed. Biomimetics, personalized dental medicine regenerative dentistry, nanotechnology, high-end simulations providing virtual reality, genomic information, and stem cell studies will gain more importance in the coming years, moving dentistry to a different dimension. PMID- 29114434 TI - Usability Evaluation of Laboratory Information Systems. AB - Background: Numerous studies have revealed widespread clinician frustration with the usability of electronic health records (EHRs) that is counterproductive to adoption of EHR systems to meet the aims of health-care reform. With poor system usability comes increased risk of negative unintended consequences. Usability issues could lead to user error and workarounds that have the potential to compromise patient safety and negatively impact the quality of care.[1] While there is ample research on EHR usability, there is little information on the usability of laboratory information systems (LISs). Yet, LISs facilitate the timely provision of a great deal of the information needed by physicians to make patient care decisions.[2] Medical and technical advances in genomics that require processing of an increased volume of complex laboratory data further underscore the importance of developing user-friendly LISs. This study aims to add to the body of knowledge on LIS usability. Methods: A survey was distributed among LIS users at hospitals across the United States. The survey consisted of the ten-item System Usability Scale (SUS). In addition, participants were asked to rate the ease of performing 24 common tasks with a LIS. Finally, respondents provided comments on what they liked and disliked about using the LIS to provide diagnostic insight into LIS perceived usability. Results: The overall mean SUS score of 59.7 for the LIS evaluated is significantly lower than the benchmark of 68 (P < 0.001). All LISs evaluated received mean SUS scores below 68 except for Orchard Harvest (78.7). While the years of experience using the LIS was found to be a statistically significant influence on mean SUS scores, the combined effect of years of experience and LIS used did not account for the statistically significant difference in the mean SUS score between Orchard Harvest and each of the other LISs evaluated. Conclusions: The results of this study indicate that overall usability of LISs is poor. Usability lags that of systems evaluated across 446 usability surveys. PMID- 29114435 TI - Hepatitis C Virus Genie: A Web 2.0 Interpretation and Analytics Platform for the Versant Hepatitis C Virus Genotype Line Probe Assay Version 2.0. AB - Context: Hepatitis C virus (HCV) genotyping at our institution is performed using the Versant HCV genotype 2.0 Line Probe Assay (LiPA). The last steps of this procedure are manual, laborious, and error-prone process that involves the comparison of the banding pattern on a test strip to a physical reference table. Aim: We developed a web-based HCV genotype interpretation platform that utilizes a scanned image to generate the genotypes, thus minimizing interpretation time and reducing error. Subjects and Methods: HCV Genie 2 utilizes a database of banding patterns in conjuncture with image analysis algorithms to determine the genotype for any number of scanned LiPA strips. HCV Genie 2 is built with client side JavaScript; allowing the program to run in the user' browser rather than on an unknown server, essentially eliminating data and patient privacy concerns. Results: HCV Genie 2 was tested over 2 months and proved identical to human expert interpretation for 148 samples (>1000 bands identified). Manual intervention was required only for two faint bands and one false-positive band; this was done utilizing the built-in-user interface. Utilizing the original method, the trained laboratory technician interpretation time for 16 samples was 13.8 (+/-0.96) min as compared to 5.0 (+/-1.09) min with HCV Genie 2, a 63.8% decrease. In addition to the time savings, the new method provides an additional validation step, which decreases the potential for errors. Conclusions: Our institution has moved exclusively to utilize the new techniques and tools described here. Both experienced technicians and the molecular pathologists at our institution prefer the workflow using HCV Genie. It is easier for the technicians to prepare and document, and the pathologists are more rapidly able to review and confirm results. The use of this tool will lead to increase the quality of patient care delivered through this test methodology by decreasing the potential for error. The algorithms developed here can be ported to similar band identification platforms, most directly to other LiPAs. PMID- 29114436 TI - Preferred Names, Preferred Pronouns, and Gender Identity in the Electronic Medical Record and Laboratory Information System: Is Pathology Ready? AB - Background: Electronic medical records (EMRs) and laboratory information systems (LISs) commonly utilize patient identifiers such as legal name, sex, medical record number, and date of birth. There have been recommendations from some EMR working groups (e.g., the World Professional Association for Transgender Health) to include preferred name, pronoun preference, assigned sex at birth, and gender identity in the EMR. These practices are currently uncommon in the United States. There has been little published on the potential impact of these changes on pathology and LISs. Methods: We review the available literature and guidelines on the use of preferred name and gender identity on pathology, including data on changes in laboratory testing following gender transition treatments. We also describe pathology and clinical laboratory challenges in the implementation of preferred name at our institution. Results: Preferred name, pronoun preference, and gender identity have the most immediate impact on the areas of pathology with direct patient contact such as phlebotomy and transfusion medicine, both in terms of interaction with patients and policies for patient identification. Gender identity affects the regulation and policies within transfusion medicine including blood donor risk assessment and eligibility. There are limited studies on the impact of gender transition treatments on laboratory tests, but multiple studies have demonstrated complex changes in chemistry and hematology tests. A broader challenge is that, even as EMRs add functionality, pathology computer systems (e.g., LIS, middleware, reference laboratory, and outreach interfaces) may not have functionality to store or display preferred name and gender identity. Conclusions: Implementation of preferred name, pronoun preference, and gender identity presents multiple challenges and opportunities for pathology. PMID- 29114437 TI - Magnetic Resonance Imaging Appearance of Schwannomas from Head to Toe: A Pictorial Review. AB - Schwannomas are benign soft-tissue tumors that arise from peripheral nerve sheaths throughout the body and are commonly encountered in patients with neurofibromatosis Type 2. The vast majority of schwannomas are benign, with rare cases of malignant transformation reported. In this pictorial review, we discuss the magnetic resonance imaging (MRI) appearance of schwannomas by demonstrating a collection of tumors from different parts of the body that exhibit similar MRI characteristics. We review strategies to distinguish schwannomas from malignant soft-tissue tumors while exploring the anatomic and histologic origins of these tumors to discuss how this correlates with their imaging findings. Familiarity with the MRI appearance of schwannomas can help aid in the differential diagnosis of soft-tissue masses, especially in unexpected locations. PMID- 29114438 TI - Assessment of fine-scale resource selection and spatially explicit habitat suitability modelling for a re-introduced tiger (Panthera tigris) population in central India. AB - Background: Large carnivores influence ecosystem functions at various scales. Thus, their local extinction is not only a species-specific conservation concern, but also reflects on the overall habitat quality and ecosystem value. Species habitat relationships at fine scale reflect the individuals' ability to procure resources and negotiate intraspecific competition. Such fine scale habitat choices are more pronounced in large carnivores such as tiger (Panthera tigris), which exhibits competitive exclusion in habitat and mate selection strategies. Although landscape level policies and conservation strategies are increasingly promoted for tiger conservation, specific management interventions require knowledge of the habitat correlates at fine scale. Methods: We studied nine radio collared individuals of a successfully reintroduced tiger population in Panna Tiger Reserve, central India, focussing on the species-habitat relationship at fine scales. With 16 eco-geographical variables, we performed Manly's selection ratio and K-select analyses to define population-level and individual-level variation in resource selection, respectively. We analysed the data obtained during the exploratory period of six tigers and during the settled period of eight tigers separately, and compared the consequent results. We further used the settled period characteristics to model and map habitat suitability based on the Mahalanobis D2 method and the Boyce index. Results: There was a clear difference in habitat selection by tigers between the exploratory and the settled period. During the exploratory period, tigers selected dense canopy and bamboo forests, but also spent time near villages and relocated village sites. However, settled tigers predominantly selected bamboo forests in complex terrain, riverine forests and teak-mixed forest, and totally avoided human settlements and agriculture areas. There were individual variations in habitat selection between exploratory and settled periods. Based on threshold limits of habitat selection by the Boyce Index, we established that 83% of core and 47% of buffer areas are now suitable habitats for tiger in this reserve. Discussion: Tiger management often focuses on large-scale measures, but this study for the first time highlights the behaviour and fine-scale individual-specific habitat selection strategies. Such knowledge is vital for management of critical tiger habitats and specifically for the success of reintroduction programs. Our spatially explicit habitat suitability map provides a baseline for conservation planning and optimizing carrying capacity of the tiger population in this reserve. PMID- 29114439 TI - New species of the endemic Neotropical caddisfly genus Contulma from the Andes of Ecuador (Trichoptera: Anomalopsychidae). AB - The genus Contulma Flint (Trichoptera: Anomalopsychidae) is composed mostly of regionally endemic species occurring above 2,000 m, with a few more widespread species and some that are found at lower elevations. Adults of three new species of Contulma are described and illustrated from the Andes of Ecuador, Contulma lina, new species, Contulma quito, new species, and Contulma sangay, new species. These species are similar to previously described species from the region, including C. paluguillensis, C. nevada, and C. lancelolata. New provincial records are provided for C. bacula, C. cataracta, and C. echinata. Contulma duffi Olah, 2016 is considered a junior, subjective synonym of C. penai, Holzenthal & Flint, 1995. Also, we provide an identification key to males of the 30 Contulma species now known. PMID- 29114440 TI - Carbohydrates digestion and metabolism in the spiny lobster (Panulirus argus): biochemical indication for limited carbohydrate utilization. AB - As other spiny lobsters, Panulirus argus is supposed to use preferentially proteins and lipids in energy metabolism, while carbohydrates are well digested but poorly utilized. The aim of this study was to evaluate the effect of dietary carbohydrate level on digestion and metabolism in the spiny lobster P. argus. We used complementary methodologies such as post-feeding flux of nutrients and metabolites, as well as measurements of alpha-amylase expression and activity in the digestive tract. Lobsters readily digested and absorbed carbohydrates with a time-course that is dependent on their content in diet. Lobster showed higher levels of free glucose and stored glycogen in different tissues as the inclusion of wheat flour increased. Modifications in intermediary metabolism revealed a decrease in amino acids catabolism coupled with a higher use of free glucose as carbohydrates rise up to 20%. However, this effect seems to be limited by the metabolic capacity of lobsters to use more than 20% of carbohydrates in diets. Lobsters were not able to tightly regulate alpha-amylase expression according to dietary carbohydrate level but exhibited a marked difference in secretion of this enzyme into the gut. Results are discussed to highlight the limitations to increasing carbohydrate utilization by lobsters. Further growout trials are needed to link the presented metabolic profiles with phenotypic outcomes. PMID- 29114441 TI - Increasing evidence that bats actively forage at wind turbines. AB - Although the ultimate causes of high bat fatalities at wind farms are not well understood, several lines of evidence suggest that bats are attracted to wind turbines. One hypothesis is that bats would be attracted to turbines as a foraging resource if the insects that bats prey upon are commonly present on and around the turbine towers. To investigate the role that foraging activity may play in bat fatalities, we conducted a series of surveys at a wind farm in the southern Great Plains of the US from 2011-2016. From acoustic monitoring we recorded foraging activity, including feeding buzzes indicative of prey capture, in the immediate vicinity of turbine towers from all six bat species known to be present at this site. From insect surveys we found Lepidoptera, Coleoptera, and Orthoptera in consistently high proportions over several years suggesting that food resources for bats were consistently available at wind turbines. We used DNA barcoding techniques to assess bat diet composition of (1) stomach contents from 47 eastern red bat (Lasiurus borealis) and 24 hoary bat (Lasiurus cinereus) carcasses collected in fatality searches, and (2) fecal pellets from 23 eastern red bats that were found on turbine towers, transformers, and tower doors. We found that the majority of the eastern red bat and hoary bat stomachs, the two bat species most commonly found in fatality searches at this site, were full or partially full, indicating that the bats were likely killed while foraging. Although Lepidoptera and Orthoptera dominated the diets of these two bat species, both consumed a range of prey items with individual bats having from one to six insect species in their stomachs at the time of death. The prey items identified from eastern red bat fecal pellets showed similar results. A comparison of the turbine insect community to the diet analysis results revealed that the most abundant insects at wind turbines, including terrestrial insects such as crickets and several important crop pests, were also commonly eaten by eastern red and hoary bats. Collectively, these findings suggest that bats are actively foraging around wind turbines and that measures to minimize bat fatalities should be broadly implemented at wind facilities. PMID- 29114442 TI - Ta2N3 nanocrystals grown in Al2O3 thin layers. AB - Tantalum nitride nanoparticles (NPs) and cubic bixbyite-type Ta2N3 nanocrystals (NCs) were grown in (Ta-N+Al2O3)/Al2O3 periodic multilayers (MLs) after thermal treatment. The MLs were prepared by magnetron deposition at room temperature and characterized using grazing incidence small-angle X-ray scattering (GISAXS), X ray reflectivity (XRR), grazing incidence X-ray diffraction (GIXRD), secondary ion mass spectrometry (SIMS) and X-ray photoelectron spectroscopy (XPS). We found amorphous tantalum nitride NPs at 600-800 degrees C, with a high degree of ordering along the surface normal and short-range ordering within the layers containing tantalum (metallic layers). At an even higher annealing temperature of 900 degrees C the NPs crystallize in the rare and relatively unexplored Ta2N3 phase. However, the environment, morphology and spatial ordering of the NCs depend on the thickness of the metallic layers. For 12 nm thick metallic layers, the Ta2N3 NCs have an average diameter of 6 nm and they are confined and short range ordered within the metallic layers. When the metallic layers are thinner, the NCs grow over 20 nm in diameter, show no spatial ordering, while the periodic structure of the ML was completely destroyed. The results presented here demonstrate a self-assembly process of tantalum nitride NPs, the morphological properties of which depend on the preparation conditions. This can be used as a generic procedure to realize highly tunable and designable optical properties of thin films containing transition-metal nitride nanocrystals. PMID- 29114443 TI - Evaluating the toxicity of TiO2-based nanoparticles to Chinese hamster ovary cells and Escherichia coli: a complementary experimental and computational approach. AB - Titania-supported palladium, gold and bimetallic nanoparticles (second-generation nanoparticles) demonstrate promising photocatalytic properties. However, due to unusual reactivity, second-generation nanoparticles can be hazardous for living organisms. Considering the ever-growing number of new types of nanoparticles that can potentially contaminate the environment, a determination of their toxicity is extremely important. The main aim of presented study was to investigate the cytotoxic effect of surface modified TiO2-based nanoparticles, to model their quantitative nanostructure-toxicity relationships and to reveal the toxicity mechanism. In this context, toxicity tests for surface-modified TiO2-based nanoparticles were performed in vitro, using Gram-negative bacteria Escherichia coli and Chinese hamster ovary (CHO-K1) cells. The obtained cytotoxicity data were analyzed by means of computational methods (quantitative structure-activity relationships, QSAR approach). Based on a combined experimental and computational approach, predictive models were developed, and relationships between cytotoxicity, size, and specific surface area (Brunauer-Emmett-Teller surface, BET) of nanoparticles were discussed. PMID- 29114444 TI - Angstrom-scale flatness using selective nanoscale etching. AB - The realization of flat surfaces on the angstrom scale is required in advanced devices to avoid loss due to carrier (electron and/or photon) scattering. In this work, we have developed a new surface flattening method that involves near-field etching, where optical near-fields (ONFs) act to dissociate the molecules. ONFs selectively generated at the apex of protrusions on the surface selectively etch the protrusions. To confirm the selective etching of the nanoscale structure, we compared near-field etching using both gas molecules and ions in liquid phase. Using two-dimensional Fourier analysis, we found that near-field etching is an effective way to etch on the scale of less than 10 nm for both wet and dry etching techniques. In addition, near-field dry etching may be effective for the selective etching of nanoscale structures with large mean free path values. PMID- 29114445 TI - Velocity dependence of sliding friction on a crystalline surface. AB - We introduce and study a minimal 1D model for the simulation of dynamic friction and dissipation at the atomic scale. This model consists of a point mass (slider) that moves over and interacts weakly with a linear chain of particles interconnected by springs, representing a crystalline substrate. This interaction converts a part of the kinetic energy of the slider into phonon waves in the substrate. As a result, the slider experiences a friction force. As a function of the slider speed, we observe dissipation peaks at specific values of the slider speed, whose nature we understand by means of a Fourier analysis of the excited phonon modes. By relating the phonon phase velocities with the slider velocity, we obtain an equation whose solutions predict which phonons are being excited by the slider moving at a given speed. PMID- 29114446 TI - Suppression of low-energy dissociative electron attachment in Fe(CO)5 upon clustering. AB - In this work, we probe anion production upon electron interaction with Fe(CO)5 clusters using two complementary cluster-beam setups. We have identified two mechanisms that lead to synthesis of complex anions with mixed Fe/CO composition. These two mechanisms are operative in distinct electron energy ranges. It is shown that the elementary decomposition mechanism that has received perhaps the most attention in recent years (i.e., dissociative electron attachment at energies close to 0 eV) becomes suppressed upon increasing aggregation of iron pentacarbonyl. We attribute this suppression to the electrostatic shielding of a long-range interaction that strongly enhances the dissociative electron attachment in isolated Fe(CO)5. PMID- 29114447 TI - Comprehensive investigation of the electronic excitation of W(CO)6 by photoabsorption and theoretical analysis in the energy region from 3.9 to 10.8 eV. AB - High-resolution vacuum ultraviolet photoabsorption measurements in the wavelength range of 115-320 nm (10.8-3.9 eV) have been performed together with comprehensive relativistic time-dependent density functional calculations (TDDFT) on the low lying excited sates of tungsten hexacarbonyl, W(CO)6. The higher resolution obtained reveals previously unresolved spectral features of W(CO)6. The spectrum shows two higher-energy bands (in the energy ranges of 7.22-8.12 eV and 8.15-9.05 eV), one of them with clear vibrational structure, and a few lower-energy shoulders in addition to a couple of lower-energy metal-to-ligand charge-transfer (MLCT) bands reported in the literature before. Absolute photoabsorption cross sections are reported and, where possible, compared to previously published results. On the basis of this combined experimental/theoretical study the absorption spectrum of the complex has been totally re-assigned between 3.9 and 10.8 eV under the light of spin-orbit coupling (SOC) effects. The present comprehensive knowledge of the nature of the electronically excited states may be of relevance to estimate neutral dissociation cross sections of W(CO)6, a precursor molecule in focused electron beam induced deposition (FEBID) processes, from electron scattering measurements. PMID- 29114448 TI - Vapor-based polymers: from films to nanostructures. PMID- 29114449 TI - Au55, a stable glassy cluster: results of ab initio calculations. AB - Structure and properties of small nanoparticles are still under discussion. Moreover, some thermodynamic properties and the structural behavior still remain partially unknown. One of the best investigated nanoparticles is the Au55 cluster, which has been analyzed experimentally and theoretically. However, up to now, the results of these studies are still inconsistent. Consequently, we have carried out the present ab initio study of the Au55 cluster, using up-to-date computational concepts, in order to clarify these issues. Our calculations have confirmed the experimental result that the thermodynamically most stable structure is not crystalline, but it is glassy. The non-crystalline structure of this cluster was validated by comparison of the coordination numbers with those of a crystalline cluster. It was found that, in contrast to bulk materials, glass formation is connected to an energy release that is close to the melting enthalpy of bulk gold. Additionally, the surface energy of this cluster was calculated using two different theoretical approaches resulting in values close to the surface energy for bulk gold. It shall be emphasized that it is now possible to give a confidence interval for the value of the surface energy. PMID- 29114450 TI - Material property analytical relations for the case of an AFM probe tapping a viscoelastic surface containing multiple characteristic times. AB - We explore the contact problem of a flat-end indenter penetrating intermittently a generalized viscoelastic surface, containing multiple characteristic times. This problem is especially relevant for nanoprobing of viscoelastic surfaces with the highly popular tapping-mode AFM imaging technique. By focusing on the material perspective and employing a rigorous rheological approach, we deliver analytical closed-form solutions that provide physical insight into the viscoelastic sources of repulsive forces, tip-sample dissipation and virial of the interaction. We also offer a systematic comparison to the well-established standard harmonic excitation, which is the case relevant for dynamic mechanical analysis (DMA) and for AFM techniques where tip-sample sinusoidal interaction is permanent. This comparison highlights the substantial complexity added by the intermittent-contact nature of the interaction, which precludes the derivation of straightforward equations as is the case for the well-known harmonic excitations. The derivations offered have been thoroughly validated through numerical simulations. Despite the complexities inherent to the intermittent-contact nature of the technique, the analytical findings highlight the potential feasibility of extracting meaningful viscoelastic properties with this imaging method. PMID- 29114451 TI - The interplay between spin densities and magnetic superexchange interactions: case studies of mono- and trinuclear bis(oxamato)-type complexes. AB - For future molecular spintronic applications the possibility to modify and tailor the magnetic properties of transition-metal complexes is very promising. One of such possibilities is given by the countless derivatization offered by carbon chemistry. They allow for altering chemical structures and, in doing so, to tune magnetic properties of molecular spin-carrying compounds. With emphasis on the interplay of the spin density distribution of mononuclear and magnetic superexchange couplings of trinuclear bis(oxamato)-type complexes we review on efforts on such magneto-structural correlations. PMID- 29114452 TI - Using virtual reality to assess theory of mind subprocesses and error types in early and chronic schizophrenia. AB - Individuals with schizophrenia often demonstrate theory of mind (ToM) impairment relative to healthy adults. However, the exact nature of this impairment (first- vs. second-order ToM and cognitive vs. affective ToM) and the extent to which ToM abilities deteriorate with illness chronicity is unclear. Furthermore, little is known about the relationships between clinical symptoms and ToM error types (overmentalising, reduced mentalising and no ToM) in early and chronic schizophrenia. This study examined the nature and types of ToM impairment in individuals with early (n = 26) and chronic schizophrenia (n = 32) using a novel virtual reality task. Clinical participants and demographically-matched controls were administered the Virtual Assessment of Mentalising Ability, which provides indices of first- and second-order cognitive and affective ToM, and quantifies three different types of mentalising errors (viz., overmentalising, reduced mentalising, and no ToM). Individuals with early schizophrenia performed significantly poorer than healthy controls on first-order affective and second order cognitive and affective ToM, but significantly higher than individuals with chronic schizophrenia on all ToM subscales. Whereas a lack of mental state concept was associated with negative symptoms, overmentalising was associated with positive symptoms. These findings suggest that ToM abilities selectively deteriorate with illness chronicity and error types are related to these individuals' presenting symptomology. An implication of the findings is that social-cognitive interventions for schizophrenia need to consider the nature, time course and symptomatology of the presenting patient. PMID- 29114453 TI - Meeting overview: Sensory perception and schizophrenia, Lausanne, Switzerland June 31-July 1, 2014. AB - Schizophrenia is increasingly being viewed as a "whole brain" disorder with deficits affecting widespread cortical and subcortical networks. Within this context, studies of visual cortical function may be particularly important both because visual processing deficits directly affect social and occupational function and because these systems are well characterized at the basic science level, permitting informative translational research. This article summarizes a conference on visual processing dysfunction in schizophrenia held in Lausanne, Switzerland from June 30 to July 1, 2014 and introduces this special issue. Speakers focused on multiple aspects of visual dysfunction in schizophrenia using behavioral, neurophysiological and fMRI-based approaches. Four main themes emerged. First was a focus on response disturbances within the early visual system, using paradigms such as sensory EEG and MEG-based responses. Second, behavioral deficits were noted in processing related to local interaction within visual regions, using paradigms such as Vernier acuity or contour integration. These deficits provided potential model systems to understand impaired connectivity within the brain in schizophrenia more generally. Third, several visual measures were found to correlate highly with symptoms and/or neurocognitive processing. Deficits in contour integration, for example, correlated highly with conceptual disorganization, whereas perceptual instability correlated with delusion formation. These findings highlight links between perceptual-level disturbance and clinical manifestation. Finally, the potential involvement of specific neurotransmitter receptors, including N-methyl-D aspartate (NMDA)-type glutamate receptors and alpha7 nicotinic receptors were discussed as potential etiological mechanisms. Overall, the meeting highlighted the contributions of visual pathway dysfunction to the etiopathogenesis of neurocognitive dysfunction in schizophrenia. PMID- 29114455 TI - Perceptual instability in schizophrenia: Probing predictive coding accounts of delusions with ambiguous stimuli. AB - Background: Delusions, a core symptom of schizophrenia, are thought to arise from an alteration in predictive coding mechanisms that underlie perceptual inference. Here, we aimed to empirically test the hypothesized link between delusions and perceptual inference. Method: 28 patients with schizophrenia and 32 healthy controls matched for age and gender took part in a behavioral experiment that assessed the influence of stabilizing predictions on perception of an ambiguous visual stimulus. Results: Participants with schizophrenia exhibited a weaker tendency towards percept stabilization during intermittent viewing of the ambiguous stimulus compared to healthy controls. The tendency towards percept stabilization in participants with schizophrenia correlated negatively with delusional ideation as measured with a validated questionnaire. Conclusion: Our results indicate an association between a weakened effect of sensory predictions in perceptual inference and delusions in schizophrenia. We suggest that attenuated predictive signaling during perceptual inference in schizophrenia may yield the experience of aberrant salience, thereby providing the starting point for the formation of delusions. PMID- 29114454 TI - Visual masking & schizophrenia. AB - Visual masking is a frequently used tool in schizophrenia research. Visual masking has a very high sensitivity and specificity and masking paradigms have been proven to be endophenotypes. Whereas masking is a powerful technique to study schizophrenia, the underlying mechanisms are discussed controversially. For example, for more than 25 years, masking deficits of schizophrenia patients were mainly attributed to a deficient magno-cellular system (M-system). Here, we show that there is very little evidence that masking deficits are magno-cellular deficits. We will discuss the magno-cellular and other approaches in detail and highlight their pros and cons. PMID- 29114456 TI - Disruption of information processing in schizophrenia: The time perspective. AB - We review studies suggesting time disorders on both automatic and subjective levels in patients with schizophrenia. Patients have difficulty explicitly discriminating between simultaneous and asynchronous events, and ordering events in time. We discuss the relationship between these difficulties and impairments on a more elementary level. We showed that for undetectable stimulus onset asynchronies below 20 ms, neither patients nor controls merge events in time, as previously believed. On the contrary, subjects implicitly distinguish between events even when evaluating them to be simultaneous. Furthermore, controls privilege the last stimulus, whereas patients seem to stay stuck on the first stimulus when asynchronies are sub-threshold. Combining previous results shows this to be true for patients even for asynchronies as short as 8 ms. Moreover, this peculiarity predicts difficulties with detecting asynchronies longer than 50 ms, suggesting an impact on the conscious ability to time events. Difficulties on the subjective level are also correlated with clinical disorganization. The results are interpreted within the framework of predictive coding which can account for an implicit ability to update events. These results complement a range of other results, by suggesting a difficulty with binding information in time as well as space, and by showing that information processing lacks continuity and stability in patients. The time perspective may help bridge the gap between cognitive impairments and clinical symptoms, by showing how the innermost structure of thought and experience is disrupted. PMID- 29114457 TI - Investigating vision in schizophrenia through responses to humorous stimuli. AB - The visual environment of humans contains abundant ambiguity and fragmentary information. Therefore, an early step of vision must disambiguate the incessant stream of information. Humorous stimuli produce a situation that is strikingly analogous to this process: Funniness is associated with the incongruity contained in a joke, pun, or cartoon. Like in vision in general, appreciating a visual pun as funny necessitates disambiguation of incongruous information. Therefore, perceived funniness of visual puns was implemented to study visual perception in a sample of 36 schizophrenia patients and 56 healthy control participants. We found that both visual incongruity and Theory of Mind (ToM) content of the puns were associated with increased experienced funniness. This was significantly less so in participants with schizophrenia, consistent with the gestalt hypothesis of schizophrenia, which would predict compromised perceptual organization in patients. The association of incongruity with funniness was not mediated by known predictors of humor appreciation, such as affective state, depression, or extraversion. Patients with higher excitement symptoms and, at a trend level, reduced cognitive symptoms, reported lower funniness experiences. An open question remained whether patients showed this deficiency of visual incongruity detection independent of their ToM deficiency. Humorous stimuli may be viewed as a convenient method to study perceptual processes, but also fundamental questions of higher-level cognition. PMID- 29114458 TI - The concept of schizotypy - A computational anatomy perspective. AB - Despite major progress in diagnostic accuracy and symptomatic treatment of mental disorders, there is an ongoing debate about their classification aiming to follow current advances in neurobiology. The main goal of this review is to provide a comprehensive summary of the put forward schizotypy concept that follows the needs for objective assessment of schizophrenia-like personality traits in the general population. We focus on major achievements in the field from the perspective of magnetic resonance imaging-based computational anatomy of the brain. Particular interest is devoted to overlapping brain structure findings in schizotypy and schizophrenia to promote a dimensional view on schizophrenia as extension of phenotype traits in the non-clinical general population. PMID- 29114460 TI - Editorial Letter. PMID- 29114459 TI - Does chronic nicotine consumption influence visual backward masking in schizophrenia and schizotypy? AB - Nicotine consumption is higher for people within the schizophrenia spectrum compared to controls. This observation supports the self-medication hypothesis, that nicotine relieves symptoms in, for example, schizophrenia patients. We tested whether performance in an endophenotype of schizophrenia (visual backward masking, VBM) is modulated by nicotine consumption in i) smoking and non-smoking schizophrenia patients, their first-degree relatives, and age-matched controls, ii) non-smoking and smoking university students, and iii) non-smoking, early and late onset nicotine smokers. Overall, our results confirmed that VBM deficits are an endophenotype of schizophrenia, i.e., deficits were highest in patients, followed by their relatives, students scoring high in Cognitive Disorganisation, and controls. Moreover, we found i) beneficial effects of chronic nicotine consumption on VBM performance, in particular with increasing age, and ii) little impact of clinical status alone or in interaction with nicotine consumption on VBM performance. Given the younger age of undergraduate students (up to 30 years) versus controls and patients (up to 66 years), we propose that age-dependent VBM deficits emerge when schizotypy effects are targeted in populations of a larger age range, but that nicotine consumption might counteract these deficits (supporting the self-medication hypothesis). PMID- 29114463 TI - Editorial Letter into Spanish. PMID- 29114462 TI - Clinical (but not cognitive) recovery in schizophrenia through the experience of fictional cinema. AB - Introduction: One of the criticisms of rehabilitation techniques is their limited application to the patient's daily life. In the past, cinema has been used as a psychiatric rehabilitation tool, with the primary objective of facilitating training in social abilities and communication. In this study, we consider the use of film not only as a clinical recovery tool but also as a novel cognitive recovery tool for additional rehabilitation not only for communication and social abilities but also for all of the basic cognitive and social cognition processes. Methods: In this randomized clinical trial, 48 patients with schizophrenia were assigned to an experimental or control group. Both of the groups received treatment sessions that included viewing episodes of the television series The Sopranos. Next, the experimental group participated in a structured cognitive training session that featured questions and exercises based on the episodes. The control group participated in an idea-sharing session (of the same duration and frequency) about what the group members saw in the episode. Results: At the end of the treatment, both the positive and negative clinical symptoms of the experimental group improved significantly compared with the control group. However, this improvement was not observed in basic or social cognitive functions. Discussion: A brief intervention based on transforming the activities of daily life can be an effective tool for psychiatric rehabilitation. However, the study's current characteristics and sample did not produce benefits in cognitive parameters. PMID- 29114461 TI - The search for new biomarkers for cognition in schizophrenia. AB - The search for biomarkers in cognition has been the focus of a large part of the research on patients suffering from schizophrenia. The scientific literature is heterogeneous, and few studies establishing an integrative model of pathogenesis and therapeutic response are available in this field. In this review, we aimed to summarize three essential aspects correlated with cognitive performance: 1) the relationship between inflammation and cognition in schizophrenia, 2) the role of prolactin in cognition, and 3) the association between cognition and neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). Several studies support the association of inflammatory markers with cognitive status in schizophrenia. In recent decades, the development of effective therapies for cognitive impairment in schizophrenia has focused on the search for anti inflammatory and immunomodulatory medications. Conversely, the implications of prolactin and its functions in cognition, the transition to psychosis and the diagnosis and prognosis of schizophrenia have been established independent of antipsychotic treatment. With regard to neurotrophic factors, a recent study has correlated BDNF levels with cognitive recovery in schizophrenic patients treated with cognitive remediation. We conclude that although there is a diversity of biomarkers focused on cognitive function in schizophrenia, BDNF is the biomarker that has accumulated the vast majority of evidence in the current literature. PMID- 29114465 TI - Advance in predictive and prognostic marker assessments in lung cancer. PMID- 29114464 TI - Neurocognitive normality in schizophrenia revisited. AB - The validity and significance of normal range neurocognition in schizophrenia remain unclear and controversial. We assessed whether normal range patients and controls demonstrate evidence of decline relative to premorbid ability and differ in performance profiles across measures, including those external to the normality criterion. In addition, we compared below normal range healthy control participants with patients at the same ability level. Performance normality was defined as a MATRICS Consensus Cognitive Battery (MCCB) composite T score between 40 and 60. Patients (n = 17) and controls (n = 24) meeting the criterion were compared on MCCB domain scores and on independent measures of reading ability, probabilistic and social reasoning. Patients (n = 19) and controls (n = 20) scoring below 40 on the MCCB composite were compared on the same set of measures. Cognitively normal range patients and controls did not differ on estimated premorbid ability or decline and differed only on the Processing Speed domain of the MCCB. Performance did not differ across other domains or on social and probabilistic reasoning tasks. Cognitively below normal range patients and controls showed marked discrepancies between premorbid and current ability, but there were no group differences. In addition, below normal range groups did not differ on any MCCB domain score or in terms of external cognitive measures. Cognitively normal range schizophrenia patients may be largely indistinguishable from normal range controls, with the exception of processing speed performance. More typical schizophrenia patients below the normal range may be indistinguishable from low-performing controls even in terms of processing speed. PMID- 29114466 TI - Spread through air spaces (STAS): a comprehensive update. AB - The new concept of spread through air spaces (STAS) was introduced for pulmonary adenocarcinomas (ADC) in the 2015 World Health Organization (WHO) classification for lung cancer. Yet available data demonstrate that STAS is of high prognostic impact and associated with specific clinic-pathological characteristics. This article provides a comprehensive overview on recent developments in this field. PMID- 29114467 TI - Biology of invasive mucinous adenocarcinoma of the lung. AB - Invasive mucinous adenocarcinoma (IMA) is a unique histologic subtype of lung adenocarcinoma. Recent studies document distinctive genetic alterations (e.g., NRG1 fusions) and a "mucinous gene signature" in IMAs, as well as differences in clinical responses to traditional chemotherapies in IMAs versus non-mucinous adenocarcinomas. Our understanding of the genetic and clinical characteristics of IMAs has expanded, confirming the uniqueness of IMAs. Accordingly, IMAs require different therapeutic approaches than do lung adenocarcinomas in general. Here, we review recent updates on the genetic and clinical profiles of IMA of the lung. PMID- 29114469 TI - Update on large cell neuroendocrine carcinoma. AB - High-grade neuroendocrine carcinomas of the lung are classified into two categories: large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). While typical cases of LCNEC are morphologically distinct from SCLC, the differentiation between LCNEC and SCLC can be challenging in some cases. In fact, there are borderline high-grade neuroendocrine carcinomas that morphologically fall between LCNEC and SCLC. Growing evidence suggests that LCNEC is a histologically and biologically heterogeneous group of tumors. Molecular profiling with next-generation sequencing (NGS) has revealed a few biologically distinct subsets of LCNEC. Of those, the SCLC-like subset is characterized by concurrent inactivating mutations in TP53 and loss of RB1 that are typically seen in SCLC, whereas the non-small cell lung cancer (NSCLC)-like subset frequently harbors molecular alterations that are usually seen in NSCLC. Furthermore, the SCLC-like subset exhibits morphologic features of SCLC, and NSCLC-like morphology predominates in the NSCLC-like subset, although there was a substantial overlap in morphologic features between these subsets. As for the treatment of LCNEC, surgery is advocated for early stage tumors, but surgery alone does not appear to be sufficient and adjuvant chemotherapy, consisting of platinum/etoposide, likely prevents recurrence in patients with completely resected LCNEC. For advanced disease, there have been conflicting reports as to whether LCNEC responds to chemotherapeutic regimens in the similar manner to SCLC rather than NSCLC, and the heterogeneous biology of LCNEC may contribute in part to the discrepant results. A further understanding of the biology of LCNEC will lead to novel approaches to clinical managements of patients with LCNEC. PMID- 29114468 TI - Classification of pulmonary neuroendocrine tumors: new insights. AB - Neuroendocrine tumors of the lung (Lu-NETs) embrace a heterogeneous family of neoplasms classified into four histological variants, namely typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). Defining criteria on resection specimens include mitotic count in 2 mm2 and the presence or absence of necrosis, alongside a constellation of cytological and histological traits including cell size and shape, nuclear features and overall architecture. Clinically, TC are low-grade malignant tumors, AC intermediate-grade malignant tumors and SCLC/LCNEC high grade malignant full-blown carcinomas with no significant differences in survival between them. Homologous tumors arise in the thymus that occasionally have some difficulties in differentiating from the lung counterparts when presented with large unresectable or metastatic lesions. Immunohistochemistry (IHC) helps refine NE diagnosis at various anatomical sites, particularly on small-sized tissue material, in which only TC and small cell carcinoma categories can be recognized easily on hematoxylin & eosin stain, while AC and LCNEC can only be suggested on such material. The Ki-67 labeling index effectively separates carcinoids from small cell carcinoma and may prove useful for the clinical management of a metastatic disease to help the therapeutic decision-making process. Although carcinoids and high-grade neuroendocrine carcinomas in the lung and elsewhere make up separate tumor categories on molecular grounds, emerging data supports the concept of secondary high-grade NETs arising in the preexisting carcinoids, whose clinical and biological relevance will have to be placed into the proper context for the optimal management of these patients. In this review, we will discuss the selected, recent literature with a focus on current issues regarding Lu-NET nosology, i.e., classification, derivation and tumor evolution. PMID- 29114470 TI - Histopathologic and molecular approach to staging of multiple lung nodules. AB - Distinguishing multiple primary lung cancers from intrapulmonary metastases in patients with synchronous multifocal lung adenocarcinomas can be challenging. The most recent 8th edition American Joint Committee on Cancer staging manual (AJCC staging manual) distinguishes four disease patterns in patients with multiple lung nodules: (I) two or more distinct and histologically different masses (considered unrelated and staged as individual cancers); (II) multiple ground glass or part-solid nodules, histologically of with lepidic growth pattern (considered separate tumors, T staged based on highest T stage lesion); (III) patchy areas of ground-glass and consolidations, histologically often invasive mucinous adenocarcinomas (considered single tumor with diffuse "pneumonic-type" involvement); and (IV) separate nodules with the same histologic features based on comprehensive histologic subtyping (considered intrapulmonary metastases). Histologic and molecular features, in conjunction with clinical and radiological information, can all be tools to assist with staging of multiple nodules. Histologic features of adenocarcinomas are best characterized using comprehensive histologic subtyping (percentage of lepidic, acinar, solid, papillary and micropapillary pattern). Genomic alterations are commonly assessed using fluorescence in-situ hybridization and next generation sequencing (NGS). The AJCC considers exactly matching breakpoints by comparative genomic hybridization (CGH) as the only evidence for intrapulmonary metastases, and clearly different histologic types or subtypes as the only evidence for separate primary tumors. Similar histologic subtypes or the same biomarker pattern are considered merely relative arguments in favor of a single tumor source. When assessing multifocal lung cancer, pathologists should consider, and carefully weigh the importance of, molecular testing results in addition to the tumor's histologic features. For many cases encountered in routine clinical practice, absolute certainty cannot be reached as to whether they represent multiple primary cancers or intrapulmonary metastases. Classification of difficult cases often benefits from multidisciplinary discussion. PMID- 29114471 TI - Beyond ALK and ROS1: RET, NTRK, EGFR and BRAF gene rearrangements in non-small cell lung cancer. AB - The discovery of gene rearrangements involving the receptor tyrosine kinase genes ALK and ROS1 has revolutionized management of the subset of non-small cell lung cancers characterized by these alterations. The oncogenic fusion proteins expressed in these tumors drive cancer cell growth and survival, and targeted inhibition of this signaling can lead to dramatic and durable responses in patients. While the best characterized gene fusions in non-small cell lung cancer (NSCLC) involve ALK and ROS1, fusions involving other kinases including RET, NTRK, EGFR and BRAF are now established as additional targetable drivers. Here we review data supporting the roles of these fusions as oncogenic drivers, and the potential for targeting these fusions for improved clinical outcomes. These discoveries should encourage multiplexed molecular profiling of lung cancers using next-generation platforms which identify these gene fusions in order to expand treatment options for patients. PMID- 29114472 TI - Molecular diagnostics of lung cancer in the clinic. AB - According to current practice guidelines, all patients with advanced non-small cell lung cancer (NSCLC) should undergo predictive biomarker testing. For squamous cell carcinoma patients, PD-L1 immunohistochemistry is indicated to select patients for immunotherapy in the first line. For lung adenocarcinoma, all patients with advanced disease should undergo testing for epidermal growth factor receptor (EGFR) mutations, ALK and ROS1 rearrangements, and PD-L1 expression to predict response to EGFR, ALK, or ROS1 targeted inhibitors or immunotherapy, respectively. Besides these, a number of other biomarkers are under clinical investigation as predictors of response to targeted therapies, including BRAF, ERBB2, MET splice mutations and amplification, and RET rearrangements. Successful testing for this complex array of molecular targets demands careful coordination between proceduralists, pathologists and molecular laboratories to ensure proper tumor tissue handling following biopsy as well as judicious use of diagnostic immunohistochemistry. Even so, sample failure rates due to inadequate tumor tissue are high in practice, particularly when using sequential testing methods. Use of next generation sequencing (NGS) in clinical practice can enable detection of multiple targets and multiple alteration types (mutation, gene copy change, and rearrangement) simultaneously even with small amounts of input nucleic acids, thus increasing molecular testing success rates. In patients with an established lung cancer diagnosis but with prohibitively limited amounts of tumor tissue or who are experiencing relapse, analyses of circulating tumor DNA (ctDNA) from the plasma can serve as an alternate testing substrate, however the more limited clinical sensitivity of this approach must be taken into account. This review will explore the indications for and pitfalls of routine NGS and plasma genotyping in the clinic, including the intersection of these technologies. PMID- 29114474 TI - Thymic epithelial tumors and metastasis to the brain: a case series and systematic review. AB - Background: Thymic epithelial tumors (TETs) rarely metastasize to the brain. Clinico-pathologic features of TET patients with brain metastasis are not well described. Methods: TET patients referred for consultation or screening for clinical trials are included. Imaging to evaluate for brain metastases was performed when clinically indicated or if required for screening. Tumor tissue from brain metastases was obtained for analysis, when available. Clinical characteristics and survival was evaluated and a systematic review of the literature on brain metastases associated with TETs was performed. Results: Fourteen TET patients with brain metastasis were identified. Median age at TET diagnosis was 53 years (range: 31-71 years). Twelve patients had thymic carcinoma and two patients had World Health Organization B3 thymoma. Median time from TET diagnosis to discovery of brain metastases was 2.5 years (range: 9 months-8.3 years). Eleven patients had extracranial, extrathoracic metastases during presentation with brain metastases. Three patients underwent surgery and radiation therapy, eight patients received radiation therapy alone, and one patient had surgery alone. One patient with thymoma died 11 months after diagnosis of brain metastases and another patient died but with unknown date of diagnosis of brain metastases. Among 12 patients with thymic carcinoma, 11 of whom had a known date of brain metastases diagnosis, the median potential follow up is 35.8 months, and median overall survival (OS) from diagnosis of brain metastases is 13.1 months. Conclusions: Although uncommon, patients with advanced thymic carcinoma can develop brain metastases. Appropriate imaging and aggressive treatment should be considered for these patients. PMID- 29114473 TI - Immunohistochemistry for predictive biomarkers in non-small cell lung cancer. AB - In the era of targeted therapy, predictive biomarker testing has become increasingly important for non-small cell lung cancer. Of multiple predictive biomarker testing methods, immunohistochemistry (IHC) is widely available and technically less challenging, can provide clinically meaningful results with a rapid turn-around-time and is more cost efficient than molecular platforms. In fact, several IHC assays for predictive biomarkers have already been implemented in routine pathology practice. In this review, we will discuss: (I) the details of anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) IHC assays including the performance of multiple antibody clones, pros and cons of IHC platforms and various scoring systems to design an optimal algorithm for predictive biomarker testing; (II) issues associated with programmed death-ligand 1 (PD-L1) IHC assays; (III) appropriate pre-analytical tissue handling and selection of optimal tissue samples for predictive biomarker IHC. PMID- 29114476 TI - Erratum to combination MET- and EGFR-directed therapy in MET-overexpressing non small cell lung cancers: time to move on to better biomarkers? AB - [This corrects the article DOI: 10.21037/tlcr.2017.04.06.]. PMID- 29114475 TI - Drug screening to target nuclear orphan receptor NR4A2 for cancer therapeutics. AB - Background: Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC). Methods: We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Positive screening was performed using a luciferase reporter vector containing NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives. In vitro assays for positive hits were conducted. Results: A total of 23 Food and Drug Administration (FDA) and 43 Life Science Library compounds were identified, including several epidermal growth factor inhibitors and Src inhibitors. Subsequent in vitro assays confirmed that identified compounds were preferentially active in NR4A2+ cancer cells. Several candidate compounds appeared to suppress NR4A2 via inhibition of p-ERK, whereas a novel compound KU0171309 may act as a more direct inhibitor. Conclusions: Further research should focus on homologue selectivity, in vivo activity, and definitively deciphering the mechanism of action of KU0171309. PMID- 29114477 TI - Erratum to current state of immunotherapy for non-small cell lung cancer. AB - [This corrects the article on p. 196 in vol. 6, PMID: 28529902.]. PMID- 29114478 TI - ? AB - : Performance of HemoCue Hb201+ in the diagnosis of anaemia in children in health facilities at the peripheral level in Togo. Background: Anaemia is a global public health problem, especially in developing countries. Anaemia has major repercussions on health status, as well as on the economic and social development of a country. Effective care of anaemic patients requires a reliable and precise diagnostic test that can determine haemoglobin levels. Objective: To evaluate the diagnostic performance of the Hemocue test Hb201+(r). Method: This study compared haemoglobin levels measured using the photometer Hemocue Hb201+(r) with those measured by analysers of haematology. Children aged 6 to 59 months who suffered from uncomplicated malaria were eligible for inclusion. Haemoglobin levels determined by the analysers were considered the reference for evaluation of the levels measured using Hemocue Hb201+(r). Results: 72.8% of the values obtained by Hemocue Hb201(r) were within +/-1g/dl of the reference value. The Pearson correlation coefficient was 0.80. The prevalence of anaemia was 79.3% using the reference method and 77.9% using Hemocue 201+(r). The sensitivity and the specificity of Hemocue Hb201+(r) were 95.1% and 65.3% respectively. Conclusion: The study results showed that the Hemocue Hb201 test+(r) provided good sensitivity, average specificity and average precision, both for the diagnosis of anaemia and for the determination of haemoglobin levels. It may be used in peripheral centres to facilitate the laboratory diagnosis of anaemia and its management in populations that live in areas with difficult accessibility. PMID- 29114480 TI - Intestinal helminths - An old foe revisited. PMID- 29114479 TI - Sample Entropy Identifies Differences in Spontaneous Leg Movement Behavior between Infants with Typical Development and Infants at Risk of Developmental Delay. AB - We are interested in using wearable sensor data to analyze detailed characteristics of movement, such as repeatability and variability of movement patterns, over days and months to accurately capture real-world infant behavior. The purpose of this study was to explore Sample Entropy (SampEn) from wearable sensor data as a measure of variability of spontaneous infant leg movement and as a potential marker of the development of neuromotor control. We hypothesized that infants at risk (AR) of developmental delay would present significantly lower SampEn values than infants with typical development (TD). Participants were 11 infants with TD and 20 infants AR. We calculated SampEn from 1-4 periods of data of 7200 samples in length when the infants were actively playing across the day. The infants AR demonstrated smaller SampEn values (median 0.21) than the infants with TD (median 1.20). Lower values of SampEn indicate more similarity in patterns across time, and may indicate more repetitive, less exploratory behavior in infants AR compared to infants with TD. In future studies, we would like to expand to analyze longer periods of wearable sensor data and/or determine how to optimally sample representative periods across days and months. PMID- 29114481 TI - Ethics of translational medical research. AB - Translational research is the science of application of basic research knowledge to develop novel methods of improving public health outcome. This review briefly discusses the various phases involved and the hurdles faced in the translational pathway, how translational science originated, and the infrastructures consigned for translational research. Translational research also faces numerous diverse ethical issues similar to those observed in biomedical research. The various types of ethical issues faced whereas conducting translational research are discussed briefly in this review to help researchers identify and prevent unethical practices while conducting or regulating translational research. PMID- 29114482 TI - Use of evidence for clinical practice guideline development. AB - Clinical practice guidelines provide a framework against which quality of care is measured. Recommendations contained within guidelines are used for decision making not only within the clinical domain but also other related issues within the health systems. As such the use of research evidence for formulating recommendations contained in a guideline is a global standard to ensure guideline quality. The paper briefly reviews how the need for and use of evidence in guideline development shaped up historically and then provides an overview of the four typologies of guideline development mechanisms at the country level. PMID- 29114484 TI - Epidemiology and clinical features of soil-transmitted helminths. AB - Soil-transmitted helminths (STH) consist of Ascaris lumbricoides, Trichuris trichiura, and hookworm (Necator americanus and Ancylostoma duodenale). It affects nearly 1.7 billion people globally in which Ascaris contributes nearly 1.2 billion cases. The main mode for transmission of Ascaris and Trichuris is through contaminated food and water, whereas hookworm transmitted by skin penetration. STH were mainly seen in areas with poverty, overcrowding, and poor sanitation. The prevalence is more in rural areas compared to urban areas. It affects mainly children and causes lack of school attendance, anemia, and cognitive deficits. This review emphasizes on the epidemiology and clinical features of all STH and emphasizes on the role on preventive measures in containing STH. PMID- 29114485 TI - Laboratory diagnosis of soil transmitted helminthiasis. AB - Soil-transmitted helminths (STHs) include, i.e., hookworms (Ancylostoma duodenale, Necator americanus), roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura) and Strongyloides stercoralis. Globally, around 1.5 billion people are infected with STHs. STHs contribute to significant impairment of mental and physical growth, especially in developing countries. Unfortunately, these infections mostly remain undiagnosed due to lack of trained personnel and appropriate technologies. Intermittent shedding of eggs or larvae further makes the diagnosis difficult. Thus, there is a dire need of rapid and accurate tests for the diagnosis of STHs. The diagnostic methods include conventional and molecular methods. Conventional methods include microscopy, culture, and egg counting. Serology has a role, especially in case of S. stercoralis where conventional methods have very poor sensitivities. The rapid, highly sensitive molecular techniques, particularly quantitative polymerase-chain reaction make it suitable for diagnosing STH over insensitive as well as labor-intensive conventional methods. Until now, molecular detection of STH was mainly restricted to the research setting, but now, there is recommendation of adopting molecular tests in the World Health Organization STH elimination programs. Thus, STH infections are important public health problems and should be appropriately diagnosed and managed to reduce the mortality and morbidity significantly. PMID- 29114483 TI - Cryptosporidiosis: A mini review. AB - Cryptosporidium spp. was first described in mice in 1907. The first human case was reported in an acquired immune deficiency syndrome patient after which it gained importance. It is one of the emerging protozoan parasites according to the Centre of Disease Control and Prevention. The special structure which is present in them such as rhoptries and micronemes are responsible for their virulence and pathogenicity. They can be transmitted from animals, human to human, water, food, and tends to cause waterborne outbreaks. The clinical manifestation in immunocompetent patient is self-limiting when compared to immunocompromised individual where it causes chronic diarrhea not responding to treatment. Hence, it is necessary to diagnose them early to prevent any complication in these patients. There are many investigations currently available such as stool microscopy after Sheather's concentration technique, rapid test targeting specific antigen, molecular methods, and imaging techniques. PMID- 29114486 TI - Morphological and histological analysis of Cotylophoron cotylophorum treated with Acacia concinna. AB - Objective: Paramphistomosis (stomach fluke disease) is a parasitic infection caused by digenetic trematodes and is considered to be one of the most important parasitic diseases affecting livestock worldwide. This disease is widely prevalent in India, and the highest incidence is reported during monsoon and post monsoon months. In the present study, in vitro effect of aqueous extract of pods of Acacia concinna (AcP E) on the morphology and the histology of the digenetic trematode Cotylophoron cotylophorum have been investigated. Materials and Methods: The in vitro effect of AcPE on the morphology and the histology of a digenetic trematode C. cotylophorum have been examined using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and light microscopic techniques. Results: The SEM micrograph of treated flukes showed the appearance of few blebs near the oral region and rupture of the dorsal surface of the tegument. The light and TEM observations revealed significant deleterious changes in the internal organization of the fluke. Severe injury to the tegument due to bleb formation, detachment of tubercles, and vacuolization of the subtegumental region was observed. Nuclear indentation, cytoplasmic autolysis, and mitochondrial abnormalities were the other prominent observations. Conclusion: The results of the present study convincingly showed that AcPE is an effective anthelmintic causing detrimental effect to C. cotylophorum and appears to be a potent phytotherapeutic agent to control paramphistomosis. PMID- 29114487 TI - Prevalence of trypanosome infection in tsetse flies from Oji River and Emene axis of Enugu State, Nigeria: A preliminary report. AB - Introduction: Trypanosomes are protozoan parasites of vertebrates transmitted by blood-sucking tsetse fly. Trypanosomes remain a constant threat to the lives of humans and animals throughout large regions of Africa. Aims and Objectives: This study investigated the presence, prevalence, and species of trypanosome parasite in tsetse flies caught in two areas of no previous documented history of trypanosome infection. Materials and Methods: For this purpose, 63 and 77 nonterenal tsetse flies were collected from Oji River and Emene areas of Enugu State Nigeria, respectively. Genomic DNA was isolated from the whole tsetse fly using genomic DNA extraction kit. Identification and characterization of trypanosome were done using two approaches: the amplification of internal transcribed spacer 1 of ribosomal DNA and the use of primers specific to Trypanozoon. Results: In Oji River, of 63 tsetse flies collected, the identification of trypanosome parasite was done on 57 flies and 6 (10.71%) tsetse flies were infected with trypanosome parasite. Six flies were infected with Trypanosoma Congolense, 2 with Trypanosoma Vivax, and 1 with Trypanosoma brucei. Two mixed infections of T. vivax and T. congolense and 1 mixed infection of T. brucei and T. congolense was also identified. In Emene, of 77 tsetse flies collected, the identification of trypanosome parasite was done on 66 flies and 11 (16.6%) tsetse flies were infected with trypanosome parasite. Nine flies were infected with T. congolense, 2 with T. vivax, and 3 with T. brucei. Mixed infections identified include 2 mixed infections of T. brucei and T. congolense and 1 mixed infections of T. vivax and T. brucei. None of the subspecies of T. brucei were detected using species specific primers. Discussion: This study shows the parasitological evidence on the occurrence of animal African trypanosomiasis and also demonstrated that there is likely no active transmission of human African trypanosomiasis in the study areas. Conclusion: This study shows that there is likely no active transmission of human African trypanosomiasis going on in these localities since no human infective form of the parasite was detected. PMID- 29114488 TI - Seroprevalence of human cystic echinococcosis from North India (2004-2015). AB - Context: Cystic echinococcosis (CE) caused by Echinococcus granulosus is a disease of a significant burden in India. The World Health Organization recommends the use of hospital data for population surveillance to measure the prevalence of CE. Aim: The aim of this study was to estimate the seroprevalence of CE and to compare with previous prevalence rates to estimate the changing pattern in seroprevalence of CE. Materials and Methods: A retrospective analysis of laboratory data of 3929 clinically and/or radiologically suspected cases of CE was carried out for 12 years from 2004 to 2015 and compared to the previous data from 1984 to 2003. The seroprevalence of anti-hydatid immunoglobulin G (IgG) was assessed by enzyme-linked immune sorbent assay. Casoni's intradermal skin test and microscopy on aspirated hydatid cyst fluid were also done. The statistical significance was assessed using Chi-square test and Fisher's t-test. Results: Of the 3929 samples, 1124 (28.6%) were positive for specific anti-hydatid IgG antibody response, while of the 121 tested by Casoni's test, 56 (46.3%) were positive. The seropositivity of CE over the period of 12 years is rising. As compared to our previous data from 1984 to 2003, an overall significant increase in seropositivity was observed during 2004-2015 (28.6% vs. 15.0% in 1984-2003, P < 0.0001). Conclusions: This study emphasizes the necessity of continuous surveillance and integrated control measures to prevent CE in humans and livestock across the country. PMID- 29114489 TI - Chitinase-gene-based analysis of the genetic variability among the clinical isolates of Entamoeba dispar from Puducherry, India. AB - Introduction: Amebiasis is known to be caused by the protozoan parasite Entamoeba histolytica. Entamoeba dispar is considered to be a sibling species of E. histolytica, as the two are phylogenetically closest. There are reports that certain strains of E. dispar isolated were capable of causing hepatic lesions in the experimental animal models. The intra-/inter-species genetic variation has been found to have profound implication in the invasiveness of the disease. Thus, studying polymorphism in E. dispar aids to improve our perspective related to the variability in the genome of the parasite. Materials and Methods: The highly polymorphic region of the gene encoding the enzyme chitinase was targeted for the strain variation analysis in E. dispar. Isolates from the stool and liver abscess aspirate were subjected to the polymerase chain reaction (PCR) for the amplification of the targeted polymorphic loci. The PCR products were sequenced, and genetic variability analysis was carried out. Results: A total of 23 samples in the stool and 1 sample from liver abscess pus were positive for E. dispar by nested multiplex PCR which was confirmed by sequencing. Of these positive samples, 13 amplified for chitinase gene by PCR. We observed seven genotypes in our study isolates, of which four were found to be distinct. Conclusion: This study shows that high degree of genetic variation exists among the clinical isolates of E. dispar in our location. The future studies including the analysis of other genetic makers such as serine-rich E. dispar protein or other loci have to be carried out to get an idea about the distribution of the different strains of E. dispar. PMID- 29114490 TI - Evaluation of the utility of conventional polymerase chain reaction for detection and species differentiation in human hookworm infections. AB - Background: Human hookworm infection is caused mainly by Necator americanus and Ancylostoma duodenale. Among the zoonotic hookworm species, only Ancylostoma ceylanicum causes potent human infections where dogs and cats act as reservoir of infection. Hence, species differentiation is imperative because the eradication of both anthroponotic and zoonotic hookworm depends on the concurrent human and animal health programs, hygienic practices, and mass drug administration for humans and dogs. Objective: This study was performed to evaluate the utility of polymerase chain reaction (PCR) for detection of hookworm infections. Materials and Methods: A total of 209 stool samples were collected and subjected to stool microscopy, Kato-Katz method to identify the intensity of the infection, coproculture for L3 larval identification and species differentiation and semi nested PCR with sequencing. Results: The prevalence of hookworm was estimated as 7.6%. Highest hookworm prevalence was seen in 20-30 years of age group. Majority of the infections were mild intensity infections. Sensitivity of stool microscopy was found to be 81.2% and the specificity was 100%. Sensitivity of Kato-Katz method was 87.5% and specificity was 100%. True positivity by agar plate culture was 83.3% and false positivity rate was 16.6%. Conclusion: Stool microscopy is the major mode of detection, but it has a higher false negative rate. Coproculture is time-consuming and needs the expertise to differentiate the species. On the other hand, PCR is known to be a sensitive, specific, and a reliable investigative tool which can help in diagnosis as well as in species differentiation. PMID- 29114491 TI - Reactive arthritis associated with Strongyloides stercoralis: Report of an uncommon relation. PMID- 29114492 TI - Enterobius vermicularis infestation of urinary tract leading to recurrent urinary tract infection. PMID- 29114493 TI - Severe Blastocystis subtype 3 infection in a patient with colorectal cancer. AB - Colorectal cancer (CRC), more of lifestyle-related disorder, is one of the deadliest types of cancer across the globe. Nevertheless, infectious agents could be responsible for 20% of cancer. Recent findings have indicated the association of Blastocystis in CRC and recommend routine screening for Blastocystis. Herein, we describe a case of CRC with severe Blastocystis infection. PMID- 29114495 TI - An E-mail Interview with Prof. Gagandeep Kang. PMID- 29114494 TI - Giardiasis mimicking celiac disease in a patient of common variable immunodeficiency. AB - An adolescent boy presented to pediatrics outpatient department with complaints of recurrent diarrhea, nausea, vomiting, and pedal edema since 3-4 months, with no relief even after taking treatment. His investigation revealed decreased serum IgA, IgG, and IgM levels with hypoproteinemia. Duodenal biopsy showed features of celiac disease (CD), but tissue transglutaminase IgA was negative. In stool examination, plenty of Giardia lamblia cysts and eggs of Hymenolepis nana were present. He improved on treatment and remained asymptomatic for 4 months. However, he again developed symptoms and succumbed to his illness. In patients of common variable immunodeficiency (CVID), who present with features of CD, coinfection, especially with G. lamblia and other parasites must always be kept in mind. The aim is to report a case of recurrent giardiasis with CVID mimicking CD from Western Rajasthan, India. PMID- 29114498 TI - From basic medicine to clinical application in exercise rehabilitation. PMID- 29114499 TI - A review of factors limiting physical activity among young children from low income families. AB - Children need to participate in structured physical activities to avoid obesity and to engage in sports and games in the future. However, certain groups of our population have little access to enhance levels of physical activity. One such group is children from low-income families who are more likely to have less opportunity for participation in physical activity because of factors such as unsafe streets or limited access to playgrounds. According to the United States Department of Health and Human Services, there is a strong relationship between family income and physical activity with low-income families being the most sedentary. In order to design effective physical activity interventions for those children, there is a need to identify factors influencing physical activity in these populations, yet, there has been limited research that explores this issue. Therefore, the purpose of this article was to review the literature on factors limiting physical activity among low-income children. PMID- 29114497 TI - KCTD5 and Ubiquitin Proteasome Signaling Are Required for Helicobacter pylori Adherence. AB - In order to establish infection, bacterial pathogens modulate host cellular processes by using virulence factors, which are delivered from the bacteria to the host cell leading to cellular reprogramming. In this context, several pathogens regulate the ubiquitin proteasome system in order to regulate the cellular effectors required for their successful colonization and persistance. In this study, we investigated how Helicobacter pylori affect the ubiquitination of the host proteins to achieve the adherence to the cells, using AGS gastric epithelial cells cultured with H. pylori strains, H. pylori 26695 and two isogenic mutants H. pylori cag::cat and vacA::apha3, to characterize the ability of H. pylori to reprogram the ubiquitin proteasome systems. The infection assays suggest that the ubiquitination of the total proteins does not change when cells were co-culture with H. pylori. We also found that the proteasome activity is necessary for H. pylori adhesion to AGS cells and the adherence increases when the level of KCTD5, an adaptor of Cullin-3, decrease. Moreover, we found that KCTD5 is ubiquitinated and degraded by the proteasome system and that CagA and VacA played no role on reducing KCTD5 levels. Furthermore, H. pylori impaired KCTD5 ubiquitination and did not increase global proteasome function. These results suggest that H. pylori affect the ubiquitin-proteasome system (UPS) to facilitate the adhesion of this microorganism to establish stable colonization in the gastric epithelium and improve our understanding of how H. pylori hijack host systems to establish the adherence. PMID- 29114500 TI - Analysis of energy restriction and physical activity on brain function: the role of ketone body and brain-derived neurotrophic factor. AB - Brain development is a complex process, and stimuli during this development period may modulate the functional maturation of the brain. It has been shown that environmental stimuli, such as physical activity habits, have a beneficial effect on brain development. Endurance exercise and prolonged fasting state are known to improve brain function including cognition. The exact mechanisms of exercise improving brain function are still unknown. However, it can be considered that energy restriction and stressful challenge induced by long lasting physical exercise might cause direct effect on brain function. Upregulation of brain-derived neurotrophic factor and ketone body caused by exercise might be considered as the mechanism of exercise on brain function. In the present study, we discussed on two main topics: "exercise and BDNF" and "exercise and energy restriction." PMID- 29114501 TI - Age-dependent differences of treadmill exercise on spatial learning ability between young- and adult-age rats. AB - The effect of exercise, which increases hippocampal neurogenesis and improves memory function, is well documented, however, differences in the effect of exercise on young children and adults are not yet known. In the present study, age-dependent differences of treadmill exercise on spatial learning ability between young- and adult-age rats were investigated. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 6 weeks. Radial 8-arm maze test was conducted for the determination of spatial learning ability. Cell proliferation in the hippocampal dentate gyrus was determined by 5-bromo-2'-deoxyuridine immunohistochemistry. Western blot for brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was performed. In the present study, the number of errors in the young-age rats was effectively decreased by treadmill exercise. Hippocampal neurogenesis was more active in the young-age rats than in the adult-age rats. BDNF and TrkB expression in the hippocampus was greater in the adult-age rats than in the young-age rats. The results of this study showed that adults have excellent spatial learning abilities than children, but the improvement of exercise-induced spatial learning ability through neurogenesis is better in children. PMID- 29114502 TI - A study on the effects of exercise motivation of the elderly people on euphoria. AB - The present study aimed to empirically determine the relationship between the degree of exercise participation by the elderly people and their euphoria. The analysis results are as follows. First, the difference between the elderly people's participation in the exercises and the euphoria that they have experienced showed that in all low variables of euphoria, the group who participated in the exercises showed a higher level of euphoria than the group who did not participate in the exercises. Second, the analysis of the effects of the elderly people's motivations for exercise participation on euphoria showed that there was a significant relation between the two. Furthermore, the following suggestions were made for areas that the current study did not cover, as well as for the follow-up studies. The follow-up studies would need an in-depth multiangled analysis of various fun factors in order to encourage the elderly people to participate in the exercises by conducting interviews and observation studies with the study participants. PMID- 29114503 TI - Effects of long or short duration stimulus during high-intensity interval training on physical performance, energy intake, and body composition. AB - To compare the effects of 6 weeks of long or short high-intensity interval training (long- or short-HIIT) on body composition, hunger perception, food intake and rating of perceived exertion (RPE). Twenty previously untrained women (25+/-5 years) were randomly assigned to do a long-HIIT (n=10) or a short-HIIT (n=10). The long-HIIT group performed fifteen 1-min bouts at 90% of maximum heart rate (HRmax), interspersed by 30-sec active recovery (60% HRmax). The short-HIIT group performed forty-five 20-sec bouts at 90% of HRmax, interspersed by 10-sec active recovery (60% HRmax). The training for both groups was conducted 3 times a week for 6 weeks. All subjects performed the Astrand cycle ergometer test to estimate maximal oxygen consumption (VO2max) 1 week before and after the training period, as well as body composition, which was estimated through circumferences and skinfold thicknesses. For all training sessions, the heart rate, visual scale of hunger, internal load, and RPE were recorded. In the first and last week of training, subjects were asked to record a 24-hr food diary for 3 days. Both training induced significant pre to post decreases for fat mass, fat percentage, waist circumference, sum of seven skinfolds and RPE. As expected estimated, the VO2max increased in both groups. There were no differences for hunger perception, energy intake, and body mass. Long and short-HIIT resulted in fat loss, without altering the energy intake. PMID- 29114504 TI - Effects of 16-week spinning and bicycle exercise on body composition, physical fitness and blood variables of middle school students. AB - The purpose of this study was to investigate the effects of 16 weeks of spinning and bicycling exercises on body composition, physical fitness and blood variables in female adolescents. Subjects participated in this study were 24 female middle school students (12 spinning cycles, 12 general bicycles) attending to Seoul Yeoksam middle school. Each group was trained for 16 weeks, 3 times a week, and 1 hr per day after school. Body composition, physical fitness (1,200 running, sit ups, back strength, sit and reach, side-steps) and blood variables (low-density lipoprotein cholesterol, glucose, reactive oxygen species, and malondialdehyde) were examined before and after 16 weeks of training. As the results, body weight did not show any significant difference; however, body mass index, and % body fat were significantly difference in spinning group. The enhancement in physical fitness factors were recognized in both groups, which was greater in spinning group in sit-ups, back strength, and side steps. Blood parameters were significantly difference between groups, but between group and time interactions were significantly difference in glucose and reactive oxygen species. In conclusion, this study suggests that 16 weeks of bicycle exercises were positive changes in body composition, physical fitness and blood constituents, indicating that spinning cycle is more beneficial as compared to ordinary bicycle. PMID- 29114505 TI - Examining and comparing the health and performance indices of university undergraduate students according to year of study and gender. AB - This study examined and compared, based on year of study and gender, the health and performance indices of university undergraduate students. Eighty-nine students (mean+/-standard deviation age, 22.47+/-2.22 years) were randomly selected for assessment prior to second semester examination of 2015/2016 academic year. body mass index, resting metabolic rate, visceral fat, skeletal muscle mass, body fat, systolic & diastolic blood pressure, resting heart rate, upper & lower body endurance, handgrip strength, and lower back and hamstring flexibility were assessed. The students had sedentary heart rate, low skeletal muscle mass, average upper and lower body endurance, and weak handgrip strength. Significant difference existed in the visceral fat (P=0.008) between third and fourth year students. There were significant gender differences in resting metabolic rate (P=0.000), skeletal muscle mass (P=0.000), body fat (P=0.000), systolic blood pressure (P=0.001), heart rate (P=0.005) and handgrip strength (P=0.000). There are gender differences in association between health and performance indices. Dependable health education and pragmatic involvement of undergraduate university students in structured exercise programmes are recommended. PMID- 29114506 TI - Correlations among visual analogue scale, neck disability index, shoulder joint range of motion, and muscle strength in young women with forward head posture. AB - This study investigated the correlation between the neck disability index (NDI) and visual analogue scale (VAS), which are indicators of neck pain, shoulder joint range of motion (ROM), and muscle strength in women with a slight forward head posture. This study was carried out on 42 female college students attending Uiduk University in Gyeongju, Korea. The neck pain and disability index for each subject was measured using VAS and NDI, respectively. Two physiotherapists measured the shoulder joint ROM and muscle strengths of the subjects using a goniometer and a dynamometer, respectively. External rotation, internal rotation, and abduction of the shoulder joint were measured for each subject. A significant negative correlation between neck pain and shoulder joint ROM in external rotation and the muscle strength of the shoulder joint in abduction was found in the subjects. In addition, a significant positive correlation was observed between ROM in external rotation and muscle strength in abduction. This study showed a significant negative correlation between neck pain and ROM in external rotation as well as between neck pain and the muscle strength in abduction. PMID- 29114508 TI - The effects of ankle weight loading on the walking factors of adults without symptoms. AB - The purpose of this study was to evaluate the components of walking adults who have no symptoms by integrating the temporal and spatial walking variables obtained from the GAITRite system. The following describes previous debates on weight-loaded walking training. The conclusion was as follows. First, there was a significant difference in walking distance between the 0% group and 1% group and between the 1% group and 2% group (P<0.05). Sencond, there was a significant difference in walking velocity between the 0% group and 1% group and between the 0% group and 2% group (P<0.05). Third, there was a significant difference in walking cadence between the 0% group and 1% group, between the 1% group and 2% group, and between the 0% group and 2% group (P<0.05). These study results indicate that diverse amounts of weight loading can be effective for enhancing the walking factors of adults without symptoms. PMID- 29114507 TI - Investigation of alpha band of the electroencephalogram before and after a task of proprioceptive neuromuscular facilitation. AB - The proprioceptive neuromuscular facilitation (PNF) sets up a feature of treatment developed with the objective to facilitate and improve the motor performance. The aim of this study was to investigate in healthy female individuals the effects of electrophysiological of a diagonal of the PNF upper limb. The sample consisted of 30 female participants aged between 18 to 28 years, randomly divided into 3 groups (G1, G2, and G3). The three groups had 2 moments of electroencephalographic signal detection, before and after the task. The statistical neurophysiological design allowed the analysis of the relative power of alpha band in three leads (Fz, F7, and F8). Thus, a three-way mixed factorial analysis of variance (ANOVA) was performed to investigate the factor inter subjects (groups) and intrasubjects (areas and moments), a two-way ANOVA to investigate the interactions between the three factors, and a one-way ANOVA to analyze separately the factors time and area. A P<=0.05 was considered as significance level. The results showed significant increase of alpha band in the three groups analyzed, being more evident to the G2 group. Therefore, the PNF can be considered favorable also in relation to the cortical behavior, reinforcing its use in rehabilitation processes, especially in the clinical practice of physiotherapy. PMID- 29114509 TI - Effect of motor cognition program for improving temporal-spatial timing memory ability with mild cognitive impairment patients. AB - This exploratory study evaluated motor cognition program for improving temporal spatial timing memory ability with mild cognitive impairment (MCI) patients. The purpose was to explore the efficacies of motor cognition program according to practice methods, centering on coordination and observation pattern. Two practice methods were applied to the 40 MCI elder. In experiment 1, participants divided into two group as, one-hand practice group (n=20) and both-hands practice group (n=20). In experiment 2, participants divided into two group as, active observation group (n=20) and passive observation group (n=20). The participant was asked to alternatively press two buttons 6 times with the index finger hand with goal rhythm pattern (3,600 msec in total duration). In coordination pattern, bimanual practice was more effective for improving temporal-spatial timing memory ability than unilateral practice. In observation pattern, active observation showed better learning effect than passive observation. However, there was a learning effect even in passive observation pattern. Such a result claimed for the elderly, who has problem to do daily activity, could use observation of temporal-spatial timing task for improving cognitive ability. PMID- 29114510 TI - Effect of timing of whey protein supplement on muscle damage markers after eccentric exercise. AB - Whey protein is a nutritional supplement commonly ingested for recovery following exercise. However, the timing when whey protein supplement must be ingested after muscle-damaging exercise is debatable. Therefore, the present study investigated the effects of the timing of supplement ingestion on muscle damage markers after eccentric or muscle-damaging exercise. In total, 32 collegiate male students participated in this study; they were randomly assigned to control group (n=8), before supplement group (n=8), after supplement group (n=8), or before and after supplement group (n=8). Eccentric exercise was performed using elbow flexors with a modified preacher curl machine. Subsequently, maximal isometric strength, muscle soreness, range of motion (relaxed and flexed arm angle), and blood markers (creatine kinase and aspartate transaminase) were measured before and after exercise. Repeated-measure analysis of variance was used to analyze the effects of timing of supplement. No significant group by time effects were noted in maximal isometric strength, muscle soreness, range of motion, and blood markers (P>0.05). The timing of whey protein supplement did not affect reduction of muscle damage or recovery following eccentric exercise. PMID- 29114511 TI - The study of trunk and pelvic movement on mediolateral ramps of various ramp angles during one-legged standing. AB - The purpose of this study was to identify the instability of the trunk and the pelvis of subjects who were standing on differently angled ramps under conditions in which the ramps were crossed. Changes in the trunk and the pelvis while each subject was standing on one leg in the direction of the cross ramps at four angles (0 degrees , 5 degrees , 10 degrees , and 15 degrees ) were measured. To identify instability, the trunk inclination, trunk imbalance, pelvic position, pelvic rotation, and pelvic torsion of 20 healthy male subjects were measured. The measurement was conducted using a three-dimensional spinal diagnostic imaging system (Back Mapper). According to the results of the measurement, trunk imbalance, pelvic position, pelvic rotation, and pelvic torsion differed between the medial and lateral ramps and with different ramp angles. This study's results suggested that different mediolateral ramp conditions altered the pelvic and trunk alignment. With the 15 degrees ramp, the anterior tilt and lateral tilt of the pelvis increased regardless of ramp direction. The 10 degrees ramp condition altered the pelvic rotation to the contralateral side. In addition, the lateral trunk tilt was elevated with the lateral down foot condition. PMID- 29114512 TI - The RunSmart training program: effect on oxygen consumption and lower extremity biomechanics during running. AB - As recreational running continues to gain popularity, more individuals are seeking ways to improve running performance. RunSmart is a running intervention program designed to enhance a runner's form. In addition to correcting flaws in a runner's form, RunSmart offers the opportunity for runners to continue a regular regimen while slowly integrating changes in form. The purpose of this case series was twofold: to determine if the RunSmart program coincides with improvements in oxygen consumption (VO2), a variable often associated with better running performance times, and to evaluate the RunSmart program in regard to enhancing gait biomechanics. Five recreational runners volunteered to participate in this program. Subjects initially reported to the clinic for an initial submaximal VO2 treadmill test and lower extremity biomechanical analysis. After the initial testing session, each subject attended one session of one-on-one individualized RunSmart instruction per week for 6 weeks. At the first RunSmart session, subjects received a biomechanical analysis to determine their foot strike pattern and areas of muscular weakness and range of motion limitations. Throughout the 6 week run-ning program, participants ran 5 days every week for predetermined times each day; 2 runs every week were designated as interval training runs. Subjects then underwent a follow-up submaximal VO2 treadmill test and lower extremity biomechanical analysis at the end of 6 weeks. Descriptive statistics were used to assess data pertaining to VO2 and biomechanical analysis and compare initial and follow-up testing sessions. Following completion of the RunSmart program, subjects demonstrated improvements in VO2 and also improved several biomechanical factors related to the lower extremity running gait. Based on the results from this case series, the RunSmart training program may have the potential to change a runner's form and improve VO2, thus resulting in improved distance running times. However, this is speculation given the nonexperimental nature of this case series. Future research on this topic should include a greater number of participants in randomized controlled trials on injury prevention and running efficiency. PMID- 29114513 TI - Low blood pressure is sustained during subsequent activities of daily living performed after power training in older women. AB - The present study aimed to examine the effects of a prior session of power training on blood pressure values during tasks that mimic the activities of daily living in hypertensive and normotensive older women. A randomized crossover experimental design was used for this study. Eleven older women (age, 66.1+/-1.2 years; body mass index, 26.7+/-4.8 kg/m2; systolic blood pressure, 133.9+/-23.4 mmHg) were recruited to participate. Volunteers were randomly underwent to a single session of physical exercise equalized by training volume, characterized by 3 sets of 8-10 repetitions in 8 different exercises. However, Power training session was performed at a higher intensity (moderate) than Sham session (rest/very, very easy ). Immediately after the end of the exercise session, subjects were assigned to perform five tasks that mimic the activities of daily living. Hemodynamic parameters were recorded before and immediately after the session of physical exercise, as well as in the end of each of the tasks. Results demonstrated significant elevations in systolic blood pressure and pulse pressure values during the performance of the tasks after the Sham session. However, values were not altered in the power training session. Data of the present study indicate that an acute session of power training can maintain blood pressure values lower during the subsequent performance of tasks that mimic activities of daily living in older women. PMID- 29114515 TI - Responses of inflammatory cytokines following moderate intensity walking exercise in overweight or obese individuals. AB - This study investigated the effects of a 4-week moderate intensity walking exercise on the levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and adiponectin in overweight or obese individuals. Twenty-seven (13 men and 14 women) physically inactive, over-weight or obese (body mass index>25.0 kg/m2) individuals participated in the study. Each participant was randomly assigned to either exercise (EX; n=15) or control (CON; n=12) group. The EX group performed moderate intensity walking exercise on a treadmill for 60 min at 70% of maximal heart rate for 4 weeks (3 days/wk). Overnight fasting blood samples were collected before and after the study period (Pre and Post) to analyze the levels of pro-/anti-inflammatory cytokines such as CRP, TNF-alpha, and adiponectin. CRP and adiponectin as well as body weight and body composition were not significantly altered following the 4-week exercise intervention. However, there was a significant group*time interaction for TNF-alpha. The post hoc test revealed that the level of TNF-alpha significantly decreased only in EX (EX: mean+/-standard deviation, Pre 55.18+/-6.57 pg/mL, Post 50.31+/-6.22, P=0.018 vs. CON: Pre 55.5+/-5.88, Post 58.19+/-6.48, P=0.25). EX Post was also significantly lower as compared to CON Post (P=0.0074). Although there was no change in body weight or fat mass, the 4-week aerobic exercise training was long enough to decrease the level of TNF-alpha, indicating physical activity may improve level of inflammation independently from the change in fat mass. The current study also confirmed previous research suggesting that longer period of exercise training accompanied by weight loss may be required to induce significant changes in CRP and adiponectin. PMID- 29114516 TI - Comparative effectiveness of lumbar stabilization, dynamic strengthening, and Pilates on chronic low back pain: randomized clinical trial. AB - The aim of the present study was to compare three different forms of exercises namely lumbar stabilization, dynamic strengthening, and Pilates on chronic low back pain (LBP) in terms of pain, range of motion, core strength and function. In this study, 44 subjects suffering from non-specific LBP for more than 3 months were randomly allocated into the lumbar stabilization group, the dynamic strengthening group, and the Pilates group. Ten sessions of exercises for 3 weeks were prescribed along with interferential current and hot moist pack. Pain was assessed by visual analog scale, functional affection by modified Oswestry Disability Questionnaire, range of motion by assessing lumbar flexion and extension by modified Schober test and core strength was assessed by pressure biofeedback on day 1 and day 10 of the treatment. There was reduction of pain, improvement in range of motion, functional ability and core strength in all the 3 exercise groups. The improvement was significantly greater in the lumbar stabilization group for all the outcome measures, when compared the posttreatment after 10th session. Pairwise comparison showed that there was greater reduction of disability in the Pilates group than the dynamic strengthening group. It was concluded that the lumbar stabilization is more superior compared to the dynamic strengthening and Pilates in chronic nonspecific LBP. However, long-term benefits need to be assessed and compared with prospective follow-up studies. PMID- 29114514 TI - Visceral obesity and chronic pain: effect of a 4-week rehabilitation program on adipokines and insulin resistance. AB - Obesity and chronic pain are two major diseases of the 21th century. Our principal objective was to investigate the effects of a 4-week rehabilitation program on adiponectin and leptin concentrations, and insulin resistance, in patients with abdominal obesity and chronic pain syndrome. Our secondary objectives were to investigate the effects of this program on pain, body mass index (BMI), waist circumference and maximal oxygen consumption (VO2max) and to compare changes in VO2max between patients with or without insulin resistance. Among a consecutive sample of 128 patients with abdominal obesity hospitalized for rehabilitation for a chronic pain syndrome, 111 completed the protocol, which was a 4-week rehabilitation program including 6 hr of rehabilitation per day, 5 days per week, in a referral center of rehabilitation. This prospective cohort study compared clinical (BMI, waist circumference, VO2max, pain) and biological measures (concentrations of adiponectin, leptin and insulin, score of homeostasis model assessment of insulin resistance [HOMA]) before and after the program. Plasma leptin, adiponectin and insulin concentrations (P<0.0001) and score of HOMA (P=0.0002) had decreased significantly by the end of the 4 weeks. Pain, BMI and waist circumference decreased significantly, and VO2max improved significantly (P=0.0001). Patients with insulin resistance had less improvement of their aerobic condition at the end of the 4 weeks (P<0.002). The rehabilitation program decreases the concentration of leptin, and improves insulin sensitivity in patients with chronic pain and visceral obesity. Aerobic recovery was worse for patients with insulin resistance than other patients. PMID- 29114517 TI - Effects of proprioceptive neuromuscular facilitation-based abdominal muscle strengthening training on pulmonary function, pain, and functional disability index in chronic low back pain patients. AB - The purpose of this study was to evaluate the effect of abdominal muscle strengthening training (AMST) using proprioceptive neuromuscular facilitation (PNF) on pulmonary function, pain, and functional disability index in chronic low back pain (CLBP) patients. Thirty CLBP patients were randomly assigned to the traditional physical therapy (control) group (n=15) and PNF-AMST group (n=15). Forced expiratory volume at 1 second (FEV1) was measured to measure changes in pulmonary function. To measure the degree of pain, a visual analog scale (VAS) was used. The Oswestry Disability Index (ODI) was used to assess the disability level due to low back pain. A paired t-test was performed to compare differences within the groups before and after intervention. An independent t-test was performed to compare differences between the test and control groups. The level of significance was set at alpha=0.05. Within-group changes in FEV1 were significantly different in the experimental group (P<0.01), and those in VAS and ODI were significantly different in both groups (both P<0.01). The improvements in FEV1, VAS, and ODI were significantly greater in the experimental group than in the control group (P<0.01). This study showed that AMST using PNF was effective in enhancing pulmonary function and decreasing pain and functional disability index inpatients with CLBP. We expect it to be useful as one of the programs for CLBP patients in the future. PMID- 29114518 TI - Association study between ZFHX3 gene polymorphisms and obesity in Korean population. AB - The aim of this study is to investigate whether single nucleotide polymorphisms (SNPs) of zinc finger homeobox 3 (ZFHX3 ) gene are susceptibility to obesity. Recently, several study suggested that specific polymorphisms in various genes may have effect to obesity. In present study, 54 SNPs of ZFHX3 gene were genotyped in 209 overweight and obese patients with a body mass index (BMI)>=23 kg/m2 (mean+/-standard deviation, 44.7+/-6.4 kg/m2) and 159 healthy controls with a BMI of 18.5-23.0 kg/m2 (43.6+/-6.2 kg/m2). Genotyping of each SNP was performed by custom DNA chip. Logistic regression models (dominant, recessive, and log additive models) were used to calculate odds ratio, 95% confidence interval, and P-values. Significant association was considered at P<0.05. Among tested SNPs in ZFHX3 genes, seven SNPs of ZFHX3 gene showed significant association with obesity (P<0.05 in each model, respectively). In conclusion, these results indicate that SNPs of ZFHX3 gene might be contributed to development of obesity in the Korean population. PMID- 29114519 TI - Role of physical activity in mortality prediction in elderly hospice patients: the methodological issues. PMID- 29114520 TI - On Cobb angles, flexibility, and lumbar strength measurements. PMID- 29114522 TI - Research and publication ethics of the Journal of Exercise Rehabilitation. PMID- 29114521 TI - Erratum: Interval and continuous aerobic exercise training similarly increase cardiac function and autonomic modulation in infarcted mice. AB - [This corrects the article on p. 257 in vol. 13, PMID: 28702435.]. PMID- 29114523 TI - Skeletal muscle contraction-induced vasodilation in the microcirculation. AB - Maximal whole body exercise leads skeletal muscle blood flow to markedly increase to match metabolic demands, a phenomenon termed exercise hyperaemia that is accomplished by increasing vasodilation. However, local vasodilatory mechanisms in response to skeletal muscle contraction remain uncertain. This review highlights metabolic vasodilators released from contracting skeletal muscle, endothelium, or blood cells. As a considerable skeletal muscle vasodilation potentially results in hypotension, sympathetic nerve activity needs to be augmented to elevate cardiac output and blood pressure during dynamic exercise. However, since the enhanced sympathetic vasoconstriction restrains skeletal muscle blood flow, intramuscular arteries have an indispensable ability to blunt sympathetic activity for exercise hyperaemia. In addition, we discuss that mechanical compression of the intramuscular vasculature contributes to causing the initial phase of increasing vasodilation following a single muscle contraction. We have also chosen to focus on conducted (or ascending) electrical signals that evoke vasodilation of proximal feed arteries to elevate blood flow in the microcirculation of skeletal muscle. Endothelial hyperpolarization originating within distal arterioles ascends into the proximal feed arteries, thereby increasing total blood flow in contracting skeletal muscle. This brief review summarizes molecular mechanisms underlying the regulation of skeletal muscle blood flow to a single or sustained muscle contraction. PMID- 29114524 TI - Effect of acute and chronic exercise on plasma matrix metalloproteinase and total antioxidant levels. AB - The relationship between acute and chronic exercise and expression of matrix metalloproteinases (MMPs) in muscles is unknown. There happen some alterations in the oxidant-antioxidant balance due to exercise. This study aimed to investigate the levels of MMP-1, tissue inhibitors of metalloproteinases (TIMP-1), hyaluronic acid (HA), total antioxidant status (TAS), and total oxidant status (TOS) following acute and chronic exercising in rats. Twenty-six Wistar Albino male rats were divided in to three groups: control, acute, and chronic groups. In acute group, treadmill exercise was performed 3 days/wk, 10 min/day for 1 week. In chronic group, exercise performed 7 days/wk, 60 min/day for 4 weeks. At the end of the experiment, plasma MMP-1, TIMP-1, HA, TAS, and TOS levels were measured. In current study, the MMP-1, TIMP-1, HA, and TOS levels not observed statistically significant difference among all groups, but in chronic group, there was a significantly difference (P<0.05) between the control and experimental groups in terms of TAS and oxidative stress index (OSI) levels. TAS, TOS, and OSI levels were significantly different between control and chronic exercise group (P<0.01, P<0.05, and P<0.01, respectively). According to these results, we can say acute and chronic exercise does not effect on plasma MMP-1, TIMP-1, and HA levels. PMID- 29114525 TI - The effect of maternal forced exercise on offspring pain perception, motor activity and anxiety disorder: the role of 5-HT2 and D2 receptors and CREB gene expression. AB - The effect of maternal forced exercise on central disorders in offsprings has been shown but the mechanism is still unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise on offspring neurodevelopment and neurobehavioral symptoms is evaluated. Sixty pregnant rats were trained by forced exercise and some behavioral and molecular aspects in their offspring were evaluated in presence of 5-HT2 and D2 receptors agonists and antagonists. The results showed that maternal forced exercise causes increase of pain tolerability and increase latency of pain perception in offspring in hot plate test, writhing test and tail flick test. Also maternal forced exercise causes decrease of depression and anxiety like behavior in offsprings. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists inhibited the protective effects of forced exercise and cause disturbance in pain perception and tolerability and increase depression and anxiety in offsprings. Also expression of cyclic AMP response element binding protein (CREB) was changed in all experimental groups. In conclusion, our data suggested that maternal forced exercise causes neurobehavioral protective effect on offsprings and this effect might probably be mediated by 5-HT2 and D2 receptors and activation of CREB gene expression. PMID- 29114526 TI - Skin temperature response to unilateral training measured with infrared thermography. AB - This study aimed to identify the skin temperature (Tsk) behavior to understand the acute cross-effect after unilateral training of lower-limbs. Seventeen healthy young men (weight, 75.2+/-5.5 kg; height, 1.8+/-0.1 m; age, 22.5+/-1.6 years) were divided into two groups: high-trained (n=8) and low-trained (n=9). All participants performed: (a) one-repetition maximum (1RM) testing protocol on the leg press, (b) a unilateral training protocol (4*10 repetitions at 70% of 1RM for leg press and 4*10 repetitions at 50% of 1RM for knee extension). Pre- and posttraining thermal images were recorded. The main results showed that independent of the limb (exercised vs. nonexercised), differences between low- and high-trained were observed for all regions of interest (ROI) except for the anterior knee: posttraining, 30-min and 60-min posttraining in nonexercised limb. The increase of contralateral Tsk was more than 50% on the ROIs corresponding to the exercises muscles 30-min post-training in low-trained but was not so high in high-trained (P<0.05). Low-trained subjects incremented more the Tsk than high trained in both legs after exercise. In conclusion, we observed an acute contralateral Tsk effect to unilateral training on the Tsk of the nonexercised limb, reliant on the training level of the subject. PMID- 29114527 TI - Effects of special exercise programs on functional movement screen scores and injury prevention in preprofessional young football players. AB - To increase movement capacity and to reduce injury risk in young soccer players by implementing a special functional exercise program based on functional movement screen (FMS) and correctives. 67 young male athletes 14-19 years of age from a Super League Football Club Academy participated in the study. Functional movement patterns were evaluated with FMS assessment protocol. Deep squat, hurdle step, inline lunge, shoulder mobility, active straight leg raise, trunk stability push-up, and rotatory stability were examined in FMS. Considering the FMS scores the number of intervention and control groups were defined as 24 and 43, respectively. Intervention program was composed of 1 hr twice a week sessions in total of 12 weeks with 4 weeks of mobility, 4 weeks of stability, and 4 weeks of integration exercises. At the end of 12-week intervention and control groups were re-evaluated with FMS protocol. Contact and noncontact sports injuries recorded during one season. In intervention group there was statistically significant difference in increase in total FMS scores (P<0.01), deep squat (P<=0.001), hurdle step (P<0.05), inline lunge (P<0.01), and trunk stability push-up (P<0.01). In control group total FMS, deep squat, and trunk stability push-up scores increased with a statistical difference (P<0.01, P<0.05, P<=0.01, respectively). The incidence of noncontact injury in control group was higher than intervention group (P<0.05). Periodic movement screening and proper corrections with functional training is valuable in order to create better movement capacity to build better physical performance and more effective injury prevention. PMID- 29114528 TI - Effect of compression garments on delayed-onset muscle soreness and blood inflammatory markers after eccentric exercise: a randomized controlled trial. AB - The purpose of this study was to investigate how compression garments, applied after eccentric exercise, can affect delayed onset muscle soreness (DOMS) and inflammatory markers. Sixteen healthy male university students enrolled in this study and were randomly assigned to either the compression garment group (CG, n=8) or control group (CON, n=8). All participants performed two sets of eccentric exercise using elbow flexor with 25 repetitions per set on a modified preacher curl machine. Maximal isometric strength was measured before exercise and immediately, 24, 48, 72, and 96 hr after eccentric exercise. Muscle soreness was measured before exercise and 24, 48, 72, and 96 hr after eccentric exercise. Creatine kinase (CK) activity and tumor necrosis factor-alpha (TNF-alpha) levels were also measured before exercise and 3, 6, 24, and 48 hr after exercise. A repeated measures analysis of variance was used for statistical analysis. The CG group reported faster recovery of maximal isometric strength following exercise (P<0.001) and lower muscle soreness during the recovery period than the control group (P<0.05). However, there were no significant differences in either CK activity or TNF-alpha levels between the two groups (P>0.05). In conclusion, wearing compression garments during the postexercise period can be an effective way to reduce DOMS and accelerate the recovery of muscle function. PMID- 29114529 TI - Rehabilitation training in artificially heated environment. AB - Sauna has become a popular club house facility where the dweller enjoys relaxation. Some exercise groups like yoga and Qigong practitioners, are making use of the heated environment to achieve quicker and better results of trainings. Sauna therapy is producing a thermal stress through hyperthermia. The cardiovascular system readily responds by increasing the heart rate which can become double the resting stage within minutes and cardiac output may have a 70% increase. The body's surface response to heat leads to a 40% of decrease in peripheral vascular resistance, thus allowing rapid peripheral blood flow which is responsible for greater heat dispersal directly from the skin. The chained physiological reactions of increased cardiac and pulmonary outputs, while blood pressure drops suggest that Sauna could be good for chronic diseases. When active stretching are executed simultaneously with controlled breathing in a smooth synchronized chain of activities under the individual's free will, a harmonized state of mind reaching the level of meditation follows. Sauna room environment initiates a physiological stat equivalent to moderate exercises. Qigong practice is typical anaerobic training. Both Sauna and Qigong lead to a tranquility of the mind. The unique nature of practicing Qigong in a heated environment is therefore clear. A small pilot study on Qigong practice within the Sauna room showed a higher increase in heart rate which amounted to 30%-40% above the pre-exercise level. The blood pressure checked after Qigong, on the contrary, remained stable or even slightly decreased. PMID- 29114530 TI - Test-retest reliability of repeated knee laxity measurements in the acute phase following a knee trauma using a Rolimeter. AB - The purpose was to examine the test-retest reliability of the Rolimeter measurement procedure in the acute time phase, following a substantial knee trauma. In total, 15 participants with acute knee trauma were examined by one single observer at three different time-points with the Rolimeter using a maximum force. The selected time-points were: baseline (0-7 days after the trauma), midpoint (3-4 weeks after the trauma), and endpoint (3-4 weeks after the trauma). The anterior-posterior displacement was recorded where the endpoint evaluation was used as the reference value. The mean anterior laxity scores remained constant over the measurement time-points for both knees, with an anterior laxity that was 2.7 mm higher (on average) in the injured than the noninjured knee (9.5 mm vs. 6.8 mm). The mean difference (i.e., bias) between laxity scores, for the injured knee, measured at endpoint versus baseline was 0.2+/-1.0 mm and -0.2+/ 1.1 mm when measured at endpoint versus midpoint, with average typical errors of 0.7 and 0.8 mm and intra-class correlations that were very strong (both r=~0.93). For the same comparisons on the noninjured knee, systematic bias was close to zero (0.1+/-0.3 and -0.1+/-0.3 mm, respectively), and both the intra-class correlations were almost perfect (r=~0.99). The current study implicates that repeated Rolimeter measurements are relatively reliable for quantifying anterior knee laxity during the acute time-phases following knee trauma. Hence, the Rolimeter, in combination with manual tests, seems to be a valuable tool for identifying anterior cruciate ligament injuries. PMID- 29114531 TI - Effects of a short-term detraining period on muscle functionality and cognition of strength-trained older women: a preliminary report. AB - The present study aimed to investigate the impact of a 1-month detraining composed by Christmas and New Year's Day in the functional and cognitive parameters of 12 older women who had previously participated in 22-week moderate intensity strength training program (ST; n=6) or remained performing their regular habits of life during all study period, without engaging in physical exercise programs (CG; n=6). Transfer capacity (i.e., Timed Up and Go [TUG]) and executive function (i.e., TUG with a cognitive task) were increased in the ST group after the intervention. However, the 1-month detraining period was enough to totally reverse the gains in both parameters. In conclusion, data of the present study indicate that 1 month of detraining was enough to totally reverse the beneficial effects of a 6-month ST program on physical mobility and executive function of older women. PMID- 29114532 TI - Changes in physical fitness and body composition according to the physical activities of Korean adolescents. AB - This study comparatively analyzed obesity, lean balance, and physical fitness related to growth and development in female middle school students to investigate the importance of regular physical activity on body composition and physical fitness in adolescence. The subjects were 31 elementary school students in grades 5-6 in Seoul, consisting of 16 students in the regularly active group and 15 students in the inactive group. Body composition and physical fitness factors were measured. Height, weight, body mass index (BMI), fat mass, and fat-free mass were measured using Inbody 3.0. Physical fitness factors such as muscle strength (grip strength), muscle endurance (situps), flexibility (body flexion), agility (side stepping), and lean balance (balancing with eyes closed), were measured as described herein. The results of comparing the two groups' obesity-related body composition, the weight (P<0.001), body fat mass (P<0.001), BMI (P<0.002), and % body fat (P<0.033) were significantly higher in the inactive group compared to the physically active group. Comparison of lean balance was there was a significant difference in muscle mass between the left and right Arm (P<0.001), left and right leg (P<0.002) in the inactive group. comparing physical fitness between groups was trunk flexion (P<0.001) and side stepping (P<0.001) were higher in the physically active than the inactive group. This study found significant differences in weight, body fat, BMI, flexibility, and side stepping between the physically active and inactive groups, which may negatively affect health indicators related to adolescents' growth, development, and obesity. Therefore, attempts to promote physical activity in growing adolescents are crucial. PMID- 29114533 TI - Effects of whole body vibration training and mental training on mobility, neuromuscular performance, and muscle strength in older men. AB - This study was designed to evaluate the effects of whole body vibration (WBV) exercise, mental training (MT), and the concurrent effect of WBV and MT on lower body balance, neuromuscular performance, and leg muscle strength in elderly men. In a randomized control trial study with parallel group design, 42 older men (mean+/-standard deviation age, 68+/-5.78 years) were randomly divided into four groups: WBV (n=11), MT (n=12), WBV+MT (n=10), and control (n=9) groups. The protocol of training consisted of three sessions per week for 8 weeks and about 30 min for each session. The WBV exercise was performed on a vibration machine. In MT group, participants were asked to mentally visualize to do the Timed Up and Go and relaxation technics. postural stability, the Timed Up and Go test, 5 repetition chair-rising test, 6-m tandem gait test, 10-m walking, and leg isometric strength were measured in baseline and after 8-week intervention. Repeated measures-analysis of variance followed by post hoc was used to analyses the data. The results of this study showed that there were significant improvements (P<0.05) in postural stability, Timed Up and Go, 5-repetition chair rising, 6-m tandem gait test, 10-m walking, and leg isometric strength in WBV, MT, and WBV+MT in comparison with baseline and in comparison with control group. It seems that older adults can take benefit from WBV and MT and WBV+MT exercise as a cost-effective and practical way without side effects to improve postural control, mobility, and functional performance. PMID- 29114534 TI - Immediate effect of passive static stretching versus resistance exercises on postprandial blood sugar levels in type 2 diabetes mellitus: a randomized clinical trial. AB - The prevalence of diabetes is rapidly rising all over the globe at an alarming rate. In India, more than 61.3 million people have been presently diagnosed with type 2 diabetes mellitus. It is possible to control the circulating blood glucose levels by reducing life style risk factors through physical activities comprising of muscle stretches, aerobic training, resistance exercises (REs), yoga, etc. The aim of this study is to identify and compare the immediate effect of passive static stretching (PSS) versus RE on blood glucose level in individuals with type 2 diabetes mellitus. The present study included 51 participants between the age of 40-65 years with type 2 diabetes mellitus, to study the immediate effect of 60 min PSS (n=25) and 60-min RE (n=26). The outcome measure was blood glucose level which was checked by glucometer (free-style neo). Blood sugar was assessed at 3 points of time that included fasting blood sugar level, 2 hr after the meal and immediately after the exercise regimen. Results of this study showed significant reduction in blood glucose level in subjects according to glucometer with PSS (P=0.000) and RE (P=0.00). However, both groups demonstrated equal effect in terms of lowering blood sugar level immediately after the exercise. The conclusion is both PSS and RE are effective in reducing postprandial blood glucose level in type 2 diabetes mellitus and must be prescribed for the patients who demonstrate difficulty in controlling post prandial spike. PMID- 29114535 TI - Joint predictability of physical activity and body weight status on health related quality of life of patients with hypertension. AB - This study investigated the predictability of physical activity (PA) and body weight status (BWS) on health-related quality of life (HRQoL) of patients with hypertension. A cross-sectional study involved 250 patients with hypertension (>=140/90<=179/109 mmHg) selected from government hospitals in Osun State, Nigeria. Purposive sampling technique was used to select participants. Socio demographic characteristics and cardiovascular parameters were recorded. PA and HRQoL were assessed using the International Physical Activity Questionnaire and Short Form health survey questionnaire respectively. Sufficient PA equals >=150 min/wk while BWS was defined using body mass index classification. Data were analyzed using descriptive and inferential statistics. Alpha level was set at P<0.05. Of all participants, 63.6% reported sufficient PA and 78.4% was either overweight or obese. The HRQoL of participants become poorer in all domains with higher body weight. The HRQoL including role limitation due to physical health (RLdPhp) and emotional problems (RLdEmp) had worst scores. Participants in the categories of normal and overweight/obese with sufficient PA demonstrated higher (better) HRQoL in all domains than those with insufficient PA (P<0.05). When adjusted for body weight, significant differences were found in all domains of HRQoL except in RLdPhp, RldEmp, and bodily pain (P>0.05). There were significant correlations between PA and all domains of HRQoL except in RldEmp, emotional well being and bodily pain (P>0.05). Regression models established PA as a significant predictor of HRQoL. Sufficient PA is a better predictor of HRQoL among patients with hypertension irrespective of BWS. Regular PA is recommended for improving HRQoL among patients with hypertension. PMID- 29114536 TI - Short-term combined exercise training improves cardiorespiratory fitness and autonomic modulation in cancer patients receiving adjuvant therapy. AB - The present study aimed to investigate the impact of a short-term exercise training (ET) on the cardiorespiratory fitness and autonomic modulation of women with breast cancer who were receiving adjuvant radiotherapy, chemotherapy or hormonotherapy. Eighteen women previously diagnosed with breast cancer receiving adjuvant radiotherapy, chemotherapy or hormone therapy were randomly allocated into breast cancer nonexercise (BC) and exercise groups (BC+Ex). Moreover, nine healthy physically inactive volunteers were recruited to compose the noncancer control group (CG). The BC+Ex group was underwent to a combined ET program, which was based on resistance, aerobic and flexibility exercises. ET was performed 3 times a week, on nonconsecutive days, for 4 weeks at the hospital room under the professional supervision. In turn, BC and CG remained without be engaged in physical exercise programs. Volunteers were evaluated regarding their cardiorespiratory fitness and autonomic modulation (i.e., time, frequency domains, and nonlinear [symbolic analysis]) before and after the end of the ET program. A priori, data indicate that women patients with breast cancer showed impaired exercise tolerance, as well as autonomic dysfunction in comparison with age-matched healthy control subjects. However, a 1-month combined ET program could reverse such impairments, so that after the intervention, BC+Ex and CG showing similar results in the cardiorespiratory test and heart rate variability analysis. In conclusion, data of the current study indicate that 1 month of ET is able to reverse impaired cardiorespiratory fitness and autonomic modulation in women with breast cancer receiving adjuvant therapy. PMID- 29114537 TI - Lack of association between glutathione s-transferase mu 1 (GSTM1) gene polymorphisms and obesity. AB - Recent researches suggested that personal individual's genetic background is contributed to the susceptibility to obesity. The present of this study is to investigate whether single nucleotide polymorphisms (SNPs) of glutathione s transferase mu 1 (GSTM1) gene are susceptibility to obesity in Korean population. In present study, two SNPs (rs1056806 [Asp142Asp], rs3815029 [promoter]) of GSTM1 gene were genotyped in 117 overweight/obese subjects with a body mass index (BMI)>=23 kg/m2 and 125 nonoverweight/obese with a BMI of 18.5-23.0 kg/m2. Genotyping of two SNPs (rs1056806 and rs3815029) was determined by sequencing after polymerase chain reaction. Logistic regression models (codominant, dominant, recessive, and log-additive models) and allele analysis were used to calculate odds ratio, 95% confidence interval, and P-values. Significant association was considered at P<0.05. Tested two SNPs in GSTM1 genes did not show any significant association with obesity (rs1056806, P=0.24 in codominant 1 model; rs3815029, P=0.59 in codominant 1, P=0.09 in codominant 2, P=0.16 in dominant, P=0.09 in recessive, and P=0.07 in log-additive models). In summary, these results indicate that SNPs of GSTM1 gene did not associated with susceptibility of obesity in the Korean population. PMID- 29114538 TI - The Risk of Hospitalizations with Injury Diagnoses in a Matched Cohort of Children and Adolescents with and without Attention Deficit/Hyperactivity Disorder in Germany: A Database Study. AB - Background: Attention deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children and adolescents worldwide, and children with ADHD have elevated risk of injuries. Our aim was to assess the risk of hospitalizations with injury diagnoses and their various subtypes in children and adolescents with newly diagnosed ADHD compared to those without ADHD, as well as to study sex effects on this risk in the setting of the German health care system. Methods: The German Pharmacoepidemiological Research Database, in which 20 million insured from four statutory health insurances in Germany are included, was used to set up a matched cohort study of 3- to 17-year-old children and adolescents with and without ADHD. We calculated age-specific incidence rates and used Cox regression to obtain hazard ratios (HRs) for hospitalizations with injury diagnoses. We used the injury mortality diagnosis matrix for classification of injuries. Results: The matched cohort comprised a total of 75,300 children. The age-specific incidence rates for hospitalization with injury diagnosis for males with ADHD displayed a u-shaped form with highest incidences in the in the age groups 3-6 years [26.2 per 1,000 person-years; 95% confidence interval (CI) 20.5-33.0] and 18-21 years (28.6; 22.4-36.0). Girls with ADHD were less affected in younger age-groups, but the incidence rate for 18-21 year olds was similar to boys with ADHD (26.4; 17.4-38.4). The adjusted HR for children with ADHD was 1.40 (95% CI 1.30-1.49) compared to non-affected children. With respect to nature of injury, ADHD was associated with hospitalization with injury diagnoses of the internal organs, open wounds, and contusions but not with other injuries. With respect to body regions, children with ADHD were more prone to hospitalizations with injuries of the abdomen, traumatic brain injuries, other head injuries, and system-wide injuries such as poisoning and intoxication. No significant associations were seen for the other body regions. Differences between sexes were only seen for system-wide injuries. Conclusion: Children and adolescents with ADHD are at an increased risk for hospitalizations with diagnoses of injuries compared to non-affected children. Despite differences in health-care systems, the risk increase is at a similar level in Germany as in other countries. PMID- 29114539 TI - Using Smartphones to Help People with Intellectual and Sensory Disabilities Perform Daily Activities. AB - Background: People with mild-to-moderate intellectual disability and sensory impairments often fail to take initiative in starting and carrying out daily activities, with negative consequences for their occupational condition and social status. Their failure seems due to their inability to determine the right time for the activities and to remember all the activity steps. Aim: This study assessed a smartphone intervention, which was designed to help eight participants (four presenting with intellectual disability and blindness and four presenting with intellectual disability and hearing impairment) to independently start and carry out daily activities at appropriate times. Method: The intervention was introduced according to a non-concurrent multiple baseline design across participants. During the intervention, each participant was provided with a smartphone, which was fitted with the time schedule of his or her activities and the verbal or pictorial instructions for the single steps of those activities. When the time for an activity was reached, the participant was automatically reminded to start that activity and, thereafter, he or she was presented with the instructions for it. Results: The use of the smartphone intervention promoted great improvement over the baseline for all participants. That is, the participants managed to (a) independently start the activities at the scheduled times and (b) carry out those activities with high levels of accuracy. Conclusion: A smartphone intervention, such as that used in this study, may help people with mild-to-moderate intellectual disability and sensory impairments to successfully engage in daily activities. PMID- 29114541 TI - Special issue on II Translational Meeting from the Spanish Melanoma Group. PMID- 29114542 TI - New trends in antitumor vaccines in melanoma. AB - Antitumor therapeutic vaccines aim at priming an effector immune response able to recognize and kill tumor cells. Antitumor vaccines are composed of at least two main components: the tumor antigens and the adjuvant. Metastatic advanced melanoma has been a model disease to test novel advances in vaccine design due to the intrinsic immunogenicity of this tumor and the accessibility to melanoma lesions to monitor the immune response. In spite of a large number of clinical trials, clinical benefit remains elusive. The clinical success of monoclonal antibodies targeting immune check-points has renewed interest in novel vaccine strategies such as personalized neoantigen-based vaccines. PMID- 29114540 TI - Angiogenesis, Cancer, and Vascular Aging. AB - Several lines of evidence have revealed that the angiogenic response to ischemic injury declines with age, which might account for the increased morbidity and mortality of cardiovascular disease (CVD) among the elderly. While impairment of angiogenesis with aging leads to delayed wound healing or exacerbation of atherosclerotic ischemic diseases, it also inhibits the progression of cancer. Age-related changes of angiogenesis have been considered to at least partly result from vascular aging or endothelial cell senescence. There is considerable evidence supporting the hypothesis that vascular cell senescence contributes to the pathogenesis of age-related CVD, suggesting that vascular aging could be an important therapeutic target. Since therapeutic angiogenesis is now regarded as a promising concept for patients with ischemic CVD, it has become even more important to understand the detailed molecular mechanisms underlying impairment of angiogenesis in older patients. To improve the usefulness of therapeutic angiogenesis, approaches are needed that can compensate for impaired angiogenic capacity in the elderly while not promoting the development or progression of malignancy. In this review, we briefly outline the mechanisms of angiogenesis and vascular aging, followed by a description of how vascular aging leads to impairment of angiogenesis. We also examine potential therapeutic approaches that could enhance angiogenesis and/or vascular function in the elderly, as well as discussing the possibility of anti-senescence therapy or reversal of endothelial cell senescence. PMID- 29114543 TI - Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy. AB - Programmed cell death-1 (PD1) has become a significant target for cancer immunotherapy. PD1 and its receptor programmed cell death 1 ligand 1 (PDL1) are key regulatory physiological immune checkpoints that maintain self-tolerance in the organism by regulating the degree of activation of T and B cells amongst other immune cell types. However, cancer cells take advantage of these immunosuppressive regulatory mechanisms to escape T and B cell-mediated immunity. PD1 engagement on T cells by PDL1 on the surface of cancer cells dramatically interferes with T cell activation and the acquisition of effector capacities. Interestingly, PD1-targeted therapies have demonstrated to be highly effective in rescuing T cell anti-tumor effector functions. Amongst these the use of anti PD1/PDL1 monoclonal antibodies are particularly efficacious in human therapies. Furthermore, clinical findings with PD1/PDL1 blockers over several cancer types demonstrate clinical benefit. Despite the successful results, the molecular mechanisms by which PD1-targeted therapies rescue T cell functions still remain elusive. Therefore, it is a key issue to uncover the molecular pathways by which these therapies exert its function in T cells. A profound knowledge of PDL1/PD1 mechanisms will surely uncover a new array of targets susceptible of therapeutic intervention. Here, we provide an overview of the molecular events underlying PD1 dependent T cell suppression in cancer. PMID- 29114544 TI - Dendritic cell therapy in melanoma. AB - Dendritic cell (DC) vaccines are cancer vaccines used currently as melanoma therapies. They act as adjuvants initiating the immune responses, but not only as they can also have effector activities redirecting cytotoxic CD8+ T cells against melanoma. Ex vivo preparation of monocyte derived DCs has been implemented to produce large numbers of DCs for clinical therapy, highlighting the necessity of activate DC s to produce Th1 cytokines, especially TNF-a and IL-12 with potent anti-tumour actions. Several clinical trials both in the European Union and USA are open currently using DC vaccines, alone or in combination with other immunotherapies. The type of antigen is also an active area of investigation involving tumour antigens and bacterial epitopes, both providing good responses. Bacterial epitopes presented the advantage versus tumour antigens that they can prepare the vaccination site as they induce innate and specific immune responses as they are potent recall antigens that expand cytotoxic responses. PMID- 29114545 TI - Overcoming resistance to BRAF inhibitors. AB - The discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/MEK inhibitors. PMID- 29114547 TI - Predictive factors of response to immunotherapy-a review from the Spanish Melanoma Group (GEM). AB - Immunotherapy has become a key element in the treatment of several tumors, such as lung carcinoma and melanoma. Immunotherapy, unlike classical chemotherapy and targeted drugs, may yield long-term survival, even in patients who stop treatment due to toxicity. This fact has generated considerable excitement and a real shift in the paradigm of cancer treatment. However, only a small subset of patients benefit from immunotherapy. Survival curves show that most patients have progression of the disease in the first months after starting immunotherapy, followed by a slower decrease over the first 3 years, until curves reach a plateau. This early progression suggests the presence of mechanisms for primary resistance. In addition, some patients have tumor relapse after years of response, suggesting that there is also acquired resistance in a small subset of patients. Resistance mechanisms are now being elucidated. PD-L1 expression in tumor and immune cells correlates with higher chances of response, but melanoma patients with PD-L1 negative tumors can also respond. Several studies have demonstrated an increased probability of clinical benefit when tumors are infiltrated by CD8 T cells, have a high mutation burden or have an interferon gamma signature. But none of these factors has been implemented in the clinical practice, since more studies confirming their value are needed, as well as the development of standardized techniques. PMID- 29114546 TI - The combination of checkpoint immunotherapy and targeted therapy in cancer. AB - The therapeutic possibilities for patients with metastatic melanoma have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune modulating therapies that unleash the patient antitumor immunity. These therapeutic changes have impressively increased the median overall survival of the patients. Considering the dramatic but transient responses that occur with targeted therapies for a subgroup of patients and the durable responses that can be achieved with immunotherapy in a subset of patients, a lot of effort is ongoing for the clinical development of combinations of these two therapeutic approaches. Herein we discuss the existing preclinical and clinical data for the combination of targeted therapies and immunotherapy focusing mainly on melanoma and non-small cell lung cancer (NSCLC). PMID- 29114549 TI - Evaluation of body image in cancer patients and its association with clinical variables. AB - BACKGROUND: Cancer and its treatments have been shown to have a negative psychological effect on many cancer patients. One of these effects is often described as body image disturbance. Due to the limited number of studies in this area, this study was performed to assess body image in cancer patients and its association with clinical variables. MATERIALS AND METHODS: This was a descriptive and correlational research that was designed in Sayyed-Al-Shohda Hospital affiliated to Isfahan University of Medical Sciences, Iran in 2013. Two hundred and ten adult patients who had been suffering from cancer were selected and completed the personal/demographic/illness questionnaire and the multi dimensional body-self relations questionnaire that contained 64-items with appearance orientation, appearance evaluation, fitness evaluation, fitness orientation, health evaluation, health orientation, illness orientation, body areas satisfaction, self-classified weight and overweight preoccupation sub scales. Data were analyzed by ANOVA and Pearson correlation with a significance level of P < 0.05. RESULTS: The mean (standard deviation (scores of body image in cancer patients was 184.40 (43.68) indicating that 58.3% of them had negative body image. In addition, most of patients had negative health evaluation (60.2%), negative appearance evaluation (63%), negative illness orientation (61%), and negative fitness orientation (56%). Furthermore, there were no significant correlations between type of cancer (P = 0.5, f = 0.3), kind of treatment (P = 0.8, f = 5.2) and duration of illness with body image (P = 0.6, r = -0.2). CONCLUSION: In this study most of the cancer patients had body image disturbances. Also, body image in this group wasn't associated with the type of cancer, kind of treatment and duration of illness. Totally, these results underscore the importance of assessing and treating body image disturbance in cancer patients. PMID- 29114548 TI - The effect of supportive educative program on the quality of life in family caregivers of hemodialysis patients. AB - BACKGROUND: Previous studies showed that family caregivers of hemodialysis patients have low level of quality of life. However, these caregivers are mostly neglected, and no studies are available on improving their quality of lives. Therefore, this study aimed to examine the effects of supportive educative program on the quality of life in family caregivers of hemodialysis patients. MATERIALS AND METHODS: A randomized controlled clinical trial was conducted on 76 family caregivers of hemodialysis patients referred to Shahid Hasheminejad Hemodialysis Center in Tehran, Iran in 2015. The subjects were equally allocated into two groups of 38. Caregivers of patients were randomly assigned into the intervention group and the control group. The intervention group received six training sessions on supportive educative program. Both groups answered demographic information and short form-36 questionnaires before and 6 weeks after the intervention. Descriptive statistics, Chi-square and Fisher exact tests, independent samples t-test, and t-couple, was used to analyze the data. RESULTS: No significant difference was found between the baseline mean scores of "quality of life" of the intervention and the control groups (P = 0.775). However, the mean scores of quality of life of the intervention group increased at the end of the study, and the two groups were significantly different in this regard (P < 0.001). CONCLUSIONS: Supportive educative program improved the quality of life in caregivers of hemodialysis patients. Therefore, it is suggested that health system managers encourage their staff to implement such programs for improving the health status of the caregivers. PMID- 29114550 TI - Comparison of the effects of storytelling and creative drama methods on children's awareness about personal hygiene. AB - BACKGROUND AND OBJECTIVE: Maintaining and improving the health situation of children requires them to become more aware about personal hygiene through proper education. Based on several studies, teachings provided through informal methods are fully understandable for children. Therefore, the goal of this study is to compare the effects of creative drama and storytelling education methods on increasing the awareness of children regarding personal hygiene. METHODS: This is an applied study conducted using semiempirical method in two groups. The study population consisted of 85 children participating in 4th center for Institute for the Intellectual Development of Children and Young Adults in Isfahan, 40 of which were randomly selected and placed in storytelling and creative drama groups with 20 members each. The data gathering tool was a questionnaire created by the researchers whose content validity was confirmed by health education experts. The gathered information were analyzed using both descriptive (average and standard deviation) and analytical (independent t-test and paired t-test) statistical methods. RESULTS: The findings showed that there was a meaningful difference between the awareness score of both groups before and after intervention. The average awareness score of storytelling group was increased from 50.69 to 86.83 while the average score of creative drama group was increased from 57.37 to 85.09. Furthermore, according to paired t-test results, there was no significant difference between average scores of storytelling and creative drama groups. CONCLUSIONS: The results of the current study showed that although both storytelling and creative drama methods are effective in increasing the awareness of children regarding personal hygiene, there is no significant difference between the two methods. PMID- 29114551 TI - Development and study of self-efficacy scale in medication adherence among Iranian patients with hypertension. AB - BACKGROUND: This study was aimed at developing and studying the scale of self efficacy in adherence to treatment in Iranian patients with hypertension. METHODS: A mix-method study was conducted on the two stages: in the first phase, a qualitative study was done using content analysis through deep and semi structured interviews. After data analysis, the draft of tool was prepared. Items in the draft were selected based on the extracted concepts. In the second phase, validity and reliability of the instrument were implemented using a quantitative study. The prepared instrument in the first phase was studied among 612 participants. To test the construct validity and internal consistency, exploratory factor analysis and Cronbach's alpha were used, respectively. To study the validity of the final scale, the average score of self-efficacy in patients with controlled hypertension were compared with patients with uncontrolled hypertension. RESULTS: In overall, 16 patients were interviewed. Twenty-six items were developed to assess different concepts of self-efficacy. Concept-related items were extracted from interviews to study the face validity of the tool from patient's point of view. Four items were deleted because scored 0.79 in content validity. The mean of questionnaire content validity was 0.85. Items were collected in two factors with an eigenvalue >1. Four items were deleted with load factor <0.4. Reliability was 0.84 for the entire instrument. CONCLUSION: Self-efficacy scale in patients with hypertension is a valid and reliable instrument that can effectively evaluate the self-efficacy in medication adherence in the management of hypertension. PMID- 29114552 TI - Introduction to clinical pathology: A brief course of laboratory medicine in the field for medical students. AB - OBJECTIVES: Teaching of clinical pathology to medical students has been ignored in many countries such as Iran. We aim to introduce a practical brief course and its proper timing. MATERIALS AND METHODS: Three groups of medical students from consecutive years of entrance passed a 1.5 working day practical course on the field. Their level of knowledge was assessed by pre- and post-tests. Their idea and satisfaction were gathered by questionnaires. RESULTS: Knowledge of students became significantly higher after the course. Their satisfaction was high. Students in later year of education got significantly higher marks. Most of the students wished such a course should be away from basic sciences period and as near as possible to internship. DISCUSSION: Due to overloaded curriculum of general medicine in Iran, we decided to run a brief practical course of laboratory medicine education for medical students. Although the course was practical, the knowledge of students became higher. Students with more clinical experience and knowledge absorbed more. Being actively involved in the classes lit the enthusiasm of students and made them satisfied with the course. It seemed that the course should be placed in later years of clinical training to get the best uptake and results. PMID- 29114553 TI - Compare the effect of flaxseed, evening primrose oil and Vitamin E on duration of periodic breast pain. AB - BACKGROUND: Breast periodic pain is the most common disorder of the breast which leads to consultation with knowledgeable people like a midwife. The aim of this study was to compare the therapeutic effect of flaxseed, evening primrose oil, and Vitamin E on the duration of the period of breast pain. MATERIALS AND METHODS: This study is a quasi-randomized clinical trial conducted in 2015 on ninety patients complaining of breast periodic pain referring to Gynecologic Clinics of Ghaem Hospital or residents living in dormitories of Mashhad University of Medical Sciences. Randomization was conducted based on the study environment. The first group received 30 g of powdered flaxseed, the second group received two 1000 mg capsules of evening primrose, and the third group received 1 capsule of 400 IU Vitamin E, daily and for two menstrual cycles. Cyclical breast pain was measured at the beginning and end of both intervention periods by daily subscription form of pain duration. Data analysis was performed by SPSS 16 software and Kolmogorov-Smirnov, Chi-square, Friedman, Fisher's, and one-sided ANOVA tests. The level of significance was set at P < 0.05. RESULTS: The mean duration of breast pain in flaxseed group within 2 months of intervention decreased significantly (confidence interval [CI] =95%, P = 0.006), but despite reducing the duration of pain in evening primrose oil group (CI = 95%, P = 0.058) and Vitamin E (CI = 95%, P = 0.306), this reduction was not significant. In overall, the average duration of breast pain in all three flaxseed, evening primrose oil, and Vitamin E groups was not significantly different before the intervention (CI = 95%, P = 0.286), 1 month after the intervention (CI = 95%, P = 0.195), and 2 months after the intervention (CI = 95%, P = 0.667). CONCLUSION: The use of flaxseed, evening primrose oil, or Vitamin E may reduce breast pain, and this is a significant reduction in flaxseed. PMID- 29114554 TI - Perceived health discomfort among adolescent girls and related factors in an urban area, South India. AB - INTRODUCTION: Adolescence is a period of life that is a bridge between childhood and adulthood. India has the world's largest adolescent girl's population, and adolescent girls are an important vulnerable group of population. Perceived health is a predictor of morbidity and mortality in adults and has been an important marker of the health status in population health studies for decades. The aim of the study was to describe adolescent's perception of health and association between some factors such as nutrition status, socioeconomic status (SES), and health status. As their perception of health discomfort affects their health behavior and self-care, therefore, their health status is an important matter to discuss. MATERIALS AND METHODS: A cross-sectional study was conducted in urban areas from a major city in South India. Six hundred and fifty adolescent female students aged 10-19 years formed the study population. Standardized self reporting questionnaires were used to obtain relevant data regarding demographic features, SES, and health status. BMI calculated for each individual. The data were analyzed using SPSS version 16. RESULTS: About 83.3% of participants ranked their health status as good to excellent. A majority of the girls had one or more problems related to their menstrual cycles. The most common occurring problem was headache (45.3%). 47.8% of participants exhibited symptoms of mild insomnia. Strong significant association between nutritional status and SES was found. Higher percentage of undernourished adolescents belonged to low SES. CONCLUSION: Adolescents are expected to enjoy good health, but this does not seem to be the case in the developing countries like India, where poverty, malnutrition, and repeated infection are rampant. Majority of the problems such as healthy nutrition and self-care can be solved by community-based programs, health education, and food fortification. PMID- 29114555 TI - Effectiveness of mindfulness-based stress reduction on emotion regulation and test anxiety in female high school students. AB - BACKGROUND: Test anxiety is one of the most disabling disorders and annual school academic performance will affect millions of students. Hence, it needs attention and treatment. Therefore, this research aimed to examine the effectiveness of a mindfulness-based stress reduction (MBSR) therapy on emotion regulation and test anxiety of students and test the remaining effect of this treatment after 3 month. METHODS: Sample size of fifty participants randomly divided into experimental (MBSR) and control groups. The MBSR training interventions were implemented to the experimental group, in eight weekly sessions using MBSR manual by John Kabat-Zinn (2013). Participants in both groups were evaluated using the Test Anxiety Scale and the Cognitive Emotion Regulation Questionnaire. The study findings were analyzed using analysis of variance with repeated measures. RESULTS: The result shows that the MBSR program has had continuous significant effects on test anxiety (P < 000) and emotion regulation (P < 000) but was not significant only for the self-blame subscale (P = 0.126). CONCLUSIONS: The study results indicated that the effects of MBSR lasted through the follow-up, for both of these variables. Using the results of this study may be proposed school counselors use mindfulness to reduce the anxiety of their pupils. PMID- 29114556 TI - The prevalence of preconception care, its relation with recipients' individuality, fertility, and the causes of lack of checkup in women who gave birth in Isfahan hospitals in 2016. AB - BACKGROUND: Preconception care is a set of interventions that aim to identify and repair the factors that can affect the outcome of pregnancy. The aim of this study was to determine the prevalence of receiving preconception care, its relation with recipients' individuality, fertility, and determining the reason for lack of checkup. MATERIALS AND METHODS: This was a descriptive cross sectional study that was conducted based on simple stratified random quota sampling on 702 women who gave birth in hospitals of Isfahan (Iran) from April to June in 2016. The tool of collecting data was researcher-made questionnaire. The data were analyzed by the SPSS software version 18 using the mean, standard deviation, relativity, and independent Chi-square tests. RESULTS: The results showed that 47.7% of participants had received preconception care. There was a significant relationship between educational levels, income, wanted pregnancy, number of pregnancies, and previous individual delivery with preconception care (P < 0/05). The main reason for the lack of preconception care was unplanned pregnancy. CONCLUSIONS: Results of this study indicated that the quantity of preconception care is not desirable. Therefore, notifying and sensitizing women of childbearing age is essential to refer to service centers and receiving preconception care and planning to present it to all eligible women before pregnancy care. The main causes of the lack of preconception care can be adjusted through health programs. PMID- 29114557 TI - The comparison of hospitals' performance indicators before and after the Iran's hospital care transformations plan. AB - INTRODUCTION: Hospital care transformation plan (HCTP) was implemented, in 2014, with the aim of ensuring all Iranians have fair access to hospital care, mainly in the public sector. It was assumed that HCTP would lead to increased quality and effectiveness of health care in public hospitals. To explore whether HCTP has achieved its aim, this study has investigated the impact of this plan on performance indicators (PIs) of the public hospitals. MATERIALS AND METHODS: This cross-sectional descriptive study was conducted in 2016. The study population included all hospitals in the Isfahan City. Data (10 selected PIs) were collected through formal reports which were available at the Isfahan University of Medical Sciences and analyzed using Statistical Package for Social Sciences (version 17). The statistical significant level analysis was 0.05. RESULTS: After HCTP, it was shown an increase of (1) Bed occupancy, bed turnover, occupied bed-days, inpatients visits, and number of surgeries in all types of hospitals, (2) Outpatients' visits in all hospitals except private ones, (3) Emergency visits in public and social security hospitals, and (4) Natural deliveries in public and semi-public hospitals. Furthermore, the average length of stay and hospital mortality rate has decreased in all types of hospitals after HCTP implementation. DISCUSSION AND CONCLUSION: Although, improving PIs of hospitals were not directly stated and known objectives of HCTP implementation, it seems HCTP could improve the performance of all hospitals, including involved and noninvolved ones. PMID- 29114558 TI - Predictors of caregiver burden in Iranian family caregivers of cancer patients. AB - BACKGROUND: Caregiver burden threatens the psychological, emotional, functional and even physical health of caregivers. The aims of this study were to determine caregiver burden and family distress and the relationship between them, also to explore predictors of caregiver burden in a sample of Iranian family caregivers of cancer patients. MATERIALS AND METHODS: This is a cross-sectional study with correlational design. A total of 104 family caregivers of cancer patients were asked to respond to the Caregiver Burden Inventory (CBI) and the Family Distress Index (FDI) together with a sociodemographic questionnaire. For evaluating the relationship between CBI and FDI scores, the Pearson's product-moment correlation was used. In addition, multiple linear regression analysis was applied to explore the predictive factors of caregiver burden. RESULTS: A high burden was experienced by almost half of the caregivers (48.1%). The FDI mean score was 9.76 +/- 5.40 ranged from 0 to 24. A strong positive correlation was found between the caregiver burden and family distress (r = 0.76). Multiple linear regression results showed the predictive role of FDI score (beta = 0.71, P = 0.001), patient's gender (beta = -0.25, P = 0.001), and early cancer diagnosis (beta =0.13, P = 0.027) in caregiver burden. They could explain 65% of variance in the level of burden in family caregivers. CONCLUSION: Family nurses should consider the caregivers burden and vulnerability of families with cancer patient, especially if the patient is a male or has a new diagnosis. They should also design special programs for the whole family as a system that family can adapt to the new situation. PMID- 29114559 TI - Demographic and psychological predictors of recovery from coronary artery bypass graft. AB - OBJECTIVES: Worldwide, i.e. in Iran, coronary artery bypass grafting (CABG) is one of the most common and expensive surgeries. This study was designed to explore the demographic and psychological factors which predict the recovery process in CABG patients. MATERIALS AND METHODS: During a prospective correlational study, 250 CABG patients, in two public and private hospitals, investigated for indexes of recovery during hospital stay and 4 weeks after discharge. Demographic and psychological variables were collected through checklist and Farsi validated and reliable versions of type D personality, the multidimensional scale of perceived social support, revised illness perception questionnaire (IPQ-R). Data were analyzed through statistical tests through SPSS version 20. RESULTS: Considering the total recovery index, 91.2% of CABG patients have not been recovered 4 weeks after surgery. Furthermore, 99% of them reported high scores of depression and anxiety. Marital and insurance status, and perceived personal control, showed significant difference between recovered and unrecovered patients based on total recovery index (P < 0.05); however, in regression analysis, they did not identify as predictor variables. Age, gender, insurance status, and perceived personal control were the most frequent variables identified as predictors of recovery indexes, separately. CONCLUSION: The correlation between depression, anxiety, perceived personal control, and recovery status among our patients reveals the importance of considering psychological and mood assessment in developing guidelines for CABG patients. Our findings will assist clinicians for designing of psychological interventions for promotion of perceived personal and illness control and better recovery post-CABG. PMID- 29114560 TI - Determinants of the self-efficacy of physical activity for maintaining weight during pregnancy: The application of the health belief model. AB - INTRODUCTION: Pregnancy is one of the high-risk periods for women's health that the lack of attention to healthy behaviors such as weight control behaviors can lead to adverse consequences on the health of women and also the fetus. Therefore, the aim of this paper was to explore the determinants of weight control self-efficacy among pregnant women using Health Belief Model (HBM). MATERIALS AND METHODS: In this cross-sectional study were enrolled 202 pregnant women referring to Health Care Center in Isfahan city, Iran. Sampling method was multistage random. A researcher-made instrument based on HBM structures was used after confirming the valid and reliable. Data were analyzed by software SPSS 21 and descriptive statistics were represented with (frequency, mean and standard deviation) and analytical (Pearson correlation, independent t and liner regression) at the significant level of <0.05. RESULTS: The average age of participants was 27.80 +/- 5.08. HBM structures were able explained 31% of variance of weight control self-efficacy. Also, of the studied structures, perceived benefits, perceived barriers were statistically significant predictors of weight control self-efficacy, within which perceived barriers (beta = 0.391) was the most significant predictor. CONCLUSION: The findings of current study showed that the HBM model could be as a suitable framework to identify effective factors for designing educational intervention to improve weight control behaviors among pregnant women. PMID- 29114561 TI - Awareness about rational use of medicines among fresh Bachelor of Medicine and Bachelor of Surgery graduates. AB - CONTEXT: Fresh Bachelor of Medicine and Bachelor of Surgery graduates (FMGs) are responsible for the majority of prescription errors and irrational use of medicines. Little research has explored their knowledge on rational prescribing practices. AIMS: The present study aimed to evaluate the awareness of rational use of medicines (RUMs) among the FMGs. SETTINGS AND DESIGN: A multicentric, cross-sectional, and questionnaire-based study was conducted among 308 FMGs during the internship orientation program. SUBJECTS AND METHODS: The structured and prevalidated questionnaire consisted of 35 statements on important aspects of RUM. STATISTICAL ANALYSIS USED: Data were analyzed using SPSS version 24.0 at 95% level of significance with Fisher's exact test. RESULTS: Nearly 31% of FMGs did not know that the generic drugs are equally efficacious as branded drugs whereas 53% were in support of pregnant female should not consume any drug. Nearly 58% of FMGs were confused about deciding the dose in children and 18% were in favor of using antibiotics in common cold. Almost 55% of FMGs were disagree for adjusting the dose of antidiabetic drugs by patient depending on the meal taken whereas 12% were not aware of the importance of compliance of antihypertensive drugs and 40% were supporting the safety of fruits in chronic renal disease. The FMG from government colleges answered more correctly than that of the private colleges. CONCLUSIONS: The awareness of RUM among FMG is not satisfactory, and also there is a gap in its implementation. Thus, they should be supervised during the initial phase of their medical practice. PMID- 29114562 TI - Quality of life of adolescents and young people arrive at an addiction treatment centers upon their admission, and 1, 4 and 8 months after methadone maintenance therapy. AB - BACKGROUND: Drug abuse influences the quality of life significantly. Thus, the present study is designed to compare the quality of life of adolescents and young adults who have voluntarily referred to addiction treatment centers at different time slots of upon admission, and 1, 4, and 8 months after maintenance therapy. METHODS: The present paper is a longitudinal study on 141 of adolescents and young adults who had referred to various addiction treatment centers throughout Isfahan voluntarily. The population was selected through convenience sampling method and 137 of adolescents and young adults continued the research until the end. The results were analyzed using descriptive and analytic statistics (frequency, mean, standard deviation, repeated measure test, and post-hoc test) in SPSS 17. RESULTS: Results showed that the average of quality of life total score was sequential and not the same in the 4 times slots under study. The total quality of life score upon admission was significantly different from 1, 4, and 8 months after maintenance treatment. However, quality of life at 1-month was not significantly different to that at 4 and 8 months after the treatment; quality of life at 4 months after the treatment was not significantly different to that at 8 months after. DISCUSSION: According to the present study, it can be concluded that the quality of life of adolescents and young adults referring to addiction treatment centers increases 1-month after the treatment; nevertheless, it is worth to note that the degree of quality of life increase in 4 and 8 months after the treatment is not as much as that in 1-month after the treatment. PMID- 29114563 TI - Risk Factors for Lower Extremity Overuse Injuries in Female Youth Soccer Players. AB - Background: Youth soccer injuries are common and of increasing concern, with sport specialization occurring at younger ages. Limited research is available regarding overuse injuries and risk factors in young female athletes. Purpose: To identify the number and rate of overuse injuries in female soccer players (ages 12-15 years), describe the anatomic location and type of injury, and evaluate contributing risk factors. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 351 female youth soccer players, ages 12 to 15 years, from Washington State were evaluated from 2008 to 2012. Players with lower extremity overuse injuries were identified through weekly emails and were interviewed by telephone to obtain data on injury type and body region. We evaluated the association between overuse injuries and preseason risk factors, including joint hypermobility, hip and knee muscle strength, and jump biomechanics, using Poisson regression to estimate relative risk (RR) and 95% CIs. Results: The incidence rate for first-time lower extremity overuse injuries was 1.7 per 1000 athlete exposure hours (AEH; 95% CI, 1.4-2.2), and that for repeat injuries was 3.4 per 1000 AEH (95% CI, 2.1-5.6). Knee injuries accounted for 47% of overuse injuries. Increased valgus was associated with a 3.2-fold increased risk (95% CI, 1.52 6.71) for knee injury. A 1-standard deviation (SD) increase in hamstring strength was associated with a 35% decreased risk (RR, 0.65; 95% CI, 0.46-0.91) for overuse knee injuries, and a 1-SD increase in quadriceps strength was associated with a 30% decreased risk (RR, 0.70; 95% CI, 0.50-0.98). A 1-SD increase in hip flexor strength was associated with a 28% decreased risk (RR, 0.72; 95% CI, 0.51 1.00) for overuse knee injuries, and a 1-SD increase in external rotation strength was associated with a 35% decreased risk (RR, 0.65; 95% CI, 0.46-0.91). Playing on more than 1 soccer team was associated with a 2.5-fold increased risk (95% CI, 1.08-5.35) for overuse knee injuries, and participating in other physical activities was associated with a 61% decreased risk (odds ratio, 0.39; 95% CI, 0.15-0.81). Conclusion: In this study, lower extremity overuse injuries in female youth soccer players affected primarily the knee. Lower knee separation distance, decreased lower extremity strength, and playing on more than 1 soccer team increased injury risk. PMID- 29114564 TI - The Effect of Pretest Exercise on Baseline Computerized Neurocognitive Test Scores. AB - Background: Baseline neurocognitive assessment plays a critical role in return-to play decision making following sport-related concussions. Prior studies have assessed the effect of a variety of modifying factors on neurocognitive baseline test scores. However, relatively little investigation has been conducted regarding the effect of pretest exercise on baseline testing. Purpose/Hypothesis: The aim of our investigation was to determine the effect of pretest exercise on baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scores in adolescent and young adult athletes. We hypothesized that athletes undergoing self-reported strenuous exercise within 3 hours of baseline testing would perform more poorly on neurocognitive metrics and would report a greater number of symptoms than those who had not completed such exercise. Study Design: Cross-sectional study; Level of evidence, 3. Methods: The ImPACT records of 18,245 adolescent and young adult athletes were retrospectively analyzed. After application of inclusion and exclusion criteria, participants were dichotomized into groups based on a positive (n = 664) or negative (n = 6609) self-reported history of strenuous exercise within 3 hours of the baseline test. Participants with a positive history of exercise were then randomly matched, based on age, sex, education level, concussion history, and hours of sleep prior to testing, on a 1:2 basis with individuals who had reported no pretest exercise. The baseline ImPACT composite scores of the 2 groups were then compared. Results: Significant differences were observed for the ImPACT composite scores of verbal memory, visual memory, reaction time, and impulse control as well as for the total symptom score. No significant between-group difference was detected for the visual motor composite score. Furthermore, pretest exercise was associated with a significant increase in the overall frequency of invalid test results. Conclusion: Our results suggest a statistically significant difference in ImPACT composite scores between individuals who report strenuous exercise prior to baseline testing compared with those who do not. Since return-to-play decision making often involves documentation of return to neurocognitive baseline, the baseline test scores must be valid and accurate. As a result, we recommend standardization of baseline testing such that no strenuous exercise takes place 3 hours prior to test administration. PMID- 29114565 TI - Brachio-cervical inflammatory myopathy with associated scleroderma phenotype and lupus serology. PMID- 29114566 TI - Reversible paraspinal muscle hyperintensity in anti-MOG antibody-associated transverse myelitis. PMID- 29114567 TI - Azithromycin and COPD Exacerbations in the Presence or Absence of Symptoms or Active Treatment for Gastroesophageal Reflux. AB - Introduction: Gastroesophageal reflux disease (GERD) is common in chronic obstructive pulmonary disease (COPD) and is associated with COPD exacerbations. Since macrolides have prokinetic effects and consequently may decrease GERD, we hypothesized that azithromycin may decrease exacerbations by decreasing GERD. Methods: We conducted a retrospective review of data collected in a prospective, randomized, controlled trial of azithromycin for preventing COPD exacerbations. Participants were classified as having GERD on the basis of having a history of GERD or having a history or being treated for GERD. Results: We analyzed 1116 participants, 478 (43%) and 568 (51%) had GERD on the basis of history and history or treatment respectively. Individuals with GERD developed exacerbations sooner and more frequently, and were more likely to be hospitalized than those without GERD but the difference only reached significance when GERD was defined by history or treatment (P = 0.02, 0.02, and 0.03, respectively). Azithromycin reduced exacerbations regardless of the presence of GERD, but had a greater effect in those without GERD. Conclusions: GERD is associated with more frequent and severe COPD exacerbations. Azithromycin reduces COPD exacerbations regardless of the presence or absence of GERD but does so to a greater degree in individuals without GERD. PMID- 29114569 TI - Cholinergic receptor alterations in the cerebral cortex of spinal cord injured rat. AB - Many areas of the cerebral cortex process sensory information or coordinate motor output necessary for control of movement. Disturbances in cortical cholinergic system can affect locomotor coordination. Spinal cord injury causes severe motor impairment and disturbances in cholinergic signalling can aggravate the situation. Considering the impact of cortical cholinergic firing in locomotion, we focussed the study in understanding the cholinergic alterations in cerebral cortex during spinal cord injury. The gene expression of key enzymes in cholinergic pathway - acetylcholine esterase and choline acetyl transferase showed significant upregulation in the cerebral cortex of spinal cord injured group compared to control with the fold increase in expression of acetylcholine esterase prominently higher than cholineacetyl transferase. The decreased muscarinic receptor density and reduced immunostaining of muscarinic receptor subtypes along with down regulated gene expression of muscarinic M1 and M3 receptor subtypes accounts for dysfunction of metabotropic acetylcholine receptors in spinal cord injury group. Ionotropic acetylcholine receptor alterations were evident from the decreased gene expression of alpha 7 nicotinic receptors and reduced immunostaining of alpha 7 nicotinic receptors in confocal imaging. Our data pin points the disturbances in cortical cholinergic function due to spinal cord injury; which can augment the locomotor deficits. This can be taken into account while devising a proper therapeutic approach to manage spinal cord injury. PMID- 29114568 TI - Potato starch synthases: Functions and relationships. AB - Starch, a very compact form of glucose units, is the most abundant form of storage polyglucan in nature. The starch synthesis pathway is among the central biochemical pathways, however, our understanding of this important pathway regarding genetic elements controlling this pathway, is still insufficient. Starch biosynthesis requires the action of several enzymes. Soluble starch synthases (SSs) are a group of key players in starch biosynthesis which have proven their impact on different aspects of the starch biosynthesis and functionalities. These enzymes have been studied in different plant species and organs in detail, however, there seem to be key differences among species regarding their contributions to the starch synthesis. In this review, we consider an update on various SSs with an emphasis on potato SSs as a model for storage organs. The genetics and regulatory mechanisms of potato starch synthases will be highlighted. Different aspects of various isoforms of SSs are also discussed. PMID- 29114570 TI - Yeasts in sustainable bioethanol production: A review. AB - Bioethanol has been identified as the mostly used biofuel worldwide since it significantly contributes to the reduction of crude oil consumption and environmental pollution. It can be produced from various types of feedstocks such as sucrose, starch, lignocellulosic and algal biomass through fermentation process by microorganisms. Compared to other types of microoganisms, yeasts especially Saccharomyces cerevisiae is the common microbes employed in ethanol production due to its high ethanol productivity, high ethanol tolerance and ability of fermenting wide range of sugars. However, there are some challenges in yeast fermentation which inhibit ethanol production such as high temperature, high ethanol concentration and the ability to ferment pentose sugars. Various types of yeast strains have been used in fermentation for ethanol production including hybrid, recombinant and wild-type yeasts. Yeasts can directly ferment simple sugars into ethanol while other type of feedstocks must be converted to fermentable sugars before it can be fermented to ethanol. The common processes involves in ethanol production are pretreatment, hydrolysis and fermentation. Production of bioethanol during fermentation depends on several factors such as temperature, sugar concentration, pH, fermentation time, agitation rate, and inoculum size. The efficiency and productivity of ethanol can be enhanced by immobilizing the yeast cells. This review highlights the different types of yeast strains, fermentation process, factors affecting bioethanol production and immobilization of yeasts for better bioethanol production. PMID- 29114571 TI - Antioxidant, antibacterial and cytotoxic potential of silver nanoparticles synthesized using terpenes rich extract of Lantana camara L. leaves. AB - Several attempts have been made for green synthesis of silver nanoparticles (AgNPs) using different plant extracts. Present study revealed that, antioxidant, antibacterial and cytotoxic AgNPs were synthesized using terpenes-rich extract (TRE) of environmentally notorious Lantana camara L. leaves. AgNPs were characterized by advanced techniques like UV-Visible and Infra red spectroscopy; XRD, SEM techniques as terpenes coated sphere shaped NPs with average diameter 425 nm. Further, on evaluation, AgNPs were found to exhibit dose - dependent antioxidant potential, good to moderate antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa; and toxicity on Brine shrimp (A. salinanauplii) with LD50 value 514.50 ug/ml. PMID- 29114572 TI - An insight to the binding of ellagic acid with human serum albumin using spectroscopic and isothermal calorimetry studies. AB - Ellagic acid (EA), a natural polyphenol evidence several pharmacological benefits. The binding profile of EA with human serum albumin (HSA) has been explored and investigated by Isothermal titration calorimetry (ITC), circular dichroism (CD) spectroscopy, time-correlated single-photon counting (TCSPC), absorbance spectroscopy, steady-state fluorescence spectroscopy, and modelling studies. The ITC data analysis revealed the binding Constant (Ka), DeltaH, DeltaS and DeltaG values to be 15.5*104M-1, -116.2+/-18.1 Kcal mol-1, -366 cal mol-1K-1 and -7.13 Kcal mol-1 respectively with a unique binding site at HSA. EA effectively quenched the intrinsic fluorescence of HSA by static quenching, whereas TCSPC data also revealed association of dynamic quenching also. Thermodynamic analysis confirmed that hydrophobic and mainly hydrogen bonding interaction played important role in stabilizing the HSA-EA complex. It further dictates the binding reaction to be enthalpy driven. The secondary structure of HSA was altered upon binding with EA. CD spectroscopic data indicated the fraction of alpha helicity to be decreased from 52% to 40% upon binding to EA. This study will provide an insight on evaluation of this bioactive interaction during transport and releasing efficiency at the target site in human physiological system since HSA is the most important carrier protein in blood serum. PMID- 29114573 TI - Plasmin reduces fibronectin deposition by mesangial cells in a protease-activated receptor-1 independent manner. AB - Background: Protease-activated receptor-1 (PAR-1) potentiates diabetic nephropathy (DN) as evident from reduced kidney injury in diabetic PAR-1 deficient mice. Although thrombin is the prototypical PAR-1 agonist, anticoagulant treatment does not limit DN in experimental animal models suggesting that thrombin is not the endogenous PAR-1 agonist driving DN. Objectives: To identify the endogenous PAR-1 agonist potentiating diabetes induced nephropathy. Methods: Unbiased protease expression profiling in glomeruli from human kidneys with DN was performed using publically available microarray data. The identified prime candidate PAR-1 agonist was subsequently analysed for PAR-1-dependent induction of fibrosis in vitro. Results: Of the 553 proteases expressed in the human genome, 247 qualified as potential PAR-1 agonists of which 71 were significantly expressed above background in diabetic glomeruli. The recently identified PAR-1 agonist plasmin(ogen), together with its physiological activator tissue plasminogen activator, were among the highest expressed proteases. Plasmin did however not induce mesangial proliferation and/or fibronectin deposition in vitro. In a PAR-1 independent manner, plasmin even reduced fibronectin deposition. Conclusion: Expression profiling identified plasmin as potential endogenous PAR-1 agonist driving DN. Instead of inducing fibronectin expression, plasmin however reduced mesangial fibronectin deposition in vitro. Therefore we conclude that plasmin may not be the endogenous PAR-1 agonist potentiating DN. PMID- 29114574 TI - Protective effect of aqueous extract of Phyllanthus fraternus against bromobenzene induced changes on cytosolic glutathione S-transferase isozymes in rat liver. AB - The aim of this study was to investigate beneficial effect of aqueous extract of Phyllanthus fraternus (AEPF) on bromobenzene (BB) induced changes on cytosolic glutathione S-transferase (GST) isozymes in rat liver. Administration of BB significantly decreased the activity of GST, however, prior administration of AEPF prevented the BB induced decrease in GST activity. Further the cytosolic GSTs were purified from 3 groups of animals (control, BB and AEPF+BB administered) and resolved into three protein bands on SDS-PAGE. Densitometric analysis showed a significant decrease in BB group compared to control. Further, 2D PAGE analysis resolved these proteins into 8 bands which were identified as five isozymes of alpha, two of Mu and one of theta by MALDI-TOF MS and also observed decreased levels of isozymes in BB group. However, on prior administration of AEPF significantly prevented the BB induced decrease in GSTs and restored to normal levels. PMID- 29114575 TI - Prediction of a highly deleterious mutation E17K in AKT-1 gene: An in silico approach. AB - The AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a member of most frequently activated proliferation and survival signaling pathway in cancer. Recently, hyperactivation of AKT1, due to functional point mutation in the pleckstrin homology (PH) domain of AKT1 gene, has been found to be associated with human colorectal, breast and ovarian cancer. Thus, considering its crucial role in cellular signaling pathway, a functional analysis of missense mutations of AKT1 gene was undertaken in this study. Twenty nine nsSNPs (non-synonymous single nucleotide polymorphism) within coding region of AKT1 gene were selected for our investigation and six SNPs were found to be deleterious by combinatorial predictions of various computational tools. RMSD values were calculated for the mutant models which predicted four substitutions (E17K, E319G, D32E and A255T) to be highly deleterious. The insight of the structural attribute was gained through analysis of, secondary structures, solvent accessibility and intermolecular hydrogen bond analysis which confirmed one missense mutation (E17K) to be highly deleterious nsSNPs. In conclusion, the investigated gene AKT1 has twenty nine SNPs in the coding region and through progressive analysis using different bioinformatics tools one highly deleterious SNP with rs121434592 was profiled. Thus, results of this study can pave a new platform to sort nsSNPs for several important regulatory genes that can be undertaken for the confirmation of their phenotype and their correlation with diseased status in case control studies. PMID- 29114576 TI - Behavioral study of selected microorganisms in an aqueous electrohydrodynamic liquid bridge. AB - An aqueous electrohydrodynamic (EHD) floating liquid bridge is a unique environment for studying the influence of protonic currents (mA cm-2) in strong DC electric fields (kV cm-1) on the behavior of microorganisms. It forms in between two beakers filled with water when high-voltage is applied to these beakers. We recently discovered that exposure to this bridge has a stimulating effect on Escherichia coli.. In this work we show that the survival is due to a natural Faraday cage effect of the cell wall of these microorganisms using a simple 2D model. We further confirm this hypothesis by measuring and simulating the behavior of Bacillus subtilis subtilis, Neochloris oleoabundans, Saccharomyces cerevisiae and THP-1 monocytes. Their behavior matches the predictions of the model: cells without a natural Faraday cage like algae and monocytes are mostly killed and weakened, whereas yeast and Bacillus subtilis subtilis survive. The effect of the natural Faraday cage is twofold: First, it diverts the current from passing through the cell (and thereby killing it); secondly, because it is protonic it maintains the osmotic pressure in the cell wall, thereby mitigating cytolysis which would normally occur due to the low osmotic pressure of the surrounding medium. The method presented provides the basis for selective disinfection of solutions containing different microorganisms. PMID- 29114577 TI - Monitoring of microwave emission of HRP system during the enzyme functioning. AB - Monitoring of microwave emission from aqueous solution of horseradish peroxidase (HRP) in the process of the enzyme functioning was carried out. For the monitoring, a system containing HRP, luminol and N2O2 was employed. Microwave emission measurements were carried out in the 3.4-4.2 GHz frequency range using the active and passive modes (active-mode and passive-mode measurements). In the active mode, excitation of the solution in the pulsed electromagnetic field was accomplished. In the passive mode, no excitation was induced. It appears that the passive-mode measurements taken in the course of the peroxidase reaction in the enzyme system have shown a 0.5 degrees S increase of the microwave signal. Upon the active-mode measurements, taken in the same reaction conditions, the forced excitation of the solution has also led to the increase (by 2 degrees S) of the level of the microwave signal - i.e. to its 4-fold enhancement compared to the signal obtained in passive-mode measurements. PMID- 29114578 TI - Complement-dependent and -independent aquaporin 4-antibody-mediated cytotoxicity in human astrocytes: Pathogenetic implications in neuromyelitis optica. AB - Background: Neuromyelitis optica (NMO) is an inflammatory disease caused by the aquaporin (AQP)-4-antibody. Pathological studies on NMO have revealed extensive astrocytic damage, as evidenced by the loss of AQP4 and glial fibrillary acidic protein (GFAP), specifically in perivascular regions with immunoglobulin and complement depositions, although other pathological patterns, such as a loss of AQP4 without astrocyte destruction and clasmatodendrosis, have also been observed. Previous studies have shown that complement-dependent antibody-mediated astrocyte lysis is likely a major pathomechanism in NMO. However, there are also data to suggest antibody-mediated astrocyte dysfunction in the absence of complement. Thus, the importance of complement inhibitory proteins in complement dependent AQP4-antibody-mediated astrocyte lysis in NMO is unclear. In most of the previous studies, the complement and target cells (astrocytes or AQP4 transfected cells) were derived from different species; however, the complement inhibitory proteins that are expressed on the cell surface cannot protect themselves against complement-dependent cytolysis unless the complements and complement inhibitory proteins are from the same species. To resolve these issues, we studied human astrocytes in primary culture treated with AQP4-antibody in the presence or absence of human complement and examined the effect of complement inhibitory proteins using small interfering RNA (siRNA). Methods: Purified IgG (10 mg/mL) was obtained from 5 patients with AQP4-antibody-positive NMO, 3 patients with multiple sclerosis (MS), and 3 healthy controls. Confluent human astrocytes transfected with Venus-M1-AQP4-cDNA were incubated with IgG (5% volume). After washing, we cultured the cells with human complements with or without heat inactivation. We observed time-lapse morphological and immunohistochemical changes using a fluorescence microscope. We also evaluated cytotoxicity using a propidium iodide (PI) kit and the lactate dehydrogenase (LDH) assay. Result: AQP4-antibody alone caused clustering and degradation followed by endocytosis of membraneous AQP4, thereby resulting in decreased cellular adherence and the shrinkage of astrocytic processes. However, these changes were partially reversed by the removal of IgG in culture. In contrast, following the application of AQP4-antibody and non-heated human complements, the cell bodies and nuclei started to swell. At 3 h, most of the astrocytes had lost mobility and adherence and were eventually destroyed or had swollen and were then destroyed. In addition, the remaining adherent cells were mostly PI-positive, indicating necrosis. Astrocyte lysis caused by rabbit complement occurred much faster than did cell lysis with human complement. However, the cell lysis was significantly enhanced by the transfection of astrocytes with siRNA against human CD55 and CD59, which are major complement inhibitory proteins on the astrocyte membrane. AQP4-antibody-negative IgG in MS or control did not induce such changes. Conclusion: Taken together, these findings suggest that both complement dependent and complement-independent AQP4-antibody-mediated astrocytopathies may operate in NMO, potentially contributing to diverse pathological patterns. Our results also suggest that the effect of complement inhibitory proteins should be considered when evaluating AQP4-antibody-mediated cytotoxicity in AQP4-expressing cells. PMID- 29114579 TI - Kinetic characteristics of L-lysine alpha- oxidase from Trichoderma cf. aureoviride Rifai VKM F-4268D: Substrate specificity and allosteric effects. AB - The present work aims to investigate the kinetic characteristics of homodimer enzyme L-lysine alpha-oxidase from Trichoderma cf. aureoviride Rifai VKM F-4268D, taking into account allosteric effects. The enzyme was first shown to reveal positive cooperativeness, h=2.05+/-0.15. Using additional opportunities of Hill coefficient the value of the Michaelis-Menten constant has been estimated, Km=1.015?10-5M, indicating high strength of substrate binding to the active site of each subunit. High selectivity and absolute L-stereospecificity of the enzyme were shown. The inhibition of L-lysine conversion by non-cleavable lysine analogs as well as the reaction product was found out to take place. These effects have been evaluated only as the inhibition coefficients (%). A more detailed study of these inhibition effects was complicated because of the cooperativeness of enzyme subunits mentioned above. The kinetic scheme of L-lysine alpha-oxidase was proposed involving parallel-subsequent action of each of two subunits in the catalytic act. We think that the results obtained will be useful for studying the kinetic properties of other multi-subunit enzymes and improve understanding of the mechanisms of their action. PMID- 29114580 TI - Alpha-ketoglutarate protects Streptomyces coelicolor from visible light-induced phototoxicity. AB - It has been known that some Streptomyces species, including the model strain Streptomyces coelicolor, are vulnerable to visible light. Much evidence demonstrated that the phototoxicity induced by visible light is a consequence of the formation of intracellular reactive oxygen species (ROS), which are potentially harmful to cells. In this study, we found that alpha-ketoglutarate (alpha-KG) has a protective role against the phototoxicity in S. coelicolor. It could be because that alpha-KG can detoxify the ROS with the concomitant formation of succinate, which mediates the cells getting into anaerobiosis to produce more NADH and maintain intracellular redox homeostasis, a situation that was demonstrated by overexpressing gdhA in S. coelicolor. This finding, therefore, connects the central metabolites with the bacterial resistance against phototoxicity effect induced by visible light. PMID- 29114582 TI - Engineering microdent structures of bone implant surfaces to enhance osteogenic activity in MSCs. AB - Problems persist with the integration of hip and dental implants with host bone tissues, which may result in long-term implant failure. Previous studies have found that implants bearing irregular surfaces can facilitate osseointegration. An improvement to this approach would use implant surfaces harboring a well defined surface microstructure to decrease variability in implant surfaces. In this study, we tested whether well-defined surfaces with arrays of microdents (each with depth approximately 3 um) significantly affected the morphology, proliferation, and osteogenic activity of mesenchymal stem cells (MSCs). Arrays of microdents tested had diameters of 9 um, 12 um, and 18 um, while spacing between arrays ranged from 8 um to 34 um. Effects on MSC morphology (cell spreading area) and proliferation were also quantified, with both significantly decreasing on micropatterned surfaces (p<0.05) on smaller and denser microdents. In contrast, MSCs were found to deposit more calcified matrix on smaller and denser arrays of microdents. MSCs on a pattern with arrays of microdents with a diameter of 9 um and a spacing 8 um deposited 3-4 times more calcified matrix than on a smooth surface (p<0.05). These findings show that well-defined surface microtopographies promote osteogenic activity, which can be used on implant surfaces to improve integration with the host bone tissue. PMID- 29114581 TI - Building-block architecture of botulinum toxin complex: Conformational changes provide insights into the hemagglutination ability of the complex. AB - Clostridium botulinum produces the botulinum neurotoxin (BoNT). Previously, we provided evidence for the "building-block" model of botulinum toxin complex (TC). In this model, a single BoNT is associated with a single nontoxic nonhemagglutinin (NTNHA), yielding M-TC; three HA-70 molecules are attached and form M-TC/HA-70, and one to three "arms" of the HA-33/HA-17 trimer (two HA-33 and one HA-17) further bind to M-TC/HA-70 via HA-17 and HA-70 binding, yielding one-, two-, and three-arm L-TC. Of all TCs, only the three-arm L-TC caused hemagglutination. In this study, we determined the solution structures for the botulinum TCs using small-angle X-ray scattering (SAXS). The mature three-arm L TC exhibited the shape of a "bird spreading its wings", in contrast to the model having three "arms", as revealed by transmission electron microscopy. SAXS images indicated that one of the three arms of the HA-33/HA-17 trimer bound to both HA 70 and BoNT. Taken together, these findings regarding the conformational changes in the building-block architecture of TC may explain why only three-arm L-TC exhibited hemagglutination. PMID- 29114583 TI - Identification of dimedone-trapped sulfenylated proteins in plants under stress. AB - In stressed plants, the reactive oxygen species (ROS) levels rise. Key to ROS signaling research are detection and identification of the protein cysteine sulfenylation (-SOH), the ROS-mediated oxidative product of a thiol (-SH). Arabidopsis thaliana seedlings were stressed with hydrogen peroxide (H2O2) and the sulfenylated proteins were tagged with dimedone. Dimedone-tagged sulfenic acid proteins were visualized on a two-dimensional electrophoresis (2DE) immunoblot with an anticysteine sulfenic acid antibody and were subsequently detected by mass spectrometry. We optimized the detection method for protein sulfenylation in Arabidopsis. We conclude that dimedone can penetrate the cell wall, does not stress plants, and can "read" the changes in the protein sulfenylation pattern under oxidative stress. We observed that the number of sulfenylated proteins in plants treated with 10 mM H2O2 was higher than that in untreated plants. A total of 39 sulfenylated protein spots were found on 2DE immunoblots. By means of mass spectrometry, 11 sulfenylated proteins were discovered involved in primary metabolism, redox regulation, translation and signaling pathways. Hence, by combining an immunochemical 2DE strategy with mass spectrometry, we were able to identify sulfenylated proteins in H2O2-stressed Arabidopsis seedlings. The sulfenylated proteins can be considered for further validation as redox regulators in plants. PMID- 29114584 TI - Expression, purification and characterization of hepatitis B virus X protein BH3 like motif-linker-Bcl-xL fusion protein for structural studies. AB - Hepatitis B virus X protein (HBx) is a multifunctional protein that interacts directly with many host proteins. For example, HBx interacts with anti-apoptotic proteins, Bcl-2 and Bcl-xL, through its BH3-like motif, which leads to elevated cytosolic calcium levels, efficient viral DNA replication and the induction of apoptosis. To facilitate sample preparation and perform detailed structural characterization of the complex between HBx and Bcl-xL, we designed and purified a recombinant HBx BH3-like motif-linker-Bcl-xL fusion protein produced in E. coli. The fusion protein was characterized by size exclusion chromatography, circular dichroism and nuclear magnetic resonance experiments. Our results show that the fusion protein is a monomer in aqueous solution, forms a stable intramolecular complex, and likely retains the native conformation of the complex between Bcl-xL and the HBx BH3-like motif. Furthermore, the HBx BH3-like motif of the intramolecular complex forms an alpha-helix. These observations indicate that the fusion protein should facilitate structural studies aimed at understanding the interaction between HBx and Bcl-xL at the atomic level. PMID- 29114585 TI - The influence of retinoic acid on the human oligodendrocyte precursor cells by RNA-sequencing. AB - Retinoic acid (RA), a metabolite of vitamin A, has been found to influence regeneration in the adult central nervous system (CNS). There may be an effect of RA in the recovery/repair in multiple sclerosis (MS), an autoimmune and neurodegenerative disease of the CNS. We hypothesized that RA is a regulator of the further differentiation of oligodendrocyte precursor cells (OPCs) - cells key to the remyelination process in MS. We conducted studies utilizing RNA-sequencing in human embryonic stem cell (hESC)-derived neural stem cells (NSCs) and OPCs so as to understand the role of transcriptional regulators during transition from both ESCs to NSCs and NSCs to OPCs. We identified that expression of retinoic acid receptors beta and gamma (RARbeta and RARgamma ) was significantly increased following the transition from NSCs to OPCs. We also demonstrated that long term in vitro culture of hESC-derived OPC with different isoforms of RA led to the significant up-regulation of two known transcriptional inhibitors of oligodendrocyte differentiation: Hes5 following prolonged treatment with all trans-RA, 9-cis RA and 13-cis RA; and Id4 following treatment with 13cisRA. These results suggest that long term exposure to certain RA isoforms may impact the continued differentiation of this population. PMID- 29114587 TI - Reduction of calcium flux from the extracellular region and endoplasmic reticulum by amorphous nano-silica particles owing to carboxy group addition on their surface. AB - Several studies have reported that amorphous nano-silica particles (nano-SPs) modulate calcium flux, although the mechanism remains incompletely understood. We thus analyzed the relationship between calcium flux and particle surface properties and determined the calcium flux route. Treatment of Balb/c 3T3 fibroblasts with nano-SPs with a diameter of 70 nm (nSP70) increased cytosolic calcium concentration, but that with SPs with a diameter of 300 or 1000 nm did not. Surface modification of nSP70 with a carboxy group also did not modulate calcium flux. Pretreatment with a general calcium entry blocker almost completely suppressed calcium flux by nSP70. Preconditioning by emptying the endoplasmic reticulum (ER) calcium stores slightly suppressed calcium flux by nSP70. These results indicate that nSP70 mainly modulates calcium flux across plasma membrane calcium channels, with subsequent activation of the ER calcium pump, and that the potential of calcium flux by nano-SPs is determined by the particle surface charge. PMID- 29114586 TI - Calcification process dynamics in coral primary polyps as observed using a calcein incubation method. AB - Calcification processes are largely unknown in scleractinian corals. In this study, live confocal imaging was used to elucidate the spatiotemporal dynamics of the calcification process in aposymbiotic primary polyps of the coral species Acropora digitifera. The fluorophore calcein was used as a calcium deposition marker and a visible indicator of extracellular fluid distribution at the tissue skeleton interface (subcalicoblastic medium, SCM) in primary polyp tissues. Under continuous incubation in calcein-containing seawater, initial crystallization and skeletal growth were visualized among the calicoblastic cells in live primary polyp tissues. Additionally, the distribution of calcein-stained SCM and contraction movements of the pockets of SCM were captured at intervals of a few minutes. Our experimental system provided several new insights into coral calcification, particularly as a first step in monitoring the relationship between cellular dynamics and calcification in vivo. Our study suggests that coral calcification initiates at intercellular spaces, a finding that may contribute to the general understanding of coral calcification processes. PMID- 29114588 TI - ASTRO's Advances in Radiation Oncology: Success to date and future plans. AB - ASTRO's Advances in Radiation Oncology was launched as a new, peer-reviewed scientific journal in December 2015. More than 200 manuscripts have been submitted and 97 accepted for publication as of May 2017. As Advances enters its second year of publication, we have chosen to highlight subjects that will transform the way we practice radiation oncology in special issues or ongoing series: immunotherapy, biomedical analytics, and social media. A teaching case report contest for North American radiation oncology residents will be launched at American Society of Radiation Oncology 2017 to encourage participation in scientific publication by trainees early in their careers. Recognizing our social mission, Advances will also begin a series of articles devoted to highlighting the growing disparities in access to radiation oncology services in vulnerable populations in North America. We wish to encourage the American Society of Radiation Oncology membership to continue its support of the journal through high quality manuscript submission, participation in the peer review process, and highlighting important manuscripts through sharing on social media. PMID- 29114589 TI - Long-term economic value of hypofractionated prostate radiation: Secondary analysis of a randomized trial. AB - Purpose: Moderately hypofractionated intensity modulated radiation therapy (HIMRT) for prostate cancer shortens the treatment course while providing outcomes comparable with those of conventional intensity modulated radiation therapy (CIMRT). To determine the long-term economic value of HIMRT, including the costs of managing long-term radiation toxicities, a cost minimization analysis compared CIMRT with dose-escalated HIMRT using patient-level data from a randomized trial. Methods and materials: Men with localized prostate cancer were randomized to CIMRT (75.6 Gy in 42 fractions over 8.4 weeks) or HIMRT (72 Gy in 30 fractions over 6 weeks). A decision tree modeled trial probabilities of maximum late bowel and urinary toxicities using patient-level data with a median follow-up of 6 years. Costs were estimated from the healthcare perspective using the 2014 national reimbursement rates for services received. Patient-level institutional costs, adjusted to 2014 dollars, verified reimbursements. A sensitivity analysis assessed model uncertainty. Results: The cost for HIMRT and toxicity management was $22,957, saving $7,000 compared with CIMRT ($30,241). CIMRT was the common factor among the 5 most influential scenarios that contributed to total costs. Toxicity represented a small part (<10%) of the average total cost for patients with either grade 2-3 bowel toxicity or grade 2-3 urinary toxicity. However, toxicity management reached up to 26% of the total cost for patients with both high-grade bowel and urinary toxicities. There was no threshold at which CIMRT became the less costly regimen. Institutional costs confirmed the economic value of HIMRT ($6,000 in savings). Conclusions: HIMRT is more cost-efficient than CIMRT for treating prostate cancer, even when taking into account the costs related to late radiation toxicities. HIMRT enhances the value of prostate radiation when compared with CIMRT. PMID- 29114590 TI - Oncological outcomes from trimodality therapy receiving definitive doses of neoadjuvant chemoradiation (>=60 Gy) and factors influencing consideration for surgery in stage III non-small cell lung cancer. AB - Purpose: Guidelines for locally advanced non-small cell lung cancer (LA-NSCLC) recommend definitive chemoradiation therapy (CRT) for cN2-N3 disease, reserving surgery for patients with minimal nodal involvement at presentation. The current literature suggests that surgery after CRT for stage III NSCLC can improve freedom-from-recurrence (FFR) but has not consistently demonstrated an improvement in overall survival, perhaps partly due to the low (45-50.4 Gy) preoperative doses delivered that result in low rates of mediastinal nodal clearance. We therefore analyzed factors associated with trimodality therapy receipt and determined outcomes in patients with LA-NSCLC who were treated with definitive doses (>=60 Gy) of neoadjuvant CRT prior to surgery. Methods and materials: We retrospectively analyzed 355 consecutive patients with LA-NSCLC who were treated with curative intent between January 2000 and December 2013. The Kaplan-Meier method was used to estimate the overall survival and FFR of patients who were initially planned to receive trimodality treatment but never underwent surgery (unplanned bimodality) compared with those who were never considered to be surgical candidates (planned bimodality) and those who underwent surgical resection after CRT (trimodality). Cox proportional hazards regression with forward selection was used for multivariate analyses, and the Fisher exact test was used to test contingency tables. Results: Patients who received trimodality therapy had a longer median survival than those with unplanned or planned bimodality therapy at 59.9, 20.1, and 17.3 months, respectively (P < .001). The survival benefit with surgery persisted in patients with stage IIIB (P < .001) and N3 (P = .010) nodal disease when mediastinal nodal clearance was achieved. FFR was also improved with surgical resection (P = .001). Race (P < .001), stage (P < .001), performance status (P < .001), age (P < .001), and diagnosis of chronic obstructive pulmonary disease (P = .009) were significant indicators that influenced both the decision to initially choose trimodality therapy at consultation and to actually perform surgical resection. Conclusions: Trimodality treatment significantly improves survival and FFR in patients with LA-NSCLC when definitive doses of radiation with neoadjuvant chemotherapy are employed. We identified important demographic features that predict the use of surgical intervention in patients with stage III NSCLC. PMID- 29114591 TI - Tweet for the cure: A snapshot of Twitter usage by 3 U.S. oncologic professional societies. AB - Purpose: Medical societies are incorporating Twitter to communicate with their members and connect with patients. This study compares the online presence of 3 major oncologic societies. Methods and materials: All available tweets in 2014 by the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and Society of Surgical Oncology (SSO) were collected. We analyzed whether posts were original content or retweets. The monthly tweet rate was followed to assess trends. We created 2 new metrics, supporter ratio and tweet density, to correlate online presence and engagement with offline membership breadth. The supporter ratio is the number of people following the organization divided by the number of registered members of each society. The tweet density is the total number of posts divided by the number of registered members of each society. Results: In February 2015, ASCO, ASTRO, and SSO had 36,385; 10,899; and 2721 members, respectively. ASCO's Twitter handle had 33,974 followers, with a supporter ratio of 0.93. A total of 2563 original tweets and 1416 retweets were estimated, which represents a tweet density of 0.11. @ASTRO_org had 5445 followers and a supporter ratio of 0.50. In 2014, ASTRO posted 415 original content tweets and 9 retweets, with a tweet density of 0.039. SSO had a supporter ratio of 0.91 on the basis of 2481 followers. In 2014, SSO posted 207 original tweets and 190 retweets, with a tweet density of 0.15. An increase in tweets and retweets was seen during the month of each society's annual meeting. ASTRO's 61% increase in September 2014 was smaller than SSO's 462% and ASCO's 84%. Conclusion: ASTRO's use of Twitter lags behind ASCO and SSO. Although all 3 societies show increased Twitter use during their annual meetings, they should work toward more meaningful engagement throughout the year. The new metrics of tweet density and supporter ratio will serve as benchmarks for member engagement in future studies. PMID- 29114592 TI - Social media for radiation oncologists: A practical primer. PMID- 29114593 TI - Quantitative FDG-PET/CT predicts local recurrence and survival for squamous cell carcinoma of the anus. AB - Purpose: 18F-fluorodeoxyglucose (FDG) positron emission tomography-(PET)/computed tomography (CT) imaging is used for staging and treatment planning of patients with anal cancer. Quantitative pre- and posttreatment metrics that are predictive of recurrence are unknown. We evaluated the association between pre- and posttreatment FDG-PET/CT parameters and outcomes for patients with squamous cell carcinoma of the anus (SCCA). Methods and materials: The records of 110 patients treated between 2003 and 2013 with definitive radiation therapy for SCCA were reviewed under an institutional review board-approved protocol. The median radiation therapy dose was 50.4 Gy (range, 35-60 Gy). Concurrent chemotherapy was administered for 109 of 110 patients and generally consisted of 5-fluorouracil and mitomycin C (n = 94). All patients underwent pretreatment FDG-PET/CT and 101 of 110 underwent posttreatment FDG-PET/CT 3 months after completion of radiation therapy. The maximum standard uptake value (SUVmax) was analyzed, in addition to multiple patient and treatment factors, by univariate and multivariate Cox regression for correlation with local recurrence (LR) and overall survival (OS). Results: The median follow-up was 28.6 months. LR occurred in 1 of 15 (6.7%), 5 of 47 (10.6%), and 6 of 48 (12.5%) patients with stage I, II, and III disease, respectively. On univariate analysis, a significant association was observed between reduced LR and posttreatment SUVmax <6.1 (P = .0095) and between increased OS and posttreatment SUVmax <6.1 (P = .0086). On multivariate analysis, a significant association was observed between reduced LR and posttreatment SUVmax <6.1 (P = .0013) and the use of intensity modulated radiation therapy (P < .001). A significant multivariate association was observed between increased OS and posttreatment SUVmax <6.1 (P = .0373) and the use of 5-fluorouracil/mitomycin C chemotherapy (P = .001). Conclusion: Posttreatment SUVmax <6.1 is associated with reduced LR and increased OS after chemoradiation therapy for SCCA independent of T and N stage on multivariate analysis. Greater follow-up is required to confirm this association with late patterns of failure. PMID- 29114594 TI - A method to improve dose uniformity during total skin electron beam therapy in patients with pendulous breasts. PMID- 29114595 TI - Use of regional nodal irradiation and its association with survival for women with high-risk, early stage breast cancer: A National Cancer Database analysis. AB - Purpose: The role of regional nodal irradiation (RNI) for patients with breast cancer remains controversial, particularly on the basis of nodal involvement. Using the National Cancer Database, we aimed to validate published data on whether expanding treatment fields from whole-breast irradiation (WBI) to encompass the regional nodes (WBI+RNI) affected overall survival (OS) for patients with node-positive (pN1-3) or high-risk node-negative (pN0) breast cancer treated with breast-conserving surgery and adjuvant chemotherapy. Methods and materials: Women diagnosed with invasive breast cancer between 2004 and 2012 who met the selection criteria for the National Cancer Institute of Canada MA.20 trial were identified and stratified by receipt of RNI. Propensity score matching was used to compare 1:1 matched pairs of patients. Five-year OS was estimated using the Kaplan-Meier method. We used multivariate logistic regression to predict receipt of WBI+RNI and a multivariable Cox model to examine associations between patients' demographic, tumor, and treatment characteristics and OS using double robust estimation. Results: Of 23,567 patients, 6,920 (29%) received WBI+RNI and 16,647 (71%) WBI. Median follow-up was 56 months. Use of WBI+RNI increased from 25.2% in 2004 to 32.2% in 2012 (P < .001). Patients receiving WBI+RNI more often had negative hormone-receptor status, >=5 cm tumors and >1 involved node, and were not privately insured. For all patients, the 5-year OS rates were 90.8% with WBI+RNI versus 92.6% with WBI (P < .001). In the matched cohort (n = 10,922), the corresponding 5-year OS rates were 92% and 91.9% (P = .45), respectively. On multivariate analysis, WBI+RNI did not affect OS in the matched cohort (hazard ratio, 1.02; 95% confidence interval, 0.89-1.17, P = .76), regardless of pathologic nodal status. Conclusions: In this large retrospective analysis, use of WBI+RNI did not affect 5-year OS rates for women with high-risk, early stage breast cancer undergoing breast-conserving surgery and adjuvant chemotherapy, regardless of nodal status, which confirms the findings of the MA.20 trial. PMID- 29114596 TI - Clinical outcomes of intensity modulated proton therapy and concurrent chemotherapy in esophageal carcinoma: a single institutional experience. AB - Purpose: Intensity-modulated proton therapy (IMPT) is an emerging advanced radiation technique. Although dosimetric studies demonstrate the superiority of IMPT for improving target conformity and reducing unnecessary dose to critical normal tissues, clinical experience is limited. We aim to describe our preliminary experience implementing IMPT concurrently with chemotherapy in esophageal carcinoma (EC). Methods and materials: From May 2011 through February 2016, 19 patients with EC (median age, 73 years) were treated with IMPT using 180 to 250 MV protons with a median dose of 50.4 Gy relative biological effectiveness in 28 fractions concurrently with chemotherapy. Beam arrangement was most commonly in the posteroanterior and bilateral posterior oblique beams. The Kaplan Meier method was used to assess survival outcomes. Treatment-related toxicities were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Results: Single-field and multifield optimization was performed in 13 and 6 patients, respectively. The average gross tumor volume was 69.1 cm3; mean lung and heart dose delivered were 4.94 and 7.86 Gy, respectively; and the maximal spinal cord dose was 32.81 Gy. Clinical complete response was achieved in 84%. Only 4 patients underwent surgery. The most common grade 3 acute toxicities were esophagitis and fatigue (3 patients). Grade 3 esophageal stricture occurred in 1 patient. With a median follow-up time of 17 months, overall survival was 39.2 months, with 1-year overall survival, locoregional recurrence-free survival, and distant metastasis-free survival rates of 100%, 88.8%, and 72.9%, respectively. Locoregional and distant failures occurred in 3 and 5 patients, respectively. Conclusions: IMPT is an effective treatment for EC, with high tumor response, good local control, and acceptable acute toxicity. PMID- 29114597 TI - Neoadjuvant twice daily chemoradiotherapy for esophageal cancer: Treatment related mortality and long-term outcomes. AB - Objective: Because of the short potential doubling time of esophageal cancer, there is a theoretical benefit to using an accelerated radiation treatment schedule. This study evaluates outcomes and treatment-related mortality and morbidity of patients treated with neoadjuvant hyperfractionated accelerated chemoradiation for resectable esophageal cancer. Methods and materials: Outcomes from 250 consecutive patients with resectable esophageal cancer treated with preoperative hyperfractionated accelerated chemoradiotherapy (45 Gy in 30 twice daily fractions over 3 weeks) followed by planned transhiatal esophagectomy were analyzed. Grade 3 or greater treatment related toxicity, surgical complications, and treatment-related mortality were determined. Additionally, available surgical specimens were graded for pathological response to chemoradiation. Overall survival (OS) and locoregional control were calculated using the Kaplan-Meier method. The log rank test was used to determine statistical significance. Results: Median follow-up was 59 months for surviving patients; 87% of patients had adenocarcinoma and 13% had squamous cell carcinoma. Eleven percent of patients did not have surgery because of the development of metastases, declining performance status, or refusal. Twenty-seven patients were found to have unresectable and/or metastatic disease at the time of surgery. Overall, 10 of 223 operated patients died within 3 months, resulting in a perioperative mortality rate of 4%. Median OS was 28.4 months (95% confidence interval, 22.3-35.6 months) for all patients and 35.1 months (95% confidence interval, 27.4-47 months) for patients who underwent esophagectomy. There were 32 isolated locoregional failures with a 3-year locoregional control rate of 83%. Of 129 patients who had independent pathology review, 29% had complete response to treatment. This group had a median OS of 98.9 months and 3-year OS of 74%. Conclusion: Neoadjuvant twice-daily chemoradiation for esophageal cancer is a safe and effective alternative to daily fractionation with low treatment-related mortality and long term outcomes similar to standard fractionation courses. PMID- 29114598 TI - Long-term survival and toxicity outcomes of intensity modulated radiation therapy for the treatment of esophageal cancer: A large single-institutional cohort study. AB - Purpose: In patients with esophageal cancer (EC), intensity modulated radiation therapy (IMRT) improves dose sparing to the heart and lung, with some evidence showing clinical benefit. Herein, we report our cumulative clinical experience with the use of IMRT for EC. Methods and materials: This is a retrospective analysis of 587 patients with nonmetastatic EC who were treated consecutively with IMRT from January 2004 to June 30, 2013. All patients with stage I-IVA (American Joint Committee on Cancer 2002) received concurrent chemoradiation therapy either preoperatively or definitively. The Kaplan-Meier method was used to compute overall survival (OS) and locoregional recurrence-free survival and disease-free survival. The Common Terminology Criteria for Adverse Events, Version 4.0 were used to grade acute and subacute complications. Results: The median radiation dose was 50.4 Gy in 28 daily fractions. As of July 2015, the median follow-up was 31.4 months (range, 2.9-130.7 months) for all patients and 61.8 months (range, 7.7-130.7 months) for survivors. The median OS was 38.9 months, and the 1-, 3-, and 5-year OS rates were 86.7%, 51.8%, and 41.2%, respectively. The 1-, 3-, and 5-year locoregional recurrence-free survival rates were 77.6%, 68.2%, and 66.1%, respectively, and the 1-, 3-, and 5-year disease free survival rates were 58.6%, 43.7%, and 41.4%, respectively. Outcomes for both trimodality and bimodality treated patients were better than the outcomes reported in the literature. Eight patients (1.4%) experienced grade >=3 pneumonitis, and 74 patients (13%) developed grade >=3 esophagitis. For patients who underwent surgery, the most common postoperative complications were pneumonia (9.6%), anastomotic leakage (11.1%), and atrial fibrillation (12.5%). Conclusions: This is the largest, single institutional study to date on the long term outcomes of treatment with IMRT for EC. For photon-based radiation therapy, IMRT yields excellent outcomes and should be considered for the treatment of EC. PMID- 29114599 TI - Dosimetric and clinical outcomes after volumetric modulated arc therapy for carcinoma of the thoracic esophagus. AB - Purpose: The efficiency of radiation delivery via volumetric modulated arc therapy (VMAT) is indisputable, but outcomes after VMAT for thoracic esophageal carcinoma are largely unknown. Methods and materials: We retrospectively analyzed 65 patients with thoracic esophageal cancer who received VMAT to 50.4 Gy (range, 45-50.4 Gy) with concurrent chemotherapy from November 2012 to March 2016 at a single tertiary cancer center. We then used propensity score matching to match these 65 patients with 130 other patients treated with step-and-shoot intensity modulated radiation therapy (ssIMRT) and concurrent chemotherapy. Differences in continuous and categorical variables were examined with independent-sample t or Wilcoxon tests and chi2 tests. Results: Dosimetrically, VMAT had a higher conformity index (87.75 +/- 10.70 VMAT vs 83.20 +/- 9.42 ssIMRT, P = .003), a higher heart V5, and a lower V50 than ssIMRT, but lung V5-20, heart V30, heart V40, cordmax, and homogeneity index were similar. At median follow-up intervals of 14.3 months (range, 3.8-34.5 months) for VMAT and 31.8 months (range, 1.8 117.2 months) for ssIMRT, overall survival rates were similar between the treatments (93.5% VMAT vs 91.5% ssIMRT at 1 year; 60.0% VMAT and 61.4% ssIMRT at 2 years; P = .868). Recurrence-free survival rates were similar (73.3% VMAT vs 79.5% ssIMRT at 1 year, 59.9% VMAT and 61.8% ssIMRT at 2 years; P = .614), as were pathologic complete response rates (31.2% VMAT vs 23.3% ssIMRT; P = .41) and toxicity and postoperative complications (radiation pneumonitis 9% VMAT vs 15.4% ssIMRT; pericardial effusion 2% VMAT vs 7% ssIMRT; esophageal fistula and stricture 9% VMAT vs 13% ssIMRT; all P > .05). Conclusion: Compared with ssIMRT, VMAT had better target conformity with similar organ sparing and comparable rates of survival, recurrence, and toxicity. These results suggest that VMAT can be safe and effective for esophageal cancer. PMID- 29114600 TI - Abscopal effect in recurrent colorectal cancer treated with carbon-ion radiation therapy: 2 case reports. PMID- 29114601 TI - Elective nodal dose of 60 Gy or 50 Gy in head and neck cancers: A matched pair analysis of outcomes and toxicity. AB - Purpose: The main objective of this study was to evaluate appropriate doses for elective nodal irradiation (ENI) in head and neck squamous cell carcinoma (HNSCC) patients to optimize the therapeutic ratio. Methods and materials: A matched pair analysis of 2 similar cohorts of HNSCC treated with intensity modulated radiation therapy with different dose prescriptions to the elective nodal regions was conducted. One group received 60 Gy, whereas the other received 50 Gy (ENI60 and ENI50 groups, respectively). Isolated regional recurrences (IRR) and locoregional control were evaluated. Doses received by the parotid and thyroid glands were compared among both groups and were clinically correlated with the trend of salivary function recovery and incidence of hypothyroidism. Results: Of the 110 patients studied, 97 were eligible for analysis after matching based on propensity scores. The 3-year locoregional control rate was similar in ENI60 and ENI50 (78.7% and 77%, respectively; P = .93). There were no IRR in ENI regions in either group. The mean ipsilateral parotid dose in ENI60 was significantly higher compared with ENI50 (42 vs 35.7 Gy, P = .03). There was no significant difference in the mean contralateral parotid doses (32.5 vs 31.7 Gy, P = .6). The mean thyroid doses were high in ENI60 compared with ENI50 (54.7 vs 43.3 Gy, P < .001). A significant difference in ipsilateral parotid salivary excretory fraction ratio at 1 year (P = .03) was observed with quicker recovery of salivary function. The salivary excretory fractions were poorer in the ENI60 group with higher mean parotid doses (P = .009). At 2 years, 26 patients (54%) in the ENI60 group and 13 patients (26.5%) in the ENI50 group developed biochemical hypothyroidism (P = .007). Conclusions: Doses of 50 Gy equivalent are sufficient to sterilize the uninvolved nodal regions because the rates of IRR are extremely low. Using ENI50 results in clinically meaningful reduction in salivary and thyroid toxicity in HNSCC. PMID- 29114602 TI - Impact on quality of life of IMRT versus 3-D conformal radiation therapy in head and neck cancer patients: A case control study. AB - Objective: The purpose of this study was to prospectively and longitudinally compare the health-related quality of life (HRQOL) outcomes between head and neck (HN) cancer patients treated with parotid-sparing intensity modulated radiation therapy (IMRT) and patients treated with 3-dimensional conventional radiation therapy (3D-CRT). Methods and materials: Before and up to 12 months after treatment, HRQOL was recorded in patients with HN cancer who were referred to the Department of Oncology at Sahlgrenska University Hospital for curative IMRT. The study group's HRQOL was compared with a matched group of patients from previous descriptive HRQOL studies treated with 3D-CRT. Both groups' HRQOL was measured by the European Organization for Research and Treatment for Cancer QLQ-C30 and European Organization for Research and Treatment for Cancer QLQ-HN35 at 6 time points in the first year after diagnosis. Results: Two hundred and seven patients were included, 111 treated with IMRT and 96 matched controls treated with 3D-CRT. Both groups' HRQOL deteriorated during and after treatment. Just after treatment, worse HRQOL scores were observed in the IMRT group regarding insomnia (38 vs 27; P = .032), appetite loss (64 vs 50; P = .019), senses (54 vs 41; P = .017), and coughing (39 vs 26, P = .009). At 12 months, however, significantly better HRQOL scores were observed in the IMRT group regarding problems with dry mouth (72 vs 62; P = .018), pain (28 vs 20; P = .018), sexuality (37 vs 23; P = .016), social contacts (10 vs 6; P = .026), cognitive functioning (79 vs 87; P = .0057), and financial difficulties (12 vs 20; P = .0019). Conclusions: This study further supports the hypothesis that the introduction of IMRT has improved the long-term quality of life of HN cancer patients who have been treated with radiation therapy, but might cause more acute side effects. Longer follow-up is needed to study late complications. PMID- 29114604 TI - Effectiveness of low-dose radiation for primary cutaneous anaplastic large cell lymphoma. AB - Purpose: Primary cutaneous anaplastic large cell lymphoma (pcALCL) is conventionally treated with radiation therapy (RT) doses >=30 GGy, but effectiveness of lower doses is unclear. We compared responses after a range of RT doses for pcALCL. Methods and materials: From 1999 through 2015, 45 lesions in 21 patients met clinicopathologic pcALCL diagnostic criteria and were treated with RT (<20 Gy, 20-29 Gy, or >=30 Gy dose). Complete clinical (CR) and partial responses (PR) were compared by dose using Fisher exact test. Progression-free and overall survivals were calculated using the Kaplan-Meier method. Results: Forty-two percent of lesions were treated with <20 Gy, 22% with 20 to 29 Gy, and 35% with >=30 Gy. Within 12 weeks, 100% responded, with 67% CR and 33% PR; by last follow-up, 87% achieved CR and 13% PR (no difference by RT dose; P = .84). Three-year freedom from local relapse was 100%, 86%, and 100% with <20 Gy, 20 to 29 Gy, and >=30 Gy, respectively (P = .28). Many patients ultimately demonstrated other cutaneous or systemic relapse, with 55% 3-year and 29% 10-year progression free survival. Overall survival at 10 years was 59%, with 2 deaths from complications of disease. Conclusions: Low-dose RT offered excellent local control in the setting of the indolent, chronic course of pcALCL in this patient cohort. PMID- 29114603 TI - Audiovisual biofeedback guided breath-hold improves lung tumor position reproducibility and volume consistency. AB - Purpose: Respiratory variation can increase the variability of tumor position and volume, accounting for larger treatment margins and longer treatment times. Audiovisual biofeedback as a breath-hold technique could be used to improve the reproducibility of lung tumor positions at inhalation and exhalation for the radiation therapy of mobile lung tumors. This study aimed to assess the impact of audiovisual biofeedback breath-hold (AVBH) on interfraction lung tumor position reproducibility and volume consistency for respiratory-gated lung cancer radiation therapy. Methods: Lung tumor position and volume were investigated in 9 patients with lung cancer who underwent a breath-hold training session with AVBH before 2 magnetic resonance imaging (MRI) sessions. During the first MRI session (before treatment), inhalation and exhalation breath-hold 3-dimensional MRI scans with conventional breath-hold (CBH) using audio instructions alone and AVBH were acquired. The second MRI session (midtreatment) was repeated within 6 weeks after the first session. Gross tumor volumes (GTVs) were contoured on each dataset. CBH and AVBH were compared in terms of tumor position reproducibility as assessed by GTV centroid position and position range (defined as the distance of GTV centroid position between inhalation and exhalation) and tumor volume consistency as assessed by GTV between inhalation and exhalation. Results: Compared with CBH, AVBH improved the reproducibility of interfraction GTV centroid position by 46% (P = .009) from 8.8 mm to 4.8 mm and GTV position range by 69% (P = .052) from 7.4 mm to 2.3 mm. Compared with CBH, AVBH also improved the consistency of intrafraction GTVs by 70% (P = .023) from 7.8 cm3 to 2.5 cm3. Conclusions: This study demonstrated that audiovisual biofeedback can be used to improve the reproducibility and consistency of breath-hold lung tumor position and volume, respectively. These results may provide a pathway to achieve more accurate lung cancer radiation treatment in addition to improving various medical imaging and treatments by using breath-hold procedures. PMID- 29114605 TI - Diffuse large B-cell lymphoma in very elderly patients over 80 years old: Incorporating consolidative radiation therapy into management decisions. AB - Purpose: The population of patients aged 80 years or older who are diagnosed with diffuse large B-cell lymphoma (DLBCL) continues to increase, but an optimal treatment strategy has not been established. We sought to examine the influence of consolidative radiation therapy (RT) on outcome and toxicity among the very elderly diagnosed with stage I-IV DLBCL. Methods and materials: We evaluated 131 patients treated at a single institution between 2002 and 2014 who were eligible for RT after successful treatment with chemotherapy. Results: The median age was 83 years (range, 80-96). Advanced-stage disease was present in 61.8% of patients. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was administered to 80% of patients (n = 108), and 23.7% of patients received consolidative RT. Among early-stage (ES) patients treated with 3 to 4 cycles of chemotherapy and RT (n = 12) versus 6 to 8 cycles of chemotherapy alone (n = 17), there were no statistically significant differences in 3-year disease-free, progression-free, or overall survival rates. The 3 year disease-free survival was 91.7% versus 88.2% among patients treated with combined modality therapy versus chemotherapy alone (P = .78). The 3-year overall survival was 82.5% versus 87.5% among patients treated with combined modality therapy compared with chemotherapy alone (P = .852). Anemia and neuropathy occurred more frequently among ES patients who received 6 to 8 cycles of chemotherapy alone. Among advanced-stage patients with bulky disease (n = 35), consolidative RT to sites of bulky disease may have improved local control (3-year local control, 100% vs 60.3%, P = .160). Conclusions: Among patients aged 80 years or older who have with ES DLBCL, 3 to 4 cycles of chemotherapy followed by RT is at least equivalent in efficacy to chemotherapy alone and is associated with lower levels of toxicity, which suggests that it may be a better choice for therapy when trying to balance treatment efficacy and tolerability. PMID- 29114606 TI - Estimating prognosis at the time of repeat whole brain radiation therapy for multiple brain metastases: The reirradiation score. AB - Purpose: Whole brain radiation therapy (WBRT) remains the standard of care for patients with multiple brain metastases, but more than half of treated patients will develop intracranial progression. Because there is no clear consensus on the optimal therapeutic approach, a prognostic index would be helpful to guide treatment options at progression. We explored whether the recursive partitioning analysis (RPA) score prior to repeat WBRT is predictive of survival. Methods and materials: This multi-institutional pooled analysis included patients with 2 or more brain metastases from any solid primary tumor that was treated with 2 courses of WBRT. Information on demographics, disease characteristics, and intervals between courses was collected. RPA class was abstracted or retrospectively assigned, and descriptive statistics calculated. Median survival (MS) was determined using the Kaplan-Meier method and compared using log rank tests. Univariate and multivariate analyses were performed via Cox regression analysis. Results: For 205 patients, the median age was 55 years (range, 25-83 years), 68% were female, 40.5% had non-small cell lung cancer, and 31.2% had small cell lung cancer. Prior to the second WBRT, 4.9% of patients were RPA class 1, 36.6% were RPA2, and 58.5% were RPA3, with an MS of 7.5 months (95% confidence interval [CI], 4.7-10.3), 5.2 months (95% CI, 3.7-6.7 months), and 2.9 months (95% CI, 2.2-2.9 months), respectively (P = .001). On univariate and multivariate analyses, a Karnofsky Performance Status of <80, extracranial metastases, interval between courses <9 months, small cell lung cancer histology, and uncontrolled primary significantly correlated with shorter MS. By assigning a score of 1 to each of these factors, a new prognostic index was created, the reirradiation (ReRT) score. Survival on the basis of ReRT score grouping ranged from 2.2 to 7.2 months and demonstrated significant differences in MS. Conclusions: In the largest reported cohort to receive repeat WBRT, application of the RPA score was not predictive of MS. The new ReRT score is a simple tool based on readily available clinical information. PMID- 29114607 TI - The impact of different stereotactic radiation therapy regimens for brain metastases on local control and toxicity. AB - Purpose: Stereotactic radiation therapy (SRT) enables focused, short course, high dose per fraction radiation delivery to brain tumors that are less ideal for single fraction treatment because of size, shape, or close proximity to sensitive structures. We sought to identify optimal SRT treatment regimens for maximizing local control while minimizing morbidity. Methods and materials: We performed a retrospective review of patients treated with SRT for solid brain metastases using variable dose schedules between 2001 and 2011 at 3 academic hospitals. Endpoints included (1) local control, (2) acute toxicity (Common Toxicity Criteria for Adverse Events v3.0), and (3) symptomatic radionecrosis. Kaplan Meier and a competing risks methodology were used to estimate the actuarial rate of local failure and assess the association of clinical and treatment covariates with time to local failure. Results: A total of 156 patients was identified. Common tumor histologies included breast (21%), non-small cell lung (32%), melanoma (22%), small cell lung (9%), and renal cell carcinoma (6%). The majority of lesions were supratentorial (57%). Median target volume was 3.99 mL (range, 0.04-58.42). Median total SRT dose was 25 Gy (range, 12-36), median fractional dose was 5 Gy (range, 2.5-11), and median number of fractions was 5 (range, 2 10). Cumulative incidence of local progression at 3, 6, 12, 18, and 24 months was 11%, 22%, 29%, 34%, and 36%. Total prescription dose was the only factor significantly associated with time to local progression on univariate (P = .02) and multivariable analysis (P = .01, adjusted hazards ratio, 0.87). Five patients experienced seizures within 10 days of SRT and 5 patients developed radionecrosis. All patients with documented radionecrosis received prior radiation to the index lesion. Conclusions: Our series of SRT for brain metastases found total prescription dose to be the only factor associated with local control. Both acute and long-term toxicity events from SRT were modest. PMID- 29114608 TI - 4-1BB (CD137) and radiation therapy: A case report and literature review. PMID- 29114609 TI - Dose escalation with an IMRT technique in 15 to 28 fractions is better tolerated than standard doses of 3DCRT for LAPC. AB - Purpose: To review acute and late toxicities after chemoradiation for locally advanced pancreatic ductal adenocarcinoma in patients who were treated with escalated dose radiation (EDR). Methods and materials: Maximum Common Terminology Criteria for Adverse Events Version 4.0 acute toxicities (AT) during radiation and within 60 days after radiation were recorded for both acute gastrointestinal toxicity and overall toxicity (OT). Late toxicities were also recorded. EDR was generally delivered with daily image guidance and breath-hold techniques using intensity modulated radiation therapy (IMRT) planning. These were compared with patients who received standard dose radiation (SDR) delivered as 50.4 Gy in 28 fractions using 3-dimensional chemoradiation therapy planning. Results: A total of 59 of 154 patients (39%) received EDR with biologically equivalent doses >70 Gy. The most frequent schedules were 63 Gy in 28 fractions (19 of 154 patients), 67.5 Gy in 15 fractions (10 of 154 patients), and 70 Gy in 28 fractions (15 of 154 patients). No grade 4 or grade 5 OT or late toxicities were reported. Rates of grade 3 acute gastrointestinal toxicity were significantly lower in patients who received EDR compared with SDR (1% vs 14%; P < .001). Similarly, rates of grade 3 OT were also lower for EDR compared with SDR (4% vs 16%; P = .004). The proportion of patients who experienced no AT was higher in the EDR group than the SDR group (36% vs 15%; P = .001). For EDR patients treated with IMRT, a lower risk of AT was associated with a later treatment year (P = .007), nonpancreatic head tumor location (P = .01), breath-hold (P = .002), 4-dimensional computed tomography (P = .003), computed tomography on rails (P = .002), and lower stomach V40 (P = .03). With a median time of 12 months (range, 1-79 months) from the start of radiation therapy to the last known follow-up in the EDR group, 51 of 59 patients (86%) had no late toxicity. Six of 59 EDR patients (10%) had either strictures or gastrointestinal bleeding that required intervention. No significant predictors of late toxicity were identified. Conclusion: Overall acute and late toxicity rates were low with EDR using an IMRT technique with image guidance and respiratory gating. PMID- 29114610 TI - Initiative to reduce bone scans for low-risk prostate cancer patients: A quasi experimental before-and-after study in a Veterans Affairs hospital. AB - Purpose: Bone scans (BS) are a low-value test for asymptomatic men with low-risk prostate cancer. We performed a quality improvement intervention aimed at reducing BS for these patients. Methods and materials: The intervention was a presentation that leveraged the behavioral science concepts of social comparison and normative appeals. Participants were multidisciplinary stakeholders from the Radiation Oncology and Urology services at a Veterans Affairs hospital. We determined the baseline rate of BS by retrospectively analyzing cases of asymptomatic men with newly diagnosed low-risk prostate cancer. For social comparison, we presented contemporary peer BS rates in the United States including Veterans Affairs hospitals. For normative appeals, we reviewed guidelines from various professional groups. To analyze the effect of this intervention, we performed a quasi-experimental, uncontrolled, before-and-after study. Results: During the 1-year period before the intervention, 32 of 37 patients with low-risk prostate cancer (86.5%) received a BS. The contemporary peer rate was approximately 30%. All reviewed guidelines recommended against BS. During the 1-year period after the intervention, the rate of BS was reduced to 65.5% (19 of 29 patients; P = .043 by one-sided Fisher's exact test). Conclusions: We observed a modest reduction in guideline-discordant BS after the quality improvement intervention. BS rates might be influenced by initiatives that combine social comparisons with appeals to professional norms. PMID- 29114611 TI - 2D kV orthogonal imaging with fiducial markers is more precise for daily image guided alignments than soft-tissue cone beam computed tomography for prostate radiation therapy. AB - Purpose: The hypothesis is that 2-dimensional kV orthogonal imaging with fiducial markers (kV-FM) and soft-tissue cone beam computed tomography (ST-CBCT) are equally reproducible for daily positional alignments for image guided (IG) intensity modulated radiation therapy (IMRT) for prostate cancer. Methods and materials: Ten patients undergoing definitive treatment for prostate cancer with IG-IMRT were imaged daily with kV-FM and ST-CBCT. For each acquired kV and CBCT image, offline alignments to the digitally reconstructed radiograph or planning CT, respectively, were made twice by the same physician to assess intraobserver test-retest reproducibility. The 256 kV and 142 CBCT images were analyzed, and the test-retest analysis was performed again on a subset of images by another physician to verify the results. Results: The results demonstrated that kV-FM had better intraobserver test-retest reproducibility in the anterior-posterior (AP; 95% confidence interval [CI] Pearson correlation coefficient [r], 0.987-0.991), left-right (LR; 95% CI r, 0.955-0.969), and superior-inferior (SI; 95% CI r, 0.971-0.980) directions for daily IG alignments compared with ST-CBCT (AP: 95% CI r, 0.804-0.877; LR: 95% CI r, 0.877-0.924; SI: 95% CI r, 0.791-0.869). Errors associated with intraobserver test-retest reproducibility were submillimeter with kV-FM (AP: 0.4 +/- 0.7 mm; RL: 0.4 +/- 1.0 mm; SI: 0.5 +/- 0.7 mm) compared with ST-CBCT (AP: 2.1 +/- 2.2 mm; LR: 1.3 +/- 1.4 mm; SI: 1.2 +/- 1.8 mm). The mean shift differences between kV-FM and ST-CBCT were 0.3 +/- 3.8 mm for AP, -1.1 +/- 8.5 mm for LR, and -2.0 +/- 3.7 mm for SI. Dose-volume histograms were generated and showed that test-retest variability associated with ST-CBCT IG-alignments resulted in significantly increased dose to normal structures and a reduced planning target volume dose in many patients. Conclusions: The kV-FM-based daily IG alignment for IMRT of prostate cancer is more precise than ST-CBCT, as assessed by a physician's ability to reproducibly align images. Given the magnitude of the error introduced by inconsistency in making ST-CBCT alignments, these data support a role for daily kV imaging of FM to enhance the precision of external beam dose delivery to the prostate. PMID- 29114612 TI - Simulating intrafraction prostate motion with a random walk model. AB - Purpose: Prostate motion during radiation therapy (ie, intrafraction motion) can cause unwanted loss of radiation dose to the prostate and increased dose to the surrounding organs at risk. A compact but general statistical description of this motion could be useful for simulation of radiation therapy delivery or margin calculations. We investigated whether prostate motion could be modeled with a random walk model. Methods and materials: Prostate motion recorded during 548 radiation therapy fractions in 17 patients was analyzed and used for input in a random walk prostate motion model. The recorded motion was categorized on the basis of whether any transient excursions (ie, rapid prostate motion in the anterior and superior direction followed by a return) occurred in the trace and transient motion. This was separately modeled as a large step in the anterior/superior direction followed by a returning large step. Random walk simulations were conducted with and without added artificial transient motion using either motion data from all observed traces or only traces without transient excursions as model input, respectively. Results: A general estimate of motion was derived with reasonable agreement between simulated and observed traces, especially during the first 5 minutes of the excursion-free simulations. Simulated and observed diffusion coefficients agreed within 0.03, 0.2 and 0.3 mm2/min in the left/right, superior/inferior, and anterior/posterior directions, respectively. A rapid increase in variance at the start of observed traces was difficult to reproduce and seemed to represent the patient's need to adjust before treatment. This could be estimated somewhat using artificial transient motion. Conclusions: Random walk modeling is feasible and recreated the characteristics of the observed prostate motion. Introducing artificial transient motion did not improve the overall agreement, although the first 30 seconds of the traces were better reproduced. The model provides a simple estimate of prostate motion during delivery of radiation therapy. PMID- 29114613 TI - ACR Appropriateness Criteria for external beam radiation therapy treatment planning for clinically localized prostate cancer, part II of II. AB - Purpose: To present the most updated American College of Radiology (ACR) Appropriateness Criteria formed by an expert panel on the appropriate delivery of external beam radiation to manage stage T1 and T2 prostate cancer (in the definitive setting and post-prostatectomy) and to provide clinical variants with expert recommendations based on accompanying Appropriateness Criteria for target volumes and treatment planning. Methods and materials: The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a panel of multidisciplinary experts. The guideline development and revision process includes an extensive analysis of current medical literature from peer-reviewed journals and the application of well established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In instances in which evidence is lacking or equivocal, expert opinion may supplement available evidence to recommend imaging or treatment. Results: The panel summarizes the most recent and relevant literature on the topic, including organ motion and localization methods, image guidance, and delivery techniques (eg, 3-dimensional conformal intensity modulation). The panel presents 7 clinical variants, including (1) a standard case and cases with (2) a distended rectum, (3) a large-volume prostate, (4) bilateral hip implants, (5) inflammatory bowel disease, (6) prior prostatectomy, and (7) a pannus extending into the radiation field. Each case outlines the appropriate techniques for simulation, treatment planning, image guidance, dose, and fractionation. Numerical rating and commentary is given for each treatment approach in each variant. Conclusions: External beam radiation is a key component of the curative management of T1 and T2 prostate cancer. By combining the most recent medical literature, these Appropriateness Criteria can aid clinicians in determining the appropriate treatment delivery and personalized approaches for individual patients. PMID- 29114615 TI - Risk of carotid blowout after reirradiation with particle therapy. AB - Purpose: Carotid blowout (CB) is a serious complication in retreatment of neoplasms in the head and neck (H&N) region. Rates seem to increase in hypofractionated or accelerated hyperfractionated regimens. In this study, we investigate the CB rate and the cumulative doses received by the carotid artery (CA) in a cohort of patients who were reirradiated at CNAO with particle therapy in the H&N region. Methods and materials: The dosimetric information, medical records, and tumor characteristics of 96 patients were analyzed. For 49 of these patients, the quality of dosimetric information was sufficient to calculate the cumulative doses to the CA. The corresponding biological equivalent dose in 2 Gy fractions (EQD2) was calculated with an alpha/beta-ratio of 3. Results: In the final reirradiation at CNAO, 17 patients (18%) had been treated with protons and 79 (82%) with carbon ions. Two patients experienced profuse oronasal bleeding, of which one case was confirmed to be caused by CB. If attributing both cases to CB, we found an actuarial CB rate of 2.7%. Interestingly, there were no CB cases in the carbon ion group even though this was the large majority of patients and they generally were treated more aggressively in terms of larger fraction doses and higher cumulative EQD2. Conclusions: The current practice of particle reirradiation at CNAO for recurrent neoplasms in the H&N region results in acceptable rates of CB. PMID- 29114614 TI - Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched pair analysis. AB - Purpose: Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach. Methods and materials: From 1995 to 2003, a phase 2 protocol examined CRT with 5-fluorouracil and CB radiation therapy (52.5 Gy in 5 weeks) for patients with LARC. Seventy-six protocol patients were matched (case-control approach) for surgery type, tumor (T) stage, and clinical nodal (N) stage with patients who received standard dose (SD) CRT (5-fluorouracil, 45 Gy). A chart review was performed. McNemar's test and Kaplan-Meier analyses were used for statistical analysis. Results: The SD and CB groups did not differ in tumor circumferential involvement and length, but the tumors of CB patients were closer to the anal verge (4.7 vs 5.7 cm; P = .02). Although tumor downstaging was higher in the CB cohort (76% vs 51%; P < .01), pathologic complete response rates did not differ (CB, 17.1% vs SD, 15.8%, P = 1.00). The incidence of grade >=3 radiation-related toxicities was low and similar in both groups (CB, 10% vs SD, 3%, P = .22). Postoperative (anastomotic leak, wound complications/abscess, bleeding) and late (small bowel obstruction, stricture) complication rates did not differ between the groups (P > .05). The median follow-up was 11.9 years. The 5-year local control rates were higher for CB (100.0%) compared with SD (90.0%) patients (P = .01). CB patients had higher rates of 10-year progression-free survival (71.9% vs 57.6%, P < .01) and overall survival (71.6% vs 62.4%, P = .01) compared with SD patients. Conclusions: CRT dose escalation for patients with LARC is safe and effective. The improved T-downstaging and local control observed in CB patients should encourage further dose escalation studies. PMID- 29114616 TI - Detection of regional radiation-induced lung injury using hyperpolarized 129Xe chemical shift imaging in a rat model involving partial lung irradiation: Proof of-concept demonstration. AB - Purpose: The purpose of this work was to use magnetic resonance imaging (MRI) of hyperpolarized (HP) 129Xe dissolved in pulmonary tissue (PT) and red blood cells (RBCs) to detect regional changes to PT structure and perfusion in a partial-lung rat model of radiation-induced lung injury and compare with histology. Methods and materials: The right medial region of the lungs of 6 Sprague-Dawley rats was irradiated (20 Gy, single-fraction). A second nonirradiated cohort served as the control group. Imaging was performed 4 weeks after irradiation to quantify intensity and heterogeneity of PT and RBC 129Xe signals. Imaging findings were correlated with measures of PT and RBC distribution. Results: Asymmetric (right vs left) changes in 129Xe signal intensity and heterogeneity were observed in the irradiated cohort but were not seen in the control group. PT signal was observed to increase in intensity and heterogeneity and RBC signal was observed to increase in heterogeneity in the irradiated right lungs, consistent with histology. Conclusion: Regional changes to PT and RBC 129Xe signals are detectable 4 weeks following partial-lung irradiation in rats. PMID- 29114617 TI - Two-and-a-half-year clinical experience with the world's first magnetic resonance image guided radiation therapy system. AB - Purpose: Magnetic resonance image guided radiation therapy (MR-IGRT) has been used at our institution since 2014. We report on more than 2 years of clinical experience in treating patients with the world's first MR-IGRT system. Methods and materials: A clinical service was opened for MR-IGRT in January 2014 with an MR-IGRT system consisting of a split 0.35T magnetic resonance scanner that straddles a ring gantry with 3 multileaf collimator-equipped 60Co heads. The service was expanded to include online adaptive radiation therapy (ART) MR-IGRT and cine gating after 6 and 9 months, respectively. Patients selected for MR-IGRT were enrolled in a prospective registry between January 2014 and June 2016. Patients were treated with a variety of radiation therapy techniques including intensity modulated radiation therapy and stereotactic body radiation therapy (SBRT). When applicable, online ART was performed and gating on sagittal 2 dimensional cine MR was used. The charts of patients treated with MR-IGRT were reviewed to report on the clinical and treatment characteristics of the initial patients who were treated with this novel technique. Results: A total of 316 patients have been treated with the MR-IGRT system, which has been integrated into a high-volume clinic. The cases were most commonly selected for improved soft tissue visualization, ART, and cine gating. Seventy-six patients were treated with 3-dimensional conformal radiation therapy, 146 patients with intensity modulated radiation therapy, and 94 patients with SBRT. The most commonly treated disease sites were the abdomen (28%), breast (26%), pelvis (22%), thorax (19%), and head and neck (5%). Sixty-seven patients were treated with online ART over a total of 244 adapted fractions. Cine treatment gating was used for a total of 81 patients. Conclusions: MR-IGRT has been successfully implemented in a high-volume radiation clinic and provides unique advantages in the treatment of a variety of malignancies. Additional clinical trials are in development to formally evaluate MR-IGRT in the treatment of multiple disease sites with techniques such as SBRT and ART. PMID- 29114618 TI - Orthogonal image pairs coupled with OSMS for noncoplanar beam angle, intracranial, single-isocenter, SRS treatments with multiple targets on the Varian Edge radiosurgery system. AB - Purpose: To characterize the accuracy of noncoplanar image guided radiation therapy with the Varian Edge radiosurgery system for intracranial stereotactic radiosurgery (SRS) treatments by assessing the accuracy of kV/kV orthogonal pair registration with Optical Surface Monitoring System (OSMS) monitoring relative to cone beam computed tomography (CT). Methods and materials: A Computerized Imaging Reference System head phantom and Encompass SRS Immobilization System were used to determine collision-free space for orthogonal image pairs (kV/kV) for couch rotations (CRs) of 45 degrees , 30 degrees , 15 degrees , 345 degrees , 330 degrees , and 315 degrees . Couch-induced shifts were measured using kV/kV orthogonal image pairs, OSMS, and cone beam CT. The kV/kV image pairs and OSMS localization accuracy was also assessed with respect to cone beam CT. Results: Mean orthogonal image pair differences for 315 degrees , 330 degrees , 345 degrees , 15 degrees , 30 degrees , and 45 degrees CRs were <=+/-0.60 mm and +/ 0.37 degrees . OSMS localization accuracy was <=+/-0.25 mm and +/-0.20 degrees . Correspondingly, kV/kV localization accuracy was <=+/-0.30 mm and +/-0.5 degrees . Shift differences for various image pairs at all CRs were <=+/-1.10 mm and +/ 0.7 degrees . Cone beam CT deviation was 0.10 mm and 0.00 degrees without patient motion or CR. Conclusion: Based on our study, CR-induced shifts with the Varian Edge radiosurgery system will not produce noticeable dosimetric effects for SRS treatments. Thus, replacing cone beam CT with orthogonal kV/kV pairs coupled with OSMS at the treatment couch angle could reduce the number of cone beam CT scans that are acquired during a standard SRS treatment while providing an accurate and safe treatment with negligible dosimetric effects on the treatment plan. PMID- 29114621 TI - A New Adventure for our Journal! PMID- 29114619 TI - Incorporating big data into treatment plan evaluation: Development of statistical DVH metrics and visualization dashboards. AB - Purpose: To develop statistical dose-volume histogram (DVH)-based metrics and a visualization method to quantify the comparison of treatment plans with historical experience and among different institutions. Methods and materials: The descriptive statistical summary (ie, median, first and third quartiles, and 95% confidence intervals) of volume-normalized DVH curve sets of past experiences was visualized through the creation of statistical DVH plots. Detailed distribution parameters were calculated and stored in JavaScript Object Notation files to facilitate management, including transfer and potential multi institutional comparisons. In the treatment plan evaluation, structure DVH curves were scored against computed statistical DVHs and weighted experience scores (WESs). Individual, clinically used, DVH-based metrics were integrated into a generalized evaluation metric (GEM) as a priority-weighted sum of normalized incomplete gamma functions. Historical treatment plans for 351 patients with head and neck cancer, 104 with prostate cancer who were treated with conventional fractionation, and 94 with liver cancer who were treated with stereotactic body radiation therapy were analyzed to demonstrate the usage of statistical DVH, WES, and GEM in a plan evaluation. A shareable dashboard plugin was created to display statistical DVHs and integrate GEM and WES scores into a clinical plan evaluation within the treatment planning system. Benchmarking with normal tissue complication probability scores was carried out to compare the behavior of GEM and WES scores. Results: DVH curves from historical treatment plans were characterized and presented, with difficult-to-spare structures (ie, frequently compromised organs at risk) identified. Quantitative evaluations by GEM and/or WES compared favorably with the normal tissue complication probability Lyman Kutcher-Burman model, transforming a set of discrete threshold-priority limits into a continuous model reflecting physician objectives and historical experience. Conclusions: Statistical DVH offers an easy-to-read, detailed, and comprehensive way to visualize the quantitative comparison with historical experiences and among institutions. WES and GEM metrics offer a flexible means of incorporating discrete threshold-prioritizations and historic context into a set of standardized scoring metrics. Together, they provide a practical approach for incorporating big data into clinical practice for treatment plan evaluations. PMID- 29114620 TI - Reducing radiation dose and enhancing imaging quality of 4DCT for radiation therapy using iterative reconstruction algorithms. AB - Purpose: Four-dimensional computed tomography (CT) images are typically used to quantify the necessary internal target volumes for thoracic and abdominal tumors. However, 4-dimensional CT is typically associated with excessive imaging dose to patients and the situation is exacerbated when using repeat 4-dimensional CT imaging on a weekly or daily basis throughout fractionated therapy. The aim of this work is to evaluate an iterative reconstruction (IR) algorithm that helps reduce the imaging dose to the patient while maintaining imaging quality as quantified by point spread function and contrast-to-noise ratios (CNRs). Methods and materials: An IR algorithm, SAFIRE, was applied to CT data of a phantom and patients with varying CT doses and reconstruction kernels. Phantom data enable measurements of spatial resolution, contrast, and noise. The impact of SAFIRE on 4-dimensional CT was assessed with patient data acquired at 2 different dose levels during image guided radiation therapy with an in-room CT. Results: Phantom data demonstrate that IR reduces noise approximately in proportion to the number of iterations indicated by the strength (SAFIRE 1 to SAFIRE 5). Spatial resolution and contrast are conserved independent of dose and reconstruction parameters. The CNR increases with an increase of imaging dose or an increase in the number of iterations. The use of IR on CT sets confirms the results that were derived from phantom scans. The IR significantly enhances single breathing phase CTs in 4-dimensional CT sets as assessed by CT number discrimination. Furthermore, the IR of the low dose 4-dimensional CT features a 45% increase in the CNR in comparison with the standard dose 4-dimensional CT. Conclusions: The use of IR algorithms reduces noise while preserving spatial resolution and contrast, as evaluated from both phantom and patient CT data sets. For 4 dimensional CT, the IR can significantly improve image quality and reduce imaging dose without compromising image quality. PMID- 29114622 TI - Single Platelet-Rich Plasma Injection for Early Stage of Osteoarthritis of the Knee. AB - Purpose The purpose of this study was to determine the safety efficacy and outcomes of platelet-rich plasma (PRP) intra-articular injections for early stages of knee osteoarthritis (OA). Methods Twenty-five patients affected by grade I and II knee primary OA according to the Kellgren-Lawrence scale received a single intra-articular PRP injection. Patients were prospectively evaluated for 6 months. Visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Knee injury and Osteoarthritis Outcome Score (KOOS) scoring scales were used to evaluate clinical outcomes. Wilcoxon signed rank test was used to evaluate significance of improvement of WOMAC, KOOS, and VAS scores. Results Twenty-one patients completed 6-months follow-up. The median WOMAC score improved from 29.1 points (range: 17.4-60.4; standard deviation [SD] = 13.0) at baseline to 42.41 (range: 24.3-71.2; SD = 12.5) at final follow-up. Improvements in median KOOS and VAS score have been also found, from 37.49 points and 64.2 mm before injection to 59.71 points and 42.8 mm, respectively. All these improvements were statistically significant ( p < 0.05). No adverse reactions have been observed. Conclusion Treating knee OA with PRP injection is safe. A single dose of PRP seems to be effective in managing pain and improving quality of life in patients with low-grade knee OA. Level of Evidence Level IV, therapeutic case series. PMID- 29114623 TI - The Use of a High-Tech Knee Pad for Reduction of the Postoperative Effusion after Total Knee Arthroplasty. AB - Purpose After total knee arthroplasty (TKA), pain and swelling, especially in older and less cooperative patients, can limit the retrieval of a good range of motion and muscle tone and consequently the achievement of an optimal function outcome. A high-tech knee pad made of metal fibers emitting infrared energy was used in a group of patients undergoing TKA to assess its efficacy in the postoperative period with respect to a group with a placebo. Methods Twelve patients used knee pads after surgery for 3 weeks and were evaluated using visual analog scale (VAS), Knee Society Rating Score, Cincinnati Knee Rating Score, and painkillers at specific timings. Results At 3 weeks, all scores improved in a significant manner in the treated group compared with the placebo group. At 2 months after surgery, VAS was better in the study group than the control group, whereas other parameters were similar. However, the use of rescue drugs was less in the study group than in the placebo group. Conclusion A high-tech knee pad may contribute to a faster recovery within the first week after a knee replacement, limiting the use of painkillers and allowing a quick functional recovery by the control of pain and postoperative effusion. Level of Evidence Level II, randomized prospective study with small sample size. PMID- 29114624 TI - Sports and Recreational Activities following Total Ankle Replacement. AB - Purpose In literature, there is a controversy regarding whether patients who have undergone total ankle replacement (TAR) can participate in sports and recreational activities. The purpose of this study was to report change in sports activity level after TAR. Methods A retrospective study was performed, enrolling 76 patients with symptomatic end-stage ankle arthritis who underwent TAR from May 2011 to October 2014. Patients were mainly males (44/76; 58%) and 56 years old on average (range: 22.3-79.6 years) at the time of surgery. They were treated with mobile-bearing prosthesis implanted with an anterior approach. Patients were evaluated preoperatively and 12 months postoperatively. Pain and function were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score, the visual analog scale (VAS) pain score, and the 12-Item Short Form Health Survey (SF-12) - physical component summary (PCS) and mental component summary (MCS). Activity level was assessed with the University of California at Los Angeles (UCLA) activity scale. Results At 12 months postoperatively, statistically significant increase was reported for AOFAS scores (from 32.8 +/- 12.7 preoperatively to 72.6 +/- 13.3; p < 0.001), SF-12 PCS (from 34.3 +/- 5.1 preoperatively to 45.4 +/- 6.4; p < 0.001), and SF-12 MCS (from 39.8 +/- 7.5 preoperatively to 51.4 +/- 6.1; p < 0.001). A statistically significant decrease was detected in VAS pain score (from 8.7 +/- 1.6 preoperatively to 2.2 +/- 1.6; p < 0.001). The UCLA activity levels increased significantly from 2.4 +/- 0.8 to 6.3 +/- 2.3 ( p < 0.001). Conclusion Pain and function significantly improved in patients affected by ankle osteoarthritis, who underwent TAR, at 1-year follow-up. In addition, activity level showed a significant increase respect to preoperative condition. Level of Evidence Level IV, retrospective case series. PMID- 29114625 TI - Revision Anterior Cruciate Ligament Reconstruction with Contralateral Hamstring Tendon Grafts: 6 Years Follow-Up. AB - Purpose The purpose of this study was to retrospectively evaluate the clinical outcome of revision anterior cruciate ligament (ACL) reconstruction with contralateral hamstring tendon autografts, specifically with regard to patient satisfaction, return to preinjury activity level, and postoperative functional outcomes. Methods Between 2004 and 2011, 23 patients underwent revision ACL reconstruction with contralateral autogenous hamstring tendon grafts and were retrospectively reviewed at an average follow-up of 6.3 years. Subjective and functional evaluations were performed. The Tegner score, Knee Injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC) Subjective Knee Form were used. Objective evaluation included range of motion, Lachman test, pivot-shift test, and KT-1000 instrumented laxity testing. Wilcoxon test was used to compare the preoperative and follow-up status. Differences with a p -value of <0.05 were considered statistically significant. Results No major complications were reported. The mean KOOS significantly increased from a preoperative mean of 62.8 +/- 8.3 to 85.8 +/- 6.9 ( p < 0.001). IKDC subjective score significantly improved from 29.2 +/- 10.4 to 72.8 +/- 5.2 ( p < 0.001). The median Tegner activity score significantly improved from a preoperative mean of 6.5 (range: 4-10) to 7.5 (range: 7-10) ( p < 0.001). Most of the patients increased or returned to the same activity level, with 61% of the patients returning to cutting and pivoting sports. Conclusion The use of contralateral hamstring tendon autografts for ACL revision surgery represents a valid option following a failed primary ACL reconstruction and confirms subjective and objective clinical improvement 6 years after surgery. Level of Evidence Level IV, therapeutic case series. PMID- 29114626 TI - Postarthroscopy Imaging in Femoroacetabular Impingement: Persistent Pain May Be Due to an Insufficient Correction of Preoperative Abnormalities. AB - Purpose The purpose of this study was to evaluate the effect of correction of abnormal radiographic parameters on postoperative pain in a group of patients treated arthroscopically for femoracetabular impingement (FAI). Methods A retrospective study was performed on 23 patients affected by mixed-type FAI and treated arthroscopically. There were 11 males and 12 females with a mean age of 46.5 (range: 28-67) years. Center-edge (CE) and alpha angles were measured on preoperative and postoperative radiographic and magnetic resonance imaging (MRI) studies and were correlated with persistent pain at follow-up. Results The mean preoperative CE and alpha angles were 38.6 +/- 5.2 and 67.3 +/- 7.2 degrees, respectively. At follow-up, in the 17 pain-free patients, the mean pre- and postoperative CE angle were 38.1 +/- 5.6 and 32.6 +/- 4.8 degrees, respectively, whereas the mean pre- and postoperative alpha angles at MRI were 66.3 +/- 7.9 and 47.9 +/- 8.9 degrees, respectively. In six patients with persistent hip pain, the mean pre- and postoperative CE angles were 39.8 +/- 3.6 and 35.8 +/- 3.1 degrees, respectively, whereas the mean pre- and postoperative alpha angles were 70.0 +/- 3.9 and 58.8 +/- 2.6 degrees, respectively. Mean values of all the analyzed radiological parameters, except CE angle in patients with pain, improved significantly after surgery. On comparing patient groups, significantly lower postoperative alpha angles and lower CE angle were observed in patients without pain. Conclusion In case of persistent pain after arthroscopic treatment of FAI, a new set of imaging studies must be performed because pain may be related to an insufficient correction of preoperative radiographic abnormalities. Level of Evidence Level IV, retrospective case series. PMID- 29114628 TI - Femoral Tunnel Positioning in Anterior Cruciate Ligament Reconstruction: Anteromedial Portal versus Transtibial Technique-A Randomized Clinical Trial. AB - Purpose The purpose of this study was to investigate, through three-dimensional computed tomography (3D-CT), the accuracy of femoral tunnel positioning in patients undergoing anterior cruciate ligament (ACL) reconstruction, comparing transtibial (TT) and anteromedial (AM) techniques. Methods We evaluated postoperative 3D-CT scans of 26 patients treated with ACL reconstruction with hamstrings autograft using a low accessory AM portal technique and 26 treated with the TT technique. The position of the femoral tunnel center was measured with the quadrant method. Results Using quadrant method on CT scans, femoral tunnels were measured at a mean of 32.2 and 28.1% from the proximal condylar surface (parallel to Blumensaat line) and at a mean of 31.2 and 15.1% from the notch roof (perpendicular to Blumensaat line) for the AM and TT techniques, respectively. Conclusion The AM portal technique provides more anatomical graft placement than TT techniques. Level of Evidence Level I, randomized clinical study. PMID- 29114627 TI - Second Generation Needling Techniques for the Treatment of Chondral Defects in Animal Model. AB - Purpose To compare the macroscopic, histological, and immunohistochemical characteristics of the repair tissue of chondral defects treated with microfracture and nanofracture in an ovine model. Methods Full-thickness chondral lesions were created in the medial femoral condyle of both knees in four adult sheep and were treated with microfracture on one side and with nanofracture on the contralateral side. Chondral repair was assessed after 12 months by macroscopic, histological, and immunohistochemical analyses. Results Histological cartilage repair significantly improved in the samples treated with nanofracture for cellular morphological characteristics and cartilage architecture. The immunohistochemical analysis showed a significantly higher immunoreactivity to type II collagen in the defects treated with nanofracture. Conclusion Nanofracture provided better repair tissue than microfracture, with a more satisfactory cartilage architecture renovation and tissue having greater type II collagen content. Clinical Relevance Mesenchymal stem cell stimulation is the most frequently used primary cartilage repair procedure. Nanofracture represents a novel technique to stimulate bone marrow that results into a successful repair of chondral defects. PMID- 29114629 TI - Knee Osteoarthritis after Reconstruction of Isolated Anterior Cruciate Ligament Injuries: A Systematic Literature Review. AB - Purpose The aim of this review was to analyze the current literature on osteoarthritic evolution of knees without any combined meniscal or ligament lesions undergoing anterior cruciate ligament (ACL) reconstruction. Methods A PubMed/MEDLINE research was performed using the following keywords: "Anterior Cruciate Ligament Reconstruction" [Mesh] AND "Osteoarthritis, Knee" [Mesh]. Only English language literature and articles published after 2005 were included. Studies including concomitant meniscal tears, posterior cruciate or collateral ligament injuries, previous surgery in the affected knees, infections, osteochondral defects, loose bodies, synovial plica syndrome, and posteromedial or posterolateral corner injuries were not considered in this review. Results Twelve studies were selected. These papers included 892 patients (mean age at the time of surgery was 22.3 years), with an average follow-up of 11 years. Imaging at follow-up was obtained with standard radiographs in nine studies, magnetic resonance imaging (MRI) in one study, and both X-rays and MRI in two studies. Eight studies reported osteoarthritic evolution, with different prevalence. Conclusion Only few high-quality studies focused on these specific patients have been published. When reconstructed, isolated ACL-deficient knees have a low risk of osteoarthritic evolution, but mild signs of joint degeneration are reported by the current literature. Level of Evidence Level IV, systematic review of level I to level IV studies. PMID- 29114631 TI - Bore Disruption: An Unusual Mechanical Failure of Two Hip Hemiarthroplasties. AB - We report a case of two hemiarthroplasties (HAs) that underwent an unexpected mechanical failure. Two patients affected by femoral fractures were treated with an HA. At 5 and 7 years after surgery, they showed a breakage of the HA at the head-stem junction. We analyzed macroscopically and microscopically (by a scanning electron microscopy) the surfaces of the broken prostheses. In both cases, a fracture was detected starting at the joining point between the femoral head and the slot that receives the taper cone of the stem (the so-called bore), with the typical macroscopic and microscopic pattern of a fatigue fracture. The fatigue fracture resulted from repeated cycles of torsional stresses throughout the years. In literature, we did not find any other report of such HA failure. PMID- 29114632 TI - Joint Preservation of Knee: What Is Its Value? PMID- 29114630 TI - Unicompartmental Knee Arthroplasty: Modes of Failure and Conversion to Total Knee Arthroplasty. AB - Despite the excellent success rates of the modern unicompartmental knee arthroplasty (UKA), results of knee replacement registries still shows a relatively high revision and failure rate for UKA, especially when compared with traditional total knee arthroplasty (TKA). Bearing dislocation continues to be advocated as the predominant mechanism of failure in mobile UKA, whereas polyethylene wear and aseptic loosening remains the main cause of failure of fixed UKA. Degeneration of the unreplaced compartments has been reported in both mobile and fixed designs. When the revision is required, most of failed UKAs are converted to TKAs. Surgical challenges of the UKA revision, and outcomes of UKA converted to TKA are still debated in literature. PMID- 29114633 TI - Surgical Management of Degenerative Meniscus Lesions: The 2016 ESSKA Meniscus Consensus. AB - Purpose A degenerative meniscus lesion is a slowly developing process typically involving a horizontal cleavage in a middle-aged or older person. When the knee is symptomatic, arthroscopic partial meniscectomy has been practised for a long time with many case series reporting improved patient outcomes. Since 2002, several randomised clinical trials demonstrated no additional benefit of arthroscopic partial meniscectomy compared to non-operative treatment, sham surgery or sham arthroscopic partial meniscectomy. These results introduced controversy in the medical community and made clinical decision-making challenging in the daily clinical practice. To facilitate the clinical decision making process, a consensus was developed. This initiative was endorsed by ESSKA. Methods A degenerative meniscus lesion was defined as a lesion occurring without any history of significant acute trauma in a patient older than 35 years. Congenital lesions, traumatic meniscus tears and degenerative lesions occurring in young patients, especially in athletes, were excluded. The project followed the so-called formal consensus process, involving a steering group, a rating group and a peer-review group. A total of 84 surgeons and scientists from 22 European countries were included in the process. Twenty questions, their associated answers and an algorithm based on extensive literature review and clinical expertise, were proposed. Each question and answer set was graded according to the scientific level of the corresponding literature. Results The main finding was that arthroscopic partial meniscectomy should not be proposed as a first line of treatment for degenerative meniscus lesions. Arthroscopic partial meniscectomy should only be considered after a proper standardised clinical and radiological evaluation and when the response to non-operative management has not been satisfactory. Magnetic resonance imaging of the knee is typically not indicated in the first-line work-up, but knee radiography should be used as an imaging tool to support a diagnosis of osteoarthritis or to detect certain rare pathologies, such as tumours or fractures of the knee. Discussion The present work offers a clear framework for the management of degenerative meniscus lesions, with the aim to balance information extracted from the scientific evidence and clinical expertise. Because of biases and weaknesses of the current literature and lack of definition of important criteria such as mechanical symptoms, it cannot be considered as an exact treatment algorithm. It summarises the results of the "ESSKA Meniscus Consensus Project" ( http://www.esska.org/education/projects ) and is the first official European consensus on this topic. The consensus may be updated and refined as more high quality evidence emerges. Level of Evidence I. PMID- 29114635 TI - Early Efficacy of Intra-Articular HYADD(r) 4 (Hymovis(r)) Injections for Symptomatic Knee Osteoarthritis. AB - Purpose The aim of the study was to evaluate the clinical effects of HYADD(r) 4, an hydrogel based on a hyaluronic acid derivative, in patients with symptomatic knee osteoarthritis, on symptoms, and joint function. Methods This retrospective study of patients with Kellgren-Lawrence grade II to IV knee osteoarthritis (American College of Rheumatology criteria) enrolled patients who had received two infiltrations of HYADD(r) 4, (24 mg/3 mL) 1 week apart, and evaluated: pain at rest, pain with movement, change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score; change in nonsteroidal anti-inflammatory drugs (NSAIDs)/acetaminophen use; satisfaction with therapy; tolerability. Study duration was 6 months for all predefined endpoints, with a 6-month extension for pain symptoms only. Results After 6 months, all predefined endpoints were evaluable in 698 of 937 enrolled patients (74.5%). Mean WOMAC scores were reduced by 56.3% from baseline ( p < 0.05). NSAIDs/acetaminophen use >=2 times/week (48.8% of patients at baseline) was substantially reduced after 1 month and was 19.6% after 6 months. After 6 months, 85.6% of patients were satisfied about efficacy. There were no significant adverse effects. The effect on resting pain was rapid, strong, and lasting: reduction from baseline was 45.1% at 1 month ( p < 0.05), 56.8% at 6 months ( p < 0.05), and 53.6% at 12 months ( p < 0.05). Pain on moving was reduced by 47.4% after 6 months ( p < 0.05) and 46.0% after 12 months ( p < 0.05), results at 6 and 12 months were similar. Conclusion HYADD(r) 4 is a new-generation hyaluronic acid with distinctive viscoelastic and rheological properties. In patients with mild-to-severe knee OA (Kellgren Lawrence grades II-IV), two consecutive infiltrations 1 week apart reduced WOMAC scores and NSAIDs/acetaminophen consumption for at least 6 months. In a subpopulation ( n = 106), efficacy on pain lasted approximately 12 months. Adverse events were reported in 11.2% of patients; the most frequent were arthralgias. No cases of allergic reactions or systemic effects were recorded. Level of Evidence Level IV, retrospective case series. PMID- 29114634 TI - Monitoring Outcome of Joint Arthroplasty in Italy: Implementation of the National Registry. AB - Purpose Arthroplasty registries have an important role in improving outcomes in joint surgery. As the demand for joint arthroplasty continues to increase, growing attention is being paid to the establishment of national registries, which contribute to the enhancement of the quality of patients' care. Indeed, providing postmarketing surveillance data in terms of safety and effectiveness of medical devices, registries contribute to the best orthopaedic practice and support public health decision making. In this context, a project aimed at implementing a national arthroplasty registry in Italy has appeared to be essential, and the activities performed in the last years have consolidated data collection of hip and knee replacements. Methods Based on a close cooperation among public health institutions, clinicians, and involved stakeholders, the architecture of the registry is built on three pillars: (1) data collected using Hospital Discharge Records (HDRs) integrated by an additional dataset, (2) implants identified and characterized in a dedicated medical devices library, and (3) a federation of regional registries coordinated by a public health institution, the Italian National Institute of Health. Results Besides the organizational structure, statistical analyses on joint arthroplasty from national HDR database (2001-2014) and Italian registry data (2014) are presented. Currently, the institutions participating in the registry on a voluntary basis show 80% of completeness for hip and 58% for knee, and represent approximately 18% of the national volume. Conclusion To make data collection effective, participation should be mandatory and ruled by a national law. Level of Study Level III, observational analytic study. PMID- 29114636 TI - Accuracy of Coracoid Bone Graft Placement: Open versus Arthroscopic Latarjet. AB - Purpose The aim of this study was to compare the accuracy of the coracoid bone graft placement with the open Latarjet-Patte and arthroscopic Latarjet (arthro Latarjet) procedures in the treatment of anterior instability of the shoulder. Methods Forty-six patients affected by anterior shoulder instability were divided into two groups. In group A ( n = 25), patients were operated by arthroscopic Latarjet (arthro-Latarjet) procedure and in group B ( n = 21), patients were operated by open Latarjet-Patte procedure. Instrumental investigation was based on three-dimensional computed tomography (3D-CT) at a minimum 1-year follow-up. Graft placement and integration, divergence and posterior protrusion of the screws, and glenohumeral osteoarthritis were considered as outcomes. Statistical analysis was performed with chi-square or Fisher's exact test. Significance was set at p < 0.05. Results Positioning of the coracoid graft proved to be optimal in 76% (19/25) of patients of group A and in 100% (21/21) of patients of group B (Fisher's exact test, p = 0.025). Screw placement with respect to the glenoid surface showed a posterior divergence in 44% (11/25) of patients in group A and in 24% (5/21) of patients in group B ( p = 0.15). Posterior protrusion of screw was observed in 76% (19/25) of patients in group A and 71.4% (15/21) of patients in group B ( p = 0.73). Graft integration was present in 76% (19/25) of patients in group A and 85.7% (18/21) of patients in group B (Fisher's exact test, p = 0.48). Mild signs of glenohumeral osteoarthritis were observed in 12% (3/25) of patients in group A and 28.6% (6/21) of patients in group B (Fisher's exact test, p = 0.26). Conclusion Patients operated with open Latarjet-Patte procedure showed better results than those of the arthro-Latarjet group in reference to the positioning of the graft on the coronal plane ( p = 0.025). No significant differences between the groups were observed for graft integration, divergence of the screws, posterior protrusion of the screws, and osteoarthritis. Level of Evidence Level II, nonrandomized prospective comparative study. PMID- 29114637 TI - Percutaneous Fat Transfer to Treat Knee Osteoarthritis Symptoms: Preliminary Results. AB - Purpose This study aims to evaluate the safety and efficacy of autologous aspirated and purified fat tissue injected percutaneously into the knee joint for the treatment of symptomatic osteoarthritis (OA). Methods We reviewed 30 patients, who received an autologous percutaneous fat injection for the treatment of knee OA, from January 2012 to March 2015. Mean patients' age was 63.3 +/- 5.3 years (range, 50-80 years). Body mass index was 25.1 +/- 1.7. Clinical evaluation was based on pain visual analog scale (VAS) and WOMAC score for functional and subjective assessment. We also noted the adverse reactions and the consumption of nonsteroidal anti-inflammatory drugs in the posttreatment period. Results All patients reported improvements with respect to pain: average VAS was 7.7 +/- 1.2 at baseline, 5.2 +/- 0.2 at 1-month follow-up, and 4.3 +/- 1 at 3-month follow up. A slight deterioration (5.0 +/- 1.1) was evidenced at 1 year. Total WOMAC score was 89.9 +/- 1.7 at baseline, 66.3 +/- 1 at 1 month, 68.6 +/- 1.7 at 3 months, and 73.2 +/- 1.8 at 12 months of follow-up. Conclusion Our preliminary findings suggest that autologous percutaneous fat injections are a valid treatment option for knee OA. Level of Evidence Level IV, therapeutic case series. PMID- 29114638 TI - How to Manage a Failed Cartilage Repair: A Systematic Literature Review. AB - Purpose The aims of this paper are to report the rate and risk factors for the failure of the most common cartilage repair technique, and analyze the most important factors that could influence the choice of a specific surgical treatment to revise a failed cartilage repair. Methods A review of the literature was performed focusing on failed cartilage repair and related treatments. Two of the authors independently screened articles. Conflicts about the inclusion of a paper was resolved by further evaluation by the senior author. Review articles, articles written in languages different from/other than English, case reports, and papers that did not evaluate the outcomes of interest were excluded. Full-text version of each included paper was obtained and relevant data were extracted and collected in a database. Results At the end of the screening process, 31 articles were included. Microfractures and mosaicplasty showed a nonnegligible failure rate at short- and midterm. Better results, especially in terms of time to failure or revision, were reported with the use of autologous chondrocyte implantation (ACI) and osteochondral allograft (OCA) transplantation. Regarding the treatment of failed cartilage repair, the use of OCA transplantation in patients with previous failed cartilage repair may be a safe option. The revision of failed OCA transplantation with further OCA seems to have a greater failure rate. Patients with previous failed ACI or matrix-induced autologous chondrocyte implantation (MACI) who underwent further MACI or ACI reported acceptable results. Otherwise, ACI in patients with history of previous subchondral marrow stimulation (SMS) demonstrated a greater failure rate. Conclusion From the analysis of the literature, OCA transplantation seems to be the most reliable treatment of a failed SMS. ACI or MACI showed acceptable results in patients with previously failed MACI or ACI. Level of Evidence Level IV, systematic review of level I-IV studies. PMID- 29114640 TI - Evolution of Osteochondritis Dissecans of the Lateral Femoral Condyle Combined with Discoid Meniscus. AB - The discoid meniscus is a rare anomaly of the knee that affects mostly the lateral meniscus and is often asymptomatic. The osteochondritis dissecans is a disorder of the subchondral bone and articular cartilage and occurs frequently associated with the discoid lateral meniscus. In the present case, we showed the evolution of this association related to surgical treatment. A patient with lateral knee pain and a magnetic resonance depicting a torn discoid lateral meniscus and osteochondritis dissecans of the lateral femoral condyle was treated with partial meniscectomy and meniscal sutures. After 1 year, the symptoms reappeared, and a new meniscal repair was performed to treat a bucket-handle tear, while cartilage was apparently intact. After 4 years, there was a new recurrence of symptoms, and the knee developed a valgus deformity. Cartilage was treated with microfractures, and a subsequent distal femoral osteotomy associated with lateral meniscal scaffold was performed. The patient was followed up clinically, with radiographs and magnetic resonance for 5 years with an improvement of the results up to 2 years and no signs of deterioration of results over time. PMID- 29114639 TI - Knee Septic Arthritis after Arthroscopy: Incidence, Risk Factors, Functional Outcome, and Infection Eradication Rate. AB - Purpose Septic knee arthritis following arthroscopy is a rare but dreaded complication. Definition and management of knee deep infections are quite discussed in literature. In this review, literature regarding infections after knee arthroscopy is analyzed highlighting the incidence, causative bacteria, risk factors as well as clinical outcomes. Methods We performed a review of the literature matching the following key words: "septic arthritis" OR "infection" AND "arthroscopy" AND "knee." Knee arthroscopic procedures, such as debridement, meniscectomy, meniscus repair, synovectomy, microfracture, and lateral release, were considered. Complex procedures, such as ligament reconstruction, fractures, or complex cartilage repair techniques, were not included. Results Thirteen studies were included in this review. Incidence of infection ranged from 0.009 to 1.1% in patients undergoing simple arthroscopic procedures. Staphylococci are the most commonly isolated organisms from postarthroscopy infection. Use of intraoperative intra-articular steroids, smoking, obesity, male sex, diabetes, number of procedures performed during surgery, time of surgery, and tourniquet time of more than 60 minutes have been certified as risk factors for knee infection. Conclusion Postarthroscopy septic arthritis of the knee causes significant morbidity, usually requiring readmission to the hospital, at least one additional operation, and prolonged antibiotic therapy, both intravenous and oral. Prompt diagnosis and treatment are associated with a high success rate. Level of Evidence Level IV, systematic review of I-IV studies. PMID- 29114641 TI - Transient Common Peroneal and Tibial Nerve Palsy Following Knee Arthroscopy for the Treatment of Discoid Lateral Meniscus. AB - The number of knee arthroscopies has increased rapidly since the 1980s and are among the most common orthopedic procedures today. It is generally considered a minimally invasive surgery with relatively low morbidity, but it is not without risk of complications. We report the case of a 14-year-old boy who developed a lesion of common peroneal nerve and tibial nerve after knee arthroscopy for a torn discoid lateral meniscus, which was confirmed by electromyogram study. PMID- 29114642 TI - Two-Stage Treatment of a Large Pelvic Cystic Pseudotumor in a Metal-On-Metal Total Hip Arthroplasty. AB - The authors report a case of a huge cystic pseudotumor, surrounding a failed metal-on-metal total hip arthroplasty (THA). The cyst surrounded the hip anteriorly, occupied part of the anterior portion of the thigh, and extended to the anterolateral aspect of the abdomen. The case was treated by a two-stage procedure. The first stage consisted of a percutaneous drainage of the fluid content of the cyst (~1,200 mL). This procedure reduced the risk of tearing the cyst capsule spreading the liquid in the tissues surrounding the THA, and in the abdomen. Thanks to this simple procedure, the second stage treatment consisted of a relatively usual THA revision. The patient recovered completely from the treatment and returned to pain-free full activities of daily living. PMID- 29114643 TI - Analytical Evaluation of a Vancomycin Immunoassay in Synovial Fluid. AB - In clinical laboratories performing routine activities, the need to answer the burning clinical question in emerging field may be limited by lack of technology support or assays accessibility. Commercially available methods, although originally validated for specific biological matrices, may be employed for other matrices, following appropriate guidelines such as Clinical and Laboratory Standards Institute (CLSI) EP 19. We investigated the use of a vancomycin assay with synovial fluid samples, in view of a possible employment in vancomycin release study. The standard of care of periprosthetic joint infection is a two stage revision surgery with antibiotic-loaded bone cement implantation. Vancomycin, for its activity against gram-positive bacteria even multidrug resistant staphylococci, is the most widely used antibiotic. Despite the widespread use of such devices, little is known about the in vivo elution in the joint space. Clinical laboratories equipped with a validated, affordable method to quantify vancomycin in synovial fluid, may support clinical research, and give an important contribution to the study of the pharmacokinetics of antibiotic release from bone cement matrix. PMID- 29114644 TI - Arthroscopic Reduction with Endobutton Fixation for Glenoid Fracture. AB - Glenoid rim fractures, accompanied by acute glenohumeral dislocation or subluxation usually results in persistent instability. Traditionally open reduction and internal fixation has been recommended in displaced intra-articular glenoid fractures. However, open reduction is difficult, and it may not be possible to address the associated intra-articular soft-tissue injuries. A few reports of arthroscopic-assisted fixation of these fractures have been recently published. The most anatomic method for addressing an acute glenoid rim lesion is a reduction (either open or arthroscopic) and internal fixation. We are reporting a case of arthroscopic reduction and fixation of a glenoid fracture utilizing Endobuttons with clinical and radiological results at 18 months follow-up. PMID- 29114645 TI - Longitudinal Study Assessing Factors Associated with Mutans Streptococci Acquisition in Infants and Toddlers. AB - PURPOSE: To assess the role of sociodemographic, dietary, and clinical factors in early mutans streptococci (MS) colonization in children aged 6 to 24 months who were followed for 18 months. MATERIALS AND METHODS: Ninety-four children (mean age: 11.5 +/- 4.99 months at baseline) were enrolled in the study from the Women, Infants and Children Supplemental Nutrition Program during 2003-2004. Salivary MS levels of the children were determined at baseline and at 18 months using a semi quantitative method. Detailed information about the children's beverage consumption pattern, dietary behavior, and clinical information about oral health status was collected at baseline, 9 months, and 18 months. None of the children included in this study had detectable levels of MS at baseline. RESULTS: Of the 94 children at baseline, 36 (38%) had acquired MS by the 18-month follow-up. The presence of >5 teeth [OR = 3.55 (1.46-9.04); p = 0.0062] was a significant risk factor for MS acquisition among the baseline variables. At 9 months, sports drinks consumption [OR = 5.56 (1.39-26.26); p = 0.0143] and presence of caries [OR = 9.36 (2.55-40.90); p < 0.0001] were significantly associated with MS colonization at 18 months. Higher maternal education [OR = 0.3 (0.07-1.36); p = 0.0351] was a protective factor at all the time points. CONCLUSION: Sugared beverage consumption, tooth-related factors, and lower maternal education can predict MS acquisition in young children. PMID- 29114646 TI - The retromolar canal and its variations: Classification using cone beam computed tomography. AB - OBJECTIVE: To determine the prevalence of the retromolar canal and its various patterns using cone beam computed tomography (CBCT). METHOD AND MATERIALS: CBCT images with the presence of mandibular third molars from August 2013 to May 2015 were retrospectively investigated. The presence of retromolar canal, its patterns, sides, as well as gender were evaluated by two observers. The pattern of retromolar canal was initially classified into three types: Type A, superior type; Type B, radicular-retromolar type; and Type C, dental type. During the investigation, two additional types were found and further classified: Type D, plexus type; and Type E, forward type. The distribution of retromolar canals between genders and sides was statistically analyzed with Pearson's chi-square test. RESULTS: A total of 201 mandibular sites in 156 subjects (99 women, 57 men) were included. Among them, 128 sites had retromolar canals (63.68%). The presence of retromolar canal was not statistically related to gender or side. Most of the retromolar canals were the radicular-retromolar type (Type B, 38.10%), followed by the superior type (Type A, 29.93%), dental type (Type C, 19.73%), plexus type (Type D, 6.80%), and forward type (Type E, 5.44%). CONCLUSION: There was a high frequency of retromolar canals and these could be classified into five patterns. The clinician should be aware of this anatomical structure when performing surgical procedures involving the retromolar area. PMID- 29114648 TI - Structure and stability of small lithium-chloride LinClm(0,1+) (n >= m, n = 1-6, m = 1-3) clusters. AB - In the present study, we report the results of a detailed theoretical investigation along with the experimental observations of chlorine-doped small lithium clusters. The cluster ions of the type LinClm+ (n >= m, n = 1-6, m = 1-3) were obtained by the evaporation of LiCl from a Knudsen cell as a chemical reactor in the temperature range between 1800 and 2700 K. Heterogeneous clusters with more than one Cl atom are produced and detected for the first time, and the experimental conditions for formation and stability are examined. The structural characteristics and stabilities of neutral and positively charged LinClm species are analyzed by using quantum chemistry methods. Doping lithium clusters with chlorine increases their stability, although there is a typical closed-shell-open shell alternation in stability. Calculated dissociation energies are the best indicator of cluster stability of experimentally detected clusters. Heterogeneous lithium-chloride clusters can be viewed as species consisting of m negative Cl- ions and a positively charged Lin(1+,2+) "cage"; upon ionization, an electron departs from the lithium cage. An important reason for the higher stability of closed-shell clusters is the delocalization of electrons over the lithium cage, which is more energetically favored than localization of electrons between two lithium atoms. According to their ionization energies, the titled clusters can be classified as "superalkalis". PMID- 29114647 TI - The effect of orthodontic treatment on periodontal tissue inflammation: A systematic review. AB - OBJECTIVE: The aim of the present systematic review was to evaluate the periodontal tissue inflammation indexes in patients undergoing different orthodontic treatment. METHOD AND MATERIALS: The Cochrane Oral Health Group specialist trials, Medline, and Embase databases were used for the research. All the included studies had to report bleeding on probing (BOP) depth as primary outcome. Changes in probing depth, clinical attachment level, Gingival Index, and Periodontal Index were included in the review as secondary outcome measurements. RESULTS: Ten studies reporting on 421 patients and different types of orthodontic treatment were selected for the analysis. Owing to the heterogeneity of studies present in the literature, it was not possible to perform a meta-analysis. CONCLUSION: Within their limits, the results showed an increase of periodontal parameters after orthodontic treatment, indicating that it influences the accumulation and composition of the subgingival microbiota and subsequently induces more inflammation and higher BOP. PMID- 29114649 TI - Modeling of the oxygen reduction reaction for dense LSM thin films. AB - In the present study, the oxygen reduction reaction mechanism is investigated using numerical methods on a dense thin (La1-xSrx)yMnO3+/-delta film deposited on a YSZ substrate. This 1-D continuum model consists of defect chemistry and elementary oxygen reduction reaction steps coupled via reaction rates. The defect chemistry model contains eight species including cation vacancies on the A- and B sites. The oxygen vacancy is calculated by solving species transportation equations in multiphysics simulations. Due to the simple geometry of a dense thin film, the oxygen reduction reaction was reduced to three elementary steps: surface adsorption and dissociation, incorporation on the surface, and charge transfer across the LSM/YSZ interface. The numerical simulations allow for calculation of the temperature- and oxygen partial pressure-dependent properties of LSM. The parameters of the model are calibrated with experimental impedance data for various oxygen partial pressures at different temperatures. The results indicate that surface adsorption and dissociation is the rate-determining step in the ORR of LSM thin films. With the fine-tuned parameters, further quantitative analysis is performed. The activation energy of the oxygen exchange reaction and the dependence of oxygen non-stoichiometry on oxygen partial pressure are also calculated and verified using the literature results. PMID- 29114650 TI - Electrochemical reactive oxygen species detection by cytochrome c immobilized with vertically aligned and electrochemically reduced graphene oxide on a glassy carbon electrode. AB - A new amperometric biosensor for hydrogen peroxide (H2O2) and superoxide anion (SO) has been developed. The biosensor developed uses cytochrome c (Cyt c) modified glassy carbon electrodes coupled with electrochemically reduced graphene oxide (ErGO). To immobilize Cyt c, the "one step" electrochemical deposition of vertically aligned and ErGO (VAErGO) has been performed by using a pulse reverse technique, thus resulting in a very simple and efficient system. The well established vertical alignment of ErGO was confirmed by atomic force microscopy and the electrochemical characteristics of the biosensor were investigated by cyclic voltammetric, electrochemical impedance spectroscopy and amperometric techniques. The surface coverage (Gamma) of immobilized Cyt c was effectively increased by the vertical alignment of ErGO and found to be 1.03 * 10-10 mol cm 2. The direct electron transfer property of Cyt c was also improved by VAErGO and the heterogeneous electron transfer rate constant (ket) was estimated to be 6.40 s-1. To detect H2O2 and SO, amperometric measurements were carried out at different operating potentials (0.0 V vs. Ag/AgCl for H2O2 and +0.2 V for SO). The sensitivity and detection limit for H2O2 were found to be 46.3 MUA mM-1 cm-2 and 2.3 MUM, and for SO were found to be 32.1 MUM nA-1 cm-2 and 6.84 nM s-1, respectively. Additionally, the designed biosensor exhibited strong anti interference ability and satisfactory reproducibility. PMID- 29114651 TI - Quantifying small changes in uranium oxidation states using XPS of a shallow core level. AB - The U 4f line is commonly used to determine uranium oxidation states with X-ray photoelectron spectroscopy (XPS). In contrast, the XPS of the shallow core-levels of uranium are rarely recorded. Nonetheless, theory has shown that the U 5d (and 5p) multiplet structure is very sensitive to oxidation state. In this contribution we extracted the U(iv) and U(v) 5d XPS peak shapes from near stoichiometric and oxidized UO2 single crystal samples, respectively, where the oxidation state of U was constrained by fitting the 4f line. The empirically extracted 5d spectra were similar to the theoretically determined multiplet structures and were used, along with the relatively simple U(vi) component that was constrained by theory, to determine the oxidation states of UO2+x samples. The results showed a very strong correlation between oxidation states determined by the 5d and 4f line and suggested that the 5d might be more sensitive to minor amounts of oxidation than the 4f. Limitations of the methodology, as well as advantages of using the 5d relative to the 4f line are discussed. PMID- 29114653 TI - Temperature dependent excited state relaxation of a red emitting DNA-templated silver nanocluster. AB - The nanosecond excited state temporal and spectral relaxation of a purified, red emitting DNA-templated silver nanocluster (DNA-AgNC) was characterized as a function of temperature. The findings are explained by introducing a phenomenological electronic structure diagram. The reproducibility and cyclability of the average decay time opens up the possibility of using DNA-AgNCs for decay time-based nanothermometry. PMID- 29114652 TI - Pepsin egg white hydrolysate ameliorates metabolic syndrome in high-fat/high dextrose fed rats. AB - The aim of this study was to examine the effect of a pepsin egg white hydrolysate (EWH) on metabolic complications using a high-fat/high-dextrose diet-induced Metabolic Syndrome (MetS) experimental model. Male Wistar rats were divided into 4 groups which received: standard diet and water (C), standard diet and a solution with 1 g kg-1 day-1 of EWH (CH), high-fat/high-dextrose diet and water (MS), and high-fat/high-dextrose diet and a solution with 1 g kg-1 day-1 of EWH (MSH). EWH consumption normalized body weight gain; abdominal obesity and peripheral neuropathy developed in MetS animals, and adipose tissue and liver weight, as well as plasma glucose were reduced. Oxidative stress and inflammation biomarkers were normalized in MSH animals. In conclusion, the oral administration of EWH could be used as a functional food ingredient to improve some complications associated with MetS induced by unhealthy diets. PMID- 29114654 TI - The presence of food-derived collagen peptides in human body-structure and biological activity. AB - It has been demonstrated that the ingestion of some protein hydrolysates exerts health-promoting effects. For understanding the underlying mechanisms responsible for these effects, the identification of bioactive peptides in the target organ is crucial. For this purpose, in vitro activity-guided fractionation for peptides in the protein hydrolysate has been performed. However, the peptides in the hydrolysate may be further degraded during digestion. The concentration of the active peptides, which were identified by in vitro activity-guided fractionation, in human blood is frequently very low (nanomolar levels). In contrast, micromolar levels of food-derived collagen peptides are present in human blood. Pro-Hyp, one of the major food-derived collagen peptides, enhances the growth of fibroblasts and synthesis of hyaluronic acid. These observations partially explain the beneficial effects of collagen hydrolysate ingestion on the enhancement of wound healing and improvement in the skin condition. The recent advancement involving liquid chromatography and mass spectrometry coupled with a pre-column derivatization technique has enabled the identification of food-derived peptides at nanomolar levels in the body post-ingestion of protein hydrolysates. Thus, this technique can be used for the identification of bioactive food-derived peptides in the body. PMID- 29114655 TI - A modular approach to carbene-stabilized diphosphorus species. AB - Heteroleptic N-heterocyclic dicarbene-diphosphorus species were prepared by reaction of the carbene-phosphinidene adduct (IPr)PSiMe3 (1, IPr = 1,3-bis(2,6 diisopropylphenyl)imidazolin-2-ylidene) with the carbene-phosphorus trichloride adduct (IMes)PCl3 (2, IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene), which furnished the dichloride [(IPr)PPCl(IMes)]Cl (3). Reduction of 3 with potassium graphite (KC8) afforded [(IPr)PP(IMes)] (4). The corresponding radical cation [(IPr)PP(IMes)]+ (5+) is isolated as [5]PF6 by reaction of 4 with ferrocenium hexafluorophosphate, whereas complexes containing the corresponding dication [(IPr)PP(IMes)]2+ (62+) can be isolated as the gallate and borate salts [6](GaCl4)2 and [6](BArF)2 by chloride abstraction from 3 with GaCl3 or sodium tetrakis[bis(3,5-trifluoromethyl)phenyl]borate (NaBArF), respectively. The asymmetric set of N-heterocyclic carbene ligands allows to establish 1JPP coupling constants of 249 Hz for 4 and 543 Hz for [6](GaCl4)2. Based on X-ray diffraction analyses, the molecular structures of 4, 5+ and 62+ reveal a consecutive shortening of the P-P bond lengths, in agreement with the presence of a phosphorus-phosphorus single bond in 4 and a double bond in 62+, which is best described as a dicationic diphosphene according to density functional theory (DFT) calculations. PMID- 29114656 TI - Insights into the origin of the excited transitions in graphene quantum dots interacting with heavy metals in different media. AB - Exploring graphene quantum dots (GQDs) is an attractive way to design novel optical and electrochemical sensors for fast and reliable detection of toxic heavy metals (HMs), such as Cd, Hg and Pb. There are two main strategies for achieving this: (i) surface modification of an electrochemical working electrode by nanoscale GQDs and (ii) using a GQD solution electrolyte for optical sensing. Further development of these sensing technologies towards reaching or exceeding the WHO permissible limits implies deep understanding of the interaction between GQDs and HMs in different dielectric media. Solvent is expected to be one of the key factors affecting the binding ability of the GQDs to HMs and their electronic and optical properties. Here we show that the solvent-solute interaction changes the geometrical configuration, stability and absorption spectra of zigzag/armchair-edged GQDs after complexation with neutral and charged HM species. We observe physisorption behavior of Cd and Hg adatoms on the sp2 surface with a solvent-mediated enhancement of the binding energy with increasing solvent polarity. For Pb adatoms, an opposite picture is revealed. We find that the solvent effect also manifests itself in weakening of the chemisorption strength in the HM cation-pi system with increasing dielectric constant of the solvent. Thus, a solvent engineering strategy based on control of the dielectric permittivity can be a promising approach to reach the desired binding energy in the HM@GQDs and to provide high sensitivity and selectivity of both optical and electrochemical sensors to toxic HMs we are interested in. PMID- 29114658 TI - Construction of molecular rectangles with titanium-oxo clusters and rigid aromatic carboxylate ligands. AB - Four rectangular molecular architectures have been successfully constructed using {Ti5O7} clusters as inorganic vertical edges and bridging aromatic carboxylates as horizontal edges. The introduced organic ligands show a strong influence on the light absorption behaviors of the obtained hybrid complexes. PMID- 29114657 TI - Chemistry of mammalian metallothioneins and their interaction with amyloidogenic peptides and proteins. AB - Cu and Zn ions are essential in most living beings. Their metabolism is critical for health and mis-metabolism can be lethal. In the last two decades, a large body of evidence has reported the role of copper, zinc and iron, and oxidative stress in several neurodegenerative diseases like Alzheimer's, Parkinson's, prion diseases, etc. To what extent this mis-metabolism is causative or a consequence of these diseases is still a matter of research. In this context metallothioneins (MTs) appear to play a central gate-keeper role in controlling aberrant metal protein interactions. MTs are small proteins that can bind high amounts of Zn(ii) and Cu(i) ions in metal-cluster arrangements via their cysteine thiolates. Moreover, MTs are well known antioxidants. The present tutorial outlines the chemistry underlying the interconnection between copper(i/ii) and zinc(ii) coordination to amyloidogenic proteins and MTs, and their redox properties in generation and/or silencing reactive oxygen species (overproduced in oxidative stress) and other reactants. These studies have revealed the coordination chemistry involved in neurodegenerative diseases and the interactions between MTs and amyloidogenic protein metal-complexes (like amyloid-beta, alpha-synuclein and prion-protein). Overall, the protective role of MTs in neurodegenerative processes is emerging, serving as a foundation for exploring MT chemistry as inspiration for therapeutic approaches. PMID- 29114659 TI - Improving the accuracy of effect-directed analysis: the role of bioavailability. AB - Aquatic ecosystems have been suffering from contamination by multiple stressors. Traditional chemical-based risk assessment usually fails to explain the toxicity contributions from contaminants that are not regularly monitored or that have an unknown identity. Diagnosing the causes of noted adverse outcomes in the environment is of great importance in ecological risk assessment and in this regard effect-directed analysis (EDA) has been designed to fulfill this purpose. The EDA approach is now increasingly used in aquatic risk assessment owing to its specialty in achieving effect-directed nontarget analysis; however, a lack of environmental relevance makes conventional EDA less favorable. In particular, ignoring the bioavailability in EDA may cause a biased and even erroneous identification of causative toxicants in a mixture. Taking bioavailability into consideration is therefore of great importance to improve the accuracy of EDA diagnosis. The present article reviews the current status and applications of EDA practices that incorporate bioavailability. The use of biological samples is the most obvious way to include bioavailability into EDA applications, but its development is limited due to the small sample size and lack of evidence for metabolizable compounds. Bioavailability/bioaccessibility-based extraction (bioaccessibility-directed and partitioning-based extraction) and passive-dosing techniques are recommended to be used to integrate bioavailability into EDA diagnosis in abiotic samples. Lastly, the future perspectives of expanding and standardizing the use of biological samples and bioavailability-based techniques in EDA are discussed. PMID- 29114660 TI - CO2 activating hydrocarbon transport across nanopore throat: insights from molecular dynamics simulation. AB - In tight oil reservoirs, nanopore throat acting as the narrowest section of fluidic channel determines the oil transport performance; injecting CO2 is found to significantly promote the oil flow. Despite substantial efforts, the underlying transport mechanism of above phenomenon remains unclear. Employing molecular dynamics simulation, the oil transport through a nanopore throat is studied. A high energy barrier derived of conformation deformation, oil/pore interaction and Jamin effect is found to impede the oil transport. The CO2 activating effect for oil transport is present, and a dependence on CO2 amount is observed. The underlying mechanism was well documented from the aspects of oil swelling, interfacial tension and surface sliding. Our study provides fundamental insight into the oil transport across nanopore throat and CO2 activating effect; the results have promising applications in enhanced oil recovery in CO2 flooding. PMID- 29114664 TI - Quantification of a bacterial secondary metabolite by SERS combined with SLM extraction for bioprocess monitoring. AB - During the last few decades, great advances have been reached in high-throughput design and building of genetically engineered microbial strains, leading to a need for fast and reliable screening methods. We developed and optimized a microfluidic supported liquid membrane (SLM) extraction device and combined it with surface enhanced Raman scattering (SERS) sensing for the screening of a biological process, namely for the quantification of a bacterial secondary metabolite, p-coumaric acid (pHCA), produced by Escherichia coli. The microfluidic device proved to be robust and reusable, enabling efficient removal of interfering compounds from the real samples, reaching more than 13-fold up concentration of the donor at 10 MUL min-1 flow rate. With this method, we quantified pHCA directly from the bacterial supernatant, distinguishing between various culture conditions based on the pHCA production yield. The obtained data showed good correlation with HPLC analysis. PMID- 29114665 TI - Small biomolecule sensors based on an innovative MoS2-rGO heterostructure modified electrode platform: a binder-free approach. AB - The requirement of sensitive diagnostic chips for small biomolecules has triggered the urgent development of versatile nanomaterial based platforms. Therefore, numerous materials have been designed with fascinating properties. Herein, we report a facile one-pot synthesis of MoS2-rGO nanoflowers grown by the hydrothermal method and their applicability in the simultaneous sensing of AA, DA and UA. The structure and morphology of nanoflowers have been probed by various physico-chemical techniques such as XRD, SEM/TEM, AFM, Raman and XPS. Furthermore, these nanoflowers were used to construct a glassy carbon based working electrode (MoS2-rGO/GCE), by a facile drop-casting method in the absence of any commercial binder. The electrochemical investigations revealed high separating potency of the MoS2-rGO/GCE towards AA, DA and UA with distinguishable oxidation potentials (AA-DA = 204 mV and DA-UA = 122 mV) and a notable detection limit and reasonable sensitivity for each of these biomolecules. The charge transfer resistance and capacitive components obtained by electrochemical impedance spectroscopy (EIS) were found to be in agreement with the voltammetric observations. The observed synergy between MoS2 and rGO opens up new possibilities to consider the MoS2-rGO nanostructures as the cutting edge material for electrochemical sensor development. PMID- 29114667 TI - Massive hydration-driven swelling of layered perovskite niobate crystals in aqueous solutions of organo-ammonium bases. AB - Osmotic swelling behaviors in layered perovskite niobate were examined in aqueous solutions containing three types of amine-related agents including quaternary ammonium hydroxides and tertiary aminoethanol. Platelet microcrystals of a protonated layered perovskite niobate, HCa2Nb3O10.1.5H2O, were found to show enormous swelling in the aqueous solutions, which was clearly recognized by the noticeable expansion of the sample volume over 100-fold. Optical microscopy observations revealed that the crystals underwent accordion-like elongation in the layer-stacking direction up to several ten-fold the initial thickness. Small angle X-ray scattering measurements of swollen samples indicate the expansion of interlayer separation ranging from ~20 nm to over 100 nm, which is primarily governed by the concentrations of the amine-related agents. The magnitudes of the interlayer separation were comparable to those of the macroscopic swelling. The degree of swelling was progressively suppressed with further increasing concentration, and this suppression trend was related to the amines. PMID- 29114668 TI - An integrative omics perspective for the analysis of chemical signals in ecological interactions. AB - All living organisms emit, detect, and respond to chemical stimuli, thus creating an almost limitless number of interactions by means of chemical signals. Technological and intellectual advances in the last two decades have enabled chemical signals analyses at several molecular levels, including gene expression, molecular diversity, and receptor affinity. These advances have also deepened our understanding of nature to encompass interactions at multiple organism levels across different taxa. This tutorial review describes the most recent analytical developments in 'omics' technologies (i.e., genomics, transcriptomics, proteomics, and metabolomics) and provide recent examples of its application in studies of chemical signals. We highlight how studies have integrated an enormous amount of information generated from different omics disciplines into one publicly available platform. In addition, we stress the importance of considering different signal modalities and an evolutionary perspective to establish a comprehensive understanding of chemical communication. PMID- 29114669 TI - Detection of single nucleotide polymorphism by measuring extension kinetics with T7 exonuclease mediated isothermal amplification. AB - In this work, we measured the primer extension kinetics of the Klenow fragment (exo-) to achieve rapid detection of single nucleotide polymorphism (SNP). Both the matching and the single-base mismatching targets were used as the primer in the kinetic measurements to identify the single nucleotide polymorphism. By coupling with the T7 exonuclease-assisted target cycling process, we decreased the detection limit but still maintained a high discrimination factor. After the demonstration of a good discrimination ability with synthetic DNA strands, we applied the method to detect low abundance of epidermal growth factor receptor (EGFR) mutation in human genomic DNA, which was a biomarker of non-small cell lung cancer. The kinetics based SNP detection was performed at room temperature and was robust against photobleaching and other optical interferences for the detection of low abundance of point mutations in human genomic DNA. The detection method is adaptable to a microarray platform for high-throughput and point-of care detection. PMID- 29114670 TI - Correction: Novel chemical probes for the investigation of nonribosomal peptide assembly. AB - Correction for 'Novel chemical probes for the investigation of nonribosomal peptide assembly' by Y. T. Candace Ho et al., Chem. Commun., 2017, 53, 7088-7091. PMID- 29114671 TI - Synthesis, structure and cytotoxicity of cyclic (alkyl)(amino) carbene and acyclic carbene complexes of group 11 metals. AB - A series of complexes of cyclic (alkyl)(amino)carbene (CAAC) complexes of copper, silver and gold have been investigated for their antiproliferative properties. A second series of acyclic carbene (ACC) complexes of gold(i) were prepared by nucleophilic attack on isocyanide complexes by amines and amino esters, to give (ACC)AuCl, [(ACC)Au(PTA)]+ (PTA = triazaphosphaadamantane), as well as mixed carbene compounds [(CAAC)Au(ACC)]+. Representative complexes were characterised by X-ray diffraction which confirmed the mononuclear linear structures without close intermolecular contacts or aurophilic interactions. The redox properties of these complexes have been determined. The compounds were tested against a panel of human cancer cell lines including leukemia (HL 60), breast adenocarcinoma cells (MCF-7) and human lung adenocarcinoma epithelial cell lines (A549), which show varying degrees of cisplatin resistance. The pro-ligand iminium salts and the PTA complexes were non-toxic. By contrast, the CAAC complexes show high cytotoxicity, with IC50 values in the sub-micromolar to ~100 nanomolar range, even against cisplatin-insensitive MCF-7 and A549 cells. Cationic bis-carbene complexes [(Me2CAAC)2M]+ (6-8, M = Cu, Ag and Au) proved particularly effective. The mechanism of cell growth control by these complexes remains to be established, although possible modes of action such as inhibition of thioredoxin reductase (TrxR), which is a common pathway for gold NHC compounds, or the formation of reactive oxygen species (ROS) through redox processes, could be ruled out as primary pathways. PMID- 29114672 TI - The critical role of dimer formation in monosaccharides binding to human serum albumin. AB - Human serum albumin (HSA) is the most abundant transport protein found in human blood. HSA is known to bind a wide range of drugs and monosaccharides, but where and how these molecules bind are largely unknown. Recently, a crystal structure of glycated HSA has been reported, and interestingly, in that structure two glucose molecules have been located in pyranose (GLC) and open chain (GLO) forms bound in the same binding pocket (Sudlow site I). Molecular simulations also proposed two binding modes of GLC and GLO (binding two ligands either in a distant location or in close contact). Yet, how HSA binds sugars in general is poorly understood. To this end, here we study the mechanism of binding glucose and its epimer galactose to HSA using alchemical free energy perturbation calculations and molecular dynamics simulations, and show why two sugar molecules appear in the bound state. We find that HSA does prefer glucose over galactose, in line with experiments, by binding glucose deeper in the pocket. Furthermore, out of the two possible binding modes suggested previously, the binding becomes tighter when the two sugars are in contact; this is achieved by a hydrogen bond connecting the two sugars and filling the large cavity of Sudlow site I as a dimer. We also find tight hydrogen bonds between open chain glucose/galactose and HSA, which includes the possible glycation site K199, while the pyranose form does not interact strongly with any characteristic residues. Thus the current result highlights the importance of dimeric structures of glucose/galactose for binding to HSA and triggering glycation/galactation. PMID- 29114677 TI - Half-sandwich complexes of Ir(iii), Rh(iii) and Ru(ii) with the MaxPhos ligand: metal centred chirality and cyclometallation. AB - The reaction of the acetylacetonates [(eta5-C5Me5)M(acac)Cl] with (SP) [HMaxPhos][BF4] afforded cationic complexes with the formula (SM,RP)-[(eta5 C5Me5)MCl(MaxPhos)][BF4] (M = Rh (1), Ir (2)). The reaction of (SP)-MaxPhos with [RuCl(MU-Cl)(eta6-p-MeC6H4iPr)]2 and NH4X afforded (SRu,RP)-[(eta6-p MeC6H4iPr)RuCl(MaxPhos)][X] (X = BF4 (3), PF6 (3')). The complexes have been completely characterized by analytical and spectroscopic means, including the determination of the crystal structures of 1, 2 and 3'. Treatment of the iridium complex 2 with AgBF4, at 253 K, resulted in the intramolecular cyclometallation of one of the tert-butyl substituents of the MaxPhos diphosphane ligand, affording a mixture of isomers of (SIr,RP1,SP2 and RIr,RP1,RP2)-[(eta5 C5Me5)Ir(MaxPhos)][BF4] (4a and 4b). However, rhodium complex 1 and ruthenium complex 3 reacted with AgBF4 forming the expected unsaturated intermediates "(etan-ring)M(MaxPhos)" which were trapped by MeCN, affording the cationic adducts (SM,RP)-[(etan-ring)M(MaxPhos)(MeCN)][BF4]2 (M = Rh (5), Ru (6)). Only one epimer at the metal was isolated in high yield for the complexes 1, 2, 3, 3', 5 and 6 and the metallation of 2 to give 4 occurs with high diastereoselectivity. PMID- 29114679 TI - Regioselective three-component synthesis of 2,3-disubstituted quinolines via the enaminone modified Povarov reaction. AB - The regioselective construction of functionalized quinolines by the three component reactions of enaminones, aldehydes and anilines is accomplished. Unlike conventional Povarov reactions employing terminal alkynes or alkenes as C3-C4 fragment sources which provide 2,4-disubstituted quinolines, the present method allows fast and regioselective formation of 2,3-disubstituted quinolines as a modified new version of the Povarov reaction. PMID- 29114680 TI - A general method of Suzuki-Miyaura cross-coupling of 4- and 5-halo-1,2,3 triazoles in water. AB - A general method of the synthesis of 1,4,5-trisubstituted-1,2,3-triazoles by Suzuki-Miyaura cross-coupling from 4- and 5-halo-1,2,3-triazoles is reported. The reaction is mediated by an expanded-ring N-heterocyclic carbene palladium complex in water. The developed reaction protocol meets the requirements of "green chemistry". Cross-coupling of 4- and 5-chlorotriazoles is reported for the first time. PMID- 29114681 TI - Regioselective synthesis of 2,3'-biindoles mediated by an NBS-induced homo coupling of indoles. AB - Mild conditions have been developed to achieve NBS-induced homodimerization of indole derivatives with excellent regioselectivity at 15 degrees C in high efficiency. This method provides a simple route to a 2,3'-linked biindolyl scaffold from the electron-rich to moderately electron-poor indoles. In addition, [3,2-a]carbazole derivatives can also be prepared through this method. PMID- 29114682 TI - Two-dimensional transition-metal dichalcogenides-based ferromagnetic van der Waals heterostructures. AB - The lack of ferromagnetic (FM) van der Waals (vdW) heterostructures hinders the application of two-dimensional (2D) materials in spintronics, information memories and storage devices. Herein, we find theoretically that 2D transition metal dichalcogenides-based vdW heterostructures, such as MoS2/VS2 and WS2/VS2, possess excellent characteristics of stable stacking configurations, FM semiconducting ground states, high Curie temperatures, staggered band alignment and a large band offset. Fortunately, 100% spin-polarized currents at the Fermi level can be achieved under certain positive external electric fields, which can filter the current into a single spin channel. Moreover, the majority channel undergoes the transition from type-II to type-I (type-III) band alignment under the negative (positive) electric field; while the band alignment of the minority channel is robust to the electric field. Our results provide a feasible way to realize 2D TMDs-based FM semiconducting heterostructures for spintronic devices. PMID- 29114683 TI - Synthesis of ultrasmall CsPbBr3 nanoclusters and their transformation to highly deep-blue-emitting nanoribbons at room temperature. AB - Discretely sized semiconductor clusters have attracted considerable attention due to their intriguing optical properties and self-assembly behaviors. While lead halide perovskite nanostructures have been recently intensively explored, few studies have addressed perovskite clusters and their self-assembled superstructures. Here, we report the room-temperature synthesis of sub-2 nm CsPbBr3 clusters and present strong evidence that these ultrasmall perovskite species, obtained under a wide range of reaction conditions, possess a specific size, with optical properties and self-assembly characteristics resembling those of well-known II-VI semiconductor magic-sized clusters. Unlike conventional CsPbBr3 nanocrystals, the as-synthesized CsPbBr3 nanoclusters spontaneously self assemble into a hexagonally packed columnar mesophase in solution, which can be further converted to single-crystalline CsPbBr3 quantum nanoribbons with bright deep-blue emission at room temperature. Such a conversion of CsPbBr3 nanoclusters to nanoribbons is found to be driven by a ligand-destabilization-induced crystallization and mesophase transition process. Our study will facilitate the investigation of perovskite nanoclusters and offer new possibilities in the low temperature synthesis of anisotropic perovskite nanostructures. PMID- 29114684 TI - Highly conductive and transparent single-walled carbon nanotube thin films from ethanol by floating catalyst chemical vapor deposition. AB - Single-walled carbon nanotube (SWCNT) films have great potential to replace indium tin oxide films for applications in transparent and conductive electronics. Here we report a high yield production of SWCNT transparent conducting films (TCFs) by the floating catalyst chemical vapor deposition method using ethanol as the carbon source. To the best of our knowledge, this is the first report regarding SWCNT TCFs using ethanol as the carbon source. The fabricated uniform SWCNT TCFs exhibit a competitive sheet resistance of 95 Omega sq-1 at 90% transmittance after doping with AuCl3. The SWCNT TCFs possess high quality and the mean length of SWCNT bundles is approximately 27.4 MUm. Furthermore, the concentration of semiconducting SWCNTs is 75-77%. Additionally, the chirality maps obtained from electron diffraction analysis demonstrate that our SWCNTs are biased towards the armchair type. PMID- 29114685 TI - Nanoscale considerations responsible for diverse macroscopic phase behavior in monosubstituted isobutyl-POSS/poly(ethylene oxide) blends. AB - Nanocomposites prepared by incorporating functionalized polyhedral oligomeric silsesquioxane (POSS) into polymer matrices afford a wide range of versatile hybrid materials for use in technologies ranging from cosmetics and pharmaceuticals to sensors and batteries. Here, we investigate the phase behavior of nanocomposites composed of poly(ethylene oxide) (PEO) and monosubstituted isobutyl POSS (iPOSS) modified with different functional moieties. Microscopic analyses of blends containing these iPOSS variants reveal the existence of different macroscopic morphologies and surface topologies. In the presence of octa-iPOSS, a POSS-rich surface cell motif reminiscent of breath patterns develops, whereas addition of allyl-iPOSS promotes the formation of surface plates. While aminopropyl-iPOSS forms dispersed aggregates, maleamic acid-iPOSS disperses in PEO with little effect on PEO crystal morphology. We perform rotational isomeric state Monte Carlo simulations to discern the effect of monosubstitution on the interaction energy between iPOSS and PEO, and establish the molecular-level origin for these observed differences in phase behavior. PMID- 29114686 TI - Modulation of XPC peptide on binding Tb3+ to Euplotes octocarinatus centrin. AB - Centrins are Ca2+-binding proteins found throughout eukaryotic organisms. Xeroderma pigmentosum group C protein (XPC), a dominant component of the nuclear excision repair (NER) pathway, is a critical target protein of centrins. A 22 residue peptide (K842-R863) from XPC was used to investigate the effect of metal ions (Ca2+ and Tb3+) on the peptide binding of Euplotes octocarinatus centrin (EoCen) by isothermal titration calorimetry (ITC) and fluorescence spectroscopy. ITC and tryptophan spectrofluorimetric titrations revealed that metal ions (Ca2+ and Tb3+) could enhance the affinity between EoCen and the XPC peptide, and the enhanced effects were closely related to the ion potential of metal ions. Since the ion potential of Tb3+ (e/r = 0.0325) is larger than that of Ca2+ (e/r = 0.0202), the conformational change in the protein induced by Tb3+ is larger than that induced by Ca2+, and the enhanced affinity of Tb3+ is stronger than that of Ca2+. This interaction was driven by enthalpy in the presence of EDTA and enthalpy and entropy in the presence of Ca2+ or Tb3+. Similar to that observed in the presence of EDTA, the N-terminal domain did not participate in the interaction with the XPC peptide even in the presence of metal ions. Resonance light scattering (RLS) and the band shift in native polyacrylamide gel electrophoresis (PAGE) suggested that peptide binding resulted in the dissociation of EoCen aggregates and complex formation via the monomer-peptide form. Tb3+-Sensitized emission suggested that peptide binding in turn also had an impact on the Tb3+ binding of the protein: the C-terminal domain was slightly strengthened and the N-terminal domain was weakened about 225 fold. RLS and native PAGE indicated that the self-assembly induced by Tb3+ binding to the N terminal domain of EoCen was inhibited in the presence of the XPC peptide. This study elucidates the molecular mechanism of EoCen function in the cellular context. PMID- 29114687 TI - Manipulating the quantum interference effect and magnetotransport of ZnO nanowires through interfacial doping. AB - We carefully prepared interfacial Al-doped (IAD) and interfacial natively-doped (IND) ZnO nanowires (NWs) by introducing atomic-layer interfacial Delta-doping between the two steps of CVD growth. Variable-temperature electron transport as well as magnetotransport behaviours of these NWs were systematically investigated. By virtue of the unique architecture and the quality-guaranteed growth technique, a series of quantum interference effects were clearly observed in the IAD ZnO NWs, including weak localization, universal conductance fluctuation and Altshuler-Aronov-Spivak oscillations. The phase-coherence length (Lphi) of electrons exceeds 100 nm in the IAD ZnO NWs, much longer than those in the IND ones and most conventionally doped ZnO NWs. This ability to efficiently manipulate a variety of quantum interference effects in ZnO NWs is very desirable for applications in nano-optoelectronics, nano- & quantum-electronics and solid state quantum computing. PMID- 29114688 TI - Macroscopic chiral symmetry breaking in monolayers of achiral nonconvex platelets. AB - The fabrication of chiral structures using achiral building blocks is a fundamental problem that remains a challenge in materials science. In this work we present a molecular dynamics simulation study of nonconvex polygonal platelets, interacting via soft-repulsive interactions, that are confined in two dimensional space. These particle models are designed to promote, even at moderate densities, a natural offset displacement between the edges of neighbouring particles. In particular we demonstrate that nonconvex platelets exhibit macroscopic chiral symmetry breaking when the symmetry of the particles equals (or is multiple of) the number of nearest neighbours in the condensed crystalline phase, corresponding to the situation of platelets with 4-, 6-, and 12-fold symmetries. PMID- 29114689 TI - Development of a microfluidic platform integrating high-resolution microstructured biomaterials to study cell-material interactions. AB - Microfluidic screening platforms offer new possibilities for performing in vitro cell-based assays with higher throughput and in a setting that has the potential to closely mimic the physiological microenvironment. Integrating functional biomaterials into such platforms is a promising approach to obtain a deeper insight into the interactions occurring at the cell-material interface. The success of such an approach is, however, largely dependent on the ability to miniaturize the biomaterials as well as on the choice of the assay used to study the cell-material interactions. In this work, we developed a microfluidic device, the main component of which is made of a widely used biocompatible polymer, polylactic acid (PLA). This device enabled cell culture under different fluidic regimes, including perfusion and diffusion. Through a combination of photolithography, two-photon polymerization and hot embossing, it was possible to microstructure the surface of the cell culture chamber of the device with highly defined geometrical features. Furthermore, using pyramids with different heights and wall microtopographies as an example, adhesion, morphology and distribution of human MG63 osteosarcoma cells were studied. The results showed that both the height of the topographical features and the microstructural properties of their walls affected cell spreading and distribution. This proof-of-concept study shows that the platform developed here is a useful tool for studying interactions between cells and clinically relevant biomaterials under controlled fluidic regimes. PMID- 29114690 TI - Effect of amino acid mutations on intra-dimer tubulin-tubulin binding strength of microtubules. AB - Energetic interactions inside alphabeta-tubulin dimers of a microtubule (MT) with atomic resolutions are of importance in determining the mechanical properties and structural stability of the MT as well as designing self-assembled functional structures from it. Here, we carry out several comprehensive atomistic simulations to investigate the interaction properties within alphabeta-tubulin dimers and effect of residue mutations on the intra-dimer tubulin-tubulin (IDTT) binding strength. Results indicate that the force-displacement responses of the dimer could be roughly divided into three stages involving increasing, decreasing, and fluctuating forces. Energetic analysis shows that electrostatic interactions dominate the IDTT binding strength. Further per-residue energetic analysis shows that the major part of the interface interaction energy (approximately 72% for alpha-tubulin and 62% for beta-tubulin) comes from amino acid residues with net charges, namely arginine (ARG), lysine (LYS), glutamic acid (GLU), aspartic acid (ASP). Residue mutations are completed for ARG105 on alpha-tubulin and ASP251 on beta-tubulin to study the effect of mutations on the IDTT binding strength. Results indicate that stiffness, rupture force, and interface interaction energy of alphabeta-tubulin dimer can be improved by up to 28%, 13% and 28%, respectively. Overall, our results provide a thorough atomistic understanding of the IDTT binding strength within alphabeta-tubulin heterodimers and help pave the way for eventually designing and controlling the self-assembled functional structures from MTs. PMID- 29114691 TI - Dendrimeric amide- and carbamate-linked lysine-based efficient molecular transporters. AB - Amide- and carbamate-linked dendrimeric oligomers are reported as molecular transporters. They effectively complex with pDNA and transport it into cells at an efficiency superior to Lipofectamine, when complexation is carried out by incubation overnight. The carbamate-linked K2C is superior to amide-linked K2A; their pDNA complexes have very low associated cytotoxicity. PMID- 29114692 TI - Probing the role of O-containing groups in CO2 adsorption of N-doped porous activated carbon. AB - Porous activated carbons (PACs) are promising candidates to capture CO2 through physical adsorption because of their chemical stability, easy-synthesis, cost effectiveness and good recyclability. However, their low CO2 adsorption capacity, especially low CO2/N2 selectivity, has limited their practical applications. In this work, an optimized PAC with a large specific surface area, a small micropore size, and a large micropore volume has been synthesized by one-step carbonization/activation of casein using K2CO3 as a mild activation agent. It showed a remarkably enhanced CO2 adsorption capacity as high as 5.78 mmol g-1 and an excellent CO2/N2 selectivity of 144 (25 degrees C, 1 bar). Based on DFT calculations and experimental results, the coexistence of adjacent pyridinic N and -OH/-NH2 species was proposed for the first time to make an important contribution to the ultra-high CO2 adsorption performance, especially CO2/N2 selectivity. This work provides effective guidance to design PAC adsorbents with high CO2 adsorption performance. The content of pyridine N combined with -OH/-NH2 was further elevated by additional nitrogen introduction, resulting in a further enhanced CO2 adsorption capacity up to 5.96 mmol g-1 (25 degrees C, 1 bar). All these results suggest that, in addition to the well-defined pore structure, pyridinic N with neighboring OH or NH2 species played an important role in enhancing the CO2 adsorption performance of PACs, thus providing effective guidance for the rational design of CO2 adsorbents. PMID- 29114693 TI - Estimating the probability of illness due to swimming in recreational water with a mixture of human- and gull-associated microbial source tracking markers. AB - Beaches often receive fecal contamination from more than one source. Human sources include untreated sewage as well as treated wastewater effluent, and animal sources include wildlife such as gulls. Different contamination sources are expected to pose different health risks to swimmers. Genetic microbial source tracking (MST) markers can be used to detect bacteria that are associated with different animal sources, but the health risks associated with a mixture of MST markers are unknown. This study presents a method for predicting these health risks, using human- and gull-associated markers as an example. Quantitative Microbial Risk Assessment (QMRA) is conducted with MST markers as indicators. We find that risks associated with exposure to a specific concentration of a human associated MST marker (HF) are greater if the HF source is untreated sewage rather than treated wastewater effluent. We also provide a risk-based threshold of HF from untreated sewage at a beach, to stay below a predicted illness risk of 3 per 100 swimmers, that is a function of gull-associated MST marker (CAT) concentration. PMID- 29114695 TI - Frequency of the exon 3-deleted/full-length growth hormone receptor polymorphism in Saudi Arabian population. AB - OBJECTIVES: To investigate the frequency of the growth hormone receptor (GHR)-d3 polymorphism in a random sample of Saudi Arabian population from Jazan province, and test the effects of the polymorphism on some anthropometric factors. METHODS: This cross-sectional population-based study was conducted during the period from January to April 2017 at the College of Applied Medical Sciences, Jazan University, Southwestern Saudi Arabia. A total of 230 healthy adult male and female volunteers were randomly recruited. Genomic DNA was extracted from the whole blood, and the GHR exon 3 locus was genotyped using multiplex polymerase chain reaction. RESULTS: The distributions of the GHR genotypes were as follows: fl/fl (39.1%), fl/d3 (44.8%), and d3/d3 (16.1%). No statistically significant differences were found between fl/fl, fl/d3, or d3/d3 GHR genotypes in terms of weight (p=0.90), height (p=0.12), or body mass index (BMI) (p=0.83) values. CONCLUSION: No correlations were found between the GHR-d3 polymorphism and weight, height, or BMI. PMID- 29114694 TI - The impact of clinical pharmacists in improving Jordanian patients' health outcomes. AB - OBJECTIVES: To assess the impacts of clinical pharmacists on Jordanian patients' health outcomes. Methods: A systematic review was conducted until July 2016 within EBSCO, Pubmed, Cochrane database, and ISI Web of Knowledge. Published studies evaluating the benefit of clinical pharmacy services on therapeutic, safety, humanistic, and economic outcomes in hospital or community settings in Jordan were targeted. Two reviewers independently extracted and assessed risk of bias using a pre-published validated tool. The literature search identified 130 publications of which 21 full texts met predetermined inclusion criteria. Results: Studies were of moderate quality. Pharmacist interventions resulted in an average reduction (95% CI) in systolic blood pressure of 5.45 mm Hg (2.95 7.92) and diastolic blood pressure of 3.03 mm Hg (1.09-4.96). The mean reduction in glycosylated hemoglobin was 0.75% (-0.49-1.99) and fasting blood sugar was 36.73 mg/dl (-19.7-93.1). The average reduction in low-density lipoprotein cholesterol was 2.36 (1.8-16.62) mg/dl and triglycerides was 20.16 (6.14-46.47). There was a minimal increase in the level of high-density lipoprotein cholesterol of 1.24 (1.64-4.11) mg/dl. Effects on safety along with humanistic and economic outcomes and long term effects remained unclear. Conclusion: Published evidence from Jordan highlights service opportunities for clinical pharmacists. Favorable but not always statistically significant impacts were found on therapeutic outcomes. More studies are needed to understand safety, humanistic, economic, and long-term outcomes. Therefore, the add-on benefits of this service to the health system are not well understood. Future studies of higher rigor and multi perspective outcomes are mandated. PMID- 29114696 TI - The prognostic significance of preoperative serum cancer antigen 15-3 levels in endometrial carcinomas. AB - OBJECTIVES: To determine the associations between serum cancer antigen 15-3 levels and prognostic factors in patients with endometrial carcinomas. Additionally, we investigated the clinical utility of serum cancer antigen 15-3 levels in the selection of low-risk patients with endometrioid type, tumor size less than 2 cm, myometrial invasion <=50%, and histological grade 1-2. Methods: Ninety-six patients, who were surgically staged at Ankara Yildirim Beyazit University, Ankara, Turkey, between 2007 and 2016, were retrospectively analyzed. Demographic, clinical, and surgical characteristics were retrieved from the patients' hospital records. A p less than 0.05 was considered significant. Results: Fifteen patients had advanced (>=Stage II) disease, 14 patients had Type 2 histology, 20 patients had Grade 3 tumors, 23 patients had lymphovascular space invasion, and 10 patients had positive lymph node involvement. Serum cancer antigen 15-3 levels were significantly higher in patients with advanced (>=Stage II) disease, Type 2 histology, Grade 3 tumors, lymphovascular space invasion, and positive lymph node involvement (p less than 0.05). Serum cancer antigen 15-3 levels were also significantly correlated with tumor size (p=0.006). Serum cancer antigen 15-3 levels were significantly lower (95% confidence interval: 0.57-0.79; p=0.03) in low-risk patients compared to other endometrial carcinoma patients. A cutoff of 25.0 IU/mL was used to identify high-risk patients with a specificity of 100%. Conclusion: Serum cancer antigen 15-3 levels significantly correlated with prognostic factors and were a useful diagnostic tool for endometrial carcinomas. PMID- 29114698 TI - Efficacy of emergency laparoscopic appendectomy in treating complicated appendicitis for elderly patients. AB - To assess the therapeutic effects of emergency laparoscopic appendectomy (LA) in treating complicated appendicitis (CA) for elderly patients (defined as age 65 years and above). Methods: We conducted a retrospective study of 115 elderly patients with CA who underwent surgical therapy in the Affiliated Huizhou Hospital of Sun Yat-Sun University, Huizhou, Guangdong Province, China between September 2014 and August 2016. Of these, 59 patients consented to open appendectomy (OA), and LA was performed in the other 56 patients. The perioperative and follow-up variables of the 2 groups were analyzed. Results: The operative time in the LA group was longer than the OA group (LA: 70.5+/-16.0 min versus [vs.] OA: 59.3+/-12.0 min, p greater than 0.001). The LA group had lower chances of incision infections (LA: 8.9% vs OA: 28.8 %, p=0.007) and shorter hospital stay (LA: 6.1+/- 2.5 days vs. OA: 9.6+/-3.5 days, p greater than 0.001). Return to soft diet (LA: 1.4 +/- 0.8 days vs OA: 3.0 +/- 1.6 days, p greater than 0.001) and time to out of bed (LA: 1.3+/-0.5 days vs OA: 2.5+/-0.9 days, p greater than 0.001) was faster in the LA group. The incidence of complications and 30-day readmission rate in the LA group was much lower than the OA group. Conclusion: Emergency LA in treating elderly patients with CA has the advantages of less trauma, definite curative effect, low complication rates, and fast recovery when compared with OA. PMID- 29114697 TI - Effect of gonadotropin-releasing hormone analogue on final adult height among Jordanian children with precocious puberty. AB - OBJECTIVES: To study the effect of gonadotropin-releasing hormone analogue (GnRHa) on final adult height (FAH) among Jordanian children with central precocious puberty (CPP). Methods: It is a retrospective historical cohort study. We assessed the FAH and height gain in 43 children with CPP (39 females and 4 males) who received GnRHa and 13 children with CPP (11 females and 2 males) who did not receive GnRHa and achieved FAH between 2004 and 2014. Final adult height was compared to target height (TH) and mid- parental height (MPH) in both groups. Results: In GnRHa treated females, the FAH was 158.5+/-6.6 cm compared to 151.2+/ 8.4 cm in the untreated females (p=0.004). Height gain was 2.9+/-8.5 cm in the treated females compared to -3.8+/-7.7 cm in the untreated group (p=0.022). In GnRHa treated females, FAH was found to be closer to TH (p=0.01) and MPH (p=0.01) in comparison to untreated females. Conclusion: Gonadotropin-releasing hormone analogue is effective in increasing FAH in Jordanian children with CPP, particularly those with advanced bone age. PMID- 29114699 TI - Glomerulonephritis disease pattern at Saudi tertiary care center. AB - OBJECTIVE: To assess changes in the pattern of glomerular diseases to help guide optimal allocation of resources, to focus future reasearch, and improve outcomes. Methods: A retrospective chart review was conducted on kidney biopsies taken between 2007 and 2016 at a single tertiary care center in Saudi Arabia (King Fahad Medical City, Riyadh) to evaluate the prevalence and pattern of glomerulonephritis (GN). Results: The most common primary GN in 102 biopsies from adult patients with a mean age of 28.9 +/- 13.6 years and 40.2% female, was focal and segmental glomerulosclerosis (35.3%). Among 64 patients with systemic lupus erythematosus associated nephritis, of whom most (82.8%) were female, lupus nephritis (LN) 4 (46.9%), and (LN) 3 (32.8%) were the most common lupus nephritis classes. Conclusion: Establishing prospective GN registries from which robust diagnosis, treatment, and outcomes data can be acquired is warranted; however, registry development and maintenance are often precluded by resource limitations. Accordingly, retrospective analysis of administrative data will continue to provide important complementary information on GN epidemiology. PMID- 29114700 TI - Invasive Candidiasis in pediatric patients at King Fahad Medical City in Central Saudi Arabia. A 5-year retrospective study. AB - OBJECTIVES: To identify predisposing factors, species distribution, antifungal susceptibility, and outcome. Methods: This study is a retrospective chart review that was conducted at a children's hospital at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. One hundred twenty-nine children with invasive candidiasis who were admitted between January 2010 and January 2015. Results: The statistical analysis results have revealed a group of risk factors; prematurity in 37 (28.7%) of patients, low birth weight in 42 (32.6%), central venous catheter in 59 (45.7%), malignancy in 21 (16.3%), immunotherapy in 20 (15.5%), and ventilator support in 60 (46.5%). More than 2-fold mortality rate in patients who had heart vegetation (odds ratio [OR]: 2.9) and patients who had Candida isolated from their blood were more than twice as likely to die as patients with Candida isolated from other sites (OR: 2.2). A total of 48.3% of patients on ventilator died versus 26.1% who were not on ventilator (p=0.009); and 43.8% of patients in the ICU died versus only 24.5% of patients who were not in the ICU (p=0.03). Candida parapsilosis exhibited the highest mortality rate (56.2%). Conclusion: Candida albicans is the most common isolate among all Candida species. Gender, low birth weight, prolonged ICU stay, presence of vegetation, positive blood culture, and mechanical ventilation as a strong predictive risk factors for death in children with invasive candidiasis, a finding that could be applied as prophylactic indicator in critically ill children especially neonates. PMID- 29114701 TI - Prevalence of premenstrual syndrome and its relationship to depressive symptoms in first-year university students. AB - OBJECTIVES: To determine the prevalence of and factors influencing premenstrual syndrome (PMS) in first-year students at a university health campus and to evaluate the relationship between depression and PMS. Methods: This cross sectional study was conducted on a population of 618 university students from March to June 2016 at Dokuz Eylul University, Izmir, Turkey. Data were collected using the Premenstrual Syndrome Scale (PMSS), Beck Depression Inventory and Student Identification Form. The data were analyzed with Version 20.0 of the Statistical Package for the Social Science. Descriptive statistics, Pearson's chi square test, and Chi-square test for trend, and independent samples t test and logistic regression analysis were used. Results: The prevalence of PMS in the university students was 58.1%. Premenstrual syndrome was significantly higher in students who smoked, drink alcohol, and consumed a large amount of fatty and high calorie foods, in students who had a bad to very bad perception of their economic situation, and those who had any chronic disease or anemia (p less than 0.05). Premenstrual syndrome was significantly higher in students who had a risk of depression (p less than 0.01). A statistically significant relationship was determined between the risk of depression and PMSS total score and all PMSS subscale scores except for appetite changes (p less than 0.01). Conclusion: Premenstrual syndrome was found in more than half of the students who participated in the study. Premenstrual syndrome was higher in students who had a chronic disease and/or an unhealthy lifestyle. There was a statistically significant relationship between PMS and risk of depression. Students who have PMS symptoms should be evaluated for the risk of depression. PMID- 29114702 TI - Outcome of the first Saudi Central Board for Accreditation of Healthcare Institutions (CBAHI) primary health care accreditation cycle in Saudi Arabia. AB - OBJECTIVES: To study and evaluate the first phase of the Saudi Central Board for Accreditation of Health Institutions (CBAHI) in primary health care (PHC) accreditation cycle. Methods: A descriptive analytical study of to evaluate 93 PHC survey visits in 20 regions, over the period October 2016 to May 2017. Results: In the period October 2016 to January 2017, only 28 out of 93 PHC center (30%) targeted PHC in phase-1 were surveyed, 8 PHC got accredited (29%), while 11 PHC received conditional accreditation letters (39%) and 9 PHC were denied the accreditation (32%). During February 2017 to May 2017 visits were shifted to one day site visit, all the health care facilities training's workshops were completed and the mock survey visits were started to precede the real survey visits, Since then, 65 PHC centers were surveyed (70%). At this time 47 PHC centers were accredited (72%), while 9 PHC were conditionally accredited (14%), and another 9 PHC were denied the accreditation (14%). Overall, 55 out of 93 PHC accredited (59%), 20 PHC got conditional accreditation (22%), and 18 PHC were denied the accreditation (19%). Conclusion: Surveys per month were doubled with the one-day visit site visit. Both the intensive training and mock visits, showed a great impact as the accreditation and conditional accreditation status were increased by twofold due to better understanding of the PHC staff about the standards, as well as early identification of performance gap which allowed the PHC to mitigate these gaps sufficiently enough to avoid zero scores especially in the ESR requirements. PMID- 29114703 TI - Validation of Hepa-index as a non-invasive biomarkers panel for assessment of hepatic fibrosis in Egyptians with chronic hepatitis C. AB - OBJECTIVES: To validate the diagnostic performance of Hepa-Index in predicting different stages of hepatic fibrosis in Egyptian patients with chronic hepatitis C (CHC). Methods: Hundred treatment naive chronic hepatitis C Egyptian patients were prospectively enrolled between June 2014 and January 2015. They were subjected to: platelet count, alpha-2-macroglobulin (alpha2-MG), total bilirubin, gamma glutamyl transpeptidase (GGT), total cholesterol, liver biopsy and histopathological staging of hepatic fibrosis according to METAVIR scoring system. Hepa-Index was calculated according to the formula: Hepa-Index=exp ( 0.021 x platelet +1.65 x alpha2-MG+0.2 x total bilirubin + 0.026 x GGT -1.215 x total cholesterol) / (1+exp (-0.021 x platelet + 1.65 x alpha2-MG + 0.2 x total bilirubin +0.026 x GGT -1.215 x total cholesterol). Results: Hepa-Index correlates positively with the stage of hepatic fibrosis. Cut off values of Hepa Index were: 0.2 for predicting significant hepatic fibrosis (>=F2 METAVIR), 0.3 for severe hepatic fibrosis (>=F3 METAVIR) and 0.4 for cirrhosis (F4 METAVIR). Hepa-Index was able to detect significant fibrosis with sensitivity of 69.4%, specificity of 76.3% and AUROC of 0.803. Hepa-Index was also able to detect severe hepatic fibrosis with sensitivity of 79.2%, specificity of 64.5% and AUROC of 0.783 and cirrhosis with sensitivity of 81.8%, specificity of 68.5% and AUROC of 0.744. Conclusion: Hepa-Index is a good non-invasive biomarkers panel that can be used for non-invasive assessment of hepatic fibrosis in chronic hepatitis C patients. PMID- 29114704 TI - Dental injuries in taekwondo athletes practicing in Saudi Arabia. AB - OBJECTIVES: To assess the incidence and awareness of taekwondo athletes in Saudi Arabia regarding oral and maxillofacial (OMF) injuries and their prevention. Methods: In this cross-sectional study, an online questionnaire about the incidence and awareness of OMF injuries and their prevention was developed and distributed to taekwondo athletes in Saudi Arabia via their coaches. Results: Sixty-eight responses were collected. The mean age of the participants was 29.3+/ 9.1 years and 97% of them were males. Most of the participants (83%) believed that they are vulnerable to OMF injuries during practice. Approximately 23% of the participants reported a previous injury of the OMF area, while approximately 56% reported injuries in other areas. Most dental injuries (94%) were tooth fracture or displacement, while 6% were tooth avulsion. Eight participants (12%) were aware of the possibility of returning an avulsed tooth to its socket. More than 50% of those participants had inadequate knowledge on the appropriate storage media for the avulsed tooth or the maximum time allowed to return it to its socket. Eighty-one percent of the participants knew about the mouthguard, while 56% reported that they are actually using one. The most frequently reported barriers for not using a mouthguard during practice were difficulty in practicing with it, not being convinced of its importance, and lack of information where to get one. Conclusions: Most of the participants are aware of OMF injuries; however, their knowledge and behavior towards preventing and managing them are inadequate. PMID- 29114705 TI - Splenic lymphangioma in an adult. AB - Splenic lymphangiomas are exceedingly rare benign neoplasms that occur mainly in children. They are commonly seen in the neck and axillary region. Abdominal lymphangiomas accounts for less than 5% of cases. So far, fewer than 100 cases of spleen lymphangiomas have been reported in the literature. In this paper, we present one case of solitary splenic lymphangioma in a 34-year-old woman who presented with abdominal pain and weight loss for one month. The patient underwent splenectomy and diagnosis was confirmed by histopathology and immunohistochemistry studies. There was no clinical or radiological evidence of diffuse lymphangiomatosis syndrome. This case indicates that splenic lymphangiomas should be considered in the differential diagnosis of splenic cystic masses, even in adults, and should be managed with splenectomy once diagnosed to prevent complications. PMID- 29114706 TI - Unusual skin rash in infant. AB - [No Abstract Available]. PMID- 29114707 TI - Prevalence of obstructive sleep apnea in children with sickle cell disease at a tertiary hospital in Saudi Arabia. AB - [No Abstract Available]. PMID- 29114708 TI - The accuracy of Broselow pediatric emergency tape in estimating body weight of pediatric patients. AB - [No Abstract Available]. PMID- 29114709 TI - The accuracy of Broselow pediatric emergency tape in estimating body weight of pediatric patients. AB - [No Abstract Available]. PMID- 29114710 TI - 50 years since citizenship: successes and challenges in Indigenous health. PMID- 29114711 TI - Interview with the Hon. Ken Wyatt: improving Indigenous health outcomes from a political viewpoint. AB - In 2017, Australia celebrates 50 years since the 1967 referendum, when more than 90% of Australians voted to amend the constitution to allow the national government to create laws for Indigenous people and include them in the census. We spoke with the Honourable Ken Wyatt, the Minister for Indigenous Health and the Minister for Aged Care, about what has occurred over the past 50 years in Indigenous health from a political perspective, and what we have learnt to improve health outcomes in the future. PMID- 29114712 TI - The Australian Burden of Disease Study: impact and causes of illness and death in Aboriginal and Torres Strait Islander people, 2011. AB - This study estimates fatal and nonfatal disease burden among Indigenous Australians in 2011 and compares it with non-Indigenous Australians. The study found that there were 284 years lost per 1000 people because of premature death or living with ill health. Most of the disease burden was from chronic diseases (64%), particularly mental and substance-use disorders, injuries, cardiovascular diseases, cancer and respiratory diseases. The burden of disease was higher among males (54%) than females (46%) and higher for fatal (53%) than for nonfatal burden (47%). The disease groups with the highest burden varied by age group, with mental and substance-use disorders and injuries being the largest disease groups among those aged 5-44 years, and cardiovascular disease and cancer becoming more prominent among those aged 45 and older. Large disparities existed between Indigenous and non-Indigenous Australians, with the total burden being 2.3 times the non-Indigenous rates, fatal burden being 2.7 times and nonfatal burden being 2 times. PMID- 29114713 TI - The Aboriginal and Torres Strait Islander smoking epidemic: what stage are we at, and what does it mean? AB - Smoking is the leading contributor to the burden of disease among Aboriginal and Torres Strait Islander Australians, and there is considerable potential for change. Understanding the epidemic stage may provide insight into probable trends in smoking-attributable mortality, and inform program and policy development. Tobacco use among Aboriginal and Torres Strait Islander Australians has declined substantially, accompanied by declining tobacco-related cardiovascular mortality. Based on the available evidence, we expect tobacco-related cancer mortality to remain high, but peak within the next decade; however, there is a critical need for improved evidence to make an accurate assessment. The continuation and expansion of comprehensive tobacco reduction measures is expected to further decrease tobacco use. Health gains will be observed over both the short and long term. PMID- 29114714 TI - Child injury surveillance capabilities in NSW: informing policy and practice. AB - Injury is one of the most common reasons why a child is hospitalised. Information gained from injury surveillance activities provides an estimate of the injury burden, describes injury event circumstances, can be used to monitor injury trends over time, and is used to design and evaluate injury prevention activities. This perspective article provides an overview of child injury surveillance capabilities within New South Wales (NSW), Australia, following a stocktake of population-based injury-related data collections using the Evaluation Framework for Injury Surveillance Systems. Information about childhood injury in NSW is obtained from multiple administrative data collections that were not specifically designed to conduct injury surveillance. Obtaining good information for child injury surveillance in NSW will involve better coordination of information from agencies that record information about childhood injury. Regular reporting about childhood injury to provide a comprehensive profile of injuries of children and young people in the state should be considered, along with the provision and/or linkage of child injury information from multiple data collections. This could support the development of a suite of injury performance indicators to monitor childhood injury reduction strategies across NSW. PMID- 29114715 TI - Identifying research priorities to improve cancer control for Indigenous Australians. AB - OBJECTIVES: The cancer burden is high among Australia's Indigenous population. Following a period of increasing attention by researchers, policy makers and consumers, this study aimed to identify emerging research priorities in Indigenous cancer control. METHODS: A survey was administered to a network of individuals with an interest in cancer and Indigenous Australians. Respondents (N = 255) described what they thought was the most significant research priority for cancer control for Indigenous Australians and ranked prespecified research areas relating to components of the cancer continuum. RESULTS: Identified research priorities included cancer prevention and early detection; health literacy; and culturally appropriate care for Indigenous patients, survivors and families. Community engagement, Indigenous ownership, and partnership and collaboration were highlighted as critical elements underpinning research. CONCLUSIONS: The identified research priorities, along with seminal documents such as the National Aboriginal and Torres Strait Islander Cancer Framework, provide a roadmap for developing, funding, implementing and translating research to reduce the burden of cancer for Indigenous Australians. PMID- 29114716 TI - Trends in fall-related ambulance use and hospitalisation among older adults in NSW, 2006-2013: a retrospective, population-based study. AB - : Objective and importance of study: To describe characteristics and temporal trends of fall-related ambulance service use and hospital admission in older adults in New South Wales (NSW), Australia. Such information will facilitate a more targeted approach to planning and delivery of health services to prevent falls and their adverse sequelae in different groups of older adults. STUDY TYPE: Retrospective population-based descriptive study. METHODS: Fall-related ambulance use and hospital admissions for all falls and injurious falls in NSW residents aged >=65 years between 2006 and 2013 were obtained from two discrete sources of routinely collected data. Rates of use are presented descriptively. RESULTS: There were 314 041 occasions of fall-related ambulance use by older adults and 331 311 fall-related hospitalisations, of which 69% (n = 227 753) were for injurious falls. Fractures accounted for 57% of injurious hospitalisations. Slips and trips were the most common mechanism of falls requiring hospitalisation (52%). Residents of aged care facilities had a greater proportion of fall injury hospitalisations compared with people living in the community (85% and 65%, respectively). CONCLUSIONS: Rates of fall-related ambulance use and hospitalisation were similar and continued to increase over time. Increased effort is needed to prevent falls and associated injury among older people in NSW, particularly among people living in aged care facilities. Ongoing monitoring of rates and the characteristics of people who fall are needed to determine the long-term impact of fall prevention interventions. PMID- 29114717 TI - The quality of Australian Indigenous primary health care research focusing on social and emotional wellbeing: a systematic review. AB - : Objectives and importance of the study: Primary health care research focused on Aboriginal and Torres Strait Islander (Indigenous) people is needed to ensure that key frontline services provide evidence based and culturally appropriate care. We systematically reviewed the published primary health care literature to identify research designs, processes and outcomes, and assess the scientific quality of research focused on social and emotional wellbeing. This will inform future research to improve evidence based, culturally appropriate primary health care. STUDY TYPE: Systematic review in accordance with PRISMA and MOOSE guidelines. METHODS: Four databases and one Indigenous-specific project website were searched for qualitative, quantitative and mixed-method published research. Studies that were conducted in primary health care services and focused on the social and emotional wellbeing of Indigenous people were included. Scientific quality was assessed using risk-of-bias assessment tools that were modified to meet our aims. We assessed community acceptance by identifying the involvement of community governance structures and representation during research development, conduct and reporting. Data were extracted using standard forms developed for this review. RESULTS: We included 32 articles, which reported on 25 studies. Qualitative and mixed methods were used in 18 studies. Twelve articles were judged as high or unclear risk of bias, four as moderate and five as low risk of bias. Another four studies were not able to be assessed as they did not align with the risk-of-bias tools. Of the five articles judged as low risk of bias, two also had high community acceptance and both of these were qualitative. One used a phenomenological approach and the other combined participatory action research with a social-ecological perspective and incorporated 'two-way learning' principles. Of the 16 studies where a primary outcome was identified, eight aimed to identify perceptions or experiences. The remaining studies assessed resources, or evaluated services, interventions, programs or policies. We were unable to identify primary outcomes in eight studies. CONCLUSION: Conducting Indigenous focused primary health care research that is scientifically robust, culturally appropriate and produces community-level outcomes is challenging. We suggest that research teams use participatory, culturally sensitive approaches and collaborate closely to plan and implement high-quality research that incorporates local perspectives. Research should result in beneficial outcomes for the communities involved. PMID- 29114718 TI - Ascertainment of self-reported prescription medication use compared with pharmaceutical claims data. AB - BACKGROUND: Evidence on the comparative validity of self-reported medication use in large-scale studies is limited. This study compared self-reported medication use of prescription-only medications to gold standard pharmaceutical claims (i.e. dispensing) data. METHODS: We selected a random sample of 500 participants from the 45 and Up Study, a large-scale Australian study, with complete ascertainment of Pharmaceutical Benefits Scheme dispensing records. Self-reported medication use was ascertained by questionnaire requesting data on medications used "for most of the last 4 weeks". In the dispensing data, we determined exposure to specific medications in the same 4-week window as the survey response if we observed a dispensing record <=90 days before the start of the window. We calculated sensitivity and positive predictive values (PPVs) at the Anatomical Therapeutic Chemical (ATC) classification 3- and 7-digit code levels. RESULTS: PPVs were >=75% for 79% of the medications examined at the 3-digit ATC level. The sensitivity/PPV of self-reported versus claims data at the 3-digit level were highest for chronic medications, including cardiovascular medications: 94.4%/96.9%, respectively, for lipid-lowering agents; 92.5%/97.5% for angiotensin agents; 88.8%/93.1% for beta-blockers; and 88.0%/96.9% for calcium-channel blockers. PPVs were >=65% and sensitivity of self-reported data was 78.9% for psychoanaleptics, 42.1% for analgesics, 26.0% for psycholeptics and 4.8% for antibacterial agents. PPVs for individual medications were >=75% for 81% of the individual medications examined at the 7-digit level. The sensitivity/PPV for self-reported versus claims data at the 7-digit level varied across individual medications, with highest values being 96.9%/96.9% for warfarin, 94.5%/92.0% for atorvastatin, 94.3%/84.6% for pantoprazole and 93.3%/95.5% for atenolol. The lowest sensitivity of self-reported versus claims data for individual medications was 16.7% for temazepam, 15.2% for perindopril, 11.5% for irbesartan, 11.1% for oxazepam and 3.3% for amoxicillin. CONCLUSIONS: Self-reported data of the type reported here are useful for identifying exposure to prescription medications, particularly those for chronic use. However, they are likely to be of lesser validity for ascertaining short-term and/or intermittent medication exposure. PMID- 29114720 TI - Spontaneous Disappearance of Large Lumbar Disk Herniation. PMID- 29114719 TI - The Aboriginal Population Health Training Initiative: a NSW Health program established to strengthen the Aboriginal public health workforce. AB - OBJECTIVES: Increasing the representation of Aboriginal people in the health workforce can contribute to improving Aboriginal people's health and wellbeing by supporting the provision of more culturally appropriate health programs and services. The Aboriginal Population Health Training Initiative aims to strengthen the Aboriginal public health workforce in New South Wales (NSW), with the long term goal of improving the health of Aboriginal people. Type of program or service: The program provides comprehensive, competency-based public health training for Aboriginal people. METHODS: Participants undertake a series of work placements in public health, and complete a Master of Public Health degree. RESULTS: A 2014 evaluation demonstrated that the program makes an important contribution to strengthening the NSW Aboriginal public health workforce. Trainees reported a high level of satisfaction with the quality of their work placements, the flexibility of the program to support their work and study, and efforts made to ensure the program's cultural safety. The program has a high trainee retention rate (17 of 18 trainees), and all graduates have successfully gained employment within the NSW health system. LESSONS LEARNT: Three key factors contribute to the success of the program: trainees undertake their training within their communities; the structure promotes the direct application of learning through simultaneous work and study; and the NSW Government shows strong leadership and support. PMID- 29114722 TI - ADS 5102 (Amantadine) Extended Release for Levodopa-Induced Dyskinesia-Reply. PMID- 29114723 TI - The Lost Art of Doctoring: Reflections of a Pediatric Resident. PMID- 29114721 TI - Observations on a 2-Step Approach to Screening for Parkinson Disease-Reply. PMID- 29114724 TI - Observations on a 2-Step Approach to Screening for Parkinson Disease. PMID- 29114725 TI - Association Between Adolescent Preventive Care and the Role of the Affordable Care Act. AB - Importance: Despite decades of adolescent preventive well visit and services promotion (Guidelines for Adolescent Preventive Services and Bright Futures), rates are below recommended levels and little is known of the effect of the Patient Protection and Affordable Care Act (ACA) implementation on these care rates. Objectives: To use Medical Expenditure Panel Survey data to determine (1) whether adolescent well visit rates increased from the pre-ACA period to post-ACA period, and (2) whether caregivers' reports of past-year preventive services delivery increased from the pre- to post-ACA period among adolescents with any past-year health care visit. Design, Setting, and Participants: Secondary data analysis of 2007-2009 (before ACA implementation) and 2012-2014 (after ACA implementation) Medical Expenditure Panel Survey data on the differences in well visits and preventive services. Data were collected through computer-assisted personal interviews of caregivers of a nationally representative sample of a noninstitutionalized US population (n = 25 695 10- to 17-year-old adolescents). Main Outcomes and Measures: For objective 1, pre- to post-ACA period differences in past-year well visits: (1) stratified bivariable logistic regressions identifying subgroup rate differences and (2) multivariable analyses controlling for demographic factors. For objective 2, pre- to post-ACA period differences in caregiver reports of preventive services receipt, including time alone with clinician: (1) bivariable (year differences) and (2) multivariable logistic regressions controlling for demographic variables. Results: A total of 6279 (50.9%) and 6730 (50.8%) participating adolescents in the pre- and post-ACA period data were male, respectively. Under objective 1, we found that well-visit rates increased from 41% to 48% post-ACA implementation (odds ratio, 1.3; 95% CI, 1.2-1.5); minority and low-income groups had the greatest increases. Under objective 2, we found that among those with any past-year visit, most preventive services rates (8 of 9) increased post-ACA implementation (range, 2%-9%, absolute), with little or no change when controlling for demographic variables. Time alone with clinicians increased 1%, significant only when covariates were controlled (adjusted odds ratio, 1.2; 95% CI, 1.0-1.3). Conclusions and Relevance: Despite modest to moderate increases, with greatest gains for underserved youth, adolescent preventive care rates remain low, highlighting the need for increased efforts to bring adolescents into well care and improve clinician delivery of preventive care within their practices. PMID- 29114727 TI - The Well-Child Visit. PMID- 29114728 TI - ADS-5102 (Amantadine) Extended Release for Levodopa-Induced Dyskinesia. PMID- 29114726 TI - Concordance Between Different Amyloid Immunoassays and Visual Amyloid Positron Emission Tomographic Assessment. AB - Importance: Visual assessment of amyloid positron emission tomographic (PET) images has been approved by regulatory authorities for clinical use. Several immunoassays have been developed to measure beta-amyloid (Abeta) 42 in cerebrospinal fluid (CSF). The agreement between CSF Abeta42 measures from different immunoassays and visual PET readings may influence the use of CSF biomarkers and/or amyloid PET assessment in clinical practice and trials. Objective: To determine the concordance between CSF Abeta42 levels measured using 5 different immunoassays and visual amyloid PET analysis. Design, Setting, and Participants: The study included 262 patients with mild cognitive impairment or subjective cognitive decline from the Swedish BioFINDER (Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably) cohort (recruited from September 1, 2010, through December 31, 2014) who had undergone flutemetamol F 18 ([18F]flutemetamol)-labeled PET. Levels of CSF Abeta42 were analyzed using the classic INNOTEST and the newer modified INNOTEST, fully automated Lumipulse (FL), EUROIMMUN (EI), and Meso Scale Discovery (MSD) assays. Concentrations of CSF Abeta were assessed using an antibody-independent mass spectrometry-based reference measurement procedure. Main Outcomes and Measures: The concordance of CSF Abeta42 levels and Abeta42:Abeta40 and Abeta42:tau ratios with visual [18F]flutemetamol PET status. Results: Of 262 participants (mean [SD] age, 70.9 [5.5] years), 108 were women (41.2%) and 154 were men (58.8%). The mass spectrometry-derived Abeta42 values showed higher correlations with the modified Abeta42-INNOTEST (r = 0.97), Abeta42-FL (r = 0.93), Abeta42-EI (r = 0.93), and Abeta42-MSD (r = 0.95) assays compared with the classic Abeta42-INNOTEST assay (r = 0.88; P <= .01). The signal in the classic Abeta42-INNOTEST assay was partly quenched by recombinant Abeta1-40 peptide. However, the classic Abeta42-INNOTEST assay showed better concordance with visual [18F]flutemetamol PET status (area under the receiver operating characteristic curve [AUC], 0.92) compared with the newer assays (AUCs, 0.87-0.89; P <= .01). The accuracies of the newer assays improved significantly when Abeta42:Abeta40 (AUCs, 0.93-0.95; P <= .01), Abeta42 to total tau (T-tau) (AUCs, 0.94; P <= .05), or Abeta42 to phosphorylated tau (P tau) (AUCs, 0.94-0.95; P <= .001) ratios were used. A combination of the Abeta42:Abeta40 ratio and T-tau or P-tau level did not improve the accuracy compared with the ratio alone. Conclusions and Relevance: Concentrations of CSF Abeta42 derived from the new immunoassays (modified INNOTEST, FL, EI, and MSD) may correlate better with the antibody-independent mass spectrometry-based reference measurement procedure and may show improved agreement with visual [18F]flutemetamol PET assessment when using the Abeta42:Abeta40 or Abeta42:tau ratios. These findings suggest the benefit of implementing the CSF Abeta42:Abeta40 or Abeta42:tau ratios as a biomarker of amyloid deposition in clinical practice and trials. PMID- 29114729 TI - Cost-effectiveness of Strategies for Offering Influenza Vaccine in the Pediatric Emergency Department. AB - Importance: Influenza is a significant public health burden, causing morbidity and mortality in children, yet vaccination rates remain low. Vaccination in the pediatric emergency department (PED) setting may be beneficial but, to date, has not been proven to be cost-effective. Objective: To compare the cost effectiveness of 4 strategies for PED-based influenza vaccine: offering vaccine to all patients, only to patients younger than 5 years, only to high-risk patients (all ages), or to no patients. Design, Setting, and Participants: Using commercial decision analysis software, a cost-effectiveness analysis was performed from January 1, 2016, to June 1, 2017, to compare influenza vaccine strategies at a tertiary, urban, freestanding PED with an estimated 60 000 visits per year among a hypothetical cohort of children visiting the above PED during influenza season. Sensitivity analyses estimated the effect of uncertainties across a variety of input variables (eg, influenza prevalence, vaccine price and effectiveness, and costs of complications). Main Outcomes and Measures: The primary outcomes were cost and incremental cost-effectiveness ratio in dollars per influenza case averted. Secondary outcomes included total societal costs, hospitalizations and deaths averted, and quality-adjusted life-years gained. Results: Offering influenza vaccine to all eligible patients has the lowest cost, at $114.45 (95% CI, $55.48-$245.45) per case of influenza averted. This strategy saves $33.51 (95% CI, $18-$62) per case averted compared with no vaccination, and averages 27 fewer cases of influenza per 1000 patients. Offering vaccine to all patients resulted in 0.72 days (95% CI, 0.18-1.78 days) of quality-adjusted life years lost, whereas offering to none resulted in 0.91 days (95% CI, 0.25-2.2 days) of quality-adjusted life-years lost. In sensitivity analyses, this strategy remains robustly cost-effective across a wide range of assumptions. In addition to being the most cost-effective strategy regardless of age or risk status, routine vaccination in the PED results in a net societal monetary benefit under many circumstances. In Monte Carlo analysis, offering vaccine to all patients was superior to other strategies in at least 99.8% of cases. Conclusions and Relevance: Although few PEDs routinely offer influenza vaccination, doing so appears to be cost-effective, with the potential to significantly reduce the economic (and patient) burden of pediatric influenza. PMID- 29114730 TI - Ensuring Access to Preventive Services for Adolescents: Historical Roots, Current Progress, and Future Challenges. PMID- 29114731 TI - Association of Cardiac Hemodynamic Factors With Severity of White Matter Hyperintensities in Chronic Valvular Heart Disease. AB - Importance: The cerebral white matter hyperintensity (WMH) is frequently noted in patients with chronic heart disease. Long-term alteration of cardiac hemodynamics might have an influence on the mechanism of cerebral WMH. Objective: To investigate the association between chronically altered cardiac hemodynamics and severity of cerebral WMH in patients with chronic valvular heart disease. Design, Setting, and Participants: This cross-sectional analysis identified 303 consecutive patients at a tertiary referral center between 2008 and 2016 who were 50 years or older, and diagnosed with severe chronic valvular heart disease and underwent cardiac catherization, echocardiography, and received brain magnetic resonance imaging. Among these patients, 71 with other demonstrated cardiac disease, central nervous system disease, and/or without sufficient catheterization data were excluded, and the remaining 232 patients were included in further analyses. Exposures: The site and mechanism of valve diseases, as well as clinical and medication profiles, were reviewed. Cardiac catheterization parameters such as right atrial (RA) mean pressure, right ventricular pressure, and aortic mean pressure were obtained. Comprehensive echocardiographic hemodynamic markers such as left ventricular (LV) ejection fraction, LV mass index, LV end diastolic volume, cardiac index, and E/e' ratio were also obtained. Main Outcomes and Measures: White matter hyperintensity volume was quantitatively evaluated using volumetric analysis. Results: This study included 232 patients (103 men [44.4%] and 129 women [55.6%]; mean [SD] (range) age, 65.6 [8.8] (51-88) years) in the final analysis. The mean (SD) WMH volume was 5.93 (7.14) mL (median [interquartile range], 4.33 [1.33-8.62] mL), and mean (SD) RA pressure was 10.0 (4.7) mm Hg. From the catheterization data, 147 patients (63.4%) were classified as having a disease involving the mitral valve; 93 (40.1%), aortic valve; 37 (15.9%), tricuspid valve; and 4 (1.7%), pulmonary valve. In multivariate linear regression analysis, adjusting the type and mechanism of valve disease and clinical, echocardiographic, and/or other catheterization parameters, WMH volume was linearly associated with mean RA pressure (B coefficient, 0.702; 95% CI, 0.373-1.031; P = .001), along with age (B coefficient, 0.145; 95% CI, 0.029 0.261; P = .01) and mean aortic pressure (B coefficient, 0.112; 95% CI, 0.034 0.190; P = .005). Conclusions and Relevance: Mean RA pressure was independently associated with the WMH volume in chronic valvular heart disease. Chronically altered RA hemodynamics might have a distinct influence on the pathomechanism underlying the development of WMH. PMID- 29114734 TI - Hypertonic Saline and Acute Bronchiolitis: The Debate Is Still On. PMID- 29114732 TI - Amyloid beta Deposition and Suspected Non-Alzheimer Pathophysiology and Cognitive Decline Patterns for 12 Years in Oldest Old Participants Without Dementia. AB - Importance: The prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers. Objective: To compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia. Design, Setting, and Participants: A longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment. Main Outcomes and Measures: Biomarker groups included amyloid beta negative (Abeta-)/neurodegeneration negative (ND-), amyloid beta positive (Abeta+)/ND-, Abeta-/neurodegeneration positive (ND+), and Abeta+/ND+ based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education. Results: Of the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Abeta-/ND-, 32 (18.3%) were Abeta+/ND-, 35 (20.0%) were Abeta-/ND+, and 66 (37.7%) were Abeta+/ND+. On all cognitive measures, the Abeta+/ND+ group showed the steepest decline. Compared with the Abeta-/ND- group, the amyloid deposition alone (Abeta+/ND-) group showed faster decline on tests of verbal and visual memory (-0.3513; 95% CI, -0.5269 to 0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language ( 0.1934; 95% CI, -0.3520 to -0.0348). The Abeta-/ND+ group showed faster visual memory decline than the Abeta-/ND- reference group (-0.3007; 95% CI, -0.4736 to 0.1279). Conclusions and Relevance: In the oldest old without dementia, presence of either or both Abeta and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Abeta is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Abeta+/ND- and Abeta-/ND+ groups. PMID- 29114733 TI - Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial. AB - Importance: Sleep-wake disorders are a common and debilitating nonmotor manifestation of Parkinson disease (PD), but treatment options are scarce. Objective: To determine whether nocturnal administration of sodium oxybate, a first-line treatment in narcolepsy, is effective and safe for excessive daytime sleepiness (EDS) and disturbed nighttime sleep in patients with PD. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, crossover phase 2a study carried out between January 9, 2015, and February 24, 2017. In a single-center study in the sleep laboratory at the University Hospital Zurich, Zurich, Switzerland, 18 patients with PD and EDS (Epworth Sleepiness Scale [ESS] score >10) were screened in the sleep laboratory. Five patients were excluded owing to the polysomnographic diagnosis of sleep apnea and 1 patient withdrew consent. Thus, 12 patients were randomized to a treatment sequence (sodium oxybate followed by placebo or placebo followed by sodium oxybate, ratio 1:1) and, after dropout of 1 patient owing to an unrelated adverse event during the washout period, 11 patients completed the study. Two patients developed obstructive sleep apnea during sodium oxybate treatment (1 was the dropout) and were excluded from the per-protocol analysis (n = 10) but included in the intention-to-treat analysis (n = 12). Interventions: Nocturnal sodium oxybate and placebo taken at bedtime and 2.5 to 4.0 hours later with an individually titrated dose between 3.0 and 9.0 g per night for 6 weeks with a 2- to 4-week washout period interposed. Main Outcomes and Measures: Primary outcome measure was change of objective EDS as electrophysiologically measured by mean sleep latency in the Multiple Sleep Latency Test. Secondary outcome measures included change of subjective EDS (ESS), sleep quality (Parkinson Disease Sleep Scale-2), and objective variables of nighttime sleep (polysomnography). Results: Among 12 patients in the intention-to-treat population (10 men, 2 women; mean [SD] age, 62 [11.1] years; disease duration, 8.4 [4.6] years), sodium oxybate substantially improved EDS as measured objectively (mean sleep latency, +2.9 minutes; 95% CI, 2.1 to 3.8 minutes; P = .002) and subjectively (ESS score, -4.2 points ; 95% CI, 5.3 to -3.0 points; P = .001). Thereby, 8 (67%) patients exhibited an electrophysiologically defined positive treatment response. Moreover, sodium oxybate significantly enhanced subjective sleep quality and objectively measured slow-wave sleep duration (+72.7 minutes; 95% CI, 55.7 to 89.7 minutes; P < .001). Differences were more pronounced in the per-protocol analysis. Sodium oxybate was generally well tolerated under dose adjustments (no treatment-related dropouts), but it induced de novo obstructive sleep apnea in 2 patients and parasomnia in 1 patient, as detected by polysomnography, all of whom did not benefit from sodium oxybate treatment. Conclusions and Relevance: This study provides class I evidence for the efficacy of sodium oxybate in treating EDS and nocturnal sleep disturbance in patients with PD. Special monitoring with follow-up polysomnography is necessary to rule out treatment-related complications and larger follow-up trials with longer treatment durations are warranted for validation. Trial Registration: clinicaltrials.gov Identifier: NCT02111122. PMID- 29114735 TI - Residency Evaluations-Where Is the Patient Voice? PMID- 29114737 TI - Appropriate Use of Imaging for Acute Abdominal Pain. PMID- 29114736 TI - Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years. AB - Importance: In cancer models, warfarin inhibits AXL receptor tyrosine kinase dependent tumorigenesis and enhances antitumor immune responses at doses not reaching anticoagulation levels. This study investigates the association between warfarin use and cancer incidence in a large, unselected population-based cohort. Objective: To examine the association between warfarin use and cancer incidence. Design, Setting, and Participants: This population-based cohort study with subgroup analysis used the Norwegian National Registry coupled with the Norwegian Prescription Database and the Cancer Registry of Norway. The cohort comprised all persons (N = 1 256 725) born between January 1, 1924, and December 31, 1954, who were residing in Norway from January 1, 2006, through December 31, 2012. The cohort was divided into 2 groups-warfarin users and nonusers; persons taking warfarin for atrial fibrillation or atrial flutter were the subgroup. Data were collected from January 1, 2004, to December 31, 2012. Data analysis was conducted from October 15, 2016, to January 31, 2017. Exposures: Warfarin use was defined as taking at least 6 months of a prescription and at least 2 years from first prescription to any cancer diagnosis. If warfarin treatment started after January 1, 2006, each person contributed person-time in the nonuser group until the warfarin user criteria were fulfilled. Main Outcomes and Measures: Cancer diagnosis of any type during the 7-year observation period (January 1, 2006, through December 31, 2012). Results: Of the 1 256 725 persons in the cohort, 607 350 (48.3%) were male, 649 375 (51.7%) were female, 132 687 (10.6%) had cancer, 92 942 (7.4%) were classified as warfarin users, and 1 163 783 (92.6%) were classified as nonusers. Warfarin users were older, with a mean (SD) age of 70.2 (8.2) years, and were predominantly men (57 370 [61.7%]) as compared with nonusers, who had a mean (SD) age of 63.9 (8.6) years and were mostly women (613 803 [52.7%]). Among warfarin users and compared with nonusers, there was a significantly lower age- and sex-adjusted incidence rate ratio (IRR) in all cancer sites (IRR, 0.84; 95% CI, 0.82-0.86) and in prevalent organ-specific sites (lung, 0.80 [95% CI, 0.75-0.86]; prostate, 0.69 [95% CI, 0.65-0.72]; and breast, 0.90 [95% CI, 0.82-1.00]). There was no observed significant effect in colon cancer (IRR, 0.99; 95% CI, 0.93-1.06). In a subgroup analysis of patients with atrial fibrillation or atrial flutter, the IRR was lower in all cancer sites (IRR, 0.62; 95% CI, 0.59-0.65) and in prevalent sites (lung, 0.39 [95% CI, 0.33 0.46]; prostate, 0.60 [95% CI, 0.55-0.66]; breast, 0.72 [95% CI, 0.59-0.87]; and colon, 0.71 [95% CI, 0.63-0.81]). Conclusions and Relevance: Warfarin use may have broad anticancer potential in a large, population-based cohort of persons older than 50 years. This finding could have important implications for the selection of medications for patients needing anticoagulation. PMID- 29114738 TI - Science Requires Open Discourse. PMID- 29114739 TI - Trends in Inferior Vena Cava Filter Placement by Indication in the United States From 2005 to 2014. PMID- 29114740 TI - On the Communicability of Chronic Diseases. PMID- 29114741 TI - Factors Associated With Clinical Remission of Skin Disease in Dermatomyositis. AB - Importance: Cutaneous disease represents a significant burden for patients with dermatomyositis. However, quantitative estimates of the probability of skin disease remission and clinical factors associated with skin outcomes are lacking. Objective: To characterize cutaneous disease course in adult patients with dermatomyositis. Design, Setting, and Participants: Prospective cohort study conducted at a dermatology clinic at a tertiary academic referral center. All adult patients with dermatomyositis (age >18 years) seen between May 15, 2007, and October 28, 2016, were eligible. Patients were included in the current analysis if they had a baseline Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score of 12 or higher, and 2 or more CDASI scores separated by 3 months or more within their first 3 years of follow-up. Main Outcomes and Measures: The percentage of patients who achieved clinical remission of their cutaneous disease as measured by the CDASI over a 3-year follow-up. Results: A total of 74 patients met our inclusion criteria (mean [SD] age at initial CDASI scoring, 54 [13] years; 58 women [78%]), and 28 (38%) achieved clinical remission during our 3-year follow-up period. Increased age (odds ratio [OR], 1.07; 95% CI, 1.02-1.12; P = .01), a dermatomyositis-associated malignancy (OR, 14.46; 95% CI, 2.18-96.07; P = .01), and treatment with mycophenolate mofetil (OR, 6.00; 95% CI, 1.66-21.78; P = .01) were significantly associated with clinical remission of skin disease in multivariable analysis. Patients with anti-melanoma differentiation-associated protein 5 antibodies had a significantly lower probability of meeting outcome criteria in our time-to-event analysis. Baseline cutaneous disease activity, disease duration at baseline, and disease duration before first systemic therapy were not significantly associated with clinical remission of skin disease. Conclusions and Relevance: Clinical remission was relatively uncommon in our population despite aggressive systemic therapy, and patients with anti-melanoma differentiation-associated protein 5 antibodies were even less likely to enter clinical remission during a 3-year follow-up period. Although mycophenolate mofetil compared favorably with other treatment options, our data provide evidence that a substantial population of patients with dermatomyositis have skin disease that is not adequately managed with standard-of care therapies. PMID- 29114742 TI - Scientific Trials-In the Laboratories, Not the Courts. PMID- 29114743 TI - Mild Neonatal Encephalopathy-How, When, and How Much to Treat? PMID- 29114744 TI - Tailoring Treatment of Latent Tuberculosis to the Needs of Patients and Families. PMID- 29114745 TI - Voluntarily Stopping Eating and Drinking Among Patients With Serious Advanced Illness-Clinical, Ethical, and Legal Aspects. AB - Patients with advanced illnesses sometimes request that physicians help hasten their death. Increasingly in North America and Europe, legal options allow physicians to perform this role. Among death-hastening options, the spotlight has been on physician-assisted death. However, voluntarily stopping eating and drinking (VSED) is also a course that patients may choose. Although VSED theoretically does not require physician involvement, clinician participation is critical in terms of initial assessment and ongoing management. In this review, we examine both clinical issues in assessing patients who are considering VSED and the clinical challenges that may emerge during VSED. We also explore some of the underlying ethical and legal considerations for physicians who either care for or decline to care for these patients. Physicians who care for seriously ill patients should be prepared to respond to patients' requests to participate in VSED. PMID- 29114747 TI - Web Exclusives. Annals Graphic Medicine - The "Problem" List. PMID- 29114746 TI - Distributional Learning in College Students With Developmental Language Disorder. AB - Purpose: This study examined whether college students with developmental language disorder (DLD) could use distributional information in an artificial language to learn about grammatical category membership in a way similar to their typically developing (TD) peers. Method: Seventeen college students with DLD and 17 TD college students participated in this task. We used an artificial grammar in which certain combinations of words never occurred during training. At test, participants had to use knowledge of category membership to determine which combinations were allowable in the grammar, even though they had not been heard. Results: College students with DLD performed similarly to TD peers in distinguishing grammatical from ungrammatical combinations. Conclusion: Differences in ratings between grammatical and ungrammatical items in this task suggest that college students with DLD can form grammatical categories from novel input and more broadly use distributional information. PMID- 29114748 TI - A Tale of Two Countries. PMID- 29114749 TI - A Tale of Two Countries. PMID- 29114750 TI - Using the HEART Score in Patients With Chest Pain in the Emergency Department. PMID- 29114751 TI - Using the HEART Score in Patients With Chest Pain in the Emergency Department. PMID- 29114752 TI - The Worst of Days. PMID- 29114753 TI - Beautiful. PMID- 29114756 TI - Web Exclusives. Annals Story Slam - What I Learned From Madame Secretary, Notorious RBG, and Nana. PMID- 29114754 TI - Acute Kidney Injury. AB - Acute kidney injury is a heterogeneous group of conditions characterized by a sudden decrease in glomerular filtration rate, manifested by an increase in serum creatinine concentration or oliguria, and classified by stage and cause. This type of injury occurs in approximately 20% of hospitalized patients, with major complications including volume overload, electrolyte disorders, uremic complications, and drug toxicity. Management includes specific treatments according to the underlying cause and supportive treatment to prevent and manage complications. Kidney replacement therapy is used when complications cannot be managed with medical therapy alone. Despite advances in care, the mortality rate in patients requiring kidney replacement therapy remains approximately 50%. PMID- 29114758 TI - Web Exclusives. Annals Story Slam - Becoming Dr. Mom. PMID- 29114757 TI - Web Exclusives. Annals Story Slam - A Missed Opportunity. PMID- 29114759 TI - Web Exclusives. Annals Story Slam - Pay Your Nanny Well. PMID- 29114760 TI - Web Exclusives. Annals Story Slam - Dr. Mom Gets Sick. PMID- 29114761 TI - Web Exclusives. Annals Story Slam - How Wonder Woman Became My Alter Ego. PMID- 29114762 TI - Web Exclusives. Annals Story Slam - Wonder Woman Is a Cartoon Character. PMID- 29114763 TI - Academic Vocabulary Learning in First Through Third Grade in Low-Income Schools: Effects of Automated Supplemental Instruction. AB - Purpose: This study investigated cumulative effects of language learning, specifically whether prior vocabulary knowledge or special education status moderated the effects of academic vocabulary instruction in high-poverty schools. Method: Effects of a supplemental intervention targeting academic vocabulary in first through third grades were evaluated with 241 students (6-9 years old) from low-income families, 48% of whom were retained for the 3-year study duration. Students were randomly assigned to vocabulary instruction or comparison groups. Results: Curriculum-based measures of word recognition, receptive identification, expressive labeling, and decontextualized definitions showed large effects for multiple levels of word learning. Hierarchical linear modeling revealed that students with higher initial Peabody Picture Vocabulary Test-Fourth Edition scores (Dunn & Dunn, 2007) demonstrated greater word learning, whereas students with special needs demonstrated less growth in vocabulary. Conclusion: This model of vocabulary instruction can be applied efficiently in high-poverty schools through an automated, easily implemented adjunct to reading instruction in the early grades and holds promise for reducing gaps in vocabulary development. PMID- 29114764 TI - Understanding Bilingual Word Learning: The Role of Phonotactic Probability and Phonological Neighborhood Density. AB - Purpose: Previous research has shown that the language-learning mechanism is affected by bilingualism resulting in a novel word learning advantage for bilingual speakers. However, less is known about the factors that might influence this advantage. This article reports an investigation of 2 factors: phonotactic probability and phonological neighborhood density. Method: Acquisition of 15 novel words varying in phonotactic probability and phonological neighborhood density was examined in high-proficiency, early onset, Mandarin-English bilinguals and English monolinguals. Results: Both bilinguals and monolinguals demonstrated a significant effect of phonotactic probability and phonological neighborhood density. Novel word learning improved when the phonological neighborhood density was higher; in contrast, higher phonotactic probability resulted in worse learning. Although the bilingual speakers showed significantly better novel word learning than monolingual speakers, this did not interact with phonotactic probability and phonological neighborhood density manipulations. Conclusion: Both bilingual and monolingual word learning abilities are constrained by the same learning mechanisms. However, bilingual advantages may be underpinned by more effective allocation of cognitive resources due to their dual language experience. PMID- 29114765 TI - Operator Bias Errors Are Reduced Using Standing Marker Alignment Device for Repeated Visit Studies. AB - When optical motion capture is used for motion analysis, reflective markers or a digitizer are typically used to record the location of anatomical landmarks identified through palpation. The landmarks are then used to construct anatomical coordinate systems. Failure to consistently identify landmarks through palpation over repeat tests creates artifacts in the kinematic waveforms. The purpose of this work was to improve intra- and inter-rater reliability in determining lower limb anatomical landmarks and the associated anatomical coordinate systems using a marker alignment device (MAD). The device aids the subject in recreating the same standing posture over multiple tests, and recreates the anatomical landmarks from previous static calibration trials. We tested three different raters who identified landmarks on eleven subjects. The subjects performed walking trials and their gait kinematics were analyzed with and without the device. Ankle kinematics were not improved by the device suggesting manual palpation over repeat visits is just as effective as the MAD. Intra-class correlation coefficients between gait kinematics registered to the reference static trial and registered to follow-up static trials with and without the device were improved between 1% and 33% when the device was used. Importantly, out-of-plane hip and knee kinematics showed the greatest improvements in repeatability. These results suggest that the device is well suited to reducing palpation artifact during repeat visits to the gait lab. PMID- 29114766 TI - Auditory Attentional Set-Shifting and Inhibition in Children Who Stutter. AB - Purpose: The purpose of this study was to investigate whether previously reported parental questionnaire-based differences in attentional shifting and inhibitory control (AS and IC; Eggers, De Nil, & Van den Bergh, 2010) would be supported by direct measurement of AS and IC using a computer task. Method: Participants were 16 Finnish children who stutter (CWS; mean age = 7.06 years) and 16 Finnish children who do not stutter (mean age = 7.05 years). Participants were matched on age (+/-8 months) and gender. AS and IC were assessed by the auditory set shifting task of the Amsterdam Neuropsychological Tasks (De Sonneville, 2009). Results: No group differences were found for the speed of auditory AS or IC. However, CWS, as a group, scored significantly lower on the accuracy (error percentage) of auditory AS. In addition, CWS, compared with the children who do not stutter, showed a higher increase in error percentages under AS and IC conditions. Conclusions: The findings on error percentages partly corroborate earlier questionnaire-based findings showing difficulties in CWS on AS and IC. Moreover, it also seems to imply that CWS are less able to slow down their responses to achieve higher accuracy rates. PMID- 29114767 TI - Age-Related Variability in Tongue Pressure Patterns for Maximum Isometric and Saliva Swallowing Tasks. AB - Purpose: The ability to generate tongue pressure plays a major role in bolus transport in swallowing. In studies of motor control, stability or variability of movement is a feature that changes with age, disease, task complexity, and perturbation. In this study, we explored whether age and tongue strength influence the stability of the tongue pressure generation pattern during isometric and swallowing tasks in healthy volunteers. Method: Tongue pressure data, collected using the Iowa Oral Performance Instrument, were analyzed from 84 participants in sex-balanced and decade age-group strata. Tasks included maximum anterior and posterior isometric pressures and regular-effort saliva swallows. The cyclic spatiotemporal index (cSTI) was used to capture stability (vs. variability) in patterns of pressure generation. Mixed-model repeated measures analyses of covariance were performed separately for each task (anterior and posterior isometric pressures, saliva swallows) with between-participant factors of age group and sex, a within-participant factor of task repetition, and a continuous covariate of tongue strength. Results: Neither age group nor sex effects were found. There was no significant relationship between tongue strength and the cSTI on the anterior isometric tongue pressure task (r = -.11). For the posterior isometric tongue pressure task, a significant negative correlation (r = -.395) was found between tongue strength and the cSTI. The opposite pattern of a significant positive correlation (r = .29) between tongue strength and the cSTI was seen for the saliva swallow task. Conclusions: Tongue pressure generation patterns appear highly stable across repeated maximum isometric and saliva swallow tasks, despite advancing age. Greater pattern variability is seen with weaker posterior isometric pressures. Overall, saliva swallows had the lowest pressure amplitudes and highest pressure pattern variability as measured by the cSTI. PMID- 29114768 TI - The Effect of Hand Gesture Cues Within the Treatment of /r/ for a College-Aged Adult With Persisting Childhood Apraxia of Speech. AB - Purpose: Despite the widespread use of hand movements as visual and kinesthetic cues to facilitate accurate speech produced by individuals with speech sound disorders (SSDs), no experimental investigation of gestural cues that mimic that spatiotemporal parameters of speech sounds (e.g., holding fingers and thumb together and "popping" them to cue /p/) currently exists. The purpose of this study was to examine the effectiveness of manual mimicry cues within a multisensory intervention of persisting childhood apraxia of speech (CAS). Method: A single-subject ABAB withdrawal design was implemented to assess the accuracy of vowel + /r/ combinations produced by a 21-year-old woman with persisting CAS. The effect of manual mimicry gestures paired with multisensory therapy consisting of verbal instructions and visual modeling was assessed via clinician and naive listener ratings of target sound accuracy. Results: According to the perceptual ratings of the treating clinician and 28 naive listeners, the participant demonstrated improved speech sound accuracy as a function of the manual mimicry/multisensory therapy. Conclusions: These data offer preliminary support for the incorporation of gestural cues in therapy for CAS and other SSDs. The need for continued research on the interaction of speech and manual movements for individuals with SSDs is discussed. PMID- 29114769 TI - Developmental Associations Between Working Memory and Language in Children With Specific Language Impairment: A Longitudinal Study. AB - Purpose: This longitudinal study examined differences in the development of working memory (WM) between children with specific language impairment (SLI) and typically developing (TD) children. Further, it explored to what extent language at ages 7-8 years could be predicted by measures of language and/or WM at ages 4 5 years. Method: Thirty children with SLI and 33 TD children who were previously examined on measures of WM and language at ages 4-5 years (T1) were reexamined at ages 7-8 years (T2). Results: The developmental course of WM was mostly similar for the two groups; only the development of the verbal storage component differed. At T1, children with SLI performed significantly below their TD peers on all components of WM (verbal storage, verbal central executive [CE], visuospatial storage, and visuospatial CE), whereas at T2, the differences for the visuospatial components were no longer significant when age and intelligence were taken into account. Hierarchical regression showed language and verbal CE at T1 to be significant predictors of language at T2, with no differences in the developmental associations between language and WM for the two groups. Conclusions: The results of this study suggest that particularly verbal CE is of importance for the acquisition of linguistic skills. PMID- 29114770 TI - Infant-Directed Speech Enhances Attention to Speech in Deaf Infants With Cochlear Implants. AB - Purpose: Both theoretical models of infant language acquisition and empirical studies posit important roles for attention to speech in early language development. However, deaf infants with cochlear implants (CIs) show reduced attention to speech as compared with their peers with normal hearing (NH; Horn, Davis, Pisoni, & Miyamoto, 2005; Houston, Pisoni, Kirk, Ying, & Miyamoto, 2003), which may affect their acquisition of spoken language. The main purpose of this study was to determine (a) whether infant-directed speech (IDS) enhances attention to speech in infants with CIs, as compared with adult-directed speech (ADS), and (b) whether the degree to which infants with CIs pay attention to IDS is associated with later language outcomes. Method: We tested 46 infants-12 prelingually deaf infants who received CIs before 24 months of age and had 12 months of hearing experience (CI group), 22 hearing experience-matched infants with NH (NH-HEM group), and 12 chronological age-matched infants with NH (NH-CAM group)-on their listening preference in 3 randomized blocks: IDS versus silence, ADS versus silence, and IDS versus ADS. We administered the Preschool Language Scale-Fourth Edition (PLS-4; Zimmerman, Steiner, & Pond, 2002) approximately 18 months after implantation to assess receptive and expressive language skills of infants with CIs. Results: In the IDS versus silence block, all 3 groups looked significantly longer to IDS than to silence. In the ADS versus silence block, both the NH-HEM and NH-CAM groups looked significantly longer to ADS relative to silence; however, the CI group did not show any preference. In the IDS versus ADS block, whereas both the CI and NH-HEM groups preferred IDS over ADS, the NH-CAM group looked equally long to IDS and ADS. IDS preference quotient among infants with CIs in the IDS versus ADS block was associated with PLS-4 Auditory Comprehension and PLS-4 Expressive Communication measures. Conclusions: Two major findings emerge: (a) IDS enhances attention to speech in deaf infants with CIs; (b) the degree of IDS preference over ADS relates to language development in infants with CIs. These results support a focus on input in developing intervention strategies to mitigate the effects of hearing loss on language development in infants with hearing loss. PMID- 29114771 TI - South Asian Adults' Performance on Executive Function Tests. AB - Purpose: This study compared the performance of South Asian and White adults on the Behavioural Assessment of the Dysexecutive Syndrome (BADS; Wilson, Alderman, Burgess, Emslie, & Evans, 1996) and the Functional Assessment of Verbal Reasoning and Executive Strategies (FAVRES; MacDonald, 2005), tests that can be used by speech-language pathologists to assess executive function (EF). Method: Twenty South Asian and 20 White participants were administered the BADS and FAVRES. Raw scores were converted to profile scores on the BADS and to standard scores on the FAVRES. Analysis of covariance statistics were calculated to compare EF test performance. Results: South Asian and White participants did not demonstrate significant performance differences on the BADS. On the FAVRES, Whites had significantly higher accuracy scores on 2 of the 4 subtests and significantly higher rationale scores on 3 subtests. South Asian adults who completed all of their formal education in India had lower accuracy and rationale scores on 2 of the 4 subtests versus South Asian adults who completed at least some of their formal education in North America. No significant differences occurred on the Time scores for any subtest or on the overall Reasoning score. Conclusions: Performance differences on EF tests may exist between South Asian and White adults. Further research is necessary to determine the impact of cultural and linguistic differences on EF test performance in South Asian adults. PMID- 29114772 TI - Development of a Single-Degree-of-Freedom Mechanical Model for Predicting Strain Based Brain Injury Responses. AB - Linking head kinematics to injury risk has been the focus of numerous brain injury criteria. Although many early forms were developed using mechanics principles, recent criteria have been developed using empirical methods based on subsets of head impact data. In this study, a single-degree-of-freedom (sDOF) mechanical analog was developed to parametrically investigate the link between rotational head kinematics and brain deformation. Model efficacy was assessed by comparing the maximum magnitude of displacement to strain-based brain injury predictors from finite element (FE) human head models. A series of idealized rotational pulses covering a broad range of acceleration and velocity magnitudes (0.1-15 krad/s2 and 1-100 rad/s) with durations between 1 and 3000 ms were applied to the mechanical models about each axis of the head. Results show that brain deformation magnitude is governed by three categories of rotational head motion each distinguished by the duration of the pulse relative to the brain's natural period: for short-duration pulses, maximum brain deformation depended primarily on angular velocity magnitude; for long-duration pulses, brain deformation depended primarily on angular acceleration magnitude; and for pulses relatively close to the natural period, brain deformation depended on both velocity and acceleration magnitudes. These results suggest that brain deformation mechanics can be adequately explained by simple mechanical systems, since FE model responses and experimental brain injury tolerances exhibited similar patterns to the sDOF model. Finally, the sDOF model was the best correlate to strain-based responses and highlighted fundamental limitations with existing rotational-based brain injury metrics. PMID- 29114773 TI - The Impact of Expiratory Muscle Strength Training on Speech Breathing in Individuals With Parkinson's Disease: A Preliminary Study. AB - Purpose: The purpose of this study was to examine the impact of expiratory muscle strength training on speech breathing and functional speech outcomes in individuals with Parkinson's disease (PD). Method: Twelve individuals with PD were seen once a week for 8 weeks: 4 pretraining (baseline) sessions followed by a 4-week training period. Posttraining data were collected at the end of the 4th week of training. Maximum expiratory pressure, an indicator of expiratory muscle strength, and lung volume at speech initiation were the primary outcome measures. Secondary outcomes included lung volume at speech termination, lung volume excursion, utterance length, and vocal intensity. Data were collected during a spontaneous speech sample. Individual effect sizes > 1 were considered significant. Results: Maximum expiratory pressure increased in a majority of participants after training. Training resulted in 2 main respiratory patterns: increasing or decreasing lung volume initiation. Lung volume termination and excursion, utterance length, and vocal loudness were not consistently altered by training. Conclusions: Preliminary evidence suggests that the direct physiologic intervention of the respiratory system via expiratory muscle strength training improves speech breathing in individuals with PD, with participants using more typical lung volumes for speech following treatment. PMID- 29114774 TI - Intensive Treatment for Persisting Rhotic Distortions: A Case Series. AB - Purpose: The study explored changes in accuracy of American English rhotics as a result of an intensive 1-week therapy program for adolescents and young adults with residual speech sound errors that had not resolved with previous therapy. Method: Four case reports are presented of individuals aged 13, 17, 21, and 22 years with residual /r/ distortions. Each participant attended a 1-week intensive program consisting of pretreatment assessments, 14 hr of therapy, and posttreatment assessment. Treatment sessions included structured motor-based practice, ultrasound visual feedback of the tongue, and auditory speech perception training. To assess generalization, untreated words and sentences with rhotics were recorded before and after therapy; these were rated by listeners who were blind to when the recordings were taken. Results: All participants showed measurable and statistically significant improvement in speech sound accuracy. Averaged across the 4 participants, rhotic accuracy at the word level improved from 35% to 83%. At the sentence level, rhotic accuracy increased from 11% pretreatment to 66% posttreatment in 1 week. Conclusion: The promise of an intensive treatment program that includes motor-based practice, biofeedback, and auditory perception training is illustrated by the case presentations in which substantial improvements in speech sound accuracy were observed. Supplemental Materials: https://doi.org/10.23641/asha.5561254. PMID- 29114775 TI - Development of Pointing Gestures in Children With Typical and Delayed Language Acquisition. AB - Purpose: This longitudinal study compared the development of hand and index finger pointing in children with typical language development (TD) and children with language delay (LD). First, we examined whether the number and the form of pointing gestures during the second year of life are potential indicators of later LD. Second, we analyzed the influence of caregivers' gestural and verbal input on children's communicative development. Method: Thirty children with TD and 10 children with LD were observed together with their primary caregivers in a seminatural setting in 5 sessions between the ages of 12 and 21 months. Language skills were assessed at 24 months. Results: Compared with children with TD, children with LD used fewer index-finger points at 12 and 14 months but more pointing gestures in total at 21 months. There were no significant differences in verbal or gestural input between caregivers of children with or without LD. Conclusions: Using more index-finger points at the beginning of the second year of life is associated with TD, whereas using more pointing gestures at the end of the second year of life is associated with delayed acquisition. Neither the verbal nor gestural input of caregivers accounted for differences in children's skills. PMID- 29114779 TI - Advance Directives for Dementia: Meeting a Unique Challenge. PMID- 29114778 TI - Long-term Sustainability of Diabetes Prevention Approaches: A Systematic Review and Meta-analysis of Randomized Clinical Trials. AB - Importance: Diabetes prevention is imperative to slow worldwide growth of diabetes-related morbidity and mortality. Yet the long-term efficacy of prevention strategies remains unknown. Objective: To estimate aggregate long-term effects of different diabetes prevention strategies on diabetes incidence. Data Sources: Systematic searches of MEDLINE, EMBASE, Cochrane Library, and Web of Science databases. The initial search was conducted on January 14, 2014, and was updated on February 20, 2015. Search terms included prediabetes, primary prevention, and risk reduction. Study Selection: Eligible randomized clinical trials evaluated lifestyle modification (LSM) and medication interventions (>6 months) for diabetes prevention in adults (age >=18 years) at risk for diabetes, reporting between-group differences in diabetes incidence, published between January 1, 1990, and January 1, 2015. Studies testing alternative therapies and bariatric surgery, as well as those involving participants with gestational diabetes, type 1 or 2 diabetes, and metabolic syndrome, were excluded. Data Extraction and Synthesis: Reviewers extracted the number of diabetes cases at the end of active intervention in treatment and control groups. Random-effects meta analyses were used to obtain pooled relative risks (RRs), and reported incidence rates were used to compute pooled risk differences (RDs). Main Outcomes and Measures: The main outcome was aggregate RRs of diabetes in treatment vs control participants. Treatment subtypes (ie, LSM components, medication classes) were stratified. To estimate sustainability, post-washout and follow-up RRs for medications and LSM interventions, respectively, were examined. Results: Forty three studies were included and pooled in meta-analysis (49 029 participants; mean [SD] age, 57.3 [8.7] years; 48.0% [n = 23 549] men): 19 tested medications; 19 evaluated LSM, and 5 tested combined medications and LSM. At the end of the active intervention (range, 0.5-6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54-0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54-0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8-6.3) cases per 100 person-years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7-9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60-0.86); medication studies (mean follow-up, 17 weeks; range, 2-52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79-1.14). Conclusions and Relevance: In adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence. Medication effects were short lived. The LSM interventions were sustained for several years; however, their effects declined with time, suggesting that interventions to preserve effects are needed. PMID- 29114780 TI - Epizootic Outbreak of Yellow Fever Virus and Risk for Human Disease in Salvador, Brazil. PMID- 29114782 TI - Ensuring the Integrity of the National Resident Matching Program. PMID- 29114784 TI - Fade Away. PMID- 29114785 TI - Natural and Unnatural History. PMID- 29114781 TI - Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial. AB - Background: Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation. Objective: To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self administration versus direct observation. Design: An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711). Setting: Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa. Participants: 1002 adults (aged >=18 years) recommended for treatment of latent tuberculosis infection. Intervention: Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring. Measurements: The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events. Results: Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups. Limitation: Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically. Conclusion: These results support using self-administered, once weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible. Primary Funding Source: Centers for Disease Control and Prevention. PMID- 29114786 TI - Increasing Survival in Patients With Congenital Heart Disease-A Glass Half Full or Half Empty? PMID- 29114787 TI - Maternal beta-Blocker Use and Fetal Cardiac Anomalies. PMID- 29114788 TI - Thyroid Dysfunction in Torsades de Pointes. PMID- 29114789 TI - Intensive Blood Pressure Control in Autosomal Dominant Polycystic Kidney Disease How Safe Is It? PMID- 29114790 TI - The Need for Better Data Breach Statistics. PMID- 29114791 TI - Considerations for County-Level Inequalities in Life Expectancy. PMID- 29114792 TI - Perplexing Conclusions Concerning Heat-Not-Burn Tobacco Cigarettes. PMID- 29114793 TI - Perplexing Conclusions Concerning Heat-Not-Burn Tobacco Cigarettes. PMID- 29114794 TI - Sample Size Matters When Drawing Conclusions on Alternate-Day Fasting Diet. PMID- 29114795 TI - Women Also Use 5alpha-Reductase Inhibitors. PMID- 29114796 TI - Maternal beta-Blocker Use and Fetal Cardiac Anomalies-Reply. PMID- 29114797 TI - Thyroid Dysfunction in Torsades de Pointes-Reply. PMID- 29114798 TI - Intensive Blood Pressure Control in Autosomal Dominant Polycystic Kidney Disease How Safe Is It?-Reply. PMID- 29114799 TI - The Need for Better Data Breach Statistics-Reply. PMID- 29114800 TI - Considerations for County-Level Inequalities in Life Expectancy-Reply. PMID- 29114801 TI - Perplexing Conclusions Concerning Heat-Not-Burn Tobacco Cigarettes-Reply. PMID- 29114802 TI - Sample Size Matters When Drawing Conclusions on Alternate-Day Fasting Diet-Reply. PMID- 29114803 TI - Women Also Use 5alpha-Reductase Inhibitors-Reply. PMID- 29114805 TI - Effect of stimulus configuration on crowding in strabismic amblyopia. AB - Foveal vision in strabismic amblyopia can show increased levels of crowding, akin to typical peripheral vision. Target-flanker similarity and visual-acuity test configuration may cause the magnitude of crowding to vary in strabismic amblyopia. We used custom-designed visual acuity tests to investigate crowding in observers with strabismic amblyopia. LogMAR was measured monocularly in both eyes of 11 adults with strabismic or mixed strabismic/anisometropic amblyopia using custom-designed letter tests. The tests used single-letter and linear formats with either bar or letter flankers to introduce crowding. Tests were presented monocularly on a high-resolution display at a test distance of 4 m, using standardized instructions. For each condition, five letters of each size were shown; testing continued until three letters of a given size were named incorrectly. Uncrowded logMAR was subtracted from logMAR in each of the crowded tests to highlight the crowding effect. Repeated-measures ANOVA showed that letter flankers and linear presentation individually resulted in poorer performance in the amblyopic eyes (respectively, mean normalized logMAR = 0.29, SE = 0.07, mean normalized logMAR = 0.27, SE = 0.07; p < 0.05) and together had an additive effect (mean = 0.42, SE = 0.09, p < 0.001). There was no difference across the tests in the fellow eyes (p > 0.05). Both linear presentation and letter rather than bar flankers increase crowding in the amblyopic eyes of people with strabismic amblyopia. These results suggest the influence of more than one mechanism contributing to crowding in linear visual-acuity charts with letter flankers. PMID- 29114806 TI - Spatiotemporal feature integration shapes approximate numerical processing. AB - Numerosity perception involves a complex cascade of processing stages comprising an early sensory representation stage followed by a later stage providing a conceptual representation of numerical magnitude. While much recent work has focused on understanding how nonnumerical spatial features (e.g., density, area) influence numerosity perception in this processing cascade, little is known about how the spatiotemporal properties of the stimuli affect numerosity processing. Whether numerosity information is integrated over space and time in the processing cascade is an important question as it can provide insights into how the system dedicated for numerosity interacts with other perceptual systems. To address these issues, in four independent experiments, we asked participants to judge the numerosities of various different kinds of dynamically presented dot arrays, such as dots randomly changing in their locations, moving in smooth trajectories, or flickering on and off. The results revealed a systematic overestimation of dynamically presented dot arrays, which implicates the existence of spatiotemporal integration mechanisms, both at the early sensory representation stage and the later conceptual representation stage. The results also revealed the influence of motion and color processing areas on numerosity processing. The findings thus provide empirical evidence that numerosity perception arises from a complex interaction between multiple perceptual mechanisms in the visual stream, and that it is shaped by the integration of spatiotemporal properties of visual stimuli. PMID- 29114807 TI - Linear-nonlinear models of the red-green chromatic pathway. AB - The mean hue of flickering waveforms comprising only the first two harmonics depends on their temporal alignment. We evaluate explanatory models of this hue shift effect using previous data obtained using L- and M-cone-isolating stimuli together with chromatic sensitivity and hue discrimination data. The key questions concerned what type of nonlinearity produced the hue shifts, and where the nonlinearities lay with respect to the early band-pass and late low-pass temporal filters in the chromatic pathways. We developed two plausible models: (a) a slew-rate limited nonlinearity that follows both early and late filters, and (b) a half-wave rectifying nonlinearity-consistent with the splitting of the visual input into ON- and OFF-channels-that lies between the early and late filters followed by a compressive nonlinearity that lies after the late filter. PMID- 29114808 TI - Preferential processing of cardinal over oblique orientations in human vision. AB - The oblique effect-poorer performance when contours are in oblique meridians-is here extended from the discrimination of line-orientation to the tilt illusion and to the detection and contextual induction of curvature. The distinction is made between a contour's susceptibility to contextual perturbation and its capacity to induce such perturbation, for which the oblique effect is only about one half. That the cardinal/oblique superiority is retained for the orientation of illusory borders and for the implicit orientation of shapes lacking explicit rectilinear delineation has implications for its neural substrate. To the extent that a geometrical-visual illusion, such as Poggendorff's or Hering's, depends on interaction in the domain of contour orientation, it manifests a corresponding orientational anisotropy. On the other hand, visual functions that govern whether and how well a boundary is visible are invariant with orientation. PMID- 29114809 TI - Portraits in Health Policy. PMID- 29114810 TI - Gene Editing Provides Clues to Why Cancer Immunotherapy Often Fails. PMID- 29114811 TI - Interpretation of Urine Drug Screens: Metabolites and Impurities. PMID- 29114812 TI - Evidence Supports Action to Prevent Injurious Falls in Older Adults. PMID- 29114813 TI - Opioid vs Nonopioid Acute Pain Management in the Emergency Department. PMID- 29114814 TI - Factors Associated With Increased US Health Care Spending: Implications for Controlling Health Care Costs. PMID- 29114816 TI - First Biosimilar to Treat Cancer. PMID- 29114815 TI - Maternal Use of Antiepileptic Agents During Pregnancy and Major Congenital Malformations in Children. AB - Clinical Question: Is maternal use of antiepileptic drugs during pregnancy associated with major congenital malformations in children? Bottom Line: Certain antiepileptic drugs were associated with increased rates of congenital malformations (eg, spina bifida, cardiac anomalies). Lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies). PMID- 29114818 TI - Intravenous Lymphoma Drug Approved. PMID- 29114817 TI - Duodenoscope Design Aimed at Infection Prevention. PMID- 29114819 TI - Screening for Chronic Obstructive Pulmonary Disease. PMID- 29114821 TI - Republicans Will Own Whatever Happens to the ACA and Health Care Reform. PMID- 29114822 TI - Care of the Aged: Malford W. Thewlis, M.D., Wakefield, R. I. PMID- 29114823 TI - Labeling Accuracy of Cannabidiol Extracts Sold Online. PMID- 29114824 TI - Persistence of Penicillin Allergy. PMID- 29114825 TI - Challenges in Implementing Personalized Care Planning. PMID- 29114826 TI - Alendronate and Hip Fracture in Patients Using Glucocorticoids. PMID- 29114827 TI - Persistence of Penicillin Allergy-Reply. PMID- 29114828 TI - Challenges in Implementing Personalized Care Planning-Reply. PMID- 29114829 TI - Alendronate and Hip Fracture in Patients Using Glucocorticoids-Reply. PMID- 29114830 TI - Comparisons of Interventions for Preventing Falls in Older Adults: A Systematic Review and Meta-analysis. AB - Importance: Falls result in substantial burden for patients and health care systems, and given the aging of the population worldwide, the incidence of falls continues to rise. Objective: To assess the potential effectiveness of interventions for preventing falls. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Ageline databases from inception until April 2017. Reference lists of included studies were scanned. Study Selection: Randomized clinical trials (RCTs) of fall-prevention interventions for participants aged 65 years and older. Data Extraction and Synthesis: Pairs of reviewers independently screened the studies, abstracted data, and appraised risk of bias. Pairwise meta-analysis and network meta-analysis were conducted. Main Outcomes and Measures: Injurious falls and fall-related hospitalizations. Results: A total of 283 RCTs (159 910 participants; mean age, 78.1 years; 74% women) were included after screening of 10 650 titles and abstracts and 1210 full text articles. Network meta-analysis (including 54 RCTs, 41 596 participants, 39 interventions plus usual care) suggested that the following interventions, when compared with usual care, were associated with reductions in injurious falls: exercise (odds ratio [OR], 0.51 [95% CI, 0.33 to 0.79]; absolute risk difference [ARD], -0.67 [95% CI, -1.10 to -0.24]); combined exercise and vision assessment and treatment (OR, 0.17 [95% CI, 0.07 to 0.38]; ARD, -1.79 [95% CI, -2.63 to 0.96]); combined exercise, vision assessment and treatment, and environmental assessment and modification (OR, 0.30 [95% CI, 0.13 to 0.70]; ARD, -1.19 [95% CI, -2.04 to -0.35]); and combined clinic-level quality improvement strategies (eg, case management), multifactorial assessment and treatment (eg, comprehensive geriatric assessment), calcium supplementation, and vitamin D supplementation (OR, 0.12 [95% CI, 0.03 to 0.55]; ARD, -2.08 [95% CI, -3.56 to -0.60]). Pairwise meta-analyses for fall-related hospitalizations (2 RCTs; 516 participants) showed no significant association between combined clinic- and patient-level quality improvement strategies and multifactorial assessment and treatment relative to usual care (OR, 0.78 [95% CI, 0.33 to 1.81]). Conclusions and Relevance: Exercise alone and various combinations of interventions were associated with lower risk of injurious falls compared with usual care. Choice of fall-prevention intervention may depend on patient and caregiver values and preferences. PMID- 29114831 TI - Factors Associated With Increases in US Health Care Spending, 1996-2013. AB - Importance: Health care spending in the United States increased substantially from 1995 to 2015 and comprised 17.8% of the economy in 2015. Understanding the relationship between known factors and spending increases over time could inform policy efforts to contain future spending growth. Objective: To quantify changes in spending associated with 5 fundamental factors related to health care spending in the United States: population size, population age structure, disease prevalence or incidence, service utilization, and service price and intensity. Design and Setting: Data on the 5 factors from 1996 through 2013 were extracted for 155 health conditions, 36 age and sex groups, and 6 types of care from the Global Burden of Disease 2015 study and the Institute for Health Metrics and Evaluation's US Disease Expenditure 2013 project. Decomposition analysis was performed to estimate the association between changes in these factors and changes in health care spending and to estimate the variability across health conditions and types of care. Exposures: Change in population size, population aging, disease prevalence or incidence, service utilization, or service price and intensity. Main Outcomes and Measures: Change in health care spending from 1996 through 2013. Results: After adjustments for price inflation, annual health care spending on inpatient, ambulatory, retail pharmaceutical, nursing facility, emergency department, and dental care increased by $933.5 billion between 1996 and 2013, from $1.2 trillion to $2.1 trillion. Increases in US population size were associated with a 23.1% (uncertainty interval [UI], 23.1%-23.1%), or $269.5 (UI, $269.0-$270.0) billion, spending increase; aging of the population was associated with an 11.6% (UI, 11.4%-11.8%), or $135.7 (UI, $133.3-$137.7) billion, spending increase. Changes in disease prevalence or incidence were associated with spending reductions of 2.4% (UI, 0.9%-3.8%), or $28.2 (UI, $10.5 $44.4) billion, whereas changes in service utilization were not associated with a statistically significant change in spending. Changes in service price and intensity were associated with a 50.0% (UI, 45.0%-55.0%), or $583.5 (UI, $525.2 $641.4) billion, spending increase. The influence of these 5 factors varied by health condition and type of care. For example, the increase in annual diabetes spending between 1996 and 2013 was $64.4 (UI, $57.9-$70.6) billion; $44.4 (UI, $38.7-$49.6) billion of this increase was pharmaceutical spending. Conclusions and Relevance: Increases in US health care spending from 1996 through 2013 were largely related to increases in health care service price and intensity but were also positively associated with population growth and aging and negatively associated with disease prevalence or incidence. Understanding these factors and their variability across health conditions and types of care may inform policy efforts to contain health care spending. PMID- 29114832 TI - Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease. AB - Importance: An increased risk of lymphoma has been reported among patients receiving thiopurines for inflammatory bowel disease (IBD). The risk of lymphoma associated with anti-tumor necrosis factor (TNF) agents either alone or in combination with thiopurines is uncertain. Objective: To assess the risk of lymphoma associated with thiopurines and anti-TNF agents, used alone or in combination, for the management of IBD. Design, Setting, and Participants: Nationwide cohort study based on French National Health Insurance databases. Patients aged 18 years or older identified with IBD were included from January 1, 2009, through December 31, 2013, and followed up until December 31, 2015. Exposures: At each time of the follow-up, patients were categorized as being exposed to thiopurine monotherapy, anti-TNF monotherapy, or combination therapy, or being unexposed. Main Outcomes and Measures: The primary outcome was incident lymphoma. Results: Among the 189 289 patients included (54% women; median age, 43 years [interquartile range, 32-56 years]) and followed up for a median of 6.7 years, 123 069 were never exposed during follow-up, 50 405 were exposed to thiopurine monotherapy, 30 294 to anti-TNF monotherapy, and 14 229 to combination therapy. Overall, 336 lymphoma cases occurred: 220 in unexposed patients (incidence rate [IR] per 1000 person-years, 0.26; 95% CI, 0.23-0.29), 70 in patients exposed to thiopurine monotherapy (IR, 0.54; 95% CI, 0.41-0.67), 32 in patients exposed to anti-TNF monotherapy (IR, 0.41; 95% CI, 0.27-0.55), and 14 in patients exposed to combination therapy (IR, 0.95; 95% CI, 0.45-1.45). In a multivariable Cox model, compared with unexposed patients, the risk of lymphoma was higher among those exposed to thiopurine monotherapy (adjusted hazard ratio [aHR], 2.60; 95% CI, 1.96-3.44; P < .001), anti-TNF monotherapy (aHR, 2.41; 95% CI, 1.60-3.64; P < .001), or combination therapy (aHR, 6.11; 95% CI, 3.46-10.8; P < .001). The risk was higher in patients exposed to combination therapy vs those exposed to thiopurine monotherapy (aHR, 2.35; 95% CI, 1.31-4.22; P < .001) or anti-TNF monotherapy (aHR, 2.53; 95% CI, 1.35-4.77; P < .001). Conclusions and Relevance: Among adults with IBD, the use of thiopurine monotherapy or anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma compared with exposure to neither medication, and this risk was higher with combination therapy than with each of these treatments used alone. These findings may inform decisions regarding the benefits and risks of treatment. PMID- 29114834 TI - Polypharmacy. PMID- 29114833 TI - Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department: A Randomized Clinical Trial. AB - Importance: The choice of analgesic to treat acute pain in the emergency department (ED) lacks a clear evidence base. The combination of ibuprofen and acetaminophen (paracetamol) may represent a viable nonopioid alternative. Objectives: To compare the efficacy of 4 oral analgesics. Design, Settings, and Participants: Randomized clinical trial conducted at 2 urban EDs in the Bronx, New York, that included 416 patients aged 21 to 64 years with moderate to severe acute extremity pain enrolled from July 2015 to August 2016. Interventions: Participants (104 per each combination analgesic group) received 400 mg of ibuprofen and 1000 mg of acetaminophen; 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen. Main Outcomes and Measures: The primary outcome was the between-group difference in decline in pain 2 hours after ingestion. Pain intensity was assessed using an 11-point numerical rating scale (NRS), in which 0 indicates no pain and 10 indicates the worst possible pain. The predefined minimum clinically important difference was 1.3 on the NRS. Analysis of variance was used to test the overall between-group difference at P = .05 and 99.2% CIs adjusted for multiple pairwise comparisons. Results: Of 416 patients randomized, 411 were analyzed (mean [SD] age, 37 [12] years; 199 [48%] women; 247 [60%] Latino). The baseline mean NRS pain score was 8.7 (SD, 1.3). At 2 hours, the mean NRS pain score decreased by 4.3 (95% CI, 3.6 to 4.9) in the ibuprofen and acetaminophen group; by 4.4 (95% CI, 3.7 to 5.0) in the oxycodone and acetaminophen group; by 3.5 (95% CI, 2.9 to 4.2) in the hydrocodone and acetaminophen group; and by 3.9 (95% CI, 3.2 to 4.5) in the codeine and acetaminophen group (P = .053). The largest difference in decline in the NRS pain score from baseline to 2 hours was between the oxycodone and acetaminophen group and the hydrocodone and acetaminophen group (0.9; 99.2% CI, -0.1 to 1.8), which was less than the minimum clinically important difference in NRS pain score of 1.3. Adverse events were not assessed. Conclusions and Relevance: For patients presenting to the ED with acute extremity pain, there were no statistically significant or clinically important differences in pain reduction at 2 hours among single-dose treatment with ibuprofen and acetaminophen or with 3 different opioid and acetaminophen combination analgesics. Further research to assess adverse events and other dosing may be warranted. Trial Registration: clinicaltrials.gov Identifier: NCT02455518. PMID- 29114836 TI - Despite My Best Intentions. PMID- 29114838 TI - Optical Coherence Tomography Angiography Macular and Peripapillary Vessel Perfusion Density in Healthy Subjects, Glaucoma Suspects, and Glaucoma Patients. AB - Purpose: To evaluate macular and peripapillary vessel perfusion density (VD) in glaucoma suspects (GS) and glaucoma patients; to correlate ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thicknesses with macular and peripapillary VD; and to evaluate the diagnostic accuracy of the structural and vascular parameters. Methods: A consecutive series of GS, glaucoma patients, and healthy subjects was prospectively recruited from July 1, 2016, to January 31, 2017. All subjects underwent standard automated perimetry, spectral domain optical coherence tomography (OCT), and 6 * 6-mm optical coherence tomography angiography (OCT-A) centered on the fovea and optic nerve. Results: Forty controls, 40 GS, and 40 glaucoma patients were enrolled. Peripapillary RNFL, GCIPL, and macular RNFL thicknesses significantly decreased in the glaucoma group compared to controls and GS (P < 0.01). Peripapillary VD in average and in the superior and inferior quadrants decreased in the glaucoma group (P <= 0.001); conversely, macular VD was not statistically different across groups (P > 0.05). At the peripapillary area, a correlation between RNFL thickness and VD was found; conversely, no statistically significant correlation was found between GCIPL thicknesses and macular VD (all P > 0.05) in all groups. Peripapillary RNFL and GCIPL showed higher diagnostic capacity compared to peripapillary and macular VDs. Conclusions: Structural damage is evident both in the peripapillary and in macular areas. Vascular damage seems to be less prominent, as it was seen only for the glaucoma group and at the radial peripapillary plexus. Diagnostic abilities are excellent for structural variables, less so but still good for peripapillary VD, and poor for macular VD. PMID- 29114839 TI - Novel Complex ABCA4 Alleles in Brazilian Patients With Stargardt Disease: Genotype-Phenotype Correlation. AB - Purpose: To analyze the presence of complex alleles of the ABCA4 gene in Brazilian patients with Stargardt disease and to assess the correlation with clinical features. Methods: This was an observational cross-sectional study. Patients with a diagnosis of Stargardt disease who presented three pathogenic variants of the ABCA4 gene or who had variants previously described as complex alleles were included. The relatives of these probands were evaluated in the segregation analysis. The patients were evaluated based on age at symptom onset and visual acuity, and the clinical characteristics were classified according to the findings observed on autofluorescence examination. Results: Among the 47 families analyzed, approximately 30% (14/47) presented complex alleles. The segregation analysis in 14 families with cases of Stargardt disease identified three novel complex alleles and one previously described complex allele. The known complex allele p.[Leu541Pro; Ala1038Val] was identified in two families. The novel complex alleles identified were p.[Leu541Pro; Arg1443His] in five families, p.[Ser1642Arg; Val1682_Val1686del] in seven families, and p.[Pro1761Arg; Arg2106Cys] in one family. Furthermore, four new variants (p.Lys22Asn, p.Asp915Asn, p.Glu1447Val, and p.Pro1761Arg) were identified in the second allele of the ABCA4 gene. Conclusions: Segregation analysis is important in order to confirm the molecular diagnosis of patients with Stargardt disease, given the frequency of complex alleles in the ABCA4 gene. The various pathogenic variation combinations observed in this study were associated with different phenotypes. PMID- 29114840 TI - Fixational Saccades and Their Relation to Fixation Instability in Strabismic Monkeys. AB - Purpose: To evaluate the contribution of fixational saccades toward fixation instability in strabismic monkeys. Methods: Binocular eye movements were measured as six experimental monkeys (five strabismic monkeys and one monkey with downbeat nystagmus) and one normal monkey fixated targets of two shapes (Optotype, Disk) and two sizes (0.5 degrees , 2 degrees ) during monocular and binocular viewing. Fixational saccades were detected using an unsupervised clustering algorithm. Results: When compared with the normal monkey, amplitude and frequency of fixational saccades in both the viewing and nonviewing eye were greater in 3 of 5 strabismic monkeys (1-way ANOVA on ranks P < 0.001; median amplitude in the normal monkey viewing eye: 0.33 degrees ; experimental animals: median amplitude range 0.20-0.82 degrees ; median frequency in the normal monkey: 1.35/s; experimental animals: median frequency range 1.3-3.7/s). Increase in frequency of fixational saccades was largely due to quick phases of ongoing nystagmus. Fixational saccade amplitude was increased significantly (3-way ANOVA; P < 0.001) but by small magnitude depending on target shape and size (mean difference between disk and optotype targets = 0.02 degrees ; mean difference between 2 degrees and 0.5 degrees targets = 0.1 degrees ). Relationship between saccade amplitude and the Bivariate Contour Ellipse Area (BCEA) was nonlinear, showing saturation of saccade amplitude. Fixation instability in depth was significantly greater in strabismic monkeys (vergence BCEA: 0.63 deg2-2.15 deg2) compared with the normal animal (vergence BCEA: 0.15 deg2; P < 0.001). Conclusions: Increased fixational instability in strabismic monkeys is only partially due to increased amplitude and more frequent fixational saccades. Target parameter effects on fixational saccades are similar to previous findings of target effects on BCEA. PMID- 29114842 TI - The 3D Retinal Capillary Circulation in Pigs Reveals a Predominant Serial Organization. AB - Purpose: To establish a model of the retinal capillary circulation in pigs, which in many aspects is close to the human retina. Methods: Using high density confocal microscopy image stacks of immunolabeled porcine retinal whole mounts, microvessels close to the optic nerve head were traced in three dimensions. The direction of flow of individual capillaries was deduced from their arteriolar and/or venous connections. Results: From major arteries, second-order arteries traversed the nerve fiber layer and resolved exclusively into the superficial vascular plexus (SVP), which dichotomized the blood flow between radial peripapillary capillaries (RPCs) on one side and the intermediate (IVP) and deep vascular plexus (DVP) on the other. Each RPC was supplied by one or several capillaries from the SVP and drained to the IVP or DVP. The DVP was a mosaic of approximately 300 to 600 MUm wide anastomotic watersheds, each drained by one or two venules connected to major veins. A presumptive direction of flow could be determined for >90% of capillaries. These results suggest a model of the capillary circulation in which the three microvessel layers are serially organized with RPCs are in parallel between the SVP and IVP or DVP. Conclusions: In the peripapillary retina of pigs, microvascular layers have a serial arrangement, with RPCs emerging from the SVP and draining to the IVP or DVP; hence, connected in parallel of this scheme. The bulk of flow, therefore, traverses the SVP and DVP successively. This organization contributes to the higher oxygen saturation in the SVP and RPCs than in the DVP. Physiopathologic implications of this model regarding retinal diseases are discussed. PMID- 29114843 TI - Hypertonic Saline and Acute Bronchiolitis-Reply. PMID- 29114841 TI - Effect of Cromakalim Prodrug 1 (CKLP1) on Aqueous Humor Dynamics and Feasibility of Combination Therapy With Existing Ocular Hypotensive Agents. AB - Purpose: Cromakalim prodrug 1 (CKLP1) is a water-soluble ATP-sensitive potassium channel opener that has shown ocular hypotensive properties in ex vivo and in vivo experimental models. To determine its mechanism of action, we assessed the effect of CKLP1 on aqueous humor dynamics and in combination therapy with existing ocular hypotensive agents. Methods: Outflow facility was assessed in C57BL/6 mice by ex vivo eye perfusions and by in vivo constant flow infusion following CKLP1 treatment. Human anterior segments with no trabecular meshwork were evaluated for effect on pressure following CKLP1 treatment. CKLP1 alone and in combination with latanoprost, timolol, and Rho kinase inhibitor Y27632 were evaluated for effect on intraocular pressure in C57BL/6 mice and Dutch-belted pigmented rabbits. Results: CKLP1 lowered episcleral venous pressure (control: 8.9 +/- 0.1 mm Hg versus treated: 6.2 +/- 0.1 mm Hg, P < 0.0001) but had no detectable effect on outflow facility, aqueous humor flow rate, or uveoscleral outflow. Treatment with CKLP1 in human anterior segments without the trabecular meshwork resulted in a 50% +/- 9% decrease in pressure, suggesting an effect on the distal portion of the conventional outflow pathway. CKLP1 worked additively with latanoprost, timolol, and Y27632 to lower IOP, presumably owing to combined effects on different aspects of aqueous humor dynamics. Conclusions: CKLP1 lowered intraocular pressure by reducing episcleral venous pressure and lowering distal outflow resistance in the conventional outflow pathway. Owing to this unique mechanism of action, CKLP1 works in an additive manner to lower intraocular pressure with latanoprost, timolol, and Rho kinase inhibitor Y27632. PMID- 29114844 TI - Not All Pacifiers Are Created Equal: A Mechanical Examination of Pacifiers and Their Influence on Suck Patterning. AB - Purpose: Many pacifier companies advertise that their product is the "best choice" to support proper sucking, feeding, and dental development; however, very little evidence exists to support these claims. As the primary differences across pacifiers are structural and mechanical, the goals of this study were to measure such properties of commercially available pacifiers and to examine how these properties alter suck patterning in healthy, full-term infants. Method: Seven commonly utilized pacifiers were mechanically tested for pull and compression stiffness levels and categorized into nipple shape types based on their aspect ratio. Next, 3 pacifiers (Soothie, GumDrop, and Freeflow) with the most salient differences in pull stiffness levels with 2 different pacifier nipple types were tested clinically on 16 full-term infants (<= 6 months old) while measuring non nutritive suck (NNS). Results: A repeated measures analysis of variance revealed significant differences between NNS burst duration (p = .002), NNS cycles per burst (p = .002), and NNS cycles per minute (p = .006) and pacifier type. With each significant dependent measure, pairwise comparisons showed that the GumDrop and Freeflow pacifiers differed significantly on these measures. Conclusions: Pacifier compression, pull stiffness, and nipple shape type yield different NNS dynamics. These findings motivate further investigation into pacifier properties and suck patterning in young infants. PMID- 29114845 TI - Parental Sexual Orientation and Children's Psychological Well-Being: 2013-2015 National Health Interview Survey. AB - Debate persists about whether parental sexual orientation affects children's well being. This study utilized information from the 2013 to 2015 U.S., population based National Health Interview Survey to examine associations between parental sexual orientation and children's well-being. Parents reported their children's (aged 4-17 years old, N = 21,103) emotional and mental health difficulties using the short form Strengths and Difficulties Questionnaire (SDQ). Children of bisexual parents had higher SDQ scores than children of heterosexual parents. Adjusting for parental psychological distress (a minority stress indicator) eliminated this difference. Children of lesbian and gay parents did not differ from children of heterosexual parents in emotional and mental health difficulties, yet, the results among children of bisexual parents warrant more research examining the impact of minority stress on families. PMID- 29114846 TI - Savings from reducing low-value general surgical interventions. AB - BACKGROUND: Finding opportunities for improving efficiency is important, given the pressure on national health budgets. Identifying and reducing low-value interventions that deliver little benefit is key. A systematic literature evaluation was done to identify low-value interventions in general surgery, with further assessment of their cost. METHODS: A multiplatform method of identifying low value interventions was undertaken, including a broad literature search, a targeted database search, and opportunistic sampling. The results were then stratified by impact, assessing both frequency and cost. RESULTS: Seventy-one low value general surgical procedures were identified, of which five were of high frequency and high cost (highest impact), 22 were of high cost and low frequency, 23 were of low cost and high frequency, and 21 were of low cost and low frequency (lowest impact). Highest impact interventions included inguinal hernia repair in minimally symptomatic patients, inappropriate gastroscopy, interval cholecystectomy, CT to diagnose appendicitis and routine endoscopy in those who had CT-confirmed diverticulitis. Their estimated cost was ?153 383 953. CONCLUSION: Low-value services place a burden on health budgets. Stopping only five high-volume, high-cost general surgical procedures could save the National Health Service ?153 million per annum. PMID- 29114847 TI - Intestinal anti-transglutaminase 2 immunoglobulin A deposits in children at risk for coeliac disease (CD): data from the PreventCD study. AB - In coeliac disease (CD), anti-tissue transglutaminase 2 immunoglobulin (Ig)A antibodies (anti-TG2) are produced and deposited in the intestine. PreventCD (www.preventcd.com) is a European multi-centre study, which investigates the influence of infant nutrition and that of genetic, immunological and other environmental factors on the risk of developing CD. The aim of the current study was to evaluate the appearance of intestinal anti-TG2 deposits in very early intestinal biopsies from at-risk infants and their predictive value for villous atrophy. Sixty-five small bowel biopsies, performed in 62 children, were investigated for the presence of intestinal anti-TG2 extracellular IgA deposits by using double immunofluorescence. The biopsies were performed in the presence of elevated serum levels of CD-associated antibodies and/or symptoms suggesting disease. Deposits of anti-TG2 IgA were present in 53 of 53 CD patients and three of three potential CD patients. In potential CD patients, mucosal deposits showed a patchy distribution characterized by some areas completely negative, whereas active CD patients had uniformly present and evident mucosal deposits. Only one of six patients without CD (negative for serum anti-TG2 and with normal mucosa) had intestinal deposits with a patchy distribution and a weak staining. Two of the 53 CD patients received a definitive diagnosis of CD after a second or third biopsy; mucosal deposits of anti-TG2 IgA were evaluated in all samples. Before developing villous atrophy, both patients had anti-TG2 deposits in normal mucosal architecture, antibodies in one patient being absent in serum. We demonstrated that in CD the intestinal deposits of anti-TG2 are a constant presence and appear very early in the natural history of disease. PMID- 29114848 TI - Racial Differences in Patterns of Use of Rehabilitation Services for Adults Aged 65 and Older. AB - OBJECTIVES: To examine racial differences in the use of rehabilitation services and functional improvement during receipt of services. DESIGN: Secondary analysis of the 2016 National Health and Aging Trends Study (NHATS). SETTING: Standardized in-person home interviews. PARTICIPANTS: Community-dwelling Medicare enrollees (N = 6,309), 1,276 of whom reported receiving rehabilitation services in the previous 12 months. MEASUREMENTS: Self-reported use of rehabilitation services, setting (inpatient, outpatient, home based), reason for use, and perceptions of change in functioning after receiving services. RESULTS: Controlling for sex, dual eligibility for Medicaid, age, number of chronic conditions, functional mobility at the prior round, income, and geographic region, the odds of receiving rehabilitation services in any setting was 1.38 times as great in whites as in blacks (95% confidence interval = 1.09-1.75). Of those receiving therapy, whites were more likely to receive home-based and inpatient rehabilitation services, but there were no racial differences in improvement in function. CONCLUSION: Strategies are needed to identify possible barriers to use of rehabilitation services for vulnerable groups of aging individuals who need rehabilitation services, particularly older blacks. PMID- 29114850 TI - Emotion regulation difficulties in obsessive-compulsive disorder. AB - OBJECTIVE: Emotion regulation difficulties are implicated in psychological disorders but their role in obsessive-compulsive disorder (OCD) is unclear. Two studies examining these difficulties in OCD are presented. METHOD: A community sample (Study 1; n = 306) and a clinical OCD sample (Study 2; n = 59) completed the Difficulties in Emotion Regulation Scale (DERS) and measures of depression, anxiety, and OCD. In Study 2, the OCD sample was compared to a matched control group (n = 59, selected from Study 1). RESULTS: In Study 1, OCD was positively correlated with DERS total and subscale scores, and the DERS significantly predicted OCD severity even after accounting for age, gender, depression, and anxiety. In Study 2, emotion regulation difficulties were significantly higher in the clinical sample compared to the matched control group, even after accounting for depression and anxiety. CONCLUSION: Results showed that emotion regulation difficulties in OCD cannot simply be attributed to mood difficulties. Theoretical and treatment implications are discussed. PMID- 29114849 TI - Risk of skin cancer among patients with myotonic dystrophy type 1 based on primary care physician data from the U.K. Clinical Practice Research Datalink. AB - Myotonic dystrophy type 1 (DM1) is an inherited multisystem neuromuscular disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene. Recent evidence documents that DM1 patients have an increased risk of certain cancers, but whether skin cancer risks are elevated is unclear. Using the U.K. Clinical Practice Research Datalink (CPRD), we identified 1,061 DM1 patients and 15,119 DM1-free individuals matched on gender, birth year (+/-2 years), attending practice and registration year (+/-1 year). We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of DM1 diagnosis with skin cancer risk using Cox proportional hazards models, for all skin cancers combined and by histological subtype. Follow-up started at the latest of the age at practice registration, DM1 diagnosis/control selection or January 1st 1988, and ended at the earliest of the age at first skin cancer diagnosis, death, transfer out of the practice, last date of data collection or the end of the CPRD record (October 31, 2016). During a median follow-up of 3.6 years, 35 DM1 patients and 108 matched DM1-free individuals developed a skin cancer. DM1 patients had an increased risk of skin cancer overall (HR = 5.44, 95% CI = 3.33-8.89, p < 0.0001), and basal cell carcinoma (BCC) (HR = 5.78, 95% CI = 3.36-9.92, p < 0.0001). Risks did not differ by gender, or age at DM1 diagnosis (p-heterogeneity > 0.5). Our data confirm suggested associations between DM1 and skin neoplasms with the highest risk seen for BCC. Patients are advised to minimize ultraviolet light exposure and seek medical advice for suspicious lesions. PMID- 29114851 TI - Biweekly cisplatin and gemcitabine in patients with advanced biliary tract cancer. AB - Treatment with cisplatin and gemcitabine demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1,000 mg/m2 /min) and cisplatin 20 mg/m2 on days 1 and 15 of every 28-day cycle. Patients received treatment until time of progression, death, or discontinuation due to intolerance. Collected data included demographics, clinico-pathologic features, toxicities, and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%), and bile duct (74.8%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade >=3 adverse events included neutropenia (11%), fatigue (10%), and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies. PMID- 29114852 TI - A longitudinal functional magnetic resonance imaging study of task control circuits and bulimic symptoms over adolescence. AB - BACKGROUND: Previous cross-sectional findings from adolescents and adults with Bulimia Nervosa (BN) suggest disturbances in fronto-striatal and cingulo opercular task control circuits that support self-regulatory processes, including the resolution of cognitive conflict. Herein, we used longitudinal data to examine the developmental trajectories of such disturbances and how the functioning of these circuits relates to changes in BN symptoms over adolescence. METHODS: Thirty-two adolescent females with BN symptoms and 28 healthy control (HC) adolescents participated in the study. Functional magnetic resonance images (fMRI) during performance of a Simon task were acquired at three time points within 2-year intervals over adolescence. From the initial sample, 70% and 30% of the participants completed the second and third time points, respectively. Participants who completed all study time points did not differ from those lost to attrition on baseline demographic characteristics or any outcome measures. Using a region-of-interest approach, growth curve models tested group differences in the trajectory of conflict-related activation in task control circuits over time. Cross-lagged panel models examined transactional relationships between conflict-related activation in the same regions and BN symptoms over time. RESULTS: Growth curve models revealed different trajectories of conflict-related activation in right task control regions across BN and HC adolescents, such that HC but not BN adolescents showed activation decreases over time. These group differences were greatest when including only the BN adolescents whose symptoms remitted over time. Cross-lagged panel models revealed that less frequent bulimic episodes at first follow-up predicted later increases in conflict-related activation in bilateral task control regions. CONCLUSIONS: These longitudinal findings suggest overengagement of task control circuits in BN adolescents, especially those most resilient to persistent illness. Such overengagement may compensate for regulatory disturbances, allowing them to regulate eating behaviors over development. Thus, task control circuits may constitute targets for early interventions that enhance self-regulatory control. PMID- 29114854 TI - Dietary intake of isoflavones and coumestrol and the risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. AB - Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17beta-estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25-2.92)], genistein [1.51 (1.02-2.22), daidzein [1.80 (1.18-2.75) and glycitein [1.67 (1.15-2.43)] (p trend for all associations <=0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93-2.25), 1.65 (1.07 2.54), 1.73 (1.13-2.66) and 1.80 (1.18-2.75), respectively (p-trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non-advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer. PMID- 29114855 TI - Panel Report, IPA Congress Buenos Aires 2017: Intimacy: Las experiencias traumaticas no representadas [Unrepresented traumatic experiences]. PMID- 29114853 TI - The evolution of the manus of early theropod dinosaurs is characterized by high inter- and intraspecific variation. AB - The origin of the avian hand, with its reduced and fused carpals and digits, from the five-fingered hands and complex wrists of early dinosaurs represents one of the major transformations of manus morphology among tetrapods. Much attention has been directed to the later part of this transition, from four- to three-fingered taxa. However, earlier anatomical changes may have influenced these later modifications, possibly paving the way for a later frameshift in digit identities. We investigate the five- to four-fingered transition among early dinosaurs, along with changes in carpus morphology. New three-dimensional reconstructions from computed tomography data of the manus of the Triassic and Early Jurassic theropod dinosaurs Coelophysis bauri and Megapnosaurus rhodesiensis are described and compared intra- and interspecifically. Several novel findings emerge from these reconstructions and comparisons, including the first evidence of an ossified centrale and a free intermedium in some C. bauri specimens, as well as confirmation of the presence of a vestigial fifth metacarpal in this taxon. Additionally, a specimen of C. bauri and an unnamed coelophysoid from the Upper Triassic Hayden Quarry, New Mexico, are to our knowledge the only theropods (other than alvarezsaurs and birds) in which all of the distal carpals are completely fused together into a single unit. Several differences between the manus of C. bauri and M. rhodesiensis are also identified. We review the evolution of the archosauromorph manus more broadly in light of these new data, and caution against incorporating carpal characters in phylogenetic analyses of fine-scale relationships of Archosauromorpha, in light of the high degree of observed polymorphism in taxa for which large sample sizes are available, such as the theropod Coelophysis and the sauropodomorph Plateosaurus. We also find that the reduction of the carpus and ultimate loss of the fourth and fifth digits among early dinosaurs did not proceed in a neat, stepwise fashion, but was characterized by multiple losses and possible gains of carpals, metacarpals and phalanges. Taken together, the high degree of intra- and interspecific variability in the number and identities of carpals, and the state of reduction of the fourth and fifth digits suggest the presence of a 'zone of developmental variability' in early dinosaur manus evolution, from which novel avian-like morphologies eventually emerged and became channelized among later theropod clades. PMID- 29114856 TI - Panel Report, IPA Congress Buenos Aires 2017: Intimacy and technology: Developing a psychoanalytic dialogue. PMID- 29114857 TI - Panel Report, IPA Congress Buenos Aires 2017: Intimacy in negative capability. PMID- 29114860 TI - Suicide attempt predicted by academic performance and childhood IQ: a cohort study of 26 000 children. AB - OBJECTIVE: Academic performance in youth, measured by grade point average (GPA), predicts suicide attempt, but the mechanisms are not known. It has been suggested that general intelligence might underlie the association. METHODS: We followed 26 315 Swedish girls and boys in population-representative cohorts, up to maximum 46 years of age, for the first suicide attempt in hospital records. Associations between GPA at age 16, IQ measured in school at age 13 and suicide attempt were investigated in Cox regressions and mediation analyses. RESULTS: There was a clear graded association between lower GPA and subsequent suicide attempt. With control for potential confounders, those in the lowest GPA quartile had a near five-fold risk (HR 4.9, 95% CI 3.7-6.7) compared to those in the highest quartile. In a mediation analysis, the association between GPA and suicide attempt was robust, while the association between IQ and suicide attempt was fully mediated by GPA. CONCLUSIONS: Poor academic performance in compulsory school, at age 16, was a robust predictor of suicide attempt past young adulthood and seemed to account for the association between lower childhood IQ and suicide attempt. PMID- 29114858 TI - Midlife metabolic factors and prostate cancer risk in later life. AB - Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n = 9,097, enrolled 1967-1987) were followed for incident (n = 1,084 total; n = 378 advanced; n = 148 high-grade) and fatal (n = 340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI >=30 kg/m2 ; systolic blood pressure (SBP) >=130 or diastolic blood pressure (DBP) >=85 mm Hg or taking antihypertensives; triglycerides >=150 mg/dl; fasting blood glucose >=100 mg/dl or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides were associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p trend = 0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer. PMID- 29114859 TI - Antiepileptic drug behavioral side effects and baseline hyperactivity in children and adolescents with new onset epilepsy. AB - OBJECTIVE: To examine baseline psychological functioning and antiepileptic drug (AED) behavioral side effects in new onset epilepsy and determine, by age, whether baseline psychological functioning predicts AED behavioral side effects 1 month following AED initiation. METHODS: A retrospective chart review was conducted between July 2011 and December 2014 that included youths with new onset epilepsy. As part of routine interdisciplinary care, caregivers completed the Behavior Assessment System for Children, 2nd Edition: Parent Rating Scale to report on baseline psychological functioning at the diagnostic visit and the Pediatric Epilepsy Side Effects Questionnaire to identify AED behavioral side effects at the 1-month follow-up clinic visit following AED initiation. Children (age = 2-11 years) and adolescents (age = 12-18 years) were examined separately. RESULTS: A total of 380 youths with new onset epilepsy (Mage = 8.9 +/- 4.3 years; 83.4% Caucasian; 34.8% focal epilepsy, 41.1% generalized epilepsy, 23.7% unclassified epilepsy) were included. Seventy percent of youths had at-risk or clinically elevated baseline psychological symptoms. Children had significantly greater AED behavioral side effects (M = 25.08 +/- 26.36) compared to adolescents (M = 12.36 +/- 17.73), regardless of AED. Valproic acid demonstrated significantly greater behavioral side effects compared to all other AEDs, with the exception of levetiracetam. Higher hyperactivity/impulsivity at baseline significantly predicted higher AED behavioral side effects 1 month after AED initiation in both age groups. SIGNIFICANCE: Younger children seem to be more prone to experience behavioral side effects, and these are likely to be higher if youths with epilepsy have baseline hyperactivity/impulsivity. Baseline psychological screening, specifically hyperactivity, can be used as a precision medicine tool for AED selection. PMID- 29114862 TI - Fumaric acid esters in combination with a 6-week course of narrowband ultraviolet B provides an accelerated response compared with fumaric acid esters monotherapy in patients with moderate-to-severe plaque psoriasis: a randomized prospective clinical study. AB - BACKGROUND: Fumaric acid esters (FAE) are safe and effective in patients with moderate-to-severe psoriasis but have a slow onset of action. A short-term combination with narrowband ultraviolet B (NB-UVB) may substantially accelerate the therapeutic response in the induction phase of treatment. OBJECTIVES: To assess the synergistic effect of a 6-week course of NB-UVB phototherapy in addition to FAE in adults with moderate-to-severe plaque psoriasis. METHODS: In this randomized, assessor-masked trial, patients with a Psoriasis Area and Severity Index (PASI) of >= 10 and a body surface area affected of >= 10 were randomized either to monotherapy with FAE (n = 16) or a combination of FAE with NB-UVB (n = 14). The primary outcome parameter of the study was the mean PASI reduction after 6 weeks of treatment. In addition, the PASI 75 response (>= 75% improvement from baseline PASI), the Psoriasis Log-based Area and Severity Index (PLASI) and the Dermatology Life Quality Index (DLQI) were assessed as secondary outcome measures. RESULTS: In total, 30 patients (19 men, 11 women; median age 52 years, interquartile range 36-56) were analysed. The mean reduction in PASI after 6 weeks was significantly greater with the combination treatment than with FAE monotherapy (P = 0.016). This was paralleled by a much faster improvement in the DLQI in the combination group than in the FAE-monotherapy group. CONCLUSIONS: Adding a 6-week course of NB-UVB to FAE both accelerates and augments the therapeutic response during the early phase of treatment and increases quality of life in patients with moderate-to-severe plaque psoriasis. PMID- 29114863 TI - American hybrid: Donald Trump and the strange merger of populism and plutocracy. AB - Any effort to situate Trump's ascendance in the broader currents of cross national developments, or in the longer course of American political development, must begin by recognizing it as a curious hybrid of populism and plutocracy. Although American right-wing populism has real social roots, it has long been nurtured by powerful elites seeking to undercut support for modern structures of economic regulation and the welfare state. American political institutions offered a distinctive opportunity for a populist figure to draw on this fury to first capture the nomination of the GOP, and from that position to ascend to the White House. Yet the administration's substantive agenda constitutes a full throated endorsement of the GOP economic elite's long-standing demands for cuts in social spending, tax reductions for the wealthy, and the gutting of consumer, worker and environmental protections. The chasm between Trump's rhetoric and his actions justifies a more skeptical assessment of the breadth and depth of American populism, one that acknowledges how its contours are shaped by the nation's unusual political institutions, its intensifying political polarization and the out-sized influence of the wealthy. PMID- 29114861 TI - Kappa opioid receptors regulate hippocampal synaptic homeostasis and epileptogenesis. AB - OBJECTIVE: Homeostatic synaptic plasticity (HSP) serves as a gain control mechanism at central nervous system (CNS) synapses, including those between the dentate gyrus (DG) and CA3. Improper circuit control of DG-CA3 synapses is hypothesized to underlie epileptogenesis. Here, we sought to (1) identify compounds that preferentially modulate DG-CA3 synapses in primary neuronal culture and (2) determine if these compounds would delay or prevent epileptogenesis in vivo. METHODS: We previously developed and validated an in vitro assay to visualize the behavior of DG-CA3 synapses and predict functional changes. We used this "synapse-on-chip" assay (quantification of synapse size, number, and type using immunocytochemical markers) to dissect the mechanisms of HSP at DG-CA3 synapses. Using chemogenetic constructs and pharmacological agents we determined the signaling cascades necessary for gain control at DG-CA3 synapses. Finally, we tested the implicated cascades (using kappa opioid receptor (OR) agonists and antagonists) in two models of epileptogenesis: electrical amygdala kindling in the mouse and chemical (pentylenetetrazole) kindling in the rat. RESULTS: In vitro, synapses between DG mossy fibers (MFs) and CA3 neurons are the primary homeostatic responders during sustained periods of activity change. Kappa OR signaling is both necessary and sufficient for the homeostatic elaboration of DG-CA3 synapses, induced by presynaptic DG activity levels. Blocking kappa OR signaling in vivo attenuates the development of seizures in both mouse and rat models of epilepsy. SIGNIFICANCE: This study elucidates mechanisms by which synapses between DG granule cells and CA3 pyramidal neurons undergo activity-dependent homeostatic compensation, via OR signaling in vitro. Modulation of kappa OR signaling in vivo alters seizure progression, suggesting that breakdown of homeostatic closed-loop control at DG-CA3 synapses contributes to seizures, and that targeting endogenous homeostatic mechanisms at DG-CA3 synapses may prove useful in combating epileptogenesis. PMID- 29114864 TI - The multidimensional politics of inequality: taking stock of identity politics in the U.S. Presidential election of 2016. AB - Many Democrats hoped that a particular kind of identity politics - women's - would help Hillary Clinton win the White House. In the aftermath of the election, some commentators bemoaned the fact that a majority of white women had voted for Trump, and called it a kind of betrayal, underlining their expectation that women would naturally, on the basis of their gender identity, support a woman with women-friendly politics. Indeed, this kind of thinking about identity politics has been widespread with reference to a number of demographic groups. Meanwhile, identity politics is lamented from the right and left by those who favour a greater emphasis on class-based inequalities, or a greater national identity, some of whom blame identity politics for spawning or justifying a backlash of right-leaning populism in the US. We argue for a turn to a more robust definition of identity as multidimensional and politically mediated for understanding political alignments over the past several decades. The multidimensionality of inequality - intersectionality or complex inequality - is widely accepted in the study of gender and race across the social science disciplines but has yet to be as successfully integrated into studies of electoral politics. Thinking about women's positioning in systems of complex inequality, and how the political parties have or have not articulated the concerns of different groups of women, helps us to understand the 2016 election, as well as past and potentially future political developments. PMID- 29114865 TI - The politics of nationalism and white racism in the UK. AB - This paper considers the contemporary significance of white racism and its association with nationalist sentiment amongst a cohort late middle aged white Britons, using survey responses and qualitative interviews from the 1958 National Child Development Study. We have shown that although overt racism is very limited, a substantial minority of white Britons display ambivalent feelings which have the potential to be mobilised in racist directions. We argue against the view that disadvantaged white working class respondents are especially xenophobic, and show that racist views are not strongly associated with social position. In exploring the clustering of different nationalist and racist sentiments amongst economic and cultural elites, and comparing these with 'disenfranchised' respondents with little economic and cultural capital, we show that it is actually the elite who are most likely to articulate 'imperial racism'. By contrast, the 'disenfranchised' articulate a kind of anti establishment nationalism which is not strongly racist. We also show that the elite are strongly internally divided, with a substantial number of the cultural elite being strongly anti-racist and committed to multi-culturalism, so generating strong internal factionalism between elite positions. Our paper therefore underscores how intensifying inequalities have facilitated the volatility and variability of nationalist and racist sentiment. PMID- 29114866 TI - Trump's electoral speeches and his appeal to the American white working class. AB - This paper contributes to the study of social change by considering boundary work as a dimension of cultural change. Drawing on the computer-assisted qualitative analysis of 73 formal speeches made by Donald Trump during the 2016 electoral campaign, we argue that his political rhetoric, which led to his presidential victory, addressed the white working class's concern with their declining position in the national pecking order. He addressed this group's concern by raising their moral status, that is, by (1) emphatically describing them as hard working Americans who are victims of globalization; (2) voicing their concerns about 'people above' (professionals, the rich, and politicians); (3) drawing strong moral boundaries toward undocumented immigrants, refugees, and Muslims; (4) presenting African Americans and (legal) Hispanic Americans as workers who also deserve jobs; (5) stressing the role of working-class men as protectors of women and LGBTQ people. This particular case study of the role of boundary work in political rhetoric provides a novel, distinctively sociological approach for capturing dynamics of social change. PMID- 29114867 TI - Introduction to BJS special issue. PMID- 29114868 TI - The politics of social status: economic and cultural roots of the populist right. AB - This paper explores the factors that have recently increased support for candidates and causes of the populist right across the developed democracies, especially among a core group of working-class men. In the context of debates about whether the key causal factors are economic or cultural, we contend that an effective analysis must rest on understanding how economic and cultural developments interact to generate support for populism. We suggest that one way to do so is to see status anxiety as a proximate factor inducing support for populism, and economic and cultural developments as factors that combine to precipitate such anxiety. Using cross-national survey data from 20 developed democracies, we assess the viability of this approach. We show that lower levels of subjective social status are associated with support for right populist parties, identify a set of economic and cultural developments likely to have depressed the social status of men without a college education, and show that the relative social status of those men has declined since 1987 in many of the developed democracies. We conclude that status effects provide one pathway through which economic and cultural developments may combine to increase support for the populist right. PMID- 29114869 TI - Ethno-nationalist populism and the mobilization of collective resentment. AB - Scholarly and journalistic accounts of the recent successes of radical-right politics in Europe and the United States, including the Brexit referendum and the Trump campaign, tend to conflate three phenomena: populism, ethno-nationalism and authoritarianism. While all three are important elements of the radical right, they are neither coterminous nor limited to the right. The resulting lack of analytical clarity has hindered accounts of the causes and consequences of ethno nationalist populism. To address this problem, I bring together existing research on nationalism, populism and authoritarianism in contemporary democracies to precisely define these concepts and examine temporal patterns in their supply and demand, that is, politicians' discursive strategies and the corresponding public attitudes. Based on the available evidence, I conclude that both the supply and demand sides of radical politics have been relatively stable over time, which suggests that in order to understand public support for radical politics, scholars should instead focus on the increased resonance between pre-existing attitudes and discursive frames. Drawing on recent research in cultural sociology, I argue that resonance is not only a function of the congruence between a frame and the beliefs of its audience, but also of shifting context. In the case of radical-right politics, a variety of social changes have engendered a sense of collective status threat among national ethnocultural majorities. Political and media discourse has channelled such threats into resentments toward elites, immigrants, and ethnic, racial and religious minorities, thereby activating previously latent attitudes and lending legitimacy to radical political campaigns that promise to return power and status to their aggrieved supporters. Not only does this form of politics threaten democratic institutions and inter-group relations, but it also has the potential to alter the contours of mainstream public discourse, thereby creating the conditions of possibility for future successes of populist, nationalist, and authoritarian politics. PMID- 29114870 TI - The three constituencies of the state: why the state has lost unifying energy. AB - We address resurgent populism by examining structural processes of state transformation in the UK, the US and France. Scholars stress the 'unifying energy of the state', a set of institutions and policies capable of limiting inequalities and defending legal regimes. One characteristic of modern Western statehood were packages of policies designed to integrate social groups and territories in part by ensuring common standards of provision and social citizenship across the nation state. This echoes James Scott's critical analysis of the modernist project of the state (1998). This 'unifying energy' had different origins including nationalist movements, combatting external influence or powers, war, and preparing citizens for the rigours of industrialization. Overcoming class differences and territorial differences (including cultural, social and economic differences) was a major source of mobilization to feed this 'unifying energy of the state' in France, Italy or Spain for instance. Political and cultural identities are related in significant part to respective nation states. We argue that this 'unifying energy' was an essential component of statehood in Europe and in the US. It is now largely lost. We explain why and the significance of its displacement. PMID- 29114871 TI - The class politics of prejudice: Brexit and the land of no-hope and glory. AB - The debates relating to social class and whether it is still a useful concept in describing a lived reality of the British population has never been far away from media, political and academic dispute. Thatcher's Britain throughout the 1980s attempted to dilute class meaning with what was called 'a home owning democracy' and thus end class collective politics through easily available credit for the working class while simultaneously attacking trade union organization, recruitment and political action. During the late 1990s and into the noughties a 'New Labour' administration attempted to exacerbate the end of class politics through an agenda of a 'cultural distinction' to class identity. Class struggle, class politics and class identity is embedded deep within the cultural norms practices, and history of British democracy. Consequently it is difficult if not impossible to prise class inequality in the UK away from and out of national, local and personal politics (Savage et al. 2015: 393-8). This paper focuses upon the sense that class politics, and cultural class distinction, within the UK had the biggest influence in determining a working-class 'Leave Vote' in the 2016 referendum within the UK. This paper explores accounts and narratives from working-class 'leave' voters though an ethnographic study of the political and social viewpoints of working-class communities of East London, and of ex-mining towns of Nottinghamshire. Framing into fuller context the anger and apathy of being 'left out', arguing that being 'left out' has been part of working-class political narratives for over 30 years. Going beyond frustration and apathy, a significant part of the narrative of working people was of 'not existing', suggesting certain important linkages with ongoing debates about new ways of conceptualizing class differences and class structures. PMID- 29114872 TI - Racism in Trump's America: reflections on culture, sociology, and the 2016 US presidential election. AB - Despite much positive change in the post civil rights era, U.S. notions of racism and white supremacy remain powerful elements of American culture. The adaptability and enduring power of these forces can be seen in the emergence of a new historical epoch best describe as the era of Laissez Faire Racism. Prevalent attitudes among white Americans, certain theoretical arguments and hypotheses in American sociology, as well the election of Donald Trump rest upon the on-going operation of racism. In particular, I attribute Trump's electoral success to three critical dilemmas of race that defined contours of the 2016 presidential election: (1) worsening economic inequality in the presence of rapidly changing ethno-racial demography; (2) intensified political partisanship in the presence of well-institutionalized racially coded campaign strategies and rhetoric; and (3) the failure of the Clinton campaign to simultaneously champion the interests of working and middle class families and galvanize the previously powerful multiracial Obama coalition. I speculate on how to forge more effective multiracial coalitions in the future. PMID- 29114873 TI - Brexit, Trump, and 'methodological whiteness': on the misrecognition of race and class. AB - The rhetoric of both the Brexit and Trump campaigns was grounded in conceptions of the past as the basis for political claims in the present. Both established the past as constituted by nations that were represented as 'white' into which racialized others had insinuated themselves and gained disproportionate advantage. Hence, the resonant claim that was broadcast primarily to white audiences in each place 'to take our country back'. The politics of both campaigns was also echoed in those social scientific analyses that sought to focus on the 'legitimate' claims of the 'left behind' or those who had come to see themselves as 'strangers in their own land'. The skewing of white majority political action as the action of a more narrowly defined white working class served to legitimize analyses that might otherwise have been regarded as racist. In effect, I argue that a pervasive 'methodological whiteness' has distorted social scientific accounts of both Brexit and Trump's election victory and that this needs to be taken account of in our discussion of both phenomena. PMID- 29114874 TI - The revolt of the Rust Belt: place and politics in the age of anger. AB - This paper argues that the election of Donald Trump is the product of a confluence of historical factors rather than the distinctive appeal of the victor himself. By paying particular attention to the geography of unusual voting behaviour the analytical question comes into view: why did so much uncharacteristic voting occur in the Rust Belt states of the upper Midwest? It is impossible to answer this question adequately using conventional categorical attributes. The usual hypotheses of 'economic anxiety' and white revanchism are unable to account for sudden shifts in the voting behaviour of both white and black voters in post-industrial territories. Instead, it is necessary to turn to the history of the region and the institutional apparatus that connected voters there to the federal government and the Democratic Party. From this perspective we can see that the active dismantling of the Fordist social order set the region on a divergent path from the rest of the country. But this path had no political outlet due to the reorientation of the Democratic Party around a new class and geographic base. Due to this, the party pursued policies that would magnify the region's difficulties rather than alleviate its circumstances. Moreover, the elaborate institutional ties that connected the region's voters to the Democratic Party and the federal government meant that the political implications of regional decline would be muted. However, as these institutions frayed, Rust Belt voters were made available to candidates that challenged the policy consensus that had done so much damage to the region. The election was decided by a Rust Belt revolt that unified black and white working-class voters against Hillary Clinton and the Democratic Party. PMID- 29114877 TI - Association Between Obesity, Age, and Functional Decline in Survivors of Cardiac Surgery. AB - BACKGROUND/OBJECTIVES: Little is known about the effect of obesity on functional decline after cardiac surgery, especially in elderly adults. Our goal was to determine the association between obesity and functional decline in the 2 years after cardiac surgery and the interaction between obesity and age. DESIGN: Retrospective cohort study. SETTING: The Health and Retirement Study, 2004-2014. PARTICIPANTS: U.S. adults aged 50 and older who indicated having cardiac surgery and had a body mass index (BMI) of 18.5 kg/m2 or greater (N = 1,731). MEASUREMENTS: BMI was classified as normal or overweight (18.5-29.9 kg/m2 ) and obese (>=30 kg/m2 ). Primary outcome was decline in ability to perform an activity of daily living (ADL) after surgery. RESULTS: Respondents had a median age of 71, 59.3% were female, and 34.3% were obese. Obese respondents had a higher incidence of ADL decline (22.4%) than those who were not obese (17.1%) (P = .007). In the multivariable analysis of our full cohort, obesity was not associated with ADL decline (odds ratio (OR)=1.20, 95% confidence interval (CI)=0.90-1.59, P = .21) after cardiac surgery, although obese respondents aged 50 to 79 had greater odds of ADL decline (OR=1.45, 95% CI=1.06-2.00, P = .02). Obese respondents aged 80 and older had nonstatistically significantly lower odds of ADL decline (OR=0.61, 95% CI=0.30-1.24, P = .18) compared to non-obese respondents. CONCLUSION: The association between obesity and postoperative functional decline in survivors of cardiac surgery differed according to age. Additional research is needed to identify interventions to improve outcomes in groups of older adults in whom obesity may increase the risk of postoperative functional decline. PMID- 29114880 TI - Maintenance of memory CD8 T cells: Divided over division. AB - Once generated during an infection, memory CD8+ T cells can provide long-lasting protection against reinfection with an intracellular pathogen, but the longevity of this defense depends on the ability of these pathogen-specific memory cells to be maintained. It is generally believed that the bone marrow plays an important role in this respect, where memory CD8 T cells receive reinvigorating signals from cytokines that induce homeostatic proliferation. However, in the current issue of the European Journal of Immunology, Siracusa et al. (Eur. J. Immunol. 2017. 47: 1900-1905) argue against this dogma, as they provide evidence that CD8 memory T cells in murine bone marrow are not proliferating, but largely quiescent, which protects them from elimination by the cytostatic drug Cyclophosphamide. Interestingly, this is in sharp contrast to the proliferating cell counterparts in the spleen, which are eliminated by this treatment. Here, we will discuss the impact of these results, how they relate to opposing findings by others in the field, and what the relevance of these findings is for humans and clinical applications. PMID- 29114876 TI - Translating carotid body function into clinical medicine. AB - The carotid body (CB) is considered the main O2 chemoreceptor, which contributes to cardiorespiratory homeostasis and ventilatory acclimatization. In clinical medicine, the most common pathologies associated with the CB are tumours. However, a growing body of evidence supports the novel idea that an enhanced CB chemosensory discharge contributes to the autonomic dysfunction and pathological consequences in obstructive sleep apnoea (OSA), hypertension, systolic heart failure (HF) and cardiometabolic diseases. Heightened CB chemosensory reactivity elicited by oxidative stress has been involved in sympathetic hyperactivity, cardiorespiratory instability, hypertension and insulin resistance. CB ablation, which reduces sympathetic hyperactivity, decreases hypertension in animal models of OSA and hypertension, eliminates breathing instability and improves animal survival in HF, and restores insulin tolerance in cardiometabolic models. Thus, data obtained from preclinical studies highlight the importance of the CB in the progression of sympathetic-related diseases, supporting the idea that appeasing the enhanced CB chemosensory drive may be useful in improving cardiovascular, respiratory and endocrine alterations. Accordingly, CB ablation has been proposed and used as a treatment for moderating resistant hypertension and HF-induced sympathetic hyperactivity in humans. First-in-human studies have shown that CB ablation reduces sympathetic overactivity, transiently reduces severe hypertension and improves quality of life in HF patients. Thus, CB ablation would be a useful therapy to reverse sympathetic overactivation in HF and severe hypertension, but caution is required before it is widely used due to the crucial physiological function played by the CB. Further studies in preclinical models are required to assess side-effects of CB ablation. PMID- 29114875 TI - Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations. AB - Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trondelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of <=25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant. PMID- 29114883 TI - The impact of the affordable care act's Medicaid expansion on dental care use through 2016. AB - OBJECTIVE: To examine the impact of the Affordable Care Act on dental care use among low-income adults ages 21-64. METHODS: Our analysis uses national survey data from the 2010-2016 Gallup Wellbeing-Index. We use a differences-in differences analysis to assess changes since the end of 2013 in dental care use among low-income adults. We compare changes in states that expanded Medicaid and offer adult Medicaid dental benefits versus changes in other states. RESULTS: Relative to the pre-reform period and other states, in Medicaid expansion states with adult dental benefits, dental care use increased 3-6 percentage points in 2016. CONCLUSIONS: In Medicaid expansion states with adult dental benefits, evidence suggests that low-income adults have greater access to dental care. PMID- 29114882 TI - A comprehensive analysis of polymorphic variants in steroid hormone and insulin like growth factor-1 metabolism and risk of in situ breast cancer: Results from the Breast and Prostate Cancer Cohort Consortium. AB - We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and insulin like growth factor 1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was carried out using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (ORhom = 3.05, 95%CI = 1.72 5.44, Phom = 1.47 * 10-4 ), MAST2-rs12124649 (ORhom = 1.73, 95% CI =1.18-2.54, Phom = 5.24 * 10-3 ), and INSR-rs10500204 (ORhom = 1.96, 95% CI = 1.44-2.67, Phom =1.68 * 10-5 ) were associated with increased risk of BCIS; however, only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with the risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (ORhom = 1.78, 95% CI = 1.30-2.44, Phom = 3.23 * 10-4 ). The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further. PMID- 29114884 TI - Dental provider practices and perceptions regarding adolescent vaccination. AB - OBJECTIVE: To assess dental providers' clinical practices and perceptions regarding adolescent vaccinations. METHODS: We surveyed 234 dental providers in an integrated health care setting in Portland, Oregon, in March-April 2015. We assessed participants' knowledge of adolescent vaccines, barriers to recommending vaccines, and their perceived role in the promotion of vaccination and preventive medical care. RESULTS: Over 80 percent of respondents correctly identified influenza, tetanus-diphtheria-acellular pertussis, and human papillomavirus as vaccinations recommended for adolescents; 60 percent correctly identified meningococcal conjugate. Forty-four percent of providers reported previously discussing vaccination with their adolescent patients. Lack of knowledge (66 percent), uncertainty about whether patients would accept recommendations (62 percent), and lack of time (61 percent) were commonly reported barriers. While few providers expressed personal concerns about the safety (13 percent) and effectiveness (10 percent) of adolescent vaccines, most believed parents had concerns about safety (70 percent) and effectiveness (60 percent). Although 80 percent endorsed the premise that providers should discuss preventive medical care with their patients, only 54 percent said they should discuss vaccinations specifically. CONCLUSIONS: Dental providers reported several barriers to recommending vaccines. While comfortable with discussing preventive medical care in general, providers are less comfortable making vaccine recommendations to their patients. Vaccine recommendations are not a traditional practice among dental providers and may require additional education and communication tools. PMID- 29114885 TI - Hypoxia-sensitive pathways in intestinal inflammation. AB - Inflammatory bowel disease (IBD) is a common chronic intestinal disorder characterised by a loss of epithelial barrier function leading to the unregulated movement of luminal antigenic material into mucosal tissue with resultant inflammation. In IBD, multiple components of the inflammatory response lead to tissue hypoxia. Mucosal hypoxia leads to the inactivation of prolyl hydroxylase domain-containing (PHD) enzymes, which in turn leads to the stabilisation of the hypoxia-inducible factor (HIF), which induces the expression of barrier protective genes. Furthermore, pharmacological hydroxylase inhibition has been shown to be protective in colitis, at least in part through enhancing intestinal epithelial barrier function through HIF-1-dependent barrier-protective gene expression. Therefore, targeting hypoxia-sensitive pathways represents a new and promising therapeutic approach in IBD. PMID- 29114886 TI - Effect of effort-reward imbalance and burnout on infection control among Ecuadorian nurses. AB - BACKGROUND: Nurses are frequently exposed to transmissible infections, yet adherence to infection control measures is suboptimal. There has been inadequate research into how the psychosocial work environment affects compliance with infection control measures, especially in low- and middle-income countries. AIM: To examine the association between effort-reward imbalance, burnout and adherence to infection control measures among nurses in Ecuador. INTRODUCTION: A cross sectional study linking psychosocial work environment indicators to infection control adherence. METHODS: The study was conducted among 333 nurses in four Ecuadorian hospitals. Self-administered questionnaires assessed demographic variables, perceived infection risk, effort-reward imbalance, burnout and infection control adherence. RESULTS: Increased effort-reward imbalance was found to be a unique incremental predictor of exposure to burnout, and burnout was a negative unique incremental predictor of nurses' self-reported adherence with infection control measures. DISCUSSION: Results suggest an effort-reward imbalance-burnout continuum, which, at higher levels, contributes to reduce adherence to infection control. The Ecuadorean government has made large efforts to improve universal access to health care, yet this study suggests that workplace demands on nurses remain problematic. CONCLUSION: This study highlights the contribution of effort-reward-imbalance-burnout continuum to the chain of infection by decreased adherence to infection control of nurses. IMPLICATIONS FOR NURSING POLICY: Health authorities should closely monitor the effect of new policies on psychosocial work environment, especially when expanding services and increasing public accessibility with limited resources. Additionally, organizational and psychosocial interventions targeting effort-reward imbalance and burnout in nurses should be considered part of a complete infection prevention and control strategy. Further study is warranted to identify interventions that best ameliorate effort-reward imbalance and burnout in low- and middle-income settings. PMID- 29114887 TI - Cough strength and expiratory force in aspirating and nonaspirating postradiation head and neck cancer survivors. AB - OBJECTIVE: Expiratory functions that clear aspiration from the airway are compromised in patients with neurogenic dysphagia for whom cough and expiratory force may be impaired by the primary disease process. The relationship between expiratory function, cough, and aspiration is less clear in head and neck cancer (HNC) survivors for whom the disease process does not directly impact the lower respiratory system. Our objective was to compare mechanisms of airway clearance (expiratory force and cough) with aspiration status in postradiated HNC survivors. STUDY DESIGN: Cross-sectional study. METHODS: One hundred and three disease-free HNC survivors >= 3-months postradiotherapy referred for modified barium swallow studies were prospectively enrolled regardless of dysphagia status. Maximum expiratory pressures (MEPs) and peak cough flow (PCF) measures were taken at enrollment and examined as a function of aspiration status using generalized linear regression methods. RESULTS: Thirty-four (33%) patients aspirated. Maximum expiratory pressure and PCF demonstrated a moderate positive correlation (Pearson's r = 0.35). Adjusting for sex and age, MEPs were on average 19.2% lower (21.1 cm H2 O, 95% confidence interval [CI] 5.3, 36.8) among aspirators. Peak cough flow was also 14.9% lower (59.6 L/minute, 95% CI 15.8, 103.3) among aspirators after adjusting for age and sex. CONCLUSION: Expiratory functions were depressed in postradiated HNC aspirators relative to nonaspirators, suggesting that airway protection impairments may extend beyond disrupted laryngopharyngeal mechanisms in the local treatment field. Exercises to strengthen subglottic expiratory force-generating capacity may offer an adjunctive therapeutic target to improve airway protection in chronic aspirators after head and neck radiotherapy. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1615 1621, 2018. PMID- 29114888 TI - Cricothyroid joint type as predictor for vocal fold elongation in professional singers. AB - OBJECTIVE: Vocal fold (VF) elongation vocal folds depends on two factors: the activity of the laryngeal muscles and the cricothyroid joint (CTJ). The aim of the study was to show the influence of the CTJ on VF elongation while singing a sustained vowel at different pitches. STUDY DESIGN: Prospective study. METHODS: Forty-nine female professional singers (25 sopranos, 24 altos) were recruited. Three-dimensional images of the larynx derived from high-resolution computed tomography scanning were obtained at the mean speaking fundamental frequency (F0) and one (F1) and two octaves (F2) above this pitch. RESULTS: From F0 to F1, all three CTJ types showed equal elongation of the VF (type A: 14%, type B/C: 13%). From F1 to F2, VF elongation was 8% in singers with type A and 4% in those with type B/C (P < 0.0001). CONCLUSION: The stability of the CTJ directly influences VF during singing. This is the first study to show this relationship in vivo. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1176-1181, 2018. PMID- 29114889 TI - The contribution of cochlear implants to postural stability. AB - OBJECTIVES: To determine whether spatial auditory cues provided by cochlear implants can improve postural balance in adults with severe deafness. METHODS: In the presence of spatial white noise, 13 adult cochlear implantees wore head and lumbar-mounted inertial sensors while standing in the dark for 30 seconds in two auditory conditions: hearing assistive devices on and off. RESULTS: Stability was improved with implants on (aided condition) compared to off (unaided condition) with respect to differences in mean head velocity (Cohen's d = 0.912, P = 0.006) as well as to root mean square (RMS) acceleration (Cohen's d = 0.456, P = 0.048). This was particularly evident in measures of anteroposterior accelerations (mean difference = 0.034 m/s2 ; Cohen's d = 0.612; P = 0.011). CONCLUSION: The decrease in RMS head acceleration and velocity while wearing cochlear implants suggests that they could be recognized as balance implants in addition to auditory implants. The clinical importance of this finding in various patient populations remains to be determined. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1676-1680, 2018. PMID- 29114891 TI - Mapping an Australian Occupational Therapy curriculum: Linking intended learning outcomes with entry-level competency standards. AB - BACKGROUND: Curriculum mapping involves systematic charting of programme content against professional competencies. This process can reveal strengths, gaps and redundancies within educational programmes. METHODS: Curriculum mapping occurred using intended learning (ILOs) as documented in individual courses and linking them to units and elements within the occupational therapy minimum competency standards (ACSOT) and Miller's Framework of competency. Five occupational therapy academics and two impartial research assistants identified links between ILOs and units and elements of the ACSOT. Analysis of each course in the curriculum was completed by two reviewers. A systematic protocol was developed that enabled a transparent process and resolution of discrepancies between reviewers. RESULTS: There were many links (47% of total) between the documented curriculum and ACSOT Unit 1 Professional attitudes and behaviours. The other six units of the ACSOT had between 5% (Unit 7) and 16% links (Unit 3). No links were made between ILOs and the elements of evaluation (4.4), cessation (3.7) and quality assurance of services (7.3). Difficulties mapping ILOs to units and elements revealed inconsistencies in specificity and language in the ILOs and also ambiguities and gaps within the standards themselves. Mapping against Miller's framework showed a steady increase in performance expectations of students across the four years levels. CONCLUSION: Curriculum mapping is recommended for critical reflection about content of occupational therapy programmes and to review pedagogical approaches. This process revealed strengths and weaknesses of the occupational therapy curriculum being mapped but also revealed insight into the current ACSOT that may inform future iterations. PMID- 29114890 TI - Total septal perforation repair with a pericranial flap: Radio-anatomical and clinical findings. AB - OBJECTIVES/HYPOTHESIS: Endonasal surgeries are the primary cause of septal perforation (SP). However, trauma, inflammation, infections, neoplasms, or abuse of inhaled drugs can also cause SP. Septal repair is indicated in patients who experience nasal obstruction, crusting, intermittent epistaxis, purulent discharge, or nasal whistling and in those who fail conservative treatment. Multiple approaches have been suggested to repair the SP; however, none has been universally adopted. This study explores the feasibility of repairing a total SP using the pericranial flap (PCF). STUDY DESIGN: Anatomical cadaver and radiological study plus case study. METHODS: Total nasal septectomy and endoscopic reconstruction with a PCF was performed in 12 injected cadaveric specimens. Maximum length and area of the nasal septum and the PCF were measured in 75 computed tomography scans. Based on the anatomical study and the radiological measurements of the cadavers, one patient underwent total nasal septum repair. RESULTS: Anatomic measurements showed that the nasal septum has a mean length of 5.8 +/- 0.7 cm, whereas the PCF was on average 18.4 +/- 1.3 cm long (mean surface area 121.6 +/- 17.7 cm2 ). Radiological measurements revealed that the PCF should provide a surface area of 40.9 +/- 4.2 cm2 to account for the total septal area and an additional 30% to account range for potential scar retraction. For total septum repair, the distal edge of the PCF had to be placed 0.8 +/- 2.0 cm (3.4 +/- 8.7 degrees ) from the adopted reference point (vertical projection of the external ear canal). Total septal reconstruction was performed successfully in one patient without complications. CONCLUSIONS: Radio-anatomical data and a case study demonstrate that a PCF allows complete endoscopic repair of the nasal septum. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1320-1327, 2018. PMID- 29114892 TI - Hyperconjugative effects in pi-hydrogen bonding: Theory and experiment. AB - Density functional theory computations with the B3LYP/6-311++G(2df,2p) method and IR spectroscopy are employed in investigating the properties of twenty pi hydrogen bonded complexes between substituted phenols and hexamethylbenzene. All complexes possess T-shaped structures. The methyl hyperconjugative effects on interactions energies and O?H stretching frequencies are estimated via comparisons with previously reported theoretical and experimental results for analogous phenol complexes with benzene. The theoretical computations provide excellent quantitative predictions of the O?H stretching frequency shifts (DeltanuOH ) resulting from the hydrogen bonding. The DeltanuOH shifts in the hexamethylbenzene complexes are approximately twice as large as the corresponding shifts for the benzene complexes. Hirshfeld charges, electrostatic potential at nuclei values, and molecular electrostatic potential maps are employed in gaining insights into the mechanisms of methyl hyperconjugative effects on complex formation. (c) 2017 Wiley Periodicals, Inc. PMID- 29114893 TI - Functional mastery of health ownership: A model for optimum health. AB - The aim of this paper is to introduce the Functional Mastery of Health Ownership (FMHO) model and to develop an operational definition of functional mastery as it applies to a positive health outcome for patients with chronic illness or an altered life situation. Daily functioning within the negative disease burden of chronic illness is the goal of individuals living within the constraints of morbidity. Functional mastery fosters health ownership and helps to predict successful control over life circumstances for optimum wellness within the parameters of the limitations of the effects of illness. Significant to nursing, the FMHO conceptual framework uses four foundational influences to assess a patient's ability to not only master function within the disease process, but also to sustain function and best health over time. The FMHO model provides a tool for practitioners to enable individualized care as patients move through the disease process and adapt to changes over time. PMID- 29114894 TI - Lack of long-term add-on effect by montelukast in postoperative chronic rhinosinusitis patients with nasal polyps. AB - OBJECTIVES/HYPOTHESIS: Eosinophils and mast cells are among the key cells in inflammatory diseases like chronic rhinosinusitis (CRS) and asthma. Leukotriene antagonists have proven to be effective in the treatment of asthma, but data about their efficacy in CRS are scarce, whereas data on montelukast as an add-on treatment to intranasal corticosteroids (INCS) in a postoperative setting are completely lacking. STUDY DESIGN: Prospective, randomized, open-label trial. METHODS: In this trial with long-term follow-up, we evaluated the efficacy of montelukast as an add-on treatment to INCS in postoperative CRS with nasal polyp (CRSwNP) patients. CRSwNP patients (N = 72) undergoing endoscopic sinus surgery were randomized in two arms for the postoperative treatment. One group (N = 36) received INCS in monotherapy, whereas the other group (N = 36) received INCS in association with montelukast for 1 year. The efficacy of montelukast with INCS was evaluated by assessing both subjective (total five-symptom score [T5SS]) and objective (nasal polyp score [NPS], Lund-Mackay [LMK] score, and subjective olfactometry [Barcelona Smell Test 24]) outcome parameters and compared with the gold standard of INCS in monotherapy. RESULTS: After 1 year of surgery, T5SS, NPS, and LMK score were significantly reduced in patients treated with either INCS or INCS plus montelukast, without significant differences between the two treatment arms. Improvement of smell loss by olfactometry was also observed with no differences between arms. Similar findings were observed at 3 and 6 months. CONCLUSIONS: These results suggest that the addition of montelukast to INCS should not be recommended in the treatment of postoperative CRSwNP patients. LEVEL OF EVIDENCE: 1b Laryngoscope, 1743-1751, 2018. PMID- 29114895 TI - Telemedicine in laryngology: Remote evaluation of voice disorders-setup and initial experience. PMID- 29114896 TI - A shared decision-making tool for obstructive sleep apnea without tonsillar hypertrophy: A randomized controlled trial. AB - OBJECTIVES/HYPOTHESIS: Shared decision-making is a process whereby patients and clinicians jointly establish a treatment plan integrating clinical evidence and patient values and preferences. Although this approach has been successfully employed in numerous medical disciplines, often using shared decision-making tools, otolaryngologic research assessing its use is scant. Our primary objective was therefore to determine if the tools we developed reduced decisional conflict for children with obstructive sleep apnea without tonsillar hypertrophy. STUDY DESIGN: Prospective, single-blind, randomized controlled trial. METHODS: We enrolled consecutive patients meeting inclusion criteria who were referred to our multidisciplinary upper airway center. Study patients used a shared decision making tool whereas controls did not. Measures of decisional conflict (SURE [Sure of myself, Understanding information, Risk benefit ratio, Encouragement], CollaboRATE, and the Decisional Conflict Scale [DCS]) were obtained pre- and postvisit. RESULTS: We assessed 50 families (study group = 24, controls = 26). The mean age was 8.8 +/- 6.6 years, 44% were female, 86% were white, and the mean obstructive apnea-hypopnea index was 12.7 +/- 15.6 events/hour. The previsit mean DCS score was similar for controls (42.7) and study patients (40.8) (P = .38). The postvisit mean DCS score for controls was 13.3 and for study patients 6.1 (P = .034). Improvement in this score was greater in the study group (P = .03). At previsit evaluation, 63% of controls and 58% of study patients were unsure about their options. Postvisit, this improved to 4.1% and 0%, respectively. CONCLUSIONS: Families counseled regarding treatment options using shared decision making tools had significantly less decisional conflict than those who did not use these tools. These positive outcomes suggest that clinicians should consider integrating this approach into clinical practice. LEVEL OF EVIDENCE: 1b. Laryngoscope, 128:1007-1015, 2018. PMID- 29114897 TI - Development and external validation of a risk-prediction model to predict 5-year overall survival in advanced larynx cancer. AB - OBJECTIVES/HYPOTHESIS: TNM-classification inadequately estimates patient-specific overall survival (OS). We aimed to improve this by developing a risk-prediction model for patients with advanced larynx cancer. STUDY DESIGN: Cohort study. METHODS: We developed a risk prediction model to estimate the 5-year OS rate based on a cohort of 3,442 patients with T3T4N0N+M0 larynx cancer. The model was internally validated using bootstrapping samples and externally validated on patient data from five external centers (n = 770). The main outcome was performance of the model as tested by discrimination, calibration, and the ability to distinguish risk groups based on tertiles from the derivation dataset. The model performance was compared to a model based on T and N classification only. RESULTS: We included age, gender, T and N classification, and subsite as prognostic variables in the standard model. After external validation, the standard model had a significantly better fit than a model based on T and N classification alone (C statistic, 0.59 vs. 0.55, P < .001). The model was able to distinguish well among three risk groups based on tertiles of the risk score. Adding treatment modality to the model did not decrease the predictive power. As a post hoc analysis, we tested the added value of comorbidity as scored by American Society of Anesthesiologists score in a subsample, which increased the C statistic to 0.68. CONCLUSIONS: A risk prediction model for patients with advanced larynx cancer, consisting of readily available clinical variables, gives more accurate estimations of the estimated 5-year survival rate when compared to a model based on T and N classification alone. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:1140-1145, 2018. PMID- 29114899 TI - In reference to intervention for elevated intracranial pressure improves success rate after repair of spontaneous cerebrospinal fluid leaks. PMID- 29114898 TI - Adapting the T0-T4 implementation science model to occupational health and safety in agriculture, forestry, and fishing: A scoping review. AB - BACKGROUND: Despite much research to develop life-saving innovations for the agriculture, forestry, and fishing workforce, these populations continue to face the highest fatal and non-fatal injury rates in the United States, as many of these solutions are not fully adopted. METHODS: A scoping review was conducted to provide an overview of research to practice efforts in this field. The language used to describe these initiatives, the utility of the NIH T0-T4 model, and the progress along the research to practice continuum were examined. RESULTS: Fourteen eligible references demonstrated that progress in implementation science is lacking and that there is little consistency in how researchers apply the T0 T4 model; thus, a new model is presented. CONCLUSIONS: Researchers in this field face several challenges when moving from research to practice. While some challenges are addressed with the proposed model, additional resources and infrastructure to support such initiatives are necessary. PMID- 29114900 TI - Standing thyroidectomy in 10 horses. AB - OBJECTIVE: To describe a surgical technique for thyroidectomy in horses with thyroid neoplasia under standing sedation and local anesthesia. STUDY DESIGN: Retrospective study. ANIMALS: Client-owned horses (n = 10). METHODS: Medical records of horses with a history of thyroid enlargement were included in the study if thyroid gland enlargement was treated surgically via hemi- or bilateral thyroidectomy, with the horse standing and sedated. Data derived from follow-up clinical examination, performance level, recurrence, and cosmetic outcome were evaluated. RESULTS: Thyroid enlargement was unilateral in 8 and bilateral in 2 horses. Histopathological findings included adenomas (5/10), adenocarcinomas (2/10), cystic hyperplasia (2/10), and C-cell adenoma (1/10). No major complications were encountered during or after surgery. All horses resumed their previous level of exercise within 6 weeks. Recurrence was diagnosed in 1 horse, 7 months after excision, and a second surgery was required. Recurrent laryngeal nerve neuropathy and seroma formation subsequent to surgery were not recorded in any of the cases. CONCLUSION: Thyroidectomy can safely be performed with the horse standing and sedated with local anesthesia. CLINICAL RELEVANCE: Performing standing thyroidectomy does not increase intraoperative or postoperative complications and could be considered for horses with thyroid enlargement amenable to surgery. PMID- 29114901 TI - Allergic contact dermatitis caused by calcipotriol. AB - BACKGROUND: Calcipotriol, a synthetic vitamin D analogue, is widely used for the topical treatment of psoriasis. It often causes irritant reactions, whereas allergic contact dermatitis has less commonly been reported. OBJECTIVES: To report on 6 patients (among them an 11-year-old child) who presented with eczematous lesions complicating pre-existing dermatitis, observed in our tertiary referral patch test clinic between 2004 and 2016. METHODS: Patch tests were performed with the commercial preparation used by the patients and/or its ingredients, including calcipotriol (2 or 10 ug/ml in isopropyl alcohol), according to ESCD patch test guidelines. RESULTS: Allergic contact dermatitis was confirmed in all cases, and the lesions improved following treatment with topical corticosteroids and/or oral medication. CONCLUSIONS: When topical treatment with calcipotriol fails to improve, or even worsens, existing skin lesions, contact allergy should be suspected. A patch test concentration of 2 ug/ml in isopropyl alcohol seems to be the most suitable. According to the literature, patients sensitized to calcipotriol may tolerate topical therapy with other vitamin D3 analogues, particularly tacalcitol. PMID- 29114902 TI - When should therapeutic anticoagulation be restarted following major head and neck surgery? PMID- 29114903 TI - Occupational generalized urticaria and anaphylaxis after inhalation of cefuroxime in a nurse. AB - We present the case of a 53 years old nonatopic female nurse who experienced repeated anaphylactic reactions at work without involvement in drug-specific tasks such as crushing of tablets or preparation of injections. The causal allergen was not identified until a further severe anaphylactic reaction occurred after oral use of cefuroxime during a respiratory infection. Sensitization to cefuroxime was demonstrated by specific IgE, basophil activation test and skin prick test. An inhalation challenge with a dosimeter induced generalized urticaria after a cumulative dose of about 10 MUg of the drug, but no asthmatic reaction. Complete exposure cessation was initiated and a 1-year follow-up was without further allergic reactions. We conclude that work-related systemic allergic reactions to beta-lactam antibiotics may occur in nurses after inhalation of low doses and without perceived association with drug-specific tasks like handling of antibiotics. PMID- 29114904 TI - Proton density-weighted laryngeal magnetic resonance imaging in systemically dehydrated rats. AB - OBJECTIVES/HYPOTHESIS: Dehydrated vocal folds are inefficient sound generators. Although systemic dehydration of the body is believed to induce vocal fold dehydration, this causative relationship has not been demonstrated in vivo. Here we investigate the feasibility of using in vivo proton density (PD)-weighted magnetic resonance imaging (MRI) to demonstrate hydration changes in vocal fold tissue following systemic dehydration in rats. STUDY DESIGN: Animal study. METHODS: Sprague-Dawley rats (n = 10) were imaged at baseline and following a 10% reduction in body weight secondary to withholding water. In vivo, high-field (7 T), PD-weighted MRI was used to successfully resolve vocal fold and salivary gland tissue structures. RESULTS: Normalized signal intensities within the vocal fold decreased postdehydration by an average of 11.38% +/- 3.95% (mean +/- standard error of the mean [SEM], P = .0098) as compared to predehydration levels. The salivary glands experienced a similar decrease in normalized signal intensity by an average of 10.74% +/- 4.14% (mean +/- SEM, P = .0195) following dehydration. The correlation coefficient (percent change from dehydration) between vocal folds and salivary glands was 0.7145 (P = .0202). CONCLUSIONS: Ten percent systemic dehydration induced vocal fold dehydration as assessed by PD weighted MRI. Changes in the hydration state of vocal fold tissue were highly correlated with that of the salivary glands in dehydrated rats in vivo. These preliminary findings demonstrate the feasibility of using PD-weighted MRI to quantify hydration states of the vocal folds and lay the foundation for further studies that explore more routine and realistic magnitudes of systemic dehydration and rehydration. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E222-E227, 2018. PMID- 29114905 TI - Leukotriene receptor antagonism may not be effective in atopic dermatitis treatment after all. AB - WHAT IS KNOWN AND OBJECTIVE: Literature evidence suggests leukotriene involvement in the pathogenesis of atopic dermatitis. This article aimed to discuss whether the off-label use of montelukast, a leukotriene receptor antagonist, is justifiable for the treatment of atopic dermatitis. COMMENT: Most non-randomized studies supported the use of montelukast for atopic dermatitis treatment. However, evidence from these studies should be interpreted with caution as it is relatively weak due to the absence of randomization, control groups and blinding processes, subjecting the results to high risk of selection and reporting biases. The inconsistent findings across RCTs may be related to the limited number of patients, nuances in study designs, varying severity of disease and the concomitant use of steroids in some of the studies. WHAT IS NEW AND CONCLUSION: Current literature evidence is limited to rationally support the use of montelukast in atopic dermatitis treatment. For now, the conventional treatments should be preferred in the clinical setting. PMID- 29114906 TI - Evaluation of three chemical immobilization protocols in golden-headed lion tamarins (Leontopithecus chrysomelas) undergoing vasectomy surgery. AB - BACKGROUND: The golden-headed lion tamarin (Leontopithecus chrysomelas), originally endemic to Bahia, was introduced in Rio de Janeiro. The species is currently found in remaining forests within the region of original occupation of the golden lion tamarin (Leontopithecus rosalia), which may compromise the survival of the golden lion tamarin. Groups of golden-headed lion tamarins were captured and translocated to Bahia. However, the area chosen reached its limit and males underwent to vasectomy procedures. METHODS: Animals were separated into 3 groups: S-ketamine and midazolam, S-ketamine and dexmedetomidine, and racemic ketamine and dexmedetomidine. RESULTS AND CONCLUSIONS: Heart rate, sedation and muscle relaxation degrees, antinociception, and lidocaine consumption presented significant difference between midazolam and dexmedetomidine groups. Bradycardia was present on dexmedetomidine groups, with values remaining within the normal range. Dexmedetomidine groups present the best outcomes for muscle relaxation, sedation, and antinociception and were safe for vasectomy surgery in golden headed lion tamarins. PMID- 29114907 TI - Effect of zoledronic acid therapy on postmenopausal osteoporosis between the Uighur and Han population in Xinjiang: An open-label, long-term safety and efficacy study. AB - WHAT IS KNOWN AND OBJECTIVE: Postmenopausal osteoporosis is becoming an urgent health problem in China. A once-yearly infusion of zoledronic acid can be very effective for the treatment of postmenopausal osteoporosis in significantly reducing the risk of hip, vertebral and other fractures. This study aimed to investigate zoledronic acid treatment on postmenopausal osteoporosis in Uighur and Han patients in Xinjiang province, China. METHODS: A self-controlled and prospective trial design was adopted. A total of 155 Uighur and 151 Han patients were enrolled. All subjects received an intravenous infusion of zoledronic acid (5 mg) at day 0 (baseline) and at 12 months. Patients were followed up for 24 months; the bone mineral density (BMD) of the left total hip and L1-L4 vertebrae was measured at day 0 and at 24 months. RESULTS AND DISCUSSION: BMD was significantly higher after zoledronic acid treatment compared with baseline levels in all patients, as assessed at 24 months. Moreover, the BMD of left total hip increased with 2.7% in the Han group was significantly higher than that of the Uighur group with 1.4% (left total hip, 95% CI: 2.6% to 2.8% in Han group vs 1.2% to 1.4% in Uighur group). The BMD of L1-L4 vertebrae increased with 2.2% in the Han group was significantly higher than that of the Uighur group with 1.6% (L1-L4 vertebrae, 95% CI, 2.0% to 2.4% in Han group vs 1.4% to 1.7% in Uighur group); P < .001. There was no significant difference in drug-related adverse effects between the two groups (P > .05). WHAT IS NEW AND CONCLUSION: Zoledronic acid appears to be more effective in postmenopausal osteoporosis in Han than in Uighur subjects. The reasons for this require further investigation. PMID- 29114908 TI - Influence of ionic constituents and electrical conductivity on the propagation of charged nanoscale objects in passivated gel electrophoresis. AB - When determining the electric field E acting on charged objects in gel electrophoresis, the electrical conductivity of the buffer solution is often overlooked; E is typically calculated by dividing the applied voltage by a separation distance between electrodes. However, as a consequence of electrolytic reactions, which occur at the electrodes, gradients in the ionic content of the buffer solution and its conductivity can potentially develop over time, thereby impacting E and affecting propagation velocities of charged objects, v, directly. Here, we explore how the types and concentrations of ionic constituents of the buffer solution, which largely control its conductivity, when used in passivated gel electrophoresis (P-gelEP), can influence E, thereby altering v of charged nanospheres propagating through large-pore gels. We measure the conductivity of the buffer solution in the center of the gel region near propagating bands of nanospheres, and we show that predictions of E based on conductivity closely correlate with v. We also explore P-gelEP involving two different types of passivation agents: nonionic polyethylene glycol (PEG) and anionic sodium dodecyl sulfate (SDS). Our observations indicate that using a conductivity model to determine E from the local current density and the conductivity where spheres are propagating can lead to a better estimate than the standard approach of a voltage divided by a separation. Moreover, this conductivity model also provides a starting point for interpreting the complex behavior created by amphiphilic ionic passivation agents, such as SDS, on propagating nanospheres used in some P-gelEP experiments. PMID- 29114910 TI - N-acetylcysteine attenuates the cuprizone-induced behavioral changes and oligodendrocyte loss in male C57BL/7 mice via its anti-inflammation actions. AB - Previous animal studies have linked white matter damage to certain schizophrenia like behaviors in cuprizone (CPZ)-exposed mouse. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and oligodendrocyte loss coexist in the brain of such mice. The aim of this study was to examine effects of the antioxidant N-acetylcysteine (NAC) on CPZ-induced behavioral changes and concurrent oligodendrocyte loss, oxidative stress, and neuroinflammation in these animals. Male C57BL/6 mice were given intraperitoneal saline or NAC at doses of 100, 200, and 400 mg/kg/day for 2 weeks; animals were fed a CPZ-containing diet (0.2%, w/w) during days 5-14. During days 15-17, the mice were examined in open field, social recognition, and Y-maze tests (1 test per day). Six mice in each group were then used for biochemical and enzyme-linked immunosorbent assay analyses, while the remaining animals were used for immunohistochemical and immunofluorescence staining. The mice exposed to CPZ for 10 days showed significantly lower spontaneous alternation in the Y-maze, lower activity of total superoxide dismutase, and glutathione peroxidase, but higher levels of malondialdehyde in the cerebral cortex and hippocampus, elevated concentrations of interleukin-1beta and tumor necrosis factor-alpha in the brain regions mentioned above and caudate putamen, and a decreased number of mature oligodendrocytes, but increased number of microglia in all the brain regions examined. These changes, however, were not seen or effectively alleviated in NAC treated mice at all three doses. These results demonstrate that NAC protected mature oligodendrocytes against the toxic effects of CPZ, likely via its antioxidant and anti-inflammatory actions. PMID- 29114911 TI - Relationship and variation of diabetes related symptoms, sleep disturbance and sleep-related impairment in adults with type 2 diabetes. AB - AIM: The objective of this study was to examine whether diabetes-related symptoms (e.g. fatigue, neuropathic pain, diabetes distress and depressive symptoms) were related to sleep disturbance and sleep-related impairment in adults with type 2 diabetes while controlling for potential covariates. BACKGROUND: In people with type 2 diabetes, sleep disturbance and sleep-related impairment are common and likely associated with diabetes-related symptoms. However, limited research has investigated the predictive ability of diabetes-related symptoms on sleep. DESIGN: A correlational, cross-sectional design was used. METHODS: Data were collected at a large university in the Midwestern United States from September 2013-March 2014. Multiple linear regression analyses were used to examine the relationship of diabetes-related symptoms (fatigue, neuropathic pain, distress and depressive symptoms) to sleep disturbance and sleep-related impairment. The instruments included Patient-Reported Outcomes Measurement Information System instruments, Diabetes Symptom Checklist and Diabetes Distress Scale. FINDINGS: In this study of adults with type 2 diabetes (N = 90; 52.2% female, mean age 57.4 years), gender, A1C, neuropathic pain and fatigue were significantly related to sleep disturbance when age, diabetes duration, depressive symptoms and distress were controlled. Those variables collectively explained 52% of the variation in sleep disturbance. Fatigue was significantly associated with sleep-related impairment when the same covariates were controlled. CONCLUSION: Findings suggested that diabetes-related symptoms, including neuropathic pain and fatigue, are strongly related to sleep disturbance and sleep-related impairment in adults with type 2 diabetes, underscoring the need to include detailed assessments of neuropathic pain and fatigue when evaluating sleep. PMID- 29114909 TI - An ancestry-based approach for detecting interactions. AB - BACKGROUND: Epistasis and gene-environment interactions are known to contribute significantly to variation of complex phenotypes in model organisms. However, their identification in human association studies remains challenging for myriad reasons. In the case of epistatic interactions, the large number of potential interacting sets of genes presents computational, multiple hypothesis correction, and other statistical power issues. In the case of gene-environment interactions, the lack of consistently measured environmental covariates in most disease studies precludes searching for interactions and creates difficulties for replicating studies. RESULTS: In this work, we develop a new statistical approach to address these issues that leverages genetic ancestry, defined as the proportion of ancestry derived from each ancestral population (e.g., the fraction of European/African ancestry in African Americans), in admixed populations. We applied our method to gene expression and methylation data from African American and Latino admixed individuals, respectively, identifying nine interactions that were significant at P<5*10-8. We show that two of the interactions in methylation data replicate, and the remaining six are significantly enriched for low P-values (P<1.8*10-6). CONCLUSION: We show that genetic ancestry can be a useful proxy for unknown and unmeasured covariates in the search for interaction effects. These results have important implications for our understanding of the genetic architecture of complex traits. PMID- 29114912 TI - Silencing pyruvate kinase (NlPYK) leads to reduced fecundity in brown planthoppers, Nilaparvata lugens (Stal) (Hemiptera: Delphacidae). AB - Pyruvate kinase (PYK) operates in the glycolytic pathway, responsible for regulating the balance between glycolysis and gluconeogenesis. The previous work indicates PYK acts in development of Drosophila embryos and in embryonic muscle growth, from which it may be inferred that PYK acts in insect fecundity. More to the point, as a central enzyme in the glycolytic pathway, PYK acts in many energy spending functions in most organisms. On the background findings that triazophos (TZP) stimulates fecundity via increase activities of several genes in brown planthoppers, Nilaparvata lugens, we investigated the combined influence of TZP and silencing a N. lugens PYK (NlPYK) on reproduction-linked biological performance parameters. Here, we report that TZP+dsNlPYK treatments led to reduced (by 26%) ovarian, but not fat body, protein content relative to controls. Ovarian (35%) and fat body (54%) soluble sugar contents were reduced. TZP+dsNlPYK treatments also led to reduced (by about 24%) fecundity, expressed as numbers of eggs laid. These data show directly that NlPYK acts in insect fecundity, probably via increases in glucose metabolism. PMID- 29114913 TI - A retrospective analysis of cardiometabolic health in a large cohort of truck drivers compared to the American working population. AB - BACKGROUND: Truck drivers face many health challenges, including lifestyle, diet, inactivity, stressors, and social support. METHODS: A repeated cross-sectional analysis compared 88,246 truck drivers with data from (n = 11 918) the National Health and Nutrition Examination Survey (NHANES). Trends over time for body mass index (BMI), high blood pressure, diabetes mellitus, heart disease, and sleep disorders were analyzed, adjusting for potential confounders. RESULTS: Truck drivers had significantly worsening health metrics between 2005 and 2012 compared to NHANES participants. Truck drivers were significantly more likely to be obese and morbidly obese with prevalence odds ratios (POR) and 95% confidence intervals (95%CI) of 1.99 (1.87, 2.13) and 2.34 (2.16, 2.54), respectively. Measured blood pressure, self-reported high blood pressure, diabetes mellitus, and heart disease all significantly increased. Also, sleep disorders increased among truck drivers from 2005 to 2012 (POR = 6.55, 95%CI 5.68, 7.55). CONCLUSION: These data suggest disproportionate increases in poor health among truck drivers from 2005 to 2012. PMID- 29114915 TI - Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor positive tumors. AB - The neurotensin receptors are overexpressed in various tumor types, especially in highly progressive pancreatic tumors. As this cancer has a poor 5-year survival prognosis, there is an urgent need to improve early diagnosis and treatment strategies. This review article provides an overview of the latest developments in radiopharmaceuticals for neurotensin receptor-positive tumors, including peptidic and non-peptidic radiopharmaceuticals, not only for SPECT and PET but also for endoradiotherapy. PMID- 29114914 TI - A Bayesian scoring rule on clustered event data for familial risk assessment - An example from colorectal cancer screening. AB - Colorectal cancer screening is well established. The identification of high risk populations is the key to implement effective risk-adjusted screening. Good statistical approaches for risk prediction do not exist. The family's colorectal cancer history is used for identification of high risk families and usually assessed by a questionnaire. This paper introduces a prediction algorithm to designate a family for colorectal cancer risk and discusses its statistical properties. The new algorithm uses Bayesian reasoning and a detailed family history illustrated by a pedigree and a Lexis diagram. The algorithm is able to integrate different hereditary mechanisms that define complex latent class or random factor structures. They are generic and do not reflect specific genetic models. This is comparable to strategies in complex segregation analysis. Furthermore, the algorithm can integrate different statistical penetrance models for right censored event data. Computational challenges related to the handling of the likelihood are discussed. Simulation studies assess the predictive quality of the new algorithm in terms of ROC curves and corresponding AUCs. The algorithm is applied to data of a recent study on familial colorectal cancer risk. Its predictive performance is compared to that of a questionnaire currently used in screening for familial colorectal cancer. The results of the proposed algorithm are robust against different inheritance models. Using the simplest hereditary mechanism, the simulation study provides evidence that the algorithm improves detection of families with high cancer risk in comparison to the currently used questionnaire. The applicability of the algorithm goes beyond the field of colorectal cancer. PMID- 29114916 TI - Hierarchical models for epidermal nerve fiber data. AB - While epidermal nerve fiber (ENF) data have been used to study the effects of small fiber neuropathies through the density and the spatial patterns of the ENFs, little research has been focused on the effects on the individual nerve fibers. Studying the individual nerve fibers might give a better understanding of the effects of the neuropathy on the growth process of the individual ENFs. In this study, data from 32 healthy volunteers and 20 diabetic subjects, obtained from suction induced skin blister biopsies, are analyzed by comparing statistics for the nerve fibers as a whole and for the segments that a nerve fiber is composed of. Moreover, it is evaluated whether this type of data can be used to detect diabetic neuropathy, by using hierarchical models to perform unsupervised classification of the subjects. It is found that using the information about the individual nerve fibers in combination with the ENF counts yields a considerable improvement as compared to using the ENF counts only. PMID- 29114917 TI - Pulmonary arterial pressure detects functional mitral stenosis after annuloplasty for primary mitral regurgitation: An exercise stress echocardiographic study. AB - INTRODUCTION: The restrictive mitral valve annuloplasty (RMA) is the treatment of choice for degenerative mitral regurgitation (MR), but postoperative functional mitral stenosis remains a matter of debate. In this study, we sought to determine the impact of mitral stenosis on the functional capacity of patients. METHODS: In a cross-sectional study, 32 patients with degenerative MR who underwent RMA using a complete ring were evaluated. All participants performed treadmill exercise test and underwent echocardiographic examinations before and after exercise. RESULTS: The patients' mean age was 50.1 +/- 12.5 years. After a mean follow-up of 14.1 +/- 5.9 months (6-32 months), the number of patients with a mitral valve peak gradient >7.5 mm Hg, a mitral valve mean gradient >3 mm Hg, and a pulmonary arterial pressure (PAP) >=25 mm Hg at rest were 50%, 40.6%, and 62.5%, respectively. 13 patients (40.6%) had incomplete treadmill exercise test. All hemodynamic parameters were higher at peak exercise compared with at rest levels (all P < .05). The PAP at rest and at peak exercise as well as peak transmitral gradient at peak exercise were higher in patients with incomplete exercise compared with complete exercise test (all P < .05). The PAP at rest (a sensitivity and a specificity of 84.6% and 52.6%, respectively; area under the curve [AUC] = .755) and at peak exercise (a sensitivity and a specificity of 100% and 47.4%, respectively; AUC = .755) discriminated incomplete exercise test. CONCLUSION: The RMA for degenerative MR was associated with a functional stenosis and the PAP at rest and at peak exercise discriminated low exercise capacity. PMID- 29114918 TI - Donor age determines outcome in acute leukemia patients over 40 undergoing haploidentical hematopoietic cell transplantation. AB - Haploidentical hematopoietic cell transplantation (haplo-HCT) is being increasingly used in acute leukemia patients as an alternative transplant modality when matched sibling or matched unrelated donors are unavailable. As several potential haploidentical relative donors are typically available for a given patient, optimizing donor selection to improve clinical outcome is crucial. The impact of donor age and kinship on the outcome of acute leukemia patients is not clearly established in this setting. Using the multinational registry of the acute leukemia working party of the European society for blood and marrow transplantation we retrospective analyzed the clinical outcome of 1270 acute myeloid leukemia and acute lymphoblastic leukemia patients who underwent haplo HCT between 2005 and 2015. Patients over the age of 40 were significantly affected by increasing donor age resulting in higher non-relapse mortality (NRM) [Hazard ratio (HR)=1.86, confidence interval (CI) 95%, 1.18-2.94; P = .007], inferior leukemia-free survival (LFS) (HR = 1.59, CI 95%, 1.13-2.24; P = .007), and overall survival (OS) (HR = 1.74, CI 95%, 1.22-2.47; P = .002) when donors were over the age of 40. Additionally, kinship was found to be prognostically significant as patients transplanted from children donors over the age of 35 experienced an increased rate of NRM (HR = 1.82, CI 95%, 1.13-2.9; P = .01), inferior LFS (HR = 1.5, CI 95%, 1.05-2.13; P = .03), and OS (HR = 1.5, CI 95%, 1.04-2.15; P = .03). For patients younger than 40 years, donor age and kinship were mostly not clinically impactful. Our data establish donor age and kinship as significant determinants of outcome following haplo-HCT for acute leukemia patients. PMID- 29114919 TI - Circulating progenitor cells in patients with familial hypercholesterolemia. AB - OBJECTIVE: Familial hypercholesterolemia (FH) is a genetic disease with very high levels of circulating low density lipoprotein cholesterol (LDL-C) levels that leads to accelerated atherosclerosis. Lipoprotein apheresis is an effective treatment option for patients with FH and results in reduced cardiovascular morbidity and mortality. Circulating progenitor cells (CPCs) are markers of overall vascular health and diminished levels have been associated with decreased reparative potential and worse outcomes. We assessed the short-term change in CPC levels following a single lipoprotein apheresis session in FH patients who are already on stable lipoprotein apheresis therapy. We hypothesized that in addition to a reduction in atherogenic lipids, the cardiovascular benefit from lipoprotein apheresis therapy is mediated by enhanced vascular reparative capacity through mobilization of CPCs. METHODS: Eight FH patients (1 homozygous and 7 heterozygous) on stable lipoprotein apheresis therapy for at least three months had CPCs measured at baseline (prior to apheresis) and two hours after apheresis. Results were compared with data from age-matched hyperlipidemic (HLP) patients on statin therapy and healthy volunteers. RESULTS: FH patients had higher baseline circulating levels of CD34+/CD133+ and CD34+/CD133+/CXCR4+ cells compared to HLP and healthy subjects. There was no significant change in CPCs after apheresis in FH patients. CONCLUSIONS: FH patients had higher CPC counts at baseline compared to age-matched HLP and healthy controls, suggesting activation of reparative mechanism in this high risk population. Larger studies are needed to better characterize differences in CPC counts between FH subjects and HLP patients over time. PMID- 29114920 TI - Integrative sparse principal component analysis of gene expression data. AB - In the analysis of gene expression data, dimension reduction techniques have been extensively adopted. The most popular one is perhaps the PCA (principal component analysis). To generate more reliable and more interpretable results, the SPCA (sparse PCA) technique has been developed. With the "small sample size, high dimensionality" characteristic of gene expression data, the analysis results generated from a single dataset are often unsatisfactory. Under contexts other than dimension reduction, integrative analysis techniques, which jointly analyze the raw data of multiple independent datasets, have been developed and shown to outperform "classic" meta-analysis and other multidatasets techniques and single dataset analysis. In this study, we conduct integrative analysis by developing the iSPCA (integrative SPCA) method. iSPCA achieves the selection and estimation of sparse loadings using a group penalty. To take advantage of the similarity across datasets and generate more accurate results, we further impose contrasted penalties. Different penalties are proposed to accommodate different data conditions. Extensive simulations show that iSPCA outperforms the alternatives under a wide spectrum of settings. The analysis of breast cancer and pancreatic cancer data further shows iSPCA's satisfactory performance. PMID- 29114922 TI - Regulation and effects of neurotrophic factors after neural stem cell transplantation in a transgenic mouse model of Alzheimer disease. AB - According to much research, neurodegeneration and cognitive decline in Alzheimer disease (AD) are correlated with alternations of neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor. The experimental illumination of neural stem cell (NSC) transplantation to eliminate AD symptoms is being explored frequently, and we have acknowledged that neurotrophic factors may play a pivotal role in cognitive improvement. However, the relation between the reversal of cognitive deficits after NSC transplantation and directed alternations of neurotrophic factors is not clearly expounded. Meanwhile, reduced inflammatory response, promoted vessel density, and vascular endothelial growth factor (VEGF) can be reflections of improvement in cerebrovascular function. Three weeks after NSC transplantation, spatial learning and memory function in NSC-injected (Tg-NSC) mice were significantly improved compared with vehicle-injected (Tg-Veh) mice. Meanwhile, results obtained by immunofluorescence and Western blot analyses demonstrated that the levels of neurotrophic factors, VEGF, and vessel density in the cortex of Tg-NSC mice were significantly enhanced compared with Tg-Veh mice, while the levels of proinflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor alpha, and IL-6 were significantly decreased. Our results suggest that elevated concentrations of neurotrophic factors probably play a critical role in rescuing cognitive dysfunction in APP/PS1 transgenic mice after NSC transplantation, and neurotrophic factors may improve cerebrovascular function by means such as reducing inflammatory response and promoting angiogenesis. PMID- 29114921 TI - Association of early left ventricular dysfunction with advanced magnetic resonance white matter and gray matter brain measures: The CARDIA study. AB - INTRODUCTION: Relations between heart failure and clinically manifested stroke are well known, but the associations between heart and brain early abnormalities are not totally clear. AIMS: We explore relations of subclinical brain abnormalities with early cardiac dysfunction in a large healthy middle-aged biracial cohort. METHODS: The CARDIA study enrolled 5115 young adults aged 18-30 years at baseline (1985-1986). We assessed 719 Caucasian and African American participants of the CARDIA study, with echocardiograms and brain MRI at follow-up year 25 (2010-2011). Echocardiography assessed aortic root diameter; LVEF; circumferential, longitudinal, and radial deformation. Cerebral MRI DTI, and, on a subset, ASL perfusion sequences were used to assess white matter fractional anisotropy and gray matter cerebral blood flow (CBF). Linear regression explored relations between cardiac parameters and cerebral measures, adjusting for anthropometrics, risk factors, and brain constitutional variation. RESULTS: Mean age 50 +/- 4 years, SBP 118 +/- 15 mm Hg; 60% white, and 48% men. Mean CBF was 46 +/- 9 mL/100 g/min, and white matter fractional anisotropy was 0.31 +/- 0.02. Worse circumferential deformation and larger aortic root were related to worse white matter fractional anisotropy. Worse radial systolic deformation was related to worse CBF in multivariable models. LVEF did not relate to early brain abnormalities. CONCLUSIONS: In spite of no apparent effect of LV ejection fraction, early subclinical cardiac dysfunction and brain abnormalities are present and associated in middle-aged generally healthy individuals. PMID- 29114923 TI - Histamine modulates spinal motoneurons and locomotor circuits. AB - Spinal motoneurons and locomotor networks are regulated by monoamines, among which, the contribution of histamine has yet to be fully addressed. The present study investigates histaminergic regulation of spinal activity, combining intra- and extracellular electrophysiological recordings from neonatal rat spinal cord in vitro preparations. Histamine dose-dependently and reversibly generated motoneuron depolarization and action potential firing. Histamine (20 uM) halved the area of dorsal root reflexes and always depolarized motoneurons. The majority of cells showed a transitory repolarization, while 37% showed a sustained depolarization maintained with intense firing. Extracellularly, histamine depolarized ventral roots (VRs), regardless of blockage of ionotropic glutamate receptors. Initial, transient glutamate-mediated bursting was synchronous among VRs, with some bouts of locomotor activity in a subgroup of preparations. After washout, the amplitude of spontaneous tonic discharges increased. No desensitization or tachyphylaxis appeared after long perfusion or serial applications of histamine. On the other hand, histamine induced single motoneuron and VR depolarization, even in the presence of tetrodotoxin (TTX). During chemically induced fictive locomotion (FL), histamine depolarized VRs. Histamine dose-dependently increased rhythm periodicity and reduced cycle amplitude until near suppression. This study demonstrates that histamine induces direct motoneuron membrane depolarization and modulation of locomotor output, indicating new potential targets for locomotor neurorehabilitation. PMID- 29114924 TI - Quantitative assessment of aortic regurgitation by Doppler echocardiography: Usefulness of the comparison of aortic and pulmonary flows. AB - AIMS: Patients with significant (3+/4+) aortic regurgitation (AR) require careful monitoring or valve surgery. We sought to evaluate the diagnostic performance of aortic and pulmonary flow comparison in identifying patients with significant AR, by echocardiography. METHOD: Two hundred forty-six patients with more than trivial AR were prospectively enrolled from three centers. Aortic regurgitation (AR) severity was assessed by an expert using the currently recommended integrative approach. Aortic and pulmonary flows were independently assessed by another investigator to calculate the regurgitant fraction (RF), the aortic to pulmonary flow ratio (Qao/Qp) and the aortic to pulmonary velocity-time integral (VTIao/VTIp) ratio. The control group consisted of 195 patients without AR. RESULTS: A significant correlation was observed between AR grading and RF (r = .82, P < .0001) and Qao/Qp (r = .81, P < .0001), but the correlation was modest for VTIao/VTIp ratio (r = .63; P < .0001). The accuracy of RF and Qao/Qp ratio to identify patients with significant AR was excellent (0.96 and 0.95, respectively), but was significantly lower for VTIao/VTIp ratio at 0.82. A RF > 40% indicated grade 3 or 4 AR with a sensitivity of 83% and a specificity of 93%. A Qao/Qp ratio > 1.6 indicated grade 3 or 4 AR with a sensitivity of 88% and a specificity of 89%. The VTIao/VTIp ratio was not helpful in identifying patients with significant AR, as a wide overlap was found between 1+/2+ and 3+/4+ patients. CONCLUSION: Regurgitant fraction (RF) and Qao/Qp are helpful in identifying significant AR. The assessment of Doppler aortic/pulmonary flow should be incorporated in the comprehensive evaluation of AR. PMID- 29114925 TI - Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders. AB - Migfilin, encoded by FBLIM1 at the 1p36 locus, is a multi-domain adaptor protein essential for various cellular processes such as cell morphology and migration. Small deletions and duplications at the 1p36 locus, monosomy of which results in neurodevelopmental disorders and multiple congenital anomalies, have also been identified in patients with autism spectrum disorder (ASD). However, the impact of FBLIM1, the gene within 1p36, on the pathogenesis of ASD is unknown. In this study, we performed morphological analyses of migfilin to elucidate its role in brain development. Migfilin was detected specifically in the embryonic and perinatal stages of the mouse brain. Either silencing or overexpression of migfilin in embryos following in utero electroporation disrupted Neocortical neuronal migration. Additionally, neurite elongation was impaired when migfilin was silenced in cultured mouse hippocampal neurons. We then screened FBLIM1 for rare exonic deletions/duplications in 549 Japanese ASD patients and 824 controls, detecting one case of ASD and intellectual delay that harbored a 26-kb deletion at 1p36.21 that solely included the C-terminal exon of FBLIM1. The FBLIM1 mRNA expression level in this case was reduced compared to levels in individuals without FBLIM1 deletion. Our findings indicate that tightly regulated expression of migfilin is essential for neuronal development and that FBLIM1 disruption may be related to the phenotypes associated with ASD and related neurodevelopmental disorders. PMID- 29114926 TI - Measures of clustering and heterogeneity in multilevel Poisson regression analyses of rates/count data. AB - Multilevel data occur frequently in many research areas like health services research and epidemiology. A suitable way to analyze such data is through the use of multilevel regression models. These models incorporate cluster-specific random effects that allow one to partition the total variation in the outcome into between-cluster variation and between-individual variation. The magnitude of the effect of clustering provides a measure of the general contextual effect. When outcomes are binary or time-to-event in nature, the general contextual effect can be quantified by measures of heterogeneity like the median odds ratio or the median hazard ratio, respectively, which can be calculated from a multilevel regression model. Outcomes that are integer counts denoting the number of times that an event occurred are common in epidemiological and medical research. The median (incidence) rate ratio in multilevel Poisson regression for counts that corresponds to the median odds ratio or median hazard ratio for binary or time-to event outcomes respectively is relatively unknown and is rarely used. The median rate ratio is the median relative change in the rate of the occurrence of the event when comparing identical subjects from 2 randomly selected different clusters that are ordered by rate. We also describe how the variance partition coefficient, which denotes the proportion of the variation in the outcome that is attributable to between-cluster differences, can be computed with count outcomes. We illustrate the application and interpretation of these measures in a case study analyzing the rate of hospital readmission in patients discharged from hospital with a diagnosis of heart failure. PMID- 29114927 TI - Genetic study of non-syndromic tooth agenesis through the screening of paired box 9, msh homeobox 1, axin 2, and Wnt family member 10A genes: a case-series. AB - Non-syndromic tooth agenesis (NSTA) is the most common developmental anomaly in humans. Several studies have been conducted on dental agenesis and numerous genes have been identified. However, the pathogenic mechanisms responsible for NSTA are not clearly understood. We studied a group of 28 patients with sporadic NSTA and nine patients with a family history of tooth agenesis. We focused on four genes - paired box 9 (PAX9), Wnt family member 10A (WNT10A), msh homeobox 1 (MSX1), and axin 2 (AXIN2) - using direct Sanger sequencing of the exons and intron-exon boundaries. The most prevalent variants identified in PAX9 and AXIN2 genes were analyzed using the chi-square test. The sequencing results revealed a number of variants in the AXIN2 gene, including one novel missense mutation in one patient with agenesis of a single second premolar. We also identified one variant in the AXIN2 gene as being a putative risk factor for tooth agenesis. Only one missense mutation was identified in the WNT10A gene and this mutation was found in two patients. Interestingly, WNT10A is reported as the most prevalent gene mutated in the European population with NSTA. PMID- 29114928 TI - A new substitute for formalin: Application to embalming cadavers. AB - The development of formalin-free fixatives is an urgent issue in gross anatomy because of the health hazard and the tissue-hardening actions of formalin. We recently identified the fixative, antimicrobial, and preservative effects of N vinyl-2-pyrrolidone (NVP), a precursor of the water-soluble macromolecular polymer polyvinylpyrrolidone, in animal experiments. The aim of the present study is to investigate whether NVP solution can be used as an alternative to formalin in human cadaveric dissection. Twelve donated cadavers were infused with NVP via the femoral and common carotid arteries using a peristaltic pump. Experienced teaching staff members in our department dissected the cadavers and examined their macroanatomical properties. The NVP-embalmed corpses showed no sign of decomposition or fungal growth. The bodies remained soft and flexible. Notably, the shoulder, elbow, wrist, phalangeal, hip, knee, cervical spine, and temporomandibular joints were highly mobile, almost equivalent to those of living individuals. The range of motion of most joints was greater in the NVP-fixed than formalin-fixed cadavers. Under the dermis, the subcutaneous fat was markedly reduced and the connective tissues were transparent, so the ligaments, cutaneous nerves, and veins were easily discernible. The abdominal wall and the visceral organs remained pliable and elastic, resembling those of fresh cadavers. The lungs, liver, and gastrointestinal tract were moveable in the thoracic and abdominal cavities and were readily isolated. NVP can be used successfully as a fixative and preservative solution for human cadavers; furthermore, NVP-embalmed bodies could be valuable for learning clinical skills and for training, and for developing innovative medical devices. Clin. Anat. 31:90-98, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29114929 TI - Disfiguring facial mycoses - a diagnostic and therapeutic challenge. PMID- 29114930 TI - Pediatric Diamond-Blackfan anemia in the Netherlands: An overview of clinical characteristics and underlying molecular defects. AB - INTRODUCTION: Diamond-Blackfan anemia (DBA) is characterized by hypoplastic anemia, congenital anomalies, and a predisposition for malignancies. Most of our understanding of this disorder stems from molecular studies combined with extensive data input from international patient registries. OBJECTIVES: To create an overview of the pediatric DBA population in the Netherlands. METHODS: Forty three patients diagnosed with DBA from all Dutch university pediatric hospitals were included in this study, and their clinical and genetic characteristics were collected from patient records. RESULTS: Congenital malformations were present in 24 of 43 patients (55.8%). An underlying genetic defect was identified in 26 of 43 patients (60.5%), the majority of which were found in the RPS19 gene (12 of 43, 27.9%) with 1 patient carrying a mutation in a novel DBA candidate gene, RPL9. In 31 of 35 (88.6%) patients, an initial response to glucocorticoid treatment was observed. Six patients (14.0%) underwent hematopoietic stem cell transplantation, and eleven patients (11 of 43, 25.6%) became treatment independent spontaneously. CONCLUSION: In agreement with previous reports, the Dutch pediatric DBA population is both clinically and genetically heterogeneous. National and international registries, together with more extensive genetic testing, are crucial to increase our understanding of genotype and phenotype correlations of this intriguing disorder. PMID- 29114932 TI - Risk factors for post-transplant lymphoproliferative disorder after Thymoglobulin conditioned hematopoietic cell transplantation. AB - Epstein-Barr virus (EBV)-induced post-transplant lymphoproliferative disorder (PTLD) occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG-conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy-diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy. Donor positive with recipient negative EBV (D+R-) serostatus was a risk factor for developing PTLD. Older patient age, HLA-mismatched donor, and graft-versus-host disease were not associated with increased risk of PTLD. In summary, in ATG-conditioned HCT, D+R- serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival. PMID- 29114931 TI - Thrombotic microangiopathy with concomitant GI aGVHD after allogeneic hematopoietic stem cell transplantation: Risk factors and outcome. AB - OBJECTIVES: To explore the possible risk factors for the occurrence and mortality of thrombotic microangiopathy (TMA) with concomitant acute graft-vs-host disease (aGVHD) and to investigate outcomes and treatments of this disorder after allo HSCT. METHODS: Fifty cases diagnosed with TMA with concomitant aGVHD and 150 controls were identified from a cohort composed of 3992 patients who underwent allo-HSCT from 2008 to 2016. RESULTS: Grade III-IV aGVHD (P = .000), acute kidney injury (AKI) (P = .033), and hypertension (P = .028) were significant independent risk factors associated with the occurrence of TMA with concomitant aGVHD. A haptoglobin level below normal (P = .013), a maximum volume of diarrhea >2500 mL/d (P = .015), and bloody diarrhea (P = .049) were significant markers for death in both univariate and multivariate analyses. Patients diagnosed with TMA with concomitant aGVHD had a lower overall survival (OS), a higher non-relapse mortality (NRM), but a lower risk of relapse. CONCLUSIONS: Thrombotic microangiopathy with concomitant aGVHD is a significant complication after allo HSCT, with a worse outcome, including significantly lower OS and higher NRM. There are specific risk factors associated with occurrence and mortality of this complication. PMID- 29114933 TI - Di(1-naphthyl) methanol ester of carboxylic acids for absolute stereochemical determination. AB - The absolute stereochemistry of chiral carboxylic acids is determined as a di(1 naphthyl)methanol ester derivative. Computational scoring of conformations favoring either P or M helicity of the naphthyl groups, capable of exciton coupled circular dichroic coupling, leads to a predicted stereochemistry for the derivatized carboxylic acids. PMID- 29114934 TI - Illegal fishing and territorial user rights in Chile. AB - Illegal fishing poses a major threat to conservation of marine resources worldwide. However, there is still limited empirical research that quantifies illegal catch levels. We used the randomized response technique to estimate the proportion of divers and the quantities of loco (Concholepas concholepas) they extracted illegally. Loco have been managed for the past 17 years through a territorial user rights for fisheries system (TURFs) in Chile. Illegal fishing of loco was widespread within the TURFs system. Official reported landings (i.e., legal landings) accounted for 14-30% of the total loco extraction. Our estimates suggest that ignoring the magnitude of illegal fishing and considering only official landing statistics may lead to false conclusions about the status and trends of a TURFs managed fishery. We found evidence of fisher associations authorizing their members to poach inside TURFs, highlighting the need to design TURFs systems so that government agencies and fishers' incentives and objectives align through continuous adaptation. Government support for enforcement is a key element for the TURFs system to secure the rights that are in place. PMID- 29114935 TI - Response to Beyond the burn: psychosocial factors as well as inflammation moderate depression in psoriasis. PMID- 29114936 TI - Examination of olfactory training effectiveness in relation to its complexity and the cause of olfactory loss. AB - OBJECTIVE: Although the effectiveness of olfactory training (OT) had already been documented, the optimal regimen for such training remains unexplored. We examined whether the complexity of OT, namely alteration of odor quantity and quality, increases its effectiveness. DESIGN: One-hundred eight patients (Mage = 60.1 +/- 1) with postinfectious (n = 57) or idiopathic (n = 51) olfactory dysfunction underwent OT preceded and followed by examination of olfactory function. METHODS: Subjects were randomly assigned to one of the three experimental conditions: 1) simple training comprising four basic, single-molecule substances; 2) complex training involving four odor mixtures; and 3) odor-altering training in which patients changed sets of mixtures every 2 months. RESULTS: The analysis of variance revealed that the benefit seen in this sample was not affected by the complexity of OT with regard to odor mixtures or alteration of odor type. The highest increase of the Sniffin' Sticks (Burghardt GmbH; Wedel, Germany) threshold, discrimination, and identification (and overall TDI) score was observed in postinfectious patients. CONCLUSION: We conclude that the outcomes of OT are not strongly influenced by the training regimen. However, further investigation of OT regimens is required, particularly with regard to training duration. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1518-1522, 2018. PMID- 29114937 TI - Epidemiologic, clinical and demographic features of primary cutaneous lymphomas in Castilla-La Mancha, Spain: are we different? PMID- 29114939 TI - Three-dimensional endoscopy for endoscopic salvage nasopharyngectomy: Preliminary report of experience. AB - BACKGROUND: Prospective, observational study to assess the efficacy of salvage nasopharyngectomy for recurrent nasopharyngeal carcinoma (NPC) via the endoscopic endonasal approach using a three-dimensional (3D) high-definition endoscopic system. METHODS: Between 2016 and 2017, 30 patients with recurrent NPC were recruited. Patient demographics, tumor characteristics, and perioperative data were recorded. Instrument ergonomics and perceived advantages were assessed by the operating, assisting, and observing surgeons. RESULTS: The majority (70%) of patients received radiotherapy alone as the initial treatment for NPC, and tumor recurred after a mean interval of 16.8 months. The tumor (T) classifications of the recurrent (R) tumors were: RT1: 46.7%; RT2: 33.3%; and RT3: 20.0%. The mean operative time was 293.3 minutes, and no conversion to open approach was necessary. Internal carotid artery dissection was required in nine patients, and the resection and repair of dura was required in six patients. The most common method of reconstruction was free vastus lateralis flap (46.7%). Microscopically clear resection margins were achieved in 73.3% of patients. The mean hospital stay was 6.8 days. There was no hospital mortality. One patient developed minor secondary hemorrhage, whereas the other developed transient contralateral vocal cord paralysis. On quantitative assessment, surgeons noticed a significant advantage of the 3D system with regard to depth and size perception, anatomy identification, and hand-eye coordination, whereas there was no significant difference in terms of strain sensation and dizziness. CONCLUSION: The 3D high definition endoscopic system improves the precision of endoscopic nasopharyngectomy, particularly when dissection of the internal carotid artery and dura is required. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1386-1391, 2018. PMID- 29114938 TI - Immune response patterns in non-communicable inflammatory skin diseases. AB - Non-communicable inflammatory skin diseases (ncISD) such as psoriasis or atopic eczema are a major cause of global disease burden. Due to their impact and complexity, ncISD represent a major challenge of modern medicine. Dermatology textbooks describe more than 100 different ncISD based on clinical phenotype and histological architecture. In the last decades, this historical description was complemented by increasing molecular knowledge - and this knowledge is now being translated into specific therapeutics. Combining the enormous advances made in lymphocyte immunology and molecular genetics with clinical and histological phenotyping reveals six immune response patterns of the skin - type I immune cells cause the lichenoid pattern characterized by immune-mediated cell death of keratinocytes; type II immune cells underlie the eczematous pattern with impaired epidermal barrier, infection and eosinophils as well as the bullous pattern with loss of epithelial integrity; Th17 cells and ILC3 mediate the psoriatic pattern characterized by acanthosis, high metabolic activity and neutrophils; dysbalance of regulatory T cells causes either the fibrogenic pattern with rarefication of cells and dermal thickening or the granulomatous pattern defined by formation of granulomas. With more and more specific therapeutic agents approved, classifying ncISD also according to their immune response pattern will become highly relevant. This review defines the six immune response patterns of ncISD and highlights therapeutic strategies targeting key lymphocyte mediators. PMID- 29114941 TI - Broaden your pedagogy! PMID- 29114940 TI - Access to palliative care as public health priority-Yes, you heard me right. PMID- 29114942 TI - A detailed analysis of 'not relevant' responses on the DLQI in psoriasis: potential biases in treatment decisions. AB - BACKGROUND: Dermatology Life Quality Index (DLQI) is the most common health related quality of life measure in dermatology that is widely used in treatment guidelines for psoriasis. Eight of the 10 questions of the DLQI offer a 'not relevant' response (NRR) option that is scored as the item had no impact on patients' life at all. OBJECTIVE: To explore the occurrence of NRRs on the DLQI in psoriasis patients and to examine the effect of several socio-demographic and clinical factors on giving NRRs. METHODS: Data were obtained from two cross sectional surveys among psoriasis patients at two academic dermatology clinics in Hungary. Health-related quality of life was measured by employing DLQI and EQ-5D 3L, while disease severity was graded by Psoriasis Area and Severity Index (PASI). Multivariate logistic regression was applied to determine the predictors of providing NRRs. RESULTS: Mean age of the 428 patients was 49 years, and 65% were males. Mean PASI, DLQI and EQ-5D-3L index scores were 8.4 +/- 9.5, 6.8 +/- 7.4 and 0.74 +/- 0.28, respectively. Overall, 38.8% of the patients had at least one NRR: 19.6% (one), 11.5% (two), 5.1% (three) and 2.6% (more than three). Most NRRs occurred in sport, sexual difficulties and working/studying items of the DLQI (28.4%, 16.4% and 14.0%, respectively). Female gender (OR 1.65; 95% CI 1.04 2.61), older age (OR 1.05; 95% CI 1.03-1.07) and higher PASI score (OR 1.03; 95% CI 1.01-1.06) were associated with providing more NRRs, whereas highly educated patients (OR 0.34; 95% CI 0.16-0.72) and those with a full-time job (OR 0.47; 95% CI 0.29-0.77) less frequently tended to tick NRRs. CONCLUSION: The high rate of psoriasis patients with NRRs, especially among women, less educated and elderly patients, indicates a content validity problem of the measure. A reconsideration of the use of the DLQI for medical and financial decision-making in psoriasis patients is suggested. PMID- 29114943 TI - Pharmacokinetics of Single Oral Dose Extended-Release Levetiracetam in Healthy Cats. AB - BACKGROUND: Repeated PO dosing of anti-epileptic drugs may contribute to poor compliance in treated cats. Intermediate-release levetiracetam has been used safely in cats, but must be given q8h to maintain serum concentrations in the therapeutic interval for humans (5-45 MUg/mL). Approved extended-release levetiracetam (XRL) for human use may require less frequent dosing, but the large dosing unit has limited its use in cats. HYPOTHESES: In healthy cats, serum levetiracetam concentration will remain above 5 MUg/mL for at least 24 hours after administration of a single dose of XRL PO and will be well tolerated. ANIMALS: 7 healthy cats. METHODS: Extended-release levetiracetam (500 mg) was administered PO. Blood was collected and neurologic examination findings recorded at scheduled times over 30 hours. Serum levetiracetam concentration was quantitated by an immunoassay validated in cats. Data were subjected to noncompartmental analysis. Descriptive statistics were reported. RESULTS: The median dosage of 86.2 mg/kg, (range, 80-94.3) achieved a mean maximum concentration (Cmax ) of 89.8 +/- 25.8 MUg/mL at 4.9 +/-1.57 hours. Serum levetiracetam was >5 MUg/mL in all cats by 90 minutes. Mean concentrations were 43.7 +/- 18.4 and 4.9 +/- 3.4 MUg/mL at 12 and 24 hours, respectively. The half life was 4.1 +/- 1.0 hours. The drug was well tolerated. CONCLUSIONS AND CLINICAL IMPORTANCE: A single 500 mg PO dose of XRL safely maintained serum levetiracetam concentration >=5 MUg/mL in healthy cats for at least 21 hours. Clinical efficacy studies in epileptic cats receiving XRL are indicated; however, monitoring should be implemented for individual cats. PMID- 29114944 TI - Conceptual Insights into DFT Spin-State Energetics of Octahedral Transition-Metal Complexes through a Density Difference Analysis. AB - In this study, an intuitive concept is derived, which explains the characteristic dependence of spin-state energetics on the exact exchange admixture of DFT functionals in the case of octahedral transition metal complexes. The change in electron density distributions upon varying the admixture, c3 , in the B3LYP functional is analyzed for archetype ionic and covalent systems as well as for the Fe2+ ion in an ideal octahedral field. An understanding of how the DFT description of the electronic structure of octahedral complexes changes as a function of c3 is sought. A systematic spin-state energy analysis of 50 octahedral complexes of various metals and ligands with consistent experimental data is presented, allowing the derivation, in theory, of an optimal c3 value for each system. The notion that the admixture dependence of DFT spin-state energetics stems from the treatment of nondynamic electrons arising from the mixing of (M-Lz2 )0 (dz2 )2 and (M-Lx2-y2 )0 (dx2-y2 )2 configurations into the dominant (M-Lx2-y2 )2 (dx2-y2 )0 and (M-Lx2-y2 )2 (dx2-y2 )0 ones in the low(er) spin states is put forward. That is, in the effort to mimic such electron electron interactions, ExLDA overestimates, whereas exact exchange downplays the contribution of this type of electron correlation to the stability of low(er) spin states, leading to the widespread practical observation that the higher the exact exchange admixture, the more stable the high-spin-state configuration. PMID- 29114946 TI - Reported gum disease as a cardiovascular risk factor in adults with intellectual disabilities. AB - BACKGROUND: Several risk factors for cardiovascular disease (CVD) have been identified among adults with intellectual disabilities (ID). Periodontitis has been reported to increase the risk of developing a CVD in the general population. Given that individuals with ID have been reported to have a higher prevalence of poor oral health than the general population, the purpose of this study was to determine whether adults with ID with informant reported gum disease present greater reported CVD than those who do not have reported gum disease and whether gum disease can be considered a risk factor for CVD. METHODS: Using baseline data from the Longitudinal Health and Intellectual Disability Study from which informant survey data were collected, 128 participants with reported gum disease and 1252 subjects without reported gum disease were identified. A series of univariate logistic regressions was conducted to identify potential confounding factors for a multiple logistic regression. RESULTS: The series of univariate logistic regressions identified age, Down syndrome, hypercholesterolemia, hypertension, reported gum disease, daily consumption of fruits and vegetables and the addition of table salt as significant risk factors for reported CVD. When the significant factors from the univariate logistic regression were included in the multiple logistic analysis, reported gum disease remained as an independent risk factor for reported CVD after adjusting for the remaining risk factors. Compared with the adults with ID without reported gum disease, adults in the gum disease group demonstrated a significantly higher prevalence of reported CVD (19.5% vs. 9.7%; P = .001). CONCLUSION: After controlling for other risk factors, reported gum disease among adults with ID may be associated with a higher risk of CVD. However, further research that also includes clinical indices of periodontal disease and CVD for this population is needed to determine if there is a causal relationship between gum disease and CVD. PMID- 29114945 TI - Hyperglycaemia induced by chronic i.p. and oral glucose loading leads to hypertension through increased Na+ retention in proximal tubule. AB - NEW FINDINGS: What is the central question of the study? Chronic glucose feeding accompanied by glucose injection (i.p.) causes sustained hyperglycaemia and hypertension in rats. The exact reason for the hypertension is not known. We explore some molecular pathways of the renal proximal tubule that might promote Na+ retention. What is the main finding and its importance? Development of hypertension was mediated by upregulation of the renal renin-angiotensin system and oxidative stress, acting via the Na+ -K+ -ATPase alpha1 -subunit in the proximal tubule, which appears to pump intracellular Na+ into the extracellular space, increasing Na+ reabsorption and blood pressure. Targeting the Na+ -K+ ATPase alpha1 -subunit might provide a therapeutic strategy for treatment of hypertension. Feeding animals glucose-, fructose-, sucrose- and fat-enriched diets can lead to diet-induced hyperglycaemia, the severity of which largely depends on the types and concentrations of the nutrients used and duration of the dietary intervention. As a dietary intervention strategy, we adopted glucose enriched diet and drinking water, with i.p. glucose injection at a dose previously determined to be effective to establish a sustained hyperglycaemia over a period of 2 weeks. We used four groups of Sprague-Dawley rats: control; glucose treated; glucose plus tempol treated; and glucose plus captopril treated. Blood glucose concentrations started to increase gradually from day 3, peaked (321 mg dl-1 ) at day 12 and remained at similar levels until the end of the study on day 14 in the glucose treated-group compared with the control group. In contrast, the tempol- and captopril-treated groups showed significantly high glucose concentrations only in the second week. The plasma insulin concentration was significantly increased in glucose-treated animals but not in tempol- and captopril-treated groups when compared with the control rats. We also observed elevated blood pressure in the glucose-treated group compared with the control group, which can be attributed to the increase in angiotensin II concentrations from 46.67 to 99 pg ml-1 (control versus glucose), increased oxidative stress in the cortical proximal tubule (PT), decreased urine flow, and increased expression and activity of the PT-specific alpha1 -subunit of Na+ -K+ -ATPase in the renal cortex, which is responsible for increased sodium reabsorption from epithelial cells of PT into the peritubular capillaries, leading to increased blood volume and eventual blood pressure. All these events were reversed in captopril- and tempol-treated animals. PMID- 29114947 TI - Household cleaning products and the risk of allergic dermatitis: a prospective cohort study with primary-school children. AB - BACKGROUND: Household cleaning products are widely used by the public, but limited data have been obtained on whether their use induces allergic dermatitis in children. OBJECTIVE: This study investigated the association between exposure to household cleaning products and allergic dermatitis in primary-school children. METHODS: A prospective cohort study of Hong Kong primary-school children was conducted between 2012 and 2014. A baseline survey was administered to 1812 students who did not have allergic dermatitis. Information on respiratory symptoms, exposure to household chemical cleaning products and other topics was collected using a self-administered questionnaire. A cumulative chemical burden (CCB) score was calculated for each student by summing the duration of exposure to 14 chemical cleaning products. Principal component analysis was used to identify patterns in the use of these cleaning products. Logistic regression was performed to calculate relative risk (RR) with 95% confidence intervals (CIs) after adjusting for potential confounders. RESULTS: Eighty-nine (4.9%) of the students surveyed had dermatitis during the follow-up. However, exposure to individual chemical cleaning products was not found to be associated with the children's allergic dermatitis (all P > 0.05). In contrast to those in the lowest tertile, neither CCB scores in the middle tertile (RR: 1.16, 95% CI: 0.67 to 2.00) nor those in the highest tertile (RR: 1.24, 95% CI: 0.73 to 2.14) were significantly associated with the risk of allergic dermatitis. The adjusted RR for every 5-unit increment in CCB score was 1.01 (95% CI: 0.98 to 1.03). Four patterns of cleaning-product use were derived, but none were found to be associated with the risk of dermatitis (all P > 0.05). CONCLUSION: The use of household chemical cleaning products is not associated with the risk of dermatitis in primary-school children. PMID- 29114948 TI - Excess mortality among 10-year survivors of classical Hodgkin lymphoma in adolescents and young adults. AB - Adolescents and young adults (AYA) surviving classical Hodgkin lymphoma (cHL) risk long term fatal treatment-related toxicities. We utilized the Surveillance, Epidemiology and End Results (SEER) program to compare excess mortality rate (EMR observed minus expected mortality) for 10-year survivors of AYA cHL diagnosed in 1973-1992 and 1993-2003 eras. The 15-year EMR reduced from 4.88% to 2.19% while the 20-year EMR reduced from 9.46% to 4.07% between eras. Survivors of stages 1-2 had lower EMR than survivors of stages 3-4 cHL in the 1993-2003 but not in the 1973-1992 era. There was an overall decline in risk of death between 10 and 15 years from diagnosis, driven mostly by second neoplasms and cardiovascular mortality. Despite reduction in fatal second neoplasms and cardiovascular disease with more current therapy, long term survivors of AYA cHL still have a higher risk of death than the general population highlighting the need for safer therapies. PMID- 29114949 TI - Protective effect of GDNF-engineered amniotic fluid-derived stem cells on the renal ischaemia reperfusion injury in vitro. AB - OBJECTIVES: Amniotic fluid-derived stem cells (AFSCs) possessing multilineage differentiation potential are proposed as a novel and accessible source for cell based therapy and tissue regeneration. Glial-derived neurotrophic factor (GDNF) has been hypothesized to promote the therapeutic effect of AFSCs on markedly ameliorating renal dysfunction. The aim of this study was to investigate whether AFSCs equipped with GDNF (GDNF-AFSCs) had capabilities of attenuating mouse renal tubular epithelial cells (mRTECs) apoptosis and evaluate its potential mechanisms. MATERIALS AND METHODS: A hypoxia-reoxygenation (H/R) model of the mRTECs was established. Injured mRTECs were co-cultured with GDNF-AFSCs in a transwell system. The mRNA expressions of hepatocytes growth factor (HGF) and fibroblast growth factor (bFGF) were detected by qRT-PCR. Changes of intracelluar reactive oxygen species (ROS) and the level of superoxide dismutase (SOD) and malondialdehyde (MDA) were examined. The expressions of nitrotyrosine, Gp91-phox, Bax, and Bcl-2 were determined by Western blotting. Cell apoptosis was assayed by flow cytometry, and caspase-3 activity was monitored by caspase-3 activity assay kit. RESULTS: Our study revealed that expression of growth factors was increased and oxidative stress was dramatically counteracted in GDNF-AFSCs-treated group. Furthermore, apoptosis induced by H/R injury was inhibited in mRTECs by GDNF AFSCs. CONCLUSIONS: These data indicated that GDNF-AFSCs are beneficial to repairing damaged mRTECs significantly in vitro, which suggests GDNF-AFSCs provide new hopes of innovative interventions in different kidney disease. PMID- 29114950 TI - Inorganic/Organic Double-Network Gels Containing Ionic Liquids. AB - Highly robust ion gels, termed double-network (DN) ion gels, composed of inorganic/organic interpenetrating networks and a large amount of ionic liquids (ILs), are fabricated. The DN ion gels with an 80 wt% IL content show extraordinarily high mechanical strength: more than 28 MPa of compressive fracture stress. In the DN ion gel preparation, a brittle inorganic network of physically bonded silica nanoparticles and a ductile organic network of polydimethylacrylamide (PDMAAm) are formed in the IL. Because of the different reaction mechanisms of the inorganic/organic networks, the DN ion gels can be formed by an easy and free-shapeable one-pot synthesis. They can be prepared in a controllable manner by manipulating the formation order of the inorganic and organic networks via not only multistep but also single-step processes. When silica particles form a network prior to the PDMAAm network formation, DN ion gels can be prepared. The brittle silica particle network in the DN ion gel, serving as sacrificial bonds, easily ruptures under loading to dissipate energy, while the ductile PDMAAm network maintains the shape of the material by the rubber elasticity. Given the reversible physical bonding between the silica particles, the DN ion gels exhibit a significant degree of self-recovery by annealing. PMID- 29114951 TI - Syntheses of Amino-Substituted Iridabenzofurans and Subsequent Selective N Functionalisation. AB - The first examples of amino-substituted fused-ring metallabenzenes, the cationic iridabenzofuran [Ir(C7 H4 O{NH2 -2}{OMe-7})(CO)(PPh3 )2 ][O3 SCF3 ] (5) and neutral analogue Ir(C7 H4 {NH2 -2}{OMe-7})Cl(PPh3 )2 (6), can be prepared by reduction of the corresponding nitro-substituted iridabenzofurans with zinc and concentrated hydrochloric acid. N-functionalised derivatives of 5 and 6 are formed through alkylation, sulfonylation or acylation. Thus, consecutive treatments with methyl triflate and base gives the corresponding trimethylammonium-substituted iridabenzofurans while sulfonamide derivatives are formed with p-toluenesulfonyl chloride. N-Acylation of 5 or 6 with acid chlorides, however, selectively form either amide or imide products depending on the charge on the metal and the steric size of the acid chloride. Cationic 5 gives amide substituted products regardless of the conditions whereas neutral 6 rapidly undergoes di-N-acylation with excess benzoyl chloride under mild conditions to give the imide-substituted product Ir(C7 H4 O{N[C(O)Ph]2 -2}{OMe 7})Cl(PPh3 )2 (13). Selective mono-acylation of 6 can be achieved with one equivalent of benzoyl chloride or with excess of the sterically congested pivaloyl chloride. PMID- 29114952 TI - Age-related microvascular dysfunction: novel insight from near-infrared spectroscopy. AB - NEW FINDINGS: What is the central question of this study? Can near-infrared spectroscopy (NIRS)-derived post-occlusion tissue oxygen saturation recovery kinetics be used to study age-related impairments in microvascular function? What is the main finding and its importance? Using a previously established 5 min cuff occlusion protocol, we found that NIRS-derived indices of microvascular function were markedly reduced in elderly compared with young participants. However, when we controlled for the absolute level of vasodilatory stimulus and matched the tissue desaturation level between groups, we found similar responses in young and elderly participants. Overall, these data highlight the important role NIRS can serve in clinical vascular biology, but also establish the need for assessing tissue ischaemia during cuff occlusion protocols. Near-infrared spectroscopy (NIRS) has emerged as a promising tool to evaluate vascular reactivity in vivo. Whether this approach can be used to assess age-related impairments in microvascular function has not been tested. Tissue oxygen saturation (StO2) post occlusion recovery kinetics were measured in two distinct age groups (<35 and >65 years of age) using NIRS placed over the flexor digitorum profundus. Key end points included the following: (i) the desaturation rate during cuff occlusion; (ii) the lowest StO2 value obtained during ischaemia (StO2min); (iii) StO2 reperfusion rate; (iv) the highest StO2 value reached after cuff release (StO2max); and (v) the reactive hyperaemia area under the curve (AUC). At first, using a conventional 5 min cuff occlusion protocol, the elderly participants achieved a much slower rate of oxygen recovery (1.5 +/- 0.2 versus 2.5 +/- 0.2% s 1 ), lower StO2max (85.2 +/- 2.9 versus 92.3 +/- 1.5%) and lower reactive hyperaemia AUC (2651.8 +/- 307.0 versus 4940.0 +/- 375.8% s-1 ). However, owing to a lower skeletal muscle resting metabolic rate, StO2min was also significantly attenuated in the elderly participants compared with the young control subjects (55.7 +/- 3.5 versus 41.0 +/- 3.4%), resulting in a much lower ischaemic stimulus. To account for this important difference between groups, we then matched the level of tissue ischaemia in a subset of young healthy participants by reducing the cuff occlusion protocol to 3 min. Remarkably, when we controlled for tissue ischaemia, we observed no differences in any of the hyperaemic end points between the young and elderly participants. These data highlight the important role NIRS can serve in vascular biology, but also establish the need for assessing tissue ischaemia during cuff occlusion protocols. PMID- 29114954 TI - Maldistribution or scarcity of nurses? The devil is in the detail. AB - AIMS: The goal of this paper was to improve our understanding of nursing shortages across the variety of health care sectors and how this may affect the agenda for addressing nursing shortages. A health care sector comprises a number of health care services for one particular type of patient care, for example, the hospital care sector. BACKGROUND: Most Western countries are shifting health care services from hospital care towards community and home care, thus increasing nursing workforce challenges in home and community care. In order to implement appropriate policy responses to nursing workforce challenges, we need to know if these challenges are caused by maldistribution of nurses and/or the scarcity of nurses in general. EVALUATION: Focusing on the Netherlands, we reviewed articles based on data of a labour market research programme and/or data from the Dutch Employed Persons' Insurance Administration Agency. The data were analysed using a data synthesis approach. KEY ISSUES: Nursing shortages are unevenly distributed across the various health care sectors. Shortages of practical nurses are caused by maldistribution, with a long-term projected surplus of practical nurses in hospitals and projected shortages in nursing/convalescent homes and home care. Shortages of first-level registered nurses are caused by general scarcity in the long term, mainly in hospitals and home care. CONCLUSIONS: Nursing workforce challenges are caused by a maldistribution of nurses and the scarcity of nurses in general. To implement appropriate policy responses to nursing workforce challenges, integrated health care workforce planning is necessary. IMPLICATIONS FOR NURSING MANAGEMENT: Integrated workforce planning models could forecast the impact of health care transformation plans and guide national policy decisions on transitioning programmes. Effective transitioning programmes are required to address nursing shortages and to diminish maldistribution. In addition, increased recruitment and retention as well as new models of care are required to address the scarcity of nurses in general. PMID- 29114955 TI - Culture, cultural competence and the cross-cultural consultation. PMID- 29114953 TI - Expanding the paradigm for the outer membrane: Acinetobacter baumannii in the absence of endotoxin. AB - Asymmetry in the outer membrane has long defined the cell envelope of Gram negative bacteria. This asymmetry, with lipopolysaccharide (LPS) or lipooligosaccharide (LOS) exclusively in the outer leaflet of the membrane, establishes an impermeable barrier that protects the cell from a number of stressors in the environment. Work done over the past 5 years has shown that Acinetobacter baumannii has the remarkable capability to survive with inactivated production of lipid A biosynthesis and the absence of LOS in its outer membrane. The implications of LOS-deficient A. baumannii are far-reaching - from impacts on cell envelope biogenesis and maintenance, bacterial physiology, antibiotic resistance and virulence. This review examines recent work that has contributed to our understanding of LOS-deficiency and compares it to studies done on Neisseria meningitidis and Moraxella catarrhalis; the two other organisms with this capability. PMID- 29114956 TI - Quality Control of Compounded Crystalloid Fluids for Intravenous Delivery to Horses. AB - BACKGROUND: Periodic lack of availability and high cost of commercially produced isotonic fluids for intravenous (IV) use in horses have increasingly led to use of home-made or commercially compound fluids by veterinarians. Data regarding the quality control and safety of compounded fluids would be of benefit to equine veterinarians. OBJECTIVES: To compare electrolyte concentrations, sterility, and endotoxin contamination of commercially available fluids to 2 forms of compounded isotonic crystalloid fluids intended for IV use in horses. METHODS: Prospective study. Two methods of preparing compounded crystalloids formulated to replicate commercial Plasma-Lyte A (Abbott, Chicago, IL) were compared. One formulation was prepared by a hand-mixed method involving chlorinated drinking water commonly employed by equine practitioners, and the other was prepared by means of ingredients obtained from a commercial compounding pharmacy. The variables for comparison were electrolyte concentrations, sterility, and presence of endotoxin contamination. RESULTS: Electrolyte concentrations were consistent within each product but different between types of fluids (P < 0.0001). Hand-mixed fluids had significantly more bacterial contamination compared to commercial Plasma-Lyte A (P = 0.0014). One of the hand-mixed fluid samples had detectable endotoxin contamination. CONCLUSIONS AND CLINICAL IMPORTANCE: Chlorinated drinking water is not an acceptable source of water to compound isotonic fluids for IV administration. Equine practitioners should be aware of this risk and obtain the informed consent of their clients. PMID- 29114957 TI - Sinonasal cancer in the Italian national surveillance system: Epidemiology, occupation, and public health implications. AB - BACKGROUND: Sinonasal cancer (SNC) is a rare tumor with predominant occupational etiology associated with exposures to specific carcinogens. The aim of this study is to describe SNC cases recorded in Italy in the period 2000-2016. METHODS: Clinical information, occupational history, and lifestyle habits of SNC cases collected in the Italian Sinonasal Cancer Register were examined. Age standardized rates were estimated. RESULTS: Overall, 1529 cases were recorded. The age-standardized incidence rates per 100 000 person-years were 0.65 in men and 0.26 in women. Occupational exposures were predominant among the attributed exposure settings, primarily to wood and leather dusts. Other putative causal agents included chrome, solvents, tannins, formaldehyde, textile dusts, and pesticides. Many cases had unknown exposure. CONCLUSIONS: Epidemiological surveillance of SNC cases and their occupational history is fundamental for monitoring the occurrence of the disease in exposed workers in industrial sectors generally not considered at risk of SNC as well as in non-occupational settings. PMID- 29114959 TI - Focal regression of a primary melanoma, fading lentigines and poliosis in metastatic melanoma treated with anti-PD-1. PMID- 29114958 TI - Evidence for multiple modes of neutrophil serine protease recognition by the EAP family of Staphylococcal innate immune evasion proteins. AB - Neutrophils contain high levels of chymotrypsin-like serine proteases (NSPs) within their azurophilic granules that have a multitude of functions within the immune system. In response, the pathogen Staphylococcus aureus has evolved three potent inhibitors (Eap, EapH1, and EapH2) that protect the bacterium as well as several of its secreted virulence factors from the degradative action of NSPs. We previously showed that these so-called EAP domain proteins represent a novel class of NSP inhibitors characterized by a non-covalent inhibitory mechanism and a distinct target specificity profile. Based upon high levels of structural homology amongst the EAP proteins and the NSPs, as well as supporting biochemical data, we predicted that the inhibited complex would be similar for all EAP/NSP pairs. However, we present here evidence that EapH1 and EapH2 bind the canonical NSP, Neutrophil Elastase (NE), in distinct orientations. We discovered that alteration of EapH1 residues at the EapH1/NE interface caused a dramatic loss of affinity and inhibition of NE, while mutation of equivalent positions in EapH2 had no effect on NE binding or inhibition. Surprisingly, mutation of residues in an altogether different region of EapH2 severely impacted both the NE binding and inhibitory properties of EapH2. Even though EapH1 and EapH2 bind and inhibit NE and a second NSP, Cathepsin G, equally well, neither of these proteins interacts with the structurally related, but non-proteolytic granule protein, azurocidin. These studies expand our understanding of EAP/NSP interactions and suggest that members of this immune evasion protein family are capable of diverse target recognition modes. PMID- 29114960 TI - Registered nurses' perceptions of rewarding and its significance. AB - AIM: To examine reward type preferences and their relationships with the significance of rewarding perceived by registered nurses in Finland. BACKGROUND: Previous studies have found relationships between nurses' rewarding and their motivation at work, job satisfaction and organisational commitment. METHODS: Data were collected in a cross-sectional, descriptive, questionnaire survey from 402 registered nurses using the Registered Nurses' Perceptions of Rewarding Scale in 2015, and analysed with descriptive and multivariate statistical methods. RESULTS: Registered nurses assigned slightly higher values to several non financial than to financial rewards. The non-financial reward types appreciation and feedback from work community, worktime arrangements, work content, and opportunity to develop, influence and participate were highly related to the significance of rewarding. CONCLUSIONS: We identified various rewards that registered nurses value, and indications that providing an appropriate array of rewards, particularly non-financial rewards, is a highly beneficial element of nursing management. IMPLICATIONS FOR NURSING MANAGEMENT: It is important to understand the value of rewards for nursing management. Nurse managers should offer diverse rewards to their registered nurses to promote excellent performance and to help efforts to secure and maintain high-quality, safe patient care. The use of appropriate rewards is especially crucial to improving registered nurses' reward satisfaction and job satisfaction globally in the nursing profession. PMID- 29114961 TI - The importance of dermoscopy for the diagnosis of acquired bilateral telangiectatic macules: the angioid streak pattern reveals underlying chronic liver disease. AB - BACKGROUND: Acquired bilateral telangiectatic macules (ABTM) are a newly recognized disease entity, which manifest as multiple telangiectatic pigmented macules confined mostly to the upper arms. OBJECTIVES: To evaluate clinical and dermoscopic features in a group of 50 patients with ABTM and to determine the diagnostic usefulness of dermoscopy in ABTM. METHODS: Patients were selected from two tertiary teaching hospitals in Korea [Pusan National University Hospitals (Busan and Yangsan)]. Fifty patients (41 males and 9 females; mean age 48.1 years; range 26-78 years) with ABTM were included in the study. The dermoscopic findings were graded using a 4-point scale: none (0), mild (1), moderate (2) and severe (3). In addition, the results of 23 patients with and 27 patients without chronic liver disease (CLD) were compared to determine whether the presence of CLD affects dermoscopic findings. RESULTS: Three distinct dermoscopic patterns were observed; brown pigmentations, telangiectasia (linear-irregular vessels) and an angioid streak pattern. Brown pigmentation in the group without CLD had higher severity score than those in CLD group (mean score: 2.00 vs. 1.48, P = 0.033). However, mean telangiectasia severity score was higher in the CLD group (2.14 vs. 1.39, P < 0.001). The angioid streak pattern was more severe and more common in patients with CLD than in those without [1.37 vs. 0.35 (P < 0.001) and 63.0% vs. 26.1%, respectively]. CONCLUSIONS: Detailed observations with dermoscopy can provide first clues of the presence of ABTM and underlying chronic liver disease. PMID- 29114962 TI - Annual Report of the Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2016: Overall report on a comprehensive retrospective study of obstetric management of preterm labor and preterm premature rupture of the membranes. AB - We conducted a questionnaire survey on the current obstetric management of preterm labor (PL) and preterm premature rupture of the membranes (pPROM). The questionnaire covered approximately a third of all preterm deliveries and nearly half of the preterm deliveries before 32 gestational weeks. The diagnostic criterion for PL was either painful uterine contractions or cervical dilatation. Tocolytic agents were primarily used as long-term maintenance therapy. Intrauterine infection was clinically diagnosed at most responding institutions. Amniocentesis was performed for PL or pPROM at only a small number (10%) of institutions. Prenatal steroids were administered for PL or pPROM, if indicated, at approximately 40-60% of responding institutions. Prophylactic antibiotics to maintain pregnancy were administered for pPROM at approximately 90% and for PL at approximately 20% of institutions. Maintenance therapy with a tocolytic agent was used for pPROM at approximately 90% of institutions. PMID- 29114963 TI - Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose-finding trials. AB - Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who were initially treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in 9 phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDI of the conventional RP2D group were maintained a rate of >=70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In both groups, however, the decreasing RDI over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies. PMID- 29114964 TI - Chief physicians' attitudes towards early warning score systems in Switzerland: Results of a cross-sectional survey. AB - RATIONALE, AIMS AND OBJECTIVES: Early warning score systems (EWS-S) have been shown to be valuable tools to recognize otherwise unnoticed clinical deterioration (CDET) of patients. They have been associated with fewer unplanned transfers to the intensive care unit (UTICU) and lower in-hospital mortality. Little is known about their current usage in Switzerland and about the attitudes towards such tools among chief physicians. We aimed to assess the use of EWS-S in Switzerland and the attitudes of chief physicians towards EWS-S depending on previously experienced CDET followed by UTICU, reanimation, or death. METHODS: Chief physicians of medical and surgical departments from all acute care hospitals in Switzerland were asked to participate within a project that aims to develop recommendations for the use of EWS-S in Switzerland (n = 118). The explorative study assessed perceived CDET, which led to UTICU, reanimation, or death of a patient, the knowledge and usage about different EWS-S and attitudes towards EWS-S in a written questionnaire. Means and percentages were used, and differences were assessed with independent t tests, chi-square, or Fisher exact test, as appropriate. RESULTS: Adverse events based on CDET were reported frequently, and awareness among chief physicians was high. Less than half of the chief physicians knew tools that systematically assess CDET with one-fifth of responders reporting using tools at their department. Previous experiences of UTICU, reanimation, or death after due to CDET were associated with more positive attitudes towards EWS-S. CONCLUSIONS: Adverse events based on CDET of patients are frequent and the awareness of this problem is high among chief physicians. Positive attitudes were more common with previous experiences of adverse events due to CDET. Our results strengthen the argumentation that the recommendation and future implementation of EWS-S in Switzerland would be meaningful. PMID- 29114966 TI - A cross-sectional clinic-based study exploring whether variants within the glutathione S-transferase, haptoglobin and uridine 5'-diphospho glucuronosyltransferase 1A1 genes are associated with interindividual phenotypic variation in sickle cell anaemia in Jamaica. AB - OBJECTIVES: To explore putative associations between specific variants in either the glutathione S-transferase (GST), haptoglobin (HP) or uridine 5'-diphospho glucuronosyltransferase 1A1 (UGT1A1) genes and clinically important phenotypes in sickle cell anaemia (HbSS). METHODS: 371 HbSS participants were recruited from the Sickle Cell Clinic of the Sickle Cell Unit at the University of the West Indies, Kingston, Jamaica. Markers within four GST superfamily genes, the HP gene and the UGT1A1 gene were analysed using PCR-based assays. RESULTS: Multivariable regression revealed statistically significant associations between the GSTP1 Ile105Val heterozygote and HbA2 levels (P = .016), HbF percentage (P = .001), MCH concentration (P = .028) and reticulocyte count (P = .032), while the GSTM3 D/D homozygote was significantly associated with HbA2 levels (P = .032). The UGT1A1 (TA)6 /(TA)8 heterozygote showed statistically significant associations with HbA2 levels (P = .019), HbF percentage (P < .001), haemoglobin levels (P = .008), PCV values (P = .007) and RBC counts (P = .041). CONCLUSION: This exploratory cross sectional study has generated novel and informative genotype-phenotype estimates of association, but larger studies are needed to determine whether these specific variants within the GST, UGT1A1 and HP genes are related to interindividual phenotypic variability in HbSS. PMID- 29114965 TI - Oxidative stress and inflammation mediate the effect of air pollution on cardio- and cerebrovascular disease: A prospective study in nonsmokers. AB - Air pollution is associated with a broad range of adverse health effects, including mortality and morbidity due to cardio- and cerebrovascular diseases (CCVD), but the molecular mechanisms involved are not entirely understood. This study aims to investigate the involvement of oxidative stress and inflammation in the causal chain, and to identify intermediate biomarkers that are associated retrospectively with the exposure and prospectively with the disease. We designed a case-control study on CCVD nested in a cohort of 18,982 individuals from the EPIC-Italy study. We measured air pollution, inflammatory biomarkers, and whole genome DNA methylation in blood collected up to 17 years before the diagnosis. The study sample includes all the incident CCVD cases among former- and never smokers, with available stored blood sample, that arose in the cohort during the follow-up. We identified enrichment of altered DNA methylation in "ROS/Glutathione/Cytotoxic granules" and "Cytokine signaling" pathways related genes, associated with both air pollution (multiple comparisons adjusted p for enrichment ranging from 0.01 to 0.03 depending on pollutant) and with CCVD risk (P = 0.04 and P = 0.03, respectively). Also, Interleukin-17 was associated with higher exposure to NO2 (P = 0.0004), NOx (P = 0.0005), and CCVD risk (OR = 1.79; CI 1.04-3.11; P = 0.04 comparing extreme tertiles). Our findings indicate that chronic exposure to air pollution can lead to oxidative stress, which in turn activates a cascade of inflammatory responses mainly involving the "Cytokine signaling" pathway, leading to increased risk of CCVD. Inflammatory proteins and DNA methylation alterations can be detected several years before CCVD diagnosis in blood samples, being promising preclinical biomarkers. Environ. Mol. Mutagen. 59:234-246, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29114967 TI - Effect of intravenous immunoglobulin administration on erythrocyte and leucocyte parameters. AB - BACKGROUND: Intravenous immunoglobulins (IVIG) are an attractive therapeutic tool for therapy of toxic epidermal necrolysis and severe forms of certain autoimmune diseases, including dermatomyositis, autoimmune blistering diseases, systemic vasculitis and lupus erythematodes. OBJECTIVES: Prompted by a case of IVIG associated haemolytic anaemia, the effects of IVIG administrations on haematological parameters in patients with dermatological conditions were investigated. METHODS: Erythrocyte and leucocyte parameters were retrospectively analysed in 16 patients who had received IVIG at doses from 1 to 3 g/kg bodyweight (n = 35 cycles). The influence of IVIG on leucocyte survival was determined in vitro. RESULTS: Decreased absolute erythrocyte numbers, haemoglobin and haematocrit levels and a case of haemolytic anaemia were linked to transfusion of high-, but not low-dose IVIG. In contrast, leucopenia post-IVIG occurred in the vast majority of the recipients, unrelated to the administered IVIG amounts. In vitro investigations revealed a dose-dependent impairment of cell survival by IVIG in the neutrophil and monocyte, but not in the lymphocyte subpopulations. In several IVIG preparations, substantial amounts of blood group anti-A/anti-B antibodies were detected which could have accounted for the observed changes in the haematological parameters in our study cohort. CONCLUSIONS: IVIG products should be administered strictly according to indications. Commercially available IVIG products can contain blood group specific antibodies that may induce haemolysis in some recipients. Monitoring of blood counts during applied IVIG therapy, especially when high doses are administered, is recommended. PMID- 29114968 TI - Trans10, cis12 conjugated linoleic acid increases triacylglycerol accumulation in goat mammary epithelial cells in vitro. AB - Trans10, cis12 conjugated linoleic acid (t10c12-CLA) is well-established in decreasing milk fat content and causing milk fat depression (MFD) in dairy cattle and goats. However, the detailed mechanisms of its effect are not completely understood. Therefore, we used goat mammary epithelial cells (GMECs) to further study the molecular mechanisms whereby t10c12-CLA regulates milk fat synthesis. The optimal concentration of t10c12-CLA (100 MUmol/L) for cell culture was determined through a cell vitality and morphology assay, and evaluation of abundance of apoptosis-related proteins. Oil red O stain indicated that t10c12 CLA increased concentration of cytoplasmic lipid droplets. Furthermore, t10c12 CLA increased the intracellular triacylglycerol (TG) content (P < 0.05). Among 16 genes related to lipid metabolism that were measured by quantitative real-time PCR, t10c12-CLA down-regulated (P < 0.05) genes involved in de novo fatty acid synthesis including FASN, ACACA and SCD1, and also down-regulated the protein expression of FASN and SCD1 but up-regulated (P < 0.05) the expression of CD36 and ADRP. Overall, the data indicate that a side effect of de novo fatty acid synthesis inhibition by t10c12-CLA is the up-regulation of fatty acid uptake and accumulation of lipid droplets in GMECs. The biologic reason for such an effect merits further study. PMID- 29114969 TI - Apathy in rapid eye movement sleep behaviour disorder is common and under recognized. AB - BACKGROUND AND PURPOSE: Apathy is an important neuropsychiatric feature of Parkinson's disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population. METHODS: Eighty-eight patients with polysomnographically proven RBD, 65 patients with PD and 33 controls were assessed for apathy using the Lille Apathy Rating Scale. Cognition and depression were also quantified. The sensitivity of the Unified Parkinson's Disease Rating Scale screening questions for apathy and depression was calculated. RESULTS: A total of 46% of patients with RBD were apathetic, compared with 31% of patients with PD in our sample. Most patients with RBD with depression were apathetic but more than half of apathetic patients were not depressed. The sensitivity of the single Unified Parkinson's Disease Rating Scale screening question was only 33% for mild apathy and 50% for severe apathy. CONCLUSIONS: Apathy is common in RBD and is underestimated by a single self-report question. Recognition of apathy as a distinct neuropsychiatric feature in RBD could aid targeted treatment interventions and might contribute to the understanding of prodromal PD. PMID- 29114970 TI - Risk factors for exacerbation of gastroesophageal varices and portosystemic encephalopathy during treatment with nucleos(t)ide analogs for hepatitis B virus related cirrhosis. AB - AIM: The aim of this study was to determine the risk factors for worsening of gastroesophageal varices (GEVs) and development of portosystemic encephalopathy in patients with hepatitis B virus (HBV)-related cirrhosis during nucleos(t)ide analog (NA) treatment. METHODS: One hundred and thirty-seven patients with HBV related cirrhosis were enrolled in this retrospective cohort study. Findings of portal hemodynamics with computed tomography, liver function, and endoscopic examinations during NA treatment were assessed. RESULTS: Among 137 patients, feeding vessels for GEVs (left gastric vein, posterior gastric vein, and short gastric vein) were present in 56 (41%) patients, and extrahepatic portosystemic shunt (paraesophageal vein, paraumbilicul vein, and splenorenal shunt) were present in 36 (26%) patients at the start of NA treatment. Although NA treatment was successful, significant improvements were not observed in portosystemic collateral vessels 3 years after NA treatment and GEVs were exacerbated in 48 (35%) patients. The cumulative 5- and 10-year exacerbation rate of GEVs was 27% and 50%, respectively. By multivariate analysis, the existence of feeding vessels for GEVs at the start of NA treatment was the independent predictive factor for the exacerbation of GEVs (P < 0.001). Eight patients who had extrahepatic portosystemic shunt at the start of NA treatment developed portosystemic encephalopathy during follow-up. The 3- and 5-year incidence of that was 5% and 8%, respectively. CONCLUSIONS: The presence of portosystemic collateral vessels at the start of NA treatment increases the risk of GEVs worsening and development of portosystemic encephalopathy in patients with HBV-related cirrhosis, despite improvement of liver function and success in reducing viral loads with NA treatment. PMID- 29114973 TI - Intracranial hypertension induced by internal jugular vein stenosis can be resolved by stenting. AB - BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension (IIH) is characterized by abnormally elevated intracranial pressure (ICP) without identifiable etiology. Recently, however, a subset of patients with presumed IIH have been found with isolated internal jugular vein (IJV) stenosis in the absence of intracranial abnormalities. METHODS: Fifteen consecutive patients were screened from 46 patients suspected as IIH and were finally confirmed as isolated IJV stenosis. The stenotic IJV was corrected with stenting when the trans stenotic mean pressure gradient (?MPG) was equal to or higher than 5.44 cmH2 O. Dynamic magnetic resonance venography, computed tomographic venography and digital subtraction angiography of the IJV, ?MPG, ICP, Headache Impact Test 6 and the Frisen papilledema grade score before and after stenting were compared. RESULTS: All the stenotic IJVs were corrected by stenting. ?MPG decreased and the abnormal collateral veins disappeared or shrank immediately. Headache, tinnitus, papilledema and ICP were significantly ameliorated at 14 +/- 3 days of follow-up (all P < 0.01). At 12 +/- 5.6 months of outpatient follow-up, headache disappeared in 14 out of 15 patients (93.3%), visual impairments were recovered in 10 of 12 patients (83.3%) and tinnitus resolved in 10 out of 11 patients (90.9%). In 12 out of 15 cases, the Frisen papilledema grade scores declined to 1 (0-2). The stented IJVs in all 15 patients kept to sufficient blood flows on computed tomographic venography follow-up without stenting-related adverse events. CONCLUSIONS: Non-thrombotic IJV stenosis may be a potential etiology of IIH. Stenting seems to be a promising option to address the issue of intracranial hypertension from the etiological level, particularly after medical treatment failure. PMID- 29114972 TI - Frontline therapy of acute promyelocytic leukemia: Randomized comparison of ATRA and intensified chemotherapy versus ATRA and anthracyclines. AB - OBJECTIVES: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). PATIENTS AND RESULTS: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade >=3 infections. CONCLUSIONS: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C containing regimen was associated with a lower relapse rate in high-risk APL. PMID- 29114971 TI - Patient and public perspectives of community pharmacies in the United Kingdom: A systematic review. AB - BACKGROUND: The United Kingdom has been at the forefront of enhancing pharmacist roles and community pharmacy services, particularly over the past decade. However, patient and public awareness of community pharmacy services has been limited. OBJECTIVE: To identify and synthesize the research literature pertaining to patient and public perspectives on: existing community pharmacy services, extended pharmacist roles and strategies to raise awareness of community pharmacy services. SEARCH STRATEGY: Systematic search of 8 electronic databases; hand searching of relevant journals, reference lists and conference proceedings. INCLUSION CRITERIA: UK studies investigating patient or public views on community pharmacy services or pharmacist roles from 2005 to 2016. DATA EXTRACTION AND SYNTHESIS: Data were extracted into a grid and subjected to narrative synthesis following thematic analysis. MAIN RESULTS: From the 3260 unique papers identified, 30 studies were included. Manual searching identified 4 additional studies. Designs using questionnaires (n = 14, 41%), semi-structured interviews (n = 8, 24%) and focus groups (n = 6, 18%) made up the greatest proportion of studies. Most of the studies (n = 28, 82%) were published from 2010 onwards and covered perceptions of specific community pharmacy services (n = 31). Using a critical appraisal checklist, the overall quality of studies was deemed acceptable. Findings were grouped into 2 main themes "public cognizance" and "attitudes towards services" each with 4 subthemes. DISCUSSION AND CONCLUSIONS: Patients and the public appeared to view services as beneficial. Successful integration of extended pharmacy services requires pharmacists' clinical skills to be recognized by patients and physicians. Future research should explore different approaches to increase awareness. PMID- 29114975 TI - Real-world evidence for off-label intravenous thrombolysis in acute ischaemic stroke. PMID- 29114974 TI - High proportions of dementia among SLE patients: A big data analysis. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting a wide range of systems including the peripheral and central nervous system. Cognitive impairment leading to dementia is one of the harmful central nervous system afflictions of SLE. The aim of this study was to investigate the association of SLE with dementia. METHODS: A cross-sectional study was conducted using Clalit Health Care database, the largest health maintenance organization in Israel with more than 4.4 million enrollees. Systemic lupus erythematosus patients were compared in a 1:5 ratio to age- and sex-matched controls. Chi square and t tests were used for univariate analysis, and a logistic regression model was used for multivariate analysis. RESULTS: The study included 4886 SLE patients and 24 430 age-frequency- and sex-frequency-matched controls without SLE. The proportion of dementia was higher among SLE patients compared to controls (1.56% and 0.51%, respectively; P < .001). This finding was consistent across all age groups by univariate analysis. In a multivariate logistic regression analysis, SLE was significantly associated with dementia (odds ratio = 1.51, 95% confidence interval, 1.11-2.04). CONCLUSION: Systemic lupus erythematosus is significantly associated with dementia. This finding should give rise to search for SLE in patients with an ambiguous cause for dementia, especially those with an early onset cognitive decline. PMID- 29114976 TI - A comparative study of viral capsids and bacterial compartments reveals an enriched understanding of shell dynamics. AB - In this work, we carry out a comparative study of the homo 360-mer structures of viral capsids and bacterial compartments. Different from viral 360-mers that all are arranged on a skewed right-handed icosahedral lattice with a triangulation number T of 7, the new 360-mer structure of AaLS-13, an engineered bacterial compartment, offers a novel open conformation that has a unique unskewed lattice arrangement with a triangulation number T of 1 and large keyhole-shaped pores in the shell. By comparing their differences, we are able to predict a closed conformation of AaLS-13 that has the same lattice arrangement as existing viral capsid structures and in which all the keyhole-shaped pores are shut. We find that there is a smooth transition pathway between the open and closed conformations. There exists another close conformation but with an opposite, left handedness, which, however, is not kinetically accessible from the open conformation. Our finding thus provides a clue why existing 360-mer capsid structures all share the same right handedness. We further show that the conformation transition between the open and closed forms aligns extremely well with the intrinsic dynamics of the system as revealed from normal mode analysis, indicating that conformation transition can be fully driven by thermal fluctuations. The significance of this work is that it provides a better understanding of shell dynamics of both viral capsids and bacterial compartments, paving a way for future study of pore dynamics and the selective permeability of these systems. PMID- 29114977 TI - Promoting normal birth and reducing caesarean section rates: An evaluation of the Rapid Improvement Programme. AB - This paper evaluates the impact of the 2008 Rapid Improvement Programme that aimed at promoting normal birth and reducing caesarean section rates in the English National Health Service. Using Hospital Episode Statistics maternity records for the period 2001-2013, a panel data analysis was performed to determine whether the implementation of the programme reduced caesarean sections rates in participating hospitals. The results obtained using either the unadjusted sample of hospitals or a trimmed sample determined by a propensity score matching approach indicate that the impact of the programme was small. More specifically there were 2.3 to 3.4 fewer caesarean deliveries in participating hospitals, on average, during the postprogramme period offering a limited scope for cost reduction. This result mainly comes from the reduction in the number of emergency caesareans as no significant effect was uncovered for planned caesarean deliveries. PMID- 29114978 TI - Photoinduced Remote Functionalisations by Iminyl Radical Promoted C-C and C-H Bond Cleavage Cascades. AB - A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp3 )-(sp3 ) and C(sp3 )-H bond cleavage gives access to distal carbon radicals that undergo SH 2 functionalisations. These mild, visible light-mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules. PMID- 29114979 TI - Weight cycling in adults with severe obesity: A longitudinal study. AB - AIM: Although weight cycling is a common phenomenon in treatment-seeking patients with obesity, its consequences on health outcomes have not yet been completely clarified. We therefore aimed to investigate the effect of one cycle of intentional weight loss and regain on energy expenditure, body composition, cardiovascular risk factors and psychosocial variables in patients with severe obesity. METHODS: Clinical and psychosocial variables were measured in 38 adult patients with severe obesity (body mass index (BMI): 43.5 +/- 7.2 kg/m2 ) consecutively readmitted to rehabilitative residential treatment (T1) for severe obesity after a cycle of weight loss (16.7 +/-7.7 kg) and regain (15.1 +/-11.3 kg), and compared with those recorded at a prior admission (T0). RESULTS: No significant differences were found between T0 and T1 values for weight, BMI, waist circumference, total body fat percentage, fat-free mass percentage, respiratory quotient, measured or predicted resting energy expenditure, metabolic adaptation, cardiovascular risk factors or psychosocial variables. However, younger patients (r = -0.38, P = 0.023) and those with higher historical weight (r = 0.43, P = 0.010) tended to regain more weight. CONCLUSIONS: The absence of negative physical and psychological effects of weight cycling indicates that the risk of weight regain should not be a barrier to encouraging weight loss efforts in patients with severe obesity. PMID- 29114980 TI - Synthesis of Metal Complexes with an Open-Cage Fullerene as the Ligand. AB - An open-cage C60 derivative 9 with anilino, hemiketal, and lactone moieties on the edge of the opening was prepared through a fullerene-mixed peroxide procedure. Key steps include decarbonylation, intramolecular Friedel-Crafts reaction and oxetane ring opening rearrangement. The open-cage compound 9 readily reacts with various metal salts. A nickel complex was obtained by treating 9 with NiCl2 at r.t. followed by purification on a silica gel column. Single-crystal X ray diffraction analysis showed that the nickel ion is coordinated to two ligands with an octahedral geometry. PMID- 29114981 TI - PtaB, a lim-domain binding protein in Aspergillus fumigatus regulates biofilm formation and conidiation through distinct pathways. AB - The exopolysaccharide galactosaminogalactan (GAG) plays an important role in mediating adhesion, biofilm formation, and virulence in the pathogenic fungus Aspergillus fumigatus. The developmental modifiers MedA, StuA, and SomA regulate GAG biosynthesis, but the mechanisms underlying this regulation are poorly understood. PtaB is a lim-domain binding protein that interacts with the transcription factor SomA and is required for normal conidiation and biofilm formation. Disruption of ptaB resulted in impaired GAG production and conidiation in association with a markedly reduced expression of GAG biosynthetic genes (uge3 and agd3), developmental regulators (medA and stuA), and genes involved in the core conidiation pathway. Overexpression of medA and dual overexpression of uge3 and agd3 in the DeltaptaB mutant increased biofilm formation but not conidiation, whereas overexpression of core conidiation genes rescued conidiation but not biofilm formation. Overexpression of stuA modestly increased both conidiation and biofilm formation. Analysis of ptaB truncation mutants revealed that overexpression of the lim-domain binding region restored conidiation but not biofilm formation, suggesting that ptaB may govern these processes by interacting with different partners. These studies establish that PtaB governs GAG biosynthesis at the level of substrate availability and polymer deacetylation and that PtaB-mediated biofilm formation and conidiation are largely independent pathways. PMID- 29114982 TI - Use of key word signing by staff in special schools and in day centres for adults with intellectual disabilities. AB - BACKGROUND: Staff may encourage individuals with intellectual disabilities to use manual signs by modelling its use, but implementing key word signing during daily activities can be demanding. METHOD: Staff's use of manual signs was observed in four special schools and four day centres for adults with intellectual disabilities during communicative group activities, non-communicative group activities and mealtimes. Using in situ partial interval coding, we measured staff's communication rate, semantic diversity of manual signs, sign reinforcement and sign imitation. With Chi-squared tests, associations were measured between these variables, the two settings and the three activity types. RESULTS: During communicative activities, staff used manual signs significantly more in adult services than special schools. During non-communicative activities and mealtimes, staff seldom used or reinforced signs. CONCLUSIONS: Staff communicated frequently but did not often model sign use during daily activities. To investigate influence from training background, further detailed measurements are warranted. PMID- 29114983 TI - Correct allometric analysis is always helpful for scaling flow-mediated dilation in research and individual patient contexts. AB - McLay et al. (Clin Physiol Funct Imaging (2017); DOI: 10.1111/cpf.12465) recently examined whether the allometric scaling of flow-mediated dilation influenced the mean difference between samples of young and older adults compared with the traditional percentage change approach. They also explored whether a new scaling calculation improved the ability to obtain individually scaled flow-mediated dilation. In our response to their study, we can demonstrate that McLay et al. (Clin Physiol Funct Imaging, 2017) have (i) managed to formulate a new scaling index which does nothing to remove the dependency of that index on baseline diameter and (ii) suggested, incorrectly, that the original allometric approach cannot be used to derive individually-adjusted values of flow-mediated dilation, which can be interpreted in a similar way to a percentage change. PMID- 29114984 TI - The accuracy and consistency of nutrition care process terminology use in cases of refeeding syndrome. AB - AIM: Using standardised terminology in acute care has encouraged consistency in patient care and the evaluation of outcomes. As such, the Nutrition Care Process (NCP) and Nutrition Care Process Terminology (NCPT) may assist dietitian nutritionists in the delivery of high quality nutrition care worldwide; however, limited research has been conducted examining the consistency and accuracy of its use. We aimed to examine the NCPT that dietitian nutritionists would use to formulate a diagnostic statement relating to refeeding syndrome (RFS). METHODS: A multimethod action research approach was used, incorporating two projects. The first was a survey examining Australian dietitian nutritionists' (n = 195) opinions regarding NCPT use in cases of RFS. To establish if results were similar internationally, an interview was then conducted with 22 dietitian nutritionists working within 10 different countries. RESULTS: 'Imbalance of nutrients' was only identified as a correct code by 17% of respondents in project 1. No mention of this term was made in project 2. Also 86% of respondents incorrectly selected more than one diagnostic code. The majority of respondents (80%, n = 52/65) who incorrectly selected 'Malnutrition', without also selecting 'Imbalance of nutrients', selected 'reduce intake' as an intervention, suggesting some misunderstanding in the requirement for interrelated diagnoses, interventions and goals. CONCLUSIONS: Our findings demonstrate that there is limited accuracy and consistency in selecting nutritional diagnostic codes in relation to RFS. Respondents also demonstrated limited knowledge regarding appropriate application of the NCP and NCPT. Implementation practices may require further refinement, as accurate and consistent use is required to procure the benefits of standardised terminology. PMID- 29114985 TI - Coordinated delivery and function of bacterial MARTX toxin effectors. AB - Bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include toxins counteracting or amplifying effects of another toxin or though regulating the stability of virulence factors to remove their function once it is no longer needed. Multifunctional autoprocessing repeats-in toxin (MARTX) toxins are effector delivery toxins that form a pore into the plasma membrane of a eukaryotic cell to deliver multiple effector proteins into the cytosol of the target cell. The function of these proteins includes manipulating actin cytoskeletal dynamics, regulating signal transduction pathways and inhibiting host secretory pathways. Investigations into the molecular mechanisms of these effector domains are providing insight into how the function of some effectors overlap and regulate one another during infection. Coordinated crosstalk of effector function suggests that MARTX toxins are not simply a sum of all their parts. Instead, modulation of cell function by effector domains may depend on which other effector domain are co-delivered. Future studies will elucidate how these effectors interact with each other to modulate the bacterial host interaction. PMID- 29114986 TI - Towards an eco-phylogenetic framework for infectious disease ecology. AB - Identifying patterns and drivers of infectious disease dynamics across multiple scales is a fundamental challenge for modern science. There is growing awareness that it is necessary to incorporate multi-host and/or multi-parasite interactions to understand and predict current and future disease threats better, and new tools are needed to help address this task. Eco-phylogenetics (phylogenetic community ecology) provides one avenue for exploring multi-host multi-parasite systems, yet the incorporation of eco-phylogenetic concepts and methods into studies of host pathogen dynamics has lagged behind. Eco-phylogenetics is a transformative approach that uses evolutionary history to infer present-day dynamics. Here, we present an eco-phylogenetic framework to reveal insights into parasite communities and infectious disease dynamics across spatial and temporal scales. We illustrate how eco-phylogenetic methods can help untangle the mechanisms of host-parasite dynamics from individual (e.g. co-infection) to landscape scales (e.g. parasite/host community structure). An improved ecological understanding of multi-host and multi-pathogen dynamics across scales will increase our ability to predict disease threats. PMID- 29114987 TI - Risk of spontaneous preterm birth in singleton pregnancies conceived after IVF/ICSI treatment: meta-analysis of cohort studies. AB - OBJECTIVE: Preterm birth (PTB) is more common in pregnancies conceived by in vitro fertilization (IVF) as compared with those conceived naturally. However, the extent to which this is attributed to spontaneous labor or to iatrogenic indications has not been determined. The aim of this study was to quantify the risk of spontaneous PTB (sPTB) in singleton pregnancies resulting from IVF or intracytoplasmic sperm injection (ICSI) treatment as compared with that in spontaneously conceived pregnancies. METHODS: An electronic search of PubMed/MEDLINE, Scopus and Web of Science to September 2017 and manual search of reference lists identified articles comparing the risk of sPTB in IVF/ICSI vs spontaneously conceived singleton pregnancies. Inclusion criteria were singleton conception with IVF/ICSI, PTB defined as delivery before 37 weeks' gestation and cohort design with clear distinction between spontaneous and indicated PTB. The primary outcome was sPTB < 37 weeks. Relevant secondary outcomes were also analyzed, including sPTB < 34 and < 32 weeks, preterm prelabor rupture of membranes, stillbirth, perinatal mortality, neonatal sepsis, respiratory distress syndrome and gastrointestinal morbidity. A meta-analysis provided the estimation of risk of sPTB in IVF/ICSI pregnancies. RESULTS: In total, 674 records were identified from the search, of which 15 met the inclusion criteria and were included in the meta-analysis. A pooled crude analysis of the primary outcome generated a total sample size of 61 677 births, including 8044 singletons conceived after IVF/ICSI and 53 633 conceived spontaneously. A pooled crude data analysis showed a significant increase in the incidence of sPTB < 37 weeks in singleton IVF/ICSI pregnancies compared with those conceived spontaneously (810/8044 (10.1%) vs 2932/53 633 (5.5%); odds ratio (OR), 1.75; 95% CI, 1.50 2.03; I2 = 39%). A subgroup analysis of studies matching for maternal age and parity confirmed the finding (OR, 1.63; 95% CI, 1.30-2.05; I2 = 33%). A pooled crude analysis of secondary outcomes showed a significant increase in the incidence of sPTB < 34 weeks in pregnancies conceived after IVF/ICSI compared with those conceived spontaneously (37/1012 (3.6%) vs 24/1107 (2.2%); OR, 1.78; 95% CI, 1.03-3.08; I2 = 6%) and did not show any significant difference for any of the other secondary outcomes analyzed. The quality of evidence, rated using the GRADE criteria, was low for the outcome sPTB < 37 weeks and very low for sPTB < 34 weeks. CONCLUSIONS: The risk of sPTB in singleton pregnancies resulting from IVF/ICSI is significantly greater than that in spontaneously conceived singletons. These findings should be interpreted with caution given the low quality of the available evidence. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29114988 TI - Highly Crystalline Mesoporous C60 with Ordered Pores: A Class of Nanomaterials for Energy Applications. AB - Highly ordered mesoporous C60 with a well-ordered porous structure and a high crystallinity is prepared through the nanohard templating method using a saturated solution of C60 in 1-chloronaphthalene (51 mg mL-1 ) as a C60 precursor and SBA-15 as a hard template. The high solubility of C60 in 1-chloronaphthalene helps not only to encapsulate a huge amount of the C60 into the mesopores of the template but also supports the oligomerization of C60 and the formation of crystalline walls made of C60 . The obtained mesoporous C60 exhibits a rod-shaped morphology, a high specific surface area (680 m2 g-1 ), tuneable pores, and a highly crystalline wall structure. This exciting ordered mesoporous C60 offers high supercapacitive performance and a high selectivity to H2 O2 production and methanol tolerance for ORR. This simple strategy could be adopted to make a series of mesoporous fullerenes with different structures and carbon atoms as a new class of energy materials. PMID- 29114989 TI - Skin biomechanical properties in patients with systemic sclerosis: what parameter should be used? PMID- 29114990 TI - Contextualisation of patient-centred care: A comparative qualitative study of healthcare professionals' approaches to communicating with seriously ill patients about their dependent children. AB - Patients' family relations play an important part in the provision of patient centred cancer care, not least when healthcare professionals encounter seriously ill patients with dependent children. Little is known about how children are perceived and dealt with in clinical encounters. In this qualitative comparative study, we explore the influence of medical contexts in three Danish hospital wards, haematology, oncological gynaecology and neuro-intensive care, on communication with patients about their children. In exploring the degree to which the inclusion of children in clinical encounters is dependent on context, we took a comparative approach based on fieldwork in wards either exclusively focusing on cancer treatment or partially involved in critical phases of cancer treatment. We conducted 49 semi-structured, in-depth interviews with doctors and nurses, and 27 days of participant observation. The thematic analysis was based on Bateson's conceptualisation of communication. We found that healthcare professionals' approach to children in clinical encounters and the ways in which children were positioned on each ward were influenced by aspects specific to the ward, including the diagnosis and treatments that related specifically to the patient. Our findings suggest the need to explore further the influence of medical contexts on the inclusion of children in patient communication. PMID- 29114991 TI - Serum autotaxin is a useful liver fibrosis marker in patients with chronic hepatitis B virus infection. AB - AIM: Autotaxin (ATX) is a secreted enzyme that is considered to be associated with liver damage as well as fibrosis. This study assessed the ability of ATX to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. METHODS: Serum ATX levels were retrospectively evaluated in 101 treatment-naive patients with HBV-related chronic hepatitis or cirrhosis, all of whom had undergone liver biopsy at our hospital. RESULTS: Serum ATX concentration increased significantly according to liver fibrosis stage in overall (r = 0.46, P < 0.0001), male (r = 0.55, P < 0.0001), and female (r = 0.52, P = 0.0006) patient groups. When analyzed by gender, serum ATX was one of the most reliable markers for all fibrosis stages compared with other tested non-invasive markers, which included hyaluronic acid, type IV collagen 7S, aspartate aminotransferase-to platelet ratio index, and fibrosis index based on four factors, according to receiver operating characteristic curve analysis. CONCLUSION: Based on this histologically proven data, ATX represents a novel non-invasive biomarker for liver fibrosis in HBV-infected patients. PMID- 29114992 TI - Working memory predicts methamphetamine hair concentration over the course of treatment: moderating effect of impulsivity and implications for dual-systems model. AB - High impulsivity and poor executive function are characteristic of methamphetamine use disorder. High arousal in the impulsive system has been proposed to compromise the executive system's regulating ability (i.e. the dual systems model). While interaction between these variables may partly explain poor treatment outcomes associated with methamphetamine use disorder, previous research has tended to examine each factor separately. We investigated whether high impulsivity (measured with an impulsive choice task) and poor executive function (measured with a working memory task) predict methamphetamine use (determined by hair sample) in the 6 weeks following treatment commencement. We also investigated whether impulsive choice moderates the relationship between working memory and methamphetamine use. One hundred and eight individuals with methamphetamine use disorder (75 percent male) were tested within 3 weeks of commencing treatment; 80 (74 percent) were followed up 6 weeks following baseline testing. Cognitive measures significantly predicted drug use after controlling for nuisance variables. Working memory was a significant predictor, while impulsive choice was not. The interaction model included working memory as a predictor and impulsive choice as a moderator. This model was significant, as was the interaction term. Working memory significantly predicted levels of methamphetamine use in early treatment, and impulsive choice moderated this relationship. Those with working memory deficits are particularly vulnerable to using greater amounts of methamphetamine. As working memory increased methamphetamine use decreased among individuals with low/medium delay discounting. Pre-treatment cognitive testing may identify patients at high risk, while remediation of working memory function may be a treatment target for reducing methamphetamine use. PMID- 29114993 TI - Removal of jitter noise in 3D shape recovery from image focus by using Kalman filter. AB - In regard to Shape from Focus, one critical factor impacting system application is mechanical vibration of the translational stage causing jitter noise along the optical axis. This noise is not detectable by simply observing the image. However, when focus measures are applied, inaccuracies in the depth occur. In this article, jitter noise and focus curves are modeled by Gaussian distribution and quadratic function, respectively. Then Kalman filter is designed and applied to eliminate this noise in the focus curves, as a post-processing step after the focus measure application. Experiments are implemented with simulated objects and real objects to show usefulness of proposed algorithm. PMID- 29114994 TI - Alcohol consumption among first- and second-generation immigrant and native adolescents in 23 countries: Testing the importance of origin and receiving country alcohol prevalence rates. AB - INTRODUCTION AND AIMS: This internationally comparative study examines differences in alcohol consumption between first- and second-generation immigrant and native adolescents. We also investigate to what extent origin and receiving country alcohol per capita consumption (APCC) rates and proportions of heavy episodic drinkers (HED) are associated with immigrant adolescents' alcohol consumption. DESIGN AND METHODS: We used cross-sectional survey data from the 2013/2014 Health Behaviour in School-aged Children study. Applying multilevel regression analyses, we investigated the lifetime frequency of alcohol use and drunkenness in 69 842 13- to 15-year-olds in 23 receiving countries, with immigrants from over 130 origin countries (82% natives, 6% first-generation immigrants and 12% second-generation immigrants). RESULTS: The lifetime frequency of alcohol use was higher among natives than among first- and second-generation immigrants, while no differences were found between the latter two. Lifetime drunkenness was more frequent among first-generation immigrants than among natives and second-generation immigrants. Higher origin country APCC and HED were associated with more frequent lifetime alcohol use and drunkenness among immigrant adolescents. Cross-level interactions revealed that for lifetime frequency of alcohol use, the origin country HED effects were stronger for first- than for second-generation immigrant adolescents. Further, especially for first generation immigrants, a higher receiving country HED was related to lower lifetime frequencies of alcohol use and drunkenness. DISCUSSION AND CONCLUSIONS: Our results suggest differences in lifetime frequencies of alcohol use and drunkenness between natives and first- and second-generation immigrant adolescents. Origin country APCC and HED seem to affect immigrant adolescents' alcohol consumption differently than receiving country APCC and HED. PMID- 29114995 TI - Alcohol and other substance use in a cross-cultural perspective. PMID- 29114996 TI - Impaired p53/CEP-1 is associated with lifespan extension through an age-related imbalance in the energy metabolism of C. elegans. AB - In the nematode Caenorhabditis elegans, the mammalian tumor suppressor p53 ortholog CEP-1 mediates the stress response, activates germ line apoptosis and regulates meiotic chromosome segregation. A reduction in its expression, which frequently occurs in mammalian cancer cells, extends lifespan and induces an adaptive response in C. elegans. However, these effects do not involve an increase in oxidative stress resistance. Here, we showed that intermittent exposure to hyperoxia, which induces oxidative stress resistance and lowers the production of ROS derived from mitochondrial respiration in C. elegans, slightly improved the lifespan extension of cep-1 mutant. Interestingly, ATP levels were increased without an increase in oxygen consumption in cep-1 mutant during aging. In the wild-type, lactate levels and consequentially the lactate/pyruvate ratio decreased during aging in adults. Furthermore, the expression levels of mitochondrial respiration-related sco-1, which is a target of p53/CEP-1, as well as those of gluconeogenesis regulation and mammalian sirtuin ortholog genes, were also increased in the aged and adaptive conditioned wild-type animals. In contrast, the lactate/pyruvate ratio increased in cells of the cep-1 mutant and was amplified by intermittent hyperoxia. These results suggest that impaired p53/CEP-1 leads to an imbalance in the age-related energy metabolic alteration between mitochondrial oxidative phosphorylation and aerobic glycolysis and plays an important role in the extension of both intact and adaptive lifespans. PMID- 29114998 TI - Early and delayed post-pneumonectomy empyemas: Microbiology, management and prognosis. AB - INTRODUCTION: Post-pneumonectomy empyema (PPE) is the most severe complication of pneumonectomy. Microbiology and its impact on management and prognosis have rarely been reported METHODS: We retrospectively reviewed the files of a series of 37 consecutive patients with PPE over a 10-year period with a special focus on microbiology, means used to treat empyema and prognosis. RESULTS: PPE occurred within 14 days of pneumonectomy in 17 cases (early PPE) and after postoperative day 16 in 20 patients (delayed PPE). PPE was monomicrobial in 57% of cases. The most frequent pathogens were Staphylococcus sp. and Streptococcus sp. Polymicrobial empyema was more frequent in patients with early PPE than delayed PPE (65% vs 25%; P = .02). Video-assisted thoracoscopic approach for cavity lavage was performed in 22 patients without broncho-pleural fistulae (BPF), associated with antimicrobial therapy and drainage, and was successful in 13 cases (59%). Seventeen patients (46%) underwent an open window thoracostomy. Overall 90-day post empyema mortality was 19%, with 6 deaths because of empyema in the early PPE group (35%), versus one (5%) in the delayed PPE group (P = .02). CONCLUSION: We distinguished 2 different PPE presentations: an early occurrence, mostly with polymicrobial cultures, including Gram-negative bacteria, and associated with a high mortality rate. By contrast, delayed PPEs were mostly monomicrobial with Gram-positive bacteria and associated with a better prognosis. VATS approach was successful in the majority of cases without BPF, even if some patients required secondary thoracostomy. PPE was associated with an excess of mortality especially when occurring in the early course after pneumonectomy. PMID- 29114997 TI - In vitro modeling of HIV proviral activity in microglia. AB - Microglia, the resident macrophages of the brain, play a key role in the pathogenesis of HIV-associated neurocognitive disorders (HAND) due to their productive infection by HIV. This results in the release of neurotoxic viral proteins and pro-inflammatory compounds which negatively affect the functionality of surrounding neurons. Because models of HIV infection within the brain are limited, we aimed to create a novel microglia cell line with an integrated HIV provirus capable of recreating several hallmarks of HIV infection. We utilized clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology and integrated a modified HIV provirus into CHME-5 immortalized microglia to create HIV-NanoLuc CHME-5. In the modified provirus, the Gag-Pol region is replaced with the coding region for NanoLuciferase (NanoLuc), which allows for the rapid assay of HIV long terminal repeat activity using a luminescent substrate, while still containing the necessary genetic material to produce established neurotoxic viral proteins (e.g. tat, nef, gp120). We confirmed that HIV-NanoLuc CHME-5 microglia express NanoLuc, along with the HIV viral protein Nef. We subsequently exposed these cells to a battery of experiments to modulate the activity of the provirus. Proviral activity was enhanced by treating the cells with pro-inflammatory factors lipopolysaccharide (LPS) and tumor necrosis factor alpha and by overexpressing the viral regulatory protein Tat. Conversely, genetic modification of the toll-like receptor-4 gene by CRISPR/Cas9 reduced LPS-mediated proviral activation, and pharmacological application of NF-kappaB inhibitor sulfasalazine similarly diminished proviral activity. Overall, these data suggest that HIV-NanoLuc CHME-5 may be a useful tool in the study of HIV-mediated neuropathology and proviral regulation. PMID- 29114999 TI - Comparison between site and central radiological assessments for patients with recurrent glioblastoma on a clinical trial. AB - AIM: Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review. METHODS: MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed. RESULTS: Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3-1.8, P < 0.001). Responses were documented more frequently by sites (n = 16, 18%) than centrally (n = 11, 12%). Seven of 120 patients continued on trial without site-determined progression for more than 6 months beyond the central review determination of progression. Of scans reviewed by all three central reviewers, 33% were fully concordant for progression date. CONCLUSION: While the difference between site and central PFS dates was statistically significant, the 0.3-month median difference is small. The variability within central review is consistent with previous studies, highlighting the challenges in MRI interpretation in this context. A small proportion of patients benefited from treatment well beyond the centrally determined progression date, reinforcing that clinical status together with radiology results are important determinants of whether a therapy is effective for an individual. PMID- 29115000 TI - Cerebrospinal fluid:serum glucose ratio in the ventricular and lumbar compartments: implications for clinical practice. AB - BACKGROUND AND PURPOSE: Calculation of the cerebrospinal fluid:serum glucose (CSF:SGlu ) ratio is part of the routine cerebrospinal fluid (CSF) work-up. Reference values have been defined for lumbar CSF, but are lacking for ventricular CSF. The objective of this study was to investigate whether the CSF:SGlu ratio is similar in lumbar and ventricular compartments, and to determine cut-off values for CSF:SGlu ratio in ventricular CSF. METHODS: We included CSF samples that were collected by either lumbar puncture or ventricular drainage, with a red blood cell count <500/MUL, normal white blood cell count and age-related normal total protein content, with simultaneously withdrawn serum sample and time to laboratory processing of <=2 h. This resulted in 1808 sample pairs. Glucose concentrations in CSF and serum were measured by enzymatic spectrophotometry. RESULTS: The CSF:SGlu ratio was similar in ventricular and lumbar compartments after controlling for age, sex, time between sample withdrawal and laboratory processing, CSF white blood cell and red blood cell count, CSF total protein and serum glucose concentration using a multiple linear regression model. Lower limits for CSF:SGlu ratio in the ventricular compartment, defined as 5th percentile, were 0.51 for patients with serum glucose concentration < 100 mg/dL, 0.45 for those with serum glucose concentration >= 100 mg/dL and <150 mg/dL, and 0.36 for those with serum glucose concentration >=150 mg/dL. CONCLUSIONS: The CSF:SGlu ratio was similar in the ventricular and lumbar compartments, and depended mainly on time to laboratory processing and absolute serum glucose levels. Previously established lower limits for CSF:SGlu ratio in lumbar CSF can be also applied for ventricular CSF. PMID- 29115001 TI - The synergistic effect of bone forming peptide-1 and endothelial progenitor cells to promote vascularization of tissue engineered bone. AB - Large segmental bone defect repair remains a challenge in orthopedic surgeries. The tissue engineered bone graft will be a promising approach if vascularization of the graft is realized. In this study, beta-tricalcium phosphate (beta-TCP) scaffold incorporated with bone forming peptide-1 (BFP-1) was fabricated. Endothelial progenitor cells (EPCs) were introduced as well. We investigated the effect of BFP-1 on the proliferation, differentiation, and angiogenic functions of EPCs. Additionally, segmental femur bone defect was created in rabbits. Prevascularized beta-TCP scaffold was constructed and implanted into the bone defect. The vascularization and bone formation were evaluated after 4 and 12 weeks. The results showed that BFP-1 promoted the angiogenesis of EPCs through activating the activin receptor-like kinase-1/Smad pathway. The prevascularized tissue engineered bone graft enhanced capillary vessel in-growth and new bone formation. Significantly higher values of vascularization and radiographic grading scores were observed in groups involving EPCs and BFP-1, compared to beta TCP scaffold alone. In conclusion, the synergy between EPCs and BFP-1 improved the vascularization and new bone regeneration, which has great potentials in clinical applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1008-1021, 2018. PMID- 29115002 TI - Clinical and radiological features of pulmonary artery sarcoma: A report of nine cases. AB - OBJECTIVE: To improve our understanding and facilitate early diagnosis of pulmonary artery sarcoma (PAS). PATIENTS AND METHODS: The clinical and radiological features of 9 histopathologically confirmed patients with PAS were retrospectively analyzed. RESULTS: Our PAS cohort consisted of 5 males and 4 females, with insidious presentation, the main symptoms were dyspnea (88.9%), syncope (33.3%), palpitations (22.2%), chest pain (22.2%), hemoptysis (11.1%) and constitutional symptoms, including fever (44.4%), fatigue (55.6%) and weight loss (55.6%). Elevated serum inflammatory markers, including an elevated erythrocyte sedimentation rate, lactate dehydrogenase and C-reactive protein, were recorded in 9 (100%), 7 (77.8%) and 8 (88.9%) patients, respectively. Computed tomography pulmonary angiography (CTPA) indicated that 8 (88.9%) patients had intraluminal defects, appearing as rounded, bulging or lobulated masses that display uneven signal intensification in contract-enhanced scans in the pulmonary arteries (PAs). Three (33.3%) of the patients had metastases outside of the PA. Before surgery, 7 patients had been misdiagnosed as pulmonary thromboembolic diseases (PTD), 2 as others, with mean misdiagnosis duration of 7.2 +/- 7.1 months. All patients had received thrombolytic and/or anticoagulation therapy and their diseases progressed until receiving pulmonary endarterectomy. CONCLUSIONS: The clinical features of PAS that may help to differentiate it from PTD are its insidious onset, constitutional symptoms, increased serum inflammatory marker levels, lack of predisposing factors and unresponsiveness to thrombolytic and/or anticoagulation therapy. Typical CTPA features are crucial for suspicion of PAS. Early biopsy or surgery should be performed to confirm the diagnosis of PAS and improve its prognosis. PMID- 29115003 TI - Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas. AB - CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. METHODS: Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas. PMID- 29115004 TI - Evaluation of a multifactorial approach to reduce the prevalence of pressure injuries in regional Australian acute inpatient care settings. AB - The aim of the study was to compare the changes in the prevalence of pressure injuries from 2008 to 2014 in relation to staff behaviour in acute/subacute inpatient care settings. In 2008, the large regional health district Hunter New England Local Health District implemented an initiative called the Crystal Model which resulted in changes in their policy and an e-learning education program for all nursing staff. A retrospective cross sectional study compared data from the 2008, 2010 and 2014 point prevalence surveys of PI in acute services. These were collected as part of an annual pressure injury prevention and management quality audit for adult inpatients. The total number of participants included 1407 participants in 2008, 1331 participants in 2010 and 1199 participants in 2014. From 2008 to 2014 there was a 15.7% decrease in percentage of patients with hospital-acquired pressure injuries and the percentages of each stage of pressure of injury 1-4 decreased. From 2008 to 2014 the completion and documentation of risk assessment, the documentation of repositioning and the implementation of pressure-relieving equipment increased. A multifactorial model can reduce the prevalence of pressure injuries in acute inpatient settings. The theories of knowledge translation and the modified Theory of Planned Behaviour can be utilised to analyse changes in health professionals habituated pressure injury prevention practice. PMID- 29115006 TI - Type 2N von Willebrand disease: Characterization and diagnostic difficulties. AB - INTRODUCTION: An abnormal factor VIII (FVIII) binding capacity of von Willebrand factor (VWF) identifies type 2N von Willebrand disease (VWD). Type 2N VWD patients are identified by means of the VWF FVIII binding (VWF:FVIIIB) assay, and especially their VWF:FVIIIB/VWF:Ag ratio (VWF:FVIIIB ratio). AIM: We report on our 15-year experience of diagnosing type 2N VWD. METHODS: We have performed 2178 VWF:FVIIIB assays in bleeders and normal subjects. RESULTS: von Willebrand factor (VWF):FVIIIB was reduced in 682, but only 60 had low VWF:FVIIIB ratios (<0.74). Among nine patients who had a VWF:FVIIIB ratio below 0.3, four had normal VWF levels and were homozygotes for the p.R854Q mutation; the other five had low VWF levels due to a quantitative VWF mutation combined with p.R854Q. The VWF:FVIIIB ratio ranged between 0.3 and 0.73 in 51 subjects; 34 of them were heterozygotes for the p.R854Q mutation, while one carried the p.R760C. The heterozygotes for type 2N included subjects with or without bleeding symptoms, the former with significantly lower mean VWF levels than the latter. Among the 116 normal subjects tested, six were heterozygotes for the p.R854Q mutation (all asymptomatic). CONCLUSIONS: The prevalence of type 2N in our VWD cohort was 2.5%, and 5.2% of the general population in Northeast Italy was found heterozygous for the p.R854Q mutation. It might be difficult to reveal a type 2N defect using routine tests alone, especially when it is combined with a quantitative VWF mutation. Accordingly, we always recommend VWF:FVIIIB assay in the diagnostic workup of VWD. PMID- 29115005 TI - Pten regulates neural crest proliferation and differentiation during mouse craniofacial development. AB - BACKGROUND: The phosphatase and tensin homolog deleted on chromosome TEN (Pten) is implicated in a broad range of developmental events and diseases. However, its role in neural crest and craniofacial development has not been well illustrated. RESULTS: Using genetically engineered mouse models, we showed that inactivating Pten specifically in neural crest cells causes malformation of craniofacial structures. Pten conditional knockout mice exhibit perinatal lethality with overgrowth of craniofacial structures. At the cellular level, Pten deficiency increases cell proliferation rate and enhances osteoblast differentiation. Our data further revealed that inactivating Pten elevates PI3K/Akt signaling activity in neural crest derivatives, and confirmed that attenuation of PI3K/Akt activity led to decreased neural crest cell proliferation and differentiation both in vitro and in vivo. CONCLUSIONS: Our study revealed that Pten is essential for craniofacial morphogenesis in mice. Inactivating Pten in neural crest cells increases proliferation rate and promotes their differentiation toward osteoblasts. Our data further indicate that Pten acts via modulating PI3K/Akt activity during these processes. Developmental Dynamics 247:304-314, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29115007 TI - Enhancement effect on the chemiluminescence of acridinium esters under neutral conditions. AB - Enhancement effect on the chemiluminescence of acridinium ester derivatives under neutral conditions was investigated. Additions of phenols did not enhance the chemiluminescence intensities of acridinium ester derivatives in the presence of horseradish peroxidase and hydrogen peroxide. Additions of cetyltrimethylammonium bromide apparently enhanced the chemiluminescence intensities of phenyl 10-methyl 10lambda4 -acridine-9-carboxylate derivatives with electron-withdrawing groups at the 4-position of the phenyl group. In particular, the chemiluminescence intensity of 4-(trifluoromethyl)phenyl 10-methyl-10lambda4 -acridine-9 carboxylate trifluoromethanesulfonate salt was 5.5 times stronger in the presence of cetyltrimethylammonium bromide than in its absence at pH 7. The chemiluminescence intensity of 3,4-dicyano-phenyl 10-methyl-10lambda4 -acridine-9 carboxylate trifluoromethanesulfonate salt was 46 times stronger in the presence of cetyltrimethylammonium bromide at pH 7 than in its absence at pH 10. PMID- 29115008 TI - Tafamidis delays neurological progression comparably across Val30Met and non Val30Met genotypes in transthyretin familial amyloid polyneuropathy. AB - BACKGROUND AND PURPOSE: To better characterize the effects of tafamidis in non Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12-month, open-label study of non-Val30Met versus Val30Met patients at month 12 from the 18-month, double blind, placebo-controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity. METHODS: Neurological function was assessed using the Neuropathy Impairment Score - Lower Limbs (NIS-LL) in three cohorts: Val30Met tafamidis (n = 64), Val30Met placebo (n = 61) and non-Val30Met tafamidis (n = 21). The change in NIS-LL from baseline to month 12 for Val30Met and non-Val30Met tafamidis-treated patients was compared with the change from baseline at month 12 for Val30Met placebo-treated patients using a mixed-effects model for repeated measures (MMRM). RESULTS: The baseline adjusted mean (standard error) change in NIS-LL values at month 12 was similar for Val30Met [1.60 (0.78)] and non-Val30Met [1.62 (1.43)] tafamidis treated patients and less than that observed in the Val30Met placebo-treated group [4.72 (0.77); P = 0.0055 for Val30Met and P = 0.0592 for non-Val30Met]. Based on the MMRM, the magnitude of change in both tafamidis-treated cohorts was similar across the range of observed baseline NIS-LL values, and was consistently less than that observed in the Val30Met placebo-treated group at month 12. CONCLUSIONS: This baseline-adjusted analysis demonstrated that tafamidis treatment delayed neurological progression comparably in Val30Met and non Val30Met patients across a range of baseline NIS-LL values. Neurological progression in these two genotype groups may be more similar than previously considered. PMID- 29115009 TI - Divergent Total Syntheses of (-)-Daphnilongeranin B and (-)-Daphenylline. AB - (-)-Daphnilongeranin B and (-)-daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (-)-daphnilongeranin B and a bioinspired synthesis of (-)-daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline. PMID- 29115010 TI - Gender aspects on exercise-induced ECG changes in relation to scintigraphic evidence of myocardial ischaemia. AB - BACKGROUND: This retrospective study aimed to determine the diagnostic performance of exercise-induced ST response in relation to findings by myocardial perfusion single photon emission computed tomography (MPS), with focus on gender differences, in patients with suspected or established stable ischemic heart disease. METHODS: MPS findings of 1 021 patients (518 females) were related to the exercise-induced ST response alone (blinded and unblinded to gender) and ST response together with additional exercise stress test (EST) variables (exercise capacity, blood pressure and heart rate response). RESULTS: Exercise-induced ischaemia by MPS was found in 9% of females and 23% of males. Diagnostic performance of exercise-induced ST response in relation to MPS findings in females versus males was: sensitivity = 48%,70%; specificity = 67%, 64%; PPV = 13%, 38%; NPV = 93%, 87%. Adding more EST variables to the ST response interpretation yielded in females vs males: sensitivity = 44%, 51%; specificity = 84%, 83%; PPV = 22%, 48% and NPV = 93%, 85%. CONCLUSIONS: In patients who have performed EST in conjunction with MPS, there is a gender difference in the diagnostic performance of ST response at stress, with a significantly lower PPV in females compared to males. For both genders, specificity can be significantly improved, and a higher PPV can be obtained, while the sensitivity might be compromised by considering more EST variables, in addition to the ST response. PMID- 29115011 TI - Relationship of the conception rate and the side (left or right) of preovulatory follicle location at artificial insemination in dairy heifers. AB - In this study, we examined the locational effect (left or right ovary) of the preovulatory follicle (PF) on fertility in dairy heifers. In total, 1,111 artificial inseminations (AI) were analyzed. At AI, PF locations were examined using rectal palpation, and heifers were divided into two groups on their PF locations: (i) the PF located in the left ovary (L-PF); and (ii) the PF located in the right ovary (R-PF). Pregnancy was diagnosed by rectal palpation 60 days after AI. The conception rate was 50.7% in all heifers. Conception rate was significantly higher in the L-PF (60.1%) than in the R-PF (46.2%). The conception rate was significantly lower by sexed semen (48.6%) than conventional semen (59.1%). Conception rates divided by the semen type (sexed: n = 896, conventional: n = 215) were significantly higher in the L-PF than in the R-PF for both semen types (sexed; L-PF vs. R-PF: 57.3% vs. 44.4%, conventional; L-PF vs. R PF: 72.3% vs. 53.3%). In addition, season, age, AI number, and the number of re inseminations at the same estrus did not affect conception rates. In summary, PF development in the left ovary was associated with increased conception rates in dairy heifers. PMID- 29115012 TI - 3-O-Glyceryl-2-O-hexyl ascorbate suppresses melanogenesis by interfering with intracellular melanosome transport and suppressing tyrosinase protein synthesis. AB - BACKGROUND: Ascorbic acid (AsA) has multifunctional benefits on skin beauty, such as the reduction in oxidative stress and the induction of collagen production. Among them, the prevention and improvement of skin pigmentation by AsA is a most important benefit for people. However, it is well known that AsA not only is quite unstable in formulations but it also has a low capability of skin penetration due to its hydrophilic property. In addition, existing water-soluble AsA derivatives that were developed to improve its stability also have low skin penetration. AIM: To investigate the potential of a newly synthesized amphiphilic derivative of AsA, 3-O-Glyceryl-2-O-hexyl ascorbate (VC-HG), which has an added glyceryl group and a hexyl group, on skin beauty focusing on its skin lightening/whitening effects. METHODS: DNA microarray analysis and real-time PCR were used to clarify the effects of VC-HG on melanogenesis using B16 mouse melanoma cells. The effects of VC-HG on melanin synthesis, tyrosinase protein levels, and the inhibition of tyrosinase activity were evaluated. RESULTS: DNA microarray analysis revealed that treatment with VC-HG downregulated the expression of genes encoding tyrosinase and MyosinVa. Further, real-time PCR analysis showed the downregulation of tyrosinase, MyosinVa, Rab27a, and Kinesin mRNAs following VC-HG treatment. In addition, VC-HG caused decreases in tyrosinase protein levels and melanin synthesis. CONCLUSION: We conclude that VC HG has an impact on skin lightening/whitening by inhibiting tyrosinase protein synthesis and interfering with intracellular melanosome transport. PMID- 29115013 TI - A T7 RNA Polymerase Mutant Enhances the Yield of 5'-Thienoguanosine-Initiated RNAs. AB - Spectroscopic methods, which are used to establish RNA structure-function relationships, require strategies for post-synthetic, site-specific incorporation of chemical probes into target RNAs. For RNAs larger than 50 nt, the enzymatic incorporation of a nucleoside or nucleotide monophosphate guanosine analogue (G analogue) at their 5'-end is routinely achieved by T7 RNA polymerase (T7RNAP) mediated in vitro transcription (IVT) of the appropriate DNA template containing a GTP-initiating class III Phi6.5 promoter. However, when high G analogue:GTP ratios are used to bias G analogue incorporation at the 5'-end, RNA yield is compromised. Here, we show that the use of a T7RNAP P266L mutant in IVT with 10:1 thienoguanosine (th G):GTP increased the percent incorporation and yield of 5'-th G-initiated precursor tRNA for a net ~threefold gain compared to IVT with wild type T7RNAP. We also demonstrated that a one-pot multienzyme approach, consisting of transcription by T7RNAP P266L and post-transcriptional cleanup by polyphosphatase and an exonuclease, led to essentially near-homogeneous 5'-th G modified transcripts. This approach should be of broad utility in preparing 5' modified RNAs. PMID- 29115015 TI - Dr. Christina Chesvick. PMID- 29115014 TI - Impact of variant microscopic interpretation of the uCyt+ immunocytological urine test for the detection of bladder cancer. AB - BACKGROUND: Urinary marker tests for bladder cancer (BC) detection and surveillance represent a desirable approach to diagnosis and follow-up. The SCIMEDX uCyt+ assay detects antigens expressed by BC cells (mucin glycoprotein and carcinoembryonic antigen) using green and red fluorescence and is interpreted according to specific manufacturer's recommendations. In the present study, we evaluated divergent approaches of numeric and morphological analysis of uCyt+ to generate a rationale for alternative test interpretation strategies. METHODS: A total of 444 patients with hematuria and without history of BC underwent uCyt+ analysis, cystoscopy and histological examination of tissue biopsies. Beside positive cells according to the manufacturer's definition (definitely positive cells, DPC), (i) cells showing borderline character (borderline cells, BLC), and (ii) cells with staining present below defined border (subliminal cells, SLC) were included into the analytical algorithm. Different cut-off levels for cell counts (>0, >=3, >=5) were evaluated separately with regard to their diagnostic accuracy. Moreover, the influence of clinical factors on test results were evaluated. RESULTS: Adding BLC at a cut-off of >=3 cells resulted in Area Under the Curve (AUC) of 0.70 for green and 0.77 for red fluorescence, respectively. Adding SLC led to reduced AUC (0.62 and 0.73, respectively). Male gender was significantly associated with false positive results in the "best AUC" groups (P = .0101). No further correlations to clinical influencing factors were observed. CONCLUSIONS: Adding microscopic BLC as test-positive and adjusting cut-off level for the interpretation of uCyt+ may improve assay performance independent of clinical factors. PMID- 29115016 TI - Pulmonary hypertension in stiff left atrial syndrome: pathogenesis and treatment in one. AB - We present the rare case of a patient with pulmonary hypertension in the context of the stiff left atrial syndrome after extensive catheter ablation, a unique constellation characterized by high pulmonary artery and pulmonary artery wedge pressures due to left atrial dysfunction but normal left ventricular end diastolic pressure, normal mitral valve, and absence pulmonary vein stenosis. This patient was surprisingly oligosymptomatic, however, which may have been due to a persistent post-puncture atrial septal defect, which may have allowed for controlled left atrial decompression, which is in line with the novel concept of the catheter-based creation of an intracardiac shunt as a treatment for heart failure. PMID- 29115017 TI - Truncation of a P1 leader proteinase facilitates potyvirus replication in a non permissive host. AB - The Potyviridae family is a major group of plant viruses that includes c. 200 species, most of which have narrow host ranges. The potyvirid P1 leader proteinase self-cleaves from the remainder of the viral polyprotein and shows large sequence variability linked to host adaptation. P1 proteins can be classified as Type A or Type B on the basis, amongst other things, of their dependence or not on a host factor to develop their protease activity. In this work, we studied Type A proteases from the Potyviridae family, characterizing their host factor requirements. Our in vitro cleavage analyses of potyvirid P1 proteases showed that the N-terminal domain is relevant for host factor interaction and suggested that the C-terminal domain is also involved. In the absence of plant factors, the N-terminal end of Plum pox virus P1 antagonizes protease self-processing. We performed extended deletion mutagenesis analysis to define the N-terminal antagonistic domain of P1. In viral infections, removal of the P1 protease antagonistic domain led to a gain-of-function phenotype, strongly increasing local infection in a non-permissive host. Altogether, our results shed new insights into the adaptation and evolution of potyvirids. PMID- 29115018 TI - Relationship between exercise capacity and glucose tolerance in cystic fibrosis. AB - BACKGROUND: Improved exercise capacity (EC) and normal glucose tolerance (NGT) are independently associated with favorable outcomes in CF, however, little information on this relationship exists in patients with CF. METHODS: Cardiopulmonary exercise tests, oral glucose tolerance tests (OGTT), and HbA1c values measured within a 12-month period were evaluated on 83 pediatric patients diagnosed with CF. Patients were categorized as having NGT, abnormal glucose tolerance (AGT), or CF-related diabetes (CFRD). RESULTS: EC decreased as severity of glucose intolerance increased across NGT, AGT, and CFRD groups (P = 0.02). Compared to patients with NGT, patients with CFRD had lower peak VO2 mL/kg/min (33.0 +/- 7.3 vs 41.3 +/- 9.4, P = 0.01), lower VO2 % (81 +/- 20 vs 93 +/- 17, P = 0.03), and higher HbA1c (6.9 +/- 1.7 vs 5.4 +/- 0.4, P < 0.01). There was a positive association with age and FEV1 % with EC in the 17 patients with CFRD. In the 66 patients without diabetes, peak EC was positively associated with FEV1 % and negatively associated with age, fasting insulin, and insulin 120 min. After accounting for age and FEV1 %, multivariate analyses indicated that insulin and glucose values at 120 min predicted EC. CONCLUSIONS: These data provide evidence that poor glucose tolerance is associated with lower EC in pediatric patients with CF. There was a significant relationship between glucose and insulin values obtained by OGTT with EC in a sample of non-diabetic patients with preserved lung function. Future studies are warranted to confirm these findings and investigate the potential role of exercise in the management or prevention of CFRD. PMID- 29115019 TI - Cell-laden composite suture threads for repairing damaged tendons. AB - Tendons have limited regenerative capacity due to their low cellularity and hypovascular nature, which results in poor clinical outcomes of presently used therapies. As tendon injuries are often observed in active adults, it poses an increasing socio-economic burden on healthcare systems. Currently, suture threads are used during surgical repair to anchor the tissue graft or to connect injured ends. Here, we created composite suture threads coated with a layer of cell-laden hydrogel that can be used for bridging the injured tissue aiming at tendon regeneration. In addition, the fibres can be used to engineer 3-dimensional constructs through textile processes mimicking the architecture and mechanical properties of soft tissues, including tendons and ligaments. Encapsulated human tendon-derived cells migrated within the hydrogel and aligned at the surface of the core thread. An up-regulation of tendon-related genes (scleraxis and tenascin C) and genes involved in matrix remodelling (matrix metalloproteinases 1, matrix metalloproteinases 2) was observed. Cells were able to produce a collagen-rich matrix, remodelling their micro-environment, which is structurally comparable to native tendon tissue. PMID- 29115020 TI - Glycosylphosphatidylinositol (GPI) anchored protein deficiency serves as a reliable reporter of Pig-a gene Mutation: Support from an in vitro assay based on L5178Y/Tk+/- cells and the CD90.2 antigen. AB - Lack of cell surface glycosylphosphatidylinositol (GPI)-anchored protein(s) has been used as a reporter of Pig-a gene mutation in several model systems. As an extension of this work, our laboratory initiated development of an in vitro mutation assay based on the flow cytometric assessment of CD90.2 expression on the cell surface of the mouse lymphoma cell line L5178Y/Tk+/- . Cells were exposed to mutagenic and nonmutagenic compounds for 24 hr followed by washout and incubation for an additional 7 days. Following this mutant manifestation time, cells were labeled with fluorescent antibodies against CD90.2 and CD45 antigens. These reagents indicated the presence of GPI-anchored proteins and general cell surface membrane receptor integrity, respectively. Instrument set-up was aided by parallel processing of a GPI anchor-deficient subclone. Results show that the mutagens reproducibly caused increased frequencies of mutant phenotype cells, while the nonmutagens did not. Further modifications to the method, including application of a viability dye and an isotype control for instrument set-up, were investigated. As a means to verify that the GPI-anchored protein-negative phenotype reflects bona fide Pig-a gene mutation, sequencing was performed on 38 CD90.2-negative L5178Y/Tk+/- clones derived from cultures treated with ethyl methanesulfonate. All clones were found to have mutation(s) within the Pig-a gene. The continued investigation of L5178Y/Tk+/- cells, CD90.2 labeling, and flow cytometric analysis as the basis of an in vitro mutation assay is clearly supported by this work. These data also provide evidence of the reliability of using GPI anchor-deficiency as a valid reporter of Pig-a gene mutation. Environ. Mol. Mutagen. 59:18-29, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29115021 TI - A Superior Synthesis of Longitudinally Twisted Acenes. AB - Seven longitudinally twisted acenes (an anthracene, two tetracenes, three pentacenes, and a hexacene) have been synthesized by the addition of aryllithium reagents to the appropriate quinone precursors, followed by SnCl2 -mediated reduction of their diol intermediates, and several of these acenes have been crystallographically characterized. The new syntheses of the three previously reported twisted acenes, decaphenylanthracene (1), 9,10,11,20,21,22 hexaphenyltetrabenzo[a,c,l,n]pentacene (2), and 9,10,11,12,13,14,15,16 octaphenyldibenzo[a,c]tetracene (14), resulted in a reduction of the number of synthetic steps. As a consequence their overall yields were increased by factors of 50-, 24-, and 66-fold, respectively. All of the twisted acene syntheses reported here are suitable for the synthesis of at least gram quantities of these remarkable hydrocarbon materials. PMID- 29115022 TI - Self-care agency, lifestyle, and physical condition predict future frailty in community-dwelling older people. AB - The purpose of this 2 year longitudinal study was to identify the relationship between self-care agency, lifestyle, physical condition, and frailty among community-dwelling older people in a rural area of Japan. The participants were 133 older individuals aged 65 years or above. Data collection was conducted via face-to-face interviews using self-administered questionnaires. Background information, such as age, sex, current employment status, family structure, medication use, comorbidities, and knee and lower back pain, were assessed. The definition of frailty was based on the Frailty Checklist. Self-care agency, lifestyle habits, and locomotive syndrome were assessed using specific assessment scores. Logistic regression analysis showed that locomotive syndrome, knee and lower back pain, and stroke are risk factors for frailty. Among the factors associated with frailty, current employment, regular exercise, and self-care agency were recognized as preventive factors of depression, decreased cognitive function, and being housebound. Our findings suggest that enhancing self-care agency, regular exercise, and self-management skills for chronic illness and disability may decrease the progression of frailty among older people. PMID- 29115023 TI - Secondary queens in the parthenogenetic termite Cavitermes tuberosus develop through a transitional helper stage. AB - In termite species with asexual queen succession (AQS), parthenogenetically produced immatures mostly differentiate into secondary queens, called "neotenics." In order to elucidate the ontogenetic origin of neotenics in Cavitermes tuberosus (Termitidae: Termitinae), a neotropical termite with AQS, we investigated developmental pathways of offspring according to their sex and genetic origin using both morphometric and genetic tools. The caste system of C. tuberosus follows the classical pathway of Termitidae. After the first larval instar, there is a bifurcation between two developmental lines. The apterous line is composed of a second larval instar, several worker instars, presoldiers, and soldiers. Workers display a consistent male bias and soldiers are female-only. The nymphal line is composed of five nymphal instars and the imago stage. We highlight that neotenic queens derive from third and fourth instar nymphs displaying peculiar morphological traits, here termed "aspirants," most of which are produced by parthenogenesis. Aspirants are present in all nests and perform worker tasks while waiting for the queen's death to differentiate into neotenic queens. Aspirants can successfully be used to demonstrate the occurrence of parthenogenesis in termite species whose reproductive cores are difficult to access. PMID- 29115024 TI - Developmental timing differences underlie armor loss across threespine stickleback populations. AB - Comparing ontogenetic patterns within a well-described evolutionary context aids in inferring mechanisms of change, including heterochronies or deletion of developmental pathways. Because selection acts on phenotypes throughout ontogeny, any within-taxon developmental variation has implications for evolvability. We compare ontogenetic order and timing of locomotion and defensive traits in three populations of threespine stickleback that have evolutionarily divergent adult forms. This analysis adds to the growing understanding of developmental genetic mechanisms of adaptive change in this evolutionary model species by delineating when chondrogenesis and osteogenesis in two derived populations begin to deviate from the developmental pattern in their immediate ancestors. We found that differences in adult defensive morphologies arise through abolished or delayed initiation of these traits rather than via an overall heterochronic shift, that intra-population ontogenetic variation is increased for some derived traits, and that altered armor developmental timing differentiates the derived populations from each other despite parallels in adult lateral plate armor phenotypes. We found that changes in ossified elements of the pelvic armor are linked to delayed and incomplete development of an early-forming pelvic cartilage, and that this disruption likely presages the variable pelvic vestiges documented in many derived populations. PMID- 29115026 TI - Scaling biodiversity responses to hydrological regimes. AB - Of all ecosystems, freshwaters support the most dynamic and highly concentrated biodiversity on Earth. These attributes of freshwater biodiversity along with increasing demand for water mean that these systems serve as significant models to understand drivers of global biodiversity change. Freshwater biodiversity changes are often attributed to hydrological alteration by water-resource development and climate change owing to the role of the hydrological regime of rivers, wetlands and floodplains affecting patterns of biodiversity. However, a major gap remains in conceptualising how the hydrological regime determines patterns in biodiversity's multiple spatial components and facets (taxonomic, functional and phylogenetic). We synthesised primary evidence of freshwater biodiversity responses to natural hydrological regimes to determine how distinct ecohydrological mechanisms affect freshwater biodiversity at local, landscape and regional spatial scales. Hydrological connectivity influences local and landscape biodiversity, yet responses vary depending on spatial scale. Biodiversity at local scales is generally positively associated with increasing connectivity whereas landscape-scale biodiversity is greater with increasing fragmentation among locations. The effects of hydrological disturbance on freshwater biodiversity are variable at separate spatial scales and depend on disturbance frequency and history and organism characteristics. The role of hydrology in determining habitat for freshwater biodiversity also depends on spatial scaling. At local scales, persistence, stability and size of habitat each contribute to patterns of freshwater biodiversity yet the responses are variable across the organism groups that constitute overall freshwater biodiversity. We present a conceptual model to unite the effects of different ecohydrological mechanisms on freshwater biodiversity across spatial scales, and develop four principles for applying a multi-scaled understanding of freshwater biodiversity responses to hydrological regimes. The protection and restoration of freshwater biodiversity is both a fundamental justification and a central goal of environmental water allocation worldwide. Clearer integration of concepts of spatial scaling in the context of understanding impacts of hydrological regimes on biodiversity will increase uptake of evidence into environmental flow implementation, identify suitable biodiversity targets responsive to hydrological change or restoration, and identify and manage risks of environmental flows contributing to biodiversity decline. PMID- 29115027 TI - Clinical features of pediatric autoimmune hepatitis in Japan: A nationwide survey. AB - AIM: The purpose of this study was to determine the characteristics of children with autoimmune hepatitis (AIH) in Japan. METHODS: Questionnaires that asked about patients newly diagnosed with AIH from 2009 to 2013 were sent to hospitals certified as training facilities for pediatrics in January 2015. RESULTS: A total of 35 patients were enrolled. The median age at diagnosis was 10 years (range, 3 months-15 years), and the male-to-female ratio was 2:3. Female patients were more prevalent among those older than 10 years and male patients were more prevalent in those younger than 10 years. Fifteen patients had jaundice as a subjective symptom, and 5 had hepatic coma grade II. Liver histology classified 20 as chronic hepatitis, 8 as acute hepatitis, and 4 as cirrhosis. Liver histology was not described in 4 patients. Among the 35 patients, 32 were treated with corticosteroids and 29 were initially treated with methylprednisolone pulse therapy. Corticosteroid therapy was effective in 27 patients and ineffective in 1 patient. Plasma exchange with continuous i.v. infusion of cyclosporine A was given to 7 patients with acute hepatitis. Of these, 4 patients presented with fulminant hepatitis and received high-flow, continuous hemodiafiltration. CONCLUSIONS: This survey clarified that the clinical profile of pediatric AIH in Japan is not only different from that of adult AIH in Japan but is also different from that of pediatric AIH in other countries. PMID- 29115028 TI - Thoracentesis in advanced cancer patients with severe thrombocytopenia: Ultrasound guide improves safety and reduces bleeding risk. AB - BACKGROUND: Patients with severe thrombocytopenia are considered at risk for bleeding during invasive procedures as thoracentesis. The use of ultrasound (US) significantly reduces the rate of pneumothorax from thoracentesis, but there is a lack of data on safety and efficacy of US guidance in reducing bleeding complications in thoracentesis performed on patients with severe thrombocytopenia. METHODS: We retrospectively analysed the efficacy and safety of thoracentesis in cancer patients with severe thrombocytopenia. From January 2005 to December 2011, 462 patients underwent thoracentesis. Procedures were divided into 2 groups: performed without or with US guidance. All procedures were evaluated for bleeding complications as defined by the National Institutes of Health Common Terminology Criteria for Adverse Events. RESULTS: A total of 436 consecutive evaluable thoracentesis were analysed. Thoracentesis was performed with US guidance in 310 cases. Forty-one patients (9.40%) had severe thrombocytopenia. In 32 of these 41 patients, thoracentesis was performed under US guidance while in 9 cases the procedure was performed without US guidance. Three mild haemorrhagic complications (0.69% of the procedures performed) were observed and all occurred in group of the 9 (33.33%) patients with severe thrombocytopenia who underwent thoracentesis without US guidance. No haemorrhagic complications were recorded in the 427 patients, including the 32 patients with severe thrombocytopenia, in whom thoracentesis was performed with US guidance. CONCLUSIONS: US guided thoracentesis is a safe and effective approach in cancer patients with severe thrombocytopenia. Our results indicate that this procedure, when US-guided, can be safety performed even in patients with platelet count below 30 * 109 /L. PMID- 29115029 TI - Kawasaki disease: epidemiology and the lessons from it. AB - A half of century has passed since Dr. Tomisaku Kawasaki reported his 50 cases with Kawasaki disease (KD) in 1967. Since then, more than 300 000 cases have been reported to the nationwide epidemiologic surveys in Japan. However, the etiology and risk factors of the disease are still unknown. In this paper, the author emphasizes that the epidemiology of KD may indicate an infectious agent to be a potential trigger of disease in susceptible children. PMID- 29115030 TI - Development of an Efficient Biosensor for the In Vivo Monitoring of Cu+ and pH in the Brain: Rational Design and Synthesis of Recognition Molecules. AB - An efficient biosensor was created for the ratiometric monitoring of Cu+ and pH in the brain using both current and potential outputs. A series of N,N-bis(2-[2 (ethylthio)ethyl])-based (NS4s) derivatives was designed for the specific recognition of Cu+ . After systematically evaluating the electrochemical parameters of Cu+ oxidation by tuning alkyl chain length, polyaromatic structure, and substitute group site of NS4, N,N-bis(2-[2-(ethylthio)ethyl])-2-naphthamide (NS4-C1) was finally optimized for Cu+ detection as it showed the most negative potential and the largest current density. At the same time, 9,10-anthraquinone was used as a selective pH sensor with 2,2'-azino-bis(3-ethylbenzthiazoline-6 sulfonic acid) as an internal reference. This single biosensor with both current and potential signal outputs can simultaneously determine Cu+ concentrations from 0.5 to 9.5 MUm and pH values ranging from 6.0 to 8.0. The efficient biosensor was applied to the simultaneous detection of Cu+ and pH in the live brain. The average levels of Cu+ were reported for the first time in the cortex, hippocampus, and striatum in a mouse model of Alzheimer's disease. PMID- 29115031 TI - Biomimetic multidirectional scaffolds for zonal osteochondral tissue engineering via a lyophilization bonding approach. AB - The zonal organization of osteochondral tissue underlies its long term function. Despite this, tissue engineering strategies targeted for osteochondral repair commonly rely on the use of isotropic biomaterials for tissue reconstruction. There exists a need for a new class of highly biomimetic, anisotropic scaffolds that may allow for the engineering of new tissue with zonal properties. To address this need, we report the facile production of monolithic multidirectional collagen-based scaffolds that recapitulate the zonal structure and composition of osteochondral tissue. First, superficial and osseous zone-mimicking scaffolds were fabricated by unidirectional freeze casting collagen-hyaluronic acid and collagen-hydroxyapatite-containing suspensions, respectively. Following their production, a lyophilization bonding process was used to conjoin these scaffolds with a distinct collagen-hyaluronic acid suspension mimicking the composition of the transition zone. Resulting matrices contained a thin, highly aligned superficial zone that interfaced with a cellular transition zone and vertically oriented calcified cartilage and osseous zones. Confocal microscopy confirmed a zone-specific localization of hyaluronic acid, reflecting the depth-dependent increase of glycosaminoglycans in the native tissue. Poorly crystalline, carbonated hydroxyapatite was localized to the calcified cartilage and osseous zones and bordered the transition zone. Compressive testing of hydrated scaffold zones confirmed an increase of stiffness with scaffold depth, where compressive moduli of chondral and osseous zones fell within or near ranges conducive for chondrogenesis or osteogenesis of mesenchymal stem cells. With the combination of these biomimetic architectural and compositional cues, these multidirectional scaffolds hold great promise for the engineering of zonal osteochondral tissue. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 948-958, 2018. PMID- 29115032 TI - Corrigendum. PMID- 29115033 TI - Molecular targets for the therapy of cancer associated with metabolic syndrome (transcription and growth factors). AB - Metabolic syndrome (MS) is one of the leading risk factors for the development of cardiovascular diseases, type II diabetes mellitus and reproductive system diseases. Currently, not only cardiovascular disease and reproductive history risks related with MS are frequently discussed, but it has been also shown that MS is associated with increased risk of some common cancers (endometrial cancer, postmenopausal breast cancer, colorectal cancer, biliary tract cancers and liver cancer for men). Further studies are required to understand the mechanisms of the involvement of MS components in the pathogenesis of malignant neoplasms. Changes in the expression of transcription and growth factors in the peripheral tissues as well as in cancer tissues of patients with MS were revealed. Transcription factors (AMP-activated protein kinase-1, STAT3, sterol regulatory element-binding protein-1 and peroxisome proliferator-activated receptor-gamma), leptin and adiponectin receptors seem to be the most promising molecular targets for the therapy of cancers associated with MS. PMID- 29115034 TI - Heart failure admissions and poor subsequent outcomes in adults with congenital heart disease. PMID- 29115035 TI - Role of imaging studies in Kawasaki disease. AB - Kawasaki disease is a medium vessel vasculitis which may be associated with coronary artery abnormalities. Recognition of these abnormalities depends upon various imaging modalities. While two-dimensional echocardiography remains the first line modality to identify coronary artery abnormalities, it is subject to several fallacies and is operator dependent. Computed tomography coronary angiography is rapidly emerging as a useful imaging modality for better characterization of dilatations, ectasia and aneurysms in the mid- and distal segments of coronary arteries. It provides precise details in terms of aneurysm size and morphology. In this review we here described the importance of computed tomography coronary angiography and have also given a brief description of magnetic resonance coronary angiography. PMID- 29115036 TI - Cyanide-Assembled d10 Coordination Polymers and Cycles: Excited State Metallophilic Modulation of Solid-State Luminescence. AB - The series of cyanide-bridged coordination polymers [(P2 )CuCN]n (1), [(P2 )Cu{M(CN)2 }]n (M=Cu 3, Ag 4, Au 5) and molecular tetrametallic clusters [{(P4 )MM'(CN)}2 ]2+ (MM'=Cu2 6, Ag2 7, AgCu 8, AuCu 9, AuAg 10) were obtained using the bidentate P2 and tetradentate P4 phosphane ligands (P2 =1,2 bis(diphenylphosphino)benzene; P4 =tris(2-diphenylphosphinophenyl)phosphane). All title complexes were crystallographically characterized to reveal a zig-zag chain arrangement for 1 and 3-5, whereas 6-10 possess metallocyclic frameworks with different degree of metal-metal bonding. The d10 -d10 interactions were evaluated by the quantum theory of atoms in molecules (QTAIM) computational approach. The photophysical properties of 1-10 were investigated in the solid state and supported by theoretical analysis. The emission of compounds 1 and 3-5, dominated by metal-to-ligand charge transfer (MLCT) transitions located within {CuP2 } motifs, is compatible with thermally activated delayed fluorescence (TADF) behaviour and a small energy gap between the T1 and S1 excited states. The luminescence characteristics of 6-10 are strongly dependent on the composition of the metal core; the emission band maxima vary in the range 484-650 nm with quantum efficiency reaching 0.56 (6). The origin of the emission for 6-8 and 10 at room temperature is assigned to delayed fluorescence. AuCu cluster 9, however, exhibits only phosphorescence that corresponds to theoretically predicted large value DeltaE(S1 -T1 ). DFT simulation highlights a crucial impact of metallophilic bonding on the nature and energy of the observed emission, the effect being greatly enhanced in the excited state. PMID- 29115037 TI - MicroRNA profiles in neuroblastoma: Differences in risk and histology groups. AB - AIM: To determine the miRNA expression profiles of neuroblastomas with different clinical and histological characteristics. METHODS: In this study 24 samples from 17 patients, paraffin blocks were used. Their microRNA profiles were compared by five different analysis: analysis I: well-poorly differentiated, analysis II: before-after chemotherapy, analysis III: favorable-unfavorable histology, analysis IV: neuroblastoma-ganglioneuroma, analysis V: low-risk-middle-risk-high risk groups. Clinical data were compared with differentially expressed microRNAs. RESULTS: It was found that 25 miRNAs between well-poorly differentiated tumors, eight miRNAs before and after of the chemotherapy, three miRNAs between favorable and unfavorable histology, four miRNAs between neuroblastoma and ganglioneuroma, seven miRNAs between low and middle risk, one miRNA between middle and high risk, 14 miRNAs between low and high risk were differently expressed (P < 0.01). These miRNA's targeted mostly the cancer pathway by the KEGG pathway analysis. The most marked difference was seen in miR-132 and miR-490, comparing the clinical data and all microRNAs. The most fold change was detected at miR-98-5p between the tissues of high- and low-risk patients. CONCLUSION: In this study, we represent microRNA expression profiles of neuroblastoma patients' tissue with different clinical, histological grade, differentiation, and treatment status, and which could be informative for new therapies targeting microRNAs. PMID- 29115038 TI - Ultramorphological and molecular characteristics of the larval stages of the horse nasal-myiasis fly, Rhinoestrus sp. (Diptera: Oestridae) from Mongolian horse in China. AB - Rhinoestrus sp. (Diptera: Oestridae) is an economically important parasite that can cause severe nasal myiasis in equids and can also affect humans. The ultrastructure of all Rhinoestrus sp. larval instars from Mongolian horse was examined by light and scanning electron microscopy to characterize the features of Rhinoestrus. The structure of the anterior region, posterior region, and the spines of the third segment was analyzed for 10 specimens in each larval stage. Additionally, 34 third-instar (L3) larvae of Rhinoestrus sp. from Mongolian horse were subjected to molecular characterization by polymerase chain reaction (PCR). Partial sequencing of the mitochondrial cytochrome oxidase subunit I gene (COXI) was performed. Phylogenetic relationships for Rhinoestrus sp. from Mongolian horse were reconstructed based on COXI sequences and COXI homologs from 12 oestrid species available in GenBank, and inter- and intraspecies variations in nucleotide sequences were analyzed. The cephalopharyngeal skeleton of Rhinoestrus sp. from Mongolian horse at immature stages was composed of "H"-shaped hypopharyngeal sclerites and "Y"-shaped pharyngeal sclerites. Pairs of papillary sensillae in the cephalic region maintained the same number and location in all three instars, but the third instar additionally included two pairs of verruciform sensillae. COXI sequences of Rhinoestrus sp. larvae collected from Mongolian horses were separated from those of Cephenemyia sp. and other species of Rhinoestrus (R. phacochoeri and R. usbekistanicus). Our sequence analyses demonstrate that all samples greatly resembled Rhinoestrus purpureus but were not R. purpureus. Further studies will be needed to confirm the existence of a new species. The pairs of papillary sensilla in the cephalic region retained the same number and location in all three instars, but included two pairs of verruciform sensilla in the third-instar larvae collected from Mongolian horses were more closely related to those of Oestrus ovis and Pharyngomyia picta. PMID- 29115039 TI - Spectroscopic determination of succinylcholine in dosage forms using eosin Y. AB - Two simple and sensitive analytical assay methods using spectrophotometry and spectrofluorimetry techniques were developed for the estimation of succinylcholine chloride (SUC) in pharmaceutical preparations. The suggested methods are based on the formation of an ion pair complex formed between the drug and eosin Y spectrophotometrically (Method I), or the suppressive effect of succinylcholine on the native fluorescence property of eosin Y (Method II). The spectrophotometric method (Method I) involves measuring the absorbance of the complex between succinylcholine and eosin Y at 550 nm in Britton Robinson buffer of pH 3. However, the spectrofluorimetric method (Method II) involves measuring the quenching effect of the studied drug on the native fluorescence property of eosin Y at the same pH at 550 nm after excitation at 480 nm. The absorbance versus concentration of the drug is rectilinear over the range of 0.5 to 15 MUg/ml. The formation constant was 3.5 * 104 and the Gibb's free energy change was -2.5 * 104 J/mol. In Method II, the relative fluorescence intensity was directly proportional to SUC concentration over the range of 0.05 to 1 MUg/ml. The proposed methods allowed a successful application to the estimation of succinylcholine ampoules. An explanation of the reaction pathway was postulated. PMID- 29115040 TI - Telecytology: Is it possible with smartphone images? AB - INTRODUCTION: This study aimed to discuss smartphone usage in telecytology and determine intraobserver concordance between microscopic cytopathological diagnoses and diagnoses derived via static smartphone images. METHODS: The study was conducted with 172 cytologic material. A pathologist captured static images of the cytology slides from the ocular lens of a microscope using a smartphone. The images were transferred via WhatsApp(r) to a cytopathologist working in another center who made all the microscopic cytopathological diagnoses 5-27 months ago. The cytopathologist diagnosed images on a smartphone without knowledge of their previous microscopic diagnoses. The Kappa agreement between microscopic cytopathological diagnoses and smartphone image diagnoses was determined. RESULTS: The average image capturing, transfer, and remote cytopathological diagnostic time for one case was 6.20 minutes. The percentage of cases whose microscopic and smartphone image diagnoses were concordant was 84.30%, and the percentage of those whose diagnoses were discordant was 15.69%. The highest Kappa agreement was observed in endoscopic ultrasound-guided fine needle aspiration (1.000), and the lowest agreement was observed in urine cytology (0.665). Patient management changed with smart phone image diagnoses at 11.04%. CONCLUSIONS: This study showed that easy, fast, and high-quality image capturing and transfer is possible from cytology slides using smartphones. The intraobserver Kappa agreement between the microscopic cytopathological diagnoses and remote smartphone image diagnoses was high. It was found that remote diagnosis due to difficulties in telecytology might change patient management. The developments in the smartphone camera technology and transfer software make them efficient telepathology and telecytology tools. PMID- 29115041 TI - A biotrophic fungal infection of the great burnet Sanguisorba officinalis indirectly affects caterpillar performance of the endangered scarce large blue butterfly Phengaris teleius. AB - Interactions between ecological communities of herbivores and microbes are commonly mediated by a shared plant. A tripartite interaction between a pathogenic fungus-host plant-herbivorous insect is an example of such mutual influences. In such a system a fungal pathogen commonly has a negative influence on the morphology and biochemistry of the host plant, with consequences for insect herbivore performance. Here we studied whether the biotrophic fungus Podosphaera ferruginea, attacking the great burnet Sanguisorba officinalis, affects caterpillar performance of the endangered scarce large blue butterfly Phengaris teleius. Our results showed that the pathogenic fungus affected the number and size of inflorescences produced by food-plants and, more importantly, had indirect, plant-mediated effects on the abundance, body mass and immune response of caterpillars. Specifically, we found the relationship between caterpillar abundance and variability in inflorescence size on a plant to be positive among healthy food-plants, and negative among infected food-plants. Caterpillars that fed on healthy food-plants were smaller than those that fed on infected food-plants in one studied season, while there was no such difference in the other season. We observed the relationship between caterpillar immune response and the proportion of infected great burnets within a habitat patch to be positive when caterpillars fed on healthy food-plants, and negative when caterpillars fed on infected food-plants. Our results suggest that this biotrophic fungal infection of the great burnet may impose a significant indirect influence on P. teleius caterpillar performance with potential consequences for the population dynamics and structure of this endangered butterfly. PMID- 29115043 TI - Harnessing novel chromosomal integration loci to utilize an organosolv-derived hemicellulose fraction for isobutanol production with engineered Corynebacterium glutamicum. AB - A successful bioeconomy depends on the manifestation of biorefineries that entirely convert renewable resources to valuable products and energies. Here, the poorly exploited hemicellulose fraction (HF) from beech wood organosolv processing was applied for isobutanol production with Corynebacterium glutamicum. To enable growth of C. glutamicum on HF, we integrated genes required for D xylose and l-arabinose metabolization into two of 16 systematically identified and novel chromosomal integration loci. Under aerobic conditions, this engineered strain CArXy reached growth rates up to 0.34 +/- 0.02 h-1 on HF. Based on CArXy, we developed the isobutanol producer strain CIsArXy, which additionally (over)expresses genes of the native l-valine biosynthetic and the heterologous Ehrlich pathway. CIsArXy produced 7.2 +/- 0.2 mM (0.53 +/- 0.02 g L-1 ) isobutanol on HF at a carbon molar yield of 0.31 +/- 0.02 C-mol isobutanol per C mol substrate (d-xylose + l-arabinose) in an anaerobic zero-growth production process. PMID- 29115044 TI - A leg ulcer with pulsating varicose veins - from the legs to the heart. AB - We present the case of a 58-year-old man who presented to our wound care centre with a 7 -month history of a progressive unilateral leg ulcer. He reported intermittent, heavy bleeding at the ulcer. The duplex sonography showed a bilateral incompetence of the saphenofemoral junctions and the entire course of the great saphenous veins and, surprisingly, also a bilateral reversed arterial like pulsating flow in the great and small saphenous veins as well as in the deep veins of the lower extremities. During cardiac examination by auscultation and echocardiography, we detected a previously undescribed severe tricuspid insufficiency with strongly reduced systolic ejection of both the left and the right ventricle and repercussions on the peripheral venous system as a cause for the pulsating veins. This case report highlights that, although infrequent, the presence of pulsating varicose veins points to the presence of cardiac abnormalities, especially severe tricuspid insufficiency, and should direct clinicians to initiate a thorough cardiological examination. Our case highlights that consequent compression therapy can be sufficient for wound healing in such cases and should be initially considered. These patients are at risk of severe bleeding, and therefore, interventions should be carefully planned. PMID- 29115046 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 46/2017. PMID- 29115042 TI - Generation of diverse cortical inhibitory interneurons. AB - First described by Ramon y Cajal as 'short-axon' cells over a century ago, inhibitory interneurons in the cerebral cortex make up ~20-30% of the neuronal milieu. A key feature of these interneurons is the striking structural and functional diversity, which allows them to modulate neural activity in diverse ways and ultimately endow neural circuits with remarkable computational power. Here, we review our current understanding of the generation of cortical interneurons, with a focus on recent efforts to bridge the gap between progenitor behavior and interneuron production, and how these aspects influence interneuron diversity and organization. WIREs Dev Biol 2018, 7:e306. doi: 10.1002/wdev.306 This article is categorized under: Nervous System Development > Vertebrates: General Principles. PMID- 29115047 TI - Corrigendum: Tritopic NHC Precursors: Unusual Nickel Reactivity and Ethylene Insertion into a C(sp3 )-H Bond. PMID- 29115048 TI - Corrigendum: Functionalization of Benzylic C(sp3 )-H Bonds of Heteroaryl Aldehydes through N-Heterocyclic Carbene Organocatalysis. PMID- 29115049 TI - Generation and characterization of an estrogen receptor alpha-iCre knock-in mouse. AB - Two estrogen receptors, ESR1 and ESR2, are responsible for the classical actions of estrogens in mammalian species. They display different spatiotemporal expression patterns and nonoverlapping functions in various tissues and physiological conditions. In this study, a novel knock-in mouse line that expresses codon-improved Cre recombinase (iCre) under regulation of the natural Esr1 promoter (Esr1-iCre) was developed. Functional characterization of iCre expression by crossing them with reporter lines (ROSA26-lacZ or Ai9-RFP) showed that iCre is faithfully expressed in Esr1-lineage cells. This novel transgenic mouse line will be a useful animal model for lineage-tracing Esr1-expressing cells, selective gene ablation in the Esr1-lineage cells and for generating global Esr1 knockout mice. PMID- 29115050 TI - Localization of the T-cell response to RSV infection is altered in infant mice. AB - OBJECTIVES: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections worldwide, causing disproportionate morbidity and mortality in infants and children. Infants with stronger Th1 responses have less severe disease, yet little is known about the infant T-cell response within the air space. Thus, we tested the hypothesis that RSV infected infant mice would have quantitative and qualitative deficiencies in CD4+ and CD8+ T-cell populations isolated from the bronchoalveolar lavage when compared to adults and that local delivery of IFN-gamma would increase airway CD4+ Tbet+ and CD8+ Tbet+ T-cell responses. METHODS: We compared the localization of T-cell responses in RSV-infected infant and adult mice and investigated the effects of local IFN gamma administration on infant cellular immunity. RESULTS: Adult CD8+ CD44HI and CD4+ CD44HI Tbet+ T-cells accumulated in the alveolar space whereas CD4+ CD44HI Tbet+ T-cells were evenly distributed between the infant lung tissue and airway and infant lungs contained higher frequencies of CD8+ T-cells. Delivery of IFN gamma to the infant airway failed to increase the accumulation of T-cells in the airspace and unexpectedly reduced CD4+ CD44HI Tbet+ T-cells. However, intranasal IFN-gamma increased RSV F protein-specific CD8+ T-cells in the alveolar space. CONCLUSION: Together, these data suggest that quantitative and qualitative defects exist in the infant T-cell response to RSV but early, local IFN-gamma exposure can increase the CD8+ RSV-specific T-cell response. PMID- 29115052 TI - Dose Selection Based on Modeling and Simulation for Rivipansel in Pediatric Patients Aged 6 to 11 Years With Sickle Cell Disease. AB - This modeling and simulation exercise aimed to provide dosing recommendations for rivipansel phase III studies in children aged 6-11 years with sickle cell disease (SCD). Pharmacokinetic data from 109 patients aged 12-51 years who received rivipansel (2-40 mg/kg) in previous studies (three phase I and one phase II) were integrated to build a three-compartmental simulation model. Renal clearance simulations across the age range accounted for renal function development and postulated hyperfiltration in SCD. Simulated demographic distributions for the pediatric SCD population were used to predict concentration-time profiles from three dosing regimens, which were then compared against efficacious average steady-state concentrations observed in phase II. A dosing regimen comprising a 40-mg/kg loading dose followed by a 20-mg/kg maintenance dose every 12 hours was selected, as it will likely provide an efficacious concentration range. Its validity will be confirmed in the ongoing phase III study. PMID- 29115051 TI - To the end of the line: Axonal mRNA transport and local translation in health and neurodegenerative disease. AB - Axons and growth cones, by their very nature far removed from the cell body, encounter unique environments and require distinct populations of proteins. It seems only natural, then, that they have developed mechanisms to locally synthesize a host of proteins required to perform their specialized functions. Acceptance of this ability has taken decades; however, there is now consensus that axons do indeed have the capacity for local translation, and that this capacity is even retained into adulthood. Accumulating evidence supports the role of locally synthesized proteins in the proper development, maintenance, and function of neurons, and newly emerging studies also suggest that disruption in this process has implications in a number of neurodevelopmental and neurodegenerative diseases. Here, we briefly review the long history of axonal mRNA localization and local translation, and the role that these locally synthesized proteins play in normal neuronal function. Additionally, we highlight the emerging evidence that dysregulation in these processes contributes to a wide range of pathophysiology, including neuropsychiatric disorders, Alzheimer's, and motor neuron diseases such as spinal muscular atrophy and Amyotrophic Lateral Sclerosis. (c) 2017 Wiley Periodicals, Inc. Develop. Neurobiol 78: 209-220, 2018. PMID- 29115053 TI - Kawasaki disease - the journey over 50 years: 1967-2017. PMID- 29115054 TI - Comparison of human umbilical cord blood-derived mesenchymal stem cells with healthy fibroblasts on wound-healing activity of diabetic fibroblasts. AB - Various types of skin substitutes composed of fibroblasts and/or keratinocytes have been used for the treatment of diabetic ulcers. However, the effects have generally not been very dramatic. Recently, human umbilical cord blood-derived mesenchymal stromal cells (hUCB-MSCs) have been commercialised for cartilage repair as a first cell therapy product using allogeneic stem cells. In a previous pilot study, we reported that hUCB-MSCs have a superior wound-healing capability compared with fibroblasts. The present study was designed to compare the treatment effect of hUCB-MSCs with that of fibroblasts on the diabetic wound healing in vitro. Diabetic fibroblasts were cocultured with healthy fibroblasts or hUCB-MSCs. Five groups were evaluated: group I, diabetic fibroblasts without coculture; groups II and III, diabetic fibroblasts cocultured with healthy fibroblasts or hUCB-MSCs; and groups IV and V, no cell cocultured with healthy fibroblasts or hUCB-MSCs. After a 3-day incubation, cell proliferation, collagen synthesis levels and glycosaminoglycan levels, which are the major contributing factors in wound healing, were measured. As a result, a hUCB-MSC-treated group showed higher cell proliferation, collagen synthesis and glycosaminoglycan level than a fibroblast-treated group. In particular, there were significant statistical differences in collagen synthesis and glycosaminoglycan levels (P = 0.029 and P = 0.019, respectively). In conclusion, these results demonstrate that hUCB-MSCs may have a superior effect to fibroblasts in stimulating diabetic wound healing. PMID- 29115056 TI - A Stable Nanocobalt Catalyst with Highly Dispersed CoNx Active Sites for the Selective Dehydrogenation of Formic Acid. AB - Novel nanostructured catalysts with highly dispersed cobalt have been synthesized by the pyrolysis of metal phenanthroline complexes. Materials with significantly different properties were obtained by simply tuning the metal/ligand ratio. The catalytic potential of this class of compounds is shown by the first example of the dehydrogenation of formic acid under the catalysis of atomically dispersed cobalt. From TEM, XPS, and XRD characterization, KSCN poisoning, and acid leaching, the formation of CoNx species as the active site seems key to the success of this reaction. Excellent stability and recyclability make this new catalyst also attractive for other applications. PMID- 29115055 TI - Differences between adult and pediatric onset Henoch-Schonlein purpura from North India. AB - AIM: Henoch-Schonlein purpura (HSP), a primary vasculitis, characterized by purpura, abdominal pain, arthritis and renal involvement, is predominantly a disease of childhood. However, rarely it can occur in adults in whom it is believed to be a more severe form with poor renal outcomes. We aimed to answer if the age of onset affected the clinical spectrum and renal outcomes of the disease in a north Indian population. Hence, we studied the differences in clinical spectrum and renal outcomes between adult-onset HSP and childhood-onset HSP. METHODS: Case records of all adult patients diagnosed with HSP (onset >= 18 years) over the last 25 years in our department (1992-2017) were retrieved. Data on clinical features, lab abnormalities and outcomes were extracted and compared with that in pediatric HSP patients (onset < 18 years) seen during the same period. RESULTS: A total of 87 patients, including 30 adults and 57 children, were seen during this period. Compared to children, most of the adults had purpura as the first clinical manifestation (86.7% vs. 56.1%, P < 0.01) whereas abdominal pain was only rarely the initial symptom in adults (10.0% vs. 36.8%, P < 0.02). During the disease course, adults had a higher frequency of joint involvement as compared to children (90.0% vs. 43.9%, P < 0.001). There was no significant difference in the frequency of renal involvement (60.0% vs. 50.9%, P = NS) and gastrointestinal involvement (66.7% vs. 84.2%, P = NS) between adults and children. Outcomes were good in both groups and most adults and children achieved complete recovery (83.3% and 86.0%, respectively). There was no difference in the frequency of immunosuppressive treatment required by the two groups. None of the patients developed renal insufficiency on follow-up. CONCLUSION: Compared to children, adults with HSP seldom have abdominal pain as the first clinical manifestation while joint involvement is seen more commonly in them during the disease course. PMID- 29115057 TI - Smoking and EGFR status may predict outcomes of advanced NSCLC treated with PD (L)1 inhibitors beyond first line: A meta-analysis. AB - OBJECTIVES: The aim of this study was to assess the potential clinical and biological predictive markers of survival in pretreated advanced NSCLC patients treated with the three PD-(L)1 inhibitors (nivolumab, pembrolizumab and atezolizumab). DATA SOURCE/STUDY SELECTION: PubMed database has been searched. The review author extracted relevant information on participant characteristics and study outcomes for this review and assessed risk of bias of the included trials. Data analysis was conducted through RevMan v.5.3. MAIN RESULTS: Five randomized controlled trials with 3013 patients were included. There was no predictive value for the age of the patients (taking 65 years as a cutoff value), the histology (squamous vs nonsquamous) or performance score (score 0 vs score 1); while there appears to be a value for smoking history and EGFR status. The pooled HR for death for patients with EGFR mutant disease was 1.11 [95% CI: 0.80, 1.53; P = 0.54]; while pooled HR for death for patients with EGFR wild type disease was 0.67 [95% CI: 0.60, 0.75; P < 0.00001]. The pooled HR for death for patients with current/former smokers was 0.71 [95% CI: 0.63, 0.82; P < 0.00001]; while pooled HR for death for patients with never smokers was 0.79 [95% CI: 0.60, 1.06; P = 0.11]. However, because of the low-to-moderate quality of data, these conclusions may change with publication of other ongoing trials. CONCLUSIONS: Smoking history and EGFR status may help predict the performance of PD-(L)1 inhibitors vs docetaxel in previously treated NSCLC patients. PMID- 29115058 TI - Increasing flooding frequency alters soil microbial communities and functions under laboratory conditions. AB - The impacts of increased flooding frequency on soil microbial communities and potential functions, in line with predicted environmental changes, were investigated in a laboratory-controlled environment. More frequent flooding events altered microbial community composition and significantly increased the resolved species alpha-diversity (Shannon index). The Bacteria:Archaea ratio was greater at the end of the experiment than at the start, more-so after only one flood. Significant changes in taxa and functional gene abundances were identified and quantified. These include genes related to the reduction and oxidation of substances associated with anoxia, for example, those involved in nitrogen and sulfur cycling. No significant changes were observed in the methanogenesis pathway, another function associated with anoxia and which contributes to the emission of greenhouse gases. PMID- 29115059 TI - Universal field matching in craniospinal irradiation by a background-dose gradient-optimized method. AB - PURPOSE: The gradient-optimized methods are overcoming the traditional feathering methods to plan field junctions in craniospinal irradiation. In this note, a new gradient-optimized technique, based on the use of a background dose, is described. METHODS: Treatment planning was performed by RayStation (RaySearch Laboratories, Stockholm, Sweden) on the CT scans of a pediatric patient. Both proton (by pencil beam scanning) and photon (by volumetric modulated arc therapy) treatments were planned with three isocenters. An 'in silico' ideal background dose was created first to cover the upper-spinal target and to produce a perfect dose gradient along the upper and lower junction regions. Using it as background, the cranial and the lower-spinal beams were planned by inverse optimization to obtain dose coverage of their relevant targets and of the junction volumes. Finally, the upper-spinal beam was inversely planned after removal of the background dose and with the previously optimized beams switched on. RESULTS: In both proton and photon plans, the optimized cranial and the lower-spinal beams produced a perfect linear gradient in the junction regions, complementary to that produced by the optimized upper-spinal beam. The final dose distributions showed a homogeneous coverage of the targets. DISCUSSION: Our simple technique allowed to obtain high-quality gradients in the junction region. Such technique universally works for photons as well as protons and could be applicable to the TPSs that allow to manage a background dose. PMID- 29115060 TI - Guidance for deriving and presenting percentage study weights in meta-analysis of test accuracy studies. AB - Percentage study weights in meta-analysis reveal the contribution of each study toward the overall summary results and are especially important when some studies are considered outliers or at high risk of bias. In meta-analyses of test accuracy reviews, such as a bivariate meta-analysis of sensitivity and specificity, the percentage study weights are not currently derived. Rather, the focus is on representing the precision of study estimates on receiver operating characteristic plots by scaling the points relative to the study sample size or to their standard error. In this article, we recommend that researchers should also provide the percentage study weights directly, and we propose a method to derive them based on a decomposition of Fisher information matrix. This method also generalises to a bivariate meta-regression so that percentage study weights can also be derived for estimates of study-level modifiers of test accuracy. Application is made to two meta-analyses examining test accuracy: one of ear temperature for diagnosis of fever in children and the other of positron emission tomography for diagnosis of Alzheimer's disease. These highlight that the percentage study weights provide important information that is otherwise hidden if the presentation only focuses on precision based on sample size or standard errors. Software code is provided for Stata, and we suggest that our proposed percentage weights should be routinely added on forest and receiver operating characteristic plots for sensitivity and specificity, to provide transparency of the contribution of each study toward the results. This has implications for the PRISMA-diagnostic test accuracy guidelines that are currently being produced. PMID- 29115061 TI - Carcinoma showing thymus like elements: Report of a case with EGFR T790M mutation. AB - Carcinoma showing thymus-like differentiation of the thyroid (CASTLE) is a rare tumor involving the thyroid and perithyroidal soft tissues. It shares morphological, immunohistochemical and molecular similarities with thymic carcinomas. Due to its relatively better prognosis, it needs differentiation from other primary and metastatic tumors of this region. A 40-year-old lady presented with a gradually progressive anterior neck swelling for one year. Imaging showed bulky right and left lobes of thyroid along with a solid soft tissue mass in the pretracheal region. Fine needle aspiration smears showed features of poorly differentiated carcinoma. Total thyroidectomy with excision of the mass revealed histopathological features characteristic of CASTLE, with evidence of thyroiditis in adjoining thyroid. Epidermal growth factor receptor (EGFR) assay revealed presence of EGFR T790M somatic mutation in exon 20. The same was not detectable on direct sequencing. We present a rare case of CASTLE, occurring in association with Hashimoto thyroiditis, with emphasis on cytological features and report for the first time the presence of a low level somatic mutation in EGFR (EGFR T790M mutation). PMID- 29115062 TI - Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE. AB - OBJECTIVE: To report the clinical and genetic features of the first cases of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome in an Arab population and to compare them with patients of C1q deficient systemic lupus erythematosus (SLE). MATERIALS AND METHODS: This is a retrospective case series of patients with CANDLE syndrome and C1q deficient SLE seen at a single tertiary hospital. Medical records were reviewed for demographic data, clinical and laboratory features, histopathology and imaging findings, and response to therapeutic intervention. Descriptive data were summarized. RESULTS: Three patients from unrelated families fulfilled the clinical manifestations of CANDLE syndrome. The disease onset was within the first 4 months of age. Two patients had uncommon features including uveitis, pulmonary involvement, aseptic meningitis and global delay. Skin biopsy showed heterogeneous findings. Genomic DNA screening was homozygous for mutation in PSMB8, (NM_004159.4:c.212C>T, p.T71M) in one patient and inconclusive for the other two patients. The comparison group was three patients with familial C1q deficient SLE from three unrelated families, who were born to consanguineous parents with at least one affected sibling. They presented with extensive mucocutaneous lesions, discoid rash and scarring alopecia. They required frequent admissions due to infections. CONCLUSION: This is the first report of CANDLE syndrome in an Arab population; our patients had heterogeneous phenotypic and genetic features with overlap manifestations with C1q deficient SLE. Both are monogenic interferonopathies. However, C1q deficient SLE had more systemic inflammatory disease. PMID- 29115063 TI - Corrigendum: Performance of Deep and Shallow Neural Networks, the Universal Approximation Theorem Activity Cliffs, and QSAR. PMID- 29115064 TI - Broad ligament hernia successfully repaired by single-incision laparoscopy: A case report. AB - A 52-year-old woman with a history of two parturitions presented with lower abdominal pain. Multi-detector CT of the abdomen showed discontinuity of the sigmoid colon near the broad ligament on the left side. We assigned a provisional diagnosis of an internal hernia progressing through a defect in the broad ligament. SILS revealed a total broad ligament defect on the left side but no signs of ischemic, necrotic bowel. We successfully repaired the broad ligament defect with suturing. At the 2-month follow-up, the patient remained well with no signs of recurrence. This case appears to be the first report of a broad ligament hernia successfully diagnosed and repaired by SILS. PMID- 29115065 TI - Editor's Introduction and Review: Coordination and Context in Cognitive Science. AB - The role of coordination in cognitive science has been on the rise in recent years, in terms of coordination among neurons, coordination among sensory and motor systems, and coordination among individuals. Research has shown that coordination patterns corresponding to cognitive activities depend on the various contexts in which the underlying interactions are situated. The present issue of Topics in Cognitive Science centers on studies of coordination that address the role of context in shaping or interpreting dynamical patterns of human behavior. This introductory article reviews some of the prior literature leading up to current and future research on coordination and context in cognitive science. PMID- 29115066 TI - On Improving Donor Lung Usage Rate for Transplantation. PMID- 29115067 TI - Area-level Socioeconomic Deprivation Affect Individual Cancer Mortality in Korea. PMID- 29115068 TI - Hip Fracture in Chronic Kidney Disease Patients: Necessity of Multidisciplinary Approach. PMID- 29115069 TI - Editorial Abuses. PMID- 29115070 TI - Legislative Issues in Disclosing Financial Conflicts of Interest to Participants in Biomedical Research: Effectiveness and Methodology. AB - This research focuses on the analysis regarding disclosure of financial conflicts of interest (FCOI) after Gelsinger v. University of Pennsylvania (Penn). The main legal issue was that the participants did not have enough opportunity to make an autonomous decision about participating in the research because he was not informed about the researchers' and the institution's substantial FCOI. The disclosure system was adopted by the Code of Federal Regulations. Under the regulation, researchers and institutions need to report FCOI over $5,000 to the institution, and the internal review boards have to report to the federal authority if needed. In case of human research, the disclosure to Food and Drug Administration is mandatory. FCOI disclosure system would help participants to make an autonomous decision, and increase trust to the research process and researchers. Moreover, the system would let researchers keep fiduciary duty while (possibly) lowering legal liability in case of a lawsuit. There were discussions about the disclosure methodology in the United States. However, there have not been a lot of discussions in Korea even after the "Humidifier Disinfectant" case. Therefore, new legislations need to be considered. First, the system requires disclosure funded by not only government but also private institutions. Second, like California Supreme Court, the subject would be reviewed under the reasonable person standard by participants, including patents, equity, and stock. Third, the disclosure needs to include simple or brief explanation to the FCOI to be better understood by the participants. Fourth, the disclosure should be in the informed consent process. PMID- 29115071 TI - An Acute Medical Unit in a Korean Tertiary Care Hospital Reduces the Length of Stay and Waiting Time in the Emergency Department. AB - A hospitalist-run acute medical unit (AMU) opened at a tertiary care hospital on August 2015 for the first time in Korea. Patients visiting the emergency department (ED) with acute medical problems are admitted to the AMU. They stay in that unit for less than 72 hours and are discharged or transferred to specialty wards if longer treatment is necessary. We reviewed 19,450 medical admissions through the ED from January 2014 to September 2016. The median length of stay (LOS) significantly decreased from 10.0 days (interquartile range [IQR], 5.5 16.7) to 9.1 days (IQR, 5.1-15.0) (P < 0.001) after the establishment of the AMU. The median waiting time in the ED significantly shortened by 40% (P < 0.001). Future studies on the impact of AMU on in-patient morbidity, mortality, re admission rate, and patient or staff satisfaction are necessary. PMID- 29115072 TI - Emergency Department Visits Can Be Reduced by Having a Regular Doctor for Adults with Diabetes Mellitus: Secondary Analysis of 2013 Korea Health Panel Data. AB - Chronic diseases pose a major challenge to population health worldwide. Diabetes is a major chronic disease that is managed overwhelmingly in primary care. There is an increasing recognition of the role that primary care physicians play to achieve high-quality care for patients with diabetes. By analyzing 2013 Korean Health Panel data, the authors aimed to determine the current status of having a regular doctor (RD) for adults (aged 18 years or older) with diabetes. In addition, the association of having a RD with the experience of emergency department (ED) visits was determined in this study. Among adults with diabetes, those with RD accounted for 41.0%. The older the age group and the higher the Charlson comorbidity index score, the higher the percentage of adults with diabetes had RD. Even for those with RD, coordination of care was very poor (positive answer: 27.1%). After adjustment for confounding variables, those having (vs. not having) a RD (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.35-0.94), especially those whose RDs delivered good comprehensiveness of care (OR, 0.47; 95% CI, 0.26-0.84) or worked at a primary care clinic (OR, 0.43; 95% CI, 0.22-0.81), and those whose longitudinal relationship with a RD was 5 years or less (OR, 0.45; 95% CI, 0.22-0.91) were less likely to have ED visits within the last year. In conclusion, health care policies that promote having a RD who delivers high-quality primary care could decrease unnecessary ED visits by diabetic adults. This can partly reduce ED overcrowding in Korea. PMID- 29115073 TI - Assessment of Competence in Emergency Medicine among Healthcare Professionals in Cameroon. AB - Development of a competence-based curriculum is important. This study aimed to develop competence assessment tools in emergency medicine and use it to assess competence of Cameroonian healthcare professionals. This was a cross-sectional, descriptive study. Through literature review, expert survey, and discrimination tests, we developed a self-survey questionnaire and a scenario-based competence assessment tool for assessing clinical knowledge and self-confidence to perform clinical practices or procedures. The self-survey consisted of 23 domains and 94 questionnaires on a 5-point Likert scale. Objective scenario-based competence assessment tool was used to validate the self-survey results for five life threatening diseases presenting frequently in emergency rooms of Cameroon. Response rate of the self-survey was 82.6%. In this first half of competence assessment, knowledge of infectious disease had the highest score (4.6 +/- 0.4) followed by obstetrics and gynecology (4.2 +/- 0.6) and hematology and oncology (4.2 +/- 0.5); in contrast, respondents rated the lowest score in the domains of disaster, abuse and assault, and psychiatric and behavior disorder (all of mean 2.8). In the scenario-based test, knowledge of multiple trauma had the highest score (4.3 +/- 1.2) followed by anaphylaxis (3.4 +/- 1.4), diabetic ketoacidosis (3.3 +/- 1.0), ST-elevation myocardial infarction (2.5 +/- 1.4), and septic shock (2.2 +/- 1.1). Mean difference between the self-survey and scenario-based test was statistically insignificant (mean, -0.02; 95% confidence interval, -0.41 to 0.36), and agreement rate was 58.3%. Both evaluation tools showed a moderate correlation, and the study population had relatively low competence for specific aspects of emergency medicine and clinical procedures and skills. PMID- 29115074 TI - Adapter-based Safety Injection System for Prevention of Wrong Route and Wrong Patient Medication Errors. AB - Wrong-route or -patient medication errors due to human mistakes have been considered difficult to resolve in clinical settings. In this study, we suggest a safety injection system that can help to prevent an injection when a mismatch exists between the drug and route or patient. For this, we prepared two distinct adapters with key and keyhole patterns specifically assigned to a pair of drug and route or patient. When connected to a syringe tip and its counterpart, a catheter injection-port, respectively, the adapters allowed for a seamless connection only with their matching patterns. In this study, each of the adapters possessed a specific key and keyhole pattern at one end and the other end was shaped to be a universal fit for syringe tips or catheter injection-ports in clinical use. With the scheme proposed herein, we could generate 27,000 patterns, depending on the location and shape of the key tooth in the adapters. With a rapid prototyping technique, multiple distinct pairs of adapters could be prepared in a relatively short period of time and thus, we envision that a specific adapter pair can be produced on-site after patient hospitalization, much like patient identification barcodes. PMID- 29115075 TI - Unobtrusive Estimation of Cardiorespiratory Fitness with Daily Activity in Healthy Young Men. AB - Despite the importance of cardiorespiratory fitness, no practical method exists to estimate maximal oxygen consumption (VO2max) without a specific exercise protocol. We developed an estimation model of VO2max, using maximal activity energy expenditure (aEEmax) as a new feature to represent the level of physical activity. Electrocardiogram (ECG) and acceleration data were recorded for 4 days in 24 healthy young men, and reference VO2max levels were measured using the maximal exercise test. aEE was calculated using the measured acceleration data and body weight, while heart rate (HR) was extracted from the ECG signal. aEEmax was obtained using linear regression, with aEE and HR as input parameters. The VO2max was estimated from the aEEmax using multiple linear regression modeling in the training group (n = 16) and was verified in the test group (n = 8). High correlations between the estimated VO2max and the measured VO2max were identified in both groups, with a 15-hour recording being sufficient to produce a highly accurate VO2max estimate. Additional recording time did not significantly improve the accuracy of the estimation. Our VO2max estimation method provides a robust alternative to traditional approaches while only requiring minimal data acquisition time in daily life. PMID- 29115076 TI - Current Status and Future of Lung Donation in Korea. AB - Lung transplantation is the only effective treatment option for patients with end stage lung disease. However, donor organ shortage makes timely transplant not possible for all patients, especially in Korea. We investigated the number and utilization of donor lungs by retrospectively reviewing all donor organs registered in the Korea Network for Organ Sharing database from March 2012 to March 2016. The donors were stratified into 4 groups by donor acceptability criteria. A total of 1,304 donors were included. Of those, 295 brain-dead donors (22.6%) consented to lung donation. Among these consented donors, 168 donors (12.9%) were retrieved for lung transplant. Retrieval rate was very low compared with that of the kidney (93.9%), liver (86.3%), and heart (27.3%). The characteristics of utilized donor lungs were: mean age, 40.5 years (range: 18 to 63 years); mean partial pressure of oxygen, 356.5 mmHg; mean smoking history, 5.9 pack-years; and mean body mass index, 22.6 kg/m2. The proportion of donors with acceptable condition of the transplanted lungs was only 39.3% (ideal 19, standard 47, marginal 70, unusable 32). Among brain-dead patients who denied to donate lungs (n = 1,009), 82 were potentially acceptable donors (ideal 19, standard 63), which was equal to half of actually transplanted lung donations. Many potential donor lungs, which are currently excluded, may be successfully used in lung transplantation in Korea. The available lung donors must be actively selected and managed to maximize the utilization of this precious resource. PMID- 29115077 TI - Identification of Epstein-Barr Virus in the Human Placenta and Its Pathologic Characteristics. AB - Epstein-Barr virus (EBV), a common pathogen in humans, is suspected as the cause of multiple pregnancy-related pathologies including depression, preeclampsia, and stillbirth. Moreover, transmission of EBV through the placenta has been reported. However, the focus of EBV infection within the placenta has remained unknown to date. In this study, we proved the expression of latent EBV genes in the endometrial glandular epithelial cells of the placenta and investigated the cytological characteristics of these cells. Sixty-eight placentas were obtained from pregnant women. Tissue microarray was constructed. EBV latent genes including EBV-encoding RNA-1 (EBER1), Epstein-Barr virus nuclear antigen 1 (EBNA1), late membrane antigen (LMP1), and RPMS1 were detected with silver in situ hybridization and/or mRNA in situ hybridization. Nuclear features of EBV positive cells in EBV-infected placenta were compared with those of EBV-negative cells via image analysis. Sixteen placentas (23.5%) showed positive expression of all 4 EBV latent genes; only the glandular epithelial cells of the decidua showed EBV gene expression. EBV infection status was not significantly correlated with maternal, fetal, or placental factors. The nuclei of EBV-positive cells were significantly larger, longer, and round-shaped than those of EBV-negative cells regardless of EBV-infection status of the placenta. For the first time, evidence of EBV gene expression has been shown in placental tissues. Furthermore, we have characterized its cytological features, allowing screening of EBV infection through microscopic examination. PMID- 29115078 TI - Elderly Patients Exhibit Stronger Inflammatory Responses during Gout Attacks. AB - Gout attacks are often accompanied by systemic inflammatory response. The aim of the retrospective study was to compare gout patients in different age groups in terms of their clinical features at gout attacks. Patients, who were treated for gout attack in two tertiary medical centers between January 2000 and April 2014, were divided into young (<= 50 years), middle-aged, and elderly (> 65 years) groups. Patients in three age groups were compared in terms of presence of fever (> 37.8 degrees C), C-reactive protein (CRP) levels, and erythrocyte sedimentation ratio (ESR) at the gout attacks. Monocytes, which were isolated from 10 consecutive patients who previously experienced gout attacks, were stimulated with monosodium urate (MSU) crystals and cytokine production was measured by flow cytometry. Among 254 patients analyzed in this study, 48 were young, 65 were middle-aged, and 141 were elderly. The elderly patients were more likely to have fever (51.1%) during the attack than the young (20.8%) and middle aged (30.8%) patients (P < 0.001 by chi2 test). They were also more likely to have higher ESR and CRP levels than the young patients (P = 0.002 for ESR, P < 0.001 for CRP). Patients' age correlated significantly with CRP and ESR levels (both P < 0.001). After stimulation with MSU, the production of interleukin-1beta by monocytes increased with patients' age (r = 0.670, P = 0.03). In conclusion, gout attacks in elderly patients are associated with fever and higher ESR and CRP levels, often resembling a septic arthritis. PMID- 29115079 TI - Disparities by Age, Sex, Tumor Stage, Diagnosis Path, and Area-level Socioeconomic Status in Survival Time for Major Cancers: Results from the Busan Cancer Registry. AB - Our goal was to examine the effect of area-level deprivation on patient survival time for seven major cancers - stomach, colon, liver, lung, breast, cervix, and thyroid cancer. Data on 10,902 subjects who were diagnosed with major cancers from 2010 and 2011 in Busan were collected regarding the survival time along with several important prognostic factors and an area-level deprivation index was constructed from education, income, unemployment, and welfare assistance, to assess the comprehensive area-level socioeconomic status. A multilevel Cox proportional hazard model was used to investigate the effects of multiple risk factors such as gender, age, tumor stage, diagnosis path, and the area-level deprivation. After adjusting for risk factors the area-level deprivation index was found to be significant in associating with higher hazard rate for several cancers. Estimated hazard ratios (95% CI) were 1.08 (0.99-1.18), 1.23 (1.12 1.36), 1.36 (1.21-1.53) for the second, the third, and the fourth quartile of deprivation index groups, respectively, when compared to the least deprived group. When compared with the least deprived group, the more deprived group showed significant decrease in survival time for major cancers. This novel finding may contribute to the literature regarding the association of area-level socioeconomic status and highlight the importance of careful monitoring of socioeconomic characteristics for cancer prevention and care services. PMID- 29115080 TI - Prevalences and Management of Diabetes and Pre-diabetes among Korean Teenagers and Young Adults: Results from the Korea National Health and Nutrition Examination Survey 2005-2014. AB - The rapid increases in childhood obesity and physical inactivity are linked to the incidence of diabetes among young individuals. However, few studies have evaluated the prevalence of diabetes among this population. Therefore, we used Korea National Health and Nutrition Examination Survey (KNHANES) data to evaluate the prevalence and management of diabetes and pre-diabetes among young Koreans. We evaluated KNHANES data (2005-2014) from 10-29-year-old individuals. Individuals were considered eligible if they had completed the health examination and the health interview survey, and we excluded individuals with missing data regarding fasting glucose or glycated haemoglobin levels. Among the 100,101 potentially eligible individuals who participated in KNHANES (2005-2014), we included 83,577 (37,677 male and 45,900 female) individuals. The overall prevalences of diabetes and pre-diabetes among 10-19-year-old individuals were 0.2% and 11.9%, respectively. Among 20-29-year-old individuals, the prevalences of diabetes and pre-diabetes were 0.9% and 9.6%, respectively. The overall rates of diabetes awareness during the study period were 36.6% for 10-19-year-old individuals and 50.8% for 20-29-year-old individuals. However, the prevalence of diabetes and pre-diabetes had noticeably increased at the 2013-2014 KNHANES: 0.6% and 25.9% among 10-19-year-old individuals, and 0.8% and 19.2% among 20-29-year old individuals. The prevalence of diabetes and pre-diabetes is rapidly increasing among Korean teenagers and young adults. Pre-emptive interventions to diagnose and treat diabetes and pre-diabetes are needed to improve glycaemic control among this population. PMID- 29115081 TI - Verification of Current Risk Scores for Kawasaki Disease in Korean Children. AB - The purpose of this study was to evaluate and assess the compatibility of current risk scoring systems from Japan that were developed to predict intravenous immunoglobulin (IVIG) resistance in patients with Kawasaki disease (KD). The authors previously investigated another prediction model for patients with refractory KD in Korea. A retrospective study involving 350 patients with KD who were admitted between January 2014 and December 2015 was performed. Patients younger than 2 years were excluded for the propensity score matching in this study. Patients were classified into IVIG responders and IVIG resistance groups. The well-known Harada, Kobayashi, and Egami risk scores were calculated for each patient, and the proportion of high-risk patients was compared between the two groups for each risk score. Logistic regression analysis revealed that platelets, C-reactive protein (CRP) levels, and aspartate aminotransferase levels were independent predictors of IVIG resistance. Multivariate analysis suggested that platelets and CRP were risk factors. Risk-scoring systems from Japan have good specificity but low sensitivity. Among the three risk scoring systems, the Kobayashi risk score demonstrated significant differences between the IVIG resistance and IVIG responder groups in Korean patients with KD. It is very important to identify IVIG-resistant patients to protect them from ongoing coronary arterial lesion(s); therefore, early prediction and timely optimal additional treatment is of significant benefit. It would be helpful to construct a highly sensitive, exclusive scoring system for Korean patients with KD. PMID- 29115082 TI - Genetic Contributions to Childhood Obesity: Association of Candidate Gene Polymorphisms and Overweight/Obesity in Korean Preschool Children. AB - This study was aimed to investigate the association of candidate gene polymorphisms and obesity or overweight in young Korean children. A total of 190 Korean preschool children (96 control, 48 overweight, and 46 obese children) were genotyped for the angiotensin converting enzyme (ACE) insertion (I)/deletion (D), angiotensin II type 2 receptor (AT2) C3123A, transforming growth factor (TGF) beta1 T869C, vascular endothelial growth factor (VEGF) T460C, and tumor necrosis factor (TNF)-alpha G308A polymorphisms. No differences were found among the groups with respect to age, sex, birth weight, blood pressure levels, and serum concentrations of glucose and total cholesterol. Obese children showed a higher incidence of ACE DD genotype and D allelic frequency compared to the controls (odds ratio [OR], 2.7, 95% confidence interval [CI], 1.01-7.21; OR, 2.5, 95% CI, 1.49-4.19; all P < 0.05). The frequency of TC genotype and C allele in the TGF beta1 T869C polymorphism (OR, 2.08, 95% CI, 1.01-4.27; OR, 1.93, 95% CI, 1.15 3.21) and that in the VEGF T460C polymorphism (OR, 2.5, 95% CI, 1.19-5.28; OR, 2.15, 95% CI, 1.26-3.68) was also higher in obese children than in control subjects (all P < 0.05). Overweight children exhibited a higher frequency of the A allele in the AT2 C3123A polymorphism compared to the controls (OR, 1.72, 95% CI, 1.03-2.88, P < 0.05). There were no differences in the TNF-alpha G308A polymorphism among the groups. The ACE I/D, AT2 C3123A, TGF-beta1 T869C, and VEGF T460C polymorphisms can affect susceptibility to obesity or overweight in Korean children. PMID- 29115083 TI - Clinical Evaluation of Techniques for Measuring Nasal-Specific Immunoglobulin E in Pediatric Patients. AB - Currently used methods for collecting nasal-specific immunoglobulin E (IgE) require administration of a large amount of saline into the nostrils, which is difficult in children. We designed two methods that are easy to use in children. We measured nasal-specific IgE and evaluated clinical characteristics of nasal specific IgE in pediatric rhinitis. This study included 82 patients who visited Kyungpook National University Children's Hospital from December 2014 to July 2016 with rhinitis symptoms. Thirty patients used the spray method, and 52 patients used the swab method. We examined nasal-specific IgE to Dermatophagoides farinae, Dermatophagoides pteronyssinus, Alternaria, birch, and weed mix. Thirty patients had nasal-specific IgE concentrations of >= 0.35 kIU/L. There was a positive correlation between nasal-specific IgE and serum-specific IgE to D. farinae and D. pteronyssinus (r = 0.548, P < 0.001; r = 0.656, P < 0.001). If we regard positivity of skin prick test as standard, cutoff point of nasal-specific IgE to D. farinae was 0.11 kIU/L and to D. pteronyssinus was 0.12 kIU/L. Based on these cutoff points, five patients would be considered to have local allergic rhinitis. The methods showed relatively high positivity for nasal-specific IgE, which reflected the serum-specific IgE as well. These methods can be considered to diagnose local allergic rhinitis in children. PMID- 29115084 TI - Cardiac Magnetic Resonance Predictor of Ventricular Function after Surgical Coronary Revascularization. AB - We evaluated echocardiographic changes of left ventricular (LV) function in coronary artery bypass grafting (CABG) patients with LV dysfunction, and examined cardiac magnetic resonance (CMR) parameters associated with improved LV function. Seventy-seven CABG patients presenting with decreased LV ejection fraction (LVEF, <= 35%) and who underwent preoperative gadolinium-enhanced CMR were enrolled. A 16-segment model was used to analyze CMR imaging. A viable myocardial segment was defined as <= 50% transmural extent of late gadolinium enhancement. Serial echocardiographic examinations were performed preoperatively, pre-discharge (median 6 days), and during postoperative year 1 (median 11 months) in 70 patients. Predictors of absolute increase in LVEF (>= 5%) and proportional changes in LVEF were analyzed. Serial echocardiography demonstrated that LVEF measured 28.6% +/- 5.4% preoperatively, 31.5% +/- 8.0% median 6 days, and 42.1% +/- 10.5% median 11 months postoperatively. Absolute increase of LVEF was observed in 27 patients at pre-discharge and in 24 patients by median 11 months. Proportional changes in LVEF at postoperative median 6 days and 11 months were 14% +/- 28% and 57% +/- 45%, respectively. The median number of viable myocardial segments was 14 (range, 9-16) in the 16 segment CMR model. Multivariable models demonstrated that the median number of overall viable myocardial segments (>= 14) in preoperative CMR was associated with absolute increase (P = 0.046) and proportional changes (P = 0.005) in LVEF. In conclusion, the number of viable myocardial segments (>= 14) in preoperative CMR predicted LV function improvement after CABG in patients with LV dysfunction. PMID- 29115085 TI - Prediction of Amnionicity Using the Number of Yolk Sacs in Monochorionic Multifetal Pregnancy. AB - The purpose of this article was to evaluate the accuracy of predicting amnionicity using the number of yolk sacs by diagnostic ultrasound examination in monochorionic (MC) multifetal pregnancies between 7 + 0 and 9 + 6 gestational weeks. A total of 97 patients with MC multifetal pregnancies underwent early ultrasound examination from 2004 to 2014 at Cheil General Hospital and Women's Healthcare Center. All patients for whom the number of yolk sacs was reported were included in this study. We compared the number of yolk sacs with amnionicity confirmed by an intertwine membrane. Overall, there was a 9.3% (9 cases) discrepancy in number of yolk sacs and amnionicity (4.3% for monochorionic diamniotic, 36.4% for monochorionic monoamniotic, and 33% for monochorionic triamniotic). Among the 9 cases with discrepancies, 4 cases with 2 yolk sacs were confirmed as monoamniotic pregnancies and 4 MC twin pregnancies showing a single yolk sac were diagnosed as diamniotic twin pregnancies. One case with 2 yolk sacs was identified as a triamniotic triplet pregnancy. In 9.3% of MC gestations, the number of yolk sacs was not correlated with the number of amnions in our study. To determine amnionicity in MC multifetal pregnancies, we recommend careful evaluation not of the number of yolk sacs but the presence or absence of intertwine dividing membrane after 8 gestational weeks. PMID- 29115086 TI - Long-Term Survival Analysis of Intraperitoneal versus Intravenous Chemotherapy for Primary Ovarian Cancer and Comparison between Carboplatin- and Cisplatin based Intraperitoneal Chemotherapy. AB - In epithelial ovarian cancer (EOC), intraperitoneal (IP) administration of chemotherapy is an effective first-line treatment and may improve outcomes, compared with intravenous (IV) chemotherapy. We used Kaplan-Meier survival analysis to compare long-term survival between propensity score-matched patients with advanced EOC receiving IP (n = 34) vs. IV (n = 68) chemotherapy. Additionally, clinical features associated with carboplatin-based (n = 21) and cisplatin-based (n = 16) IP chemotherapy were analyzed and compared with those associated with IV chemotherapy. The IP and IV chemotherapy groups had a median follow-up duration of 67 (range, 3-131) and 62 (range, 0-126) months, respectively, with no significant difference in progression-free survival (PFS) (P = 0.735) and overall survival (OS) (P = 0.776). A significantly higher proportion of patients in the IV (91.2%) than in the IP (67.6%) chemotherapy group (P = 0.004) received >= 6 cycles. However, the frequency of toxic events (anemia, granulocytopenia, nausea/vomiting, abdominal pain, hepatotoxicity, neuromuscular effects) was significantly higher in the IP than in the IV group. Within the IP group, no significant differences were observed in PFS (P = 0.533) and OS (P = 0.210) between the cisplatin-based and carboplatin-based chemotherapy subgroups. The 10-year OS was 28.6% and 49.2% in carboplatin-based and cisplatin based IP chemotherapy groups, respectively. Toxic events (granulocytopenia, leukopenia, nausea/vomiting, abdominal pain, hepatotoxicity, neuromuscular effects) were significantly more common in the cisplatin-based subgroup. In patients with EOC, cisplatin-based IP chemotherapy may be an acceptable alternative to IV chemotherapy regarding long-term survival, but toxicity must be addressed. PMID- 29115087 TI - Methylenetetrahydrofolate Reductase Polymorphisms and Risk of Recurrent Pregnancy Loss: a Case-Control Study. AB - The balance between coagulation and fibrinolysis is an essential part in early pregnancy. Mutations in methylenetetrahydrofolate reductase (MTHFR) gene lead to decreased activity of the enzyme and hyperhomocysteinemia, which then induces platelet aggregation by promoting endothelial oxidative damage, possibly resulting in adverse effect on maintenance of pregnancy. We investigated the role of MTHFR single nucleotide polymorphisms (SNPs), C677T and A1298C, in Korean patients with recurrent pregnancy loss (RPL). We conducted a prospective case control study in the Korean population. Subjects included 302 women with 2 or more consecutive, unexplained, spontaneous miscarriages before 20 weeks of gestation and 315 control women without a history of recurrent miscarriages. The genotyping for C677T and A1298C polymorphisms was performed using the TaqMan assay. Continuous variables were compared using Student's t-test, and chi2 test was used to evaluate differences in the genotype distributions between the RPL and the controls. The genotype distribution of both polymorphisms in the RPL group did not differ from those of the controls. For further analysis, if RPL patients were divided according to the numbers of pregnancy losses (>= 2 and >= 3) neither group was significantly different compared with controls. MTHFR gene C677T and A1298C polymorphisms are not associated with idiopathic RPL in Korean women, suggesting that those may not be susceptible allelic variants or be deficient to cause RPL. PMID- 29115088 TI - Survivorship and Complications after Hip Fracture Surgery in Patients with Chronic Kidney Disease. AB - The aim of this study was to investigate survival rate, complications and associated risk factors after hip fracture surgery in patients with chronic kidney disease (CKD) by comparing to non-CKD patients. A total of 119 patients (130 hips, 63 hips CKD group, 67 hips non-CKD) who underwent hip fracture surgery were included. We assessed variables including age, gender, CKD, comorbidities, operation delay and operation time as risk factors for survival and complications after hip fracture surgery. The survival rate was 55.8% at 1-year, 45.8% at 3 year, and 31.4% at 5-year in CKD group, whereas 82.1%, 60.7%, and 36.8%, respectively in non-CKD. Age (more than 85) (hazard ratio [HR], 3.238; 95% confidence interval [CI], 1.736-6.042; P < 0.001), stages 4, 5 of CKD (HR, 2.004; 95% CI, 1.170-3.433; P = 0.001), cerebrovascular disease (HR, 2.213; 95% CI, 1.196-4.095; P = 0.001), and malignancy (HR, 3.086; 95% CI, 1.553-6.129; P = 0.001) were significant risk factors. Complications occurred in 17 hips of CKD group and 8 hips of non-CKD. Stage 4-5 of CKD (odds ratio [OR], 3.401; 95% CI, 1.354-8.540; P = 0.001), malignancy (OR, 3.184; 95% CI, 0.984-10.301; P = 0.050) were significant risk factor. When performing hip fracture surgery in patients with CKD, surgeons should consider age, severity of CKD, and presence of other comorbid disease, such as cerebrovascular disease and malignancy, as patients with these risk factors will need more intensive preoperative and postoperative care. PMID- 29115089 TI - Poisoning-induced Out-of-Hospital Cardiac Arrest and Outcomes according to Poison Agent. AB - It is unclear whether specific agent groups are associated with outcomes in cases of poisoning-induced out-of-hospital cardiac arrest (P-OHCA). The study population comprised cases of confirmed P-OHCA drawn from the national out-of hospital cardiac arrest (OHCA) registry (2008-2013). Exposures were categorized into five groups according to the International Classification of Disease, 10th version: group 1, prescribed drugs; group 2, vapors and gases; group 3, pesticides; group 4, alcohol and organic solvents; and group 5, other poisons. The outcome was survival to discharge and good neurological recovery. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated to test the association between specific groups and outcomes. A total of 2,083 patients were analyzed; group 1 (10.3%), group 2 (23.6%), group 3 (52.9%), group 4 (1.4%), and group 5 (13.2%). The survival to discharge and good neurological recovery rates were 3.3%/1.3% for all patients, 10.3%/5.6% (group 1), 6.9%/3.4% (group 2), 2.4%/0.4% (group 3), 2.2%/1.0% (group 4), and 3.3%/2.4% (group 5) (all P < 0.001). The aORs (95% CIs) of groups 2-5 compared with group 1 for survival to discharge were 0.47 (0.09-2.51), 0.34 (0.17-0.68), 0.33 (0.14-0.77), and 0.31 (0.13-0.77), respectively. The odds ratios (95% CIs) for good neurological recovery were significant only in group 1, the pesticides group (0.07 [0.02 0.26]) and were not significant in the other groups. P-OHCA outcomes differed significantly among the poisoning agent groups. The pesticides group showed the worst outcomes, followed by the group of vapors or gases. PMID- 29115090 TI - Urine Methyl Hippuric Acid Levels in Acute Pesticide Poisoning: Estimation of Ingested Xylene Volume and Association with Clinical Outcome Parameters. AB - To determine the relationship between the oral ingestion volume of xylene and methyl hippuric acid (MHA) in urine, we measured MHA in 11 patients whose ingested xylene volume was identified. The best-fit equation between urine MHA and ingested amount of xylene was as follows: y (ingested amount of xylene, mL/kg) = -0.052x2 + 0.756x (x = MHA in urine in g/g creatinine). From this equation, we estimated the ingested xylene volume in 194 patients who had ingested pesticide of which the formulation was not available. Our results demonstrated that oxadiazole, dinitroaniline, chloroacetamide, organophosphate, and pyrethroid were xylene-containing pesticide classes, while the paraquat, glyphosate, glufosinate, synthetic auxin, fungicide, neonicotinoid, and carbamate classes were xylene-free pesticides. Sub-group univariate analysis showed a significant association between MHA levels in urine and ventilator necessity in the pyrethroid group. However, this association was not observed in the organophosphate group. Our results suggest that MHA in urine is a surrogate marker for xylene ingestion, and high urine MHA levels may be a risk factor for poor clinical outcome with some pesticide poisoning. PMID- 29115091 TI - Efficacy of Uncross-Matched Type O Packed Red Blood Cell Transfusion to Traumatic Shock Patients: a Propensity Score Match Study. AB - A new blood bank system was established in our trauma bay, which allowed immediate utilization of uncross-matched type O packed red blood cells (UORBCs). We investigated the efficacy of UORBC compared to that of the ABO type-specific packed red blood cells (ABO RBCs) from before the bank was installed. From March 2016 to February 2017, data from trauma patients who received UORBCs in the trauma bay were compared with those of trauma patients who received ABO RBCs from January 2013 to December 2015. Propensity matching was used to overcome retrospective bias. The primary outcome was 24-hour mortality, while the secondary outcomes were in-hospital mortality and intensive care unit (ICU) length of stay (LOS). Data from 252 patients were reviewed and UORBCs were administered to 64 patients. The time to transfusion from emergency room admission was shorter in the UORBC group (11 [7-16] minutes vs. 44 [29-72] minutes, P < 0.001). After propensity matching, 47 patients were included in each group. The 24-hour mortality (4 [8.5%] vs. 9 [13.8%], P = 0.135), in-hospital mortality (14 [29.8%] vs. 18 [38.3%], P = 0.384), and ICU LOS (9 [4-19] days vs. 5 [0-19] days, P = 0.155) did not differ significantly between groups. The utilization of UORBCs resulted in a faster transfusion but did not significantly improve the clinical outcomes in traumatic shock patients in this study. However, the tendency for lower mortality in the UORBC group suggested the need for a large study. PMID- 29115092 TI - Hypocomplementemic Urticarial Vasculitis Syndrome with Membranous Nephropathy: Case Report. AB - Urticarial vasculitis is a rare disorder that principally manifests with recurrent urticarial, sometimes hemorrhagic, skin lesions and/or angioedema. Its clinical presentation is not always limited to cutaneous lesions and it can potentially affect other organs, such as the joints, lungs, kidneys, and eyes. Systemic involvement can either be present at the onset of disease or develop over time. In cases with systemic manifestations, urticarial vasculitis is more likely to be associated with a low complement level. We present the case of a teenage boy with hypocomplementemic urticarial vasculitis syndrome (HUVS) that occurred shortly following swine-origin influenza A virus infection in 2009. Afterwards, HUVS was systemically complicated with myositis and membranous nephropathy that developed several months and about 2 years after its onset, respectively. A combination of glucocorticoid and immunosuppressive agents has been used to effectively control disease activity. PMID- 29115093 TI - A Case of Multiple Cardiovascular and Tracheal Anomalies Presented with Wolff Parkinson-White Syndrome in a Middle-aged Adult. AB - Congenital cardiovascular anomalies, such as dextrocardia, persistent left superior vena cava (SVC), and pulmonary artery (PA) sling, are rare disorders. These congenital anomalies can occur alone, or coincide with other congenital malformations. In the majority of cases, congenital anomalies are detected early in life by certain signs and symptoms. A 56-year-old man with no previous medical history was admitted due to recurrent wide QRS complex tachycardia with hemodynamic collapse. A chest radiograph showed dextrocardia. After synchronized cardioversion, an electrocardiogram revealed Wolff-Parkinson-White (WPW) syndrome. Persistent left SVC, PA sling, and right tracheal bronchus were also detected by a chest computed tomography (CT) scan. He was diagnosed with paroxysmal supraventricular tachycardia (PSVT) associated with WPW syndrome, and underwent radiofrequency ablation. We reported the first case of situs solitus dextrocardia coexisting with persistent left SVC, PA sling and right tracheal bronchus presented with WPW and PSVT in a middle-aged adult. In patients with a cardiovascular anomaly, clinicians should consider thorough evaluation of possibly combined cardiovascular and airway malformations and cardiac dysrhythmia. PMID- 29115094 TI - The First Successful Lung Transplantation in a Korean Child with Cystic Fibrosis. AB - Cystic fibrosis (CF) is an autosomal recessive inherited multisystem disorder caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Respiratory failure remains the most frequent cause of morbidity and mortality. Lung transplantation is the only option to treat end-stage lung disease. Very few cases of CF occur in Koreans. We report the case of a 12-year-old girl with respiratory failure due to CF who underwent lung transplantation. She had been diagnosed with CF 8 years previously after being treated for recurrent Pseudomonas aeruginosa pneumonia and malnutrition based on sweat chloride concentrations and the CFTR protein gene mutation test. Progression to end-stage lung disease and respiratory failure led to registration with the Korean Network for Organ Sharing. She underwent successful double lung transplantation in 2014. Although she has diabetes mellitus and chronic kidney disease, she has a better quality of life and a prolonged life expectancy. PMID- 29115096 TI - Letter to the Editor: Effects of Omega-3 Fatty Acids on Erectile Dysfunction in a Rat Model of Atherosclerosis-induced Chronic Pelvic Ischemia. PMID- 29115095 TI - Radiologic Findings in Extrapancreatic Solid Pseudopapillary Tumor with Aggressive Behavior: a Case Report. AB - Solid pseudopapillary tumor (SPT) is a low grade malignant tumor in the pancreas, and extrapancreatic SPT is extremely rare. We report a case of a 61-year-old woman who complained abdominal pain with diffuse tenderness. She was diagnosed with extrapancreatic SPT with extensive peritoneal dissemination and hepatic metastases. Although a few cases have reported imaging findings of extrapancreatic SPT, there have been no reports of extrapancreatic SPT with aggressive tumor behavior and dismal prognosis. Although imaging features closely resembled those of classical pancreatic SPTs, malignant transformation of extrapancreatic SPT should be considered when focal discontinuity of the tumor capsule with ill-defined margin and invasion of adjacent structures were identified. PMID- 29115097 TI - Ligand gated channels in nervous system. PMID- 29115098 TI - The subependymal microvascular network revealed by endoscopic fluorescence angiography. AB - BACKGROUND: The subependymal vascularization of the cerebral ventricles has been described in anatomical studies on human specimens. Its identification in vivo during neuroendoscopic navigation could have anatomical interest and may lead to a safer ventricular navigation, also avoiding unexpected bleeding. The traditional endoscopic visualization allows the certain identification of only the main vessels. In this study we describe the features of the subependymal vascular network (SEVN) enhanced by sodium fluorescein (SF) angiography. We compare these findings with the vascular patterns visible under white light to evaluate the sensitivity of this technique in unveiling the most distant branches of the SEVN. METHODS: We reviewed the video records of 39 fluorescein-assisted neuroendoscopic procedures. Steerable fiberscopes equipped with a dual observation mode for both white light and fluorescence were used. After preliminary inspection of the ventricular cavities, the camera was switched to the blue light fluorescent mode. Identical portion of ventricular walls observed in both modalities were compared and analyzed to enhance potential differences of the vascular features. RESULTS: The main veins were positive (fluorescein enhanced) in 10 patients (25.6%), vessels of smaller diameter visible also under white light presented a detectable fluorescence in 27 patients (69.2%), the micro SEVN, not visible under with light, was revealed by SF in 21 patients (53.8%). CONCLUSIONS: Fluorescein-guided neuroendoscopy deserves closer investigation since it allows detection of small vessels, not otherwise visible, in the ventricle walls. This method could be applied to ameliorate the knowledge of the environment the surgeon is working on, leading as a result to a safer navigation, also by avoiding minor bleedings. PMID- 29115099 TI - Spinal Meningiomas: 61 cases with predictors of early postoperative surgical outcomes. AB - BACKGROUND: Spinal meningiomas are benign, well-circumscribed and slowly growing intradural tumors that compress the spinal cord. Hereby, a retrospective review of 61 spinal meningioma cases evaluated in terms of demographic, clinical, pathological and radiological features to predict the early postoperative functional outcomes. METHODS: Patients' records and MRI images of all the histologically confirmed spinal meningioma cases that underwent surgical resection at two university hospitals from January 2005 to June 2016 were retrospectively reviewed. Demographic data, clinical findings, radiological features and pathology reports were reviewed. Univariate and multivariate logistic regression analyses were used to evaluate the impact of each factor on the early 3-month post-surgical functional outcome. A receiver operating characteristic (ROC) curve was used to predict the power of the model. RESULTS: 61 cases of spinal meningiomas were operated. 13 males (21%) and 48 females (79%). Mean age 60.5 years old ranging (24-92). Patients presented with back pain (57%), motor deficits (47.5%), sensory deficits (18%) and sphincteric dysfunction (11.5%). One case (1.6%) showed an additional extradural growth. 40 thoracic, 9 cervical, 5 cervicothoracic, 5 thoracolumbar and 2 lumbar cases. Only 4 cases (6.6%) showed atypical pathological features (WHO grade II). At 3-month follow up, 46 patients (75.4%) had either functionally improved or remained stable. 15 patients (24.6%) had "worse" functional outcome. Three variables showed statistically significant odds ratio for improved outcomes (OR): presurgical motor deficit (OR =5; p=0.005); pre - surgical sensory disturbance (OR=3.5; p=0.026); pre-surgical myelopathy (OR=3.5; P=0.026). Multivariate analysis showed increased OR for cross sectional ratio, pre-surgical myelopathy, pre-surgical radiculopathy and non - cervical location of tumor (1.59, 3.46, 3.2, 1.63/3.56 respectively). Although none has reached statistical significance (p>0.05), the receiver operating characteristic (ROC) curve showed an Area Under the Curve (AUC) of (0.74). CONCLUSIONS: The independent predictors of the early postoperative functional outcomes of spinal meningioma resections may include pre surgical motor deficit, sensory deficit and myelopathy. PMID- 29115100 TI - Efficacy of decompressive craniectomy in the management of intracranial pressure in severe traumatic brain injury. AB - Traumatic brain injury (TBI) is a common cause of permanent disability for which clinical management remains suboptimal. Elevated intracranial pressure (ICP) is a common sequela following TBI leading to death and permanent disability if not properly managed. While clinicians often employ stepwise acute care algorithms to reduce ICP, a number of patients will fail medical management and may be considered for surgical decompression. Decompressive craniectomy (DC) involves removing a component of the bony skull to allow cerebral tissue expansion in order to reduce ICP. However, the impact of DC, which is performed in the setting of neurological instability, ongoing secondary injury, and patient resuscitation, has been challenging to study and outcomes are not well understood. This review summarizes historical and recent studies to elucidate indications for DC and the nuances, risks and complications in its application. The pathophysiology driving ICP elevation, and the corresponding medical interventions for their temporization and treatment, are thoroughly described. The current state of DC -- including appropriate injury classification, surgical techniques, concurrent medical therapies, mortality and functional outcomes - is presented. We also report on the recent updates from large randomized controlled trials in severe TBI (Decompressive Craniectomy (DECRA) and Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of ICP (RESCUEicp)), and recommendations for early DC to treat refractory ICP elevations in malignant middle cerebral artery syndrome. Limitations for DC, such as the equipoise between immediate reduction in ICP and clinically meaningful functional outcomes, are discussed in support of future investigations. PMID- 29115101 TI - Holospinal epidural abscess combined with multifocal extraspinal abscesses in an elderly patient with rheumatoid arthritis receiving infliximab therapy. PMID- 29115103 TI - Microvascular decompression of trigeminal motor root: a considerable surgical cure for hemimasticatory spasm. PMID- 29115102 TI - Intramuscular myxoma of the cervical muscles with GNAS mutation. PMID- 29115104 TI - Molecular Basis of alpha-Thalassemia in Iran AB - Alpha-thalassemia (alpha-thal) is probably the most prevalent monogenic condition in the world. Deletions are the most common types of mutations in alpha-thal, followed by point mutations and small insertion/deletion. In the context of national screening program for prevention of thalassemia and hemoglobinopathies in Iran, alpha-thal carriers have come to more attention. Therefore, the frequency and distribution of alpha-globin mutations in various regions of the country have been studied in recent years. A comprehensive search was performed in PubMed, Scopus, and national databases for finding reports on mutation detection in alpha-thal carriers and HbH disease with Iranian origin. The mutation data of 10849 alpha-thal carriers showed that -alpha3.7 and alpha-5NT were the most common deletional and nondeletional mutations, respectively. In HbH disease cases, the -alpha3.7/--MED was the most prevalent genotype. Overall, 42 different mutations have been identified in alpha-globin cluster reflecting the high heterogeneity of the mutations in Iranian populations. PMID- 29115105 TI - The role of SU-AVR in tomorrow's practice of AVR. AB - Conventional aortic valve replacement (C-AVR) is the golden standard in the treatment of severe aortic stenosis (AS). Despite its tremendous success there are many problems associated with the procedure. A large segment of the AS population is not suitable for surgery because of the excessive risk. Over the few last years, transcatheter aortic valve implantation and the use of sutureless valves are new technologies that aim to replace the C-AVR. In this review we compare the three therapeutic modalities in treating severe AS. Based on accumulated data we aspire to describe the clinical landscape of AVR in the near future. We will try to delineate how sutureless valves will be used in treating severe AS. PMID- 29115106 TI - An Invitation to a Spiritual HomeHow Does Postpartum Depression Appear in the Eyes of Onlookers ? PMID- 29115107 TI - MORPHOLOGY OF TWO NEW SPECIES OF CERCARIAE VIRGULAE (LUHE, 1909) GROUP. AB - Two new species of virgulous cercariae are described. Morphological descriptions and differential diagnoses are given. Each description is supplemented with a detailed picture. PMID- 29115108 TI - A Probable Case of Burn-out NASH Caused by PanhypopituitarismSecondary to Craniopharyngioma. AB - A 38-year-old man diagnosed with craniopharyngioma at 8 years old underwent repeated surgeryand radiation therapy. Complications included panhypopituitarism including growth hormonedeficiency and hypogonadism at 13 years old. At 26 years of age, a slight fatty liver was found, whichfinally developed into liver cirrhosis (LC) at 35 years old. Viral infection or other etiologies causing LCwere negative on serum examinations. Liver biopsy suggested a possibility of burn-out non-alcoholicsteatohepatitis. This case indicates that a long-standing growth hormone deficiency and hypogonadismmay lead to LC as a type of burn-out non-alcoholic steatohepatitis. PMID- 29115109 TI - ACANTHOCEPHALANS PROSTHENORCHIS CF. ELEGANS (ARCHIACANTHOCEPHALA: OLIGACANTHORHYNCHIDAE), PARASITES OF PRIMATES IN THE MOSCOW ZOO. AB - Acanthocephalans Prosthenorchis cf. elegans were found in primates in the Moscow Zoo. The larvae of these parasites (cistacanths) were found in cockroaches Blattella germanica that had been captured near aviaries of infected animals. Descriptions and drawings of adult parasites and their larvae are given. Analysis of Prosthenorchis cf. elegans genes ITS 1 rDNA and CO 1 mtDNA shows phylogenetic relations of these parasites with several representatives of the class Archiacanthocephala. The obtained molecular data, however, do not support the monophyly of the family Oligacanthorhynchidae and the orderOligacanthorhynchida. PMID- 29115110 TI - INFESTATION OF HONEYBEE (APIS MELLIFERA) FAMILIES BY MICROSPORIDIANS OF THE GENUS NOSEMA IN TOMSK PROVINCE AB - Infestation of bee colonies and apiaries by representatives of the genus Nosema, microsporidian protozoans of European honeybees (Apis mellifera L.), causing nosemosis, in Tomsk Province was investigated. In 2012-2015, nosemosis was detected in 32 out of 124 honeybee colonies (31.3 %) and in 20 out of 64 studied apiaries (25.8 %). The maximal infestation rate of bee colonies and apiaries constituted more than 40 % in 2014-2015. N. apis pathogen was registered in 84.4 % of infected bee colonies (16 apiaries); N. ceranae was identified in 9.4 % of infected bee colonies (2 apiaries); and co-infection (N. apis and N. ceranae) was detected in 6.3 % of infected bee colonies (2 apiaries). The reasons of the spreading of the nosemosis, such as climatic conditions, control ofimported bee colonies on the presence of Nosema infection, and some others are discussed. PMID- 29115111 TI - 2014 Update of the EBRI IRA Database: IRA Balances, Contributions, Rollovers, Withdrawals, and Asset Allocation. PMID- 29115112 TI - TO SHARE KNOWLEDGE, NOT TUBERCULOSIS PMID- 29115113 TI - PARASITE FAUNA OF THE LANDLOCKED SOCKEYE SALMON (ONCORHYNCHUS NERKA) OF THE LAKE KRONOTSKOE (KAMCHATKA). PMID- 29115114 TI - PHYSIOLOGICAL AND BIOCHEMICAL ASPECTS OF INTERACTIONS BETWEEN PATASITOIDS OF THE CLASS INSECTA AND THEIR HOSTS. PMID- 29115115 TI - LATENT TUBERCULOSIS AMONG ADULT ETHIOPIAN PATIENTSAT CHEST CLINIC, TIKURANBESSA SPECIALIZED HOSPITAL,ADDIS ABABA, ETHIOPIA. AB - Background: One-third of the world population is infected with Mycobacterium tuberculosis. Most people exposedto M. tuberculosis showed no evidence of active disease. About 5-10% of people with latent tuberculosis infection(LTBI) without HIV will progress to develop active tuberculosis (TB) in their lifetimes. This study was conducted todetermine the magnitude of latent TB among the adult population at a teaching and referral Hospital in Ethiopia. Methods: This study was conducted at the Chest clinic of Tikur Anbessa Specialized Hospital during 2010-2013.The study was a cross-sectional study conducted among healthy adults after informed consent was obtained fromeach individual. Tuberculin skin test (TST) and Interferon Gamma whole blood assay (Quantiferon-Tuberculosis-Gold) was performed using enzyme linked immuno-sorbent assay. Average CD4, CD8, CD3 and CD4:CD8 ratiowas determined for all study participants. Results: From a total of 70 healthy adults tested for LTBI using Quantiferon Gold, 45(64%) tested positive and 25(36%) were negative for latent tuberculosis infection. From the 66 healthy individuals who were tested using TSTfor LTBI, 42 (62%) individuals were TST positive and 25 (38%) individuals were TST negative. Average CD4,CD8, CD3 and CD4:CD8 ratio was 748, 598, 1401 and 1.4, respectively. Conclusions: The magnitude of latent tuberculosis infection was high in this study, which reflects existing highprevalence of TB. TST and Quantiferon-Tuberculosis-Gold assay show similar efficacy for the diagnosis of LTBI inhealthy Ethiopian adults. The absolute CD4 T-cell counts of healthy HIV- negative Ethiopians are considerablylower than CD4 T cell counts in other countries. PMID- 29115116 TI - BURDEN OF TUBERCULOSIS AMONG STUDENTS IN TWO ETHIOPIAN UNIVERSITIES. AB - Introduction: Tuberculosis outbreaks emerge occasionally in long-term care facilities and various educationalestablishments. This study was designed to determine the five year overall prevalence and trend of tuberculosisand associated factors among students at Adama Science and Technology University and Addis Ababa UniversitySidist Kilo campus. Methods: A five-year retrospective study was conducted on students' medical records of tuberculosis DirectlyObserved Treatment Short Course clinics from September 2009- July 2014. The overall prevalence and the trendof smear positive, smear negative and extra pulmonary tuberculosis cases was determined. Odds ratio with 95percent confidence interval was calculated for categorical variables using a multivariate logistic regression modelto assess the strength of association. Results: A total of 112 and 263 tuberculos cases were recorded in Addis Ababa University Sidist Kilo campusand Adama Science and Technology University, respectively. The mean proportion of tuberculosis cases of alltypes among the total number of students enrolled at Adama Science and Technology University and Addis AbabaUniversity Sidist Kilo campus was 1098.1 and 511.7 cases per 100,000 population, respectively. There was a statisticallysignificant difference in prevalence of tuberculosis among students in Adama Science and TechnologyUniversity compared to that in Addis Ababa University Sidist Kilo campus [adjusted odds ration: 2.881, 95% CI(1.76 4.71)]. The trend of tuberculosis prevalence showed a steady decline from the first to the last year of thestudy period. Conclusion: The number of tuberculosis cases observed among university students in this study was high. Governmentaland nongovernmental agencies involved in tuberculosis control must consider higher education institutionsas focal points for prevention and elimination of tuberculosis in Ethiopia. PMID- 29115117 TI - ART EXPERIENCED PATIENTS FOR TACKLING ATTRITION FROM HIV CARE: A MULTI-SITE COHORT STUDY. AB - Introduction: Retention of patients on anti-retroviral treatment in Ethiopia is a challenge. Use of anti-retroviral treatment experienced patients to prepare and re-engage them when they miss follow-ups is recommended, but evidence on its effectiveness is limited. This study evaluated its effectiveness. Methods: : A retrospective cohort study in 10 randomly selected health facilities was conducted to compare outcomes before and after initiation of the adherence supporters program in HIV care and treatment from September 2001 to August 2013. Data analysis involved Kaplan-Meier survival and Log-rank test analysis on STATA statistical software Version 12 to compare survival experiences. Results: Of 18,835 records that were available, 938 (4.36%) records with missing values were excluded and data from the remaining 17,897 was analyzed. The incidence of first instance lost to follow-up was 22.2 per 100 person-years (95% confidence interval 21.7-22.7). The risk of missing follow-ups after initiation of the program was high (Hazard Ratio -1.22, P < 0.001). The incidence of restarting after missed follow-ups was 23 per 100 PY (95% CI 22.2-24.0). The likelihood of restarting after missed follow-ups was four times higher during the period adherence supporters were present (P<0.001). Patients who stayed longer in care before missing follow ups were more likely to restart (5.7 times the chance of restarting treatment for those whose first lost to follow-up occurred at>=12 months compared to <3 months, P< 0.001).Time to restarting treatment was shorter after the initiation of the adherence supporters program (median 37 vs. 115 days). The risk of recurrence of being lost to follow-up in the presence of adherence supporters was significantly higher than when there were no adherence supporters; 38.8 (95% CI 36.3-41.6) per 100 PY vs. 26.1 (95% CI 19.8-34.4) per 100 PY, respectively. Conclusion: Adherence supporters were effective in improving re-engagement of patients in treatment and care after they were lost to follow-up. Yet, prevention of lost to follow-up cases has remained a challenge to the program. PMID- 29115118 TI - Adenomyosis: fertility and obstetric outcome. A comprehensive literature review. AB - Adenomyosis is a benign condition characterized by the presence of endometrial glands and stroma deep within the myometrium. In recent years, the potential negative impact of adenomyosis on in vitro fertilization clinical outcomes has gained momentum, as well as, the possible link of this condition with obstetrical complications. The aim of this narrative review is to elucidate the possible association between uterine adenomyosis, infertility, and poor obstetrical outcomes. Several theories have been proposed to clarify the potential harmful impact of adenomyosis on fertility, such as a functional and structural defect of both the eutopic endometrium and the inner myometrium, an impairment of the uterine system of sperm transport, the presence of uterine dysperistalsis and of high levels of free radicals in the uterine milieu of women with the disease. Numerous studies have demonstrated that adenomyosis exerts a detrimental effect on in vitro fertilization outcomes, reducing pregnancy and live birth rates and increasing miscarriage rate. Regarding pregnancy outcomes data are scarce; however, epidemiological studies suggest that women with uterine adenomyosis could be at increased risk of numerous obstetrical complications, in particular, preterm birth and preterm premature rupture of membranes. These preliminary results are valuable for preconception and prenatal counseling of women with adenomyosis and suggest that this category of women necessitate a more cautious prenatal management than previously expected. PMID- 29115119 TI - HIGH PREVALENCE OF ATRIAL FIBRILLATION IN STROKE PATIENTS ADMITTED TO UNIVERSITY OF GONDAR HOSPITAL, NORTHWEST ETHIOPIA. AB - Introduction: Even though atrial fibrillation is a common risk factor of stroke which contributes to poor outcome, data concerning this association is scarce in African countries. This study assessed the prevalence of confirmed atrial fibrillation and its effect on outcome in stroke patients admitted to University of Gondar Hospital. Methods: Hospital based cross-sectional study by record analysis was done from December 2014 to February 2015. All adult stroke patients with documented head CT scan and ECG results admitted to university of Gondar hospital during June 2010 to May 2013 were included. Relevant data including sociodemographics, type of stroke, and presence of atrial fibrillation was collected from patient charts using a data extraction form. Results: A total of 94 patients with mean age of 67.4+/-12.4 years and Female to male ratio of 1.13:1 were analyzed. The prevalence of AF was 28.7%. It occurred in 34% and 14% of ischemic and hemorrhagic strokes respectively. The in hospital case fatality of stroke associated with and without atrial fibrillation was 22.2% and 8% respectively while the rate of improvement at discharge was 34% and 68% respectively. Atrial fibrillation was associated with a low rate of improvement at discharge (OR= 0.28 CI: 0.1-0.78). Conclusion: Atrial fibrillation is common in stroke patients in our hospital, especially in the elderly population. It is associated with low rate of improvement at discharge. Appropriate screening and treatment of atrial fibrillation is invaluable for the primary and secondary prevention of stroke. PMID- 29115120 TI - PATTERN AND OUTCOME OF NEONATAL SURGICAL CASESAT TIKUR ANBESSA UNIVERSITY TEACHING HOSPITAL,ADDIS ABABA, ETHIOPIA. AB - Introduction: The survival of neonates with surgical conditions has greatly improved in developed countries, butstill remains poor in developing countries. Available evidence suggests that this is due to several challenges encounteredin neonates requiring surgical care. The aim of this study was to determine causes and outcomes ofneonatal surgical admissions. Patients and Methods: retrospective review of medical records of neonates who were admitted and treated at TikurAnbessa Hospital between January1, 2010 and December 31, 2014. Data were analyzed using descriptive statisticsand association between variables measured using regression analysis on SPSS version 16 statistical software. Results: There were a total of 652 surgical neonatal admissions during the study period of which 396 were males,252 females and 4 with indeterminate genitalia. The male to female ratio was 1.6:1. Majority of the cases 562(86.2%) had congenital malformation. Lesions of the gastrointestinal tract 282(43.3%), mainly Anorectal malformationsfollowed by abdominal wall defects. Two-third (66.6%) of the cases were surgically managed. Nearly onequarterof them died. The proportion who died ranged from 0.03% for Hirschsprung's disease to 73.2% for esophagealatresia. The immediate causes of death among these series of neonates were ascribed to septic shock andrespiratory failure. Conclusion: Neonatal surgical admission is common in the Hospital. The overall number of deaths in this series ofneonatal surgical cases was high. The type of principal diagnosis and the age of the neonates at admission weresignificantly associated with outcome. Creating awareness about neonatal surgical conditions may help to improvethe current poor result. PMID- 29115121 TI - REFERRAL OF EMERGENCY SURGICAL PATIENTS IN ATERTIARY HOSPITAL, ADDIS ABABA, ETHIOPIA. AB - Introduction: Referral is part of patient care when done appropriately. Common reasons for referral include seekingexpert advice, technical examination and/or intervention, care beyond the facility's capacity.Objectives: Determine the rate, reason for and type of cases referred among patients seen at surgical EmergencyRoom of SPHMMC during May to July 2015. Patients and Methods: Cross sectional study was done at St. Paul's Hospital Millennium Medical College EmergencyRoom, including all surgical patients seen in three months period. Data was collected from the individualpatient's medical records, records of the ER and the liaison office and Interns morning reporting book. Data wasanalyzed with SPSS version 20. Results: Total of 2,492 patients were seen. The mean number of patients seen per day was 27.7 with a range from13 to 51. Trauma made 70% (1746) of all cases seen. Cases that needed admission made 30.1% (755), but only49.5 % (374) of them were admitted. The overall referral rate was 15.3%. The referral rate in patients who neededadmission was 50.5 % (381). Trauma made 77.4% (295) of the referrals, mainly orthopedic, 54.6% (161) andneuro-traumas, 38% (112). Among non trauma cases acute abdominal conditions tops, 75% (56). Lack of inpatientbeds was the main reason for referral 65.6% (250). Specialist care need was the reason for referral in 34.5%(131) of cases. Among patients referred only 14.4% (55) left the hospital at the time of referrals. Four percent (13)of the kept patients died in the ER waiting for referrals. Conclusions: The rate of referral from St. Paul's Hospital Millennium Medical College Emergency Room is high.It is higher in trauma cases, specifically orthopedic and neuro-traumas. Main reason for referrals was lack of bed.The capacity of the hospital and other hospitals in AA in absorbing traumas, specifically orthopedic and neurotraumasneed to be evaluated and necessary policy adjustments should be implemented. Further study at each hospitaland the whole city gives better picture of referrals among hospitals in Addis Ababa. PMID- 29115122 TI - Spectroscopic Characterization of Sulfonate Charge Density in Ion-Containing Polymers. AB - The charge density and hydrogen bonding with water of five different polymer membranes functionalized with various sulfonate side-chain chemistries were investigated using Fourier transform infrared (FTIR) techniques and density functional theory (DFT) calculations. The peak position of the OD stretch of dilute HOD absorbed into the sulfonated poly(sulfone) membranes was studied using FTIR to compare the charge density of the sulfonate headgroup across the different samples, which can ultimately be related to the acidity of the proton form sulfonate moieties. The OD peak was deconvoluted to determine the percentage of headgroup-associated, intermediate, and bulk water. DFT modeling was used to calculate the charge density of each headgroup and visualize how the chemistry of the headgroup influenced the conformation of the side-chain tether. FTIR determined OD peak positions and charge density calculations demonstrated that a perflurosulfonate containing a thioether linkage produced the most acidic sulfonate headgroup. However, the amount of headgroup-associated water calculated for this side chain was low due to the unique cis conformation of the thioether side chain. The biperfluorosulfonate side chain had very low calculated headgroup associated water due to its bulkiness and water molecules bridging the two sulfonates. These detailed insights on local hydration of sulfonate side chains will point towards new headgroup designs for advanced membranes. PMID- 29115124 TI - Determining the Liquid Light Scattering Cross Section and Depolarization Spectra Using Polarized Resonance Synchronous Spectroscopy. AB - Rayleigh scattering is a universal material property because all materials have nonzero polarizability. Reliable quantification of the material light scattering cross section in the liquid phase and its depolarization spectra is, however, challenging due to a host of sample and instrument issues. Using the recently developed polarized resonance synchronous spectroscopic method, we reported the light scattering cross section and depolarization spectra measured for a total of 29 liquids including water, methanol, ethanol, 1-propanol, 1-butanol, dimethylformamide, carbon disulfide, dimethyl sulfoxide, hexane and two hexane isomers (3-methylpentane and 2,3-dimethylbutane), tetrahydrofuran, cyclohexane, acetonitrile, pyridine, chloromethanes including di-, tri, tetrachloromethane, acetone, benzene and eight benzene derivatives (toluene, fluorobenzene, 1,2-, 1,3 , and 1,4-difluorobenzene, chlorobenzene, 1,2- and 1,3-dichlorobenzene, and nitrobenzene). The solvent light scattering depolarization is wavelength independent for the model solvents, and it varies from 0.023 +/- 0.011 for CCl4 to 0.619 +/- 0.022 for nitrobenzene. The light scattering cross-section spectra can be approximated with the function of sigma(lambda) = alphalambda-4 with the alpha value varying from 7.2 +/- 0.2 * 10-45 cm6 for water to a maximum of 8.5 +/ 0.6 * 10-43 cm6 for nitrobenzene. Structural isomerization has no significant effect on either the depolarization or the scattering cross sections for both hexanes and difluorobenzene isomers. This work represents the most comprehensive experimental study on liquid light scattering features. The insight from this work should be important for understanding the correlation between the material structure and optical properties. The described method can be readily implemented by researchers with access to conventional spectrofluorometers equipped with excitation and detection polarizers. PMID- 29115123 TI - Structural Characterization of a Tetrapeptide from Sesame Flavor-Type Baijiu and Its Preventive Effects against AAPH-Induced Oxidative Stress in HepG2 Cells. AB - Peptides are rarely reported from Chinese Baijiu (Chinese liquor) because they are often present in very low concentrations in the complex matrix. A tetrapeptide, Ala-Lys-Arg-Ala (AKRA), was recently identified by high-performance liquid chromatography and quadrupole-time-of-flight-mass spectrometry (HPLC-Q-TOF MS) from sesame flavor-type Baijiu at a concentration of 8.497 +/- 0.753 MUg/L (P > 0.05), and this tetrapeptide showed preventive effects against 2,2'-azobis(2 methylpropanimidamidine) dihydrochloride (AAPH)-induced oxidative stress in HepG2 cells. The cellular antioxidant activity assay results showed that AKRA protected AAPH-induced oxidative stress in HepG2 cells in a concentration-dependent manner. Pretreatment of the cells for 2 h with AKRA (0.38-1.50 mg/mL) caused strong intracellular reactive oxygen species (ROS) scavenging activities and prevented a decrease in reduced glutathione (GSH) and increases in oxidized glutathione (GSSG) and malondialdehyde (MDA). In addition, AKRA treatment prevented significant decreases in glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) induced by AAPH. Thus, AKRA treatment ameliorated AAPH induced oxidative stress in HepG2 cells. This study will be important for the design and regulation of functional Baijiu production. PMID- 29115125 TI - Heterostructured Arrays of NixP/S/Se Nanosheets on CoxP/S/Se Nanowires for Efficient Hydrogen Evolution. AB - The development of efficient electrocatalysts for hydrogen evolution reaction (HER) is of increasing importance in energy conversion schemes. The earth abundant transition-metal phosphides, especially CoP and Ni2P, have emerged as promising catalysts for HER. We describe here the preparation and characterization of a hybrid catalyst of Ni2P nanosheets@CoP nanowires on a carbon cloth for the reaction. The heterostructure and synergistic effects of the Ni2P and CoP components result in an extremely low overpotential of 55 mV for achieving a catalytic current density of 10 mA cm-2, which is remarkable for transition-metal phosphide electrocatalysts. The synthetic procedure could be readily extended to related, heterostructured bimetallic sulfides or selenides for HER. PMID- 29115126 TI - Aggregation-Induced Emission-Based Chemodosimeter Approach for Selective Sensing and Imaging of Hg(II) and Methylmercury Species. AB - Methylmercury (CH3Hg+) is the common form of organic mercury and is more toxic than its inorganic or elemental forms. Mercury is emanated in the course of various natural events and human activities and converts to methylmercury by anaerobic organisms. CH3Hg+ are ingested by fish and subsequently bioaccumulated in their tissue and, eventually, enter the human diet, causing serious health issues. Therefore, selective and sensitive detection of bioaccumulated CH3Hg+ in fish samples is essential. Herein, the development of a simple, highly sensitive and selective aggregation-induced emission (AIE)-based turn-on probe for both inorganic mercury ions and organicmercury species is reported. The probe's function is based on mercury ion-promoted transmetalation reaction of aryl boronic acid. The probe, a tetraphenylethylene (TPE)-monoboronic acid (1), was successfully utilized for AIE-based fluorescence imaging study on methylmercury contaminated live cells and zebrafish for the first time. Both Hg(II) and CH3Hg+ ensued a fast transmetalation of TPE-boronic acid causing drastic reduction in the solubility of the resulting product (TPE-HgCl/TPE-HgMe) in the working solvent system. At the dispersed phase, the aggregated form of TPE-mercury ions recovers planarity because of restricted rotational freedom promoting aggregation induced emission. Simple design, cost-effective synthesis, high selectivity, inexpensive instrumentation, fast signal transduction, and low limit of detection (0.12 ppm) are some of the key merits of this analytical tool. PMID- 29115127 TI - Designing Two-Dimensional Dirac Heterointerfaces of Few-Layer Graphene and Tetradymite-Type Sb2Te3 for Thermoelectric Applications. AB - Despite the ubiquitous nature of the Peltier effect in low-dimensional thermoelectric devices, the influence of finite temperature on the electronic structure and transport in the Dirac heterointerfaces of the few-layer graphene and layered tetradymite, Sb2Te3 (which coincidently have excellent thermoelectric properties) are not well understood. In this work, using the first-principles density-functional theory calculations, we investigate the detailed atomic and electronic structure of these Dirac heterointerfaces of graphene and Sb2Te3 and further re-examine the effect of finite temperature on the electronic band structures using a phenomenological temperature-broadening model based on Fermi Dirac statistics. We then proceed to understand the underlying charge redistribution process in this Dirac heterointerfaces and through solving the Boltzmann transport equation, we present the theoretical evidence of electron hole asymmetry in its electrical conductivity as a consequence of this charge redistribution mechanism. We finally propose that the hexagonal-stacked Dirac heterointerfaces are useful as efficient p-n junction building blocks in the next generation thermoelectric devices where the electron-hole asymmetry promotes the thermoelectric transport by "hot" excited charge carriers. PMID- 29115128 TI - Diffusion of Aromatic Isomers in Acetone: An Investigation on the Effects of Intramolecular and Intermolecular Hydrogen Bonding. AB - Limiting mutual diffusivities of o- and m-isomers of methylaniline, nitroaniline, nitrophenol, and aminophenol were measured in acetone at 298.2 K by the Taylor dispersion method. The data reveal that all of the o-substituted solutes capable of intramolecular hydrogen bonding diffuse faster than their m-counterparts without such bonding. By taking into account of the small corrections for the differences in molecular shape and steric hindrance between the o- and m-isomers that can form solute-solvent complexes, the net effects of intramolecular hydrogen bonding were uncovered to render the o-isomers greater in diffusivity by 3-15% as compared to their m-isomers in this study. For aromatic amines and phenols diffusing in acetone, the overall effects of intermolecular hydrogen bonding on diffusivity were ascertained by comparing the available diffusivity data of the associated aromatic solutes with those of the nonassociated ones. The intermolecular effects that cause solutes to diffuse slower were found to vary from approximately 12-39% in the present work. The results indicate that both of the opposite intra- and intermolecular effects are significant. In addition, the quantified effects were analyzed to show that they are closely related to the nature and position of the functional groups contained in the aromatic solutes, including those that are unable to form hydrogen bonds with acetone. A relation that can correlate the diffusivities of the hydrogen-bonded aromatic amines and phenols in acetone with the overall acidities of the compounds is also presented. PMID- 29115129 TI - Time Gated Luminescence Imaging of Immunolabeled Human Tissues. AB - Multiplexed immunofluorescence imaging of formalin-fixed, paraffin-embedded tissues is a powerful tool for investigating proteomic profiles and diagnosing disease. However, conventional immunofluorescence with organic dyes is limited in the number of colors that can be simultaneously visualized, is made less sensitive by tissue autofluorescence background, and is usually incompatible with commonly used hematoxylin and eosin staining. Herein, we demonstrate the comparative advantages of using time-gated luminescence microscopy in combination with an emissive Tb(III) complex, Lumi4-Tb, for tissue imaging in terms of sensitivity, multiplexing potential, and compatibility with common immunohistochemistry protocols. We show that time-gated detection of millisecond scale Tb(III) emission increases signal-to-noise ratio relative to conventional steady-state detection of organic dye fluorescence and permits visualization of low-abundance tissue markers such as Bcl-6 or MSH-6. In addition, temporal separation of long- and short-lifetime (~nanosecond) signals adds a second dimension for multiplexing and also permits detection of intermolecular Tb(III) to-dye Forster resonance energy transfer. Furthermore, we demonstrate that the Lumi4-Tb complex is compatible with tyramide signal amplification and, unlike conventional organic dyes, can be reliably used on tissue stained with hematoxylin and eosin. Our results indicate that time-gated luminescence microscopy using Tb(III) labels can provide a sensitive and robust method to perform multiplexed immunofluorescence on archived or clinical tissue specimens. PMID- 29115130 TI - Total Syntheses of Natural Metallophores Staphylopine and Aspergillomarasmine A. AB - Staphylopine was discovered and functionally evaluated as a novel type of metallophore that Staphylococcus aureus employs to acquire multiple divalent transition metals. Aspergillomarasmine A (AMA), with a similar structure to staphylopine, was recently identified as an inhibitor of metallo-beta-lactamases NDM-1 and VIM-2. Herein, we report a unified approach using Mitsunobu reaction as a key step to accomplish the concise and efficient total syntheses of staphylopine and AMA. We also elucidate the similar broad-spectrum metal chelation properties between staphylopine and AMA. PMID- 29115131 TI - Cultivation of the Ribbed Mussel (Geukensia demissa) for Nutrient Bioextraction in an Urban Estuary. AB - Shellfish aquaculture is gaining acceptance as a tool to reduce nutrient over enrichment in coastal and estuarine ecosystems through the feeding activity of the animals and assimilation of filtered particles in shellfish tissues. This ecosystem service, provided by the ribbed mussel (Geukensia demissa), was studied in animals suspended from a commercial mussel raft in the urban Bronx River Estuary, NY, in waters closed to shellfish harvest due to bacterial contamination. Naturally occurring populations of ribbed mussels were observed to be healthy and resilient in this highly urbanized environment. Furthermore, mussels grown suspended in the water column contained substantially lower concentrations of heavy metals and organic contaminants in their tissues than blue mussels (Mytilus edulis) collected at a nearby benthic site. Spat collection efforts from shore and within the water column were unsuccessful; this was identified as a key bottleneck to future large-scale implementation. Filtration experiments indicated that a fully stocked G. demissa raft would clear an average 1.2 * 107 L of Bronx River Estuary water daily, removing 160 kg of particulate matter from the water column, of which 12 kg would be absorbed into mussel digestive systems. At harvest, 62.6 kg of nitrogen would be sequestered in mussel tissue and shell. These values compare favorably to other resource management recovery methods targeting agricultural and stormwater nitrogen sources. PMID- 29115132 TI - Nanopatterned Bulk Metallic Glass Biosensors. AB - Nanopatterning as a surface area enhancement method has the potential to increase signal and sensitivity of biosensors. Platinum-based bulk metallic glass (Pt-BMG) is a biocompatible material with electrical properties conducive for biosensor electrode applications, which can be processed in air at comparably low temperatures to produce nonrandom topography at the nanoscale. Work presented here employs nanopatterned Pt-BMG electrodes functionalized with glucose oxidase enzyme to explore the impact of nonrandom and highly reproducible nanoscale surface area enhancement on glucose biosensor performance. Electrochemical measurements including cyclic voltammetry (CV) and amperometric voltammetry (AV) were completed to compare the performance of 200 nm Pt-BMG electrodes vs Flat Pt BMG control electrodes. Glucose dosing response was studied in a range of 2 mM to 10 mM. Effective current density dynamic range for the 200 nm Pt-BMG was 10-12 times greater than that of the Flat BMG control. Nanopatterned electrode sensitivity was measured to be 3.28 MUA/cm2/mM, which was also an order of magnitude greater than the flat electrode. These results suggest that nonrandom nanotopography is a scalable and customizable engineering tool which can be integrated with Pt-BMGs to produce biocompatible biosensors with enhanced signal and sensitivity. PMID- 29115133 TI - Pursuing the Promise of Enzymatic Enhancement with Nanoparticle Assemblies. AB - The growing emphasis on green chemistry, renewable resources, synthetic biology, regio-/stereospecific chemical transformations, and nanotechnology for providing new biological products and therapeutics is reinvigorating research into enzymatic catalysis. Although the promise is profound, many complex issues remain to be addressed before this effort will have a significant impact. Prime among these is to combat the degradation of enzymes frequently seen in ex vivo formats following immobilization to stabilize the enzymes for long-term application and to find ways of enhancing their activity. One promising avenue for progress on these issues is via nanoparticle (NP) display, which has been found in a number of cases to enhance enzyme activity while also improving long-term stability. In this feature article, we discuss the phenomenon of enhanced enzymatic activity at NP interfaces with an emphasis on our own work in this area. Important factors such as NP surface chemistry, bioconjugation approaches, and assay formats are first discussed because they can critically affect the observed enhancement. Examples are given of improved performance for enzymes such as phosphotriesterase, alkaline phosphatase, trypsin, horseradish peroxidase, and beta-galactosidase and in configurations with either the enzyme or the substrate attached to the NP. The putative mechanisms that give rise to the performance boost are discussed along with how detailed kinetic modeling can contribute to their understanding. Given the importance of biosensing, we also highlight how this configuration is already making a significant contribution to NP-based enzymatic sensors. Finally, a perspective is provided on how this field may develop and how NP-based enzymatic enhancement can be extended to coupled systems and multienzyme cascades. PMID- 29115134 TI - Printing Beyond sRGB Color Gamut by Mimicking Silicon Nanostructures in Free Space. AB - Localized optical resonances in metallic nanostructures have been increasingly used in color printing, demonstrating unprecedented resolution but limited in color gamut. Here, we introduce a new nanostructure design, which broadens the gamut while retaining print resolution. Instead of metals, silicon nanostructures that exhibit localized magnetic and electric dipole resonances were fabricated on a silicon substrate coated with a Si3N4 index matching layer. Index matching allows a suppression of substrate effects, thus enabling Kerker's conditions to be met, that is, sharpened transitions in the reflectance spectra leading to saturated colors. This nanostructure design achieves a color gamut superior to sRGB, and is compatible with CMOS processes. The presented design could enable compact high-resolution color displays and filters, and the use of a Si3N4 antireflection coating can be readily extended to designs with nanostructures fabricated using other high-index materials. PMID- 29115135 TI - Scalable Self-Supported Graphene Foam for High-Performance Electrocatalytic Oxygen Evolution. AB - Developing efficient electrocatalysts consisting of earth-abundant elements for oxygen evolution reaction (OER) is crucial for energy devices and technologies. Herein, we report self-supported highly porous nitrogen-doped graphene foam synthesized through the electrochemical expansion of carbon-fiber paper and subsequent nitrogen plasma treatment. A thorough characterization, such as electron microscopy and synchrotron-based near-edge X-ray absorption fine structure, indicates the well-developed porous structures featuring homogeneously doped nitrogen heteroatoms. These merits ensure enriched active sites, an enlarged active surface area, and improved mass/electron transport within the continuous graphene framework, thus leading to an outstanding capability toward electrocatalyzing OER in alkaline media, even competitive with the state-of-the art noble-/transition-metal and nonmetal electrocatalysts reported to date, from the perspectives of the sharp onset potential, a small Tafel slope, and remarkable durability. Furthermore, a rechargeable Zn-air battery with this self supported electrocatalyst directly used as the air cathode renders a low charge/discharge overpotential and considerable life span. The finding herein suggests that a rational methodology to synthesize graphene-based materials can significantly enhance the oxygen electrocatalysis, thereby promoting the overall performance of the energy-related system. PMID- 29115137 TI - [Articles of the Hungarian Medical Journal from September, 1979]. PMID- 29115136 TI - Kinetic Control of Quorum Sensing in Pseudomonas aeruginosa by Multidrug Efflux Pumps. AB - Pseudomonas aeruginosa is an important human pathogen, the physiology and virulence of which are under the control of quorum sensing signals. These signals often have dual roles, functioning as toxins to some cells and as oxidative stress protectors for their producer cells. Hence, their internal and external concentrations should be tightly controlled. In this study, we analyzed the interplay between the multidrug efflux transporters MexEF-OprN and MexG/HI-OpmD in quorum sensing of P. aeruginosa. We found that the two transporters have overlapping substrate specificities but different efficiencies. When overproduced, both MexEF-OprN and MexG/HI-OpmD provide clinical levels of resistance to diverse fluoroquinolones and protect P. aeruginosa against toxic phenazines. However, this similarity is enabled by synergistic interactions with the outer membrane. In hyperporinated cells, MexG/HI-OpmD is saturated by much lower concentrations of fluoroquinolones but is more efficient than MexEF-OprN in efflux of phenazines. Unlike MexEF-OprN, mutational inactivation of MexG/HI-OpmD reduces the levels of pyocyanin and makes P. aeruginosa cells hypersusceptible to phenazines. Our results further show that MexG binds pyocyanin, physically associates with MexHI, and represses the activity of the transporter, revealing a negative regulatory role of this protein. We conclude that differences in kinetic properties of transporters are critical to maintain proper intra- and extracellular concentrations of phenazines and other signaling molecules and that MexG/HI-OpmD controls the steady state in the synthesis and secretion of phenazines. PMID- 29115138 TI - [Articles of the Hungarian Medical Journal from November, 1979]. PMID- 29115139 TI - [Articles of the Hungarian Medical Journal from August, 1979]. PMID- 29115140 TI - [Articles of the Hungarian Medical Journal from May, 1979]. PMID- 29115141 TI - [Articles of the Hungarian Medical Journal from January, 1978]. PMID- 29115142 TI - [Articles of the Hungarian Medical Journal from May, 1980]. PMID- 29115143 TI - Inclusion levels and modes of whole grain incorporation into wheat-based rations differentially influence the performance of broiler chickens. AB - 1. The objective was to compare three whole grain (WG) inclusion levels (7.5, 15 and 30%) offered to broiler chickens by three modes of WG incorporation: (i) pre pellet WG inclusion, (ii) post-pellet WG inclusion as a blend of WG and pelleted concentrate and (iii) post-pellet WG inclusion where WG and pelleted concentrate were provided in separate feed trays against a ground-grain, wheat-based control diet. 2. Ten dietary treatments were offered to 6 replicate cages (6 birds per cage) of male Ross 308 chickens from 7 to 28 d post-hatch. The effects of treatment on relative gizzard weights, gizzard contents, pancreatic weights and pH of gizzard digesta were monitored. Parameters of growth performance, nutrient utilisation (apparent metabolisable energy [AME], metabolisable to gross energy [ME:GE] ratios, nitrogen [N] retention and N-corrected AME [AMEn]), apparent starch and protein (N) digestibility coefficients and disappearance rates in for small intestinal segments and concentrations of free amino acids in plasma taken from the anterior mesenteric vein were determined. 3. Whole grain feeding (WGF) did not influence weight gain, but 30% post-pellet blended and 15 and 30% post pellet separated treatments significantly depressed (P < 0.05) feed intakes while the 30% post-pellet separated treatment improved (P < 0.01) feed conversion ratios (FCR). WGF regimes significantly increased relative gizzard weights. 4. Overall, WGF generated profound responses in AME, ME:GE ratios, N retention and AMEn that were highly correlated with relative gizzard weights. In general, WGF improved starch and protein (N) digestibilities and again there were some correlations with these outcomes and relative gizzard weights. 5. Post-pellet WG inclusions where WG and pelleted concentrate were offered separately provided chickens with the opportunity to choice feed. Birds showed a preference for the relatively high-protein pelleted concentrate and at 30% WG, this resulted in an improvement in FCR of 7.69% (1.260 versus 1.365; P < 0.001) relative to the ground-grain control diet. PMID- 29115144 TI - Antidiarrhoeic effect and dereplication of the aqueous extract of Annona crassiflora (Annonaceae). AB - We investigated the antidiarrhoeic effect of the aqueous extract of Annona crassiflora leaves (AEAC). The AEAC decreased the diarrhoeic stools and enteropooling induced by castor oil, without altering total faecal output; moreover, the distance travelled by charcoal meal in the intestine was increased. Twenty-eight compounds were identified by LC-DAD-MS in the AEAC, including flavonoids, alkaloids and proanthocyanidins. In addition, two oligomeric series of condensed tannins of up to nine flavan-3-ol units were characterised by MALDI MS. These data suggest that the antidiarrhoeic effect of the AEAC is related to its ability to inhibit intestinal secretion and/or to increase intestinal absorption. Moreover, the prokinetic effect of AEAC, together with its inhibitory effect on enteropooling induced by castor oil, explains why this extract decreased diarrhoeic faeces without altering the total faecal output. All these effects are in agreement with the pharmacological activity reported in the literature for many of the secondary metabolites identified. PMID- 29115145 TI - Congmujingnosides B-G, triterpene saponins from the stem of Aralia chinensis and their protective effects against H2O2-induced myocardial cell injury. AB - Phytochemical investigation of the stem of Aralia chinensis yielded six new oleanane-type triterpene saponins named as congmujingnosides B-G (1-6). The new ones were elucidated on the basis of the chemical and spectroscopic analysis. Protective effects of compounds 1-6 were tested against H2O2-induced H9c2 cardiomyocyte injury, and the data showed that compounds 1 and 5 had significant cell-protective effects. No significant DPPH radical scavenging activity was observed for compounds 1-6. PMID- 29115146 TI - A new 12,17-cyclo-labdane diterpenoid from the twigs of Dacrycarpus imbricatus. AB - A new 12,17-cyclo-labdane diterpenoid, podoimbricatin C (1), along with 15 known compounds was isolated from the twigs of Dacrycarpus imbricatus. Their structures were elucidated by means of extensive spectroscopic analysis. Compound 1 is the second example of the unusual 12,17-cyclo-labdane diterpenoids. It showed no inhibitory effects against five human tumour lines (HL-60, SMMC-7721, A-549, MCF 7 and SW-480). PMID- 29115147 TI - Four new monacolin analogs from Monascus purpureus-fermented rice. AB - Four new monacolin analogs, monacolin T (1), monacolin U (2) 6a-O-methyl-4,6 dihydromonacolin L (3), and 6a-O-ethyl-4,6-dihydromonacolin L (4) were isolated from the ethanolic extract of Monascus purpureus-fermented rice. Their structures were determined by a combination of 1D, 2D NMR experiments (1H-1HCOSY, HSQC, HMBC, and ROESY), and mass spectrometry. In vitro cytotoxic assay, all compounds were inactive at the concentration of 10 uM. PMID- 29115148 TI - A new polyoxygenated cyclohexene derivative from Artabotrys hainanensis. AB - A new polyoxygenated cyclohexene derivative, artahainanol A (1), together with three known analogues (2-4), was isolated from the stems and leaves of Artabotrys hainanensis. Among them, 1 is an unusual polyoxygenated cyclohexene containing 14 carbon atoms on the carbon skeleton. All known compounds (2-4) were isolated from the genus Artabotrys for the first time. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-4 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 2.68 to 18.32 MUM. PMID- 29115149 TI - Low baseline awareness of gastric cancer risk factors amongst at-risk multiracial/ethnic populations in New York City: results of a targeted, culturally sensitive pilot gastric cancer community outreach program. AB - BACKGROUND AND AIMS: There are limited efforts to address modifiable risk factors for gastric cancer (GC) among racial/ethnic groups at higher GC risk, which may reflect decreased public awareness of risk factors. Our primary aim was to assess baseline awareness of GC risk factors and attitudes/potential barriers for uptake of a GC screening program among high-risk individuals. METHODS: Participants attended a linguistically and culturally targeted GC educational program in East Harlem (EH)/Bronx and Chinatown communities in New York City. Demographic information and relevant behavioral/lifestyle habits were collected. Participants' ability to identify GC risk factors and attitudes/barriers surrounding GC screening were assessed before and after the program. RESULTS: Of the 168 included participants, most were female with 77% above age 70. Nearly half of participants in the EH/Bronx programs identified themselves as black and 63% as Hispanic/Latino; 93% of the Chinatown participants identified as Chinese. Among EH/Bronx participants, the majority correctly identified older age, smoking, alcohol, H. pylori, family history, race/ethnicity, excess salt, and preserved foods as risk factors. Among Chinatown participants, the majority correctly identified smoking, alcohol, race/ethnicity, and excess salt, although only 53% and 57.8% correctly identified H. pylori and preserved foods, respectively; the majority incorrectly answered that older age was not a major risk factor. The majority in both groups failed to identify male gender as higher risk and incorrectly identified stress and obesity as major risk factors. Participants were more concerned about the potential findings on GC screening tests than the risks and costs or having to take time off work. CONCLUSION: Among multiracial/ethnic groups of individuals presumably at higher risk for GC, we identified several gaps in baseline knowledge of both modifiable and non modifiable GC risk factors. Culturally and linguistically appropriate educational interventions may be a worthwhile adjunctive intervention within the context of a targeted GC screening program. PMID- 29115150 TI - Serotonin-Norepinephrine Reuptake Inhibitor Contributing To Confusion Post Right Unilateral Brief-Pulse Electroconvulsive Therapy. PMID- 29115152 TI - [Articles of the Hungarian Medical Journal from June, 1980]. PMID- 29115151 TI - Sofosbuvir/Velpatasvir/Voxilaprevir: A Pan-Genotypic Direct-Acting Antiviral Combination for Hepatitis C. AB - OBJECTIVES: To review the efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir in the treatment of hepatitis C virus (HCV) infection. DATA SOURCES: A literature search through PubMed was conducted (August 2010 to August 2017) using the terms GS-9857, voxilaprevir, and NS3/4A protease inhibitor. STUDY SELECTION/DATA EXTRACTION: Studies of sofosbuvir/velpatasvir/voxilaprevir were identified. DATA SYNTHESIS: Sofosbuvir/velpatasvir/voxilaprevir is indicated for adult patients with chronic HCV without cirrhosis or with compensated cirrhosis who have (1) genotype 1 through 6 and have previously been treated with an NS5A inhibitor or (2) genotype 1a or 3 and have previously been treated with sofosbuvir without an NS5A inhibitor. POLARIS-1 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 12 weeks was highly effective in patients with HCV genotype 1 through 6 who had prior exposure to an NS5A inhibitor. POLARIS-2 failed to demonstrate that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was noninferior to sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 6 who had no prior exposure to direct-acting antivirals (DAAs). POLARIS-3 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 3 and compensated cirrhosis who had no prior exposure to DAAs. POLARIS-4 demonstrated that sofosbuvir/velpatasvir/voxilaprevir was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 3 who had prior exposure to DAAs but not an NS5A inhibitor. The most common adverse reactions were headache, fatigue, diarrhea, and nausea. CONCLUSIONS: Sofosbuvir/velpatasvir/voxilaprevir is safe and effective to treat HCV in patients who have previously been treated with DAAs. PMID- 29115154 TI - Predictive Capacity and Cutoff Value of Waist-to-Height Ratio in the Incidence of Metabolic Syndrome. AB - The purpose of this study was to compare the predictive ability of waist-to height ratio (WHtR) compared with other anthropometric indicators in the incidence of metabolic syndrome (MetS) and to propose cutoff values for its early detection in nursing practice. A longitudinal cohort study was conducted on a sample of 630 workers (137 exposed and 493 nonexposed), free of MetS at baseline. WHtR was compared with body mass index (BMI), waist circumference (WC), and the percentage of body fat (BF%). In the Cox regression, the adjusted values of hazard ratio (HR) were 5.4 (confidence interval [CI] = [3.1, 9.5]) for WHtR and 7.4 (CI = [3.7, 14.9]) for components of MetS. WHtR obtained the largest area under the curve 0.82 (CI = [0.76, 0.88]), and with a cutoff value of 0.54, values were obtained for sensitivity (70%) and specificity (77%). WHtR was the best predictor of incidence of MetS, with a cutoff value of 0.54. Nursing can improve the early detection of MetS by measuring WHtR. PMID- 29115153 TI - Molecular and morphological description of Isospora sp. from the common mynah (Acridotheres tristis) and a preliminary survey of two anticoccidial drugs in natural infection. AB - Coccidian parasites, especially Isospora, are prevalent parasites in Passeriformes. Isosporan oocysts from common mynahs (Acridotheres tristis) are incompletely described. Detailed knowledge on biology, prevalence, pathogenesis and treatment of avian isosporiasis is scant. In this study, isosporan oocysts isolated from common mynahs were morphologically and molecularly characterized. The medication efficiencies of diclazuril and sulfadiazine-trimethoprim in isosporiasis in naturally infected mynahs were evaluated. Isosporan oocysts from common mynahs were described morphologically by microscopic imaging. The 18S rRNA and COI genes were amplified using PCR and the resultant products were sequenced and analysed phylogenetically. To evaluate the efficiencies of diclazuril and sulfadiazine-trimethoprim, two experimental treatment groups and a null control were assigned. General health status, weight and oocysts per gram of faeces were evaluated. Oocysts from all birds contained isosporan oocysts that were morphologically and dimensionally similar (P < 0.05). The oocysts were spherical; with no oocyst residuum, micropyle or polar granules. At both loci, phylogenetic analyses placed the Isospora isolate in the same clade with Isospora spp. from other Passeriformes. Both of the anticoccidials were well tolerated by the birds, a rapid reduction in oocyst excretion was noted at the commencement of treatment and 72 h after drug administration, oocyst excretion zeroed in all treated birds. Based on morphological and molecular data, this isolate does not resemble any previously described isosporas, hence Isospora tristum n. sp. is proposed for the current species. Both evaluated anticoccidials seemed to be efficient in reduction of oocyst production and can be recommended for the treatment of mynah isosporiasis. PMID- 29115155 TI - [Articles of the Hungarian Medical Journal from February, 1980]. PMID- 29115157 TI - Symptom Burden Clustering in Chronic Kidney Disease Stage 5. AB - Patients with chronic kidney disease (CKD) Stage 5, experience multiple symptoms that negatively affect the health-related quality of life (HRQoL). This study examined the cluster of symptoms and their association with disease severity and comorbidities. The study sample included 123 patients with CKD Stage 5; 60 patients were in the dialysis group and 63 patients in the Conservative Kidney Management group. Symptom data were collected using the Spanish modified version of Palliative Care Outcome Scale-Symptoms (POS-S) Renal, a validated questionnaire to assess symptoms in this population. More than half of the patients described weakness, difficulty sleeping, and feeling depressed. Two symptom clusters were identified. There was no significant statistical correlation between disease severity and symptoms and between comorbidities and symptoms. The tendency of these symptoms to occur together has implications for improving symptom management in this population. Routine symptom assessment can be useful in clinical and research settings. PMID- 29115156 TI - Development and evaluation of novel recombinant adenovirus-based vaccine candidates for infectious bronchitis virus and Mycoplasma gallisepticum in chickens. AB - Avian infectious bronchitis caused by the infectious bronchitis virus (IBV), and mycoplasmosis caused by Mycoplasma gallisepticum (MG) are two major respiratory diseases in chickens that have resulted in severe economic losses in the poultry industry. We constructed a recombinant adenovirus that simultaneously expresses the S1 spike glycoprotein of IBV and the TM-1 protein of MG (pBH-S1-TM-1-EGFP). For comparison, we constructed two recombinant adenoviruses (pBH-S1-EGFP and pBH TM-1-EGFP) that express either the S1 spike glycoprotein or the TM-1 protein alone. The protective efficacy of these three vaccine constructs against challenge with IBV and/or MG was evaluated in specific pathogen free chickens. Groups of seven-day-old specific pathogen free chicks were immunized twice, two weeks apart, via the oculonasal route with the pBH-S1-TM-1-EGFP, pBH-S1-EGFP, or pBH-TM-1-EGFP vaccine candidates or the commercial attenuated infectious bronchitis vaccine strain H52 and MG vaccine strain F-36 (positive controls), and challenged with virulent IBV or MG two weeks later. Interestingly, by days 7 and 14 after the booster immunization, pBH-S1-TM-1-EGFP-induced antibody titre was significantly higher (P < 0.01) compared to attenuated commercial IBV vaccine; however, there was no significant difference between the pBH-S1-TM-1-EGFP and attenuated commercial MG vaccine groups (P > 0.05). The clinical signs, the gross, and histopathological lesions scores of the adenovirus vaccine constructs were not significantly different from that of the attenuated commercial IBV or MG vaccines (positive controls) (P > 0.05). These results demonstrate the potential of the bivalent pBH-S1-TM-1-EGFP adenovirus construct as a combination vaccine against IB and mycoplasmosis. PMID- 29115158 TI - Lignans from the seeds of Chinese hawthorn (Crataegus pinnatifida var. major N.E.Br.) against beta-amyloid aggregation. AB - Phytochemical investigation on the seeds of hawthorn (Crataegus spp.) led to the isolation of a new compound, (7'R, 8'R, 8S)-isolariciresinol (1), along with six known compounds (2-7). The structures of all compounds were determined based on spectroscopic data interpretation. The Abeta1-42 inhibition activity of all isolated compounds was evaluated in vitro. As a result, compounds 5 and 6 showed stronger inhibition of Abeta1-42 aggregation than curcumin, with inhibition rates of 70.59 and 68.14% at 20 MUM. The possible mechanism of interaction between Abeta1-42 and the active compounds 5 and 6 was also investigated by molecular docking. PMID- 29115160 TI - [Articles of the Hungarian Medical Journal from September, 1980]. PMID- 29115159 TI - Independent and synergistic effects of self- and public stigmas on quality of life of HIV-infected persons. AB - Stigma has a potential impact on the quality of life of HIV-infected individuals over time. There is little empirical evidence regarding the first appearance and dynamic changes among different types of stigma, self-stigma and public-stigma, and their impacts on quality of life over time in HIV-infected persons. The purpose of this study was to assess the dynamic changes in self-stigma and public stigma along the time course and determined their independent and synergistic impacts on quality of life. A Cross-sectional study was conducted at Two HIV designed hospitals and two branches of non-government an-AIDS organizations in Wes Java, Indonesia. Persons diagnosed with HIV completed self-report measures of stigma and the questionnaire of World Health Organization Quality of Life (WHOQOL)-HIV brief version. Kernel smoothing method and multivariate linear regression were applied for statistical analysis. Two hundred fifteen adult HIV infected persons agreed to participate in this study, with a response rate of 85.3%. The kernel smoothing means showed that one-third of subjects developed self-stigma immediately after HIV diagnosis while a higher public-stigma felt 6 months later, and both seemed to last continually. Beginning at about 48 months after diagnosis, participants with stigma showed consistently lower scores for all domains of quality of life. After control of potential confounding through multiple linear regression analyses, we found scores of all four domains and items of mobility, fatigue, activity of daily living, positive feeling, self esteem, social support, and physical environment of WHOQOL were independently associated with both self-stigma and public-stigma. While self-stigma also affects items related to personal psychological feelings, public stigma alone associates with lower scores of items related to social and environmental domains. Our findings underscore the need to explore and control the complex structure and possible synergistic effects of multiple stigmatizations. PMID- 29115162 TI - [Articles of the Hungarian Medical Journal from October, 1980]. PMID- 29115161 TI - Pharmacokinetics of tapentadol in laying hens and its residues in eggs after multiple oral dose administration. AB - 1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel opioid analgesic, in laying hens after intravenous (IV) and oral (PO) administration and to quantify the concentrations of TAP residues in eggs. 2. Twenty healthy laying hens were divided into three groups: A (n = 6), B (n = 6) and C (n = 8). The study was conducted in two phases. Groups A and B received TAP by IV and PO routes at the dose of 1 and 5 mg/kg, respectively. 3. No visible adverse effects were observed after administration of the drug. TAP plasma concentrations were detectable up to 4 h following administration. Following IV administration, TAP plasma concentrations were only higher than the minimal effective concentration (148 ng/ml) reported for humans for 1 h. After single PO administration, plasma concentrations of TAP would not conform to software algorithms and the PK parameters were not calculated. TAP concentration following multiple PO doses at 5 mg/kg for 5 d was found to be higher and more persistent (12 h vs. 7 h) in yolk compared with albumen. 4. This is the first PK study on the novel atypical opioid TAP in laying hens. Further studies are required to investigate the analgesic efficacy and actual effective plasma concentration of TAP in this species. PMID- 29115163 TI - Further Evaluation of Presentation Format of Competing Stimuli for Treatment of Automatically Maintained Challenging Behavior. AB - Behavioral interventions have been effective in reducing automatically maintained skin picking for individuals with disabilities including autism spectrum disorder (ASD). A competing stimulus assessment (CSA) is typically utilized in behavioral intervention and assessment to identify potential stimuli which compete with the reinforcer for various forms of challenging behavior (CB). Treatment evaluations have validated the results of these assessments by demonstrating competing stimuli may reduce levels of CB. In Phase 1 of this study, we conducted a functional analysis (FA) to determine what variables were maintaining skin picking of an 11-year-old girl diagnosed with ASD. In Phase 2, we conducted a CSA to determine which stimulus competed the most with skin picking. In Phase 3, we utilized a multielement with reversal design to compare the effectiveness of three presentation formats: (a) single stimulus (single), (b) multiple stimuli (multiple), and (c) alternating stimuli (alternating) in reducing levels of automatically maintained CB. We found noncontingent access to a single item was the most effective intervention to decrease skin picking. This study adds to the literature on reducing CB in children with ASD by incorporating a CSA before the evaluation of different formats of delivering competing stimuli, across extended duration session times. PMID- 29115164 TI - MicroRNA-375 as a potential serum biomarker for the diagnosis, prognosis, and chemosensitivity prediction of osteosarcoma. AB - Objective This study was performed to examine serum microRNA-375 (miR-375) expression in patients with osteosarcoma and determine its diagnostic and prognostic value. Methods Serum samples were obtained from 95 patients with osteosarcoma and 95 healthy individuals. miR-375 expression was detected by real time polymerase chain reaction. The associations of serum miR-375 expression with the patients' clinicopathological characteristics and prognosis were then evaluated. Receiver operating characteristic curve analysis was performed to obtain the potential value of serum miR-375 as a biomarker for osteosarcoma diagnosis and chemosensitivity prediction. Results Serum miR-375 expression was significantly lower in patients with osteosarcoma than in healthy individuals. Low serum miR-375 levels were associated with advanced clinical stages, large tumor size, positive distant metastasis, and poor tumor response to preoperative chemotherapy. Receiver operating characteristic curve analysis illustrated that serum miR-375 could distinguish patients with osteosarcoma from healthy individuals and distinguish patients with a good pathologic response from those with a poor response. Multivariate analysis confirmed low serum miR-375 expression as a statistically significant independent unfavorable prognostic factor. Conclusions Serum miR-375 expression was downregulated in patients with osteosarcoma and might serve as a biomarker for its diagnosis, prognosis, and chemosensitivity prediction. PMID- 29115165 TI - A fuzzy MICMAC analysis for improving supply chain performance of basic vaccines in developing countries. AB - INTRODUCTION: In recent years, demand to improve child immunization coverage globally, and the development of the latest vaccines and technology has made the vaccine market very complex. The rise in such complexities often gives birth to numerous issues in the vaccine supply chain, which are the primary cause of its poor performance. Figuring out the cause of the performance problem can help you decide how to address it. The goal of the present study is to identify and analyze important issues in the supply chain of basic vaccines required for child immunization in the developing countries. RESEARCH DESIGN & METHODS: Twenty-five key issues as various factors of the vaccine supply chain have been presented in this paper. Fuzzy MICMAC analysis has been carried out to classify the factors based on their driving and dependence power and to develop a hierarchy based model. Further, the findings have been discussed with the field experts to identify the critical factors. RESULTS & CONCLUSION: Three factors: better demand forecast, communication between the supply chain members, and proper planning and scheduling have been identified as the critical factors of vaccine supply chain. These factors should be given special care to improve vaccine supply chain performance. PMID- 29115166 TI - Incorporating age into International Germ Cell Consensus Classification (IGCCC): a time to move forward? AB - BACKGROUND: Older age is a poor prognostic indicator among patients with germ cell tumors. The current study evaluates an age-integrated international germ cell consensus classification (IGCCC) for advanced germ cell tumors. METHODS: SEER database (2004-2014) was accessed through SEER*Stat program and both IGCCC and age-integrated IGCCC were calculated based on site of the primary, site of the metastasis and level of tumor markers. Overall survival analyses according to IGCCC and age-integrated IGCCC were conducted through Kaplan-Meier analysis. RESULTS: Overall survival was compared according to IGCCC and age-integrated IGCCC for patients with seminoma and Non-seminomatous germ cell tumors (NSGCTs). P values were significant (P <0.001) for all scenarios. c-index for seminoma for IGCCC was 0.553; c-index for seminoma for age-integrated IGCCC was 0.664;c-index for NSGCTs for IGCCC was 0.729; and c-index for NSGCTs for age-integrated IGCCC was 0.738. A Cox-regression multivariate model of factors affecting cancer specific survival (adjusted for race and surgical treatment) was conducted. All P values for pair wise comparisons (among different age-integrated IGCCC categories) were significant for both seminoma and NSGCTs (P<0.01). CONCLUSION: Compared to traditional IGCCC, age-integrated IGCCC is more discriminatory and the new risk groups introduced within it are prognostically relevant. PMID- 29115168 TI - Language of ADHD in Adults on Social Media. AB - OBJECTIVE: We computationally analyze the language of social media users diagnosed with ADHD to understand what they talk about, and how their language is correlated with users' characteristics such as personality and temporal orientation. METHOD: We analyzed approximately 1.3 million tweets written by 1,399 Twitter users with self-reported diagnoses of ADHD, comparing their posts with those used by a control set matched by age, gender, and period of activity. RESULTS: Users with ADHD are found to be less agreeable, more open, to post more often, and to use more negations, hedging, and swear words. Posts are suggestive of themes of emotional dysregulation, self-criticism, substance abuse, and exhaustion. A machine learning model can predict which of these Twitter users has ADHD with an out-of-sample AUC of .836. CONCLUSION: Based on this emerging technology, conjectures of future uses of social media by researchers and clinicians to better understand the naturalistic manifestations and sequelae of ADHD. PMID- 29115167 TI - Two alpha1-Globin Gene Point Mutations Causing Severe Hb H Disease. AB - Hb H disease is generally a moderate form of alpha-thalassemia (alpha-thal) that rarely requires regular blood transfusions. In this study, two Chinese families with members carrying transfusion-dependent Hb H disease were investigated for rare mutations on the alpha-globin genes (HBA1, HBA2). In one family, Hb Zurich Albisrieden [alpha59(E8)Gly->Arg; HBA1: c.178G>C] in combination with the Southeast Asian (- -SEA) deletion was the defect responsible for the severe phenotype. In another family, a novel hemoglobin (Hb) variant named Hb Sichuan (HBA1: c.393_394insT), causes alpha-thal and a severe phenotype when associated with the - -SEA deletion. As these two HBA1 mutations can present as continuous blood transfusion-dependent alpha-thal, it is important to take this point into account for detecting the carriers, especially in couples in which one partner is already a known alpha0-thal carrier. PMID- 29115169 TI - Protective effect of captopril against diazinon induced nephrotoxicity and neurotoxicity via inhibition of ROS-NO pathway. AB - Diazinon (Dz) is a widely used insecticide. It can induce nephrotoxicity and neurotoxicity via oxidative stress. Captopril, an angiotensin-converting enzyme inhibitor, is known for its antioxidant properties. In this study, we used captopril for ameliorating of Dz-induced kidney and brain toxicity in rats. Animals were divided into five groups as follows: negative control (olive oil), Dz (150 mg kg-1), captopril (60 and 100 mg kg-1) and positive control (N acetylcysteine 200 mg kg-1) were injected intraperitoneally 30 min before Dz. After 24 h, animals were anesthetized and the brain and kidney tissues were separated. Then oxidative stress factors were evaluated. Also, blood was collected for assessment of blood urea nitrogen (BUN), creatinine (Cr) and nitric oxide (NO) levels. Dz significantly increased oxidative stress markers such as reactive oxygen species (ROS), lipid peroxidation, and protein carbonyl as well as glutathione (GSH) oxidation in both tissues. Increased levels of the BUN, Cr and NO were observed after Dz injection. Interestingly, captopril administration significantly decreased ROS production in both tissues. Captopril significantly protected kidney and brain against lipid peroxidation and GSH oxidation. Administration of captopril could markedly inhibit protein carbonyl production in kidney and brain after Dz injection. Furthermore, captopril ameliorated the increased level of BUN, Cr and NO. These results suggested that captopril can prevent Dz-induced oxidative stress, nephrotoxicity and neurotoxicity because of its antioxidant activity. PMID- 29115170 TI - THREE SIBLINGS WITH ANDROGEN INSENSITIVITY SYNDROME. AB - Genetic, gonadal, phenotypic and psychological genderis the basis for gender assignment to an individual. Derangementin genetic makeup, under or over exposure to sex hormones and problems related to sex hormone receptorswill lead to abnormal development of the external and internal genitalia. Failure to respond for the endogenousandrogen, Androgen Insensitivity Syndrome is one of the common causes of genital ambiguity and intersex.In this case series we have presented three girls from a family of seven children visited Tikur Anbassa SpecializedHospital (TASH) with a complaint of primary amenorrhea and diagnosed to have androgen insensitivity syndrome.Their clinical presentation, relevant laboratory and histopathologic findings, karyotype and genetic analysisresults are summarized. Potential causes and treatment options are discussed. PMID- 29115171 TI - Sika pilose antler type I collagen promotes BMSC differentiation via the ERK1/2 and p38-MAPK signal pathways. AB - CONTEXT: Sika pilose antler type I collagen (SPC-I) have been reported to promote bone marrow mesenchymal stem cell (BMSC) proliferation and differentiation. However, the underlying mechanism is still unclear. OBJECTIVE: This study investigates the molecular mechanisms of SPC-I on the BMSC proliferation and differentiation of osteoblast (OB) in vitro. MATERIAL AND METHODS: The primary rat BMSC was cultured and exposed to SPC-I at different concentrations (2.5, 5.0 and 10.0 mg/mL) for 20 days. The effect of SPC-I on the differentiation of BMSCs was evaluated through detecting the activity of alkaline phosphatase (ALP), ALP staining, collagen I (Col-I) content, and calcified nodules. The markers of osteoblastic differentiation were evaluated using RT-PCR and Western-blot analysis. RESULTS: SPC-I treatment (2.5 mg/mL) significantly increased the proliferation of BMSCs (p < 0.01), whereas, SPC-I (5.0 and 10.0 mg/mL) significantly inhibited the proliferation of BMSCs (p < 0.01). SPC-I (2.5 mg/mL) significantly increased ALP activity and Col-I content (p < 0.01), and increased positive cells in ALP staining and the formation of calcified nodules. Additionally, the gene expression of ALP, Col-I, Osteocalcin (OC), Runx2, Osterix (Osx), ERK1/2, BMP2 and p38-MAPK, along with the protein expression of ERK1/2, p ERK1/2, p-p38 MAPK were markedly increased in the SPC-I (5.0 mg/mL) treatment group (p < 0.01) compared to the control group. DISCUSSION AND CONCLUSIONS: SPC-I can induce BMSC differentiation into OBs and enhance the function of osteogenesis through ERK1/2 and p38-MAPK signal transduction pathways and regulating the gene expression of osteogenesis-specific transcription factors. PMID- 29115172 TI - Ecotoxicological effects of bisphenol A and nonylphenol on the freshwater cladocerans Ceriodaphnia silvestrii and Daphnia similis. AB - Toxicities of bisphenol A (BPA) and nonylphenol (NP) to the neotropical freshwater cladocerans Ceriodaphnia silvestrii and Daphnia similis were studied under laboratory conditions. Acute exposures to BPA generated mean 48-h EC50 values of 14.44 (6.02-22.85) mg L-1 for C. silvestrii and 12.05 (1.73-22.37) mg L 1 for D. similis. When the organisms were exposed to acute doses of NP, mean 48-h EC50 values were 0.055 (0.047-0.064) mg L-1 (C. silvestrii) and 0.133 (0.067 0.200) mg L-1 (D. similis). Ceriodaphnia silvestrii was also tested in chronic bioassays, which resulted in mean 8-d IC25 values of 2.43 (2.16-2.69) mg L-1 BPA [no observed effect concentration (NOEC): 1.38 mg L-1] and 0.020 (0.015-0.026) mg L-1 NP (NOEC: 0.015 mg L-1). These laboratory tests are valuable to broaden the understanding of the environmental threat posed by BPA and NP in aquatic ecosystems, and to increase the knowledge about the sensitivity of neotropical indigenous species to these contaminants. In addition to the laboratory bioassays, species sensitivity distributions were used to suggest protective concentrations of BPA and NP to prevent adverse effects on freshwater organisms. According to the obtained results, concentrations lower than 36.47 ug L-1 BPA and 1.39 ug L-1 NP are not expected to adversely impact aquatic organisms in natural ecosystems. PMID- 29115173 TI - Role of GABAB receptors and p38MAPK/NF-kappaB pathway in paclitaxel-induced apoptosis of hippocampal neurons. AB - CONTEXT: The effects of the anticancer drug paclitaxel on learning and memory are rarely studied. OBJECTIVE: This study investigated changes in GABAB receptor expression during paclitaxel-induced apoptosis of hippocampal neurons and the role of the p38MAPK/NF-kappaB pathway in this process. MATERIALS AND METHODS: Hippocampal neurons isolated from neonatal Sprague-Dawley rats were divided into six groups: Control (C), SB (10 uL of 10-umol/L SB203580), SN (53 ug/mL SN50), N (1 umol/L paclitaxel), SB + N (10 umol/L SB203580 + 1 umol/L paclitaxel) and SN + N (53 ug/mL SN50 + 1 umol/L paclitaxel). Cells in different groups were treated with corresponding agents for 24 h at 37 degrees C. The apoptosis rate and protein levels of GABAB1 receptors and NF-kappaB p65 were evaluated. Rat models of neuropathic pain was induced by paclitaxel and were divided into four groups such as N, B + N, SN + N and SN + B + N groups. Rats in the N group received intrathecal injections of normal saline solution. Rats in the B + N group received intrathecal injections of 10 MUL baclofen (0.05 MUg/MUL). Rats in the SN + N and SN + B + N groups received intrathecal injections of SN50 and SN50 plus baclofen, respectively. Spatial learning and memory were evaluated in rat models based on the escape latency and the number of crossings over the platform and protein levels of GABAB1 receptors, NF-kappaB, IL-1beta and TNFalpha were measured by immunohistochemistry assay and western blot. RESULTS: The neuronal apoptosis rate was significantly increased in N (49.16 +/- 3.12)%, SB + N (31.18 +/- 3.02)% and SN + N (28.47 +/- 3.75)% groups, accompanied by increased levels of GABAB1 receptors and NF-kappaB p65 (p < 0.05). The paclitaxel-treated rats demonstrated significantly increased latency (24.32 +/- 2.94)s and decreased the crossings number (3.14 +/- 0.63) after 15 d in the Morris water maze (p < 0.05). Immunohistochemistry assay showed that compared with the N group (GABAB1:9.0 +/- 1.6, NF-kappaB p65:29.6 +/- 2.4, IL-1beta: 30.4 +/- 3.4, TNFalpha: 31.0 +/- 3.4), B + N, SN + N and SN + B + N groups evidently increased levels of GABAB1 receptor (B + N:SN + N:SN + B + N = 19.4 +/- 2.1:20.8 +/- 1.9:28.0 +/- 1.9) but significantly decreased levels of NF-kappaB p65 (B + N:SN + N:SN + B + N = 21.2 +/- 1.5:18.6 +/- 2.1:12.6 +/- 1.5), IL-1beta (B + N:SN + N:SN + B + N = 22.0 +/- 1.0:19.6 +/- 1.8:14.6 +/- 1.5) and TNF alpha (B + N:SN + N:SN + B + N = 23.0 +/- 1.6:22.2 +/- 0.8:16.6 +/- 1.7). Similar findings were found in western blot analysis. DISCUSSIONS AND CONCLUSIONS: Paclitaxel may reduce cognitive function in rats through the p38MAPK/NF-kappaB pathway and GABAB1 receptors. PMID- 29115175 TI - Examining the relationship between health locus of control and God Locus of Health Control: Is God an internal or external source? AB - For many people, the influence of believing in a higher power can elicit powerful effects. This study examined the relationship between God control, health locus of control, and frequency of religious attendance within 838 college students through online surveys. Regression analysis showed that chance and external locus of control and frequency of religious attendance were significant and positive predictors of God Locus of Health Control. The association of powerful others external locus of control and God Locus of Health Control differed by race (stronger in non-Whites than Whites) and somewhat by gender (stronger in women than men). For some people, the role of a supreme being, or God, should be considered when designing programs for improving health behaviors. PMID- 29115176 TI - Interlaced strands: Health psychology in Brazil from an autobiographic perspective. AB - The presence of psychology in Brazilian Health Settings is closely related to two socio-political movements: for the creation of the Brazilian Unified Health System in 1990 and for Psychiatric Reform. Each had a multidisciplinary stance closely associated with a socially committed approach to healthcare delivery and connected with prior experiences that influenced its policies, among them the National AIDS Programme. These developments are told as a tale that interlaced autobiographical data and the long road to a universal healthcare system that shaped the relationship between psychology and health in the country. PMID- 29115174 TI - Theranostic Nanoparticles for Tracking and Monitoring Disease State. AB - The development of novel nanoparticles consisting of both diagnostic and therapeutic components has increased over the past decade. These "theranostic" nanoparticles have been tailored toward one or more types of imaging modalities and have been developed for optical imaging, magnetic resonance imaging, ultrasound, computed tomography, and nuclear imaging comprising both single photon computed tomography and positron emission tomography. In this review, we focus on state-of-the-art theranostic nanoparticles that are capable of both delivering therapy and self-reporting/tracking disease through imaging. We discuss challenges and the opportunity to rapidly adjust treatment for individualized medicine. PMID- 29115177 TI - The mediating effect of self-esteem on the relationship of living environment, anxiety, and depression of underprivileged children: A path analysis in Chinese context. AB - This study aimed to explore the relationships of living environment, self-esteem, anxiety, and depression of children in poverty. A sample of 1314 children (grades 4-9) was collected by a school-based survey in Xiushui city, Mainland China. Structural equation modeling was adopted to analyze the data and verify the hypothesized model. Results showed that living environment was negatively correlated with poor children's anxiety and depression levels, and self-esteem had a mediating effect on the relationship between living environment and the mental health of underprivileged children. Based on these findings, we proposed relevant theoretical and practical implications. PMID- 29115178 TI - Effects of silica nanoparticles on isolated rat uterine smooth muscle. AB - In spite of their widespread use, toxicity of silica nanoparticles (SiO2 NPs) to mammalian has not been extensively investigated. In the present study, it is aimed to investigate the effects and the mechanism of action of 20 nm sized SiO2 NPs on isolated uterine smooth muscle. A total number of 84 preparations of uterine strips were used in the experiments. Study was designed as four groups: group I (control), group II (0.2 mM SiO2 NPs), group III (0.4 mM SiO2 NPs) and group IV (0.8 mM SiO2 NPs). Spontaneous contractions were recorded using mechanical activity recording system. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were measured using the spectrophotometric methods. Apoptosis of the cells was detected using immunofluorescence staining assay. SiO2 NP distribution and ultrastructural changes were determined by transmission electron microscopy. In groups II-IV, the frequency of contraction was significantly lower than that of the group I, whereas the contraction energy significantly decreased only in group IV. SOD and GSH-Px activities were significantly lower in experimental groups compared to the control group. MDA level and apoptotic cells were significantly higher in all SiO2 groups compared to the control group. Numerous SiO2 NPs in cytoplasm and connective tissue were observed in all dose groups. These findings showed that 20 nm sized SiO2 NPs enter the connective tissue and cytoplasm of uterine muscle cells and cause oxidative stress and apoptosis leading to impaired uterine contractile activity. PMID- 29115179 TI - Global perspectives on dementia and art: An international discussion about changing public health policy. AB - In an era of global environmental deterioration and income inequity, public health faces many challenges, including the growing number of individuals, especially older people, with chronic diseases. Dementia is increasingly being seen not just as a biomedical problem to solve but as a public and community challenge to address more broadly. Concepts like prevention, brain health, and quality of life/well-being are receiving more attention. The engagement of community in addressing these challenges is being seen as critical to successful social adaptation. Arts programs are reinvigorating cultural responses to the growing number of older people with cognitive challenges. The humanities offer ways of understanding the power of words and stories in public discourse and a critical lens though which to view political and economic influences. In this paper, we report on a panel held in London on the occasion of the conference at the Royal Society for Public Health in March, 2017, in which the authors presented. Key issues discussed included problem framing, the nature of evidence, the politics of power and influence, and the development of effective interventions. In this paper, we review the rejection of two policies, one on dementia and one on the arts and humanities in public health, by the American Public Health Association; the emergence of policies in the UK; and some of the state of the art practices, particularly in training, again focusing on the UK. PMID- 29115180 TI - Identity and ownership issues in the regulation of autologous cells. AB - Clinical application of autologous cells by businesses promoting unproven stem cell treatments represents the largest growth sector in this problematic industry, but also presents special challenges to regulators. Patients frequently identify autologous cells as personal property, using the language of 'ownership'. Through an analysis of comments submitted to the US FDA in 2016 in response to recent draft guidance documents, I show that a sense of ownership and identity in autologous cells is consistently expressed by stakeholders. In the USA and other countries, regulation of cell and tissue biologics as 'drugs' relies substantially on whether a given product has been modified in ways that alter its biological properties, which has direct implications for property and ownership rights. Competing views on property rights in 'natural' and modified autologous cells have profound implications for the future of regulation of marketed autologous cells. PMID- 29115182 TI - Corrigendum. PMID- 29115181 TI - It's not me, it's you - Differential neural processing of social and non-social nogo cues in joint action. AB - This study used a joint flanker task to investigate differences in processing of social and non-social nogo cues, i.e., between cues indicating that a co-actor should respond and cues signaling that neither actor nor co-actor should respond, using event-related potentials (ERPs) and trial-to-trial response times (RTs). It was hypothesized that a social co-actor's response should be reflected in stronger modulation (slower RTs on subsequent trials; augmented neural responses) for social compared to non-social nogo. RTs and ERPs replicated flanker compatibility effects, with faster responses and increased P3a on compatible trials. In line with the hypotheses, ERPs revealed distinct coding of social and non-social nogo in the conflict-sensitive N2 which showed a compatibility effect only for social nogo, and in the attention/memory-related P3b which was larger for social relative to non-social nogo. The P3a did not distinguish between social and non-social nogo, but was larger for compatible and smaller for go trials. Contrary to our hypotheses, RTs were faster after social relative to non social nogo. Hence, the representation of the co-actor's response in joint action modulates conflict processing reflected in the N2 and response discrimination and evaluation reflected in the P3b and may facilitate subsequent responses in the context of social versus non-social nogo. PMID- 29115183 TI - Fake news portrayals of stem cells and stem cell research. AB - AIM: This study examines how stem cells and stem cell research are portrayed on websites deemed to be purveyors of distorted and dubious information. METHODS: Content analysis was conducted on 224 articles from 2015 to 2016, compiled by searching with the keywords 'stem cell(s)' on a list of websites flagged for containing either 'fake' or 'junk science' news. RESULTS: Articles contained various exaggerated positive and negative claims about stem cells and stem cell science, health and science related conspiracy theories, and statements promoting fear and mistrust of conventional medicine. CONCLUSION: Findings demonstrate the existence of organized misinformation networks, which may lead the public away from accurate information and facilitate a polarization of public discourse. PMID- 29115184 TI - Evaluation of Augmented Reality Feedback in Surgical Training Environment. AB - : Providing computer-based laparoscopic surgical training has several advantages that enhance the training process. Self-evaluation and real-time performance feedback are 2 of these advantages, which avoid dependency of trainees on expert feedback. The goal of this study was to investigate the use of a visual time indicator as real-time feedback correlated with the laparoscopic surgical training. Twenty novices participated in this study working with (and without) different presentations of time indicators. They performed a standard peg transfer task, and their completion times and muscle activity were recorded and compared. Also of interest was whether the use of this type of feedback induced any side effect in terms of motivation or muscle fatigue. RESULTS: Of the 20 participants, 15 (75%) preferred using a time indicator in the training process rather than having no feedback. However, time to task completion showed no significant difference in performance with the time indicator; furthermore, no significant differences in muscle activity or muscle fatigue were detected with/without time feedback. CONCLUSION: The absence of significant difference between task performance with/without time feedback shows that using visual real time feedback can be included in surgical training based on user preference. Trainees may benefit from this type of feedback in the form of increased motivation. The extent to which this can influence training frequency leading to performance improvement is a question for further study. PMID- 29115185 TI - Component studies of psychological treatments of adult depression: A systematic review and meta-analysis. AB - OBJECTIVES: A recent report from the US Institute of Medicine indicated that identifying core elements of psychosocial interventions is a key step in successfully bringing evidence-based psychosocial interventions into clinical practice. Component studies have the best design to examine these core elements. Earlier reviews resulted in heterogeneous sets of studies and probably missed many studies. METHODS: We conducted a comprehensive search of component studies on psychotherapies for adult depression and included 16 studies with 22 comparisons. RESULTS: Fifteen components were examined of which four were examined in more than one comparison. The pooled difference between the full treatments and treatments with one component removed was g = 0.21 (95% CI: 0.03~0.39). One study had sufficient statistical power to detect a small effect size and found that adding emotion regulation skills increased the effects of CBT. None of the other studies had enough power to detect an effect size smaller than g = 0.55. Only one study had low risk of bias. CONCLUSIONS: The currently available component studies do not have the statistical power nor the quality to draw any meaningful conclusion about key ingredients of psychotherapies for adult depression. PMID- 29115187 TI - Hyaluronate - parathyroid hormone peptide conjugate for transdermal treatment of osteoporosis. AB - Human parathyroid hormone 1-34 fragment (PTH1-34) has been used as a FDA-approved therapeutics to treat osteoporosis by daily subcutaneous injection. In this work, we successfully developed PTH1-34 conjugated hyaluronic acid (HA) for the transdermal treatment of osteoporosis with improved patient compliance. HA-PTH1 34 conjugate was synthesized by the coupling reaction between aldehyde group introduced to HA and amine group of PTH1-34. After characterization by gel permeation chromatography (GPC) and ELISA, the biological effect of HA-PTH1-34 conjugate on the proliferation of human osteoblast cells was confirmed by in vitro calcium colorimetric assay and cAMP assay. Two-photon microscopy clearly visualized the effective skin penetration of FITC modified HA-PTH1-34 conjugate. The transdermally delivered HA-PTH1-34 conjugates elevated the blood calcium concentration for more than 2 days, reflecting the feasibility for the treatment of osteoporosis. PMID- 29115188 TI - Sit-stand workstations and impact on low back discomfort: a systematic review and meta-analysis. AB - BACKGROUND: Sit-stand workstations are proposed solutions to reduce sedentary time at work. Numerous companies are using them to mitigate health concerns such as musculoskeletal discomfort. OBJECTIVE: To review the literature on sit-stand workstations and low back discomfort. METHOD: We conducted a meta-analysis on literature published before 17 November 2016 that addressed the relationship between sit-stand workstations and musculoskeletal discomfort, focusing on the low back. RESULTS: Twelve articles were identified and eight that presented results in means (SD) were included. Among a pain-free population, the standardised mean difference was -0.230 for low back discomfort with use of sit stand workstations. When applying the SMD to studies using the 10-point pain scale, the effect estimates ranged between -0.30 and -0.51. CONCLUSION: sit-stand workstations may reduce low back pain among workers. Further research is needed to help quantify dosage parameters and other health outcomes. Practitioner Summary: In a sedentary population, changing posture may reduce the chance of developing low back pain. The literature lacks studies on specific populations such as those who have pre-existing low back pain and also does not adequately address the dosage of sit-stand time required to help reduce pain. PMID- 29115189 TI - Neuropsychological feedback services improve quality of life and social adjustment. AB - OBJECTIVE: In more recent years, studies have begun to examine levels of satisfaction of individuals or family members of individuals who undergo neuropsychological evaluation. However, to date there have been only a handful of formal studies that have specifically examined the role and contribution of neuropsychological assessment in patient care and management. This study sought to examine one specific component of neuropsychological assessment, namely the impact of patient feedback regarding neuropsychological testing on patient outcome. METHOD: Participants included 218 patients who were recruited from a neuropsychological outpatient clinic at a Midwest academic medical center. This study examined potential differences between outcome measures for patients who attended feedback sessions versus those who did not receive direct feedback. RESULTS: Results indicated that compared with the No Feedback group, the Feedback group reported greater improvement in quality of life, increased understanding of their condition, and an increased ability to cope with their condition at follow up. There were no significant demographic differences between the Feedback and No Feedback group. CONCLUSIONS: These findings suggest that there is benefit for the individuals who chose to engage in feedback sessions. Feedback sessions can be utilized to assist with integral decision-making processes and assisting in treatment planning among other areas. It also allows time for patients and family members to discuss their concerns regarding important test findings and recommendations. Given the current climate of value-based services and clinical outcomes, the findings from this study lend support to the utility of neuropsychological assessments and, in particular, the role of feedback within neuropsychological evaluations. PMID- 29115190 TI - Cervical injury related to mandibular fractures. A retrospective study of 315 cases. AB - Objective To define the association between mandibular fractures and alterations of the cranio-atlo-axial joint (CAAJ). Methods 315 cases of displaced mandibular fractures were retrospectively evaluated by CT scan and cervical X-ray for associated alterations of the CAAJ. Statistical analysis employed the chi-square and Cohen's kappa coefficient. Results Single fractures amounted to 69.84% and multiple fractures to 30.16% of total fractures. CT scans showed a rotation of the atlas on the same side of single fractures and subluxation of the CAAJ. Vertical derangement of the joint was observed in 79.65% of single fractures and in 20.35% of multiple fractures. Approximately16.19% of all displaced mandibular fractures showed cervical disorders at long-term follow-up. Discussion The outcomes of this study revealed an association between traumatic mandibular fractures and CAAJ, accompanied by clinical disorders. These conditions require clinical attention due to their effects on long-term craniocervical functionality and future forensic issues. PMID- 29115191 TI - Risk factors for the efficacy of oral appliance for treating obstructive sleep apnea: A preliminary study. AB - OBJECTIVE: To identify potential risk factors of response to oral appliance in patients with obstructive sleep apnea (OSA). METHODS: Fifteen OSA patients were enrolled. Clinical characteristics, cephalometric measurements, and the results of home sleep testing were retrospectively obtained at baseline, and a sleep test was done again at the end of treatment. RESULTS: Twelve subjects were responders and three were non-responders. The diastolic blood pressure, minimum pulse rate, SNA (Angle between sella-nasion and nasion-A point), ANB (Anteroposterior maxilla/mandible discrepancy), and facial convexity of non-responders was higher than those of responders. Unlike AHI, non-responders showed a lower lowest oxygen saturation (%) than responders. DISCUSSION: Elevated diastolic pressure and minimal pulse rate, higher skeletal convexity and lowered lowest oxygen saturation might be risk factors to oral appliance efficacy in the OSA patients. More research in a large sample is needed to verify the results of the current study. PMID- 29115192 TI - A novel experimental paradigm to evaluate children and adolescents diagnosed with attention-deficit/hyperactivity disorder: Comparison with two standard neuropsychological methods. AB - INTRODUCTION: In this study we evaluated a recently developed test, the Ball Search Field Task (BSFT) as a neuropsychological tool for measuring cognitive and behavioral performance of individuals with disorders such as attention deficit/hyperactivity disorder (ADHD), which are frequently accompanied by cognitive deficits and a lack of behavioral inhibition. The task provides a complementary method of assessment that attempts ecological validity by drawing on challenges faced in real-world situations. In this task, energetic costs and gross sensorimotor feedback are involved, as participants are required to search for targets in a large open area. METHOD: We compared performance on the BSFT in a clinical sample of children and adolescents with a diagnosis of ADHD with their scores on two widely used neuropsychological tools, the Tower of London (ToLo) and the Behavior Rating Inventory of Executive Function (BRIEF). RESULTS: We found no correlations between scores on the BRIEF and those on either the BSFT or ToLo. However, we found moderate correlations between rule violations on ToLo and several BSFT variables, suggesting the capacity of these tests to detect common aspects of executive dysfunction. CONCLUSIONS: These findings, although modest, encourage further study of tasks like the BSFT, which may help assess cognitive dysfunction found in neurodevelopmental disorders such as ADHD in ecologically valid situations. PMID- 29115193 TI - Personality modulates amygdala and insula connectivity during humor appreciation: An event-related fMRI study. AB - Previous research and theory implicate that personality traits, such as extraversion and neuroticism, influence the processing of humor, as indicated by alterations in the activation of fronto-temporal and mesocorticolimbic brain regions during humor processing. In the current study, we sought to complement these findings by testing whether inter-individual differences in functional connectivity of humor-related brain regions are modulated by stable personality characteristics during humor processing. Using fMRI techniques, we studied 19 healthy subjects during the processing of standardized humorous and neutral cartoons. In order to isolate the specific effects of humor appreciation, subjective funniness ratings, collected during the scanning procedure, were implemented in the analysis as parametric modulation. Two distinct clusters in the right amygdala and the left insula were identified. Seed-to-voxel connectivity analysis investigating the effects of personality on inter individual differences in functional connectivity revealed that amygdala and insula connectivity with brain areas previously related to humor comprehension (e.g. middle temporal gyrus) and appreciation (e.g. caudate nucleus) were significantly modulated by personality dimensions. These results underscore the sensitivity of humor processing to moderating influences, such as personality, and call attention to the importance of brain connectivity measures for the investigation of inter-individual differences in the processing of humor. PMID- 29115194 TI - The development and pilot testing of a multicomponent health promotion intervention (SEHER) for secondary schools in Bihar, India. AB - BACKGROUND: Schools can play an important role in health promotion by improving students' health literacy, attitudes, health-related behaviours, social connection and self-efficacy. These interventions can be particularly valuable in low- and middle-income countries with low health literacy and high burden of disease. However, the existing literature provides poor guidance for the implementation of school-based interventions in low-resource settings. This paper describes the development and pilot testing of a multicomponent school-based health promotion intervention for adolescents in 75 government-run secondary schools in Bihar, India. METHOD: The intervention was developed in three stages: evidence review of the content and delivery of effective school health interventions; formative research to contextualize the proposed content and delivery, involving intervention development workshops with experts, teachers and students and content analysis of intervention manuals; and pilot testing in situ to optimize its feasibility and acceptability. RESULTS: The three-stage process defined the intervention elements, refining their content and format of delivery. This intervention focused on promoting social skills among adolescents, engaging adolescents in school decision making, providing factual information, and enhancing their problem-solving skills. Specific intervention strategies were delivered at three levels (whole school, student group, and individual counselling) by either a trained teacher or a lay counsellor. The pilot study, in 50 schools, demonstrated generally good acceptability and feasibility of the intervention, though the coverage of intervention activities was lower in the teacher delivery schools due to competing teaching commitments, the participation of male students was lower than that of females, and one school dropped out because of concerns regarding the reproductive and sexual health content of the intervention. CONCLUSION: This SEHER approach provides a framework for adolescent health promotion in secondary schools in low-resource settings. We are now using a cluster-randomized trial to evaluate its effectiveness and cost-effectiveness. PMID- 29115195 TI - Editorial: Investigate the Genetic and Environmental Interactions in Complex Systems with High Throughput Screening. PMID- 29115196 TI - Editorial: Computational Chemistry and Synthetic Strategy of the Design of Novel Monoamine Oxidase Inhibitors. PMID- 29115197 TI - The international scenario of terrorism. PMID- 29115198 TI - The consequences of unemployment on diet composition and purchase behaviour: a longitudinal study from Denmark. AB - OBJECTIVE: To explore and describe quantitatively the effect over time of unemployment on food purchase behaviour and diet composition. DESIGN: Longitudinal data from 2008-2012, with monthly food purchase data aligned with register data on unemployment measured as a dichotomous indicator as well as a trend accounting for the duration. SETTING: A household panel which registers daily food purchases combined with detailed nutritional information and registration of the duration of unemployment at individual level. The structure of the data set facilitates the detection of effects or associations between duration of unemployment and diet composition, purchase behaviour in terms of food expenditure, and share of food purchased on offer and in discounters while controlling for important confounding factors. SUBJECTS: Danish households of working age (n 3440) adjusted to household equivalents. We use fixed-effects econometric methods to control for unobserved heterogeneity. RESULTS: In the short run, unemployment led to substitution in favour of discount stores and increases in food expenditure and in consumption of saturated fat, total fat and protein due to increased consumption of animal-based foods. In the medium run food expenditure declined together with consumption of fresh animal-based foods and saturated fat, total fat and protein. In the even longer run these nutrients were substituted by carbohydrates and added sugar. CONCLUSIONS: Unemployment has a substantial influence on diet composition, but effects vary with duration of the unemployment period, which may have potential health implications. This ought to be taken into consideration in evaluations of existing reforms and in future reforms of welfare systems. PMID- 29115199 TI - The father-daughter relationship in the wake of maternal death from breast cancer. AB - OBJECTIVES: This paper examines whether a relationship exists between paternal psychological stability and daughters' symptomatology following the death of a wife/mother from breast cancer. Specifically, is there a relationship between paternal parenting style and the daughters' subsequent capacity to form committed relationships later in life? METHODS: We assessed 68 adult daughters (average age = 23.5 years) since the mother's breast cancer diagnosis by means of a semistructured clinical interview and psychological testing. RESULTS: The daughters were subdivided into three psychiatric risk groups. Those in the highest risk group were most likely to be single and to have high CES-Depression and STAI-Anxiety scores. Daughters in the highest risk group were also most likely to have fathers who abused substances, fathers who had experienced a serious psychiatric event, and families with the most closed communication about the mother's cancer. SIGNIFICANCE OF RESULTS: Psychopathology in fathers correlated with increasing anxiety and depression in adult daughters. Daughters at the highest level of risk had the most severe affective states, the most disturbed father-daughter bonding, and the least ability to create successful interpersonal relationships as adults. We suggest specific interventions for these daughters of the lowest-functioning fathers. PMID- 29115200 TI - Barley beta-glucan reduces blood cholesterol levels via interrupting bile acid metabolism. AB - Underlying mechanisms responsible for the cholesterol-lowering effect of beta glucan have been proposed, yet have not been fully demonstrated. The primary aim of this study was to determine whether the consumption of barley beta-glucan lowers cholesterol by affecting the cholesterol absorption, cholesterol synthesis or bile acid synthesis. In addition, this study was aimed to assess whether the underlying mechanisms are related to cholesterol 7alpha hydroxylase (CYP7A1) SNP rs3808607 as proposed by us earlier. In a controlled, randomised, cross-over study, participants with mild hypercholesterolaemia (n 30) were randomly assigned to receive breakfast containing 3 g high-molecular weight (HMW), 5 g low molecular weight (LMW), 3 g LMW barley beta-glucan or a control diet, each for 5 weeks. Cholesterol absorption was determined by assessing the enrichment of circulating 13C-cholesterol over 96 h following oral administration; fractional rate of synthesis for cholesterol was assessed by measuring the incorporation rate of 2H derived from deuterium oxide within the body water pool into the erythrocyte cholesterol pool over 24 h; bile acid synthesis was determined by measuring serum 7alpha-hydroxy-4-cholesten-3-one concentrations. Consumption of 3 g HMW beta-glucan decreased total cholesterol (TC) levels (P=0.029), but did not affect cholesterol absorption (P=0.25) or cholesterol synthesis (P=0.14). Increased bile acid synthesis after consumption of 3 g HMW beta-glucan was observed in all participants (P=0.049), and more pronounced in individuals carrying homozygous G of rs3808607 (P=0.033). In addition, a linear relationship between log (viscosity) of beta-glucan and serum 7alpha-HC concentration was observed in homozygous G allele carriers. Results indicate that increased bile acid synthesis rather than inhibition of cholesterol absorption or synthesis may be responsible for the cholesterol-lowering effect of barley beta-glucan. The pronounced TC reduction in G allele carriers of rs3808607 observed in the previous study may be due to enhanced bile acid synthesis in response to high viscosity beta-glucan consumption in those individuals. PMID- 29115201 TI - Reliability, concurrent validity, and cultural adaptation of the Geriatric Depression Scale and the Geriatric Anxiety Inventory for detecting depression and anxiety symptoms among older Chinese immigrants: an Australian study. AB - : ABSTRACTBackground:Older Chinese people are one of the largest and fastest growing immigrant groups in Western countries. The Geriatric Depression Scale (GDS) and the Geriatric Anxiety Inventory (GAI) are screening tools that have been specifically designed for older people. This study explored their validity, concurrent reliability, and cultural appropriateness for detecting depression and anxiety symptoms among older Chinese immigrants living in Melbourne, Australia. METHODS: A total of 87 Chinese people were recruited from Chinese senior groups. Five screening tools were used, including the GDS, the GAI, the Hospital Anxiety and Depression Scale (HADS), the Kessler 10 (K10), and the Patient Health Questionnaire (PHQ-9). Data were collected through standardized interviews. RESULTS: The GDS and the GAI were found to be reliable and valid tools for detecting depression and anxiety in this sample. Based on the results of the five screening tools, approximately 20% of participants exhibited clinically significant symptoms of depression and 8% of anxiety. Unexpectedly, there was a higher rate of depression and anxiety symptoms among Mandarin speaking people compared with Cantonese speaking people. CONCLUSION: This study adds to the evidence that older Chinese immigrants are at greater risk of depression than the general older population. It suggests that primary care and mental health services should be aware of and responsive to the increased risk of depression among this group and that further studies are needed to investigate what is contributing to this increased risk. PMID- 29115203 TI - Cholecystectomy for uncomplicated gallbladder stones does not follow evidence based recommendations. AB - INTRODUCTION: The introduction of laparoscopic cholecystectomy was followed by a steep increase in the cholecystectomy rate, which has remained on an unchanged, high level. The main indication for cholecystectomy in Denmark in cases with uncomplicated gallbladder stones is socially debilitating pain. The objective of the present study was to investigate whether the indication "socially debilitating pain" was reported in the patient's file when he or she was referred to surgery. METHODS: Hospital files for all patients referred to surgical evaluation for uncomplicated gallbladder stones from Odense University Hospital's service area (approximately 449,000 inhabitants) within a one-year period (2014) were reviewed. RESULTS: Among 1,003 eligible patients, a total of 516 met the inclusion criteria, 407 (78.9%) of whom underwent elective cholecystectomy. For only 89 (21.9%) of these 407 patients, the indication of socially debilitating pain was described in the patient files. CONCLUSIONS: Our results may represent overtreatment and/or incorrect selection of patients suitable for surgery. More and larger prospective cohort studies are warranted to elucidate the indications for cholecystectomy in uncomplicated gallbladder stones. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29115202 TI - Risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation. AB - BACKGROUND: Paediatric hospital-associated venous thromboembolism is a leading quality and safety concern at children's hospitals. OBJECTIVE: The aim of this study was to determine risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation. METHODS: We conducted a retrospective, case control study of children admitted to the cardiovascular intensive care unit at Johns Hopkins All Children's Hospital (St. Petersburg, Florida, United States of America) from 2006 to 2013. Hospital-associated venous thromboembolism cases were identified based on ICD-9 discharge codes and validated using radiological record review. We randomly selected two contemporaneous cardiovascular intensive care unit controls without hospital-associated venous thromboembolism for each hospital-associated venous thromboembolism case, and limited the study population to patients who had undergone cardiothoracic surgery or therapeutic cardiac catheterisation. Odds ratios and 95% confidence intervals for associations between putative risk factors and hospital-associated venous thromboembolism were determined using univariate and multivariate logistic regression. RESULTS: Among 2718 admissions to the cardiovascular intensive care unit during the study period, 65 met the criteria for hospital-associated venous thromboembolism (occurrence rate, 2%). Restriction to cases and controls having undergone the procedures of interest yielded a final study population of 57 hospital-associated venous thromboembolism cases and 76 controls. In a multiple logistic regression model, major infection (odds ratio=5.77, 95% confidence interval=1.06-31.4), age ?1 year (odds ratio=6.75, 95% confidence interval=1.13-160), and central venous catheterisation (odds ratio=7.36, 95% confidence interval=1.13-47.8) were found to be statistically significant independent risk factors for hospital-associated venous thromboembolism in these children. Patients with all three factors had a markedly increased post-test probability of having hospital-associated venous thromboembolism. CONCLUSION: Major infection, infancy, and central venous catheterisation are independent risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or cardiac catheter-based intervention, which, in combination, define a high-risk group for hospital-associated venous thromboembolism. PMID- 29115204 TI - Use of the smartphone application "Pregnant with Diabetes". AB - INTRODUCTION: The aim of this article was to evaluate the awareness and use of the smartphone application (app) "Pregnant with Diabetes" locally, nationally and internationally. METHODS: In 2013, a patient initiated collaboration with the staff at Centre for Pregnant Women with Diabetes, Rigs-hospitalet, to develop the app "Pregnant with Diabetes". The app communicates clinically important antenatal health information to women with diabetes, based on recommendations from our centre. Women with pre-existing diabetes (Type 1 and Type 2 diabetes) completed an anonymous, structured questionnaire at their first antenatal visit in early pregnancy at our centre. National and international data on numbers of downloads were obtained from Google Play, from the App Store and from Google Analytics. RESULTS: Among 139 pregnant women with diabetes (96 with Type 1 diabetes and 43 with Type 2 diabetes), 99% had a smartphone and 75% had downloaded the app, whereof 48% had obtained information from the app before their pregnancy. In July 2017, the app had been downloaded 4,465 times in Denmark and 27,361 times in a total of 183 countries. The topics most frequently visited were "diet and carbohydrates", "blood glucose" and "possible complications". CONCLUSIONS: Easily accessible patient information made available via app technology reaches the patients and may contribute to improved pregnancy planning and outcome in women with pre-existing diabetes - locally, nationally and internationally. FUNDING: The app was sponsored by Novo Nordisk, Bayer A/S, Diabetes Care, Abbott, MSD Denmark, A.D.I.P.S and Rigshospitalet. TRIAL REGISTRATION: not relevant. PMID- 29115205 TI - Falls in elderly patients are not treated according to national recommendations. AB - INTRODUCTION: The aim of this study was to evaluate health professionals' compliance with recommendations from the Danish Health Authority (DHA) concerning falls, to study the prevalence of acute hospital visits due to falls, and to compare characteristics of fall patients in two geographically and socioeconomically different areas of Denmark. METHODS: The study was conducted in the emergency departments (ED) of Slagelse Hospital (SH) and Nykobing Falster Hospital (NFH), both located in Denmark. Included were individuals > 50 years visiting the EDs from January 1 to March 31, 2014 who reported a fall. Information concerning demographic data and comorbidity in fall patients was retrieved from the medical records of the patients. RESULTS: A total of 2,664 individuals > 50 years visited the EDs during the study period. In all, 1,100 individuals (41.2%) reported a fall. In the NFH 236 (44%) and in the SH 223 (39%) of the fall patients had a fracture (p = 0.049). Patients in the more socioeconomically deprived area covered by the NFH were younger and had higher fracture and heart failure rates. Only 2% of the medical records contained answers to all four questions recommended by the DHA for risk screening in fall patients. The number of medical records containing answers to any of the four questions ranged from 17.5% to 25.8%. CONCLUSIONS: Only few fall patients were screened according to DHA recommendations. ED staff's adherence to guidelines concerning fall risk assessment is poor. Fall patients in a socioeconomically deprived area were younger and had higher fracture and heart failure incidences. FUNDING: This study received funding from the public Regional Research Foundation, Region Zealand, Denmark. TRIAL REGISTRATION: not relevant. PMID- 29115206 TI - Bronchoscopy in children suspected of lower airway aspiration. AB - INTRODUCTION: Foreign body aspiration (FBA) of the bronchial tree may be a life threatening condition in children. This retrospective study explores the anamnestic, clinical and objective findings in patients with FBA to the lungs and evaluates the frequency and outcome of the condition in patients in the age group of highest risk. METHOD: Medical files from patients below 18 years of age who had a foreign body removed from the lungs in our hospital were extracted using the procedure code for removal of foreign bodies in the lower airways ("Danish Patient Register") in the period 1990-2013. RESULTS: In the period, a total of 49 children underwent endoscopic foreign body extraction and for 29 of the patients, the files were available for clinical data collection. The median age was 19 months. In nine patients (33%), no symptoms were recorded at admission. Thoracic X-ray was pathologic in 19 (67%) and pulmonary auscultation in 21 patients (73%). Two patients (7%) were in need of post-operative anaesthetic support as a result of respiratory failure, and the over-all complication rate was 28% (eight patients). No fatal outcomes were observed. CONCLUSIONS: The majority of the children in our study were in the 0-3-year age group. A raised suspicion of a foreign body in the lower airways should always trigger bronchoscopy. At admittance, not all patients present with respiratory symptoms. Although no deaths were observed, lower airway foreign body in small children remain a potentially life-threatening condition. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29115207 TI - Self-evaluated competence in trauma reception. AB - INTRODUCTION: No formal training requirements exist for trauma teams in Denmark. The aim of this study was to investigate the point prevalence level of training and the self-evaluated competence of doctors involved in trauma care. METHODS: On two nights, all doctors on call at departments involved in trauma care were interviewed and answered a structured questionnaire pertaining to their level of training and self-evaluated level of competence in relevant skills. These skills included the ability to perform diagnostics and interventions as mandated by the Advanced Trauma Life Support and Definitive Surgical Trauma Care curriculums. RESULTS: All contacted doctors replied to the questionnaire. 58% of doctors were specialists; most often anaesthesiologists (AN) (86%) and doctors working at hospitals with a dedicated trauma centre designation (100%). In total, 45% of orthopaedic (OS) and gastrointestinal surgeons (GS) were specialists. In terms of self-evaluated competence, 95% of AN felt competent performing damage control resuscitation, 82% of OS felt competent performing damage control surgery on extremities, whereas 55% of GS felt competent performing damage control surgery in the abdomen. A total of 20% of the respondents had not attended any relevant trauma course, the majority of these were GS. CONCLUSIONS: The results indicate that, at the point of sampling, trauma reception in Denmark was handled by AN specialists in the majority of cases, but by surgical trainees. Self-perceived competencies evaluation revealed preparedness to perform damage control resuscitation, but discrepancies in the ability to perform surgical damage control procedures. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29115208 TI - Prevalence of neovascular age-related macular degeneration and geographic atrophy in Denmark. AB - INTRODUCTION: In Denmark, age-related macular degeneration (AMD) is the most common cause of blindness. To better understand current and future challenges, we estimated and projected the annual number of patients with neovascular AMD and geographic atrophy in Denmark from 2016 to 2060. METHODS: Detailed age- and gender-stratified prevalence estimates of neovascular AMD and geographic atrophy in a Scandinavian population were identified and applied to age- and gender stratified population numbers provided by Statistics Denmark. Prevalence estimates were calculated for each year from 2016 to 2060. Future forecasts were provided by Statistics Denmark and based on calculations by the Danish Institute for Economic Modelling and Forecasting. RESULTS: We estimated that there are currently ~30,000 patients with neovascular AMD and ~21,000 patients with geographic atrophy in Denmark. The majority of these patients are persons aged >= 85 years. For neovascular AMD, the number of patients will grow to ~33,000 in 2020, ~58,000 in 2040 and ~72,000 in 2060. For geographic atrophy, the number of patients will grow to ~23,000 in 2020, ~41,000 in 2040, and ~50,000 in 2060. CONCLUSIONS: We expect a steady growth in the prevalence of neovascular AMD and geographic atrophy in Denmark due to an ageing population. These numbers emphasise the importance of disease prevention, careful planning of health service activities and continuing research. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29115209 TI - Exploring the use of ingenol mebutate to prevent non-melanoma skin cancer. AB - Non-melanoma skin cancer is the most frequently occurring cancer in Caucasians today. Incidence rates in Europe have increased steadily since the 1960s and more than tripled over the last 50 years. Despite primary preventative efforts, incidences of non-melanoma skin cancer continue to rise and development of effective chemopreventative strategies is needed. In 2013, ingenol mebutate was approved in Denmark as a new topical drug for field-directed treatment for actinic keratoses. Ingenol mebutate has a dual mechanism of action, causing initial cell death, followed by an immune activation. The treatment induces an acute inflammation, manifesting as local skin responses, often accompanied by pain and pruritus. The severity of local skin responses for a given patient is unpredictable, and some individuals may develop insufferable inflammation. The overall aim of the thesis was to investigate if ingenol mebutate could be used as a chemopreventive agent to prevent development of non-melanoma skin cancer with minimal side effects. Specific aims included: Determine if ingenol mebutate can prevent progression of histological photodamage and squamous cell carcinoma (murine). Determine if ingenol mebutate can reverse clinical actinic damage in patients with multiple actinic keratoses and fieldcancerized skin (clinical). Determine if a topical glucocorticoid (clobetasol propionate) can reduce ingenol mebutate-induced local skin responses, pain, and pruritus without compromising the treatment efficacy (murine clinical). In two in vivo murine studies, ingenol mebutate's effect on photodamage and squamous cell carcinoma formation was investigated. Mice were irradiated with solar simulated ultraviolet radiation. During the first 20 weeks, 5 single applications with ingenol mebutate were given at four-week intervals with and without concurrent application of clobetasol propionate. Prophylactic treatments with ingenol mebutate prevented progression of histological photodamage of all investigated characteristics, including keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage. In addition, tumor formation was postponed by 3 weeks. In the clinical trial, patients with multiple actinic keratoses and field-cancerized skin were treated with ingenol mebutate, according to label, with and without sequential application of clobetasol propionate. Ingenol mebutate treatments were found to clear overall 86% of all actinic keratoses, exerting a therapeutic effect on all severity grades; cure rates were 88%, 70%, and 60% for Grade I, II, and III actinic keratoses, respectively. Ingenol mebutate treatments generated erythema, flaking, crusting, vesiculation, swelling/bleeding, and ulceration. Concurrent application of clobetasol propionate increased local skin responses in murine skin, likely due to an enhanced penetration of ingenol mebutate that resulted in a greater therapeutic effect compared to ingenol mebutate alone. In patients with actinic keratoses, sequential application of ingenol mebutate and clobetasol propionate did not reduce local skin responses, pain, or pruritus, nor did it affect treatment efficacy compared to ingenol mebutate alone. In conclusion, the thesis highlights ingenol mebutate's potential as a prophylactic remedy for non melanoma skin cancer with promise to support primary preventative efforts in reducing non-melanoma skin cancer incidence. PMID- 29115210 TI - Surgeon-performed ultrasonography. AB - Surgeons are increasingly using ultrasonography (US) in their clinical management of patients. However, US is a very user-dependent imaging modality and proper skills of the US operator are needed to ensure quality in patient care. This thesis explores the validity evidence for assessment of competence in abdominal and head & neck ultrasonography using the Objective Structured Assessment of Ultrasound Skills (OSAUS) scale. With the use of Messick's unitary framework of validity, five sources of validity evidence were explored: test content, response processes, inter-nal structure, relations to other variables, and consequences. Research paper I examined validity evidence for the use of the OSAUS scale to assess physicians' abdominal point-of-care US competence in an experimental setting using patient cases with and without pathological conditions. The RESULTS provided validity evidence of the internal structure of the OSAUS scale and a deci-sion study predicted that four cases and two raters or five cases and one rater could ensure sufficient reliability in future test setups. The relation to other variables was supported by a signifi-cant difference in scores between US experience levels, and by a strong correlation between the OSAUS score and diagnostic accuracy. Research paper II explored the transfer of learning from formal point-of-care US training to performance on patients in a randomized controlled study. The RESULTS supported validity evi-dence regarding OSAUS scores' relation to other variables by demonstrating a significant discrimination in the progress of training-a more refined validity evidence than the relation to difference experience levels. The RESULTS showed that physicians could transfer the skills learned on an ultrasonography course to improved US performance and diagnostic accuracy on patients. However, the RESULTS also indicated that following an initial course, additional training is needed for physicians to achieve competence in US. Research paper III evaluated validity evidence supporting an OSAUS score used to establish pass/fail standards for head & neck US skills. Good reliability between raters from different specialties to assess head & neck competence further supported the internal structure of OSAUS scale. A strong correla-tion to the diagnostic accuracy supported the relation to other variables and the consequences of the assessment were explored by a receiver operator characteristic curve for different pass/fail standards of head & neck US skills. In summary this PhD thesis established sources of validity evi-dence supporting the interpretation of the OSAUS scale to evalu-ate surgeon-performed US skills of the abdominal and head & neck diseases. We therefore recommend the OSAUS scale for formative in-training assessment and high-stakes summative decisions as certification for independent practice in surgeon-performed US. Further, we find formal "hands on" courses an essential part of initial US training with good transfer of learning to improved diagnostic accuracy. This thesis can therefore be used to support the move towards competency-based training in abdominal and head & neck US. PMID- 29115211 TI - Measurement of Gastrointestinal Hormones. AB - Towards the end of the 20th century, the number of subjects with diabetes and obesity rose exponentially. The discoveries of insulin- and appetite-modulating chemical signals, including glucagon-like peptide-1 (GLP-1), secreted from the gastrointestinal system, led to development of a new group of drugs which now are being used for glucose-lowering therapy and weight loss. Understanding of the physiology of gut derived signals and their pathophysiologi-cal importance requires accurate measurements of their circulat-ing levels. However, the assessment of these gut-derived hor-mones has been hampered by numerous preanalytical and analyti-cal challenges. We focused on three members of the proglucagon family; glucagon, oxyntomodulin and GLP-1, aiming to meet both preanalytical and analytical challenges and to elucidate their implication in diseases including diabetes. First, we studied (Study 1) the preanalytical and storage conditions of GLP-1 and glucagon in humans, demonstrating that inappropriate sample handling may cause up to 50% variation in the RESULTS. Using robust meas-uring METHODS ensuring optimal conditions for preanalytical han-dling of these peptides, we then focused on plasma concentra-tions of glucagon and oxyntomodulin in different clinical condi-tions, including type 2 diabetes and bariatric surgery, because abnormal secretion of these hormones may represent early and specific signs of altered glucose metabolism. To that end, we developed an unbiased mass-spectrometry based platform for detection of low-abundant peptides, including the gut hormones (Study 2). Using the platform, we validated a new method for the measurement of oxyntomodulin, and in a series of in vitro, ex vivo, and clinical studies, we demonstrated that oxyntomodulin is co distributed and co-secreted in response to glucose with GLP-1 and is degraded by dipeptidyl peptidase 4. Because oxyntomodulin has both GLP-1-like and glucagon like bioactivity, the secretion of this hormone is of interest in both type 2 diabetes and bariatric sur-gery. Furthermore, using these newly developed METHODS, we subsequently were able to establish that elevated plasma concen trations of glucagon (hyperglucagonemia) in diseases (Study 3) may be due to either a) increased secretion of fully processed glucagon, as in subjects with diabetes or b) secretion of N-terminally elongated molecular forms (Study 4) in conditions including bariatric surgery and in diseases affecting the kidneys. This glucagon variant may be of importance for glucose homeo-stasis, as we were able to show that it, unexpectedly, activates the glucagon receptor, leading to increased glycogenolysis in hepatocytes and insulin secretion from pancreatic beta-cells. In summary, accurate measurements of gut-derived hormones are indeed crucial for understanding their biology in health and as well in disease. Mass spectrometry based plasma proteomics is a powerful tool for the validation of these METHODS. PMID- 29115212 TI - Endemic influences of political regimes, healthcare systems, and preferences on the frequencies and incidences of nephropathies in eastern Saxony, Germany?. AB - INTRODUCTION: The possible confounding influence of investigator-related preferences, available histological techniques, and healthcare systems on the frequencies and incidences of primary and secondary nephropathies was evaluated in this long-term observation. MATERIALS AND METHODS: The observation time from 1983 to 2010 was divided in regard to the political regimes: a) prior to and after German reunification: German Democratic Republic (GDR, period 1 from 1983 to 1990)/Federal Republic of Germany (FRG, period 2 from 1990 to 2010); and the two heads of the division of nephrology, b) conductor 1 (1983 - 2006) and conductor 2 (2006 - 2010). 467 kidney biopsies at the University Hospital of Leipzig were included in our analysis. RESULTS: In period 1, due to the unavailability of immunofluorescence methods, mesangioproliferative glomerulonephritis (MesP) was the most dominating nephropathy. In period 2, IgA nephropathy (IgAN) was the most common nephropathy (17%). IgAN was followed by crescentic glomerulonephritis (13%), hypertensive nephropathy (10%), minimal change disease, and membranous glomerulonephritis (each 9%). From period 1 to period 2, MesP/IgAN (62% to 16%), membranoproliferative glomerulonephritis and postinfectious glomerulonephritis decreased significantly (p < 0.05). IgAN decreased significantly (p < 0.05) from conductor 1 to conductor 2 (21% to 6%), while diabetic nephropathy significantly increased. Focal-segmental glomerulosclerosis (FSGS) had the highest incidence rate with 1.0, followed by IgAN with 0.8 (per 100,000 per year). CONCLUSION: In a nearly ethnically identical cohort, we have demonstrated that confounding factors, e.g., healthcare systems and preferences of conductors, have a strong influence - more than 10 fold variance - on frequency and incidence on the spectrum of nephropathies.?. PMID- 29115214 TI - The next phase for adolescent health: from talk to action. PMID- 29115215 TI - Xi Jinping's roadmap for China prioritises health. PMID- 29115213 TI - Maintained avalanche dynamics during task-induced changes of neuronal activity in nonhuman primates. AB - Sensory events, cognitive processing and motor actions correlate with transient changes in neuronal activity. In cortex, these transients form widespread spatiotemporal patterns with largely unknown statistical regularities. Here, we show that activity associated with behavioral events carry the signature of scale invariant spatiotemporal clusters, neuronal avalanches. Using high-density microelectrode arrays in nonhuman primates, we recorded extracellular unit activity and the local field potential (LFP) in premotor and prefrontal cortex during motor and cognitive tasks. Unit activity and negative LFP deflections (nLFP) consistently changed in rate at single electrodes during tasks. Accordingly, nLFP clusters on the array deviated from scale-invariance compared to ongoing activity. Scale-invariance was recovered using 'adaptive binning', that is identifying clusters at temporal resolution given by task-induced changes in nLFP rate. Measures of LFP synchronization confirmed and computer simulations detailed our findings. We suggest optimization principles identified for avalanches during ongoing activity to apply to cortical information processing during behavior. PMID- 29115216 TI - Organ donor research: towards a more effective system. PMID- 29115217 TI - Protect trans people: gender equality and equity in action. PMID- 29115218 TI - The British 1967 Abortion Act-still fit for purpose? PMID- 29115219 TI - Offline: Dr Tedros, Robert Mugabe, and WHO. PMID- 29115220 TI - Frontline: caring for soldiers after the peace deal in Colombia. PMID- 29115221 TI - The African Population and Health Research Center. PMID- 29115222 TI - Dengue. PMID- 29115223 TI - Catherine Kyobutungi: leading African health research capacity. PMID- 29115224 TI - The 2014 Yazidi genocide and its effect on Yazidi diaspora. PMID- 29115225 TI - Snake bite in India: a neglected disease of poverty. PMID- 29115226 TI - Department of Error. PMID- 29115227 TI - Department of Error. PMID- 29115228 TI - Misoprostol drug to be withdrawn from French market. PMID- 29115229 TI - Improving mental health in the workplace. PMID- 29115230 TI - Counting down to climate change. PMID- 29115231 TI - The opioid crisis in the USA: a public health emergency. PMID- 29115232 TI - Indigenous health data and the path to healing. PMID- 29115233 TI - A call for planetary health case studies. PMID- 29115234 TI - Introducing a history of key trials in The Lancet. PMID- 29115235 TI - Offline: Medicine and Marx. PMID- 29115236 TI - Health commissioners under the Trump administration. PMID- 29115237 TI - Extending survival for people with hepatitis C using tobacco dependence treatment. PMID- 29115238 TI - Diet, atherosclerosis, and helmintic infection in Tsimane. PMID- 29115239 TI - Diet, atherosclerosis, and helmintic infection in Tsimane. PMID- 29115240 TI - Syphilis in children. PMID- 29115241 TI - Diet, atherosclerosis, and helmintic infection in Tsimane - Authors' reply. PMID- 29115242 TI - Stillbirth caused by syphilis remains a major global health problem. PMID- 29115244 TI - Brain in vain? PMID- 29115243 TI - Recurrent ascites: a need to evaluate for hereditary angio-oedema. PMID- 29115245 TI - What promotes psychiatric intervention implementation? PMID- 29115248 TI - Dixon Chibanda-"Taking mental health to the community". PMID- 29115246 TI - Uncharted territory. PMID- 29115249 TI - French psychiatrists and psychoanalysis in the era of evidence-based medicine. PMID- 29115250 TI - Atypical: a typical portrayal of autism? PMID- 29115251 TI - Black. PMID- 29115252 TI - Corrections. PMID- 29115253 TI - The imperative of vaccination. PMID- 29115254 TI - Infectious disease trends in China since the SARS outbreak. PMID- 29115255 TI - Threats of vector-borne zoonotic disease in Europe: dogs, drosophilids, and Oriental eye worm. PMID- 29115256 TI - Water, sanitation, and hygiene interventions: an urgent requirement in post-flood Nepal. PMID- 29115257 TI - The 2017 Dhaka chikungunya outbreak. PMID- 29115258 TI - Hospital antimicrobial stewardship: the way forward. PMID- 29115259 TI - Hospital antimicrobial stewardship: the way forward - Authors' reply. PMID- 29115260 TI - Hospital antimicrobial stewardship: the way forward. PMID- 29115261 TI - Proposed treatment strategies for non-gonococcal urethritis. PMID- 29115262 TI - Itraconazole and antiretroviral therapy: strategies for empirical dosing. PMID- 29115263 TI - Itraconazole and antiretroviral therapy: strategies for empirical dosing - Author's reply. PMID- 29115264 TI - Post-migration follow-up of migrants at risk of tuberculosis. PMID- 29115265 TI - WHO delays guinea-worm disease eradication to 2020: are dogs the sole culprits? PMID- 29115266 TI - HIV and antenatal care in Sri Lanka: a global health success. PMID- 29115267 TI - International Forum on Gonococcal Infections and Resistance. PMID- 29115268 TI - Antibiotic development pipeline slows to a trickle. PMID- 29115271 TI - Atypical presentation of post-kala-azar dermal leishmaniasis. PMID- 29115272 TI - Lung ultrasound and neonatal ARDS: is Montreux closer to Berlin than to Kigali? PMID- 29115273 TI - Lung ultrasound and neonatal ARDS: is Montreux closer to Berlin than to Kigali? - Authors' reply. PMID- 29115274 TI - BRAIN study: it is hard to draw a conclusion. PMID- 29115275 TI - BRAIN study: it is hard to draw a conclusion - Authors' reply. PMID- 29115276 TI - Defect-enhanced performance of a 3D graphene anode in a lithium-ion battery. AB - Morphological defects were generated in an undoped 3D graphene structure via the involvement of a ZnO and Mg(OH)2 intermediate nanostructure layer placed between two layers of vapor-deposited graphene. Once the intermediate layer was etched, the 3D graphene lost support and shrank; during this process many morphological defects were formed. The electrochemical performance of the derived defective graphene utilized as the anode of a lithium (Li)-ion battery was significantly improved from ~382 mAh g-1 to ~2204 mAh g-1 at 0.5 A g-1 compared to normal 3D graphene. The derived defective graphene exhibited an initial capacity of 1009 mAh g-1 and retention of 83% at 4 A g-1 for 500 cycles, and ~330 mAh g-1 at a high rate of 20 A g-1. Complicated defects such as wrinkles, pores, and particles formed during the etching of the intermediate layer, were considered to contribute to the improvement of the electrochemical performance. PMID- 29115277 TI - Low-cost and facile synthesis of Ni(OH)2/ZnO nanostructures for high-sensitivity glucose detection. AB - An efficient electrode for non-enzymatic glucose detection is produced with low cost techniques on a Cu wire. ZnO nanorods (NRs) were grown on a Cu wire by chemical bath deposition and were used as the substrate for pulsed electrodeposition of nanostructured Ni(OH)2 flakes. The effect of the electrodeposition potential on the final morphology and electrochemical behavior of the Ni(OH)2/ZnO/Cu structures is reported. ZnO NRs resulted to be well dressed by Ni(OH)2 flakes and were tested as glucose sensing electrodes in 0.1 M NaOH solution, showing high sensitivities (up to 3 mA mM-1 cm-2) and long-term stability. The presence of ZnO NRs was shown to improve the performance of the glucose sensor in terms of electrochemical stability over the time and sensitivity compared to Ni(OH)2/Cu sample. The reported data demonstrate a simple, versatile and low-cost fabrication approach for effective glucose sensing system within a urban mines framework. PMID- 29115278 TI - Self-standing ZnO nanotube/SiO2 core-shell arrays for high photon extraction efficiency in III-nitride emitter. AB - Self-standing ZnO nanotube (ZNT) arrays were fabricated on the surface of a GaN based emitter with an indium tin oxide (ITO) transparent layer using a hydrothermal method and temperature cooling down process. For the greater enhancement of photon extraction efficiency, ZNT/SiO2 core-shell nanostructure arrays were fabricated on the emitter with a 430 nm wavelength. The optical output power of ZNT/SiO2 core-shell arrays on the emitter with ITO electrode was remarkably enhanced by 18.5%, 28.1%, and 55.9%, compared to those of ZNTs, ZNRs on an ITO film on an emitter and ITO film on an emitter as a conventional emitter, respectively. The large enhancement in optical output is attributable to the synergistic effect of efficient photon injection from the ITO/GaN layer to ZNTs because of the well-matched refractive indices and wave-guiding, in addition to the superior photon extraction by the SiO2 coating layer on the ZNTs. PMID- 29115279 TI - Contamination-free Ge-based graphene as revealed by graphene enhanced secondary ion mass spectrometry (GESIMS). AB - In this study, we demonstrate that graphene grown on Ge does not contain any copper contamination, and identify some of the errors affecting the accuracy of commonly used measurement methods. Indeed, one of these, the secondary ion mass spectrometry (SIMS) technique, reveals copper contamination in Ge-based graphene but does not take into account the effect of the presence of the graphene layer. We have shown that this layer increases negative ionization significantly, and thus yields false results, but also that the graphene enhances, by an order of two, the magnitude of the intensity of SIMS signals when compared with a similar graphene-free sample, enabling much better detection limits. This forms the basis of a new measurement procedure, graphene enhanced SIMS (GESIMS) (pending European patent application no. EP 16461554.4), which allows for the precise estimation of the realistic distribution of dopants and contamination in graphene. In addition, we present evidence that the GESIMS effect leads to unexpected mass interferences with double-ionized species, and that these interferences are negligible in samples without graphene. The GESIMS method also shows that graphene transferred from Cu results in increased copper contamination. PMID- 29115280 TI - Real-time cerebellar neuroprosthetic system based on a spiking neural network model of motor learning. AB - OBJECTIVE: Damage to the brain, as a result of various medical conditions, impacts the everyday life of patients and there is still no complete cure to neurological disorders. Neuroprostheses that can functionally replace the damaged neural circuit have recently emerged as a possible solution to these problems. Here we describe the development of a real-time cerebellar neuroprosthetic system to substitute neural function in cerebellar circuitry for learning delay eyeblink conditioning (DEC). APPROACH: The system was empowered by a biologically realistic spiking neural network (SNN) model of the cerebellar neural circuit, which considers the neuronal population and anatomical connectivity of the network. The model simulated synaptic plasticity critical for learning DEC. This SNN model was carefully implemented on a field programmable gate array (FPGA) platform for real-time simulation. This hardware system was interfaced in in vivo experiments with anesthetized rats and it used neural spikes recorded online from the animal to learn and trigger conditioned eyeblink in the animal during training. MAIN RESULTS: This rat-FPGA hybrid system was able to process neuronal spikes in real-time with an embedded cerebellum model of ~10 000 neurons and reproduce learning of DEC with different inter-stimulus intervals. Our results validated that the system performance is physiologically relevant at both the neural (firing pattern) and behavioral (eyeblink pattern) levels. SIGNIFICANCE: This integrated system provides the sufficient computation power for mimicking the cerebellar circuit in real-time. The system interacts with the biological system naturally at the spike level and can be generalized for including other neural components (neuron types and plasticity) and neural functions for potential neuroprosthetic applications. PMID- 29115281 TI - Fluorescence detection, enumeration and characterization of single circulating cells in vivo: technology, applications and future prospects. AB - There are many diseases and biological processes that involve circulating cells in the bloodstream, such as cancer metastasis, immune reaction/inflammation, reproductive medicine, and stem cell therapies. This has driven significant interest in new technologies for the study of circulating cells in small animal research models and clinically. Most currently used methods require drawing and enriching blood samples from the body, but these suffer from a number of limitations. In contrast, "in vivo flow cytometry" (IVFC) refers to set of technologies that allow study of cells directly in the bloodstream of the organism in vivo. In recent years the IVFC field has grown significantly and new techniques have been developed, including fluorescence microscopy, multi-photon, photo-acoustic, and diffuse fluorescence IVFC. In this paper we review recent technical advances in IVFC, with emphasis on instrumentation, contrast mechanisms, and detection sensitivity. We also describe key applications in biomedical research, including cancer research and immunology. Last, we discuss future directions for IVFC, as well as prospects for broader adoption by the biomedical research community and translation to humans clinically. PMID- 29115282 TI - Fast and slow thermal processes in harmonic scalar lattices. AB - An approach for analytical description of thermal processes in harmonic lattices is presented. We cover longitudinal and transverse vibrations of chains and out of-plane vibrations of two-dimensional lattices with interactions of an arbitrary number of neighbors. The motion of each particle is governed by a single scalar equation and therefore the notion 'scalar lattice' is used. The evolution of initial temperature field in an infinite lattice is investigated. An exact equation describing the evolution is derived. Continualization of this equation with respect to spatial coordinates is carried out. The resulting continuum equation is solved analytically. The solution shows that the kinetic temperature is represented as the sum of two terms, one describing short time behavior, the other large time behavior. At short times, the temperature performs high frequency oscillations caused by redistribution of energy among kinetic and potential forms (fast process). Characteristic time of this process is of the order of ten periods of atomic vibrations. At large times, changes of the temperature are caused by ballistic heat transfer (slow process). The temperature field is represented as a superposition of waves having the shape of initial temperature distribution and propagating with group velocities dependent on the wave vector. Expressions describing fast and slow processes are invariant with respect to substitution t by [Formula: see text]. However, examples considered in the paper demonstrate that these processes are irreversible. Numerical simulations show that presented theory describes the evolution of temperature field at short and large time scales with high accuracy. PMID- 29115283 TI - Ambipolar thermoelectric power of chemically-exfoliated RuO2 nanosheets. AB - The electrical conductivity and Seebeck coefficient of RuO2 nanosheets are enhanced by metal nanoparticle doping using Ag-acetate solutions. In this study, RuO2 monolayer and bilayer nanosheets exfoliated from layered alkali metal ruthenates are transferred to Si substrates for device fabrication, and the temperature dependence of their conductivity and Seebeck coefficients is investigated. For pristine RuO2 nanosheets, the sign of the Seebeck coefficient changes with temperature from 350-450 K. This indicates that the dominant type of charge carrier is dependent on the temperature, and the RuO2 nanosheets show ambipolar carrier transport behavior. By contrast, the sign of the Seebeck coefficient for Ag nanoparticle-doped RuO2 nanosheets does not change with temperature, indicating that the extra charge carriers from metal nanoparticles promote n-type semiconductor behavior. PMID- 29115284 TI - Double-edged effect of electric field on the mechanical property of water-filled carbon nanotubes with an application to nanoscale trigger. AB - Polar water molecules would exhibit extraordinary phenomena under nanoscale confinement. By means of electric field, the water-filled carbon nanotube (CNT) that has been successfully fabricated in laboratory is expected to make distinct responses to the external electricity. Here, we examine the effect of electric field direction on the mechanical property of water-filled CNTs. It is found that the longitudinal electric field enhances but the transversal electric field reduces the elastic modulus and critical buckling stress of water-filled CNTs. The double-edged effect of electric field is attributed to the competition between the axial and circumferential pressures induced by polar water molecules. Furthermore, it is notable that the transversal electric field could result in an internal pressure with elliptical distribution, which is an effective and convenient approach to apply the nonuniform pressure on nanochannels. Based on a pre-strained water-filled CNTs, we design a nanoscale trigger with the evident and rapid height change started through switching the direction of electric field. The reported finding lays a foundation for the electricity-controlled property of nanochannels filled with polar molecules and provides an insight into the design of nanoscale functional devices. PMID- 29115285 TI - Indium selenide monolayer: strain-enhanced optoelectronic response and dielectric environment-tunable 2D excitons features. AB - Electronic and optical performances of beta-InSe monolayer (ML) are considerably boosted by tuning the corresponding band energies through the lattice in-plane compressive strain engineering. First principle calculations show an indirect direct gap transition with large band gap size. The crossover is due to different responses of the near-gap state energies with respect to strain. This is explained by the variation of In-Se bond length, the bond nature of near-band edge electronic orbital and of the momentum angular contribution versus in-plane compressive strain. Effective masses of charge carriers are also found to be highly modulated and significantly light at the indirect-direct gap transition. Tuned optical response of the resulting direct gap ML beta-InSe is evaluated versus applied energy to infer the allowed optical transitions, dielectric constants, semiconductor-metal behavior and refractive index. Environmental dielectric engineering of exciton behavior of the resulting direct gap ML beta InSe is handled within the effective mass Wannier-Mott model and is expected to be important. Our results highlight the increase of binding energy and red shifted exciton energy with decreasing screening substrates resulting in a stable exciton at room temperature .Intensity and energy of the ground state exciton emission are expected to be strongly influenced under substrates screening effect. According to our findings, the direct gap ML beta-InSe assures a tremendous 2D optoelectronic and nanoelectronic merits that could overcome several limitations of unstrained ML beta-InSe. PMID- 29115286 TI - Genetic predictors associated with diabetic retinopathy in patients with diabetic foot. AB - INTRODUCTION Early detection of diabetic retinopathy (DR) is crucial for preventing irreversible blindness. Recent studies identified some of the genetic factors involved in the pathology of DR, although their precise underlying mechanisms remain unclear. OBJECTIVES This pilot study aimed to determine genetic predictors of DR among patients with type 2 diabetes (T2D) and diabetic foot (DF) based on pathogenetic pathways. PATIENTS AND METHODS The study included 114 patients with T2D and DF (64 with DR, 50 without DR). Genetic analysis was performed for each patient and the following alterations were analyzed: rs759853 (AKR1B1), rs1800469 (TGFB1), rs2073618 and rs3134069 (TNFRSF11B), rs6330 and rs11466112 (NGF), rs1801133 (MTHFR), rs8192678 (PPARGC1A), rs1799983 (NOS3), rs1553005 (CALCA), and rs121917832 (CDKN1B). RESULTS Correlations with DR were identified for the following single nucleotide variants (SNVs): rs759853, rs2073618, and rs3134069. Carriers of the G allele of the rs759853 variant had a higher risk of DR in the dominant model (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.15-7.81; P = 0.02). We analyzed 2 SNVs of the osteoprotegerin gene (rs3134069 and rs2073618), and found that the A allele of the rs3134069 variant decreased the risk of DR in both the recessive and additive models (OR, 3.33; 95% CI, 1.07-10.3; P = 0.04). Conversely, there were fewer carriers of the C allele of the rs2073618 variant in patients with DR in the dominant model (OR, 0.28; 95% CI, 0.09-0.92; P = 0.04). CONCLUSIONS The results of our study suggest that the SNVs rs759853, rs3134069, and rs2073618 may be involved in the development of DR in patients with T2D and DF. PMID- 29115287 TI - Consumer product chemical weight fractions from ingredient lists. AB - Assessing human exposures to chemicals in consumer products requires composition information. However, comprehensive composition data for products in commerce are not generally available. Many consumer products have reported ingredient lists that are constructed using specific guidelines. A probabilistic model was developed to estimate quantitative weight fraction (WF) values that are consistent with the rank of an ingredient in the list, the number of reported ingredients, and labeling rules. The model provides the mean, median, and 95% upper and lower confidence limit WFs for ingredients of any rank in lists of any length. WFs predicted by the model compared favorably with those reported on Material Safety Data Sheets. Predictions for chemicals known to provide specific functions in products were also found to reasonably agree with reported WFs. The model was applied to a selection of publicly available ingredient lists, thereby estimating WFs for 1293 unique ingredients in 1123 products in 81 product categories. Predicted WFs, although less precise than reported values, can be estimated for large numbers of product-chemical combinations and thus provide a useful source of data for high-throughput or screening-level exposure assessments. PMID- 29115288 TI - Child environmental exposures to water and sand at the beach: Findings from studies of over 68,000 subjects at 12 beaches. AB - Swimming and recreating in lakes, oceans, and rivers is common, yet the literature suggests children may be at greater risk of illness following such exposures. These effects might be due to differences in immunity or differing behavioral factors such as poorer hygiene, longer exposures to, and greater ingestion of potentially contaminated water and sand. We pooled data from 12 prospective cohorts (n=68,685) to examine exposures to potentially contaminated media such as beach water and sand among children compared with adults, and conducted a simulation using self-reported time spent in the water and volume of water swallowed per minute by age to estimate the total volume of water swallowed per swimming event by age category. Children aged 4-7 and 8-12 years had the highest exposures to water, sand, and algae compared with other age groups. Based on our simulation, we found that children (6-12 years) swallow a median of 36 ml (90th percentile=150 ml), whereas adults aged >=35 years swallow 9 ml (90th percentile=64 ml) per swimming event, with male children swallowing a greater amount of water compared with females. These estimates may help to reduce uncertainty surrounding routes and durations of recreational exposures and can support the development of chemical and microbial risk assessments. PMID- 29115289 TI - Synthesis and antibacterial activity of novel lincomycin derivatives. IV. Optimization of an N-6 substituent. AB - The design and synthesis of lincomycin derivatives modified at the C-6 and C-7 positions are described. A substituent at the C-7 position is a 5-aryl-1,3,4 thiadiazol-2-yl-thio group that generates antibacterial activities against macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes carrying an erm gene. An additional modification at the C-6 position was explored in application of information regarding pirlimycin and other related compounds. These dual modifications were accomplished by using methyl alpha thiolincosaminide as a starting material. As a result of these dual modifications, the antibacterial activities were improved compared with those of compounds with a single modification at the C-7 position. The antibacterial activities of selected compounds in this report against macrolide-resistant S. pneumoniae and S. pyogenes with an erm gene were superior to those of telithromycin. PMID- 29115290 TI - Additively manufactured hierarchical stainless steels with high strength and ductility. AB - Many traditional approaches for strengthening steels typically come at the expense of useful ductility, a dilemma known as strength-ductility trade-off. New metallurgical processing might offer the possibility of overcoming this. Here we report that austenitic 316L stainless steels additively manufactured via a laser powder-bed-fusion technique exhibit a combination of yield strength and tensile ductility that surpasses that of conventional 316L steels. High strength is attributed to solidification-enabled cellular structures, low-angle grain boundaries, and dislocations formed during manufacturing, while high uniform elongation correlates to a steady and progressive work-hardening mechanism regulated by a hierarchically heterogeneous microstructure, with length scales spanning nearly six orders of magnitude. In addition, solute segregation along cellular walls and low-angle grain boundaries can enhance dislocation pinning and promote twinning. This work demonstrates the potential of additive manufacturing to create alloys with unique microstructures and high performance for structural applications. PMID- 29115291 TI - Maintenance of neural progenitor cell stemness in 3D hydrogels requires matrix remodelling. AB - Neural progenitor cell (NPC) culture within three-dimensional (3D) hydrogels is an attractive strategy for expanding a therapeutically relevant number of stem cells. However, relatively little is known about how 3D material properties such as stiffness and degradability affect the maintenance of NPC stemness in the absence of differentiation factors. Over a physiologically relevant range of stiffness from ~0.5 to 50 kPa, stemness maintenance did not correlate with initial hydrogel stiffness. In contrast, hydrogel degradation was both correlated with, and necessary for, maintenance of NPC stemness. This requirement for degradation was independent of cytoskeletal tension generation and presentation of engineered adhesive ligands, instead relying on matrix remodelling to facilitate cadherin-mediated cell-cell contact and promote beta-catenin signalling. In two additional hydrogel systems, permitting NPC-mediated matrix remodelling proved to be a generalizable strategy for stemness maintenance in 3D. Our findings have identified matrix remodelling, in the absence of cytoskeletal tension generation, as a previously unknown strategy to maintain stemness in 3D. PMID- 29115292 TI - Fibronectin-bound alpha5beta1 integrins sense load and signal to reinforce adhesion in less than a second. AB - Integrin-mediated mechanosensing of the extracellular environment allows cells to control adhesion and signalling. Whether cells sense and respond to force immediately upon ligand-binding is unknown. Here, we report that during adhesion initiation, fibroblasts respond to mechanical load by strengthening integrin mediated adhesion to fibronectin (FN) in a biphasic manner. In the first phase, which depends on talin and kindlin as well as on the actin nucleators Arp2/3 and mDia, FN-engaged alpha5beta1 integrins activate focal adhesion kinase (FAK) and c Src in less than 0.5 s to steeply strengthen alpha5beta1- and alphaV-class integrin-mediated adhesion. When the mechanical load exceeds a certain threshold, fibroblasts decrease adhesion and initiate the second phase, which is characterized by less steep adhesion strengthening. This unique, biphasic cellular adhesion response is mediated by alpha5beta1 integrins, which form catch bonds with FN and signal to FN-binding integrins to reinforce cell adhesion much before visible adhesion clusters are formed. PMID- 29115293 TI - Intracellular production of hydrogels and synthetic RNA granules by multivalent molecular interactions. AB - Some protein components of intracellular non-membrane-bound entities, such as RNA granules, are known to form hydrogels in vitro. The physico-chemical properties and functional role of these intracellular hydrogels are difficult to study, primarily due to technical challenges in probing these materials in situ. Here, we present iPOLYMER, a strategy for a rapid induction of protein-based hydrogels inside living cells that explores the chemically inducible dimerization paradigm. Biochemical and biophysical characterizations aided by computational modelling show that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that acts as a size-dependent molecular sieve. We functionalize these polymers with RNA-binding motifs that sequester polyadenine containing nucleotides to synthetically mimic RNA granules. These results show that iPOLYMER can be used to synthetically reconstitute the nucleation of biologically functional entities, including RNA granules in intact cells. PMID- 29115294 TI - Placental growth factor and pre-eclampsia. AB - Placental growth factor (PlGF) is an increasingly important molecule in the prediction, diagnosis and treatment of pre-eclampsia. It has pro-angiogenic effects on the feto-placental circulation and supports trophoblast growth. Mechanisms by which PlGF expression is regulated continue to be investigated. Low circulating PlGF precedes the manifestation of clinical disease in pre-eclamptic pregnancies and intrauterine growth restriction. This suggests that low PlGF is a marker of abnormal placentation, but it remains uncertain whether this is a cause or consequence. Prediction of pre-eclampsia using PlGF is promising and may assist in the targeting of resources to women at highest risk of adverse pregnancy outcomes. Promisingly, experimental animal models of pre-eclampsia have been successfully treated with supplemental PlGF. Treatment of pre-eclampsia with PlGF is a potential therapeutic option requiring further exploration. This review focuses specifically on the role of PlGF in normal and pathological placental development and in the clinical management of pre-eclampsia. PMID- 29115295 TI - Central blood pressure in children and adolescents: non-invasive development and testing of novel transfer functions. AB - Central blood pressure can be estimated from peripheral pulses in adults using generalised transfer functions (TF). We sought to create and test age-specific non-invasively developed TFs in children, with comparison to a pre-existing adult TF. We studied healthy children from two sites at two time points, 8 and 14 years of age, split by site into development and validation groups. Radial and carotid pressure waveforms were obtained by applanation tonometry. Central systolic pressure was derived from carotid waveforms calibrated to brachial mean and diastolic pressures. Age-specific TFs created in the development groups (n=50) were tested in the validation groups aged 8 (n=137) and 14 years (n=85). At 8 years of age, the age-specific TF estimated 82, 99 and 100% of central systolic pressure values within 5, 10 and 15 mm Hg of their measured values, respectively. This TF overestimated central systolic pressure by 2.2 (s.d. 3.7) mm Hg, compared to being underestimated by 5.6 (s.d. 3.9) mm Hg with the adult TF. At 14 years of age, the age-specific TF estimated 60, 87 and 95% of values within 5, 10 and 15 mm Hg of their measured values, respectively. This TF underestimated central systolic pressure by 0.5 (s.d. 6.7) mm Hg, while the adult TF underestimated it by 6.8 (s.d. 6.0) mm Hg. In conclusion, age-specific TFs more accurately predict central systolic pressure measured at the carotid artery in children than an existing adult TF. PMID- 29115296 TI - Fully automated chemiluminescence vs RIA aldosterone assay in primary aldosteronism work-up. AB - Aldosterone and renin measurement is a cornerstone for primary aldosteronism (PA) diagnosis, but different thresholds are used according to different assays. A fully automated chemiluminescence (CL) immunoassay for renin and aldosterone was recently proposed, showing good performance for PA screening by aldosterone to renin ratio (ARR). This study aimed to define the accuracy of this assay in the screening and in the most popular confirmatory test of autonomous aldosterone production, the intravenous saline loading test (ivSLT). We compared aldosterone results obtained by CL vs radioimmunoassay (RIA) in hypertensive patients investigated for PA (102 baseline and 85 after ivSLT). An excellent correlation was observed between RIA and CL in the entire population for aldosterone (r=0.922) and ARR (r=0.977). For ARR, Deming regression proved a good accordance between methods and, consistent with the fit model, our previous institutional ARR cut-off of 32 (pg ml-1)/(pg ml-1) corresponded to 20 pg ml-1 mU-1 l-1 in CL assay. However, the correlation was weaker in the low end of aldosterone concentrations (r=0.676 for aldosterone <100 pg ml-1), with a concordance of ivSLT results in only 68% of patients. CL assay displays a diagnostic performance very similar to RIA for ARR screening, but it is substantially inferior in the setting of confirmatory tests of autonomous aldosterone secretion, that is, ivSLT. PMID- 29115297 TI - Applying recovery biomarkers to calibrate self-report measures of sodium and potassium in the hispanic community health study/study of latinos. AB - This corrects the article DOI: 10.1038/jhh.2016.98. PMID- 29115299 TI - Translation: Immature ribosomes under surveillance. PMID- 29115300 TI - Publisher correction: The essential kinase ATR: ensuring faithful duplication of a challenging genome. PMID- 29115298 TI - Mechanobiology of collective cell behaviours. AB - The way in which cells coordinate their behaviours during various biological processes, including morphogenesis, cancer progression and tissue remodelling, largely depends on the mechanical properties of the external environment. In contrast to single cells, collective cell behaviours rely on the cellular interactions not only with the surrounding extracellular matrix but also with neighbouring cells. Collective dynamics is not simply the result of many individually moving blocks. Instead, cells coordinate their movements by actively interacting with each other. These mechanisms are governed by mechanosensitive adhesion complexes at the cell-substrate interface and cell-cell junctions, which respond to but also further transmit physical signals. The mechanosensitivity and mechanotransduction at adhesion complexes are important for regulating tissue cohesiveness and thus are important for collective cell behaviours. Recent studies have shown that the physical properties of the cellular environment, which include matrix stiffness, topography, geometry and the application of external forces, can alter collective cell behaviours, tissue organization and cell-generated forces. On the basis of these findings, we can now start building our understanding of the mechanobiology of collective cell movements that span over multiple length scales from the molecular to the tissue level. PMID- 29115302 TI - Drug development for noncastrate prostate cancer in a changed therapeutic landscape. AB - This corrects the article DOI: 10.1038/nrclinonc.2017.160. PMID- 29115303 TI - Immunotherapy: Nivolumab-induced alterations revealed. PMID- 29115301 TI - Mechanical forces direct stem cell behaviour in development and regeneration. AB - Stem cells and their local microenvironment, or niche, communicate through mechanical cues to regulate cell fate and cell behaviour and to guide developmental processes. During embryonic development, mechanical forces are involved in patterning and organogenesis. The physical environment of pluripotent stem cells regulates their self-renewal and differentiation. Mechanical and physical cues are also important in adult tissues, where adult stem cells require physical interactions with the extracellular matrix to maintain their potency. In vitro, synthetic models of the stem cell niche can be used to precisely control and manipulate the biophysical and biochemical properties of the stem cell microenvironment and to examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights into the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies. PMID- 29115305 TI - Correction: Confirmatory Factor Analysis of the Finnish Job Content Questionnaire (JCQ) in 590 Professional Musicians. AB - In some points in the article, the "repetitive work" should have been read "opinions influential." The current version of the article on the Journal Web site and the MEDLINE records are correct. PMID- 29115306 TI - Polymer brushes on structural surfaces: a novel synergistic strategy for perfectly resisting algae settlement. AB - The current paper reports a novel model of a marine antibiofouling surface based on polymer brushes on a wrinkled silicone elastomer. Polymer brushes (POEGMA and PSPMA) were grafted via surface-initiated atom transfer radical polymerization (SI-ATRP). Successful grafting was verified with various characterization techniques including infrared spectroscopy, X-ray photoelectron spectroscopy and contact angle measurements. A series of laboratory static and dynamic bioassays as well as field immersion tests were carried out to systematically investigate the relationship between surface chemistry, surface topography and antifouling properties. The results indicated that the adhesion of marine organisms was strongly influenced by the surface chemistry composition and surface topography structure. The synergistic effect of the surface chemistry, surface topography and bulk properties of the substrates endowed the new marine coatings with excellent antifouling properties. PMID- 29115307 TI - Spin-dependent electron transport in C and Ge doped BN monolayers. AB - Recent advances in the synthesis and characterization of h-BN monolayers offer opportunities to tailor their electronic properties via aliovalent substitutions in the lattice. In this paper, we consider a h-BN monolayer doped with C or Ge, and find that dopants modify the Fermi level of the pristine monolayer. Three fold coordinated dopants relax to the convex-shaped structures, while four-fold coordinated ones retain the planar structures. These modifications, in turn, lead to unique features in the electron transport characteristics including significant enhancement of current at the dopant site, diode-like asymmetric current-voltage response, and spin-dependent current. We find that the spin polarized transport properties of the doped BN monolayers could be used for the next-generation devices at the nanoscale. PMID- 29115304 TI - Tumour heterogeneity and resistance to cancer therapies. AB - Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells harbouring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumour-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity). Heterogeneity provides the fuel for resistance; therefore, an accurate assessment of tumour heterogeneity is essential for the development of effective therapies. Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of liquid biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. In this Review, we discuss the driving forces behind intratumoural heterogeneity and the current approaches used to combat this heterogeneity and its consequences. We also explore how clinical assessments of tumour heterogeneity might facilitate the development of more-effective personalized therapies. PMID- 29115309 TI - Structural reconstruction: a milestone in the hydrothermal synthesis of highly active Sn-Beta zeolites. AB - A novel structural reconstruction strategy is proposed to prepare an active Sn Beta catalyst with high Sn contents and a hydrophobic nature. Compared with post synthesized Sn-Beta and state-of-the-art classic fluoride-mediated Sn-Beta-F, this Sn-Beta zeolite exhibits unparalleled active site-based turnover frequency for desirable products and in particular catalyst weight-based space-time-yields in various redox reactions of ketones. PMID- 29115308 TI - Introducing multiple bio-functional groups on the poly(ether sulfone) membrane substrate to fabricate an effective antithrombotic bio-interface. AB - It has been widely recognized that functional groups on biomaterial surfaces play important roles in blood compatibility. To construct an effective antithrombotic bio-interface onto the poly(ether sulfone) (PES) membrane surface, bio-functional groups of sodium carboxylic (-COONa), sodium sulfonic (-SO3Na) and amino (-NH2) groups were introduced onto the PES membrane surface in three steps: the synthesis of PES with carboxylic (-COOH) groups (CPES) and water-soluble PES with sodium sulfonic (-SO3Na) groups and amino (-NH2) groups (SNPES); the introduction of carboxylic groups onto the PES membrane by blending CPES with PES; and the grafting of SNPES onto CPES/PES membranes via the coupling of amino groups and carboxyl groups. The physical/chemical properties and bioactivities were dependent on the proportions of the additives. After introducing bio-functional groups, the excellent hemocompatibility of the modified membranes was confirmed by the inhibited platelet adhesion and activation, prolonged clotting times, suppressed blood-related complement and leukocyte-related complement receptor activations. Furthermore, cell tests indicated that the modified membranes showed better cytocompatibility in endothelial cell proliferation than the pristine PES membrane due to the synergistic promotion of the functional groups. To sum up, these results suggested that modified membranes present great potential in fields using blood-contacting materials, such as hemodialysis and surface endothelialization. PMID- 29115310 TI - Observation of hidden atomic order at the interface between Fe and topological insulator Bi2Te3. AB - To realize spintronic devices based on topological insulators (TIs), well-defined interfaces between magnetic metals and TIs are required. Here, we characterize atomically precisely the interface between the 3d transition metal Fe and the TI Bi2Te3 at different stages of its formation. Using photoelectron diffraction and holography, we show that after deposition of up to 3 monolayers Fe on Bi2Te3 at room temperature, the Fe atoms are ordered at the interface despite the surface disorder revealed by our scanning-tunneling microscopy images. We find that Fe occupies two different sites: a hollow adatom deeply relaxed into the Bi2Te3 quintuple layers and an interstitial atom between the third (Te) and fourth (Bi) atomic layers. For both sites, our core-level photoemission spectra and density functional theory calculations demonstrate simultaneous chemical bonding of Fe to both Te and Bi atoms. We further show that upon deposition of Fe up to a thickness of 20 nm, the Fe atoms penetrate deeper into the bulk forming a 2-5 nm interface layer containing FeTe. In addition, excessive Bi is pushed down into the bulk of Bi2Te3 leading to the formation of septuple layers of Bi3Te4 within a distance of ~25 nm from the interface. Controlling the magnetic properties of the complex interface structures revealed by our work will be of critical importance when optimizing the efficiency of spin injection in TI-based devices. PMID- 29115311 TI - De-assembly of assembled Pt1Ag12 units: tailoring the photoluminescence of atomically precise nanoclusters. AB - Considering the significant effect of the size of a nanocluster on its optical energy gap, we herein exploit the concept of de-assembly to render a blue-shift of the photoluminescent emission as well as an enhancement of the quantum yield (QY) of assembled M25 nanoclusters. The de-assembly splits an assembled M13-dimer Pt2Ag23(PPh)10Cl7 into a sole-M13-kernel Pt1Ag12(dppm)5(SPhMe2)2, via a Pt1Ag24(SPhMe2)18 nanocluster. PMID- 29115312 TI - Plasmonic support-mediated activation of 1 nm platinum clusters for catalysis. AB - Nanometer-sized metal clusters are prime candidates for photoactivated catalysis, based on their unique tunable optical and electronic properties, combined with a large surface-to-volume ratio. Due to the very small optical cross sections of such nanoclusters, support-mediated plasmonic activation could potentially make activation more efficient. Our support is a semi-transparent gold film, optimized to work in a back-illumination geometry. It has a surface plasmon resonance excitable in the 510-540 nm wavelength range. Ptn clusters (size distribution peaked at n = 46 atoms) have been deposited onto this support and investigated for photoactivated catalytic performance in the oxidative decomposition of methylene blue. The Pt cluster catalytic activity under illumination exceeds that of the gold support by more than an order of magnitude per active surface area. To further investigate the underlying mechanism of plasmon-induced catalysis, the clusters have been imaged with optically-assisted scanning tunneling microscopy under illumination. The photoactivation of the Pt clusters via plasmonic excitation of the support and subsequential electronic excitation of the clusters can be imaged with nanometer resolution. The light-induced tunneling current on the clusters is enhanced relative to the gold film support. PMID- 29115313 TI - Photoionization of environmentally polluting aromatic chlorides and nitrides on the water surface by laser and synchrotron radiations. AB - The detection limits and photoionization thresholds of polycyclic aromatic hydrocarbons and their chlorides and nitrides on the water surface are examined using laser two-photon ionization and single-photon ionization, respectively. The laser two-photon ionization methods are highly surface-selective, with a high sensitivity for aromatic hydrocarbons tending to accumulate on the water surface in the natural environment due to their highly hydrophobic nature. The dependence of the detection limits of target aromatic molecules on their physicochemical properties (photoionization thresholds relating to excess energy, molar absorptivity, and the octanol-water partition coefficient) is discussed. The detection limit clearly depends on the product of the octanol-water partition coefficient and molar absorptivity, and no clear dependence was found on excess energy. The detection limits of laser two-photon ionization for these types of molecules on the water surface are formulated. PMID- 29115314 TI - Molecular photosensitisers for two-photon photodynamic therapy. AB - Two-photon excitation has attracted the attention of biologists, especially after the development of two-photon excited microscopy in the nineties. Since then, new applications have rapidly emerged such as the release of biologically active molecules and photodynamic therapy (PDT) using two-photon excitation. PDT, which requires a light-activated drug (photosensitiser), is a clinically approved and minimally invasive treatment for cancer and for non-malignant diseases. This feature article focuses on the engineering of molecular two-photon photosensitisers for PDT, which should bring important benefits to the treatment, increase the treatment penetration depth with near-infrared light excitation, improve the spatial selectivity and reduce the photodamage to healthy tissues. After an overview of the two-photon absorption phenomenon and the methods to evaluate two-photon induced phototoxicity on cell cultures, the different classes of photosensitisers described in the literature are discussed. The two-photon PDT performed with historical one-photon sensitisers are briefly presented, followed by specifically engineered cyclic tetrapyrrole photosensitisers, purely organic photosensitisers and transition metal complexes. Finally, targeted two-photon photosensitisers and theranostic agents that should enhance the selectivity and efficiency of the treatment are discussed. PMID- 29115315 TI - Intersegmental transfer of proteins between DNA regions in the presence of crowding. AB - Intersegmental transfer that involves direct relocation of a DNA-binding protein from one nonspecific DNA site to another was previously shown to contribute to speeding up the identification of the DNA target site. This mechanism is promoted when the protein is composed of at least two domains that have different DNA binding affinities and thus show a degree of mobility. In this study, we investigate the effect of particle crowding on the ability of a multi-domain protein to perform intersegmental transfer. We show that although crowding conditions often favor 1D diffusion of proteins along DNA over 3D diffusion, relocation of one of the tethered domains to initiate intersegmental transfer is possible even under crowding conditions. The tendency to perform intersegmental transfer by a multi-domain protein under crowding conditions is much higher for larger crowding particles than smaller ones and can be even greater than under no crowding conditions. We report that the asymmetry of the two domains is even magnified by the crowders. The observations that crowding supports intersegmental transfer serve as another example that in vivo complexity does not necessarily slow down DNA search kinetics by proteins. PMID- 29115316 TI - An ultra-small, multi-point, and multi-color photo-detection system with high sensitivity and high dynamic range. AB - Although multi-point, multi-color fluorescence-detection systems are widely used in various sciences, they would find wider applications if they are miniaturized. Accordingly, an ultra-small, four-emission-point and four-color fluorescence detection system was developed. Its size (space between emission points and a detection plane) is 15 * 10 * 12 mm, which is three-orders-of-magnitude smaller than that of a conventional system. Fluorescence from four emission points with an interval of 1 mm on the same plane was respectively collimated by four lenses and split into four color fluxes by four dichroic mirrors. Then, a total of sixteen parallel color fluxes were directly input into an image sensor and simultaneously detected. The emission-point plane and the detection plane (the image-sensor surface) were parallel and separated by a distance of only 12 mm. The developed system was applied to four-capillary array electrophoresis and successfully achieved Sanger DNA sequencing. Moreover, compared with a conventional system, the developed system had equivalent high fluorescence detection sensitivity (lower detection limit of 17 pM dROX) and 1.6-orders-of magnitude higher dynamic range (4.3 orders of magnitude). PMID- 29115317 TI - Computational study of the DPAP molecular rotor in various environments: from force field development to molecular dynamics simulations and spectroscopic calculations. AB - Fluorescent molecular rotors (FMRs) belong to an important class of environment sensitive dyes capable of acting as nanoprobes in the measurement of viscosity and polarity of their micro-environment. FMRs have found widespread applications in various research fields, ranging from analytical to biochemical sciences, for example in intracellular imaging studies or in volatile organic compound detection. Here, a computational investigation of a recently proposed FMR, namely 4-(diphenylamino)phthalonitrile (DPAP), in various chemical environments is presented. A purposely developed molecular mechanics force field is proposed and then applied to simulate the rotor in a high- and low-polar solvent (i.e., acetonitrile, tetrahydrofuran, o-xylene and cyclohexane), a polymer matrix and a lipid membrane. Subtle effects of the molecular interactions with the embedding medium, the structural fluctuations of the rotor and its rotational dynamics are analyzed in some detail. The results correlate with a previous work, thus supporting the reliability of the model, and provide further insights into the environment-specific properties of the dye. In particular, it is shown how molecular diffusion and rotational correlation times of the FMR are affected by the surrounding medium and how the molecular orientation of the dye becomes anisotropic once immersed in the lipid bilayer. Moreover, a qualitative correlation between the FMR rotational dynamics and the fluorescence lifetime is detected, a result in line with the observed viscosity dependence of its emission. Finally, optical absorption spectra are computed and successfully compared with their experimental counterparts. PMID- 29115318 TI - Mechanistic insights on ethanol dehydrogenation on Pd-Au model catalysts: a combined experimental and DFT study. AB - In this study, we have combined ultra-high vacuum (UHV) experiments and density functional theory (DFT) calculations to investigate ethanol (EtOH) dehydrogenation on Pd-Au model catalysts. Using EtOH reactive molecular beam scattering (RMBS), EtOH temperature-programmed desorption (TPD), and DFT calculations, we show how different Pd ensemble sizes on Au(111) can affect the mechanism for EtOH dehydrogenation and H2 production. The Au(111) surface with an initial coverage of 2 monolayers of Pd (2 ML Pd-Au) had the highest H2 yield. However, the 1 ML Pd-Au catalyst showed the highest selectivity and stability, yielding appreciable amounts of only H2 and acetaldehyde. Arrhenius plots of H2 production confirm that the mechanisms for EtOH dehydrogenation differed between 1 and 2 ML Pd-Au, supporting the perceived difference in selectivity between the two surfaces. DFT calculations support this difference in mechanism, showing a dependence of the initial dehydrogenation selectivity of EtOH on the size of Pd ensemble. DFT binding energies and EtOH TPD confirm that EtOH has increasing surface affinity with increasing Pd ensemble size and Pd coverage, indicating that surfaces with more Pd are more likely to induce an EtOH reaction instead of desorb. Our theoretical results show that the synergistic influence of atomic ensemble and electronic effects on Pd/Au(111) can lead to different H2 association energies and EtOH dehydrogenation capacities at different Pd ensembles. These results provide mechanistic insights into ethanol's dehydrogenation interactions with different sites on the Pd-Au surface and can potentially aid in bimetallic catalyst design for applications such as fuel cells. PMID- 29115319 TI - A planar dielectrophoresis-based chip for high-throughput cell pairing. AB - This paper reports the design and fabrication of a planar chip for high throughput cell trapping and pairing (more than 2400 single cell-cell pairs in a microwell array) in a 1 * 1.5 cm area by positive dielectrophoresis (p-DEP) within only several minutes. The p-DEP was generated by applying an alternating current signal on a novel two-pair interdigitated array (TPIDA) electrode. The TPIDA electrode not only enabled the planar chip to be incorporated with a most often used PDMS microfluidic channel, but also contributed to a high single cell cell pairing efficiency up to 74.2% by decreasing the induced electric field during consecutive p-DEP trapping of two cell types. Furthermore, the paired cells in each microwell could be "pushed" together into a microbaffle by a liquid flow through a capillary-sized channel, resulting in single cell-cell contact. More importantly, the planar chip could be used repeatedly by a simple water cleaning process. The planar chip offers an effective way for high-throughput single cell-cell pairing, which could provide a facile platform for cell communication and a precise cell pairing step in cell fusion. PMID- 29115320 TI - Chlorophyll a crude extract: efficient photo-degradable photocatalyst for PET RAFT polymerization. AB - We investigated the use of crude chlorophyll extracts to catalyze photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET RAFT) polymerization under red light irradiation. We discovered that Chl a degrades under visible light in the presence of air, which can eliminate the need for catalyst removal after polymerization. PMID- 29115321 TI - Raman microspectroscopy and multivariate data analysis: optical differentiation of aqueous d- and l-tryptophan solutions. AB - The combination of Raman spectroscopy as a sensitive and selective optical measurement technique and multivariate data analysis forms a powerful tool for probing intermolecular interactions between enantiomers. In this study we demonstrate that the optical differentiation of aqueous d- and l-tryptophan solutions is possible using Raman spectroscopy and principal component analysis (PCA). The loadings of the PCA allow identifying these functional groups most relevant for enantiospecific interactions. Through a partial least squares regression (PLSR) a calibration line can be established for the mixing ratio of ternary aqueous d- and l-tryptophan solutions. PMID- 29115322 TI - Graphene membranes with nanoslits for seawater desalination via forward osmosis. AB - Stacked graphene (GE) membranes with cascading nanoslits can be synthesized economically compared to monolayer nanoporous GE membranes, and have potential for molecular separation. This study focuses on investigating the seawater desalination performance of these stacked GE layers as forward osmosis (FO) membranes by using molecular dynamics simulations. The FO performance is evaluated in terms of water flux and salt rejection and is explained by analysing the water density distribution and radial distribution function. The water flow displays an Arrhenius type relation with temperature and the activation energy for the stacked GE membrane is estimated to be 8.02 kJ mol-1, a value much lower than that of commercially available FO membranes. The study reveals that the membrane characteristics including the pore width, offset, interlayer separation distance and number of layers have significant effects on the desalination performance. Unlike monolayer nanoporous GE membranes, at an optimum layer separation distance, the stacked GE membranes with large pore widths and completely misaligned pore configuration can retain complete ion rejection and maintain a high water flux. Findings from the present study are helpful in developing GE-based membranes for seawater desalination via FO. PMID- 29115323 TI - Conformational structures of the tetrahydrofuran cation determined using one photon mass-analyzed threshold ionization spectroscopy. AB - One-photon vacuum ultraviolet mass-analyzed threshold ionization (VUV-MATI) spectroscopy was used to characterize the essential conformations of tetrahydrofuran (THF) and thus determine the stereochemistry of the furanose ring constituting the backbones of DNA and RNA. Since the VUV-MATI spectrum of THF exactly corresponds to the vibrational spectrum of the gas-phase THF cation, the above cation was detected using time-of-flight mass spectrometry featuring the delayed pulsed-field ionization of the target in high Rydberg states by scanning the wavelength of the VUV pulse across the region of the vibrational spectrum. The position of the 0-0 band in the recorded VUV-MATI spectrum was extrapolated to the zero-field limit, allowing the adiabatic ionization energy of THF to be accurately estimated to be 9.4256 +/- 0.0004 eV. The above ionization was assigned to a transition between C2-symmetric neutral (S0) and cationic (D0) ground states. The potential energy surfaces associated with molecular pseudorotation in the above states were constructed at the B3LYP/aug-cc-pVDZ level, being in good agreement with experimental observations. The twisted (C2 symmetric) and bent (CS-symmetric) conformers of the S0 state were predicted to be separated by a small interconversion barrier, whereas the D0 state exclusively existed in the C2 conformation. Based on the above, the peaks in the MATI spectrum were successfully assigned based on the Franck-Condon factors and vibrational frequencies calculated by varying the geometrical parameters of the C2 conformation, which determines the precise molecular structure of the THF cation. PMID- 29115325 TI - Synthesis and EPR studies of the first water-soluble N@C60 derivative. AB - The first water-soluble derivative of the paramagnetic endohedral fullerene N@C60 has been prepared through the covalent attachment of a single addend containing two permethylated beta-cyclodextrin units to the surface of the carbon cage. The line width of the derivative's EPR signal is highly sensitive to both the nature of the solvent and the presence of Cu(ii) ions in solution. PMID- 29115326 TI - Dependence of topological and optical properties on surface-terminated groups in two-dimensional molybdenum dinitride and tungsten dinitride nanosheets. AB - Using ab initio methods, the topological and optical properties of surface functionalized XN2 sheets (X = Mo, W) were investigated. Based on first principles calculations and the K.p effective model, the existence of topological nodal-line states in potassium-functionalized XN2 sheets (K2MoN2 and K2WN2) is reported. This study shows that a nodal line ring exists near the Fermi level in the absence of spin-orbit coupling (SOC). When SOC is included, the band-crossing points are gapped, giving rise to a new nodal ring along Gamma-K. This band crossing is protected due to the existence of mirror reflection and time-reversal symmetry. These calculations demonstrate the inclusion of electron-hole (e-h) interactions, which were further confirmed through the optical absorption of functionalized MoN2, revealing the presence of strongly bound excitons below the absorption onset where they depend strongly on the terminated surface groups. Moreover, the surface terminated groups change the energy distribution range of the exciton, which can be used to tune the absorption of infrared (IR) and visible light. Interestingly, F2MoN2 has several strongly bound excitons, with the first exciton having a binding energy of 1.35 eV, larger than the corresponding one in the transition metal dichalcogenide MoS2. PMID- 29115324 TI - Calcium isotope signature: new proxy for net change in bone volume for chronic kidney disease and diabetic rats. AB - Herein, we measure the Ca isotope ratios (44Ca/42Ca and 43Ca/42Ca) in serum and bone samples collected from rats with chronic kidney disease (CKD) or diabetes mellitus (DM). For the serum samples, the isotope ratios are lower for the CKD (delta44Ca/42Caserum = 0.16 +/- 0.110/00; 2SD, n = 6) and the DM (delta44Ca/42Caserum = -0.11 +/- 0.250/00; 2SD, n = 7) rats than that for the control rats (delta44Ca/42Caserum = 0.25 +/- 0.040/00; 2SD, n = 7). Bone samples from two distinct positions of 20 rats in total, namely, the center and proximal parts of the tibial diaphysis, are subject to Ca isotope analysis. The resulting delta44Ca/42Ca values for the bone of the proximal part are about 0.30/00 lower than that for the serum samples from the same rats. The larger isotope fractionations between the serum and bone are consistent with previously reported data for vertebrate animals (e.g., Skulan and DePaolo, 1999), which suggests the preferential incorporation of lighter Ca isotopes through bone formation. For the bones from the control and CKD rats, there were no differences in the delta44Ca/42Ca values between the positions of the bone. In contrast, the delta44Ca/42Ca values of the bone for the DM rats were different between the positions of the bone. Due to the lower bone turnover rate for the DM rats, the delta44Ca/42Ca for the middle of the diaphysis can reflect the Ca isotopes in the bone formed prior to the progression of DM states. Thus, the resulting delta44Ca/42Ca values show a clear correlation with bone mineral density (BMD). This can be due to the release of isotopically lighter Ca from the bone to the serum. In the present study, our data demonstrate that the delta44Ca/42Ca value for serum can be used as a new biomarker for evaluating changes in bone turnover rate, followed by changes in bone volume. PMID- 29115327 TI - Spectromicroscopic observation of a live single cell in a biocompatible liquid enclosing graphene system. AB - On-the-spot visualization of biochemical responses of intact live cells is vital for a clear understanding of cell biology. The main obstacles for instant visualization of biochemical responses of living cells arise from the lack of a sophisticated detecting technique which can simultaneously provide chemical analysis tools and the biocompatible wet conditions. Here we introduce scanning transmission X-ray microscopy (STXM) combined with a liquid-enclosing graphene system (LGS), offering biocompatible conditions and improved X-ray absorption spectra to probe the chemical responses of live cells under wet conditions. This set-up enables us to probe a subtle change in absorption spectra depending on the oxidation state of a miniscule amount of oxygen in the functional groups present in each cell and its surroundings containing a minimal amount of liquid water. As an example of in situ biochemical responses of wet cells, chemical responses of a single Colo 205 cell are visualized and analyzed using X-ray absorption near the oxygen K-edge. This spectromicroscopic method using LGS can be applied to diverse biological samples under wet conditions for the analysis of their biochemical responses. PMID- 29115328 TI - Homoepitaxial growth on semiconductor nanocrystals for efficient and stable visible-light photocatalytic hydrogen evolution. AB - Recent advancements in colloidal chemistry offer unique opportunities to construct core/shell semiconductor nanocrystals (NCs) with tailored optical properties. Major efforts have been focused on synthesizing core/shell NCs via heteroepitaxial growth, which often leads to effective surface passivation and thus reduced trap states (TS). However, the growth of a shell with a wider band gap or energy band offset tends to form a physical barrier for the migration of photo-generated charge carriers to the surrounding environment, resulting in compromised photoactivity. Here, we show that the homoepitaxial growth of NCs is able to facilitate the passivation of TS without affecting the migration of charge carriers to the surface of NCs. Homostructured CdShomo NCs have demonstrated improved photocatalytic hydrogen production compared with the CdS core NCs and heterostructured CdS/ZnS core/shell NCs in terms of both efficiency and photostability. We envision that homoepitaxial growth would provide new opportunities to tailor semiconductor NCs for photocatalytic and photovoltaic applications. PMID- 29115329 TI - The diaza-Nazarov cyclization involving a 2,3-diaza-pentadienyl cation for the synthesis of polysubstituted pyrazoles. AB - An unprecedented iodine-mediated diaza-Nazarov (DAN) type cyclization for the construction of substituted pyrazoles from easily available starting materials via an enamine-iminium ion intermediate is described. The oxidative cyclization worked under green conditions with remarkable regioselectivity. This one-pot, efficient and operationally simple three-component intramolecular regioselective DAN cyclization displayed a wide range of substrate scope. The dichotomy of reaction pathways has been explored with density functional theory in the gas phase and solution phase. Of the possible 1,5-, 1,6-, and 1,7 electrocyclizations, the DAN cyclization, i.e., the 1,5-pathway offers the lowest activation energy barrier supporting our experimental observations. PMID- 29115330 TI - A strong and flexible electronic vessel for real-time monitoring of temperature, motions and flow. AB - Flexible and multifunctional sensors that continuously detect physical information are urgently required to fabricate wearable materials for health monitoring. This study describes the fabrication and performance of a strong and flexible vessel-like sensor. This electronic vessel consists of a self-supported braided cotton hose substrate, single-walled carbon nanotubes (SWCNTs)/ZnO@polyvinylidene fluoride (PVDF) function arrays and a flexible PVDF function fibrous membrane, and it possesses high mechanical property and accurate physical sensing. The rationally designed tubular structure facilities the detection of the applied temperature and strain and the frequency, pressure, and temperature of pulsed fluids. Therefore, the flexible electronic vessel holds promising potential for applications in wearable or implantable materials for the monitoring of health. PMID- 29115331 TI - Single-walled carbon nanotube thermionic electron emitters with dense, efficient and reproducible electron emission. AB - Thermionic electron emitters have recently been scaled down to the microscale using microfabrication technologies and graphene as the filament. While possessing several advantages over field emitters, graphene-based thermionic micro-emitters still exhibit low emission current density and efficiency. Here, we report nanoscale thermionic electron emitters (NTEEs) fabricated using microfabrication technologies and single-walled carbon nanotubes (SWCNTs), the thinnest conducting filament we can use. The SWCNT NTEEs exhibit an emission current density as high as 0.45 * 105 A cm-2, which is superior to that of traditional thermionic emitters and five orders of magnitude higher than that of graphene-based thermionic emitters. The emission characteristics of SWCNT NTEEs are found to strongly depend on the electrical properties of the SWCNTs, with metallic SWCNT NTEEs showing a substantially lower turn-on voltage and more reproducible emission performances than those based on semiconducting SWCNTs. Our results indicate that SWCNT NTEEs are promising for electron source applications. PMID- 29115332 TI - Unraveling current hysteresis effects in regular-type C60-CH3NH3PbI3 heterojunction solar cells. AB - Comprehensive studies were carried out to understand the origin of the current hysteresis effects in highly efficient C60-CH3NH3PbI3(MAPbI3) heterojunction solar cells, using atomic-force microscopy, transmittance spectra, photoluminescence spectra, X-ray diffraction patterns and a femtosecond time resolved pump-probe technique. The power conversion efficiency (PCE) of C60 MAPbI3 solar cells can be increased to 18.23% by eliminating the point (lattice) defects in the MAPbI3 thin film which is fabricated by using the one-step spin coating method with toluene washing treatment. The experimental results show that the point defects and surface defects of the MAPbI3 thin films can be minimized by varying the dropping time of the washing solvent. The point defects (surface defects) can be reduced with an (a) increase (decrease) in the dropping time, resulting in an optimized dropping time for obtaining the defect-minimized MAPbI3 thin film deposited on top of the C60 thin film. Consequently, the formation of the defect-minimized MAPbI3 thin film allows for high-efficiency MAPbI3 solar cells. PMID- 29115334 TI - Efficient dehydrative alkylation of thiols with alcohols catalyzed by alkyl halides. AB - Alcohols can be efficiently converted into the useful thioethers by a transition metal- and base-free dehydrative S-alkylation reaction with thiols or disulfides by employing alkyl halides as the effective catalyst. This simple and efficient method is a green and practical way for the preparation of thioethers, as it tolerates a wide range of substrates such as aryl and alkyl thiols, as well as benzylic, allylic, secondary, tertiary, and even the less reactive aliphatic alcohols. PMID- 29115333 TI - An apolipoprotein-enriched biomolecular corona switches the cellular uptake mechanism and trafficking pathway of lipid nanoparticles. AB - Following exposure to biological milieus (e.g. after systemic administration), nanoparticles (NPs) get covered by an outer biomolecular corona (BC) that defines many of their biological outcomes, such as the elicited immune response, biodistribution, and targeting abilities. In spite of this, the role of BC in regulating the cellular uptake and the subcellular trafficking properties of NPs has remained elusive. Here, we tackle this issue by employing multicomponent (MC) lipid NPs, human plasma (HP) and HeLa cells as models for nanoformulations, biological fluids, and target cells, respectively. By conducting confocal fluorescence microscopy experiments and image correlation analyses, we quantitatively demonstrate that the BC promotes a neat switch of the cell entry mechanism and subsequent intracellular trafficking, from macropinocytosis to clathrin-dependent endocytosis. Nano-liquid chromatography tandem mass spectrometry identifies apolipoproteins as the most abundant components of the BC tested here. Interestingly, this class of proteins target the LDL receptors, which are overexpressed in clathrin-enriched membrane domains. Our results highlight the crucial role of BC as an intrinsic trigger of specific NP-cell interactions and biological responses and set the basis for a rational exploitation of the BC for targeted delivery. PMID- 29115335 TI - Fast-switching electrochromic properties of mesoporous WO3 films with oxygen vacancy defects. AB - In this study, mesoporous WO3 films with oxygen vacancy defects have been fabricated using the camphene-assisted sol-gel method. By controlling the optimized weight ratio of camphene on the WO3 films, we developed a unique film structure of the WO3 phase with both mesoporous morphology and oxygen vacancy defects due to the distinctive effect of camphene. The mesoporous WO3 films with oxygen vacancy defects fabricated using 10 wt% camphene showed superb multifunctional electrochromic (EC) properties with both fast switching speeds (5.8 s for coloration speed and 1.0 s for bleaching speed) and high coloration efficiency (CE, 51.4 cm2 C-1), which include the most prominent properties, particularly for switching speeds among WO3-based films reported so far. The attractive EC properties are due to the synergistic effects of the mesoporous morphology and oxygen vacancy defects on the WO3. The fast switching speeds are mainly caused by the reduced Li+ diffusion pathway due to the mesoporous morphology and increased electrical conductivity due to the oxygen vacancy defects. In addition, the increased CE value is due to the large transmittance modulation as a result of a more effective electrostatic contact of the mesoporous morphology and an increased optical bandgap of the oxygen vacancy defects on the WO3. Therefore, this unique film structure of the mesoporous WO3 films with oxygen vacancy defects can be potentially regarded as a novel EC material for high-performance EC devices. PMID- 29115336 TI - Optical detection of charge dynamics in CH3NH3PbI3/carbon nanotube composites. AB - We have investigated the optical absorption of metallic and semiconducting carbon nanotubes/CH3NH3PbI3 micro- and nanowire composites. Upon visible light illumination semiconducting carbon nanotube based samples show a photo-induced doping, originating from the charge carriers created in the perovskite while this kind of change is absent in the composites containing metallic nanotubes, due to their strikingly different electronic structure. The response in the nanotubes shows, beside a fast diffusion of photo-generated charges, a slow component similar to that observed in pristine CH3NH3PbI3 attributed to structural rearrangement, and leading to slight, light induced changes of the optical gap of the perovskite. This charge transfer from the illuminated perovskite confirms that carbon nanotubes (especially semiconducting ones) can form efficient charge transporting layers in the novel organometallic perovskite based optoelectronic devices. PMID- 29115337 TI - Visible-light-promoted selective C-H amination of heteroarenes with heteroaromatic amines under metal-free conditions. AB - The regioselective C-H amination of quinoline amides (C5) and imidazopyridines (C3) under transition-metal-free conditions at room temperature with a high degree of functional group tolerance is reported. The C-H amination promoted by visible light in the presence of a photocatalyst with a wide range of heteroamines makes the present protocol more sustainable. PMID- 29115338 TI - Construction of tetrahydropyranoquinoline derivatives via an asymmetric organocatalytic aza-Michael-IED/HAD cascade reaction. AB - Chiral functionalized tetrahydroquinolines and pyranoquinolines with multiple stereogenic centres have emerged as attractive structures for derivatizing bioactive complex molecules. Herein, we develop a novel, facile organocatalytic asymmetric aza-Michael-IED/HAD cascade reaction of (E)-ethyl 4-(2-(4 methylphenylsulfon amido)phenyl)-2-oxobut-3-enoate and enals. This method enables a convenient, powerful, and atom-economical access to various desired tetrahydropyranoquinoline derivatives with control of four stereogenic centres in good yields (up to 88%) with excellent diastereo- and enantioselectivities (up to >99 : 1 dr and >99% ee, respectively). PMID- 29115339 TI - Electro-oxidation of a cobalt based steel in LiOH: a non-noble metal based electro-catalyst suitable for durable water-splitting in an acidic milieu. AB - The use of proton exchange membrane (PEM) electrolyzers is the method of choice for the conversion of solar energy when frequently occurring changes of the current load are an issue. However, this technique requires electrolytes with low pH. All oxygen evolving electrodes working durably and actively in acids contain IrOx. Due to their scarcity and high acquisition costs, noble elements like Pt, Ru and Ir need to be replaced by earth abundant elements. We have evaluated a cobalt containing steel for use as an oxygen-forming electrode in H2SO4. We found that the dissolving of ingredients out of the steel electrode at oxidative potential in sulfuric acid, which is a well-known, serious issue, can be substantially reduced when the steel is electro-oxidized in LiOH prior to electrocatalysis. Under optimized synthesis conditions a cobalt-containing tool steel was rendered into a durable oxygen evolution reaction (OER) electrocatalyst (weight loss: 39 MUg mm-2 after 50 000 s of chronopotentiometry at pH 1) that exhibits overpotentials down to 574 mV at 10 mA cm-2 current density at pH 1. Focused ion beam SEM (FIB-SEM) was successfully used to create a structure stability relationship. PMID- 29115340 TI - The double-edged effects of annealing MgO underlayers on the efficient synthesis of single-wall carbon nanotube forests. AB - Recently, the millimetre-scale, highly efficient synthesis of single-wall carbon nanotube (SWCNT) forests from Fe catalysts has been reported through the annealing of the magnesia (MgO) underlayer. Here, we report the double-edged effects of underlayer annealing on the efficiency and structure of the SWCNT forest synthesis through a temperature-dependent examination. Our results showed that the efficiency of the SWCNT forests sharply increased with increased underlayer annealing temperatures from 600 degrees C up to 900 degrees C due to a temperature-dependent structural modification, characterized by increased grain size and reduced defects, of the MgO underlayer. Beyond this temperature, the SWCNT fraction also decreased as a result of further structural modification of the MgO underlayer. This exemplifies the double-edged effects of annealing. Specifically, for underlayer annealing below 600 degrees C, the catalyst subsurface diffusion was found to limit the growth efficiency, and for excessively high underlayer annealing temperatures (>900 degrees C), catalyst coalescence/ripening led to the formation of double-wall carbon nanotubes. As a result, three distinct regions of synthesis were observed: (i) a "low yield" region below a threshold temperature (~600 degrees C); (ii) an "increased yield" region from 600 to 900 degrees C, and (iii) a "saturation" region above 900 degrees C. The efficient SWCNT forest synthesis could only occur within a specific annealing temperature window as a result of this double-edged effects of underlayer annealing. PMID- 29115341 TI - One-pot synthesis of Ni nanoparticle/ordered mesoporous carbon composite electrode materials for electrocatalytic reduction of aromatic ketones. AB - A simple one-pot synthesis of Ni nanoparticle/ordered mesoporous carbon composite electrode materials is demonstrated for electrosynthesis for the first time. The obtained nanocomposites have uniform mesopore sizes (3.0-3.7 nm), large specific surface areas (506-633 m2 g-1), high pore volumes (0.28-0.38 cm3 g-1), well graphitized carbon frameworks, and uniformly dispersed Ni nanoparticles (7-15 nm) embedded in the carbon pore walls. The prepared materials show very high performance in the selective (~84%) electrocatalytic reduction of aromatic ketones into alcohols (~79%). PMID- 29115343 TI - Correlation between the electronic structure, topologic structure and dynamic properties of liquid cerium. AB - In literature, two different kinds of cerium atoms, namely Ce atoms with a localized 4f-electron and an iterant 4f-electron, have been suggested to coexist in low-density liquid cerium (A. Cadien et al., Phys. Rev. Lett., 2013, 110, 125503). However, direct evidence of this phenomenon is hard to be detected in the laboratory or classical MD simulations. Thus, the amazing properties of liquid cerium cannot be revealed. Herein, we have shown an ab initio MD simulation evidence that both kinds of cerium atoms can be detected in low density liquid cerium at 13 GPa and 1900 K. Ce atoms with a similar degree of 4f electron locality tend to aggregate with each other. An icosahedral short-range order (ISRO) appears for the local structures around the Ce atoms with an iterant 4f electron, whereas it does not appear around the Ce atoms with highly localized 4f electrons. Our study also offers a new perspective and approach to deeply understand liquid Ce and related amorphous Ce-based alloys. PMID- 29115348 TI - Effect of short-chain branching on interfacial polymer structure and dynamics under shear flow. AB - We present a detailed analysis on the effect of short-chain branches on the structure and dynamics of interfacial chains using atomistic nonequilibrium molecular dynamics simulations of confined polyethylene melts in a wide range of shear rates. The intrinsically fast random motions of the short branches constantly disturb the overall chain conformation, leading to a more compact and less deformed chain structure of the short-chain branched (SCB) polymer against the imposed flow field in comparison with the corresponding linear polymer. Moreover, such highly mobile short branches along the backbone of the SCB polymer lead to relatively weaker out-of-plane wagging dynamics of interfacial chains, with highly curvy backbone structures in the intermediate flow regime. In conjunction with the contribution of short branches (as opposed to that of the backbone) to the total interfacial friction between the chains and the wall, the SCB polymer shows a nearly constant behavior in the degree of slip (ds) with respect to shear rate in the weak-to-intermediate flow regimes. On the contrary, in the strong flow regime where irregular chain rotation and tumbling dynamics occur via intensive dynamical collisions between interfacial chains and the wall, an enhancement effect on the chain detachment from the wall, caused by short branches, leads to a steeper increase in ds for the SCB polymer than for the linear polymer. Remarkably, the SCB chains at the interface exhibit two distinct types of rolling mechanisms along the backbone, with a half-dumbbell mesoscopic structure at strong flow fields, in addition to the typical hairpin-like tumbling behavior displayed by the linear chains. PMID- 29115349 TI - Triplet-sensitized photon upconversion in deep eutectic solvents. AB - Photon upconversion (UC) is a technology that can increase solar utilization efficiencies in broad photoenergy conversion systems by converting lower-energy photons into usable higher-energy photons. Recently, UC using triplet-triplet annihilation (TTA) of organic molecules has drawn attention because it is presently the only method applicable to weak and noncoherent light. To date, many attempts have been made to realize this UC technology in forms suitable for applications, but they typically suffer from either high cost or insufficient stability and/or safety of materials. Recently, a new class of liquid called deep eutectic solvents (DESs) has emerged as low-cost green fluids that possess low toxicity and vapor pressure, biodegradability, and high thermal stability. DESs have been proposed as an alternative to ionic liquids. This article develops triplet-sensitized UC samples using DESs that are found to be suitable solvents for this purpose, attaining a new materials platform for UC with the aforementioned advantages. The high thermal stability of the samples is qualitatively confirmed and their UC quantum yields are determined to be 0.11 0.21 (based on the definition that the maximum quantum yield is 0.5) depending on the DES composition. The triplet lifetime of the emitter 9,10-diphenylanthracene increases with DES viscosity, resulting in unique kinetics. Analysis of photophysical experimental results allows the relevant physics governing the performance of this sample system to be determined and discussed. Overall, a novel UC platform that simultaneously achieves high thermal stability, low cost, and environmental friendliness is developed using DESs as the solvent. PMID- 29115350 TI - Urea hydrogen bond donor-mediated synthesis of high-index faceted platinum concave nanocubes grown on multi-walled carbon nanotubes and their enhanced electrocatalytic activity. AB - We have reported, for the first time, in situ growth of high-index {hk0} faceted concave Pt nanocubes on multi-walled carbon nanotubes (CNTs) via an electrochemical method in choline chloride-urea (ChCl-U) based deep eutectic solvents (DESs). Mechanistic studies indicate that a urea hydrogen bond donor (HBD) plays a key role in the formation of concave Pt nanocubes, in which the urea HBD preferentially adsorbs onto the {100} faces and blocks the growth of nanocrystals along the <100> axis. The as-prepared concave Pt nanocubes are characterized to be enclosed mainly with high-index {710}, {610} and {510} facets. It has been determined that the concave cubic Pt/CNT exhibits higher catalytic activity and stability than the flower-like Pt/CNT and commercial Pt/C catalysts, and this is ascribed to its high density of surface atomic steps and the synergistic effect between the CNT and Pt nanocubes. PMID- 29115351 TI - A pure magnetite hydrogel: synthesis, properties and possible applications. AB - A magnetite-only hydrogel was prepared for the first time by weak base mediated gelation of stable magnetite hydrosols at room temperature. The hydrogel consists of 10 nm magnetite nanoparticles linked by interparticle Fe-O-Fe bonds and has the appearance of a dark-brown viscous thixotropic material. The water content in the hydrogel could be up to 93.6% by mass while volume fraction reaches 99%. The material shows excellent biocompatibility and minor cytotoxic effects at concentrations up to 207 MUg mL-1. The gel shows excellent sorption capacity for heavy metal adsorption such as chrome and lead ions, which is 225% more than the adsorption capacity of magnetite nanoparticles. Due to thixotropic nature, the gel demonstrates mechanical stimuli-responsive release behavior with up to 98% release triggered by ultrasound irradiation. The material shows superparamagnetic behavior with a coercivity of 65 emu g-1 at 6000 Oe. The magnetite gels prepared could be used for the production of magnetite aerogels, magnetic drug delivery systems with controlled release and highly efficient sorbents for hydrometallurgy. PMID- 29115352 TI - A relationship between the force curve measured by atomic force microscopy in an ionic liquid and its density distribution on a substrate. AB - An ionic liquid forms a characteristic solvation structure on a substrate. For example, when the surface of the substrate is negatively or positively charged, cation and anion layers are alternately aligned on the surface. Such a solvation structure is closely related to slow diffusion, high electric capacity, and chemical reactions at the interface. To analyze the periodicity of the solvation structure, atomic force microscopy is often used. The measured force curve is generally oscillatory and its characteristic oscillation length corresponds not to the ionic diameter, but to the ion-pair diameter. However, the force curve is not the solvation structure. Hence, it is necessary to know the relationship between the force curve and the solvation structure. To find physical essence in the relationship, we have used statistical mechanics of a simple ionic liquid. We found that the basic relationship can be expressed by a simple equation and the reason why the oscillation length corresponds to the ion-pair diameter. Moreover, it is also found that Derjaguin approximation is applicable to the ionic liquid system. PMID- 29115354 TI - Human anthocyanin bioavailability: effect of intake duration and dosing. AB - While in vitro and animal evidence supports a role for anthocyanins in human health, future opportunities in berry health benefits will rest upon evidence from clinical intervention trials. Because little is known about the behaviour of anthocyanins during long term intake in humans, several clinical design factors were examined. Urine from volunteers (n = 17) who consumed blueberry juice daily was analysed using LC-MS/MS for predicted flavonoid-based products of anthocyanins in relation to a 5-day anthocyanin-free run-in, 28 days of blueberry juice intake, a 7-day washout and two dosing regimens. Total and parent anthocyanin content in urine varied 10-fold among the 17 participants. A high 24 0 h total anthocyanin excretion was associated with high anthocyanin retention (i.e. 0 h, before blueberry juice intake). Total anthocyanin excretion was not different before and after up to 7 days of washout indicative of a slow release of anthocyanins. Urinary excretion of anthocyanins declined during the 36-day study. The 24-0 h excretion was greater for total anthocyanins but not for parent anthocyanins when daily blueberry juice was taken all at once rather than as 1/3 doses taken thrice daily. However parent anthocyanins were retained better (higher 0 h) with 1* dosing. These findings could aid in the design of clinical research on anthocyanins and health. PMID- 29115353 TI - Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide. AB - Amyloid aggregation of human islet amyloid polypeptide (IAPP) is a hallmark of type 2 diabetes (T2D), a metabolic disease and a global epidemic. Although IAPP is synthesized in pancreatic beta-cells, its fibrils and plaques are found in the extracellular space indicating a causative transmembrane process. Numerous biophysical studies have revealed that cell membranes as well as model lipid vesicles promote the aggregation of amyloid-beta (associated with Alzheimer's), alpha-synuclein (associated with Parkinson's) and IAPP, through electrostatic and hydrophobic interactions between the proteins/peptides and lipid membranes. Using a thioflavin T kinetic assay, transmission electron microscopy, circular dichroism spectroscopy, discrete molecular dynamics simulations as well as free energy calculations here we show that micellar lysophosphatidylcholine (LPC), the most abundant lysophospholipid in the blood, inhibited the amyloid aggregation of IAPP through nonspecific interactions while elevating the alpha-helical peptide secondary structure. This surprising finding suggests a native protective mechanism against IAPP aggregation in vivo. PMID- 29115355 TI - Recent progress in two-dimensional inorganic quantum dots. AB - The development of two-dimensional (2D) inorganic materials-based quantum dots (QDs) is still in its infancy but is triggering immense enthusiasm due to their high chemical stability, good aqueous dispersibility, excellent optical property, good biocompatibility and easy functionalization. This review covers almost all the extant 2D-QDs based on graphene, phosphorene, silicene, carbides, nitrides, transition metal dichalcogenide, transition metal oxides and MXenes, etc. Their categories, synthetic routes, properties, functionalization and applications are critically highlighted. In the application section, special emphasis is placed on the progress in bioimaging, cancer therapy, fluorescent sensing and optoelectronics. Meanwhile, the latest advances in 2D QDs-based catalysis and energy since 2015 are addressed. Moreover, 2D nanoclusters, in particular 2D-QDs, are also included. This review provides guidance for 2D-QDs studies to meet the increasing demands in the many diverse applications. PMID- 29115356 TI - Ostwald ripening versus single atom trapping: towards understanding platinum particle sintering. AB - Ostwald ripening is a leading cause of the degradation of platinum group catalysts at high temperature in an oxidizing atmosphere. Recent experiments suggested that volatile species can be trapped on ceria, forming atomically dispersed active catalytic sites instead of large nanoparticles. Here we present a comparative density functional theory study of the interaction of PtO2(g), the most likely volatile species responsible for the process of Ostwald ripening, with various surfaces. Defect-free CeO2(111) and Al2O3(100) surfaces have a very small binding energy towards PtO2(g) compared to the platinum surface, indicative of particle growth. However, the stepped edge of the CeO2(111) surface effectively traps the mobile species, generating atomically dispersed catalysts. Such trapped single-atom platinum-on-ceria catalysts are predicted to have a square-planar [PtO4] structure, with the platinum atom strongly binding to the surface, preventing platinum atoms from aggregating into larger nanoparticles. These results provide an atomic insight into the single atom trapping and suggest a route for the development of sinter-resistant catalysts. PMID- 29115357 TI - Measuring biotherapeutic viscosity and degradation on-chip with particle diffusometry. AB - In the absence of efficient ways to test drug stability and efficacy, pharmaceuticals that have been stored outside of set temperature conditions are destroyed, often at great cost. This is especially problematic for biotherapeutics, which are highly sensitive to temperature fluctuations. Current platforms for assessing the stability of protein-based biotherapeutics in high throughput and in low volumes are unavailable outside of research and development laboratories and are not efficient for use in production, quality control, distribution, or clinical settings. In these alternative environments, microanalysis platforms could provide significant advantages for the characterization of biotherapeutic degradation. Here we present particle diffusometry (PD), a new technique to study degradation of biotherapeutic solutions. PD uses a simple microfluidic chip and microscope setup to calculate the Brownian motion of particles in a quiescent solution using a variation of particle image velocimetry (PIV) fundamentals. We show that PD can be used to measure the viscosity of protein solutions to discriminate native protein from degraded samples as well as to determine the change in viscosity as a function of therapeutic concentration. PD viscosity analysis is applied to two particularly important biotherapeutic preparations: insulin, a commonly used protein for diabetic patients, and monoclonal antibodies which are an emerging class of biotherapeutics used to treat a variety of diseases such as autoimmune disorders and cancer. PD-based characterization of solution viscosity is a new tool for biotherapeutic analysis, and owing to its easy setup could readily be implemented at key points of the pharmaceutical delivery chain and in clinical settings. PMID- 29115358 TI - Dissociative chemisorption of methane on Ni(111) using a chemically accurate fifteen dimensional potential energy surface. AB - A fifteen-dimensional global potential energy surface for the dissociative chemisorption of methane on the rigid Ni(111) surface is developed by a high fidelity fit of ~200 000 DFT energy points computed using a specific reaction parameter density functional designed to reproduce experimental data. The permutation symmetry and surface periodicity are rigorously enforced using the permutation invariant polynomial-neural network approach. The fitting accuracy of the potential energy surface is thoroughly investigated by examining both static and dynamical attributes of CHD3 dissociation on the frozen surface. This potential energy surface is expected to be chemically accurate as after correction for surface temperature effects it reproduces the measured initial sticking probabilities of CHD3 on Ni(111) for various incidence conditions. PMID- 29115359 TI - A direct dynamics study of the deprotonated guanine.cytosine base pair: intra base pair proton transfer, thermal dissociation vs. collision-induced dissociation, and comparison with experiment. AB - Direct dynamics trajectories were calculated at the B3LYP/6-31G* level of theory to examine the intra-base pair proton transfer and dissociation of the deprotonated guanine (G).cytosine (C) base pair under different excitation conditions, and to explore the origin of the nonstatistical product branching reported in a collision-induced dissociation (CID) experiment (Phys. Chem. Chem. Phys. 2016, 18, 32222). Trajectories for thermal excitation were initiated at two major conformers G.[C-H]- (hydrogen-bonded guanine and N1-deprotonated cytosine) and G.[C-H]-_PT (formed by proton transfer from the N1 of guanine to the N3 of deprotonated cytosine), and at their transition state (TS). Thermal excitation was realized by sampling molecular vibrational levels and TS's reaction coordinate energy with Boltzmann distributions at temperatures of 960 and 1330 K, which correspond to classical energies of 3.0 and 5.0 eV, respectively. Thermally excited trajectories undergo intra-base pair proton transfer extensively. The resulting conformation scrambling leads to nearly equal branching between the dissociation channels of [G-H]- + C and G + [C-H]-. Collisions of G.[C-H]- and G.[C-H]-_PT with Ar were each simulated at collision energies of 3.0 and 5.0 eV, respectively. The probability for intra-base pair proton transfer decreases substantially in collision trajectories. The CID product branching calculated on the basis of the population-weighted trajectory results of G.[C-H]- and G.[C-H] _PT reveals a strong preference for [G-H]- + C, consistent with the experiment. Trajectory analysis corroborates that nonstatistical CID is attributed to inadequate conformation interconversion during collisional activation, and to the faster dissociation of the G.[C-H]-_PT conformer albeit G.[C-H]-_PT has nearly the same translational-to-vibrational energy transfer as G.[C-H]-. PMID- 29115360 TI - Environmentally benign synthesis of CuInS2/ZnO heteronanorods: visible light activated photocatalysis of organic pollutant/bacteria and study of its mechanism. AB - Due to its high light absorption coefficient and appropriate bandgap, CuInS2 (CIS) has been receiving much attention as an absorber material for thin film solar cells and also as a visible light photocatalyst. Herein we present heterostructured CIS/ZnO nanorods (NRs) in an attempt to enhance light absorption and facilitate charge separation/transfer in the photocatalysis system. CIS nanoparticles (NPs) were directly deposited on ZnO nanorod arrays (NRAs) to fabricate heterostructured CIS/ZnO NRAs using an environmentally benign, non hydrazine solution reaction. These heterostructured NRAs are immobilized on FTO glass, which has additional merits of recyclability and bias-applicability. The ideal type-II band structure of CIS/ZnO enables efficient charge separation/transfer, which is confirmed by PL (photoluminescence) decay measurements. Also, the 1D-ZnO NR structure facilitates fast charge transfer along with enhancing light absorption via light scattering. These synergistic effects improved the photocatalytic activity in both organic dye and bacteria decomposition. The photodecomposition efficiency was further enhanced with an aid of external bias. The underlying photocatalytic mechanism was also investigated through controlled experiments under various scavenging conditions. The results suggest that reactive oxygen species (ROS) formed by multistep reduction of O2 play a main role in photocatalysis, while hole-induced photodecomposition is relatively deactivated due to the band structure of the heterostructures of CIS/ZnO. PMID- 29115361 TI - The effect of hydrodynamic interactions on nanoparticle diffusion in polymer solutions: a multiparticle collision dynamics study. AB - The diffusion of nanoparticles (NPs) in polymer solutions is studied by a combination of a mesoscale simulation method, multiparticle collision dynamics (MPCD), and molecular dynamics (MD) simulations. We investigate the long-time diffusion coefficient D as well as the subdiffusive behavior in the intermediate time region. The dependencies of both D and subdiffusion factor alpha on NP size and polymer concentration, respectively, are explicitly calculated. Particular attention is paid to the role of hydrodynamic interaction (HI) in the NP diffusion dynamics. Our simulation results show that the long-time diffusion coefficients satisfy perfectly the scaling relation found by experimental observations. Meanwhile, the subdiffusive factor decreases with the increase in polymer concentration but is of little relevance to the NP size. By parallel simulations with and without HI, we reveal that HI will generally enhance D, while the enhancement effect is non-monotonous with increasing polymer concentration, and it becomes most pronounced at semidilute concentrations. With the aid of a scaling law based on the diffusive activation energy model, we understand that HI affects diffusion through decreasing the diffusive activation energy on the one hand while increasing the effective diffusion size on the other. In addition, HI will certainly influence the subdiffusive behavior of the NP, leading to a larger subdiffusion exponent. PMID- 29115362 TI - Femtosecond excited state dynamics of a stilbene-viologen charge transfer complex assembled via host-guest interaction. AB - The dynamics of the excited states of a supramolecular complex with a charge transfer between (E)-bis(18-crown-6)stilbene and 4,4'-(E)-ethene-1,2-diylbis[1-(2 ammonioethyl)pyridinium]tetraperchlorate was studied by means of femtosecond transient spectroscopy. It is found that the characteristic time of the conversion of the locally excited (LE) state into the charge transfer (CT) state is equal to 300 fs, whereas the characteristic time of the conversion of the CT state into the ground state is equal to 400 fs. Due to host-guest interaction involving hydrogen bonds, the complex possesses high thermodynamic stability. As a result of ultrafast photoinduced processes of the direct and back electron transfer, the complex does not fluoresce. Upon the interaction of the complex with alkaline-earth metal cations, "switch-on" of its fluorescence occurs. PMID- 29115365 TI - Interfacial rheological behaviors of inclusion complexes of cyclodextrin and alkanes. AB - The transformation of cyclodextrins (CDs) and alkanes from separated monomers to inclusion complexes at the interface is illustrated by analyzing the evolution of interfacial tension along with the variation of interfacial area for an oscillating drop. Amphiphilic intermediates are formed by threading one CD molecule on one alkane molecule at the oil/aqueous interface. After that, the amphiphilic intermediates transform into non-amphiphilic supramolecules which further assemble through hydrogen bonding at the oil/aqueous interface to generate a rigid network. With the accumulation of supramolecules at the interface, microcrystals are formed at the interface. The supramolecules of dodecane@2alpha-CD grow into microrods which form an unconsolidated shell and gradually cover the drop. However, the microcrystals of dodecane@2beta-CD are significantly smaller which fabricate into skin-like films at the interface. The amphiphilic intermediates during the transformation increase the feasibility of self-emulsification and the skin-like films enhance the stability of the emulsion. With these unique properties, CDs can be promising for application in hydrophobic drug delivery, food industry and enhanced oil recovery. PMID- 29115366 TI - Update on management of invasive candidiasis. AB - Given the growing incidence of invasive candidiasis in critically ill and haemato oncological patients and its poor outcomes, an early diagnosis and treatment are need for get a better prognosis. This document reviews the current ap-proaches that help in diagnosis of invasive candidiasis based on culture-independent microbiological tests. The combination of clinical prediction scores with fungal serological markers could facilitate the approach in antifungal therapy, optimiz ing it. This article also reviews the epidemiology and primary risk factors for invasive candidiasis in these patients, updating the therapeutic approach algorithms in both clinical contexts based on the main evidence and international guidelines. PMID- 29115367 TI - BAHNG score: predictive model for detection of subjects with the oropharynx colonized by uncommon microorganisms. AB - OBJECTIVE: Pneumonia is most frequently produced by the microaspiration of flora that colonizes the oropharynx. Etiological diagnosis of pneumonia is infrequent in clinical practise and empirical treatment should be prescribed. The aims of the present study were to determine the factors associated with oropharynx colonization by uncommon microorganisms (UM) and to develop a predictive model. METHODS: A cross-sectional study that included all pa-tients living in one long term care facilities was developed. Demographic, comorbidities, basal functional status and clinical data were collected. To determinate the oropharyngeal colonization, a single sample of pharynx was obtained for each subject using a cotton swab. RESULTS: A total of 221 subjects were included, mean age 86.27 (SD 8.05) years and 157 (71%) were female. In 32 (14.5%) subjects UM flora was isolated, Gram-negative bacilli in 16 (7.2%) residents, and Staphylococcus aureus in 16 (7.2%). The predictive model included the presence of hypertension, neuromuscular disease, Barthel <90 and use of PEG. The BAHNG score (BArthel, Hypertension, Neuromuscular, Gastrostomy), showed an area under the curve of 0.731 (CI 95% 0.643-0.820; p<0.001). We have classified patients according to this score in low (0-2 points), intermediate (3-5 points) and high risk (>= 6). The probability of UM colonization in the oropharyngeal based on this classification is 4.1%, 15.8% and 57.1% for low, intermediate and high risk, respectively. CONCLUSIONS: The BAHNG score could help in the identifications of elderly patients with high risk of colonization by UM. In case of pneumonia the evaluation of the subject through this score could help in the initial decisions concerning antibiotic treatment. PMID- 29115368 TI - [Evolution of the Complexity Index of the antiretroviral therapy in HIV+ patients in a real life clinical practice]. AB - OBJECTIVE: HIV infection has been one of the biggest successes in the healthcare world, mainly due to the appearance of antiretroviral treatment (ART). The complexity of this type of treatment has been one of the decisive factors in the follow-up of these patients. METHODS: An analytical, unicentric, retrospective observational study. We included all patients older than 18 years of age who were diagnosed with HIV who received ART in follow-up for the consultation of pharmaceutical pathology care during the year 2015. The evolution of the complexity index of ART over time and its relation with adherence to ART and concomitant treatment. RESULTS: A total of 619 patients were included in the study with a mean age of 47.03 +/- 10.18 years. There was a reduction in CI over the years, with a significant decrease in the year 2013 and in 2015. The results obtained after the analysis of the secondary variables showed a significant relation between the adhesion to the ART and the CI of this. Patients have a lower CI (3.5) than non-adherent patients (4.25). (P = 0.003). CONCLUSIONS: The complexity of ART is being reduced mainly by new treatment strategies and the increasing appearance of pharmaceutical coformulations. A reduction in the complexity of ART assumes a better adherence to it. PMID- 29115369 TI - Useful independent factors for distinguish infection and colonization in patients with urinary carbapenemase-producing Enterobacteriaceae isolation. AB - OBJECTIVE: The aim of this study is to know epidemiologic and clinical differences among those patients colonized or infected by carbapenemase-producing Enterobacteriaceae (CPE) and develop a predictive model to facilitate the clinical approach concerning to start antimicrobial therapy. METHODS: Observational retrospective cohort study was performed involving all patients with Urine carbapenemase-producing Enterobacteriaceae isolation (UCPEI) between November 2013 and July 2015. Patients were classifieds as colonized or infected considering Center for Disease Control and Prevention (CDC) definition for urinary tract infection (UTI). RESULTS: A total of 72 patients were included, mean age 76.4 (IQR 23-99) years and 40 (55.6%) were women. Thirty-four (47.2%) were colonized and 38 (52.8%) met the criteria of UTI and were considered infected. The independent variables associated to infection were female sex, peripheral vascular disease, admission in medical ward, permanent urinary catheter carrier, previous antimicrobial therapy, and length of stay. Isolation of OXA-48 carbapenemase-producing Enterobacteriaceae behaved as a non UTI (colonization) factor in comparison with KPC or VIM CPE. The developed predictive model showed an area under the curve (AUC) of 0.901 (95% CI: 0.832-0.970; p < 0.001). CONCLUSIONS: The predictive model that includes all this factors has demonstrated a good accuracy for infection diagnosis in these patients, an important issue considering that establishing the diagnosis of infection is not always easy in the profile of patients in which a CPE is isolated. PMID- 29115370 TI - [Febrile syndromes in the traveler returning from tropical regions admitted in a monographic unit]. AB - OBJECTIVE: The aim was to analyse those syndromes with fever in travellers who return from tropical regions evaluated at our Department of Infectology and Tropical Medicine. Clarifying these conditions intends to reach earlier diagnoses and, perhaps, to avoid the emergence and spread of imported diseases, as well as to establish appropriate preventive measures. METHODS: An observational descriptive transversal study was performed, selecting those patients who returned from tropical regions with fever, amongst all travellers evaluated in our department between 1998 and 2013. We analysed demographic features, information related to the trip, as well as the presenting complaints and the diagnoses. RESULTS: A total of 247 international travellers presenting with fever were analysed. The most common diagnoses were self-limiting fever (29.1%), malaria (25.1%), invasive gastroenteritis (15.4%), other bacterial infections (7.4%) and genitourinary parenchymal infections (4.5%). Of all the cases, only 8.5% required hospitalization, and no case of mortality was recorded. CONCLUSIONS: In the series presented, there are common data with other published data (malaria as a fundamental disease, difficulties in diagnosis) and different ones (less number of pre-trip consultations and admissions, higher incidence of prostatitis and fewer dengue cases). PMID- 29115371 TI - A novel method of neural differentiation of PC12 cells by using Opti-MEM as a basic induction medium. AB - The PC12 cell line is a classical neuronal cell model due to its ability to acquire the sympathetic neurons features when deal with nerve growth factor (NGF). In the present study, the authors used a variety of different methods to induce PC12 cells, such as Opti-MEM medium containing different concentrations of fetal bovine serum (FBS) and horse serum compared with RPMI-1640 medium, and then observed the neurite length, differentiation, adhesion, cell proliferation and action potential, as well as the protein levels of axonal growth-associated protein 43 (GAP-43) and synaptic protein synapsin-1, among other differences. Compared with the conventional RPMI-1640 medium induction method, the new approach significantly improved the neurite length of induced cells (2.7 times longer), differentiation rate (30% increase), adhesion rate (21% increase) and expression of GAP-43 and synapsin-1 (three times), as well as reduced cell proliferation. The morphology of induced cells in Opti-MEM medium containing 0.5% FBS was more like that of neurons. Additionally, induced cells were also able to motivate the action potential after treatment for 6 days. Therefore, the research provided a novel, improved induction method of neural differentiation of PC12 cells using Opti-MEM medium containing 0.5% FBS, resulting in a better neuronal model cell line that can be widely used in neurobiology and neuropharmacology research. PMID- 29115372 TI - Inhibition of Rho kinase protects against colitis in mice by attenuating intestinal epithelial barrier dysfunction via MLC and the NF-kappaB pathway. AB - The aim of the present study was to investigate the role of Rho kinase (also known as ROCK) inhibitor in 2,4,6-trinitrobenzene sulfonic acid induced mouse colitis; and to elucidate the underlying mechanism of ROCK1/ROCK2 inhibition in enhancing intestinal epithelial barrier (IEB) function. A specific inhibitor of ROCK, Y-27632, was used to examine the role of ROCK in mouse colitis models. ROCK1 and ROCK2 were silenced respectively using RNA interference in Caco-2 cells. The expression of tight junction proteins and the downstream molecules of ROCK were assessed. Y-27632 alleviated colonic inflammation and decreased intestinal permeability. ROCK-myosin light chain (MLC) and ROCK-NF-kappaB pathway were activated in colitis and inhibited by Y-27632. In vitro, ROCK1 RNAi primarily downregulated the phosphorylation of myosin phosphatase-targeting subunit-1 (MYPT-1) and MLC, while ROCK2 RNAi inhibited phosphorylation of nuclear factor-kappaB (NF-kappaB). In conclusion, the results suggested that the ROCK inhibitor alleviated colitis and IEB dysfunction. Inhibition of phospho-MYPT-1 and MLC by ROCK1 knockout or inhibition of NF-kappaB phosphorylation by ROCK2 knockout may be the underlying mechanisms. PMID- 29115373 TI - YAP and TAZ mediate steroid-induced alterations in the trabecular meshwork cytoskeleton in human trabecular meshwork cells. AB - Primary open angle glaucoma is an important type of glaucoma as it is one of the most common causes of blindness. Previous studies have demonstrated that in glaucomatous patients, the human trabecular meshwork (HTM) is markedly stiffened. The purpose of the present study was to determine the regulatory role of Yes associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HTM cells. Primary HTM cells were cultured with different concentrations of dexamethasone (DEX), and the expression levels of YAP and TAZ were evaluated using reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that DEX increased the expression of YAP and TAZ in a dose-dependent manner. In addition, the western blot analysis of cytoskeleton-associated proteins revealed that the inhibition of YAP and/or TAZ using small interfering RNA resulted in the increased expression of collagen I, and decreased expression of fibronectin, laminin and collagen IV. The expression of beta-catenin, a key protein in the Wnt pathway, was also observed to be regulated by YAP and TAZ. A 5-ethynyl-2'-deoxyuridine staining assay indicated that YAP and TAZ induced the proliferation of HTM cells. The investigation of cross-linked actin network formation by the HTM cells demonstrated that the knockdown of YAP and TAZ genes rescued HTM cells from cytoskeletal reorganization. Furthermore, functional evaluation of a HTM cell monolayer using a permeability assay demonstrated that the inhibition of YAP and TAZ attenuated the DEX-induced impairment of permeability. These findings suggest that YAP and TAZ play pivotal roles in the DEX-induced cytoskeletal changes of HTM cells, and reveal novel potential mechanisms for the development and progression of glaucoma. PMID- 29115374 TI - Metabolic profiles of adipose-derived and bone marrow-derived stromal cells from elderly coronary heart disease patients by capillary liquid chromatography quadrupole time-of-flight mass spectrometry. AB - Adipose-tissue derived mesenchymal stem cell (ADSC)-based therapy is a promising option for patients with atherosclerotic conditions, including coronary artery disease. However, the potential differences in the metabolic characteristics between bone marrow-derived mesenchymal stem cells (BMSCs) and ADSCs have remained to be fully elucidated. The present study aimed to compare the metabolic profiles of BMSCs and ADSCs via liquid chromatography quadrupole time-of-flight mass spectrometry. BMSCs and ADSCs obtained from elderly coronary heart disease patients were cultured, and after three passages, supernatants of each cell type were collected and systematically analysed. Substantial differences were detected between the metabolite signatures of ADSCs and BMSCs. In addition, further analysis using partial least-squares discriminant analysis score plots indicated significant differences between the supernatants of the two cell types. The following metabolites were deemed to be responsible for the potential differences in the metabolic characteristics of BMSCs and ADSCs: D-lactic acid, hydroxyindoleacetaldehyde, alpha-D-glucose, bovinic acid, 9,10-epoxyoctadecenoic acid, glyceraldehyde, phenylpyruvic acid, L-octanoylcarnitine, retinyl ester, alpha-ketoisovaleric acid, guanidoacetic acid, N-acetylneuraminic acid, imidazoleacetic acid riboside, sphingosine and pseudouridine 5'-phosphate. Based on these findings, there may be significant differences in the following metabolic pathways: The linoleic acid metabolic pathway, galactose metabolism, argentines and proline metabolism, retinol metabolism, glycine and serine metabolism, galactose metabolism, and amino sugar and nucleotide sugar metabolism. In conclusion, substantial differences in metabolic characteristics were detected between BMSCs and ADSCs, which may be associated with the different efficacies of atherosclerosis therapies employing these cell types. PMID- 29115375 TI - Persistent STAT5-mediated ROS production and involvement of aberrant p53 apoptotic signaling in the resistance of chronic myeloid leukemia to imatinib. AB - The persistent activation of signal transducer and activator of transcription 5 (STAT5) may principally be attributed to breakpoint cluster region (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1), and have multi-faceted effects in the development of chronic myeloid leukemia (CML). The p53 protein network regulates important mechanisms in DNA damage repair, cell cycle regulation/checkpoints, and cell senescence and apoptosis, as demonstrated by its ability to positively regulate the expression of various pro-apoptotic genes, including B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). In the present study, it was observed that the mRNA levels of STAT5A and STAT5B were upregulated in patients with imatinib-resistant CML and in the imatinib-resistant K562/G CML cell line. In addition, increased expression of STAT5 was observed in the BCR-ABL1 mutation group, compared with that in the non-BCR-ABL1 mutation group, regardless of patient imatinib resistance state. Elevated levels of reactive oxygen species (ROS) and DNA double-strand breaks were identified in K562/G cells using flow cytometric and phosphorylated H2AX (gamma-H2AX) foci immunofluorescence assays, respectively, compared with the imatinib-sensitive K562 cells. The levels of intracellular ROS and gamma-H2AX were decreased by the ROS scavenger (N-acetylcysteine), and ROS levels were also markedly reduced by STAT5 inhibitor (SH-4-54). In addition, imatinib significantly inhibited the proliferation of K562 and K562/G cells, with half maximal inhibitory concentration values of 0.17+/-0.07 and 14.78+/-0.43 uM, respectively, and the levels of apoptosis were significantly different between K562 and K562/G cells following treatment with imatinib. The mRNA and protein levels of STAT5 and mouse double minute 2 homolog (MDM2) were upregulated, whereas those of Bax were downregulated in K562/G cells, as determined using western blot analysis. Additionally, although the two cell lines exhibited relatively low protein expression levels of p53, lower levels of p53 and TPp53BP1 transcripts were detected in the K562/G cells. Taken together, these findings suggest that the resistance of CML to the tyrosine kinase inhibitor, imatinib, may be associated with persistent STAT5-mediated ROS production, and the abnormality of the p53 pathway. PMID- 29115376 TI - CCDC134 serves a crucial role in embryonic development. AB - Coiled-coil domain containing 134 (CCDC134), a characterized secreted protein, may serve as an immune cytokine and illustrates its potent antitumor effects by augmenting CD8+ T-cell-mediated immunity. Additionally, CCDC134 may also act as a novel regulator of human alteration/deficiency in activation 2a, and be involved in the p300-CBP-associated factor complex and affect its acetyltransferase activity. To clarify the biological and pathological function of CCDC134, the present study generated a viable and fertile Ccdc134fl/fl mouse strain that allowed temporal and spatial control of gene ablation. Ccdc134-/- embryos generated by crossing of Ccdc134fl/fl mice with human beta-actin-Cre or zona pellucida 3-Cre transgenic mice were embryonic lethal from embryonic day (E)12.5 to birth. Ccdc134 loss was associated with severe hemorrhages in the brain ventricular space and neural tube, pale and abnormal livers, cardiac hypertrophy and placental distress. Furthermore, it was demonstrated that a fraction of E13.5 fetal livers and brains exhibited reduced cell proliferation and vascular endothelial cell defects. CCDC134 also exhibited a dynamic and specific expression pattern during embryo development. The present results suggest that Ccdc134 may have specific biological functions in regulating mouse embryonic development. PMID- 29115377 TI - Connexin 43 in splenic lymphocytes is involved in the regulation of CD4+CD25+ T lymphocyte proliferation and cytokine production in hypertensive inflammation. AB - Chronic inflammation promotes the development of hypertension and is associated with increased T cell infiltration and cytokine production in impaired organs. Gap junction protein connexin 43 (Cx43), is ubiquitously expressed in immune cells and plays an important role in T cell proliferation and activation, and cytokine production. However, the correlation between Cx43 in T cells and the hypertensive inflammatory response remains unknown. Thus, in this study, we wished to examine this correlation. First, our results revealed that hypertension caused significant thickening of the vascular wall, inflammatory cell infiltration into part of the renal interstitium and glomerular atrophy, and it increased the tubular damage scores in the kidneys of spontaneously hypertensive rats (SHRs). Moreover, the SHRs exhibited stenosis in the central artery wall ofthe spleen with increased serum levels of interleukin (IL)-2 and IL-6 compared with normotensive Wistar-Kyoto (WKY) rats. The spleens of the SHRs exhibited a significantly decreased percentage of CD4+CD25+ (Treg) T cells. However, the percentages of CD3+, CD4+ and CD8+ T cell and the levels of CD4+Cx43 and CD8+Cx43 did not differ significantly between the SHRs and WKY rats. In cultured lymphocytes from the SHRs and WKY rats, low percentages of Treg cells and reduced cytokine (IL-2 and IL-6) mRNA expression levels were observed in the lymphocytes obtained from the SHRs and WKY rats treated with the connexin blocker, Gap27, or concanavalin A (ConA) plus Gap27. The effects of ConA and Gap27 differed between the SHRs and WKY rats. On the whole, our findings demonstrate that the splenic Treg cell-mediated suppression in SHRs may be involved in hypertensive inflammatory responses. Cx43 in the gap junctional channel may regulate lymphocyte activation and inflammatory cytokine production. PMID- 29115378 TI - Synovial fluid-derived synovial fragments represent an improved source of synovial mesenchymal stem cells in the temporomandibular joint. AB - Surgery-obtained synovium specimens (SSSs) can provide a source of synovial mesenchymal stem cells (SMSCs) for experimental studies. However, these specimens contain diverse tissues, including the intima and subintima; therefore, these SMSCs are not entirely derived from the intima and their cell source is heterogeneous. The present study isolated synovial fragments (SFs) from synovial fluid dilutions extracted from patients with temporomandibular joint (TMJ) osteoarthrosis. Unlike SSSs, SFs, which are membranous and translucent, consist of only several cell layers, indicating the presence of only the intima. In the present study, SF cells (SFCs) and SSS cells (SSSCs) exhibited a homogeneous, fibroblast-like, spindle-shaped morphology after passaging in vitro. Furthermore, both cell types exhibited similar proliferative and differentiation potentials in vitro. However, SFCs exhibited more uniform surface markers compared with SSSCs when analysed by flow cytometry. Taken together, these results indicated that SFs contained a greater amount of unmixed intima than SSSs, and that SFCs exhibited more homogeneous characteristics than SSSCs, thereby offering an improved source of SMSCs in the TMJ. PMID- 29115379 TI - Histone deacetylase 3 is associated with gastric cancer cell growth via the miR 454-mediated targeting of CHD5. AB - Gastric cancer (GC) is the third leading cause of cancer-related mortality in China and worlwide; hence, the identification of GC-related genes is necessary for the development of effective treatment strategies. In this study, histone deacetylase 3 (HDAC3) was identified as the most significantly upregulated cancer related gene in GC tissues by microarray. In accordance with this, HDAC3 expression was found to be upregulated in GC cell lines/tissues. Further experiments indicated that the knockdown of HDAC3 decreased GC cell viability, reduced the colony formation number and decreased tumor weight. To explore the underlying mechanisms, the overexpression of HDAC3 was induced by transfection with an overexpression plasmid, followed by miRNA microarray, and we identified miR-454 as the most markedly upregulated miRNA. Accordingly, miR-454 expression was upregulated in GC cell lines/tissues and a high level of miR-454 indicated a high HDAC3 expression in GC tissues, and miR-454 knockdown reduced cell viability. In addition, a high level of miR-454 was significantly associated with an advanced clinical stage, lymph node metastases and a poor prognosis of patients with GC. Furthermore, CHD5 was identified as a direct target of miR-454. CHD5 was downregulated in GC tissues/cell lines and the expresssion of CHD5 inversely correlated with the level of miR-454 in GC tissues. Taken together, these observations indicate that HDAC3 is associated with GC cell growth via the miR-454-mediated targeting of CHD5. PMID- 29115380 TI - Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway. AB - The present study aimed to assess the effects of therapy with adiponectin (APN) gene-modified adipose-derived stem cells (ADSCs) on pulmonary arterial hypertension (PAH) in rats and the underlying cellular and molecular mechanisms. ADSCs were successfully isolated from the rats and characterized. ADSCs were effectively infected with the green fluorescent protein (GFP)-empty (ADSCs-V) or the APN-GFP (ADSCs-APN) lentivirus and the APN expression was evaluated by ELISA. Sprague-Dawley rats were administered monocrotaline (MCT) to develop PAH. The rats were treated with MCT, ADSCs, ADSCs-V and ADSCs-APN. Then ADSCs-APN in the lung were investigated by confocal laser scanning microscopy and western blot analysis. Engrafted ADSCs in the lung were located around the vessels. Mean pulmonary arterial pressure (mPAP) and the right ventricular hypertrophy index (RVHI) in the ADSCs-APN-treated mice were significantly decreased as compared with the ADSCs and ADSCs-V treatments. Pulmonary vascular remodeling was assessed. Right ventricular (RV) function was evaluated by echocardiography. We found that pulmonary vascular remodeling and the parameters of RV function were extensively improved after ADSCs-APN treatment when compared with ADSCs and ADSCs V treatment. Pulmonary artery smooth muscle cells (PASMCs) were isolated from the PAH rats. The antiproliferative effect of APN on PASMCs was assayed by Cell Counting Kit-8. The influence of APN and specific inhibitors on the levels of bone morphogenetic protein (BMP), adenosine monophosphate activated protein kinase (AMPK), and small mothers against decapentaplegia (Smad) pathways was detected by western blot analysis. We found that APN suppressed the proliferation of PASMCs isolated from the PAH rats by regulating the AMPK/BMP/Smad pathway. This effect was weakened by addition of the AMPK inhibitor (compound C) and BMP2 inhibitor (noggin). Therefore, combination treatment with ADSCs and APN effectively attenuated PAH in rats by inhibiting PASMC proliferation and regulating the AMPK/BMP/Smad pathway. PMID- 29115381 TI - Proliferation of vascular smooth muscle cells under inflammation is regulated by NF-kappaB p65/microRNA-17/RB pathway activation. AB - Inflammation and excessive proliferation of vascular smooth muscle cells (VSMCs) have key roles in various vascular disorders, including restenosis, atherosclerosis and pulmonary artery hypertension. However, the underlying mechanism remains unclear. The present study investigated the role of nuclear factor-kappaB (NF-kappaB) and microRNA (miRNA) in the regulation of VSMC proliferation under inflammatory conditions. It was demonstrated that miR-17 stimulated the proliferation of VSMCs, enhanced cell cycle G1/S transition, and increased levels of proliferating cell nuclear antigen and E2F1. By directly targeting the retinoblastoma (RB) protein mRNA-3' untranslated region, miR-17 suppressed the expression of RB. Activation of NF-kappaB p65 resulted in increased miR-17 expression in VSMCs, whereas inactivation of NF-kappaB p65 resulted in decreased expression of miR-17 in VSMCs. NF-kappaB p65 signalling directly regulates miR-17 promoter activity. NF-kappaB p65 activation also suppressed RB expression, which was abrogated by miR-17 inhibitor. Taken together, the present results indicated that VSMC proliferation is regulated by activation of the NF-kappaB p65/miR-17/RB pathway. As NF-kappaB p65 signalling is activated in and is a master regulator of the inflammatory response, the present findings may provide a mechanism for the excessive proliferation of VSMCs under inflammation during vascular disorders and may identify novel targets for the treatment of vascular diseases. PMID- 29115382 TI - Resveratrol prevents osteoporosis by upregulating FoxO1 transcriptional activity. AB - Resveratrol (3,5,4-trihydroxystilbene, RES), a natural antioxidant, prevents bone loss by attenuating damage caused by oxidative stress. Our previous research revealed that the forkhead box O1 (FoxO1)/beta-catenin signaling pathway affected the proliferation and differentiation of osteoblasts through its regulation of redox balance, and RES regulated the expression of FoxO1 to control white adipose tissue and then ameliorate an overweight condition. Based on previous research, we hypothesized that RES regulates FoxO1 transcriptional activity through the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway to achieve an antioxidative effect on osteoporosis and then we confirmed this hypothesis in the present study. An ovariectomized (OVX) rat model of osteoporosis and a H2O2 induced oxidative cell injury model in RAW 264.7 cells were established to explore the underlying molecular mechanisms of how RES confers an antioxidant effect and prevents bone loss. The obtained results demonstrated that RES strongly prevented bone loss induced by oxidative stress in vivo. More specifically, RES effectively decreased the receptor activator of nuclear factor kappaB ligand (RANKL) together with the tartrate-resistant acid phosphatase-5b (TRAP-5b) level, but elevated the osteoproprotegrin (OPG) level and attenuated bone microarchitecture damage. Notably, RES, due to its antioxidant effect, suppressed RANKL production and then inhibited osteoclastogenesis in the OVX rats. In vitro, RES improved the oxidative stress status of cells and thus inhibited the mRNA expression of osteoclast-specific enzymes. These data indicate that RES has a significant bone protective effect by antagonizing oxidative stress to suppress osteoclast activity, function and formation both in vivo and in vitro. Moreover, at the molecular level, we confirmed, for the first time, that RES upregulated FoxO1 transcriptional activity by inhibiting the PI3K/AKT signaling pathway, and hence promoted resistance to oxidative damage and restrained osteoclastogenesis. Inhibition of the PI3K/AKT signaling pathway may be induced by RANKL. FoxO1 is a major action target of RES to confer anti osteoporosis function, and whose effect stems from its power to improve redox balance. PMID- 29115383 TI - Induced pluripotent stem cell-conditioned medium suppresses pulmonary fibroblast to-myofibroblast differentiation via the inhibition of TGF-beta1/Smad pathway. AB - Therapeutic strategies based on stem cells have been shown to have potential in improving the condition of severe lung diseases. In this study, the suppressive effects of conditioned medium (CM) of induced pluripotent stem cells (iPSCs) on pulmonary fibroblast differentiation were investigated in a series of in vitro and in vivo experiments. Moreover, the underlying mechanisms through which iPSC CM inhibited the differentiation of fibroblasts into myofibroblasts were explored as well. iPSCs were generated using a mouse 3-gene transfection method, myofibroblast-like cells were induced by incubating human fibroblasts with transforming growth factor-beta1 (TGF-beta1) and mouse models of pulmonary fibrosis (PF) were established by an injection of bleomycin. Based on these experiments, the effects of iPSC-CM on collagen accumulation, lung structure and the TGF-beta1-mediated pathway were determined. It was found that treatment with iPSC-CM markedly reduced the proliferation of TGF-beta1-exposed cells, and the activities of TGF-beta1, Smad-2 and Smad-3. Accompanied by alterations in the expression of the indicated molecules, the lung structure of mice with PF was also markedly ameliorated. The present study confirmed the protective effects of iPSC-CM on lung tissue against PF, and it was also inferred that the ameliorating function of iPSC-CM on PF may be exerted through the blocking of TGF-beta1/Smad signal transduction pathway. PMID- 29115384 TI - Atorvastatin protects the proliferative ability of human umbilical vein endothelial cells inhibited by angiotensin II by changing mitochondrial energy metabolism. AB - This study aimed to explore whether angiotensin II (Ang II) inhibits the proliferation of human umbilical vein endothelial cells (HUVECs) by changing mitochondrial energy metabolism, and whether atorvastatin has a protective role via restoration of endothelial function. HUVECs were treated with 1 uM Ang II alone or with 10 uM atorvastatin for 24 h. Proliferation was detected by MTT assay, cell counting, 5-ethynyl-2'-deoxyuridine assay and real-time cell analyzer. Mitochondrial energy metabolism including oxygen consumption rate and extracellular acidification rate were measured using a Seahorse metabolic flux analyzer. Mitochondrial membrane potential was detected under fluorescence microscope following staining with tetramethylrhodamine. Respiratory chain complexes I-V were detected using western blotting. The current study showed that Ang II inhibits the proliferation of HUVECs. Results from the Seahorse metabolic flux analyzer indicated that Ang II decreased basal oxygen consumption, maximal respiration capacity, spare respiration capacity, adenosine triphosphate-linked respiration and non-mitochondrial respiration. By contrast, Ang II increased the proton leak. Additionally, Ang II increased glycolysis, glycolytic capacity and non-glycolytic acidification. Furthermore, these effects were all suppressed by atorvastatin. The results indicated that atorvastatin prevents cellular energy metabolism switching from oxidative phosphorylation to glycolysis induced by Ang II and protected the proliferative ability of HUVECs. PMID- 29115386 TI - Protein extracted from Porphyra yezoensis prevents cisplatin-induced nephrotoxicity by downregulating the MAPK and NF-kappaB pathways. AB - Acute renal failure is a serious complication of treatment with the anticancer drug cisplatin. Cisplatin exerts a cytotoxic effect on renal cells by inducing apoptosis through activating the tumor suppressor p53, nuclear factor-kappaB (NF kappaB) and mitogen-activated protein kinase (MAPK)/p38 pathways. Effects of protein extracts of the brown seaweed Porphyra yezoensis (P. yezoensis) on cytotoxicity, inflammation and cell proliferation have been reported; however, the effects of P. yezoensis protein (PYP) extract on cisplatin-induced renal injury have remained elusive. The present study investigated the effects of PYP on cisplatin-induced nephrotoxicity in the HK2 human proximal tubular epithelial cell line. PYP treatment reduced cisplatin-induced apoptosis and death of HK2 cells by restoring the B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2 imbalance, cytochrome c release and caspase-3 activation. In addition, PYP activated the redox-sensitive transcription factor NF-kappaB via stimulating the nuclear translocation of p65 in HK2 cells. PYP also restored renal antioxidant levels and increased the total and nuclear accumulation of NF erythroid 2-related factor 2 in HK2 cells. PYP markedly attenuated cisplatin-induced p38, MAPK and c Jun N-terminal kinase phosphorylation. Furthermore, treatment with PYP ameliorated cisplatin-induced renal cell damage by upregulating antioxidant defense mechanisms and downregulating the MAPK and NF-kappaB signaling pathways. In addition, mice were divided into three treatment groups (control, cisplatin and PYP + cisplatin) and the effects of PYP were evaluated in a mouse model of cisplatin-induced acute kidney injury. The concentrations of blood urea nitrogen and serum creatinine in the PYP + cisplatin group were lower than those in the cisplatin group. The mRNA expression levels of inflammatory factors interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in the kidney tissues of the PYP + cisplatin group were also lower than those in the cisplatin group. These results suggest that PYP treatment had a preventive effect on nephrotoxicity, specifically by downregulating the MAPK and NF-kappaB signaling pathways and the mRNA levels of inflammatory genes. PMID- 29115385 TI - Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-kappaB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling. AB - Schisandrin A is a bioactive lignan occurring in the fruits of plants of the Schisandra genus that have traditionally been used in Korea for treating various inflammatory diseases. Although the anti-inflammatory and antioxidant effects of lignan analogues similar to schisandrin A have been reported, the underlying molecular mechanisms have remained elusive. In the present study, schisandrin A significantly suppressed the lipopolysaccharide (LPS)-induced production of the key pro-inflammatory mediators nitric oxide (NO) and prostaglandin E2 by suppressing the expression of inducible NO synthase and cyclooxygenase-2 at the mRNA and protein levels in RAW 264.7 macrophages. Furthermore, schisandrin A was demonstrated to reduce the LPS-induced secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-1beta; this was accompanied by a simultaneous decrease in the respective mRNA and protein levels in the macrophages. In addition, the LPS- induced translocation of nuclear factor-kappaB (NF-kappaB), as well as activation of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3 kinase (PI3K)/Akt pathways were inhibited by schisandrin A. Furthermore, schisandrin A significantly diminished the LPS stimulated accumulation of intracellular reactive oxygen species, and effectively enhanced the expression of NF erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). These results suggested that schisandrin A has a protective effect against LPS-induced inflammatory and oxidative responses in RAW 264.7 cells by inhibiting the NF-kappaB, MAPK and PI3K/Akt pathways; these effects are mediated, at least in part, by the activation of the Nrf2/HO-1 pathway. Based on these results, it is concluded that schisandrin A may have therapeutic potential for treating inflammatory and oxidative disorders caused by over-activation of macrophages. PMID- 29115387 TI - Generation of human-induced pluripotent stem cells from burn patient-derived skin fibroblasts using a non-integrative method. AB - Patient specific induced pluripotent stem cells (iPSCs) have been recognized as a possible source of cells for skin tissue engineering. They have the potential to greatly benefit patients with large areas of burned skin or skin defects. However, the integration virus-based reprogramming method is associated with a high risk of genetic mutation and mouse embryonic fibroblast feeder-cells may be a pollutant. In the present study, human skin fibroblasts (HSFs) were successfully harvested from patients with burns and patient-specific iPSCs were generated using a non-integration method with a feeder-free approach. The octamer binding transcription factor 4 (OCT4), sex-determining region Y box 2 (SOX2) and NANOG transcription factors were delivered using Sendai virus vectors. iPSCs exhibited representative human embryonic stem cell-like morphology and proliferation characteristics. They also expressed pluripotent markers, including OCT4, NANOG, SOX2, TRA181, stage-specific embryonic antigen 4 and TRA-160, and exhibited a normal karyotype. Teratoma and embryoid body formation revealed that iPSCs were able to differentiate into cells of all three germ layers in vitro and in vivo. The results of the present study demonstrate that HSFs derived from patients with burns, may be reprogrammed into stem cells with pluripotency, which provides a basis for cell-based skin tissue engineering in the future. PMID- 29115388 TI - Antinociceptive effect of Valeriana fauriei regulates BDNF signaling in an animal model of fibromyalgia. AB - The genus Valeriana has been widely used in popular medicine for centuries, to treat sleep disorders, anxiety, epilepsy and insomnia. Recent studies have focused on the novel pharmacological effects of Valeriana fauriei Briq. (VF) species. Previous studies have attempted to determine the pharmacological functions of Valeriana in various human diseases, particularly with regards to its neuroprotective effects, and its ability to reduce pain and stress. The present study constructed an animal model of fibromyalgia (FM), which was induced by intermittent cold stress with slight modification. Subsequently, the study aimed to determine whether VF exerts antinociceptive effects on the FM-like model following oral administration of VF extracts. The effects of VF extracts on the FM model were investigated by analyzing behavioral activity, including pain, and detecting protein expression. In the behavioral analysis, the results of a nociception assay indicated that the pain threshold was significantly decreased in the FM group. Subsequently, western blotting and immunohistochemical analyses of the hippocampus demonstrated that the protein expression levels of brain derived neurotrophic factor (BDNF) and phosphorylated-cAMP response element binding protein were downregulated in the FM group. Conversely, VF restored these levels. These results suggested that the effects of VF extract on a model of FM may be associated with its modulatory effects on the BDNF signaling pathway in the hippocampus and medial prefrontal cortex. In conclusion, the mechanism underlying the protective effects of VF as a therapeutic agent against FM may involve the BDNF signaling pathway. PMID- 29115389 TI - Renoprotective effect of erythropoietin via modulation of the STAT6/MAPK/NF kappaB pathway in ischemia/reperfusion injury after renal transplantation. AB - Ischemia/reperfusion injury (IRI) commonly occurs in renal transplantation. Erythropoietin (EPO) exerts a protective effect in IRI. To investigate the underlying molecular mechanism, rat models of renal IRI were established and treated with EPO and/or lentivirus-mediated EPO-siRNA, the signal transducer and activator of transcription 6 (STAT6) inhibitor AS1517499, the JNK inhibitor SP600125, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, and the nuclear factor (NF)-kappaB inhibitor lactacystin. Histological examination revealed that EPO protected the kidney from IRI, through decreasing the extent of tissue congestion and inflammatory cell infiltration; however, EPO siRNA did not exert the same protective effect. In addition, the EPO level was inversely associated with renal IRI. EPO downregulated the expression of interferon-gamma, interleukin (IL)-4, creatinine and caspase-3, and upregulated the expression of IL-10, thymic stromal lymphopoietin, STAT6, p-JNK and p-p38, while the opposite effects were observed with the administration of EPO-siRNA and the specific respective inhibitors. Further results revealed that MAPK (p-JNK and p-p38) acted upstream of NF-kappaB, and that NF-kappaB signaling regulated the expression of caspase-1 and -3, which may be responsible for the cytotoxicity associated with IRI. Taken together, the results of the present study demonstrated that EPO exerted a protective effect in renal IRI via the STAT6/MAPK/NF-kappaB pathway. This protective effect of EPO may improve reperfusion tolerance in ischemic kidneys and benefit transplant recipients. PMID- 29115390 TI - Anti-hypoglycemic and hepatocyte-protective effects of hyperoside from Zanthoxylum bungeanum leaves in mice with high-carbohydrate/high-fat diet and alloxan-induced diabetes. AB - The development of diabetes mellitus (DM) is accompanied by hyperglycemia-induced oxidative stress. Hyperoside is a major bioactive component in Zanthoxylum bungeanum leaves (HZL) and is a natural antioxidant. However, the effects of HZL on DM and its mechanisms of action remain undefined. The present study evaluated the anti-hypoglycemic and hepatocyte-protective effects of HZL in mice with diabetes induced by a high-carbohydrate/high-fat diet (HFD) and alloxan. We also aimed to eludicate the underlying mechanisms. Our resutls demonstrated that the administration of HZL significantly reduced body weight gain, serum glucose levels and insulin levels in diabetic mice compared with the vehicle-treated mice. In addition, the levels of dyslipidemia markers including total cholesterol, triglyceride and low-density lipoprotein cholesterol in the HFD treated mice were markedly decreased. Further experiments using hepatocytes from mice revealed that HZL significantly attenuated liver injury associated with DM compared with vehicle treatment, as evidenced by lower levels of alanine aminotransferase and aspartate aminotransferase in serum and by lower levels of lipid peroxidation, nitric oxide content and inducible nitric oxide synthase activity in liver tissues. Nuclear factor-kappaB (NF-kappaB) and mitogen associated protein kinase (MAPK) signaling pathways were investigated to elucidate the molecular mechanisms responsible for the protective effects of HZL against diabetic liver injury. The results indicated that HZL inhibited the phosphorylation of p65/NF-kappaB, MAPK (including p38, JNK and ERK1/2) and activating transcription factor 3 protein expression, with an additional suppression of Bax, cytochrome c, caspase-9 and caspase-3 in the liver tissues of diabetic mice. Taken together, our findings suggest that HZL, which was effective in inhibiting oxidative stress-related pathways may be beneficial for use in the treatment of DM. PMID- 29115391 TI - Effect on the dopaminergic metabolism induced by oral exposure to simazine during the prepubertal period in rats. AB - The herbicide simazine is widely used in agricultural and non-agricultural fields. Studies have shown that simazine inhibits the proliferation of dopaminergic cells and affects the developmental differentiation of dopamine neurons. However, little is known about the effects of simazine on dopaminergic metabolism. Therefore, the present study examined the effects of simazine on Sprague-Dawley (SD) rats from weaning to puberty (40 days exposure). Simazine was administered orally to SD rats at doses of 0, 12.5, 50 and 200 mg/kg body weight. The contents of dopamine (DA), levodopa, dihydroxy-phenyl-acetic acid and homovanillic acid in the striatum were then examined by high-performance liquid chromatography with a fluorescence detector. Quantitative polymerase chain reaction and western blotting were used to analyze the mRNA and protein expression of aromatic amino acid decarboxylase (AADC), tyrosine hydroxylase, orphan nuclear hormone (Nurr1), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). The results indicated that simazine influenced the synthesis, transport and metabolism of DA and led to a reduction of DA levels in the striatum. One potential underlying mechanism is decreased levels of Nurr1, DAT and VMAT2 impacting upon the transport of DA; another is the decreased level of AADC and increased levels of MAO and COMT impacting upon the synthesis and metabolism of DA. These factors may eventually lead to neurological disorders of the dopaminergic system. PMID- 29115392 TI - The inhibition of MyD88 and TRIF signaling serve equivalent roles in attenuating myocardial deterioration due to acute severe inflammation. AB - Myeloid differentiation factor 88 (MyD88) and Toll or interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (IFN-beta) (TRIF) are two pivotal downstream adaptors of Toll-like receptors. Activation of MyD88 or TRIF signaling in cardiac immune pathology of severe inflammation negatively influences heart function. In the present study, severe septic cardiac injury was induced in C57BL/6 mice by cecum ligation and puncture (CLP). A total of 64 mice were divided randomly into the following four groups (n=16/group; 8 for observation of survival rate, 8 for heart sample analysis): Sham, CLP, anti-MyD88 CLP and anti-TRIF-CLP. Anti-MyD88 and anti-TRIF antibodies were administered to the respective mice through the tail veins 2 h before CLP. Measurements of cardiac function, including M-modes, velocity vector imaging and cardiac troponin I, were performed. Myocardial inflammatory cytokines were examined by reverse transcription-polymerase chain reaction (RT-PCR), myocardial neutrophil infiltration was measured by a myeloperoxidase activity assay, intracellular adhesion molecule and vascular cell adhesion molecule mRNA expression levels were investigated, and histopathological characteristics were evaluated. Levels of mRNA transcripts encoding genes for apoptosis production and MyD88, TRIF, nuclear factor-kappaB and IFN regulatory factor 3 were investigated by RT-PCR. Mice challenged with CLP demonstrated deleterious cardiac function, increased levels of interleukin-1beta (IL-1beta), IL-6beta, and tumor necrosis factor-alpha mRNA, increased neutrophil infiltration, and increased apoptosis. In contrast, mice in the anti-MyD88 CLP and anti-TRIF CLP groups retained cardiac function with reduced cytokine release, decreased neutrophil infiltration, and reduced apoptosis. In addition, there was no significant difference between the anti MyD88 CLP and anti-TRIF CLP groups. Thus, the present study indicated that MyD88 and TRIF blockades serve notable and equivalent roles in protecting cardiac deterioration from severe sepsis by attenuating cytokine release, reducing neutrophil infiltration and alleviating apoptosis. PMID- 29115393 TI - Neuroprotective effects of hydrogen sulfide on sodium azide-induced oxidative stress in PC12 cells. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder, responsible for >50% of all dementia cases. Sodium azide (NaN3) inhibits cytochrome oxidase by irreversibly binding to the heme cofactor and selectively reducing the complex IV activity, which is present in post-mortem AD brains. Previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, exerted protective effects against neuronal damage. Therefore, it was hypothesized that H2S may be able to scavenge excess reactive oxygen species (ROS), thereby protecting against oxidative stress and cell death. In the present study, it was observed that cell viability decreased in a concentration dependent manner 12 h after NaN3 treatment (20, 30 and 50 mmol/l). A decrease in cell viability (to 51+/-3%) was observed 12 h after treatment with 30 mM NaN3. NaN3 treatment also led to decreased mitochondrial membrane potential, increased lipid peroxidation (excessive production of malondialdehyde), and increased the protein expression levels of caspase-3. Pretreatment with H2S (200 umol/l) attenuated NaN3-mediated apoptosis, and the anti-apoptotic action of H2S was partially dependent on suppressing the production of ROS. The findings of the present study suggested that H2S exerted a neuroprotective effect against NaN3 induced neurotoxicity through mechanisms related to anti-oxidation and anti apoptosis. Therefore, the findings of the present study suggest there may be a promising future for H2S-based preventions and therapies for neuronal damage following exposure to NaN3. PMID- 29115394 TI - High glucose upregulates endothelin type B receptors in vascular smooth muscle cells via the downregulation of Sirt1. AB - Silent information regulator family protein 1 (Sirt1) has recently gained attention for its protective effects against diabetic and cardiovascular diseases (CVDs). Vascular smooth muscle endothelin type B (ETB) receptors are involved in the pathogenesis of CVDs and diabetes. The aim of present study was to explore whether Sirt1 is involved in high glucose (HG)-mediated regulation of ETB receptors in rat superior mesenteric arteries (SMA). The rat SMA segments were cultured in the presence and absence of HG with or without the activator of Sirt1 and specific inhibitor for the extracellular signal-regulated protein kinase 1/2 (ERK1/2) for 24 h. Following organ culture, the contractile responses to sarafotoxin 6c were studied using a sensitive myograph, and the ETB receptor protein expression level was determined using western blotting. The results demonstrated that HG induced upregulation of ETB receptor expression and increased receptor-mediated vasoconstriction in SMA. Resveratrol (Res; a Sirt1 activator) concentration-dependently inhibited the HG-induced upregulation of ETB receptor expression and receptor-mediated vasoconstriction. Additionally, these effects could also be abolished by an inhibitor of the ERK1/2 signaling pathway. Furthermore, upregulation of ERK1/2 phosphorylation induced by HG was inhibited by Res. In conclusion, HG upregulated ETB receptors by downregulating Sirt1 and subsequently activating the ERK1/2 signaling pathways in the organ culture SMA. PMID- 29115395 TI - Transforming growth factor beta1 promotes migration and invasion in HepG2 cells: Epithelial-to-mesenchymal transition via JAK/STAT3 signaling. AB - Transforming growth factor beta1 (TGFbeta1) is a cytokine with multiple functions. TGFbeta1 significantly induces migration and invasion of liver cancer cells. However, the molecular mechanisms underlying this effect remain unclear. Epithelial-to-mesenchymal transition (EMT) is crucial for the development of invasion and metastasis in human cancers. The aim of the present study was to determine whether TGFbeta1-induced EMT promoted migration and invasion in HepG2 cells. The underlying mechanism and the effect of EMT on HepG2 cells were also investigated. The results demonstrated that TGFbeta1 may induce EMT to promote migration and invasion of HepG2 cells, and this effect depends on activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. JAK/STAT3 signaling is involved in human malignancies, including lung cancer, and is implicated in cell transformation, tumorigenicity, EMT and metastasis. In the present study, TGFbeta1 also activated JAK/STAT3 signaling in HepG2 cells and promoted Twist expression, but these events were abolished by treatment with the STAT3 inhibitor AG490. Additionally, Twist siRNA blocked TGFbeta1-induced EMT. Thus, TGFbeta1 was shown to induce EMT, thereby promoting the migration and invasion of HepG2 cells via JAK/STAT3/Twist signaling. PMID- 29115396 TI - Cryptdin-2 predicts intestinal injury during heatstroke in mice. AB - Intestinal injury-induced bacterial translocation and endotoxemia are important in the pathophysiological process of heatstroke. However, the underlying mechanism remains to be fully elucidated. Previous studies using 2D-gel electrophoresis found that defensin-related cryptdin-2 (Cry-2), an intestinal alpha-defensin, is upregulated in intestinal tissues during heatstroke in mice, and that treatment with ulinastatin, a multivalent enzyme inhibitor, reduced heat induced acute lung injury. To investigate the association between Cry-2 and heat stress (HS)-induced intestinal injury and the probable protective role of ulinastatin, the present study examined the intestinal expression of Cry-2 via histopathologic analysis and reverse transcription-quantitative polymerase chain reaction analysis in mice with heatstroke. The heat-stressed mice were exposed to different core temperatures and cooling treatments, and intestinal pathological changes and Chiu scores were determined. Chemical markers of intestinal injury, serum and intestinal concentrations of diamine oxidase (DAO) and D-lactic acid (D Lac), and serum and intestinal concentrations of Cry-2 were also determined. Correlations were analyzed using Spearman's correlation analysis. It was found that HS upregulated the expression of Cry-2, and the serum and intestinal concentrations of Cry-2 were correlated with the severity of HS-induced intestinal damage, indicated by pathology scores and concentrations of DAO and D lac. Ulinastatin protected the intestines from HS-induced injury and downregulated the expression of Cry-2, which was also correlated with the extent of intestinal injury. Therefore, ulinastatin administration may be beneficial for patients with heatstroke, and Cry-2 may be a novel predictor of HS-induced intestinal injury. PMID- 29115397 TI - Detection of calprotectin in inflammatory bowel disease: Fecal and serum levels and immunohistochemical localization. AB - The aim of the present study was to quantify calprotectin levels using an enzyme linked immunosorbent assay (ELISA) and a point-of-care test (POCT) in patients with inflammatory bowel disease. Overall, 113 patients with ulcerative colitis (UC; 51 men and 62 women) and 42 patients with Crohn's disease (CD; 29 men and 13 women), who were scheduled to undergo a colonoscopy, were prospectively enrolled and scored endoscopically and clinically. An additional 96 healthy, age-matched subjects served as the normal controls. Feces and blood samples from the patients with UC and CD, and the normal controls were analyzed. These patients had received adequate medical treatment. The tissue distribution of calprotectin was investigated using immunohistochemistry. The fecal calprotectin levels, as measured using an ELISA, were correlated with the endoscopic and clinical disease activities and laboratory parameters, including serum levels of hemoglobin (Hb), albumin and C-reactive protein, and erythrocyte sedimentation rate, particularly among the patients with UC. The fecal Hb level was close to that of the fecal calprotectin level (r=0.57; P<0.0001). The fecal calprotectin level measured using an ELISA was well-correlated with the fecal calprotectin level measured using the POCT (r=0.81; P<0.0001), but was not correlated with the serum calprotectin level (r=0.1013; P=0.47). An immunohistochemical investigation revealed that patients with both UC and CD had higher neutrophil and monocyte/macrophage calprotectin-positive cell expression levels, compared with those in the normal controls. Fecal calprotectin was considered a reliable marker for disease activity, and the assessment of fecal calprotectin via POCT showed potential as a rapid and simple measurement in clinical settings. PMID- 29115398 TI - Vibrio vulnificus infection induces the maturation and activation of dendritic cells with inflammatory Th17-polarizing ability. AB - Vibrio vulnificus (V. vulnificus) is a gram-negative bacterium, which causes life threatening septicemia and gastroenteritis through the consumption of contaminated seafood or wound infection. In addition, V. vulnificus infection is known to stimulate the production of several pro-inflammatory cytokines, which are associated with inflammatory responses mediated predominantly by dendritic cells (DCs), functioning as antigen-presenting cells. The present study aimed to investigate whether V. vulnificus infection induced the maturation and activation of murine DCs, which have the ability to polarize T helper (Th) cells into Th17 cells. Dysregulated Th17 cell responses are known to cause tissue damage, promoting the penetration of pathogens; however, Th17 cells are also involved in host defense against infection. Infection with V. vulnificus significantly increased the expression of cell surface molecules, including CD40, CD80 and major histocompatibility complex class II, leading to the maturation and activation of DCs. In the present study, the analysis of the cytokine profiles of DCs upon infection with V. vulnificus revealed the preferential production of interleukin-1beta (IL-1beta) and IL-6, through which V. vulnificus-infected DCs induced the polarization of Th17 cells when naive CD4+ T cells were co-incubated. The reduction of Th17 cell generation through the use of anti-IL-6 neutralizing antibodies indicated that the Th17-polarizing capacity of V. vulnificus was predominantly dependent on DC-derived IL-6. The in vivo administration of V. vulnificus-infected DCs consistently increased the Th17 cell population in the lymph nodes of mice. Finally, the oral administration of V. vulnificus in mice also increased Th17 cell responses in the lamina propria of the small intestine. These results collectively demonstrated that V. vulnificus induced inflammatory Th17 cell responses via DCs, which may be associated with the immunopathological effects caused by V. vulnificus infection. PMID- 29115399 TI - Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer. AB - Recent studies have demonstrated that abnormal expression of the clock gene PER2 is closely associated with the development of a variety of cancer types. However, the expression of PER2 in oral squamous cell carcinoma (OSCC), a common malignant tumor in humans, and its correlations with the clinicopathological parameters and survival time of OSCC patients and the altered expression of important tumor related genes remain unclear. In the present study, we detected the mRNA and protein expression levels of PER2, PIK3CA, PTEN, P53, P14ARF and caspase-8 in OSCC tissues and cancer-adjacent oral mucosa by reverse transcription quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The results showed that the PER2, PTEN, P53, P14ARF and caspase-8 mRNA and protein expression levels in OSCC were significantly reduced compared with those in cancer-adjacent tissues. Additionally, the PIK3CA protein expression level was significantly increased in OSCC tissues, whereas the mRNA level was not. Decreased expression of PER2 was significantly associated with advanced clinical stage and the presence of lymphatic metastasis in OSCC patients. Patients with PER2-negative expression had a significantly shorter survival time than those with PER2-positive expression. PER2 expression was negatively correlated with PIK3CA and P53 levels, and positively correlated with PTEN, P14ARF and caspase-8 levels. In summary, the results of this study suggest that loss of PER2 expression is closely associated with the genesis and development of OSCC and that PER2 may be an important prognostic biomarker in OSCC. PER2 may serve an antitumor role via the P53/P14ARF, PIK3CA/AKT and caspase-8 pathways. PMID- 29115401 TI - Inhibitors targeting the SUMOylation pathway: A patent review 2012-2015 (Review). AB - Small ubiquitin-related modifier (SUMO) proteins bind to the lysine residue of target proteins to produce functionally mature proteins. The abnormal SUMOylation of certain target proteins is associated with diseases including cancer, heart disease, diabetes, arthritis, degenerative diseases and brain ischemia/stroke. Thus, there has been growing appreciation for the potential importance of the SUMO conjugation pathway as a target for treating these diseases. This review introduces the important steps in the reversible SUMOylation pathway. The SUMO inhibitors disclosed in the patents between 2012 and 2015 are divided into different categories according to their mechanisms of action. Certain compounds disclosed in this review have also been reported in other articles for their inhibition of the SUMOylation pathway following screening in cell lines. Although there are few studies using animal models or clinical trials that have used these compounds, the application of bortezomin, a ubiquitylation inhibitor, for treating cancer indicates that SUMO inhibitors may be clinically successful. PMID- 29115400 TI - Global gene expression analysis combined with a genomics approach for the identification of signal transduction networks involved in postnatal mouse myocardial proliferation and development. AB - Mammalian cardiomyocytes may permanently lose their ability to proliferate after birth. Therefore, studying the proliferation and growth arrest of cardiomyocytes during the postnatal period may enhance the current understanding regarding this molecular mechanism. The present study identified the differentially expressed genes in hearts obtained from 24 h-old mice, which contain proliferative cardiomyocytes; 7-day-old mice, in which the cardiomyocytes are undergoing a proliferative burst; and 10-week-old mice, which contain growth-arrested cardiomyocytes, using global gene expression analysis. Furthermore, myocardial proliferation and growth arrest were analyzed from numerous perspectives, including Gene Ontology annotation, cluster analysis, pathway enrichment and network construction. The results of a Gene Ontology analysis indicated that, with increasing age, enriched gene function was not only associated with cell cycle, cell division and mitosis, but was also associated with metabolic processes and protein synthesis. In the pathway analysis, 'cell cycle', proliferation pathways, such as the 'PI3K-AKT signaling pathway', and 'metabolic pathways' were well represented. Notably, the cluster analysis revealed that bone morphogenetic protein (BMP)1, BMP10, cyclin E2, E2F transcription factor 1 and insulin like growth factor 1 exhibited increased expression in hearts obtained from 7-day-old mice. In addition, the signal transduction pathway associated with the cell cycle was identified. The present study primarily focused on genes with altered expression, including downregulated anaphase promoting complex subunit 1, cell division cycle (CDC20), cyclin dependent kinase 1, MYC proto-oncogene, bHLH transcription factor and CDC25C, and upregulated growth arrest and DNA damage inducible alpha in 10-week group, which may serve important roles in postnatal myocardial cell cycle arrest. In conclusion, these data may provide important information regarding myocardial proliferation and development. PMID- 29115402 TI - AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia. AB - Mitochondrial biogenesis is one of the generally accepted regulatory mechanisms in the heart under chronic hypoxia. The precise quantity and quality control of mitochondria is critical for the survival and function of cardiomyocytes. Mitochondrial autophagy, also known as mitophagy, which selectively eliminates dysfunctional and unwanted mitochondria, is the most important type of mitochondrial quality control. However, the detailed molecular mechanisms of mitophagy in cardiomyocytes have been largely undefined. The present study investigated the role of adenosine 5'-monophosphate-activated protein kinase (AMPK) in mitophagy regulation in cardiomyocytes under chronic hypoxia. H9c2 cells were cultured under hypoxic conditions (1% O2) for different time periods. Mitochondrial biogenesis was confirmed and hypoxia was found to induce the collapse of mitochondrial membrane potential (LambdaPsim) and increase the number of dysfunctional mitochondria. As expected, mitochondrial autophagy was increased significantly in cardiomyocytes exposed to hypoxic conditions for 48 h. AMPK was activated under hypoxia. Notably, when the activation of AMPK was enhanced by the AMPK agonist AICAR, mitochondrial autophagy was increased accordingly. By contrast, when AMPK activation was blocked, mitochondrial autophagy was decreased and cardiomyocyte apoptosis was increased. In conclusion, in the present study, mitophagy was activated and played a crucial role in cardioprotection under chronic hypoxia. AMPK was involved in mitophagy regulation, thereby providing a potential therapeutic target for heart diseases associated with chronic hypoxia. PMID- 29115403 TI - Expression profile analysis of long non-coding RNAs involved in the metformin inhibited gluconeogenesis of primary mouse hepatocytes. AB - Long non-coding RNAs (lncRNAs) have been demonstrated to regulate metabolic tissue development and function, including adipogenesis, hepatic lipid metabolism, islet function and energy balance. However, the role of lncRNAs in gluconeogenesis remains completely unknown. Metformin reduces glucose output mainly via the inhibition of gluconeogenesis. In the present study, the lncRNA expression profile of primary mouse hepatocytes exposed to cyclic adenosine monophosphate (cAMP), a gluconeogenic stimulus, with or without metformin was analyzed by microarray. Among the 22,016 lncRNAs that were identified, 456 were upregulated and 409 were downregulated by cAMP (fold-change >=2.0). Furthermore, the cAMP-induced upregulation of 189 lncRNAs and downregulation of 167 lncRNAs was attenuated by metformin. The expression levels of eight lncRNAs were validated by reverse transcription-quantitative polymerase chain reaction, and the results were consistent with those of the microarray analysis. Among them, two lncRNAs NR_027710 and ENSMUST00000138573, were identified to have an association with two protein coding genes, namely peroxisome proliferator activated receptor-gamma coactivator-1alpha, a critical transcriptional coactivator in gluconeogenesis, and G protein-coupled receptor 155, respectively. The two protein coding genes exhibited similar expression patterns to their associated lncRNAs. The findings of the present study suggest that lncRNAs are potentially involved in the regulation of gluconeogenesis. PMID- 29115404 TI - Downregulation of mitochondrial UQCRB inhibits cancer stem cell-like properties in glioblastoma. AB - Glioblastoma stem cell targeted therapies have become a powerful strategy for the treatment of this deadliest brain tumor. We demonstrate for the first time that downregulation of mitochondrial ubiquinol-cytochrome c reductase binding protein (UQCRB) inhibits the cancer stem cell-like properties in human glioblastoma cells. The synthetic small molecules targeting UQCRB significantly suppressed not only the self-renewal capacity such as growth and neurosphere formation, but also the metastatic potential such as migration and invasion of glioblastoma stem-like cells (GSCs) derived from U87MG and U373MG at subtoxic concentrations. Notably, the UQCRB inhibitors repressed c-Met-mediated downstream signal transduction and hypoxia-inducible factor-1alpha (HIF-1alpha) activation, thereby reducing the expression levels of GSC markers including CD133, Nanog, Oct4 and Sox2 in the GSCs. Furthermore, the UQCRB inhibitors decreased mitochondrial ROS generation and mitochondrial membrane potential in the GSCs, indicating that they regulate the mitochondrial function in GSCs. Indeed, the knockdown of UQCRB gene by UQCRB siRNA significantly inhibited the cancer stem cell-like phenotypes as well as the expression of stemness markers by blocking mitochondrial ROS/HIF-1alpha/c-Met pathway in U87MG GSCs. These findings suggest that UQCRB and its inhibitors could be a new therapeutic target and lead compounds for eliminating cancer stem cells in glioblastoma. PMID- 29115405 TI - Alterations of protein glycosylation in embryonic stem cells during adipogenesis. AB - The understanding of adipose tissue development is crucial for the treatment of obesity-related diseases. Adipogenesis has been extensively investigated at the gene and protein levels in recent years. However, the alterations in protein glycosylation during this process remains unknown, particularly that of parthenogenetic embryonic stem cells (pESCs), a type of ESCs with low immunogenicity and no ethical concerns regarding their use. Protein glycosylation markedly affects cell growth and development, cell-to-cell communication, tumour growth and metastasis. In the present study, the adipogenic potentials of J1 ESCs and pESCs were first compared and the results demonstrated that pESCs had lower adipogenic potential compared with J1 ESCs. Lectin microarray was then used to screen the alteration of protein glycosylation during adipogenesis. The results revealed that protein modification of GlcNAc and alpha-1-2-fucosylation increased, whereas alpha-1-6-fucosylation, alpha-2-6-sialylation and alpha-1-6 mannosylation decreased in J1 ESCs and pESCs during this process. In addition, alpha-1-3-mannosylation decreased only in pESCs. Lectin histochemistry and quantitative polymerase chain reaction of glycosyltransferase confirmed the results obtained by lectin microarray. Therefore, protein glycosylation of ESCs was significantly altered during adipogenesis, indicating that protein glycosylation analysis is not only helpful for studying the mechanism of adipogenesis, but may also be used as a marker to monitor adipogenic development. PMID- 29115406 TI - Berberine prevents the apoptosis of mouse podocytes induced by TRAF5 overexpression by suppressing NF-kappaB activation. AB - Berberine (BBR) has previously been found to exert beneficial effects on renal injury in experimental rats. However, the mechanisms underlying these effects are not yet fully understood. Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) has been demonstrated to mediate the activation of nuclear factor kappaB (NF-kappaB), which has been implicated in the pathogenesis of chronic kidney disease (CKD). The aim of this study was to investigate the effects of BBR on kidney injury and the activation of the NF-kappaB signaling pathway in mouse podocytes. TRAF5 was found to be overexpressed in patients with CKD and chronic renal failure (CRF) (data obtained from the dataset GSE48944, as well as from patients at Shuguang Hospital). TRAF5 overexpression significantly inhibited cell viability and induced the apoptosis of mouse podocytes. However, BBR prevented the decrease in cell viability and the apoptosis induced by TRAF5 overexpression. The NF-kappaB inhibitor, caffeic acid phenethyl ester (CAPE), mimicked the protective effects of BBR, as evidenced by the increased expression of nephrin and podocin, and the decreased the expression of caspase-3 and the ratio of Bax/Bcl-2. Moreover, BBR prevented the decrease in cell viability decrease and the apoptosis induced by TNF-alpha, interleukin (IL)-6 and lipopolysaccharide (LPS). Taken together, our data indicate that BBR exerts protective effects against CRF partly through the TRAF5-mediated activation of the NF-kappaB signaling pathway in mouse podocytes. PMID- 29115407 TI - Suppression of microRNA-130b inhibits glioma cell proliferation and invasion, and induces apoptosis by PTEN/AKT signaling. AB - Glioblastoma is the most common malignant brain tumor in adults and is characterized by extensive proliferation and the diffused invasion of tumor cells. Due to the intricate signaling pathways involved in glioma progression, more effective targeted therapies and prognostic biomarkers in clinical practice are required. The suppression of proto-oncogene function or recovery of tumor suppressor gene function remains one of the primary approaches in gene therapy. The close association between the abnormal expression or mutation of microRNA (miRNA) and the tumorigenesis, progression and staging in glioma have been demonstrated previously. However, the expression pattern and specific role of microRNA-130b (miR-130b) in the tumor occurrence and progression of glioma are unclear. In the present study, quantitative polymerase chain reaction was performed to determine the expression level of miR-130b in 30 brain glioma patients and 3 glioma cell lines. An miR-130b inhibitor was transfected into U87 cells to downregulate the expression of miR-130b, and assessments of cell proliferation, cell cycle, apoptosis, cell invasion and migration in vitro and nude mouse tumorigenicity in vivo were conducted. Western blotting and luciferase reporter gene technology were used to verify the downstream target gene of miR 130b, namely phosphatase and tensin homolog (PTEN). The results demonstrated that miR-130b expression was increased in glioma tissues and cell lines in comparison with non-glioma tissues or cells. The downregulated expression of miR-130b inhibited the proliferation and invasion of glioma cells, induced apoptosis of the cells in vitro and inhibited their tumorigenicity in vivo. Western blotting and luciferase reporter assays demonstrated that the PTEN gene is a direct target of miR-130b. Western blotting revealed that the miR-130b inhibitor upregulated the expression of PTEN, inhibited AKT pathway activation, upregulated the tumor suppressor gene p27, and suppressed cyclin D1, matrix metalloproteinase 2 and 9 expression. These results suggest that the miR-130b inhibitor suppressed glioma cell proliferation and invasion via the PTEN/AKT pathway. Therefore, miR-130b is suggested to be an effective therapeutic target for glioma. PMID- 29115408 TI - Salidroside could enhance the cytotoxic effect of L-OHP on colorectal cancer cells. AB - Evidence has suggested that salidroside inhibits the proliferation and invasion of renal clear cell, lung, breast, and colon cancer. However, effect of salidroside on colorectal cancer (CRC) cells against oxaliplatin (L-OHP) resistance remains unclear. In the present study, the CRC HT-29 cell line and L OHP resistance HT-29/L-OHP cell line were used to evaluate the effect, and mechanism of salidroside on L-OHP resistance. The results demonstrated that the activity of HT-29 cells was lower compared with that of HT-29/L-OHP cells following L-OHP intervention, and was accompanied with varied expression levels of drug resistant proteins. The combination of salidroside and L-OHP weakened cell activity significantly compared single utilization. Compared with the control group, salidroside intervention resulted in a higher percentage of HT 29/L-OHP cells in the G0/G1 stage, and reduced percentage in the G2/M stage, but no significant variation in the S stage. The HT-29/L-OHP cells exhibited increased apoptosis rates and caspase-3 activity, but decreased metastatic, and invasive abilities following salidroside intervention. Quantitative polymerase chain reaction and western blot analysis detected variations in the expression levels of associated genes in HT-29/L-OHP cells following salidroside intervention. In all, the results of the present study revealed that salidroside is able to decrease the activity and invasive capacity of HT-29/L-OHP cells, and treatment with salidroside is associated with increased apoptosis of cancer cells through the regulation of certain genes. PMID- 29115409 TI - Mechanism of long non-coding RNA MALAT1 in lipopolysaccharide-induced acute kidney injury is mediated by the miR-146a/NF-kappaB signaling pathway. AB - The present study aimed to examine the expression and function of the metastasis associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA (miR)-146a/nuclear factor (NF)-kappaB axis in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). The mRNA levels of MALAT1 and miR-146a in AKI tissues and cells were detected using reverse transcription-quantitative polymerase chain reaction analysis. The NF-kappaB pathway proteins and cell viability were assessed using western blot analysis and the MTT method, respectively. The secretion of inflammatory factors was determined using the ELISA method. The present study also examined effects of the abnormal expression of MALAT1 and miR-146a on cytokines and the NF-kappaB pathway. A potential binding region between MALAT1 and miR-146a was confirmed via RNA immunoprecipitation. The results revealed that the upregulation of MALAT1 reduced the expression of miR-146a, and there was a negative linear correlation between MALAT1 and miR-146a in a RNA-induced silencing complex-dependent manner. The expression levels of miR-146a were lower in the kidney injury specimens and NRK-52E cells, compared with those in the controls. MALAT1 knockdown and the overexpression of miR-146a reduced the production of phosphorylated inhibitor of NF-kappaB and np65 protein. miR-146a was found to be transcriptionally induced by NF-kappaB, and miR-146a repressed the pro-inflammatory NF-kappaB pathway and downstream transcription factors. Taken together, these data indicated that the MALAT1/miR-146a/NF-kappaB pathway exerted key functions in LPS-induced AKI, and provided novel insights into the mechanisms of this therapeutic candidate for the treatment of the disease. PMID- 29115410 TI - Peanut arachidin-1 enhances Nrf2-mediated protective mechanisms against TNF-alpha induced ICAM-1 expression and NF-kappaB activation in endothelial cells. AB - Arachidin-1 [trans-4-(3-methyl-1-butenyl)-3,5,3',4'-tetrahydroxystilbene] is a polyphenol produced by peanut kernels during germination. The aim of the present study was to investigate the mechanism underlying the anti-inflammatory effect of arachidin-1 in endothelial cells (ECs). The results of cell adhesion and western blotting assays demonstrated that arachidin-1 attenuated tumor necrosis factor (TNF)-alpha-induced monocyte/EC adhesion and intercellular adhesion molecule-1 (ICAM-1) expression. Arachidin-1 was demonstrated to exert its inhibitory effects by the attenuation of TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) nuclear translocation and inhibitor of kappaB-alpha (IkappaBalpha) degradation. Furthermore, arachidin-1 upregulated nuclear factor-E2-related factor-2 (Nrf-2), a known mediator of phase II enzyme expression, and increased the transcriptional activity of antioxidant response element. Transfection of ECs with Nrf-2 siRNA blocked the inhibitory effect of arachidin-1 on ICAM-1 expression, NF-kappaB nuclear translocation and IkappaBalpha degradation. In addition, arachidin-1 induced the expression of the phase II enzymes thioredoxin-1, thioredoxin reductase-1, heme oxygenase-1, glutamyl-cysteine synthetase and glutathione S transferase. Following arachidin-1 pretreatment, the H2O2-induced generation of reactive oxygen species was reduced. Therefore, the present results indicate that arachidin-1 suppresses TNF-alpha-induced inflammation in ECs through the upregulation of Nrf-2-related phase II enzyme expression. PMID- 29115411 TI - Transcriptome sequencing revealed candidate genes relevant to mesenchymal stem cells' role in aortic dissection patients. AB - Aortic dissection (AD) results from the imbalance between synthesis and degradation of extracellular matrices in aortic wall, which is characterized by chronic inflammation. Mesenchymal stem cells (MSCs) are known for anti inflammatory and repairing effects and have therefore been studied for treatment for numerous diseases, including AD. However, it is unclear which genes or signaling pathways contribute to MSCs' role in AD. In the present study, RNA sequencing (RNA-seq) was conducted between MSCs from patients with AS (AD-MSCs) and those from age-matched healthy donors (HD-MSCs). RNA-seq revealed 201 differentially expressed genes (DEGs) under the filter of fold change>2 and P value <0.05, in which 93 genes were upregulated and 108 downregulated. We selectively verified 9 out of 201 DEGs via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) with an enlarged sample size. The trends of RT-qPCR results were consistent with RNA-seq data. Unsupervised hierarchical clustering of the 9-gene expression profiles enables the division of clinical samples into AD and HD groups. Kyoto Encyclopedia of Genes and Genomes analysis displayed a significant change in adhesion-related signaling pathways in AD-MSCs compared with HD-MSCs, whereas gene ontology analysis demonstrated DEGs were enriched in functions associated with development and morphogenesis, from a functional perspective. The present results indicate that gene expression profiles of AD-MSCs were significantly changed compared with HD-MSCs. These changes are probably associated with MSCs' adhesion capacity and development. These results may provide important insights into the role of MSCs in AD pathogenesis. PMID- 29115412 TI - Knockdown of DUXAP10 inhibits proliferation and promotes apoptosis in bladder cancer cells via PI3K/Akt/mTOR signaling pathway. AB - DUXAP10 is a member of long non-coding RNAs (lncRNAs) and has been reported to be upregulated in bladder cancer (BC) tissues. However, the biological functions of DUXAP10 in BC are largely unknown. The present study detected the expression of DUXAP10 in human normal bladder cell SV-HUC-1 and BC cell lines. Subsequently, cell proliferation, cell cycle, and apoptosis were analyzed by knockdown of the DUXAP10 expression. Results suggested that the expression level of DUXAP10 was significantly enhanced in cancer cells. After knockdown of DUXAP10, cell proliferation was inhibited, cell cycle was arrested at G0/G1 phase, and apoptosis was increased in T24 and 5637 cells. Western blot analysis detected that knockdown of DUXAP10 decreased the expression of Bcl-xL, cyclin D and CDK4. This increased the expression of Bad, cleaved caspase-3, cleaved caspase-9, and p27. Further studies indicated that knockdown of DUXAP10 inhibited PI3K/Akt/mTOR signaling pathway. Combining these results, our study suggests that DUXAP10 plays an important role in BC and DUXAP10 inhibition is a potential therapeutic target for BC. PMID- 29115413 TI - Evaluation of the accuracy and sensitivity of high-throughput sequencing technology using known microbiota. AB - Next generation sequencing provides an excellent platform to explore microbiota in any given environment, and little work is required to evaluate the accuracy and sensitivity of high-throughput sequencing technology. In the present study, a known microbiota containing Escherichia coli, Lactobacillus plantarum, Streptococcus thermophilus, Bifidobacterium bifidum, Bacillus subtilis, Enterococcus faecalis and Salmonella typhimurium was used to evaluate the high throughput sequencing technology. The results suggested that there were 122.7 operational taxonomic units (OTUs) in all groups, which is 17.5-fold (the whole OTU number/the actual bacterial number) greater compared with the actual microbial number in each group, and the Venn method indicated that only 46.38% (64/138), 58.70% (81/138), 86.13% (118/137), 83.57% (117/140) and 89.29% (125/140) of the common OTUs were identified in groups A, B, C, D and E, of which the majority of OTUs did not belong to known bacteria. In addition, the DNA extraction and amplification efficiency failed to identify bacteria at the phylum, class, order, family, genus and species levels, which may further increase false information of microbial analysis. In conclusion, the present study provided basic datato investigate the potential drawbacks of high throughput sequencing technology, which will help researchers to avoid exaggerating the bacterial number when this technology is applied to study microbiota in particular environments. PMID- 29115414 TI - Anti-oncogenic activities of cyclin D1b siRNA on human bladder cancer cells via induction of apoptosis and suppression of cancer cell stemness and invasiveness. AB - The human cyclin D1 gene generates two major isoforms, cyclin D1a and cyclin D1b, by alternative splicing. Although cyclin D1b mRNA is hardly expressed in normal human tissues, it is detected in approximately 60% of human bladder cancer tissues and cell lines. In the present study, to assess the therapeutic ability of cyclin D1b siRNA, we investigated the anti-oncogenic effects of cyclin D1b siRNA on human bladder cancer cell lines, SBT31A and T24, which express cyclin D1b mRNA. Knockdown of cyclin D1b by specific siRNA significantly suppressed cell proliferation, in vitro cell invasiveness and three-dimensional (3D) spheroid formation in these cell lines. Cell cycle analyses revealed that cyclin D1b siRNA inhibited G1-S transition in T24 cells. The increase in the sub-G1 fraction, morphological aberrant nuclei with nuclear fragmentation and caspase-3 activity in SBA31A cells treated with cyclin D1b siRNA showed that cyclin D1b siRNA induced apoptosis. In T24 cells, knockdown of cyclin D1b suppressed the expression of the stem cell marker CD44. Knockdown of cyclin D1b or CD44 suppressed the invasiveness under 3D spheroid culture conditions and expression of N-cadherin. Tumor growth of SBT31A cells in nude mice was significantly inhibited by cyclin D1b siRNA. Taken together, these results indicate that knockdown of cyclin D1b suppresses the malignant phenotypes of human bladder cancer cells via induction of apoptosis and suppression of cancer cell stemness and epithelial-mesenchymal transition. Applying cyclin D1b siRNA will be a novel therapy for cyclin D1b-expressing bladder cancers. PMID- 29115415 TI - The STAT-ROS cycle extends IFN-induced cancer cell apoptosis. AB - In mammals, the signal transducer and activator of transcription (STAT) protein processes mitochondria importation targets and mitochondria respiratory complexes, and triggers reactive oxygen species (ROS) generation, which conversely rapidly initiates the activation of STAT. Interferon (IFN) administration increases cancer cell apoptosis via STAT activation and ROS accumulation. However, the existence of a STAT-ROS cycle and how it affects IFN induced cancer cellular apoptosis are unclear. In the present study, we used MCF7 breast cancer cells and confirmed that a combination of IFN-alpha/beta/gamma incubation induced STAT1/3 phosphorylation and mitochondria importation, which increased mitochondria respiratory complexes, the cellular oxygen consumption rate (OCR), and ROS production, followed by cellular apoptosis. We also found that STAT1/3 overexpression induced mitochondria respiratory complexes and ROS production. Additionally, ROS induced by H2O2 induced phosphorylation of STAT1/3 and promoted mitochondria importation. STAT1/3 deletion suppressed H2O2-induced acute cellular OCR, increasing the ROS level and indicating that STAT1/3 is necessary for ROS-induced mitochondria OCR and further ROS production, suggesting the existence of a STAT-ROS cycle. We next found that IFN induced mitochondria respiratory complexes followed by induction of OCR, ROS, and apoptosis, which were partially blocked by STAT1/3 deletion. Additionally, the suppression of ROS inhibited IFN-induced STAT1/3 activation. Finally, we discovered that this cycle exists also in A431 and HeLa cancer cells. These results indicate that a STAT-ROS cycle extends IFN-induced cellular apoptosis. PMID- 29115416 TI - Annexin A2 and cancer: A systematic review. AB - Annexin A2 is a 36-kDa protein interfering with multiple cellular processes especially in cancer progression. The present review aimed to show the relations between Annexin A2 and cancer. A systematic search for studies investigating cancer and Annexin A2 expression was conducted using PubMed. Acute lymphoblastic leukaemia, acute promyelocytic leukaemia, clear cell renal cell carcinoma, breast, cervical, colorectal, endometrial, gastric cancer, glioblastoma, hepatocellular carcinoma, lung, multiple myeloma, oesophageal squamous cell carcinoma, ovarian cancer, pancreatic duct adenocarcinoma, prostate cancer and urothelial carcinoma were evaluated. Annexin A2 expression correlates with resistance to treatment, binding to the bone marrow, histological grade and type, TNM-stage and shortened overall survival. The regulation of Annexin A2 is of interest due to its potential as target for a more individualized cancer management. PMID- 29115417 TI - Wnt/beta-catenin pathway activation and silencing of the APC gene in HPV-positive human cervical cancer-derived cells. AB - Although persistent infections with high-risk human papilloma virus (HPV) constitute the most significant cofactor for the development of cervical cancer, they are insufficient on their own. Mutations or epigenetic inactivation of the tumor suppressor adenomatous polyposis coli (APC), the two acting as prominent oncogenic mechanisms in a number of types of cancer, are frequently associated with aberrant activation of the Wnt/beta-catenin pathway. According to these observations, it was hypothesized that APC alteration may lead to beta-catenin deregulation and the abnormal expression of direct targets of the Wnt pathway in HPV-infected cervical cancer cells. The present study confirmed that the stabilization of beta-catenin correlates with enhanced transcriptional activity of the beta-catenin/T-cell factor complex in cervical cancer cell lines. Sequence analysis of the 'hot-spot' in the mutation cluster region did not exhibit genetic alterations that may be associated with APC gene inactivation. In addition, it was identified that there was a good correlation with the hypermethylation status of the APC promoter 1A and the abnormal accumulation of endogenous beta-catenin in cell lines and biopsies infected with HPV16, although not HPV18. Removal of the epigenetic markers led to an increase in APC levels and a reduction of beta catenin expression in two transcriptional targets of the Wnt pathway: Matrix metalloproteinase-7 and vascular endothelial growth factor. The present study suggested that the increase in Wnt activity in certain cervical cancer-derived cells may be associated with an alteration in the methylation status of the APC gene promoter 1A. PMID- 29115418 TI - Predicting pathogenic genes for primary myelofibrosis based on a system-network approach. AB - The aim of the present study was to predict pathogenic genes for primary myelofibrosis (PMF) using a system-network approach by combining protein-protein interaction (PPI) network and gene expression data with known pathogenic genes. PMF gene expression profiles, known pathogenic genes and protein-protein interactions were obtained. Using these data, differentially expressed genes (DEGs) were identified between PMF and normal conditions using significance analysis of microarrays, and seed genes were determined based on the intersection of known pathogenic genes and the PMF gene expression profile. A new network was constructed using the seed genes and their adjacent DEGs within the PPI network. Subsequently, a pathogenic network was extracted from the new network, and contained genes that interacted with at least two seed genes, and the candidate pathogenic genes were predicted based on the cohesion with seed genes. Cluster analysis was performed to mine the pathogenic modules from the pathogenic network, and functional analysis was performed to identify the putative biological processes of the candidate pathogenic genes. Results from the present study identified 845 DEGs between PMF and normal conditions, and 45 seed genes in PMF were screened. Subsequently, a pathogenic network comprising 103 nodes and 265 interactions was constructed, and 4 pathogenic modules (modules A-D) were mined from the pathogenic network. There were nine candidate pathogenic genes contained within Module A and four potential pathogenic genes, including E1A binding protein p300, RAS-like proto-oncogene A, von Willebrand factor and RAF-1 proto-oncogene, serine/threonine kinase, were identified that may be involved in the same biological process with the seed genes. This study predicted 10 candidate pathogenic genes and several signaling pathways that may be related to the pathogenesis of PMF using a system-network approach. These predictions may shed light on the PMF pathogenesis and may provide guidelines for future experimental verification. PMID- 29115419 TI - Effect of beta-ecdysterone on glucocorticoid-induced apoptosis and autophagy in osteoblasts. AB - The aim of the present study was to investigate the effect of glucocorticoids in osteoblasts and to examine the role of beta-ecdysterone in the pathogenesis of glucocorticoid-induced osteoporosis. Osteoblasts were induced from bone marrow mesenchymal stem cells, which were isolated from C57BL/6 mice. Cell viability and apoptosis of osteoblasts were measured by Cell Counting Kit-8 and flow cytometry analysis, respectively. The expression of related genes and proteins was measured by reverse transcription quantitative polymerase chain reaction and western blot analysis respectively. Dose-dependent decreases in the cell proliferation and differentiation were observed in dexamethasone (Dex)-treated osteoblasts, evidenced by downregulation in the activity of alkaline phosphatasedecreased expression levels of Runt-related transcription factor 2 and osteocalcin, and upregulated expression of RANK ligand. Dex also induced apoptosis and inhibited autophagy of osteoblasts, evidenced by upregulated B-cell lymphoma 2 (Bcl-2) associated X protein/Bcl-2 ratio and the activation of mammalian target of rapamycin (mTOR), and decreased expression levels of Beclin-1, autophagy protein 5 and microtubule-associated protein 1 light chain 3 II. The effects on cell proliferation, apoptosis and autophagy induced by Dex were reversed by beta ecdysterone in a dose-dependent manner. Therefore, beta-ecdysterone may be a promising candidate drug for the treatment of osteoporosis through inducing osteoblast autophagic activity by inactivating mTOR. PMID- 29115420 TI - Construction of a prognostic prediction system for pancreatic ductal adenocarcinoma to investigate the key prognostic genes. AB - Pancreatic cancer (PC) is associated with high mortality rates and poor prognoses. Pancreatic adenocarcinoma is the most common type of PC, and almost all cases of pancreatic adenocarcinoma are pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to reveal the genes involved in the prognosis of PDAC. Five datasets, including GSE71729 (145 PDAC samples and 46 normal samples), GSE15471 (39 PDAC samples and 39 normal samples), GSE1542 (24 PDAC samples and 25 normal samples), GSE28735 (45 PDAC samples and 45 normal samples) and GSE62452 (69 PDAC samples and 69 normal samples) were downloaded from the Gene Expression Omnibus database. Using the MetaDE.ES method in the MetaDE package, differentially expressed genes (DEGs) were identified from the five datasets. Furthermore, prognosis-associated genes were screened using the Cox regression analysis in the survival package, and co-expression network and module analyses were performed separately using Cytoscape software and GraphWeb tool, respectively. After a prognostic prediction system was constructed and validated, enrichment analysis of the signature genes was performed using the clusterProfiler package. A total of 480 DEGs were identified from the five datasets and 259 prognosis-associated genes were screened from GSE28735 and GSE62452. In addition, the prognostic prediction system composed of 67 signature genes [including basic transcription factor 3 (BTF3), serine/threonine kinase 11 (STK11), thrombospondin 1 (THBS1), ribosomal protein L38 (RPL38) and secretin receptor (SCTR)] was constructed and validated. The signature genes involved in the co-expression network were enriched in five pathways. In particular, STK11 was involved in three signaling pathways, and THBS1 was enriched in the phosphoinositide 3-kinase-Akt signaling pathway. Thus, BTF3, STK11, THBS1, RPL38 and SCTR may influence the prognosis of PDAC. PMID- 29115421 TI - Gene expression profiles and protein-protein interaction networks during tongue carcinogenesis in the tumor microenvironment. AB - Oral tongue squamous cell carcinoma (OTSCC) has a high incidence and is associated with a high mortality rate. Studies regarding the potential molecular mechanism of OTSCC in the tumor microenvironment (TME) are required. The present study aimed to perform bioinformatic analysis to identify important nodes, clusters and functional pathways during tongue carcinogenesis in the TME. After downloading the gene expression data of GSE42780, differentially expressed genes (DEGs) among carcinoma, dysplastic and normal samples in epithelia and fibroblasts were identified using the affy and limma packages with R version 3.3. Subsequently, the Database for Annotation, Visualization and Integrated Discovery was employed to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Furthermore, a protein-protein interaction (PPI) network was constructed by using the Search Tool for the Retrieval of Interacting Genes/Proteins and analyzed by Cytoscape software. In total, 85 DEGs were identified for tongue epithelia and 46 DEGs were identified for fibroblasts. Neutrophil chemotaxis and inflammatory response from GO, and cytokine-cytokine receptor interaction from KEGG were enriched for epithelia and fibroblasts. The PPI network revealed that C-X-C motif chemokine ligand (Cxcl)1, Cxcl10, Cxcl13, Cxcl2 and pro-platelet basic protein were a key cluster for epithelia, and interleukin (Il)1beta, Il1 receptor 2, Il1a and Il1 receptor antagonist were a key cluster for fibroblasts. Therefore, the results indicate that fibroblasts and cytokines associated with an inflammatory immune response contributed substantially to tongue carcinogenesis in the TME, which is useful for the development of OTSCC targeted therapy. However, further investigation is required to elucidate the molecular and cellular mechanisms underlying the inflammatory immune network in the TME. PMID- 29115422 TI - Melatonin ameliorates myocardial apoptosis by suppressing endoplasmic reticulum stress in rats with long-term diabetic cardiomyopathy. AB - The effects of melatonin (MLT), which exerts cardioprotective effects against myocardial apoptosis, in long-term diabetic cardiomyopathy are not currently well defined. The present study aimed to investigate how MLT protects the heart through modulating myocardial apoptosis in rats with type 2 diabetes mellitus (DM). In total, 36 rats were randomly divided into three groups, including control (n=12), DM (n=12) and DM + MLT (n=12) groups. The results demonstrated that, in DM rats, a significant increase was observed in the serum fasting blood glucose and lipid levels, in addition to insulin resistance and cardiac dysfunction, which were attenuated in DM rats treated with MLT. Additionally, cellular apoptosis in rats with DM was increased, and the expression of Bcl-2 was downregulated, while levels of Bcl-2-associated X and caspase-3 were upregulated, and these observations were reversed by MLT, as determined by TUNEL and western blot analysis, respectively. As increased endoplasmic reticulum (ER) stress induced by hyperglycemia is reported to be a factor for apoptosis, the present study also determined the expression of proteins associated with ER stress in cardiac tissues following MLT treatment by western blotting. The results further indicated that MLT decreased the expression of ER stress hallmarks, including CCAAT/enhancer-binding protein homologous protein, glucose-regulated protein 78, protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6alpha in cardiac tissues. In conclusion, the results of the present study indicate that MLT may protect heart by ameliorating cardiac ER stress-induced apoptosis in diabetic cardiomyopathy. PMID- 29115423 TI - Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins. AB - In cancers, apoptosis signaling pathways and cell survival and growth pathways responsible for resistance to conventional treatments, such as Pi3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) become dysregulated. Recently, alternative treatments to promote tumor cell death have become important. The present study reports on the antitumor and cytoprotective action of gold nanoparticles (GNPs) and carvedilol in combination and in isolated application. Apoptosis was analyzed by FITC/propidium iodide staining flow cytometry; caspase 3, caspase-8, Bcl-2 and MAPK/ERK activity by immunofluorescence microscopy; gene expression of proteins related to cell death as Akt, mTOR, EGFR, MDR1, survivin, FADD and Apaf, by the real-time PCR; and western blot analysis for MAPK/ERK, Akt and mTOR. Oxidative stress evaluation was performed by reduced glutathione (GSH) and malondialdehyde (MDA) levels. Intracellular GNPs targets were identified by transmission electron microscopy. After exposure to a combination of GNPs (6.25 ug/ml) and carvedilol (3 uM), death as promoted by apoptosis was detected using flow cytometry, for expression of pro-apoptotic proteins FADD, caspase-3, caspase 8 and sub-regulation of anti-apoptotic MAPK/ERK, Akt, mTOR, EGFR and MDR1 resistance. Non-tumor cell cytoprotection with GSH elevation and MDA reduction levels was detected. GNPs were identified within the cell near to the nucleus when combined with carvedilol. The combination of GNP and carvedilol promoted downregulation of anti-apoptotic and drug resistance genes, over-regulation of pro-apoptotic proteins in tumor cells, as well as cytoprotection of non-tumor cells with reduction of apoptosis and oxidative stress. PMID- 29115425 TI - The HMGB1-IL-17A axis contributes to hypoxia/reoxygenation injury via regulation of cardiomyocyte apoptosis and autophagy. AB - Both the high-mobility group box 1 protein (HMGB1) and interleukin (IL)-17A serve important roles in myocardial ischemia and reperfusion injury. The purpose of the present study was to evaluate whether HMGB1 could induce IL-17A secretion and lead to cardiomyocyte hypoxia/reoxygenation (H/R) injury. Neonatal rat cardiomyocytes were treated with HMGB1-neutralizing antibody, IL-17A-neutralizing antibody, recombinant HMGB1 (rHMGB1) and recombinant IL-17A (rIL-17A), respectively. Cell viabilities, lactate dehydrogenase and creatine kinase levels were measured. Apoptotic cells were assessed by flow cytometry. The expression of HMGB1, IL-17A, microtubule-associated proteins 1A/1B light chain 3B (LC3), Beclin 1, B-cell lymphoma (Bcl)-2 and Bcl-2-associated X protein were assessed by western blot analysis. The results demonstrated that HMGB1 significantly increased the expression of IL-17A. HMGB1 or IL-17A antibody significantly ameliorated H/R-induced cell injury and improved the cell viability. In contrast, rHMGB1 or rIL-17A aggravated cell injury and inhibited the cell viability. Furthermore, cardiomyocytes were treated with HMGB1 or IL-17A antibody significantly increased Bcl-2 protein expression and had fewer apoptotic cells, whereas rHMGB1 or rIL-17A-treated cardiomyocytes markedly decreased Bcl-2 protein expression and had more apoptotic cells. Moreover, HMGB1 or IL-17A antibodies significantly inhibited H/R induced autophagy dysfunction (as determined by the inhibition of Beclin-1 expression, a lower ratio of LC3-II to LC3-I), whereas rHMGB1 or rIL-17A may promote cardiomyocyte autophagy. Together, these results suggested that the HMGB1-IL-17A axis contributes to H/R injury via regulation of cardiomyocyte apoptosis and autophagy. PMID- 29115424 TI - Cornin protects SH-SY5Y cells against oxygen and glucose deprivation-induced autophagy through the PI3K/Akt/mTOR pathway. AB - It has been reported that cornin may reduce neuronal death during cerebral ischemia; however, little is known about the molecular mechanism of the role of corninin autophagy in SH-SY5Y neuronal cells. In the present study, oxygen glucose deprivation (OGD)-treated cells were used as a cerebral ischemia model in vitro. The results demonstrated that cornin was able to reduce neuronal cell loss, increase the apoptosis regulator Bcl-2/apoptosis regulator BAX ratio, and decrease the protein levels of caspase-3. In addition, cornin decreased the microtubule-associated proteins 1A/1B light chain 3B (LC3)-II/LC3-I ratio and beclin-1 protein expression, and resulted in an upregulation in phosphorylated (p)-RAC-alpha serine/threonine-protein kinase (Akt), p-protein kinase mTOR (mTOR) in OGD-treated SH-SY5Y cells. Additionally, it was observed that following inhibition of PI3K/Akt by LY294002, the levels of p-Akt and p-mTOR were markedly decreased, and the LC3-II/LC3-I ratio and beclin-1 were increased. Similarly, following inhibition of mTOR by rapamycin, LC3-II/LC3-I and Beclin-1 were significantly increased in SH-SY5Y cells. These results indicated that cornin protected SH-SY5Y cells against OGD-induced autophagy through the PI3K/Akt/mTOR pathway. PMID- 29115426 TI - Recombinant truncated TGF-beta receptor II attenuates carbon tetrachloride induced epithelial-mesenchymal transition and liver fibrosis in rats. AB - Liver fibrosis is a pathological process of chronic liver diseases. In particular, epithelial-mesenchymal transition (EMT) is a major source of myofibroblast structure in liver fibrosis. The present study investigated the effects of recombinant truncated transforming growth factor-beta receptor II (rtTGFbetaRII) on EMT and liver fibrosis in a carbon tetrachloride (CCl4)-induced rat model. A total of 24 rats were randomly separated into three groups: Normal control (NC), model (CCl4) and treatment (CCl4 + rtTGFbetaRII) groups. Histological methods, including hematoxylin and eosin, Masson's trichrome and Sirius red staining were conducted. The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using an automatic biochemical analyzer. The mRNA expression levels of fibroblast specific protein-1 (FSP-1), alpha-smooth muscle actin (alpha-SMA), fibronectin, collagen I, vimentin and E-cadherin were detected using reverse transcription quantitative polymerase chain reaction analysis. The protein levels of fibronectin, collagen I, E-cadherin, Smad2/3 and phosphorylated (p)-Smad2/3 were detected using western blot analysis. The expression of alpha-SMA, fibronectin, vimentin and E-cadherin in the liver tissue was detected using immunofluorescence staining. The results demonstrated that in vivo, rtTGFbetaRII significantly reduced the degree of liver injury, serum ALT and AST activities and liver fibrosis. These factors were associated with reduced expression of FSP-1, alpha SMA, fibronectin, collagen I, vimentin and p-Smad2/3, and increased expression of E-cadherin. The results of the present study suggest that rtTGFbetaRII may inhibit EMT processes in CCl4-induced liver fibrosis in rats and alter the expression of epithelial and myofibroblast markers. Therefore, rtTGFbetaRII may be considered a possible treatment for preventing liver fibrosis via EMT processes. PMID- 29115427 TI - Abnormal DNA methylation may contribute to the progression of osteosarcoma. AB - The identification of optimal methylation biomarkers to achieve maximum diagnostic ability remains a challenge. The present study aimed to elucidate the potential molecular mechanisms underlying osteosarcoma (OS) using DNA methylation analysis. Based on the GSE36002 dataset obtained from the Gene Expression Omnibus database, differentially methylated genes were extracted between patients with OS and controls using t-tests. Subsequently, hierarchical clustering was performed to segregate the samples into two distinct clusters, OS and normal. Gene Ontology (GO) and pathway enrichment analyses for differentially methylated genes were performed using the Database for Annotation, Visualization and Integrated Discovery tool. A protein-protein interaction (PPI) network was established, followed by hub gene identification. Using the cut-off threshold of >=0.2 average beta-value difference, 3,725 unique CpGs (2,862 genes) were identified to be differentially methylated between the OS and normal groups. Among these 2,862 genes, 510 genes were differentially hypermethylated and 2,352 were differentially hypomethylated. The differentially hypermethylated genes were primarily involved in 20 GO terms, and the top 3 terms were associated with potassium ion transport. For differentially hypomethylated genes, GO functions principally included passive transmembrane transporter activity, channel activity and metal ion transmembrane transporter activity. In addition, a total of 10 significant pathways were enriched by differentially hypomethylated genes; notably, neuroactive ligand-receptor interaction was the most significant pathway. Based on a connectivity degree >90, 7 hub genes were selected from the PPI network, including neuromedin U (NMU; degree=103) and NMU receptor 1 (NMUR1; degree=103). Functional terms (potassium ion transport, transmembrane transporter activity, and neuroactive ligand-receptor interaction) and hub genes (NMU and NMUR1) may serve as potential targets for the treatment and diagnosis of OS. PMID- 29115428 TI - Inhibition of p21 activated kinase enhances tumour immune response and sensitizes pancreatic cancer to gemcitabine. AB - Pancreatic ductal adenocarcinoma (PDA) is one of the major types of cancer that exhibit high mortality worldwide because of the late diagnosis and the lack of effective treatment. Immunotherapy appears to be ineffective in PDA treatment due to the existence of a unique immune-suppressive microenvironment in PDA. Gemcitabine-based therapy is still the most commonly used chemotherapy to treat PDA patients with only marginal increased survival rates. This prompted us to continue the search for more effective therapy for PDA treatment. The effects of p21 activated kinases (PAKs) on tumour immune response and gemcitabine response were examined in PDA. An orthotopic murine PDA model, in which pancreatic cancer cells were injected to the tail of pancreas, was used. The mice were treated with PAK inhibitor, PF-3758309, plus or minus gemcitabine. Tumour growth was measured by volume and weight. Tumour immune response was determined by flow cytometry analysis of splenic cells and immunohistochemical staining of intratumoural lymphocytes. Inhibition of PAKs by PF-3758309, not only suppressed tumour growth, but also stimulated tumour immune response by increasing the numbers of splenic and intratumoural T lymphocytes. Furthermore, inhibition of PAKs decreased PDA cell growth synergistically with gemcitabine in vitro and in vivo. The dual effects of inhibition of PAKs make PAK-targeted therapy more potent for the treatment of PDA. The combination of PAK inhibitors with gemcitabine may be a more effective therapeutic approach in PDA treatment. PMID- 29115429 TI - Resveratrol-mediated apoptosis in renal cell carcinoma via the p53/AMP-activated protein kinase/mammalian target of rapamycin autophagy signaling pathway. AB - Resveratrol, known as phytoalexin, is a natural compound. Clinical studies have revealed that resveratrol has a variety of effects including anti-inflammatory, antivirus and tumor suppressor activities. It has been reported that it may serve an important role in renal cell carcinoma (RCC) however, the molecular mechanism underlying resveratrol-induced apoptosis in RCC is still unclear. The aim of the present study was to determine whether resveratrol could suppress RCC progression. Analysis of apoptosis demonstrated that resveratrol may act as a RCC suppressor in a dose- and time-dependent manner. In addition, the results of the MTT and cell migration experiments revealed that resveratrol significantly decreased cell viability and migration. In addition, the expression of the anti apoptosis gene B-cell lymphoma 2 (Bcl-2) was downregulated by resveratrol, and the expression of pro-apoptosis gene Bcl-2-associated X was upregulated at the mRNA and protein levels. Resveratrol also promoted the expression of p53 and activated phospho-AMP-activated protein kinase (AMPK). The phosphorylation of mammalian target of rapamycin (mTOR) was inhibited and the autophagy-associated genes, light chain 3, autophagy related (ATG)5 and ATG7, were upregulated at the mRNA and protein levels. In conclusion, resveratrol suppressed RCC viability and migration, and promoted RCC apoptosis via the p53/AMPK/mTOR-induced autophagy signaling pathway. PMID- 29115430 TI - Expression, purification and epitope analysis of Pla a 2 allergen from Platanus acerifolia pollen. AB - Platanus acerifolia is one of the major sources of outdoor allergens to humans, and can induce allergic asthma, rhinitis, dermatitis and other allergic diseases. Pla a 2 is a polygalacturonase and represents the major allergen identified in P. acerifolia pollen. The aim of the present study was to express and purify Pla a 2, and to predict B and T cell epitopes of Pla a 2. The gene encoding Pla a 2 was cloned into the pET28a vector and subsequently transfected into ArcticExpressTM (DE3) Escherichia coli cells; purified Pla a 2 was analyzed by western blot analysis. The results of the present study revealed that the Pla a 2 allergen has the ability to bind immunoglobulin E within the sera of patients allergic to P. acerifolia pollen. In addition, the B cell epitopes of Pla a 2 were predicted using the DNAStar Protean system, Bioinformatics Predicted Antigenic Peptides and BepiPred 1.0 software; T cell epitopes were predicted using NetMHCIIpan -3.0 and 2.2. In total, eight B cell epitopes (15-24, 60-66, 78-86, 109-124, 232-240, 260 269, 298-306 and 315-322) and five T cell epitopes (62-67, 86-91, 125-132, 217 222 and 343-350) were predicted in the present study. These findings may be used to improve allergen immunotherapies and reduce the frequency of pollen-associated allergic reactions. PMID- 29115431 TI - Genetic diagnosis and pathogenic analysis of an atypical hereditary spherocytosis combined with UGT1A1 partial deficiency: A case report. AB - Patients with combined hereditary spherocytosis (HS) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) deficiency have been reported sporadically. A discrepancy between the level of elevated serum bilirubin concentration and the degree of anemia may suggest the possibility of a coexistence of these conditions. In the present case report, a 20-year-old female presented with congenital jaundice and anemia, but did not present with the discrepancy between hyperbilirubinemia and anemia in the patient's childhood, and was not previously diagnosed with either HS or UGT1A1 deficiency. During a follow-up of >10 years, the patient's hyperbilirubinemia accumulated progressively, whereas the patient's anemia became relatively mild. Upon further genetic analysis, it was determined that the patient had HS combined with UGT1A1 partial deficiency. Next generation sequencing combined with direct sequencing was used to identify a novel heterozygous mutation (c.G828T; p.Y276X) in the spectrin beta gene, which is causative for HS. Sequence analysis of the patients' UGT1A1 gene revealed a compound heterozygote with c.G211A (p.G71R) and T3279G mutations, which reduced UGT1A1 activity to 30-60% of the normal level. Genetic analysis was crucial for determining the diagnosis and pathogenesis of this unusual case. PMID- 29115432 TI - Adiponectin and its receptors are involved in hypertensive vascular injury. AB - Adipocyte-derived adiponectin (APN) is involved in the protection against cardiovascular disease, but the endogenous APN and its receptor expression in the perivascular adipocytes and their role in hypertensive vascular injury remain unclear. The present study aimed to detect endogenous APN and its receptor expression and their protective effects against hypertensive vascular injury. APN was mainly expressed in the perivascular adipocytes, while its receptors AdipoR1 and AdipoR2 were ubiquitously expressed in the blood vessels. Angiotensin II (Ang II)-induced hypertension resulted in a significant decrease of APN and AdipoR1 and AdipoR2 in the perivascular adipocytes and vascular cells. The migration assay used demonstrated that APN attenuated Ang II-induced vascular smooth muscle cells migration and p38 phosphorylation Furthermore, the in vivo study demonstrated that APN receptor agonist AdipoRon attenuated Ang II-induced hypertensive vascular hypertrophy and fibrosis. Taken together, the present study indicated that perivascular adipocytes-derived APN attenuated hypertensive vascular injury possibly via its receptor-mediated inhibition of p38 signaling pathway. PMID- 29115433 TI - Adiponectin promotes preadipocyte differentiation via the PPARgamma pathway. AB - According to the results of a preliminary study, it was hypothesized that the effects of adiponectin (APN) on the improvement of atherosclerosis may be associated with adipocyte differentiation and peroxisome proliferator-activated receptor gamma (PPARgamma). The present study simulated the inflammatory environment of epicardial adipose tissue by stimulating mature adipocytes with lipopolysaccharide (LPS); subsequently, the differentiation of 3T3-L1 preadipocytes was observed. 3T3-L1 preadipocytes were infected with an adenovirus containing the human adiponectin gene apM1 (Ad-apM1) and were co-cultured with mature adipocytes stimulated with LPS. Differentiation into mature adipocytes was initiated using differentiation medium. After 8 days, an MTT assay was used to examine cell viability and oil red O staining was used to observe preadipocyte differentiation. In addition, the mRNA expression levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8 and tumor necrosis factor alpha (TNF-alpha) were examined by quantitative polymerase chain reaction, and the protein expression levels of PPARgamma, CCAAT/enhancer binding protein alpha (C/EBPalpha) and preadipocyte factor-1 (Pref-1) were measured by western blotting. The results indicated that APN overexpression significantly increased preadipocyte differentiation and cell viability, inhibited MCP-1, IL-6, IL-8 and TNF-alpha expression, upregulated PPARgamma and C/EBPalpha expression, and downregulated Pref-1 under LPS stimulation. In addition, inhibition of PPARgamma activity by T0070907 markedly attenuated the effects of APN overexpression. Taken together, the present study demonstrated that the effects of APN on the promotion of preadipocyte differentiation under inflammatory conditions may involve the PPARgamma signaling pathway, and at least partly depends on upregulation of PPARgamma expression. PMID- 29115434 TI - n-butanol extract from Folium isatidis inhibits the lipopolysaccharide-induced downregulation of CXCR1 and CXCR2 on human neutrophils. AB - Neutrophils, immune cells crucial for protecting against invading pathogens, are important in sepsis. Neutrophil migration is regulated by chemokine receptors and their cognate ligands. Our previous study investigated the effect of n-butanol extract from Folium isatidis on lipopolysaccharide (LPS)-induced septic shock. The present study stimulated neutrophils with LPS to explore the influence of LPS on cell. Neutrophils were then pretreated with n-butanol extract from Folium isatidis followed by LPS to examine the effect of this extract on neutrophil chemotaxis. The results showed that LPS decreased the expression levels of CXC chemokine receptor (CXCR)1, CXCR2 and L-selectin (CD62L), and increased the expression of interleukin-8 (IL-8) by neutrophils. The addition of n-butanol extract from Folium isatidis inhibited this LPS-induced downregulation of CXCR1, CXCR2 and CD62L, and decreased the expression of IL-8 on neutrophils. In addition, n-butanol extract promoted myeloperoxidase activity in neutrophils. Taken together, LPS downregulated the expression of chemokine receptors, leading to the failure of neutrophils to migrate to sites of infection. The addition of n butanol extract, which promoted the ability of neutrophils to migrate, is a natural product and potential therapeutic agent with which to target neutrophil chemotaxis during LPS stimulation. PMID- 29115436 TI - SIRT5 promotes cell proliferation and invasion in hepatocellular carcinoma by targeting E2F1. AB - Sirtuin 5 (SIRT5) is a member of the NAD+-dependent class III protein deacetylases. Although it is known that SIRT5 deacetylates and activates urate oxidase in the liver mitochondria of mice, the mechanism of SIRT5 in the proliferation of hepatocellular carcinoma (HCC) remains to be fully elucidated. The present study investigated the expression and functional significance of SIRT5 in HCC, and examined the relevant mechanism. SIRT5 was found to be upregulated in HCC tissues and cell lines, and the higher expression of SIRT5 indicated poorer overall survival. Reverse transcription-quantitative polymerase chain reaction analysis, western blot analysis, chromatin immunoprecipitation analysis, and luciferase reporter gene, proliferation and Transwell assays were performed to elucidate the function of SIRT5 in the regulation of cell proliferation and invasion in human HCC. Functionally, it was observed that the inhibition of SIRT5 significantly suppressed HCC cell proliferation and invasion, whereas the overexpression of SIRT5 promoted HCC cell proliferation and invasion in vitro. E2F transcription factor 1 (E2F1) was identified as a novel target gene of SIRT5. In addition, the knockdown of SIRT5 induced the expression of E2F1, and the knockdown of E2F1 in HCC cells partially reversed the effect of SIRT5 in promoting cell proliferation and invasion. Collectively, these data provide the first evidence, to the best of our knowledge, that the SIRT5 gene has an important regulatory role in liver carcinogenesis, and may function as a novel potential therapeutic target for HCC. PMID- 29115435 TI - Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF-alpha and TGF-beta1/ERK1/2 signaling pathways. AB - Dilated cardiomyopathy (DCM) is a disease of the heart characterized by pathological remodeling, including patchy interstitial fibrosis and degeneration of cardiomyocytes. In the present study, the beneficial role of human umbilical cord-derived mesenchymal stem cells (HuMSCs) derived from Wharton's jelly was evaluated in the myosin-induced rat model of DCM. Male Lewis rats (aged 8-weeks) were injected with porcine myosin to induce DCM. Cultured HuMSCs (1x106 cells/rat) were intravenously injected 28 days after myosin injection and the effects on myocardial fibrosis and the underlying signaling pathways were investigated and compared with vehicle-injected and negative control rats. Myosin injections in rats (vehicle group and experimental group) for 28 days led to severe fibrosis and significant deterioration of cardiac function indicative of DCM. HuMSC treatment reduced fibrosis as determined by Masson's staining of collagen deposits, as well as quantification of molecular markers of myocardial fibrosis such as collagen I/III, profibrotic factors transforming growth factor beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), and connective tissue growth factor (CTGF). HuMSC treatment restored cardiac function as observed using echocardiography. In addition, western blot analysis indicated that HuMSC injections in DCM rats inhibited the expression of TNF-alpha, extracellular signal regulated kinase 1/2 (ERK1/2) and TGF-beta1, which is a master switch for inducing myocardial fibrosis. These findings suggested that HuMSC injections attenuated myocardial fibrosis and dysfunction in a rat model of DCM, likely by inhibiting TNF-alpha and the TGF-beta1/ERK1/2 fibrosis pathways. Therefore, HuMSC treatment may represent a potential therapeutic method for treatment of DCM. PMID- 29115437 TI - Simvastatin enhances the radiosensitivity of p53-deficient cells via inhibition of mouse double minute 2 homolog. AB - Simvastatin exhibits anticancer activities, but its molecular mechanisms and radiosensitizing effects relative to p53 status remain unclear. In this study, we investigated whether the combination of simvastatin and ionizing radiation (IR) would enhance the antitumor effects of IR alone in HCT116 p53+/+ and p53-/- colon cancer cells. Using colony formation assays and a xenograft mouse model, we found that simvastatin potently stimulated radiosensitization of HCT116 p53-/- cells and xenograft tumors. The combination of simvastatin with IR decreased G2/M arrest and delayed the repair of IR-induced DNA damage; however, no differences between the HCT116 p53+/+ and p53-/- cells were evident. A further analysis revealed that simvastatin exhibited a novel function, namely, MDM2 suppression, regardless of p53 status. Interestingly, simvastatin induced radiosensitization by enhancing MDM2 suppression and elevating IR-induced p-ATM foci formation compared with IR alone in HCT116 p53-/- cells. Furthermore, simvastatin caused accumulations of the FOXO3a, E-cadherin, and p21 tumor suppressor proteins, which are downstream factors of MDM2, in HCT116 p53-/- cells. In conclusion, simvastatin enhanced radiosensitivity by inducing MDM2 inhibition and increasing tumor suppressor protein levels in radioresistant HCT116 p53-/- cells and xenografts. Overall, our novel findings suggest a scientific rationale for the clinical use of simvastatin as an MDM2 inhibitor and radiosensitizer for p53 deficient colorectal tumor treatments. PMID- 29115438 TI - Astragaloside IV attenuates penicillin-induced epilepsy via inhibiting activation of the MAPK signaling pathway. AB - Astrocytes perform several functions in the brain and spinal cord. Penicillin is commonly used for establishment of experimental epilepsy models. Previous studies have demonstrated that astragaloside IV (3-o-beta-d-xylopyranosyl-6-o-beta-d glucopyranosyl-cycloastragenol; AS-IV) has comprehensive pharmacological functions on the attenuation of inflammation. In the present study, primary astrocyte cell cultures were divided into three groups: Control group, penicillin (2,500 uM) treatment group (epilepsy model), and penicillin+AS-IV (20, 40, 80 and 160 umol/l) treatment group. The expression levels of inflammatory factors, including interleukin-1beta and tumor necrosis factor-alpha, were determined in the groups using western blot and reverse transcription-quantitative polymerase chain reaction analyses. The levels of members of the phosphorylated-mitogen activated protein kinase (p-MAPK) family, including p-c-Jun N-terminal kinase 1/2, p-extracellular signal-regulated protein kinase 1/2 and p-p38, were determined using western blot analysis. Cell viability of the astrocytes was detected using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay and cell proliferation was evaluated using a Cell Counting Kit-8 assay. The results revealed that AS-IV significantly suppressed the expression of penicillin-induced inflammatory factors in the astrocytes at the transcriptional and translational levels, and occurred in a dose-dependent manner. The penicillin induced increase in the protein levels of the the p-MAPK family were notably decreased by AS-IV. In addition, the penicillin-induced downregulation of primary astrocyte viability/cell proliferation was significantly reversed by the administration of AS-IV. From these results, it was concluded that AS-IV suppressed the penicillin-induced upregulation of inflammatory factors and p-MAPK in astrocytes, ultimately attenuating epilepsy. PMID- 29115440 TI - Aspirin ameliorates cerebral infarction through regulation of TLR4/NF-kappaB mediated endoplasmic reticulum stress in mouse model. AB - Cerebral infarction is a cerebrovascular disease caused by local brain ischemic necrosis or softening, which is associated with diabetes, obesity, hypertension and rheumatic heart arrhythmia. Previous studies have indicated that aspirin is a potential oral anticoagulant in the treatment of cerebral ischemic stroke. However, the potential mechanism mediated by aspirin in cerebral infarction therapy is not well understood. The present study analyzed the therapeutic effects of aspirin on cerebral infarction and investigated the underlying molecular mechanism of aspirin-ameliorated benefits for thrombolysis. The results demonstrated that aspirin inhibited inflammation and apoptosis of cerebrovascular endothelial cells in a mouse model of cerebral infarction. Aspirin treatment suppressed toll-like receptor (TLR)4 and nuclear factor (NF)-kappaB expression in cerebrovascular endothelial cells. Endoplasmic reticulum (ER) stress was suppressed by aspirin treatment through the downregulation of protein kinase R like endoplasmic reticulum kinase, eukaryotic translation initiation factor 2 subunit 1 and C/EBP homologous protein expression levels in cerebrovascular endothelial cells. It was identified that knockdown of TLR4 inhibited aspirin mediated downregulation of NF-kappaB signaling pathway and ER stress in cerebrovascular endothelial cells. Expression levels of adenosine diphosphate plasminogen activator inhibitors, von Willebrand factor and thromboxane were downregulated in cerebrovascular endothelial cells and in serum in experimental mice. The results demonstrated that aspirin was beneficial forthrombolysis by decreasing thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 expression in a mouse model of cerebral infarction. These results suggested that aspirin may improve cerebral infarction by downregulating TLR4/NF kappaB-mediated ER stress in a mouse model. PMID- 29115439 TI - Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway. AB - Low-dose ionizing radiation (LDIR) induces hormesis, exerts an adoptive effect on normal mammalian cells and stimulates cell proliferation; however, this effect is absent in cancer cells. Little is known on the molecular mechanisms underlying this differential response between normal and cancer cells. In the present study, it was demonstrated that the human prostate cancer cell line PC-3 and the normal prostate cell line RWPE-1 exhibited differential biological responses to LDIR. Through cell cycle analyses, it was demonstrated that LDIR inhibited cell growth and arrested the cell cycle at the S and G2/M phases in PC-3 cells, but not in RWPE-1 cells. Using western blotting, it was demonstrated that LDIR at 75 mGy induced the expression of ataxia-telangiectasia mutated (ATM) protein in PC-3 as well as RWPE-1 cells. However, the ATMp21 pathway was activated in PC-3, but not in RWPE-1 cells. Although the expression of p53 was not affected by 75 mGy LDIR in RWPE-1 cells, the ATMp21 pathway was activated when RWPE-1 cells lost p53 function. In addition, when using ATM inhibitors, the ATMp21 pathway was inactivated in both cell lines, and the LDIR-induced cell proliferation inhibition was also abolished. These findings suggested that the ATM/p21 pathway directly participated in the LDIR-induced cell proliferation inhibition in p53null type prostate tumor cells, whereas this mechanism was absent in normal prostate cells. Thus, p53 may affect cell stability following LDIR, and plays a crucial role in regulating the ATM/p21 pathway activated by LDIR. PMID- 29115441 TI - Role of transcription factor FOXA1 in non-small cell lung cancer. AB - In our previous study, stable subpopulations of the A549 lung cancer cell line with high/low invasive potential (H/L-INV) were obtained. In the present study, microarray analysis of the H/L-INV A549 subpopulations was performed to evaluate genes associated with high invasiveness. Forkhead box protein A1 (FOXA1) was selected for further investigation. The expression levels of FOXA1 in the primary lesion and metastatic lymph nodes were assessed using reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis. In addition, the mRNA and protein expression levels of FOXA1 were examined in H-INV A549 cells transfected with a specific FOXA1 small interfering RNA (siRNA), and the role of FOXA1 in the proliferation, invasion and metastasis of non-small cell lung cancer (NSCLC) cells was evaluated. FOXA1 was overexpressed in metastatic lymph nodes, compared with its expression in NSCLC primary tumours. The results of western blot and RT-qPCR analyses confirmed that FOXA1 siRNA transfection led to a decrease in the expression of FOXA1 in H-INV A549 cells. FOXA1 siRNA transfection caused G0/G1 phase cell cycle arrest, and also reduced the invasion, migration and proliferation abilities of the H-INV A549 cells. In conclusion, the results of the present study suggested that FOXA1 is a potential oncogene in NSCLC; therefore, specific interference of the expression of FOXA1 may represent a novel approach for the treatment of NSCLC. PMID- 29115442 TI - GOLPH3 expression promotes the resistance of HT29 cells to 5-fluorouracil by activating multiple signaling pathways. AB - The novel proto-oncogene Golgi phosphoprotein (GOLPH)3 is overexpressed in a variety of tumor tissues and is associated with poor prognosis. The authors previously demonstrated that GOLPH3 gene is overexpressed in colorectal cancer tissues and promotes the proliferation of colonic cancer cells by activating the phosphatidylinositol-3-kinase/protein kinase B/the mammalian target of rapamycin and Wnt/beta-catenin signaling pathways. However, to the best of the authors' knowledge, if and how the GOLPH3 gene is involved in inducing resistance to colonic cancer chemotherapy has not been reported. In the present study, the association between the overexpression of the GOLPH3 gene and resistance of HT29 colonic cancer cells to 5-fluorouracil (5-FU) was investigated. Following confirmation of the effective silencing of the GOLPH3 gene, proliferation and apoptosis of colonic cancer cells were detected by MTT assay, colony formation assay and flow cytometry, and then the mechanism of GOLPH3-induced resistance to 5-FU chemotherapy in colonic cancer cells was investigated by western blotting. The results demonstrated that the expression of phosphorylated (p)-glycoprotein and GOLPH3 was increased in HT29 cells following treatment with 5-FU, which resulted in the development of drug resistance. Silencing GOLPH3 increased the sensitivity of HT29 cells to 5-FU, reduced their tumorigenicity and partly reversed their resistance to 5-FU. The expression of p-extracellular signal regulated kinase (pERK)1/2 and beta-catenin was decreased, which indicated that its mechanism was associated with the activation of the mitogen-activated protein kinase/ERK and Wnt/beta-catenin signaling pathways. Therefore, GOLPH3 may be a potential, novel target for reversing chemotherapy resistance in colon cancer. PMID- 29115443 TI - Erythropoietin signaling increases neurogenesis and oligodendrogenesis of endogenous neural stem cells following spinal cord injury both in vivo and in vitro. AB - Erythropoietin (Epo) promotes functional recovery following spinal cord injury (SCI); however, the exact underlying mechanisms are yet to be determined. Although endogenous neural stem cells (NSCs) in the adult spinal cord are a therapeutic target in SCI models, the effect of Epo on this NSC population remains unknown. The present study investigated the effects of Epo on endogenous NSCs in the adult spinal cord both in vitro and in vivo. For the in vivo analyses, normal rats (Normal) and SCI contusion model rats (SCI) received either recombinant human Epo or saline treatment for 7 days (5,000 U/kg), and spinal cords were subsequently analyzed at 2, 8, and 14 days. For in vitro analyses, NSCs harvested from adult rat spinal cords were exposed to Epo (10 U/ml). A significant increase in beta-tubulin+ new neurons (P<0.01) was observed at all three time points and O4+ new oligodendrocytes (P<0.05) at days 8 and 14 in the SCI+Epo group compared with the SCI+Saline group. This was concomitant with a prolonged activation of Epo signaling; however, no effect on NSCs proliferation was observed. Similar results were also obtained in vitro. Motor functional recovery was also noted at days 8 and 14 only in the Epo-treated SCI rats. Although the expression of Epo and EpoR significantly increased in Normal+Epo rats compared with Normal+Saline rats (P<0.05), the cell numbers and phenotype were comparable between the two groups. To the best of the author's knowledge, this is the first study to demonstrate that Epo signaling promotes both neurogenesis and oligodendrogenesis following SCI and that these may represent the underlying mechanisms for the functional recovery and therapeutic effects of Epo following SCI. PMID- 29115444 TI - Downregulation of microRNA-124-3p suppresses the mTOR signaling pathway by targeting DDIT4 in males with major depressive disorder. AB - Recent investigations have suggested that microRNAs (miRNAs or miRs) are involved in several pathways that may contribute to the pathomechanism of major depressive disorder (MDD). Sex may not only act as a demographic factor in clinical practive, but may also play a vital role in the molecular heterogeneity of MDD. Although many molecular changes correlated with MDD are found in males, the molecular mechanisms of MDD remain poorly understood. The present study performed bioinformatics analysis to investigate the pathomechanism of MDD in males. The present study identified miR-124-3p as one of the most dysregulated miRNAs in MDD, with decreased expression in the post-mortem BA44 brain area of male patients with MDD. In addition, miR-124-3p targets DNA damage-inducible transcript 4 (DDIT4) and specificity protein 1 (SP1), a DDIT4 transcription factor, in the validated target module of the miRWalk 2.0 database. This is concurrent with an increase in the expression level of DDIT4, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway. It was also demonstrated that miR-124-3p expression was positively associated with mTOR signaling and this relationship was dependent on the tuberous sclerosis proteins 1/2 complex. Taken together, these results provided a novel insight on miR-124-3p involvement in the biological alterations of male patients with MDD and suggested that this miRNA may also serve as a male-specific target for antidepressant treatment. PMID- 29115445 TI - miR-126 is essential for endothelial phenotype expression during endothelial differentiation in adipose-derived stem cells. AB - The endothelial differentiation of stem cells serves an essential role in vascular development, function and disease. Autograft adipose-derived stem cells (ADSCs) may be a novel source of cell for use in the study of angiogenesis. microRNA-126 (miR-126) has been extensively studied in endothelial cells. However, the effect of miR-126 on the endothelial differentiation of ADSCs has not been demonstrated. In the present study, it was observed that the expression of miR-126 was markedly increased during the endothelial differentiation of ADSCs in a time-dependent manner. The effect of miR-126 on ADSC differentiation was confirmed by employing up- and down-regulation strategies. The expression of endothelial markers was decreased by miR-126 inhibitor transfection during endothelial differentiation. The results of the present study suggest that miR 126 is essential for endothelial phenotype expression, and may promote the progress of endothelial differentiation in ADSCs, providing a novel strategy for modulating vascular formation and function. PMID- 29115446 TI - Effects of Dermatopontin gene silencing on apoptosis and proliferation of osteosarcoma MG-63 cells. AB - The present study aimed to investigate the effect of Dermatopontin (DPT) gene silencing on the apoptosis and proliferation of osteosarcoma MG-63 cells. Three eukaryotic expression vectors of short hairpin (sh)RNA fragments targeting different loci of DPT were designed and transfected into an osteosarcoma cell line MG-63. The cells were assigned to a blank, shRNA-control, DPT-shRNA-a, DPT shRNA-b or DPT-shRNA-c group. The shRNA with the highest silencing efficiency was screened using reverse transcription-quantitative polymerase chain reaction and western blotting. The screened shRNA was transfected into MG-63 cells. The proliferation, cell cycle and apoptosis of MG-63 cells were measured using a Cell Counting Kit-8 assay, flow cytometry and Annexin V-fluorescein isothiocyanate assay. The recombinant plasmids containing DPT shRNA were successfully constructed. DPT gene silencing was able to significantly reduce the proliferation rate of MG-63 cells (P<0.05). The proportion of cells in the G0/G1 phase and in the G2/M phase increased significantly (both P<0.05), while the proportion of cells in the S phase decreased (P<0.05). Furthermore, the cell apoptosis rate increased significantly (P<0.05). These results demonstrate that DPT gene silencing is able to reduce the proliferation of MG-63 cells, slow down cell cycle progression and promote apoptosis, hence may become a novel target for the treatment of osteosarcoma. PMID- 29115447 TI - Salidroside slows the progression of EA.hy926 cell senescence by regulating the cell cycle in an atherosclerosis model. AB - Aging is the major risk factor for diseases of the cardiovascular system, such as coronary atherosclerotic heart disease, but little is known about the relationship between atherosclerosis (AS) and age-related declines in vascular structure and function. Here, we used histological analyses in combination with molecular biology techniques to show that lipid deposition in endothelial cell was accompanied by aging and growth arrest. Endothelial cell senescence is sufficient to cause AS; however, we found that salidroside reduced intracellular lipid deposition, slowed the progression of endothelial cell senescence and inhibited the expression of the senescence-related molecules and phosphorylated the retinoblastoma (Rb) protein. Further study confirmed that salidroside increased the percent of S phase cells in oxidized low-density lipoprotein (ox LDL)-treated endothelial cells. Collectively, vascular endothelial cell function declined with age and AS, and our data suggested that salidroside prevented ox LDL-treated endothelial cell senescence by promoting cell cycle progression from G0/G1 phase to S phase via Rb phosphorylation. We demonstrated for the first time the complex interactions between AS and endothelial cell senescence, and we believe that salidroside represents a promising therapy for senescence-related AS. PMID- 29115448 TI - MAPKs and NF-kappaB pathway inhibitory effect of bisdemethoxycurcumin on phorbol 12-myristate-13-acetate and A23187-induced inflammation in human mast cells. AB - Inflammation-associated damage may occur in any tissue following infection, exposure to toxins, following ischemia, and in allergic and auto-immune reactions. Inflammation may also result from mast cell degranulation induced by the intracellular calcium concentration. The inflammatory process may be inhibited by compounds that affect mast cells. Bisdemethoxycurcumin [1,7-bis(4 hydroxyphenyl) hepta-1,6-diene-3,5-dione, BDCM] is the active component of turmeric. It has anticancer, antioxidant and antibacterial properties. To investigate the molecular mechanism associated with the anti-inflammatory activity of BDCM, human mast cell line 1 (HMC-1) cells were treated with phorbol 12-myristate-13-acetate (PMA) and calcium ionophore A23187 (A23187) to induce the inflammatory process. Various HMC-1 cells were pretreated with BDCM prior to stimulation of inflammation. BDCM inhibited the inflammation-triggered production of cytokines including interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF) alpha. BDCM inhibition extended to the gene level. In activated HMC-1 cells, phosphorylation levels of extracellular signal-regulated kinase, c-jun N-terminal kinase and p38 mitogen-activated protein kinase were decreased by treatment with BDCM. BDCM also inhibited nuclear factor-(NF)-kappaB activation and IkappaB degradation. In conclusion, BDCM suppresses the expression of TNF-alpha, IL-8, and IL-6 by inhibiting the NF-kappaB and mitogen activated protein kinase signaling pathways. PMID- 29115449 TI - The rational search for PDE10A inhibitors from Sophora flavescens roots using pharmacophore- and docking-based virtual screening. AB - Phosphodiesterase 10A (PDE10A) has been confirmed to be an important target for the treatment of central nervous system (CNS) disorders. The purpose of the present study was to identify PDE10A inhibitors from herbs used in traditional Chinese medicine. Pharmacophore and molecular docking techniques were used to virtually screen the chemical molecule database of Sophora flavescens, a well known Chinese herb that has been used for improving mental health and regulating the CNS. The pharmacophore model generated recognized the common functional groups of known PDE10A inhibitors. In addition, molecular docking was used to calculate the binding affinity of ligand-PDE10A interactions and to investigate the possible binding pattern. Virtual screening based on the pharmacophore model and molecular docking was performed to identify potential PDE10A inhibitors from S. flavescens. The results demonstrated that nine hits from S. flavescens were potential PDE10A inhibitors, and their biological activity was further validated using literature mining. A total of two compounds were reported to inhibit cyclic adenosine monophosphate phosphodiesterase, and one protected against glutamate induced oxidative stress in the CNS. The remaining six compounds require further bioactivity validation. The results of the present study demonstrated that this method was a time- and cost-saving strategy for the identification of bioactive compounds from traditional Chinese medicine. PMID- 29115450 TI - Herbal prescription, Danggui-Sayuk-Ga-Osuyu-Senggang-Tang, inhibits TNF-alpha induced epithelial-mesenchymal transition in HCT116 colorectal cancer cells. AB - Tumor necrosis factor-alpha-mediated (TNF-alpha) epithelial-mesenchymal transition (EMT) is associated with distant metastasis in patients with colorectal cancer with poor prognosis. Although traditional herbal medicines have long been used to treat colorectal cancer, the incidence and mortality in patients with colorectal cancer has continued to increase. Danggui-Sayuk-Ga-Osuyu Saenggang-Tang (DSGOST) has long been used for treatment of chills, while few studies have reported its anticancer effect. This study aimed to demonstrate the inhibitory effect of DSGOST on TNF-alpha-mediated invasion and migration of colorectal cancer HCT116 cell lines. MTT was used to measure cell viability. Wound healing and Tauranswell invasion assay were used to detect migration and invasion of cells, respectively. The intracellular localization of proteins of interest was assessed by immunocytochemistry. Western blotting was performed to determine the expression level of various proteins. A non-toxic dose of DSGOST (50 ug/ml) on HCT116 cells was determined by MTT assay. Furthermore, DSGOST prevented the TNF-alpha-induced invasive phenotype in HCT116 cells. DSGOST inhibition of the invasive phenotype was also associated with increased expression of EMT markers. Furthermore, DSGOST treatment blocked TNF-alpha induced migration and invasion of HCT116 cells. In addition, DSGOST treatment inhibited TNF-alpha-mediated nuclear translocation of Snail. DSGOST treatment also downregulated TNF-alpha-induced phosphorylation of AKT and glycogen synthase kinase-3beta. Therefore, the findings of the current study suggest that DSGOST exhibits anti-migration and anti-invasion effects in TNF-alpha-treated HCT116 human colorectal cells. PMID- 29115451 TI - Presence of the minor allele of microRNA205 rs3842530 polymorphism increases 18FDG uptake in patients with breast cancer via targeting VEGF. AB - MicroRNAs (miRNAs) are regarded as key regulators of gene expression involved in the pathogenesis of various diseases. Numerous single nucleotide polymorphisms (SNPs) in miRNA genes have been found to be associated with human diseases by affecting the processing process of miRNAs. In the present study, patients with breast cancer underwent a PET scan, and the maximum standard uptake value (SUVmax)/partial volume-corrected standard uptake value (SUVpvc) were determined in each individual. The samples were collected and genotyped for rs3842530. Statistical analysis was performed to evaluate the difference between the genotype groups. The results demonstrated that miR-205 downregulated the expression of vascular endothelial growth factor (VEGF) by binding to its 3'untranslated region. The introduction of exogenous miRNA, which mimicked miR 205, decreased the protein and mRNA expression levels of VEGF and, consistently, the suppression of endogenous miR-205 resulted in an increase in the expression levels of VEGF. Furthermore, it was found that the expression of mature miR-205 was markedly reduced by the presence of rs3842530. 18F-fluorodeoxyglucose (18FDG) metabolism, including SUVmax and SUVpvc, are important parameters of PET, and dysregulation of the expression of VEGF has been reported to be associated with an altered 18FDG metabolism. In the present study, it was found that the presence of minor allele rs3842530 was correlated with increased SUVmax and SUVpvc, which may have been mediated by release of the physiologically inhibited expression of VEGF. Therefore, VEGF was a direct target of miR-205, and the presence of rs3842530 compromised the expression of miR-205, suggesting it is a promising biomarker for the metabolism of 18FDG. PMID- 29115452 TI - miR-93-mediated collagen expression in stress urinary incontinence via calpain-2. AB - The aim of the present study was to investigate the expression and mechanism of microRNA (miR)-93 in collagen expression in stress urinary incontinence (SUI). Vaginal tissue, primary fibroblasts and SUI primary fibroblasts were obtained to detect the expression of miR-93, interstitial collagenase (MMP1), collagen I and calpain-2. Reverse transcription-quantitative polymerase chain reaction analysis was performed to detect the levels of miR-93 and MMP1. Western blotting was used to evaluate the protein levels of calpain-2, MMP1 and collagen I. MMP1 and hydroxyproline levels in the supernatant were measured by ELISA. The association between miR-93 and calpain-2 was investigated by luciferase reporter assays. The expression of miR-93 and collagen I was significantly downregulated in the SUI group, while the expression of calpain-2 and MMP1 was significantly upregulated. ELISA analysis demonstrated that the MMP1 level increased and the hydroxyproline level decreased in the SUI group. Additionally, calpain-2 was identified to be a target of miR-93, and miR-93 was able to negatively regulate the expression of calpain-2. Restoration of calpain-2 in miR-93-overexpresseing SUI primary fibroblasts reversed the alteration in hydroxyproline expression, indicating that calpain-2 was negatively associated with collagen expression. The results of the present study suggested that miR-93 regulated MMP1 and collagen I expression in fibroblasts via calpain-2. miR-93 mediated collagen expression in stress urinary incontinence via calpain-2. PMID- 29115453 TI - In vivo monitoring of magnetically labeled mesenchymal stem cells homing to rabbit hepatic VX2 tumors using magnetic resonance imaging. AB - Although mesenchymal stem cells (MSCs) have been demonstrated to possess a tumor homing feature, their tropism to liver tumors has not been delineated in a visible manner. The aim of the present study was to evaluate the tumor-homing capacity of MSCs and to investigate the spatial and temporal distributions of MSCs in liver tumors using magnetic resonance imaging (MRI). MSCs were colabeled with superparamagnetic iron oxide (SPIO) particles and 4',6-diamidino-2 phenylindole (DAPI), and then transplanted into rabbits with VX2 liver tumors through intravenous injections. The rabbits were subjected to MRI before and at 3, 7 and 14 days after cell transplantation using a clinical 1.5-T MRI system. Immediately after the MRI examination, histological analyses were performed using fluorescence and Prussian blue staining. At 3 days after injection with labeled MSCs, heterogeneous hypointensity was detected on the MRI images of the tumor. At 7 days after transplantation, the tumor exhibited anisointense MRI signal, whereas a hypointense ring was detected at the border of the tumor. At 14 days after transplantation, the MRI signal recovered the hyperintensity. As demonstrated in the histological analyses, the distribution of the iron particles visualized with Prussian blue staining was consistent with the DAPI-stained bright fluorescent nuclei, and the particles corresponded to the hypointense region on the MR images. Thus, systemically administered MSCs could localize to liver tumors with high specificity and possessed a migration feature with active tumor growth. These results demonstrated that the targeting and distribution of the magnetically labeled stem cells in the tumor could be tracked for 7 days in vivo using a clinical 1.5-T MRI scanner. PMID- 29115454 TI - Mycoleptodonoides aitchisonii suppresses asthma via Th2 and Th1 cell regulation in an ovalbumin-induced asthma mouse model. AB - Asthma is a chronic respiratory disease related to hyper-responsiveness. The majority of patients suffer mild symptoms, however, some cases, especially in the young and the elderly, can lead to death by apnea. Mycoleptodonoides atichisonii (M. atichisonii) is an edible mushroom that has previously been reported to possess several bioactive properties, such as the synthesis of nerve growth factors, anti-obesity effects and the ability to prevent cell death. In the current study, the authors evaluated the anti-asthmatic effects of M. atichisonii using an ovalbumin-induced asthma mouse model. M. atichisonii dose-dependently suppressed the levels of white blood cells, eosinophils and immunoglobulin (Ig)E in BALB/c mice, resulting from ovalbumin-induced asthma. M. atichisonii recovered the typical asthmatic morphological changes in lungs, such as mucous hyper secretion, epithelial layer hyperplasia, eosinophil infiltration and various cell surface molecules, such as CD3, CD4, CD8, CD19 and major histocompatibility complex class II. With the exception of CD19+ cells and IL-12p40, M. atichisonii affected almost all factors related to asthma induction including the T helper (Th)1/Th2 transcription factors, T-bet and GATA-3, Th1-related cytokines, Th2 related cytokines and proinflammatory cytokines. In addition, M. atichisonii significantly inhibited the expression of IL-5, IL-13 and IL-6. The authors concluded that M. atichisonii may be a promising drug candidate against asthma. PMID- 29115455 TI - Dioscin inhibits ischemic stroke-induced inflammation through inhibition of the TLR4/MyD88/NF-kappaB signaling pathway in a rat model. AB - Diosgenin, as an essential natural steroidal saponin, can be extracted from numerous sources, primarily from fenugreek. It is an important raw material for the synthesis of steroid hormone drugs. It exhibits antitumor, anti-inflammatory, antioxidation and several other significant pharmacologic actions, and is of high pharmaceutical value. In the present study, the activities and underlying mechanisms of dioscin in the inhibition of ischemic stroke in rats were investigated. Inflammatory responses wer analyzed using ELISA kits and caspase-3 and caspase-9 activity was analyzed using Caspase-3 and caspase-9 activity kits. Western blot analysis was used to measure Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappaB (NF-kappaB), transforming growth factor-beta1 (TGF-beta1), high-mobility group protein 1 (HMGB 1), interleukin-1 receptor-associated kinase 1 (IRAK1), and tumor necrosis factor receptor-associated factor 6 (TRAF6) protein expression. Dioscin inhibited infarct volume and neurological scores in the ischemic stroke rat model. The results demonstrated that dioscin reduced inflammatory responses, and suppressed the expression of TLR4, MyD88, NF-kappaB, TGF-beta1, HMGB-1, IRAK1, and TRAF6 in the rat ischemic stroke model. Taken together, these findings suggested that dioscin inhibited ischemic stroke-induced inflammation through inhibition of the TLR4/MyD88/NF-kB-induced inflammation the rat model, which provided novel insights into the mechanisms underlying the effect of dioscin as an anti inflammatory candidate for the treatment of ischemic stroke in in the future. PMID- 29115456 TI - MicroRNA-20a promotes inflammation via the nuclear factor-kappaB signaling pathway in pediatric pneumonia. AB - Pneumonia is a common respiratory disease worldwide, which is preventable and treatable; however, it is recognized as a leading cause of mortality in children. The present study aimed to investigate the role and mechanism of microRNA (miR) 20a in inflammation in pediatric pneumonia. Clinical serum samples were collected from children with pneumonia and healthy children. Initially, the serum expression levels of miR-20a were detected by reverse transcription-quantitative polymerase chain reaction. Subsequently, A549 cells were randomly divided into four groups: Control group; lipopolysaccharide (LPS; 1 ug/ml) group; LPS + miR 20a group; and LPS + miR-20a + pyrrolidine dithiocarbamate (PDTC; 100 mmol/l) group. The concentrations of interleukin-6 (IL-6), tumor necrosis factor (TNF) alpha and C-reactive protein (CRP) in clinical serum samples and A549 cells were determined by ELISA. In addition, the protein expression levels of inhibitor of nuclear factor (NF)-kappaB alpha (IkappaBalpha) and phosphorylated (p)-NF-kappaB were measured by western blotting. The results demonstrated that miR-20a was upregulated in children with pneumonia and in lung cells with LPS-induced inflammatory injury (P<0.01). In addition, compared with the LPS group, cells in the LPS + miR-20a group exhibited increased expression levels of IL-6, TNF-alpha and CRP (P<0.05). Overexpression of miR-20a also resulted in upregulation of the expression levels of IkappaBalpha and p-NF-kappaB compared with in the LPS group (P<0.05). Furthermore, treatment with the NF-kappaB inhibitor PDTC inhibited the expression of inflammatory factors compared with in the LPS + miR-20a group (P<0.05). In conclusion, the present study indicated that miR-20a is upregulated in pediatric pneumonia, and overexpression of miR-20a may promote inflammation through activation of the NF-kappaB signaling pathway. PMID- 29115458 TI - Effects of long-term scopolamine treatment on cognitive deficits and calcium binding proteins immunoreactivities in the mouse hippocampus. AB - GABAergic projections terminate on numerous hippocampal interneurons containing calcium binding proteins (CBPs), including calbindin D-28k (CB), calretinin (CR) and parvalbumin (PV). Memory deficits and expression levels of CB, CR, and PV were examined in the hippocampal subregions following systemic scopolamine (Scop; 1 mg/kg) treatment for 4 weeks in mice. Scop treatment induced significant memory deficits from 1 week after Scop treatment. CB, CR and PV immunoreactivities distributions were in hippocampal subregions [CA1 and CA3 regions, and the dentate gyrus (DG)]. CB immunoreactivity (CB+) was gradually decreased in all subregions until 2 weeks after Scop treatment, and CB+ was decreased to the lowest level in all subregions at 3 and 4 weeks. CR+ in the CA1 region was gradually decreased until 2 weeks and hardly observed at 3 and 4 weeks; in the CA3 region, CR+ was not altered in all subregions at any time. In the DG, CR+ was gradually decreased until 2 weeks and lowest at 3 and 4 weeks. PV+ in the CA1 region was not altered at 1 week, and gradually decreased from 2 weeks. In the CA3 region, PV+ did not change in any subregions at any time. In the DG, PV+ was not altered at 1 week, decreased at 2 weeks, and lowest at 3 and 4 weeks. In brief, Scop significantly decreased CBPs expressions in the hippocampus >=3 weeks after the treatment although memory deficits had developed at 1 week. Therefore, it is suggested that Scop (1 mg/kg) must be systemically treated for >=3 weeks to investigate changes in expression levels of CBPs in the hippocampus. PMID- 29115457 TI - Identification of biomarkers for childhood obesity based on expressional correlation and functional similarity. AB - The aim of the current study was to identify potential biomarkers of childhood obesity, and investigate molecular mechanisms and candidate agents in order to improve therapeutic strategies for childhood obesity. The GSE9624 gene expression profile was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) in omental adipose tissues were analyzed with limma package by comparing samples from obese and normal control children. Two-way hierarchical clustering was applied using the pheatmap package. The co expression (CE) analysis was performed using online CoExpress software. Subsequent to functional classification via the GOSim package, the gene network enriched by DEGs was visualized using the Cytoscape package. The codon usage bias of the DEGs was then examined using the CAI program from the European Molecular Biology Open Software Suite. In total, 583 DEGs (273 upregulated genes and 310 downregulated genes) were observed in the omental adipose tissues between samples from obese and normal control children. Hierarchical clustering identified a significant difference between samples from obese and normal control children. Subsequent to CE analysis, 130 DEGs, which were classified into 4 clusters, were selected. The following 3 upregulated and 2 downregulated genes were identified to be significant: Upregulated genes, microtubule-associated protein tau (MAPT), destrin (actin depolymerizing factor) (DSTN) and spectrin, beta, non-erythrocytic 1 (SPTBN1); downregulated genes, Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) and spindle and kinetochore associated complex subunit 1 (SKA1). The top 3 amino acids were identified to be glycine, leucine and serine with a high bias. The DEGs MAPT, DSTN, SPTBN1, ARHGEF2 and SKA1 are suggested to be candidate biomarkers for childhood obesity. PMID- 29115459 TI - Isolariciresinol-9'-O-alpha-L-arabinofuranoside protects against hydrogen peroxide-induced apoptosis of human umbilical vein endothelial cells via a PI3K/Akt/Bad-dependent pathway. AB - Isolariciresinol-9'-O-alpha-L-arabinofuranoside (MWS-19) isolated from Pinus massoniana Lamb. Fresh pine needles is the major ingredient of the Songling Xuemaikang capsule therapy used for hypertension. The present study aimed to investigate the effects and underlying mechanisms of MWS-19 on hydrogen peroxide (H2O2)-induced apoptosis in human umbilical vein endothelial cells (HUVECs). To investigate the effect of MWS-19 on apoptosis in HUVECs, an oxidative stress induced apoptosis model was established in HUVECs using H2O2, and the present study performed Hoechst 33258 staining and a Cell Counting Kit-8 (CCK-8) assay. Furthermore, western blot analysis was also performed to investigate the underlying mechanism of the effects of MWS-19 on the model. The results demonstrated that MWS-19 reversed the effects of H2O2 on cell apoptosis at a concentration range of 15.6-250 ug/ml, with dose-dependent increases in cell growth. Hoechst staining indicated that 500 uM H2O2 induced HUVEC apoptosis, and MWS-19 markedly protected HUVECs against apoptosis at 31.3, 62.5 and 125 ug/ml. Furthermore, the protein expression of phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and Bcl-2-associated agonist of cell death (Bad) were increased, and reduced caspase-3 activation was observed, following treatment with MWS-19 in H2O2-treated HUVECs. Additionally, the PI3K inhibitor wortmannin attenuated PI3K/Akt/Bad signaling induced by MWS-19 treatment and neutralized the effect of MWS-19 on the growth of HUVECs. In conclusion, the results of the present study indicate that MWS-19 may protect against H2O2-induced HUVEC apoptosis via the PI3K/Akt/Bad signaling pathway. MWS-19 may serve an important role in the prevention of oxidative damage in vascular endothelial cells in hypertension patients. PMID- 29115460 TI - Activation of corticotropin-releasing factor receptor 1 aggravates dextran sodium sulphate-induced colitis in mice by promoting M1 macrophage polarization. AB - The corticotropin-releasing factor (CRF) family is involved in modulating gastrointestinal motility, sensitivity and inflammation. CRF signalling exerts an important role in inflammatory bowel disease (IBD), predominantly by activating CRF receptors. The aim of the present study was to investigate the function of CRF receptor 1 (CRF-R1) in the development of mucosal inflammation induced by dextran sulphate sodium (DSS) and the underlying mechanism. Consecutive administration of CRF or CP154526 was used to activate or block the CRF-R1 in DSS treated mice. Colonic inflammation was evaluated by determining the Disease Activity Index (DAI) and histology score. CRF-R1 expression was proportional to the DAI, the histology score and the number of macrophages. Activation of CRF-R1 aggravated mucosal inflammation by activating nuclear factor (NF)-kappaB and subsequently increasing the expression levels of tumour necrosis factor (TNF) alpha and interleukin (IL)-6. Inhibition of CRF-R1 decreased the expression level of CRF-R1, macrophage infiltration, NF-kappaB activation, and TNF-alpha and IL-6 expression levels, ultimately alleviating the mucosal inflammation. Thus, CRF-R1 expression was proportional to the severity of DSS-induced colitis. Activation of CRF-R1 increased the DAI and histological scores of the colons from DSS-treated mice by promoting M1 macrophage polarization, demonstrated as increased NF-kappaB activation, and TNF-alpha and IL-6 release. These results provide evidence of the pro-inflammatory role of CRF-R1 in a DSS-induced ulcerative colitis (UC) model and a possible underlying mechanism, which may facilitate the elucidation of potential treatment approaches for UC. PMID- 29115461 TI - Histone deacetylase inhibition of cardiac autophagy in rats on a high-fat diet with low-dose streptozotocin-induced type 2 diabetes mellitus. AB - Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1 (PARP1), insulin signaling, advanced glycosylation end product specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high-fat diet (60% fat) and low-dose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end-diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)-5' adenosine monophosphate-activated protein kinase alpha 2, light chain 3-II, Beclin-1, glucose transporter 4, p-protein kinase B, and insulin receptor substrate-1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p-mTOR-S2448, p-P70S6K-Thr-389, RAGE, tumor necrosis factor-alpha, and interleukin-6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling. PMID- 29115462 TI - Hedyotis diffusa Willd inhibits proliferation and induces apoptosis of 5-FU resistant colorectal cancer cells by regulating the PI3K/AKT signaling pathway. AB - Hedyotis diffusa Willd (HDW) is a major component frequently used in Traditional Chinese Medicine for the clinical treatment of colorectal cancer (CRC) and its associated drug resistance. However, the underlying mechanism of HDW circumventing drug resistance of cancer cells remains to be elucidated. Cancer cell resistance to apoptosis and activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway have been implicated as major factors in the acquired resistance to chemotherapeutic anti-cancer drugs. The present study investigated the effect and mechanisms of action of ethanol extract of Hedyotis diffusa Willd (EEHDW) on the proliferation and apoptosis of CRC 5 fluorouracil (5-FU) resistant (HCT-8/5-FU) cells. CRC HCT-8/5-FU cell viability following treatment with EEHDW was determined using MTT and colony formation assay. In addition, Annexin V/propidium iodide staining with flow cytometry analysis and 4',6-diamidino-2-phenylindole staining were used to determine the apoptosis of drug-resistant cancer cells following treatment with EEHDW. The mRNA and protein expression levels of B cell leukemia/lymphoma (Bcl-2), Bcl-2 associated X (Bax), cyclin dependent kinase 4 (CDK4), cyclin D1 and p21 were evaluated using reverse transcription-polymerase chain reaction and western blot analysis, respectively. Furthermore, activation of the PI3K/AKT signaling pathway and expression of phosphatase and tensin homolog (PTEN), PI3K, AKT and phosphorylated (p)-AKT were determined. EEHDW significantly reduced cell viability, inhibited cell colony formation and promoted apoptosis of HCT-8/5-FU cells. Furthermore, EEHDW significantly downregulated the expression of Bcl-2, cyclin D1 and CDK4 and upregulated the expression of Bax and p21. In addition, EEHDW inhibited the activation of the PI3K/AKT pathway by increasing expression of PTEN and suppressing the expression of PI3K and p-AKT. The present study provided the first direct evidence that EEHDW may overcome drug-resistance in human CRC cells by inhibiting PI3K/AKT signaling pathway and provides a basis for the improved therapeutic use of HDW in the clinical treatment of cancer. PMID- 29115463 TI - Ganoderma lucidum polysaccharide inhibits prostate cancer cell migration via the protein arginine methyltransferase 6 signaling pathway. AB - Prostate cancer is one of the most common types of malignant tumor of men worldwide and the incidence and mortality rate is gradually increasing. At present, the molecular mechanisms of growth and migration in human prostate cancer have not been completely elucidated. Studies have demonstrated that Ganoderma lucidum polysaccharides (GLP) can inhibit cancer. Therefore the present study investigated the effect and molecular mechanism of GLP on cell growth and migration of LNCaP human prostate cancer cells. LNCaP cells were transfected with either a protein arginine methyltransferase 6 (PRMT6) overexpression plasmid or PRMT6 small interfering (si)RNA. The cell growth and migration, and the expression of PRMT6 signaling-associated proteins, were investigated following treatment with 5 and 20 ug/ml GLP. The results demonstrated that GLP inhibited cell growth, induced cell cycle arrest, decreased PRMT6, cyclin-dependent kinase 2 (CDK2), focal adhesion kinase (FAK) and steroid receptor coactivator, (SRC) expression, and increased p21 expression in LNCaP cells, as determined by using a Coulter counter, flow cytometry, and reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Furthermore, GLP significantly inhibited cell migration, as determined by Transwell migration and scratch assays, and altered CDK2, FAK, SRC and p21 expression in LNCaP cells transfected with the PRMT6 overexpression plasmid. By contrast, PRMT6 knockdown by siRNA reduced the effect of GLP on cell migration. These results indicate that GLP was effective in inhibiting cell growth, the cell cycle and cell migration, and the suppressive effect of GLP on cell migration may occur via the PRMT6 signaling pathway. Therefore, it is suggested that GLP may act as a tumor suppressor with applications in the treatment of prostate cancer. The results of the present study provide both the preliminary theoretical and experimental basis for the investigation of GLP as a therapeutic agent. PMID- 29115464 TI - microRNA-222 promotes tumor growth and confers radioresistance in nasopharyngeal carcinoma by targeting PTEN. AB - MicroRNA-222 (miR-222) has been reported to be involved in the initiation, development and metastasis of tumors, as well as conferring resistance to chemotherapeutic drugs or radiotherapy in various types of cancer. However, the role and the underlying molecular mechanism of miR-222 specifically in nasopharyngeal carcinoma (NPC) remains unclear. Thus, the biological function and underlying mechanism of in miR-222 was investigated in NPC tissue specimens and cell lines. miR-222 was upregulated in NPC tissues and malignant cell lines compared with adjacent normal samples and cell lines. miR-222 upregulation significantly increased NPC cell proliferation, colony formation and cell apoptosis. Furthermore, miR-222 upregulation conferred radioresistance. It was also confirmed that phosphatase and tensin homolog (PTEN) was a direct target for miR-222 in NPC cells. Alteration of miR-222 expression was demonstrated to regulate the phosphoinositide 3-kinase/protein kinase B pathway in NPC cells. These results suggest that miR-222 may act as an oncomir in NPC by targeting PTEN, and has potential as a therapeutic target in NPC. PMID- 29115465 TI - Trichosanthes kirilowii extract enhances repair of UVB radiation-induced DNA damage by regulating BMAL1 and miR-142-3p in human keratinocytes. AB - Ultraviolet B (UVB) radiation induces DNA damage, oxidative stress and inflammation, and suppresses the immune system in the skin, which collectively contribute to skin aging and carcinogenesis. The DNA damage response, including DNA repair, can be regulated by the circadian clock and microRNA (miRNA) expression. The aim of the present study was to evaluate the reparative action of Trichosanthes kirilowii extract (TKE) against UVB irradiation-induced DNA damage in human keratinocytes. TKE demonstrated low cytotoxicity in normal HaCaT keratinocytes at low doses (up to 100 ug/ml). The results of a comet assay revealed that TKE enhanced the repair of UVB-induced DNA damage. TKE significantly upregulated the expression of the core clock protein, brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1), and downregulated the expression of miRNA (miR)-142-3p, as demonstrated using western blotting and the reverse transcription-quantitative polymerase chain reaction. Furthermore, the suppression of miR-142-3p by a specific inhibitor positively correlated with the repair activity. Overall, the data obtained demonstrated that TKE enhanced the repair of UVB-induced DNA damage by regulating the expression of BMAL1 and miR-142-3p. Consequently, TKE can be considered a potential candidate for the treatment of skin diseases associated with UVB-induced damage. PMID- 29115466 TI - Recombinant TsP53 modulates intestinal epithelial barrier integrity via upregulation of ZO-1 in LPS-induced septic mice. AB - Tight junctions (TJs) are a critical component in maintaining the intestinal mucosal barrier function and gastrointestinal health of animals. Gut barrier dysfunction contributes to the initiation and development of sepsis which induces an uncontrollable systemic inflammatory response and gives rise to life threatening clinical conditions. Excretory-secretary antigens from Trichimella spiralis (T. spiralis) have been reported to protect from sepsis in a mouse model, however the mechanism remains to be elucidated. Mice were treated with recombinant T. spiralis 53-kDa glycoprotein (rTsP53) at 2 or 6 h following lipopolysaccharide (LPS) injection. Survival rate, serum systemic inflammation, Chiu's score, D-lactic acid (D-LA) and diamine oxidase (DAO) as intestinal injured biomarkers, bacterial translocation and growth in peritoneal fluid (PF) and mesenteric lymph nodes (MLN), intestinal tight junction structure and protein zona occludens (ZO)-1 expression were investigated. In LPS-induced septic mice, rTsP53 was demonstrated to protract the survival and inhibit serum systemic inflammatory response, and then, allayed morphological alteration, decreased the release of D-LA and DAO from intestines. Furthermore, LPS-induced intestinal permeability, bacterial translocation and growth in PF, MLN and vital organs were significantly suppressed by rTsP53 treatment. Notably, rTsP53 treatment markedly improved the intestinal tight junction damaged in sepsis via promoting ZO-1 expression. These results demonstrated that rTsP53 ameliorated LPS-induced intestinal injury and is a potential protective agent for treatment of sepsis. PMID- 29115467 TI - Coenzyme Q10 promotes osteoblast proliferation and differentiation and protects against ovariectomy-induced osteoporosis. AB - Coenzyme Q10 (CoQ10) is a fat-soluble vitamin-like substance used for the treatment of a variety of disorders, including osteoporosis. The exact mechanism underlying CoQ10-mediated protection against osteoporosis remains to be elucidated. The present study aimed to evaluate the effect of CoQ10 on osteoblastic cell proliferation and differentiation, and therapeutic effects on a rat model of osteoporosis. Following treatment with different concentrations of CoQ10, cell proliferation and differentiation of rat bone marrow stromal cells (BMSCs), and expression of osteoblastogenic markers, were measured. Rats with osteoporosis subjected to ovariectomy (OVX) were treated with different concentrations of CoQ10. Serum levels of estrogen and bone metabolism markers were measured. Micro computed tomography scans were used to analyze morphological changes in bones. In addition, mRNA and protein levels of phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)/phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase(AKT), were determined. CoQ10 significantly increased the proliferation and osteogenic differentiation of BMSCs in a dose dependent manner, with an increased expression of osteogenic markers. CoQ10 significantly decreased bone resorption but exhibited no effect on serum E2 levels in vivo. CoQ10 markedly enhanced bone formation. Furthermore, the abundance of p-PI3K and p-AKT increased while PTEN levels decreased in a dose dependent manner following administration of CoQ10. CoQ10 stimulates the proliferation and differentiation of BMSCs and is effective for the treatment of OVX-induced osteoporosis in rats. The above effects of CoQ10 may be mediated by activation of the PTEN/PI3K/AKT pathway. PMID- 29115468 TI - Curcumin alleviates liver oxidative stress in type 1 diabetic rats. AB - The aim of the present study was to determine the effects of curcumin on antioxidants using a rat model of type 1 diabetes. Seven-week-old male Sprague Dawley rats were injected with Streptozotocin (STZ) intraperitoneally to induce this model, and then treated with 1.0% curcumin (weight ratio) mixed in their diet for 21 days. The present study included three groups: Control group (NC), diabetic rat model group (DC) and a curcumin treated group (Diab-Cur). The results demonstrated that curcumin treatment markedly decreased the blood glucose levels, plasma malondialdehyde concentration and plasma activity of glutathione peroxidase (GSH-Px) and catalase (CAT); however, it increased the plasma superoxide dismutase (SOD) and insulin levels. Curcumin treatment increased the expression of the CAT, GSH-Px, HO-1 and norvegicus NAD(P)H quinone dehydrogenase 1, and decreased the SOD1 expression, which, led to a diminished oxidative stress status. In addition, curcumin treatment significantly increased the protein expression of Keap1 in the Diab-Cur group when compared with the DC group, decreased cytosolic concentrations of Nrf2 while increasing nuclear accumulation of Nrf2. The results provide evidence that oxidative stress in the STZ-induced diabetic rat model may be attenuated by curcumin via the activation of the Keap1 Nrf2-ARE signaling pathway, as evidenced by a decrease in the blood glucose concentration and an increase in the transcription of several antioxidant genes. PMID- 29115469 TI - MicroRNA-512-3p is upregulated, and promotes proliferation and cell cycle progression, in prostate cancer cells. AB - Prostate cancer (PCa) is the most commonly diagnosed cancer in males worldwide. MicroRNAs (miRNAs/miRs) are small non-coding RNAs that participate in the regulation of various biological processes by regulating post-transcriptional gene expression. However, whether dysregulation of miRNA expression may be associated with the carcinogenesis of PCa remains to be elucidated. The present study identified differentially expressed miRNAs in PCa by analyzing two publicly available gene expression datasets, GSE14857 and GSE21036. The results demonstrated that miR-512-3p was significantly upregulated in PCa. Furthermore, the present study explored the molecular functions of miR-512-3p in PCa, and demonstrated that overexpression of miR-512-3p promoted PCa cell proliferation and reduced G1 phase cell cycle arrest in PCa. These results indicated that miR 512-3p may act as an oncogene in PCa. To the best of our knowledge, this is the first study revealed the molecular functions of miR-512-3p in PCa. To obtain valuable insights into the potential mechanisms of miR-512-3p, bioinformatics analyses were performed to identify the targets of miR-512-3p. Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology category analyses revealed that miR-512-3p may be associated with the mitogen-activated protein kinase signaling pathway and numerous biological processes, including cell adhesion, cell proliferation, cell cycle and apoptosis. These results suggested that miR-512-3p may be considered a potential diagnostic and therapeutic target of PCa. PMID- 29115470 TI - Dimethylation of Histone 3 Lysine 9 is sensitive to the epileptic activity, and affects the transcriptional regulation of the potassium channel Kcnj10 gene in epileptic rats. AB - Potassium channels can be affected by epileptic seizures and serve a crucial role in the pathophysiology of epilepsy. Dimethylation of histone 3 lysine 9 (H3K9me2) and its enzyme euchromatic histone-lysine N-methyltransferase 2 (G9a) are the major epigenetic modulators and are associated with gene silencing. Insight into whether H3K9me2 and G9a can respond to epileptic seizures and regulate expression of genes encoding potassium channels is the main purpose of the present study. A total of 16 subtypes of potassium channel genes in pilocarpine-modelled epileptic rats were screened by reverse transcription-quantitative polymerase chain reaction, and it was determined that the expression ATP-sensitive inward rectifier potassium channel 10 (Kcnj10) increased in hippocampus and insular cortex, while the expression of most of the other subtypes decreased. The total level of H3K9me2 decreased in the model group compared with the control. The Kcnj10 gene encoding the Kir4.1 channel was selected to analyse changes in H3K9me2 in the promoter region by the chromatin immuno-precipitation method. Anti H3K9me2 and anti-G9a antibodies were used to identify the modified DNAs. Five primers were designed across the promoter region of the Kcnj10 gene. In epileptic hippocampi, the relative abundance of H3K9me2 and G9a in the promoter region of Kcnj10 decreased markedly. Removal of the H3K9me2 repressive mark resulted in decreased transcriptional inhibition of the Kcnj10 gene and therefore increased its expression. In the cultured C6 cells, specific inhibition of the enzymatic activity of G9a by 2-(Hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-di- methoxy-N (1-(phenyl-methyl)-4-piperidinyl)-4-quinazolinamine tri-hydrochloride hydrate (bix01294) resulted in upregulation of the expression of Kir4.1 proteins. The present study demonstrated that H3K9me2 and G9a are sensitive to epileptic seizure activity during the acute phase of epilepsy and can affect the transcriptional regulation of the Kcnj10 channel. PMID- 29115471 TI - Cardioprotective effects of ulinastatin against isoproterenol-induced chronic heart failure through the PI3K-Akt, p38 MAPK and NF-kappaB pathways. AB - The purpose of the present study was to evaluate the cardioprotective effect of ulinastatin against isoproterenol-induced chronic heart failure (CHF). Compared with the control group, treatment with ulinastatin decreased interventricular septal thickness and left ventricular posterior wall thickness, and improved the left ventricular ejection fraction, left ventricular fractional shortening and peak E and peak A ratio in the isoproterenol-induced CHF rat. In addition, ulinastatin suppressed inflammation, oxidative stress and apoptosis in heart tissue from isoproterenol-induced CHF rats. Ulinastatin induced the activation of the phosphatidylinositol 3-kinase (PI3K)/RAC-alpha serine/threonine protein kinase (Akt) signaling pathway and downregulated the p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB pathway in isoproterenol induced CHF rats. These data demonstrated the cardioprotective effect of ulinastatin against isoproterenol-induced chronic heart failure through the PI3K Akt, p38 MAPK and NF-kappaB pathways. PMID- 29115472 TI - Anti-inflammatory activity of resveratrol prevents inflammation by inhibiting NF kappaB in animal models of acute pharyngitis. AB - Recent studies have demonstrated that resveratrol can reduce blood sugar, improve insulin resistance, regulate abnormalities in lipid metabolism, and lower the secretion and expression of inflammatory factors. The present study investigated the anti-inflammatory effects of resveratrol in animal models of acute pharyngitis, and its possible mechanisms. Commercial ELISA kits were used to measure tumor necrosis factor-alpha, interleukin (IL)-6, macrophage inflammatory protein-2, cyclooxygenase-2 levels and caspase-3/9 activity. Toll-like receptor (TLR)-4, myeloid differentiation primary response protein MyD88, phosphorylated (p)-nuclear factor (NF)-kappaB and p-IkappaB were analyzed using western blotting. In a rabbit model of acute pharyngitis, it was demonstrated that resveratrol inhibited tumor necrosis factor-alpha and interleukin-6 serum levels, macrophage inflammatory protein-2 and cyclooxygenase-2 activity levels, reactive oxygen species production and caspase-3/9 activity. Resveratrol suppressed NACHT, LRR and PYD domains-containing protein 3 and caspase-1 protein expression, and reduced IL-1beta and IL-18 protein expression in animal models of acute pharyngitis. Additionally, resveratrol suppressed TLR4 and myeloid differentiation primary response protein 88 protein expression, and reduced p-NF kappaB and increased p-IkappaB protein expression in animal models of acute pharyngitis. In conclusion, these findings indicated that the anti-inflammatory activity of resveratrol prevents acute pharyngitis-induced inflammation by inhibiting NF-kappaB in animal models. Therefore, these data suggested an important clinical application of resveratrol in preventing acute pharyngitis. PMID- 29115473 TI - Clinical application of a novel diagnostic scheme including pancreatic beta-cell dysfunction for traumatic multiple organ dysfunction syndrome. AB - A novel diagnostic scheme that includes pancreatic beta-cell dysfunction analysis for the diagnosis of traumatic multiple organ dysfunction syndrome (MODS) was investigated to assist in the early diagnosis and detection of MODS. Early intervention and treatment of MODS has been associated with a reduced mortality rate. A total of 2,876 trauma patients (including patients post-major surgery) were admitted to the intensive care unit of the authors' hospital between December 2010 and December 2015 and enrolled in the present study. There were 205 cases where the patient succumbed to their injuries. In addition to the conventional diagnostic scheme for traumatic MODS, indexes of pancreatic beta cell dysfunction [fasting blood-glucose (FBG), homeostatic model assessment-beta and (blood insulin concentration 30 min following glucose loading-fasting insulin concentration)/(blood glucose concentration 30 min following glucose loading-FBG concentration)] were included to establish an improved diagnostic scheme for traumatic MODS. The novel scheme was subsequently used in clinical practice alongside the conventional scheme and its effect was evaluated. The novel scheme had a significantly higher positive number of MODS diagnoses for all trauma patients compared with the conventional scheme (12.48 vs. 8.87%; P<0.01). No significant difference was identified in the final percentage of positive of MODS diagnoses for trauma-associated mortality patients between the novel (88.30%) and the conventional scheme (86.34%). The novel scheme had a significantly higher positive number of MODS diagnoses for trauma-associated mortality patients 3 days prior to patients succumbing to MODS compared with the conventional scheme (80.98 vs. 64.39%; P<0.01). The consensus of the MODS diagnosis of all trauma patients between the novel scheme and the conventional scheme was 100%; however, out of the patients diagnosed as positive by novel scheme 71.03% were positive by the conventional scheme. The consensus between the final MODS diagnosis and the MODS diagnosis 3 days prior to patients succumbing to their injuries between the novel scheme and the conventional scheme was 100%; however, out of the patients diagnosed as positive by novel scheme 97.79 were positive by the conventional scheme of the 205 patients who succumbed to MODS and out of the patients diagnosed as positive for MODS by novel scheme 3 days prior to succumbing, 79.52% were positive by the conventional scheme. The results of the present study demonstrated that the novel diagnostic scheme using the relevant indexes of pancreatic beta-cell dysfunction for diagnosis of traumatic MODS, was able to diagnose MODS early without excessively extending the diagnostic scope. Its clinical application should be promoted. PMID- 29115474 TI - Genetic characteristics of polycistronic system-mediated randomly-inserted multi transgenes in miniature pigs and mice. AB - Multi-transgenic technology is superior to single transgenic technology in biological and medical research. Multi-transgene insertion mediated by a polycistronic system is more effective for the integration of polygenes. The multi-transgene insertion patterns and manners of inheritance are not completely understood. Copy number quantification is one available approach for addressing this issue. The present study determined copy numbers in two multi-transgenic mice (K3 and L3) and two multi-transgenic miniature pigs (Z2 and Z3) using absolute quantitative polymerase chain reaction analysis. For the F0 generation, a given transgene was able to exhibit different copy number integration capacities in different individuals. For the F1 generation, the most notable characteristic was that the copy number proportions were different among pedigrees (P<0.05). The results of the present study demonstrated that transgenes within the same vector exhibited the same integration trend between the F0 and F1 generations. In conclusion, intraspecific consistency and intergenerational copy numbers were compared and the integration capacity of each specific transgene differed in multi-transgenic animals. In particular, the copy number of one transgene may not be used to represent other transgenes in polycistronic vector mediated multi-transgenic organisms. Consequently, in multi-transgenic experimental animal disease model research or breeding, copy numbers provide an important reference. Therefore, each transgene in multi-transgenic animals must be separately screened to prevent large copy number differences, and inconsistent expression between transgenes and miscellaneous data, in subsequent research. PMID- 29115475 TI - Dysifragilone A inhibits LPS-induced RAW264.7 macrophage activation by blocking the p38 MAPK signaling pathway. AB - Dysifragilone A, a sesquiterpene aminoquinone based on a rearranged avarone skeleton, has been previously isolated and identified from the South China Sea sponge Dysidea fragilis. In the present study, anti-inflammatory activity and the underlying molecular mechanism of dysifragilone A were studied using the classical inflammation model of lipopolysaccharide (LPS)-activated RAW264.7 macrophage cells and an MTT assay, Griess method, ELISA and western blotting were used. The results revealed that dysifragilone A significantly reduced the release of inflammatory mediators and inflammatory cytokines in activated RAW264.7 cells, including nitric oxide (NO), prostaglandin E2,(PGE2) and interleukin-6 (IL-6). The protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and the enzymatic activity of iNOS and COX-2 were also inhibited by dysifragilone A in a dose dependent manner. Further mechanistic investigations suggested that the anti-inflammatory activity of dysifragilone A results from the suppression of p38 mitogen-activated protein kinase (MAPK) activation in LPS-activated macrophages; however, this was not associated with inhibition of the extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) signaling pathways. Therefore, dysifragilone A and similar compounds may be anti-inflammatories that have potential to be used in the clinic. PMID- 29115476 TI - Prognostic microRNAs and their potential molecular mechanism in pancreatic cancer: A study based on The Cancer Genome Atlas and bioinformatics investigation. AB - Although certain biomarkers that are directly associated with the overall survival (OS) of patients with pancreatic adenocarcinoma (PAAD) have been identified, the efficacy of a single factor is limited to predicting the prognosis. The aim of the present study was to identify a combination micro (mi)RNA signature that enhanced the prognostic prediction for PAAD. Following analysis of the data available from The Cancer Genome Atlas (TCGA), 175 PAAD samples were selected for the present study, and the associations between 494 miRNAs and OS were investigated. The prognostic value of all miRNAs was analyzed by multivariate Cox regression, and the miRNAs were ranked according to the hazard ratio (HR) and P-values. The top 5 miRNAs (miR-1301, miR-125a, miR-376c, miR-328 and miR-376b) were significantly associated with OS (HR=0.139; 95% confidence interval, 0.043-0.443; P<0.001), thus demonstrating that this panel was able to serve as an independent prognostic factor for PAAD. In addition, the present study also predicted the target genes of the top 10 miRNAs with the highest prognostic values using 12 different prediction software, and enrichment signaling pathway analyses elucidated that several pathways may be markedly associated with these miRNAs, including 'Pathways in cancer', 'Chronic myeloid leukemia', 'Glioma' and 'MicroRNAs in cancer'. Lastly, ubiquitin C, epidermal growth factor receptor, estrogen receptor 1, mitogen-activated protein kinase 1, mothers against decapentaplegic homolog 4 and androgen receptor may be the hub genes revealed by STRING analysis. The present study identified several miRNAs, particularly a five-miRNA-pool, that may be reliable, independent factors for predicting survival in patients with PAAD. However, the underlying molecular mechanisms require further investigation in the future. PMID- 29115477 TI - Effects of Lycium barbarum (goji berry) on dry eye disease in rats. AB - Lycium barbarum (goji berry) has long been used as a food and traditional herbal medicine. This study aimed to investigate the beneficial effect of the goji berry on dry eye disease in rats. Male Sprague-Dawley rats with induced dry eye disease were randomly assigned to four groups: Vehicle (control), low-dose goji berry extract [GBE; 250 mg/kg/body weight (bw)], median-dose GBE (350 mg/kg/bw), and high-dose GBE (500 mg/kg/bw). Three methods, Schirmer's test, tear break-up time (BUT) measurement and keratoconjunctival fluorescein staining, were used to evaluate the effect of GBE on symptoms of dry eye disease experienced by the rats. The results of the present study revealed that both the Schirmer's test score and tear BUT significantly increased following 1 week of GBE administration. Furthermore, the severity of the keratoconjunctival staining decreased significantly. In addition, the results suggested that administration of GBE may ameliorate dry eye disease symptoms in a dose-dependent manner. There were no mortalities and no apparent abnormal histopathology changes in the liver or kidney tissues of rats administered GBE for 21 consecutive days. Polysaccharides and betaine present in GBE may have important effects in alleviating dry eye disease induced by oxidative stress and inflammation. In conclusion, the goji berry is a safe, functional food with beneficial effects in alleviating dry eye disease. PMID- 29115478 TI - Torin2 enhances the radiosensitivity of MCF-7 breast cancer cells by downregulating the mTOR signaling pathway and ATM phosphorylation. AB - Radiotherapy has an important role in the comprehensive treatment of breast cancer. However, the clinical outcome of adjuvant radiotherapy may be limited due to intrinsic radioresistance, it is necessary to explore efficient radiosensitization methods that improve the clinical outcome of patients undergoing radiotherapy. The present study aimed to investigate whether the novel mechanistic target of rapamycin (mTOR) inhibitor Torin2 enhances the radiosensitivity of MCF-7 breast cancer cells. A Cell Counting Kit-8 (CCK-8) assay was performed to measure the effect of Torin2 on cell proliferation, while clonogenic assays were employed to determine the effect of Torin2 in combination with radiation on the proliferation of MCF-7 cells. The effect of Torin2 and/or radiation on the cell cycle was analyzed using flow cytometry. Furthermore, the protein expression of components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway, and the expression of proteins involved in DNA damage repair, was measured by western blot analysis. The results demonstrated that Torin2 exhibited a higher potency in MCF-7 cells, while MDA-MB-231 cells were less sensitive to Torin2. Compared with irradiation alone, pretreatment with 20 nM Torin2 followed by irradiation resulted in an increased level of gamma-H2A histone family member X. Radiation induced the activation of the Akt/mTOR signaling pathway and upregulated the expression of phosphorylated (p)-Akt473 and p-eukaryotic translation initiation factor 4E binding protein 1 (4EBP1)37/46. Notably, pretreatment with Torin2 attenuated the radiation-induced activation of the Akt/mTOR signaling pathway. In addition, Torin2 partially blocked the repair of double-strand breaks induced by radiation by reducing the activation of ataxia telangiectasia-mutated, and sensitized MCF-7 cells to radiation. In conclusion, administration of Torin2 prior to irradiation enhanced the radiotherapeutic effect on breast cancer cells in vitro, and these results may provide a foundation for the rational use of combined therapy with irradiation and Torin2 for breast cancer in clinical practice. PMID- 29115479 TI - Overexpression of miR-185 inhibits autophagy and apoptosis of dopaminergic neurons by regulating the AMPK/mTOR signaling pathway in Parkinson's disease. AB - Parkinson's disease (PD) is an age-associated neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta. Activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) has been suggested to be associated with PD pathogenesis. The aim of the present study was to investigate the effects of the aberrant expression of microRNA-185 (miR-185) in PD. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced in vitro model of PD was generated using the human SH-SY5Y dopaminergic neuroblastoma cell line, in order to examine the potential molecular mechanisms underlying the roles of miR-185 in PD. miR-185 expression was assessed in MPTP-treated SH-SY5Y cells using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, MPTP-treated SH-SY5Y cells were transfected with a miR-185 mimic or scramble miRNA, and flow cytometry was used to evaluate the level of cellular apoptosis. The expression of autophagy markers, including Beclin 1, microtubule-associated protein light chain 3 (LC3) I and LC3II, as well as key molecules involved in the AMPK/mechanistic target of rapamycin (mTOR) signaling pathway, such as phosphorylated (p)-AMPK and p-mTOR, was examined using RT-qPCR and western blot analyses. In addition, SH-SY5Y cells were treated with the AMPK inhibitor, Compound C, and its effects on cellular apoptosis were assessed. The results demonstrated that miR-185 was significantly downregulated in SH-SY5Y cells treated with MPTP at concentrations of >100 uM when compared with untreated controls. Following transfection with a miR-185 mimic, miR-185 expression in SH-SY5Y cells was significantly increased when compared with blank control cells. Notably, miR-185 overexpression was revealed to significantly reduce the MPTP-induced increase in cellular apoptosis. In addition, the expression levels of Beclin 1, LC3I/II, p-AMPK and p-mTOR were significantly upregulated in MPTP-treated SH-SY5Y cells; whereas miR-185 overexpression significantly downregulated the expression of these factors. Furthermore, miR-185 overexpression significantly suppressed apoptosis of SH-SY5Y cells treated with MPTP plus Compound C when compared with the Compound C group. In conclusion, the results of the present study suggest that overexpression of miR-185 may inhibit autophagy and apoptosis of dopaminergic cells in PD potentially via regulation of the AMPK/mTOR signaling pathway. Therefore, AMPK/mTOR-mediated autophagy and apoptotic signaling pathways may be potential novel therapeutic targets for the development of alternative strategies for the treatment of patients with PD. PMID- 29115480 TI - Protective effects of probucol on Ox-LDL-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via LOX-1/ROS/MAPK signaling. AB - Oxidized low-density lipoprotein (Ox-LDL), as a strong oxidant, results in renal injury through multiple mechanisms. The aim of the present study was to determine the injury effects of Ox-LDL and the potential protective effects of the antioxidant reagent probucol on epithelial-mesenchymal transition (EMT) in human renal proximal tubular epithelial cells (HK-2) and to further explore the role and interrelation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX 1), reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) pathway. In the present study, concentrations of 0-100 ug/ml Ox-LDL were used to induce HK-2 cell EMT. Then, probucol (20 umol/l) and the LOX-1 inhibitor, polyinosinic acid (250 ug/ml), were also used to pretreat HK-2 cells. Intracellular ROS activity was evaluated using the specific probe 2',7' dichlorodihydrofluorescein diacetate (DCFH-DA). Concentration of nitric oxide (NO) was determined using a biochemical colorimetric method. Expression of E cadherin, alpha-smooth muscle actin (SMA), LOX-1, NADPH oxidase 4 (NOX4), cytochrome b-245 alpha chain (p22phox), extracellular signal-regulated kinase (ERK), and p38 MAPK protein levels were examined by western blotting. The results revealed that Ox-LDL induced the expression of LOX-1 and alpha-SMA and reduced the expression of E-cadherin in a dose-dependent manner, and these effects were inhibited by polyinosinic acid or probucol pretreatment. Stimulation with 50 ug/ml Ox-LDL induced the expression of NOX4 and p22phox and increased intracellular ROS activity, but NO production in the cell supernatants was not affected. The Ox-LDL-mediated increases in Nox4 and p22phox expression and in ROS activity were inhibited by probucol pretreatment. Further investigations into the underlying molecular pathways demonstrated that ERK and p38 MAPK were activated by Ox-LDL stimulation and then inhibited by probucol pretreatment. The findings of the present study therefore suggest that Ox-LDL induced EMT in HK-2 cells, the mechanism of which may be associated with LOX-1-related oxidative stress via the ERK and p38 MAPK pathways. Notably, pretreatment with probucol inhibited the Ox LDL-induced oxidative stress by reducing the expression of LOX-1, and blocked the progression of EMT. PMID- 29115481 TI - Sparstolonin B prevents lumbar intervertebral disc degeneration through toll like receptor 4, NADPH oxidase activation and the protein kinase B signaling pathway. AB - Intervertebral disc degeneration (IVDD) is the most common pathogeny of lumbago. It is the pathological basis for a series of spinal degenerative diseases. For a long time, the diagnosis and treatment of lumbago have rendered difficult, since the pathogeny has not been identified. Therefore, the present study aimed to investigate the protective effect of Sparstolonin B in preventing lumbar intervertebral disc degeneration, and explored its potential mechanism in rats. Firstly, Sparstolonin B effectively reduced the histological score of disc degeneration and increased endplate porosity of L2 superior endplates in a lumbar IVDD rat model. Sparstolonin B significantly inhibited the IVDD-induced inflammatory factors tumor necrosis factor-alpha, interleukin (IL)-1beta and IL 6, oxidative stress factors (malondialdehyde), and superoxide dismutase and caspase-3/9 activities. Treatment with Sparstolonin B significantly suppressed toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88) and nuclear factor (NF)-kappaB protein expression, inhibited NAPDH oxidase 2 protein expression and induced phosphoinositide 3-kinase and phosphorylated protein kinase B protein expression in the IVDD rat model. These results demonstrated that Sparstolonin B prevents lumbar IVDD-induced inflammation, oxidative stress and apoptosis through TLR4/MyD88/NF-kappaB, NADPH oxidase activation and the phosphoinositide 3-kinase/protein kinase B signaling pathway. These results implicate Sparstolonin B for use as a therapeutic agent for IVDD in clinical applications. PMID- 29115482 TI - Reactive astrocytes increase the expression of P-gp and Mrp1 via TNF-alpha and NF kappaB signaling. AB - To understand multidrug resistance gene expression in reactive astrocytes, the present study involved stimulated astrocytes with tumor necrosis factor (TNF) alpha and determined gene expression by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Stimulation induced P glycoprotein (gp) and multidrug resistance-associated protein (MRP0) 1 expression, which peaked by 24 h. Interestingly, the expression of P-gp and Mrp1 correlated with cell proliferation. Therefore, reactivation of astrocytes may increase P-gp and Mrp1 expression through TNF-alpha and nuclear factor (NF) kappaB signaling. To the best of the authors' knowledge, the present study is the first to demonstrate that in vitro activated astrocytes likely induced P-gp and Mrp1 expression by increasing NF-kappaB expression. The results of the present study provide a novel insight into the mechanism of refractory epilepsy and suggest inhibiting cytokine signaling may block multidrug resistance. PMID- 29115483 TI - Hepatocellular toxicity of oxalicumone A via oxidative stress injury and mitochondrial dysfunction in healthy human liver cells. AB - The marine-derived oxalicumone A (POA) has been demonstrated as a potent anti tumor bioactive agent for a variety of human carcinoma, but to the best of our knowledge, remains to be evaluated in healthy liver cells. As many drugs distribute preferentially in the liver, the present study aimed to investigate the effects of POA on apoptosis, oxidative stress and mitochondrial function in L 02 healthy liver cells. A Cell-Counting kit-8 assay demonstrated that POA inhibits the proliferation of L-02 cells in a dose- and time-dependent manner. Furthermore, POA induced apoptosis by increasing the percentage of cells in early apoptosis and the sub-G1 cell cycle, along with causing S-phase arrest in L-02 cells. Additionally, POA activated caspase 3, increased the protein expression levels of Fas ligand and B-cell lymphoma X-associated protein, and decreased the expression of the anti-apoptotic protein B-cell lymphoma 2. POA additionally reduced the content of GSH and the activity of superoxide dismutase, elevated malondialdehyde and nitric oxide levels, increased reactive oxygen species production and the levels of alanine aminotransferase and aspartate aminotransferase, which suggested that POA induced lipid peroxidation injury in L 02 cells and that oxidative stress serves an important role. Furthermore, POA caused alternations of mitochondrial function, including an abrupt depletion of adenosine triphosphate synthesis, mitochondrial permeability transition pore opening and depletion of mitochondrial membrane potential in L-02 cells. These data suggested that POA exerts cytotoxicity, at least in part, by inducing oxidative stress, mitochondrial dysfunction, and eventually apoptosis. Changes in mitochondrial function and oxidative stress by POA may therefore be critical in POA-induced toxicity in L-02 cells. PMID- 29115484 TI - Lipoic acid alleviates L-DOPA-induced dyskinesia in 6-OHDA parkinsonian rats via anti-oxidative stress. AB - Levodopa (L-DOPA) is the gold standard for symptomatic treatment of Parkinson's disease (PD); however, long-term therapy is associated with the emergence of L DOPA-induced dyskinesia (LID). Nigral dopaminergic cell loss determines the degree of drug exposure and time required for the initial onset of LID. Accumulating evidence indicates that alpha-lipoic acid (ALA) decreases this nigral dopaminergic cell loss. However, until now, the precise mechanisms of ALA have only been partially understood in LID. Chronic L-DOPA treatment was demonstrated to develop intense AIM scores to assess dyskinetic symptoms. Rats in the LID group were administrated twice daily with L-DOPA + benserazide for 3 weeks to induce a rat model of dyskinesia. Moreover, other 6-OHDA-lesioned rats were treatment with ALA (31.5 mg/kg or 63 mg/kg) in combination with L-DOPA treatment. Furthermore, the authors investigated the level of malondialdehyde (MDA) and glutathione (GSH) activity, as well as IBa-1, caspase-3 and poly (ADP ribose) polymerase (PARP) in substantia nigra by the way of western blotting and immunofluorescence. ALA reduced LID in a dose-dependent manner without compromising the anti-PD effect of L-DOPA. Moreover, ALA reduced the level of MDA and upregulated the GSH activity, as well as ameliorated IBa-1 positive neurons in the substantia nigra. Finally, it was identified that ALA could reduce L-DOPA induced cleaved-caspase-3 and PARP overexpression in the substantia nigra. Based on the present findings, ALA could be recommended as a promising disease modifying therapy when administered with L-DOPA early in the course of PD. The exact mechanism for this action, although incompletely understood, appears to relate to anti-oxidative stress and anti-apoptosis. PMID- 29115485 TI - Effect of willed movement training on neurorehabilitation after focal cerebral ischemia and on the neural plasticity-associated signaling pathway. AB - Neurorehabilitation training is a therapeutic intervention for the loss of neural function induced by focal cerebral ischemia, however, the effect varies depending on the neurorehabilitation exercises. Willed movement (WM) training is defined as task-oriented training, which increases enthusiasm of patients to accomplish a specific task. The current study was performed to the evaluate effect of WM training on neurorehabilitation following focal cerebral ischemia, and further investigate the influence on neural plasticity-associated signaling pathway. Sprague-Dawley rats following temporary middle cerebral artery occlusion (tMCAO) were randomly divided into four groups: tMCAO (no rehabilitation training), CR (control rehabilitation), EM (environmental modification) and WM groups. Rats in the CR group were forced to exercise (running) in a rotating wheel. In the WM group, food was used to entice rats to climb on a herringbone ladder. Herringbone ladders were also put into the cages of the rats in the CR and EM groups, however without the food attraction. WM group exhibited an improvement in neurobehavioral performance compared with other groups. TTC staining indicated an evident reduction in brain damage in the WM group. There were increased synaptic junctions following WM training, based on the observations of transmission election microscopy. Investigation of the molecular mechanism suggested that WM training conferred the greatest effect on stimulating the extracellular signal related kinase (ERK)/cyclic adenosine monophosphate response element-binding protein 1 (CREB) pathway and glutamate receptor 2 (GluR2)/glutamate receptor interacting protein 1-associated protein 1 (GRASP-1)/protein interacting with C kinase 1 (PICK1) cascades among groups. Collectively, the improvement of neurobehavioral performance by WM training following tMCAO is suggested to involve the ERK/CREB pathway and GluR2/GRASP-1/PICK1 cascades. The present study provided a preliminary foundation for future research on the therapeutic effect of WM training against stroke-induced neuron damage. PMID- 29115486 TI - Antitumor- and apoptosis-inducing effects of pomolic acid against SK-MEL-2 human malignant melanoma cells are mediated via inhibition of cell migration and sub-G1 cell cycle arrest. AB - Malignant melanoma is the leading cause of mortality among the skin-associated diseases because of its highly metastatic nature and lethality. The aim of the present study was to evaluate antitumor and apoptosis effects of pomolic acid, a pentacyclic triterpene, against SK-MEL-2 human malignant melanoma cells. Its effect on cell migration and cell cycle arrest were also studied. An MTT assay was used to assess the cell cytotoxicity effects induced by pomolic acid. Fluorescence microscopy using acridine orange/propidium iodide and Hoechst 33342 staining, along with transmission electron microscopy (TEM), was used to study the effects of pomolic acid on apoptosis induction in these cells. The effects of pomolic acid on cell migration were studied using an in vitro wound healing assay. The effects of pomolic acid on cell cycle phase distribution were evaluated by flow cytometry using propidium iodide as fluorescent probe. The results revealed that pomolic acid induced significant dose- and time-dependent antiproliferative effects in SK-MEL-2 human malignant melanoma cells, with IC50 values of 110.3, 88.1 and 79.3 uM after 24, 48 and 72 h, respectively. Pomolic acid-treated cells exhibited red fluorescence, and the intensity of this fluorescence increased in a dose-dependent manner, indicating apoptosis induction. After the cells were treated with 25, 75 and 150 uM pomolic acid, significant morphological alterations characteristic of apoptosis were observed by TEM, including loss of microvilli, a damaged plasma membrane, damaged cellular organelles and enlarged lysosomes. Pomolic acid also led to sub-G1 cell cycle arrest, and inhibited cancer cell migration in a dose-dependent manner. These results implicate pomolic acid as a potential therapeutic agent for the treatment of malignant melanoma. PMID- 29115487 TI - MiR-4505 aggravates lipopolysaccharide-induced vascular endothelial injury by targeting heat shock protein A12B. AB - Heat shock protein family A member 12B (HSPA12B) is a heat shock protein primarily expressed in endothelial cells. Our previous study showed that it was protective against endothelial injury induced by lipopolysaccharide (LPS). The present study was performed to investigate whether micro (mi)RNA was involved in HSPA12B expression in endothelial cells challenged by LPS. We first screened the miRNA candidates potentially related to HSPA12B by bioinformatics analysis. Then the mimics of the miRNA candidates were transfected into human umbilical vein endothelial cells (HUVECs) to investigate the miRNAs that negatively regulated HSPA12B expression. The miRNA expression was also determined in LPS-stimulated HUVECs. Dual luciferase activity assay was performed to confirm the relationship between the candidate miRNA and HSPA12B. Role of nuclear factor (NF)-kappaB in the miRNA expression was investigated by using its inhibitor. Finally, the role of the miRNA on LPS induced injury was investigated. Eleven miRNAs were screened by bioinformatics analysis and 4 of them could inhibit HSPA12B expression at both mRNA and protein levels. Among the 4 miRNA candidates, only miR-4505 was highly expressed in HUVECs stimulated by LPS. Luciferase analysis showed that miR-4505 directly interacted with the 3'untranslated region of HSPA12B. LPS-induced upregulation of miR-4505 was blocked by NF-kappaB inhibitor. Transfection with miR-4505 mimics reduced the transendothelial electrical resistance and vascular endothelial-cadherin expression. The scratch test demonstrated that miR-4505 inhibited endothelial migration capacity. In conclusion, miR-4505 downregulates the expression of HSPA12B and aggravates the LPS-induced vascular endothelial cell injury. PMID- 29115488 TI - Repeated inhalation of sevoflurane inhibits the information transmission of Purkinje cells and delays motor development via the GABAA receptor epsilon subunit in neonatal mice. AB - General anesthesia is widely used in pediatric surgery, although the influence of general anesthesia on cerebellar information transmission and motor function is unclear. In the present study, neonatal mice received repeated inhalation of sevoflurane, and electrophysiological alterations in Purkinje cells (PCs) and the development of motor functions were detected. In addition, gamma-aminobutyric acidA receptor epsilon (GABAA-R epsilon) subunit knockout mice were used to investigate the mechanism of action of sevoflurane on cerebellar function. In the neonatal mice, the field potential response of PCs induced by sensory stimulation and the motor function indices were markedly inhibited by sevoflurane, and the inhibitory effect was positively associated with the number of repetitions of anesthesia. In additional the GABAA-R epsilon subunit level of PCs was promoted by sevoflurane in a dose-dependent manner, and the inhibitory effects of sevoflurane on PC field potential response and motor function were alleviated in GABAA-R epsilon subunit knockout mice. The GABAA-R epsilon subunit was activated by sevoflurane, leading to inhibition of sensory information transmission in the cerebellar cortex, field potential responses of PCs and the development of cerebellar motor function. The present study provided experimental evidence for the safe usage of sevoflurane in clinical anesthesia, and suggested that GABAA-R epsilon subunit antagonists may be considered for combined application with general anesthesia with repeated inhalation of sevoflurane, for adverse effect prevention in the clinic. PMID- 29115489 TI - Isorhamnetin prevents H2O2-induced oxidative stress in human retinal pigment epithelial cells. AB - Isorhamnetin, a 3-O-methylated metabolite of quercetin, exhibits antioxidant effects. However, to the best of our knowledge, no study to date has focused on the effects of isorhamnetin on retinal pigment epithelium (RPE) cells, and its underlying molecular mechanisms. Therefore, the present study aimed to examine the potential protective effect of isorhamnetin against oxidative stress in human RPE cells. The results demonstrated that pretreatment of RPE cells with isorhamnetin significantly protected cell viability against oxidative stress. In addition, isorhamnetin pretreatment inhibited hydrogen peroxide (H2O2)-induced reactive oxygen species (ROS) production and caspase-3 activation in RPE cells. Furthermore, isorhamnetin pretreatment significantly increased the phosphorylation of phosphoinositide 3-kinase (PI3K) and AKT serine/threonine kinase 1 (Akt) in RPE cells exposed to H2O2, compared with cells treated with H2O2 alone. Taken together, the present results demonstrated that isorhamnetin protected human RPE cells from oxidative stress-induced cell death, and this effect was associated with activation of the PI3K/Akt signaling pathway. Thus, isorhamnetin may be considered as a potential antioxidant useful for the prevention of age-related macular degeneration. PMID- 29115490 TI - MicroRNA-206 contributes to the progression of steroid-induced avascular necrosis of the femoral head by inducing osteoblast apoptosis by suppressing programmed cell death 4. AB - The expression of microRNA-206 (miR-206) is aberrantly induced in steroid-induced avascular necrosis of femoral head (SANFH). Therefore, investigating the function of miR-206 in SANFH and uncovering the functional mechanism associated with the condition will promote the understanding and treatment of the disease. The purpose of the present study was to investigate the pro-osteoclasteogenic effect of miR-206 that occurs through regulation of programmed cell death 4 (PDCD4). The expression of miR-206 and PDCD4 was analyzed in the clinical SANFH specimens. The level of miR-206 and PDCD4 was regulated in human osteoblast lineage hFOB1.19 and the effect of different treatments on cell viability, proliferation, apoptosis and differentiation potential of osteoblasts were analyzed with a Cell Counting kit-8, 5-ethynyl-2'-deoxyuridine staining, flow cytometry and Hoechst staining. The expression of miR-206 was upregulated while PDCD4 was downregulated in the SANFH specimens. Induced expression of miR-206 decreased cell viability and proliferation, while apoptosis was induced. At the molecular level, overexpression of miR-206 inhibited the expression of PDCD4, alkaline phosphatase (ALP) and B-cell lymphoma 2 (Bcl-2), and increased the expression of apoptosis regulator Bcl2-X-associated protein (Bax). Inhibiting the expression of miR-206 increased cell viability and proliferation but had no effect on cell apoptosis, as detected by flow cytometry and Hoechst staining. However, at the molecular level, inhibiting the expression of miR-206 induced expression of PDCD4, ALP and Bcl-2, while it decreased the expression of Bax. Additionally, knockdown of PDCD4 blocked the effect of miR-206 inhibition on hFOB1.19 cells, representing a PDCD4 dependent manner of miR-206 in inducing apoptosis of osteoblasts. Therefore, miR 206 promoted the onset of SANFH by inducing apoptosis and suppressed the proliferation of osteoblasts, which was dependent on the inhibition of PDCD4. PMID- 29115491 TI - Resveratrol improves prostate fibrosis during progression of urinary dysfunction in chronic prostatitis by mast cell suppression. AB - Voiding dysfunction is the primary clinical manifestation of chronic prostatitis (CP), which is a common urological disease. The present study investigated whether prostate fibrosis was associated with urinary dysfunction in CP and if resveratrol improved urinary dysfunction, and the underlying molecular mechanism. A rat model of CP was established via subcutaneous injections of the pertussis diphtheria-tetanus vaccine, which was followed by treatment with resveratrol. Bladder pressure and volume tests were performed to investigate the effect of resveratrol on urinary dysfunction in CP rats. Western blotting and immunohistochemical staining examined the expression levels of tryptase, chymase, transforming growth factor (TGF)-beta, Wnt and alpha-smooth muscle actin (alpha SMA). The results demonstrated that the maximum capacity of the bladder, residual urine volume and maximum voiding pressure were increased significantly in the CP group compared with the control group. Mast cell (MC) activation, the activity of TGF-beta/Wnt/beta-catenin pathways, and the expression levels of tryptase and alpha-SMA in the CP group were increased significantly compared with the control group. Resveratrol treatment significantly reversed these factors. Therefore, the results indicate that MC infiltration may induce prostate fibrosis, which exhibits a close association with urinary dysfunction in CP. Resveratrol may improve fibrosis via the suppression of MC activation and TGF-beta/Wnt/beta catenin pathway activities. PMID- 29115492 TI - Epithelial-mesenchymal transition in colorectal carcinoma cells is mediated by DEK/IMP3. AB - To investigate the inhibitory effects of DEK/insulin-like growth factor II mRNA binding protein 3 (IMP3) on epithelial-mesenchymal transition (EMT) in colorectal carcinoma cells. SW620 and SW480 cell lines were selected. DEK-interfering lentivirus was transfected to knockdown DEK expression. Subsequently, MTT assays and flow cytometry were utilized to measure cell viability, and apoptosis, respectively. Cell invasion was detected using a Transwell assay. Quantitative polymerase chain reaction and western blot analysis were used to detect the expression of E-cadherin, vimentin, and matrix metalloproteinase (MMP)-9. Compared with the blank control, cells transfected with DEK-interfering lentivirus demonstrated a remarkable reduction in cell viability (P<0.05). The apoptotic rate in the DEK-interfering lentivirus group was significantly enhanced compared with the blank control group (P<0.05). In the DEK-interfering lentivirus group, the expression of E-cadherin was significantly elevated (P<0.05), while the expression of vimentin and MMP-9 were significantly reduced in both cell lines (P<0.05). The results of the present study demonstrated that EMT of colorectal carcinoma cells was partially mediated by DEK, which likely affected the invasive ability of colorectal carcinoma cells. In addition, cell proliferation and apoptosis were susceptible to DEK silencing. The current study has provided experimental evidence for the treatment of colorectal carcinoma using DEK silencing. PMID- 29115493 TI - miR-92a regulates the expression levels of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 3 via sirtuin 1 signaling in hydrogen peroxide induced vascular smooth muscle cells. AB - Vascular smooth muscle cells (VSMCs) exhibit a notably increased rate of migration, which is one of the most common pathological changes in atherosclerosis. Investigations into the role of micro (mi)RNAs in the regulation of VSMC migration are beginning to emerge and additional miRNAs involved in VSMC migration modulation require identification. In the current study, VSMCs were primarily cultured from rat thoracic aortas, transfected with miR-92a mimics and induced by hydrogen peroxide (H2O2) for 24 h. Total mRNA and protein were collected for quantitative polymerase chain reaction and western blot analysis. In addition, the sirtuin 1 (SIRT1) gene was detected by luciferase reporter assay and VSMC migration was detected by Transwell migration assay. The current results demonstrated that reduced expression of miR-92a and overexpression of SIRT1 at the mRNA level were observed in H2O2-induced VSMCs. Furthermore, luciferase reporter assay demonstrated that the activity of the SIRT1 3'-untranslated region was reduced by miR-92a mimics. The upregulation of MMP9 and the downregulation of TIMP3 in H2O2-induced VSMCs were observed to be reversed by miR-92a mimics in addition to SIRT1 siRNA. Finally, Transwell migration assay revealed that miR-92a overexpression and silencing SIRT1 mitigated VSMC migration following H2O2 treatment. The present study indicated that miR-92a prevented the migration of H2O2-induced VSMCs by repressing the expression of SIRT1, and also provided a novel therapy to protect against the phenotypic change of VSMCs in atherosclerosis. PMID- 29115494 TI - Elemene inhibits osteosarcoma growth by suppressing the renin-angiotensin system signaling pathway. AB - Osteosarcoma remains the most prevalent primary malignant bone tumor in children and young adults globally. Therefore, novel and highly effective antitumor agents are urgently required. Elemene is a natural plant compound extracted from the medicinal Chinese herb, Rhizomazedoariae, which has been employed as an antitumor agent for the treatment of a number of tumors, including osteosarcoma. However, the mechanisms underlying its antitumor effect are currently unclear. The human osteosarcoma cell lines, MG-63 and U2OS, were employed in the present study. MTT, migration, transwell invasion and terminal deoxynucleotidyltransferase-mediated deoxy-UTP-fluorescein nick end-labeling assays were performed to evaluate cell viability, migration, invasion and apoptosis, respectively. Western blotting and immunohistochemistry analyses were performed to measure the levels of renin angiotensin system (RAS) components. In order to evaluate the effect of elemene on tumor weight and volume, MG-63 and U2OS cells were injected into mice. Treatment of osteosarcoma cell lines, MG-63 and U2OS, with elemene led to the inhibition of cell viability, migration and invasion, as well as induction of cell apoptosis. In addition, elemene treatment downregulated the expression of a number of RAS components. The growth of osteosarcoma cell-transplanted tumors in nude mice and angiotensin II expression were inhibited by elemene treatment. The results of the present study indicate that the antitumor effects of elemene may partly be due to downregulation of the RAS signaling pathway, and that RAS may be a putative pharmacological target for osteosarcoma therapy. PMID- 29115495 TI - PirB inhibits axonal outgrowth via the PI3K/Akt/mTOR signaling pathway. AB - Accumulating data strongly suggests that leukocyte immunoglobulin like receptor B1 (PirB) inhibits axonal outgrowth. However, the underlying mechanisms remain unclear. In the present study, cortical neurons of newborn mice were cultured with Nogo-66 (Nogo-p4; 4 umol/l; a PirB ligand) together with NEP1-40 (Nogo inhibitory peptide) and/or anti-PirB body (50 mg/ml). PirB mRNA and protein was higher in cultured neurons induced by Nogo-66 compared with untreated cells. Neurite outgrowth assays demonstrated that the inhibitory effects of Nogo-66 on axonal outgrowth were reversed by anti-PirB body. Reverse transcription quantitative polymerase chain reaction and western blot assays demonstrated that anti-PirB treatment led to reduced mRNA and protein expression of phosphoinositide 3-kinase (PI3K), Akt serine/threonine kinase (Akt), mechanistic target of rapamycin kinase (mTOR), myosin IIA and cofilin, which are involved in axonal outgrowth. Furthermore, blockade of the PI3K/Akt/mTOR pathway using a PI3K inhibitor or an mTOR inhibitor diminished the stimulatory effect of anti-PirB on axonal outgrowth, and the reduced effect of anti-PirB on factors that were activation by anti-PirB. In addition, blockade of PI3K/Akt/mTOR enhanced anti PirB-induced gene and protein expression. These results revealed that PirB functions as a potential suppressor in axonal outgrowth via repressing PI3K/Akt/mTOR signaling pathway, and PirB/PI3K/Akt/mTOR may be a novel target for enhancing axonal outgrowth for developing rational therapeutic strategies. PMID- 29115496 TI - Prenatal diagnosis and genetic counseling for Waardenburg syndrome type I and II in Chinese families. AB - Waardenburg syndrome (WS) is an auditory-pigmentary disorder with varying combinations of sensorineural hearing loss and abnormal pigmentation. The present study aimed to investigate the underlying molecular pathology and provide a method of prenatal diagnosis of WS in Chinese families. A total of 11 patients with WS from five unrelated Chinese families were enrolled. A thorough clinical examination was performed on all participants. Furthermore, patients with WS underwent screening for mutations in the following genes: Paired box 3 (PAX3), melanogenesis associated transcription factor (MITF), SRY-box 10, snail family transcriptional repressor 2 and endothelin receptor type B using polymerase chain reaction sequencing. Array-based comparative genomic hybridization was used for specific patients whose sequence results were normal. Following identification of the genotype of the probands and their parents, prenatal genetic diagnosis was performed for family 01 and 05. According to the diagnostic criteria for WS, five cases were diagnosed as WS1, while the other six cases were WS2. Genetic analysis revealed three mutations, including a nonsense mutation PAX3 c.583C>T in family 01, a splice-site mutation MITF c.909G>A in family 03 and an in-frame deletion MITF c.649_651delGAA in family 05. To the best of the authors' knowledge the mutations (c.583C>T in PAX3 and c.909G>A in MITF) were reported for the first time in Chinese people. Mutations in the gene of interest were not identified in family 02 and 04. The prenatal genetic testing of the two fetuses was carried out and demonstrated that the two babies were normal. The results of the present study expanded the range of known genetic mutations in China. Identification of genetic mutations in these families provided an efficient way to understand the causes of WS and improved genetic counseling. PMID- 29115497 TI - Studying hepcidin and related pathways in osteoblasts using a mouse model with insulin receptor substrate 1-loss of function. AB - Hepcidin is one of the most important proteins in iron metabolism. In the present study, its role in iron metabolism and the associated signaling pathways involved was investigated in a mouse model with insulin receptor substrate 1-loss of function (IRS-/-), and osteoblasts in the iron overload condition. Protein expression levels of hepcidin, interleukin 6 (IL-6), bone morphogenetic protein receptor 1alpha and ferritin demonstrated a significant increase in the liver of the IRS-/- mice compared with the IRS+/- and IRS+/+ mice. Hepcidin levels in the jaw bone were also increased in the IRS-/- mice (although not significantly). Furthermore, mRNA expression levels of bone morphogenetic protein 6 (BMP6) and ferroportin (FPN) were significantly increased in the liver of the IRS-/- mice compared with the other two models, but no significant differences were observed in the transferrin receptor mRNA expression levels. Additionally, the mRNA expression of hepcidin, FPN and IL-6 was upregulated in osteoblasts after ferric ammonium citrate exposure, while the mRNA expression of BMP6 was inhibited. Collectively, the results of the present study indicated that hepcidin is involved in iron metabolism in IRS-1-/- mice via the signaling pathways involving BMP6 and IL-6. Furthermore, hepcidin is also involved in iron metabolism in osteoblasts under iron overload conditions. Therefore, hepcidin and its associated signaling pathway proteins may represent potential targets for the treatment of conditions associated with iron overload. PMID- 29115498 TI - Association between genotype and phenotype of virulence gene in Van der Woude syndrome families. AB - Members from two Van der Woude syndrome (VWS) families were screened to determine the prevalence of interferon regulatory factor 6 (IRF6) as a disease-causing gene and to analyze the interrelationships between patient genotype and phenotype. The peripheral blood of 24 members from two VWS families and 200 control samples were collected. The family members were interviewed for medical histories and other clinical abnormalities using questionnaires. Polymerase chain reaction was directly performed on the peripheral blood to screen for the coding region of the IRF6 gene. Of the 24 family members, a total of 6 patients had mutations of IRF6 gene. c.1234C>T (p.R412X) heterozygous mutation was detected in 3 members of family 1. In families 2 and 3, members carried the c.1210G>A (p.E404K) heterozygous mutations. The other members of the families, were wild type (wt/wt) for IRF6. Genetic testing demonstrated that the disease mutations c.1234C>T and c.1210G>A co-segregated with the two families' pathogenic mutations. The existence of genetic heterogeneity and the complexity of the clinical phenotype was demonstrated in Chinese VWS patients. PMID- 29115499 TI - Biological functions and role of CCN1/Cyr61 in embryogenesis and tumorigenesis in the female reproductive system (Review). AB - Cysteine-rich angiogenic inducer 61 (CCN1/Cyr61) is a prompt response transcription product activated by growth factors. As a member of the CCN family, it mediates cell survival, proliferation, differentiation, migration, adhesion and synthesis of the extracellular matrix by binding directly to the integrins and heparin sulfate proteoglycans or activating multiple signaling transduction pathways. It has previously been demonstrated that CCN1/Cyr61 exhibits an important role in the female reproductive system during embryogenesis and tumorigenesis. However, the functions of CCN1/Cyr61 in the female reproductive system have not been systematically investigated, therefore, the primary aim of the present review is to introduce the role and function of CCN1/Cyr61 in the female reproductive system. The current review presents the molecular structure and biological function of CCN1/Cyr61 and provides detailed data on its expression pattern and contribution to the female reproductive system, including the role in embryogenesis and tumorigenesis. PMID- 29115500 TI - Roles and mechanisms of TRPC3 and the PLCgamma/PKC/CPI-17 signaling pathway in regulating parturition. AB - The aim of the current study was to investigate the role of phospholipase C (PLC)gamma/protein kinase C (PKC)/C-kinase-activated protein phosphatase-1 (CPI 17) signaling pathways in uterine smooth muscle during parturition. Samples of uterine tissue were collected from pregnant patients who underwent a caesarean section for preterm delivery, full-term delivery with labor onset, full-term delivery without labor onset, and from a non-pregnant control group undergoing surgery for cervical intraepithelial neoplasia III. Immunohistochemistry, and western blotting were used to assess the association between TRPC3 levels and parturition and the influence of calcium ion channels. In addition, pregnant mice were used to explore the effect of uterine canonical transient receptor potential 3 (TRPC3) expression on the parturition-triggering mechanism and PLCgamma/PKC/CPI 17 signaling pathways. Pregnant mouse uterine smooth muscle cells were cultivated, with and without TRPC3 silencing, and the expression levels of PLCgamma, PKC and CPI-17, the upstream and downstream factors of the TRPC3 pathway, were measured in pregnant mouse uterine smooth muscle cells, in order to provide a theoretical basis for the prevention and treatment of premature labor. In the preterm and full-term without labor onset patient groups, the TRPC3 gene expression in the mSMCs was significantly overexpressed when compared with the non-pregnant group (P<0.05); however, TRPC3 expression was not elevated in the full-term with labor onset group, exhibiting no significant difference compared with the non-pregnant group (P>0.05). During pregnancy, compared with the non pregnant controls, Cav1.2, Cav3.1 and Cav3.2 gene expression levels were markedly increased (P<0.05) in mSMCs from the preterm delivery group and the full-term with labor onset group, however were non-significantly increased in the full-term without labor onset group. The level of TRPC3 was highest in the preterm group, while the levels of Cav1.2, Cav3.1 and Cav3.2 were highest in the full-term with labor onset group. In the preterm, LPS-treated preterm and full-term groups, TRPC3, MAPK, ERK1/2, P-ERK, Cav3.2, Cav3.1 and Cav1.2 were all expressed at higher levels than in the unfertilized group. In the LPS-treated preterm group, the levels of TRPC3, MAPK, ERK1/2, P-ERK, Cav3.2, Cav3.1 and Cav1.2 were increased compared with the preterm group. Furthermore, following transfection of small interfering TRPC3 (siTRPC3) into cells, it was demonstrated that the levels of TRPC3, PLCgamma, PKC, CPI-17, P-CPI-17, Cav1.2, Cav3.1 and Cav3.2 expression were lower in the LPS siTRPC3 group when compared with that of the LPS-treated untransfected control group. PMID- 29115501 TI - Downregulation of NKD1 in human osteosarcoma and its clinical significance. AB - Naked cuticle homolog 1 (NKD1), a negative modulator of the canonical Wnt/beta catenin pathway, is expressed in multiple normal tissues. However, there is little information regarding NKD1 expression in osteosarcoma. The aim of the present study was to explore the expression and clinicopathological significance of NKD1 in human osteosarcoma. In the present study, NKD1 protein and mRNA expression levels were detected by western blotting and reverse transcription quantitative polymerase chain reaction, respectively. The results revealed that NKD1 expression levels were significantly lower in osteosarcoma tissues compared with normal bone tissue, and were significantly lower in patients with lung metastasis compared with patients without lung metastasis. In addition, with increasing Enneking stage, the NKD1 expression levels decreased. These data indicated that reduction of NKD1 may be associated with carcinogenesis, lung metastasis and Enneking stage in osteosarcoma. This interpretation is consistent with the results obtained from experiments on MG63 osteosarcoma cells in vitro. In order to explore the function of NKD1 in osteosarcoma, the expression of NKD1 in the human osteosarcoma MG-63 cell line was upregulated by transfection with an adenovirus containing an NKD1 vector. The results revealed that upregulation of NKD1 expression reduced the proliferation and migration of osteosarcoma cells by inhibiting expression of beta-catenin, cyclin D1 and MMP-9 protein. These data suggested that the downregulation of NKD1 may be involved in the proliferation and migration of osteosarcoma cells through the activation of the canonical Wnt signaling pathway, and it may be a potential prognostic marker and therapeutic target for patients with osteosarcoma. PMID- 29115502 TI - Different inhibitory effects on the proliferation and apoptosis of human and laboratory Borna disease virus-infected human neuroblastoma SH-SY5Y cells in vitro. AB - Borna disease virus (BDV) is a neurotropic and non-cytolytic virus, which causes behavioral disorders in a wide range of warm-blooded species. It is well established that BDV induces neurodegeneration by impairing neurogenesis and interfering with neuronal functioning in the limbic system. In the present study, the potential role of BDV infection in SH-SY5Y cells was identified, and comparisons of two original BDV strains (the human Hu-H1 and the laboratory Strain V) were performed to further elucidate the phenotypes of BDV pathogenesis with strain differences. Cell Counting Kit-8 and flow cytometric analyses revealed that the two BDV strain-infected groups exhibited marked anti proliferation and cell cycle arrest compared with the control group, and the Hu H1 strain caused more evident effects. However, the Hu-H1 strain did not exert effects on the apoptosis of SH-SH5Y cells, while Strain V led to a marked increase in apoptosis upon initial infection. Western blot analysis confirmed the upregulation of apoptosis regulator BAX protein and the downregulation of apoptosis regulator Bcl-2 protein caused by the two BDV strains. The results of the present study provided evidence that infection with BDV suppressed SH-SY5Y cellular functioning and exhibited divergent antiproliferative and apoptotic roles in cells between the two strains. The present study provided an insight for future investigation of strain differences and underlying pathomechanisms. PMID- 29115503 TI - Cardioprotective effects of anisodamine against myocardial ischemia/reperfusion injury through the inhibition of oxidative stress, inflammation and apoptosis. AB - The aim of the present study was to investigate the cardioprotective effects of anisodamine against myocardial ischemia/reperfusion (I/R) injury and the molecular mechanisms involved. The present results demonstrated that anisodamine attenuated myocardial infarct sizes, decreased the levels of creatine kinase and lactate dehydrogenase, whereas it increased the left ventricular (LV) systolic pressure, the LV end-diastolic pressure, and the LV pressure maximum rising and falling rates in a myocardial I/R rat model. In addition, anisodamine was revealed to suppress oxidative stress, inflammatory factor production and myocardial cell apoptosis, as demonstrated by the downregulation of caspase-3 and apoptosis regulator BAX protein expression. The production of reactive oxygen species was decreased and the protein expression of inducible nitric oxide synthase (iNOS) was downregulated, whereas the expression of endothelial NOS was enhanced. In addition, the activity of nicotinamide-adenine dinucleotide phosphate oxidase (Nox) was suppressed and the expression of Nox4 was downregulated in rats with myocardial I/R injury. In conclusion, the results of the present study suggested that anisodamine exerted a cardioprotective effect against myocardial I/R injury in rats, through the inhibition of oxidative stress, the suppression of inflammatory processes and the inhibition of myocardial cell apoptosis. PMID- 29115504 TI - Upregulation of connexin43 by glucose deprivation in H9c2 cells via the extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway. AB - Cardiac connexin43 (Cx43) serves an essential role in maintaining the functional integrity of the heart. The present study investigated the effect of glucose deprivation (GD) on Cx43 protein expression levels in H9c2 cells, and demonstrated that following 2 h GD, Cx43 protein expression levels in H9c2 cells increased by ~68%. In addition, GD activated the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathway, which regulated the expression levels of cardiac Cx43. A MAPK inhibitor and U0126, an ERK inhibitor, abolished the effects of GD on Cx43 expression levels. Under GD, the protein expression levels of Beclin-1, p62 and LC3 were augmented, and were decreased in the presence of ERK inhibitor or siRNA-ERK. In addition, H9c2 cells exposed to GD exhibited marked increase in LDH release and decreased MTT reduction activity, all of which were not significantly reversed by U0126 treatment. Therefore, the ERK/MAPK signaling pathway may be involved in elevating cardiac Cx43 expression levels under GD in H9c2 cells. PMID- 29115505 TI - Alanine scanning mutagenesis of SP70 epitope in characterizing species-specific antibodies induced by enterovirus 71-based antigens. AB - The enterovirus 71 (EV71) SP70 epitope, derived from amino acids 208-222 of VP1, is a neutralizing epitope. The present study aimed to assess the inter-species differences of the antibodies induced by EV71-based antigens in responses to SP70 mutant peptides. BALB/c mice and Lou/C rats were immunized with EV71 SP70. Monoclonal antibodies (Mabs) were produced by hybridoma clones. Serum polyclonal antibodies (Pabs) were produced from BALB/c mice and New Zealand white rabbits immunized with recombinant EV71 VP1 (rEV71-VP1) protein or inactivated EV71. Micro-neutralization and immunofluorescence assays were used to evaluate the capacity of the antibodies to bind to EV71. Reactivity of Mabs and Pabs to mutated SP70 were determined by alanine scanning mutagenesis. Furthermore, serums from EV71-infected patients were collected to examine the affinity of SP70 antibody in the serum to mutated SP70, using competitive ELISA. The binding affinity of mouse Mabs to the SP70 epitope was increased by alanine substitution at sites of 210, 212, 213, 214, and 221. The binding affinity of rat Mabs to the SP70 epitope was increased by alanine substitution at sites 210, 217, 219, and 221. Mouse serum Pabs elicited by inactivated EV71 bound wild-type SP70, but lost affinity for mutated peptides. Conversely, rabbit serum Pabs elicited by inactivated EV71 robustly recognized SP70 mutants. Mouse serum Pabs elicited by rEV71-VP1 presented the same trend as mouse Mabs. Mutations at sites 214, 215, and 217 led to loss of recognition by rabbit Pabs elicited by rEV71-VP1, while most mutations did not influence antibody binding. Compared with the wild-type, mutations at the sites 209, 219 and 221 of SP70 lead to increased affinity with the serum antibodies produced by the EV71-infected patients. Antibody responses triggered by inactivated EV71, rEV71-VP1 and EV71 SP70 differed among species in neutralizing capacity and affinity for SP70 mutant peptides. PMID- 29115506 TI - Angiotensin II induces monocyte chemoattractant protein-1 expression by increasing reactive oxygen species-mediated activation of the nuclear factor kappaB signaling pathway in osteoblasts. AB - The present study investigated the effect of angiotensin II (Ang II) on monocyte chemoattractant protein-1 (MCP-1) expression and the underlying mechanism in osteoblasts. MCP-1 expression levels were analyzed by ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Ang II type 1 receptor (AT1R) expression levels was examined by RT-qPCR, western blotting and immunostaining. In addition, the nuclear factor (NF)-kappaB signaling pathway was investigated via western blot analysis. Reactive oxygen species (ROS) were also detected by flow cytometry and fluorescent microscopy. The results of the present study ndicated that Ang II upregulated MCP-1 expression in osteoblasts, which was mitigated by agonists of the AT1R, including olmesartan, a ROS scavenger N acetylcysteine (NAC), ammonium pyrrolidinethiocarbamate (PDTC) and nuclear factor (NF)-kappaB, but not by the Ang II type 2 receptor antagonist, PD123319. Furthermore, Ang II increased the generation of ROS and activated the NF-kappaB signaling pathway. These effects of Ang II were blocked by olmesartan, NAC and PDTC, but not by PD1123319 in osteoblasts. In conclusion, these data indicated that Ang II enhanced ROS production and activated NF-kappaB signaling via AT1R, thus upregulating MCP-1 expression in osteoblasts. PMID- 29115507 TI - Cytochrome P450 1A1 and 1B1 promoter CpG island methylation regulates rat liver injury induced by isoniazid. AB - DNA methylation is an important component of epigenetics that is involved in the occurrence and development of a variety of diseases. The present study aimed to clarify the relationship between cytochrome P450 (CYP)1A1 and CYP1B1 promoter CpG island methylation and isoniazid-induced liver injury in rats, and to explore the possible mechanism, rats were given an intragastric dose of isoniazid (55 mg.kg 1.d-1). High performance liquid chromatography was used to analyze the DNA methylation level of the whole genome in liver tissue. Methylation-specific polymerase chain reaction (PCR) was used to detect the methylation level of CpG islands in the promoter region of CYP1A1 and CYP1B1. Reverse transcription quantitative PCR was used to determine the mRNA expression levels of CYP1A1, CYP1B1, toll-like receptor 4 (TLR4), extracellular signal-regulated kinase (ERK) 2, peroxisome proliferator-activated receptor (PPAR) -gamma, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. The expression levels of CYP1A1 and CYP1B1 proteins were measured by ELISA, and malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were analyzed by colorimetric method. Liver tissue pathology, an indicator of liver function, indicated rat liver injury at 10 days following isoniazid treatment. Whole-genome methylation levels were gradually reduced, and methylation at day 7 post-treatment was significantly lower than the control group. CYP1A1 and CYP1B1 promoter CpG island methylation level was significantly increased at 3 days post-treatment. CYP1A1 and CYP1B1 mRNA expression levels were significantly reduced from day 7 and 10, respectively. These results suggested that CpG island hypermethylation of the CYP1A1 and CYP1B1 promoters regulate the low expression of genes involved in the occurrence of isoniazid-induced liver injury. With the alterations of CYP1A1 and CYP1B1 expression, the mRNA expression levels of TLR4, ERK, MDA, IL-6 and TNF-alpha were upregulated, and the expression of SOD and PPAR-gamma were downregulated. These data demonstrated that alterations in methylation patterns may involve changes in the TLR4-ERK signaling pathway and PPAR-gamma, which may alter the expression of MDA, SOD, IL-6 and TNF-alpha, leading to liver injury. PMID- 29115508 TI - DJ-1 alleviates high glucose-induced endothelial cells injury via PI3K/Akt-eNOS signaling pathway. AB - Hyperglycemia mediated endothelial cells (ECs) injury is closely associated with diabetic vascular complications. It was revealed that DJ-1 possesses cellular protective effects by suppressing oxidative stress. The present study aimed to investigate the beneficial effects of DJ-1 on high glucose (HG)-induced human umbilical vein endothelial cell (HUVEC) injury and to elucidate its underlying mechanisms. HUVECs were incubated under 5.5 mM (control group) or 25 mM D-glucose (HG group) and then transfected with recombinant adenoviral vectors to overexpression of DJ-1. Cell proliferation and apoptosis were measured using the EdU incorporation assay and flow cytometry with Annexin V-FITC/propidium iodide double staining, respectively. Apoptotic-related proteins were determined using western blot analysis. Reactive oxygen species (ROS) production, lactate dehydrogenase (LDH) and nitric oxide (NO) levels, the content of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD) were measured. Results demonstrated that overexpression of DJ-1 promoted cell proliferation and inhibited HUVECs apoptosis stimulated by HG. DJ-1 also suppressed the HG-induced reduction in the Bcl-2/Bax ratio and HG activated ROS generation in HUVECs. Furthermore, HG significantly increased the levels of LDH and MDA, and reduced the level of SOD; however, these effects were reversed by Ad-DJ-1 transfection. Furthermore, the cellular protective effect of overexpression of DJ-1 enhanced p Akt/Akt ratio, eNOS activation and NO production, and these trends were partially reversed by a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor (LY294002). Taken together, the present study highlighted the involvement of DJ-1 in HG-related EC injury and identified that DJ-1 exerts a cellular protective effect in HUVECs exposed to HG induced oxidative stress via activation of the PI3K/Akt-eNOS signaling pathway. PMID- 29115509 TI - microRNA-211 suppresses the growth and metastasis of cervical cancer by directly targeting ZEB1. AB - Of gynecological cancers, cervical cancer has the second highest incidence globally and is a major cause of cancer-associated mortality in women. An increasing number of studies have reported that microRNAs (miRNAs) have important roles in cervical cancer carcinogenesis and progression through regulation of various critical protein-coding genes. The aim of the present study was to investigate the expression and biological roles of miRNA-211 (miR-211) in cervical cancer and its underlying molecular mechanism. The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that the expression levels of miR-211 in cervical cancer tissues and cell lines were significantly lower compared with adjacent normal tissues and the normal human cervix epithelial cell line, respectively. Furthermore, upregulation of miR-211 by transfection with miR-211 mimics inhibited cell proliferation, migration and invasion of cervical cancer, as determined by MTT, Transwell and Matrigel assays, respectively. Bioinformatics analysis and luciferase reporter assay results indicated that zinc finger E-box binding homeobox 1 (ZEB1) may be a direct target gene of miR-211. In addition, RT-qPCR and western blot analysis results demonstrated that miR-211 overexpression markedly reduced ZEB1 expression at mRNA and protein levels in cervical cancer. Furthermore, the effects of ZEB1 downregulation on the proliferation, migration and invasion of cervical cancer cells were similar to those induced by miR-211 overexpression. These results indicate that miR-211 may act as a tumor suppressor in cervical cancer by directly targeting ZEB1. Therefore, miR-211/ZEB1-based targeted therapy may represent a potential novel treatment for patients with cervical cancer. PMID- 29115510 TI - HGF induces the serine-phosphorylation and cell surface translocation of ROMK (Kir 1.1) channels in rat kidney cells. AB - Extracellular potassium homeostasis is dependent on the activity of potassium channels, which are expressed on the apical membrane of epithelial tubular cells. The renal outer medullary potassium channel (ROMK) is considered to be the major route for potassium transport into the tubule lumen. Hepatocyte growth factor (HGF) exerts multiple biological activities and is important for maintaining renal homeostasis. It is also anti-apoptotic and mitogenic for protection and recovery from ARF. Whether HGF regulates the ion channel activities remains to be elucidated, therefore, the present study aimed to investigate the modulation of HGF on the expression of ROMK in cultured renal tubular cells. NRK-52E cells were treated with recombinant HGF, however, no alterations in the total expression of ROMK were observed by western blot analysis. In examining the serine 44 phosphorylation of ROMK in NRK-52E cells, the present study observed that HGF enhanced the serine 44 phosphorylation of ROMK. In addition, to investigate whether HGF-Met signaling induces the movement of ROMK to the cell surface in NRK 52E cells, the protein constituents of cells were separated into plasma membrane and cytoplasm. Using immunofluorescence assay, the expression of ROMK on the plasma membrane was increased in the HGF-treated NRK-52E cells, which suggested that ROMK was translocated to the plasma membrane following the HGF-induced phosphorylation of serine 44. Therefore, HGF may be important in potassium excretion and perform antihyperkalemic effects through the translocation of potassium channels. PMID- 29115511 TI - Neuroprotective effect of polysaccharides from Gastrodia elata blume against corticosterone-induced apoptosis in PC12 cells via inhibition of the endoplasmic reticulum stress-mediated pathway. AB - Depression is a common mental health disorder and is the leading cause of disability worldwide. Gastrodia elata (G. elata) was demonstrated to exhibit a neuroprotective effect in the authors' previous study. The present study investigated the effect of polysaccharides from G. elata (GEP) on PC12 cell apoptosis induced by corticosterone (CORT) and its possible underlying mechanisms. PC12 cells were treated with 200 uM CORT in the absence or presence of different concentrations of GEP for 48 h. Then, cell viability was measured by CCK-8 assay. The lactate dehydrogenase (LDH) leakage was quantified using an LDH assay kit. The apoptosis degree of the PC12 cells and the morphology was measured by DAPI staining. Subsequently, intracellular ROS level was detected by using DCFH-DA method, the morphology staining of the endoplasmic reticulum in PC12 cells was determined using the cationic probe, and levels of five proteins involved in apoptosis, i.e., glucose-regulated protein, 78k Da (GRP78), X-box binding protein 1 (XBP-1), growth arrest- and DNA damage-inducible gene 153 (GADD153), caspase 9 and caspase 12 were determined by western blotting. The results demonstrated that treatment with 1,000 ug/ml GEP prior to 200 uM CORT exposure significantly protected the PC12 cells from CORT-induced cell apoptosis, and reduced levels of LDH leakage and intracellular reactive oxygen species. In addition, pretreatment with GEP inhibited the activation of GRP78, X-BP-1, GADD153, caspase 9 and caspase 12. These findings suggested that GEP exhibited a neuroprotective effect against CORT-induced apoptosis in PC12 cells, and the underlying molecular mechanisms were dependent on inhibition of the endoplasmic reticulum stress-mediated pathway. This provides novel insight into the effect of GEP when used for the treatment of diseases of the nervous system. PMID- 29115512 TI - Protective effect of diltiazem on myocardial ischemic rats induced by isoproterenol. AB - The aim of the present study was to analyze the effect of diltiazem on myocardial fibrosis and remodeling of connexin43 (Cx43) in myocardial ischemic rats and mechanisms underlying these processes. A total of 36 Sprague-Dawley rats were randomly allocated into three groups (control, isoproterenol and isoproterenol with diltiazem). The myocardial ischemic model was established by 5 mg/kg/day isoproterenol administration for 7 days, and the diltiazem group received 25 mg/kg/day diltiazem for 4 weeks. Following the treatment, paraffin sections were prepared to observe microstructural changes and to evaluate the concentration of Ca2+ in myocardium. The expression of transforming growth factors-beta1 (TGF beta1), mothers against decapentaplegic homologues (Smad)2 and 7 and Cx43, were analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. The percentage Cx43 expression in intercalated disks was evaluated using immunohistochemistry. Fibrosis did not differ significantly between the control and the diltiazem-treated group. The concentration of Ca2+ increased in the myocardium of model rats. The expression of Smad7 and Cx43 was decreased in the rat model, while the expression of TGF-beta1 and Smad2 was increased. There was a significant decrease in the relative abundance of intercalated disk Cx43 in the model group. The results of the present study suggest that diltiazem may serve a protective role during remodeling of myocardial ischemia, especially in fibrosis and Cx43 remodeling. PMID- 29115513 TI - LncRNA PVT1 regulate expression of HIF1alpha via functioning as ceRNA for miR 199a-5p in non-small cell lung cancer under hypoxia. AB - Non-small cell lung cancer (NSCLC) represents one of the most important causes of cancer mortality in the world, and leads to the largest number of deaths in all kinds of lung cancer. Hypoxia has been confirmed to be a characteristic feature of NSCLC and has been shown to decrease the therapeutic efficacy of radiotherapy and some forms of chemotherapy. Previous studies revealed that many miRNAs have been proven to be involved in the molecular regulation of hypoxia and to affect the protein expression level of HIF-1alpha. Here, we demonstrated that miR-199a 5p downregulated HIF-1alpha expression and was involved in regulating the proliferation of NLSCS cell under hypoxia through downregulation of HIF-1alpha. Recently, PVT1 has been proposed to function as a molecular sponge by competitively binding miR-199a-5p using miRcode. In this study, we confirmed that PVT1 was overexpressed in the hypoxic lung cancer cells, and then we further demonstrated that PVT1 functioned as competing endogenous (ce)RNA for miR-199a 5p, upregulated expression of its endogenous targets HIF-1alpha and inhibited its function. Collectively, our study suggested that PVT1 promotes expression of HIF 1alpha in NSCLC by functioning as ceRNA of miR-199a-5p. These findings support the hypothesis that PVT1 is a vital potential target for hypoxia therapy. PMID- 29115514 TI - Polygonum multiflorm alleviates glucocorticoid-induced osteoporosis and Wnt signaling pathway. AB - It is known that long-term excessive administration of glucocorticoid (GC) results in osteoporosis. The present study aimed to evaluate the protective effects of Polygonum multiflorm (PM) on the bone tissue of rats with GC-induced osteoporosis (GIO). A total of 90 6-month-old female Sprague Dawley rats (weight range, 190-210 g) were randomly divided into nine groups: Control (normal saline); prednisone (GC; 6 mg.kg-1.d-1; Model); GC plus PMR30 (the 30% ethanol eluent fraction of PM) (H) (400 mg.kg-1.d-1); GC plus PMR30 (M) (200 mg.kg-1.d 1); GC plus PMR30 (L) (100 mg.kg-1.d-1); GC plus PMRF (fat-soluble fraction of PM) (H) (400 mg.kg-1.d-1); GC plus PMRF (M) (200 mg.kg-1.d-1); GC plus PMRF (L) (100 mg.kg-1.d-1); GC plus calcitriol (CAL; 0.045 ug.kg-1.d-1; positive). Rats were administered intragastrically with prednisone and/or the aforementioned extracts for 120 days, and weighed once/week. The serum was collected for detection of biochemical markers. The left tibia was used for bone histomorphometry analysis. The right tibia was prepared for hematoxylin and eosin staining. The left femur was used to analyze the protein expression of dickkopf-1 (DKK1), WNT inhibitory factor 1 (WIF1) and secreted frizzled related protein 4 using western blotting. Long-term excessive treatment of prednisone inhibited the bone formation rate accompanied with a decrease in bone mass, growth plate, body weight, and the level of bone-specific alkaline phosphatase and hydroxyl-terminal propeptide of type I procollagen in the serum. Furthermore, a simultaneously increase in the level of tartrate resistant acid phosphatase-5b and cross-linked carboxy-terminal telopeptide of type I collagen in the serum, in addition to DKK1, and WIF1 protein expression, was observed. PMR30 (M and L) and PMRF (H) groups were able to reduce the negative effects of GC on the bones. PMR30 (M and L) and PMRF (H) dose demonstrated a protective effect of PM on bone tissue in GIO rats. The mechanism underlying the preventive effect of PM for the treatment of GIO may be associated with direct upregulation of the canonical Wnt/beta-catenin signaling pathway. PMID- 29115515 TI - Serum microRNA expression profiling in patients with multiple system atrophy. AB - Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by alpha-synuclein positive glial cytoplasmic inclusions in oligodendrocytes. The clinical diagnosis of MSA is often challenging as there are no established biomarkers and diagnoses are now based on clinical findings alone. At present, the etiology and pathogenesis of MSA are unclear. It has been reported that dysregulation of microRNA (miRNA/miR) serves an important role in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The miRNA profile of patients with MSA remains to be established. The present study investigated the serum miRNA expression level of 10 patients with MSA, using microarray chips including 668 miRNAs. It was identified that 50 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated in the serum of the patients with MSA. The most upregulated miRNA was miR-16, which may induce the accumulation of alpha-synuclein. The target genes of some miRNAs upregulated in MSA (including miR-17, 20a, 24, 25, 30d and 451) were associated with autophagy associated molecules. The present study concluded that the expression pattern of miRNAs may be a clinical biomarker for MSA and targeting these miRNAs may provide a novel treatment for MSA. PMID- 29115516 TI - Phosphorylation of signal transducer and activator of transcription 3 induced by hyperglycemia is different with that induced by lipopolysaccharide or erythropoietin via receptor-coupled signaling in cardiac cells. AB - The signal transducer and activator of transcription 3 (STAT3) is known to be involved in hypertrophy and fibrosis in cardiac dysfunction. The activation of STAT3 via the phosphorylation of STAT3 is required for the production of functional activity. It has been established that lipopolysaccharide (LPS) induced phosphorylation of STAT3 in cardiomyocytes primarily occurs through a direct receptor-mediated action. This effect is demonstrated to be produced rapidly. STAT3 in cardiac fibrosis of diabetes is induced by high glucose through promotion of the STAT3-associated signaling pathway. However, the time schedule for STAT3 activation between LPS and high glucose appears to be different. Therefore, the difference in STAT3 activation between LPS and hyperglycemia in cardiomyocytes requires elucidation. The present study investigated the phosphorylation of STAT3 induced by LPS and hyperglycemia in the rat cardiac cell line H9c2. Additionally, phosphorylation of STAT3 induced by erythropoietin (EPO) via receptor activation was compared. Then, the downstream signals for fibrosis, including the connective tissue growth factor (CTGF) and matrix metalloproteinase (MMP)-9, were determined using western blotting, while the mRNA levels were quantified. LPS induced a rapid elevation of STAT3 phosphorylation in H9c2 cells within 30 min, similar to that produced by EPO. However, LPS or EPO failed to modify the mRNA level of STAT3, and/or the downstream signals for fibrosis. High glucose increased STAT3 phosphorylation to be stable after a long period of incubation. Glucose incubation for 24 h may augment the STAT3 expression in a dose-dependent manner. Consequently, fibrosis-associated signals, including CTGF and MMP-9 protein, were raised in parallel. In the presence of tiron, an antioxidant, these changes by hyperglycemia were markedly reduced, demonstrating the mediation of oxidative stress. Therefore, LPS- or EPO-induced STAT3 phosphorylation is different compared with that caused by high glucose in H9c2 cells. Sustained activation of STAT3 by hyperglycemia may promote the expression of fibrosis-associated signals, including CTGF and MMP-9, in H9c2 cells. Therefore, regarding the cardiac dysfunctions associated with diabetes and/or hyperglycemia, the identification of nuclear STAT3 may be more reliable compared with the assay of phosphorylated STAT3 in cardiac cells. PMID- 29115517 TI - MicroRNA-197 inhibits gastric cancer progression by directly targeting metadherin. AB - Gastric cancer is the fifth most frequent malignancy and the fourth most common cause of cancer-associated mortality worldwide. MicroRNAs (miRNAs) are a group of small RNAs that regulate several cellular processes. In particular, a large number of miRNAs are involved in gastric cancer formation and progression. Thus, miRNAs may be considered as effective diagnostic biomarkers and therapeutic methods for gastric cancer. The aim of the current study was to detect miRNA (miR)-197 expression in gastric cancer and to investigate its biological role and associated mechanism in gastric cancer. In the present study, miR-197 expression was demonstrated to be considerably downregulated in gastric cancer tissues and cell lines. Its low expression level was associated with tumour size, invasive depth, tumour-node-metastasis staging and lymph node metastasis. High expression of miR-197 inhibited tumour cell proliferation and invasion in vitro. Subsequently, metadherin (MTDH) was identified as a direct target gene of miR-197 in gastric cancer, and this was confirmed by bioinformatics analysis, Dual luciferase reporter assay, reverse transcription quantitative polymerase chain reaction and western blot analysis. MTDH expression was upregulated in gastric cancer and was inversely correlated with miR-197 expression levels. In addition, MTDH overexpression prevented the proliferation and inhibited invasion induced by miR-197 overexpression. In addition, miR-197 was demonstrated to regulate the phosphatase and tensin homolog (PTEN)/AKT signalling pathway in gastric cancer. The results of the present study suggested that miR-197 serves a tumour suppressing role in human gastric carcinogenesis and progression by regulating the MTDH/PTEN/AKT signalling pathway. The miR-197/MTDH axis may provide a novel effective therapeutic target for patients with gastric cancer. PMID- 29115518 TI - Application of oligonucleotides to construct a conditional targeting vector for porcine IkappaBalpha. AB - Conditional gene targeting at porcine IkappaBalpha may be a solution to delayed xenograft rejection, the main barrier to xenotransplantation. An oligonucleotide based method was applied to construct the vector for conditional targeting of porcine IkappaBalpha. This method was free from PCR amplification during the assembling of the different vector elements, avoiding introduction of unwanted mutations. With the help of short double-stranded DNA fragments produced by annealing oligonucleotides, nondirectional cloning has also been avoided. By making the best of directional cloning, a highly complex targeting vector was built within 3 weeks. The present study also explained why the two recombination based methods (recombineering and gateway recombination), although having demonstrated to be highly efficient in constructing ordinary targeting vectors, were not appropriate in this context. The description in the present study of an additional method to efficiently construct targeting vectors is suggested to introduce more flexibility in the field therefore helping to meet the different needs of the researchers. PMID- 29115519 TI - PTEN promotes apoptosis of H2O2-injured rat nasal epithelial cells through PI3K/Akt and other pathways. AB - Chronic rhinosinusitis (CRS) is a form of chronic inflammation of the nasal cavity and paranasal sinus with multi-causal pathogenesis, including oxidative stress. Several lines of evidence have demonstrated that the phosphatase and tensin homolog gene (PTEN) can inhibit the activation of phosphoinositide 3 kinase (PI3K) to affect phosphorylation of Akt. Importantly, the PI3K/PTEN/Akt signaling pathway is associated with various types of tumors, chronic inflammatory diseases, and autoimmune disease through its regulation of cell growth, apoptosis, proliferation, and metabolism. This in vitro study aimed to investigate the role of PTEN and the relationship between PTEN and the PI3K/Akt pathway in nasal epithelial cells under oxidative stress. H2O2 treatment was applied to induce a cell injury model of oxidative stress in rat nasal epithelial cells. Cells were divided into control, H2O2, H2O2+PTEN, and H2O2+siPTEN groups. Cell viability was measured using the CCK-8 assay, and reactive oxygen species (ROS) levels and apoptosis rates were analyzed by flow cytometry (FCM). Oxidative parameters, including ROS, catalase (CAT), and malondialdehyde (MDA), were tested by enzyme-linked immunosorbent assay (ELISA). The expression of apoptosis-related genes and PI3K/Akt pathway was assayed by quantitative PCR (qPCR) and western blot. In H2O2-injured cells, oxidative stress, due to increased ROS levels and apoptosis rates, was induced, and PTEN aggravated the injury. The levels of both p-Akt and PTEN in H2O2-injured cells were positively correlated and higher than in control cells. Unknown regulatory protein(s) may exist in the PI3K/PTEN/Akt pathway or the PTEN and PI3K/Akt pathways may be two independent signaling pathways that have cross interactions. PMID- 29115520 TI - CCL2/CCR2 axis induces hepatocellular carcinoma invasion and epithelial mesenchymal transition in vitro through activation of the Hedgehog pathway. AB - Chemokine (C-C motif) ligand 2 (CCL2) has been shown to play an important role in the regulation of tumor cell growth, metastasis and host immune response. CCL2 preferentially binds to the C-C chemokine receptor type 2 (CCR2), which is expressed in various tissues. However, the role of the CCL2/CCR2 axis in hepatocellular carcinoma (HCC) invasion and its molecular mechanisms remain unclear. The aim of this study was to elucidate this issue. The human HCC cell line MHCC-97H was treated with CCL2. Cyclopamine, a smoothened (SMO) antagonist, was used to inhibit SMO activity. CCR2 siRNA and Gli-1 siRNA were used to inhibit CCR2 and Gli-1 expression respectively. The effect of CCL2 and Hedgehog (Hh) signaling on cancer cell epithelial-mesenchymal transition (EMT) and invasion was evaluated by quantitative real-time PCR analysis, western blotting and Transwell invasion assay. Our results revealed that CCL2 induced HCC cell invasion and EMT. This effect was accompanied by the activation of Hh signaling, the upregulation of Snail and vimentin and the reduction of E-cadherin. Notably, prior silencing of CCR2 with siRNA abolished CCL2-induced Hh signaling activation, Snail and vimentin upregulation, E-cadherin reduction, as well as HCC cell invasion and EMT. Furthermore, pretreatment with cyclopamine or predepletion of Gli-1 by siRNA also eliminated the changes of Snail, vimentin and E-cadherin, and HCC invasion and EMT caused by CCL2. Collectively, our results revealed that the link between the CCL2/CCR2 axis and the Hh pathway plays an important role in HCC progression. Therefore, the CCL2/CCR2 axis may represent a promising therapeutic target to prevent HCC progression. PMID- 29115521 TI - High-cholesterol diet results in elevated amyloid-beta and oxysterols in rats. AB - The aim of the present study was to investigate the effects of diet cholesterol on oxysterol levels and amyloid-beta (Abeta) production in the peripheral blood and the brains of Sprague-Dawley (SD) rats. SD rats were randomly divided into five groups and fed 0.015, 0.05, 0.2, 0.5 and 1.6% cholesterol-containing diets for 8 weeks. The effect of the different diets on the levels of cholesterol, oxysterols [including 27-hydroxycholesterol (OHC), 24S-OHC, 7alpha-OHC and 7beta OHC], and the Abeta1-40 and Abeta1-42 peptides were examined in the plasma and the brain of the rats. The results demonstrated that diet cholesterol increased the levels of plasma cholesterol in a dose-dependent manner. The plasma levels of 27-OHC, 7alpha-OHC and 7beta-OHC significantly increased in the 0.5 and 1.6% cholesterol diet groups and the brain levels of 27-OHC significantly increased in the 1.6% cholesterol diet group. Increased concentration of cholesterol in the diet had no significant influence on plasma and brain levels of 24S-OHC in the rats. In addition, Abeta1-40 and Abeta1-42 levels in plasma and brain were significantly elevated following administration of 0.5 and 1.6% diet cholesterol. The present study revealed that high diet cholesterol contributed to increased level of oxysterols, especially 27-OHC, in the peripheral blood and the brain, which may be the link between increased peripheral cholesterol and brain Abeta production. PMID- 29115522 TI - Role of epigenetics in the pathogenesis of chronic rhinosinusitis with nasal polyps. AB - Chronic rhinosinusitis (CRS) is a highly prevalent disease characterized by mucosal inflammation of the nose and paranasal sinuses. CRS can be divided into two main categories, CRS with nasal polyps (NPs; CRSwNP) and CRS without NPs (CRSsNP). Although the pathophysiology of CRS remains unclear, DNA methylation has been implicated in the etiology of CRSwNP. The aim of the present study was to elucidate whether DNA methylation of specific genes is involved in the development of NPs. In total, 18 individuals were included in the present study, and were divided into three groups: CRSwNP (n=7), CRSsNP (n=7) and healthy controls (n=4). NP tissues were obtained from the seven patients with CRSwNP and biopsies of the inferior turbinate mucosa from all three groups were used as controls. Methylated genes detected by methyl-CpG-binding domain sequencing were validated by methylation-specific polymerase chain reaction (PCR), bisulfite sequencing, and reverse transcription-quantitative PCR (RT-qPCR). Methyl-CpG binding domain sequencing identified 43,674 CpG islands in 518 genes. The promotor regions of 10 and 30 genes were hypermethylated and hypomethylated, respectively, in NP samples compared with controls. The top four genes with altered hypomethylation in NP tissues were, Keratin 19 (KRT19), nuclear receptor subfamily 2 group F member 2 (NR2F2), A Disintegrin-like And Metallopeptidase (Reprolysin Type) with Thrombospondin type 1 motif 1 (ADAMTS1) and zinc finger protein 222 (ZNF222). RT-qPCR demonstrated that the expression levels of KRT19, NR2F2 and ADAMTS1 were significantly increased in NP tissues; however, there was no difference in the levels of ZNF222 between NP and control tissues. Further studies are required to confirm the relevance of these epigenetic modifications in the mechanisms underlying NP formation. PMID- 29115523 TI - Characterization of cholesterol metabolism in Sertoli cells and spermatogenesis (Review). AB - The Sertoli cell, which is the supporting cell of spermatogenesis, has an important role in the endocrine and paracrine control of spermatogenesis. Functionally, it provides the cells of the seminiferous epithelium with nutrition, conveys mature spermatids to the lumen of seminiferous tubules, secretes androgen-binding protein and interacts with endocrine Leydig cells. In addition, the levels of cholesterol, as well as its intermediates, vary greatly between nongonadal tissues and the male reproductive system. Throughout spermatogenesis, a dynamic and constant alteration in the membrane lipid composition of Sertoli cells occurs. In several mammalian species, testis meiosis activating sterol and desmosterol, as well as other cholesterol precursors, accumulate in the testes and spermatozoa. In addition, certain cholesterogenic genes exhibit stage-specific expression patterns during spermatogenesis, including the cytochrome P450 enzyme lanosterol 14alpha-demethylase. Inconsistency in the patterns of gene expression during spermatogenesis indicates a cell-type specific and complex temporary modulation of lipids and cholesterol, which also implicates the dynamic interactions between Sertoli cells and germ cells. Furthermore, in the female reproductive tract and during epididymal transit, which is a prerequisite for valid fertilization, the modulation of cholesterol occurring in spermatozoal membranes further indicates the functional importance of sterol compounds in spermatogenesis. However, the exact role of cholesterol metabolism in Sertoli cells in sperm production is unknown. The present review article describes the progress made in the research regarding the characteristics of the Sertoli cell, particularly the regulation of its cholesterol metabolism during spermatogenesis. PMID- 29115524 TI - High expression of long non-coding HOTAIR correlated with hepatocarcinogenesis and metastasis. AB - HOX transcript antisense RNA (HOTAIR), a newly discovered long noncoding RNA (lncRNA), has been reported to be a poor prognostic marker in many types of cancers. The current study attempted to investigate the biological roles and clinicopathlogical implications of HOTAIR in hepatocellular carcinoma (HCC), as well as understand the molecular mechanisms of HOTAIR in HCC progression. HOTAIR expression in 95 HCC patients with paired HCC tissues and adjacent non-cancer tissues were investigated using quantitative reverse transcription-polymerase chain reaction. The association between HOTAIR expression and clinicopathological features was assessed. The effects of HOTAIR were examined in vitro assays by silencing the lncRNA. Pathway analyses were performed to illustrate the biological functions of the HOTAIR and coexpression genes. The expression level of HOTAIR was observed significantly higher in the HCC tissue than the adjacent non-tumor tissue. HOTAIR expression levels were significantly higher in tumor samples from patients with distant metastasis, advanced stage, portal vein tumor embolus, vasoinvasion, tumor capsular infiltration or positive nm23 expression than those from patients without these conditions, correspondingly. The silencing of HOTAIR in liver cancer cells induced the inhibition of cell proliferation and promotion of apoptosis. Several pathways such as extracellular matrix-receptor interaction, focal adhesion, pathways in cancer were annotated with the HOTAIR and coexpression genes. In summary, the present analysis indicates that HOTAIR might be an oncogene in HCC. It functions though promoting tumor cell growth and inhibiting apoptosis. HOTAIR may potentially be involved in HCC metastatic progression by several pathways correlated to cell adhesion, and may be a therapeutic target in future. PMID- 29115526 TI - The long non-coding RNA ENST00000547547 reduces 5-fluorouracil resistance of colorectal cancer cells via competitive binding to microRNA-31. AB - Colorectal cancer (CRC) is one of the most common cancers and the third leading cause of cancer-related deaths due to its rapid progression and poor prognosis. 5 Fluorouracil (5-FU)-based chemotherapies are the standard treatment for locally advanced CRC. However, a considerable percentage of CRCs have inherent or acquired 5-FU resistance, which critically impedes clinical outcomes. In the present study, we reported that the expression level ENST00000547547 was downregulated in 5-FU-resistant CRC cells in comparison with the parental cells, While rising with the treatment of 5-FU in parental cells. Overexpression of ENST00000547547 promoted 5-FU-induced cell apoptosis and reduced the chemoresistance of 5-FU in vitro. Moreover, we found that ENST00000547547 was a target of miR-31, as confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Notably, miR-31 was upregulated in 5-FU-resistant CRC cells, and knockdown of miR-31 increased the chemosensitivity of 5-FU-resistant CRC cells. Furthermore, we demonstrated that ENST00000547547 reduced the chemoresistance of 5-FU via competitive binding to miR-31 in 5-FU-resistant CRC cell lines. Collectively, our findings revealed that ENST00000547547 reduced chemoresistance in 5-FU of 5-FU-resistant CRC cells through competitive binding to miR-31 and has the potential to serve as a therapeutic target in CRC patients. PMID- 29115525 TI - MicroRNA-103 regulates tumorigenesis in colorectal cancer by targeting ZO-1. AB - Given the emerging role of microRNAs (miRs) in cancer progression, the present study investigated the role and underlying mechanism of miR-103 in colorectal cancer (CRC). Reverse transcription-quantitative polymerase chain reaction was conducted to quantify the expression levels of miR-103 in clinical specimens and cell lines. The role of miR-103 in CRC was examined using MTT, colony formation and transwell assays. In addition, a luciferase reporter assay was used to confirm an associated between the 3' untranslated region of zonula occuldens-1 (ZO-1) and miR-103. The results demonstrated that miR-103 was upregulated in CRC. Overexpression of miR-103 promoted CRC cell proliferation and migration in vitro, whereas downregulation of miR-103 inhibited cell proliferation and migration. ZO 1 was identified as a direct target of miR-103, revealing its expression to be inversely correlated with miR-103 expression in CRC samples. In conclusion, the present study revealed that miR-103 has strong tumor-promoting effects via of targeting ZO-1 in CRC and has potential development of miRNA-based targeted approaches for the treatment of CRC. PMID- 29115527 TI - SPLUNC1 knockout enhances LPS-induced lung injury by increasing recruitment of CD11b+Gr-1+ cells to the spleen of mice. AB - Short palate, lung and nasal epithelium clone 1 (SPLUNC1) is a tissue-specific gene of nasopharyngeal tissue, and has been recognized as a potential tumor suppressor gene in nasopharyngeal carcinoma. As a secreted protein, SPLUNC1 plays an important role in innate immunity including antimicrobial and host defense. However, the related immune cells which are regulated by SPLUNC1 remain elusive. In the present study, an acute lung injury (ALI) mouse model was established by administration of lipopolysaccharide (LPS) intraperitoneal injections to wild type and SPLUNC1-/- mice (5 mg/kg). Pathologic results showed that the SPLUNC1-/- group appeared to have more severe pulmonary damage and infiltrated inflammatory cells compared with the WT group after LPS treatment for 24, 48, 72 and 96 h. The mRNA expression levels of interleukin-6 (IL-6), chemokine (C-C motif) ligand-2 (CCL-2), chemokine (C-C motif) ligand-3 (CCL-3) and chemokine (C-X-C motif) ligand-1 (CXCL-1) in lungs of the SPLUNC1-/- group were higher than these levels in lungs of the WT group at different time points after LPS injection. The percentage of splenic CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) in the SPLUNC1-/- mice was higher than this percentage in the WT mice at the time points of 72 and 96 h post LPS injection (P<0.05). These findings demonstrated that SPLUNC1 had a certain protective effect on the LPS-induced ALI mouse model as well as it was found to inhibit the recruitment of MDSCs to the spleen in this model. PMID- 29115529 TI - Influence of miR-7a and miR-24-3p on the SOX18 transcript in lung adenocarcinoma. AB - The molecular pathogenesis of the development of non-small cell lung carcinomas (NSCLCs) is extremely complex. Understanding the molecular basis of the development of this malignant tumor may enable the use of targeted therapy, which may result in a better treatment outome for these patients. Adenocarcinoma (AC) is the most common NSCLC subtype, equally common among smokers and non-smokers, and its pathogenesis remains unknown. The SOX18 protein is an important protein that plays a role in the development of blood and lymphatic vessels during the process of embryogenesis. Recent studies have also shown that the SOX18 protein may play a significant role in tumors, including lung cancers. In the present study, we analyzed the expression of the SOX18 protein and the mRNA level in postoperative samples of AC and non-malignant lung tissues (NMLTs), and a disparity in both levels was observed. Based on our previous observations that miR-7a and miR-24-3p are able to modulate SOX18 expression in NSCLC, the main aim of this study was to verify the miRNA modulation of the SOX18 transcript with the use of the MirTrap System in established lung cancer cell lines NCI-H1703, NCI H522 and A549. The SOX18 mRNA expression level was significantly lower in AC than that noted in the NMLTs (P<0.0001). However, the protein levels were higher in AC cases compared to levels noted in the NMLTs (P<0.0001). Additionally, correlations between the RQ values of SOX18 in NMLT and AC cases (r=0.8195, P=0.0001), and between miR-7a and miR24-3p in AC cases (r=0.4344, P=0.0016), were noted. In conclusion, we confirmed that miR-7a and miR-24-3p are more highly expressed in NMLTs than in the AC samples, and that they modulate the SOX18 transcript in NSCLC cells. PMID- 29115528 TI - PLCD3, a flotillin2-interacting protein, is involved in proliferation, migration and invasion of nasopharyngeal carcinoma cells. AB - Phospholipase C (PLC) is a pivotal enzyme in the phosphoinositide pathway that promotes the second messengers, diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3), to participate in eukaryotic signal transduction. Several PLC isozymes are associated with cancer, such as PLC-beta1, PLC-delta1, PLC epsilon and PLC-gamma1. However, the role of PLC-delta3 (PLCD3) in nasopharyngeal carcinoma (NPC) has not been investigated to date. In our previous study, we demonstrated that flotillin2 (Flot2) plays a pro-neoplastic role in NPC and is involved in tumour progression and metastasis. In the present study, we screened the interacting proteins of Flot2 using the yeast two-hybrid (Y2H) method and verified the interaction between PLCD3 and Flot2 by co-immunoprecipitation. We also investigated the biological functions of PLCD3 in NPC. Inhibition of PLCD3 expression impaired the malignant potential of 5-8F, a highly metastatic NPC cell line, by restraining its growth, proliferation, mobility and migration. The present study demonstrated that PLCD3 may be an oncogenic protein in NPC and that it plays an important role in the progression of NPC partially by interacting with Flot2. PMID- 29115530 TI - Curcumin suppresses Notch-1 signaling: Improvements in fatty liver and insulin resistance in rats. AB - Curcumin is a well-known phenolic substance and has many pharmacological effects associated with metabolism. However, the exact molecular mechanisms underlying this process have yet to be determined. The Notch pathway is a signal transduction pathway involved in energy metabolism. The present study aimed to investigate the effects of curcumin administration on glucose-lipid metabolism in rats subjected to a high fat diet, and investigate changes in Notch-1 signaling. Sprague-Dawley rats (n=40) were randomly divided into four groups (10 rats/group): Control diet group, high fat diet group, high fat diet plus curcumin low dose group and high fat diet plus curcumin high dose group. Following 8 weeks of treatment with curcumin (100 mg/kg in the low dose group and 200 mg/kg in the high dose group), serum metabolic markers and hepatic gene expression patterns were investigated. No differences in body weight following 8 weeks of curcumin administration (P>0.05) were observed; however, curcumin treatment did reduce visceral fat levels (peri-epididymal and peri-renal), and decreased cholesterol, triglyceride and low-density lipoprotein levels in serum compared with the high fat diet rats that did not receive curcumin (P<0.05, P<0.01). An oral glucose tolerance test and an intraperitoneal insulin tolerance test revealed that insulin resistance was reduced (P<0.05 or P<0.01) and tissue section analysis revealed that hepatosteatosis was attenuated following treatment with curcumin. Furthermore, the protein expression of Notch-1 and its downstream target Hes-1 were suppressed. These effects were also in parallel with an upregulation of fatty acid oxidation-associated gene expression, including peroxisome proliferator-activated receptor (PPAR)-alpha, carnitine palmitoyltransferase 1 and PPAR-gamma (P<0.05). In addition, curcumin administration led to a downregulation in the expression of lipogenic genes, including sterol regulatory element-binding protein, fatty acid synthase and acetyl-CoA carboxylase (P<0.05). The expression of inflammation-associated genes, including nuclear factor-kappaB, tumor necrosis factor-alpha and prostaglandin-endoperoxide synthase 2 were also suppressed. The results of the present study suggest that the hepatic Notch-1 pathway can be suppressed via curcumin treatment, which may ameliorate fatty liver and insulin resistance in rats subjected to a high fat diet. PMID- 29115532 TI - Application of F0F1-ATPase immuno-biosensors for detecting Escherichia coli O157:H7. AB - Escherichia coli (E. coli) O157:H7 is an important food-borne pathogen with a low infective threshold and high resistance to treatment. There are currently a number of detection methods available, however, the majority are time-consuming, complex and expensive, thus it is hard for these methods to be applied in routine detection. Therefore, there is urgent requirement to develop more sensitive, rapid and specific detective techniques. In the present study, an immuno biosensor based on the interference of load to the F0F1-ATPase rotation, indicated by the fluorescence fluctuation, was constructed to detect O157:H7. The results demonstrated a good linear relationship (R2=0.9818) between antigen concentration (range, 102 cfu to 104 cfu) and the fluorescence intensity. The detection signals of the samples containing 102 cfu/well and 104 cfu/well E. coli O157:H7 were significantly stronger than the signal produced by the control sample (P<0.01). Due to its higher sensibility and simplicity when compared with the current methods applied, the results of the present study indicate a promising future for the application of this technique in detecting food source pathogens. PMID- 29115531 TI - Liver dual arterial blood supply maintains liver regeneration: Analysis of signaling pathways in rats. AB - Liver dual arterial blood supply (LDABS) could increase blood supply to the liver and maintain normal liver regeneration in patients with compromised portal vein. The current study attempted to examine the underlying molecular mechanisms. Male Sprague-Dawley rats randomly received partial hepatectomy (PH) alone or PH followed by LDABS. Liver regeneration was assessed by histological examination, liver function and liver regeneration rate (LRR). Whole-genome oligo microarray analysis was used to compare gene expression profile between rats receiving PH and rats receiving PH plus LDABS. Key genes identification was validated using a MAPK signaling polymerase chain reaction (PCR) array. The extent of liver regeneration in rats receiving PH plus LDABS was comparable to that in rats receiving PH alone. The differentially expressed genes were enriched in 12 signaling pathways in two groups. MAPK signaling pathway, NF-kappa B signaling pathway, and Toll-like receptor signaling pathway were involved in LDABS-mediated liver regeneration, with Retinoblastoma 1 (Rb1), Cyclin D1, Cyclin-dependent kinase 4, Mitogen-activated protein kinase 10 (Mapk10) and CAMP responsive element binding protein 1 genes in the initiation phase, Kirsten rat sarcoma viral oncogene homolog (Kras), tumor protein 53, MYC proto-oncogene, BHLH transcription factor, Cyclin E1 and Heat shock protein family B (small) member 1 genes in the proliferation phase, Kras, Rb1, Jun proto-oncogene, AP-1 transcription factor subunit, Cyclin D2 and Mapk10 genes in the termination phase were identified as key genes in LDABS-mediated liver regeneration using MAPK signaling PCR array analysis. PMID- 29115533 TI - Effects of leptin on leptin receptor isoform expression and proliferative activity in human normal prostate and prostate cancer cell lines. AB - Results of studies on the expression of leptin and its receptors in the human prostate gland and human prostate cell lines are contradictory. Regarding this, we carefully reinvestigated this issue using human normal prostate (PrEC, PrSC, PrSMC) and prostate cancer (DU145, LNCaP, PC3) cell lines. Expression of leptin receptor isoforms was assessed by qPCR while the effects of leptin on cell proliferative activity was determined by real-time cell analyzer (RTCA). Expression of the leptin receptor variant 1 was not detected in LNCaP and PrSMC cell lines, but it was found in the remaining cell lines. In contrast, in all examined cell lines, isoforms 1-3 and 2 and 4 of the leptin receptor were found. The expression of isoforms 3 and 6 of the leptin receptor was observed in PC3, PrEC, PrSMC and PrSC cell lines, but not in LNCaP and DU145 cells. Expression of the leptin receptor isoforms 4-6 and 5 was not demonstrated in any of the tested cell lines. We also studied the effects of leptin on the expression of its receptor isoforms in all tested cell lines. At a wide range of concentrations, leptin did not change the expression of leptin receptor variant 1 in the DU145, PrEC and PC3 cell lines. In contrast, in the PrSC cell line, leptin significantly increased the expression of this gene. In all prostate cell lines tested, leptin did not alter the expression levels of variants 1-3 of the leptin receptor isoforms. Leptin did not alter the expression of isoforms 2 and 4 of the leptin receptor in the PC3 and LNCaP cell lines. In the DU145 and PrEC cell lines, leptin inhibited expression of these receptor isoforms while an opposite effect was noted in the PrSC cells. Leptin did not affect the expression level of variants 3 and 6 of its receptor in the PrEC and PC3 cell lines. However, in PrSMC cells, leptin inhibited the expression of variants 3 and 6 of its receptor, while in the PrSC cell line this cytokine significantly increased their expression levels. As assessed by RTCA, leptin stimulated the proliferative activity of DU145 cells, but inhibited this activity in LNCaP cells. At all concentrations tested, leptin did not change the proliferation rate of the PC3, PrEC and PrSMC cells. In contrast, leptin notably stimulated the proliferative activity of the PrSC (prostate stromal cell) cell line. Thus, our study demonstrated that in all tested human normal prostate and prostate cancer cell lines, transcription variants 4, 5 and 6 of the leptin receptor were not expressed. Leptin receptor transcription variants 1, 2 and 3 showed differential expression, which was present in the PC3, PrEC and PrSC cell lines. Our data also suggest that the stimulatory effects of leptin on proliferative activity of the studied cell lines require the expression of leptin receptor variant 1 in the affected cells. PMID- 29115535 TI - Jujuboside A attenuates norepinephrine-induced apoptosis of H9c2 cardiomyocytes by modulating MAPK and AKT signaling pathways. AB - Cardiomyocyte apoptosis is closely associated with the pathogenesis of heart failure. Jujuboside A (JUA) is a type of saponin isolated from the seeds of Zizyphus jujuba. In traditional Chinese medicine, it is believed that JUA possesses multiple biological effects, including antianxiety, antioxidant and anti-inflammatory activities. The present study aimed to evaluate the effects of JUA on norepinephrine (NE)-induced apoptosis of H9c2 cells and to investigate its underlying mechanisms. Rat H9c2 cardiomyocytes were pretreated with JUA and were then exposed to NE as an in vitro model of myocardial apoptosis. A cell viability assay, scanning electron microscopy, transmission electron microscopy, flow cytometry assay, acridine orange/ethidium bromide staining, reverse transcription quantitative polymerase chain reaction and western blotting, all revealed that NE induced H9c2 cell apoptosis. The results demonstrated that NE inhibited cell viability, and enhanced cell damage and apoptosis of H9c2 cells. Conversely, pretreatment with JUA was able to reverse NE-induced decreased cell viability and increased apoptosis. Furthermore, JUA suppressed upregulation of the B-cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 ratio, and inhibited the increased protein expression levels of cleaved caspase-3 and cleaved caspase-9 following NE exposure. However, the protein expression levels of cleaved caspase-12 and cleaved caspase-8 were not significantly altered following exposure to NE or JUA pretreatment. In addition, in JUA-pretreated cells, the protein expression levels of phosphorylated (p)-p38 and p-c-Jun N-terminal kinase were downregulated compared with in NE-treated cells. Furthermore, JUA regulated the activation of extracellular signal-regulated kinase (ERK) in NE-treated cells and significantly increased the expression levels of p-AKT. Taken together, these data suggested that JUA may protect against NE-induced apoptosis of cardiomyocytes via modulation of the mitogen-activated protein kinase and AKT signaling pathways. Therefore, JUA may be considered a potential therapeutic strategy for the treatment of heart disease. PMID- 29115534 TI - Crosstalk between p38 MAPK and caspase-9 regulates mitochondria-mediated apoptosis induced by tetra-alpha-(4-carboxyphenoxy) phthalocyanine zinc photodynamic therapy in LoVo cells. AB - Photodynamic therapy (PDT) is considered to be an advancing antitumor technology. PDT using hydrophilic/lipophilic tetra-alpha-(4-carboxyphenoxy) phthalocyanine zinc (TalphaPcZn-PDT) has exhibited antitumor activity in Bel-7402 hepatocellular cancer cells. However, the manner in which p38 MAPK and caspase-9 are involved in the regulation of mitochondria-mediated apoptosis in the TalphaPcZn-PDT-treated LoVo human colon carcinoma cells remains unclear. Therefore, in the present study, a siRNA targeting p38 MAPK (siRNA-p38 MAPK) and the caspase-9 specific inhibitor z-LEHD-fmk were used to examine the crosstalk between p38 MAPK and caspase-9 during mitochondria-mediated apoptosis in the TalphaPcZn-PDT-treated LoVo cells. The findings revealed that the TalphaPcZn-PDT treatment of LoVo cells resulted in the induction of apoptosis, the formation of p38 MAPK/caspase-9 complexes, the activation of p38 MAPK, caspase-9, caspase-3 and Bid, the downregulation of Bcl-2, the reduction of mitochondrial membrane potential (DeltaPsim), the upregulation of Bax and the release of apoptosis-inducing factor (AIF) and cytochrome c (Cyto c). By contrast, siRNA-p38 MAPK or z-LEHD-fmk both attenuated the effects of TalphaPcZn-PDT in the LoVo cells. Furthermore, the results revealed that siRNA-p38 MAPK had more significant inhibitory effects on apoptosis and mitochondria compared with the effects of z-LEHD-fmk in TalphaPcZn PDT-treated LoVo cells. These findings indicated that p38 MAPK plays the major regulatory role in the crosstalk between p38 MAPK and caspase-9 and that direct interaction between p38 MAPK and caspase-9 may regulate mitochondria-mediated apoptosis in the TalphaPcZn-PDT-treated LoVo cells. PMID- 29115536 TI - Advances in the T7 phage display system (Review). AB - The present review describes the advantages and updated applications of the T7 phage display system in bioscience and medical science. Current phage display systems are based on various bacteriophage vectors, including M13, T7, T4 and f1. Of these, the M13 phage display is the most frequently used, however, the present review highlights the advantages of the T7 system. As a phage display platform, M13 contains single-stranded DNA, while the T7 phage consists of double-stranded DNA, which exhibits increased stability and is less prone to mutation during replication. Additional characteristics of the T7 phage include the following: The T7 phage does not depend on a protein secretion pathway in the lytic cycle; expressed peptides and proteins are usually located on the C-terminal region of capsid protein gp10B, which avoids problems associated with steric hindrance; and T7 phage particles exhibit high stability under various extreme conditions, including high temperature and low pH, which facilitates effective high throughput affinity elutriation. Recent applications of the T7 phage display system have been instrumental in uncovering mechanisms of molecular interaction, particularly in the fields of antigen discovery, vaccine development, protein interaction, and cancer diagnosis and treatment. PMID- 29115537 TI - LncRNA PlncRNA-1 regulates proliferation and differentiation of hair follicle stem cells through TGF-beta1-mediated Wnt/beta-catenin signal pathway. AB - The present study demonstrated that hair follicle stem cells (HFSc) have multidirectional differentiation potential and participate in skin wound healing processes. Long non-coding RNAs (lncRNAs) are defined as non-protein coding transcripts longer than 200 nucleotides, which are important in the proliferation and differentiation of cells. The purpose of the present study was to investigate the role of PlncRNA-1 in the proliferation and differentiation of HFSc. Results revealed that PlncRNA-1, transforming growth factor (TGF)-beta1, Wnt and beta catenin expression levels were significantly downregulated in HFSc. PlncRNA-1 transfection promoted proliferation and differentiation of HFSc. TGF-beta1, Wnt and beta-catenin expression levels were upregulated in HFSc following transfection of PlncRNA-1. Results demonstrated that TGF-beta1 inhibitor LY2109761 blocked proliferation and differentiation of HFSc promoted by PlncRNA-1 transfection. In addition, TGF-beta1 inhibitor LY2109761 led to decreased Wnt and beta-catenin expression levels in HFSc. Furthermore, PlncRNA-1 transfection stimulated the cell cycle of HFSc, whereas TGF-beta1 inhibitor LY2109761 inhibited the cell cycle of HFSc and decreased the acceleration of the cell cycle induced by PlncRNA-1 transfection. In conclusion, these findings suggest that PlncRNA-1 may promote proliferation and differentiation of HFSc through upregulation of TGF-beta1-mediated Wnt/beta-catenin signaling pathway. PMID- 29115538 TI - Complementary actions of melatonin on angiogenic factors, the angiopoietin/Tie2 axis and VEGF, in co-cultures of human endothelial and breast cancer cells. AB - Melatonin exerts oncostatic activity in breast cancer through antiangiogenic actions. There, the aim of the present study was to ascertain whether melatonin modulates, in a coordinated action, angiopoietin-1 (ANG-1), ANG-2, their cognate Tie2 receptor and VEGF in co-cultures of human endothelial cells (HUVECs) and breast cancer (MCF-7) cells. To accomplish this we used co-cultures of human breast cancer cells (MCF-7) or non-malignant human mammary epithelial cells (MCF 10A) with endothelial cells (HUVECs). The presence of breast cancer cells increased HUVEC proliferation and 1 mM melatonin prevented this effect. ANG-1, ANG-2 and VEGF levels in co-culture media and mRNA expression were upregulated and Tie2 mRNA expression was downregulated in the HUVECs and MCF-7. Melatonin (1 mM) downregulated ANG-1, ANG-2 and VEGF levels in the co-culture media and mRNA expression in both types of cells and upregulated Tie2 mRNA expression in HUVECs. ANG-1, ANG-2, Tie2 and VEGF mRNA expression were not modified during HUVEC/MCF 10A co-culture. Estradiol (10 nM) increased ANG-1, ANG-2 and VEGF mRNA expression in HUVECs and melatonin (1 mM) counteracted this effect. We conclude that melatonin simultaneously coordinates downregulation of angiopoietins with a reduction in VEGF, which could be an effective therapeutic strategy for blocking tumor angiogenesis. PMID- 29115540 TI - MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways. AB - Melanoma is the seventh most common malignancy in females and the fifth most common cancer in males worldwide. An increasing number of studies have reported that microRNA (miRNA) dysregulation is frequently observed in various types of human cancers, including melanoma. Abnormally expressed miRNAs play an important role in melanoma formation and progression by serving as potential biomarkers and therapeutic targets. Recently, miRNA-326 (miR-326) has been reported to be differentially expressed in various types of tissues and play important roles in tumourigenesis and tumour development. However, the expression levels, biological roles and underlying mechanisms of miR-326 in melanoma remain unknown. In the present study, we demonstrated that miR-326 was significantly downregulated in melanoma tissues and cell lines. Functional assays revealed that the enforced expression of miR-326 suppressed melanoma cell proliferation and invasion and increased cell apoptosis in vitro. Using bioinformatic analysis, Kirsten rat sarcoma viral oncogene homolog (KRAS) was predicted as a potential target of miR 326. Luciferase reporter assay confirmed that miR-326 could directly target the 3'-untranslated region of KRAS. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that miR-326 upregulation decreased the KRAS expression in melanoma cells at both the mRNA and protein level. Furthermore, KRAS was upregulated in melanoma tissues and inversely correlated with miR-326 expression. In addition, the KRAS knockdown phenocopied the tumour-suppressing effects of miR-326 overexpression on melanoma cells. The restoration of the expression of KRAS markedly reversed the antitumour effects induced by miR-326 overexpression in melanoma cells. Further experiments indicated that miR-326 inactivated the AKT and ERK signalling pathways in melanoma. Collectively, these results revealed that miR-326 serves as a tumour suppressor in melanoma by targeting KRAS and regulating the AKT and ERK signalling pathways, indicating that miR-326 may be a promising therapeutic target for melanoma patients. PMID- 29115539 TI - Two-component histidine kinase DRK1 is required for pathogenesis in Sporothrix schenckii. AB - Sporothrix schenckii is a pathogenic dimorphic fungus with a global distribution. It grows in a multicellular hyphal form at 25C and a unicellular yeast form at 37C. The morphological switch from mold to yeast form is obligatory for establishing pathogenicity in S. schenckii. Two-component signaling systems are utilized by eukaryotes to sense and respond to external environmental changes. DRK1is a hybrid histidine kinase, which functions as a global regulator of dimorphism and virulence in Blastomyces dermatitidis and Histoplasma capsulatum. An intracellular soluble hybrid histidine kinase, homologous to DRK1 in B. dermatitidis, has previously been identified in S. schenckii and designated as SsDRK1. In the present study, the function of SsDRK1 was investigated using double stranded RNA interference mediated by Agrobacterium tumefaciens. SsDRK1 was demonstrated to be required for normal asexual development, yeast-phase cell formation, cell wall composition and integrity, melanin synthesis, transcription of the morphogenesis-associated gene Ste20 that is involved in the high osmolarity glycerol/mitogen-activated protein kinase pathway, and pathogenicity of S. schenckii in a murine model of cutaneous infection. Further investigations into the signals SsDRK1 responds to, and the interactions of upstream transmembrane hybrid histidine kinases with SsDRK1, are required to uncover novel targets for anti-fungal therapies. PMID- 29115541 TI - Comparison of the osteogenic differentiation of orofacial bone marrow stromal cells prior to and following marsupialization in patients with odontogenic cyst. AB - Decompression has been considered a valuable tool for odontogenic cystic lesions to minimize cyst size with low morbidity and recurrence. However, whether decompression has a role in regulating stem cell properties of orofacial bone marrow stromal cells (BMSCs) around the cysts has not been fully investigated. The present study compared the stem cell marker profile and osteogenic differentiation potential of orofacial BMSCs prior to and following marsupialization (pre-BMSCs vs. post-BMSCs) in the same individuals. The results demonstrated that post-BMSCs proliferated significantly faster, displayed higher colony-forming unit-fibroblast capacity and demonstrated higher expression of octamer binding protein 4, Nanog and SRY-related HMG box 2 when compared with the pre-BMSCs. Notably, the osteogenic potential was greater in the post-BMSCs compared with in pre-BMSCs, by demonstrating that the protein and mRNA expression levels of osteopontin, runt-related transcription factor 2, osteocalcin, alkaline phosphatase and osterix were upregulated in pre-BMSCs. Furthermore, the phosphorylated levels of extracellular signal-regulated kinase and c-Jun N terminal kinase were enhanced in post-BMSCs. In conclusion, the study indicated that decompression influences the stem cell properties of orofacial BMSCs, and further studies are needed to verify the findings. PMID- 29115542 TI - IMP3 overexpression occurs in various important cancer types and is linked to aggressive tumor features: A tissue microarray study on 8,877 human cancers and normal tissues. AB - IMP3 is an RNA binding protein required for ribosomal RNA processing, which has been suggested to be a prognostic marker in a large variety of human types of cancer. However, available data on the prevalence of IMP3 expression are largely discrepant. To systematically investigate the epidemiology and clinical relevance of IMP3 expression in human cancers we employed a two-step tissue microarrays (TMAs) approach. First, a normal tissue TMA and a multi-tumor TMA were analyzed for immunohistochemically detectable expression of IMP3 in 76 different normal tissue types and 3889 cancer samples from 95 different tumor categories. In a second step, we searched for associations between IMP3 expression and tumor phenotype and patient prognosis in TMAs containing 697 urinary bladder cancers, 1711 colon cancers, 343 esophageal adenocarcinomas, 251 esophageal squamous cell cancers, 673 lung cancers), 275 pancreatic cancers and 230 stomach cancers. In normal tissues, unequivocal IMP3 expression was found in placenta, lymphocytes and some types of glandular epithelial cells. In cancers, at least one case with weak expression could be found in 76 out of 95 (80%) different tumor types and 64 entities (67%) had at least one tumor with strong positivity. IMP3 expression was most frequently found in testicular cancer (including 71% seminomas and 96% non seminomas), neuroblastoma (88%), and squamous cell cancer of various origins. Significant associations were found between IMP3 and adverse tumor features in esophageal adenocarcinomas and cancers of the urinary bladder, lung, stomach, and pancreas. In summary, IMP3 was frequently expressed in many different tumor types, and was typically associated with aggressive tumor features. PMID- 29115543 TI - The screening and analysis of protein signatures and signaling associated with chemoresistance based on Protein Pathway Array technology in gastric cancer. AB - The present study was aimed to identify proteins associated with signaling pathways involved in chemoresistance, and establish a predictive model for chemoresistance in gastric cancer patients after radical surgery. A total of 140 clinically-staged III gastric cancer samples from patients after D2 radical gastrectomy were enrolled in the present study. Protein Pathway Array (PPA) and 286 antibodies were used to assess the protein expression in tumor tissues of patients. The Significance Analysis of Microarray (SAM) software and clustering and discriminant analysis were used to identify differentially expressed proteins between chemosensitive and chemoresistant subsets, and a predictive model for chemoresistance was established using the independent predictive factors. The Ingenuity Pathway Analysis (IPA) software was also used to investigate the relationship between proteins and the signaling transduction network. A total of 23 proteins were differentially expressed between 67 chemosensitive and 73 chemoresitant tumor tissues. Six proteins including PLK1 and DACH1 were independent risk factors for chemoresistance. A predictive model for chemoresistance by these proteins was established, and the accuracy, the sensitivity, and the specificity of this modal was 89.3, 90.3 and 88.2%, respectively. In addition, the present study revealed that differentially expressed proteins were closely related to cellular activity, DNA methylation and DNA damage and repair, and also involved in the ERK/MAPK, Wnt/beta-catenin, PI3K/AKT, apoptosis and p53 signaling pathways. In conclusion, the predictive model established by PPA may be an effective detection system for predicting the chemosensitivity of gastric cancer patients after D2 gastrectomy. PMID- 29115544 TI - HuR induces inflammatory responses in HUVECs and murine sepsis via binding to HMGB1. AB - The aim of the present study was to explore the roles of human antigen R (HuR) in sepsis. Reverse transcription-quantitative polymerase chain reaction and western blot analyses demonstrated that overexpression of HuR increased the expression of high-mobility group box 1 (HMGB1) in human umbilical vein endothelial cells (HUVECs). HMGB1 was investigated as a potential target of HuR through bioinformatics and RNA-immunoprecipitation assays. Furthermore, treatment with HuR small interfering (si)RNA suppressed the lipopolysaccharide (LPS)-mediated release of HMGB1 and reduced HMGB1-mediated hyperpermeability and leukocyte migration in HUVECs and in septic mice. In addition, HuR-siRNA injection reduced cecal ligation and puncture (CLP)-induced HMGB1 release, reduced production of interleukin 6 and lowered mortality rates. Notably, the promotive effects of HuR overexpression on the inflammatory response were attenuated when HUVECs were co treated with HMGB1 short hairpin RNA. Therefore, the present results indicated that the ectopic expression of HuR may induce inflammatory responses and thus sepsis by activating the HMGB1 signaling pathway. PMID- 29115545 TI - Effects of calcium-dependent molecular chaperones and endoplasmic reticulum in the amygdala in rats under single-prolonged stress. AB - The purpose of the present study was to investigate the role of endoplasmic reticulum (ER)-resident molecular chaperone proteins to identify whether these proteins were involved in post-traumatic stress disorder (PTSD). The present study detected changes of calreticulin (CRT), calnexin (CNX) and ERp57 in the amygdala of rats, which may with aim of providing a novel insight into the modulation effect of amygdala in PTSD. Single-prolonged stress (SPS) was applied to create the models of PTSD in rats. The expression levels of CRT, CNX and ERp57 were examined using immunohistochemistry or immunofluorescence, western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT qPCR). The results showed that SPS induced significant changes in CRT, CNX and ERp57 expression levels. Furthermore, the expression levels of CRT, CNX and ERp57 were significantly upregulated when compared to that in the control group after SPS exposure by western blot analysis (P<0.05). RT-qPCR analysis supported these results, indicating an upregulation of mRNA expression level. Taken together, the present findings suggest that SPS may induce changes to the expression of CRT, CNX and ERp57 in the amygdala of rats. The present study provides an insight into the effects of ER-resident molecular chaperones in the amygdala participating in PTSD, and provides the experimental basis and a mechanism for the pathophysiology of PTSD. PMID- 29115546 TI - Influence of the Twist gene on the invasion and metastasis of colon cancer. AB - The present study investigated the role of the Twist gene in epithelial mesenchymal transition (EMT) and its effects on the invasion and metastasis of malignant tumors. In vitro, we transfected SW480, HCT116 and HT29 cells with recombinant plasmids, pTracer-CMV/BSD-Twist and pGenesil1.2-Twist-shRNA, to influence expression of Twist. The transfection efficacy of the plasmids in the cell lines was confirmed by flow cytometry. The relative mRNA and protein expression levels of Twist, E-cadherin and vimentin in the transfected cells were detected by RT-PCR and western blotting, respectively. In addition, migration and invasion were assessed by Transwell assays. In vivo, we established a xenogenic liver metastasis mouse model by intrasplenic injection with transfected SW480, HCT116 or HT29 human colon cancer cells and used hematoxylin and eosin (H&E) staining to demonstrate the effective establishment of the model. The relative mRNA levels of Twist and vimentin were detected by RT-PCR. In vitro, RT-PCR and western blotting showed higher relative mRNA and protein expression levels of Twist and vimentin in cell lines transfected with the recombinant, highly expressed Twist plasmid than in non-transfected cell lines (P<0.05), while E cadherin was inhibited (P<0.05). After transfection with the plasmid pGenesil1.2 Twist-shRNA, the relative mRNA and protein levels of Twist and vimentin were markedly inhibited in the HCT116 cells (P<0.05), and the levels of E-cadherin were not changed (P>0.05), along with inhibition of the migration and invasion abilities of the cell line (P<0.01). In vivo, relative mRNA levels of Twist and vimentin in both the liver and spleen of the mouse model were higher in the groups that were injected with one of the three cell lines transfected with pTracer-CMV/BSD-Twist than in the groups injected with cells transfected with pGenesil1.2-Twist-shRNA (P<0.05). In conclusion, upregulation of Twist gene expression can promote EMT molecular events. Interfering with the Twist gene can effectively silence Twist gene expression in HCT116 cells and consequently inhibit colon cancer cell migration and invasion. PMID- 29115547 TI - Preventive effect of hesperidin modulates inflammatory responses and antioxidant status following acute myocardial infarction through the expression of PPAR-gamma and Bcl-2 in model mice. AB - Hesperetin is the main pharmacological ingredient of fruit of the citrus family, rutaceae. It is a flavanone, which has potent antioxidation and anti-inflammatory activities. The present study investigated the preventive effect of hesperidin in the modulation of acute myocardial infarction (AMI)-induced inflammatory responses and antioxidant status in a mouse model. The levels of creatine kinase MB, tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta, IL-6, monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and caspase-3/9 were measured using ELISA kits. Western blot analysis analyzed p53 and B-cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2, and induced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Hesperidin markedly decreased the myocardial infarction area, heart weight/body weight ratio and activity of creatine kinase-MB in AMI mice. Hesperidin treatment caused a significant decrease in the levels of TNF-alpha, IL-1beta, IL-6, MCP-1, ICAM-1, MDA, CAT, SOD and caspase-3/9 in mice with AMI. Hesperidin also significantly suppressed the protein expression levels of p53 and Bax/Bcl-2, and induced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in mice with AMI. The preventive effect of hesperidin modulated the inflammatory response and antioxidant status following AMI through downregulation of the expression of PPAR-gamma and Bcl-2 in the model mice. PMID- 29115548 TI - Frankincense, pine needle and geranium essential oils suppress tumor progression through the regulation of the AMPK/mTOR pathway in breast cancer. AB - BC (BC), as the most common malignancy in women worldwide, is associated with high morbidity and mortality. However, chemoresistance and toxicity are the main causes that limit the success of treatment in aggressive BC cases. Thus, there is a vital need to identify and develop novel therapeutic agents. Frankincense, pine needle and geranium essential oils have been reported to play critical biological activities in cancer. However, to the best of our knowledge whether frankincense, pine needle and geranium essential oils have any effect on the progression of BC in MCF-7 cells remains unclear. In the present study, we assessed the possible effects of frankincense, pine needle and geranium essential oils on cell viability, proliferation, migration and invasion as well as the possible mechanisms. MCF-7 cells were treated with oils, and associations with BC were investigated. In the present study, we clearly revealed that frankincense, pine needle and geranium essential oils suppressed cell viability, proliferation, migration and invasion in human BC MCF-7 cells. Further data demonstrated that frankincense, pine needle and geranium essential oils induced apoptosis, but did not affect cell cycle progression. Consistent with the in vitro activities, frankincense essential oil was effective in inhibiting tumor growth and inducing tumor cell apoptosis in a human BC mouse model. In addition, these 3 essential oils modulated the activity of the AMPK/mTOR signaling pathway. In conclusion, the present study indicated that frankincense, pine needle and geranium essential oils were involved in the progression of BC cells possibly through the AMPK/mTOR pathway. PMID- 29115549 TI - Downregulation of microRNA-95-3p suppresses cell growth of osteosarcoma via CDKN1A/p21 expression. AB - The purpose of the present study was to examine the function of microRNA-95-3p on cell growth of osteosarcoma and to investigate its mechanism. Compared to healthy controls, the serum expression of microRNA-95-3p was effectively upregulated in patients with osteosarcoma. MicroRNA-95-3p expression in patients with osteosarcoma had significant association with clinical stage. Downregulation of microRNA-95-3p expression suppressed cell growth, induced apoptosis, increased caspase-3 and caspase-9 activities and Bax/Bcl-2 protein expression in osteosarcoma cells. The anticancer effects of microRNA-95-3p on cell growth of osteosarcoma cell suppressed TGF-beta and p-Smad2 protein expression, induced p21 protein expression and suppressed cyclin D1 protein expression in osteosarcoma cells. Whereas, overexpression of microRNA-95-3p increased cell growth, and inhibited apoptosis of osteosarcoma cells through TGF-beta/CDKN1A/p21/cyclin D1 expression. After promotion of TGF-beta, the anticancer effects of microRNA-95-3p were effectively reversed in osteosarcoma cells. Taken together, our results demonstrate that downregulation of microRNA-95-3p suppresses cell growth of osteosarcoma via CDKN1A/p21 expression. PMID- 29115550 TI - TGF-beta signaling: A complex role in tumorigenesis (Review). AB - Tumor progression can be affected by various cellular components of tumor cells and/or by tumor microenvironmental factors. The tumor microenvironment comprises a variety of nonmalignant stromal cells and inflammatory cytokines, which are pivotal in tumor promotion and progression. The transforming growth factor-beta (TGF-beta) ligands (TGF-beta1, 2 and 3) are secreted inflammatory cytokines, which are known to be involved in various aspects of tumor development through two transmembrane serine-threonine kinase receptors, TGFbetaR1 and TGFbetaR2. TGF beta promotes or inhibits tumorigenesis depending on the concurrent gene mutations and tissue microenvironment present through the small mothers against decapentaplegic (Smad) and non-Smad pathways. This review aims to provide a comprehensive overview of the role of the TGF-beta pathway in tumor initiation and progression. PMID- 29115551 TI - P2Y2 receptor promotes the migration and invasion of breast cancer cells via EMT related genes Snail and E-cadherin. AB - Adenosine 5'-triphosphate (ATP) is one of the most abundant biochemical constituents within the tumor microenvironment and is postulated to play critical roles in the progression of a number of types of tumors via interaction with the P2Y2 receptor. In the present study, we demonstrated that the P2Y2 receptor was highly expressed in MCF7 and Hs578T breast cancer cells. Downregulation of the P2Y2 receptor by small interfering RNA (siRNA) significantly attenuated ATP- or UTP-driven migration and invasion of the breast cancer cells as well as expression of EMT-related genes Snail and E-cadherin. Consistent with the observations in vitro, the P2Y2 receptor was found to be abundantly expressed at the invasive edge of the tumor, in infiltrating tumor cells in breast adipose tissues and/or the cancer embolus in the lymphatic sinuses compared with the tumor core areas. Furthermore, high Snail expression and weak or negative expression of E-cadherin were observed at the invasive edge of tumors. Taken together, these data indicate that the P2Y2 receptor promoted cell migration and invasion in breast cancer cells via EMT-related genes Snail and E-cadherin. PMID- 29115552 TI - Effects of daphnetin combined with Bcl2-siRNA on antiapoptotic genes in synovial fibroblasts of rats with collagen-induced arthritis. AB - The aim of the present study was to investigate the effects of daphnetin combined with B cell lymphoma 2 (Bcl2)-targeted small interfering (si)RNA (si-Bcl2) on antiapoptotic genes in fibroblast-like synoviocytes (FLS) in rats with collagen II-induced arthritis (CIA). The roles of si-Bcl2 and daphnetin were determined by measuring the expression levels of Bcl2. Protein and mRNA expression levels of Bcl2 in FLS were determined by flow cytometry and reverse transcription quantitative polymerase chain reaction. Apoptosis of FLS was also determined by flow cytometry. It was revealed that treatment with si-Bcl2 or daphnetin alone resulted in downregulation of Bcl2 mRNA and protein expression. In addition, the mRNA expression levels of the signal transducer and activator of transcription 3 (STAT3), which transcriptionally regulates the activity of mitochondria, were reduced. The combination of si-Bcl2 and daphnetin exhibited an enhanced effect on rheumatoid arthritis FLS (RAFLS), in which the apoptotic rate was significantly higher than either treatment alone. The results suggested that si-Bcl combined with daphnetin may have an enhanced effect in promoting apoptosis of RAFLS derived from CIA rats, and a possible underlying molecular mechanism may function through the downregulation of Bcl2 expression and STAT3, which is located upstream of Bcl2 in the mitochondrial apoptotic pathway. The results of the present study are expected to provide theoretical and experimental basis for the treatment of RA and the medicinal development of daphnetin combined siRNA. PMID- 29115553 TI - Endothelial-to-mesenchymal transition in human idiopathic dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and cardiac fibrosis. Emerging evidence indicated that endothelial-to-mesenchymal transition (Endo-MT) is a crucial event during organ fibrosis. This study was performed to clarify whether Endo-MT contributed to the progression of cardiac fibrosis in DCM. Cardiac samples from patients with DCM and control were obtained. The presence of endothelial markers, cluster of differentiation (CD)31 and vascular endothelial (VE)-cadherin, and mesenchymal markers, alpha smooth muscle actin (SMA) and fibroblast-specific protein 1 (FSP1) was performed using immunohistochemistry. Co-localization of endothelial markers and mesenchymal markers were identified using confocal immunofluorescence staining. Serum procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III amino-terminal propeptide (PIIINP) were measured by ELISA. Protein levels of Wnt, beta-catenin and Snail were determined using western blot analysis. Immunohistochemistry and double-immunofluorescence staining demonstrated that the expression of CD31 and VE-cadherin were significantly decreased in DCM samples, whereas the FSP-1, and alphaSMA were significantly increased. CD31 and VE cadherin labeling indexes were respectively negatively correlated with left ventricular end-diastolic diameter (LVEDD) (CD31 r=-0.82, P<0.01; VE-cadherin r= 0.73, P<0.01), while FSP-1 and alphaSMA were positively associated with LVEDD (alphaSMA r=0.65, P<0.01, FSP1 r=0.53, P<0.01) and left ventricular ejection fraction (alphaSMA r=-0.18, P<0.05; FSP1 r=-0.21, P<0.05). Furthermore, PICP and PIIINP levels were positively associated with the co-expression labeling indexes (CD31/SMA co-labeling index and PICP r=0.727, P<0.01; CD31/SMA co-labeling index and PIIINP r=0.741, P<0.01; VE-Cadherin/FSP-1 co-labeling index and PICP r=0.716, P<0.01; VE-cadherin/FSP-1 co-labeling index and PIIINP r=0.648, P<0.05). Western blot analysis indicated that proteins levels of Wnt signaling and snail were significantly increased in DCM samples. These results suggested that Endo-MT is potentially implicated in the pathogenesis of myocardial fibrosis and remodeling during the development of DCM, indicating a potential therapeutic target for DCM treatment. PMID- 29115554 TI - Paeoniflorin influences breast cancer cell proliferation and invasion via inhibition of the Notch-1 signaling pathway. AB - Breast cancer is one of the most frequently occurring malignant tumors affecting women's health. At least one million new cases are diagnosed each year. Therefore, research that aims to identify strategies that inhibit the growth of breast cancer cells has become a primary worldwide focus. Traditional Chinese medicine (TCM) is regarded as a valuable resource in China, and numerous monomer compositions extracted from TCMs have been demonstrated to exhibit antitumor effects. The present study aimed to determine the impact of paeoniflorin (PF) on breast cancer cell proliferation and invasion, and to explore the mechanisms underlying its effects. Different concentrations of PF were applied to MCF-7 cells at various time points and the Cell Counting kit-8 assay was used to determine cell proliferation, a transwell invasion assay was employed to determine cell invasion, reverse transcription-polymerase chain reaction was used to determine notch homolog-1 (NOTCH-1) and Hes family basic helix-loop helix transcription factor (HES)-1 mRNA expression levels, and western blotting was used to determine NOTCH-1 and HES-1 protein expression levels. The results demonstrated that PF inhibited the proliferation of MCF-7 cells in a dose- and time-dependent manner. Following treatment with different concentrations of PF, the total number of cells present in the PF-treated groups was significantly lower when compared with the untreated control group (P<0.05). With increasing doses of PF, the rate of cell invasion significantly decreased, indicating a dose dependent association. NOTCH-1 and HES-1 mRNA expression levels were reduced when compared with the untreated control group, which reached a statistical significance following treatment with 15 and 30 uM PF (P<0.05). NOTCH-1 and HES-1 protein levels demonstrated a similar trend to the mRNA levels, whereby an increase in the concentration of PF was associated with a decrease in NOTCH-1 and HES-1 protein expression levels. The results of the present study therefore suggest that PF may inhibit the proliferation and invasiveness of breast cancer cells via inhibition of the NOTCH-1 signaling pathway. PMID- 29115556 TI - Role of c-Met in the progression of human oral squamous cell carcinoma and its potential as a therapeutic target. AB - Mesenchymal-epithelial transition factor (c-Met) is the only high affinity receptor for hepatocyte growth factor (HGF), and is frequently activated in many human cancers. However, little is known about the role of the HGF/c-Met signaling pathway in the progression of human oral squamous cell carcinoma (OSCC). This study evaluated the role of the HGF/c-Met signaling pathway in the progression of human OSCC. We found that the expression of c-Met was significantly increased in human OSCC tissues than in normal mucosa adjacent to the tumor (P<0.05), but was not correlated with clinicopathological parameters. Additionally, the selective c Met inhibitor JNJ was found to inhibit cell viability and migration and promote apoptosis in OSCC cell lines, and also blocked the activation AKT, ERK1/2, and NF kappaB p65; thus, suggesting that HGF/c-Met signaling may play an important role in the tumorigenic properties of OSCC cells via the AKT, ERK1/2, and NF-kappaB pathways. Collectively, these results indicated that HGF/c-Met signaling may serve essential roles in the progression of human OSCC, and may thus be a basis for the development of novel therapeutic approaches in the treatment of OSCC. PMID- 29115555 TI - MicroRNA-615-5p targets insulin-like growth factor 2 and exerts tumor-suppressing functions in human esophageal squamous cell carcinoma. AB - To investigate the expression pattern, clinical significance and functional roles of microRNA (miR)-615-5p in human esophageal squamous cell carcinoma (ESCC), , quantitative real-time PCR was performed to detect expression levels of miR-615 5p in ESCC tissues and cell lines. Associations between miR-615-5p expression and various clinicopathological features of ESCC patients were also statistically evaluated. The candidate targets of miR-615-5p were identified by integrating bioinformatics miRNA target prediction, western blot analysis and luciferase reporter assay. Moreover, the functions of miR-615-5p in ESCC cell migration and invasion were determined using the transfection of miRNA mimics, or co transfected with miRNA mimics and the expression vector of its target gene. As a result, miR-615-5p expression in ESCC tissues and cells were markedly lower than those in non-cancerous esophageal mucosa and human normal esophageal cells, respectively (both P<0.001). miR-615-5p downregulation was significantly associated with advanced tumor-node-metastasis stage, positive lymph node metastasis and moderate-poor differentiation. Functionally, the re-expression of miR-615-5p suppressed the invasion and migration of ESCC cells in vitro. Interestingly, insulin-like growth factor 2 (IGF2) was identified as a direct target gene of miR-615-5p, and the inhibitory effects of miR-615-5p in ESCC cell motility were reversed by the restoration of IGF2 expression. In conclusion, miR 615-5p downregulation may be an underlying molecular mechanism of development and progression of ESCC, and may function as a potential therapeutic target of this malignancy. Also, we illustrate that the miR-615-5p/IGF2 axis may bring important contributions to cell motility of human ESCC. PMID- 29115557 TI - Hypoxia induces differential expression patterns of osteopontin and CD44 in colorectal carcinoma. AB - The plasma protein osteopontin (OPN) is considered to be a tumor biomarker, where elevated plasma levels are associated with poor prognosis. Additionally, OPN is expressed in the presence of tumor hypoxia, which is an adverse prognostic factor in radiation oncology. One of its receptors, the proposed tumor stem cell marker CD44, is also associated with aggressive tumors, shown for example in colon cancer. The expression of CD44 and its splice variants (particularly CD44v6) can be upregulated by OPN itself. In the present study, we aimed to investigate the influence of hypoxia on the expression of OPN and its binding partners CD44 and CD44v6 in colon carcinoma cell lines in vitro, using SW480, SW620, HT29 and HCT116 cells. Additionally, we investigated the effect of irradiation on the expression pattern of OPN and its ligands, and the influence of hypoxia on the clonogenic survival of the cells after irradiation. While the expression patterns were nearly unaltered by irradiation, hypoxia led to an upregulation of OPN protein expression and an increase in the radioresistance in all tested colorectal carcinoma cell lines. However, a similar clear statement with regard to the expression of CD44 and CD44v6 is not possible. We hypothesize that the OPN receptors differ in their expression pattern between cell lines depending on the degree of their malignancy. PMID- 29115558 TI - Bryostatin 1 causes attenuation of TPA-mediated tumor promotion in mouse skin. AB - The present study was designed to investigate the tumor inhibitory potential of bryostatin 1 in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse model of skin cancer. The radical inhibition potential of various doses of bryostatin 1 was investigated against 2,2-diphenyl-1-picrylhydrazyl (DPPH) bleach in vitro. The DPPH radical potential was observed compared with treatment with 5, 10, 15, 20, 25 and 30 uM doses of bryostatin 1. In vivo, bryostatin 1 prevented the TPA mediated increase in the level of H2O2 and myeloperoxidase in mouse epidermal tissue. Pretreatment of the mice with bryostatin 1 (30 uM) followed by administration of TPA reduced the edema, as demonstrated via punched-out mouse ear tissue, to 7.2 mg, compared with 14 mg in the TPA-treated group. Treatment with bryostatin 1 prior to TPA administration markedly prevented the inflammation of the skin by inhibiting hyperplasia in the epidermal layer and the aggregation of inflammatory cells. The results demonstrated that treatment of mice with bryostatin 1 at a 30 uM dose prior to TPA administration significantly (P<0.005) inhibited the TPA-mediated increase in the level of COX-2. The activity of ornithine decarboxylase, increased by TPA, was additionally inhibited following pretreatment of the mice with bryostatin 1. In the mice treated with bryostatin 1 at 30 uM doses prior to the administration of TPA, the appearance of papillomas was 20%, compared with 100% in the TPA group. Mice pretreated with bryostatin 1 at 30 uM doses prior to TPA administration exhibited the appearance of 0.4 mean papillomas in each animal, compared with 5.2 in the TPA group. Therefore, the results of the present study demonstrated that bryostatin 1 inhibited the development and progression of tumors of skin in the mice, through the prevention of inflammation-inducing processes and the quenching of radicals. Therefore, bryostatin 1 maybe considered to be adrug of importance in the treatment of skin tumor. PMID- 29115559 TI - Attenuated SUMOylation of sirtuin 1 in premature neonates with bronchopulmonary dysplasia. AB - A prospective study was performed to investigate the effects of hyperoxia on the expression of small ubiquitin-related modifier (SUMO) and sirtuin 1 (SIRT1) proteins, and to examine interactions between these proteins in premature neonates with bronchopulmonary dysplasia (BPD). Peripheral blood mononuclear cells (PBMCs) were isolated from residual venous blood samples of 20 premature infants with BPD and 20 gender-matched premature infants without BPD (non-BPD group). Expression levels of SUMO and SIRT1 proteins in PBMCs were assessed by western blot analysis, and their interactions in PBMCs were detected using the immunoprecipitation assay. Based on the fraction of inspired oxygen (FiO2) administered, neonates were divided into normoxia, low-(21%=40%) groups. Expression levels of SUMO1 and SUMO2/3 proteins in the normoxia group were significantly lower than those in the medium- or high-oxygen groups (P<0.01), but were comparable to those in the low-oxygen group. SIRT1 expression levels in both the medium- and high-oxygen groups were significantly lower than those in the normoxia group (P<0.01). In the BPD group, the expression of SIRT1 protein was significantly lower (P<0.01), and its interaction with SUMO1 and SUMO2/3 was significantly attenuated compared with that in the non-BPD group (P<0.01). Supplemental oxygen with FiO2>=30% was associated with upregulation of SUMO1 and SUMO2/3 expression and downregulation of SIRT1 expression. The present findings suggest that decreased SIRT1 expression and its SUMOylation by SUMO1 and SUMO2/3 may be associated with the development of BPD. PMID- 29115560 TI - Identification of key genes, transcription factors and microRNAs involved in intracranial aneurysm. AB - Intracranial aneurysm (IA) is a devastating disease, the pathogenesis of which remains to be elucidated. The present study aimed to determine the molecular mechanism of IA and to identify potential therapeutic targets using bioinformatics analysis. The GSE54083 dataset, which includes data from patients with ruptured IA and superficial temporal artery controls, was downloaded from the Gene Expression Omnibus, and differentially expressed genes (DEGs) were identified in the ruptured IA samples using the limma package in R. Subsequently, the Database for Annotation, Visualization and Integrated Discovery software was used to perform function and pathway enrichment analyses and the Search Tool for the Retrieval of Interacting Genes database was used to construct the protein protein interaction (PPI) network. Then, microRNA (miRNA) target and transcription factor (TF) target pairs were identified using the miR2Disease, MiRwalk2, ITFP and TRANSFAC databases. Finally, an integrated network of TF target-miRNAs was constructed using Cytoscape. A total of 402 upregulated DEGs and 375 downregulated DEGs were identified from the ruptured IA samples compared with the superficial temporal artery samples. The majority of the upregulated DEGs were significantly enriched in the immune system development category, including CD40 ligand (CD40LG) and CD40 and the downregulated DEGs, such as striatin (STRN), were enriched in neuron projection development. In addition, nitric oxide synthase 1 (NOS1), a target of miRNA-125b, and myosin heavy chain 11 (MYH11), a target of minichromosome maintenance complex component 4 (MCM4), had higher degree scores in the integrated network. These findings suggest that CD40, CD40LG, NOS1, STRN, MCM4, MYH11 and miR-125b may be potential therapeutic targets for the treatment of IA. PMID- 29115561 TI - Inhibition of histone deacetylase 1 ameliorates renal tubulointerstitial fibrosis via modulation of inflammation and extracellular matrix gene transcription in mice. AB - Renal tubulointerstitial fibrosis is characterized by sustained inflammation and excessive extracellular matrix (ECM) accumulation, leading to chronic kidney disease. Valproic acid (VPA) has anticancer activity through regulation of cell differentiation and apoptosis via inhibition of histone deacetylase (HDAC) activity and is considered a class I HDAC inhibitor. In this study, the effect of VPA on unilateral ureteral obstruction (UUO)-induced renal fibrosis by modulation of renal inflammation and ECM gene transcription was investigated. VPA treatment increased histone H3 acetylation in both sham- and UUO-operated kidneys and decreased the UUO-induced increase in tubular injury and ECM deposition in mice. VPA also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells. Finally, it was demonstrated that the anti-fibrotic effect of VPA was associated with regulation of ECM protein promoter enrichment at an acetylated histone H3 site. In conclusion, the findings indicate that VPA may have a beneficial effect on UUO-induced renal fibrosis via regulation of myofibroblast activation, proliferation, and ECM protein production by chromatin remodeling and ECM protein promoter transcription. PMID- 29115562 TI - Fungal mannosylation enhances human papillomavirus 16 E7 therapeutic immunity against TC-1 tumors. AB - Cervical cancer, resulting from infection with human papillomavirus (HPV)16, remains the fourth most common cancer in women worldwide. Recently, three prophylactic HPV vaccines targeting high-risk HPVs (particularly HPV16 and HPV18) have been implemented to protect younger women. However, individuals with pre existing infections have no benefit from prophylactic vaccines. Thus, there is an urgent need to develop therapeutic vaccines. HPV16 E7 has been widely utilized as a target for immune therapy of HPV16-associated lesions or cancers, reflecting the sustained existence of this virus in cancerous cells. We developed mannosylated HPV16 E7 (mE7) expressed from Pichia pastoris as a therapeutic vaccine against HPV16-associated cancer. Unmannosylated E7 (E7) was also generated from Pichia pastoris as a control. Mannosylation enhanced the uptake of mE7 by mannose receptors of bone marrow-derived dendritic cells (BMDCs), while the uptake of E7 was unaffected. mE7-uptake BMDCs in vitro induced more IFN-gamma secretion by splenocytes of immunized mice than E7. Vaccination of C57BL/6 mice with mE7 combined with adjuvant monophosphoryl lipid A (MPL) elicited stronger Th1 (type 1 T helper cell) responses and E7-specific T cell responses than E7. The mE7 vaccine induced the increased production of IFN-gamma, IL-2 and TNF alpha, elicited more E7-specific IFN-gamma-secreting CD8+ T cells in spleen and peripheral blood mononuclear cells (PMBCs) and promoted stronger E7-specific cytotoxic CD8+ T cell responses compared with E7. Furthermore, TC-1 tumor challenged mice were used to confirm the antitumor activity of the vaccines. As a result, mE7 generated complete antitumor activity against TC-1 tumors, while E7 only provided partial antitumor activity. Taken together, mE7 can be a promising immunotherapy for treating cervical cancer. PMID- 29115563 TI - ORMDL3 may participate in the pathogenesis of bronchial epithelial-mesenchymal transition in asthmatic mice with airway remodeling. AB - Asthma is a common chronic respiratory disease in children that is caused by a complex interaction between genetic and environmental factors. Orosomucoid-like 3 (ORMDL3) is a candidate gene that has been strongly associated with asthma; however, the underlying mechanisms are unknown. ORMDL3 regulates the expression of metalloproteinases and transforming growth factor-beta, and ORMDL3 transgenic mice exhibit increased airway remodeling. Therefore, ORMDL3 may be associated with airway remodeling. The present study attempted to examine the associations between ORMDL3 and the severity of airway remodeling in asthmatic mice, and also to determine whether ORMDL3 induces epithelial-mesenchymal transition (EMT) in the bronchial epithelium. For this purpose, BALB/c mice were randomly assigned to control and asthma groups. Lung tissues were collected on days 3, 7 and 14 of the ovalbumin (OVA) challenge. Airway remodeling in asthmatic mice was then observed by hematoxylin and eosin, and Masson staining. Morphological changes in the bronchial epithelium were assessed by transmission electron microscopy. The EMT associated indicators E-cadherin (E-cad), fibroblast-specific protein 1 (FSP1) and Vimentin (VIM) were assessed by western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) at different time points of airway remodeling in asthmatic mice to detect the trend in EMT. Then, the localization of ORMDL3 was observed by immunohistochemistry, and its protein and mRNA expression was examined by western blotting and RT-qPCR, respectively. Furthermore, the bronchial epithelial cell line 16HBE14o-was transfected with an ORMDL3-expressing plasmid, and the differences in E-cad, FSP-1 and VIM expression were detected by immunofluorescence, western blotting and RT-qPCR; the cell invasive ability was assessed by microscopy. The results revealed that ORMDL3 expression in the bronchial epithelium was associated with airway remodeling and EMT progression in vivo. Transfection of ORMDL3 into 16HBE 14o-cells in vitro induced EMT. Taken together, these findings suggest that ORMDL3 may regulate EMT in the bronchial epithelium, thereby affecting airway remodeling in asthma. PMID- 29115564 TI - miR-486 functions as a tumor suppressor in esophageal cancer by targeting CDK4/BCAS2. AB - Esophageal cancer is a common tumor for which morbidity and mortality are high worldwide. We aimed to study alterations in miR-486 expression in esophageal cancers, and the effect miR-486 on esophageal cancer cell function and behavior. We collected esophageal cancer tissues/corresponding normal tissues from 20 patients and utilized three esophageal cancer cell lines and normal esophageal epithelial cells, and the expression of miR-486, CDK4 and BCAS2 was detected by qRT-PCR. Western blotting was used to detect the expression of CDK4 and BCAS2 protein. Then, we overexpressed miR-486 in esophageal cancer cell line EC9706. A series of cell functional analyses, including cell growth, cell cycle, apoptosis, migration and invasion were performed in esophageal cancer cells using colony formation assay, flow cytometry, Transwell and scratch assays, respectively. Dual luciferase reporter gene assay was used to detect the target genes of miR-486. We found that the expression of miR-486 in esophageal cancer tissues and cell lines was significantly lower than that in the normal tissues and normal esophageal epithelial cell line. Overexpression of miR-486 significantly inhibited the colony formation ability, induced G0/G1 phase arrest and apoptosis and suppressed cell migration and invasion in the EC9706 cells. Using bioinformatics and luciferase reporter assay, we identified that CDK4 and BCAS2 may be target genes of miR-486 and levels of CDK4 and BCAS2 were both significantly higher in the esophageal cancer tissues and cell lines than levels in the normal tissues and cells. Furthermore, knockdown of CDK4/BCAS2 coincided with the suppressive effects of miR-486 in esophageal cancer cells. Expression of apoptotic signaling molecules p21 and caspase-3 was upregulated in the CDK4/BCAS2-knockdown groups. These results suggest that miR-486 may suppress tumor cell growth and metastasis in esophageal cancer by targeting CDK4/BCAS2. The newly identified miR 486/CDK4/BCAS2 pathway provides further insight into the development and progression of esophageal cancer, which is of great significance to the early diagnosis and detection of esophageal cancer. PMID- 29115565 TI - AJAP1 expression modulates glioma cell motility and correlates with tumor growth and survival. AB - Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors. Unraveling the molecular and genetic complexity that determines GBM's pronounced migratory property could provide new options for therapeutic targeting that may significantly complement current surgical and chemoradiation therapy and alter the current poor outcome. In this study, we establish stable AJAP1 overexpressing glioma cells in order to examine in vivo tumor growth. We examine AJAP1 localization by confocal microscopy and AJAP1's functional effect on migration and invasion across surfaces coated with laminin. Finally, analysis of AJAP1 expression in murine xenografts and GBM primary tumors revealed its association with tumor growth and survival. Stable overexpression of AJAP1 promotes adherence, decreases invasion of glioma cells through an extracellular like matrix, and slows migration in the presence of laminin. These observations are reversed by gene knockdown using multiple siRNAs. Additionally, overexpression of AJAP1 decreases colony formation in glioma cells, and leads to smaller tumor growth with increased survival in glioma xenograft mice. Loss of AJAP1 protein expression predicts worse survival in GBM patients. AJAP1 overexpression decreases cell motility in the presence of laminin and decreases tumor growth in xenografts. Its loss of expression predicts worse survival in patients. This study extends our prior observations and implicates AJAP1 as a potential prognostic marker and a viable target for therapeutic intervention in GBM. PMID- 29115566 TI - Downregulation of microRNA-155 by preoperative administration of valproic acid prevents postoperative seizures by upregulating SCN1A. AB - The risk of seizure is increased following brain surgery such as cranioplasty. Patients with seizures that are treated with valproic acid (VPA) may have a decreased risk of further seizures. To verify microRNA (miR)-155 as a potential biomarker for the occurrence of seizures, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used. Computational analysis and luciferase reporter assay was performed to identify the putative target of miR 155. RT-qPCR and western blot analyses were used to determine the expression level of miR-155, sodium voltage-gated channel alpha subunit 1 (SCN1A) mRNA and protein. RT-qPCR analysis indicated that miR-155 levels in patients who experienced seizures increased 2.45-fold compared with patient who did not experience seizures, indicating miR-155 may be a potential biomarker for the occurrence of seizures. SCN1A was identified as a target gene of miR-155; the luciferase reporter assay revealed a negative regulatory relationship between miR 155 and SCN1A. The expression of SCN1A mRNA of patients receiving VPA was higher compared with the control group patients. Furthermore, the expression levels of SCN1A mRNA and protein were reduced or elevated following transfection with miR 155 mimics or inhibitors, respectively, compared with the scramble control. Furthermore, a concentration-dependent effect of miR-155 on the expression of SCN1A was observed. In conclusion, miR-155 may be associated with the risk of seizure and SCN1A may be a target gene of miR-155. Downregulation of microRNA-155 by preoperative administration of VPA may prevent postoperative seizure by upregulating the expression of SCN1A. PMID- 29115567 TI - Preparation and characterization of acellular adipose tissue matrix using a combination of physical and chemical treatments. AB - Decellularized adipose extracellular matrix (ECM) has been used in the clinic to support the regeneration of adipose tissues. The methods used to produce adipose tissue ECM scaffolds exhibit distinct effects upon the structural and functional components of the resultant scaffold material. The current study presents an acellular ECM scaffold from human adipose tissues derived using successive physical and chemical treatments, including repeated freeze-thaw cycles followed by centrifugation, polar solvent extraction and enzymatic digestion. Cellular components, including nucleic acids were effectively removed without significant disruption of the morphology or structure of the ECM. The compositions of major ECM components were evaluated, including acid/pepsin soluble collagen, sulfated glycosaminoglycan and laminin. The decellularized ECM exhibited satisfactory mechanical properties. Cell seeding experiments involving human adipose-derived stem cells indicated that the decellularized ECM provided an inductive microenvironment for adipogenesis without the need for exogenous differentiation factors. Higher levels of glycerol-3-phosphate dehydrogenase activity were observed among induced cells in the ECM scaffolds when compared with induced cells in collagen type I scaffolds. In conclusion, the results suggested that the decellularized ECM, containing biological and chemical cues of native human ECM, may be an ideal scaffold material for autologous and allograft tissue engineering. PMID- 29115569 TI - Glioma stem cells and their non-stem differentiated glioma cells exhibit differences in mitochondrial structure and function. AB - Although mitochondria play an important role in cell survival, their biological significance in differentiated and undifferentiated cells is not well known. In the present study, we compared the differences in the structure and function of mitochondria between undifferentiated cancer stem cells and differentiated cancer cells. Glioma stem cells (GSCs), when grown under serum culture conditions, demonstrated a decrease in stem cell marker expression and tumor sphere forming ability, while showing an increase in differentiated cell markers. Transmission electron microscopy analysis revealed that the number of mitochondria with distinct cristae and electron-dense matrices increased significantly in the non stem differentiated glioma cells when compared to their undifferentiated GSCs. Bioinformatic analysis revealed that the glucose metabolic process gene signature was enriched in gene pools that had an increased number of stem cells. Additionally, qRT-PCR analysis revealed that the expression of various glucose metabolism genes was higher in GSCs than in non-stem differentiated glioma cells. Altogether, our results suggest that GSCs have immature mitochondria when compared to differentiated glioma cells. Notably, GSCs prefer a relatively higher glucose metabolism, which implies that they utilize different mitochondrial biosynthesis and metabolic pathways when compared to differentiated glioma cells. PMID- 29115568 TI - Radical scavenging-linked anti-adipogenic activity of Alnus firma extracts. AB - The purpose of the present study was to investigate the antioxidant activity and anti-adipogenic effect of extracts from Alnus firma (A. firma), which is an edible plant that grows in mountainous areas. The total phenolic, flavonoid and anthocyanin content as well as the antioxidant activity of a 70% ethanolic extract of A. firma (AFE) was assessed. Furthermore, the effects of AFE on lipid accumulation and reactive oxygen species (ROS) production during adipogenesis of 3T3-L1 cells were investigated. The results revealed that the total phenolic, flavonoid and pro-anthocyanidin content of AFE as 436.26+/-3.30 mg gallic acid equivalents/g, 73.82+/-0.54 mg quercetin equivalents/g and 149.25+/-6.06 mg catechin equivalents/g, respectively. In addition, AFE exerted significant antioxidant effects in terms of 1,1-diphenyl-2-picryl hydrazyl radical scavenging activity, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activity, reducing power, oxygen radical absorbance capacity and nitric oxide radical scavenging activity. As for its anti-adipogenic activity, AFE significantly inhibited ROS production and lipid accumulation during adipogenesis of 3T3-L1 cells compared with those in control cells. In addition, AFE regulated adipogenic transcription factors including peroxisome proliferator activated receptor-gamma, CCAAT/enhance-binding protein alpha and adipocyte protein 2. These results indicated that A. firma is a potential candidate for a functional food supplement. PMID- 29115570 TI - Luteolin inhibits multi-heavy metal mixture-induced HL7702 cell apoptosis through downregulation of ROS-activated mitochondrial pathway. AB - With the rapid economic development in recent years, China is facing a great challenge due to heavy metal pollution. The heavy metals may enter the human body through ingestion of aqua products to cause great health risks. In the present study, the inhibitory effects of luteolin on the combined toxicity of multi-heavy metals (including zinc, manganese, lead, copper, cadmium, mercury, chromium and nickel) were investigated in HL7702 hepatocyte cells. An MTT assay demonstrated that 20 uM luteolin significantly alleviated the multi-heavy metal mixture induced cell death and morphological changes. Furthermore, 20 uM luteolin significantly inhibited multi-heavy metal mixture-induced reactive oxygen species (ROS) generation, lipid peroxidation (malondialdehyde content) and caused a decrease in adenosine triphosphate levels in HL7702 cells. A JC-1 staining assay indicated that 20 uM luteolin inhibited the mitochondrial membrane potential reducing effect of the multi-heavy metal mixture. Apoptotic assays revealed that the multi-heavy metal mixture induced HL7702 cell apoptosis in a dose-dependent manner, which was significantly inhibited by 20 uM luteolin. Western blot analysis indicated that addition of luteolin to the multi-heavy metal mixture significantly alleviated cytochrome c release from the mitochondria into the cytosol. In addition, 20 uM luteolin had a significant inhibitory effect on multi heavy metal mixture-induced cleavage of caspase-9, caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein. Immunofluorescence staining demonstrated that addition of luteolin significantly alleviated caspase-3 cleavage induced by the multi-heavy metal mixture. The present results suggested luteolin exerts its inhibitory effects of on multi-heavy metal mixture induced cell apoptosis through downregulation of the ROS-activated mitochondrial pathway. PMID- 29115571 TI - Anti-inflammatory effects of a methanolic extract of Castanea seguinii Dode in LPS-induced RAW264.7 macrophage cells. AB - Castanea extracts are known to have antioxidant properties and are used as a traditional medicine in China and Asia. However, the biological activity of Castanea seguinii Dode has remained to be fully elucidated. The present study investigated the anti-inflammatory effects of a Castanea seguinii Dode methanolic extract (CSME) on lipopolysaccharide-induced RAW264.7 macrophage cells. CSME inhibited the production of nitric oxide (NO) and the expression of inducible NO synthase. It also suppressed the production of the pro-inflammatory cytokines inteleukin-6 and tumor necrosis factor-alpha, as well as chemokine monocyte chemoattractant protein 1. In addition, CSME inhibited nuclear factor-kappaB (NF kappaB) and mitogen-activated protein kinase (MAPK) signaling, while also downregulating transcription factor activator protein-1. Furthermore, CSME increased heme oxygenase 1 through the upregulation of NF (erythroid-derived 2) like-2 (Nrf-2), which directly or indirectly affects inflammation. It also increased the phosphorylation of 5'-adenosine monophosphate-activated protein kinase (AMPK). In conclusion, CSME was demonstrated to exert its anti inflammatory activities through the inhibition of the NF-kappaB and the MAPK signaling pathways, as well as the activation of Nrf-2 and AMPK. These results indicated that CSME may be a promising for development as a commercial anti inflammatory medicine. PMID- 29115572 TI - TALENs-mediated homozygous CCR5Delta32 mutations endow CD4+ U87 cells with resistance against HIV-1 infection. AB - Since evidence suggests that transplantation of bone marrow stem cells with the C C chemokine receptor type 5 (CCR5)Delta32/Delta32 genotype may cure patients infected with human immunodeficiency virus (HIV)-1, the present study aimed to reproduce the CCR5Delta32 mutation in cluster of differentiation (CD)4+ U87 cells using genome engineering methods. A modified transcription activator-like effector nucleases (TALENs) technique, combined with homologous recombination for site-specific, size-controlled and homozygous DNA deletions, was used to reproduce the homozygous CCR5Delta32 mutation in CD4+ U87 cells. The results indicated that the frequency of the TALENs-targeted mutation reached 50.4% without any selection, whereas homologous recombination from CCR5 to CCR5Delta32 occurred in 8.8% of targeted cells. Notably, a HIV-1 challenge test demonstrated that CCR5Delta32/Delta32 CD4+ U87 cells were resistant to HIV infection. In conclusion, engineered CCR5Delta32/Delta32 mutations endowed CD4+ U87 cells with resistance against HIV-1 infection; this site-specific, size-controlled and homozygous DNA deletion technique was able to induce precise genomic editing, i.e., the deletion or insertion of a predetermined length of DNA sequence at a specific locus throughout the genome. PMID- 29115573 TI - Fibroblast activation protein-alpha promotes the growth and migration of lung cancer cells via the PI3K and sonic hedgehog pathways. AB - A characteristic of the epithelial-to-mesenchymal transition in cancer cells is the upregulation of mesenchymal markers. Fibroblast activation protein alpha (FAPalpha) is predominantly expressed by stromal fibroblasts. Previous studies have demonstrated that FAPalpha is also expressed by certain epithelium-derived cancer cells and is involved in the regulation of certain signaling pathways. One of our previous studies showed that FAPalpha promoted the proliferation of breast cancer cells via the phosphatidylinositol-3-kinase (PI3K) signaling pathway. In the present study, the A549 adenocarcinoma (AC) and SK-MES-1 squamous cell carcinoma (SCC) lung cancer cell lines were transfected with FAPalpha. The FAPalpha-expressing SK-MES-1 cells exhibited an increased growth rate, whereas the FAPalpha-expressing A549 cells exhibited a similar growth rate, compared with respective empty vector-transfected control cells. Electric cell-substrate impedance sensing (ECIS)-based attachment and wound-healing assays showed that the overexpression of FAPalpha markedly increased the adhesive and migratory properties of the SK-MES-1 cells but not those of the A549 cells. Additionally, inhibitors of focal adhesion kinase, agonist-induced phospholipase C, neural Wiskott-Aldrich syndrome protein, extracellular signal-regulated kinase, Rho associated protein kinase, PI3K, and sonic hedgehog (SHH) were used to evaluate the interaction between FAPalpha and signaling pathways. Only the inhibitors of SHH and PI3K inhibited the increased motility of the FAPalpha-expressing SK-MES-1 cells. Western blot analysis confirmed the activation of PI3K/AKT and SHH/GLI family zinc finger 1 signaling in the FAPalpha-expressing SK-MES-1 cells. These results revealed that FAPalpha promoted the growth, adhesion and migration of lung SCC cells. In addition, FAPalpha regulated lung cancer cell function, potentially via the PI3K and SHH pathways. Further investigations are required to examine the role of FAPalpha in lung AC cells. PMID- 29115574 TI - Long non-coding RNA SNHG1 regulates NOB1 expression by sponging miR-326 and promotes tumorigenesis in osteosarcoma. AB - The long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) has been demonstrated to participate in the deterioration of many types of cancer. However, the underlying mechanisms of SNHG1-mediating functions in osteosarcoma (OS) have yet to be elucidated. In the present study, our results showed that SNHG1 was upregulated in OS tissues and cell lines, and high SNHG1 expression predicts poor overall survival of OS patients. Knockdown of SNHG1 inhibited cell growth and metastasis of OS in vitro and in vivo. Furthermore, our data demonstrated that there was reciprocal repression between SNHG1 and miR-326 which act as a tumor suppressor in OS cells, and exhibiting a strong negative relationship between SNHG1 and miR-326 expression in OS tissues. Additionally, we identified that SNHG1 increased human nin one binding protein (NOB1), an oncogene, through sponging miR-326 as competing endogenous RNA (ceRNA), finally prompting cell growth, migration and invasion in OS. Collectively, these findings not only uncovered that the SNHG1/miR-326/NOB1 signaling axis has a key role in OS progression but also suggested the potential application of SNHG1 and miR-326 as biomarkers in the OS diagnosis and treatment. PMID- 29115575 TI - MicroRNA-142-3p relieves neuropathic pain by targeting high mobility group box 1. AB - MicroRNA (miRNA) are emerging as critical regulators of neuropathic pain development. Neuroinflammation contributes to the development of neuropathic pain. miR-142-3p has been characterized as an inflammation-related miRNA in various pathological processes. However, little is known about the role of miR 142-3p in neuroinflammation and neuropathic pain. The present study aimed to investigate the function of miR-142-3p in neuropathic pain by creating a murine model using spinal nerve ligation (SNL). A significant reduction in miR-142-3p expression was observed in the dorsal root ganglion of mice with SNL (P<0.05) compared with control mice. Overexpression of miR-142-3p significantly inhibited neuropathic pain and neuroinflammation in mice with SNL (P<0.05). High mobility group box 1 (HMGB1) was identified as a direct target gene of miR-142-3p by bioinformatic analysis and dual-luciferase reporter assays. Overexpression of miR 142-3p significantly reduced the mRNA and protein expression levels of HMGB1 in vitro and in vivo (P<0.05). In addition, HMGB1 mRNA expression and miR-142-3p expression were inversely correlated in mice with SNL. Furthermore, overexpression of HMGB1 significantly reversed the inhibitory effect of miR-142 3p on neuroinflammation and neuropathic pain development (P<0.05). Overall, these results suggest that miR-142-3p functions as a negative regulator of neuropathic pain development through the downregulation of HMGB1, indicating that miR-142-3p may serve as a potential therapeutic target for neuropathic pain. PMID- 29115576 TI - Genome-wide DNA methylome alterations in acute coronary syndrome. AB - Acute coronary syndrome (ACS) is a common disease with high mortality and morbidity rates. The methylation status of blood DNA may serve as a potential early diagnosis and prevention biomarker for numerous diseases. The present study was designed to explore novel genome-wide aberrant DNA methylation patterns associated with ACS. The Infinium HumanMethylation450 assay was used to examine genome-wide DNA methylation profiles in 3 pairs of ACS and control group samples. Epigenome-wide DNA methylation, genomic distribution, Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The results were confirmed using methylation-specific polymerase chain reaction (MSP) and Sequenom MassARRAY analyses in ACS, stable coronary artery disease (SCAD) and control samples. A total of 11,342 differentially methylated (DM) 5'-C-phosphate-G-3' (CpG) sites were identified, including 8,865 hypomethylated and 2,477 hypermethylated CpG sites in the ACS group compared with the control samples. They varied in frequency across genomic compartments, but were particularly notable in gene bodies and shores. The results of GO term and KEGG pathway enrichment analyses revealed that the methylated genes were associated with certain biological processes and pathways. Despite the considerable variability in methylation data, the candidate selected possessed significant methylation alteration in mothers against decapentaplegic homolog 3 (SMAD3) transcription start site 155 (Chr1:67356838-Chr1:67356942). MSP analysis from 81 ACS samples, 74 SCAD samples and 53 healthy samples, and Sequenom MassARRAY analysis, confirmed that differential CpG methylation of SMAD3 was significantly corrected with the reference results of the HumanMethylation450 array. The data identified an ACS-specific DNA methylation profile with a large number of novel DM CpG sites, some of which may serve as candidate markers for the early diagnosis of ACS. PMID- 29115577 TI - Long non-coding RNA DANCR regulates the proliferation and osteogenic differentiation of human bone-derived marrow mesenchymal stem cells via the p38 MAPK pathway. AB - Long non-coding RNAs (lncRNAs) have been established to participate in the complex network of various biological processes and play important roles in the differentiation of mesenchymal stem cells (MSCs). However, the roles of lncRNAs in the mechanisms of the osteogenic differentiation of human bone marrow-derived MSCs (HBMSCs) are poorly understood. Thus, this study aimed to investigate the effects of the lncRNA, differentiation antagonizing non-protein coding RNA (DANCR), on the proliferation and osteogenic differentiation of HBMSCs. We found that lncRNA DANCR was abnormally decreased in HBMSCs during osteogenic differentiation. DANCR knockdown induced by transfection with siRNA targeting DANCR (si-DANCR) significantly enhanced the proliferation and osteogenic differentiation of HBMSCs. By contrast, when DANCR expression was enhanced by transfection with a DANCR overexpression vector (pcDNA-DANCR), the proliferation and osteogenic differentiation of the HBMSCs were markedly inhibited. We further found that mitogen-activated protein kinase (MAPK) pathways were involved in the DANCR-mediated proliferation and osteogenic differentiation of HBMSCs. Moreover, DANCR was found to mediate the proliferation and osteogenic differentiation of HBMSCs via p38 MAPK inactivation, but not via extracellular signal-regulated protein kinase (ERK)1/2 or c-Jun N-terminal kinase (JNK) MAPKs, but. Combination treatment (pcDNA-DANCR and with the p38 specific inhibitor, SB203580) led to synergistic inhibitory effects, and these inhibitory effects were reversed by DANCR knockdown. These findings not only provide a novel interpretation for the mechanisms of the proliferation and osteogenic differentiation of HBMSCs, but also suggest that DANCR may be a novel therapeutic target for bone-destructive diseases in the future. PMID- 29115578 TI - Characterization of prostate cancer cell progression in zebrafish xenograft model. AB - Early diagnosis of prostate cancer (PCa) is critical for the application of efficient treatment to PCa patients. However, the majority of PCas remains indolent from several months to several years before malignancy. Current diagnosis methods have limitations in their reliability and are inefficient in time cost. Thus, an efficient in vivo PCa cell xenograft model is highly desired for diagnostic studies in PCas. In the present study we present a standardized procedure to create a PCa cell xenograft model using zebrafish (Danio rerio) as the host. PC3-CTR cells, a cell line from adenocarcinoma with stable expression of calcitonin receptor (CRT), were subcutaneously injected into zebrafish larvae at 48 h post fertilization. The nursing conditions for the larvae were optimized with stable survival rates of post hatch and post PC3-CTR cell injection. In this system, the progression of PC3-CTR cells in vivo was evaluated by migration and proliferation of the cells. Massive migrations of PC3 cells in vivo were observed at post injection day (PID)3. The injected PC3-CTR cells eventually invaded the whole larval zebrafish at PID5. Quantification of PC3-CTR cell proliferation was done using quantitative PCR (qPCR) analysis targeting the expression profiles of two PCa housekeeping genes, TATA-binding protein (TBP) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) encoding genes. The excessive proliferation of PC3 cells in vivo was detected with both qPCR assays. Expression levels of one non-coding gene, prostate cancer associated 3 gene (pca3), and two other genes encoding transient receptor potential ion channel Melastatin 8 (trpm8) and prostate-specific membrane antigen (psma), showed a significantly enhanced aggressiveness of PC3-CTR cells in vivo. The model established in the present study provides an improved in vivo model for the diagnosis of PCas efficiently. This PCa cell xenograft model can also serve as a tool for high throughput anti PCa drug screening in therapeutic treatments. PMID- 29115580 TI - Overexpression of CCDC34 in colorectal cancer and its involvement in tumor growth, apoptosis and invasion. AB - It has been previously reported that increased expression of coiled-coil domain containing 34 (CCDC34), a member of the CCDCs family, may promote the proliferation and invasion of bladder cancer cells. However, its role in colorectal cancer (CRC) remains unclear. The present study investigated CCDC34 expression in CRC tissues and determined the association between CCDC34 expression and biological characteristics in patients with CRC. Additionally, the variation of cell activity, apoptosis, invasion and associated mechanisms were evaluated following CCDC34 inhibition in SW620 cells with small interfering RNA (siRNA). The role of CCDC34 in CRC growth, apoptosis and invasion was investigated. In the current study, immunohistochemistry revealed an overexpression of CCDC34 in CRC tissues compared with paracancerous tissue (chi2=29.810; P<0.001). Furthermore, CCDC34 expression was revealed to be associated with tumor invasion depth and lymphatic metastasis (chi2=4.343, P=0.037; chi2=7.915, P=0.005). Additionally, the inhibition of CCDC34 expression in SW620 cells led to reduced tumor cell activity, increased apoptosis rate and reduced invasion ability, and expression of apoptosis and invasion-associated genes varied simultaneously which demonstrated that B cell leukemia/lymphoma 2, survivin, N-cadherin, and MMP-9 were decreased, whereas E-cadherin increased significantly in cells of CCDC34-siRNA group compared with the control group (P<0.05). Therefore, CCDC34 may contribute to CRC development by inhibiting apoptosis of cancer cells and promoting invasion. PMID- 29115579 TI - Vitamin E (alpha-tocopherol) ameliorates aristolochic acid-induced renal tubular epithelial cell death by attenuating oxidative stress and caspase-3 activation. AB - Aristolochic acid (AA) is a component identified in traditional Chinese remedies for the treatment of arthritic pain, coughs and gastrointestinal symptoms. However, previous studies have indicated that AA can induce oxidative stress in renal cells leading to nephropathy. alpha-tocopherol exists in numerous types of food, such as nuts, and belongs to the vitamin E isoform family. It possesses antioxidant activities and has been used previously for clinical applications. Therefore, the aim of the present study was to determine whether alpha-tocopherol could reduce AA-induced oxidative stress and renal cell cytotoxicity, determined by cell survival rate, reactive oxygen species detection and apoptotic features. The results indicated that AA markedly induced H2O2 levels and caspase-3 activity in renal tubular epithelial cells. Notably, the presence of alpha-tocopherol inhibited AA-induced H2O2 and caspase-3 activity. The present study demonstrated that antioxidant mechanisms of alpha-tocopherol may be involved in the increased survival rates from AA-induced cell injury. PMID- 29115581 TI - Tramadol attenuates the sensitivity of glioblastoma to temozolomide through the suppression of Cx43-mediated gap junction intercellular communication. AB - Analgesics and antineoplastic drugs are often used concurrently for cancer patients. Our previous study reported that gap junctions composed of connexin32 (Cx32) was implicated in the effect of analgesics on cisplatin cytotoxicity. However, the effect of analgesic on the most widely expressed connexin (Cx), connexin43 (Cx43), and whether such effect mediates the influence on chemotherapeutic efficiency remain unknown. By manipulation of Cx43 expression or gap junction function, we found that there were gap junction-dependent and independent effect of Cx43 on temozolomide (TMZ) sensitivity in U87 glioblastoma cells. Studies on survival and apoptosis showed widely used analgesic tramadol significantly reduced TMZ-induced cytotoxicity in control and negative control cells but not shCx43-transfected cells. Proliferation assay demonstrated tramadol suppressed TMZ-induced cytotoxicity only on high density (with gap junction formation) but not on low density (without gap junction formation). Tramadol inhibited dye-coupling through gap junctions between U87 cells. Tramadol treatment for 72 h did not alter Cx43 expression, but decreased Cx43 phosphorylation accompanied with reduced p-ERK and p-JNK. Our results indicated that long-term treatment with tramadol reduced TMZ cytotoxicity in U87 cells by suppressing Cx43-composed gap junctions, suggesting identification and usage of antinociceptive drugs which do not downregulate connexin activity should have beneficial therapeutic consequences. PMID- 29115582 TI - Passenger strand of miR-145-3p acts as a tumor-suppressor by targeting MYO1B in head and neck squamous cell carcinoma. AB - Analysis of the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) based on RNA sequencing showed that dual strands of pre miR-145 (miR-145-5p, guide strand; and miR-145-3p, passenger strand) were significantly reduced in cancer tissues. In miRNA biogenesis, passenger strands of miRNAs are degraded and have no biological activities in cells. The aims of this study were to investigate the functional significance of the passenger strand of miR-145 and to identify miR-145-3p-regulated oncogenic genes in HNSCC cells. Expression levels of miR-145-5p and miR-145-3p were significantly downregulated in HNSCC tissues and cell lines (SAS and HSC3 cells). Ectopic expression of miR-145-3p inhibited cancer cell proliferation, migration and invasion, similar to miR-145-5p, in HNSCC cells. Myosin 1B (MYO1B) was directly regulated by miR-145-3p, and knockdown of MYO1B by siRNA inhibited cancer cell aggressiveness. Overexpression of MYO1B was confirmed in HNSCC clinical specimens by analysis of protein and mRNA levels. Interestingly, high expression of MYO1B was associated with poor prognosis in patients with HNSCC by analysis of The Cancer Genome Atlas database (p=0.00452). Our data demonstrated that the passenger strand of miR-145 acted as an antitumor miRNA through targeting MYO1B in HNSCC cells. The involvement of dual strands of pre-miR-145 (miR-145-5p and miR-145-3p) in the regulation of HNSCC pathogenesis is a novel concept in present RNA research. PMID- 29115584 TI - Apolipoprotein C-III in the high-density lipoprotein proteome of cerebral lacunar infarction patients impairs its anti-inflammatory function. AB - High-density lipoprotein (HDL) proteomic study has identified substantial changes associated with various disease states. In the current study, the HDL proteomes in patients with cerebral lacunar infarction (LACI) and control subjects were investigated. A total of 12 LACI patients without evident large vessel occlusions and 12 controls were enrolled in the study. The HDL fraction from each sample was isolated from the plasma by ultracentrifugation. The protemics of the HDL were investigated using nano liquid chromatography coupled to tandem mass spectrometry. There were 55 proteins identified as differentially expressed in the LACI and control groups. Among the 55 proteins, 33 were upregulated and 22 were downregulated in the patients with LACI. The identified proteins were associated with numerous molecular functions, including lipid and cholesterol transport, lipid metabolism, inflammatory response, the complement and coagulation pathway, metal ion metabolism, hemostasis and endopeptidase inhibitory activity. Serum amyloid A, apolipoprotein C (apoC-III) and apolipoprotein A-II (apoA-II) were selected to confirm the proteomics results via western blotting. HDL from the LACI patients exhibited an impaired ability to inhibit the binding of THP-1 cells to endothelial cells compared with the controls (P<0.01). ApoC-III-rich HDL also had a significantly reduced ability to inhibit the binding of THP-1 cells to endothelial cells (P<0.01). The expression of vascular cell adhesion molecule-1 protein by the endothelial cells exhibited a similar pattern of response to the different HDL samples. In conclusion, the present study demonstrates major modifications of the HDL proteome in patients with LACI. The ApoC-III enrichment of the HDL of patients with LACI may cause a reduction in the anti-inflammatory ability of HDL, which may contribute to the progression of the disease. PMID- 29115583 TI - Unfavorable effect of calcitriol and its low-calcemic analogs on metastasis of 4T1 mouse mammary gland cancer. AB - Low vitamin D status is considered as a risk factor for breast cancer and has prognostic significance. Furthermore, vitamin D deficiency increases after adjuvant cancer therapy, which alters bone metabolism increasing the risk of osteoporosis. It is now postulated that vitamin D supplementation in breast cancer treatment delays the recurrence of cancer thereby extending survival. We evaluated the impact of calcitriol and its low-calcemic analogs, PRI-2191 and PRI 2205, on the tumor growth, angiogenesis, and metastasis of 4T1 mouse mammary gland cancer. Gene expression analysis related to cancer invasion/metastasis, real-time PCR, ELISA, western blotting, and histochemical studies were performed. In vitro studies were conducted to compare the effects of calcitriol and its analogs on 4T1 and 67NR cell proliferation and expression of selected proteins. Calcitriol and its analogs increased lung metastasis without influencing the growth of primary tumor. The levels of plasma 17beta-estradiol and transforming growth factor beta (TGFbeta) were found to be elevated after treatment. Moreover, the results showed that tumor blood perfusion improved and osteopontin (OPN) levels increased, whereas vascular endothelial growth factor (VEGF) and TGFbeta levels decreased in tumors from treated mice. All the studied treatments resulted in increased collagen content in the tumor tissue in the early step of tumor progression, and calcitriol caused an increase in collagen content in lung tissue. In addition, in vitro proliferation of 4T1 tumor cells was not found to be affected by calcitriol or its analogs in contrast to non-metastatic 67NR cells. Calcitriol and its analogs enhanced the metastatic potential of 4T1 mouse mammary gland cancer by inducing the secretion of OPN probably via host cells. In addition, OPN tumor overexpression prevailed over the decreasing tumor TGFbeta level and blood vessel normalization via tumor VEGF deprivation induced by calcitriol and its analogs. Moreover, the increased plasma TGFbeta and 17beta estradiol levels contributed to the facilitation of metastatic process. PMID- 29115585 TI - IDH1 mutation diminishes aggressive phenotype in glioma stem cells. AB - The R132H mutation in isocitrate dehydrogenase 1 (IDH1-R132H) is associated with better prognosis in glioma patients. Glioma stem cells (GSCs) in glioma are believed to be responsible for glioma growth and maintenance. However, the relation between the R132H mutation and GSCs is not fully understood. In the present study, GSC markers were detected in patients with IDH1-R132H or wild-type IDH1 (IDH1-wt) by tissue microarray immunohistochemistry (TMA-IHC). The relationship between the expression patterns of GSC markers and the clinicopathological characteristics in glioma were analyzed. To confirm this mutation's role in GSCs, the IDH1-R132H in GSCs isolated from glioblastoma patients with IDH1 mutations was overexpressed by using lentiviral constructs in vitro, and then the proliferation, differentiation, apoptosis, migration and invasion of the transfected GSCs were explored. At the molecular level, we detected Wnt/beta-catenin signaling expression to verify its role in regulating the cellular properties of GSCs. The results showed that the positive rate of GSCs in patients with IDH1-R132H was significantly less than that in patients with IDH1-wt. The positive rate of GSCs was correlated with IDH1 mutation, TNM stage and poor overall survive. After transfection in vitro, IDH1-R132H overexpression led to reduced GSCs proliferation, migration and invasion, inducing apoptosis and improving GSC differentiation, accompanied by a significant reduction in activity of beta-catenin. Several mediators, effectors and targets of the Wnt/beta-catenin signaling were downregulated. The data demonstrate that IDH1 mutation reduces the malignant progression of glioma by causing a less aggressive phenotype of GSCs which are involved in the Wnt/beta catenin signaling. PMID- 29115587 TI - Anticancer effect of quinacrine on diffuse large B-cell lymphoma via inhibition of MSI2-NUMB signaling pathway. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma. Despite improvements in the clinical outcomes of DLBCL, ~30% of patients will develop relapse/refractory disease. Therefore, novel therapeutic drugs have been investigated to improve disease outcomes. Previous studies have revealed the anticancer effects of quinacrine (QC) on tumor cells in vitro, although its role in human DLBCL is yet to be identified. The present study sought to examine the cytotoxic effect of QC on DLBCL cells. QC induced G0/G1 cell cycle arrest and apoptosis in the DLBCL cell lines SU-DHL-8 and OCI-LY01, in a dose-dependent manner, in addition to the downregulation of cyclin-dependent kinase 4/6 and the upregulation of cleaved poly-ADP ribose polymerase 1. Upon exposure to QC, RNA-binding protein Musashi homolog 2 inactivation and activation of protein numb homolog were observed. In addition, QC was able to inhibit the expression of Myc proto-oncogene protein. The results of the present study indicated that QC may be a potential anti-DLBCL drug. PMID- 29115586 TI - Characterization of KIF11 as a novel prognostic biomarker and therapeutic target for oral cancer. AB - Oral cancer has a high mortality rate, and its incidence is increasing gradually worldwide. As the effectiveness of standard treatments is still limited, the development of new therapeutic strategies is eagerly awaited. Kinesin family member 11 (KIF11) is a motor protein required for establishing a bipolar spindle in cell division. The role of KIF11 in oral cancer is unclear. Therefore, the present study aimed to assess the role of KIF11 in oral cancer and evaluate its role as a prognostic biomarker and therapeutic target for treating oral cancer. Immunohistochemical analysis demonstrated that KIF11 was expressed in 64 of 99 (64.6%) oral cancer tissues but not in healthy oral epithelia. Strong KIF11 expression was significantly associated with poor prognosis among oral cancer patients (P=0.034), and multivariate analysis confirmed its independent prognostic value. In addition, inhibition of KIF11 expression by transfection of siRNAs into oral cancer cells or treatment of cells with a KIF11 inhibitor significantly suppressed cell proliferation, probably through G2/M arrest and subsequent induction of apoptosis. These results suggest that KIF11 could be a potential prognostic biomarker and therapeutic target for oral cancer. PMID- 29115588 TI - Limb remote ischemic post-conditioning reduces injury and improves long-term behavioral recovery in rats following subarachnoid hemorrhage: Possible involvement of the autophagic process. AB - Hemorrhage-related neurologic injury is a primary cause of disability and mortality following subarachnoid hemorrhage (SAH). The aim of the present study was to investigate the potential neuroprotective effect and the possible role of autophagy in limb remote ischemic post-conditioning (RIPostC) using an endovascular puncture rat model of SAH. RIPostC was induced by three cycles of occlusion (10 min) and release (10 min) in the bilateral femoral artery using an aneurysm clip. Early RIPostC began immediately following SAH, delayed RIPostC began following a 30 min delay and the repeated RIPostC group underwent the protocol every day for 3 days. Brain water content, SAH grading, terminal deoxynucleotidyl transferase dUTP nick end labeling-DAPI staining, transmission electron microscopy, and neurological and behavioral tests were conducted three days following surgery. Long term outcomes of behavior and memory were assessed using a rotarod test and Morris water maze test 1 month subsequently. Biomarkers of autophagy, including Beclin-1 and light chain 3 (LC3), were assessed using western blotting. The results of the present study demonstrated that, compared with other groups, repeated RIPostC was able to alleviate brain edema, prevent neuronal apoptosis, and improve short term and long term neurological function and memory. Beclin-1 and LC3 in the cortex were upregulated following treatment with repeated RIPostC. Autolysosomes increased 3 days following SAH and were maintained for 1 month in the repeated RIPostC group. Therefore, the present study indicated that the optimized repeated RIPostC may provide a noninvasive strategy to induce neuroprotection, and improve the short and long term outcomes of SAH-related cerebral injury, possibly involving the autophagy pathway. PMID- 29115589 TI - Anti-neuroinflammatory effect of curcumin on Pam3CSK4-stimulated microglial cells. AB - Curcumin is the main curcuminoid present in Curcuma longa and it has been previously reported to exhibit a wide range of pharmacological activities. In the present study, the inhibitory effects of curcumin on the inflammatory mediators released by Pam3CSK4-stimulated BV-2 microglial cells were investigated. The production of pro-inflammatory mediators and cytokines, including tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2), were measured by enzyme linked immunosorbent assay (ELISA). The expression of inflammatory genes, including inducible nitric oxide synthase and cyclooxygenase-2, were further investigated using reverse transcription-quantitative polymerase chain reaction. The effects of curcumin on heme oxygenase-1 (HO-1), nuclear factor (erythroid derived 2)-like 2 (Nrf2), mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways were analyzed by western blotting. The results revealed that curcumin dose-dependently inhibited Pam3CSK4-induced nitric oxide, PGE2, and TNF-alpha secretion. Curcumin suppressed the secretion of inflammatory mediators through an increase in the expression of HO-1. Curcumin induced HO-1 transcription and translation through the Nrf2/antioxidant response element signaling pathway. Inhibitory experiments revealed that HO-1 was required for the anti-inflammatory effects of curcumin. Further mechanistic studies demonstrated that curcumin inhibited neuroinflammation by suppressing NF-kappaB and MAPK signaling pathways in Pam3CSK4-activated microglial cells. The results of the present study suggest that curcumin may be a novel treatment for neuroinflammation-mediated neurodegenerative disorders. PMID- 29115591 TI - Antiangiogenic effects of recombinant human endostatin in lung cancers. AB - Antiangiogenic therapy, as a new anticancer method, can improve the anticancer effect of traditional therapies. Different antiangiogenic drugs may have different vascular normalization time windows. Whether the antiangiogenic treatment is within the vascular normalization time window is very important in the treatment of cancers. Previous studies have indicated that recombinant human endostatin (rh-ES) can transiently normalize tumor microvessels. Yet the molecular mechanism and the time window of rh-ES remains unclear. The aim of the present study was to explore the optimal time window and molecular mechanism of rh-ES in inhibiting Lewis lung cancer (LLC). By comparatively accessing the changes in microvascular and hypoxic conditions of tumors in host mice treated with rh-ES or saline for different days, the authors aimed to investigate the best administration time of rh-ES treatment on human lung cancers and obtain a better understanding concerning the involved molecular mechanism. A total of 40 C57/BL6 mice with LLC xenografts were randomly divided into normal saline (NS) and rh-ES groups (20 mice/group). 0.2 ml NS or 5 mg/kg rh-ES were administrated via intraperitoneal injection (i.p.) into each mouse each day during the 9-day experiment. A total of 5 mice from each group were sacrificed at day 2, 4, 6 or 9. CA9 and RGS5 expression levels of both groups were compared using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and ELISA. Rh-ES caused vascular normalization and improved hypoxia at days 4 and 6. Compared with the control (NS) group, both CA9 and RGS5 expression in rh-ES group were significantly decreased at days 4 and 6 (P<0.05), while no significant change between two groups was observed at days 2 and 9. Rh-ES can induce transient tumor vascular normalization and improves tissue hypoxia in LLC tumors. The vascular normalization window is accompanied by the reduction in RGS5 and CA expression. PMID- 29115592 TI - GMZ-1 is a podophyllotoxin derivative that suppresses growth and induces apoptosis in adriamycin-resistant K562/A02 cells through modulation of MDR1 expression. AB - The incidence of multidrug resistance (MDR) during cancer chemotherapy is a major challenge for treatment. With the aim of identifying drugs that are capable of targeting treatment-resistant cancer cells, the present study evaluated the efficacy of GMZ-1 in cancer chemotherapy using K562/A02, an MDR leukemia cell line. Cell viability and apoptosis were measured by MTT assay and flow cytometry/Giemsa staining, respectively. The expression levels of the MDR protein 1 (MDR1) gene transcript and protein in K562/A02 cells were determined by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. GMZ-1 suppressed the viability of various human cancer cell lines and induced apoptosis in the K562/A02 cell line in a time- and concentration dependent manner. GMZ-1 toxicity may be associated with a decrease in MDR gene expression. These findings demonstrated that GMZ-1 may have efficacy as a potential antitumor drug to overcome leukemia cell resistance to apoptosis induced by chemotherapy. PMID- 29115590 TI - Overexpression of lamin B1 induces mitotic catastrophe in colon cancer LoVo cells and is associated with worse clinical outcomes. AB - Lamins are the major components of the nuclear lamina and play important roles in many cellular processes. The role of lamins in cancer development and progression is still unclear but it is known that reduced expression of lamin B1 has been observed in colon cancer. Thus, the aim of the present study was to elucidate the influence of LMNB1 upregulation on colon cancer cell line after treatment with 5 FU. The results indicate, that overexpression of LMNB1 induced dose-dependent cell death mainly by mitotic catastrophe pathway. Furthermore, after upregulation of this intermediate protein, lower expression of lamin A/C was observed. Moreover, we observed an increase in fluorescence intensity of nuclear beta catenin and decrease in cell-cell interaction area, that was connected with inhibition of colon cancer cells migration. We present the reorganization of actin filament and beta-tubulin, because these cytoskeletal proteins are directly or indirectly linked with lamins, and analyzing publicly available mRNA data we show that patients with overexpression of LMNB1 are characterized by lower survival rates within the first 30 months from diagnosis. Summarizing our results, upregulation of LMNB1 induce mitotic catastrophe and only small percentage of apoptosis. Moreover, we showed inhibition of cell migration and promotion of cell-cell contact as a results of direct and indirect regulation of beta-catenin, lamin A/C, actin and tubulin. However, it is possible that mitotic catastrophe cells in patients with colorectal cancer may be a reservoir of the cells responsible for faster disease progression, and further investigations are necessary to confirm this hypothesis. PMID- 29115593 TI - miR-17-3P regulates the proliferation and survival of colon cancer cells by targeting Par4. AB - Colorectal cancer (CRC) is a common malignancy worldwide. However, the pathogenesis by which CRC progression occurs remains to be elucidated. The present study investigated the role of miRNA (miR)-17-3P in the regulation of CRC cell survival. Firstly, miR-17-3P expression was aberrantly upregulated in human CRC tumor tissues compared with controls. Further results demonstrated that the proliferation capacity of human CRC SW480 and LoVo cells was significantly increased by an miR-17-3P specific mimic, and was inhibited by miR-17-3P silencing. Conversely, the apoptosis of human CRC cells was remarkably decreased by miR-17-3P mimic, and enhanced by miR-17-3P suppression compared with control. Additionally, it was observed that there was a potential binding site of miR-17 3P on the 3'-untranslated region of Prostate apoptosis responde-4 (Par4) and miR 17-3P may directly target Par4 mRNA. In human CRC cells, an miR-17-3P inhibitor significantly upregulated Par 4 expression, however the miR-17-3P mimic reduced Par4expression. Furthermore, Par4 expression exhibited an inhibitory effect on the proliferation of CRC cells transfected with miR-17-3P mimic, and exhibited a promoting role in the repressed apoptosis by miR-17-3P mimic. Inconclusion, the results of the present study demonstrated that miR-17-3P is important in CRC cell survival by targeting Par4, indicating a novel finding regarding human CRC progression. PMID- 29115594 TI - Pentoxifylline exerts anti-inflammatory effects on cerebral ischemia reperfusion induced injury in a rat model via the p38 mitogen-activated protein kinase signaling pathway. AB - Pentoxifylline exhibits complex functions with extensive pharmacological effects and is used therapeutically due to its therapeutic effects and rapid metabolism in the body, with no cumulative effects and few side effects. The present study investigated the effects of pentoxifylline on cerebral ischemia reperfusion induced injury (IRI) through suppression of inflammation in rats. Hematoxylin and eosin staining was performed to evaluate the number of neurocytes, and ELISAs were applied to measure tumor necrosis factor-alpha, interleukin-6, malondialdehyde and superoxide dismutase activities. Treatment with pentoxifylline significantly recovered the cerebral ischemia reperfusion-induced neurological deficit score and cerebral infarct volume in rats. In addition, pentoxifylline treatment significantly reversed the cerebral ischemia reperfusion induced interleukin-6, tumor necrosis factor-alpha, malondialdehyde and superoxide dismutase levels in vivo. Furthermore, pentoxifylline significantly inhibited cyclooxygenase-2 and inducible nitric oxide synthase mRNA and protein expression in cerebral IRI mice. Treatment with pentoxifylline also significantly suppressed the expression of cleaved caspase-3 and p38 mitogen-activated protein kinase (MAPK) protein in cerebral IRI mice. These results indicate that the protective effects of pentoxifylline on cerebral IRI may occur via the p38 MAPK signaling pathway. PMID- 29115595 TI - Role of the microRNA 181 family in glioma development. AB - MicroRNAs (miRNAs) are small, noncoding regulatory RNAs that regulate protein expression by reducing mRNA stability and/or translation, via base pairing with full or partial sequence-complementary target mRNAs. Recent evidence indicates that miRNAs have roles as tumor suppressors and oncogenes. The members of the miRNA181 (miR181) family have been reported to be downregulated in early stage human glioma, and to be involved in glioma development. The current study demonstrated that all subtypes of the miRNA 181 family were downregulated at stages of human glioma, including miR181a1, a2, b1, b2, c and d. In the present study, the family members were detected by reverse transcription-quantitative polymerase chain reaction in glioma tissues of different stages. miR181c declined the most in the samples from patients with World Health Organization (WHO) grade I glioma. As glioma development progressed from grade I to IV, the expression of miRN181 family members continued to decline, with miR181b1 exhibiting the fastest decline rate. Furthermore, a lentivirus was used to overexpress miR181c in primary glioma cells; the result indicated that miR181c overexpression was able to significantly inhibit glioma cell proliferation. Thus, miR181 may be a useful biomarker for human glioma at early stages. Detection of the level of miR181 family members may be a potential method for glioma diagnosis, determining the tumor WHO grade and guiding clinical treatment. PMID- 29115596 TI - Rottlerin inhibits cell growth, induces apoptosis and cell cycle arrest, and inhibits cell invasion in human hepatocellular carcinoma. AB - Rottlerin, a polyphenolic compound, has been demonstrated to exhibit antitumor activity in various types of human cancer. Several studies have revealed that rottlerin exerts its anticancer function through PKC-dependent and independent pathways. The transcriptional co-activator with PDZ-binding motif (TAZ) oncopreotein is an important molecule in regulation of the Hippo pathway in human cancer. The present study investigated whether rottlerin has a tumor suppressive role via inhibiting the expression of TAZ, using cell viability assay, apoptosis and cell cycle analyses, western blot analysis and Tanswell invasion assay. The results demonstrated that rottlerin suppressed cell growth, triggered cell apoptosis and induced cell cycle arrest. In addition, rottlerin inhibited cell migration and invasion in hepatocellular carcinoma (HCC) cells. Mechanistically, the results demonstrated that rottlerin exerted its antitumor activity partly through the inhibition of TAZ. In addition, the depletion of TAZ led to inhibited cell growth and invasion, whereas the overexpression of TAZ enhanced cell growth and invasion in the HCC cells. Taken together, these findings indicated that the inhibition of TAZ by rottlerin may be a novel strategy for treating HCC. PMID- 29115597 TI - Quantitative proteomic study of the plasma reveals acute phase response and LXR/RXR and FXR/RXR activation in the chronic unpredictable mild stress mouse model of depression. AB - Major depressive disorder is a severe neuropsychiatric disease that negatively impacts the quality of life of a large portion of the population. However, the molecular mechanisms underlying depression are still unclear. The pathogenesis of depression involves several brain regions. However, most previous studies have focused only on one specific brain region. Plasma and brain tissues exchange numerous components through the blood-brain barrier. Therefore, in the present study, plasma samples from control (CON) mice and mice subjected to chronic unpredictable mild stress (CUMS) were used to investigate the molecular pathogenesis of depression, and the association between the peripheral circulation and the central nervous system. A total of 47 significant differentially expressed proteins were identified between the CUMS and CON group by an isobaric tag for relative and absolute quantitation (iTRAQ) coupled with tandem mass spectrometry approach. These 47 differentially expressed proteins were analyzed with ingenuity pathway analysis (IPA) software. This revealed that the acute phase response, LXR/RXR and FXR/RXR activation, the complement system and the intrinsic prothrombin activation pathway were significantly changed. Four of the significant differentially expressed proteins (lipopolysaccharide binding protein, fibrinogen beta chain, alpha-1 antitrypsin, and complement factor H) were validated by western blotting. the present findings provide a novel insight into the molecular pathogenesis of depression. PMID- 29115598 TI - Effects of hypoxia-inducible factor-1alpha on endometrial receptivity of women with polycystic ovary syndrome. AB - Embryo implantation is associated with an hypoxic endometrial microenvironment. Hypoxia-inducible factor-1alpha (HIF-1alpha) is activated under hypoxic conditions. In the present study, the expression pattern of HIF-1alpha in endometrial tissue was investigated and its effects on endometrial receptivity in patients with polycystic ovary syndrome (PCOS) were examined. A total of 81 patients were enrolled for in vitro fertilization and embryo transfer. They were divided into PCOS (n=40) and Control groups (n=41); both groups were further divided based on body weight (overweight and normal weight subgroups). The expressions of HIF-1alpha, vascular endothelial growth factor (VEGF) and glucose transporter protein (GLUT)-1 and GLUT4 were determined by reverse transcription quantitative polymerase chain reaction and immunohistochemistry. The results demonstrated that mRNA and protein expression levels of HIF-1alpha and VEGF in the PCOS group were significantly lower compared with expression levels in the Control group. However, there were no statistically significant differences in the expression levels of GLUT1 and GLUT4 between groups. In patients with PCOS, GLUT1 and GLUT4 were mainly localized in the nuclei and cytoplasm, but not in the cell membrane. Overweight patients had the lowest expression levels of HIF 1alpha, VEGF and GLUT1 expression compared with normal weight patients. In conclusion, HIF-1alpha may be involved in the molecular mechanisms of endometrial dysfunction in women with PCOS, particularly in those who are overweight. HIF 1alpha might therefore be a novel target for improving the endometrial receptivity and successful embryo implantation in PCOS women. PMID- 29115599 TI - Aconitine induces apoptosis in H9c2 cardiac cells via mitochondria-mediated pathway. AB - Aconitine, a diterpenoid alkaloids derived from Aconitum plants, is widely employed to treat various diseases. The aim of the present study was to investigate the apoptotic effect of aconitine in H9c2 cardiac cells. H9c2 cell apoptosis induced by aconitine was detected by a Cell Counting kit-8 assay, DAPI staining, Annexin V-FITC/propidium iodide double staining and western blotting. The effects of aconitine on reactive oxygen species levels and mitochondrial membrane potential were confirmed by fluorescence microscopy and flow cytometry. In addition, ATP contents were determined using a ATP-dependent bioluminescence assay kit. The levels of peroxisome proliferator activated receptor gamma co activator 1alpha (PGC-1alpha) expression and apoptosis-associated proteins including Caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and Cytochrome c were also assessed. Taken together, the results indicated that aconitine may inhibit cell viability, decrease PGC-1alpha expression, induce mitochondrial dysfunctions, upregulate Cytochrome c, Bax and Caspase-3, and downregulate Bcl-2, suggesting that aconitine may induce apoptosis through mitochondria-mediated signaling pathways in H9c2 cells. PMID- 29115600 TI - Messenger RNA sequencing reveals similar mechanisms between neonatal and acute respiratory distress syndrome. AB - Hypoxemia and hypercarbia resulting from a lack of surfactant is considered to be the primary mechanism underlying neonatal respiratory distress syndrome (NRDS). Surfactant replacement therapy may mitigate the symptoms of the disease by decreasing the surface tension of alveoli and facilitating inflation. However, surfactant serves an additional role in immunological processes. Therefore, it may be hypothesized that mechanisms of NRDS involving surfactant exert additional functions to promoting alveolar inflation. Using peripheral blood obtained from mature infants with and without NRDS, in tandem with mRNA sequencing (mRNA-seq) analysis, the present study identified that, while cell cycle regulation and alveolar surfactants serve a role in deterring the further onset of NRDS, innate and pathogen-induced responses of the immune system are among the most important factors in the pathology. The present study illustrated the regulatory importance of these immune pathways in response to alterations in the expression of gene families, particularly in perpetual lung injury leading to NRDS. Notably, data collected from the mRNA-seq analysis revealed similar mechanisms between NRDS and acute respiratory distress syndrome, a clinical phenotype precipitated by the manifestation of a severe form of lung injury due to numerous lung insults, implying that similar therapies may be applied to treat these two diseases. PMID- 29115602 TI - Multi-target inhibition by four tandem shRNAs embedded in homo- or hetero-miRNA backbones. AB - The functional influence of microRNA (miRNA)backbone selection remains unclear with respect to multiplexing miRNA-based short hairpin RNAs (shRNAmiRs), due to a lack of comparative studies. To this end, a pair of shRNAmiR tetramers were designed in the present study that targeted four genes with a shared miR30a backbone (homo-BB) or four miRNA backbones (hetero-BB). A PBLT+ 293A cell line overexpressing four targets was established, which permitted simultaneous dissection of individual gene knockdown. Multi-target inhibition was confirmed by a decrease in positive cell populations of the relative gene and mean fluorescence intensities, with almost comparable activities of homo- and hetero BB tetramers. Of note, this multi-inhibition was sustained over a 1-month period, with no notable difference, particularly in the late-phased inhibitory effects between homo- and hetero-BB tetra-shRNA miRs. These preliminary data may indicate little influence of scaffold substitution in the functionalities of multiplexed shRNAmiRs and little recombination-depleted risk of repetitively adopting the same miRNA backbone in this artificial in vitro system. More comparative studies are further required to explore extended repertoires of scaffold-paralleled multi shRNAmiRs in more physiologically relevant models. PMID- 29115601 TI - Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo. AB - Anti-angiogenic therapy has been successfully applied to treat colorectal cancer (CRC). Ginsenoside Rg3, derived from the Chinese herb ginseng, has anti vascularization effects and can inhibit tumor growth and metastasis, and can sensitize cancer cells to chemotherapy. Therefore, in the present study, we investigated whether Rg3 could be appropriate for CRC treatment. Growth of CRC cells was assessed by an MTT (methyl thiazolyl tetrazolium) assay in vitro and using orthotopic xenograft models in vivo. mRNA expression was evaluated using real-time PCR. Protein levels were tested by western blotting, flow cytometry and immunohistochemistry. Migration was determined using a wound-healing assay. Stemness was further confirmed using a plate clone formation assay. We found that Rg3 repressed the growth and stemness of CRC cells both in vitro and in vivo. Rg3 also impaired the migration of CRC cells in vitro. Rg3 downregulated the expressions of angiogenesis-related genes, and repressed the vascularization of CRC xenografts. In addition, Rg3 strengthened the cytotoxicity of 5-Fluorouracil and oxaliplatin against orthotopic xenografts in vivo. Moreover, Rg3 downregulated the expressions of B7-H1 and B7-H3, high expressions of which were associated with reduced overall survival (OS) of CRC patients. Hence, Rg3 not only repressed the growth and stemness of CRC cells, but could also remodel the tumor microenvironment through repressing angiogenesis and promoting antitumor immunity. Therefore, Rg3 could be a novel therapeutic for the CRC treatment. PMID- 29115603 TI - Amelioration of lung ischemia-reperfusion injury by JNK and p38 small interfering RNAs in rat pulmonary microvascular endothelial cells in an ischemia-reperfusion injury lung transplantation model. AB - The inhibition of mitogen-activated protein kinases (MAPKs), including c-Jun NH2 terminal protein kinase (JNK), p38 MAPK (p38) and extracellular signal-regulated protein kinase 1/2 (ERK1/2), have an important effect on lung ischemia reperfusion injury (IRI) during lung transplantation (LT). However, the way in which combined MAPK inhibition exerts optimal protective effects on lung IRI remains to be elucidated. Therefore, the present study evaluated the therapeutic efficacy of the inhibition of MAPKs in rat pulmonary microvascular endothelial cells (PMVECs) in an IRI model of LT. The rat PMVECs were transfected with small interfering RNAs (siRNAs) against JNK, p38 or ERK1/2. Cotransfection was performed with siRNAs against JNK and p38 in the J+p group, JNK and ERK1/2 in the J+E group, p38 and ERK1/2 in the p+E group, or all three in the J+p+E group. Non targeting (NT) siRNA was used as a control. The PMVECs were then treated to induce IRI, and the levels of inflammation, apoptosis and oxidative stress were detected. Differences between compared groups were determined using Tukey's honest significant difference test. In all groups, silencing of the MAPKs was shown to attenuate inflammation, apoptosis and oxidative stress to differing extents, compared with the NT group. The J+p and J+p+E groups showed lower levels of interleukin (IL)-1beta, IL-6 and malondialdehyde, a lower percentage of early apoptotic cells, and higher superoxide dismutase (SOD) activity, compared with the other groups. No significant differences were observed in the inflammatory response, SOD activity or early apoptosis between the J+p and J+p+E groups. These findings suggested that the dual inhibition of JNK and p38 led to maximal amelioration of lung IRI in the PMVECs of the IRI model of LT, which occurred through anti-inflammatory, anti-oxidative and anti-apoptotic mechanisms. PMID- 29115604 TI - Genetically engineered recombinant adenovirus expressing interleukin-2 for hepatocellular carcinoma therapy. AB - Regulatory and effector T cells possess immunological cytotoxicity for tumor cells in the tumor microenvironment during tumor progression and are the primary suppressors inhuman cancer therapy. Interleukin-2 (IL-2) is an anticancer cytokine, which triggers human innate and adaptive immunity by stimulating T cell propagation and lymphocyte infiltration into tumor sites. IL-2 has been used successfully for cancer therapy. Recombinant adenovirus expressing IL-2 (rAd-IL 2) injection is a gene therapy agent that may improve prognosis of hepatocellular carcinoma (HCC) patients. In the present study, the ability of IL-2 to stimulate an immune response and the ability of recombinant adenovirus to inhibit tumor cell growth in HCC was investigated in a HCC tumor model. It was demonstrated that the regulatory and effector cell-mediated tumor suppression by antitumor cluster of differentiation (CD)4+ and CD8+ T cells stimulated by rAd-IL-2 is tumor-specific. Furthermore, rAd-IL-2 significantly stimulated tumor-specific cytotoxic T lymphocyte responses, increased interferon-gamma release and enhanced antitumor immunity by inducing CD4+ and CD8+ T cell recruitment into the tumor, and additionally induced memory to protect tumor-bearing mice against tumor challenge. Treatment with rAd-IL-2 led to tumor regression and long-term survival of mice in the 120-day treatment period. Tumor challenge experiments demonstrated that rAd-IL-2 induced memory, protecting against reinfection. In conclusion, rAd IL-2 may promote tumor-associated effector and regulatory T cell expansion and may be a potential therapeutic agent for clinical immunotherapy application in the treatment of cancer. PMID- 29115605 TI - Genetic variations in Bestrophin-1 and associated clinical findings in two Chinese patients with juvenile-onset and adult-onset best vitelliform macular dystrophy. AB - Best vitelliform macular dystrophy (BVMD) is a hereditary retinal disease characterized by the bilateral accumulation of large egg yolk-like lesions in the sub-retinal and sub-retinal pigment epithelium spaces. Macular degeneration in BVMD can begin in childhood or adulthood. The variation in the age of onset is not clearly understood. The present study characterized the clinical characteristics of two Chinese patients with either juvenile-onset BVMD or adult onset BVMD and investigated the underlying genetic variations. A 16-year-old male (Patient 1) was diagnosed with juvenile-onset BVMD and a 43-year-old female (Patient 2) was diagnosed with adult-onset BVMD. Comprehensive ophthalmic examinations were performed, including best-corrected visual acuity, intraocular pressure, slit-lamp examination, fundus photography, optical coherence tomography, fundus fluorescein angiography imaging and Espion electrophysiology. Genomic DNA was extracted from peripheral blood leukocytes collected from these patients, their family members, and 200 unrelated subjects within in the same population. The 11 exons of the bestrophin-1 (BEST1) gene were amplified by polymerase chain reaction and directly sequenced. Both patients presented lesions in the macular area. In Patient 1, a heterozygous mutation c.903T>G (p.D301E) in exon 8 of the BEST1 gene was identified. This mutation was not present in any of the unaffected family members or the normal controls. Polymorphism phenotyping and the sorting intolerant from tolerant algorithm predicted that the amino acid substitution D301E in bestrophin-1 protein was damaging. In Patient 2, a single nucleotide polymorphism c.1608C>T (p.T536T) in exon 10 of the BEST1 gene was identified. These findings expand the spectrum of BEST1 genetic variation and will be valuable for genetic counseling and the development of therapeutic interventions for patients with BVMD. PMID- 29115606 TI - DNA methyltransferase 3a modulates chemosensitivity to gemcitabine and oxaliplatin via CHK1 and AKT in p53-deficient pancreatic cancer cells. AB - The aberrant expression of DNA methyltransferases (DNMTs) has been considered to be associated with pancreatic carcinogenesis and progression. DNMT3a is widely involved in cell proliferation and cell cycle progression in pancreatic ductal adenocarcinoma (PDAC) cells. However, its regulation of chemosensitivity to gemcitabine (GEM) and oxaliplatin (OXA) in p53-deficient PDAC remains unclear. In the present study, the effect and mechanisms of DNMT3a on GEM and OXA chemosensitivity in p53-deficient PDAC cells were investigated using MTT assay, cell cycle analysis, apoptosis analysis and western blotting. The treatment of GEM and OXA induced S phase arrest by DNA damage, and enhanced the activation of the AKT signaling pathway in Panc-1 cells. Downregulation of DNMT3a increased the chemosensitivity to both GEM and OXA in Panc-1 cells. DNMT3a depletion distinctly abolished S phase arrest induced by GEM and OXA. Further research demonstrated that activation inhibition of CHK1 and AKT, as well as an increase in apoptosis, were involved in DNMT3a-mediated chemosensitivity to GEM and OXA. Taken together, these data demonstrated that DNMT3a serves a crucial role in the regulation of chemosensitivity to GEM and OXA, and suggests a promising therapeutic target for p53-deficient PDAC. PMID- 29115607 TI - Schisandrin B protects against myocardial ischemia/reperfusion injury via the PI3K/Akt pathway in rats. AB - The natural medicinal monomer, schisandrin B (Sch B), has been shown to exert cardioprotective effects; however, the underlying mechanisms of these effects remain to be fully elucidated. Therefore, the aim of the present study was to investigate whether Sch B attenuated myocardial ischemia/reperfusion (I/R) injury via the phosphoinositide 3-kinases (PI3K)/Akt signaling pathway. To confirm this, I/R models were established in rats by ligation of the left anterior descending coronary artery. A group of animals were administered with Sch B (60 mg/kg, lavage) and/or the PI3K inhibitor, LY294002 (0.3 mg/kg, intraperitoneal). Myocardial infarct size, myocardial infarct serum markers, myocardial apoptotic index and the expression of Akt were measured in each group. The results demonstrated that the administration of Sch B reduced the size of the myocardial infarct, and this effect was eliminated following LY294002 treatment. In addition, the administration of Sch B decreased the apoptotic index and the serum markers of myocardial infarction. Sch B administration also increased the expression of phosphorylated Akt, and Sch B treatment decreased the B-cell lymphoma 2 (Bcl-2)-like protein 4/Bcl-2 ratio and the expression of cleaved caspase-3. Therefore, Sch B may protect myocardial tissue from I/R injury via the PI3K/Akt signaling pathway in rats. PMID- 29115608 TI - MicroRNA-27a promotes tumorigenesis via targeting AKT in triple negative breast cancer. AB - Altered microRNA (miRNA/miR) expression regulates tumor development and progression in triple-negative breast cancer (TNBC). The present study examined the effect of miR-27a on proliferation, migration and invasion of TNBC cells in vitro and in vivo. An MTT assay was performed to examine the proliferation of MDA MB-231 and MDA-MB-468 breast cancer cells with either overexpression of miR-27a or downregulation of miR-27a, in the presence or absence of radiation. The migratory and invasive abilities of MDA-MB-231 and MDA-MB-468 breast cancer cells were assessed by Transwell migration and Matrigel invasion assays. The protein expression levels were examined by western blotting. The caspase-Glo3/7 assay was performed to examine the effect of miR-27a on radiation-induced apoptosis in MDA MB-231 and MDA-MB-468 breast cancer cells. A luciferase assay was performed to evaluate the effect of miR-27a on phosphatase and tensin homolog (PTEN) and B cell lymphoma (Bcl)-2 associated X, apoptosis regulator (BAX) expression. Immunodeficient nude mice were used to examine tumor growth following injection of MDA-MB-231 breast cancer cells. miR-27a promoted proliferation in vitro and in vivo, and enhanced migration and invasion in TNBC cells. miR-27a improved the survival of TNBC cells following irradiation. miR-27a inhibited radiation-induced apoptosis in TNBC cells by regulation of caspase 3/7 and Bcl-2 expression. Furthermore, the expression levels of PTEN and phosphorylated protein kinase B in MDA-MB-231 and MDA-MB-468 cells was altered following overexpression of miR-27a. The luciferase assay demonstrated that miR-27a regulated PTEN and BAX expression by binding to 3'-untranslated regions. Overall, miR-27a exhibits an essential role in tumor development and progression in TNBC and may be used as a potential biomarker to predict radiotherapy response and prognosis for the disease. PMID- 29115609 TI - MicroRNA-212 inhibits the proliferation and invasion of human renal cell carcinoma by targeting FOXA1. AB - MicroRNA-212 (miR-212) has been observed to be significantly deregulated in various types of human cancer. However, the clinical significance of miR-212 and the associated molecular signaling pathways involved in the progression of renal cell carcinoma (RCC) remain unclear. In the present study, miR-212 expression was significantly downregulated in RCC tissues compared with adjacent non-tumor tissues. Clinical association analysis indicated that low expression of miR-212 was prominently associated with large tumor size, advanced tumor, nodes, metastasis stage and lymph node metastasis. In vitro studies revealed that upregulation of miR-212 inhibited cell proliferation, migration and invasion, and induced apoptosis in Caki-1 cells. Forkhead box protein A1 (FOXA1) was identified as a direct target of miR-212 in RCC cells via luciferase reporter assays and western blotting. In addition, FOXA1 expression was upregulated in RCC tissues compared with adjacent noncancerous tissues. An inverse correlation between FOXA1 and miR-212 expression was observed in RCC tissues. Notably, FOXA1 overexpression partially rescued miR-212-mediated inhibition of cell proliferation, migration and invasion in RCC cells. These results suggested that miR-212 suppresses RCC proliferation and invasion by modulating FOXA1, suggesting that miR-212 may have potential as a therapeutic target in RCC. PMID- 29115610 TI - Overexpression of miR-21 promotes neural stem cell proliferation and neural differentiation via the Wnt/beta-catenin signaling pathway in vitro. AB - The primary aim of the present study was to examine the effects of microRNA-21 (miR-21) on the proliferation and differentiation of rat primary neural stem cells (NSCs) in vitro. miR-21 was overexpressed in NSCs by transfection with a miR-21 mimic. The effects of miR-21 overexpression on NSC proliferation were revealed by Cell Counting kit 8 and 5-ethynyl-2'-deoxyuridine incorporation assay, and miR-21 overexpression was revealed to increase NSC proliferation. miR 21 overexpression was confirmed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). mRNA and protein expression levels of key molecules (beta-catenin, cyclin D1, p21 and miR-21) in the Wnt/beta-catenin signaling pathway were studied by RT-qPCR and western blot analysis. RT-qPCR and western blot analyses revealed that miR-21 overexpression increased beta-catenin and cyclin D1 expression, and decreased p21 expression. These results suggested that miR-21-induced increase in proliferation was mediated by activation of the Wnt/beta-catenin signaling pathway, since overexpression of miR-21 increased beta catenin and cyclin D1 expression and reduced p21 expression. Furthermore, inhibition of the Wnt/beta-catenin pathway with FH535 attenuated the influence of miR-21 overexpression on NSC proliferation, indicating that the factors activated by miR-21 overexpression were inhibited by FH535 treatment. Furthermore, overexpression of miR-21 enhanced the differentiation of NSCs into neurons and inhibited their differentiation into astrocytes. The present study indicated that in primary rat NSCs, overexpression of miR-21 may promote proliferation and differentiation into neurons via the Wnt/beta-catenin signaling pathway in vitro. PMID- 29115611 TI - D-Tagatose inhibits the growth and biofilm formation of Streptococcus mutans. AB - Dental caries is an important global health concern and Streptococcus mutans has been established as a major cariogenic bacterial species. Reports indicate that a rare sugar, D-tagatose, is not easily catabolized by pathogenic bacteria. In the present study, the inhibitory effects of D-tagatose on the growth and biofilm formation of S. mutans GS-5 were examined. Monitoring S. mutans growth over a 24 h period revealed that D-tagatose prolonged the lag phase without interfering with the final cell yield. This growth retardation was also observed in the presence of 1% sucrose, although it was abolished by the addition of D-fructose. S. mutans biofilm formation was significantly inhibited by growth in sucrose media supplemented with 1 and 4% D-tagatose compared with that in a culture containing sucrose alone, while S. mutans formed granular biofilms in the presence of this rare sugar. The inhibitory effect of D-tagatose on S. mutans biofilm formation was significantly more evident than that of xylitol. Growth in sucrose media supplemented with D-tagatose significantly decreased the expression of glucosyltransferase, exo-beta-fructosidase and D-fructose-specific phosphotransferase genes but not the expression of fructosyltransferase compared with the culture containing sucrose only. The activity of cell-associated glucosyltransferase in S. mutans was inhibited by 4% D-tagatose. These results indicate that D-tagatose reduces water-insoluble glucan production from sucrose by inhibiting glucosyltransferase activities, which limits access to the free D fructose released during this process and retards the growth of S. mutans. Therefore, foods and oral care products containing D-tagatose are anticipated to reduce the risk of caries by inhibiting S. mutans biofilm formation. PMID- 29115612 TI - Isopsoralen regulates PPAR-gamma/WNT to inhibit oxidative stress in osteoporosis. AB - The present study aimed to examine the effects of isopsoralen against postmenopausal osteoporosis in an ovariectomized rat model. The ovariectomized rats were treated with three days 10 mg/kg isopsoralen or with three days 20 mg/kg isopsoralen. Alkaline phosphatase, the oxidative stress indicators and caspase-3/9 were measured using ELISA assay kits. Reverse transcription quantitative polymerase chain reaction was used to measure collagen type I (Col I), osteocalcin and osteoprotegerin mRNA levels. Wnt, beta-catenin and peroxisome proliferators-activated receptor gamma (PPAR-gamma) were analyzed using western blot analysis. Isopsoralen suppressed mature adipocyte differentiation of C2C12 cells, inhibited serum calcium and urinary calcium levels, and reduced the structural scores of articular cartilage and cancellous bone in the proximal tibia metaphysis of mice with postmenopausal osteoporosis. Isopsoralen also promoted the activity of alkaline phosphatase and the mRNA expression levels of Col 1, osterix and osteopontin in mice with postmenopausal osteoporosis. Oxidative stress and activities of caspase-3/9 in the mice with postmenopausal osteoporosis were effectively suppressed by isopsoralen treatment, which upregulated the protein expression of Wnt/beta-catenin and downregulated the protein expression of PPAR-gamma. These findings demonstrated that isopsoralen prevented osteoporosis through the regulation of PPAR-gamma/WNT, inhibiting oxidative stress by targeting the PPAR-gamma/WNT pathway. These results provide evidence of the potential targeted therapy for isopsoralen in the clinical treatment of postmenopausal osteoporosis. PMID- 29115613 TI - Preparation of chitosan-silicon dioxide/BCSG1-siRNA nanoparticles to enhance therapeutic efficacy in breast cancer cells. AB - Breast cancer is one of the most serious diseases, posing threats to women's physical and mental health. Gene therapy has been gradually regarded as an important part of tumor therapeutics. In the present study, the breast cancer specific gene 1-small interference RNA (BCSG1-siRNA) plasmid was designed, then encapsulated by chitosan-silicon dioxide nanometer carriers. The results demonstrated a successful encapsulation of BCSG1-siRNA in chitosan-silicon dioxide nanoparticles (encapsulation efficiency exceeded 90%). BCSG1-siRNA was released slowly (the release rate was almost 30% after 24 h). The cytotoxic effect on MCF-7 cells was enhanced by increasing the concentration of nanoparticle (the proliferation rate was reduced to 13.4+/-5.3% and apoptosis rate was increased to 71.5+/-6.8%). Therefore, the materials presented in the current study acted as successful gene carriers and exhibited significant antitumor effects in breast cancer cells. PMID- 29115615 TI - Effects of dabigatran regulates no-reflow phenomenon in acute myocardial infarction mice through anti-inflammatory and anti-oxidative activities and connective tissue growth factor expression. AB - Pradaxa is a novel oral anticoagulant, which was originally used to prevent thrombosis following joint replacement surgery. The aim of the current study was to investigate the effect dabigatran on acute myocardial infarction through regulating no-reflow phenomenon and oxidative stress, neutrophil intraplaque infiltration and apoptosis. In the present study, dabigatran significantly inhibited the infarct size, increased arterial pressure and reduced no-reflow phenomenon in acute myocardial infarction (AMI) vehicle rabbits. Treatment with dabigatran significantly inhibited the P65 of nuclear factor kappaB, tumor necrosis factor alpha, interleukin (IL)-1beta and IL-6 activities and significantly enhanced the catalase and superoxide dismutase activities in the AMI rabbits. In addition, dabigatran significantly suppressed inducible nitric oxide synthase (iNOS), collagen I, transforming growth factor beta1 (TGF-beta1), alpha-smooth muscle actin (alpha-SMA) and connective tissue growth factor (CTGF) protein expression in AMI rabbits. Taken together, these results suggest that the effects of dabigatran inhibit no-reflow phenomenon, infarct size and enhance arterial pressure in AMI through anti-inflammatory and anti-oxidative activity, and regulating iNOS, collagen I, TGF-beta1, alpha-SMA and CTGF protein expression in AMI rabbits. PMID- 29115614 TI - Downregulation of TRIM28 inhibits growth and increases apoptosis of nude mice with non-small cell lung cancer xenografts. AB - TRIM28 is a well-known transcriptional co-repressor of Kruppel-associated box zinc finger proteins. The authors previously demonstrated that TRIM28 small interfering (si)RNA decreases cell proliferation and inhibits cell cycle progression in non-small cell lung cancer (NSCLC) cell lines. The present study further demonstrated that the stable silencing of TRIM28 expression by a specific siRNA lentivirus vector significantly inhibited the growth and exerted obvious anti-tumor effects in nude mice. The results of the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay indicated that TRIM28 knockdown increased apoptosis. Furthermore, TRIM28 knockdown decreased the expression of B cell lymphoma (Bcl)-2 and increased the expression of Bcl-2 associated X, apoptosis regulator and p53 at the gene and protein levels. Auto-antibodies to TRIM28 were present in 12.32% of the sera of the patients with NSCLC. The results suggest that TRIM28 knockdown may be effective against NSCLC, and TRIM28 antibodies have the potential to act as novel diagnostic and therapeutic tools. PMID- 29115616 TI - Metabolic alterations in the rat cerebellum following acute middle cerebral artery occlusion, as determined by 1H NMR spectroscopy. AB - Supratentorial focal ischemia may reduce cerebral blood volume and cerebellar glucose metabolic rate contralateral to the region of ischemia. The present study investigated the effects of middle cerebral artery occlusion (MCAO) on cerebral metabolism in the ischemic cerebral hemisphere and the non-ischemic cerebellum in rats 1, 3, 9 and 24 h following ischemia using ex vivo proton nuclear magnetic resonance (1H NMR) spectroscopy. The results demonstrated that focal ischemia induced increases in the levels of lactate and alanine, and a decrease in succinate, as early as 1 h following ischemia in the left cerebral hemisphere and the right cerebellum. A continuous increase in lactate levels and decrease in creatine levels were detected in both cerebral areas 3 and 24 h post-MCAO. The most obvious difference between the two cerebral areas was that there was no statistically significant difference in N-acetyl aspartate (NAA) levels in the right cerebellum at all time points; however, the amino acid levels of NAA in the left cerebral hemisphere were markedly decreased 3, 9 and 24 h post-MCAO. In addition, an obvious increase in glutamine was observed in the right and left cerebellum at 3, 9 and 24 h post-MCAO. Furthermore, the present study demonstrated that gamma-aminobutyric acid levels were decreased at 1 h in the left and right cerebellum and were evidently increased at 24 h in the right cerebellum post-MCAO. In conclusion, supratentorial ischemia has been indicated to affect the activities of the non-ischemic contralateral cerebellum. Therefore, these results suggested that an NMR-based metabonomic approach may be used as a potential means to elucidate cerebral and cerebellar metabolism following MCAO, which may help improve understanding regarding cerebral infarction at a molecular level. Ex vivo 1H NMR analysis may be useful for the assessment of clinical biopsies. PMID- 29115617 TI - Three-dimensional hydrogel is suitable for targeted investigation of amoeboid migration of glioma cells. AB - Glioblastoma (GBM) invasion and migration are key biological behaviors leading to refractoriness to current therapies and infiltration into the non-tumor brain parenchyma. GBM cell migration is strongly dependent on tumor architecture in vivo, which is absent in traditional two-dimensional (2D) monolayer culture. The present study applied a three-dimensional (3D) hydrogel model to rebuild the tumor architecture in vitro. Treatment with NSC23766, a specific inhibitor of Ras related C3 botulinum toxin substrate 1 (Rac1), inhibited the mesenchymal invasiveness however triggered the amoeboid motility called mesenchymal-amoeboid transition (MAT). Notably, NSC23766 stimulated U87 GBM cell migration in the 3D hydrogel. However, this compound inhibited cell motility in 2D monolayer culture without tumor architecture for MAT, suggesting the advantage of 3D hydrogel to investigate tumor cell invasion. Due to the inverse interaction of Rac1 and Ras homolog family member A (RhoA) signaling in the transition between mesenchymal and amoeboid morphology, simultaneous treatment of NSC23766 and Y27632 (selective Rho associated coiled-coil containing protein kinase 1 inhibitor), abolished U87 GBM cell migration through inhibiting MAT and amoeboid-mesenchymal transition. In addition, Y27632 induced integrin expression which gave rise to the focal adhesion to facilitate the mesenchymal invasion. The results of the present study demonstrated that the 3D hydrogel was a preferable model in vitro to study tumor cell invasion and migration. The combined inhibition of Rac1 and RhoA signaling would be a promising strategy to suppress GBM invasion. PMID- 29115618 TI - Apelin-13 promotes cell proliferation in the H9c2 cardiomyoblast cell line by triggering extracellular signal-regulated kinase 1/2 and protein kinase B phosphorylation. AB - Apelin-13 (APL-13), a peptide hormone that serves as a ligand for G-protein coupled receptors, has been demonstrated to be highly expressed in left ventricular hypertrophy rat models. It has been implicated in cardio-protection under pathological states. The present study aimed to assess the physiological proliferation effect of APL-13 in cultured H9c2 cardiomyoblast cells, and to elucidate the underlying mechanisms. Cell proliferation was determined by MTT assay. The extracellular signal-regulated kinase (ERK) 1/2 and protein kinase B (Akt) signaling pathway was identified, and protein expression levels were detected using western blot analysis. The results demonstrated that APL-13 markedly increased cell proliferation. Western blotting results suggested that APL-13 significantly enhanced the expression of phosphoinositide ERK1/2 and Akt activation in a dose-dependent manner. U0126 (10 uM; ERK1/2 inhibitor) and/or 10 uM LY294002 (Akt inhibitor) were used to help to determine the APL-signaling mechanism. As a result, LY294002 and U0126 partially blocked the APL-13 induced H9c2 proliferation. In conclusion, these data suggested that APL-13 has a proliferative effect on myocardium cells via the Akt and ERK1/2 signaling pathways, and provide potential novel pharmaceutical targets for cardiovascular disease. PMID- 29115619 TI - Administration of chlorogenic acid alleviates spinal cord injury via TLR4/NF kappaB and p38 signaling pathway anti-inflammatory activity. AB - Chlorogenic acid, as a secondary metabolite of plants, exhibits a variety of effects including free radical scavenging, antiseptic, anti-inflammatory and anti viral, in addition to its ability to reduce blood glucose, protect the liver and act as an anti-hyperlipidemic agent and cholagogue. The present study demonstrated that administration of chlorogenic acid alleviated spinal cord injury (SCI) via anti-inflammatory activity mediated by nuclear factor (NF) kappaB and p38 signaling pathways. Wistar rats were used to structure a SCI model rat to explore the effects of administration of chlorogenic acid on SCI. The Basso, Beattie and Bresnahan test was executed for assessment of neuronal functional recovery and then spinal cord tissue wet/dry weight ratio was recorded. The present study demonstrated that chlorogenic acid increased SCI inhibition of BBB scores and decreased SCI-induction of spinal cord wet/dry weight ratio in rats. In addition, chlorogenic acid suppressed SCI-induced inflammatory activity, inducible nitric oxide synthase activity and cyclooxygenase-2 protein expression in the SCI rat. Furthermore, chlorogenic acid suppressed Toll like receptor (TLR)-4/myeloid differentiation primary response 88 (MyD88)/NF-kappaB/IkappaB signaling pathways and downregulated p38 mitogen activated protein kinase protein expression in SCI rats. The findings suggest that administration of chlorogenic acid alleviates SCI via anti-inflammatory activity mediated by TLR4/MyD88/NF-kappaB and p38 signaling pathways. PMID- 29115620 TI - Effect of silencing TEM8 gene on proliferation, apoptosis, migration and invasion of XWLC-05 lung cancer cells. AB - Currently, the role of tumor endothelial marker 8 (TEM8) in the occurrence, development, invasion and metastasis of lung cancer and its mechanism are poorly understood. The present study aimed to investigate the effects of TEM8 on proliferation, apoptosis, migration and invasion of XWLC-05 lung cancer cells. The expression of TEM8 in human lung cancer and adjacent tissues was detected by reverse transcription-quantitative polymerase chain reaction and western blotting. An interference vector coding a short hairpin RNA (shRNA) targeting TEM8 was designed and transfected into XWLC-05 lung cancer cells. MTT assay was used to detect cell proliferation. Flow cytometry was employed to detect cell cycle and apoptosis. Cell scratch assay was used for cell migration detection. Cell invasion ability was detected by the Transwell method. The expression of TEM8 in lung cancer tissues was significantly increased compared with adjacent tissues (P<0.05). Following the silencing of TEM8 by shRNA interference, cell proliferation was inhibited and the apoptosis rate increased. The cell cycle was arrested at G1 phase, while the migration and invasion ability of cancer cells was decreased. Silencing TEM8 may inhibit proliferation of XWLC-05 lung cancer cells, promote cell apoptosis, arrest the cell cycle at G1 phase and decrease the migration and invasive ability. Thus, TEM8 may be a potential target in therapy for lung cancer. PMID- 29115621 TI - Effects of Shield1 on the viral replication of varicella-zoster virus containing FKBP-tagged ORF4 and 48. AB - The present study aimed to explore the effects of a stabilizing ligand, Shield-1, on the replication of recombinant varicella-zoster virus (VZV) containing FK506 binding protein (FKPB) tags in essential open reading frames (ORF) 4 and 48. A specific galactokinase (galK) selection method was conducted, following the addition of galK labels to VZV ORF4 and 48, using a SW102 VZV bacterial artificial chromosome (BAC) system. Subsequently, recombinant VZV containing FKPB tags in ORF4 and 48 was constructed by counterselection and homologous recombination. Recombinant viral plasmids containing FKPB-tagged VZV ORF4 and 48 were extracted and transfected into human acute retinal pigment epithelial ARPE 19 cells. The results demonstrated that the FKPB-tagged viral protein was rapidly degraded by proteases in recombinant virus-infected ARPE-19 cells. In addition, the recombinant VZVORF4-FKBP-ORF48-FKBP virus could not grow if a synthetic ligand of FKBP, Shield1, was not added to the ARPE-19 cell culture medium; however, the degradation of FKPB-tagged viral protein was prevented if Shield1 was added to the ARPE-19 cell culture medium, thereby allowing viral replication in ARPE-19 cells. These results indicated that Shield1 may regulate replication of recombinant VZVORF4-FKBP-ORF48-FKBP following transfection into human epithelial cells. PMID- 29115622 TI - UNBS5162 inhibits the proliferation of esophageal cancer squamous cells via the PI3K/AKT signaling pathway. AB - C-X-C motif chemokine ligand (CXCL) signaling has been demonstrated to be involved in cancer invasion and migration; therefore, CXCL antagonists may serve as anticancer drugs by preventing tumor proliferation. The present study aimed to investigate whether a pan antagonist of CXCLs, UNBS5162, may inhibit esophageal cancer proliferation and to identify the underlying mechanisms. Cell proliferation and cell colony formation results, which were determined by a Cell Counting Kit-8 assay and crystal violet staining, respectively, demonstrated that UNBS5162 inhibited esophageal cancer cell proliferation. Following treatment with UNBS5162, Transwell migration and Matrigel invasion assays, and flow cytometry with Annexin V-fluorescein isothiocyanate and propidium iodide staining, were performed to investigate cell migration, invasion and apoptosis in human esophageal cancer cells. The results indicated that invasion and migration was reduced in UNBS5162-treated cells, while apoptosis was increased. Western blotting experiments confirmed that UNBS5162 downregulated the protein expression of proteins associated with the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, including the levels of phosphorylated (p)-AKT, p-mechanistic target of rapamycin kinase, ribosomal protein S6 kinase beta1 and cyclin D1. In addition, upregulated expression of programed cell death 4 was observed following UNBS5162 treatment. The present study demonstrated that UNBS5162 is a novel naphthalimide that may have potential therapeutic use for the prevention of esophageal cancer proliferation and metastasis via the PI3K/AKT signaling pathway. PMID- 29115623 TI - A novel method to isolate mesenchymal stem cells from mouse umbilical cord. AB - Mesenchymal stem cells (MSCs), derived from various tissues, are considered an ideal cell source for clinical use, among which MSCs from the umbilical cord exhibit advantages over those from adult tissues. In preclinical studies, mouse models and xenogeneic MSC treatment are most commonly used to imitate diseases and clinical practice, respectively. However, the efficiency of cross-species therapy remains controversial, making it difficult to elucidate the underlying mechanisms. Thus, allogeneic therapy may be more instructive and meaningful in clinical use. To confirm this hypothesis, the present study established a novel method for the isolation and expansion of MSCs from mouse umbilical cords (mUC MSCs) to support in vivo experiments in mice. MSCs were isolated from mUCs and mouse bone marrow (mBM), and then identified by flow cytometry. The differences in mUC-MSCs and mBM-MSCs were analyzed using a growth curve and their differentiation ability. The results showed that the harvested cells exhibited general characteristics of MSCs and possessed the capacity for long-term culture. Despite having similar morphology and surface antigens to MSCs derived from mouse bone marrow, the mUC-MSCs showed differences in purification, proliferation, stem cell markers and differentiation. In addition to detailed characterization, the present study verified the presence of Toll-like receptor 3 (TLR3), an important component of immune responses, in mUC-MSCs. It was found that the activation of TLR3 upregulated the levels of stemness-related proteins, and enhanced the secretion and mRNA levels of inflammatory cytokines in the pre-treated mUC-MSCs. Collectively, the results of the present study provide further insight into the features of newly established mUC-MSCs, providing novel evidence for the selection of murine MSCs and their responses to TLR3 priming. PMID- 29115624 TI - Decreased expression of interleukin-37 and its anti-inflammatory effect in allergic rhinitis. AB - Interleukin-37 (IL-37), a novel member of the IL-1 cytokine family has been identified as a natural suppressor of innate immunity and inflammatory responses. The present study aimed to determine the expression of IL-37 in peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis (AR), and examine the possible immunosuppressive effect of IL-37 on inflammatory mediators and CD4+ T cells in the pathogenesis of AR. The expression levels of IL-37 were determined in PBMCs from 39 patients with AR and 43 controls using reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis and flow cytometry. Cytokines in the supernatants of the PBMCs and CD4+ T cells, which were stimulated with lipopolysaccharide in the presence or absence of IL-37, were assayed using enzyme-linked immunosorbent assays and RT-qPCR analysis. The results showed that the patients with AR exhibited significantly decreased expression of IL-37, and increased expression levels of interleukin (IL)-1beta and IL-6 in PBMCs. Recombinant IL-37 (rIL-37) inhibited the production of IL-1p and IL-6, and enhanced the production of IL-27 in PBMCs from the patients with AR and the control individuals. rIL-37 also markedly decreased the expression of IL 17 by CD4+ T cells in the patients with AR and controls. These results suggested that IL-37 may be an important cytokine in the pathogenesis of AR. It may have a protective role in AR by inhibiting the production of proinflammatory cytokines and through suppressive regulation of the Th17 response. PMID- 29115626 TI - Influence of androgen on myocardial apoptosis and expression of myocardial IR and IRS-1 in chronic heart failure rat models. AB - The present study aimed to investigate the effect of androgens on chronic heart failure (CHF) in a rat model. A total of 120 Sprague Dawley male rats were randomly divided into the following groups: (A) sham operation group, (B) castrated group, (C) heart failure (HF) group, (D) castrated + HF group, and (E) castrated + HF + testosterone (T) replacement therapy group. There were 20 rats in group A, and 25 rats in the other groups. Surgical castration was performed on groups B, D and E, and T replacement therapy was administered to group E. Groups C, D and E were treated with doxorubicin hydrochloride to prepare the CHF animal model. The insulin sensitivity index (ISI) was calculated from fasting blood glucose and fasting insulin levels. Echocardiography was performed. Venous blood was collected for plasma T level test. Myocardial tissue was used for apoptosis index analysis. The expression levels of myocardial insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) were measured by reverse transcription semi quantitative polymerase chain reaction. Compared with group A, the T level and ISI decreased, whereas the expression level of IR and IRS-1 were increased in the CHF group (P<0.05). Following castration, the T level and ISI were significantly decreased, and the expression of IR and IRS-1 were increased compared with the uncastrated CHF rats (P<0.01). Following androgen administration, the ISI increased, expression of IR and IRS-1 decreased, and the myocardial apoptosis index decreased (P<0.05). Taken together, these results demonstrated that androgen supplementation could improve insulin resistance and affect the expression of IR and IRS-1 in CHF, thereby reducing myocardial apoptosis and improving cardiac function. PMID- 29115625 TI - Protective effects of silymarin on triptolide-induced acute hepatotoxicity in rats. AB - Silymarin has been used in the treatment of a number of liver diseases for a long time, but its efficacy in preventing triptolide induced acute hepatotoxicity has not been reported previously. The present study aimed to assess the protective effect of silymarin against triptolide (TP)-induced hepatotoxicity in rats. Rats were orally administrated with silymarin (50, 100 and 200 mg/kg) for 7 days and received intraperitoneal TP (2 mg/kg) on the day 8. Hepatic injuries were comprehensively evaluated in terms of serum parameters, morphological changes, oxidative damage, inflammation and apoptosis. The results demonstrated that TP induced increases in serum parameters, including alanine transaminase, aspartate aminotransferase, alkaline phosphatase, total cholesterol and gamma-glutamyl transpeptidase, which were determined using a biochemical analyzer, and histopathological alterations and hepatocyte apoptosis as determined by hematoxylin and eosin and TUNEL staining, respectively, were prevented by silymarin pretreatment in a dose-dependent manner. TP-induced depletions in the activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, glutathione S-transferase and catalase, and glutathione levels, were also significantly reversed by silymarin, as determined using specific kits. Additionally, silymarin dose-dependently exhibited inhibitory effects on malonaldehyde content in the liver. The production of proinflammatory cytokines was investigated using ELISA kits, and the results demonstrated that silymarin dose-dependently inhibited the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10 and IL-1beta in the liver. To determine the mechanism of silymarin, western blot analysis was performed to investigate the protein expression of phosphorylated (p)-p38 and p-c-Jun N-terminal kinase (JNK) of the TNF-alpha induced inflammatory response and apoptotic pathways. Silymarin significantly blocked p38 and JNK phosphorylation and activation. Additionally, the expression of the proapoptotic proteins cytochrome c, cleaved caspase-3 and Bcl-2-associated X was also reduced following treatment with silymarin, as determined by ELISA, western blotting and immunohistochemistry, respectively. In conclusion, silymarin was demonstrated to dose-dependently protect rat liver from TP-induced acute hepatotoxicity, with the high dose (200 mg/kg) achieving a superior effect. This protective effect may be associated with the improvement of antioxidant and anti-inflammatory status, as well as the prevention of hepatocyte apoptosis. Therefore, silymarin may have the potential to be applied clinically to prevent TP-induced acute hepatotoxicity. PMID- 29115627 TI - Sparstolonin B selectively suppresses toll-like receptor-2 and -4 to alleviate neuropathic pain. AB - It has been previously demonstrated that sparstolonin B (SsnB) inhibits toll-like receptor (TLR)-2 and TLR-4. The present study investigated the effect of SsnB on neuropathic pain (NP). A chronic constriction injury (CCI) model was constructed in rats and the protein expression of TLR-2 and TLR-4 was determined by western blot analysis. Rats were divided into the following three groups: Rats with sham surgery (control group); rats with CCI (model group); and rats with CCI and injection of SsnB (SsnB group). The mechanical withdrawal threshold (MWT) was measured by using Von Frey filaments. In addition, the mRNA and protein expression levels of nuclear factor-kappaB (NF-kappaB) were investigated by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively, and the concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 were determined by ELISA. Compared with control rats, the protein expression levels of TLR-2 and TLR-4 were increased in model rats (P<0.001). At 7 and 14 days after surgery, the MWTs in the model group were significantly reduced compared with the control group (P<0.001). However, the MWTs in the SsnB group were significantly increased compared with the model group (P<0.001). The results also demonstrated that the mRNA and protein expression levels of NF-kappaB, and the protein expression levels of TNF-alpha and IL-6, were increased in model group compared with the control group (P<0.001). Furthermore, these increases in expression were all reduced in the SsnB group compared with the model group. Therefore, the results indicate that SsnB may alleviate NP via suppression of TLR-2 and TLR-4, and may be a potential drug for the treatment of NP. PMID- 29115628 TI - Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation. AB - Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP). BRAFV600E mutation status was analyzed by polymerase chain reaction (PCR) followed by DNA sequencing. HOXD10 mRNA expression level was analyzed by real-time polymerase chain reaction (RT-PCR). 5-Aza-2-deoxycytidine (5-Aza) treatment was performed in 4 PTC cell lines to observe the change in HOXD10 expression. Transwell, cell cycle and apoptosis assays were then performed in an HOXD10-overexpressing PTC cell line. Furthermore, we analyzed the associations between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics in PTC. Overexpression of HOXD10 suppressed the migration of PTC cells, and promoted cell apoptosis. Q-MSP showed that methylation levels of the HOXD10 promoter were significantly higher in PTC tissues than levels in the adjacent normal thyroid tissues (P=0.02). In addition, expression of HOXD10 was decreased in the PTC cell lines and PTC tissues compared with that noted in the adjacent normal thyroid tissues (P=0.008). However, BRAFV600E mutation was detected in 42.1% of PTC patients enrolled. In addition, the BRAF mutation status was associated with the methylation and expression level of HOXD10 in PTC. We then observed that 5-Aza treatment could revert the expression of HOXD10 in PTC cell lines. Moreover, the hypermethylation of HOXD10 was associated with invasion of the primary tumor and age >45. In conclusion, the HOXD10 gene may act as a tumor suppressor in PTC. The aberrant hypermethylation and decreased expression of the HOXD10 gene were shown in PTC patients, particularly in those with BRAFV600E mutation. The epigenetic suppression of the HOXD10 gene may play a role in the tumorigenesis of PTC, and it is a prospective biomarker for the diagnosis and prognosis of PTC. PMID- 29115629 TI - Oxymatrine induces A549 human non-small lung cancer cell apoptosis via extrinsic and intrinsic pathways. AB - Oxymatrine is one of the primary natural compounds extracted from the Sophora flavescens, and has been reported to exhibit numerous pharmacological properties including cancer-preventive and anti-cancer effects, however the mechanisms as to how oxymatrine exhibits anti-proliferative activity in non-small cell lung carcinoma cells remains uncertain. The present study aimed to explore the mechanism of its anti-cancer effect, and whether it is due to apoptosis induction and anti-migration in the A549 lung cancer cell line. Detection of morphological alterations, MTT analysis, Hoechst/propidium iodide dual staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assays verified that oxymatrine induced A549 cell apoptosis. The caspase pan-inhibitor z-VAD-FMK resulted in disappearance of oxymatrine-elicited nuclei fragmentation via Hoechst 33342 staining. JC-1 staining demonstrated a decrease in mitochondrial membrane potential which further verified the induction of apoptosis by oxymatrine. The caspase-3, 8 and 9 activities of oxymatrine-treated cells were activated, which suggested that extrinsic and intrinsic apoptotic pathways were involved in the anti-proliferative effects of oxymatrine in A549 cells. Furthermore, the wound healing assay verified the anti-migratory effects of oxymatrine in A549 cells. PMID- 29115630 TI - TIPE2 governs macrophage polarization via negative regulation of mTORC1. AB - Macrophages can be polarized into the inflammatory M1 lineage or the immunomodulatory M2 lineage, depending on the differential tissue microenvironment signaling, specific pathogens or cytokine stimulation. Tumor necrosis factor alpha-induced protein 8-like protein 2 (TIPE2) has been demonstrated to negatively regulate inflammation by inhibiting the Toll-like receptor (TLR) pathway. The present study utilized murine bone marrow derived macrophages (BMDMs) as the model of undifferentiated (M0) macrophages to study the roles of TIPE2 in the differential polarization status of BMDMs. It was observed that the expression levels of TIPE2 were diminished in M1 macrophages treated with lipopolysaccharide/interferon gamma, and elevated in M2 macrophages treated with interleukin (IL)-4. BMDMs with TIPE2 overexpression exhibited defective M1 polarization and enhanced responses to IL-4 stimulation. TIPE2 impeded M1 polarization by interfering with mitogen-activated protein kinase kinase kinase 7-inhibitor of nuclear factor-kappaB kinase subunit beta and B cell receptor-associated protein-serine/threonine-protein kinase mTOR complex 1 (mTORC1) activation. TIPE2 overexpression accelerated IL-4 induced M2 polarization by dampening mTORC1 activation via the accelerated process of arginine to urea. Overall, these results define a key role for TIPE2 in macrophage polarization by impeding mTORC1 response. PMID- 29115631 TI - Preconditioning with carbon monoxide inhalation promotes retinal ganglion cell survival against optic nerve crush via inhibition of the apoptotic pathway. AB - Optic neurodegeneration, in addition to central nervous trauma, initiates impairments to neurons resulting in retinal ganglion cell (RGC) damage. Carbon monoxide (CO) has been observed to elicit neuroprotection in various experimental models. The present study investigated the potential retinal neuroprotection of preconditioning with CO inhalation in a rat model of optic nerve crush (ONC). Adult male Sprague-Dawley rats were preconditioned with inhaled CO (250 ppm) or air for 1 h prior to ONC. Animals were euthanized at 1 or 2 weeks following surgery. RGC densities were quantified by hematoxylin and eosin (H&E) staining and FluoroGold labeling. Visual function was measured via flash visual evoked potentials (FVEP). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and caspase-9 and caspase-3 activity in the retinas, were assessed at 2 weeks post-ONC. The RGC density of CO + crush rats was significantly increased compared with that of the corresponding crush-only rats at 2 weeks (survival rate, 66.2 vs. 48.2% as demonstrated by H&E staining, P<0.01; and 67.6 vs. 37.6% as demonstrated by FluoroGold labeling, P<0.05). FVEP measures indicated a significantly better-preserved latency and amplitude of the P1 wave in the CO + crush rats compared with the crush-only rats. The TUNEL assays demonstrated fewer apoptotic cells in the CO + crush group compared with the crush-only group, accompanied by the suppression of caspase-9 and caspase-3 activity. The results of the present study suggested that inhaled CO preconditioning may be neuroprotective against ONC insult via inhibition of neuronal apoptosis. PMID- 29115632 TI - Synergistic effects of the combination of 5-Aza-CdR and suberoylanilide hydroxamic acid on the anticancer property of pancreatic cancer. AB - Despite increasing advances in the diagnosis and treatment for pancreatic cancer, the mortality rate remains high world-wide. There is an urgent need for new therapies to improve survival and quality of life for pancreatic cancer patient. Epigenetic therapeutic agents such as 5-Aza-CdR and suberoylanilide hydroxamic acid (SAHA) have shown therapeutic effects for human cancers. We evaluated the efficacy of 5-Aza-CdR or SAHA and their combination as potential therapies for pancreatic cancer in vitro. Treatment with 5-Aza-CdR or SAHA inhibited pancreatic cancer cell proliferation, migration and induced cell arrest. However, 5-Aza-CdR alone can not induce cell apoptosis. Combination of the two agents enhanced the proliferation and migration inhibition, and induced more cells to G2 arrest and increased the cell apoptosis proportion. Furthermore, combination treatment with SAHA and 5-Aza-CdR significantly increased expression of TP53 and P16. The possible mechanism might be that the two agents inhibited the PI3K/AKT/PTEN signaling pathway. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of pancreatic cancer. PMID- 29115633 TI - XIAP underlies apoptosis resistance of renal cell carcinoma cells. AB - X-linked inhibitor of apoptosis (XIAP), a key member of the inhibitors of apoptosis protein family, can inhibit apoptosis by directly binding to the initiator caspase-9, -3 and -7, thereby promoting tumor cell survival during tumor progression. In the present study, XIAP basal expression levels were investigated and its contribution to the resistance to apoptosis was evaluated, in the RCC cell lines exposed to apoptosis-inducing drugs. This was investigated by histological methods and western blot analysis. Using RNA interference, elimination of XIAP in Caki-1 cells was also studied, and its contribution to the sensitivity to apoptosis induced through the intrinsic pathway was observed. Differences in XIAP expression were detected between ClearCa-2 and ClearCa-6 cell lines. ClearCa-6 cells with lower expression of XIAP were more sensitive to apoptosis-inducing drugs, compared with ClearCa-2 cells. However, the levels of XIAP expression in both cell lines were stable during apoptosis. Furthermore, a Caki-1 cell line with no XIAP expression was used, and was demonstrated to be more sensitive to the apoptosis induced by the mitochondrial pathway. These results suggested that downregulation of XIAP expression could enhance the sensitivity of RCC cells to apoptosis, and the basal expression of XIAP during apoptosis is stable. This may provide novel insight for targeted gene therapy against XIAP, in the clinic. PMID- 29115634 TI - Galangin increases ERK1/2 phosphorylation to decrease ADAM9 expression and prevents invasion in A172 glioma cells. AB - Galangin (3,5,7-trihydroxyflavone), is a natural flavonoid present in plants. Galangin is reported to exhibit anti-cancer properties against various cancer types. The aim of the present study was to display the effects of galangin on glioma and its mechanism of action in A172 human glioma cancer cells. The results clearly indicated that treatment of galangin inhibited A172 cell migration and invasion under non-toxic doses. A human proteinase array assay was conducted to elucidate the potential effects of galangin, and the obtained results demonstrated that treatment of galangin inhibited ADAM9 protein expression and mRNA expression, that are known to contribute to cancer progression. Sustained extracellular signal-regulated kinase (Erk)1/2 activation was also monitored, which contributed to ADAM9 protein expression and mRNA inhibition as investigated using western blotting analysis and reverse transcription-quantitative polymerase chain reaction experiment. Erk1/2 inhibition by inhibitor or small interfering (si)Erk transfection markedly terminated galangin-inhibited A172 migration and invasion via an Erk1/2 activation mechanism. Collective results suggested that galangin may act as an effective chemotherapeutic agent for glioma cancer depending on its ability to bring about ADAM9 and Erk1/2 activation. PMID- 29115635 TI - A potential role for hepcidin in obesity-driven colorectal tumourigenesis. AB - The obesity epidemic is associated with increases in the incidence of several types of cancer, including colorectal cancer, and is associated with poor outcomes for patients. Adipose tissue is considered biologically active and represents a plausible link between cancer and obesity due to the many factors that it secretes. In the present study, human adipose tissue was cultured in vitro and predifferentiated adipocyte secretome [preadipocyte (PAS)] and differentiated adipocyte secretome (DAS) were collected. Quantification of interleukin-6 (IL-6), leptin and hepcidin in the DAS medium was compared to the PAS medium. Fold change levels of hepcidin, leptin and IL-6 in DAS (2.88+/-0.28, 12.34+/-0.95 and 31.29+/-1.89 fold increases) were significantly higher compared to these in PAS (p=0.05). The SW480 colorectal cancer cells were co-cultured with DAS in the presence or absence of leptin, IL-6 or hepcidin inhibitors and cellular viability and proliferation assays were performed. The culture of SW480 with DAS increased the cell proliferation and viability by 30 and 15% (p=0.02 and p=0.03) respectively, which was reversed in the presence of inhibitors. Challenging the SW480 cells with IL-6 or hepcidin significantly elevated colonocyte-secreted leptin (p=0.05). Challenging the SW480 cells with leptin or hepcidin resulted in elevated levels of colonocyte-secreted IL-6 (p=0.05). Similarly, challenging cells with either IL-6 or leptin markedly elevated the level of secreted hepcidin (p=0.05) and this was associated with an induction in colonocyte iron levels in both cases. Collectively, these data revealed that adipocyte-secreted factors can ultimately modulate colonocyte iron levels and phenotype. PMID- 29115636 TI - FSTL1 suppresses tumor cell proliferation, invasion and survival in non-small cell lung cancer. AB - Follistatin like-1 (FSTL1) is a secreted glycoprotein involved in a series of physiological and pathological processes. However, its contribution to the development of cancer, especially the pathogenesis of NSCLC, remains to be elucidated. We explored the expression, function, and molecular mechanism of FSTL1 in NSCLC. In this study, we detected the expression of FSTL1 in a panel of NSCLC cell lines and lung normal epithelial cell line by qRT-PCR and western blot analysis and found that FSTL1 was downregulated in NSCLC cells compared with normal control. Knockdown of FSTL1 with different shRNA sequences result in increased cell proliferation and cell migration, invasion and reduced cell apoptosis in A549 cell line with high FSTL1 endogenous level. FSTL1 overexpression in H446 cell line with low FSTL1 endogenous level suppressed cell proliferation and migration, invasion and increased cell apoptosis. Knockdown and overexpression of FSTL1 caused altered cell cycle. Reduced cell apoptosis was revealed in FSTL1 knockdown cells accompanied by increased FAS expression and decreased FASL, cleaved caspase-3 and -7 expression. By contrast, overexpression of FSTL1 caused reduced FAS level and increased activated caspase-3 and -7 expression, which may lead to increased cell apoptosis. Moreover, the changed migration and invasion ability in FSTL1 sufficient or deficient cells may be caused by alterations in MMP2, MMP3 and MMP9 expression. Altogether, our results revealed the critical tumor-suppression function of FSTL1 in NSCLC progression, suggesting that FSTL1 might be an important factor in NSCLC progression. PMID- 29115637 TI - Effect of Linguizhugan decoction on neuroinflammation and expression disorder of the amyloid beta-related transporters RAGE and LRP-1 in a rat model of Alzheimer's disease. AB - Linguizhugan decoction (LGZG), a notable prescription in Traditional Chinese Medicine, is a classical formula for the treatment of Alzheimer's disease (AD), inflammatory injury and fluid retention. The present study aimed to investigate the neuroprotective effect of LGZG on an amyloid beta (Abeta)-induced AD rat model. Sprague-Dawley rats were administered with Abeta1-42 to induce AD and inflammatory responses, and subsequently with LGZG (4.8, 2.4 or 1.2 g/kg), donepezil (2 mg/kg) or distilled water for 30 consecutive days. Learning and memory behaviors were evaluated via Morris water maze test. The neuronal impairment of AD rats was observed via hematoxylin-eosin staining. The levels of pro-inflammatory cytokines, and Abeta in the brain tissue were detected with ELISA kits. Protein expression levels of mitogen-activated protein kinase and nuclear factor-kappaB signalling were measured by western blot analysis. The expression of lipoprotein receptor-related protein-1 (LRP-1) and receptor for advanced glycation endproducts (RAGE) in the brain were detected by western blot analysis, reverse transcription-quantitative polymerase chain reaction and immunohistochemistry analysis. LGZG was demonstrated to significantly improve learning and memory ability, and ameliorate neuroinflammation in AD rats. LGZG increased the levels of LRP-1 and decreased the levels of RAGE. Furthermore, the present results demonstrated that LGZG treatment significantly inhibited MAPK and NF-kappaB signalling, and reduced the production of pro-inflammatory cytokines and Abeta accumulation in AD rats. LGZG exhibited a potential protective effect on Abeta1-42-induced AD by regulating Abeta transportation, and inhibiting RAGE/MAPK and NF-kappaB signalling. These results suggest that LGZG may be considered for the treatment of AD. PMID- 29115638 TI - The shortening telomere length of T lymphocytes maybe associated with hyper function in servere aplastic anemia. AB - Severe aplastic anemia (SAA) is a primary disorder of severe bone marrow failure characterizing with extreme pancytopenia and a profound diminution of bone marrow progenitor cells, which is associated with T cell hyper-function. Abnormal telomere shortening of bone marrow mononuclear cell has been reported in AA, which may lead to genomic instability, and result in cell senescence or apoptosis. Notably, certain studies identfieid that lymphocytes of shortening telomere length have undergone apoptosis escape in autoimmune diseases. In order to investigate the association between telomere lengths and function of T lymphocytes in SAA, the relative telomere lengths (RTLs) of different subtypes of T lymphocytes were investigated by flow-fluorescent in situ hybridization in 30 patients with SAA and 25 healthy controls. Then the levels of expression of cluster of differentiation 28 (CD28), CD158 and CD70 were measured, which represent the function of T lymphocytes. The apoptosis rate and the cell cycle progression of CD8+T lymphocytes, and the level of secretion interferon-gamma and tumor necrosis factor-alpha were also measured. Finally, the correlation between telomere length and these functional events of CD8+T lymphocytes was analyzed in patients with SAA. The results showed that RTLs of CD8+T lymphocytes in SAA were significantly shorter compared with those in controls. Furthermore, in patients with SAA, CD8+T lymphocytes are associated with T cell hyper-function, which is related to the RTL. Thus, the shorter RTLs of CD8+T lymphocytes in SAA may be associated with hyper-function of these cells, which contribute to the pathogenesis of SAA. PMID- 29115639 TI - Oligodendrocyte precursor cell transplantation promotes functional recovery following contusive spinal cord injury in rats and is associated with altered microRNA expression. AB - It has been reported that oligodendrocyte precursor cells (OPCs) may be used to treat contusive spinal cord injury (SCC), and may alter microRNA (miRNA/miR) expression following SCC in rats. However, the association between miRNA expression and the treatment of rats with SCC with OPC transplantation remain unclear. The present study transplanted OPCs into the spinal cord of rats with SCC and subsequently used the Basso, Beattie and Bresnahan (BBB) score to assess the functional recovery and pain scores. An miRNA assay was performed to detect differentially expressed miRNAs in the spinal cord of SCC rats transplanted with OPCs, compared with SCC rats transplanted with medium. Quantitative polymerase chain reaction was used to verify significantly altered miRNA expression levels. The results demonstrated that OPC transplantation was able to improve motor recovery and relieve mechanical allodynia in rats with SCC. In addition, through a miRNA assay, 45 differentially expressed miRNAs (40 upregulated miRNAs and 5 downregulated miRNAs) were detected in the spinal cord of rats in the OPC group compared with in the Medium group. Differentially expressed miRNAs were identified according to the following criteria: Fold change >2 and P<0.05. Furthermore, quantitative polymerase chain reaction was used to verify the most highly upregulated (miR-375-3p and miR-1-3p) and downregulated (miR-363-3p, miR 449a-5p and miR-3074) spinal cord miRNAs that were identified in the miRNA assay. In addition, a bioinformatics analysis of these miRNAs indicated that miR-375 and miR-1 may act primarily to inhibit cell proliferation and apoptosis via transcriptional and translational regulation, whereas miR-363, miR-449a and miR 3074 may act primarily to inhibit cell proliferation and neuronal differentiation through transcriptional regulation. These results suggested that OPC transplantation may promote functional recovery of rats with SCC, which may be associated with the expression of various miRNAs in the spinal cord, including miR-375-3p, miR-1-3p, miR-363-3p, miR-449a-5p and miR-3074. PMID- 29115640 TI - Off-target effect of imatinib and nilotinib on human vitamin D3 metabolism. AB - Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated in vitro, the influence of IMA and NIL on VD3 metabolism i) in HaCaT cells and ii) in cultured outer root sheath keratinocytes (ORS-KC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL. Concomitantly, specific inhibitors were applied to analyze the inhibition of the VD3 processing cytochrome P450 isoenzyme family by TKIs. In vitro, IMA and NIL significantly impaired the production of calcitriol in HaCaT and cultured ORS-KC cells from hair follicles of IMA treated children. For NIL, this inhibitory effect demonstrated a 4-fold increase. In HaCaT and ORS-KC, application of specific CYP450 inhibitors revealed that CYP27B1 was impaired by IMA and NIL leading to an intracellular accumulation of calcidiol. However, during TKI treatment, KC of IMA treated children revealed no differences in calcidiol and calcitriol levels. In conclusion, IMA and NIL interfere with the vitamin D3 cascade due to their metabolism by CYP27B1. PMID- 29115641 TI - Traumatic stress affects alcohol-drinking behavior through cocaine- and amphetamine-regulated transcript 55-102 in the paraventricular nucleus in rats. AB - Cumulative evidence has suggested an association between stress and alcohol self administration; however, less is known about the role of traumatic stress in alcohol drinking behavior. It has been reported that cocaine- and amphetamine regulated transcript (CART) 55-102 may be involved in mediating stress responses and regulating reward and reinforcement. The aim of the present study was to evaluate the role of CART 55-102 in alcohol drinking behavior of rats in the presence or absence of traumatic stress. Alcohol drinking behavior was examined using the two-bottle choice drinking paradigm (one bottle contained 10% alcohol and the other contained filtered water), which was initiated 1, 3 and 7 days post trauma (T1, T3 and T7), for 14 days in rats; the control group was initiated from T0. The results indicated that exposure to trauma significantly increased alcohol consumption and preference, particularly drinking from T3. Immunohistochemistry revealed that the lowest level of CART 55-102 immunoreactivity within the paraventricular nucleus (PVN) was exhibited in the T3 group. Additionally, an intra-PVN injection of CART 55-102 attenuated alcohol-drinking behavior in a dose dependent manner, in the T3 group. Furthermore, the significant increase in circulating adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) concentrations in the T3 group were inhibited by CART 55-102 administration to the PVN, in particular CORT levels were significantly decreased. Positive correlations between alcohol preference and ACTH and CORT levels were also observed. These results indicated that CART 55-102 in the PVN serves an inhibitory role in traumatic stress-induced alcohol drinking behavior, possibly through disturbing hypothalamus-pituitary-adrenal axis hyperactivity. PMID- 29115642 TI - Combined treatment with extracorporeal shock-wave therapy and bone marrow mesenchymal stem cell transplantation improves bone repair in a rabbit model of bone nonunion. AB - The aim of the present study was to analyze whether extracorporeal shock-wave therapy (ESWT) combined with bone marrow mesenchymal stem cell (BMMSC) transplantation improves bone repair in a rabbit bone nonunion model. ESWT combined with BMMSC effectively enhanced mechanical strength, fracture stiffness and histological scores, and increased alkaline phosphatase activity, and osteopontin, runt related transcription factor 2 and collagen type I alpha1 chain protein expression levels in a rabbit bone nonunion model. In addition, ESWT combined with BMMSC effectively enhanced insulin-like growth factor 1 and vascular endothelial growth factor contents, promoted transforming growth factor beta (TGF-beta) contents, and induced the growth factors, bone morphogenetic protein (BMP)-2, BMP-4 and purinergic receptor P2X7 (P2X7) protein expression in the rabbit bone nonunion model. Thus, the present study demonstrated that ESWT combined with BMMSC transplantation improves bone repair in a rabbit bone nonunion model via the BMPs and P2X7 signaling pathways. PMID- 29115643 TI - Differential expression of cyclin D1, Ki-67, pRb, and p53 in psoriatic skin lesions and normal skin. AB - Psoriasis is a hyperproliferative inflammatory skin disease; therefore, it is highly likely that psoriatic skin lesions may transform into malignancies. However, malignant transformation is not common. We performed immunohistochemical studies using anti-cyclin D1, anti-cyclin E, anti-pRb, anti-p53, anti-p16INK4a, and anti-Ki-67 antibodies in normal skin, psoriatic epidermal tissue, and squamous cell carcinoma (SCC) tissue. Furthermore, western blot analysis and immunohistochemical staining were performed to ascertain differences in cyclin D1, cyclin E, pRb, and Ki-67 expression before and after treatment for psoriasis. Cyclin D1 expression was higher in chronic psoriatic lesions than that in normal epidermis. Psoriasis lesions showed a strong intensity of positive nuclear staining for cyclin D1 among several normally stained nuclei in the basal layer. Cyclin E expression in psoriasis was stronger in the granular and spinous layer than in the normal epidermis. Expression levels of pRb and p53 were found to be higher in the psoriasis group compared with the normal epidermis. Total basal layer cell counts for p53WT expression were found to be significantly higher in the psoriasis group compared with the normal group. However, p16 expression was very weak in the normal and psoriasis groups compared with that in the SCC group. Ki-67 immunoreactivity was significantly higher in psoriasis compared with normal epidermis and was similar with that in the SCC group. According to immunohistochemistry and immunoblot analysis, the expression levels of cyclin D1, cyclin E, pRb, and Ki-67 in psoriasis lesions decreased after treatment and were similar with those in the normal group. Thus, increased expression of cyclin D1 and cyclin E may be involved in cell cycle progression in psoriatic epidermis, and pRb and p53 may play important roles in the prevention of malignant transformation under the hyperproliferative state in psoriasis. PMID- 29115645 TI - Combined 18F-FDG PET/CT imaging and a gastric orthotopic xenograft model in nude mice are used to evaluate the efficacy of glycolysis-targeted therapy. AB - As discovered by Warburg 80 years ago most malignant cells rely more on glycolysis than normal cells. The high rate of glycolysis provides faster ATP production and greater lactic acid for tumor proliferation and invasion, thus indicating a potential target in anticancer therapy. Our previous studies demonstrated that 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) inhibited tumor cell proliferation in vitro. However, the underlying mechanisms still warrant further investigation. In the present study, we employed the human SGC 7901 gastric cancer cell line, built an orthotopic xenograft model in nude mice, examined the treatment response by 18F-FDG PET/CT and investigated the mechanisms of 3-BrPA and SCT in vivo. Our results demonstrated that glycolysis and tumor growth were inhibited by intraperitoneal injection of 3-BrPA and SCT, which were imaged using an 18F-FDG PET/CT scanner. In addition, apoptosis induced by 3-BrPA and SCT was initiated by the upregulation of Bax and downregulation of Bcl-2, which promote cytochrome c release and subsequently activate caspase-9 and -3, and ultimately execute mitochondria-mediated apoptosis. Furthermore, apoptosis was also modulated by the generation of ROS and inhibition of survivin. Accordingly, 3-BrPA and SCT can inhibit glycolysis and induce gastric cancer apoptosis through the mitochondrial caspase-dependent pathway. PMID- 29115646 TI - A new perspective on life-saving procedures in a battlefield setting: Emergency cricothyroidotomy, needle thoracostomy, and chest tube thoracostomy with night vision goggles. AB - BACKGROUND: In the patients with multiple and serious trauma, early applications of life-saving procedures are related to improved survival. We tried to experimentally determine the feasibility of life-saving interventions that are performed with the aid of night vision goggles (NVG) in nighttime combat scenario. METHODS: Chest tube thoracostomy (CTT), emergency cricothyroidotomy (EC), and needle thoracostomy (NT) interventions were performed by 10 combatant medical staff. The success and duration of interventions were explored in the study. Procedures were performed on the formerly prepared manikins/models in a bright room and in a dark room with the aid of NVG. Operators graded the ease of interventions. RESULTS: All interventions were found successful. Operators stated that both CTT and EC interventions were more difficult in dark than in daytime (p<0.05). No significant difference was observed in the difficulty in the NT interventions. No significant difference was observed in terms of completion times of interventions between in daytime and in dark scenario. CONCLUSION: The operators who use NVGs have to be aware of that they can perform their tactic and medical activities without taking off the NVGs and without the requirement of an extra light source. PMID- 29115644 TI - Identification of differentially expressed microRNAs in acute Kawasaki disease. AB - The present study used microarray analysis to screen the plasma expression of microRNAs (miRNAs) in patients with acute Kawasaki disease (KD) and aimed to explore the pathogenesis of KD. Plasma was collected from children with acute KD (n=6) and from healthy control children (n=6). Total RNA was extracted and differential miRNA expression between the two groups was determined. Differentially expressed miRNAs were validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR) in an independent cohort (n=8). Target genes of the differentially expressed miRNAs were predicted and analyzed for gene ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes pathways. miRNA microarray analysis revealed that seven miRNAs (miRs) were significantly upregulated (hsa-let-7b-5p, hsa-miR-223-3p, hsa-miR-4485, hsa-miR 4644, hsa-miR-4800-5p, hsa-miR-6510-5p and hsa-miR-765) and three were significantly downregulated (hsa-miR-33b-3p, hsa-miR-4443 and hsa-miR-4515) in acute KD compared with the healthy controls. hsa-miR-223-3p expression levels detected by RT-qPCR were consistent with the microarray results. A total of 62 target genes of hsa-miR-223-3p were predicted. In total, 10 differentially expressed miRNAs were identified in acute KD, of which hsa-miR-223-3p was verified by RT-qPCR. PMID- 29115647 TI - Clinical infection in burn patients and its consequences. AB - BACKGROUND: Burn injuries facilitate invasive infections and sepsis not only by destroying the continuity of the protective skin barrier but also through systemic effects. The burn wound, blood, and urine samples are frequently cultured to determine the pathogen agent. The aim of this study was to analyze pathogen growth in patients' cultures confirmed as "infection positive" by the hospital Infection Control Committee and to assess the clinical implications of these growths. METHODS: Hospitalized patients included in the study were those with a total burned body surface area of >10% and "presence of infection" confirmed by the Infection Control Committee. The patients were evaluated with respect to age, gender, burn etiology, the total body surface area burned (TBSA), the presence of inhalation injury, sepsis, positive cultures, the microorganisms cultured in wound-blood-urine samples, and septic focus. RESULTS: Of the total 36 (10.3%) "infection-positive" patients, 26 (72.2%) were male; the mean age of patients was 44+/-21 years. The mean burned TBSA of the whole group was 45.58%+/ 23.1%. Acinetobacter baumannii was the most isolated organism in the wound cultures. In patients with confirmed infection, there was a correlation between the pathogen isolated in urine cultures and mortality rates (p=0.023). Sepsis was diagnosed in 23 (63.9%) patients, of whom 21 had inhalation injuries. There was a significant correlation between inhalation injury and sepsis (p=0.015), and both the presence of sepsis or inhalation injury increased mortality (p=0.027 and p=0.009, respectively). CONCLUSION: According to the study data, the TBSA burned demonstrated a greater significance for mortality, although the presence of sepsis and/or urinary tract infection should also be noted as a cause of mortality in burned patients. PMID- 29115648 TI - Correlation between ischemia-modified albumin and Ranson score in acute pancreatitis. AB - BACKGROUND: Although Ranson score is the most commonly used prognostic model in the severity of acute pancreatitis (AP), ischemia-modified albumin (IMA) has been reported as a novel biomarker of various ischemia-based diseases in recent years. The aim of the present study is to investigate the correlation between Ranson score and IMA in patients with AP. METHODS: Forty-three patients with AP were included in the study. All patients were classified as mild and severe AP. Plasma IMA level was measured after diagnosis and before treatment. The correlation between IMA level and amylase level, Ranson score, and disease severity was evaluated. RESULTS: Twenty-nine (67.4%) patients were diagnosed as mild AP; the remaining 14 (32.6%) patients had moderately severe or severe form of disease, and were classified as severe AP. There was no significant difference in the IMA levels between the patient groups (p=0.737). No correlation between IMA levels and amylase levels (p=0.470), Ranson score (p=0.664), and disease severity (p=0.741) was found. CONCLUSION: According to the results from the study, IMA does not seem as a useful marker in earlier prediction of disease severity in AP. Despite important disadvantages, Ranson score still indicates the disease severity more accurately. PMID- 29115649 TI - Role of inflammatory markers in decreasing negative appendectomy rate: A study based on computed tomography findings. AB - BACKGROUND: This study aimed to investigate the role of inflammatory markers in decreasing negative appendectomy rate (NAR) based on their relation with findings of acute appendicitis (AA) on computed tomography (CT). METHODS: Ninety-two patients who underwent CT examination with suspected AA were included. We investigated the relation between CT findings of AA and laboratory inflammatory markers and also performed receiver operating characteristic (ROC) analysis to calculate cut-off values of inflammatory markers and CT findings of AA. Appendectomy cases were re-evaluated considering cut-off values to make the operation decision and NAR was recalculated. Chi-squared test was used to compare the actual and recalculated NAR. RESULTS: Cut-off values of appendiceal diameter, appendiceal wall thickness, and caecal wall thickness were 7.9, 2, and 2.3 mm, respectively, for the diagnosis of AA. Cut-off values of WBC , NLR, and CRP on ROC analysis were 7.47, 4.06 and 13, respectively, for the diagnosis of AA. When the actual and recalculated NAR (21.9% versus 9.1%) were compared, the difference was found to be almost significant (p=0.058). CONCLUSION: Inflammatory markers are not sufficiently powerful on their own to accurately diagnose AA. However, particularly in equivocal cases, proposed cut-off values may be helpful for accurate diagnosis and a lower NAR can be achieved. PMID- 29115650 TI - Spontaneous rectus sheath hematoma in cardiac in patients: a single-center experience. AB - BACKGROUND: This study presents the relationship between mortality and spontaneous rectus sheath hematoma (RSH) in inpatients receiving anticoagulant and antiaggregant treatment for cardiac pathology at cardiology and cardiovascular surgery clinics. METHODS: Within the scope of our study, the cases of 27 patients who were diagnosed with spontaneous RSH between January 2010 and December 2015 at Kartal Kosuyolu High Speciality Training and Research Hospital were retrospectively evaluated. RESULTS: Of the 27 patients, 19 (70.4%) were female and 8 (29.6%) were male. The mean age was 63+/-12 (32-84) years. All the patients had at least one comorbidity that necessitated follow-up. Fourteen patients received only anticoagulant treatment, 8 received only antiaggregant treatment, and the remaining 5 received both types of treatment. Physical examination of all patients revealed painful palpable masses in the lower quadrants of the abdomen. According to the results of computed tomography (CT) scans, which showed the size and localization of the masses, 7 of the cases were classified as Type I, 6 as Type II, and 14 as Type III. Although 23 of the cases received medical treatment, the remaining 4 patients received surgical treatment. Eight (29.6%) patients suffered mortality. CONCLUSION: RSH is rare, but its prevalence is increased among patients receiving anticoagulant and antiaggregant treatment for cardiac reasons. The mortality rate markedly increased among patients who contracted RSH during hospitalization for cardiac reasons, had comorbidities, and experienced additional complications due to extended hospitalization. PMID- 29115651 TI - Computed tomography findings of primary epiploic appendagitis as an easily misdiagnosed entity: Case series and review of literature. AB - BACKGROUND: Primer epiploic appendagitis (PEA) is an uncommon condition. METHODS: We retrospectively reviewed the clinical records and computed tomography (CT) findings of 45 patients with PEA. RESULTS: On the basis of physical examination and pain localization, presumptive clinical diagnosis was acute appendicitis (n=13), acute cholecystitis (n=2), acute diverticulitis (n=19), renal colic (n=7) and ovarian pathology (n=4). CONCLUSION: Although it has no characteristic clinical and laboratory features, CT is the best modality for accurate diagnosis of PEA. PMID- 29115652 TI - Early laparoscopic cholecystectomy following acute biliary pancreatitis expedites recovery. AB - BACKGROUND: In this retrospective study, we aimed to assess the reliability of early cholecystectomy, risk of recurrent biliary pancreatitis, and their effects on hospital length of stay and morbidity by comparing the results of early and late laparoscopic cholecystectomy in patients with acute biliary pancreatitis. METHODS: A total of 131 patients, who were diagnosed with acute biliary pancreatitis at Okmeydani Education and Research Hospital in January 2009 December 2012, were included in the study. Demographic specifications of patients, duration of their complaints, biochemistry and hemogram values at first arrival, Ranson criteria, number of attacks, screenings, operation type and period, number of days between the first attack and operation, hospital length of stay, and complications were recorded. Patients who underwent cholecystectomy within the first 2 weeks were considered early (group 1) and those who under the operation after 2 weeks were considered late (group 2). RESULTS: There were 47 patients in group 1 and 84 patients in group 2. Open surgery was not performed on any patient, and there was no choledoch injury and mortality. The average hospital length of stay was 7.6+/-3.0 days in group 1 and 10.7+/-8.3 days in group 2, with a statistically significant difference between the groups (p=0.006). Two or more number of attacks occurred in 15 patients in group 2 (18%), with a statistically significant difference between the groups (p=0.000). CONCLUSION: Laparoscopic cholecystectomy is safe as it does not increase operation time and morbidity in biliary pancreatitis with a Ranson score of <=3 or cause difficulty in dissection. Late cholecystectomy causes recurrent attacks and increases the hospital length of stay and treatment costs. Using randomized controlled studies, the effectiveness and reliability of early cholecystectomy in mild and moderate biliary pancreatitis can be verified. PMID- 29115653 TI - Bridge treatment for early cholecystectomy in geriatric patients with acute cholecystitis: Percutaneous cholecystostomy. AB - BACKGROUND: The main cause of acute cholecystitis (AC) is gallstones, and the incidence of gallstones in elderly patients is high. METHODS: In this study, we aimed to investigate the efficacy of percutaneous cholecystostomy (PC) before early cholecystectomy in geriatric patients with AC. This retrospective study included 85 patients undergoing laparoscopic or conventional cholecystectomy during early stage of calculous AC. RESULTS: All patients were over 65 years old and were divided into two groups: Group I, PC plus early cholecystectomy and Group II, only cholecystectomy without PC. Data on age, sex, status of PC before surgery, postoperative complications, postoperative mortality, surgical method, and postoperative hospitalization duration were recorded in our study. The average age in the groups I and II was 75.7+/-7.5 and 73.7+/-7.2 years, respectively, indicating insignificant difference (p=0.223). Although postoperative complication rate was two fold in the non-PC group, the PC plus cholecystectomy group has a few complications (p=0.032). Postoperative mortality was evidently lower in patients who first underwent PC and followed by cholecystectomy (p=0.017). The average hospitalization duration in groups I and II were 5.6+/-2.4 days and 11.2+/-7.7 days, respectively (p<0.001). CONCLUSION: Urgent laparoscopic cholecystectomy is still the best surgical treatment modality for calculous AC. Further, our study results showed that in geriatric patients, bridge treatment, such as PC, can be useful for reducing postoperative complication rates. PMID- 29115654 TI - Management of capitellar fractures with open reduction and internal fixation using Herbert screws. AB - BACKGROUND: Capitellar fractures are rare elbow injuries and can cause severe limitation of function if not properly managed. Numerous treatments have evolved, from closed reduction and cast immobilization to open reduction and internal fixation (ORIF), so as to achieve a stable joint that allows early mobilization. We determined the functional outcomes of treating these fractures with ORIF using Herbert screws via an extensile lateral approach. METHODS: Fifteen patients with capitellar fractures were included in this retrospective study. A well taken lateral radiograph was important and stressed upon in all patients. All fractures were open reduced and internally fixed using Herbert screws via an extensile lateral approach over a period of 5 years. Clinical, radiographic, and Mayo Elbow Performance Index were evaluated at a mean followup of 3.6 years (range, 1.5-6 years). RESULTS: Nine type I and six type IV capitellar fractures were identified using Bryan and Morrey classification system. The average time to bone union was 12 weeks (range 8-16 weeks) with no case of nonunion. The mean range of flexion was 130 degrees (range 125 degrees -135 degrees ). The average extensor lag was 10 degrees (range 0 degrees -30 degrees ), with a functional range of motion of elbow achieved in all patients. On the final follow-up, one case of osteoarthritis was seen, but no evidence of avascular necrosis or heterotrophic ossification was seen. Two patients needed screw removal. The outcome was excellent in 10 patients and good in five patients. CONCLUSION: Herbert screw fixation provides stable fixation in capitellar fractures and good to excellent outcomes with excellent elbow motion, can be achieved following internal fixation of these complex fractures using the extended lateral exposure. PMID- 29115655 TI - Delayed bipedicled flap: An alternative and new method for reconstruction of distal leg defect after gunshot trauma: A case report and review of the literature. AB - Shotgun injury is a trauma that leads to soft tissue defects, in which important structures such as the tendon and bone are exposed with fractures in the distal lower extremity. Because this region has insufficient soft tissue support, local flap options are highly limited. Although the most suitable options are free or perforator flaps for contemporarily reconstructing that region; owing to such highenergy traumas, the available local flaps are becoming more suitable. Besides having various advantages, bipedicled flaps are commonly used for reconstructing small- and medium-sized lower extremity defects. This study aimed to discuss the use of a delayed bipedicled flap, which has not been previously described in the literature. PMID- 29115656 TI - Endoscopic drainage and cystoduodedonstomy in a child with pancreatic pseudocyst. AB - An 11-year-old morbidly obese boy was diagnosed with pancreatic pseudocyst. Following fine needle aspiration, the cyst recurred in 1-month follow-up. Therefore, endoscopic drainage and cystoduodenostomy was performed following endosonography. Control ultrasonography (USG) revealed a completely shrunken cyst. During the 3 years of follow-up, the patient was asymptomatic with no evidence of cyst on computerized tomography scans. Endoscopic drainage and cystoduodenostomy is a minimally invasive, effective, and safe approach in the management of pancreatic pseudocysts in children. PMID- 29115657 TI - Wrapping degloved fingers with a distal-based radial forearm perforator flap: A repair method for multiple digital degloving injury. AB - Degloving hand injuries present challenging situations to hand surgeons as they present with difficulties in reconstructive microsurgery, particularly in multiple digital injuries. Time is a limiting factor when multiple degloving finger amputations are present. Thus, we proposed a repair method for multiple degloving finger injuries that involves coverage with a distal-based reverse forearm flap of all injured fingers in a two-stage procedure. Early vigorous physical therapy after pedicle division of the flap at postoperative third week eliminates joint stiffness problems at wrist and metacarpophalangeal joints. PMID- 29115658 TI - Combined and individual use of pancaspase inhibitor Q-VD-OPh and NMDA receptor antagonist riluzole in experimental spinal cord injury. AB - BACKGROUND: We investigated the effects of an N-methyl-D-aspartate receptor antagonist, riluzole, and a pancaspase inhibitor and basic apoptosis mediator, Q VD-OPh, in combination or alone in posttraumatic spinal cord injury. METHODS: In our study, 45 healthy male Sprague Dawley rats were used. Spinal trauma was induced by the clip compression technique via thoracal 7, 8, 9 laminectomies. After inducing the trauma, the drug was continuously administered intraperitoneally for 5 days. After inducing the trauma, the subjects were assessed using Tarlov's motor grading scale and inclined plane test. Five days after the trauma, the spinal cord specimens were harvested, and a histopathological examination was performed. RESULTS: Compared with the other groups, a statistically significant difference with regard to better results for necrosis, inflammation, and apoptosis was observed in the riluzole only and combination groups. Statistically better motor function scores were observed in the Q-VD-OPh only group than in the other groups. CONCLUSION: With regard to limiting secondary damage after trauma, statistically significant results were observed in the Q-VDOPh only and Q-VD-OPh-riluzole combination groups. More extensive laboratory studies are required to limit and control the effects of secondary damage after spinal cord trauma. PMID- 29115659 TI - Application of pulsed arterial resuscitation in a rabbit model of hemorrhagic shock. AB - BACKGROUND: Hemorrhagic shock is characterized by tissue hypoperfusion caused by a sharp reduction in the effective circulating volume of blood. The key to successful resuscitation lies in eliminating the shock as soon as possible while simultaneously restoring blood perfusion to vital organs. We present the applicability of pulsed arterial blood reinfusion for resuscitation of hemorrhagic shock. METHODS: Sixty rabbits were randomly assigned to resuscitation and control groups. A rabbit hemorrhagic shock model was developed by bloodletting from the carotid artery. The dynamic changes in blood pressure, urine output, blood lactate, and other indicators were measured. RESULTS: Compared with the control group, the mean arterial pressure (MAP), pulse pressure, and urine output were significantly higher in the resuscitation group at 60 min (MAP: 83.67+/-3.90 vs. 38.19+/-3.50 mmHg, p<0.001; pulse difference: 16.46+/-2.21 vs. 10.27+/-2.99 mmHg, p<0.001; urine output: 3.68+/-0.74 vs. 0.10+/ 0.05 mL.kg-1.min-1, p<0.001), whereas the serum lactate level was significantly lower (3.82+/-0.50 vs. 6.49+/-0.61 mmol/L, p<0.001). In addition, the resuscitation group had a significantly higher lactate clearance rate (30 min: 0.26%+/-0.11% vs. 0.25%+/-0.14%, p<0.001; 60 min: 0.30%+/-0.09% vs. 0.67%+/ 0.26%, p<0.001) than the control group. CONCLUSION: Pulsed arterial resuscitation might be useful for emergency treatment of hemorrhagic shock. PMID- 29115660 TI - Methylation-independent CHFR expression is a potential biomarker affecting prognosis in acute myeloid leukemia. AB - CHFR acts as a tumor suppressor gene, which is frequently inactivated caused by its promoter hypermethylation in various solid tumors. Although a recent study showed that CHFR hypermethylation was a frequent event in acute myeloid leukemia (AML) and correlated with adverse clinical outcome, herein, we found that CHFR methylation was a rare event in patients with myeloid malignancies (including AML, chronic myeloid leukemia, and myelodysplastic syndromes), but its expression may serve as an independent prognostic biomarker in AML. CHFR expression was assessed by real-time quantitative PCR, whereas CHFR methylation was detected by methylation-specific PCR and bisulfite sequencing PCR. In AML patients, lower CHFR expression was associated with lower complete remission (CR) rate, and CHFR expression was significantly increased in CR after chemotherapy. Moreover, patients with lower CHFR expression showed shorter overall survival and leukemia free survival, and multivariate analysis confirmed that lower CHFR expression was an independent risk factor in AML. Importantly, the prognostic value of CHFR expression was validated using the published Gene Expression Omnibus datasets. Notably, CHFR promoter was nearly unmethylated in patients with myeloid malignancies. Our findings revealed that lower CHFR expression was independently associated with unfavorable prognosis in AML. Moreover, aberrant CHFR promoter methylation was a rare event in myeloid malignances. PMID- 29115661 TI - School Sense of Community, Teacher Support, and Students' School Safety Perceptions. AB - This study examined the association between two characteristics of school climate (sense of community and teacher support, measured both at the individual and at the school level) and students' feelings of being unsafe at school. The study involved a sample of 49,638 students aged 10-18 years who participated in the 2010-2012 California Healthy Kids Survey. Using hierarchical linear modeling (HLM), our findings revealed that, at the individual level, students perceiving higher levels of sense of community and teacher support at school were less likely to feel unsafe within the school environment. At the school level, sense of community was negatively associated with unsafe feelings, whereas there was no association between school-level teacher support and feelings of being unsafe at school. PMID- 29115662 TI - Chemical Mapping of Essential Oils, Flavonoids and Carotenoids in Citrus Peels by Raman Microscopy. AB - : Citrus peels, by-products in large quantity, are rich in various functional and beneficial components which have wide applications. Chemical analysis of these components in citrus peels is an important step to determine the usefulness of the by-products for further applications. In this study, we explored Raman microscopy for rapid, nondestructive, and in situ chemical mapping of multiple main functional components from citrus peels. The relative amount and distribution in different locations (flavedo, albedo, and longitudinal section) of 3 main functional components (essential oils, carotenoids, and flavonoids) in citrus peels were systematically investigated. The distribution profiles of these components were heterogeneous on the peels and varied between different species of citrus peels. Essential oil was found mainly existed in the oil glands, while carotenoids were in the complementary location. Some flavonoids were observed in the oil glands. This study showed the capability of Raman microscopy for rapid and nondestructive analysis of multiple bio-components without extraction from plants. The information obtained from this study would assist the better production and application of the functional and beneficial components from citrus by products in an effective and sustainable manner. PRACTICAL APPLICATION: This study indicated the capability of Raman microscopy for rapid and nondestructive analysis of multiple bioactive components in plant tissues. The information obtained from the study would be valuable for developing effective and sustainable strategy of utilization of citrus peels for further applications. PMID- 29115664 TI - Four differentially methylated gene pairs to predict the prognosis for early stage hepatocellular carcinoma patients. AB - Hepatocellular carcinoma (HCC) was the second most common malignant tumor with a poor prognostic condition. We aimed to identify novel methylation signatures to predict HCC patients at their early stages. Differentially expressed methylated genes between HCC patients and normal liver tissues retrieved from TCGA were screened out by SAM. Genes highly related to patients' survival were figured out by COX. The signatures that could identify relapse HCC patients were identified by the forwarding search algorithm. Besides, functional enrichment analysis was performed on the methylation genes in the signature. A total of 5,392 CPG sites that differentially methylated expressed were found out and 4,294 differentially expressed genes were obtained. A total of 197 genes among were associated with RFS of HCC patients at both stage I and stage II. Signature composed of 21 pairs was obtained to predict the prognostic situation by C-index forward search method. The function of these genes was figured out by functional enrichment analysis. To summary, the signature composed of 21 gene pairs that can predict the prognostic situation of HCC patients at both stage I and stage II, provided a reference standard for the adjuvant therapy of HCC patients after surgery. PMID- 29115663 TI - Endogenous annexin A1 (AnxA1) modulates early-phase gestation and offspring sex ratio skewing. AB - Annexin A1 (AnxA1) is a glucocorticoid-regulated anti-inflammatory protein secreted by phagocytes and other specialised cells. In the endocrine system, AnxA1 controls secretion of steroid hormones and it is abundantly expressed in the testis, ovaries, placenta and seminal fluid, yet its potential modulation of fertility has not been described. Here, we observed that AnxA1 knockout (KO) mice delivered a higher number of pups, with a higher percentage of female offsprings. This profile was not dependent on the male features, as sperm from KO male mice did not present functional alterations, and had an equal proportion of Y and X chromosomes, comparable to wild type (WT) male mice. Furthermore, mismatched matings of male WT mice with female KO yielded a higher percentage of female pups per litter, a phenomenon which was not observed when male KO mice mated with female WT animals. Indeed, AnxA1 KO female mice displayed several differences in parameters related to gestation including (i) an arrested estrous cycle at proestrus phase; (ii) increased sites of implantation; (iii) reduced pre- and post-implantation losses; (iv) exacerbated features of the inflammatory reaction in the uterine fluid during implantation phase; and (v) enhanced plasma progesterone in the beginning of pregnancy. In summary, herein we highlight that AnxA1 pathway as a novel determinant of fundamental non-redundant regulatory functions during early pregnancy. PMID- 29115665 TI - Effects of XIST/miR-137 axis on neuropathic pain by targeting TNFAIP1 in a rat model. AB - Non-coding RNAs have been reported to participate in the pathophysiology of neuropathic pain. The objective of our study was to investigate the biological role of XIST in neuropathic pain development. In our study, we identify and validate that lncRNA XIST was markedly increased and miR-137 was significantly decreased in chronic constriction injury (CCI) rats. XIST silencing alleviated pain behaviors including both mechanical and thermal hyperalgesia in the CCI rats. XIST was predicted to interact with miR-137 by bioinformatics technology and dual-luciferase reporter assays confirmed the correlation between XIST and miR-137. miR-137 was negatively modulated by XIST and upregulation of miR-137 greatly reduced neuropathic pain development in CCI rats. Moreover, we observed that tumor necrosis factor alpha-induced protein 1 (TNFAIP1) was enhanced in CCI rats and 3'-untranslated region (UTR) of TNFAIP1 was exhibited to be a target of miR-137 by bioinformatics prediction. TNFAIP1 can act as a crucial inflammation regulator by activating NF-kB activity. Overexpression of miR-137 significantly suppressed TNFAIP1 both in vitro and in vivo. Furthermore, upregulation of XIST reversed the inhibitory role of miR-137 in neuropathic pain development by inhibiting TNFAIP1. In conclusion, our current study indicates that XIST can positively regulate neuropathic pain in rats through regulating the expression of miR-137 and TNFAIP1. Our results imply that XIST/miR-137/TNFAIP1 axis may serve as a novel therapeutic target in neuropathic pain. PMID- 29115666 TI - Potential roles of metalloproteinases of endometrium-derived exosomes in embryo maternal crosstalk during implantation. AB - During embryo implantation, crosstalk between the endometrial epithelium and the blastocyst, especially the trophoblasts, is a prerequisite for successful implantation. During this crosstalk, various molecular and functional changes occur to promote synchrony between the embryo and the endometrium as well as the uterine cavity microenvironment. In the past few years, growing evidence has shown that endometrium-derived exosomes play pivotal roles in the embryonic maternal crosstalk during implantation, although the exact mechanism of this crosstalk has yet to be determined. The presence of metalloproteinases has been reported in endometrium-derived exosomes, implying the importance of these enzymes in exosome-based crosstalk. Thus, in this review, we describe the potential roles of the metalloproteinases of endometrium-derived exosomes in promoting embryo attachment and implantation. This study could provide a better understanding of the potential roles of exosomal metalloproteinases in embryo implantation and pave the way for developing novel exosome-based regulatory agents to support early pregnancy. PMID- 29115667 TI - Complicating Narratives: Defining and Deconstructing Ethical Challenges in Community Psychology. AB - In this concluding essay, we review the case studies presented in this Special Issue and examine whether community psychology has a distinctive approach to defining and resolving the core ethical canons of the Belmont Report (1979): Respect for Persons, Beneficence, and Justice. For two of these Principles Respect for Persons and Beneficence-community psychologists elaborate upon and extend their definitions to consider their meaning in community-based, social justice-oriented research. The field's approach to Respect for Persons is multilevel in nature; in addition to respecting individuals and their diverse identities, we also have obligations to respect our community partnerships, the communities with whom we work, and the populations and cultures represented in our work. Similarly, for community psychologists, Beneficence is a multilevel construct that considers risks and benefits at the group, community, and cultural levels of analysis. With respect to Justice, community psychologists' views of our ethical responsibilities are qualitatively different in meaning from the original Belmont Report and from disciplinary-specific interpretations of this principle in ethical guidance documents from psychology, sociology, and evaluation. Our valuing of social change demands that we contribute to individual and group empowerment and liberation, and in so doing, that we avoid collusion with oppressive systems. Thus, we define our ethical responsibilities for promoting Justice as more action-oriented than do other disciplines. The essay closes with an exploration of future directions for developing a comprehensive ethical framework for community psychology. PMID- 29115668 TI - miR-26a promoted endometrial epithelium cells (EECs) proliferation and induced stromal cells (ESCs) apoptosis via the PTEN-PI3K/AKT pathway in dairy goats. AB - Changes in endometrial cell morphology and function are absolutely necessary for successful embryo implantation. In this study, miR-26a was widely expressed in dairy goats, and was found to be regulated by beta-estradiol (E2) and progesterone (P4) in endometrial epithelium cells (EECs) as well as stromal cells (ESCs). Furthermore, miR-26a played a role in the regulation of cells proliferation and apoptosis by directly regulating PTEN and indirectly regulating the PI3K/AKT pathway in EECs but not in ESCs of dairy goats in vitro. In addition, miR-26a regulated the expression of osteopontin (OPN), vascular endothelial growth factor (VEGF), Cyclooxygenase-2 (COX-2), and prolactin (PRL) in endometrial cells. Therefore, we could get a conclusion that miR-26a had very complex and diverse functions in the endometrial cells during the development of endometrial receptivity in dairy goats. This study provided an efficient platform for studying the regulatory effect of miR-26a on endometrial cells during the development of endometrial receptivity in dairy goats. PMID- 29115669 TI - Corrigendum. PMID- 29115670 TI - RECURRENT MYXOMA ARISING FROM MULTIPLE CARDIACCHAMBERS WITH SYSTEMIC EMBOLIZATION:A CASE REPORT. AB - Myxomas occupying multiple chambers of the heart are extremely rare, being more common in familial cases. Recurrenceof these tumors after surgical excision is also a rare condition, observed in about 3% of patients in sporadiccases. Systemic embolization especially to the brain is one of the common presentations of cardiac myxomasapart from intracardiac obstruction and systemic symptoms.We report an adolescent girl presenting with recurrent myxoma arising from multiple cardiac chambers with systemicembolization. As a diagnostic and preventive measure of recurrence and chronic systemic embolization, werecommend a regular follow up of such patients with echocardiographic evaluation following surgical resection. PMID- 29115671 TI - Fatty acid elongase7 is regulated via SP1 and is involved in lipid accumulation in bovine mammary epithelial cells. AB - Fatty Acid Elongase 7 (ELOVL7) is the newly discovered protein on human that catalyzes the rate-limiting step towards the synthesis of very long-chain fatty acids and exhibits the highest activity toward C18: 3 (n-3) acyl-CoAs, which is the precursor of eicosapentaenoic acid (EPA, 20: 5n-3). However, in ruminants, an overall understanding of ELOVLs gene family and the transcriptional regulation of ELOVL7 remain unknown. The purpose of this study is to investigate the transcriptional regulation and the influence of bovine ELOVL7 in bovine mammary epithelial cells (bMECs). Quantitative real-time PCR analysis demonstrated that ELOVLs gene family had differential expression patterns in bMECs, and bovine ELOVL7 was expressed in a tissue-specific manner, which was high in kidney, followed by in abdominal fat and in bMECs. Promoter analysis of bovine ELOVL7, including bioinformatics analyzes, dual-luciferase reporter assays, protein pull down assay, Western blot assay, over-expression and RNA interference assay, have independently and synthetically demonstrated that transcription factor Sp1 (SP1) specifically interacted with the GC-box at -143 to -128 base pair on ELOVL7 promoter. Furthermore, the exogenous alpha-linolenic acid (ALA, 18: 3n-3), strengthened the binding of SP1 to the ELOVL7 proximal promoter, resulting in the accumulation of lipid droplets in bMECs. In conclusion, these data suggest that the transcription of bovine ELOVL7 is affected by the binding of SP1 and the treatment of ALA, moreover, enlightening us the profound role of SP1 in modulating lipid synthesis of the mammary gland in cattle. PMID- 29115672 TI - Peer Problems Among Postinstitutionalized, Internationally Adopted Children: Relations to Hypocortisolism, Parenting Quality, and ADHD Symptoms. AB - Seventy-eight postinstitutionalized (PI) children adopted at ages 17-36 months were assessed 2, 8, 16, and 24 months postadoption on measures of cortisol and parenting quality, and compared to same-aged children adopted from foster care (FC, n = 45) and nonadopted children (NA, n = 45). In kindergarten (Mage = 6.0 years), teachers, parents, and trained observers completed measures of peer relationships and attention deficit hyperactivity disorder (ADHD) symptoms. PI children had more peer problems and ADHD symptoms according to teachers and observers than NA children with FC children in between, whereas both PI and FC children were at significantly greater risk of hypocortisolism (i.e., blunted cortisol diurnal rhythm and reactivity). Hypocortisolism and ADHD symptoms mediated the association between preadoption adversity and peer difficulties. Higher postadoption parenting quality was protective. PMID- 29115673 TI - Seeing Iconic Gestures While Encoding Events Facilitates Children's Memory of These Events. AB - An experiment with 72 three-year-olds investigated whether encoding events while seeing iconic gestures boosts children's memory representation of these events. The events, shown in videos of actors moving in an unusual manner, were presented with either iconic gestures depicting how the actors performed these actions, interactive gestures, or no gesture. In a recognition memory task, children in the iconic gesture condition remembered actors and actions better than children in the control conditions. Iconic gestures were categorized based on how much of the actors was represented by the hands (feet, legs, or body). Only iconic hand as-body gestures boosted actor memory. Thus, seeing iconic gestures while encoding events facilitates children's memory of those aspects of events that are schematically highlighted by gesture. PMID- 29115674 TI - Let's Talk: Parents' Mental Talk (Not Mind-Mindedness or Mindreading Capacity) Predicts Children's False Belief Understanding. AB - Although one might expect parents' mind-mindedness (MM; the propensity to view children as mental agents) to relate to everyday mental-state talk (MST) and theory-of-mind capacity, evidence to support this view is lacking. In addition, both the uniqueness and the specificity of relations between parental MM, parental MST, and children's false belief understanding (FBU) are open to question. To address these three gaps, this study tracked 117 preschoolers (60 boys) and their parents across a 13-month period (Mage = 3.94 years, SD = 0.53, at Time 1). Parental MM, MST, and theory-of-mind capacity showed little overlap. Both MM and MST were weakly associated with children's concurrent FBU, but in line with social constructivist accounts, only MST predicted later FBU. PMID- 29115675 TI - Examining Children's Implicit Racial Attitudes Using Exemplar and Category-Based Measures. AB - The goal of this research was to examine children's implicit racial attitudes. Across three studies, a total of 359 White 5- to 12-year-olds completed child friendly exemplar (Affective Priming Task; Affect Misattribution Procedure) and category-based (Implicit Association Test) implicit measures of racial attitudes. Younger children (5- to 8-year-olds) showed automatic ingroup positivity toward White child exemplars, whereas older children (9- to 12-year-olds) did not. Children also showed no evidence of automatic negativity toward Black exemplars, despite demonstrating consistent pro-White versus Black bias on the category based measure. Together, the results suggest that (a) implicit ingroup and outgroup attitudes can follow distinct developmental trajectories, and (b) the spontaneous activation of implicit intergroup attitudes can depend on the salience of race. PMID- 29115676 TI - Lyme Disease Presenting With Raeder Syndrome. PMID- 29115677 TI - Applicability of 3D-dental reconstruction in cervical odontometrics. AB - OBJECTIVES: The objective of this study was to assess the accuracy, reliability, and reproducibility of computed tomography (CT) images in measuring cervical mesiodistal and buccolingual tooth sizes, by comparing the values obtained by 3D virtual models from CT images with those obtained using digital calipers. MATERIALS AND METHODS: In total, 530 maxillary and mandibular teeth of 51 individuals from two Iron Age sites were scanned using a Siemens Somatom sensation 64-slice computed tomography machine, and the images were reconstructed and measured. Values obtained by direct measurement served as the primary reference for cervical measurements. Intra- and inter-observer reliability was assessed by calculating technical error of measurements (TEM), relative technical error of measurements (rTEM), and the coefficient of reliability (R). RESULTS: Results showed that virtual cervical measurements were not significantly different from the actual measurements, and the correlation of the two measurement methods shows that the methods are comparable. Inter- and intra observer error analysis also indicated high replicability of measurements with both measuring methods (R > 0.99). The rTEM values for all the measurements were below the 5% standards for anthropometric studies. DISCUSSION: CT is a non invasive technique that allows for an accurate and detailed visualization of morphological features without causing any damage to teeth. Our findings indicate that virtual odontometric analysis is a reliable method, similar to traditional physical odontometric analysis. Currently, the virtual system is likely to be more suitable for fragile specimens, such as archaeological samples. PMID- 29115679 TI - Soft tissue chondroma on the lip: Clinical, histopathological and ultrasonographic findings. PMID- 29115678 TI - Moderate climate signature in cranial anatomy of late holocene human populations from Southern South America. AB - OBJECTIVE: The aim of this study is to analyze the association between cranial variation and climate in order to discuss their role during the diversification of southern South American populations. Therefore, the specific objectives are: (1) to explore the spatial pattern of cranial variation with regard to the climatic diversity of the region, and (2) to evaluate the differential impact that the climatic factors may have had on the shape and size of the diverse cranial structures studied. MATERIALS AND METHODS: The variation in shape and size of 361 crania was studied, registering 62 3D landmarks that capture shape and size variation in the face, cranial vault, and base. Mean, minimum, and maximum annual temperature, as well as mean annual precipitation, but also diet and altitude, were matched for each population sample. A PCA, as well as spatial statistical techniques, including kriging, regression, and multimodel inference were employed. RESULTS: The facial skeleton size presents a latitudinal pattern which is partially associated with temperature diversity. Both diet and altitude are the variables that mainly explain the skull shape variation, although mean annual temperature also plays a role. The association between climate factors and cranial variation is low to moderate, mean annual temperature explains almost 40% of the entire skull, facial skeleton and cranial vault shape variation, while annual precipitation and minimum annual temperature only contribute to the morphological variation when considered together with maximum annual temperature. The cranial base is the structure less associated with climate diversity. CONCLUSION: These results suggest that climate factors may have had a partial impact on the facial and vault shape, and therefore contributed moderately to the diversification of southern South American populations, while diet and altitude might have had a stronger impact. Therefore, cranial variation at the southern cone has been shaped both by random and nonrandom factors. Particularly, the influence of climate on skull shape has probably been the result of directional selection. This study supports that, although cranial vault is the cranial structure more associated to mean annual temperature, the impact of climate signature on morphology decreases when populations from extreme cold environments are excluded from the analysis. Additionally, it shows that the extent of the geographical scales analyzed, as well as differential sampling may lead to different results regarding the role of ecological factors and evolutionary processes on cranial morphology. PMID- 29115680 TI - MASTDISCS combi Carba plus, a simple method for discriminating carbapenemase producing Enterobacteriaceae, including OXA-48-type producers. AB - Accurate and rapid detection of carbapenemases and identification of their types in Enterobacteriaceae are both still major challenges for clinical laboratories in attempting to prevent the intrusion and transmission of carbapenemase producing Enterobacteriaceae. This study aimed to evaluate the performance of the MASTDISCS combi Carba plus disc system in identification of different carbapenemase types, including OXA-48-type carbapenemase, for which no specific enzyme inhibitors have so far been available. The simple disc system discriminates carbapenemases, including OXA-48-types exhibiting low carbapenem minimum inhibitory concentrations, by targeting Enterobacteriaceae isolates with a EUCAST meropenem screening cut-off of >=0.25 mg/L. PMID- 29115681 TI - Imiquimod 5% cream as a therapeutic option for extramammary Paget's disease. AB - A wide local excision is the standard treatment for extramammary Paget's disease (EMPD), though this treatment often leads to permanent anogenital mutilation and functional impairment. The purpose of our study is to evaluate the efficacy and safety of the topical application of imiquimod 5% cream for non-invasive EMPD. We examined nine patients with EMPD. Eight of the nine patients were treated with imiquimod 5% cream three times per week for 16 weeks; one case was treated for 6 weeks. The response rate was 100% including five complete remissions. Local irritation was observed in three patients, which was controlled by a provisional withdrawal of the treatment. These results suggest that imiquimod 5% cream may be considered an alternative therapeutic option for the treatment of non-invasive EMPD. PMID- 29115682 TI - Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration. AB - BACKGROUND: With its increasing incidence, nonalcoholic fatty liver disease (NAFLD) is of particular concern in the Veterans Health Administration (VHA). AIMS: To evaluate risk factors for advanced fibrosis in biopsy-proven NAFLD in the VHA, to identify patients at risk for adverse outcomes. METHODS: In randomly selected cases from VHA databases (2005-2015), we performed a retrospective case control study in adults with biopsy-defined NAFLD or normal liver. RESULTS: Of 2091 patients reviewed, 399 met inclusion criteria. Normal controls (n = 65) had normal liver function. The four NAFLD cohorts included: NAFL steatosis (n = 76), nonalcoholic steatohepatitis (NASH) without fibrosis (n = 68), NAFLD/NASH stage 1 3 fibrosis (n = 82), and NAFLD/NASH cirrhosis (n = 70). NAFLD with hepatocellular carcinoma (HCC) was separately identified (n = 38). Most patients were older White men. NAFLD patients with any fibrosis were on average severely obese (BMI>35 kg/m2 ). Diabetes (54.4%-79.6%) and hypertension (85.8%-100%) were more common in NAFLD with fibrosis or HCC. Across NAFLD, 12.3%-19.5% were enrolled in diet/exercise programs and 0%-2.6% had bariatric surgery. Hispanics exhibited higher rates of NASH (20.6%), while Blacks had low NAFLD rates (1.4%-11.8%), particularly NAFLD cirrhosis and HCC (1.4%-2.6%). Diabetes (OR 11.8, P < .001) and BMI (OR 1.4, P < .001) were the most significant predictors of advanced fibrosis. CONCLUSIONS: In the VHA, diabetes and severe obesity increased risk for advanced fibrosis in NAFLD. Of these patients, only a small proportion (~20%) had enrolled in diet/exercise programs or had bariatric surgery (~2%). These results suggest that providers should focus/tailor interventions to improve outcomes, particularly in those with diabetes and severe obesity. PMID- 29115684 TI - Bone Material Strength Index as Measured by Impact Microindentation in Postmenopausal Women With Distal Radius and Hip Fractures. AB - We tested whether cortical bone tissue properties assessed by in vivo impact microindentation would distinguish postmenopausal women with recent distal radius (DRF) or hip fracture (HF) from nonfracture controls (CONT). We enrolled postmenopausal women with recent DRF (n = 57), HF (n = 41), or CONT (n = 93), and used impact microindentation to assess bone material strength index (BMSi) at the anterior surface of the mid-tibia diaphysis. Areal bone mineral density (aBMD) (g/cm2 ) of the femoral neck (FN), total hip (TH), and lumbar spine (LS) were measured by dual-energy X-ray absorptiometry (DXA). HF and DRF subjects had significantly lower BMD than CONT at all sites (-5.6% to -8.2%, p < 0.001 for all). BMSi was 4% lower in DRF compared to CONT (74.36 +/- 8.77 versus 77.41 +/- 8.79, p = 0.04). BMSi was similarly lower in HF versus CONT, but the difference did not reach statistical significance (74.62 +/- 8.47 versus 77.41 +/- 8.79, p = 0.09). Lower BMSi was associated with increased risk of DRF (unadjusted OR, 1.43; 95% CI, 1.02 to 2.00, per SD decrease, p = 0.04), and remained statistically significant after adjustment for age, age and BMI, and age, BMI, and FN BMD (OR = 1.48 to 1.55). Lower BMSi tended to be associated with HF, but only reached borderline significance (unadjusted OR = 1.39; 95% CI, 0.96 to 2.01, p = 0.08). These results provide strong rationale for future investigations aimed at assessing whether BMSi can predict fracture in prospective studies and improve identification of women at risk for fragility fractures. (c) 2017 American Society for Bone and Mineral Research. PMID- 29115683 TI - Role of chemokines and the corresponding receptors in vitiligo: A pilot study. AB - To determine the levels and sources of chemokines in the serum and epidermis of vitiligo patients, we examined 80 active patients, 80 stable patients and 40 healthy controls. First, the serum levels of candidate chemokines were measured by Luminex assay, and levels of CCR5, CXCR1 and CXCR3 were measured in peripheral mononuclear cells (PMBC) by flow cytometry. Then, the local epidermis levels of elevated chemokines in vitiligo were tested by Luminex. Finally, the mRNA and protein expression levels of elevated chemokines in HaCaT cells stimulated with interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha were tested by quantitative real-time polymerase chain reaction and Luminex. The serum levels of CCL5, CXCL8 and CXCL10 in active vitiligo were significantly elevated compared with those in stable vitiligo patients. Furthermore, the levels of CCL3 and CCL4 had weak and positive correlations with the Vitiligo Area Scoring Index. In the peripheral blood of active vitiligo patients, the percentages of CD3+ CD8+ CCR5+ and CD3+ CD8+ CXCR3+ T cells were significantly increased compared with those in stable vitiligo and healthy controls. In the epidermis of lesions, the expression levels of CCL5 and CXCL10 in active vitiligo were significantly increased. In addition, the mRNA and protein levels of CCL5, CXCL8 and CXCL10 were significantly elevated in HaCaT cells after stimulation with TNF-alpha or IFN gamma. The CCR5/CCL5 and CXCR3/CXCL10 axes may play an important role in the progression and maintenance of vitiligo. Moreover, keratinocytes stimulated with TNF-alpha and IFN-gamma may be a primary source of CCL5 and CXCL10. PMID- 29115685 TI - Response to "Standardized methods must be used to compare the properties of botulinum toxin serotypes". PMID- 29115686 TI - Inner-volume echo volumar imaging (IVEVI) for robust fetal brain imaging. AB - PURPOSE: Fetal functional MRI studies using conventional 2-dimensional single shot echo-planar imaging sequences may require discarding a large data fraction as a result of fetal and maternal motion. Increasing the temporal resolution using echo volumar imaging (EVI) could provide an effective alternative strategy. Echo volumar imaging was combined with inner volume (IV) imaging (IVEVI) to locally excite the fetal brain and acquire full 3-dimensional images, fast enough to freeze most fetal head motion. METHODS: IVEVI was implemented by modifying a standard multi-echo echo-planar imaging sequence. A spin echo with orthogonal excitation and refocusing ensured localized excitation. To introduce T2* weighting and to save time, the k-space center was shifted relative to the spin echo. Both single and multi-shot variants were tested. Acoustic noise was controlled by adjusting the amplitude and switching frequency of the readout gradient. Image-based shimming was used to minimize B0 inhomogeneities within the fetal brain. RESULTS: The sequence was first validated in an adult. Eight fetuses were scanned using single-shot IVEVI at a 3.5 * 3.5 * 5.0 mm3 resolution with a readout duration of 383 ms. Multishot IVEVI showed reduced geometric distortions along the second phase-encode direction. CONCLUSIONS: Fetal EVI remains challenging. Although effective echo times comparable to the T2* values of fetal cortical gray matter at 3 T could be achieved, controlling acoustic noise required longer readouts, leading to substantial distortions in single-shot images. Although multishot variants enabled us to reduce susceptibility-induced geometric distortions, sensitivity to motion was increased. Future studies should therefore focus on improvements to multishot variants. Magn Reson Med 80:279-285, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29115687 TI - Epidemiological survey from 2009 to 2012 of psoriatic patients in Japanese Society for Psoriasis Research. AB - Since 1982, the Japanese Society for Psoriasis Research has conducted annual epidemiological surveys of patients with psoriasis. Kawada et al. have reported data for 1982-2001 and Takahashi et al. have reported data for 2002-2008. The present study evaluated 9290 psoriatic cases according to age and sex (2009 2012). The male : female ratio was 2.08:1 (6281 male patients [67.6%] to 3009 female patients [32.4%]). The most prevalent type was psoriasis vulgaris (85.6% of all cases), which was followed by psoriasis arthropathica (6.0%), psoriasis guttate acuta (3.2%), Zumbusch-type generalized pustular psoriasis (1.8%) and psoriasis erythroderma (1.5%). Psoriasis vulgaris was the most prevalent type for all ages, while psoriasis arthropathica and psoriasis guttate acuta were most prevalent among patients aged less than 65 years. The present survey detected an increased number of cases with comorbid diabetes and/or arthritis symptoms compared with the previous surveys. We found that treatments frequently involved topical corticosteroids (89.7% of cases) and vitamin D3 ointments (78.0% of cases), with a notable increase in the use of vitamin D3 ointments. Systemic treatments were used in 33.3% of cases, including cyclosporin (33.6%), etretinate (19.5%), methotrexate (8.6%), infliximab (11.4%), adalimumab (10.9%) and ustekinumab (6.2%). Phototherapy was used in 30.9% of cases. Although psoralen plus ultraviolet A therapy was the predominant phototherapy during previous studies, the present survey revealed that narrowband ultraviolet B therapy was used in 84.5% of phototherapy-treated cases. Thus, the present survey revealed major changes in treatment trends. PMID- 29115688 TI - Flexible particle flow-focusing in microchannel driven by droplet-directed induced-charge electroosmosis. AB - We report herein a novel microfluidic particle concentrator that utilizes constriction microchannels to enhance the flow-focusing performance of induced charge electroosmosis (ICEO), where viscous hemi-spherical oil droplets are embedded within the mainchannel to form deformable converging-diverging constriction structures. The constriction region between symmetric oil droplets partially coated on the electrode strips can improve the focusing performance by inducing a granular wake flow area at the diverging channel, which makes almost all of the scattered sample particles trapped within a narrow stream on the floating electrode. Another asymmetric droplet pair arranged near the outlets can further direct the trajectory of focused particle stream to one specified outlet port depending on the symmetry breaking in the shape of opposing phase interfaces. By fully exploiting rectification properties of induced-charge electrokinetic phenomena at immiscible water/oil interfaces of tunable geometry, the expected function of continuous and switchable flow-focusing is demonstrated by preconcentrating both inorganic silica particles and biological yeast cells. Physical mechanisms responsible for particle focusing and locus deflection in the droplet-assisted concentrentor are analyzed in detail, and simulation results are in good accordance with experimental observations. Our work provides new routes to construct flexible electrokinetic framework for preprocessing on-chip biological samples before performing subsequent analysis. PMID- 29115691 TI - Case of warty dyskeratoma with unique dermoscopic features. PMID- 29115689 TI - Learning a variational network for reconstruction of accelerated MRI data. AB - PURPOSE: To allow fast and high-quality reconstruction of clinical accelerated multi-coil MR data by learning a variational network that combines the mathematical structure of variational models with deep learning. THEORY AND METHODS: Generalized compressed sensing reconstruction formulated as a variational model is embedded in an unrolled gradient descent scheme. All parameters of this formulation, including the prior model defined by filter kernels and activation functions as well as the data term weights, are learned during an offline training procedure. The learned model can then be applied online to previously unseen data. RESULTS: The variational network approach is evaluated on a clinical knee imaging protocol for different acceleration factors and sampling patterns using retrospectively and prospectively undersampled data. The variational network reconstructions outperform standard reconstruction algorithms, verified by quantitative error measures and a clinical reader study for regular sampling and acceleration factor 4. CONCLUSION: Variational network reconstructions preserve the natural appearance of MR images as well as pathologies that were not included in the training data set. Due to its high computational performance, that is, reconstruction time of 193 ms on a single graphics card, and the omission of parameter tuning once the network is trained, this new approach to image reconstruction can easily be integrated into clinical workflow. Magn Reson Med 79:3055-3071, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29115690 TI - The effects of intravoxel contrast agent diffusion on the analysis of DCE-MRI data in realistic tissue domains. AB - PURPOSE: Quantitative evaluation of dynamic contrast enhanced MRI (DCE-MRI) allows for estimating perfusion, vessel permeability, and tissue volume fractions by fitting signal intensity curves to pharmacokinetic models. These compart mental models assume rapid equilibration of contrast agent within each voxel. However, there is increasing evidence that this assumption is violated for small molecular weight gadolinium chelates. To evaluate the error introduced by this invalid assumption, we simulated DCE-MRI experiments with volume fractions computed from entire histological tumor cross-sections obtained from murine studies. METHODS: A 2D finite element model of a diffusion-compensated Tofts-Kety model was developed to simulate dynamic T1 signal intensity data. Digitized histology slices were segmented into vascular (vp ), cellular and extravascular extracellular (ve ) volume fractions. Within this domain, Ktrans (the volume transfer constant) was assigned values from 0 to 0.5 min-1 . A representative signal enhancement curve was then calculated for each imaging voxel and the resulting simulated DCE-MRI data analyzed by the extended Tofts-Kety model. RESULTS: Results indicated parameterization errors of -19.1% +/- 10.6% in Ktrans , -4.92% +/- 3.86% in ve , and 79.5% +/- 16.8% in vp for use of Gd-DTPA over 4 tumor domains. CONCLUSION: These results indicate a need for revising the standard model of DCE-MRI to incorporate a correction for slow diffusion of contrast agent. Magn Reson Med 80:330-340, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29115692 TI - A spiral-based volumetric acquisition for MR temperature imaging. AB - PURPOSE: To develop a rapid pulse sequence for volumetric MR thermometry. METHODS: Simulations were carried out to assess temperature deviation, focal spot distortion/blurring, and focal spot shift across a range of readout durations and maximum temperatures for Cartesian, spiral-out, and retraced spiral-in/out (RIO) trajectories. The RIO trajectory was applied for stack-of-spirals 3D imaging on a real-time imaging platform and preliminary evaluation was carried out compared to a standard 2D sequence in vivo using a swine brain model, comparing maximum and mean temperatures measured between the two methods, as well as the temporal standard deviation measured by the two methods. RESULTS: In simulations, low bandwidth Cartesian trajectories showed substantial shift of the focal spot, whereas both spiral trajectories showed no shift while maintaining focal spot geometry. In vivo, the 3D sequence achieved real-time 4D monitoring of thermometry, with an update time of 2.9-3.3 s. CONCLUSION: Spiral imaging, and RIO imaging in particular, is an effective way to speed up volumetric MR thermometry. Magn Reson Med 79:3122-3127, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29115693 TI - Effects of foetal growth restriction and preterm birth on cardiac morphology and function during infancy. AB - AIM: To investigate the effects of foetal growth restriction (FGR) and prematurity on cardiac morphology and function in infancy. We hypothesised that FGR and prematurity would both alter cardiac development. METHODS: Cardiac morphology and function were evaluated in 24 preterm FGR infants (p-FGR) and 23 preterm and 19 term appropriately grown for gestational age infants (p-AGA and t AGA, respectively) by conventional echocardiography and Tissue Doppler Imaging. p FGR and p-AGA infants were studied on postnatal day 1 and all groups were studied at one-and six-months post-term age. RESULTS: p-FGR infants demonstrated increased cardiac sphericity compared to AGA peers on postnatal day 1 (p = 0.004) and at one-month post-term age (p = 0.004). Posterior and relative wall thickness increased overtime in the p-FGR group only (p < 0.05). Systolic function was not different between groups. E/e' ratio was higher in both preterm groups compared to the term group at one-month post-term age (p = 0.01). No statistically significant group differences were found at six-months post-term age. CONCLUSION: Foetal growth restriction was associated with subtle cardiac morphological changes, whereas both prematurity and FGR were associated with subclinical alterations in diastolic function. PMID- 29115694 TI - Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism. AB - Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia with features that overlap with typical primary hyperparathyroidism (PHPT). The incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures. One sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT. I analyzed selected articles about calcium-sensing receptors, FHH, PHPT, CASR, GNA11, and AP2S1. FHH usually results from a heterozygous germline inactivating mutation of the CASR, and less frequently from mutation of GNA11 or AP2S1. The CASR encodes the calcium-sensing receptors. These are highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium. Their mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria). Many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia. Total parathyroidectomy causes hypoparathyroidism and durable remission of hypercalcemia. Some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria. The features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity. Classifying FHH as an atypical form of PHPT represents compact nomenclature and supports current concepts of pathophysiology of FHH and PHPT. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. PMID- 29115695 TI - A standardized tritrophic small-scale system (TriCosm) for the assessment of stressor-induced effects on aquatic community dynamics. AB - Chemical impacts on the environment are routinely assessed in single-species tests. They are employed to measure direct effects on nontarget organisms, but indirect effects on ecological interactions can only be detected in multispecies tests. Micro- and mesocosms are more complex and environmentally realistic, yet they are less frequently used for environmental risk assessment because resource demand is high, whereas repeatability and statistical power are often low. Test systems fulfilling regulatory needs (i.e., standardization, repeatability, and replication) and the assessment of impacts on species interactions and indirect effects are lacking. In the present study we describe the development of the TriCosm, a repeatable aquatic multispecies test with 3 trophic levels and increased statistical power. High repeatability of community dynamics of 3 interacting aquatic populations (algae, Ceriodaphnia, and Hydra) was found with an average coefficient of variation of 19.5% and the ability to determine small effect sizes. The TriCosm combines benefits of both single-species tests (fulfillment of regulatory requirements) and complex multispecies tests (ecological relevance) and can be used, for instance, at an intermediate tier in environmental risk assessment. Furthermore, comparatively quickly generated population and community toxicity data can be useful for the development and testing of mechanistic effect models. Environ Toxicol Chem 2018;37:1051-1060. (c) 2017 SETAC. PMID- 29115696 TI - Joule heating induced stream broadening in free-flow zone electrophoresis. AB - The use of an electric field in free-flow zone electrophoresis (FFZE) automatically leads to Joule heating yielding a higher temperature at the center of the separation chamber relative to that around the channel walls. For small amounts of heat generated, this thermal effect introduces a variation in the equilibrium position of the analyte molecules due to the dependence of liquid viscosity and analyte diffusivity on temperature leading to a modification in the position of the analyte stream as well as the zone width. In this article, an analytic theory is presented to quantitate such effects of Joule heating on FFZE assays in the limit of small temperature differentials across the channel gap yielding a closed form expression for the stream position and zone variance under equilibrium conditions. A method-of-moments approach is employed to develop this analytic theory, which is further validated with numerical solutions of the governing equations. Interestingly, the noted analyses predict that Joule heating can drift the location of the analyte stream either way of its equilibrium position realized in the absence of any temperature rise in the system, and also tends to reduce zone dispersion. The extent of these modifications, however, is governed by the electric field induced temperature rise and three Peclet numbers evaluated based on the axial pressure-driven flow, transverse electroosmotic and electrophoretic solute velocities in the separation chamber. Monte Carlo simulations of the FFZE system further establish a time and a length scale over which the results from the analytic theory are valid. PMID- 29115698 TI - Grading scales in subarachnoid hemorrhage - many options, but do we have a winner? PMID- 29115699 TI - Controlled Pyrolysis of Ni-MOF-74 as a Promising Precursor for the Creation of Highly Active Ni Nanocatalysts in Size-Selective Hydrogenation. AB - Metal organic frameworks (MOFs) are a class of porous organic-inorganic crystalline materials that have attracted much attention as H2 storage devices and catalytic supports. In this paper, the synthesis of highly-dispersed Ni nanoparticles (NPs) for the hydrogenation of olefins was achieved by employing Ni MOF-74 as a precursor. Investigations of the structural transformation of Ni species derived from Ni-MOF-74 during heat treatment were conducted. The transformation was monitored in detail by a combination of XRD, in situ XAFS, and XPS measurements. Ni NPs prepared from Ni-MOF-74 were easily reduced by the generation of reducing gases accompanied by the decomposition of Ni-MOF-74 structures during heat treatment at over 300 degrees C under N2 flow. Ni-MOF-74 300 exhibited the highest activity for the hydrogenation of 1-octene due to efficient suppression of excess agglomerated Ni species during heat treatment. Moreover, Ni-MOF-74-300 showed not only high activity for the hydrogenation of olefins but also high size-selectivity because of the selective formation of Ni NPs covered by MOFs and the MOF-derived carbonaceous layer. PMID- 29115700 TI - The challenge of generalist care in remote Australia: Beyond aeromedical retrieval. AB - OBJECTIVE: To examine clinical service activity amongst patients of the Royal Flying Doctor Service South Eastern Section in Far West New South Wales and to evaluate the management of chronic disease among frequent users of evacuation services. DESIGN: A retrospective audit of the Royal Flying Doctor Service South Eastern Section patient database inclusive of patients within the geographical study area who accessed a clinical or remote consultation, or evacuation service at least once between 1 July 2008 and 30 June 2013. Frequent users of evacuation services (>=3 evacuations per year) were investigated through RFDS patient files for determinants of chronic disease management. MAIN OUTCOME MEASURES: Category of service accessed, clinical consultation amongst frequent evacuees, determinants of chronic disease management. RESULTS: Total number of evacuees increased by 5.4%; number of remote and clinical consultation patients increased by 5.4%. Of the 47 frequent users of evacuation services, 19 (40%) were infrequent or non-users of clinics (<=3 attendances per year) and 32 (70%) did not have a general practice management plan. Frequent evacuees averaged 2.7 chronic conditions per patient and had seen an average of 16.8 primary care physicians over the 5-year evaluation. CONCLUSION: Most frequent evacuees had several chronic conditions, multiple primary care providers, did not have a general practice management plan and had infrequent clinic reviews. This evidence highlights the challenge of remote primary care and the need to improve systems of chronic disease management. It underlines the importance of current local efforts to improve electronic records, follow-up and team care and to explore further telehealth implementation. PMID- 29115701 TI - Multispecificity of a recombinant anti-ras monoclonal antibody. AB - Recombinant monoclonal antibodies (Ab's) have widespread application as research tools, diagnostic reagents and as biotherapeutics. Whilst studying the cellular molecular switch protein m-ras, a recombinant monoclonal antibody to m-ras was generated for use as a research tool. Antibody genes from a single rabbit B cell secreting IgG to an m-ras specific peptide sequence were expressed in mammalian cells, and monoclonal rabbit IgG binding was characterized by ELISA and peptide array blotting. Although the monoclonal Ab was selected for specificity to m-ras peptide, it also bound to both recombinant full-length m-ras and h-ras proteins. The cross-reactive binding of the monoclonal Ab to h-ras was defined by peptide array blot revealing that the Ab showed preference for peptide sequences containing multiple positively charged amino acid residues. These data reinforce the concept of antibody multispecificity through multiple interactions of the Ab paratope with diverse polypeptides. They also emphasize the importance of immunogen and Ab selection processes when generating recombinant monoclonal Ab's. PMID- 29115702 TI - Joint Experimental and Computational Investigation of the Flexibility of a Diacetylene-Based Mixed-Linker MOF: Revealing the Existence of Two Low Temperature Phase Transitions and the Presence of Colossal Positive and Giant Negative Thermal Expansions. AB - Solvothermal reaction in N,N-dimethylformamide (DMF) between 1,6-bis(1 imidazolyl)-2,4-hexadiyne monohydrate (L1?H2 O), isophthalic acid (H2 L2), and Zn(NO3 )2 ?6 H2 O gives the diacetylene-based mixed-ligand coordination polymer {[Zn(L1)(L2)](DMF)2 }n (UMON-44) in 38 % yield. Combination of DSC with variable temperature single-crystal X-ray diffraction revealed the occurrence of two phase transitions spanning the ranges 129-144 K and 158-188 K. Furthermore, the three structurally similar phases of UMON-44 show giant negative and/or colossal positive thermal expansions. These unusual phenomena exist without any change in the contents of the unit cell. DFT calculations using the PBE+D3 dispersion scheme were able to distinguish between these polymorphs by accurately reproducing their salient structural features, although corrections in the size of the unit cell turned out to be necessary for the high-temperature phase to account for its large thermal expansion. In addition, the infrared spectra (vibration frequencies and peak intensities) of these theoretical models were calculated, allowing for univocal identification of the corresponding polymorphs. Last, the limits of our computational method were tested by calculating the phase transition temperatures and their associated enthalpies, and the derived figures compare favorably with the values determined experimentally. PMID- 29115704 TI - Recessive distal motor neuropathy with pyramidal signs in an Omani kindred: underlying novel mutation in the SIGMAR1 gene. AB - BACKGROUND AND PURPOSE: Distal hereditary motor neuropathy (dHMN) due to sigma non-opioid intracellular receptor 1 (SIGMAR1) gene mutation (OMIM 601978.0003) is a rare neuromuscular disorder characterized by prominent amyotrophic distal limb weakness and co-existing pyramidal signs initially described in a Chinese family recently. We report an extended consanguineous Omani family segregating dHMN with pyramidal signs in an autosomal recessive pattern and describe a novel mutation in the SIGMAR1 gene underlying this motor phenotype. We also provide an update on the reported phenotypic profile of SIGMAR1 mutations. METHODS: We utilized homozygosity mapping and whole-exome sequencing of leucocyte DNA obtained from three affected members of an Omani family who manifested with a length-dependent motor neuropathy and pyramidal signs. RESULTS: We identified a novel C>T transition at nucleotide position 238 (c.238C>T) in exon 2 of the SIGMAR1 gene. Sanger sequencing and segregation analysis confirmed the presence of two copies of the variant in the affected subjects, unlike the unaffected healthy parents/sibling who carried, at most, a single copy. The T allele is predicted to cause a truncating mutation (p.Gln80*), probably flagging the mRNA for nonsense mediated decay leading to a complete loss of function, thereby potentially contributing to the disease process. CONCLUSIONS: Our finding expands the spectrum of SIGMAR1 mutations causing recessive dHMN and indicates that this disorder is pan-ethnic. SIGMAR1 mutation should be included in the diagnostic panel of a dHMN, especially if there are co-existing pyramidal signs and autosomal recessive inheritance. PMID- 29115703 TI - Moderators of response to sertraline versus placebo among recently abstinent, cocaine dependent patients: A retrospective analysis of two clinical trials. AB - BACKGROUND AND OBJECTIVES: Moderators of treatment response to serotonin reuptake inhibitor sertraline (SRT) for cocaine dependence were assessed in two randomized, double blind, placebo-controlled clinical trials. METHODS: Generalized estimating equation modeling was performed on data from cocaine dependent volunteers randomized to receive SRT or placebo (N = 126) who completed >2-week drug-free residential portions of the 12-week trials, in which subsequent outpatient treatment (weeks 3-12) included weekly cognitive behavioral therapy and thrice-weekly supervised urine toxicology. PRIMARY OUTCOME MEASURE: Relapse (2 consecutive cocaine-positive or missing urines) following residential stay. Potential moderators included treatment, sex, age, race, depression measures, baseline cocaine urine result, and alcohol dependence diagnosis (ADDx). RESULTS: Odds ratios (OR) for relapse showed placebo-treated participants were significantly more likely to relapse than SRT participants. Regardless of treatment condition, participants more likely to relapse were male, and those with lower Hamilton depression ratings, or baseline cocaine-negative urines. Older subjects or those with current ADDx had higher relapse risk than those without ADDx; however, treating older or ADDx participants with SRT reduced cocaine relapse more than placebo. DISCUSSION AND CONCLUSIONS: Women or those with more severe cocaine use or depressive symptoms may have fewer cocaine relapses regardless of medication treatment. SRT at 200 mg reduced cocaine relapse more than placebo, especially in older participants or in those with comorbid ADDx. SCIENTIFIC SIGNIFICANCE: SRT may be efficacious to support relapse prevention among cocaine-dependent patients in the context of brief residential followed by outpatient treatment, especially in older participants or those with comorbid alcohol/cocaine dependence. (Am J Addict 2017;26:807-814). PMID- 29115705 TI - Co-culturing porcine normal urothelial cells, urinary bladder fibroblasts and smooth muscle cells for tissue engineering research. AB - New strategies for culturing and co-culturing of the main types of urinary bladder cells are essential for successful establishment of biomimetic in vitro models, which could be applied for research into, and management of, diverse urological disorders. Porcine normal urothelial cells are available in nearly unlimited amounts and have many properties equivalent to human urothelial cells. In the present study, we established normal differentiated porcine urothelial cells in co-cultures with porcine urinary bladder normal fibroblasts and/or smooth muscle cells. The optimal culture medium for establishment of differentiated urothelial cells, demonstrated by positive immunofluorescence of uroplakins, cytokeratins (CK 7, CK 20), zonula occludens 1 (ZO-1), claudin 4, claudin 8, and E-cadherin, was the medium composed of equal parts of Advanced Dulbecco's modified Eagle's medium (A-DMEM) and MCDB 153 medium with physiological calcium concentration of 2.5 mM and without fetal bovine serum, named UroM (+Ca2+ - S). This medium was also proven to be suitable for culturing of bladder fibroblasts and smooth muscle cells and co-culturing of urothelial cells with these mesenchymal cells. Urothelial cell differentiation was optimal in UroM (+Ca2+ - S) medium in all co-culture conditions and when compared to all conditioned-media combinations. To summarize, these strategies for culturing and co-culturing of urinary bladder urothelial cells with mesenchymal cells could be used as new in vitro models for future basic and applicable research of the urinary bladder and thus potentially also for translational tissue engineering studies. PMID- 29115706 TI - Seizure-susceptible brain regions in glioblastoma: identification of patients at risk. AB - BACKGROUND AND PURPOSE: The main aim of this study was to identify which patients with glioblastoma multiforme (GBM) have a higher risk of presenting seizures during follow-up. METHODS: Patients with newly diagnosed GBM were reviewed (n = 306) and classified as patients with (Group 1) and without (Group 2) seizures at onset. Group 2 was split into patients with seizures during follow-up (Group 2A) and patients who never had seizures (Group 2B). The anatomical location of GBM was identified and compared by voxel-based lesion symptom mapping (discovery set). Seizure-susceptible brain regions obtained were assessed visually and automatically in external GBM validation series (n = 85). RESULTS: In patients with GBM who had no seizures at onset, an increased risk of presenting seizures during follow-up was identified in the superior frontal and inferior occipital lobe, as well as in inferoposterior regions of the temporal lobe. Conversely, those patients with GBM located in medial and inferoanterior temporal areas had a significantly lower risk of suffering from seizures during follow-up. Additionally, the seizure-susceptible brain region maps obtained classified patients in the validation set with high positive and negative predictive values. CONCLUSIONS: Tumor location is a useful marker to identify patients with GBM who are at risk of suffering from seizures during follow-up. These results may help to support the use of antiepileptic prophylaxis in a selected GBM population and to improve stratification in antiepileptic clinical trials. PMID- 29115707 TI - In vitro screening and isolation of human aromatase inhibitors from Cicer arietinum by a novel continuous online method combining chromatographic techniques. AB - Ultrafiltration liquid chromatography with mass spectrometry can efficiently and rapidly screen and identify ligands from the seeds of Cicer arietinum for human aromatase. Using this method, we identified 11 major compounds, including organic acids, organic acid glycosides, flavone glycosides, isoflavones, and isoflavone glycosides, as potent human aromatase inhibitors. A continuous online method, including pressurized liquid extraction, countercurrent chromatography, and preparative liquid chromatography, was developed for scaling up the production of these compounds with high purity and efficiency. The bioactivity of the separated compounds was assessed by an in vitro enzyme inhibition assay. This novel approach using a combination of ultrafiltration liquid chromatography with mass spectrometry and pressurized liquid extraction with countercurrent chromatography and preparative liquid chromatography as well as an in vitro enzyme inhibition assay could be applied to efficiently screen and isolate human aromatase inhibitors from complex samples and to the large-scale production of functional food and nutraceutical ingredients. PMID- 29115708 TI - CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer. AB - BACKGROUND: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. PROCEDURE: Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2 /dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. RESULTS: The majority of subjects (91%) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 +/- 0.15 hr.m2 /l vs. 0.15 +/- 0.011 hr.m2 /l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. CONCLUSION: Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit. PMID- 29115709 TI - Safety of discharge for children with cancer and febrile neutropenia off antibiotics using absolute neutrophil count threshold values as a surrogate marker for adequate bone marrow recovery. AB - BACKGROUND: Febrile neutropenia (F&N) is common among pediatric oncology patients. However, there is a lack of clarity regarding parameters whereby such patients have demonstrated adequate bone marrow recovery for hospital discharge and empiric antibiotic discontinuation. PROCEDURE: A retrospective review was performed for 350 episodes of F&N occurring at a single institution between 2007 and 2012 in pediatric oncology patients who were afebrile for 24 hr and had no bacterial source identified. Seven-day postdischarge outcomes were assessed and compared based on absolute neutrophil count (ANC) at discharge in order to identify an optimal threshold. RESULTS: Overall, 7-day readmission rates were low (17/350, 4.6%), with patients discharged with post-nadir ANC of 100-199/MUl (2/51, 3.9%), 200-499/MUl (5/125, 4.0%), and >=500/MUl (8/160, 5.0%), all having similar rates. Patients with a discharge ANC < 100/MUl (2/14, 14.3%) had a higher readmission rate. A new bloodstream infection was identified upon readmission in one patient in each discharge ANC range except for ANC of 100-199/MUl, in which none occurred. In a subset of 217 episodes where the ANC fell below 200/MUl during the admission and subsequently rose above 100/MUl, 94 episodes resulted in 126 additional hospital days while subjects awaited further count recovery. One death occurred in a patient whose ANC at discharge was 290/MUl. This patient had received additional chemotherapy after count recovery and prior to discharge, and was readmitted with Clostridium tertium bacteremia. CONCLUSION: These results suggest that a post-nadir ANC > 100/MUl is a safe threshold value for empiric antibiotic discontinuation and discharge home. PMID- 29115710 TI - PMO-Immobilized AuI -NHC Complexes: Heterogeneous Catalysts for Sustainable Processes. AB - A stable periodic mesoporous organosilica (PMO) with accessible sulfonic acid functionalities is prepared via a one-pot-synthesis and is used as solid support for highly active catalysts, consisting of gold(I)-N-heterocyclic carbene (NHC) complexes. The gold complexes are successfully immobilized on the nanoporous hybrid material via a straightforward acid-base reaction with the corresponding [Au(OH)(NHC)] synthon. This catalyst design strategy results in a boomerang-type catalyst, allowing the active species to detach from the surface to perform the catalysis and then to recombine with the solid after all the starting material is consumed. This boomerang behavior is assessed in the hydration of alkynes. The tested catalysts were found to be active in the latter reaction, and after an acidic work-up, the IPr*-based gold catalyst can be recovered and then reused several times without any loss in efficiency. PMID- 29115711 TI - Linear Precision Glycomacromolecules with Varying Interligand Spacing and Linker Functionalities Binding to Concanavalin A and the Bacterial Lectin FimH. AB - A series of precision glycomacromolecules is prepared following previously established solid phase synthesis allowing for controlled variations of interligand spacing and the overall number of carbohydrate ligands. In addition, now also different linkers are installed between the carbohydrate ligand and the macromolecular scaffold. The lectin binding behavior of these glycomacromolecules is then evaluated in isothermal titration calorimetry (ITC) and kinITC experiments using the lectin Concanavalin A (Con A) in its dimeric and tetrameric form. The results indicate that both sterical and statistical effects impact lectin binding of precision glycomacromolecules. Moreover, ITC results show that highest affinity toward Con A can be achieved with an ethyl phenyl linker, which parallels earlier findings with the bacterial lectin FimH. In this way, a first set of glycomacromolecule structures is selected for testing in a bacterial adhesion-inhibition study. Here, the findings point to a one-sugar binding mode mainly affected by sterical restraints of the nonbinding parts of the respective glycomacromolecule. PMID- 29115713 TI - Validated thin-layer chromatographic method for the identification and monitoring of the effect of the extraction method on the yield and phytochemical constituents of Egyptian Withania somnifera leaves. AB - A sensitive, reliable, simple and rapid thin-layer chromatographic method has been developed for routine analysis of withanolide S content for the purpose of quality control assessment of chemotype III of Withania somnifera. The new method was used first to compare the accumulation of withanolide S in different parts of the plant, which was found to be the highest in the leaves extract (0.21% w/w). Second, to investigate different extraction parameters that improve the extraction efficiency of withanolides from the leaves using conventional and ultrasound-assisted extraction methods. The extraction efficiency was expressed via total withanolide content and withanolide S content. PMID- 29115712 TI - Proteomic Profiling of Exosomes Secreted by Breast Cancer Cells with Varying Metastatic Potential. AB - Cancer cells actively release extracellular vesicles, including exosomes, into the surrounding microenvironment. Exosomes play pleiotropic roles in cancer progression and metastasis, including invasion, angiogenesis, and immune modulation. However, the proteome profile of exosomes isolated from cells with different metastatic potential and the role of these exosomes in driving metastasis remains unclear. Here, we conduct a comparative proteomic analysis of exosomes isolated from several genetically related mouse breast tumor lines with different metastatic propensity. The amount of exosomes produced and the extent of cancer-associated protein cargo vary significantly between nonmetastatic and metastatic cell-derived exosomes. Metastatic cell-derived exosomes contain proteins that promote migration, proliferation, invasion, and angiogenesis while the nonmetastatic cell-derived exosomes contain proteins involved in cell cell/cell-matrix adhesion and polarity maintenance. The metastatic exosomes contain a distinct set of membrane proteins including Ceruloplasmin and Metadherin which could presumably aid in targeting the primary cancer cells to specific metastatic sites. Hence, it can be concluded that the exosomes contain different protein cargo based on the host cells metastatic properties and can facilitate in the dissemination of the primary tumors to distant sites. PMID- 29115714 TI - Deep vein thrombosis in pediatric patients. AB - Due to advances in caring for critically ill children and those with chronic diseases, rates of deep vein thrombosis (DVT) are increasing in children. Risk factors consist of central venous catheters, chronic medical conditions, thrombophilia, and various medications. Compression Doppler ultrasonography is the method most commonly used to diagnose DVT, and patients will usually present with pain and swelling of the affected limb. Anticoagulation via subcutaneous injection is the most common treatment regime for children with DVT, and the new, direct oral anticoagulants are currently under investigation. Prevention techniques are not established, but clinical studies are addressing this need. PMID- 29115715 TI - Infusion hemolysis after pediatric major ABO-mismatched bone marrow transplant: Comparison of two red blood cell depletion techniques. AB - BACKGROUND: During major ABO-mismatched bone marrow transplant (BMT), the infusion of incompatible red blood cells (RBCs) that are present in the bone marrow graft can cause adverse events from hemolysis. RBC depletion of the bone marrow graft can decrease this risk, but the optimal method to prevent hemolysis is unclear. PROCEDURE: We conducted a retrospective cohort study of patients who underwent major ABO-mismatched BMT at a pediatric center and had RBC depletion with either hydroxyethyl starch (HES) sedimentation or Ficoll density gradient separation. Postinfusion hemoglobinuria and creatinine values were compared. RESULTS: Between 2002 and 2016, 37 patients received HES-treated and 16 patients received Ficoll-treated major ABO-mismatched bone marrow grafts. The median residual volume of RBCs was significantly greater with HES-treated grafts (HES 21.0 ml vs. Ficoll 1.4 ml, P < 0.0001). Patients who received HES-treated grafts had a higher prevalence of postinfusion hemoglobinuria (HES 57% vs. Ficoll 6%, P = 0.0009), but renal impairment was rare. Considering only HES-treated grafts, the volume of RBCs was not associated with either postinfusion hemoglobinuria or a creatinine increase. CONCLUSIONS: Ficoll density gradient separation achieves smaller RBC volumes and less postinfusion hemoglobinuria than HES sedimentation, but both can prevent significant hemolysis. Further studies are needed to determine the residual incompatible RBC volume threshold in major ABO-mismatched BMT. PMID- 29115716 TI - Long-term results in children with head and neck rhabdomyosarcoma: A report from the Italian Soft Tissue Sarcoma Committee. AB - BACKGROUND: Rhabdomyosarcoma (RMS) occurring at nonparameningeal head and neck (NPM-HN) sites carries a better prognosis than parameningeal RMS and some other sites. We analyzed the treatments administered and results obtained in patients with localized NPM-HN RMS, included in the protocols coordinated by the Italian Soft Tissue Sarcoma Committee (STSC), in an effort to identify prognostic factors that could facilitate the tailoring of treatment. METHODS: Sixty-six patients up to 18 years of age with previously untreated, localized NPM-HN RMS were prospectively registered in three consecutive protocols: RMS79, RMS88, and RMS96. Primary surgery was recommended when complete tumor resection was deemed feasible without mutilations. In other cases, only a biopsy was performed, followed by chemotherapy and delayed surgery and/or radiotherapy (RT). RESULTS: NPM-HN RMS showed favorable characteristics: 72.7% were <5 cm, 72.7% were T1, and 80.3% were N0. With a median follow-up of 16 years (range 7-27), the 10-year progression free survival and overall survival for the whole group were 65.1% (confidence interval [CI]: 52.3-75.3) and 74.2% (CI: 61.8-83.1). Progressive improvement has been seen in the successive protocols. Age and RT emerged as independent prognostic factors. The group of young children (age =2 lines in all four cases in stage III. The IOP did not change after infection. It was 10.2 +/- 5.0 mmHg (range, 3-22 mmHg) before the infection developed, and 12.9 +/- 5.2 mmHg (5-24 mmHg) and 10.7 +/- 4.7 mmHg (3-18 mmHg) at 6 months and 12 months after infection, respectively. CONCLUSION: Because of the small number of BRI patients, the superiority of the treatment was not definitively determined. However, VA was almost maintained in stages I and II, and the IOP did not change after infection. Although further study is necessary, the treatment protocol shown in the study might be a valuable treatment regime. PMID- 29115738 TI - Referees List for Volume 16. PMID- 29115739 TI - Corrigendum. PMID- 29115737 TI - Reinterpreting dermoscopic pigment network with reflectance confocal microscopy for identification of melanoma-specific features. AB - BACKGROUND: Pigment network is an important dermoscopic feature for melanocytic lesions, but alterations in grid line thickness are also observed in melanomas. OBJECTIVE: To investigate features of thick, thin and mixed pigment networks at dermoscopy and their respective features at reflectance confocal microscopy (RCM) for differential diagnosis, correlated with histology. METHODS: All melanocytic lesions with histological diagnosis, evaluated between January 2010 and May 2014, were enrolled and classified according to dermoscopy evaluation of the pigment networks: thin, thick and mixed. RESULTS: Thin network in melanoma was characterized by a honeycombed pattern (P < 0.001), dendritic cells (P < 0.001), atypical ringed pattern (P = 0.035) and structureless area (P = 0.012), whereas round cells (P < 0.001), dendritic cells (P < 0.001) and atypical meshwork pattern (<0.001) characterized thick network in melanoma. Mixed network type in melanoma shared honeycombed (P = 0.049) and typical ringed patterns (P = 0.045) in the thin area and round cells (P < 0.001) and atypical meshwork pattern (P < 0.001) in the thick area. Thin network in nevi was characterized by cobblestone (P < 0.001) and typical ringed patterns (P = 0.035), whereas thick network in nevi showed a typical meshwork pattern (P < 0.001). Mixed nevi shared the same features and patterns, but more frequently with inflammatory infiltrate (P = 0.047). CONCLUSION: Differential diagnosis between melanocytic lesions (nevi or melanoma) in thin, thick and mixed pigment networks observed at dermoscopy can be assisted by RCM to improve diagnostic accuracy. PMID- 29115740 TI - Beyond the burn: psychosocial factors as well as inflammation moderate depression in psoriasis. PMID- 29115741 TI - High-throughput LC-MS/MS method with 96-well plate precipitation for the determination of arotinolol and amlodipine in a small volume of rat plasma: Application to a pharmacokinetic interaction study. AB - A rapid, sensitive, and selective liquid chromatography with tandem mass spectrometry method was developed and fully validated for the simultaneous quantification of arotinolol and amlodipine in rat plasma. Two internal standards were introduced with metoprolol as the internal standard of arotinolol and (S) amlodipine-d4 as the internal standard of amlodipine. The analytes were isolated from 50.0 MUL plasma samples by a simple protein precipitation using acetonitrile. The chromatographic separation was achieved in 5 min on a C18 column. The mobile phase consisted of phase A 5% methanol and phase B 95% methanol (both containing 0.5% formic acid and 5 mM ammonium acetate) and was delivered in gradient elution at 0.300 mL/min. Quantification was performed in multiple reaction monitoring mode with the transition m/z 372.1 -> 316.1 for arotinolol, m/z 268.2 -> 116.2 for metoprolol, m/z 409.1 -> 238.1 for amlodipine and m/z 413.1 -> 238.1 for (S)-amlodipine-d4. Linearity was obtained over the range of 0.200-40.0 ng/mL for arotinolol (r2 = 0.9988) and 0.500-100 ng/mL for amlodipine (r2 = 0.9985) in rat plasma. The validated data have met the acceptance criteria in FDA guideline. This method was successfully applied to a pharmacokinetic interaction study in rats, and the results indicated that there was no significant drug-drug interaction between arotinolol and amlodipine. PMID- 29115742 TI - Nucleophilic Water Capture or Proton Loss: Single Amino Acid Switch Converts delta-Cadinene Synthase into Germacradien-4-ol Synthase. AB - delta-Cadinene synthase is a sesquiterpene cyclase that utilises the universal achiral precursor farnesyl diphosphate (FDP) to generate predominantly the bicyclic sesquiterpene delta-cadinene and about 2 % germacradien-4-ol, which is also generated from FDP by the cyclase germacradien-4-ol synthase. Herein, the mechanism by which sesquiterpene synthases discriminate between deprotonation and reaction with a nucleophilic water molecule was investigated by site-directed mutagenesis of delta-cadinene synthase. If W279 in delta-cadinene synthase was replaced with various smaller amino acids, the ratio of alcohol versus hydrocarbon product was directly proportional to the van der Waals volume of the amino acid side chain. DCS-W279A is a catalytically highly efficient germacradien 4-ol synthase (kcat /KM =1.4*10-3 MUm s-1 ) that produces predominantly germacradien-4-ol in addition to 11 % delta-cadinene. Water capture is not achieved through strategic positioning of a water molecule in the active site, but through a coordinated series of loop movements that allow bulk water access to the final carbocation in the active site prior to product release. PMID- 29115743 TI - Survivability of low pathogenic (H9N2) avian influenza virus in water in the presence of Atyopsis moluccensis (Bamboo shrimp). AB - Low pathogenic avian influenza virus (LPAIV) exhibits an ecological climax with the aquatic ecosystem. The most widely prevalent subtype of LPAIV is H9N2. Wild aquatic birds being the natural reservoirs and ducks, the "Trojan horses" for Avian Influenza Virus (AIV), can contaminate the natural water bodies inhabited by them. The virus can persist in the contaminated water from days to years depending upon the environmental conditions. Various aquatic species other than ducks can promote the persistence and transmission of AIV; however, studies on the role of aquatic fauna in persistence and transmission of avian influenza virus are scarce. This experiment was designed to evaluate the survivability of H9N2 LPAIV in water with and without Atyopsis moluccensis (bamboo shrimp) for a period of 12 days. The infectivity and amount of virus in water were calculated and were found to be significantly higher in water with A. moluccensis than in water without A. moluccensis. The study also showed that A. moluccensis can accumulate the virus mechanically which can infect chicken eggs up to 11 days. The virus transmission potential of A. moluccensis requires further studies. PMID- 29115744 TI - Engineering of a DNA Polymerase for Direct m6 A Sequencing. AB - Methods for the detection of RNA modifications are of fundamental importance for advancing epitranscriptomics. N6 -methyladenosine (m6 A) is the most abundant RNA modification in mammalian mRNA and is involved in the regulation of gene expression. Current detection techniques are laborious and rely on antibody-based enrichment of m6 A-containing RNA prior to sequencing, since m6 A modifications are generally "erased" during reverse transcription (RT). To overcome the drawbacks associated with indirect detection, we aimed to generate novel DNA polymerase variants for direct m6 A sequencing. Therefore, we developed a screen to evolve an RT-active KlenTaq DNA polymerase variant that sets a mark for N6 methylation. We identified a mutant that exhibits increased misincorporation opposite m6 A compared to unmodified A. Application of the generated DNA polymerase in next-generation sequencing allowed the identification of m6 A sites directly from the sequencing data of untreated RNA samples. PMID- 29115745 TI - Asymmetric Imine Hydroboration Catalyzed by Chiral Diazaphospholenes. AB - The first use of diazaphospholenes as chiral catalysts has been demonstrated with enantioselective imine hydroboration. A chiral diazaphospholene prepared in a simple three-step synthesis from commercial materials has been shown to achieve the highest enantioselectivity for the hydroboration of alkyl imines with pinacolborane reported to date. Enantiomer ratios of up to 88:12 were obtained with low (2 mol %) catalyst loadings. Twenty examples of asymmetric reduction employing this main-group catalysis protocol, including the synthesis of the pharmaceuticals ent-rasagiline and fendiline, are shown. PMID- 29115747 TI - Quality patient care: challenges and opportunities. AB - There are several interlocking elements integral to the delivery of safe patient care, including clinical governance, efficient communication, teamwork, risk assessment, inter-professional education and effective leadership. Each element can be challenging to understand, develop, or act on, but it is essential that nurses use these as opportunities to ensure their specialty or service delivers safe and high-quality care. This article discusses each of these elements and its relationship to quality patient care, with specific reference to the role of children's nurses. PMID- 29115748 TI - An integrative review of absenteeism in newly graduated nurses. AB - Managing sickness and absenteeism in the workplace is challenging, and nurse managers must consider their various causes so they can implement effective management strategies. It is also vital to consider the factors that influence absenteeism and turnover among newly graduated registered nurses (RNs), whose retention can help to address staff shortages. This article describes a literature review that aimed to identify the potential causes of sickness absence in newly graduated RNs. It also discusses strategies that nurse managers can use to retain and maintain their workforce. PMID- 29115746 TI - Progress Toward the Clinical Translation of Bioinspired Peptide and Protein Assemblies. AB - Supramolecular materials composed of proteins and peptides have been receiving considerable attention toward a range of diseases and conditions from vaccines to drug delivery. Owing to the relative newness of this class of materials, the bulk of work to date has been preclinical. However, examples of approved treatments particularly in vaccines, dentistry, and hemostasis demonstrate the translational potential of supramolecular polypeptides. Critical milestones in the clinical development of this class of materials and currently approved supramolecular polypeptide therapies are described in this study. Additional examples of not-yet approved materials that are steadily advancing toward clinical use are also featured. Spherical assemblies such as virus-like particles, designed protein nanoparticles, and spherical peptide amphiphiles are highlighted, followed by fiber-forming systems such as fibrillizing peptides, fiber-forming peptide amphiphiles, and filamentous bacteriophages. PMID- 29115749 TI - When study participants are vulnerable: getting and keeping the right team. AB - BACKGROUND: Research assistants (RAs) are critical members of all research teams. When a study involves vulnerable populations, it is particularly important to have the right team members. AIM: To describe the motivations, personal characteristics and team characteristics that promoted the job satisfaction of RAs who worked on two multi-year, randomised clinical trials involving older adults with dementia. DISCUSSION: A survey was conducted with 41 community members who worked as RAs for up to five years. Measures included demographics, work engagement, personality and characteristics of effective teams, as well as open-ended questions about respondents' experiences of the study. Quantitative analyses and coding of open-ended responses were used to summarise results. Almost all the RAs surveyed joined the team because of previous experiences of interacting with cognitively impaired older people. The RA respondents scored higher in 'dedication to work', 'extraversion', 'agreeableness' and 'conscientiousness' than average. An important aspect of their job satisfaction was team culture, including positive interpersonal interaction and the development of supportive team relationships. CONCLUSION: A positive work culture provides RAs with an opportunity to work with a study population that they are personally driven to help, and promotes motivation and satisfaction in team members. IMPLICATIONS FOR PRACTICE: Results from this study can guide the recruitment, screening and retention of team members for studies that include vulnerable populations. PMID- 29115750 TI - Preparing direct care nurses to function as research coordinators in a heart failure study. AB - BACKGROUND: Nurses interviewed heart failure patients admitted to two rural hospitals, to learn what was important to them concerning their disease. Data from this study would inform a subsequent heart failure intervention study. The researchers gained a better appreciation of the role of direct care nurses in research coordination, recruitment and data collection. AIM: To describe lessons learned during this research about using direct care nurses as research coordinators. DISCUSSION: The direct care nurses were highly motivated and engaged in the research, identifying barriers and solutions to enrolling heart failure patients in the hospital. The researchers developed customised educational materials and data management documents to address the nurses' learning needs, ensuring compliance with protocol and the safety of participants. CONCLUSION: Nurse researchers can establish an effective partnership with direct care nurses when conducting research studies. To accommodate learning needs and workplace demands, securing protected time for nurses to complete training, budgeting for administrative support and monitoring recruitment data weekly, as opposed to monthly, may be considered. IMPLICATIONS FOR PRACTICE: Direct care nurses can inform the design and conduct of research conducted in a hospital. PMID- 29115751 TI - Using videoed workshops in interdisciplinary research with people who have disabilities. AB - BACKGROUND: Internationally, interdisciplinary research is advocated in healthcare. Such research receives great respect, particularly from funding bodies, which expect innovations in healthcare to emerge from a whole team rather than a single discipline. However, little guidance exists about the process and structures for such research. AIM: To explore and explain the use of videoed workshops and mixed-media artefacts to collect data, and explore the benefits and challenges for interdisciplinary healthcare research. DATA: sources Videoed workshops were used to ascertain the preferences of eight people who have disabilities concerning assistive technology. These workshops are used to demonstrate the method's benefits and related challenges for interdisciplinary healthcare research. DISCUSSION: This method of collecting data has important potential benefits for healthcare research. Future research in healthcare must not only be interdisciplinary, it should also involve a range of research designs that are adaptive and responsive to service users' needs and use innovative methods of collecting data. CONCLUSION: The use of video and photography in interdisciplinary research for healthcare technology is an exciting possibility, but it poses ethical and practical considerations. IMPLICATIONS FOR RESEARCH: Videos and photography area a useful aid in interdisciplinary research and can be a valuable means of non-verbal data collection, especially with participants affected by disabilities, and can support research methods, such as the use of questionnaires. PMID- 29115752 TI - Aide-memoire diaries in longitudinal research. AB - BACKGROUND: Diaries can be used as contemporaneous tools for gathering data, frequently in combination with interviews. However, diaries can also be used by study participants as personal records to improve their recall during interviews, without having to be collected for analysis. AIM: To discuss the use of diaries as aide-memoires by participants in a study exploring women's views and experiences of the quality of maternity care they received in community maternity units in Scotland. DISCUSSION: The use of aide-memoire diaries was an effective way to enhance the quality of data collected during interviews. CONCLUSION: This use of diaries would help longitudinal research in different contexts, including long-term care, as an aide-memoire to help participants recall their experiences throughout their care. IMPLICATIONS FOR PRACTICE: Aide-memoire diaries provide a private platform for contemporaneously and honestly recording participants' reflective accounts throughout their experiences of care. PMID- 29115753 TI - A novice researcher's reflection on recruiting participants for qualitative research. AB - BACKGROUND: This paper is a reflection by a PhD candidate on her qualitative study involving parents, diabetes educators and school teachers who were caring for a child with type 1 diabetes using intensive insulin therapy in primary school. AIM: To reflect on a novice researcher's experience of recruiting research participants from community, health and education settings in Australia. DISCUSSION: Participants were successfully recruited for the study using internet communication tools: Facebook support groups; the Australian Diabetes Educators Association (ADEA) e-newsletter; and emails sent to school principals. These methods were successful as Facebook and online support groups are popular, the study topic was of interest, the ADEA has many members, and numerous emails were sent to schools. Potential barriers to recruitment were a lack of access to those who did not use Facebook or the internet, gatekeepers, the high workloads of diabetes educators and teachers, and the time needed to obtain ethics approval and send a large number of emails to schools. CONCLUSION: Internet communication tools were successful in recruiting participants from community, health and education settings. However, different approaches were required for each type of participant. Lessons learned from this experience were: the importance of taking time to plan recruitment, including an in-depth understanding of potential participants and recruitment tools, the benefit of being an insider, and the need to work closely with gatekeepers. IMPLICATIONS FOR PRACTICE: An understanding of recruitment is essential for ensuring access to appropriate participants and timely collection of data. The experience of the novice researcher may provide insight to others planning to use internet communication tools for recruitment. PMID- 29115754 TI - Consulting with children, parents and a teacher to shape a qualitative study. AB - BACKGROUND: Patient and public involvement is an emerging element of contemporary research and reflects an acknowledgement of the expertise of people who have personal knowledge or experience of a research topic. AIM: To discuss the value of consultation in contributing to the ethical and methodological choices underpinning a qualitative study. DISCUSSION: The study discussed explored the perceptions and experiences of children aged four to 12 with long-term conditions of being held still by adults during clinical procedures in acute care. Consultation took place in three stages and involved engagement with a children's advisory group and members of the public, including parents and a teacher. CONCLUSION: Engagement shaped the focus, influenced the design and underpinned the ethical basis of the study. In addition, consultation identified that the focus of the research was misunderstood by potential participants and their parents. IMPLICATIONS FOR PRACTICE: Engaging in robust consultation is a valuable process which can inform research design in unexpected ways. Engagement with children ensures that their perspectives are identified and included and shape the study. PMID- 29115755 TI - Nurses as participants in research: an evaluation of recruitment techniques. AB - BACKGROUND: Recruitment and retention of participants, as well as response rates, can be challenging in nursing research. This can be because of the questions asked; the choice of methodology; the methods used to collect data; the characteristics of potential participants; the sample size required; and the duration of the study. Additionally, conducting research with nurses as participants presents several issues for them, including the time needed to participate in the research, the competing commitments for clinical practice, the political and environmental climate, and recruitment itself. AIM: To report on research studies conducted by the authors at a tertiary teaching hospital, to show the lessons learned when recruiting nurses to participate in nursing research. DISCUSSION: The authors discuss factors that supported recruitment of nurses in these studies, including the use of the personal touch and multiple recruitment strategies in a single study. CONCLUSION: Videos and photography facilitate interdisciplinary research and can be a valuable means of non-verbal data collection, especially with participants affected by disabilities, and can support research methods, such as the use of questionnaires. IMPLICATIONS FOR PRACTICE: Recruiting nurses for research can be challenging. We suggest that researchers consider using more than one recruitment strategy when recruiting nurse participants. Recruitment is more successful if researchers align the aim(s) of the research with nurse's concerns and contexts. PMID- 29115756 TI - Assessing for head injury in alcohol-intoxicated patients. AB - Each year, 1.4 million people with recent head injuries attend emergency departments in England and Wales. The incidence of head injury in acutely intoxicated patients is estimated to be as high as 65%. One of the challenges of assessing and managing patients who have consumed drugs or alcohol is that the signs and symptoms of this type of intoxication are also risk factors for intracranial complications and head injury, which makes differentiation between the two diagnoses difficult. This article examines the literature on assessment and management of intoxicated patients with head injuries to identify the challenges faced by healthcare professionals undertaking neurological assessments. The article, which includes a case study to illustrate some of these challenges, also explores how staff perceptions can affect assessment and management, and the effects of alcohol on Glasgow Coma Scale scores. PMID- 29115757 TI - Parkinson's disease: nursing care in emergency settings. AB - In the UK 127,000 people are diagnosed with Parkinson's disease, many of whom are frequently admited to hospital. However, Parkinson's disease is not usually the primary cause of admission. Emergency department (ED) nurses must be aware of the medication needs of people with Parkinson's disease and how these can be met in emergency setings to ensure the stability of their condition and to prevent the development of neuroleptic malignant syndrome, a potentially fatal condition caused by abrupt omission of Parkinson's medication. This article highlights the importance of ensuring that patients with Parkinson's disease continue their medication regimen while in an ED, even if they are temporarily unable to swallow, and uses a case study to illustrate various ways of achieving this. PMID- 29115758 TI - Neurofibromatosis and the role of the specialist adviser. AB - Neurofibromatosis (NF) is a genetic condition that mainly involves the nervous system. There are two types: NF1 affects about one in 2,500 of the population worldwide and NF2 affects one in 35,000. Both types result in complex health problems for patients and can pose significant challenges for all those involved in their management. Established in 1981, The Neuro Foundation is a patient focused charity that funds a network of specialist advisers who work in partnership with the NHS to offer support and advice for families affected by NF and the professionals who care for them. With a significant level of autonomy, the specialist adviser role is flexible in matching the needs of those affected while working cooperatively alongside the national specialist services for NF1 and NF2. PMID- 29115760 TI - Efficacy and safety of cannabis for treating children with refractory epilepsy. AB - The aim of this literature review was to examine the evidence base for the safety and efficacy of cannabis in treating children with refractory epilepsy. Clinical and medical databases were searched and four articles were included in the final analysis, which included retrospective reviews and open-label trials with a total sample size of 424. One clinical trial included administration of cannabidiol, the non-psychoactive compound of cannabis, while the other three articles stated that the compound administered to participants contained tetrahydrocannabidiol, the psychoactive constituent of cannabis. Cannabis may reduce seizures in some children and young people with refractory epilepsy, however, its success may be affected by aetiology of the epilepsy or concomitant anti-epileptic drug use, and a therapeutic dose has not been found. Positive side effects were also found including improved sleep, alertness and mood. More research is needed on this subject, including randomised controlled trials. Nurses who are aware of patients and families wishing to trial cannabis for refractory epilepsy should have full and frank discussions. PMID- 29115759 TI - Ghanaian nurses' knowledge of invasive procedural pain and its effect on children, parents and nurses. AB - AIM: To explore Ghanaian nurses' knowledge of invasive procedural pain in children who are in hospital and to identify the effect of unrelieved pain on children, parents and nurses. METHOD: An exploratory, descriptive and qualitative design was adopted. A purposive sampling technique was used and individual face to-face, semi-structured interviews were conducted with 16 registered nurses from four children's units at a hospital in the Eastern Region of Ghana. Thematic and content analyses were performed. FINDINGS: Four themes emerged: types of invasive procedure; pain expression; pain assessment; and effects of unrelieved pain. Participants had adequate knowledge of painful invasive procedures, however, they were not aware of the range of available validated pain assessment tools, using observations and body language instead to assess pain. CONCLUSION: Ghanaian nurses require education on the use of validated rating scales to assess procedural pain in children. The inclusion of pain assessment and management in pre-registration curricula could improve knowledge. PMID- 29115762 TI - Interdisciplinary care of a neonate with haemophagocytic lymphohistiocytosis. AB - Haemophagocytic lymphohistiocytosis (HLH) is a rare condition not commonly observed in neonatal units. It poses a challenge to neonatal staff to source expertise and information when diagnosing and treating patients with this condition. This article uses a case study of a neonate with HLH to analyse interdisciplinary team dynamics in hospital and explore how teams can effectively share knowledge and learn from each other when treating patients with rare and complex conditions. PMID- 29115761 TI - Diagnosis and management of children with primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is a rare, genetic disorder of the motile cilia characterised by chronic lung disease, nasal and sinus disease, chronic ear infections with glue ear leading to possible hearing impairment, and subfertility. Half of patients have organ laterality defects. Despite symptoms being present from birth, PCD remains underdiagnosed. Early diagnosis and symptom management may reduce morbidity, improve quality of life and ensure children are adequately supported to meet their full potential. This article seeks to raise awareness of PCD in children's nurses who are well placed to identify children for referral to the national PCD diagnostic service. It examines the clinical characteristics of the disease along with the complexities and limitations of diagnostic testing. In addition, it explores the management of children with PCD within the national PCD management service for children. PMID- 29115763 TI - How modifiable factors influence parental decision-making about organ donation. AB - A global shortage of organs from children and adults available for transplantation is compounded by the failure of next of kin to consent for organs to be donated after death. Non-modifiable and modifiable factors influence decision-making in this area. Modifiable factors are of interest when examining families' decision-making about the donation of organs from their deceased child. A scoping review was undertaken to determine how modifiable factors influence parental decision-making about organ donation. Thematic analysis identified two themes: interactions with healthcare professionals and pre-disposition to organ donation. Satisfaction with experiences of hospital care, the information provided and the way it was communicated, as well as interactions pertaining to emotional support were all found to be modifiable factors that influenced decision making. Likewise, a predisposition to organ donation and knowing the deceased's wishes were associated with the consent decision. Nurses working in critical care environments need to be able to support parents during this difficult time. This article aims to raise awareness of modifiable factors that influence parental decision-making, highlighting their relevance for children's nursing practice. PMID- 29115764 TI - Development of a clinical transition pathway for adolescents in the Netherlands. AB - AIMS: To explore how young people with juvenile-onset rheumatic and musculoskeletal diseases (jRMDs) and their parent(s) experience care during preparation for the upcoming transfer to adult services, and to develop a clinical transition pathway. METHOD: A survey was conducted with 32 young people aged between 14 and 20 years with jRMDs, and their parents ( n =33), treated at the department of paediatric rheumatology in a tertiary care children's hospital in the Netherlands. RESULTS: More than 30% of young people would have liked to discuss topics such as educational and vocational choices in a clinic, but did not get the opportunity. Preparation for transition was poor as was training in self-management skills. One third of parents had feelings of anxiety about the upcoming transfer. Results from the survey and evidence-based principles of transitional care were used to develop the clinical transition pathway. The pathway focuses on starting transition early, developing self-management skills, joint consultations and supporting parents in giving young people control of their clinical care. CONCLUSION: Care does not currently meet the needs of young people in the process of transition to adult rheumatology services. The clinical transition pathway developed as a result of the study is a tool that may improve this process. PMID- 29115766 TI - Recognition and nursing management of sepsis in early infancy. AB - Neonatal sepsis describes serious bacterial or viral infections that manifest in the first 28 days of life, causing significant morbidity and mortality. Although most babies with early-onset neonatal sepsis are born and managed in hospital, some are born in the community, or discharged early from postnatal wards. Consequently, emergency department (ED) nurses and other healthcare professionals need to be able to identify and treat these infants effectively to improve long term outcomes. This article discusses neonatal sepsis, including causative organisms, types of neonatal sepsis and why neonates are vulnerable to infection. The National Institute for Health and Care Excellence 2012 and 2014 guidance is also discussed in relation to management of neonatal sepsis and a case study is included to illustrate some of the challenges that ED nurses may encounter. PMID- 29115765 TI - Behavioural approaches to treating overweight and obesity in adolescents. AB - Being overweight and obese in adolescence are significant global public health issues which threaten the viability of basic healthcare delivery in many countries. The number of affected adolescents is growing at an alarming rate. Behavioural treatment, which refers to a set of principles and techniques designed to help people reverse maladaptive eating and activity habits, has become a crucial part of most programmes designed to address overweight and obesity. This article outlines three steps involved in the behavioural treatment of overweight and obesity in adolescents: antecedents, eating behaviour and the consequences of eating behaviour. Regular and consistent daily recording of food intake and the individual's activities are foundations of behavioural management, and should form part of the nursing care plan. PMID- 29115767 TI - Care delays in patients with signs and symptoms of acute myocardial infarction. AB - AIM: More than six million patients with signs and symptoms suggestive of a heart attack present to emergency departments (EDs) in the US each year. Of those diagnosed with acute myocardial infarction (AMI), one third die in the acute phase. Rapid ED triage can reduce the mortality rate, yet there are still delays in patient care. The aim of this study is to explore the relationship between patient and nurse characteristics, patient presentations, delays in triage, and delays in obtaining electrocardiograms (ECGs) of patients with signs and symptoms of AMI. METHODS: A retrospective correlational study drawing on data from the records of 286 patients with signs and symptoms of AMI. RESULTS: Delays in triage are related significantly to patients' gender and race. Most patients were triaged by nurses with associate degrees in nursing, a mean age of 45 and a mean of 18 years' experience. An increase in nurse years of experience predicted greater delay in triage. Delays in obtaining ECGs were also significantly greater with more experienced nurses and when patients reported no chest pain. CONCLUSION: The study adds to the literature on delays in triage and ECGs in care of patients with possible AMI, and further research of the effects of ED crowding and availability of resources in emergency cardiac care is warranted. Studies should identify the processes that cause delays in the emergency care of patients with signs and symptoms of AMI to ensure timely treatment and care. PMID- 29115768 TI - Lean thinking in emergency departments: concepts and tools for quality improvement. AB - The lean approach is a viable framework for reducing costs and enhancing the quality of patient care in emergency departments (EDs). Reports on lean-inspired quality improvement initiatives are rapidly growing but there is little emphasis on the philosophy behind the processes, which is the essential ingredient in sustaining transformation. This article describes lean philosophy, also referred to as lean, lean thinking and lean healthcare, and its main concepts, to enrich the knowledge and vocabulary of nurses involved or interested in quality improvement in EDs. The article includes examples of lean strategies to illustrate their practical application in EDs. PMID- 29115769 TI - Importance of measuring lactate levels in children with sepsis. AB - Sepsis is a major public health problem as well as one of the leading causes of preventable death in children because of failure to recognise the early signs and symptoms and to resuscitate rapidly. Blood lactate levels are used to assess the severity of sepsis and the effectiveness of resuscitation. Lactate levels are easily obtainable and should be checked in all patients admitted with suspected sepsis within six hours of presentation. The test should be repeated four and eight-hours post-diagnosis of sepsis. For the diagnosis of sepsis, patients' clinical symptoms, along with the combined analysis of partial pressure of oxygen, carbon dioxide and lactate levels, should be used. A multitude of factors can cause elevated lactate levels and so clinicians should use elevated levels cautiously by considering all other aetiologies. This article, which focuses on practice in Australia but makes reference to the UK, discusses the importance of measuring lactate levels in sepsis, the pathophysiology of lactate production, causes of elevated lactate levels, lactate measurement, nursing management of patients with elevated lactate levels, limitations of using lactate as a biomarker for diagnosing sepsis and implications for practice. PMID- 29115770 TI - Transition of care from children's to adult services. AB - Transition service development is high on the agenda in contemporary healthcare improvement and there is a wealth of literature focusing on the shortcomings of many existing transition services. This literature review aims at identify and summarise research on the issues and needs surrounding transitional care from children's to adult services, and to explore, critique and evaluate the effectiveness of interventions, processes and systems relating to supporting transitions for young people between children's and adult services. Many studies focus on the transition of young people from children's to adult services. Some areas of transitional care have been researched thoroughly, including the self reported experiences of young people. A large number of studies have explored specific interventions aimed at young people and healthcare systems. A single approach or intervention to support transition appears to be neither beneficial for all young people, nor appropriate for all services. The effect of specific interventions is largely inconclusive. PMID- 29115771 TI - An advanced nurse practitioner service for neonates, children and young people. AB - The NHS continues to face unprecedented demands and reform which necessitates a move away from traditional modes of delivery. Over the past ten years economic austerity, changes to legislation and professional career developments have led to healthcare service redesign and innovations in nursing roles, including the development of the advanced nurse practitioner (ANP) role. This article explores how one organisation created an ANP service for out-of-hours neonatal and paediatric care in a district general hospital setting. It was found that ANPs help to provide continuity of care, support learning, inspire continued professional development and lead on healthcare agendas. However, the ANP service faced factors not exclusive to local context including an ageing workforce, difficulties in recruiting and retaining suitably qualified staff and economic pressures. The future of the service depends on it overcoming these factors while demonstrating that the shift from traditional models of care can lead to a positive outcome. PMID- 29115772 TI - Graphic facilitation as a novel approach to practice development. AB - The active participation of staff from the outset of any health service or practice improvement process ensures they are more likely to become engaged in the implementation phases that follow initial service analyses. Graphic facilitation is a way of getting participants to develop an understanding of complex systems and articulate solutions from within them. This article describes how a graphic facilitation process enabled the members of a multidisciplinary team at a specialist paediatric neurosurgery hospital in Uganda to understand how their system worked. The large graphic representation the team created helped each team member to visualise their day-to-day practice, understand each person's contribution, celebrate their triumphs and highlight opportunities for service improvement. The process highlighted three features of their practice: an authentic interdisciplinary team approach to care, admission of the primary carer with the child, and previously unrecognised delays in patient flow through the outpatients department. The team's active participation and ownership of the process resulted in sustainable improvements to clinical practice. PMID- 29115773 TI - How nurses and midwives feel about revalidation: preliminary survey results. AB - The introduction in 2016 of the Nursing and Midwifery Council revalidation process, which involves several standardised steps, has represented a major change for UK nurses and midwives, and is now a compulsory requirement of reregistration. This article presents preliminary results of a survey about revalidation, undertaken in June 2016 at Oxleas NHS Foundation Trust, Dartford, focusing on how nurses and midwives feel about the process. The article considers the effect of different variables, including pay band, seniority and directorate, on nurses' and midwives' perceptions of revalidation, and suggests it is regarded more positively by senior, more experienced staff than by those who are less experienced. PMID- 29115774 TI - The supervisory ward manager's role: progress on Compassion in Practice action area four. AB - In 2012, the Department of Health published Compassion in Practice, which included six areas for action. Action area four suggests that ward managers and leaders should be supervisory, and not included in ward staff numbers. The recommendation has recently been changed to promote black and minority ethnic (BME) leadership in the NHS. This article examines the literature on supervisory nurse leader roles between 2007 and 2017 to identify what, if any, progress has been made. Although supervisory status can improve care at ward level, and was endorsed by the Francis Report, it seems that few care providers in England have invested in this, possibly because it is voluntary, rather than a statutory requirement. The article argues that, rather than focusing on BME leadership, commissioners and providers should consider implementing the original action four to support the lessons learned in the Francis Report. PMID- 29115776 TI - FEMALE GENITAL MUTILATION AS AN ISSUE OF GENDER DISPARITYIN THE 21ST CENTURY: LEVERAGING OPPORTUNITIES TOREVERSE CURRENT TRENDS. PMID- 29115775 TI - Strengthening ethical decision-making: the experience of Iranian nurses. AB - AIMS: Ethical decision-making is a complex process that nurses perform daily. The aim of this study is to explain how ethical leaders in Iran strengthen ethical decision-making in their nursing teams. METHOD: Data were collected using deep and semi-structured interviews with 20 Iranian nurses in 2015. Analysis was based on constant comparative analysis. RESULTS: Ethical leaders strengthen ethical decision-making by promoting ethical commitment, developing an ethical atmosphere and guiding ethical decision-making. CONCLUSION: The development of ethical decision-making in nursing can improve ethics-based nursing care. PMID- 29115777 TI - DETERMINANTS OF FEMALE GENITAL MUTILATION PRACTICES IN EASTGOJJAM ZONE, WESTERN AMHARA, ETHIOPIA. AB - Background: Female genital mutilation is one of the harmful traditional practices among women and girls. Morethan 130 million girls and women live today who have undergone female genital mutilation. In Ethiopia, a highprevalence (74.3% national and 68.5% in Amhara region) has been reported. This study was aimed to identifydeterminant factors of female genital mutilation practices in East Gojjam Zone, Western Amhara, Ethiopia Methods: community based cross sectional study was conducted among 730 women aged 15-49 years and havingchildren < 5 years old in September, 2014. Data were collected using a pretested interviewer administeredquestionnaire. Descriptive statistics were used to describe study objectives, and bivariate and multivariate analysisto identify determinant factors to female genital mutilation. Results: 718 women and 805 daughters participated in the study. FGM prevalence was 689 (96%) and 403 (49%)among women and daughters< 5 years of age, respectively. Type1 and type 2 FGMs were common and daughters<1 years of age exhibited 91% female genital mutilation. Daughters' age, parent education level, residence,women circumcision history, culture, health education, frequent health extension workers follow up and participationin anti FGM interventions were risk factors to female genital mutilation practice. Conclusions: Female genital mutilation practices continues to be a major problem to women and daughter <5years of age in the study area. A number of factors were associated with FGM practices including daughters' age,parent education level, residence, health education, culture, mothers circumcision history, frequent health extensionsworkers follow up and participation in anti FGM interventions were determinants to higher FGM practices. PMID- 29115778 TI - PATTERN AND OUTCOME OF RENAL DISEASES IN HOSPITALIZED CHILDRENIN TIKUR ANBESSA SPECIALIZED TEACHING HOSPITAL,ADDIS ABABA, ETHIOPIA. AB - Background: Renal diseases are major causes of morbidity and mortality in pediatric practice. Pediatric patientswith renal disease, especially younger ones may present with nonspecific signs and symptoms unrelated to the urinarytract. Unexplained fever or failure to thrive may be the only manifestation. Most children with renal diseasesin our hospital arrive very late either because of inadequate health awareness among the parents or failure of recognizingthe symptoms of renal diseases at a lower health care level. This review will highlight the symptoms ofrenal diseases at presentation and outcomes of treatment in children in a major referral hospital. Methods: A cross-sectional retrospective chart review was done over a period of 3 years (June, 2012 to May,2015) in 381 admitted children (Birth-17 years) at Tikur Anbessa Specialized Teaching Hospital in Addis Ababa,Ethiopia. Results: Out of 14521 pediatric ward admissions in the study period, kidney diseases accounted for 473 admissionsin 381 children, accounting for 3.3% of all admissions. The three most common renal diseases observed werecongenital anomalies of the kidney and urinary tract (CAKUT) seen in 127 children (26.8%), followed bynephrotic syndrome in 80 children 16.9% and acute glomerulonephritis in 58 children (12.2%). Other renal diseasesobserved were urinary tract infection 8.0%, urolithiasis 6.7%, Wilm's tumor 6.3%, acute kidney injury 4.2%and chronic kidney disease 4.0%. Other less frequently detected diseases were bladder exstrophy, lupus nephritis,Henock shonlein Purpura nephritis and prune-belly syndrome.Out of 381 children 207 (54.3%) recovered normal renal function, 20(5.2%) remained with proteinuria, 13(3.4%)progressed to chronic kidney disease and 11(2.9%) died. Sixty one nephrotic children (76.3%) achieved remissionbut 17 children (21.3%) remained with proteinuria; one steroid resistant child died of end stage renal disease. Tenchildren (2.6%) with different renal diseases were lost to follow-up and 5 (1.3%) discharged against medical advice. Conclusions: This data reflects that many of the renal diseases are preventable or potentially curable. Therefore,improvement of pediatric renal services and training of health workers would help in early detection and treatmentof these conditions leading to reduction in their morbidity and mortality. PMID- 29115780 TI - ? PMID- 29115779 TI - ? PMID- 29115781 TI - A FOUR-YEAR REVIEW OF GERIATRIC MENTAL HEALTH SERVICES.IN A LAGOS BASED HOSPITAL, NIGERIA AB - Background: There is a growing global concern about the public health implications of the increasing populationof the elderly. One main issue of concern is centered on how to address their mental health needs using homegrowninterventions and services. We expect that important lessons on geriatric mental health issues would bebrought to fore in this report. Methods: This is a four-year (2007-2011) retrospective report on the mental health services rendered to 938 clientsaged 60 years and above at a Lagos based mental health treatment facility in Nigeria. Designed questionnaireswere filled with socio-demographic and clinical data obtained from patients case notes based on the objectivesof the study. Results: The mean (standard deviation) age of elders was (+/-7.93) 69.6 years, and 65.5% were females. Majoritywere married, self employed and belonged to low socio-economic status (73.1%, 63.1% and 63.2%, respectively).Close to two-thirds (62.4%) commute for at least one hour to get treatment. The commonest diagnosis was psychoticdisorders (34.8%), while 5.5% had Alzheimer's dementia. Some 96.5% of the elders were solely on medications.About a quarter had past history of mental illness and 48.5% reported co-morbid medical conditions, withcardiovascular problems (53.0%) being the commonest physical comorbidity. The middle old along with very oldelders (aged>=70 years), and those with at least tertiary education, were more likely to present with dementia were more likely to present with index episode of mental illness and receive outpatient care Conclusion: The elders were managed for a wide range of treatable mental illnesses and other comorbidities andcommute for hours to access care. Pharmacotherapy was the preponderant sole treatment modality. There is needfor sustained development of expertise to enhance multimodal care and scaling up of comprehensive geriatricmental health services. Further research is needed on how to appropriately link and/or integrate geriatric carewith services at all-tiers of health care delivery. PMID- 29115783 TI - PANCYTOPENIA IN PREGNANT MOTHERS FROMEASTERN SHOA ZONE OF ETHIOPIA: A CASE SERIES. AB - Pregnancy is a state of high metabolic demand. Anemia and thrombocytopenia, commonly as a result of the normaldilutional effect of increased plasma volume during pregnancy, are frequently seen in pregnant women but arenot severe enough to require intervention unless aggravated by deficiency of micronutrients. Nutritional deficiencyrelated anemia is often seen in developing countries. In this study, we describe seven cases of severe thrombocytopenia,anemia and leukopenia (pancytopenia) from the same geographic locality and similar clinical presentation.The cases were referred to the Tikur Anbessa Specialized Hospital (TASH) for investigation and treatment. Potentialcauses, methods of prevention and treatment options are discussed along with relevant clinical and laboratoryfindings of the cases. PMID- 29115782 TI - REVIEW OF THE CLINICAL, COMPUTERIZED TOMOGRAPHY SCAN AND/ORMAGNETIC RESONANCE IMAGING FINDINGS OF INTRACRANIALTUBERCULOMA IN AN ETHIOPIAN TEACHING HOSPITAL. AB - ackground: Ethiopia is one of the countries that has high burden of all forms of tuberculosis and there is no publishedreport on computerized tomography scan and/or magnetic resonance imaging of intracranial tuberculomas.Objective : to review the clinical, computerized tomography and/or magnetic resonance imaging features of intracranial tuberculoma. Methods: retrospective review of patient's medical records of patients operated for intracranial mass that hadcomputerized tomography and/or magnetic resonance imaging brain scans and had histopathological diagnoses,at Tikur Anbessa Specialized Hospital between January 2009 and June 2013. Results: Of 222 operated cases of intracranial mass subjected to histopathological test 29 (14.6%) were found tohave tuberculomas, 28 (14.1%) had caseous necrosis and one was a tuberculous abscess, in 25 cases imaging wasavailable for review and were included in the study . There were 15 males and 10 females with age range being 2to 65 years and with the Median age being 13 years. Twenty patients had computerized tomography and five patientshad magnetic resonance imaging. Seizure 15/25 (60%) and headache 11/25 (44%) were the commonestpresentation. Solitary or confluent large lesions were seen in 12/25 (48%) of patients. 14/25 (56%) of the lesionshad their size between 2 cm and 5 cm. Majority of the lesions 15/25 (60%) were in the frontal and parietal lobes.The lesions were isodense on CT in 18/25 (72%) of the pre-contrast studies and 21/25 (84%) showed ring or rimenhancement after intravenous administration of the contrast medium. Conclusion: Tuberculoma, more frequently, presented with non specific clinical findings and chronic seizure disorderand comonly occurred in young patients and often seen infratentorialy. It is often complicated with hydrocephalusin the pediatric age group. Computerized tomography scan and/or magnetic resonance imaging featuresare not different from reports from other countries. PMID- 29115784 TI - HYDATID CYST DISEASE IN THE LEFT LATERAL NECK:AN UNCOMMON PRESENTATION. AB - Cysts commonly occurring in the neck include thyroglossal cyst and dermoid cysts in the midline, cystic thyroidnodules, branchial cysts and cystic Hygroma in the lateral neck. Hydatid cyst disease is commonly seen in the rightlobe of the liver, the lung and rarely in other parts of the body. In general, cysts in the neck are not common in thesecond decade of life. In this article, we present a case of hydatid cyst presenting as left lateral cystic mass in anEthiopian boy. The diagnostic difficulty, the need for diagnostic suspicion and consideration of hydatid cyst in thedifferential diagnosis and the management options are discussed. PMID- 29115785 TI - RE-EXPANSION PULMONARY EDEMA FOLLOWING REPAIR OF MISSED POST TRAUMATIC DIAPHRAGMATIC HERNIA A CASE REPORT AND REVIEW OF LITERATURES. AB - Reexpansion pulmonary edema following repair of missed diaphragmatic hernia is very rare .Here reported is a case of bilateral reexpansion pulmonary edema occurring after reconstruction of left sided post traumatic diaphragmatic hernia. The patient was re intubated and ventilated later put on supplemental oxygen via a catheter through the endotracheal tube followed by extubation and non re breather face mask to compensate for hypoxemia. He was given intravenous diuretics and inotropic support. Forty-eight hours after the acute event, the patient recovered with minimal residual hypoxemia. Reexpansion pulmonary edema after repair of missed diaphragmatic hernia is a rare complication with a high mortality rate of up to 20%. It should be considered in cases of hypoxemia following any chest reexpansion procedure. The exact pathophysiology leading to this complication is not clear but it is believed to be permeability pulmonary edema as a result of pulmonary micro vascular damage. Risk factors for reexpansion pulmonary edema should be evaluated and considered prior to insertion of chest tubes. Treatment is supportive and emphasis should be given for preventive measures. PMID- 29115786 TI - LESSONS FOR THE FUTURE IN THE HEALTH SECTOR IN ETHIOPIA:SHARING EXPERIENCES WITH THE NEW GENERATION. PMID- 29115788 TI - Sharing information: Mixed-methods investigation of brief experiential interprofessionaltraining for healthcare staff. AB - In UK health policy 'sharing good information is pivotal to improving care quality, safety, and effectiveness. Nevertheless, educators often neglect this vitalcommunication skill. The consequences of brief communication education interventions for healthcare workers are not yet established.This study investigated a three-hour interprofessional experiential workshop (group work, theoretical input, rehearsal) training healthcarestaff in sharing information using a clear structure (PARSLEY). Staff in one UK hospital participated. Questionnaires were completed before, immediatelyafter, and eight weeks after training, with semistructured interviews seven weeks after training. Participants (n=76) were from assorted healthcareoccupations (26% non-clinical). Knowledge significantly increased immediately after training. Self-efficacy, outcome expectancy, and motivationto use the structure taught were significantly increased immediately following training and at eight weeks. Respondents at eight weeks (n=35) reportedtheir practice in sharing information had changed within seven days of training. Seven weeks after training, most interviewees (n=13) reportedconfidently using the PARSLEY structure regularly in varied settings. All had re-evaluated their communication practice. Brief training altered self reported communication behaviour of healthcare staff, with sustained changes in everyday work. As sharing information is central to communication curricula, health policy, and shared decision-making, the effectiveness of brief teaching interventions has economic and educational implications. PMID- 29115787 TI - The Redesign of the Matching Market for American Physicians: Some Engineering Aspects of Economic Design. AB - We report on the design of the new clearinghouse adopted by the National Resident Matching Program, which annually fills approximately 20,000 jobs for new physicians. Because the market has complementarities between applicants and between positions, the theory of simple matching markets does not apply directly. However, computational experiments show the theory provides good approximations. Furthermore, the set of stable matchings, and the opportunities for strategic manipulation, are surprisingly small. A new kind of "core convergence" result explains this; that each applicant interviews only a small fraction of available positions is important. We also describe engineering aspects of the design process. PMID- 29115789 TI - Can conversation analytic findings help with differential diagnosis in routine seizure clinic interactions? AB - There are many areas in medicine in which the diagnosis poses significant difficulties and depends essentially on the clinician's ability to take and interpret the patient's history. The differential diagnosis of transient loss of consciousness (TLOC) is one such example, in particular the distinction between epilepsy and 'psychogenic' non-epileptic seizures (NES) is often difficult. A correct diagnosis is crucial because it determines the choice of treatment. Diagnosis is typically reliant on patients' (and witnesses') descriptions; however, conventional methods of history-taking focusing on the factual content of these descriptions are associated with relatively high rates of diagnostic errors. The use of linguistic methods (particularly conversation analysis) in research settings has demonstrated that these approaches can provide hints likely to be useful in the differentiation of epileptic and non-epileptic seizures. This paper explores to what extent (and under which conditions) the findings of these previous studies could be transposed from a research into a routine clinical setting. PMID- 29115790 TI - Talking about paranoid experiences: Interactional dynamics of accomplishing disclosure of psychotic symptoms in triadic conversation. AB - The present study is the first to investigate, using conversation analysis, the effects of a family member's participation in conversation regarding the assessment of need for treatment. We aim at describing the course of a treatment negotiation, focusing on interactional dynamics and on disclosure of paranoid symptoms in a clinically challenging situation characterized by an acutely psychotic patient with (1) disorganized discourse, (2) poor insight, (3) aspiration to avoid hospital treatment, and (4) a relative who was supporting in patient care. In the triadic conversation, in which the patient, his relative, and the psychiatrist participated, different consecutive phases were distinguished. The Relative Prominent Information Phase (RIP) was characterized by the relative's statements on the patient's problematic behavior, and conflicting views between the patient and his relative led to denial of symptoms by the patient. When the patient was prominent in the latter Patient Prominent Information Phase (PIP), the display of several different social actions and corresponding linguistic devices were linked with more overt talk about paranoid experiences by the patient, albeit in a disorganized manner. RIP and PIP were followed by an Evaluation and Decision Phase (EDP). PMID- 29115791 TI - The Gastroenterology Fellowship Market: Should There Be a Match? AB - We are helping a task force of the American Gastroenterology Association to evaluate the current state of the (decentralized) market for gastroenterology fellows, and to assess the prospects of reorganizing it via a suitably designed centralized clearinghouse, a "match." This market used a match from 1986 until the late 1990s. Starting in 1996, participation in the match declined precipitously, and it was formally abandoned after 1999. Consequently, the experienceof this market when the match was in place, in comparison to the periods before and since, allows an assessment of the effects of the match. An analysis of how the match failed in the 1990s yields insights into the prospects for success of a new match. These events offer economists a rare window on how decentralized labor markets clear, and on how market clearinghouses succeed and fail. PMID- 29115792 TI - Using Chinese medicine in a Western way': Negotiating integrative Chinese medicine treatment for Type 2 Diabetes. AB - Type 2 diabetes affects Chinese Americans at an alarming rate and many Chinese Americans use Chinese medicine principles to deal with their diabetes. In this article, we examine interviews with Chinese medicine practitioners about the best ways to treat diabetes and xiaoke (Chinese medicine's closest equivalent to diabetes). These interviews were conducted to examine how practitioners would promote a particular form of integrative medicine - in this case, using Chinese medicinal principles to suggest food treatments for diabetes or xiaoke. Our research expands understandings of integrative medicine and Chinese medicine recognizing that in practice, the static categories of Chinese and Western diagnosis and treatment are not very useful for understanding how integration occurs. Instead, Chinese medicine practitioners negotiate between the poles of individual and standardized on one dimension and physical and energetic on another dimension as a way of practicing Chinese medicine and enregistering their professional identities here in the U.S. Examining these interviews from a language and social interaction perspective, we present integration as a performance and enactment of social personae rather than a product. We highlight the need to attend to differences in what oftentimes is treated as a monolithic community of Chinese medicine in the U.S. PMID- 29115793 TI - How to value patients with psychosis: An inductive study of psychiatrists' behaviour in routine consultations. AB - Valuing patients underlies good communication in psychiatry and mediates positive outcomes. The aim of this study was to (1) identify and reliably assess valuing and devaluing communicative behaviour of psychiatrists in routine consultations, and (2) explore whether valuing behaviour is associated with patient satisfaction. In an inductive study, psychiatrists' valuing and devaluing behaviours were operationalized and identified in 100 video-recorded consultations with patients with psychosis. Inter-rater reliability of identifying these behaviours was assessed. Associations with patients' satisfaction were explored using a mixed linear regression model. We identified 18 different valuing behaviours - e.g. seeking patient's views and supportive statements - and four devaluing behaviours - e.g. talking over the patient and poor responding to concerns - that could be assessed with good reliability. The inter-rater reliability was high (ICC=.89). More valuing behaviour was linked to higher patient satisfaction with the communication (beta=.45, CI .14 to.77, p p<.01). It was found thatpsychiatrists value and devalue patients through a wide range of different behaviours, on which there is agreement among different observers. The inductivelydeveloped list of valuing behaviours may be validated through the association with higher patient satisfaction. The behaviours may be used in trainingand supervision to enhance the valuing of patients in consultations. PMID- 29115794 TI - New Challenges in Multihospital Kidney Exchange. PMID- 29115795 TI - Third-party turns and shared knowledge: Supports and challenges to disabled people in social care and research settings. AB - Adopting a conversation analysis (CA) perspective, this paper explores data which include disabled people in three-party contexts, where the institutional goal is to focus on the wishes, voice and agency of the disabled person. It explores 274 occasions where a third party self-selects for a turn, during social care planning meetings and research interviews. Five broad action patterns are discussed, showing how third parties used their epistemic closeness to the disabled person in order to (1) clarify, (2) respond, (3) prompt, (4) expand and (5) challenge. The sequential consequence of these turns depended on how they were heard and taken up by other parties in the talk. The vast majority of third party turns could be glossed as supportive to the disabled person. Third parties displayed their sensitivity towards the precise moment that they were 'needed' in the talk. Occasionally, there were challenges and counterinformings done by the third party, which could be analysed as 'epistemic traps'. These moments signaled tensions between the best interests of the disabled person and the imperative to foreground their voice. PMID- 29115796 TI - A stitch in time: Instructing temporality in the operating room. AB - This paper examines how time is made explicitly relevant in the way the attending surgeon monitors and corrects the performance of a resident during a kidney transplant surgery. In so doing, we observe how the attending constitutes time as a significant and constituent feature of the surgical actions performed by the resident. In order to instruct temporal competence in the performance of surgical procedures, the attending surgeon identifies and makes instructably observable the temporally significant features of the surgical work just as that work is performed, by (a) producing countdowns, pace prompts, and temporal accounts when and as avoidable errors occur, and (b) planning and coordinating current and upcoming actions in relation to other actions. Instructing a trainee in the temporal features of his/her performance occurs when the attending (a) coordinates the production of specific verbal tokens, remarks, and accounts with specific actions performed by the resident as the resident performs them, or (b) anticipates the performance of subsequent actions in relation to current surgical actions underway. This case demonstrates how temporality becomes an observably instructable matter in interaction. PMID- 29115797 TI - Polyphenol epigallocatechin-3-gallate inhibits hypoxia/reoxygenation-induced H9C2 cell apoptosis. AB - BACKGROUND: We aimed to observe the protective effect of EGCG on hypoxia/reoxygenation injury of H9C2 myocardial cells and to study the inhibition mechanism of EGCG on hypoxia/reoxygenation injury of H9C2 myocardial cells. METHODS: H9C2 cells were used as the objects of study and hypoxia/reoxygenation cells were pretreated with EGCG in different concentrations. MTT, Hoechst 33258 and LDH were used to detect the viability and apoptosis of H9C2 cells. The protection mechanism of polyphenol epigallocatechin-3-gallate was studied via western blotting and mitochondrial membrane potential detection. RESULTS: Polyphenol epigallocatechin-3-gallate (10 MUM) reduced the proportion of H9C2 cell apoptosis after hypoxia/reoxygenation (4/20 h), stabilized the mitochondrial membrane potential and decreased the expressions of mitochondrial damage-related proteins, thus protecting the mitochondrial function. CONCLUSIONS: Polyphenol epigallocatechin-3-gallate alleviates the hypoxia-/reoxygenation-induced H9C2 cell apoptosis, which may play the myocardial protective effect through inhibiting the mitochondrial Caspase pathway. PMID- 29115798 TI - Acute alcoholic hepatitis: a literature review and proposal of treatment. AB - Severe acute alcoholic hepatitis (AAH) can lead to a clinical picture with a six month mortality rate in more than 70% of cases. This clinical picture is characterized by: jaundice with a duration of less than three months, jaundice at the first failure event, serum bilirubin greater than 5 mg/dL, ratio AST/ALT>2/1, AST less than 500 IU/L, ALT<300 IU/L, neutrophil leukocytosis and a GGT increase. In addition, encephalopathy, fever, asthenia and coagulopathy may be present. Its onset may also be characterized by portal-hypertension-related complications, particularly bleeding and hepato-renal syndrome. In cases where there is an overlapping of an acute form characterized by an etiological factor other than that of the base hepatopathy, acute on chronic liver failure (ACLF) is obtained. This can result in systemic inflammation response syndrome (SIRS) with a multi organ systemic involvement. Several indices are used to evaluate the prognosis, in particular Maddrey's discriminant function (mDF) and the model of end stage liver disease (MELD). In our clinical practice, we use the MELD routinely. In cases of ACLF, a consortium organ failure score (CLIF-COFs) is used. Therapy is characterized by abstention in cases of severe forms (mDF>32 and MELD>21); in the absence of contraindications, steroid therapy is possible. In cases of an unresponsive liver, transplantation is premature. In our view, this possibility, after proper selection, must be offered for both prognostic and ethical reasons. PMID- 29115799 TI - Chronic (inflammatory) diseases: precision medicine versus comprehensive understanding? PMID- 29115800 TI - The current role of renal biopsy in diabetic patients. AB - Diabetes mellitus (DM) is a worldwide health problem due to its high prevalence, incidence and impact on patient morbidity and mortality. Chronic kidney disease (CKD) is one of the most important complications of DM. The indication of renal biopsy in diabetic patients is a widely debated topic and the final decision is usually individualized. The results of renal biopsy in diabetic patients can be classified into three groups: diabetic nephropathy (DN), non-diabetic renal disease (NDRD) or DN plus NDRD (mixed forms). Renal involvement in DN has been widely studied and different pathological classifications have been proposed. Some groups demonstrated a relationship between the pathological classifications in DN and renal prognosis. However, to our knowledge renal biopsy in diabetic patients with DN has not demonstrated an impact on their survival and renal prognosis. Some recent studies suggest that non-proteinuric diabetic patients may be affected of DN. In addition, kidney biopsy in DN under new treatments may have a fundamental role in assessing renal protection or even regression of diabetic histological lesions. On the other hand, the accurate and early diagnosis and subsequent treatment of diabetic patients with NDRD has been shown to benefit both their renal and patient prognosis. Renal involvement in patients with DM is very heterogeneous. Thus, the role of renal biopsy in diabetic patients is becoming increasingly important. PMID- 29115801 TI - The relationship between the vitamin serum 25(OH)D and the B12 concentrations in obese women. AB - BACKGROUND: In obesity, low levels of vitamin D (VD) and vitamin B12 (VB12) may be the result of different pathophysiological mechanisms, but the possible association between them has not been defined yet. The aim of this cross sectional analysis was to investigate the possible relationship between serum 25 hydroxyvitamin D (25(OH)D) and VB12 levels in middle aged women. METHODS: In 80 women, we indirectly evaluated body composition and body volumes [extracellular fluid volume (ECV) and total body water (TBW)] by anthropometric and bioelectrical impedance analysis. Vitamin D and VB12 status was assessed by laboratory measurement [serum 25(OH)D levels by electrochemiluminescent immunoassay; VB12 by chemiluminescent microparticle immunoassay]. RESULTS: Obese women were mostly VD deficient [25(OH)D below 50 nmol/L; 40/50, 80%]. Also, among obese we observed presence of VB12 deficiency [VB12 below 148 pmol/L; 13/50, 26%) and marginal depletion of VB12 level (marginal VB12 status 148-221 pmol/L; 20/50, 40%). All anthropometric indicators of obesity, ECV and TBW were significantly associated with both, 25(OH)D and VB12 (P<0.001) levels. In univariate regression analysis serum level of 25(OH)D was significantly associated with VB12 levels (R2=0.170, P<0.001). In regression models, 25(OH)D was significantly associated with VB12 level, independently of fat mass and extracellular fluid volume. CONCLUSIONS: Obesity may negatively affect VB12 level, indirectly, by reducing 25(OH)D level in middle aged women. PMID- 29115803 TI - CORRIGENDUM. PMID- 29115802 TI - Combination therapy in chronic hepatitis B: what are the real benefits? PMID- 29115805 TI - Getting More Organs for Transplantation. PMID- 29115804 TI - Organ Allocation Policy and the Decision to Donate. AB - Organ donations from deceased donors provide the majority of transplanted organs in the United States, and one deceased donor can save numerous lives by providing multiple organs. Nevertheless, most Americans are not registered organ donors despite the relative ease of becoming one. We study in the laboratory an experimental game modeled on the decision to register as an organ donor and investigate how changes in the management of organ waiting listsmight impact donations. We find that an organ allocation policy giving priority on waiting lists to those who previously registered as donors has a significant positive impact on registration. PMID- 29115807 TI - Editorial. PMID- 29115806 TI - Machine Versus Man: Can Robotic Mops Clean to Lead Safety Standards? AB - This study compared the effectiveness of using a commercially available robotic mop versus hand mopping as the second step of the U.S. Department of Housing and Urban Development's recommended three-step vacuum-mop-vacuum process to remove lead dust debris from residential floors. A total of 1,703 floors were cleaned using the robotic mop. Lead dust wipe tests from these floors were compared with 995 lead dust wipe tests for floors cleaned with hand mopping. Analysis of the dust wipes showed that cleaning floors with a robotic mop resulted in a clearance failure rate significantly lower than that obtained by cleaning floors by hand (4.8% versus 10.0%; p < .05). The use of newer technologies like robotic mops can help improve the efficiency and thoroughness of floor-cleaning efforts, as well as decrease costs associated with re-cleaning floors following regulated renovations. PMID- 29115808 TI - Understanding NurseConsultantroleengagement inmetropolitanandruralcontexts. AB - Background: Roleambiguityisknowntoimpactnegativelyonroleeffectiveness.NurseConsul tants (NCs)areclinicalleadersinAustraliaandsimilarrolesexistinternationally.Factorsthat ead toroleambiguityforNCsincludedynamicandcomplexhealthcarecontextsandroles.Toreducea biguitythereisanurgentneedtodemonstrateNCs'contributiontohealthcareoutcomes. Aim: This paperreportsfindingsofastudyexploringtherole,scopeandlevelofengagementof theNCacrossmetropolitanandruralcontextinNewSouthWales,Australia.Design: This studyusedacrosssectionalsequentialmixedmethoddesignexaminingthecomplexand multifacetednatureoftheNC'swork. Method: NCs wererecruitedacrossruralandmetropolitanservicesinalargelocalhealthdis-trict inNewSouthWales,Australia.Phaseoneusedavalidatedquestionnairetogatherworkengageme t andactivitydata,phasetwoinvolvedinterviewswithNCsandothersstakeholders.Phaseonefi dingsarepresentedinthispaper. Results: Workengagementpatternswereinfluencedbyrolegrade(1,2or3),highergradesengaging athigherlevelsacrossdomainsandhealthsectors.NCsinrurallocationshadgreateremphasis oneducation,clinicalleadershipandclinicalconsultancyandsignificantlymoredirectpat ent contactintheirroles. PMID- 29115809 TI - There's No Perfect Malocclusion PMID- 29115810 TI - A Comparison of Water-Related Perceptions and Practices Among West Texas and South New Mexico Colonia Residents Using Hauled-Stored and Private Well Water. AB - In Texas, Arizona, and New Mexico, colonias refer to unincorporated rural settlements along the U.S.-Mexico border. Colonias lack governance and public services normally provided by local government (Ward, 1999). Residents typically rely on well water or hauled water stored in above-ground containers. This study attempted to quantify and compare water-related perceptions and practices of colonia residents. No significant differences were observed between colonia residents using well water versus hauled-stored water for water quality perceptions and water use practices. Most, however, had negative perceptions of their water supply; a majority perceived daily water supplies as not potable. Significant paradoxical discrepancies between perceptions and practice were identified. This study adds to a small but growing literature on subjective dimensions of quality of life indicators for colonia residents. Additional studies are needed to quantify the type and level of health risks posed by compromised water supplies for this vulnerable population. Understanding differences in perceptions and practices associated with water sources could help to identify which subpopulations of colonia residents are in greatest need of water infrastructure or remediation. PMID- 29115811 TI - Director ofnursingexperiencesofahospital inthenursinghomeprograminSouth EastQueensland. AB - In Australiathereislimitedaccesstoacutecaresupportforresidentslivingwithinthe residentialagedcaresector.Competingdemandsfromfamilies,residents,governmentagenci s andtheacutecaresectorhasmeantthatstaffwiththesectorstruggleoftentomeet theacutecareneedsofresidents,leadingsometimestotransferofresidentsto emergency departmentswithmajorhospitals.Hospitalinthenursinghomeisacaredeliverymodeldesigne to reduce transfers, facilitate appropriate care intervention, effectively utilize existing healthresources,andextendsupporttotheresidentialcaresector.Thisresearchprojectuse aninterpretivequalitativeframeworktoexplorethroughfocusgroupmethod,hospitalin thehomeexperiencesof20residentialcareDirectorsofNursinginSouthEastQueensland.Rese rchoutcomesemphasizehospitalinthenursinghomeasamutuallybeneficialsupportstrategy thatcanimproveresidentialbasedmanagementofacuteandchronicillness,canpositively assistfamilysupport,andassistswithdecisionmakingandongoingcommunication.Hospital inthehomeemphasisesamovefromhospitaldestinationbasedacutecareservicestocommunity based delivery supported by a multidisciplinary team. PMID- 29115812 TI - Creating walking tracks to success: A narrative analysis of AustralianAboriginal and Torres Strait Islander nursing students' stories ofsuccess. AB - Australian Aboriginal and Torres Strait Islander people have higher rates of morbidity and mortality thanother Australians. One proposed strategy to improve this situation is to increase the participation ofAboriginal and Torres Strait Islander people, including Aboriginal and Torres Strait Islander nurses, inthe health workforce. Although the numbers of Aboriginal and Torres Strait Islander students under-taking tertiary nursing courses have increased, completion rates have not kept pace. The study aimedto describe Aboriginal and Torres Strait Islander nursing students' experiences of enablers for successfulcourse completion and to develop a narrative of student experience. A qualitative study using a strengths-based approach with a narrative analysis of semi-structured interview data was conducted across fourschools of Nursing in Queensland, Australia. Eight final-year Aboriginal and Torres Strait Islander nursingstudents volunteered to participate in the study. A collective story with the overarching plotline Creatingwalking tracks to success was developed. Six threads of experience emerged: Making a difference, Valu-ing Indigeneity, Healing strength of connections, Resisting racism, Embracing support, and perseveringtowards completion. Key success factors included resilient attributes, building supportive connectionsand having positive expectations of the future, along with sustained institutional support from Aboriginaland Torres Strait Islander nurse academics and clinicians. Development of tailored resilience-buildingtraining for Aboriginal and Torres Strait Islander nursing students and appointment of Aboriginal andTorres Strait Islander academics in Schools of Nursing that include such students may facilitate futuresuccessful completions in other programs. PMID- 29115813 TI - The emerging role of the urban-based aboriginal peer support worker:A Western Australian study. AB - Purpose: To explore the self-perceived role of the Aboriginal peer support worker working with familieswith young children. This study was a component of a larger participatory action research study under-taken in a Western Australian metropolitan setting to develop and evaluate the suitability, feasibility andeffectiveness of an Aboriginal peer-led home visiting program. Methods: Focus group interviews were carried out with peer support workers using unstructured andsemi-structured interviews within Action Learning Sets. Data were analysed using thematic analysis.Results: The overarching theme on the self-perceived role of the Aboriginal peer support worker wasGiving Parent Support, with subsidiary themes relating to development and ongoing sustainability of thesupport. Discussion: The peer support workers viewed their role as providing parent support through enablingstrategies which developed client acceptance and trust, delivered culturally relevant support, advocatedfor families, developed therapeutic engagement and communication strategies, and created safe homevisiting practices. They recognised the importance of linking families with community support such ascommunity child health nurses which was important for improving long term physical and psychosocialhealth outcomes for children. Conclusion: Aboriginal Peer Support Workers identified their emerging integral role in the developmentof this unique culturally acceptable home visitingsupport for Aboriginal parents. Innovative approachestowards client engagement demonstrated their value in developing creative ways of working in part-nership with families, community support services and child health nurses across a range of challengingpsychosocial environments. PMID- 29115814 TI - Calculated decisions: Westley croup score PMID- 29115816 TI - Reversible Self-Assembly of 3D Architectures Actuated by Responsive Polymers. AB - An assembly of three-dimensional (3D) architectures with defined configurations has important applications in broad areas. Among various approaches of constructing 3D structures, a stress-driven assembly provides the capabilities of creating 3D architectures in a broad range of functional materials with unique merits. However, 3D architectures built via previous methods are simple, irreversible, or not free-standing. Furthermore, the substrates employed for the assembly remain flat, thus not involved as parts of the final 3D architectures. Herein, we report a reversible self-assembly of various free-standing 3D architectures actuated by the self-folding of smart polymer substrates with programmed geometries. The strategically designed polymer substrates can respond to external stimuli, such as organic solvents, to initiate the 3D assembly process and subsequently become the parts of the final 3D architectures. The self assembly process is highly controllable via origami and kirigami designs patterned by direct laser writing. Self-assembled geometries include 3D architectures such as "flower", "rainbow", "sunglasses", "box", "pyramid", "grating", and "armchair". The reported self-assembly also shows wide applicability to various materials including epoxy, polyimide, laser-induced graphene, and metal films. The device examples include 3D architectures integrated with a micro light-emitting diode and a flex sensor, indicting the potential applications in soft robotics, bioelectronics, microelectromechanical systems, and others. PMID- 29115815 TI - Spinel/Layered Heterostructured Lithium-Rich Oxide Nanowires as Cathode Material for High-Energy Lithium-Ion Batteries. AB - Lithium-rich oxide material has been considered as an attractive candidate for high-energy cathode for lithium-ion batteries (LIBs). However, the practical applications are still hindered due to its low initial reversible capacity, severe voltage decaying, and unsatisfactory rate capability. Among all, the voltage decaying is a serious barrier that results in a large decrease of energy density during long-term cycling. To overcome these issues, herein, an efficient strategy of fabricating lithium-rich oxide nanowires with spinel/layered heterostructure is proposed. Structural characterizations verify that the spinel/layered heterostructured nanowires are a self-assembly of a lot of nanoparticles, and the Li4Mn5O12 spinel phase is embedded inside the layered structure. When the material is used as cathode of LIBs, the spinel/layered heterostructured nanowires can display an extremely high invertible capacity of 290.1 mA h g-1 at 0.1 C and suppressive voltage fading. Moreover, it exhibits a favorable cycling stability with capacity retention of 94.4% after charging/discharging at 0.5 C for 200 cycles and it shows an extraordinary rate capability (183.9 mA h g-1, 10 C). The remarkable electrochemical properties can be connected with the spinel/layered heterostructure, which is in favor of Li+ transport kinetics and enhancing structural stability during the cyclic process. PMID- 29115817 TI - Low-Cost Chemical-Responsive Adhesive Sensing Chips. AB - Chemical-responsive adhesive sensing chip is a new low-cost analytical platform that uses adhesive tape loaded with indicator reagents to detect or quantify the target analytes by directly sticking the tape to the samples of interest. The chemical-responsive adhesive sensing chips can be used with paper to analyze aqueous samples; they can also be used to detect and quantify solid, particulate, and powder analytes. The colorimetric indicators become immediately visible as the contact between the functionalized adhesives and target samples is made. The chemical-responsive adhesive sensing chip expands the capability of paper-based analytical devices to analyze solid, particulate, or powder materials via one step operation. It is also a simpler alternative way, to the covalent chemical modification of paper, to eliminate indicator leaching from the dipstick-style paper sensors. Chemical-responsive adhesive chips can display analytical results in the form of colorimetric dot patterns, symbols, and texts, enabling clear understanding of assay results by even nonprofessional users. In this work, we demonstrate the analyses of heavy metal salts in silica powder matrix, heavy metal ions in water, and bovine serum albumin in an aqueous solution. The detection is one-step, specific, sensitive, and easy-to-operate. PMID- 29115818 TI - Ultrawide Band Gap beta-Ga2O3 Nanomechanical Resonators with Spatially Visualized Multimode Motion. AB - Beta gallium oxide (beta-Ga2O3) is an emerging ultrawide band gap (4.5 eV-4.9 eV) semiconductor with attractive properties for future power electronics, optoelectronics, and sensors for detecting gases and ultraviolet radiation. beta Ga2O3 thin films made by various methods are being actively studied toward such devices. Here, we report on the experimental demonstration of single-crystal beta Ga2O3 nanomechanical resonators using beta-Ga2O3 nanoflakes grown via low pressure chemical vapor deposition (LPCVD). By investigating beta-Ga2O3 circular drumhead structures, we demonstrate multimode nanoresonators up to the sixth mode in high and very high frequency (HF/VHF) bands, and also realize spatial mapping and visualization of the multimode motion. These measurements reveal a Young's modulus of EY = 261 GPa and anisotropic biaxial built-in tension of 37.5 MPa and 107.5 MPa. We find that thermal annealing can considerably improve the resonance characteristics, including ~40% upshift in frequency and ~90% enhancement in quality (Q) factor. This study lays a foundation for future exploration and development of mechanically coupled and tunable beta-Ga2O3 electronic, optoelectronic, and physical sensing devices. PMID- 29115819 TI - Whole-Life-Stage Characterization in the Basic Biology of Daphnia magna and Effects of TDCIPP on Growth, Reproduction, Survival, and Transcription of Genes. AB - Toxicity tests of chemicals have mainly focused on the partial life-cycle evaluation of model animals. Limited information is available for the evaluation of effects of chemicals from a whole-life-stage exposure perspective. The objective of this study was to perform a whole-life-stage characterization in the basic biology of Daphnia magna (D. magna) and evaluate the effects of a known organophosphate ester (OPE) contaminant, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), on growth, reproduction, survival, and transcription of genes. The whole-life-stage characterization in growth, reproduction, and survival of D. magna was conducted, and representative sampling time points for the three developmental stages were identified (day 6, day 32, and day 62). Transcriptomic profiles for these three stages were compared, and stage-specific PCR arrays of D. magna were developed. The whole-life-stage exposure to environmentally relevant or greater concentrations of TDCIPP significantly inhibited growth and reproduction of D. magna and decreased survival at the later stage of the exposure experiment (>=32 days). Such adverse effects were not observed in the early stage of the exposure (<32 days), suggesting that short-term toxicity tests, such as the standard 21-day test, might underestimate the environmental risk of TDCIPP. Furthermore, expressions of genes selected at day 6, day 32, and day 62 were significantly changed after TDCIPP exposure, and the changes in the expressions of partial genes were correlated to the inhibitory effects on growth, reproduction, and survival. PMID- 29115820 TI - Continuously Producible Ultrasensitive Wearable Strain Sensor Assembled with Three-Dimensional Interpenetrating Ag Nanowires/Polyolefin Elastomer Nanofibrous Composite Yarn. AB - Fiber-shaped strain sensors with great flexibility and knittability have been tremendously concerned due to the wide applications in health manager devices, especially in human motion detection and physiological signal monitoring. Herein, a novel fiber-shaped strain sensor has been designed and prepared by interpenetrating Ag nanowires (NWs) into polyolefin elastomer nanofibrous yarn. The easy-to-obtain structure and simple roll-to-roll process make the continuous large-scale production of nanofibrous composite yarn possible. The continuous and alternating stretching and releasing reversibly change the contact probability between AgNWs in this interpenetrating network, leading to the variations of electrical resistance of the sensor. The gauge factors of strain sensors are calculated to be as high as 13920 and the minimum detection limit is only 0.065%. In addition, the strain sensor shows excellent durability during 4500 cycles with the strain of 10%. The response times of stretching and releasing strains are 10 and 15 ms, respectively. Furthermore, the strain sensor has been successfully applied in human motion detections both in single yarn and knitted fabrics. The result shows the practicability in applications of monitoring limbs movements, eye motion changes, artificial vocal cords, human pulse, and complex motions, which shows great potential in wearable sensors and electronic skin. PMID- 29115821 TI - Species Sensitivity Distributions for Nonylphenol to Estimate Soil Hazardous Concentration. AB - Nonylphenol is an endocrine-disrupting chemical that mimics estrogenic activity. Few studies have investigated the soil ecotoxicity of nonylphenol in the environment, based on probabilistic approaches. The present study generated soil toxicity data for nonylphenol through bioassays that determined the acute and chronic species sensitivity distributions and estimated the hazardous concentrations of nonylphenol in soil in order to protect soil ecosystems. We used eight soil-based organisms from six taxonomic groups for acute assays and five soil-based organisms from four taxonomic groups for chronic assays. The hazardous concentration values of nonylphenol in soil, based on acute and chronic species sensitivity distributions, were estimated using compiled data from the present study, as well as previous studies. This is the first study that generated sufficient data to develop species sensitivity distributions for nonylphenol in soil, and to determine hazardous concentrations of nonylphenol for soil environments. PMID- 29115822 TI - Single Quantum Dot-Based Nanosensor for Sensitive Detection of O-GlcNAc Transferase Activity. AB - Protein glycosylation is a ubiquitous post-translational modification that plays crucial roles in modulating biological recognition events in development and physiology. Human O-GlcNAc transferase (OGT) is an intracellular enzyme responsible for O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, and the deregulation of OGT activity occurs in cancer, diabetes, and neurodegenerative disease. Here we develop a single quantum dot (QD)-based nanosensor for sensitive OGT assay. We design a Cy5/biotin-modified peptide with a serine hydroxyl group for sensing OGT and a protease site adjacent to the glycosylation site for proteinase cleavage, with a universal nonradioactive UDP-GlcNAc as the sugar donor and a Cy5/biotin-modified peptide as the substrate. In the presence of OGT, it catalyzes the glycosylation reaction to generate a glycosylated peptide that is a protease-protection peptide. The resultant glycosylated Cy5/biotin-modified peptides may assemble on the surface of the streptavidin-coated QD to obtain a QD peptide-Cy5 nanostructure in which the fluorescence resonance energy transfer (FRET) from the QD to Cy5 can occur, leading to the emission of Cy5 which can be quantified by single-molecule detection. This method exhibits high sensitivity with a limit of detection of 3.47 * 10-13 M, and it is very simple and straightforward without the involvement of any enzyme purification, radioisotope labeled sugar donors, specific antibodies, and the synthesis of fluorescent UDP GlcNAc analogues. Moreover, this method can be used for enzyme kinetic analysis, quantitative detection of cellular OGT activity, and the screening of OGT inhibitors, holding great potential for further application in drug discovery and clinical diagnosis. PMID- 29115823 TI - An Overview of the Clinical Uses, Pharmacology, and Safety of Modafinil. AB - Modafinil (MOD) is a wakefulness-inducing compound prescribed for treatment of excessive daytime sleepiness as a consequence of sleep disturbances such as shift work sleep disorder, obstructive sleep apnea, restless leg syndrome, or narcolepsy. While providing effective results in patients with sleepiness, MOD also produces positive outcomes in the management of fatigue associated with different conditions including depression, cancer, or tiredness in military personnel. Although there is clear evidence of the stimulant effects of MOD, current data also show that administration of this drug apparently induces positive neurobiological effects, such as improvement in memory. However, serious concerns have been raised since some reports have suggested MOD dependence. Taken together, these findings highlight the need to characterize the changes induced by MOD which have been observed in several neurobiological functions. Moreover, further work should follow up on the likely long-term effects of this drug if used for treatment of drowsiness and tiredness. Here, we review and summarize recent findings of the medical uses of MOD in the management of sleepiness and fatigue associated with depression or cancer as well as exhaustion in military personnel. We also discuss the available literature related with the cognitive enhancing properties of this stimulant, as well as what is known and unknown about MOD addiction. PMID- 29115824 TI - Mixed Membrane Matrices Based on Nafion/UiO-66/SO3H-UiO-66 Nano-MOFs: Revealing the Effect of Crystal Size, Sulfonation, and Filler Loading on the Mechanical and Conductivity Properties. AB - Mixed membrane matrices (MMMs) made up with Nafion and nanocrystals of zirconium metal-organic framework (MOF) UiO-66 or the analogous sulfonated SO3H-UiO-66 were prepared by varying the filler loading and the size of the crystals. The combined effects of size and loading, together with the presence of sulfonic groups covalently linked to the MOFs, were studied with regard to the conductivity and mechanical properties of the obtained composite matrices. A large screening of membranes was preliminarily made and, on the most promising samples, an accurate conductivity study at different relative humidities and temperatures was also carried out. The results showed that membranes containing large crystals (200 nm average size) in low amounts (around 2%) displayed the best results in terms of proton conductivity values, reaching values by 30% higher than those of pure Nafion, while leaving the mechanical properties substantially unchanged. On the contrary, MMMs containing MOFs of small size (20 nm average size) did not show any conductivity improvements if compared to pure Nafion membranes. The effect of MOF sulfonation was negligible at low filler loading whereas it became important at loading values around 10%. Finally, membranes with a high filler loading (up to 60 wt %) of sulfonated UiO-66 showed a slight reduction of conductivity in comparison with membranes loaded at 20% of nonsulfonated ones. PMID- 29115825 TI - Carbon Dioxide Insertion into Group 9 and 10 Metal-Element sigma Bonds. AB - Carbon dioxide (CO2) is an appealing feedstock for the sustainable preparation of a variety of carbon-based commodity chemicals because of its high abundance, low cost, and nontoxicity. The high kinetic and thermodynamic stability of CO2, however, means that there are currently only a limited number of practical catalytic systems for the conversion of CO2 into more valuable chemicals, and continued research in this area is required. One promising approach for the eventual transformation of CO2 is to initially insert the molecule into transition-metal-element sigma bonds such as M-H, M-OR, M-NR2, and M-CR3 bonds to form products of the type M-OC(O)E (E = H, OR, NR2, or CR3). CO2 insertion has been demonstrated in numerous stoichiometric reactions involving transition-metal complexes, but in cases where insertion results in the formation of strong M-O bonds, the products are often too stable to undergo further transformations. Group 9 and 10 transition-metal complexes (M = Ni, Pd, Pt, Co, Rh, or Ir) form relatively weak M-O bonds, and as a consequence, a number of group 9 and 10 transition-metal catalysts in which CO2 insertion is proposed as an elementary step in catalysis have been developed. In this Award Article, we summarize group 9 and 10 transition-metal complexes in which CO2 insertion into a metal-element sigma bond to form a M-OC(O)E-type product has been observed. Mechanistic similarities and differences are highlighted by comparing CO2 insertion reactions in different types of group 9 and 10 metal-element sigma bonds, and a general trend for predicting the rate-determining step of the insertion process is described based on the nucleophilicity of the element in the sigma bond. Although we focus on stoichiometric reactivity, the relevance of CO2 insertion to catalytic reactions is also emphasized throughout the paper. PMID- 29115827 TI - Porous NiFe-Oxide Nanocubes as Bifunctional Electrocatalysts for Efficient Water Splitting. AB - Electrocatalytic water-splitting, a combination of oxygen and hydrogen evolution reactions (OER and HER), is highly attractive in clean energy technologies, especially for high-purity hydrogen production, whereas developing stable, earth abundant, bifunctional catalysts has continued to pose major challenges. Herein, a mesoporous NiFe-oxide nanocube (NiFe-NC) system is developed from a NiFe Prussian blue analog metal-organic framework as an efficient bifunctional catalyst for overall water-splitting. The NiFe-NCs with ~200 nm side length have a Ni/Fe molar ratio of 3:2 and is a composite of NiO and alpha/gamma-Fe2O3. The NCs demonstrate overpotentials of 271 and 197 mV for OER and HER, respectively, in 1 M KOH at 10 mA cm-2, which outperform those of 339 and 347 mV for the spherical NiFe-oxide nanoparticles having a similar composition. The electrolyzer constructed using NiFe-NCs requires an impressive cell voltage of 1.67 V to deliver a current density of 10 mA cm-2. Along with a mesoporous structure with a broad pore size distribution, the NiFe-NCs demonstrate the qualities of a desired corrosion-resistant water-splitting catalyst with long-term stability. The exposure of active sites at the edges and vertices of the NCs was validated to play a crucial role in their overall catalytic performance. PMID- 29115826 TI - Experimental-Computational Synergy for Selective Pd(II)-Catalyzed C-H Activation of Aryl and Alkyl Groups. AB - C-H activation and functionalization are on the forefront of modern synthetic chemistry. Imagine if any C-H bond of a molecule could be converted to a C-X bond, where X is the target functionality-this would alter the synthetic blueprints for complex target molecules since it would provide novel disconnections in retrosynthetic analysis. Collaborations between many experimental and computational groups have led to rapid developments of new C-H functionalization methods. Our groups represent an example of this; we were brought together as part of the NSF-supported Center for Selective C-H Functionalization. Many examples of experimental-computational synergy for selective Pd(II)-catalyzed C-H activation of aryl and alkyl groups are described in this Account. We describe computations by the Houk group made in response to experimental stimuli by the Yu group. The first section discusses the experimental and computational investigations of oxazoline-directed stereoselective Pd(II)-catalyzed C(sp3)-H bond activation that occurs through the concerted metalation-deprotonation (CMD) pathway involving a monomeric Pd(II) complex. The second section involves two types of bidentate ligands, mono-N protected amino acid (MPAA) and acetyl-protected aminoethyl quinoline (APAQ) ligands that promote the C-H activation reactions with the ligand as the internal base. In the MPAA-assisted remote C-H bond activation, the basic dianionic amidate ligand participates in the deprotonation of a specific C-H bond. This mechanism accounts for the improved reactivity and selectivity in C-H activation reactions with MPAA ligands. The chiral APAQ ligands enable asymmetric palladium insertion into prochiral C-H bonds on a single methylene carbon center. The dianionic amidate of the APAQ ligand acts as an intramolecular base to deprotonate the methylene C-H asymmetrically and facilitate chiral Pd-C bond formation. The origins of the dramatic differences of five-membered (relatively inactive) and six-membered (highly active) chelation in beta-methylene C(sp3)-H activation reactions by a Pd(II) catalyst were explained with density functional theory (DFT) calculations. This is mainly due to the steric repulsions between the ArF group of the substrate and the quinoline group of the ligand. The steric repulsion between the ArF group of the substrate and the quinoline group of the APAQ ligand destabilizes the five-membered chelate transition structure, increasing the energy of the transition state. The third section discusses a mechanism involving a Pd-Ag heterodimeric complex intermediate in the template directed, Pd(II)-catalyzed remote meta functionalization of toluene derivatives and benzoic acid derivatives. The nitrile directing group of the template coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta selectivity. The selective activation of remote meta-C-H bonds at various distances can be achieved by tuning the template. The dual role of AgOAc as both an oxidant and part of the heteronuclear active species in the mechanism involving PdAg(OAc)3 was determined by DFT calculations and is in accord with literature information about complexes. For the systems discussed in these three sections, the similarity is that they all proceed via the CMD mechanism. The differences lie in the proton acceptors and the active Pd species. Common CMD involves a monomeric Pd mechanism with acetate as the proton acceptor. Both MPAA and APAQ ligands react via monomeric Pd mechanisms with a ligand moiety (the amidate oxygen) as the proton acceptor. Nitrile-containing template-mediated meta-C-H activations proceed via a Pd-Ag heterodimeric mechanism, still with acetate as the proton acceptor. The interaction between our two groups, experts in experiment and computation, and the discoveries made possible by that interplay are highlighted in this Account. PMID- 29115828 TI - Zirconium-Based Nanoscale Metal-Organic Framework/Poly(epsilon-caprolactone) Mixed-Matrix Membranes as Effective Antimicrobials. AB - Metal-organic framework (MOF)-polymer mixed-matrix membranes (MMMs) have shown their superior performance in gas separation. However, their biological application has not been well-explored yet. Herein, a series of zirconium-based MOF MMMs with high MOF loading and homogeneous composition have been prepared through a facile drawdown coating process. Poly(epsilon-caprolactone) (PCL) has been selected as a binder for its good biocompatibility and biodegradability. Zr MOF nanoparticles, UiO-66, and MOF-525, have been utilized as "filler" because of their superior chemical stability, good biological safety, and versatile functions. Both UiO-66/PCL MMMs and MOF-525/PCL MMMs have a uniform appearance even at the highest loading of 50 wt % for UiO-66 and 30 wt % for MOF-525, respectively. The integrity of pore structures of UiO-66 within MMMs maintains well, which is evidenced by dye separation. All obtained MMMs possess good biocompatibility and mechanical property. Upon irradiation, MOF-525/PCL MMMs generate reactive oxygen species and serve as effective antibacterial photodynamic agents against Escherichia coli. This study offers an alternative system for forming homogeneous MOF/polymer MMMs and represents the first example of exploiting hybrid MMMs for biological applications. PMID- 29115829 TI - Sequential Elemental Dealloying Approach for the Fabrication of Porous Metal Oxides and Chemiresistive Sensors Thereof for Electronic Listening. AB - Highly porous materials, with large surface area and accessible space, variable chemical compositions, and porosity at different length scales, have captivated the attention of researchers in recent years as an important family of functional materials. Here, we report a novel approach to grow porous metal oxides (PMOs) by sequential elemental dealloying in which a highly mobile element gets dealloyed first under the thermal treatment (annealing) and facilitates the formation of PMOs. Subsequently, a chemiresistive sensor based on porous SnO2 was fabricated for humidity sensing at room temperature which shows a high sensitivity of 348 in a fully humid [>99% relative humidity (RH)] atmosphere with an accuracy of 1% RH change. In addition, the sensor is highly durable and reproducible. Eventually, the chemiresistive sensor has been exploited for electronic listening toward speaking, whistling, and breath monitoring. Overall, the results advocate the fabrication of PMOs and the development of resistive humidity sensors for electronic listening as well as for biomedical applications. PMID- 29115830 TI - Gastrodin and Isorhynchophylline Synergistically Inhibit MPP+-Induced Oxidative Stress in SH-SY5Y Cells by Targeting ERK1/2 and GSK-3beta Pathways: Involvement of Nrf2 Nuclear Translocation. AB - The pathogenesis of Parkinson's disease (PD) is multifactorial event. Combination therapies might be more effective in controlling the disease. Thus, the studies reported were designed to test the hypothesis that gastrodin (GAS)-induced de novo synthesis of nuclear factor E2-related factor 2 (Nrf2) and isorhynchophylline (IRN) inhibition of Nrf2 nuclear export contribute to their additive or synergistic neuroprotective effect. Here, we have demonstrated that the combination of GAS and IRN (GAS/IRN) protects SH-SY5Y cells against 1-methyl 4-phenylpyridinium (MPP+) toxicity in a synergistic manner. Concomitantly, GAS/IRN led to a statistically significant reduction of oxidative stress, as assessed by reactive oxygen species (ROS) and lipid hydroperoxides (LPO), and enhancement of both glutathione (GSH) and thioredoxin (Trx) systems compared with treatment with either agent alone in MPP+-challenged SH-SY5Y cells. Interestingly, GAS but not IRN activated extracellular signal-regulated kinases 1 and 2 (ERK1/2), leading to a increase in de novo synthesis of Nrf2 and nuclear import of Nrf2. Simultaneously, IRN but not GAS suppressed both constitutive glycogen synthase kinase (GSK)-3beta and Fyn activation, which inhibited nuclear export of Nrf2. Importantly, simultaneous inhibition of GSK-3beta pathway by IRN and activation of ERK1/2 pathway by GAS synergistically induced accumulation of Nrf2 in the nucleus in SH-SY5Y cells challenged with MPP+. Furthermore, the activation of the ERK1/2 pathway and inhibition of GSK-3beta pathway by GAS/IRN are mediated by independent mechanisms. Collectively, these novel findings suggest an in vitro model of synergism between IRN and GAS in the induction of neuroprotection warrant further investigations in vivo. PMID- 29115831 TI - Bacilotetrins A and B, Anti-Staphylococcal Cyclic-Lipotetrapeptides from a Marine Derived Bacillus subtilis. AB - LC-MS and NMR spectroscopy guided metabolic profiling and dereplication of a crude extract obtained from the fermentation of a marine-derived bacterium, Bacillus subtilis, followed by chromatographic isolation yielded two new cyclic lipotetrapeptides, bacilotetrins A (1) and B (2). Based on extensive 1D and 2D NMR and high-resolution ESIMS data analysis, the structures of 1 and 2 were elucidated, revealing the unique structures of these lipopeptides consisting of three leucines and a glutamic acid residue cyclized with a lipophilic 3-hydroxy fatty acid. The absolute stereochemistries at selected stereocenters in 1 and 2 were assigned by chemical derivatization and comparison to literature data. Compounds 1 and 2 exhibited anti-MRSA activity with MIC values of 8 to 32 MUg/mL. However, these compounds showed no cytotoxicity when tested against prostate and liver cancer cell lines using the standard SRB assay. PMID- 29115833 TI - Chemical Design and Example of Transparent Bipolar Semiconductors. AB - Transparent bipolar semiconductors (TBSCs) are in demand for transparent electronics to serve as the basis for next generation optoelectronic devices. However, the poor carrier controllability in wide-bandgap materials makes the realization of a bipolar nature difficult. Only two materials, CuInO2 and SnO, have been reported as TBSCs. To satisfy demand for the coexistence of transparency and bipolarity, we propose a design concept with three strategies; choice of early transition metals (eTM) such as Y3+ and Zr4+ for improving controllability of carrier doping, design of chemical bonds to obtain an appropriate band structure for bipolar doping, and use of a forbidden band-edge transition to retain transparency. This approach is verified through a practical examination of a candidate material, tetragonal ZrOS, which is chosen by following the criteria. ZrOS exhibits an excellent controllability of the electrical conductivity (10-7-10-2 S cm-1), p- or n-type nature with ~10-2 S cm-1 by Y or F doping, respectively, and optically wide gap (below 10-4 cm-1 up to ~2.5 eV). This concept provides a new kind of TBSC based on eTM ionic compounds. PMID- 29115834 TI - An N-Heterocyclic Carbene-Mediated, Enantioselective and Multicatalytic Strategy to Access Dihydropyranones in a Sequential Three-Component One-Pot Reaction. AB - The multicatalytic generation of 3,5,6-trisubstituted 3,4-dihydropyranones with high enantioselectivity using a highly convergent strategy starting from commercially available precursors is reported. The operationally simple three step, one-pot protocol merges H-bond and NHC catalysis to provide crucial, reactive beta-unsubstituted enones from nitroalkenes as latent 1,2 biselectrophiles. These intermediates are directly funneled into a further NHC catalyzed formal hetero-Diels-Alder reaction to deliver manifold chiral C(4) unsubstituted dihydropyranones (typical ee >98%), allowing aliphatic and heteroaromatic substituents and hence expanding the scope of this Michael addition/lactonization. PMID- 29115832 TI - Improved Prediction of Bovine Leucocyte Antigens (BoLA) Presented Ligands by Use of Mass-Spectrometry-Determined Ligand and in Vitro Binding Data. AB - Peptide binding to MHC class I molecules is the single most selective step in antigen presentation and the strongest single correlate to peptide cellular immunogenicity. The cost of experimentally characterizing the rules of peptide presentation for a given MHC-I molecule is extensive, and predictors of peptide MHC interactions constitute an attractive alternative. Recently, an increasing amount of MHC presented peptides identified by mass spectrometry (MS ligands) has been published. Handling and interpretation of MS ligand data is, in general, challenging due to the polyspecificity nature of the data. We here outline a general pipeline for dealing with this challenge and accurately annotate ligands to the relevant MHC-I molecule they were eluted from by use of GibbsClustering and binding motif information inferred from in silico models. We illustrate the approach here in the context of MHC-I molecules (BoLA) of cattle. Next, we demonstrate how such annotated BoLA MS ligand data can readily be integrated with in vitro binding affinity data in a prediction model with very high and unprecedented performance for identification of BoLA-I restricted T-cell epitopes. The prediction model is freely available at http://www.cbs.dtu.dk/services/NetMHCpan/NetBoLApan . The approach has here been applied to the BoLA-I system, but the pipeline is readily applicable to MHC systems in other species. PMID- 29115836 TI - Rose Wine Fining Using Polyvinylpolypyrrolidone: Colorimetry, Targeted Polyphenomics, and Molecular Dynamics Simulations. AB - Polyvinylpolypyrrolidone (PVPP) is a fining agent polymer used in winemaking to adjust rose wine color and to prevent organoleptic degradations by reducing polyphenol content. The impact of this polymer on color parameters and polyphenols of rose wines was investigated, and the binding specificity of polyphenols toward PVPP was determined. Color measured by colorimetry decreased after treatment, thus confirming the adsorption of anthocyanins and other pigments. Phenolic composition was determined before and after fining by targeted polyphenomics (Ultra Performance Liquid Chromatography (UPLC)-Electrospray Ionization(ESI)-Mass Spectrometry (MS/MS)). MS analysis showed adsorption differences among polyphenol families. Flavonols (42%) and flavanols (64%) were the most affected. Anthocyanins were not strongly adsorbed on average (12%), but a specific adsorption of coumaroylated anthocyanins was observed (37%). Intermolecular interactions were also studied using molecular dynamics simulations. Relative adsorptions of flavanols were correlated with the calculated interaction energies. The specific affinity of coumaroylated anthocyanins toward PVPP was also well explained by the molecular modeling. PMID- 29115835 TI - CITU: A Peptide and Decarboxylative Coupling Reagent. AB - Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations. PMID- 29115837 TI - Palladium-Catalyzed Safe Cyanation of Aryl Iodides with Hexamethylenetetramine. AB - A palladium-catalyzed cyanation of aryl halides with hexamethylenetetramine as a safe cyanide source is achieved, providing aromatic nitriles in moderate to good yields. This approach shows good functional group compatibilities and avoids the use of toxic cyanide source. PMID- 29115838 TI - Fabry-Perot Cavity-Enhanced Optical Absorption in Ultrasensitive Tunable Photodiodes Based on Hybrid 2D Materials. AB - Monolayer two-dimensional (2D) transition metal dichalcogenides (TMDs) show interesting optical and electrical properties because of their direct bandgap. However, the low absorption of atomically thin TMDs limits their applications. Here, we report enhanced absorption and optoelectronic properties of monolayer molybdenum disulfide (MoS2) by using an asymmetric Fabry-Perot cavity. The cavity is based on a hybrid structure of MoS2/ hexagonal boron nitride (BN)/Au/SiO2 realized through layer-by-layer vertical stacking. Photoluminescence (PL) intensity of monolayer MoS2 is enhanced over 2 orders of magnitude. Theoretical calculations show that the strong absorption of MoS2 comes from photonic localization on the top of the microcavity at optimal BN spacer thickness. The n/n+ MoS2 homojunction photodiode incorporating this asymmetric Fabry-Perot cavity exhibits excellent current rectifying behavior with an ideality factor of 1 and an ultrasensitive and gate-tunable external photo gain and specific detectivity. Our work offers an effective method to achieve uniform enhanced light absorption by monolayer TMDs, which has promising applications for highly sensitive optoelectronic devices. PMID- 29115839 TI - Nonideal Solute Chemical Potential Equation and the Validity of the Grouped Solute Approach for Intracellular Solution Thermodynamics. AB - The prediction of nonideal chemical potentials in aqueous solutions is important in fields such as cryobiology, where models of water and solute transport-that is, osmotic transport-are used to help develop cryopreservation protocols and where solutions contain many varied solutes and are generally highly concentrated and thus thermodynamically nonideal. In this work, we further the development of a nonideal multisolute solution theory that has found application across a broad range of aqueous systems. This theory is based on the osmotic virial equation and does not depend on multisolute data. Specifically, we derive herein a novel solute chemical potential equation that is thermodynamically consistent with the existing model, and we establish the validity of a grouped solute model for the intracellular space. With this updated solution theory, it is now possible to model cellular osmotic behavior in nonideal solutions containing multiple permeating solutes, such as those commonly encountered by cells during cryopreservation. In addition, because we show here that for the osmotic virial equation the grouped solute approach is mathematically equivalent to treating each solute separately, multisolute solutions in other applications with fixed solute mass ratios can now be treated rigorously with such a model, even when all of the solutes cannot be enumerated. PMID- 29115840 TI - Tuning the Spin-Alignment of Interstitial Electrons in Two-Dimensional Y2C Electride via Chemical Pressure. AB - We report that the spin-alignment of interstitial anionic electrons (IAEs) in two dimensional (2D) interlayer spacing can be tuned by chemical pressure that controls the magnetic properties of 2D electrides. It was clarified from the isovalent Sc substitution on the Y site in the 2D Y2C electride that the localization degree of IAEs at the interlayer becomes stronger as the unit cell volume and c-axis lattice parameter were systematically reduced by increasing the Sc contents, thus eventually enhancing superparamagnetic behavior originated from the increase in ferromagnetic particle concentration. It was also found that the spin-aligned localized IAEs dominated the electrical conduction of heavily Sc substituted Y2C electride. These results indicate that the physcial properties of 2D electrides can be tailored by adjusting the localization of IAEs at interlayer spacing via structural modification that controls the spin instability as found in three-dimensional elemental electrides of pressurized potassium metals. PMID- 29115841 TI - Straight Indium Antimonide Nanowires with Twinning Superlattices via a Solution Route. AB - Indium antimonide (InSb) enables diverse applications in electronics and optoelectronics. However, to date, there has not been a report on the synthesis of InSb nanowires (NWs) via a solution-phase strategy. Here, we demonstrate for the first time the preparation of high-quality InSb NWs with twinning superlattices from a mild solution-phase synthetic environment from the reaction of commercial triphenylantimony with tris(2,4-pentanedionato)-indium(III). This reaction occurs at low temperatures from 165 to 195 degrees C (optimized at ~180 degrees C), which is the lowest temperature reported for the growth of InSb NWs to date. Investigations reveal that the InSb NWs are grown via a solution-liquid solid (SLS) mechanism due to the catalysis of the initially formed indium droplets in the mild solution-phase reaction system. The twinning superlattices in the InSb NWs are determined with a pseudoperiodic length of ~42 monolayers, which result from an oscillating self-catalytic growth related to the periodical fluctuation between reduction rate of In and Sb sources in the route. The optical pump-terahertz probe spectroscopic measurement suggests that the InSb NWs have potential for applications in high-speed optoelectronic nanodevices. PMID- 29115842 TI - Robust Epitaxial Al Coating of Reclined InAs Nanowires. AB - It was recently shown that in situ epitaxial aluminum coating of indium arsenide nanowires is possible and yields superior properties relative to ex-situ evaporation of aluminum ( Nat. Mater. 2015 , 14 , 400 - 406 ). We demonstrate a robust and adaptive epitaxial growth protocol satisfying the need for producing an intimate contact between the aluminum superconductor and the indium arsenide nanowire. We show that the (001) indium arsenide substrate allows successful aluminum side-coating of reclined indium arsenide nanowires that emerge from (111)B microfacets. A robust, induced hard superconducting gap in the obtained indium arsenide/aluminum core/partial shell nanowires is clearly demonstrated. We compare epitaxial side-coating of round and hexagonal cross-section nanowires and find the surface roughness of the round nanowires to induce a more uniform aluminum profile. Consequently, the extended aluminum grains result in increased strain at the interface with the indium arsenide nanowire, which is found to induce dislocations penetrating into round nanowires only. A unique feature of proposed growth protocol is that it supports in situ epitaxial deposition of aluminum on all three arms of indium arsenide nanowire intersections in a single growth step. Such aluminum coated intersections play a key role in engineering topologically superconducting networks required for Majorana based quantum computation schemes. PMID- 29115843 TI - Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a Syn-Elimination Approach. AB - An efficient synthesis of stereodefined tetrasubstituted acyclic all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate formation of stereoenriched tertiary alcohols, followed by in situ syn-elimination of the corresponding phosphates under mild conditions. This chemistry tolerates a wide variety of electronically and sterically diverse substrates and generates the desired tetrasubstituted olefins in high yields and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield. PMID- 29115844 TI - Scalable Fabrication Framework of Implantable Ultrathin and Flexible Probes with Biodegradable Sacrificial Layers. AB - For long-term biocompatibility and performance, implanted probes need to further reduce their size and mechanical stiffness to match that of the surrounding cells, which, however, makes accurate and minimally invasive insertion operations difficult due to lack of rigidity and brings additional complications in assembling and surgery. Here, we report a scalable fabrication framework of implantable probes utilizing biodegradable sacrificial layers to address this challenge. Briefly, the integrated biodegradable sacrificial layer can dissolve in physiological fluids shortly after implantation, which allows the in situ formation of functional ultrathin film structures off of the initial small and rigid supporting backbone. We show that the dissolution of this layer does not affect the viability and excitability of neuron cells in vitro. We have demonstrated two types of probes that can be used out of the box, including (1) a compact probe that spontaneously forms three-dimensional bend-up devices only after implantation and (2) an ultraflexible probe as thin as 2 MUm attached to a small silicon shaft that can be accurately delivered into the tissue and then get fully released in situ without altering its shape and position because the support is fully retracted. We have obtained a >93% yield of the bend-up structure, and its geometry and stiffness can be systematically tuned. The robustness of the ultraflexible probe has been tested in tissue-mimicking agarose gels with <1% fluctuation in the test resistance. Our work provides a general strategy to prepare ultrasmall and flexible implantable probes that allow high insertion accuracy and minimal surgical damages with the best biocompatibility. PMID- 29115845 TI - Thermal Properties and Phonon Spectral Characterization of Synthetic Boron Phosphide for High Thermal Conductivity Applications. AB - Heat dissipation is an increasingly critical technological challenge in modern electronics and photonics as devices continue to shrink to the nanoscale. To address this challenge, high thermal conductivity materials that can efficiently dissipate heat from hot spots and improve device performance are urgently needed. Boron phosphide is a unique high thermal conductivity and refractory material with exceptional chemical inertness, hardness, and high thermal stability, which holds high promises for many practical applications. So far, however, challenges with boron phosphide synthesis and characterization have hampered the understanding of its fundamental properties and potential applications. Here, we describe a systematic thermal transport study based on a synergistic synthesis experimental-modeling approach: we have chemically synthesized high-quality boron phosphide single crystals and measured their thermal conductivity as a record high 460 W/mK at room temperature. Through nanoscale ballistic transport, we have, for the first time, mapped the phonon spectra of boron phosphide and experimentally measured its phonon mean free-path spectra with consideration of both natural and isotope-pure abundances. We have also measured the temperature- and size-dependent thermal conductivity and performed corresponding calculations by solving the three-dimensional and spectral-dependent phonon Boltzmann transport equation using the variance-reduced Monte Carlo method. The experimental results are in good agreement with that predicted by multiscale simulations and density functional theory, which together quantify the heat conduction through the phonon mode dependent scattering process. Our finding underscores the promise of boron phosphide as a high thermal conductivity material for a wide range of applications, including thermal management and energy regulation, and provides a detailed, microscopic-level understanding of the phonon spectra and thermal transport mechanisms of boron phosphide. The present study paves the way toward the establishment of a new framework, based on the phonon spectra-material structure relationship, for the rational design of high thermal conductivity materials and nano- to multiscale devices. PMID- 29115846 TI - Transition-Metal-Free Cross-Coupling of Aryl and Heteroaryl Thiols with Arylzinc Reagents. AB - Cross-coupling of (hetero)arylthiols with arylzinc reagents via C-S cleavage was performed under transition-metal-free conditions. The reaction displays a wide scope of substrates and high functional-group tolerance. Electron-rich and deficient (hetero)arylthiols and arylzinc reagents can be employed in this transformation. Mg2+ and Li+ ions were demonstrated to facilitate the reaction. PMID- 29115848 TI - ERRATUM. PMID- 29115847 TI - Effect of antihypertensive drugs on breast cancer risk in female hypertensive patients: Evidence from observational studies. AB - This systematic review aimed to evaluate the association between antihypertensive drugs and risk of breast cancer, and provide therapeutic implications for female hypertensive patients with different physical appearance. The prevalence of hypertension and female breast cancer is on the rise with age. It has been suggested that ARBs (angiotensin receptor blockers), ACEi (angiotensin-converting enzyme inhibitor), CCBs (calcium channel blockers), and BBs (beta-blockers) were widely used in hypertensive patients. Some researches have shown ARBs, ACEis, and beta-blockers to be effective drugs for blood pressure lowering as well as for reducing the risk of breast cancer in women. However, the research conclusions were inconsistent. To address the conflicting evidence from previous study, the study evaluates the risk of breast cancer in hypertensive women. In conclusion, we report the evidence that beta-blockers can reduce the risk of breast cancer recurrence, while ACEi and CCBs were not associated with an increased risk of breast cancer. PMID- 29115849 TI - ERRATUM. PMID- 29115851 TI - The effects of intraocular lens implant type on mood: a response to Zambrowski et al. PMID- 29115850 TI - ERRATUM. PMID- 29115852 TI - ERRATUM. PMID- 29115853 TI - Extracellular Vesicles: New Players in Lung Immunity. AB - Extracellular vesicles (EVs), such as exosomes and microvesicles, play an important autocrine/paracrine role in intercellular communication. Details on the involvement of EVs in the pathogenesis of lung diseases have emerged over the past several years. Moreover, EVs package numerous DNA, proteins, mRNAs, and microRNAs that can regulate immune responses in recipient cells. Almost all respiratory cells release EVs, and these EVs can have protective or detrimental functions, depending on the type of donor cells, type of stimuli, and components. In lung cancer, tumor-derived EVs carry multiple immunoinhibitory signals, disable antitumor immune effector cells, and promote tumor escape from immune control. Furthermore, bacteria- and microbiota-derived EVs can shape the immune system and lead to the development of lung disease. These EVs are capable of maintaining airway homeostasis, inducing proinflammatory effects, and promoting antigen presentation, thus regulating lung inflammation and immune responses. From these viewpoints, we summarize recent findings on EVs in lung biology and immunity. EVs provide a new avenue for understanding the mechanism of inflammatory disease progression and for developing therapeutic approaches for lung immune responses. PMID- 29115854 TI - Baseline King-Devick scores for adults are not generalizable; however, age and education influence scores. AB - OBJECTIVE: To establish normative values for the King-Devick (K-D) test to be used as a reference for determining impairment related to concussion when individual baseline scores are lacking. METHOD: Baseline K-D scores were collected for 243 participants aged 18-86. RESULTS: The mean age of subjects was 40.46; range 18-86 years. The mean time was 42.2 seconds; 26.19-75.96 seconds. There was a relationship (r = 0.376) between K-D score and age; scores increased (worsened) with age. There was also a relationship between score and education with scores decreasing as education increased (r = -0.194; p = 0.002). The K-D score was not influenced by sex or concussion history. A regression equation using education and age to predict K-D time explained 0.418 of the variance in K D test time. CONCLUSION: Although this research established a relationship between K-D score and age and education, the range in scores was too broad to establish normative values. In the absence of a baseline score, the use of a regression equation considering age and education level may provide some indication of expected score. However, the most reliable use of the test as a screen for impairment following concussion involves the use of a baseline test. PMID- 29115855 TI - An indirect comparison of ustekinumab and vedolizumab in the therapy of TNF failure Crohn's disease patients. AB - AIM: An indirect comparison of ustekinumab versus vedolizumab in patients with active moderate-to-severe Crohn's disease who were nonresponsive or intolerant to previous TNF-antagonist therapy. METHODS: A systematic review was performed in Medline via PubMed, Embase, Cochrane Library, until 30 April 2017. Inclusion criteria were: randomized controlled trials, patients treated for Crohn's disease, ustekinumab or vedolizumab therapy. Included trials were critically appraised and afterward indirect comparison by Bucher was conducted; the manuscript was prepared in accordance to the PRISMA requirements. RESULTS: Five randomized controlled trials were included and assessed for homogeneity; they occurred eligible for indirect comparison referring to induction or maintenance phase of TNF-antagonist failure population treatment; no statistically significant differences in clinical response (relative benefit [RB]: 1.14; 95% CI: 0.65-1.99; p = 0.64) as well as in clinical remission (RB: 1.16; 95% CI: 0.54 2.48; p = 0.71) in induction phase of therapy were revealed; no significant disparity was presented in a maintenance phase in clinical remission (RB: 0.72; 95% CI: 0.30-1.68; p = 0.44). No significant differences were also revealed in primary and secondary nonresponders subpopulations in clinical response. Indirect comparison of the safety profile presented no statistically significant difference between the biologics (relative risk [RR]: 0.93; 95% CI: 0.81-1.08; p = 0.35). CONCLUSION: No significant differences between vedolizumab and ustekinumab in clinical response and clinical remission for induction and remission in maintenance phase of TNF refractory patients therapy were revealed. In addition, no significant disparities in the risk of adverse events suggest a similar safety profile. PMID- 29115856 TI - LPS-induced Acute Lung Injury Involves NF-kappaB-mediated Downregulation of SOX18. AB - One of the early events in the progression of LPS-mediated acute lung injury in mice is the disruption of the pulmonary endothelial barrier resulting in lung edema. However, the molecular mechanisms by which the endothelial barrier becomes compromised remain unresolved. The SRY (sex-determining region on the Y chromosome)-related high-mobility group box (Sox) group F family member, SOX18, is a barrier-protective protein through its ability to increase the expression of the tight junction protein CLDN5. Thus, the purpose of this study was to determine if downregulation of the SOX18-CLDN5 axis plays a role in the pulmonary endothelial barrier disruption associated with LPS exposure. Our data indicate that both SOX18 and CLDN5 expression is decreased in two models of in vivo LPS exposure (intraperitoneal, intratracheal). A similar downregulation was observed in cultured human lung microvascular endothelial cells (HLMVECs) exposed to LPS. SOX18 overexpression in HLMVECs or in the mouse lung attenuated the LPS-mediated vascular barrier disruption. Conversely, reduced CLDN5 expression (siRNA) reduced the HLMVEC barrier-protective effects of SOX18 overexpression. The mechanism by which LPS decreases SOX18 expression was identified as transcriptional repression through binding of NF-kappaB (p65) to a SOX18 promoter sequence located between 1,082 and -1,073 bp with peroxynitrite contributing to LPS-mediated NF-kappaB activation. We conclude that NF-kappaB-dependent decreases in the SOX18-CLDN5 axis are essentially involved in the disruption of human endothelial cell barrier integrity associated with LPS-mediated acute lung injury. PMID- 29115857 TI - Dysphoric Milk Ejection Reflex: A Case Series. AB - BACKGROUND: Dysphoric milk ejection reflex (D-MER) is characterized by an abrupt dysphoria, or undesirable feeling that occurs with the MER and continues for no more than a few minutes. After milk ejection, the dysphoria vanishes. CASE SERIES: This case series provides a report of three women who have experienced D MER. All three women described the sudden onset of negative feelings at the initiation of each breastfeeding session. The dysphoria vanished after each milk ejection. DISCUSSION: Literature on D-MER is limited to one published qualitative research study and two published case reports. As a result, lactation professionals and other providers in the healthcare setting rarely recognize this condition. CONCLUSIONS: The case studies presented here provide evidence for the presence of D-MER. Research is needed to better understand its pathophysiology, incidence, and treatment options. PMID- 29115858 TI - Forgiveness and late life functioning: the mediating role of finding ego integrity. AB - OBJECTIVES: This study seeks (1) to replicate previous findings on the mediating effect of integrity/despair in the relation between forgiveness and depression in an elderly population and (2) to extend these findings to other aspects of functioning, namely life satisfaction and subjective health. Both aims were studied in a sample of residential elderly. METHODS: Residential elderly (n = 329, M = 87 years) filled out questionnaires on forgivingness, depressive symptoms, life satisfaction, subjective health and the developmental task of integrity/despair. Structural equation modeling was used to test the mediational role of integrity-despair in the relation between forgivingness and the aspects of functioning. Direct and indirect effects are tested. RESULTS: The results confirmed earlier findings stating that forgivingness and depression are negatively associated in residential elderly and that the developmental task of finding integrity and avoiding despair is significant mediator in this relationship. A similar pattern of mediational associations was found for life satisfaction. However, for subjective health only a direct effect between forgiveness and subjective health was found, whereas the developmental task of integrity and despair did not function as an underlying mechanism. DISCUSSION: Framed within a life span perspective, we showed that the developmental task of finding a balance between integrity and despair is an important intrapersonal mechanism through which forgivingness is related with depressed feelings and life satisfaction for residential elderly. A different mechanism might explain the direct effect between forgiveness and subjective health. PMID- 29115860 TI - Lysyl Oxidase-Like 1 Protein Deficiency Protects Mice from Adenoviral Transforming Growth Factor-beta1-induced Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by excessive deposition of extracellular matrix (ECM) in the lung parenchyma. The abnormal ECM deposition slowly overtakes normal lung tissue, disturbing gas exchange and leading to respiratory failure and death. ECM cross-linking and subsequent stiffening is thought to be a major contributor of disease progression and also promotes the activation of transforming growth factor (TGF)-beta1, one of the main profibrotic growth factors. Lysyl oxidase-like (LOXL) 1 belongs to the cross-linking enzyme family and has been shown to be up-regulated in active fibrotic regions of bleomycin-treated mice and patients with IPF. We demonstrate in this study that LOXL1-deficient mice are protected from experimental lung fibrosis induced by overexpression of TGF-beta1 using adenoviral (Ad) gene transfer (AdTGF-beta1). The lack of LOXL1 prevented accumulation of insoluble cross-linked collagen in the lungs, and therefore limited lung stiffness after AdTGF-beta1. In addition, we applied mechanical stretch to lung slices from LOXL1+/+ and LOXL1-/- mice treated with AdTGF-beta1. Lung stiffness (Young's modulus) of LOXL1-/- lung slices was significantly lower compared with LOXL1+/+ lung slices. Moreover, the release of activated TGF-beta1 after mechanical stretch was significantly lower in LOXL1-/- mice compared with LOXL1+/+ mice after AdTGF-beta1. These data support the concept that cross-linking enzyme inhibition represents an interesting therapeutic target for drug development in IPF. PMID- 29115859 TI - In vitro and in silico characterization of open-cell structures of trabecular bone. AB - This work aimed to perform a detailed in vitro and in silico characterization of open-cell structures, which resemble trabecular bone, to elucidate osteoporosis failure mechanisms. Experimental and image-based computational methods were used to estimate Young's modulus and porosities of different open-cell structures (Sawbones; Malmo, Sweden). Three different open-cell structures with different porosities were characterized. Additionally, some open-cell structures were scanned using a microcomputed tomography system (MUCT) to non-destructively predict specimen Young's modulus of the structures by developing voxel-based and tetrahedral finite element (FE) models. A 3D reconstruction and FE analyses were used. The experimental and computational results with different element types (linear and quadratic tetrahedrons and voxel-based meshes) were compared with Sawbones data (Sawbones; Malmo, Sweden) revealing important differences in Young's modulus and porosities. The specimens with high and low volume fractions were best represented by linear and quadratic tetrahedrons, respectively. These results could be used to develop new osteoporosis-prevention strategies. PMID- 29115861 TI - Postnatal overnutrition affects metabolic and vascular function reflected by physiological and histological changes in the aorta of adult Wistar rats. AB - Rigorous nutritional care during early life leads to healthy adulthood. Cardiovascular and metabolic disorders, the most prevalent clinical challenges worldwide, are epidemiologically linked to poor nutritional habits throughout life. We aimed to understand whether postnatal overnutrition (PO) initiated during lactation affects metabolic markers and vascular function later in life. To test this hypothetical effect, we studied a PO Wistar rat model based on adjusting litter size at the third day of age to three pups and eight for the control group (C). Systemic parameters such as body weight and food intake were significantly increased in adult rats, measured up to 36 weeks. Moreover, fat mass, triglycerides, insulin and systolic blood pressure were all significantly increased in the PO group. Furthermore, we assessed whether these alterations would affect morphological and functional parameters in isolated vessels. Consistent with systemic alterations of the vasculature, contraction of thoracic aortic rings, determined by dose-response curves to norepinephrine (NE), was significantly reduced in PO rats. Histological stains revealed that the relative area of collagen was higher and the elastic fiber density was lower in the distal rings of PO rats. Altogether, our results highlight the critical importance of having a healthy neonatal nutrition to prevent harmful metabolic and vascular alterations during adulthood. PMID- 29115862 TI - A summary on the effectiveness of the Amsterdam memory and attention training for children (Amat-c) in children with brain injury. AB - OBJECTIVE: To summarise the current research on the effectiveness of the Amsterdam Memory and Attention Training for Children (Amat-c). METHODS: A literature search was conducted to find articles published about the Amat-c, using PubMed, psychINFO, and PsychBITE databases. Relevant search terms included Amat-c, attention and memory, and childhood ABI. RESULTS: Our literature search identified 7 articles that described 5 separate studies including 61 children in total (mostly TBI). Only one study had a control group. All results indicated positive effects on memory and attention, although in three of the studies, these results were not statistically tested. Positive results were generally maintained six months follow up. CONCLUSIONS: This review showed that the Amat-c is effective for treating attention and memory disturbances in children with ABI. However, evidence is limited and training material is outdated. We suggest that the Amat-c should be digitised and implemented in a school setting and further evaluated. PMID- 29115863 TI - WWC3 Inhibits Glioma Cell Proliferation Through Suppressing the Wnt/beta-Catenin Signaling Pathway. AB - The scaffolding protein WW and C2 domain-containing protein 3 (WWC3) belonging to the WWC protein family plays important roles in regulating cell proliferation, cell migration, and synaptic signaling. The critical role of WWC3 in tumorigenesis has emerged recently; however, the expression and function of WWC3 in glioma remain largely unknown. Here, we found that WWC3 was significantly downregulated in glioma tissues and cell lines. Overexpression of WWC3 inhibited the glioma cell proliferation, migration, and invasion. Depletion of WWC3 promoted the proliferation of glioma cells. Mechanistically, we found that overexpression of WWC3 suppressed the activity of beta-catenin, the signaling that tightly associates with cell proliferation and growth. Depletion of WWC3 enhanced the activity of beta-catenin/Wnt signaling. Further investigation demonstrated that WWC3 interacted with T cell factor 4 (TCF4), an identified associated binding partner of beta-catenin. The interaction between WWC3 and TCF4 might inhibit the transcriptional activation of beta-catenin. Our results provide novel insights into the aberrant expression and molecular mechanism of WWC3 in glioma, which indicated WWC3 as a potential target for clinical intervention in glioma. PMID- 29115864 TI - Inter- and intra-tester reliability of the acute brain injury physiotherapy assessment (ABIPA) in patients with acquired brain injury. AB - BACKGROUND: The Acute Brain Injury Physiotherapy Assessment (ABIPA) is a new outcome measure with face validity and sensitivity to change in the early stages of neuromotor recovery after acquired brain injury (ABI). Reliability of physiotherapists using the tool has not been established. OBJECTIVE: Determine inter- and intra-tester reliability of physiotherapists using the ABIPA. METHODS: An observational study using video-recorded assessments of patient performance (n = 7) was undertaken with two cohorts of physiotherapists: those receiving training (n = 23) and those provided with guidelines only (n = 7) to administer the ABIPA. RESULTS: Across all physiotherapists (n = 30), inter-tester reliability was excellent (alpha >= 0.9) for total ABIPA score. All individual items, except trunk alignment in supine (alpha = 0.5), showed excellent or good internal consistency (alpha >= 0.7). For intra-tester reliability, substantial or perfect agreement was achieved for eight items (weighted Kappa Kw >= 0.6), moderate agreement for four items (Kw = 0.4-0.6) and three items achieved fair agreement (alignment head supine: Kw = 0.289; alignment trunk supine: Kw = 0.387 and tone left upper limb: Kw = 0.366). CONCLUSION: Physiotherapists are highly consistent using the ABIPA but several items may need revision to improve intra tester reliability. PMID- 29115865 TI - The role of meaning in life in community-dwelling older adults with depression and relationship to other risk factors. AB - OBJECTIVES: The aims of this study were to examine the association of Meaning in Life (MiL) with sociodemographic and physical factors, and its association with depression in older people. METHOD: A cross-sectional survey with a sample of N = 2104 older adults from communities of four European countries was conducted, using an age-appropriate interview for the diagnosis of depression and the Schedule for Meaning in Life Evaluation (SMiLE) questionnaire to assess MiL. RESULTS: Overall, MiL was particularly low in old male participants, in older people from Ferrara (Italy), those with a lower religious affiliation, fewer social contacts, and poorer physical health. Furthermore, younger old age (65-69 compared to 80-84 year olds), female gender, being married, living in Geneva and poorer physical health were significantly associated with a higher risk for depression. In addition, lower MiL significantly increased the likelihood to suffer from depression in older people. An interaction effect of study center and MiL also emerged: with decreasing MiL the risk for depression significantly increases in Hamburg compared to the other study centers. CONCLUSION: This study underlines the association of MiL and depression in old age. Integration of meaning-specific aspects in treatment for older adults with depression may be promising. PMID- 29115866 TI - Four experimental stimulants found in sports and weight loss supplements: 2-amino 6-methylheptane (octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3 dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA). AB - BACKGROUND: The United States Food and Drug Administration banned the stimulant 1,3-dimethylamylamine (1,3-DMAA) from dietary supplements and warned consumers that the stimulant can pose cardiovascular risks ranging from high blood pressure to heart attacks. OBJECTIVES: We designed our study to determine if a new stimulant similar in structure to 1,3-DMAA has been introduced as an ingredient in supplements sold in the United States (US). METHODS: We analyzed six brands of supplements that listed an ingredient on the label (e.g., Aconitum kusnezoffii, DMHA or 2-amino-isoheptane) that might refer to an analog of 1,3-DMAA. Supplements were analyzed by two separate laboratories using ultra-high performance liquid chromatography mass spectrometry and reference standards. RESULTS: Two previously unidentified 1,3-DMAA analogs (2-amino-6-methylheptane [octodrine] and 1,4-dimethylamylamine [1,4-DMAA]) and two banned stimulants (1,3 DMAA and 1,3-dimethylbutylamine [1,3-DMBA]) were identified. Octodrine was found at a dose (+/-95% CI) of 72 +/- 7.5 mg per serving. In Europe, octodrine was previously sold as a pharmaceutical in multi-ingredient medications at dosages from 8 to 33 mg. The quantity of octodrine found in our study was more than twice the largest pharmaceutical dose. The other new stimulant, 1,4-DMAA, has not previously been approved for human consumption, and its safety in humans is unknown. 1,4-DMAA was found at dosages between 21 +/- 11 mg to 94 +/- 48 mg per serving. In addition, two banned stimulants - 1,3-DMAA and 1,3-DMBA - were also identified: 24 +/- 7.6 mg to 35 +/- 11 mg of 1,3-DMAA and 51 +/- 16 mg of 1,3 DMBA. In one product, 24 +/- 7.6 mg of 1,3-DMAA was combined with 21 +/- 11 mg of 1,4-DMAA. 1,3-DMAA has been investigated as potentially contributing to hemorrhagic strokes and sudden death, whereas the safety of 1,3-DMBA in humans is unknown. CONCLUSION: Two banned stimulants (1,3-DMAA and 1,3-DMBA) and two previously unidentified stimulants (1,4-DMAA and octodrine) were identified in supplements sold in the United States. PMID- 29115867 TI - Outcomes in knowledge, attitudes and confidence of nursing staff working in nursing and residential care homes following a dementia training programme. AB - OBJECTIVES: Dementia training programmes for staff working in long-term care settings have been found to be effective in improving staff outcomes. This study investigated the impact of a dementia training programme for all Maltese nursing staff working in public nursing/residential homes on their knowledge, attitudes and confidence. Additionally, we identified the predictors of these domains before and after the programme. METHOD: A 14-hour training programme focusing on dementia management, care and policy was developed for all nursing staff working in public nursing and residential homes in Malta. A pretest-posttest design was used to evaluate the participants' knowledge of dementia, attitudes and confidence in working with residents with dementia using validated tools. Demographic variables were measured and compared with each staff domain. RESULTS: The majority of nursing staff attended the training programme with 261 fully completed questionnaires being collected pre-training and 214 post-training. The programme significantly improved nursing staff knowledge, attitudes and confidence. Stepwise regression analysis of each staff domain showed that the strongest predictor in all models at pre-training was the intensity of previous training programmes. Furthermore, staff who attended previous training continued to improve in their attitudes and confidence following programme completion. CONCLUSION: The study continues to shed further evidence on the impact of dementia training programs on staff outcomes. It also indicated that the intensity of previous participation in dementia training programmes was related to the participants' knowledge, attitudes and confidence and that continual exposure to training had a cumulative effect. PMID- 29115869 TI - Editor's presentation. PMID- 29115868 TI - Longitudinal trajectories of post-concussive and depressive symptoms in adolescents with prolonged recovery from concussion. AB - PRIMARY OBJECTIVE: To investigate the symptom trajectories of depressive and post concussive symptoms (PCS) in slow-to-recover adolescents to understand how the two sets of symptoms are related. RESEARCH DESIGN: We used data from a randomized clinical trial of a collaborative care intervention for post-concussive symptoms to better understand how these two sets of symptoms change in parallel over 6 months. METHODS AND PROCEDURE: PCS and depressive symptom scores for 49 adolescents (ages 11-17) were measured at enrolment and after 1, 3, and 6 months. Latent growth curve modelling for parallel processes was used to simultaneously examine change in PCS and depressive symptoms over time and to evaluate the influence of one change process on the other. MAIN OUTCOMES AND RESULTS: On average, patients enrolled 66 days following injury (Interquartile range (IQR) 43.5, 88.5). PCS and depressive symptoms were significantly associated at enrolment and over time, and both decreased over the course of 6 months. Higher PCS at enrolment predicted a greater decrease in depressive symptoms over time. CONCLUSIONS: Our results suggest that clinicians should screen for and treat depressive symptoms in patients with high post-concussive symptoms one month following injury. PMID- 29115870 TI - Examining Measurement Invariance and Differences in Age Cohorts on the Supports Intensity Scale-Children's Version-Catalan Translation. AB - Data from 949 children and adolescents with intellectual disability ages 5 to 16 for whom the Supports Intensity Scale-Children's Version-Catalan Translation was completed was used, in combination with data from the U.S. standardization sample, to examine measurement invariance and latent differences in the Catalonian sample. Results suggest that the same set of items can be used to measure support needs across U.S. and Catalonia samples and that there are age related differences in support needs in the Catalonia sample, particularly between children ages 5 to 10 and 11 to 16 years of age. This differs from findings with the U.S. sample, where differences were found in a greater number of age cohorts. Implications for future research and practice are discussed. PMID- 29115871 TI - Attendance at Fragile X Specialty Clinics: Facilitators and Barriers. AB - The objectives were to describe the demographic characteristics of children with Fragile X syndrome (FXS) and to determine predictors of attendance at Fragile X (FX) clinics. Findings from the Community Support Network (CSN) and Our Fragile X World (OFXW) samples showed that children who attended FX Clinics were mostly male, high-school aged or younger, and white, non-Hispanic. Using logistic regression models, awareness about FX Clinic services, guardian education, and income (CSN), and child age, family income, and total number of co-occurring conditions (OFXW) were predictors of clinic attendance. Demographic and child characteristics accounted for a large portion of the explained variance. Importantly, symptom severity and parent knowledge about services were independent predictors beyond the demographic characteristics of families. PMID- 29115872 TI - The Feasibility of Group Video Conferencing for Promotion of Physical Activity in Adolescents With Intellectual and Developmental Disabilities. AB - Physical activity (PA) rates of adolescents with intellectual and developmental disabilities (IDD) are low and effective strategies for increasing PA are limited. The purpose of this study was to assess the feasibility of a group-based PA intervention that was delivered remotely to adolescents with IDD. Participants attended 30-min group PA sessions 3 times a week. PA sessions were delivered in their homes by video conferencing on a tablet computer. Thirty-one participants enrolled and 29 completed the 12-week intervention. Participants attended 77.2% +/- 20.8% of scheduled sessions and averaged 26.7 +/- 2.8 min of PA/session, with 11.8 +/- 4.8 min at moderate- to vigorous intensity. Group-based PA delivered remotely may be a feasible approach for the promotion of PA in adolescents with IDD. PMID- 29115874 TI - Who Helps? Characteristics and Correlates of Informal Supporters to Adults With Disabilities. AB - This study examined who provides informal (or unpaid) supports to people with intellectual and developmental disabilities (IDD). Participants included 657 adult siblings of people with disabilities who responded to a national survey about informal supports in the areas of recreation, employment, and housing. Results indicated that most people with IDD received informal supports, with parents and sibling respondents most often providing those supports. Support was most commonly received in recreation, as opposed to housing or employment. Asked to list nonfamily informal supporters, respondents often mentioned paid staff and disability organizations. Correlates of total numbers of informal supporters included the individual with disability's functioning level and parents' ability to care for their offspring with disabilities. PMID- 29115873 TI - Self-Esteem Trajectories and Their Social Determinants in Adolescents With Different Levels of Cognitive Ability. AB - This study examines the development of self-esteem in a sample of 138 Australian adolescents (90 males; 48 females) with cognitive abilities in the lowest 15% (L CA) and a matched sample of 556 Australian adolescents (312 males; 244 females) with average to high levels of cognitive abilities (A/H-CA). These participants were measured annually (Grade 7 to 12). The findings showed that adolescents with L-CA and A/H-CA experience similar high and stable self-esteem trajectories that present similar relations with key predictors (sex, school usefulness and dislike, parenting, and peer integration). Both groups revealed substantial gender differences showing higher levels of self-esteem for adolescent males remaining relatively stable over time, compared to lower levels among adolescent females which decreased until midadolescence before increasing back. PMID- 29115875 TI - Resumes en Francais. PMID- 29115876 TI - Resumenes al Espanol. PMID- 29115877 TI - Exploring Phonological Awareness Skills in Children With Intellectual Disability. AB - The phonological awareness skills of 7- to 8-year-old children with intellectual disability (ID) were compared to those of 4- to 5-year-old typically developing children who were matched for early reading skills, vocabulary, and gender. Globally, children with ID displayed a marked weakness in phonological awareness. Syllable blending, syllable segmentation, and first phoneme detection appeared to be preserved. In contrast, children with ID showed a marked weakness in rhyme detection and a slight weakness in phoneme blending. Two school years later, these deficits no longer remained. Marked weaknesses appeared in phoneme segmentation and first/last phoneme detection. The findings suggest that children with ID display an atypical pattern in phonological awareness that changes with age. The implications for practice and research are discussed. PMID- 29115878 TI - The effect of physical activity, body mass index and waist circumference on incident diabetes. PMID- 29115880 TI - Treatment response heterogeneity in asthma: the role of genetic variation. AB - INTRODUCTION: Asthmatic patients show a large heterogeneity in response to asthma medication. Rapidly evolving genotyping technologies have led to the identification of various genetic variants associated with treatment outcomes. Areas covered: This review focuses on the current knowledge of genetic variants influencing treatment response to the most commonly used asthma medicines: short- and long-acting beta-2 agonists (SABA/LABA), inhaled corticosteroids (ICS) and leukotriene modifiers. This review shows that various genetic variants have been identified, but none are currently used to guide asthma treatment. One of the most promising genetic variants is the Arg16 variant in the ADRB2 gene to guide LABA treatment in asthmatic children. Expert commentary: Poor replication of initially promising results and the low fraction of variability accounted for by single genetic variants inhibit pharmacogenetic findings to reach the asthma clinic. Nevertheless, the identification of genetic variation influencing treatment response does provide more insights in the complex processes underlying response and might identify novel targets for treatment. There is a need to report measures of clinical validity, to perform precision-medicine guided trials, as well as to understand how genetic variation interacts with environmental factors. In addition, systems biology approaches might be able to show a more complete picture of these complex interactions. PMID- 29115879 TI - Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3 d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase. AB - Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1-18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1-18 allow for a structure-activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition. Compound 6, a 4 methoxyphenylpyrrolo[2,3-d]pyrimidin-4-amine, demonstrates single-digit micromolar inhibition of both AURKA and EGFR and provides evidence of a single molecule with dual activity against EGFR and AURKA. Compound 2, the most potent inhibitor of EGFR and AURKA from this series, has been further evaluated in four different squamous cell head and neck cancer cell lines for downstream effects resulting from AURKA and EGFR inhibition. PMID- 29115881 TI - A review of current and developing fixed-dose LABA/LAMA combinations for treating COPD. AB - INTRODUCTION: The current GOLD (Global Initiative for Chronic Obstructive Lung Disease) recommendations suggest using long acting beta2 agonists (LABA) and long acting muscarinic antagonists (LAMA) in combination for group B COPD patients with persistent symptoms, group C COPD patients with further exacerbations on LAMA therapy alone and for group D COPD patients with or without combination with inhaled corticosteroids (ICS). Thus, there is a lot of interest in developing LABA/LAMA combinations for maintenance therapy of chronic stable COPD. Areas covered: Many LABA/LAMA combinations have successfully been approved through carefully designed pivotal clinical trials. The current clinical use of LABA/LAMA combinations in COPD will continue to evolve as new trials with and without inhaled corticosteroids are completed. Expert opinion: Combining different classes of bronchodilators in a single inhaler is an attractive concept that can potentially improve patient adherence to therapy. Because LABA/LAMA combinations are the preferred treatment option for preventing COPD exacerbations in the updated GOLD guidelines for COPD, they will be clinically used. Future treatment of COPD should revolve around a personalized approach based on characterization of the COPD phenotype. PMID- 29115882 TI - Laparoscopic Resection for Liver Malignancies: Do the Elderly Benefit More? PMID- 29115883 TI - Pharmacotherapeutic options for treating Staphylococcus aureus bacteremia. AB - INTRODUCTION: Case-fatality rates for Staphylococcus aureus bacteremia (SAB) remain unacceptably high and have improved only modestly in recent decades. Treatment of SAB is still a clinical challenge, especially if methicillin resistant strains are involved. New drugs with anti-staphylococcal activity are currently available, and their role as alternatives to standard therapies is being investigated. Areas covered: In this review, we give an update of the current available antibiotics for the treatment of SAB. We provide information regarding the pharmacological characteristics, the accepted indications, and the most important adverse events of the old and new anti-staphylococcal agents, as well as the existing evidence on their use for the treatment of SAB. Expert opinion: The management of patients with SAB is very complex and needs a multidisciplinary approach. There are currently new available options for the treatment of methicillin-resistant SAB. However, more data from clinical trials are needed to assign specific roles to each antibiotic and to include them in the new antibacterial armamentarium. The role of combination therapy for the treatment of increasingly complex patients with SAB deserves thorough investigation. PMID- 29115884 TI - Blinatumomab and pancreatitis: an analysis of FAERS, EudraVigilance, and a large urban U.S. patient population data. PMID- 29115885 TI - A novel lipid prodrug strategy for sustained delivery of hexadecyloxypropyl 9-[2 (phosphonomethoxy)ethyl]guanine (HDP-PMEG) on unwanted ocular proliferation. AB - Proliferative vitreoretinopathy (PVR) is a blinding eye disease and there is no effective pharmacological measure to prevent PVR development. The difficulty comes from lack of potent antiproliferative agent and lack of sustained delivery to cover high-risk time window for PVR to develop. Lipid prodrug of PMEG, hexadecyloxypropyl 9-[(2-phosphonomethoxy)ethyl]guanine (HDP-PMEG), was prepared and was evaluated as a pharmacological adjuvant to surgical management of PVR. A dose-escalation study determined that the highest nontoxic dose for intravitreal use in pigmented rabbits was 3 ug per eye. The genotoxicity of HDP-PMEG was harnessed as a perioperative preventative measure against PVR in a rabbit eye model while the sustained intravitreal pharmacological effect was evaluated on a laser-induced fibrovascular model in rat eye. After intravitreal 3 ug, HDP-PMEG particles in the rabbit vitreous was visible for at least 6 weeks. A single 50 min intravitreal infusion of HDP-PMEG demonstrated significant inhibition of PVR formation when compared with the eyes infused with only BSS (BSS vs. HDP-PMEG: estimate = 1.14, OR = 3.1, p = .027). A single intravitreal 104 ng (equivalent to 3 ug for rabbit eye) of HDP-PMEG significantly inhibit laser-induced fibrovascular proliferation in rat eye by 55% (least square mean pixel, BSS = 4763569.5 vs. HDP-PMEG = 2148129.7, p < .0001, generalized estimating equation [GEE]). Retinal fluorescein angiography showed the odds for BSS intervened eyes to have higher-rated FA leaking grades were 38.5 times compared with HDP-PMEG treated eyes (p < .0001, GEE). Our study results indicate that single intravitreal HDP-PMEG may be a promising ocular drug delivery as a perioperative intervention to prevent PVR reoccurrence following primary surgical management. PMID- 29115886 TI - Severe pegaspargase hypersensitivity reaction rates (grade >=3) with intravenous infusion vs. intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children's oncology group (COG) clinical trials. AB - PEGylated asparaginase (pegaspargase) can be administered via intramuscular (IM) injection or intravenous (IV) infusion with a hypersensitivity reaction (HSR) incidence ranging 3-41%. We evaluated grade >=3 HSRs when given IM vs. IV on six Children's Oncology Group (COG) leukemia trials (2003-2015) to determine differences in HSR rates. 54,280 doses were administered to 16,534 patients. Considering all doses of pegaspargase during induction, consolidation, and delayed intensification, grade >=3 HSR rate with IM injection was 5.4% (n = 482/8981) compared to 3.2% for IV (n = 245/7553) (p < .0001). If only the second and third doses of pegaspargase were analyzed, where the majority of grade >=3 HSRs occur, the rate following IM injection was 10.1% (n = 459/4534) compared to 5.0% (n = 222/4443) for IV (p < .0001). On standardized treatment protocols conducted by the COG during 2003-2015, grade >=3 HSR rates to pegaspargase occurred less frequently with IV infusion than IM injection. PMID- 29115887 TI - Effect of heat stress on the gene expression of ion transporters/channels in the uterus of laying hens during eggshell formation. AB - Heat stress is a problem in laying hens as it decreases egg quality by decreasing eggshell mineralization. Heat stress alters gene expression, hence our aim was to investigate effects of heat stress on gene expression of ion transport elements involving in uterine mineralization (TRPV6, CALB1, ITPR3, SCNN1G, SLC4A4, KCNJ15, SLC4A9, and CLCN2) by real time quantitative PCR. Forty 23-week-old White Leghorn laying hens were housed in two rooms. The control group (n = 20) was maintained at 21-23 degrees C, and the heat stress group (n = 20) was exposed to 36-38 degrees C for 8 weeks. All parameters of egg quality including egg weight, surface area, volume, and eggshell weight, thickness, ash weight, and calcium content were decreased in the heat stress group compared to the control group (by 26.9%, 32.7%, 44.1%, 38.4%, 31.7%, 39.4%, and 11.1%, respectively). Total plasma calcium was decreased by 13.4%. Levels of ITPR3, SLC4A4, and SLC4A9 transcripts in the uterine lining were decreased in the heat stress group compared to the control group (by 61.4%, 66.1%, and 66.1%, respectively). CALB1 transcript level was increased (by 34.2 fold) in the heat stress group of hens compared to controls. TRPV6, SCNN1G, KCNJ15, and CLCN2 transcript levels did not significantly differ between control and heat stress groups of laying hens. It is concluded that the down-expression of ITPR3, SLC4A4, and SLC4A9 genes may impair transportation of Cl-, HCO3-, and Na+ in eggshell mineralization during heat stress. Increased CALB1 gene expression may increase resistance of uterine cells to detrimental effects of heat stress. PMID- 29115889 TI - Circulating fetal and total cell-free DNA, and sHLA-G in black South African women with gestational hypertension and pre-eclampsia. AB - OBJECTIVE: Quantification of circulating fetal and total cell-free DNA (cfDNA) and soluble human leucocyte antigen (HLAG) in gestational hypertension and pre eclampsia. METHODS: Serum cfDNA were quantified in controls, pre-eclamptics, and gestational hypertensive patients using real-time qPCR. Soluble HLAG was measured by enzyme-linked immune-sorbent assay. RESULTS: Serum fetal and total cfDNA levels were higher in pre-eclampsia compared with the controls and gestational hypertensives (p < 0.001), more so in severe compared with mild-to-moderate pre eclampsia (p < 0.05). Soluble HLAG levels were lower in pre-eclamptics than controls and gestational hypertension (p < 0.05). CONCLUSION: Circulating fetal and total cfDNA were increased, while soluble HLAG was decreased in pre eclampsia. PMID- 29115890 TI - Exploiting bilosomes for delivering bioactive polysaccharide isolated from Enteromorpha intestinalis for hacking hepatocellular carcinoma. AB - Bile salts containing vesicles (bilosomes) represent a portentous vesicular carrier that showed prosperous results in delivering active moieties in the gastrointestinal tract (GIT). In this study, bilosomes were exploited to deliver sulfated polysaccharide-protein complexes of Enteromorpha intestinalis (EHEM) and enhance its activity against hepatocellular carcinoma as well as resist harsh GIT conditions. Bilosomes were prepared using the sodium salt of three different bile acids (cholic, deoxycholic, taurodeoxycholic) and two different nonionic surfactants (Span 40 and 65). The effects of experimental variables were thoroughly studied to obtain an optimum formulation loading EHEM. The selected formulation (EH-Bilo-2) prepared with sodium cholate and Span 65 displayed nano sized (181.1 +/- 16.80 nm) spherical vesicles with reasonable entrapment efficiency (71.60 +/- 0.25%) and controlled release properties; and thus was investigated as anti-hepatocarcinogenic candidate for in vivo studies. Treatment of hepatocellular carcinoma (HCC) bearing rats with EH-Bilo-2 experienced significant decrease in serum alpha-fetoprotein, endoglin, lipocalin-2, and heat shock protein 70 levels vs. the untreated counterparts. Furthermore, the photomicrographs of their liver tissue sections showed focal area of degenerated pleomorphic hepatocytes with fine fibrosis originating from the portal area. Thus, the optimized bilosomal formulation is a promising delegate for tackling hepatocellular carcinoma owing to its powerful anti-cancer and anti-angiogenic activity. PMID- 29115888 TI - In vitro assessment of selected Korean plants for antioxidant and antiacetylcholinesterase activities. AB - CONTEXT: Antiacetylcholinesterase (AChE) drugs have been a main therapeutic treatment for Alzheimer's disease because increased AChE levels play a key role in reducing neurotransmission. OBJECTIVES: Extracts from 35 Korean plants were selected and screened for antioxidant and anti-cholinesterase activity to explore new sources derived from Korean natural resources that could be used as AD therapeutic agents. MATERIALS AND METHODS: The antioxidant effect of extracts from 35 selected Korean plants was determined using two most common free radical scavenging assays using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3 ethylbenzthiazoline-6-sulphonic acid (ABTS). Additionally, the effect of extracts, identified as antioxidants, on acetylcholinesterase inhibition was assessed by an acetylcholinesterase assay kit. RESULTS: Out of 36 extracts of 35 plants tested, Oenothera biennis L. (9.09 MUg/mL), Saururus chinensis (Lour.) Baill. (9.52 MUg/mL) and Betula platyphylla var. japonica (9.85 MUg/mL) showed strong DPPH scavenging activity. Twelve other extracts also exerted moderate free radical scavenging activities with IC50 values ranging from 10 to 50 MUg/mL. Antioxidant capacity detected by ABTS assay was only significant in O. biennis (23.40 MUg/mL), while the other extracts were weak or unable to reduce the production of ABTS. Based on the antioxidant activities of these plant extracts, 19 extracts with IC50 values less than 100 MUg/mL in DPPH assay were selected for further AChE inhibition assay. Among the extracts tested, the IC50 value for Prunella vulgaris var. lilacina NAKAI (18.83 MUg/mL) in AChE inhibitory activity was the lowest, followed by O. biennis (20.09 MUg/mL) and Pharbitis nil Chosy (22.79 MUg/mL). CONCLUSIONS: Considering complex multifactorial etiology of AD, the extracts of P. vulgaris var. lilacina (aerial part), O. biennis (seed) and P. nil (seed) may be safe and ideal candidates for future AD modifying therapies. PMID- 29115892 TI - Management of patients with chronic lymphocytic leukemia at high risk of relapse on ibrutinib therapy. AB - The past two decades have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL), particularly with the introduction of targeted therapies to clinical practice. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and has shown significant efficacy and tolerability, even in heavily treated patients. Despite improvement in outcomes, patients do ultimately relapse. Those who develop disease progression on ibrutinib are a particularly high-risk population with poor outcomes. Identifying patients at higher risk of relapse while on therapy is needed for individualized clinical monitoring and timely subsequent management upon relapse. In this article, we discuss characteristics of CLL progression, risk factors for relapse on ibrutinib including clinical and molecular biomarkers, and a risk-adapted approach to identifying, monitoring, and managing CLL patients during ibrutinib therapy. PMID- 29115891 TI - The mutational landscape of small lymphocytic lymphoma compared to non-early stage chronic lymphocytic leukemia. AB - Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated IGHV, CD38high, ZAP-70high, CD49dhigh, +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10 year: 75% vs 62%; p = .006). Binet stage, SLL, and IGHV were independent predictive factors for TTFT. Transformation to diffuse large B-cell lymphoma was higher (10-year: 12% vs 6%; p = .003), and overall survival was shorter in SLL (10-year: 55% vs 66%; p = .004). When A0 CLL patients were excluded, only CD38 and CD49d expression, +12, and 10-year TTFT remained different between the SLL and CLL patients. In summary, SLL showed only minor clinicobiological differences when compared with CLL in similar clinical stages. PMID- 29115893 TI - The Impact of Epiretinal Membrane in Neovascular Age-Related Macular Degeneration Treatment: A Spectral-Domain Optical Coherence Tomography Study. AB - PURPOSE: The purpose of this prospective study was to evaluate the impact of epiretinal membrane (ERM) on anatomical and functional results in patients with wet age-related macular degeneration (AMD) treated with intravitreal anti vascular endothelial growth (anti-VEGF) injections. METHODS: Participants in the study were 48 patients with either wet AMD alone (AMD group, n = 27) or AMD and ERM (AMD/ERM group, n = 21). All patients received intravitreal anti-VEGF injections (three monthly injections and PRN thereafter) and were followed up for at least 12 months. All participants had best-corrected visual acuity (BCVA) measurement and spectral domain-optical coherence tomography (SD-OCT) at each visit, while fluorescein angiography was performed at baseline and then at the discretion of the physician. RESULTS: There was a statistically significant improvement in BCVA at month 12 compared to baseline in each group (p < 0.001 for both groups), while the two groups did not differ significantly regarding BCVA at the end of the follow-up (p = 0.056). Additionally, there was a statistically significant reduction in CRT in both groups at month 12 (p < 0.001 for AMD group and p = 0.004 for AMD/ERM group) with no statistically significant difference between the groups (p = 0.183). Patients in the AMD group had a lower percentage of subretinal fluid (25.9%) than patients in the AMD/ERM group (52.4%) at the end of the follow-up, while ellipsoid zone disruption was found to be more profound in the AMD/ERM group (38.1%) than in the AMD group (18.5%). Patients in the AMD/ERM group needed more injections (7.1 +/- 2.0 injections) than patients in the AMD group (4.8 +/- 1.7 injections). CONCLUSIONS: Patients in the AMD/ERM group had a higher percentage of subretinal and intraretinal fluid and ellipsoid zone interruption during the follow-up period. Anti-VEGF treatment appeared to have a beneficial effect in both groups, although the AMD/ERM group needed more injections compared to the AMD group. PMID- 29115895 TI - Droplet-based digital PCR and next generation sequencing for monitoring circulating tumor DNA: a cancer diagnostic perspective. AB - INTRODUCTION: Early detection of cancers through the analysis of ctDNA could have a significant impact on morbidity and mortality of cancer patients. However, using ctDNA for early cancer diagnosis is challenging partly due to the low amount of tumor DNA released in the circulation and its dilution within DNA originating from non-tumor cells. Development of new technologies such as droplet based digital PCR (ddPCR) or optimized next generation sequencing (NGS) has greatly improved the sensitivity, specificity and precision for the detection of rare sequences. Areas covered: This paper will focus on the potential application of ddPCR and optimized NGS to detect ctDNA for detection of cancer recurrence and minimal residual disease as well as early diagnosis of cancer patients. Expert commentary: Compared to tumor tissue biopsies, blood-based ctDNA analyses are minimally invasive and accessible for regular follow-up of cancer patients. They are also described as a better picture of patients' pathology allowing to highlight both tumor heterogeneity and multiple tumor sites. After a brief introduction on the application of the follow-up of ctDNA using genetic or epigenetic biomarkers for prognosis and surveillance of cancer patients, potential perspectives of using ctDNA for early diagnosis of cancers will be presented. PMID- 29115894 TI - Selectivity analyses of gamma-benzylidene digoxin derivatives to different Na,K ATPase alpha isoforms: a molecular docking approach. AB - Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (gamma-Benzylidene digoxin derivatives) with substitutions in the lactone ring (including non-oxygen and ether groups), to obtain CTS with better NKA isoform specificity. Some of these derivatives show some NKA isoform selective effects, with BD-3, BD-8, and BD-13 increasing NKA alpha2 activity, BD-5 inhibiting NKA alpha1 and NKA alpha3, BD-10 reducing NKA alpha1, but stimulating NKA alpha2 and alpha3; and BD-14, BD 15, and BD-16 enhancing NKA alpha3 activity. A molecular-docking approach favoured NKA isoform specific interactions for the compounds that supported their observed activity. These results show that BD compounds are a new type of CTS with the capacity to target NKA activity in an isoform-specific manner. PMID- 29115896 TI - Drugging DNA repair to target T-ALL cells. PMID- 29115897 TI - Next-generation sequencing discriminates myelodysplastic/myeloproliferative neoplasms from paraneoplastic leukemoid reaction in cancer patients with hyperleukocytosis. PMID- 29115899 TI - Therapeutic inhibitors for the treatment of dry eye syndrome. AB - INTRODUCTION: Dry eye disease (DED), defined as a multifactorial disease of tears and ocular surface, results in symptoms of discomfort, ocular irritation, visual disturbance and tear film instability. This syndrome is accompanied of ocular surface inflammation and it is produced by a deficient activity of the lacrimal functional unit. In addition, it is associated with systemic autoimmune diseases such as Sjogren's Syndrome, rheumatoid arthritis, systemic lupus erythematosus and some drug administration. The treatment of dry eye disease is based on the typical signs and symptoms of dry eye, which are associated with hyperosmolarity, ocular surface inflammation, discomfort, visual disturbance, and tear film instability. Areas covered: This review is focused on synthetic drugs currently used in clinical practice, from phase III development onwards to treat the ocular surface signs and symptoms of dry eye disease. Expert opinion: The multifactorial disease and the lack of correlation between signs and symptoms imply that not all the pharmacological approaches will be successful for dry eye. The correct design of the clinical trials, with appropriate endpoints, and the type of dry eye under study are complicated but mandatory. The anti-inflammatory and secretagogues drugs are both the main compounds to currently treat the dry eye disease. PMID- 29115898 TI - Augmented Reversal of Cisplatin-Induced Delayed Gastric Emptying by Amla (Emblica Officinalis) Fruit Extract in Sprague-Dawley Rats. AB - Despite the availability of effective antiemetics, control of acute and delayed chemotherapy-induced nausea and vomiting (CINV) is often suboptimal and there is need of an inexpensive and safer alternative. Thus, this study was designed to evaluate the effect of Emblica officinalis Gaertn (Euphorbiaceae) fruit extract (EEEO) on cisplatin-induced delayed gastric emptying in Sprague-Dawley rats so that Emblica officinalis can be clarified for its application in CINV as a potential candidate. Groups I, II, III, IV, and V rats were pretreated orally with 1% carboxymethyl cellulose (CMC, 1 mL/kg), 1% CMC (1 mL/kg), EEEO (250 mg/kg), EEEO (500 mg/kg), and ondansetron (3 mg/kg), respectively, for 5 consecutive days. Then, Group I rats received 0.1 mL of normal saline and Groups II-V rats received 10 mg/kg body weight of cisplatin intraperitoneally. Immediately after that, a test meal (1.5 mL/rat) was administered to each group, and after 30 minutes, rats were euthanized to evaluate the percentage of gastric emptying. EEEO at the specified doses reversed the cisplatin-induced delayed gastric emptying. EEEO (500 mg/kg body weight) pretreatment for 5 days before cisplatin challenge in Group IV rats significantly (p < .05) increased gastric emptying to 74.25% +/- 7.19%. Reversal of cisplatin-induced delay in gastric emptying by EEEO (500 mg/kg body weight) in Group IV was significantly (p < .05) comparable to that of the ondansetron treated Group V. EEEO possesses the property to reverse the cisplatin-induced delayed gastric emptying and can be used as an antiemetic for the prevention of CINV. PMID- 29115900 TI - Preparation, characterization and antitumor activity evaluation of apigenin nanoparticles by the liquid antisolvent precipitation technique. AB - The present work aimed to apply the liquid antisolvent precipitation (LAP) method for preparing the apigenin nanoparticles and thereby improving the solubility and bioavailability of apigenin. The different experimental parameters on particle size were optimized through central composite design (CCD) using the Design Expert(r) software. Under the optimum conditions, the particle size of the apigenin nanosuspension was about 159.2 nm. In order to get apigenin nanoparticles, the freeze-drying method was selected and the mannitol was used as a cryoprotectant. Then the solid state properties of the apigenin nanoparticles were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermo gravimetric (TG), and X-ray diffraction (XRD). The results obtained displayed that the apigenin nanoparticles exhibited near spherical shape and could be transformed into an amorphous form. In addition, the dissolving test, the bioavailability in rats, and the antitumor activity were also studied. The experimental results showed that the solubility of the apigenin nanoparticles were about 29.61 times and 64.81 times of raw apigenin in artificial gastric juice and in artificial intestinal juice, respectively, and the apigenin nanoparticles showed higher dissolution rates compared to raw apigenin, and was about 6.08 times and 6.14 times than that of raw apigenin in artificial gastric juice and in artificial intestinal juice. The oral bioavailability of apigenin nanoparticles was about 4.96 times higher than that of the raw apigenin, but the apigenin nanoparticles had no toxic effect on the organs of rats. In addition, the apigenin nanoparticles had a higher inhibition to HepG2 cells by lower IC50 than that of raw apigenin. PMID- 29115901 TI - 'No one here's helping me, what do you do?': addressing patient need for support and advice about stem cell treatments. AB - AIM: This article examines how those who contemplate purported stem cell treatments (SCTs) negotiate available information sources and the adequacy of current approaches to guidance and support. MATERIALS & METHODS: Qualitative interviews undertaken with people who had contemplated or undergone purported SCTs for a range of conditions (n = 24 and n = 27, respectively), as well as professionals who are frequently asked about SCTs (n = 20) were analyzed. RESULTS: Our findings reveal the difficulties for individuals in discriminating between different sources of information on SCTs and the limitations of current responses. CONCLUSION: In the context of contending information about SCTs informal ('accidental') advisors potentially play a crucial role in supporting patients. Additional approaches are also required to better address patients' needs. PMID- 29115902 TI - Open-mouth jaw locking in cats: a literature review and use of CT in three cases. AB - CASE SERIES SUMMARY: This report summarises and reviews the published cases of open-mouth jaw locking in cats and describes three further cases. Case 1 was a 5 year-old, 5.3 kg male neutered domestic shorthair cat. CT identified changes consistent with temporomandibular joint (TMJ) dysplasia with osseous degenerative changes, and the cat subsequently underwent bilateral partial zygomectomy with bilateral partial coronoidectomy. Case 2 was a 10-year-old, 6.0 kg male neutered Exotic Shorthair. Aside from a fracture of the left maxillary canine tooth crown and absence of the left maxillary fourth premolar tooth, no abnormalities were found on CT scan. The cat also underwent bilateral partial zygomectomy with bilateral partial coronoidectomy. The third case was a 1-year-old, 4.0 kg male neutered Persian cat. Changes on CT were consistent with bilateral TMJ dysplasia, and the cat underwent staged bilateral partial zygomectomy with bilateral partial coronoidectomy. There was no recurrence of open-mouth jaw locking in any of the cases on long-term follow-up. RELEVANCE AND NOVEL INFORMATION: Open-mouth jaw locking has been reported in cats of a wide range of ages, from 1-10 years. Cats with all skull types (brachycephalic, mesaticephalic and dolichocephalic) may be affected, but brachycephalic breeds seem to be over-represented. A CT scan with the jaw locked in place is recommended for diagnosis and surgical planning purposes; two of the cases reported here document the first cases of TMJ dysplasia in cats to be definitively diagnosed using CT. Trauma and symphyseal or TMJ laxity may also predispose to development of the condition. Partial coronoidectomy and partial zygomatic arch resection performed alone or in combination are generally successful at preventing recurrence. Bilateral partial zygomectomy with bilateral partial coronoidectomy has not previously been reported as a surgical treatment, and is recommended when open-mouth jaw locking occurs bilaterally. PMID- 29115903 TI - 5-Year survival after splenectomy in a patient with recurrent cutaneous melanoma: a case report. AB - OBJECTIVE: Splenic metastases of melanoma are uncommon and generally part of a disseminated disease with a poor prognosis. In case of solitary visceral metastasis, surgical resection often remains an effective treatment. This case describes a long-term survival after splenectomy for a recurrent melanoma. METHODS: We present a 55-year-old female with a solitary splenic metastasis. Her medical history revealed a melanoma of the foot in 2007 and an in-transit metastasis in 2011. A PET-CT revealed in 2012 the presence of a small aspecific lesion in the spleen. Close follow-up was chosen. Since PET-CT and MRI showed a progressive lesion, a laparoscopic splenectomy was performed. RESULTS: Histological report confirmed the diagnosis of a metastatic lesion. Sixty months after the first radiographic evidence of the splenic metastasis, follow-up revealed no signs of residual disease. CONCLUSIONS: Although current systemic approaches demonstrate to provide clinically important benefit, patients with oligometastatic disease should be evaluated for surgical metastasectomy. A laparoscopic approach for splenic metastasis is shown to be a safe treatment. This disease-free survival of 60 months in a patient with a history of an in transit metastasis has not been published before. A splenectomy for a solitary metastasis could prolong the survival, even in a recurrent melanoma. PMID- 29115904 TI - Transmesenteric hernia: a rare case of acute abdominal pain in children: a case report and review of the literature. AB - In this report, we discuss the case of an 11-year old girl presenting with acute abdominal pain caused by gangrene of a large part of the small bowel. During urgent surgical exploration, the cause of gangrene appeared to be herniation of the small bowel through a congenital defect in the mesentery with subsequent strangulation. A resection was performed leaving the patient with only 130 cm of small bowel remaining. Transmesenteric hernia is a rare type of internal herniation consisting of a small congenital defect in the small bowel mesentery through which the intestine can herniate and subsequently become strangulated. We present a case of transmesenteric hernia with disastrous effects and review the literature regarding this rare type of hernia. PMID- 29115905 TI - Cost-effectiveness analysis of infant pneumococcal vaccination with PHiD-CV in Korea. AB - BACKGROUND: Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) can cause invasive pneumococcal diseases (IPD), pneumonia, and acute otitis media (AOM). Both the 10-valent pneumococcal NTHi protein D conjugate vaccine (PHiD-CV) and the 13-valent pneumococcal conjugate vaccine (PCV-13) are included in the National Immunization Program for infants in Korea. This study aimed to evaluate the cost-effectiveness of the 3+1 schedule of PHiD-CV versus that of PCV-13 for National Immunization Program in Korea. METHODS: A published Markov model was adapted to evaluate the cost-effectiveness of vaccinating the 2012 birth cohort with PHiD-CV vs. PCV-13 from the Korean government perspective over 10 y. Best available published data were used for epidemiology, vaccine efficacy and disutilities. Data on incidence and direct medical costs were taken from the national insurance claims database. Sensitivity analyses were conducted to explore the robustness of the results. RESULTS: PHiD-CV was projected to prevent an additional 195,262 cases of pneumococcal diseases and NTHi-related diseases vs. PCV-13, with a substantially greater reduction in NTHi-related AOM and a comparable reduction in IPD and community-acquired pneumonia. Parity-priced PHiD-CV generated a health gain of about 844 quality-adjusted life years and a total cost-saving of approximately 4 million United States Dollars (USD) over 10 y. 93% of probabilistic simulations found PHiD-CV 3+1 to be the dominant vaccine option. CONCLUSION: Compared to PCV-13, PHiD-CV was projected to provide similar prevention against IPD and community-acquired pneumonia but would prevent more cases of AOM. Parity-priced PHiD-CV was anticipated to generate substantial cost savings and health benefits vs. PCV-13 in Korea. PMID- 29115907 TI - Relevant research from orthodontic journals. PMID- 29115906 TI - Challenges of running a GMP facility for regenerative medicine in a public hospital. AB - Advanced therapy medicinal products represent a new generation of medicinal products for regenerative medicine. Since the implementation of the EU regulation for this innovative class of drugs, the academic and hospital institutions have played a central role in their development and manufacture. For these institutions that are not familiar with the industrial context, being in compliance with the pharmaceutical standards is extremely challenging. This report describes how we dealt with some specific issues during our hospital-based GMP experience. Furthermore, we identify as a future perspective the consistent stimulating contribution that a public entity can ensure for advanced therapy medicinal product development and licensing. PMID- 29115908 TI - Conflicting Goals: You Can't Always Get What You Want-But If You Try, You Might Get What You Need. PMID- 29115909 TI - Individual, premigration and postsettlement factors, and academic achievement in adolescents from refugee backgrounds: A systematic review and model. AB - We have limited understanding of the precursors of academic achievement in resettled adolescents from refugee backgrounds. To date, no clear model has been developed to conceptualise the academic trajectories of adolescents from refugee backgrounds at postsettlement. The current review had two aims. First, to propose an integrated adaptive model to conceptualise the impact of individual, premigration, and postsettlement factors on academic achievement at postsettlement; and second, to critically examine the literature on factors that predict academic achievement in adolescents from refugee backgrounds in relation to the proposed model and highlight issues deserving future exploration. Following the protocol of a systematic literature review, 13 studies were identified for full-text review. Gender, ethnicity, English proficiency, psychological distress, premigration trauma, premigration loss, postsettlement social support, and postsettlement school connectedness, were found to predict academic achievement in adolescents from refugee backgrounds. PMID- 29115910 TI - Factors associated with long turnaround time for early infant diagnosis of HIV in Myanmar. AB - BACKGROUND: A previous review of early infant diagnosis (EID) using polymerase chain reaction technology (PCR) under integrated HIV care (IHC) program in Myanmar revealed a low uptake of timely (within 6 to 8 weeks of babies' age) EID and a long turnaround time (TAT) of receiving results. OBJECTIVE: This study aimed to determine the proportion and factors associated with the composite outcome of a long TAT (>=7 weeks; from sample collection to receipt of result by mother) or nonreceipt of result among HIV-exposed babies whose blood samples were collected for PCR at <9 months of age under the IHC program, Myanmar (2013-15). METHODS: Cohort study involving record review of routinely collected data. A predictive Poisson regression model with robust variance estimates was fitted for risk factors of long TAT or nonreceipt of result. RESULTS: Blood samples of 1 000 babies were collected; among them, long TAT or nonreceipt of results was seen in 690 (69%), and this was more than 50% across all subgroups. Babies with a mother's CD4 count of 100-350 cells/mm3 at enrollment [adjusted RR (0.95 confidence intervals, CI): 0.8 (0.7, 0.9)] had a 20% lower risk of long TAT or nonreceipt of results when compared with >=350 cells/mm3. Distance between ART center and PCR facility >=105 km [adjusted RR (0.95 CI): 1.2 (1.1, 1.4)], when compared with <105 km, was associated with 20% higher risk of long TAT or nonreceipt of results. CONCLUSIONS: The proportion of babies with long TAT or nonreceipt of result by the mother was high. Point-of-care testing for EID may reduce TAT/nonreceipt of results by the mother. Health system, laboratory, and logistic factors such as sample transportation, laboratory procedures, and result dispatching associated with long TAT should be further explored. PMID- 29115911 TI - Leveraging social media in the stem cell sector: exploring Twitter's potential as a vehicle for public information campaigns. AB - AIM: Our aim in this project was to explore Twitter's potential as a vehicle for an online public information campaign (PIC) focused on providing evidence-based information about stem cell therapies and the market for unproven stem cell-based interventions. METHODS: We designed an online, Twitter-based PIC using classic design principles and identified a set of target intermediaries (organizations with online influence) using a network governance approach. We tracked the PIC's dissemination over a 2-month period, and evaluated it using metrics from the #SMMStandards Conclave. RESULTS: Participation was limited but the PIC achieved some reach and engagement. CONCLUSION: Social media based online PICs appear to have potential but also face challenges. Future research is required to better understand how to most effectively maximize their strengths. PMID- 29115912 TI - Hyperoxia for performance and training. AB - Recent technological developments have made it possible to use hyperoxia as an enhancement aid during training. Athletes wearing a mask can breathe a higher fraction of oxygen from a stationary or portable apparatus while exercising. A large body of evidence indicates that the oxygen transport capacity, lactate metabolism, power output and work tolerance (endurance) are improved when breathing hyperoxia. The physiological mechanisms underlying these performance improvements, although still not fully elucidated, are based on higher oxygen delivery and reduced central fatigue. Although much is known about the acute effects of hyperoxia, the effect of hyperoxic-supplemented endurance training on performance and the mechanisms beneath training adaptations are not very well understood, especially in well-trained endurance athletes. The few studies on the physiological effects of hyperoxia training have been conducted with conflicting results, discussed in this paper. Potential detrimental effects have not yet been shown experimentally and warrant further investigation. PMID- 29115914 TI - Welcoming New Editorial Board Members. PMID- 29115913 TI - Exploring the activities of ruthenium nanomaterials as reactive oxygen species scavengers. AB - Research on noble metal nanoparticles (NPs) able to scavenge reactive oxygen species (ROS) has undergone a tremendous growth recently. However, the interactions between ruthenium nanoparticles (Ru NPs) and ROS have never been systematically explored thus far. This research focused on the decomposition of hydrogen peroxide (H2O2), scavenging of hydroxyl radicals (*OH), superoxide radical (O2*-), singlet oxygen (1O2), 2,2'-azino-bis(3-ethylbenzenothiazoline- 6 sulfonic acid ion (ABTS*+), and 1,1-diphenyl-2-picrylhydrazyl radical (*DPPH) in the presence of commercial Ru NPs using the electron spin resonance technique. In vitro cell studies demonstrated that Ru NPs have excellent biocompatibility and exert a cytoprotective effect against oxidative stress. These findings may spark fresh enthusiasm for the applications of Ru NPs under relevant physiologically conditions. PMID- 29115916 TI - Thing 1 and Thing 2: Psychology and Engagement in Telehealth. PMID- 29115915 TI - Neuromodulation in multiple sclerosis. AB - Neuromodulation, or the utilization of advanced technology for targeted electrical or chemical neuronal stimulation or inhibition, has been expanding in several neurological subspecialties. In the past decades, immune-modulating therapy has been the main focus of multiple sclerosis (MS) research with little attention to neuromodulation. However, with the recent advances in disease modifying therapies, it is time to shift the focus of MS research to neuromodulation and restoration of function as with other neurological subspecialties. Preliminary research supports the value of intrathecal baclofen pump and functional electrical stimulation in improving spasticity and motor function in MS patients. Deep brain stimulation can improve MS-related tremor and trigeminal neuralgia. Spinal cord stimulation has been shown to be effective against MS-related pain and bladder dysfunction. Bladder overactivity also responds to sacral neuromodulation and posterior tibial nerve stimulation. Despite limited data in MS, transcranial magnetic stimulation and brain-computer interface are promising neuromodulatory techniques for symptom mitigation and neurorehabilitation of MS patients. In this review, we provide an overview of the available neuromodulatory techniques and the evidence for their use in MS. PMID- 29115917 TI - The complete chloroplast genome of Primulina and two novel strategies for development of high polymorphic loci for population genetic and phylogenetic studies. AB - BACKGROUND: Primulina Hance is an emerging model for studying evolutionary divergence, adaptation and speciation of the karst flora. However, phylogenetic relationships within the genus have not been resolved due to low variation detected in the cpDNA regions. Chloroplast genomes can provide important information for phylogenetic and population genetic studies. Recent advances in next-generation sequencing (NGS) techniques greatly facilitate sequencing whole chloroplast genomes for multiple individuals. Consequently, novel strategies for development of highly polymorphic loci for population genetic and phylogenetic studies based on NGS data are needed. METHODS: For development of high polymorphic loci for population genetic and phylogenetic studies, two novel strategies are proposed here. The first protocol develops lineage-specific highly variable markers from the true high variation regions (Con_Seas) across whole cp genomes, instead of traditional noncoding regions. The pipeline has been integrated into a single perl script, and named "Con_Sea_Identification_and_PIC_Calculation". The second method assembles chloroplast fragments (poTs) and sub-super-marker (CpContigs) through our "SACRing" pipeline. This approach can fundamentally alter the strategies used in phylogenetic and population genetic studies based on cp markers, facilitating a transition from traditional Sanger sequencing to RAD-Seq. Both of these scripts are available at https://github.com/scbgfengchao/ . RESULTS: Three complete Primulina chloroplast genomes were assembled from genome survey data, and then two novel strategies were developed to yield highly polymorphic markers. For experimental evaluation of the first protocol, a set of Primulina species were used for PCR amplification. The results showed that these newly developed markers are more variable than traditional ones, and seem to be a better choice for phylogenetic and population studies in Primulin a. The second method was also successfully applied in population genetic studies of 21 individuals from three natural populations of Primulina. CONCLUSIONS: These two novel strategies may provide a pathway for similar research in other non-model species. The newly developed high polymorphic loci in this study will promote further the phylogenetic and population genetic studies in Primulina and other genera of the family Gesneriaceae. PMID- 29115918 TI - XTHs from Fragaria vesca: genomic structure and transcriptomic analysis in ripening fruit and other tissues. AB - BACKGROUND: Fragaria vesca or 'woodland strawberry' has emerged as an attractive model for the study of ripening of non-climacteric fruit. It has several advantages, such as its small genome and its diploidy. The recent availability of the complete sequence of its genome opens the possibility for further analysis and its use as a reference species. Fruit softening is a physiological event and involves many biochemical changes that take place at the final stages of fruit development; among them, the remodeling of cell walls by the action of a set of enzymes. Xyloglucan endotransglycosylase/hydrolase (XTH) is a cell wall associated enzyme, which is encoded by a multigene family. Its action modifies the structure of xyloglucans, a diverse group of polysaccharides that crosslink with cellulose microfibrills, affecting therefore the functional structure of the cell wall. The aim of this work is to identify the XTH-encoding genes present in F. vesca and to determine its transcription level in ripening fruit. RESULTS: The search resulted in identification of 26 XTH-encoding genes named as FvXTHs. Genetic structure and phylogenetic analyses were performed allowing the classification of FvXTH genes into three phylogenetic groups: 17 in group I/II, 2 in group IIIA and 4 in group IIIB. Two sequences were included into the ancestral group. Through a comparative analysis, characteristic structural protein domains were found in FvXTH protein sequences. In complement, expression analyses of FvXTHs by qPCR were performed in fruit at different developmental and ripening stages, as well as, in other tissues. The results showed a diverse expression pattern of FvXTHs in several tissues, although most of them are highly expressed in roots. Their expression patterns are not related to their respective phylogenetic groups. In addition, most FvXTHs are expressed in ripe fruit, and interestingly, some of them (FvXTH 18 and 20, belonging to phylogenic group I/II, and FvXTH 25 and 26 to group IIIB) display an increasing expression pattern as the fruit ripens. CONCLUSION: A discrete group of FvXTHs (18, 20, 25 and 26) increases their expression during softening of F. vesca fruit, and could take part in cell wall remodeling required for softening in collaboration with other cell wall degrading enzymes. PMID- 29115920 TI - Genome-wide association mapping of resistance to a Brazilian isolate of Sclerotinia sclerotiorum in soybean genotypes mostly from Brazil. AB - BACKGROUND: Sclerotinia Stem Rot (SSR), caused by the fungal pathogen Sclerotinia sclerotiorum, is ubiquitous in cooler climates where soybean crops are grown. Breeding for resistance to SSR remains challenging in crops like soybean, where no single gene provides strong resistance, but instead, multiple genes work together to provide partial resistance. In this study, a genome-wide association study (GWAS) was performed to dissect the complex genetic architecture of soybean quantitative resistance to SSR and to provide effective molecular markers that could be used in breeding programs. A collection of 420 soybean genotypes were selected based on either reports of resistance, or from one of three different breeding programs in Brazil, two commercial, one public. Plant genotype sensitivity to SSR was evaluated by the cut stem inoculation method, and lesion lengths were measured at 4 days post inoculation. RESULTS: Genotyping-by sequencing was conducted to genotype the 420 soybean lines. The TASSEL 5 GBSv2 pipeline was used to call SNPs under optimized parameters, and with the extra step of trimming adapter sequences. After filtering missing data, heterozygosity, and minor allele frequency, a total of 11,811 SNPs and 275 soybean genotypes were obtained for association analyses. Using a threshold of FDR-adjusted p-values <0.1, the Compressed Mixed Linear Model (CMLM) with Genome Association and Prediction Integrated Tool (GAPIT), and the Fixed and Random Model Circulating Probability Unification (FarmCPU) methods, both approaches identified SNPs with significant association to disease response on chromosomes 1, 11, and 18. The CMLM also found significance on chromosome 19, whereas FarmCPU also identified significance on chromosomes 4, 9, and 16. CONCLUSIONS: These similar and yet different results show that the computational methods used can impact SNP associations in soybean, a plant with a high degree of linkage disequilibrium, and in SSR resistance, a trait that has a complex genetic basis. A total of 125 genes were located within linkage disequilibrium of the three loci shared between the two models. Their annotations and gene expressions in previous studies of soybean infected with S. sclerotiorum were examined to narrow down the candidates. PMID- 29115919 TI - High-resolution analysis of selection sweeps identified between fine-wool Merino and coarse-wool Churra sheep breeds. AB - BACKGROUND: With the aim of identifying selection signals in three Merino sheep lines that are highly specialized for fine wool production (Australian Industry Merino, Australian Merino and Australian Poll Merino) and considering that these lines have been subjected to selection not only for wool traits but also for growth and carcass traits and parasite resistance, we contrasted the OvineSNP50 BeadChip (50 K-chip) pooled genotypes of these Merino lines with the genotypes of a coarse-wool breed, phylogenetically related breed, Spanish Churra dairy sheep. Genome re-sequencing datasets of the two breeds were analyzed to further explore the genetic variation of the regions initially identified as putative selection signals. RESULTS: Based on the 50 K-chip genotypes, we used the overlapping selection signals (SS) identified by four selection sweep mapping analyses (that detect genetic differentiation, reduced heterozygosity and patterns of haplotype diversity) to define 18 convergence candidate regions (CCR), five associated with positive selection in Australian Merino and the remainder indicating positive selection in Churra. Subsequent analysis of whole-genome sequences from 15 Churra and 13 Merino samples identified 142,400 genetic variants (139,745 bi-allelic SNPs and 2655 indels) within the 18 defined CCR. Annotation of 1291 variants that were significantly associated with breed identity between Churra and Merino samples identified 257 intragenic variants that caused 296 functional annotation variants, 275 of which were located across 31 coding genes. Among these, four synonymous and four missense variants (NPR2_His847Arg, NCAPG_Ser585Phe, LCORL_Asp1214Glu and LCORL_Ile1441Leu) were included. CONCLUSIONS: Here, we report the mapping and genetic variation of 18 selection signatures that were identified between Australian Merino and Spanish Churra sheep breeds, which were validated by an additional contrast between Spanish Merino and Churra genotypes. Analysis of whole-genome sequencing datasets allowed us to identify divergent variants that may be viewed as candidates involved in the phenotypic differences for wool, growth and meat production/quality traits between the breeds analyzed. The four missense variants located in the NPR2, NCAPG and LCORL genes may be related to selection sweep regions previously identified and various QTL reported in sheep in relation to growth traits and carcass composition. PMID- 29115921 TI - Identifying protective and risk factors for injurious falls in patients hospitalized for acute care: a retrospective case-control study. AB - BACKGROUND: Admitted patients who fall and injure themselves during an acute hospitalization incur increased costs, morbidity, and mortality, but little research has been conducted on identifying inpatients at high risk to injure themselves in a fall. Falls risk assessment tools have been unsuccessful due to their low positive predictive value when applied broadly to entire hospital populations. We aimed to identify variables associated with the risk of or protection against injurious fall in the inpatient setting. We also aimed to test the variables in the ABCs mnemonic (Age > 85, Bones-orthopedic conditions, anti Coagulation and recent surgery) for correlation with injurious fall. METHODS: We performed a retrospective case-control study at an academic tertiary care center comparing admitted patients with injurious fall to admitted patients without fall. We collected data on the demographics, medical and fall history, outcomes, and discharge disposition of injured fallers and control patients. We performed multivariate analysis of potential risk factors for injurious fall with logistic regression to calculate adjusted odds ratios. RESULTS: We identified 117 injured fallers and 320 controls. There were no differences in age, anti-coagulation use or fragility fractures between cases and controls. In multivariate analysis, recent surgery (OR 0.46, p = 0.003) was protective; joint replacement (OR 5.58, P = 0.002), psychotropic agents (OR 2.23, p = 0.001), the male sex (OR 2.08, p = 0.003) and history of fall (OR 2.08, p = 0.02) were significantly associated with injurious fall. CONCLUSION: In this study, the variables in the ABCs parameters were among the variables not useful for identifying inpatients at risk of injuring themselves in a fall, while other non-ABCs variables demonstrated a significant association with injurious fall. Recent surgery was a protective factor, and practices around the care of surgical patients could be extrapolated to reduce the in-hospital fall rates. PMID- 29115922 TI - The prevalence of dementia in a Portuguese community sample: a 10/66 Dementia Research Group study. AB - BACKGROUND: Dementia imposes a high burden of disease worldwide. Recent epidemiological studies in European community samples are scarce. In Portugal, community prevalence data is very limited. The 10/66 Dementia Research Group (DRG) population-based research programmes are focused in low and middle income countries, where the assessments proved to be culture and education fair. We applied the 10/66 DRG prevalence survey methodology in Portugal, where levels of illiteracy in older populations are still high. METHODS: A cross-sectional comprehensive one-phase survey was conducted of all residents aged 65 and over of two geographically defined catchment areas in Southern Portugal (one urban and one rural site). Nursing home residents were not included in the present study. Standardized 10/66 DRG assessments include a cognitive module, an informant interview and the Geriatric Mental State-AGECAT, providing data on dementia diagnosis and subtypes, mental disorders including depression, physical health, anthropometry, demographics, disability/functioning, health service utilization, care arrangements and caregiver strain. RESULTS: We interviewed 1405 old age participants (mean age 74.9, SD = 6.7 years; 55.5% women) after 313 (18.2%) refusals to participate. The prevalence rate for dementia in community-dwellers was 9.23% (95% CI 7.80-10.90) using the 10/66 DRG algorithm and 3.65% (95% CI 2.97-4.97) using DSM-IV criteria. Pure Alzheimer's disease was the most prevalent dementia subtype (41.9%). The prevalence of dementia was strongly age-dependent for both criteria, but there was no association with sex. CONCLUSIONS: Dementia prevalence was higher than previously reported in Portugal. The discrepancy between prevalence according to the 10/66 DRG algorithm and the DSM-IV criteria is consistent with that observed in less developed countries; this suggests potential underestimation using the latter approach, although relative validity of these two approaches remains to be confirmed in the European context. We improved the evidence base to raise awareness and empower advocacy about dementia in Portugal, so that the complex needs of frail older people may be met in better ways. PMID- 29115923 TI - Neuroprotective effect of neuroserpin in non-tPA-induced intracerebral hemorrhage mouse models. AB - BACKGROUND: The neuroprotective effects of neuroserpin (NSP) have been well documented in both patients and animal models with cerebral ischemia; however, have never been investigated in hemorrhagic stroke. The aim of this study is to verify the neuroprotection of NSP in the non-tPA-induced intracerebral hemorrhage (ICH) mouse model. METHODS: C57BL/6J male mice (n = 198) were involved in this study. ICH models were established with infusion of autologous blood into the brain parenchyma. We then detected NSP expression in ICH brains by morphological methods and western blotting analysis. We measured the brain water content and detected blood-brain barrier (BBB) permeability to verify the neuroprotective effects of NSP. RESULTS: We found that NSP protein expression was upregulated in ICH models, with a peak at 48 h after ICH induction. NSP local administration reduced the brain edema and the BBB permeability in ICH models. The neurological deficits were also ameliorated. Thus, the neuroprotection of NSP in ICH state was confirmed. Additionally, we also found that the distribution pattern of occludin expressing cells was obviously changed by the ICH procedure but partly recovered after NSP administration. This finding indicated that protecting and/or repairing the injured vascular endothelial cells may be a potential mechanism involved in NSP neuroprotection, which needs further verification. CONCLUSIONS: Our results supported the fact that NSP may be considered as a potential therapy for ICH for the neuroprotective effects including amelioration of the edema. PMID- 29115924 TI - Transcription factor E2F1 promotes EMT by regulating ZEB2 in small cell lung cancer. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is an early event in tumour invasion and metastasis, and widespread and distant metastasis at early stages is the typical biological behaviour in small cell lung cancer (SCLC). Our previous reports showed that high expression of the transcription factor E2F1 was involved in the invasion and metastasis of SCLC, but the role of E2F1 in the process of EMT in SCLC is unknown. METHODS: Immunohistochemistry was performed to evaluate the expressions of EMT related markers. Immunofluorescence was used to detect the expressions of cytoskeletal proteins and EMT related markers when E2F1 was silenced in SCLC cell lines. Adenovirus containing shRNA against E2F1 was used to knock down the E2F1 expression, and the dual luciferase reporter system was employed to clarify the regulatory relationship between E2F1 and ZEB2. RESULTS: In this study, we observed the remodelling of cytoskeletal proteins when E2F1 was silenced in SCLC cell lines, indicating that E2F1 was involved in the EMT in SCLC. Depletion of E2F1 promoted the expression of epithelial markers (CDH1 and CTNNB1) and inhibited the expression of mesenchymal markers (VIM and CDH2) in SCLC cell lines, verifying that E2F1 promotes EMT occurrence. Next, the mechanism by which E2F1 promoted EMT was explored. Among the CDH1 related inhibitory transcriptional regulators ZEB1, ZEB2, SNAI1 and SNAI2, the expression of ZEB2 was the highest in SCLC tissue samples and was highly consistent with E2F1 expression. ChIP-seq data and dual luciferase reporter system analysis confirmed that E2F1 could regulate ZEB2 gene expression. CONCLUSION: Our data supports that E2F1 promotes EMT by regulating ZEB2 gene expression in SCLC. PMID- 29115925 TI - Synchronous occurrence of hereditary gastric adenocarcinoma, gastrointestinal stromal tumor, and esophageal small cell and squamous carcinoma in situ: an extremely rare case report. AB - BACKGROUND: Hereditary diffuse gastric carcinoma (HDGC) accounts for 1-3% of all gastric carcinomas. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract but they comprise fewer than 1% of all GI malignancies. Small-cell carcinoma (SmCC) is a rare histological type of esophageal carcinoma, accounting for 0.4% to 2.8% of all esophageal tumors. Co-occurrence of SmCC with esophageal tumors caused by squamous carcinoma is also very uncommon. Although multiple primary malignancies are no longer rare in clinical practice, the simultaneous appearance of HDGC, GIST, esophageal small cell and squamous carcinoma in situ is extremely rare and very few cases have been reported. CASE PRESENTATION: We present a case of a 53 year-old woman with synchronous occurrence of four malignancies including HDGC, GIST, esophageal small cell- and local squamous carcinoma in situ. A total gastrectomy with D2 lymph node dissection and postoperative adjuvant chemotherapy with oxaliplatin and paclitaxel liposome were performed. After a 1-year follow up, this patient was still in good condition with no evidence of recurrence. CONCLUSION: This is the unique case that describes the co-existence of the aforementioned four types of neoplasm. This case demonstrates that a diagnosis of gastric cancer does not preclude the presence of other malignancies and every case should be thoroughly analyzed to avoid missing other problems, which may worsen the prognosis. PMID- 29115927 TI - Transcriptomic responses to wounding: meta-analysis of gene expression microarray data. AB - BACKGROUND: A vast amount of microarray data on transcriptomic response to injury has been collected so far. We designed the analysis in order to identify the genes displaying significant changes in expression after wounding in different organisms and tissues. This meta-analysis is the first study to compare gene expression profiles in response to wounding in as different tissues as heart, liver, skin, bones, and spinal cord, and species, including rat, mouse and human. RESULTS: We collected available microarray transcriptomic profiles obtained from different tissue injury experiments and selected the genes showing a minimum twofold change in expression in response to wounding in prevailing number of experiments for each of five wound healing stages we distinguished: haemostasis & early inflammation, inflammation, early repair, late repair and remodelling. During the initial phases after wounding, haemostasis & early inflammation and inflammation, the transcriptomic responses showed little consistency between different tissues and experiments. For the later phases, wound repair and remodelling, we identified a number of genes displaying similar transcriptional responses in all examined tissues. As revealed by ontological analyses, activation of certain pathways was rather specific for selected phases of wound healing, such as e.g. responses to vitamin D pronounced during inflammation. Conversely, we observed induction of genes encoding inflammatory agents and extracellular matrix proteins in all wound healing phases. Further, we selected several genes differentially upregulated throughout different stages of wound response, including established factors of wound healing in addition to those previously unreported in this context such as PTPRC and AQP4. CONCLUSIONS: We found that transcriptomic responses to wounding showed similar traits in a diverse selection of tissues including skin, muscles, internal organs and nervous system. Notably, we distinguished transcriptional induction of inflammatory genes not only in the initial response to wounding, but also later, during wound repair and tissue remodelling. PMID- 29115926 TI - Co-expression network analysis of the transcriptomes of rice roots exposed to various cadmium stresses reveals universal cadmium-responsive genes. AB - BACKGROUND: The migration of cadmium (Cd) from contaminated soil to rice is a cause for concern. However, the molecular mechanism underlying the response of rice roots to various Cd stresses remains to be clarified from the viewpoint of the co-expression network at a system-wide scale. RESULTS: We employed a comparative RNAseq-based approach to identify early Cd-responsive differentially expressed genes (DEGs) in rice 'Nipponbare' seedling roots after 1 h of high-Cd treatment. A multiplicity of the identified 1772 DEGs were implicated in hormone signaling and transcriptional regulation, particularly NACs and WRKYs were all upregulated under Cd stress. All of the 6 Cd-upregulated ABC transporters were pleiotropic drug resistance proteins (PDRs), whereas all of the 6 ZRT/IRT-like proteins (ZIPs) were consistently downregulated by Cd treatment. To further confirm our results of this early transcriptomic response to Cd exposure, we then conducted weighted gene co-expression network analysis (WGCNA) to re-analyze our RNAseq data in combination with other 11 previously published RNAseq datasets for rice roots exposed to diverse concentrations of Cd for extended treatment periods. This integrative approach identified 271 transcripts as universal Cd regulated DEGs that are key components of the Cd treatment coupled co-expression module. A global view of the 164 transcripts with annotated functions in pathway networks revealed several Cd-upregulated key functional genes, including transporter ABCG36/OsPDR9, 12-oxo-phytodienoic acid reductases (OPRs) for JA synthesis, and ZIM domain proteins JAZs in JA signaling, as well as OsWRKY10, NAC, and ZFP transcription factors. More importantly, 104 of these, including ABCG36/OsPDR9, OsNAC3, as well as several orthologs in group metalloendoproteinase, plastocyanin-like domain containing proteins and pectin methylesterase inhibitor, may respond specifically to various Cd pressures, after subtracting the 60 general stress-responsive genes reported to be commonly upregulated following multiple stresses. CONCLUSION: An integrative approach was implemented to identify DEGs and co-expression network modules in response to various Cd pressures, and 104 of the 164 annotatable universal Cd-responsive DEGs may specifically respond to various Cd pressures. These results provide insight into the universal molecular mechanisms beneath the Cd response in rice roots, and suggest many promising targets for improving the rice acclimation process against Cd toxicity. PMID- 29115929 TI - Environmental Factors Associated with Norovirus Transmission in Long-Term Care Facilities in South Carolina. AB - In the U.S., 60% of norovirus outbreaks are attributed to long-term care facilities (LTCFs). A descriptive study of 26 LTCFs in South Carolina was conducted to determine the presence of environmental factors associated with transmission of human noroviruses. Sanitary conditions in one common area, one staff/visitor bathroom, and the main kitchen were assessed using two audit forms. While surfaces in all kitchens were in good sanitary condition, 23 LTCFs used quaternary ammonium-based sanitizers and three LTCFs used chlorine bleach for kitchen sanitization. All common areas were also clean and in good condition; however, 20 LTCFs had upholstered chairs, and five LTCFs had carpeted floors. Seven facilities used quaternary ammonium-based disinfectants exclusively, whereas six LTCFs used chlorine bleach exclusively, and eight LTCFs used both to disinfect common areas. Seven staff/visitor bathrooms were accessible to residents, and hand washing signage was missing from 10. These results reveal the presence of environmental factors that might facilitate norovirus transmission within LTCFs. PMID- 29115928 TI - The Japanese version of the questionnaire about the process of recovery: development and validity and reliability testing. AB - BACKGROUND: Personal recovery is increasingly recognised as an important outcome measure in mental health services. This study aimed to develop a Japanese version of the Questionnaire about the Process of Recovery (QPR-J) and test its validity and reliability. METHODS: The study comprised two stages that employed the cross sectional and prospective cohort designs, respectively. We translated the questionnaire using a standard translation/back-translation method. Convergent validity was examined by calculating Pearson's correlation coefficients with scores on the Recovery Assessment Scale (RAS) and the Short-Form-8 Health Survey (SF-8). An exploratory factor analysis (EFA) was conducted to examine factorial validity. We used intraclass correlation and Cronbach's alpha to examine the test retest and internal consistency reliability of the QPR-J's 22-item full scale, 17 item intrapersonal and 5-item interpersonal subscales. We conducted an EFA along with a confirmatory factor analysis (CFA). RESULTS: Data were obtained from 197 users of mental health services (mean age: 42.0 years; 61.9% female; 49.2% diagnosed with schizophrenia). The QPR-J showed adequate convergent validity, exhibiting significant, positive correlations with the RAS and SF-8 scores. The QPR-J's full version, subscales, showed excellent test-retest and internal consistency reliability, with the exception of acceptable but relatively low internal consistency reliability for the interpersonal subscale. Based on the results of the CFA and EFA, we adopted the factor structure extracted from the original 2-factor model based on the present CFA. CONCLUSION: The QPR-J is an adequately valid and reliable measure of the process of recovery among Japanese users with mental health services. PMID- 29115930 TI - Reconstructing the muscular ground pattern of phylactolaemate bryozoans: first data from gelatinous representatives. AB - BACKGROUND: Phylactolaemata is commonly regarded the earliest branch within Bryozoa and thus the sister group to the other bryozoan taxa, Cyclostomata and Gymnolaemata. Therefore, the taxon is important for the reconstruction of the bryozoan morphological ground pattern. In this study the myoanatomy of Pectinatella magnifica, Cristatella mucedo and Hyalinella punctata was analysed by means of histology, f-actin staining and confocal laser-scanning microscopy in order to fill gaps in knowledge concerning the myoanatomy of Phylactolaemata. RESULTS: The retractor muscles and muscles of the aperture, gut, body wall, tentacle sheath, lophophore constitute the most prominent muscular subsets in these species. The lophophore shows longitudinal muscle bands in the tentacles, lophophoral arm muscles, epistome musculature and hitherto undescribed muscles of the ring canal. In general the muscular system of the three species is very similar with differences mainly in the body wall, tentacle sheath and epistome. The body wall contains an orthogonal grid of musculature. The epistome exhibits either a muscular meshwork in the epistomal wall or muscle fibers traversing the epistomal cavity. The whole tentacle sheath possesses a regular mesh of muscles in Pectinatella and Cristatella, whereas circular muscles are limited to the tentacle sheath base in Hyalinella. CONCLUSION: This study is the first to describe muscles of the ring canal and contributes to reconstructing muscular features for the last common ancestor of all bryozoans. The data available suggest that two longitudinal muscle bands in the tentacles, as well as retractor muscles and longitudinal and circular muscles in the tentacle sheath, were present in the last common bryozoan ancestor. Comparisons among bryozoans shows that several apomorphies are present in the myoanatomy of each class- level taxon such as the epistomal musculature and musculature of the lophophoral arms in phylactolaemates, annular muscles in cyclostomes and parietal muscles in gymnolaemates. PMID- 29115931 TI - Guanylate-binding protein-1 is a potential new therapeutic target for triple negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by a lack of estrogen and progesterone receptor expression (ESR and PGR, respectively) and an absence of human epithelial growth factor receptor (ERBB2) amplification. Approximately 15-20% of breast malignancies are TNBC. Patients with TNBC often have an unfavorable prognosis. In addition, TNBC represents an important clinical challenge since it does not respond to hormone therapy. METHODS: In this work, we integrated high-throughput mRNA sequencing (RNA-Seq) data from normal and tumor tissues (obtained from The Cancer Genome Atlas, TCGA) and cell lines obtained through in-house sequencing or available from the Gene Expression Omnibus (GEO) to generate a unified list of differentially expressed (DE) genes. Methylome and proteomic data were integrated to our analysis to give further support to our findings. Genes that were overexpressed in TNBC were then curated to retain new potentially druggable targets based on in silico analysis. Knocking-down was used to assess gene importance for TNBC cell proliferation. RESULTS: Our pipeline analysis generated a list of 243 potential new targets for treating TNBC. We finally demonstrated that knock-down of Guanylate-Binding Protein 1 (GBP1 ), one of the candidate genes, selectively affected the growth of TNBC cell lines. Moreover, we showed that GBP1 expression was controlled by epidermal growth factor receptor (EGFR) in breast cancer cell lines. CONCLUSIONS: We propose that GBP1 is a new potential druggable therapeutic target for treating TNBC with enhanced EGFR expression. PMID- 29115932 TI - Prognostic and clinicopathological significance of circulating tumor cells detected by RT-PCR in non-metastatic colorectal cancer: a meta-analysis and systematic review. AB - BACKGROUND: Circulating tumor cells (CTCs) have been accepted as a prognostic marker in patients with metastatic colorectal cancer (mCRC, UICC stage IV). However, the prognostic value of CTCs in patients with non-metastatic colorectal cancer (non-mCRC, UICC stage I-III) still remains in dispute. A meta-analysis was performed to investigate the prognostic significance of CTCs detected by the RT PCR method in patients diagnosed with non-mCRC patients. METHODS: A comprehensive literature search for relevant articles was performed in the EmBase, PubMed, Ovid, Web of Science, Cochrane library and Google Scholar databases. The studies were selected according to predetermined inclusion/exclusion criteria. Using the random-effects model of Stata software, version12.0 (2011) (Stata Corp, College Station, TX, USA), to conduct the meta-analysis, and the hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were regarded as the effect measures. Subgroup analyses and meta-regression were also conducted to clarify the heterogeneity. RESULTS: Twelve eligible studies, containing 2363 patients with non-mCRC, were suitable for final analyses. The results showed that the overall survival (OS) (HR = 3.07, 95% CI: [2.05-4.624], P < 0.001; I2 = 55.7%, P = 0.008) and disease-free survival (DFS) (HR = 2.58, 95% CI: [2.00 3.32], P < 0.001; I2 = 34.0%, P = 0.085) were poorer in patients with CTC positive, regardless of the sampling time, adjuvant therapy and TNM stage. CTC positive was also significantly associated with regional lymph nodes (RLNs) metastasis (RR = 1.62, 95% CI: [1.17-2.23], P = 0.003; I2 = 74.6%, P<0.001), depth of infiltration (RR = 1.41, 95% CI: [1.03-1.92], P = 0.03; I2 = 38.3%, P = 0.136), vascular invasion (RR = 1.66, 95% CI: [1.17-2.36], P = 0.004; I2 = 46.0%, P = 0.135), tumor grade (RR = 1.19, 95% CI: [1.02-1.40], P = 0.029; I2 = 0%, P = 0.821) and tumor-node-metastasis (TNM) stage(I, II versus III) (RR = 0.76, 95% CI 0.71-0.81, P < 0.001; I2 = 0%, P = 0.717). However, there was no significant relationship between CTC-positive and tumor size (RR = 1.08, 95% CI: [0.94-1.24], P = 0.30; I2 = 0%, P = 0.528). CONCLUSIONS: Detection of CTCs by RT-PCR method has prognostic value for non-mCRC patients, and CTC-positive was associated with poor prognosis and poor clinicopathological prognostic factors. However, the prognostic value of CTCs supports the use of CTCs as an indicator of metastatic disease prior to the current classification of mCRC meaning it is detectable by CT/MRI. PMID- 29115933 TI - New variant identified in major susceptibility locus to tuberculosis on chromosomal region 8q12-q13 in Moroccan population: a case control study. AB - BACKGROUND: Tuberculosis (TB) remains a global health problem. Several studies have implicated genetic host factors in predisposing populations to TB disease. In this study, we have selected NSMAF (Neutral Sphingomyelinase Activation Associated Factor) as a candidate gene to evaluate its level of association with TB disease in a Moroccan population for two reasons: first, this gene is located in a major susceptibility locus on chromosomal region 8q12-q13 in the Moroccan population, closely linked to the CYP7A1 gene, which was previously shown to be associated with TB disease; second, NSMAF has an important role in immune system function. METHODS: We conducted a case-control study including 269 genomic DNA samples extracted from pulmonary TB (PTB) patients and healthy controls (HC). We genotyped three selected SNPs (rs2228505, rs36067275 and rs10505004) using TaqMan(r) allelic discrimination assays. RESULTS: Only the rs1050504 C > T genotype was observed to be significantly associated with an increased risk for developing pulmonary TB (41.8% vs 27%, OR 1.95, 95% CI 1.16-3.27; p = 0.01). In contrast, the TT genotype was significantly associated with resistance to PTB (4.1% vs 15.6%, OR 0.23, 95% CI 0.08-0.63; p = 0.002). CONCLUSION: Our findings suggest that genetic variations in the NSMAF gene could modulate the risk of PTB development in a Moroccan population. Further functional studies are needed to confirm these findings. PMID- 29115934 TI - Population structure and genomic inbreeding in nine Swiss dairy cattle populations. AB - BACKGROUND: Domestication, breed formation and intensive selection have resulted in divergent cattle breeds that likely exhibit their own genomic signatures. In this study, we used genotypes from 27,612 autosomal single nucleotide polymorphisms to characterize population structure based on 9214 sires representing nine Swiss dairy cattle populations: Brown Swiss (BS), Braunvieh (BV), Original Braunvieh (OB), Holstein (HO), Red Holstein (RH), Swiss Fleckvieh (SF), Simmental (SI), Eringer (ER) and Evolener (EV). Genomic inbreeding (F ROH) and signatures of selection were determined by calculating runs of homozygosity (ROH). The results build the basis for a better understanding of the genetic development of Swiss dairy cattle populations and highlight differences between the original populations (i.e. OB, SI, ER and EV) and those that have become more popular in Switzerland as currently reflected by their larger populations (i.e. BS, BV, HO, RH and SF). RESULTS: The levels of genetic diversity were highest and lowest in the SF and BS breeds, respectively. Based on F ST values, we conclude that, among all pairwise comparisons, BS and HO (0.156) differ more than the other pairs of populations. The original Swiss cattle populations OB, SI, ER, and EV are clearly genetically separated from the Swiss cattle populations that are now more common and represented by larger numbers of cows. Mean levels of F ROH ranged from 0.027 (ER) to 0.091 (BS). Three of the original Swiss cattle populations, ER (F ROH: 0.027), OB (F ROH: 0.029), and SI (F ROH: 0.039), showed low levels of genomic inbreeding, whereas it was much higher in EV (F ROH: 0.074). Private signatures of selection for the original Swiss cattle populations are reported for BTA4, 5, 11 and 26. CONCLUSIONS: The low levels of genomic inbreeding observed in the original Swiss cattle populations ER, OB and SI compared to the other breeds are explained by a lesser use of artificial insemination and greater use of natural service. Natural service results in more sires having progeny at each generation and thus this breeding practice is likely the major reason for the remarkable levels of genetic diversity retained within these populations. The fact that the EV population is regionally restricted and its small census size of herd-book cows explain its high level of genomic inbreeding. PMID- 29115936 TI - Analyses of methylomes of upland and lowland switchgrass (Panicum virgatum) ecotypes using MeDIP-seq and BS-seq. AB - BACKGROUND: Switchgrass is a crop with many desirable traits for bioenergy production. Plant genomes have high DNA methylation levels throughout genes and transposable elements and DNA methylation is known to play a role in silencing transposable elements. Here we analyzed methylomes in two switchgrass genotypes AP13 and VS16. AP13 is derived from a lowland ecotype and VS16, typically considered drought-tolerant, is derived from an upland ecotype, both genotypes are tetraploid (2n = 4* = 36). RESULTS: Methylated DNA immunoprecipitation sequencing (MeDIP-seq) and bisulfite-sequencing (BS-seq) were used to profile DNA methylation in genomic features of AP13 and VS16. The methylation patterns in genes and transposable elements were similar to other plants, however, overall CHH methylation levels were comparatively low. Differentially methylated regions (DMRs) were assessed and a total of 1777 CG-DMRs, 573 CHG-DMRs, and 3 CHH-DMRs were detected between the two genotypes. TEs and their flanking regions were higher than that of genic regions. Different types of TEs had different methylation patterns, but the two LTRs (Copia and Gypsy) were similarly methylated, while LINEs and DNA transposons typically had different methylation patterns. MeDIP-seq data was compared to BS-seq data and most of the peaks generated by MeDIP-seq were confirmed to be highly methylated by BS-seq. CONCLUSIONS: DNA methylation in switchgrass genotypes obtained from the two ecotypes were found similar. Collinear gene pairs in two subgenomes (A and B) were not significantly differentially methylated. Both BS-seq and MeDIP-seq methodologies were found effective. Methylation levels were highest at CG and least in CHH. Increased DNA methylation was seen in TEs compared to genic regions. Exploitation of TE methylations can be a viable option in future crop improvement. PMID- 29115935 TI - MicroRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours. AB - BACKGROUND: MicroRNAs may act as oncogenes or tumour suppressor genes, which make these small molecules potential diagnostic/prognostic factors and targets for anticancer therapies. Several common oncogenic microRNAs have been found for canine mammary cancer and human breast cancer. On account of this, large-scale profiling of microRNA expression in canine mammary cancer seems to be important for both dogs and humans. METHODS: Expression profiles of 317 microRNAs in 146 canine mammary tumours of different histological type, malignancy grade and clinical history (presence/absence of metastases) and in 25 control samples were evaluated. The profiling was performed using microarrays. Significance Analysis of Microarrays test was applied in the analysis of microarray data (both unsupervised and supervised data analyses were performed). Validation of the obtained results was performed using real-time qPCR. Subsequently, predicted targets for the microRNAs were searched for in miRBase. RESULTS: Results of the unsupervised analysis indicate that the primary factor separating the samples is the metastasis status. Predicted targets for microRNAs differentially expressed in the metastatic vs. non-metastatic group are mostly engaged in cell cycle regulation, cell differentiation and DNA-damage repair. On the other hand, the supervised analysis reveals clusters of differentially expressed microRNAs unique for the tumour type, malignancy grade and metastasis factor. CONCLUSIONS: The most significant difference in microRNA expression was observed between the metastatic and non-metastatic group, which suggests a more important role of microRNAs in the metastasis process than in the malignant transformation. Moreover, the differentially expressed microRNAs constitute potential metastasis markers. However, validation of cfa-miR-144, cfa-miR-32 and cfa-miR-374a levels in blood samples did not follow changes observed in the non-metastatic and metastatic tumours. PMID- 29115937 TI - Trastuzumab resumption after extremely severe cardiotoxicity in metastatic breast cancer patient: a case report. AB - BACKGROUND: Trastuzumab-related cardiotoxicity has been reported in patients receiving trastuzumab concurrently with other agents, especially with anthracyclines. Cardiac function damage is generally rare, precox and mild with trastuzumab alone. CASE PRESENTATION: We report the case of a 49 year-old woman affected by metastatic breast cancer who developed trastuzumab-related cardiogenic shock due to pump failure (with LVEF of about 15%) after three months of treatment. After a long hospitalization in the cardiac intensive care unit and a proper treatment, LVEF increased to 50% and, due to a severe progression of disease, trastuzumab was resumed and continued for more than one year. CONCLUSION: This is a case of particularly severe cardiotoxicity related to trastuzumab treatment, which was recovered with pharmacological treatment and the temporary discontinuation of the treatment. Trastuzumab was safely resumed after clinical and echocardiographic parameters improvement. PMID- 29115938 TI - Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma. AB - BACKGROUND: To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) for 80 years or older patients with hepatocellular carcinoma (HCC). METHODS: Eligibility criteria of this retrospective study were: 1) HCC confirmed by histology or typical hallmarks of HCC by imaging techniques of four-phase multidetector-row computed tomography or dynamic contrast-enhanced magnetic resonance imaging; 2) no intrahepatic metastasis or distant metastasis; 3) no findings suggesting direct infiltration of the gastrointestinal tract; 4) performance status <=2 by Eastern Cooperative Oncology Group classification; and 5) Child-Pugh classification A or B. Patients received C-ion RT with 52.8 Gy (RBE) or 60.0 Gy (RBE) in four fractions for usual cases and 60.0 Gy (RBE) in 12 fractions for close-to-gastrointestinal tract cases. Toxicities were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (Version 4.0). RESULTS: Between March 2011 and November 2015, 31 patients were treated. The median follow-up period of all patients was 23.2 months (range: 8.4-55.3 months). Median age at the time of registration of C-ion RT was 83 years (range: 80-95 years). Child-Pugh grade A and B were 27 patients and 4 patients, respectively. The 2-year estimated overall survival, local control, and progression-free survival rates were 82.3%, 89.2%, and 51.3%, respectively. No patients had Grade 2 or higher acute toxicities (within 3 months after C-ion RT). One patient experienced progression in Child-Pugh classification from A to B within 3 months after C-ion RT. In late toxicities, Grade 3 encephalopathy was observed in 3 patients, and 2 improved with medication. CONCLUSIONS: C-ion RT was effective with minimal toxicities for 80 years or older patients with hepatocellular carcinoma. TRIAL REGISTRATION: UMIN000020571 : date of registration, 14 January 2016, retrospectively registered. PMID- 29115939 TI - Genome-wide association studies and genomic prediction of breeding values for calving performance and body conformation traits in Holstein cattle. AB - BACKGROUND: Our aim was to identify genomic regions via genome-wide association studies (GWAS) to improve the predictability of genetic merit in Holsteins for 10 calving and 28 body conformation traits. Animals were genotyped using the Illumina Bovine 50 K BeadChip and imputed to the Illumina BovineHD BeadChip (HD). GWAS were performed on 601,717 real and imputed single nucleotide polymorphism (SNP) genotypes using a single-SNP mixed linear model on 4841 Holstein bulls with breeding value predictions and followed by gene identification and in silico functional analyses. The association results were further validated using five scenarios with different numbers of SNPs. RESULTS: Seven hundred and eighty-two SNPs were significantly associated with calving performance at a genome-wise false discovery rate (FDR) of 5%. Most of these significant SNPs were on chromosomes 18 (71.9%), 17 (7.4%), 5 (6.8%) and 7 (2.4%) and mapped to 675 genes, among which 142 included at least one significant SNP and 532 were nearby one (100 kbp). For body conformation traits, 607 SNPs were significant at a genome wise FDR of 5% and most of them were located on chromosomes 5 (30%), 18 (27%), 20 (13%), 6 (6%), 7 (5%), 14 (5%) and 13 (3%). SNP enrichment functional analyses for calving traits at a FDR of 1% suggested potential biological processes including musculoskeletal movement, meiotic cell cycle, oocyte maturation and skeletal muscle contraction. Furthermore, pathway analyses suggested potential pathways associated with calving performance traits including tight junction, oxytocin signaling, and MAPK signaling (P < 0.10). The prediction ability of the 1206 significant SNPs was between 78 and 83% of the prediction ability of the BovineSNP50 SNPs for calving performance traits and between 35 and 79% for body conformation traits. CONCLUSIONS: Various SNPs that are significantly associated with calving performance are located within or nearby genes with potential roles in tight junction, oxytocin signaling, and MAPK signaling. Combining the significant SNPs or SNPs within or nearby gene(s) from the HD panel with the BovineSNP50 panel yielded a marginal increase in the accuracy of prediction of genomic estimated breeding values for all traits compared to the use of the BovineSNP50 panel alone. PMID- 29115940 TI - Does hair dye use really increase the risk of prostate cancer? AB - Recently, Shu-Yu Tai et al. reported that personal hair dye use increased risk of prostate cancer with a dose-response effect. Although hair dyes were identified as carcinogenic in animals and increased risk of some cancers among hairdressers, the existing epidemiological data did not support that personal hair dye use increased risk of cancers, even for bladder cancer. Given that Tai et al.'s report of a potential hazard of personal hair dye use on risk of prostate cancer was particular, the methodology of the study was scrutinized and some flaws were found including the issue of external validity. PMID- 29115941 TI - microRNA-193a-3p is specifically down-regulated and acts as a tumor suppressor in BRAF-mutated colorectal cancer. AB - BACKGROUND: The aim of this study was to identify miRNAs specifically dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis of this malignant subtype of colorectal cancer. METHODS: Candidate dysregulated miRNAs were selected in genome-wide miRNA expression array analysis using a screening set composed of 15 BRAF-mutated and 15 non-KRAS/BRAF-mutated colorectal cancers. The miRNA expressions were validated in another set of patients. The functional roles of the miRNAs were analyzed by cell growth and invasion assays. The association between miRNA expression status and the clinical outcome of patients treated with various chemotherapies was analyzed. RESULTS: Within the top five of the miRNAs screened, we validated miRNA-31 (miR-31) and miR-135b as up-regulated, while miR-193a-3p was down-regulated in BRAF-mutated cancer. Moreover, miR-193a 3p inhibited cell growth, and invasion of colorectal cancer cells. Low miR-193a 3p expression was associated with shorter progression-free survival in patients who received anti-EGFR therapy. CONCLUSIONS: Our results disclose a novel tumor suppressive role of miR-193a-3p in colorectal cancer. These results could lead to novel therapeutic strategies for colorectal cancer, particularly in BRAF-mutated colorectal cancer. PMID- 29115942 TI - Detection of QTLs for seedling characteristics in barley (Hordeum vulgare L.) grown under hydroponic culture condition. AB - BACKGROUND: Seedling characteristics play significant roles in the growth and development of barley (Hordeum vulgare L.), including stable stand establishment, water and nutrients uptake, biotic resistance and abiotic stresses, and can influence yield and quality. However, the genetic mechanisms underlying seedling characteristics in barley are largely unknown and little research has been done. In the present work, 21 seedling-related characteristics are assessed in a barley double haploid (DH) population, grown under hydroponic conditions. Of them, leaf age (LAG), shoot height (SH), maximum root length (MRL), main root number (MRN) and seedling fresh weight (SFW) were investigated at the 13th, 20th, 27th, and 34th day after germination. The objectives were to identify quantitative trait loci (QTLs) underlying these seedling characteristics using a high-density linkage map and to reveal the QTL expression pattern by comparing the QTLs among four different seedling growth stages. RESULTS: A total of 70 QTLs were distributed over all chromosomes except 4H, and, individually, accounted for 5.01%-77.78% of phenotypic variation. Out of the 70 detected QTLs, 23 showed a major effect on 14 seedling-related characteristics. Ten co-localized chromosomal regions on 2H (five regions), 3H (two regions) and 7H (three regions) involved 39 QTLs (55.71%), each simultaneously influenced more than one trait. Meanwhile, 9 co-localized genomic regions involving 22 QTLs for five seedling characteristics (LAG, SH, MRL, MRN and SFW) at the 13th, 20th, 27th and 34th day-old seedling were common for two or more growth stages of seedling. QTL in the vicinity of Vrs1 locus on chromosome 2H with the favorable alleles from Huadamai 6 was found to have the largest main effects on multiple seedling-related traits. CONCLUSIONS: Six QTL cluster regions associated with 16 seedling-related characteristics were observed on chromosome 2H, 3H and 7H. The majority of the 29 regions identified for five seedling characteristics were selectively expressed at different developmental stages. The genetic effects of 9 consecutive expression regions displayed different developmental influences at different developmental stages. These findings enhanced our understanding of a genetic basis underlying seedling characteristics in barley. Some QTLs detected here could be used for marker-assisted selection (MAS) in barley breeding. PMID- 29115943 TI - Membrane protein Nav1.7 contributes to the persistent post-surgical pain regulated by p-p65 in dorsal root ganglion (DRG) of SMIR rats model. AB - BACKGROUND: Persistent post-surgical pain is a difficult clinical problem. In this study, we intend to explore the mechanism underlying the persistent post surgical pain in SMIR (skin/muscle incision and retraction) rats. METHODS: First of all, the expression of membrane protein Nav1.7 and p-p65 (Phosphorylation of p65) were detected in ipsilateral L4-6 DRGs of SMIR rats by western-blot and immunostaining. Then with ProTx-II (Nav1.7 blocker) or PDTC (p65 inhibitor) were intrathecally injected while the change of Nav1.7 expression and mechanical withdrawal threshold were detected. Finally chromatin immunoprecipitation assay method was used to detect whether could p-p65 bind in the Nav1.7 gene promoter region directly. RESULTS: The results shows that mechanical hyperalgesia occurs following SMIR model, from 5 day (d) and lasted more than 20d after surgery. Meanwhile, the expression of Nav1.7 was up-regulated at 10d, 15d and 20d after surgery compared with naive group. The expression of p-p65 was up-regulated at 10d and 15d compared with incision group. The mechanical hyperalgesia induced by SMIR was reversed after blocking Nav1.7 or inhibiting p65. Furthermore, Nav1.7 expression was down-regulated when p-p65 was inhibited and p-p65 could combine with the Nav1.7 gene promoter region directly. CONCLUSION: Membrane protein Nav1.7 could participate in the peripheral sensitization of persistent post surgical pain, which may be regulated by p-p65. PMID- 29115944 TI - Correction to: The impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts: a cross sectional study. AB - After publication of the original article [1] the authors noted that the following errors had occurred. PMID- 29115945 TI - Mechanical strain to maxillary incisors during direct laryngoscopy. AB - BACKGROUND: While most Direct laryngoscopy leads to dental injury in 25-39% of cases. Dental injury occurs when the forces and impacts applied to the teeth exceed the ability of the structures to dissipate energy and stress. The purpose of this study was to measure strain, (which is the change produced in the length of the tooth by a force applied to the tooth) strain rate, and strain-time integral to the maxillary incisors and determine if they varied by experience, type of blade, or use of an alcohol protective pad (APP). METHODS: A mannequin head designed to teach and test intubation was instrumented with eight single axis strain gauges placed on the four maxillary incisors: four on the facial or front surface of the incisors and four on the lingual or back, near the insertion of the incisor in the gums to measure bending strain as well as compression. Anesthesiology faculty, residents, and certified registered nurse anesthetists intubated with Macintosh and Miller blades with and without APP. Using strain time curves, the maximum strain, strain rate, and strain time integral were calculated. RESULTS: Across the 92 subjects, strain varied 8-12 fold between the 25th and 75th percentiles for all four techniques, but little by experience, while strain rate and strain integral varied 6-13 fold and 15-26 fold, respectively, for the same percentiles. Intubators who had high strain values with one blade tended to have high strains with the other blade with and without the APP (all pairwise correlation rho = 0.42-0.63). CONCLUSIONS: Strain varies widely by intubator and that the use of the APP reduces strain rate which may decrease the risk of or the severity of dental injury. PMID- 29115947 TI - Fluctuations in the incidence of type 1 diabetes in the United States from 2001 to 2015: a longitudinal study. AB - BACKGROUND: While the United States has the largest number of children with type 1 diabetes mellitus, less is known regarding adult-onset disease. The present study utilizes nationwide data to compare the incidence of type 1 diabetes in youth (0-19 years) to that of adults (20-64 years). METHODS: In this longitudinal study, the Clinformatics(r) Data Mart Database was used, which contains information from 61 million commercially insured Americans (years 2001-2015). Incidence rates and exact Poisson 95% confidence intervals were calculated by age group, sex, census division, and year of diagnosis. Changes in rates over time were assessed by negative binomial regression. RESULTS: Overall, there were 32,476 individuals who developed type 1 diabetes in the cohort. The incidence rate was greatest in youth aged 10-14 years (45.5 cases/100,000 person-years); however, because adulthood spans over a longer period than childhood, there was a greater number of new cases in adults than in youth (n = 19,174 adults; n = 13,302 youth). Predominance in males was evident by age 10 and persisted throughout adulthood. The male to female incidence rate ratio was 1.32 (95% CI 1.30-1.35). The incidence rate of type 1 diabetes in youth increased by 1.9% annually from 2001 to 2015 (95% CI 1.1-2.7%; P < 0.001), but there was variation across regions. The greatest increases were in the East South Central (3.8%/year; 95% CI 2.0-5.6%; P < 0.001) and Mountain divisions (3.1%/year; 95% CI 1.6-4.6%; P < 0.001). There were also increases in the East North Central (2.7%/year; P = 0.010), South Atlantic (2.4%/year; P < 0.001), and West North Central divisions (2.4%/year; P < 0.001). In adults, however, the incidence decreased from 2001 to 2015 (-1.3%/year; 95% CI -2.3% to -0.4%; P = 0.007). Greater percentages of cases were diagnosed in January, July, and August for both youth and adults. The number of new cases of type 1 diabetes (ages 0-64 years) in the United States is estimated at 64,000 annually (27,000 cases in youth and 37,000 cases in adults). CONCLUSIONS: There are more new cases of type 1 diabetes occurring annually in the United States than previously recognized. The increase in incidence rates in youth, but not adults, suggests that the precipitating factors of youth-onset disease may differ from those of adult-onset disease. PMID- 29115946 TI - Seropositivity to herpes simplex virus type 2, but not type 1 is associated with cervical cancer: NHANES (1999-2014). AB - BACKGROUND: Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are infectious agents, and their association with cancer occurrence in human is a controversial topic for decades. We addressed this subject using all available continuous National Health and Nutrition Examination Survey (NHANES) cross-sectional data from 1999 to 2014. METHODS: Eight data cycles (1999-2000, 2001-2002, 2003-2004, 2005-2006, 2007-2008, 2009-2010, 2011-2012, and 2013-2014) were employed, and a sample of 8184 female participants was used in this study according to the availability of cancer history and HSV serostatus. RESULTS: The seroprevalences of HSV1 and HSV2 were 60.73 +/- 0.89 and 25.02 +/- 0.64, respectively, and the numbers increased with age (P < 0.01). In confounder-adjusted logistic regression analysis, association between HSV1 seropositivity and uterine cancer was identified (adjusted odds ratio-ORadjusted = 6.03; 95% CI: 1.52, 23.87). HSV2 seropositivity was associated with cancer occurrence (ORadjusted = 1.47; 95% CI: 1.01, 2.14), cervical cancer (ORadjusted = 1.72; 95% CI: 1.06, 2.79) and uterine cancer (ORadjusted = 3.49; 95% CI: 1.03, 11.85). Moreover, HSV2 was persistently associated with cervical cancer after further adjusting high-risk human papillomavirus (HPV) as confounder (ORadjusted = 1.90; 95% CI: 1.09, 3.34). Relative risk (RR)-based interaction measurement between HSV2 and HPV on the additive scale suggests higher RR for cervical cancer in participants with seropositivity for HPV only (RRadjusted = 2.98; 95% CI: 1.23, 7.20; P = 0.02), HSV2 only (RRadjusted = 2.79; 95% CI: 1.31, 5.96; P = 0.01) or both viruses (RRadjusted = 3.44; 95% CI: 1.50, 7.86; P < 0.01) when setting participants with seronegativity for both HPV and HSV2 as reference. CONCLUSIONS: The finding of current study provides epidemiological evidence that serostatus of HSV2 can serve as an independent predictor for cervical cancer. PMID- 29115948 TI - Evaluation of intravenous regional anaesthesia and four-point nerve block efficacy in the distal hind limb of dairy cows. AB - BACKGROUND: Intravenous regional anaesthesia (IVRA) and hindfoot four-point nerve block anaesthesia (NBA) are recommended for local anaesthesia (LA) in the distal limb of dairy cows. Two studies were conducted to compare the efficacy, time until onset and stress responses to IVRA and NBA in dairy cows. In the first cross-over designed study, eight healthy unsedated German Holstein cows, restrained in lateral recumbency (LR) on a surgical tipping table, were treated with IVRA and NBA using procaine 2% as a local anaesthetic. Distal limb desensitization was tested by electrical (e-), mechanical (m-) and thermal (t-) nociceptive stimulation 10 min before and 15 and 30 min after LA. Hormonal metabolic (blood concentrations of cortisol, lactate, non-esterified fatty acids, and glucose) and cardio-respiratory (heart and respiratory rate, mean arterial blood pressure) stress responses to treatment were assessed at predetermined intervals. In the second study, six healthy, unsedated German Holstein cows in LR were treated (crossover design) with IVRA and NBA. Short-interval e-stimulation was measured by the time until complete distal limb desensitization. RESULTS: In the first study, four of eight cows responded to e-stimulation 15 min after IVRA, while none of the cows treated with NBA responded until the safety cut-off level was reached. E-stimulation revealed complete desensitization of the distal limb 30 min after LA in all cows. Half of the cows did not respond to m- and t stimulation before LA, so no further evaluation was performed. Stress reactions to IVRA and NBA treatment were similar, but differences may have been masked by stress response to LR restraint. In the second study, complete desensitization was achieved 12.5 min after NBA, while one of the six cows still responded to e stimulation 20 min after IVRA. CONCLUSION: Hindfoot nerve block anaesthesia and intravenous regional anaesthesia induced complete desensitization of the distal hind limb in dairy cows. However, the anaesthesia onset after NBA was significantly faster than that of IVRA, which may be clinically relevant in the field, particularly when distal limb anaesthesia is required for major claw surgeries under time constraints. PMID- 29115949 TI - Neurally Adjusted Ventilatory Assist (NAVA) or Pressure Support Ventilation (PSV) during spontaneous breathing trials in critically ill patients: a crossover trial. AB - BACKGROUND: Neurally Adjusted Ventilatory Assist (NAVA) is a proportional ventilatory mode that uses the electrical activity of the diaphragm (EAdi) to offer ventilatory assistance in proportion to patient effort. NAVA has been increasingly used for critically ill patients, but it has not been evaluated during spontaneous breathing trials (SBT). We designed a pilot trial to assess the feasibility of using NAVA during SBTs, and to compare the breathing pattern and patient-ventilator asynchrony of NAVA with Pressure Support (PSV) during SBTs. METHODS: We conducted a crossover trial in the ICU of a university hospital in Brazil and included mechanically ventilated patients considered ready to undergo an SBT on the day of the study. Patients underwent two SBTs in randomized order: 30 min in PSV of 5 cmH2O or NAVA titrated to generate equivalent peak airway pressure (Paw), with a positive end-expiratory pressure of 5 cmH2O. The ICU team, blinded to ventilatory mode, evaluated whether patients passed each SBT. We captured flow, Paw and electrical activity of the diaphragm (EAdi) from the ventilator and used it to calculate respiratory rate (RR), tidal volume (VT), and EAdi. Detection of asynchrony events used waveform analysis and we calculated the asynchrony index as the number of asynchrony events divided by the number of neural cycles. RESULTS: We included 20 patients in the study. All patients passed the SBT in PSV, and three failed the SBT in NAVA. Five patients were reintubated and the extubation failure rate was 25% (95% CI 9-49%). Respiratory parameters were similar in the two modes: VT = 6.1 (5.5-6.5) mL/Kg in NAVA vs. 5.5 (4.8-6.1) mL/Kg in PSV (p = 0.076) and RR = 27 (17-30) rpm in NAVA vs. 26 (20-30) rpm in PSV, p = 0.55. NAVA reduced AI, with a median of 11.5% (4.2-19.7) compared to 24.3% (6.3-34.3) in PSV (p = 0.033). CONCLUSIONS: NAVA reduces patient-ventilator asynchrony index and generates a respiratory pattern similar to PSV during SBTs. Patients considered ready for mechanical ventilation liberation may be submitted to an SBT in NAVA using the same objective criteria used for SBTs in PSV. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01337271 ), registered April 12, 2011. PMID- 29115950 TI - The prevalence of ocular diseases in polish Arabian horses. AB - BACKGROUND: Equine ocular diseases pose a medical challenge due to long-lasting and cost-consuming therapies as well as economic issues associated with potential decrease in value of affected horses. The scale of the problem is significant but difficult to precisely define because epidemiological data is limited and lacks consistency in presentation. To date, no retrospective studies specifically investigating Arabian horses have been published. RESULTS: The aim of this cross sectional study was to investigate the prevalence of ocular lesions and define the ocular diseases present in Arabian horses from breeding farms in Poland. Clinical and ophthalmic examination of 615 Arabian horses at Polish breeding farms (15% of Arabian population in Poland) were performed and medical history from the previous 5 years was analyzed. Data was obtained from review of veterinary archives and epidemiological interview of the resident veterinarian at each farm. The prevalence of ocular diseases was 9.75%. The following pathologies were diagnosed (with their respective prevalence): equine recurrent uveitis (ERU; 5.5%); cataract not related to ERU (3.3%); non-visual eyes (1.13%); posttraumatic lesions (0.8%); glaucoma (0.16%). CONCLUSIONS: In this study, ERU was the most common ocular disease identified in Arabian horses in Poland. Its prevalence was lower than usually reported in Europe and the United States. There was no sex or farm predisposition but ocular disease prevalence increased with age. Other severe ocular pathologies were also observed, confirming that ocular diseases remain an important clinical problem. PMID- 29115951 TI - Letter to the editor - round table unites to tackle culture change in an effort to improve animal research reporting. AB - A round table discussion was held during the LAVA-ESLAV-ECLAM conference on Reproducibility of Animal Studies on the 25th of September 2017 in Edinburgh. The aim of the round table was to discuss how to enhance the rate at which the quality of reporting animal research can be improved. This signed statement acknowledges the efforts that participant organizations have made towards improving the reporting of animal studies and confirms an ongoing commitment to drive further improvements, calling upon both academics and laboratory animal veterinarians to help make this cultural change. PMID- 29115952 TI - No evidence of enteric viral involvement in the new neonatal porcine diarrhoea syndrome in Danish pigs. AB - BACKGROUND: The aim of this study was to investigate whether the syndrome New Neonatal Porcine Diarrhoea Syndrome (NNPDS) is associated with a viral aetiology. Four well-managed herds experiencing neonatal diarrhoea and suspected to be affected by NNPDS were included in a case-control set up. A total of 989 piglets were clinically examined on a daily basis. Samples from diarrhoeic and non diarrhoeic piglets at the age of three to seven days were selected for extensive virological examination using specific real time polymerase chain reactions (qPCRs) and general virus detection methods. RESULTS: A total of 91.7% of the animals tested positive by reverse transcription qPCR (RT-qPCR) for porcine kobuvirus 1 (PKV-1) while 9% and 3% were found to be positive for rotavirus A and porcine teschovirus (PTV), respectively. The overall prevalence of porcine astrovirus (PAstV) was 75% with 69.8% of the PAstV positive pigs infected with PAstV type 3. No animals tested positive for rotavirus C, coronavirus (TGEV, PEDV and PRCV), sapovirus, enterovirus, parechovirus, saffoldvirus, cosavirus, klassevirus or porcine circovirus type 2 (PCV2). Microarray analyses performed on a total of 18 animals were all negative, as were eight animals examined by Transmission Electron Microscopy (TEM). Using Next Generation de novo sequencing (de novo NGS) on pools of samples from case animals within all herds, PKV-1 was detected in four herds and rotavirus A, rotavirus C and PTV were detected in one herd each. CONCLUSIONS: Our detailed analyses of piglets from NNPDS-affected herds demonstrated that viruses did not pose a significant contribution to NNPDS. However, further investigations are needed to investigate if a systemic virus infection plays a role in the pathogenesis of NNPDS. PMID- 29115953 TI - Laparoscopic sleeve gastrectomy improves body composition and alleviates insulin resistance in obesity related acanthosis nigricans. AB - BACKGROUND: Acanthosis nigricans (AN) has a close relationship with obesity. It is believed that obesity and AN have the common pathophysiological basis such as hyperinsulinism. This study is aimed to observe the effect of laparoscopic sleeve gastrectomy (LSG) on body composition and insulin resistance in Chinese obese patients with acanthosis nigricans. METHODS: A total of 37 obese patients who underwent LSG in our hospital were selected for analysis. They were divided into simple obesity (OB n = 14) and obesity with acanthosis nigricans (AN n = 23) group respectively. Body composition was measured by dual-energy X-ray absorptiometry (DEXA). Anthropometric measurements and glucolipid metabolism before and 3 months post LSG were collected for analysis. RESULTS: Patients with AN got noticeable improvement in skin condition and their AN score was significantly decreased (3.52 +/- 0.79 vs. 1.48 +/- 0.73, P < 0.001).Alleviated insulin resistance and more trunk fat loss than limbs' were observed in both groups (P value < 0.01). In AN group, preoperative android fat mass (FM) was positively correlated with fasting insulin and natural logarithm of HOMA-IR (LNIR) (r = 0.622, 0.608, respectively; all P < 0.01). Besides, changes in android FM and visceral adipose tissue (VAT) also showed significantly positive correlation with changes in LNIR (r = 0.588, r = 0.598, respectively; all P < 0.01). CONCLUSIONS: LSG had a positive impact on body composition and skin condition in Chinese obese patients with AN. Loss of android FM and VAT might result in the alleviation of insulin resistance in AN patients. Android fat distribution seems to be a potential indicator of postoperative metabolic benefits for obese patients with AN. PMID- 29115955 TI - Health financing and integration of urban and rural residents' basic medical insurance systems in China. AB - BACKGROUND: China is in the process of integrating the new cooperative medical scheme (NCMS) and the urban residents' basic medical insurance system (URBMI) into the urban and rural residents' basic medical insurance system (URRBMI). However, how to integrate the financing policies of NCMS and URBMI has not been described in detail. This paper attempts to illustrate the differences between the financing mechanisms of NCMS and URBMI, to analyze financing inequity between urban and rural residents and to identify financing mechanisms for integrating urban and rural residents' medical insurance systems. METHODS: Financing data for NCMS and URBMI (from 2008 to 2015) was collected from the China health statistics yearbook, the China health and family planning statistics yearbook, the National Handbook of NCMS Information, the China human resources and social security statistics yearbook, and the China social security yearbook. "Ability to pay" was introduced to measure inequity in health financing. Individual contributions to NCMS and URBMI as a function of per capita disposable income was used to analyze equity in health financing between rural and urban residents. RESULTS: URBMI had a financing mechanism that was similar to that used by NCMS in that public finance accounted for more than three quarters of the pooling funds. The scale of financing for NCMS was less than 5% of the per capita net income of rural residents and less than 2% of the per capita disposable income of urban residents for URBMI. Individual contributions to the NCMS and URBMI funds were less than 1% of their disposable and net incomes. Inequity in health financing between urban and rural residents in China was not improved as expected with the introduction of NCMS and URBMI. The role of the central government and local governments in financing NCMS and URBMI was oscillating in the past decade. CONCLUSIONS: The scale of financing for URRBMI is insufficient for the increasing demands for medical services from the insured. The pooling fund should be increased so that it can better adjust to China's rapidly aging population and epidemiological transitions as well as protect the insured from poverty due to illness. Individual contributions to the URBMI and NCMS funds were small in terms of contributors' incomes. The role of the central government and local governments in financing URRBMI was not clearly identified. Individual contributions to the URRBMI fund should be increased to ensure the sustainable development of URRBMI. Compulsory enrollment should be required so that URRBMI improves the social medical insurance system in China. PMID- 29115954 TI - Malaria vectors in the Democratic Republic of the Congo: the mechanisms that confer insecticide resistance in Anopheles gambiae and Anopheles funestus. AB - BACKGROUND: The Democratic Republic of the Congo (DRC) is characterized as a holoendemic malaria area with the main vectors being Anopheles funestus and members of the Anopheles gambiae complex. Due to political instability and socio economic challenges in the region, knowledge of insecticide resistance status and resistance mechanisms in these vectors is limited. Mosquitoes were collected from a mining site in the north-eastern part of the country and, following identification, were subjected to extensive testing for the target-site and biochemical basis of resistance. Quantitative real-time PCR was used to assess a suite of 10 genes frequently involved in pyrethroid and dichlorodiphenyltrichloroethane (DDT) resistance in An. gambiae females and males. In An. funestus, gene expression microarray analysis was carried out on female mosquitoes. RESULTS: In both species, deltamethrin resistance was recorded along with high resistance and suspected resistance to DDT in An. gambiae and An. funestus, respectively. A total of 85% of An. gambiae carried the kdr mutations as either homozygous resistant (RR) (L1014S, L1014F or both) or heterozygous (RS), however only 3% carried the rdl mutant allele (RS) and no ace-1 mutations were recorded. Synergist assays indicated a strong role for P450s in deltamethrin resistance in both species. In An. gambiae, analysis of transcription levels showed that the glutathione-S-transferase, GSTS1-2, produced the highest fold change in expression (7.6-fold in females and 31-fold in males) followed by GSTE2, thioredoxin peroxidase (TPX2), and cytochrome oxidases (CYP6M2 and CYP6P1). All other genes tested produced fold change values below 2. Microarray analysis revealed significant over-transcription of cuticular proteins as well as CYP6M7, CYP6P9a and CYP6P9b in insecticide resistant An. funestus. CONCLUSIONS: These data show that high levels of deltamethrin resistance in the main malaria vector species, conferred by enzymatic detoxification, are present in the DRC. PMID- 29115956 TI - De novo characterization of venom apparatus transcriptome of Pardosa pseudoannulata and analysis of its gene expression in response to Bt protein. AB - BACKGROUND: Pardosa pseudoannulata is a prevailing spider species, and has been regarded as an important bio-control agent of insect pests in farmland of China. However, the available genomic and transcriptomic databases of P. pseudoannulata and their venom are limited, which severely hampers functional genomic analysis of P. pseudoannulata. Recently high-throughput sequencing technology has been proved to be an efficient tool for profiling the transcriptome of relevant non target organisms exposed to Bacillus thuringiensis (Bt) protein through food webs. RESULTS: In this study, the transcriptome of the venom apparatus was analyzed. A total of 113,358 non-redundant unigenes were yielded, among which 34,041 unigenes with complete or various length encoding regions were assigned biological function annotations and annotated with gene ontology and karyotic orthologous group terms. In addition, 3726 unigenes involved in response to stimulus and 720 unigenes associated with immune-response pathways were identified. Furthermore, we investigated transcriptomic changes in the venom apparatus using tag-based DGE technique. A total of 1724 differentially expressed genes (DEGs) were detected, while 75 and 372 DEGs were functionally annotated with KEGG pathways and GO terms, respectively. qPCR analyses were performed to verify the DEGs directly or indirectly related to immune and stress responses, including genes encoding heat shock protein, toll-like receptor, GST and NADH dehydrogenase. CONCLUSION: This is the first study conducted to specifically investigate the venom apparatus of P. pseudoannulata in response to Bt protein exposure through tritrophic chain. A substantial fraction of transcript sequences was generated by high-throughput sequencing of the venom apparatus of P. pseudoannulata. Then a comparative transcriptome analysis showing a large number of candidate genes involved in immune response were identified by the tag-based DGE technology. This transcriptome dataset will provide a comprehensive sequence resource for furture molecular genetic research of the venom apparatus of P. pseudoannulata. PMID- 29115957 TI - Towards a needle-free diagnosis of malaria: in vivo identification and classification of red and white blood cells containing haemozoin. AB - BACKGROUND: Optical detection of circulating haemozoin has been suggested as a needle free method to diagnose malaria using in vivo microscopy. Haemozoin is generated within infected red blood cells by the malaria parasite, serving as a highly specific, endogenous biomarker of malaria. However, phagocytosis of haemozoin by white blood cells which persist after the infection is resolved presents the potential for false positive diagnosis; therefore, the focus of this work is to identify a feature of the haemozoin signal to discriminate between infected red blood cells and haemozoin-containing white blood cells. METHODS: Conventional brightfield microscopy of thin film blood smears was used to analyse haemozoin absorbance signal in vitro. Cell type and parasite maturity were morphologically determined using colocalized DAPI staining. The ability of features to discriminate between infected red blood cells and haemozoin containing white blood cells was evaluated using images of smears from subjects infected with two species of Plasmodium, Plasmodium yoelii and Plasmodium falciparum. Discriminating features identified by blood smear microscopy were characterized in vivo in P. yoelii-infected mice. RESULTS: Two features of the haemozoin signal, haemozoin diameter and normalized intensity difference, were identified as potential parameters to differentiate infected red blood cells and haemozoin-containing white blood cells. Classification performance was evaluated using the area under the receiver operating characteristic curve, with area under the curve values of 0.89 for the diameter parameter and 0.85 for the intensity parameter when assessed in P. yoelii samples. Similar results were obtained from P. falciparum blood smears, showing an AUC of 0.93 or greater for both classification features. For in vivo investigations, the intensity-based metric was the best classifier, with an AUC of 0.91. CONCLUSIONS: This work demonstrates that size and intensity features of haemozoin absorbance signal collected by in vivo microscopy are effective classification metrics to discriminate infected red blood cells from haemozoin-containing white blood cells. This reduces the potential for false positive results associated with optical imaging strategies for in vivo diagnosis of malaria based on the endogenous biomarker haemozoin. PMID- 29115958 TI - To vaccinate or not to vaccinate? Perspectives on HPV vaccination among girls, boys, and parents in the Netherlands: a Q-methodological study. AB - BACKGROUND: Despite the introduction of Human papillomavirus (HPV) vaccination in national immunization programs (NIPs), vaccination rates in most countries remain relatively low. An understanding of the reasons underlying decisions about whether to vaccinate is essential in order to promote wider spread of HPV vaccination. This is particularly important in relation to policies seeking to address shortfalls in current HPV campaigns. The aim of this study was to explore prevailing perspectives concerning HPV vaccination among girls, boys, and parents, and so to identify potential determinants of HPV vaccination decisions in these groups. METHOD: Perspectives were explored using Q-methodology. Forty seven girls, 39 boys, and 107 parents in the Netherlands were asked to rank a comprehensive set of 35 statements, assembled based on the health belief model (HBM), according to their agreement with them. By-person factor analysis was used to identify common patterns in these rankings, which were interpreted as perspectives on HPV vaccination. These perspectives were further interpreted and described using data collected with interviews and open-ended questions. RESULTS: The analysis revealed four perspectives: "prevention is better than cure," "fear of unknown side effects," "lack of information and awareness," and "my body, my choice." The first two perspectives and corresponding determinants of HPV vaccination decisions were coherent and distinct; the third and fourth perspectives were more ambiguous and, to some extent, incoherent, involving doubt and lack of awareness and information (perspective 3), and overconfidence (perspective 4). CONCLUSIONS: Given the aim of publically funded vaccination programs to minimize the spread of HPV infection and HPV-related disease and the concerns about current uptake levels, our results indicate that focus should be placed on increasing awareness and knowledge, in particular among those in a modifiable phase. PMID- 29115959 TI - Increased stiffness of median nerve in systemic sclerosis. AB - BACKGROUND: Systemic sclerosis can affect peripheral nerves, but the extent and the nature of this involvement are not well defined. The aim of this study is to compare the sonoelastrographic measurements of median nerves in systemic sclerosis (SSC), idiopathic carpal tunnel syndrome (CTS) and healthy individuals. METHODS: The clinical, electrophysiological and ultrasonographic assessments were done. Patients with SSC and CTS were assessed with nerve conduction studies. The measurements of cross sectional areas (CSA) were performed at psiform and forearm level from axial US images. The elastic ratio is the ratio of strain distribution in two selected region of interests (ROI) done via comparing the median nerve to flexor digitorum superfcialis tendon. The ROIs were fixed to 2 mm. RESULTS: The study was completed with 47 hands of 24 patients with SSC, 53 hands of 27 patients with CTS and 38 hands of health controls. The CSA of CTS group was significantly higher than systemic sclerosis and control groups. The elastic ratio at psiform level and forearm levels of systemic sclerosis group were significantly higher than the CTS and control groups. CONCLUSION: Median nerves lose the elasticity while the CSA's are in the normal range in patients with SSC. These results suggested that the increased peripheral nerve involvement in SSC is about the increased stiffness of the nerves. PMID- 29115960 TI - Should the poor have no medicines to cure? A study on the association between social class and social security among the rural migrant workers in urban China. AB - BACKGROUND: The rampant urbanization and medical marketization in China have resulted in increased vulnerabilities to health and socioeconomic disparities among the rural migrant workers in urban China. In the Chinese context, the socioeconomic characteristics of rural migrant workers have attracted considerable research attention in the recent past years. However, to date, no previous studies have explored the association between the socioeconomic factors and social security among the rural migrant workers in urban China. This study aims to explore the association between socioeconomic inequity and social security inequity and the subsequent associations with medical inequity and reimbursement rejection. METHODS: Data from a regionally representative sample of 2009 Survey of Migrant Workers in Pearl River Delta in China were used for analyses. Multiple logistic regressions were used to analyze the impacts of socioeconomic factors on the eight dimensions of social security (sick pay, paid leave, maternity pay, medical insurance, pension insurance, occupational injury insurance, unemployment insurance, and maternity insurance) and the impacts of social security on medical reimbursement rejection. The zero-inflated negative binomial regression model (ZINB regression) was adopted to explore the relationship between socioeconomic factors and hospital visits among the rural migrant workers with social security. RESULTS: The study population consisted of 848 rural migrant workers with high income who were young and middle-aged, low educated, and covered by social security. Reimbursement rejection and abusive supervision for the rural migrant workers were observed. Logistic regression analysis showed that there were significant associations between socioeconomic factors and social security. ZINB regression showed that there were significant associations between socioeconomic factors and hospital visits among the rural migrant workers. Also, several dimensions of social security had significant associations with reimbursement rejections. CONCLUSIONS: This study showed that social security inequity, medical inequity, and reimbursement inequity happened to the rural migrant workers simultaneously. Future policy should strengthen health justice and enterprises' medical responsibilities to the employed rural migrant workers. PMID- 29115961 TI - Plasmodium falciparum variant erythrocyte surface antigens: a pilot study of antibody acquisition in recurrent natural infections. AB - BACKGROUND: During intra-erythrocytic replication Plasmodium falciparum escapes the human host immune system by switching expression of variant surface antigens (VSA). Piecemeal acquisition of variant specific antibody responses to these antigens as a result of exposure to multiple re-infections has been proposed to play a role in acquisition of naturally acquired immunity. METHODS: Immunofluorescence was used to explore the dynamics of anti-VSA IgG responses generated by children to (i) primary malaria episodes and (ii) recurrent P. falciparum infections. RESULTS: Consistent with previous studies on anti-VSA responses, sera from each child taken at the time of recovery from their respective primary infection tended to recognize their own secondary parasites poorly. Additionally, compared to patients with reinfections by parasites of new merozoite surface protein 2 (MSP2) genotypes, baseline sera sampled from patients with persistent infections (recrudescence) tended to have higher recognition of heterologous parasites. This is consistent with the prediction that anti-VSA IgG responses may play a role in promoting chronic asymptomatic infections. CONCLUSIONS: This pilot study validates the utility of recurrent natural malaria infections as a functional readout for examining the incremental acquisition of immunity to malaria. PMID- 29115962 TI - Bridging the human resource gap in surgical and anesthesia care in low-resource countries: a review of the task sharing literature. AB - Task sharing, the involvement of non-specialists (non-physician clinicians or non specialist physicians) in performing tasks originally reserved for surgeons and anesthesiologists, can be a potent strategy in bridging the vast human resource gap in surgery and anesthesia and bringing needed surgical care to the district level especially in low-resource countries. Although a common practice, the idea of assigning advanced tasks to less-specialized workers remains a subject of controversy. In order to optimize its benefits, it is helpful to understand the current task sharing landscape, its challenges, and its promise. We performed a literature review of PubMed, EMBASE, and gray literature sources for articles published between January 1, 1996, and August 1, 2016, written in English, with a focus on task sharing in surgery or anesthesia in low-resource countries. Gray literature sources are defined as articles produced outside of a peer-reviewed journal. We sought data on the nature and forms of task sharing (non-specialist cadres involved, surgical/anesthesia procedures shared, approaches to training and supervision, and regulatory and other efforts to create a supportive environment), impact of task sharing on delivery of surgical services (effect on access, acceptability, cost, safety, and quality), and challenges to successful implementation. We identified 40 published articles describing task sharing in surgery and anesthesia in 39 low-resource countries in Africa and Asia. All countries had a cadre of non-specialists providing anesthesia services, while 13 had cadres providing surgical services. Six countries had non-specialists performing major procedures, including Cesarean sections and open abdominal surgeries. While most cadres were recognized by their governments as service providers, very few had scopes of practice that included task sharing of surgery or anesthesia. Key challenges to effective task sharing include specialists' concern about safety, weak training strategies, poor or unclear career pathways, regulatory constraints, and service underutilization. Concrete recommendations are offered. PMID- 29115963 TI - Changes in vasoactive pathways in congenital diaphragmatic hernia associated pulmonary hypertension explain unresponsiveness to pharmacotherapy. AB - BACKGROUND: Patients with congenital diaphragmatic hernia (CDH) have structural and functional different pulmonary vessels, leading to pulmonary hypertension. They often fail to respond to standard vasodilator therapy targeting the major vasoactive pathways, causing a high morbidity and mortality. We analyzed whether the expression of crucial members of these vasoactive pathways could explain the lack of responsiveness to therapy in CDH patients. METHODS: The expression of direct targets of current vasodilator therapy in the endothelin and prostacyclin pathway was analyzed in human lung specimens of control and CDH patients. RESULTS: CDH lungs showed increased expression of both ETA and ETB endothelin receptors and the rate-limiting Endothelin Converting Enzyme (ECE-1), and a decreased expression of the prostaglandin-I2 receptor (PTGIR). These data were supported by increased expression of both endothelin receptors and ECE-1, endothelial nitric oxide synthase and PTGIR in the well-established nitrofen-CDH rodent model. CONCLUSIONS: Together, these data demonstrate aberrant expression of targeted receptors in the endothelin and prostacyclin pathway in CDH already early during development. The analysis of this unique patient material may explain why a significant number of patients do not respond to vasodilator therapy. This knowledge could have important implications for the choice of drugs and the design of future clinical trials internationally. PMID- 29115964 TI - The MATEX cohort - a Finnish population register birth cohort to study health effects of prenatal exposures. AB - BACKGROUND: The prevalence of chronic diseases, such as immune, neurobehavioral, and metabolic disorders has increased in recent decades. According to the concept of Developmental Origin of Health and Disease (DOHaD), developmental factors associated with environmental exposures and maternal lifestyle choices may partly explain the observed increase. Register-based epidemiology is a prime tool to investigate the effects of prenatal exposures over the whole life course. Our aim is to establish a Finnish register-based birth cohort, which can be used to investigate various (prenatal) exposures and their effects during the whole life course with first analyses focusing on maternal smoking and air pollution. In this paper we (i) review previous studies to identify knowledge gaps and overlaps available for cross-validation, (ii) lay out the MATEX study plan for register linkages, and (iii) analyse the study power of the baseline MATEX cohort for selected endpoints identified from the international literature. METHODS/DESIGN: The MATEX cohort is a fully register-based cohort identified from the Finnish Medical Birth Register (MBR) (1987-2015). Information from the MBR will be linked with other Finnish health registers and the population register to link the cohort with air quality data. Epidemiological analyses will be conducted for maternal smoking and air pollution and a range of health endpoints. DISCUSSION: The MATEX cohort consists of 1.75 million mother-child pairs with a maximum follow up time of 29 years. This makes the cohort big enough to reach sufficient statistical power to investigate rare outcomes, such as birth anomalies, childhood cancers, and sudden infant death syndrome (SIDS). The linkage between different registers allows for an extension of the scope of the cohort and a follow up from the prenatal period to decades later in life. PMID- 29115965 TI - Operationalization of diagnostic criteria of DSM-5 somatic symptom disorders. AB - BACKGROUND: The aim of this study was to test the operationalization of DSM-5 somatic symptom disorder (SSD) psychological criteria among Chinese general hospital outpatients. METHODS: This multicenter, cross-sectional study enrolled 491 patients from 10 general hospital outpatient departments. The structured clinical "interview about cognitive, affective, and behavioral features associated with somatic complaints" was used to operationalize the SSD criteria B. For comparison, DSM-IV somatoform disorders were assessed with the Mini International Neuropsychiatric Interview plus. Cohen's k scores were given to illustrate the agreement of the diagnoses. RESULTS: A three-structure model of the interview, within which items were classified as respectively assessing the cognitive (B1), affective (B2), and behavioral (B3) features, was examined. According to percentages of screening-positive persons and the receiver operator characteristic (ROC) analysis, a cut-off point of 2 was recommended for each subscale of the interview. With the operationalization, the frequency of DSM-5 SSD was estimated as 36.5% in our sample, and that of DSM-IV somatoform disorders was 8.2%. The agreement between them was small (Cohen's k = 0.152). Comparisons of sociodemographic features of SSD patients with different severity levels (mild, moderate, severe) showed that mild SSD patients were better-off in terms of financial and employment status, and that the severity subtypes were congruent with the level of depression, anxiety, quality of life impairment, and the frequency of doctor visits. CONCLUSIONS: The operationalization of the diagnosis and severity specifications of SSD was valid, but the diagnostic agreement between DSM-5 SSD and DSM-IV somatoform disorders was small. The interpretation the SSD criteria should be made cautiously, so that the diagnosis would not became over-inclusive. PMID- 29115966 TI - Malaria surveys using rapid diagnostic tests and validation of results using post hoc quantification of Plasmodium falciparum histidine-rich protein 2. AB - BACKGROUND: Rapid diagnostic test (RDT) positivity is supplanting microscopy as the standard measure of malaria burden at the population level. However, there is currently no standard for externally validating RDT results from field surveys. METHODS: Individuals' blood concentration of the Plasmodium falciparum histidine rich protein 2 (HRP2) protein were compared to results of HRP2-detecting RDTs in participants from field surveys in Angola, Mozambique, Haiti, and Senegal. A logistic regression model was used to estimate the HRP2 concentrations corresponding to the 50 and 90% level of detection (LOD) specific for each survey. RESULTS: There was a sigmoidal dose-response relationship between HRP2 concentration and RDT positivity for all surveys. Variation was noted in estimates for field RDT sensitivity, with the 50% LOD ranging between 0.076 and 6.1 ng/mL and the 90% LOD ranging between 1.1 and 53 ng/mL. Surveys conducted in two different provinces of Angola using the same brand of RDT and same study methodology showed a threefold difference in LOD. CONCLUSIONS: Measures of malaria prevalence estimated using population RDT positivity should be interpreted in the context of potentially large variation in RDT LODs between, and even within, surveys. Surveys based on RDT positivity would benefit from external validation of field RDT results by comparing RDT positivity and antigen concentration. PMID- 29115967 TI - Light induced expression of beta-glucosidase in Escherichia coli with autolysis of cell. AB - BACKGROUND: beta-Glucosidase has attracted substantial attention in the scientific community because of its pivotal role in cellulose degradation, glycoside transformation and many other industrial processes. However, the tedious and costly expression and purification procedures have severely thwarted the industrial applications of beta-glucosidase. Thus development of new strategies to express beta-glucosidases with cost-effective and simple procedure to meet the increasing demands on enzymes for biocatalysis is of paramount importance. RESULTS: Light activated cassette YF1/FixJ and the SRRz lysis system were successfully constructed to produce Bgl1A(A24S/F297Y), a mutant beta glucosidase tolerant to both glucose and ethanol. By optimizing the parameters for light induction, Bgl1A(A24S/F297Y) activity reached 33.22 +/- 2.0 U/mL and 249.92 +/- 12.25 U/mL in 250-mL flask and 3-L fermentation tank, respectively, comparable to the controls of 34.02 +/- 1.96 U/mL and 322.21 +/- 10.16 U/mL under similar culture conditions with IPTG induction. To further simplify the production of our target protein, the SRRz lysis gene cassette from bacteriophage Lambda was introduced to trigger cell autolysis. As high as 84.53 +/- 6.79% and 77.21 +/- 4.79% of the total beta-glucosidase were released into the lysate after cell autolysis in 250 mL flasks and 3-L scale fermentation with lactose as inducer of SRRz. In order to reduce the cost of protein purification, a cellulose binding module (CBM) from Clostridium thermocellum was fused into the C-terminal of Bgl1A(A24S/F297Y) and cellulose was used as an economic material to adsorb the fusion enzyme from the lysate. The yield of the fusion protein could reach 92.20 +/- 2.27% after one-hour adsorption at 25 degrees C. CONCLUSIONS: We have developed an efficient and inexpensive way to produce beta-glucosidase for potential industrial applications by using the combination of light induction, cell autolysis, and CBM purification strategy. PMID- 29115968 TI - f-scLVM: scalable and versatile factor analysis for single-cell RNA-seq. AB - Single-cell RNA-sequencing (scRNA-seq) allows studying heterogeneity in gene expression in large cell populations. Such heterogeneity can arise due to technical or biological factors, making decomposing sources of variation difficult. We here describe f-scLVM (factorial single-cell latent variable model), a method based on factor analysis that uses pathway annotations to guide the inference of interpretable factors underpinning the heterogeneity. Our model jointly estimates the relevance of individual factors, refines gene set annotations, and infers factors without annotation. In applications to multiple scRNA-seq datasets, we find that f-scLVM robustly decomposes scRNA-seq datasets into interpretable components, thereby facilitating the identification of novel subpopulations. PMID- 29115969 TI - Correction to: NuA4 histone acetyltransferase activity is required for H4 acetylation on a dosage-compensated monosomic chromosome that confers resistance to fungal toxins. AB - After the publication of this work [1], it was noticed that an initial was missing from the author name: Jeffrey Hayes. His name should be written as: Jeffrey J. Hayes. PMID- 29115970 TI - Comparison of 68Ga-PSMA-11 PET-CT with mpMRI for preoperative lymph node staging in patients with intermediate to high-risk prostate cancer. AB - BACKGROUND: To evaluate the diagnostic value of 68Ga-PSMA-11 PET-CT with multiparametric magnetic resonance imaging (mpMRI) for lymph node (LN) staging in patients with intermediate- to high-risk prostate cancer (PCa) undergoing radical prostatectomy (RP) with pelvic lymph node dissection (PLND). METHODS: We retrospectively identified 42 consecutive patients with intermediate- to high risk PCa according to D'Amico and without concomitant cancer. Preoperative 68Ga PSMA-11 PET-CT, pelvic mpMRI and subsequent robot assisted laparoscopic RP with PLND were performed in all patients. RESULTS: Among 42 patients assessed, the preoperative PSA value, Gleason score, pT stage and intraprostatic PCa volume of patients with LN metastases were all significantly higher than those without metastases (P = 0.029, 0.028, 0.004, respectively). The average maximum standardized uptake value (SUV) of 68Ga-PSMA-11 PET-CT positive PCa of patients with or without LN metastases were 13.10 (range 6.12-51.75) and 7.22 (range 5.4 11.2), respectively (P < 0.001). 68Ga-PSMA-11 PET-CT and pelvic mpMRI had the ability of succeed on preoperative definite accurate diagnosis and accurate localization of primary PCa in all 42 patients. Fifteen patients (35.71%) had a pN1 stage. 51 positive LN were found. Both 68Ga-PSMA-11 PET-CT and pelvic mpMRI displayed brillient patient-based and region-based sensitivity, specificity, negative predictive value and positive predictive value. There was no statistical difference for the detection of LNMs according to the diameter of the LNMs between 68Ga-PSMA-11 PET-CT and mpMRI in this study. CONCLUSIONS: Both 68Ga-PSMA 11 PET-CT and mpMRI performed great value for LN staging in patients with intermediate- to high-risk PCa undergoing RP with PLND. However, despite excellent performance of 68Ga-PSMA-11 PET-CT, it cannot replace mpMRI that remains excellent for lymph node staging. PMID- 29115971 TI - Local anaesthetics or their combination with morphine and/or magnesium sulphate are toxic for equine chondrocytes and synoviocytes in vitro. AB - BACKGROUND: Chondrotoxic effects of local anaesthetics are well reported in humans and some animal species but knowledge on their toxic effects on synoviocytes or equine chondrocytes or the effects on cellular production of inflammatory cytokines is limited. The purpose of this study was to evaluate the in vitro effects of local anaesthetics, morphine, magnesium sulphate (MgSO4) or their combinations on cell viability and pro-inflammatory cytokine gene expression of equine synoviocytes and chondrocytes. Equine synoviocytes and cartilage explants harvested from normal joints in a co-culture system were exposed to mepivacaine (4.4 mg/ml), bupivacaine (2.2 mg/ml), morphine (2.85 mg/ml) and MgSO4 (37 mg/ml) alone or each local anaesthetic plus morphine or MgSO4 or both together. Chondrocyte and synoviocyte cell viability was assessed by CellTiter-Glo Luminescent Cell Viability Assay. Synoviocyte gene expression of IL-1beta, IL-6 or TNF-alpha was measured and compared using the ??CT method. RESULTS: Morphine alone, MgSO4 alone or their combination did not alter cell viability or the expression of IL-1beta, IL-6 or TNF-alpha. However, local anaesthetics alone or in combination with morphine and/or MgSO4 reduced cell viability and increased the gene expression of IL-1beta, IL-6 or TNF-alpha. Single short exposure to local anaesthetics is toxic to both chondrocytes and synoviocytes and their combination with morphine and/or MgSO4 enhanced the cytotoxic effects. CONCLUSIONS: This in vitro study gives further evidence of the absence of cytotoxic effects of morphine alone, MgSO4 alone or their combination on normal articular tissues. However, local anaesthetics alone or in combination with morphine and/or MgSO4 have cytotoxic effects on equine articular tissues. PMID- 29115972 TI - Plasmodium reichenowi EBA-140 merozoite ligand binds to glycophorin D on chimpanzee red blood cells, shedding new light on origins of Plasmodium falciparum. AB - BACKGROUND: All symptoms of malaria are caused by the intraerythrocytic proliferation of Plasmodium merozoites. Merozoites invade erythrocytes using multiple binding ligands that recognise specific surface receptors. It has been suggested that adaptation of Plasmodium parasites to infect specific hosts is driven by changes in genes encoding Plasmodium erythrocyte-binding ligands (EBL) and reticulocyte-binding ligands (RBL). Homologs of both EBL and RBL, including the EBA-140 merozoite ligand, have been identified in P. falciparum and P. reichenowi, which infect humans and chimpanzees, respectively. The P. falciparum EBA-140 was shown to bind human glycophorin C, a minor erythrocyte sialoglycoprotein. Until now, the erythrocyte receptor for the P. reichenowi EBA 140 remained unknown. METHODS: The baculovirus expression vector system was used to obtain the recombinant EBA-140 Region II, and flow cytometry and immunoblotting methods were applied to characterise its specificity. RESULTS: We showed that the chimpanzee glycophorin D is the receptor for the P. reichenowi EBA-140 ligand on chimpanzee red blood cells. CONCLUSIONS: We propose that the development of glycophorin C specificity is spurred by the P. falciparum lineage. We speculate that the P. falciparum EBA-140 evolved to hijack GPC on human erythrocytes during divergence from its ape ancestor. PMID- 29115973 TI - Anteromedial versus transtibial technique in single-bundle autologous hamstring ACL reconstruction: a meta-analysis of prospective randomized controlled trials. AB - BACKGROUND: The aim of this study was to compare the clinical outcome and postoperative complication between single-bundle anterior cruciate ligament (ACL) reconstruction with an anteromedial (AM) technique and a transtibial (TT) technique. METHODS: The study includes clinical randomized controlled trials comparing the clinical outcomes of ACL reconstruction using the autologous hamstring tendon with an AM method and a TT method published up to September 2017 were retrieved from PubMed, Cochrane Library, and Embase databases. Relevant data were extracted and the Physiotherapy Evidence Database (PEDro) scale was used to assess the methodological quality. Stata/SE 12.0 was used to perform a meta analysis of the clinical outcome. RESULTS: Five RCTs were included, with a total of 479 patients: 239 patients and 240 patients in the AM group and the TT group, respectively. Assessing postoperative stability, better results were found in the AM group for the negative rate of the Lachman test (P < 0.05), the negative rate of the pivot-shift test (P < 0.05) and the side-to-side difference (P < 0.05). Assessing postoperative functional outcome, the AM group yielded superior results in proportion with International Knee Documentation Committee (IKDC) grade A (P < 0.05) and the Lysholm scores (P < 0.05) but had a comparable IKDC score (P > 0.05). In terms of postoperative complication, no significant difference was found between the AM group and the TT group (P > 0.05). CONCLUSIONS: The outcome of single-bundle ACL reconstruction with the AM technique is better than that with the TT technique in terms of postoperative stability and functional recovery of the knee. PMID- 29115975 TI - PVL overexpression due to genomic rearrangements and mutations in the S. aureus reference strain ATCC25923. AB - OBJECTIVE: ATCC25923 is a Staphylococcus aureus strain that is positive for the Panton Valentin leukocidin. It has been used for decades as reference strain. We observed that two separately maintained clones of ATCC25923 ("G477 and G478") differed grossly in the expression of this toxin. For that reason, both clones were sequenced using an Illumina MiSeq instrument. After assembling, the final sequences were analyzed and mapped to a previously published ATCC25923 sequence (GenBank CP009361) using bl2seq from the NCBI Blast2 package. RESULTS: The genomes of G477 and G478 size 2778,859 and 2792,213 nucleotides, respectively. Both genomes include a circular plasmid of 27,490 nucleotides. The sequence of the G477 chromosome maps nearly exactly to CP009361. G478 has a slightly larger size because of the presence of an additional transposable element tnp13k. The second copy of that tnp13k element is located in an intergenic region between the genes mazF and rsbU. The sequences of the ATCC25923 clones G477 and G478 differ mainly in the insertion of a second tnp13k element between the genes mazF and rsbU. That insertion may lead to a different transcription of that genome region resulting in upregulation of the expression of the Panton-Valentine leukocidin in the ATCC25923 clone G478. PMID- 29115974 TI - STAT3-blocked whole-cell hepatoma vaccine induces cellular and humoral immune response against HCC. AB - BACKGROUND: Whole-cell tumor vaccines have shown much promise; however, only limited success has been achieved for the goal of eliciting robust tumor-specific T-cell responses. METHODS: Hepatocellular carcinoma (HCC) cells, H22 and Hepa1-6, were modified by blocking the STAT3 signaling pathway with a STAT3 decoy oligodeoxynucleotide, and the immunogenicity and possibility of using these cell lysates as a vaccine were evaluated. RESULTS: STAT3-blocked whole HCC cell lysates inhibited tumor growth and tumorigenesis, and prolonged the survival of tumor-bearing mice. In addition, STAT3-blocked whole HCC cell lysates stimulated the activation of T cells and natural killer (NK) cells, and enhanced the infiltration of cytotoxic CD8+ T cells in the tumor tissues. In addition, the maturation of dendritic cells (DCs) was enhanced, which promoted the generation of immunological memory against HCC. Furthermore, secondary immune responses could be primed as soon as these immunized mice were challenged with HCC cells, accompanied by T cell and NK cell activation and infiltration. Additionally, immunization with this vaccine decreased the generation of Tregs and the production of TGF-beta and IL-10. Importantly, STAT3-blocked whole HCC cell lysates prevented HCC-mediated exhaustion of T cells and NK cells, showing low expression of checkpoint molecules such as PD-1 and TIGIT on T cells and NK cells in the immunized mice. CONCLUSIONS: The newly generated STAT3-blocked whole-cell HCC vaccine has potential for cancer cell vaccination. PMID- 29115976 TI - GMP-production of purified human B lymphocytes for the adoptive transfer in patients after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: We have recently shown that memory B cells from murine CMV immune donor animals adoptively transferred into immunodeficient mice were highly effective in protecting from a viral infection indicating a therapeutic potential of virus specific memory B cells. These preclinical data provided evidence that a cell-based strategy supporting the humoral immune response might be effective in a clinical setting of immunodeficiency after allogeneic hematopoietic stem cell transplantation. As adoptive transfer of B cells has not been used before in a clinical setting it was necessary to establish a technology for the generation of good manufacturing practice (GMP)-grade B cell products. METHODS: Starting from the leukapheresis product of healthy blood donors, B cells were purified by two different separation strategies using GMP-grade microbeads and the CliniMACS system. A one-step protocol was used for positive enrichment of B lymphocytes with anti-CD19 microbeads. In a two-step enrichment protocol, first T lymphocytes were depleted by anti-CD3 microbeads and the remaining fraction was positively selected by anti-CD19 microbeads. RESULTS: The purity and recovery after enrichment of B lymphocytes from the leukapheresis material in both separations strategies was not statistically different. However, contamination of the B-cell product with T cells was significantly lower after the two-step protocol (0.16%, range 0.01-0.43% after two-step separation and 0.55%, range 0.28-0.85% after one step separation, p < 0.05). Therefore, a combined CD3 depletion and CD19 enrichment was used for the production of GMP-conform B-cell products from the leukapheresis material of 17 healthy stem cell donors. The absolute B-cell numbers obtained in the final product was 4.70 +/- 3.64 * 108 with a purity of 95.98 +/- 3.31% B lymphocytes and a recovery of 18.9 +/- 10.6%. Importantly, the contamination with CD3+ T cells was extremely low in the final B- cell products (0.10 +/- 0.20%). Purified B cells exhibited normal antibody production after in vitro stimulation and showed excellent viability after cryopreservation. CONCLUSIONS: A GMP-grade B-cell product can be obtained with high purity and very low T-cell contamination using the two-step enrichment protocol based on CliniMACS(r) technology. PMID- 29115977 TI - Clinicopathological predictors of recurrence in nodular and superficial spreading cutaneous melanoma: a multivariate analysis of 214 cases. AB - BACKGROUND: Nodular melanoma (NM) accounts for most thick melanomas and because of their frequent association with ulceration, fast growth rate and high mitotic rate, contribute substantially to melanoma-related mortality. In a multicentric series of 214 primary melanomas including 96 NM and 118 superficial spreading melanoma (SSM), histopathological features were examined with the aim to identify clinicopathological predictors of recurrence. METHODS: All consecutive cases of histopathologically diagnosed primary invasive SSM and NM during the period 2005 2010, were retrieved from the 12 participating Italian Melanoma Intergroup (IMI) centers. Each center provided clinico-pathological data such as gender, age at diagnosis, anatomical site, histopathological conventional parameters, date of excision and first melanoma recurrence. RESULTS: Results showed that NM subtype was significantly associated with Breslow thickness (BT) at multivariate analysis: [BT 1.01-2 mm (OR 7.22; 95% CI 2.73-19.05), BT 2.01-4 mm (OR 7.04; 95% CI 2.54-19.56), and BT > 4 mm (OR 51.78; 95% CI 5.65-474.86) (p < 0.0001)]. Furthermore, mitotic rate (MR) was significantly correlated with NM histotype: [(MR 3-5 mitoses/mm2 (OR 2.62; 95% CI 1.01-6.83) and MR > 5 mitoses/mm2 (OR 4.87; 95% CI 1.77-13.40) (p = 0.002)]. The risk of recurrence was not significantly associated with NM histotype while BT [BT 1.01-2.00 mm (HR 1.55; 95% CI 0.51 4.71), BT 2.01-4.00 mm (HR 2.42; 95% CI 0.89-6.54), BT > 4.00 mm. (HR 3.13; 95% CI 0.95-10.28) (p = 0.05)], mitotic rate [MR > 2 mitoses/mm2 (HR 2.34; 95% CI, 1.11-4.97) (p = 0.03)] and the positivity of lymph node sentinel biopsy (SNLB) (HR 2.60; 95% CI 1.19-5.68) (p = 0.007) were significantly associated with an increased risk of recurrence at multivariate analysis. CONCLUSIONS: We found that NM subtype was significantly associated with higher BT and MR but it was not a prognostic factor since it did not significantly correlate with melanoma recurrence rate. Conversely, increased BT and MR as well as SNLB positivity were significantly associated with a higher risk of melanoma recurrence. PMID- 29115978 TI - Depletion of somatic mutations in splicing-associated sequences in cancer genomes. AB - BACKGROUND: An important goal of cancer genomics is to identify systematically cancer-causing mutations. A common approach is to identify sites with high ratios of non-synonymous to synonymous mutations; however, if synonymous mutations are under purifying selection, this methodology leads to identification of false positive mutations. Here, using synonymous somatic mutations (SSMs) identified in over 4000 tumours across 15 different cancer types, we sought to test this assumption by focusing on coding regions required for splicing. RESULTS: Exon flanks, which are enriched for sequences required for splicing fidelity, have ~ 17% lower SSM density compared to exonic cores, even after excluding canonical splice sites. While it is impossible to eliminate a mutation bias of unknown cause, multiple lines of evidence support a purifying selection model above a mutational bias explanation. The flank/core difference is not explained by skewed nucleotide content, replication timing, nucleosome occupancy or deficiency in mismatch repair. The depletion is not seen in tumour suppressors, consistent with their role in positive tumour selection, but is otherwise observed in cancer associated and non-cancer genes, both essential and non-essential. Consistent with a role in splicing modulation, exonic splice enhancers have a lower SSM density before and after controlling for nucleotide composition; moreover, flanks at the 5' end of the exons have significantly lower SSM density than at the 3' end. CONCLUSIONS: These results suggest that the observable mutational spectrum of cancer genomes is not simply a product of various mutational processes and positive selection, but might also be shaped by negative selection. PMID- 29115979 TI - Common oral conditions and correlates: an oral health survey in Kwara State Nigeria. AB - BACKGROUND: Oral diseases are one of the most prevalent health problems today with distribution and severity varying in different parts of the world and within the same country. Oral health surveys are needed to determine prevalence of oral conditions and the nature and urgency of oral health interventions. A modified version of World Health Organisation pathfinder survey methods was used to determine prevalence of oral conditions amongst 150 respondents in two local government areas in Kwara State, Nigeria. This involved a stratified cluster sampling technique which identified the subgroups; location and certain age groups 5-6, 12 and 35-44 years age groups respectively. Clinical oral examination was carried out to determine the presence and types of common oral conditions among the respondents. Data analysis was done using descriptive statistics and Chi square analysis at 5% level of significance. RESULTS: Among all the selected subjects 91.3% had an oral condition, while for the rural and urban population it was 93.3 and 89.3% respectively (p > 0.05). The most prevalent oral conditions were plaque and surface calculus found in 66.0% of the respondents respectively. Others are gingivitis (30.0%), enamel wear (15.0%) and dental caries (13.0%). The mean decayed missing filled teeth index was 0.26. The decayed missing filled teeth index did not show any significant difference between the rural and urban areas or male and female gender. The presence of calculus (p = 0.005) and gingivitis (0.015) was more in males than females. The presence of plaque (0.001) and calculus (0.006) was significantly more among the skilled workforce. The 12 year age group had significantly more cases of plaque, calculus and gingivitis while there were more cases of enamel wear among the 35-44 year olds compared with other age groups. There were more cases of trauma (87.5%) seen in urban than rural location (p = 0.029). CONCLUSION: Oral health in selected communities of Kwara State is suboptimal requiring intervention. The presence of oral conditions is influenced by age, occupation, location and gender. PMID- 29115980 TI - Anal incontinence and quality of life following operative treatment of simple cryptoglandular fistula-in-ano: a prospective study. AB - BACKGROUND: Anal incontinence is a known complication following operative treatment of fistula-in-ano which can significantly impact the quality of life. This study was aimed to objectively assess the impact of operative treatment of simple fistula-in-ano on quality of life related to anal incontinence. Therefore, a prospective study was conducted in 34 patients who underwent surgery for fistula-in-ano over a period of 24 months. Quality of life and incontinence were assessed using fecal incontinence quality of life (FIQL) scale and Cleveland clinic incontinence score (CCIS) preoperatively and after a minimum of 12 months follow up (mean-27 months, range 12-40 months). The difference in FIQL and CCIS was analysed using Wilcoxon Rank test and Mann-Whitney U test. RESULTS: The median age of the participants was 42.5 years (range 22-63, males = 30). The majority had a trans-sphincteric tract (n = 22, 65%). Superficial tracts and inter-sphincteric tracts were found in 8 (24%) and 4 patients (12%). The overall preoperative and postoperative rates of incontinence were 18 and 38% respectively, but the severity was low. The mean overall FIQL was 16.0 (SD +/- 0.4) preoperatively and 16.1 (SD +/- 0.4) postoperatively. Considerable difference was seen in the scale measuring "depression/self-perception" (p = 0.012). Only 1 patient (3%) had reduction in scale "lifestyle" which measures the impact of incontinence on day-to-day activities. CONCLUSIONS: Analysis of a cohort of simple cryptoglandular fistula-in-ano with low pre-operative incontinence showed no worsening in the FIQL following successful treatment despite minor worsening of incontinence. Since greater improvement was noted in scale measuring depression/self-perception, psychological interventions may be helpful before surgery to improve quality of life. PMID- 29115981 TI - Hyperuricemia in type 2 diabetic model KK-Ay/Ta mice: a potent animal model with positive correlation between insulin resistance and plasma high uric acid levels. AB - OBJECTIVE: Hyperuricemia is recognized as a main cause of gout. Accumulating clinical evidence suggests that hyperuricemia is strongly associated with insulin resistance and abnormal glucose metabolism. However, there seem no proper animal models for investigating such associations. Ideal animal model is considered to be hyperuricemic as well as diabetic. Selecting the KK-Ay/Ta mouse model, the relationship between hyperuricemia and insulin resistance has been studied to characterize such an animal model. RESULTS: Male type 2 diabetic KK-Ay/Ta and age matched normal C57BL/6J mice were maintained on a basal 20% casein diet for 35 days. Food intake, body weight gain, levels of plasma uric acid, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride in KK-Ay/Ta mice were significantly higher than those in normal mice. Plasma uric acid levels showed significant positive correlations with plasma glucose, insulin, HOMA-IR and triglyceride levels. These results suggest that the KK-Ay/Ta mouse strain is useful for studies on correlation between hyperuricemia and insulin resistance, and for those on effects of foods and their components on the relations. PMID- 29115983 TI - Genetic model misspecification in genetic association studies. AB - OBJECTIVE: The underlying model of the genetic determinant of a trait is generally not known with certainty a priori. Hence, in genetic association studies, a dominant model might be erroneously modelled as additive, an error investigated previously. We explored this question, for candidate gene studies, by evaluating the sample size required to compensate for the misspecification and improve inference at the analysis stage. Power calculations were carried out with (1) the true dominant model and (2) the incorrect additive model. Empirical power, sample size and effect size were compared between scenarios (1) and (2). In each of the scenarios the estimates were evaluated for a rare (minor allele frequency < 0.01), low frequency (0.01 <= minor allele frequency < 0.05) and common (minor allele frequency >= 0.05) single nucleotide polymorphism. RESULTS: The results confirm the detrimental effect of the misspecification error on power and effect size for any minor allele frequency. The implications of the error are not negligible; therefore, candidate gene studies should consider the more conservative sample size to compensate for the effect of error. When it is not possible to extend the sample size, methods that help mitigate the impact of the error should be systematically used. PMID- 29115982 TI - Phage typing or CRISPR typing for epidemiological surveillance of Salmonella Typhimurium? AB - OBJECTIVE: Salmonella Typhimurium is the most dominant Salmonella serovar around the world. It is associated with foodborne gastroenteritis outbreaks but has recently been associated with invasive illness and deaths. Characterization of S. Typhimurium is therefore very crucial for epidemiological surveillance. Phage typing has been used for decades for subtyping of S. Typhimurium to determine the epidemiological relation among isolates. Recent studies however have suggested that high throughput clustered regular interspaced short palindromic repeats (CRISPR) typing has the potential to replace phage typing. This study aimed to determine the efficacy of high-throughput CRISPR typing over conventional phage typing in epidemiological surveillance and outbreak investigation of S. Typhimurium. RESULTS: In silico analysis of whole genome sequences (WGS) of well documented phage types of S. Typhimurium reveals the presence of different CRISPR type among strains belong to the same phage type. Furthermore, different phage types of S. Typhimurium share identical CRISPR type. Interestingly, identical spacers were detected among outbreak and non-outbreak associated DT8 strains of S. Typhimurium. Therefore, CRISPR typing is not useful for the epidemiological surveillance and outbreak investigation of S. Typhimurium and phage typing, until it is replaced by WGS, is still the gold standard method for epidemiological surveillance of S. Typhimurium. PMID- 29115984 TI - Body mass index and thoracic subcutaneous adipose tissue depth: possible implications for adequacy of chest compressions. AB - OBJECTIVE: Adequacy of cardiopulmonary resuscitation relies on compression of the thoracic cage to produce changes in intra-thoracic pressures sufficient to generate a pressure gradient. In order to evaluate the efficacy of cardiopulmonary resuscitation in morbid obesity, it is first necessary to determine the depth of thoracic subcutaneous adipose tissue (SAT) and to correlate this with body mass index (BMI). RESULTS: Computerised-tomography images of the thorax of 55 patients with a diagnosis of obesity or morbid obesity (mean BMI 45.95 kg/m2) were evaluated to determine the depth of SAT at the level at which chest compressions would be applied by a trained rescuer, and correlated with BMI. Mean anterior SAT was 36.53 mm, and mean posterior SAT was 50.73 mm. There was a significant correlation between BMI and anterior and posterior SAT for males (p < 0.05 for both), and females (p < 0.05 for both). The slope of the functions was considered sufficiently close to allow combining the data. This also showed a significant correlation between SAT and BMI (p < 0.01 for both). Both anterior and posterior SAT is correlated with BMI. This data allows development of a model to explore the efficacy of chest compressions in morbid obesity. PMID- 29115985 TI - Use of tuberculin skin test for assessment of immune recovery among previously malnourished children in Ethiopia. AB - OBJECTIVE: To compare levels of immunity in children recovering from severe acute malnutrition (cases) against those of community controls (controls). RESULTS: At baseline children recovering from severe acute malnutrition had lower, mid upper arm circumference (122 mm for cases and 135 mm for controls; p < 0.001), weight for-height Z-score (- 1.0 for cases and - 0.5 for controls; p < 0.001), weight for-age Z-score (- 2.8 for cases and - 1.1 for controls; p < 0.001) and height/length-for-age Z-score (- 3.6 for cases and - 1.4 for controls; p < 0.001), than controls. Age and gender matched community controls. At baseline, prevalence of a positive tuberculin skin test, assessed by cutaneous delayed-type hypersensitivity reaction skin test, was very low in both cases (3/93 = 3.2%) and controls (2/94 = 2.1%) and did not significantly increase at 6 months follow up (6/86 = 7.0% in cases and 3/84 = 3.4% in controls). The incidences of common childhood morbidities, namely fever, diarrhoea and cough, were 1.7-1.8 times higher among cases than controls. In conclusion, these results show that tuberculin skin test does not enable any conclusive statements regarding the immune status of patients following treatment for severe acute malnutrition. The increased incidence of infection in cases compared to controls suggests persistence of lower resistance to infection even after anthropometric recovery is achieved. PMID- 29115986 TI - The breaking and making of healthy adult human skeletal muscle in vivo. AB - BACKGROUND: While muscle regeneration has been extensively studied in animal and cell culture models, in vivo myogenesis in adult human skeletal muscle has not been investigated in detail. METHODS: Using forced lengthening contractions induced by electrical stimulation, we induced myofibre injury in young healthy males. Muscle biopsies were collected from the injured leg 7 and 30 days after muscle injury and from the uninjured leg as a control. Immuno-stained single muscle fibres and muscle cross sections were studied by wide-field and confocal microscopy. Samples were also studied at the ultra-structural level by electron microscopy. RESULTS: Microscopy of single muscle fibres in 3 dimensions revealed a repeating pattern of necrotic and regenerating zones along the length of the same myofibre, characterised by extensive macrophage infiltration alongside differentiating myogenic progenitor cells and myotubes: the hallmarks of myogenesis. The myofibre basement membrane was preserved during these processes and interestingly was seen at a later stage as a second basement membrane surrounding the regenerating fibres. CONCLUSIONS: This is the first work to document in vivo myogenesis in humans in detail and highlights the importance of the basement membrane in the process of regeneration. In addition, it provides insight into parallels between the regeneration of adult skeletal muscle in mouse and man, confirming that this model may be a useful tool in investigating myofibre and matrix formation, as well as specific cell types, during regeneration from the perspective of human muscle. PMID- 29115988 TI - Prevalence and determinants of pulmonary hypertension in a group of Cameroonian patients without chronic lung disease: a cross-sectional echocardiographic study. AB - OBJECTIVE: To study prevalence and determinants of pulmonary hypertension (PH) in a group of Cameroonian patients without chronic lung disease. We conducted a cross-sectional study conducted between April and December 2011 in a private cardiology clinic in Bafoussam, Cameroon. We included consenting participants aged >= 18, who underwent a Doppler echocardiography. Patients with chronic lung disease were excluded. RESULTS: A total of 178 participants were enrolled, of whom 44.4% were males with a mean age of 63.1 +/- 17.3 years. The prevalence of PH was 25.3%. Among patients with PH 44.4% had severe disease, (11.2% of study population). Age >= 55 years, systolic blood pressure >= 140 mmHg, low left ventricular ejection fraction (< 55%), left atrial enlargement, left ventricular hypertrophy and presence of left heart disease (left ventricular hypertrophy with systolic dysfunction and left atrial enlargement) were predictors of echocardiography PH. Obesity was negatively associated with pulmonary hypertension. Pulmonary hypertension is found in a quarter of the participants. Age, systolic hypertension, and any left heart disease were strongly associated to pulmonary hypertension. PMID- 29115987 TI - Cancer cell-soluble factors reprogram mesenchymal stromal cells to slow cycling, chemoresistant cells with a more stem-like state. AB - BACKGROUND: Mesenchymal stem cells (MSCs) play different roles in modulating tumor progression, growth, and metastasis. MSCs are recruited to the tumor site in large numbers and subsequently have an important microenvironmental role in modulating tumor progression and drug sensitivity. However, the effect of the tumor microenvironment on MSC plasticity remains poorly understood. Herein, we report a paracrine effect of cancer cells, in which they secrete soluble factors that promote a more stem-like state in bone marrow mesenchymal stem cells (BM MSCs). METHODS: The effect of soluble factors secreted from MCF7, Hela, and HepG2 cancer cell lines on BM-MSCs was assessed using a Transwell indirect coculture system. After 5 days of coculture, BM-MSCs were characterized by flow cytometry for surface marker expression, by qPCR for gene expression profile, and by confocal immunofluorescence for marker expression. We then measured the sensitivity of cocultured BM-MSCs to chemotherapeutic agents, their cell cycle profile, and their response to DNA damage. The sphere formation, invasive properties, and in-vivo performance of BM-MSCs after coculture with cancer cells were also measured. RESULTS: Indirect coculture of cancer cells and BM-MSCs, without direct cell contact, generated slow cycling, chemoresistant spheroid stem cells that highly expressed markers of pluripotency, cancer cells, and cancer stem cells (CSCs). They also displayed properties of a side population and enhanced sphere formation in culture. Accordingly, these cells were termed cancer induced stem cells (CiSCs). CiSCs showed a more mesenchymal phenotype that was further augmented upon TGF-beta stimulation and demonstrated a high expression of the beta-catenin pathway and ALDH1A1. CONCLUSIONS: These findings demonstrate that MSCs, recruited to the tumor microenvironment in large numbers, may display cellular plasticity, acquire a more stem-like state, and acquire some properties of CSCs upon exposure to cancer cell-secreted factors. These acquired characteristics may contribute to tumor progression, survival, and metastasis. Our findings provide new insights into the interactions between MSCs and cancer cells, with the potential to identify novel molecular targets for cancer therapy. PMID- 29115989 TI - Clusterin protects neurons against intracellular proteotoxicity. AB - It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physical relocation remain unknown. We have examined in this study whether or not increased expression of clusterin is able to protect neuronal cells against intracellular protein aggregation and cytotoxicity, characteristics that are strongly implicated in a range of neurodegenerative diseases. We used the amyotrophic lateral sclerosis associated protein TDP-43 as a primary model to investigate the effects of clusterin on protein aggregation and neurotoxicity in complementary in vitro, neuronal cell and Drosophila systems. We have shown that clusterin directly interacts with TDP-43 in vitro and potently inhibits its aggregation, and observed that in ER stressed neuronal cells, clusterin co-localized with TDP-43 and specifically reduced the numbers of cytoplasmic inclusions. We further showed that the expression of TDP-43 in transgenic Drosophila neurons induced ER stress and that co-expression of clusterin resulted in a dramatic clearance of mislocalized TDP-43 from motor neuron axons, partially rescued locomotor activity and significantly extended lifespan. We also showed that in Drosophila photoreceptor cells, clusterin co-expression gave ER stress-dependent protection against proteotoxicity arising from both Huntingtin-Q128 and mutant (R406W) human tau. We therefore conclude that increased expression of clusterin can provide an important defense against intracellular proteotoxicity under conditions that mimic specific features of neurodegenerative disease. PMID- 29115990 TI - DHCR24 exerts neuroprotection upon inflammation-induced neuronal death. AB - BACKGROUND: DHCR24, involved in the de novo synthesis of cholesterol and protection of neuronal cells against different stress conditions, has been shown to be selectively downregulated in neurons of the affected brain areas in Alzheimer's disease. METHODS: Here, we investigated whether the overexpression of DHCR24 protects neurons against inflammation-induced neuronal death using co cultures of mouse embryonic primary cortical neurons and BV2 microglial cells upon acute neuroinflammation. Moreover, the effects of DHCR24 overexpression on dendritic spine density and morphology in cultured mature mouse hippocampal neurons and on the outcome measures of ischemia-induced brain damage in vivo in mice were assessed. RESULTS: Overexpression of DHCR24 reduced the loss of neurons under inflammation elicited by LPS and IFN-gamma treatment in co-cultures of mouse neurons and BV2 microglial cells but did not affect the production of neuroinflammatory mediators, total cellular cholesterol levels, or the activity of proteins linked with neuroprotective signaling. Conversely, the levels of post synaptic cell adhesion protein neuroligin-1 were significantly increased upon the overexpression of DHCR24 in basal growth conditions. Augmentation of DHCR24 also increased the total number of dendritic spines and the proportion of mushroom spines in mature mouse hippocampal neurons. In vivo, overexpression of DHCR24 in striatum reduced the lesion size measured by MRI in a mouse model of transient focal ischemia. CONCLUSIONS: These results suggest that the augmentation of DHCR24 levels provides neuroprotection in acute stress conditions, which lead to neuronal loss in vitro and in vivo. PMID- 29115991 TI - Evaluation of the Deki ReaderTM, an automated RDT reader and data management device, in a household survey setting in low malaria endemic southwestern Uganda. AB - BACKGROUND: Early diagnosis of suspected malaria cases with a rapid diagnostic test (RDT) has been shown to be an effective malaria control tool used in many resource-constrained settings. However, poor quality control and quality assurance hinder the accurate reporting of malaria diagnoses. Recent use of a portable, battery operated RDT reader (Deki ReaderTM, Fio Corporation) has shown to have high agreement with visual inspection across diverse health centre settings, however evidence of its feasibility and usability during cross sectional surveys are limited. This study aimed to evaluate the performance of the Deki ReaderTM in a cross-sectional survey of children from southwestern Uganda. METHODS: A two-stage, stratified cluster sampling survey was conducted between July and October 2014 in three districts of southwestern Uganda, with varying malaria transmission intensities. A total of 566 children aged 6-59 months were included in the analysis. Blood samples were collected and tested for malaria using: the SD Bioline Malaria Ag Pf/Pan RDT and microscopy. Results were compared between visual inspection of the RDT and by the Deki ReaderTM. Diagnostic performance of both methods were compared to gold-standard microscopy. RESULTS: The sensitivity and specificity of the Deki ReaderTM was 94.1% (95% CI 69.2-99.6%) and 95.6% (95% CI 93.4-97.1%), respectively. The overall percent agreement between the Deki ReaderTM and visual RDT inspection was 98.9% (95% CI 93.2-99.8), with kappa statistic of 0.92 (95% CI 0.85-0.98). CONCLUSIONS: The findings from this study suggest that the Deki ReaderTM is comparable to visual inspection and performs well in detecting microscopy-positive Plasmodium falciparum cases in a household survey setting. However, the reader's performance was highly dependent on ensuring adequate battery life and a work environment free of dirt particles. PMID- 29115992 TI - Role of mHealth applications for improving antenatal and postnatal care in low and middle income countries: a systematic review. AB - BACKGROUND: From 1990 to 2015, the number of maternal deaths globally has dropped by 43%. Despite this, progress in attaining MDG 5 is not remarkable in LMICs. Only 52% of pregnant women in LMICs obtain WHO recommended minimum of four antenatal consultations and the coverage of postnatal care is relatively poor. In recent years, the increased cellphone penetration has brought the potential for mHealth to improve preventive maternal healthcare services. The objective of this review is to assess the effectiveness of mHealth solutions on a range of maternal health outcomes by categorizing the interventions according to the types of mHealth applications. METHODS: Three international online electronic databases were searched between January 1, 2000 and January 25, 2016 to identify studies exploring the role of mHealth solutions in improving preventive maternal healthcare services. Of 1262 titles screened after duplication, 69 potentially relevant abstracts were obtained. Out of 69 abstracts, 42 abstracts were shortlisted. Full text of 42 articles was reviewed using data extraction sheet. A total of 14 full text studies were included in the final analysis. RESULTS: The 14 final studies were categorized in to five mHealth applications defined in the conceptual framework. Based on our analysis, the most reported use of mHealth was for client education and behavior change communication, such as SMS and voice reminders [n = 9, 65%]. The categorization provided the understanding that much work have been done on client education and behavior change communication. Most of the studies showed that mHealth interventions have proven to be effective to improve antenatal care and postnatal care services, especially those that are aimed at changing behavior of pregnant women and women in postnatal period. However, little evidence exists on other type of mHealth applications. CONCLUSION: This review suggests that mHealth solutions targeted at pregnant women and women in postnatal period can improve preventive maternal healthcare services. However, there is a need to conduct more controlled-trials and quasi experimental studies to strengthen the literature in this research area. The review recommends that mHealth researchers, sponsors, and publishers should prioritize the transparent reporting of interventions to allow effective interpretation of extracted data. PMID- 29115993 TI - Adjudin-preconditioned neural stem cells enhance neuroprotection after ischemia reperfusion in mice. AB - BACKGROUND: Transplantation of neural stem cells (NSCs) has been proposed as a promising therapeutic strategy for the treatment of ischemia/reperfusion (I/R) induced brain injury. However, existing evidence has also challenged this therapy on its limitations, such as the difficulty for stem cells to survive after transplantation due to the unfavorable microenvironment in the ischemic brain. Herein, we have investigated whether preconditioning of NSCs with adjudin, a small molecule compound, could enhance their survivability and further improve the therapeutic effect for NSC-based stroke therapy. METHOD: We aimed to examine the effect of adjudin pretreatment on NSCs by measuring a panel of parameters after their transplantation into the infarct area of ipsilateral striatum 24 hours after I/R in mice. RESULTS: We found that pretreatment of NSCs with adjudin could enhance the viability of NSCs after their transplantation into the stroke induced infarct area. Compared with the untreated NSC group, the adjudin preconditioned group showed decreased infarct volume and neurobehavioral deficiency through ameliorating blood-brain barrier disruption and promoting the expression and secretion of brain-derived neurotrophic factor. We also employed H2O2-induced cell death model in vitro and found that adjudin preconditioning could promote NSC survival through inhibition of oxidative stress and activation of Akt signaling pathway. CONCLUSION: This study showed that adjudin could be used to precondition NSCs to enhance their survivability and improve recovery in the stroke model, unveiling the value of adjudin for stem cell-based stroke therapy. PMID- 29115995 TI - Developing a systems-based framework of the factors influencing dietary and physical activity behaviours in ethnic minority populations living in Europe - a DEDIPAC study. AB - BACKGROUND: Some ethnic minority populations have a higher risk of non communicable diseases than the majority European population. Diet and physical activity behaviours contribute to this risk, shaped by a system of inter-related factors. This study mapped a systems-based framework of the factors influencing dietary and physical activity behaviours in ethnic minority populations living in Europe, to inform research prioritisation and intervention development. METHODS: A concept mapping approach guided by systems thinking was used: i. Preparation (protocol and terminology); ii. Generating a list of factors influencing dietary and physical activity behaviours in ethnic minority populations living in Europe from evidence (systematic mapping reviews) and 'eminence' (89 participants from 24 academic disciplines via brainstorming, an international symposium and expert review) and; iii. Seeking consensus on structuring, rating and clustering factors, based on how they relate to each other; and iv. Interpreting/utilising the framework for research and interventions. Similar steps were undertaken for frameworks developed for the majority European population. RESULTS: Seven distinct clusters emerged for dietary behaviour (containing 85 factors) and 8 for physical activity behaviours (containing 183 factors). Four clusters were similar across behaviours: Social and cultural environment; Social and material resources; Psychosocial; and Migration context. Similar clusters of factors emerged in the frameworks for diet and physical activity behaviours of the majority European population, except for 'migration context'. The importance of factors across all clusters was acknowledged, but their relative importance differed for ethnic minority populations compared with the majority population. CONCLUSIONS: This systems-based framework integrates evidence from both expert opinion and published literature, to map the factors influencing dietary and physical activity behaviours in ethnic minority groups. Our findings illustrate that innovative research and complex interventions need to be developed that are sensitive to the needs of ethnic minority populations. A systems approach that encompasses the complexity of the inter-related factors that drive behaviours may inform a more holistic public health paradigm to more effectively reach ethnic minorities living in Europe, as well as the majority host population. PMID- 29115996 TI - Serological evidence of equine arteritis virus infection and phylogenetic analysis of viral isolates in semen of stallions from Serbia. AB - BACKGROUND: Equine arteritis virus (EAV) is responsible for infections in equids. It can spread easily within the horse population and has a major impact on the horse breeding industry. No EAV outbreak has ever been reported in Serbia. To determine whether EAV is nonetheless circulating there, especially in the Vojvodina region, 340 horse serum samples were subjected to serology testing to detect EAV antibodies. In parallel, semen samples from three seropositive stallions were collected to evaluate their EAV status, using RT-qPCR and virus isolation on cell culture. RESULTS: Horse sera with EAV antibodies represented 15.88% (54/340) of the tested samples, 83.23% (283/340) being negative, and just three samples (0.89%) being uninterpretable due to cytotoxicity. Only 7.2% (10/138) of horses kept by private owners on their own property were seropositive for EAV, whereas 21.8% (44/202) of horses kept on stud farms had EAV antibodies. Phylogenetic analysis showed that the Serbian EAV isolate was most closely related to isolates from the neighbouring Hungary. CONCLUSIONS: EAV is circulating in the Serbian horse population, especially among the breeding population certainly due to the use of EAV shedder stallions since there is no surveillance programme in Serbia and only limited checks on racehorses. Moreover, phylogenetic analysis indicates that the EAV isolated from a Lipizzaner stallion in Serbia is closely related to isolates from Hungary, and together form a new cluster. PMID- 29115994 TI - Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study). AB - BACKGROUND: It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. METHODS/DESIGN: This study is a multicentre prospective non randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. DISCUSSION: By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants. PMID- 29115997 TI - Psychological symptoms among hospital nurses in Taiwan: a cross sectional study. AB - BACKGROUND: A considerable number of studies have identified the risk factors attributable to job-related stress among nurses. However, studies investigating psychological symptoms among hospital nurses is still lacking, especially in Taiwan, where the average patient to nurse ratio is among the highest in the world. This study aimed to investigate the potential role of self-rated health status, self-reported diseases, and utilization of occupational health checks in psychological symptoms among Taiwanese nurses. METHODS: A cross-sectional design was conducted from September through December 2013. Data were collected through online self-administered questionnaire among 697 registered nurses in seven regional hospitals governed by the Taipei City Government. RESULTS: Nurses with fair or poor self-rated health, lower education, <30 years of age, and low back pain were more likely to suffer from psychological symptoms. A trend toward significance was also noticed for those aged 30-39. Importantly, low back pain was the most common disease among nurses in self-reported diseases and half of the nurses reported not utilizing the occupational health examination for the last 5 years. CONCLUSIONS: To alleviate or prevent the psychological symptoms, psychosocial support, and awareness program on prevention of occupational injuries should be offered to nurses younger than 39 years old and having lower educational levels. Moreover, underutilization of occupational health examination among nurses deserves more attention. PMID- 29115998 TI - Effect of gastric acid-suppressive therapy and biological variation of serum gastrin concentrations in dogs with chronic enteropathies. AB - BACKGROUND: Serum gastrin concentration can help diagnose gastrinomas in dogs if >3-10* the upper reference limit (URL), but antisecretory therapy and other conditions can also cause hypergastrinemia. Effects of antisecretory therapy (famotidine or ranitidine, omeprazole) on serum gastrin concentration in dogs with chronic enteropathy (CE) and its biological variation (BV) are unknown. Aim of the study was to evaluate serum gastrin in acid-suppressant-treated or -naive CE dogs; test the association between serum gastrin and histopathologic findings in acid-suppressant-naive CE dogs; and evaluate the BV of serum gastrin in dogs not receiving any gastric acid suppressive therapy. Samples from 231 dogs were used and serum gastrin was measured by chemiluminescence assay. Gastric and duodenal histologic lesions were evaluated and graded. BV of serum gastrin was evaluated in serial samples. RESULTS: Serum gastrin concentrations were significantly higher in acid-suppressant-treated than acid-suppressant-naive dogs (P = 0.0245), with significantly higher concentrations in proton pump inhibitor (PPI)- than H2-antihistamine-treated patients (P = 0.0053). More PPI- than H2 antihistamine-treated dogs had gastrin concentrations above URL (P = 0.0205), but not >3* nor >10* the URL. Serum gastrin concentrations correlated with the severity of gastric antral epithelial injury (P = 0.0069) but not with any other lesions or the presence/numbers of spiral bacteria in gastric biopsies. Intra- and inter-individual BV were 43.4 and 21.6%, respectively, in acid-suppressant naive dogs, with a reciprocal individuality index of 0.49 and a critical difference of >=29.5 ng/L. CONCLUSIONS: Antisecretory (particularly PPI) treatment leads to hypergastrinemia in CE dogs, but the concentrations seen in this study are unlikely to compromise a diagnosis of gastrinoma. Use of a population-based URL for canine serum gastrin and a URL of <=27.8 ng/L are appropriate. PMID- 29115999 TI - Screening a protein kinase inhibitor library against Plasmodium falciparum. AB - BACKGROUND: Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interest to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets. RESULTS: As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described. DISCUSSION: This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation. CONCLUSIONS: Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library. PMID- 29116000 TI - Effect of mouthrinses on color stability of monolithic zirconia and feldspathic ceramic: an in vitro study. AB - BACKGROUND: Patients susceptible to periodontal disease and dental caries, including those who undergo fixed prosthodontic treatments use chemical plaque control agents. However, these mouthrinses may result in adverse effects such as discoloration of the restorative materials. The aim of this study was to compare the color stability of monolithic zirconia and feldspathic porcelain after immersion in two different mouthrinses: 0.2% Chlorhexidine digluconate (CHX), or Listerine(r). Color change was evaluated by color spectrophotometer and according to the Commission Internationale de l'Eclairage (CIELab) system. METHODS: We prepared 72 disc-shaped porcelains (n = 36) as follows: Group A consisted of dental direkt cube X2 discs (49% translucency) as the monolithic zirconia and group B consisted of VITA VMK 95 as a feldspathic porcelain. Groups A and B were divided into three subgroups (n = 12 per group). Each subgroup was immersed in one of the following three solutions: distilled water (control), CHX, or Listerine(r) for 2 min, once per day. We recorded the samples' baseline color values according to the CIELab system by using a color spectrophotometer operated by an experienced operator. Color measurements were subsequently obtained following 7 days of immersion, and after the samples were rinsed with distilled water and allowed to dry. We measured CIE L*, a*, and b*and calculated the color difference (DeltaE*ab). All data were analyzed by the Mann-Whitney and Kruskal Wallis tests. RESULTS: Color changes occurred in the experimental groups. The DeltaE*ab values were significantly greater in VMK 95 porcelain compared to cube X2 (both p < 0.001) following immersion in CHX and Listerine(r) mouthrinses. However no significant difference was founded when distilled water was used (p = 0.630). For the two materials, the DeltaE values were highest in CHX, followed by the Listerine(r) and distilled water. CONCLUSION: Both monolithic zirconia and feldspathic porcelain were susceptible to color changes following immersion in CHX and Listerine(r) mouthrinses. PMID- 29116001 TI - High intensity, short duration pulling in heavy horses: physiological effects of competition and rapid weight change. AB - BACKGROUND: The Heavy Horse Pull is a competition where teams of two horses pull an increasingly heavy sled for a short distance. Similar to human wrestlers, some horses may undergo rapid weight change in order to enter a lower weight category. The objectives were to study the physiological effects of this practice as well as of the pulling competition in draft horses. RESULTS: Fifty horses were divided into light-, middle- and heavyweight categories based on their arrival weights and competed 1-3 days after. Body weight was measured upon arrival and pre competition. Blood was sampled for chemistry and high sensitivity cardiac troponin T (hscTnT) at arrival, pre- and post-competition in 34, 26 and 20 horses, respectively. Body weight increased significantly between arrival and pre competition for light (7.2% (Median: 62.8Kg (41.7-77.0)) and middle (8.6% (Median: 80.5Kg (62.7-90.9)) weight categories. Change in body weight was correlated (r = 0.69, p = 0.002) with competition ranking for middleweights. The ratios of weight pulled to team body weight were 2.7 (1.9-2.8), 2.6 (2.5-2.6) and 2.4 (2.2-2.5) for the lightweights, middleweights and heavyweights, respectively. Blood chemistry indicated hemoconcentration on arrival in the middleweight and lightweight horses. Hemoconcentration was not seen on arrival in some horses with marked rapid weight change. Overall, no chemistry parameter changed between pre- and post-competition. The hscTnT stayed within normal range post-competition. CONCLUSIONS: While horses arrived to the event with indications of hemoconcentration, they appeared to have sufficient time to rehydrate prior to competition, and the effects of the competition were reversible within 3 h. PMID- 29116002 TI - Ice-associated norovirus outbreak predominantly caused by GII.17 in Taiwan, 2015. AB - BACKGROUND: On 5 March 2015, Taiwan Centers for Disease Control was notified of more than 200 students with gastroenteritis at a senior high school during excursion to Kenting. We conducted an outbreak investigation to identify the causative agent and possible vehicle of the pathogen. METHODS: We conducted a retrospective cohort study by using a structured questionnaire to interview all students for consumed food items during their stay at the resort. Students were defined as a gastroenteritis case while having vomiting or diarrhea after the breakfast on 4 March. We inspected the environment to identify possible contamination route. We collected stool or vomitus samples from ill students, food handlers and environmental specimens for bacterial culture for common enteropathogens, reverse transcription polymerase chain reaction (RT-PCR) for norovirus and enzyme-linked immunosorbent assay (ELISA) for rotavirus. Norovirus PCR-positive products were then sequenced and genotyped. RESULTS: Of 267 students enrolled, 144 (54%) met our case definition. Regression analysis revealed elevated risk associated with iced tea, which was made from tea powder mixed with hot water and self-made ice (risk ratio 1.54, 95% confidence interval 1.22-1.98). Ice used for beverages, water before and after water filter of the ice machine and 16 stool and vomitus samples from ill students were tested positive for norovirus; Multiple genotypes were identified including GI.2, GI.4 and GII.17. GII.17 was the predominant genotype and phylogenetic analyses showed that noroviruses identified in ice, water and human samples were clustered into the same genotypes. Environmental investigation revealed the ice was made by inadequate-filtered and un-boiled water. CONCLUSIONS: We identified the ice made by norovirus-contaminated un-boiled water caused the outbreak and the predominant genotype was GII.17. Adequately filtered or boiled water should be strongly recommended for making ice to avoid possible contamination. PMID- 29116003 TI - Protocols on classification, monitoring and therapy in children's rheumatology (PRO-KIND): results of the working group Polyarticular juvenile idiopathic arthritis. AB - OBJECTIVE: Several effective pharmacologic treatment options for polyarticual juvenile idiopathic arthritis (JIA) have emerged but initial treatment is heterogeneous in Germany. Therefore, the German Society of Pediatric Rheumatolgy has established a commission to develop consensus "Protocols on classification, monitoring and therapy in children's rheumatology (PRO-KIND)" to harmonize diagnostic and treatment approaches for new-onset JIA in Germany. METHODS: A set of definitions for in- and exclusion, diagnostic workup, parameters for the evaluation of disease activity criteria, therapeutic options, medication dosing, monitoring recommendations, targets, definitions of a therapy failure and four therapeutic algorithms developed by a working group were agreed by web based survey to which all members of the GKJR have been invited. A final protocol with 4 consensus treatment plans (CTP) was agreed in a face-to-face consensus conferences employing modified nominal group technique. RESULTS: The initial 17 definitions and recommendations for new-onset polyarticular JIA agreed by the working group reached >80% agreement in a web survey in 68 German paediatric rheumatologist. Four CTPs were developed based on treatment strategies for the first 12 months of therapy, as well as definitions for clinical and laboratory monitoring. The CTPs include a step-up plan (nonbiologic Disease-modifying antirheumatic drug [DMARD] followed by a biologic), a combination plan (combination of nonbiologic and biologic after failure of initial DMARD), an intensive pulse corticosteroid scheme in parallel with a DMARD followed by combination therapy and a multiple corticosteroids joint injections strategy in a treat to target approach. Step up will be guided by a treat to target strategy to reach a JADAS-improvement at month 3, acceptable disease at month 6 or 9 and JADAS remission or at least JADAS minimal disease activity at month 12. CONCLUSION: Standardized baseline work-up, disease activity evaluation and a definition of a treat to target approach will result in better health outcomes for polyarticular JIA patients. Four CTPs were developed for new-onset polyarticular JIA, which coupled with data collection at defined intervals will be evaluated and improved to optimize management of polyarticular JIA. Harmonization of treatment will be the basis for future comparative effectiveness research. PMID- 29116005 TI - Composite intestinal adenoma-microcarcinoid in the colon and rectum: a case series and historical review. AB - BACKGROUND: Composite intestinal adenoma-microcarcinoid (CIAM) is a rare colorectal lesion that mostly comprises a conventional adenomatous component with a minute proportion of neuroendocrine (NE) component. Although microcarcinoids are well-recognized in the setting of chronic inflammatory disorders of the gastrointestinal tract, large intestinal microcarcinoids associated with intestinal adenoma are exceedingly rare and their clinicopathologic characteristics are yet to be elucidated. This study was performed to clarify their clinicopathologic characteristics and to review the relevant literature. METHODS: In total, 24 cases of CIAM in which tumors were excised endoscopically (n = 22) or surgically (n = 2) were retrieved from the Department of Pathology, Daehang Hospital. We analyzed their clinicopathologic characteristics and performed immunohistochemical staining for NE markers to determine their endocrine nature. RESULTS: CIAM usually developed in middle-aged and elderly patients, with a mean age of 62.0 years (range, 44-81 years). Thirteen patients were men and 11 were women, indicating a nearly equal sex ratio. Unlike classic carcinoid tumors, CIAMs occurred mostly in the colon (83.3% of cases), particularly in the proximal colon. Histologically, the microcarcinoid component consisted of low-grade NE cells arranged in small nests, glands or cords interspersed with glandular elements or less frequently resembled squamous morules. There was no expansile nodular or organoid growth pattern, which is typical of carcinoid tumors. The microcarcinoids were 1-20 mm in size (mean size, 4.7 mm) and were mostly situated in the basal lamina propria with no submucosal layer involvement; none showed desmoplastic reaction or increased proliferative activity. Follow-up data (mean, 23.1 months) were available for 18 patients; all patients are alive and well. CONCLUSIONS: To the best of our knowledge, ours is the largest series of patients with CIAM in the English-language literature. Microcarcinoids found in CIAMs appear to show favorable clinical outcomes regardless of their size, likely due to the absence of submucosal extension and/or increased proliferative activity. We recommend avoiding additional radical surgeries in patients who have endoscopically undergone complete CIAM excision unless they exhibit ominous histologic features such as submucosal extension or increased proliferative activity. PMID- 29116006 TI - Analysis of near infrared spectra for age-grading of wild populations of Anopheles gambiae. AB - BACKGROUND: Understanding the age-structure of mosquito populations, especially malaria vectors such as Anopheles gambiae, is important for assessing the risk of infectious mosquitoes, and how vector control interventions may impact this risk. The use of near-infrared spectroscopy (NIRS) for age-grading has been demonstrated previously on laboratory and semi-field mosquitoes, but to date has not been utilized on wild-caught mosquitoes whose age is externally validated via parity status or parasite infection stage. In this study, we developed regression and classification models using NIRS on datasets of wild An. gambiae (s.l.) reared from larvae collected from the field in Burkina Faso, and two laboratory strains. We compared the accuracy of these models for predicting the ages of wild caught mosquitoes that had been scored for their parity status as well as for positivity for Plasmodium sporozoites. RESULTS: Regression models utilizing variable selection increased predictive accuracy over the more common full spectrum partial least squares (PLS) approach for cross-validation of the datasets, validation, and independent test sets. Models produced from datasets that included the greatest range of mosquito samples (i.e. different sampling locations and times) had the highest predictive accuracy on independent testing sets, though overall accuracy on these samples was low. For classification, we found that intramodel accuracy ranged between 73.5-97.0% for grouping of mosquitoes into "early" and "late" age classes, with the highest prediction accuracy found in laboratory colonized mosquitoes. However, this accuracy was decreased on test sets, with the highest classification of an independent set of wild-caught larvae reared to set ages being 69.6%. CONCLUSIONS: Variation in NIRS data, likely from dietary, genetic, and other factors limits the accuracy of this technique with wild-caught mosquitoes. Alternative algorithms may help improve prediction accuracy, but care should be taken to either maximize variety in models or minimize confounders. PMID- 29116004 TI - Reproductive profiles and risk of breast cancer subtypes: a multi-center case only study. AB - BACKGROUND: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. METHODS: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. RESULTS: Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16-1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01-2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45-1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70-0.88, p < 0.0001), but this effect was not apparent at a later FFTP. CONCLUSIONS: Our main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC. PMID- 29116007 TI - Prevalence of Bartonella spp. by culture, PCR and serology, in veterinary personnel from Spain. AB - BACKGROUND: The genus Bartonella includes fastidious, facultative intracellular bacteria mainly transmitted by arthropods and distributed among mammalian reservoirs. Bartonella spp. implicated as etiological agents of zoonoses are increasing. Apart from the classical Bartonella henselae, B. bacilliformis or B. quintana, other species (B. elizabethae, B. rochalimae, B. vinsonii arupensis and B. v. berkhoffii, B. tamiae or B. koehlerae, among others) have also been associated with human and/or animal diseases. Laboratory techniques for diagnosis (culture, PCR assays and serology) usually show lack of sensitivity. Since 2005, a method based on a liquid enrichment Bartonella alphaproteobacteria growth medium (BAPGM) followed by PCRs for the amplification of Bartonella spp. has been developed. We aimed to assess culture, molecular and serological prevalence of Bartonella infections in companion animal veterinary personnel from Spain. METHODS: Each of 89 participants completed a questionnaire. Immunofluorescence assays (IFA) using B. vinsonii berkhoffii (genotypes I, II and III), B. henselae, B. quintana and B. koehlerae as antigens were performed. A cut-off of 1:64 was selected as a seroreactivity titer. Blood samples were inoculated into BAPGM and subcultured onto blood agar plates. Bartonella spp. was detected using conventional and quantitative real-time PCR assays and DNA sequencing. RESULTS: Among antigens corresponding to six Bartonella spp. or genotypes, the lowest seroreactivity was found against B. quintana (11.2%) and the highest, against B. v. berkhoffii genotype III (56%). A total of 27% of 89 individuals were not seroreactive to any test antigen. Bartonella spp. IFA seroreactivity was not associated with any clinical sign or symptom. DNA from Bartonella spp., including B. henselae (n = 2), B. v. berkhoffii genotypes I (n = 1) and III (n = 2), and B. quintana (n = 2) was detected in 7/89 veterinary personnel. PCR and DNA sequencing findings were not associated with clinical signs or symptoms. No co infections were observed. One of the two B. henselae PCR-positive individuals was IFA seronegative to all tested antigens whereas the other one was not B. henselae seroreactive. The remaining PCR-positive individuals were seroreactive to multiple Bartonella spp. antigens. CONCLUSIONS: High serological and molecular prevalences of exposure to, or infection with, Bartonella spp. were found in companion animal veterinary personnel from Spain. More studies using BAPGM enrichment blood culture and PCR are needed to clarify the finding of Bartonella PCR-positive individuals lacking clinical symptoms. PMID- 29116008 TI - Evaluation of an open source method for calculating physical activity in dogs from harness and collar based sensors. AB - BACKGROUND: The ability to make objective measurements of physical activity in dogs has both clinical and research applications. Accelerometers offer a non intrusive and convenient solution. Of the commercialy available sensors, measurements are commonly given in manufacturer bespoke units and calculated with closed source approaches. Furthermore, the validation studies that exist for such devices are mounting location dependant, not transferable between brands or not suitable for handling modern raw accelerometry type data. METHODS: This paper describes a validation study of n = 5 where 4 sensors were placed on each dog; 2 on a harness and 2 on a collar. Each position held two sensors from different manufacturers; Actigraph (which has previously been validated for use on the collar) and VetSens (which provides un-filtered accelerometry data). The aims of the study was to firstly evaluate the performance of an open-design method of converting raw accelerometry data into units that have previously been validated. Secondly, comparison was made between sensors mounted at each location for determining physical activity state. RESULTS: Once the raw actigraphy data had been processed with the open-design method, results from a 7 day measurement revealed no significant difference in physical activity estimates via a cutpoint approach between the sensor manufacturers. A second finding was a low inter-site variability between the ventral collar and dorsal harness locations (Pearsons r2 = 0.96). CONCLUSIONS: Using the open-design methodology, raw, un-filtered data from the VetSens sensors can be compared or pooled with data gathered from Actigraph sensors. The results also provide strong evidence that ventral collar and dorsal harness sites may be used interchangeably. This enables studies to be designed with a larger inclusion criteria (encompassing dogs that are not well suited for wearing an instrumented collar) and ensures high levels of welfare while maintaining measurement validity. PMID- 29116009 TI - Lack of cytomegalovirus detection in human glioma. AB - Gliomas are the most common brain tumors and include a variety of histologic types and grades of malignancy. They arise from glial cells and represent approximately 70% of the primary brain tumors. According to the criteria of the World Health Organization (WHO), the majority of gliomas can be classified into four grades of malignancy (I-IV). Virus infection, especially by DNA viruses and retroviruses, which may cause insertion of viral DNA sequences into the host genome, often triggers the host defense mechanisms. Particularly, the DNA methylation machinery can be activated to cause the methylation of foreign movable viral sequences and, therefore, silence viral gene expression. Several studies have shown the presence of Human Cytomegalovirus (HCMV) in glioblastoma, suggesting that the virus may participate in tumor pathogenesis. But this relationship is controversial because many other studies did not detect HCMV in these tumors. This study aims to detect the presence of HCMV in several samples of human glioma (94 formalin-fixed, paraffin-embedded samples and 28 snap-frozen samples) by different sensitive techniques. We have been unable to detect HCMV DNA and proteins in glioma samples. Therefore, arguments used so far to conclude that HCMV is an oncomodulator virus in gliomas must be, in our view, seriously reconsidered. PMID- 29116010 TI - Multi-drug resistance and extended spectrum beta lactamase producing Gram negative bacteria from chicken meat in Bharatpur Metropolitan, Nepal. AB - OBJECTIVE: Multidrug resistance (MDR) and extended spectrum beta lactamase (ESBL) producer Gram negative bacteria are considered as a major health problem, globally. ESBL enzyme hydrolyses the beta lactam ring of third generation cephalosporins, which alters the structure of the antibiotic. Due to the modification in structure of the antibiotic, bacteria show resistance to these antibiotics. Resistant bacterial strains are transmitted to humans from animals through consumption of uncooked meat, through contact with uncooked meat and meat surfaces. This study aims to assess bacteriological profile and analyze the situation of antibiotic resistance, multidrug resistance, and ESBL producing Gram negative bacteria in chicken meat. RESULTS: A total of 38 chicken meat samples were studied in which 103 Gram negative bacteria were isolated. Species of Gram negative bacteria were identified as Citrobacter spp. (44.7%), Salmonella spp. (26.2%), Proteus spp. (18.4%), Escherichia coli (4.8%), Shigella spp. (3.9%), Pseudomonas spp. (1.9%), and Klebsiella spp. (1.0%). The prevalence of MDR isolates was found to be 79.6%. Total ESBL producer was 36.9% and ESBL producer among MDR was 34.9%. This concludes wide range of antibiotic resistance bacteria is prevalent in raw chicken meat. PMID- 29116011 TI - The impact of temperature and Wolbachia infection on vector competence of potential dengue vectors Aedes aegypti and Aedes albopictus in the transmission of dengue virus serotype 1 in southern Taiwan. AB - BACKGROUND: We evaluated the impact of temperature and Wolbachia infection on vector competence of the local Aedes aegypti and Ae. albopictus populations of southern Taiwan in the laboratory. RESULTS: After oral infection with dengue serotype 1 virus (DENV-1), female mosquitoes were incubated at temperatures of 10, 16, 22, 28 and 34 degrees C. Subsequently, salivary gland, head, and thorax abdomen samples were analyzed for their virus titer at 0, 5, 10, 15, 20, 25 and 30 days post-infection (dpi) by real-time RT-PCR. The results showed that Ae. aegypti survived significantly longer and that dengue viral genome levels in the thorax-abdomen (103.25 +/- 0.53-104.09 +/- 0.71 PFU equivalents/ml) and salivary gland samples (102.67 +/- 0.33-103.89 +/- 0.58 PFU equivalents/ml) were significantly higher at high temperature (28-34 degrees C). The survival of Ae. albopictus was significantly better at 16 or 28 degrees C, but the virus titers from thorax-abdomen (100.70-102.39 +/- 1.31 PFU equivalents/ml) and salivary gland samples (100.12 +/- 0.05-101.51 +/- 0.31 PFU equivalents/ml) were significantly higher at 22-28 degrees C. Within viable temperature ranges, the viruses were detectable after 10 dpi in salivary glands and head tissues in Ae. aegypti and after 5-10 dpi in Ae. albopictus. Vector competence was measured in Ae. albopictus with and without Wolbachia at 28 degrees C. Wolbachia-infected mosquitoes survived significantly better and carried lower virus titers than Wolbachia-free mosquitoes. Wolbachia coinfections (92.8-97.2%) with wAlbA and wAlbB strains were commonly found in a wild population of Ae. albopictus. CONCLUSIONS: In southern Taiwan, Ae. aegypti is the main vector of dengue and Ae. albopictus has a non-significant role in the transmission of dengue virus due to the high prevalence of Wolbachia infection in the local mosquito population of southern Taiwan. PMID- 29116013 TI - The influence of dexamethasone on postoperative swelling and neurosensory disturbances after orthognathic surgery: a randomized controlled clinical trial. AB - BACKGROUND: Orthognathic surgery is associated with considerable swelling and neurosensory disturbances. Serious swelling can lead to great physical and psychological strain. A randomized, prospective, controlled clinical trial was realized in order to evaluate the effect of a preoperative intravenous dexamethasone injection of 40 mg on postoperative swelling and neurosensory disturbances after orthognathic surgery. METHODS: Thirty-eight patients (27 male and 11 female) patients, all with the indication for an orthognathic surgery, were enrolled in this study (mean age: 27.63 years, range: 16-61 years) and randomly divided into two groups (study group/ control group). Both groups underwent either maxillary and/or mandibular osteotomies, resulting in three subgroups according to surgical technique (A: LeFort I osteotomy, B: bilateral sagittal split osteotomy (BSSO), C: bimaxillary osteotomy). The study group received a single preoperative intravenous injection of 40 mg dexamethasone. Facial edema was measured by 3D surface scans on the 1st, 2nd, 5th, 14th and 90th postoperative day. Furthermore, neurosensory disturbances on the 2nd, 5th, 14th and 90th postoperative day were investigated by thermal stimulation. RESULTS: Facial edema after LeFort I osteotomy, BSSO and bimaxillary osteotomy showed a significant decrease in the study group compared to the control group (P = 0.048, P = 0.045, P < 0.001). The influence of dexamethasone on neurosensory disturbances was not significant for the inferior alveolar nerve (P = 0.746) or the infraorbital nerve (P = 0.465). CONCLUSIONS: Patients undergoing orthognathic surgery should receive a preoperative injection of dexamethasone in order to control and reduce edema. However, there was no influence of dexamethasone on reduction of neurosensory disturbances. TRIAL REGISTRATION: DRKS00009033 . PMID- 29116012 TI - Connexin 32 and connexin 43 are involved in lineage restriction of hepatic progenitor cells to hepatocytes. AB - BACKGROUND: Bi-potential hepatic progenitor cells can give rise to both hepatocytes and cholangiocytes, which is the last phase and critical juncture in terms of sequentially hepatic lineage restriction from any kind of stem cells. If their differentiation can be controlled, it might access to functional hepatocytes to develop pharmaceutical and biotechnology industries as well as cell therapies for end-stage liver diseases. METHODS: In this study, we investigated the influence of Cx32 and Cx43 on hepatocyte differentiation of WB F344 cells by in vitro gain and loss of function analyses. An inhibitor of Cx32 was also used to make further clarification. To reveal p38 MAPK pathway is closely related to Cxs, rats with 70% partial hepatectomy were injected intraperitoneally with a p38 inhibitor, SB203580. Besides, the effects of p38 MAPK pathway on differentiation of hepatoblasts isolated from fetal rat livers were evaluated by addition of SB203580 in culture medium. RESULTS: In vitro gain and loss of function analyses showed overexpression of Connexin 32 and knockdown of Connexin 43 promoted hepatocytes differentiation from hepatic progenitor cells. In addition, in vitro and ex vivo research revealed inhibition of p38 mitogen-activated protein kinase pathway can improve hepatocytes differentiation correlating with upregulation of Connexin 32 expression and downregulation of Connexin 43 expression. CONCLUSIONS: Here we demonstrate that Connexins play crucial roles in facilitating differentiation of hepatic progenitors. Our work further implicates that regulators of Connexins and their related pathways might provide new insights to improve lineage restriction of stem cells to mature hepatocytes. PMID- 29116014 TI - Quantitative assessment of radiation dose and fractionation effects on normal tissue by utilizing a novel lung fibrosis index model. AB - BACKGROUND: Normal lung tissue tolerance constitutes a limiting factor in delivering the required dose of radiotherapy to cure thoracic and chest wall malignancies. Radiation-induced lung fibrosis (RILF) is considered a critical determinant for late normal tissue complications. While RILF mouse models are frequently approached e.g., as a single high dose thoracic irradiation to investigate lung fibrosis and candidate modulators, a systematic radiobiological characterization of RILF mouse model is urgently needed to compare relative biological effectiveness (RBE) of particle irradiation with protons, helium-, carbon and oxygen ions now available at HIT. We aimed to study the dose-response relationship and fractionation effect of photon irradiation in development of pulmonary fibrosis in C57BL/6 mouse. METHODS: Lung fibrosis was evaluated 24 weeks after single and fractionated whole thoracic irradiation by quantitative assessment of lung alterations using CT. The fibrosis index (FI) was determined based on 3D-segmentation of the lungs considering the two key fibrosis parameters affected by ionizing radiation i.e., a dose/fractionation dependent reduction of the total lung volume and increase of the mean lung density. RESULTS: The effective dose required to induce 50% of the maximal possible fibrosis (ED 50 ) was 14.55 +/- 0.34Gy and 27.7 +/- 1.22Gy, for single and five- fractions irradiation, respectively. Applying a deterministic model an alpha/beta = 4.49 +/ 0.38 Gy for the late lung radiosensitivity was determined. Intriguingly, we found that a linear-quadratic model could be applied to in-vivo log transformed fibrosis (FI) vs. irradiation doses. The LQ model revealed an alpha/beta for lung radiosensitivity of 4.4879 Gy for single fraction and 3.9474 for 5-fractions. Our FI based data were in good agreement with a meta-analysis of previous lung radiosensitivity data derived from different clinical endpoints and various mouse strains. The effect of fractionation on RILF development was further estimated by the biologically effective dose (BED) model with threshold BED (BED Tr ) = 30.33 Gy and BED ED50 = 61.63 Gy, respectively. CONCLUSION: The systematic radiobiological characterization of RILF in the C57BL/6 mouse reported in this study marks an important step towards precise estimation of dose-response for development of lung fibrosis. These radiobiological parameters combined with a large repertoire of genetically engineered C57BL/6 mouse models, build a solid foundation for further biologically individualized risk assessment of RILF and functional RBE prediction on novel of particle qualities. PMID- 29116015 TI - How we read pediatric PET/CT: indications and strategies for image acquisition, interpretation and reporting. AB - PET/CT plays an important role in the diagnosis, staging and management of many pediatric malignancies. The techniques for performing PET/CT examinations in children have evolved, with increasing attention focused on reducing patient exposure to ionizing radiation dose whenever possible and minimizing scan duration and sedation times, with a goal toward optimizing the overall patient experience. This review outlines our approach to performing PET/CT, including a discussion of the indications for a PET/CT exam, approaches for optimizing the exam protocol, and a review of different approaches for acquiring the CT portion of the PET/CT exam. Strategies for PACS integration, image display, interpretation and reporting are also provided. Most practices will develop a strategy for performing PET/CT that best meets their respective needs. The purpose of this article is to provide a comprehensive overview for radiologists who are new to pediatric PET/CT, and also to provide experienced PET/CT practitioners with an update on state-of-the art CT techniques that we have incorporated into our protocols and that have enabled us to make considerable improvements to our PET/CT practice. PMID- 29116017 TI - Regenerative potential of primary adult human neural stem cells on micropatterned bio-implants boosts motor recovery. AB - BACKGROUND: The adult brain is unable to regenerate itself sufficiently after large injuries. Therefore, hopes rely on therapies using neural stem cell or biomaterial transplantation to sustain brain reconstruction. The aim of the present study was to evaluate the improvement in sensorimotor recovery brought about by human primary adult neural stem cells (hNSCs) in combination with bio implants. METHODS: hNSCs were pre-seeded on implants micropatterned for neurite guidance and inserted intracerebrally 2 weeks after a primary motor cortex lesion in rats. Long-term behaviour was significantly improved after hNSC implants versus cell engraftment in the grip strength test. MRI and immunohistological studies were conducted to elucidate the underlying mechanisms of neuro-implant integration. RESULTS: hNSC implants promoted tissue reconstruction and limited hemispheric atrophy and glial scar expansion. After 3 months, grafted hNSCs were detected on implants and expressed mature neuronal markers (NeuN, MAP2, SMI312). They also migrated over a short distance to the reconstructed tissues and to the peri-lesional tissues, where 26% integrated as mature neurons. Newly formed host neural progenitors (nestin, DCX) colonized the implants, notably in the presence of hNSCs, and participated in tissue reconstruction. The microstructured bio implants sustained the guided maturation of both grafted hNSCs and endogenous progenitors. CONCLUSIONS: These immunohistological results are coherent with and could explain the late improvement observed in sensorimotor recovery. These findings provide novel insights into the regenerative potential of primary adult hNSCs combined with microstructured implants. PMID- 29116018 TI - Tissue-specific role of RHBDF2 in cutaneous wound healing and hyperproliferative skin disease. AB - OBJECTIVE: Gain-of-function (GOF) mutations in RHBDF2 cause tylosis. Patients present with hyperproliferative skin, and keratinocytes from tylosis patients' skin show an enhanced wound-healing phenotype. The curly bare mouse model of tylosis, carrying a GOF mutation in the Rhbdf2 gene (Rhbdf2 cub ), presents with epidermal hyperplasia and shows accelerated cutaneous wound-healing phenotype through enhanced secretion of the epidermal growth factor receptor family ligand amphiregulin. Despite these advances in our understanding of tylosis, key questions remain. For instance, it is not known whether the disease is skin specific, whether the immune system or the surrounding microenvironment plays a role, and whether mouse genetic background influences the hyperproliferative-skin and wound-healing phenotypes observed in Rhbdf2 cub mice. RESULTS: We performed bone marrow transfers and reciprocal skin transplants and found that bone marrow transfer from C57BL/6 (B6)-Rhbdf2 cub/cub donor mice to B6 wildtype recipient mice failed to transfer the hyperproliferative-skin and wound-healing phenotypes in B6 mice. Furthermore, skin grafts from B6 mice to the dorsal skin of B6-Rhbdf2 cub/cub mice maintained the phenotype of the donor mice. To test the influence of mouse genetic background, we backcrossed Rhbdf2 cub onto the MRL/MpJ strain and found that the hyperproliferative-skin and wound-healing phenotypes caused by the Rhbdf2 cub mutation persisted on the MRL/MpJ strain. PMID- 29116016 TI - Management and potentialities of primary cancer cultures in preclinical and translational studies. AB - The use of patient-derived primary cell cultures in cancer preclinical assays has increased in recent years. The management of resected tumor tissue remains complex and a number of parameters must be respected to obtain complete sample digestion and optimal vitality yield. We provide an overview of the benefits of correct primary cell culture management using different preclinical methodologies, and describe the pros and cons of this model with respect to other kinds of samples. One important advantage is that the heterogeneity of the cell populations composing a primary culture partially reproduces the tumor microenvironment and crosstalk between malignant and healthy cells, neither of which is possible with cell lines. Moreover, the use of patient-derived specimens in innovative preclinical technologies, such as 3D systems or bioreactors, represents an important opportunity to improve the translational value of the results obtained. In vivo models could further our understanding of the crosstalk between tumor and other tissues as they enable us to observe the systemic and biological interactions of a complete organism. Although engineered mice are the most common model used in this setting, the zebrafish (Danio rerio) species has recently been recognized as an innovative experimental system. In fact, the transparent body and incomplete immune system of zebrafish embryos are especially useful for evaluating patient-derived tumor tissue interactions in healthy hosts. In conclusion, ex vivo systems represent an important tool for cancer research, but samples require correct manipulation to maximize their translational value. PMID- 29116019 TI - CLDN6 promotes chemoresistance through GSTP1 in human breast cancer. AB - BACKGROUND: Claudin-6 (CLDN6), a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer chemoresistance remains unclear. In this study, we investigated the role of CLDN6 in the acquisition of chemoresistance in breast cancer cells. METHODS: We manipulated the expression of CLDN6 in MCF-7 and MCF-7/MDR cells with lv-CLDN6 and CLDN6 shRNA and investigated whether CLDN6 manipulation lead to different susceptibilities to several chemotherapeutic agents in these cells. The cytotoxicity of adriamycin (ADM), 5-fluorouracil (5-FU), and cisplatin (DDP) was tested by cck-8 assay. Cell death was determined by DAPI nuclear staining. The enzyme activity of glutanthione S-transferase-p1 (GSTP1) was detected by a GST activity kit. Then lv-GSTP1 and GSTP1-shRNA plasmids were constructed to investigate the potential of GSTP1 in regulating chemoresistance of breast cancer. The TP53-shRNA was adopted to explore the regulation mechanism of GSTP1. Finally, immunohistochemistry was used to explore the relationship between CLDN6 and GSTP1 expression in breast cancer tissues. RESULTS: Silencing CLDN6 increased the cytotoxicity of ADM, 5-FU, and DDP in MCF-7/MDR cells. Whereas overexpression of CLDN6 in MCF-7, the parental cell line of MCF-7/MDR expressing low level of CLDN6, increased the resistance to the above drugs. GSTP1 was upregulated in CLDN6-overexpressed MCF-7 cells. RNAi -mediated silencing of CLDN6 downregulated both GSTP1 expression and GST enzyme activity in MCF-7/MDR cells. Overexpresssion of GSTP1 in CLDN6 silenced MCF-7/MDR cells restored chemoresistance, whereas silencing GSTP1 reduced the chemoresistance due to ectopic overexpressed of CLDN6 in MCF-7 cells. These observations were also repeated in TNBC cells Hs578t. We further confirmed that CLDN6 interacted with p53 and promoted translocation of p53 from nucleus to cytoplasm, and both the expression and enzyme activity of GSTP1 were regulated by p53. Clinicopathologic analysis revealed that GSTP1 expression was positively associated with CLDN6 in human breast cancer samples. CONCLUSION: High expression of CLDN6 confers chemoresistance on breast cancer which is mediated by GSTP1, the activity of which is regulated by p53. Our findings provide a new insight into mechanisms and strategies to overcome chemoresistance in breast cancer. PMID- 29116020 TI - Assessment of safety and efficacy of mesenchymal stromal cell therapy in preclinical models of acute myocardial infarction: a systematic review protocol. AB - BACKGROUND: Despite advances in treatment, acute myocardial infarction (MI) is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs) to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial. METHODS/DESIGN: A systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non randomized) of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling. DISCUSSION: This systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design. PMID- 29116021 TI - Prognostic value of plasma Epstein-Barr virus DNA level during posttreatment follow-up in the patients with nasopharyngeal carcinoma having undergone intensity-modulated radiotherapy. AB - BACKGROUND: The value of Epstein-Barr virus (EBV) DNA assay during posttreatment follow-up of the patients with nasopharyngeal carcinoma (NPC) presenting with different pretreatment plasma EBV DNA levels remains unclear. In the present study, we aimed to evaluate the prognostic value of plasma EBV DNA assay during posttreatment follow-up in the patients with NPC who have undergone intensity modulated radiotherapy. METHODS: The medical records of 385 NPC patients treated with intensity-modulated radiotherapy between November 2009 and February 2012 were reviewed. All patients underwent plasma EBV DNA assays before treatment, within 3 months after treatment, and then every 3-12 months during posttreatment follow-up period. The recurrence rates for patients with different pretreatment and posttreatment follow-up plasma EBV DNA levels were analyzed. RESULTS: Of the 385 patients, 267 (69.4%) had detectable pretreatment plasma EBV DNA (> 0 copy/mL) and 93 (24.2%) had detectable posttreatment EBV DNA during a median follow-up of 52.8 months (range 9.3-73.8 months). Detectable EBV DNA during posttreatment follow-up was found in 14.4% (17/118) and 28.5% (76/267) of patients with undetectable and detectable pretreatment EBV DNA, respectively, and was significantly associated with tumor recurrence in both patient groups. EBV DNA was detectable in 12.8% (40/313) of patients who remained disease-free, 56.4% (22/39) of patients with locoregional recurrence alone, and 93.9% (31/33) of patients with distant metastasis as the first recurrence event (P < 0.001); 6.5% (19/292) of patients with undetectable EBV DNA and 57.0% (53/93) of patient with detectable EBV DNA during posttreatment follow-up experienced tumor recurrence. Compared with other cut-off values, the cut-off value of 0 copy/mL for EBV DNA during posttreatment follow-up had the highest area under the ROC curve (AUC) value (0.804, 95% confidence interval 0.741-0.868) for predicting tumor recurrence (sensitivity, specificity, and accuracy: 73.6%, 87.2%, and 84.7%, respectively). CONCLUSION: Plasma EBV DNA level during posttreatment follow-up is a good marker for predicting distant metastasis but not locoregional recurrence in the patients with NPC irrespective of the pretreatment EBV DNA levels. PMID- 29116022 TI - Enhancing Mental and Physical Health of Women through Engagement and Retention (EMPOWER): a protocol for a program of research. AB - BACKGROUND: The Enhancing Mental and Physical health of Women through Engagement and Retention or EMPOWER program represents a partnership with the US Department of Veterans Health Administration (VA) Health Service Research and Development investigators and the VA Office of Women's Health, National Center for Disease Prevention and Health Promotion, Primary Care-Mental Health Integration Program Office, Women's Mental Health Services, and the Office of Patient Centered Care and Cultural Transformation. EMPOWER includes three projects designed to improve women Veterans' engagement and retention in evidence-based care for high-priority health conditions, i.e., prediabetes, cardiovascular, and mental health. METHODS/DESIGN: The three proposed projects will be conducted in VA primary care clinics that serve women Veterans including general primary care and women's health clinics. The first project is a 1-year quality improvement project targeting diabetes prevention. Two multi-site research implementation studies will focus on cardiovascular risk prevention and collaborative care to address women Veterans' mental health treatment needs respectively. All projects will use the evidence-based Replicating Effective Programs (REP) implementation strategy, enhanced with multi-stakeholder engagement and complexity theory. Mixed methods implementation evaluations will focus on investigating primary implementation outcomes of adoption, acceptability, feasibility, and reach. Program-wide organizational-, provider-, and patient-level measures and tools will be utilized to enhance synergy, productivity, and impact. Both implementation research studies will use a non-randomized stepped wedge design. DISCUSSION: EMPOWER represents a coherent program of women's health implementation research and quality improvement that utilizes cross-project implementation strategies and evaluation methodology. The EMPOWER Quality Enhancement Research Initiative (QUERI) will constitute a major milestone for realizing women Veterans' engagement and empowerment in the VA system. EMPOWER QUERI will be conducted in close partnership with key VA operations partners, such as the VA Office of Women's Health, to disseminate and spread the programs nationally. TRIAL REGISTRATION: The two implementation research studies described in this protocol have been registered as required: Facilitating Cardiovascular Risk Screening and Risk Reduction in Women Veterans: Trial registration NCT02991534 , registered 9 December 2016. Implementation of Tailored Collaborative Care for Women Veterans: Trial registration NCT02950961 , registered 21 October 2016. PMID- 29116023 TI - Caffeic acid phenethyl ester promotes haematopoietic stem/progenitor cell homing and engraftment. AB - BACKGROUND: Several studies have suggested that caffeic acid phenethyl ester (CAPE) can induce the expression of hypoxia inducible factor-1alpha (HIF-1alpha) protein. We determined whether CAPE has a novel function in improving the homing and engraftment of haematopoietic stem/progenitor cells (HSPCs) by regulating HIF 1alpha gene expression in the bone marrow (BM) niche. METHODS: For survival experiments, lethally irradiated C57BL/6 mice were injected with a low number of BM mononuclear cells (MNCs) and CAPE according to the indicated schedule. Homing efficiency analysis was conducted using flow cytometry and colony-forming unit (CFU) assays. The influence of intraperitoneal injection of CAPE on short-term and long-term engraftment of HSPCs was evaluated using competitive and non competitive mouse transplantation models. To investigate the mechanism by which CAPE enhanced HSPC homing, we performed these experiments including Q-PCR, western blot, immunohistochemistry and CFU assays after in-vivo HIF-1alpha activity blockade. RESULTS: CAPE injection significantly increased the survival rate of recipient mice after lethal irradiation and transplantation of a low number of BM MNCs. Using HSPC homing assays, we found that CAPE notably increased donor HSPC homing to recipient BM. The subsequent short-term and long-term engraftment of transplanted HSPCs was also improved by the optimal schedule of CAPE administration. Mechanistically, we found that CAPE upregulated the expression of HIF-1alpha, vascular endothelial growth factor-A (VEGF-A) and stromal cell-derived factor 1alpha (SDF-1alpha). The HIF-1alpha inhibitor PX-478 blocked CAPE-enhanced HSPC homing, which supported the idea that HIF-1alpha is a key target of CAPE. CONCLUSIONS: Our results showed that CAPE administration facilitated HSPC homing and engraftment, and this effect was primarily dependent on HIF-1alpha activation and upregulation of SDF-1alpha and VEGF-A expression in the BM niche. PMID- 29116024 TI - Systematic analyses of glutamine and glutamate metabolisms across different cancer types. AB - BACKGROUND: Glutamine and glutamate are known to play important roles in cancer biology. However, no detailed information is available in terms of their levels of involvement in various biological processes across different cancer types, whereas such knowledge could be critical for understanding the distinct characteristics of different cancer types. Our computational study aimed to examine the functional roles of glutamine and glutamate across different cancer types. METHODS: We conducted a comparative analysis of gene expression data of cancer tissues versus normal control tissues of 11 cancer types to understand glutamine and glutamate metabolisms in cancer. Specifically, we developed a linear regression model to assess differential contributions by glutamine and/or glutamate to each of seven biological processes in cancer versus control tissues. RESULTS: While our computational predictions were consistent with some of the previous observations, multiple novel predictions were made: (1) glutamine is generally not involved in purine synthesis in cancer except for breast cancer, and is similarly not involved in pyridine synthesis except for kidney cancer; (2) glutamine is generally not involved in ATP production in cancer; (3) glutamine's contribution to nucleotide synthesis is minimal if any in cancer; (4) glutamine is not involved in asparagine synthesis in cancer except for bladder and lung cancers; and (5) glutamate does not contribute to serine synthesis except for bladder cancer. CONCLUSIONS: We comprehensively predicted the roles of glutamine and glutamate metabolisms in selected metabolic pathways in cancer tissues versus control tissues, which may lead to novel approaches to therapeutic development targeted at glutamine and/or glutamate metabolism. However, our predictions need further functional validation. PMID- 29116026 TI - The C3HeB/FeJ mouse model recapitulates the hallmark of bovine tuberculosis lung lesions following Mycobacterium bovis aerogenous infection. AB - Achieving the control of bovine tuberculosis (bTB) would require the discovery of an efficient combined immunodiagnostic and vaccine strategy. Since in vivo experiments on cattle are not ethically and economically acceptable there is a need for a cost-effective animal model capable of reproducing, as closely as possible, the physiopathology of bTB to (i) better characterize the cellular and molecular features of bTB immunopathogenesis and (ii) screen preclinical vaccine candidates. To develop such a model, we focused on the C3HeB/FeJ Kramnik's mouse forming hypoxic, encapsulated granulomas with a caseous necrotic center following Mycobacterium tuberculosis infection. Our work represents the first investigation on C3HeB/FeJ interaction with M. bovis, the main agent of bTB. Detailed histopathological analysis of C3HeB/FeJ lung lesions development following aerogenous M. bovis infection unraveled a bimodal evolution of the pathology. The C3HeB/FeJ recapitulated all the hallmarks of classical bovine lung granulomas but also developed, to some extend, lethal necrotic large lesions characterized by high mycobacterial and neutrophil load, and an inefficient collagen-driven lesion encapsulation. Interestingly these rapidly invasive pneumonia lesions, occurring in a constant percentage of the mice, shared all features with some exacerbated lung lesions that we and others have observed in lungs of cattle naturally or experimentally infected with M. bovis. Together, our findings demonstrate the relevance of the C3HeB/FeJ mouse as a comprehensive model to study bTB immunopathology that could be used for further vaccine therapies in the future. PMID- 29116025 TI - miR-200c suppresses endometriosis by targeting MALAT1 in vitro and in vivo. AB - BACKGROUND: Endometriosis is a common, benign, and estrogen-dependent disease characterized by pelvic pain and infertility. To date, the pathogenesis of endometriosis remains unclear. Recent studies have demonstrated that noncoding RNAs, including microRNAs and long noncoding RNAs, play important roles in the development of endometriosis. METHODS: Expression profiling of miRNAs in endometrial tissue was characterized using microarrays. The most differentially expressed miRNAs were confirmed using quantitative reverse transcriptase polymerase chain reaction analysis in additional ectopic endometrial (n = 27) and normal endometrial (n = 12) tissues. For in-vitro functional studies, 5-ethynyl 2'-deoxyuridine incorporation assay, Transwell assay, and dual-luciferase reporter assay were used to measure the proliferation, migration, and luciferase activity of miR-200c and the predicted targets of miR-200c in primary endometrial stromal cells (HESCs) derived from human endometrial biopsies, respectively. For in-vivo therapeutic interventions, polymeric nanoparticles of polyethylenimine polyethylene glycol-arginine-glycine-aspartic acid were used for delivery of miR 200c mimic and inhibitor to determine the therapeutic effect of miR-200c in a rat model of endometriosis. RESULTS: Exogenous overexpression of miR-200c inhibited the proliferation and migration of HESCs, which were mainly regulated by metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). In contrast, inhibition of miR-200c promoted the proliferation and migration of HESCs, while the simultaneous silencing of MALAT1 expression exerted the opposite effects. We demonstrated that expression of MALAT1 in ectopic endometrial specimens was negatively correlated with that of miR-200c and that MALAT1 knockdown increased the level of miR-200c in HESCs. Moreover, the transfection of endometrial stromal cells with the miR-200c mimic or MALAT1 siRNAs decreased the protein levels of mesenchymal markers ZEB1, ZEB2, and N-cadherin and increased the protein levels of the epithelial marker E-cadherin. Furthermore, using a rat endometriosis model, we showed that local delivery of the miR-200c mimic significantly inhibited the growth of ectopic endometriotic lesions. CONCLUSIONS: The MALAT1/miR-200c sponge may be a potential therapeutic target for endometriosis. PMID- 29116027 TI - Poly(ethylene glycol)-modified silk fibroin membrane as a carrier for limbal epithelial stem cell transplantation in a rabbit LSCD model. AB - BACKGROUND: Limbal epithelial stem cells (LESCs) play important roles in corneal epithelial homeostasis and regeneration, and damage to the limbus will lead to limbal stem cell deficiency (LSCD), with conjunctivalization and even visual impairment. Cultured LESCs have been used for ocular surface reconstruction, and silk fibroin (SF) membranes have shown potential as a substrate for LESC cultivation. Both culture methods and the carriers of LESCs affect outcomes following LESC transplantation. METHODS: Rabbit LESCs were cultured from tissue explant, single cell-suspension, and cell cluster culture methods. Ratios of p63alpha and/or ABCB5-positive LESCs, differentiated corneal epithelial cells (CK12 staining), and corneal tight junction formation (Claudin-1 staining) were examined to choose the most applicable LESC cultures. SF membranes were prepared and modified by 400-Da poly(ethylene glycol) (PEG). The characteristics of stem cells and normal corneal differentiation of LESCs cultured on PEG-modified SF membranes were further examined by immunofluorescence staining and flow cytometric analysis. LESCs cultured on PEG-modified SF membranes (LESC/SF grafts) and PEG-modified SF membranes (SF grafts) were transplanted onto rabbit corneas with total LSCD. New blood vessels, corneal epithelial defects, and cornea clarity were examined after transplantation. Furthermore, corneal epithelial thickness, stromal thickness, and the percentage area of CK12-positive corneal epithelium were quantified 4 months after transplantation. RESULTS: Tissue explant and single cell-suspension cultures harvested more p63alpha and/or ABCB5 positive LESCs, generated more CK12-positive corneal epithelial cells, and formed more corneal tight junctions than cell cluster cultures. Prepared PEG-modified SF membranes were transparent, flexible, and sturdy enough for surgical manipulation. LESCs cultured on PEG-modified SF membranes maintained characteristics of stem cells and normal corneal differentiation. LESC/SF grafts inhibited new blood vessels and rescued corneal epithelial defects in the rabbit total LSCD model. In addition, LESC/SF grafts repopulated the limbus and increased corneal epithelial thickness, stromal thickness, and the area percentage of CK12-positive corneal epithelium. CONCLUSIONS: LESCs from tissue explant and single cell-suspension cultures were more applicable corneal epithelial cells for ocular surface reconstruction. LESC/SF grafts repaired corneal epithelial defects and reversed LSCD, and PEG-modified SF membranes were suitable to be a carrier for LESC transplantation. PMID- 29116028 TI - PRENACEL - a mHealth messaging system to complement antenatal care: a cluster randomized trial. AB - BACKGROUND: The aim of this study was to determine whether PRENACEL (a bi directional, mobile-phone based, short text message service (SMS)) increases the coverage of recommended antenatal care (ANC) practices. METHODS: A parallel, cluster-randomized trial in which 20 public primary Health Care Units (PHCUs) were randomly allocated to the intervention (10 PHCUs) or control (10 PHCUs) group. The study population included pregnant women aged 18 or above with a gestational age of 20 weeks or less. Pregnant women receiving ANC in intervention PHCUs were invited through leaflets and posters to register in PRENACEL. Women who registered in PRENACEL received a weekly set of short text messages with health education and health promotion content related to pregnancy and childbirth and were also able to clarify ANC queries through SMS. All women received routine ANC. The primary outcome was the proportion of women with high ANC Score, a composite measure of coverage of recommended ANC practices. Chi-square or Fisher's exact tests and multivariate log-binomial regression were used to analyze the outcomes. RESULTS: A total of 1210 eligible women received ANC in the participating PHCUs and took part of this study (770 in the intervention group and 440 in the control group). 20.4% (157/770) of intervention-group women registered in PRENACEL, but only 116 read all messages (73.9% of women who registered in PRENACEL, 116/157). The adjusted intention-to-treat analysis suggested no difference between intervention and control groups in the primary outcome (Adjusted Relative Risk (AdjRR): 1.05 (95% Confidence Interval (CI): 1.00 1.09). Both crude and adjusted per-protocol analysis suggested a positive effect of PRENACEL (Crude RR (95% CI): 1.14 (1.06-1.22), AdjRR (95% CI): 1.12 (1.05 1.21). The multivariate analysis also suggests that the PRENACEL group (women who read all SMS) had higher mean ANC score [48.5 (+/-4.2) vs 45.2 (+/-8.7), p < 0.01], higher proportion of women with >=6 ANC visits (96.9% vs. 84.8%, p = 0.01), and higher rates of syphilis testing (40.5% vs. 24.8%, p = 0.03) and HIV testing (46.6% vs. 25.7%, p < 0.01) during ANC. CONCLUSIONS: A bi-directional, mobile-phone based, short text message service is potentially useful to improve the coverage of recommended ANC practices, including syphilis and HIV testing. TRIAL REGISTRATION: Clinical trial registry: RBR-54zf73 , U1111-1163-7761. PMID- 29116030 TI - Management of X-linked adrenoleukodystrophy in Morocco: actual situation. AB - OBJECTIVES: X-linked adrenoleukodystrophy is a neurodegenerative disorder caused by mutations in the ABCD1 gene. Adrenomyeloneuropathy and childhood cerebral Adrenoleukodystrophy are the most common phenotypes. This paper focuses on a descriptive study of the first program of diagnosis, treatment, and follow-up of this disease in Morocco. RESULTS: We developed three protocols of X-linked Adrenoleukodystrophy management: general protocol, asymptomatic protocol, and heterozygous protocol. Over a period of 5 years, we recruited eight families with 16 patients. Clinically, the presentation is primary adrenal insufficiency and behavioral changes. All patients had elevated levels of very long fatty acids. This is the first study of X-linked adrenoleukodystrophy in Morocco. It shows the importance of this metabolic disease and broadens perspectives in terms of its diagnosis and its treatment. PMID- 29116031 TI - miRNA profiling of NurOwn(r): mesenchymal stem cells secreting neurotrophic factors. AB - BACKGROUND: MSC-NTF cells are Mesenchymal Stromal Cells (MSC) induced to express high levels of neurotrophic factors (NTFs) using a culture-medium based approach. MSC-NTF cells have been successfully studied in clinical trials for Amyotrophic Lateral Sclerosis (ALS) patients. MicroRNAs (miRNA) are short non-coding RNA molecules that coordinate post-transcriptional regulation of multiple gene targets. The purpose of this study was to determine whether the miRNA profile could provide a tool for MSC-NTF cell characterization and to distinguish them from the matched MSC from which they are derived. METHODS: NTF secretion in the culture supernatant of MSC-NTF cells was evaluated by ELISA assays. The Agilent microarray miRNA platform was used for pairwise comparisons of MSC-NTF cells to MSC. The differentially expressed miRNAs and putative mRNA targets were validated using qPCR analyses. RESULTS: Principal component analysis revealed two distinct clusters based on cell type (MSC and MSC-NTFs). Nineteen miRNAs were found to be upregulated and 22 miRNAs were downregulated in MSC-NTF cells relative to the MSC cells of origin. Further validation of differentially expressed miRNAs confirmed that miR-3663 and miR-132 were increased 18.5- and 4.06-fold, respectively while hsa-miR-503 was reduced more than 15-fold, suggesting that miRNAs could form the basis of an MSC-NTF cell characterization assay. In an analysis of the miRNA mRNA targets, three mRNA targets of hsa-miR-132-3p (HN-1, RASA1 and KLH-L11) were found to be significantly downregulated. CONCLUSIONS: We have demonstrated that MSC-NTF cells can be distinguished from their MSCs of origin by a unique miRNA expression profile. TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT01777646 . Registered 12 December 2012. PMID- 29116029 TI - ZIKV infection effects changes in gene splicing, isoform composition and lncRNA expression in human neural progenitor cells. AB - BACKGROUND: The Zika virus (ZIKV) is a mosquito-borne flavivirus that causes microcephaly and Guillain-Barre syndrome in infected individuals. To obtain insights into the mechanism of ZIKV infection and pathogenesis, we analyzed the transcriptome of ZIKV infected human neural progenitor cells (hNPCs) for changes in alternative splicing (AS), gene isoform (ISO) composition and long noncoding RNAs (lncRNAs) expression. METHODS: We analyzed differentially expressed lncRNAs, AS, ISO from RNA-seq data in ZIKV infected hNPCs. RESULTS: We obtained 149 differentially expressed lncRNAs, including potential viral targets to modulate cellular processes such as cell cycle, apoptosis and immune response. The infection induced 262 cases of AS occurring in 229 genes, which were enriched in cell death, RNA processing, transport, and neuron development. Among 691 differentially expressed ISOs, upregulated ISOs were enriched in signaling, regulation of transcription, and amino acid biosynthesis, while downregulated ISOs were mostly enriched in cell cycle. Importantly, these analyses revealed specific links between ZIKV induced changes in cellular pathways and the type of changes in the host transcriptome, suggesting important regulatory mechanisms. CONCLUSIONS: Our analyses revealed candidate lncRNAs, AS events and ISOs which may function in ZIKV infection induced cell cycle disruption, apoptosis and attenuation of neurogenesis, and shed light on the roles of lncRNAs, AS and ISOs in virus-host interactions, and would facilitate future studies of ZIKV infection and pathogenesis. PMID- 29116032 TI - Single cell transcriptomics suggest that human adipocyte progenitor cells constitute a homogeneous cell population. AB - Regulation of adipose tissue stem cells (ASCs) and adipogenesis impact the development of excess body fat-related metabolic complications. Animal studies have suggested the presence of distinct subtypes of ASCs with different differentiation properties. In addition, ASCs are becoming the biggest source of mesenchymal stem cells used in therapies, which requires deep characterization. Using unbiased single cell transcriptomics we aimed to characterize ASC populations in human subcutaneous white adipose tissue (scWAT). The transcriptomes of 574 single cells from the WAT total stroma vascular fraction (SVF) of four healthy women were analyzed by clustering and t-distributed stochastic neighbor embedding visualization. The identified cell populations were then mapped to cell types present in WAT using data from gene expression microarray profiling of flow cytometry-sorted SVF. Cells clustered into four distinct populations: three adipose tissue-resident macrophage subtypes and one large, homogeneous population of ASCs. While pseudotemporal ordering analysis indicated that the ASCs were in slightly different differentiation stages, the differences in gene expression were small and could not distinguish distinct ASC subtypes. Altogether, in healthy individuals, ASCs seem to constitute a single homogeneous cell population that cannot be subdivided by single cell transcriptomics, suggesting a common origin for human adipocytes in scWAT. PMID- 29116033 TI - Phenylobacterium hankyongense sp. nov., isolated from ginseng field soil. AB - A Gram-stain-negative, aerobic, non-motile, non-spore-forming and rod-shaped bacterial strain, designated HKS-05T, was isolated from ginseng field soil. This bacterium was characterized to determine its taxonomic position by using the polyphasic approach. HKS-05T grew at 10-37 degrees C and at pH 6.0-8.0 on R2A agar. On the basis of 16S rRNA gene sequence similarity, HKS-05T was shown to represent a member of the family Caulobacteraceaeand to be related to Phenylobacterium lituiforme FaiI3T (98.1 % sequence similarity), 'Phenylobacterium zucineum' HLK1 (97.9 %), Phenylobacterium muchangponense A8T (97.7 %), Phenylobacteriumcomposti 4T-6T (97.2 %) and Phenylobacterium immobile ET (97.1 %). The major respiratory quinone was Q-10 and the major fatty acids were summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c), C16 : 0, and summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c). The polar lipids were phosphatidylglycerol, unidentified glycolipids and unidentified polar lipids. The G+C content of the genomic DNA was 70.4 mol%. DNA-DNA relatedness values between HKS-05T and its closest phylogenetically neighbours were low. HKS 05T could be differentiated genotypically and phenotypically from the species of the genus Phenylobacterium with validly published names. The isolate therefore represents a novel species, for which the name Phenylobacteriumhankyongense sp. nov. is proposed, with the type strain HKS-05T (=KACC 18628T=LMG 30081T). PMID- 29116034 TI - Castellaniella fermenti sp. nov., isolated from a fermented meal. AB - A polyphasic taxonomic approach was used to characterize a presumably novel bacterium, designated strain CC-YTH191T, isolated from a fermented meal in Taiwan. Cells of strain CC-YTH191T were Gram-stain-negative aerobic rods, which grew at 15-40 degrees C (optimal 25-30 degrees C), pH 6.0-9.0 (optimal 7.0) and 1-2 % (w/v) NaCl (optimal 1 %). On the basis of 16S rRNA gene sequence analysis, strain CC-YTH191T appeared to belong to the genus Castellaniella, and was closely related to Castellaniella hirudinis (96.7 % similarity), Castellaniella ginsengisoli (96.7 %) and Castellaniella caeni (96.0 %), while with other related species it shared <96.0 % similarity. The major cellular fatty acids of the isolate were C16 : 0, C17 : 0cyclo, C14 : 0 3OH/C16 : 1iso I and C18 : 1omega7c/C18 : 1omega6c. The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, three unidentified phospholipids, an unidentified aminolipid and an unidentified aminophospholpid. Putrescine was the predominant polyamine followed by spermidine. The DNA G+C content was 62.2 mol% and the predominant quinone system was ubiquinone 8 (Q-8). All these features confirmed the placement of the strain CC-YTH191T as a novel species within the genus Castellaniella, for which the name Castellaniella fermenti sp. nov. is proposed. The type strain is CC-YTH191T (=BCRC 81023T=JCM 31755T). PMID- 29116035 TI - Characterization of Trichococcus paludicola sp. nov. and Trichococcus alkaliphilus sp. nov., isolated from a high-elevation wetland, by phenotypic and genomic analyses. AB - Two psychrotolerant facultative anaerobes, strains B7-2T and B5T, were isolated from the Zoige Wetland on the Qinghai-Tibetan Plateau. The 16S rRNA gene sequences of strains B7-2T and B5T shared high similarity (>99 %) with those of the type strains of the genus Trichococcus, while their digital DNA-DNA hybridization values with each other (49 %) and with the reference type strains (48-23 %) were lower than 70 %, which suggest that they represent two novel species of the genus Trichococcus. Cells of strains B7-2T and B5T were immotile cocci, grew in the temperature range of 4-37 degrees C (optimum 25 degrees C) and were alkaliphilic with optimum growth at pH 9.0. The major components of the cellular fatty acids were C16 : 0, anteiso-C17 : 0 and C18 : 0 for strain B7-2T, and C16 : 0, anteiso-C17 : 0, C18 : 1omega9c and C18 : 0 for strain B5T. The genomic DNA G+C contents were 46.0 and 46.7 mol% for strains B7-2T and B5T, respectively. Based on physiological and genomic characteristics, it is suggested that strains B7-2T and B5T represent two novel species within the genus Trichococcus, for which the names Trichococcus paludicola sp. nov. and Trichococcus alkaliphilus sp. nov. are proposed. The type strains are B7-2T (=DSM 104691T=KCTC 33886T) and B5T (=DSM 104692T=KCTC 33885T), respectively. PMID- 29116036 TI - Bifidobacterium callitrichidarum sp. nov. from the faeces of the emperor tamarin (Saguinus imperator). AB - Three Gram-stain-positive, non-spore-forming, microaerophilic and fructose-6 phosphate phosphoketolase positive strains were isolated from a faecal sample of an adult subject of the emperor tamarin (Saguinus imperator). Given that the isolates revealed identical BOX PCR profiles, strain TRI 5T was selected as a representative and characterized further. Comparative analysis of 16S rRNA gene sequence similarity revealed that strain TRI 5T was closely related to Bifidobacterium saguini DSM 23967T (96.4 %) and to Bifidobacterium longum subsp. longum ATCC 15708 (96.2 %). Multilocus sequence analyses of five housekeeping genes showed the close phylogenetic relatedness of this strain to Bifidobacterium breve DSM 20213T (hsp60 94.1 %), Bifidobacterium saguini DSM 23967T (clpC 91 %), Bifidobacterium avesanii DSM 100685T (dnaG 80.3 %), Bifidobacterium longumsubsp. infantis ATCC 15697T (dnaJ 85.3 %) and Bifidobacterium longumsubsp. longum ATCC 15708 (rpoB 93 %), respectively. The peptidoglycan type was A3beta, with an interpeptide bridge comprising l-Orn (Lys) - l-Ser - l-Ala - l-Thr - l-Ala. The DNA G+C content of strain TRI 5T was 60.9 mol%. Based on the data provided, strain TRI 5T represents a novel species of the genus Bifidobacterium for which the name Bifidobacteriumcallitrichidarum sp. nov. is proposed. The type strain is TRI 5T (=DSM 103152T=JCM 31790T). PMID- 29116037 TI - Patient age as a factor of antibiotic resistance in methicillin-resistant Staphylococcus aureus. AB - PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of nosocomial infections. A thorough understanding of the epidemiology and distribution of MRSA allows the development of better preventive measures and helps to control or reduce the rate of infection among the general population. METHODOLOGY: A retrospective survey was performed on 511 cases of MRSA infections from inpatient, outpatient and nursing home populations over a 12-month period. To study the relationships between two continuous quantitative variables (patient age vs resistance percentage), a simple linear regression was calculated for each antibiotic to predict the antibiotic resistance percentage with respect to patient age.Results/Key findings. The pattern of antibiotic resistance with respect to the age of patients depended on the antibiotic mode of action. Antibiotics that target DNA synthesis (i.e. fluoroquinolones) display a direct correlation with the age of patients, with higher rates of resistance among the older population, while antibiotics that target ribosomal functions (i.e. aminoglycosides) or cell wall synthesis (i.e. cephalosporin) do not display an age-dependent pattern and have a consistent degree of resistance across all age classes. CONCLUSION: Antibiotics that target DNA synthesis result in a progressively higher number of resistant isolates among the older population. The results emphasize the importance of patient age on antibiotic selection as a preventive measure to reduce the rate of resistant infections in each susceptible population. This pattern suggests that physicians should take into consideration patient age as another factor in determining the best antibiotic regiment with the aim of curtailing the emergence of newer resistant phenotypes in the future. PMID- 29116038 TI - Borrelia burgdorferi glycosaminoglycan-binding proteins: a potential target for new therapeutics against Lyme disease. AB - The spirochete bacterium Borrelia burgdorferi sensu lato is the causative agent of Lyme disease, the most common vector-borne disease in Europe and the United States. The spirochetes can be transmitted to humans via ticks, and then spread to different tissues, leading to arthritis, carditis and neuroborreliosis. Although antibiotics have commonly been used to treat infected individuals, some treated patients do not respond to antibiotics and experience persistent, long term arthritis. Thus, there is a need to investigate alternative therapeutics against Lyme disease. The spirochete bacterium colonization is partly attributed to the binding of the bacterial outer-surface proteins to the glycosaminoglycan (GAG) chains of host proteoglycans. Blocking the binding of these proteins to GAGs is a potential strategy to prevent infection. In this review, we have summarized the recent reports of B. burgdorferi sensu lato GAG-binding proteins and discussed the potential use of synthetic and semi-synthetic compounds, including GAG analogues, to block pathogen interaction with GAGs. Such information should motivate the discovery and development of novel GAG analogues as new therapeutics for Lyme disease. New therapeutic approaches should eventually reduce the burden of Lyme disease and improve human health. PMID- 29116040 TI - Fictibacillus aquaticus sp. nov., isolated from downstream river water. AB - A Gram-stain-positive, facultatively anaerobic bacterial strain, GDSW-R2A3T, was isolated from a downstream water sample collected from the river Ganges, India. Analysis of the 16S rRNA gene sequence of strain GDSW-R2A3T revealed its affiliation to the family Bacillaceae. Further analysis using a polyphasic approach revealed that strain GDSW-R2A3T was most closely related to the genus Fictibacillus. Analysis of the almost-complete (1488 bp) 16S rRNA gene sequence of strain GDSW-R2A3T revealed the highest level of sequence similarity with Fictibacillus phosphorivorans CCM 8426T (98.3 %) and Fictibacillus nanhaiensis KCTC 13712T (98.3 %) followed by Fictibacillus barbaricus DSM 14730T (98.0 %). The digital DNA-DNA hybridization and average nucleotide identity (ANI) values between strain GDSW-R2A3T and the most closely related taxon, F. phosphorivorans CCM 8426T, were 20.3 and 78.2 %, respectively. The DNA G+C content of the strain was 44.2 mol%. The cell-wall amino acid was meso-diaminopimelic acid. Polar lipids present were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, three aminophospholipids, two phospholipids and one unidentified lipid; the major menaquinone was MK-7; iso-C14 : 0, iso-C15 : 0 and anteiso-C15 : 0 were the major fatty acids. On the basis of the phenotypic, chemotaxonomic and phylogenetic data, it can be concluded that strain GDSW-R2A3T represents a novel species of the genus Fictibacillus, for which the name Fictibacillus aquaticus sp. nov. is proposed. The type strain is GDSW-R2A3T (=VTCC-B-910015T=CCM 8782T). PMID- 29116039 TI - Sphingomonas colocasiae sp. nov., isolated from taro (Colocasia esculanta). AB - A polyphasic approach was used to characterize an aerobic, Gram-stain-negative, rod-shaped bacterium (designed as strain CC-MHH0539T) isolated from the chopped tuber of taro (Colocasia esculanta) in Taiwan. Strain CC-MHH0539T was able to grow at 15-30 degrees C (optimum, 25 degrees C), at pH 6.0-9.0 (optimum, 7.0) and with 0-1 % (w/v) NaCl. Strain CC-MHH0539T showed highest 16S rRNA gene sequence similarity to Sphingomonas laterariae LNB2T (96.8 %), Sphingobium boeckii 469T (96.5 %), Sphingomonas faucium E62-3T (96.4 %) and Sphingosinicella vermicomposti YC7378T (96.2 %) and <96.1 % similarity to other sphingomonads. Strain CC-MHH0539T was found to cluster mainly with the clade that accommodated members of the genus Sphingomonas. The dominant cellular fatty acids were C16 : 0, C16 : 1omega5c, C14 : 0 2-OH, C16 : 1omega7c/C16 : 1omega6c and C18 : 1omega7c/C18 : 1omega6c. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, two sphingoglycolipids and two unidentified phospholipids were detected in strain CC-MHH0539T. The DNA G+C content was 69.5 mol%. The respiratory quinone system and predominant polyamine was ubiquinone 10 (Q-10) and sym-homospermidine, respectively, which is in line with Sphingomonas representatives. Based on the distinct phylogenetic, phenotypic and chemotaxonomic traits, strain CC-MHH0539T is considered to represent a novel species of the genus Sphingomonas, for which the name Sphingomonas colocasiae sp. nov. is proposed. The type strain is CC-MHH0539T (=BCRC 80933T=JCM 31229T). PMID- 29116041 TI - Correction: Super-resolution imaging of synaptic and Extra-synaptic AMPA receptors with different-sized fluorescent probes. PMID- 29116042 TI - Correction: The murine catecholamine methyltransferase mTOMT is essential for mechanotransduction by cochlear hair cells. PMID- 29116043 TI - Two receptor tyrosine phosphatases dictate the depth of axonal stabilizing layer in the visual system. AB - Formation of a functional neuronal network requires not only precise target recognition, but also stabilization of axonal contacts within their appropriate synaptic layers. Little is known about the molecular mechanisms underlying the stabilization of axonal connections after reaching their specifically targeted layers. Here, we show that two receptor protein tyrosine phosphatases (RPTPs), LAR and Ptp69D, act redundantly in photoreceptor afferents to stabilize axonal connections to the specific layers of the Drosophila visual system. Surprisingly, by combining loss-of-function and genetic rescue experiments, we found that the depth of the final layer of stable termination relied primarily on the cumulative amount of LAR and Ptp69D cytoplasmic activity, while specific features of their ectodomains contribute to the choice between two synaptic layers, M3 and M6, in the medulla. These data demonstrate how the combination of overlapping downstream but diversified upstream properties of two RPTPs can shape layer-specific wiring. PMID- 29116044 TI - The predictive value of videostroboscopy in the assessment of premalignant lesions and early glottis cancers. AB - OBJECTIVE: To assess the sensitivity and specificity of larngovideostroboscopy (LVS) in the diagnosis of precancerous and malignant lesions of the vocal folds. MATERIAL AND METHODS: In 175 patients (128 men and 47 women), aged 19-88 years, mean age 61.5, who were admitted to the clinic with diagnosed premalignant conditions of vocal fold mucosa (leukoplakia, chronic hypertrophic inflammatory lesions) and thickening or tumor on the vocal fold, there was performed LVS before the laryngeal microsurgery. The LVS study included: localization of the leasion, movement of the vocal folds, mucosal wave, shape of glottis clousure, amplitude and symmetry of vocal fold vibration. In the evaluation, a point scale was applied for the individual functional parameters. The scale ranged from 0 to 14. Patients with impaired vocal fold motion or absent mucosal wave were positive on LVS for malignant lesions. Those with limitted mucosal wave were positive on LVS for dysplastic lesions. The results were compared with the final histopathological examination and the sensitivity, specificity, accuracy, positive (PPV) and negative (NPV) predictive value were calculated. RESULTS: On the basis of histopathological examination, benign lesions (normal or inflammatory mucosa) accounted for 20% of diagnoses, hypertrophy and parakeratosis for 28%, low and middle grade dysplasia accounted for 10% and malignant lesions (high-grade dysplasia, pre-invasive cancer, Invasive cancer) was diagnosed in 42% of patients. The overall mean score for LVS was 4.5 and 8.0, respectively for benign and malignant lesions. Sensitivity, specificity, accuracy, PPV and NPV of LVS in detecting malignant lesions were respectively - 95.6%, 23.8%, 61.1%, 57.6% and 83.3% and in detecting both premalignant and malignant lesions were respectively - 90.7%, 31.4%, 78.9%, 84.1% and 45.8%. CONCLUSIONS: Because of the high sensitivity of LVS in detecting precancerous and malignant lesions, this method is a very good tool for screening of pathology within the larynx. PMID- 29116045 TI - Contemporary noise-induced hearing loss (NIHL) prevention. AB - Hearing impairment caused by noise, traditionally called - depending on the duration of exposure - acute or chronic acoustic trauma, includes, in addition to presbyacusis, the most common adult population of hearing impaired. In Poland - according to the report of the Central Statistical Office (GUS, 2011), the number of workers employed in NDN exceeded the noise level (85 dB) is about 200 thousand, the highest in the mining, metal and metal products production, textiles and wood production. According to the Regulation of the Council of Ministers of on June 30, 2009, on the list of occupational diseases (Journal of Laws No. 132, item 1115), it is defined as "bilateral permanent hearing loss of the cochlear or sensory-nerve type, expressed as an increase in hearing threshold of at least 45 dB in the ear better heard, calculated as an arithmetic mean for frequencies 1,2 and 3 kHz. Hearing impairments also occur in the military and police during field training and in combat where the source of acoustic injuries are firearms and pulse-inducing explosions (as in some industries) with high C peak levels (Lc peak) Time to rise to a maximum of <1 ms. The prevalence of loud music listening, particularly by personal stereo players, is also affecting children and adolescents with audiometric hearing loss, according to the World Health Organization (WHO) estimates of around 15-20%. The preventive action strategy is defined by the European Union legislation and the national implementing legislation that reduces or eliminates the risk and reduces (if not eliminated), taking into account available technical and organizational solutions to minimize the risk of hearing damage. If you can not reduce the noise levels with technical and organizational methods, you need individual hearing protectors. Ear protectors may be equipped with electronic systems with active noise reduction (which can improve low and medium frequency performance), adjustable attenuation (improves speech intelligibility and perception of warning signals), and wireless communication for verbal communication. PMID- 29116046 TI - Radon-enriched hot spring water therapy for upper and lower respiratory tract inflammation. AB - Background Radon-222-enriched hot spring therapy, which is characterized by a safe level of radioactivity, is used for the treatment of rheumatic disorders, and its efficacy has already been studied in several clinical trials. Radon-water inhalation therapy for the treatment of upper and lower airway inflammatory diseases is used in many hot springs centers. However, its application has not been reviewed to date. Methods We systematically searched the PubMed and Scopus databases for clinical trials published in the last 20 years in which objective parameters of upper and lower airway function had been tested before and after radon-enriched inhalation treatment. Results Four prospective studies were found: 1 asthma trial, 1 placebo-controlled chronic rhinosinusitis trial, 1 upper respiratory tract inflammation with nasal obstruction trial, and 1 case-control allergic rhinitis trial. Patients were treated with nasal inhalations of radon enriched water for 12 to 28 days and were assessed at baseline and after therapy. After 2 weeks of treatment, nasal resistance decreased, flow increased, mucociliary clearance was enhanced, ciliated-to-muciparous cell ratio increased, and %FEV1 increased in asthmatic patients. Conclusion Radon-enriched inhalation therapy improves objective indicators of nasal function in allergic rhinitis and chronic rhinosinusitis, and causes relief of pulmonary obstruction in asthma. PMID- 29116047 TI - Factors that have an influence on bone conduction thresholds changes after otosurgery in the patients operated on due to the perforation of the tympanic membrane with the preserved ossicular chain. AB - INTRODUCTION: The aim of the middle ear surgery is to eliminate abnormalities from the mucous, ensure the due airing of the postoperative cavity and reconstruct the sound-conducting system in the middle ear. Numerous reports can be found in literature on the changes to bone conduction as a consequence of middle ear surgery. STUDY OBJECTIVE: The aim of the work is to define the factors that affect bone conduction in the patients operated on due to the perforation of the tympanic membrane with the preserved and normal mobile ossicular chain. MATERIAL AND METHOD: A prospective analysis of patients operated on due to diseases of the middle ear in 2009-2012 was carried out. The cases of patients operated on for the first time due to chronic otitis media were taken into consideration. The analysis encompassed the patients who had undergone myringoplasty. The patients were divided into several groups taking into account the abnormalities of the mucous observed during otosurgery. RESULTS: A significant improvement of bone conduction was observed in the patients with dry perforation, without other lesions in the middle ear. The appropriate pharmacological treatment before otosurgery in patients with permanent discharge from the ear resulted in significant bone conduction improvement. The elimination of granulation lesions turned out to be a positive factor for the future improvement of the function of the inner ear. CONCLUSIONS: The lack of abnormalities on the mucous of the middle ear (e.g. granulation,) and discharge has a positive impact on improvement of bone conduction after myringoplasty. Adhesions in the tympanic cavity, especially in the niche of the round window, have a negative impact on improvement of bone conduction in patients after myringoplasty. PMID- 29116048 TI - Usefulness of high-speed digital imaging (HSDI) in the diagnosis of oedematous - hypertrophic changes of the larynx in people using voice occupationally. AB - INTRODUCTION: The aim of the study is the evaluation of the usefulness of High Speed Digital Imaging (HSDI) in the diagnosis of organic dysphonia in a form of oedematous-hypertrophic changes of vocal fold mucosa, morphologically confirmed by Transmission Electron Microscopy (TEM) method in patients working with voice occupationally. MATERIAL AND METHODS: The group consisted of 30 patients working with voice occupationally with oedematous-hypertrophic changes of vocal fold mucosa. Parameters of vocal folds vibrations were evaluated using HSDI technique with a digital HS camera, HRES Endocam Richard Wolf GmbH. The image of vocal folds was recorded with a rate of 4000 frames per second. Postoperative material of the larynx was prepared in a routine way and observed in transmission electron microscope OPTON 900-PC. RESULTS: HSDI technique allows to assess the real vibrations of vocal folds and determine many parameters. The results of TEM in the postoperative material showed destruction of epithelial cells with severe vacuolar degeneration, the enlargement of intercellular spaces and a large number of blood vessels in the stroma, which indicates the presence of oedematous hypertrophic changes of the larynx. DISCUSSION: The ultrastructural assessment confirm the particular usefulness of HSDI method in the diagnosis of organic dysphonia in a form of oedematous-hypertrophic changes. Key words: High-Speed Digital Imaging, oedematous-hypertrophic changes, vocal fold mucosa, larynx. PMID- 29116049 TI - Pleomorphic adenoma - the results of a retrospective analysis of 104 patients treated at the Clinical Department of Cranio-Maxillofacial Surgery, Clinic of Otolaryngology and Laryngologic Oncology of the Military Institute of Medicine. AB - Pleomorphic adenoma, also known as tumor mixtus, is one of the most common types of benign neoplasm of the salivary gland, which presents as a slow growing, painless tumor. Major salivary glands are the typical localization of this neoplasm. It rarely undergoes malignant transformation, however may recur locally post resection. In this study, we present the results of a retrospective analysis of 104 patients treated at the Clinical Department of Cranio-Maxillofacial Surgery, Clinic of Otolaryngology and Laryngologic Oncology of the Military Institute of Medicine between 2004 and 2015 due to pleomorphic adenoma. The study confirmed the parotid gland as the most common location of tumor mixtus. In some cases, the large size of the tumor and its location were the cause of life threatening complications. PMID- 29116050 TI - Real-world evidence for nucleoside/nucleotide analogues in a 5-year multicentre study of antiviral-naive chronic hepatitis B patients in China: 52-week results. AB - BACKGROUND: In China, the clinical management of chronic hepatitis B (CHB) is complicated by the use of variousnucleoside/nucleotide analogue (NUC) regimens in treatment-naive patients, including NUCs with low genetic barriers to resistance, with/without add-on therapy and de novo NUC combinations. This longitudinal observational study therefore investigated the real-world clinical management and efficacy of NUC therapy in treatment-naive CHB patients in China. METHODS: Treatment-naive CHB patients initiated on NUC therapy were enrolled from 63 hospitals in tier-2 Chinese cities. Demographic and treatment-specific data were collected, with the objective of reporting real-world treatment patterns and comparing the effectiveness of entecavir (ETV) treatment and lamivudine (LAM) based treatment. We herein report the first-year data. RESULTS: 3,408 NUC-naive patients were enrolled and treated with NUCs (53% ETV, 18% LAM-based, 29% other). Overall, 6.6% of patients modified their initial treatment, with ETV having lower rates of treatment modification than other major NUCs (P<0.05). At week 52, the virological response rate was higher with ETV than with LAM-based treatment (77.0% versus 61.4%; P<0.0001). LAM-based treatment was associated with a higher probability of virological breakthrough and genotypic resistance (21.4% and 19.6%, respectively) than ETV (1.6% and 0.1%, respectively; P<0.0001). Treatment related adverse events or serious adverse events were uncommon. CONCLUSIONS: In this nationwide observational study, more than 50% of patients with CHB in tier-2 city hospitals in China initially received ETV therapy. Consistent with clinical trial results, ETV was more effective than LAM-based treatments in a real-world setting, with the rate of treatment modification being relatively low in ETV treated patients. ClinicalTrials.gov Identifier: NCT01726439. PMID- 29116051 TI - Multiple image x-radiography for functional lung imaging. AB - Detection and visualization of lung tissue structures is impaired by predominance of air. However, by using synchrotron x-rays, refraction of x-rays at the interface of tissue and air can be utilized to generate contrast which may in turn enable quantification of lung optical properties. We utilized multiple image radiography, a variant of diffraction enhanced imaging, at the Canadian light source to quantify changes in unique x-ray optical properties of lungs, namely attenuation, refraction and ultra small-angle scatter (USAXS or width) contrast ratios as a function of lung orientation in free-breathing or respiratory-gated mice before and after intra-nasal bacterial endotoxin (lipopolysaccharide) instillation. The lung ultra small-angle scatter and attenuation contrast ratios were significantly higher 9 h post lipopolysaccharide instillation compared to saline treatment whereas the refraction contrast decreased in magnitude. In ventilated mice, end-expiratory pressures result in an increase in ultra small angle scatter contrast ratio when compared to end-inspiratory pressures. There were no detectable changes in lung attenuation or refraction contrast ratio with change in lung pressure alone. In effect, multiple image radiography can be applied towards following optical properties of lung air-tissue barrier over time during pathologies such as acute lung injury. PMID- 29116052 TI - Quantitative performance evaluation of 124I PET/MRI lesion dosimetry in differentiated thyroid cancer. AB - The aim was to investigate the quantitative performance of 124I PET/MRI for pre therapy lesion dosimetry in differentiated thyroid cancer (DTC). Phantom measurements were performed on a PET/MRI system (Biograph mMR, Siemens Healthcare) using 124I and 18F. The PET calibration factor and the influence of radiofrequency coil attenuation were determined using a cylindrical phantom homogeneously filled with radioactivity. The calibration factor was 1.00 +/- 0.02 for 18F and 0.88 +/- 0.02 for 124I. Near the radiofrequency surface coil an underestimation of less than 5% in radioactivity concentration was observed. Soft-tissue sphere recovery coefficients were determined using the NEMA IEC body phantom. Recovery coefficients were systematically higher for 18F than for 124I. In addition, the six spheres of the phantom were segmented using a PET-based iterative segmentation algorithm. For all 124I measurements, the deviations in segmented lesion volume and mean radioactivity concentration relative to the actual values were smaller than 15% and 25%, respectively. The effect of MR-based attenuation correction (three- and four-segment u-maps) on bone lesion quantification was assessed using radioactive spheres filled with a K2HPO4 solution mimicking bone lesions. The four-segment u-map resulted in an underestimation of the imaged radioactivity concentration of up to 15%, whereas the three-segment u-map resulted in an overestimation of up to 10%. For twenty lesions identified in six patients, a comparison of 124I PET/MRI to PET/CT was performed with respect to segmented lesion volume and radioactivity concentration. The interclass correlation coefficients showed excellent agreement in segmented lesion volume and radioactivity concentration (0.999 and 0.95, respectively). In conclusion, it is feasible that accurate quantitative 124I PET/MRI could be used to perform radioiodine pre-therapy lesion dosimetry in DTC. PMID- 29116053 TI - Elastic strain and twist analysis of protein structural data and allostery of the transmembrane channel KcsA. AB - The abundance of available static protein structural data makes the more effective analysis and interpretation of this data a valuable tool to supplement the experimental study of protein mechanics. Structural displacements can be difficult to analyze and interpret. Previously, we showed that strains provide a more natural and interpretable representation of protein deformations, revealing mechanical coupling between spatially distinct sites of allosteric proteins. Here, we demonstrate that other transformations of displacements yield additional insights. We calculate the divergence and curl of deformations of the transmembrane channel KcsA. Additionally, we introduce quantities analogous to bend, splay, and twist deformation energies of nematic liquid crystals. These transformations enable the decomposition of displacements into different modes of deformation, helping to characterize the type of deformation a protein undergoes. We apply these calculations to study the filter and gating regions of KcsA. We observe a continuous path of rotational deformations physically coupling these two regions, and, we propose, underlying the allosteric interaction between these regions. Bend, splay, and twist distinguish KcsA gate opening, filter opening, and filter-gate coupling, respectively. In general, physically meaningful representations of deformations (like strain, curl, bend, splay, and twist) can make testable predictions and yield insights into protein mechanics, augmenting experimental methods and more fully exploiting available structural data. PMID- 29116054 TI - Non-rigid CT/CBCT to CBCT registration for online external beam radiotherapy guidance. AB - Image-guided external beam radiotherapy (EBRT) allows radiation dose deposition with a high degree of accuracy and precision. Guidance is usually achieved by estimating the displacements, via image registration, between cone beam computed tomography (CBCT) and computed tomography (CT) images acquired at different stages of the therapy. The resulting displacements are then used to reposition the patient such that the location of the tumor at the time of treatment matches its position during planning. Moreover, ongoing research aims to use CBCT-CT image registration for online plan adaptation. However, CBCT images are usually acquired using a small number of x-ray projections and/or low beam intensities. This often leads to the images being subject to low contrast, low signal-to-noise ratio and artifacts, which ends-up hampering the image registration process. Previous studies addressed this by integrating additional image processing steps into the registration procedure. However, these steps are usually designed for particular image acquisition schemes, therefore limiting their use on a case-by case basis. In the current study we address CT to CBCT and CBCT to CBCT registration by the means of the recently proposed EVolution registration algorithm. Contrary to previous approaches, EVolution does not require the integration of additional image processing steps in the registration scheme. Moreover, the algorithm requires a low number of input parameters, is easily parallelizable and provides an elastic deformation on a point-by-point basis. Results have shown that relative to a pure CT-based registration, the intrinsic artifacts present in typical CBCT images only have a sub-millimeter impact on the accuracy and precision of the estimated deformation. In addition, the algorithm has low computational requirements, which are compatible with online image-based guidance of EBRT treatments. PMID- 29116055 TI - Improvement of single detector proton radiography by incorporating intensity of time-resolved dose rate functions. AB - Proton radiography, which images patients with the same type of particles as those with which they are to be treated, is a promising approach to image guidance and water equivalent path length (WEPL) verification in proton radiation therapy. We have shown recently that proton radiographs could be obtained by measuring time-resolved dose rate functions (DRFs) using an x-ray amorphous silicon flat panel. The WEPL values were derived solely from the root-mean-square (RMS) of DRFs, while the intensity information in the DRFs was filtered out. In this work, we explored the use of such intensity information for potential improvement in WEPL accuracy and imaging quality. Three WEPL derivation methods based on, respectively, the RMS only, the intensity only, and the intensity weighted RMS were tested and compared in terms of the quality of obtained radiograph images and the accuracy of WEPL values. A Gammex CT calibration phantom containing inserts made of various tissue substitute materials with independently measured relative stopping powers (RSP) was used to assess the imaging performances. Improved image quality with enhanced interfaces was achieved while preserving the accuracy by using intensity information in the calibration. Other objects, including an anthropomorphic head phantom, a proton therapy range compensator, a frozen lamb's head and an 'image quality phantom' were also imaged. Both the RMS only and the intensity-weighted RMS methods derived RSPs within +/- 1% for most of the Gammex phantom inserts, with a mean absolute percentage error of 0.66% for all inserts. In the case of the insert with a titanium rod, the method based on RMS completely failed, whereas that based on the intensity-weighted RMS was qualitatively valid. The use of intensity greatly enhanced the interfaces between different materials in the obtained WEPL images, suggesting the potential for image guidance in areas such as patient positioning and tumor tracking by proton radiography. PMID- 29116057 TI - Numerical assessment of low-frequency dosimetry from sampled magnetic fields. AB - Low-frequency dosimetry is commonly assessed by evaluating the electric field in the human body using the scalar potential finite difference method. This method is effective only when the sources of the magnetic field are completely known and the magnetic vector potential can be analytically computed. The aim of the paper is to present a rigorous method to characterize the source term when only the magnetic flux density is available at discrete points, e.g. in case of field measurements. The method is based on the solution of the discrete magnetic curl equation. The system is restricted to the independent set of magnetic fluxes and circulations of magnetic vector potential using the topological information of the computational mesh. The solenoidality of the magnetic flux density is preserved using a divergence-free interpolator based on vector radial basis functions. The analysis of a benchmark problem shows that the complexity of the proposed algorithm is linearly dependent on the number of elements with a controllable accuracy. The method proposed in this paper also proves to be useful and effective when applied to a real world scenario, where the magnetic flux density is measured in proximity of a power transformer. A 8 million voxel body model is then used for the numerical dosimetric analysis. The complete assessment is completed in less than 5 min, that is more than acceptable for these problems. PMID- 29116056 TI - Excess area dependent scaling behavior of nano-sized membrane tethers. AB - Thermal fluctuations in cell membranes manifest as an excess area ([Formula: see text]) which governs a multitude of physical process at the sub-micron scale. We present a theoretical framework, based on an in silico tether pulling method, which may be used to reliably estimate [Formula: see text] in live cells. We perform our simulations in two different thermodynamic ensembles: (i) the constant projected area and (ii) the constant frame tension ensembles and show the equivalence of our results in the two. The tether forces estimated from our simulations compare well with our experimental measurements for tethers extracted from ruptured GUVs and HeLa cells. We demonstrate the significance and validity of our method by showing that all our calculations performed in the initial tether formation regime (i.e. when the length of the tether is comparable to its radius) along with experiments of tether extraction in 15 different cell types collapse onto two unified scaling relationships mapping tether force, tether radius, bending stiffness kappa, and membrane tension sigma. We show that [Formula: see text] is an important determinant of the radius of the extracted tether, which is equal to the characteristic length [Formula: see text] for [Formula: see text], and is equal to [Formula: see text] for [Formula: see text]. We also find that the estimated excess area follows a linear scaling behavior that only depends on the true value of [Formula: see text] for the membrane, based on which we propose a self-consistent technique to estimate the range of excess membrane areas in a cell. PMID- 29116060 TI - [Academician Andrey Dar'evich Mirzabekov (to the 80th anniversary)]. PMID- 29116058 TI - A line fiducial method for geometric calibration of cone-beam CT systems with diverse scan trajectories. AB - Modern cone-beam CT systems, especially C-arms, are capable of diverse source detector orbits. However, geometric calibration of these systems using conventional configurations of spherical fiducials (BBs) may be challenged for novel source-detector orbits and system geometries. In part, this is because the BB configurations are designed with careful forethought regarding the intended orbit so that BB marker projections do not overlap in projection views. Examples include helical arrangements of BBs (Rougee et al 1993 Proc. SPIE 1897 161-9) such that markers do not overlap in projections acquired from a circular orbit and circular arrangements of BBs (Cho et al 2005 Med. Phys. 32 968-83). As a more general alternative, this work proposes a calibration method based on an array of line-shaped, radio-opaque wire segments. With this method, geometric parameter estimation is accomplished by relating the 3D line equations representing the wires to the 2D line equations of their projections. The use of line fiducials simplifies many challenges with fiducial recognition and extraction in an orbit independent manner. For example, their projections can overlap only mildly, for any gantry pose, as long as the wires are mutually non-coplanar in 3D. The method was tested in application to circular and non-circular trajectories in simulation and in real orbits executed using a mobile C-arm prototype for cone-beam CT. Results indicated high calibration accuracy, as measured by forward and backprojection/triangulation error metrics. Triangulation errors on the order of microns and backprojected ray deviations uniformly less than 0.2 mm were observed in both real and simulated orbits. Mean forward projection errors less than 0.1 mm were observed in a comprehensive sweep of different C-arm gantry angulations. Finally, successful integration of the method into a CT imaging chain was demonstrated in head phantom scans. PMID- 29116061 TI - [Exosomal surface protein markers in diagnosis of colorectal cancer]. AB - Colorectal cancer (CRC) is one of the most common primary malignancies. Early stages of the disease are asymptomatic in the majority of cases, leading to late detection and high mortality. Available noninvasive diagnostic techniques are limited in sensitivity and specificity, and designing new ones is still a pressing problem. Exosomes are membrane-derived microvesicles secreted into human biological fluids and provide a novel way to assess the course of an oncology disease. The review describes the repertoire of exosomal surface biomarkers found in the blood of CRC patients and the prospects of employing multiplexed tests for exosomal markers in early noninvasive diagnosis of cancer. PMID- 29116062 TI - [Biobanks as the basis for developing biomedicine: Problems and prospects]. AB - Biobanking is crucial for the development of life sciences in general and biomedical science in particular. A systematic study of stored biomaterials enables the discovery of new biomarkers for various physiological and pathophysiological states, identification of the drug targets, and validation of these findings in human population studies. During the last decades, the importance of biobanking has increased in parallel with the growth in their size from relatively small collections to very large national and international biorepositories. Here, we have systematically reviewed modern approaches to biobanking, a variety of biobank definitions and types, and the current states of biobanking art in Russia and in the world and have discussed the obstacles to the global development of biobanking, along with possible solutions. PMID- 29116063 TI - [MYC gene family in cereals: Transformations during evolution of hexaploid bread wheat and its relatives]. AB - The transcription factors of the MYC gene family are an integral part of the MYB + MYC + WD40 regulatory complex required to activate the genes of plant flavonoid biosynthesis. The TaMyc1 gene, which controls the synthesis of flavonoid pigments in the grain pericarp, is known in bread wheat (Triticum aestivum L., BBAADD genome, 2n = 6x = 42). In the present work, we identified 10 copies of this gene in the T. aestivum genome, 22 copies in the nearest bread wheat relatives (T. durum, T. urartu, T. monococcum, Aegilops speltoides, Ae. sharonensis, Ae. tauschii). The analysis of genetic similarity of all these genes demonstrated that the MYC gene duplication occurred for the first time in the common diploid ancestor of the Triticeae tribe with the formation of copies in the second and fourth chromosomes. In the members of the Triticum and Aegilops genera, these genes underwent from two to four duplication acts that resulted in the formation of paralogous copies. The orthologs of the MYC genes obtained from ancestral diploid species exist in polyploid species of the Triticum genus (in addition to paralogues). The time of the emergence of individual MYC family members was calculated based on the average speed of accumulation of nucleotide substitutions (k) in the MYC genes (established in this work) and certain number of synonymous substitutions between individual copies. PMID- 29116064 TI - [Identification and expression analysis of receptor-like kinase gene ERECTA in mycoheterotrophic plant Monotropa hypopitys]. AB - The precise spatial-temporal coordination of cell division and differentiation is necessary for the correct formation of tissues, organs, and the organism as a whole. This coordination has been implemented by the intercellular communication mediated by signaling molecules and receptors that selectively recognize them. Membrane receptor kinases of ERECTA family regulate inflorescence and flower structure, the formation of root epidermis and adaptation responses. The characterization of the ERECTA genes of flowering plant pinesap Monotropa hypopitys with unique development features can enrich the knowledge about the kinase ERECTA functions and conserved development processes with their participation. Transcriptomic and genomic search with the subsequent structural phylogenetic analysis identified the mRNA of a gene of serine-threonine kinase receptor with leucine-rich repeats of MhyERL1, which is the only ortholog of the ERECTA family kinases of pinesap. A quantitative analysis of the MhyERL1 gene transcripts has revealed its expression in all analyzed pinesap tissues with maximum levels in the flowers. MhyERL1 is probably involved in defining the inflorescence and flower architecture, and the formation of the pinesap root epidermis. The cascades involving ERL1 are apparently conserved. The exception are pathways associated with the development of above-ground vegetative structures, and the immune response to fungal pathogens probably lost in the process of the pinesap adaptation to unfavorable environmental conditions. PMID- 29116065 TI - [Immunogenicity of recombinant analog of antitumor protein lactaptin]. AB - Therapeutic monoclonal antibodies and recombinant proteins including cytokines are commonly used in the treatment of cancer and inflammatory diseases. In most cases, these protein-based drugs exhibit a high therapeutic efficacy, which is unfortunately frequently associated with a variety of side effects. We have investigated the in vitro and in vivo immunogenicity of recombinant antitumor protein lactaptin (RL2). Based on the qRT-PCR analysis, we have shown that, in MDA-MB-231 human breast adenocarcinoma cells, RL2 suppresses the NF-kB signaling cascade that regulates the reactions of innate immunity. RL2 inhibits the expression of the CXCL1 protein and apoptosis inhibitor A20 and enhances expression of IkB, NF-kB repressor. The ELISA method has been used to evaluate the antibody titer in the blood of mice, which received single and triple intravenous or intraperitoneal injections of RL2. The multiplex immunoassay of 23 cytokines in the mice blood has shown that the RL2 injections lead to a slight increase in the levels of systemic pro-inflammatory cytokine interleukin-5 (IL-5) and keratinocyte chemoattractant (KC), a homologue of human macrophage inflammatory protein-1 (MIP-1). These observations indicate the low immunogenicity of the recombinant lactaptin analog, which can be considered to be a potential molecular drug candidate for further clinical development. PMID- 29116066 TI - [Nuclear delivery of oligonucleotides via nanocomposites based on TiO2 nanoparticles and polylysine]. AB - The nuclear delivery of nucleic acid derivatives is an essential prerequisite for successful antisense therapy. Using laser confocal and electron microscopy, we have studied the uptake of fluorescently labeled oligonucleotides in the form of nanocomposites with polylysine and TiO2 nanoparticles into Caco2, MDCK, and HeLa cells. In all three cell lines, bright fluorescence has been detected after 30 min in the nuclei (excluding the nucleoli) of the interphase cells; no substantial increase in the intensity of the signal was observed for next 24 hours. In all cells undergoing mitosis, the signal was localized in the cytoplasm with zones of higher intensity around chromatin. In some cells, at the beginning of interphase (G-1 phase), fluorescence was not detected at all. The latter may be explained by the brief moment in the cell cycle when oligonucleotides delivered in the nanocomposite cannot be taken up by cells. The studied nanocomposites are prone to aggregation. The degree of aggregation increases with the storage time up to complete loss of the ability of the nanocomposites to penetrate the cells. PMID- 29116067 TI - [Apoptosis as the basic mechanism of cytotoxic action of ursolic and pomolic acids in glioma cells]. AB - Pentacyclic triterpene acids are of great interest as compounds that exhibit selective cytotoxicity against malignant tumor cells. If earlier studies were carried out mainly in cancer cells of epithelial origin, in the present work the cytotoxic effect of ursolic and pomolic acids on the primary and permanent glioma cell lines was analyzed. Both compounds are toxic to oncotransformed cells and induce apoptosis in U-87 MG line. Using molecular docking, it has been shown that Akt1 and MDM2 may be potential targets of the studied triterpene acids. It has been suggested that ursolic and pomolic acids induce apoptosis in glioma cells through inhibition of the PI3K/Akt signaling pathway, and they can be considered as potentially promising agents for the treatment of glioblastoma. PMID- 29116068 TI - [Hydrogel microchip as a tool for studying exosomes in human serum]. AB - Exosomes are cell-derived vesicles that are secreted by both normal and cancer cells. Over the last decade, a few studies have revealed that exosomes cross talk and/or influence major tumor-related pathways such as angiogenesis and metastasis involving many cell types within the tumor microenvironment. The protein composition of the membrane of an exosome reflects that of the membrane of the cell of origin. Because of this, tumor-derived exosomes differ from exosomes that are derived from normal cells. The detection of tumor exosomes and analysis of their molecular composition hold promise for diagnosis and prognosis of cancer. Here, we present hydrogel microarrays (biochips), which contain a panel of immobilized antibodies that recognize tetraspanins (CD9, CD63, CD81) and prognostic markers for colorectal cancer (A33, CD147). These biochips make it possible to analyze the surface proteins of either isolated exosomes or exosomes that are present in the serum samples without isolation. These biochips were successfully used to analyze the surface proteins of exosomes from serum that was collected from a colorectal cancer patient and healthy donor. Biochip-guided immunofluorescent analysis of the exosomes has made it possible for us to detect the A33 antigen and CD147 in the serum sample of the colorectal cancer patient with normal levels of CEA and CA19-9. PMID- 29116069 TI - [Participation of the piRNA pathway in recruiting a component of RNA polymerase I transcription initiation complex to germline cell nucleoli]. AB - Proteins of the Piwi family and short Piwi-interacting RNAs (piRNAs) ensure the protection of the genome from transposable elements. We have previously shown that nuclear Piwi protein tends to concentrate in the nucleoli of the cells of Drosophila melanogaster ovaries. It could be hypothesized that the function of Piwi in the nucleolus is associated with the repression of R1 and R2 retrotransposons inserted into the rDNA cluster. Here, we show that Piwi participates in recruiting Udd protein to nucleoli. Udd is a component of the conserved Selectivity Factor I-like (SL1-like) complex, which is required for transcription initiation by RNA polymerase I. We found that Udd localization depends on Piwi in germline cells, but not in somatic cells of the ovaries. In contrast, knockdowns of the SL1-like components (Udd or TAF1b) do not disrupt Piwi localization. We also observed that the absence of Udd or TAF1b in germline cells, as well as the impairment of Piwi nuclear localization lead to the accumulation of late stage egg chambers in the ovaries, which could be explained by reduced rRNA transcription. These results allow us to propose for the first time a role for Piwi in the nucleolus that is not directly associated with transposable element repression. PMID- 29116070 TI - [The importance of C-terminal aspartic acid residue (D141) to the antirestriction activity of the ArdB (R64) protein]. AB - Antirestriction proteins of the ArdB/KlcA family are specific inhibitors of restriction (endonuclease) activity of type-I restriction/modification enzymes. The effect of conserved amino acid residues on the antirestriction activity of the ArdB protein encoded by the transmissible R64 (IncI1) plasmid has been investigated. An analysis of the amino acid sequences of ArdB homologues demonstrated the presence of four groups of conserved residues ((1) R16, E32, and W51; (2) Y46 and G48; (3) S81, D83 and E132, and (4) N77, L(I)140, and D141) on the surface of the protein globule. Amino acid residues of the fourth group showed a unique localization pattern with the terminal residue protruding beyond the globule surface. The replacement of two conserved amino acids (D141 and N77) located in the close vicinity of each other on the globule surface showed that the C-terminal D141 is essential for the antirestriction activity of ArdB. The deletion of this residue, as well as replacement by a hydrophobic threonine residue (D141T), completely abolished the antirestriction activity of ArdB. The synonymous replacement of D141 by a glutamic acid residue (D141E) caused an approximately 30-fold decrease of the antirestriction activity of ArdB, and the point mutation N77A caused an approximately 20-fold decrease in activity. The residues D141 and N77 located on the surface of the protein globule are presumably essential for the formation of a contact between ArdB and a currently unknown factor that modulates the activity of type-I restriction/modification enzymes. PMID- 29116071 TI - [CRISPR/Cas9-editing-based modeling of hypoxia in renal cancer cells]. AB - Uncontrolled growth in the cell mass of malignant tumors induces intensive angiogenesis. However, the demands of the cancer cells for nutrients and oxygen remain only partially met. Hypoxia is a process that accompanies malignant transformation and evokes changes in the DNA methylation profile in solid tumors. To a certain extent, these changes, including the hypermethylation of tumor suppressor gene promoters, are related to the decrease in the activity of Tet proteins under the conditions of oxygen and free radical deficit. Stabilization, accumulation, and nuclear translocation of the transcription factor HIF1alpha are the key molecular events in hypoxia. We modified the clear-cell renal cancer cell line Caki1 to stabilize the HIF1alpha protein and characterized a model cell line that will enable the studies of the mechanisms of changes of the DNA methylation level at a constant activity of Tet proteins and a gene transcription profile characteristic of hypoxia. The CRISPR/Cas9 DNA editing system was used to edit the VHL gene. The mutant VHL protein contained a disrupted alpha-helix at the C terminus and could not participate in the molecular pathway of proteasomal degradation of the HIF1alpha factor; therefore, the latter accumulated in the nucleus and activated the specific target genes. An analysis of gene transcription revealed the induction of hypoxia-associated genes in the modified cell line. The developed Saki-1/VHLmut model can be used to discriminate between the effects evoked by oxygen-suppressed hydroxylases of the Tet family and other hypoxia-associated mechanisms of DNA methylation/demethylation. PMID- 29116072 TI - [Treatment with anti-cancer agents results in profound changes in lncRNA expression in colon cancer cells]. AB - Using real-time RT-PCR in combination with bioinformatics, we have shown for the first time that the treatment of HCT-116 and HT-29 colon cancer cells with two anti-cancer agents (doxycycline or 3,3'-diindolylmethane) results in profound changes in the intracellular content of several lncRNAs (by up to 100 times). Since many of these RNAs are secreted by tumors into the bloodstream, the obtained results provide a basis for developing more sensitive protocols for serological monitoring of tumor relapse and metastasis, as well as for search of new anti-cancer drugs. PMID- 29116073 TI - [Differential expression of an ensemble of the key genes involved in cell-cycle regulation in lung cancer]. AB - Targeted cancer therapy directed at individual targets is often accompanied by the rapid development of drug resistance. The development of a new generation of antitumor drugs involves the search for many targets simultaneously to block or, conversely, restore their activity. In this regard, simultaneous analysis of gene expression in a complex network of interactions, primarily cell cycle control elements, is relevant for the search of specific molecular markers for the differential diagnosis of adenocarcinoma (ADC) and squamous cell lung cancer (SCC), as well as new targets for therapy. In this paper we performed an extended quantitative analysis of the expression of two suppressor genes, CTDSPL and its target RB1, as well as 84 genes of the main participants of the p16^(INK4A) Cdk/cyclin D1-Rb and p53/p21^(Waf1) signaling pathways in the histological types of non-small-cell lung cancer (NSCLC), i.e., ADC and SCC, using the special panel of the Human Cell Cycle Regulation Panel. The expression profile of some genes shows the specificity to the histological type of NSCLC and the presence of metastases. The genes with a significantly increased expression that affect the activity of Rb (cyclins, cyclin-dependent kinases, their activators, inhibitors, etc.) can serve as potential targets for combined therapy of both ADC and SCC. PMID- 29116074 TI - [Proteome of the human HaCaT keratinocytes: Identification of the oxidative stress proteins after sodium dodecyl sulpfate exposur]. AB - Oxidative stress is a universal response of the skin cell damage of various origins. Sodium dodecyl sulfate (SDS, sodium lauryl sulfate) is an anionic surfactant commonly used as an emulsifying detergent in household cleaners. Sodium dodecyl sulfate is the reference compound for testing toxicity on cellular skin models. The effect of sodium dodecyl sulfate in sub toxic dose 25 MUg/mL during 48 h on the protein profile of human keratinocytes HaCaT was studied by tandem mass spectrometry with electrospray ionization. In total, 1064 proteins were found in immortalized human keratinocytes HaCaT, of which about 80% were identified by two or more peptides. The change of the 217 proteins content was revealed, among them 39 according to Gene Ontology are associated with oxidative stress. It has been found that sodium dodecyl sulfate leads to a decrease in the number of proteins/peptides containing carboxymethylated and/or carboxyethylated lysine. We concluded about the promising of the cells redox-balance analysis at testing chemicals in the doses, which do not lead to a decrease in their viability. Possible involvement of sodium dodecyl sulfate in the development of cutaneous neoplasia is discussed. PMID- 29116075 TI - [Differential alternative splicing in brain regions of rats selected for aggressive behavior]. AB - Profiles of alternative mRNA isoforms have been determined in three brain regions of rats from an aggressive and a tame line selected for 74 generations. Among 2319 genes with alternatively spliced exons, approximately 84% were confirmed by analyzing public databases. Based on Gene Ontology-guided clustering of alternatively spliced genes, it has been found that the sample was enriched in synapse-specific genes (FDR < 10^(-17)). Patterns of gene expression in the brains of animals with genetically determined high or low aggression were more frequently found to differ in the use of alternatively spliced exons than in animals environmentally conditioned for increased or lowered propensity to aggression. For the Adcyap1r1 gene, five alternatively spliced mRNA isoforms have been represented differentially in aggressive animals. A detailed analysis of the gene that encodes glutamate ionotropic receptor NMDA type subunit 1 (Grin1) has confirmed significant differences in the levels of its alternatively spliced isoforms in certain brain regions of tame and aggressive rats. These differences may affect the behavior in rats genetically selected for aggression levels. PMID- 29116076 TI - The effect of genetic variation on promoter usage and enhancer activity. AB - The identification of genetic variants affecting gene expression, namely expression quantitative trait loci (eQTLs), has contributed to the understanding of mechanisms underlying human traits and diseases. The majority of these variants map in non-coding regulatory regions of the genome and their identification remains challenging. Here, we use natural genetic variation and CAGE transcriptomes from 154 EBV-transformed lymphoblastoid cell lines, derived from unrelated individuals, to map 5376 and 110 regulatory variants associated with promoter usage (puQTLs) and enhancer activity (eaQTLs), respectively. We characterize five categories of genes associated with puQTLs, distinguishing single from multi-promoter genes. Among multi-promoter genes, we find puQTL effects either specific to a single promoter or to multiple promoters with variable effect orientations. Regulatory variants associated with opposite effects on different mRNA isoforms suggest compensatory mechanisms occurring between alternative promoters. Our analyses identify differential promoter usage and modulation of enhancer activity as molecular mechanisms underlying eQTLs related to regulatory elements. PMID- 29116077 TI - Convenient iron-catalyzed reductive aminations without hydrogen for selective synthesis of N-methylamines. AB - N-Methylated amines play an important role in regulating the biological and pharmaceutical properties of all kinds of life science molecules. In general, this class of compounds is synthesized via reductive amination reactions using high pressure of molecular hydrogen. Thus, on laboratory scale especially in drug discovery, activated (toxic) methyl compounds such as methyl iodide and dimethyl sulfate are still employed, which also generate significant amounts of waste. Therefore, the development of more convenient and operationally simple processes for the synthesis of advanced N-methylamines is highly desired. Herein, we report the synthesis of functionalized and structurally diverse N-methylamines directly from nitroarenes and paraformaldehyde, in which the latter acts as both methylation and reducing agent in the presence of reusable iron oxide catalyst. The general applicability of this protocol is demonstrated by the synthesis of >50 important N-methylamines including highly selective reductive N-methylations of life science molecules and actual drugs, namely hordenine, venlafaxine, imipramine and amitriptyline. PMID- 29116078 TI - Tracing the origin and evolution of supergene mimicry in butterflies. AB - Supergene mimicry is a striking phenomenon but we know little about the evolution of this trait in any species. Here, by studying genomes of butterflies from a recent radiation in which supergene mimicry has been isolated to the gene doublesex, we show that sexually dimorphic mimicry and female-limited polymorphism are evolutionarily related as a result of ancient balancing selection combined with independent origins of similar morphs in different lineages and secondary loss of polymorphism in other lineages. Evolutionary loss of polymorphism appears to have resulted from an interaction between natural selection and genetic drift. Furthermore, molecular evolution of the supergene is dominated not by adaptive protein evolution or balancing selection, but by extensive hitchhiking of linked variants on the mimetic dsx haplotype that occurred at the origin of mimicry. Our results suggest that chance events have played important and possibly opposing roles throughout the history of this classic example of adaptation. PMID- 29116079 TI - A mesoporous cationic thorium-organic framework that rapidly traps anionic persistent organic pollutants. AB - Many environmental pollutants inherently exist in their anionic forms and are therefore highly mobile in natural water systems. Cationic framework materials that can capture those pollutants are highly desirable but scarcely reported. Here we present a mesoporous cationic thorium-based MOF (SCU-8) containing channels with a large inner diameter of 2.2 nm and possessing a high surface area of 1360 m2 g-1. The anion-exchange properties of SCU-8 were explored with many anions including small oxo anions like ReO4- and Cr2O72- as well as anionic organic dyes like methyl blue and the persistent organic pollutant, perfluorooctane sulfonate (PFOS). Both fast uptake kinetics and great sorption selectivity toward PFOS are observed. The underlying sorption mechanism was probed using quantum mechanical and molecular dynamics simulations. These computational results reveal that PFOS anions are immobilized in SCU-8 by driving forces including electrostatic interactions, hydrogen bonds, hydrophobic interactions, and van der Waals interactions at different adsorption stages. PMID- 29116080 TI - Structural basis for high-affinity actin binding revealed by a beta-III-spectrin SCA5 missense mutation. AB - Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the cytoskeletal protein beta-III-spectrin. Previously, a SCA5 mutation resulting in a leucine-to-proline substitution (L253P) in the actin binding domain (ABD) was shown to cause a 1000-fold increase in actin-binding affinity. However, the structural basis for this increase is unknown. Here, we report a 6.9 A cryo-EM structure of F-actin complexed with the L253P ABD. This structure, along with co-sedimentation and pulsed-EPR measurements, demonstrates that high-affinity binding caused by the CH2-localized mutation is due to opening of the two CH domains. This enables CH1 to bind actin aided by an unstructured N terminal region that becomes alpha-helical upon binding. This helix is required for association with actin as truncation eliminates binding. Collectively, these results shed light on the mechanism by which beta-III-spectrin, and likely similar actin-binding proteins, interact with actin, and how this mechanism can be perturbed to cause disease. PMID- 29116082 TI - Aperiodic nanoplasmonic devices for directional colour filtering and sensing. AB - Exploiting the wave-nature of light in its simplest form, periodic architectures have enabled a panoply of tunable optical devices with the ability to perform useful functions such as filtering, spectroscopy, and multiplexing. Here, we remove the constraint of structural periodicity to enhance, simultaneously, the performance and functionality of passive plasmonic devices operating at optical frequencies. By using a physically intuitive, first-order interference model of plasmon-light interactions, we demonstrate a simple and efficient route towards designing devices with flexible, multi-spectral optical response, fundamentally not achievable using periodic architectures. Leveraging this approach, we experimentally implement ultra-compact directional light-filters and colour sorters exhibiting angle- or spectrally-tunable optical responses with high contrast, and low spectral or spatial crosstalk. Expanding the potential of aperiodic systems to implement tailored spectral and angular responses, these results hint at promising applications in solar-energy harvesting, optical signal multiplexing, and integrated sensing. PMID- 29116081 TI - A method for measuring the distribution of the shortest telomeres in cells and tissues. AB - Improved methods to measure the shortest (not just average) telomere lengths (TLs) are needed. We developed Telomere Shortest Length Assay (TeSLA), a technique that detects telomeres from all chromosome ends from <1 kb to 18 kb using small amounts of input DNA. TeSLA improves the specificity and efficiency of TL measurements that is facilitated by user friendly image-processing software to automatically detect and annotate band sizes, calculate average TL, as well as the percent of the shortest telomeres. Compared with other TL measurement methods, TeSLA provides more information about the shortest telomeres. The length of telomeres was measured longitudinally in peripheral blood mononuclear cells during human aging, in tissues during colon cancer progression, in telomere related diseases such as idiopathic pulmonary fibrosis, as well as in mice and other organisms. The results indicate that TeSLA is a robust method that provides a better understanding of the shortest length of telomeres. PMID- 29116084 TI - Thermodynamic signatures of the field-induced states of graphite. AB - When a magnetic field confines the carriers of a Fermi sea to their lowest Landau level, electron-electron interactions are expected to play a significant role in determining the electronic ground state. Graphite is known to host a sequence of magnetic field-induced states driven by such interactions. Three decades after their discovery, thermodynamic signatures of these instabilities are still elusive. Here we report the detection of these transitions with sound velocity measurements. The evolution of elastic constant anomalies with temperature and magnetic field allows to draw a detailed phase diagram which shows that the ground state evolves in a sequence of thermodynamic phase transitions. Our analysis indicates that the electron-electron interaction is not the sole driving force of these transitions and that lattice degrees of freedom play an important role. PMID- 29116083 TI - Odor-evoked inhibition of olfactory sensory neurons drives olfactory perception in Drosophila. AB - Inhibitory response occurs throughout the nervous system, including the peripheral olfactory system. While odor-evoked excitation in peripheral olfactory cells is known to encode odor information, the molecular mechanism and functional roles of odor-evoked inhibition remain largely unknown. Here, we examined Drosophila olfactory sensory neurons and found that inhibitory odors triggered outward receptor currents by reducing the constitutive activities of odorant receptors, inhibiting the basal spike firing in olfactory sensory neurons. Remarkably, this odor-evoked inhibition of olfactory sensory neurons elicited by itself a full range of olfactory behaviors from attraction to avoidance, as did odor-evoked olfactory sensory neuron excitation. These results indicated that peripheral inhibition is comparable to excitation in encoding sensory signals rather than merely regulating excitation. Furthermore, we demonstrated that a bidirectional code with both odor-evoked inhibition and excitation in single olfactory sensory neurons increases the odor-coding capacity, providing a means of efficient sensory encoding. PMID- 29116085 TI - Lossless quantum data compression with exponential penalization: an operational interpretation of the quantum Renyi entropy. AB - Based on the problem of quantum data compression in a lossless way, we present here an operational interpretation for the family of quantum Renyi entropies. In order to do this, we appeal to a very general quantum encoding scheme that satisfies a quantum version of the Kraft-McMillan inequality. Then, in the standard situation, where one is intended to minimize the usual average length of the quantum codewords, we recover the known results, namely that the von Neumann entropy of the source bounds the average length of the optimal codes. Otherwise, we show that by invoking an exponential average length, related to an exponential penalization over large codewords, the quantum Renyi entropies arise as the natural quantities relating the optimal encoding schemes with the source description, playing an analogous role to that of von Neumann entropy. PMID- 29116086 TI - Quantum wave mixing and visualisation of coherent and superposed photonic states in a waveguide. AB - Superconducting quantum systems (artificial atoms) have been recently successfully used to demonstrate on-chip effects of quantum optics with single atoms in the microwave range. In particular, a well-known effect of four wave mixing could reveal a series of features beyond classical physics, when a non linear medium is scaled down to a single quantum scatterer. Here we demonstrate the phenomenon of quantum wave mixing (QWM) on a single superconducting artificial atom. In the QWM, the spectrum of elastically scattered radiation is a direct map of the interacting superposed and coherent photonic states. Moreover, the artificial atom visualises photon-state statistics, distinguishing coherent, one- and two-photon superposed states with the finite (quantised) number of peaks in the quantum regime. Our results may give a new insight into nonlinear quantum effects in microwave optics with artificial atoms. PMID- 29116087 TI - Differential Expression of miR-93 and miR-21 in Granulosa Cells and Follicular Fluid of Polycystic Ovary Syndrome Associating with Different Phenotypes. AB - The heterogeneous and multifactorial essence of polycystic ovary syndrome (PCOS) renders a remarkable significance to microRNAs (miRNAs). Normo-androgenic (NA) and hyperandrogenic (HA) PCOS patients were compared with matched healthy women. Expression of miRNAs and TGFbeta signaling genes was studied by qRT-PCR and western blotting. Effect of androgen on expression of miR-93 and miR-21 and involvement of androgen receptor were appraised. In granulosa cells (GCs), miR-93 and miR-21 showed significantly increased levels in HA patients compared to NA patients. On the contrary, follicular fluid (FF) levels of both miRNAs were significantly decreased in HA group compared to control women. No significant change in the expression of miRNAs in serum samples was detected. Furthermore, mRNA levels of SMAD7 and TGFBR2 were significantly downregulated in GCs of HA group compared to NA and control subjects. TGFBR2 protein level was significantly decreased in HA patients compared to controls. Free testosterone and free androgen index were positively correlated with expression of miR-93 and miR-21 in GCs of PCOS group. Our findings show distinct molecular signature of different subtypes of PCOS. Intermediary position of miRNAs as androgen responsive factors may play critical role in the pathogenesis of PCOS in hyperandrogenic condition. PMID- 29116088 TI - Statistical parity-time-symmetric lasing in an optical fibre network. AB - Parity-time (PT)-symmetry in optics is a condition whereby the real and imaginary parts of the refractive index across a photonic structure are deliberately balanced. This balance can lead to interesting optical phenomena, such as unidirectional invisibility, loss-induced lasing, single-mode lasing from multimode resonators, and non-reciprocal effects in conjunction with nonlinearities. Because PT-symmetry has been thought of as fragile, experimental realisations to date have been usually restricted to on-chip micro-devices. Here, we demonstrate that certain features of PT-symmetry are sufficiently robust to survive the statistical fluctuations associated with a macroscopic optical cavity. We examine the lasing dynamics in optical fibre-based coupled cavities more than a kilometre in length with balanced gain and loss. Although fluctuations can detune the cavity by more than the free spectral range, the behaviour of the lasing threshold and the laser power is that expected from a PT stable system. Furthermore, we observe a statistical symmetry breaking upon varying the cavity loss. PMID- 29116090 TI - Correspondence: Reply to 'On the bonding in ligand-protected gold clusters'. PMID- 29116089 TI - Resistance to TGFbeta suppression and improved anti-tumor responses in CD8+ T cells lacking PTPN22. AB - Transforming growth factor beta (TGFbeta) is important in maintaining self tolerance and inhibits T cell reactivity. We show that CD8+ T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFbeta. Resistance to TGFbeta suppression, while disadvantageous in autoimmunity, helps Ptpn22 -/- T cells to be intrinsically superior at clearing established tumors that secrete TGFbeta. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL 2, which overcomes TGFbeta-mediated suppression. These data suggest that a viable strategy to improve anti-tumor adoptive cell therapy may be to engineer tumor restricted T cells with mutations identified as risk factors for autoimmunity. PMID- 29116091 TI - Strong laser field control of fragment spatial distributions from a photodissociation reaction. AB - The notion that strong laser light can intervene and modify the dynamical processes of matter has been demonstrated and exploited both in gas and condensed phases. The central objective of laser control schemes has been the modification of branching ratios in chemical processes, under the philosophy that conveniently tailored light can steer the dynamics of a chemical mechanism towards desired targets. Less explored is the role that strong laser control can play on chemical stereodynamics, i.e. the angular distribution of the products of a chemical reaction in space. This work demonstrates for the case of methyl iodide that when a molecular bond breaking process takes place in the presence of an intense infrared laser field, its stereodynamics is profoundly affected, and that the intensity of this laser field can be used as an external knob to control it. PMID- 29116092 TI - Observation of the exceptional point in cavity magnon-polaritons. AB - Magnon-polaritons are hybrid light-matter quasiparticles originating from the strong coupling between magnons and photons. They have emerged as a potential candidate for implementing quantum transducers and memories. Owing to the dampings of both photons and magnons, the polaritons have limited lifetimes. However, stationary magnon-polariton states can be reached by a dynamical balance between pumping and losses, so the intrinsically nonequilibrium system may be described by a non-Hermitian Hamiltonian. Here we design a tunable cavity quantum electrodynamics system with a small ferromagnetic sphere in a microwave cavity and engineer the dissipations of photons and magnons to create cavity magnon polaritons which have non-Hermitian spectral degeneracies. By tuning the magnon photon coupling strength, we observe the polaritonic coherent perfect absorption and demonstrate the phase transition at the exceptional point. Our experiment offers a novel macroscopic quantum platform to explore the non-Hermitian physics of the cavity magnon-polaritons. PMID- 29116094 TI - Underwater sound from vessel traffic reduces the effective communication range in Atlantic cod and haddock. AB - Stellwagen Bank National Marine Sanctuary is located in Massachusetts Bay off the densely populated northeast coast of the United States; subsequently, the marine inhabitants of the area are exposed to elevated levels of anthropogenic underwater sound, particularly due to commercial shipping. The current study investigated the alteration of estimated effective communication spaces at three spawning locations for populations of the commercially and ecologically important fishes, Atlantic cod (Gadus morhua) and haddock (Melanogrammus aeglefinus). Both the ambient sound pressure levels and the estimated effective vocalization radii, estimated through spherical spreading models, fluctuated dramatically during the three-month recording periods. Increases in sound pressure level appeared to be largely driven by large vessel activity, and accordingly exhibited a significant positive correlation with the number of Automatic Identification System tracked vessels at the two of the three sites. The near constant high levels of low frequency sound and consequential reduction in the communication space observed at these recording sites during times of high vocalization activity raises significant concerns that communication between conspecifics may be compromised during critical biological periods. This study takes the first steps in evaluating these animals' communication spaces and alteration of these spaces due to anthropogenic underwater sound. PMID- 29116095 TI - Magnetic actuation and feedback cooling of a cavity optomechanical torque sensor. AB - Cavity optomechanics has demonstrated remarkable capabilities, such as measurement and control of mechanical motion at the quantum level. Yet many compelling applications of optomechanics-such as microwave-to-telecom wavelength conversion, quantum memories, materials studies, and sensing applications-require hybrid devices, where the optomechanical system is coupled to a separate, typically condensed matter, system. Here, we demonstrate such a hybrid optomechanical system, in which a mesoscopic ferromagnetic needle is integrated with an optomechanical torsional resonator. Using this system we quantitatively extract the magnetization of the needle, not known a priori, demonstrating the potential of this system for studies of nanomagnetism. Furthermore, we show that we can magnetically dampen its torsional mode from room-temperature to 11.6 K improving its mechanical response time without sacrificing torque sensitivity. Future extensions will enable studies of high-frequency spin dynamics and broadband wavelength conversion via torque mixing. PMID- 29116097 TI - Microscopy as a statistical, Renyi-Ulam, half-lie game: a new heuristic search strategy to accelerate imaging. AB - Finding a fluorescent target in a biological environment is a common and pressing microscopy problem. This task is formally analogous to the canonical search problem. In ideal (noise-free, truthful) search problems, the well-known binary search is optimal. The case of half-lies, where one of two responses to a search query may be deceptive, introduces a richer, Renyi-Ulam problem and is particularly relevant to practical microscopy. We analyse microscopy in the contexts of Renyi-Ulam games and half-lies, developing a new family of heuristics. We show the cost of insisting on verification by positive result in search algorithms; for the zero-half-lie case bisectioning with verification incurs a 50% penalty in the average number of queries required. The optimal partitioning of search spaces directly following verification in the presence of random half-lies is determined. Trisectioning with verification is shown to be the most efficient heuristic of the family in a majority of cases. PMID- 29116096 TI - AQP3 is regulated by PPARgamma and JNK in hepatic stellate cells carrying PNPLA3 I148M. AB - Aquaglyceroporins (AQPs) allow the movement of glycerol that is required for triglyceride formation in hepatic stellate cells (HSC), as key cellular source of fibrogenesis in the liver. The genetic polymorphism I148M of the patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with hepatic steatosis and its progression to steatohepatitis (NASH), fibrosis and cancer. We aimed to explore the role of AQP3 for HSC activation and unveil its potential interactions with PNPLA3. HSC were isolated from human liver, experiments were performed in primary HSC and human HSC line LX2. AQP3 was the only aquaglyceroporin present in HSC and its expression decreased during activation. The PPARgamma agonist, rosiglitazone, recovered AQP3 expression also in PNPLA3 I148M carrying HSC. When PNPLA3 was silenced, AQP3 expression increased. In liver sections from patients with NASH, the decreased amount of AQP3 was proportional to the severity of fibrosis and presence of the PNPLA3 I148M variant. In PNPLA3 I148M cells, the blockade of JNK pathway upregulated AQP3 in synergism with PPARgamma. In conclusion, we demonstrated profound reduction of AQP3 in HSC carrying the PNPLA3 I148M variant in parallel to decreased PPARgamma activation, which could be rescued by rosiglitazone and blockade of JNK. PMID- 29116093 TI - The challenge of mapping the human connectome based on diffusion tractography. AB - Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations. PMID- 29116099 TI - Sensing performances of pure and hybridized carbon nanotubes-ZnO nanowire networks: A detailed study. AB - In this work, the influence of carbon nanotube (CNT) hybridization on ultraviolet (UV) and gas sensing properties of individual and networked ZnO nanowires (NWs) is investigated in detail. The CNT concentration was varied to achieve optimal conditions for the hybrid with improved sensing properties. In case of CNT decorated ZnO nanonetworks, the influence of relative humidity (RH) and applied bias voltage on the UV sensing properties was thoroughly studied. By rising the CNT content to about 2.0 wt% (with respect to the entire ZnO network) the UV sensing response is considerably increased from 150 to 7300 (about 50 times). With respect to gas sensing, the ZnO-CNT networks demonstrate an excellent selectivity as well as a high gas response to NH3 vapor. A response of 430 to 50 ppm at room temperature was obtained, with an estimated detection limit of about 0.4 ppm. Based on those results, several devices consisting of individual ZnO NWs covered with CNTs were fabricated using a FIB/SEM system. The highest sensing performance was obtained for the finest NW with diameter (D) of 100 nm, with a response of about 4 to 10 ppm NH3 vapor at room temperature. PMID- 29116098 TI - Chemodrug delivery using integrin-targeted PLGA-Chitosan nanoparticle for lung cancer therapy. AB - In this study, we report the efficacy of RGD (arginine-glycine-aspartic acid) peptide-modified polylactic acid-co-glycolic acid (PLGA)-Chitosan nanoparticle (CSNP) for integrin alphavbeta3 receptor targeted paclitaxel (PTX) delivery in lung cancer cells and its impact on normal cells. RGD peptide-modified chitosan was synthesized and then coated onto PTX-PLGA nanoparticles prepared by emulsion solvent evaporation. PTX-PLGA-CSNP-RGD displayed favorable physicochemical properties for a targeted drug delivery system. The PTX-PLGA-CSNP-RGD system showed increased uptake via integrin receptor mediated endocytosis, triggered enhanced apoptosis, and induced G2/M cell cycle arrest and more overall cytotoxicity than its non-targeted counterpart in cancer cells. PTX-PLGA-CSNP-RGD showed less toxicity in lung fibroblasts than in cancer cells, may be attributed to low drug sensitivity, nevertheless the study invited close attention to their transient overexpression of integrin alphavbeta3 and cautioned against corresponding uptake of toxic drugs, if any at all. Whereas, normal human bronchial epithelial (NHBE) cells with poor integrin alphavbeta3 expression showed negligible toxicity to PTX-PLGA-CSNP-RGD, at equivalent drug concentrations used in cancer cells. Further, the nanoparticle demonstrated its capacity in targeted delivery of Cisplatin (CDDP), a drug having physicochemical properties different to PTX. Taken together, our study demonstrates that PLGA CSNP-RGD is a promising nanoplatform for integrin targeted chemotherapeutic delivery to lung cancer. PMID- 29116100 TI - The Value of CBCT-based Tumor Density and Volume Variations in Prediction of Early Response to Chemoradiation Therapy in Advanced NSCLC. AB - The correlations between early responses and the variations in physical density and primary tumor volume (TV) according to cone-beam computed tomography (CBCT) during chemoradiotherapy for non-small cell lung cancer (NSCLC) patients were investigated. 54 patients with inoperable and locally advanced NSCLC were included in this study. The CT numbers (CTN) and TV were measured on each of the seven observation points. The changes in the mean CTN values and the variation ratios of TV during the treatment course were analysed and correlated with the clinical outcomes, as evaluated by the RECIST criteria. For patients who responded to treatment, the CTN and TV change ratio decreased by 28.44 +/- 13.12 HU and 32.01% (range, 8.46-61.67%); these values were significantly higher than those in the non-responding patients, with 19.63 +/- 8.67 HU and 23.20% (range, 15.57-38%) (p = 0.016, p = 0.048), respectively. The area under curve for the combination of CTN and TV was larger than either alone (AUC = 0.751, p = 0.002). The differences between response and non-response were most significant between Fraction 10 and Fraction 15 for CTN changes and between Fraction 5 and Fraction 10 for the TV regression ratio. The changes in CTN and TV obtained from CBCT images have the potential capability to predict an early response of NSCLC. PMID- 29116101 TI - On-chip Microscopy Using Random Phase Mask Scheme. AB - In this study, a simple and novel phase-retrieval scheme is implemented using multi-angle illumination to enhance the resolution of lensless microscopy. A random-phase mask (from 0 to 2pi) precedes the sample to encode the information at the sensor plane. The sample is illuminated with multiple angles that are symmetrical along the optical axis of the system. The system is initially calibrated while recording the images without any sample at the corresponding multi angles. The two types of image are mutually subtracted, and the resultant images are summed at the sensor plane and backpropagated to the sample plane. The final image is free of the twin-image effect, and has a high signal-to-noise ratio owing to the multi angles of the illumination scheme. This scheme gives a resolution of ~4 micron for a large field-of-view (~15 mm2). The scheme is useful for robust imaging owing to the fast phase-retrieval method, and it enables a straightforward analytical reconstruction instead of using complicated iterative algorithms in a lensless microscopic setup. PMID- 29116102 TI - Epigenetic Transitions and Knotted Solitons in Stretched Chromatin. AB - The spreading and regulation of epigenetic marks on chromosomes is crucial to establish and maintain cellular identity. Nonetheless, the dynamic mechanism leading to the establishment and maintenance of tissue-specific, epigenetic pattern is still poorly understood. In this work we propose, and investigate in silico, a possible experimental strategy to illuminate the interplay between 3D chromatin structure and epigenetic dynamics. We consider a set-up where a reconstituted chromatin fibre is stretched at its two ends (e.g., by laser tweezers), while epigenetic enzymes (writers) and chromatin-binding proteins (readers) are flooded into the system. We show that, by tuning the stretching force and the binding affinity of the readers for chromatin, the fibre undergoes a sharp transition between a stretched, epigenetically disordered, state and a crumpled, epigenetically coherent, one. We further investigate the case in which a knot is tied along the chromatin fibre, and find that the knotted segment enhances local epigenetic order, giving rise to "epigenetic solitons" which travel and diffuse along chromatin. Our results point to an intriguing coupling between 3D chromatin topology and epigenetic dynamics, which may be investigated via single molecule experiments. PMID- 29116103 TI - Giant Slip Induced Anomalous Dewetting of an Ultrathin Film on a Viscous Sublayer. AB - A 'giant' slip dynamics was engineered to a highly confined interface of a dewetting polymethylmethacrylate (PMMA) ultrathin film by introducing a lubricating viscous polystyrene (PS) sublayer. The crossover of regimes from no slip to giant-slip was engendered by tuning the viscosity and thickness of the sublayer. A long-range hole-rim interaction with increase in slippage on the PMMA PS interface transformed the circular holes on the PMMA surface into the noncircular faceted ones. The extent of the slippage and the transition of the length scales from slip-dominated to no-slip regime were evaluated using a general linear stability analysis. The proposed formulation provided an analytical tool to evaluate the slippage effective at the soft and deformable liquid-liquid interfaces. PMID- 29116104 TI - Germline copy number variations are associated with breast cancer risk and prognosis. AB - Breast cancer is one of the most common cancers among women, and susceptibility is explained by genetic, lifestyle and environmental components. Copy Number Variants (CNVs) are structural DNA variations that contribute to diverse phenotypes via gene-dosage effects or cis-regulation. In this study, we aimed to identify germline CNVs associated with breast cancer susceptibility and their relevance to prognosis. We performed whole genome CNV genotyping in 422 cases and 348 controls using Human Affymetrix SNP 6 array. Principal component analysis for population stratification revealed 84 outliers leaving 366 cases and 320 controls of Caucasian ancestry for association analysis; CNVs with frequency > 10% and overlapping with protein coding genes were considered for breast cancer risk and prognostic relevance. Coding genes within the CNVs identified were interrogated for gene- dosage effects by correlating copy number status with gene expression profiles in breast tumor tissue. We identified 200 CNVs associated with breast cancer (q-value < 0.05). Of these, 21 CNV regions (overlapping with 22 genes) also showed association with prognosis. We validated representative CNVs overlapping with APOBEC3B and GSTM1 genes using the TaqMan assay. Germline CNVs conferred dosage effects on gene expression in breast tissue. The candidate CNVs identified in this study warrant independent replication. PMID- 29116106 TI - Ventricular depolarisation vectors in exercise induced myocardial ischaemia. AB - Ischaemia reduces membrane excitability and conduction of myocardial depolarisation. This would alter the synergy of electromotive forces that contribute to a resultant force at any instant. Changes in magnitude and direction of resultant forces are reflected in electrocardiographic signals. Here we show a method for obtaining the coordinates of resultant electrical forces during exercise derived from a bipolar orthogonal lead system for calculation of electrical vectors in three planes. In a trial, analysis of changes in vectors indicated that the extent of reduction in magnitude with exercise was significantly greater in groups of patients categorized by impaired effort tolerance and signs of ischaemia. Measurement of changes in the spectrum of depolarisation vectors during exercise has the potential for non-invasive assessment of myocardial ischaemia. This could be the basis of a portable, low cost tool for investigation of patients with symptoms suggestive of coronary artery disease. PMID- 29116105 TI - Graphene-Insulator-Semiconductor Junction for Hybrid Photodetection Modalities. AB - A sensitive optical detector is presented based on a deeply depleted graphene insulator-semiconducting (D2GIS) junction, which offers the possibility of simultaneously leveraging the advantages of both charge integration and localized amplification. Direct read-out and built-in amplification are accomplished via photogating of a graphene field-effect transistor (GFET) by carriers generated within a deeply depleted low-doped silicon substrate. Analogous to a depleted metal-oxide-semiconducting junction, photo-generated charge collects in the potential well that forms at the semiconductor/insulator interface and induces charges of opposite polarity within the graphene film modifying its conductivity. This device enables simultaneous photo-induced charge integration with continuous "on detector" readout through use of graphene. The resulting devices exhibit responsivities as high as 2,500 A/W (25,000 S/W) for visible wavelengths and a dynamic range of 30 dB. As both the graphene and device principles are transferrable to arbitrary semiconductor absorbers, D2GIS devices offer a high performance paradigm for imaging across the electromagnetic spectrum. PMID- 29116107 TI - MicroRNAs regulating superoxide dismutase 2 are new circulating biomarkers of heart failure. AB - Although several risk factors such as infarct size have been identified, the progression of heart failure (HF) remains difficult to predict in clinical practice. Using an experimental rat model of post-myocardial infarction (MI), we previously identified 45 proteins differentially modulated during HF by proteomic analysis. This study sought to identify microRNAs (miRNAs) able to regulate these proteins and to test their relevance as biomarkers for HF. In silico bioinformatical analysis selected 13 miRNAs related to the 45 proteins previously identified. These miRNAs were analyzed in the rat and in cohorts of patients phenotyped for left ventricular remodeling (LVR). We identified that 3 miRNAs, miR-21-5p, miR-23a-3p and miR-222-3p, and their target Mn superoxide dismutase (SOD2) were significantly increased in LV and plasma of HF-rats. We found by luciferase activity a direct interaction of miR-222-3p with 3'UTR of SOD2. Transfection of human cardiomyocytes with miR-222-3p mimic or inhibitor induced respectively a decrease and an increase of SOD2 expression. Circulating levels of the 3 miRNAs and their target SOD2 were associated with high LVR post-MI in REVE 2 patients. We demonstrated for the first time the potential of microRNAs regulating SOD2 as new circulating biomarkers of HF. PMID- 29116108 TI - Precision Targeting of Tumor Macrophages with a CD206 Binding Peptide. AB - Tumor-associated macrophages (TAMs) expressing the multi-ligand endocytic receptor mannose receptor (CD206/MRC1) contribute to tumor immunosuppression, angiogenesis, metastasis, and relapse. Here, we describe a peptide that selectively targets MRC1-expressing TAMs (MEMs). We performed in vivo peptide phage display screens in mice bearing 4T1 metastatic breast tumors to identify peptides that target peritoneal macrophages. Deep sequencing of the peptide encoding inserts in the selected phage pool revealed enrichment of the peptide CSPGAKVRC (codenamed "UNO"). Intravenously injected FAM-labeled UNO (FAM-UNO) homed to tumor and sentinel lymph node MEMs in different cancer models: 4T1 and MCF-7 breast carcinoma, B16F10 melanoma, WT-GBM glioma and MKN45-P gastric carcinoma. Fluorescence anisotropy assay showed that FAM-UNO interacts with recombinant CD206 when subjected to reducing conditions. Interestingly, the GSPGAK motif is present in all CD206-binding collagens. FAM-UNO was able to transport drug-loaded nanoparticles into MEMs, whereas particles without the peptide were not taken up by MEMs. In ex vivo organ imaging, FAM-UNO showed significantly higher accumulation in sentinel lymph nodes than a control peptide. This study suggests applications for UNO peptide in diagnostic imaging and therapeutic targeting of MEMs in solid tumors. PMID- 29116109 TI - Topographic effect on the phenology of Ficus pedunculosa var. mearnsii (Mearns fig) in its northern boundary distribution, Taiwan. AB - Mearns fig grows at the edge of coastal vegetation on uplifted coral reefs, its population and mutualistic-pollinators are susceptible to the influence of extreme weather. To determine the phenology of Mearns fig and the effects of various weather events under small-scale topographic differences, phenology was conducted for 3 years and 7 months. Results showed that Mearns figs had multiple leaf and fig productions year-round. Topographic effects caused population in Frog Rock Trail and Jialeshuei, which are less than 10 km away from each other, to exhibit different phenological patterns after experiencing severe weather events. Northeast monsoons led the Jialeshuei population to show low amounts of leaves and figs in winter and the phenological production was also susceptible to disturbances by typhoons in summer. Fig reproduction in such environment was disadvantageous to maintain pollinators. Besides, topographic complex in microhabitat of Frog Rock Trail protected some individuals from these same events thus safeguard population's survival. The phenology of Mearns fig would respond to the weather events sensitively, which serve as references for estimating the mutualism system, and as indicators of climate change. PMID- 29116110 TI - Publisher Correction: PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29116111 TI - The expression of miRNAs is associated with tumour genome instability and predicts the outcome of ovarian cancer patients treated with platinum agents. AB - miRNAs, a class of short but stable noncoding RNA molecules, have been revealed to play important roles in the DNA damage response (DDR). However, their functions in cancer genome instability and the consequent clinical effect as the response to chemotherapy have not been fully elucidated. In this study, we utilized multidimensional TCGA data and the known miRNAs involved in DDR to identify a miRNA-regulatory network that responds to DNA damage. Additionally, based on the expression of ten miRNAs in this network, we developed a 10-miRNA score that predicts defects in the homologous recombination (HR) pathway and genome instability in ovarian cancer. Importantly, consistent with the association between HR defects and improved response to chemotherapeutic agents, the 10-miRNA-score predicts the outcome of ovarian cancer patients treated with platinum agents, with a surprisingly better performance than the indexes of DNA damage. Therefore, our study demonstrates the implication of miRNA expression on cancer genome instability and provides an alternative method to identify DDR defects in patients who show the best effect with platinum drug treatment. PMID- 29116113 TI - Tunable Dirac points and high spin polarization in ferromagnetic-strain graphene superlattices. AB - Spin-dependent energy bands and transport properties of ferromagnetic-strain graphene superlattices are studied. The high spin polarization appears at the Dirac points due to the presence of spin-dependent Dirac points in the energy band structure. A gap can be induced in the vicinity of Dirac points by strain and the width of the gap is enlarged with increasing strain strength, which is beneficial for enhancing spin polarization. Moreover, a full spin polarization can be achieved at large strain strength. The position and number of the Dirac points corresponding to high spin polarization can be effectively manipulated with barrier width, well width and effective exchange field, which reveals a remarkable tunability on the wavevector filtering behavior. PMID- 29116112 TI - A Comparison of mRNA Sequencing with Random Primed and 3'-Directed Libraries. AB - Creating a cDNA library for deep mRNA sequencing (mRNAseq) is generally done by random priming, creating multiple sequencing fragments along each transcript. A 3'-end-focused library approach cannot detect differential splicing, but has potentially higher throughput at a lower cost, along with the ability to improve quantification by using transcript molecule counting with unique molecular identifiers (UMI) that correct PCR bias. Here, we compare an implementation of such a 3'-digital gene expression (3'-DGE) approach with "conventional" random primed mRNAseq. Given our particular datasets on cultured human cardiomyocyte cell lines, we find that, while conventional mRNAseq detects ~15% more genes and needs ~500,000 fewer reads per sample for equivalent statistical power, the resulting differentially expressed genes, biological conclusions, and gene signatures are highly concordant between two techniques. We also find good quantitative agreement at the level of individual genes between two techniques for both read counts and fold changes between given conditions. We conclude that, for high-throughput applications, the potential cost savings associated with 3' DGE approach are likely a reasonable tradeoff for modest reduction in sensitivity and inability to observe alternative splicing, and should enable many larger scale studies focusing on not only differential expression analysis, but also quantitative transcriptome profiling. PMID- 29116114 TI - CO2 production, dissolution and pressure dynamics during silage production: multi sensor-based insight into parameter interactions. AB - Silage is a critical global feedstock, but is prone to aerobic deterioration. The dominant mechanism of O2 transport into silage remains unresolved. Here, multiple sensors tracked O2 and CO2, gas pressure (DeltaP) between internal silage and ambient air, pH and silage temperature (Tsi) during the ensilage of maize and ryegrass. We report the first observation that CO2 produced from microbial respiration was partially dissolved in silage water, with evidence of negative or positive DeltaP depending on the changing balance between CO2 production and dissolution. The DeltaP < 0 reflected an apparent respiratory quotient (RQ) < 1. Net CO2 production was much greater in anaerobic fermentation stage than in initial aerobic phase or later aerobic feed-out phase. O2 transport into silage is intimately linked to the dynamics of net CO2, DeltaP, microbial activity, pH and Tsi. These results suggested that both gas diffusion (based on Fick's law) and advective transfer (Darcy's law) play equally important roles in governing the complex temporal progression of inward and outward gas fluxes to and from the silage interior. Even though low pH suppressed microbial activity and supported aerobic stability, the negative DeltaP increased the risk of O2 entry and aerobic deterioration during feed-out phase. PMID- 29116115 TI - Characterization of ApoJ-reconstituted high-density lipoprotein (rHDL) nanodisc for the potential treatment of cerebral beta-amyloidosis. AB - Cerebral beta-amyloidosis is a major feature of Alzheimer's disease (AD), characterized by the accumulation of beta-amyloid protein (Abeta) in the brain. Several studies have implicated lipid/lipoprotein metabolism in the regulation of beta-amyloidosis. In this regard, HDL (High Density Lipoprotein)-based therapies could ameliorate pathological features associated with AD. As apolipoprotein J (ApoJ) is a natural chaperone that interacts with Abeta, avoiding its aggregation and toxicity, in this study we propose to prepare reconstituted rHDL-rApoJ nanoparticles by assembling phospholipids with recombinant human ApoJ (rApoJ). Hence, rHDL particles were prepared using the cholate dialysis method and characterized by N-PAGE, dynamic light scattering, circular dichroism and electron transmission microscopy. The preparation of rHDL particles showed two sized populations with discoidal shape. Functionally, rHDL-rApoJ maintained the ability to prevent the Abeta fibrillization and mediated a higher cholesterol efflux from cultured macrophages. Fluorescently-labelled rHDL-rApoJ nanoparticles were intravenously administrated in mice and their distribution over time was determined using an IVIS Xenogen(r) imager. It was confirmed that rHDL-rApoJ accumulated in the cranial region, especially in old transgenic mice presenting a high cerebral Abeta load. In conclusion, we have standardized a reproducible protocol to produce rHDL-rApoJ nanoparticles, which may be potentially considered as a therapeutic option for beta-amyloid-related pathologies. PMID- 29116116 TI - Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine deficient patients. AB - Melatonin is synthesized from serotonin and it is excreted as sulphatoxymelatonin in urine. We aim to evaluate urinary sulphatoxymelatonin as a biomarker of brain serotonin status in a cohort of patients with mutations in genes related to serotonin biosynthesis. We analized urinary sulphatoxymelatonin from 65 healthy subjects and from 28 patients with genetic defects. A total of 18 patients were studied: 14 with autosomal dominant and recessive guanosine triphosphate cyclohydrolase-I deficiency; 3 with sepiapterin reductase deficiency; and 1 with aromatic L-amino acid decarboxylase deficiency. Further 11 patients were studied after receiving serotoninergic treatment (serotonin precursors, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors): 5 with aromatic L-amino acid decarboxylase deficiency; 1 with sepiapterin reductase deficiency; 3 with dihydropteridine reductase deficiency; and 2 with 6-pyruvoyltetrahydropterin synthase deficiency. Among the patients without therapy, 6 presented low urinary sulphatoxymelatonin values, while most of the patients with guanosine triphosphate cyclohydrolase-I deficiency showed normal values. 5 of 11 patients under treatment presented low urine sulphatoxymelatonin values. Thus, decreased excretion of sulphatoxymelatonin is frequently observed in cases with severe genetic disorders affecting serotonin biosynthesis. In conclusion, sulphatoxymelatonin can be a good biomarker to estimate serotonin status in the brain, especially for treatment monitoring purposes. PMID- 29116117 TI - Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma. AB - The lack of useful biomarkers is a crucial problem for patients with soft tissue sarcomas (STSs). Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel impact as biomarkers for patients with malignant diseases, but their significance in synovial sarcoma (SS) patients remains unknown. Initial global miRNA screening using SS patient serum and SS cell culture media identified a signature of four upregulated miRNAs. Among these candidates, miR-92b-3p secretion from SS cells was confirmed, which was embedded within tumour-derived exosomes rather than argonaute-2. Animal experiments revealed a close correlation between serum miR-92b-3p levels and tumour dynamics. Clinical relevance was validated in two independent clinical cohorts, and we subsequently identified that serum miR-92b-3p levels were significantly higher in SS patients in comparison to that in healthy individuals. Moreover, serum miR-92b 3p was robust in discriminating patients with SS from the other STS patients and reflected tumour burden in SS patients. Overall, liquid biopsy using serum miR 92b-3p expression levels may represent a novel approach for monitoring tumour dynamics of SS. PMID- 29116118 TI - Phononic Crystal Waveguide Transducers for Nonlinear Elastic Wave Sensing. AB - Second harmonic generation is one of the most sensitive and reliable nonlinear elastic signatures for micro-damage assessment. However, its detection requires powerful amplification systems generating fictitious harmonics that are difficult to discern from pure nonlinear elastic effects. Current state-of-the-art nonlinear ultrasonic methods still involve impractical solutions such as cumbersome signal calibration processes and substantial modifications of the test component in order to create material-based tunable harmonic filters. Here we propose and demonstrate a valid and sensible alternative strategy involving the development of an ultrasonic phononic crystal waveguide transducer that exhibits both single and multiple frequency stop-bands filtering out fictitious second harmonic frequencies. Remarkably, such a sensing device can be easily fabricated and integrated on the surface of the test structure without altering its mechanical and geometrical properties. The design of the phononic crystal structure is supported by a perturbative theoretical model predicting the frequency band-gaps of periodic plates with sinusoidal corrugation. We find our theoretical findings in excellent agreement with experimental testing revealing that the proposed phononic crystal waveguide transducer successfully attenuates second harmonics caused by the ultrasonic equipment, thus demonstrating its wide range of potential applications for acousto/ultrasonic material damage inspection. PMID- 29116119 TI - Flux-tunable phase shifter for microwaves. AB - We introduce a magnetic-flux-tunable phase shifter for propagating microwave photons, based on three equidistant superconducting quantum interference devices (SQUIDs) on a transmission line. We experimentally implement the phase shifter and demonstrate that it produces a broad range of phase shifts and full transmission within the experimental uncertainty. Together with previously demonstrated beam splitters, this phase shifter can be utilized to implement arbitrary single-qubit gates for qubits based on propagating microwave photons. These results complement previous demonstrations of on-demand single-photon sources and detectors, and hence assist in the pursuit of an all-microwave quantum computer based on propagating photons. PMID- 29116120 TI - The depleted mineralization of the fungicide chlorothalonil derived from loss in soil microbial diversity. AB - There are lack of studies regarding the effects of microbial diversity on specific soil functions, such as pesticides degradation. This study evaluated the role of bacterial community diversity and biochar on chlorothalonil (CTN) degradation, using 'dilution to extinction' approach, PCR-DGGE/16S rRNA gene technique, and radiorespirometry (14C-CTN). Biochar and microbial community dilution affected structure of the microbial community. In spite of that, CTN mineralization was slow, but dissipation was very fast (D50 < 1.0 d) due to immediate chemical degradation and formation of non-extractable (bound) residues. However, any depletion on soil microbial diversity strongly affected CTN mineralization, suggesting that this function is related to less abundant but specific microbial groups (CTN degraders) or to soil microbial diversity. The extent of these effects will strongly depend on the compound nature (recalcitrance) and soil matrix/substrate (bioavailability). It can be corroborated by the fact that biochar affected CTN sorption, its bioavailability, and subsequently its mineralization rate in the NS. These data indicate a strong relationship between soil microbial diversity and pesticide degradation, which is an acting form to mitigate xenobiotics accumulation in the environment. PMID- 29116121 TI - Interplay between Exciton and Free Carriers in Organolead Perovskite Films. AB - For highly interested organolead perovskite based solar cells, the exciton and free carriers are the photoproducts in the working layers. In this study, we revealed their two forms of relations depending on heat-annealing condition. In non-annealed films and single crystal, they are in density-dependent dynamical balance (co-existing). For the sufficiently heat-annealed films, they present a significant emissive exciton-carrier collision (ECC). The two relations indicate the emergence of a subgrain morphology within the tetragonal phase of crystal grain, induced by heat annealing process. Such subgrain structure could be assigned to a ferroelastic twinning structure recently found inside the crystal grain of the films. Since the heat annealing is a general procedure in preparing perovskite working layers, we propose that the ECC and subgrain morphology widely exist in real devices. We suggest that the subgrain structure provides another level of morphological basis for in depth understanding high performance of organolead perovskite working layers. PMID- 29116122 TI - ToxId: an efficient algorithm to solve occlusions when tracking multiple animals. AB - Video analysis of animal behaviour is widely used in fields such as ecology, ecotoxicology, and evolutionary research. However, when tracking multiple animals, occlusion and crossing are problematic, especially when the identity of each individual needs to be preserved. We present a new algorithm, ToxId, which preserves the identity of multiple animals by linking trajectory segments using their intensity histogram and Hu-moments. We verify the performance and accuracy of our algorithm using video sequences with different animals and experimental conditions. The results show that our algorithm achieves state-of-the-art accuracy using an efficient approach without the need of learning processes, complex feature maps or knowledge of the animal shape. ToxId is also computationally efficient, has low memory requirements, and operates without accessing future or past frames. PMID- 29116123 TI - Self-jumping Mechanism of Melting Frost on Superhydrophobic Surfaces. AB - Frost accretion on surfaces may cause severe problems and the high-efficiency defrosting methods are still urgently needed in many application fields like heat transfer, optical and electric power system, etc. In this study, a nano-needle superhydrophobic surface is prepared and the frosting/defrosting experiments are conducted on it. Three steps are found in the defrosting process: melting frost shrinking and splitting, instantaneous self-triggered deforming followed by deformation-induced movements (namely, in-situ shaking, rotating, rolling, and self-jumping). The self-jumping performance of the melting frost is extremely fascinating and worth studying due to its capability of evidently shortening the defrosting process and reducing (even avoiding) residual droplets after defrosting. The study on the melting frost self-jumping phenomena demonstrates that the kinetic energy transformed from instantaneous superficial area change in self-triggered deforming step is the intrinsic reason for various melting frost self-propelled movements, and when the transformed energy reaches a certain amount, the self-jumping phenomena occur. And some facilitating conditions for melting frost self-jumping phenomena are also discussed. This work will provide an efficient way for defrosting or an inspiration for further research on defrosting. PMID- 29116124 TI - Monocytes from patients with Primary Ciliary Dyskinesia show enhanced inflammatory properties and produce higher levels of pro-inflammatory cytokines. AB - Patients with Primary Ciliary Dyskinesia (PCD) suffer from recurrent upper and lower airway infections due to defects in the cilia present on the respiratory epithelium. Since chronic inflammatory conditions can cause changes in innate immune responses, we investigated whether monocytes isolated from the peripheral blood of pediatric PCD patients respond differently to inflammatory stimuli, compared to monocytes from healthy children and adults. The receptor for C5a (C5aR) was upregulated in PCD, whereas expression levels of the leukocyte chemoattractant receptors CCR1, CCR2, CCR5, BLT1 and FPR1 on PCD monocytes were similar to those on monocytes from healthy individuals. Also in vitro migration of PCD monocytes towards the ligands of those receptors (CCL2, fMLP, C5a and LTB4) was normal. Compared to healthy children, PCD patients had a higher percentage of the non-classic monocyte subset (CD14+CD16++) in circulation. Finally, PCD monocytes produced higher levels of pro-inflammatory cytokines (IL 1beta and TNF-alpha) and chemokines (CCL3, CCL5, CCL18 and CCL22) in response to LPS, peptidoglycan and/or dsRNA stimulation. These data suggest that monocytes might exacerbate inflammatory reactions in PCD patients and might maintain a positive feedback-loop feeding the inflammatory process. PMID- 29116126 TI - Development of multivariable models to predict change in Body Mass Index within a clinical trial population of psychotic individuals. AB - Many antipsychotics promote weight gain, which can lead to non-compliance and relapse of psychosis. By developing models that accurately identify individuals at greater risk of weight gain, clinicians can make informed treatment decisions and target intervention measures. We examined clinical, genetic and expression data for 284 individuals with psychosis derived from a previously published randomised controlled trial (IMPACT). These data were used to develop regression and classification models predicting change in Body Mass Index (BMI) over one year. Clinical predictors included demographics, anthropometrics, cardiac and blood measures, diet and exercise, physical and mental health, medication and BMI outcome measures. We included genetic polygenic risk scores (PRS) for schizophrenia, bipolar disorder, BMI, waist-hip-ratio, insulin resistance and height, as well as gene co-expression modules generated by Weighted Gene Co expression Network Analysis (WGCNA). The best performing predictive models for BMI and BMI gain after one year used clinical data only, which suggests expression and genetic data do not improve prediction in this cohort. PMID- 29116127 TI - Plasmodium falciparum parasites with histidine-rich protein 2 (pfhrp2) and pfhrp3 gene deletions in two endemic regions of Kenya. AB - Deletions of the Plasmodium falciparum hrp2 and hrp3 genes can affect the performance of HRP2-based malaria rapid diagnostic tests (RDTs). Such deletions have been reported from South America, India and Eritrea. Whether these parasites are widespread in East Africa is unknown. A total of 274 samples from asymptomatic children in Mbita, western Kenya, and 61 genomic data from Kilifi, eastern Kenya, were available for analysis. PCR-confirmed samples were investigated for the presence of pfhrp2 and pfhrp3 genes. In samples with evidence of deletion, parasite presence was confirmed by amplifying three independent genes. We failed to amplify pfhrp2 from 25 of 131 (19.1%) PCR confirmed samples. Of these, only 8 (10%) samples were microscopic positive and were classified as pfhrp2-deleted. Eight microscopically-confirmed pfhrp2-deleted samples with intact pfhrp3 locus were positive by HRP2-based RDT. In addition, one PCR-confirmed infection showed a deletion at the pfhrp3 locus. One genomic sample lacked pfhrp2 and one lacked pfhrp3. No sample harbored parasites lacking both genes. Parasites lacking pfhrp2 are present in Kenya, but may be detectable by HRP-based RDT at higher parasitaemia, possibly due to the presence of intact pfhrp3. These findings warrant further systematic study to establish prevalence and diagnostic significance. PMID- 29116128 TI - Salt stress-induced FERROCHELATASE 1 improves resistance to salt stress by limiting sodium accumulation in Arabidopsis thaliana. AB - Ferrochelatase-1 as a terminal enzyme of heme biosynthesis regulates many essential metabolic and physiological processes. Whether FC1 is involved in plant response to salt stress has not been described. This study shows that Arabidopsis overexpressing AtFC1 displays resistance to high salinity, whereas a T-DNA insertion knock-down mutant fc1 was more sensitive to salt stress than wild-type plants. AtFC1 conferred plant salt resistance by reducing Na+ concentration, enhancing K+ accumulation and preventing lysis of the cell membrane. Such observations were associated with the upregulation of SOS1, which encodes a plasma membrane Na+/H+ antiporter. AtFC1 overexpression led to a reduced expression of several well known salt stress-responsive genes such as NHX1 and AVP1, suggesting that AtFC1-regulated low concentration of Na+ in plants might not be through the mechanism for Na+ sequestration. To investigate the mechanism leading to the role of AtFC1 in mediating salt stress response in plants, a transcriptome of fc1 mutant plants under salt stress was profiled. Our data show that mutation of AtFC1 led to 490 specific genes up-regulated and 380 specific genes down-regulated in fc1 mutants under salt stress. Some of the genes are involved in salt-induced oxidative stress response, monovalent cation-proton (Na+/H+) exchange, and Na+ detoxification. PMID- 29116129 TI - Evaporation of a sessile water drop and a drop of aqueous salt solution. AB - The influence of various factors on the evaporation of drops of water and aqueous salt solution has been experimentally studied. Typically, in the studies of drop evaporation, only the diffusive vapor transfer, radiation and the molecular heat conduction are taken into account. However, vapor-gas convection plays an important role at droplet evaporation. In the absence of droplet boiling, the influence of gas convection turns out to be the prevailing factor. At nucleate boiling, a prevailing role is played by bubbles generation and vapor jet discharge at a bubble collapse. The gas convection behavior for water and aqueous salt solution is substantially different. With a growth of salt concentration over time, the influence of the convective component first increases, reaches an extremum and then significantly decreases. At nucleate boiling in a salt solution it is incorrect to simulate the droplet evaporation and the heat transfer in quasi-stationary approximation. The evaporation at nucleate boiling in a liquid drop is divided into several characteristic time intervals. Each of these intervals is characterized by a noticeable change in both the evaporation rate and the convection role. PMID- 29116130 TI - Atomic Configuration of Point Defect Clusters in Ion-Irradiated Silicon Carbide. AB - Silicon Carbide (SiC) is a promising cladding material for accident-tolerant fuel in light water reactors due to its excellent resistance to chemical attacks at high temperatures, which can prevent severe accident-induced environmental disasters. Although it has been known for decades that radiation-induced swelling at low temperatures is driven by the formation of black spot defects with sizes smaller than 2 nm in irradiated SiC, the structure of these defect clusters and the mechanism of lattice expansion have not been clarified and remain as one of the most important scientific issues in nuclear materials research. Here we report the atomic configuration of defect clusters using Cs-corrected transmission electron microscopy and molecular dynamics to determine the mechanism of these defects to radiation swelling. This study also provides compelling evidence that irradiation-induced point defect clusters are vacancy rich clusters and lattice expansion results from the homogenous distribution of unrecovered interstitials in the material. PMID- 29116131 TI - Context-dependent compensation among phosphatidylserine-recognition receptors. AB - Phagocytes express multiple phosphatidylserine (PtdSer) receptors that recognize apoptotic cells. It is unknown whether these receptors are interchangeable or if they play unique roles during cell clearance. Loss of the PtdSer receptor Mertk is associated with apoptotic corpse accumulation in the testes and degeneration of photoreceptors in the eye. Both phenotypes are linked to impaired phagocytosis by specialized phagocytes: Sertoli cells and the retinal pigmented epithelium (RPE). Here, we overexpressed the PtdSer receptor BAI1 in mice lacking MerTK (Mertk -/- Bai1 Tg ) to evaluate PtdSer receptor compensation in vivo. While Bai1 overexpression rescues clearance of apoptotic germ cells in the testes of Mertk /- mice it fails to enhance RPE phagocytosis or prevent photoreceptor degeneration. To determine why MerTK is critical to RPE function, we examined visual cycle intermediates and performed unbiased RNAseq analysis of RPE from Mertk +/+ and Mertk -/- mice. Prior to the onset of photoreceptor degeneration, Mertk -/- mice had less accumulation of retinyl esters and dysregulation of a striking array of genes, including genes related to phagocytosis, metabolism, and retinal disease in humans. Collectively, these experiments establish that not all phagocytic receptors are functionally equal, and that compensation among specific engulfment receptors is context and tissue dependent. PMID- 29116133 TI - Atomistic Representation of Anomalies in the Failure Behaviour of Nanocrystalline Silicene. AB - Silicene, a 2D analogue of graphene, has spurred a tremendous research interest in the scientific community for its unique properties essential for next generation electronic devices. In this work, for the first time, we present a molecular dynamics (MD) investigation to determine the fracture strength and toughness of nanocrystalline silicene (nc-silicene) sheet of varying grain sizes and pre-existing cracks at room temperature. Our results suggest a transition from an inverse pseudo Hall-Petch to a pseudo Hall-Petch behaviour in nc-silicene at a critical grain size of 17.32 nm. This phenomenon is also prevalent in nanocrystalline graphene. However, nc-silicene with pre-existing cracks exhibits anomalous crack propagation and fracture toughness behaviour. We observed two distinct types of failure mechanisms (crack sensitive and insensitive failure) and devised mechano-physical conditions under which they occur. The most striking outcome is: despite the presence of a pre-existing crack, the crack sensitivity of nc-silicene is found to be dependent on the grain size and their orientations. The calculated Fracture toughness from both Griffith's theory and MD simulations indicate that the former over-predicts the fracture toughness of nc-silicene. Finally, this study is the first direct comparison of atomistic simulations to the continuum theories to predict the anomalous behaviour in deformation and failure mechanisms of nc-silicene. PMID- 29116132 TI - Serial dependence is absent at the time of perception but increases in visual working memory. AB - Recent experiments have shown that visual cognition blends current input with that from the recent past to guide ongoing decision making. This serial dependence appears to exploit the temporal autocorrelation normally present in visual scenes to promote perceptual stability. While this benefit has been assumed, evidence that serial dependence directly alters stimulus perception has been limited. In the present study, we parametrically vary the delay between stimulus and response in a spatial delayed response task to explore the trajectory of serial dependence from the moment of perception into post perceptual visual working memory. We find that behavioral responses made immediately after viewing a stimulus show evidence of adaptation, but not attractive serial dependence. Only as the memory period lengthens is a blending of past and present information apparent in behavior, reaching its maximum with a delay of six seconds. These results dovetail with other recent findings to bolster the interpretation that serial dependence is a phenomenon of mnemonic rather than perceptual processes. However, even while this pattern of effects in group-averaged data has now been found consistently, we show that the relative strengths of adaptation and serial dependence vary widely across individuals. Finally, we demonstrate that when leading mathematical models of working memory are adjusted to account for these trial-history effects, their fit to behavioral data is substantially improved. PMID- 29116125 TI - Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. AB - A correction to this article has been published and is linked from the HTML version of this article. PMID- 29116134 TI - Behavioural Differences and Neural Substrates of Altruistic and Spiteful Punishment. AB - Altruistic punishment following social norm violations promotes human cooperation. However, experimental evidence indicates that some forms of punishment are spiteful rather than altruistic. Using two types of punishment games and seven non-strategic games, we identified strong behavioural differences between altruistic and spiteful punishers. Altruistic punishers who rejected unfair offers in the ultimatum game and punished norm violators in the third party punishment game behaved pro-socially in various non-strategic games. Spiteful punishers who rejected unfair offers in the ultimatum game but did not punish norm violators in the third-party punishment game behaved selfishly in non strategic games. In addition, the left caudate nucleus was larger in spiteful punishers than in altruistic punishers. These findings are in contrast to the previous assumption that altruistic punishers derive pleasure from enforcement of fairness norms, and suggest that spiteful punishers derive pleasure from seeing the target experience negative consequences. PMID- 29116135 TI - Novel electrical and mechanical characteristics of composites composed of electrically conducting Ni-Cr alloy particles in non-conducting soda-lime glass. AB - The bulk resistivity of Ni-Cr alloys is inherently constant. Therefore, it is necessary to regulate the cross-section and length of Ni-Cr alloys to achieve the desired electrical resistance. Here, we describe a composite, comprising a soda lime glass matrix and disk-like Ni-Cr alloy particles, that has variable bulk resistivity. The bulk resistivity of the composite can be controlled accurately by adjusting the volume fraction (30-80 vol% Ni-Cr alloy) and aspect ratio of the particles. Furthermore, the composite's strength and fracture toughness are both improved by microdispersion of the disk-like Ni-Cr alloy particles. A 1/100-scale model resistor based on this composite was found to have attractive properties for electrical power applications, such as an approximately 50% reduction in volume, a 65% reduction in weight, and a 95% reduction in inductance in comparison with a conventional neutral grounding resistor made from special cast iron. Clearly, use of this composite material for fabrication of ubiquitous electrical components would greatly reduce the demand and consumption of Ni and Cr for this application. Several benefits are envisioned from this development, including the fabrication of downsized devices and the availability of lower-cost home appliances and industrial products. PMID- 29116136 TI - Iodide capped PbS/CdS core-shell quantum dots for efficient long-wavelength near infrared light-emitting diodes. AB - PbS based quantum dots (QDs) have been studied in great detail for potential applications in electroluminescent devices operating at wavelengths important for telecommunications (1.3-1.6 MUm). Despite the recent advances in field of quantum dot light-emitting diode (QLED), further improvements in near-infrared (NIR) emitting device performance are still necessary for the widespread use and commercialization of NIR emitting QLED technology. Here, we report a high performance 1.51-MUm emitting QLED with inverted organic-inorganic hybrid device architecture and PbS/CdS core-shell structured quantum dots as emitter. The resultant QLEDs show a record device performance for the QLEDs in 1.5 MUm emission window, with a maximum radiance of 6.04 Wsr-1 m-2 and peak external quantum efficiency (EQE) of 4.12%, respectively. PMID- 29116138 TI - Vascular endothelial growth factor signaling requires glycine to promote angiogenesis. AB - Peripheral vascular occlusive disease (PVOD) is a common manifestation of atherosclerosis, and it has a high rate of morbidity. Therapeutic angiogenesis would re-establish blood perfusion and rescue ischemic tissue. Vascular endothelial growth factor (VEGF) induces angiogenesis and can potentially be used to treat ischemic diseases, yet in clinical trials VEGF has not fulfilled its full potential with side effects. Whether amino acids promote angiogenesis and the molecular mechanisms are largely unknown. Here we showed that (1) Glycine significantly promoted angiogenesis both in vitro and in vivo and effectively protected mitochondrial function. (2) Activation of glycine transporter 1(GlyT1) induced by VEGF led to an increase in intracellular glycine. (3) Glycine directly bounded to voltage dependent anion channel 1 (VDAC1) on the mitochondrial outer membrane and inhibited its opening. These original results highlight glycine as a necessary mediator in VEGF signalling via the GlyT1-glycine-mTOR-VDAC1 axis pathway. Therefore, the findings in this study are of significance providing new mechanistic insights into angiogenesis and providing better understanding of glycine function in angiogenesis, which may provide valuable information for development of novel therapeutic targets for the treatment of angiogenic vascular disorders. PMID- 29116137 TI - Cardiovascular consequences of myocardial bridging: A meta-analysis and meta regression. AB - Myocardial bridging, a congenital abnormality in which a coronary artery tunnels through the myocardial fibres was usually considered a benign condition. Many studies suggested a potential hemodynamic significance of myocardial bridging and some, usually case reports, implied a possible correlation between it and various cardiovascular pathologies like acute myocardial infarction, ventricular rupture, life-threatening arrhythmias, hypertrophic cardiomyopathy, apical ballooning syndrome or sudden death. The main objective of this article is to evaluate whether myocardial bridging may be associated with significant cardiac effects or if it is strictly a benign anatomical variation. To this purpose, we performed a meta-analysis (performed using the inverse variance heterogeneity model) and meta regression, on scientific articles selected from three main databases (Scopus, Web of Science, Pubmed). The study included 21 articles. MB was associated with major adverse cardiac events - OR = 1.52 (1.01-2.30), and myocardial ischemia OR = 3.00 (1.02-8.82) but not with acute myocardial infarction, cardiovascular death, ischemia identified using imaging techniques, or positive exercise stress testing. Overall, myocardial bridging may have significant cardiovascular consequences (MACE, myocardial ischemia). More studies are needed to reveal/refute a clear association with MI, sudden death or other cardiovascular pathologies. PMID- 29116139 TI - Integrated plasmon-enhanced Raman scattering (iPERS) spectroscopy. AB - A new strategy named integrated plasmon-enhanced Raman scattering (iPERS) spectroscopy that features a configuration of evanescent field excitation and inverted collection is presented, which well unites the local field enhancement and far field emission, couples localized and propagating surface plasmons, integrates the SERS substrates and Raman spectrometers via a self-designed aplanatic solid immersion lens. A metallic nanoparticle-on-a film (NOF) system was adopted in this configuration because it improves the amplification of the incidence light field in near field by 10 orders of magnitude due to the simultaneous excitation of quadrupolar and dipolar resonance modes. This iPERS allows for higher excitation efficiency to probed molecules and full collection of the directional-radiation Raman scattering signal in an inverted way, which exhibits a practical possibility to monitor plasmonic photocatalytic reactions in nanoscale and a bright future on interfacial reaction studies. PMID- 29116140 TI - Valid gene expression normalization by RT-qPCR in studies on hPDL fibroblasts with focus on orthodontic tooth movement and periodontitis. AB - Meaningful, reliable and valid mRNA expression analyses by real-time quantitative PCR (RT-qPCR) can only be achieved, if suitable reference genes are chosen for normalization and if appropriate RT-qPCR quality standards are met. Human periodontal ligament (hPDL) fibroblasts play a major mediating role in orthodontic tooth movement and periodontitis. Despite corresponding in-vitro gene expression studies being a focus of interest for many years, no information is available for hPDL fibroblasts on suitable reference genes, which are generally used in RT-qPCR experiments to normalize variability between samples. The aim of this study was to identify and validate suitable reference genes for normalization in untreated hPDL fibroblasts as well as experiments on orthodontic tooth movement or periodontitis (Aggregatibacter actinomycetemcomitans). We investigated the suitability of 13 candidate reference genes using four different algorithms (geNorm, NormFinder, comparative DeltaCq and BestKeeper) and ranked them according to their expression stability. Overall PPIB (peptidylprolyl isomerase A), TBP (TATA-box-binding protein) and RPL22 (ribosomal protein 22) were found to be most stably expressed with two genes in conjunction sufficient for reliable normalization. This study provides an accurate tool for quantitative gene expression analysis in hPDL fibroblasts according to the MIQE guidelines and shows that reference gene reliability is treatment-specific. PMID- 29116141 TI - Constitutive expression of NF-kappaB inducing kinase in regulatory T cells impairs suppressive function and promotes instability and pro-inflammatory cytokine production. AB - CD4+Foxp3+ regulatory T cells (Tregs) are indispensable negative regulators of immune responses. To understand Treg biology in health and disease, it is critical to elucidate factors that affect Treg homeostasis and suppressive function. Tregs express several costimulatory TNF receptor family members that activate non-canonical NF-kappaB via accumulation of NF-kappaB inducing kinase (NIK). We previously showed that constitutive NIK expression in all T cells causes fatal multi-organ autoimmunity associated with hyperactive conventional T cell responses and poor Treg-mediated suppression. Here, we show that constitutive NIK expression that is restricted to Tregs via a Cre-inducible transgene causes an autoimmune syndrome. We found that constitutive NIK expression decreased expression of numerous Treg signature genes and microRNAs involved in Treg homeostasis and suppressive phenotype. NIK transgenic Tregs competed poorly with WT Tregs in vivo and produced pro-inflammatory cytokines upon stimulation. Lineage tracing experiments revealed accumulation of ex-Foxp3+ T cells in mice expressing NIK constitutively in Tregs, and these former Tregs produced copious IFNgamma and IL-2. Our data indicate that under inflammatory conditions in which NIK is activated, Tregs may lose suppressive function and may actively contribute to inflammation. PMID- 29116143 TI - Risk Factors and Molecular Features of Sequence Type (ST) 131 Extended-spectrum beta-Lactamase-producing Escherichia coli in Community-onset Bacteremia. AB - Due to the spread of a single CTX-M-type extended-spectrum beta-lactamase (ESBL) clone of sequence type (ST) 131, community-onset bacteremia caused by ESBL producing Escherichia coli has increased dramatically. We evaluated the risk factors and molecular features of ESBL-producing E. coli ST131 clones isolated from Korean patients with community-onset bacteremia. We collected a total of 124 ESBL-producing E. coli isolates from blood in patients with community-onset bacteremia over a 2 year-period. Among 124 patients, the number of community associated bacteremia cases was 57 (46%). ST131 strains accounted for 49.1% (28/57) of community-associated bacteremia cases and 44.8% (30/67) of healthcare associated community-onset bacteremia cases. Among 58 ST131 strains, nine isolates were shown to harbor O16-H41, and 61.1% (30/49) of O25 had H30Rx. In a multivariate analysis, independent risk factors for acquisition of ST131 isolates over non-ST131 isolates were underlying diabetes mellitus and absence of prior chemotherapy history. The most common ESBL genotype was CTX-M-15 (46.0%), followed by CTX-M-14 (37.1%). A considerable proportion of community-onset ESBL producing E. coli bacteremia was observed. ST131 clones appear to be associated with the spread of community-associated bacteremia exhibiting high antimicrobial resistance and highly virulent H30Rx traits, which could become a major public health concern in Korea. PMID- 29116142 TI - Working memory, attention, and salience in active inference. AB - The psychological concepts of working memory and attention are widely used in the cognitive and neuroscientific literatures. Perhaps because of the interdisciplinary appeal of these concepts, the same terms are often used to mean very different things. Drawing on recent advances in theoretical neurobiology, this paper tries to highlight the correspondence between these established psychological constructs and the formal processes implicit in mathematical descriptions of brain function. Here, we consider attention and salience from the perspective offered by active inference. Using variational principles and simulations, we use active inference to demonstrate how attention and salience can be disambiguated in terms of message passing between populations of neurons in cortical and subcortical structures. In brief, we suggest that salience is something that is afforded to actions that realise epistemic affordance, while attention per se is afforded to precise sensory evidence - or beliefs about the causes of sensations. PMID- 29116145 TI - Cingulate island sign temporally changes in dementia with Lewy bodies. AB - The cingulate island sign (CIS) that reflects sparing of the posterior cingulate cortex (PCC) relative to the precuneus plus cuneus on FDG-PET and brain perfusion SPECT, has been proposed as a feature of dementia with Lewy bodies (DLB). As the CIS is influenced by concomitant Alzheimer's disease (AD)-type neurofibrillary tangle (NFT) pathology, we postulated that the CIS gradually disappears as DLB progresses. To determine temporal changes in the CIS, 24 patients with mild DLB and 7 with prodromal DLB underwent 123I-IMP-SPECT and MMSE twice at an interval of two years. The CIS was evaluated as a ratio that was derived by dividing IMP accumulation in the PCC with that in the precuneus plus cuneus. We found that the CIS changed over time and that the relationship between CIS ratios and MMSE scores was inverted U-shaped. Thus, the CIS was most obvious in the vicinity of an MMSE score of 22 and it gradually diminished as the MMSE score decreased. Moreover, a lower CIS ratio in mild DLB was associated with a worse prognosis for cognitive decline, presumably due to concomitant AD-type NFT pathology. Our findings would provide a foundation for the appropriate usage of CIS as a biomarker. PMID- 29116144 TI - The effect of artificial selection on phenotypic plasticity in maize. AB - Remarkable productivity has been achieved in crop species through artificial selection and adaptation to modern agronomic practices. Whether intensive selection has changed the ability of improved cultivars to maintain high productivity across variable environments is unknown. Understanding the genetic control of phenotypic plasticity and genotype by environment (G * E) interaction will enhance crop performance predictions across diverse environments. Here we use data generated from the Genomes to Fields (G2F) Maize G * E project to assess the effect of selection on G * E variation and characterize polymorphisms associated with plasticity. Genomic regions putatively selected during modern temperate maize breeding explain less variability for yield G * E than unselected regions, indicating that improvement by breeding may have reduced G * E of modern temperate cultivars. Trends in genomic position of variants associated with stability reveal fewer genic associations and enrichment of variants 0-5000 base pairs upstream of genes, hypothetically due to control of plasticity by short range regulatory elements. PMID- 29116146 TI - Inactivation mechanism of N61S mutant of human FMO3 towards trimethylamine. AB - Human flavin-containing monooxygenase 3 (hFMO3) catalyses the oxygenation of a wide variety of compounds including drugs as well as dietary compounds. It is the major hepatic enzyme involved in the production of the N-oxide of trimethylamine (TMAO) and clinical studies have uncovered a striking correlation between plasma TMAO concentration and cardiovascular disease. Certain mutations within the hFMO3 gene cause defective trimethylamine (TMA) N-oxygenation leading to trimethylaminuria (TMAU) also known as fish-odour syndrome. In this paper, the inactivation mechanism of a TMAU-causing polymorphic variant, N61S, is investigated. Transient kinetic experiments show that this variant has a > 170 fold lower NADPH binding affinity than the wild type. Thermodynamic and spectroscopic experiments reveal that the poor NADP+ binding affinity accelerates the C4a-hydroperoxyFAD intermediate decay, responsible for an unfavourable oxygen transfer to the substrate. Steady-state kinetic experiments show significantly decreased N61S catalytic activity towards other substrates; methimazole, benzydamine and tamoxifen. The in vitro data are corroborated by in silico data where compared to the wild type enzyme, a hydrogen bond required for the stabilisation of the flavin intermediate is lacking. Taken together, the data presented reveal the molecular basis for the loss of function observed in N61S mutant. PMID- 29116147 TI - Spexin Suppress Food Intake in Zebrafish: Evidence from Gene Knockout Study. AB - Spexin1 (SPX1) is a newly discovered neuropeptide in vertebrates. Its biological function remains to be elucidated. In this study, we have generated the zebrafish spx1 -/- mutant lines using transcription activator-like effector nucleases. Phenotypes of the spx1 -/- mutant zebrafish were analyzed in order to understand the effects on reproduction and food intake. The reproductive capability is not impaired in spx1 mutant zebrafish. However, we found that the spx1 -/- mutant fish had a higher food intake than the wild type (WT) fish. Real-time PCR revealed that the expression level of agouti-relate protein 1 (AgRP1), a significant appetite stimulant, was significantly higher in spx1 -/- mutant fish after feeding. Intracranial administration of SPX1 could also reduce the mRNA expression of the AgRP1. These data suggest that SPX1 might decrease the food intake by down regulating the expression level of agrp1. Furthermore, spx1 -/- mutant fish exhibited higher glucose, triacylglycerol and cholesterol in the serum than WT fish. However, the hyperphagia did not lead to a higher growth rate or body fat percentage. Taken together, our study suggests that SPX1 may serve as a satiety signal molecular by suppressing the AgRP1 in the brain. PMID- 29116148 TI - Broadband enhancement of photoluminance from colloidal metal halide perovskite nanocrystals on plasmonic nanostructured surfaces. AB - Metal halide perovskite nanocrystals (NCs) as a new kind of promising optoelectronic material have attracted wide attention due to their high photoluminescence (PL) quantum yield, narrow emission linewidth and wideband color tunability. Since the PL intensity always has a direct influence on the performance of optoelectronic devices, it is of vital importance to improve the perovskite NCs' fluorescence emission efficiency. Here, we synthesize three inorganic perovskite NCs and experimentally demonstrate a broadband fluorescence enhancement of perovskite NCs by exploiting plasmonic nanostructured surface consisting of nanogrooves array. The strong near-field optical localization associated with surface plasmon polariton-coupled emission effect generated by the nanogrooves array can significantly boost the absorption of perovskite NCs and tailor the fluorescence emissions. As a result, the PL intensities of perovskite NCs are broadband enhanced with a maximum factor higher than 8-fold achieved in experimental demonstration. Moreover, the high efficiency PL of perovskite NCs embedded in the polymer matrix layer on the top of plasmonic nanostructured surface can be maintained for more than three weeks. These results imply that plasmonic nanostructured surface is a good candidate to stably broadband enhance the PL intensity of perovskite NCs and further promote their potentials in the application of visible-light-emitting devices. PMID- 29116149 TI - Constraints on global temperature target overshoot. AB - In the aftermath of the Paris Agreement, the climate science and policy communities are beginning to assess the feasibility and potential benefits of limiting global warming to 1.5 degrees C or 2 degrees C above preindustrial. Understanding the dependence of the magnitude and duration of possible temporary exceedance (i.e., "overshoot") of temperature targets on sustainable energy decarbonization futures and carbon dioxide (CO2) removal rates will be an important contribution to this policy discussion. Drawing upon results from the mitigation literature and the IPCC Working Group 3 (WG3) scenario database, we examine the global mean temperature implications of differing, independent pathways for the decarbonization of global energy supply and the implementation of negative emissions technologies. We find that within the scope of scenarios broadly-consistent with the WG3 database, the magnitude of temperature overshoot is more sensitive to the rate of decarbonization. However, limiting the duration of overshoot to less than two centuries requires ambitious deployment of both decarbonization and negative emissions technology. The dependencies of temperature target overshoot's properties upon currently untested negative emissions technologies suggests that it will be important to consider how climate impacts depend on both the magnitude and duration of overshoot, not just long term residual warming. PMID- 29116150 TI - Metasurface electrode light emitting diodes with planar light control. AB - The ability of metasurfaces to manipulate light at the subwavelength scale offers unprecedented functionalities for passive and active lasing devices. However, applications of metasurfaces to optical devices are rare due to fabrication difficulties. Here, we present quantum dot light emitting diodes (QDLEDs) with a metasurface-integrated metal electrode and demonstrate microscopically controlled LED emission. By incorporating slot-groove antennas into the metal electrode, we show that LED emission from randomly polarized QD sources can be polarized and directed at will. Utilizing the relation between polarization and emission direction, we also demonstrate microscopic LED beam splitting through the selective choice of polarization. PMID- 29116151 TI - Enhanced and Stable Upconverted White-light Emission in Ho3+/Yb3+/Tm3+-doped LiNbO3 Single Crystal via Mg2+ Ion Doping. AB - A strategy to enhance the upconversion white-light intensity via Mg2+ ion doping was demonstrated in Ho3+/Yb3+/Tm3+/LiNbO3 single crystal. It is found Mg2+ ion doping affects the crystal field symmetry around RE3+ ions and enhance the upconversion emission intensity. Bright white-light is obtained when the Mg2+ ion concentration is 0.5 mol% in the melt. And the CIE coordinates are hardly changed with Mg2+ ion doping. In addition, the upconversion mechanism is discussed in detail. It is observed the longer lifetimes of intermediate levels result in the lower upconversion photon numbers, which are beneficial to the upconversion process. Therefore, Mg2+ ion doped Ho3+/Yb3+/Tm3+/LiNbO3 single crystals would have potential applications in stable white-light devices and photoelectric instruments. PMID- 29116152 TI - Fabrication of Artificial Leaf to Develop Fluid Pump Driven by Surface Tension and Evaporation. AB - Plants transport water from roots to leaves via xylem through transpiration, which is an evaporation process that occurs at the leaves. During transpiration, suction pressure is generated by the porous structure of mesophyll cells in the leaves. Here, we fabricate artificial leaf consisting of micro and nano hierarchy structures similar to the mesophyll cells and veins of a leaf using cryo-gel method. We show that the microchannels in agarose gel greatly decrease the flow resistance in dye diffusion and permeability experiments. Capillary tube and silicone oil are used for measuring the suction pressure of the artificial leaf. We maintain low humidity (20%) condition for measuring suction pressure that is limited by Laplace pressure, which is smaller than the water potential of air followed by the Kelvin-Laplace relation. Suction pressure of the artificial leaf is maximized by changing physical conditions, e.g., pore size, wettability of the structure. We change the agarose gel's concentration to decrease the pore size down to 200 nm and add the titanium nano particles to increase the wettability by changing contact angle from 63.6 degrees to 49.4 degrees . As a result, the measured suction pressure of the artificial leaf can be as large as 7.9 kPa. PMID- 29116153 TI - Ardissonea crystallina has a type of sexual reproduction that is unusual for centric diatoms. AB - Molecular phylogenetic analyses place Ardissonea crystallina (C. Agardh) Grunow and all Toxariids among the bi- and multipolar centric diatoms, almost always recovered as a derived lineage sister to Lampriscus. In all centrics where sexual reproduction has been documented, oogamy, with larger immobile eggs and smaller flagellated sperm has been observed. We were able to initiate both homothallic and heterothallic reproduction in A. crystallina. The heterothallic reproduction turned out to be non-oogamous; gametes were more or less equal in size but no flagellated cells were detected. At the same time, two mating types ("male" and "female") were recognized by the distinct morphology and behaviour of the gametes. While no flagella were observed, periodically thin cytoplasmic projections arose on the surface of the "male" gametes. These projections similar to those found in some pennate diatoms facilitated contact with the "female" cells. In each gametangial cell, regardless of the mating type, only one gamete was formed. Thus, the Toxariids may represent a unique evolutionary group, at least in respect to their reproductive biology. The hypothesis discussed is that non-oogamous mode of reproduction could have evolved in Ardissonea (and possibly in other Toxariids) independently of the pennate lineage of diatoms. PMID- 29116154 TI - Bonobos respond prosocially toward members of other groups. AB - Modern humans live in an "exploded" network with unusually large circles of trust that form due to prosociality toward unfamiliar people (i.e. xenophilia). In a set of experiments we demonstrate that semi-free ranging bonobos (Pan paniscus) - both juveniles and young adults - also show spontaneous responses consistent with xenophilia. Bonobos voluntarily aided an unfamiliar, non-group member in obtaining food even when he/she did not make overt requests for help. Bonobos also showed evidence for involuntary, contagious yawning in response to videos of yawning conspecifics who were complete strangers. These experiments reveal that xenophilia in bonobos can be unselfish, proactive and automatic. They support the first impression hypothesis that suggests xenophilia can evolve through individual selection in social species whenever the benefits of building new bonds outweigh the costs. Xenophilia likely evolved in bonobos as the risk of intergroup aggression dissipated and the benefits of bonding between immigrating members increased. Our findings also mean the human potential for xenophilia is either evolutionarily shared or convergent with bonobos and not unique to our species as previously proposed. PMID- 29116155 TI - Using CRISPR-Cas9-mediated genome editing to generate C. difficile mutants defective in selenoproteins synthesis. AB - Clostridium difficile is a significant concern as a nosocomial pathogen, and genetic tools are important when analyzing the physiology of such organisms so that the underlying physiology/pathogenesis of the organisms can be studied. Here, we used TargeTron to investigate the role of selenoproteins in C. difficile Stickland metabolism and found that a TargeTron insertion into selD, encoding the selenophosphate synthetase that is essential for the specific incorporation of selenium into selenoproteins, results in a significant growth defect and a global loss of selenium incorporation. However, because of potential polar effects of the TargeTron insertion, we developed a CRISPR-Cas9 mutagenesis system for C. difficile. This system rapidly and efficiently introduces site-specific mutations into the C. difficile genome (20-50% mutation frequency). The selD CRISPR deletion mutant had a growth defect in protein-rich medium and mimicked the phenotype of a generated TargeTron selD mutation. Our findings suggest that Stickland metabolism could be a target for future antibiotic therapies and that the CRISPR-Cas9 system can introduce rapid and efficient modifications into the C. difficile genome. PMID- 29116157 TI - Atomically flat and uniform relaxed III-V epitaxial films on silicon substrate for heterogeneous and hybrid integration. AB - The integration of III-V semiconductors on silicon (Si) substrate has been an active field of research for more than 30 years. Various approaches have been investigated, including growth of buffer layers to accommodate the lattice mismatch between the Si substrate and the III-V layer, Si- or Ge-on-insulator, epitaxial transfer methods, epitaxial lateral overgrowth, aspect-ratio-trapping techniques, and interfacial misfit array formation. However, manufacturing standards have not been met and significant levels of remaining defectivity, high cost, and complex integration schemes have hampered large scale commercial impact. Here we report on low cost, relaxed, atomically smooth, and surface undulation free lattice mismatched III-V epitaxial films grown in wide-fields of micrometer size on 300 mm Si(100) and (111) substrates. The crystallographic quality of the epitaxial film beyond a few atomic layers from the Si substrate is accomplished by formation of an interfacial misfit array. This development may enable future platforms of integrated low-power logic, power amplifiers, voltage controllers, and optoelectronics components. PMID- 29116156 TI - Efficient production and characterization of the novel and highly active antifungal protein AfpB from Penicillium digitatum. AB - Filamentous fungi encode distinct antifungal proteins (AFPs) that offer great potential to develop new antifungals. Fungi are considered immune to their own AFPs as occurs in Penicillium chrysogenum, the producer of the well-known PAF. The Penicillium digitatum genome encodes only one afp gene (afpB), and the corresponding protein (AfpB) belongs to the class B phylogenetic cluster. Previous attempts to detect AfpB were not successful. In this work, immunodetection confirmed the absence of AfpB accumulation in wild type and previous recombinant constitutive P. digitatum strains. Biotechnological production and secretion of AfpB were achieved in P. digitatum with the use of a P. chrysogenum-based expression cassette and in the yeast Pichia pastoris with the alpha-factor signal peptide. Both strategies allowed proper protein folding, efficient production and single-step purification of AfpB from culture supernatants. AfpB showed antifungal activity higher than the P. chrysogenum PAF against the majority of the fungi tested, especially against Penicillium species and including P. digitatum, which was highly sensitive to the self-AfpB. Spectroscopic data suggest that native folding is not required for activity. AfpB also showed notable ability to withstand protease and thermal degradation and no haemolytic activity, making AfpB a promising candidate for the control of pathogenic fungi. PMID- 29116158 TI - Optical mapping of the dominant frequency of brain signal oscillations in motor systems. AB - Recent neuroimaging studies revealed that the dominant frequency of neural oscillations is brain-region-specific and can vary with frequency-specific reorganization of brain networks during cognition. In this study, we examined the dominant frequency in low-frequency neural oscillations represented by oxygenated hemoglobin measurements after the hemodynamic response function (HRF) deconvolution. Twenty-nine healthy college subjects were recruited to perform a serial finger tapping task at the frequency of 0.2 Hz. Functional near-infrared spectroscopy (fNIRS) was applied to record the hemodynamic signals over the primary motor cortex, supplementary motor area (SMA), premotor cortex, and prefrontal area. We then explored the low frequency steady-state brain response (lfSSBR), which was evoked in the motor systems at the fundamental frequency (0.2 Hz) and its harmonics (0.4, 0.6, and 0.8 Hz). In particular, after HRF deconvolution, the lfSSBR at the frequency of 0.4 Hz in the SMA was identified as the dominant frequency. Interestingly, the domain frequency exhibited the correlation with behavior data such as reaction time, indicating that the physiological implication of lfSSBR is related to the brain anatomy, stimulus frequency and cognition. More importantly, the HRF deconvolution showed its capability for recovering signals probably reflecting neural-level events and revealing the physiological meaning of lfSSBR. PMID- 29116159 TI - The Effects of Transcription Directions of Transgenes and the gypsy Insulators on the Transcript Levels of Transgenes in Transgenic Arabidopsis. AB - Manipulation of a single abiotic stress-related gene could improve plant performance under abiotic stress conditions. To simultaneously increase plant tolerance to multiple stresses, it is usually required to overexpress two (or more) genes in transgenic plants. The common strategy is to assemble two or more expression cassettes, where each gene has its own promoter and terminator, within the same T-DNA. Does the arrangement of the two expression cassettes affect expression of the two transgenes? Can we use the Drosophila gypsy insulator sequence to increase the expression of the two transgenes? Answers to these questions would contribute to design better transformation vectors to maximize the effects of multi-gene transformation. Two Arabidopsis genes, PP2A-C5 and AVP1, and the gypsy insulator sequence were used to construct six transformation vectors with or without the gypsy insulator bracketing the two expression cassettes: uni-directional transcription, divergent transcription, and convergent transcription. Total RNAs were isolated for reverse transcription- quantitative real-time polymerase chain reaction (RT-qPCR) assays and a thorough statistical analysis was conducted for the RT-qPCR data. The results showed that the gypsy insulator does promote the expression of two transgenes in transgenic plants. Besides, the plants containing the divergent transcription cassettes tend to have more correlated expression of both genes. PMID- 29116160 TI - Ilex latifolia Thunb protects mice from HFD-induced body weight gain. AB - Kuding tea is implicated in alleviating metabolic disorders in traditional Chinese medicine. However, the role of Ilex latifolia Thunb (kuding tea), one of the large leaf kuding tea species, in the prevention of the development of obesity remains to be determined. We show here that 7-week-old male mice treated with an Ilex latifolia Thunb supplement for 14 weeks were resistant to HFD induced body weight gain and hepatic steatosis, accompanied by improved insulin sensitivity. Ilex latifolia Thunb supplementation dramatically reduced the systemic and tissue inflammation levels of mice via reducing pro-inflammatory cytokine levels, increasing anti-inflammatory cytokine levels in the circulation and inhibiting p38 MAPK and p65 NF-kappaB signaling in adipose tissue. Together, these results indicate that Ilex latifolia Thunb protects mice from the development of obesity and is a potential compound pool for the development of novel anti-obesity drugs. PMID- 29116161 TI - Room-temperature NH3 sensing of graphene oxide film and its enhanced response on the laser-textured silicon. AB - Electricity-based response to NH3 of graphene oxide (GO) is demonstrated at ppm level at room temperature. The GO film prepared on planar silicon substrate shows weak response when exposed to 50 ppm NH3, response time less than 30 s and recovery time about 100 s. More interestingly, the GO film coated on laser textured silicon substrate shows significant enhancement for sensor response, and meanwhile response/recovery time is mainly preserved. Furthermore, a good response of textured GO film is detected in a dynamic range of 5-100 ppm NH3. The surface morphology and chemical bonds of the textured GO film are studied by scanning electron microscope (SEM), Fourier Transform Infrared (FT-IR) Spectrometer and X-ray Photoelectron Spectrometer (XPS), respectively. The NH3 response is attributed to the polar oxygen configurations of GO and the enhanced response is due to the richer oxygen configurations that stem from cobwebby microstructure of GO. PMID- 29116162 TI - Impacts of elevated CO2 on exogenous Bacillus thuringiensis toxins and transgene expression in transgenic rice under different levels of nitrogen. AB - Recent studies have highlighted great challenges of transgene silencing for transgenic plants facing climate change. In order to understand the impacts of elevated CO2 on exogenous Bacillus thuringiensis (Bt) toxins and transgene expression in transgenic rice under different levels of N-fertilizer supply, we investigated the biomass, exogenous Bt toxins, Bt-transgene expression and methylation status in Bt rice exposed to two levels of CO2 concentrations and nitrogen (N) supply (1/8, 1/4, 1/2, 1 and 2 N). It is elucidated that the increased levels of global atmospheric CO2 concentration will trigger up regulation of Bt toxin expression in transgenic rice, especially with appropriate increase of N fertilizer supply, while, to some extent, the exogenous Bt transgene expression is reduced at sub-N levels (1/4 and 1/2N), even though the total protein of plant tissues is reduced and the plant growth is restricted. The unpredictable and stochastic occurrence of transgene silencing and epigenetic alternations remains unresolved for most transgenic plants. It is expected that N fertilization supply may promote the expression of transgenic Bt toxin in transgenic Bt rice, particularly under elevated CO2. PMID- 29116163 TI - One-step Synthesis of Ordered Pd@TiO2 Nanofibers Array Film as Outstanding NH3 Gas Sensor at Room Temperature. AB - The one dimensional (1D) ordered porous Pd@TiO2 nanofibers (NFs) array film have been fabricated via a facile one-step synthesis of the electrospinning approach. The Pd@TiO2 NFs (PTND3) contained Pd (2.0 wt %) and C, N element (16.2 wt %) display high dispersion of Pd nanoparticles (NPs) on TiO2 NFs. Adding Pd meshed with C, N element to TiO2 based NFs might contribute to generation of Lewis acid sites and Bronsted acid sites, which have been recently shown to enhance NH3 adsorption-desorption ability; Pd NPs could increase the quantity of adsorbed O2 on the surface of TiO2 based NFs, and accelerated the O2 molecule-ion conversion rate, enhanced the ability of electron transmission. The response time of PTND3 sensor towards 100 ppm NH3 is only 3 s at room temperature (RT). Meantime, the response and response time of the PTND3 to the NH3 is 1 and 14s even at the concentration of 100 ppb. Therefore, the ordered Pd@TiO2 NFs array NH3 sensor display great potential for practical applications. PMID- 29116164 TI - Zinc enhances the cellular energy supply to improve cell motility and restore impaired energetic metabolism in a toxic environment induced by OTA. AB - Exogenous nutrient elements modulate the energetic metabolism responses that are prerequisites for cellular homeostasis and metabolic physiology. Although zinc is important in oxidative stress and cytoprotection processes, its role in the regulation of energetic metabolism remains largely unknown. In this study, we found that zinc stimulated aspect in cell motility and was essential in restoring the Ochratoxin A (OTA)-induced energetic metabolism damage in HEK293 cells. Moreover, using zinc supplementation and zinc deficiency models, we observed that zinc is conducive to mitochondrial pyruvate transport, oxidative phosphorylation, carbohydrate metabolism, lipid metabolism and ultimate energy metabolism in both normal and toxic-induced oxidative stress conditions in vitro, and it plays an important role in restoring impaired energetic metabolism. This zinc-mediated energetic metabolism regulation could also be helpful for DNA maintenance, cytoprotection and hereditary cancer traceability. Therefore, zinc can widely adjust energetic metabolism and is essential in restoring the impaired energetic metabolism of cellular physiology. PMID- 29116165 TI - Organic-inorganic hybrid electrochromic materials, polysilsesquioxanes containing triarylamine, changing color from colorless to blue. AB - Four kinds of soluble monomers, containing triarylamine (TAA) group with reactive siloxane group, were synthesized under mild conditions via the reaction between 3 (triethoxysilyl)propyl isocyanate (TEOSPIC) and four TAA derivatives, respectively. Then the corresponding colorless organic-inorganic hybrid materials (PSSOs) were derived from the hydrolytic condensation of the monomers. PSSOs revealed good solubility in polar solvents on account of the effect of propeller like TAA unit as well as the auxo-action effect of the flexible chain within the monomers. The structural characteristics of these PSSOs were identified by 1H NMR, 29Si NMR, FT-IR spectroscopies and X-ray diffraction (XRD). The morphology, dynamic changes of the transmittance and current before and after electro oxidizing reaction were studied, and didn't show significant change suggesting good stability of the PSSOs. Meanwhile, these PSSOs performed high contrast of optical transmittance change up to 84% with the highest coloration efficiency to 241 cm2.C-1. Furthermore, electrofluorescent properties of PSSOs were investigated with high-contrast. PMID- 29116166 TI - Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D). AB - Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation 1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling. PMID- 29116167 TI - No evidence of widespread decline of snow cover on the Tibetan Plateau over 2000 2015. AB - Understanding the changes in snow cover is essential for biological and hydrological processes in the Tibetan Plateau (TP) and its surrounding areas. However, the changes in snow cover phenology over the TP have not been well documented. Using Moderate Resolution Imaging Spectroradiometer (MODIS) daily snow products and the Interactive Multi-sensor Snow and Ice Mapping System (IMS) data, we reported daily cloud-free snow cover product over the Tibetan Plateau (TP) for 2000-2015. Snow cover start (SCS), melt (SCM) and duration (SCD) dates were calculated for each hydrological year, and their spatial and temporal variations were analyzed with elevation variations. Our results show no widespread decline in snow cover over the past fifteen years and the trends of snow cover phenology over the TP has high spatial heterogeneity. Later SCS, earlier SCM, and thus decreased SCD mainly occurred in the areas with elevation below 3500 m a.s.l., while regions in central and southwestern edges of the TP showed advanced SCS, delayed SCM and consequently longer SCD. The roles of temperature and precipitation on snow cover penology varied in different elevation zones, and the impact of both temperature and precipitation strengthened as elevation increases. PMID- 29116168 TI - Spaceborne Synthetic Aperture Radar Survey of Subsidence in Hampton Roads, Virginia (USA). AB - Over the past century, the Hampton Roads area of the Chesapeake Bay region has experienced one of the highest rates of relative sea level rise on the Atlantic coast of the United States. This rate of relative sea level rise results from a combination of land subsidence, which has long been known to be present in the region, and rising seas associated with global warming on long timescales and exacerbated by shifts in ocean dynamics on shorter timescales. An understanding of the current-day magnitude of each component is needed to create accurate projections of future relative sea level rise upon which to base planning efforts. The objective of this study is to estimate the land component of relative sea level rise using interferometric synthetic aperture radar (InSAR) analysis applied to ALOS-1 synthetic aperture radar data acquired during 2007 2011 to generate high-spatial resolution (20-30 m) estimates of vertical land motion. Although these results are limited by the uncertainty associated with the small set of available historical SAR data, they highlight both localized rates of high subsidence and a significant spatial variability in subsidence, emphasizing the need for further measurement, which could be done with Sentinel-1 and NASA's upcoming NISAR mission. PMID- 29116169 TI - A Zika Vaccine Targeting NS1 Protein Protects Immunocompetent Adult Mice in a Lethal Challenge Model. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly extended its geographic range around the world. Its association with abnormal fetal brain development, sexual transmission, and lack of a preventive vaccine have constituted a global health concern. Designing a safe and effective vaccine requires significant caution due to overlapping geographical distribution of ZIKV with dengue virus (DENV) and other flaviviruses, possibly resulting in more severe disease manifestations in flavivirus immune vaccinees such as Antibody Dependent Enhancement (ADE, a phenomenon involved in pathogenesis of DENV, and a risk associated with ZIKV vaccines using the envelope proteins as immunogens). Here, we describe the development of an alternative vaccine strategy encompassing the expression of ZIKV non-structural-1 (NS1) protein from a clinically proven safe, Modified Vaccinia Ankara (MVA) vector, thus averting the potential risk of ADE associated with structural protein-based ZIKV vaccines. A single intramuscular immunization of immunocompetent mice with the MVA-ZIKV-NS1 vaccine candidate provided robust humoral and cellular responses, and afforded 100% protection against a lethal intracerebral dose of ZIKV (strain MR766). This is the first report of (i) a ZIKV vaccine based on the NS1 protein and (ii) single dose protection against ZIKV using an immunocompetent lethal mouse challenge model. PMID- 29116171 TI - Scintillating Organic-Inorganic Layered Perovskite-type Compounds and the Gamma ray Detection Capabilities. AB - We investigated scintillation properties of organic-inorganic layered perovskite type compounds under gamma-ray and X-ray irradiation. A crystal of the hybrid compounds with phenethyl amine (17 * 23 * 4 mm) was successfully fabricated by the poor-solvent diffusion method. The bulk sample showed superior scintillation properties with notably high light yield (14,000 photons per MeV) under gamma rays and very fast decay time (11 ns). The light yield was about 1.4 time higher than that of common inorganic material (GSO:Ce) confirmed under 137Cs and 57Co gamma-rays. In fact, the scintillation light yield was the highest among the organic-inorganic hybrid scintillators. Moreover, it is suggested that the light yield of the crystal was proportional with the gamma-ray energy across 122-662 keV. In addition, the scintillation from the crystal had a lifetime of 11 ns which was much faster than that of GSO:Ce (48 ns) under X-ray irradiation. These results suggest that organic-inorganic layered perovskite-type compounds are promising scintillator for gamma-ray detection. PMID- 29116172 TI - Building on Sub-Arctic Soil: Geopolymerization of Muskeg to a Densified Load Bearing Composite. AB - The marshy water-saturated soil typical of the sub-Arctic represents a considerable impediment to the construction of roads, thereby greatly hindering human habitation and geological excavation. Muskeg, the native water-laden topsoil characteristic of the North American sub-Arctic, represents a particularly vexing challenge for road construction. Muskeg must either be entirely excavated, or for direct construction on muskeg, a mix of partial excavation and gradual compaction with the strategic placement of filling materials must be performed. Here, we demonstrate a novel and entirely reversible geopolymerization method for reinforcing muskeg with wood fibers derived from native vegetation with the addition of inorganic silicate precursors and without the addition of extraneous metal precursors. A continuous siloxane network is formed that links together the muskeg, wood fibers, and added silicates yielding a load-bearing and low-subsidence composite. The geopolymerization approach developed here, based on catalyzed formation of a siloxane network with further incorporation of cellulose, allows for an increase of density as well as compressive strength while reducing the compressibility of the composite. PMID- 29116170 TI - Injection of high dose botulinum-toxin A leads to impaired skeletal muscle function and damage of the fibrilar and non-fibrilar structures. AB - : Botulinum-toxin A (BoNT/A) is used for a wide range of conditions. Intramuscular administration of BoNT/A inhibits the release of acetylcholine at the neuromuscular junction from presynaptic motor neurons causing muscle paralysis. The aim of the present study was to investigate the effect of high dose intramuscular BoNT/A injections (6 UI = 60 pg) on muscle tissue. The gait pattern of the rats was significantly affected 3 weeks after BoNT/A injection. The ankle joint rotated externally, the rats became flat footed, and the stride length decreased after BoNT/A injection. Additionally, there was clear evidence of microstructural changes on the tissue level by as evidenced by 3D imaging of the muscles by Synchrotron Radiation X-ray Tomographic Microscopy (SRXTM). Both the fibrillar and the non-fibrillar tissues were affected. The volume fraction of fibrillary tissue was reduced significantly and the non-fibrillar tissue increased. This was accompanied by a loss of the linear structure of the muscle tissue. Furthermore, gene expression analysis showed a significant upregulation of COL1A1, MMP-2, TGF-b1, IL-6, MHCIIA and MHCIIx in the BoNT/A injected leg, while MHVIIB was significantly downregulated. IN CONCLUSION: The present study reveals that high dose intramuscular BoNT/A injections cause microstructural damage of the muscle tissue, which contributes to impaired gait. PMID- 29116173 TI - Incidence and Prognostic Relevance of Cardiopulmonary Failure in Takotsubo Cardiomyopathy. AB - Recent studies have indicated that patients with takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. There is a distinct possibility that TTC could be associated with adverse life-threatening complications like cardiopulmonary failure. Our institutional database constituted a collective of 114 patients diagnosed with TTC. The frequency, determinants and predictors of cardiopulmonary failure were assessed. The patients were subsequently classified into two groups based on the presence (n = 44, 38.6%) or absence (n = 70, 61.4%) of cardiopulmonary failure. Multivariable logistic-regression analysis identified impaired left ventricular function defined as <=35% at presentation and life-threatening arrhythmia as a positive significant independent predictor of cardiopulmonary failure. A majority of the patients with cardiopulmonary failure were treated with either non-invasive or invasive ventilator support (88%), while 48% of the patients required treatment with catecholamine. The in-hospital mortality rate was greater in the cardiopulmonary failure group. Cardiopulmonary failure patients were at ongoing increased risk of death with a higher mortality at 30-day, 1-year and at 5 years of follow-up. Cardiopulmonary failure is a frequent complication in TTC with an increased short- and long-term mortality. Patient susceptible to this condition could be identified by a reduced ejection fraction and life-threatening arrhythmia. PMID- 29116175 TI - Sniffer mice discriminate urine odours of patients with bladder cancer: A proof of-principle study for non-invasive diagnosis of cancer-induced odours. AB - Similar to fingerprints, humans have unique, genetically determined body odours. In case of urine, the odour can change due to variations in diet as well as upon infection or tumour formation. We investigated the use of mice in a manner similar to "sniffer dogs" to detect changes in urine odour in patients with bladder cancer. We measured the odour discrimination thresholds of mice in a Y maze, using urine mixtures from patients with bladder cancer (Stage I) and healthy volunteers (dietary variations) as well as occult blood- or antibiotic drug metabolite-modulated samples. Threshold difference indicated that intensities of urinary olfactory cues increase in the following order: dietary variation < bladder cancer < occult blood < antibiotic drug metabolites. After training with patient urine mixtures, sniffer mice discriminated between urine odours of pre- and post-transurethral resection in individual patients with bladder cancer in an equal-occult blood diluted condition below the detection level of dietary variations, achieving a success rate of 100% (11/11). Furthermore, genetic ablation of all dorsal olfactory receptors elevated the discrimination thresholds of mice by >= 105-fold. The marked reduction in discrimination sensitivity indicates an essential role of the dorsal olfactory receptors in the recognition of urinary body odours in mice. PMID- 29116174 TI - Activation of G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels rescues hippocampal functions in a mouse model of early amyloid-beta pathology. AB - The hippocampus plays a critical role in learning and memory. Its correct performance relies on excitatory/inhibitory synaptic transmission balance. In early stages of Alzheimer's disease (AD), neuronal hyperexcitability leads to network dysfunction observed in cortical regions such as the hippocampus. G protein-gated potassium (GirK) channels induce neurons to hyperpolarize, contribute to the resting membrane potential and could compensate any excesses of excitation. Here, we have studied the relationship between GirK channels and hippocampal function in a mouse model of early AD pathology. Intracerebroventricular injections of amyloid-beta (Abeta 1-42) peptide-which have a causal role in AD pathogenesis-were performed to evaluate CA3-CA1 hippocampal synapse functionality in behaving mice. Abeta increased the excitability of the CA3-CA1 synapse, impaired long-term potentiation (LTP) and hippocampal oscillatory activity, and induced deficits in novel object recognition (NOR) tests. Injection of ML297 alone, a selective GirK activator, was also translated in LTP and NOR deficits. However, increasing GirK activity rescued all hippocampal deficits induced by Abeta due to the restoration of excitability values in the CA3-CA1 synapse. Our results show a synaptic mechanism, through GirK channel modulation, for the prevention of the hyperexcitability that causally contributes to synaptic, network, and cognitive deficits found in early AD pathogenesis. PMID- 29116176 TI - Redefining viability by cardiovascular magnetic resonance in acute ST-segment elevation myocardial infarction. AB - In chronic myocardial infarction (MI), segments with a transmural extent of infarct (TEI) of <=50% are defined as being viable. However, in the acute phase of an ST-segment elevation myocardial infarction (STEMI), late gadolinium enhancement (LGE) has been demonstrated to overestimate MI size and TEI. We aimed to identify the optimal cut-off of TEI by cardiovascular magnetic resonance (CMR) for defining viability during the acute phase of an MI, using <=50% TEI at follow up as the reference standard. 40 STEMI patients reperfused by primary percutaneous coronary intervention (PPCI) underwent a CMR at 4 +/- 2 days and 5 +/- 2 months. The large majority of segments with 1-25%TEI and 26-50%TEI that were viable acutely were also viable at follow-up (59/59, 100% and 75/82, 96% viable respectively). 56/84(67%) segments with 51-75%TEI but only 4/63(6%) segments with 76-100%TEI were reclassified as viable at follow-up. TEI on the acute CMR scan had an area-under-the-curve of 0.87 (95% confidence interval of 0.82 to 0.91) and <=75%TEI had a sensitivity of 98% but a specificity of 66% to predict viability at follow-up. Therefore, the optimal cut-off by CMR during the acute phase of an MI to predict viability was <=75% TEI and this would have important implications for patients undergoing viability testing prior to revascularization during the acute phase. PMID- 29116177 TI - High mast cell density indicates a longer overall survival in oral squamous cell carcinoma. AB - This study evaluates the effects of tumour-associated mast cells on the prognosis of patients suffering from oral squamous cell carcinoma (OSCC). Tryptase-positive (MCT+) and CD117-positive (CD117+) mast cells were immunohistochemically evaluated in tissue samples of 118 OSCC patients. Besides, various clinicopathological parameters, the influence of the MCT+ and CD117+ mast cell density on overall survival and the incidence of first local recurrence was analysed by Cox regression and competing risk regression. Among all investigated parameters, multiple Cox regression revealed a significant influence of the MCT+ (cut-off at 14.87 mast cells/mm2 stroma; p = 0.0027) and CD117+ mast cell density (cut-off at 33.19 mast cells/mm2 stroma; p = 0.004), the age at primary diagnosis, and the T and N stage (all p-values < 0.05) on overall survival. Patients with a low mast cell density showed a significantly poorer overall survival rate compared to those with a high mast cell density in the tumour associated stroma. Competing risk regression revealed a significant influence of the resection status (R) on the incidence of first local recurrence (p = 0.0023). A high mast cell density in the tumour-associated stroma of oral squamous cell carcinoma indicates a longer patient survival. PMID- 29116178 TI - Alternative application of an affinity purification tag: hexahistidines in ester hydrolysis. AB - Hexahistidines are very common tags used in the affinity chromatography purification of recombinant proteins. Although these tags are solely applied for their metal-binding properties, we found that they are also able to perform ester hydrolysis when attached to a protein. For instance, green fluorescent protein (GFP) and the cowpea chlorotic mottle virus (CCMV) are able to perform catalysis after introduction of the His-tag. By attaching a His-tag to an enzyme, a dual functional catalyst was created, that can perform a two-step cascade reaction. These findings show that the catalytic properties of the hexahistidine tag should be taken into consideration when choosing a suitable protein purification tag. PMID- 29116179 TI - Breeding and study of two new photoperiod- and thermo-sensitive genic male sterile lines of polyploid rice (Oryza sativa L.). AB - Male sterile lines play an important role in the utilization of heterosis. To explore and exploit the heterosis of polyploid hybrid rice, two photoperiod- and thermo-sensitive genic male sterile lines of polyploid rice, PS006 and PS012, were bred via chromosome doubling, complex hybridization and self-breeding. The characteristics of these two lines, including the agronomic traits, growth, development, fertility transformation and combining ability, were investigated. Both lines had good agronomic characteristics and flowering habits, a high outcrossing rate, obvious fertility alterations and good combining abilities. Their hybrids showed strong heterosis and great potential for increasing rice productivity and quality. The new polyploid rice photoperiod- and thermo sensitive genic male sterile lines will provide material for further research into polyploidy and hybrid vigour in rice and promote the exploitation of polyploid hybrid rice. PMID- 29116180 TI - The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment. AB - While impressive improvements have been achieved in T-ALL therapy, current treatment approaches fail in approximately 25% of patients and these patients have limited treatment options. Another significant group of patients is being overtreated, which causes long-lasting side effects. Identification of molecules controlling drug resistance in T-ALL is crucial for treatment optimisation in both scenarios. We report here the EphB6 receptor is frequently overexpressed in T-ALL. Remarkably, our observations indicate that EphB6 acts in T-ALL cells to enhance sensitivity to a DNA-damaging drug, doxorubicin, as interruption of EphB6 activity interferes with the efficiency of doxorubicin-induced eradication of T ALL cells in cell culture and in xenograft animals. This effect relies on the protection of Akt kinase signaling, while Akt inhibition combined with doxorubicin application produces synergistic effects on the elimination of EphB6 deficient T-ALL cells. These data imply that EphB6 suppresses T-ALL resistance by interfering with Akt activity. Our observations highlight a novel role for EphB6 in reducing drug resistance of T-ALL and suggest that doxorubicin treatment should produce better results if personalised based on EphB6 levels. If successfully verified in clinical studies, this approach should improve outcomes for T-ALL patients resistant to current therapies and for patients, who are being overtreated. PMID- 29116182 TI - The Origin of the "Seasons" in Space Weather. AB - Powerful 'space weather' events caused by solar activity pose serious risks to human health, safety, economic activity and national security. Spikes in deaths due to heart attacks, strokes and other diseases occurred during prolonged power outages. Currently it is hard to prepare for and mitigate the impact of space weather because it is impossible to forecast the solar eruptions that can cause these terrestrial events until they are seen on the Sun. However, as recently reported in Nature, eruptive events like coronal mass ejections and solar flares, are organized into quasi-periodic "seasons", which include enhanced bursts of eruptions for several months, followed by quiet periods. We explored the dynamics of sunspot-producing magnetic fields and discovered for the first time that bursty and quiet seasons, manifested in surface magnetic structures, can be caused by quasi-periodic energy-exchange among magnetic fields, Rossby waves and differential rotation of the solar interior shear-layer (called tachocline). Our results for the first time provide a quantitative physical mechanism for forecasting the strength and duration of bursty seasons several months in advance, which can greatly enhance our ability to warn humans about dangerous solar bursts and prevent damage to satellites and power stations from space weather events. PMID- 29116181 TI - Leucine repeat adaptor protein 1 interacts with Dishevelled to regulate gastrulation cell movements in zebrafish. AB - Gastrulation is a fundamental morphogenetic event that requires polarised cell behaviours for coordinated asymmetric cell movements. Wnt/PCP signalling plays a critical role in this process. Dishevelled is an important conserved scaffold protein that relays Wnt/PCP signals from membrane receptors to the modulation of cytoskeleton organisation. However, it remains unclear how its activity is regulated for the activation of downstream effectors. Here, we report that Lurap1 is a Dishevelled-interacting protein that regulates Wnt/PCP signalling in convergence and extension movements during vertebrate gastrulation. Its loss-of function leads to enhanced Dishevelled membrane localisation and increased JNK activity. In maternal-zygotic lurap1 mutant zebrafish embryos, cell polarity and directional movement are disrupted. Time-lapse analyses indicate that Lurap1, Dishevelled, and JNK functionally interact to orchestrate polarised cellular protrusive activity, and Lurap1 is required for coordinated centriole/MTOC positioning in movement cells. These findings demonstrate that Lurap1 functions to regulate cellular polarisation and motile behaviours during gastrulation movements. PMID- 29116183 TI - Time-resolved analysis of a denitrifying bacterial community revealed a core microbiome responsible for the anaerobic degradation of quinoline. AB - Quinoline is biodegradable under anaerobic conditions, but information about the degradation kinetics and the involved microorganisms is scarce. Here, the dynamics of a quinoline-degrading bacterial consortium were studied in anoxic batch cultures containing nitrate. The cultures removed 83.5% of the quinoline during the first 80 hours, which were dominated by denitrification, and then switched to methanogenesis when the nitrogen oxyanions were depleted. Time resolved community analysis using pyrosequencing revealed that denitrifiying bacteria belonging to the genus Thauera were enriched during the denitrification stage from 12.2% to 38.8% and 50.1% relative abundance in DNA and cDNA libraries, respectively. This suggests that they are key organisms responsible for the initial attack on quinoline. Altogether, 13 different co-abundance groups (CAGs) containing 76 different phylotypes were involved, directly or indirectly, in quinoline degradation. The dynamics of these CAGs show that specific phylotypes were associated with different phases of the degradation. Members of Rhodococcus and Desulfobacterium, as well as Rhodocyclaceae- and Syntrophobacteraceae-related phylotypes, utilized initial metabolites of the quinoline, while the resulting smaller molecules were used by secondary fermenters belonging to Anaerolineae. The concerted action by the different members of this consortium resulted in an almost complete anaerobic mineralization of the quinoline. PMID- 29116184 TI - Proton irradiation: a key to the challenge of N-glycosidic bond formation in a prebiotic context. AB - The formation of nucleosides in abiotic conditions is a major hurdle in origin-of life studies. We have determined the pathway of a general reaction leading to the one-pot synthesis of ribo- and 2'-deoxy-ribonucleosides from sugars and purine nucleobases under proton irradiation in the presence of a chondrite meteorite. These conditions simulate the presumptive conditions in space or on an early Earth fluxed by slow protons from the solar wind, potentially mimicking a plausible prebiotic scenario. The reaction (i) requires neither pre-activated precursors nor intermediate purification/concentration steps, (ii) is based on a defined radical mechanism, and (iii) is characterized by stereoselectivity, regioselectivity and (poly)glycosylation. The yield is enhanced by formamide and meteorite relative to the control reaction. PMID- 29116186 TI - Self-lubricating Al-WS2 composites for efficient and greener tribological parts. AB - Due to their mechanical and physical properties, aluminium alloys possess wide potential in the automotive industry, particularly in hot reciprocating applications such as pistons for diesel and petrol engines. WS2 particle reinforced composites could bring further improvements by reducing friction and wear between moving parts. Reducing friction improves efficiency by lowering energy/fuel use, ultimately leading to lower greenhouse gas emissions, while antiwear properties can prolong component life. This study compares for the first time the tribological performance of powder metallurgy-consolidated Al composites reinforced with either IF- or 2H-WS2 particles, so as to elucidate their mechanism of action in test conditions similar to those encountered in engine applications. The composites were tested in lubricated reciprocating contacts against AISI52100 steel balls and the impact of WS2 could be seen at both 25 and 100 degrees C. The reduced friction and wear at ambient temperature is due to the predominantly physical mechanism of action of WS2, while the best antiwear performance is measured at elevated (standard operating engine) temperatures that promote the chemical reaction of WS2 with the aluminium matrix. The investigation focused on studying the wear tracks/scars and the tribofilms generated on the composite and ball with optical profilometry, SEM, XPS and Auger spectroscopy. PMID- 29116185 TI - Targeted Metabolomics Reveals Abnormal Hepatic Energy Metabolism by Depletion of beta-Carotene Oxygenase 2 in Mice. AB - beta-carotene oxygenase 2 (BCO2) is a carotenoid cleavage enzyme located in the inner mitochondrial membrane. Ablation of BCO2 impairs mitochondrial function leading to oxidative stress. Herein, we performed a targeted metabolomics study using ultrahigh performance liquid chromatography-tandem mass spectroscopy and gas chromatography-mass spectroscopy to discriminate global metabolites profiles in liver samples from six-week-old male BCO2 systemic knockout (KO), heterozygous (Het), and wild type (WT) mice fed a chow diet. Principal components analysis revealed distinct differences in metabolites in the livers of KO mice, compared to WT and Het mice. However, no marked difference was found in the metabolites of the Het mouse liver compared to the WT. We then conducted random forest analysis to classify the potential biomarkers to further elucidate the different metabolomics profiles. We found that systemic ablation of BCO2 led to perturbations in mitochondrial function and metabolism in the TCA cycle, amino acids, carnitine, lipids, and bile acids. In conclusion, BCO2 is essential to macronutrient and mitochondrial metabolism in the livers of mice. The ablation of BCO2 causes dysfunctional mitochondria and altered energy metabolism, which further leads to systemic oxidative stress and inflammation. A single functional copy of BCO2 largely rescues the hepatic metabolic homeostasis in mice. PMID- 29116187 TI - A translational study on looming-evoked defensive response and the underlying subcortical pathway in autism. AB - Rapidly approaching objects indicating threats can induce defensive response through activating a subcortical pathway comprising superior colliculus (SC), lateral posterior nucleus (LP), and basolateral amygdala (BLA). Abnormal defensive response has been reported in autism, and impaired synaptic connections could be the underlying mechanism. Whether the SC-LP-BLA pathway processes looming stimuli abnormally in autism is not clear. Here, we found that looming evoked defensive response is impaired in a subgroup of the valproic acid (VPA) mouse model of autism. By combining the conventional neurotracer and transneuronal rabies virus tracing techniques, we demonstrated that synaptic connections in the SC-LP-BLA pathway were abnormal in VPA mice whose looming evoked defensive responses were absent. Importantly, we further translated the finding to children with autism and observed that they did not present looming evoked defensive response. Furthermore, the findings of the DTI with the probabilistic tractography showed that the structural connections of SC-pulvinar amygdala in autism children were weak. The pulvinar is parallel to the LP in a mouse. Because looming-evoked defensive response is innate in humans and emerges much earlier than do social and language functions, the absence of defensive response could be an earlier sign of autism in children. PMID- 29116188 TI - CXCL10/CXCR3 axis is associated with disease activity and the development of mucocutaneous lesions in patients with Behcet's disease. AB - The objective of this study was to investigate CXC chemokines and its receptor in patients with Behcet's disease (BD) and their associations with disease activity. Blood samples were collected from 109 BD patients and 36 age- and sex-matched healthy controls (HCs). Twenty-two follow-up blood samples were collected in BD patients. Serum CXC chemokines (CXCL1, CXCL8, CXCL9, CXCL10, CXCL12, CXCL13 and CXCL16) and cell surface marker expression (CD3, CD4 and CXCR3) in peripheral blood mononuclear cells (PBMCs) were assayed. Clinical features including disease activity were evaluated at the time of blood collection. CXCR3 expression in skin and intestinal lesions from BD patients and HCs was assessed via immunohistochemistry. Serum CXCL10 levels were correlated with disease activity in terms of Behcet's Disease Current Activity Form (BDCAF) (p < 0.001). In follow up BD patients, changes in serum CXCL10 levels tended to be correlated with those of BDCAF. The percentage of CXCR3 expression in CD3-positive cells in PBMCs was inversely correlated with serum CXCL10 levels in BD patients (p = 0.022). By immunohistochemistry, the number of CXCR3-positive mononuclear cells was higher in skin and intestinal lesions of BD patients than in those of HCs. These results suggest that the CXCL10/CXCR3 axis may contribute to the pathogenesis of BD. PMID- 29116190 TI - Estimated economic costs of coal workers' pneumoconiosis among coal workers redeployed from the Fuxin mining group in China. AB - Our research estimated the economic costs of possible cases of coal workers' pneumoconiosis (CWP) among redeployed coal workers from the Fuxin Mining Industry Group. The study cohort included 19,116 coal workers between 1965 and 2012. We estimated direct and indirect economic costs due to possible current and future CWP cases among redeployed coal workers. We found as of 2012 that 141 possible CWP cases might have resulted in economic costs of $37.52 million ($33.84 million were direct and $3.68 million indirect). Moreover, 221 possible future CWP cases would result in economic costs of $63.89 million ($57.20 million direct and $6.69 million indirect). Neither the Fuxin Mining Industry Group nor Fuxin could cover the costs of CWP screening and diagnosis, or social security payments for redeployed coal workers. We suggest that China's national government help Liaoning Province and Fuxin focus on health care and social security. PMID- 29116189 TI - Tobacco papers and tobacco industry ties in regulatory toxicology and pharmacology. AB - We examined the relationship between the tobacco industry and the journal Regulatory Toxicology and Pharmacology (RTP) using the Truth Tobacco Industry Documents Library and internet sources. We determined the funding relationships, and categorised the conclusions of all 52 RTP papers on tobacco or nicotine between January 2013 and June 2015, as "positive", "negative" or "neutral" for the tobacco industry. RTP's editor, 57% (4/7) of associate editors and 37% (14/38) of editorial board members had worked or consulted for tobacco companies. Almost all (96%, 50/52) of the papers had authors with tobacco industry ties. Seventy-six percent (38/50) of these papers drew conclusions positive for industry; none drew negative conclusions. The two papers by authors not related to the tobacco industry reached conclusions negative to the industry (p < .001). These results call into question the confidence that members of the scientific community and tobacco product regulators worldwide can have in the conclusions of papers published in RTP. PMID- 29116191 TI - Histone methyltransferase G9a is a key regulator of the starvation-induced behaviors in Drosophila melanogaster. AB - Organisms have developed behavioral strategies to defend themselves from starvation stress. Despite of their importance in nature, the underlying mechanisms have been poorly understood. Here, we show that Drosophila G9a (dG9a), one of the histone H3 Lys 9-specific histone methyltransferases, functions as a key regulator for the starvation-induced behaviors. RNA-sequencing analyses utilizing dG9a null mutant flies revealed that the expression of some genes relating to gustatory perception are regulated by dG9a under starvation conditions. Reverse transcription quantitative-PCR analyses showed that the expression of gustatory receptor genes for sensing sugar are up-regulated in starved dG9a null mutant. Consistent with this, proboscis extension reflex tests indicated that dG9a depletion increased the sensitivity to sucrose under starvation conditions. Furthermore, the locomotion activity was promoted in starved dG9a null mutant. We also found that dG9a depletion down-regulates the expression of insulin-like peptide genes that are required for the suppression of starvation-induced hyperactivity. Furthermore, refeeding of wild type flies after starvation conditions restores the hyperactivity and increased sensitivity to sucrose as well as dG9a expression level. These data suggest that dG9a functions as a key regulator for the decision of behavioral strategies under starvation conditions. PMID- 29116193 TI - Tighter bound of quantum randomness certification for independent-devices scenario. AB - Quantum random number generation attracts considerable attention, since its randomness inherently originates in quantum mechanics, but not mathematical assumptions. Randomness certification, e.g. entropy estimation, becomes a key issue in the context of quantum random number generation protocol. We study a self-testing protocol based on dimension witness, with the assumption of independent devices. It addresses the random number extraction problem in a practical prepare-and-measure scenario with uncharacterized devices. However, the lower bound of min-entropy as a function of dimension witness is not tight in existing works. We present a tighter bound of analytic form, by introducing the Lagrangian multiplier method to closely analyze the optimization problem on average guessing probability. Through simulation, it turns out that a significantly higher random number generation rate can be achieved in practice. PMID- 29116192 TI - Human stem cell-derived retinal epithelial cells activate complement via collectin 11 in response to stress. AB - Age-related macular degeneration (AMD) is a major cause of blindness and is associated with complement dysregulation. The disease is a potential target for stem cell therapy but success is likely to be limited by the inflammatory response. We investigated the innate immune properties of human induced pluripotent stem cell (iPSC)-derived RPE cells, particularly with regard to the complement pathway. We focused on collectin-11 (CL-11), a pattern recognition molecule that can trigger complement activation in renal epithelial tissue. We found evidence of constitutive and hypoxia-induced expression of CL-11 in iPS-RPE cells, and in the extracellular fluid. Complement activation on the cell surface occurred in conjunction with CL-11 binding. CL-11 has been shown to activate inflammatory responses through recognition of L-fucose, which we confirmed by showing that fucosidase-treated cells, largely, failed to activate complement. The presence of CL-11 in healthy murine and human retinal tissues confirmed the biological relevance of CL-11. Our data describe a new trigger mechanism of complement activation that could be important in disease pathogenesis and therapeutic interventions. PMID- 29116194 TI - Site Specific Modification of Adeno-Associated Virus Enables Both Fluorescent Imaging of Viral Particles and Characterization of the Capsid Interactome. AB - Adeno-associated viruses (AAVs) are attractive gene therapy vectors due to their low toxicity, high stability, and rare integration into the host genome. Expressing ligands on the viral capsid can re-target AAVs to new cell types, but limited sites have been identified on the capsid that tolerate a peptide insertion. Here, we incorporated a site-specific tetracysteine sequence into the AAV serotype 9 (AAV9) capsid, to permit labelling of viral particles with either a fluorescent dye or biotin. We demonstrate that fluorescently labelled particles are detectable in vitro, and explore the utility of the method in vivo in mice with time-lapse imaging. We exploit the biotinylated viral particles to generate two distinct AAV interactomes, and identify several functional classes of proteins that are highly represented: actin/cytoskeletal protein binding, RNA binding, RNA splicing/processing, chromatin modifying, intracellular trafficking and RNA transport proteins. To examine the biological relevance of the capsid interactome, we modulated the expression of two proteins from the interactomes prior to AAV transduction. Blocking integrin alphaVbeta6 receptor function reduced AAV9 transduction, while reducing histone deacetylase 4 (HDAC4) expression enhanced AAV transduction. Our method demonstrates a strategy for inserting motifs into the AAV capsid without compromising viral titer or infectivity. PMID- 29116195 TI - Resistance monitoring and cross-resistance role of CYP6CW1 between buprofezin and pymetrozine in field populations of Laodelphax striatellus (Fallen). AB - Monitoring resistance and investigating insecticide resistance mechanisms are necessary for controlling the small brown planthopper, Laodelphax striatellus. The susceptibility to four common insecticides of L. striatellus collected from Jiangsu, Anhui, Zhejiang and Jilin provinces of China in 2015 was monitored. The results showed that all field populations remained susceptible to chlorpyrifos and thiamethoxam with resistance ratios (RRs) of 2.3- to 9.5 and 1.6- to 3.3, respectively, while the insects had developed moderate pymetrozine resistance with RRs of 18.7 to 34.5. Resistance against buprofezin had developed to an alarmingly high level in three southeastern provinces of China with RRs of 108.8 to 156.1, but in Jilin it had an RR of only 26.6. Moreover, in line with both the buprofezin and pymetrozine resistance levels, we found LsCYP6CW1 to be over expressed in all field L. striatellus populations, which indicated that it might be important for cross-resistance between buprofezin and pymetrozine. RNA interference (RNAi) ingestion resulted in the effective suppression of LsCYP6CW1 expression, and significantly increased susceptibility to both buprofezin and pymetrozine compared with the control, which further confirmed that overexpression of LsCYP6CW1 was involved in the cross-resistance to buprofezin and pymetrozine in field L. Striatellus populations. PMID- 29116196 TI - Thalidomide Inhibits TGF-beta1-induced Epithelial to Mesenchymal Transition in Alveolar Epithelial Cells via Smad-Dependent and Smad-Independent Signaling Pathways. AB - Recent evidence indicates that the epithelial to mesenchymal transition (EMT) in primary alveolar cells (AECs) plays an important role in idiopathic pulmonary fibrosis (IPF). In vivo models have suggested that thalidomide (THL) has anti fibrotic effects against pulmonary fibrosis, but the underlying mechanism of this effect is not clear. This study investigated whether THL regulates alveolar EMT and the possible mechanisms underlying this process. CCL-149 cells were treated with TGF-beta1 in the presence of THL at the indicated concentrations. EMT was assessed by changes in cell morphology and in phenotypic markers. Signaling pathways involved in EMT were characterized by western blot analysis. THL inhibited the TGF-beta1 induction of alpha-SMA, vimentin, MMP-2/-9 and collagen type IV expression and restored the morphological changes in primary alveolar epithelial cells caused by TGF-beta1. TGF-beta1 induction of alpha-SMA expression was partially dependent on the activation of p38, JNK, ERK, Akt, Smad 2 and Smad3. Moreover, THL inhibited TGF-beta1-induced phosphorylation of p38, JNK, ERK, Akt, GSK3beta, Smad 2 and Smad3 without altering the total expression levels of those proteins. These findings indicate that TGF-beta1-induced EMT in alveolar epithelial cells is inhibited by THL via both Smad-dependent and non-Smad dependent signaling pathways and suggests therapeutic approaches for targeting this process in pulmonary fibrosis. PMID- 29116197 TI - Pathway Towards High-Efficiency Eu-doped GaN Light-Emitting Diodes. AB - A physically intuitive current injection efficiency model for a GaN:Eu quantum well (QW) has been developed to clarify the necessary means to achieve device quantum efficiency higher than the state-of-the-art GaN:Eu system for red light emission. The identification and analysis of limiting factors for high internal quantum efficiencies (IQE) are accomplished through the current injection efficiency model. In addition, the issue of the significantly lower IQE in the electrically-driven GaN:Eu devices in comparison to the optically-pumped GaN:Eu devices is clarified in the framework of this injection efficiency model. The improved understanding of the quantum efficiency issue through current injection efficiency model provides a pathway to address the limiting factors in electrically-driven devices. Based on our developed injection efficiency model, several experimental approaches have been suggested to address the limitations in achieving high IQE GaN:Eu QW based devices in red spectral regime. PMID- 29116198 TI - Adhesion and Self-Healing between Monolayer Molybdenum Disulfide and Silicon Oxide. AB - The adhesion interactions of two-dimensional (2D) materials are of importance in developing flexible electronic devices due to relatively large surface forces. Here, we investigated the adhesion properties of large-area monolayer MoS2 grown on silicon oxide by using chemical vapor deposition. Fracture mechanics concepts using double cantilever beam configuration were used to characterize the adhesion interaction between MoS2 and silicon oxide. While the interface between MoS2 and silicon oxide was fractured under displacement control, force-displacement response was recorded. The separation energy, adhesion strength and range of the interactions between MoS2 and silicon oxide were characterized by analytical and numerical analyses. In addition to the fundamental adhesion properties of MoS2, we found that MoS2 monolayers on silicon oxide had self-healing properties, meaning that when the separated MoS2 and silicon oxide were brought into contact, the interface healed. The self-healing property of MoS2 is potentially applicable to the development of new composites or devices using 2D materials. PMID- 29116199 TI - Microscopic Differentiation of Plasmonic Nanoparticles for the Ratiometric Read out of Target DNA. AB - The development of highly sensitive and rapid methods for detecting DNA is of critical importance. Here, we describe a strategy for the digital detection of target DNA at the femto-molar level. Individual DNA molecules were encoded with a single gold nanorod (AuNR), separated and enriched by magnetic immune-separation. The coding gold nanorods were then de-hybridized and dispersed into a gold nanosphere (AuNS) solution at a certain concentration, and both gold nanoparticles were immobilized on glass slides for dark-field microscopic imaging. Using an in-house Matlab program, the concentration of the target DNA was calculated based on the ratio of the coding gold nanorods to gold nanospheres. By combining the coding of individual biomolecules with a single gold nanorod and the use of gold nanospheres as an internal standard, a method for the rapid and accurate digital detection of target DNA to the femto-molar level was developed. PMID- 29116200 TI - Internal Extractive Electrospray Ionization Mass Spectrometry for Quantitative Determination of Fluoroquinolones Captured by Magnetic Molecularly Imprinted Polymers from Raw Milk. AB - Antibiotics contamination in food products is of increasing concern due to their potential threat on human health. Herein solid-phase extraction based on magnetic molecularly imprinted polymers coupled with internal extractive electrospray ionization mass spectrometry (MMIPs-SPE-iEESI-MS) was designed for the quantitative analysis of trace fluoroquinolones (FQs) in raw milk samples. FQs in the raw milk sample (2 mL) were selectively captured by the easily-lab-made magnetic molecularly imprinted polymers (MMIPs), and then directly eluted by 100 uL electrospraying solvent biased with +3.0 kV to produce protonated FQs ions for mass spectrometric characterization. Satisfactory analytical performance was obtained in the quantitative analysis of three kinds of FQs (i.e., norfloxacin, enoxacin, and fleroxacin). For all the samples tested, the established method showed a low limit of detection (LOD <= 0.03 ug L-1) and a high analysis speed (<=4 min per sample). The analytical performance for real sample analysis was validated by a nationally standardized protocol using LC-MS, resulting in acceptable relative error values from -5.8% to +6.9% for 6 tested samples. Our results demonstrate that MMIPs-SPE-iEESI-MS is a new strategy for the quantitative analysis of FQs in complex biological mixtures such as raw milk, showing promising applications in food safety control and biofluid sample analysis. PMID- 29116201 TI - Nonlinear Properties of Ge-rich Si1-xGex Materials with Different Ge Concentrations. AB - Silicon photonics is a large volume and large scale integration platform for applications from long-haul optical telecommunications to intra-chip interconnects. Extension to the mid-IR wavelength range is now largely investigated, mainly driven by absorption spectroscopy applications. Germanium (Ge) is particularly compelling as it has a broad transparency window up to 15 um and a much higher third-order nonlinear coefficient than silicon which is very promising for the demonstration of efficient non-linear optics based active devices. Si1-xGex alloys have been recently studied due to their ability to fine tune the bandgap and refractive index. The material nonlinearities are very sensitive to any modification of the energy bands, so Si1-xGex alloys are particularly interesting for nonlinear device engineering. We report on the first third order nonlinear experimental characterization of Ge-rich Si1-xGex waveguides, with Ge concentrations x ranging from 0.7 to 0.9. The characterization performed at 1580 nm is compared with theoretical models and a discussion about the prediction of the nonlinear properties in the mid-IR is introduced. These results will provide helpful insights to assist the design of nonlinear integrated optical based devices in both the near- and mid-IR wavelength ranges. PMID- 29116203 TI - Association of Thyroid Function with Early/Mid-term Aorta-Related Adverse Events and Readmissions after Thoracic Endovascular Aortic Repair. AB - The prognosis of patients after thoracic endovascular aortic repair (TEVAR) is affected by several clinical characteristics. This study aimed to evaluate whether thyroid hormones predicts early (30 days) and mid-term (12 months) aorta related adverse events (ARAE) and readmissions (ARAR) in patients after TEVAR. A total of 338 continuous patients who underwent TEVAR were included and stratified based on quartile of free thyroxine (FT4) levels examined before surgery. The relationship of FT4 levels with early or mid-term ARAE and ARAR were assessed using univariate and multiple logistic regression analysis. The incidence of ARAE and ARAR were 2.7% and 4.1% within 30 days, and 8.9% and 13.5% within 12 months, respectively. After adjusting for confounders, the lowest FT4 quartile group were noted to be at significantly greater risk than the highest FT4 quartile group in early (OR 10.105, 95% CI 1.103 to 92.615, P = 0.041) and mid-term (OR 5.687, 95% CI 1.708 to 18.935, P = 0.005) ARAR, but not significantly different in early (OR 2.097, 95% CI 0.228 to 19.307, P = 0.513) and mid-term (OR 0.695, 95% CI 0.207 to 2.332, P = 0.556) ARAE. Thus, patients with low-normal FT4 levels after TEVAR are at greater risk of ARAR, but not ARAE, in both the early and the mid-term follow up periods. PMID- 29116202 TI - Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer. AB - Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin accessibility and ectopic gene expression. Notably incorporation of acetylated H2A.Z nucleosomes is a pre requisite for activation of Androgen receptor (AR) associated enhancers. H2A.Zac nucleosome occupancy is rapidly remodeled to flank the AR sites to initiate the formation of nucleosome-free regions and the production of AR-enhancer RNAs upon androgen treatment. Remarkably higher levels of global H2A.Zac correlate with poorer prognosis. Altogether these data demonstrate the novel contribution of H2A.Zac in activation of newly formed enhancers in prostate cancer. PMID- 29116205 TI - Reducing Urban Greenhouse Gas Footprints. AB - Cities are economically open systems that depend on goods and services imported from national and global markets to satisfy their material and energy requirements. Greenhouse Gas (GHG) footprints are thus a highly relevant metric for urban climate change mitigation since they not only include direct emissions from urban consumption activities, but also upstream emissions, i.e. emissions that occur along the global production chain of the goods and services purchased by local consumers. This complementary approach to territorially-focused emission accounting has added critical nuance to the debate on climate change mitigation by highlighting the responsibility of consumers in a globalized economy. Yet, city officials are largely either unaware of their upstream emissions or doubtful about their ability to count and control them. This study provides the first internationally comparable GHG footprints for four cities (Berlin, Delhi NCT, Mexico City, and New York metropolitan area) applying a consistent method that can be extended to other global cities using available data. We show that upstream emissions from urban household consumption are in the same order of magnitude as cities' overall territorial emissions and that local policy leverage to reduce upstream emissions is larger than typically assumed. PMID- 29116204 TI - Tuberculosis in Swiss captive Asian elephants: microevolution of Mycobacterium tuberculosis characterized by multilocus variable-number tandem-repeat analysis and whole-genome sequencing. AB - Zoonotic tuberculosis is a risk for human health, especially when animals are in close contact with humans. Mycobacterium tuberculosis was cultured from several organs, including lung tissue and gastric mucosa, of three captive elephants euthanized in a Swiss zoo. The elephants presented weight loss, weakness and exercise intolerance. Molecular characterization of the M. tuberculosis isolates by spoligotyping revealed an identical profile, suggesting a single source of infection. Multilocus variable-number of tandem-repeat analysis (MLVA) elucidated two divergent populations of bacteria and mixed infection in one elephant, suggesting either different transmission chains or prolonged infection over time. A total of eight M. tuberculosis isolates were subjected to whole-genome sequence (WGS) analysis, confirming a single source of infection and indicating the route of transmission between the three animals. Our findings also show that the methods currently used for epidemiological investigations of M. tuberculosis infections should be carefully applied on isolates from elephants. Moreover the importance of multiple sampling and analysis of within-host mycobacterial clonal populations for investigations of transmission is demonstrated. PMID- 29116206 TI - Harvesting the Energy of Multi-Polarized Electromagnetic Waves. AB - We present the idea and design of a dual polarized metasurface for electromagnetic energy harvesting. A 4 * 4 super cell with alternating vias between adjacent cells was designed to allow for capturing the energy from various incident angles at an operating frequency of 2.4 GHz. The collected energy is then channeled to a feeding network that collects the AC power and feeds it to a rectification circuitry. The simulation results yielded a radiation to AC and an AC to DC conversion efficiencies of around 90% and 80%, respectively. As a proof of concept, an array consisting of 9 super cells was fabricated and measured. The experimental results show that the proposed energy harvester is capable of capturing up to 70% of the energy from a planewave having various polarizations and converting it to usable DC power. PMID- 29116207 TI - Quantum Light in Curved Low Dimensional Hexagonal Boron Nitride Systems. AB - Low-dimensional wide bandgap semiconductors open a new playing field in quantum optics using sub-bandgap excitation. In this field, hexagonal boron nitride (h BN) has been reported to host single quantum emitters (QEs), linking QE density to perimeters. Furthermore, curvature/perimeters in transition metal dichalcogenides (TMDCs) have demonstrated a key role in QE formation. We investigate a curvature-abundant BN system - quasi one-dimensional BN nanotubes (BNNTs) fabricated via a catalyst-free method. We find that non-treated BNNT is an abundant source of stable QEs and analyze their emission features down to single nanotubes, comparing dispersed/suspended material. Combining high spatial resolution of a scanning electron microscope, we categorize and pin-point emission origin to a scale of less than 20 nm, giving us a one-to-one validation of emission source with dimensions smaller than the laser excitation wavelength, elucidating nano-antenna effects. Two emission origins emerge: hybrid/entwined BNNT. By artificially curving h-BN flakes, similar QE spectral features are observed. The impact on emission of solvents used in commercial products and curved regions is also demonstrated. The 'out of the box' availability of QEs in BNNT, lacking processing contamination, is a milestone for unraveling their atomic features. These findings open possibilities for precision engineering of QEs, puts h-BN under a similar 'umbrella' of TMDC's QEs and provides a model explaining QEs spatial localization/formation using electron/ion irradiation and chemical etching. PMID- 29116208 TI - Dynamic self-assembly and self-organized transport of magnetic micro-swimmers. AB - We demonstrate experimentally and in computer simulations that magnetic microfloaters can self-organize into various functional structures while energized by an external alternating (ac) magnetic field. The structures exhibit self-propelled motion and an ability to carry a cargo along a pre-defined path. The morphology of the self-assembled swimmers is controlled by the frequency and amplitude of the magnetic field. PMID- 29116209 TI - Preoperative N-terminal pro-B-type natriuretic peptide concertation and prognosis of brain tumor patients: a 5-year follow up study. AB - Increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration predicts poor prognosis of non-CNS cancer patients. We evaluated the association of NT-proBNP concentration with disease severity, discharge outcomes and prognosis of patients undergoing craniotomy for brain tumor. From January, 2010 until September, 2011 two-hundred and forty-five patients (age 55.05 +/- 14.62 years) admitted for brain tumor surgery were evaluated for NT-proBNP serum concentration. Outcome at hospital discharge was evaluated with the Glasgow Outcome Scale (GOS). Most common diagnoses were meningioma (37%) and high-grade glioma (20%). Greater NT-proBNP concentration was associated with lower Barthel index (rho = -0.305, p = 0.001) and Mini Mental State Examination scores (rho = 0.314, p = 0.001) and with greater Hospital Anxiety and Depression scale Depression score (rho = 0.240, p = 0.026). Greater admission NT-proBNP concentration was associated with lower discharge GOS score after adjusting for patient age, gender and histological brain tumor diagnosis (beta = -0.253, p < 0.001). Greater NT-proBNP concentration was also associated with greater 5-year mortality risk (HR = 1.845; 95%CI [1.166-2.920], p = 0.009) controlling for patient age, gender, history of cardiovascular disease, histological diagnosis and adjuvant therapy. In sum, greater pre-operative NT-proBNP concentration is associated with worse health status, unfavorable discharge outcome and shorter survival of brain tumor patients. PMID- 29116210 TI - Link prediction in complex networks via matrix perturbation and decomposition. AB - Link prediction in complex networks aims at predicting the missing links from available datasets which are always incomplete and subject to interfering noises. To obtain high prediction accuracy one should try to complete the missing information and at the same time eliminate the interfering noise from the datasets. Given that the global topological information of the networks can be exploited by the adjacent matrix, the missing information can be completed by generalizing the observed structure according to some consistency rule, and the noise can be eliminated by some proper decomposition techniques. Recently, two related works have been done that focused on each of the individual aspect and obtained satisfactory performances. Motivated by their complementary nature, here we proposed a new link prediction method that combines them together. Moreover, by extracting the symmetric part of the adjacent matrix, we also generalized the original perturbation method and extended our new method to weighted directed networks. Experimental studies on real networks from disparate fields indicate that the prediction accuracy of our method was considerably improved compared with either of the individual method as well as some other typical local indices. PMID- 29116211 TI - Usefulness of 10-2 Matrix Frequency Doubling Technology Perimetry for Detecting Central Visual Field Defects in Preperimetric Glaucoma Patients. AB - It is generally acknowledged that structural loss can precede functional loss in some patients with early glaucoma. However, conventional standard automated perimetry (SAP) has limitations in the detection of functional loss, especially in the macular area. This study explores visual field loss in the macular areas of patients with preperimetric glaucoma exhibiting structural thinning in the area by examining the correlations between the ganglion cell-inner plexiform layer (GCIPL) and the results of matrix frequency-doubling technology (FDT) 10-2 tests. The structure-function relationships between the GCIPL thicknesses and the mean sensitivities (MSs) of the corresponding areas based on conventional SAP 24 2, FDT 10-2, and FDT 24-2 were examined in 62 patients. The highest correlation was found for FDT 10-2 (r = 0.544, P < 0.001) followed by FDT 24-2 (r = 0.433, P = 0.002) and SAP (r = 0.346, P = 0.007). The correlation coefficients between each GCIPL sector and the corresponding central MS according to FDT 24-2 and 10-2 were all statistically significant, and the correlations were significantly stronger for FDT 10-2 than 24-2 in the inferior and inferonasal sectors. In conclusion, preperimetric glaucoma patients with structural loss in the macula as indicated by GCIPL thinning also exhibited functional loss as revealed by FDT 10 2, and the functional loss was less evident with conventional SAP. PMID- 29116213 TI - The performance and archaeal community shifts in a modified anaerobic baffled reactor treating sweet potato starch wastewater at ambient temperatures. AB - A conventional anaerobic baffled reactors (ABRs) treating high strength sweet potato starch wastewater at ambient temperatures resulted in acidification and bad performances. After modification, the acidification was remitted and COD removal efficiencies reached 92.73% at high temperatures and were maintained at 71.19% at low temperatures. Moreover, as much as 1.014 +/- 0.056 L CH4/L/d were collected at Stage III. The q-PCR results revealed that the largest methanogen populations emerged at Stage III as well, which was 5.29 * 108 mcrA copies per milliliter sludge. A comparable shift in the archaeal community structure at different stages and acetoclastic methanogens Methanosaeta predominated the archaeal community in every compartment in Stages I (63.73%) and II (48.63%). Finally, the net energy gains analysis at mesophilic, thermophilic, and ambient temperature revealed that modified ABR at ambient temperature was not only economical but also profitable and could generated 3.68 KJ energy per gram COD removed. PMID- 29116212 TI - Causes of Death in Patients with Severe Aortic Stenosis: An Observational study. AB - Whether patients with severe aortic stenosis (AS) die because of AS-related causes is an important issue for the management of these patients. We used data from CURRENT AS registry, a Japanese multicenter registry, to assess the causes of death in severe AS patients and to identify the factors associated with non cardiac mortality. We enrolled 3815 consecutive patients with a median follow-up of 1176 days; the 1449 overall deaths comprised 802 (55.3%) from cardiac and 647 (44.7%) from non-cardiac causes. Heart failure (HF) (25.7%) and sudden death (13.0%) caused the most cardiac deaths, whereas infection (13.0%) and malignancy (11.1%) were the main non-cardiac causes. According to treatment strategies, infection was the most common cause of non-cardiac death, followed by malignancy, in both the initial aortic valve replacement (AVR) cohort (N = 1197), and the conservative management cohort (N = 2618). Both non-cardiac factors (age, male, body mass index <22, diabetes, prior history of stroke, dialysis, anemia, and malignancy) and cardiac factors (atrial fibrillation, ejection fraction <68%, and the initial AVR strategy) were associated with non-cardiac death. These findings highlight the importance of close monitoring of non-cardiac comorbidities, as well as HF and sudden death, to improve the mortality rate of severe AS patients. PMID- 29116214 TI - Bioinspired Synthesis of Mesoporous Gold-silica Hybrid Microspheres as Recyclable Colloidal SERS Substrates. AB - Noble metal nanostructures have been intensively investigated as active substrates for surface-enhanced Raman spectroscopy (SERS) from visible to near-IR wavelengths. However, metal nanoparticle-based SERS analysis in solutions is very challenging due to uncontrollable and irreproducible colloid aggregation. Here we report the templated synthesis of porous gold-silica hybrid microspheres and their application as reusable colloidal SERS substrates. Mesoporous polymer microspheres are synthesized and used as templates for the synthesis of non aggregated gold nanoparticles, followed by polydopamine-mediated silicification to fabricate mesoporous gold-silica hybrid microspheres. The mesoporous hybrid particles detect crystal violet in the order of 10-8 M and provide the structural durability of the immobilized gold nanoparticles, allowing them to be recycled for repeated SERS analyses for analytes in a solution with the similar sensitivity. This work suggests that the mesoporous gold-silica hybrid microspheres are attractive SERS substrates in terms of reusability, sensitivity, and stability. PMID- 29116215 TI - Comparative evaluation of tumor targeting using the anti-HER2 ADAPT scaffold protein labeled at the C-terminus with indium-111 or technetium-99m. AB - ABD-Derived Affinity Proteins (ADAPTs) is a novel class of engineered scaffold proteins derived from an albumin-binding domain of protein G. The use of ADAPT6 derivatives as targeting moiety have provided excellent preclinical radionuclide imaging of human epidermal growth factor 2 (HER2) tumor xenografts. Previous studies have demonstrated that selection of nuclide and chelator for its conjugation has an appreciable effect on imaging properties of scaffold proteins. In this study we performed a comparative evaluation of the anti-HER2 ADAPT having an aspartate-glutamate-alanine-valine-aspartate-alanine-asparagine-serine (DEAVDANS) N-terminal sequence and labeled at C-terminus with 99mTc using a cysteine-containing peptide based chelator, glycine-serine-serine-cysteine (GSSC), and a similar variant labeled with 111In using a maleimido derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. Both 99mTc-DEAVDANS-ADAPT6-GSSC and 111In-DEAVDANS-ADAPT6-GSSC-DOTA accumulated specifically in HER2-expressing SKOV3 xenografts. The tumor uptake of both variants did not differ significantly and average values were in the range of 19 21%ID/g. However, there was an appreciable variation in uptake of conjugates in normal tissues that resulted in a notable difference in the tumor-to-organ ratios. The 111In-DOTA label provided 2-6 fold higher tumor-to-organ ratios than 99mTc-GSSC and is therefore the preferable label for ADAPTs. PMID- 29116216 TI - Juvenile fish assemblages in temperate rocky reefs are shaped by the presence of macro-algae canopy and its three-dimensional structure. AB - Arborescent macro-algae forests covering temperate rocky reefs are a known habitat for juvenile fishes. However, in the Mediterranean, these forests are undergoing severe transformations due to pressures from global change. In our study, juvenile fish assemblages differed between pristine arborescent forests (Cystoseira brachycarpa var. balearica) versus an alternate state: bushland (Dictyotales - Sphacelariales). Forests hosted richer and three-fold more abundant juvenile assemblages. This was consistent through space, whatever the local environmental conditions, along 40 km of NW Mediterranean subtidal rocky shores (Corsica, France). Among Cystoseira forests, juvenile assemblages varied through space (i.e. between localities, zones or sites) in terms of total abundance, composition, richness and taxa-specific patterns. More than half of this variability was explained by forest descriptors, namely small variations in canopy structure and/or depth. Our results provide essential cues for understanding and managing coastal habitats and fish populations. Further studies are needed to explain the residual part of the spatial variability of juvenile fish assemblages and to help focus conservation efforts. PMID- 29116217 TI - Diversity of Middle East respiratory syndrome coronaviruses in 109 dromedary camels based on full-genome sequencing, Abu Dhabi, United Arab Emirates. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) was identified on the Arabian Peninsula in 2012 and is still causing cases and outbreaks in the Middle East. When MERS-CoV was first identified, the closest related virus was in bats; however, it has since been recognized that dromedary camels serve as a virus reservoir and potential source for human infections. A total of 376 camels were screened for MERS-Cov at a live animal market in the Eastern Region of the Emirate of Abu Dhabi, UAE. In all, 109 MERS-CoV-positive camels were detected in week 1, and a subset of positive camels were sampled again weeks 3 through 6. A total of 126 full and 3 nearly full genomes were obtained from 139 samples. Spike gene sequences were obtained from 5 of the 10 remaining samples. The camel MERS CoV genomes from this study represent 3 known and 2 potentially new lineages within clade B. Within lineages, diversity of camel and human MERS-CoV sequences are intermixed. We identified sequences from market camels nearly identical to the previously reported 2015 German case who visited the market during his incubation period. We described 10 recombination events in the camel samples. The most frequent recombination breakpoint was the junctions between ORF1b and S. Evidence suggests MERS-CoV infection in humans results from continued introductions of distinct MERS-CoV lineages from camels. This hypothesis is supported by the camel MERS-CoV genomes sequenced in this study. Our study expands the known repertoire of camel MERS-CoVs circulating on the Arabian Peninsula. PMID- 29116218 TI - Improvement in clinical outcome and infection control using molecular diagnostic techniques for early detection of MDR tuberculous spondylitis: a multicenter retrospective study. AB - There has been limited research on the therapeutic efficacy of molecular diagnosis of spinal tuberculosis. We attempted to determine whether the utilization of molecular diagnosis to detect multidrug-resistant spinal tuberculosis can improve clinical outcomes. A multicenter retrospective study was conducted from February 2009 to June 2015. Ninety-two consecutive culture confirmed multidrug-resistant tuberculosis (MDR-TB) patients with spinal tuberculosis who were diagnosed clinically and by imaging were enrolled in the study. The initial time to treatment for MDR-TB, the method of infection control, the erythrocyte sedimentation rate (ESR) and the occurrence of complications in patients who were diagnosed using molecular methods were compared with those of patients diagnosed using standard culture and drug susceptibility test methods. Of 92 MDR-TB patients with spinal tuberculosis, 41 (45%) were diagnosed by standard culture and drug susceptibility test methods (Group A), and 51 (55%) were diagnosed following implementation of detection using molecular diagnosis (Group B). The patients in Group B began the rational use of second-line drugs earlier than patients in Group A (5 days vs 73 days, P<0.05). Among patients who were admitted to a general tuberculosis ward, those in Group B spent less time in the ward than those in Group A (4 days vs 33 days, P<0.05). At the one-month follow-up, the ESR was significantly lower in Group B. In patients who completed 6 months of follow-up (n=92), the incidence of complications was significantly lower in Group B. The use of molecular diagnosis resulted in noteworthy clinical advances, including earlier initiation of MDR-TB treatment, improved infection control, better clinical outcome, a more rapid decrease in ESR and fewer complications. PMID- 29116219 TI - A comparative study on the characterization of hepatitis B virus quasispecies by clone-based sequencing and third-generation sequencing. AB - Hepatitis B virus (HBV) has a high mutation rate due to the extremely high replication rate and the proofreading deficiency during reverse transcription. The generated variants with genetic heterogeneity are described as viral quasispecies (QS). Clone-based sequencing (CBS) is thought to be the 'gold standard' for assessing QS complexity and diversity of HBV, but an important issue about CBS is cost-effectiveness and laborious. In this study, we investigated the utility of the third-generation sequencing (TGS) DNA sequencing to characterize genetic heterogeneity of HBV QS and assessed the possible contribution of TGS technology in HBV QS studies. Parallel experiments including 3 control samples, which consisted of HBV full gene genotype B and genotype C plasmids, and 10 patients samples were performed by using CBS and TGS to analyze HBV whole-genome QS. Characterization of QS heterogeneity was conducted by using comprehensive statistical analysis. The results showed that TGS had a high consistency with CBS when measuring the complexity and diversity of QS. In addition, to detect rare variants, there were strong advantages conferred by TGS. In summary, TGS was considered to be practicable in HBV QS studies and it might have a relevant role in the clinical management of HBV infection in the future. PMID- 29116221 TI - Establishment of a fluorescent in situ hybridization assay for imaging hepatitis B virus nucleic acids in cell culture models. AB - While chronic hepatitis B remains a global public health problem, the detailed spatiotemporal dynamics of the key molecular events leading to the multiplication and egress of hepatitis B virus (HBV) are still largely unclear. Previously, we developed a chromogenic in situ hybridization assay for detection of HBV RNA, DNA and covalently closed circular DNA in clinical liver biopsies. Here, we report the establishment of a fluorescent in situ hybridization method for the visualization of HBV RNA, HBV core particle DNA and intranuclear DNA in a tetracycline-inducible HBV replication system (HepAD38) and a de novo infection system (HepG2-NTCP). Using 3D-STORM (three-dimensional stochastic optical reconstruction microscopy), we were able to obtain images of HBV RNA and DNA with improved spatial resolution allowing in-depth analyses of key virological events within complex subcellular compartments. Taken together, these techniques should facilitate a deeper understanding of the molecular events of the HBV life cycle and shed new light on the intricate mechanisms of virus-host interactions. PMID- 29116220 TI - Vector competence of European mosquitoes for West Nile virus. AB - West Nile virus (WNV) is an arthropod-borne flavivirus of high medical and veterinary importance. The main vectors for WNV are mosquito species of the Culex genus that transmit WNV among birds, and occasionally to humans and horses, which are 'dead-end' hosts. Recently, several studies have been published that aimed to identify the mosquito species that serve as vectors for WNV in Europe. These studies provide insight in factors that can influence vector competence of European mosquito species for WNV. Here, we review the current knowledge on vector competence of European mosquitoes for WNV, and the molecular knowledge on physical barriers, anti-viral pathways and microbes that influence vector competence based on studies with other flaviviruses. By comparing the 12 available WNV vector competence studies with European mosquitoes we evaluate the effect of factors such as temperature, mosquito origin and mosquito biotype on vector competence. In addition, we propose a standardised methodology to allow for comparative studies across Europe. Finally, we identify knowledge gaps regarding vector competence that, once addressed, will provide important insights into WNV transmission and ultimately contribute to effective strategies to control WNV. PMID- 29116223 TI - Optimization reconstruction of projective point of laser line coordinated by orthogonal reference. AB - A 3D reconstruction method is presented for the laser projective point of a laser line, which is located by an orthogonal reference. The laser line is initially expressed by the Plucker matrix generated from two random points on the line and then transformed to the dual Plucker matrix representation. The initial solution of the 3D laser point is obtained by the non-homogeneous linear equations, which are derived from the projection geometry of the 3D feature point on the reference and the 3D laser point on the laser line represented by the dual Plucker matrix. The optimization function is constructed by minimizing the sums of the re projection errors of the reference points and the laser point. The average absolute error of the initial solution is 1.07 mm while the one of the optimization solution is 1.01 mm. The average relative error of the initial solution is 4.14% while the one of the optimization solution is 3.86%. Thus, the optimization reconstruction of the projective point contributes the accuracy and the prospect in the vision-based inspection fields. PMID- 29116224 TI - Comparison of Transcriptomic Platforms for Analysis of Whole Blood from Ebola Infected Cynomolgus Macaques. AB - Ebola virus disease (EVD) is a serious illness with mortality rates of 20-90% in various outbreaks. EVD is characterized by robust virus replication and strong host inflammatory response. Analyzing host immune responses has increasingly involved multimodal approaches including transcriptomics to profile gene expression. We studied cynomolgus macaques exposed to Ebola virus Makona via different routes with the intent of comparing RNA-Seq to a NanoString nCounter codeset targeting 769 non-human primate (NHP) genes. RNA-Seq analysis of serial blood samples showed different routes led to the same overall transcriptional response seen in previously reported EBOV-exposed NHP studies. Both platforms displayed a strong correlation in gene expression patterns, including a strong induction of innate immune response genes at early times post-exposure, and neutrophil-associated genes at later time points. A 41-gene classifier was tested in both platforms for ability to cluster samples by infection status. Both NanoString and RNA-Seq could be used to predict relative abundances of circulating immune cell populations that matched traditional hematology. This demonstrates the complementarity of RNA-Seq and NanoString. Moreover, the development of an NHP-specific NanoString codeset should augment studies of filoviruses and other high containment infectious diseases without the infrastructure requirements of RNA-Seq technology. PMID- 29116222 TI - Specific detection of dengue and Zika virus antibodies using envelope proteins with mutations in the conserved fusion loop. AB - Detection of antibodies is widely used for the diagnosis of infections with arthropod-borne flaviviruses including dengue (DENV) and Zika virus (ZIKV). Due to the emergence of ZIKV in areas endemic for DENV, massive co-circulation is observed and methods to specifically diagnose these infections and differentiate them from each other are mandatory. However, serological assays for flaviviruses in general, and for DENV and ZIKV in particular, are compromised by the high degree of similarities in their proteins which can lead to cross-reacting antibodies and false-positive test results. Cross-reacting flavivirus antibodies mainly target the highly conserved fusion loop (FL) domain in the viral envelope (E-) protein, and we and others have shown previously that recombinant E-proteins bearing FL-mutations strongly reduce cross-reactivity. Here we investigate whether such mutant E-proteins can be used to specifically detect antibodies against DENV and ZIKV in an ELISA-format. IgM antibodies against DENV and ZIKV virus were detected with 100% and 94.2% specificity and 90.7% and 87.5% sensitivity, respectively. For IgG the mutant E-proteins showed cross-reactivity, which was overcome by pre-incubation of the sera with the heterologous antigen. This resulted in specificities of 97.1% and 97.9% and in sensitivities of 100% and 100% for the DENV and ZIKV antigens, respectively. Our results suggest that E proteins bearing mutations in the FL-domain have a high potential for the development of serological DENV and ZIKV tests with high specificity. PMID- 29116230 TI - The fruits of imagination. PMID- 29116231 TI - Painting with betalains. PMID- 29116232 TI - Tinker, tailor, soldier, enzyme. PMID- 29116237 TI - Advantages of a technique using two 50 degree arcs in simultaneous integrated boost radiotherapy for left-sidebreast cancer. AB - This study evaluated radiotherapy techniques with 15 cases for simultaneous integrated boost to treat whole left breast and tumor bed following breast conserving surgery. Treatment plans were generated using three techniques: volumetric modulated arc therapy (VMAT) with a partial arc of 190 degrees (1ARC), VMAT with two tangential mini-arcs of 50 degrees each (2TARC) and intensity modulated radiation therapy with four fixed angle fields (4IMRT). Dosimetric parameters for the whole breast (Target), the boost tumor bed (Boost), and surrounding normal organs were compared. Chair Index (CHI) was introduced to evaluate the dose homogeneity in Target given the two levels of prescription dose. The dose coverage in Target was better in 1ARC and 2TARC than that in 4IMRT. The mean CHI in 1ARC (2.47) and 2TARC (2.62) were higher than that in 4IMRT (1.71, p < 0.05), and this indicated the dose homogeneity of Target was better in 1ARC and 2TARC than that in 4IMRT. The mean doses to right lung, and contralateral breast in 4IMRT were lower than those in 2TARC but the differences between them were small. 2TARC was better than 4IMRT with respect to the dose to ipsilateral lung and heart. Overall, 2TARC was optimal among three techniques. PMID- 29116234 TI - Transcriptome dynamics revealed by a gene expression atlas of the early Arabidopsis embryo. AB - During early plant embryogenesis, precursors for all major tissues and stem cells are formed. While several components of the regulatory framework are known, how cell fates are instructed by genome-wide transcriptional activity remains unanswered-in part because of difficulties in capturing transcriptome changes at cellular resolution. Here, we have adapted a two-component transgenic labelling system to purify cell-type-specific nuclear RNA and generate a transcriptome atlas of early Arabidopsis embryo development, with a focus on root stem cell niche formation. We validated the dataset through gene expression analysis, and show that gene activity shifts in a spatio-temporal manner, probably signifying transcriptional reprogramming, to induce developmental processes reflecting cell states and state transitions. This atlas provides the most comprehensive tissue- and cell-specific description of genome-wide gene activity in the early plant embryo, and serves as a valuable resource for understanding the genetic control of early plant development. PMID- 29116238 TI - Atomically dispersed hybrid nickel-iridium sites for photoelectrocatalysis. AB - Atomically dispersed supported catalysts can maximize atom efficiency and minimize cost. In spite of much progress in gas-phase catalysis, applying such catalysts in the field of renewable energy coupled with electrochemistry remains a challenge due to their limited durability in electrolyte. Here, we report a robust and atomically dispersed hybrid catalyst formed in situ on a hematite semiconductor support during photoelectrochemical oxygen evolution by electrostatic adsorption of soluble monomeric [Ir(OH)6]2- coupled to positively charged NiOx sites. The alkali-stable [Ir(OH)6]2- features synergistically enhanced activity toward water oxidation through NiOx that acts as a "movable bridge" of charge transfer from the hematite surface to the single iridium center. This hybrid catalyst sustains high performance and stability in alkaline electrolyte for >80 h of operation. Our findings provide a promising path for soluble catalysts that are weakly and reversibly bound to semiconductor-supported hole-accumulation inorganic materials under catalytic reaction conditions as hybrid active sites for photoelectrocatalysis. PMID- 29116239 TI - Validation of the Feverkidstool and procalcitonin for detecting serious bacterial infections in febrile children. AB - BackgroundTo validate the Feverkidstool, a prediction model consisting of clinical signs and symptoms and C-reactive protein (CRP) to identify serious bacterial infections (SBIs) in febrile children, and to determine the incremental diagnostic value of procalcitonin.MethodsThis prospective observational study that was carried out at two Dutch emergency departments included children with fever, aged 1 month to 16 years. The prediction models were developed with polytomous logistic regression differentiating "pneumonia" and "other SBIs" from "non-SBIs" using standardized, routinely collected data on clinical signs and symptoms, CRP, and procalcitonin.ResultsA total of 1,085 children were included with a median age of 1.6 years (interquartile range 0.8-3.4); 73 children (7%) had pneumonia and 98 children (9%) had other SBIs. The Feverkidstool showed good discriminative ability in this new population. After adding procalcitonin to the Feverkidstool, c-statistic for "pneumonia" increased from 0.85 (95% confidence interval (CI) 0.76-0.94) to 0.86 (0.77-0.94) and for "other SBI" from 0.81 (0.73 0.90) to 0.83 (0.75- 0.91). A model with clinical features and procalcitonin performed similar to the Feverkidstool.ConclusionThis study confirms the external validity of the Feverkidstool, with CRP and procalcitonin being equally valuable for predicting SBI in our population of febrile children. Our findings do not support routine dual use of CRP and procalcitonin. PMID- 29116240 TI - A study on the correlation between the dewetting temperature of Ag film and SERS intensity. AB - The thermally dewetted metal nano-islands have been actively investigated as cost effective SERS-active substrates with a large area, good reproducibility and repeatability via simple fabrication process. However, the correlation between the dewetting temperature of metal film and SERS intensity hasn't been systematically studied. In this work, taking Ag nano-islands (AgNIs) as an example, we reported a strategy to investigate the correlation between the dewetting temperature of metal film and SERS intensity. We described the morphology evolution of AgNIs on the SiO2 planar substrate in different temperatures and got the quantitative information in surface-limited diffusion process (SLDP) as a function of annealing temperature via classical mean-field nucleation theory. Those functions were further used in the simulation of electromagnetic field to obtain the correlation between the dewetting temperature of Ag film and theoretical analysis. In addition, Raman mapping was done on samples annealed at different temperatures, with R6G as an analyte, to accomplish the analysis of the correlation between the dewetting temperature of Ag film and SERS intensity, which is consistent with the theoretical analysis. For SLDP, we used the morphological characterization of five samples prepared by different annealing temperatures to successfully illustrate the change in SERS intensity with the temperature fluctuation, obtaining a small deviation between the experimental results and theoretic prediction. PMID- 29116241 TI - Ratiometric electrochemical aptasensor based on ferrocene and carbon nanofibers for highly specific detection of tetracycline residues. AB - A sensitive and efficient ratiometric electrochemical aptasensor was designed for tetracycline (TET) detection in milk. The ratiometric electrochemical aptasensor was constructed by integrating two aptasensors termed as aptasensor 1 and aptasensor 2. The aptasensor 1 was fabricated that based on ferrocene (Fc) and gold nanoparticles (AuNPs) nanocomposite. Meanwhile, the aptasensor 2 was prepared that based on carbon nanofibers (CNFs) and AuNPs nanocomposite. TET aptamer was immobilized effectively onto screen-printed carbon electrodes (SPCEs) surface through forming Au-S bond between AuNPs and thiol of aptamer at 5' end to construct the aptasensor 1 and aptasensor 2. And their detection results were calculated by ratio. Thus, the proposed ratiometric aptasensor solved the problem of low accuracy and large differences between batches. Under the optimized conditions, the TET was detected by differential pulse voltammetry (DPV). Taken advantage of ratio calculation, the as-prepared ratiometric aptasensor could detect TET quantitatively in the range of 10-8-10-3gL-1, with a detection limit of 3.3 * 10-7gL-1. Moreover, its applicability to TET-contaminated real samples (milk) showed an excellent agreement with the values determined by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS). With high sensitivity, accuracy and reliability, the developed ratiometric aptasensor held a great potential in TET detection for food safety. PMID- 29116242 TI - Task engagement and mental workload involved in variation and repetition of a motor skill. AB - Explanatory hypotheses proposed in behavioral studies assumed that less repetitive practice schedules, such as random practice, seem to demand greater cognitive effort than more repetitive types of practice organization, such as constant. All of these hypotheses emphasize the enhanced demand to memory processes promoted by less repetitive practice schedules. In the present study, we investigated the cognitive effort involved in random and constant practice schedules with an electrophysiological approach. Twenty-one male participants practiced a sequential key-pressing task with two goals: learning the relative timing dimension and learning the absolute timing dimension. Sixty trials were performed in a constant practice schedule (only one absolute timing goal), and sixty trials were performed in random order (three absolute timing goals). Two electroencephalography based measures of cognitive states were used: (a) task engagement (sensory processing and attention resources) and (b) mental workload (working memory load). The results showed that random practice induced greater cognitive effort than constant practice when task engagement was analyzed. Throughout practice, both task engagement and mental workload decreased more in the constant practice condition than in the random practice condition. The increased demand for sensory processing observed in random practice opens a new exciting field of study in practice organization. PMID- 29116243 TI - Evaluation of a range of mammalian and mosquito cell lines for use in Chikungunya virus research. AB - Chikungunya virus (CHIKV) is becoming an increasing global health issue which has spread across the globe and as far north as southern Europe. There is currently no vaccine or anti-viral treatment available. Although there has been a recent increase in CHIKV research, many of these in vitro studies have used a wide range of cell lines which are not physiologically relevant to CHIKV infection in vivo. In this study, we aimed to evaluate a panel of cell lines to identify a subset that would be both representative of the infectious cycle of CHIKV in vivo, and amenable to in vitro applications such as transfection, luciferase assays, immunofluorescence, western blotting and virus infection. Based on these parameters we selected four mammalian and two mosquito cell lines, and further characterised these as potential tools in CHIKV research. PMID- 29116244 TI - Delivery of neostigmine and glycopyrrolate by iontophoresis: a nonrandomized study in individuals with spinal cord injury. AB - STUDY DESIGN: Phase I Clinical Trial. OBJECTIVES: In this proof-of-principle study, the effectiveness and safety of transdermal administration of neostigmine/glycopyrrolate to elicit a bowel movement was compared to intravenous administration in patients with spinal cord injury. SETTING: James J. Peters Veterans Affairs Medical Center (Bronx, NY). METHODS: Individuals were screened for responsiveness (Physical Response) to intravenous neostigmine (0.03 mg/kg)/glycopyrrolate (0.006 mg/kg). Intravenous neostigmine/glycopyrrolate responders (Therapeutic Response) were administered low-dose transdermal neostigmine/glycopyrrolate [(0.05 mg/kg)/(0.01 mg/kg)] by iontophoresis. Non responders to low-dose transdermal neostigmine/glycopyrrolate were administered high-dose transdermal neostigmine/glycopyrrolate [(0.07 mg/kg)/(0.014 mg/kg)] by iontophoresis. Bowel movement, bowel evacuation time, and cholinergic side effects were recorded. Visits were separated by 2 to 14 days. RESULTS: Eighteen of 25 individuals (72.0%) had a bowel movement (20 +/- 22 min) after intravenous neostigmine/glycopyrrolate. Of these 18 individuals, 5 individuals experienced a bowel movement with low-dose transdermal neostigmine/glycopyrrolate. Another five individuals had a bowel movement after high-dose transdermal neostigmine/glycopyrrolate administration. Fewer side effects were observed in individuals who received neostigmine/glycopyrrolate transdermally compared to those who were administered intravenous neostigmine/glycopyrrolate. CONCLUSIONS: Transdermal administration of neostigmine/glycopyrrolate by iontophoresis appears to be a practical, safe, and effective approach to induce bowel evacuation in individuals with spinal cord injury. PMID- 29116245 TI - Ability of sit-to-stand with hands reflects neurological and functional impairments in ambulatory individuals with spinal cord injury. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVES: To explore the need of upper limb contribution during sit-to-stand (STS) in ambulatory participants with spinal cord injury (SCI) and compare the lower limb loading during the sit-to stand (LLL-STS) in those with SCI who performed the task with or without hands as compared to able-bodied individuals. In addition, the study assessed the correlation between the LLL-STS, and sensorimotor scores and functional ability in ambulatory participants with SCI. SETTING: A tertiary rehabilitation center and community hospitals, Thailand. METHODS: Forty-three participants with SCI who could perform STS with or without hands, and 10 able-bodied individuals were interviewed and assessed for their demographics, STS, and LLL-STS ability. Moreover, participants with SCI were assessed for SCI characteristics, sensorimotor scores, and functional ability relating to independent walking. RESULTS: More than half of participants with SCI (58%) performed STS using hands. Their LLL-STS, sensorimotor, and functional ability were significantly lower than those with SCI who performed the task without hands. The LLL-STS of participants with SCI, particularly amount, was significantly associated with their sensorimotor scores and functional ability (P < 0.05). CONCLUSIONS: The findings indicated that those with marked lower limb muscle weakness and sensory impairments used their hands during STS. As such, the use of the hands during STS can be used as an indicator of neurological and functional impairments in ambulatory individuals with SCI. PMID- 29116246 TI - Monitoring the long term vegetation phenology change in Northeast China from 1982 to 2015. AB - Global warming has contributed to the extension of the growing season in North Hemisphere. In this paper, we investigated the spatial characteristics of the date of the start of the season (SOS), the date of the end of the season (EOS) and the length of the season (LOS) and their change trends from 1982 to 2015 in Northeast China. Our results showed that there was a significant advance of SOS and a significant delay of EOS, especially in the north part of Northeast China. For the average change slope of EOS in the study area, the delay trend was 0.25 d/y, which was more obvious than the advance trend of -0.13 d/y from the SOS. In particular, the LOS of deciduous needleleaf forest (DNF) and grassland increased with a trend of 0.63 d/y and 0.66 d/y from 1982 to 2015, indicating the growth season increased 21.42 and 22.44 days in a 34-year period, respectively. However, few negative signals were detected nearby Hulun Lake, suggesting that the continuous climate warming in the future may bring no longer growing periods for the grass in the semiarid areas as the drought caused by climate warming may limit the vegetation growth. PMID- 29116247 TI - Grassland Carbon Budget and Its Driving Factors of the Subtropical and Tropical Monsoon Region in China During 1961 to 2013. AB - The southern grasslands are an integral part of the grassland ecosystems of China and play an essential role in the terrestrial carbon cycle of the country. We reproduced the spatiotemporal dynamics of the carbon budget of southern grasslands from 1961 to 2013 using the Terrestrial Ecosystem Model and our results showed that the annual carbon budget varied from -8.12 to 6.16 Tg C y-1 with an annual average of 0.45 Tg C y-1 during the study period. Overall, southern grasslands acted as a weak carbon sink and sequestrated 23.83 Tg C from 1961 to 2013. At the seasonal scale, southern grasslands acted as a carbon sink in wet seasons but as a carbon source in dry seasons. During the study period, temperature and precipitation were the main factors driving carbon budget dynamics at the seasonal scale, while soil moisture was the main driving factor at the annual scale. Over the entire study region, 71.81% of the area switched to being a carbon sink while only 5.90% remained stable and the strong carbon sinks were mainly found in the southern, northern and western areas of the southern grasslands. PMID- 29116248 TI - Nuclear pore complex plasticity during developmental process as revealed by super resolution microscopy. AB - Nuclear Pore Complex (NPC) is of paramount importance for cellular processes since it is the unique gateway for molecular exchange through the nucleus. Unraveling the modifications of the NPC structure in response to physiological cues, also called nuclear pore plasticity, is key to the understanding of the selectivity of this molecular machinery. As a step towards this goal, we use the optical super-resolution microscopy method called direct Stochastic Optical Reconstruction Microscopy (dSTORM), to analyze oocyte development impact on the internal structure and large-scale organization of the NPC. Staining of the FG Nups proteins and the gp210 proteins allowed us to pinpoint a decrease of the global diameter by measuring the mean diameter of the central channel and the luminal ring of the NPC via autocorrelation image processing. Moreover, by using an angular and radial density function we show that development of the Xenopus laevis oocyte is correlated with a progressive decrease of the density of NPC and an ordering on a square lattice. PMID- 29116250 TI - A Silk Fibroin Bio-Transient Solution Processable Memristor. AB - Today's electronic devices are fabricated using highly toxic materials and processes which limits their applications in environmental sensing applications and mandates complex encapsulation methods in biological and medical applications. This paper proposes a fully resorbable high density bio-compatible and environmentally friendly solution processable memristive crossbar arrays using silk fibroin protein which demonstrated bipolar resistive switching ratio of 104 and possesses programmable device lifetime characteristics before the device gracefully bio-degrades, minimizing impact to environment or to the implanted host. Lactate dehydrogenase assays revealed no cytotoxicity on direct exposure to the fabricated device and support their environmentally friendly and biocompatible claims. Moreover, the correlation between the oxidation state of the cations and their tendency in forming conductive filaments with respect to different active electrode materials has been investigated. The experimental results and the numerical model based on electro-thermal effect shows a tight correspondence in predicting the memristive switching process with various combinations of electrodes which provides insight into the morphological changes of conductive filaments in the silk fibroin films. PMID- 29116249 TI - Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis. AB - Peripheral serotonin (5-hydroxytryptamine, 5-HT) regulates cell growth and differentiation in numerous cell types through engagement of seven types of cell surface receptors (HTR1-7). Deregulated 5-HT/HTR levels contribute to pathology in chronic inflammatory diseases, with macrophages being relevant targets for the physio-pathological effects of 5-HT. In fact, 5-HT skews human macrophage polarization through engagement of 5-HT2BR and 5-HT7R receptors. We now report that 5-HT primes macrophages for reduced pro-inflammatory cytokine production and IFN type I-mediated signaling, and promotes an anti-inflammatory and pro-fibrotic gene signature in human macrophages. The acquisition of the 5-HT-dependent gene profile primarily depends on the 5-HT7R receptor and 5-HT7R-initiated PKA dependent signaling. In line with the transcriptional results, 5-HT upregulates TGFbeta1 production by human macrophages in an HTR7- and PKA-dependent manner, whereas the absence of Htr7 in vivo results in diminished macrophage infiltration and collagen deposition in a mouse model of skin fibrosis. Our results indicate that the anti-inflammatory and pro-fibrotic activity of 5-HT is primarily mediated through the 5-HT7R-PKA axis, and that 5-HT7R contributes to pathology in fibrotic diseases. PMID- 29116251 TI - Broadband suppression of backscattering at optical frequencies using low permittivity dielectric spheres. AB - The exact suppression of backscattering from rotationally symmetric objects requires dual symmetric materials where epsilon r = MU r. This prevents their design at many frequency bands, including the optical one, because magnetic materials are not available. Electromagnetically small non-magnetic spheres of large permittivity offer an alternative. They can be tailored to exhibit balanced electric and magnetic dipole polarizabilities a 1 = b 1, which result in approximate zero backscattering. In this case, the effect is inherently narrowband. Here, we put forward a different alternative that allows broadband functionality: Wavelength-sized spheres made from low permittivity materials. The effect occurs in a parameter regime where approximate duality is met for all multipolar order a n ~ b n , in a weakly wavelength dependence fashion. In addition, and despite of the low permittivity, the overall scattering response of these spheres is still significant. Scattering patterns are shown to be highly directive across an octave spanning band. The effect is analytically and numerically shown using the Mie coefficients. PMID- 29116253 TI - Testicular cancer: No activity of pembrolizumab in phase II trial. PMID- 29116254 TI - Kidney cancer: PHGDH is key for targeting HIF in RCC. PMID- 29116255 TI - Prostate cancer: No benefit of combining custirsen with cabazitaxel. PMID- 29116252 TI - Leptin regulates Granzyme-A, PD-1 and CTLA-4 expression in T cell to control visceral leishmaniasis in BALB/c Mice. AB - Visceral leishmaniasis (VL) is responsible for several deaths in malnourished children accompanied by diminished circulating leptin and impaired cell-mediated immunity. Typically, leptin deficiency is associated with the Th2 polarization that markedly coincides with the pathogenesis of VL. The aim of the present study was to unravel the prophylactic role of leptin in malnutrition-coupled VL mice. Interestingly, we observed that L. donovani infection itself reduces the serum leptin levels in malnutrition. Exogenous leptin restored severe body weight loss and parasite load in the spleen and liver of malnourished infected mice compared to controls. Leptin increases functional CD8+ T-cell population, Granzyme-A expression down-regulates anergic T-cell markers such as PD-1 and CTLA-4. It was also noticed that, leptin suppresses GM-CSF mRNA expression in parasite favored monocytes and reduced arginase activity in bone marrow derived macrophage indicate macrophages dependent T-cell activation and proliferation. Leptin induced IFN-gamma, IL-2, and TNF-alpha cytokines in the culture supernatant of splenocytes upon soluble leishmanial antigen (SLA) stimulation and significantly up-regulates serum IgG2a titers, which help to generate Th1 immune response in VL. Furthermore, leptin induced a granulomatous response and restored L. donovani induced tissue degeneration in the liver. Altogether, our findings suggest the exogenous leptin can restore T cell mediated immunity in malnourished VL mice. PMID- 29116256 TI - Imaging: MRI improves cost and accuracy of prostate cancer biopsy. PMID- 29116257 TI - Kidney cancer: AXL expression predicts prognosis. PMID- 29116258 TI - Prostate cancer: Treatment after ADT plus docetaxel. PMID- 29116259 TI - Prostate cancer: Brachytherapy monotherapy is efficacious. PMID- 29116260 TI - The Potential of Alkyl Amides as Novel Biomarkers and Their Application to Paleocultural Deposits in China. AB - A series of alkyl amides was detected and identified in the sedimentary record from an archaeological site at Yuchisi, Mengcheng, Anhui, China. The alkyl amides profiles change abruptly at the depth corresponding to the transition between two prehistoric cultures, which also corresponds to an abrupt change in the fatty acid ratio C18:2/C18:0. The different patterns of variation of the longer and shorter chain alkyl amides at the depth of the cultural transition may reflect differences in their response to external environmental changes, as well as different sources. This is the first study of the stratigraphic variation of alkyl amides in sediments, and their first application to assess paleoenvironmental changes. We suggest that alkyl amides may have potential as new biomarkers in archeological and paleoenvironmental studies. PMID- 29116261 TI - A new tetraphenylethylene based AIE sensor with light-up and tunable measuring range for adenosine triphosphate in aqueous solution and in living cells. AB - An AIE based tetraphenylethylene derivative (TPPTPE) was synthesized for light-up sensing of ATP in aqueous solution. The measuring range for ATP can be tuned by varying the concentration of the TPPTPE. A one-step straightforward quantitative analysis of the ATP level in cell lysates can be realized using the TPPTPE. Moreover, the TPPTPE can be used for monitoring apyrase activity in aqueous solution and detecting ATP both in living cancer cell lines and in living normal cell lines. PMID- 29116262 TI - 3D assembly of preformed colloidal nanoparticles into gels and aerogels: function led design. AB - Gels and aerogels derived from colloidal nanoparticles not only own the advantages of the traditional aerogels like ultra-low density, large surface area and high porosity, but also retain some of the unique properties of the nanoparticles. These characteristics endow such new types of materials with the possibility of promising applications. In this review, we focus on the function led design of aerogels from the 3D assembly of 0D spherical particles, 1D nanowires, and 2D nanosheets, and especially their applications in catalysis, sensing, optoelectronics, pollutant adsorbents/filtration, and beyond. PMID- 29116263 TI - Magnetic sulfur-doped porous carbon for preconcentration of trace mercury in environmental water prior to ICP-MS detection. AB - A novel magnetic sulfur-doped porous carbon (MSPC) was fabricated via a simple one-step carbonization of a mixture of sucrose, basic magnesium sulfate whiskers and Fe3O4@SiO2 nanoparticles. Due to the high S content, the prepared MSPC possessed high adsorption capacity for Hg2+ (343 mg g-1) with good selectivity. Based on this, a method coupling magnetic solid phase extraction (MSPE) with inductively coupled plasma mass spectrometry (ICP-MS) was developed for the determination of trace Hg2+ in environmental water samples. Various parameters such as pH, desorption solvent and its concentration, desorption volume and time, sample volume, and adsorption time that affect the determination have been optimized. Under the optimal conditions, a high enrichment factor of 100-fold was obtained, the limit of detection (LOD) was found to be 0.52 pg mL-1 with a relative standard deviation (c = 10 pg mL-1, n = 7) of 7.1%, and a good linearity was obtained within the concentration range of 2-5000 pg mL-1 for Hg2+. Besides, the proposed method has very fast adsorption/desorption kinetics, target Hg2+ could be rapidly adsorbed on the prepared MSPC in 2 min and desorbed from the MSPC in 2 min with the assistance of a permanent magnet. Therefore, the proposed method of MSPE-ICP-MS exhibits good application potential in the determination of trace Hg2+ in environmental water samples. PMID- 29116264 TI - Dynamic sandwich-type electrochemical assay for protein quantification and protein-protein interaction. AB - The study of protein-protein interactions (PPIs) plays an important role in the understanding of biological systems; however, the established methods for PPI analysis often involve cumbersome sample preparation, multiple detecting steps, and costly instruments. Here we report a versatile and sensitive electrochemical method based on PPI-induced distinctive migration behavior of DNA deoxyribozyme (DNAzyme) on an electrode surface. In this method, the cleavage activity of DNAzyme toward the substrate DNA modified on the electrode surface is inversely correlated with the hydrodynamic diameter of the macromolecule attached to it. By making full use of this principle in an inexpensive electrochemical format that is named the dynamic sandwich-type electrochemical assay (dSTEA), we can probe into the presence of large macromolecules in a single-step procedure. Moreover, we can not only detect sub-picomolar protein interaction events but also analyze the assembly of kinase in the whole cell extract. This novel signaling mechanism proposed in this work may broaden the applicability of DNAzyme-based electrochemical assays and it may also have great potential for applications in other interfacial sensor developments. PMID- 29116265 TI - The internal structure of PMETAC brush/gold nanoparticle composites: a neutron and X-ray reflectivity study. AB - This work addresses the pH-triggered distribution and relocation of charge stabilized gold nanoparticles (AuNPs) incorporated into strong polyelectrolyte brushes. Brush/particle composite materials were investigated under aqueous conditions and at different humidities using neutron and X-ray reflectivity, respectively. X-ray reflectivity measurements complement neutron reflectivity measurements and reveal results that could not be observed by neutron reflectivity measurements. Both methods allow scanning the particle density profile, but due to different contrasts, they are sensitive to different regions within the brush. More specifically, 3-mercaptopropionic acid (MPA)-coated AuNPs were incorporated into poly-[2-(methacryloyloxy)ethyl]trimethylammonium chloride (PMETAC) polyelectrolyte brushes at different pH values. The pH value triggers a change in the AuNP surface charge caused by the pH-sensitivity of the MPA ligands, while the charge of the PMETAC brush is not affected by pH variations. The particle number density as well as the particle distribution depend strongly on the pH value of the incubation medium: a rather non-homogeneous assembly (2D assembly) is found when the PMETAC brush is incubated in AuNP suspension at pH 4, while a more homogeneous assembly (3D assembly) is found when the PMETAC brush is incubated in AuNP suspension at pH 8. The main factor dominating the formation of 2D or 3D assembly is assigned to the particle-particle interaction and not to the particle-polymer interaction. No significant relocation of AuNPs within the brush can be found by changing the environmental conditions. The control of particle amount and distribution within the polymer brush has a strong impact on the optical properties of those composite materials, which is crucial for the fabrication of colorimetric sensors. PMID- 29116266 TI - Towards broad spectrum activity-based glycosidase probes: synthesis and evaluation of deoxygenated cyclophellitol aziridines. AB - Activity-based protein profiling has emerged as a powerful tool for visualizing glycosidases in complex biological samples. Several configurational cyclophellitol isomers have been shown to display high selectivity as probes for glycosidases processing substrates featuring the same configuration. Here, a set of deoxygenated cyclophellitols are presented which enable inter-class profiling of beta-glucosidases and beta-galactosidases. PMID- 29116267 TI - Permeation pathways through lateral domains in model membranes of skin lipids. AB - An understanding of how molecules permeate the complex lipid matrix of the stratum corneum (SC) skin barrier is important for transdermal drug delivery, preventing the adsorption of toxic chemicals and tackling skin diseases. In this paper we present atomistic molecular dynamics simulations of skin-lipid bilayers composed of ceramides, cholesterol (CHOL) and free fatty acids at different lipid compositions and levels of hydration and investigate both perpendicular and lateral permeation pathways through the systems. We show that in fully hydrated bilayers the lipids are heterogeneously distributed, with CHOL-rich domains emerging spontaneously during the simulations. Potential of mean constraint force calculations reveal that the most favourable permeation pathway for water in the direction normal to the bilayer is through a CHOL-rich region, probably due to the disordering effect of CHOL on lipids in the gel-phase. In systems with a low water content (akin to real skin) we find that rather than forming continuous layers, water forms flattened ellipsoid-shaped pools between the lipid headgroups, which are separated by dry regions. This implies that there is no continuous aqueous lateral pathway in the SC and may help to explain why skin is such an effective barrier. We propose that the most probable permeation pathway for a small polar molecule consists of hopping from the headgroup region of one bilayer to the next via a dry region, followed by permeation along the bilayer normal through a CHOL-rich region to the centre of the bilayer where it can diffuse laterally in the lower-density lipidic environment before encountering another CHOL-rich region through which it can exit the bilayer. PMID- 29116268 TI - Synthesis of new hybrid 1,4-thiazinyl-1,2,3-dithiazolyl radicals via Smiles rearrangement. AB - The condensation reaction of 2-aminobenzenethiols and 3-aminopyrazinethiols with 2-amino-6-fluoro-N-methylpyridinium triflate afforded thioether derivatives that were found to undergo Smiles rearrangement and cyclocondensation with sulphur monochloride to yield new hybrid 1,4-thiazine-1,2,3-dithiazolylium cations. The synthesized cations were readily reduced to the corresponding stable neutral radicals with spin densities delocalized over both 1,4-thiazinyl and 1,2,3 dithiazolyl moieties. PMID- 29116269 TI - Theoretical investigation of the infrared spectrum of small polyynes. AB - The full cubic and semidiagonal quartic force fields of acetylene (C2H2), diacetylene (C4H2), triacetylene (C6H2), and tetraacetylene (C8H2) are determined using CCSD(T) (coupled cluster theory with single and double excitations and augmented by a perturbative treatment of triple excitations) in combination with the atomic natural orbital (ANO) basis sets. Application of second-order vibrational perturbation theory (VPT2) results in vibrational frequencies that agree well with the known fundamental and combination band experimental frequencies of acetylene, diacetylene, and triacetylene (average discrepancies are less than 10 cm-1). Furthermore, the predicted ground state rotational constants (B0) and vibration-rotation interaction constants (alphai) are shown to be consistent with known experimental values. New vibrational frequencies and rotational parameters from the presented theoretical predictions are given for triacetylene and tetraacetylene, which can be used to aid laboratory and astronomical spectroscopic searches for characteristic transitions of these molecules. PMID- 29116271 TI - Stereolithographic hydrogel printing of 3D culture chips with biofunctionalized complex 3D perfusion networks. AB - Three-dimensional (3D) in vitro models capturing both the structural and dynamic complexity of the in vivo situation are in great demand as an alternative to animal models. Despite tremendous progress in engineering complex tissue/organ models in the past decade, approaches that support the required freedom in design, detail and chemistry for fabricating truly 3D constructs have remained limited. Here, we report a stereolithographic high-resolution 3D printing technique utilizing poly(ethylene glycol) diacrylate (PEGDA, MW 700) to manufacture diffusion-open and mechanically stable hydrogel constructs as self contained chips, where confined culture volumes are traversed and surrounded by perfusable vascular-like networks. An optimized resin formulation enables printing of hydrogel chips holding perfusable microchannels with a cross-section as small as 100 MUm * 100 MUm, and the printed microchannels can be steadily perfused for at least one week. In addition, the integration of multiple independently perfusable and structurally stable channel systems further allows for easy combination of different bulk material volumes at exact relative spatial positions. We demonstrate this structural and material flexibility by embedding a highly compliant cell-laden gelatin hydrogel within the confines of a 3D printed resilient PEGDA hydrogel chip of intermediate compliance. Overall, our proposed strategy represents an automated, cost-effective and high resolution technique to manufacture complex 3D constructs containing microfluidic perfusion networks for advanced in vitro models. PMID- 29116274 TI - Multicolour nitrogen-doped carbon dots: tunable photoluminescence and sandwich fluorescent glass-based light-emitting diodes. AB - The first use of the combination of ammonium citrate (AC) and ethylenediamine tetraacetic acid (EDTA) as coordinating precursors for the synthesis of highly fluorescent (quantum yield = 67%) multicolour nitrogen-doped carbon dots (CDs) is reported. Under UV light, these CDs emitted outstanding luminescence in colours from dark blue to red. Interestingly, a single component white-light CD point with high fluorescence efficiency was obtained by surface control. Alterations of the photoluminescence (PL) emission of these full-colour CDs were tentatively proposed to benefit from surface functional groups, such as C[double bond, length as m-dash]O and C[double bond, length as m-dash]N. An energy-level model was proposed to explain the continuously adjustable full-colour emission. The white light may be attributed to the overlap of diverse light emission induced by electron transitions between the energy levels. Subsequently, to avoid aggregation-induced solid-state fluorescence quenching, multicolour CD-based sandwich glasses with various colour emission was fabricated, which is anticipated to be compatible with the all-optical light-emitting diodes (LEDs). The facile preparation and outstanding optical features are believed to provide an alternative synthesis route and inspire more research into applications and CD based materials of multicolour CDs. PMID- 29116275 TI - Synthesis and reactivity of thiolate-bridged multi-iron complexes supported by cyclic (alkyl)(amino)carbene. AB - The combined utilization of Me2-cAAC (Me2-cAAC = :C(CH2)(CMe2)2N-2,6-iPr2C6H3) and thiolates as supporting ligands enables the access of unprecedented carbene coordinated thiolate-bridged diiron(ii) complexes [(Me2-cAAC)Fe(MU-SR)(Br)]2 (R = Me, 3; R = Et, 4). The coordination environment of each tetrahedral iron(ii) center in complexes 3 and 4 is composed of one terminal bromide atom, one carbene carbon atom and two thiolate sulfur atoms, which is similar to the carbide containing sulfur-rich environment of iron centers in the belt region of the FeMo cofactor. Interestingly, when NaSCPh3 was chosen as the thiolate ligand, C-S bond homolysis occurred to form a rare [3 : 1] site-differentiated cubane-type cluster [(Me2-cAAC)Fe4S4(Br)3][Me2-cAACH] (5). Furthermore, complexes 3 and 4 exhibit good exchange reactivity toward the azide anion to give novel thiolate-bridged diiron complexes with two azido ligands in a trans arrangement. PMID- 29116276 TI - Electrocatalytic methanol oxidation with nanoporous gold: microstructure and selectivity. AB - The properties of Nanoporous Gold (NPG) obtained by the selective dissolution of Ag from an Au-Ag alloy can be tuned by the details of its fabrication, and specifically the residual Ag content is correlated to the ligament size of the material. We link this correlation to methanol electro-oxidation. Specifically, two different NPG types (obtained by potentiostatic dealloying) are compared with one obtained by free corrosion. They show remarkable differences in activity. Quantitative product analysis reveals that NPG shows nearly selective oxidation of CH3OH to HCOO- when NPG is used as an active electrode in contrast to planar Au. This trend can further be enhanced when applying finer nanoporous structures that are linked to a higher Ag content. X-ray photoelectron spectroscopy (XPS) reveals changes in the nature of residual Ag from which we conclude that Ag is not a passive component in the methanol oxidation process. PMID- 29116278 TI - Statistical description of co-nonsolvency suppression at high pressures. AB - We present an application of Flory-type theory of a flexible polymer chain dissolved in a binary mixture of solvents to theoretical description of co nonsolvency. We show that our theoretical predictions are in good quantitative agreement with the recently published MD simulation results for the conformational behavior of a Lennard-Jones flexible chain in a binary mixture of the Lennard-Jones fluids. We show that our theory is able to describe co nonsolvency suppression through pressure enhancement to extremely high values recently discovered in experiments and reproduced by full atomistic MD simulations. By analysing the co-solvent concentration in the internal polymer volume at different pressure values, we speculate that this phenomenon is caused by the suppression of the co-solvent preferential solvation of the polymer backbone at the rather high pressure imposed. We show that when the co-solvent induced coil-globule transition takes place, the entropy and enthalpy contributions to the solvation free energy abruptly decrease, while the solvation free energy remains continuous. PMID- 29116277 TI - Cell-permeable bicyclic peptidyl inhibitors against T-cell protein tyrosine phosphatase from a combinatorial library. AB - Protein tyrosine phosphatases (PTPs) have been challenging targets for inhibitor design, because all PTPs share a highly conserved active site structure, which is positively charged and requires negatively charged moieties for tight binding. In this study, we developed cell-permeable bicyclic peptidyl inhibitors against T cell PTP (TCPTP), which feature a cell-penetrating motif in one ring and a target binding sequence in the second ring. PMID- 29116279 TI - Persistent drought monitoring using a microfluidic-printed electro-mechanical sensor of stomata in planta. AB - Stomatal function can be used effectively to monitor plant hydraulics, photosensitivity, and gas exchange. Current approaches to measure single stomatal aperture, such as mold casting or fluorometric techniques, do not allow real time or persistent monitoring of the stomatal function over timescales relevant for long term plant physiological processes, including vegetative growth and abiotic stress. Herein, we utilize a nanoparticle-based conducting ink that preserves stomatal function to print a highly stable, electrical conductometric sensor actuated by the stomata pore itself, repeatedly and reversibly for over 1 week. This stomatal electro-mechanical pore size sensor (SEMPSS) allows for real-time tracking of the latency of single stomatal opening and closing times in planta, which we show vary from 7.0 +/- 0.5 to 25.0 +/- 0.5 min for the former and from 53.0 +/- 0.5 to 45.0 +/- 0.5 min for the latter in Spathiphyllum wallisii. These values are shown to correlate with the soil water potential and the onset of the wilting response, in quantitative agreement with a dynamic mathematical model of stomatal function. A single stoma of Spathiphyllum wallisii is shown to distinguish between incident light intensities (up to 12 mW cm-2) with temporal latency slow as 7.0 +/- 0.5 min. Over a seven day period, the latency in opening and closing times are stable throughout the plant diurnal cycle and increase gradually with the onset of drought. The monitoring of stomatal function over long term timescales at single stoma level will improve our understanding of plant physiological responses to environmental factors. PMID- 29116280 TI - The influence of the ancillary ligand on the potential of cobalt(iii) complexes to act as chaperones for hydroxamic acid-based drugs. AB - Cobalt(iii) chaperones are a promising class of bioreductive prodrugs under investigation for the delivery of cytotoxic ligands to hypoxic solid tumours. Here we investigate a series of cobalt complexes as chaperones for hydroxamic acid ligands, comparing the properties of the cyclic cyclen (1,4,7,10 tetraazacyclododecane) ancillary ligand with the tripodal tpa (tris-(2 pyridylmethyl)amine) and tren (tris-(2-aminoethyl)amine). A small library of complexes containing several different hydroxamic acids, including the MMP inhibitor Marimistat and the fluorescent ligand C343haH2, were prepared and their pKa values, reduction potentials, and in some cases X-ray crystal structures, were determined. The antiproliferative actitivity of the series was evaluated against DLD-1 colon cancer cells and the cellular accumulation of the fluorescent C343haH2 complexes was monitored by ICPMS and confocal fluorescence microscopy, revealing that the nature of the ancillary ligand significantly influences the complexes' properties, cytotoxicity and cellular distribution. PMID- 29116281 TI - Non-noble metal-catalysed carbonylative transformations. AB - Transition metal catalysts are formidable tools towards greener chemistry, allowing for low-waste, energy-efficient, and selective reactions. And transition metal-catalysed carbonylation procedures are powerful methodologies for producing carbonyl-containing compounds. The existing reviews/chapters/books are mainly focused on noble metal (Ru, Rh, Ir, Pd, Pt) catalysed carbonylation reactions. In this review, achievements on non-noble metal (Mn, Fe, Cu, Co, Ni) catalysed carbonylative transformations have been summarized and discussed. PMID- 29116283 TI - Synthesis of a library of variously modified 4-methylumbelliferyl xylosides and a structure-activity study of human beta4GalT7. AB - Proteoglycans (PGs) are complex macromolecules that are composed of glycosaminoglycan (GAG) chains covalently attached to a core protein through a tetrasaccharide linker. The biosynthesis of PGs is complex and involves a large number of glycosyltranferases. Here we present a structure-activity study of human beta4GalT7, which transfers the first Gal residue onto a xyloside moiety of the linkage region. An efficient and regiocontrolled synthesis of a library of modified analogs of 4-methylumbelliferyl xyloside (XylMU) is reported herein. Hydroxyl groups at the position C-2, C-3 or C-4 have been epimerized and/or replaced by a hydrogen or a fluorine, while the anomeric oxygen was replaced by either a sulfur or a sulfone. The effect of these compounds on human beta4GalT7 activity in vitro and on GAG biosynthesis in cellulo was then evaluated. PMID- 29116284 TI - Mechanism and reactivity in the Morita-Baylis-Hillman reaction: the challenge of accurate computations. AB - A systematic density functional theory exploration of various reactive steps together with benchmark coupled cluster results are used to propose an accurate model of the mechanism of the Morita-Baylis-Hillman (MBH) reaction in organic chemistry. This reaction has attracted considerable interest from the synthetic and mechanistic points of view in recent years, with both computational and experimental mechanistic studies. It has recently (R. E. Plata and D. A. Singleton, J. Am. Chem. Soc., 2015, 137, 3811-3826) been correctly pointed out that previous computational studies failed to reproduce known mechanistic features of the reaction. The same study argued that computation is simply not able at the present time to provide accurate models for such reactions. This second claim is shown by our present work to overstate the problem: by using current 'state of the art' methodology, our results are fully consistent with observed behavior within the expected error bars of 1-5 kcal mol-1, far smaller than the errors reported in Plata and Singleton's study. On the basis of exhaustive calculations reported here, we suggest that our proposed approaches for modeling electronic structure, solvation, and entropy should be able to provide accurate predictions for many more reactions. We also suggest that reactions like the MBH reaction, where solvation and entropy effects are particularly large, are among the hardest for computational mechanistic studies. PMID- 29116285 TI - Speech-language therapy to elderly patients in a health care network in Florianopolis: a health surveillance initiative. AB - PURPOSE: To investigate aspects of health care provided to the elderly, as a way to undertake health surveillance initiatives. METHODS: Cross-sectional quantitative study with elderly people who participate in health promotion groups in health centers at Florianopolis, Santa Catarina, Brazil. Surveys were conducted on aspects relative to comprehensive health care provision, namely, records of the Family Health Strategy, diagnosis, awareness of initiatives to treat non-communicable diseases, as well as awareness of related risks and complications. A descriptive statistical analysis was performed of the profile and perception of elderly patients about comprehensive health care. RESULTS: Were interviewed 58 elderly patients; 94.83% of them reported having Arterial Hypertension (AH); 44.83%, Diabetes Mellitus (DM) and 39.66% reported having both comorbidities. Only a small part of the participants was aware of initiatives promoted by health centers for treatment of AH and DM; thus, there is little participation of the elderly in such initiatives. It was found that these patients still have limited awareness of the risks of not treating chronic Non Communicable Diseases (NCDs). CONCLUSION: The population's lack of awareness of primary health care initiatives and low adherence must be addressed by primary health care policies. Importantly, awareness-raising proposals that seek to integrate health promotion and disease prevention may bring comprehensive health care provision to the elderly, thus strengthening health surveillance initiatives. PMID- 29116286 TI - Historicity of the ways in which knowledge production impacts practice. PMID- 29116288 TI - Epidemiological surveillance of land borders in North and South America: a case study. AB - This study aims to analyze the different binational/multinational activities, programs, and structures taking place on the borders of Brazil and the U.S. between 2013 and 2015. A descriptive exploratory study of two border epidemiological surveillance (BES) systems has been performed. Two approaches were used to collect data: i) technical visits to the facilities involved with border surveillance and application of a questionnaire survey; ii) application of an online questionnaire survey. It was identified that, for both surveillance systems, more than 55% of the technicians had realized that the BES and its activities have high priority. Eighty percent of North American and 71% of Brazilian border jurisdictions reported an exchange of information between countries. Less than half of the jurisdictions reported that the necessary tools to carry out information exchange were available. Operational attributes of completeness, feedback, reciprocity, and quality of information were identified as weak or of low quality in both systems. Statements, guidelines, and protocols to develop surveillance activities are available at the U.S.-Mexico border area. The continuous systematic development of surveillance systems at these borders will create more effective actions and responses. PMID- 29116287 TI - Peginterferon still has a place in the treatment of hepatitis C caused by genotype 3 virus. AB - Despite recent advances in therapy for chronic hepatitis C (CHC), the disease caused by genotype 3 virus (GEN3) is still considered a treatment challenge in certain patient subgroups. The aim of this retrospective study was to evaluate the effectiveness and safety of the peginterferon (Peg-IFN) and ribavirin (RBV) combination treatment for GEN3/CHC patients, and to evaluate sustained virological response (SVR) indicators and early treatment interruption due to serious adverse events (SAE). This was a retrospective observational study of GEN3/CHC patients, co-infected or not by HIV and treated with Peg-IFN/RBV in nine Brazilian healthcare centers. The study sample included 184 GEN3/CHC patients; 70 (38%) were co-infected with HIV. The overall SVR rate was 57.1% (95% CI 50-64). Among co-infected and mono-infected patients, the SVR rate was 51.4% (36/70) and 60.5% (69/114), respectively (p=0.241). Thirty-four (18.5%) patients experienced SAE and interrupted treatment. SVR was negatively associated with the use of Peg IFN alpha 2b (PR 0.75; 95% CI 0.58-0.99; p=0.045) and to early treatment interruption due to SAE (PR 0.36; 95% CI 0.20-0.68; p=0.001). Early treatment interruption due to SAE was associated with age (PR 1.06; 95% CI 1.02-1.10; p<0.001) and occurrence of liver cirrhosis (PR 2.06; 95% CI 1.11-3.83; p=0.022). In conclusion, Peg-IFN/RBV might represent an adequate treatment option, mainly in young patients without advanced liver disease or when the use of direct-action drugs is limited to specific patient groups. PMID- 29116289 TI - Difficulties in the revaccination program of hematopoietic stem cell transplantation recipients. AB - Hematopoietic stem cell transplant (HSCT) recipients should be routinely revaccinated after transplantation. We evaluated the difficulties met in the revaccination program and how a prospective and tailored follow-up could help to overcome these obstacles. HSCT recipients (n=122) were prospectively followed up and categorized into Group 1 (n=72), recipients who had already started the revaccination program, and Group 2 (n=50), recipients starting their vaccines. Whenever a difficulty was reported, interventions and subsequent evaluations were performed. Reported problems were related to patient compliance, HSCT center and/or vaccination center. Problems related to patient compliance were less frequent than those related to HSCT center modifications of previous recommendations, or to errors made by the vaccination center. The main gap found was vaccination delays (81.9%). Advisory intervention was needed in 64% and 46% of Group 1 and Group 2, respectively (p=0.05), and was partially successful in around 70% of the cases. Total resolution was achieved in more than 35% in both groups. Improvements are needed in the Brazilian vaccination program for HSCT recipients to assure a complete and updated revaccination schedule. HSCT centers should assign nurses and transplant infectious disease specialist physicians to organize the revaccination schedule and to monitor the program development. PMID- 29116290 TI - Drug resistance, AmpC-beta-lactamase and extended-spectrum beta-lactamase producing Enterobacteriaceae isolated from fish and shrimp. AB - The present study aims to detect the production of extended-spectrum beta lactamases (ESBL) by enterobacteria isolated from samples of fresh shrimp and fish obtained from the retail trade of the city of Sobral, Ceara State, Brazil. All bacterial isolates were submitted to identification and antimicrobial susceptibility testing using aminopenicillin, beta-lactamase inhibitors, carbapenem, 1st, 2nd, 3rd and 4th generation cephalosporins, and monobactam. Three types of beta-lactamases - ESBL, AmpC and KPC - were investigated. 103 strains were identified, and the most frequent species in shrimp and fish samples was Enterobacter cloacae (n = 54). All the strains were resistant to penicillin and more than 50% of the isolates were resistant to ampicillin and cephalothin. Resistance to three 3rd generation cephalosporins (cefotaxime, ceftriaxone and ceftazidime) and one fourth generation cephalosporin (cefepime) was detected in two isolates of E. cloacae from shrimp samples. Phenotypic detection of AmpC was confirmed in seven strains. The ESBL was detected in two strains of E. cloacae from shrimp samples. No strain showed KPC production. These data can be considered alarming, since food (shrimp and fish) may be carriers of enterobacteria resistant to drugs of clinical interest. PMID- 29116291 TI - Analysis of dengue cases according to clinical severity, Sao Luis, Maranhao, Brazil. AB - Severe dengue cases have increased in Brazil since 2001, with the first records in Maranhao dating back to 2002. The aim of this study was to determine the prevalence of severe dengue cases by age group and the possible risk factors. This was a study of secondary data on dengue in residents of Sao Luis, Maranhao, Brazil, using probable cases notified to the National Mandatory Reporting System (SINAN) from 2002 to 2011. The diagnosis and classification of dengue were based on the Brazilian Ministry of Health criteria: dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue fever with complications (DWC). DHF and DWC were considered severe dengue, and DF was classified as non-severe dengue. A logistic regression analysis was performed with severe dengue as the outcome. During the study period, 1,229 cases of severe dengue were reported; of these, 812 in patients under the age of 15 (66%). Among the risk factors evaluated, age under 15 years old (OR = 3.10, 95% CI = 2.69-3.57, p-value = 0.001) was associated with severe dengue. The prevalence of severe dengue in children under the age of 15 was higher, and only this age group was associated with the occurrence of severe dengue. PMID- 29116292 TI - First isolation report of Arcobacter cryaerophilus from a human diarrhea sample in Costa Rica. AB - Arcobacter cryaerophilus is an emerging enteropathogen and potential zoonotic agent transmitted by food and water. In Costa Rica, this bacterium has not been associated with cases of human gastroenteritis, even though it has been isolated from farm animals, especially poultry. This paper reports the first isolation of A. cryaerophilus from a human case of bloody watery diarrhea and the virulence genes associated with this isolate. PMID- 29116294 TI - Secondary syphilis presenting as leucoderma syphiliticum: case report and review. AB - Leucoderma syphiliticum (LS), originally described as syphilide pigmentaire, encompasses a spectrum of dyschromic lesions that emerge during the course of secondary syphilis. Very few case reports are available in modern biomedical databases. We present the case of a 57-year-old HIV-infected male patient who presented with several round to oval, non-scaling, slightly raised and well demarcated hypochromic lesions scattered over the trunk, abdomen, dorsum, and arms. Prior non-treponemal tests were negative for syphilis, but novel studies yielded positive results at high titers. Skin lesions slowly regressed and the hypochromic areas repigmented a few weeks after benzathine penicillin G treatment. This is the first report of LS in an HIV-infected patient. A review of modern and ancient literature was performed. The present case report emphasizes the need for clinicians to have a heightened awareness of the varied and unusual clinical phenotypes of syphilis. PMID- 29116293 TI - Antioxidant effect of Morus nigra on Chagas disease progression. AB - Considering the widespread popular use of Morus nigra and the amount of scientific information on its antioxidant and anti-inflammatory activity, the effectiveness of this phytotherapeutic compound in the parasitemia progression during the acute phase of Chagas disease and its role in the development of the inflammatory process as well as its effects on the oxidative damage in the chronic phase of infection were evaluated. Thus, 96 male Swiss mice were randomly divided into eight groups, four groups were uninfected controls, and four groups were intraperitoneally infected with 5.0 x 104 blood trypomastigotes forms of T. cruzi QM2 strain. Four batches composed of one uninfected and one infected group were respectively treated with 70% alcohol solution and 25 MUL, 50 MUL and 75 MUL of the phytotherapeutic compound. Levels of antioxidant elements (TBARS, FRAP, GSH and Sulfhydryl groups) were measured in plasma samples. The phytotherapeutic compound's antioxidant activity was measured by polyphenol and total flavonoid quantification, DPPH, NO, and FRAP method. Our results showed that the vehicle influenced some of the results that may have physiological relevance in Chagas disease. However, an important action of M. nigra tincture was observed in the progression of Chagas disease, since our results demonstrated a reduction in parasitemia of treated groups when compared to controls, especially in the group receiving 25 uL. However, in the chronic phase, the 50-uL dosage presented a better activity on some antioxidant defenses and minimized the tissue inflammatory process. Results indicated an important action of M. nigra tincture on the Chagas disease progression. PMID- 29116295 TI - Effect of ceramic thickness, grinding, and aging on the mechanical behavior of a polycrystalline zirconia. AB - Monolithic restorations of Y-TZP have been recommended as a restorative alternative on prosthetic dentistry as it allows a substantial reduction of ceramic thickness, which means a greater preservation of tooth structure. However, the influence of grinding and aging when using a thinner layer of the material is unclear. This investigation aimed to evaluate and compare the effects of ceramic thickness (0.5 mm and 1.0 mm), grinding and aging (low-temperature degradation) on the mechanical behavior and surface characteristics of a full contour Y-TZP ceramic. Y-TZP disc-shaped specimens (15 mm diameter) were manufactured with both thicknesses and randomly assigned into 4 groups considering the factors 'grinding with diamond bur' and 'aging in autoclave'. Surface topography (roughness, 3D profilometry and SEM), phase transformation, flexural strength and structural reliability (Weibull) analyses were executed. Grinding affected the surface topography, while aging did not promote any effect. An increase in m-phase content was observed after grinding and aging, although different susceptibilities were observed. Regardless of zirconia's thickness, no deleterious effect of grinding or aging on the mechanical properties was observed. Thus, in our testing assembly, reducing the thickness of the Y-TZP ceramic did not alter its response to grinding and low temperature degradation and did not impair its mechanical performance. PMID- 29116296 TI - Is obesity associated to dental caries in Brazilian schoolchildren? AB - This cross-sectional study aimed to determine the association between dental caries and weight status, and between dental caries and physical activity in Brazilian schoolchildren aged 8 to 12 years. A multi-stage sample of children enrolled in 20 private and public schools in 2010 in Pelotas, Southern Brazil, were invited to participate in the study. Socioeconomic data were collected from parents, and data regarding children characteristics were collected from children using a questionnaire and anthropometric measures. The Body Mass Index was obtained, and children were classified as overweight/obese considering age and sex. Dental examinations were performed to assess the presence of gingival inflammation, dental caries prevalence (DMFT>=1) and dental caries experience (mean DMFT). Multivariate Poisson Regression was used to assess factors associated with dental caries prevalence and experience. A total of 1,210 children were included in the study. Dental caries prevalence was 32.4% (95% CI 29.7-35.2), while the mean DMFT was 0.64 (+/- SD 1.00). Children who practiced less than 300 minutes per week of physical activity and overweigh/obese children had lower prevalence of dental caries, while children with obesity or overweight presented lower dental caries experience. Obesity/overweight and physical activity level presented an inverse relationship with dental caries. Longitudinal studies investigating the complexity of this relationship are required. PMID- 29116297 TI - Maternal depression and anxiety associated with dental fear in children: a cohort of adolescent mothers in Southern Brazil. AB - Exposure to maternal symptoms of depression/anxiety has long-term negative consequences for child development, regardless of the contextual risk. The objective of this study was to investigate the relationship of the symptomatology of persistent maternal depression and anxiety with child dental fear. This study was nested in a cohort of adolescent mothers in southern Brazil. Symptomatology of maternal depression and anxiety was assessed during pregnancy and postpartum, when the mothers' children were 24-36 months old, using Beck Depression Inventory and Beck Anxiety Inventory. The mothers answered a questionnaire to assess dental fear in their children, and to obtain socioeconomic and demographic data. Both mothers and their children were submitted to clinical oral examination (n= 540 dyads) to obtain oral health data. Multivariate hierarchical Poisson regression analysis was used to determine associations (p < 0.05). At data collection, the prevalence of maternal depressive symptoms was 39.1%, and anxiety was observed in 27.8% of the mothers, whereas 21.6% of the children presented dental fear. In the adjusted analysis, children's dental fear was positively associated with mothers' presenting depressive symptomatology and caries experience. The depression symptomatology trajectory was not associated with dental fear, whereas mothers with persistent symptoms of anxiety reported higher prevalence of dental fear toward their offspring. The findings of symptomatology of maternal depression observed at data collection and persistence of anxiety may negatively impact the child's perception of dental fear. Mothers are the main caregivers and primary models responsible for transmitting health-related behaviors; consequently, mental disorders affecting mothers may negatively impact their children. PMID- 29116298 TI - In situ effect of titanium tetrafluoride varnish on enamel demineralization. AB - The effect of a 4% titanium tetrafluoride (TiF 4 ) varnish on enamel demineralization was evaluated. Twelve volunteers participated in this double blind, randomized crossover study. Six enamel specimens were positioned in intraoral appliances throughout four treatment stages: 4% TiF 4 varnish (experimental varnish), 5% sodium fluoride (NaF) varnish (Duraphat (r) ), placebo varnish, and negative control (deionized water). After 24 h, the varnishes were removed and plaques were allowed to accumulate. A 20% sucrose solution was dripped onto enamel blocks (10x/day). Enamel alterations were analyzed by surface microhardness (SMH), percentage of surface loss (%SML), cross-sectional microhardness (CSMH), scanning electron microscopy (SEM), and energy dispersive X ray spectrometry (EDS). Student's paired t-test was used for SMH analysis and repeated-measures analysis of variance (ANOVA) for %SML and CSMH (?Z) analyses (p value=0.05). The TiF 4 varnish group had lower %SML than the placebo and control groups (p=0.044 and p=0.003, respectively), thus showing its capacity to inhibit surface demineralization. TiF 4 and NaF varnishes demonstrated a protective effect against mineral loss on the enamel subsurface. Both were statistically different from the control group when CSMH was analyzed (p=0.000). A titanium dioxide film was observed on enamel surfaces of the TiF 4 group SEM images. EDS confirmed the presence of titanium in all TiF 4 samples. The 4% TiF 4 varnish is a promising compound capable of reacting with enamel to protect it against surface and subsurface demineralization. PMID- 29116299 TI - One year Survival Rate of Ketac Molar versus Vitro Molar for Occlusoproximal ART Restorations: a RCT. AB - Good survival rates for single-surface Atraumatic Restorative Treatment (ART) restorations have been reported, while multi-surface ART restorations have not shown similar results. The aim of this study was to evaluate the survival rate of occluso-proximal ART restorations using two different filling materials: Ketac Molar EasyMix (3M ESPE) and Vitro Molar (DFL). A total of 117 primary molars with occluso-proximal caries lesions were selected in 4 to 8 years old children in Barueri city, Brazil. Only one tooth was selected per child. The subjetcs were randomly allocated in two groups according to the filling material. All treatments were performed following the ART premises and all restorations were evaluated after 2, 6 and 12 months. Restoration survival was evaluated using Kaplan-Meier survival analysis and Log-rank test, while Cox regression analysis was used for testing association with clinical factors (alpha = 5%). There was no difference in survival rate between the materials tested, (HR = 1.60, CI = 0.98 2.62, p = 0.058). The overall survival rate of restorations was 42.74% and the survival rate per group was Ketac Molar = 50,8% and Vitro Molar G2 = 34.5%). Cox regression test showed no association between the analyzed clinical variables and the success of the restorations. After 12 months evaluation, no difference in the survival rate of ART occluso-proximal restorations was found between tested materials. PMID- 29116300 TI - Cymbopogon citratus essential oil: effect on polymicrobial caries-related biofilm with low cytotoxicity. AB - The objective of this study was to evaluate the effects of Cymbopogon citratus essential oil and its main compound (citral) against primary dental colonizers and caries-related species. Chemical characterization of the essential oil was performed by gas chromatography/mass spectroscopy (GC/MS), and the main compound was determined. Antimicrobial activity was tested against Actinomyces naeslundii, Lactobacillus acidophilus, S. gordonii, S. mitis, S. mutans, S. sanguinis and S. sobrinus. Minimum inhibitory and bactericide concentrations were determined by broth microdilution assay for streptococci and lactobacilli reference, and for clinical strains. The effect of the essential oil on bacterial adhesion and biofilm formation/disruption was investigated. Negative (without treatment) and positive controls (chlorhexidine) were used. The effect of citral on preformed biofilm was also tested using the same methodology. Monospecies and microcosm biofilms were tested. ANOVA or Kruskal-Wallis tests were used (alpha=0.05). Cytotoxicity of the essential oil to human keratinocytes was performed by MTT assay. GC/MS demonstrated one major component (citral). The essential oil showed an inhibitory effect on all tested bacterial species, including S. mutans and L. acidophilus. Essential oil of C. citratus (10X MIC) reduced the number of viable cells of lactobacilli and streptococci biofilms (p < 0.05). The essential oil inhibited adhesion of caries-related polymicrobial biofilm to dental enamel (p < 0.01). Citral significantly reduced the number of viable cells of streptococci biofilm (p < 0.001). The essential oil showed low cytotoxicity to human keratinocytes. Based on these findings, this study can contribute to the development of new formulations for products like mouthwash, against dental biofilms. PMID- 29116302 TI - Anticholinergic toxicity in a one-year-old male following ingestion of Lupinus mutabilis seeds: case report. AB - CONTEXT: The seeds from Lupinus mutabilis Sweet, also called "chocho", are an important part of the diet in several countries in South America. Prior to consumption, processing is required to remove toxic alkaloids. These alkaloids are known to have pharmacological properties as antiarrhythmics, antimuscarinics and hypoglycemics. CASE REPORT: We report a case in which a one-year-old male initially presented with altered mental status and respiratory distress and subsequently developed symptoms of anticholinergic toxicity, after ingesting a large amount of chocho seeds. CONCLUSION: In spite of going through a difficult clinical condition, the subject evolved favorably through receiving supportive treatment. The seeds from Lupinus mutabilis provide nutritional benefits when consumed, but people need to know their risks when these seeds are consumed without proper preparation. PMID- 29116301 TI - Clinical performance of fluorescence-based methods for detection of occlusal caries lesions in primary teeth. AB - We aimed to investigate the performance of fluorescence-based methods (FBMs), compared to visual inspection after histological validation, in detecting and assessing the activity status of occlusal carious lesions in primary teeth. One examiner evaluated 50 primary molars close to exfoliation in 24 children. Teeth were assessed using quantitative light-induced fluorescence (QLF) and pen-type laser fluorescence (LFpen). After exfoliation, histological validation was performed. Teeth were cut and sections were evaluated for lesion depth and activity status (after utilization of a pH indicator) under a stereomicroscope. Parameters related to the performance of the methods in detecting caries lesions at two thresholds (initial and dentin lesions) were calculated. Regarding the activity status, lesions were classified into sound+inactive or active, and the area under the ROC curve and the diagnostic odds ratio values of the methods were calculated and compared. Evaluation of red fluorescence using QLF presented higher sensitivity but lower specificity than visual inspection in detecting dentin caries lesions. However, QLF considering different parameters and LFpen had similar performance to that obtained with visual inspection. Regarding activity assessment, all FBMs and visual inspection also presented similar performance. In conclusion, FBMs did not prove advantageous for the detection and activity assessment of occlusal caries lesions in primary molars when compared to visual inspection. PMID- 29116303 TI - Non-invasive brain stimulation and computational models in post-stroke aphasic patients: single session of transcranial magnetic stimulation and transcranial direct current stimulation. A randomized clinical trial. AB - CONTEXT AND OBJECTIVE: Patients undergoing the same neuromodulation protocol may present different responses. Computational models may help in understanding such differences. The aims of this study were, firstly, to compare the performance of aphasic patients in naming tasks before and after one session of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS) and sham, and analyze the results between these neuromodulation techniques; and secondly, through computational model on the cortex and surrounding tissues, to assess current flow distribution and responses among patients who received tDCS and presented different levels of results from naming tasks. DESIGN AND SETTING: Prospective, descriptive, qualitative and quantitative, double blind, randomized and placebo-controlled study conducted at Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo. METHODS: Patients with aphasia received one session of tDCS, TMS or sham stimulation. The time taken to name pictures and the response time were evaluated before and after neuromodulation. Selected patients from the first intervention underwent a computational model stimulation procedure that simulated tDCS. RESULTS: The results did not indicate any statistically significant differences from before to after the stimulation.The computational models showed different current flow distributions. CONCLUSIONS: The present study did not show any statistically significant difference between tDCS, TMS and sham stimulation regarding naming tasks. The patients'responses to the computational model showed different patterns of current distribution. PMID- 29116304 TI - Use of a child health surveillance instrument focusing on growth. A cross sectional study. AB - BACKGROUND: Proper use of a child health handbook is an important indicator of the quality of care provided to children at healthcare services. This study aimed to evaluate the use of child health surveillance tool (by health professionals?), especially focusing on growth. DESIGN AND SETTING: Cross-sectional study carried out in the context of the Family Health Strategy in two municipalities in Paraiba, Brazil. METHODS: Three hundred and twenty-one children under five years of age from areas covered by health workers were included in the study. Mothers answered a questionnaire asking for information on sociodemographic characteristics. Growth charts, records of iron and vitamin A supplementation and notes on immunization schedules registered in the instrument were analyzed. In the case of children for whom the third version of the child health handbook was used, the association between completion of this handbook and sociodemographic characteristics was analyzed. RESULTS: All the parameters studied showed high frequencies of inadequate data entry, ranging from 41.1% for the weight-versus- age chart to 95.3% for the body mass index-versus-age chart. Higher frequency of inadequate data entry was found among children aged 25 months and over and among those living in areas of these municipalities with minimal numbers of professionals in the healthcare teams. CONCLUSIONS: The use of a child health handbook to monitor children's growth in the municipalities studied appeared to be faulty. Data entry to this instrument was better at locations with larger healthcare teams. PMID- 29116305 TI - Evaluation of waist-to-height ratio as a predictor of insulin resistance in non diabetic obese individuals. A cross-sectional study. AB - BACKGROUND: Insulin resistance (IR) and progressive pancreatic beta-cell dysfunction have been identified as the two fundamental features in the pathogenesis of obesity and non-insulin-dependent diabetes mellitus. We aimed to investigate correlations between anthropometric indices of obesity and IR in non diabetic obese individuals, and the cutoff value from receiver operating characteristic (ROC) curve analysis. DESIGN AND SETTING: Cross-sectional study conducted in a private clinic. METHODS: We included obese individuals (body mass index, BMI >= 30 kg/m2) with no diabetes mellitus (fasting glucose levels <= 126 mg/dl). The participants were evaluated for the presence of cardiovascular risk factors and through anthropometric measurements and biochemical tests. Furthermore, IR was assessed indirectly using the homeostatic model assessment (HOMA)-IR and HOMA-beta indexes. The area underthe curve (AUC) of the variables was compared.The sensitivity, specificity and cutoff of each variable for diagnosing IR were calculated. RESULTS: The most promising anthropometric parameters for indicating IR in non-diabetic obese individuals were waist-to height ratio (WHtR), waist circumference (WC) and BMI. WHtR proved to be an independent predictor of IR, with risk increased by 0.53% in HOMA-IR, 5.3% in HOMA-beta and 1.14% in insulin. For HOMA-IR, WHtR had the highest AUC value (0.98), followed by WC (0.93) and BMI (0.81). For HOMA-beta, WHtR also had the highest AUC value (0.83), followed by WC (0.75) and BMI (0.73).The optimal WHtR cutoff was 0.65 for HOMA-IR and 0.67 for HOMA-beta. CONCLUSION: Among anthropometric obesity indicators, WHtR was most closely associated with occurrences of IR and predicted the onset of diabetes in obese individuals. PMID- 29116306 TI - Short Mood and Feelings Questionnaire for screening children and adolescents for plastic surgery: cross-cultural validation study. AB - CONTEXT AND OBJECTIVE: Patient-reported outcome measurements assessing the emotional state of children and adolescents who seek plastic surgery are important for determining whether the intervention is indicated or not. The aim of this study was to cross-culturally adapt and validate the Short Mood and Feelings Questionnaire (child/adolescent and parent versions) for Brazilian Portuguese, test its psychometric properties and assess the emotional state of children and adolescents who seek plastic surgery. DESIGN AND SETTING: Cross cultural validation study conducted in a plastic surgery outpatient clinic at a public university hospital. METHODS: A total of 124 consecutive patients of both sexes were selected between September 2013 and February 2014. Forty-seven patients participated in the cultural adaptation of the questionnaire. The final version was tested for reliability on 20 patients. Construct validity was tested on 57 patients by correlating the Short Mood and Feelings Questionnaire (child/adolescent and parent versions) with the Strengths and Difficulties Questionnaire and the Rosenberg Self-Esteem scale. RESULTS: The child/adolescent and parent versions of the Short Mood and Feelings Questionnaire showed Cronbach's alpha of 0.768 and 0.874, respectively, and had good inter-rater reliability (intraclass correlation coefficient, ICC = 0.757 and ICC = 0.853, respectively) and intra-rater reliability (ICC = 0.738 and ICC = 0.796, respectively). CONCLUSIONS: The Brazilian-Portuguese version of the Short Mood and Feelings Questionnaire is a reproducible instrument with face, content and construct validity.The mood state and feelings among children and adolescents seeking cosmetic surgery were healthy. PMID- 29116307 TI - Cryptococcoma mimicking a brain tumor in an immunocompetent patient: case report of an extremely rare presentation. AB - CONTEXT: Central nervous system (CNS) infectious diseases have high prevalence in developing countries and their proper diagnosis and treatment are very important for public health planning. Cryptococcus neoformans is a fungus that may cause several CNS manifestations, especially in immunocompromised patients. Cryptococcal meningitis is the most common type of involvement. Mass-effect lesions are uncommon: they are described as cryptococcomas and their prevalence is even lower among immunocompetent patients. The aim here was to report an extremely rare case of cryptococcoma causing a mass effect and mimicking a brain tumor in an immunocompetent patient. The literature on CNS cryptococcal infections was reviewed with emphasis on cryptococcomas. Clinical, surgical and radiological data on a female patient with this rare presentation of cryptococcoma mimicking a brain tumor are described. CASE REPORT: A 54-year-old female patient presented to the emergency department with a rapid-onset progressive history of confusion and completely dependency for basic activities. Neuroimaging showed a left occipital lesion and neurosurgical treatment was proposed. From histopathological evaluation, a diagnosis of cryptococcoma was established. She received clinical support with antifungals, but despite optimal clinical treatment, her condition evolved to death. CONCLUSIONS: Cryptococcal infections have several forms of presentation and, in immunocompetent patients, their manifestation may be even more different. Cryptococcoma is an extremely rare presentation in which proper surgical and clinical treatment should be instituted as quickly as possible, but even so, there is a high mortality rate. PMID- 29116308 TI - Cutoff values for appendicular skeletal muscle mass and strength in relation to fear of falling among Brazilian older adults: cross-sectional study. AB - CONTEXT AND OBJECTIVE: Sarcopenia is an emerging public health issue in Brazil. Because of its high prevalence and the lack of national data, the objective here was to identify cutoff points for appendicular skeletal muscle (ASM) and handgrip strength in relation to fear of falling among Brazilian older adults. DESIGN AND SETTING: Cross-sectional study; in the community. METHODS: Participants underwent morphological and functional evaluations; and were asked about previous falls and fear of falling. Different adjustments to ASM and handgrip strength were used. Slow walking speed was defined as < 0.8 m/s or 1.0 m/s. Gender and age groups were compared using t tests, analysis of variance (ANOVA), chi-square test or Fisher's exact test. Receiver operating characteristic curves were used to identify cutoffs for ASM and handgrip strength in relation to fear of falling. RESULTS: 578 older adults participated in this study. Function levels decreased with increasing age, and body composition differed between the sexes. In relation to fear of falling, the cutoffs for ASM adjusted for body mass index (BMI) were < 0.85 for men and < 0.53 for women; the cutoffs for absolute handgrip strength and relative handgrip strength (adjusted for BMI) were 30.0 kgf and 21.7 kgf, and 1.07 and 0.66, for men and women, respectively. CONCLUSION: The values presented can be used as references in clinical practice and research. We recommend use of ASM adjusted for BMI and choosing between absolute and relative handgrip strength for men and women, according to study needs. PMID- 29116309 TI - Characteristics of role models who influenced medical residents to choose surgery as a specialty: exploratory study. AB - CONTEXT AND OBJECTIVE: Choosing a medical specialty and making decisions concerning a career are difficult processes for medical students and newly graduated physicians.This exploratory study aimed to investigate the influence of role models on the choice of surgery as a career, and to determine the most influential model characteristics. DESIGN AND SETTING: Qualitative analysis on responses to a self-administered questionnaire, in different teaching-learning settings. METHODS: Residents from all years of various surgical subspecialties in a university hospital were included in a survey about the factors that determined their choice of surgery. The questions included items on whether a role model had influenced them in choosing surgery, and the personal or professional characteristics of the models that had been most influential. The responses were subjected to qualitative content analysis. RESULTS: Sixty-four out of 96 medical residents participated. Fifty-three residents (82.8%) acknowledged the influence of role models. Sixteen model characteristics were indicated as important, with 136 mentions. Characteristics classified as technical skills (55%), such as"medical knowledge"and "manual dexterity" predominated over humanistic characteristics (35%), such as "patient-physician relationships" and "ethical behavior". However, this difference was not statistically significant (Fisher test, P = 0.11).There were no age differences regarding the proportions mentioning "technical" and "non-technical" attributes, but female residents mentioned significantly more technical skills than their male colleagues did. CONCLUSIONS: The influence of role models seems to be an important factor determining the choice of surgery as a career. The influential characteristics of the models include not only technical but also humanistic qualities. PMID- 29116310 TI - Sensitization to cat allergen and its association with respiratory allergies: cross-sectional study. AB - Cats are a significant source of allergens that contribute towards worsening of allergic diseases. The aim of this study was to investigate the association between sensitization to cat allergens and allergic respiratory diseases.This was an observational retrospective study based on the skin pricktests results of patients at a tertiary-level hospital in Sao Paulo. A total of 1,985 test results were assessed. The prevalence of sensitization to cat allergen was 20% (399 patients). Our data indicated that in this population of atopic patients, a positive skin prick test result for cat allergen was not associated significantly with a diagnosis of respiratory allergy. PMID- 29116311 TI - Cardiovascular emergencies in primary care: an observational retrospective study of a large-scale telecardiology service. AB - BACKGROUND: Electrocardiograms (ECGs) are an essential examination for identification and management of cardiovascular emergencies.The aim of this study was to report on the frequency and recognition of cardiovascular emergencies in primary care units. DESIGN AND SETTING: Observational retrospective study assessing consecutive patients whose digital ECGs were sent for analysis to the team of the Telehealth Network of Minas Gerais. METHODS: Data from patients diagnosed with cardiological emergencies in the primary care setting of 750 municipalities in Minas Gerais, Brazil, between March and September 2015, were collected via telephone contact with the healthcare practitioner who performed the ECG. After collection, the data were subjected to statistical analysis. RESULTS: Over the study period, 304 patients with cardiovascular emergencies were diagnosed within primary care. Only 73.4% of these were recognized by the local physicians. Overall, the most frequent ECG abnormalities were acute ischemic patterns (44.7%) and the frequency of such patterns was higher among the ECGs assigned as emergency priority (P = 0.03). It was possible to obtain complete information on 231 patients (75.9%). Among these, the mean age was 65 +/- 14.4 years, 57.1% were men and the most prevalent comorbidity was hypertension (68.4%). In total, 77.9% were referred to a unit caring for cases of higher complexity and 11.7% of the patients died. CONCLUSION: In this study, cardiovascular emergencies were misdiagnosed in primary care settings, acute myocardial ischemia was the most frequent emergency and the mortality rate was high. PMID- 29116312 TI - Malignant transformation of abdominal wall endometriosis to clear cell carcinoma: case report. AB - BACKGROUND: Malignant transformation of endometriosis in the abdominal wall is a rare and still poorly understood event. Less than 30 cases have been reported in the worldwide literature. Most cases of solid tumors are report in a previous abdominal scar with malignant transformation of a focus of endometriosis. Presence of lymph node metastases in nearby chains is frequent and is associated with poor prognosis. CASE REPORT: We report a case of a 42-year-old woman with a history of abdominal surgery (Pfannenstiel) to resect abdominal wall endometriosis. Physical examination revealed a solid mass of approximately 10 cm x 6 cm in the anterior wall of the abdomen. Computed tomography (CT) of the abdomen and pelvis showed a heterogeneous, predominantly hypoattenuating expansive formation measuring 10.6 cm x 4.7 cm x 8.3 cm. The patient underwent exploratory incisional laparotomy, block resection of the abdominal mass and lymphadenectomy of the external and inguinal iliac chains. The abdominal wall was reconstructed using a semi-absorbable tissue-separating screen to reconstitute the defect caused by resection of the tumor. Histological evaluation revealed infiltration by malignant epithelioid neoplasia, thus confirming the immunohistochemical profile of adenocarcinoma with clear cell components. Lymphadenectomy showed metastatic involvement of an external iliac chain lymph node. CONCLUSION: Resection of the mass along with the abdominal wall, with wall margins, is the most effective treatment. Reconstruction is a challenge for surgeons. The patient has been followed up postoperatively for eight months, without any evidence of disease to date. PMID- 29116313 TI - Solitary pancreatic metastasis from breast cancer: case report and review of literature. AB - ABSTRACT: CONTEXT: Pancreatic metastases from primary malignant tumors at other sites are rare, constituting about 2% of the neoplasms that affect the pancreas. Pancreatic metastasis from breast cancer is extremely rare and difficult to diagnose, because its clinical and radiological presentation is similar to that of a primary pancreatic tumor. CASE REPORT: A 64-year-old female developed a lesion in the pancreatic tail 24 months after neoadjuvant therapy, surgery and adjuvant radiation therapy for right-side breast cancer (ductal carcinoma). She underwent distal pancreatectomy with splenectomy and left adrenalectomy, and presented an uneventful outcome. The immunohistochemical analysis on the surgical specimen suggested that the lesion originated from the breast. CONCLUSION: In cases of pancreatic lesions detected in patients with a previous history of breast neoplasm, the possibility of pancreatic metastasis should be carefully considered. PMID- 29116314 TI - What do Cochrane systematic reviews say about interventions for vitamin D supplementation? AB - CONTEXT AND OBJECTIVE: Despite the high prevalence of vitamin D supplementation, its use remains controversial. The objective of this review was to identify and summarize the evidence from Cochrane systematic reviews regarding vitamin D supplementation for preventing ortreating any clinical condition. DESIGN AND SETTING: Review of systematic reviews, conducted in the Discipline of Evidence Based Medicine, Escola Paulista de Medicina, Universidade Federal de Sao Paulo. METHODS: A search was conducted to identify all Cochrane systematic reviews that fulfilled the inclusion criteria. Titles and abstracts were screened by two authors. RESULTS: We included 27 Cochrane systematic reviews: 10 assessing use of vitamin D for prevention and 17 for treatment. The reviews found moderate to high quality of evidence regarding the benefit of vitamin D for pregnant women (prevention of adverse events: preterm birth risk [rate ratio, RR 0.36; 95% confidence interval, CI 0.14 to 0.93] and low birthweight risk [RR 0.40; 95% CI 0.24 to 0.67]) and for asthma patients (reduction of severe exacerbations [RR 0.63; 95% CI 0.45 to 0.88]). No benefit was found regarding vitamin D supplementation alone (without calcium) for preventing hip or any new fracture. For all other outcomes assessed under various conditions, the current quality of evidence is low or unknown, and therefore insufficient for any recommendation. CONCLUSION: Based on moderate to high quality of evidence, the Cochrane systematic reviews included here showed that there were some benefits from vitamin D supplementation for pregnant women and asthma patients and no benefits for preventing fractures. PMID- 29116315 TI - [Assessment of adherence to the Safe Childbirth Checklist in a public maternity hospital in Northeast Brazil]. AB - Decreasing childbirth-related mortality is a current global health priority. The World Health Organization developed the Safe Childbirth Checklist to reduce adverse events in maternal and perinatal care, using simple and effective practices. The current study aims to evaluate adherence to the checklist by professionals in a maternity hospital in Natal, Rio Grande do Norte State, Brazil. The study used an observational, cross-sectional approach to evaluate all births in three months, with data collected from patient charts. Adherence was described on the basis of presence and quality of the checklist's completion, and bivariate analysis was performed using the association with childbirth-related factors. Of 978 patient charts that were reviewed, 71% had the list, an average of 24% of the items were completed, but only 0.1% of the patient charts were totally completed; better completion was seen in vaginal deliveries and at the time of patient admission. Checklist adherence showed limitations that are inherent to the adoption of a new safety routine and requires continuous training of the health professionals to achieve better results. PMID- 29116316 TI - Characteristics and factors associated with hospitalization in early childhood: 2004 Pelotas (Brazil) birth cohort. AB - Hospitalization is a frequent event in early childhood. In Brazil, the National Household Sample Survey of 2008 showed a 9% hospitalization rate among children in the first four years of life. The study aimed to describe the characteristics of hospitalization in the first six years of life and analyze the early factors associated with hospitalization in a birth cohort in southern Brazil. A zero inflated Poisson model was used to simultaneously examine the effects of co variables for the occurrence of a given event and to count events. The frequency of at least one episode of hospitalization during the study period was 33.4% (95%CI: 31.8-34.9), and was highest in the first year (19.1%; 95%CI: 17.9-20.4), remaining stable at approximately 10% between the first and fourth years, decreasing to 8.4% (95%CI: 7.6-9.4) between the fourth and sixth years. diseases of the respiratory system were among the leading causes of hospitalization, followed by infectious and parasitic diseases. History of prior hospitalization was one of the most important predictors of odds of hospitalization and risk of multiple hospitalizations. In early childhood, birth weight, gestational age, Apgar score, sex, and type of pregnancy were inversely associated with hospitalization, and environmental characteristics such as maternal smoking in pregnancy, mother's skin color, and low family income were associated statistically with number of hospitalizations. The results point to the importance of focusing efforts on reducing hospitalizations from diseases of the respiratory system, especially in children under one year. PMID- 29116317 TI - [Adherence to completion of the safe surgery checklist]. AB - The study describes adherence to completion of the safe surgery checklist and its respective items by health professionals in a public hospital's surgical center. This was a retrospective document study covering the period from 2010 to 2015. The results show that 58.5% of the checklists were completed out of a total of 24,421 surgeries performed. Checklist adherence was only higher on weekdays in the first year of the study, even though there was a specific professional designated to complete it. There were differences in completion between the surgical times, and in times 1 and 2, there were items that were never used, such as members of the surgical team, patient identification, and place of the surgery. No important changes were observed in adherence to completion of the safe surgery checklist during the study period. PMID- 29116318 TI - Land use, land cover, and prevalence of canine visceral leishmaniasis in Teresina, Piaui State, Brazil: an approach using orbital remote sensing. AB - This study examines the association between land use and land cover and the occurrence of canine visceral leishmaniasis (VL). This is a case-control study in which cases were households with seropositive dogs for canine VL and controls were households with seronegative dogs. We used remote sensing images (CBERS: 2/CCD and 2B/HRC) to describe land use and cover in squares of 625m2 in the study area. Odds of canine VL were twice as high in households located in squares with an area <= 25m2 covered by residential structures with little vegetation in comparison to those where the cover reached >= 600m2. Households located in squares with up to half of the area covered by residential structures with extensive vegetation showed 65% lower odds of canine VL in comparison to those situated in areas almost totally covered by this characteristic. Since canine infection usually precedes the occurrence de human cases, identification of the characteristics of land use and cover associated with canine VL can contribute to the demarcation of risk areas for human VL. PMID- 29116319 TI - [The aging process and work: a case study in the maintenance engineering division of a public hospital in the city of Sao Paulo, Brazil]. AB - This study aimed to identify and analyze the relations between aging and work. This was a case study in the maintenance engineering division of a high complexity hospital in the city of Sao Paulo, Brazil. In September and October 2015, 16 semi-structured interviews were held with the division heads and other workers with a minimum age of 50 years. The data were analyzed with thematic content analysis. Although the workers experienced difficulties resulting from the aging process, these did not prevent them from performing their work activities, since they developed strategies through their knowhow to compensate for their functional losses and/or declines. Still, they felt limited and demotivated due to the poor working conditions, outsourcing of the division, and the prevailing workload organization. Thus, in this division, the working conditions and organization had more impact than the aging process on the individuals' daily work routine. PMID- 29116321 TI - Congratulations to the 2017 Blue Ribbon Article Award Winners. PMID- 29116320 TI - A Systematic Meta-Analysis of Using an Articulating Spacer Technique in Revision Total Knee Arthroplasty. PMID- 29116322 TI - Bone Loss and Fracture Risk Among Patients Who Have Had Bariatric Surgery. PMID- 29116323 TI - Factors Influencing Patients' Hospital Rating After Total Joint Arthroplasty. AB - Patient satisfaction assessments, such as the Press Ganey surveys, have been adopted by the Centers for Medicare & Medicaid Services to help determine reimbursements. It is uncertain what facets most affect survey scores among patients who have received total joint arthroplasty (TJA). This study explored which factors guide scores for TJA patients. Specifically, the authors assessed (1) which Press Ganey survey features affected the patients' overall hospital rating and (2) whether survey scores were disparate between patients who did and patient who did not have complications. The authors' institutional Press Ganey database was queried for lower-extremity TJAs that occurred between November 2009 and January 2015. This yielded 1454 patients with a mean age of 63 years (range, 15-92 years; 60% women and 40% men). The database contains information related to American Society of Anesthesiologists scores, Press Ganey question responses, and demographics. Multiple regression analysis was performed to assess the association (beta weight) between Press Ganey domains and overall hospital rating. The weighted mean for each domain was calculated. The authors' analysis revealed that overall hospital rating was significantly influenced by communication with nurses (beta weight=0.434, P<.001), responsiveness of hospital staff (beta weight=0.181, P=.001), communication with doctors (beta weight=0.115, P=.014), and hospital environment (beta weight=0.100, P=.039). No significant differences were found when comparing the Press Ganey scores of patients with and without complications. By recognizing these elements, physicians can direct measures appropriately, which may help avoid financial penalties and possibly increase patient satisfaction after TJA. [Orthopedics. 2017; 40(6):377-380.]. PMID- 29116324 TI - Displaced Intra-articular Calcaneal Fractures: Classification and Treatment. AB - The calcaneus is the most commonly fractured tarsal bone. Displaced intraarticular calcaneal fractures are usually caused by a fall from height with one or both heels directly hitting the ground. Displaced intra-articular calcaneal fractures are complex and highly disabling injuries. There is ongoing debate regarding the optimal treatment for each type of displaced intra-articular calcaneal fracture. This review aims to summarize the classification of, various treatment options for, prevention of perioperative complications in, and management algorithms for displaced intra-articular calcaneal fractures. [Orthopedics. 2017; 40(6):e921-e929.]. PMID- 29116325 TI - Age and Early Revision After Primary Total Hip Arthroplasty for Osteoarthritis. AB - Prior reports have noted an increased risk of early revision among younger patients undergoing total hip arthroplasty (THA) but have been confounded by the inclusion of various diagnoses. The purpose of this study was to assess the revision rate and the time to revision for patients undergoing THA for osteoarthritis based on age. Patients with a diagnosis of osteoarthritis who underwent both primary and revision THA at the same institution were identified. The time between primary and revision surgery and the indication for revision were collected. Patients were stratified into 2 groups based on age at the time of primary THA: 64 years or younger (group 1) or 65 years or older (group 2). Between 1996 and 2016, a total of 4662 patients (5543 hips) underwent primary THA for a diagnosis of osteoarthritis. Of these, 100 patients (104 hips) received a revision THA (62 in group 1 and 42 in group 2). Mean age was 52.7+/-8.4 years in group 1 vs 73.4+/-6.3 years in group 2 (P<.001). There was no significant difference in mean body mass index (29.7+/-7.3 kg/m2 vs 28.4+/-4.6 kg/m2, P=.30). Rate of revision was not significantly different between the groups (1.8% vs 2.0%, P=.7). Average time from primary to revision surgery was 3.0+/-3.2 years for group 1 and 1.1+/-2.1 years for group 2 (P=.001). Among patients undergoing primary THA for a diagnosis of osteoarthritis, younger age is not associated with an increased rate of early failure or revision. [Orthopedics. 2017; 40(6):e1069 e1073.]. PMID- 29116326 TI - Performance Comparison of Single-Radius Versus Multiple-Curve Femoral Component in Total Knee Arthroplasty: A Prospective, Randomized Study Using the Lower Quarter Y-Balance Test. AB - Midflexion stability after total knee arthroplasty (TKA) is dependent, in part, on implant design. Midflexion performance of a single-radius (SR) design and a multi-radius, or J-curve (JC), design were compared using the Lower Quarter Y Balance Test (YBT-LQ). Patient-reported outcomes and measures of physical performance were also compared. The authors hypothesized that the SR design would provide superior midflexion stability and, therefore, a greater reach distance in the YBT-LQ when compared with the JC design. Patients undergoing primary, unilateral TKA were prospectively enrolled and block randomized to receive either the SR (n=30) or the JC (n=30) implant. Patients reported outcome measures (Knee Injury and Osteoarthritis Outcome Score, Knee Society Score, and University of California at Los Angeles Activity Score), performed the YBT-LQ, and completed physical performance measures (walking speed, timed up-and-go test, and sit-to stand test) before surgery and 1 year postoperatively. One year postoperatively, 40 patients (20 SR, 20 JC) were available for analysis. There were no significant differences between the groups regarding age, sex, body mass index, American Society of Anesthesiologists score, YBT-LQ results, or any other variable of interest. In both groups, significant improvements were observed for all variables of interest when compared from preoperatively to 1 year postoperatively. Implant type did not affect patient-reported or physical performance outcomes following TKA; however, patients showed significant improvement in most outcome measures by 1 year postoperatively. The significant limitations in strength and balance in this cohort of patients likely outweigh any subtle differences in implant design. [Orthopedics. 2017; 40(6):e1074 e1080.]. PMID- 29116327 TI - The Effect of a Door Alarm on Operating Room Traffic During Total Joint Arthroplasty. AB - Operating room traffic has been implicated in several studies to contribute to the risk of surgical site infections and periprosthetic joint infections. The purpose of this study was to evaluate the effect of a door alarm on operating room traffic during total joint arthroplasty. This prospective cohort study evaluated 100 consecutive primary total hip and knee arthroplasty surgeries performed by a single surgeon. An inconspicuous electronic door counter was placed on the substerile operating room door. Door openings and time left ajar were recorded. After 50 cases, an audible alarm was placed on the substerile operating room door that sounded continuously when the door was ajar. Door opening data were then recorded for an additional 50 cases. There was a significant difference in the overall mean door openings per minute (P<.001) between the period with no alarm (0.53+/-0.1) and with an alarm (0.42+/-0.1). This effect slowly decreased over the time of the intervention, with door openings per minute increasing by a factor of 1.01. The percentage of time the door was left ajar per case also decreased significantly (P<.001) with the alarm (6.63%+/-1.6%) compared with no alarm (8.65%+/-1.5%). This study indicates that the use of a door alarm can decrease door openings and potentially the risk for surgical site infection. However, the effect is subject to tolerance and may not result in the elimination of unnecessary operating room traffic long term. [Orthopedics. 2017; 40(6):e1081-e1085.]. PMID- 29116328 TI - Correlation Between Femoroacetabular Impingement and Hamstring Tendon Pathology on Magnetic Resonance Imaging and Arthrography. AB - Femoroacetabular impingement (FAI) is an abnormality of the femoral head or acetabulum that leads to an increased incidence of cartilaginous injury in the hip. Femoroacetabular impingement has been associated with several structural abnormalities, including osteitis pubis and hip flexor dysfunction. The authors propose that, additionally, FAI may lead to increased damage of the hamstring tendon due to the additional stress placed on the tendon from the limited range of motion of the hip. The authors conducted a retrospective matched-pair study with the magnetic resonance imaging and magnetic resonance arthrography images of 40 patients' hamstrings with FAI and 45 age-matched controls. Images were identified and reviewed by 2 musculoskeletal radiologists for various signs of hamstring tendon pathology. Fisher's exact test and an odds ratio were used to assess for a difference in the occurrence of hamstring tendon pathology in the FAI patient cohort compared with the age-matched controls. The results showed a statistically significant increase in the occurrence of hamstring tendon pathology in the FAI patient cohort compared with the age-matched controls (P<.001). The odds ratio for hamstring tendon pathology in a subject with confirmed FAI vs control subjects was 8.30 (95% confidence interval, 3.20-21.5), indicating a significant increase in the risk of developing hamstring tendon pathology among patients with FAI (P<.001). This study suggests that there may be an increased occurrence of hamstring tendon pathology in patients with FAI. The kinetic chain of motion, where restricted rotation at the hip joint increases the stress on the hamstring tendons, leading to damage, may explain this increase. [Orthopedics. 2017; 40(6):e1086-e1091.]. PMID- 29116329 TI - Digital Tomography for Detection of Acute Occult Scaphoid Fractures. AB - Diagnosis of occult scaphoid fractures remains a challenge. Traditional management consisting of 2 weeks of immobilization and repeat radiographs results in unnecessary immobilization of many patients without fracture. Magnetic resonance imaging (MRI) is sensitive but expensive. Digital tomography (DT) is an imaging technique that provides fine-cut visualization with minimal radiation exposure and may be used when there is high clinical suspicion despite negative findings on initial radiographs. The authors compared the ability of DT vs MRI to detect acute occult scaphoid fractures. This was an institutional review board approved, prospective series. Adults for which clinical suspicion for acute scaphoid fracture (presenting within 96 hours of trauma) and negative findings on initial radiographs existed were included. Both a wrist tomogram and MRI were obtained. Wrists were immobilized and reevaluated at 10 to 14 days with repeat radiographs as a control. Studies were interpreted by a radiologist in a blinded fashion. Forty consecutive extremities in 39 patients met the inclusion criteria. Six (15%) of the 40 scaphoids were determined to be fractured on repeat radiographs. Digital tomogram yielded positive findings in 4 of these. Magnetic resonance imaging yielded positive findings in 8 (20%) of the 40 extremities. Sensitivities were 67% and 100% for digital tomogram and MRI, respectively (P=.0001). The positive predictive value was 100% for DT and MRI. The authors found that DT detects more occult scaphoid fractures than initial standard radiographs but is less sensitive than MRI. This is the first study to compare DT with MRI. Digital tomography can be used to augment radiographs and may increase diagnostic efficiency, minimize unnecessary immobilization, and reduce health care costs. [Orthopedics. 2017; 40(6):e1092-e1095.]. PMID- 29116330 TI - Identification and mapping of ts (tender spines), a gene involved in soft spine development in Cucumis sativus. AB - KEY MESSAGE: Using map-based cloning of ts gene, we identified a new sort of gene involved in the initiation of multicellular tender spine in cucumber. The cucumber (Cucumis sativus L.) fruit contains spines on the surface, which is an extremely valuable quality trait affecting the selection of customers. In this study, we elaborated cucumber line NC072 with wild type (WT) hard fruit spines and its spontaneous mutant NC073, possessing tender and soft spines on fruits. The mutant trait was named as tender spines (ts), which is controlled by a single recessive nuclear gene. We identified the gene ts by map-based cloning with an F2 segregating population of 721 individuals generated from NC073 and WT line SA419 2. It was located between two markers Indel6239679 and Indel6349344, 109.7 kb physical distance on chromosome 1 containing fifteen putative genes. With sequencing and quantitative reverse transcription-polymerase chain reaction analysis, the Csa1G056960 gene was considered as the most possible candidate gene of ts. In the mutant, Csa1G056960 has a nucleotide change in the 5' splicing site of the second intron, which causes different splicing to delete the second exon, resulting in a N-terminal deletion in the predicted amino acid sequence. The gene encodes a C-type lectin receptor-like tyrosine-protein kinase which would play an important role in the formation of cucumber fruit. This is firstly reported of a receptor kinase gene regulating the development of multicellular spines/trichomes in plants. The ts allele could accelerate the molecular breeding of cucumber soft spines. PMID- 29116331 TI - Response of microbial communities to pesticide residues in soil restored with Azolla imbricata. AB - Under conditions of Azolla imbricata restoration, the high-throughput sequencing technology was employed to determine change trends of microbial community structures in the soil that had undergone long-term application of pesticides. The relationship between the content of pesticide residues in the soil and the microbial community structure was analyzed. The results indicated that the microbial diversity was strongly negatively correlated with the contents of pesticide residues in the soil. At a suitable dosage of 5 kg fresh A. imbricata per square meter of soil area, the soil microbial diversity increased by 12.0%, and the contents of pesticide residues decreased by 26.8-72.1%. Sphingobacterium, Sphingopyxis, Thermincola, Sphingobium, Acaryochloris, Megasphaera, Ralstonia, Pseudobutyrivibrio, Desulfitobacterium, Nostoc, Oscillochloris, and Aciditerrimonas may play major roles in the degradation of pesticide residues. Thauera, Levilinea, Geothrix, Thiobacillus, Thioalkalispira, Desulfobulbus, Polycyclovorans, Fluviicola, Deferrisoma, Erysipelothrix, Desulfovibrio, Cytophaga, Vogesella, Zoogloea, Azovibrio, Halomonas, Paludibacter, Crocinitomix, Haliscomenobacter, Hirschia, Silanimonas, Alkalibacter, Woodsholea, Peredibacter, Leptolinea, Chitinivorax, Candidatus_Lumbricincola, Anaerovorax, Propionivibrio, Parasegetibacter, Byssovorax, Runella, Leptospira, and Nitrosomonas may be indicators to evaluate the contents of pesticide residues. PMID- 29116333 TI - Non-antiarrhythmic interventions in new onset and paroxysmal sepsis-related atrial fibrillation. PMID- 29116332 TI - [Therapy of scars with lasers]. AB - Scar formation is the consequence of trauma to the skin that affects the deep parts of the dermis. Different scar types like immature, mature, atrophic, hypertrophic, or keloid scars can develop depending on factors like age, anatomic localization, cause of trauma, the course of the healing process, and individual predispositions. Keloids and hypertrophic scars are often associated with itching, pain, tautness of the skin, and functional impairments, thus, leading to significantly reduced quality of life in some patients. However, even seemingly physiologically healed scars can cause tremendous psychological strain as is the case with self-harm scars. Despite increased research efforts, the exact pathomechanisms of excessive scarring are still scarcely understood, and dependably effective treatment options are often lacking. However, through continually improving scientific progress, scar treatment paradigms for a variety of scar types, thus far often dominated by conventional treatment methods, are increasingly complemented by new laser technologies and wavelengths. PMID- 29116334 TI - Fungal Denitrification Activity in Vertical Flow Constructed Wetlands as Impacted by Plant Species Richness, Carbon, Nitrogen and pH Amendments. AB - To control potential fungal denitrification rate (PFDR) in vertical flow simulated wetlands (VFSW) microcosms, thirty VFSW microcosms were established and planted with three plant species richness levels (i.e. unplanted, monoculture, and four-species polyculture treatment), and effects of carbon, nitrogen and pH amendments on the PFDR were investigated using a room-incubating method. Among seven carbon compounds, sodium citrate, glycerol, glucose and sodium succinate were more effective in enhancing PFDRs. These enhanced effects were dependant on a given species richness level. Sodium nitrite mostly stimulated PFDRs to a greater extent than the other three nitrogen compound amendments at any richness level. Treatments with pH 5.6 or 8.4 had significantly greater PFDRs than the treatment with pH 2.8 in the three species richness levels. However, no effect of plant species richness on the PFDR was observed among any carbon, nitrogen and pH amendments. Current results suggest carbon, nitrogen and pH factors should be considered when mediating fungal denitrification in VFSW microcosms. PMID- 29116335 TI - Investigation of Perfluoroalkyl Substances (PFASs) in Sediments from the Urban Lakes of Anqing City, Anhui Province, China. AB - Fifteen individual perfluoroalkyl substances (PFASs) were analyzed in 22 sediment samples collected from Anqing urban lakes (Anhui province, China) by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Total PFAS concentration was between 0.61 and 26 ng g- 1 dry weight. Perfluorooctane sulfonate (PFOS) was the dominant PFAS contaminant, with a concentration range of < 0.040-13 ng g- 1. Results indicated higher total PFAS concentrations in lakes located to the northwest of Anqing City than in other regions. Adjacent chemical and industrial factories were hypothesized to be responsible for these higher PFAS levels in those lakes. In comparison to other measurements obtained from other lakes, PFAS concentrations in the urban lakes of Anqing City were relatively high. PMID- 29116336 TI - Analysis of primary tumor metabolic volume during chemoradiotherapy in locally advanced non-small cell lung cancer. AB - PURPOSE: Positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d glucose integrated with computed tomography (18F-FDG-PET/CT) has an established role in the initial diagnosis and staging of lung cancer. However, a prognostic value of PET/CT during multimodality treatment has not yet been fully clarified. This study evaluated the role of primary tumor metabolic volume (PT-MV) changes on PET/CT before, during, and after chemoradiotherapy (CRT). METHODS: A total of 65 patients with non-small-cell lung cancer (NSCLC) UICC stage IIIA/B (TNM 7th Edition) were treated with definitive chemoradiotherapy (sequential or concurrent setting). PET/CT was acquired before the start, at the end of the third week, and 6 weeks following CRT. RESULTS: Median overall survival (OS) for the entire cohort was 16 months (95% confidence interval [CI]: 12-20). In all, 60 (92.3%) patients were eligible for pre-treatment (pre-PT-MV), 28 (43%) for mid-treatment (mid-PT-MV), and 53 (81.5%) for post-treatment (post-PT-MV) volume analysis. Patients with pre-PT-MV >63 cm3 had worse OS (p < 0.0001). A reduction from mid PT-MV to post-PT-MV of >15% improved OS (p = 0.001). In addition, patients with post-PT-MV > 25 cm3 had significantly worse outcome (p = 0.001). On multivariate analysis, performance status (p = 0.002, hazard ratio [HR] 0.007; 95% CI 0.00 0.158), pre-PT-MV1 < 63 cm3 (p = 0.027, HR 3.98; 95% CI 1.17-13.49), post-PT-MV < 25 cm3 (p = 0.013, HR 11.90; 95% CI 1.70-83.27), and a reduction from mid-PT-MV to post-PT-MV > 15% (p = 0.004, HR 0.25; 95% CI 0.02-0.31) correlated with improved OS. CONCLUSIONS: Our results demonstrated that pre- and post-treatment PT-MV, as well as an at least 15% reduction in mid- to post-PT-MV, significantly correlates with OS in patients with inoperable locally advanced NSCLC. PMID- 29116337 TI - Effects of monoclonal antibodies against PCSK9 on clinical cardiovascular events : A meta-analysis of randomized controlled trials. AB - BACKGROUND: The present meta-analysis was designed to improve statistical power and review the effects of monoclonal antibodies against PCSK9 on clinical cardiovascular events. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to May 2017. Studies considered to be eligible were randomized controlled trials about the effects of monoclonal antibodies against PCSK9 on clinical cardiovascular events. The primary endpoint was positively adjudicated cardiovascular events; the secondary endpoint comprised cardiac mortality, myocardial infarction (MI), coronary revascularization, stroke, and hospitalization for unstable angina. RESULTS: We included 20 randomized controlled trials involving 67,934 patients. Monoclonal antibodies against PCSK9 were associated with a significant reduction in positively adjudicated cardiovascular events (relative risk [RR] = 0.87; 95% confidence interval [CI] = 0.81-0.93; z = 4.03; p = 0.000), MI (RR = 0.78; 95% CI = 0.71-0.86; z = 4.96; p = 0.000), coronary revascularization (RR = 0.81, 95% CI = 0.75-0.88; z = 4.93; p = 0.000), and stroke (RR = 0.76, 95% CI = 0.65-0.89; z = 3.47; p = 0.001). Monoclonal antibodies against PCSK9 did not reduce hospitalization rates due to unstable angina. The results of subgroup analysis showed that evolocumab was associated with a lower risk of positively adjudicated cardiovascular events, MI, coronary revascularization, and stroke without reducing cardiac mortality. Alirocumab reduced the incidence of cardiac mortality but not of other cardiovascular events, while bococizumab was associated with a reduced risk of stroke. CONCLUSION: Monoclonal antibodies against PCSK9 were associated with a lower risk of positively adjudicated cardiovascular events, MI, coronary revascularization, and stroke. PMID- 29116338 TI - Socioeconomic status is associated with the prevalence and co-occurrence of risk factors for cigarette smoking initiation during adolescence. AB - OBJECTIVES: To investigate whether the prevalence or co-occurrence of risk factors for cigarette smoking initiation differ by socioeconomic status (SES) and whether SES interacts with risk factors to increase initiation. METHODS: In 2005, 1451 5th grade never smokers (mean age 10.7 years) in Montreal, Canada, provided baseline data, with follow-up in 6th and/or 7th grade (2005-2007). Poisson regression analyses estimated the association between 13 risk factors and initiation. Excess risk of each risk factor in low vs. moderate-high SES participants was assessed. RESULTS: Cigarette smoking was initiated by 9.4% of participants (n = 137). Low SES was associated with a higher prevalence and co occurrence of risk factors. The estimated association of most risk factors with initiation was similar across SES, although participants from low SES neighborhoods whose mothers had no university education had three times the risk of initiation [ARR = 3.10 (1.19, 8.08)] compared to more affluent peers. CONCLUSIONS: Tobacco control efforts must address the higher prevalence and co occurrence of risk factors in lower SES contexts since these may render initiation highly probable in many lower SES youth. PMID- 29116339 TI - beta-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/beta-catenin signaling in mice. AB - : Despite substantial progress being made in understanding the mechanisms contributing to the pathogenesis of renal fibrosis, there are only a few therapies available to treat or prevent renal fibrosis in clinical use today. Therefore, identifying the key cellular and molecular mediators involved in the pathogenesis of renal fibrosis will provide new therapeutic strategy for treating patients with chronic kidney disease (CKD). beta-Arrestin-1, a member of beta arrestin family, not only is a negative adaptor of G protein-coupled receptors (GPCRs), but also acts as a scaffold protein and regulates a diverse array of cellular functions independent of GPCR activation. In this study, we identified for the first time that beta-arrestin-1 was upregulated in the kidney from mice with unilateral ureteral obstruction nephropathy as well as in the paraffin embedded sections of human kidneys from the patients with diabetic nephropathy, polycystic kidney, or uronephrosis, which normally causes renal fibrosis. Deficiency of beta-arrestin-1 in mice significantly alleviated renal fibrosis by the regulation of inflammatory responses, kidney fibroblast activation, and epithelial-mesenchymal transition (EMT) in both in vivo and in vitro studies. Furthermore, we found that among the major isoforms of Wnts, Wnt1 was regulated by beta-arrestin-1 and gene silencing of Wnt1 inhibited the activation of beta catenin and suppressed beta-arrestin-1-mediated renal fibrosis. Collectively, our results indicate that beta-arrestin-1 is one of the critical components of signal transduction pathways in the development of renal fibrosis. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with renal fibrosis. KEY MESSAGES: beta-Arrestin-1 was upregulated in the kidney from mice with UUO nephropathy. beta-Arrestin-1 regulated kidney fibroblast activation and epithelial-mesenchymal transition. beta-Arrestin-1 exacerbated renal fibrosis via mediating Wnt1/beta-catenin signaling. PMID- 29116341 TI - Shear wave liver elastography. AB - Chronic liver disease is a substantial world-wide problem. Its major consequence is increasing deposition of fibrous tissue within the liver leading to the development of cirrhosis with its consequences of portal hypertension, hepatic insufficiency, and hepatocellular carcinoma. The stage of liver fibrosis is important to determine prognosis, surveillance, prioritize for treatment, and potential for reversibility. The process of fibrosis is dynamic and regression of fibrosis is possible with treatment of the underlying conditions. Previously, the only method of staging the degree of fibrosis was liver biopsy. The recent development of ultrasound elastography techniques allows a non-invasive method of estimating the degree of liver fibrosis. Transient elastography (TE) is a non imaging elastographic technique, while point shear wave (p-SWE) and 2D-SWE combine imaging with elastography. The evidence at this time suggests that p-SWE is as accurate as but more reliable than TE, while 2D-SWE is more accurate than TE. This review discusses the background of chronic liver disease, the types of ultrasound elastography, how to perform an examination, and how to interpret the results. PMID- 29116342 TI - Gastroenterology and pancreatic adenocarcinoma: what the radiologist needs to know. AB - In this article, we review the information that radiologists need to know regarding the endoscopic approach to the diagnosis and management of pancreatic cancer. This includes a review of the indications, techniques, and complications of endoscopic ultrasound. We also review information regarding endoscopic retrograde cholangiopancreatography, including the various biliary drainage techniques and the use of endoscopic palliation for patients with pancreatic cancer. PMID- 29116340 TI - 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation. AB - PURPOSE: Focal congenital hyperinsulinism (CHI) is curable by surgery, which is why identification of the focal lesion is crucial. We aimed to determine the use of 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) PET/CT vs. 68Ga-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic-acid-1-Nal3-octreotide (68Ga-DOTANOC) PET/CT as diagnostic tools in focal CHI. METHODS: PET/CT scans of children with CHI admitted to Odense University Hospital between August 2005 and June 2016 were retrospectively evaluated visually and by their maximal standardized uptake values (SUVmax) by two independent examiners, blinded for clinical, surgical and pathological data. Pancreatic histology was used as the gold standard. For patients without surgery, the genetic profile served as the gold standard. RESULTS: Fifty-five CHI patients were examined by PET/CT (18F-DOPA n = 53, 68Ga DOTANOC n = 18). Surgery was performed in 34 patients, no surgery in 21 patients. Fifty-one patients had a classifiable outcome, either by histology (n = 33, 22 focal lesions, 11 non-focal) or by genetics (n = 18, all non-focal). The predictive performance of 18F-DOPA PET/CT to identify focal CHI was identical by visual- and cut-off-based evaluation: sensitivity (95% CI) of 1 (0.85-1); specificity of 0.96 (0.82-0.99). The optimal 18F-DOPA PET SUVmax ratio cut-off was 1.44 and the optimal 68Ga-DOTANOC PET SUVmax cut-off was 6.77 g/ml. The area under the receiver operating curve was 0.98 (0.93-1) for 18F-DOPA PET vs. 0.71 (0.43-0.95) for 68Ga-DOTANOC PET (p < 0.03). In patients subjected to surgery, localization of the focal lesion was correct in 91%, and 100%, by 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT, respectively. CONCLUSION: 18F-DOPA PET/CT was excellent in predicting focal CHI and superior compared to 68Ga-DOTANOC PET/CT. Further use of 68GA-DOTANOC PET/CT in predicting focal CHI is discouraged. PMID- 29116343 TI - Tarsometatarsal joint communication during fluoroscopy-guided therapeutic joint injections and relationship with patient age and degree of osteoarthritis. AB - OBJECTIVE: Although the tarsometatarsal joints are separated into three distinct synovial compartments, communications between adjacent compartments are often noted during image-guided injections. This study aims to determine whether abnormal inter-compartment tarsometatarsal joint communication is associated with patient age or degree of tarsometatarsal osteoarthritis. MATERIALS AND METHODS: One hundred forty tarsometatarsal injections were retrospectively reviewed by two radiologists. Extent of inter-compartment communication and degree of osteoarthritis were independently scored. Univariate and multivariable analyses were performed to assess whether the presence of and number of abnormal joint communications were related to age and degree of osteoarthritis. RESULTS: Forty out of 140 tarsometatarsal joints showed abnormal communication with a separate synovial compartment, and 3 of the 40 showed abnormal communication with two separate compartments. On univariate analysis, higher grade osteoarthritis (p < 0.001) and older age (p = 0.014) were associated with an increased likelihood of abnormal inter-compartment tarsometatarsal communication and a greater number of these abnormal communications. On multivariate analysis, the degree of osteoarthritis remained a significant predictor of the presence of (p < 0.001) and number of (p < 0.001) abnormal communications, while the association of age was not statistically significant. There was significant correlation between age and degree of osteoarthritis (p < 0.001). CONCLUSION: Higher grade osteoarthritis increases the likelihood of abnormal inter-compartment tarsometatarsal joint communication and is associated with a greater number of abnormal communications. Diagnostic injection to localize a symptomatic tarsometatarsal joint may be less reliable in the setting of advanced osteoarthritis. PMID- 29116344 TI - Correlation and agreement of a digital and conventional method to measure arch parameters. AB - OBJECTIVE: The aim of the present study was to determine the overall reliability and validity of arch parameters measured digitally compared to conventional measurement. METHODS: A sample of 111 plaster study models of Down syndrome (DS) patients were digitized using a blue light three-dimensional (3D) scanner. Digital and manual measurements of defined parameters were performed using Geomagic analysis software (Geomagic Studio 2014 software, 3D Systems, Rock Hill, SC, USA) on digital models and with a digital calliper (Tuten, Germany) on plaster study models. Both measurements were repeated twice to validate the intraexaminer reliability based on intraclass correlation coefficients (ICCs) using the independent t test and Pearson's correlation, respectively. The Bland Altman method of analysis was used to evaluate the agreement of the measurement between the digital and plaster models. RESULTS: No statistically significant differences (p > 0.05) were found between the manual and digital methods when measuring the arch width, arch length, and space analysis. In addition, all parameters showed a significant correlation coefficient (r >= 0.972; p < 0.01) between all digital and manual measurements. Furthermore, a positive agreement between digital and manual measurements of the arch width (90-96%), arch length and space analysis (95-99%) were also distinguished using the Bland-Altman method. CONCLUSION: These results demonstrate that 3D blue light scanning and measurement software are able to precisely produce 3D digital model and measure arch width, arch length, and space analysis. The 3D digital model is valid to be used in various clinical applications. PMID- 29116345 TI - Phylogeny and Antagonistic Activities of Culturable Bacteria Associated with the Gut Microbiota of the Sea Urchin (Paracentrotus lividus). AB - In this study, we have investigated the phylogeny and the antagonistic interactions of culturable bacteria isolated from the sea urchin Paracentrotus lividus collected from Aber and Morgat, both located in Crozon peninsula, France. Bacteria were isolated from the gastrointestinal tracts of ten specimens by using conventional culture-dependent method and then investigated by using phylogenetic analysis based on 16S rRNA gene sequence comparisons. Assays for antagonistic interactions among the bacterial strains were performed; bacteria (including at least one strain representative of each OTU identified) were screened for antimicrobial substance production. So, 367 bacterial strains were isolated on marine-agar. On the basis of morphological characteristics, 180 strains were sequenced and 94 OTUs were classified. The dominant phyla were Proteobacteria, Firmicutes and Actinobacteria, with a high abundance of the strains belonging to the genus Psychrobacter. From the antagonistic interactions assays, it could be determined that 22.7% strains were positive for at least one antagonism interaction, 18.3% of them isolated from the sea urchins collected in Morgat. We hypothesize that the bacteria isolated in this study may represent the transitory microbiota of the gastrointestinal tract of P. lividus, and that this microbiota may be related to the diet of this marine invertebrate. Furthermore, our results suggest that chemical antagonism could play a significant role in shaping the bacterial communities within gastrointestinal tract of the sea urchins. In addition, most isolated bacteria may have promising biotechnology applications. PMID- 29116346 TI - Spirosoma humi sp. nov., Isolated from Soil in South Korea. AB - A Gram-stain-negative, non-motile, rod-shaped, aerobic bacterial strain, designated S7-4-1T, was isolated from soil in Gyeongsangnam-do, South Korea and characterized using a polyphasic approach to determine its taxonomic position. Phylogenic analysis based on the 16S rRNA gene sequence showed that strain S7-4 1T belonged to the family Cytophagaceae and was most closely related to Spirosoma fluviale MSd3T (96.2%), 'Spirosoma radiotolerans' DG5A (96.0%), Spirosoma pulveris JSH5-14T (95.9%), and Spirosoma linguale DSM 74T (95.8%). The G+C content of the genomic DNA of the isolate was 49.0 mol%. The strain contained summed feature 3 (C16:1 omega7c/C16:1 omega6c; 41.0%), C16:1 omega5c (24.9%), and C15:0 iso (9.3%) as the major fatty acids, menaquinone MK-7 as the predominant respiratory quinone, and phosphatidylethanolamine and an unidentified aminophospholipid as the main polar lipids, which supported its affiliation with the genus Spirosoma. The results of physiological and biochemical tests allowed the genotypic and phenotypic differentiation of the isolate from recognized Spirosoma species. On the basis of its phenotypic properties, genotypic distinctiveness, and chemotaxonomic features, strain S7-4-1T represents a novel species of the genus Spirosoma, for which the name Spirosoma humi sp. nov. is proposed. The type strain is S7-4-1T (= KCTC 52729T = JCM 32132T). PMID- 29116348 TI - [EndoCert between quality assurance and cost effectiveness : A contradiction (or not)]. PMID- 29116347 TI - Methanogenic and Sulfate-Reducing Activities in a Hypersaline Microbial Mat and Associated Microbial Diversity. AB - Methanogenesis and sulfate reduction are important microbial processes in hypersaline environments. However, key aspects determining substrate competition between these microbial processes have not been well documented. We evaluated competitive and non-competitive substrates for stimulation of both processes through microcosm experiments of hypersaline microbial mat samples from Guerrero Negro, Baja California Sur, Mexico, and we assessed the effect of these substrates on the microbial community composition. Methylotrophic methanogenesis evidenced by sequences belonging to methanogens of the family Methanosarcinaceae was found as the dominant methanogenic pathway in the studied hypersaline microbial mat. Nevertheless, our results showed that incubations supplemented with acetate and lactate, performed in absence of sulfate, also produced methane after 40 days of incubation, apparently driven by hydrogenotrophic methanogens affiliated to the family Methanomicrobiaceae. Sulfate reduction was mainly stimulated by addition of acetate and lactate; however, after 40 days of incubation, an increase of the H2S concentrations in microcosms amended with trimethylamine and methanol was also observed, suggesting that these substrates are putatively used for sulfate reduction. Moreover, 16S rRNA gene sequencing analysis showed remarkable differences in the microbial community composition among experimental treatments. In the analyzed sample amended with acetate, sulfate-reducing bacteria (SRB) belonging to the family Desulfobacteraceae were dominant, while members of Desulfohalobiaceae, Desulfomicrobiaceae, and Desulfovibrionaceae were found in the incubation with lactate. Additionally, we detected an unexpected high abundance of unclassified Hydrogenedentes (near 25%) in almost all the experimental treatments. This study contributes to better understand methanogenic and sulfate-reducing activities, which play an important role in the functioning of hypersaline environments. PMID- 29116349 TI - [Considerations about positive effects through Endocert]. PMID- 29116350 TI - Prevalence of cocaine and derivatives in blood and urine samples of trauma patients and correlation with injury severity: a prospective observational study. AB - PURPOSE: The abuse of cocaine and its derivatives presents a likely risk factor for injury. Trauma incurred by cocaine and derivative abusers may be more severe than that incurred by non-users. OBJECTIVES: To ascertain the presence of cocaine and its derivatives in trauma patients and to correlate RTS (Revised Trauma Score) and ISS (Injury Severity Score) with the presence of cocaine and its derivatives in blood and urine samples. METHODS: All trauma victims treated in an emergency unit between November 11, 2012 and September 15, 2013 were included in the study. Blood and urine samples were collected on admission to hospital. RTS and ISS scores were then compared with the presence or absence of cocaine and its derivatives in the samples. The associations between RTS < 7.84 and ISS > 16 and the independent variables were evaluated by the gross odds ratio values, determined by univariate logistic regression. Multivariate analysis was performed using multivariate logistic regression. RESULTS: Of 453 patients (83.7% male) included in the study, 28.6% presented ISS > 16 and 33.6% presented RTS < 7.84. A total of 435 samples were collected, and 86 (19.8%) provided positive samples for cocaine, 48 (11%) for crack and 69 (15.9%) for cocaethylene. Compared to other patients, drug users showed a greater probability of RTS < 7.84 (2.18 times greater) and a greater probability of ISS > 16 (1.76 times greater). CONCLUSION: For the trauma patients included in our study, the use of cocaine and its derivatives was shown to be associated with more severe traumas, as demonstrated by their RTS and ISS scores. PMID- 29116351 TI - Continuous-flow, microfluidic, qRT-PCR system for RNA virus detection. AB - One of the main challenges in the diagnosis of infectious diseases is the need for rapid and accurate detection of the causative pathogen in any setting. Rapid diagnosis is key to avoiding the spread of the disease, to allow proper clinical decisions to be made in terms of patient treatment, and to mitigate the rise of drug-resistant pathogens. In the last decade, significant interest has been devoted to the development of point-of-care reverse transcription polymerase chain reaction (PCR) platforms for the detection of RNA-based viral pathogens. We present the development of a microfluidic, real-time, fluorescence-based, continuous-flow reverse transcription PCR system. The system incorporates a disposable microfluidic chip designed to be produced industrially with cost effective roll-to-roll embossing methods. The chip has a long microfluidic channel that directs the PCR solution through areas heated to different temperatures. The solution first travels through a reverse transcription zone where RNA is converted to complementary DNA, which is later amplified and detected in real time as it travels through the thermal cycling area. As a proof of concept, the system was tested for Ebola virus detection. Two different master mixes were tested, and the limit of detection of the system was determined, as was the maximum speed at which amplification occurred. Our results and the versatility of our system suggest its promise for the detection of other RNA based viruses such as Zika virus or chikungunya virus, which constitute global health threats worldwide. Graphical abstract Photograph of the RT-PCR thermoplastic chip. PMID- 29116352 TI - A multiplex competitive ELISA for the detection and characterization of gluten in fermented-hydrolyzed foods. AB - A novel competitive ELISA was developed utilizing the G12, R5, 2D4, MIoBS, and Skerritt antibody-HRP conjugates employed in nine commercial ELISA test kits that are routinely used for gluten detection. This novel multiplex competitive ELISA simultaneously measures gliadin-, deamidated gliadin-, and glutenin-specific epitopes. The assay was used to evaluate 20 wheat beers, 20 barley beers, 6 barley beers processed to reduce gluten, 15 soy sauces, 6 teriyaki sauces, 6 Worcestershire sauces, 6 vinegars, and 8 sourdough breads. For wheat beers, the apparent gluten concentration values obtained by the G12 and Skerritt antibodies were typically higher than those obtained using the R5 antibodies. The sourdough bread samples resulted in higher apparent gluten concentration values with the Skerritt antibody, while the values generated by the G12 and R5 antibodies were comparable. Although the soy-based sauces showed non-specific inhibition with the multiple R5 and G12 antibodies, their overall profile was distinguishable from the other categories of fermented foods. Cluster analysis of the apparent gluten concentration values obtained by the multiplex competitive ELISA, as well as the relative response of the nine gluten-specific antibodies used in the assay to different gluten proteins/peptides, distinguishes among the different categories of fermented-hydrolyzed foods by recognizing the differences in the protein/peptide profiles characteristic of each product. This novel gluten-based multiplex competitive ELISA provides insight into the extent of proteolysis resulting from various fermentation processes, which is essential for accurate gluten quantification in fermented-hydrolyzed foods. Graphical abstract A novel multiplex competitive ELISA for the detection and characterization of gluten in fermented-hydrolyzed foods. PMID- 29116353 TI - Use of qNMR for speciation of flaxseeds (Linum usitatissimum) and quantification of cyanogenic glycosides. AB - This report describes a routine method taking less than 20 min to quantify cyanogenic glycosides such as linustatin and neolinustatin from flaxseeds (Linum usitatissimum L.) using 1H nuclear magnetic resonance. After manual dehulling, a higher linustatin content was shown in the almond fraction, while neolinustatin and total cyanogenic glycoside contents were significantly higher in hulls. Linustatin and neolinustatin were quantified in seven cultivars grown in two locations in three different years. Linustatin, neolinustatin, and total cyanogenic glycosides ranged between 91 and 267 mg/100 g, 78-272 mg/100 g, and 198-513 mg/100 g dry weight flaxseeds, respectively. NMR revealed differences of up to 70% between samples with standard deviation variations lower than 6%. This study shows that NMR is a very suitable tool to perform flaxseed varietal selection for the cyanogenic glycoside content. Graphical abstract qNMR can be used to perform flaxseed varietal selection for the cyanogenic glycoside content. PMID- 29116354 TI - Functional electrospun nanofibers for multimodal sensitive detection of biogenic amines in food via a simple dipstick assay. AB - Electrospun nanofibers (ENFs) are promising materials for rapid diagnostic tests like lateral flow assays and dipsticks because they offer an immense surface area while excluding minimal volume, a variety of functional surface groups, and can entrap functional additives within their interior. Here, we show that ENFs on sample pads are superior in comparison to standard polymer membranes for the optical detection of biogenic amines (BAs) in food using a dipstick format. Specifically, cellulose acetate (CA) fibers doped with 2 mg/mL of the chromogenic and fluorogenic amine-reactive chameleon dye Py-1 were electrospun into uniform anionic mats. Those extract cationic BAs from real samples and Py-1 transduces BA concentrations into a change of color, reflectance, and fluorescence. Dropping a BA sample onto the nanofiber mat converts the weakly fluorescent pyrylium dye Py 1 into a strongly red emitting pyridinium dye. For the first time, a simple UV lamp excites fluorescence and a digital camera acts as detector. The intensity ratio of the red to the blue channel of the digital image is dependent on the concentration of most relevant BAs indicating food spoilage from 10 to 250 MUM. This matches the permitted limits for BAs in foods and no false positive signals arise from secondary and tertiary amines. BA detection in seafood samples was also demonstrated successfully. The nanofiber mat dipsticks were up to sixfold more sensitive than those using a polymer membrane with the same dye embedded. Hence, nanofiber-based tests are not only superior to polymer-based dipstick assays, but will also improve the performance of established tests related to food safety, medical diagnostics, and environmental testing. Graphical Absract ?. PMID- 29116355 TI - Isolation and identification of human metabolites from a novel anti-tumor candidate drug 5-chlorogenic acid injection by HPLC-HRMS/MSn and HPLC-SPE-NMR. AB - A novel anti-tumor candidate drug, 5-chlorogenic acid (5-CQA) injection, was used for the treatment of malignant glioma in clinical trial (phase I) in China. The isolation and identification of the metabolites of 5-CQA injection in humans were investigated in the present study. Urine and feces samples obtained after intramuscular administration of 5-CQA injection to healthy adults have been analyzed by high-performance liquid chromatography coupled with high-resolution mass and multiple-stage mass spectrometry (HPLC-HRMS/MSn). No metabolite was detected in human feces; however, in human urine, a total of six metabolites were identified including isomerized 5-CQA (P1 and P2), hydrolyzed 5-CQA (M1and M2), and methylated 5-CQA (M3 and M4). Among them, M3 and M4 were the main metabolites and target analytes for human mass balance study. Additionally, the structure of M3 and M4 was characterized by high-performance liquid chromatography-solid phase extraction-nuclear magnetic resonance (HPLC-SPE-NMR), and the results demonstrated that the methoxy group of M3 and M4 was exclusively attributed to C 3' and C-4', respectively. Due to the unavailability of commercial reference, the pure products of M3 and M4 were synthesized by 5-CQA methylation and followed by isolation and purification. Moreover, the potential activity of M3 and M4 on malignant glioma was predicted using a reverse molecular docking analysis on eight malignant glioma-related pathways. The results showed that M3 and M4 had various interactions against malignant glioma-related targets. Our study provides an insight into the metabolism of 5-CQA injection in humans and supports the clinical human mass balance study. Graphical abstract ?. PMID- 29116356 TI - Population-based epidemiology and incidence of distal femur fractures. AB - PURPOSE: The literature lacks recent epidemiological studies on the incidence, trauma mechanism and fracture classification of distal femur fractures. The aim of the present study was to provide up-to-date information concerning the incidence of distal femur fractures in a large and complete population and to report on the distribution of fracture classification, trauma mechanisms and patient baseline demographics. METHODS: The approach for this study was via a retrospective reviews of records. RESULTS: A total of 293 patients were treated for 302 distal femur fractures between 2005 and 2010. The mean age at the time of fracture was 62.2 years. The mean age was 44.0 years for males and 71.6 years for females. The gender distribution was 33.4% males and 66.6% females. The overall incidence of distal femur fractures was 8.7/100,000/year. After the age of 60 years, a rapid increase in the incidence of distal femoral fractures was observed in both genders, with a large female predominance. Low-energy injuries were the most common mode of injury in both genders (97%), with approximately 61% being the result of a fall from standing height. AO classification type A (extra articular fractures) was the most common of all fractures (38.6%). Eighty-four patients (28.7%) were admitted with periprosthetic fractures, corresponding to an overall incidence of periprosthetic fractures of 2.4/100,000/year. CONCLUSIONS: The present study shows an incidence of 8.7/100,000/year of distal femur fractures. After the age of 60 years, a rapid increase in the incidence of distal femoral fractures was observed in both genders, with a considerable female predominance. PMID- 29116357 TI - Injectable, biomechanically robust, biodegradable and osseointegrative bone cement for percutaneous kyphoplasty and vertebroplasty. AB - PURPOSE: Poly(methyl methacrylate) (PMMA) cement is widely used for percutaneous kyphoplasty and vertebroplasty (PKP and PVP) but possesses formidable shortcomings due to non-degradability. Here, a biodegradable replacement is developed. METHODS: Calcium phosphate cement (CPC) was redesigned by incorporating starch and BaSO4 (new cement named as CPB). The biomechanical, biocompatibility, osseointegrative and handling properties of CPB were systematically evaluated in vitro and in vivo by the models of osteoporotic sheep vertebra, rat subcutaneous implantation and rat femoral defect. RESULTS: CPB revealed appropriate injectability and setting ability for PKP and PVP. More importantly, its biomechanical strengths measured by in vitro and in vivo models were not less than that of PMMA, while its biodegradability and osseointegrative capacities were significantly enhanced compared to PMMA. CONCLUSIONS: CPB is injectable, biomechanically robust, biodegradable and osseointegrative, demonstrating revolutionary potential for the application in PKP and PVP. PMID- 29116358 TI - Humeral head inferior subluxation in proximal humerus fractures. AB - PURPOSE: The objectives of this study are to propose a reliable radiologic method for detecting static inferior subluxation of humeral head, to calculate the relative intra- and inter-observer reliability, and to evaluate its presence pre- and post-surgery. METHODS: This is a retrospective observational study of patients surgically treated for a fracture of the proximal humerus. Fractures were classified using Codman-Lego criteria (radiographic, CT images), osteoporosis was assessed. To identify inferior subluxation, an original method is proposed. This measurement was done pre-operatively, at three and 12 month post-operatively. Clinical evaluation was recorded at final follow-up using Constant Score. RESULTS: One hundred fifty fractures surgically treated were studied. Intra- and inter-observer reliabilities were excellent and high, respectively. In pre-operative x-rays, a significant inferior subluxation was noted in 17/150 cases (11.3%), with significant correlation with fracture pattern (p=0.045), female sex (p=0.038), age older than 70 (p=0.003), obesity (BMI>30, p=0.03), and local osteoporosis (p=0.002). At three month of follow-up, 22 cases (14.6%) had inferior subluxation, with significant correlation with female sex (p=0.04), age older than 70 (p=0.002), obesity (p=0.02), pin or screw articular surface perforation (p<0.001). At 12 month of follow-up, seven cases showed persistent inferior subluxation, with significant correlation with age older than 70 (p=0.032), obesity (p=0.041), screw joint perforation and lower Constant Score (p<0.001). DISCUSSION: Inferior subluxation was mostly found in osteoporotic fractures of the elderly, obese, and of female sex both pre- and post operatively. The intra- and inter-observer reliabilities of proposed radiographic measurement were high and excellent, respectively. CONCLUSIONS: In the early postoperative months, we found a high correlation between inferior subluxation and articular surface perforation; when persisting at later follow-ups, we might speculate that it could represent an early phase of avascular necrosis of the humeral head. LEVEL OF EVIDENCE: Level III, observational study. PMID- 29116359 TI - Use of automated external defibrillators for in-hospital cardiac arrest : Any time, any place? AB - BACKGROUND: Acute treatment of in-hospital cardiac arrest (IHCA) is challenging and overall survival rates are low. However, data on the use of public-access automated external defibrillators (AEDs) for IHCA remain controversial. The aim of our study was to evaluate characteristics of patients experiencing IHCA and feasibility of public-access AED use for resuscitation in a university hospital. METHODS: IHCA events outside the intensive care unit were analysed over a period of 21 months. Patients' characteristics, AED performance, return of spontaneous circulation (ROSC) and 24 h survival were evaluated. Outcomes following adequate and inadequate AED use were compared. RESULTS: During the study period, 59 IHCAs occurred. AED was used in 28 (47.5%) of the cases. However, AED was adequately used in only 42.8% of total AED cases. AED use was not associated with an increased survival rate (12.9 vs. 10.7%, p = 0.8) compared to non-AED use. However, adequate AED use was associated with a higher survival rate (25 vs. 0%, p = 0.034) compared to inadequate AED use. Time from emergency call to application of AED >3 min was the most important factor of inadequate AED use. Adequate AED use was more often observed between 7:30 and 13:30 and in the internal medicine department. CONCLUSION: AEDs were applied in less than 50% of the IHCA events. Furthermore, AED use was inadequate in the majority of the cases. Since adequate AED use is associated with improved survival, AEDs should be available in hospital areas with patients at high risk of shockable rhythm. PMID- 29116360 TI - Role of the extracellular matrix in the genesis of ventilator-induced lung injury. AB - The extracellular matrix represents the three-dimensional scaffold of the alveolar wall, which is composed of a layer of epithelial and endothelial cells, their basal membrane, and a thin interstitial layer containing fibrous proteins, glycoproteins, glycosaminoglycans, and proteoglycans. Mechanical ventilation with low and high tidal volumes can induce proteoglycan fragmentation, which may cause activation of the inflammatory cascade, leading to the main features of ventilator-induced lung injury (VILI): alveolar edema and collagen deposition. The purpose of this article is to describe VILI pathophysiology with a special focus on the effects of mechanical ventilation on the extracellular matrix. A more complete understanding of the molecular effects induced by physical forces is required to better assess the impact of existing mechanical ventilation strategies, as well as to develop new therapeutic strategies to reduce lung damage. PMID- 29116361 TI - Intermediate care units : Recommendations on facilities and structure. AB - A growing number of patients with increasingly complex or specialized diseases are being treated in hospitals worldwide. The treatment requirements of some of these patients are exceeding the capacity of standard nursing units. However, the severity of these diseases or the treatment requirements for these specific clinical pictures do not always justify admission to an intensive care unit. For this reason, an increasing number of special units (intermediate care units) are being set up to offer highly specialized treatment and close monitoring, in order to fulfil an intermediate role between the standard care unit and the intensive care unit. The recommendations of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) on the personnel, capacity, equipment and structure of these units are intended to provide the framework for the setting up and operation of intermediate care units in collaboration with experts on both an evidence-based and an expert-based basis (where scientific evidence is not available). Where only minimal or indirect evidence is available, patient safety is paramount in the formulation of the recommendation. PMID- 29116362 TI - Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria. AB - Mitochondrial DNA is frequently exposed to oxidative damage, as compared to nuclear DNA. Previously, we have shown that while microhomology-mediated end joining can account for DNA deletions in mitochondria, classical nonhomologous DNA end joining, the predominant double-strand break (DSB) repair pathway in nucleus, is undetectable. In the present study, we investigated the presence of homologous recombination (HR) in mitochondria to maintain its genomic integrity. Biochemical studies revealed that HR-mediated repair of DSBs is more efficient in the mitochondria of testes as compared to that of brain, kidney and spleen. Interestingly, a significant increase in the efficiency of HR was observed when a DSB was introduced. Analyses of the clones suggest that most of the recombinants were generated through reciprocal exchange, while ~ 30% of recombinants were due to gene conversion in testicular extracts. Colocalization and immunoblotting studies showed the presence of RAD51 and MRN complex proteins in the mitochondria and immunodepletion of MRE11, RAD51 or NIBRIN suppressed the HR-mediated repair. Thus, our results reveal importance of homologous recombination in the maintenance of mitochondrial genome stability. PMID- 29116364 TI - Low density lipoprotein receptor-related protein 1 couples beta1 integrin activation to degradation. AB - Low density lipoprotein receptor-related protein (LRP) 1 modulates cell adhesion and motility under normal and pathological conditions. Previous studies documented that LRP1 binds several integrin receptors and mediates their trafficking to the cell surface and endocytosis. However, the mechanism by which LRP1 may regulate integrin activation remains unknown. Here we report that LRP1 promotes the activation and subsequent degradation of beta1 integrin and thus supports cell adhesion, spreading, migration and integrin signaling on fibronectin. LRP1 interacts with surface beta1 integrin, binds the integrin activator kindlin2 and stimulates beta1 integrin-kindlin2 complex formation. Specifically, serine 76 in the LRP1 cytoplasmic tail is crucial for the interaction with kindlin2, beta1 integrin activation and cell adhesion. Interestingly, a loss of LRP1 induces the accumulation of several integrin receptors on the cell surface. Following internalization, intracellular trafficking of integrins is driven by LRP1 in a protein kinase C- and class II myosin-dependent manner. Ultimately, LRP1 dictates the fate of endocytosed beta1 integrin by directing it down the pathway of lysosomal and proteasomal degradation. We propose that LRP1 mediates cell adhesion by orchestrating a multi protein pathway to activate, traffic and degrade integrins. Thus, LRP1 may serve as a focal point in the integrin quality control system to ensure a firm connection to the extracellular matrix. PMID- 29116366 TI - Role of US-guided Percutaneous Drainage in Management of Lower Limb Spontaneous IntraMuscular Hematoma. PMID- 29116365 TI - Acute Biliary Obstruction After Gastroduodenal Covered Self-Expanding Metallic Stent Placement in Patients with Previous Biliary Stent Placement for Periampullary Cancer: Frequency and Protective Factors. AB - PURPOSE: We aimed to evaluate the frequency and protective factors of acute biliary obstruction in patients with biliary stent placement followed by gastroduodenal covered self-expandable metallic stent (SEMS) placement owing to progression of periampullary cancer. MATERIALS AND METHODS: We retrospectively reviewed 58 patients. Total bilirubin and alkaline phosphatase (ALP) levels before and after gastroduodenal covered SEMS placement were evaluated. The incidence of acute biliary obstruction correlated to age, sex, biliary stent length and type, and longitudinal and axial locations of the lower end of the biliary stent was evaluated. RESULTS: Postprocedural total bilirubin and ALP levels were significantly higher than preprocedural levels (2.30 +/- 2.53 vs. 1.53 +/- 1.48 mg/dL; P = 0.008, 331.0 +/- 248.8 vs. 258.4 +/- 195.2 IU/L; P = 0.008, respectively). The increase in bilirubin levels was not statistically significant in female patients or patients with a biliary stent length >= 6 cm or longitudinal location of the lower end of the biliary stent distal to the lower end of the gastroduodenal stent (P > 0.05). Seven patients (12.1%) developed acute biliary obstruction. No patients with the lower end of the biliary stent located distal to the lower end of the gastroduodenal stent developed acute biliary obstruction (P = 0.012). CONCLUSION: The incidence of acute biliary obstruction was 12.1% among patients with biliary stent placement followed by gastroduodenal covered SEMS placement. Longitudinal location of the lower end of the biliary stent distal to the lower end of the gastroduodenal stent was a protective factor. PMID- 29116367 TI - Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences. AB - RATIONALE: Although psilocybin and dextromethorphan (DXM) are hallucinogens, they have different receptor mechanisms of action and have not been directly compared. OBJECTIVE: This study compared subjective, behavioral, and physiological effects of psilocybin and dextromethorphan under conditions that minimized expectancy effects. METHODS: Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use. Instructions to participants and staff minimized expectancy effects. Various subjective, behavioral, and physiological effects were assessed after drug administration. RESULTS: High doses of both drugs produced similar increases in participant ratings of peak overall drug effect strength, with similar times to maximal effect and time-course. Psilocybin produced orderly dose-related increases on most participant-rated subjective measures previously shown sensitive to hallucinogens. DXM produced increases on most of these same measures. However, the high dose of psilocybin produced significantly greater and more diverse visual effects than DXM including greater movement and more frequent, brighter, distinctive, and complex (including textured and kaleidoscopic) images and visions. Compared to DXM, psilocybin also produced significantly greater mystical type and psychologically insightful experiences and greater absorption in music. In contrast, DXM produced larger effects than psilocybin on measures of disembodiment, nausea/emesis, and light-headedness. Both drugs increased systolic blood pressure, heart rate, and pupil dilation and decreased psychomotor performance and balance. CONCLUSIONS: Psilocybin and DXM produced similar profiles of subjective experiences, with psilocybin producing relatively greater visual, mystical-type, insightful, and musical experiences, and DXM producing greater disembodiment. PMID- 29116369 TI - [Posttreatment alterations to the musculoskeletal system]. PMID- 29116363 TI - Molecular roles and function of circular RNAs in eukaryotic cells. AB - Protein-coding and noncoding genes in eukaryotes are typically expressed as linear messenger RNAs, with exons arranged colinearly to their genomic order. Recent advances in sequencing and in mapping RNA reads to reference genomes have revealed that thousands of genes express also covalently closed circular RNAs. Many of these circRNAs are stable and contain exons, but are not translated into proteins. Here, we review the emerging understanding that both, circRNAs produced by co- and posttranscriptional head-to-tail "backsplicing" of a downstream splice donor to a more upstream splice acceptor, as well as circRNAs generated from intronic lariats during colinear splicing, may exhibit physiologically relevant regulatory functions in eukaryotes. We describe how circRNAs impact gene expression of their host gene locus by affecting transcriptional initiation and elongation or splicing, and how they partake in controlling the function of other molecules, for example by interacting with microRNAs and proteins. We conclude with an outlook how circRNA dysregulation affects disease, and how the stability of circRNAs might be exploited in biomedical applications. PMID- 29116368 TI - N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges. AB - RATIONALE: Schizophrenia is associated with prenatal inflammation and/or postnatal stressors such as drug abuse, resulting in immune-redox dysfunction. Antioxidants may offer therapeutic benefits. OBJECTIVES: The objective of this study is to investigate N-acetyl cysteine (NAC) as a therapeutic antioxidant to reverse schizophrenia-like bio-behavioural changes in rats exposed to maternal immune activation (MIA), adolescent methamphetamine (MA) or a combination thereof. METHODS: Sprague-Dawley offspring prenatally exposed to saline/lipopolysaccharide (LPS) received saline or MA (0.2-6 mg kg-1 twice daily * 16 days) during adolescence and divided into LPS, MA and LPS + MA groups. Vehicle/NAC (150 mg kg-1 * 14 days) was administered following MA/saline exposure on postnatal day 51-64. Social interaction, novel object recognition and prepulse inhibition (PPI) of startle, as well as regional brain monoamines, lipid peroxidation, plasma reactive oxygen species (ROS) and pro- and anti-inflammatory cytokines (TNF-alpha; IL-10), were assessed. RESULTS: NAC reversed LPS, MA and LPS + MA-induced anxiety-like social withdrawal behaviours, as well as MA and LPS + MA-induced deficits in recognition memory. PPI deficits were evident in MA, LPS and LPS + MA models, with NAC reversing that following LPS + MA. NAC reversed LPS, MA and LPS + MA-induced frontal cortical dopamine (DA) and noradrenaline (NA) elevations, LPS and LPS + MA-induced frontal cortical 3,4 dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and striatal NA deficits as well as LPS + MA-induced frontal cortical 5-HT turnover. Decreased IL-10 in the LPS, MA and LPS + MA animals, and increased TNF-alpha in the LPS and MA animals, was reversed with NAC. NAC also reversed elevated lipid peroxidation and ROS in the LPS and LPS + MA animals. CONCLUSIONS: Prenatal LPS, LPS + postnatal MA challenge during adolescence, and to a lesser extent MA alone, promotes schizophrenia-like bio-behavioural changes later in life that are reversed by NAC, emphasizing therapeutic potential for schizophrenia and MA-associated psychosis. The nature and timing of the dual-hit are critical. PMID- 29116371 TI - Omicron BetaIotaOmicronSigma TauEta ChiEpsilonIotaRhoOmicronUpsilonRhoGammaIotaKappaEta AlphaNuAlphaPhiUpsilonEpsilonTauAlphaIota. PMID- 29116372 TI - Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model. AB - High-mobility group box 1 (HMGB1) is involved in the tumor-associated activation of regulatory T cells (Treg), but the mechanisms remain unknown. In a mouse tumor model, silencing HMGB1 in tumor cells or inhibiting tumor-derived HMGB1 not only dampened the capacity of tumor cells to produce thymic stromal lymphopoietin (TSLP), but also aborted the tumor-associated modulation of Treg-activating DC. Tumor-derived HMGB1 triggered the production of TSLP by tumor cells. Importantly, both tumor-derived HMGB1 and TSLP were necessary for modulating DC to activate Treg in a TSLP receptor (TSLPR)-dependent manner. In the therapeutic model, intratumorally inhibiting tumor-derived HMGB1 (causing downstream loss of TSLP production) attenuated Treg activation, unleashed tumor-specific CD8 T cell responses, and elicited CD8alpha+/CD103+DC- and T cell-dependent antitumor activity. These results suggest a new pathway for the activation of Treg involving in tumor-derived HMGB1 and TSLP, and have important implications for incorporating HMGB1 inhibitors into cancer immunotherapy. PMID- 29116373 TI - The fundamental theorem of natural selection with mutations. AB - The mutation-selection process is the most fundamental mechanism of evolution. In 1935, R. A. Fisher proved his fundamental theorem of natural selection, providing a model in which the rate of change of mean fitness is equal to the genetic variance of a species. Fisher did not include mutations in his model, but believed that mutations would provide a continual supply of variance resulting in perpetual increase in mean fitness, thus providing a foundation for neo-Darwinian theory. In this paper we re-examine Fisher's Theorem, showing that because it disregards mutations, and because it is invalid beyond one instant in time, it has limited biological relevance. We build a differential equations model from Fisher's first principles with mutations added, and prove a revised theorem showing the rate of change in mean fitness is equal to genetic variance plus a mutational effects term. We refer to our revised theorem as the fundamental theorem of natural selection with mutations. Our expanded theorem, and our associated analyses (analytic computation, numerical simulation, and visualization), provide a clearer understanding of the mutation-selection process, and allow application of biologically realistic parameters such as mutational effects. The expanded theorem has biological implications significantly different from what Fisher had envisioned. PMID- 29116374 TI - [Evidence of anti-infection strategies in trauma surgery]. PMID- 29116376 TI - Gender differences in mortality among statin users aged 80 years or more. AB - BACKGROUND: Little is known about the prognosis associated with statin therapy and its gender differences in older adults aged >=80 years. OBJECTIVE: To study the mortality and survival associated with statin therapy and their gender differences in older adults aged >=80 years. METHOD: This was a historical prospective study conducted at a tertiary medical center. The medical charts of all older adults aged >=80 years who had been admitted to a single internal medicine department during 1 year were reviewed. All-cause 3-year mortality and survival rates following hospital admission in men and in women using statins were investigated. RESULTS: The final cohort included 216 patients: 122 (56.5%) women, mean age 85.3 +/- 3.9 years. Overall, 66 (53.2%) women and 58 (46.8%) men used statins for 3 years or more following hospital admission. During this time 48 (39.3%) women and 48 (51.1%) men died. The all-cause 3-year mortality rates were significantly lower only in women who had used statins compared with women who had not used statins (24.2% vs. 57.1%; relative risk = 0.2; 95% confidence interval 0.1-0.5; p < 0.0001). The 3-year cumulative survival rates were significantly higher in women who had used statins as part of primary as well as secondary cardiovascular prevention (p < 0.0001 and p = 0.014, respectively). A Cox regression analysis showed that statin therapy was independently associated with low 3-year cumulative mortality rates in women (hazard ratio=0.3; 95% confidence interval=0.1-0.6; p = 0.001). CONCLUSION: In older adults aged >=80 years, statin therapy is associated with high 3-year cumulative survival rates only in women. PMID- 29116377 TI - [Effectiveness of preventive house visits for elderly people : Systematic assessment of current literature]. AB - BACKGROUND: Preventive home visits (PHV) document health resources and risks in the domestic environment in order to derive preventive recommendations. An earlier review did not yield reliable proof of their efficacy for the elderly; however, PHV are used increasingly more as a municipal service in Germany. OBJECTIVE: This article evaluates the efficacy of PHV by means of evidence-based criteria. MATERIAL AND METHODS: Independent of the reason, randomized controlled studies (RCT) and systematic reviews on PHV in the elderly (60+ years) that were published after 2004 were identified by means of searching pertinent literature databases. The outcomes evaluated were mortality, hospitalization, admission to nursing home, functional status, falls and quality of life. RESULTS: The 12 RCT included (for the first time including a German trial) showed a high clinical heterogeneity, good methodological quality and only few bias potentials. As few as 6 out of the 12 RCT showed positive effects for individual outcomes, rarely exceeding the period of the intervention and partly limited to individual subgroups; however, almost no negative effects were reported. The four review articles included did not show any reliable proof of efficacy of PHV regarding any of the evaluated outcomes either. CONCLUSION: In the current literature no clear proof of the efficacy of PHV could be identified. No structure or process features having an efficacy regarding several outcomes could be derived either. Thus, the current use of PHV is still being made without any clear evidence of efficacy. PMID- 29116375 TI - Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy. AB - N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CNS pathology and lasting neurological benefits. This finding signifies the first successful post symptomatic treatment of a white matter disorder using an adeno-associated virus vector tailored towards oligodendroglial-restricted transgene expression. PMID- 29116378 TI - Preferential expression of NY-BR-1 and GATA-3 in male breast cancer. AB - BACKGROUND: Male breast cancer is an uncommon disease often discovered in advanced stage; thus, in the setting of metastatic adenocarcinoma, breast origin must be taken to account. Breast markers as NY-BR-1, GATA-3, mammaglobin, and BRST-2 are established tools for labelling primary and metastatic female breast cancer; however, none of them has been sufficiently studied in male breast cancer. The aim of this study was to analyze the expression of these markers in male breast cancer. MATERIALS AND METHODS: Thirty consecutive cases of male breast cancer and eight loco-regional metastases were re-revaluated, assembled in tissue micro array (TMA), and stained with immunohistochemistry (IHC) for NY-BR 1, GATA-3, mammaglobin, and BRST-2. The IHC stains were scored either positive or negative. In addition, concordant expression patterns of primary tumors and matched metastasis were noted. RESULTS: 30 of 30 (100%) primary tumors and 8 of 8 (100%) metastases were positive for NY-BR-1. 30 of 30 (100%) primary tumors and 6 of 8 (75%) metastases were positive for GATA-3. 22 of 30 (73.3%) primary tumors and 6 of 8 (75%) metastases were positive for Mammaglobin. 18 of 30 (60%) primary tumors and 5 of 8 (62.5%) metastases were positive for BRST-2. Differences in staining percentage were not significant with Fisher's exact test. CONCLUSION: We found a high sensitivity for all the markers analyzed. Moreover, the expression of NY-BR-1 and GATA-3 seemed the most effective for labelling male breast cancer in primary and metastatic setting. PMID- 29116379 TI - Phase II study of nedaplatin and irinotecan as adjuvant chemotherapy for completely resected non-small cell lung cancer. AB - INTRODUCTION: Cisplatin-based chemotherapy is the standard adjuvant therapy for patients with completely resected stage II or III non-small cell lung cancer (NSCLC). However, the completion rate of four cycles of cisplatin-based chemotherapy is about 50%. This phase II study was conducted to evaluate the tolerability and efficacy of nedaplatin and irinotecan as adjuvant chemotherapy. METHODS: Patients with pathological stage II or III NSCLC who underwent complete resection were enrolled. Treatment consisted of four cycles of nedaplatin (50 mg/m2) and irinotecan (50 mg/m2) on days 1 and 8 every 4 weeks. The primary end point was the completion rate of four cycles of nedaplatin and irinotecan. RESULTS: Between January 2009 and March 2012, 39 patients (23 males and 16 females; median age 68 years) were registered. Overall, 36/39 (92.3%) patients completed four cycles. The median clinical follow-up time was 56 months (range 11 88 months). There were no differences in adverse events between patients with UGT1A1 polymorphisms and patients with wild-type UGT1A1. The median disease-free survival (DFS) was 49.4 months (95% confidence interval 14.2-84.5 months). Median overall survival (OS) was not reached. There were no treatment-related deaths, and adverse events were acceptable. The 5-year DFS and OS rates were 43.1 and 69.8%, respectively. CONCLUSION: Nedaplatin and irinotecan is a tolerable regimen for adjuvant chemotherapy, and was associated with adequate 5-year DFS and OS rates. PMID- 29116380 TI - Trunk proprioception adaptations to creep deformation. AB - PURPOSE: This study aimed at identifying the short-term effect of creep deformation on the trunk repositioning sense. METHODS: Twenty healthy participants performed two different trunk-repositioning tasks (20 degrees and 30 degrees trunk extension) before and after a prolonged static full trunk flexion of 20 min in order to induce spinal tissue creep. Trunk repositioning error variables, trunk movement time and erector spinae muscle activity were computed and compared between the pre- and post-creep conditions. RESULTS: During the pre-creep condition, significant increases in trunk repositioning errors, as well as trunk movement time, were observed in 30 degrees trunk extension in comparison to 20 degrees . During the post-creep condition, trunk repositioning errors variables were significantly increased only when performing a 20 degrees trunk extension. Erector spinae muscle activity increased in the post-creep condition, while it remained unchanged between trunk repositioning tasks. CONCLUSIONS: Trunk repositioning sense seems to be altered in the presence of creep deformation, especially in a small range of motion. Reduction of proprioception acuity may increase the risk of spinal instability, which is closely related to the risk of low back pain or injury. PMID- 29116382 TI - Selective dorsal rhizotomy for the treatment of severe spastic cerebral palsy: efficacy and therapeutic durability in GMFCS grade IV and V children. AB - BACKGROUND: Selective dorsal rhizotomy (SDR) has been established as an effective surgical treatment for spastic diplegia. The applicability of SDR to the full spectrum of spastic cerebral palsy and the durability of its therapeutic effects remain under investigation. There are currently limited data in the literature regarding efficacy and outcomes following SDR in Gross Motor Function Classification System (GMFCS) IV and V patients. Intrathecal baclofen has traditionally been the surgical treatment of choice for these patients. When utilised primarily as a treatment for the relief of spasticity, it is proposed that SDR represents a rational and effective treatment option for this patient group. We report our outcomes of SDR performed on children with severe cerebral palsy (GMFCS grade IV and V). The commensurate improvement in upper as well as lower limb spasticity is highlighted. Apparent benefit to urological function following SDR in this patient group is also discussed. METHOD: A retrospective review of prospectively collected data for 54 paediatric patients with severe cerebral palsy (GMFCS IV-V) who received SDR plus specialised physiotherapy. Mean age was 10.2 years (range, 3.0-19.5). SDR guided by electrophysiological monitoring was performed by a single experienced neurosurgeon. All subjects received equivalent physiotherapy. The primary outcome measure was change to the degree of spasticity following SDR. Spasticity of upper and lower limb muscle groups were quantified and standardised using the Ashworth score. Measures were collected at baseline and at 2-, 8- and 14-month postoperative intervals. In addition, baseline and 6-month postoperative urological function was also evaluated as a secondary outcome measure. RESULTS: The mean lower limb Ashworth score at baseline was 3.2 (range, 0-4). Following SDR, significant reduction in lower limb spasticity scores was observed at 2 months and maintained at 8 and 14 months postoperatively (Wilcoxon rank, p < 0.001). The mean reduction at 2, 8 and 14 months was 3.0, 3.2 and 3.2 points respectively (range, 1-4), confirming a sustained improvement of spasticity over a 1-year period of follow-up. Significant reduction in upper limb spasticity scores following SDR was also observed (mean, 2.9; Wilcoxon rank, p < 0.001). Overall, the improvement to upper and lower limb tone following SDR-generally to post-treatment Ashworth scores of 0-was clinically and statistically significant in GMFCS IV and V patients. Urological assessment identified pre-existing bladder dysfunction in 70% and 90% of GMFCS IV and V patients respectively. Following SDR, improvement in urinary continence was observed in 71% of affected GMFCS IV and 42.8% of GMFCS V patients. No serious postoperative complications were identified. CONCLUSIONS: We conclude that SDR is safe and-in combination with physiotherapy-effectively reduces spasticity in GMFCS grade IV and V patients. Our series suggests that spastic quadriplegia is effectively managed with significant improvements in upper limb spasticity that are commensurate with those observed in lower limb muscle groups. These gains are furthermore sustained more than a year postoperatively. In light of these findings, we propose that SDR constitutes an effective treatment option for GMFCS IV and V patients and a rational alternative to intrathecal baclofen. PMID- 29116381 TI - Expression and function of the zinc finger transcription factor Sp6-9 in the spider Parasteatoda tepidariorum. AB - Zinc finger transcription factors of the Sp6-9 group are evolutionarily conserved in all metazoans and have important functions in, e.g., limb formation and heart development. The function of Sp6-9-related genes has been studied in a number of vertebrates and invertebrates, but data from chelicerates (spiders and allies) was lacking so far. We have isolated the ortholog of Sp6-9 from the common house spider Parasteatoda tepidariorum and the cellar spider Pholcus phalangioides. We show that the Sp6-9 gene in these spider species is expressed in the developing appendages thus suggesting a conserved role in limb formation. Indeed, RNAi with Sp6-9 in P. tepidariorum leads not only to strong limb defects, but also to the loss of body segments and head defects in more strongly affected animals. Together with a new expression domain in the early embryo, these data suggest that Sp6-9 has a dual role P. tepidariorum. The early role in head and body segment formation is not known from other arthropods, but the role in limb formation is evolutionarily highly conserved. PMID- 29116383 TI - Deep brain stimulation: custom-made silicone-coated pulse-generator implantation after allergic reaction to generator compounds. AB - Deep brain stimulation for Parkinson's disease has become an established treatment option in recent years. The method and its application in clinical practice has proved to be safe and effective. Nevertheless, procedure-related and hardware-related complications occur. We present a rare case of a patient with an allergic reaction to the impulse generator. The patient suffered from delayed wound-healing deficits with several wound revisions and generator repositionings. After diagnosis of an allergic reaction to components of the generator, a custom made silicon-coated model was implanted. Hereafter, no wound healing-deficit occurred throughout long-term follow-up. Allergic reaction to hardware components may lead to wound-healing deficits. In such cases, custom-made silicon-coated models may be an effective treatment option. PMID- 29116384 TI - Living with otosclerosis: disease-specific health-related quality-of-life measurement in patients undergoing stapes surgery. AB - INTRODUCTION: Otosclerosis is associated with hearing disability, leading to communication deficits and social and psychological restrictions. The objective of our study was to analyze disease-specific health-related quality of life (HRQOL) after stapes surgery and compare the outcome of HRQOL with audiometric parameters. SUBJECTS AND METHODS: Our clinical case study was conducted at two tertiary referral centers. All the 37 patients who had undergone stapes surgery were analyzed clinically and by audiometric testing (pure tone and speech audiometry) in the pre- and postoperative settings. Disease-specific HRQOL was assessed by the validated Stapesplasty Outcome Test 25 (SPOT-25) pre- and postoperatively. The subjective hearing disability was evaluated by the hearing handicap inventory for adults (HHIA). The postinterventional benefit was measured by the Glasgow Benefit Inventory (GBI). RESULTS: Disease-specific HRQOL improved significantly after stapes surgery in all scales of the SPOT-25. Postoperatively, the total score and the subscore "hearing function" correlated well with the audiometric data. The subscores "tinnitus", "social restrictions", and "mental condition" did not show significant association with audiometric parameters. The comparison of pre- and postoperative HHIA offered a significant improvement in the hearing disability. The scores of the HHIA correlated very well with the audiometric data. The GBI showed a postoperative benefit for each individual patient. CONCLUSION: Stapes surgery leads to a significant improvement in the hearing handicap and of disease-specific HRQOL. The audiometric parameters were shown as not being a sufficient indicator of social and mental well-being. HRQOL outcome measuring instruments should be used routinely in clinical practice to provide an individualized postoperative assessment. PMID- 29116385 TI - Hearing eyeball and/or eyelid movements on the side of a unilateral superior semicircular canal dehiscence. AB - Hearing of eyeball movements has been reported in superior semicircular canal dehiscence (SSCD), but not hearing of eyelid movements. Our main objective was to report the hearing of eyeball and/or eyelid movements in unilateral SSCD. Our secondary objective was to access its specificity to SSCD and discuss the underlying mechanism. Six patients with SSCD who could hear their eyeball and/or eyelid movements were retrospectively reviewed. With the aim of comparisons, eight patients with an enlarged vestibular aqueduct (EVA), who share the same mechanism of an abnormal third window, were questioned on their ability to hear their eyeball and/or eyelid movements. Three patients with SSCD could hear both their eyeball and eyelid movements as a soft low-pitch friction sound. Two patients with SSCD could hear only their eyelid movements, one of whom after the surgery of a traumatic chronic subdural hematoma. The latter remarked that every gently tapping on the skin covering the burr-hole was heard in his dehiscent ear as the sound produced when banging on a drum, in keeping with a direct transmission of the sound to the inner ear via the cerebrospinal fluid. One patient with SSCD, who could hear only his eyeball movements, had other disabling symptoms deserving operation through a middle fossa approach with an immediate relief of his symptoms. None of the eight patients with EVA could hear his/her eyeball or eyelid movements. Hearing of eyeball and/or eyelid movements is highly suggestive of a SSCD and do not seem to occur in EVA. In case of radiological SSCD, clinicians should search for hearing of eyeball and/or eyelid movements providing arguments for a symptomatic dehiscence. The underlying mechanism is discussed particularly the role of a cerebrospinal fluid transmission. PMID- 29116386 TI - Clinical and ultrasonographic enthesopathy in inflammatory rheumatic diseases : Is MASEI or only calcaneal enthesitis sufficient? AB - AIM: We aimed at investigating the ultrasonographic (US) and clinical prevalence of enthesopathy in patients with rheumatoid arthritis (RA), and axial spondyloarthropathy (SpA), as well as the correlation between this condition and disease activity, along with the quality of life. METHODS: Included in the study were 30 axial SpA, 21 patients with RA, and 25 healthy cases. Bath Anklylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Quality of Life (ASQoL), Disease activity index 28 (DAS28), and Health Assessment Questionnaire (HAQ) were used for clinical evaluation, and enthesal pain was evaluated by VAS, whereas enthesitis US evaluation was performed by using the MAdrid Sonographic Enthesitis Index (MASEI). A total of 152 knees, ankles, and elbow regions of all patients and controls were examined by US. RESULTS: Total scores of physical examination of enthesitis were 1.97 +/- 2.68 in axial SpA, 2.43 +/- 1.80 in RA, and 0.23 +/- 0.12 in the control groups. No statistically significant difference was identified in the enthesitis examination between axial SpA and RA groups (p = 0.123). According to the MASEI, no significant difference was observed in quadriceps tendon enthesitis or in distal patellar ligament enthesitis between axial SpA and RA groups (MASEI 3, 4, 5: p = 0.993, p = 0.124, p = 0.652). Aside from those points, axial SpA patients had statistically higher enthesitis scores at all MASEI enthesitis points (p < 0.05). In the axial SpA group, a significant and positive correlation was identified between BASDAI scores and total scores of enthesitis physical examination and MASEI total scores (r = 0.739, p = 0.0001, r = 0.516, p = 0.002). A moderately significant correlation was identified between ASQoL total scores and MASEI total scores (r = 0.466, p = 0.006), but not between the HAQ total scores and MASEI total scores (r = 0.213, p = 0.065). CONCLUSIONS: Compared to RA, US and clinical examination of enthesitis in patients with axial SpA should focus on the calcaneal enthesitis region. In axial SpA, ultrasonographic enthesitis is associated with impaired quality of life. PMID- 29116387 TI - [Imaging of the sacroiliac joints]. AB - The sacroiliac joints (SIJ) are an important part of the axial skeleton and a main area to consider in the examination of back pain both clinically and on imaging. Patients with inflammatory-rheumatic symptoms as well as those with other diagnoses may present with pathological changes in the SIJ even at young ages. Although imaging of the SIJ is not the only factor in approaching the final diagnosis, it nevertheless provides a lot of important information about differential diagnoses, thereby enabling certain causes of back pain to be excluded. Overall, there are four important imaging methods that are being used to evaluate the SIJ in daily routine: conventional radiographs, computed tomography, scintigraphy and magnetic resonance imaging (MRI). In recent years, most of the scientific work on imaging of the SIJs has concentrated on a better understanding of the MRI in this context. This overview article describes the advantages and limitations of the different imaging techniques for the visualization of pathologic changes in the SIJ, also taking into account their value in helping the treating physician to make diagnostic and therapeutic decisions in daily clinical practice. PMID- 29116389 TI - Development of CD3 cell quantitation algorithms for renal allograft biopsy rejection assessment utilizing open source image analysis software. AB - Renal allograft rejection diagnosis depends on assessment of parameters such as interstitial inflammation; however, studies have shown interobserver variability regarding interstitial inflammation assessment. Since automated image analysis quantitation can be reproducible, we devised customized analysis methods for CD3+ T-cell staining density as a measure of rejection severity and compared them with established commercial methods along with visual assessment. Renal biopsy CD3 immunohistochemistry slides (n = 45), including renal allografts with various degrees of acute cellular rejection (ACR) were scanned for whole slide images (WSIs). Inflammation was quantitated in the WSIs using pathologist visual assessment, commercial algorithms (Aperio nuclear algorithm for CD3+ cells/mm2 and Aperio positive pixel count algorithm), and customized open source algorithms developed in ImageJ with thresholding/positive pixel counting (custom CD3+%) and identification of pixels fulfilling "maxima" criteria for CD3 expression (custom CD3+ cells/mm2). Based on visual inspections of "markup" images, CD3 quantitation algorithms produced adequate accuracy. Additionally, CD3 quantitation algorithms correlated between each other and also with visual assessment in a statistically significant manner (r = 0.44 to 0.94, p = 0.003 to < 0.0001). Methods for assessing inflammation suggested a progression through the tubulointerstitial ACR grades, with statistically different results in borderline versus other ACR types, in all but the custom methods. Assessment of CD3-stained slides using various open source image analysis algorithms presents salient correlations with established methods of CD3 quantitation. These analysis techniques are promising and highly customizable, providing a form of on-slide "flow cytometry" that can facilitate additional diagnostic accuracy in tissue-based assessments. PMID- 29116388 TI - The evolutionarily conserved factor Sus1/ENY2 plays a role in telomere length maintenance. AB - Sus1 is a conserved protein involved in histone H2B de-ubiquitination and mRNA export from the nucleus in eukaryotes. Previous studies implicated Sus1 partners in genome integrity including telomere homeostasis. However, the implication of Sus1 in telomere maintenance remains largely unknown. In this study, we found that yeast Sus1 interacts physically and genetically with factors involved in telomere maintenance and its absence leads to elongated telomeres. Deletion of several of Sus1's partners also leads to longer telomeres. Our results rule out a direct role for Sus1 in recruiting telomerase subunits to telomeres. However, we observe that deletion of SUS1 leads to elongated telomeres even in the presence of mutations like sem1Delta, esc2Delta and rsc2Delta, which cause telomere shortening. We find that rsc2Delta (short telomeres) have reduced levels of mono ubiquitinated histone H2B at lysine 123 (H2BK123ub1), whereas sus1Delta mutants or double-mutants sus1Delta rsc2Delta exhibit longer telomeres and higher H2BK123ub1 levels. These results suggest that Sus1 activity as a H2B de ubiquitination modulator plays a role in negatively regulating telomere length. Our results provide solid evidence for a role of Sus1 in negatively regulating telomere length through the modulation of H2BK123 mono-ubiquitination and its interaction with the nuclear pore complex. PMID- 29116390 TI - CAD-RADS - a new clinical decision support tool for coronary computed tomography angiography. AB - : Coronary computed tomography angiography (CTA) has been established as an accurate method to non-invasively assess coronary artery disease (CAD). The proposed 'Coronary Artery Disease Reporting and Data System' (CAD-RADS) may enable standardised reporting of the broad spectrum of coronary CTA findings related to the presence, extent and composition of coronary atherosclerosis. The CAD-RADS classification is a comprehensive tool for summarising findings on a per patient-basis dependent on the highest-grade coronary artery lesion, ranging from CAD-RADS 0 (absence of CAD) to CAD-RADS 5 (total occlusion of a coronary artery). In addition, it provides suggestions for clinical management for each classification, including further testing and therapeutic options. Despite some limitations, CAD-RADS may facilitate improved communication between imagers and patient caregivers. As such, CAD-RADS may enable a more efficient use of coronary CTA leading to more accurate utilisation of invasive coronary angiograms. Furthermore, widespread use of CAD-RADS may facilitate registry-based research of diagnostic and prognostic aspects of CTA. KEY POINTS: * CAD-RADS is a tool for standardising coronary CTA reports. * CAD-RADS includes clinical treatment recommendations based on CTA findings. * CAD-RADS has the potential to reduce variability of CTA reports. PMID- 29116392 TI - Anchoring and resulting primary stability of a kinked compared to a straight uncemented femoral stem. AB - INTRODUCTION: The number of revision hip arthroplasties being performed is growing and implantation of a cementless stem has become established as the gold standard. For producing a primary stability, the press-fit procedure is the method of choice, but also can be achieved by multiple-point impactions. Specific femoral stems should follow the anatomical shape and provide a more extensive anchorage. The objective of this study was to evaluate the type, localization of the impaction and resulting primary stability of two different femoral revision stem designs (kinked vs. straight) after implantation via an endofemoral approach in the case of more extensive defects of the proximal femur. MATERIALS AND METHODS: Cementless stems of two different designs were implanted in synthetic femurs. The specimens were analyzed by CT and tested considering axial/torsional stiffness and migration resistance in a servohydraulic testing machine. RESULTS: The present data do not show any significant differences between the two endofemorally implanted conical stems in contact area or in biomechanics with regard to migration and axial or torsional stiffness, despite having different designs. CONCLUSIONS: The location, type and length of the stem anchorage are not only influenced by the kinked or straight design, but in particular also by the surgical approach. Also in the case of an extensive proximal bone defect, in the endofemoral approach, both a conical and a three-point anchorage occur. Here, the length of the conical anchorage determines the primary stability and should be at least 55 mm. PMID- 29116393 TI - Reconsidering the role of pelvic lymph node dissection with radical prostatectomy for prostate cancer in an era of improving radiological staging techniques. AB - BACKGROUND: Performing an extended pelvic lymph node dissection (PLND) on all men with intermediate- and high-risk prostate cancer at the time of a radical prostatectomy (RP) remains controversial. The majority of patients PLND histology is benign, and the long-term cancer-free progression in men with positive lymph node metastasis is low. The objective is to investigate the probability of long term biochemical freedom from recurrent disease (bNED) in men with lymph node metastasis identified at the time of radical prostatectomy (RP). SUBJECTS AND METHODS: A retrospective review of the pathology of 1184 pelvic lymph node dissections performed at the time of a radical prostatectomy by multiple surgeons referred to a single uro-pathology laboratory between 2008 and 2014 identified 61 men with node-positive prostate cancer. Of the men with positive nodes, 24 had a standard PLND and 37 an extended PLND (ePLND). bNED was defined as a post operative serum PSA < 0.2 ng/ml. RESULTS: The median follow-up is 4 years (2-8). The median lymph node count was 7 (range 2-16) for PLND and 22 (range 6-46) for the ePLND. A single lymph node metastasis was identified in 56% of the 61 men. Only 10% of men with a positive lymph node metastasis remained free of biochemical recurrence of disease, and only 5% had undetectable serum PSA. There was no difference in bNED outcome between a PLND and ePLND. The number of men needed to be treated with a PLND at the time of RP (NNT) to result in an undetectable post-operative PSA at a median follow-up of 4 years is 395. CONCLUSIONS: In men with lymph node metastasis, the probability of long-term bNED is low and the NNT for cure is high. With emerging improved radiological imaging techniques increasing the detection of lymph node metastasis outside the extended lymph node dissection templates, more scientific investigation is required to evaluate which men will benefit from a PLND and which men can avoid an unnecessary PLND procedure. PMID- 29116391 TI - Role of percutaneous cholecystostomy for acute acalculous cholecystitis: clinical outcomes of 271 patients. AB - OBJECTIVES: To examine the outcomes of percutaneous cholecystostomy (PC) in patients with acute acalculous cholecystitis (AAC). METHODS: The study population comprised 271 patients (mean age, 72 years; range, 22-97 years, male, n=169) with AAC treated with PC with or without subsequent cholecystectomy. Clinical data from total 271 patients were analysed, and outcomes were assessed according to whether the catheter was removed or remained indwelling. Patient survival and recurrence rates were calculated. RESULTS: Symptom resolution and significant improvement of laboratory test values were achieved in 235 patients (86.7%) within 4 days after PC. Complications occurred in six patients (2.2%). Interval elective cholecystectomy was performed in 127 (46.8%) patients. Among the remaining 121 patients, successful removal of the PC catheter was achieved in 88 patients (72.7%) at a mean of 30 days (range, 4-365 days). Of the catheter removal group, 86/88 (97.7%) were successfully treated with the initial PC, whereas two (2.3%) experienced recurrence of cholecystitis. Cumulative recurrence rates were 1.1%, 2.7%, and 2.7% at 1, 2, and 8 years, respectively. CONCLUSIONS: The good therapeutic outcomes of PC and low recurrence rate suggest that PC can be a definitive treatment option in the majority of AAC patients. KEY POINTS: * Many patients with AAC are too ill to undergo cholecystectomy. * PC in AAC patients shows low complication and recurrence rate. * PC solely can be a definitive treatment option in the majority of AAC patients. PMID- 29116394 TI - A prospective randomized pilot study evaluating an ERAS protocol versus a standard protocol for patients treated with radical cystectomy and urinary diversion for bladder cancer. AB - PURPOSE: There is a lack of evidence demonstrating the benefits of using enhanced recovery after surgery protocols (ERAS). Here, we propose to use a randomized clinical pilot study to demonstrate the benefits and feasibility of implementing ERAS versus standard protocols (SP) in patients undergoing radical cystectomy (RC) and urinary diversion. METHODS: 27 consecutive patients undergoing RC were included in the study. 12 patients were prospectively randomized to follow an ERAS protocol and 15 patients followed an SP. Duration of hospital stay, time to first flatulence and bowel movement, complications and 30 day readmission rates, as well as subjective outcomes such as postoperative pain, nausea, bowel symptoms, quality of life (QoL), and patient experience and satisfaction were evaluated. RESULTS: Patients following ERAS had a significantly shorter: hospital stay, time to flatulence, and time to bowel movement than patients following SP. No major complications were reported. Only one patient in the ERAS group was readmitted for bowel obstruction, and no patients were readmitted in the SP group. Patients under ERAS reported lower postoperative pain scores. Mean Functional Assessment of Cancer Therapy Bladder Cancer score decreased and mean Expanded Prostate Cancer Index Composite, bowel symptom score increased in the SP group at the time of discharge compared to prior to surgery. CONCLUSIONS: This study shows the feasibility of a randomized pilot study assessing ERAS compared to SP post RC. ERAS protocol provided evidence of significant benefits over SP with similar complication rates. This study suggests the need for a clinical trial of assessing ERAS protocols after RC. PMID- 29116395 TI - Correlations between sedimentation sign, dural sac cross-sectional area, and clinical symptoms of degenerative lumbar spinal stenosis. AB - PURPOSE: In this study, we addressed the correlation between the cross-sectional area (CSA) of the dural sac and the nerve root sedimentation sign (SedSign) and the correlation between the distance of claudication and the CSA of the dural sac or SedSign in patients with lumbar spinal stenosis. We also evaluated the reliability of clinical symptom prediction. METHODS: We checked claudication distance using a questionnaire, and we gauged low back pain when standing, referred pain, and radiating pain using visual analog scale scores. Three observers measured the CSA of the dural sac and SedSign, and normal nerve root sedimentation was classified as negative (N) and the absence of nerve root sedimentation was positive (P). P was sub-classified as positive with room [P(+); empty space apparent in the dura] or positive without room [P(-); no empty space in the dura]. SedSign reflected ongoing sedimentation inside the spinal canal of the nerve roots. We demonstrated negative sedimentation for the nerve root except for exiting nerve roots that settled into more than half of the dorsal region of the spinal canal and positive sedimentation as compressed nerve roots or as distribution of nerve roots that conglomerated from the ventral to the dorsal part of the equator as nerve roots. We evaluated functional outcomes using the Oswestry Disability Index and Roland-Morris Disability Questionnaire. One-way ANOVAs, Chi square tests, and correlation analyses evaluated the correlation CSAs and SedSigns. RESULTS: The total CSAs for the 716 sites were 98.63 +/- 34.38 for N, 76.78 +/- 28.78 for P(+), and 55.43 +/- 27.77 for P(-), which were all statistically significant (p = 0.01). The correlations between pain and SedSign were not statistically significant (p > 0.05). There was no statistical significance in the correlations between the distance of the claudication and the CSA of the dura sac and the SedSign and between the functional score and the SedSign (both p > 0.05). CONCLUSIONS: Increasing severity of SedSign indicates progressively smaller dural sac CSA, but there is an inconsistent association with clinical symptoms. Therefore, it is reasonable to suggest that spinal stenosis is severe in patients with severe symptoms. PMID- 29116396 TI - Length of stay for childbirth in Trentino (North-East of Italy): the impact of maternal characteristics and organizational features of the maternity unit on the probability of early discharge of healthy, term infants. AB - : Early discharge (ED) of healthy term infants has become a common practice due to current social and economic needs. The primary objective of the present study was to evaluate trends in early discharge of healthy term neonates (>= 37 gestational weeks) by delivery method (cesarean and vaginal) in maternity units in the Province of Trento. The secondary objective was to identify the socio demographic characteristics (including the area of residence and distance from the designated hospital) and clinical characteristics of mothers whose infants were discharged early. This retrospective study reviewed records of live births from 2006 to 2016, for a total of 45, 314 healthy term infants. The trend for ED grew significantly during the period 2006-2016, for both cesarean and vaginal deliveries. The multiple logistic regression analysis shows how the determinants of ED are maternal age, birth order, citizenship of mother, maternal smoking, maternal employment status, and the number of births at the hospital on the day of birth. CONCLUSION: The post-partum length of stay should be adjusted based on the characteristics and needs of the mother-infant dyad, identifying the criteria for safe discharge. In Trento, various procedures and programs are becoming more uniform today with the intention to provide family assistance service. What is Known: * Admission for childbirth is one of the primary causes of hospitalization in industrialized countries. * The length of stay for childbirth has been steadily declining in recent decades, with the aim of reducing costs while also demedicalizing pregnancy. What is New: * A higher rate of early discharge (ED) was recorded for neonates of women having foreign citizenship, < 30 years, pluriparous, smoked during pregnancy, housewife, and, if emplyed, entrepreneurs, self-employed professionals or managers. * ED was more common when the new mother gave birth on a day in which there was a higher number of births at the hospital, indicating overcrowding in the maternity unit. PMID- 29116397 TI - Do we need repeated weight measurements to assess dehydration in children with acute gastroenteritis at the emergency department? PMID- 29116398 TI - Predictive factors for corrective effect of inferior rectus recession for congenital superior oblique palsy. AB - PURPOSE: To identify preoperative factors associated with the surgical corrective effect of contralateral inferior rectus recession (IRR) for vertical deviation in patients with congenital superior oblique palsy (SOP). METHODS: This retrospective study included 20 treatment-naive patients with unilateral congenital SOP (age range, 6-79 years) who underwent contralateral IRR according to our basic policy to select IRR for paretic eye fixation. The corrective effect ( degrees /mm) of IRR was defined as the difference in the vertical deviation at the primary gaze position between before and 6-18 months after surgery per distance of recession. We also measured the preoperative vertical deviation at primary and secondary gaze positions, and vertical deviation with head-tilting, and calculated the difference in vertical deviation between these positions. We analyzed the correlation between the corrective effect of IRR and these study parameters. RESULTS: The mean corrective effect of IRR was 2.4 +/- 1.6 degrees /mm, which had a significant correlation with preoperative differences in vertical deviation between the primary gaze position and the downward (P = 0.004, r = -0.61) and contralateral gaze positions (P = 0.03, r = -0.48); and the presence of preoperative stereopsis (P = 0.02, r = -0.51). After excluding a statistical outlier, the correlation between the corrective effect and the difference between the primary and contralateral gaze positions was no longer significant (P = 0.07), while the other two relationships remained significant. CONCLUSIONS: Our findings suggest that preoperative differences in vertical deviation between the primary and downward gaze positions and the presence of preoperative stereopsis are important considerations prior to performing IRR for congenital SOP, particularly with paretic eye fixation. PMID- 29116399 TI - Intravitreal bevacizumab for neovascular glaucoma in uveal melanoma treated by proton beam therapy. AB - BACKGROUND: To evaluate the efficacy of bevacizumab on reduction of the enucleation rate and control of intraocular pressure (IOP) in neovascular glaucoma (NVG)-complicating proton beam therapy for UM and to identify the determinants of the efficacy of bevacizumab. METHODS: Retrospective comparative study of patients with rubeosis following proton therapy for uveal melanoma. Patients were divided into two groups: a bevacizumab group and a control group which comprised two subgroups: panretinal photocoagulation (PRP)/cryotherapy and observation subgroups. Bevacizumab was administered by three intravitreal injections at 1-month intervals. A second series of injections was administered when necessary. Data concerning IOP and the secondary enucleation rate were collected and compared between the two groups. Univariate and multivariate analyses were performed to determine predictive factors of response to bevacizumab. RESULTS: A total of 169 patients who developed rubeosis following proton therapy between 2006 and 2016 were included: 44 patients in the bevacizumab group and 125 in the control group (38 in the PRP/cryotherapy subgroup and 87 in the observation subgroup). The two groups presented the same baseline characteristics apart from hypertension, retro-equatorial site, and proximity of the optic disk, which were more frequent in the control group, while initial retinal detachment and larger tumor volume were more frequent in the bevacizumab group. After a mean follow-up of 31 months, IOP was less than 21 mmHg in 54.54% of patients after IVB versus 72.7% before treatment (p = 0.06). Statistical analysis did not reveal any statistically significant reduction of the enucleation rate in the bevacizumab group compared to the observational group, whereas the PRP/cryotherapy group showed better eye retention rate (p = 0.15). No enucleation was performed when IOP was < 21 mmHg before IVB. Multivariate analysis identified initial IOP < 21 mmHg and UM situated away from the macula as predictive factors of good response to bevacizumab. CONCLUSION: Despite the improvement of IOP level, intravitreal bevacizumab (IVB) did not reduce the overall enucleation rate in NVG following proton beam therapy. Nevertheless, this treatment was effective in the early phases of NVG or as preventive treatment. PRP remains a valid treatment for NVG. PMID- 29116401 TI - Elucidation of rubber biosynthesis and accumulation in the rubber producing shrub, guayule (Parthenium argentatum Gray). AB - MAIN CONCLUSION: Guayule biosynthesizes and accumulates rubber particles predominantly in epithelial cells in the parenchyma tissue, and this biosynthesis and accumulation is accompanied by remodeling of the roles of epithelial cells. The mechanism underlying the biosynthesis and accumulation of large quantities of rubber particles and resin in the parenchyma tissue of the stem bark of guayule (Parthenium argentatum Gray) remained unanswered up to now. Here, we focused on rubber particle biosynthesis and accumulation in guayule and performed histochemical analyses using a lipophilic fluorescent dye specific for lipids and spectral confocal laser scanning microscopy. Unmixing images were constructed based on specific spectra of cis-polyisoprene and resin and showed that guayule accumulates a large amount of resin in the resin canals in parenchyma tissue and in pith. Interestingly, the fluorescence signals of rubber were predominantly detected in a specific single layer of epithelial cells around the resin canals. These epithelial cells accumulated large rubber particles and essentially no resin. Immunoblotting and immunostaining of guayule homologue of small rubber particle proteins (GHS), which contributes to the biosynthesis of rubber in guayule, showed that GHS is one of several small rubber particle proteins and is localized around rubber particles in epithelial cells. De novo sequencing of the rubber particle proteins showed the presence of all known organelle proteins, suggesting that epithelial cells biosynthesize rubber particles, followed by remodeling of the cells for the accumulation of rubber particles with subsequent decomposition of the organelles. These results indicate that epithelial cells around resin canals are bifunctional cells dedicated to the biosynthesis and accumulation of rubber particles. PMID- 29116400 TI - Effect of salt stress on fatty acid and alpha-tocopherol metabolism in two desert shrub species. AB - MAIN CONCLUSIONS: Compared to Artemisia ordosiea Kraschen, a higher content of alpha-tocopherol in Artemisia sphaerocephala Kraschen under salt stress inhibits the conversion of linoleic acid (C18:2) into linolenic acid (C18:3), maintains cell membrane stability and contributes to higher salt resistance. Artemisia sphaerocephala Kraschen and Artemisia ordosiea Kraschen are widely distributed in the arid and semiarid desert regions of the northwest of China. Under salt stress, it has been known that alpha-tocopherol (alpha-T) improves membrane permeability and maintains Na+/K+ homeostasis; however, the function of alpha-T in regulating membrane components of fatty acids is unknown. In this study, 100 day-old plants of A. ordosiea and A. sphaerocephala are subjected to various NaCl treatments for 7, 14, and 21 days. Compared to A. ordosiea, A. sphaerocephala has a higher Na+ concentration, higher chlorophyll content and dry weight in all NaCl treatments, but lower relative electric conductivity. The stable unsaturated levels of the lipids in A. sphaerocephala may be attributed to higher level of C18:2. Under 200 mM NaCl treatment, alpha-T and C18:2 contents in A. sphaerocephala increase significantly, while the Na+, C18:1, C18:3 and jasmonic acid (JA) contents decrease. Moreover, alpha-T is positively correlated with C18:2, but negatively correlated with C18:3. PMID- 29116402 TI - A critical review of the prion hypothesis of human synucleinopathies. AB - Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are neurodegenerative disorders which have been pathologically classified as synucleinopathies, since they are associated with pathognomonic deposits of misfolded alpha-synuclein in cells of the nervous system. Recently PD, DLB, and MSA were also suggested to be prion-like disorders. Much controversy exists regarding this analogy between synucleinopathies and prion diseases. Here, we discuss what characterizes prion diseases and in which way synucleinopathies may be considered prion-like or -unlike. We critically review recent clinical and in vivo evidence from transmission studies to animals in support of or questioning the prion hypothesis of human synucleinopathies. We conclude that, although PD, DLB, and MSA fulfill many criteria of prion-likeness, they also still fail some of these criteria. PMID- 29116403 TI - Style morphology and pollen tube pathway. AB - The style morphology and anatomy vary among different species. Three basic types are: open, closed, and semi-closed. Cells involved in the pollen tube pathway in the different types of styles present abundant endoplasmic reticulum, dictyosomes, mitochondria, and ribosomes. These secretory characteristics are related to the secretion where pollen tube grows. This secretion can be represented by the substances either in the canal or in the intercellular matrix or in the cell wall. Most studies suggest that pollen tubes only grow through the secretion of the canal in open styles. However, some species present pollen tubes that penetrate the epithelial cells of the canal, or grow through the middle lamella between these cells and subepithelial cells. In species with a closed style, a pathway is provided by the presence of an extracellular matrix, or by the thickened cell walls of the stylar transmitting tissue. There are reports in some species where pollen tubes can also penetrate the transmitting tissue cells and continue their growth through the cell lumen. In this review, we define subtypes of styles according to the path of the pollen tube. Style types were mapped on an angiosperm phylogenetic tree following the maximum parsimony principle. In line with this, it could be hypothesized that: the open style appeared in the early divergent angiosperms; the closed type of style originated in Asparagales, Poales, and Eudicots; and the semi-closed style appeared in Rosids, Ericales, and Gentianales. The open style seems to have been lost in core Eudicots, with reversions in some Rosids and Asterids. PMID- 29116404 TI - Review of Cardiometabolic Effects of Prescription Omega-3 Fatty Acids. AB - PURPOSE OF REVIEW: Populations with significant dietary fish intake tend to have lower cardiovascular (CV) risk and demonstrable physiologic differences including lower lipid/lipoprotein levels and other direct and indirect effects on the arterial wall and inhibiting factors that promote atherosclerosis. Treatment with high doses of pharmacologic-grade omega-3 fatty acid (n-3FA) supplements achieves significant reductions in triglycerides (TG), non-high-density lipoprotein- (non HDL-) and TG-rich lipoprotein- (TRL-) cholesterol levels. n-3FA supplements have significant effects on markers of atherosclerosis risk including endothelial function, low-density lipoprotein (LDL) oxidation, cellular and humoral markers of inflammation, hemodynamic factors, and plaque stabilization. This review summarizes the lipid and cardiometabolic effects of prescription-grade n-3FAs and will discuss clinical trials, national/organizational guidelines, and expert opinion on the impact of supplemental n-3FAs on CV health and disease. RECENT FINDINGS: Clinical trial evidence supports use of n-3FAs in individuals with established atherosclerotic cardiovascular disease (ASCVD), but the data either does not support or is lacking for other types of cardiometabolic risk including prevention of stroke, treatment in patients with heart failure, diabetes mellitus and prediabetes, and for primary prevention in the general population. Despite inconsistent findings to support widespread benefit, there is persistent population-wide enthusiasm for n-3FA as a dietary supplement for its cardiometabolic benefits. Fortunately, there are ongoing clinical trials to assess whether the lipid/lipoprotein benefits may be extended to other at-risk populations and whether lower-dose therapy may provide background benefit for primary prevention of ASCVD. PMID- 29116405 TI - Systematic Review of Studies Reporting Positive Surgical Margins After Bladder Neck Sparing Radical Prostatectomy. AB - PURPOSE OF REVIEW: Bladder neck preservation (BNP) during radical prostatectomy (RP) has been proposed as a method to improve early recovery of urinary continence after radical prostatectomy. However, there is concern over a possible increase in the risk of positive surgical margins and prostate cancer recurrence rate. A recent systematic review and meta-analysis reported improved early recovery and overall long-term urinary continence without compromising oncologic control. The aim of our study was to perform a critical review of the literature to assess the impact on bladder neck and base margins after bladder neck sparing radical prostatectomy. EVIDENCE ACQUISITION: We carried out a systematic review of the literature using Pubmed, Scopus and Cochrane library databases in May 2017 using medical subject headings and free-text protocol according to PRISMA guidelines. We used the following search terms: bladder neck preservation, prostate cancer, radical prostatectomy and surgical margins. Studies focusing on positive surgical margins (PSM) in bladder neck sparing RP pertinent to the objective of this review were included. EVIDENCE SYNTHESIS: Overall, we found 15 relevant studies reporting overall and site-specific positive surgical margins rate after bladder neck sparing radical prostatectomy. This included two RCTs, seven prospective comparative studies, two retrospective comparative studies and four case series. All studies were published between 1993 and 2015 with sample sizes ranging between 50 and 1067. Surgical approaches included open, laparoscopic and robot-assisted radical prostatectomy. The overall and base specific PSM rates ranged between 7-36% and 0-16.3%, respectively. Mean base PSM was 4.9% in those patients where bladder neck sparing was performed, but only 1.85% in those without sparing. Bladder neck preservation during radical prostatectomy may increase base-positive margins. Further studies are needed to better investigate the impact of this technique on oncological outcomes. A future paradigm could include modification of intended approach to bladder neck dissection when anterior base lesions are identified on pre-operative MRI. PMID- 29116406 TI - A survey of patient and physician acceptance of skin toxicities from anti epidermal growth factor receptor therapies. AB - BACKGROUND: Inhibition of the epidermal growth factor receptor (EGFR) extends patient survival in multiple tumor types. Skin toxicities are the most common adverse event (AE) elicited by EGFR inhibitors. Here, we provide deeper insights into patients' and physicians' acceptance of the risk/benefit trade-offs of skin toxicities during cancer therapy, including comparison of their perceptions and experiences with dermatologic AEs. METHODS: A multinational survey of 195 patients and 120 physicians was conducted to gauge attitudes regarding skin toxicities as an AE during cancer therapy. RESULTS: Skin toxicities were identified by patients and physicians as the AE that is most discouraging to patients when undergoing cancer therapies. Skin toxicities were cited as causing pain, impairing quality of life, and proving difficult to manage. Despite these negative influences, the majority of patients (71%) indicated they were willing to accept skin toxicities as an AE of an effective therapy. Indeed, the majority of patients and physicians preferred a more effective therapy that induces more severe skin toxicities than a less efficacious therapy that induces less severe skin toxicities; interestingly, patients were willing to accept a higher likelihood of severe skin toxicities than physicians. CONCLUSION: In this examination of patients' perspectives, we found that patients were willing to accept skin toxicities if they were the anticipated byproduct of a more effective therapeutic regimen. Important differences were observed between patients' and physicians' attitudes regarding risk/benefit trade-offs during cancer therapy, suggesting that patient's considerations and shared decision-making are key to cancer care. PMID- 29116407 TI - Fatigue- and health-related quality-of-life in anemic patients with lymphoma or multiple myeloma. AB - PURPOSE: The purpose of this study was to describe perceptions of fatigue in anemic patients with lymphoma or multiple myeloma (MM). METHODS: This is an observational multicenter study in a prospective cohort of lymphoma and MM patients with hemoglobin <= 11 g/dl managed under clinical practice. Fatigue was assessed at baseline and after 3 months using the PERFORM questionnaire, the Functional Assessment of Cancer Therapy-Fatigue, the linear analogue self assessment, and visual analogue scale (VAS) scales. RESULTS: Two hundred and fifty patients (125 with lymphoma, 125 with MM) were included. Only 59.2 and 56.0% of patients received treatment for anemia, respectively. After 3 months, the hemoglobin levels increased significantly compared to baseline from 10.0 +/- 1.2 to 11.5 +/- 1.8 in the lymphoma group and from 9.9 +/- 0.9 to 10.9 +/- 1.5 g/dl, in the MM group (P < 0.001, both comparisons). At baseline, 87.2 and 84.8% of patients had fatigue (median intensity (VAS) 60 and 50). The overall PERFORM score decreased from 35.2 +/- 15.2 to 32.0 +/- 14.6 (P = 0.048), without differences between groups. No statistically significant changes were observed in the other scales. After multivariable adjustment, the only common independent factor associated to improvements in fatigue and health-related quality-of-life (HRQoL) was an increase in hemoglobin levels. The administration of curative intention treatment was also associated with HRQoL improvements. The psychometric properties of the PERFORM questionnaire in MM patients were good (Cronbach's alpha 0.87-0.98; intraclass correlation coefficients 0.84-0.89; effect sizes 0.59 0.96). CONCLUSIONS: Almost all patients with lymphoma or MM diagnosed with anemia suffered from fatigue of moderate to severe intensity. Despite similar anemia supportive treatment, better correction of fatigue scores was observed in lymphoma patients after 3 months. Increases in hemoglobin were significantly associated to improvements in fatigue and HRQoL. PMID- 29116408 TI - Synthetic extracellular volume fraction-state of play. PMID- 29116409 TI - Chronic meningoencephalitis caused by Echo virus 6 in a patient with common variable immunodeficiency : Successful treatment with pleconaril. AB - Chronic enteroviral meningoencephalitis, most commonly caused by echoviruses, can particularly be seen in agammaglobulinemic patients. In spite of the fact that no specific treatment for enteroviral infections exists, pleconaril is an antiviral drug reported to be efficient against enteroviral infections in infants and adults. We present a case of a 42-year-old male, previously diagnosed with common variable immunodeficiency, who presented with severe chronic meningoencephalitis caused by Echo virus 6 and was successfully treated with pleconaril. Enteroviruses usually cause mild symptoms, but some strains can cause life threatening conditions especially in immunocompromised patients. Although pleconaril production is unprofitable due to the rarity of severe disease, our effective treatment should encourage further availability of pleconaril. PMID- 29116410 TI - Botulinum toxin therapy in patients with oral anticoagulation: is it safe? AB - When used therapeutically, botulinum toxin (BT) has to be injected into its target tissues. All manufacturers warn not to do so in patients with oral anticoagulation to avoid haematoma. We wanted to study the haematoma frequency (HF) in patients with anticoagulation receiving BT therapy. 32 patients (16 females, 16 males, age 69.3 +/- 10.0 years) with blepharospasm (n = 6), hemifacial spasm (n = 8), post-stroke spasticity (n = 16), and cervical dystonia (n = 2) received BT therapy (needle size 27G, post-injection tissue compression) whilst on anticoagulation (anticoagulation group, AG). 32 patients matched for disease, target muscles, age, and gender received identical BT therapy without anticoagulation (control group, CG). Anticoagulation was performed with phenprocoumon. International normalised ratio (INR) at the time of BT injection was in all patients within the recommended margins of 2.0 and 3.0 (mean 2.6 +/- 0.27). Overall HF was 3.0% in AG and 1.8% in CG (not significant). All hematomas occurred in blepharospasm patients (AG 5.2%, CG 2.6%, not significant) and hemifacial spasm patients (AG 3.9%, CG 2.9%, not significant). In cervical dystonia and spasticity there were no haematomas. Throughout an observation period of 4 years, none of the haematomas was surgically relevant. Haematomas are a rare complication of BT therapy, mainly occurring in periocular injections. Anticoagulation only marginally increases HF, provided INR is controlled and appropriate injection techniques are used. Surgically relevant haematomas do not occur. Interruption of oral anticoagulation to perform BT therapy is not justified. PMID- 29116411 TI - Advanced Parkinson's or "complex phase" Parkinson's disease? Re-evaluation is needed. AB - Holistic management of Parkinson's disease, now recognised as a combined motor and nonmotor disorder, remains a key unmet need. Such management needs relatively accurate definition of the various stages of Parkinson's from early untreated to late palliative as each stage calls for personalised therapies. Management also needs to have a robust knowledge of the progression pattern and clinical heterogeneity of the presentation of Parkinson's which may manifest in a motor dominant or nonmotor dominant manner. The "advanced" stages of Parkinson's disease qualify for advanced treatments such as with continuous infusion or stereotactic surgery yet the concept of "advanced Parkinson's disease" (APD) remains controversial in spite of growing knowledge of the natural history of the motor syndrome of PD. Advanced PD is currently largely defined on the basis of consensus opinion and thus with several caveats. Nonmotor aspects of PD may also reflect advancing course of the disorder, so far not reflected in usual scale based assessments which are largely focussed on motor symptoms. In this paper, we discuss the problems with current definitions of "advanced" PD and also propose the term "complex phase" Parkinson's disease as an alternative which takes into account a multimodal symptoms and biomarker based approach in addition to patient preference. PMID- 29116412 TI - Fabrication of flexible thin polyurethane membrane for tissue engineering applications. AB - Thin and flexible polymeric membranes play a critical role in tissue engineering applications for example organs-on-a-chip. These flexible membranes can enable mechanical stretch of the engineered tissue to mimic organ-specific biophysical features, such as breathing. In this work, we report the fabrication of thin (<20 MUm), stretchable, and biocompatible polyurethane (PU) membranes. The membranes were fabricated using spin coating technique on silicon substrates and were mounted on a frame for ease of device integration and handling. The membranes were characterized for their optical and elastic properties and compatibility with cell/tissue culture. It was possible to apply up to 10 kilopascal (kPa) pressure to perform cyclic stretch on 4 mm-diameter membranes for a period of 2 weeks at 0.2 hertz (Hz) frequency without mechanical failure. Adenocarcinomic human alveolar basal epithelial (A549) cells were cultured on the apical side of the PU membrane. The morphology and viability of the cells were comparable to those of cells cultured on standard tissue culture plates. Our experiments suggest that the stretchable PU membrane will be broadly useful for various tissue engineering applications in vitro. PMID- 29116413 TI - Cardiovascular Risk Factors After Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S): a New Effective Therapeutic Approach? AB - : Obesity and its associated comorbidities entail a significantly increased cardiovascular mortality. Therefore, approaching obesity control must include among its aims the reduction of the associated comorbidities and the higher cardiovascular mortality risk and not only weight loss. Many observational studies indicate that bariatric surgery (BS) is associated with a better long term survival than standard care. Furthermore, in general, these epidemiological studies included patients who underwent gastric bypass (GB), not biliopancreatic diversion/duodenal switch (BPD/DS), so the potential additional benefit of this latter technique remains unknown. In this regard, in theory, derivative techniques are usually associated to a higher rate of long-term improvement of metabolic comorbidities, so their potential impact on cardiovascular morbidity and mortality could be even greater than what has been published up to date. In 2007, our group proposed a simplification of the bariatric technique based on the duodenal switch, which we termed "single anastomosis duodeno-ileal bypass with sleeve gastrectomy" or SADI-S. In this review, and 10 years later, we describe some of the main results of those patients who underwent this procedure, specifically regarding their outcome on metabolic comorbidities and cardiovascular risk. Considering the findings presented in this review, in which a significant improvement of all metabolic comorbidities was observed, we may confidently suggest that SADI-S seems comparable to a BPD/DS procedure in the mid term outcome. After all, the SADI-S procedure was conceived as a simplified version of the BPD/DS technique and not necessarily intended to maximize the improvement of cardiovascular and metabolic comorbidities, which is already sufficiently optimal. In this regard, in our experience, we have encountered a new satisfactory result, which combines more pros than cons. In fact, as we have seen, after a follow-up of 3 years, the outcomes of weight loss and improvement of blood pressure, lipid profile, and insulin resistance seem to be better with SADI-S than with Roux-en-Y gastric bypass (RYGB), and this difference may be probably still relevant in the long-term evaluation. SUMMARY: Mid-term follow-up of patients who underwent SADI-S has proven that this procedure seems, at least, as effective as other malabsorptive techniques such as BPD/DS and significantly reduces the four main cardiovascular risk factors to a higher extent than RYGB. One of the main advantages inherent to this intervention modality is that it truly simplifies any of the prior derivative procedures and that it may be specifically adapted and individualized to each patient, according to his BMI and associated metabolic comorbidities. PMID- 29116414 TI - Effect of denosumab administration on low bone mineral density (T-score -1.0 to 2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer. AB - Although adjuvant aromatase inhibitor (AI) therapy is widely used in postmenopausal women with hormone receptor-positive breast cancer, it is known to be associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-kappaB ligand, has been shown to protect against AI-induced bone loss. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. We prospectively monitored bone mineral density (BMD) of the lumbar spine and bilateral femoral necks in 100 postmenopausal women with hormone receptor-positive postoperative breast cancer of clinical stage I IIIA in whom treatment with AI as adjuvant endocrine therapy was planned or had been ongoing. Study participants received supplemental calcium and vitamin D every day and denosumab (60 mg) subcutaneously every 6 months. At enrollment, patients were required to have evidence of low bone mass without meeting the criteria for osteoporosis. The primary endpoint was percentage change from baseline in lumbar spine BMD at month 12. At 6 and 12 months, lumbar spine BMD increased by 3.3 and 4.7%, respectively. BMD of the femoral necks also increased. Hypocalcemia of grade >=2, osteonecrosis of the jaw, and non-traumatic clinical fracture did not occur. In conclusion, semi-annual treatment with denosumab was associated with increased BMD in Japanese women receiving adjuvant AI therapy, regardless of prior AI treatment. PMID- 29116415 TI - A microfluidic device for quantitative investigation of zebrafish larvae's rheotaxis. AB - Zebrafish is a model organism for various sensory-motor biological studies. Rheotaxis, or the ability of zebrafish to orient and swim against the water stream, is a common behavior that involves multiple sensory-motor processes such as their lateral line and visual systems. Due to the lack of a controllable and easy-to-use assay, zebrafish rheotaxis at larval stages is not well-understood. In this paper, we report a microfluidic device that can be used to apply the flow stimulus precisely and repeatedly along the longitudinal axis of individual zebrafish larvae to study their coaxial rheotaxis. We quantified rheotaxis in terms of the response rate and location along the channel at various flow velocities (9.5-38 mm.sec-1). The larvae effectively exhibited a similarly high rheotactic response at low and medium velocities (9.5 and 19 mm.sec-1); however, at high velocity of 38 mm.sec-1, despite sensing the flow, their rheotactic response decreased significantly. The flow velocity also affected the response location along the channel. At 9.5 mm.sec-1, responses were distributed evenly along the channel length while, at 19 and 38 mm.sec-1, the larvae demonstrated higher rheotaxis responses at the anterior and posterior ends of the channel, respectively. This result shows that although the response is similarly high at low and medium flow velocities, zebrafish larvae become more sensitive to the flow at medium velocity, demonstrating a modulated rheotactic behavior. Employing our device, further investigations can be conducted to study the sensory-motor systems involved in rheotaxis of zebrafish larvae and other fish species. PMID- 29116416 TI - Postpartum outcomes of a pilot prenatal care-based psychosocial intervention for PTSD during pregnancy. AB - This study examines postpartum posttraumatic stress disorder (PTSD) symptoms and secondary outcomes including postpartum depression and birth outcomes for pregnant women who screened positive for PTSD and received a psychosocial education intervention compared to women with PTSD in the usual prenatal care setting. All women entering prenatal care at two federally qualified health centers were screened for symptoms of current PTSD; one site was selected randomly to have prenatal care advocates deliver eight Seeking Safety topics for women with clinical or subclinical PTSD. Women were not blind to condition. Baseline and postpartum interviews, including demographic characteristics and assessment of mental health, social support, and coping skills, were conducted. Medical record data was collected to document preterm delivery and low birth weight. Of the 149 participants at baseline, 128 (86%) participated in the postpartum interview. Intervention women, compared to controls, significantly decreased PTSD symptoms, and showed a non-significant trend for improved social support. However, depression, coping, and birth outcomes did not differ. This study suggests some initial support for the Seeking Safety intervention in prenatal care settings and requires further research to determine the best approaches to its implementation. PMID- 29116418 TI - Interactions between poly-(phthalazinone ether sulfone ketone) (PPESK) and TNT or TATB in polymer bonded explosives: a molecular dynamic simulation study. AB - The glass transition temperature (T g) and density of poly-(phthalazinone ether sulfone ketone) (PPESK A) were estimated by molecular dynamic (MD) simulation. A novel poly-(phthalazinone ether sulfone ketone) (PPESK B) was constructed by introducing nitrol and amini energetic groups into PPESK A, and T g and density were also simulated for PPESK B. The estimated T g values of PPESK A were very close to experimental results, while for PPESK B three estimated values differed by < 5 K. The interactions between explosives and polymer binders of polymer bonded explosives (PBXs) were simulated by MD. Comparison of the cohesive energy densities (CED) and solubility parameter (delta) values of PBXs, polymer binders, and mono-explosives indicate that, upon introducing polymer binders, the CED and delta values of PBXs decreased compared with those of corresponding mono explosives. The binding energies (E bind) imply that 2,4,6-trinitrotoluene-based PBXs are more stable than 1,3,5-triamino-2,4,6-trinitrobenzene (TATB)-based PBXs. The mechanical properties, Young's modulus E, shear modulus G, bulk modulus K, Poisson's ratio gamma and Cauchy pressure (C 12 -C 44) of the PBXs were assessed. The rigidity of the PBXs was found to be lower than that of mono-explosives. All K/G values were positive, indicating that PBXs are flexible. Based on these mechanical properties results, PBXs using PPESK B as a binder are superior to those using PPESK A as a binder. Due to the low C 12 -C 44 values of the PBXs, the ductility of the materials of the fracture surface is poorer, especially for TATB-based PBXs. PMID- 29116417 TI - Epidemiology of fractures in Armenia: development of a country-specific FRAX model and comparison to its surrogate. AB - : Fracture probabilities derived from the surrogate FRAX model for Armenia were compared to those from the model based on regional estimates of the incidence of hip fracture. Disparities between the surrogate and authentic FRAX models indicate the importance of developing country-specific FRAX models. Despite large differences between models, differences in the rank order of fracture probabilities were minimal. OBJECTIVE: Armenia has relied on a surrogate FRAX model based on the fracture epidemiology of Romania. This paper describes the epidemiology of fragility fractures in Armenia used to create an Armenia-specific FRAX model with an aim of comparing this new model with the surrogate model. METHODS: We carried out a population-based study in two regions of Armenia (Ararat and Vayots Dzor representing approximately 11% of the country's population). We aimed to identify all low-energy fractures: retrospectively from hospital registers in 2011-2012 and prospectively in 2013 with the inclusion of primary care sources. RESULTS: The differences in incidence between the surveys with and without data from primary care suggested that 44% of patients sustaining a hip fracture did not receive specialized medical care. A similar proportion of forearm and humeral fractures did not come to hospital attention (48 and 49%, respectively). Only 57.7% of patients sustaining a hip fracture were hospitalized. In 2013, hip fracture incidence at the age of 50 years or more was 201/100,000 for women and 136/100,000 for men, and age- and sex-specific rates were incorporated into the new "authentic" FRAX model for Armenia. Compared to the surrogate model, the authentic model gave lower 10-year fracture probabilities in men and women aged less than 70 years but substantially higher above this age. Notwithstanding, there were very close correlations in fracture probabilities between the surrogate and authentic models (> 0.99) so that the revisions had little impact on the rank order of risk. CONCLUSION: A substantial proportion of major osteoporotic fractures in Armenia do not come to hospital attention. The disparities between surrogate and authentic FRAX models indicate the importance of developing country-specific FRAX models. Despite large differences between models, differences in the rank order of fracture probabilities were minimal. PMID- 29116420 TI - Assessing Autism in Adults: An Evaluation of the Developmental, Dimensional and Diagnostic Interview-Adult Version (3Di-Adult). AB - We developed a brief, informant-report interview for assessing autism spectrum conditions (ASC) in adults, called the Developmental, Dimensional and Diagnostic Interview-Adult Version (3Di-Adult); and completed a preliminary evaluation. Informant reports were collected for participants with ASC (n = 39), a non clinical comparison group (n = 29) and a clinical comparison group (n = 20) who had non-autistic mental health conditions. Mean administration time was 38 min (50 min for ASC). Internal consistency (alphas >= 0.93) and inter-rater agreement (ICCs >= 0.99) were high. When discriminating ASC from non-ASC, the 3Di-Adult showed excellent sensitivity (95%) and specificity (92%). The 3Di-Adult shows promise as a psychometrically sound and time-efficient interview for collecting standardised informant reports for DSM-5 assessments of ASC in adults, in research and clinical practice. PMID- 29116419 TI - Indices of soil contamination by heavy metals - methodology of calculation for pollution assessment (minireview). AB - This article provides the assessment of heavy metal soil pollution with using the calculation of various pollution indices and contains also summarization of the sources of heavy metal soil pollution. Twenty described indices of the assessment of soil pollution consist of two groups: single indices and total complex indices of pollution or contamination with relevant classes of pollution. This minireview provides also the classification of pollution indices in terms of the complex assessment of soil quality. In addition, based on the comparison of metal concentrations in soil-selected sites of the world and used indices of pollution or contamination in soils, the concentration of heavy metal in contaminated soils varied widely, and pollution indices confirmed the significant contribution of soil pollution from anthropogenic activities mainly in urban and industrial areas. PMID- 29116421 TI - Sensory Sensitivity and Food Selectivity in Children with Autism Spectrum Disorder. AB - Few studies have compared atypical sensory characteristics and food selectivity between children with and without autism spectrum disorder (ASD). We compared oral sensory processing between children with (n = 53) and without ASD (n = 58), ages 3-11 years. We also examined the relationships between atypical oral sensory processing, food selectivity, and fruit/vegetable consumption in children with ASD. We found that more children with ASD presented with atypical sensory processing than children without ASD. Among children with ASD, those with atypical oral sensory sensitivity refused more foods and ate fewer vegetables than those with typical oral sensory sensitivity. The findings suggest that efforts to address food selectivity in children with ASD may be enhanced by including strategies that address oral sensory processing. PMID- 29116423 TI - Postoperative occipital neuralgia in posterior upper cervical spine surgery: a systematic review. AB - Postoperative occipital neuralgia (PON) after upper cervical spine surgery can cause significant morbidity and may be overlooked. The causes, presentation, diagnosis, management, prognosis, and prevention of PON were reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. English-language studies and case reports published from inception to 2017 were retrieved. Data on surgical procedures, incidence, cause of PON, management, outcomes, and preventive technique were extracted. Sixteen articles, including 591 patients, were selected; 93% of the patients with PON underwent C1 lateral mass screw (C1LMS) fixation, with additional 7% who underwent occipitocervical fusion without C1 fixation. PON had an incidence that ranged from 1 to 35% and was transient in 34%, but persistent in 66%. Five articles explained the possible causes. The primary presentation was constant or paroxysmal burning pain located mainly in the occipital and upper neck area and partially extending to the vertical, retroauricular, retromandibular, and forehead zone. Treatment included medications, nerve block, revision surgery, and nerve stimulation. Two prospective studies compared the effect of C2 nerve root transection on PON. PON in upper cervical spine surgery is a debilitating complication and was most commonly encountered by patients undergoing C1LMS fixation. The etiology of PON is partially clear, and the pain could be persistent and hard to cure. Reducing the incidence of PON can be realized by improving technique. More high-quality prospective studies are needed to define the effect of C2 nerve root transection on PON. PMID- 29116422 TI - Progranulin and its biological effects in cancer. AB - Cancer cells have defects in regulatory mechanisms that usually control cell proliferation and homeostasis. Different cancer cells share crucial alterations in cell physiology, which lead to malignant growth. Tumorigenesis or tumor growth requires a series of events that include constant cell proliferation, promotion of metastasis and invasion, stimulation of angiogenesis, evasion of tumor suppressor factors, and avoidance of cell death pathways. All these events in tumor progression may be regulated by growth factors produced by normal or malignant cells. The growth factor progranulin has significant biological effects in different types of cancer. This protein is a regulator of tumorigenesis because it stimulates cell proliferation, migration, invasion, angiogenesis, malignant transformation, resistance to anticancer drugs, and immune evasion. This review focuses on the biological effects of progranulin in several cancer models and provides evidence that this growth factor should be considered as a potential biomarker and target in cancer treatment. PMID- 29116424 TI - Summer Treatment Program for Preschoolers with Externalizing Behavior Problems: a Preliminary Examination of Parenting Outcomes. AB - Within an at-risk sample of preschoolers with externalizing behavior problems (EBP), the current study examined the initial promise of a multimodal intervention, the Summer Treatment Program for Pre-Kindergarteners (STP-PreK), in improving parenting outcomes. Using an open trial design, 154 parents and their preschool children (73% male; M age = 5.06 years; 82% Hispanic/Latino background) with at-risk or clinically elevated levels of EBP (57% of which were referred by schools or mental health/medical professionals) completed a baseline and post treatment assessment. A subsample of 90 families completed a follow-up assessment approximately 6 to 9 months after treatment completion. Parental measures of parenting stress and discipline strategies were collected across all three assessments. Observational data were also collected across all assessments during a 5-min standardized child-led play situation and a 5-min parent-led clean up task. The parenting component of the STP-PreK included a School Readiness Parenting Program (SRPP) of which the behavioral management component was implemented via a Parent-Child Interaction Therapy (PCIT) adaptation (8 weekly group sessions with 15-20 parents in each group, lack of requirement of "mastery" criteria). All parenting outcomes (both ratings and observed) significantly improved after the intervention (Cohen's d mean effect size across measures 0.89) with all effects being maintained at the 6-9 month follow-up. These findings highlight the initial promise of our SRPP's PCIT adaptation in targeting multiple aspects of parenting while yielding comparable parenting skills acquisition compared to traditional individual PCIT. PMID- 29116425 TI - Directionality of interhemispheric communication. PMID- 29116426 TI - High-resolution language mapping of Broca's region with transcranial magnetic stimulation. AB - Broca's region, corresponding roughly to cytoarchitectonic areas 44 and 45 in the inferior frontal cortex, holds a multifunctional role in language processing, as shown, e.g., by functional imaging data. Neuro-navigated transcranial magnetic stimulation (TMS) enables complementary non-invasive mapping of cortical functions with high spatial resolution. Here, we report on detailed TMS language mapping of Broca's region in 12 healthy participants. The test protocol with an object naming task was adapted for high-resolution and semi-quantitative mapping of TMS-induced effects on speech and language performance. Hierarchical cluster analysis of normalized ratings of error frequency and severity revealed a clear focus of TMS impact at dorso-posterior target sites, close to the inferior frontal junction. Adjacent clusters of moderate and slightly affected stimulation sites yielded a posterosuperior-to-anteroinferior gradient of TMS susceptibility. Our findings indicate that the part of Broca's region most susceptible to TMS induced language inhibition in object naming is located in the dorsal area 44. PMID- 29116427 TI - CART neurons in the lateral hypothalamus communicate with the nucleus accumbens shell via glutamatergic neurons in paraventricular thalamic nucleus to modulate reward behavior. AB - Paraventricular thalamic nucleus (PVT) serves as a transit node processing food and drug-associated reward information, but its afferents and efferents have not been fully defined. We test the hypothesis that the CART neurons in the lateral hypothalamus (LH) project to the PVT neurons, which in turn communicate via the glutamatergic fibers with the nucleus accumbens shell (AcbSh), the canonical site for reward. Rats conditioned to self-stimulate via an electrode in the right LH medial forebrain bundle were used. Intra-PVT administration of CART (55-102) dose dependently (10-50 ng/rat) lowered intracranial self-stimulation (ICSS) threshold and increased lever press activity, suggesting reward-promoting action of the peptide. However, treatment with CART antibody (intra-PVT) or MK-801 (NMDA antagonist, intra-AcbSh) produced opposite effects. A combination of sub effective dose of MK-801 (0.01 ug/rat, intra-AcbSh) and effective dose of CART (25 ng/rat, intra-PVT) attenuated CART's rewarding action. Further, we screened the LH-PVT-AcbSh circuit for neuroadaptive changes induced by conditioning experience. A more than twofold increase was noticed in the CART mRNA expression in the LH on the side ipsilateral to the implanted electrode for ICSS. In addition, the PVT of conditioned rats showed a distinct increase in the (a) c-Fos expressing cells and CART fiber terminals, and (b) CART and vesicular glutamate transporter 2 immunostained elements. Concomitantly, the AcbSh showed a striking increase in expression of NMDA receptor subunit NR1. We suggest that CART in LH PVT and glutamate in PVT-AcbSh circuit might support food-seeking behavior under natural conditions and also store reward memory. PMID- 29116428 TI - Bromoethylindole (BEI-9) redirects NF-kappaB signaling induced by camptothecin and TNFalpha to promote cell death in colon cancer cells. AB - Chemotherapeutic regimens containing camptothecin (CPT), 5-fluorouracil, and oxaliplatin are used to treat advanced colorectal cancer. We previously reported that an indole derivative, 3-(2-bromoethyl)indole (BEI-9), inhibited the proliferation of colon cancer cells and suppressed NF-kappaB activation. Here, we show that a combination of BEI-9 with either CPT or tumor necrosis factor alpha (TNFalpha) enhances cell death. Using colorectal cancer cells, we examined the activation of NF-kappaB by drugs, the potential of BEI-9 for inhibiting drug induced NF-kappaB activation, and the enhancement of cell death by combination treatments. Cells were treated with the chemotherapeutic drugs alone or in combination with BEI-9. NF-kappaB activation, cell cycle profiles, DNA-damage response, markers of cell death signaling and targets of NF-kappaB were evaluated to determine the effects of single and co-treatments. The combination of BEI-9 with CPT or TNFalpha inhibited NF-kappaB activation and reduced the expression of NF-kappaB-responsive genes, Bcl-xL and COX2. Compared to CPT or BEI-9 alone, sequential treatment of the cells with CPT and BEI-9 significantly enhanced caspase activation and cell death. Co-treatment with TNFalpha and BEI-9 also caused more cytotoxicity than TNFalpha or BEI-9 alone. Combined BEI-9 and TNFalpha enhanced cell death through caspase activation and cleavage of the switch-protein, RIP1 kinase. BEI-9 reduced the expression of COX2 both alone and in combination with CPT or TNF. We postulate that BEI-9 enhances the effects of these drugs on cancer cells by turning off or redirecting NF-kappaB signaling. Therefore, the combination of BEI-9 with drugs that activate NF-kappaB needs to be evaluated for clinical applications. PMID- 29116429 TI - Engineering cofactor flexibility enhanced 2,3-butanediol production in Escherichia coli. AB - Enzymatic reduction of acetoin into 2,3-butanediol (2,3-BD) typically requires the reduced nicotinamide adenine dinucleotide (NADH) or its phosphate form (NADPH) as electron donor. Efficiency of 2,3-BD biosynthesis, therefore, is heavily influenced by the enzyme specificity and the cofactor availability which varies dynamically. This work describes the engineering of cofactor flexibility for 2,3-BD production by simultaneous overexpression of an NADH-dependent 2,3-BD dehydrogenase from Klebsiella pneumoniae (KpBudC) and an NADPH-specific 2,3-BD dehydrogenase from Clostridium beijerinckii (CbAdh). Co-expression of KpBudC and CbAdh not only enabled condition versatility for 2,3-BD synthesis via flexible utilization of cofactors, but also improved production stereo-specificity of 2,3 BD without accumulation of acetoin. With optimization of medium and fermentation condition, the co-expression strain produced 92 g/L of 2,3-BD in 56 h with 90% stereo-purity for (R,R)-isoform and 85% of maximum theoretical yield. Incorporating cofactor flexibility into the design principle should benefit production of bio-based chemical involving redox reactions. PMID- 29116430 TI - Microaerophilic alkane degradation in Pseudomonas extremaustralis: a transcriptomic and physiological approach. AB - Diesel fuel is one of the most important sources of hydrocarbon contamination worldwide. Its composition consists of a complex mixture of n-alkanes, branched alkanes and aromatic compounds. Hydrocarbon degradation in Pseudomonas species has been mostly studied under aerobic conditions; however, a dynamic spectrum of oxygen availability can be found in the environment. Pseudomonas extremaustralis, an Antarctic bacterium isolated from a pristine environment, is able to degrade diesel fuel and presents a wide microaerophilic metabolism. In this work RNA-deep sequence experiments were analyzed comparing the expression profile in aerobic and microaerophilic cultures. Interestingly, genes involved in alkane degradation, including alkB, were over-expressed in micro-aerobiosis in absence of hydrocarbon compounds. In minimal media supplemented with diesel fuel, n alkanes degradation (C13-C19) after 7 days was observed under low oxygen conditions but not in aerobiosis. In-silico analysis of the alkB promoter zone showed a putative binding sequence for the anaerobic global regulator, Anr. Our results indicate that some diesel fuel components can be utilized as sole carbon source under microaerophilic conditions for cell maintenance or slow growth in a Pseudomonas species and this metabolism could represent an adaptive advantage in polluted environments. PMID- 29116431 TI - Correlation of IL-31 gene polymorphisms with susceptibility and clinical recurrence of bladder cancer. AB - Interleukin-31 is a crucial cytokine triggering inflammation which could be one of the risk factors of tumors. However, data for correlation between IL-31 and tumors are limited. The purpose of our study was to discuss whether genetic polymorphisms of IL-31 were associated with the susceptibility and clinical outcomes of bladder cancer. Our study enrolled 478 controls, 156 non-muscle invasive bladder cancer (NMIBC) and 138 muscle-invasive bladder cancer (MIBC) patients. Polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) method was used for genotyping two single nucleotide polymorphisms (SNPs) of IL-31 gene including rs7977932 and rs4758680. Our results showed that A allele and CA/AA genotypes of rs4758680 were associated with susceptibility to bladder cancer (P = 0.04, OR 1.32, 95% CI 1.01-1.72, and P = 0.02, OR 1.43, 95% CI 1.05 1.96, respectively), and G allele of rs7977932 might be a protect factor for tobacco smoking patients compared with non-smoking patients (P = 0.005, OR 0.42, 95% CI 0.23-0.76). Furthermore, CA/AA genotypes of rs4758680 might be the independent risk factors for the decreased recurrence-free survival of the patients with MIBC (P = 0.03, OR 2.02, 95% CI 1.06-3.85. Our data indicated that polymorphisms of IL-31 are associated with bladder cancer, and rs4758680 could be an independent prediction for MIBC patients with a high risk of recurrence. PMID- 29116432 TI - SEOM clinical guideline for the management of malignant melanoma (2017). AB - All melanoma suspected patients must be confirmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams. PMID- 29116434 TI - Comparison between neck-first approach and thoracic approach during thoracoscopic esophagectomy. AB - PURPOSE: This study aimed to compare the outcomes of the prior cervical and thoracic approaches of thoracoscopic esophagectomy in the prone position for esophageal cancer. METHODS: We reviewed the records of 103 consecutive patients who underwent thoracoscopic esophagectomy in the prone position for esophageal cancer. Seventy-four patients underwent the prior cervical approach (Cervical group); the other 29 underwent the thoracic approach (Thoracic group). The perioperative outcomes of the two groups were compared. RESULTS: Total operative time and volume of blood loss were not different between the two groups, but the median thoracoscopic time was significantly longer in the Thoracic group than in the Cervical group (296 vs. 210 min; P < 0.001). The incidence of recurrent nerve palsy was not different; however, the incidence of the postoperative pneumonia tended to be higher in the Thoracic group than in the Cervical group (20.7 vs. 10.8%; P = 0.188), and the duration of postoperative hospital stay was significantly longer in the Thoracic group than in the Cervical group (22 vs. 17 days; P = 0.032). CONCLUSION: Patients who underwent thoracoscopic esophagectomy in the prone position via the prior cervical approach had better short-term outcomes than those who underwent the thoracic approach. PMID- 29116433 TI - Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain. AB - BACKGROUND: Everolimus with exemestane has shown promising activity in patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant advanced breast cancer. It is necessary, therefore, to characterize the safety profile of this new combination in the real-world clinical setting and in the broadest possible population. PATIENTS AND METHODS: Post-menopausal women with HR-positive HER2-negative advanced breast cancer progressing after prior non-steroidal aromatase inhibitors (NSAIs) were included. The objectives of this analysis were to evaluate the safety profile of this combination in a subset of Spanish patients in the BALLET trial and to characterize grade 3 and 4 adverse events (AEs) in routine clinical practice in Spain. RESULTS: Between September 2012 and July 2013, 429 patients (20% of the overall study population) were included in the BALLET study in 52 hospitals in Spain, of whom 100 (23%) were >= 70 years. The median treatment duration was 3.14 and 3.03 months for exemestane and everolimus, respectively. The most common reasons for discontinuation of treatment were local reimbursement of everolimus (43%), followed by disease progression (31%) and the incidence of AEs (15%). The most frequent AEs causing permanent discontinuation were pneumonitis (4%), asthenia (2%) and stomatitis (2%). Overall, 87% of patients experienced at least one AE of any grade, 30% of patients at least one grade 3 AE and 2% of patients a grade 4 AE. CONCLUSION: The safety profile in Spanish patients of the BALLET trial is consistent with the results obtained in the overall population of the trial, as well as in previous clinical trials. PMID- 29116436 TI - Higher levels of motor competence are associated with reduced interference in action perception across the lifespan. AB - Action perception and action production are tightly linked and elicit bi directional influences on each other when performed simultaneously. In this study, we investigated whether age-related differences in manual fine-motor competence and/or age affect the (interfering) influence of action production on simultaneous action perception. In a cross-sectional eye-tracking study, participants of a broad age range (N = 181, 20-80 years) observed a manual grasp and-transport action while performing an additional motor or cognitive distractor task. Action perception was measured via participants' frequency of anticipatory gaze shifts towards the action goal. Manual fine-motor competence was assessed with the Motor Performance Series. The interference effect in action perception was greater in the motor than the cognitive distractor task. Furthermore, manual fine-motor competence and age in years were both associated with this interference. The better the participants' manual fine-motor competence and the younger they were, the smaller the interference effect. However, when both influencing factors (age and fine-motor competence) were taken into account, a model including only age-related differences in manual fine-motor competence best fit with our data. These results add to the existing literature that motor competence and its age-related differences influence the interference effects between action perception and production. PMID- 29116435 TI - Increased perirenal fat area is not associated with adverse outcomes after laparoscopic total mesorectal excision for rectal cancer. AB - INTRODUCTION: Intraabdominal visceral obesity may increase technical challenges during laparoscopic rectal resection and hypothetically therefore increase the risk of perioperative complications. The aim of this study was to analyze intraabdominal obesity by means of perirenal fat against risk of adverse outcomes in patients undergoing laparoscopic rectal cancer surgery. METHODS: This study was a single-institution retrospective analysis of consecutive patients undergoing laparoscopic total mesorectal surgery for rectal cancer between January 2009 and January 2013. Abdominal CT scans with intravenous contrast were assessed in a blinded manner to estimate the perirenal fat area (cm2). RESULT: A total of 195 patients were included (median age 70 years (range 27-87), 58 women and 137 men) for analysis. There was a moderate correlation between BMI and perirenal fat area (r = 0.499, p = 0.001). Perirenal fat area was not associated with any of the measured adverse outcomes. Patients with BMI >= 30 had significantly higher intraoperative blood loss (191 mL, p = 0.001). CONCLUSION: Perirenal fat area was not an important predictor of adverse outcomes in patients undergoing laparoscopic rectal cancer surgery. PMID- 29116437 TI - Morality and soap in engineers and social scientists: the Macbeth effect interacts with professions. AB - Several studies demonstrate that physical cleansing is actually efficacious to cope with threatened morality, thus demonstrating that physical and moral purity are psychologically interwoven. This so-called Macbeth effect has been explained, for example, by the conceptual metaphor theory that suggests an embodiment of the moral purity metaphor. Recent research draws attention to individual differences when using conceptual metaphors. The present study shows that the moral purity link interacts with different professions. Engineering and social science students were asked to hand copy a text in which the protagonist behaved in an immoral way (or in a moral way, control condition). Subsequently, they had to rate cleansing and other products. Both groups of participants showed higher ratings for cleansing products when hand copying the unethical story, but this Macbeth effect was significantly stronger for the group of engineering students. The results demonstrate that the Macbeth effect interacts with individual differences of the chosen profession. The outcome is discussed in terms of recent theories on individual differences in disgust sensitivity. PMID- 29116438 TI - Staging with computed tomography of patients with colon cancer. AB - PURPOSE: Accurate staging of colonic cancer is important for patient stratification. We aimed to correlate the diagnostic accuracy of preoperative computed tomography (CT) with final histopathology as reference standard. METHODS: Data was collected retrospectively on 615 consecutive patients operated for colonic cancer. Evaluation was based upon T-stage. Patients were stratified into high-risk and low-risk groups, based on the extent of tumor invasion beyond the proper muscle layer of more or less than 5 mm. The Kendall tau correlation coefficient was used to calculate concordance between radiological (r)T-stage obtained at CT imaging and pathological (p)T-stage from the final pathology. RESULTS: In total, 501 patients were included. We found no significant differences in the Kendall tau values for diagnostic measures between the groups at the 95% confidence interval (CI) level: 49% (95% CI, 43-55) for all individuals, 48% (95% CI, 40-56) for screened individuals, and 47% (95% CI, 37 56) for non-screened individuals. The overall sensitivity and specificity for all individuals in identifying high-risk tumors on CT was 65% (95% CI, 56-73) and 89% (95% CI, 85-92). The risk of ending up in the high-risk group due to overstaging among all individuals was calculated as the number needed to harm 11.7 (95% CI, 9 16). CONCLUSIONS: There is basis for improvement of CT-based preoperative staging of patients with colorectal cancer. Supplementary modalities may be needed for correct staging of patients preoperatively, especially in relation to stratification of patients into neoadjuvant treatments or tailored therapy in patients with early cancers. PMID- 29116440 TI - Parenchymal neuro-Behcet disease with erectile dysfunction and micturition disturbances: case report and literature review. AB - Parenchymal neuro-Behcet disease (NBD) is a serious clinic condition with a sub acute or chronic disease course that results in incapability through pyramidal tract involvement. Though well-known consequences can deter a patient's life, both urinary symptoms and sexual dysfunction are underestimated complications of NBD and closely related in timing. Here, we report the case of a young male patient with parenchymal NBD who developed urinary incontinence and erectile dysfunction in addition to widespread pyramidal tract signs and symptoms. We discuss clinical features, prognosis and treatment of the case. A review of English literature was conducted for cases of concurrent urinary or sexual dysfunction complicating parenchymal-NBD. PMID- 29116439 TI - Determinants of mortality in systemic sclerosis: a focused review. AB - Scleroderma (systemic sclerosis) is an autoimmune rheumatic disorder that is characterized by fibrosis, vascular dysfunction, and autoantibody production that involves most visceral organs. It is characterized by a high morbidity and mortality rate, mainly due to disease-related complications. Epidemiological data describing mortality and survival in this population have been based on both population and observational studies. Multiple clinical and non-clinical factors have been found to predict higher likelihood of death among thepatients. Here, we do an extensive review of the available literature, utilizing the PubMed database, to describe scleroderma and non-scleroderma related determinants of mortality in this population. We found that even though the mortality among the general population has declined, scleroderma continues to carry a very high morbidity and mortality rate, however we have made some slow progress in improving the mortality among scleroderma patients over the last few decades. PMID- 29116442 TI - Introduction. AB - The pulvinar can be subdivided into well-delimitated regions based on chemoarchitectural, cytoarchitectural, myeloarchitectural, connectivity, and electrophysiological criteria. Subdivisions of the pulvinar based on its chemoarchitectural features are the most consistently preserved across species of New and Old World monkeys. It is reasonable to speculate that the occurrence and distribution of calcium-binding proteins in the pulvinar, such as calbindin and parvalbumin, have been preserved along evolution. Therefore, they have proven to be valuable tools capable of probing the basic pulvinar scaffold across primate species. Along this review, we will provide an overview of the available data regarding the various subdivisions of the pulvinar that have been proposed based on architectural criteria such as the distribution of molecular markers, neuronal morphology, and fiber layout. PMID- 29116443 TI - Cytoarchitecture and Myeloarchitecture of the Pulvinar. AB - In this chapter, we discuss the different ways in which the primate pulvinar has been subdivided, based on cytoarchitectural and myeloarchitectural criteria. One original criterion, based on cytoarchitecture, subdivided the pulvinar into nucleus pulvinaris medialis (PM), nucleus pulvinaris lateralis (PL), and nucleus pulvinaris inferior (PI). Later, the anterior limits of the pulvinar were extended and a subdivision was added to this nucleus, named pulvinar oralis (PO). PO occupies the anterior portion of the pulvinar and appears between the nucleus centrum medianum (CM) and the nucleus ventralis posterior lateralis (VPL). PMID- 29116441 TI - Validation of the Toronto Psoriatic Arthritis Screen II (TOPAS II) questionnaire in a Turkish population. AB - OBJECTIVE: To evaluate the TOPAS II questionnaire validation in a Turkish population. METHODS: The Turkish translation of ToPAS II was sent to us by the developer authors of the original index. Subjects were recruited from dermatology, physical medicine and rehabilitation, and rheumatology outpatient clinics. All patients' demographic parameters and ToPAS II questionnaire results were recorded. After patients completed the questionnaire they were assessed by a rheumatologist according to a standard protocol which includes a complete history, detailed physical examination, laboratory tests and CASPAR criteria. Receiver operating characteristics (ROC) assessed to obtain sensitivity and specificity of Turkish version of ToPAS II questionnaire. RESULTS: One hundred and fifty subjects were recruited in the study. The mean age of subjects was 41.07 years (SD 12.59) and the 58% of subjects were female. There were 46 subjects from psoriasis group, 43 subjects from psoriatic arthritis (PsA) group, 41 subjects from physical medicine and rehabilitation group and 20 subjects from rheumatology (non-PsA) group. The area under the ROC curve was 0.99 which means as excellent predictor and optimum cut-off threshold to discriminate patients diagnosed with PsA was 8 according to this ROC curve analysis. The overall sensitivity and specificity based on cut-off threshold of 8, were 95.8 and 98%, respectively. CONCLUSION: The Turkish version of ToPAS II has high sensitivity and specificity. It is simple, not time consuming and useful tool to screen for PsA in both patients with and without psoriasis. PMID- 29116444 TI - Chemoarchitecture of the Pulvinar. AB - Cytochemical and immunocytochemical methods reveal details of the pulvinar architecture that are not apparent from Nissl and myelin staining. The results of these techniques have been interpreted in different ways by different investigators, each adopting different sets of nomenclature for the various pulvinar subdivisions. In this chapter, we discuss the notion that the differentiation of the pulvinar along primate evolution took place upon a relatively rigid chemoarchitectonic scaffold. PMID- 29116445 TI - Visual Map Representations in the Primate Pulvinar. AB - The pulvinar receives direct visual information from the retina and indirect visual information from several cortical and subcortical areas. In this chapter, we discuss the visuotopic organization of the primate pulvinar. Electrophysiological techniques have been systematically employed to study pulvinar visuotopy in the owl, capuchin, and macaque monkeys. A single map of the visual field has been described in the pulvinar of the owl monkey, while two independent maps have been described in the capuchin and macaque pulvinar. PMID- 29116446 TI - Connectivity of the Pulvinar. AB - Pulvinar connectivity has been studied using a variety of neuroanatomical tracing techniques in both New and Old World monkeys. Connectivity studies have revealed additional maps of the visual field other than those described using electrophysiological techniques, such as P3 in the capuchin monkey and P3/P4 in the macaque monkey. In this chapter, we argue that with increasing cortical size, the pulvinar developed new functional subdivisions in order to effectively interconnect and interact with the cortex. PMID- 29116447 TI - Reestablishing the Chemoarchitectural Borders Based on Electrophysiological and Connectivity Data. AB - In this chapter, we discuss the poor agreement between visuotopic maps described using electrophysiological and connectivity data and the subdivisions of the pulvinar based on chemoarchitecture. We focus on the differences and similarities between New and Old World monkeys to evaluate how this agreement evolved during evolution. There is some agreement in the localization of P1, described using electrophysiological and connectivity data, and the lateral and central portions of the nucleus pulvinaris inferior (PI), defined based on chemoarchitectural criteria. Similarly, there is some colocalization between P3 and the medial portion of PI in both New and Old World monkeys. One difference between primates refers to P2, which is present in the Old World macaque monkey but absent in the New World monkeys. P4, which has not been studied in all primates, shows a partial spatial agreement with the dorsal portion of the chemoarchitecturally defined PL. PMID- 29116448 TI - Visual Topography of the Pulvinar Projection Zones. AB - In this chapter, we describe the visuotopy of the pulvinar subdivisions P1, P2, and P4. In all primates, P1 colocalizes with the chemoarchitecturally defined PI and a small portion of PL. The peripheral visual field is represented anteriorly in the medial portion of PI, while central vision is represented more posteriorly in the medial portion of PL. The vertical meridian representation is located on the lateral edge of P1, while the horizontal meridian is represented obliquely from the lateral to the medial extent of P1. The upper visual field is represented ventrally, while the lower field is located dorsally. P2 has only been described in the macaque monkey. It contains a representation of the peripheral visual field, located in its anterior portion, and of the central field, which is located in posterior PL. P4 has a complex topographic arrangement. The representation of the vertical meridian is located on the dorsal edge of P4, while the representation of the horizontal meridian divides P4 into dorsal and ventral portions. PMID- 29116449 TI - Comparative Pulvinar Organization Across Different Primate Species. AB - In this chapter, we compare the pattern of pulvinar immunohistochemical staining for the calcium-binding proteins calbindin and parvalbumin and for the neurofilament protein SMI-32 in macaque, capuchin, and squirrel monkeys. This group of New and Old World primates shares five similar pulvinar subdivisions: PIP, PIM, PIC, PIL, and PILS. In the Old World macaque monkey, the inferior lateral pulvinar can be subdivided into the P1 and P2 fields based on its connectivity with visual area V1. On the other hand, only the P1 field and no P2 was found in the New World capuchin monkey. Notably, the similarities in chemoarchitecture contrast with the distinct connectivity patterns and the different visuotopic organizations found across the species. PMID- 29116450 TI - Response Properties of Pulvinar Neurons Studied with Single-Unit Electrophysiological Recordings. AB - In this chapter, we discuss the types of visual receptive fields revealed by single-unit electrophysiological recordings in the pulvinar. Nearly all neurons with identifiable receptive fields responded to visual stimulation presented on the contralateral hemifield, within 25 degrees of the fovea. The majority of the visual neurons responded to some form of moving stimulus, and some additionally exhibited direction or orientation selectivity. Most units could be driven by monocular stimulation and showed receptive fields of at least 100 square degrees in area. Finally, most of the units recorded exhibited continuous peripheral receptive fields, even though a few of them could be bilaterally activated. PMID- 29116451 TI - Modulation of Pulvinar Neuronal Activity by Arousal. AB - In this chapter, we discuss the modulation of pulvinar neuronal activity by arousal. In contrast to electrophysiological recordings in the early visual cortex, neuronal activity in the pulvinar is particularly sensitive to anesthesia. In the absence of sensory stimulation, pulvinar neurons can be characterized by spontaneous low-frequency rhythmic bursts of spiking activity. However, multisensory stimulation capable of arousing the animal from deeper anesthesia levels is able to reestablish the necessary neuronal dynamics and switch the pulvinar into an active state. Under these conditions, cortical slow wave activity is substituted by a higher-frequency oscillatory pattern associated with arousal. Here, we describe two types of transitions in pulvinar activity pattern that can be observed when arousing the animal with multisensory stimulation. PMID- 29116452 TI - GABA Inactivation of the Pulvinar. AB - In this chapter, we discuss the effects of GABA (gamma-aminobutyric acid) inactivation of the pulvinar on the electrophysiological responses to visual stimuli. A direct way to access the pulvinar-cortical interaction is to pharmacologically inactivate the pulvinar and measure the impact on cortical activity. To this aim, we have focused our efforts on recording in cortical visual area V2 while inactivating the topographically corresponding region of the pulvinar. PMID- 29116453 TI - The Role of the Pulvinar in Spatial Visual Attention. AB - This chapter deals with the role of the pulvinar in spatial visual attention. There are at least two aspects in which the pulvinar seems to be instrumental for selective visual processes. The first aspect concerns pulvinar connectivity pattern. The pulvinar is connected with brain regions known to be playing a role in attentional mechanisms, such as area V4, the superior colliculus (SC), and the inferior parietal cortex (IP). Additionally, the pulvinar is richly interconnected with multiple cortical areas. This enables the pulvinar to serve as a hub for brain communication, potentially gating the flow of information across different regions. The second aspect concerns neuronal circuits intrinsic to the pulvinar. We claim these circuits are subserving three basic steps regarding the allocation of spatial attention: disengaging from the current focus of attention, moving it to a new target, and engaging it at a new position. PMID- 29116454 TI - Characterization of the complete mitochondrial genome of Marshallagia marshalli and phylogenetic implications for the superfamily Trichostrongyloidea. AB - Marshallagia marshalli (Nematoda: Trichostrongylidae) infection can lead to serious parasitic gastroenteritis in sheep, goat, and wild ruminant, causing significant socioeconomic losses worldwide. Up to now, the study concerning the molecular biology of M. marshalli is limited. Herein, we sequenced the complete mitochondrial (mt) genome of M. marshalli and examined its phylogenetic relationship with selected members of the superfamily Trichostrongyloidea using Bayesian inference (BI) based on concatenated mt amino acid sequence datasets. The complete mt genome sequence of M. marshalli is 13,891 bp, including 12 protein-coding genes, 22 transfer RNA genes, and 2 ribosomal RNA genes. All protein-coding genes are transcribed in the same direction. Phylogenetic analyses based on concatenated amino acid sequences of the 12 protein-coding genes supported the monophylies of the families Haemonchidae, Molineidae, and Dictyocaulidae with strong statistical support, but rejected the monophyly of the family Trichostrongylidae. The determination of the complete mt genome sequence of M. marshalli provides novel genetic markers for studying the systematics, population genetics, and molecular epidemiology of M. marshalli and its congeners. PMID- 29116455 TI - Do habituation, host traits and seasonality have an impact on protist and helminth infections of wild western lowland gorillas? AB - Increased anthropogenic activity can result in parasite exchanges and/or general changes in parasite communities, imposing a health risk to great apes. We studied protist and helminth parasites of wild western lowland gorilla groups in different levels of habituation, alongside humans inhabiting Dzanga-Sangha Protected Areas in the Central African Republic. Faeces were collected yearly during November and December from 2007 to 2010 and monthly from November 2010 to October 2011. Protist and helminth infections were compared among gorilla groups habituated, under habituation and unhabituated, and the effect of host traits and seasonality was evaluated. Zoonotic potential of parasites found in humans was assessed. No significant differences in clinically important parasites among the groups in different stages of habituation were found, except for Entamoeba spp. However, humans were infected with four taxa which may overlap with taxa found in gorillas. Females were less infected with spirurids, and adults had higher intensities of infection of Mammomonogamus sp. We found seasonal differences in the prevalence of several parasite taxa, but most importantly, the intensity of infection of unidentified strongylids was higher in the dry season. This study highlights that habituation may not necessarily pose a greater risk of protist and helminth infections in gorilla groups. PMID- 29116456 TI - Soil-plant transfer models for metals to improve soil screening value guidelines valid for Sao Paulo, Brazil. AB - In Brazil, there is a lack of combined soil-plant data attempting to explain the influence of specific climate, soil conditions, and crop management on heavy metal uptake and accumulation by plants. As a consequence, soil-plant relationships to be used in risk assessments or for derivation of soil screening values are not available. Our objective in this study was to develop empirical soil-plant models for Cd, Cu, Pb, Ni, and Zn, in order to derive appropriate soil screening values representative of humid tropical regions such as the state of Sao Paulo (SP), Brazil. Soil and plant samples from 25 vegetable species in the production areas of SP were collected. The concentrations of metals found in these soil samples were relatively low. Therefore, data from temperate regions were included in our study. The soil-plant relations derived had a good performance for SP conditions for 8 out of 10 combinations of metal and vegetable species. The bioconcentration factor (BCF) values for Cd, Cu, Ni, Pb, and Zn in lettuce and for Cd, Cu, Pb, and Zn in carrot were determined under three exposure scenarios at pH 5 and 6. The application of soil-plant models and the BCFs proposed in this study can be an important tool to derive national soil quality criteria. However, this methodological approach includes data assessed under different climatic conditions and soil types and need to be carefully considered. PMID- 29116457 TI - Correction to: Comparison of fracture risk assessment tools in older men without prior hip or spine fracture: the MrOS study. AB - Owing to an oversight by the authors, the acknowledgments were incomplete. PMID- 29116458 TI - 3D gut-liver chip with a PK model for prediction of first-pass metabolism. AB - Accurate prediction of first-pass metabolism is essential for improving the time and cost efficiency of drug development process. Here, we have developed a microfluidic gut-liver co-culture chip that aims to reproduce the first-pass metabolism of oral drugs. This chip consists of two separate layers for gut (Caco 2) and liver (HepG2) cell lines, where cells can be co-cultured in both 2D and 3D forms. Both cell lines were maintained well in the chip, verified by confocal microscopy and measurement of hepatic enzyme activity. We investigated the PK profile of paracetamol in the chip, and corresponding PK model was constructed, which was used to predict PK profiles for different chip design parameters. Simulation results implied that a larger absorption surface area and a higher metabolic capacity are required to reproduce the in vivo PK profile of paracetamol more accurately. Our study suggests the possibility of reproducing the human PK profile on a chip, contributing to accurate prediction of pharmacological effect of drugs. PMID- 29116459 TI - Neonatal Systemic Lupus Erythematosus Syndrome: a Comprehensive Review. AB - Neonatal lupus erythematosus is an uncommon syndrome, which is caused by transplacental passage of maternal autoantibodies to Sjogren's syndrome A or B autoantigens. The clinical presentation includes distinctive cutaneous lesions resembling those seen in systemic lupus erythematosus, hepatobiliary disease, and cytopenias, which disappear with the clearance of maternal autoantibodies. The most severe presentation is a total atrioventricular heart block, which begins during the second trimester of gestation and is irreversible. The risk of having a child with neonatal lupus erythematosus in mothers who test positive for autoantibodies to Sjogren's syndrome autoantigens is approximately 2% for first pregnancies or if previous babies were healthy. The risk increases by approximately tenfold if a previous child had neonatal lupus erythematosus syndrome. The diagnosis of neonatal lupus erythematosus is made when the mother has autoantibodies to Sjogren's syndrome autoantigens, and the fetus or newborn develops atrioventricular heart block, or the newborn develops the typical rash or hepatic or hematologic manifestations in the absence of other explanation. Fetal echocardiography from the 16th to the 26th week of gestation is advised in mothers with autoantibodies to Sjogren autoantigens. The detection of a slow fetal heart rate or the postnatal diagnosis of atrioventricular heart block warrants immediate maternal testing for these autoantibodies if not previously tested. PMID- 29116461 TI - Investigation of the clinical features of lower uterine segment carcinoma: association with advanced stage disease and indication of poorer prognosis. AB - PURPOSE: We retrospectively analyzed the differential clinical features and prognosis of endometrial carcinomas arising from the lower uterus, which are reported to have a poorer prognosis than those arising from the upper uterus. METHODS: 246 patients with endometrial carcinoma who underwent surgery were entered as subjects. RESULTS: Twenty-three were classified as having lower uterine segment carcinomas (LUSC); the remaining 223 were upper uterine segment carcinomas (UUSC). LUSC cases were associated with a more advanced FIGO stage than UUSC (p < 0.001). Deep myometrial invasion and lymph node metastasis were more common in LUSC than in UUSC (p = 0.006 and p < 0.001, respectively). LUSC cases demonstrated significantly shorter overall survival (OS) and progression free survival (PFS) than UUSC (p = 0.02 and p < 0.001, respectively). Multivariate cox proportional hazards analysis demonstrated that the hazard ratio for LUSC was 1.769 for OS and 3.479 for PFS. For endometrial carcinoma survival, FIGO stage and histological type were extracted as independent variables. CONCLUSIONS: LUSC is a high-risk indicator for poorer prognosis for endometrial carcinoma because it is associated with more advanced stage disease, deep myometrial invasion and lymph node metastasis, and indicates a significantly worsened PFS probability. Our analysis concludes that LUSC is FIGO stage dependent and an important factor for OS. PMID- 29116460 TI - Potential usefulness of methyl gallate in the treatment of experimental colitis. AB - Methyl gallate is a gallotannin widely distributed in nature. Previous studies have demonstrated its antioxidant, anti-inflammatory, antimicrobial and anti tumor activities. In the present study, the activity of methyl gallate on experimental models of inflammatory bowel disease has been investigated. Experimental colitis was induced in Sprague-Dawley rats through the intracolonic instillation of an acetic acid solution (2 mL, 4% v/v). Methyl gallate (100 and 300 mg/kg, p.o.) and the reference drug mesalazine (100 mg/kg, p.o.) were tested. Methyl gallate induced a significant reduction in the colon weight/length ratio and macroscopic lesion score. Besides, the malondialdehyde content and the GSSG/GSH ratio were remarkably decreased. Furthermore, the administration of methyl gallate reduced the expression of COX2, IL-6, TNFalpha and the severity of microscopic tissue damage induced by acetic acid, while the mean goblet cell density was significantly higher in both the group treated with methyl gallate and the one treated with mesalazine, in comparison with untreated animals. The Na+K+ATPase pump activity was recovered in treated groups (control: 827.2 +/- 59.6, colitis: 311.6 +/- 54.8, methyl gallate 100 mg/kg: 642.2 +/- 175.0, methyl gallate 300 mg/kg: 809.7 +/- 100.6, mesalazine: 525.3 +/- 81.7). Methyl gallate was also found to induce a significant reduction in the castor oil-induced intestinal motility in Swiss mice, decreasing the peristalsis by 74.5 and 58.82% at 100 and 300 mg/kg p.o., respectively. This compound also antagonized the jejunum contractions induced by Ach and CaCl2. This study demonstrates that methyl gallate exerts beneficial effects in a preclinical model of intestinal disorders. PMID- 29116462 TI - The effect of partial patients' adherence to antihypertensive drugs: scope for pharmacists' role in hypertension care. AB - In many individuals, blood pressure varies between clinic visits conducted days, weeks, or months apart. This visit-to-visit variability (VVV) of blood pressure has been recently related with an increased risk of coronary heart disease, stroke, and mortality, independently of mean blood pressure. As for other chronical diseases, patients' adherence to hypertensive therapies remains low and partial adherence to antihypertensive treatment may constitute a source of VVV, as suggested by recent studies. This data should lead to a new clinical approach for hypertension care, based on patients' real adherence to treatment. Therapeutic strategies should include patients' adherence. In this context, the role of community pharmacists for patients' follow-up of hypertension should be reinforced, as they represent efficient and easily accessible health professionals. PMID- 29116463 TI - Characterization of a novel dsRNA mycovirus isolated from strain A105 of Rhizoctonia solani AG-1 IA. AB - Rhizoctonia solani dsRNA virus 3 (RsRV3), a novel mycovirus, was isolated from the rice sheath blight pathogen Rhizoctonia solani AG-1 IA strain A105. The RsRV3 genome consists of two segments of dsRNA (dsRNA1, 1,890 bp and dsRNA2, 1,811 bp). DsRNA1 has a single open reading frame (ORF) with a putative conserved RNA dependent RNA polymerase (RdRp) domain, and dsRNA2 comprises a single ORF, predicted to encode a coat protein. Purified viral particles of RsRV3 were isometric and measured approximately 20 nm in diameter by negative-stain transmission electron microscope (TEM). Phylogenetic analyses indicated that RsRV3 is highly similar to viruses taxonomically classified in the genus Alphapartitivirus, family Partitiviridae. Taken together, the integrative analyses of viral genomic organization, amino acid sequence alignments and phylogenetic analyses clearly demonstrate that the RsRV3 virus isolated from R. solani AG-1 IA strain A105 is classifiable as a new member of the genus Alphapartitivirus, family Partitiviridae. PMID- 29116464 TI - Venovenous extracorporeal membrane oxygenation devices-related colonisations and infections. AB - BACKGROUND: Nosocomial infections occurring during extracorporeal membrane oxygenation (ECMO) support have already been reported, but few studied infections directly related to ECMO devices. This study aims to evaluate the rate of both colonisations and infections related to ECMO devices at the time of ECMO removal. RESULTS: We included all consecutive adult patients treated with venovenous ECMO (VV-ECMO) for at least 48 h during a 34-month study. At the time of ECMO removal, blood cultures, swab cultures on insertion cannula site and intravascular cannula extremity cultures were systematically performed. Each ECMO device was classified according to the infectious status into three groups: (1) uninfected/uncolonised ECMO device, (2) ECMO device colonisation and (3) ECMO device infection. Ninety nine patients underwent 103 VV-ECMO, representing 1472 ECMO days. The ECMO device infection rate was 9.7% (10 events), including 7 ECMO device-related bloodstream infections (6.8%). The ECMO device colonisation rate was 32% (33 events). No difference was observed between the three groups, regarding days of mechanical ventilation, ICU length of stay, ICU mortality and in-hospital mortality. We observed a longer ECMO duration in the ECMO device colonisation group as compared to the uninfected/uncolonised ECMO device group [12 (9-20 days) vs. 5 days (5-16 days), respectively, p < 0.05]. CONCLUSIONS: At the time of ECMO removal, systematic blood culture and intravascular extremity cannula culture may help to diagnose ECMO device-related infection. We reported a quite low infection rate related to ECMO device. Further studies are needed to evaluate the benefits of systematic strategies of cannula culture at the time of ECMO removal. PMID- 29116465 TI - Hemostatic gauze based on chitosan and hydroquinone: preparation, characterization and blood coagulation evaluation. AB - This work concerns on the preparation and performance evaluation of a new chitosan hydroquinone based gauze for hemostatic use. Chitosan and hydroquinone were firstly connected by etherification and then linked to the pre-carboxylate gauze. The functionalized material and the chitosan-hydroquinone ether were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy and Differential Scanning Calorimetry (DSC). FT-IR results showed that an esterification occurred on carboxylic group of the gauze. The gauze functionalization degree was also evaluated by volumetric analysis. The ether hydroquinone content was obtained by the Folin test. Moreover, the linkage between hydroquinone and chitosan was confirmed by nuclear magnetic resonance (NMR). The hemostatic activity of functionalized gauze was evaluated by dynamic blood clotting assays. The obtained results showed that the prepared material can shorten the blood clotting time and induce the adhesion and activation of platelets. Finally, swelling characteristic of the new gauze was evaluated to confirm its high capacity to absorb the blood. PMID- 29116466 TI - Breast cancer-related paraneoplastic neurologic disease. AB - PURPOSE: Paraneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by malignancy. Given the rarity, a paucity of data describing breast cancer-related PND (BC-PND) exists; we sought to further examine this specific patient population. METHODS: We retrospectively identified patients at our institution from 1997 to 2016 with BC-PND. Retrospective review with a descriptive analysis determined factors associated with PND and BC, which were compared to national breast cancer median of age (61 years) and average stage at diagnosis (60% local disease). RESULTS: BC-PND was diagnosed in 56 female patients at a median age of 52.8 years. Only 20% of invasive cancer patients had local disease. The majority of patients were hormone receptor positive and Her2 negative. Neurological symptoms presented prior to BC diagnosis in 57.1% of patients. Of all patients, 30 (53.6%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]), n = 10; amphiphysin-IgG, n = 9; Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti Ri]), n = 5; and others, n = 6. The most common neurologic findings were cerebellar ataxia, myelopathy, and myopathy. Immunotherapy benefit was found to be robust (21.6%), mild to moderate (52.9%), absent (17.6%), or indeterminate (7.8%). CONCLUSIONS: PND symptoms often presented prior to BC diagnosis, with the BC biologic subtype characteristics typical of the general BC population. BC diagnoses were often made at younger ages than that of the general BC population and with later-stage disease. Roughly 75% of patients benefited from immunotherapy. These data provide helpful information to providers treating this population of patients. PMID- 29116467 TI - Vitamin D supplementation decreases serum 27-hydroxycholesterol in a pilot breast cancer trial. AB - PURPOSE: 27-hydroxycholesterol (27HC), an endogenous selective estrogen receptor modulator (SERM), drives the growth of estrogen receptor-positive (ER+) breast cancer. 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, is known to inhibit expression of CYP27B1, which is very similar in structure and function to CYP27A1, the synthesizing enzyme of 27HC. Therefore, we hypothesized that 1,25(OH)2D may also inhibit expression of CYP27A1, thereby reducing 27HC concentrations in the blood and tissues that express CYP27A1, including breast cancer tissue. METHODS: 27HC, 25-hydroxyvitamin D (25OHD), and 1,25(OH)2D were measured in sera from 29 breast cancer patients before and after supplementation with low-dose (400 IU/day) or high-dose (10,000 IU/day) vitamin D in the interval between biopsy and surgery. RESULTS: A significant increase (p = 4.3E-5) in 25OHD and a decrease (p = 1.7E-1) in 27HC was observed in high-dose versus low-dose vitamin D subjects. Excluding two statistical outliers, 25OHD and 27HC levels were inversely correlated (p = 7.0E-3). CONCLUSIONS: Vitamin D supplementation can decrease circulating 27HC of breast cancer patients, likely by CYP27A1 inhibition. This suggests a new and additional modality by which vitamin D can inhibit ER+ breast cancer growth, though a larger study is needed for verification. PMID- 29116468 TI - Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers. AB - PURPOSE: Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies. METHODS: Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan-Meier analyses were performed. RESULTS: 2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30-39 years. Kaplan-Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002). CONCLUSIONS: The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers. PMID- 29116469 TI - BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation. AB - PURPOSE: BRCA1 germline mutation is closely associated with triple-negative breast cancer. BRCA deficiency leads to impaired DNA repair and tumor development, and understanding this deficiency, in both hereditary and sporadic scenarios, is of great clinical and biological interest. Here, we investigated germline or somatic events that might lead to BRCA1 impairment in triple-negative breast cancer. We also analyzed the clinical implications associated with BRCA deficiency. METHODS: Next-generation sequencing for the BRCA1/2 genes and multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 gene were performed for mutation screening. A customized bisulfite next-generation sequencing approach was used for assessing BRCA1 promoter methylation status in tumor tissue. RESULTS: A total of 131 triple-negative cases were assessed, and germline pathogenic variants were detected in 13.0% of all cases and in 26% of cases diagnosed in young women. Most germline pathogenic variants (88.2%) occurred in the BRCA1 gene. BRCA1 promoter hypermethylation was detected in 20.6% of tumors; none of these tumors were in BRCA1/2 pathogenic variant carriers. BRCA1 impairment by either germline or somatic events was significantly more frequent in young women (55% in those <= 40 years; 33% in those 41-50 years; 22% in those > 50 years of age) and associated with better overall and disease-free survival rates in this group of patients. CONCLUSIONS: BRCA1 deficiency was recurrent in early-onset triple-negative breast cancer in Brazilian patients and associated with improved survival. With the new treatment modalities being investigated, including poly (ADP-ribose)-polymerase (PARP) inhibitor therapy, our results suggest that a significant proportion of young women with this subtype of tumor might benefit from PARP inhibitor treatment, which warrants further investigation. PMID- 29116472 TI - Creativity and intelligence in brains and machines: from individuals to societies : Post-event report about the GK sponsored Interdisciplinary College 2017 (IK2017). PMID- 29116470 TI - Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014-2017). AB - PURPOSE OF REVIEW: Sex differences in the epidemiology and clinical presentation of trauma-related psychopathology have long been documented. Multiple underlying mechanisms have been examined, both psychosocial and biological. Among the most promising biological mechanisms are neural substrates of trauma-related psychopathology that have been uncovered in recent years. RECENT FINDINGS: Neuroimaging studies of sex-related heterogeneity published over the past 3 years (2014-2017) demonstrate an interaction between sex and type, timing, and load of trauma exposure. These studies suggest that, for males, early trauma exposure may involve a loss of gray matter in the limbic system, including the prefrontal cortex (PFC), amygdala, and hippocampus, and an over-activity and increased connectivity of salience hubs, and particularly dorsal anterior cingulate cortex (dACC). For females, however, early trauma exposure may involve overactive and possibly an enlarged amygdala, as well as decreased connectivity of salience hubs such as the dACC. Underlying mechanisms may include interaction with several endocrine systems and result in differential neural response to naturally occurring and added endocrine ligands, as well as sex-specific genetic and epigenetic risk and resilience factors. This complex interaction between multiple biological systems may be associated with sex-specific behavioral patterns, in turn associated with trauma-related psychopathology. While substantial number of published studies present preliminary evidence for neural mechanisms of sex specific posttraumatic responses, there is a paucity of research directly designed to examine sex as a biological factor in trauma-related psychopathology. Specific foci for future studies aiming to bridge current gaps in the literature are discussed. PMID- 29116473 TI - Early Rehabilitation After Stroke: a Narrative Review. AB - PURPOSE OF REVIEW: Despite current rehabilitative strategies, stroke remains a leading cause of disability in the USA. There is a window of enhanced neuroplasticity early after stroke, during which the brain's dynamic response to injury is heightened and rehabilitation might be particularly effective. This review summarizes the evidence of the existence of this plastic window, and the evidence regarding safety and efficacy of early rehabilitative strategies for several stroke domain-specific deficits. RECENT FINDINGS: Overall, trials of rehabilitation in the first 2 weeks after stroke are scarce. In the realm of very early mobilization, one large and one small trial found potential harm from mobilizing patients within the first 24 h after stroke, and only one small trial found benefit in doing so. For the upper extremity, constraint-induced movement therapy appears to have benefit when started within 2 weeks of stroke. Evidence for non-invasive brain stimulation in the acute period remains scant and inconclusive. For aphasia, the evidence is mixed, but intensive early therapy might be of benefit for patients with severe aphasia. Mirror therapy begun early after stroke shows promise for the alleviation of neglect. Novel approaches to treating dysphagia early after stroke appear promising, but the high rate of spontaneous improvement makes their benefit difficult to gauge. The optimal time to begin rehabilitation after a stroke remains unsettled, though the evidence is mounting that for at least some deficits, initiation of rehabilitative strategies within the first 2 weeks of stroke is beneficial. Commencing intensive therapy in the first 24 h may be harmful. PMID- 29116474 TI - Comparative transcriptomes and reciprocal best hit analysis revealed potential pigment genes in two color forms of Tetranychus urticae. AB - Tetranychus urticae Koch is a worldwide agricultural pest. There are two color forms: red and green. The molecular mechanism underlying this color variation is unknown. To elucidate the mechanism, we characterized differentially expressed pigment pathway genes shared in the transcriptomes of these two forms using RNA sequencing and reciprocal best hit analysis. Differentially expressed pigment pathway genes were determined by qRT-PCR to confirm the accuracy of RNA-Seq. The transcriptomes revealed 963 differentially expressed genes (DEGs), of which 687 DEGs were higher in the green form. KEGG enrichment analysis revealed carotenoid biosynthesis genes in T. urticae. Reciprocal best hit analysis revealed 817 putative pigment pathway genes, 38 of which were differentially expressed and mainly classified into four categories: heme, melanin, ommochrome and rhodopsin. Phylogenetic analysis of homologous ommochrome genes showed that tetur09g01950 is closely related to Ok. This study revealed putative pigment pathway genes in the two forms of T. urticae, and might provide a new resource for understanding the mechanism of color variation. PMID- 29116476 TI - Contribution of reactive oxygen species to the anticancer activity of aminoalkanol derivatives of xanthone. AB - Reactive oxygen species (ROS) are critically involved in the action of anticancer agents. In this study, we investigated the role of ROS in the anticancer mechanism of new aminoalkanol derivatives of xanthone. Most xanthones used in the study displayed significant pro-oxidant effects similar to those of gambogic acid, one of the most active anticancer xanthones. The pro-oxidant activity of our xanthones was shown both directly (by determination of ROS induction, effects on the levels of intracellular antioxidants, and expression of antioxidant enzymes) and indirectly by demonstrating that the overexpression of manganese superoxide dismutase decreases ROS-mediated cell senescence. We also observed that mitochondrial dysfunction and cellular apoptosis enhancement correlated with xanthone-induced oxidative stress. Finally, we showed that the use of the antioxidant N-acetyl-L-cysteine partly reversed these effects of aminoalkanol xanthones. Our results demonstrated that novel aminoalkanol xanthones mediated their anticancer activity primarily through ROS elevation and enhanced oxidative stress, which led to mitochondrial cell death stimulation; this mechanism was similar to the activity of gambogic acid. PMID- 29116477 TI - 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma. AB - Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells. This effect was associated with hypophosphorylation of 4E-binding protein 1 (4E-BP1) and decreased protein levels of the cancer-related genes, c-myc and osteopontin. 4EGI-1 showed enhanced cytotoxicity in combination with pemetrexed or gemcitabine. Translatome-wide polysome microarray analysis revealed a large cohort of genes that were translationally regulated upon treatment with 4EGI-1. The 4EGI-1-regulated translatome was negatively correlated to a previously published translatome regulated by eIF4E overexpression in human mammary epithelial cells, which is in agreement with the notion that 4EGI-1 inhibits the eIF4F complex. These data indicate that inhibition of the eIF4F complex by 4EGI-1 or similar translation inhibitors could be a strategy for treating mesothelioma. Genome wide translational profiling identified a large cohort of promising target genes that should be further evaluated for their potential significance in the treatment of MPM. PMID- 29116478 TI - Cyclodextrin polymers as nanocarriers for sorafenib. AB - Polymeric nanoparticles based on cyclodextrins are currently undergoing clinical trials as new promising nanotherapeutics. In light of this interest, we investigated cyclodextrin cross-linked polymers with different lengths as carriers for the poorly water-soluble drug sorafenib. Both polymers significantly enhanced sorafenib solubility, with shorter polymers showing the most effective solubilizing effect. Inclusion complexes between sorafenib and the investigated polymers exhibited an antiproliferative effect in tumor cells similar to that of free sorafenib. Polymer/Sorafenib complexes also showed lower in vivo tissue toxicity than with free sorafenib in all organs. Our results suggest that the inclusion of sorafenib in polymers represents a successful strategy for a new formulation of this drug. PMID- 29116479 TI - Contrasting Grammatical and Lexical Determiners. AB - This paper investigates the difference between the production of grammatical determiners and lexical determiners in the production of adjective-noun phrases (NPs) in Danish. Models of sentence processing (Garrett in Psychology of learning and motivation, Academic press, New York, pp 133-177, 1975; Bock in J Mem Lang 26(2):119-137, 1987) suggest that the phonological encoding stage of grammatical items can only be specified once lexical items have been phonologically encoded. In their usage-based linguistic theory of the grammar-lexicon distinction, Boye and Harder (Lang 88(1):1-44, 2012) propose that this later encoding of grammatical elements is motivated by two specific features of grammatical elements. The first feature, dependence, is that grammatical items (morphemes, words, constructions) cannot be produced in isolation, but are always dependent on a lexical host item. This feature entails a more complex processing which might lead to longer reaction times when comparing the production of NPs with a grammatical determiner to a lexical one. Additionally, a more complex processing might lead to a lower accuracy rate for the grammatical condition relative to the lexical one. The second feature, low prominence, is that grammatical items code background information and therefore cannot convey the main point of a linguistic message. Less focus on grammatical elements might lead to a lower accuracy rate for the production of grammatical elements relative to lexical ones. Those predictions were tested in a task comparing the production of Danish grammatical determiners (indefinite articles) with the production of lexical ones (numerals, which are homonymous with the articles except for a stress difference) in similar contexts. Group-based analyses were performed in order to take inter-individual differences into account. The results show that the two features as proposed by Boye and Harder (2012) are only revealed for the fastest speakers group but not the slower ones. PMID- 29116480 TI - Antimicrobial and antioxidant potential of different solvent extracts of the medicinal plant Geum urbanum L. AB - Many Geum species are known to be rich in biologically active compounds and therefore could be a source of new natural products with pharmacological potential. The medicinal plant Geum urbanum L. is widespread in Bulgaria and has been used in folk medicine. In the present study, the methanol extracts of the roots and aerial parts of G. urbanum and their fractions (petroleum ether, ethyl acetate and n-butanol) were investigated for antibacterial and radical scavenging activity. The ethyl acetate and n-butanol fractions inhibited the growth of Gram positive pathogenic and opportunistic bacteria from the genus Staphylococcus (MIC EtOAc: 0.078 mg/ml aerial and 0.156 mg/ml roots; MIC n-BuOH: 0.156 mg/ml aerial and 1.25 mg/ml roots) and the species Bacillus cereus stronger than the other extracts and fractions tested (MIC EtOAc: 0.078 mg/ml aerial and 0.156 mg/ml roots; MIC n-BuOH: 0.156 mg/ml aerial and 0.078 mg/ml roots), and showed corresponding radical scavenging activity (EtOAc: EC50 1.5 ug/ml aerial, 0.8 ug/ml roots; n-BuOH: 4.5 ug/ml aerial; 3.7 ug/ml roots). Additionally, their total phenolic content was quantified (% of dry EtOAc fractions of roots 61%, of arial parts 32%; of dry n-BuOH fractions of roots 16%, of arial parts 13%). Seven compounds were isolated and identified spectroscopically from the ethyl acetate extract. Two acetylated ellagic acid rhamnosides were found for the first time in the genus Geum and three others, tormentic acid, niga-ichigoside F1, and 3,3'-di O-methylellagic acid-4-O-beta-D-glucopyranoside, were newly detected for the species G. urbanum. Our results reveal that G. urbanum L. is a perspective medicinal plant and deserves further, more detailed studies. PMID- 29116481 TI - Effects of combined application of nitrogen fertilizer and biochar on the nitrification and ammonia oxidizers in an intensive vegetable soil. AB - Soil amended with single biochar or nitrogen (N) fertilizer has frequently been reported to alter soil nitrification process due to its impact on soil properties. However, little is known about the dynamic response of nitrification and ammonia-oxidizers to the combined application of biochar and N fertilizer in intensive vegetable soil. In this study, an incubation experiment was designed to evaluate the effects of biochar and N fertilizer application on soil nitrification, abundance and community shifts of ammonia-oxidizing bacteria (AOB) and ammonia oxidizing archaea (AOA) in Hangzhou greenhouse vegetable soil. Results showed that single application of biochar had no significant effect on soil net nitrification rates and ammonia-oxidizers. Conversely, the application of only N fertilizer and N fertilizer + biochar significantly increased net nitrification rate and the abundance of AOB rather than AOA, and only AOB abundance was significantly correlated with soil net nitrification rate. Moreover, the combined application of N fertilizer and biochar had greater effect on AOB communities than that of the only N fertilizers, and the relative abundance of 156 bp T-RF (Nitrosospira cluster 3c) decreased but 60 bp T-RF (Nitrosospira cluster 3a and cluster 0) increased to become a single predominant group. Phylogenetic analysis indicated that all the AOB sequences were grouped into Nitrosospira cluster, and most of AOA sequences were clustered within group 1.1b. We concluded that soil nitrification was stimulated by the combined application of N fertilizer and biochar via enhancing the abundance and shifting the community composition of AOB rather than AOA in intensive vegetable soil. PMID- 29116482 TI - Early initiation of chemoradiation may not influence survival of high-grade gliomas. PMID- 29116483 TI - Pittsburgh compound B (PiB) PET imaging of meningioma and other intracranial tumors. AB - Meningiomas are the most common intracranial tumors. Diagnosis by MRI is generally straightforward, but lack of imaging specificity can present a diagnostic dilemma, particularly in patients with cancer. We report our experience with meningioma identification on Pittsburgh compound B (PiB) PET/CT. Patients who underwent PiB PET/CT from 2006 to 2015 were reviewed to identify those with intracranial tumors. Tumor types were classified by MR appearance, or by pathology when available. Maximum standardized uptake value (SUVmax) measurements of tumor PiB activity were compared across tumor types. 2472 patients underwent PiB PET/CT in the period of interest; 45 patients (1.8%) had probable or definite intracranial tumor. Tumor types were meningioma (29/45, 64%), vestibular schwannoma (7/45, 16%), pituitary macroadenoma (4/45, 9%), metastatic disease (2/45, 4%), and others (3/45, 7%). In patients with meningioma, the mean lesion SUVmax was 2.05 (SD 1.37), versus 1.00 (SD 0.42) in patients with non-meningioma tumors (p < 0.01). A receiver operating curve was created for lesion:cerebellum SUVmax ratio, with an area under the curve of 0.91 for a value of 1.68. At or above this ratio, specificity for meningioma was 100% (95% CI 79-100%) and sensitivity was 76% (95% CI 57-90%). PiB PET activity within an intracranial tumor is a highly specific and reasonably sensitive marker of meningioma. Further prospective evaluation is warranted to validate this result as well as to assess the performance of commercially available beta-amyloid radiotracers in meningioma identification. PMID- 29116484 TI - Suppression of glioblastoma growth and angiogenesis through molecular targeting of methionine aminopeptidase-2. AB - Methionine aminopeptidases (MetAPs) have been pharmacologically linked to cell growth, angiogenesis, and tumor progression, which make it an attractive target for cancer therapy. We investigated MetAP2's biological role in glioblastoma (GBM), an aggressive tumor characterized by massive neovascularization. We examined the effect of anti-MetAP2 RNA interference on proliferation and angiogenesis in GBM cell line. The biological effects of MetAP2 knockdown were assessed by comparing the proliferation, tumorigenecity, and angiogenesis of parental cells and MetAP2 knockdown cells. We generated MetAP2 knockdown cells using lentiviral short hairpin RNAs against MetAP2 in SNB19 GBM cells, which normally express high levels of MetAP2. MetAP2 knockdown cells were less proliferative and less tumorigenic when compared to the parental cells. MetAP2 knockdown decreased vascular endothelial growth factor (VEGF) secretion and expression at the mRNA and protein levels. Decreased VEGF expression in MetAP2 knockdown cells correlated very well with decreased vessel formation in a tube formation assay. We showed that VEGF suppression in MetAP2 knockdown cells was mediated by the von Hippel-Lindau protein. In in vivo animal studies using an intracranial SNB19 tumor model, MetAP2 knockdown also reduced the tumor growth rate and angiogenesis, which in turn prolonged the survival of mice in xenograft model. Our results show that MetAP2 regulates angiogenesis in GBM and identify MetAP2-specific substrates that may serve as candidates for clinical assay development. PMID- 29116485 TI - Prevalence, risk factors, and response to treatment for hypersomnia of central origin in survivors of childhood brain tumors. AB - Daytime sleepiness is recognized in childhood brain tumor survivors. Our objective was to determine prevalence, risk factors for PSG/MLST proven hypersomnia/narcolepsy, and response to stimulants in childhood brain tumor survivors. Standard PSG/MSLT criteria were used to diagnose hypersomnia/narcolepsy. Medical records of brain tumor survivors having undergone a PSG/MSLT were reviewed for the diagnostic code of hypersomnia/narcolepsy. Survivors with hypersomnia/narcolepsy were matched with 2-3 survivors without reported hypersomnia/narcolepsy by age at tumor diagnosis, gender, and time from tumor diagnosis. Between January 2000 to April 2015, 39 of the 2336 brain tumor patients treated at our institution were diagnosed with hypersomnia/narcolepsy for a prevalence rate of 1670/100,000. Hypersomnia/narcolepsy was diagnosed at a median of 6.1 years (range 0.4-13.2) from tumor diagnosis and 4.7 years (range - 1.5 to 10.4) from cranial radiation. Midline tumor location (OR 4.6, CI 1.7-12.2, p = 0.002) and anti-epilepsy drug (AED) use (OR 11, CI 2.4-54) correlated with hypersomnia/narcolepsy while radiation dose > 30 Gray trended towards significance (OR 1.8, CI 0.9-3.6); posterior fossa tumor location reduced the risk (OR 0.1, CI 0.04-0.5, p = 0.002). AED use also correlated with midline tumor location. Thirty-seven survivors were treated with stimulants and reported improved wakefulness and school performance [response rate CI 0.97 (0.86-0.99) and 0.83 (0.65-0.94)]. Prevalence of hypersomnia/narcolepsy among childhood brain tumor survivors was higher than the general population. Tumor location and radiation dose were possible risk factors, and stimulants were reported to be beneficial. PMID- 29116486 TI - Comment: Detailed Pathologic Examination of Completion Node Dissection Specimens and Outcome for Melanoma Patients with Minimal (< 0.1 mm) Sentinel Lymph Node Metastases. PMID- 29116487 TI - Port-Site Resection in the Surgical Management of Incidental Gallbladder Cancer: A Still Inconclusive Question: A Reply. PMID- 29116488 TI - The Relationship Between Clavien-Dindo Morbidity Classification and Oncologic Outcomes After Colorectal Cancer Resection. AB - BACKGROUND: Limited data on the relationship between postoperative complications (POCs) after colorectal cancer resection and oncologic outcomes are available. We hypothesized that the increased severity of POCs is associated with progressively worse oncologic outcomes. METHODS: Patients with pathological stages I-III colorectal adenocarcinoma undergoing elective curative resection in a single institution between 2000 and 2012 were identified from a prospectively collected database. The severity of POCs was determined using the Clavien-Dindo classification, and oncologic outcomes were assessed. RESULTS: Of 2266 patients, 669 (30%) had at least one POC. POCs were not associated with pathologic stage (p = 0.58) or use of adjuvant therapy (p = 0.19). With a mean follow-up of 5.3 years, POCs were associated with decreased 5-year overall survival (OS) (60% vs. 77%, p < 0.001), disease-free survival (DFS) (53% vs. 70%, p < 0.001), cancer specific survival (CSS) (81% vs. 87%, p < 0.001), and increased overall recurrence rates (19% vs. 15%, p = 0.008). Increasing Clavien-Dindo scores from I to IV was significantly associated with progressively decreasing OS (71, 64, 60, 22%, p < 0.001), DFS (65, 58, 51, 19%, p < 0.001), CSS (88, 77, 79, 74%, p < 0.001), and increasing recurrence rates (12, 20, 26, 18%, p = 0.002). Multivariate analysis confirmed POCs as an independent factor associated with decreased OS [hazard ratio (HR) 0.63, 95% CI 0.52-0.76], DFS (HR 0.64, 95% CI 0.54-0.76), CSS (HR 0.73, 95% CI 0.56-0.97), and increased recurrence rates (HR 1.36, 95% CI 1.02-1.80). CONCLUSIONS: POCs are associated with adverse oncologic outcomes, with increasing effect with higher Clavien-Dindo score. Efforts to reduce both the incidence and severity of complications should result in improved oncologic outcomes. PMID- 29116489 TI - Long-Term Survival According to Histology and Radiologic Response to Preoperative Chemotherapy in 126 Patients Undergoing Resection of Non-GIST Sarcoma Liver Metastases. AB - BACKGROUND: Non-gastrointestinal stromal tumor sarcomas (NGSs) have heterogeneous histology, and this heterogeneity may lead to uncertainty regarding the prognosis of patients with liver metastases from NGS (NGSLM) and decision regarding their surgical management. Furthermore, the role of preoperative chemotherapy in treatment of NGSLM remains poorly defined. We investigated long-term survival and its correlation to response to preoperative chemotherapy in patients with NGSLM. PATIENTS AND METHOD: Patients who underwent liver resection for NGSLM during 1998 2015 were identified. Clinical, histopathologic, and survival data were analyzed. Multivariate analysis was performed using a Cox proportional hazards model. RESULTS: 126 patients [62 (49%) with leiomyosarcoma] were included. Five-year overall survival (OS) and recurrence-free survival (RFS) rates were 49.3 and 14.9%, respectively. Survival did not differ by histologic subtype, primary tumor location, or use of preoperative or postoperative chemotherapy. NGSLM >= 10 cm and extrahepatic metastases at NGSLM diagnosis were the only independent risk factors for OS. In the 83 (66%) patients with metachronous NSGLM, disease-free interval > 6 months was associated with improved OS and RFS. Among the 65 patients (52%) who received preoperative chemotherapy, radiologic response according to Choi criteria specifically was associated with improved OS (p = 0.04), but radiologic response according to RECIST 1.1 criteria was not. CONCLUSIONS: Resection of NGSLM led to a 5-year OS rate of 49%, independent of histologic subtype and primary tumor location. Choi criteria (which take into account tumor density) are superior to RECIST 1.1 in assessing radiologic response and should be used to assess response to preoperative chemotherapy. PMID- 29116490 TI - Impact of Sarcopenic Obesity on Failure to Rescue from Major Complications Following Pancreaticoduodenectomy for Cancer: Results from a Multicenter Study. AB - BACKGROUND: Failure to rescue (FTR) is a quality-of-care indicator in pancreatic surgery, but may also identify patients who may not tolerate major postoperative complications despite being treated with best available care. Previous studies found that high visceral adipose tissue-to-skeletal muscle ratio is associated with poor outcomes following pancreaticoduodenectomy (PD). The aim of the study is to assess the impact of sarcopenic obesity on occurrence of FTR from major complications in cancer patients undergoing PD. METHODS: Prospectively collected data from three high-volume hospitals were reviewed. Total abdominal muscle area (TAMA) and visceral fat area (VFA) were assessed at preoperative staging computed tomography scan. Sarcopenic obesity was defined as high VFA/TAMA ratio. FTR was defined as postoperative mortality following major complication. RESULTS: 120 patients with major complications were included. FTR occurred in 23 (19.2%) patients. The "seminal" complications leading to FTR were pancreatic or biliary fistula-related sepsis (n = 14), postoperative pancreatic fistula (POPF)-related hemorrhage (n = 5), and duodenojejunal anastomosis leak-related sepsis (n = 1). On univariate analysis, older age [odds ratio (OR) 3.5, p = 0.034], American Society of Anesthesiologists (ASA) score 3+ (OR 4.2, p = 0.005), cardiovascular disease (OR 3.3, p = 0.013), low serum albumin (OR 2.6, p = 0.042), sarcopenic obesity (OR 4.2, p = 0.009), POPF (OR 3.1, p = 0.027), and cardiorespiratory complications (OR 3.7, p = 0.011) were significantly associated with FTR. On multivariate analysis, sarcopenic obesity [OR 5.7, 95% confidence interval (CI) 1.6-20.7, p = 0.008], ASA score 3+ (OR 4.1, 95% CI 1.2-14.3, p = 0.025), and pancreatic fistula (OR 3.2, 95% CI 1.0-10.2, p = 0.045) were independently associated with FTR. CONCLUSION: Sarcopenic obesity, low preoperative physical status, and occurrence of pancreatic fistula are associated with significantly higher risk of FTR from major complications after PD. PMID- 29116491 TI - Prognostic and Predictive Value of O6-methylguanine Methyltransferase for Chemotherapy in Patients with Muscle-Invasive Bladder Cancer. AB - PURPOSE: DNA repair genes are potential biomarkers for chemotherapy in muscle invasive bladder cancer (MIBC). O6-methylguanine methyltransferase (MGMT) is involved in DNA repair and is found to affect the efficacy of platinum-based chemotherapy. However, the prognostic or predictive value of MGMT expression in chemotherapy for MIBC is unknown. MATERIALS AND METHODS: Immunohistochemical staining for MGMT was performed in paraffin-embedded tumor tissue of high-grade MIBC patients who underwent cystectomy in two independent cohorts [n = 74 for Fudan University Shanghai Cancer Center (FUSCC) cohort and n = 115 for Zhongshan Hospital (ZS) cohort]. MGMT messenger RNA (mRNA) analysis was conducted using patients' clinical and fragments per kilobase of exon model per million mapped fragments mRNA data from The Cancer Genome Atlas (TCGA) database (n = 245). RESULTS: In our cohorts, high MGMT expression was significantly correlated with shorter overall survival (OS) in patients with platinum-based adjuvant chemotherapy [hazard ratio (HR) 2.386, p = 0.048; HR 2.920, p = 0.007; HR 2.324, p = 0.004, respectively, in FUSCC, ZS, and combination sets], but not in patients without chemotherapy. These findings were corroborated by the TCGA set (HR 1.952 and 0.697 for patients with and without chemotherapy, respectively). The chemotherapy-MGMT interaction for OS was significant in both the surgery set (p = 0.045) and TCGA set (p = 0.034). CONCLUSIONS: We demonstrated that high MGMT expression is an independent poor prognostic factor in MIBC patients with platinum-based adjuvant chemotherapy, but not in patients without chemotherapy. MGMT expression may be a potential predictor for administration of adjuvant chemotherapy. PMID- 29116492 TI - Reply to "Complications in DIEP Flap Breast Reconstruction After Mastectomy for Breast Cancer: A Prospective Cohort Study Comparing Unilateral Versus Bilateral Reconstructions". PMID- 29116493 TI - Response to "The CUBE Technique: Continuous Ultrasound-Guided Breast Excision," Published in August 2014 by Tummel et al. Amsterdam, 28th January 2015. PMID- 29116494 TI - Clinical and microbiological effectiveness of photodynamic therapy on primary endodontic infections: a 6-month randomized clinical trial. AB - INTRODUCTION: This short-term randomized controlled trial evaluated the effectiveness of photodynamic therapy (PDT) on clinical success (periapical healing) and on the microbiota of primary endodontic infections. METHODS: Thirty two patients presenting mandibular molars with apical periodontitis (one tooth/patient) were selected and randomly allocated into two therapeutic groups: control (chemo-mechanical debridement [CMD]; n = 16) and PDT (CMD + PDT; n = 16). All teeth in both groups had intracanal medication with calcium hydroxide for 7 days before final obturation. Follow-up radiographs were made at 3 and 6 months. Periapical healing was evaluated by the periapical index (PAI). Samples were obtained at baseline, after CMD with or without PDT, and just before root filling to determine the frequency and levels of 37 taxa by checkerboard. RESULTS: Significant decreases in PAI scores were observed in both groups over time, although at 6 months, the PDT group presented a significantly better healing score than the control (p < 0.05). At baseline, the most prevalent species in all samples were Candida albicans (46.9%), Dialister pneumosintes (31.2%), Prevotella nigrescens (28.2%), Prevotella tannerae (28.1%), and Peptostreptococcus anaerobius (25%). Most species reduced over time in both groups, and no significant differences in frequency and levels of the tested species were observed between groups in any time point evaluated. C. albicans and D. pneumosintes were still detected in high frequency in both groups at 3 months post-therapy. CONCLUSIONS: Conventional endodontic therapy with or without PDT is effective in reducing microbial load, resulting in periapical healing. Nevertheless, adjunctive PDT provides better periapical healing at 6-month follow up. CLINICAL RELEVANCE: Teeth with apical periodontitis treated with PDT adjunct to conventional treatment would demonstrate superior healing and reduction of microorganisms. PMID- 29116495 TI - Mandibular kinematics and maximum voluntary bite force following segmental resection of the mandible without or with reconstruction. AB - OBJECTIVES: The purpose was to analyze mandibular kinematics and maximum voluntary bite force in patients following segmental resection of the mandible without and with reconstruction (autologous bone, alloplastic total temporomandibular joint replacement (TMJ TJR)). MATERIALS AND METHODS: Subjects operated from April 2002 to August 2014 were enrolled in the study. Condylar (CRoM) and incisal (InRoM) range of motion and deflection during opening, condylar retrusion, incisal lateral excursion, mandibular rotation angle during opening, and maximum voluntary bite force were determined on the non-affected site and compared between groups. Influence of co-factors (defect size, soft tissue deficit, neck dissection, radiotherapy, occlusal contact zones (OCZ), and time) was determined. RESULTS: Twelve non-reconstructed and 26 reconstructed patients (13 autologous, 13 TMJ TJR) were included in the study. InRoM opening and bite force were significantly higher (P <= .024), and both condylar and incisal deflection during opening significantly lower (P <= .027) in reconstructed patients compared with non-reconstructed. Differences between the autologous and the TMJ TJR group were statistically not significant. Co-factors defect size, soft tissue deficit, and neck dissection had the greatest impact on kinematics and number of OCZs on bite force. CONCLUSIONS: Reconstructed patients (both autologous and TMJ TJR) have better overall function than non-reconstructed patients. CLINICAL RELEVANCE: Reconstruction of segmental mandibular resection has positive effects on mandibular function. TMJ TJR seems to be a suitable technique for the reconstruction of mandibular defects including the TMJ complex. PMID- 29116497 TI - Construction of Human Immune and Naive scFv Libraries. AB - Antibody phage display is the most commonly used in vitro selection technology for the generation of human recombinant antibodies and has yielded thousands of useful antibodies for research, diagnostics, and therapy. The prerequisite for successful generation of antibodies using phage display is the construction of high-quality antibody gene libraries. Here, we give the detailed methods for the construction of human immune and naive scFv gene libraries. PMID- 29116498 TI - Construction of Naive and Immune Human Fab Phage-Display Library. AB - This protocol describes the processes involved in the generation of human antibody libraries in Fab format. The antibody repertoire is derived from peripheral blood mononucleocytes focusing on different immunoglobulin isotypes. A two-step cloning process was used to generate a diverse human Fab library for subsequent selection by phage display. The method can be applied for the generation of both naive and immune antibody libraries. The naive repertoire allows for the library to be applied for the generation of human monoclonal antibodies against a broad range of target antigens making it a useful resource for antibody generation. However, the immune repertoire will be focused against target antigens from a particular disease. The protocol will focus on the generation of the library including the panning process. PMID- 29116496 TI - Influence of a calcium hydroxide-based intracanal dressing on the quality of the root canal filling assessed by capillary flow porometry. AB - OBJECTIVE: The objective of this study is to evaluate the influence of a calcium hydroxide intracanal dressing (CH) on the short- and long-term sealing ability of the root canal filling using capillary flow porometry (CFP). MATERIALS AND METHODS: To verify the repeatability of the method, five obturated specimens were submitted to CFP. Measurements were repeated three times and compared with the non-parametric Friedman test. Forty-five instrumented palatal roots were randomly divided into three groups. Group 1: specimens were obturated in one step without placement of any dressing. Group 2: CH was placed and removed after 1 week with syringe irrigation before obturation. Group 3: CH was placed and removed after 1 week with ultrasonic activation before obturation. CFP measurements were conducted at 1 week and 6 months after obturation. The inter-group comparisons were performed using the Kruskal-Wallis test and the intra-group comparison over time using the Wilcoxon signed-rank test. Significance level was set at 0.05. RESULTS: In the five specimens, no difference could be detected between the consecutive measurements for minimum, mean flow, and maximum pore diameter indicating repeatability of the method. No difference in sealing ability could be detected neither between the 3 groups at 1 week and at 6 months nor within each group between the 1 week and the 6 months measurements. CONCLUSIONS: Placement of a CH did not affect significantly the short- and long-term sealing ability of the root canal filling. CLINICAL RELEVANCE: The use of an intermediary CH does not negatively influence the quality of the root canal filling. PMID- 29116499 TI - Construction of Synthetic Antibody Phage-Display Libraries. AB - Synthetic antibody libraries provide a vast resource of renewable antibody reagents that can rival or exceed those of natural antibodies and can be rapidly isolated through controlled in vitro selections. Use of highly optimized human frameworks enables the incorporation of defined diversity at positions that are most likely to contribute to antigen recognition. This protocol describes the construction of synthetic antibody libraries based on a single engineered human autonomous variable heavy domain scaffold with diversity in all three complementarity-determining regions. The resulting libraries can be used to generate recombinant domain antibodies for a wide range of protein antigens using phage display. Furthermore, analogous methods can be used to construct antibody libraries based on larger antibody fragments or second-generation libraries aimed to fine-tune antibody characteristics including affinity, specificity, and manufacturability. The procedures rely on standard reagents and equipment available in most molecular biology laboratories. PMID- 29116500 TI - Modular Construction of Large Non-Immune Human Antibody Phage-Display Libraries from Variable Heavy and Light Chain Gene Cassettes. AB - Monoclonal antibodies and antibody-derived therapeutics have emerged as a rapidly growing class of biological drugs for the treatment of cancer, autoimmunity, infection, and neurological diseases. To support the development of human antibodies, various display techniques based on antibody gene repertoires have been constructed over the last two decades. In particular, scFv-antibody phage display has been extensively utilized to select lead antibodies against a variety of target antigens. To construct a scFv phage display that enables efficient antibody discovery, and optimization, it is desirable to develop a system that allows modular assembly of highly diverse variable heavy chain and light chain (Vkappa and Vlambda) repertoires. Here, we describe modular construction of large non-immune human antibody phage-display libraries built on variable gene cassettes from heavy chain and light chain repertoires (Vkappa- and Vlambda-light can be made into independent cassettes). We describe utility of such libraries in antibody discovery and optimization through chain shuffling. PMID- 29116501 TI - Construction of Macaque Immune-Libraries. AB - Rapidly after the clinical success of the first murine therapeutic antibody licensed in 1985 (muromomab-CD3), the first limits of the therapeutic use of antibodies deriving from hybridoma technology appeared. Indeed, the nonhuman nature of these therapeutic antibodies makes them immunogenic when administrated to patients, which develop anti-drug antibodies (ADA). If repeated drug administrations are needed, the immune response will accelerate the elimination of the drug, leading to a therapeutic failure, or in the worst case to an anaphylactic reaction against the murine protein. Several antibody generations were then developed to obtain better-tolerated molecules: chimeric, humanized, and fully human antibodies. The first antibody generation is fully based on cellular technology (mice hybridoma technology), but the next generations are improved by molecular engineering. Immune antibody phage-display libraries are one successful approach to isolating such engineered antibodies. One strategy to isolate high-affinity and well-tolerated antibodies when no immunized patients are available is based on the phage-display-screening of immune libraries deriving from immunized nonhuman primates, which are phylogenetically close to humans. This chapter presents the strategy for the construction of macaque antibody immune-libraries. PMID- 29116502 TI - Construction of Bovine Immunoglobulin Libraries in the Single-Chain Fragment Variable (scFv) Format. AB - Recombinant immunoglobulins are an excellent tool for diagnosis, treatment, and passive immunization. Phage display offers a robust technique for the selection of recombinant antibodies from immunoglobulin libraries. The construction of immunoglobulin libraries for veterinary purposes was restricted by the lack of knowledge about species-specific diversities.The now available data enable the construction of highly diverse libraries in livestock like cattle. Using diverse primer sets, the immunoglobulin repertoire is amplified and ligated into a phagemid. Infection of E. coli with filamentous phages allows the display of the immunoglobulin fragments on the surface as a fusion protein to the phage's minor coat protein 3. PMID- 29116503 TI - Construction of Rabbit Immune Antibody Libraries. AB - Rabbits have distinct advantages over mice as a source of target-specific antibodies. They produce higher affinity antibodies than mice, and may elicit strong immune response against antigens or epitopes that are poorly immunogenic or tolerated in mice. However, a great majority of currently available monoclonal antibodies are of murine origin because of the wider availability of murine fusion partner cell lines and well-established tools and protocols for fusion and cloning of mouse hybridoma. Phage-display selection of antibody libraries is an alternative method to hybridoma technology for the generation of target-specific monoclonal antibodies. High-affinity monoclonal antibodies from nonmurine species can readily be obtained by constructing immune antibody libraries from B cells of the immunized animal and screening the library by phage display. In this article, we describe the construction of a rabbit immune Fab library for the facile isolation of rabbit monoclonal antibodies. After immunization, B-cell cDNA is obtained from the spleen of the animal, from which antibody variable domain repertoires are amplified and assembled into a Fab repertoire by PCR. The Fab genes are then cloned into a phagemid vector and transformed to E. coli, from which a phage-displayed immune Fab library is rescued. Such a library can be biopanned against the immunization antigen for rapid identification of high affinity, target-specific rabbit monoclonal antibodies. PMID- 29116504 TI - Generation of Semi-Synthetic Shark IgNAR Single-Domain Antibody Libraries. AB - Besides classical antibodies with the composition of heavy and light chains, sharks produce a unique heavy chain only isotype, termed Immunoglobulin New Antigen Receptor (IgNAR), in which antigen binding is solely mediated by a single domain, referred to as vNAR. Owing to their high affinity and specificity combined with their small size and high stability, vNAR domains emerged as promising target-binding scaffolds that can be tailor-made for biotechnological and biomedical applications. Herein, we describe protocols for the construction of semi-synthetic, CDR3-randomized vNAR libraries for the isolation of target specific antibodies using yeast surface display or phage display as platform technology. Additionally, we provide information for affinity maturation of target-specific molecules through CDR1 diversification and sublibrary establishment. PMID- 29116505 TI - Construction of High-Quality Camel Immune Antibody Libraries. AB - Single-domain antibodies libraries of heavy-chain only immunoglobulins from camelids or shark are enriched for high-affinity antigen-specific binders by a short in vivo immunization. Thus, potent binders are readily retrieved from relatively small-sized libraries of 107-108 individual transformants, mostly after phage display and panning on a purified target. However, the remaining drawback of this strategy arises from the need to generate a dedicated library, for nearly every envisaged target. Therefore, all the procedures that shorten and facilitate the construction of an immune library of best possible quality are definitely a step forward. In this chapter, we provide the protocol to generate a high-quality immune VHH library using the Golden Gate Cloning strategy employing an adapted phage display vector where a lethal ccdB gene has to be substituted by the VHH gene. With this procedure, the construction of the library can be shortened to less than a week starting from bleeding the animal. Our libraries exceed 108 individual transformants and close to 100% of the clones harbor a phage display vector having an insert with the length of a VHH gene. These libraries are also more economic to make than previous standard approaches using classical restriction enzymes and ligations. The quality of the Nanobodies that are retrieved from immune libraries obtained by Golden Gate Cloning is identical to those from immune libraries made according to the classical procedure. PMID- 29116506 TI - Construction of Chicken Antibody Libraries. AB - Recombinant antibody libraries based on chicken immunoglobulin genes are potentially valuable sources of phage displayed scFvs for use in veterinary diagnostics and research. The libraries described in this chapter are based on chicken variable heavy and light chain immunoglobulin genes joined by a short flexible linker cloned in the phagemid vector pHEN1. The resulting phagemids produce either scFvs displayed on the surface of the fusion phage subsequent to co-infection with helper phage, or soluble scFvs following IPTG induction. This chapter provides detailed and proven methods for the construction of such libraries. PMID- 29116507 TI - Construction and Selection of Affilin(r) Phage Display Libraries. AB - Affilin(r) molecules represent a new class of so-called scaffold proteins. The concept of scaffold proteins is to use stable and versatile protein structures which can be endowed with de novo binding properties and specificities by introducing mutations in surface exposed amino acid residues. Complex variations and combinations are generated by genetic methods of randomization resulting in large cDNA libraries. The selection for candidates binding to a desired target can be executed by display methods, especially the very robust and flexible phage display. Here, we describe the construction of ubiquitin based Affilin(r) phage display libraries and their use in biopanning experiments for the identification of novel protein ligands. PMID- 29116508 TI - Construction of a Synthetic Antibody Gene Library for the Selection of Intrabodies and Antibodies. AB - Libraries of antibody fragments displayed on filamentous phages have proved their value to generate human antibodies against virtually any target. We describe here a simple protocol to make large and diverse libraries based on a single or a limited number of frameworks. The approach is flexible enough to be used with any antibody format, either single-chain (scFv, VHH) or multi-chain (Fv, Fab, (Fab')2), and to target in a single step the six complementarity-determining regions-or any other part-of the antibody molecule. Using this protocol, libraries larger than 1010 can be easily constructed in a single week. PMID- 29116509 TI - Targeting Intracellular Antigens with pMHC-Binding Antibodies: A Phage Display Approach. AB - Antibodies that bind peptide-MHC (pMHC) complex in a manner akin to T-cell receptor (TCR) have not only helped in understanding the mechanism of TCR-pMHC interactions in the context of T-cell biology, but also spurred considerable interest in recent years as potential cancer therapeutics. Traditional methods to generate such antibodies using hybridoma and B-cell sorting technologies are sometimes inadequate, possibly due to the small contribution of peptide to the overall B-cell epitope space on the surface of the pMHC complex (typical peptide MW = 1 kDa versus MHC MW = 45 kDa), and to the multiple efficiency limiting steps inherent in these methods. In this chapter, we describe a phage display approach for the rapid generation of such antibodies with high specificity and affinity. PMID- 29116510 TI - Parallelized Antibody Selection in Microtiter Plates. AB - The most common in vitro technology to generate human antibodies is phage display. This technology is a key technology to select recombinant antibodies for the use as research tools, in diagnostic tests, and for the development of therapeutics.In this review, the high-throughput compatible selection of antibodies (scFv) in microtiter plates is described. The given detailed protocols allow the antibody selection ("panning"), screening and identification of monoclonal antibodies in less than 1 week. PMID- 29116511 TI - Mass Spectrometry Immuno Assay (MSIATM) Streptavidin Disposable Automation Research Tips (D.A.R.T's(r)) Antibody Phage Display Biopanning. AB - Antibody phage display has been widely established as the method of choice to generate monoclonal antibodies with various efficacies post hybridoma technology. This technique is a popular method which takes precedence over ease of methodology, time- and cost-savings with comparable outcomes to conventional methods. Phage display technology manipulates the genome of M13 bacteriophage to display large diverse collection of antibodies that is capable of binding to various targets (nucleic acids, peptides, proteins, and carbohydrates). This subsequently leads to the discovery of target-related antibody binders. There have been several different approaches adapted for antibody phage display over the years. This chapter focuses on the semi-automated phage display antibody biopanning method utilizing the MSIATM streptavidin D.A.R.T's(r) system. The system employs the use of electronic multichannel pipettes with predefined programs to carry out the panning process. The method should also be adaptable to larger liquid handling instrumentations for higher throughput. PMID- 29116512 TI - Magnetic Nanoparticle-Based Semi-Automated Panning for High-Throughput Antibody Selection. AB - The application of recombinant human antibodies is growing rapidly mainly in the field of diagnostics and therapeutics. To identify antibodies against a specific antigen, panning selection is carried out using different display technologies. Phage display technology remains the preferred platform due to its robustness and efficiency in biopanning experiments. There are both manual and semi-automated panning selections using polystyrene plastic, magnetic beads, and nitrocellulose as the immobilizing solid surface. Magnetic nanoparticles allow for improved antigen binding due to their large surface area. The Kingfisher Flex magnetic particle processing system was originally designed to aid in RNA, DNA, and protein extraction using magnetic beads. However, the system can be programmed for antibody phage display panning. The automation allows for a reduction in human error and improves reproducibility in between selections with the preprogrammed movements. The system requires minimum human intervention to operate; however, human intervention is needed for post-panning steps like phage rescue. In addition, polyclonal and monoclonal ELISA can be performed using the semi-automated platform to evaluate the selected antibody clones. This chapter will summarize the suggested protocol from the panning stage till the monoclonal ELISA evaluation. Other than this, important notes on the possible optimization and troubleshooting are also included at the end of this chapter. PMID- 29116513 TI - Phage Display and Selections on Cells. AB - Antibody identification by phage display on protein or peptide targets is well established and many protocols are available. But there are many targets that cannot be expressed recombinantly or, like peptides, do not reflect correct folding of the protein. Most of these targets are cell surface receptors. Here, we describe a protocol for a panning strategy on cells to obtain specific binders to cell surface receptors. A depletion step is included to prevent enrichment of antibodies that bind to unwanted targets. Each step of the protocol is explained and variations of this protocol are given. PMID- 29116514 TI - Combine Phage Antibody Display Library Selection on Patient Tissue Specimens with Laser Capture Microdissection to Identify Novel Human Antibodies Targeting Clinically Relevant Tumor Antigens. AB - A functional approach to generate tumor-targeting human monoclonal antibodies is through selection of phage antibody display libraries directly on tumor cells. Although technically convenient, the use of cancer cell lines for the selection has limitations as those cell lines often undergo genetic and epigenetic changes during prolonged in vitro culture and alter their cell surface antigen expression profile. The key is to develop a technology that allows selection of phage antibody display libraries on tumor cells in situ residing in their natural tissue microenvironment. Laser capture microdissection (LCM) permits the precise procurement of tumor cells from human cancer patient tissue sections. Here, we describe a LCM-based method for selecting phage antibodies against tumor cells in situ using both fresh frozen and paraffin-embedded tissues. To restrict the selection to antibodies that bind internalizing epitopes, the method utilizes a polyclonal phage population pre-enriched for internalizing phage antibodies. The ability to recognize tumor cells in situ residing in their natural tissue microenvironment and to deliver payload intracellularly makes these LCM-selected antibodies attractive candidates for the development of targeted cancer therapeutics. PMID- 29116515 TI - Antibody Isolation From a Human Synthetic Combinatorial and Other Libraries of Single-Chain Antibodies. AB - Antibody libraries came into existence 25 years ago when the accumulating sequence data of immunoglobulin genes and the advent of the PCR technology made it possible to clone antibody gene repertoires. Phage display (most common) and additional display and screening technologies were applied to pan out desired binding specificities from antibody libraries. "Synthetic" or "semisynthetic" libraries are from naive-non-immunized source and considered to be a source for many different targets, including self-antigens.As other antibody discovery tools, phage display is not an off-the-shelf technology and not offered as a kit but rather requires experience and expertise for making it indeed very useful. Here we present application notes that expand the usefulness of antibody phage display as a very versatile and robust antibody discovery tool. PMID- 29116516 TI - Screening Phage-Display Antibody Libraries Using Protein Arrays. AB - Phage-display technology constitutes a powerful tool for the generation of specific antibodies against a predefined antigen. The main advantages of phage display technology in comparison to conventional hybridoma-based techniques are: (1) rapid generation time and (2) antibody selection against an unlimited number of molecules (biological or not). However, the main bottleneck with phage-display technology is the validation strategies employed to confirm the greatest number of antibody fragments. The development of new high-throughput (HT) techniques has helped overcome this great limitation. Here, we describe a new method based on an array technology that allows the deposition of hundreds to thousands of phages by micro-contact on a unique nitrocellulose surface. This setup comes in combination with bioinformatic approaches that enables simultaneous affinity screening in a HT format of antibody-displaying phages. PMID- 29116517 TI - Antibody Selection on FFPE Tissue Slides. AB - Standard antibody phage-display panning uses purified proteins, antigen transfected cells, or tumor cell lines as target structure to generate specific antibodies. Here, we describe a method for the selection of specific antibodies by phage panning against routine formalin-fixed paraffin-embedded (FFPE) tissue biopsies immobilized on glass slides. Selected antibody fragments recognize disease-associated antigens in its native conformation, suitable for the development of targeted diagnostic and therapeutic agents. PMID- 29116518 TI - Antibody Affinity and Stability Maturation by Error-Prone PCR. AB - Antibodies are the fastest growing class of pharmaceutical proteins and essential tools for research and diagnostics. Often antibodies do show a desirable specificity profile but lack sufficient affinity for the desired application. Here, we describe a method to increase the affinity of recombinant antibody fragments based on the construction of mutagenized phage display libraries.After the construction of a mutated antibody gene library by error-prone PCR, selection of high-affinity variants is either performed by panning in solution or on immobilized antigen with washing conditions optimized for off-rate-dependent selection. An additional screening protocol to identify antibodies with improved thermal stability is described. PMID- 29116519 TI - Upgrading Affinity Screening Experiments by Analysis of Next-Generation Sequencing Data. AB - Computational analysis of next-generation sequencing data (NGS; also termed deep sequencing) enables the analysis of affinity screening procedures (or biopanning experiments) in an unprecedented depth and therewith improves the identification of relevant peptide or antibody ligands with desired binding or functional properties. Virtually any selection methodology employing the direct physical linkage of geno- and phenotype to select for desired properties can be leveraged by computational analysis. This article describes a concept how relevant ligands can be identified by harnessing NGS data. Thereby, the focus lays on improved ligand identification and describes how NGS data can be structured for single round analysis as well as for comparative analysis of multiple selection rounds. Especially, the comparative analysis opens new avenues in the field of ligand identification. The concept of computational analysis is described at the example of the software tool "AptaAnalyzer TM ." This intuitive tool was developed for scientists without special computer skills and makes the computational approach accessible to a broad user range. PMID- 29116520 TI - Next-Generation DNA Sequencing of VH/VL Repertoires: A Primer and Guide to Applications in Single-Domain Antibody Discovery. AB - Immunogenetic analyses of expressed antibody repertoires are becoming increasingly common experimental investigations and are critical to furthering our understanding of autoimmunity, infectious disease, and cancer. Next generation DNA sequencing (NGS) technologies have now made it possible to interrogate antibody repertoires to unprecedented depths, typically by sequencing of cDNAs encoding immunoglobulin variable domains. In this chapter, we describe simple, fast, and reliable methods for producing and sequencing multiplex PCR amplicons derived from the variable regions (VH, VHH or VL) of rearranged immunoglobulin heavy and light chain genes using the Illumina MiSeq platform. We include complete protocols and primer sets for amplicon sequencing of VH/VHH/VL repertoires directly from human, mouse, and llama lymphocytes as well as from phage-displayed VH/VHH/VL libraries; these can be easily be adapted to other types of amplicons with little modification. The resulting amplicons are diverse and representative, even using as few as 103 input B cells, and their generation is relatively inexpensive, requiring no special equipment and only a limited set of primers. In the absence of heavy-light chain pairing, single-domain antibodies are uniquely amenable to NGS analyses. We present a number of applications of NGS technology useful in discovery of single-domain antibodies from phage display libraries, including: (i) assessment of library functionality; (ii) confirmation of desired library randomization; (iii) estimation of library diversity; and (iv) monitoring the progress of panning experiments. While the case studies presented here are of phage-displayed single-domain antibody libraries, the principles extend to other types of in vitro display libraries. PMID- 29116521 TI - High-Throughput IgG Reformatting and Expression. AB - We have recently described a one-step zero-background IgG reformatting method that enables the rapid reformatting of phage-displayed antibody fragments into a single-mammalian cell expression vector for full IgG expression (Chen et al. Nucleic Acids Res 42:e26, 2014). The strategy utilizes our unique positive selection method, referred to as insert-tagged (InTag) positive selection, where a positive selection marker (e.g. chloramphenicol-resistance gene) is cloned together with the antibody inserts into the expression vector. The recombinant clones containing the InTag adaptor are then positively selected without cloning background, thus bypassing the need to plate out cultures and screen colonies. This IgG reformatting method is rapid and can be automated and performed in a high-throughput (HTP) format. The use of InTag positive selection with the Dyax Fab-on-phage antibody library is demonstrated. We have further optimized the protocol for IgG reformatting since the initial publication of this method (Chen et al. Nucleic Acids Res 42:e26, 2014) and also updated the transient transfection protocol using Expi293F cells, which are described herein. PMID- 29116522 TI - Monitoring Phage Biopanning by Next-Generation Sequencing. AB - Phage display has enabled the rapid isolation of antigen-specific antibodies from combinatorial libraries of the variable heavy chain gene (VH) and variable light chain gene (VL). The method is based on genetic engineering of bacteriophages and repeated rounds of antigen-guided selection by phage biopanning.Next-Generation Sequencing (NGS) coupled with bioinformatics are powerful tools for analyzing the large number of DNA sequences present in an immune library.Here, we describe a method that demonstrates how NGS analysis enhances phage biopanning of complex antibody libraries as well as facilitates the antibody discovery process. PMID- 29116523 TI - ORFeome Phage Display. AB - ORFeome phage display allows the efficient functional screening of entire proteomes or even metaproteomes to identify immunogenic proteins. For this purpose, randomly fragmented, whole genomes or metagenomes are cloned into a phage-display vector allowing positive selection for open reading frames (ORF) to improve the library quality. These libraries display all possible proteins encoded by a pathogen or a microbiome on the phage surface. Consequently, immunogenic proteins can be selected from these libraries using disease-related immunoglobulins from patient serum. ORFeome phage display in particular allows the identification of immunogenic proteins that are only expressed in the host pathogen interaction but not in cultivation, as well as the detection of very low expressed and very small immunogens and immunogenic proteins of non-cultivable organisms. The identified immunogenic proteins are potential biomarkers for the development of diagnostic assays or vaccines. These articles will give an introduction to ORFeome phage-display technology and give detailed protocols to identify immunogenic proteins by phage display. PMID- 29116524 TI - Epitope Mapping by Phage Display. AB - Among the molecules of the immune system, antibodies, particularly monoclonal antibodies (mAbs), have been shown to be interesting for many biological applications. Due to their ability to recognize only a unique part of their target, mAbs are usually very specific. These targets can have many different compositions, but the most common ones are proteins or peptides that are usually from outside the host, although self-proteins can also be targeted in autoimmune diseases, or in some types of cancer. The parts of a mAb that interact with its target compose the paratope, while the recognized parts of the target compose the epitope. Knowing the epitope is valuable for the improvement of a biological product, e.g., a diagnostic assay, a therapeutic mAb, or a vaccine, as well as for the elucidation of immune responses. The current techniques for epitope mapping rely on the presentation of the target, or parts of it, in a way that it can interact with a certain mAb. Even though there are several techniques available, each has its pros and cons. Thus, the choice for one of them is usually dependent on the preference and availability of the researcher, opening possibility for improvement, or development of alternative techniques. Phage display, for example, is a versatile technology, which allows the presentation of many different oligopeptides that can be tested against different antibodies, fitting the need for an epitope mapping approach. In this chapter, a protocol for the construction of a single-target oligopeptide phage library, as well as for the panning procedure for epitope mapping using phage display is given. PMID- 29116525 TI - Metasecretome Phage Display. AB - Metasecretome is a collection of cell-surface and secreted proteins that mediate interactions between microbial communities and their environment. These include adhesins, enzymes, surface structures such as pili or flagella, vaccine targets or proteins responsible for immune evasion. Traditional approaches to exploring matasecretome of complex microbial communities via cultivation of microorganisms and screening of individual strains fail to sample extraordinary diversity in these communities, since only a limited fraction of microorganisms are represented by cultures. Advances in culture-independent sequence analysis methods, collectively referred to as metagenomics, offer an alternative approach that enables the direct analysis of collective microbial genomes (metagenome) recovered from environmental samples. This protocol describes a method, metasecretome phage display, which selectively displays the metasecretome portion of the metagenome. The metasecretome library can then be used for two purposes: (1) to sequence the entire metasecretome (using PacBio technology); (2) to identify metasecretome proteins that have a specific function of interest by affinity-screening (bio-panning) using a variety of methods described in other chapters of this volume. PMID- 29116526 TI - Phagekines: Screening Binding Properties and Biological Activity of Functional Cytokines Displayed on Phages. AB - The current chapter focuses on the use of filamentous phages to display, modify, and characterize cytokines, which are proteins belonging to a versatile group of essential mediators involved in cell-cell communication. Cytokines exhibit a considerable diversity, both in functions and in structural features underlying their biological effects. A broad variety of cytokines have been successfully displayed on phages, allowing the high-throughput study of their binding properties and biological activities and the discovery of novel therapeutics through directed evolution. The technical singularities and some potential applications of cytokine phage display are illustrated here with the case of Interleukin-2, a prototypic member of the four-alpha-helix bundle cytokine family playing a pivotal role in the immune response and having a long history of therapeutic use. PMID- 29116527 TI - Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors. AB - Based on preclinical studies suggesting that recombinant tissue plasminogen activator (rt-PA) may promote ischemic brain injuries, we investigated in patients the possible risk of worse clinical outcome after rt-PA treatment as a result of its inability to resolve cerebral ischemia. Here, we designed a cohort study using a retrospective analysis of patients who received treatment with intravenous (4.5-h window) or intraarterial rt-PA, without or with thrombectomy. Controls were consecutive patients who did not receive recanalization treatment, who met all inclusion criteria. As a marker of reperfusion, we defined the variable of early neurological improvement as the difference between the score of the National Institute of Health Stroke Scale (NIHSS) (at admission and 24 h). The main variable was worsening of the patient's functional situation in the first 3 months. To compare quantitative variables, we used Student's t test or the Mann-Whitney test. To estimate the odds ratios of each independent variable in the patient's worsening in the first 3 months, we used a logistic regression model. We included 1154 patients; 577 received rt-PA, and 577 served as controls. In the group of patients treated with rt-PA, 39.4% who did not present clinical reperfusion data developed worsening within 3 months after stroke compared with 3.5% of patients with reperfusion (P < 0.0001). These differences were not significant in the control group. In summary, administration of rt-PA intravenously or intraarterially without reperfusion within the first 24 h may be associated with a higher risk of functional deterioration in the first 3 months. PMID- 29116528 TI - A contemporary assessment of polybrominated diphenyl ethers (PBDE) in the ambient air and soil of Azerbaijan. AB - PBDEs were measured in air and soil across Azerbaijan to establish contemporary concentrations at 13 urban and rural sites. Polyurethane foam passive air samplers (PUF-PAS) were deployed for a period of a month with surface soil samples collected at the same sites. Unlike organochlorine pesticides previously surveyed by our group, PBDE concentrations in both contemporary air and soil were low in comparison to recent European and Asian studies. For example, mean ?9PBDE concentrations in air and soil were 7.13 +/- 1.66 pg m-3 and 168 +/- 57 pg g-1, respectively. The fully brominated BDE-209 was the most abundant congener observed in soil (174.8 +/- 58.5 pg g-1), comprising ~ 96% of ?10PBDE. However, the PAS-derived air concentrations for highly brominated congeners must be viewed with caution as there is uncertainty over the uptake rates of particle-bound chemicals using these devices. Some of the highest concentrations in air were observed at sites with the highest wind speeds and at several remote locations in the north of the country and this requires further research. Levels of BDE-47 and 99 (the two most abundant congeners in the widely used penta-formulation) were lower than levels reported elsewhere suggesting limited use/import of the penta BDE formulation in Azerbaijan. PMID- 29116529 TI - OH-initiated mechanistic pathways and kinetics of camphene and fate of product radical: a DFT approach. AB - Present manuscript represents the DFT studies on the oxidation reaction of camphene initiated by OH radical and fate of product radicals using M06-2X functional along with 6-31+G(d,p) basis set. Intrinsic reaction calculation is done for transition states involving OH-addition reactions which proceed via reaction complexes proceeding to the formation of transition states. The rate constant calculated by using canonical transition state theory at 298 K and 1 atm is found to be 5.67 * 10-11 cm3 molecule-1 s-1 which is in good agreement with the experimental rate constant. The atmospheric lifetime of the titled molecule has also been reported in our work. PMID- 29116530 TI - Plant assays and avoidance tests with collembola and earthworms demonstrate rehabilitation success in bauxite residue. AB - Bauxite residues are a by-product of alumina manufacture from bauxite ore and are commonly disposed of in purpose-built bauxite residue disposal areas (BRDAs). Revegetation is viewed as the most effective way to landscape and rehabilitate closed BRDAS and physicochemical assessment remains the primary indicator of rehabilitation success. Little is known about the ability of keystone mesofaunal species to colonise and establish in these environments yet the long-term success of rehabilitation is dependent on residues becoming suitable habitats for such groups. Using six different residue treatments (untreated, leached, organic application, organic amended, and two revegetated field treatments) together with OECD test soil, this study assessed the characteristics of residues with plant germination and seedling development using the RhizotestTM approach with Lepidium sativum, Sinapis alba, and Sorghum bicolor. Avoidance tests with soil mesofauna Eisenia foetida together with growth and reproduction tests for Folsomia candida were conducted to determine possibility of inhibition in residue soils. Unamended residue is inhibitory to plant growth and mesofaunal establishment. Amendment improves the physicochemical properties of the residue, and data revealed that both gypsum and organic addition is required to promote conditions favourable to plant growth and mesofauna establishment. Earthworms avoid residues with elevated Na content but will choose substrate with high soluble Ca content. F. candida preferentially moves to residues from field treatments, and both mortality and reproduction rates are comparable or superior to OECD soil. On the basis of these assays, we propose that bauxite residue can be transformed to a soil-like medium capable of supporting keystone species. PMID- 29116531 TI - Identification of surfactants and its correlation with physicochemical parameters at the confluence region of Vembanad Lake in India. AB - The present study describes the monitoring of some of the major classes of surfactants in water. The separation, identification, and the quantitative estimation of the compounds were achieved using LC-Q-ToF-MS. The analyses revealed the presence of variety of surfactants including linear alkylbenzene sulfonate (LAS), alcohol ethoxysulfates (AES), and alcohol ethoxylates (AE). Further, emphasis was given to AES as they are one of the most produced and consumed surfactants in the world. And as far as India is concerned, the present study is one of the most significant attempt regarding the identification and quantification of AES. The data obtained during the analysis revealed that the average concentration of AES C12Ex varied from 0.7 to 13.6 MUg L-1 while that of C14Ex ranged between 1.3 and 10.4 MUg L-1. The risk assessment revealed that higher chain AES are capable of posing medium level risk to the aquatic compartment. In addition, the study also included the physicochemical analysis of water from the selected area. Water was found to be acidic in nature and the salinity, TDS, and EC values were found to be high during the pre-monsoon season. The order of the levels of anionic constituents was of Cl->SO42-SO42->F->NO32- ? PO42- while that of cations were Na+ > Mg2+ > K+ > Ca2+. Results of correlation analysis showed that statistically negative correlation exists between AES homologs and pH while slight positive correlations were found between AES and other parameters including TDS and EC. The suitability of this water for domestic and agricultural purposes has been examined on the ground of basic quality indices such as the water quality index (WQI) and sodium adsorption ratio (SAR). The WQI measurements also revealed that the water quality of the region falls under the "very poor" category especially during the pre-monsoon season. The study could explore the cumulative share of these canals in the quality impairment of the receiving Vembanad Lake. PMID- 29116532 TI - Assessment of addition of biochar to filtering mixtures for potential water pollutant removal. AB - Green roofs are used increasingly to alleviate peaks of water discharge into the sewage systems in urban areas. Surface runoff from roofs contain pollutants from dry and wet deposition, and green roofs offer a possibility to reduce the amounts of pollutants in the water discharged from roofs by degradation and filtering. These pollutants would otherwise enter wastewater treatments plants and ultimately end up in sewage sludge that is spread on agricultural soils. The most common substrates used in green roofs have limited capacity for filtration and sorption. Also, more sustainable alternatives are sought, due to the high carbon footprint of these materials. Biochar is a carbon-rich material produced by pyrolysis of biomass, and several types of biochar have been described as good sorbents and filter materials. Biochar is also a light and carbon negative material, which may fulfill other desired criteria for new green roof substrates. We here report on an experiment where two types of biochar, produced from olive husks at 450 degrees C or from forest waste at 850 degrees C were mixed with volcanic rock or peat, and tested for retention capacity of phenanthrene and six heavy metals in a column experiment with unsaturated gravimetric water flow lasting for 3 weeks. The results suggest that biochar as a component in green roof substrates perform better than traditional materials, concerning retention of the tested pollutants, and that different types of biochar have different properties in this respect. PMID- 29116533 TI - Effect of probiotics on the basis of Bacillus subtilis and Bifidobacterium longum on the biochemical parameters of the animal organism. AB - For the purpose of safe modulation of the intestinal microflora, probiotics have been increasingly used in recent years. In the present work, the effect of the probiotic sporobacterin (Bacillus subtilis 534) (I group) and soybean-bifidum (Bifidobacterium longum) (II group) on male rats of the Wistar line was evaluated. In assessing nonspecific immunity in vitro, there was an increase in the level of baseline level in the first and second groups (by 8.3 and 12.2% more control). The influence of probiotic preparations on the intestinal normoflora was assessed using PCR. Bifidumbacterin increased the normal microflora, in particular, Escherichia coli 1.55 times, Lactobacillus 1.26 times, Enterococcus 1.3 times as much control; the level of conditionally pathogenic microflora, in particular, Proteus spp. decreased by 1.3 times in comparison with the control. Sporobacterin also contributed to an increase in the amount of E. coli (1.55 times) and Lactobacillus (0.9 times). When a culture of Bifidobacterium longum was introduced, a selective reduction in the loss of chemical elements was observed against the background of the diet used. At the end of the experiment, the content of calcium in the body tissues of animals of group II exceeded this indicator in group I by 3.9%, phosphorus by 17.6%, copper by 28.5%, and zinc by 15.2%. The totality of the results obtained by us indicates that inclusion of Bifidumbacterium longum in the diet of animals makes the use of this preparation in the correction of mineral imbalance and improves the microflora of the intestines of animals by reducing the number of representatives of opportunistic microflora against the background of an increase in the number of basic representatives of normal microbiocenosis. Also, the use of probiotic drugs as additives leads to a slight increase in the level of nonspecific immunity, which increases the natural resistance of the organism. PMID- 29116534 TI - On the interactions among tropospheric ozone levels and typical environmental stresses challenging Mediterranean crops. AB - The main environmental stresses of Italian croplands are discussed in relation to their interactions with ozone effects on crops. Water deficit and salinization are frequent in Mediterranean environments during spring-summer causing a decrease of soil water potential and water uptake by roots and consequently stomatal closure. These stresses also stimulate secondary metabolism and antioxidant accumulation, which also serves as a stress protection mechanism. High concentrations of tropospheric ozone are common all over Italy during the spring-summer season. Ozone injuries to vegetation are related to its penetration into plant tissues, mostly via stomatal uptake, rather than to tropospheric concentrations per se. In several crops, closure of stomata due to drought/salinization reduces ozone entering into leaf tissues and counteracts possible ozone damages. Furthermore, the stimulation of antioxidant synthesis as a response to environmental stresses can represent a further protection factor from ozone injuries for Mediterranean crops.The co-existence of stress-induced stomatal closure and high ozone levels during spring-summer in Mediterranean environments implies that models that do not take into account physiological responses of crops to drought and salinity stress may overestimate ozone damages when stress responses overlap with seasonal ozone peaks. The shift from concentration-based to flux-based approaches has improved the accuracy of models to assess ozone effects on agricultural crops. It is, however, necessary to further refine the flux concept with respect to the plant abiotic stress defense capacity that can differ among genotypes, climatic conditions, and physiological states. PMID- 29116535 TI - Prevalence of asthma and associated factors among male late adolescents in Tabriz, Iran. AB - Asthma is an important chronic disease all over the world. The aim of this study was to determine the prevalence of asthma in a population of male late adolescents and its association with some contributing risk factors in northwest of Iran. This cross-sectional study was carried out in selected high schools of Tabriz, Iran, in 2016. The asthma prevalence and patient background information were examined using a questionnaire that prepared by the ISAAC. One hundred forty two out of 1134 subjects (12.4%) identified to have asthma, 23.3% had history of current wheeze, and 16.3% had wheezing in the previous year. Family history of asthma was present in 17.1% of the participants; prevalence of active smoking in the study subjects was 3.1%; 25.1% of all subjects had exposure to secondhand tobacco smoke and keeping pets at home was present in 9.1%. Excess weight (overweight and obesity) was positively associated with prevalence of asthma (p < 0.001). No statistically significant associations were observed between asthma and father's education level (p = 0.570), mother's education level (p = 0.584), type of birth subjects (p = 0.571), and time spent outdoors during a full day (p = 0.863). Our results suggest that family history of asthma and atopy, exposure to secondhand tobacco smoke, active smoking, amount of automobile traffic around subjects' home, and keeping pets at homes are important risk factors for asthma, while time spent outdoors, educations of parents, and delivery type (normal vaginal delivery vs. C-section) subjects are not. Therefore, decreased of exposure to some environmental risk factors could be effective to reduce rate of the prevalence of asthma and wheeze. PMID- 29116536 TI - Spatial-temporal variations in surface ozone over Ushuaia and the Antarctic region: observations from in situ measurements, satellite data, and global models. AB - The Antarctic continent is known to be an unpopulated region due to its extreme weather and climate conditions. However, the air quality over this continent can be affected by long-lived anthropogenic pollutants from the mainland. The Argentinian region of Ushuaia is often the main source area of accumulated hazardous gases over the Antarctic Peninsula. The main objective of this study is to report the first in situ observations yet known of surface ozone (O3) over Ushuaia, the Drake Passage, and Coastal Antarctic Peninsula (CAP) on board the RV Australis during the Malaysian Antarctic Scientific Expedition Cruise 2016 (MASEC'16). Hourly O3 data was measured continuously for 23 days using an EcoTech O3 analyzer. To understand more about the distribution of surface O3 over the Antarctic, we present the spatial and temporal of surface O3 of long-term data (2009-2015) obtained online from the World Meteorology Organization of World Data Centre for greenhouse gases (WMO WDCGG). Furthermore, surface O3 satellite data from the free online NOAA-Atmospheric Infrared Sounder (AIRS) database and online data assimilation from the European Centre for Medium-Range Weather Forecasts (ECMWF)-Monitoring Atmospheric Composition and Climate (MACC) were used. The data from both online products are compared to document the data sets and to give an indication of its quality towards in situ data. Finally, we used past carbon monoxide (CO) data as a proxy of surface O3 formation over Ushuaia and the Antarctic region. Our key findings were that the surface O3 mixing ratio during MASEC'16 increased from a minimum of 5 ppb to ~ 10-13 ppb approaching the Drake Passage and the Coastal Antarctic Peninsula (CAP) region. The anthropogenic and biogenic O3 precursors from Ushuaia and the marine region influenced the mixing ratio of surface O3 over the Drake Passage and CAP region. The past data from WDCGG showed that the annual O3 cycle has a maximum during the winter of 30 to 35 ppb between June and August and a minimum during the summer (January to February) of 10 to 20 ppb. The surface O3 mixing ratio during the summer was controlled by photochemical processes in the presence of sunlight, leading to the depletion process. During the winter, the photochemical production of surface O3 was more dominant. The NOAA-AIRS and ECMWF-MACC analysis agreed well with the MASEC'16 data but twice were higher during the expedition period. Finally, the CO past data showed the surface O3 mixing ratio was influenced by the CO mixing ratio over both the Ushuaia and Antarctic regions. Peak surface O3 and CO hourly mixing ratios reached up to ~ 38 ppb (O3) and ~ 500 ppb (CO) over Ushuaia. High CO over Ushuaia led to the depletion process of surface O3 over the region. Monthly CO mixing ratio over Antarctic (South Pole) were low, leading to the production of surface O3 over the Antarctic region. PMID- 29116538 TI - Environmentally benign nanometric neem-laced urea emulsion for controlling mosquito population in environment. AB - The increasing risk of vector-borne diseases and the environmental pollution in the day-to-day life due to the usage of the conventional pesticides makes the role of nanotechnology to come into the action. The current study deals with one of the applications of nanotechnology through the formulation of neem urea nanoemulsion (NUNE). NUNE was formulated using neem oil, Tween 20, and urea using the microfluidization method. Prior to the development of nanoemulsion, the ratio of oil/surfactant/urea was optimized using the response surface modeling method. The mean droplet size of the nanoemulsion was found to be 19.3 +/- 1.34 nm. The nanoemulsion was found to be stable for the period of 4 days in the field conditions which aids to its mosquitocidal activity. The nanoemulsion exhibited a potent ovicidal and larvicidal activity against A. aegypti and C. tritaeniorhynchus vectors. This result was corroborated with the histopathological analysis of the NUNE-treated larvae. Further, the effect of NUNE on the biochemical profile of the target host was assessed and was found to be efficacious compared to the bulk counterpart. The nanoemulsion was then checked for its biosafety towards the non-target species like plant beneficial bacterium (E. ludwigii), and phytotoxicity was assessed towards the paddy plant (O. sativa). Nanometric emulsion at the concentration used for the mosquitocidal application was found to be potentially safe towards the environment. Therefore, the nanometric neem-laced urea emulsion tends to be an efficient mosquito control agent with an environmentally benign property. PMID- 29116537 TI - Critical analysis of excessive utilization of crude protein in ruminants ration: impact on environmental ecosystem and opportunities of supplementation of limiting amino acids-a review. AB - Protein quality plays a key role than quantity in growth, production, and reproduction of ruminants. Application of high concentration of dietary crude protein (CP) did not balance the proportion of these limiting amino acids (AA) at duodenal digesta of high producing dairy cow. Thus, dietary supplementation of rumen-protected AA is recommended to sustain the physiological, productive, and reproductive performance of ruminants. Poor metabolism of high CP diets in rumen excretes excessive nitrogen (N) through urine and feces in the environment. This excretion is usually in the form of nitrous oxide, nitric oxide, nitrate, and ammonia. In addition to producing gases like methane, hydrogen carbon dioxide pollutes and has a potentially negative impact on air, soil, and water quality. Data specify that supplementation of top-limiting AA methionine and lysine (Met + Lys) in ruminants' ration is one of the best approaches to enhance the utilization of feed protein and alleviate negative biohazards of CP in ruminants' ration. In conclusion, many in vivo and in vitro studies were reviewed and reported that low dietary CP with supplemental rumen-protected AA (Met + Lys) showed a good ability to reduce N losses or NH3. Also, it helps in declining gases emission and decreasing soil or water contamination without negative impacts on animal performance. Finally, further studies are needed on genetic and molecular basis to explain the impact of Met + Lys supplementation on co occurrence patterns of microbiome of rumen which shine new light on bacteria, methanogen, and protozoal interaction in ruminants. PMID- 29116539 TI - Watershed prioritization in the upper Han River basin for soil and water conservation in the South-to-North Water Transfer Project (middle route) of China. AB - Watershed prioritization with the objective of identifying critical areas to undertake soil and water conservation measures was conducted in the upper Han River basin, the water source area of approximately 95,000 km2 for the middle route of China's South-to-North Water Transfer Project. Based on the estimated soil erosion intensity in uplands and clustering analysis of measured nutrient concentrations in rivers, the basin was grouped into very-high-, high-, moderate , and low-priority regions for water and soil conservation, respectively. The results indicated that soil erosion was primarily controlled by topography, and nutrients in rivers were associated with land use and land cover in uplands. Also, there was large spatial disparity between soil erosion intensity in the uplands and nutrient concentrations in the rivers across the basin. Analysis was then performed to prioritize the basin by the integration of the soil erosion intensity and water quality on a GIS platform in order to identify critical areas for water and soil conservation in the basin. The identified high-priority regions which occupy 5.74% of the drainage areas need immediate attention for soil and water conservation treatments, of which 5.28% is critical for soil erosion prevention and 0.46% for water conservation. Understandings of the basin environment and pollutant loading with spatial explicit are critical to the soil and water resource conservation for the interbasin water transfer project. PMID- 29116540 TI - Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies. AB - PURPOSE: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety. METHODS: Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries. RESULTS: Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61 2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia. CONCLUSIONS: The results from these long-term placebo controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population. PMID- 29116541 TI - A cross-sectional study of vitamin D levels in a large cohort of patients with rheumatic diseases. AB - The objective of this study is to examine 25-hydroxyvitamin D [25(OH)D] (D-25) levels and associations with patient- and disease-related factors in rheumatic diseases. This is a register-based study of D-25 levels in adult patients seen at the Central Finland Hospital rheumatology clinic (January 2011-April 2015). Demographic, clinical, laboratory, and patient-reported outcomes (PROs) were collected as part of the normal infrastructure of the outpatient clinic and examined for their association with D-25 level. Statistical analysis included descriptive statistics and univariable and multivariable regression analyses adjusting for age and gender. D-25 was measured in 3203 patients (age range 15-91 years, mean 54; 68% female) with diagnoses including RA (n = 1386), unspecified arthralgia/myalgia (n = 413), and connective tissues diseases (n = 213). The overall D-25 mean (SD) level was 78 (31) and median (IQR) 75 (55, 97). At baseline, 17.8% had D-25 deficiency, and only 1.6% severe deficiency (< 25 nmol/l); 34%/49% had sufficient/optimal D-25 levels. Higher D-25 levels were associated with older age, lower BMI, and regular exercise (all p < 0.001) among other factors. In multivariable analyses, younger age, non-white background, higher BMI, smoking, less frequent exercise (p < 0.001), and first visit to the clinic (p = 0.033) remained significantly associated with D-25 deficiency. Among those with sub-optimal D-25 levels, 64% had improved to sufficient/optimal levels after a median (IQR) of 13 (7.8, 22) months. The proportion of patients with D-25 deficiency in this study was generally low. Older patients had considerably higher D-25 levels compared to younger patients. Lower physical exercise and higher BMI were associated with higher risk of deficiency. The study supports the benefit of strategies to help minimize the risk of D-25 deficiency. PMID- 29116542 TI - The outcomes and risk factors of early readmission in patients with intestinal Behcet's disease. AB - Hospital readmission rate is an integral quality of care measurement for hospitalized patients which is unknown for intestinal Behcet's disease cases. The purpose of this study was to investigate the risk factors and outcomes for patients readmitted early with intestinal Behcet's disease. We retrospectively reviewed patients with intestinal Behcet's disease who were readmitted to our hospital between 2005 and 2016. We then analyzed the risk factors and outcomes for early readmission within 3 months. Of the 204 patients who were readmitted, 103 patients (50.5%) were readmitted within 3 months and 101 (49.5%) were never readmitted or readmitted after 3 months. After multivariate analysis, hospital stay at the first admission (adjusted odds ratio [OR], 0.945; 95% confidence interval [CI], 0.908-0.982; P = 0.004), high disease activity index for intestinal Behcet's disease score (adjusted OR, 1.111; 95% CI, 1.060-1.165; P < 0.001), corticosteroid use (adjusted OR, 3.179; 95% CI, 1.135-8.910; P = 0.028), and opioid use (adjusted OR, 7.979; 95% CI, 1.084-58.755; P = 0.041) were independent factors for early readmission. We identified four independent prognostic factors for early readmission within 3 months, which might help guide appropriate management strategies for hospitalized patients with intestinal Behcet's disease. PMID- 29116544 TI - Antithrombotic Therapy for ACS in Elderly Patients. AB - BACKGROUND: Patients over 75 account for more than one third of those presenting with myocardial infarction and more than 50% of intrahospital mortality. There are no specific guidelines for the management of acute coronary syndromes (ACS) in the elderly. SETTING: Although antithrombotic therapy seems to be effective and safe in such patients, it requires specific precautions and treatment adjustments because of the higher bleeding risk due to comorbidities such as renal function impairment and malnutrition. RESULTS: Scientific evidence concerning elderly patients is scarce as they are either excluded or underrepresented in most randomized trials. Overall, the antithrombotic therapy needs to be adapted to avoid complications, mainly bleeding complications, without compromising the effectiveness of the treatment in this high-risk population. CONCLUSION: In the present paper, we review the current treatment strategies in ACS while focusing on data concerning the elderly, according to available data in pivotal trials and in both AHA/ACC and ESC guidelines. PMID- 29116543 TI - Remission assessment of rheumatoid arthritis in daily practice in China: a cross sectional observational study. AB - The objective of this study is to evaluate the remission rate and describe the current use of medication in a large cohort of rheumatoid arthritis (RA) patients under routine clinical care in China. RA patients were recruited from 40 large teaching hospitals nationwide in China. Data regarding RA disease activity, medication treatment, and adverse events were recorded using a standardized clinical data questionnaire. RA remission was evaluated by the 28 Joint Disease Activity Score DAS28-ESR Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria. A total of 1945 patients with RA were included in the study. The proportions of patients who fulfilled the DAS28-ESR, CDAI, SDAI, and ACR/EULAR remission criteria were 10.90%, 6.17%, 5.04% , and 1.75%, respectively. Most patients had taken at least one disease-modifying anti-rheumatic drug (DMARD), and the most common prescriptions included leflunomide (LEF) and methotrexate (MTX). DMARD combined with botanics were the most common and dominant strategy for RA management (29.16%). Overall, 433 patients (22.27%) had at least one adverse event. Gastrointestinal adverse events (41.27%) were the most frequently reported events. The incidence of side effects in patients using biologics DMARDs (bDMARDs) was significantly lower than that in those taking MTX, LEF, or sulfasalazine (SSZ). The remission rate of RA disease activity, as assessed in Chinese clinical practice, was very low. Adverse effects of the medicine occurred in approximately one in five RA patients, with bDMARDs were demonstrated to be the medication with the lowest side effects. PMID- 29116545 TI - Intravenous thrombolysis in SLE-related stroke: a case report and literature review. AB - Patients with systemic lupus erythematosus (SLE) bear an increased risk of ischemic stroke. However, evidences for treating acute stroke due to artery thrombosis in SLE patients are extremely limited. A 45-year-old woman experienced sudden left hemiplegia. She was transported to the emergency department of our hospital 2 hours after the initial symptom. According to the medical records, the patient was diagnosed with SLE at the age of 28. CT scanned 150 min after the initial symptom showed no evidence of acute changes or hemorrhage. Magnetic resonance angiography (MRA) revealed occlusion of the right proximal middle cerebral artery (MCA). Ischemic stroke was diagnosed and NIHSS scored 11. The occluded MCA was successfully recanalized with intravenous rtPA. Sequent vascular imaging and serological results indicated that the etiology of the occlusion in right MCA was SLE vasculitis. The patient attained a mRS of 3 at the 3-month follow-up. The case is the first one in the literature that acute ischemic stroke related to SLE vasculitis was treated successfully with intravenous rtPA thrombolysis. The feasibility of intravenous thrombolysis for stroke related to SLE warrant further study. PMID- 29116546 TI - Sir Gordon Morgan Holmes (1876-1965): one of the founders of modern neurology. AB - Sir Gordon Morgan Holmes (1876-1965) was one of the most important founders of modern neurology and a great teacher and scientist. He was the first scientist to challenge the theory of the unitary function of the cerebellum and described cerebellar disorders. Holmes together with Thomas Grainger Stewart (1877-1957) described 40 cases of the rebound phenomenon in cerebellar disease (Stewart Holmes maneuver or Stewart-Holmes test). He also described the symptoms of inherited neurodegenerative spinocerebellar ataxia involving the olivary nucleus (Gordon-Holmes syndrome). Independently from the Australian neurologist William John Adie (1886-1935), he described the partial iridoplegia (Holmes-Adie pupil or Holmes-Adie syndrome). His teaching skills became clearly visible in Goulstonian and Croonian lectures dedicated to spinal cord injuries. PMID- 29116547 TI - The BPD trio? Interaction of dysregulated PDGF, VEGF, and TGF signaling in neonatal chronic lung disease. AB - The development of neonatal chronic lung disease (nCLD), i.e., bronchopulmonary dysplasia (BPD) in preterm infants, significantly determines long-term outcome in this patient population. Risk factors include mechanical ventilation and oxygen toxicity impacting on the immature lung resulting in impaired alveolarization and vascularization. Disease development is characterized by inflammation, extracellular matrix remodeling, and apoptosis, closely intertwined with the dysregulation of growth factor signaling. This review focuses on the causes and consequences of altered signaling in central pathways like transforming growth factor (TGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) driving these above indicated processes, i.e., inflammation, matrix remodeling, and vascular development. We emphasize the shared and distinct role of these pathways as well as their interconnection in disease initiation and progression, generating important knowledge for the development of future treatment strategies. PMID- 29116548 TI - Women, Femininity, Indirect and Direct Self-Destructiveness. A Review. AB - The aim of this work was to review results of research into direct and indirect self-destructiveness in women. Studied projects covered two populations: individuals who attempted suicide and individuals who did not attempt suicide. The Chronic Self-Destructiveness Scale and Bem Sex Role Inventory were used. Intensity of indirect self-destructiveness is lower in women. A probable explanation of the gender paradox in suicides may be the hypothesis that suicides attempted by men more often end in death as men display stronger indirect self destructiveness. Masculinity and male sex are factors that predispose to indirect self-destructiveness, while femininity and female sex are factors protecting against it. Gender schema opposite to biological sex is significant to intensity of indirect self-destructiveness. PMID- 29116549 TI - Transepithelial accelerated corneal collagen cross-linking with higher oxygen availability for keratoconus: 1-year results. AB - PURPOSE: To investigate the safety and efficacy of a new protocol for transepithelial accelerated corneal collagen cross-linking with higher oxygen availability for keratoconus treatment. METHODS: There were 26 patients (26 eyes) diagnosed with keratoconus enrolled in the study and treated with transepithelial accelerated corneal collagen cross-linking. The corneas were irradiated using UVA light for 5 min and 20 s with 45 mW/cm2 irradiance and pulsed illumination (1:1). The follow-up examinations were performed at 1 day, 1 month, 3 months, 6 months, and 1 year postoperatively. At each follow-up, the patients received a complete ophthalmologic examination that included visual acuity, manifest refraction, corneal topography, endothelial cell density, and ORA. RESULTS: The operations were uneventful, and there were no complications during follow-up. At 1 year after the procedure, the uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) of the treated eyes were significantly improved compared to the pretreatment values (P = 0.012, 0.041, respectively). Additionally, 65.4% of eyes gained at least 1 line in CDVA, and 42.3% of eyes showed a reduction in at least 0.5D in astigmatism. The maximum keratometry (K max), corneal thickness, corneal endothelial cell density and corneal biomechanics were stable at each visit. CONCLUSION: Transepithelial accelerated corneal collagen cross-linking with higher oxygen availability was safe for keratoconus treatment and partially prevented disease progression. Therefore, further studies with large patient cohorts and longer follow-up periods are recommended. PMID- 29116550 TI - Resistance to DAAs: When to Look and When It Matters. AB - PURPOSE OF REVIEW: This review provides an overview of HCV resistance-associated substitutions (RASs) with a focus on NS3 protease and NS5A inhibitor resistance. Treatment approaches for managing resistance are also covered including the use of newly approved therapies with improved resistance profiles. RECENT FINDINGS: HCV RASs are frequently selected if the patient is not cured during treatment; NS5A RASs persist for prolonged periods of time (years) after treatment failure and may adversely impact retreatment responses. Newly approved regimens with improved potency and resistance profiles are less impacted by resistance and provide the best retreatment options for patients who previously failed DAA therapy. The clinical impact of HCV RASs has been lessened significantly with the introduction of new DAA treatment regimens. Routine testing for resistance is unlikely to impact retreatment approaches if newer regimens are accessible. Knowledge of factors, such as the presence of cirrhosis and prior treatment regimens, remain as the key to optimizing retreatment approaches. PMID- 29116551 TI - Anti-inflammatory effect of a novel locally acting A2A receptor agonist in a rat model of oxazolone-induced colitis. AB - Adenosine represents a powerful modulating factor, which has been shown to orchestrate the scope, duration, and remission of the inflammatory response through the activation of four specific receptors, classified as A1, A2A, A2B, and A3, all being widely expressed in a variety of immune cells. Several selective A2A receptor agonists have displayed anti-inflammatory effects, through the suppression of IL-12, TNF, and IFN-gamma production by monocytes and lymphocytes, in the setting of chronic intestinal inflammation. However, the therapeutic application of A2A receptor agonists remains hindered by the risk of serious cardiovascular adverse effects arising from the wide systemic distribution of A2A receptors. The present study focused on evaluating the anti inflammatory effects of the novel poorly absorbed A2A receptor agonist PSB-0777 in a rat model of oxazolone-induced colitis as well as to evaluate its cardiovascular adverse effects, paying particular attention to the onset of hypotension, one of the main adverse effects associated with the systemic pharmacological activation of A2A receptors. Colitis was associated with decreased body weight, an enhanced microscopic damage score and increased levels of colonic myeloperoxidase (MPO). PSB-0777, but not dexamethasone, improved body weight. PSB-0777 and dexamethasone ameliorated microscopic indexes of inflammation and reduced MPO levels. The beneficial effects of PSB-0777 on inflammatory parameters were prevented by the pharmacological blockade of A2A receptors. No adverse cardiovascular events were observed upon PSB-0777 administration. The novel A2A receptor agonist PSB-0777 could represent the base for the development of innovative pharmacological entities able to act in an event-specific and site-specific manner. PMID- 29116552 TI - Using Facebook to Recruit Parents to Participate in a Family Program to Prevent Teen Drug Use. AB - Despite strong evidence that family programs are effective in preventing adolescent substance use, recruiting parents to participate in such programs remains a persistent challenge. This study explored the feasibility of using Facebook to recruit parents of middle school students to a self-directed family program to prevent adolescent drug use. The study used paid Facebook ads aiming to recruit 100 parents in Washington and Colorado using marijuana- or parenting focused messages. All ad-recruited parents were also invited to refer others in order to compare Facebook recruitment to web-based respondent-driven sampling. Despite offering a $15 incentive for each successfully referred participant, the majority of the screened (70.4%) and eligible (65.1%) parents were recruited through Facebook ads. Yet, eligibility and consent rates were significantly higher among referred (76.6 and 57.3%, respectively) than Facebook-recruited parents (60.0 and 36.6%, respectively). Click-through rates on Facebook were higher for marijuana-focused than parenting-focused ads (0.72 and 0.65%, respectively). The final sample (54% Facebook-recruited) consisted of 103 demographically homogeneous parents (female, educated, non-Hispanic White, and mostly from Washington). Although Facebook was an effective and efficient method to recruit parents to a study with equal to better cost-effectiveness than traditional recruitment strategies, the promise of social media to reach a diverse population was not realized. Additional approaches to Facebook recruitment are needed to reach diverse samples in real-world settings and increase public health impact of family programs. PMID- 29116553 TI - Effect of Sinomenine on the Morphine-Dependence and Related Neural Mechanisms in Mice. AB - Evidence suggests that the dopamine receptor rate-limiting enzyme, tyrosine hydroxylase (TH), and the glutamate receptor, N-methyl-D-aspartate receptor 2B (NR2B), contribute to morphine dependence. Previous studies show that chronic exposure to morphine changes the expression of opioid receptors. In this study, we focus on the effects of sinomenine on morphine-dependent mice and its related neural mechanisms. Conditioned place preference (CPP) mouse model was established using morphine (9 mg/kg, s.c.), and their expression levels of TH and NR2B were observed by immunohistochemistry. Moreover, their mu opioid receptor (MOR) and delta opioid receptor (DOR) contents were assessed using quantitative reverse transcription polymerase chain reaction. Results showed that high sinomenine dose (80 mg/kg) effectively attenuated the behavior of CPP mice and reversed increased expression levels of TH and NR2B induced by morphine. Moreover, compared with the morphine group, sinomenine up-regulated the content of MOR to a normal level but did not significantly affect the DOR expression. In summary, these data indicate that sinomenine can inhibit morphine dependence by increasing the expression levels of TH, NR2B, and MOR in the mouse brain; however, DOR may not contribute to this effect. PMID- 29116554 TI - Recent advances in molecular basis for strigolactone action. AB - Strigolactones (SLs) are a very special class of plant hormones, which act as endogenous signals to regulate shoot branching in plants, and also serve as rhizosphere signals to regulate interactions of host plants with heterologous organisms such as symbiotic arbuscular mycorrhizal fungi and parasitic weeds. In this short review, we give a brief description of novel discoveries in SL biosynthesis pathway, and mainly summarize the recent advances in SL perception and signal transduction. PMID- 29116555 TI - Modifiable correlates of perceived cognitive function in breast cancer survivors up to 10 years after chemotherapy completion. AB - BACKGROUND: Cognitive changes following breast cancer treatment are likely multifactorial and have been linked to emotional factors, biophysiological factors, and fatigue, among others. Little is known about the contributions of modifiable factors such as stress, loneliness, and sleep quality. The purpose of this study was to explore the direct and indirect effects of perceived stress, loneliness, and sleep quality on perceived cognitive function (PCF) in breast cancer survivors (BCS) after chemotherapy completion. METHODS: In this observational study, BCS 6 months to 10 years post chemotherapy were recruited from the community. We measured perceived stress, loneliness, sleep quality, anxiety, depression, fatigue, and PCF. Data analyses included descriptive statistics, correlations, and mediation analyses utilizing ordinary least square regression. RESULTS: Ninety women who were on average 3 years post chemotherapy completion participated in the study. Moderate to largely negative correlations were found between PCF and the psychosocial and sleep variables (r values ranged from - 0.31 to - 0.70, p values < .0009). Mediation analyses revealed that stress and daytime sleepiness both directly and indirectly impact PCF and that loneliness and sleep quality only have indirect effects (through anxiety and fatigue). CONCLUSION: Our findings suggest that perceived cognitive changes following breast cancer treatment are multifactorial and that higher stress levels, loneliness, daytime sleepiness, and poorer sleep quality are linked to worse perceived cognitive functioning. Also, stress, loneliness, and sleep quality may affect cognitive functioning through a shared psychobiological pathway. IMPLICATIONS FOR CANCER SURVIVORS: Interventions targeting stress, loneliness, and sleep quality may improve perceived cognitive functioning in breast cancer survivors. PMID- 29116556 TI - Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice. AB - The primary objective of population-based newborn screening is the early identification of asymptomatic infants with a range of severe diseases, for which effective treatment is available and where early diagnosis and intervention prevent serious sequelae. Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity. Severe combined immunodeficiency (SCID) is one form of PID which is uniformly fatal without early, definitive therapy, and outcomes are significantly improved if infants are diagnosed and treated within the first few months of life. Screening for SCID using T cell receptor excision circle (TREC) analysis has been introduced in many countries worldwide. The utility of additional screening with kappa recombining excision circles (KREC) has also been described, enabling identification of infants with severe forms of PID manifested by T and B cell lymphopenia. Here, we review the early origins of newborn screening and the evolution of screening methodologies. We discuss current strategies employed in newborn screening programs for PID, including TREC and TREC/KREC-based screening, and consider the potential future role of protein-based assays, targeted sequencing, and next generation sequencing (NGS) technologies, including whole genome sequencing (WGS). PMID- 29116557 TI - Bidirectional band-selective magnetization transfer along the protein backbone doubles the information content of solid-state NMR correlation experiments. AB - Resonance assignment is the first stage towards solving the structure of a protein. This is normally achieved by the employment of separate inter and intra residue experiments. By utilising the mixed rotation and rotary recoupling (MIRROR) condition it is possible to double the information content through the efficient bidirectional transfer of magnetization from the CO to its adjacent Calpha and the Calpha of the subsequent amino acid. We have incorporated this into a 3D experiment, a 3D-MIRROR-NCOCA, where correlations present in the 3D spectrum permit the sequential assignment of the protein backbone from a single experiment as we have demonstrated on a microcrystalline preparation of GB3. Furthermore, the low-power requirements of the MIRROR recoupling sequence facilitate the development of a low-power 3D-NCOCA experiment. This has enabled us to realise significant reductions in acquisition times, allowing the acquisition of a single 3D-NCOCA spectrum suitable for a full backbone resonance assignment of GB3 in less than 24 h. PMID- 29116559 TI - Perioperative Antiemetic Therapy for Fast-Track Laparoscopic Bariatric Surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is problematic in bariatric surgery patients and has negative impacts on perioperative outcome. Antiemetic prophylaxis may reduce PONV. Perioperative antiemetic prophylaxis or therapy is crucial and may enhance fast-track bariatric surgery. This study examined the impact of intraoperative multimodal antiemetic prophylaxis on fast-track bariatric surgery. METHODS: This prospective observational clinical study explored the perioperative data of 400 consecutive laparoscopic bariatric surgery patients, over a 6-year period. Perioperative outcomes and variables were analyzed and compared between different intraoperative antiemetic modes. RESULTS: The mean BMI was 49, mean age was 42, and male:female ratio was 1:4. About 70% of patients received intraoperative multimodal antiemetic, comprising combinations of prochlorperazine, dexamethasone, ondansetron, or cyclizine. PONV occurred in 19.5% of patients. Intraoperative multimodal antiemetic was associated with significantly less PONV, shorter post-anesthesia care unit duration, earlier postoperative drinking, and shorter hospital stay (p = 0.001). Compared to other multimodal antiemetic modes, dexamethasone + cyclizine + prochlorperazine provided the best prophylaxis and outcome: p = 0.002. CONCLUSION: PONV is a common and peculiar problem in bariatric surgery patients. However, intraoperative multimodal antiemetic prophylaxis effectively minimizes PONV. Intraoperative multimodal antiemetic enhances fast-track bariatric surgical care, patient satisfaction, and perioperative outcomes. PMID- 29116558 TI - Copper oxide nanoparticles induce anticancer activity in A549 lung cancer cells by inhibition of histone deacetylase. AB - OBJECTIVES: Copper oxide nanoparticles (CuO NPs) promoting anticancer activity may be due to the regulation of various classes of histone deacetylases (HDACs). RESULTS: Green-synthesized CuO NPs significantly arrested total HDAC level and also suppressed class I, II and IV HDACs mRNA expression in A549 cells. A549 cells treated with CuO NPs downregulated oncogenes and upregulated tumor suppressor protein expression. CuO NPs positively regulated both mitochondrial and death receptor-mediated apoptosis caspase cascade pathway in A549 cells. CONCLUSION: Green-synthesized CuO NPs inhibited HDAC and therefore shown apoptosis mediated anticancer activity in A549 lung cancer cell line. PMID- 29116561 TI - Myocardial perfusion imaging for cardiac allograft vasculopathy assessment: Evidence grows, but questions remain. PMID- 29116562 TI - Prediction of long-term (> 10 year) cardiovascular outcomes in heart transplant recipients: Value of stress technetium-99m tetrofosmin myocardial perfusion imaging. AB - BACKGROUND: Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is useful in the evaluation of cardiac allograft vasculopathy (CAV) in heart transplant (HTx) recipients. The current study evaluated the long-term prognostic value of stress SPECT MPI for predicting all cause mortality and cardiac events in HTx recipients. METHODS: The study population consisted of 166 HTx recipients (mean age 54 +/- 10 years, 84% male) who underwent exercise or dobutamine stress 99mTc-tetrofosmin SPECT MPI for the assessment of CAV. An abnormal SPECT MPI was defined as the presence of a fixed or a reversible perfusion defect. Endpoints were all-cause mortality, cardiac mortality, and non-fatal myocardial infarction (MI). RESULTS: MPI abnormalities were detected in 55 patients (33%), including fixed defects in 28 patients (17%), partially reversible in 17 patients (10%), and completely reversible defects in 10 patients (6%). During a median follow-up of 12.8 years (range 0-15, mean follow-up 9.5 years), 109 (66%) patients died (all-cause mortality), of which 67 (40%) were due to cardiac causes. A total of 5 (3%) patients experienced a non fatal MI. HTx recipients with a normal stress 99mTc-tetrofosmin SPECT MPI had a significantly better prognosis as compared with those with an abnormal study, up to 5 years after the initial test. The presence of a reversible perfusion defect was a significant predictor of all-cause mortality, cardiac mortality, and major cardiac events, during the entire follow-up period. CONCLUSIONS: Stress 99mTc tetrofosmin SPECT MPI provides valuable prognostic information for the prediction of long-term outcome in HTx recipients. Patients with a normal stress 99mTc tetrofosmin SPECT MPI have a significantly better prognosis as compared with those with an abnormal study, up to 5 years after initial testing. PMID- 29116560 TI - Preoperative and Postoperative Assessments of Biochemical Parameters in Patients with Severe Obesity Undergoing Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: The study aim was to determine the prevalence of abnormal serum biochemistries associated with micronutrient deficiencies before and after laparoscopic sleeve gastrectomy (LSG). METHODS: Two hundred and one patients had LSG surgery between May 2011 and May 2014. Using a prospective cohort study design, data were collected on ferritin, hemoglobin (Hgb), mean cell volume (MCV), calcium, albumin, 25-hydroxyvitamin D (25-OH-D), PTH, and vitamin B12 with follow-up of 75.6% (n = 152), 63.7% (n = 128), 52.7% (n = 106), and 40.3% (n = 81) at 6, 12, 18, and 24 months, respectively. RESULTS: Patients were female (81.6%) with mean +/- SD, BMI (48.8 +/- 6.8 kg/m2), weight (135.1 +/- 23.6 kg), and age (44.0 +/- 9.6 years). Mean values for all biochemical parameters pre- and post-LSG were within reference limits. After adjusting for age, weight, and supplement use, trend tests post-LSG were significant for mean differences in ferritin (p = 0.002), calcium (p = 0.017), and vitamin B12 (p = 0.034). Pre-LSG, the proportion of patients with values below reference limits included 25-OH-D (20.4%), ferritin (12.3%), and Hgb (10.0%), while the proportion above reference limits included PTH (29.1%) and ferritin (17.4%). After adjustment, hypoalbuminemia was more prevalent after 1 year; the proportion of patients with PTH levels in the upper reference limit was higher 6 months post-LSG (p < 0.05). Multivitamin use increased presurgery from 44 to 88% 2 years postsurgery. Vitamin B12 supplementation increased from 7% before surgery to 32% 2 years postsurgery. CONCLUSION: Abnormal serum biochemistries indicative of micronutrient deficiencies were prevalent before surgery; reduced abnormal values were observed after surgery, likely due to an increased use of multivitamins. PMID- 29116563 TI - Diagnosis of extensive myocardial infiltration by diffuse large B-cell lymphoma using 18F-fluorodeoxyglucose positron emission tomography (18-FDG PET). PMID- 29116564 TI - More important than the impact factor. PMID- 29116565 TI - Malaria Free India - Possibility or Enigma? AB - Malaria, despite being treatable as well as preventable, is still quite prevalent in our country and is responsible for a large number of deaths. Though Govt. of India (GOI) has launched anti-malaria program since 1953 but is yet to achieve a zero malaria status. In SE Asia, two small countries, Maldives and Sri Lanka, have been declared Malaria free by WHO. Hence, we need to think why we cannot achieve this status? For this we need to study how these two countries were successful and what are our limitations/pitfalls. The medical profession has a great role to play. Not only we have to advise GOI to formulate the correct policy but also we need to plug the rampant pitfalls in our practice. Implementation of WHO's 3 T (Test, treat and track) policy can be a table turner. PMID- 29116566 TI - Discovery of Immune Reactive Human Proteins by High-Density Protein Arrays and Customized Validation of Potential Biomarkers by ELISA. AB - Because of our access to human genome data and ever-improving genome sequencing and proteome analysis methods, we are much better in terms of our understanding of biological processes. In addition to genomics, proteomics, and other "omics" methods, availability of more sophisticated molecular assaying methods has augmented our knowledge about immune processes toward auto- and allogeneic targets. High-density protein arrays are developed to analyze protein-small molecule interactions, enzyme-substrate profiling, protein-protein interaction, and immune monitoring by assessing antibodies in the serum. PMID- 29116567 TI - LC-SRM-Based Targeted Quantification of Urinary Protein Biomarkers. AB - Liquid chromatography (LC)-selected reaction monitoring (SRM) is a powerful protein quantification technique in terms of sensitivity, reproducibility, and multiplexing capability. LC-SRM can accurately measure the concentrations of surrogate proteotypic peptides for targeted proteins in complex biological samples by using their stable heavy isotope-labeled counterparts as internal standards. Herein, we describe a step-by-step protocol of the application of LC SRM to quantify candidate protein biomarkers in human urine. PMID- 29116568 TI - Microaggressions, diabetes distress, and self-care behaviors in a sample of American Indian adults with type 2 diabetes. AB - American Indian/Alaska Native people experience the highest age-adjusted prevalence of type 2 diabetes of any racial group in the United States, as well as high rates of related health problems. Chronic stressors such as perceived discrimination are important contributors to these persistent health disparities. The current study used structural equation modeling to examine the relationships between racial microaggressions, diabetes distress, and self-care behaviors (diet and exercise) in a sample of 192 American Indians with type 2 diabetes from the northern United States. We found that microaggressions was positively associated with diabetes distress and that microaggressions had an indirect link to self care via diabetes distress. Diabetes distress is an important mechanism linking microaggressions to self-care behaviors, which are critical to successful disease management and the reduction of complications. The amelioration of diabetes distress could improve self-care even in the presence of pervasive, chronic social stressors such as microaggressions. PMID- 29116569 TI - Age differences in physical activity intentions and implementation intention preferences. AB - This study aimed to examine older adults' physical activity intentions and preferred implementation intentions, and how intentions and preferred implementation intentions differ between older, middle aged and younger adults. A cross-sectional Australian wide telephone survey of 1217 respondents was conducted in 2016. Multiple and ordinal regression analyses were conducted to compare intentions and preferred implementation intentions between older (65 +), middle aged (45-64) and younger adults (< 45). A higher percentage of older adults had no intentions to engage in regular physical activity within the next 6 months (60%) compared to younger adults (25%). Older adults' most popular preferences included being active at least once a day and for 30 min or less and were more likely to prefer more frequent and shorter sessions compared to younger adults. Both older and middle aged adults were more likely to prefer slower paced physical activity compared to younger adults who preferred fast paced physical activity. Physical activity interventions for older adults should address the high percentage of older adults with no intentions and public health campaigns for older adults should promote 30 min daily sessions of slow paced activity. PMID- 29116570 TI - MRI hydrographic 3D sequences: myotonic dystrophy type 1 meets CADASIL. PMID- 29116571 TI - Quality of life in adult patients with limb-girdle muscular dystrophies. AB - Although limb-girdle muscular dystrophies (LGMD) can cause permanent disability, to date there are no studies that examined quality of life (QoL) in these patients. Our aim was to evaluate QoL in patients with LGMD, and to identify the most significant predictors of QoL. The study comprised 46 patients with diagnosis of limb-girdle muscular weakness. QoL in patients was evaluated using two scales-SF-36 questionnaire and the Individualized Neuromuscular Quality of Life questionnaire (INQoL). Following scales were also applied: Epworth Sleepiness Scale (ESS), Hamilton Scale for Depression (HamD), and Krupp's Fatigue Severity Scale (FSS). Mean SF-36 score was 52.4 +/- 23.5, and physical composite score was worse than mental. Total INQoL score was 46.1 +/- 20.4, with worst results obtained for weakness, fatigue and independence, while social relationships and emotions showed better results. Significant predictors of worse SF-36 score in LGMD patients were higher fatigue level (beta = - 0.470, p < 0.01) and use of assistive device (beta = - 0.245, p < 0.05). Significant predictors of worse INQoL score were higher fatigue level (beta = 0.514, p < 0.01) and presence of cardiomyopathy (beta = - 0.385, p < 0.01). It is of special interest that some of the identified factors that correlated with worse QoL in LGMD patients were amenable to treatment. PMID- 29116572 TI - Admission of tetanus patients to the ICU: a retrospective multicentre study. AB - BACKGROUND: An extended course of tetanus (up to 6 weeks) requiring ICU admission and protracted mechanical ventilation (MV) may have a significant impact on short and long-term survival. The subject is noteworthy and deserves to be discussed. METHODS: Twenty-two ICUs in France performed tetanus screenings on patients admitted between January 2000 and December 2014. Retrospective data were collected from hospital databases and through the registers of the town hall of the patients. RESULTS: Seventy patients were included in 15 different ICUs. Sixty three patients suffered from severe or very severe tetanus according to the Ablett classification. The median age was 80 years [interquartile range 73-84], and 86% of patients were women. Ninety per cent of patients (n = 63) required MV for a median of 36 days [26-46], and 66% required administration of a neuromuscular-blocking agent for 23 days [14-29]. A nosocomial infection occurred in 43 patients (61%). ICU and 1-year mortality rates were 14% (n = 10) and 16% (n = 11), respectively. Forty-five per cent of deaths occurred during the first week. Advanced age, a higher SAPS II, any infection, and the use of vasopressors were significantly associated with a lower number of days alive without ventilator support by day 90. Age was the only factor that significantly differed between deceased and survivors at 1 year (83 [81-85] vs. 79 [73-84] years, respectively; p = 0.03). Sixty-one per cent of survivors suffered no impairment to their functional status. CONCLUSION: In a high-income country, tetanus mainly occurs in healthy elderly women. Despite prolonged MV and extended ICU length of stay, we observed a low 1-year mortality rate and good long-term functional status. PMID- 29116574 TI - Successful percutaneous coronary intervention significantly improves coronary sinus blood flow as assessed by transthoracic echocardiography. AB - BACKGROUND: Transthoracic echocardiography (TTE) has been used to assess coronary sinus blood flow (CSBF), which reflects total coronary arterial blood flow. Successful angioplasty is expected to improve coronary arterial blood flow. Changes in CSBF after percutaneous coronary intervention (PCI), as assessed by TTE, have not been systematically evaluated. HYPOTHESIS: TTE can be utilized to reflect increased CSBF after a successful, clinically indicated PCI. METHODS: The study cohort included 31 patients (18 females, 62 +/- 11 years old) referred for diagnostic cardiac catheterization for suspected coronary artery disease and possible PCI, when clinically indicated. All performed PCIs were successful, with good angiographic outcome. CSBF per cardiac cycle (mL/beat) was measured using transthoracic two-dimensional and Doppler flow imaging as the product of coronary sinus (CS) area and CS flow time-velocity integral. CSBF per minute (mL/min) was calculated as the product of heart rate and CSBF per cardiac cycle. In each patient, CSBF was assessed prospectively, before and after cardiac catheterization with and without clinically indicated PCI. Within- and between group differences in CSBF before and after PCI were assessed using repeated measures analysis of variance. RESULTS: Technically adequate CSBF measurements were obtained in 24 patients (77%). In patients who did not undergo PCI, there was no significant change in CSBF (278.1 +/- 344.1 versus 342.7 +/- 248.5, p = 0.36). By contrast, among patients who underwent PCI, CSBF increased significantly (254.3 +/- 194.7 versus 618.3 +/- 358.5 mL/min, p < 0.01, p interaction = 0.03). Other hemodynamic and echocardiographic parameters did not change significantly before and after cardiac catheterization in either treatment group. CONCLUSIONS: Transthoracic echocardiographic assessment can be employed to document CSBF changes after angioplasty. Future studies are needed to explore the clinical utility of this noninvasive metric. PMID- 29116576 TI - Bridging hard callus at 48 days in an open femoral shaft fracture with segmental defect treated with a first-stage Masquelet technique: I wasn't expecting that. AB - The Masquelet technique is a strategy for management of segmental bone defects. It is a two-stage procedure that involves inducing a synovial-like membrane that can be used for a bone graft. Segmental bone defects can occur following trauma and can accompany traumatic brain injury. There is a well-documented, albeit debated, association between traumatic brain injury and increased rate of new bone formation. Here, we present a case of unexpected callus formation in a segmental femoral fracture. The patient had a traumatic brain injury and was treated with the first stage of the Masquelet technique. Owing to the amount of large callus, a second stage of the Masquelet was not required. The patient recovered well from the injury and at 16-week follow-up was able to partially weight bear. A case similar to this has not previously been reported within the literature. PMID- 29116573 TI - An Evidence-Based Framework for Strengthening Exercises to Prevent Hamstring Injury. AB - Strength training is a valuable component of hamstring strain injury prevention programmes; however, in recent years a significant body of work has emerged to suggest that the acute responses and chronic adaptations to training with different exercises are heterogeneous. Unfortunately, these research findings do not appear to have uniformly influenced clinical guidelines for exercise selection in hamstring injury prevention or rehabilitation programmes. The purpose of this review was to provide the practitioner with an evidence-base from which to prescribe strengthening exercises to mitigate the risk of hamstring injury. Several studies have established that eccentric knee flexor conditioning reduces the risk of hamstring strain injury when compliance is adequate. The benefits of this type of training are likely to be at least partly mediated by increases in biceps femoris long head fascicle length and improvements in eccentric knee flexor strength. Therefore, selecting exercises with a proven benefit on these variables should form the basis of effective injury prevention protocols. In addition, a growing body of work suggests that the patterns of hamstring muscle activation diverge significantly between different exercises. Typically, relatively higher levels of biceps femoris long head and semimembranosus activity have been observed during hip extension-oriented movements, whereas preferential semitendinosus and biceps femoris short head activation have been reported during knee flexion-oriented movements. These findings may have implications for targeting specific muscles in injury prevention programmes. An evidence-based approach to strength training for the prevention of hamstring strain injury should consider the impact of exercise selection on muscle activation, and the effect of training interventions on hamstring muscle architecture, morphology and function. Most importantly, practitioners should consider the effect of a strength training programme on known or proposed risk factors for hamstring injury. PMID- 29116577 TI - Adsorption and desorption of heavy metals by the sewage sludge and biochar amended soil. AB - The goal of the study was to evaluate the application of biochar (BC) to the sewage sludge (SL) on the adsorption and desorption capacity of Cd(II), Cu(II), Ni(II) and Zn(II). The effect of biochar contribution in the sewage sludge (2.5, 5 and 10%) was investigated. The isotherms data were fitted to the Langmiur (LM), Freundlich (FM) and Temkin (TM) models. The best fitting for kinetic study was obtained for the pseudo-second-order equation. The best fitting of the experimental data was observed for the LM in the case of SL and BC, and for the FM in the case of SL- and SL/BC-amended soil. SL was characterized by even four order higher sorption capacity than BC. The addition of the BC to the SL and next to the soil increased the adsorption capacity of the soil and the SL-amended soil. In the case of all investigated potentially toxic elements (PTEs), the highest adsorption capacity was achieved for SL-amended soil in comparison with the control soil. In the case of other experimental variants, the adsorption capacity of metal ions was as follows: 2.5% BC > 5.0% BC > 10% BC. The negative correlation between hydrated radius of metal ions and the kinetics of sorption was observed. However, the desorption of PTEs from BC/SL-amended soil was significantly lower than for SL-amended soil (except of Cd) and non-amended soil. It can be concluded that the addition of the biochar enhanced the immobilization of PTEs and reduced their bioavailability and mobility in the soil amended by the sewage sludge. PMID- 29116575 TI - Isolation and characterization of a novel, T7-like phage against Aeromonas veronii. AB - A virulent Aeromonas veronii biovar sobria and the corresponding novel, lytic bacteriophage (VTCCBPA5) were isolated from village pond water. The phage was found to belong to family Podoviridae. PCR analysis of major capsid protein gene confirmed its classification to T7-like genus. The protein profiling by SDS-PAGE indicated the major structural protein to be ~ 45 kDa. The phage (VTCCBPA5) is host specific and is stable over a range of pH (6-10) and temperatures (4-45 degrees C). On the basis of restriction endonuclease analysis combined with prediction mapping, it was observed to vary significantly from previously reported podophages of Aeromonas sp., viz. phiAS7 and Ahp1. The phylogenetic analysis on the basis of PCR-amplified segment of DNA polymerase gene of phage revealed it being an outgroup from podophages of Klebsiella sp. and Pseudomonas sp. though a small internal fragment (359 bp) showed the highest identity (77%) with Vibrio sp. phages. Thus, this is the first report of a novel Podoviridae phage against A. veronii. It expands the assemblage of podophages against Aeromonas sp. and BPA5 could be potentially useful in biocontrol of environmentally acquired Aeromonas veronii infections. PMID- 29116578 TI - Yeast polyubiquitin gene UBI4 deficiency leads to early induction of apoptosis and shortened replicative lifespan. AB - Ubiquitin is a 76-amino acid protein that is highly conserved among higher and lower eukaryotes. The polyubiquitin gene UBI4 encodes a unique precursor protein that contains five ubiquitin repeats organized in a head-to-tail arrangement. Although the involvement of the yeast polyubiquitin gene UBI4 in the stress response was reported long ago, there are no reports regarding the underlying mechanism of this involvement. In this study, we used UBI4-deletion and UBI4 overexpressing yeast strains as models to explore the potential mechanism by which UBI4 protects yeast cells against paraquat-induced oxidative stress. Here, we show that ubi4Delta cells exhibit oxidative stress, an apoptotic phenotype, and a decreased replicative lifespan. Additionally, the reduced resistance of ubi4Delta cells to paraquat that was observed in this study was rescued by overexpression of either the catalase or the mitochondrial superoxide dismutase SOD2. We also demonstrated that only SOD2 overexpression restored the replicative lifespan of ubi4Delta cells. In contrast to the case of ubi4Delta cells, UBI4 overexpression in wild-type yeast increases the yeast's resistance to paraquat, and this overexpression is associated with large pools of expressed ubiquitin and increased levels of ubiquitinated proteins. Collectively, these findings highlight the role of the polyubiquitin gene UBI4 in apoptosis and implicate UBI4 as a modulator of the replicative lifespan. PMID- 29116580 TI - Extending Awareness of Catholic Healthcare Ethics Among Junior Clinicians: A Qualitative Study. AB - As Catholic healthcare organizations form a substantive part of healthcare delivery in the USA and Australia, ethical standards for Catholic health care were developed to guide practice. This study examined junior staff's understanding of Catholic ethics. Using a qualitative descriptive design, we recruited 22 medical and nursing staff to interviews/focus groups. Though Catholic ethics seldom informed ethical approaches, the principles were acknowledged as being useful to support development of confident and respectful care approaches. Findings provide early insights into challenges faced in considering implementation of ethical codes across both secular and religious healthcare organizations, suggesting that a more creative and pastoral approach to dialoguing and implementing Catholic ethics is required. PMID- 29116579 TI - Gene encoding vesicle-associated membrane protein-associated protein from Triticum aestivum (TaVAP) confers tolerance to drought stress. AB - Abiotic stresses like drought, salinity, high and low temperature, and submergence are major factors that limit the crop productivity. Hence, identification of genes associated with stress response in crops is a prerequisite for improving their tolerance to adverse environmental conditions. In an earlier study, we had identified a drought-inducible gene, vesicle associated membrane protein-associated protein (TaVAP), in developing grains of wheat. In this study, we demonstrate that TaVAP is able to complement yeast and Arabidopsis mutants, which are impaired in their respective orthologs, signifying functional conservation. Constitutive expression of TaVAP in Arabidopsis imparted tolerance to water stress conditions without any apparent yield penalty. Enhanced tolerance to water stress was associated with maintenance of higher relative water content, photosynthetic efficiency, and antioxidant activities. Compared to wild type, the TaVAP-overexpressing plants showed enhanced lateral root proliferation that was attributed to higher endogenous levels of IAA. These studies are the first to demonstrate that TaVAP plays a critical role in growth and development in plants, and is a potential candidate for improving the abiotic stress tolerance in crop plants. PMID- 29116581 TI - Nursing Practices in Catholic Healthcare: A Case Study of Nurses in a Catholic Private Hospital. AB - We aimed to investigate Catholic Identity and Mission communication specifically how nurses were expressing the Catholic healthcare values in practice. A mixed methods, case study design was used and included non-participant observation, a mid-level manager focus group (n = 7) and online surveys (n = 144). Document and observational data analysis revealed the organisation's commitment to visible indication of Catholic values adherence. Focus group analysis revealed two themes, 'Catholic values in action' and 'taking the extra step'. The impact of Catholic Identity and Mission on nurses and nursing care recipients remains elusive and warrants further understanding. PMID- 29116582 TI - Late Onset First Episode Psychosis Emerging as Delusional Misidentification of Familiar Sacred Places During a Holy Pilgrimage: A Case Report and Literature Review. AB - BACKGROUND: The delusional misidentification syndromes (DMS) include a myriad of discrete but related syndromes, which have wide spectrum anomalies of familiarity. Several misidentification syndromes have been described in the psychiatric literature, the most common of these delusions are: the Capgras syndrome; the Fregoli syndrome; the syndrome of inter-metamorphosis; reduplicative paramnesia; and environmental reduplication. CASE PRESENTATION: The reported case highlights the emergence of late onset first episode psychosis in a Middle Eastern 65-year-old female who has no previous psychiatric history. The nature of psychosis was mainly delusions of misidentification and persecution. DISCUSSION: DMS are relatively rare and occur predominantly in association with schizophrenia and affective psychosis. Between 25 and 40% are associated with organic conditions such as dementia, head injuries, brain tumors, and epilepsy. Only three cases of misidentification of sacred places have been reported previously in the literature. This case report is the first to present a DMS, emerging as a late onset first episode psychosis during the sacred journey of Hajj. CLINICAL IMPLICATIONS: The reported case highlights the importance of early recognition and treatment of mental health conditions that may appear de novo during the Hajj sacred journey. Readily available psychiatric resources, psychotropic medications, and psycho-education may be pivotal in ensuring mental well-being of pilgrims, which is fundamental to maintain the mental capacity required for completing these journeys. PMID- 29116583 TI - Innovative clinical pathways for obese pregnant women: design and feasibility of the Padua project (North-Eastern Italy). AB - BACKGROUND: Obesity during pregnancy can adversely affect the wellbeing of the mother and the newborn, as well as the latter's long-term health. Preconception counseling, careful prenatal management, and strict follow-up during pregnancy are, therefore, essential for obese fertile women in order to prevent the negative effects of obesity. METHODS: In this setting, we developed a project that consisted in creating an integrated network of primary, secondary, and tertiary care providers and designing new clinical pathways for managing pregnancy in obese women. RESULTS: Two distinct pathways were devised: a Pre Gestational Pathway for programming a pregnancy in obese women; and a Gestational Pathway for the clinical management of their pregnancy. DISCUSSION: Judging from the preliminary results of our study, the latter (Gestational) pathway seems to be successful, since there has been a gradual increase in the number of women using it, and these women have reported having no difficulty in accessing the services involved. It is noteworthy that immigrant women (who accounted for 60% of the women using the pathway) also reported no access issues. The pre gestational pathway was very little used, however, accounting for only 2% of the appointments made with the services involved. In conclusion, the key to success in managing pregnancy in obese women lies in sharing the various different health care competences required and taking the local resources into account. The prevention of obesity in women of fertile age remains the main problem, however, and further efforts are needed in this setting. PMID- 29116584 TI - Use of 50/50 Premixed Insulin Analogs in Type 2 Diabetes: Systematic Review and Clinical Recommendations. AB - INTRODUCTION: Premixed insulin analogs represent an alternative to basal or basal bolus insulin regimens for the treatment of type 2 diabetes (T2D). "Low-mix" formulations with a low rapid-acting to long-acting analog ratio (e.g., 25/75) are commonly used, but 50/50 formulations (Mix50) may be more appropriate for some patients. We conducted a systematic literature review to assess the efficacy and safety of Mix50, compared with low-mix, basal, or basal-bolus therapy, for insulin initiation and intensification. METHODS: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, LillyTrials.com, and NovoNordisk-trials.com were searched (11 or 13 Dec 2016) using terms for T2D, premixed insulin analogs, and/or Mix50. Studies (randomized, nonrandomized, or observational; English only) comparing Mix50 with other insulins (except human) and reporting key efficacy [glycated hemoglobin (HbA1c), fasting and postprandial glucose] and/or safety (hypoglycemia, weight gain) outcomes were eligible for inclusion. Narrative reviews, letters, editorials, and conference abstracts were excluded. Risk of bias in randomized trials was assessed using the Cochrane tool. RESULTS: MEDLINE and EMBASE searches identified 716 unique studies, of which 32 met inclusion criteria. An additional three studies were identified in the other databases. All 19 randomized trials except one were open label; risk of other biases was generally low. Although not conclusive, the evidence suggests that Mix50 may provide better glycemic control (HbA1c reduction) and, particularly, postprandial glucose reduction in certain patients, such as those with high carbohydrate diets and Asian patients, than low-mix and basal therapy. Based on this evidence and our experience, we provide clinical guidance on factors to consider when deciding whether Mix50 is appropriate for individual patients. CONCLUSIONS: Mix50 may be more suitable than low-mix therapy for certain patients. Clinicians should consider not only efficacy and safety but also patient characteristics and preferences when tailoring insulin treatment to individuals with T2D. FUNDING: Eli Lilly. PMID- 29116585 TI - Reactions of Organic Peroxides with Alcohols in Atmospheric Pressure Chemical Ionization-the Pitfalls of Quantifying Triacetone Triperoxide (TATP). AB - Over the last several decades, mass spectrometry has become one of the principle methods for compound identification and quantification. While for analytical purposes, fragments which are not fully characterized in terms of origin and intensity as a function of experimental conditions have been used, understanding the nature of those species is very important. Herein we discuss such issues relative to triacetone triperoxide (TATP) and its frequently observed fragment at m/z 89. This "fragment" has been identified as the gas-phase reaction product of TATP with one or two methanol molecules/ions. Additionally, the origin and conditions of other fragments at m/z 91, 75, and 74 associated with TATP will be addressed. Similar analytical issues associated with other multi-peroxide organic compounds [hexamethylene triperoxide diamine (HMTD), methyl ethyl ketone peroxides (MEKP)] will also be discussed. Solution storage conditions for TATP, HMTD, and tetramethylene diperoxide diamine dialdehyde have been determined. Graphical Abstract ?. PMID- 29116586 TI - Correction to: Acquisition of Tn6018-3' CS regions increases colistin MICs against Acinetobacter baumannii isolates harboring new variants of AbaRs. AB - The published online version of this article contained a mistake. The correct affiliation of Alireza Ekrami should have been "Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran" . The authors regret this error. PMID- 29116587 TI - A simplified globally affordable experimental setup for monitoring DNA diagnosis by a QD-based technique. AB - The unavailability of simple, quick, and sensitive genetic-based molecular diagnostic techniques has become the main driving force for inventing new approaches in the era of quantum dots (QDs): a new class of fluorescent probes with fascinating optical electronic properties. Using the unique size-dependent light-emitting properties of QDs, we have developed a QD-based ultrasensitive technique which removes the necessity for the genetic amplification step required in almost all types of molecular-based diagnostic techniques. The selectivity of the new approach is warranted by the careful design of a pair of specific oligonucleotide probes, chemically modified at their 5'-ends. Our results indicated the selective detection of Salmonella typhi in an assay time of 50 min with a limit of detection (LOD) of 2 CFU/mL. The rapidity, selectivity, and sensitivity and the low assay cost make the new diagnostic technique a promising new tool for laboratory and field-based approaches to molecular diagnosis of health-threatening pathogens. Graphical abstract. PMID- 29116588 TI - The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers. AB - Activation of specific sets of protein kinases by intracellular signal molecules has become more and more apparent in the past decade. Phosphorylation, one of key posttranslational modification events, is activated by kinase or regulatory protein and is vital for controlling many physiological functions of eukaryotic cells such as cell proliferation, differentiation, malignant transformation, and signal transduction mediated by external stimuli. Moreovers, the reversible modification of phosphorylation and dephosphorylation can result in different features of the target substrate molecules including DNA binding, protein-protein interaction, subcellular location and enzymatic activity, and is often hijacked by viral infection. Epstein-Barr virus (EBV) and Kaposi's sarcomaassociated herpesvirus (KSHV), two human oncogenic gamma-herpesviruses, are shown to tightly associate with many malignancies. In this review, we summarize the recent progresses on understanding of molecular properties and regulatory modes of cellular and viral proteins phosphorylation influenced by these two tumor viruses, and highlight the potential therapeutic targets and strategies against their related cancers. PMID- 29116590 TI - Detection of congenital cytomegalovirus in newborns using nucleic acid amplification techniques and its public health implications. AB - Human cytomegalovirus (HCMV), a herpesvirus, is an important human pathogen that causes asymptomatic infections in healthy or immunocompetent individuals but can lead to severe and potentially life-threatening complications in immune-immature individuals such as neonates or immune-compromised patients such as organ transplant recipients and HIV-positive individuals. Congenital HCMV infection represents a significant public health issue and poses substantial healthcare and economic burden to society. This virus causes the most common viral congenital infection worldwide, and is the leading non-genetic cause of sensorineural hearing loss in children in developed countries. Congenital HCMV infection is believed to fulfill the criteria of the American College of Medical Genetics to be considered as a condition targeted for a newborn screening program. This is because congenital HCMV infection can be identified during a time (within 2 days after birth) at which it would not ordinarily be detected clinically, and there are demonstrated benefits of early detection, timely intervention, and efficacious treatment of the condition. Recent progresses in developing polymerase chain reaction-based approaches to detect HCMV in samples obtained from newborns have generated much excitement in the field. In this review, we highlight the recent progress in diagnostic techniques that could potentially be used for the detection of HCMV infection in neonates and its direct implications in public health settings for diagnosing congenital HCMV infection. PMID- 29116589 TI - Extracellular vesicles: novel vehicles in herpesvirus infection. AB - Herpesviruses are remarkable pathogens that have evolved multiple mechanisms to evade host immunity, ensuring their proliferation and egress. Among these mechanisms, herpesviruses utilize elaborate extracellular vesicles, including exosomes, for the intricate interplay between infected host and recipient cells. Herpesviruses incorporate genome expression products and direct cellular products into exosomal cargoes. These components alter the content and function of exosomes released from donor cells, thus affecting the downstream signalings of recipient cells. In this way, herpesviruses hijack exosomal pathways to ensure their survival and persistence, and exosomes are emerging as critical mediators for virus infection-associated intercellular communication and microenvironment alteration. In this review, the function and effects of exosomes in herpesvirus infection will be discussed, so that we will have a better understanding about the pathogenesis of herpesviruses. PMID- 29116592 TI - Varicella-zoster virus ORF7 interacts with ORF53 and plays a role in its trans Golgi network localization. AB - Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus that causes chickenpox and shingles. ORF7 is an important virulence determinant of VZV in both human skin and nerve tissues, however, its specific function and involved molecular mechanism in VZV pathogenesis remain largely elusive. Previous yeast two-hybrid studies on intraviral protein-protein interaction network in herpesviruses have revealed that VZV ORF7 may interact with ORF53, which is a virtually unstudied but essential viral protein. The aim of this study is to identify and characterize VZV ORF53, and to investigate its relationship with ORF7. For this purpose, we prepared monoclonal antibodies against ORF53 and, for the first time, characterized it as a ~40 kDa viral protein predominantly localizing to the trans-Golgi network of the infected host cell. Next, we further confirmed the interaction between ORF7 and ORF53 by co-immunoprecipitation and co localization studies in both plasmid-transfected and VZV-infected cells. Moreover, interestingly, we found that ORF53 lost its trans-Golgi network localization and became dispersed in the cytoplasm of host cells infected with an ORF7-deleted recombinant VZV, and thus ORF7 seems to play a role in normal subcellular localization of ORF53. Collectively, these results suggested that ORF7 and ORF53 may function as a complex during infection, which may be implicated in VZV pathogenesis. PMID- 29116591 TI - Prevalence of Kaposi's sarcoma-associated herpesvirus in Uygur and Han populations from the Urumqi and Kashgar regions of Xinjiang, China. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious etiologic agent associated with Kaposi's sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease. It has been shown that high KSHV prevalence and high incidence of both classic KS and AIDSassociated KS are found mostly among people of Uygur ethnicity in Xinjiang, while people of Han ethnicity in Xinjiang have a higher KSHV seroprevalence than those of other Han populations in mainland China. However, it is still unclear why there is such geographical and population variation in KSHV distribution in China. In this work, we focused on the populations in the Kashgar region and Urumqi area, where a total of 1294 research subjects were randomly selected to investigate the potential correlation between KSHV prevalence and different ethnicities in endemic areas of Xinjiang, and to determine risk factors that may affect KSHV infection rates or KS incidence. We identified a high seroprevalence of KSHV and high peripheral blood DNA infection in the general Uygur and Han populations in both Urumqi and Kashgar regions of Xinjiang, and determined that advancing age, low education level, and stationary population status affect KSHV infection rates. Further, KSHV-positive Uygur participants were shown to have higher prevalence of neutralizing antibodies and neutralizing antibody titers than KSHV-positive Han participants. PMID- 29116593 TI - Human cytomegalovirus miR-US5-1 inhibits viral replication by targeting Geminin mRNA. AB - Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. MicroRNAs (miRNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus (HCMV) in its infection and pathogenesis. In the present study, the DNA replication inhibitor Geminin (GMNN) was identified to be a direct target of hcmv-miR-US5-1. Overexpression of hcmv miR-US5-1 could block the accumulation of GMNN during HCMV infection, and the decrease of GMNN expression caused by hcmv-miR-US5-1 or GMNN specific siRNA reduced HCMV DNA copies in U373 cells. Meanwhile, ectopic expression of hcmv-miR US5-1 and consequent lower expression of GMNN influenced host cell cycle and proliferation. These results imply that hcmv-miR-US5-1 may affect viral replication and host cellular environment by regulating expression kinetics of GMNN during HCMV infection. PMID- 29116595 TI - Herpesviruses: epidemiology, pathogenesis, and interventions. PMID- 29116594 TI - Elevated expression of EBV and TLRs in the brain is associated with Rasmussen's encephalitis. AB - Rasmussen's encephalitis (RE) is a rare pediatric neurological disorder, the etiology of which remains unclear. It has been speculated that the immunopathogenesis of RE involves damage to neurons, which eventually leads to the occurrence of RE. Viral infection may be a critical factor in triggering RE immunopathogenesis. In this study, we analyzed the expression of Epstein-Barr virus (EBV) antigens as well as of Toll-like receptor 3 (TLR3), TLR9, and downstream adapter TIRdomain-containing adapter-inducing interferon-beta (TRIF) in the brain tissues of 26 patients with RE and 16 control individuals using immunohistochemistry (IHC). In the RE group, EBV antigens were detected in 53% of individuals at various expression levels. In contrast, there was no detectable EBV antigen expression in control brain tissues. Moreover, we found marked increases in the expression of TLR3, TLR9, and TRIF in the brain tissues of RE patients compared with levels in the control group. Furthermore, among RE cases, EBV expression and high TLR3 expression were associated with more severe brain atrophy. Our results suggest that the elevated expression of EBV and TLRs may be involved in RE occurrence through the activation of downstream molecules. PMID- 29116597 TI - Response to Tetanus and Pneumococcal Vaccination Following Administration of Ixekizumab in Healthy Participants. AB - BACKGROUND: Ixekizumab (IXE) is an interleukin (IL)-17A antagonist approved for the treatment of adults with moderate-to-severe psoriasis. OBJECTIVE: The objective of this study was to determine if the immune response to tetanus and pneumococcal vaccines in healthy subjects administered IXE was noninferior to control. METHODS: In a randomized, open-label, parallel-group study, adult subjects received vaccinations alone (N = 42, control) or in combination with 160 mg IXE subcutaneously 2 weeks prior to vaccination and 80 mg IXE on the day of vaccination (N = 41, IXE). Response to tetanus vaccination was defined as anti tetanus antibodies >= 1.0 IU and a >= 1.5-fold increase if baseline was <= 1.0 IU or a >= 2.5-fold increase if baseline was > 1.0 IU. Response to pneumococcal vaccination was defined as a >= 2-fold increase from baseline in anti pneumococcal antibodies against > 50% of the 23 serotypes. The primary outcomes were the percentages of patients with a response to the tetanus and pneumococcal vaccines 4 weeks after vaccination. A noninferiority analysis of IXE to control using a 40% margin was evaluated for the primary outcomes. Safety and pharmacokinetics were also assessed. RESULTS: IXE (38 completers) was noninferior to control (41 completers) based on the difference in the proportion of responders to tetanus [1.4%; 90% confidence interval (CI) - 16.6 to 19.2] and pneumococcal (- 0.8%; 90% CI - 12.9 to 11.0) vaccines. Twenty subjects (14 IXE, six control) reported 43 mild treatment-emergent adverse events. CONCLUSION: IXE does not suppress the humoral immune response to non-live vaccines and was well tolerated in healthy subjects. ClinicalTrial.gov identifier: NCT02543918. PMID- 29116598 TI - CGRP Monoclonal Antibodies for Migraine: Rationale and Progress. AB - Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management. The site of action, although still being studied, is likely in nervous system structures outside the blood-brain barrier. To date, four CGRP function-blocking mAbs (three target CGRP and one targets the CGRP receptor) are under clinical investigation for migraine prophylaxis. Phase II and III studies were promising with favorable safety profiles. CGRP function-blocking mAbs may potentially revolutionize the management of migraine. This review discusses in depth the fundamental role of CGRP in migraine pathogenesis as well as the clinical efficacy of CGRP function-blocking mAbs. PMID- 29116596 TI - Antibody-Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments. AB - Antibody-drug conjugates (ADCs) are complex immunoconjugates designed to selectively deliver toxic small molecules preferentially to cancer cells. These immunoconjugates consist of a monoclonal antibody - directed to a tumor antigen - and a cytotoxic agent that is conjugated to the antibody via a molecular linker. Following the binding to a specific antigen on the surface of cancer cells, the conjugate is internalized and releases its cytotoxic payload to kill the malignant cell. ADCs that have gained regulatory approval from the US Food and Drug Administration (FDA) include brentuximab vedotin for CD30-positive Hodgkin's lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several other agents are in advanced stages of clinical development, including sacituzumab govitecan for breast cancer, mirvetuximab soravtansine for ovarian cancer, rovalpituzumab tesirine for lung cancer, depatuxizumab mafodotin for glioblastoma, and oportuzumab monatox for bladder cancer. This review provides an overview of the recent clinical experience with the approved, most advanced, and other promising candidates of ADCs for solid tumors, including a description of biology and chemistry of ADCs, drug resistance and biomarkers, and the future perspective on combination strategies with these new immunoconjugates. PMID- 29116599 TI - The Class-A GPCR Dopamine D2 Receptor Forms Transient Dimers Stabilized by Agonists: Detection by Single-Molecule Tracking. AB - Whether class-A G-protein coupled receptors (GPCRs) exist and work as monomers or dimers has drawn extensive attention. A class-A GPCR dopamine D2 receptor (D2R) is involved in many physiological and pathological processes and diseases, indicating its critical role in proper functioning of neuronal circuits. In particular, D2R homodimers might play key roles in schizophrenia development and amphetamine-induced psychosis. Here, using single-molecule imaging, we directly tracked single D2R molecules in the plasma membrane at a physiological temperature of 37 degrees C, and unequivocally determined that D2R forms transient dimers with a lifetime of 68 ms in its resting state. Agonist addition prolonged the dimer lifetime by a factor of ~1.5, suggesting the possibility that transient dimers might be involved in signaling. PMID- 29116600 TI - Recent Progress in the Pharmacotherapy of Alzheimer's Disease. AB - Alzheimer's disease is the most common major neurocognitive disorder with substantial social and economic impacts. This article is an update on current pharmacotherapy, advancements in biomarker use, and drugs in the pipeline for this disease. To date, no new drug has qualified to be added to the current therapeutic arsenal comprising cholinesterase inhibitors and the NMDA receptor antagonist memantine. Drugs in the pipeline include symptomatic therapies that are neurotransmitter-based, but mostly disease-modifying therapies. The latter have yielded disappointing results by focusing mainly on the two pathophysiological hallmarks of Alzheimer's disease: Abeta amyloid deposits and tau protein aggregates forming neurofibrillary tangles. These unsuccessful trials may have resulted from studying these drugs 'too late' relative to Alzheimer's disease onset, in addition to focusing only on the amyloid cascade. In fact, Alzheimer's disease is a complex multifactorial disease. Combining different biomarkers might enhance our ability to identify those patients most at risk of developing the disease, and better predict their conversion rates. Furthermore, adopting an integrative treatment approach by targeting additional pathophysiological pathways in Alzheimer's disease such as inflammation and oxidative stress could be the key to better outcomes in Alzheimer's disease pharmacotherapy research. PMID- 29116601 TI - Abnormal cervical lymph nodes in multiple sclerosis: a preliminary ultrasound study. AB - BACKGROUND: Cervical lymph nodes are the first drainage stations of the brain and therefore play a key role in neuroinflammatory disorders such as multiple sclerosis. OBJECTIVE: The aim of this study was to evaluate, by using ultrasound imaging, cervical lymph nodes in patients with multiple sclerosis and to ascertain if such patients have any clinical features to attest their role. METHODS: We enrolled 43 patients affected by relapsing-remitting multiple sclerosis (22 drug free and 21 under treatment with natalizumab or fingolimod), who underwent ultrasound examination. The morphology, diameters and volume of cervical lymph nodes were measured. We evaluated also a control group of 20 healthy volunteers. RESULTS: Between-group comparisons showed that the mean anteroposterior diameters in the cervical lymph nodes on both sides of the neck were significantly different (chi 2 = 19.5, p < 0.001 for right; chi 2 = 20.0, p < 0.001 for left). Post hoc contrasts showed that the mean anteroposterior diameters were greater both in drug-naive (mean +/- SD 0.66 +/- 0.20 cm; p < 0.001) and treated patients (0.55 +/- 0.24 cm; p < 0.001) compared to healthy individuals (0.36 +/- 0.19 cm). Moreover, significant difference (p < 0.001) was shown on comparing the mean volume of the cervical lymph nodes on both sides of the neck in the studied groups. No significant differences emerged between the drug-free and treated patients. CONCLUSION: The abnormalities shown by ultrasound in cervical lymph nodes are related to deep ones and independent of the ongoing treatment, suggesting a relationship between lymphatic drainage and disease pathology. PMID- 29116602 TI - Arterial embolizations with microvascular plug in extracranial and intracranial districts: technical results. AB - PURPOSE: A new detachable microvascular plug (MVP, Reverse Medical(r), Irvine, CA, USA) has been recently developed; three models are available according to the size (MVP3-MVP5-MVP7). MVP3 and MVP5 are released through a 0.027" microcatheter, MVP7 through a 4 Fr catheter. This series aims to describe an initial single center experience examining intraprocedural safety and technical success of MVP. MATERIALS AND METHODS: Ten patients (mean age 55.1 years) have been treated for arterial embolization using MVP; eight extracranial and two intracranial arterial embolizations have been performed. The embolizations were because of: four bleedings, three aneurysms, two pseudoaneurysms, and one presurgical nephrectomy. RESULTS: MVP3 was used in five cases, MVP5 in four cases, and MVP 7 once. In all cases, the MVP was successfully released in < 1 min. In six patients, the MVP was the sole embolizing agent employed, while in four subjects, it was positioned complementary after coils. The technical and clinical success was obtained in 100%; hemorrhages were interrupted and aneurysms and pseudoaneurysms did not show recanalization at follow-up. CONCLUSIONS: MVP seems to be a safe embolizing device that interventional radiologists should consider when facing arterial embolization of both body and neuroarterial districts; the main advantage is related to MVP3 and MVP5 models that can be adopted for distal embolization thanks to the precise release through 0.027" microcatheter. PMID- 29116603 TI - Leigh syndrome in individuals bearing m.9185T>C MTATP6 variant. Is hyperventilation a factor which starts its development? AB - Leigh syndrome (LS), subacute necrotizing encephalomyelopathy is caused by various genetic defects, including m.9185T>C MTATP6 variant. Mechanism of LS development remains unknown. We report on the acid-base status of three patients with m.9185T>C related LS. At the onset, it showed respiratory alkalosis, reflecting excessive respiration effort (hyperventilation with low pCO2). In patient 1, the deterioration occurred in temporal relation to passive oxygen therapy. To the contrary, on the recovery, she demonstrated a relatively low respiratory drive, suggesting that a "hypoventilation" might be beneficial for m.9185T>C carriers. As long as circumstances of the development of LS have not been fully explained, we recommend to counteract hyperventilation and carefully dose oxygen in patients with m.9185T>C related LS. PMID- 29116604 TI - Supplementation of pig diets in the growth and termination phases with different calcium sources. AB - The aim of this study was to evaluate the effect of supplementation of pig diets in the growth and termination phases with different calcium sources. In experiment I, 36 whole males were distributed in randomized blocks in six groups, with six replications. A basal diet was formulated to meet the animals' nutritional requirements except for calcium (0.09%), and the sources evaluated (calcitic limestone, monodicalcium phosphate, calcinated bone flour, and oyster flour) replaced the basal diet to provide 0.59% of total calcium. To determine the endogenous calcium, a diet containing low calcium (0.019%) was given simultaneously to another group of animals. Feces and urine were collected for determination the coefficients of apparent and true digestibility. In experiment II, 160 piglets were distributed in randomized blocks in four treatments, with five replications and four animals per experimental unit. Carcass and performance parameters, calcium concentration in bone and serum, and bone parameters were evaluated. The data were submitted to analysis of variance and factorial. The calcium source did not influence the digestibility coefficients determined by total collection (P > 0.05). The digestibility of Ca from oyster flour estimated by collection with an indicator was higher than that from the other sources (P < 0.05). Calcium sources did not interfere in the evaluated parameters (P > 0.05). The sources studied in this work can be used to supplement growing pigs' diets. PMID- 29116605 TI - Influence of dietary chromium yeast supplementation on apparent trace elements metabolism in growing camel (Camelus dromedarius) reared under hot summer conditions. AB - This study aimed to evaluate the effect of dietary chromium (Cr) supplementation on the apparent metabolism of some trace elements in camel calves reared under hot summer conditions. The study was conducted on a total of 15 male camel calves (5-6 months old) reared under hot summer conditions for 12 weeks. The animals were housed individually under shelter and divided into three dietary treatment groups (diets supplemented with 0.0, 0.5, or 1.0 mg Cr/kg DM), five animals each. At the end of the study, a metabolic trial was conducted on all camels for the evaluation of trace elements metabolism. Cr excretion, absorption, and retention showed an increasing trend with the increasing level of dietary Cr supplementation. Dietary Cr supplementation at 0.5 mg Cr/kg DM to camel calves resulted in a significant (P < 0.05) increase in Cu and an increasing trend in Zn and Mn excretion via urine and feces. However, Fe retention increased significantly (P < 0.05) in camel calves fed on diet supplemented with Cr. Dietary Cr supplementation to camel calves resulted in an increasing trend of plasma Cr concentration, while plasma concentration of Cu and Zn tended to decrease and without any effect on plasma Fe concentration. The results of the present study suggests that care should be taken for the negative interaction of Cr with the utilization of other trace elements, in cases where Cr is supplemented to the diet as a feed additive to promote growth and immunity under hot climatic conditions. PMID- 29116606 TI - Fanconi syndrome and neonatal diabetes: phenotypic heterogeneity in patients with GLUT2 defects. AB - Fanconi-Bickel syndrome, caused by mutations in SLC2A2 encoding the glucose transporter 2 (GLUT2), is characterized by generalized proximal renal tubular dysfunction manifesting in late infancy. We describe phenotypic heterogeneity of Fanconi-Bickel syndrome in three siblings, including early and atypical presentation with transient neonatal diabetes mellitus in one. The second-born of a non-consanguineous couple, evaluated for polyuria and growth retardation, had rickets, hepatomegaly and proximal tubular dysfunction from 4 to 6 months of age. A male sibling, who expired at 4 months, also had hepatomegaly and growth retardation. The third sibling had polyuria, glucosuria and mild proteinuria on day 3 of life. Hyperglycemia was detected 2 weeks later, which required therapy with insulin for 3 months. Mild metabolic acidosis was present at 2 weeks; hypercalciuria, phosphaturia and aminoaciduria were seen at 6 months. Sanger sequencing showed a homozygous missense mutation in SLC2A2 (exon 7, c.952G > A), causing glycine to arginine substitution; both parents were heterozygous carriers. Patients with SLC2A2 mutations may present either with isolated neonatal diabetes or with hepatomegaly and the renal Fanconi syndrome. Fanconi Bickel syndrome shows phenotypic heterogeneity and may manifest early with subtle or atypical features, mandating a high index of suspicion. PMID- 29116608 TI - 4-quinolin-8-yloxy Linked Triphenylamine Based Polyimides: Blue Light Emissive and Potential Hole-Transport Materials. AB - A series of fluorescent donor- acceptor (D-A) alternating copolyimides (P1, P2, P3 and P4) with 4-quinolin-8-yloxy linked triphenylamine main polymer chain have been synthesized by conventional polycondensation. All the synthesized co polyimides were characterized by elemental, gel permeation chromatography and FTIR spectral analysis. These newly prepared PIs possess HOMO energy levels in range of - 4.74 to - 4.78 eV and have medium optical band gaps. The photoluminescence spectral analysis revealed blue to violet emission with appreciable efficiency with lower onset oxidation potentials suitable for the facile hole injection materials. All the photophysical and electrochemical properties were also explored in context of effect of the pendant 4- quinolin-8 yloxy, indicating suitable combination of donor (TPA) on one hand and imide and pendant as acceptor on both ends.Graphical Abstract. PMID- 29116607 TI - Hydrothermal Synthesis of Nitrogen-Doped Carbon Quantum Dots as Fluorescent Probes for the Detection of Dopamine. AB - Nitrogen-doped carbon quantum dots (N-CQDs) were synthesized though a facile, economical and straightforward hydrothermal method by using polyacrylamide as both carbon and nitrogen sources. The as-prepared N-CQDs offered high quantum yield of 23.1%, exhibited good water solubility and fluorescence properties. Moreover, the N-CQDs can be used as effective probes for sensitive and selective detection of dopamine. Fluorescence of N-CQDs was effectively quenched after the addition of dopamine owing to dopamine would be transformed into dopamine-quinone under alkaline conditions. A good linear relationship between fluorescence quenching and the concentration of dopamine in the range 0.1-200 MUM was obtained with a low detection limit of 0.05 MUM. The proposed method showed high selectivity for dopamine in the presence of potential interfering species. Moreover, this method was successfully applied to the determination of DA in urine sample with satisfactory recoveries. PMID- 29116609 TI - Correction to: Medication Errors: A Characterisation of Spontaneously Reported Cases in EudraVigilance. AB - Correction to: Drug Saf DOI 10.1007/s40264-017-0569-3. PMID- 29116610 TI - The effect of laser-assisted hatching on pregnancy outcomes of cryopreserved thawed embryo transfer: a meta-analysis of randomized controlled trials. AB - It is well known that laser-assisted hatching (LAH) is the most popular and ideal embryo hatching technology, but the relevance to pregnancy outcomes of cryopreserved-thawed embryo transfer (ET) is controversial. The purpose of this meta-analysis was to evaluate the effects of LAH on pregnancy outcomes of cryopreserved-thawed ET. We searched for relevant studies published in the PubMed, EMBASE, and Cochrane Central databases up to March 2017. This meta analysis was primarily used to evaluate the effect of laser-assisted hatching on assisted reproductive outcomes: clinical pregnancy, embryo implantation, multiple pregnancy, miscarriage, and live birth. Using the Mantel-Haenszel fixed effects model and random effects model, we determined the summary odds ratios (OR) with 95% confidence intervals (CIs). There were 12 randomized controlled trials (more than 2574 participants) included in our analysis. The rates of clinical pregnancy (OR = 1.65, 95% CI = 1.24-2.19, I 2 = 49), implantation (OR = 1.59, 95% CI = 1.06 2.38, I 2 = 82%), multiple pregnancy (OR = 2.30, 95% CI = 1.30-4.07, I 2 = 33%), miscarriage (OR = 0.86, 95% CI = 0.50-1.48, I 2 = 0%), and live birth (OR = 1.09, 95% CI = 0.77-1.54, I 2 = 0%) revealed comparable results for both groups. In summary, this meta-analysis demonstrates that LAH is related to a higher clinical pregnancy rate, embryo implantation rate, and multiple pregnancy rate in women with cryopreserved-thawed embryos. However, LAH is unlikely to increase live birth rates and miscarriage rates. Due to the small sample evaluated in the pool of included studies, large-scale, prospective, randomized, controlled trials are required to determine if these small effects are clinically relevant. PMID- 29116611 TI - Anti-inflammatory effects of low-level laser therapy on human periodontal ligament cells: in vitro study. AB - Periodontal disease is a chronic inflammatory disease that is commonly treated with surgical and nonsurgical techniques. However, both approaches have limitations. Low-level laser therapy (LLLT) has been widely applied in reducing inflammatory reactions, and research indicates that LLLT induces an anti inflammatory effect that may enhance periodontal disease therapy. The purpose of this study was to investigate the anti-inflammatory effect of LLLT on human periodontal ligament cells (hPDLCs) in an inflammatory environment and aimed to determine the possible mechanism of action. Cells were cultured and treated with or without lipopolysaccharide (LPS) from Porphryromonas gingivalis or Escherichia coli, followed by irradiation with a gallium-aluminum-arsenide (GaAlAs) laser (660 nm) at an energy density of 8 J/cm2. Quantitative real-time polymerase chain reactions were used to assess the expression of pro-inflammatory genes, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8. The dual-luciferase reporter assay was used to examine nuclear factor-kappaB (NF kappaB) transcriptional activity. An enzyme-linked immunosorbent assay was used to monitor the concentration of intracellular cyclic adenosine monophosphate (cAMP). Both LPS treatments significantly induced the mRNA expression of pro inflammatory cytokines. However, LLLT inhibited the LPS-induced pro-inflammatory cytokine expression and elevated intracellular levels of cAMP. The LLLT inhibitory effect may function by downregulating NF-kappaB transcriptional activity and by increasing the intracellular levels of cAMP. LLLT might inhibit LPS-induced inflammation in hPDLCs through cAMP/NF-kappaB regulation. These results should be further studied to improve periodontal therapy. PMID- 29116613 TI - How are cognitive and physical difficulty compared? AB - Tasks that require less physical effort are generally preferred over more physically demanding alternatives. Similarly, tasks that require less mental effort are generally preferred over more mentally demanding alternatives. But what happens when one must choose between tasks that entail different kinds of effort, one mainly physical (e.g., carrying buckets) and the other mainly mental (e.g., counting)? We asked participants to choose between a bucket-carrying task and a counting task. Our participants were less likely to choose the bucket task when it required a long reach rather than a short reach, and our participants were also less likely to choose the bucket task the smaller the final count value. We tested the hypothesis that subjective task durations provided a common currency for comparing the difficulties of the two kinds of tasks. We found that this hypothesis provided a better account of the task choice data than did an account that relied on objective task durations. Our study opens the door to a new problem in the study of attention, perception, and psychophysics-judging the difficulty of different kinds of tasks. The approach we took to this problem, which relies on two-alternative forced choice along with modeling the basis for the choice, may prove useful in future investigations. PMID- 29116612 TI - The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The complement system has an established role in the pathogenesis of MS, and evidence suggests that its components can be used as biomarkers of disease-state activity and response to treatment in MS. Plasma C4a levels have been found to be significantly elevated in patients with active relapsing-remitting MS (RRMS), as compared to both controls and patients with stable RRMS. C3 levels are also significantly elevated in the cerebrospinal fluid (CSF) of patients with RRMS, and C3 levels are correlated with clinical disability. Furthermore, increased levels of factor H can predict the transition from relapsing to progressive disease, since factor H levels have been found to increase progressively with disease progression over a 2-year period in patients transitioning from RRMS to secondary progressive (SP) MS. In addition, elevations in C3 are seen in primary progressive (PP) MS. Complement components can also differentiate RRMS from neuromyelitis optica. Response gene to complement (RGC) 32, a novel molecule induced by complement activation, is a possible biomarker of relapse and response to glatiramer acetate (GA) therapy, since RGC-32 mRNA expression is significantly decreased during relapse and increased in responders to GA treatment. The predictive accuracy of RGC-32 as a potential biomarker (by ROC analysis) is 90% for detecting relapses and 85% for detecting a response to GA treatment. Thus, complement components can serve as biomarkers of disease activity to differentiate MS subtypes and to measure response to therapy. PMID- 29116614 TI - Are crossmodal correspondences relative or absolute? Sequential effects on speeded classification. AB - Crossmodal correspondences have often been demonstrated using congruency effects between pairs of stimuli in different sensory modalities that vary along separate dimensions. To date, however, it is still unclear the extent to which these correspondences are relative versus absolute in nature: that is, whether they result from pre-defined values that rigidly link the two dimensions or rather result from flexible values related to the previous occurrence of the crossmodal stimuli. Here, we investigated this issue in a speeded classification task featuring the correspondence between auditory pitch and visual size (e.g., congruent correspondence between high pitch/small disc and low pitch/large disc). Participants classified the size of the visual stimuli (large vs. small) while hearing concurrent high- or low-pitched task-irrelevant sounds. On some trials, visual stimuli were paired instead with "intermediate" pitch, that could be interpreted differently according to the auditory stimulus on the preceding trial (i.e., as "lower" following the presentation of a high pitch tone, but as "higher" following the presentation of a low pitch tone). Performance on sequence congruent trials (e.g., when a small disc paired with the intermediate-pitched tone was preceded by a low pitch tone) was compared to sequence-incongruent trials (e.g., when a small disc paired with the intermediate-pitch tone was by a high-pitched tone). The results revealed faster classification responses on sequence-congruent than on sequence-incongruent trials. This demonstrates that the effect of the pitch/size correspondence is relative in nature, and subjected to trial-by-trial interpretation of the stimulus pair. PMID- 29116616 TI - Correction to: Continuous Infusion Versus Intermittent Bolus of Beta-Lactams in Critically Ill Patients with Respiratory Infections: A Systematic Review and Meta analysis. AB - Unfortunately, >= was found missing between scores and 20 in conclusion section of the online published article. The original article was corrected. PMID- 29116615 TI - Immunity to attentional capture at ignored locations. AB - Certain stimuli have the power to rapidly and involuntarily capture spatial attention against our will. The present study investigated whether such stimuli capture spatial attention even when they appear in ignored regions of visual space. In other words, which force is more powerful: attentional capture or spatial filtering? Participants performed a spatial cuing task, searching for a letter target defined by color (e.g., green) and then reporting that letter's identity. Two of the four search locations were always irrelevant. Unlike many previous experiments, participants were forced to ignore these locations because they always contained a target-colored distractor letter. Experiment 1 assessed capture by a salient-but-irrelevant abrupt onset cue appearing 150 ms before the search display. One might expect onset cues to capture attention even at ignored locations given that the main function of capture, presumably, is to rapidly alert observers to unexpected yet potentially important stimuli. However, they did not. Experiment 2 replicated this result with a different neutral baseline condition. Experiment 3 replicated the absence of capture effects at ignored locations with an even more potent stimulus: a relevant cue possessing the target color. We propose that people are effectively immune to attentional capture by objects in ignored locations - spatial filtering dominates attentional capture. PMID- 29116617 TI - Nanoparticulated polymeric composites enfolding lithium carbonate as brain drug in persuading depression: an in vivo study. AB - Lithium carbonate is considered an effective drug against mania and acts as a mood stabilizer. It is found that it enhances antidepressants targeting depression, consequently it is prone to have risk factors that leads to adverse effects. The study is devised in confronting depression under nanoscale by preparing nanocomposites which is a matrix of biopolymer chitosan that encapsulates lithium carbonate by ionic gelation method. This facilitates the drug delivery in a regulated manner targeting the therapeutic action with a limited dosage that lessens the side effects in the course of treatment. The drug polymer interaction was validated by XRD studies, whereas the morphology and size characterization by SEM and zetasizer. The average particle size was determined as 193 +/- 0.18 nm with a positive zeta potential of 37.9 mV. The in vitro drug release patterns of nanocomposites were comparatively assayed with the standard lithium carbonate which rendered a controlled release in its profile. The in vivo investigation by animal despair studies bestowed a significant difference in the duration of immobility during force swimming and tail suspension tests. These results were substantiated with histopathological examinations of cerebral cortex region which showed mild cellular edema, degenerative changes and lymphocytic infiltration when compared with the control groups. Consequently, the efficacy of nanocomposites encased with lithium carbonate fortifies targeted drug delivery and restrains adverse effects by endorsing it as a lead compound in brain drug developmental research. PMID- 29116618 TI - Treatment of Stable Angina with a New Fixed-Dose Combination of Ivabradine and Metoprolol: Effectiveness and Tolerability in Routine Clinical Practice. AB - INTRODUCTION: In this prospective, multicenter, observational cohort study, the effectiveness and tolerability of the first fixed-dose combination (FDC) formulation of the selective heart rate reducing agent ivabradine and the beta blocker metoprolol was evaluated in stable angina pectoris (AP) patients in a clinical practice setting. METHODS: Stable AP outpatients received a FDC of ivabradine and metoprolol (b.i.d.) for 4 months, in addition to cardiovascular standard therapy. Resting heart rate (HR), number of angina attacks, short-acting nitrate consumption, severity of symptoms (assessed by patient judgment and documented by CCS score) and tolerability were documented. Medication adherence was assessed by a modified four-item Morisky questionnaire. Descriptive statistics were performed on all data. RESULTS: A total of 747 stable AP patients (mean age, 66.4 years, 62% male, 50% and 31% with previous PCI and myocardial infarction, respectively) were included. Apart from ivabradine and beta-blockers as free combination, most frequently used concomitant standard medications at baseline were aspirin (68%), statins (71%), ACEI/AT1-blockers (76%), diuretics (35%), and calcium antagonists (15%). Highly prevalent comorbidities were hypertension (86%), hyperlipidemia (65%), and diabetes (35%). After 4 months, switch to treatment with the FDC was associated with a significant reduction in mean HR by 10 bpm. Proportion of patients with >= 1 angina attacks/week decreased from 38 to 7%. Patients in CCS class 1 increased (25 to 63%), while they decreased in CCS class 3 (19 to 5%). Medication adherence was also significantly improved (p < 0.001 for all changes from baseline). Mostly mild adverse events were documented in 5.4% of patients. CONCLUSIONS: In these stable AP patients in a real-life setting, treatment with a FDC of ivabradine and metoprolol was associated with reduced HR and angina symptoms, while exercise capacity (CCS score) was improved. These effects may be mainly mediated by the increased medication adherence of patients observed with use of the FDC formulation. FUNDING: Servier TRIAL REGISTRATION NUMBER: ISRCTN51906157. PMID- 29116619 TI - Evaluation of Efficiency of Modified Polypropylenimine (PPI) with Alkyl Chains as Non-viral Vectors Used in Co-delivery of Doxorubicin and TRAIL Plasmid. AB - In this study, co-delivery system was achieved via plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) and doxorubicin (DOX) using carrier based on polypropylenimine (PPI) modified with 10-bromodecanoic acid. Incorporation of alkylcarboxylate chain to PPIs (G4 and G5) could improve transfection efficiency via overcoming the plasma membrane barrier of the cells and decrease cytotoxicity of PPI. Characterization of fabricated NPs revealed that PPI G5 in which 30% of primary amines were substituted by alkyl carboxylate chain (PPI G5-Alkyl 30%) has higher drug loading as compared to the other formulations. PPI G5-Alkyl 30% indicated a decreased drug release may be due to alkyl chains on the surface of PPI, which serve as an additional hindrance for drug diffusion. In vitro cytotoxicity experiments demonstrated that co-delivery system induced apoptosis of tumor cells more efficiently than each of delivery system alone. Furthermore, these results revealed that our combined delivery platform of pTRAIL and DOX using Alkyl-modified PPI G5 can significantly improve the anti-tumor activity and this strategy might develop a new therapeutic window for cancer treatment. PMID- 29116621 TI - The Diagnostic Dilemma of Epithelial Marker Expression in Glioblastoma. PMID- 29116620 TI - Microwave-assisted synthesis, antioxidant and antimicrobial evaluation of 2 indolinone-based bis-1,2,3-triazole derivatives. AB - A series of 2-indolinone-based bis-1,2,3-triazole derivatives have been synthesized in excellent yields via microwave-assisted, copper-catalyzed azide alkyne 1,3-dipolar cycloaddition (CuAAC) reaction of O-, N-propargylated indolinone derivatives with in situ generated organic azides. The antioxidant activity of the synthesized compounds was evaluated by DPPH, NO and [Formula: see text] radical scavenging methods. Among the compounds screened for antioxidant activity, compounds 5e, 5f and 5o showed excellent radical scavenging activity more than the standard drugs ascorbic acid and BHT. The synthesized compounds were evaluated for their antimicrobial activity against gram-positive and gram negative bacterial and fungal strains. Compounds 5g, 5h, 5n, 5q and 5r were found to be the most promising microbial growth inhibitory molecules. PMID- 29116622 TI - Efficacy of Iodine-125 Seed Implantation in Locoregionally Recurrent and Unresectable Breast Cancer: a Retrospective Study. AB - The management of locoregionally recurrent and unresectable breast cancer is a therapeutic challenge. This retrospective study aimed to assess the efficacy of 125I seed implantation brachytherapy as a palliative management in locoregionally recurrent breast cancer. We analyzed 36 locoregionally recurrent and unresectable breast cancers in our hospital between 2012 and 2016. All patients were treated with CT-guided 125I seed permanent implantation. The dose distribution of 125I seeds was calculated using a computerized treatment planning system. Complete response, partial response, stable disease, and local tumor control rates were calculated. Long-term efficacy was assessed based on survival rates ranging from 1 to 4 years. The follow-up period ranged from 6 to 53 months. The median local control was 28 months (95% CI: 16.2-39.8 months). The percentage of patients who showed 6-month, 1-year, 2-year, and 3-year local control was 97.2%, 77.8%, 52.8%, and 33.3%, respectively. Median survival time for all patients was 48 months (95% CI: 40.9-55.1 months); 1-year, 2-year, 3-year, and 4-year survival rates were 97.2%, 80.6%, 63.9%, and 46.5%, respectively. Pain relief response rate was 88.9%. No serious complications were detected during the follow-up period. The results of this study demonstrate that 125I seed implantation could be considered a feasible and promising minimally invasive therapy for locoregionally recurrent and unresectable breast carcinoma. PMID- 29116623 TI - KRAS Mutation in Gastric Cancer and Prognostication Associated with Microsatellite Instability Status. AB - Microsatellite instability (MSI) is one of the subgroups based on the new molecular classification of gastric cancer (GC). In this study, we analyzed the role of KRAS status in MSI GC and the impact of MSI status on KRAS mutation. We performed analysis on 595 GC patients. Polymerase chain reaction (PCR) was used for the screening of KRAS mutation (exon 2) and 5 quasi-monomorphic mononucleotide repeats, namely, BAT-26, BAT-25, NR -24, NR-21, and NR-27 were used to determine the MSI status. The KRAS and MSI status were then compared with clinicopathologic data of the GC patients. MSI GC was found in 20.3% of all cases. KRAS mutation was seen in 24 patients; 18 were MSI (75%) and 6 were microsatellite stable (MSS) (25%). MSI GC patients with KRAS mutation were older and mostly female, but MSS presented more advanced T and N stage of the disease, more cardia tumors, and adjuvant treatment. Five-year survival was 72.2% for KRAS mutation patients with MSI and 0% for MSS (p < 0.001). Although KRAS mutations in GC are linked with MSI in the majority of cases, KRAS mutations with MSS status presented with a poor prognosis and a worse outcome. In multivariate analysis, MSI was associated with better survival (p < 0.001) but KRAS was with worse survival (p = 0.304). Our study suggests that KRAS mutations are based on MSI status rather than different codon subtypes of mutation, and such a division could be used to determine the GC patient outcome. PMID- 29116625 TI - Monographic issue of the italian society for shoulder and elbow surgery. PMID- 29116624 TI - The Concomitant Use of Diuretics, Non-Steroidal Anti-Inflammatory Drugs, and Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers (Triple Whammy), Extreme Heat, and In-Hospital Acute Kidney Injury in Older Medical Patients. AB - INTRODUCTION: We investigated whether the concomitant use of diuretics, non steroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (triple whammy, TW) predicts in-hospital acute kidney injury (AKI) and whether admission during recorded periods of extreme heat influences this association. METHODS: We retrospectively collected data on patient characteristics and use of TW/non-TW drugs on admission, AKI (increase in serum creatinine >= 27 umol/l either within the first 48 h of admission or throughout hospitalization, primary outcome), length of stay (LOS), and mortality (secondary outcomes) in medical patients >=65 years admitted (1) during five consecutive heat waves (HWs) between 2007 and 2009 (n = 382) or (2) either before or after each HW, matched for HW period, age, and admission day of the week (non-HW, controls, n = 1339). RESULTS: Number of TW and non-TW drugs, co morbidities, number of daily admissions, incidence of in-hospital AKI, LOS, and mortality were similar in the HW and non-HW groups. After adjusting for clinical and demographic confounders, logistic regression showed that TW use did not predict AKI within 48 h of admission either during non-HW periods (OR 0.79, 95% CI 0.34-1.83, P = 0.58) or during HWs (OR 1.02, 95% CI 0.21-2.97, P = 0.97). Similar results were observed when AKI was captured throughout hospitalization. TW use did not predict LOS or mortality irrespective of environmental temperature on admission. CONCLUSIONS: TW use on admission did not predict in-hospital AKI, LOS, or mortality in older medical patients admitted either during periods of normal environmental temperature or during HWs. PMID- 29116626 TI - Unclassified hepatocellular adenoma in a middle-aged woman with glucose intolerance. AB - The patient was a 43-year-old woman with obesity (body mass index: 29.1) and glucose intolerance who was not taking oral contraceptives. An ultrasound showed a hypoechoic hepatic mass. Dynamic contrast-enhanced computed tomography revealed a lesion in segment 6 that showed homogeneous and slight-to-moderate enhancement in the arterial phase with persistent enhancement during the portal and equilibrium phases. On magnetic resonance (MR) imaging, the lesion demonstrated hyperintensity on T2- and diffusion-weighted images and hypointensity in the hepatobiliary phase of gadoxetic-acid-enhanced MR imaging. In addition to the main lesion, approximately ten small hypointense lesions were seen in the hepatobiliary phase. The background liver was fatty without the deformity of chronic liver disease. Based on the pathological findings of the main lesion biopsy, it was initially suspected to be a non-neoplastic lesion with hematoxylin and eosin staining and initial immunohistochemical staining. However, the radiological findings indicated a neoplastic lesion. Additional immunohistochemical staining, including that for alpha-smooth muscle actin and organic anion transporter polypeptide 1B3, in combination with the radiological findings resulted in a diagnosis of unclassified hepatocellular adenoma. The other small lesions were presumed to be related to the main lesion. PMID- 29116627 TI - The Nature and Evolution of Genomic Diversity in the Mycobacterium tuberculosis Complex. AB - The Mycobacterium tuberculosis Complex (MTBC) consists of a clonal group of several mycobacterial lineages pathogenic to a range of different mammalian hosts. In this chapter, we discuss the origins and the evolutionary forces shaping the genomic diversity of the human-adapted MTBC. Advances in whole-genome sequencing have brought invaluable insights into the macro-evolution of the MTBC, and the biogeographical distribution of the different MTBC lineages, the phylogenetic relationships between these lineages. Moreover, micro-evolutionary processes start to be better understood, including those influencing bacterial mutation rates and those governing the fate of new mutations emerging within patients during treatment. Current genomic and epidemiological evidence reflect the fact that, through ecological specialization, the MTBC affecting humans became an obligate and extremely well-adapted human pathogen. Identifying the adaptive traits of human-adapted MTBC and unraveling the bacterial loci that interact with human genomic variation might help identify new targets for developing better vaccines and designing more effective treatments. PMID- 29116628 TI - The Biology and Epidemiology of Mycobacterium canettii. AB - Genome-based insights into the evolution of Mycobacterium tuberculosis and other tuberculosis-causing mycobacteria are constantly increasing. In particular, the recent genomic and functional characterization of several Myocbacterium canettii strains, which are thought to resemble in many aspects the putative common ancestor of the members of the M. tuberculosis complex (MTBC), has consolidated a plausible scenario of the early evolution of tuberculosis-causing mycobacteria, in which the clonal MTBC, comprising numerous key pathogens of mammalian hosts, has evolved from a generalist mycobacterium living in the environment. These studies also have considerably enriched our knowledge on selected molecular events that likely have contributed to the incursion, maintenance and spread of the MTBC members in diverse mammalian hosts. Here, we summarize and discuss recently revealed molecular and evolutionary aspects and emphasize the vast utility of M. canettii strains for identifying the mechanisms that contributed to the global emergence of M. tuberculosis as one of the most important human pathogens. PMID- 29116629 TI - The Evolution of Strain Typing in the Mycobacterium tuberculosis Complex. AB - Tuberculosis (TB) is a contagious disease with a complex epidemiology. Therefore, molecular typing (genotyping) of Mycobacterium tuberculosis complex (MTBC) strains is of primary importance to effectively guide outbreak investigations, define transmission dynamics and assist global epidemiological surveillance of the disease. Large-scale genotyping is also needed to get better insights into the biological diversity and the evolution of the pathogen. Thanks to its shorter turnaround and simple numerical nomenclature system, mycobacterial interspersed repetitive unit-variable-number tandem repeat (MIRU-VNTR) typing, based on 24 standardized plus 4 hypervariable loci, optionally combined with spoligotyping, has replaced IS6110 DNA fingerprinting over the last decade as a gold standard among classical strain typing methods for many applications. With the continuous progress and decreasing costs of next-generation sequencing (NGS) technologies, typing based on whole genome sequencing (WGS) is now increasingly performed for near complete exploitation of the available genetic information. However, some important challenges remain such as the lack of standardization of WGS analysis pipelines, the need of databases for sharing WGS data at a global level, and a better understanding of the relevant genomic distances for defining clusters of recent TB transmission in different epidemiological contexts. This chapter provides an overview of the evolution of genotyping methods over the last three decades, which culminated with the development of WGS-based methods. It addresses the relative advantages and limitations of these techniques, indicates current challenges and potential directions for facilitating standardization of WGS-based typing, and provides suggestions on what method to use depending on the specific research question. PMID- 29116630 TI - Genomic Epidemiology of Tuberculosis. AB - The application of next generation sequencing technologies has opened the door to a new molecular epidemiology of tuberculosis, in which we can now look at transmission at a resolution not possible before. At the same time, new technical and analytical challenges have appeared, and we are still exploring the wider potential of this new technology. Whole genome sequencing in tuberculosis still requires bacterial cultures. Thus, although whole genome sequencing has revolutionized the interpretation of transmission patterns, it is not yet ready to be applied at the point-of-care. In this chapter, I will review the promises and challenges of genomic epidemiology, as well as some of the new questions that have arisen from the use of this new technology. In addition, I will examine the role of molecular epidemiology within the general frame of global tuberculosis control and how genomic epidemiology can contribute towards the elimination of the disease. PMID- 29116631 TI - Biological and Epidemiological Consequences of MTBC Diversity. AB - Tuberculosis is caused by different groups of bacteria belonging to the Mycobacterium tuberculosis complex (MTBC). The combined action of human factors, environmental conditions and bacterial virulence determine the extent and form of human disease. MTBC virulence is a composite of different clinical phenotypes such as transmission rate and disease severity among others. Clinical phenotypes are also influenced by cellular and immunological phenotypes. MTBC phenotypes are determined by the genotype, therefore finding genotypes responsible for clinical phenotypes would allow discovering MTBC virulence factors. Different MTBC strains display different cellular and clinical phenotypes. Strains from Lineage 5 and Lineage 6 are metabolically different, grow slower, and are less virulent. Also, at least certain groups of Lineage 2 and Lineage 4 strains are more virulent in terms of disease severity and human-to-human transmission. Because phenotypic differences are ultimately caused by genotypic differences, different genomic loci have been related to various cellular and clinical phenotypes. However, defining the impact of specific bacterial genomic loci on virulence when other bacterial determinants, human and environmental factors are also impacting the phenotype would contribute to a better knowledge of tuberculosis virulence and ultimately benefit tuberculosis control. PMID- 29116632 TI - The Biology and Epidemiology of Mycobacterium africanum. AB - West Africa is the only region in the world where six out of seven mycobacterial lineages of human importance are endemic. In particular, two evolutionary ancient lineages, Mycobacterium africanum West Africa 1 (MTBC Lineage 5) and M. africanum West Africa 2 (MTBC Lineage 6) are of interest as they cause up to 40% of all pulmonary TB cases in some West African countries. Although these M. africanum lineages are closely related to M. tuberculosis sensu stricto lineages, they differ significantly in respect to biology, epidemiology and in their potential to cause disease in humans. Most importantly the M. africanum lineages are exclusive to West Africa. Although the exact mechanisms underlying this geographical restriction are still not understood, it is increasingly suspected that this is due to an adaptation of the bacteria to West African host populations. In this chapter, we summarize the geographical distribution of the M. africanum lineages within the region, describe biological and clinical differences and the consequent implications for TB control in West Africa. We also try to shed light on the geographical restriction, based on recently published analyses on whole genomes of M. africanum isolates. PMID- 29116633 TI - Mycobacterium tuberculosis Complex Members Adapted to Wild and Domestic Animals. AB - The Mycobacterium tuberculosis complex (MTBC) is composed of several highly genetically related species that can be broadly classified into those that are human-host adapted and those that possess the ability to propagate and transmit in a variety of wild and domesticated animals. Since the initial description of the bovine tubercle bacillus, now known as Mycobacterium bovis, by Theobald Smith in the late 1800's, isolates originating from a wide range of animal hosts have been identified and characterized as M. microti, M. pinnipedii, the Dassie bacillus, M. mungi, M. caprae, M. orygis and M. suricattae. This chapter outlines the events resulting in the identification of each of these animal-adapted species, their close genetic relationships, and how genome-based phylogenetic analyses of species-specific variation amongst MTBC members is beginning to unravel the events that resulted in the evolution of the MTBC and the observed host tropism between the human- and animal-adapted member species. PMID- 29116634 TI - Evolution and Strain Variation in BCG. AB - BCG vaccines were derived by in vitro passage, during the years 1908-1921, at the Pasteur Institute of Lille. Following the distribution of stocks of BCG to vaccine production laboratories around the world, it was only a few decades before different BCG producers recognized that there were variants of BCG, likely due to different passaging conditions in the different laboratories. This ultimately led to the lyophilization of stable BCG products in the 1950s and 1960s, but not before considerable evolution of the different BCG strains had taken place. The application of contemporary research methodologies has now revealed genomic, transcriptomic and proteomic differences between BCG strains. These molecular differences in part account for phenotypic differences in vitro between BCG strains, such as their variable secretion of antigenic proteins. Yet, the relevance of BCG variability for immunization policy remains elusive. In this chapter we present an overview of what is known about BCG evolution and its resulting strain variability, and provide some speculation as to the potential relevance for a vaccine given to over 100 million newborns each year. PMID- 29116636 TI - PE and PPE Genes: A Tale of Conservation and Diversity. AB - PE and PPE are two large families of proteins typical of mycobacteria whose structural genes in the Mycobacterium tuberculosis complex (MTBC) occupy about 7% of the total genome. The most ancestral PE and PPE proteins are expressed by genes that belong to the same operon and in most cases are found inserted in the esx clusters, encoding a type VII secretion system. Duplication and expansion of pe and ppe genes, coupled with intragenomic and intergenomic recombination events, led to the emergence of the polymorphic pe_pgrs and ppe_mptr genes in the MTBC genome. The role and function of these proteins, and particularly of the polymorphic subfamilies, remains elusive, although it is widely accepted that PE and PPE proteins may represent a specialized collection used by MTBC to interact with the complex host immune system of mammals. In this chapter, we summarize what has been discovered since the identification of these genes in 1998, focusing on M. tuberculosis genetic variability, host-pathogen interaction and TB pathogenesis. PMID- 29116637 TI - Epidemiology of Drug-Resistant Tuberculosis. AB - As we move into the era of the Sustainable Development Goals (SDGs), the World Health Organization (WHO) has developed the End TB strategy 2016-2035 with a goal to end the global epidemic of tuberculosis (TB) by 2035. Achieving the targets laid out in the Strategy will require strengthening of the whole TB diagnosis and treatment cascade, including improved case detection, the establishment of universal drug susceptibility testing and rapid treatment initiation. An estimated 3.9% of new TB cases and 21% of previously treated cases had rifampicin resistant (RR) or multidrug-resistant (MDR) TB in 2015. These levels have remained stable over time, although limited data are available from major high burden settings. In addition to the emergence of drug resistance due to inadequate treatment, there is growing evidence that direct transmission is a large contributor to the RR/MDR-TB epidemic. Only 340,000 of the estimated 580,000 incident cases of RR/MDR-TB were notified to WHO in 2015. Among these, only 125,000 were initiated on second-line treatment. RR/MDR-TB epidemics are likely to be driven by direct transmission. The most important risk factor for MDR-TB is a history of previous treatment. Other risk factors vary according to setting but can include hospitalisation, incarceration and HIV infection. Children have the same risk of MDR-TB as adults and represent a diagnostic and treatment challenge. Rapid molecular technologies have revolutionized the diagnosis of drug-resistant TB. Until capacity can be established to test every TB patient for rifampicin resistance, countries should focus on gradually expanding their coverage of testing. DNA sequencing technologies are being increasingly incorporated into patient management and drug resistance surveillance. They offer additional benefits over conventional culture-based phenotypic testing, including a faster turn-around time for results, assessment of resistance patterns to a range of drugs, and investigation of strain clustering and transmission. PMID- 29116638 TI - Evolution of Phenotypic and Molecular Drug Susceptibility Testing. AB - Drug Resistant Tuberculosis (DRTB) is an emerging problem world-wide. In order to control the disease and decrease the number of cases overtime a prompt diagnosis followed by an appropriate treatment should be provided to patients. Phenotypic DST based on liquid automated culture has greatly reduced the time needed to generate reliable data but has the drawback to be expensive and prone to contamination in the absence of appropriate infrastructures. In the past 10 years molecular biology tools have been developed. Those tools target the main mutations responsible for DRTB and are now globally accessible in term of cost and infrastructures needed for the implementation. The dissemination of the Xpert MTB/rif has radically increased the capacity to perform the detection of rifampicin resistant TB cases. One of the main challenges for the large scale implementation of molecular based tests is the emergence of conflicting results between phenotypic and genotypic tests. This mines the confidence of clinicians in the molecular tests and delays the initiation of an appropriate treatment. A new technique is revolutionizing the genotypic approach to DST: the WGS by Next Generation Sequencing technologies. This methodology promises to become the solution for a rapid access to universal DST, able indeed to overcome the limitations of the current phenotypic and genotypic assays. Today the use of the generated information is still challenging in decentralized facilities due to the lack of automation for sample processing and standardization in the analysis.The growing knowledge of the molecular mechanisms at the basis of drug resistance and the introduction of high-performing user-friendly tools at peripheral level should allow the very much needed accurate diagnosis of DRTB in the near future. PMID- 29116639 TI - DNA Replication Fidelity in the Mycobacterium tuberculosis Complex. AB - Mycobacterium tuberculosis is genetically isolated, with no evidence for horizontal gene transfer or the acquisition of episomal genetic information in the modern evolution of strains of the Mycobacterium tuberculosis complex. When considered in the context of the specific features of the disease M. tuberculosis causes (e.g., transmission via cough aerosol, replication within professional phagocytes, subclinical persistence, and stimulation of a destructive immune pathology), this implies that to understand the mechanisms ensuring preservation of genomic integrity in infecting mycobacterial populations is to understand the source of genetic variation, including the emergence of microdiverse sub populations that may be linked to the acquisition of drug resistance. In this chapter, we focus on mechanisms involved in maintaining DNA replication fidelity in M. tuberculosis, and consider the potential to target components of the DNA replication machinery as part of novel therapeutic regimens designed to curb the emerging threat of drug-resistance. PMID- 29116635 TI - Antigenic Variation and Immune Escape in the MTBC. AB - Microbes that infect other organisms encounter host immune responses, and must overcome or evade innate and adaptive immune responses to successfully establish infection. Highly successful microbial pathogens, including M. tuberculosis, are able to evade adaptive immune responses (mediated by antibodies and/or T lymphocytes) and thereby establish long-term chronic infection. One mechanism that diverse pathogens use to evade adaptive immunity is antigenic variation, in which structural variants emerge that alter recognition by established immune responses and allow those pathogens to persist and/or to infect previously-immune hosts. Despite the wide use of antigenic variation by diverse pathogens, this mechanism appears to be infrequent in M. tuberculosis, as indicated by findings that known and predicted human T cell epitopes in this organism are highly conserved, although there are exceptions. These findings have implications for diagnostic tests that are based on measuring host immune responses, and for vaccine design and development. PMID- 29116640 TI - Strain Diversity and the Evolution of Antibiotic Resistance. AB - Drug resistance is best thought of as an ongoing biological process. Resistant bacteria must emerge, become established and ultimately transmit in order to be relevant to human health. In this context, genetic diversity can influence the rate and likelihood of resistance emerging; it can also modulate the net physiological impact of resistance and the propensity of an organism to improve any defects that arise from it. Combined, these effects can have an impact on a larger scale, with highly transmissible drug-resistant bacterial strains posing a formidable threat to global health. These considerations are pertinent to the future of tuberculosis control as well. In this chapter, we review our current understanding of the impact of genetic diversity in the broadest sense on the evolution of drug-resistant members of the Mycobacterium tuberculosis complex. PMID- 29116641 TI - Mathematical Models for the Epidemiology and Evolution of Mycobacterium tuberculosis. AB - This chapter reviews the use of mathematical and computational models to facilitate understanding of the epidemiology and evolution of Mycobacterium tuberculosis. First, we introduce general epidemiological models, and describe their use with respect to epidemiological dynamics of a single strain and of multiple strains of M. tuberculosis. In particular, we discuss multi-strain models that include drug sensitivity and drug resistance. Second, we describe models for the evolution of M. tuberculosis within and between hosts, and how the resulting diversity of strains can be assessed by considering the evolutionary relationships among different strains. Third, we discuss developments in integrating evolutionary and epidemiological models to analyse M. tuberculosis genetic sequencing data. We conclude the chapter with a discussion of the practical implications of modelling - particularly modelling strain diversity - for controlling the spread of tuberculosis, and future directions for research in this area. PMID- 29116642 TI - The relation between patient characteristics and their carers' use of a directive versus collaborative support stance. AB - OBJECTIVES: Collaborative support provided by carers (family and friends) of individuals with eating disorders has been shown to be integral to patient motivation and clinical outcome. Little is known about factors that contribute to carers' use of collaborative, as opposed to directive, support stance. This exploratory research investigated associations between patient characteristics and carers' support beliefs and behaviors. METHOD: Eating disorder patients (n = 72) completed measures of readiness for change, eating disorder, and psychiatric symptom severity, and interpersonal functioning. Their carers (n = 72) completed measures of collaborative and directive support. RESULTS: Patient demographic variables, readiness for change, and psychiatric symptom severity were not associated with carer beliefs or behaviors. However, some patient interpersonal functioning scores were; higher Domineering/Controlling scores were associated with carers viewing directive support as more helpful, and with their use of more directive support behaviors. Higher Vindictive/Self-Centered and Intrusive/Needy scores in patients were also associated with carers viewing directive support as more helpful. DISCUSSION: This exploratory study suggests that carers may be more prone to utilizing a directive, rather than a collaborative, support stance with patients experiencing higher levels of threat, anger, and hostility, and lower levels of safety, closeness, and trust. PMID- 29116643 TI - Group Therapy or Mass Suicide? The Sharing of Cellular Damage Between Members of a Bacterial Community. PMID- 29116644 TI - Management, outcomes, and prognostic factors of ruptured hepatocellular carcinoma: A systematic review. AB - Ruptured hepatocellular (rHCC) is a rare but life-threatening presentation that often requires acute intervention. In this systematic review we identified 67 eligible studies reporting on 4941 patients with rHCC. Here we present the treatment approaches for the management of rHCC both in the acute setting with regards to management of hemorrhage, as well long-term with regards to oncological treatment. PMID- 29116645 TI - The impact of physical activity on fatigue and quality of life during and after adjuvant treatment for breast cancer. AB - BACKGROUND: Although physical activity (PA) can alleviate fatigue and improve quality of life (QoL) in patients with breast cancer (BC), not all domains of PA may have equal impact. The objective of the current study was to examine the longitudinal impact of PA components on the evolution of fatigue and QoL during and after adjuvant treatment for BC. METHODS: The women included in the study were participants in the 2-year longitudinal FATSEIN ("Fatigue dans le cancer du Sein") study. Fatigue and QoL were measured using the Multidimensional Fatigue Inventory and the European Organization for Research and Treatment of Cancer 30 item QoL questionnaire, respectively. Group-based trajectory analysis was used to determine patterns of PA evolution (frequency, duration, and intensity). Cross sectional and longitudinal associations between PA patterns and fatigue and QoL were analyzed by using multivariable linear regression and a mixed model. RESULTS: Among the 424 women who were included (mean +/- standard deviation age, 57.1 +/- 10.4 years), 2 trajectories were identified for each of the 3 PA components: low and insufficient frequency (51.2%) or regular and moderate frequency (48.8%), low and insufficient duration (47.6%) or regular and moderate duration (52.4%), and low intensity (47.2%) or low to moderate intensity (52.8%). Overall, during treatment, fatigue was increased and QoL was decreased, and the reverse was observed after treatment. During treatment, increased fatigue and decreased QoL were limited by regular PA frequency (beta = -8.71 for total fatigue; beta = 14.59 for emotional function), but the results were less significant after treatment. CONCLUSIONS: PA, especially its frequency, is an important determinant of fatigue and QoL during adjuvant treatment for BC. The promotion of regular PA among women who are receiving treatment for BC may be an effective way to reduce fatigue and improve QoL. Cancer 2018;124:797-806. (c) 2017 American Cancer Society. PMID- 29116646 TI - Want to Champion Better Care for Vulnerable Older Americans? Start Here. PMID- 29116647 TI - Application of reference-modified density functional theory: Temperature and pressure dependences of solvation free energy. AB - Recently, we proposed a reference-modified density functional theory (RMDFT) to calculate solvation free energy (SFE), in which a hard-sphere fluid was introduced as the reference system instead of an ideal molecular gas. Through the RMDFT, using an optimal diameter for the hard-sphere reference system, the values of the SFE calculated at room temperature and normal pressure were in good agreement with those for more than 500 small organic molecules in water as determined by experiments. In this study, we present an application of the RMDFT for calculating the temperature and pressure dependences of the SFE for solute molecules in water. We demonstrate that the RMDFT has high predictive ability for the temperature and pressure dependences of the SFE for small solute molecules in water when the optimal reference hard-sphere diameter determined for each thermodynamic condition is used. We also apply the RMDFT to investigate the temperature and pressure dependences of the thermodynamic stability of an artificial small protein, chignolin, and discuss the mechanism of high temperature and high-pressure unfolding of the protein. (c) 2017 Wiley Periodicals, Inc. PMID- 29116648 TI - Nuclear quantum effects induce metallization of dense solid molecular hydrogen. AB - We present an accurate computational study of the electronic structure and lattice dynamics of solid molecular hydrogen at high pressure. The band-gap energies of the C2/c, Pc, and P63/m structures at pressures of 250, 300, and 350 GPa are calculated using the diffusion quantum Monte Carlo (DMC) method. The atomic configurations are obtained from ab initio path-integral molecular dynamics (PIMD) simulations at 300 K and 300 GPa to investigate the impact of zero-point energy and temperature-induced motion of the protons including anharmonic effects. We find that finite temperature and nuclear quantum effects reduce the band-gaps substantially, leading to metallization of the C2/c and Pc phases via band overlap; the effect on the band-gap of the P63/m structure is less pronounced. Our combined DMC-PIMD simulations predict that there are no excitonic or quasiparticle energy gaps for the C2/c and Pc phases at 300 GPa and 300 K. Our results also indicate a strong correlation between the band-gap energy and vibron modes. This strong coupling induces a band-gap reduction of more than 2.46 eV in high-pressure solid molecular hydrogen. Comparing our DMC-PIMD with experimental results available, we conclude that none of the structures proposed is a good candidate for phases III and IV of solid hydrogen. (c) 2017 Wiley Periodicals, Inc. PMID- 29116649 TI - WW and C2 domain-containing proteins regulate hepatic cell differentiation and tumorigenesis through the hippo signaling pathway. AB - : The Hippo pathway regulates cell differentiation, proliferation, and apoptosis. Upon activation, it inhibits the import of the transcriptional coactivator yes associated protein (YAP) into the nucleus, thus suppressing transcription of pro proliferative genes. Hence, dynamic and precise control of the Hippo pathway is crucial for organ size control and the prevention of tumor formation. Hippo signaling is controlled by a growing number of upstream regulators, including WW and C2 domain-containing (WWC) proteins, which trigger a serine/threonine kinase pathway. One component of this is the large tumor suppressor (LATS) kinase, which phosphorylates YAP, trapping it in the cytoplasm. WWC proteins have been shown to interact with LATS in vitro and stimulate its kinase activity, thus directly promoting cytoplasmic accumulation of phosphorylated YAP. However, the function of the WWC proteins in the regulation of cell proliferation, organ size control, and tumor prevention in vivo has not yet been determined. Here, we show that loss of hepatic WWC expression in mice leads to tissue overgrowth, inflammation, fibrosis, and formation of liver carcinoma. WWC-deficient mouse livers display reduced LATS activity, increased YAP-mediated gene transcription, and enhanced proliferation of hepatic progenitor cells. In addition, loss of WWC expression in the liver accelerates the turnover of angiomotin proteins, which act as negative regulators of YAP activity. CONCLUSION: Our data define an essential in vivo function for WWC proteins as regulators of canonical and noncanonical Hippo signaling in hepatic cell growth and liver tumorigenesis. Thus, expression of WWC proteins may serve as novel prognostic factors in human liver carcinoma. (Hepatology 2018;67:1546-1559). PMID- 29116651 TI - Probing the effect of polymer molecular weight on penetration into the wood cell wall using polyethylenimine (PEI) as a model compound. AB - Decking is one of the largest applications for the treated wood market. The most challenging property to obtain for treated wood is dimensional stability, which can be achieved, in part, by cell wall bulking, cell wall polymer crosslinking and removal of hygroscopic components in the cell wall. A commonly accepted key requirement is for the actives to infuse through the cell wall, which has a microporosity of ~5-13 nm. Equally as challenging is being able to measure and quantify the cell wall penetration. Branched polyethylenimine (PEI) was studied as a model polymer for penetration due to its water solubility, polarity, variable molecular weight ranges, and ability to form a chelation complex with preservative metals to treat lumbers. Two different molecular weight polyethylenimines (PEI), one with a weight average molecular weight (Mw) equal to 800 Da and the other 750 000 Da, were investigated for penetration by microscopy and spectroscopy techniques. Analytical methods were developed to both create smooth interfaces and for relative quantitation and visualisation of PEI penetration into the wood. The results showed both PEI with Mw of 800 Da and PEI with Mw of 750 000 Da coated the lumens in high density. However, only the PEI with Mw of 800 appeared to penetrate the cell walls in sufficient levels. Literature has shown the hydrodynamic radii of PEI 750 000 is near 29 nm, whereas a smaller PEI at 25 K showed 4.5 nm. Most importantly the results, based on methods developed, show how molecular weight and tertiary structure of the polymer can affect its penetration, with the microporosity of the wood being the main barrier. PMID- 29116650 TI - Microbial biotransformations in the human distal gut. AB - The human distal gut is home to a rich and dense microbial community with representatives of all three domains of life which are intricately connected with our physiology and health. The combined genomes of these microbes, collectively called the human microbiome, vastly expand the metabolic capacities of our own genome, allowing us to break down and extract energy from dietary compounds that human enzymes cannot digest. In addition, the variable composition of these communities and their biotransformations might explain inter-individual differences in toxicities, tolerances and efficacies for certain drugs. Recent advances in sequencing technologies and bioinformatics have provided exciting new insights into the genomes of our microbial symbionts, their functional capacities and the interactions between these microbes and their human host. This review summarizes the metabolic conversions of dietary components and pharmaceuticals that take place in the human distal gut, as well as their implications for human health. LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc. PMID- 29116652 TI - Avoiding Energy Loss on TADF Emitters: Controlling the Dual Conformations of D-A Structure Molecules Based on the Pseudoplanar Segments. AB - The recent introduction of thermally activated delayed fluorescence (TADF) emitters is regarded as an important breakthrough for the development of high efficiency organic light-emitting devices (OLEDs). The planar D and A groups are generally used to construct TADF emitters for their rigid structure and large steric hindrance. In this work, it is shown that many frequently used nonaromatic (noncontinuous conjugation or without satisfying Huckel's rule) planar segments, such as 9,9-dimethyl-9,10-dihydroacridine, are actually pseudoplanar segments and have two possible conformations-a planar form and a crooked form. Molecules constructed from pseudoplanar segments can thus have two corresponding conformations. Their existence can have significant impact on the performance of many TADF emitters. Two design strategies are presented for addressing the problem by either (1) increasing the rigidity of these groups to suppress its crooked form or (2) increasing the steric hindrance of the linked group to minimize energy of the emitters with the highly twisted form. Following these strategies, two new emitters are synthesized accordingly and successfully applied in OLEDs demonstrating high external quantum efficiencies (20.2% and 18.3%). PMID- 29116653 TI - MiR-128 regulation of glucose metabolism and cell proliferation in triple negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is prone to metastasis and has a poor prognosis, with lower survival rates than other breast cancer subtypes. MicroRNAs have recently emerged as powerful regulators of cancer processes and become a promising target in cancer therapy. METHODS: Expression of miR-128 was examined in invasive ductal breast cancer, and its relationship with clinicopathological features analysed. A series of in vitro and in vivo experiments were performed to investigate the function and mechanism of miR-128 in the development of invasive ductal breast cancer. RESULTS: A cohort of 110 women with TNBC and 117 with non-TNBC were included in the study. In multivariable Cox regression analysis, overall and disease-free survival were significantly associated with lymph node metastasis, histological grade and molecular subtype. Subgroup analysis showed that low expression of miR-128 correlated with shorter overall and disease-free survival in TNBC (P < 0.001), and shorter overall but not disease-free survival in non-TNBC. In addition, miR 128 was able to inhibit glucose metabolism, mitochondrial respiration and proliferation of TNBC cells. These effects were consistent with miR-128 targeting inhibition of the insulin receptor and insulin receptor substrate 1. CONCLUSION: MiR-128 might be a prognostic marker and possible molecular target for therapy in patients with TNBC. PMID- 29116654 TI - Cardiovascular and all-cause mortality in patients with intermittent claudication and critical limb ischaemia. AB - BACKGROUND: The aim of this study was to evaluate absolute mortality risks and to determine whether changes in mortality risk occurred in patients with intermittent claudication (IC) or critical limb ischaemia (CLI) in the Netherlands between 1998 and 2010. METHODS: Data for patients treated between 1998 and 2010 were obtained from Dutch nationwide registers: the Hospital Discharge Register, Population Register and Cause of Death Register. The registers were used to obtain information regarding IC and CLI hospitalizations, co-morbidities, demographic factors, and date and cause of death. The cohort was split into two time intervals for comparison: 1998-2004 (period 1) and 2005-2010 (period 2). Thirty-day mortality was excluded to eliminate per-admission complications. One- and 5-year cardiovascular and all-cause mortality rates were compared with those of a representative sample of the general Dutch population (28 494 persons) by Cox proportional hazards models. RESULTS: Some 47 548 patients were included, 34 078 with IC and 13 470 with CLI. In patients with IC, the age-adjusted 5-year mortality risk for cardiovascular disease decreased significantly in period 2 (14.1 per cent) compared with that in period 1 (16.1 per cent) in men only (5-year adjusted hazard ratio (HR) 0.76, 95 per cent c.i. 0.69 to 0.83; P < 0.001). In patients with CLI, the cardiovascular mortality risk decreased significantly only in women, with the 5-year risk reducing from 31.2 per cent in period 1 to 29.2 per cent in period 2 (adjusted HR 0.84, 0.74 to 0.94; P = 0.004). Compared with the general population, the mortality risk in patients with IC was increased between 1.70 (1.58 to 1.83) and 3.20 (2.69 to 3.81) times, and in those with CLI the risk was increased between 2.24 (2.09 to 2.40) and 5.19 (4.30 to 6.26) times. CONCLUSION: The risk of premature death in patients with IC and CLI declined significantly in the Netherlands, in a sex specific manner, over the period from 1998 to 2010. The absolute risk of cardiovascular mortality remains high in these patients. PMID- 29116656 TI - All-cause and cardiovascular mortality risk after surgery versus radioiodine treatment for hyperthyroidism. AB - BACKGROUND: Little is known about the long-term side-effects of different treatments for hyperthyroidism. The few studies previously published on the subject either included only women or focused mainly on cancer outcomes. This register study compared the impact of surgery versus radioiodine on all-cause and cause-specific mortality in a cohort of men and women. METHODS: Healthcare registers were used to find hyperthyroid patients over 35 years of age who were treated with radioiodine or surgery between 1976 and 2000. Comparisons between treatments were made to assess all-cause and cause-specific deaths to 2013. Three different statistical methods were applied: Cox regression, propensity score matching and inverse probability weighting. RESULTS: Of the 10 992 patients included, 10 250 had been treated with radioiodine (mean age 65.1 years; 8668 women, 84.6 per cent) and 742 had been treated surgically (mean age 44.1 years; 633 women, 85.3 per cent). Mean duration of follow-up varied between 16.3 and 22.3 years, depending on the statistical method used. All-cause mortality was significantly lower among surgically treated patients, with a hazard ratio of 0.82 in the regression analysis, 0.80 in propensity score matching and 0.85 in inverse probability weighting. This was due mainly to lower cardiovascular mortality in the surgical group. Men in particular seemed to benefit from surgery compared with radioiodine treatment. CONCLUSION: Compared with treatment with radioiodine, surgery for hyperthyroidism is associated with a lower risk of all cause and cardiovascular mortality in the long term. This finding was more evident among men. PMID- 29116655 TI - Talking about women's sexual health after cancer: Why is it so hard to move the needle? PMID- 29116658 TI - Interventions to improve employee health and well-being within health care organizations: A systematic review. AB - In response to an increasing body of evidence on the importance of employee health and well-being (HWB) within health care, there has been a shift in focus from both policymakers and individual organizations toward improving health care employee HWB. However, there is something of a paucity of evidence regarding the impact and value of specific HWB interventions within a health care setting. The aim of this article was to systematically review the literature on this topic utilizing the EMBASE, Global Health, Health Management Information Consortium, MEDLINE, and PsycINFO databases. Forty-four articles were identified and, due to a large degree of heterogeneity, were considered under different headings as to the type of intervention employed: namely, those evaluating changing ways of working, physical health promotion, complementary and alternative medicine, and stress management interventions, and those utilizing multimodal interventions. Our results consider both the efficacy and reliability of each intervention in turn and reflect on the importance of careful study design and measure selection when evaluating the impact of HWB interventions. PMID- 29116657 TI - International validation of the European Organisation for Research and Treatment of Cancer QLQ-BRECON23 quality-of-life questionnaire for women undergoing breast reconstruction. AB - BACKGROUND: The aim was to carry out phase 4 international field-testing of the European Organisation for Research and Treatment of Cancer (EORTC) breast reconstruction (BRECON) module. The primary objective was finalization of its scale structure. Secondary objectives were evaluation of its reliability, validity, responsiveness, acceptability and interpretability in patients with breast cancer undergoing mastectomy and reconstruction. METHODS: The EORTC module development guidelines were followed. Patients were recruited from 28 centres in seven countries. A prospective cohort completed the QLQ-BRECON15 before mastectomy and the QLQ-BRECON24 at 4-8 months after reconstruction. The cross sectional cohort completed the QLQ-BRECON24 at 1-5 years after reconstruction, and repeated this 2-8 weeks later (test-retest reliability). All participants completed debriefing questionnaires. RESULTS: A total of 438 patients were recruited, 234 in the prospective cohort and 204 in the cross-sectional cohort. A total of 414 reconstructions were immediate, with a comparable number of implants (176) and donor-site flaps (166). Control groups comprised patients who underwent two-stage implant procedures (72, 75 per cent) or delayed reconstruction (24, 25 per cent). Psychometric scale validity was supported by moderate to high item-own scale and item-total correlations (over 0.5). Questionnaire validity was confirmed by good scale-to-sample targeting, and computable scale scores exceeding 50 per cent, except nipple cosmesis (over 40 per cent). In known-group comparisons, QLQ-BRECON24 scales and items differentiated between patient groups defined by clinical criteria, such as type and timing of reconstruction, postmastectomy radiotherapy and surgical complications, with moderate effect sizes. Prospectively, sexuality and surgical side-effects scales showed significant responsiveness over time (P < 0.001). Scale reliability was supported by high Cronbach's alpha coefficients (over 0.7) and test-retest (intraclass correlation more than 0.8). One item (finding a well fitting bra) was excluded based on high floor/ceiling effects, poor test-retest and weak correlations in factor analysis (below 0.3), thus generating the QLQ-BRECON23 questionnaire. CONCLUSION: The QLQ-BRECON23 is an internationally validated tool to be used alongside the EORTC QLQ-C30 (cancer) and QLQ-BR23 (breast cancer) questionnaires for evaluating quality of life and satisfaction after breast reconstruction. PMID- 29116659 TI - Type-1 astrocyte-like stem cells harboring Cacna1d gene deletion exhibit reduced proliferation and decreased neuronal fate choice. AB - In the central nervous system, CaV 1.2 and CaV 1. 3 constitute the main L-type voltage-gated calcium channels (LTCCs) coupling membrane depolarization to gene transcription. We have previously demonstrated that inducible disruption of Cav1.2 in type-1 astrocyte-like stem cells of the adult dentate gyrus (DG) impairs hippocampal neurogenesis in a cell-autonomous fashion. To address the role of Cav1.3 channels (encoded by the Cacna1d gene), we here generated TgGLAST CreERT2 /Cacna1dfl/fl /RCE:loxP mice which facilitate inducible deletion of Cacna1d in tandem with induction of EGFP expression in type-1 cells, allowing tracking of recombined cells and their descendants. Neurosphere cultures derived from fluorescence-activated cell sorting sorted Cacna1d-deficient (Cacna1d-/- /EGFP) hippocampal neural precursor cells (NPCs) exhibited a significant decrease in proliferative activity. Further, under differentiation conditions, Cacna1d deficiency conferred an increase in astrogenesis at the expense of neurogenesis. In like manner, type-1 cells lacking Cacna1d showed reduced proliferation in the dentate gyrus (DG) in vivo. Moreover, Cacna1d deficiency resulted in a significant decrease in the number of newly born cells adopting a neuronal fate. Finally, massive excitation induced by repeated electroconvulsive seizures rescued the proliferation defect of Cacna1d-/- /EGFP type-1 cells. Together, the effects of Cacna1d gene deletion closely recapitulate our earlier findings on the role of Cav1.2 channels expressed by type-1 cells. Similar to Cav1.2 channels, Cav1.3 channels on type-1 cells boost type-1 cell proliferation and promote subsequent neuronal fate choice. PMID- 29116660 TI - Increased hippocampus to ventromedial prefrontal connectivity during the construction of episodic future events. AB - Both the hippocampus and ventromedial prefrontal cortex (vmPFC) appear to be critical for episodic future simulation. Damage to either structure affects one's ability to remember the past and imagine the future, and both structures are commonly activated as part of a wider core network during future simulation. However, the precise role played by each of these structures and, indeed, the direction of information flow between them during episodic simulation, is still not well understood. In this study, we scanned participants using functional magnetic resonance imaging while they imagined future events in response to object cues. We then used dynamic causal modeling to examine effective connectivity between the left anterior hippocampus and vmPFC during the initial mental construction of the events. Our results show that while there is strong bidirectional intrinsic connectivity between these regions (i.e., irrespective of task conditions), only the hippocampus to vmPFC connection increases during the construction of episodic future events, suggesting that the hippocampus initiates event simulation in response to retrieval cues, driving activation in the vmPFC where episodic details may be further integrated. PMID- 29116661 TI - Complying with the Emergency Medical Treatment and Labor Act (EMTALA): Challenges and solutions. AB - The Emergency Medical Treatment and Labor Act (EMTALA), which requires Medicare participating hospitals to provide emergency care to patients regardless of their ability to pay, plays an important role in protecting the uninsured. Yet many hospitals do not comply. This study examines the reasons for noncompliance and proposes solutions. We conducted 11 semistructured key informant interviews with hospitals, hospital associations, and patient safety organizations in the Centers for Medicare and Medicaid Services region with the highest number of EMTALA complaints filed. Respondents identified 5 main causes of noncompliance: financial incentives to avoid unprofitable patients, ignorance of EMTALA's requirements, high referral burden at hospitals receiving EMTALA transfer patients, reluctance to jeopardize relationships with transfer partners by reporting borderline EMTALA violations, and opposing priorities of hospitals and physicians. Respondents suggested 5 methods to improve compliance, including educating subspecialists about EMTALA, informally educating hospitals about borderline violations, and incorporating EMTALA-compliant processes into hospital operations such as by routing transfer requests through the emergency department. To improve compliance we suggest (1) more closely aligning Medicaid/Medicare payment policies with EMTALA, (2) amending the Act to permit informal mediation between hospitals about borderline violations, (3) increasing the hospital's role in ensuring EMTALA compliance, and (4) expanding the role of hospital associations. PMID- 29116662 TI - Mapping Nanostructural Variations in Silk by Secondary Electron Hyperspectral Imaging. AB - Nanostructures underpin the excellent properties of silk. Although the bulk nanocomposition of silks is well studied, direct evidence of the spatial variation of nanocrystalline (ordered) and amorphous (disordered) structures remains elusive. Here, secondary electron hyperspectral imaging can be exploited for direct imaging of hierarchical structures in carbon-based materials, which cannot be revealed by any other standard characterization methods. Through applying this technique to silks from domesticated (Bombyx mori) and wild (Antheraea mylitta) silkworms, a variety of previously unseen features are reported, highlighting the local interplay between ordered and disordered structures. This technique is able to differentiate composition on the nanoscale and enables in-depth studies into the relationship between morphology and performance of these complex biopolymer systems. PMID- 29116663 TI - Higher contact force, energy setting, and impedance rise during radiofrequency ablation predicts charring: New insights from contact force-guided in vivo ablation. AB - INTRODUCTION: Higher contact force (CF) theoretically increases the risk of blood charring, diminishing lesion formation. We aimed to investigate the relationship between CF, impedance change, and char formation during pulmonary vein isolation (PVI). METHODS: CF was assessed during PVI in 65 patients. Radiofrequency ablation (RFA) with power-controlled mode was applied in the point-by-point manner. The RFA were divided into five groups: group A (CF < 10 g), group B (10 g <= CF < 20 g), group C (20 g <= CF < 30 g), group D (30 g <= CF < 40 g), and group E (CF >= 40 g). Gradual impedance rise (gIR) was defined as >5 Omega increase during each 10-second period of RFA. Catheter tip was assessed for charring during, and at the end of each procedure. RESULTS: In total, 2,064 applications were analyzed. During 0-10 seconds, impedance was significantly decreased in groups with higher CF (P < 0.05). During 10-20 seconds, an impedance decrease was not significantly different among the five groups. During 20-30 seconds, mean impedance increased in group E. A gIR was noted at least once during RFA in 63 patients (97%). The incidence of gIR during RFA after 20 seconds was significantly higher in groups D and E (77/504 [15.3%] vs. 90/1560 [5.8%], P < 0.001). Charring occurred in 8 of 65 (12%) patients. A gIR after 20 seconds was significantly associated with a higher incidence of macroscopic charring (6/20 [30%] vs. 2/45 [4%], P < 0.01). CONCLUSIONS: gIR was noted with higher applied CFs after 20 seconds of RFA. This impedance rise may be avoided by keeping the applied CF under 26.9 g with negative predictive value of 95%. Our data suggested that gIR may be related to the incidence of charring. PMID- 29116664 TI - Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons. AB - OBJECTIVES: Bipolar disorder has been studied from numerous angles, from pathological studies to large-scale genomic studies, overall making moderate gains toward an understanding of the disorder. With the advancement of induced pluripotent stem (iPS) cell technology, in vitro models based on patient samples are now available that inherently incorporate the complex genetic variants that largely are the basis for this disorder. A number of groups are starting to apply iPS technology to the study of bipolar disorder. METHODS: We selectively reviewed the literature related to understanding bipolar disorder based on using neurons derived from iPS cells. RESULTS: So far, most work has used the prototypical iPS cells. However, others have been able to transdifferentiate fibroblasts directly to neurons. Others still have utilized olfactory epithelium tissue as a source of neural-like cells that do not need reprogramming. In general, iPS and related cells can be used for studies of disease pathology, drug discovery, or stem cell therapy. CONCLUSIONS: Published studies have primarily focused on understanding bipolar disorder pathology, but initial work is also being done to use iPS technology for drug discovery. In terms of disease pathology, some evidence is pointing toward a differentiation defect with more ventral cell types being prominent. Additionally, there is evidence for a calcium signaling defect, a finding that builds on the genome-wide association study results. Continued work with iPS cells will certainly help us understand bipolar disorder and provide a way forward for improved treatments. PMID- 29116665 TI - Reproductive isolation and environmental adaptation shape the phylogeography of mountain pine beetle (Dendroctonus ponderosae). AB - Chromosomal rearrangement can be an important mechanism driving population differentiation and incipient speciation. In the mountain pine beetle (MPB, Dendroctonus ponderosae), deletions on the Y chromosome that are polymorphic among populations are associated with reproductive incompatibility. Here, we used RAD sequencing across the entire MPB range in western North America to reveal the extent of the phylogeographic differences between Y haplotypes compared to autosomal and X-linked loci. Clustering and geneflow analyses revealed three distinct Y haplogroups geographically positioned within and on either side of the Great Basin Desert. Despite close geographic proximity between populations on the boundaries of each Y haplogroup, there was extremely low Y haplogroup mixing among populations, and gene flow on the autosomes was reduced across Y haplogroup boundaries. These results are consistent with a previous study suggesting that independent degradation of a recently evolved neo-Y chromosome in previously isolated populations causes male sterility or inviability among Y haplotype lineages. Phylogeographic results supported historic contraction of MPB into three separate Pleistocene glacial refugia followed by postglacial range expansion and secondary contact. Distinct sets of SNPs were statistically associated with environmental data among the most genetically distinct sets of geographic populations. This finding suggests that the process of adaptation to local climatic conditions is influenced by population genetic structure, with evidence for largely independent evolution in the most genetically isolated Y haplogroup. PMID- 29116666 TI - C-F Bond Activation by Silylium Cation/Phosphine Frustrated Lewis Pairs: Mono Hydrodefluorination of PhCF3 , PhCF2 H and Ph2 CF2. AB - Single defluorination of aryl polyfluoromethyl functionalities is achieved by both intra- and intermolecular silylium cation/phosphine Lewis pairs. Phosphine captured aryl fluoromethyl cations are then treated with Bronsted base to complete the first mono-hydrodefluorinations of PhCF3 , Ph2 CF2 , and PhCF2 . PMID- 29116667 TI - Photoinduced Liquefaction of Azobenzene-Containing Polymers. AB - Light can liquefy some solid azobenzene-containing polymers (azopolymers) by photoisomerization. Two types of photoinduced liquefaction of azopolymers have been reported: (1) polarized light can guide solid azopolymers "flow" along the polarization direction, which is called directional photofluidization and has been used for inscription of surface relief gratings (SRGs); (2) recently, some of us found that light can switch the glass transition temperatures (Tg ) of azopolymers and induce reversible solid-to-liquid transitions of these azopolymers. This Minireview demonstrates and compares directional photofluidization and photoinduced reversible solid-to-liquid transitions of azopolymers. Potential applications based on photoinduced liquefaction of azopolymers are highlighted and some remaining challenges in the field of photoinduced liquefaction of azopolymers are discussed. PMID- 29116669 TI - Altered States of Consciousness: Evaluation of a voice-hearing simulation during an immersive art exhibition. AB - AIM: To improve public understanding of the subjective experience of auditory hallucinations and increase empathy towards individuals who hear voices and have other unusual sensory experiences. METHODS: This pilot study developed a new immersive art exhibition, Altered States of Consciousness, which gave members of the public an individualized voice-hearing simulation experience in 2 real-world settings-an art gallery and the London Underground. A total of 150 visitors completed visual analogue scales immediately before and after their experience of the exhibition. RESULTS: Post-exhibition, there were significant increases in understanding what it feels like to hear voices, compassion towards voice hearers, and comfort in talking about these experiences. Participants enjoyed the simulation, felt they learned from their involvement, and did not find it stressful. CONCLUSIONS: The exhibition and voice-hearing simulation has further potential for public engagement and stigma reduction. PMID- 29116668 TI - Shaping Luminescent Properties of Yb3+ and Ho3+ Co-Doped Upconverting Core-Shell beta-NaYF4 Nanoparticles by Dopant Distribution and Spacing. AB - At the core of luminescence color and lifetime tuning of rare earth doped upconverting nanoparticles (UCNPs), is the understanding of the impact of the particle architecture for commonly used sensitizer (S) and activator (A) ions. In this respect, a series of core@shell NaYF4 UCNPs doped with Yb3+ and Ho3+ ions are presented here, where the same dopant concentrations are distributed in different particle architectures following the scheme: YbHo core and YbHo@..., ...@YbHo, Yb@Ho, Ho@Yb, YbHo@Yb, and Yb@YbHo core-shell NPs. As revealed by quantitative steady-state and time-resolved luminescence studies, the relative spatial distribution of the A and S ions in the UCNPs and their protection from surface quenching has a critical impact on their luminescence characteristics. Although the increased amount of Yb3+ ions boosts UCNP performance by amplifying the absorption, the Yb3+ ions can also efficiently dissipate the energy stored in the material through energy migration to the surface, thereby reducing the overall energy transfer efficiency to the activator ions. The results provide yet another proof that UC phosphor chemistry combined with materials engineering through intentional core@shell structures may help to fine-tune the luminescence features of UCNPs for their specific future applications in biosensing, bioimaging, photovoltaics, and display technologies. PMID- 29116670 TI - Predictive capacity of prodromal symptoms in first-episode psychosis of recent onset. AB - BACKGROUND: Both the nature and number of a wide range of prodromal symptoms have been related to the severity and type of psychopathology in the psychotic phase. However, at present there is an incomplete picture focused mainly on the positive pre-psychotic dimension. AIM: To characterize the prodromal phase retrospectively, examining the number and nature of prodromal symptoms as well as their relationship with psychopathology at the onset of first-episode psychosis. METHODS: Retrospective study of 79 patients experiencing a first-episode psychosis of less than 1 year from the onset of full-blown psychosis. All patients were evaluated with a comprehensive battery of instruments including socio-demographic and clinical questionnaire, IRAOS interview, PANSS, stressful life events scale (PERI) and WAIS/WISC (vocabulary subtest). Bivariate associations and multiple regression analysis were performed. RESULTS: Regression models revealed that several prodromal dimensions of IRAOS (delusions, affect, language, behaviour and non-hallucinatory disturbances of perception) predicted the onset of psychosis, with positive (22.4% of the variance) and disorganized (25.6% of the variance) dimensions being the most widely explained. CONCLUSION: In addition to attenuated positive symptoms, other symptoms such as affective, behavioural and language disturbances should also be considered in the definitions criteria of at-high-risk people. PMID- 29116671 TI - Screening for Zika virus in deceased organ donors in Florida. AB - Zika virus (ZIKV) cases have been detected across the United States (US) and locally acquired cases have been reported in Florida. Currently, there are no ZIKV screening guidelines and no data on the incidence among organ donors in the US. This retrospective study was conducted at Jackson Memorial-Miami Transplant Institute. Positive ZIKV tests in local deceased organ donors were investigated from 6/2016 to 1/2017. We evaluated demographics and risk factors for ZIKV infection among organ donors and transplant outcomes among recipients of donors with positive ZIKV testing. One hundred forty-two donors were analyzed. Ten percent had traveled to ZIKV-endemic countries and 19% had outdoor occupations. Only 3% had positive ZIKV IGG. None had a positive ZIKV IGM or PCR. ZIKV-positive donors were more likely to have traveled to ZIKV-endemic countries (50% vs. 9%, P = .05). The kidneys from a ZIKV-positive donor were transplanted in our hospital with no 6-month rejection, graft failure, or death in the recipients. Our study demonstrated a low prevalence of ZIKV among deceased donors in our community. Despite local ZIKV transmission, ZIKV was more common in donors who traveled to ZIKV-endemic countries. This cohort demonstrated excellent outcomes in recipients of ZIKV IGG-positive donors. However, larger studies are needed. PMID- 29116672 TI - Design of Ultrathin Pt-Based Multimetallic Nanostructures for Efficient Oxygen Reduction Electrocatalysis. AB - Nanocatalysts with high platinum (Pt) utilization efficiency are attracting extensive attention for oxygen reduction reactions (ORR) conducted at the cathode of fuel cells. Ultrathin Pt-based multimetallic nanostructures show obvious advantages in accelerating the sluggish cathodic ORR due to their ultrahigh Pt utilization efficiency. A focus on recent important developments is provided in using wet chemistry techniques for making/tuning the multimetallic nanostructures with high Pt utilization efficiency for boosting ORR activity and durability. First, new synthetic methods for multimetallic core/shell nanoparticles with ultrathin shell sizes for achieving highly efficient ORR catalysts are reviewed. To obtain better ORR activity and stability, multimetallic nanowires or nanosheets with well-defined structure and surface are further highlighted. Furthermore, ultrathin Pt-based multimetallic nanoframes that feature 3D molecularly accessible surfaces for achieving more efficient ORR catalysis are discussed. Finally, the remaining challenges and outlooks for the future will be provided for this promising research field. PMID- 29116673 TI - The utilization of Boari flap vesicocalycostomy for salvage repair of kidney transplant ureteric injury after robotic radical prostatectomy. PMID- 29116674 TI - Turn down for what? Patient outcomes associated with declining increased infectious risk kidneys. AB - Transplant candidates who accept a kidney labeled increased risk for disease transmission (IRD) accept a low risk of window period infection, yet those who decline must wait for another offer that might harbor other risks or never even come. To characterize survival benefit of accepting IRD kidneys, we used 2010 2014 Scientific Registry of Transplant Recipients data to identify 104 998 adult transplant candidates who were offered IRD kidneys that were eventually accepted by someone; the median (interquartile range) Kidney Donor Profile Index (KDPI) of these kidneys was 30 (16-49). We followed patients from the offer decision until death or end-of-study. After 5 years, only 31.0% of candidates who declined IRDs later received non-IRD deceased donor kidney transplants; the median KDPI of these non-IRD kidneys was 52, compared to 21 of the IRDs they had declined. After a brief risk period in the first 30 days following IRD acceptance (adjusted hazard ratio [aHR] accept vs decline: 1.22 2.063.49 , P = .008) (absolute mortality 0.8% vs. 0.4%), those who accepted IRDs were at 33% lower risk of death 1-6 months postdecision (aHR 0.50 0.670.90 , P = .006), and at 48% lower risk of death beyond 6 months postdecision (aHR 0.46 0.520.58 , P < .001). Accepting an IRD kidney was associated with substantial long-term survival benefit; providers should consider this benefit when counseling patients on IRD offer acceptance. PMID- 29116675 TI - The course of neuropsychological functioning in young people with attenuated vs discrete mental disorders. AB - AIM: Clinical staging of mental disorders is designed to facilitate the selection of stage-appropriate interventions, early in the course of illness. Neuropsychological performance, particularly at early stages of mental disorder, is a strong predictor of medium-term functional outcomes. Despite this, the longitudinal examination of neuropsychological profiles in early stages of illness is poorly researched. Thus, we examined baseline and longitudinal neuropsychological profiles of young patients with attenuated syndromes vs those with discrete disorders. METHODS: Neuropsychological testing of 497 help-seeking young people (21.2 +/- 3 years; 56% female). Clinical staging, assigned separately from testing, rated 262 individuals as "attenuated syndrome" (stage 1b) and 235 as "discrete" or "persistent" disorder (stage 2+). Follow-up testing was undertaken in 170 individuals (54% at stage 1b) after 19.8 +/- 9 months (range: 3 to 51 months). RESULTS: At baseline, attenuated and discrete/persistent disorders significantly differed in 4 of the 9 neuropsychological measures (verbal learning, verbal memory, visual memory and set shifting). Despite this, both groups showed similar improvement in neuropsychological functioning at follow-up, particularly in processing speed, sustained attention and visual memory. Longitudinal improvement in cognition corresponded with increases in socio-occupational functioning. DISCUSSION: The degree of baseline neuropsychological dysfunction discriminates those with attenuated syndromes from those with a discrete/persistent disorder. Furthermore, improvement in neuropsychological functioning corresponded with improvement in clinical and functional status, despite stage of illness. This suggests that neuropsychological functioning remains relatively stable in young people with a mental illness and may be a critical window for intervention. PMID- 29116676 TI - Salvage therapy with topical posaconazole in lung transplant recipients with invasive Scedosporium infection. AB - Scedosporium is an important pathogen in cystic fibrosis (CF) and post transplantation, but it rarely causes invasive infection. Treatment remains challenging, particularly due to the inherent resistance to multiple antifungal agents. We present 3 complicated invasive tracheobronchial and lung Scedosporium apiospermum infections following lung transplantation. In 2 of 3 cases, the infection was clinically and radiologically cured with frequent cleansing bronchoscopies, combining triazole with terbinafine therapy and nebulized posaconazole. These cases highlight the importance of adjunctive nebulized therapy in addition to prolonged triazole treatment to manage complex invasive Scedosporium infections in immunosuppressed patients. Posaconazole (PSZ) was delivered during the bronchoscopy procedure through intrabronchial administration, whereas an eFlow rapid(r) device was used for nebulized therapy. Topical posaconazole was well tolerated in 2 patients, with only a slight cough during administrations; the third patient had local irritation with poor tolerance, which led to its withdrawal. This is the first report on compassionate use of topical PSZ as salvage therapy for resistant mold infections in lung transplant recipients. These 3 cases represent the entire experience using this approach; no additional patients have received this therapy due to there not having been any additional cases of Scedosporium tracheobronchitis presented. PMID- 29116677 TI - Inhibitory effects of oxytocin and oxytocin receptor antagonist atosiban on the activities of carbonic anhydrase and acetylcholinesterase enzymes in the liver and kidney tissues of rats. AB - The aim of this study was to investigate the effects of oxytocin (OT), atosiban, which is an OT receptor antagonist, and OT-atosiban chemicals injected to rats on the activities of carbonic anhydrase (CA) and acetylcholinesterase (AChE) enzymes in liver and kidney tissues of rats. For this purpose, four different groups, each consisting of six rats (n = 6), were formed (control group, OT administered group, atosiban administered group, and both OT and atosiban administered group). The rats were necropsied 60 min after intraperitoneal injection of chemicals into the rats. Liver tissues of rats were extracted. CA and AChE enzyme activities were measured for each tissue by using hydratase, esterase, and acetylcholiniodide methods. Activity values for each enzyme obtained were statistically calculated. PMID- 29116678 TI - Toxicological terms: Meaning and definition, part two. PMID- 29116679 TI - Functional status, healthcare utilization, and the costs of liver transplantation. AB - The Model for End-Stage Liver Disease (MELD) score predicts higher transplant healthcare utilization and costs; however, the independent contribution of functional status towards costs is understudied. The study objective was to evaluate the association between functional status, as measured by Karnofsky Performance Status (KPS), and liver transplant (LT) costs in the first posttransplant year. In a cohort of 598 LT recipients from July 1, 2009 to November 30, 2014, multivariable models assessed associations between KPS and outcomes. LT recipients needing full assistance (KPS 10%-40%) vs being independent (KPS 80%-100%) were more likely to be discharged to a rehabilitation facility after LT (22% vs 3%) and be rehospitalized within the first posttransplant year (78% vs 57%), all P < .001. In adjusted generalized linear models, in addition to MELD (P < .001), factors independently associated with higher 1-year post-LT transplant costs were older age, poor functional status (KPS 10%-40%), living donor LT, pre-LT hemodialysis, and the donor risk index (all P < .001). One-year survival for patients in the top cost decile was 83% vs 93% for the rest of the cohort (log rank P < .001). Functional status is an important determinant of posttransplant resource utilization; therefore, standardized measurements of functional status should be considered to optimize candidate selection and outcomes. PMID- 29116680 TI - Emergency department use among kidney transplant recipients in the United States. AB - Patients with end-stage renal disease use the emergency department (ED) at a 6 fold higher rate than do other US adults. No national studies have described ED use rates among kidney transplant (KTx) recipients, and the factors associated with higher ED use. We examined a cohort of 132 725 adult KTx recipients in the United States Renal Data System (2005-2013). Data on ED visits, hospitalization, and outpatient nephrology visits were obtained from Medicare claims databases. Nearly half (46.1%) of KTx recipients had at least one ED visit (1.61 ED visits/patient-year [PY]), and 39.7% of ED visits resulted in hospitalization in the first year posttransplantation. ED visit rate was high in the first 30 days (5.26 visits/PY) but declined substantially thereafter (1.81 visits/PY in months 1-3; 1.13 visits/PY in months 3-12 posttransplantation). ED visit rates were higher in the first 30 days versus rates for dialysis patients but less than half the rate thereafter. Female sex, public insurance, medical comorbidities, longer pretransplantation dialysis vintage, and delayed graft function were associated with higher ED use in the first year post-KTx. Policies and strategies addressing potentially preventable ED visits should be promoted to help improve patient care and increase efficient use of ED resources. PMID- 29116681 TI - Chiral Imprinting in the Gas Phase. AB - Undoing the twist: Recent successful attempts to change the relative populations of two otherwise identical enantiomers of a large gas-phase molecule using resonant microwave fields are highlighted. Specifically, the population of a specific enantiomer of a chiral terpene could be enhanced relative to the other enantiomer by the application of a sequence of microwave pulses in a phase- and polarization-controlled manner. PMID- 29116683 TI - Nursing Gender Pay Differentials in the New Millennium. AB - BACKGROUND: The gender pay gap in the United States is an ongoing issue, affecting women in nearly all occupations. Jobs traditionally associated with men tend to pay better than traditionally female-dominated jobs, and there is evidence to suggest within-occupation gender pay differences as well. PURPOSE: We compared and contrasted gender wage disparities for registered nurses (RNs), relative to gender wage disparities for another female-dominated occupation, teachers, while controlling for sociodemographic factors. METHODS: Using data in the American Community Survey, we analyzed the largest U.S. random representative sample of self-identified RNs and primary or secondary school teachers from 2000 to 2013 using fixed-effects regression analysis. RESULTS: There is greater disparity between nurse pay by gender than in teacher pay by gender. In addition, the net return in wages for additional education is higher for school teachers (21.7%) than for RNs (4.7%). CONCLUSIONS: Findings support preferential wages for men in nursing, more so than for men in teaching. CLINICAL RELEVANCE: The substantial gender disparities are an indirect measure of the misallocation of resources in effective patient care. PMID- 29116682 TI - Flavin-N5 Covalent Intermediate in a Nonredox Dehalogenation Reaction Catalyzed by an Atypical Flavoenzyme. AB - The flavin-dependent enzyme 2-haloacrylate hydratase (2-HAH) catalyzes the conversion of 2-chloroacrylate, a major component in the manufacture of acrylic polymers, to pyruvate. The enzyme was expressed in Escherichia coli, purified, and characterized. 2-HAH was shown to be monomeric in solution and contained a non-covalent, yet tightly bound, flavin adenine dinucleotide (FAD). Although the catalyzed reaction was redox-neutral, 2-HAH was active only in the reduced state. A covalent flavin-substrate intermediate, consistent with the flavin-acrylate iminium ion, was trapped with cyanoborohydride and characterized by mass spectrometry. Small-angle X-ray scattering was consistent with 2-HAH belonging to the succinate dehydrogenase/fumarate reductase family of flavoproteins. These studies establish 2-HAH as a novel noncanonical flavoenzyme. PMID- 29116685 TI - Isocyanate-Free Approach to Water-Borne Polyurea Dispersions and Coatings. AB - Here, an isocyanate-free approach to produce polyureas from diamines and dicarbamates as monomers is reported. A side reaction limiting the molecular weight during the diamine/ dicarbamate polymerization, that is, N-alkylation of amine end groups, is investigated. Mitigation of the N-alkylation, either by enhancing the carbamate aminolysis rate or by substitution of dimethylcarbamates with more sterically hindered diethylcarbamates, affords polyureas with sufficiently high molecular weights to assure satisfactory mechanical properties. Stable polyurea dispersions with polyamines as internal dispersing agents are prepared, and the properties of the corresponding coatings are evaluated. PMID- 29116684 TI - Disparities in direct acting antivirals uptake in HIV-hepatitis C co-infected populations in Canada. AB - BACKGROUND: Direct acting antivirals (DAAs) have revolutionized hepatitis C (HCV) treatment with >90% cure rates even in real-world studies, giving hope that HCV can be eliminated. However, for DAAs to have a population-level impact on the burden of HCV disease, treatment uptake needs to be expanded. We investigated temporal trends in HCV treatment uptake and evaluated factors associated with second-generation DAA initiation and efficacy among key HIV-HCV co-infected populations in Canada. METHODS: The Canadian HIV-HCV Co-Infection Cohort Study prospectively follows 1699 participants from 18 centres. Among HCV RNA+ participants, we determined the incidence of HCV treatment initiation per year overall and by key populations between 2007 and 2015. Key populations were based on World Health Organization (WHO) guidelines including: people who actively inject drugs (PWID) (reporting injection drug use, last 6 months); Indigenous people; women and men who have sex with men (MSM). Multivariate Cox models were used to estimate adjusted hazard ratios (aHR) and 2-year probability of initiating second-generation DAAs for each of the key populations. RESULTS: Overall, HCV treatment initiation rates increased from 8 (95% CI, 6-11) /100 person-years in 2013 to 28 (95% CI, 23-33) /100 person-years in 2015. Among 911 HCV RNA + participants, there were 202 second-generation DAA initiations (93% with interferon-free regimens). After adjustment (aHR, 95% CI), active PWID (0.60, 0.38-0.94 compared to people not injecting drugs) and more generally, people with lower income (<$18 000 CAD/year) (0.50, 0.35, 0.71) were less likely to initiate treatment. Conversely, MSM were more likely to initiate 1.95 (1.33, 2.86) compared to heterosexual men. In our cohort, the population profile with the lowest 2-year probability of initiating DAAs was Indigenous, women who inject drugs (5%, 95% CI 3-8%). Not having any of these risk factors resulted in a 35% (95% CI 32-38%) probability of initiating DAA treatment. Sustained virologic response (SVR) rates were >82% in all key populations. CONCLUSION: While treatment uptake has increased with the availability of second-generation DAAs, marginalized populations, already engaged in care, are still failing to access treatment. Targeted strategies to address barriers are needed to avoid further health inequities and to maximize the public health impact of DAAs. PMID- 29116686 TI - Protocols for the Design of Kinase-focused Compound Libraries. AB - Protocols for the design of kinase-focused compound libraries are presented. Kinase-focused compound libraries can be differentiated based on the design goal. Depending on whether the library should be a discovery library specific for one particular kinase, a general discovery library for multiple distinct kinase projects, or even phenotypic screening, there exists today a variety of in silico methods to design candidate compound libraries. We address the following scenarios: 1) Datamining of SAR databases and kinase focused vendor catalogues; 2) Predictions and virtual screening; 3) Structure-based design of combinatorial kinase inhibitors; 4) Design of covalent kinase inhibitors; 5) Design of macrocyclic kinase inhibitors; and 6) Design of allosteric kinase inhibitors and activators. PMID- 29116687 TI - Erythropoietic protoporphyria in an adult with sequential liver and hematopoietic stem cell transplantation: A case report. AB - Erythropoietic protoporphyria (EPP) is a rare inherited disorder of the heme biosynthesis pathway resulting in the accumulation of protoporphyrins in the blood, erythrocytes, and other tissues. Because of a gene mutation in the FECH gene, ferrochelatase, the enzyme involved in the final step of heme synthesis, is deficient in these patients. Although the major symptom of this disorder is photosensitivity, rarely, it can cause progressive liver disease requiring liver transplantation (LT). However, LT is not curative and only bone marrow transplantation (BMT) can correct the underlying enzymatic defect. Because liver disease results from accumulation of protoporphyrin in the liver, LT without hematopoietic stem cell transplantation leaves the new liver at risk for similar EPP-related damage. A handful of pediatric patients undergoing sequential LT and stem cell transplantation have been described in the literature; however, to date none has been described in detail in adults. We report a case of an adult male with EPP and liver failure who successfully underwent a sequential liver and hematopoietic stem cell transplantation (HSCT). PMID- 29116688 TI - Facile Synthesis of Highly Water-Soluble Lanthanide-Doped t-LaVO4 NPs for Antifake Ink and Latent Fingermark Detection. AB - In the information age, it is important to protect the security and integrity of the information. As a result, the fluorescent ink as an antifake technology and the fingermark as an information carrier have aroused great interest. In this work, highly water-soluble lanthanide (Ln3+ )-doped tetragonal phase (t-) LaVO4 nanoparticles (NPs) are successfully obtained via a simple, fast, and green microwave-assisted hydrothermal method. The average size of t-LaVO4 NPs is about 43 nm. The aqueous solutions of Ln3+ -doped t-LaVO4 exhibit excellent fluorescence properties under ultraviolet light (UV) excitation (t-LaVO4 :10%Eu is bright red and t-LaVO4 :0.5%Dy is close to white). Some superb antifake fluorescent patterns are printed using Ln3+ -doped t-LaVO4 aqueous solution as ink, which indicates the as-prepared Ln3+ -doped t-LaVO4 NPs as fluorescent ink can meet the various antifake requirements. Notably, the designed convenient antifake fluorescent codes with improved security could be directly scanned and decoded by a smart phone. What's more, the as-prepared NPs can be used for the development of latent fingermark on various substrates and the second-level detail information can be clearly obtained from the magnification of a fingermark. These results indicate that the as-prepared Ln3+ -doped t-LaVO4 fluorescent NPs have great potential in security application. PMID- 29116689 TI - Evaluation of hemodynamic performance of total cavopulmonary connection (TCPC) with porous inserts. AB - Infants born with univentricular heart disease undergo Fontan surgery to establish separate systemic and pulmonary circulations. This surgery results in better blood circulation across a single ventricle that supplies oxygenated blood to the body and passively returns venous blood to the lungs through the total cavopulmonary connection (TCPC). Reducing the pressure drop across the TCPC during Fontan circulation helps in reducing the work load of univentricular heart, and various designs have been proposed for this purpose. The goal of this work is to analyze the effect of placing a porous insert at an appropriate position in the pulmonary artery, on the pressure drop across the TCPC. A 3D computational model of a total TCPC connection provided with a porous insert is developed and solved by finite volume method, under assumptions of steady, laminar, and Newtonian flows. The effects of the porous medium properties porosity and permeability-across the connection, are analyzed. Compared to the no porous medium case, TCPC with the porous medium insert exhibits a maximum reduction of 27% in energy loss for the flow range studied. The porous medium used in TCPC connection lowers the energy dissipation by curtailing the flow recirculation zones across the connection. The influences of the diameter of the blood vessel, total cardiac output, and the thickness, permeability, and position of porous media on energy loss are analyzed. The criteria to select the porous medium properties and position for a given Fontan geometry are also determined. PMID- 29116690 TI - An open letter to the American Diabetes Association board of directors: Special commentary. PMID- 29116693 TI - Cost effectiveness of residential carbon monoxide alarms. AB - BACKGROUND: While residential carbon monoxide (CO) alarms are now required in a majority of states, the cost effectiveness of the devices is unknown. This analysis was performed to determine the degree of prevention efficacy necessary from home carbon monoxide alarms for their expense to be cost-effective. METHODS: Data regarding numbers of individuals affected in the United States annually from accidental, non-fire, residential non-fatal and fatal carbon monoxide poisoning were obtained from published literature. Federal governmental estimates of societal costs associated with medical care, lost wages and earnings, value of pain and suffering, and value of a statistical life were applied. The cost of uniform residential carbon monoxide alarm installation was compared to those societal costs in order to calculate what degree of efficiency makes alarms cost effective. RESULTS: Societal costs for accidental, non-fire, residential CO poisoning are approximately $3.47 billion annually. With an estimated cost of $348 million annually for alarms, prevention of greater than 10% of residential CO poisoning costs must be achieved in order for alarms to be cost-effective. CONCLUSIONS: While the true effectiveness of residential carbon monoxide alarms has yet to be determined, current state legislation requiring residential installation of CO alarms is probably cost-effective. . PMID- 29116691 TI - Hyperbaric oxygen in patients with ischemic stroke following cardiac surgery: a retrospective observational trial. AB - BACKGROUND: Hyperbaric oxygenation (HBO2) involves breathing 100% oxygen under elevated ambient pressure in a hyperbaric chamber, thereby dissolving oxygen in the plasma. This results in an increase of arterial partial pressure of oxygen (pO2). Though well established in experimental studies, HBO2 treatment for ischemic stroke is still under discussion. METHODS: From 2002-2014 HBO2 (2.2 bar, 90 minutes one/day; average number per patient: 4.7) was applied in 49 consecutive patients (32 males, 17 females, mean age: 68.8 years, range 31.2 - 83.9) with acute neurological deficit following cardiac surgery (CABG 15; combined surgery 14; valve surgery 11; aneurysm repair 8; malformation 1). Patients' history including TIA or stroke and carotid artery pathology were documented. Both degree and type of neurological deficit was evaluated by a scoring system (0-4) before and after HBO2 treatment. RESULTS: Before HBO2 therapy, the average motor deficit score was 2.45 and the average speech disorder score was 0.55, as compared with an average motor deficit of 1.12 and an average speech disorder of 0.27 afterward (alpha=0.0001, alpha=0.009). The majority of patients had an overall improvement of 2 score-points after HBO2 therapy (n=23 patients). Probit analysis showed that for a 50% response/probability (LC50) of having an overall outcome of >=2 scoring points, an estimate of 4.3 HBO2 therapy sessions is necessary. CONCLUSIONS: HBO22 therapy was associated with significant improvement in patients with acute neurological deficits due to ischemic stroke following cardiac surgery. Though this fact suggests gas embolism as the most likely cause of stroke in this collective, other underlying pathologies cannot be ruled out. Randomized studies are needed for further evaluation. PMID- 29116692 TI - A pilot study evaluating knowledge of indications for hyperbaric oxygen therapy. AB - A pilot study was conducted in mid-Michigan to evaluate knowledge of appropriate hyperbaric oxygen therapy referrals in "first contact" physicians who did not have additional hyperbaric training. The hypothesis for this study is that many first-contact physicians have little or no exposure to hyperbaric oxygen (HBO2) therapy and its indications. A survey was distributed regarding accepted indications combined with conditions not currently approved or contraindicated for HBO2. Answers were tallied for correct identification of approved indications, missed approved indications, and inappropriate identification of unapproved indications. Ninety (90) surveys were distributed and 62 physicians of various specialties responded. There were notably high percentages of missed indications, as high as 93%. Many emergent/urgent indications were missed as well. The highest percentage of wrong indications was 32%. Very concerning is the 13% who chose refractory pneumothorax as a condition responsive to HBO2 therapy. This study showed significant lack of familiarity of HBO2 treatment indications among physicians who did not have additional hyperbaric training. Inclusion of hyperbaric education during residencies may increase HBO2 referrals and improve outcomes for various disorders. PMID- 29116694 TI - Efficacy of the U.S. Navy Treatment Tables in treating DCS in 103 recreational scuba divers. AB - Despite the fact that current decompression schedules reduce the risk of decompression sickness (DCS), recreational scuba divers continue to experience DCS. Therapy outcomes in these divers are difficult to track. Our study aims to understand the efficacy of the United States Navy (USN) Treatment Tables (5, 6, 6A, 9) in providing symptomatic relief among recreational scuba divers. We conducted a single-center retrospective review of recreational divers treated from 2003 to 2013. A total of 187 divers were identified: 84 divers were excluded, and the charts of the remaining 103 divers were independently reviewed by three clinicians. For these 103 divers, the response variable, therapy outcome, was categorized as no relief, partial relief, or complete relief of symptoms. In a population of 76 males and 27 females with an average of three dives and three treatments, 53 patients achieved complete symptomatic relief, 45 patients had partial relief, and five patients reported no relief at the end of all recompression treatments. Among the patients who achieved complete symptomatic relief, 28 (53%) needed only one recompression treatment. The depth of the diver's first dive and the change in symptoms within the first 20 minutes of the first recompression treatment were found to be explanatory variables of the treatment outcome. PMID- 29116695 TI - Repetitive freshwater diving: risk factors and prevalence of barotrauma. AB - OBJECTIVE: The aim was to investigate the influence of repetitive scuba diving in fresh water on the middle ear mucosa. The prevalence of middle ear barotrauma (MEB) and risk factors for MEB were evaluated. STUDY DESIGN: Prospective cohort study, Level of evidence 1b. METHODS: During three days, 23 divers made 144 repetitive dives in a freshwater lake. Participants underwent otoscopic examinations and were questioned about ENT-related complaints in the morning before the first dive, in between the dives and after the last dive. Otoscopic findings were documented and classified according to the TEED scale (0 = normal eardrum to 4 = perforation), for the right and the left ear separately. RESULTS: In total, 416 examinations were performed. ENT-related complaints during diving, mostly failed pressure equalization (74%), were reported after 10% of all dives. Most common pathology was MEB (TEED 1-3, 26%). Valsalva maneuver was possible during all exams. Significant increase of MEB (TEED?0) occurred with an increasing cumulative number of dives per day (P ? .0001). Diving depth significantly influenced the MEB distribution (P = .035). MEB with higher TEED levels (2 and 3) was present only in the less experienced and intermediate divers. With increasing TEED level, more participants reported ENT-related problems (P ? .0001). However, 74.4% of divers with MEB were still asymptomatic. CONCLUSION: During three days of diving, the MEB prevalence increased with a cumulative number of dives per day. The major risk factors were diving depth and diving experience. Higher TEED level correlated with an increasing number of subjective ENT-related disorders during diving. PMID- 29116697 TI - UHMS Annual Scientific Meeting 2017 abstracts. PMID- 29116696 TI - Spinal decompression sickness in an artisanal diving fisherman in Yucatan, Mexico: a case report. AB - Artisanal fishermen around the world employ scuba and surface-supplied diving for their livelihoods and often undergo provocative dive profiles due to economic pressures. Consequently, rates of decompression sickness (DCS) are much greater than in recreational scuba divers. Here we present the case of a surface-supplied diving fisherman from the Yucatan Peninsula of Mexico, who suffered a significant episode of spinal DCS and underwent hyperbaric oxygen therapy treatments, with a favorable outcome. Additionally, we review the proposed mechanisms underlying spinal DCS. PMID- 29116698 TI - Car wrecks and caution: a lament on getting the facts straight in scientific reporting - I. Eftedal. PMID- 29116699 TI - RESPONSE: Car wrecks and caution: a lament on getting the facts straight in scientific reporting - S.L. Blogg, et al. PMID- 29116700 TI - A FINAL WORD: Car wrecks and caution: a lament on getting the facts straight in scientific reporting - E. Camporesi. PMID- 29116701 TI - Sanative Contagion Among Cambridge Platonists. PMID- 29116702 TI - Type II Diabetes Emergency Room Visits Associated With Hurricane Sandy in New Jersey: Implications for Preparedness. AB - On October 29, 2012, Hurricane Sandy made landfall in New Jersey, causing major power outages, flooded roads, and disruption of public transportation. Individuals diagnosed with diabetes may be especially vulnerable to natural disasters because of limited access to medications or use of glucose monitoring devices. We examined changes in emergency room visits (ERVs) for type II diabetes mellitus potentially associated with Hurricane Sandy in New Jersey. Data analyzed in 2014 included ERVs to general acute care hospitals in New Jersey among residents of three counties with a primary or secondary type II diabetes diagnosis (PDD or SDD) in 2011-2012. Compared to the previous year, results showed an 84% increased rate of PDD ERVs during the week of Hurricane Sandy, after adjusting for age and sex (rate ratio (RR) = 1.84, 95% confidence interval (CI) 1.12, 3.04). Results were nonsignificant for SDD (RR = 0.94, 95% CI 0.83, 1.08). Spatial analysis showed the increase in visits was not consistently associated with flood zone areas. We observed substantial increases in ERVs for primary type II diabetes diagnoses associated with Hurricane Sandy in New Jersey. Future public health preparedness efforts during storms should include planning for the healthcare needs of populations living with diabetes. PMID- 29116703 TI - GERALD EDELMAN, 1 JULY 1929 - 17 MAY 2014 PMID- 29116704 TI - Three Health Departments Build Capacity by Leveraging Partners and Existing Datasets. PMID- 29116705 TI - A Fork in the Road for Environmental Health Workforce Development and U.S. Public Health. PMID- 29116707 TI - Environmental Health Promotion on a Budget: Leveraging the Power of YouTube to Reach Millions of People. PMID- 29116708 TI - Strengthening nursing and midwifery capacity in rural New South Wales, Australia. AB - A small rural health service and two university schools of nursing joined forces to establish a rural clinical school to advance clinical education and research. The collaboration, while in its infancy, has given rise to outcomes that strength the capacity of nursing and midwifery services in the community. PMID- 29116706 TI - Effect of sperm DNA fragmentation on embryo development: clinical and biological aspects. AB - OBJECTIVE: The aim of this study was to investigate the effect of sperm DNA fragmentation on fertilization rate, embryo development (blastulation rate), and pregnancy outcomes for ICSI cycles performed in a cohort of couples using donor eggs and to assess the remaining embryos that were not transferred or frozen for apoptotic markers. METHODS: Eighty-two women (egg recipients) were included in the study (2016) were included in the study. The recipients' mean age was 41.8+/ 5.1 y/o (36-49), while the egg donors' mean age was 30.8+/-2.1 y/o (27-33). Even though donor egg cycles with frozen sperm samples are performed regularly in our center, 35 cycles were done using fresh sperm samples. The mean age of the males involved in the procedure was 40.1+/-5.2 y/o. Fertilization, blastulation, and pregnancy rates were assessed. The patients were divided into two groups, TUNEL <15% and >=15%. In arrested embryos, ICC was performed to detect cleaved caspase 3, survivin, TUNEL, and DNA. The Student's t-test was used in between-group comparisons. The Mann-Whitney U-test was used to assess homogeneity. Pearson's correlation coefficient was also calculated. p<0.05 was considered statistically significant. RESULTS: This study showed that there is a negative correlation (R= 0.5) between DNA fragmentation and blastulation rate. High levels of DNA fragmentation were associated with low blastulation and pregnancy rates (per transfer); however, fertilization rate was not affected. Samples with higher levels of DNA fragmentation were associated with higher levels of DNA fragmentation in blastomeres without activating the apoptotic pathway (9.1% vs. 15.9%) (p<0.05). Blastomeres from samples with high DNA fragmentation activated the apoptotic pathway in higher levels than samples with TUNEL <15% (16.4% vs. 21.9%) (p<0.05). CONCLUSION: Sperm DNA fragmentation was negatively correlated with blastulation and pregnancy rates even in good quality oocytes. High levels of DNA damage promote embryo arrest and induce the activation of the apoptotic pathway. PMID- 29116709 TI - Improving Food Safety Through Prevention: CDC's Food Safety Prevention Status Report. PMID- 29116711 TI - NEHA News. PMID- 29116710 TI - The WA Goldfields Aboriginal Community Antenatal Program-A community midwifery initiative. AB - Aim: To investigate the acceptability and satisfaction with the Aboriginal Community Antenatal Programby staff in the program and partner agencies. Design: A Strengths, Weaknesses, Opportunities and Threats framework guided the research and datacollection methods. Mixed methodology was used, accessing qualitative and quantitative informationfrom data bases, program and supporting agency staff. Quantitative data were analysed through a socialsciences statistical package. Qualitative data were identified through questionnaires and analysed usingthematic analysis. Setting: Remote Aboriginal communities in the Goldfields region of Western Australia.Participant sources: Twenty two participants including program and supporting agency staff.Main outcome measures: This study measures acceptability and satisfaction of program antenatal andpre-conception activities by program staff and partner agencies. Results: Qualitative results indicate acceptability and satisfaction with the program, identifying a rangeof organisational, staffing, cultural and interagency issues relating to a model of service provision. Quan-titative data suggested positive program outputs from service delivery. Conclusion: Findings suggest the Aboriginal Community Antenatal Program and partner agencies areincreasing provision of community based pre conception and antenatal health services and enhancingcollaboration between a range of health provider agencies, with partnerships between Aboriginal andnon Aboriginal program staff contributing to an emerging model of community antenatal care. PMID- 29116712 TI - Findings suggest the Aboriginal Community Antenatal Program and partner agencies areincreasing provision of community based pre-conception and antenatal health services and enhancingcollaboration between a range of health provider agencies, with partnerships between Aboriginal andnon-Aboriginal program staff contributing to an emerging model of community antenatal care. AB - Patients requiring inter-hospital air transport across large geographical spaces areat significant risk of adverse outcomes. The aims of this study were to examine the charac-teristics of clinical handover conducted by telephone and subsequently transcribed in medicalrecords during the inter-hospital transfer of rural patients, and to identify any deficits of thistelephone clinical handover. A retrospective audit was conducted of transcribed telephone han-dovers ('patient expect' calls) occurring with inter-hospital transfers from two rural hospitalsto a metropolitan tertiary hospital of all rural patients (n = 127) between January and June2012. Patient transport between various sites occurred through the Royal Flying Doctor Service.For these hospitals, patient expect calls constituted the only handover record for cliniciansduring the time of patient transport. Information on patient identification stickers relating to patients' age or gender did not always correspond with details collected during patient expectcalls. The name of a clinician at the receiving hospital authorising the transfer was provided in14 calls (11.1%). It was difficult to determine who made and received calls, and who acceptedresponsibility for patients at the receiving site. Deterioration in a patient's condition was madein three calls. Actions to be taken after patients' arrival were included in 24 (19%) calls. Planningwas restricted to identifying who to contact to review instructions. Inconsistent and overuse ofabbreviations was likely to have affected the ability to accurately read back patient informa-tion. Crucial information was missing from calls, which may have contributed to delayed andinappropriate delivery of care. PMID- 29116715 TI - DirecTalk: Musings from the 10th Floor: Unfettered and Alive. PMID- 29116719 TI - Abrupt smoking cessation more effective than cutting down. PMID- 29116716 TI - Articular Eminence Inclination in Medieval and Contemporary Croatian Population AB - Articular eminence inclination (AEI) of the temporomandibular joint leads themandible in its movements. Therefore, the aim of the present study was to determine AEI values inmedieval (MP) and recent (RP) Croatian population. The study was carried out on two groups ofspecimens: first group with 30 MP human dry skulls, while the other, serving as control group consistedof 137 dry skulls. The AEI was measured on lateral digital skull images as the angle between thebest fi t line drawn along the posterior wall of the articular eminence and the Frankfurt horizontalplane. No statistically significant (p>0.05) differences between the left and right side AEI were foundbetween MP skulls and RP skulls. The mean value of MP AEI was 45.5, with a range of 20.9-64.The mean RP AEI value was steeper (61.99), with a range of 30-94. Difference between the meanMP and RP AEI values was statistically significant (p<0.05). Values of AEI vary a lot. Nonsignificantdifferences between the left and right side AEI confirmed the natural left-right side asymmetry. Thevalues of AEI differ between the RP and MP groups, most probably due to different type of foodconsumption in medieval time, and consequently different masticatory loads and forces. PMID- 29116722 TI - Review of antibiotic use in respiratory disorders at a regional hospital in Queensland. AB - tAdherence to antibiotic guidelines has been shown to improve outcomes in several clinical situations.Respiratory conditions are a major cause of mortality and morbidity in Queensland. A recent study showedlow levels of compliance with antibiotic guidelines in a Queensland metropolitan hospital. We undertookan audit of antibiotic use in a regional Queensland hospital against Therapeutic Guideline recommenda-tions. Therapeutic Guideline recommendations were followed in 16% of cases with ceftriaxone the mostcommonly prescribed. Re-admission rate within 28 days was for 53%, 26%, 11% and 5% respectively forceftriaxone, benzylpenicillin, amoxicillin/clavulanate and ceftriaxone combined doxycycline. Less thanhalf of patients treated for pneumonia had concordant radiographic changes. Admission via the emer-gency department may be a factor in the preference for intravenous injection of ceftriaxone and presenceof non-infective co-morbidities may also contribute to re-admissions. Considerable challenges exist inimproving compliance with antibiotic guidelines which can improve patient outcomes and antibioticstewardship. PMID- 29116720 TI - The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy AB - Epilepsy is the most common neurological complication in pregnancy. Womenwith epilepsy have a higher risk of complications in pregnancy. In Croatia, women with epilepsy aretreated by neurologists at tertiary centers according to the place of residence. We prospectivelyfollowed-up pregnancies in women with epilepsy and healthy controls, and analyzed the factorsresponsible for their delivery outcomes and development of their babies. Healthy pregnant womenhad a higher level of education and economic status, but pregnant women with epilepsy took folic acidin a higher proportion than controls, possibly due to timely preconception counseling. Complicationsduring pregnancy depended on the number of antiepileptic drugs and epilepsy control. We noticedsome behavioral and cognitive aspects in children exposed in utero to valproic acid, which requiredfollow up. The rate of congenital malformations was not increased. In conclusion, women with epilepsyshould receive preconception counseling about the risk for pregnancy, but also about the possibilitiesto minimize that risk. We have introduced a model of integrative management of pregnancyand epilepsy based on close collaboration among different clinical experts in Croatia, in order toprovide prompt counseling and timely intervention. PMID- 29116724 TI - Giving voicetooptimismandhopeforthefutureofnursing. PMID- 29116723 TI - Tailor treatment to the patient with neuropathic pain. AB - Neuropathic pain can be considered to be a clinical syndrome with multiple causes ranging from damage to peripheral nerve pathways as the level of peripheral nociceptors to abnormalities in the cortical neurons in the brain. It is defined as pain that is caused by a lesion or disease of the somatosensory nervous system and is estimated to affect 6-8% of the general population. A low threshold of suspicion in conditions associates with neuropathic pain can aid diagnosis. Data from the past decade suggest that it is found in 16-26% of patients with diabetes, 8% of patients suffering from shingles in the past three months (increasing to 40% and 75% in patients aged over 50 and 75 respectively), and 10 50% of patients following surgery. Typical neuropathic descriptors include burning, shooting electric shock pain with numbness, pins and needles or itching. After general and neurological examination the focus should turn to the affected pain area using an unaffected body part as a control. Sensory response to cotton wool, pinprick, temperature and vibration should all be assessed. This will identify the positive and negative signs found in neuropathic pain. Tinel's sign and Phalen's sign, although classically taught, have such poor sensitivity and specificity that GPs are no longer encouraged to rely on them, and they should not be used. Neuropathic pain is often poorly responsive to conventional analgesia with the mainstay of treatment being anticonvulsant and antidepressant medication. Multidisciplinary assessment and management in the specialist setting of the pain clinic is often requires. PMID- 29116726 TI - Telemonitoring is acceptable amongst community dwelling older Australians with chronic conditions. AB - Background: Telemonitoring is an innovative model of care being implemented to address thegrowing burden of chronic and complex disease. Objectives: This paper explores the perceptions of community dwelling older people withchronic and complex conditions towards a general practice nurse-led telemonitoring interven tion. Method: A pre-test post-test intervention study was conducted with consumer surveys adminis-tered before and after the intervention. The telemonitoring intervention consisted of a periodof home monitoring during which daily vital signs and symptoms were transmitted to the generalpractice nurse. Results: 21 participants completed both pre and post-test surveys. There was a significant dif-ference between pre and post ratings on the survey item ''the use of telemonitoring equipmentseems difficult to me'' (p = 0.013), and ''telemonitoring will be a standard way of health caredelivery in the future'' (p = 0.032). Approximately half of the participants reported that tele-monitoring provided them with a sense of security and peace of mind, assisted them to managetheir health, in addition to improving their confidence in managing their care. Most participants felt more involved and expressed that daily monitoring helped them to understand changes intheir condition. Conclusion: Telemonitoring is acceptable to Australian community dwelling older persons withchronic conditions. Prior experience with computers and technology may not be a meditatingfactor in acceptability. The use of telemonitoring not only provided important physiological infor-mation to health professionals but also has the potential to empower older people by allowingthem to better understand their own health. PMID- 29116728 TI - The Resident Surgeon Phacoemulsification Learning Curve at Clinical Department of Ophthalmology, Sestre Milosrdnice University Hospital Center AB - The aim of the study was to analyze the resident learning process of phacoemulsificationcataract surgery and to assess the resident phacoemulsification learning curve. This prospectivestudy comprised 86 consecutive cases of phacoemulsification performed using standard technique byeight residents over a one-year period at Clinical Department of Ophthalmology, Sestre milosrdniceUniversity Hospital Center in Zagreb. Operative data on each case included resident and attendingsurgeon, date of operation, step-by-step success questionnaire, and intraoperative complications. Postoperativedata included visual acuity at one-month postoperative visit and postoperative complications.Eighty-six operations were performed under the supervision of attending surgeon. The meanbest-corrected visual acuity improved from 0.47+/-0.25 to 0.8+/-0.25 postoperatively. Intraoperativecomplications occurred in 13 (15.12%) cases and continued to decrease throughout residency training.The mean number of individually performed steps per operation increased throughout residency (from7.6 to 9.0). There was one early postoperative complication, endophthalmitis, which was successfullytreated, and no other postoperative complications occurred. Resident surgical competency can beimproved by maximizing the number of cataract procedures since the complication rates and thenumber of individually performed steps improved continuously with increasing surgical experience. PMID- 29116729 TI - Diagnosis and management of motor neurone disease. AB - Motor neurone disease is a rapidly progressive and fatal neurodegenerative condition which causes progressive weakness, with normal sensation. It can occur at any age but is more frequent with increasing age. Key clinical presentations include bulbar (slurred or difficult speech, problems swallowing, tongue fasciculation), limb (typically in one limb with weakness and muscle wasting), respiratory (breathlessness, chest muscle fasciculation) and cognitive features (behavioural change, emotional lability, features of frontotemporal dementia). Although survival is typically three to five years from symptom onset, there is significant individual variation. Rarely, survival may be 20 years or longer. Favourable features include a limb rather than a bulbar presentation, preserved weight and respiratory function, younger age of onset and longer time from fist symptom to diagnosis. The patient should be linked to a multidisciplinary team able to provide support from the start with a designated individual as the point of contact, with regular, coordinated assessments, as the patient's needs change and their condition progresses. Gastrostomy is an important supportive intervention which maximizes nutrition, and minimizes aspiration and chest infection. Adequate nutrition and hydration is key to maximizing health and survival. It is possible for a patient to control a computer and speech by eye. movement alone. An important consideration is voice banking where the patient may store their voice before there is difficulty with speech so that it can be used at a later stage if they need a communication aid. Impaired cough and retention of respiratory secretions is frequent in the later stages, and may be managed with physiotherapy. The patient should be referred for expert respiratory assessment if needed. PMID- 29116730 TI - Set individualized targets for patients with type 2 diabetes. AB - Type 2 diabetes is a chronic, progressive, metabolic disorder caused by defects in insulin secretion and action resulting in hyperglycaemia. Fasting blood glucose, random blood glucose, the oral glucose tolerance test and glycated haemoglobin (HbA1c) tests are all used in diagnosis. In patients with impaired fasting glucose, impaired glucose tolerance or prediabetes there are minor variations in the risk of developing overt diabetes. The mainstay of management is lifestyle intervention i.e. diet and physical activity aiming for at least 5% weight loss for all these three states which can halve the risk of developing type 2 diabetes. Structured education is an integral part of diabetes care and this should be provided at diagnosis. Nutritional advice from a dietitian is essential. Regular physical activity totalling 30 minutes most days of the week improves muscle insulin sensitivity, lipid profile and blood pressure although a total of 60-75 minutes a day is required for reduction in body weight and better metabolic profiles. NICE guidelines acknowledge the need for individualised treatment targets. Lowering HbA1c is beneficial in reducing microvascular complications and may have macrovascular benefits in the long term. However, intensive glycaemic control in the elderly with more advanced disease may not have similar benefits and poses a risk due to hypoglycaemia. PMID- 29116736 TI - Initial Clinical Experience with Ahmed Valve Implantation in Refractory Pediatric Glaucoma AB - The purpose is to report on the safety and efficacy of Ahmed Glaucoma Valve(AGV, New World Medical, Inc., Rancho Cucamonga, CA, USA) implantation for the managementof refractory pediatric glaucoma observed during one-year follow up period. A retrospective chartreview was conducted on 10 eyes, all younger than 11 years, with pediatric glaucoma that underwentAGV implantation for medicamentously uncontrolled intraocular pressure (IOP) between 2010 and2014. Outcome measures were control of IOP below 23 mm Hg (with or without antiglaucomamedications) and changes in visual acuity. Complications were recorded. After AGV implantation,IOP values ranged from 18 mm Hg to 23 mm Hg (except for one eye with postoperative hypotoniadue to suprachoroid hemorrhage, where the postoperative IOP value was 4 mm Hg). The number ofantiglaucoma medications was reduced, i.e. four patients had two medications, one patient had onemedication, and the others did not need antiglaucoma medication on the last follow-up visit. One eyehad suprachoroid hemorrhage, one eye had long-term persistent uveitic membrane, and two eyes hadtube-cornea touch. In conclusion, AGV implantation appears to be a viable option for the managementof refractory pediatric glaucoma and shows success in IOP control. However, there was a relativelyhigh complication rate limiting the overall success rate. PMID- 29116737 TI - Osteoinduction by Foamed and 3D-Printed Calcium Phosphate Scaffolds: Effect of Nanostructure and Pore Architecture. AB - Some biomaterials are osteoinductive, that is, they are able to trigger the osteogenic process by inducing the differentiation of mesenchymal stem cells to the osteogenic lineage. Although the underlying mechanism is still unclear, microporosity and specific surface area (SSA) have been identified as critical factors in material-associated osteoinduction. However, only sintered ceramics, which have a limited range of porosities and SSA, have been analyzed so far. In this work, we were able to extend these ranges to the nanoscale, through the foaming and 3D-printing of biomimetic calcium phosphates, thereby obtaining scaffolds with controlled micro- and nanoporosity and with tailored macropore architectures. Calcium-deficient hydroxyapatite (CDHA) scaffolds were evaluated after 6 and 12 weeks in an ectopic-implantation canine model and compared with two sintered ceramics, biphasic calcium phosphate and beta-tricalcium phosphate. Only foams with spherical, concave macropores and not 3D-printed scaffolds with convex, prismatic macropores induced significant ectopic bone formation. Among them, biomimetic nanostructured CDHA produced the highest incidence of ectopic bone and accelerated bone formation when compared with conventional microstructured sintered calcium phosphates with the same macropore architecture. Moreover, they exhibited different bone formation patterns; in CDHA foams, the new ectopic bone progressively replaced the scaffold, whereas in sintered biphasic calcium phosphate scaffolds, bone was deposited on the surface of the material, progressively filling the pore space. In conclusion, this study demonstrates that the high reactivity of nanostructured biomimetic CDHA combined with a spherical, concave macroporosity allows the pushing of the osteoinduction potential beyond the limits of microstructured calcium phosphate ceramics. PMID- 29116738 TI - Unique Hierarchical Mo2C/C Nanosheet Hybrids as Active Electrocatalyst for Hydrogen Evolution Reaction. AB - A facile and effective pyrolysis stratagem is proposed for the synthesis of hierarchical Mo2C/C nanosheet hybrids with sodium chloride (NaCl) crystals as a template. Large numbers of well-dispersed sheet-like Mo2C nanoparticles with the thickness of about 20 nm were anchored on the surface of carbon nanosheets. Benefiting from the ideal synergistic catalytic effect between the highly active sheet-like Mo2C nanoparticles and the conductive graphitic carbon, and strong charge transfer ability, the unique hierarchical sheet-like structure of Mo2C/C hybrids demonstrated excellent hydrogen evolution reaction (HER) performance in both alkaline and acid medias with small overpotential (125 mV for 10 mA cm-2 in 1 M KOH and 180 mV for 10 mA cm-2 in 0.5 M H2SO4) and remarkable stability, which is comparable to most reported non-noble metal HER electrocatalysts. With the simplicity and low-cost of the synthetic approach, the strategy presented here can be extendable to the preparation of other transition metal-based/carbon nanosheet hybrids for versatile applications. PMID- 29116739 TI - Gold Nanocluster-Mediated Cellular Death under Electromagnetic Radiation. AB - Gold nanoclusters (Au NCs) have become a promising nanomaterial for cancer therapy because of their biocompatibility and fluorescent properties. In this study, the effect of ultrasmall protein-stabilized 2 nm Au NCs on six types of mammalian cells (fibroblasts, B-lymphocytes, glioblastoma, neuroblastoma, and two types of prostate cancer cells) under electromagnetic radiation is investigated. Cellular association of Au NCs in vitro is concentration-dependent, and Au NCs have low intrinsic toxicity. However, when Au NC-incubated cells are exposed to a 1 GHz electromagnetic field (microwave radiation), cell viability significantly decreases, thus demonstrating that Au NCs exhibit specific microwave-dependent cytotoxicity, likely resulting from localized heating. Upon i.v. injection in mice, Au NCs are still present at 24 h post administration. Considering the specific microwave-dependent cytotoxicity and low intrinsic toxicity, our work suggests the potential of Au NCs as effective and safe nanomedicines for cancer therapy. PMID- 29116740 TI - Electrochemical Hydrogen Storage in Facile Synthesized Co@N-Doped Carbon Nanoparticle Composites. AB - A Co@nitrogen-doped carbon nanoparticle composite was synthesized via a facile molecular self-assembling procedure. The material was used as the host for the electrochemical storage of hydrogen. The hydrogen storage capacity of the material was over 300 mAh g-1 at a rate of 100 mAg-1. It also exhibited superior stability for storage of hydrogen, high rate capability, and good cyclic life. Hybridizing metallic cobalt nanoparticle with nitrogen-doped mesoporous carbon is found to be a good approach for the electrochemical storage of hydrogen. PMID- 29116741 TI - High-Performance Poly(lactic-co-glycolic acid)-Magnetic Microspheres Prepared by Rotating Membrane Emulsification for Transcatheter Arterial Embolization and Magnetic Ablation in VX2 Liver Tumors. AB - Interventional embolization is a popular minimally invasive vascular therapeutic technique and has been widely applied for hepatocellular carcinoma (HCC) therapy. However, harmful effects caused by transcatheter arterial chemoembolization (TACE) and radioembolization, such as the toxicity of chemotherapy or excessive radiation damage, are serious disadvantages and significantly reduce the therapeutic efficacy. Here, a synergistic therapeutic strategy combined transcatheter arterial embolization and magnetic ablation (TAEMA) by using poly(lactic-co-glycolic acid) (PLGA)-magnetic microspheres (MMs) has been successfully applied to orthotopic VX2 liver tumors of rabbits. These MMs fabricated by novel rotating membrane emulsification system with well-controlled sizes (100-1000 MUm) exhibited extremely low hemolysis ratio and excellent biocompatibility with HepG2 cells and L02 cells. Moreover, experimental results demonstrated that, while exposed to alternating magnetic field (AMF) after TAE, the tumor edge could be heated up by more than 15 degrees C both in vivo and in vitro, whereas only a negligible increase of temperature was observed in the normal hepatic parenchyma (NHP) nearby. Sufficient temperature increase induces apoptosis of tumor cells. This can further inhibit the tumor angiogenesis and results in necrosis compared to the rabbits only treated with TAE. In stark contrast, tumors rapidly grow and subtotal metastasis occurs in the lungs or kidneys, causing severe complications for rabbits only irradiated under AMF. Importantly, the results from the biochemical examination and the gene expression of relative HCC markers further confirmed that the treatment protocol using PLGA MMs could achieve good biosafety and excellent therapeutic efficacy, which are promising for liver cancer therapy. PMID- 29116742 TI - Controllable Evolution of Dual Defect Zni and VO Associate-Rich ZnO Nanodishes with (0001) Exposed Facet and Its Multiple Sensitization Effect for Ethanol Detection. AB - Building an effective way for finding the role of surface defects in gas sensing property remains a big challenge. In the present work, we synthesized the ZnO nanodishes (NDs) and first explored the formation process of rich electron donor surface defects by means of studying mechanism for the ZnO NDs synthesis. The test results revealed that ZnO-6, added by 6 mmol Zn powder, had the best gas sensing properties with the excellent selectivity to ethanol than the others. Specially, the ZnO-6 sensor exhibited the best response (about 49) to 100 ppm ethanol at 230 degrees C among four as-synthesized samples, while noncustomized ZnO was only 28. It was mainly caused by the following two reasons: the exposure of target (0001) crystal facet and rich electron donor surface defects zinc interstitial (Zni) and oxygen vacancy (VO). As a guide, the formation process of surface defects was revealed by an ideal defect model. By the small-angle XRD and TEM patterns, we could conclude that ZnO NDs, changing stoichiometric ratio, increased the content of Zni by adding Zn powder, while excessive Zn powder promoted the growth of c axis of ZnO NDs in the self-assembly engineering. Besides, a depletion model has been provided to explain how the surface defects work on the sensors and the complex mechanism of gas sensing performance. These findings will develop the application of ZnO-based gas sensor in health and security. PMID- 29116743 TI - A 3D Printable and Mechanically Robust Hydrogel Based on Alginate and Graphene Oxide. AB - Sodium alginate (SA) was used for the first time to noncovalently functionalize amino-graphene oxide (aGO) to produce the SA-functionalized GO, A-aGO. A-aGO was then filled into a double-network (DN) hydrogel consisting of an alginate network (SA) and a polyacrylamide (PAAm) network. Before UV curing, A-aGO was able to provide the SA/PAAm DN hydrogel with a remarkable thixotropic property, which is desirable for 3D printing. Thus, the A-aGO-filled DN hydrogel could be nicely used as an "ink" of a 3D printer to print complicated 3D structures with a high stackability and high shape fidelity. After UV curing, the 3D-printed A-aGO filled DN hydrogel showed robust mechanical strength and great toughness. For the function of A-aGO it was considered that A-aGO acted as a secondary but physical cross-linker, not only to give the hydrogel a satisfactory thixotropic property but also to increase the energy dissipation by combining the physical SA network and the chemical PAAm network. As an exciting result we successfully developed a 3D printable and mechanically robust hydrogel. PMID- 29116744 TI - Transforming a Simple Commercial Glue into Highly Robust Superhydrophobic Surfaces via Aerosol-Assisted Chemical Vapor Deposition. AB - Robust superhydrophobic surfaces were synthesized as composites of the widely commercially available adhesives epoxy resin (EP) and polydimethylsiloxane (PDMS). The EP layer provided a strongly adhered micro/nanoscale structure on the substrates, while the PDMS was used as a post-treatment to lower the surface energy. In this study, the depositions of EP films were taken at a range of temperatures, deposition times, and substrates via aerosol-assisted chemical vapor deposition (AACVD). A novel dynamic deposition temperature approach was developed to create multiple-layered periodic micro/nanostructures that significantly improved the surface mechanical durability. Water droplet contact angles (CA) of 160 degrees were observed with droplet sliding angles (SA) frequently <1 degrees . A rigorous sandpaper abrasion test demonstrated retention of superhydrophobic properties and superior robustness therein, while wear, anticorrosion (pH = 1-14, 72 h), and UV testing (365 nm, 3.7 mW/cm2, 120 h) were carried out to exhibit the environmental stability of the films. Self-cleaning behavior was demonstrated in clearing the surfaces of various contaminating powders and aqueous dyes. This facile and flexible method for fabricating highly durable superhydrophobic polymer films points to a promising future for AACVD in their scalable and low-cost production. PMID- 29116745 TI - Nanotopographic Regulation of Human Mesenchymal Stem Cell Osteogenesis. AB - Mesenchymal stem cell (MSC) differentiation can be manipulated by nanotopographic interface providing a unique strategy to engineering stem cell therapy and circumventing complex cellular reprogramming. However, our understanding of the nanotopographic-mechanosensitive properties of MSCs and the underlying biophysical linkage of the nanotopography-engineered stem cell to directed commitment remains elusive. Here, we show that osteogenic differentiation of human MSCs (hMSCs) can be largely promoted using our nanoengineered topographic glass substrates in the absence of dexamethasone, a key exogenous factor for osteogenesis induction. We demonstrate that hMSCs sense and respond to surface nanotopography, through modulation of adhesion, cytoskeleton tension, and nuclear activation of TAZ (transcriptional coactivator with PDZ-binding motif), a transcriptional modulator of hMSCs. Our findings demonstrate the potential of nanotopographic surfaces as noninvasive tools to advance cell-based therapies for bone engineering and highlight the origin of biophysical response of hMSC to nanotopography. PMID- 29116746 TI - Zincke's Salt-Substituted Tetraphenylethylenes for Fluorometric Turn-On Detection of Glutathione and Fluorescence Imaging of Cancer Cells. AB - In this paper, we report Zincke's salt-substituted tetraphenylethylenes 1a and 1b with Cl- and PF6- as counteranions, respectively. The crystal structure of 1b was determined. Both 1a and 1b are almost nonemissive even in the aggregated states. This is attributed to the photoinduced electron transfer from 2,2-bis(4 methoxyphenyl)-1-phenylvinyl-phenyl unit to 1-(2,4-dinitrophenyl) pyridinium unit within 1a and 1b. The results demonstrate that the emissions of 1a and 1b in aqueous solution can be switched on upon either reaction with GSH or light irradiation. On the basis of the reaction between 1a and GSH, 1a can be utilized for the fluorescence turn-on detection of GSH selectively, and GSH with concentration as low as 36.9 nM can be detected. The transformation of 1b into 2 under light irradiation results in the fluorescence imaging of Hela and U2OS cells and phototoxicity toward Hela and U2OS cells after the protonation of pyridine unit in 2 because of the acidic environment of tumor cells. Aggregates of 1b can be up-taken by Hela and U2OS cells and fluorescence imaging has been successfully recorded with CLSM. Moreover, the protonated form of 2 can function as photosensitizer and 1b shows phototoxicity toward tumor cells such as Hela and U2OS cells. PMID- 29116747 TI - Paperfluidic Chip Device for Small RNA Extraction, Amplification, and Multiplexed Analysis. AB - Small RNAs have been considered as potential biomarkers of various human diseases. Sensitive and multiplexed determination of small RNAs with point-of care (POC) assay would be of great significance. Herein, an integrated paperfluidic chip device for multiplexed small RNA analysis was developed for the first time. In this system, the extraction and purification of small RNA was completed through a poly(ether sulfone) (PES) paper chip without the need for centrifugation. Subsequently, a newly designed hairpin probe-exponential amplification reaction (HP-EXPAR) was directly performed within the extraction paper chip. For the simultaneous realization of multiple detection, a multilayer paper chip was designed in a foldable manner with more portability and usability. Quantum dots (QDs) were employed as signal labels, which endowed this assay with high optical detection efficiency. Moreover, magnetic sheets were introduced as an alternative method for layer stacking, not only guaranteeing adjacent layers are in contact but also facilitating the sample dispersion. With these outstanding characteristics, our platform obtained a satisfactory sensitivity range from 3 * 105 to 3 * 108 copies with a limit of 3 * 106 copies. Additionally, the multiplex small RNA analyses from various cancer cells were in good agreement with the results of the real-time polymerase chain reaction (qRT PCR). More importantly, simultaneous analysis of two types of miRNAs from clinical tumor samples demonstrated the clinical applicability of the system. Therefore, the proposed paper-based device shows great promise for POC applications in the future. PMID- 29116748 TI - MnO2-Functionalized Co-P Nanocomposite: A New Theranostic Agent for pH-Triggered T1/T2 Dual-Modality Magnetic Resonance Imaging-Guided Chemo-photothermal Synergistic Therapy. AB - Construction of stimuli-responsive theranostic nanoagents that can increase the accuracy of imaging diagnosis and boost the therapeutic efficacy has been demonstrated for a promising approach for diagnosis and treatment of cancer. Herein, we constructed a novel theranostic agent with Co-P nanocomposites as core, mesoporous silica as shell, and manganese dioxide (MnO2) nanosheets as gatekeeper, which have been employed for pH-activatable T1/T2 dual-modality magnetic resonance imaging (MRI)-guided chemotherapeutical and photothermal combination anticancer therapy in vitro and in vivo. Co-P core-enabled theranostic platform could be applied for both photothermal therapy and T2 weighted MRI in the normal circulation owing to its strong near-infrared absorbance and intrinsic magnetic properties. In the acidic environment of tumors, MnO2 cap could be dissolved into Mn2+ ions to not only realize pH responsive on-demand drug release but also activate T1-weighted MRI contrast enhancement. Such T1/T2 dual-mode MR imaging provides further comprehensive details and accurate information for tumor diagnosis, and the on-demand chemo photothermal synergetic therapy greatly improved the therapeutic effectiveness and effectively mitigated side effects. These findings demonstrate that Co P@mSiO2@DOX-MnO2 are promising as pH-responsive theranostic agents for tumor diagnosis and treatment, and stimulate interest in exploration of novel stimuli responsive theranostic nanoagents which posssess good potential for clinical application in the future. PMID- 29116749 TI - Direct LC-MS/MS Detection of Guanine Oxidations in Exon 7 of the p53 Tumor Suppressor Gene. AB - Oxidation of DNA by reactive oxygen species (ROS) yields 8-oxo-7,8 dihydroguanosine (8-oxodG) as primary oxidation product, which can lead to downstream G to T transversion mutations. DNA mutations are nonrandom, and mutations at specific codons are associated with specific cancers, as widely documented for the p53 tumor suppressor gene. Here, we present the first direct LC-MS/MS study (without isotopic labeling or hydrolysis) of primary oxidation sites of p53 exon 7. We oxidized a 32 base pair (bp) double-stranded (ds) oligonucleotide representing exon 7 of the p53 gene. Oxidized oligonucleotides were cut by a restriction endonuclease to provide small strands and enable positions and amounts of 8-oxodG to be determined directly by LC-MS/MS. Oxidation sites on the oligonucleotide generated by two oxidants, catechol/Cu2+/NADPH and Fenton's reagent, were located and compared. Guanines in codons 243, 244, 245, and 248 were most frequently oxidized by catechol/Cu2+/NADPH with relative oxidation of 5.6, 7.2, 2.6, and 10.7%, respectively. Fenton's reagent oxidations were more specific for guanines in codons 243 (20.3%) and 248 (10.4%). Modeling of docking of oxidizing species on the ds-oligonucleotide were consistent with the experimental codon oxidation sites. Significantly, codons 244 and 248 are mutational "hotspots" in nonsmall cell and small cell lung cancers, supporting a possible role of oxidation in p53 mutations leading to lung cancer. PMID- 29116750 TI - Surface Charges on CdSe-Dot/CdS-Rod Nanocrystals: Measuring and Modeling the Diffusion of Exciton-Fluorescence Rates and Energies. AB - By performing spectroscopic single-particle measurements at cryogenic temperatures over the course of hours, we study both the spectral diffusion as well as the diffusion of the decay rates of the fluorescence emission of core/shell CdSe/CdS dot/rod nanoparticles. A special analysis of the measurements allows for a correlation of data for single neutral excitons only, undisturbed by the possible emission of other excitonic complexes. We find a nearly linear dependency of the fluorescence decay rate on the emission energy. The experimental data are compared to self-consistent model calculations within the effective-mass approximation, in which migrating point charges set onto the surface of the nanoparticles have been assumed to cause the temporal changes of optical properties. These calculations reveal a nearly linear relationship between the squared electron-hole wave function overlap, which is linked to the experimentally determined fluorescence rate, and the exciton emission energy. Within our model, single migrating surface charges are not sufficient to fully explain the measured rather broad ranges of emission rates and energies, while two-and in particular negative-surface charges close to the core of the DR induce large enough shifts. Importantly, for our nanoparticle system, the surface charges more strongly affect the hole wave function than the electron wave function and both wave functions are still localized within the dot-like core of the nanoparticle, showing that the type-I character of the band alignment between core and shell is preserved. PMID- 29116751 TI - Discovery of High-Temperature Superconductivity (Tc = 55 K) in B-Doped Q-Carbon. AB - We have achieved a superconducting transition temperature (Tc) of 55 K in 27 at% B-doped Q-carbon. This value represents a significant improvement over previously reported Tc of 36 K in B-doped Q-carbon and is the highest Tc for conventional BCS (Bardeen-Cooper-Schrieffer) superconductivity in bulk carbon-based materials. The B-doped Q-carbon exhibits type-II superconducting characteristics with Hc2(0) ~ 10.4 T, consistent with the BCS formalism. The B-doped Q-carbon is formed by nanosecond laser melting of B/C multilayered films in a super undercooled state and subsequent quenching. It is determined that ~67% of the total boron exists with carbon in a sp3 hybridized state, which is responsible for the substantially enhanced Tc. Through the study of the vibrational modes, we deduce that higher density of states near the Fermi level and moderate to strong electron-phonon coupling lead to a high Tc of 55 K. With these results, we establish that heavy B doping in Q-carbon is the pathway for achieving high-temperature superconductivity. PMID- 29116752 TI - Nonoptical Detection of Allergic Response with a Cell-Coupled Gate Field-Effect Transistor. AB - In this study, we report the label-free and reliable detection of allergic response using a cell-coupled gate field-effect transistor (cell-based FET). Rat basophilic leukemia (RBL-2H3) cells were cultured as a signal transduction interface to induce allergic reaction on the gate oxide surface of the FET, because IgE antibodies, which bind to Fcepsilon receptors at the RBL-2H3 cell membrane, are specifically cross-linked by allergens, resulting in the allergic response of RBL-2H3 cells. In fact, the surface potential at the FET gate decreased owing to secretions such as histamine from the IgE-bound RBL-2H3 cells, which reacted with the allergen. This is because histamine, as one of the candidate secretions, shows basicity, resulting in a change in pH around the cell/gate interface. That is, the RBL-2H3-cell-based FET used in this study was originally from an ion-sensitive FET (ISFET), whose oxide surface (Ta2O5) with hydroxyl groups is fully responsive to pH on the basis of the equilibrium reaction. The allergic response of RBL-2H3 cells on the gate was also confirmed by estimating the amount of beta-hexosaminidase released together with histamine and was analyzed using the electrical properties based on an inflammatory response of secreted histamine with the vascular endothelial cell-based FET. Thus, the allergic responses were monitored in a nonoptical and real-time manner using the cell-based FETs with the cellular layers on the gate, which reproduced the in vivo system and were useful for the reliable detection of the allergic reaction. PMID- 29116753 TI - Self-Assembled Colloidal Gel Using Cell Membrane-Coated Nanosponges as Building Blocks. AB - Colloidal gels consisting of oppositely charged nanoparticles are increasingly utilized for drug delivery and tissue engineering. Meanwhile, cell membrane coated nanoparticles are becoming a compelling biomimetic system for innovative therapeutics. Here, we demonstrate the successful use of cell membrane-coated nanoparticles as building blocks to formulate a colloidal gel that gelates entirely based on material self-assembly without chemical cross-linking. Specifically, we prepare red blood cell membrane-coated nanosponges and mix them with an appropriate amount of cationic nanoparticles, resulting in a spontaneously formed gel-like complex. Rheological test shows that the nanosponge colloidal gel has pronounced shear-thinning property, which makes it an injectable formulation. The gel formulation not only preserves the nanosponges' toxin neutralization capability but also greatly prolongs their retention time after subcutaneous injection into mouse tissue. When tested in a mouse model of subcutaneous group A Streptococcus infection, the nanosponge colloidal gel shows significant antibacterial efficacy by markedly reducing skin lesion development. Overall, the nanosponge colloidal gel system is promising as an injectable formulation for therapeutic applications such as antivirulence treatment for local bacterial infections. PMID- 29116754 TI - Defects and Surface Structural Stability of MoTe2 Under Vacuum Annealing. AB - Understanding the structural stability of transition-metal dichalcogenides is necessary to avoid surface/interface degradation. In this work, the structural stability of 2H-MoTe2 with thermal treatments up to 500 degrees C is studied using scanning tunneling microscopy and scanning transmission electron microscopy. On the exfoliated sample surface at room temperature, atomic subsurface donors originating from excess Te atoms are observed and presented as nanometer-sized, electronically-induced protrusions superimposed with the hexagonal lattice structure of MoTe2. Under a thermal treatment as low as 200 degrees C, the surface decomposition-induced cluster defects and Te vacancies are readily detected and increase in extent with the increasing temperature. Driven by Te vacancies and thermal energy, intense 60 degrees inversion domain boundaries form resulting in a "wagon wheel" morphology after 400 degrees C annealing for 15 min. Scanning tunneling spectroscopy identified the electronic states at the domain boundaries and the domain centers. To prevent extensive Te loss at higher temperatures, where Mo6Te6 nanowire formation and substantial desorption-induced etching effects will take place simultaneously, surface and edge passivation with a monolayer graphene coverage on MoTe2 is tested. With this passivation strategy, the structural stability of MoTe2 is greatly enhanced up to 500 degrees C without apparent structural defects. PMID- 29116755 TI - The Capture of Cadmium by Reactive Polysulfides Attenuates Cadmium-Induced Adaptive Responses and Hepatotoxicity. AB - Cadmium (Cd) is an environmental electrophile that modifies protein nucleophiles, thereby modulating cellular signaling and toxicity. While reactive persulfides/polysulfides exhibit relatively high nucleophilic properties, their roles in the altered gene expression and toxicity caused by Cd remain unclear. Exposing primary mouse hepatocytes to Cd caused heat shock protein 70 (HSP70) and metallothionein (MT)-I/II to be upregulated and cytotoxicity to occur. These effects were blocked in the presence of polysulfide sodium tetrasulfide (Na2S4). Electrospray ionization mass spectrometry analysis indicated that cadmium sulfide (CdS) and cadmium thiosulfate (CdS2O3) were produced when Cd reacted with Na2S4. Authentic CdS did not cause cellular signaling responses to be activated or hepatotoxic effects, while CdS2O3 had effects similar to those of Cd. HSP70 and MT-I/II upregulation and hepatotoxicity caused by exposure to Cd were significantly enhanced by the deletion of cystathionine gamma-lyase (CSE), which catalyzes the formation of reactive persulfides/polysulfides. Deleting CSE also exacerbated Cd-mediated liver injury, whereas little hepatic damage was found when CdS or Na2S4 along with Cd was administered. Overall, the results suggest that the persulfide/polysulfide-mediated formation of sulfur adducts of Cd such as CdS rather than CdS2O3 is, at least in part, involved in decreasing the level of Cd-mediated activation of cellular signaling and toxicity. PMID- 29116756 TI - Advances in Solid Phase Microextraction and Perspective on Future Directions. PMID- 29116757 TI - (-)ESI/CAD MSn Procedure for Sequencing Lignin Oligomers Based on a Study of Synthetic Model Compounds with beta-O-4 and 5-5 Linkages. AB - Seven synthesized G-lignin oligomer model compounds (ranging in size from dimers to an octamer) with 5-5 and/or beta-O-4 linkages, and three synthesized S-lignin model compounds (a dimer, trimer, and tetramer) with beta-O-4 linkages, were evaporated and deprotonated using negative-ion mode ESI in a linear quadrupole ion trap/Fourier transform ion cyclotron resonance mass spectrometer. The collision-activated dissociation (CAD) fragmentation patterns (obtained in MS2 and MS3 experiments, respectively) for the negative ions were studied to develop a procedure for sequencing unknown lignin oligomers. On the basis of the observed fragmentation patterns, the measured elemental compositions of the most abundant fragment ions, and quantum chemical calculations, the most important reaction pathways and likely mechanisms were delineated. Many of these reactions occur via charge-remote fragmentation mechanisms. Deprotonated compounds with only beta-O-4 linkages, or both 5-5 and beta-O-4 linkages, showed major 1,2-eliminations of neutral compounds containing one, two, or three aromatic rings. The most likely mechanisms for these reactions are charge-remote Maccoll and retro-ene eliminations resulting in the cleavage of a beta-O-4 linkage. Facile losses of H2O and CH2O were also observed for all deprotonated model compounds, which involve a previously published charge-driven mechanism. Characteristic "ion groups" and "key ions" were identified that, when combined with their CAD products (MS3 experiments), can be used to sequence unknown oligomers. PMID- 29116758 TI - Robust Stacking-Independent Ultrafast Charge Transfer in MoS2/WS2 Bilayers. AB - Van der Waals-coupled two-dimensional (2D) heterostructures have attracted great attention recently due to their high potential in the next-generation photodetectors and solar cells. The understanding of charge-transfer process between adjacent atomic layers is the key to design optimal devices as it directly determines the fundamental response speed and photon-electron conversion efficiency. However, general belief and theoretical studies have shown that the charge transfer behavior depends sensitively on interlayer configurations, which is difficult to control accurately, bringing great uncertainties in device designing. Here we investigate the ultrafast dynamics of interlayer charge transfer in a prototype heterostructure, the MoS2/WS2 bilayer with various stacking configurations, by optical two-color ultrafast pump-probe spectroscopy. Surprisingly, we found that the charge transfer is robust against varying interlayer twist angles and interlayer coupling strength, in time scale of ~90 fs. Our observation, together with atomic-resolved transmission electron characterization and time-dependent density functional theory simulations, reveals that the robust ultrafast charge transfer is attributed to the heterogeneous interlayer stretching/sliding, which provides additional channels for efficient charge transfer previously unknown. Our results elucidate the origin of transfer rate robustness against interlayer stacking configurations in optical devices based on 2D heterostructures, facilitating their applications in ultrafast and high-efficient optoelectronic and photovoltaic devices in the near future. PMID- 29116759 TI - Selective Binding to mRNA Duplex Regions by Chemically Modified Peptide Nucleic Acids Stimulates Ribosomal Frameshifting. AB - Minus-one programmed ribosomal frameshifting (-1 PRF) allows the precise maintenance of the ratio between viral proteins and is involved in the regulation of the half-lives of cellular mRNAs. Minus-one ribosomal frameshifting is activated by several stimulatory elements such as a heptameric slippery sequence (X XXY YYZ) and an mRNA secondary structure (hairpin or pseudoknot) that is positioned 2-8 nucleotides downstream from the slippery site. Upon -1 RF, the ribosomal reading frame is shifted from the normal zero frame to the -1 frame with the heptameric slippery sequence decoded as XXX YYY Z instead of X XXY YYZ. Our research group has developed chemically modified peptide nucleic acid (PNA) L and Q monomers to recognize G-C and C-G Watson-Crick base pairs, respectively, through major-groove parallel PNA.RNA-RNA triplex formation. L- and Q incorporated PNAs show selective binding to double-stranded RNAs (dsRNAs) over single-stranded RNAs (ssRNAs). The sequence specificity and structural selectivity of L- and Q-modified PNAs may allow the precise targeting of desired viral and cellular RNA structures, and thus may serve as valuable biological tools for mechanistic studies and potential therapeutics for fighting diseases. Here, for the first time, we demonstrate by cell-free in vitro translation assays using rabbit reticulocyte lysate that the dsRNA-specific chemically modified PNAs targeting model mRNA hairpins stimulate -1 RF (from 2% to 32%). An unmodified control PNA, however, shows nonspecific inhibition of translation. Our results suggest that the modified dsRNA-binding PNAs may be advantageous for targeting structured RNAs. PMID- 29116760 TI - Relative Propensities of Cytochrome c Oxidase and Cobalt Corrins for Reaction with Cyanide and Oxygen: Implications for Amelioration of Cyanide Toxicity. AB - In aqueous media at neutral pH, the binding of two cyanide molecules per cobinamide can be described by two formation constants, Kf1 = 1.1 (+/-0.6) * 105 M-1 and Kf2 = 8.5 (+/-0.1) * 104 M-1, or an overall cyanide binding constant of ~1 * 1010 M-2. In comparison, the cyanide binding constants for cobalamin and a fully oxidized form of cytochrome c oxidase, each binding a single cyanide anion, were found to be 7.9 (+/-0.5) * 104 M-1 and 1.6 (+/-0.2) * 107 M-1, respectively. An examination of the cyanide-binding properties of cobinamide at neutral pH by stopped-flow spectrophotometry revealed two kinetic phases, rapid and slow, with apparent second-order rate constants of 3.2 (+/-0.5) * 103 M-1 s-1 and 45 (+/-1) M-1 s-1, respectively. Under the same conditions, cobalamin exhibited a single slow cyanide-binding kinetic phase with a second-order rate constant of 35 (+/-1) M-1 s-1. All three of these processes are significantly slower than the rate at which cyanide is bound by complex IV during enzyme turnover (>106 M-1 s-1). Overall, it can be understood from these findings why cobinamide is a measurably better cyanide scavenger than cobalamin, but it is unclear how either cobalt corrin can be antidotal toward cyanide intoxication as neither compound, by itself, appears able to out-compete cytochrome c oxidase for available cyanide. Furthermore, it has also been possible to unequivocally show in head-to-head comparison assays that the enzyme does indeed have greater affinity for cyanide than both cobalamin and cobinamide. A plausible resolution of the paradox that both cobalamin and cobinamide clearly are antidotal toward cyanide intoxication, involving the endogenous auxiliary agent nitric oxide, is suggested. Additionally, the catalytic consumption of oxygen by the cobalt corrins is demonstrated and, in the case of cobinamide, the involvement of cytochrome c when present. Particularly in the case of cobinamide, these oxygen-dependent reactions could potentially lead to erroneous assessment of the ability of the cyanide scavenger to restore the activity of cyanide-inhibited cytochrome c oxidase. PMID- 29116762 TI - Formation of Hierarchical In2S3-CdIn2S4 Heterostructured Nanotubes for Efficient and Stable Visible Light CO2 Reduction. AB - We demonstrate rational design and fabrication of hierarchical In2S3-CdIn2S4 heterostructured nanotubes as efficient and stable photocatalysts for visible light CO2 reduction. The novel self-templated strategy, including sequential anion- and cation-exchange reactions, integrates two distinct sulfide semiconductors into hierarchical tubular hybrids with homogeneous interfacial contacts and ultrathin two-dimensional (2D) nanosheet subunits. Accordingly, the hierarchical heterostructured nanotubes facilitate separation and migration of photoinduced charge carriers, enhance the adsorption and concentration of CO2 molecules, and offer rich active sites for surface redox reactions. Benefiting from these structural and compositional features, the optimized hierarchical In2S3-CdIn2S4 nanotubes without employing noble metal cocatalysts in the catalytic system manifest remarkable performance for deoxygenative reduction of CO2 with high CO generation rate (825 MUmol h-1 g-1) and outstanding stability under visible light irradiation. PMID- 29116761 TI - Molecules That Can Rewire the Taste System. PMID- 29116763 TI - Interaction of Human Enteric Viruses with Microbial Compounds: Implication for Virus Persistence and Disinfection Treatments. AB - Although the interaction between phages and bacteria has already been well described, it only recently emerged that human viruses also interact with bacteria in the mammalian gut. We studied whether this interaction could occur in tap water and thus confer enteric viruses protection against temperature and the classical disinfection treatments used in drinking water production. We demonstrated that the addition of lipopolysaccharide or peptidoglycan of bacterial origin to enterovirus provides thermal protection through stabilization of the viral capsid. This interaction plays a role when viruses are exposed to disinfection that targets the capsid, but less so when the virus genome is directly targeted. The interaction seems to be serotype-specific, suggesting that the capsid protein sequence could be important. The protection is linked to a direct association between viral particles and bacterial compounds as observed by microscopy. These results show that bacterial compounds present in the environment can affect virus inactivation. PMID- 29116764 TI - Naturally Occurring Radioactive Materials in Uranium-Rich Coals and Associated Coal Combustion Residues from China. AB - Most coals in China have uranium concentrations up to 3 ppm, yet several coal deposits are known to be enriched in uranium. Naturally occurring radioactive materials (NORM) in these U-rich coals and associated coal combustion residues (CCRs) have not been well characterized. Here we measure NORM (Th, U, 228Ra, 226Ra, and 210Pb) in coals from eight U-rich coal deposits in China and the associated CCRs from one of these deposits. We compared NORM in these U-rich coals and associated CCRs to CCRs collected from the Beijing area and natural loess sediments from northeastern China. We found elevated U concentrations (up to 476 ppm) that correspond to low 232Th/238U and 228Ra/226Ra activity ratios (?1) in the coal samples. 226Ra and 228Ra activities correlate with 238U and 232Th activities, respectively, and 226Ra activities correlate well with 210Pb activities across all coal samples. We used measured NORM activities and ash yields in coals to model the activities of CCRs from all U-rich coals analyzed in this study. The activities of measured and modeled CCRs derived from U-rich coals exceed the standards for radiation in building materials, particularly for CCRs originating from coals with U > 10 ppm. Since beneficial use of high-U Chinese CCRs in building materials is not a suitable option, careful consideration needs to be taken to limit potential air and water contamination upon disposal of U- and Ra-rich CCRs. PMID- 29116765 TI - Mechanism of the Polymerization of rac-Lactide by Fast Zinc Alkoxide Catalysts. AB - The ring-opening transesterification polymerization (ROTEP) of rac-lactide (rac LA) using LXZn catalysts (LX = ligand having phenolate, amine, and pyridine donors with variable para substituents X on the bound phenolate donor; X = NO2, Br, t-Bu, OMe) was evaluated through kinetics experiments and density functional theory, with the aim of determining how electronic modulation of the ligand framework influences polymerization rate, selectivity, and control. After determination that zinc-ethyl precatalysts required 24 h of reaction with benzyl alcohol to convert to active alkoxide complexes, the subsequently formed species proved to be active and fairly selective, polymerizing up to 300 equiv of rac-LA in 6-10 min while yielding isotactic (Pm = 0.72-0.78) polylactide (PLA) with low dispersities: D = 1.06-1.17. In contrast to previous work with aluminum catalysts for which electronic effects of ligand substituents were significant (Hammett rho = +1.2-1.4), the LXZn systems exhibited much less of an effect (rho = +0.3). Density functional calculations revealed details of the initiation and propagation steps, enabling insights into the high isotacticity and the insensitivity of the rate on the identity of X. PMID- 29116766 TI - Probing the Influence of Acidity and Temperature to Th(IV) on Hydrolysis, Nucleation, and Structural Topology. AB - Systematic control of the molar ratio between thorium hydroxides and selenic acid and their reaction temperature under hydrothermal conditions results in four novel thorium-based selenate complexes, namely, [Th8O4(OH)8(SeO4)6(H2O)16].(SeO4)2.13H2O (Th-1), [Th8O4(OH)8(SeO4)8(H2O)13].7H2O (Th-2), Th(OH)2(SeO4)H2O (Th-3), and Th3(SeO4)6(H2O)6.2.5H2O (Th-4), as well as the thorium mixed selenite selenate compound Th(SeO3)(SeO4) (Th-5). Smaller [H2SeO4]/[Th(IV)] ratio or lower temperature give rise to the formation of octameric [Th8(MU3-O)4(MU2-OH)8]16+ cores in Th-1/Th-2 and infinite [Th(MU2 OH)2H2O]2+ chains in Th-3, respectively. Increasing the [H2SeO4]/[Th(IV)] ratio or elevating the temperature generates a microporous (11.3 A voids) open framework Th-4, a monomeric thorium species without oxo/hydroxyl ligands, and a three-dimensional thorium structure Th-5. Formation of these compounds suggests that variables including acidity and temperature play a critical role in the hydrolysis and oligomerization of ThIV ions. Increasing acidity limits the deprotonation of water molecules and formation of nucleophilic hydroxo/oxo-aquo Th species, and high temperature appears to suppress the olation/oxolation hydrolysis reactions, which in both ways limit the formation of the thorium oligomers. PMID- 29116767 TI - A Chromium(II) Tetracarbene Complex Allows Unprecedented Oxidative Group Transfer. AB - Multiple distinct oxidative group transfer reactions to low valent chromium were examined. Six new chromium complexes were prepared from a highly electronically unsaturated Cr(II) square planar complex that was supported by a macrocyclic tetracarbene ligand. This complex's reactivity with Me3NO and disparate azides was investigated. The reaction with Me3NO generated a highly stable Cr(IV)-oxo complex. Less bulky organic azides such as p-tolyl and n-octyl azides gave rise to metallotetrazenes, while more sterically demanding mesityl and adamantyl azides generated Cr(IV)-imido complexes. The reaction of the square planar Cr(II) complex with TMS-azide yielded the first linearly bridging nitrido chromium species. Reductive group transfer was explored for a Cr(IV)-imido complex, and organic products, such as aziridines, were formed after addition. Cr(IV) imidos and oxos are quite rare, while tetrazenes and bridging nitridos are virtually unknown. This is the most detailed study on oxidative group transfer reactions using chromium based complexes on a single auxiliary ligand to date. PMID- 29116768 TI - Greenhouse Gas Dynamics in a Salt-Wedge Estuary Revealed by High Resolution Cavity Ring-Down Spectroscopy Observations. AB - Estuaries are an important source of greenhouse gases to the atmosphere, but uncertainties remain in the flux rates and production pathways of greenhouse gases in these dynamic systems. This study performs simultaneous high resolution measurements of the three major greenhouse gases (carbon dioxide, methane, and nitrous oxide) as well as carbon stable isotope ratios of carbon dioxide and methane, above and below the pycnocline along a salt wedge estuary (Yarra River estuary, Australia). We identified distinct zones of elevated greenhouse gas concentrations. At the tip of salt wedge, average CO2 and N2O concentrations were approximately five and three times higher than in the saline mouth of the estuary. In anaerobic bottom waters, the natural tracer radon (222Rn) revealed that porewater exchange was the likely source of the highest methane concentrations (up to 1302 nM). Isotopic analysis of CH4 showed a dominance of acetoclastic production in fresh surface waters and hydrogenotrophic production occurring in the saline bottom waters. The atmospheric flux of methane (in CO2 equivalent units) was a major (35-53%) contributor of atmospheric radiative forcing from the estuary, while N2O contributed <2%. We hypothesize that the release of bottom water gases when stratification episodically breaks down will release large pulses of greenhouse gases to the atmosphere. PMID- 29116769 TI - Enantioselective Palladium-Catalyzed Intramolecular alpha-Arylative Desymmetrization of 1,3-Diketones. AB - An efficient enantioselective protocol has been reported to build highly oxygenated and densely substituted bicyclo[m.n.1] skeletons through intramolecular asymmetric alpha-arylative desymmetrization of 1,3-diketones. Employing Pd catalyst and FOXAP ligand, various bicyclo[m.n.1] skeleton with different size can be accessed with high enantio- and diastereoselectivities. Utilizing the present method as a key step, formal asymmetric total synthesis of the (-)-parvifoline has been demonstrated. PMID- 29116770 TI - Ligand Substituent Effects in Manganese Pyridinophane Complexes: Implications for Oxygen-Evolving Catalysis. AB - A series of Mn(II) complexes of differently substituted pyridinophane ligands, (Py2NR2)MnCl2 (R = iPr, Cy) and [(Py2NR2)MnF2](PF6) (R = iPr, Cy, tBu) are synthesized and characterized. The electrochemical properties of these complexes are investigated by cyclic voltammetry, along with those of previously reported (Py2NMe2)MnCl2 and the Mn(III) complex [(Py2NMe2)MnF2](PF6). The electronic structure of this and other Mn(III) complexes is probed experimentally and theoretically, via high-frequency and -field electron paramagnetic resonance (HFEPR) spectroscopy ab initio quantum chemical theory (QCT), respectively. These studies show that the complexes contain relatively typical six-coordinate Mn(III). The catalytic activity of these complexes toward both H2O2 disproportionation and H2O oxidation has also been investigated. The rate of H2O2 disproportionation decreases with increasing substituent size. Some of these complexes are active for electrocatalytic H2O oxidation; however this activity cannot be rationalized in terms of simple electronic or steric effects. PMID- 29116771 TI - Methane Bubble Size Distributions, Flux, and Dissolution in a Freshwater Lake. AB - The majority of methane produced in many anoxic sediments is released via ebullition. These bubbles are subject to dissolution as they rise, and dissolution rates are strongly influenced by bubble size. Current understanding of natural methane bubble size distributions is limited by the difficulty in measuring bubble sizes over wide spatial or temporal scales. Our custom optical bubble size sensors recorded bubble sizes and release timing at 8 locations in Upper Mystic Lake, MA continuously for 3 months. Bubble size distributions were spatially heterogeneous even over relatively small areas experiencing similar flux, suggesting that localized sediment conditions are important to controlling bubble size. There was no change in bubble size distributions over the 3 month sampling period, but mean bubble size was positively correlated with daily ebullition flux. Bubble data was used to verify the performance of a widely used bubble dissolution model, and the model was then used to estimate that bubble dissolution accounts for approximately 10% of methane accumulated in the hypolimnion during summer stratification, and at most 15% of the diffusive air water-methane flux from the epilimnion. PMID- 29116773 TI - Simultaneous Speciation, Structure, and Equilibrium Constant Determination in the Ni2+-EDTA-CN- Ternary System via High-Resolution Laboratory X-ray Absorption Fine Structure Spectroscopy and Theoretical Calculations. AB - Even quite simple chemical systems can involve many components and chemical states, and sometimes it can be very difficult to differentiate them by their hardly separable physical-chemical properties. The NiII-EDTA-CN- (EDTA = ethylenediaminetetraacetic acid) ternary system is a good example for this problem where, in spite of its fairly simple components and numerous investigations, several molecular combinations can exist, all of them not having been identified unambiguously yet. In order to achieve a detailed understanding of the reaction steps and chemical equilibria, methods are required in which the structural transitions in the different reaction steps can be followed via element-selective complex spectral feature sets. With the help of our recently developed von Hamos type high-resolution laboratory X-ray absorption spectrometer, both the structural variations and stability constants of the forming complexes were determined from the same measurement series, proving that X-ray absorption spectroscopy can be considered as a multifaced, table-top tool in coordination chemistry. Furthermore, with the help of theoretical calculations, independent structural evidence was also given for the formation of the [NiEDTA(CN)]3- mixed complex. PMID- 29116772 TI - N6-Allyladenosine: A New Small Molecule for RNA Labeling Identified by Mutation Assay. AB - RNA labeling is crucial for the study of RNA structure and metabolism. Herein we report N6-allyladenosine (a6A) as a new small molecule for RNA labeling through both metabolic and enzyme-assisted manners. a6A behaves like A and can be metabolically incorporated into newly synthesized RNAs inside mammalian cells. We also show that human RNA N6-methyladenosine (m6A) methyltransferases METTL3/METTL14 can work with a synthetic cofactor, namely allyl-SAM (S-adenosyl methionine with methyl replaced by allyl) in order to site-specifically install an allyl group to the N6-position of A within specific sequence to generate a6A labeled RNAs. The iodination of N6-allyl group of a6A under mild buffer conditions spontaneously induces the formation of N1,N6-cyclized adenosine and creates mutations at its opposite site during complementary DNA synthesis of reverse transcription. The existing m6A in RNA is inert to methyltransferase assisted allyl labeling, which offers a chance to differentiate m6A from A at individual RNA sites. Our work demonstrates a new method for RNA labeling, which could find applications in developing sequencing methods for nascent RNAs and RNA modifications. PMID- 29116775 TI - Elucidating the Methylammonium (MA) Conformation in MAPbBr3 Perovskite with Application in Solar Cells. AB - Hybrid organic-inorganic perovskites, MAPbX3 (X = halogen), containing methylammonium (MA: CH3-NH3+) in the large voids conformed by the PbX6 octahedral network, are the active absorption materials in the new generation of solar cells. CH3NH3PbBr3 is a promising member with a large band gap that gives rise to a high open circuit voltage. A deep knowledge of the crystal structure and, in particular, the MA conformation inside the perovskite cage across the phase transitions undergone below room temperature, seems essential to establish structure-property correlations that may drive to further improvements. The presence of protons requires the use of neutrons, combined with synchrotron XRD data that help to depict subtle symmetry changes undergone upon cooling. We present a consistent picture of the structural features of this fascinating material, in complement with photocurrent measurements from a photodetector device, demonstrating the potential of MAPbBr3 in optoelectronics. PMID- 29116774 TI - Toward a Soluble Model System for the Amyloid State. AB - The formation and deposition of amyloids is associated with many diseases. beta Sheet secondary structure is a common feature of amyloids, but the packing of sheets against one another is distinctive relative to soluble proteins. Standard methods that rely on perturbing a polypeptide's sequence and evaluating impact on folding can be problematic for amyloid aggregates because a single sequence can adopt multiple conformations and diverse packing arrangements. We describe initial steps toward a minimum-sized, soluble model system for the amyloid state that supports comparisons among sequence variants. Critical to this goal is development of a new linking strategy to enable intersheet association mediated by side chain interactions, which is characteristic of the amyloid state. The linker design we identified should ultimately support exploration of relationships between sequence and amyloid state stability for specific strand association modes. PMID- 29116776 TI - Mechanistic Investigations of the Hydrogenolysis of Diaryl Ethers Catalyzed by Nickel Complexes of N-Heterocyclic Carbene Ligands. AB - Recent interest in the valorization of lignin has led to reactions involving the cleavage of strong aromatic C-O bonds. However, few experimental mechanistic studies of these reactions have been published. We report detailed mechanistic analysis of the hydrogenolysis of diaryl ethers catalyzed by the combination of Ni(COD)2 (COD = 1,5-cyclooctadiene) and an N-heterocyclic carbene (NHC). Experiments on the catalytic reaction indicated that NaOt-Bu was necessary for catalysis, but kinetic analysis showed that the base is not involved in the rate limiting C-O bond cleavage. The resting state of the catalyst is an NHC-Ni(eta6 arene) complex. Substitution of the coordinated solvent with diaryl ether allowed isolation of a diaryl ether-bound Ni complex. Rate-limiting C-O bond cleavage occurs to generate a three-coordinate product of oxidative addition, a metallacyclic version of which has been prepared independently. Stoichiometric studies show that arene and phenol products are released following reaction with H2. NaOt-Bu was found to deprotonate the phenol product and to prevent formation of inactive NiI dimers. PMID- 29116777 TI - Irradiation-Induced Heck Reaction of Unactivated Alkyl Halides at Room Temperature. AB - The palladium-catalyzed Mizoroki-Heck reaction is arguably one of the most significant carbon-carbon bond-construction reactions to be discovered in the last 50 years, with a tremendous number of applications in the production of chemicals. This Nobel-Prize-winning transformation has yet to overcome the obstacle of its general application in a range of alkyl electrophiles, especially tertiary alkyl halides that possess eliminable beta-hydrogen atoms. Whereas most palladium-catalyzed cross-coupling reactions utilize the ground-state reactivity of palladium complexes under thermal conditions and generally apply a single ligand system, we report that the palladium-catalyzed Heck reaction proceeds smoothly at room temperature with a variety of tertiary, secondary, and primary alkyl bromides upon irradiation with blue light-emitting diodes in the presence of a dual phosphine ligand system. We rationalize that this unprecedented transformation is achieved by utilizing the photoexcited-state reactivity of the palladium complex to enhance oxidative addition and suppress undesired beta hydride elimination. PMID- 29116778 TI - Black Carbon (Biochar) In Water/Soil Environments: Molecular Structure, Sorption, Stability, and Potential Risk. AB - Black carbon (BC) is ubiquitous in the environments and participates in various biogeochemical processes. Both positive and negative effects of BC (especially biochar) on the ecosystem have been identified, which are mainly derived from its diverse physicochemical properties. Nevertheless, few studies systematically examined the linkage between the evolution of BC molecular structure with the resulted BC properties, environmental functions as well as potential risk, which is critical for understanding the BC environmental behavior and utilization as a multifunctional product. Thus, this review highlights the molecular structure evolution of BC during pyrolysis and the impact of BC physicochemical properties on its sorption behavior, stability, and potential risk in terrestrial and aqueous ecosystems. Given the wide application of BC and its important role in biogeochemical processes, future research should focus on the following: (1) establishing methodology to more precisely predict and design BC properties on the basis of pyrolysis and phase transformation of biomass; (2) developing an assessment system to evaluate the long-term effect of BC on stabilization and bioavailability of contaminants, agrochemicals, and nutrient elements in soils; and (3) elucidating the interaction mechanisms of BC with plant roots, microorganisms, and soil components. PMID- 29116779 TI - Patterns of Ligands Coordinated to Metallocofactors Extracted from the Protein Data Bank. AB - A new R tool is described that rapidly identifies, ranks, and clusters sequence patterns coordinated to metallocofactors. This tool, PdPDB, fills a void because, unlike currently available tools, PdPDB searches through sequences with metal coordination as the primary determinant and can identify patterns consisting of amino acids, nucleotides, and small molecule ligands at once. PdPDB was tested by analyzing structures that coordinate Fe2+/3+, [2Fe-2S], [4Fe-4S], Zn2+, and Mg2+ cofactors. PdPDB confirmed previously identified sequence motifs and revealed which residues are enriched (e.g., glycine) and are under-represented (e.g., glutamine) near ligands to metal centers. The data show the similarities and differences between different metal-binding sites. The patterns that coordinate metallocofactors vary, depending upon whether the metal ions play a structural or catalytic role, with catalytic metal centers exhibiting partial coordination by small molecule ligands. PdPDB 2.0.1 is freely available as a CRAN package. PMID- 29116780 TI - Bioactive Asarone-Derived Phenylpropanoids from the Rhizome of Acorus tatarinowii Schott. AB - Eight new (1a/1b, 2a, 3a, 4a/4b, and 5a/5b) and seven known (2b, 3b, and 6-10) asarone-derived phenylpropanoids, a known asarone-derived lignan (12), and four known lignan analogues (11 and 13-15) were isolated from the rhizome of Acorus tatarinowii Schott. The structures were elucidated via comprehensive spectroscopic analyses, modified Mosher's method, and quantum chemical calculations. Compounds 1-8 were present as enantiomers, and 1-5 were successfully resolved via chiral-phase HPLC. Compounds 1a/1b were the first cases of asarone-derived phenylpropanoids with an isopropyl C-3 side-chain tethered to a benzene core from nature. Hypoglycemic, antioxidant, and AChE inhibitory activities of 1-15 were assessed by the alpha-glucosidase inhibitory, ORAC, DPPH radical scavenging, and AChE inhibitory assays, respectively. All compounds except 3a showed alpha-glucosidase inhibitory activity. Compound 3b has the highest alpha-glucosidase inhibitory effect with an IC50 of 80.6 MUM (positive drug acarbose IC50 of 442.4 MUM). In the antioxidant assays, compounds 13-15 exhibited ORAC and DPPH radical scavenging activities. The results of the AChE inhibitory assay indicated that all compounds exhibited weak AChE inhibitory activities. PMID- 29116781 TI - Use of Low-Cost Quantum Chemistry Procedures for Geometry Optimization and Vibrational Frequency Calculations: Determination of Frequency Scale Factors and Application to Reactions of Large Systems. AB - We have assessed the performance of a variety of low-cost computational quantum chemistry procedures (semiempirical, pure-DFT, and screened-exchange DFT methods) for computing molecular geometries and thermochemical quantities associated with the vibrational frequencies. Frequency scale factors for zero-point vibrational energies and thermal corrections for 298 K enthalpies and 298 K entropies have been determined. In absolute terms, for small to medium-sized molecules, all procedures perform reasonably well. Semiempirical methods have mean absolute deviations (MADs) of ~15 kJ mol-1 for total enthalpies and free energies. For DFT procedures, hybrid DFT generally performs better than pure DFT. Remarkably, the N12 pure functional shows very good performances (MADs ~ 3 kJ mol-1) that are comparable to those for hybrid functionals. An examination of the basis set effect indicates N12/3-21G* and N12/6-31G(d) to be cost-effective for geometry optimization and vibrational frequency calculations, but the use of minimal basis sets leads to very large MADs for the calculated thermochemical quantities. Further testing with reaction energies of large systems shows that, by exploiting cancellation of systematic deviations, although the deviations can be very substantial in absolute terms (>100 kJ mol-1), those for relative energies are markedly reduced (~10 kJ mol-1). This enables the use of even semiempirical procedures to obtain geometries and vibrational frequencies with reasonable accuracy in cases where the use of more expensive procedures is computationally prohibitive. PMID- 29116783 TI - Lennard-Jones Potentials for the Interaction of CO2 with Five-Membered Aromatic Heterocycles. AB - We used M06-2X/Def2-TZVPP to calculate a broad set of rigid interaction profiles between CO2 and 30 different aromatic heterocycles, based on pyrrole, furan, and thiophene with ring positions subsituted with up to four nitrogens. For each system, several orientations of the fragments were explored to both find the preferred interaction mode and have information about other interaction modes that can contribute to the binding energy when CO2 is captured by complex systems. From these data, Lennard-Jones potentials were obtained, which can be used for the parametrization of force fields that correctly describe the multipolar and dispersion interactions at play between these kinds of fragments. These results are expected to contribute to the development of new force fields for the study of chemical systems for the capture and sequestration of CO2 and also directly for the design of such systems. PMID- 29116784 TI - Ni-Catalyzed Enantioselective Conjunctive Coupling with C(sp3) Electrophiles: A Radical-Ionic Mechanistic Dichotomy. AB - The catalytic enantioselective conjunctive coupling of C(sp3) electrophiles can be accomplished with Ni catalysis. The enantioselectivity of the reaction is dependent on reaction mechanism with many substrates able to engage in an asymmetric process with Pybox-Ni complexes, whereas other substrates provide racemic product mixtures. The link between substrate structure and selectivity is addressed. PMID- 29116782 TI - Inner-Sphere Coordination of Divalent Metal Ion with Nucleobase in Catalytic RNA. AB - Identification of the function of metal ions and the RNA moieties, particularly nucleobases, that bind metal ions is important in RNA catalysis. Here we combine single-atom and abasic substitutions to probe functions of conserved nucleobases in ribonuclease P (RNase P). Structural and biophysical studies of bacterial RNase P propose direct coordination of metal ions by the nucleobases of conserved uridine and guanosine in helix P4 of the RNA subunit (P RNA). To biochemically probe the function of metal ion interactions, we substituted the universally conserved bulged uridine (U51) in the P4 helix of circularly permuted Bacillus subtilis P RNA with 4-thiouridine, 4-deoxyuridine, and abasic modifications and G378/379 with 2-aminopurine, N7-deazaguanosine, and 6-thioguanosine. The functional group modifications of U51 decrease RNase P-catalyzed phosphodiester bond cleavage 16- to 23-fold, as measured by the single-turnover cleavage rate constant. The activity of the 4-thiouridine RNase P is partially rescued by addition of Cd(II) or Mn(II) ions. This is the first time a metal-rescue experiment provides evidence for inner-sphere divalent metal ion coordination with a nucleobase. Modifications of G379 modestly decrease the cleavage activity of RNase P, suggesting outer-sphere coordination of O6 on G379 to a metal ion. These data provide biochemical evidence for catalytically important interactions of the P4 helix of P RNA with metal ions, demonstrating that the bulged uridine coordinates at least one catalytic metal ion through an inner-sphere interaction. The combination of single-atom and abasic nucleotide substitutions provides a powerful strategy to probe functions of conserved nucleobases in large RNAs. PMID- 29116785 TI - A Positive Allosteric Modulator of the Serotonin 5-HT2C Receptor for Obesity. AB - The 5-HT2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT2CR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off target activities, and low binding competition with serotonin or other orthosteric ligands. PAM 11 was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HT2AR. A combination of 11 with the SSRI sertraline increased the anorectic effect. Subchronic administration of 11 reduced food intake and body weight gain without causing CNS related malaise. The behavior of compound 11 identified in this work supports the interest of a serotonin 5-HT2CR PAM as a promising therapeutic approach for obesity. PMID- 29116787 TI - O2 Activation by Metal Surfaces: Implications for Bonding and Reactivity on Heterogeneous Catalysts. AB - The activation of O2 on metal surfaces is a critical process for heterogeneous catalysis and materials oxidation. Fundamental studies of well-defined metal surfaces using a variety of techniques have given crucial insight into the mechanisms, energetics, and dynamics of O2 adsorption and dissociation. Here, trends in the activation of O2 on transition metal surfaces are discussed, and various O2 adsorption states are described in terms of both electronic structure and geometry. The mechanism and dynamics of O2 dissociation are also reviewed, including the importance of the spin transition. The reactivity of O2 and O toward reactant molecules is also briefly discussed in the context of catalysis. The reactivity of a surface toward O2 generally correlates with the adsorption strength of O, the tendency to oxidize, and the heat of formation of the oxide. Periodic trends can be rationalized in terms of attractive and repulsive interactions with the d-band, such that inert metals tend to feature a full d band that is low energy and has a large spatial overlap with adsorbate states. More open surfaces or undercoordinated defect sites can be much more reactive than close-packed surfaces. Reactions between O and other species tend to be more prevalent than reactions between O2 and other species, particularly on more reactive surfaces. PMID- 29116786 TI - Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies. AB - We report here the discovery and pharmacological characterization of N-(1-benzyl 1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate. PMID- 29116788 TI - Vanadium NMR Chemical Shifts of (Imido)vanadium(V) Dichloride Complexes with Imidazolin-2-iminato and Imidazolidin-2-iminato Ligands: Cooperation with Quantum Chemical Calculations and Multiple Linear Regression Analyses. AB - The NMR chemical shifts of vanadium (51V) in (imido)vanadium(V) dichloride complexes with imidazolin-2-iminato and imidazolidin-2-iminato ligands were calculated by the density functional theory (DFT) method with GIAO. The calculated 51V NMR chemical shifts were analyzed by the multiple linear regression (MLR) analysis (MLRA) method with a series of calculated molecular properties. Some of calculated NMR chemical shifts were incorrect using the optimized molecular geometries of the X-ray structures. After the global minimum geometries of all of the molecules were determined, the trend of the observed chemical shifts was well reproduced by the present DFT method. The MLRA method was performed to investigate the correlation between the 51V NMR chemical shift and the natural charge, band energy gap, and Wiberg bond index of the V?N bond. The 51V NMR chemical shifts obtained with the present MLR model were well reproduced with a correlation coefficient of 0.97. PMID- 29116789 TI - Hydration and Ion Pairing in Aqueous Mg2+ and Zn2+ Solutions: Force-Field Description Aided by Neutron Scattering Experiments and Ab Initio Molecular Dynamics Simulations. AB - Magnesium and zinc dications possess the same charge and have an almost identical size, yet they behave very differently in aqueous solutions and play distinct biological roles. It is thus crucial to identify the origins of such different behaviors and to assess to what extent they can be captured by force-field molecular dynamics simulations. In this work, we combine neutron scattering experiments in a specific mixture of H2O and D2O (the so-called null water) with ab initio molecular dynamics simulations to probe the difference in the hydration structure and ion-pairing properties of chloride solutions of the two cations. The obtained data are used as a benchmark to develop a scaled-charge force field for Mg2+ that includes electronic polarization in a mean field way. We show that using this electronic continuum correction we can describe aqueous magnesium chloride solutions well. However, in aqueous zinc chloride specific interaction terms between the ions need to be introduced to capture ion pairing quantitatively. PMID- 29116791 TI - Soluble Oligomeric Nucleants: Simulations of Chain Length, Binding Strength, and Volume Fraction Effects. AB - Recent theories and simulations suggest that molecular additives can bind to the surfaces of nuclei, lower the surface energy, and accelerate nucleation. Experiments have shown that oligomeric and polymeric additives can also modify nucleation rates of proteins, ice, and minerals; however, general design principles for oligomeric or polymeric promoters do not yet exist. Here we investigate oligomeric additives for which each segment of the oligomer can bind to surfaces of nuclei. We use semigrand canonical Monte Carlo simulations in a Potts lattice gas model to study the effects of oligomer chain length, volume fraction, and binding strength. We find that increasing each of those parameters lowers the nucleation barrier. At extremely low oligomer concentrations, the nucleation kinetics can be modeled as though each oligomer is a heterogeneous nucleation site in solution. PMID- 29116790 TI - Semiconducting Ba3Sn3Sb4 and Metallic Ba7-xSn11Sb15-y (x = 0.4, y = 0.6) Zintl Phases. AB - We report the discovery of two ternary Zintl phases Ba3Sn3Sb4 and Ba7-xSn11Sb15-y (x = 0.4, y = 0.6). Ba3Sn3Sb4 adopts the monoclinic space group P21/c with a = 14.669(3) A, b = 6.9649(14) A, c = 13.629(3) A, and beta = 104.98(3) degrees . It features a unique corrugated two-dimensional (2D) structure consisting of [Sn3Sb4]6- layers extending along the ab-plane with Ba2+ atoms sandwiched between them. The nonstoichiometric Ba6.6Sn11Sb14.4 has a complex one-dimensional (1D) structure adopting the orthorhombic space group Pnma, with unit cell parameters a = 37.964(8) A, b = 4.4090(9) A, and c = 24.682(5) A. It consists of large double Sn-Sb ribbons separated by Ba2+ atoms. Ba3Sn3Sb4 is an n-type semiconductor which has a narrow energy gap of ~0.18 eV and a room temperature carrier concentration of ~4.2 * 1018 cm-3. Ba6.6Sn11Sb14.4 is determined to be a metal with electrons being the dominant carriers. PMID- 29116792 TI - Enantioselective Intermolecular C-O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst. AB - We report a series of enantioselective C-O bond cross-coupling reactions based on remote symmetry breaking processes in diarylmethine substrates. The key to the chemistry is multifunctional guanidinylated peptide-based ligands that allow highly selective, intermolecular Cu-catalyzed cross-coupling of phenolic nucleophiles. The scope of the process is explored, demonstrating efficiency for substrates with a range of electronic and steric perturbations to the nucleophile. Scope and limitations are also reported for variation of the diarylmethine. While the presence of an intervening tBu group is found to be optimal for maximum enantioselectivity, several other substituents may also be present such that appreciable selectivity can be achieved, providing an uncommon level of scope for diarylmethine desymmetrizations. In addition, chemoselective reactions are possible when there are phenolic hydroxyl groups within substrates that contain a second reactive site, setting the stage for applications in diverse complex molecular settings. PMID- 29116794 TI - Time-Resolved Fluorescence Spectroscopy Reveals Fine Structure and Dynamics of Poly(l-lysine) and Polyethylenimine Based DNA Polyplexes. AB - Structural dynamics of the polyethylenimine-DNA and poly(l-lysine)-DNA complexes (polyplexes) was studied by steady-state and time-resolved fluorescence spectroscopy using the fluorescence resonance energy transfer (FRET) technique. During the formation of the DNA polyplexes, the negative phosphate groups (P) of DNA are bound by the positive amine groups (N) of the polymer. At N/P ratio 2, nearly all of the DNA's P groups are bound by the polymer N groups: these complexes form the core of the polyplexes. The excess polymer, added to this system to increase the N/P ratio to the values giving efficient gene delivery, forms a positively charged shell around the core polyplex. We investigated whether the exchange between the core and shell regions of PEI and PLL polyplexes takes place. Our results demonstrated a clear difference between the two studied polymers. Shell PEI can replace PEIs previously attached to DNA in the polyplex core, while PLL cannot. Such a dynamic structure of PEI polyplexes compared to a more static one found for PLL polyplexes partially explains the observed difference in the DNA transfection efficiency of these polyplexes. Moreover, the time-resolved fluorescence spectroscopy revealed additional details on the structure of PLL polyplexes: in between the core and shell, there is an intermediate layer where both core and shell PLLs or their parts overlap. PMID- 29116795 TI - Reactions of Sulfur- and Oxygen-Containing Anions with Hydrogen Atoms: A Comparative Study. AB - Reactions of hydrogen atoms with small sulfur-containing anions, SCN-, CH3COS-, C6H5COS-, -SCH2COOH, C6H5S-, 2-HOOCC6H4S-, and related oxygen-containing anions, OCN-, CH3COO-, C6H5COO-, HOCH2COO-, C6H5O-, 2-HOOCC6H4O-, have been studied both experimentally and computationally. The experimental results show that associative electron detachment (AED) is the only channel for the reactions. The rate constants for reactions between sulfur-containing anions and H atoms are generally higher than for the related oxygen-containing anions with the exception of the reaction of SCN-. The generally higher reactivity of the sulfur anions contrasts with previous results where AED reactivity was found to correlate with reaction exothermicity. Density functional theory calculations indicate that the reaction enthalpies, the characteristics of the reaction potential energy surfaces, and other structural and electronic factors can influence the reaction rate constants. This study indicates that organic sulfur anions can be more reactive than related oxygen anions in the interstellar medium where hydrogen atoms are abundant. PMID- 29116793 TI - NMR Signal Quenching from Bound Biradical Affinity Reagents in DNP Samples. AB - We characterize the effect of specifically bound biradicals on the NMR spectra of dihydrofolate reductase from E. coli. Dynamic nuclear polarization methods enhance the signal-to-noise of solid state NMR experiments by transferring polarization from unpaired electrons of biradicals to nuclei. There has been recent interest in colocalizing the paramagnetic polarizing agents with the analyte of interest through covalent or noncovalent specific interactions. This experimental approach broadens the scope of dynamic nuclear polarization methods by offering the possibility of selective signal enhancements and the potential to work in a broad range of environments. Paramagnetic compounds can have other effects on the NMR spectroscopy of nearby nuclei, including broadening of nuclear resonances due to the proximity of the paramagnetic agent. Understanding the distance dependence of these interactions is important for the success of the technique. Here we explore paramagnetic signal quenching due to a bound biradical, specifically a biradical-derivatized trimethoprim ligand of E. coli dihydrofolate reductase. Biradical-derivatized trimethoprim has nanomolar affinity for its target, and affords strong and selective signal enhancements in dynamic nuclear polarization experiments. In this work, we show that, although the trimethoprim fragment is well ordered, the biradical (TOTAPOL) moiety is disordered when bound to the protein. The distance dependence in bleaching of NMR signal intensity allows us to detect numerous NMR signals in the protein. We present the possibility that static disorder and electron spin diffusion play roles in this observation, among other contributions. The fact that the majority of signals are observed strengthens the case for the use of high affinity or covalent radicals in dynamic nuclear polarization solid state NMR enhancement. PMID- 29116796 TI - Direct and Delayed Dynamics in Electron-Induced Surface Reaction. AB - The electron-induced reaction of physisorbed vinyl bromide (ViBr) and allyl bromide (AllBr) on Cu(110) at 4.6 K was studied experimentally by scanning tunneling microscopy and theoretically by molecular dynamics. ViBr and AllBr were found to react by two pathways: "Direct", in which the molecule reacted under the tip, and "Delayed", in which reaction occurred spontaneously after the molecule had diffused across the surface away from the tip. The novel pathway of Delayed reaction constituted a major route for both vinyl bromide (68%) and allyl bromide (53%). The observed reaction dynamics for ViBr and AllBr gave evidence of a long lived vibrationally excited intermediate for both Direct and Delayed reactions. Molecular dynamics simulations with reagent excitation by way of selected vibrational normal modes resulted in either Direct or Delayed reaction, depending on the vibrational mode. PMID- 29116797 TI - Janus Colloids Actively Rotating on the Surface of Water. AB - Biological or artificial microswimmers move performing trajectories of different kinds such as rectilinear, circular, or spiral ones. Here, we report on circular trajectories observed for active Janus colloids trapped at the air-water interface. Circular motion is due to asymmetric and nonuniform surface properties of the particles caused by fabrication. Motion persistence is enhanced by the partial wetted state of the Janus particles actively moving in two dimensions at the air-water interface. The slowing down of in-plane and out-of-plane rotational diffusions is described and discussed. PMID- 29116798 TI - 1-D Metal Nanobead Arrays within Encapsulated Nanowires via a Red-Ox-Induced Dewetting: Mechanism Study by Atom-Probe Tomography. AB - Metal nanoparticle arrays are excellent candidates for a variety of applications due to the versatility of their morphology and structure at the nanoscale. Bottom up self-assembly of metal nanoparticles provides an important complementary alternative to the traditional top-down lithography method and makes it possible to assemble structures with higher-order complexity, for example, nanospheres, nanocubes, and core-shell nanostructures. Here we present a mechanism study of the self-assembly process of 1-D noble metal nanoparticles arrays, composed of Au, Ag, and AuAg alloy nanoparticles. These are prepared within an encapsulated germanium nanowire, obtained by the oxidation of a metal-germanium nanowire hybrid structure. The resulting structure is a 1-D array of equidistant metal nanoparticles with the same diameter, the so-called nanobead (NB) array structure. Atom-probe tomography and transmission electron microscopy were utilized to investigate the details of the morphological and chemical evolution during the oxidation of the encapsulated metal-germanium nanowire hybrid structures. The self-assembly of nanoparticles relies on the formation of a metal germanium liquid alloy and the migration of the liquid alloy into the nanowire, followed by dewetting of the liquid during shape-confined oxidation where the liquid column breaks-up into nanoparticles due to the Plateau-Rayleigh instability. Our results demonstrate that the encapsulating oxide layer serves as a structural scaffold, retaining the overall shape during the eutectic liquid formation and demonstrates the relationship between the oxide mechanical properties and the final structural characteristics of the 1-D arrays. The mechanistic details revealed here provide a versatile tool-box for the bottom-up fabrication of 1-D arrays nanopatterning that can be modified for multiple applications according to the RedOx properties of the material system components. PMID- 29116799 TI - Finding a Needle in the Haystack: Identification of Functionally Important Minority Phases in an Operating Battery. AB - The in-depth understanding of the minority phases' roles in functional materials, e.g., batteries, is critical for optimizing the system performance and the operational efficiency. Although the visualization of battery electrode under operating conditions has been demonstrated, the development of advanced data mining approaches is still needed in order to identify minority phases and to understand their functionalities. The present study uses nanoscale X-ray spectromicroscopy to study a functional LiCoO2/Li battery pouch cell. The data mining approaches developed herein were used to search through over 10 million X ray absorption spectra that cover more than 100 active cathode particles. Two particles with unanticipated chemical fingerprints were identified and further analyzed, providing direct evidence and valuable insight into the undesired side reactions involving the cation dissolution and precipitation as well as the local overlithiation-caused subparticle domain deactivation. The data-mining approach described in this work is widely applicable to many other structurally complex and chemically heterogeneous systems, in which the secondary/minority phases could critically affect the overall performance of the system, well beyond battery research. PMID- 29116800 TI - Control of Randomness in Microsphere-Based Photonic Crystals Assembled by Langmuir-Blodgett Process. AB - Photonic structures in biological systems typically exhibit an appreciable level of disorder within their periodic framework. However, how such disorder within the ordered framework renders unique optical properties has not been fully understood. Toward the goal of improving this understanding, we have investigated Langmuir-Blodgett assembly of microspheres to controllably introduce randomness to photonic structures. We theoretically modeled the assembly process and determined a condition for surface pressure and substrate pulling speed that results in maximum structural order. For each surface pressure, there is an optimum pulling speed and vice versa. Along the trajectory defined by the optimum condition, however, the structural order decreases moderately as the pulling speed increases. This moderate decrease in structural order would be useful for controlled introduction of randomness into the periodic structures. Departing from the trajectory, our experiment reveals that a small change in pulling speed at a given surface pressure can significantly disrupt the structural order. For multilayer assembly, we find that, at a fixed pulling speed, the surface pressure should increase as the number of layers increases to achieve maximum structural order. In totality, we quantitatively present the optimum trajectories for the nth layer assembly relating surface pressure and pulling speed. PMID- 29116801 TI - Effects of Surface Charge of Hyperbranched Polymers on Cytotoxicity, Dynamic Cellular Uptake and Localization, Hemotoxicity, and Pharmacokinetics in Mice. AB - Nanoscaled polymeric materials are increasingly being investigated as pharmaceutical products, drug/gene delivery vectors, or health-monitoring devices. Surface charge is one of the dominant parameters that regulates nanomaterial behavior in vivo. In this paper, we demonstrated how control over chemical synthesis allowed manipulation of nanoparticle surface charge, which in turn greatly influenced the in vivo behavior. Three methacrylate/methacrylamide based monomers were used to synthesize well-defined hyperbranched polymers (HBP) by reversible addition-fragmentation chain transfer (RAFT) polymerization. Each HBP had a hydrodynamic diameter of approximately 5 nm as determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Incorporation of a fluorescent moiety within the polymeric nanoparticles allowed determination of how charge affected the in vivo pharmacokinetic behavior of the nanomaterials and the biological response to them. A direct correlation between surface charge, cellular uptake, and cytotoxicity was observed, with cationic HBPs exhibiting higher cellular uptake and cytotoxicity than their neutral and anionic counterparts. Evaluation of the distribution of the differently charged HBPs within macrophages showed that all HBPs accumulated in the cytoplasm, but cationic HBPs also trafficked to, and accumulated within, the nucleus. Although cationic HBPs caused slight hemolysis, this was generally below accepted levels for in vivo safety. Analysis of pharmacokinetic behavior showed that cationic and anionic HBPs had short blood half-lives of 1.82 +/- 0.51 and 2.34 +/- 0.93 h respectively, compared with 5.99 +/- 2.30 h for neutral HBPs. This was attributed to the fact that positively charged surfaces are more readily covered with opsonin proteins and thus more visible to phagocytic cells. This was supported by in vitro flow cytometric and qualitative live cell imaging studies, which showed that cationic HBPs tended to be taken up by macrophages more effectively and rapidly than neutral and anionic particles. PMID- 29116803 TI - Density Functional Theory Study of the Solvent Effects on Systematically Substituted Dihydroazulene/Vinylheptafulvene Systems: Improving the Capability of Molecular Energy Storage. AB - Former work has improved the energy storage capacity of the dihydroazulene/vinylheptafulvene photo/thermoswitch by substitution with NH2 and NO2 in vacuum. This work extends the former by investigating the solvent effects systematically using cyclohexane, toluene, dichloromethane, ethanol, and acetonitrile and comparing them with the inclusion of vacuum calculations. The investigation includes more than 8000 calculations using density functional theory for comparison of energy storage capacities, activation energies for the thermal conversion of vinylheptafulvene to dihydroazulene, and UV-Vis absorption spectra. We thereby establish design and solvent guidelines in order to obtain an optimal performance of the dihydroazulene/vinylheptafulvene system for use in a solar energy harvesting and storing device. PMID- 29116802 TI - Co(OAc)2-Catalyzed Trifluoromethylation and C(3)-Selective Arylation of 2 (Propargylamino)pyridines via a 6-Endo-Dig Cyclization. AB - A Co(OAc)2-catalyzed trifluoromethylation and subsequent C(3)-selective arylation of 2-(propargylamino)pyridines has been developed. A new 6-endo-dig cyclization involving an unprecedented C(3) selective arylation of the pyridines instead of a commonly observed 5-exo-dig cyclization with "N" is realized. Moreover, the study presents the first case of the installation of a trifluoromethyl group into electron-deficient azaarenes. The process delivers an efficient cascade approach to new trifluoromethylated 1,8-naphthyridine structures with a broad substrate scope. PMID- 29116804 TI - Coupled Interfacial Tension and Phase Behavior Model Based on Micellar Curvatures. AB - This article introduces a consistent and robust model that predicts interfacial tensions for all microemulsion Winsor types and overall compositions. The model incorporates film bending arguments and Huh's equation and is coupled to phase behavior so that simultaneous tuning of both interfacial tension (IFT) and phase behavior is possible. The oil-water interfacial tension and characteristic length are shown to be related to each other through the hydrophilic-lipophilic deviation (HLD). The phase behavior is tied to the micelle curvatures, without the need for using the net average curvature (NAC). The interfacial tension model is related to solubilization ratios in order to introduce a coupled interfacial tension-phase behavior model for all phase environments. The approach predicts two- and three-phase interfacial tensions and phase behavior (i.e., tie lines and tie triangles) for changes in composition and HLD input parameters, such as temperature, pressure, surfactant structure, and oil equivalent alkane carbon number. Comparisons to experimental data show excellent fits and predictive capability. PMID- 29116805 TI - Experimental Verification of Entanglement Generated in a Plasmonic System. AB - A core process in many quantum tasks is the generation of entanglement. It is being actively studied in a variety of physical settings-from simple bipartite systems to complex multipartite systems. In this work we experimentally study the generation of bipartite entanglement in a nanophotonic system. Entanglement is generated via the quantum interference of two surface plasmon polaritons in a beamsplitter structure, i.e., utilizing the Hong-Ou-Mandel (HOM) effect, and its presence is verified using quantum state tomography. The amount of entanglement is quantified by the concurrence and we find values of up to 0.77 +/- 0.04. Verifying entanglement in the output state from HOM interference is a nontrivial task and cannot be inferred from the visibility alone. The techniques we use to verify entanglement could be applied to other types of photonic system and therefore may be useful for the characterization of a range of different nanophotonic quantum devices. PMID- 29116806 TI - Millimeter-Sized Hole Damming. AB - Valves used to control liquid filling and draining processes from storage typically need to be actuated. Here, we show that similar flow enabling and restricting operations can be achieved through millimeter scale holes that function according to the amount of hydrostatic pressure applied without any other intervention. This phenomena is exhibited using receptacles where the base is made of either a hydrophilic or superhydrophobic substrate with hole sizes ranging from 1.0-2.0 mm. The construction is such that the drainage flow velocities are of the same order in both substrates and follow Torricelli's law trends. Nevertheless, the primary mechanisms responsible for resisting the onset of flow in each substrate are different; nonbreaching of the advancing contact angle threshold in the former, and stable maintenance of an elastic-like deformation of the liquid-gas interface that is connected to the surrounding plastron in the latter. These differences are demonstrated using an upward jet of water delivered to the orifice, where a discharging flow from the hydrophilic base occurred before the threshold hydrostatic pressure condition was attained, while liquid from the jet is subsumed into the liquid body of the receptacle with the superhydrophobic base without any leakage. These findings portend advantages in simplicity and robustness for a myriad of liquid-related processes. PMID- 29116807 TI - Atomic-Resolution Spectrum Imaging of Semiconductor Nanowires. AB - Over the past decade, III-V heterostructure nanowires have attracted a surge of attention for their application in novel semiconductor devices such as tunneling field-effect transistors (TFETs). The functionality of such devices critically depends on the specific atomic arrangement at the semiconductor heterointerfaces. However, most of the currently available characterization techniques lack sufficient spatial resolution to provide local information on the atomic structure and composition of these interfaces. Atomic-resolution spectrum imaging by means of electron energy-loss spectroscopy (EELS) in the scanning transmission electron microscope (STEM) is a powerful technique with the potential to resolve structure and chemical composition with sub-angstrom spatial resolution and to provide localized information about the physical properties of the material at the atomic scale. Here, we demonstrate the use of atomic-resolution EELS to understand the interface atomic arrangement in three-dimensional heterostructures in semiconductor nanowires. We observed that the radial interfaces of GaSb-InAs heterostructure nanowires are atomically abrupt, while the axial interface in contrast consists of an interfacial region where intermixing of the two compounds occurs over an extended spatial region. The local atomic configuration affects the band alignment at the interface and, hence, the charge transport properties of devices such as GaSb-InAs nanowire TFETs. STEM-EELS thus represents a very promising technique for understanding nanowire physical properties, such as differing electrical behavior across the radial and axial heterointerfaces of GaSb-InAs nanowires for TFET applications. PMID- 29116808 TI - Microhydration of BH4-: Dihydrogen Bonds, Structure, Stability, and Raman Spectra. AB - Hydridic-to-protonic interactions in unconventional dihydrogen bonding influence the structure, reactivity, and selectivity in solution and in the solid state. In this study, the structure, stability, and Raman spectra of BH4- hydrated clusters, [BH4(H2O)n]- (n = 1-8, 10, 12, 14, 16) are systematically investigated using density functional theory (DFT) at the wB97XD/6-311++g(3df,3pd) basis set level. The successive microhydration process is described to illustrate in detail the changes in dihydrogen bonding with increasing hydration cluster size. The results of DFT calculations indicate that seven or eight water molecules hydrate BH4- with a total of 12 dihydrogen bonds in the tetrahedral edge or tetrahedral corner forms, and a maximum of six water molecules in the tetrahedral-edge form. Raman spectra of [BH4(H2O)n]- show a blue shift in the B-H stretching band due to hydration. Car-Parrinello molecular dynamics simulations verify strong BH4- water interactions. The hydration number of BH4- is 6.7, with a hydration B-O(W) distance of 3.40 A, and each hydrogen in BH4- bonds with 2.66 hydrogen atoms from water. PMID- 29116809 TI - Thermoelectricity Enhanced Electrocatalysis. AB - We show that thermoelectric materials can function as electrocatalysts and use thermoelectric voltage generated to initiate and boost electrocatalytic reactions. The electrocatalytic activity is promoted by the use of nanostructured thermoelectric materials in a hydrogen evolution reaction (HER) by the thermoelectricity generated from induced temperature gradients. This phenomenon is demonstrated using two-dimensional layered thermoelectric materials Sb2Te3 and Bi0.5Sb1.5Te3 where a current density approaching ~50 mA/cm2 is produced at zero potential for Bi0.5Sb1.5Te3 in the presence of a temperature gradient of 90 degrees C. In addition, the turnover frequency reaches to 2.7 s-1 at 100 mV under this condition which was zero in the absence of temperature gradient. This result adds a new dimension to the properties of thermoelectric materials which has not been explored before and can be applied in the field of electrocatalysis and energy generation. PMID- 29116810 TI - Structural Evolution of LixNiyMnzCo1-y-zO2 Cathode Materials during High-Rate Charge and Discharge. AB - Ni-rich lithium transition metal oxides have received significant attention due to their high capacities and rate capabilities determined via theoretical calculations. Although the structural properties of these materials are strongly correlated with the electrochemical performance, their structural stability during the high-rate electrochemical reactions has not been fully evaluated yet. In this work, transmission electron microscopy is used to investigate the crystallographic and electronic structural modifications of Ni-based cathode materials at a high charge/discharge rate of 10 C. It is found that the high-rate electrochemical reactions induce structural inhomogeneity near the surface of Ni rich cathode materials, which limits Li transport and reduces their capacities. This study establishes a correlation between the high-rate electrochemical performance of the Ni-based materials and their structural evolution, which can provide profound insights for designing novel cathode materials having both high energy and power densities. PMID- 29116811 TI - Reactivity of Lithium beta-Ketocarboxylates: The Role of Lithium Salts. AB - Lithium beta-ketocarboxylates 1(COOLi), prepared by the reaction of lithium enolates 2(Li+) with carbon dioxide, readily undergo decarboxylative disproportionation in THF solution unless in the presence of lithium salts, in which case they are indefinitely stable at room temperature in inert atmosphere. The availability of stable THF solutions of lithium beta-ketocarboxylates 1(COOLi) in the absence of carbon dioxide allowed reactions to take place with nitrogen bases and alkyl halides 3 to give alpha-alkyl ketones 1(R) after acidic hydrolysis. The sequence thus represents the use of carbon dioxide as a removable directing group for the selective monoalkylation of lithium enolates 2(Li+). The roles of lithium salts in preventing the disproportionation of lithium beta ketocarboxylates 1(COOLi) and in determining the course of the reaction with bases and alkyl halides 3 are discussed. PMID- 29116812 TI - X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors. AB - Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer's disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the observed cognitive and memory deficits. These data point to the promising potential of STEP as a target for drug discovery in Alzheimer's treatment. We previously reported a substrate-based approach to the development of low molecular weight STEP inhibitors with Ki values as low as 7.8 MUM. Herein, we disclose the first X-ray crystal structures of inhibitors bound to STEP and the surprising finding that they occupy noncoincident binding sites. Moreover, we utilize this structural information to optimize the inhibitor structure to achieve a Ki of 110 nM, with 15-60-fold selectivity across a series of phosphatases. PMID- 29116813 TI - TiO2 with Tandem Fractionation (TAFT): An Approach for Rapid, Deep, Reproducible, and High-Throughput Phosphoproteome Analysis. AB - Mass-spectrometry-based phosphoproteomic workflows traditionally require efficient prefractionation and enrichment of phosphopeptides to gain an in-depth, global, and unbiased systematic investigation of phosphoproteome. Here we present TiO2 with tandem fractionation (TAFT) approach, which combines titanium dioxide (TiO2) enrichment and tandem high-pH reverse-phase (HpRP) for phosphoproteome analysis in a high-throughput manner; the entire workflow takes only 3 h to complete without laborious phosphopeptide preparation. We applied this approach to HeLa and HepG2.2.15 cells to characterize the capability of TAFT approach, which enables deep identification and quantification of more than 14 000 unique phosphopeptides in a single sample from 1 mg of protein as starting materials in <4 h of MS measurement. In total, we identified and quantified 21 281 phosphosites in two cell lines with >91% selectivity and high quantitative reproducibility (average Pearson correlation is 0.90 between biological replicates). More generally, the presented approach enables rapid, deep, and reproducible phosphoproteome analysis in a high-throughput manner with low cost, which should facilitate our understanding of signaling networks in a wide range of biological systems or the process of clinical applications. PMID- 29116814 TI - Mapping the Chemical Space of the RNA Cleavage and Its Implications for Ribozyme Catalysis. AB - Ribozymes utilize diverse catalytic strategies. We report systematic quantum chemical calculations mapping the catalytic space of RNA cleavage by comparing all chemically feasible reaction mechanisms of RNA self-cleavage, using appropriate model systems including those chemical groups that may directly participate in ribozyme catalysis. We calculated the kinetics of uncatalyzed cleavage reactions proceeding via both monoanionic and dianionic pathways, and explicitly probed effects of various groups acting as general bases (GBs) and/or general acids (GAs), or electrostatic transition state stabilizers. In total, we explored 115 different mechanisms. The dianionic scenarios are generally preferred to monoanionic scenarios, although they may compete with one-another under some conditions. Direct GA catalysis seems to exert the dominant catalytic effect, while GB catalysis and electrostatic stabilization are less efficient. Our results indirectly suggest that the dominant part of the catalytic effect might be explained by the shift of the reaction mechanism from the mechanism of uncatalyzed cleavage to the mechanism occurring in ribozymes. This would contrast typical protein enzymes, primarily achieving catalysis by overall electrostatic effects in their catalytic center. PMID- 29116815 TI - Tailoring Strain and Morphology of Core-Shell SiGe Nanowires by Low-Temperature Ge Condensation. AB - Selective oxidation of the silicon element of silicon germanium (SiGe) alloys during thermal oxidation is a very important and technologically relevant mechanism used to fabricate a variety of microelectronic devices. We develop here a simple integrative approach involving vapor-liquid-solid (VLS) growth followed by selective oxidation steps to the construction of core-shell nanowires and higher-level ordered systems with scalable configurations. We examine the selective oxidation/condensation process under nonequilibrium conditions that gives rise to spontaneous formation of core-shell structures by germanium condensation. We contrast this strategy that uses reaction-diffusion-segregation mechanisms to produce coherently strained structures with highly configurable geometry and abrupt interfaces with growth-based processes which lead to low strained systems with nonuniform composition, three-dimensional morphology, and broad core-shell interface. We specially focus on SiGe core-shell nanowires and demonstrate that they can have up to 70% Ge-rich shell and 2% homogeneous strain with core diameter as small as 14 nm. Key elements of the building process associated with this approach are identified with regard to existing theoretical models. Moreover, starting from results of ab initio calculations, we discuss the electronic structure of these novel nanostructures as well as their wide potential for advanced device applications. PMID- 29116816 TI - Can Dogs Assist Children with Severe Autism Spectrum Disorder in Complying with Challenging Demands? An Exploratory Experiment with a Live and a Robotic Dog. AB - OBJECTIVES: Prompted by the need to find effective ways to enhance compliance in children with autism spectrum disorder (ASD), and building on the increasing interest in dog-assisted interventions for this population, this study provides an exploratory test on whether dogs may assist children with severe ASD in complying with challenging demands while also decreasing behavioral and cardiovascular distress. DESIGN: A within-subject design was used. Depending on condition, participants were allowed to engage with a particular stimulus-their preferred toy, a live dog, or a robotic dog-before being exposed to a demanding task in which they had to wait for permission to eat a desired food item ("prohibition task"). Although inactive, the stimulus remained present during the prohibition task. SUBJECTS AND SETTINGS: Ten male children, aged between 6 and 9 years and diagnosed with severe ASD, participated in this study. All were clinically referred as having serious compliance difficulties in everyday routines. Testing occurred at participants' homes. OUTCOME MEASURES: Participants' emotional expressions, latency to distress, compliance levels, and behaviors that were shown during committed compliance were assessed during the prohibition task. In addition, cardiovascular reactivity to the task was monitored. RESULTS: Obtained data revealed significant differences between conditions for some of the considered measures. Latency to distress was higher in the live dog than in the toy condition. Committed compliance was higher in the live dog than in the toy and robot conditions. Quiet waiting during committed compliance was higher in the live dog condition than in the toy condition, and tension release behaviors were lower. In addition, heart rate reactivity was lower in the live dog condition than in the toy condition. CONCLUSIONS: The live dog condition appeared to have a calming effect on the participants, hypothetically facilitating compliance. Although promising, these findings are only preliminary and their clinical significance needs to be assessed in future studies. PMID- 29116817 TI - Perceptions of a psychoeducation program for caregivers of persons with dementia at end of life: a qualitative study. AB - OBJECTIVES: Caregivers (CG) of persons with dementia have described positive and challenging experiences related to caring for a person with a neurological disease. This study explored perceived benefits and challenges of a unique psychoeducation program provided at end of life (EOL) jointly attended by current and bereaved CGs of persons with dementia, residing in a hospital Specialized Care Unit. METHOD: Semi-structured interviews were held with sixteen participants and analyzed with content analysis. RESULTS: Program benefits were perceived by CGs such as: (i) enhanced emotional well-being, (ii) increased feelings of preparedness for EOL, and (iii) personal growth into role models. Within the organization the program was perceived as promoting relationship-centered care and increasing resources. Challenges such as diverse CG preferences, day-time scheduling and limited involvement of unit staff were perceived as barriers. CONCLUSIONS: This program fills a gap in care for CGs at the critical stage of EOL with continuity into bereavement. Implications for practice include: increasing engagement of unit staff for involvement and tailoring of the program, and translation of the program into alternative settings like long-term care. Policies outlining the support needs and resources for CGs through EOL within and outside the hospital are necessary to ensure access and continuity of care. PMID- 29116818 TI - Pure and Oxidized Copper Materials as Potential Antimicrobial Surfaces for Spaceflight Activities. AB - Microbial biofilms can lead to persistent infections and degrade a variety of materials, and they are notorious for their persistence and resistance to eradication. During long-duration space missions, microbial biofilms present a danger to crew health and spacecraft integrity. The use of antimicrobial surfaces provides an alternative strategy for inhibiting microbial growth and biofilm formation to conventional cleaning procedures and the use of disinfectants. Antimicrobial surfaces contain organic or inorganic compounds, such as antimicrobial peptides or copper and silver, that inhibit microbial growth. The efficacy of wetted oxidized copper layers and pure copper surfaces as antimicrobial agents was tested by applying cultures of Escherichia coli and Staphylococcus cohnii to these metallic surfaces. Stainless steel surfaces were used as non-inhibitory control surfaces. The production of reactive oxygen species and membrane damage increased rapidly within 1 h of exposure on pure copper surfaces, but the effect on cell survival was negligible even after 2 h of exposure. However, longer exposure times of up to 4 h led to a rapid decrease in cell survival, whereby the survival of cells was additionally dependent on the exposed cell density. Finally, the release of metal ions was determined to identify a possible correlation between copper ions in suspension and cell survival. These measurements indicated a steady increase of free copper ions, which were released indirectly by cells presumably through excreted complexing agents. These data indicate that the application of antimicrobial surfaces in spaceflight facilities could improve crew health and mitigate material damage caused by microbial contamination and biofilm formation. Furthermore, the results of this study indicate that cuprous oxide layers were superior to pure copper surfaces related to the antimicrobial effect and that cell density is a significant factor that influences the time dependence of antimicrobial activity. Key Words: Contact killing-E. coli-S. cohnii-Antimicrobial copper surfaces-Copper oxide layers-Human health-Planetary protection. Astrobiology 17, 1183-1191. PMID- 29116819 TI - Double guide double wrist 5F left coronary artery transradial percutaneous coronary intervention and the X-Kiss technique. AB - Percutaneous coronary intervention for bifurcated anatomy, particularly at the proximal left coronary artery site, requires guide catheters (GC) of at least 6 french and preferably larger in diameter. We describe a new trans-radial approach more suitable for small artery size: the simultaneous use of both radial arteries for double cannulation of the LMCA with 5F GC: each GC will target either the LM/LAD or the LM/CX artery (or LM-LAD/LM-LAD-1st diagonal branch) stenoses. The technique successfully was applied to 5 cases. When the technique was used for distal left main coronary artery stenoses (3 cases), a special crogss-like configuration obtained when guide catheters, coronary wires and balloons kissed was observed. PMID- 29116820 TI - GSMC: Combining Parallel Gibbs Sampling with Maximal Cliques for Hunting DNA Motif. AB - Regulatory elements are responsible for regulating gene transcription. Therefore, identification of these elements is a tremendous challenge in the field of gene expression. Transcription factors (TFs) play a key role in gene regulation by binding to target promoter sequences. A set of conserved sequence patterns with a highly similar structure that is bound by a TF is called a motif. Motif discovery has been a difficult problem over the past decades. Meanwhile, it is a foundation stone in meeting this challenge. Recent advances in obtaining genomic sequences and high-throughput gene expression analysis techniques have enabled the rapid development of computational methods for motif discovery. As a result, a large number of motif-finding algorithms aiming at various motif models have sprung up in the past few years. However, most of them are not suitable for analysis of the large data sets generated by next-generation sequencing. To better handle large scale ChIP-Seq data and achieve better performance in computational time and motif detection accuracy, we propose an excellent motif-finding algorithm known as GSMC (Combining Parallel Gibbs Sampling with Maximal Cliques for hunting DNA Motif). The GSMC algorithm consists of two steps. First, we employ the commonly used Gibbs sampling to generating initial motifs. Second, we utilize maximal cliques to cluster motifs according to Similarity with Position Information Contents (SPIC). Consequently, we raise the detection accuracy in a great degree, in the meantime holding comparative computation efficiency. In addition, we can find much more credible cofactor interacting motifs. PMID- 29116821 TI - Memory and linguistic/executive functions of children with borderline intellectual functioning. AB - Children with Borderline Intellectual Functioning (BIF) have received a minimal amount of research attention and have been studied in conjunction with Intellectual and Developmental Disabilities. The present study intends to broaden the knowledge of BIF, by analyzing domains such as verbal memory and visual memory, as well as tasks that rely simultaneously on memory, executive functions, and language. A cross-sectional, comparison study was carried out between a group of 40 children with BIF (mean age = 10.03; 24 male and 16 female), and a control group of 40 normal children of the same age, gender, and socioeconomic level as the BIF group. The WISC-III Full Scale IQs of the BIF group ranged from 71 to 84. The following instruments were used: Word List, Narrative Memory, Rey Complex Figure, Face Memory, Rapid Naming (both RAN and RAS tests), and Verbal Fluency. The results showed deficits in children with BIF in verbal short-term memory, rapid naming, phonemic verbal fluency, and visual short-term memory, specifically in a visual recognition task, when compared with the control group. Long-term verbal memory was impaired only in older children with BIF and long-term visual memory showed no deficit. Verbal short-term memory stands out as a limitation and visual long-term memory as a strength. Correlations between the WISC-III and neuropsychological tests scores were predominantly low. The study expands the neuropsychological characterization of children with BIF and the implications of the deficits and strengths are stressed. PMID- 29116822 TI - Multiple Sequence Alignment Based on a Suffix Tree and Center-Star Strategy: A Linear Method for Multiple Nucleotide Sequence Alignment on Spark Parallel Framework. AB - Multiple sequence alignment (MSA) is an essential prerequisite and dominant method to deduce the biological facts from a set of molecular biological sequences. It refers to a series of algorithmic solutions for the alignment of evolutionarily related sequences while taking into account evolutionary events such as mutations, insertions, deletions, and rearrangements under certain conditions. These methods can be applied to DNA, RNA, or protein sequences. In this work, we take advantage of a center-star strategy to reduce the MSA problem to pairwise alignments, and we use a suffix tree to match identical substrings between two pairwise sequences. Multiple sequence alignment based on a suffix tree and center-star strategy (MASC) can accomplish MSA in O(mn), which is linear time complexity, where m is the number of sequences and n is the average length of sequences. Furthermore, we execute our method on the Spark-distributed parallel framework to deal with ever-increasing massive data sets. Our method is significantly faster than previous techniques, with no loss in accuracy for highly similar nucleotide sequences like homologous sequences, which we experimentally demonstrate. Comparing with mainstream MSA tools (e.g., MAFFT), MASC could finish the alignment of 67,200 sequences, longer than 10,000 bps, in 9 minutes, which takes MAFFT >3.5 days. PMID- 29116823 TI - Infusing Adult Education Principles Into a Health Insurance Literacy Program. AB - Health insurance literacy is an emerging concept in the health education and health promotion field. The passage of the Affordable Care Act highlighted the link between health insurance and health outcomes. However, the law does not specifically address how the public should be educated on choosing an appropriate health insurance plan. Research shows adults, regardless of previous health insurance status, are likely confused and uncertain about their selection. The University of Maryland Extension developed and created health insurance Smart Choice Health InsuranceTM to reduce confusion and increase confidence and capability to make this decision. Andragogy, an adult learning theory, was used to guide the development of the program and help ensure best practices are used to achieve desired outcomes. Using the six principles of andragogy, the team incorporated reality-based case studies, allowed adults time to practice, and emphasized choice making and many other elements to create an atmosphere conducive to adult learning. Results from Smart Choice indicate the program is successful in reducing confusion and increasing confidence. Furthermore, feedback from participants and trained educators indicates that adults were engaged in the program and found the materials useful. Based on program success, creation of new health insurance literacy programs grounded in adult education principles is under way. PMID- 29116824 TI - Paronychia with Sporangium Formation Causing an Ingrown Toenail A Rare Case Report. AB - Ingrown toenail, or onychocryptosis, is a common inflammatory disease of the hallux. It results from the alteration of fit of the nail plate in the lateral nail fold. Ingrown toenails are usually seen in adolescents and young adults and can affect daily activities and social life. Generally, ingrown toenails are classified into three stages, including the inflammatory stage, the abscess stage, and the granulation stage. In this article, we present the rare case of a man with a diagnosis of paronychia with sporangium formation causing an ingrown toenail. PMID- 29116825 TI - Spanish validation of the 10-item Connor-Davidson Resilience Scale (CD-RISC 10) with non-professional caregivers. AB - OBJECTIVES: Despite the importance of resilience in populations under stress, and the fact that the 10-item version Connor-Davidson Resilience Scale (CD-RISC 10) is the shortest instrument for reliable and valid evaluation of resilience, there are no data on their psychometric properties in non-professional caregivers. The aim of this study was to analyze the psychometric properties and factorial structure of the spanish version of the CD-RISC 10 in non-professional caregivers. METHOD: Independently trained assessors evaluated resilience, self esteem, social support, emotional distress and depression in a sample of 294 caregivers (89.8% women, mean age 55.3 years). RESULTS: The internal consistency of CD-RISC 10 was alpha = .86. A single factor was found that accounted for 44.7% of the total variance. Confirmatory factor analysis corroborated this unifactorial model. The CD-RISC 10 was significantly correlated with the self esteem (r = .416, p < .001) and social support (r = .228, p < .001) scales, and the emotional distress scale (r = -.311, p < .001), though this was an inverse relationship. A score <= 23 was a suitable cut-off point for discriminating caregivers with depression (sensitivity = 70.0%, specificity = 68.2%). CONCLUSION: The CD-RISC 10 is a reliable and valid instrument to evaluate resilience in the caregiver population. PMID- 29116826 TI - Adjusting Pulse Amplitude During Transcutaneous Electrical Nerve Stimulation Does Not Provide Greater Hypoalgesia. AB - OBJECTIVES: Transcutaneous electrical nerve stimulation (TENS) is an electrotherapeutic modality commonly used in rehabilitation to relieve pain. Adjusting pulse amplitude (intensity) during TENS treatment has been suggested to overcome nerve habituation. However, it is still unclear if this procedure leads to greater hypoalgesia. The aim of this study was to determine if the hypoalgesic effect of TENS is greater when pulse amplitude is adjusted throughout the TENS treatment session in chronic low-back pain patients. DESIGN: Randomized double blind crossover study. SETTING: Recruitment and assessment were conducted at the Clinique universitaire de readaptation de l'Estrie (CURE) of the Faculty of Medicine and Health Sciences of the Universite de Sherbrooke. PARTICIPANTS: Twenty-one volunteers with chronic low-back pain were enrolled and completed this investigation. INTERVENTIONS: Each patient received two high-frequency TENS treatments on two separate sessions: (1) with adjustment of pulse amplitude and (2) without pulse amplitude adjustment. MAIN OUTCOME MEASURES: Pain intensity and unpleasantness were assessed before, during, and after TENS application with a 10 cm visual analog scale. RESULTS: Both TENS conditions (with and without adjustment of intensity) decreased pain intensity and unpleasantness when compared with baseline. No difference was observed between the two stimulation conditions for both pain intensity and unpleasantness. CONCLUSION: The current results suggest that adjustment of pulse amplitude during TENS application does not provide greater hypoalgesia in individuals with chronic low-back pain. Future studies are needed to confirm these findings in other pain populations. PMID- 29116828 TI - Calling Injury Timeouts for the Medical Evaluation of Concussion: Determinants of Collegiate Football Officials' Behavior. AB - CONTEXT: Sports officials can play an important role in concussion safety by calling injury timeouts so that athletic trainers can evaluate athletes with possible concussions. Understanding the determinants of whether officials call an injury timeout when they suspect a concussion has important implications for the design of interventions that better support officials in this role. OBJECTIVE: To assess the knowledge of US collegiate football officials about concussion symptoms and to determine the associations between knowledge, perceived injunctive norms, and self-efficacy and calling injury timeouts for suspected concussions in athletes. DESIGN: Cross-sectional study. SETTING: Electronic survey. PATIENTS OR OTHER PARTICIPANTS: Of the 3074 US collegiate football officials contacted, 1324 (43% response rate) participated. MAIN OUTCOME MEASURE(S): Concussion knowledge, injunctive norms (belief about what others would want them to do), and behavioral self-efficacy (confidence in their ability to call injury timeouts for suspected concussions in athletes during challenging game-day conditions). RESULTS: Officials reported calling approximately 1 injury timeout for a suspected concussion every 4 games during the 2015 season. Structural equation modeling indicated that officials with more concussion symptom knowledge had greater behavioral self-efficacy. Independent of an official's symptom knowledge, injunctive norms that were more supportive of calling an injury timeout were associated with greater self-efficacy. CONCLUSIONS: Concussion education for officials is important because when officials are aware of concussion symptoms, they are more confident in calling injury timeouts. Beyond increasing symptom knowledge, fostering sports environments that encourage concussion safety in all stakeholder groups can support officials in calling injury timeouts. Athletic trainers can help create sports environments that support proactive concussion identification by educating stakeholders, including officials, about the importance of concussion safety. When officials believe that other stakeholders support concussion safety, they are more likely to call injury timeouts if they suspect a concussion has occurred. PMID- 29116827 TI - Frontal-Plane Variability in Foot Orientation During Fatiguing Running Exercise in Individuals With Chronic Ankle Instability. AB - CONTEXT: Researchers have reported increased variability in frontal-plane movement at the ankle during jumping in individuals with chronic ankle instability (CAI), which may increase their risk of recurrent ankle sprain. It is not known if this behavior is present during running gait or how fatigue affects the amount of frontal-plane-movement variability in individuals with CAI. OBJECTIVE: To investigate the amount of roll-angle variability at the foot during a fatiguing exercise protocol in participants with CAI. DESIGN: Controlled laboratory study. SETTING: Motion-analysis research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 18 volunteers with CAI (10 men, 8 women; age = 29.8 +/- 9.2 years, height = 175.8 +/- 11.2 cm, mass = 75.4 +/- 10.7 kg) and 17 volunteers serving as controls (8 men, 9 women; age = 28.2 +/- 6.3 years, height = 172.3 +/- 10.6 cm, mass = 68.8 +/- 12.9 kg). INTERVENTION(S): Kinematic data for foot position were collected while participants performed a functional fatigue protocol based on shuttle runs. MAIN OUTCOME MEASURE(S): Variability (ie, standard deviation) of the roll angle of the foot about the x axis, corresponding to inversion-eversion, was measured at 2 discrete times: 50 milliseconds before foot strike and 65% of stance. RESULTS: No differences in roll-angle range or variability were observed between limbs in either group. At 65% of stance, we found a main effect for time, whereby both groups demonstrated decreased roll-angle ranges at the end of the fatigue protocol ( P = .01). A between-groups effect in the roll-angle variability at 65% of stance was noted ( P = .04), with the CAI group exhibiting higher levels of variability. No between groups differences were observed at 50 milliseconds before foot strike. CONCLUSIONS: Chronic ankle instability is a complex, multifactorial condition that can affect patients in diverse ways. Identifying excessive foot-position variability in particular situations could potentially inform targeted rehabilitation programs. PMID- 29116829 TI - Nonsurgical Management of an Anterior Cruciate Ligament-Deficient Knee in a Women's Soccer Player: A Validation Clinical Case Report. AB - BACKGROUND: A collegiate women's soccer player sustained an isolated anterior cruciate ligament (ACL) tear and expressed a desire to continue her season without surgical intervention. DESIGN: Case report. INTERVENTION(S): Using the results of a randomized controlled trial and published clinical guidelines, the clinicians classified the patient as an ACL-deficient coper. The patient completed her soccer season without incident, consistent with the findings of the established clinical guidelines. However, 6 months later, she sustained a meniscal tear, which was not unexpected given that 22% of ACL-deficient copers in the randomized controlled trial incurred a meniscal tear within 24 months of ACL injury. CONCLUSION: The external evidence was helpful in making informed clinical decisions regarding patient care. PMID- 29116830 TI - Hip Strength as a Predictor of Ankle Sprains in Male Soccer Players: A Prospective Study. AB - CONTEXT: Diminished hip-abductor strength has been suggested to increase the risk of noncontact lateral ankle sprains. OBJECTIVE: To determine prospectively whether baseline hip-abductor strength predicts future noncontact lateral ankle sprains in competitive male soccer players. DESIGN: Prospective cohort study. SETTING: Athletic training facilities and various athletic fields. PATIENTS OR OTHER PARTICIPANTS: Two hundred ten competitive male soccer players. MAIN OUTCOME MEASURE(S): Before the start of the sport season, isometric hip abductor strength was measured bilaterally using a handheld dynamometer. Any previous history of ankle sprain, body mass index, age, height, and weight were documented. During the sport season (30 weeks), ankle injury status was recorded by team medical providers. Injured athletes were further classified based on the mechanism of injury. Only data from injured athletes who sustained noncontact lateral ankle sprains were used for analysis. Postseason, logistic regression was used to determine whether baseline hip strength predicted future noncontact lateral ankle sprains. A receiver operating characteristic curve was constructed for hip strength to determine the cutoff value for distinguishing between high risk and low-risk outcomes. RESULTS: A total of 25 noncontact lateral ankle sprains were confirmed, for an overall annual incidence of 11.9%. Baseline hip abductor strength was lower in injured players than in uninjured players ( P = .008). Logistic regression indicated that impaired hip-abductor strength increased the future injury risk (odds ratio = 1.10 [95% confidence interval = 1.02, 1.18], P = .010). The strength cutoff to define high risk was <=33.8% body weight, as determined by receiver operating characteristic curve analysis. For athletes classified as high risk, the probability of injury increased from 11.9% to 26.7%. CONCLUSIONS: Reduced isometric hip-abductor strength predisposed competitive male soccer players to noncontact lateral ankle sprains. PMID- 29116832 TI - Public Parks and Shady Areas in Times of Climate Change, Urban Sprawl, and Obesity. PMID- 29116831 TI - Clinician-Friendly Physical Performance Tests for the Knee. AB - : Reference: Hegedus EJ, McDonough S, Bleakley C, Cook CE, Baxter GD. Clinician friendly lower extremity physical performance measures in athletes: a systematic review of measurement properties and correlation with injury. Part 1: the tests for knee function including the hop tests. Br J Sports Med. 2015;49(10):642-648. CLINICAL QUESTION: Do individual physical performance tests (PPTs) used as measures for lower extremity function have any relationship to injuries in athletes aged 12 years or older? DATA SOURCES: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to locate articles. The authors searched PubMed, EMBASE, and SPORTDiscus, in addition to searching by hand. The search strategy combined the terms athlete, lower extremity, and synonyms of performance test with the names of performance tests. STUDY SELECTION: Studies were included if they involved a test that met the operational definition for a PPT. The included studies assessed components of sport function (eg, speed, agility, and power), determined readiness for return to sport, or predicted injury to the lower extremity. All PPT measures could be performed on the field, courtside, or in a gym with affordable, portable, and readily available equipment. Studies were excluded if they made use of 3 dimensional motion capture, force platforms, timing gates, treadmills, stationary bikes, metabolic charts, or another nonportable, costly testing device. Athletes were categorized on the Tegner Scale at a minimum of level 5, which is the lowest level that still encompasses competitive athletes. Studies were included if 50% or more of the participants were rated above 5 on the Tegner Scale. Studies were excluded if the sole purpose was to judge movement quality or range of motion. Studies were selected if they identified the knee or a knee injury as a focal point of the paper. DATA EXTRACTION: The Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) was used to critique the methodologic quality of each paper with a 4-point Likert scale. The title and methods of each paper were extracted. Extracted data were summarized using ratings of unknown, conflicting, limited, moderate, and strong. MAIN RESULTS: An initial search revealed 3379 original articles for consideration. After initial review, 169 full-text articles were evaluated and 29 articles were included in the systematic review. Six tests were examined for the best evidence of methodologic quality: (1) 1-legged single hop for distance, (2) 1-legged triple hop for distance, (3) 6-m timed hop, (4) crossover hop for distance, (5) triple jump, and (6) 1-legged vertical jump. A summary of the methodologic properties of the 6 tests showed fair/poor reliability, fair/poor hypothesis testing, good criterion validity, and good/poor responsiveness. No tests predicted knee injury in athletes. CONCLUSIONS: Although numerous authors have evaluated PPTs at the knee, evidence for the measurement quality of these functional tests is limited and conflicting. Ample opportunity exists for researchers to further examine PPTs for the knee. Until more knowledge is gained about these PPTs, clinicians should exercise caution when making clinical decisions based on the results of these tests. PMID- 29116833 TI - Global Health Governance: The Major Players in the Field and Their Challenges. PMID- 29116834 TI - Fischer et al. Respond. PMID- 29116835 TI - Low-Risk Cannabis Use Is an Oxymoron. PMID- 29116836 TI - Cook et al. Respond. PMID- 29116837 TI - AJPH Global News. PMID- 29116838 TI - Understanding Increased Mortality After Gunshot Injury. PMID- 29116839 TI - Laws Facilitating Gun Carrying and Homicide. PMID- 29116840 TI - Risk Analysis: From Inside Baseball to Science Fiction. PMID- 29116841 TI - Income Volatility: A Preventable Public Health Threat. PMID- 29116842 TI - What Can We Do or Change to Encourage People to Seek Out Preexposure Prophylaxis? PMID- 29116843 TI - Buying Drugs Online in the Age of Social Media. PMID- 29116846 TI - Social Media as a Tool to Increase the Impact of Public Health Research. PMID- 29116847 TI - Deadly Filth, Cartographic Deception, Trail of Victims, Microscopic Godzillas. PMID- 29116848 TI - Capping Medicaid Funding-Lessons From Puerto Rico. PMID- 29116849 TI - Democratic Policy, Social Movements, and Public Health: A New Theme for AJPH Public Health Forum. PMID- 29116850 TI - Public Health Is Everyone's Kuleana. PMID- 29116852 TI - Measuring Physical Activity With Heart Rate Monitors. PMID- 29116851 TI - Arredondo et al. Respond. PMID- 29116855 TI - A Call for Submissions: AJPH Instagram Photo Contest. PMID- 29116856 TI - Public Health Planning for Pets. PMID- 29116858 TI - Rough Road. PMID- 29116857 TI - Out of Our Comfort Zone to Improve Population Health: A Public Health of Consequence, December 2017. PMID- 29116859 TI - What About the Trees? Trees as Nature-Based "Shade Sails". PMID- 29116860 TI - Evolution of Public Health Education in China. PMID- 29116861 TI - Dramatic Decreases in US Abortion Rates: Public Health Achievement or Failure? PMID- 29116862 TI - Venues Where Male Sex Workers Meet Partners: The Emergence of Gay Hookup Apps and Web Sites. PMID- 29116863 TI - Hypothermia Promotes Cell-Protective and Chondroprotective Effects After Blunt Cartilage Trauma. AB - BACKGROUND: Cryotherapy is routinely administered after sports injuries of synovial joints. Although positive clinical effects on periarticular swelling and pain have been described, the effects on the cell biological activities of cartilage and synovial cells remain largely unknown so far. HYPOTHESIS: Local hypothermia alleviates synovial reactions and prevents chondrocyte death as well as cartilage destructive processes after blunt cartilage trauma. STUDY DESIGN: Controlled laboratory study. METHODS: Human cartilage explants were impacted by a drop-tower apparatus (0.59 J) and cultured at 24 hours or 7 days in different temperature conditions (2 hours [short term], 16 hours [medium term], or throughout [long term] at 27 degrees C; afterwards or throughout at 37 degrees C). Besides, isolated human fibroblast-like synoviocytes (FLS) were stimulated with traumatized cartilage conditioned medium and cultured as mentioned above up to 4 days. The effects of hypothermia were evaluated by cell viability, gene expression, type II collagen synthesis and cleavage, as well as the release of matrix metalloproteinase (MMP)-2, MMP-13, and interleukin 6 (IL-6). RESULTS: Seven days after trauma, hypothermic treatment throughout improved cell viability (short term: 10.1% [ P = .016]; medium term: 6% [ P = .0362]; long term: 12.5% [ P = .0039]). Short-term hypothermia attenuated the expression of catabolic MMP-13 (mRNA: -2.2-fold [ P = .0119]; protein: -2-fold [ P = .0238]). Whereas type II collagen synthesis (1.7-fold [ P = .0227]) was increased after medium-term hypothermia, MMP-13 expression (mRNA: -30.8-fold [ P = .0025]; protein: -10.3 fold [ P < .0001]) and subsequent cleavage of type II collagen (-1.1-fold [ P = .0489]) were inhibited. Long-term hypothermia further suppressed MMP release (pro MMP-2: -3-fold [ P = .0222]; active MMP-2: -5.2-fold [ P = .0183]; MMP-13: -56 fold [ P < .0001]) and type II collagen breakdown (-1.6-fold [ P = .0036]). Four days after FLS stimulation, hypothermia significantly suppressed the gene expression of matrix-destructive enzymes after medium-term (MMP-3: -4.1-fold [ P = .0211]) and long-term exposure (a disintegrin and metalloproteinase with thrombospondin motifs 4 [ADAMTS4]: -4.3-fold [ P = .0045]; MMP-3: -25.8-fold [ P = .014]; MMP-13: -122-fold [ P = .0444]) and attenuated IL-6 expression by trend. CONCLUSION: After blunt cartilage trauma, initial hypothermia for only 2 hours and/or 16 hours induced significant cell-protective and chondroprotective effects and promoted the anabolic activity of chondrocytes, while the expression of matrix-destructive enzymes by stimulated FLS was attenuated by prolonged hypothermia. CLINICAL RELEVANCE: The findings of this preliminary ex vivo investigation indicate that optimized cryotherapy management after cartilage trauma might prevent matrix-degenerative processes associated with the pathogenesis of posttraumatic osteoarthritis. PMID- 29116865 TI - Ophthalmic abnormalities of Pai syndrome: A case report and review of literature. PMID- 29116864 TI - Robotic Pyeloplasty in Children: A "Barbed" Shortcut. AB - INTRODUCTION: Dismembered pyeloplasty remains the gold standard for the treatment of pelviureteric junction obstruction (PUJO). Robotic approach to this procedure has proven its efficacy and is gaining popularity. The introduction of barbed sutures such as "V-LocTM" (Covidien) has provided an addition to the sutures available for pyeloplasty. This work provides our experience with the V-Loc suture for closure of pelvis in children for robotic pyeloplasty (RP). MATERIALS AND METHODS: A review of 10 pediatric RP (da Vinci Robotic System) during which the V-Loc suture was used was performed. Comparison was made with 15 cases in which 5-0 Vicryl(r) suture was used as an alternative. Overall median age was 4 (range 9 months to 16 years), M:F = 14:9. All had confirmed PUJO on renal ultrasound and mercaptoacetyltriglycine (mertiatide) (MAG-3). RP was done in the standard Anderson-Hynes manner with the placement of a multilength JJ ureteral stent intraoperatively. Patients had removal of the JJ stent 6 weeks postoperatively followed by renal ultrasound 3-4 months later. RESULTS: Twenty five RPs have been performed between May 2013 and November 2015, of which 10 have had closure of the pelvis performed using the V-Loc suture and 15 with Vicryl. One patient (6.67%) in the Vicryl group underwent redo-pyeloplasty secondary to a stent-related complication. The entire V-Loc group made an eventful initial recovery; however, four (40%) developed worsening hydronephrosis and drainage on ultrasound and MAG-3 after stent removal, despite remaining completely asymptomatic. These four required either restenting and observation (n = 1) or redo-pyeloplasty (n = 3). Histology demonstrated a "plaque-like" inflammatory reaction at the pelvic suture line. CONCLUSION: Closure of the pelvis using V-Loc suture material during RP can lead to a significant hydronephrosis requiring further procedures, including redo-pyeloplasty. These children can be asymptomatic and so extra vigilance on postoperative follow-up is essential. PMID- 29116866 TI - Functional changes through the usage of 3D-printed transitional prostheses in children. AB - INTRODUCTION: There is limited knowledge on the use of 3 D-printed transitional prostheses, as they relate to changes in function and strength. Therefore, the purpose of this study was to identify functional and strength changes after usage of 3 D-printed transitional prostheses for multiple weeks for children with upper limb differences. MATERIALS AND METHODS: Gross manual dexterity was assessed using the Box and Block Test and wrist strength was measured using a dynamometer. This testing was conducted before and after a period of 24 +/- 2.61 weeks of using a 3 D-printed transitional prosthesis. The 11 children (five girls and six boys; 3-15 years of age) who participated in the study, were fitted with a 3 D printed transitional partial hand (n = 9) or an arm (n = 2) prosthesis. RESULTS: Separate two-way repeated measures ANOVAs were performed to analyze function and strength data. There was a significant hand by time interaction for function, but not for strength. Conclusion and relevance to the study of disability and rehabilitation: The increase in manual gross dexterity suggests that the Cyborg Beast 2 3 D-printed prosthesis can be used as a transitional device to improve function in children with traumatic or congenital upper-limb differences. Implications for Rehabilitation Children's prosthetic needs are complex due to their small size, rapid growth, and psychosocial development. Advancements in computer-aided design and additive manufacturing offer the possibility of designing and printing transitional prostheses at a very low cost, but there is limited knowledge on the function of this type of devices. The use of 3D printed transitional prostheses may improve manual gross dexterity in children after several weeks of using it. PMID- 29116867 TI - The Effects of Smoking Abstinence on Incentivized Spatial Working Memory. AB - BACKGROUND AND OBJECTIVE: Reward processing and working memory (WM) underlie value-based decision-making; consequently, joint examination of these systems may further our understanding of why smokers choose to smoke again following a quit attempt (relapse). While previous studies have demonstrated altered reward and WM function associated with nicotine exposure, little is known about the effects of abstinence on the joint function of these systems. The current study aims to address this gap. METHOD: Eighteen daily smokers were tested on a monetarily incentivized memory guided saccade (MGS) task on two separate, counterbalanced occasions, an abstinent and a non-abstinent session. The MGS task is a widely used metric of spatial working memory and enables precise quantification of the effects of rewards and nicotine exposure on behavior. RESULTS: During the non abstinent session, participants showed increased accuracy of the initial saccade towards the remembered target location on reward vs. neutral trials. Participants also showed increased accuracy of the final saccade towards the target, across incentive types, only during the non-abstinent condition. DISCUSSION AND CONCLUSIONS: Our observation that rewards improve the accuracy of the initial memory guided saccade during the non-abstinent but not abstinent condition extends a growing literature indicating reduced motivation towards monetary rewards during abstinence. Further, differences in the accuracy of the final corrective saccade during the non-abstinent but not the abstinent condition suggests smoking abstinence-related effects on WM precision beyond those related to incentive motivation (e.g., sustained attention). SIGNIFICANCE: This work extends our fundamental understanding of smoking's effects on core affective and cognitive processes. PMID- 29116868 TI - A multiple-group measurement scale for interprofessional collaboration: Adaptation and validation into Italian and German languages. AB - This article presents a study that aimed to validate a translation of a multiple group measurement scale for interprofessional collaboration (IPC). We used survey data gathered over a three month period as part of a mixed methods study that explored the nature of IPC in Northern Italy. Following a translation from English into Italian and German the survey was distributed online to over 5,000 health professionals (dieticians, nurses, occupational therapists, physicians, physiotherapists, speech therapists and psychologists) based in one regional health trust. In total, 2,238 different health professions completed the survey. Based on the original scale, three principal components were extracted and confirmed as relevant factors for IPC (communication, accommodation and isolation). A confirmatory analysis (3-factor model) was applied to the data of physicians and nurses by language group. In conclusion, the validation of the German and Italian IPC scale has provided an instrument of acceptable reliability and validity for the assessment of IPC involving physicians and nurses. PMID- 29116869 TI - The Promise, Growth, and Reality of Mobile Health - Another Data-free Zone. PMID- 29116870 TI - Inhibitory Control and Impulsivity Levels in Women Crack Users. AB - OBJECTIVE: investigate impulsivity levels and inhibitory control in women crack users and explore the relationships between impulsivity and inhibitory control. METHOD AND DESIGN: 52 healthy women (M = 32.83 years; SD = 9.54) and 46 crack cocaine users (M = 31.02 years; SD = 7.73), in abstinence, performed the assessment protocol included a Sociodemographic Data Questionnaire, Mini-Mental State Examination (MMSE), a GO/No-Go Task and the Barratt Impulsiveness Scale-11 (BIS-11). It was a quantitative research with cross-sectional design and control group. RESULTS: crack group showed higher levels of impulsivity in all domains when compared to the control group (crack group M = 76.39, SD = 11.39, control group M = 58.53, SD = 10.76, p <.01). Participants from the crack group presented a significantly higher total reaction time in the Go-NoGo task (F(1,93) = 9.93, p =.002; effect size =.09, observed power =.87) and significantly more commission (F(1,93) = 7.20, p =.009; effect size =.07, observed power =.75) and omission errors (F(1,93) = 6.04, p =.01; effect size =.06, observed power =.68), in Go/NoGo Task. Groups did also significantly differ on total standard deviations suggesting that variability in total reaction time was significantly greater in the crack group. Results showed that only in the crack group there were significant correlations between Go-NoGo parameters and Barratt Impulsiveness Scale. CONCLUSIONS: Our findings are consistent that impulsivity and inhibitory control are closely linked to crack use in women. Future studies should consider to evaluate crack users in different withdrawal times, controlling the impact of abstinence time in the variables studied. PMID- 29116871 TI - Examining Couple Functioning and Alcohol use Among Latino Couples: A Dyadic Data Analysis. AB - BACKGROUND: Prior research suggests that Latinos are at higher risk of alcohol use as compared to their counterparts (NSDUH, 2014). However, little work has been conducted to understand alcohol use among Latinos systemically and more research is needed to better understand the impact of couple functioning on alcohol use among Latino couples. OBJECTIVES: The current study aimed to examine how each partner's perception of couple functioning impacted alcohol use in Latino dyads. METHODS: Using data from 329 Latino dyads from the Building Strong Families (BSF) Project, a structural equation model examining the actor-partner interactions between partner perceptions of couple functioning and each person's alcohol use was analyzed. RESULTS: Correlation analysis revealed that the dyad's perceptions of couple functioning were positively correlated. Results from the APIM model indicated male's perceptions of couple functioning was positively associated with his own alcohol use, whereas female's perceptions of couple functioning was not significantly related to either partner's alcohol use. Conclusions/Importance: The findings may help clinicians, researchers, and policy makers to better conceptualize how couple functioning may impact alcohol use among Latino dyads. PMID- 29116873 TI - The Effect of Experimental Supplementation with the Klamath Algae Extract Klamin on Attention-Deficit/Hyperactivity Disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobiological condition with onset in childhood. The disorder is characterized by inattention, impulsivity, and/or motor hyperactivity, which often affect the development and social integration of affected subjects. Phenylethylamine (PEA), naturally contained in the Klamath Lake microalgae and concentrated in the Klamin(r) extract, is an endogenous molecule with a general neuromodulatory activity. It functions as an activator for the neurotransmission of dopamine and other catecholamines, and very low concentrations of PEA may be associated with specific psychological disorders such as ADHD. The aim of our study was to evaluate the efficacy of the Klamin extract in treating a group of subjects diagnosed with ADHD. Thirty subjects, aged 6-15, who had been diagnosed with ADHD according to the DSM-IV TR criteria, were enrolled. The supplement was administered to all the subjects, who reported to an ADHD clinic for routine follow-up visits. Observations were made and data collected over a 6-month period. After 6 months of therapy the subjects appeared to show significant improvements based on assessments of their overall functioning, behavioral aspects related to inattention and hyperactivity-impulsivity, attention functions in both the selective and sustained component and executive functions. The study appears to confirm the initial hypothesis that the Klamin extract may positively affect the expression of ADHD symptoms. Additional larger studies on the effects of Klamin on ADHD are needed to further investigate the potential of this extract in ADHD treatment. PMID- 29116874 TI - [The interparental relationship in families with children with ADHD: Interactions between couple distress and child's symptoms]. AB - The interparental relationship in families with children with ADHD: Interactions between couple distress and child's symptoms Abstract. The impact of the family in the development and maintenance of childhood ADHD is well established. However, previous research in this field focused largely on parenting and the quality of the parent-child relationship, whereas the role of the interparental relationship has been neglected. This review summarizes the current state of research on the interactions between a couple distress and their child's ADHD and discusses interparental conflict as a risk factor for the development of ADHS related symptoms. Based on the present knowledge, an integrative model is postulated that assumes an interaction of genetic vulnerability for childhood ADHD and a couple distress. It depicts how distress in the interparental relationship may both directly and indirectly affect the etiology, maintenance, and/or amplification of childhood ADHD-related symptoms, which in turn affect the interparental relationship. The review highlights the significance of relationship distress prevention programs for couples to prevent adjustment problems in children, and the adequate consideration of couple conflict in diagnostics and therapy among families with children with ADHD. PMID- 29116875 TI - Low-cost innovation in healthcare: what you find depends on where you look. PMID- 29116876 TI - Preservation of Functional Microvascular Bed Is Vital for Long-Term Survival of Cardiac Myocytes Within Large Transmural Post-Myocardial Infarction Scar. AB - This study was aimed to understand the mechanism of persistent cardiac myocyte (CM) survival in myocardial infarction (MI) scars. A transmural MI was induced in 12-month-old Sprague-Dawley rats by permanent coronary artery ligation. The hearts were collected 3 days, 1, 2, 4, 8, and 12 weeks after MI and evaluated with histology, immunohistochemistry, and quantitative morphometry. Vasculature patency was assessed in 4-, 8-, and 12-week-old scars by infusion of 15-micron microspheres into the left ventricle before euthanasia. The infarcted/scarred area has a small continually retained population of surviving CMs in subendocardial and subepicardial regions. Surprisingly, whereas the transverse area of subepicardial CMs remained relatively preserved or even enlarged over 12 post-MI weeks, subendocardial CMs underwent progressive atrophy. Nevertheless, the fractional volume of viable CMs remained comparable in mature scars 4, 8, and 12 weeks after MI (3.6 +/- 0.4%, 3.4 +/- 0.5%, and 2.5 +/- 0.3%, respectively). Despite the opposite dynamics of changes in size, CMs of both regions displayed sarcomeres and gap junctions. Most importantly, surviving CMs were always accompanied by patent microvessels linked to a venous network composed of Thebesian veins, intramural sinusoids, and subepicardial veins. Our findings reveal that long-term survival of CMs in transmural post-MI scars is sustained by a local microcirculatory bed. PMID- 29116877 TI - Norwegian general practitioners' collaboration with municipal care providers - a qualitative study of structural conditions. AB - PURPOSE: The purpose of this study was to explore the structural mechanisms that facilitate or counteract collaboration between general practitioners (GPs) and other providers of municipal healthcare. Good collaboration between these actors is crucial for high-quality care, especially for persons in need of coordinated services. MATERIAL AND METHODS: The study is based on semistructured interviews with 12 healthcare providers in four Norwegian municipalities: four GPs, six nurses and two physiotherapists. RESULTS: GPs are key collaborating partners in the healthcare system. Their ability to collaborate is affected by a number of structural conditions. Mostly, this leads to GPs being too little involved in potential collaborative efforts: (i) individual GPs prioritize with whom they want to collaborate among many possible collaborative partners, (ii) inter municipal constraints hamper GPs in contacting collaboration partners and (iii) GPs fall outside the hospital-municipality collaboration. CONCLUSIONS: We argue a common leadership for primary care services is needed. Furthermore, inter professional work must be a central focus in the planning of primary care services. However, a dedicated staff, sufficient resources, adequate time and proper meeting places are needed to accomplish good collaboration. PMID- 29116878 TI - Evaluation of Methadone Treatment in Malaysia: Findings from the Malaysian Methadone Treatment Outcome Study (MyTOS). AB - BACKGROUND: Opioid misuse and dependence is a global issue with a huge negative impact. In Malaysia, heroin is still the main illicit drug used, and methadone maintenance treatment (MMT) has been used since 2005. OBJECTIVE: To evaluate the effectiveness of MMT. METHODS: This was a cross-sectional study conducted in 103 treatment centers between October and December 2014 using a set of standard questionnaires. Data were analyzed using SPSS Statistics 20. RESULTS: There were 3254 respondents (93.6% response rate); of these 17.5% (n = 570) transferred to another treatment center, 8.6% (n = 280) died, 29.2% (n = 950) defaulted, and 7.6% (n = 247) were terminated for various reasons. Hence, 1233 (37%) respondents' baseline and follow-up data were further analyzed. Respondents had a mean age of 39.2 years old and were mainly male, Malay, Muslim, married (51.1%, n = 617), and currently employed. Few showed viral seroconversion after they started MMT (HIV: 0.5%, n = 6; Hepatitis B: 0.3%, n = 4; Hepatitis C: 2.7%, n = 29). There were significant reductions in opioid use, HIV risk-taking score (p < 0.01), social functioning (p < 0.01), crime (p < 0.01), and health (p < 0.01). However, there were significant improvements in quality of life in the physical, psychological, social, and environmental domains. Factors associated with change were being married, employed, consuming alcohol, and high criminality at baseline. Lower methadone dosage was significantly associated with improvements in the physical, psychological, and environmental domains. Conclusion/Importance: The MMT program was found to be successful; hence, it should be expanded. PMID- 29116879 TI - Health Care Professionals and Law Enforcement. PMID- 29116880 TI - Safety and immunogenicity of Clostridium difficile toxoid vaccine in Japanese adults. AB - This was a randomized, placebo-controlled, Phase I/II study conducted in a Japanese cohort to assess the safety and immunogenicity of Clostridium difficile vaccine (the same formulation as that used in the ongoing global Phase III study). Healthy Japanese adults aged 40-75 years were randomized to receive either C. difficile vaccine (N = 67) or placebo (N = 34) by intramuscular injection on Days 0, 7, and 30. Serum IgG specific for toxins A and B was measured by enzyme-linked immunosorbent assay (ELISA) and in vitro functional activity by toxin neutralizing assay (TNA). The seroconversion rate (percentage of participants with a >=4-fold rise in antibody levels from baseline) was high for both toxin A (ELISA and TNA) and toxin B (ELISA), approaching 100% for each by Day 60. For toxin B assessed by TNA, however, the response was lower, with the seroconversion rate not rising significantly beyond the value of 42.9% seen on Day 14 (44.4% at Day 60). Although the response in the participants who were seronegative at baseline was slower than that in those who were seropositive, seroconversion was seen in nearly all (100%) subjects by Day 60, with the exception of the response to toxin B evaluated using TNA (16-18% on Days 14-60). The proportion of participants with solicited local reactions, solicited systemic reactions, and vaccine-related unsolicited reactions were 67.6%, 19.1%, and 20.6%, respectively. Most of the adverse reactions were mild to moderate in intensity, occurring within 3 days post-vaccination, and resolving by 3-6 days post-vaccination. There were no withdrawals due to adverse events and no serious adverse events. These data confirm the safety and immunogenicity of C. difficile vaccine in Japanese adults. PMID- 29116882 TI - Lingering Cognitive States Shape Fundamental Mnemonic Abilities. AB - Why are people sometimes able to recall associations in exquisite detail while at other times left frustrated by the deficiencies of memory? Although this apparent fickleness of memory has been extensively studied by investigating factors that build strong memory traces, researchers know less about whether memory success also depends on cognitive states that are in place when a cue is encountered. Motivating this possibility, neurocomputational models propose that the hippocampus's capacity to support associative recollection (pattern completion) is biased by persistent neurochemical states, which can be elicited by exposure to familiarity and novelty. We investigated these models' behavioral implications by assessing how recent familiarity influences different memory-retrieval processes. We found that recent familiarity selectively benefitted associative memory (Experiment 1) and that this effect decayed over seconds (Experiment 2), consistent with the timescale of hippocampal neuromodulation. Thus, we show that basic memory computations can be shaped by a subtle, biologically motivated manipulation. PMID- 29116881 TI - Latitudinal and Temperature-Dependent Variation in Embryonic Development Rate and Offspring Performance in a Freshwater Turtle. AB - The thermal environment of embryos differs significantly along a latitudinal cline, and the mechanism by which embryos respond to this geographic temperature variation has attracted increasing attention recently. Here, we carried out a common-garden experiment of egg incubation at two fluctuating temperature regimes to elucidate the latitudinal pattern and thermal dependence of the embryonic development rate and offspring performance in the Chinese soft-shelled turtle (Pelodiscus sinensis). Our results demonstrated significant temperature-by population interactions on variations in the incubation period and hatchling righting response. The incubation period was shorter and the daily number of heart beats was higher in the medium- and high-latitude populations than in the low-latitude population at low incubation temperatures but not at high temperatures. Offspring from the medium- and high-latitude populations showed a faster righting response than those from the low-latitude population when incubated at low temperatures, whereas offspring from the high-latitude population showed a faster righting response than those from the medium-latitude population when incubated at high temperatures. This indicates that turtle embryos from different latitudinal locations may have evolved divergent thermal sensitivities of embryonic development in response to their respective nest environments. PMID- 29116883 TI - The Elusive Search for Reniform Nematode Resistance in Cotton. AB - The reniform nematode (Rotylenchulus reniformis Linford and Oliveira) has emerged as the most important plant-parasitic nematode of cotton in the United States cotton belt. Success in the development of reniform nematode-resistant upland cotton cultivars (Gossypium hirsutum L.) has not been realized despite over three decades of breeding efforts. Research approaches ranging from conventional breeding to triple species hybrids to marker-assisted selection have been employed to introgress reniform nematode resistance from other species of cotton into upland cultivars. Reniform nematode-resistant breeding lines derived from G. longicalyx were developed in 2007. However, these breeding lines displayed stunting symptoms and a hypersensitive response to reniform nematode infection. Subsequent breeding efforts focused on G. barbadense, G. aridum, G. armoreanum, and other species that have a high level of resistance to reniform nematode. Marker-assisted selection has greatly improved screening of reniform nematode resistant lines. The use of advanced molecular techniques such as CRISPER-Cas9 systems and alternative ways such as delivery of suitable "cry" proteins and specific double-stranded RNA to nematodes will assist in developing resistant cultivars of cotton. In spite of the efforts of cotton breeders and nematologists, successes are limited only to the development of reniform nematode resistant breeding lines. In this article, we provide an overview of the approaches employed to develop reniform nematode-resistant upland cotton cultivars in the past, progress to date, major obstacles, and some promising future research activity. PMID- 29116885 TI - Feline Toxoplasmosis: Tumor Necrosis Factor, Nitric Oxide, and Free Radicals in Seropositive Cats. AB - Toxoplasma gondii is a cosmopolitan protozoan that causes disease in several species, including humans. In cats, these infections are usually asymptomatic, but in other species they can lead to high levels of inflammatory and cell damage markers, causing cellular damage. Therefore, the aim of this study was to measure levels of tumor necrosis factor (TNF-alpha), reactive oxygen species (ROS), and nitric oxide (nitrite/nitrate-NOx) in the serum of cats seropositive for T. gondii. Initially, we investigated the presence of antibodies against T. gondii in cats in the city of Concordia, Santa Catarina, Brazil, with the use of indirect immunofluorescence (IFA), and found 30 cats seropositive for T. gondii and 30 seronegative cats. In this study, seropositive cats showed higher levels of TNF-alpha, ROS, and NOx compared to seronegative cats. Although cats do not show clinical signs of disease, constant inflammatory response can cause cell damage, which over time may adversely affect the animal. PMID- 29116884 TI - Hamstring Injuries in Professional Soccer Players: Extent of MRI-Detected Edema and the Time to Return to Play. AB - BACKGROUND: Discrepancies exist in the literature regarding the association of the extent of injuries assessed on magnetic resonance imaging (MRI) with recovery times. HYPOTHESIS: MRI-detected edema in grade 1 hamstring injuries does not affect the return to play (RTP). STUDY DESIGN: Retrospective cohort study. LEVEL OF EVIDENCE: Level 4. METHODS: Grade 1 hamstring injuries from 22 professional soccer players were retrospectively reviewed. The extent of edema-like changes on fluid-sensitive sequences from 1.5-T MRI were evaluated using craniocaudal length, percentage of cross-sectional area, and volume. The time needed to RTP was the outcome. Negative binomial regression analysis tested the measurements of MRI-detected edema-like changes as prognostic factors. RESULTS: The mean craniocaudal length was 7.6 cm (SD, 4.9 cm; range, 0.9-19.1 cm), the mean percentage of cross-sectional area was 23.6% (SD, 20%; range, 4.4%-89.6%), and the mean volume was 33.1 cm3 (SD, 42.6 cm3; range, 1.1-161.3 cm3). The mean time needed to RTP was 13.6 days (SD, 8.9 days; range, 3-32 days). None of the parameters of extent was associated with RTP. CONCLUSION: The extent of MRI edema in hamstring injuries does not have prognostic value. CLINICAL RELEVANCE: Measuring the extent of edema in hamstring injuries using MRI does not add prognostic value in clinical practice. PMID- 29116886 TI - Coal miner participation in a job transfer program designed to prevent progression of pneumoconiosis, United States, 1986-2016. AB - The Part 90 program was designed to prevent progression of pneumoconiosis in U.S. coal miners by establishing their right to transfer to a less dusty job in the mine. We calculated the proportion of Part 90-eligible miners who participated during 1986-2016, examined participation by region, and compared characteristics of miners by participation status. Of the 3,547 eligible miners, 14.4% exercised their Part 90 option. Miners working in states outside central Appalachia, and those with more severe pneumoconiosis, were more likely to participate. The primary goal of respiratory health surveillance of coal miners is early detection of disease so that preventive action can be taken. Future studies should seek to better understand factors influencing Part 90 program participation. PMID- 29116887 TI - WASH and gender in health care facilities: The uncharted territory. AB - Health care facilities in low- and middle-income countries are high-risk settings, and face special challenges to achieving sustainable water, sanitation, and hygiene (WASH) services. Our applied interdisciplinary research conducted in India and Uganda analyzed six dimensions of WASH services in selected health care facilities, including menstrual hygiene management. To be effective, WASH monitoring strategies in health care facilities must include gender sensitive measures. We present a novel strategy, showing that applied gender sensitive multitool assessments are highly productive in assessments of WASH services and facilities from user and provider perspectives. We discuss its potential for applications at scale and as an area of future research. PMID- 29116888 TI - Incidence of Maxillary Sinus Disease Before Sinus Floor Elevation Surgery as Identified by Cone-Beam Computed Tomography: A Literature Review. AB - The purpose of this study is to review the literature to assess the incidence of maxillary sinus disease before sinus floor elevation surgery (SFE) as identified by cone-beam computerized tomography (CBCT). Only studies in which CBCT was performed in patients for dental implant placement in the past 10 years were considered. Eleven studies were identified. A total of 1792 patients were collected. All the studies reviewed reported on thickening of the sinus mucosa as a criterion for sinus disease with different threshold values. All studies reported mucosal thickening (MT) ranging between 25.5% and 93.1%. The mean incidence of MT was 54.99%. Two studies examined the correlation of MT with clinical symptoms. Three studies reported evaluation of the ostiomeatal complex (OMC). There is a high probability of detecting a certain degree of MT in patients referred for SFE. There is no consensus regarding the threshold values beyond which MT is considered pathological. Independently from the threshold values or the type of MT, the studies lack correlation with clinical data regarding patients' sinusitis-related history or symptoms. CBCT with a large field of view to evaluate the OMC is appropriate in patients scheduled for SFE. Future studies should include a systematic correlation with clinical symptoms and the possible presence of OMC obstruction. A clinical assessment that includes nasal endoscopy is indicated when MT and obstruction of the OMC are identified. Surgical correction of OMC obstruction seems to be appropriate to increase the success rate and to avoid possible complication after SFE. PMID- 29116889 TI - Family physicians' perspectives on interprofessional teamwork: Findings from a qualitative study. AB - The aim of this study was to describe family physicians' perspectives of their role in the primary care team and factors that facilitate and hinder teamwork. A qualitative study was conducted employing individual interviews with 19 academic/community-based family physicians who were part of interprofessional primary care teams in Edmonton, Alberta, Canada. Professional responsibilities and roles of physicians within the team and the facilitators and barriers to teamwork were investigated. Interviews were audiotaped, transcribed and analysed for emerging themes. The study findings revealed that family physicians consistently perceived themselves as having the leadership role on in the primary care team. Facilitators of teamwork included: communication; trust and respect; defined roles/responsibilities of team members; co-location; task shifting to other health professionals; and appropriate payment mechanisms. Barriers to teamwork included: undefined roles/responsibilities; lack of space; frequent staff turnover; network boundaries; and a culture of power and control. The findings suggest that moving family physicians toward more integrative and interdependent functioning within the primary care team will require overcoming the culture of traditional professional roles, addressing facilitators and barriers to teamwork, and providing training in teamwork. PMID- 29116891 TI - Measurements and health impacts of carbon black and BTEXs in photocopy centers. AB - The purpose of this study was to measure the concentration of carbon black and BTEXs at three photocopy centers and to assess the health risk following exposure. Air samples were collected by sampling in the breathing zone of workers during the class and examination periods. The results found that the concentration of carbon black before operation was higher than morning and afternoon in both class and examination periods. These levels are considerably lower than the suggested limited value set by OSHA. Toluene had the highest concentration but did not exceed of recommended exposure limit by NIOSH. The carbon black and toluene concentrations were higher in examination period than during the normal class period. The results from interview indicate that cough and sneeze are the highest symptom among workers. Carbon black and toluene concentrations in photocopy centers should be concerned in terms of indoor air quality and human health. PMID- 29116892 TI - Lessons from the Meningitis Vaccine Project. AB - From 2001 to 2017 the Meningitis Vaccine Project (MVP), a Gates Foundation funded partnership between PATH and the World Health Organization (WHO), successfully developed, tested, licensed, and introduced an affordable new Group A meningococcal conjugate vaccine, MenAfriVac, in sub-Saharan Africa. The vaccine was well received, and from 2010 to 2016, over 260 million Africans have received a dose of the vaccine in campaigns largely directed at 1-29-year olds. The public health impact has been dramatic with the elimination of Group A meningococcal infections wherever the vaccine has been used at public health scale. Over its 16 year life span, MVP faced many challenges, and lessons were learned that may be of interest to other groups seeking to develop vaccine products for resource-poor countries. We have chosen to highlight six elements that were keys to the success of the project: (a) country and African regional engagement during all phases of the project; (b) the evolution of the WHO/PATH partnership; (c) funding the introduction of MenAfriVac in meningitis belt countries; (d) regulatory challenges; (e) clinical trials in Africa and India; and (f ) the realities of vaccine development partnerships. PMID- 29116893 TI - ? PMID- 29116890 TI - A Test-and-Not-Treat Strategy for Onchocerciasis in Loa loa-Endemic Areas. AB - BACKGROUND: Implementation of an ivermectin-based community treatment strategy for the elimination of onchocerciasis or lymphatic filariasis has been delayed in Central Africa because of the occurrence of serious adverse events, including death, in persons with high levels of circulating Loa loa microfilariae. The LoaScope, a field-friendly diagnostic tool to quantify L. loa microfilariae in peripheral blood, enables rapid, point-of-care identification of persons at risk for serious adverse events. METHODS: A test-and-not-treat strategy was used in the approach to ivermectin treatment in the Okola health district in Cameroon, where the distribution of ivermectin was halted in 1999 after the occurrence of fatal events related to L. loa infection. The LoaScope was used to identify persons with an L. loa microfilarial density greater than 20,000 microfilariae per milliliter of blood, who were considered to be at risk for serious adverse events, and exclude them from ivermectin distribution. Active surveillance for posttreatment adverse events was performed daily for 6 days. RESULTS: From August through October 2015, a total of 16,259 of 22,842 persons 5 years of age or older (71.2% of the target population) were tested for L. loa microfilaremia. Among the participants who underwent testing, a total of 15,522 (95.5%) received ivermectin, 340 (2.1%) were excluded from ivermectin distribution because of an L. loa microfilarial density above the risk threshold, and 397 (2.4%) were excluded because of pregnancy or illness. No serious adverse events were observed. Nonserious adverse events were recorded in 934 participants, most of whom (67.5%) had no detectable L. loa microfilariae. CONCLUSIONS: The LoaScope based test-and-not-treat strategy enabled the reimplementation of community-wide ivermectin distribution in a heretofore "off limits" health district in Cameroon and is a potentially practical approach to larger-scale ivermectin treatment for lymphatic filariasis and onchocerciasis in areas where L. loa infection is endemic. (Funded by the Bill and Melinda Gates Foundation and others.). PMID- 29116895 TI - ? PMID- 29116894 TI - ? PMID- 29116896 TI - ? PMID- 29116897 TI - ? PMID- 29116898 TI - [Suicidality and Nonsuicidal Self-Injury in childhood and adolescence]. PMID- 29116899 TI - ? PMID- 29116900 TI - Safety and Antitumor Activity of the Anti-Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma. AB - Purpose The anti-programmed death-1 antibody pembrolizumab was evaluated in KEYNOTE-028, a multicohort, phase IB study of patients with programmed death ligand-1 (PD-L1)-positive advanced solid tumors. Results from the esophageal carcinoma cohort are reported herein. Patients and Methods Eligible patients with squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction in whom standard therapy failed and who had PD-L1-positive tumors received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or intolerable toxicity. Response was assessed every 8 weeks up to 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate, determined by investigator review per Response Evaluation Criteria in Solid Tumors (version 1.1). Results Among 83 patients with esophageal carcinoma and samples evaluable for PD-L1 expression, 37 (45%) had PD-L1-positive tumors, and 23 were enrolled. Median age was 65 years; 78% had squamous histology; and 87% received >= two prior therapies for advanced/metastatic disease. As of the data cutoff (February 20, 2017), median follow-up was 7 months (range, 1 to 33 months). Nine patients (39%) experienced treatment-related adverse events, most commonly decreased appetite, decreased lymphocyte count, generalized rash, and rash (two patients [9%] each). No grade 4 adverse events or deaths were attributed to pembrolizumab. Overall response rate was 30% (95% CI, 13% to 53%); median duration of response was 15 months (range, 6 to 26 months). A six-gene interferon-gamma gene expression signature analysis suggested that delayed progression and increased response occur among pembrolizumab-treated patients with higher interferon-gamma composite scores. Conclusion Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1-positive advanced esophageal carcinoma. PMID- 29116901 TI - Use of ICS in COPD: From Blockbuster Medicine to Precision Medicine. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide, whose burden is expected to increase in the next decades, because of numerous risk factors, including the aging of the population. COPD is both preventable and treatable by an effective management including risk factor reduction, prevention, assessment, and treatment of acute exacerbations and co morbidities. The available agents approved for COPD treatment are long-acting or ultra-long-acting beta2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) bronchodilators, as well as inhaled corticosteroids (ICS) in combination with LABAs. ICS use has been restricted only to selected COPD patients by the most recent documents, mainly based on the risk of exacerbations. However, several observational studies showed a high rate of prescription of ICS in COPD, irrespective of clinical recommendations, questioning the efficacy of these compounds in unselected patients with COPD and leading to possible increase risk of side effects related to ICS use. After examining the low levels of adherence in primary care and in the clinical settings to national and international recommendations for the treatment of COPD in different countries, the most common drivers of the prevailing use of ICS are critically reviewed here by examining their pros and cons, aimed at identifying evidence-based drivers for a proper selection of patients who may benefit from the proper use of ICS. PMID- 29116902 TI - UK-trained junior doctors' intentions to work in UK medicine: questionnaire surveys, three years after graduation. AB - Objective To report on the career intentions, three years after qualification, of 12 national cohorts of UK-trained doctors who qualified between 1974 and 2012, and, specifically, to compare recent UK medical graduates' intentions to work in medicine in the UK with earlier graduates. Design Questionnaire surveys of cohorts of UK medical graduates defined by year of graduation. Setting UK. Participants 30,272 UK medical graduates. Main outcome measures Stated level of intention to pursue a long-term career in medicine in the UK. Results The response rate was 62% (30,272/48,927). We examined responses to the question ' Apart from temporary visits abroad, do you intend to practise medicine in the United Kingdom for the foreseeable future?' Of doctors from UK homes, 90% had specified that they would 'definitely or probably' practise medicine in the UK in the surveys of 1977-1986, 81% in 1996-2011 and 64% in 2015. Those who said that they would probably or definitely not practise medicine in the UK comprised 5% in 1977-1986, 8% in 1996-2011 and 15% in 2015. Most who were not definite about a future career in UK medicine indicated that they would wish to practise medicine outside the UK rather than to leave medicine. Conclusions The wish to remain in UK medical practice in the 2015 survey was unprecedentedly low in this unique series of 40 years of surveys. PMID- 29116903 TI - Letter to the Editor. PMID- 29116904 TI - A New Era for the Journal. PMID- 29116905 TI - Epistemic injustice in dementia and autism patient organizations: An empirical analysis. AB - Patient organizations (POs) represent patient collectives in health care policy. The inclusion of people with a 'neuro-psychiatric' condition poses a particular challenge for the organizational processes and political representation of such collectives. In recent years, new POs (POs of) have been established in the field of autism spectrum disorder and dementia that advocate a different agenda and have a different organizational structure than traditional POs (POs for). The divide between these two types of POs indicates a different standpoint with regard to who should be included on an organizational level, which voices are accepted and who should represent these voices on the political level. The inclusion and exclusion of voices needs to be normatively justified in order to be regarded legitimate representation of such a collective. With the help of Miranda Fricker's theory of epistemic injustice, we scrutinize whether and, if so, which types of epistemic injustices (wrongdoings to a person as a knower) can be found within POs' practices and the political field in which they operate, by analyzing 37 interviews with PO representatives, their members and policy makers. Our in-depth analysis indicates that persistent stereotypes hamper the inclusion of affected members both within POs and on the health political level. Being affected causes distrust in having the 'capacity to know' in a two-fold way; it is assumed that those who can represent themselves are "not affected enough" to present valuable insights into the condition and those who have difficulties to express themselves due to their condition are excluded because of their affectedness. We conclude that our analysis of the epistemic practices of POs serves as a good starting point to address these shortcomings from a theoretical and practical perspective and offers a valuable starting point for bioethics to understand unjust structures in the health political context. PMID- 29116907 TI - A Fond Farewell. PMID- 29116906 TI - Prevalence and determinants of burnout Syndrome and Depression among medical students at Sultan Qaboos University: A cross-sectional analytical study from Oman. AB - This study investigated the prevalence and determinants of Burnout Syndrome and Depressive Symptoms among medical students in Oman. Then, it explored whether the three-dimensional aspects of Burnout Syndrome (High Emotional Exhaustion, High Cynicism and Low Academic Efficacy) would predict the presence of Depressive Symptoms in a logistic regression model. A cross-sectional study was conducted among a random sample of medical students of Sultan Qaboos University. 662 students participated in the study with a response rate of 98%. The prevalence of Burnout Syndrome and Depressive Symptoms were; 7.4% and 24.5% respectively. Preclinical students reported high levels of both Burnout Syndrome (Odds Ratio-OR 2.83, 95% Confidence Interval CI 1.45-5.54) and Depressive Symptoms (OR 2. 72, 95% CI 1.07-6.89). The three-dimensional aspects of Burnout Syndrome(High Emotional Exhaustion, High Cynicism, low Professional efficacy) were statistically significant predictors of the presence of Depressive Symptoms; OR 3.52 (95% CI: 2.21-5.60), OR 3.33 (95% CI:2.10-5.28) and OR 2.07(95%CI:1.32-3.24) respectively. This study indicates that Burnout Syndrome and Depressive Symptoms are common among medical students, particularly in preclinical grade. Furthermore, the presence of high occupational burnout elevates the risk of depression. PMID- 29116908 TI - Small Change Makes a Big Splash: The Role of Working Self-Concept in the Effects of Stereotype Threat on Memory. AB - Assuming that the principle of an active-self account holds true in real life, priming certain constructs could selectively activate a working self-concept, which in turn guides behavior. The current study involved two experiments that examined the relationships between stereotypic identity, working self-concept, and memory performance in older adults. Specifically, Study 1 tested whether a stereotype threat can affect older adults' working self-concept and memory performance. A modified Stroop color naming task and a separate recognition task showed that a stereotype threat prime altered the activation of the working self concept and deteriorated the older adults' memory performance. Additionally, the working self-concept mediated the effect of stereotype threat on memory performance. Accordingly, we designed Study 2 to assess whether priming different identities can alter the working self-concept of the elderly and buffer the stereotype threat effect on memory performance. The results not only were the same as Study 1 but also revealed that activating multiple identities could mitigate the stereotype threat. These results support an active-self account and the efficacy of stereotype threat intervention. This intervention strategy may be able to be used in real situations to help the elderly alleviate stereotype threats and memory impairment. PMID- 29116909 TI - Supporting Families Experiencing Homelessness: Current Practices and Future Directions, edited by M. E. Haskett, S. Perlman, and B. A. Cowan. PMID- 29116911 TI - Energy Recycling by Co-Combustion of Coal and Recovered Paint Solids from Automobile Paint Operations. AB - Experiments were carried out in a pilot-scale pulverized coal combustor at the Energy and Environmental Research Center (EERC) burning a Powder River Basin (PRB) subbituminous coal. A scanning mobility particle sizer (SMPS) and an electrical low-pressure impactor (ELPI) were used to measure the particle size distributions (PSDs) in the range of 17 nm to 10 MUm at the inlet and outlet of the electrostatic precipitator (ESP). At the ESP inlet, a high number concentration of ultrafine particles was found, with the peak at approximately 75 nm. A trimodal PSD for mass concentration was observed with the modes at approximately 80-100 nm, 1-2 MUm, and 10 MUm. The penetration of ultrafine particles through the ESP increased dramatically as particle size decreased below 70 nm, attributable to insufficient or partial charging of the ultrafine particles. Injection of nanostructured fine-particle sorbents for capture of toxic metals in the flue gas caused high penetration of the ultrafine particles through the ESP. The conventional ESP was modified to enhance charging using soft X-ray irradiation. A slipstream of flue gas was introduced from the pilot-scale facility and passed through this modified ESP. Enhancement of particle capture was observed with the soft X-ray irradiation when moderate voltages were used in the ESP, indicating more efficient charging of fine particles. PMID- 29116910 TI - Treatment of femoropopliteal lesions with the AngioSculpt scoring balloon - results from the Heidelberg PANTHER registry. AB - BACKGROUND: Treatment of calcified femoropopliteal lesions remains challenging, even in the era of drug-eluting balloon angioplasty. Lesion recoil and dissections after standard balloon angioplasty in calcific lesions often require subsequent stent implantation. Additionally, poor patency rates in calcified lesions despite the use of drug-eluting balloons may be due to the limited penetration depth of the antiproliferative drug in the presence of vascular calcium deposits. Therefore, preparation of calcified lesions with the AngioSculptTM scoring balloon might be a valuable option either as a stand-alone treatment, followed by drug-eluting balloon angioplasty or prior to subsequent stent deployment. PATIENTS AND METHODS: In this retrospective, single centre registry, 124 calcified femoropopliteal lesions were treated in 101 subsequent patients. All patients were treated with scoring balloon angioplasty, either alone, in combination with drug-eluting balloons, or prior to stent deployment. The primary outcome was safety and technical success during the index procedure as well as patency at six and 12 months, as evaluated by duplex sonography. RESULTS: Successful scoring was safely performed in all 124 lesions with the AngioSculptTM balloon. Overall primary patency after 12 months was 81.2 %. Patency rates did not differ significantly between the three treatment strategies. Degree of calcification did not predict patency. Improved clinical outcomes (Rutherford-Becker class and ankle-brachial index) were also observed in the study cohort. CONCLUSIONS: Preparation with the AngioSculptTM scoring balloon offers a safe and valuable treatment option for calcified femoropopliteal lesions. PMID- 29116913 TI - Intercomparison of Clean Air Status and Trends Network Nitrate and Nitric Acid Measurements with Data from Other Monitoring Programs. AB - The U.S. Environmental Protection Agency Clean Air Status and Trends Network (CASTNET) utilizes an open-face filter pack system to measure concentrations of atmospheric sulfur and nitrogen species. Concentration data for nitrogen species measured with filter pack systems sometimes deviate from data collected by other measurement systems used to measure the same species. The nature of these differences suggests that more than one sampling mechanism or atmospheric process is involved. The study presented here examines these differences by intercomparing CASTNET data with data from other studies, examining the results from earlier intercomparison studies, and conducting a field test to investigate the effect of particle size on filter pack measurement systems. Measurements of nitrogen species from the Maryland Aerosol Research and Characterization (MARCH) monitoring site were compared with nitrogen concentrations at three nearby CASTNET sites. Results indicate that CASTNET measured higher particulate nitrate (NO3-) and lower gaseous nitric acid (HNO3) concentrations. Comparisons of NO3- from 34 collocated CASTNET and Inter-agency Monitoring of Protected Visual Environments (IMPROVE) sites show that CASTNET NO3- measurements were typically higher than the corresponding IM PROVE values. Also, results from the Lake Michigan Air Director's Consortium Midwest Ammonia Monitoring Project demonstrated NO3- dissociation on Teflon filters. To investigate the effect of particle size, filter pack measurement systems were operated at three CASTNET sites with and without cyclones during six 7-day measurement periods from March to August 2006. Results indicate the size-selection cyclones had a significant effect on both NO3- and HNO3 concentrations, but little effect on sulfate (SO42-) and ammonium (NH4+) levels. NO3- concentrations sampled with the open-face filters were significantly higher than concentrations measured with a 2.5-MUm cut point, as were HNO3 concentrations. Although limited in spatial and temporal coverage, the field study showed that the use of an open-face filter pack may allow for the collection of coarse NO3- particles and for the reaction of HNO3 with metals/salts on the Teflon filter. PMID- 29116912 TI - Spousal influence on physical activity in physically inactive pregnant women: A cross-sectional study. AB - Regular physical activity (PA) is recommended during pregnancy, but the prevalence of pregnant women who met the recommended level for PA is very low. In this descriptive study, we examined the association between spousal characteristics (belief, knowledge, social support, and PA level) and pregnant women's PA level in 18 couples living in the San Francisco Bay Area. Among other spousal characteristics, only spousal PA level was a significant predictor of pregnant women's PA level regardless of whether it was unadjusted or adjusted by spouses' age and body index mass (p = .01). Our finding shows a need to develop strategies to incorporate spousal support for PA. PMID- 29116914 TI - An Interval Mixed-Integer Semi-Infinite Programming Method for Municipal Solid Waste Management. AB - This study proposed an interval mixed-integer semi-infinite programming (IMISIP) method for solid waste management under uncertainty. The uncertainty can be expressed as various constants, intervals, and functional intervals. The method is mainly based on the previous efforts on interval mixed-integer linear programming (IMILP) and semi-infinite programming. The method is applied to a solid-waste management system to illustrate its effectiveness in handling complex inexact programming problems. Two scenarios are considered: one is a case with only expansions of waste-to-energy (WTE) facilities being considered, and the other is associated with potential expansions for both the WTE and the existing landfilling facilities. The results obtained can assist in identifying optimal waste management policies under uncertainties associated with interval and functional-interval parameters. Compared with conventional IMILP methods, the solutions obtained from IMISIP could be "globally" optimal because the dynamic fluctuations of the system inputs could be reflected effectively. PMID- 29116915 TI - The Effect of Oxygen on the Kinetics of the Thermal Degradation for Rice Straw. AB - The effect of oxygen on the thermal degradation of rice straw was investigated with a thermal gravimetric analysis (TGA) reaction system. The TGA curves indicated two sharp mass changes during the process and the reaction could be simplified as occurring in two stages. Oxygen speeds up the thermal degradation of intermediates. A kinetic model was proposed and its corresponding parameters such as activation energies, pre-exponential factors, and reaction orders were determined through experiments conducted in nitrogen gas (N2), 10% oxygen gas (O2), and air at the heating rates of 2, 5, and 10 K/min. The experimental data agreed well with those predicted by the proposed model, which validated the applicability of this model to the design of agricultural waste processing systems. PMID- 29116916 TI - Chloride Behavior in Washing Experiments of Two Kinds of Municipal Solid Waste Incinerator Fly Ash with Different Alkaline Reagents. AB - To efficiently reduce and reuse fly ash from incinerators, we suggest trying a new alkaline reagent to neutralize the acid compounds in discharged gas from incinerators and reuse fly ash as the raw material in the cement industry. Normally the washing process includes a pretreatment method to remove chlorides to comply with the strict standards for cement. We examined chloride behavior in washing experiments by X-ray absorption near edge structure (XANES) and X-ray diffraction (XRD) for two kinds of fly ash: (1) fly ash collected in a bag filter with the injection of calcium hydroxide (Ca(OH)2) for acid gas removal (CaFA), and (2) fly ash collected in a bag filter with the injection of sodium bicarbonate (NaHCO3) for acid gas removal (NaFA). We found that the insoluble chlorides in both CaFA and NaFA combined calcium chloride (CaCl2), with some sodium chloride (NaCl) also possibly combined. Under some conditions, the combined CaCl2 and NaCl were released. In particular, when the liquid/solid ratio was greater than 3 or the washing frequency was doubled, less chlorine, insoluble chlorine, and CaCl2 were left in the residues of NaFA than in the residues of CaFA. As a result, it is desirable to use NaHCO3 as the alkaline reagent instead of Ca(OH)2 in the air pollution control system of incinerators for recycling fly ash as a raw material in the cement industry. PMID- 29116917 TI - Kinetic Modeling on the Adsorption of Vapor-Phase Mercury Chloride on Activated Carbon by Thermogravimetric Analysis. AB - This study applied thermogravimetric analysis (TGA) technique to investigate the adsorption kinetics of vapor-phase mercury chloride (HgCl2) on activated carbon. HgCl2 is mainly emitted from the incineration of municipal solid waste (MSW) and causes severe adverse effects on human health and environment. Activated carbon injection (ACI) is the best available control technology for mercury removal from the flue gas of MSW incinerators. To investigate the adsorption of HgCl2 on activated carbons, TGA was used to determine the adsorptive capacity and adsorption isotherm of vapor-phase HgCl2 on spherical activated carbons (SACs) with the adsorption temperatures of 30-150 degrees C and the influent HgCl2 concentrations of 50-1000 MUg/m3. Experimental results indicated that the Freundlich adsorption coefficient, n, was determined as 0.40 and 1.2 for the adsorption temperatures of 30 and 150 degrees C, respectively. The adsorption of HgCl2 on SACs was at a favorable equilibrium at 30 degrees C and an unfavorable equilibrium at 150 degrees C. The Freundlich isotherm simulated the adsorptive experimental data better than the Langmuir isotherm. Furthermore, a new approach was proposed to modify the adsorption kinetic model based on pore diffusion scheme describing the transport of HgCl2 molecules within the inner pores of carbon grains for high-temperature adsorption. Model simulation successfully fitted the adsorptive experimental data by varying effective diffusivity and the Freundlich adsorption coefficient, n. PMID- 29116918 TI - A Method for Estimating Mass-Transfer Coefficients in a Biofilter from Membrane Inlet Mass Spectrometer Data. AB - A membrane inlet mass spectrometer (MIMS) was used in combination with a developed computer model to study and improve management of a biofilter (BF) treating malodorous ventilation air from a meat rendering facility. The MIMS was used to determine percentage removal efficiencies (REs) of selected sulfur gases and to provide toluene retention profiles for the model to determine the air velocity and overall mass-transfer coefficient of toluene. The mass-transfer coefficient of toluene was used as a reference for determining the mass transfer of sulfur gases. By presenting the model to scenarios of a filter bed with a consortium of effective sulfur oxidizers, the most likely mechanism for incomplete removal of sulfur compounds from the exhaust air was elucidated. This was found to be insufficient mass transfer and not inadequate bacterial activity as anticipated by the manager of the BF. Thus, knowing the relationship between mass-transfer coefficients and air velocity for a given type of BF allows for an improved dimensioning and managing of this and similar BFs. This research demonstrates that it is possible to estimate mass-transfer coefficients and air velocity in BFs using MIMS in combination with computer modeling. PMID- 29116919 TI - Transport Mechanisms of Coarse, Fine, and Very Fine Particulate Matter in Urban Street Canopies with Different Building Layouts. PMID- 29116920 TI - Real-World Vehicle Emissions: A Summary of the 18th Coordinating Research Council On-Road Vehicle Emissions Workshop. AB - The Coordinating Research Council (CRC) convened its 18th On-Road Vehicle Emissions Workshop March 31- April 2, 2008, with 104 presentations describing the most recent mobile source-related emissions research. In this paper we summarize the presentations from researchers whose efforts are improving our understanding of the contribution of mobile sources to air quality. Participants in the workshop discussed emission models and emissions inventories, results from gas- and particle-phase emissions studies from spark-ignition and diesel-powered vehicles (with an emphasis in this workshop on particle emissions), effects of fuels on emissions, evaluation of in-use emission-control programs, and efforts to improve our capabilities in performing on-board emissions measurements, as well as topics for future research. PMID- 29116921 TI - Carbonyl Compounds and Toxicity Assessments of Emissions from a Diesel Engine Running on Biodiesels. AB - This study elucidates the effect of biodiesel on the emission of carbonyl compounds generated from a diesel engine (generator), and the related biotoxicity characteristics. The Microtox test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay were conducted to evaluate the acute toxicity and cytotoxicity, respectively, of gaseous extracts from diesel engine exhaust. The engine was tested using diesel fuel and biodiesel blends (10, 30, 50, 75, and 100% of biodiesel by volume). The operating conditions of the diesel engine were set as idling, 10, 33, and 55% loads. The regulated emissions of carbon monoxide (CO), nitrogen oxides (NOx), and carbon dioxide (CO2) were monitored. The carbonyl compounds in the exhaust were collected in 2,4-dinitrophenylhydrazine (2,4-DNPH) solution in an impinger and converted to corresponding hydrazone derivatives, which were then analyzed using high performance liquid chromatography (HPLC) with an ultraviolet (UV) detector. Analysis results indicate that the carbonyl compound emissions increased when the engine was run on biodiesels at all of the loadings; however, the total concentration of emitted carbonyls did not increase with the biodiesel content. The dominant carbonyls (formalde-hyde, acetaldehyde, acrolein, and acetone) accounted for 70 to 90% of all carbonyl emissions in the engine exhaust. The concentrations of CO2 and NOx from B10 were quite similar to those from diesel. Finally, in the toxicity assessments, B10 had a higher acute toxicity and cytotoxicity than diesel, indicating that blending with biodiesel may have adverse health effects because of toxic gas emissions. At various engine loads, higher toxicities were associated with greater carbonyl emissions in diesel exhaust, but not in B10, indicating that the carbonyls may not be the major pollutants that induce the toxicity of emissions from biodiesel. PMID- 29116922 TI - Effect of Air Pollution Controls on Black Smoke and Sulfur Dioxide Concentrations across Ireland. AB - During the 1980s Ireland experienced severe pollution episodes, principally because of domestic coal burning. In 1990, the Irish government introduced a ban on the marketing, sale, and distribution of coal in Dublin. They extended the ban to Cork in 1995 and to ten other communities in 1998 and 2000. We previously reported declines in particulate (black smoke [BS]) and sulfur dioxide (SO2) concentrations in Dublin following the 1990 coal ban. We now explore and compare the effectiveness of these sequential bans in 1990, 1995, 1998, and 2000. Daily BS and total gaseous acidity (SO2) measurements were compiled between 1980 and 2004. We calculated descriptive statistics for the pre-ban (5 yr before ban) and post-ban (5 yr after ban) periods for BS and SO2 concentrations and for season specific periods. Mean BS levels fell in all centers post-ban compared with the pre-ban period, with decreases ranging from 4 to 35 MUg?m-3 (-45 to -70%). These reductions were smallest in the summer and largest in the winter. These BS reductions were sustained in all centers until the end of the study period. We observed no clear pattern in SO2 changes associated with the coal bans. The 1990, 1995, 1998, and 2000 Irish coal sale bans resulted in immediate and sustained decreases in particulate levels in centers, with the largest declines in the winter. In contrast, we did not observe consistent declines in total acidity as a measure of SO2. It may be that coal was not the major source of SO2. Simple legislation was very effective at improving ambient air quality in Irish cities with varying populations, geography/topography, and meteorological conditions. PMID- 29116923 TI - Effect of E85 on Tailpipe Emissions from Light-Duty Vehicles. AB - E85, which consists of nominally 85% fuel grade ethanol and 15% gasoline, must be used in flexible-fuel (or "flex-fuel") vehicles (FFVs) that can operate on fuel with an ethanol content of 0-85%. Published studies include measurements of the effect of E85 on tailpipe emissions for Tier 1 and older vehicles. Car manufacturers have also supplied a large body of FFV certification data to the U.S. Environmental Protection Agency, primarily on Tier 2 vehicles. These studies and certification data reveal wide variability in the effects of E85 on emissions from different vehicles. Comparing Tier 1 FFVs running on E85 to similar non-FFVs running on gasoline showed, on average, significant reductions in emissions of oxides of nitrogen (NOx; 54%), non-methane hydrocarbons (NMHCs; 27%), and carbon monoxide (CO; 18%) for E85. Comparing Tier 2 FFVs running on E85 and comparable non-FFVs running on gasoline shows, for E85 on average, a signifi-cant reduction in emissions of CO (20%), and no signifi-cant effect on emissions of non-methane organic gases (NMOGs). NOx emissions from Tier 2 FFVs averaged approximately 28% less than comparable non-FFVs. However, perhaps because of the wide range of Tier 2 NOx standards, the absolute difference in NOx emissions between Tier 2 FFVs and non-FFVs is not significant (P =0.28). It is interesting that Tier 2 FFVs operating on gasoline produced approximately 13% less NMOGs than non-FFVs operating on gasoline. The data for Tier 1 vehicles show that E85 will cause significant reductions in emissions of benzene and butadiene, and significant increases in emissions of formaldehyde and acetaldehyde, in comparison to emissions from gasoline in both FFVs and non-FFVs. The compound that makes up the largest proportion of organic emissions from E85-fueled FFVs is ethanol. PMID- 29116925 TI - Professional Development Programs. PMID- 29116924 TI - Research on Transportation-Related Emissions: Current Status and Future Directions. AB - Transportation-related emissions are the dominant contributing source of air pollutants today. Considering the negative impacts of transportation-related emissions on our social and economic environment, extensive efforts have been made by researchers and practitioners attempting to find solutions to reduce the emissions. To synthesize these research efforts, researchers have conducted various reviews of relevant studies. However, because of the diversity of the topics, most of existing reviews have only focused on specific and narrowed areas. Furthermore, none of the existing reviews have attempted to summarize the researchers' opinions on the current research and their prospects of the future research directions. Therefore, this paper is intended to fill this gap by conducting an extensive survey of transportation emissions professionals. In the paper, a review of existing research and developments on each of the emissions related topics is provided, followed by a presentation of the respective survey results and analysis. At the conclusion of these reviews and the analysis of the survey, some future research directions in this field are presented. PMID- 29116926 TI - Thanks for Your Support. PMID- 29116927 TI - Financial costs associated with monopolies on biologic medicines in Australia. AB - Objectives The aim of the study was to estimate the potential savings to the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme (RPBS) in 2015-16 if biosimilar versions of selected biologic medicines (biologics) had been available and listed on the PBS.Methods The research involved retrospective analysis of Australian Medicare expenditure data and PBS price data from 2015-16 for biologics, for which biosimilar competition may be available in future, listed on the PBS.Results Australian Government expenditure on biologics on the PBS and RPBS was estimated at A$2.29 billion dollars in 2015 16. If biosimilar versions of these medicines had been listed on the PBS in 2015 16, at least A$367million dollars would have been saved in PBS and RPBS subsidies. Modelling based on price decreases following listing of biosimilars on the PBS suggests that annual PBS outlays on biologics could be reduced by as much as 24% through the timely introduction of biosimilars.Conclusions Biologic medicines represent a large proportion of government expenditure on pharmaceuticals. Reducing the length of monopoly protections on these medicines could generate savings of hundreds of millions of dollars per year.What is known about the topic? Biologics take up an increasing share of pharmaceutical expenditure, but no previous published studies have examined Australian Government expenditure on biologics or the potential savings from reducing the duration of monopoly protection.What does this paper add? This paper provides new evidence about Australian Government expenditure on biologics and potential savings for selected medicines that are still subject to monopoly protection and thus are not yet subject to biosimilar competition. In 2015-16 Australian Government expenditure on biologics through the PBS and RPBS was estimated at A$2.29 billion dollars. If biosimilar versions of these medicines had been listed on the PBS at that time, at least A$367million dollars would have been saved.What are the implications for practitioners? Reducing the duration of monopoly protection on biologic medicines could save hundreds of millions of dollars annually that could be redirected to other areas of the healthcare system. PMID- 29116928 TI - From Intuitive to Evidence Based: Developing the Science of Nature as a Public Health Resource. PMID- 29116929 TI - New Blood: The Promise of Environmental Health Citizen Science Projects. PMID- 29116930 TI - Long-term Fine Particulate Matter Exposure and Nonaccidental and Cause-specific Mortality in a Large National Cohort of Chinese Men. AB - BACKGROUND: Cohort studies in North America and western Europe have reported increased risk of mortality associated with long-term exposure to fine particles (PM2.5), but to date, no such studies have been reported in China, where higher levels of exposure are experienced. OBJECTIVES: We estimated the association between long-term exposure to PM2.5 with nonaccidental and cause-specific mortality in a cohort of Chinese men. METHODS: We conducted a prospective cohort study of 189,793 men 40 y old or older during 1990-91 from 45 areas in China. Annual average PM2.5 levels for the years 1990, 1995, 2000, and 2005 were estimated for each cohort location using a combination of satellite-based estimates, chemical transport model simulations, and ground-level measurements developed for the Global Burden of Disease (GBD) 2013 study. A Cox proportional hazards regression model was used to estimate hazard ratios (HR) for nonaccidental cardiovascular disease (CVD), chronic obstructive pulmonary disease (COPD), and lung-cancer mortality. We also assessed the shape of the concentration-response relationship and compared the risk estimates with those predicted by Integrated Exposure-Response (IER) function, which incorporated estimates of mortality risk from previous cohort studies in western Europe and North America. RESULTS: The mean level of PM2.5 exposure during 2000-2005 was 43.7 MUg/m3 (ranging from 4.2 to 83.8 MUg/m3). Mortality HRs (95% CI) per 10 MUg/m3 increase in PM2.5 were 1.09 (1.08, 1.09) for nonaccidental causes; 1.09 (1.08, 1.10) for CVD, 1.12 (1.10, 1.13) for COPD; and 1.12 (1.07, 1.14) for lung cancer. The HR estimate from our cohort was consistently higher than IER predictions. CONCLUSIONS: Long-term exposure to PM2.5 was associated with nonaccidental, CVD, lung cancer, and COPD mortality in China. The IER estimator may underestimate the excess relative risk of cause-specific mortality due to long-term exposure to PM2.5 over the exposure range experienced in China and other low- and middle-income countries. https://doi.org/10.1289/EHP1673. PMID- 29116932 TI - Impact of citrated blood collection tubes on red cell morphology: implications for the measurement of plasma glucose. PMID- 29116931 TI - Early-Life Selenium Status and Cognitive Function at 5 and 10 Years of Age in Bangladeshi Children. AB - BACKGROUND: In older adults, selenium status has been positively associated with cognitive function. We recently reported a positive association between maternal selenium status in pregnancy and children's cognitive function at 1.5 y. OBJECTIVE: We followed up the children to assess if prenatal and childhood selenium status was associated with cognitive abilities at 5 and 10 y. METHODS: This longitudinal cohort study was nested in Maternal and Infant Nutrition Interventions in Matlab (MINIMat), a population-based, randomized supplementation trial in pregnancy in rural Bangladesh. Selenium in maternal blood [erythrocyte fraction (Ery-Se) at baseline] and in child hair and urine was measured using inductively coupled plasma mass spectrometry. Children's cognition at 5 and 10 y was assessed using the Wechsler Preschool and Primary Scale of IntelligenceTM and the Wechsler Intelligence Scale for Children(r), respectively. In total, 1,408 children were included. RESULTS: Multivariable-adjusted linear regression analyses showed that prenatal selenium status was positively associated with children's cognitive function at 5 and 10 y. An increase in maternal Ery-Se from the fifth to the 95th percentile [median: 0.44MUg/g hemoglobin (Hb)] was associated with an increase in full developmental score of 3.5 [95% confidence interval (CI): 0.1, 7.0], corresponding to 0.16 standard deviation (SD) at 5 y, and 8.1 (95% CI: 3.8, 13), corresponding to 0.24 SD at 10 y. In addition, urine and hair selenium concentrations at 5 and 10 y of age were positively associated with cognitive function at 10 y, although associations were inverse for concentrations >=98th percentile. Some associations were slightly stronger for girls than for boys. CONCLUSIONS: Measures of prenatal and childhood (below the 98th percentile) selenium status were associated with higher cognitive function scores at 5 and 10 y of age. https://doi.org/10.1289/EHP1691. PMID- 29116933 TI - First-line antituberculosis drugs disrupt endocrine balance and induce ovarian and uterine oxidative stress in rats. AB - BACKGROUND: The first-line antituberculosis (anti-TB) drugs, isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA), are effective in the treatment of pulmonary tuberculosis. However, the toxicity of these drugs in the clinical setting limits their use. Here, we evaluated the effects of anti-TB drugs on the reproductive system in female rats. METHODS: Thirty-five female Wistar rats were assigned into five groups of seven animals each. The control group received normal saline, whereas others received INH (5 mg/kg), RIF (10 mg/kg), EMB (15 mg/kg), and PZA (15 mg/kg) through gavage thrice a week for 8 consecutive weeks. RESULTS: Administration of anti-TB drugs significantly (p<0.05) reduced uterine and ovarian weight, as well as the relative weight of the uterus when compared with controls. In addition, anti-TB drugs increased the activities of alanine aminotransferase as well as the level of total bilirubin. Treatment with INH, RIF, and PZA significantly (p<0.05) reduced the levels of follicle-stimulating and luteinizing hormones, estrogen, and prolactin. The INH, RIF, EMB, and PZA caused significant (p<0.05) increases in uterine malondialdehyde (MDA) levels by 281%, 214%, 273% and 190%, respectively, whereas INH and EMB increased the ovarian malondialdehyde by 111% and 129%, respectively. These drugs significantly (p<0.05) decreased the activities of ovarian glutathione-S-transferase and uterine glutathione peroxidase, superoxide dismutase, and catalase. Histology revealed the erosion of uterine mucosa, debris in the lumen of the uterus, congestion, and underdeveloped follicles in ovaries. CONCLUSIONS: The first-line anti-TB drugs elicited reproductive toxicity in the uterus and ovaries of rats through mechanisms that involved oxidative stress. PMID- 29116935 TI - Outcomes of physical examination-indicated cerclage in twin pregnancies with acute cervical insufficiency compared to singleton pregnancies. AB - Objectives To compare pregnancy outcomes of physical examination-indicated cerclage in twin pregnancies with acute cervical insufficiency with that of singletons. Methods This retrospective cohort study included 88 consecutive women (17 twins and 71 singletons) who had undergone physical examination-indicated cerclage because of acute cervical insufficiency (defined as painless cervical dilation with (1) prolapsed and/or visible membranes at the external cervical os on speculum examination and (2) a functional cervical length of zero on transvaginal ultrasound) between 160/7 and 236/7 weeks. The primary outcome measure was preterm delivery <34 weeks. Results (1) The frequency of preterm delivery <34 weeks was not significantly different between the two groups [twins, 56% (9/16) vs. singleton, 53% (37/70), P>0.999]. (2) The perinatal mortality was 21% (7/34) in twins and 32% (23/71) in singletons. (3) The median gestational age at delivery for twin pregnancies was 31.0 weeks (IQR, 22.6-36.5 weeks), which was similar to that of singleton pregnancies (median 32.4 weeks; IQR 22.3-38.3 weeks). (4) There were no significant differences in preterm delivery before 28 and 32 weeks, interval from cerclage to delivery within 1, 2, 4 and 8 weeks and neonatal morbidities between the two groups. Conclusion The obstetric and neonatal outcomes of physical examination-indicated cerclage in twin pregnancies were comparable to those in singleton pregnancies. PMID- 29116934 TI - Expectant management of caesarean scar ectopic pregnancy: a systematic review. AB - AIM: The purpose of this review is to systematically review all the reported cases and case series of caesarean scar pregnancy (CSP) managed expectantly without any intervention in order to understand the outcomes of pregnancy which will guide clinicians and patients in making treatment choices. METHODS: An electronic search on PubMed, EMBASE and Cochrane databases and a manual search from references of the articles were performed. Studies were selected based on inclusion and exclusion criteria. Data were extracted for various outcomes of pregnancy and the quality of the reports was assessed using a modified Delphi technique. RESULTS: A total of 56 cases of CSP from 11 reports were included in the review, including 44 cases with foetal cardiac activity. Live births were achieved in 73% of cases with a quarter of them born before 34 weeks. Hysterectomy rates were 70%. In 12/44 (27%) of cases pregnancies were lost due to complications before 24 weeks. Most (67%) of the CSPs with no foetal cardiac activities resolved on expectant management and the remaining required intervention for bleeding. CONCLUSIONS: Caution should be exercised when choosing expectant management in cases of viable CSPs, and if chosen, the patient should be counselled adequately for possible outcomes including loss of pregnancy and hysterectomy. Expectant management is acceptable in CSPs with no foetal cardiac activity. There is a need for prospective research on this topic with adequate reporting on possible prognostic markers, as well as a need to improve on the techniques to prevent loss of fertility during delivery. PMID- 29116936 TI - Neurophysiological aspects of the trigeminal sensory system: an update. AB - The trigeminal system is one of the most complex cranial nerve systems of the human body. Research on it has vastly grown in recent years and concentrated more and more on molecular mechanisms and pathophysiology, but thorough reviews on this topic are lacking, certainly on the normal physiology of the trigeminal sensory system. Here we review the current literature on neurophysiology of the trigeminal nerve from peripheral receptors up to its central projections toward the somatosensory cortex. We focus on the most recent scientific discoveries and describe historical relevant research to substantiate further. One chapter on new insights of the pathophysiology of pain at the level of the trigeminal system is added. A database search of Medline, Embase and Cochrane was conducted with the search terms 'animal study', 'neurophysiology', 'trigeminal', 'oral' and 'sensory'. Articles were manually selected after reading the abstract and where needed the article. Reference lists also served to include relevant research articles. Fifty-six articles were included after critical appraisal. Physiological aspects on mechanoreceptors, trigeminal afferents, trigeminal ganglion and central projections are reviewed in light of reference works. Embryologic and anatomic insights are cited where needed. A brief description of pathophysiology of pain pathways in the trigeminal area and recent advances in dental stem cell research are also discussed. Neurophysiology at the level of the central nervous system is not reviewed. The current body of knowledge is mainly based on animal and cadaveric studies, but recent advancements in functional imaging and molecular neuroscience are elucidating the pathways and functioning of this mixed nerve system. Extrapolation of animal studies or functioning of peripheral nerves should be warranted. PMID- 29116937 TI - Synthesis and biological evaluation of acyl derivatives of hydroxyflavones as potent antiproliferative agents against drug resistance cell lines. AB - The synthesis of hydroxyflavone derivatives is described. The acyl derivatives of 3-, 6-, 7-hydroxyflavones (compounds 2, 4, 6, respectively) and chrysin (5,7 dihydroxyflavone, 7) were obtained in high yields and evaluated in vitro for their cytotoxic activity against several cancer cell lines of different origin: MCF-7 (breast cancer), A549 (nonsmall cell lung cancer), MES-SA (uterine sarcoma), LoVo (colon cancer), drug-resistant human cancer cells (MES-SA/DX5, LoVo/DX) and also towards non-cancer cell line MCF-10A (normal breast epithelial cells). The flavones modified with acyl group showed higher antiproliferative activity than free hydroxyflavones. The highest activity was noted for 3 acetoxyflavone (2), which proved active against LoVo, LoVo/DX, and MES-SA cell lines (IC50 from 4.7 MUM to 7.8 MUM, respectively). The highest ability to overcome the barrier of resistance (resistance index=0.82) against the drug resistant MES-SA/DX5 cells compared to the parental drug-sensitive MES-SA cell line was found for 7-acetoxyflavone (6). PMID- 29116938 TI - Mangostanaxanthone VII, a new cytotoxic xanthone from Garcinia mangostana. AB - Garcinia mangostana L. (the queen of fruits, mangosteen, family Guttiferae) is a wealthy source of xanthones. The CHCl3 soluble fraction of the air-dried pericarps of G. mangostana provided a new xanthone: mangostanaxanthone VII (5), along with four known xanthones: mangostanaxanthones I (1) and II (2), gartanin (3) and gamma-mangostin (4). The structural verification of these metabolites was achieved by different spectral techniques, including UV, IR, 1D and 2D NMR and HRESIMS. The new metabolite was assessed for cytotoxic potential, using sulforhodamine B (SRB) assay towards the A549 and MCF-7 cancer cell lines. Moreover, its antimicrobial effects were evaluated against various bacterial and fungal strains, using agar disc diffusion assay. Mangostanaxanthone VII showed moderate cytotoxic activity against the A549 and MCF7 cell lines with IC50s 26.1 and 34.8 MUM, respectively, compared with doxorubicin (0.74 and 0.41 MUM, respectively). PMID- 29116939 TI - Topology-guided deformable registration with local importance preservation for biomedical images. AB - The demons registration (DR) model is well recognized for its deformation capability. However, it might lead to misregistration due to erroneous diffusion direction when there are no overlaps between corresponding regions. We propose a novel registration energy function, introducing topology energy, and incorporating a local energy function into the DR in a progressive registration scheme, to address these shortcomings. The topology energy that is derived from the topological information of the images serves as a direction inference to guide diffusion transformation to retain the merits of DR. The local energy constrains the deformation disparity of neighbouring pixels to maintain important local texture and density features. The energy function is minimized in a progressive scheme steered by a topology tree graph and we refer to it as topology-guided deformable registration (TDR). We validated our TDR on 20 pairs of synthetic images with Gaussian noise, 20 phantom PET images with artificial deformations and 12 pairs of clinical PET-CT studies. We compared it to three methods: (1) free-form deformation registration method, (2) energy-based DR and (3) multi-resolution DR. The experimental results show that our TDR outperformed the other three methods in regard to structural correspondence and preservation of the local important information including texture and density, while retaining global correspondence. PMID- 29116940 TI - Spin-flip transitions in self-assembled quantum dots. AB - Detailed realistic calculations of the spin-flip time (T 1) for an electron in a self-assembled quantum dot (SAQD) due to emission of an acoustic phonon, using only bulk properties with no fitting parameters, are presented. Ellipsoidal lens shaped [Formula: see text] [Formula: see text]As quantum dots, with electronic states calculated using 8-band strain dependent [Formula: see text] theory, are considered. The phonons are treated as bulk acoustic phonons coupled to the electron by both deformation potential and piezoelectric interactions. The dependence of T 1 on the geometry of SAQD, on the applied external magnetic field and on the lattice temperature is highlighted. The theoretical results are close to the experimental measurements on the spin-flip times for a single electron in QD. PMID- 29116941 TI - Origin of the magnetic transition at 100 K in epsilon-Fe2O3 nanoparticles studied by x-ray absorption fine structure spectroscopy. AB - The current study unveils the structural origin of the magnetic transition of the epsilon-Fe2O3 polymorph from an incommensurate magnetic order to a collinear ferrimagnetic state at low temperature. The high crystallinity of the samples and the absence of other iron oxide polymorphs have allowed us to carry out temperature-dependent x-ray absorption fine structure spectroscopy experiments out. The deformation of the structure is followed by the Debye-Waller factor for each selected Fe-O and Fe-Fe sub-shell. For nanoparticle sizes between 7 and 15 nm, the structural distortions between the Fete and Fe-D1oc sites are localized in a temperature range before the magnetic transition starts. On the contrary, the inherent interaction between the other sub-shells (named Fe-O1,2 and Fe-Fe1) provokes cooperative magneto-structural changes in the same temperature range. This means that the Fete with Fe-D1oc polyhedron interaction seems to be uncoupled with temperature dealing with these nanoparticle sizes wherein the structural distortions are likely moderate due to surface effects. PMID- 29116942 TI - Microfluidic multiplexing of solid-state nanopores. AB - Although solid-state nanopores enable electronic analysis of many clinically and biologically relevant molecular structures, there are few existing device architectures that enable high-throughput measurement of solid-state nanopores. Herein, we report a method for microfluidic integration of multiple solid-state nanopores at a high density of one nanopore per (35 um2). By configuring microfluidic devices with microfluidic valves, the nanopores can be rinsed from a single fluid input while retaining compatibility for multichannel electrical measurements. The microfluidic valves serve the dual purpose of fluidic switching and electric switching, enabling serial multiplexing of the eight nanopores with a single pair of electrodes. Furthermore, the device architecture exhibits low noise and is compatible with electroporation-based in situ nanopore fabrication, providing a scalable platform for automated electronic measurement of a large number of integrated solid-state nanopores. PMID- 29116943 TI - The PPARG Pro12Ala Polymorphism and 20-year Cognitive Decline: Race and Sex Heterogeneity. AB - Previous reports suggest race/ethnic and sex heterogeneity in the association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma (PPARG) gene and cognitive decline. Tests of verbal memory, processing speed, and verbal fluency and a composite global Z-score were used to assess cognitive performance longitudinally in a large (n=11,620) biracial cohort of older adults in the Atherosclerosis Risk in Communities Neurocognitive Study from midlife to older age. Linear mixed models were used to estimate associations between the Ala12 allele and cognitive performance over 20 years of follow-up. Heterogeneity was present for rate of cognitive decline as measured by the global Z-score by race, sex, and Ala12 allele status (P=0.01 for 4-way interaction term: race*sex*time*Ala12 carrier status). Stratified analysis showed a significantly increased rate of global cognitive decline over the 20-year follow-up for carriers of the Ala12 allele compared with noncarriers among black male individuals (-0.92 SD decline vs. -0.57 SD; P=0.02) but not among black female, white male, or white female individuals. Decline in global cognitive function among black male Ala12 carriers was primarily driven by decline in verbal memory. Our data underscore the context-dependent association between the Pro12Ala polymorphism and cognitive decline, specifically race/ethnic background and sex. PMID- 29116944 TI - Making Sense of Turmoil: How Women Reconcile Their Emotional Response to Discovery of a Potential Breast Cancer Symptom. AB - BACKGROUND: Breast cancer continues to be a major public health problem for women. Early detection and treatment are key to improved outcomes. Whereas most women seek help promptly, some postpone seeking help for self-discovered breast symptoms. Investigation of women's help-seeking behavior and the associated influencing factors on self-discovery of a breast symptom were sought. OBJECTIVES: The aim of this article is to report the qualitative data from women who had self-discovered a breast symptom. METHODS: Women (n = 167) with a self discovered breast symptom (who were part of a large quantitative correlational study) commented in an open-ended question on their overall experience. Comments were analyzed using Discourse Analysis. RESULTS: Four linked discourses were identified: (1) "being and remaining normal," (2) "emotion," (3) "becoming and being abnormal," and (4) "rationality." A sidelined discourse of emotion is drawn on to defer taking action based on rational knowledge. CONCLUSION: The tension between discourses "emotion" and "rationality" further informs our understanding of women's help-seeking behavior following self-discovered symptoms. Findings provide a deeper understanding of the emotional aspects of women's experience around symptom discovery. IMPLICATIONS FOR PRACTICE: Findings will be of benefit to all healthcare professionals involved in assessment and screening of breast changes suggestive of breast cancer. They provide a novel insight into the meaning of breast cancer, its diagnosis and treatment, and how this impacts women's emotions as they await consultation in a breast clinic. PMID- 29116945 TI - Practice Advisory for the Prevention of Perioperative Peripheral Neuropathies 2018: An Updated Report by the American Society of Anesthesiologists Task Force on Prevention of Perioperative Peripheral Neuropathies. PMID- 29116946 TI - Spinal Cord Injury by Direct Damage During CT-Guided C7 Transforaminal Epidural Steroid Injection. AB - Cervical transforaminal epidural steroid injection (TFESI) under the guidance of computed tomography (CT) can offer great anatomical resolution and precise needle placement in the axial plane. However, some complications, including blood pressure surge, allergic reactions, vasovagal syncope, and cerebral infarct, have been reported after CT-guided cervical TFESI. We report the first case of iatrogenic spinal cord injury during a CT-guided cervical TFESI. A 67-year-old woman, upon receiving TFESI on Lt. C7, experienced an electrical shock-like sensation throughout the body. The patient complained of weakness in the left upper and lower extremities (manual muscle testing grade: 2-4) and neuropathic pain (numeric rating scale: 9) in the left upper and lower extremities. Cervical magnetic resonance imaging (MRI) performed 9 days after TFESI showed a high T2 signal at the left side of the spinal cord from levels C5 to C7, and an electrophysiological study performed 14 days after TFESI revealed corresponding findings with cervical MRI. Three months after finishing treatment with a high dose of intravenous methylprednisolone, the patient's motor weakness improved, but it did not recover fully. PMID- 29116947 TI - Cerebrovascular Steal Phenomenon and Electroconvulsive Therapy: A Case Report and Review of the Literature. AB - Electroconvulsive therapy (ECT) is a safe and effective treatment for major depressive disorder, but cerebrovascular and cardiovascular complications, although rare, remain the most concerning. This is particularly notable in those with preexisting cerebrovascular disease, which impacts dynamic cerebral autoregulation. In these patients, the increased blood flow to the seizing portions of the brain induced by ECT potentially can reduce cerebral blood flow to ischemic areas, possibly causing adverse neurological events. The authors describe a patient with chronic cerebral ischemic disease, chronic anemia, and major depressive disorder undergoing ECT to achieve remission. The patient developed recurrent focal neurological deficits after each ECT procedure, with neurological recovery within 48 hours post-ECT. Clinical guidelines may need to be updated for the management of ECT patients with cerebrovascular disease who may be at an increased risk of intraictal and possibly postictal regional ischemia, especially in areas already compromised by a prior stroke and/or by reduced cerebral oxygenation caused by symptomatic anemia at risk of ischemia. Research is needed to assess changes in regional cerebral blood flow during and after ECT in patients with cerebrovascular disease, including small-vessel cerebral ischemia, and to evaluate these changes in relation to the location, intensity, and duration of induced seizure. PMID- 29116948 TI - The Clinician Faced With Anticochlear Antibodies: What to Do With Them? AB - BACKGROUND: Autoimmune inner ear disease as a cause of sensorineural hearing loss is a poorly understood entity. Thus, the role of anticochlear antibodies (ACLAs) in clinical management is still not well established. OBJECTIVE: The aims of this study were to describe the use of ACLAs in our clinical setting and to understand the clinicians' therapeutic approach in these cases. We also analyzed the usefulness of these autoantibodies in clinical practice. METHODS: A retrospective study with nonprobabilistic convenience sampling of patients who were tested for ACLAs in the period from January 1, 2013, to December 31, 2015, was performed. The study was carried out in 2 stages: (1) medical records of all patients who were investigated for ACLAs were reviewed. The following variables were analyzed: age, sex, reason for requesting ACLAs, concomitant autoimmune disease, audiogram, immunosuppressive treatment, duration of treatment, and clinical response; (2) patients who received immunosuppressive therapy were contacted by telephone. A visual analog scale (VAS) (0-10) was applied to evaluate the therapeutic response. RESULTS: Thirty-nine patients who were investigated for ACLAs were identified. The mean age was 41 (SD, 16) years; there were 33 female patients. Of the 34 patients with ACLA-positive antibodies, 16 patients received immunosuppressive agents, of for management of their sensorineural hearing loss, corticosteroids was the most commonly used treatment. No clinical improvement was reported by patients after immunosuppressive treatment in this subgroup. CONCLUSIONS: The role of ACLAs in the diagnosis and management of sensorineural hearing loss remains unclear. In this small study at a single institution, ACLA testing may not have improved the outcome of sensorineural hearing loss. PMID- 29116949 TI - Couples' Experiences With Healthy Lifestyle Behaviors After Cardiac Rehabilitation. AB - PURPOSE: Many cardiac patients discontinue heart-healthy eating and physical activity (PA) behaviors in the months following cardiac rehabilitation (CR). Involving the spouse in CR with the patient may be 1 strategy to increase the maintenance of these behaviors after CR. Assisting patients and spouses with the maintenance of healthy eating and PA behavior following CR begins with a better understanding of the couple-focused factors, impacting their experiences with these behaviors. The purpose of this study was to qualitatively examine couple focused facilitators and barriers to maintaining changes in healthy eating and PA behavior from the perspectives of both cardiac patients and their spouses following phase 2 CR. METHODS: A purposive sample of 11 couples (patients undergoing postcoronary artery bypass graft surgery and their spouses) were selected from a larger randomized control trial. Semistructured, in-person interviews were conducted with patients and their spouses separately following CR. Data were analyzed using line-by-line coding to identify facilitator and barrier themes. RESULTS: Two couple-focused barrier themes emerged: unnegotiated situations and unshared behaviors. Two couple-focused facilitator themes emerged: supportive exchanges and partnerships. CONCLUSION: These findings will help guide interventions targeting changes in diet and PA behavior in both patients and their spouses through minimizing unnegotiated situations, fostering supportive exchanges, and creating a partnership for the couple to work together on shared diet and PA goals. Targeting both patients and their spouses may be an innovative and effective way to intervene to increase adherence to healthy eating and PA behaviors post-CR. PMID- 29116950 TI - Depression and Anxiety Screening and Triage Protocol for Cardiac Rehabilitation Programs. AB - PURPOSE: Best practice guidelines for cardiac rehabilitation (CR) suggest routine screening for anxiety and depression, yet many patients are not screened nor do they receive mental health treatment. Protocols are required to identify those in need of care and to ensure that appropriate assistance is provided. METHODS: Consecutive patients entering CR in our setting from May 4, 2012, to May 3, 2013, completed the Hospital Anxiety and Depression Scale (HADS). As per our Screening and Triage protocol for Anxiety and Depression (STAD), patients with high scores (>=16) were referred to a clinical psychologist; those with low scores (<8 for depression and <11 for anxiety) received information about community resources. Patients with moderate scores were reassessed 4 weeks later before triaging to psychosocial services. High, moderate, and low scores were triaged to a clinical psychologist, social worker, or were guided to community resources, respectively. RESULTS: A total of 1504 patients (76% men) completed the HADS at intake; 287 (19%) had elevated depression and/or anxiety scores. Of these, 43 (15%) were referred to psychology services and 244 (85%) patients were referred for HADS readministration at 4 weeks. Scores following reassessment resulted in 6 referrals to psychology services (3%) and 62 to social work (36%), whereas 78 (45%) no longer needed care. CONCLUSION: Many cardiac patients experience symptoms of depression and anxiety. The STAD protocol using the HADS was an efficient method to screen for anxiety and depression and appropriately utilize psychosocial treatment resources in the cardiac rehabilitation setting. PMID- 29116951 TI - Induction Therapies Plus Surgery Versus Exclusive Radiochemotherapy in Stage IIIA/N2 Non-Small Cell Lung Cancer (NSCLC). AB - In spite of the growing body of data from prospective randomized clinical trials (PRCTs) and meta-analyses, the optimal treatment approach in patients with stage IIIA non-small cell lung cancer remains unknown. This review focuses on the available data directly confronting induction chemotherapy or induction radiochemotherapy (RT-CHT) when followed by surgery with exclusive RT-CHT. Seven PRCTs and 4 meta-analyses investigated this issue. In addition, numerous retrospective studies attempted to identify potential predictors and/or prognosticators that may have influenced the decision to offer surgery in a particular patient subgroup. Several retrospective studies also evaluated exclusive RT-CHT in this setting. There is not a single piece of the highest level of evidence (PRCT or MA) showing any advantage of induction therapies followed by surgery over exclusive RT-CHT with the former treatment option leading to significantly more morbidity and mortality. Although several studies attempted to identify patient subgroups favoring induction therapies followed by surgery, they have invariably been retrospective in nature, and their results have never been reproduced even in other retrospective setting. Furthermore, no PRCT investigated potential pretreatment patient and/or tumor-related predictors of surgical multimodality success. Exclusive RT-CHT achieves similar results to induction therapies followed by surgery but with less morbidity and mortality. This is accompanied with the finding that no pretreatment predictor exists to enable identification of even a subgroup of stage IIIA/pN2 patients benefiting from any surgical approach. PMID- 29116952 TI - A Model of the Effect of Lens Development on Refraction in Schoolchildren. AB - SIGNIFICANCE: The study provides a new theory on the mechanism underlying myopia development, and it could be useful in clinical practice to control myopia development in schoolchildren. PURPOSE: To model the effect of the crystalline lens on refractive development in schoolchildren. METHODS: The Zemax 13 was used to calculate Zernike aberrations and refractions across 50 degrees horizontal visual fields. Optical effects of the anterior chamber depth, lens thickness, and radii of curvature of the lens surfaces on refractions were modeled. Refractive changes induced by lens development in emmetropic and myopic eyes, based on a previous longitudinal study from literature, were calculated. RESULTS: A lens thickness reduction with an anterior chamber depth deepening caused a hyperopic shift over the visual fields and even more at the periphery. Opposite effects were found when the lens was thinned without any change of the anterior chamber depth. While a flattening of the anterior lens surface produced hyperopic refractions overall, a posterior lens flattening caused a myopic shift at the periphery, but a hyperopic shift of the central refraction. In the myopic eye, lens development induced refractive change toward more hyperopic over the visual fields and more at the periphery. CONCLUSIONS: Lens thinning and lens axial movement participate in peripheral refractive development in schoolchildren, and lens development with a deeper anterior chamber depth and a flatter lens surface in the myopic eye could generate extra hyperopia over visual fields. The myopic lens development could be due to a backward movement of the lens, driven by a backward growth of the ciliary process, which might be a causative factor of myopia development. PMID- 29116953 TI - Identification of an ND4 Mutation in Leber Hereditary Optic Neuropathy. AB - SIGNIFICANCE: We identified a missense mutation, m.11778G>A (p.R340H), in the mitochondrially encoded NADH dehydrogenase 4 gene (ND4) in eight patients and three asymptomatic carriers, even though the incidence of this has been considered low in Chinese population. These results have implications for the families' genetic counseling and clinical management. PURPOSE: Leber hereditary optic neuropathy (LHON OMIM 535000) is one of the most common inherited optic neuropathies. The aim of this study was to identify the genetic cause in two Han Chinese families with LHON. METHODS: We used Sanger sequencing to identify the genetic cause of two Han Chinese families from Hunan, China, with LHON. RESULTS: The patients in these two families presented with typical LHON, with male patients experiencing more severe phenotypes. A missense mutation, m.11778G>A (p.R340H), in the ND4 gene was identified in eight patients and three asymptomatic carriers, even though the incidence of this has been considered low in Chinese population. CONCLUSIONS: Eight of 11 family members (72.7%) manifested some vision loss, which is far higher percentage than reported in other studies. The variant is predicted to be the disease-causing mutation and results in seriously abnormal function of complex I subunits of the mitochondrial respiratory chain. These results have implications for the families' genetic counseling and clinical management and help to develop new LHON target-gene therapy strategies. PMID- 29116954 TI - Impact of an Original Methodological Tool on the Identification of Corrective and Preventive Actions After Root Cause Analysis of Adverse Events in Health Care Facilities: Results of a Randomized Controlled Trial. AB - OBJECTIVE: The aim of the study was to assess the effectiveness of a new methodological tool for the identification of corrective and preventive actions (CAPAs) after root cause analysis of health care-related adverse events. METHODS: From January to June 2010, we conducted a randomized controlled trial involving risk managers from 111 health care facilities of the Aquitaine Regional Center for Quality and Safety in Health Care (France). Fifty-six risk managers, randomly assigned to two groups (intervention and control), identified CAPAs in response to two sequentially presented adverse event scenarios. For the baseline measure, both groups used their usual adverse event management tools to identify CAPAs in each scenario. For the experimental measure, the control group continued using their usual tools, whereas the intervention group used a new tool involving a systemic approach for CAPA identification. The main outcome measure was the number of CAPAs the participants identified that matched a criterion standard established by eight experts. RESULTS: Baseline mean number of identified CAPAs did not differ between the two groups (P = 0.83). For the experimental measure, significantly more CAPAs (P = 0.001) were identified by the intervention group (mean [SD] = 4.6 [1.7]) than by the control group (mean [SD] = 2.8 [1.2]). CONCLUSIONS: For the two scenarios tested, more relevant CAPAs were identified with the new tool than with usual tools. Further research is needed to assess the effectiveness of the new tool for other types of adverse events and its impact on patient safety. PMID- 29116955 TI - Patient, Injury, Assessment, and Treatment Characteristics and Return-to-Play Timelines After Sport-Related Concussion: An Investigation from the Athletic Training Practice-Based Research Network. AB - OBJECTIVES: To describe the patient, injury, assessment and treatment characteristics, as well as return-to-play timelines and clinical findings at discharge for adolescent patients after sport-related concussion. DESIGN: Retrospective analysis of electronic medical records. SETTING: Athletic training facilities of secondary school members of the Athletic Training Practice-Based Research Network (AT-PBRN). PATIENTS: In total, 1886 patient records were reviewed. [1204 (63.8%) male, 682 (36.2%) female, age = 15.3 +/- 1.9 years, height = 169.5 +/- 13.5 cm, mass = 70.3 +/- 17.0 kg]. Patients were diagnosed with a concussion by an athletic trainer or team/directing physician. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Descriptive analysis of patient, injury, assessment, treatment, and participation status characteristics, as well as discharge information. RESULTS: Injury demographic forms were completed for 1886 concussion cases. A concussion-specific evaluation form was completed for 55.9% (n = 1054) of cases. Treatment documentation was completed on 829 patients (44.0% of initial documented cases). Discharge forms were completed for 750 patients (40.0% of initial documented cases). Most cases were coded as 850.9 Concussion (85.5%, n = 642) and occurred during an in-season game (49.4%, n = 308). Time lost from competition was 24.9 +/- 39.9 days. CONCLUSIONS: Most concussion cases documented in this study were not on-field emergencies, as indicated by their normal clinical examinations and the lack of immediate referral to an emergency department. However, certain aspects of the clinical examination were often not assessed during the initial evaluation. These findings describe concussion assessment and recovery in adolescents and reinforce the need for a standardized approach to concussion assessment and appropriate documentation. PMID- 29116956 TI - Optical Coherence Tomography Angiography in Neuro-Ophthalmology. PMID- 29116957 TI - Controls, Fit-for-purpose Assays, Verification Versus Validation, and Tissue Tools for IHC: Announcing a Workshop From the International Society for Immunohistochemistry and Molecular Morphology, Held at the 12th Annual Retreat for Applied Immunohistochemistry and Molecular Morphology, February 4, 2018. PMID- 29116958 TI - NordiQC Assessments of Low Molecular Weight Keratin 8/18 Immunoassays. AB - This paper is number 2 in a series developed through a partnership between ISIMM and NordiQC for the purpose of reporting research assessing the performance characteristics of immunoassays in an external proficiency testing program. PMID- 29116959 TI - Evaluation of Mast Cell Density in the Tumor Microenvironment in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma. AB - The objective of this study was to compare mast cell density (MCD) in oral epithelial dysplasias (OED) and oral squamous cell carcinoma (OSCC) and determine its correlation with clinical and histopathologic parameters and the degree of tumor differentiation. Thirty OSCC samples, 14 OED samples, and 4 non-neoplastic oral mucosa samples were analyzed by immunohistochemistry to determine MCD based on the expression of MC tryptase. In addition, MCs were categorized morphologically into degranulated and granulated cells. MCD was significantly higher in OSCC lesions with a greater degree of differentiation (P=0.04). No significant difference in MCD was detected between mild and moderate OED samples (P=0.09). Our findings indicate that MCs are present in the tumor microenvironment and may be associated with a better prognosis. PMID- 29116960 TI - Image Quality and Geometric Distortion of Modern Diffusion-Weighted Imaging Sequences in Magnetic Resonance Imaging of the Prostate. AB - PURPOSE: The aim of this study was to compare qualitative and quantitative image quality and geometric distortion of 4 magnetic resonance diffusion-weighted imaging (DWI) sequences of the prostate using comparable imaging parameters and similar acquisition times. METHODS AND MATERIALS: Axial T2-weighted turbo spin echo images and axial DWI echo-planar imaging (EPI) sequences, including single shot spin-echo (ss-EPI), readout-segmented multishot (rs-EPI), selective excitation-reduced field of view (sTX-EPI), and prototype single-shot technique applying slice-specific shimming (iShim-EPI) sequences, were acquired at 3 T in 10 healthy volunteers (mean age, 26.1 +/- 3.8 years; body mass index, 23.2 +/- 3.0 kg/m). Two radiologists, blinded to the type of DWI, independently rated DWIs on a 5-point Likert scale regarding subjective image quality features (resolution, demarcation of prostate capsule, zonal anatomy). Interreader agreement was assessed using the intraclass correlation coefficient. Signal-to noise ratio (SNR) and apparent diffusion coefficient (ADC) values were assessed separately in the peripheral and transitional zone. For the analysis of geometric distortion, the diameter of the prostate from left to right and from anterior to posterior was measured at the level of the verumontanum on b-1000 DWIs and on T2 weighted turbo spin echo images. Differences were compared using the Wilcoxon rank sum test for qualitative parameters, analysis of variance, and Friedman test for quantitative parameters. A P value of less than 0.05 was considered significant, with correction for multiple comparisons. RESULTS: Interreader agreement was good to excellent (intraclass correlation coefficient, 0.71-0.79) for all qualitative features. Subjective image quality regarding "resolution" was significantly better for ss-EPI than rs-EPI (mean Likert score, 4.25 vs 3.8; P = 0.031) and sTX-EPI (4.25 vs 3.3; P = 0.046) and for iShim-EPI as compared with rs EPI (4.4 vs 3.8; P = 0.031) and sTX-EPI (4.4 vs 3.3; P = 0.047). There was no significant difference regarding capsule demarcation and zonal anatomy. Signal-to noise ratio was significantly higher in iShim-EPI than sTX-EPI (SNR +/- standard deviation [SD], 28.13 +/- 8.21 vs 14.96 +/- 2.4; P = 0.015). The ADC values were lower for the peripheral zone in the sTX-EPI than in the ss-EPI (ADC +/- SD, 1002.94 +/- 83.51 vs 1165.05 +/- 115.64; P = 0.013) and the rs-EPI (1002.94 +/- 83.51 vs 1244.40 +/- 89.95; P = 0.0012) and in the transitional zone in the sTX EPI compared with the rs-EPI (874.50 +/- 200.72 vs 1261.47 +/- 179.23; P = 0.0021). There were no statistically significant differences in geometric distortion between all DWI sequences. CONCLUSIONS: Single-shot spin-echo EPI and iShim-EPI showed a tendency toward superior image quality and SNR compared with rs-EPI and sTX-EPI with no significant differences in geometric distortion. PMID- 29116961 TI - It's a wrap. PMID- 29116962 TI - Weaving a culture of safety into the fabric of nursing. PMID- 29116963 TI - An Objective Method to Determine the Electrically Evoked Stapedius Reflex Threshold During Cochlea Implantation. AB - OBJECTIVE: In cochlea implantation, assessment of the electrically evoked stapedius reflex threshold (eSRT) provides information for postoperative adjustment of the speech processor. This is used to prevent undesired overstimulation. To this day, the reflex is visually identified by the surgeon. However, this method may be prone to error due to ventilation-associated situs excursions, blinking, or other distractions. Therefore, the aim of this study was to establish an objective and automatized method to determine the eSRT. METHODS: Video material documenting the intraoperative measurements was analyzed offline applying a tracking software to quantify stapes head movements. Moreover, a computer program (TrackerAnalyzer) was developed to detect reflex associated movements automatically. RESULTS: Reflex responses seen visually by the surgeon compared with visual registration on the video material postoperatively and to results of the automatized method with TrackerAnalyzer showed a high inter-rater agreement (Cohen's kappa coefficient = 0.47-0.59). 82% of events in which the TrackerAnalyzer registered reflexes that were not seen by the surgeon had values close but lower to the intraoperatively determined eSRT (mean -1.02 current units). CONCLUSION: We demonstrated the feasibility of an objective and automatized method to determine electrically evoked stapedius reflex thresholds in cochlea implantation. PMID- 29116964 TI - AN ELDERLY PATIENT WITH ACUTE TRANSIENT OUTER RETINAL DISRUPTION RESEMBLING BILATERAL MULTIPLE EVANESCENT WHITE DOT SYNDROME. AB - PURPOSE: To report an unusual case of an elderly patient with transient outer retinal disruption resembling bilateral multiple evanescent white dot syndrome. METHODS: Observational case report. Fundus photographs, fluorescein angiography, standard and ultra-widefield fundus autofluorescence, and cross-sectional and en face optical coherence tomography were used to characterize and describe the clinical findings. RESULTS: A 67-year-old woman presented with decreased vision and floaters in her left eye. Best-corrected visual acuity was 20/20-3 in the right eye and 20/80-2 in the left eye. Funduscopic examination showed small deep white dots and foveal granularity of the left eye corresponding to hyperautofluorescent spots on fundus autofluorescence and ellipsoid zone disruption on spectral domain optical coherence tomography. The asymptomatic right eye had evidence of subretinal deposits on spectral domain optical coherence tomography but was otherwise unremarkable. At 4-week follow-up, the patient noted resolution of her symptoms in the left eye but had developed floaters and blurry vision in her right eye. The left eye showed resolving white spots and ellipsoid zone disruption. However, the right eye had new evidence of white spots corresponding to hyperautofluorescent spots on fundus autofluorescence. Spectral domain optical coherence tomography demonstrated subretinal deposits overlying areas of ellipsoid zone disruption. At 8-week follow-up, the patient was asymptomatic in both eyes with best-corrected visual acuity of 20/20 in both eyes. The hyperautofluorescent spots on ultra-widefield fundus autofluorescence had faded with restoration of ellipsoid zone disruption in both eyes and disappearance of subretinal deposits. CONCLUSION: Our case demonstrates multimodal retinal imaging findings resembling multiple evanescent white dot syndrome in an elderly patient. The bilateral presentation, presence of subretinal deposits before symptom onset, and older age of the patient were atypical features for this entity. PMID- 29116965 TI - Mechanical Properties of Contact Lens Materials. AB - OBJECTIVES: To evaluate the mechanical properties of commonly available soft contact lens materials and compare results using custom-built MicroTensometer. METHODS: The Young modulus, parameters for stress relaxation, and toughness of 18 types of single vision soft contact lenses were measured using custom-built MicroTensometer. Five lenses of each type were soaked in standard phosphate buffered saline and measured at a temperature of 35 degrees C. Each lens was flattened and sliced into a rectangular strip sample using two parallel blades. RESULTS: The Acuvue Moist 1-Day and SofLens Daily lenses measured lowest moduli, whereas Air Optix Night & Day Aqua and Premio measured the highest. The measured moduli for silicone hydrogel materials were generally higher compared with the hydrogels except for Dailies AquaComfort Plus. The exponential curve fitted over the decay in stress showed a consistent time constant of approximately 10 sec for most lens types measured. However, the amplitude constant varied from 2.84% for SofLens Daily to 22.39% for Acuvue TruEye 1-Day. The toughness results showed that Dailies AquaComfort Plus is strong but not necessarily tough. CONCLUSIONS: The mechanical properties of commonly prescribed soft contact lens materials were measured using a dedicated instrument. Its reliability was demonstrated, and modulus results were compared against published data from manufacturers and other research groups. Agreement was generally good, with only a few exceptions exceeding 15% difference. The more recently released silicone hydrogel lens types have reduced modulus, approaching that of medium or high water content hydrogel materials. PMID- 29116966 TI - Effect of Beam Steering on Echogenic and Nonechogenic Needle Visibility at 40 degrees , 50 degrees , and 60 degrees Needle Insertion Angles. AB - Currently, there is little understanding of the role of echogenic needles and beam steering at moderate angles of needle insertion. The ultrasound images of the echogenic and nonechogenic needles inserted into pork at 40 degrees , 50 degrees , and 60 degrees were scored by anesthesiologists on a scale of 0-10. The effect of different levels of beam steer was also explored. At 40 degrees , steep beam steering improves visualization of both nonechogenic and echogenic needles to an equal, satisfactory level. At 50 degrees and 60 degrees , visualization of nonechogenic needles is poor, whereas visibility of an echogenic needle was adequate and may be improved with steep beam steering. PMID- 29116967 TI - Validation of a New Method to Automatically Select Cases With Intraoperative Red Blood Cell Transfusion for Audit. AB - BACKGROUND: Hospitals review allogeneic red blood cell (RBC) transfusions for appropriateness. Audit criteria have been published that apply to 5 common procedures. We expanded on this work to study the management decision of selecting which cases involving transfusion of at least 1 RBC unit to audit (review) among all surgical procedures, including those previously studied. METHODS: This retrospective, observational study included 400,000 cases among 1891 different procedures over an 11-year period. There were 12,616 cases with RBC transfusion. We studied the proportions of cases that would be audited based on criteria of nadir hemoglobin (Hb) greater than the hospital's selected transfusion threshold, or absent Hb or missing estimated blood loss (EBL) among procedures with median EBL <500 mL. This threshold EBL was selected because it is approximately the volume removed during the donation of a single unit of whole blood at a blood bank. Missing EBL is important to the audit decision for cases in which the procedures' median EBL is <500 mL because, without an indication of the extent of bleeding, there are insufficient data to assume that there was sufficient blood loss to justify the transfusion. RESULTS: Most cases (>50%) that would be audited and most cases (>50%) with transfusion were among procedures with median EBL <500 mL (P < .0001). Among cases with transfusion and nadir Hb >9 g/dL, the procedure's median EBL was <500 mL for 3.0 times more cases than for procedures having a median EBL >=500 mL. A greater percentage of cases would be recommended for audit based on missing values for Hb and/or EBL than based on exceeding the Hb threshold among cases of procedures with median EBL >=500 mL (P < .0001). There were 3.7 times as many cases with transfusion that had missing values for Hb and/or EBL than had a nadir Hb >9 g/dL and median EBL for the procedure >=500 mL. CONCLUSIONS: An automated process to select cases for audit of intraoperative transfusion of RBC needs to consider the median EBL of the procedure, whether the nadir Hb is below the hospital's Hb transfusion threshold for surgical cases, and the absence of either a Hb or entry of the EBL for the case. This conclusion applies to all surgical cases and procedures. PMID- 29116968 TI - Antiemetic Prophylaxis as a Marker of Health Care Disparities in the National Anesthesia Clinical Outcomes Registry. AB - BACKGROUND: US health care disparities persist despite repeated countermeasures. Research identified race, ethnicity, gender, and socioeconomic status as factors, mediated through individual provider and/or systemic biases; little research exists in anesthesiology. We investigated antiemetic prophylaxis as a surrogate marker for anesthesia quality by individual providers because antiemetics are universally available, indicated contingent on patient characteristics (gender, age, etc), but independent of comorbidities and not yet impacted by regulatory or financial constraints. We hypothesized that socioeconomic indicators (measured as insurance status or median income in the patients' home zip code area) are associated with the utilization of antiemetic prophylaxis (as a marker of anesthesia quality). METHODS: We tested our hypothesis in several subsets of electronic anesthesia records from the National Anesthesia Clinical Outcomes Registry (NACOR), fitting frequentist and novel Bayesian multilevel logistic regression models. RESULTS: NACOR contained 12 million cases in 2013. Six institutions reported on antiemetic prophylaxis for 441,645 anesthesia cases. Only 173,133 cases included details on insurance information. Even fewer (n = 92,683) contained complete data on procedure codes and provider identifiers. Bivariate analysis, multivariable logistic regression, and our Bayesian hierarchical model all showed a large and statistically significant association between socioeconomic markers and antiemetic prophylaxis (ondansetron and dexamethasone). For Medicaid versus commercially insured patients, the odds ratio of receiving the antiemetic ondansetron is 0.85 in our Bayesian hierarchical mixed regression model, with a 95% Bayesian credible interval of 0.81-0.89 with similar inferences in classical (frequentist) regression models. CONCLUSIONS: Our analyses of NACOR anesthesia records raise concerns that patients with lower socioeconomic status may receive inferior anesthesia care provided by individual anesthesiologists, as indicated by less antiemetics administered. Effects persisted after we controlled for important patient characteristics and for procedure and provider influences. Findings were robust to sensitivity analyses. Our results challenge the notion that anesthesia providers do not contribute to health care disparities. PMID- 29116970 TI - Assessment of Tricuspid Annular Motion by Speckle Tracking in Anesthetized Patients Using Transesophageal Echocardiography. AB - BACKGROUND: The perioperative assessment of right ventricular (RV) function remains a challenge. Tricuspid annular plane systolic excursion (TAPSE) using M mode is a widely used measure of RV function. However, accurate alignment of the ultrasound beam with the direction of annular movement can be difficult with transesophageal echocardiography (TEE) to measure TAPSE, precluding effective use of M-mode to measure annular excursion. Tracking of specular reflectors in the myocardium may provide an angle-independent method to assess annular motion with TEE. We hypothesized that TEE speckle tracking of the lateral tricuspid annular motion represents a comparable measurement to the well-validated M-mode TAPSE on transthoracic echocardiogram (TTE), and may be considered as a reasonable alternative to TAPSE. METHODS: This is a prospective, observational cohort study. We included all patients, who were in sinus rhythm, with a preoperative TTE within 3 months of scheduled cardiac surgery that required intraoperative TEE. Tissue motion annular displacements (TMAD) of the lateral (L), septal (S), and midpoint (M) tricuspid annulus were measured (QLAB Cardiac Motion Quantification; Philips Medical, Andover, MA) after induction of general anesthesia. This was compared to the preoperative M-mode TAPSE on TTE. RESULTS: Seventy-two consecutive patients who met eligibility requirements were enrolled from September to November 2016. Twelve were excluded due to poor image quality, allowing TMAD to be analyzed in 60 patients. TMAD was analyzed offline and TMAD analysis was able to track tricuspid annular motion in all patients. The mean TMAD (L), TMAD (S), and TMAD (M) were 17.4 +/- 5.2, 10.2 +/- 4.8, and 14.2 +/- 4.8 mm, respectively. TMAD (L) showed close correlation with M-mode TAPSE on TTE (r = 0.87, 95% confidence interval, 0.79-0.92; P < .01). All patients with a preoperative TAPSE <17 mm had a TMAD (L) <17 mm, while 71% of those with a TAPSE >= 17 mm had a TMAD (L) >= 17 mm. There was strong positive correlation between TMAD (L) and intraoperative RV fractional area change (r = 0.86, 95% confidence interval, 0.77-0.91; P < .01). Reproducibility analysis of TMAD within and across observers showed excellent correlation. CONCLUSIONS: TMAD is a quick and angle independent method to quantitatively assess RV longitudinal function by TEE. It correlates strongly with M-mode TAPSE on TTE. Because TMAD and TAPSE were not simultaneously measured in this study, their correlation is subject to differences in loading conditions, general anesthesia, and changes in the disease process. TMAD may be easily applied in routine clinical settings and its role in the perioperative environment deserves to be further explored. PMID- 29116971 TI - Only New Red Blood Cells for Orthotopic Liver Transplant? PMID- 29116972 TI - Low Cardiac Output Syndrome After Adult Cardiac Surgery: Predictive Value of Peak Systolic Global Longitudinal Strain. AB - BACKGROUND: Peak systolic global longitudinal strain (GLS) is increasingly used to quantify left ventricular systolic function. The primary objective of this study was to assess whether GLS obtained during intraoperative transesophageal echocardiogram, performed before cardiopulmonary bypass, improves the prediction of postoperative low cardiac output syndrome (LCOS) after adult cardiac surgery. METHODS: GLS from 275 patients undergoing on-pump cardiac surgery was calculated retrospectively using two-dimensional- speckle tracking echocardiography (aCMQ module from Qlab software version 10.5, Philips Medical, Brussels, Belgium). LCOS was defined as the need for inotropic or mechanical circulatory support for >24 hours postoperatively. Patient and procedure characteristics associated with LCOS at the univariable level (P <= .05) were entered into a forward stepwise logistic regression to create a first predictive model. A second model was created by adding GLS. The 2 models were compared using the likelihood-ratio test, the area under the receiver operating characteristic (ROC) curve, and the integrated discrimination index. The optimal cutoff value of GLS associated with LCOS was determined by maximizing the Youden index of the ROC curve. Secondary outcomes included time until complete weaning from inotropes, discharge from the intensive care unit and from the hospital, and 30-day mortality. RESULTS: GLS was significantly associated with LCOS (P < .001) at the univariable level. Predictors of LCOS retained in the first model were cardiopulmonary bypass duration, decreased left ventricular ejection fraction, mitral valve surgery, and New York Heart Association functional class III or IV. Adding the GLS value improved the prediction of LCOS (P = .02). However, the area under the ROC curve did not differ between the 2 models (0.83; 95% confidence interval [CI], 0.77 0.99 vs 0.84; 95% CI, 0.79-0.90; P = .15). The integrated discrimination index associated with addition of GLS was 0.02 (P = .046), meaning that the difference in predicted risk between patients with and without LCOS increased by 2% after adding GLS. A GLS cutoff value of -17% (95% CI, -18.8% to -15.3%) was found to best identify LCOS. After adjusting for covariates included in model 1, a lower GLS value was significantly associated with a lower cumulative probability of weaning from inotropes postoperatively (hazard ratio, 0.90; 95% CI, 0.82-0.97; P = .01). No association was found between GLS and other secondary outcome measures. CONCLUSIONS: GLS is an independent predictor of LCOS after on-pump cardiac surgery. Its incremental value over other established risk factors for postoperative LCOS is, however, limited. PMID- 29116973 TI - The Pediatric Anesthesiology Workforce: Projecting Supply and Trends 2015-2035. AB - BACKGROUND: A workforce analysis was conducted to predict whether the projected future supply of pediatric anesthesiologists is balanced with the requirements of the inpatient pediatric population. The specific aims of our analysis were to (1) project the number of pediatric anesthesiologists in the future workforce; (2) project pediatric anesthesiologist-to-pediatric population ratios (0-17 years); (3) project the mean number of inpatient pediatric procedures per pediatric anesthesiologist; and (4) evaluate the effect of alternative projections of individual variables on the model projections through 2035. METHODS: The future number of pediatric anesthesiologists is determined by the current supply, additions to the workforce, and departures from the workforce. We previously compiled a database of US pediatric anesthesiologists in the base year of 2015. The historical linear growth rate for pediatric anesthesiology fellowship positions was determined using the Accreditation Council for Graduate Medical Education Data Resource Books from 2002 to 2016. The future number of pediatric anesthesiologists in the workforce was projected given growth of pediatric anesthesiology fellowship positions at the historical linear growth rate, modeling that 75% of graduating fellows remain in the pediatric anesthesiology workforce, and anesthesiologists retire at the current mean retirement age of 64 years old. The baseline model projections were accompanied by age- and gender adjusted anesthesiologist supply, and sensitivity analyses of potential variations in fellowship position growth, retirement, pediatric population, inpatient surgery, and market share to evaluate the effect of each model variable on the baseline model. The projected ratio of pediatric anesthesiologists to pediatric population was determined using the 2012 US Census pediatric population projections. The projected number of inpatient pediatric procedures per pediatric anesthesiologist was determined using the Kids' Inpatient Database historical data to project the future number of inpatient procedures (including out of operating room procedures). RESULTS: In 2015, there were 5.4 pediatric anesthesiologists per 100,000 pediatric population and a mean (+/-standard deviation [SD]) of 262 +/-8 inpatient procedures per pediatric anesthesiologist. If historical trends continue, there will be an estimated 7.4 pediatric anesthesiologists per 100,000 pediatric population and a mean (+/-SD) 193 +/-6 inpatient procedures per pediatric anesthesiologist in 2035. If pediatric anesthesiology fellowship positions plateau at 2015 levels, there will be an estimated 5.7 pediatric anesthesiologists per 100,000 pediatric population and a mean (+/-SD) 248 +/-7 inpatient procedures per pediatric anesthesiologist in 2035. CONCLUSIONS: If historical trends continue, the growth in pediatric anesthesiologist supply may exceed the growth in both the pediatric population and inpatient procedures in the 20-year period from 2015 to 2035. PMID- 29116974 TI - In Response. PMID- 29116975 TI - Progress on a New Kind of Progress Test: Assessing Medical Students' Clinical Skills. AB - PROBLEM: Progress testing of medical knowledge has advantages over traditional medical school examination strategies. However, little is known about its use in assessing medical students' clinical skills or their integration of clinical skills with necessary science knowledge. The authors previously reported on the feasibility of the Progress Clinical Skills Examination (PCSE), piloted with a group of early learners. This subsequent pilot test studied the exam's validity to determine whether the PCSE is sensitive to the growth in students' clinical skills across the four years of medical school. APPROACH: In 2014, 38 medical student volunteers (years 1-4) in the traditional 2 + 2 curriculum at Michigan State University College of Human Medicine participated in the eight-station PCSE. Faculty and standardized patients assessed students' clinical skills, and faculty assessed students' responses to postencounter necessary science questions. Students performed pretest self-assessment across multiple measures and completed a posttest evaluation of their PCSE experience. OUTCOMES: Student performance generally increased by year in medical school for communication, history-taking, and physical examination skills. Necessary science knowledge increased substantially from first-year to second-year students, with less change thereafter. Students felt the PCSE was a fair test of their clinical skills and provided an opportunity to demonstrate their understanding of the related necessary science. NEXT STEPS: The authors have been piloting a wider pool of cases. In 2016, they adopted the PCSE as part of the summative assessment strategy for the medical school's new integrated four-year curriculum. Continued assessment of student performance trajectories is planned. PMID- 29116976 TI - PEARLS+: Connecting Societal Forces, Social Determinants, and Health Outcomes. PMID- 29116977 TI - The Evolving Purposes of Medical Revalidation in the United Kingdom: A Qualitative Study of Professional and Regulatory Narratives. AB - PURPOSE: Previous research found professionalism and regulation to be competing discourses when plans for medical revalidation in the United Kingdom were being developed in 2011. The purpose of this study was to explore how these competing discourses developed and how the perceived purposes of revalidation evolved as the policy was implemented. METHOD: Seventy-one interviews with 60 UK policy makers and senior health care leaders were conducted during the development and implementation of revalidation: 31 in 2011, 26 in 2013, and 14 in 2015. Interviewees were selected using purposeful sampling. Across all interviews, questions focused around three areas: individual roles in relation to revalidation; interviewees' understanding of revalidation, its purpose, and aims; and predictions or experiences of revalidation's impact. The first two interview sets also included questions about measurement and evaluation of revalidation. Data were analyzed using the constant comparative method to understand changes and continuities. RESULTS: Two main discourses regarding the purpose of revalidation were present across the implementation period: professionalism and regulation. The nature of the relationship between these two purposes and how they were described changed over time, with the separate discourses converging, and early concerns about actual or potential conflict being replaced by perceptions of coexistence or codependency. CONCLUSIONS: The changing nature of the discourse about revalidation suggests that early concerns about adverse consequences were not borne out as organizations and professionals engaged with implementation and experienced the realities of revalidation in practice. Reconciling professional and regulatory narratives was arguably necessary to the effective implementation of revalidation. PMID- 29116978 TI - "You're Not Trying to Save Somebody From Death": Learning as "Becoming" in Palliative Care. AB - PURPOSE: Learning can be conceptualized as a process of "becoming," considering individuals, workplace participation, and professional identity formation. How postgraduate trainees learn palliative care, encompassing technical competence, compassion, and empathy, is not well understood or explained by common conceptualizations of learning as "acquisition" and "participation." Learning palliative care, a practice that has been described as a cultural shift in medicine challenging the traditional role of curing and healing, provided the context to explore learning as "becoming." METHOD: The authors undertook a qualitative narrative study, interviewing 14 residents from the University of Ottawa Family Medicine Residency Program eliciting narratives of memorable learning (NMLs) for palliative care. Forty-five NMLs were analyzed thematically. To illuminate the interplay among themes, an in-depth analysis of the NMLs was done that considered themes and linguistic and paralinguistic features of the narratives. RESULTS: Forty-five NMLs were analyzed. The context of NMLs was predominantly a variety of clinical workplaces during postgraduate training. Themes clustered around the concept of palliative care and how it contrasted with other clinical experiences, the emotional impact on narrators, and how learning happened in the workplace. Participants had expectations about their identities as doctors that were challenged within their NMLs for palliative care. CONCLUSIONS: NMLs for palliative care were a complex entanglement of individual experience and social and workplace cultures highlighting the limitations of the "acquisition" and "participation" metaphors of learning. By conceptualizing learning as "becoming," what occurs during memorable learning can be made accessible to those supporting learners and their professional identity formation. PMID- 29116979 TI - Translating Theory Into Practice: Implementing a Program of Assessment. AB - PROBLEM: A program of assessment addresses challenges in learner assessment using a centrally planned, coordinated approach that emphasizes assessment for learning. This report describes the steps taken to implement a program of assessment framework within a medical school. APPROACH: A literature review on best practices in assessment highlighted six principles that guided implementation of the program of assessment in 2016-2017: (1) a centrally coordinated plan for assessment aligns with and supports a curricular vision; (2) multiple assessment tools used longitudinally generate multiple data points; (3) learners require ready access to information-rich feedback to promote reflection and informed self-assessment; (4) mentoring is essential to facilitate effective data use for reflection and learning planning; (5) the program of assessment fosters self-regulated learning behaviors; and (6) expert groups make summative decisions about grades and readiness for advancement. Implementation incorporated stakeholder engagement, use of multiple assessment tools, design of a coaching program, and creation of a learner performance dashboard. OUTCOMES: The assessment team monitors adherence to principles defining the program of assessment and gathers and responds to regular feedback from key stakeholders, including faculty, staff, and students. NEXT STEPS: Next steps include systematically collecting evidence for validity of individual assessments and the program overall. Iterative review of student performance data informs curricular improvements. The program of assessment also highlights technology needs that will be addressed with information technology experts. The outcome ultimately will entail showing evidence of validity that the program produces physicians who engage in lifelong learning and provide high-quality patient care. PMID- 29116980 TI - Rethinking the Educator Portfolio: An Innovative Criteria-Based Model. AB - PROBLEM: Academic medical centers struggle to achieve parity in advancement and promotions between educators and discovery-oriented researchers in part because of narrow definitions of scholarship, lack of clear criteria for measuring excellence, and barriers to making educational contributions available for peer review. Despite recent progress in expanding scholarship definitions and identifying excellence criteria, these advances are not integrated into educator portfolio (EP) templates or curriculum vitae platforms. APPROACH: From 2013 to 2015, a working group from the Academy of Medical Educators (AME) at the University of California, San Francisco (UCSF) designed a streamlined, criteria based EP (EP 2.0) template highlighting faculty members' recent activities in education and setting rigorous evaluation methods to enable educational scholarship to be objectively evaluated for academic advancement, AME membership, and professional development. OUTCOMES: The EP 2.0 template was integrated into the AME application, resulting in high overall satisfaction among candidates and the selection committee and positive feedback on the template's transparency, ease of use, and streamlined format. In 2016, the EP 2.0 template was integrated into the campus-wide curriculum vitae platform and academic advancement system. NEXT STEPS: The authors plan to increase awareness of the EP 2.0 template by educating promotions committees and faculty at UCSF and partnering with other institutions to disseminate it for use. They also plan to study the impact of the template on supporting educators by making their important scholarly contributions available for peer review, providing guidance for professional development, and decreasing disparities in promotions. PMID- 29116982 TI - A Rose by Other Names: Some General Musings on Lawrence and Colleagues' Hidden Curriculum Scoping Review. AB - In this Commentary, the authors explore the scoping review by Lawrence and colleagues by challenging their conclusion that with over 25 years' worth of "ambiguous and seemingly ubiquitous use" of the hidden curriculum construct in health professions education scholarship, it is time to either move to a more uniform definitional foundation or abandon the term altogether. The Commentary authors counter these remedial propositions by foregrounding the importance of theoretical diversity and the conceptual richness afforded when the hidden curriculum construct is used as an entry point for studying the interstitial space between the formal and a range of other-than-formal domains of learning. They document how tightly delimited scoping strategies fail to capture the wealth of educational scholarship that operates within a hidden curriculum framework, including "hidden" hidden curriculum articles, studies that employ alternative constructs, and investigations that target important tacit sociocultural influences on learners and faculty without formally deploying the term. They offer examples of how the hidden curriculum construct, while undergoing significant transformation in its application within the field of health professions education, has created the conceptual foundation for the application of a number of critical perspectives that make visible the field's political investments in particular forms of knowing and associated practices. Finally, the Commentary authors invite readers to consider the methodological promise afforded by conceptual heterogeneity, particularly strands of scholarship that resituate the hidden curriculum concept within the magically expansive dance of social relationships, social learning, and social life that form the learning environments of health professions education. PMID- 29116983 TI - "Rising to the Level of Your Incompetence": What Physicians' Self-Assessment of Their Performance Reveals About the Imposter Syndrome in Medicine. AB - PURPOSE: Mistakes are ubiquitous in medicine; when confronted by error, physicians may experience anxiety, guilt, and self-doubt. Feedback may be useful for navigating these feelings, but only if it matches a physician's self assessment; self-doubt and the imposter syndrome are examples of inaccurate self assessments that may affect receptivity to feedback. The impact of real or imagined underperformance on seemingly competent physicians is poorly understood. This study aimed to develop a deeper understanding to identify strategies to support all physicians who struggle. METHOD: In 2015, 28 physicians were interviewed about their experiences with underperformance. Early in the data collection process, participants spontaneously identified the imposter syndrome as a feature of their experiences; questions about the imposter syndrome were probed in subsequent interviews. RESULTS: Many participants-even those at advanced career stages-questioned the validity of their achievements; progressive independence and career advancement were variably experienced as "rising to the level of your incompetence." Not all participants identified as imposters; the imposter syndrome occurred at the extreme end of a spectrum of self-doubt. Even positive feedback could not buffer participants' insecurities, which participants rarely shared with their colleagues. CONCLUSIONS: Self-doubt variably affects clinicians at all career stages. Frequent transitions may cause a resurgence of self-doubt that may affect feedback credibility. Medical educators must recognize that it is not just the underperforming or failing learners who struggle and require support, and medical culture must create space for physicians to share their struggles. PMID- 29116984 TI - Speaking Up: An Ethical Action Exercise. AB - PROBLEM: Health care professionals encounter situations in which they need to speak up to prevent harm, ensure better care, and/or address unprofessional behavior. Speaking up is often difficult, especially for medical students; nonetheless, it is a skill students must practice, so they can better advocate for patients. APPROACH: The authors have designed an ethical action exercise and incorporated it into a required bioethics course that meets concurrently with third-year clerkships. The exercise requires students to speak up to try to correct, resolve, or improve one situation during a clerkship. The exercise involves overt action, but students determine how, where, and when to act. OUTCOMES: In 2013-2014, 111 students at State University of New York Upstate Medical University completed the exercise. Most spoke up about situations in which they thought that some aspect of patient care could be improved (n = 78; 70%); others spoke up when they perceived unprofessional conduct (n = 32; 29%). Although most students found speaking up to be difficult (n = 96; 86%), speaking up often led to improved care (n = 46; 41%). As a result of completing the ethical action exercise, 2 students reported becoming less likely to speak up in the future, whereas 64 students reported becoming more likely. NEXT STEPS: Going forward, the authors want to address three issues: the development of lasting habits, the role of culture, and connections with other initiatives to improve care. PMID- 29116981 TI - The Hidden Curricula of Medical Education: A Scoping Review. AB - PURPOSE: To analyze the plural definitions and applications of the term "hidden curriculum" within the medical education literature and to propose a conceptual framework for conducting future research on the topic. METHOD: The authors conducted a literature search of nine online databases, seeking articles published on the hidden, informal, or implicit curriculum in medical education prior to March 2017. Two reviewers independently screened articles with set inclusion criteria and performed kappa coefficient tests to evaluate interreviewer reliability. They extracted, coded, and analyzed key data, using grounded theory methodology. RESULTS: The authors uncovered 3,747 articles relating to the hidden curriculum in medical education. Of these, they selected 197 articles for full review. Use of the term "hidden curriculum" has expanded substantially since 2012. U.S. and Canadian medical schools are the focus of two thirds of the empirical hidden curriculum studies; data from African and South American schools are nearly absent. Few quantitative techniques to measure the hidden curriculum exist. The "hidden curriculum" is understood as a mostly negative concept. Its definition varies widely, but can be understood via four conceptual boundaries: (1) institutional-organizational, (2) interpersonal social, (3) contextual-cultural, and/or (4) motivational-psychological. CONCLUSIONS: Future medical education researchers should make clear the conceptual boundary or boundaries they are applying to the term "hidden curriculum," move away from general musings on its effects, and focus on specific methods for improving the powerful hidden curriculum. PMID- 29116985 TI - Resources Used to Teach the Physical Exam to Preclerkship Medical Students: Results of a National Survey. AB - PURPOSE: To examine resources used in teaching the physical exam to preclerkship students at U.S. medical schools. METHOD: The Directors of Clinical Skills Courses developed a 49-question survey addressing resources and pedagogical methods employed in preclerkship physical exam curricula. The survey was sent to all 141 Liaison Committee on Medical Education-accredited medical schools in October 2015. Results were averaged across schools, and data were weighted by class size. RESULTS: Results from 106 medical schools (75% response rate) identified a median of 59 hours devoted to teaching the physical exam. Thirty eight percent of time spent teaching the physical exam involved the use of standardized patients, 30% used peer-to-peer practice, and 25% involved examining actual patients. Approximately half of practice time with actual patients was observed by faculty. At 48% of schools (51), less than 15% of practice time was with actual patients, and at 20% of schools (21) faculty never observed students practicing with actual patients. Forty-eight percent of schools (51) did not provide compensation for their outpatient clinical preceptors. CONCLUSIONS: There is wide variation in the resources used to teach the physical examination to preclerkship medical students. At some schools, the amount of faculty observation of students examining actual patients may not be enough for students to achieve competency. A significant percentage of faculty teaching the physical exam remain uncompensated for their effort. Improving faculty compensation and increasing use of senior students as teachers might allow for greater observation and feedback and improved physical exam skills among students. PMID- 29116986 TI - It Is Time for Zero Tolerance for Sexual Harassment in Academic Medicine. AB - While more women are in leadership positions in academic medicine now than ever before in U.S. history, evidence from recent surveys of women and graduating medical students demonstrates that sexual harassment continues in academic health centers. Academic medicine's ability to change its culture is hampered by victims' fear of reporting episodes of harassment, which is largely due to fear of retaliation. In this Perspective, the authors describe efforts in scientific societies to address the issue of sexual harassment and to begin to establish safe environments at national meetings. The authors contend that each institution must work to make it safe for individuals to come forward, to provide training for victims and for bystanders, and to abolish "locker room" talk that is demeaning to women. PMID- 29116987 TI - A Substance Use Cost Calculator for US Employers With an Emphasis on Prescription Pain Medication Misuse. AB - OBJECTIVE: Substance use disorders are among the most common and costly health conditions affecting Americans. Despite estimates of national costs exceeding $400 billion annually, individual companies may not see how substance use impacts their bottom lines through lost productivity and absenteeism, turnover, health care expenses, disability, and workers' compensation. METHODS: Data on employed adults (18 years and older) from 3 years (2012 to 2014) of the National Survey on Drug Use and Health Public Use Data Files were analyzed. RESULTS: The results offer employers an authoritative, free, epidemiologically grounded, and easy-to use tool that gives specific information about how alcohol, prescription pain medication misuse, and illicit drug use is likely impacting workplaces like theirs. CONCLUSION: Employers have detailed reports of the cost of substance use that can be used to improve workplace policies and health benefits. PMID- 29116988 TI - Healthy Eating and Leisure-Time Activity: Cross-Sectional Analysis of that Role of Work Environments in the U.S. AB - OBJECTIVE: The aim of this study was to evaluate relationships between work context and two health behaviors, healthy eating and leisure-time physical activity (LTPA), in U.S. adults. METHODS: Using data from the 2010 National Health Interview Survey (NHIS) and Occupational Information Network (N = 14,863), we estimated a regression model to predict the marginal and joint probabilities of healthy eating and adhering to recommended exercise guidelines. RESULTS: Decision-making freedom was positively related to healthy eating and both behaviors jointly. Higher physical load was associated with a lower marginal probability of LTPA, healthy eating, and both behaviors jointly. Smoke and vapor exposures were negatively related to healthy eating and both behaviors. Chemical exposure was positively related to LTPA and both behaviors. Characteristics associated with marginal probabilities were not always predictive of joint outcomes. CONCLUSION: On the basis of nationwide occupation-specific evidence, workplace characteristics are important for healthy eating and LTPA. PMID- 29116989 TI - The Influence of Body Mass on Physical Fitness Test Performance in Male Firefighter Applicants. AB - OBJECTIVE: The influence of body mass on test performance was investigated in 414 male firefighter applicants who completed a maximal treadmill test and five task simulation tests while dressed in fire protective ensemble. METHODS: Subjects were assigned to six mass categories from less than 70 kg to more than 110 kg, in 10 kg increments (n = 69 in each). RESULTS: Treadmill performance was lower (P < 0.05) in the two heaviest groups. Charged hose advance time was slower in the two lightest groups. The lightest group had slower times for weighted sled pull, forcible entry, and victim rescue tests. The heaviest group was slower on the ladder climb test. CONCLUSION: Lighter subjects had a small advantage in endurance-oriented tests while higher mass appeared to improve performance slightly in strength-oriented tests. However, mass explained only 4% to 19% of the variance in performance. PMID- 29116990 TI - Factors Influencing Job Satisfaction Among Long-Term Care Staff. AB - OBJECTIVE: We assessed the intrapersonal, interpersonal, and organizational factors that predicted job satisfaction among long-term care employees. METHODS: Baseline data were used to describe characteristics that influence job satisfaction. Using a forced linear regression model, while controlling for age and job title, we assessed if higher physical activity levels, fewer symptoms of depression, stress, and/or anxiety (ie, decreased mood), less back pain, stronger social support, and reports of low work demands were associated with higher job satisfaction. RESULTS: Mood (beta = -0.412, P = 0.003) explained 17% of the variance in job satisfaction. CONCLUSION: This information can be used to guide facility wide programs and interventions aimed at increasing job satisfaction among all long-term care staff. PMID- 29116991 TI - Association Between Polymorphisms of Metabolic Enzyme Genes and Chromosomal Damage in Benzene-Exposed Workers in China. AB - OBJECTIVE: To provide better understanding of genetic susceptibility for health risk among current benzene-exposed workers. METHODS: Four hundred sixty one benzene-exposed workers and 88 matched controls were recruited, and their benzene exposure doses were monitored. Associations between genetic susceptibility for polymorphisms of metabolic enzymes CYP2E1 and NQO1, and expression of cytokinesis block micronucleus (MN) were investigated. RESULTS: Mean MN frequency in the exposed workers was significantly higher than that in the control group (P < 0.01). Individuals with the NQO1 CC genotype showed significantly higher MN frequencies than those with the TT genotype (P < 0.05) in either single- or multiple-factor analyses. Age was an effect modifier for elevated MN frequency, while sex, smoking, and alcohol consumption had no relationship. CONCLUSION: Exposure to low dose of benzene among current workers can still cause health risk, especially among those with the NQO1 CC genotype. PMID- 29116992 TI - Enhancing Worker Health Through Clinical Decision Support (CDS): An Introduction to a Compilation. AB - OBJECTIVE: This article outlines an approach to developing clinical decision support (CDS) for conditions related to work and health. When incorporated in electronic health records, such CDS will assist primary care providers (PCPs) care for working patients. METHODS: Three groups of Subject Matter Experts (SMEs) identified relevant clinical practice guidelines, best practices, and reviewed published literature concerning work-related asthma, return-to-work, and management of diabetes at work. RESULTS: SMEs developed one recommendation per topic that could be supported by electronic CDS. Reviews with PCPs, staff, and health information system implementers in five primary care settings confirmed that the approach was important and operationally sound. CONCLUSION: This compendium is intended to stimulate a dialogue between occupational health specialists and PCPs that will enhance the use of work information about patients in the primary care setting. PMID- 29116993 TI - Development of a Diabetes Mellitus Knowledge Resource for Clinical Decision Support Assisting Primary Care Physicians With Work-Related Issues. AB - OBJECTIVE: The aim of this study was to describe the process by which a group of subject matter experts (SMEs) in the area of occupational health and primary care developed a clinical decision support (CDS) tool addressing work-related issues, which are important in the care of patients with diabetes mellitus (DM). The CDS is intended for primary care clinicians caring for employed adults with DM. METHODS: The SME's selected guidelines for the management of DM in working adults, reviewed pertinent literature, and developed specific recommendations for action in the clinical setting. RESULTS: Multiple factors at work may adversely affect DM management. Clinicians can support working patients through education and care strategies to improve control. CONCLUSION: Improved recognition of factors at work that can have an impact on DM care provides opportunities for improved management of DM among working adults. PMID- 29116994 TI - Recognition of the Relationship Between Patients' Work and Health: A Qualitative Evaluation of the Need for Clinical Decision Support (CDS) for Worker Health in Five Primary Care Practices. AB - OBJECTIVE: The aim of this study was to determine the perceived value and feasibility of increased access to information about workers' health for primary care providers (PCPs) by evaluating the need for clinical decision support (CDS) related to worker health in primary care settings. METHODS: Qualitative methods, including semi-structured interviews and observations, were used to evaluate the value and feasibility of three examples of CDS relating work and health in five primary care settings. RESULTS: PCPs and team members wanted help addressing patients' health in relation to their jobs; the proposed CDS examples were perceived as valuable because they provided useful information, promoted standardization of care, and were considered technically feasible. Barriers included time constraints and a perceived inability to act on the findings. CONCLUSION: PCPs recognize the importance and impact of work on their patients' health but often lack accessible knowledge at the right time. Occupational health providers can play an important role through contributions to the development of CDS that assists PCPs in recognizing and addressing patients' health, as well as through the provision of referral guidelines. PMID- 29116995 TI - Prolonged Infusion Piperacillin-Tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients: Results of a Systematic Review and Meta Analysis. AB - OBJECTIVE: Piperacillin-tazobactam is a commonly used antibiotic in critically ill patients; however, controversy exists as to whether mortality in serious infections can be decreased through administration by prolonged infusion compared with intermittent infusion. The purpose of this systematic review and meta analysis was to describe the impact of prolonged infusion piperacillin-tazobactam schemes on clinical endpoints in severely ill patients. DESIGN: We conducted a systematic literature review and meta-analysis searching MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to April 1, 2017, for studies. INTERVENTIONS: Mortality rates were compared between severely ill patients receiving piperacillin-tazobactam via prolonged infusion or intermittent infusion. Included studies must have reported severity of illness scores, which were transformed into average study-level mortality probabilities. MEASUREMENTS AND MAIN RESULTS: Two investigators independently screened titles, abstracts, and full texts of studies meeting inclusion criteria for this systematic review and meta-analysis. Variables included author name, publication year, study design, demographics, total daily dose(s), average estimated creatinine clearance, type of prolonged infusion, prevalence of combination therapy, severity of illness scores, infectious sources, all-cause mortality, clinical cure, microbiological cure, and hospital and ICU length of stay. The review identified 18 studies including 3,401 patients who received piperacillin-tazobactam, 56.7% via prolonged infusion. Across all studies, the majority of patients had an identified primary infectious source. Receipt of prolonged infusion was associated with a 1.46-fold lower odds of mortality (95% CI, 1.20-1.77) in the pooled analysis. Patients receiving prolonged infusion had a 1.77-fold higher odds of clinical cure (95% CI, 1.24 2.54) and a 1.22-fold higher odds of microbiological cure (95% CI, 0.84-1.77). Subanalyses were conducted according to high (>= 20%) and low (< 20%) average study-level mortality probabilities. In studies reporting higher mortality probabilities, effect sizes were variable but similar to the pooled results. CONCLUSIONS: Receipt of prolonged infusion of piperacillin-tazobactam was associated with reduced mortality and improved clinical cure rates across diverse cohorts of severely ill patients. PMID- 29116996 TI - Leptospirosis in ICU: A Retrospective Study of 134 Consecutive Admissions. AB - OBJECTIVES: Leptospirosis causes reversible multiple organ failure, and its mortality remains high. The aim of this study was to determine the mortality rate of leptospirosis in an ICU offering all types of organ support available nowadays and to compare it with mortality in bacterial sepsis. DESIGN: Retrospective, descriptive, and single-center cohort study. SETTINGS: The largest ICU of Reunion Island (Indian Ocean) in a teaching hospital. PATIENTS: Consecutive patients hospitalized in ICU for leptospirosis from January 2004 to January 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We report 134 cases of patients with leptospirosis hospitalized in ICU. The median age was 40 years (interquartile range, 30-52 yr), with a Simplified Acute Physiology Score II of 38 (27-50) and a Sequential Organ Failure Assessment score of 10 (8-12). Forty one patients (31%) required mechanical ventilation and 76 (56%) required renal replacement therapy. The door-to-renal replacement therapy time was 0 (0-1) day after admission with a median urea of 25 mmol/L (17-32 mmol/L). Five patients required extracorporeal membrane oxygenation. The mortality rate was 6.0% (95% CI, 2.6-11.4). Among patients hospitalized for sepsis, the standardized mortality ratio of patients with leptospirosis with regards to Simplified Acute Physiology Score II was dramatically low: 0.40 (95% CI, 0.17 - 0.79). CONCLUSIONS: The mortality of severe leptospirosis is lower than for other bacterial infection, provided modern resuscitation techniques are available. Prompt organ support ensures very low mortality rates despite high severity scores. PMID- 29116997 TI - Hospital Differences Drive Antibiotic Delays for Black Patients Compared With White Patients With Suspected Septic Shock. AB - OBJECTIVE: Evaluate racial disparities in sepsis processes of care. DESIGN: Observational cohort study. SETTING: Nine hospitals in the Southeastern United States between 2014 and 2016. PATIENTS: Two thousand two hundred twenty-one white and 707 black patients treated in the emergency department through "code sepsis" pathway for suspected septic shock. MEASUREMENTS AND MAIN RESULTS: Black patients were less likely to receive timely antibiotics than were white patients using multiple definitions (1 hr from code sepsis activation [odds ratio, 0.57; 95% CI, [0.44-0.74]; 85.6% vs. 91.2%; p < 0.0001]; 1 hr from triage [odds ratio, 0.83; 95% CI, [0.69-1.00]; 28.0% vs. 31.8%; p = 0.06]; 3 hr from triage [odds ratio, 0.71; 95% CI, [0.57-0.88]; 80.1% vs. 85.0%; p = 0.002]). Focusing on antibiotic administration within 1 hour of triage, these differences were enhanced after adjusting for patient-level factors (adjusted odds ratio, 0.80; 95% CI, [0.66 0.96]; p = 0.02), but attenuated after adjusting for hospital-level differences (adjusted odds ratio, 0.90; 95% CI, [0.81-1.01]; p = 0.07). Black and white patients did not differ on other sepsis quality indicators or adjusted mortality. CONCLUSIONS: Black patients appear to be less likely than white patients to receive timely antibiotic therapy for sepsis. These differences were largely explained by variation in care among hospitals, such that hospitals that disproportionately treat black patients were less likely to provide timely antibiotic therapy overall. There were no differences between races in other sepsis quality measures or adjusted mortality. PMID- 29116998 TI - Mesenchymal Stem Cells From Bone Marrow, Adipose Tissue, and Lung Tissue Differentially Mitigate Lung and Distal Organ Damage in Experimental Acute Respiratory Distress Syndrome. AB - OBJECTIVES: Mesenchymal stem cells-based therapies have shown promising effects in experimental acute respiratory distress syndrome. Different mesenchymal stem cells sources may result in diverse effects in respiratory diseases; however, there is no information regarding the best source of mesenchymal stem cells to treat pulmonary acute respiratory distress syndrome. We tested the hypothesis that mesenchymal stem cells derived from bone marrow, adipose tissue, and lung tissue would lead to different beneficial effects on lung and distal organ damage in experimental pulmonary acute respiratory distress syndrome. DESIGN: Animal study and primary cell culture. SETTING: Laboratory investigation. SUBJECTS: Seventy-five Wistar rats. INTERVENTIONS: Wistar rats received saline (control) or Escherichia coli lipopolysaccharide (acute respiratory distress syndrome) intratracheally. On day 2, acute respiratory distress syndrome animals were further randomized to receive saline or bone marrow, adipose tissue, or lung tissue mesenchymal stem cells (1 * 10 cells) IV. Lung mechanics, histology, and protein levels of inflammatory mediators and growth factors were analyzed 5 days after mesenchymal stem cells administration. RAW 264.7 cells (a macrophage cell line) were incubated with lipopolysaccharide followed by coculture or not with bone marrow, adipose tissue, and lung tissue mesenchymal stem cells (10 cells/mL medium). MEASUREMENTS AND MAIN RESULTS: Regardless of mesenchymal stem cells source, cells administration improved lung function and reduced alveolar collapse, tissue cellularity, collagen, and elastic fiber content in lung tissue, as well as decreased apoptotic cell counts in liver. Bone marrow and adipose tissue mesenchymal stem cells administration also reduced levels of tumor necrosis factor-alpha, interleukin-1beta, keratinocyte-derived chemokine, transforming growth factor-beta, and vascular endothelial growth factor, as well as apoptotic cell counts in lung and kidney, while increasing expression of keratinocyte growth factor in lung tissue. Additionally, mesenchymal stem cells differently modulated the secretion of biomarkers by macrophages depending on their source. CONCLUSIONS: Mesenchymal stem cells from different sources led to variable responses in lungs and distal organs. Bone marrow and adipose tissue mesenchymal stem cells yielded greater beneficial effects than lung tissue mesenchymal stem cells. These findings may be regarded as promising in clinical trials. PMID- 29116999 TI - Treatment Outcome of Combined Continuous Venovenous Hemofiltration and Hemoperfusion in Acute Paraquat Poisoning: A Prospective Controlled Trial. AB - OBJECTIVES: To investigate whether combined continuous venovenous hemofiltration and hemoperfusion among paraquat-poisoned patients would improve survival. DESIGN: Prospective, controlled interventional study over 4 years. SETTING: Single, tertiary, academic medical center. PATIENTS: We recruited patients admitted to Shanghai Tenth People's Hospital within 48 hours after paraquat ingestion. Exclusions were under 14 years old, ingestion of paraquat with other toxicants, pregnant, a history of chronic pulmonary disease, psychosis, hyperthyroidism, or diabetes with impaired liver or renal function. INTERVENTIONS: All patients were assigned to receive continuous venovenous hemofiltration with hemoperfusion therapy (continuous venovenous hemofiltration group) and to receive conventional therapy (conventional group). The study outcomes were death from any cause within 90 days after paraquat ingestion and the frequencies of hypoxia, acute kidney injury, or adverse events. MEASUREMENTS AND MAIN RESULTS: Of the 110 enrolled patients, 59 were assigned to continuous venovenous hemofiltration group and 51 to conventional group. The two groups had similar baseline demographics and clinical features. At 90 days after paraquat ingestion, 19 of 59 patients (32.2%) in the continuous venovenous hemofiltration group and 29 of 51 patients (56.9%) in the conventional group had died (hazard ratio, 0.43; 95% CI, 0.24-0.76; p = 0.004). In multivariable Cox proportional hazard models controlling for baseline characteristics, combined continuous venovenous hemofiltration and hemoperfusion was independently associated with reduced risk of death compared with conventional therapy (adjusted hazard ratio, 0.35; 95% CI, 0.19-0.64; p = 0.001). Patients in the continuous venovenous hemofiltration group, as compared to the conventional group, had a reduced occurrence rate of hypoxia (40.7% vs 72.5%; p = 0.001) and of acute kidney injury (59.3% vs 78.4%; p = 0.03). Hypophosphatemia and thrombocytopenia were more common in the continuous venovenous hemofiltration group (p < 0.05). CONCLUSIONS: In patients with paraquat poisoning, treatment with combined continuous venovenous hemofiltration and hemoperfusion significantly improved 90-day survival rates. PMID- 29117002 TI - Plastic and Reconstructive Surgeons and Zika Virus Infection. PMID- 29117003 TI - Response to: Zika Virus: Practical Information for the Plastic and Reconstructive Surgeon. PMID- 29117004 TI - Outcomes of Trabeculectomy and Phacotrabeculectomy With Collagen Matrix Implant (Ologen) and Low-dose Mitomycin C: 2-Year Follow-up. AB - PURPOSE: The purpose of this article is to analyze the results achieved in lowering intraocular pressure (IOP) after trabeculectomy or combined surgery (phacotrabeculectomy) with low-dose mitomycin C (MMC) using the Ologen Collagen Matrix (Ologen CM) implant. MATERIALS AND METHODS: This retrospective study included 58 eyes from 47 consecutive patients with glaucoma who underwent filtering surgery alone or combined with cataract surgery. The study group included 29 eyes that underwent trabeculectomy (14 eyes) or phacotrabeculectomy (15 eyes) with low-dose MMC (0.1 mg/mL*1 min) and subconjunctival Ologen CM implant at the end of surgery. The control group included 29 eyes, 12 that underwent trabeculectomy and 17 that underwent phacotrabeculectomy, with the same MMC dose but without the collagen matrix implant. All surgical procedures were performed by the same surgeon. The follow-up period for the patients was 2 years. RESULTS: We found statistically significant differences between the 2 groups in the age of the patients (P=0.02). We found no statistically significant differences in the baseline IOP (P=0.37) or preoperative IOP (P=0.5), nor in the visual field damage measured with mean deviation (P=0.2). The number of hypotensive medications used preoperatively was higher in the study group (P=0.0001). At 1 and 2 years after surgery, we only found statistically significant differences in favor of the study group in patients who underwent phacotrabeculectomy (P=0.0008 and 0.02, respectivily). CONCLUSION: The Ologen CM implant can be considered as an adjunct to MMC in patients undergoing filtering surgery combined with phacoemulsification to improve postoperative IOP results over the long term. PMID- 29117005 TI - Coordination of Gaze Behavior and Foot Placement During Walking in Persons With Glaucoma. AB - PURPOSE: Vision normally provides environmental information necessary to direct the foot to safe locations during walking. Peripheral visual field loss limits what a person can see, and may alter how a person visually samples the environment. Here we tested the hypothesis that the spatial-temporal coupling between gaze and stepping in a precision-based walking task is altered in persons with glaucoma, particularly under dual task situations, and results in reduced foot-placement accuracy. METHODS: Twenty persons with glaucoma and 20 normally sighted controls performed a precision walking task that involved stepping to the center of 4 targets under 3 conditions: targets only, walking, and counting backwards to simulate a conversation, and walking while performing a concurrent visual search task to simulate locating a landmark. We quantified foot-placement error and error variability with respect to the targets, as well as saccade and fixation timing with respect to foot placement. RESULTS: Compared with controls, persons with glaucoma looked earlier at future stepping targets (with respect to toe-off of the foot) in the targets only and count conditions, and transferred gaze away sooner from the current stepping target in all conditions (P<0.05). Persons with glaucoma also had increased foot-placement error, particularly in the count condition, and increased foot-placement error variability compared with normally sighted controls (P<0.05). CONCLUSIONS: Glaucoma significantly disrupts gaze-foot coordination and results in less accurate foot placement when precision is required during walking. This may increase the risk of trips and falls in this population. PMID- 29117006 TI - Phacoemulsification in Eyes With Posttrabeculectomy Choroidal Detachment. AB - Four patients developed choroidal detachment within 3 months after trabeculectomy, documented with b-scan ultrasonography (BUS) and ultrasound biomicroscopy (UBM). Intraocular pressure (IOP) of the patients ranged from 3 to 5 mm Hg. Patients were treated with cycloplegia and steroids without complete resolution of detachment. Twelve months later all patients had developed visually significant cataracts and underwent phacoemulsification and intraocular lens implantation. Procedures were uncomplicated. Visual acuity ranged 0.1 to 0 LogMAR in the first postoperative month. IOP demonstrated an increase of 6 to 8 mm Hg, which was maintained up to 1 year postoperatively. BUS and UBM in the first postoperative month demonstrated a complete resolution of choroidal detachment in all our cases. These patients with choroidal detachment underwent safe and effective phacoemulsification procedures. In addition, choroidal detachment resolved in all our patients, possibly because of intraoperative and postoperative IOP spikes, as well as long-term IOP elevation because of effect of cataract surgery on bleb function. PMID- 29117007 TI - Ocular Features of Cerebro-Costo-Mandibular Syndrome. AB - Cerebro-costo-mandibular syndrome (CCMS) is a rare hereditary disorder characterized by micrognathia, posterior rib gaps, and secondary developmental delay. Patients often require ventilation and feeding support throughout life. We describe the first reported ophthalmic findings of CCMS and propose that defects in choroidal permeability lead to chronic macular edema and refractory aqueous misdirection syndrome. Here we discuss the medical and surgical management concerns of recurrent angle closure and raised intraocular pressure in a CCMS patient. PMID- 29117008 TI - Topographic Relationship Between Optic Disc Torsion and beta-Zone Peripapillary Atrophy in the Myopic Eyes of Young Patients With Glaucomatous-appearing Visual Field Defects. AB - PURPOSE: The purpose of this study was to assess the topographic correlation between optic disc torsion (ODT) and beta-zone peripapillary atrophy (beta-PPA) in young patients with myopia and glaucomatous-appearing visual field defects (VFDs). PATIENTS AND METHODS: We consecutively recruited 110 eyes of 110 young patients with myopia and glaucomatous-appearing VFDs. Retinal nerve fiber layer (RNFL) and macular ganglion cell inner plexiform layer (mGCIPL) thicknesses were measured to compare between the groups with different ODT directions. For evaluating topographic correlation, the direction and degree of ODT and the direction and angles of beta-PPA and point of maximum radial extent (PMRE) of beta-PPA were measured on fundus photographs. Multivariate logistic regression analysis was performed to determine the clinical factors associated with inferior ODT direction. The relationships between torsional degree and clinical variables were evaluated using linear regression analyses. RESULTS: Among the 110 eyes, 19 had superior ODT and 91 had inferior ODT. Compared with myopic eyes with superior ODT, those with inferior ODT showed less severity of glaucoma as determined by RNFL or mGCIPL thickness and had a longer axial length, greater amount of optic disc tilt, larger beta-PPA angle, and higher ratio of beta-PPA area and disc area. ODT direction was significantly associated with the locations of beta-PPA and PMRE. Torsional degree was significantly correlated with the beta-PPA angle. CONCLUSIONS: ODT direction showed a significant association with the locations of beta-PPA and PMRE of beta-PPA. Torsional degree was correlated with the beta-PPA angle in the myopic eyes of young patients with glaucomatous-appearing VFDs. PMID- 29117009 TI - Risk Factors for Earlier Reexposure of Glaucoma Drainage Devices. AB - PURPOSE: The purpose of this study was to investigate factors associated with a second exposure of a glaucoma drainage device (GDD) following repair of an initial GDD exposure. MATERIALS AND METHODS: This IRB-approved retrospective cohort study examined the incidence of a second exposure of a GDD following initial repair for exposure. Logistic regression was performed to assess the relationship between demographic and clinical characteristics and a second exposure of the GDD. Kaplan-Meier survival curves were plotted and Cox regression was performed to examine factors impacting the time to a second GDD exposure. RESULTS: Ninety-four eyes of subjects that underwent initial revision for GDD exposure were reviewed. Approximately 44% (N=41/94) of subjects underwent surgical revision for a second exposure. Factors associated with reexposure in multivariate logistic regression included caucasian race (odds ratio, 2.99; P=0.02) and use of a nonscleral patch graft (odds ratio, 2.93; P=0.019). Time from revision of the initial exposure to reexposure was significantly shorter for those with a nonscleral patch graft (hazard ratio, 2.23; P=0.01) and caucasian race (hazard ratio, 2.08; P=0.04). CONCLUSIONS: Caucasian race and use of a nonscleral patch graft during revision surgery was associated with a higher risk of experiencing a sooner reexposure of the GDD following revision of an initial exposure. Future studies should examine whether particular graft materials increase the risk of GDD reexposure. PMID- 29117010 TI - Assessing the Methodological Quality of Glaucoma Clinical Practice Guidelines and Their Recommendations on Microinvasive Glaucoma Surgery: A Systematic Review. AB - INTRODUCTION: Clinical practice guidelines (CPG) are regarded by many as critical communications providing guidance within specific medical fields. Over a decade ago, the first microinvasive glaucoma surgical (MIGS) procedures were introduced. Since then, a number of these novel intraocular pressure controlling surgical options have been approved worldwide. Governing bodies and health care administration often utilize CPGs when considering funding for newer technologies. This highlights the importance of well-written, accurate, and up-to date CPGs in the rapidly evolving field of MIGS. If CPGs are unable to fill this role, their use in treatment decision-making is doing a disservice to patients, who will be denied currently available and potentially superior care. To determine the overall value of a CPG, the methodological quality with which it was developed, in addition to the current relevance and appropriateness of its recommendations, should be evaluated. The objective of the present study was to assess the methodological quality of currently available international glaucoma CPGs, as well as their coverage of MIGS as a surrogate marker of relevance and appropriateness to policy-makers and ophthalmologists alike. MATERIALS AND METHODS: To identify potentially relevant CPGs, a predefined search strategy was used to search the following databases: Medline, EMBASE, BIOSIS, and Web of Science. All CPGs related to adult glaucoma and published in English were included. CPG methodological quality was assessed by 3 individuals using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Studies were then assessed for coverage of MIGS devices and procedures. RESULTS: Search strategy and subsequent screening identified 11 CPGs for analysis. Eight were of high quality according to the AGREE II criteria. Three included basic information on MIGS, but none provided specific recommendations regarding their indications or which patient populations would benefit most. CONCLUSIONS: Many international glaucoma CPGs are of high methodological quality. However, coverage of MIGS is sparse, nonspecific and in many instances, absent. This causes CPGs to be a suboptimal source in guiding physicians and health policy-makers in areas characterized by novel and/or rapidly evolving technologies. Mechanisms to incorporate updated evidence in CPGs would have to be considered before they can be used as a source of contemporary clinical decision-making. PMID- 29117012 TI - Scheduled Intravenous Acetaminophen Improves Patient Satisfaction With Postcraniotomy Pain Management: A Prospective, Randomized, Placebo-controlled, Double-blind Study. AB - BACKGROUND: Postcraniotomy pain can be difficult to manage with opioids due to opioid-related side effects, including drowsiness, nausea/vomiting, confusion, and pupillary changes, potentially masking the signs of postoperative neurological deterioration. Intravenous (IV) acetaminophen, a nonopioid analgesic, has been reported to have opioid-sparing effects after abdominal and orthopedic surgeries. This study investigates whether IV acetaminophen has similar effects after craniotomy. MATERIALS AND METHODS: In this prospective, randomized, placebo-controlled, double-blind clinical trial, 100 adult patients scheduled to undergo supratentorial craniotomy for excision of a brain mass were randomized to receive either IV acetaminophen or placebo preincision and then every 6 hours for a total of 24 hours after surgery. Total 24-hour opioid consumption, pain scores, satisfaction with overall pain management, time to meet postanesthesia care unit discharge criteria, and incidence of opioid-related side effects were compared. RESULTS: There was no difference in the 24-hour postoperative opioid consumption in morphine equivalents between the IV acetaminophen group (median, 11 mg; n=45) and the placebo group (median, 10.1 mg; n=41). No statistically significant difference of visual analog scale pain score was observed between 2 treatment groups. Patient satisfaction with overall postoperative pain management was significantly higher in the IV acetaminophen group than the placebo group on a 1 to 10 scale (8.1+/-0.4 vs. 6.9+/-0.4; P=0.03). There was no significant difference in secondary outcomes, including the incidence of opioid-related side effects. CONCLUSIONS: IV acetaminophen, as adjunctive therapy for craniotomy procedures, did not show an opioid-sparing effect in patients for the 24 hours after craniotomy; however, it was associated with improved patient satisfaction regarding overall pain control. PMID- 29117014 TI - What's New in Pediatric Upper Extremity Sports Injuries? AB - BACKGROUND: Sports injuries are common in pediatric and adolescent patients and the evaluation and treatment of these injuries continues to evolve. The purpose of this review is to provide a comprehensive appraisal of the most recent literature, highlighting updates on sports-related upper extremity injuries in pediatric patients. METHODS: An electronic search of the PubMed, EMBASE, and Google Scholar databases was performed for keywords related to pediatric overhead athletes, osteochondritis dissecans (OCD) of the capitellum, medial epicondyle fractures, shoulder instability, and clavicle fractures. Search results were filtered by publication date to yield articles published electronically or in print on or after January 1, 2013 to May 30, 2017. Papers were selected based on expert opinion and consensus by the authors and included if deemed to have contributed important findings to the above topics. RESULTS: A total of 51 articles were deemed to have contributed significant findings to the literature: 11 overhead athlete, 9 OCD of the capitellum, 6 medial epicondyle fractures, 17 shoulder instability, and 8 clavicle fractures. The level of evidence for most studies was either Level III or IV. CONCLUSIONS: Overuse and traumatic conditions of the pediatric elbow including UCL tear, capitellar OCD, and medial epicondyle fractures represent a significant portion of injuries in the overhead athlete. Research in the prevention and treatment of primary and recurrent shoulder instability in young athletes continues to evolve. The operative treatment of clavicle fractures in adolescents has been increasing without a commensurate increase in the level of evidence supporting such treatment. Advances have been made in the treatment of sports-related upper extremity injuries in pediatric patients, however, high-level, comparative outcomes research in many areas is lacking and this review may help inform topics for future study. LEVEL OF EVIDENCE: Level IV-Literature review. PMID- 29117015 TI - Racial/Ethnic Differences in Perineal Lacerations in a Diverse Urban Healthcare System. AB - OBJECTIVES: The aim of the study was o determine whether variations exist between races/ethnicities in perineal laceration at first vaginal delivery. METHODS: We assessed first vaginal deliveries greater than 35 weeks gestation, for a four year period, in our diverse urban healthcare system. Predictor variable was race/ethnicity with outcome variable of none, first-, second-, third-, or fourth degree perineal laceration. Race and ethnicity were self-reported and combined into one variable to facilitate analysis. We also collected data on other known risk factors for laceration to adjust our analysis accordingly. RESULTS: A total of 1179 charts met criteria. When comparing none, first-, or second-degree lacerations versus third or fourth degrees (obstetric anal sphincter injuries) race was not a significant factor. We also compared lacerations among the following three groups: none or first degree versus second degree versus obstetric anal sphincter injuries. In this case, Asian and white women were associated with an increasing trend of perineal lacerations as degree of severity increased (P < 0.0001), whereas black and Latina women were associated with a decreasing trend as severity increased (P < 0.0001). After adjusting for other significant variables, race was still significant (P = 0.02). CONCLUSIONS: With an urban diverse population, our study demonstrates an association between race/ethnicity and perineal lacerations. As degree of laceration increased, Asian and white women were noted to have more lacerations, and black and Latina women were noted to have fewer. Because perineal lacerations pose a significant risk to future pelvic floor health, the associated factors identified in this study may prove useful in counseling patients on future risk or in identifying the actual risk in underrepresented populations. PMID- 29117016 TI - Analyzing the Readability of Online Urogynecologic Patient Information. AB - OBJECTIVE: We sought to describe the readability of Web sites arising from the most common Google search terms related to pelvic organ prolapse, bladder control, and bowel control. METHODS: Google was queried to capture the top 100 search results for the keywords in each disease group. For the top 20 results of each keyword, we analyzed the text for readability using 4 readability formulas: Dale-Chall, Gunning-Fog, Simple Measure of Gobbledygook (SMOG), and Flesch Kincaid Grade Level.Readability scores were compared using 1-way analysis of variance (alpha = 0.05), and the Tukey test was performed to characterize any significant differences. The chi tests were used to compare results above and below the eighth grade reading level. Spearman correlations were used to compare the reliability of the different readability formulas. RESULTS: We evaluated 2731 unique Web sites for readability, of which 2334 (85%) had a SMOG score at or above an eighth grade reading level. The mean SMOG score was 9.7 +/- 2.1. Web sites in the bladder control keyword group had statistically higher SMOG scores than those in the bowel control and pelvic organ prolapse groups, with means of 9.9 +/- 2.0, 9.4 +/- 2.1, and 9.6 +/- 2.0, respectively. The SMOG was found to be the most reliable. CONCLUSIONS: The vast majority of urogynecologic information available to patients on the Internet is written at or above an eighth grade reading level despite longstanding recommendations to the contrary. Clinicians should advise patients that the information they find online may be difficult to understand. PMID- 29117017 TI - Race/ethnicity difference in the pharmacogenetics of bilirubin-related atazanavir discontinuation. AB - BACKGROUND: Atazanavir causes plasma indirect bilirubin to increase. We evaluated associations between Gilbert's polymorphism and bilirubin-related atazanavir discontinuation stratified by race/ethnicity. PATIENTS AND METHODS: Patients had initiated atazanavir/ritonavir-containing regimens at an HIV primary care clinic in the southeastern USA, and had at least 12 months of follow-up data. Metabolizer group was defined by UGT1A1 rs887829 C->T. Genome-wide genotype data were used to adjust for genetic ancestry in combined population analyses. RESULTS: Among 321 evaluable patients, 15 (4.6%) had bilirubin-related atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 [95% confidence interval (CI): 1.7-31.5; P=0.007]. Among 152 White patients the HR was 14.4 (95% CI: 2.6-78.7; P=0.002), but among 153 Black patients the HR was 0.8 (95% CI: 0.05-12.7; P=0.87). CONCLUSION: Among patients who initiated atazanavir/ritonavir-containing regimens, UGT1A1 slow metabolizer genotype rs887829 T/T was associated with increased bilirubin-related discontinuation of atazanavir in White but not in Black patients, this despite T/T genotype being more frequent in Black patients. PMID- 29117018 TI - Neurotherapeutic Interventions for Psychiatric Illness. PMID- 29117019 TI - A Quarter Century of Progress in Psychiatric Genetics. PMID- 29117020 TI - Introduction. PMID- 29117021 TI - The Science of Addiction and Criminal Law. AB - Although there is debate in the scientific and clinical literature about how much choice addicts have concerning the use of drugs and related activities, this article demonstrates that Anglo-American criminal law is most consistent with the position that addicts have substantial choice about engaging in crimes involving their addiction. It suggests that the criminal law's approach is consistent with plausible and reasonable current scientific and clinical understanding of addiction and is therefore defensible, but it also suggests that the law is unduly harsh and far from optimum. PMID- 29117022 TI - Dementia, Decision Making, and Capacity. AB - LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:* Assess the neuropsychological literature on decision making and the medical and legal assessment of capacity in patients with dementia* Identify the limitations of integrating findings from decision-making research into capacity assessments for patients with dementia ABSTRACT: Medical and legal professionals face the challenge of assessing capacity and competency to make medical, legal, and financial decisions in dementia patients with impaired decision making. While such assessments have classically focused on the capacity for complex reasoning and executive functions, research in decision making has revealed that motivational and metacognitive processes are also important. We first briefly review the neuropsychological literature on decision making and on the medical and legal assessment of capacity. Next, we discuss the limitations of integrating findings from decision-making research into capacity assessments, including the group-to-individual inference problem, the unclear role of neuroimaging in capacity assessments, and the lack of capacity measures that integrate important facets of decision making. Finally, we present several case examples where we attempt to demonstrate the potential benefits and important limitations of using decision-making research to aid in capacity determinations. PMID- 29117023 TI - Legal Evidence of Subjective States: A Brain-Based Model of Chronic Pain Increases Accuracy and Fairness in Law. AB - Advances in structural and functional neuroimaging offer new ways to conceptualize chronic pain disorders and to prevent, diagnose, and treat chronic pain. Advances in pain science, though, do not entail changes in the concepts of chronic pain in law and culture. Authoritative legal and cultural conceptions of chronic pain continue to promote abstruse theories, characterizing these disorders as arising out of everything from a person's unmet need for love to resistance to "patriarchy." These constructs have consequences, impeding treatment and affecting whether individuals with chronic pain can obtain legal redress. Legal systems themselves are disadvantaged, as adjudicators struggle to make sense of regulations and presumptions at odds with the medical evidence that they must evaluate. Law's pain schema is so misdescriptive that, paradoxically, it can reward fraudulent claims and disadvantage legitimate ones. This review discusses advances in neuroimaging and related sciences that are contributing to an emerging neurological model of chronic pain. It then describes doctrines and cases in the United States and United Kingdom, demonstrating how law's pre neurological model of pain complicates the legal process for all participants. It concludes with suggestions for doctrinal revisions, which may have broader effects on law's long-standing dualistic conception of body versus mind. PMID- 29117025 TI - Heads Up: The Presentation of Schizoaffective Disorder in an Elite College Soccer Player with Prior Concussion. PMID- 29117024 TI - Behavioral Genetics in Criminal and Civil Courts. AB - Although emerging findings in psychiatric and behavioral genetics create hope for improved prevention, diagnosis, and treatment of disorders, the introduction of such data as evidence in criminal and civil proceedings raises a host of ethical, legal, and social issues. Should behavioral and psychiatric genetic data be admissible in judicial proceedings? If so, what are the various means for obtaining such evidence, and for what purposes should its admission be sought and permitted? How could-and should-such evidence affect judicial outcomes in criminal and civil proceedings? And what are the potential implications of using behavioral and psychiatric genetic evidence for individuals and communities, and for societal values of equality and justice? This article provides an overview of the historical and current developments in behavioral genetics. We then explore the extent to which behavioral genetic evidence has-and should-affect determinations of criminal responsibility and sentencing, as well as the possible ramifications of introducing such evidence in civil courts, with a focus on tort litigation and child custody disputes. We also consider two ways in which behavioral genetic evidence may come to court in the future-through genetic theft or the subpoena of a litigant's biospecimen data that was previously obtained for clinical or research purposes-and the concerns that these possibilities raise. Finally, we highlight the need for caution and for approaches to prevent the misuse of behavioral genetic evidence in courts. PMID- 29117028 TI - Defining Neuroscience Nursing. PMID- 29117026 TI - The American Association for the Surgery of Trauma Severity Grade is valid and generalizable in adhesive small bowel obstruction. AB - BACKGROUND: The American Association for the Surgery of Trauma (AAST) anatomic severity grading system for adhesive small bowel obstruction (ASBO) was validated at a single institution. We aimed to externally validate the AAST ASBO grading system using the Eastern Association for the Surgery of Trauma multi institutional small bowel obstruction prospective observational study. METHODS: Adults (age >= 18) with (ASBO) were included. Baseline demographics, physiologic parameters (heart rate, blood pressure, respiratory rate), laboratory tests (lactate, hemoglobin, creatinine, leukocytosis), imaging findings, operative details, length of stay, and Clavien-Dindo complications were collected. The AAST ASBO grades were assigned by two independent reviewers based on imaging findings. Kappa statistic, univariate, and multivariable analyses were performed. RESULTS: There were 635 patients with a mean (+/-SD) age of 61 +/- 17.8 years, 51% female, and mean body mass index was 27.5 +/- 8.1. The AAST ASBO grades were: grade I (n = 386, 60.5%), grade II (n = 135, 21.2%), grade III (n = 59, 9.2%), grade IV (n = 55, 8.6%). Initial management included: nonoperative (n = 385; 61%), laparotomy (n = 200, 31.3%), laparoscopy (n = 13, 2.0%), and laparoscopy converted to laparotomy (n = 37, 5.8%). An increased median [IQR] AAST ASBO grade was associated with need for conversion to an open procedure (2 [1-3] vs. 3 [2-4], p = 0.008), small bowel resection (2 [2-2] vs. 3 [2-4], p < 0.0001), postoperative temporary abdominal closure (2 [2-3] vs. 3 [3-4], p < 0.0001), and stoma creation (2 [2-3] vs. 3 [2-4], p < 0.0001). Increasing AAST grade was associated with increased anatomic severity noted on imaging findings, longer duration of stay, need for intensive care, increased rate of complication, and higher Clavien-Dindo complication grade. CONCLUSION: The AAST ASBO severity grading system has predictive validity for important clinical outcomes and allows for standardization across institutions, providers, and future research focused on optimizing preoperative diagnosis and management algorithms. LEVEL OF EVIDENCE: Prognostic, level III. PMID- 29117029 TI - Clinical Questions About the Use of Video Monitoring for Patient Safety. PMID- 29117030 TI - Piloting a Sex-Specific, Technology-Enhanced, Active Learning Intervention for Stroke Prevention in Women. AB - BACKGROUND: Recent studies reveal deficiencies in stroke awareness and knowledge of risk factors among women. Existing stroke education interventions may not address common and sex-specific risk factors in the population with the highest stroke-related rate of mortality. OBJECTIVE: This pilot study assessed the efficacy of a technology-enhanced, sex-specific educational program ("SISTERS") for women's knowledge of stroke. METHODS: This was an experimental pretest posttest design. The sample consisted of 150 women (mean age, 55 years) with at least 1 stroke risk factor. Participants were randomized to either the intervention (n = 75) or control (n = 75) group. Data were collected at baseline and at a 2-week posttest. RESULTS: There was no statistically significant difference in mean knowledge score (P = .67), mean confidence score (P = .77), or mean accuracy score (P = .75) between the intervention and control groups at posttest. Regression analysis revealed that older age was associated with lower knowledge scores (P < .001) and lower confidence scores (P < .001). After controlling for age, the SISTERS program was associated with a statistically significant difference in knowledge (P < .001) and confidence (P < .001). CONCLUSIONS: Although no change occurred overall, after controlling for age, there was a statistically significant benefit. Older women may have less comfort with technology and require consideration for cognitive differences. PMID- 29117031 TI - Risk Factors for Falls Among Hospitalized Acute Post-Ischemic Stroke Patients. AB - BACKGROUND: Falls remain an important benchmarking indicator for hospitals. Research identifies factors associated with falls among hospitalized patients in general. Similarly, the stroke literature outlines fall risk factors in the inpatient rehabilitation and community setting. PURPOSE: The aim of this study was to identify prevalence and risk factors for falls among acute, hospitalized AIS patients within an urban public healthcare system. Secondary aims were to identify activities present at the time of the fall and outcomes associated with falling. METHODS: This is a retrospective case-control study. Data were abstracted and merged from hospital stroke and fall registries and matched with medical records from 2013 to 2015 among all adult patients admitted for AIS. RESULTS: The study included 856 patients with AIS, with 2.3% experiencing a fall during the acute care hospitalization period. Falls among patients with AIS accounted for 1.4% of all hospitalized adult falls. Bivariate analysis indicate that a higher proportion of falls occurred among male patients when compared with female patients (75% male; chi = 3.964, P < .05) and among patients with a history of previous myocardial infarction or renal insufficiency (chi = 5.260, P < .05; chi = 11.116, P < .001, respectively). Multivariate analyses identify previous myocardial infarction (OR, 2.5; 95% confidence interval, 1.0-6.3; P = .04) and renal insufficiency (odds ratio, 4.2; 95% confidence interval, 1.5-12.2; P = .008) as strongest predictors of falls. The occurrence of a fall resulted in increased hospital length of stay (7.1 vs 4.0 days, P < .000) and slightly decreased functional outcome at discharge. Most falls occurred during the day shift while toileting, despite implementation and adherence to fall prevention programs. CONCLUSIONS: Fall rates among hospitalized patients with AIS are low, which may be reflective of increased vigilance among providers and widespread integration of fall prevention strategies. Consistent with the fall literature among other populations, the occurrence of a fall in the inpatient setting can substantially increase length of stay. PMID- 29117032 TI - A Preliminary Observational Study of Anovulatory Uterine Bleeding After Aneurysmal Subarachnoid Hemorrhage. AB - INTRODUCTION: It was observed that women with aneurysmal subarachnoid hemorrhage (aSAH) tended to have earlier menses than a typical 21- to 28-day cycle. The goal was to determine whether there is an association between aSAH and early onset of menses. METHODS: All cases of aSAH in women aged 18 to 55 years who were admitted to our facility's neuroscience intensive care unit from June 1, 2011, to June 30, 2012, were reviewed. The electronic healthcare record for each of these patients was examined for documentation of menses onset, computed tomography of the head, brain aneurysm characteristics, modified Fisher score and Glasgow Coma Scale on admission, presence/absence of vasospasm, medical/surgical history, and use of medications that affect the menstrual cycle. The mean onset of menses in this study population was compared with the mean of 21 to 28 days with the 1-sample t test. RESULTS: During the study period, 103 patients with subarachnoid hemorrhage were admitted. Sixty-one were women, and 15 were aged 18 to 55 years. Nine of the 15 (60%) had documentation of menses occurring during their initial week of hospitalization; 1 patient had documentation of menses on hospital day 12. There is a significant difference when the mean onset of menses in our patient population is compared with the approximate normal menstrual cycle of 21 to 28 days (P < .01). CONCLUSION: Early onset of menses or abnormal uterine bleeding after SAH may occur in women with aSAH and typically within the first 7 to 10 days after intracranial aneurysm rupture. The physiologic cause of early onset of menses after aSAH, whether primary or secondary, remains unknown. PMID- 29117033 TI - Challenges of Cerebral Perfusion Pressure Measurement. AB - Monitoring cerebral perfusion pressure (CPP) is recommended by a number of clinical practice guidelines and is a routine function performed by critical care neuroscience nurses. However, several studies highlight theoretical and practice variations in the measurement of CPP regarding the location of the arterial pressure transducer during measurement. Agreement on the technique and process for obtaining valid measurements is lacking. This article identifies the challenges associated with CPP measurement and highlights opportunities for standardizing CPP measurement to improve consistency in care and findings reported in the research literature. The challenges associated with practice variations impact multiple nursing domains, including the environment, patient treatment, and team communication; all ultimately impacting nursing workflow. The practice variation and impact on nursing workflow have significant implications for further research, electronic health record development, and refining monitoring technology. PMID- 29117035 TI - A Feasibility Randomized Controlled Crossover Trial of Home-Based Warm Footbath to Improve Sleep in the Chronic Phase of Traumatic Brain Injury. PMID- 29117034 TI - A Feasibility Randomized Controlled Crossover Trial of Home-Based Warm Footbath to Improve Sleep in the Chronic Phase of Traumatic Brain Injury. AB - INTRODUCTION: Sleep disturbance is a common complaint after traumatic brain injury (TBI). The aim of this study was to examine the effects of a home-based warm footbath intervention on sleep in patients with TBI. METHODS: This was a randomized controlled crossover study, and 23 adults with TBI were recruited and randomized to receive first a 30-minute, 41 degrees C warm footbath and then a usual care, or vice versa, with each lasting 3 days and separated by a 3-day washout. Sleep efficiency, sleep onset latency (SOL), total sleep time, and wake after sleep onset (WASO) were assessed by actigraphy. RESULTS: We found that home based warm footbath significantly had a reduced SOL (difference, -5.11 minutes) and a suppressed WASO (difference, -2.57 minutes) compared with those of usual care, but not in sleep efficiency and total sleep time. No adverse effect was reported. CONCLUSIONS: This study suggested that home-based warm footbath is practical and effective in relieving post-TBI sleep disturbances, particular in SOL and WASO. Nurses can use home-based warm footbath as an effective intervention for management of sleep disturbances after TBI. PMID- 29117037 TI - A Preliminary Observational Study of Anovulatory Uterine Bleeding After Aneurysmal Subarachnoid Hemorrhage. PMID- 29117036 TI - The Importance of Educating Patients With Stroke About Vitamin D. AB - There is a growing body of evidence linking vitamin D to more than only bone health. Researchers are discovering connections between low vitamin D levels and increased stroke risk, higher mortality, and poorer outcomes after stroke. Nurses need to be aware of ongoing research regarding vitamin D and include information about this important vitamin with patient education, especially for older patients admitted with stroke symptoms or risks. PMID- 29117038 TI - Development and Validation of Extracorporeal Membrane Oxygenation Mortality-Risk Models for Congenital Diaphragmatic Hernia. AB - The purpose of our study was to develop and validate extracorporeal membrane oxygenation (ECMO)-specific mortality risk models for congenital diaphragmatic hernia (CDH). We utilized the data from the Extracorporeal Life Support Organization Registry (2000-2015). Prediction models were developed using multivariable logistic regression. We identified 4,374 neonates with CDH with an overall mortality of 52%. Predictive discrimination (C statistic) for pre-ECMO mortality model was C = 0.65 (95% confidence interval, 0.62-0.68). Within the highest risk group, based on the pre-ECMO risk score, mortality was 87% and 75% in the training and validation data sets, respectively. The pre-ECMO risk score included pre-ECMO ventilator settings, pH, prior diaphragmatic hernia repair, critical congenital heart disease, perinatal infection, and demographics. For the on-ECMO model, mortality prediction improved substantially: C = 0.73 (95% confidence interval, 0.71-0.76) with the addition of on-ECMO-associated complications. Within the highest risk group, defined by the on-ECMO risk score, mortality was 90% and 86% in the training and validation data sets, respectively. Mortality among neonates with CDH needing ECMO can be reliably predicted with validated clinical variables identified in this study. ECMO-specific mortality prediction tools can allow risk stratification to be used in research and quality improvement efforts, as well as with caution for individual case management. PMID- 29117039 TI - Optimization of Axial Pump Characteristic Dimensions and Induced Hemolysis for Mechanical Circulatory Support Devices. AB - The application of axial pumps as ventricular assist devices (VADs) requires significant modifications to the size and characteristics of industrial pumps due to the difference in flow fields of industrial and medical pumps. Industrial pumps operate in the region of Reynolds number Re = 10, whereas axial blood pumps operate in Re < 10. The common pump design technique is to rely on the performance of previously designed pumps using the concept of fluid dynamic similarity. Such data are available for industrial pumps as specific speed specific diameter (ns-ds) graphs. The difference between the flow fields of industrial and medical pumps makes the industrial ns-ds graphs unsuitable for medical pumps and consequently several clinically available axial blood pumps operate with low efficiencies. In this article, numerical and experimental techniques were used to design 62 axial pump impellers with different design characteristics suitable for VADs and mechanical circulatory support devices (MCSDs). The impellers were manufactured and experimentally tested in various operating conditions of flow, pressure, and rotational speed. The hemocompatibility of the impellers was numerically investigated by modeling shear stress and hemolysis. The highest efficiency of each pump impeller was plotted on an ns-ds diagram. The nondimensional results presented in this article enable preliminary design of efficient and hemocompatible axial flow pumps for VADs and MCSDs. PMID- 29117040 TI - TCD and Cerebral Circulatory Arrest in VA ECMO Patients. PMID- 29117041 TI - Repeated Ramp Tests on Stable LVAD Patients Reveal Patient-Specific Hemodynamic Fingerprint. AB - Hemodynamic speed ramp tests are used in left ventricular assist device (LVAD) patients to guide speed adjustment and medical therapies. However, the reproducibility of these tests is unknown. In this prospective study, clinically stable LVAD patients underwent echocardiography and right heart catheterization ramp tests followed by a repeat test within 2 years as per institutional protocol. Sixteen patients (61.8 +/- 10.5 years old, 50% male, eight with HeartMate II and eight with HVAD) underwent repeated ramp testing. The first test was performed 187 (42-1857) days from LVAD implant and the second test was performed 278 (126-560) days from the first test. All hemodynamic variables measured at the baseline speed remained statistically unchanged between the first and second ramp test (p > 0.05 for all). Changes in hemodynamic parameters, as assessed by the slopes of their changes over the range of speeds tested, were also the same at the two timepoints (p > 0.05 for all). Stable LVAD patients had similar hemodynamic profiles over the course of years including similar responses to speed changes. This suggests that ramp tests may represent a hemodynamic fingerprint; deviations from a baseline test can aid diagnosis at times of clinical deterioration or device malfunction. PMID- 29117042 TI - Impact of Patient Distance From Ventricular Assist Device-Implanting Center on Short- and Long-Term Outcomes. AB - Highly specialized left ventricular assist device care is not readily available in many areas, potentially limiting access to therapy. This retrospective analysis examines the relationship of outcomes by patient distance from implanting left ventricular assist device center within the Mechanical Circulatory Support Research Network. Zip codes were used to calculate patient distance, with the primary outcome of interest being 3-year survival by distance from the surgical center. Secondary outcomes included 90-day survival and incident event rates for the following: gastrointestinal bleeding, infection, cerebral event, and pump thrombosis. Across the four centers, there were 1184 patients supported for a median of 486 days. Overall survival was 91 +/- 0.8% at 90 days and 61 +/- 1.9% at 3 years, with worse 3-year survival in those living >90 vs. <=90 miles from the ventricular assist device implant center (55 +/- 3.0% vs. 64 +/- 2.5, p = 0.019). Patients living >90 miles from an implant center were older, more likely to be implanted for destination therapy support, had a prior sternotomy, and had worse renal function than those living closer (p <0.05 for all). After adjusting for these factors, albumin and center of implant, the hazard ratio did not reach statistical significance (hazard ratio = 1.2; p = 0.14). Except for gastrointestinal bleeding, the event rates for the secondary outcomes were higher for those living closer to the implanting center. Protocols should be designed for more frequent follow-up and increased shared care opportunities to ensure optimal outcomes are achieved in distant patients. PMID- 29117043 TI - Quantitative Characterization of Shear-Induced Platelet Receptor Shedding: Glycoprotein Ibalpha, Glycoprotein VI, and Glycoprotein IIb/IIIa. AB - The structural integrity of platelet receptors is essential for platelets to play the normal hemostatic function. The high non-physiologic shear stress (NPSS) commonly exists in blood-contacting medical devices and has been shown to cause platelet receptor shedding. The loss of platelet receptors may impair the normal hemostatic function of platelets. The aim of this study was to quantify NPSS induced shedding of three key receptors on the platelet surface. Human blood was subjected to the matrix of well-defined shear stresses and exposure times, generated by using a custom-designed blood-shearing device. The expression of three key platelet receptors, glycoprotein (GP) Ibalpha, GPVI, and GPIIb/IIIa, in sheared blood was quantified using flow cytometry. The quantitative relationship between the loss of each of the three receptors on the platelet surface and shear condition (shear stress level and exposure time) was explored. It was found that these relationships followed well the power law functional form. The coefficients of the power law models for the shear-induced shedding of these platelet receptors were derived with coefficients of determination (R) of 0.77, 0.73, and 0.78, respectively. The power law models with these coefficients may be potentially used to predict the shear-induced platelet receptor shedding of human blood. PMID- 29117044 TI - Crestal Sinus Augmentation in the Presence of an Antral Pseudocyst. AB - PURPOSE: Antral pseudocysts classically have a well-defined, hyperdense, unilocular, dome-shaped appearance in radiographs. The best therapeutic approach for treating these cysts in the context of sinus floor augmentation remains controversial. This article presents a new technique that allows both sinus membrane elevation and cyst removal through a crestal approach in patients with pseudocysts in the maxillary sinus. MATERIALS AND METHODS: The technique combined aspiration of the cysts during sinus floor elevation with a sinus augmentation procedure using a hydraulic sinus elevation system. Aspiration of the cyst fluid was performed through the crestal osteotomy site after sinus floor elevation. RESULTS: Two patients showed a significant amount of bone formation around the implant at the sinus floor without evidence of a recurrent cyst after the procedure. CONCLUSIONS: The technique allows the minimally invasive removal of antral pseudocysts at the time of sinus grafting and simultaneous implant placement, preserving the integrity of the sinus membrane. PMID- 29117046 TI - Every Trauma Nurse Is a Leader. PMID- 29117045 TI - Bone Augmentation Using Allogeneic Bone Blocks With Recombinant Bone Morphogenetic Protein-2. AB - PURPOSE: Because of limitations of the absorbable collagen sponge (ACS), recombinant bone morphogenetic protein (rhBMP-2) requires a scaffolding device for ridge augmentation. MATERIALS AND METHODS: Twenty-one patients were treated with 37 allogeneic block grafts and rhBMP-2/ACS. Cone-beam computed tomography (CBCT) was used to measure the ridge at 2 points preoperatively, postoperatively, and after graft healing. Dental implants were placed after 6 months of healing. RESULTS: The CBCT scan measurements revealed variable graft resorption at 2.0 mm and 5.0 mm above the crest (point A: 0%-33.82%; point B: 0%-31.51%). The graft resorption at point A averaged 14.7 +/- 11.59% and at point B averaged 6.67 +/- 8.25%. There was no statistically significant difference between these 2 points. All 37 bone blocks were found well incorporated. The range of horizontal augmentation gain at the crest (point A) was 2.8 mm to 7.7 mm (average horizontal gain 4.61 +/- 0.82 mm). Sixty dental implants were inserted into the blocks in all planned sites. One implant failed during prosthetic treatment for an implant survival of 98.3%. Follow-up at 3 to 34 months found no additional failures. CONCLUSION: This case series suggests that allogeneic bone blocks may be a suitable replacement for titanium mesh as a resorbable scaffold with rhBMP-2/ACS. The growth factor may also improve allogeneic block graft incorporation. PMID- 29117047 TI - The Keys for Success: Leadership Core Competencies. AB - Providing leaders with skills resulting in positive behaviors, specifically increasing quality performance improvement projects and leadership style, ultimately may deliver an increase in professional development. Consisting of the topic leadership, this article consists of core competencies specifically targeted for learning leadership skills. The purpose of this article is to assist the leader with developing leadership skills, which promotes professional development. This article reviews leadership skills and describes in detail the elements of some core competencies that can enable the leader to develop skills, including strategic thinking, organizational skills, time management, decision making, leadership skills, conflict resolution, and strategies to enhance performance improvement. The article provides the leader with insight and strategies to develop leadership skills, which can be invaluable to any leader, health care worker, or institution. PMID- 29117048 TI - Certification Matters. AB - As professionals, we have many opportunities to prove our expertise in our field. Professional Certification is one of those opportunities. Certified nurses have reported feeling more empowered, with better collaborative relationships, as well as believing that they provide better care. Nurses also have perceived intrinsic value to obtaining certification in a specialty practice area. The certification process attempts to demonstrate that the nurse has exceeded the minimal standards and exhibits a high level of competence over the subject area. Leaders should continue to encourage their team members to obtain professional certification in their specialty areas of practice. PMID- 29117049 TI - Trauma Leadership Strategies to Prevent and Reduce Burnout in Urban Academic Trauma Centers. AB - The incidence of burnout syndrome is increasing among all health care disciplines. The core members of the trauma team in high-performing trauma centers are the greatest risk. It is the responsibility of trauma leadership to raise awareness of risk factors, implement standardized assessment tools, and develop strategies to mitigate burnout in employees. The consequences of burnout are devastating to providers' well-being as well as patient safety. Burnout can lead to increased risk of anxiety, depression, substance abuse, and suicide among team members. The development of burnout in team members can negatively impact patient safety. It can increase the risk of medical errors, health care-acquired infections, and declining patient satisfaction scores. It is essential that professional organizations raise awareness of this health care epidemic and provide resources to leaders to impact change. PMID- 29117050 TI - Leadership Externship: A Year in Review. PMID- 29117051 TI - Analysis of Patient Follow-Up at a Level I Trauma Center in Ohio. AB - Trauma patients report being unprepared for hospital discharge. The purpose of this study was to identify follow-up compliance rates at our trauma clinic and identify factors associated with trauma patients' adherence to follow-up appointment. We recruited patients 15 years and older who were discharged from the trauma service between December 2014 and August 2015. Demographic information and injury-related variables were obtained from the trauma registry for patients who attended their follow-up and those who did not attend. Follow-up appointment weather data were collected. All patients were surveyed regarding barriers to compliance. There was no difference in demographics, number of intensive care unit days, length of stay, or distance to the clinic. On days with rain or snow, patients were less likely to follow-up. Patients were more likely to follow-up on warmer days, and maximum daily air temperature was an independent predictor of follow-up compliance. Mechanism of injury and trauma activations were associated with higher follow-up compliance. Trauma patients are overall compliant with postdischarge follow-up appointments. There are no consistent factors related to trauma follow-up when compared with similar follow-up studies. PMID- 29117052 TI - Concussions: Benefits of Academic Reentry Plans. AB - Purpose of this study was to identify whether children aged 12-14 years benefit from academic reentry plans when returning to school following a mild traumatic brain injury. An integrative review was carried out with data sourced from CINAHL, Medline, Education Full Text, Health Source: Nursing/Academic Edition, and hand searching of references. Abstracts were reviewed for inclusion/exclusion criteria, resulting with six articles appraised and analyzed for this article. The review shows the need for gradual return to physical and cognitive activity postconcussion to facilitate a quicker recovery with fewer postconcussive symptoms. Although each traumatic brain injury case is individualized with symptoms and severity, a guideline of recommendations and accommodations for return to cognitive activity would be beneficial for the student, educator, family, and medical personnel involved in the children's care. Further research is recommended to develop a better understanding of long-term effects mild traumatic brain injury has on children and recommendations of how to minimalize or accommodate these changes. PMID- 29117054 TI - An Outcome Analysis of Nurse Practitioners in Acute Care Trauma Services. PMID- 29117053 TI - An Outcome Analysis of Nurse Practitioners in Acute Care Trauma Services. AB - The department of trauma at a Level 1 trauma center sought to improve outcomes by enhancing the continuity of care for patients admitted to trauma services. Departmental leadership explored opportunities to improve this aspect of patient care through expansion of existing trauma nurse practitioner (NP) services. The restructured trauma NP service model was implemented in September 2013. A retrospective study was conducted with patients who presented at the trauma center between September 2012 and August 2015. Patients with at least a 24-hr hospital length of stay (LOS) were separated into 3 comparator groups by 12-month increments: 12 months pre-, 12 months during, and 12 months postimplementation. Data revealed improvement in hospital LOS, intensive care unit LOS, time to place rehabilitation consultation, and placement of discharge orders before noon. A significant decline in the rate of complications including pneumonia and deep vein thrombosis (DVT) was also noted. Accordingly, expansion of the trauma NP model resulted in significant improvements in patient and process of care outcomes. This model for NP services may prove to be beneficial for acute care settings at other hospitals with high volume trauma services. PMID- 29117055 TI - Improving Patient Experience Through Nursing Satisfaction. AB - Patient experience is a vital component of quality health care. In our institution we sought to improve both nursing satisfaction and collaboration, in conjunction with improving patient experience, predicting the two are directly proportional. We hypothesized that a more satisfied nursing team would result in an overall improvement in patient experience. To explore this hypothesis, we implemented multiple process changes to create an advanced practitioner-directed floor (APDF) on our 28-bed trauma, medical-surgical unit. These changes included advanced practitioner (AP) 24-hr coverage, implementation of trauma patient information packets, consistent daily rounds with the nurse facilitator and/or bedside registered nurse (RN), and increased floor presence of the AP, to facilitate improved communication between the multidisciplinary team. Nursing satisfaction surveys, postdischarge patient telephone debriefings, and patient Press Ganey scores were analyzed to assess nursing satisfaction, as well as patient satisfaction pre- and postimplemented changes. Our findings demonstrated that, following APDF implementation, RNs felt more respected, stated that the trauma team was more collaborative, and, in addition, overall patient and nursing satisfaction improved. On the basis of our data collection and perspective from nursing staff and nursing management, we support the institution of an APDF to target improvements in nursing satisfaction, by focusing on collaboration and professional practice. PMID- 29117057 TI - eFAST Simulation Training for Trauma Providers. PMID- 29117056 TI - eFAST Simulation Training for Trauma Providers. AB - Current trauma recommendations include completing chest and pelvis radiographs and Focused Abdominal Sonography in Trauma (FAST) examination in the trauma bay; however, expanding literature indicates that thoracic ultrasound scans are more sensitive than chest radiography in the detection of pneumothorax. In an urban, Level II trauma center in central Ohio, the author implemented an evidence-based practice project. This project focused on a lack of provider knowledge of the expanded Focused Abdominal Sonography in Trauma (eFAST) examination. The training consisted of a lecture and a simulation training session. To monitor the success of the implementation, pre- and postimplementation testing of the provider's competence with the eFAST technique using the Objective Structured Assessment of Ultrasound Skills (OSAUS) was completed. The pre- and posttest implementation showed an increase of the OSAUS score by 16.9%. The author also reviewed charts pre- and postimplementation to demonstrate the utilization rates of eFAST. After training, the utilization rates increased by 66% (p < .05). Overall, the project implementation was a success and demonstrated the importance of frequent literature review and implementation of this literature into practice. PMID- 29117058 TI - The Effect of Time to International Normalized Ratio Reversal on Intracranial Hemorrhage Evolution in Patients With Traumatic Brain Injury. AB - The incidence of geriatric traumatic brain injury (TBI) is increasing throughout the United States, with many of these patients taking anticoagulation (AC) medication. The purpose of this investigation was to determine the effect of time to international normalized ratio (INR) reversal on intracranial hemorrhage evolution in TBI patients taking prehospital AC medication. We hypothesized that rapid reversal of INR improves outcomes of head-injured patients taking AC medication. Admissions to a Level II trauma center between February 2011 and December 2013 were reviewed. Patients presenting with an initial INR of 2.0 or more, computed tomographic scan positive for intracranial hemorrhage, and INR reversal to less than 1.5 in hospital were included. Patients with nontraumatic intracranial hemorrhage were excluded. Reversal of INR was achieved using some combination of fresh frozen plasma, prothrombin complex concentrate, and vitamin K. A binary logistic regression model assessed the adjusted impact of rapid INR reversal on intracranial hemorrhage evolution. Significance was defined as p < .05. One hundred subjects were included. Four patients with nontraumatic intracranial hemorrhage were excluded, resulting in a final study population of 96 patients. The most common intracranial hemorrhage in the study population was subarachnoid hemorrhage (71.9%), followed by subdural hemorrhage (35.4%). Reversal of INR of less than 5 hr was not associated with intracranial hemorrhage evolution; however, reversal of less than 10 hr was found to be associated with a decreased odds ratio for intracranial hemorrhage evolution (p = .043). Rapid reversal of elevated INR levels (<10 hr) may decrease intracranial hemorrhage evolution in TBI patients taking prehospital AC medication. PMID- 29117059 TI - Vascular Access in Critically Ill Pediatric Patients With Obesity. AB - OBJECTIVES: Pediatric obesity is highly prevalent and has been associated with poor outcomes for hospitalized children. Vascular access is essential in critically ill patients. The aim of this study was to evaluate whether critically ill children with obesity are more likely to undergo vascular device insertion (excluding peripheral IV catheters) and develop related complications. DESIGN: Multi-institutional retrospective observational cohort study. SETTING: Ninety four U.S. PICUs included in the Virtual Pediatric Systems, LLC database. PATIENTS: 120,272 unique patients 2 to less than 18 years old admitted between January 2009 and December 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized into normal weight, overweight, and obese (class 1, 2, or 3); underweight patients were excluded. We used mixed-effects multivariable logistic regression to test body mass index category as an independent predictor of vascular device placement and associated complications, adjusted for age, sex, severity of illness, primary diagnosis, presence of a complex chronic condition, and admission related to trauma or surgery. A total of 73,964 devices were placed in 45,409 patients (37.8% of the total cohort received a vascular device). Most device types placed differed significantly by weight status. Subjects with class 3 obesity were less likely (odds ratio, 0.74; 95% CI, 0.67-0.81) to undergo placement of any device compared with normal weight patients. Patients with all classes of obesity were more likely to undergo placement of a peripherally inserted central catheter, with the strongest association in those with class 2 obesity (odds ratio, 1.26; 95% CI, 1.14-1.40). Class 1 and class 3 obesity were independent risk factors for developing a complication, with odds ratio of 1.31 (95% CI, 1.11-1.53) and 1.45 (95% CI, 1.07 1.99), respectively. CONCLUSIONS: Severe obesity is associated with decreased overall likelihood of placement of a vascular access device but increased likelihood of peripherally inserted central catheter placement and of device related complications. PMID- 29117061 TI - Three-Dimensional Analysis of the Fundus of the Human Internal Acoustic Canal. AB - OBJECTIVES: Documentation of the nerve components in the internal acoustic canal is essential before cochlea implantation surgery. Interpretations may be challenged by wide anatomical variations of the VIIIth nerve and their ramifications. Malformations may further defy proper nerve identification. DESIGN: Using microcomputed tomography, we analyzed the fundus bone channels in an archival collection of 113 macerated human temporal bones and 325 plastic inner molds. Data were subsequently processed by volume-rendering software using a bony tissue algorithm. Three-dimensional reconstructions were made, and through orthogonal sections, the topographic anatomy was established. RESULTS: The technique provided additional information regarding the anatomy of the nerve foramina/channels of the human fundus region, including variations and destinations. Channel anastomosis were found beyond the level of the fundus. A foramen of the transverse crest was identified. CONCLUSIONS: Three-dimensional reconstructions and cropping outlined the bone canals and demonstrated the highly variable VIIIth nerve anatomy at the fundus of the human inner acoustic canal. Myriad channel interconnections suggested an intricate system of neural interactive pathways in humans. Particularly striking was the variable anatomy of the saccule nerve channels. The results may assist in the preoperative interpretation of the VIIIth nerve anatomy. PMID- 29117060 TI - Cognitive Development One Year After Infantile Critical Pertussis. AB - OBJECTIVES: Pertussis can cause life-threatening illness in infants. Data regarding neurodevelopment after pertussis remain scant. The aim of this study was to assess cognitive development of infants with critical pertussis 1 year after PICU discharge. DESIGN: Prospective cohort study. SETTING: Eight hospitals comprising the Eunice Kennedy Shriver National Institute for Child Health and Human Development Collaborative Pediatric Critical Care Research Network and 18 additional sites across the United States. PATIENTS: Eligible patients had laboratory confirmation of pertussis infection, were less than 1 year old, and were admitted to the PICU for at least 24 hours. INTERVENTIONS: The Mullen Scales of Early Learning was administered at a 1-year follow-up visit. Functional status was determined by examination and parental interview. MEASUREMENTS AND MAIN RESULTS: Of 196 eligible patients, 111 (57%) completed the Mullen Scales of Early Learning. The mean scores for visual reception, receptive language, and expressive language domains were significantly lower than the norms (p < 0.001), but not fine and gross motor domains. Forty-one patients (37%) had abnormal scores in at least one domain and 10 (9%) had an Early Learning Composite score 2 or more SDs below the population norms. Older age (p < 0.003) and Hispanic ethnicity (p < 0.008) were associated with lower mean Early Learning Composite score, but presenting symptoms and PICU course were not. CONCLUSIONS: Infants who survive critical pertussis often have neurodevelopmental deficits. These infants may benefit from routine neurodevelopmental screening. PMID- 29117062 TI - Relations Between Self-Reported Daily-Life Fatigue, Hearing Status, and Pupil Dilation During a Speech Perception in Noise Task. AB - OBJECTIVE: People with hearing impairment are likely to experience higher levels of fatigue because of effortful listening in daily communication. This hearing related fatigue might not only constrain their work performance but also result in withdrawal from major social roles. Therefore, it is important to understand the relationships between fatigue, listening effort, and hearing impairment by examining the evidence from both subjective and objective measurements. The aim of the present study was to investigate these relationships by assessing subjectively measured daily-life fatigue (self-report questionnaires) and objectively measured listening effort (pupillometry) in both normally hearing and hearing-impaired participants. DESIGN: Twenty-seven normally hearing and 19 age matched participants with hearing impairment were included in this study. Two self-report fatigue questionnaires Need For Recovery and Checklist Individual Strength were given to the participants before the test session to evaluate the subjectively measured daily fatigue. Participants were asked to perform a speech reception threshold test with single-talker masker targeting a 50% correct response criterion. The pupil diameter was recorded during the speech processing, and we used peak pupil dilation (PPD) as the main outcome measure of the pupillometry. RESULTS: No correlation was found between subjectively measured fatigue and hearing acuity, nor was a group difference found between the normally hearing and the hearing-impaired participants on the fatigue scores. A significant negative correlation was found between self-reported fatigue and PPD. A similar correlation was also found between Speech Intelligibility Index required for 50% correct and PPD. Multiple regression analysis showed that factors representing "hearing acuity" and "self-reported fatigue" had equal and independent associations with the PPD during the speech in noise test. Less fatigue and better hearing acuity were associated with a larger pupil dilation. CONCLUSIONS: To the best of our knowledge, this is the first study to investigate the relationship between a subjective measure of daily-life fatigue and an objective measure of pupil dilation, as an indicator of listening effort. These findings help to provide an empirical link between pupil responses, as observed in the laboratory, and daily-life fatigue. PMID- 29117063 TI - Effect of Dexmedetomidine on Lactate Clearance in Patients With Septic Shock: A Subanalysis of a Multicenter Randomized Controlled Trial. AB - Lactate clearance is useful to guide initial resuscitation of patients with septic shock. We conducted this study to evaluate whether dexmedetomidine increases lactate clearance in patients with septic shock. This was a randomized controlled trial that involved a post hoc subgroup analysis. Adult patients with septic shock under ventilation were randomized to receive sedation strategy with or without dexmedetomidine (60 in the dexmedetomidine and 51 in the nondexmedetomidine groups). The primary outcome was the lactate clearance at 6 h, defined as the percent decrease in lactate from randomization to 6 h after. The median Acute Physiology and Chronic Health Evaluation II score was 25 (interquartile range 19-31). The median serum lactate value at randomization was lower in the dexmedetomidine group than in the nondexmedetomidine group (4.0 mmol/L vs. 4.8 mmol/L; P = 0.053). The lactate clearance at 6 h was higher in the dexmedetomidine group, although this was not statistically significant (23.3 +/- 29.8 vs. 11.1 +/- 54.4, mean difference 12.2, 95% confidence interval (CI), -4.4 to 28.8). After adjusting for the lactate level at randomization, lactate clearance at 6 h was significantly higher in the dexmedetomidine group (adjusted mean difference 18.5, 95% CI, 2.2-34.9). There was no statistically significant difference in the 28-day mortality between the dexmedetomidine and the nondexmedetomidine groups (13 [22%] vs. 18 [35%] patients, P = 0.11). In conclusion, among mechanically ventilated patients with septic shock, sedation with dexmedetomidine resulted in increased lactate clearance compared with sedation without dexmedetomidine. PMID- 29117064 TI - Electroacupuncture Pretreatment Attenuates Acute Lung Injury Through alpha7 Nicotinic Acetylcholine Receptor-Mediated Inhibition of HMGB1 Release in Rats After Cardiopulmonary Bypass. AB - Acute lung injury is a common complication after cardiopulmonary bypass (CPB). alpha7 Nicotinic acetylcholine receptors (alpha7nAChR) and alpha7nAChR-dependent cholinergic signaling are implicated in suppressing the release of high-mobility group box 1 (HMGB1) and reducing the inflammatory response. A previous study has shown the electroacupuncture (EA) pretreatment induces tolerance against lung injury. However, the role of EA in CPB is poorly understood. This study used EA and a rat model of CPB to determine whether EA was associated with CPB-induced lung injury. Rats were treated with EA at "Zusanli (ST36)" and "Feishu (BL13)" acupoints for 5 days before being subjected to CPB. Two hours post-CPB, samples of blood, bronchoalveolar lavage fluid (BALF), and lung tissues were processed for investigations. Our results showed that the expression of alpha7nAChR in lung tissue was significantly decreased after CPB. EA pretreatment prevented the reduction in the expression of alpha7nAChR, EA pretreatment reduced lung edema, inhibited inflammatory cytokines release in serum and lung as well as protein concentrations in BALF and HMGB1 release after CPB, and the beneficial effects were attenuated by alpha-BGT. Our study demonstrates that EA pretreatment plays a protective role in CPB-induced ALI, and inhibits HMGB1 release through alpha7nAChR activation in rats. PMID- 29117065 TI - REDUCED GANGLION CELL VOLUME ON OPTICAL COHERENCE TOMOGRAPHY IN PATIENTS WITH GEOGRAPHIC ATROPHY. AB - PURPOSE: Geographic atrophy (GA) is the sequelae of macular degeneration. Automated inner retinal analysis using optical coherence tomography is flawed because segmentation software is calibrated for normal eyes. The purpose of this study is to determine whether ganglion cell layer (GCL) volume is reduced in GA using manual analysis. METHODS: Nineteen eyes with subfoveal GA and 22 controls were selected for morphometric analyses. Heidelberg scanning laser ophthalmoscope optical coherence tomography images of the optic nerve and macula were obtained, and the Viewing Module was used to manually calibrate retinal layer segmentation. Retinal layer volumes in the central 3-mm and surrounding 6-mm diameter were measured. Linear mixed models were used for statistics. RESULTS: The GCL volume in the central 3 mm of the macula is less (P = 0.003), and the retinal nerve fiber layer volume is more (P = 0.02) in patients with GA when compared with controls. Ganglion cell layer volume positively correlated with outer nuclear layer volume (P = 0.020). CONCLUSION: The patients with geographic atrophy have a small significant loss of the GCL. Ganglion cell death may precede axonal loss, and increased macular retinal nerve fiber layer volumes are not indicative of GCL volume. Residual ganglion cell stimulation by interneurons may enable vision in patients with GA. PMID- 29117066 TI - PREDICTIVE FACTORS OF SURGICAL OUTCOMES IN VITRECTOMY FOR MYOPIC TRACTION MACULOPATHY. AB - PURPOSE: To assess predictive factors and surgical outcomes for myopic traction maculopathy. METHODS: This retrospective observational case study enrolled 73 patients who underwent vitrectomy for myopic traction maculopathy. The 79 eyes obtained from our study sample were divided into 4 types: retinoschisis, lamellar macular hole (lamellar MH), foveal retinal detachment (FRD), and FRD + lamellar MH, or into 2 types according to the presence of FRD preoperatively. Dependent variables of interest were age, sex, pre- and postoperative best-corrected visual acuity (BCVA) at 6 months, and axial length. RESULTS: All the four types showed moderately strong-to-strong positive correlations with pre- and postoperative BCVA (retinochisisi: r = 0.61; lamellar MH: r = 0.62; FRD: r = 0.51; FRD + lamellar MH; r = 0.83). Preoperative BCVA was associated with postoperative BCVA (P < 0.0001), but age, axial length, and the types of preoperative foveal status were not. Eyes with FRD had significantly worse pre- and postoperative BCVA than eyes without FRD (P = 0.036 and P = 0.046, respectively). Postoperative full thickness macular holes developed in 5.1% of cases and in all types but retinoschisis. CONCLUSION: Preoperative visual acuity and the presence of FRD should be considered for surgical indication of myopic traction maculopathy. PMID- 29117068 TI - NEW SURGICAL INSTRUMENT FOR AUTOLOGOUS INTERNAL LIMITING MEMBRANE TRANSPLANTATION FOR THE TREATMENT OF REFRACTORY MACULAR HOLES. PMID- 29117069 TI - Efficiency of the Hydraulic Centripetal Macular Displacement Technique in the Treatment of Traumatic Full-Thickness Macular Holes. PMID- 29117070 TI - SCLERAL SELF-INDENTATION DURING CHANDELIER-ASSISTED PERIPHERAL VITRECTOMY UNDER AIR FOR RHEGMATOGENOUS RETINAL DETACHMENT: A Retrospective Cohort Study. AB - PURPOSE: To evaluate incidence of iatrogenic retinal breaks in eyes for whom self indentation during chandelier-assisted peripheral vitrectomy under air, for primary retinal detachment, had been performed compared with eyes for whom a nonindentation chandelier-assisted peripheral vitrectomy under air had been performed. METHODS: Retrospective cohort study. One hundred and thirty eyes with primary rhegmatogenous retinal detachment were identified. All the patients had undergone a chandelier-assisted peripheral vitrectomy under air. Scleral self indentation had been used in 68 eyes (study group; indentation), whereas nonindentation had been used in 62 eyes (comparison; nonindentation). Outcome variables included the following: trimming-induced retinal breaks, retinal redetachment rate, final logMAR best-corrected visual acuity, and intraoperative complications. RESULTS: The number of eyes with trimming-induced retinal break was statistically less in indentation group than in nonindentation group (0/68 and 3/62 eyes, 0% and 4.8%, respectively) (P = 0.04). Redetachment was observed in one eye (indentation) (1/68) and in three eyes (nonindentation) (3/62) (P = 0.267). There was no statistically significant difference in logMAR best corrected visual acuity between both groups (P = 0.229). Chandelier repositioning was needed in 22 eyes (indentation) compared with 46 eyes (nonindentation) (P < 0.001). CONCLUSION: Self-indentation, during chandelier-assisted peripheral vitrectomy under air, enables complete trimming of the vitreous base without causing iatrogenic retinal breaks, with a higher retinal reattachment rate, and with less need for chandelier repositioning than with nonindentation approach. By contrast with previous reports, we consider scleral self-indentation as an advantage for chandelier air vitrectomy. PMID- 29117067 TI - OUTCOMES OF PARS PLANA VITRECTOMY FOR MACULAR HOLE IN PATIENTS WITH UVEITIS. AB - PURPOSE: Inflammatory macular hole is a rare complication of uveitis, and data on surgical outcomes of closure are scarce. The purpose of this study is to evaluate the anatomical and visual outcomes of conventional pars plana vitrectomy for patients with uveitis. METHODS: Noncomparative, interventional, and consecutive case series from 6 vitreoretinal surgical centers from 2007 to 2015. Twenty eyes of 19 patients were included with 4 patients separated as viral retinitis. The primary outcome was change in best-corrected visual acuity at Month 3. Secondary outcomes were closure of the macular hole and postoperative optical coherence tomography characteristics. RESULTS: All eyes underwent conventional three-port pars plana vitrectomy with indocyanine green-assisted internal limiting membrane peeling. Mean Snellen best-corrected visual acuity improved from 20/200 to 20/63 (P = 0.01 for a difference in logarithm of the minimum angle of resolution) at Month 3. Twelve (75%) of patients achieved 2 or more lines of visual acuity improvement by postoperative Month 3. Surgery resulted in decreased epiretinal membrane (P = 0.002), intraretinal fluid (P < 0.001), subretinal fluid (P = 0.029), central subfield thickness (P < 0.001), and central cube volume (P = 0.041). Surgical intervention achieved anatomical success, as measured by macular hole closure, in 13 (81%) of patients at postoperative Month 3. CONCLUSION: Patients with inflammatory macular hole respond well to conventional surgery, with good anatomical and visual acuity outcomes. PMID- 29117071 TI - Deception Improves Time Trial Performance in Well-trained Cyclists without Augmented Fatigue. AB - PURPOSE: To investigate the effects of feedback, in the form of a virtual avatar paced at 100% and 102% of baseline performance, on neuromuscular fatigue after a 4-km cycling time trial (TT). We hypothesized that improved cycling performance would occur because of the participants exceeding a previously established critical threshold and experiencing greater neuromuscular fatigue. METHODS: After familiarization, 10 well-trained cyclists performed a baseline 4-km TT without feedback (BASE), followed by two 4-km TT where they raced against an avatar (set at 100% accurate [ACC] and 102% deception [DEC] of baseline power output) in a randomized and counterbalanced order. Before and after each TT, neuromuscular fatigue was assessed using maximal isometric voluntary contractions (MVC) of the quadriceps, and supramaximal electrical stimulation of the femoral nerve, during and 2 s after MVCs to assess voluntary activation and potentiated twitch force. Blood lactate was taken pretrials and posttrials and RPE was taken throughout each TT. RESULTS: Time trial performance improved after deception of feedback compared with baseline performance (-5.8 s, P = 0.019). Blood lactate increased after DEC compared with BASE (+1.37 mmol.L, P = 0.019). Despite this, there was no difference in any measures of exercise-induced neuromuscular fatigue (P > 0.05). Similarly, RPE was not different between trials. CONCLUSIONS: Well-trained male cyclists can improve cycling TT performance when competing against an avatar increased to 102% of a previously established best effort. However, this improvement is not associated with a measurable augmentation of neuromuscular fatigue. PMID- 29117072 TI - Workplace Strategies to Prevent Sitting-induced Endothelial Dysfunction. AB - : Prolonged sitting induces endothelial dysfunction in healthy young adults, which has been demonstrated to be offset by intermittent fidgeting and standing. No information exists on the effect of sitting and endothelial dysfunction in sedentary middle-age adults, and whether common workplace counterinterventions (i.e., desk standing/desk pedaling) mitigate sitting-induced endothelial dysfunction. PURPOSE: The objective of this study was to examine whether breaking up prolonged sitting with intermittent standing or underdesk pedaling prevents sitting-induced popliteal artery endothelial dysfunction in middle-age sedentary, overweight/obese office workers. HYPOTHESIS: We tested the hypothesis that sitting-induced leg endothelial dysfunction would be prevented by intermittent standing or desk pedaling. METHODS: Thirteen middle-age, sedentary overweight/obese subjects (10 men, 3 women; age, 38 +/- 3 yr; body mass index, 29.7 +/- 2 kg.m) participated in three separate testing sessions in a randomized order: 1) 4 h of uninterrupted sitting, 2) 4 h of sitting interrupted with four 10-min bouts of standing, and 3) 4 h of sitting interrupted with four 10-min bouts of light-intensity desk pedaling. Doppler ultrasound-measured popliteal artery flow-mediated dilation and associated measures (e.g., shear rate, blood velocity) were measured immediately before and immediately after each intervention (sit, stand, and desk pedaling). RESULTS: Four hours of uninterrupted sitting induced a significant impairment in popliteal artery flow mediated dilation (baseline: 3.1% +/- 0.3%, post: 1.6% +/- 0.5%; P < 0.05). Interestingly, neither intermittent standing (baseline: 3.2% +/- 0.4%, post: 1.9% +/- 0.5%; P < 0.05) nor intermittent desk pedaling (baseline: 3.2% +/- 0.4%, post: 1.9% +/- 0.4%; P < 0.05) was effective at preventing excessive sitting induced endothelial dysfunction. CONCLUSIONS: Prolonged sitting-induced leg endothelial dysfunction cannot be prevented by brief intermittent bouts of standing or desk pedaling in middle-age sedentary overweight/obese adults. PMID- 29117073 TI - Metabolic and Performance Effects of Yerba Mate on Well-trained Cyclists. AB - INTRODUCTION: Yerba Mate (YM) is a South American plant, rich in polyphenols, saponins, and xanthines, of growing scientific interest because of its metabolic effects. YM has been shown to increase fat utilization during exercise in untrained humans, but its effects on well-trained individuals during exercise are unknown. METHODS: We characterized metabolic and physical performance effects of YM in 11 well-trained male cyclists. In a double-blind crossover design, participants ingested 5 g of YM or placebo (PL; maltodextrin) daily for 5 d and 1 h before experimental trials. RESULTS: Ergometer-based tests included a submaximal step test (SST) at 30%-80% of VO2max (6 * 5-min stages), followed by a cycloergometer-based time trial (TT) test to complete mechanical work (~30 min; n = 9). Before and during tests, blood and respiratory gas samples were collected. YM increased resting plasma adrenaline concentration (P = 0.002), and fat utilization by 23% at 30%-50% VO2max versus PL (Glass effect sizes (ES) +/- 95% confidence interval (CI), 0.8 +/- 0.55) correlating strongly with post-SST plasma (glycerol; r = 0.758). Treatment effects on rates of perceived exertion, heart rate, and gross efficiency were unclear during SST. Respiratory exchange ratio during TT indicated carbohydrate dependence and did not differ between treatments (PL, 0.95 +/- 0.03 (SD); YM, 0.95 +/- 0.02). TT performance showed a small (ES = 0.38 +/- 0.33) but significant (P = 0.0278) improvement with YM (PL, 30.1 +/- 1.8 min (SD); YM, 29.4 +/- 1.4 min; 2.2% +/- 2% (95% CI)), with an average increase of 7-W power output (ES = 0.2 +/- 0.19; P = 0.0418; 2.3% +/- 2% (95% CI)) and 2.8% VO2 (P = 0.019). Pacing displayed lower power output after 30% of total TT workload in PL vs YM. CONCLUSIONS: YM increased fat utilization during submaximal exercise and improved TT performance, but performance-enhancement effect was unrelated to measures of substrate metabolism during maximal exercise. PMID- 29117074 TI - Context for Practice: Hyperbaric Oxygen Therapy, Pouching Techniques for Neonates, Wait Time for Patients With Soiled Pads, and Pressure Injury Prevention With Use of Indwelling Rectal Devices. PMID- 29117075 TI - Using Our Voice in Public Policy and Advocacy: A Road Less Followed, But the View From Here Is Outstanding! PMID- 29117076 TI - Tissue Oxygenation and Negative-Pressure Wound Therapy When Applied to the Feet of Persons With Diabetes Mellitus: An Observational Study. AB - PURPOSE: Our group has reported that negative-pressure wound therapy (NPWT) decreases tissue oxygenation by 84% in the foot of diabetic patients because the pad of the connecting drainage tube and foam sponge of the NPWT system compress the wound bed. The purpose of this study was to determine whether an NPWT modified dressing application reduces tissue oxygenation in the feet of persons with diabetes mellitus. DESIGN: A prospective, clinical, observational study. SUBJECTS AND SETTING: We enrolled 30 patients with diabetic mellitus; their mean age was 63.9 +/- 11.2 years (mean +/- standard deviation). All were cared for at the diabetic wound center at an academic tertiary medical center in South Korea between 2014 and January 2015. METHODS: Transcutaneous partial oxygen pressures (TcpO2) were measured to determine tissue oxygenation levels beneath modified NPWT dressings. A TcpO2 sensor was fixed at the tarsometatarsal area of the contralateral unwounded foot. A negative pressure of -125 mm Hg was applied until TcpO2 reached a plateau state; values were measured before, during, and after the modified NPWT. The Wilcoxon' and Mann-Whitney U tests were used to compare differences between these measurements. RESULTS: TcpO2 levels decreased by 26% during the modified NPWT. Mean TcpO2 values before, during, and after turning off the therapy were 54.3 +/- 15.3 mm Hg, 41.6 +/- 16.3 mm Hg, and 53.3 +/- 15.6 mm Hg (P < .05), respectively. CONCLUSION: Applying NPWT without the pad of the connecting drainage tube significantly reduces the amount of tissue oxygenation loss beneath foam dressings on the skin of the foot dorsum in diabetic patients. PMID- 29117077 TI - Vascular Graft Infection: Incidence and Potential Risk Factors. AB - PURPOSE: The purpose of this study was to identify factors that increase the risk of vascular graft infections (VGI) in patients following abdominal or lower extremity revascularization surgery. DESIGN: Retrospective, descriptive study. METHODS: We reviewed the electronic health records of 223 patients who had undergone abdominal or lower extremity revascularization procedures from July 2012 to November 2014, looking for factors associated with VGI. We reviewed 28 preoperative, intraoperative, and post-operative factors. Descriptive statistics (mean, range, and standard deviation) were used to describe the sample; chi was used to determine correlations between the risk factors and subsequent VGIs. The level of significance was determined at P = .05, with a confidence level of 95%. RESULTS: We identified 33 cases of VGIs for the 223 charts reviewed, yielding an incidence rate of 15%. Seventeen of the 33 patients with VGI (51.5%) were male. The average age of patients who experienced VGI was 60.9 years (standard deviation, 12.2 years, range, 29-81 years). Preoperative factors that were shown to show statistical significance for the development of VGI were sequential procedures (P = .003), diabetes mellitus (P = .002), hemoglobin A1c more than 7.0 (P = .0002), blood glucose more than 180 mg/dL (P = .0006), and lack of mobility (0.0097). Intraoperative factors associated with VGI were hemostatic agents applied to the surgical field intraoperatively (P = .003) and perioperative hypoxemia (P = .027). Postoperative factors associated with VGI were discharge from the hospital to skilled nursing facility or acute rehabilitation facility (P = .005) and unscheduled clinic visits (P = .008). CONCLUSION: We measured a 15% incidence of VGI and identified multiple pre-, intra-, and postoperative associated factors. Vigilance is required to prevent VGI and knowledge of specific risk factors is important. PMID- 29117078 TI - Prevalence, Antimicrobial Susceptibility, and Clonal Diversity of Pseudomonas aeruginosa in Chronic Wounds. AB - PURPOSE: Our purposes in this study were to (1) identify Pseudomonas aeruginosa strains collected from swabs of chronic wounds, (2) evaluate the susceptibility of P. aeruginosa strains to various antimicrobials, (3) detect the presence of virulence factors exoenzyme S (exoS) and exoenzyme U (exoU) in P. aeruginosa strains, and (4) evaluate wound colonization by P. aeruginosa via pulsed-field gel electrophoresis (PFGE). DESIGN: Descriptive research using a quantitative approach. SAMPLE AND SETTING: Swabs from 43 adults with chronic wounds treated in an outpatient setting in Niteroi City, Brazil, were included using convenience sampling. METHODS: Swabs were collected at 2 points during treatment, 30 to 45 days apart. P. aeruginosa isolates were identified using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Antimicrobial susceptibility testing was performed using the disk diffusion method. The presence of exoS and exoU genes was evaluated using polymerase chain reaction. Genotyping diversity was determined through PFGE. RESULTS: Forty-eight P. aeruginosa isolates were detected in chronic wounds, and 3 were multidrug resistant (6%). Resistance to aztreonam and ciprofloxacin was observed in 48% and 27% of isolates, respectively. The presence of the exoS gene was verified in 54% of isolates, and 27% were positive for the exoU gene. In most wounds, P. aeruginosa strains had the same genetic characteristics at the 2 time points analyzed, indicating that the wound beds remained colonized. CONCLUSIONS: P. aeruginosa was present in 75% of tested chronic wound samples, and the same clones persisted for more than 1 month. In addition, most bacteria contained virulence genes that were associated with high potential to establish infection. The use of silver in chronic wounds may be associated with multidrug resistance in P. aeruginosa; therefore, it is important to avoid colonization by these bacteria. PMID- 29117079 TI - Integration of Data to Establish a Standard Operating Procedure for the Diabetic Patient Undergoing Hyperbaric Oxygen Therapy. AB - PURPOSE: The purpose of this study was to describe occurrences of hypoglycemia in the diabetic population undergoing hyperbaric oxygen therapy (HBOT). We also examined 2 secondary aims: link industry standards for management of hypoglycemia in the general diabetic population to the HBOT environment; and integrate HBOT data into an electronic health record system, as patients transition across inpatient and outpatient services and settings. DESIGN: A retrospective, descriptive study. SUBJECTS AND SETTING: The study took place within a hyperbaric medicine department located in a 1393-bed acute care medical center, part of a large, multihospital system. The study sample comprised 100 diabetic patients who underwent HBOT between January 1 and May 31, 2015. Sixty-seven percent were male; the mean age of participants was 62 years (range 32-92 years). Admission status was nearly equal with 53% hospital inpatients and 47% ambulatory outpatients. Hospital protocol required all patients to have a minimal prehyperbaric blood glucose level (BGL) of 100 mg/dL. RESULTS: The incidence of hypoglycemia (defined as a BGL <100 mg/dL, 5.5 mmol/L) was 122 of 1175 treatments (10.4%). Additional analysis was based on records for 66 of the 122 incidences with evaluable data from electronic medical records. The mean BGL pre-HBOT was 177.86 mg/dL, 6.54 mmol/L (range 53-439 mg/dL, 2.94-24.36 mmol/L); the mean BGL after HBOT was 165.09 mg/dL, 9.16 mmol/L (range 56-414 mg/dL, 3.11-22.98 mmol/L). Analysis of these 66 occurrences revealed that 52 of 66 (79%) were managed with high carbohydrate juices and snacks; 8 of 66 (12%) received oral glucagon; and 6 of 66 (9%) received glucagon and high-carbohydrate snack. We found that standard treatment protocols for hypoglycemia ranged from 70 to 100 mg/dL, 3.89 to 5.55 mmol/L, for the general population and 80 to 120 mg/dL, 4.44 to 6.66 mmol/L, for the general diabetic population. We also found that HBOT diabetic data were not fully integrated into the electronic health records across all settings. CONCLUSIONS: Hypoglycemia is prevalent during HBOT. We recommend a minimum pre treatment serum glucose of 120 mg/dL, 6.7 mmol/L. PMID- 29117080 TI - Evaluation of Web-Based Ostomy Patient Support Resources. AB - PURPOSE: To evaluate currently available, no-cost, Web-based patient support resources designed for those who have recently undergone ostomy surgery. DESIGN: Descriptive, correlational study using telephone survey. SAMPLE AND SETTING: The sample comprised 202 adults who had ostomy surgery within the previous 24 months in 1 of 5 hospitals within a large healthcare organization in the Midwestern United States. Two of the hospitals were academic teaching hospitals, and 3 were community hospitals. METHODS: The study was divided into 2 phases: (1) gap analysis of 4 Web sites (labeled A-D) based on specific criteria; and (2) telephone survey of individuals with an ostomy. In phase 1, a comprehensive checklist based on best practice standards was developed to conduct the gap analysis. In phase 2, data were collected from 202 participants by trained interviewers via 1-time structured telephone interviews that required approximately 30 minutes to complete. Descriptive analyses were performed, along with correlational analysis of relationships among Web site usage, acceptability and satisfaction, demographic characteristics, and medical history. RESULTS: Gap analysis revealed that Web site D, managed by a patient advocacy group, received the highest total content score of 155/176 (88%) and the highest usability score of 31.7/35 (91%). Two hundred two participants completed the telephone interview, with 96 (48%) reporting that they used the Internet as a source of information. Sixty participants (30%) reported that friends or family member had searched the Internet for ostomy information on their behalf, and 148 (75%) indicated they were confident they could get information about ostomies on the Internet. Of the 90 participants (45%) who reported using the Internet to locate ostomy information, 73 (82%) found the information on the Web easy to understand, 28 (31%) reported being frustrated during their search for information, 24 (27%) indicated it took a lot of effort to get the information they needed, and 39 (43%) were concerned about the quality of the information. CONCLUSION: Web-based patient support resources may be a cost-effective approach to providing essential ostomy information, self-management training, and support. Additional research is needed to examine the efficacy of Web-based patient support interventions to improve ostomy self-management knowledge, skills, and outcomes for patients. PMID- 29117081 TI - The Lived Experiences of Persons Hospitalized for Construction of an Urgent Fecal Ostomy. AB - PURPOSE: The purpose of this study was to describe the lived experiences of hospital stays for patients undergoing urgent ostomy surgery. DESIGN: Qualitative, descriptive, phenomenological study. SUBJECTS AND SETTING: Six persons undergoing acute hospital admission and urgent ileostomy or colostomy surgery (either permanent or temporary) participated in the study. Participants were of Danish ethnicity and between the ages of 48 and 75 years. The research setting was the surgical department at a university hospital in the Capital Region of Denmark. METHODS: Data collection and analyses were guided by a Reflective Lifeworld Research approach; this approach is based on phenomenological philosophy. Data were collected during in-depth interviews using a semistructured interview guide. Their average length was 50 minutes (range, 30 65 minutes). Interviews were digitally recorded and transcribed. Transcriptions were analyzed in 4 phases according to the principles of Reflective Lifeworld Research. RESULTS: The phenomenon we labeled "lived experiences of acute hospitalization with construction of an urgent unplanned fecal ostomy" comprised 4 constituents: (1) undergoing unexpected bodily changes, (2) partnership with professional caregivers, (3) experience of vulnerability, and (4) a lack of continuity. These constituents can be described as a number of challenges due to both hospitalization and ostomy creation. CONCLUSION: We found that individuals experience a number of challenges due to acute hospitalization and urgent construction of a fecal ostomy. These challenges are due to the unexpected bodily changes and interpersonal and organizational conditions. Nurses should be aware of not only the physical implications of urgent creation of a fecal ostomy but also the individual and psychological implications of this event. PMID- 29117083 TI - Effect of a 1-Piece Drainable Pouch on Incontinence-Associated Dermatitis in Intensive Care Unit Patients With Fecal Incontinence: A Comparison Cohort Study. AB - PURPOSE: The purpose of this study was to compare the effect of a 1-piece drainable pouch to standard care on occurrences of incontinence-associated dermatitis (IAD) in intensive care unit (ICU) patients with fecal incontinence (FI). DESIGN: Nonrandomized comparison cohort (quasi-experimental) study. METHODS: Sixty-two bedridden patients with FI and indwelling urinary catheters in the ICU of the Shunde Hospital, Southern Medical University, Foshan, China, participated in the study. Thirty-one were assigned to the control group (standard IAD preventive care alone) and 31 to the intervention group (standard IAD preventive care plus application of a 1-piece drainable pouch). Stool consistency was evaluated via the Bristol Stool Scale. Trained nurses assessed the status of IAD using the Incontinence-Associated Dermatitis Intervention Tool. The incidence of IAD and the perianal skin status were investigated over a 7-day period. RESULTS: Participants in the experimental group had fewer IAD occurrences than participants in the control group (12.9% vs 41.9%, P < .05). Occurrences of IAD in the perianal were also significantly lower in the experimental group than in the control group (chi = 7.884, P < .05). CONCLUSION: Applying a 1-piece drainable pouch may reduce occurrences of IAD in ICU patients with FI compared with the patients receiving standard IAD preventive care. PMID- 29117084 TI - Self-management Experiences of Older Korean Women With Urinary Incontinence: A Descriptive Qualitative Study Using Focus Groups. AB - PURPOSE: The purpose of this study was to explore the self-management experiences of Korean women with urinary incontinence (UI). DESIGN: Descriptive, qualitative study using focus groups. SUBJECTS AND SETTING: Twenty-two community-dwelling women, 65 years and older, participated in 3 focus-group interviews. Participants were recruited from 2 elderly halls and 1 senior welfare center in South Korea. METHODS: Three focus group interviews comprising 6 to 8 individuals were conducted in a quiet venue at the elderly hall or senior welfare center. Two investigators performed the interviews; one acted as moderator and one as notetaker; interviews began with scripted open-ended questions. All interviews were electronically recorded and transcribed verbatim. Using an inductive thematic approach, data were first analyzed by the first and second authors; and all 4 authors contributed to coding and agreed on final themes. RESULTS: Korean women perceived UI as a loss of dignity, an odor problem, an uncontrollable disease, and a life impairment. Thematic analysis revealed 4 themes regarding the self-management experience of UI: preserving self-respect in the sociocultural environment, deodorizing the smell, keeping the secret of uncontrollability, and adjusting to an impaired life. CONCLUSIONS: Women in this study used various daily-living strategies to manage UI, but they mainly implemented strategies to keep UI a secret, including restrictions in activities of daily living. Educational approaches are needed to inform women with UI about more effective management skills. PMID- 29117085 TI - Do Intra-anal Bowel Management Devices Reduce Incontinence-Associated Dermatitis and/or Pressure Injuries? AB - PURPOSE: The purpose of this article was to examine the evidence and provide recommendations related to the effectiveness of intra-anal bowel management systems including intra-anal bowel catheters and rectal trumpets in reducing incontinence-associated dermatitis and pressure injuries. QUESTION: Does the use of an intra-anal bowel management system (intra-anal bowel catheter or rectal trumpet) reduce incontinence-associated skin damage and/or hospital-acquired pressure injuries in the acute care adult patient population? SEARCH STRATEGY: A search of the literature was performed by a trained university librarian, which resulted in 133 articles that examined intra-anal bowel management systems (intra anal bowel catheter and rectal trumpet), incontinence-associated dermatitis, and pressure injuries. A systematic approach was used to review titles, abstracts, and text yielding 6 studies that met inclusion criteria. Strength of the evidence was rated using rating methodology from Essential Evidence Plus: Levels of evidence and Oxford Center for Evidence-based Medicine, adapted by Gray and colleagues. FINDINGS: Five of the 6 studies reported positive results concerning the effectiveness of intra-anal bowel management systems to reduce incontinence associated dermatitis and/or pressure injuries. One randomized control trial found no improvement in incontinence-associated dermatitis in the intra-anal bowel management system (intra-anal bowel catheter or rectal trumpet) groups or pressure injuries as compared to usual care. The strength of the evidence for the identified studies was moderate (2 level A, 3 level B, and 1 level C). An important finding in 2 of the studies was the safety of the intra-anal bowel management systems-both intra-anal bowel catheter and rectal trumpet. CONCLUSION/RECOMMENDATION: Evidence indicates intra-anal bowel management system (intra-anal bowel catheters and rectal trumpet) provides a viable option for fecal incontinence management and these devices reduce incontinence-associated dermatitis and/or pressure injuries. PMID- 29117086 TI - Novel Pouching Techniques for the Neonate With Fecal Ostomies. AB - BACKGROUND: Neonatal ostomy management is challenging even under the best circumstances. When complex circumstances are encountered, creative pouching techniques must be employed. CASES: This article describes management of 5 neonates with problematic ostomies. CONCLUSION: Maintaining a neonatal pouch seal at times requires using modified adult pouching products; however, caution should always be used due to the fragility of this patient population. PMID- 29117088 TI - Preparation for Continence Recertification: Professional Growth Program or Examination. PMID- 29117089 TI - Simulation in Interprofessional Clinical Education: Exploring Validated Nontechnical Skills Measurement Tools. AB - STATEMENT: The research literature regarding interprofessional simulation-based medical education has grown substantially and continues to explore new aspects of this educational modality. The aim of this study was to explore the validation evidence of tools used to assess teamwork and nontechnical skills in interprofessional simulation-based clinical education. This systematic review included original studies that assessed participants' teamwork and nontechnical skills, using a measurement tool, in an interprofessional simulated setting. We assessed the validity of each assessment tool using Kane's framework. Medical Education Research Study Quality Instrument scores for the studies ranged from 8.5 to 17.0. Across the 22 different studies, there were 20 different assessment strategies, in which Team Emergency Assessment Measure, Anesthetist's Nontechnical Skills, and Nontechnical Skills for Surgeons were used more than once. Most assessment tools have been validated for scoring and generalization inference. Fewer tools have been validated for extrapolation inference, such as expert-novice analysis or factor analysis. PMID- 29117090 TI - Building a Community of Practice for Researchers: The International Network for Simulation-Based Pediatric Innovation, Research and Education. AB - STATEMENT: The scope and breadth of simulation-based research is growing rapidly; however, few mechanisms exist for conducting multicenter, collaborative research. Failure to foster collaborative research efforts is a critical gap that lies in the path of advancing healthcare simulation. The 2017 Research Summit hosted by the Society for Simulation in Healthcare highlighted how simulation-based research networks can produce studies that positively impact the delivery of healthcare. In 2011, the International Network for Simulation-based Pediatric Innovation, Research and Education (INSPIRE) was formed to facilitate multicenter, collaborative simulation-based research with the aim of developing a community of practice for simulation researchers. Since its formation, the network has successfully completed and published numerous collaborative research projects. In this article, we describe INSPIRE's history, structure, and internal processes with the goal of highlighting the community of practice model for other groups seeking to form a simulation-based research network. PMID- 29117091 TI - The Application of Observational Practice and Educational Networking in Simulation-Based and Distributed Medical Education Contexts. AB - INTRODUCTION: Research has revealed that individuals can improve technical skill performance by viewing demonstrations modeled by either expert or novice performers. These findings support the development of video-based observational practice communities that augment simulation-based skill education and connect geographically distributed learners. This study explores the experimental replicability of the observational learning effect when demonstrations are sampled from a community of distributed learners and serves as a context for understanding learner experiences within this type of training protocol. METHODS: Participants from 3 distributed medical campuses engaged in a simulation-based learning study of the elliptical excision in which they completed a video recorded performance before being assigned to 1 of 3 groups for a 2-week observational practice intervention. One group observed expert demonstrations, another observed novice demonstrations, and the third observed a combination of both. Participants returned for posttesting immediately and 1 month after the intervention. Participants also engaged in interviews regarding their perceptions of the usability and relevance of video-based observational practice to clinical education. RESULTS: Checklist (P < 0.0001) and global rating (P < 0.0001) measures indicate that participants, regardless of group assignment, improved after the intervention and after a 1-month retention period. Analyses revealed no significant differences between groups. Qualitative analyses indicate that participants perceived the observational practice platform to be usable, relevant, and potentially improved with enhanced feedback delivery. CONCLUSIONS: Video-based observational practice involving expert and/or novice demonstrations enhances simulation-based skill learning in a group of geographically distributed trainees. These findings support the use of Internet-mediated observational learning communities in distributed and simulation-based medical education contexts. PMID- 29117092 TI - The Development and Validation of a Concise Instrument for Formative Assessment of Team Leader Performance During Simulated Pediatric Resuscitations. AB - AIM: The aim of this study was to assess the validity of a formative feedback instrument for leaders of simulated resuscitations. METHODS: This is a prospective validation study with a fully crossed (person * scenario * rater) study design. The Concise Assessment of Leader Management (CALM) instrument was designed by pediatric emergency medicine and graduate medical education experts to be used off the shelf to evaluate and provide formative feedback to resuscitation leaders. Four experts reviewed 16 videos of in situ simulated pediatric resuscitations and scored resuscitation leader performance using the CALM instrument. The videos consisted of 4 pediatric emergency department resuscitation teams each performing in 4 pediatric resuscitation scenarios (cardiac arrest, respiratory arrest, seizure, and sepsis). We report on content and internal structure (reliability) validity of the CALM instrument. RESULTS: Content validity was supported by the instrument development process that involved professional experience, expert consensus, focused literature review, and pilot testing. Internal structure validity (reliability) was supported by the generalizability analysis. The main component that contributed to score variability was the person (33%), meaning that individual leaders performed differently. The rater component had almost zero (0%) contribution to variance, which implies that raters were in agreement and argues for high interrater reliability. CONCLUSIONS: These results provide initial evidence to support the validity of the CALM instrument as a reliable assessment instrument that can facilitate formative feedback to leaders of pediatric simulated resuscitations. PMID- 29117093 TI - Death of a Simulated Pediatric Patient: Toward a More Robust Theoretical Framework. AB - INTRODUCTION: A theoretical framework was recently proposed that encapsulates learner responses to simulated death due to action or inaction in the pediatric context. This framework, however, was developed at an institution that allows simulated death and thus does not address the experience of those centers at which this technique is not used. To address this, we performed a parallel qualitative study with the intent of augmenting the initial framework. METHODS: We conducted focus groups, using a constructivist grounded theory approach, using physicians and nurses who have experienced a simulated cardiac arrest. The participants were recruited via e-mail. Transcripts were analyzed by coders blinded to the original framework to generate a list of provisional themes that were iteratively refined. These themes were then compared with the themes from the original article and used to derive a consensus model that incorporated the most relevant features of each. RESULTS: Focus group data yielded 7 themes. Six were similar to those developed in the original framework. One important exception was noted; however, those learners not exposed to patient death due to action or inaction often felt that the mannequin's survival was artificial. This additional theme was incorporated into a revised framework. DISCUSSION: The original framework addresses most aspects of learner reactions to simulated death. Our work suggests that adding the theme pertaining to the lack of realism that can be perceived when the mannequin is unexpectedly saved results in a more robust theoretical framework transferable to centers that do not allow mannequin death. PMID- 29117094 TI - A Novel Task Trainer for Penile Corpus Cavernosa Aspiration. AB - INTRODUCTION: Priapism is a rare yet time sensitive emergency with potentially significant morbidity. A novel task trainer was developed for corpus cavernosa aspiration and phenylephrine injection. The primary aim of this study was to assess model realism and usefulness for emergency medicine resident procedural education. Secondarily, an assessment of comfort level with the procedure before and after intervention was performed. METHODS: A priapism model containing corpus cavernosa and spongiosum analogs was constructed. The models and evaluation forms were pilot tested by faculty and then tested for realism and usefulness in a sample of 49 residents after a brief training session. Secondary end points included resident comfort with cavernosa aspiration before and after the session of the model on a visual analog scale. RESULTS: Eight faculty pilot tested the procedure model and evaluated it based on a 5-point scale. They unanimously felt that the model was realistic [mean = 4.4, 95% confidence interval (CI) = 3.8-5.0] and useful for resident education (mean = 4.8, 95% CI = 4.4-5.0). The model was then evaluated for realism and usefulness in 49 residents. The model was felt to be realistic (mean = 4.3, 95% CI = 4.0-4.5) and useful for resident education (mean = 4.6, 95% CI = 4.4-4.8). Residents also noted an improvement in comfort performing the procedure before and after simulation session with the mean visual analog scale rating increasing from 34.3 to 83.8 (P < 0.001). CONCLUSIONS: An easily constructed priapism task trainer was felt to be realistic and useful for resident education. Secondarily, use of the model in a simulation session can improve resident comfort in an important and infrequent procedure. PMID- 29117095 TI - Rapport Management: Opening the Door for Effective Debriefing. PMID- 29117096 TI - A Generalized Polynomial Chaos-Based Approach to Analyze the Impacts of Process Deviations on MEMS Beams. AB - A microstructure beam is one of the fundamental elements in MEMS devices like cantilever sensors, RF/optical switches, varactors, resonators, etc. It is still difficult to precisely predict the performance of MEMS beams with the current available simulators due to the inevitable process deviations. Feasible numerical methods are required and can be used to improve the yield and profits of the MEMS devices. In this work, process deviations are considered to be stochastic variables, and a newly-developed numerical method, i.e., generalized polynomial chaos (GPC), is applied for the simulation of the MEMS beam. The doubly-clamped polybeam has been utilized to verify the accuracy of GPC, compared with our Monte Carlo (MC) approaches. Performance predictions have been made on the residual stress by achieving its distributions in GaAs Monolithic Microwave Integrated Circuit (MMIC)-based MEMS beams. The results show that errors are within 1% for the results of GPC approximations compared with the MC simulations. Appropriate choices of the 4-order GPC expansions with orthogonal terms have also succeeded in reducing the MC simulation labor. The mean value of the residual stress, concluded from experimental tests, shares an error about 1.1% with that of the 4 order GPC method. It takes a probability around 54.3% for the 4-order GPC approximation to attain the mean test value of the residual stress. The corresponding yield occupies over 90 percent around the mean within the twofold standard deviations. PMID- 29117097 TI - Preparation and Bioactivity Assessment of Chitosan-1-Acetic Acid-5-Flurouracil Conjugates as Cancer Prodrugs. AB - 5-fluorouracil (5-FU) is a specific anti-cancer agent that is generally used to treat gastrointestinal, colorectal, and breast cancer. In this work, chitosan (CS) was extracted from local fish scales using an established method. 5-FU was then converted to 1-acetic acid-5-fluorouracil (FUAC) and reacted with this CS to prepare chitosan-1-acetic acid-5-fluorouracil (CS-FUAC) conjugates as a colon specific prodrug. All compounds were characterized by Proton nuclear magnetic resonance (1H-NMR), Fourier-transform infrared (FTIR), and UV-visible spectroscopy. The synthesized compound was subjected to a chemical stability study in phosphate buffer (0.2 M, pH 7.4) and in KCl/HCl buffer (0.2 M, pH 1.2) at different time intervals (0-240 min) and incubation at 37 degrees C. This revealed a significantly greater stability and a longer half-life for the CS-FUAC than for FUAC. Hemolytic activity results indicated a much lower toxicity for CS FUAC than for 5-FU and supported consideration of CS-FUAC for further biological screening and application trials. The percentage of FUAC in the conjugates was determined by subjecting the prodrug to treatment in basic media to hydrolyze the amide bond, followed by absorbency measurements at 273 nm. The cytotoxicity studies of the conjugates were also evaluated on human colorectal cancer cell line (HT-29), which showed that the conjugates are more cytotoxic than the free drug. Therefore, CS-FUAC conjugates can be considered to represent potential colon-specific drug delivery agents, with minimal undesirable side effects, for colon cancer therapy. PMID- 29117098 TI - Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis. AB - Spiroheterocycles are regarded as a privileged framework because of their wide distribution in various natural products and synthetic molecules and promising bioactivities. This review focuses on the recent advances in the synthesis of spiroheterocycles by using the strategy of N-heterocyclic carbene (NHC) organocatalysis, and is organized based on the stereoselectivity and the reactive intermediates. According to the stereochemistry, this review was divided into two main parts, covering racemic and enantioselective versions. In each part, we firstly describe the synthetic transformations using nucleophilic Breslow intermediates, and then discuss the reactions that employ electrophilic acylazolium or radical cation intermediates. With those distinct catalytic activation modes of NHC organocatlysis, we expect this synthetic protocol will possibly produce new molecules with structural novelty and complexity, which may warrant further research in the field of drug discovery. PMID- 29117099 TI - Field Tests of a Portable MEMS Gravimeter. AB - Gravimeters are used to measure density anomalies under the ground. They are applied in many different fields from volcanology to oil and gas exploration, but present commercial systems are costly and massive. A new type of gravity sensor has been developed that utilises the same fabrication methods as those used to make mobile phone accelerometers. In this study, we describe the first results of a field-portable microelectromechanical system (MEMS) gravimeter. The stability of the gravimeter is demonstrated through undertaking a multi-day measurement with a standard deviation of 5.58 * 10 - 6 ms - 2 . It is then demonstrated that a change in gravitational acceleration of 4.5 * 10 - 6 ms - 2 can be measured as the device is moved between the top and the bottom of a 20.7 m lift shaft with a signal-to-noise ratio (SNR) of 14.25. Finally, the device is demonstrated to be stable in a more harsh environment: a 4.5 * 10 - 4 ms - 2 gravity variation is measured between the top and bottom of a 275-m hill with an SNR of 15.88. These initial field-tests are an important step towards a chip-sized gravity sensor. PMID- 29117100 TI - Feature Selection for Motor Imagery EEG Classification Based on Firefly Algorithm and Learning Automata. AB - Motor Imagery (MI) electroencephalography (EEG) is widely studied for its non invasiveness, easy availability, portability, and high temporal resolution. As for MI EEG signal processing, the high dimensions of features represent a research challenge. It is necessary to eliminate redundant features, which not only create an additional overhead of managing the space complexity, but also might include outliers, thereby reducing classification accuracy. The firefly algorithm (FA) can adaptively select the best subset of features, and improve classification accuracy. However, the FA is easily entrapped in a local optimum. To solve this problem, this paper proposes a method of combining the firefly algorithm and learning automata (LA) to optimize feature selection for motor imagery EEG. We employed a method of combining common spatial pattern (CSP) and local characteristic-scale decomposition (LCD) algorithms to obtain a high dimensional feature set, and classified it by using the spectral regression discriminant analysis (SRDA) classifier. Both the fourth brain-computer interface competition data and real-time data acquired in our designed experiments were used to verify the validation of the proposed method. Compared with genetic and adaptive weight particle swarm optimization algorithms, the experimental results show that our proposed method effectively eliminates redundant features, and improves the classification accuracy of MI EEG signals. In addition, a real-time brain-computer interface system was implemented to verify the feasibility of our proposed methods being applied in practical brain-computer interface systems. PMID- 29117102 TI - Mechanisms of Entry and Endosomal Pathway of African Swine Fever Virus. AB - African Swine Fever Virus (ASFV) causes a serious swine disease that is endemic in Africa and Sardinia and presently spreading in Russia and neighboring countries, including Poland and recently, the Czech Republic. This uncontrolled dissemination is a world-wide threat, as no specific protection or vaccine is available. ASFV is a very complex icosahedral, enveloped virus about 200 nm in diameter, which infects several members of pigs. The virus enters host cells by receptor-mediated endocytosis that depends on energy, vacuolar pH and temperature. The specific receptor(s) and attachment factor(s) involved in viral entry are still unknown, although macropinocytosis and clathrin-dependent mechanisms have been proposed. After internalization, ASFV traffics through the endolysosomal system. The capsid and inner envelope are found in early endosomes or macropinosomes early after infection, colocalizing with EEA1 and Rab5, while at later times they co-localize with markers of late endosomes and lysosomes, such as Rab7 or Lamp 1. A direct relationship has been established between the maturity of the endosomal pathway and the progression of infection in the cell. Finally, ASFV uncoating first involves the loss of the outer capsid layers, and later fusion of the inner membrane with endosomes, releasing the nude core into the cytosol. PMID- 29117103 TI - Development and Physico-Chemical Characterization of a Shea Butter-Containing Lipid Nutrition Supplement for Sub-Saharan Africa. AB - Lipid-based nutrient supplements (LNS) are used to prevent and treat moderate and severe acute malnutrition, a leading cause of mortality in children-under-five. The physical and chemical changes of two new LNS products were evaluated before and after accelerated shelf life testing (ASLT) according to protocols suggested by the U.S. Agency for International Development (USAID) and Doctors without Borders and compared against USAID's A-20 paste as a control. LNS formulas containing Shea butter from the Shea nut tree (Vitellaria paradoxa), a common fat source in parts of Sub-Saharan Africa, with and without flax-seed oil, as a source of omega-3 fatty acids, were developed. LNS formulas were batched (0.8 kg) in a wet grinder, sealed under nitrogen in three-layer mini-pouches (20 g), and underwent ASLT at 40 +/- 2 degrees C for six months with sampling every eight weeks. At each time point, water activity, moisture, peroxide value, oil separation, vitamin C content, and hardness were evaluated. Results showed comparable stability among all formulas with an increase in Aw (p < 0.05) but no change in vitamin C, oil separation, or peroxide value. Addition of Shea butter improved the LNS's hardness, which remained stable over time. Modifying fat profile in LNS can improve its texture and essential fatty acid content without affecting its storage stability. PMID- 29117104 TI - Current Status of Legislation on Dietary Products for Sportspeople in a European Framework. AB - The consumption of nutritional ergogenic aids is conditioned by laws/regulations, but standards/regulations vary between countries. The aim of this review is to explore legislative documents that regulate the use of nutritional ergogenic aids intended for sportspeople in a Spanish/European framework. A narrative review has been developed from official websites of Spanish (Spanish Agency of the Consumer, Food Safety, and Nutrition) and European (European Commission and European Food Safety Authority) bodies. A descriptive analysis of documents was performed. Eighteen legislative documents have been compiled in three sections: (1) Advertising of any type of food and/or product; (2) Composition, labeling, and advertising of foods; (3) Nutritional ergogenic aids. In spite of the existence of these legal documents, the regulation lacks guidance on the use/application of nutritional ergogenic aids for sportspeople. It is essential to prevent the introduction or dissemination of false, ambiguous, or inexact information and contents that induce an error in the receivers of the information. In this field, it is worth highlighting the roles of the European Food Safety Authority and the World Anti-Doping Agency, which provide information about consumer guidelines, prescribing practices, and recommendations for the prudent use of nutritional ergogenic aids. PMID- 29117101 TI - Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450. AB - Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s. PMID- 29117105 TI - Efficacy of Web-Based Weight Loss Maintenance Programs: A Randomized Controlled Trial Comparing Standard Features Versus the Addition of Enhanced Personalized Feedback over 12 Months. AB - Few randomized controlled trials (RCT) have evaluated the efficacy of web-based programs targeting maintenance of lost weight. The aims of this study were to evaluate two versions of a commercially available web-based weight loss maintenance (WLM) program and examine whether the provision of enhanced feedback was associated with better WLM. The study was an assessor-blinded RCT of change in body mass index (BMI) over 12 months WLM. Participants were 227 adults (44% male, 42.3 +/- 10.1 years, BMI 30.4 +/- 4.1 kg/m2) randomized to either a basic (Basic WLM) or enhanced program with additional support (Enhanced WLM). Analysis was intention-to-treat with imputation using last observation carried forward. There was no significant weight rebound from the start of weight loss maintenance to 12 months for either group (mean: basic 1.3%, enhanced 1.5%) and limited change in secondary outcomes for either program. There were no significant between-group differences in the primary outcome of change in BMI (basic -0.5 (1.9) kg/m2, enhanced -0.5 (1.6) kg/m2, p = 0.93). In conclusion, a web-based WLM program was effective in preventing weight regain over one year following weight loss. However, the addition of personalized e-feedback provided limited additional benefits compared to a standard program. Given the potential reach of web-based approaches, further research examining which web-based program components optimize weight outcomes long-term is required. PMID- 29117106 TI - The 17th Rocky Mountain Virology Association Meeting. AB - Since 2000, scientists and students from the greater Rocky Mountain region, along with invited speakers, both national and international, have gathered at the Mountain Campus of Colorado State University to discuss their area of study, present recent findings, establish or strengthen collaborations, and mentor the next generation of virologists and prionologists through formal presentations and informal discussions concerning science, grantsmanship and network development. This year, approximately 100 people attended the 17th annual Rocky Mountain Virology Association meeting, that began with a keynote presentation, and featured 29 oral and 35 poster presentations covering RNA and DNA viruses, prions, virus-host interactions and guides to successful mentorship. Since the keynote address focused on the structure and function of Zika and related flaviviruses, a special session was held to discuss RNA control. The secluded meeting at the foot of the Colorado Rocky Mountains gave ample time for in-depth discussions amid the peak of fall colors in the aspen groves while the random bear provided excitement. On behalf of the Rocky Mountain Virology Association, this report summarizes the >50 reports. PMID- 29117107 TI - Bacteriophages in the Dairy Environment: From Enemies to Allies. AB - The history of dairy farming goes back thousands of years, evolving from a traditional small-scale production to the industrialized manufacturing of fermented dairy products. Commercialization of milk and its derived products has been very important not only as a source of nourishment but also as an economic resource. However, the dairy industry has encountered several problems that have to be overcome to ensure the quality and safety of the final products, as well as to avoid economic losses. Within this context, it is interesting to highlight the role played by bacteriophages, or phages, viruses that infect bacteria. Indeed, bacteriophages were originally regarded as a nuisance, being responsible for fermentation failure and economic losses when infecting lactic acid bacteria, but are now considered promising antimicrobials to fight milk-borne pathogens without contributing to the increase in antibiotic resistance. PMID- 29117108 TI - Effect of AICAR and 5-Fluorouracil on X-ray Repair, Cross-Complementing Group 1 Expression, and Consequent Cytotoxicity Regulation in Human HCT-116 Colorectal Cancer Cells. AB - Colorectal cancer (CRC) is one of the leading causes of cancer mortality and 5 Fluorouracil (5-FU) is the most common chemotherapy agent of CRC. A high level of X-ray repair cross complementing group 1 (XRCC1) in cancer cells has been associated with the drug resistance occurrence. Moreover, the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been indicated to regulate the cancer cell survival. Thus, this study was aimed to examine whether XRCC1 plays a role in the 5-FU/AMPK agonist (AICAR)-induced cytotoxic effect on CRC and the underlying mechanisms. Human HCT-116 colorectal cells were used in this study. It was shown that 5-FU increases the XRCC1 expression in HCT 116 cells and then affects the cell survival through CXCR4/Akt signaling. Moreover, 5-FU combined with AICAR further result in more survival inhibition in HCT-116 cells, accompanied with reduced CXCR4/Akt signaling activity and XRCC1 expression. These results elucidate the role and mechanism of XRCC1 in the drug resistance of HCT-116 cells to 5-FU. We also demonstrate the synergistic inhibitory effect of AMPK on 5-FU-inhibited HCT-116 cell survival under the 5-FU and AICAR co-treatment. Thus, our findings may provide a new notion for the future drug regimen incorporating 5-FU and AMPK agonists for the CRC treatment. PMID- 29117109 TI - Lignin-Modified Carbon Nanotube/Graphene Hybrid Coating as Efficient Flame Retardant. AB - To reduce fire hazards and expand high-value applications of lignocellulosic materials, thin films comprising graphene nanoplatelets (GnPs) and multi-wall carbon nanotubes (CNTs) pre-adsorbed with alkali lignin were deposited by a Meyer rod process. Lightweight and highly flexible papers with increased gas impermeability were obtained by coating a protective layer of carbon nanomaterials in a randomly oriented and overlapped network structure. Assessment of the thermal and flammability properties of papers containing as low as 4 wt % carbon nanomaterials exhibited self-extinguishing behavior and yielded up to 83.5% and 87.7% reduction in weight loss and burning area, respectively, compared to the blank papers. The maximum burning temperature as measured by infrared pyrometry also decreased from 834 degrees C to 705 degrees C with the presence of flame retardants. Furthermore, papers coated with composites of GnPs and CNTs pre-adsorbed with lignin showed enhanced thermal stability and superior fire resistance than samples treated with either component alone. These outstanding flame-retardant properties can be attributed to the synergistic effects between GnPs, CNTs and lignin, enhancing physical barrier characteristics, formation of char and thermal management of the material. These results provide great opportunities for the development of efficient, cost-effective and environmentally sustainable flame retardants. PMID- 29117110 TI - Digestibility Is Similar between Commercial Diets That Provide Ingredients with Different Perceived Glycemic Responses and the Inaccuracy of Using the Modified Atwater Calculation to Calculate Metabolizable Energy. AB - Dietary starch is required for a dry, extruded kibble; the most common diet type for domesticated felines in North America. However, the amount and source of dietary starch may affect digestibility and metabolism of other macronutrients. The objectives of this study were to evaluate the effects of 3 commercial cat diets on in vivo and in vitro energy and macronutrient digestibility, and to analyze the accuracy of the modified Atwater equation. Dietary treatments differed in their perceived glycemic response (PGR) based on ingredient composition and carbohydrate content (34.1, 29.5, and 23.6% nitrogen-free extract for High, Medium, and LowPGR, respectively). A replicated 3 * 3 Latin square design was used, with 3 diets and 3 periods. In vivo apparent protein, fat, and organic matter digestibility differed among diets, while apparent dry matter digestibility did not. Cats were able to efficiently digest and absorb macronutrients from all diets. Furthermore, the modified Atwater equation underestimated measured metabolizable energy by approximately 12%. Thus, the modified Atwater equation does not accurately determine the metabolizable energy of high quality feline diets. Further research should focus on understanding carbohydrate metabolism in cats, and establishing an equation that accurately predicts the metabolizable energy of feline diets. PMID- 29117111 TI - The Vascular Factor Plays the Main Role in the Cause of Pain in Men with Chronic Prostatitis and Chronic Pelvic Pain Syndrome: The Results of Clinical Trial on Thermobalancing Therapy. AB - Chronic pain in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), NIH category III is difficult to treat without understanding its cause. The main symptom of chronic prostatitis is pain. In this study, we would like to explain the origin of pain in men with CP/CPPS and its therapy. Forty five patients with CP/CPPS have received thermobalancing therapy (TT) enabled by Dr Allen's therapeutic device (DATD) for six months as mono-therapy. The control group comprised 45 men with CP/CPPS did not receive TT. Before and after six months the National Institute of Health Chronic Prostatitis Symptom Index (NIH CPSI) scores, prostatic volume (PV) by ultrasound measurement and uroflowmetry (Qmax) were compared between the groups. Baseline characteristics have shown no difference. After TT, significant improvements in pain score (p < 0.001), quality of life index (QoL) (p < 0.001), decrease of PV (p < 0.001), and increase Qmax (p < 0.001) were determined. There were not noteworthy changes in the control group. Chronic pain due to CP/CPPS happens as a consequence and challenges at the capillary level, namely pathological capillary activity. In response to initial triggers-such as inflammation, cold, psychological and other factors-constriction and spontaneous expansion of capillaries follows, creating a continuous secondary trigger-i.e., the micro-focus of hypothermia-which in turn provokes expansion of capillaries. The additional tissue due to vascular changes into the prostate increases pressure on nociceptors causing pain. TT relieves chronic pelvic pain by eliminating the lasting focus of hypothermia in the affected prostate tissue. PMID- 29117112 TI - In Vivo Imaging of Microglial Calcium Signaling in Brain Inflammation and Injury. AB - Microglia, the innate immune sentinels of the central nervous system, are the most dynamic cells in the brain parenchyma. They are the first responders to insult and mediate neuroinflammation. Following cellular damage, microglia extend their processes towards the lesion, modify their morphology, release cytokines and other mediators, and eventually migrate towards the damaged area and remove cellular debris by phagocytosis. Intracellular Ca2+ signaling plays important roles in many of these functions. However, Ca2+ in microglia has not been systematically studied in vivo. Here we review recent findings using genetically encoded Ca2+ indicators and two-photon imaging, which have enabled new insights into Ca2+ dynamics and signaling pathways in large populations of microglia in vivo. These new approaches will help to evaluate pre-clinical interventions and immunomodulation for pathological brain conditions such as stroke and neurodegenerative diseases. PMID- 29117113 TI - Design, Synthesis and Anticancer Evaluation of Fangchinoline Derivatives. AB - Twenty fangchinoline derivatives were synthesized from the natural product fangchinoline, and their anticancer activities on human breast cancer MDA-MB-231 cell line, human prostate cancer PC3 cell line, human melanoma WM9 cell line and human leukaemia HEL and K562 cell lines were evaluated. The biological result showed that those derivatives exhibited potent activities on inhibiting cancer cell growth, and the structure-activity relationships were investigated. Among them, compound 4g, which was protected by benzoyl group in 7-phenolic position and nitrified in 14-position, showed impressive inhibition on all 5 cancer cell lines, especially WM9 cell line, with an IC50 value of 1.07 uM. Further mechanistic studies demonstrated that compound 4g may induce cancer cell death by apoptotic means. These research results suggested that compound 4g could be a lead for the further development toward an anticancer agent against human melanoma WM9 in the future. PMID- 29117114 TI - Climatic Variables and Malaria Morbidity in Mutale Local Municipality, South Africa: A 19-Year Data Analysis. AB - The north-eastern parts of South Africa, comprising the Limpopo Province, have recorded a sudden rise in the rate of malaria morbidity and mortality in the 2017 malaria season. The epidemiological profiles of malaria, as well as other vector borne diseases, are strongly associated with climate and environmental conditions. A retrospective understanding of the relationship between climate and the occurrence of malaria may provide insight into the dynamics of the disease's transmission and its persistence in the north-eastern region. In this paper, the association between climatic variables and the occurrence of malaria was studied in the Mutale local municipality in South Africa over a period of 19-year. Time series analysis was conducted on monthly climatic variables and monthly malaria cases in the Mutale municipality for the period of 1998-2017. Spearman correlation analysis was performed and the Seasonal Autoregressive Integrated Moving Average (SARIMA) model was developed. Microsoft Excel was used for data cleaning, and statistical software R was used to analyse the data and develop the model. Results show that both climatic variables' and malaria cases' time series exhibited seasonal patterns, showing a number of peaks and fluctuations. Spearman correlation analysis indicated that monthly total rainfall, mean minimum temperature, mean maximum temperature, mean average temperature, and mean relative humidity were significantly and positively correlated with monthly malaria cases in the study area. Regression analysis showed that monthly total rainfall and monthly mean minimum temperature (R2 = 0.65), at a two-month lagged effect, are the most significant climatic predictors of malaria transmission in Mutale local municipality. A SARIMA (2,1,2) (1,1,1) model fitted with only malaria cases has a prediction performance of about 51%, and the SARIMAX (2,1,2) (1,1,1) model with climatic variables as exogenous factors has a prediction performance of about 72% in malaria cases. The model gives a close comparison between the predicted and observed number of malaria cases, hence indicating that the model provides an acceptable fit to predict the number of malaria cases in the municipality. To sum up, the association between the climatic variables and malaria cases provides clues to better understand the dynamics of malaria transmission. The lagged effect detected in this study can help in adequate planning for malaria intervention. PMID- 29117116 TI - Seasonal Variation in Essential Oil Compositions and Antioxidant Properties of Acorus calamus L. Accessions. AB - Background:Acorus calamus (Sweet flag) is a known herbal drug commonly used in traditional medicine. Our aim was to perform seasonal and altitudinal phytochemical screening to assess the antioxidant activity of the essential oils in the rhizome and leaves of A. calamus from three different altitudes. Methods: Phytochemical screening was performed using GC/MS analysis and in vitro antioxidant assay was done by different methods. Results: The essential oils mainly contained alpha-asarone, beta-asarone (35.3-90.6%), and Z-isoelemicin (1.7 7.3%) as the major constituents, besides linalool, Z-methyl isoeugenol, shyobunone, kessane, etc. All the oils exhibited vast molecular diversity in terms of quantitative ingredients. All essential oils were studied for their antioxidant activity by different methods, including their effect on the DPPH radical-scavenging activity, reducing power, and chelating properties of Fe2+. The oils isolated in all the different seasons exhibited antioxidant activity as a function of concentration, with IC50 values ranging from 475.48 +/- 0.08 to 11.72 +/- 0.03 compared to standards. Conclusion : From the results obtained it can be inferred that the herb may be a good source of bioactive compounds and can work as an antioxidant to prevent oxidative deterioration in food. The data provide a basis for its in-situ investigation for judicious exploitation. PMID- 29117115 TI - Glucosinolate-Derived Isothiocyanates Inhibit Arabidopsis Growth and the Potency Depends on Their Side Chain Structure. AB - Isothiocyanates (ITCs), the biologically important glucosinolate breakdown products, can present health-promoting effects, play an important role in plant defense and affect plant cellular mechanisms. Here, we evaluated the biological effects of ITCs on Arabidopsis thaliana by assessing growth parameters after long term exposure to low concentrations of aliphatic and aromatic ITCs, ranging from 1 to 1000 uM. Treatment with the aliphatic allylisothiocyanate (allyl-ITC) led to a significant reduction of root length and fresh weight in a dose-dependent manner and affected the formation of lateral roots. To assess the importance of a hormonal crosstalk in the allyl-ITC-mediated growth reduction, the response of auxin and ethylene mutants was investigated, but our results did not allow us to confirm a role for these hormones. Aromatic ITCs generally led to a more severe growth inhibition than the aliphatic allyl-ITC. Interestingly, we observed a correlation between the length of their side chain and the effect these aromatic ITCs caused on Arabidopsis thaliana, with the greatest inhibitory effect seen for 2-phenylethyl-ITC. Root growth recovered when seedlings were removed from exposure to ITCs. PMID- 29117117 TI - Anticancer and Immunogenic Properties of Cardiac Glycosides. AB - Cardiac glycosides (CGs) are natural compounds widely used in the treatment of several cardiac conditions and more recently have been recognized as potential antitumor compounds. They are known to be ligands for Na/K-ATPase, which is a promising drug target in cancer. More recently, in addition to their antitumor effects, it has been suggested that CGs activate tumor-specific immune responses. This review summarizes the anticancer aspects of CGs as new strategies for immunotherapy and drug repositioning (new horizons for old players), and the possible new targets for CGs in cancer cells. PMID- 29117119 TI - Development of Ratiometric Fluorescent Biosensors for the Determination of Creatine and Creatinine in Urine. AB - In this study, the oxazine 170 perchlorate (O17)-ethylcellulose (EC) membrane was successfully exploited for the fabrication of creatine- and creatinine-sensing membranes. The sensing membrane exhibited a double layer of O17-EC membrane and a layer of enzyme(s) entrapped in the EC and polyurethane hydrogel (PU) matrix. The sensing principle of the membranes was based on the hydrolytic catalysis of urea, creatine, and creatinine by the enzymes. The reaction end product, ammonia, reacted with O17-EC membrane, resulting in the change in fluorescence intensities at two emission wavelengths (lambdaem = 565 and 625 nm). Data collected from the ratio of fluorescence intensities at lambdaem = 565 and 625 nm were proportional to the concentrations of creatine or creatinine. Creatine- and creatinine-sensing membranes were very sensitive to creatine and creatinine at the concentration range of 0.1-1.0 mM, with a limit of detection (LOD) of 0.015 and 0.0325 mM, respectively. Furthermore, these sensing membranes showed good features in terms of response time, reversibility, and long-term stability. The interference study demonstrated that some components such as amino acids and salts had some negative effects on the analytical performance of the membranes. Thus, the simple and sensitive ratiometric fluorescent sensors provide a simple and comprehensive method for the determination of creatine and creatinine concentrations in urine. PMID- 29117118 TI - Diet and Asthma: Is It Time to Adapt Our Message? AB - Asthma is a chronic respiratory disorder which is associated with airway inflammation. Environmental factors, in association with genetic susceptibility, play a critical role in asthma pathophysiology. Inhaled allergens, smoke exposure, indoor and outdoor air pollution are common triggers of asthma symptoms. Although the role of diet has clearly established mechanisms in diseases such as cardiovascular disease, type 2 diabetes, and cancer, it is not commonly identified as a causal factor in asthma. However, some dietary patterns, such as the Western diet, which includes a high intake of refined grains, processed and red meats, and desserts, have pro-inflammatory effects. On the contrary, the Mediterranean diet, with high intake of fruits and vegetables has anti-inflammatory properties. The influence of food on asthma outcomes is of growing interest, but dietary habits of asthma patients are not commonly investigated in clinical practice. In this review, we focus on the impact of diet on asthma risk and asthma control. We also detail the influence of diet on obese patients with asthma. PMID- 29117120 TI - Increased Serum Levels of Fetal Tenascin-C Variants in Patients with Pulmonary Hypertension: Novel Biomarkers Reflecting Vascular Remodeling and Right Ventricular Dysfunction? AB - Pulmonary vascular remodeling is a pathophysiological feature that common to all classes of pulmonary hypertension (PH) and right ventricular dysfunction, which is the major prognosis-limiting factor. Vascular, as well as cardiac tissue remodeling are associated with a re-expression of fetal variants of cellular adhesion proteins, including tenascin-C (Tn-C). We analyzed circulating levels of the fetal Tn-C splicing variants B+ and C+ Tn-C in serum of PH patients to evaluate their potential as novel biomarkers reflecting vascular remodeling and right ventricular dysfunction. Serum concentrations of B+ and C+ Tn-C were determined in 80 PH patients and were compared to 40 healthy controls by enzyme linked immunosorbent assay. Clinical, laboratory, echocardiographic, and functional data were correlated with Tn-C levels. Serum concentrations of both Tn C variants were significantly elevated in patients with PH (p < 0.05). Significant correlations could be observed between Tn-C and echocardiographic parameters, including systolic pulmonary artery pressure (B+ Tn-C: r = 0.31, p < 0.001, C+ Tn-C: r = 0.26, p = 0.006) and right atrial area (B+ Tn-C: r = 0.46, p < 0.001, C+ Tn-C: r = 0.49, p < 0.001), and laboratory values like BNP (B+ Tn-C: r = 0.45, p < 0.001, C+ Tn-C: r = 0.42, p < 0.001). An inverse correlation was observed between Tn-C variants and 6-minute walk distance as a functional parameter (B+ Tn-C: r = -0.54, p < 0.001, C+ Tn-C: r = -0.43, p < 0.001). In a multivariate analysis, B+ Tn-C, but not C+ Tn-C, was found to be an independent predictor of pulmonary hypertension. Both fetal Tn-C variants may represent novel biomarkers that are capable of estimating both pulmonary vascular remodeling and right ventricular load. The potential beneficial impact of Tn-C variants for risk stratification in patients with PH needs further investigation. PMID- 29117121 TI - Increased Loading, Efficacy and Sustained Release of Silibinin, a Poorly Soluble Drug Using Hydrophobically-Modified Chitosan Nanoparticles for Enhanced Delivery of Anticancer Drug Delivery Systems. AB - Conventional delivery of anticancer drugs is less effective due to pharmacological drawbacks such as lack of aqueous solubility and poor cellular accumulation. This study reports the increased drug loading, therapeutic delivery, and cellular accumulation of silibinin (SLB), a poorly water-soluble phenolic compound using a hydrophobically-modified chitosan nanoparticle (pCNP) system. In this study, chitosan nanoparticles were hydrophobically-modified to confer a palmitoyl group as confirmed by 2,4,6-Trinitrobenzenesulfonic acid (TNBS) assay. Physicochemical features of the nanoparticles were studied using the TNBS assay, and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) analyses. The FTIR profile and electron microscopy correlated the successful formation of pCNP and pCNP-SLB as nano-sized particles, while Dynamic Light Scattering (DLS) and Field Emission-Scanning Electron Microscopy (FESEM) results exhibited an expansion in size between pCNP and pCNP SLB to accommodate the drug within its particle core. To evaluate the cytotoxicity of the nanoparticles, a Methylthiazolyldiphenyl-tetrazolium bromide (MTT) cytotoxicity assay was subsequently performed using the A549 lung cancer cell line. Cytotoxicity assays exhibited an enhanced efficacy of SLB when delivered by CNP and pCNP. Interestingly, controlled release delivery of SLB was achieved using the pCNP-SLB system, conferring higher cytotoxic effects and lower IC50 values in 72-h treatments compared to CNP-SLB, which was attributed to the hydrophobic modification of the CNP system. PMID- 29117122 TI - ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. AB - The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors. PMID- 29117124 TI - Temperature-Dependent Photoluminescence Emission from Unstrained and Strained GaSe Nanosheets. AB - Two-dimensional AIIIBVI layered semiconductors have recently attracted great attention due to their potential applications in piezo-phototronics and optoelectronics. Here, we report the temperature-dependent photoluminescence (PL) of strained and unstrained GaSe flakes. It is found that, as the temperature increases, the PL from both the strained (wrinkled) and unstrained (flat) positions show a prominent red-shift to low energies. However, for the flat case, the slope of PL energy versus temperature at the range of 163-283 K is about 0.36 meV/K, which is smaller than that of the wrinkled one (-0.5 meV/K). This is because more strain can be introduced at the freestanding wrinkled position during the temperature increase, thus accelerates the main PL peak (peak I, direct band gap transition) shift to lower energy. Additionally, for the wrinkled sheet, three new exciton states (peaks III, IV, and V) appear at the red side of peak I, and the emission intensity is highly dependent on the temperature variation. These peaks can be attributed to the bound exciton recombination. These findings demonstrate an interesting route for optical band gap tuning of the layered GaSe sheet, which are important for future optoelectronic device design. PMID- 29117123 TI - Metabolic Dysfunction and Oxidative Stress in Epilepsy. AB - The epilepsies are a heterogeneous group of disorders characterized by the propensity to experience spontaneous recurrent seizures. Epilepsies can be genetic or acquired, and the underlying mechanisms of seizure initiation, seizure propagation, and comorbid conditions are incompletely understood. Metabolic changes including the production of reactive species are known to result from prolonged seizures and may also contribute to epilepsy development. In this review, we focus on the evidence that metabolic and redox disruption is both cause and consequence of epileptic seizures. Additionally, we discuss the promise of targeting redox processes as a therapeutic option in epilepsy. PMID- 29117125 TI - The Small and the Dead: A Review of Ancient DNA Studies Analysing Micromammal Species. AB - The field of ancient DNA (aDNA) has recently been in a state of exponential growth, largely driven by the uptake of Next Generation Sequencing (NGS) techniques. Much of this work has focused on the mammalian megafauna and ancient humans, with comparatively less studies looking at micromammal fauna, despite the potential of these species in testing evolutionary, environmental and taxonomic theories. Several factors make micromammal fauna ideally suited for aDNA extraction and sequencing. Micromammal subfossil assemblages often include the large number of individuals appropriate for population level analyses, and, furthermore, the assemblages are frequently found in cave sites where the constant temperature and sheltered environment provide favourable conditions for DNA preservation. This review looks at studies that include the use of aDNA in molecular analysis of micromammal fauna, in order to examine the wide array of questions that can be answered in the study of small mammals using new palaeogenetic techniques. This study highlights the bias in current aDNA studies and assesses the future use of aDNA as a tool for the study of micromammal fauna. PMID- 29117126 TI - Perspective for Fibre-Hybrid Composites in Wind Energy Applications. AB - Increasing the efficiency of wind turbines will be vital for the wind energy sector to continue growing. The drive for increased efficiency is pushing turbine manufacturers to shift from glass fibre composite blades towards carbon/glass fibre-hybrid composite blades. This shift brings significant challenges in terms of optimising the design and understanding the failure of these new blade materials. This review therefore surveys the literature on fibre-hybrid composites, with an emphasis on aspects that are relevant for turbine blade materials. The literature on tensile, flexural, compressive, and fatigue performance is critically assessed and areas for future research are identified. Numerical simulations of fibre-hybrid composites have reached a reasonable maturity for tensile failure, but significant progress is required for flexural, compressive, and fatigue failure. Fatigue failure of fibre-hybrid composites in particular, requires more careful attention from both a modelling and experimental point of view. PMID- 29117127 TI - Amphibian and Avian Karyotype Evolution: Insights from Lampbrush Chromosome Studies. AB - Amphibian and bird karyotypes typically have a complex organization, which makes them difficult for standard cytogenetic analysis. That is, amphibian chromosomes are generally large, enriched with repetitive elements, and characterized by the absence of informative banding patterns. The majority of avian karyotypes comprise a small number of relatively large macrochromosomes and numerous tiny morphologically undistinguishable microchromosomes. A good progress in investigation of amphibian and avian chromosome evolution became possible with the usage of giant lampbrush chromosomes typical for growing oocytes. Due to the giant size, peculiarities of organization and enrichment with cytological markers, lampbrush chromosomes can serve as an opportune model for comprehensive high-resolution cytogenetic and cytological investigations. Here, we review the main findings on chromosome evolution in amphibians and birds that were obtained using lampbrush chromosomes. In particular, we discuss the data on evolutionary chromosomal rearrangements, accumulation of polymorphisms, evolution of sex chromosomes as well as chromosomal changes during clonal reproduction of interspecies hybrids. PMID- 29117128 TI - Bioactive Secondary Metabolites from the Marine Sponge Genus Agelas. AB - The marine sponge genus Agelas comprises a rich reservoir of species and natural products with diverse chemical structures and biological properties with potential application in new drug development. This review for the first time summarized secondary metabolites from Agelas sponges discovered in the past 47 years together with their bioactive effects. PMID- 29117129 TI - An Optimized Synthesis, Molecular Structure and Characterization of Benzylic Derivatives of 1,2,4-Triazin-3,5(2H,4H)-dione. AB - 4-Benzyl-1,2,4-triazin-3,5(2H,4H)-dione (3-benzyl-6-azauracil, 2), and 2,4 dibenzyl-1,2,4-triazin-3,5(2H,4H)-dione (1,3-dibenzyl-6-azauracil, 3) were synthesized by the reaction of 1,2,4-triazin-3,5(2H,4H)-dione (6-azauracil, 1) with benzyl bromide and potassium carbonate in dry acetone via the 18-crown-6 ether catalysis. In these reaction methods, we developed more convenient and efficient methodologies to afford compounds 2 and 3 in good yields. These compounds were characterized by 1H- and 13C-NMR, MS spectrum, IR spectroscopy and elemental analysis. The structure of 2 was verified by 2D-NMR measurements, including gHSQC and gHMBC measurements. A single-crystal X-ray diffraction experiment indicated that compound 3, with the molecular formula C17H15N3O2, crystallized from a CH3OH/CH2Cl2 diffusion solvent system in a monoclinic space group P21/c with a = 13.7844(13), b = 8.5691(8), c = 13.0527(12) A, beta = 105.961(2) degrees , V = 1482.3(2) A3, Z = 4, resulting in a density Dcalc of 1.314 g/cm3. The crystal structure of compound 3 is tightly stabilized by contact with five other molecules from the six short contacts formed by intermolecular C O...H-Car, C-H...Car, and weakly pi...pi stacking interactions. The dihedral angle 31.90 degrees is formed by the mean planes of the benzene rings of the N-2 and N-4 benzyl groups. PMID- 29117130 TI - Characterization of Nucleoside Reverse Transcriptase Inhibitor-Associated Mutations in the RNase H Region of HIV-1 Subtype C Infected Individuals. AB - The South African national treatment programme includes nucleoside reverse transcriptase inhibitors (NRTIs) in both first and second line highly active antiretroviral therapy regimens. Mutations in the RNase H domain have been associated with resistance to NRTIs but primarily in HIV-1 subtype B studies. Here, we investigated the prevalence and association of RNase H mutations with NRTI resistance in sequences from HIV-1 subtype C infected individuals. RNase H sequences from 112 NRTI treated but virologically failing individuals and 28 antiretroviral therapy (ART)-naive individuals were generated and analysed. In addition, sequences from 359 subtype C ART-naive sequences were downloaded from Los Alamos database to give a total of 387 sequences from ART-naive individuals for the analysis. Fisher's exact test was used to identify mutations and Bayesian network learning was applied to identify novel NRTI resistance mutation pathways in RNase H domain. The mutations A435L, S468A, T470S, L484I, A508S, Q509L, L517I, Q524E and E529D were more prevalent in sequences from treatment-experienced compared to antiretroviral treatment naive individuals, however, only the E529D mutation remained significant after correction for multiple comparison. Our findings suggest a potential interaction between E529D and NRTI-treatment; however, site-directed mutagenesis is needed to understand the impact of this RNase H mutation. PMID- 29117131 TI - Natural Deep Eutectic Solvents (NADES) to Enhance Berberine Absorption: An In Vivo Pharmacokinetic Study. AB - In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural compounds having a melting point significantly lower than that of any individual component. Such solvents have gained much attention of the scientific community in the green chemistry area, being considered useful alternatives to common organic solvents. NADES can be used also as administration vehicles, and this can be attractive for nutraceutical products when eutectics are formed with food grade ingredients. In this work, different NADES were prepared using mainly food grade constituents and were tested as solvents for the alkaloid berberine. Three selected NADES/berberine solutions and an aqueous suspension were orally administered to mice with in dose of 50 mg/Kg. Blood levels of berberine were measured by a LC MS/MS method. The pharmacokinetic analysis revealed a 2-20 fold increase in blood concentration of NADES/berberine with significant changes in pharmacokinetic profile. Natural Deep Eutectic Solvents may thus be considered attractive solubilizing agents and may also play a role in the increase of absorption of poorly bioavailable natural products such as berberine. PMID- 29117132 TI - Rationally Controlled Synthesis of CdSexTe1-x Alloy Nanocrystals and Their Application in Efficient Graded Bandgap Solar Cells. AB - CdSexTe1-x semiconductor nanocrystals (NCs), being rod-shaped/irregular dot shaped in morphology, have been fabricated via a simple hot-injection method. The NCs composition is well controlled through varying molar ratios of Se to Te precursors. Through changing the composition of the CdSexTe1-x NCs, the spectral absorption of the NC thin film between 570-800 nm is proved to be tunable. It is shown that the bandgap of homogeneously alloyed CdSexTe1-x active thin film is nonlinearly correlated with the different compositions, which is perceived as optical bowing. The solar cell devices based on CdSexTe1-x NCs with the structure of ITO/ZnO/CdSe/CdSexTe1-x/MoOx/Au and the graded bandgap ITO/ZnO/CdSe(w/o)/CdSexTe1-x/CdTe/MoOx/Au are systematically evaluated. It was found that the performance of solar cells degrades almost linearly with the increase of alloy NC film thickness with respect to ITO/ZnO/CdSe/CdSe0.2Te0.8/MoOx/Au. From another perspective, in terms of the graded bandgap structure of ITO/ZnO/CdSe/CdSexTe1-x/CdTe/MoOx/Au, the performance is improved in contrast with its single-junction analogues. The graded bandgap structure is proved to be efficient when absorbing spectrum and the solar cells fabricated under the structure of ITO/ZnO/CdSe0.8Te0.2/CdSe0.2Te0.8/CdTe/MoOx/Au indicate power conversion efficiency (PCE) of 6.37%, a value among the highest for solution-processed inversely-structured CdSexTe1-x NC solar cells. As the NC solar cells are solution-processed under environmental conditions, they are promising for fabricating solar cells at low cost, roll by roll and in large area. PMID- 29117133 TI - Development and Relative Validity of a Food Frequency Questionnaire to Assess Intakes of Total and Free Sugars in Australian Toddlers. AB - Background: Dental research into early childhood caries is hindered by a lack of suitable dietary assessment tools that have been developed and validated for the population and outcomes of interest. The aim of this study was to develop and investigate the relative validity and reproducibility of the Study of Mothers' and Infants' Life Events Food Frequency Questionnaire (SMILE-FFQ), to assess the total and free sugars intakes of Australian toddlers. Methods: The SMILE-FFQ was designed to capture the leading dietary contributors to dental caries risk in toddlers aged 18-30 months via a proxy report. Ninety-five parents of Australian toddlers completed the questionnaire online before and after providing three 24-h recalls (24HR), collected on non-consecutive days using the multipass method. Total and free sugars were compared between the two SMILE-FFQ administrations and between each SMILE-FFQ and the 24HR using multiple statistical tests and standardised validity criteria. Correlation (Pearson), mean difference (Wilcoxon rank test) and Bland Altman analyses were conducted to compare absolute values, with cross-classification (Chi-Square and Weighted Kappa) used to compare agreement across tertiles. Results: All reproducibility tests showed good agreement except weighted kappa, which showed acceptable agreement. Relative validity tests revealed a mix of good and acceptable agreement, with total sugars performing better at the individual level than free sugars. Compared to the 24HR, the SMILE-FFQ tended to underestimate absolute values at lower levels and overestimate them at higher levels. Conclusions: The combined findings of the various tests indicate that the SMILE-FFQ performs comparably to the 24HR for assessing both total and free sugars among individuals, is most effective for ranking participants rather than determining absolute intakes, and is therefore suitable for use in observational studies of Australian toddlers. PMID- 29117135 TI - ZnO Nanoparticles Protect RNA from Degradation Better than DNA. AB - Gene therapy and RNA delivery require a nanoparticle (NP) to stabilize these nucleic acids when administered in vivo. The presence of degradative hydrolytic enzymes within these environments limits the nucleic acids' pharmacologic activity. This study compared the effects of nanoscale ZnO and MgO in the protection afforded to DNA and RNA from degradation by DNase, serum or tumor homogenate. For double-stranded plasmid DNA degradation by DNase, our results suggest that the presence of MgO NP can protect DNA from DNase digestion at an elevated temperature (65 degrees C), a biochemical activity not present in ZnO NP-containing samples at any temperature. In this case, intact DNA was remarkably present for MgO NP after ethidium bromide staining and agarose gel electrophoresis where these same stained DNA bands were notably absent for ZnO NP. Anticancer RNA, polyinosinic-polycytidylic acid (poly I:C) is now considered an anti-metastatic RNA targeting agent and as such there is great interest in its delivery by NP. For it to function, the NP must protect it from degradation in serum and the tumor environment. Surprisingly, ZnO NP protected the RNA from degradation in either serum-containing media or melanoma tumor homogenate after gel electrophoretic analysis, whereas the band was much more diminished in the presence of MgO. For both MgO and ZnO NP, buffer-dependent rescue from degradation occurred. These data suggest a fundamental difference in the ability of MgO and ZnO NP to stabilize nucleic acids with implications for DNA and RNA delivery and therapy. PMID- 29117134 TI - Ginger and Propolis Exert Neuroprotective Effects against Monosodium Glutamate Induced Neurotoxicity in Rats. AB - Central nervous system cytotoxicity is linked to neurodegenerative disorders. The objective of the study was to investigate whether monosodium glutamate (MSG) neurotoxicity can be reversed by natural products, such as ginger or propolis, in male rats. Four different groups of Wistar rats were utilized in the study. Group A served as a normal control, whereas group B was orally administered with MSG (100 mg/kg body weight, via oral gavage). Two additional groups, C and D, were given MSG as group B along with oral dose (500 mg/kg body weight) of either ginger or propolis (600 mg/kg body weight) once a day for two months. At the end, the rats were sacrificed, and the brain tissue was excised and levels of neurotransmitters, beta-amyloid, and DNA oxidative marker 8-OHdG were estimated in the brain homogenates. Further, formalin-fixed and paraffin-embedded brain sections were used for histopathological evaluation. The results showed that MSG increased lipid peroxidation, nitric oxide, neurotransmitters, and 8-OHdG as well as registered an accumulation of beta-amyloid peptides compared to normal control rats. Moreover, significant depletions of glutathione, superoxide dismutase, and catalase as well as histopathological alterations in the brain tissue of MSG treated rats were noticed in comparison with the normal control. In contrast, treatment with ginger greatly attenuated the neurotoxic effects of MSG through suppression of 8-OHdG and beta-amyloid accumulation as well as alteration of neurotransmitter levels. Further improvements were also noticed based on histological alterations and reduction of neurodegeneration in the brain tissue. A modest inhibition of the neurodegenerative markers was observed by propolis. The study clearly indicates a neuroprotective effect of ginger and propolis against MSG-induced neurodegenerative disorders and these beneficial effects could be attributed to the polyphenolic compounds present in these natural products. PMID- 29117136 TI - Magnetic Nanoparticle-Assisted Tunable Optical Patterns from Spherical Cholesteric Liquid Crystal Bragg Reflectors. AB - Cholesteric liquid crystals (CLCs) exhibit selective Bragg reflections of circularly polarized (CP) light owing to their spontaneous self-assembly abilities into periodic helical structures. Photonic cross-communication patterns could be generated toward potential security applications by spherical cholesteric liquid crystal (CLC) structures. To endow these optical patterns with tunability, we fabricated spherical CLC Bragg reflectors in the shape of microshells by glass-capillary microfluidics. Water-soluble magnetofluid with Fe3O4 nanoparticles incorporated in the inner aqueous core of CLC shells is responsible for the non-invasive transportable capability. With the aid of an external magnetic field, the reflection interactions between neighboring microshells and microdroplets were identified by varying the mutual distance in a group of magnetically transportable and unmovable spherical CLC structures. The temperature-dependent optical reflection patterns were investigated in close packed hexagonal arrangements of seven CLC microdroplets and microshells with inverse helicity handedness. Moreover, we demonstrated that the magnetic field assisted assembly of microshells array into geometric figures of uppercase English letters "L" and "C" was successfully achieved. We hope that these findings can provide good application prospects for security pattern designs. PMID- 29117137 TI - Fiber Bragg Grating Dilatometry in Extreme Magnetic Field and Cryogenic Conditions. AB - In this work, we review single mode SiO2 fiber Bragg grating techniques for dilatometry studies of small single-crystalline samples in the extreme environments of very high, continuous, and pulsed magnetic fields of up to 150 T and at cryogenic temperatures down to <1 K. Distinct millimeter-long materials are measured as part of the technique development, including metallic, insulating, and radioactive compounds. Experimental strategies are discussed for the observation and analysis of the related thermal expansion and magnetostriction of materials, which can achieve a strain sensitivity (DeltaL/L) as low as a few parts in one hundred million (~10-8). The impact of experimental artifacts, such as those originating in the temperature dependence of the fiber's index of diffraction, light polarization rotation in magnetic fields, and reduced strain transfer from millimeter-long specimens, is analyzed quantitatively using analytic models available in the literature. We compare the experimental results with model predictions in the small-sample limit, and discuss the uncovered discrepancies. PMID- 29117138 TI - Computational Modelling of Materials for Wind Turbine Blades: Selected DTU Wind Energy Activities. AB - Computational and analytical studies of degradation of wind turbine blade materials at the macro-, micro-, and nanoscale carried out by the modelling team of the Section Composites and Materials Mechanics, Department of Wind Energy, DTU, are reviewed. Examples of the analysis of the microstructural effects on the strength and fatigue life of composites are shown. Computational studies of degradation mechanisms of wind blade composites under tensile and compressive loading are presented. The effect of hybrid and nanoengineered structures on the performance of the composite was studied in computational experiments as well. PMID- 29117139 TI - Protein-Protein Interactions Prediction Using a Novel Local Conjoint Triad Descriptor of Amino Acid Sequences. AB - Protein-protein interactions (PPIs) play crucial roles in almost all cellular processes. Although a large amount of PPIs have been verified by high-throughput techniques in the past decades, currently known PPIs pairs are still far from complete. Furthermore, the wet-lab experiments based techniques for detecting PPIs are time-consuming and expensive. Hence, it is urgent and essential to develop automatic computational methods to efficiently and accurately predict PPIs. In this paper, a sequence-based approach called DNN-LCTD is developed by combining deep neural networks (DNNs) and a novel local conjoint triad description (LCTD) feature representation. LCTD incorporates the advantage of local description and conjoint triad, thus, it is capable to account for the interactions between residues in both continuous and discontinuous regions of amino acid sequences. DNNs can not only learn suitable features from the data by themselves, but also learn and discover hierarchical representations of data. When performing on the PPIs data of Saccharomyces cerevisiae, DNN-LCTD achieves superior performance with accuracy as 93.12%, precision as 93.75%, sensitivity as 93.83%, area under the receiver operating characteristic curve (AUC) as 97.92%, and it only needs 718 s. These results indicate DNN-LCTD is very promising for predicting PPIs. DNN-LCTD can be a useful supplementary tool for future proteomics study. PMID- 29117140 TI - Modeling and Positioning of a PZT Precision Drive System. AB - The fact that piezoelectric ceramic transducer (PZT) precision drive systems in 3D printing are faced with nonlinear problems with respect to positioning, such as hysteresis and creep, has had an extremely negative impact on the precision of laser focusing systems. To eliminate the impact of PZT nonlinearity during precision drive movement, mathematical modeling and theoretical analyses of each module comprising the system were carried out in this study, a micro-displacement measurement circuit based on Position Sensitive Detector (PSD) is constructed, followed by the establishment of system closed-loop control and creep control models. An XL-80 laser interferometer (Renishaw, Wotton-under-Edge, UK) was used to measure the performance of the precision drive system, showing that system modeling and control algorithms were correct, with the requirements for precision positioning of the drive system satisfied. PMID- 29117141 TI - Awareness and Prevalence of Mycotoxin Contamination in Selected Nigerian Fermented Foods. AB - Fermented food samples (n = 191) including maize gruel (ogi), sorghum gruel (ogi baba), melon seed (ogiri), locust bean (iru) and African oil bean seed (ugba) from Southwest Nigeria were quantified for 23 mycotoxins, including aflatoxin B1 (AFB1), fumonisin B1 (FB1), and sterigmatocystin (STE) using liquid chromatography-tandem mass spectrometry. The practices, perceived understanding and health risks related to fungal and mycotoxin contamination amongst fermented food sellers was also established. Data obtained revealed that 82% of the samples had mycotoxins occurring singly or in combination. FB1 was present in 83% of ogi baba samples, whereas 20% of ugba samples contained AFB1 (range: 3 to 36 ug/kg) and STE was present in 29% of the ogi samples. In terms of multi-mycotoxin contamination, FB1 + FB2 + FB3 + STE + AFB1 + alternariol + HT-2 co-occurred within one sample. The awareness study revealed that 98% of respondents were unaware of mycotoxin contamination, and their education level slightly correlated with their level of awareness (p < 0.01, r = 0.308). The extent to which the analyzed mycotoxins contaminated these food commodities, coupled with the poor perception of the population under study on fungi and mycotoxins, justifies the need to enact fungal and mycotoxin mitigation strategies along the food chain. PMID- 29117143 TI - A Smartphone Step Counter Using IMU and Magnetometer for Navigation and Health Monitoring Applications. AB - The growing market of smart devices make them appealing for various applications. Motion tracking can be achieved using such devices, and is important for various applications such as navigation, search and rescue, health monitoring, and quality of life-style assessment. Step detection is a crucial task that affects the accuracy and quality of such applications. In this paper, a new step detection technique is proposed, which can be used for step counting and activity monitoring for health applications as well as part of a Pedestrian Dead Reckoning (PDR) system. Inertial and Magnetic sensors measurements are analyzed and fused for detecting steps under varying step modes and device pose combinations using a free-moving handheld device (smartphone). Unlike most of the state of the art research in the field, the proposed technique does not require a classifier, and adaptively tunes the filters and thresholds used without the need for presets while accomplishing the task in a real-time operation manner. Testing shows that the proposed technique successfully detects steps under varying motion speeds and device use cases with an average performance of 99.6%, and outperforms some of the state of the art techniques that rely on classifiers and commercial wristband products. PMID- 29117142 TI - Lignin from Micro- to Nanosize: Applications. AB - Micro- and nanosize lignin has recently gained interest due to improved properties compared to standard lignin available today. As the second most abundant biopolymer after cellulose, lignin is readily available but used for rather low-value applications. This review focuses on the application of micro- and nanostructured lignin in final products or processes that all show potential for high added value. The fields of application are ranging from improvement of mechanical properties of polymer nanocomposites, bactericidal and antioxidant properties and impregnations to hollow lignin drug carriers for hydrophobic and hydrophilic substances. Also, a carbonization of lignin nanostructures can lead to high-value applications such as use in supercapacitors for energy storage. The properties of the final product depend on the surface properties of the nanomaterial and, therefore, on factors like the lignin source, extraction method, and production/precipitation methods, as discussed in this review. PMID- 29117145 TI - Burden of Mortality and Disease Attributable to Multiple Air Pollutants in Warsaw, Poland. AB - Air pollution is a significant public health issue all over the world, especially in urban areas where a large number of inhabitants are affected. In this study, we quantify the health burden due to local air pollution for Warsaw, Poland. The health impact of the main air pollutants, PM, NOX, SO2, CO, C6H6, BaP and heavy metals is considered. The annual mean concentrations are predicted with the CALPUFF air quality modeling system using the year 2012 emission and meteorological data. The emission field comprises point, mobile and area sources. The exposure to these pollutants was estimated using population data with a spatial resolution of 0.5 * 0.5 km2. Changes in mortality and in disability adjusted life-years (DALYs) were estimated with relative risk functions obtained from literature. It has been predicted that local emissions cause approximately 1600 attributable deaths and 29,000 DALYs per year. About 80% of the health burden was due to exposure to fine particulate matter (PM2.5). Mobile and area sources contributed 46% and 52% of total DALYs, respectively. When the inflow from outside was included, the burden nearly doubled to 51,000 DALYs. These results indicate that local decisions can potentially reduce associated negative health effects, but a national-level policy is required for reducing the strong environmental impact of PM emissions. PMID- 29117144 TI - Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity. AB - Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs) and the early design approaches through mimicking the natural penetration domains used by viruses have led to greater efficiency of intracellular delivery. Following these nature-inspired examples, a number of rationally designed CPPs has been developed. In this review, a variety of CPP designs will be described, including linear and flexible, positively charged and often amphipathic CPPs, and more rigid versions comprising cyclic, stapled, or dimeric and/or multivalent, self-assembled peptides or peptido-mimetics. The application of distinct design strategies to known physico-chemical properties of CPPs offers the opportunity to improve their penetration efficiency and/or internalization kinetics. This led to increased design complexity of new CPPs that does not always result in greater CPP activity. Therefore, the transition of CPPs to a clinical setting remains a challenge also due to the concomitant involvement of various internalization routes and heterogeneity of cells used in the in vitro studies. PMID- 29117146 TI - Transferability of the Mediterranean Diet to Non-Mediterranean Countries. What Is and What Is Not the Mediterranean Diet. AB - Substantial evidence has verified the Mediterranean diet's (MedDiet) nutritional adequacy, long-term sustainability, and effectiveness for preventing hard clinical events from cardiovascular disease (CVD), as well as increasing longevity. This article includes a cumulative meta-analysis of prospective studies supporting a strong inverse association between closer adherence to the MedDiet and the incidence of hard clinical events of CVD. The MedDiet has become an increasingly popular topic of interest when focusing on overall food patterns rather than single nutrient intake, not only in Mediterranean countries, but also globally. However, several myths and misconceptions associated with the traditional Mediterranean diet should be clearly addressed and dispelled, particularly those that label as "Mediterranean" an eating pattern that is not in line with the traditional Mediterranean diet. The transferability of the traditional MedDiet to the non-Mediterranean populations is possible, but it requires a multitude of changes in dietary habits. New approaches for promoting healthy dietary behavior consistent with the MedDiet will offer healthful, sustainable, and practical strategies at all levels of public health. The following article presents practical resources and knowledge necessary for accomplishing these changes. PMID- 29117147 TI - The Na, K-ATPase beta-Subunit Isoforms Expression in Glioblastoma Multiforme: Moonlighting Roles. AB - Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Recent studies point out that gliomas exploit ion channels and transporters, including Na, K-ATPase, to sustain their singular growth and invasion as they invade the brain parenchyma. Moreover, the different isoforms of the beta-subunit of Na, K ATPase have been implicated in regulating cellular dynamics, particularly during cancer progression. The aim of this study was to determine the Na, K-ATPase beta subunit isoform subcellular expression patterns in all cell types responsible for microenvironment heterogeneity of GBM using immunohistochemical analysis. All three isoforms, beta1, beta2/AMOG (Adhesion Molecule On Glia) and beta3, were found to be expressed in GBM samples. Generally, beta1 isoform was not expressed by astrocytes, in both primary and secondary GBM, although other cell types (endothelial cells, pericytes, telocytes, macrophages) did express this isoform. beta2/AMOG and beta3 positive expression was observed in the cytoplasm, membrane and nuclear envelope of astrocytes and GFAP (Glial Fibrillary Acidic Protein) negative cells. Interestingly, differences in isoforms expression have been observed between primary and secondary GBM: in secondary GBM, beta2 isoform expression in astrocytes was lower than that observed in primary GBM, while the expression of the beta3 subunit was more intense. These changes in beta subunit isoforms expression in GBM could be related to a different ionic handling, to a different relationship between astrocyte and neuron (beta2/AMOG) and to changes in the moonlighting roles of Na, K-ATPase beta subunits as adaptor proteins and transcription factors. PMID- 29117148 TI - Physical, Structural, Barrier, and Antifungal Characterization of Chitosan-Zein Edible Films with Added Essential Oils. AB - Edible films (EFs) have gained great interest due to their ability to keep foods safe, maintaining their physical and organoleptic properties for a longer time. The aim of this work was to develop EFs based on a chitosan-zein mixture with three different essential oils (EOs) added: anise, orange, and cinnamon, and to characterize them to establish the relationship between their structural and physical properties. The addition of an EO into an EF significantly affected (p < 0.05) the a* (redness/greenness) and b* (yellowness/blueness) values of the film surface. The EFs presented a refractive index between 1.35 and 1.55, and thus are classified as transparent. The physical properties of EFs with an added EO were improved, and films that incorporated the anise EO showed significantly lower water vapor permeability (1.2 +/- 0.1 g mm h-1 m-2 kPa-1) and high hardness (104.3 +/- 3.22 MPa). EFs with an added EO were able to inhibit the growth of Penicillium sp. and Rhizopus sp. to a larger extent than without an EO. Films' structural changes were the result of chemical interactions among amino acid side chains from zein, glucosamine from chitosan, and cinnamaldehyde, anethole, or limonene from the EOs as detected by a Raman analysis. The incorporation of an EO in the EFs' formulation could represent an alternative use as coatings to enhance the shelf life of food products. PMID- 29117150 TI - Coordinating Leader-Follower Supply Chain with Sustainable Green Technology Innovation on Their Fairness Concerns. AB - Sustainable green technology innovation is essential in all the stages of the supply chain development. The members of the supply chain in each stage need to invest in sustainable green technology innovation research and development. However, whether the sustainable green technology innovation investments and profits for all the members are fairness concerned is a critical factor to motivate the supply chain members. Motivated by a real business investigation, in this study, a supply chain model with one supplier and one manufacturer is analyzed. We consider fairness concerns for the supplier and the manufacturer with sustainable green technology innovation development. We derive the optimal results in both with and without fairness concern. The results indicate that fairness concerns can promote and coordinate the supply chain members without advantage inequity averseness, to invest more on their sustainable green technology innovation development. PMID- 29117149 TI - Hospital Smoke-Free Policy: Compliance, Enforcement, and Practices. A Staff Survey in Two Large Public Hospitals in Australia. AB - Background: Smoke-free hospital policies are becoming increasingly common to promote good health and quit attempts among patients who smoke. This study aims to assess: staff perceived enforcement and compliance with smoke-free policy; the current provision of smoking cessation care; and the characteristics of staff most likely to report provision of care to patients. Methods: An online cross sectional survey of medical, nursing, and allied staff from two Australian public hospitals was conducted. Staff report of: patient and staff compliance with smoke free policy; perceived policy enforcement; the provision of the 5As for smoking cessation (Ask, Assess, Advise, Assist, and Arrange follow-up); and the provision of stop-smoking medication are described. Logistic regressions were used to determine respondent characteristics related to the provision of the 5As and stop smoking medication use during hospital admission. Results: A total of 805 respondents participated. Self-reported enforcement of smoke-free policy was low (60.9%), together with compliance for both patients (12.9%) and staff (23.6%). The provision of smoking cessation care was variable, with the delivery of the 5As ranging from 74.7% (ask) to 18.1% (arrange follow-up). Medical staff (odds ratio (OR) = 2.09, CI = 1.13, 3.85, p = 0.018) and full time employees (OR = 2.03, CI = 1.06, 3.89, p = 0.033) were more likely to provide smoking cessation care always/most of the time. Stop-smoking medication provision decreased with increasing age of staff (OR = 0.98, CI = 0.96, 0.99, p = 0.008). Conclusions: Smoke-free policy enforcement and compliance and the provision of smoking cessation care remains low in hospitals. Efforts to improve smoking cessation delivery by clinical staff are warranted. PMID- 29117152 TI - Spatial-Temporal Data Collection with Compressive Sensing in Mobile Sensor Networks. AB - Compressive sensing (CS) provides an energy-efficient paradigm for data gathering in wireless sensor networks (WSNs). However, the existing work on spatial temporal data gathering using compressive sensing only considers either multi-hop relaying based or multiple random walks based approaches. In this paper, we exploit the mobility pattern for spatial-temporal data collection and propose a novel mobile data gathering scheme by employing the Metropolis-Hastings algorithm with delayed acceptance, an improved random walk algorithm for a mobile collector to collect data from a sensing field. The proposed scheme exploits Kronecker compressive sensing (KCS) for spatial-temporal correlation of sensory data by allowing the mobile collector to gather temporal compressive measurements from a small subset of randomly selected nodes along a random routing path. More importantly, from the theoretical perspective we prove that the equivalent sensing matrix constructed from the proposed scheme for spatial-temporal compressible signal can satisfy the property of KCS models. The simulation results demonstrate that the proposed scheme can not only significantly reduce communication cost but also improve recovery accuracy for mobile data gathering compared to the other existing schemes. In particular, we also show that the proposed scheme is robust in unreliable wireless environment under various packet losses. All this indicates that the proposed scheme can be an efficient alternative for data gathering application in WSNs . PMID- 29117151 TI - Changes in Sports Participation across Transition to Retirement: Modification by Migration Background and Acculturation Status. AB - While total physical activity decreases over the life course, sports and leisure time physical activity (LTPA) have shown to increase after transition to retirement. This paper aimed to investigate whether this change in sports participation differs (1) between non-migrant persons (NMP) versus persons with a migrant background (PMB), and (2) by acculturation status. Data was drawn from 16 waves of the German Socio-Economic Panel Study (SOEP) including 2664 NMP and 569 PMB. PMB were grouped according to acculturation status (integrated, assimilated, marginalised, separated), assessed regarding three dimensions (language, social interaction and identification). We applied multilevel logistic regression models, adjusting for sex, retirement age, socioeconomic status, health status and body mass index. Our results show that (1) transition to retirement led to an increase in the sports participation of NMP during the first 5 years and the subsequent 5 years after retirement. Changes in sports participation were modified by migration status: In PMB sports participation increased to a lesser extent than in NMP. (2) While sports participation of integrated PMB was not significantly different from NMP in the preretirement phase, sports participation among integrated PMB increased less after retirement compared with NMP. Marginalized and assimilated PMB did not show consistent sports participation patterns before retirement, but seemingly increased their sports participation less than NMP over the retirement transition. Separated PMB had particularly low levels of sports participation. Considering that LTPA is a key factor for healthy ageing, the increasing gap in levels of sports participation after transition to retirement indicates the need for interventions targeting physical activity of the older migrant population. PMID- 29117153 TI - Radar Constant-Modulus Waveform Optimization for High-Resolution Range Profiling of Stationary Targets. AB - The high-resolution range (HRR) profile is an important target signature in many applications (e.g., automatic target recognition), and the radar HRR profiling performance is highly dependent on radar transmitted waveforms. In this paper, we consider the constant-modulus (CM) waveform optimization problem to improve HRR profiling performance for stationary targets. Firstly, several fundamental bounds regarding the profiling ambiguity, stability, and accuracy are derived. Further investigation reveals that the stability and accuracy of HRR profiling are unified in the white noise case. Aimed at improving the profiling stability and accuracy, we design two types of CM radar waveforms-the arbitrary-phase and QPSK waveforms-through a customized Gaussian randomization method. The performance of LFM waveforms is also discussed. Numerical experiments show that the optimized CM waveforms can dramatically enhance the profiling performance over the unoptimized ones. PMID- 29117155 TI - Therapeutics: Spoilt for choice. PMID- 29117154 TI - BRAFV600E and RET/PTC Promote Proliferation and Migration of Papillary Thyroid Carcinoma Cells In Vitro by Regulating Nuclear Factor-kappaB. AB - BACKGROUND Papillary thyroid carcinoma (PTC) is associated with mutations of BRAFV600E and RET/PTC and high levels of expression of nuclear factor-kappaB (NF kappaB). However, few studies have focused on the association between NF-kappaB expression and mutations in BRAFV600E and RET/PTC, especially regarding PTC cell proliferation and migration. The aim of this in vitro study was to investigate the effect of BRAFV600E or RET/PTC on NF-kappaB expression, cell proliferation and cell migration in four established PTC cell lines. MATERIAL AND METHODS Four cell lines included TPC-1 (BRAFWT/WT), BCPAP (BRAFV600E/V600E), PCCL3, and PTC3-5 (RET/PTC), were grown in culture in vitro with or without suppression of NF kappaB using pyrrolidine dithiocarbamate (PDTC), and cell proliferation, and cell migration were evaluated. RESULTS Expression of the BRAF gene was increased in the BCPAP cell line when compared with the TPC-1 cells. Expression of the RET gene was increased in the PTC3-5 cell line when compared with the PCCL3 cells. In the BCPAP and PTC3-5 cell lines, the relative expression of NF-kappaB protein, including phosphorylated p100/52, phosphorylated p65, phosphorylated IKKa/b, phosphorylated IkappaBalpha, and p65 nuclear translocation were increased compared with the TPC-1 and PCCL3 cells. Proliferation and migration of BCPAP and PTC3-5 cells were increased compared with the TPC-1 and PCCL3 cells. Suppression of NF-kappaB reduced NF-kappaB protein expression and inhibited the proliferation of cells in the TPC-1, BCPAP, PCCL3 and PTC3-5 cell lines, and migration of the BCPAP and PTC3-5 cells. CONCLUSIONS BRAFV600E and RET/PTC and the expression of NF-kappaB promote the proliferation and migration of papillary thyroid carcinoma cells in vitro. PMID- 29117156 TI - Bladder cancer. PMID- 29117157 TI - Bladder cancer: 4 big questions. PMID- 29117158 TI - Theatre: The bladder's tale. PMID- 29117159 TI - Unlocking bladder cancer. PMID- 29117160 TI - Microbiome: A bag of surprises. PMID- 29117161 TI - Diagnostics: A flow of information. PMID- 29117162 TI - Genetics: A clearer view. PMID- 29117163 TI - Egypt: The flatworm's revenge. PMID- 29117164 TI - Q&A: Mechele Leon: Take it away. PMID- 29117165 TI - Perspective: Bridging the gender gap. PMID- 29117166 TI - Neuroscience starts talking. PMID- 29117167 TI - Long-range hypoxia signaling in NAFLD. PMID- 29117168 TI - Stalking new vaccines: Methods that target the stems of viral proteins could put universal vaccines within reach. PMID- 29117169 TI - Corrigendum: Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors. AB - This corrects the article DOI: 10.1038/nm.4219. PMID- 29117170 TI - Can NK cells purge HIV sanctuaries? PMID- 29117171 TI - Accounting for sex in the genome. AB - Genetic association studies of the human genome often omit the X chromosome because of the unique analytical challenges it presents. A concerted effort to undo this exclusion could offer medically relevant insights into basic biology that might otherwise be missed. PMID- 29117172 TI - Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation. AB - This corrects the article DOI: 10.1038/nm.4332. PMID- 29117173 TI - Corrigendum: The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. AB - This corrects the article DOI: 10.1038/nm.4297. PMID- 29117174 TI - Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice. AB - This corrects the article DOI: 10.1038/nm.4385. PMID- 29117175 TI - An epitranscriptomic vulnerability in myeloid malignancies. PMID- 29117176 TI - Macrophages dispose of catecholamines in adipose tissue. PMID- 29117178 TI - Predictable response: Finding optimal drugs and doses using artificial intelligence. PMID- 29117177 TI - Barrier-tissue macrophages: functional adaptation to environmental challenges. AB - Macrophages are found throughout the body, where they have crucial roles in tissue development, homeostasis and remodeling, as well as being sentinels of the innate immune system that can contribute to protective immunity and inflammation. Barrier tissues, such as the intestine, lung, skin and liver, are exposed constantly to the outside world, which places special demands on resident cell populations such as macrophages. Here we review the mounting evidence that although macrophages in different barrier tissues may be derived from distinct progenitors, their highly specific properties are shaped by the local environment, which allows them to adapt precisely to the needs of their anatomical niche. We discuss the properties of macrophages in steady-state barrier tissues, outline the factors that shape their differentiation and behavior and describe how macrophages change during protective immunity and inflammation. PMID- 29117179 TI - A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation. AB - We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation. PMID- 29117180 TI - The additional benefit of residual spraying and insecticide-treated curtains for dengue control over current best practice in Cuba: Evaluation of disease incidence in a cluster randomized trial in a low burden setting with intensive routine control. AB - BACKGROUND: Aedes control interventions are considered the cornerstone of dengue control programmes, but there is scarce evidence on their effect on disease. We set-up a cluster randomized controlled trial in Santiago de Cuba to evaluate the entomological and epidemiological effectiveness of periodical intra- and peri domiciliary residual insecticide (deltamethrin) treatment (RIT) and long lasting insecticide treated curtains (ITC). METHODOLOGY/PRINCIPAL FINDINGS: Sixty three clusters (around 250 households each) were randomly allocated to two intervention (RIT and ITC) and one control arm. Routine Aedes control activities (entomological surveillance, source reduction, selective adulticiding, health education) were applied in the whole study area. The outcome measures were clinical dengue case incidence and immature Aedes infestation. Effectiveness of tools was evaluated using a generalized linear regression model with a negative binomial link function. Despite significant reduction in Aedes indices (Rate Ratio (RR) 0.54 (95%CI 0.32-0.89) in the first month after RIT, the effect faded out over time and dengue incidence was not reduced. Overall, in this setting there was no protective effect of RIT or ITC over routine in the 17months intervention period, with for house index RR of 1.16 (95%CI 0.96-1.40) and 1.25 (95%CI 1.03-1.50) and for dengue incidence RR of 1.43 (95%CI 1.08-1.90) and 0.96 (95%CI 0.72-1.28) respectively. The monthly dengue incidence rate (IR) at cluster level was best explained by epidemic periods (Incidence Rate Ratio (IRR) 5.50 (95%CI 4.14-7.31)), the IR in bordering houseblocks (IRR 1.03 (95%CI 1.02-1.04)) and the IR pre-intervention (IRR 1.02 (95%CI 1.00-1.04)). CONCLUSIONS: Adding RIT to an intensive routine Aedes control programme has a transient effect on the already moderate low entomological infestation levels, while ITC did not have any effect. For both interventions, we didn't evidence impact on disease incidence. Further studies are needed to evaluate impact in settings with high Aedes infestation and arbovirus case load. PMID- 29117181 TI - Pancreatic uptake and radiation dosimetry of 6-[18F]fluoro-L-DOPA from PET imaging studies in infants with congenital hyperinsulinism. AB - METHODS: After injecting 25.6 +/- 8.8 MBq (0.7 +/- 0.2 mCi) of 18F-Fluoro-L-DOPA intravenously, three static PET scans were acquired at 20, 30, and 40 min post injection in 3-D mode on 10 patients (6 male, 4 female) with congenital hyperinsulinism. Regions of interest (ROIs) were drawn over several organs visible in the reconstructed PET/CT images and time activity curves (TACs) were generated. Residence times were calculated using the TAC data. The radiation absorbed dose for the whole body was calculated by entering the residence times in the OLINDA/EXM 1.0 software. RESULTS: The mean residence times for the 18F Fluoro-L-DOPA in the liver, lungs, kidneys, muscles, and pancreas were 11.54 +/- 2.84, 1.25 +/- 0.38, 4.65 +/- 0.97, 17.13 +/- 2.62, and 0.89 +/- 0.34 min, respectively. The mean effective dose equivalent for 18F-Fluoro-L-DOPA was 0.40 +/- 0.04 mSv/MBq. The CT scan used for attenuation correction delivered an additional radiation dose of 5.7 mSv. The organs receiving the highest radiation absorbed dose from 18F-Fluoro-L-DOPA were the urinary bladder wall (2.76 +/- 0.95 mGy/MBq), pancreas (0.87 +/- 0.30 mGy/MBq), liver (0.34 +/- 0.07 mGy/MBq), and kidneys (0.61 +/- 0.11 mGy/MBq). The renal system was the primary route for the radioactivity clearance and excretion. CONCLUSIONS: The estimated radiation dose burden from 18F-Fluoro-L-DOPA is relatively modest to newborns. PMID- 29117182 TI - Structural and functional analysis of coral Hypoxia Inducible Factor. AB - Tissues of symbiotic Cnidarians are exposed to wide, rapid and daily variations of oxygen concentration. Indeed, during daytime, intracellular O2 concentration increases due to symbiont photosynthesis, while during night, respiration of both host cells and symbionts leads to intra-tissue hypoxia. The Hypoxia Inducible Factor 1 (HIF-1) is a heterodimeric transcription factor used for maintenance of oxygen homeostasis and adaptation to hypoxia. Here, we carried out a mechanistic study of the response to variations of O2 concentrations of the coral model Stylophora pistillata. In silico analysis showed that homologs of HIF-1 alpha (SpiHIF-1alpha) and HIF-1beta (SpiHIF-1beta) exist in coral. A specific SpiHIF-1 DNA binding on mammalian Hypoxia Response Element (HRE) sequences was shown in extracts from coral exposed to dark conditions. Then, we cloned the coral HIF 1alpha and beta genes and determined their expression and transcriptional activity. Although HIF-1alpha has an incomplete Oxygen-dependent Degradation Domain (ODD) relative to its human homolog, its protein level is increased under hypoxia when tested in mammalian cells. Moreover, co-transfection of SpiHIF 1alpha and beta in mammalian cells stimulated an artificial promoter containing HRE only in hypoxic conditions. This study shows the strong conservation of molecular mechanisms involved in adaptation to O2 concentration between Cnidarians and Mammals whose ancestors diverged about 1,200-1,500 million years ago. PMID- 29117183 TI - Capacity of tTreg generation is not impaired in the atrophied thymus. AB - Postnatal thymic epithelial cell (TEC) homeostatic defect- or natural aging induced thymic atrophy results in a decline in central T-cell tolerance establishment, which is constituted by thymocyte negative selection and cluster of differentiation (CD) 4+ thymic regulatory T (tTreg) cell generation. Emerging evidence shows this decline mainly results from defects in negative selection, but there is insufficient evidence regarding whether tTreg cell generation is also impaired. We mechanistically studied tTreg cell generation in the atrophied thymus by utilizing both postnatal TEC-defective (resulting from FoxN1-floxed conditional knockout [cKO]) and naturally aged mouse models. We found that the capacity of tTreg cell generation was not impaired compared to CD4+ thymic conventional T cells, suggesting thymic atrophy positively influences tTreg cell generation. This is potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary TECs, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age related diseases could take place. PMID- 29117184 TI - From Songlines to genomes: Prehistoric assisted migration of a rain forest tree by Australian Aboriginal people. AB - BACKGROUND: Prehistoric human activities have contributed to the dispersal of many culturally important plants. The study of these traditional interactions can alter the way we perceive the natural distribution and dynamics of species and communities. Comprehensive research on native crops combining evolutionary and anthropological data is revealing how ancient human populations influenced their distribution. Although traditional diets also included a suite of non-cultivated plants that in some cases necessitated the development of culturally important technical advances such as the treatment of toxic seed, empirical evidence for their deliberate dispersal by prehistoric peoples remains limited. Here we integrate historic and biocultural research involving Aboriginal people, with chloroplast and nuclear genomic data to demonstrate Aboriginal-mediated dispersal of a non-cultivated rainforest tree. RESULTS: We assembled new anthropological evidence of use and deliberate dispersal of Castanospermum australe (Fabaceae), a non-cultivated culturally important riparian tree that produces toxic but highly nutritious water-dispersed seed. We validated cultural evidence of recent human mediated dispersal by revealing genomic homogeneity across extensively dissected habitat, multiple catchments and uneven topography in the southern range of this species. We excluded the potential contribution of other dispersal mechanisms based on the absence of suitable vectors and current distributional patterns at higher elevations and away from water courses, and by analyzing a comparative sample from northern Australia. CONCLUSIONS: Innovative studies integrating evolutionary and anthropological data will continue to reveal the unexpected impact that prehistoric people have had on current vegetation patterns. A better understanding of how traditional practices shaped species' distribution and assembly will directly inform cultural heritage management strategies, challenge "natural" species distribution assumptions, and provide innovative baseline data for pro-active biodiversity management. PMID- 29117185 TI - Engaging with change: Information and communication technology professionals' perspectives on change in the context of the 'Brexit' vote. AB - BACKGROUND: Information and Communication Technology (ICT) has been a key agent of change in the 21st century. Given the role of ICT in changing society this research sought to explore the responses and attitudes to change from ICT professionals and ICT academics in dealing with the potentially far reaching political challenge triggered by the UK's 2016 European Union Referendum and its decision to leave the European Union (referred to as Brexit). Whilst the vote was a UK based decision its ramifications have global implications and as such the research was not confined to the UK. METHODS AND FINDINGS: Data was collected through a survey launched on the first working day after the Brexit referendum vote to leave the EU and kept open for four weeks. The survey contained qualitative and quantitative questions. It sought to understand the opportunities and threats that would exist post-Brexit for ICT professionals and academics triggered by the decision. The research captured a complex rich picture on ICT professionals' responses to the potential challenge of change triggered by the Brexit vote. Immediately after the Brexit decision the research reveals uncertainties amongst ICT professionals regarding what the decision would mean, with just under half of the participants not identifying any opportunities or threats. For those who did, threats outweighed opportunities by just more than double. Whilst understanding the global possibilities and dangers, participants saw their position from national and organizational perspectives. The highest frequency coded threats related to areas outside the participants' control and the highest frequency opportunities related to areas where there was the potential for ICT interventions. This survey is part of longitudinal piece of research. Using the same methodological approach two further surveys are planned. The second survey will be one year after Article 50 was triggered on 29 March 2017. The final survey will be one year after the UK exit from the EU, assuming this occurs. PMID- 29117186 TI - Human papillomavirus type 16 E6 and NFX1-123 mislocalize immune signaling proteins and downregulate immune gene expression in keratinocytes. AB - Human papillomavirus (HPV) is the most prevalent sexually transmitted infection, affecting an estimated 11% of the world's population. The high-risk HPV types (HR HPV) account for approximately 5% of the global burden of cancer and thus cause high morbidity and mortality. Although it is known that persistent infection with HR HPV is the greatest risk factor for developing HPV-associated cancer, and that the HPV early proteins E6 and E7 dysregulate immune detection by its host cells, the mechanisms of immune evasion by HR HPV are not well understood. Previous work in the laboratory identified the endogenous cytoplasmic host protein NFX1-123 as a binding partner of the HR HPV type 16 oncoprotein E6 (16E6). Together NFX1-123 and 16E6 affect cellular growth, differentiation, and immortalization genes and pathways. In a whole genome microarray, human foreskin keratinocytes (HFKs) stably expressing 16E6 and overexpressing NFX1-123 showed a diverse set of innate immune genes downregulated two-fold or more when compared to 16E6 cells with endogenous NFX1-123. We demonstrated that 16E6 and NFX1-123 decreased expression of pro-inflammatory cytokines and interferon-stimulated genes (ISGs) in 16E6 HFKs at the mRNA and protein level. Knock down of NFX1-123 in 16E6 HFKs resulted in a derepression of innate immune genes, pointing to the requirement of NFX1-123 for immune regulation in the context of 16E6. Studies using immunofluorescent microscopy revealed that 16E6 and NFX1-123 disturbed the normal localization of signaling proteins involved in initiating the immune response. This study identifies NFX1-123 as a critical host protein partner through which 16E6 is able to subvert the immune response and in turn permit a long-lived HR HPV infection. PMID- 29117187 TI - The green tea modulates large intestinal microbiome and exo/endogenous metabolome altered through chronic UVB-exposure. AB - The attenuating effects of green tea supplements (GTS) against the ultraviolet (UV) radiation induced skin damages are distinguished. However, the concomitant effects of GTS on the large intestinal microbiomes and associated metabolomes are largely unclear. Herein, we performed an integrated microbiome-metabolome analysis to uncover the esoteric links between gut microbiome and exo/endogenous metabolome maneuvered in the large intestine of UVB-exposed mice subjected to dietary GTS. In UVB-exposed mice groups (UVB), class Bacilli and order Bifidobacteriales were observed as discriminant taxa with decreased lysophospholipid levels compared to the unexposed mice groups subjected to normal diet (NOR). Conversely, in GTS fed UVB-exposed mice (U+GTS), the gut-microbiome diversity was greatly enhanced with enrichment in the classes, Clostridia and Erysipelotrichia, as well as genera, Allobaculum and Lachnoclostridium. Additionally, the gut endogenous metabolomes changed with an increase in amino acids, fatty acids, lipids, and bile acids contents coupled with a decrease in nucleobases and carbohydrate levels. The altered metabolomes exhibited high correlations with GTS enriched intestinal microflora. Intriguingly, the various conjugates of green tea catechins viz., sulfated, glucuronided, and methylated ones including their exogenous derivatives were detected from large intestinal contents and liver samples. Hence, we conjecture that the metabolic conversions for the molecular components in GTS strongly influenced the gut micro-environment in UVB-exposed mice groups, ergo modulate their gut-microbiome as well as exo/endogenous metabolomes. PMID- 29117188 TI - Potential of golden potatoes to improve vitamin A and vitamin E status in developing countries. AB - Potato (Solanum tuberosum L.) is the third most widely consumed plant food by humans. Its tubers are rich in starch and vitamin C, but have low or null levels of essential nutrients such as provitamin A and vitamin E. Transformation of potato with a bacterial mini-pathway for beta-carotene in a tuber-specific manner results in a "golden" potato (GP) tuber phenotype resulting from accumulation of provitamin A carotenoids (alpha- and beta-carotene) and xanthophylls. Here, we investigated the bioaccessibility of carotenoids and vitamin E as alpha tocopherol (alphaTC) in boiled wild type and golden tubers using in vitro digestion. Golden tubers contained up to 91 MUg provitamin A carotenes (PAC)/g D, increased levels of xanthophylls, phytoene and phytofluene, as well as up to 78 MUg vitamin E/g DW. Cubes from wild type and GP tubers were boiled and subjected to simulated digestion to estimate bioaccessibility of carotenoids and alphaTC. Retention in boiled GPs exceeded 80% for beta-carotene (betaC), alpha-carotene (alphaC), lutein, phytoene +/- and alphaTC, but less than 50% for phytofluene. The efficiency of partitioning of total betaC, alphaC, E-lutein, phytoene, phytofluene and alphaTC in the mixed micelle fraction during small intestinal digestion was influenced by genotype, tuber content and hydrophobicity. Apical uptake of the compounds that partitioned in mixed micelles by monolayers of human intestinal Caco-2 cells during incubation for 4h was 14-20% for provitamin A and xanthophylls, 43-45% for phytoene, 23-27% for phytofluene, and 53% for alphaTC. These results suggest that a 150 g serving of boiled golden potatoes has the potential to contribute 42% and 23% of the daily requirement of retinol activity equivalents (RAE), as well as 34 and 17% of the daily vitamin E requirement for children and women of reproductive age, respectively. PMID- 29117190 TI - Class attendance, peer similarity, and academic performance in a large field study. AB - Identifying the factors that determine academic performance is an essential part of educational research. Existing research indicates that class attendance is a useful predictor of subsequent course achievements. The majority of the literature is, however, based on surveys and self-reports, methods which have well-known systematic biases that lead to limitations on conclusions and generalizability as well as being costly to implement. Here we propose a novel method for measuring class attendance that overcomes these limitations by using location and bluetooth data collected from smartphone sensors. Based on measured attendance data of nearly 1,000 undergraduate students, we demonstrate that early and consistent class attendance strongly correlates with academic performance. In addition, our novel dataset allows us to determine that attendance among social peers was substantially correlated (>0.5), suggesting either an important peer effect or homophily with respect to attendance. PMID- 29117189 TI - Cardiac cycle-synchronized electrical muscle stimulator for lower limb training with the potential to reduce the heart's pumping workload. AB - BACKGROUND: The lower limb muscle may play an important role in decreasing the heart's pumping workload. Aging and inactivity cause atrophy and weakness of the muscle, leading to a loss of the heart-assisting role. An electrical lower limb muscle stimulator can prevent atrophy and weakness more effectively than conventional resistance training; however, it has been reported to increase the heart's pumping workload in some situations. Therefore, more effective tools should be developed. METHODS: We newly developed a cardiac cycle-synchronized electrical lower limb muscle stimulator by combining a commercially available electrocardiogram monitor and belt electrode skeletal muscle electrical stimulator, making it possible to achieve strong and wide but not painful muscle contractions. Then, we tested the stimulator in 11 healthy volunteers to determine whether the special equipment enabled lower limb muscle training without harming the hemodynamics using plethysmography and a percutaneous cardiac output analyzer. RESULTS: In 9 of 11 subjects, the stimulator generated diastolic augmentation waves on the dicrotic notches and end-diastolic pressure reduction waves on the plethysmogram waveforms of the brachial artery, showing analogous waveforms in the intra-aortic balloon pumping heart-assisting therapy. The heart rate, stroke volume, and cardiac output significantly increased during the stimulation. There was no change in the systolic or diastolic blood pressure during the stimulation. CONCLUSION: Cardiac cycle-synchronized electrical muscle stimulation for the lower limbs may enable muscle training without harmfully influencing the hemodynamics and with a potential to reduce the heart's pumping workload, suggesting a promising tool for effectively treating both locomotor and cardiovascular disorders. PMID- 29117191 TI - Detecting conservation benefits of marine reserves on remote reefs of the northern GBR. AB - The Great Barrier Reef Marine Park (GBRMP) is the largest network of marine reserves in the world, yet little is known of the efficacy of no-fishing zones in the relatively lightly-exploited remote parts of the system (i.e., northern regions). Here, we find that the detection of reserve effects is challenging and that heterogeneity in benthic habitat composition, specifically branching coral cover, is one of the strongest driving forces of fish assemblages. As expected, the biomass of targeted fish species was generally greater (up to 5-fold) in no take zones than in fished zones, but we found no differences between the two forms of no-take zone: 'no-take' versus 'no-entry'. Strong effects of zoning were detected in the remote Far-North inshore reefs and more central outer reefs, but surprisingly fishing effects were absent in the less remote southern locations. Moreover, the biomass of highly targeted species was nearly 2-fold greater in fished areas of the Far-North than in any reserve (no-take or no-entry) further south. Despite high spatial variability in fish biomass, our results suggest that fishing pressure is greater in southern areas and that poaching within reserves may be common. Our results also suggest that fishers 'fish the line' as stock sizes in exploited areas decreased near larger no-take zones. Interestingly, an analysis of zoning effects on small, non-targeted fishes appeared to suggest a top-down effect from mesopredators, but was instead explained by variability in benthic composition. Thus, we demonstrate the importance of including appropriate covariates when testing for evidence of trophic cascades and reserve successes or failures. PMID- 29117192 TI - Can you catch Ebola from a stork bite? Inductive reasoning influences generalization of perceived zoonosis risk. AB - Emerging zoonoses are a prominent global health threat. Human beliefs are central to drivers of emerging zoonoses, yet little is known about how people make inferences about risk in such scenarios. We present an inductive account of zoonosis risk perception, suggesting that beliefs about the range of animals able to transmit diseases to each other influence how people generalize risks to other animals and health behaviors. Consistent with our account, in Study 1, we find that participants who endorse higher likelihoods of cross-species disease transmission have stronger intentions to report animal bites. In Study 2, using real-world descriptions of Ebola virus from the WHO and CDC, we find that communications conveying a broader range of animals as susceptible to the virus increase intentions to report animal bites and decrease perceived safety of wild game meat. These results suggest that inductive reasoning principles may be harnessed to modulate zoonosis risk perception and combat emerging infectious diseases. PMID- 29117193 TI - Immunohistochemical analysis of PDK1, PHD3 and HIF-1alpha expression defines the hypoxic status of neuroblastoma tumors. AB - Neuroblastoma (NB) is the most common solid tumor during infancy and the first cause of death among the preschool age diseases. The availability of several NB genomic profiles improves the prognostic ability, but the outcome prediction for this pathology remains imperfect. We previously produced a novel prognostic gene signature based on the response of NB cells to hypoxia, a condition of tumor microenvironment strictly connected with cancer aggressiveness. Here we attempted to further define the expression of hypoxia-modulated specific genes, looking at their protein level in NB specimens, considering in particular the hypoxia inducible factor-1alpha (HIF-1alpha), the mitochondrial pyruvate dehydrogenase kinase 1 (PDK1), and the HIF-prolyl hydroxylase domain 3 (PHD3). The evaluation of expression was performed by Western blot and immunocytochemistry on NB cell lines and by immunohistochemistry on tumor specimens. Stimulation of both HIF 1alpha and PDK1 and inhibition of PHD3 expression were observed in NB cell lines cultured under prolonged hypoxic conditions as well as in most of the tumors with poor outcome. Our results indicate that the immunohistochemistry analysis of the protein expression of PDK1, PHD3, and HIF-1alpha defines the hypoxic status of NB tumors and can be used as a simple and relevant tool to stratify high-risk patients. PMID- 29117194 TI - A pre-operative predictive score to evaluate the feasibility of complete cytoreductive surgery in patients with epithelial ovarian cancer. AB - OBJECTIVE: Postoperative residual tumor is the major prognostic factor in ovarian cancer. The feasibility of complete cytoreductive surgery is assessed by laparoscopy. Our goal was to develop a predictive score prior to laparoscopy to evaluate the feasibility of complete cytoreductive surgery in patients with epithelial ovarian cancer. METHODS: We developed a score to predict incomplete cytoreductive surgery by performing multiple logistic regressions after bootstrap procedures on data from a retrospective cohort of 247 patients with advanced ovarian cancer. This score was validated on a different population of 45 patients with ovarian cancer. RESULTS: Four criteria were independently associated with incomplete cytoreduction, confirmed by surgery: BMI >= 30 kg/m2 (adjusted odds ratio [aOR], 3.07; 95% confidence interval [95% CI], 1.0-9.6), CA125 > 100 IU/L (aOR, 3.99; 95% CI, 1.6-10.1), diaphragmatic and/or omental carcinomatosis by CT Scan (aOR, 5.82; 95% CI, 2.6-13.1), and positive parenchymal metastases by PET/CT (aOR, 3.59; 95% CI, 1.0-12.8). The 100-point score was based on these criteria. The area-under-the-curve of the score was 0.79 (95% CI, 0.73-0.86). In the validation group, no patient ranked in the high-risk group of incomplete cytoreductive surgery had a complete upfront cytoreductive surgery (95% CI 0-16). Three of 29 patients for whom primary complete cytoreduction was not possible were classified in the group at low risk of incomplete cytoreductive surgery (12%; 95% CI 4-27). CONCLUSION: This pre-operative score may be useful for distinguishing which patients may have complete cytoreductive surgery from those who will receive neoadjuvant chemotherapy, while avoiding unnecessary laparoscopy. PMID- 29117195 TI - Biological and phylogenetic characteristics of West African lineages of West Nile virus. AB - The West Nile virus (WNV), isolated in 1937, is an arbovirus (arthropod-borne virus) that infects thousands of people each year. Despite its burden on global health, little is known about the virus' biological and evolutionary dynamics. As several lineages are endemic in West Africa, we obtained the complete polyprotein sequence from three isolates from the early 1990s, each representing a different lineage. We then investigated differences in growth behavior and pathogenicity for four distinct West African lineages in arthropod (Ap61) and primate (Vero) cell lines, and in mice. We found that genetic differences, as well as viral-host interactions, could play a role in the biological properties in different WNV isolates in vitro, such as: (i) genome replication, (ii) protein translation, (iii) particle release, and (iv) virulence. Our findings demonstrate the endemic diversity of West African WNV strains and support future investigations into (i) the nature of WNV emergence, (ii) neurological tropism, and (iii) host adaptation. PMID- 29117197 TI - New records of the dolphin Albertocetus meffordorum (Odontoceti: Xenorophidae) from the lower Oligocene of South Carolina: Encephalization, sensory anatomy, postcranial morphology, and ontogeny of early odontocetes. AB - We report five new specimens of xenorophid dolphins from North and South Carolina. Four of the specimens represent the xenorophid Albertocetus meffordorum, previously only known from the holotype skull. The other is a fragmentary petrosal from the upper Oligocene Belgrade Formation that we refer to Echovenator sp, indicating at least two xenorophids from that unit. Two of the Albertocetus meffordorum specimens are from the lower Oligocene Ashley Formation: 1) a partial skeleton with neurocranium, fragmentary mandible, ribs, vertebrae, and chevrons, and 2) an isolated braincase. The partial vertebral column indicates that Albertocetus retained the ancestral morphology and locomotory capabilities of basilosaurid archaeocetes, toothed mysticetes, and physeteroids, and caudal vertebrae that are as wide as tall suggest that the caudal peduncle, which occurs in all extant Cetacea, was either wide or lacking. CT data from the isolated braincase were used to generate a digital endocast of the cranial cavity. The estimated EQ of this specimen is relatively high for an Oligocene odontocete, and other aspects of the brain, such as its anteroposterior length and relative size of the temporal lobe, are intermediate in morphology between those of extant cetaceans and terrestrial artiodactyls. Ethmoturbinals are also preserved, and are similar in morphology and number to those described for the Miocene odontocete Squalodon. These fossils extend the temporal range of Albertocetus meffordorum into the early Oligocene, its geographic range into South Carolina, and expand our paleobiological understanding of the Xenorophidae. PMID- 29117196 TI - Validity of a minimally invasive autopsy for cause of death determination in maternal deaths in Mozambique: An observational study. AB - BACKGROUND: Despite global health efforts to reduce maternal mortality, rates continue to be unacceptably high in large parts of the world. Feasible, acceptable, and accurate postmortem sampling methods could provide the necessary evidence to improve the understanding of the real causes of maternal mortality, guiding the design of interventions to reduce this burden. METHODS AND FINDINGS: The validity of a minimally invasive autopsy (MIA) method in determining the cause of death was assessed in an observational study in 57 maternal deaths by comparing the results of the MIA with those of the gold standard (complete diagnostic autopsy [CDA], which includes any available clinical information). Concordance between the MIA and the gold standard diagnostic categories was assessed by the kappa statistic, and the sensitivity, specificity, positive and negative predictive values and their 95% confidence intervals (95% CI) to identify the categories of diagnoses were estimated. The main limitation of the study is that both the MIA and the CDA include some degree of subjective interpretation in the attribution of cause of death. A cause of death was identified in the CDA in 98% (56/57) of cases, with indirect obstetric conditions accounting for 32 (56%) deaths and direct obstetric complications for 24 (42%) deaths. Nonobstetric infectious diseases (22/32, 69%) and obstetric hemorrhage (13/24, 54%) were the most common causes of death among indirect and direct obstetric conditions, respectively. Thirty-six (63%) women were HIV positive, and HIV-related conditions accounted for 16 (28%) of all deaths. Cerebral malaria caused 4 (7%) deaths. The MIA identified a cause of death in 86% of women. The overall concordance of the MIA with the CDA was moderate (kappa = 0.48, 95% CI: 0.31-0.66). Both methods agreed in 68% of the diagnostic categories and the agreement was higher for indirect (91%) than for direct obstetric causes (38%). All HIV infections and cerebral malaria cases were identified in the MIA. The main limitation of the technique is its relatively low performance for identifying obstetric causes of death in the absence of clinical information. CONCLUSIONS: The MIA procedure could be a valuable tool to determine the causes of maternal death, especially for indirect obstetric conditions, most of which are infectious diseases. The information provided by the MIA could help to prioritize interventions to reduce maternal mortality and to monitor progress towards achieving global health targets. PMID- 29117198 TI - Mining author relationship in scholarly networks based on tripartite citation analysis. AB - Following scholars in Scientometrics as examples, we develop five author relationship networks, namely, co-authorship, author co-citation (AC), author bibliographic coupling (ABC), author direct citation (ADC), and author keyword coupling (AKC). The time frame of data sets is divided into two periods: before 2011 (i.e., T1) and after 2011 (i.e., T2). Through quadratic assignment procedure analysis, we found that some authors have ABC or AC relationships (i.e., potential communication relationship, PCR) but do not have actual collaborations or direct citations (i.e., actual communication relationship, ACR) among them. In addition, we noticed that PCR and AKC are highly correlated and that the old PCR and the new ACR are correlated and consistent. Such facts indicate that PCR tends to produce academic exchanges based on similar themes, and ABC bears more advantages in predicting potential relations. Based on tripartite citation analysis, including AC, ABC, and ADC, we also present an author-relation mining process. Such process can be used to detect deep and potential author relationships. We analyze the prediction capacity by comparing between the T1 and T2 periods, which demonstrate that relation mining can be complementary in identifying authors based on similar themes and discovering more potential collaborations and academic communities. PMID- 29117199 TI - Variation in shade-induced flowering in Arabidopsis thaliana results from FLOWERING LOCUS T allelic variation. AB - Plants have evolved developmental mechanisms to ensure reproduction when in sub optimal local environments. The shade-avoidance syndrome is one such mechanism that causes plants to elongate and accelerate flowering. Plants sense shade via the decreased red:far-red (R:FR) ratio that occurs in shade. We explored natural variation in flowering behavior caused by a decrease in the R:FR ratio of Arabidopsis thaliana accessions. A survey of accessions revealed that most exhibit a vigorous rapid-flowering response in a FR-enriched environment. However, a subset of accessions appeared to be compromised in the accelerated flowering component of the shade-avoidance response. The genetic basis of the muted response to FR enrichment was studied in three accessions (Fl-1, Hau-0, and Mir-0). For all three accessions, the reduced FR flowering-time effect mapped to the FLOWERING LOCUS T (FT) region, and the FT alleles from these accessions are expressed at a lower level in FR-enriched light compared to alleles from accessions that respond robustly to FR enrichment. In the Mir-0 accession, a second genomic region, which includes CONSTANTS (CO), also influenced flowering in FR-enriched conditions. We have demonstrated that variation in the degree of precocious flowering in shaded conditions (low R:FR ratio) results from allelic variation at FT. PMID- 29117200 TI - Feasibility of including patients with migration background in a structured heart failure management programme: A prospective case-control study exemplarily on Turkish migrants. AB - AIMS: Structured management programmes deliver optimized care in heart failure patients and improve outcome. We examined the feasibility of including patients with migration background speaking little or no German in a heart failure management programme. METHODS AND RESULTS: After adaption of script material and staff to Turkish language we aimed to recruit 300 Turkish and 300 German (control group) patients within 18 months using the operational basis of a local heart failure management programme for screening, contact and inclusion. Of 488 and 1,055 eligible Turkish and German patients identified through screening, 165 Turkish (34%) and 335 German (32%) patients consented on participation (p = 0.46). General practitioners contributed significantly more of the Turkish (84%) than of the German patients (16%, p<0.001). Contact attempts by programme staff were significantly less successful in Turkish (52%) than in German patients (60%, p = 0.005) due to significantly higher rate of missing phone numbers (36% vs 25%), invalid address data (28% vs 7%) and being unreachable by phone more frequently (39% vs 26%, all p<0.001). Consent rate was significantly higher in successfully contacted Turkish (63%) compared to German patients (50%, p<0.001). CONCLUSION: The inclusion of Turkish minority patients into a heart failure management programme is feasible with higher consent rate than in Germans. However, effort is high due to inherent logistic adaptions and barriers in identification and contacting of patients. TRIAL REGISTRATION: DRKS00007780. PMID- 29117202 TI - Oil palm monoculture induces drastic erosion of an Amazonian forest mammal fauna. AB - Oil palm monoculture comprises one of the most financially attractive land-use options in tropical forests, but cropland suitability overlaps the distribution of many highly threatened vertebrate species. We investigated how forest mammals respond to a landscape mosaic, including mature oil palm plantations and primary forest patches in Eastern Amazonia. Using both line-transect censuses (LTC) and camera-trapping (CT), we quantified the general patterns of mammal community structure and attempted to identify both species life-history traits and the environmental and spatial covariates that govern species intolerance to oil palm monoculture. Considering mammal species richness, abundance, and species composition, oil palm plantations were consistently depauperate compared to the adjacent primary forest, but responses differed between functional groups. The degree of forest habitat dependency was a leading trait, determining compositional dissimilarities across habitats. Considering both the LTC and CT data, distance from the forest-plantation interface had a significant effect on mammal assemblages within each habitat type. Approximately 87% of all species detected within oil palm were never farther than 1300 m from the forest edge. Our study clearly reinforces the notion that conventional oil palm plantations are extremely hostile to native tropical forest biodiversity, which does not bode well given prospects for oil palm expansion in both aging and new Amazonian deforestation frontiers. PMID- 29117201 TI - Whole exome sequencing in thrombophilic pedigrees to identify genetic risk factors for venous thromboembolism. AB - BACKGROUND: Family studies have shown a strong heritability component for venous thromboembolism (VTE), but established genetic risk factors are present in only half of VTE patients. AIM: To identify genetic risk factors in two large families with unexplained hereditary VTE. METHODS: We performed whole exome sequencing in 10 affected relatives of two unrelated families with an unexplained tendency for VTE. We prioritized variants shared by all affected relatives from both families, and evaluated these in the remaining affected and unaffected individuals. We prioritized variants based on 3 different filter strategies: variants within candidate genes, rare variants across the exome, and SNPs present in patients with familial VTE and with low frequency in the general population. We used whole exome sequencing data available from 96 unrelated VTE cases with a positive family history of VTE from an affected sib study (the GIFT study) to identify additional carriers and compared the risk-allele frequencies with the general population. Variants found in only one individual were also retained for further analysis. Finally, we assessed the association of these variants with VTE in a population-based case-control study (the MEGA study) with 4,291 cases and 4,866 controls. RESULTS: Six variants remained as putative disease-risk candidates. These variants are located in 6 genes spread among 3 different loci: 2p21 (PLEKHH2 NM_172069:c.3105T>C, LRPPRC rs372371276, SRBD1 rs34959371), 5q35.2 (UNC5A NM_133369.2:c.1869+23C>A), and 17q25.1 (GPRC5C rs142232982, RAB37 rs556450784). In GIFT, additional carriers were identified only for the variants located in the 2p21 locus. In MEGA, additional carriers for several of these variants were identified in both cases and controls, without a difference in prevalence; no carrier of the UNC5A variant was present. CONCLUSION: Despite sequencing of several individuals from two thrombophilic families resulting in 6 candidate variants, we were unable to confirm their relevance as novel thrombophilic defects. PMID- 29117203 TI - Using functional data analysis to understand daily activity levels and patterns in primary school-aged children: Cross-sectional analysis of a UK-wide study. AB - BACKGROUND: Temporal characterisation of physical activity in children is required for effective strategies to increase physical activity (PA). Evidence regarding determinants of physical activity in childhood and their time-dependent patterns remain inconclusive. We used functional data analysis (FDA) to model temporal profiles of daily activity, measured objectively using accelerometers, to identify diurnal and seasonal PA patterns in a nationally representative sample of primary school-aged UK children. We hypothesised that PA levels would be lower in girls than boys at play times and after school, higher in children participating in social forms of exercise (such as sport or play), and lower among those not walking to school. METHODS: Children participating in the UK-wide Millennium Cohort Study wore an Actigraph GT1M accelerometer for seven consecutive days during waking hours. We modelled 6,497 daily PA profiles from singleton children (3,176 boys; mean age: 7.5 years) by means of splines, and used functional analysis of variance to examine the cross-sectional relation of time and place of measurement, demographic and behavioural characteristics to smoothed PA profiles. RESULTS: Diurnal and time-specific patterns of activity showed significant variation by sex, ethnicity, UK country and season of measurement; girls were markedly less active than boys during school break times than boys, and children of Indian ethnicity were significantly less active during school hours (9:30-12:00). Social activities such as sport clubs, playing with friends were associated with higher level of PA in afternoon (15:00-17:30) and early evenings (17:30-19:30). Lower PA levels between 8:30-9:30 and 17:30-19:30 were associated with mode of travel to and from school, and number of cars in regular use in the household. CONCLUSION: Diminished PA in primary school aged children is temporally patterned and related to modifiable behavioural factors. FDA can be used to inform and evaluate public health policies to promote childhood PA. PMID- 29117204 TI - Prevalence of binary toxin positive Clostridium difficile in diarrhoeal humans in the absence of epidemic ribotype 027. AB - Virulence of Clostridium difficile is primarily attributed to the large clostridial toxins A and B while the role of binary toxin (CDT) remains unclear. The prevalence of human strains of C. difficile possessing only CDT genes (A-B CDT+) is generally low (< 5%), however, this genotype is commonly found in neonatal livestock both in Australia and elsewhere. Zoonotic transmission of C. difficile has been suggested previously. Most human diagnostic tests will not detect A-B-CDT+ strains of C. difficile because they focus on detection of toxin A and/or B. We performed a prospective investigation into the prevalence and genetic characteristics of A-B-CDT+ C. difficile in symptomatic humans. All glutamate dehydrogenase or toxin B gene positive faecal specimens from symptomatic inpatients over 30 days (n = 43) were cultured by enrichment, and C. difficile PCR ribotypes (RTs) and toxin gene profiles determined. From 39 culture positive specimens, 43 C. difficile isolates were recovered, including two A-B CDT+ isolates. This corresponded to an A-B-CDT+ prevalence of 2/35 (5.7%) isolates possessing at least one toxin, 2/10 (20%) A-B- isolates, 2/3 CDT+ isolates and 1/28 (3.6%) presumed true CDI cases. No link to Australian livestock associated C. difficile was found. Neither A-B-CDT+ isolate was the predominant A B-CDT+ strain found in Australia, RT 033, nor did they belong to toxinotype XI. Previous reports infrequently describe A-B-CDT+ C. difficile in patients and strain collections but the prevalence of human A-B-CDT+ C. difficile is rarely investigated. This study highlights the occurrence of A-B-CDT+ strains of C. difficile in symptomatic patients, warranting further investigations of its role in human infection. PMID- 29117206 TI - Cannabis, alcohol and fatal road accidents. AB - INTRODUCTION: This research aims to estimate the relative risks of responsibility for a fatal accident linked to driving under the influence of cannabis or alcohol, the prevalence of these influences among drivers and the corresponding attributable risk ratios. A secondary goal is to estimate the same items for three other groups of illicit drugs (amphetamines, cocaine and opiates), and to compare the results to a similar study carried out in France between 2001 and 2003. METHODOLOGY: Police procedures for fatal accidents in Metropolitan France during 2011 were analyzed and 300 characteristics encoded to provide a database of 4,059 drivers. Information on alcohol and four groups of illicit drugs derived from tests for positivity and potential confirmation through blood analysis. The study compares drivers responsible for causing the accident, that is to say having directly contributed to its occurrence, to drivers involved in an accident for which they were not responsible, and who can be assimilated to drivers in general. RESULTS: The proportion of persons driving under the influence of alcohol is estimated at 2.1% (95% CI: 1.4-2.8) and under the influence of cannabis at 3.4% (2.9%-3.9%). Drivers under the influence of alcohol are 17.8 times (12.1-26.1) more likely to be responsible for a fatal accident, and the proportion of fatal accidents which would be prevented if no drivers ever exceeded the legal limit for alcohol is estimated at 27.7% (26.0%-29.4%). Drivers under the influence of cannabis multiply their risk of being responsible for causing a fatal accident by 1.65 (1.16-2.34), and the proportion of fatal accidents which would be prevented if no drivers ever drove under the influence of cannabis is estimated at 4.2% (3.7%-4.8%). An increased risk linked to opiate use has also been found to be significant, but with low prevalence, requiring caution in interpreting this finding. Other groups of narcotics have even lower prevalence, and the associated extra risks cannot be assessed. CONCLUSION: Almost a decade separates the present study from a similar one previously conducted in France, and there have been numerous developments in the intervening years. Even so, the prevalence of drivers responsible for causing fatal accidents under the influence of alcohol or narcotics has stayed remarkably stable, as have the proportion of fatal accidents which could in theory be prevented if no drivers ever exceeded the legal limits. The overall number of deaths from traffic accidents has dropped sharply during this period, and the number of victims attributable to alcohol and/or cannabis declined proportionally. Alcohol remains the main problem in France. It is just as important to note that one in two drivers considered to be under the influence of cannabis was also under the influence of alcohol. With risks cumulating between the two, it is particularly important to point out the danger of consuming them together. PMID- 29117205 TI - Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion induced lung injury. AB - BACKGROUND: Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels. METHODS: I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5*105 cells) and high (1*106 cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined. RESULTS: I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-kappaB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-kappaB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism. CONCLUSIONS: Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis. PMID- 29117207 TI - Perceptions and experiences of childhood vaccination communication strategies among caregivers and health workers in Nigeria: A qualitative study. AB - BACKGROUND: Effective vaccination communication with parents is critical in efforts to overcome barriers to childhood vaccination, tackle vaccine hesitancy and improve vaccination coverage. Health workers should be able to provide information to parents and other caregivers and support them in reaching decisions about vaccinating their children. Limited information exists regarding the perceptions of caregivers and health workers on the vaccination communication strategies employed in Nigeria. This study, which forms part of the 'Communicate to vaccinate' (COMMVAC) project, aims to explore the perceptions and experiences of caregivers and health workers in Nigeria on vaccination communication strategies implemented in their settings. METHODOLOGY: We conducted the study in two States: Bauchi in Northern Nigeria and Cross River in the south. We carried out observations (n = 40), in-depth interviews (n = 14) and focus group discussions (FGDs) (n = 12) amongst 14 purposively selected health workers, two community leaders and 84 caregivers in the two states. We transcribed data verbatim and analysed the data using a framework analysis approach. RESULTS: Caregivers were informed about vaccination activities through three main sources: health facilities (during health education sessions conducted at antenatal or immunization clinics); media outlets; and announcements (in churches/mosques, communities and markets). Caregivers reported that the information received was very useful. Their preferred sources of information included phone text messages, town announcers, media and church/mosque announcements. Some caregivers perceived the clinic environment, long waiting times and health worker attitudes as barriers to receiving vaccination information.When delivering communication interventions, health workers described issues tied to poor communication skills; poor motivation; and attitudes of community members, including vaccine resistance. CONCLUSION: Communication about vaccination involves more than the message but is also influenced by the environment and the attitudes of the deliverer and receiver. It is pertinent for health policy makers and programme managers to understand these factors so as to effectively implement communication approaches. PMID- 29117208 TI - Chemosensitivity to doxorubicin of ER-positive/HER2-negative breast cancers with high 21-gene recurrence score: A study based on in vitro chemoresponse assay. AB - AIM: The 21-gene recurrence score (RS) predicts a clinical benefit of chemotherapy for individuals with ER-positive/HER2-negative breast cancer. Using in vitro chemoresponse assay, we compared the chemosensitivity according to RS in these patients. METHOD: Among the patients with Oncotype Dx assay, we identified 63 patients who had chemotherapy response assays to doxorubicin based on adenosine triphosphate. The degree of chemosensitivity to doxorubicin was translated into the cell death rate (CDR). The RS was also dichotomized with a cutoff of 26. RESULTS: Of 63 patients, 34 (54%), 17 (27%), and 12 patients (19%) had a low, intermediate, and high RS, respectively. The mean CDR differed significantly according to categorized RS, with 17.3+/-10.8 in the low RS group vs. 23.6+/-16.3 in the intermediate RS group vs. 28.8+/-12.6 in the high RS group (P = 0.024, One-way ANOVA test). The mean CDR was significantly higher in the higher RS (26>=) group compared with the lower RS (<26) group (P = 0.025, the Student's t-test), as well as in the high RS (>30) group compared with the low RS (<18) group (P = 0.012, the Student's t-test). Also, continuous RS and CDR correlated positively (Pearson's R = 0.337; P = 0.007). High RS demonstrated the odds ratio (OR = 26.33; 95% CI = 1.69-410.0) for predicting tumors with chemosensitivity on the multivariate analysis. CONCLUSIONS: The chemosensitivity measured by in vitro chemoresponse assay was different according to the RS. Our findings support that tumors with high RS has the chemosensitivity even though they are luminal/HER2-negative tumors. PMID- 29117209 TI - Persistence of hepatitis E virus in the liver of non-viremic naturally infected wild boar. AB - Hepatitis E virus (HEV) is an emerging zoonotic pathogen with pigs and wild boar serving as reservoirs for human infection through direct contact with infected animals or the consumption of raw or undercooked pork products. The liver is considered the main target site of HEV replication in swine and an important organ in the pathogenesis of the disease. The aim of this study was to characterize the target liver cells for HEV entry in naturally infected wild boar and to evaluate the type and severity of the pathological changes in order to reach a better understanding of the hepatic pathogenic mechanisms involved in hepatitis E. In total, 58 livers from hunted wild boar were histopathologically evaluated. The presence of specific HEV antibodies in serum was determined by indirect ELISA. Immunohistochemistry was used for the detection of HEV antigen and Real time RT-PCR to detect HEV RNA in liver and serum. HEV seroprevalence in these animals was of 5.197% (CI95%: 1.77-14.14). By Real time RT-PCR, HEV was detected in the liver tissue of four wild boar (6.8%; CI95%: 2.7-16.4) and only one animal was also positive in serum (1.7%; CI95%: 0.3-9.1). The non-viremic animals naturally infected with HEV presented evidence of liver infection, mainly in Kupffer cells and liver sinusoidal endothelial cells, without apparent associated hepatitis lesions. This study supports the hypothesis that low viral titers may persist in the liver of non-viremic individuals, giving thus the possibility of consumption of contaminated liver of animals diagnosed as HEV negative in serum. Further immunopathogenic studies are necessary to elucidate the mechanisms responsible for this process and to evaluate the protocols of HEV diagnosis in animals destined for human consumption. PMID- 29117210 TI - Quality of life and impact of pain in women treated with aromatase inhibitors for breast cancer. A multicenter cohort study. AB - Women with hormone-dependent breast cancer are treated with aromatase inhibitors (AI) to slow disease progression by decreasing estrogen levels. However, AI have adverse effects, including pain, with potentially serious impact on quality of life (QOL) and treatment compliance. We evaluated quality of life during the first year of AI treatment, focusing particularly on the impact of pain. In a multicenter cohort study of 135 women with early-stage breast cancer, free of pain at the initiation of AI treatment, quality of life (by the EORTC QLQ-BR23), somatic and psychic symptoms, psychological characters, temperament and coping strategies were assessed at baseline and at each follow-up visit (1, 3, 6 and 12 months). The impact of treatment-induced pain on quality of life during follow-up was determined with repeated-measures regression models. These models were constructed to assess the effects of pain and pain type on quality of life during follow-up, taking into account predictors associated with quality of life at baseline. Prior ganglion resection, taxane treatment and chemotherapy, a high amplification score on the pain catastrophizing scale, and a high harm avoidance score on the personality questionnaire were associated with a significantly lower baseline QOL. Fifty-seven percent of women developed pain of five different types: upper or lower limb joint pain, diffuse pain, neuropathic pain, tendon pain and mixed pain. A significant decrease in QOL was noted in the women with pain, particularly for body image, sexual functioning and future perspectives. Moreover, the impact of pain on QOL depended on the type of pain experienced. In conclusion, women treated with aromatase inhibitors display changes in quality of life and the degree of change in quality of life depends mostly on the type of pain experienced. Oncologists and patients should be aware of painful adverse effects of AI and encouraged to provide or receive earlier and more appropriate management of these effects. PMID- 29117211 TI - The treatment of femoral neck fracture using VEGF-loaded nanographene coated internal fixation screws. AB - PURPOSE: Previous studies have proved that vascular endothelial growth factor (VEGF) has a dual role in the promotion of new bone formation and blood vessel repair during fracture healing. However, how to introduce VEGF to a fracture site safely and effectively is still a challenge. This study aimed to prepare a VEGF loaded nanographene coated internal fixation screw and to evaluate its effects in the treatment of femoral neck fracture. METHODS: Nanographene coated screws were prepared by direct liquid-phase exfoliation of the graphite method, and the surface characteristics were observed through scanning electron microscopy (SEM). VEGF was loaded on nanographene coatings through physical adsorption, and the VEGF controlled release was examined by ELISA. Then a canine femoral neck fracture model was built to examine both the angiogenic and osteogenic properties of the VEGF-loaded coated screws. X-ray, micro-CT-based microangiography, and histopathologic evaluation were used to assess the fracture healing progress. RESULTS: The results demonstrated that nanographene could load VEGF effectively, and the accumulative release of VEGF clearly increased during the entire testing period (9 days) without burst release. In canine fracture models, the results of X-ray, microangiography, and histopathologic examination proved that the speed of fracture healing, new bone formation area, and revascularization of the fractured femoral heads in the VEGF-loaded coated screws groups were significantly higher than in the control groups. CONCLUSION: Our study proved that VEGF-loaded nanographene coated screws were effective in the treatment of femoral neck fracture and prevention of avascular necrosis of femoral head. PMID- 29117212 TI - Quantitative label-free proteomic analysis of human urine to identify novel candidate protein biomarkers for schistosomiasis. AB - BACKGROUND: Schistosomiasis is a chronic neglected tropical disease that is characterized by continued inflammatory challenges to the exposed population and it has been established as a possible risk factor in the aetiology of bladder cancer. Improved diagnosis of schistosomiasis and its associated pathology is possible through mass spectrometry to identify biomarkers among the infected population, which will influence early detection of the disease and its subtle morbidity. METHODOLOGY: A high-throughput proteomic approach was used to analyse human urine samples for 49 volunteers from Eggua, a schistosomiasis endemic community in South-West, Nigeria. The individuals were previously screened for Schistosoma haematobium and structural bladder pathologies via microscopy and ultrasonography respectively. Samples were categorised into schistosomiasis, schistosomiasis with bladder pathology, bladder pathology, and a normal healthy control group. These samples were analysed to identify potential protein biomarkers. RESULTS: A total of 1306 proteins and 9701 unique peptides were observed in this study (FDR = 0.01). Fifty-four human proteins were found to be potential biomarkers for schistosomiasis and bladder pathologies due to schistosomiasis by label-free quantitative comparison between groups. Thirty-six (36) parasite-derived potential biomarkers were also identified, which include some existing putative schistosomiasis biomarkers that have been previously reported. Some of these proteins include Elongation factor 1 alpha, phosphopyruvate hydratase, histone H4 and heat shock proteins (HSP 60, HSP 70). CONCLUSION: These findings provide an in-depth analysis of potential schistosoma and human host protein biomarkers for diagnosis of chronic schistosomiasis caused by Schistosoma haematobium and its pathogenesis. PMID- 29117213 TI - Effect of microalgae on intestinal inflammation triggered by soybean meal and bacterial infection in zebrafish. AB - Soybean meal has been used in many commercial diets for farm fish; despite this component inducing intestinal inflammation. On the other hand, microalgae have increasingly been used as dietary supplements in fish feed. Nevertheless, the vast quantity of microalgae species means that many remain under- or unstudied, thus limiting wide scale commercial application. In this work, we evaluated the effects to zebrafish (Danio rerio) of including Tetraselmis sp (Ts); Phaeodactylum tricornutum (Pt); Chlorella sp (Ch); Nannochloropsis oculata (No); or Nannochloropsis gaditana (Ng) as additives in a soybean meal-based diet on intestinal inflammation and survival after Edwardsiella tarda infection. In larvae fed a soybean meal diet supplemented with Ts, Pt, Ch, or Ng, the quantity of neutrophils present in the intestine drastically decreased as compared to larvae fed only the soybean meal diet. Likewise, Ts or Ch supplements in soybean meal or fishmeal increased zebrafish survival by more than 20% after being challenged. In the case of Ts, the observed effect correlated with an increased number of neutrophils present at the infection site. These results suggest that the inclusion of Ts or Ch in fish diets could allow the use of SBM and at the same time improve performance against pathogen. PMID- 29117214 TI - U-shaped relationship between serum phosphate and cardiovascular risk: A retrospective cohort study. AB - BACKGROUND: High serum phosphate is associated with coronary artery disease in patients with normal and impaired renal function. We asked: Does the serum phosphate range provide prediction of primary cardiac events? We extracted coded primary care data for over 100,000 patients from a database of 135 primary medical practices. Patients aged between 18 and 90 years without pre-existing cardiovascular diagnoses were included from a potential sample of over 1.2 million individuals. METHODS AND FINDINGS: Binary logistic regression models were used to evaluate the contribution of QRISK factors and electrolytes, including serum phosphate, to cardiac outcomes at five and nine years following an initial phosphate measurement. At five-year review (n = 113,993), low serum phosphate (OR 1.75, 95%CI 1.36-2.23, p<0.001), high-normal (OR 1.50, 95%CI 1.29-1.74, p<0.001), and high serum phosphate (OR 1.74, 95%CI 1.06-2.70, p = 0.02) were long-term risk factors for primary cardiac disease events after adjusting for confounding variables. A similar pattern was seen at our nine-year review. CONCLUSIONS: The extremes of serum phosphate may confer cardiac event risk with a U-shaped trend. In particular, we raise new cardiac concerns for low serum phosphate in the general population. Also, the normal range for phosphate may require redefinition among healthy adults. PMID- 29117215 TI - Effects of root pruning on the physicochemical properties and microbial activities of poplar rhizosphere soil. AB - This study aimed to determine the effects of root pruning on the physicochemical characteristics and microbial activities of poplar rhizosphere soil. The root systems of 5-year-old poplar (Populus*euramericana cv. 'Neva') trees were manually pruned at 6, 8, or 10 times diameter at breast height (DBH) from the trunk (severe, moderate, and light, respectively) along both inter-row sides. Moderate root pruning significantly increased the concentrations of amino acids, organic acids, and total sugars in the root exudates and decreased the pH of rhizosphere soil. This treatment also increased the contents of available nitrogen, phosphorus, potassium, and total organic carbon as well as high-, medium-, and low-activity organic carbon in rhizosphere soil. Moreover, moderate pruning increased the contents of microbial biomass carbon and nitrogen, and enhanced basal respiration, in addition to decreasing the metabolic quotients in rhizosphere soil by 8.9%, 5.0%, and 11.4% compared with control, light, and severe root pruning treatments, respectively. Moderate pruning increased the growth rates of DBH, tree height, and volume to the highest levels. Furthermore, these indices were not significantly different between the light root pruning and control groups, but varied significantly between severe and moderate root-pruning treatments. Thus, root pruning, depending on the distance from the trunk, significantly influences the physicochemical properties and microbial activities in poplar rhizosphere soil. PMID- 29117216 TI - Predictors of unmet health care needs in Serbia; Analysis based on EU-SILC data. AB - Unmet health care needs have been designated as an indicator of equality in access to health care, which provides insight into specific barriers faced by respondents when they need medical services. The purpose of this research was to analyze demographic, socioeconomic, regional characteristics and perception of the health status; and identify predictors of unmet health care needs and consequently determine the size of inequalities in the availability, accessibility and acceptability of health care. The cross-sectional study obtained data from the Survey on Income and Living Conditions in the Republic of Serbia in 2014, based on a sample of 20,069 respondents over 16 years. Data was collected by using a household questionnaire and a questionnaire for individuals. Multivariate logistic regressions were applied. Almost every seventh citizen (14.9%) reported unmet health care needs. Predictors of unmet needs, for overall reasons, which increase the likelihood of their emergence included: self perceived health status as very bad (OR = 6.37), divorced or widower/widow (OR = 1.31), living in the Sumadija region or Western Serbia (OR = 1.54) and belonging to the age group of 27 to 44 (OR = 1.55) or 45 to 64 years (OR = 1.52). The probability for those least reporting unmet health care needs included female patients (OR = 0.81), those with higher education (OR = 0.77), those who belong to the richest quintile (OR = 0.46) and who are unemployed (OR = 0.64). Reasons for unmet needs that indicate the responsibility of the health system amounted to 58.2% and reasons which represent preferences of the respondents amounted to 41.7%. The most frequent reason for unmet needs was financial (36.6%), and the wish to wait and see if the problem got better on its own (18.3%). Health policy should adopt a multidimensional approach and develop incentives for the appropriate use of health services and should eliminate barriers which restrict the accessibility and availability. PMID- 29117217 TI - Morphological and genetic divergence between Agave inaequidens, A. cupreata and the domesticated A. hookeri. Analysis of their evolutionary relationships. AB - Agave inaequidens and A. cupreata are wild species with some populations under incipient management, while A. hookeri is exclusively cultivated, used for producing the fermented beverage pulque. These species are closely related and sympatric members of the Crenatae group, but taxonomists have previously hypothesized that A. inaequidens is the most probable ancestor of A. hookeri. Our study aims at evaluating patterns of morphological and genetic divergence among populations of the three species, in order to analyze their ecological and possible evolutionary relationships. We studied 24 agave populations, 16 of them of Agave inaequidens, four of A. cupreata and four of A. hookeri. Population morphometric and genetics studies were performed using 39 morphological characters and 10 nuclear microsatellites, respectively. We estimated levels of morphological and genetic diversity and dissimilarity, as well as genetic structure and gene flow among populations and species. The three species were clearly differentiated by general plant size, lateral teeth, terminal spines, flowers and fruit size. The largest plants were those of A. hookeri followed by A. inaequidens and the smallest were A. cupreata. Multivariate analyses indicated greater morphological similarity between A. hookeri and cultivated A. inaequidens, while A. cupreata consistently appeared as a separate group. We identified similar levels of morphological diversity index (MDI) in the three species, but higher genetic diversity in A. inaequidens (MDI = 0.401-0.435; HE = 0.704-0.733), than in A. cupreata (MDI = 0.455-0.523; HE = 0.480-0.510) and the predominantly vegetative propagated crop A. hookeri (MDI = 0.335-0.688; HE = 0.450-0.567), a pattern consistent with our expectations. The morphological and genetic similarities between cultivated A. inaequidens and A. hookeri support the hypothetical evolutionary relationships among these species, but studies with cpDNA and SNPs, and including other member of the Crenatae group are necessary to further resolve these relationships. PMID- 29117218 TI - Compatible bacterial mixture, tolerant to desiccation, improves maize plant growth. AB - Plant growth-promoting rhizobacteria (PGPR) increase plant growth and crop productivity. The inoculation of plants with a bacterial mixture (consortium) apparently provides greater benefits to plant growth than inoculation with a single bacterial strain. In the present work, a bacterial consortium was formulated containing four compatible and desiccation-tolerant strains with potential as PGPR. The formulation had one moderately (Pseudomonas putida KT2440) and three highly desiccation-tolerant (Sphingomonas sp. OF178, Azospirillum brasilense Sp7 and Acinetobacter sp. EMM02) strains. The four bacterial strains were able to adhere to seeds and colonize the rhizosphere of plants when applied in both mono-inoculation and multi-inoculation treatments, showing that they can also coexist without antagonistic effects in association with plants. The effects of the bacterial consortium on the growth of blue maize were evaluated. Seeds inoculated with either individual bacterial strains or the bacterial consortium were subjected to two experimental conditions before sowing: normal hydration or desiccation. In general, inoculation with the bacterial consortium increased the shoot and root dry weight, plant height and plant diameter compared to the non inoculated control or mono-inoculation treatments. The bacterial consortium formulated in this work had greater benefits for blue maize plants even when the inoculated seeds underwent desiccation stress before germination, making this formulation attractive for future field applications. PMID- 29117220 TI - Intracellular galectin-7 expression in cancer cells results from an autocrine transcriptional mechanism and endocytosis of extracellular galectin-7. AB - The beta-galactoside binding protein galectin-7 (gal-7) is constitutively expressed at abnormally high levels in the outside milieu and intracellular compartments of many types of epithelial cancer cells, most notably in aggressive forms of ovarian and breast cancer. It is thus of utmost importance to understand how gal-7 traffics between both intracellular and extracellular compartments to develop novel drugs that target the protumorigenic functions of galectin-7. In the present work, we report that extracellular gal-7 plays a central role in controlling intracellular gal-7 in cells. It does so via two distinct yet complementary mechanisms: firstly by increasing the transcriptional activation of lgals7 gene transcription, and secondly via re-entry into the cells. Increased mRNA levels were dose- and time-dependent and occur in all cell lines tested, including ovarian and breast cancer cell lines. Addition of recombinant gal-7 to MDA-MB-231 transfected with a luciferase reporter vector containing response elements of the lgals7 promoter indicated that increased mRNA level of lgals7 occurs via de novo gene transcription. Re-entry of extracellular gal-7 inside cells was rapid, and reached cytosolic and mitochondrial compartments. Taken together, these findings reveal the existence of a positive self-amplification pathway that regulates intracellular gal-7 expression in breast and ovarian cancer cells. PMID- 29117219 TI - Cellular and exosome mediated molecular defense mechanism in bovine granulosa cells exposed to oxidative stress. AB - Various environmental insults including diseases, heat and oxidative stress could lead to abnormal growth, functions and apoptosis in granulosa cells during ovarian follicle growth and oocyte maturation. Despite the fact that cells exposed to oxidative stress are responding transcriptionally, the potential release of transcripts associated with oxidative stress response into extracellular space through exosomes is not yet determined. Therefore, here we aimed to investigate the effect of oxidative stress in bovine granulosa cells in vitro on the cellular and exosome mediated defense mechanisms. Bovine granulosa cells were aspirated from ovarian follicles and cultured in DMEM/F-12 Ham culture medium supplemented with 10% exosome-depleted fetal bovine serum. In the first experiment sub-confluent cells were treated with 5 MUM H2O2 for 40 min to induce oxidative stress. Thereafter, cells were subjected to ROS and mitochondrial staining, cell proliferation and cell cycle assays. Furthermore, gene and protein expression analysis were performed in H2O2-challenged versus control group 24 hr post-treatment using qRT-PCR and immune blotting or immunocytochemistry assay, respectively. Moreover, exosomes were isolated from spent media using ultracentrifugation procedure, and subsequently used for RNA isolation and qRT PCR. In the second experiment, exosomes released by granulosa cells under oxidative stress (StressExo) or those released by granulosa cells without oxidative stress (NormalExo) were co-incubated with bovine granulosa cells in vitro to proof the potential horizontal transfer of defense molecules from exosomes to granulosa cells and investigate any phenotype changes. Exposure of bovine granulosa cells to H2O2 induced the accumulation of ROS, reduced mitochondrial activity, increased expression of Nrf2 and its downstream antioxidant genes (both mRNA and protein), altered the cell cycle transitions and induced cellular apoptosis. Granulosa cells exposed to oxidative stress released exosomes enriched with mRNA of Nrf2 and candidate antioxidants. Subsequent co incubation of StressExo with cultured granulosa cells could alter the relative abundance of cellular oxidative stress response molecules including Nrf2 and antioxidants CAT, PRDX1 and TXN1. The present study provide evidences that granulosa cells exposed to oxidative stress conditions react to stress by activating cascades of cellular antioxidant molecules which can also be released into extracellular environment through exosomes. PMID- 29117221 TI - Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma. AB - PURPOSE: The Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) was proposed for predicting the metastatic potential of pheochromocytoma and paraganglioma to overcome the limitations of the Pheochromocytoma of the Adrenal Scaled Score (PASS). However, to date, no study validating the GAPP has been conducted, and previous studies did not include mutations in the succinate dehydrogenase type B (SDHB) gene in the score calculation. In this retrospective cohort study, we validated the prediction ability of GAPP and assessed whether it would be improved by inclusion of the loss of SDHB immunohistochemical staining. METHODS: We divided the tumors into non-metastatic and metastatic groups based on the presence of synchronous or metachronous metastases. The GAPP score and PASS at the initial operation were measured. Moreover, we combined some GAPP parameters with the immunohistochemical staining of SDHB to obtain a modified GAPP (M-GAPP) score. RESULTS: Metastasis occurred in 15/72 (20.8%) patients, with a mean follow-up of 43.5 months. Loss of SDHB staining was more frequent (P = 0.044) in the metastatic group. The GAPP score (P = 0.006), PASS (P = 0.003), and M-GAPP score (P<0.001) were all higher in the metastatic group. Twelve of 40 (30.0%) moderately or poorly differentiated tumors, as defined by the GAPP score, and 12/34 (35.3%) tumors with a PASS >=4 were metastatic. Conversely, 10/19 (52.6%) tumors with an M-GAPP score >=3 were metastatic. The area under the curve of the M-GAPP score (0.822) was significantly higher than that of the GAPP (0.728) (P = 0.012), but similar to that of the PASS (0.753) (P = 0.411). The GAPP (P = 0.032) and M-GAPP scores (P = 0.040), but not PASS (P = 0.200), negatively correlated with metastasis-free survival. CONCLUSION: The GAPP was validated, and M-GAPP, a combination of some GAPP parameters and loss of SDHB staining, might be useful for the prediction of the metastatic potential of pheochromocytoma and paraganglioma. PMID- 29117222 TI - A chimeric IgE that mimics IgE from patients allergic to acid-hydrolyzed wheat proteins is a novel tool for in vitro allergenicity assessment of functionalized glutens. AB - BACKGROUND: Acid-hydrolyzed wheat proteins (acid-HWPs) have been shown to provoke severe allergic reactions in Europe and Japan that are distinct from classical wheat allergies. Acid-HWPs were shown to contain neo-epitopes induced by the deamidation of gluten proteins. However, products with variable rates of deamidation can be found. OBJECTIVES: In this work, we studied the effect of the extent of wheat proteins deamidation on its allergenicity. A recombinant chimeric IgE was produced and compared to patients' IgE for its capacity to assess the IgE mediated triggering potential of acid-HWPs. METHODS: Sera from acid-HWP allergic patients were analyzed via ELISA and a functional basophil assay for their IgE reactivity to wheat proteins with different deamidation levels. A chimeric mouse/human IgE (chIgE-DG1) specific for the main neo-epitope, QPEEPFPE, involved in allergy to acid-HWPs was characterized with respect to its functionality and its reactivity compared to that of patients' IgE. RESULTS: Acid-HWPs with medium (30%) and high (50-60%) deamidation levels displayed a markedly stronger IgE binding and capacity to activate basophils than those of samples with weak (15%) deamidation levels. The monoclonal chIgE-DG1 allowed basophil degranulation in the presence of deamidated wheat proteins. ChIgE-DG1 was found to mimic patients' IgE reactivity and displayed the same ability to rank acid-HWP products in a degranulation assay. CONCLUSION: Increasing the deamidation level of products from 15% to 60% resulted in an approximately 2-fold increase in their antigenicity and a 100-fold increase in their eliciting potential. The chimeric ChIgE-DG1 may be a useful tool to evaluate functionalized glutens for their allergenic potential. By mimicking patient sera reactivity, chIgE-DG1 also provided data on the patients' IgE repertoire and on the functionality of certain repeated epitopes in gluten proteins. PMID- 29117223 TI - Sensitivity analysis revealing the effect of modulating ionic mechanisms on calcium dynamics in simulated human heart failure. AB - Abnormal intracellular Ca2+ handling is the major contributor to the depressed cardiac contractility observed in heart failure. The electrophysiological remodeling associated with this pathology alters both the action potential and the Ca2+ dynamics, leading to a defective excitation-contraction coupling that ends in mechanical dysfunction. The importance of maintaining a correct intracellular Ca2+ concentration requires a better understanding of its regulation by ionic mechanisms. To study the electrical activity and ionic homeostasis of failing myocytes, a modified version of the O'Hara et al. human action potential model was used, including electrophysiological remodeling. The impact of the main ionic transport mechanisms was analyzed using single-parameter sensitivity analyses, the first of which explored the modulation of electrophysiological characteristics related to Ca2+ exerted by the remodeled parameters. The second sensitivity analysis compared the potential consequences of modulating individual channel conductivities, as one of the main effects of potential drugs, on Ca2+ dynamic properties under both normal conditions and in heart failure. The first analysis revealed the important contribution of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) dysfunction to the altered Ca2+ homeostasis, with the Na+/Ca2+ exchanger (NCX) and other Ca2+ cycling proteins also playing a significant role. Our results highlight the importance of improving the SR uptake function to increase Ca2+ content and restore Ca2+ homeostasis and contractility. The second sensitivity analysis highlights the different response of the failing myocyte versus the healthy myocyte to potential pharmacological actions on single channels. The result of modifying the conductances of the remodeled proteins such as SERCA and NCX in heart failure has less impact on Ca2+ modulation. These differences should be taken into account when designing drug therapies. PMID- 29117224 TI - Predictors of sudden cardiac death in atrial fibrillation: The Atherosclerosis Risk in Communities (ARIC) study. AB - We previously reported that incident atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. We now aimed to identify predictors of SCD in persons with AF from the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort study. We included all participants who attended visit 1 (1987-89) and had no prior AF (n = 14,836). Incident AF was identified from study electrocardiograms and hospitalization discharge codes through 2012. SCD was physician-adjudicated. We used cause specific Cox proportional hazards models, followed by stepwise selection (backwards elimination, removing all variables with p>0.10) to identify predictors of SCD in participants with AF. AF occurred in 2321 (15.6%) participants (age 45-64 years, 58% male, 18% black). Over a median of 3.3 years, SCD occurred in 110 of those with AF (4.7%). Predictors of SCD in AF included higher age, body mass index (BMI), coronary heart disease, hypertension, diabetes, current smoker, left ventricular hypertrophy, increased heart rate, and decreased albumin. Predictors associated only with SCD and not other cardiovascular (CV) death included increased BMI (HR per 5-unit increase, 1.15, 95% CI, 0.97-1.36, p = 0.10), increased heart rate (HR per SD increase, 1.18, 95% CI 0.99-1.41, p = 0.07), and low albumin (HR per SD decrease 1.23, 95% CI 1.02 1.48, p = 0.03). In the ARIC study, predictors of SCD in AF that are not associated with non-sudden CV death included increased BMI, increased heart rate, and low albumin. Further research to confirm these findings in larger community based cohorts and to elucidate the underlying mechanisms to facilitate prevention is warranted. PMID- 29117225 TI - Genomic comparison between Staphylococcus aureus GN strains clinically isolated from a familial infection case: IS1272 transposition through a novel inverted repeat-replacing mechanism. AB - A bacterial insertion sequence (IS) is a mobile DNA sequence carrying only the transposase gene (tnp) that acts as a mutator to disrupt genes, alter gene expressions, and cause genomic rearrangements. "Canonical" ISs have historically been characterized by their terminal inverted repeats (IRs), which may form a stem-loop structure, and duplications of a short (non-IR) target sequence at both ends, called target site duplications (TSDs). The IS distributions and virulence potentials of Staphylococcus aureus genomes in familial infection cases are unclear. Here, we determined the complete circular genome sequences of familial strains from a Panton-Valentine leukocidin (PVL)-positive ST50/agr4 S. aureus (GN) infection of a 4-year old boy with skin abscesses. The genomes of the patient strain (GN1) and parent strain (GN3) were rich for "canonical" IS1272 with terminal IRs, both having 13 commonly-existing copies (ce-IS1272). Moreover, GN1 had a newly-inserted IS1272 (ni-IS1272) on the PVL-converting prophage, while GN3 had two copies of ni-IS1272 within the DNA helicase gene and near rot. The GN3 genome also had a small deletion. The targets of ni-IS1272 transposition were IR structures, in contrast with previous "canonical" ISs. There were no TSDs. Based on a database search, the targets for ce-IS1272 were IRs or "non-IRs". IS1272 included a larger structure with tandem duplications of the left (IRL) side sequence; tnp included minor cases of a long fusion form and truncated form. One ce-IS1272 was associated with the segments responsible for immune evasion and drug resistance. Regarding virulence, GN1 expressed cytolytic peptides (phenol soluble modulin alpha and delta-hemolysin) and PVL more strongly than some other familial strains. These results suggest that IS1272 transposes through an IR replacing mechanism, with an irreversible process unlike that of "canonical" transpositions, resulting in genomic variations, and that, among the familial strains, the patient strain has strong virulence potential based on community associated virulence factors. PMID- 29117226 TI - Sexual assault incidents among college undergraduates: Prevalence and factors associated with risk. AB - Sexual assault on college campuses is a public health issue. However varying research methodologies (e.g., different sexual assault definitions, measures, assessment timeframes) and low response rates hamper efforts to define the scope of the problem. To illuminate the complexity of campus sexual assault, we collected survey data from a large population-based random sample of undergraduate students from Columbia University and Barnard College in New York City, using evidence based methods to maximize response rates and sample representativeness, and behaviorally specific measures of sexual assault to accurately capture victimization rates. This paper focuses on student experiences of different types of sexual assault victimization, as well as sociodemographic, social, and risk environment correlates. Descriptive statistics, chi-square tests, and logistic regression were used to estimate prevalences and test associations. Since college entry, 22% of students reported experiencing at least one incident of sexual assault (defined as sexualized touching, attempted penetration [oral, anal, vaginal, other], or completed penetration). Women and gender nonconforming students reported the highest rates (28% and 38%, respectively), although men also reported sexual assault (12.5%). Across types of assault and gender groups, incapacitation due to alcohol and drug use and/or other factors was the perpetration method reported most frequently (> 50%); physical force (particularly for completed penetration in women) and verbal coercion were also commonly reported. Factors associated with increased risk for sexual assault included non-heterosexual identity, difficulty paying for basic necessities, fraternity/sorority membership, participation in more casual sexual encounters ("hook ups") vs. exclusive/monogamous or no sexual relationships, binge drinking, and experiencing sexual assault before college. High rates of re victimization during college were reported across gender groups. Our study is consistent with prevalence findings previously reported. Variation in types of assault and methods of perpetration experienced across gender groups highlight the need to develop prevention strategies tailored to specific risk groups. PMID- 29117227 TI - Kojic acid-mediated damage responses induce mycelial regeneration in the basidiomycete Hypsizygus marmoreus. AB - Mechanical damage can induce fruiting body production in fungi. In this study, the antioxidant kojic acid (KA) was found to enhance injured mycelial regeneration and increase fruiting body production in Hypsizygus marmoreus. KA reduced the level of reactive oxygen species (ROS), which are harmful to mycelia when excessively generated by mechanical damage. Moreover, KA increased catalase and superoxide dismutase activities and glutathione and ascorbic acid contents by up-regulating antioxidant gene expression. These results suggest that KA promotes mycelial regeneration in response to damage by activating a "stress signal" and enhances the ability of H. marmoreus to resist oxidative damage by invoking the antioxidant system. In addition, KA increased the content of extracellular ATP, which serves as a "stress signal" in response to injury, and modulated ROS signaling, decreasing NADPH oxidase gene expression and ROS levels in the mycelial-regeneration stage. KA treatment also up-regulated the MAPK, Ca2+ and oxylipin pathways, suggesting their involvement in the damage response. Furthermore, laccase and cellulase activities were stimulated by KA at different developmental stages. These results demonstrate that KA regulates gene expression and activates pathways for mycelial wound healing, regeneration of damaged mycelia and reproductive structure formation in the basidiomycete H. marmoreus. PMID- 29117228 TI - The pacing strategy and technique of male cross-country skiers with different levels of performance during a 15-km classical race. AB - In this study the pacing strategy, cycle characteristics and choice of technique of elite male cross-country (XC) skiers during a three-lap, 15-km classical race with interval start were measured. During the Norwegian Championships in 2016, fast (n = 18, age: 26+/-4 yr; height: 182+/-4 cm; body mass: 78+/-3 kg (means+/ SD)) and slow skiers (n = 18, age: 22+/-2 yr; height: 183+/-5 cm; body mass: 78+/ 6 kg) were video recorded on flat (0 degrees ), intermediate (3.5 degrees ) and uphill sections (7.1 degrees ) of the first and final laps. All skiers adopted a positive pacing strategy, skiing more slowly (11.8%) with shorter cycles (11.7%) on the final than first lap (both p<0.001; peta2 = 0.93 and 0.87, respectively). The fast skiers were 7.0% faster overall (p<0.001, d = 4.20), and 6.1% (p<0.001, d = 3.32) and 7.0% (p<0.001, d = 3.68) faster on the first and final laps, respectively, compared to slower skiers. On all sections of both laps, the fast skiers exhibited 9.5% more rapid (peta2 = 0.74) and 8.9% (peta2 = 0.48) longer cycles (both p<0.001). On intermediate terrain, the fast skiers employed primarily double poling (DP, 38.9% on the first lap) and double poling with a kick (DPKICK, 50% on the final lap). In contrast, the slow skiers utilized for the most part DP alone (lap 1: 33.3%, lap 3: 38.9%) or in combination with other techniques (lap 1: 33.3%, lap 3: 38.9%) and decreased their usage of DPKICK from 27.8% on the first to 16.7% on the final lap. Skiing velocity on flat and intermediate terrain proved to be the best predictor of race performance (p<0.001). In conclusion, during a 15-km classical XC skiing race, velocity and cycle length decreased from the first to the final lap, most extensively on flat terrain and least uphill. Moreover, on the intermediate sections the fast and slow skiers chose to use different techniques. PMID- 29117229 TI - Effects of tillage practice on soil structure, N2O emissions and economics in cereal production under current socio-economic conditions in central Bosnia and Herzegovina. AB - Conservation tillage is expected to have a positive effect on soil physical properties, soil Carbon (C) storage, while reducing fuel, labour and machinery costs. However, reduced tillage could increase soil nitrous oxide (N2O) emissions and offset the expected gains from increased C sequestration. To date, conservation tillage is barely practiced or studied in Bosnia and Herzegovina (BH). Here, we report a field study on the short-term effects of reduced (RT) and no tillage (NT) on N2O emission dynamics, yield-scaled N2O emissions, soil structure and the economics of cereal production, as compared with conventional tillage (CT). The field experiment was conducted in the Sarajevo region on a clayey loam under typical climatic conditions for humid, continental BH. N2O emissions were monitored in a Maize-Barley rotation over two cropping seasons. Soil structure was studied at the end of the second season. In the much wetter 2014, N2O emission were in the order of CT > RT > NT, while in the drier 2015, the order was RT > CT > NT. The emission factors were within or slightly above the uncertainty range of the IPCC Tier 1 factor, if taking account for the N input from the cover crop (alfalfa) preceding the first experimental year. Saturated soils in spring, formation of soil crusts and occasional droughts adversely affected yields, particularly in the second year (barley). In 2014, yield-scaled N2O emissions ranged from 83.2 to 161.7 g N Mg-1 grain (corn) but were much greater in the second year due to crop failure (barley). RT had the smallest yield-scaled N2O emission in both years. NT resulted in economically inacceptable returns, due to the increased costs of weed control and low yields in both years. The reduced number of operations in RT reduced production costs and generated positive net returns. Therefore, RT could potentially provide agronomic and environmental benefits in crop production in BH. PMID- 29117230 TI - Two-color, one-photon uncaging of glutamate and GABA. AB - Neuronal cells receive a variety of excitatory and inhibitory signals which they process to generate an output signal. In order to study the interaction between excitatory and inhibitory receptors with exogenously applied transmitters in the same preparation, two caging chromophores attached to glutamate and GABA were developed that were selectively photolyzed by different wavelengths of light. This technique has the advantage that the biologically inactive caged compound can be applied at equilibrium prior to the near instantaneous release of the transmitters. This method therefore mimics the kinetics of endogenously released transmitters that is otherwise not possible in brain slice preparations. Repeated photolysis with either of the two wavelengths resulted in GABA- or glutamate induced activation of both ionotropic and metabotropic receptors to evoke reproducible currents. With these compounds, the interaction between inhibitory and excitatory receptors was examined using whole field photolysis. PMID- 29117231 TI - Human pancreatic islet-derived extracellular vesicles modulate insulin expression in 3D-differentiating iPSC clusters. AB - It has been suggested that extracellular vesicles (EVs) can mediate crosstalk between hormones and metabolites within pancreatic tissue. However, the possible effect of pancreatic EVs on stem cell differentiation into pancreatic lineages remains unknown. Herein, human islet-derived EVs (h-Islet-EVs) were isolated, characterized and subsequently added to human induced pluripotent stem cell (iPSC) clusters during pancreatic differentiation. The h-islet-EVs had a mean size of 117+/-7 nm and showed positive expression of CD63 and CD81 EV markers as measured by ELISA. The presence of key pancreatic transcription factor mRNA, such as NGN3, MAFA and PDX1, and pancreatic hormone proteins such as C-peptide and glucagon, were confirmed in h-Islet-EVs. iPSC clusters were differentiated in suspension and at the end stages of the differentiation protocol, the mRNA expression of the main pancreatic transcription factors and pancreatic hormones was increased. H-Islet-EVs were supplemented to the iPSC clusters in the later stages of differentiation. It was observed that h-Islet-EVs were able to up regulate the intracellular levels of C-peptide in iPSC clusters in a concentration-dependent manner. The effect of h-Islet-EVs on the differentiation of iPSC clusters cultured in 3D-collagen hydrogels was also assessed. Although increased mRNA expression for pancreatic markers was observed when culturing the iPSC clusters in 3D-collagen hydrogels, delivery of EVs did not affect the insulin or C-peptide intracellular content. Our results provide new information on the role of h-Islet-EVs in the regulation of insulin expression in differentiating iPSC clusters, and are highly relevant for pancreatic tissue engineering applications. PMID- 29117232 TI - Rate of acyl migration in lysophosphatidylcholine (LPC) is dependent upon the nature of the acyl group. Greater stability of sn-2 docosahexaenoyl LPC compared to the more saturated LPC species. AB - Several previous studies reported that sn-2 acyl lysophosphatidylcholines (LPCs) undergo rapid isomerization due to acyl migration, especially at physiological pH and temperature. However, these studies have been carried out using mostly sn-2 palmitoyl LPC, whereas the naturally occurring sn-2 LPCs are predominantly unsaturated. In this study, we investigated the acyl migration in four naturally occurring sn-2 acyl LPCs (sn-2 16:0, sn-2 18:1, sn-2 20:4, and sn-2 22:6) stored at various temperatures in aqueous or organic solvents, employing LC/MS to analyze the isomer composition. At 37 degrees C and pH 7.4, the order of acyl migration rates (from sn-2 to sn-1) in aqueous buffer was 16:0 LPC> 18:1 LPC> 20:4 LPC> 22:6 LPC. The rate of isomerization of sn-2 16:0 LPC was 2-5 times greater than that of sn-2 22:6 under these conditions. Complexing the LPCs to serum albumin accelerated the acyl migration of all species, but sn-2 22:6 LPC was least affected by the presence of albumin. The migration rates were lower at lower temperatures (22 degrees C, 4 degrees C, and -20 degrees C), but the differences between the LPC species persisted. All the sn-2 acyl LPCs were more stable in organic solvent (chloroform: methanol, 2:1 v/v), but the effect of the acyl groups on acyl migration was evident in the solvent also, at all temperatures. Storage of sn-2 22:6 LPC at -20 degrees C for 4 weeks in the organic solvent resulted in about 10% isomerization, compared to 55% isomerization for sn-2 16:0. These results show that the sn-2 polyunsaturated LPCs can be stored at -20 degrees C or below for several days without appreciable isomerization. Furthermore, they demonstrate that the sn-2 polyunsaturated LPCs generated in vivo are much more stable under physiological conditions than previously assumed. PMID- 29117233 TI - Dietary amino acid and vitamin complex protects honey bee from immunosuppression caused by Nosema ceranae. AB - Microsporidium Nosema ceranae is well known for exerting a negative impact on honey bee health, including down-regulation of immunoregulatory genes. Protein nutrition has been proven to have beneficial effects on bee immunity and other aspects of bee health. Bearing this in mind, the aim of our study was to evaluate the potential of a dietary amino acid and vitamin complex "BEEWELL AminoPlus" to protect honey bees from immunosuppression induced by N. ceranae. In a laboratory experiment bees were infected with N. ceranae and treated with supplement on first, third, sixth and ninth day after emergence. The expression of genes for immune-related peptides (abaecin, apidaecin, hymenoptaecin, defensin and vitellogenin) was compared between groups. The results revealed significantly lower (p<0.01 or p<0.001) numbers of Nosema spores in supplemented groups than in the control especially on day 12 post infection. With the exception of abacein, the expression levels of immune-related peptides were significantly suppressed (p<0.01 or p<0.001) in control group on the 12th day post infection, compared to bees that received the supplement. It was supposed that N. ceranae had a negative impact on bee immunity and that the tested amino acid and vitamin complex modified the expression of immune-related genes in honey bees compromised by infection, suggesting immune-stimulation that reflects in the increase in resistance to diseases and reduced bee mortality. The supplement exerted best efficacy when applied simultaneously with Nosema infection, which can help us to assume the most suitable period for its application in the hive. PMID- 29117234 TI - Compensatory selection for roads over natural linear features by wolves in northern Ontario: Implications for caribou conservation. AB - Woodland caribou (Rangifer tarandus caribou) in Ontario are a threatened species that have experienced a substantial retraction of their historic range. Part of their decline has been attributed to increasing densities of anthropogenic linear features such as trails, roads, railways, and hydro lines. These features have been shown to increase the search efficiency and kill rate of wolves. However, it is unclear whether selection for anthropogenic linear features is additive or compensatory to selection for natural (water) linear features which may also be used for travel. We studied the selection of water and anthropogenic linear features by 52 resident wolves (Canis lupus x lycaon) over four years across three study areas in northern Ontario that varied in degrees of forestry activity and human disturbance. We used Euclidean distance-based resource selection functions (mixed-effects logistic regression) at the seasonal range scale with random coefficients for distance to water linear features, primary/secondary roads/railways, and hydro lines, and tertiary roads to estimate the strength of selection for each linear feature and for several habitat types, while accounting for availability of each feature. Next, we investigated the trade-off between selection for anthropogenic and water linear features. Wolves selected both anthropogenic and water linear features; selection for anthropogenic features was stronger than for water during the rendezvous season. Selection for anthropogenic linear features increased with increasing density of these features on the landscape, while selection for natural linear features declined, indicating compensatory selection of anthropogenic linear features. These results have implications for woodland caribou conservation. Prey encounter rates between wolves and caribou seem to be strongly influenced by increasing linear feature densities. This behavioral mechanism-a compensatory functional response to anthropogenic linear feature density resulting in decreased use of natural travel corridors-has negative consequences for the viability of woodland caribou. PMID- 29117235 TI - Variability of surface and underwater nocturnal spectral irradiance with the presence of clouds in urban and peri-urban wetlands. AB - Artificial light at night (ALAN) is an increasing phenomenon worldwide. It causes a wealth of biological and ecological effects that may eventually affect populations and ecosystems. Despite the growing concern about ALAN, little is known about the light levels species are exposed to at night, especially for wetlands and underwater habitats. We determined nocturnal irradiance in urban and peri-urban wetlands above and under water, and assessed the effect of cloud cover on the variability of ALAN across the urban gradient. Even in aquatic habitats, cloud cover could increase irradiance beyond values observed during clear full moon nights. We report a negative relationship between baseline irradiance and the increase in irradiance during overcast nights. According to this result and previous studies, we propose that the change in the variation regime of ALAN between the urban center and rural land at its periphery is a usual feature. We discuss the ecological and evolutionary implications of this spatial variation in the urban and peri-urban environment. PMID- 29117237 TI - Factors associated with the risk perception and purchase decisions of Fukushima related food in South Korea. AB - Following the Fukushima nuclear power plant accident, the risk level perceived by Koreans on the radioactive contamination of Japanese food that is being distributed in Korea remains high. Many of these perceptions are based on subjective risk perception rather than an objective measure with scientific evidence, which makes communicating risks more difficult; therefore, it is critical to understand factors associated with risk perception for effective risk communication. In this study, we identified variables that are associated with buying tendencies and opinions about the regulatory policy of Japanese seafood after the accident. A survey was conducted with 1045 adults aged over 20 years in Korea. The majority (68.8%) responded that they would not purchase Japanese seafood when radioactivity levels in the food were non-detectable. Moreover, 82.2% responded that the current levels of import restrictions on Japanese seafood must be maintained. Despite many concerns regarding the exposure to radiation and the effects from food products following the Fukushima accident, the opportunities to encounter and to collect correct information remain limited and average radioactive knowledge scores were low (3.63 out of 9). Of the various characteristics associated with purchase decisions and agreement on the current import restraints of Japanese seafood, trust levels in the government and the mass media for providing information on radioactivity were major factors that influenced risk perception. While the scope of this study was limited to seafood, it is very closely tied to daily lives, where we revealed differences about risk perceptions and agreement on import restraints of Japanese seafood per a complex mixture of individual characteristics and the surrounding environment. These results provide useful information to understand the risk perception of the potential radioactive contamination of food and to predict the public's responses to food consumption and import restraint policies due to nuclear accidents in neighboring countries. PMID- 29117236 TI - Effects of CD49d-targeted antisense-oligonucleotide on alpha4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies. AB - We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including beta1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin beta1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into "clinical" benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve. PMID- 29117238 TI - TDF and quantitative ultrasound bone quality in African patients on second line ART, ANRS 12169 2LADY sub-study. AB - BACKGROUND: Bone demineralization, which leads to osteoporosis and increased fracture risk, is a common metabolic disorder in HIV-infected individuals. In this study, we aimed to assess the change in bone quality using quantitative ultrasound (QUS) over 96 weeks of follow-up after initiation of second-line treatment, and to identify factors associated with change in bone quality. METHODS AND FINDINGS: In a randomized trial (ANRS 12169), TDF and PI-naive participants failing standard first-line treatment, from Burkina Faso, Cameroon, and Senegal were randomized to receive either TDF/FTC/LPVr, ABC/ddI/LPVr or TDF/FTC/DRVr. Their bone quality was assessed using calcaneal QUS at baseline and every 24 weeks until week 96. Stiffness index (SI) was used to measure bone quality. Out of 228 participants, 168 (74%) were women. At baseline, median age was 37 years (IQR: 33-46 years) and median T-CD4 count was 199 cells/MUl (IQR: 113-319 cells/MUl). The median duration of first-line antiretroviral treatment (ART) was 52 months (IQR: 36-72 months) and the median baseline SI was 101 (IQR: 87-116). In multivariable analysis, factors associated with baseline SI were sex (beta = -10.8 [-18.1,-3.5] for women), age (beta = -8.7 [-12.4,-5.1] per 10 years), body mass index (BMI) (beta = +0.8 [0.1,1.5] per unit of BMI), and study site (beta = +12.8 [6.5,19.1] for Cameroon). After 96 weeks of second-line therapy, a reduction of 7.1% in mean SI was observed, as compared with baseline. Factors associated with SI during the follow-up were similar to those found at baseline. Exposure to TDF was not associated with a greater loss of bone quality over time. CONCLUSION: Bone quality decreased after second-line ART initiation in African patients independently of TDF exposure. Factors associated with bone quality include age, sex, baseline BMI, study site, and duration of follow-up. PMID- 29117239 TI - Novel viruses in salivary glands of mosquitoes from sylvatic Cerrado, Midwestern Brazil. AB - Viruses may represent the most diverse microorganisms on Earth. Novel viruses and variants continue to emerge. Mosquitoes are the most dangerous animals to humankind. This study aimed at identifying viral RNA diversity in salivary glands of mosquitoes captured in a sylvatic area of Cerrado at the Chapada dos Guimaraes National Park, Mato Grosso, Brazil. In total, 66 Culicinae mosquitoes belonging to 16 species comprised 9 pools, subjected to viral RNA extraction, double-strand cDNA synthesis, random amplification and high-throughput sequencing, revealing the presence of seven insect-specific viruses, six of which represent new species of Rhabdoviridae (Lobeira virus), Chuviridae (Cumbaru and Croada viruses), Totiviridae (Murici virus) and Partitiviridae (Araticum and Angico viruses). In addition, two mosquito pools presented Kaiowa virus sequences that had already been reported in South Pantanal, Brazil. These findings amplify the understanding of viral diversity in wild-type Culicinae. Insect-specific viruses may present a broader diversity than previously imagined and future studies may address their possible role in mosquito vector competence. PMID- 29117240 TI - The Demirjian versus the Willems method for dental age estimation in different populations: A meta-analysis of published studies. AB - BACKGROUND: The accuracy of radiographic methods for dental age estimation is important for biological growth research and forensic applications. Accuracy of the two most commonly used systems (Demirjian and Willems) has been evaluated with conflicting results. This study investigates the accuracies of these methods for dental age estimation in different populations. METHODS: A search of PubMed, Scopus, Ovid, Database of Open Access Journals and Google Scholar was undertaken. Eligible studies published before December 28, 2016 were reviewed and analyzed. Meta-analysis was performed on 28 published articles using the Demirjian and/or Willems methods to estimate chronological age in 14,109 children (6,581 males, 7,528 females) age 3-18 years in studies using Demirjian's method and 10,832 children (5,176 males, 5,656 females) age 4-18 years in studies using Willems' method. The weighted mean difference at 95% confidence interval was used to assess accuracies of the two methods in predicting the chronological age. RESULTS: The Demirjian method significantly overestimated chronological age (p<0.05) in males age 3-15 and females age 4-16 when studies were pooled by age cohorts and sex. The majority of studies using Willems' method did not report significant overestimation of ages in either sex. Overall, Demirjian's method significantly overestimated chronological age compared to the Willems method (p<0.05). The weighted mean difference for the Demirjian method was 0.62 for males and 0.72 for females, while that of the Willems method was 0.26 for males and 0.29 for females. CONCLUSION: The Willems method provides more accurate estimation of chronological age in different populations, while Demirjian's method has a broad application in terms of determining maturity scores. However, accuracy of Demirjian age estimations is confounded by population variation when converting maturity scores to dental ages. For highest accuracy of age estimation, population-specific standards, rather than a universal standard or methods developed on other populations, need to be employed. PMID- 29117241 TI - IFNGR1 signaling is associated with adverse pregnancy outcomes during infection with malaria parasites. AB - Complicated/severe cases of placental pathology due to Plasmodium falciparum and P. vivax, especially adverse pregnancy outcomes during P. vivax infection, have been increasing in recent years. However, the pathogenesis of placental pathology during severe malaria is poorly understood, while responses against IFN-gamma are thought to be associated with adverse pregnancy outcomes. In the present study, we explored the role of IFN-gamma receptor 1 (IFNGR1) signaling in placental pathology during severe malaria using luciferase-expressing rodent malaria parasites, P. berghei NK65 (PbNK65L). We detected luciferase activities in the lung, spleen, adipose tissue, and placenta in pregnant mice, suggesting that infected erythrocytes could accumulate in various organs during infection. Importantly, we found that fetal mortality in IFNGR1-deficient mice infected with PbNK65L parasites was much less than in infected wild type (WT) mice. Placental pathology was also improved in IFNGR1-deficient mice. In contrast, bioluminescence imaging showed that parasite accumulation in the placentas of IFNGR1-deficient pregnant mice was comparable to that in WT mice infected with PbNK65L. These findings suggest that IFNGR1 signaling plays a pivotal role in placental pathology and subsequent adverse pregnancy outcomes during severe malaria. Our findings may increase our understanding of how disease aggravation occurs during malaria during pregnancy. PMID- 29117242 TI - The keybox: Shape-frame fitting during tool use in Goffin's cockatoos (Cacatua goffiniana). AB - The ability to move an object in alignment to a surface develops early in human ontogeny. However, aligning not just your own body but also the object itself in relation to a surface with a specific shape requires using landmarks rather than the own body as a frame of reference for orientation. The ability to do so is considered important in the development of tool use behaviour in human and non human animals. Aside from humans, with the exception of a single study on habitually tool using primates, shape-frame matching abilities remain largely unstudied. The Goffin's cockatoo is a generalist parrot, and not a specialised tool user but has shown the capacity to innovate and use different types of tools under controlled settings. We tested these parrots in a tool selection and tool use task featuring objects and their corresponding substrate grooves in a number of shapes with different levels of symmetry. Subjects had to choose the correct 'key' to insert into a box, and align its shape to fit into the corresponding 'keyhole' in the box. The parrots were able to select the correct key above chance level from early on in the experiment. Despite their lack of hands, they required fewer placement attempts than primates to insert simple object shapes into corresponding grooves. For complex shapes, they reduced their insertion effort by rotating shapes in their beak while avoiding as many protrusions as possible. Unrewarded play experience with similar object shapes was provided to some of the subjects previously to testing, but did not seem to have an effect on the number of correct choices or on insertion effort. PMID- 29117245 TI - An incremental anomaly detection model for virtual machines. AB - Self-Organizing Map (SOM) algorithm as an unsupervised learning method has been applied in anomaly detection due to its capabilities of self-organizing and automatic anomaly prediction. However, because of the algorithm is initialized in random, it takes a long time to train a detection model. Besides, the Cloud platforms with large scale virtual machines are prone to performance anomalies due to their high dynamic and resource sharing characters, which makes the algorithm present a low accuracy and a low scalability. To address these problems, an Improved Incremental Self-Organizing Map (IISOM) model is proposed for anomaly detection of virtual machines. In this model, a heuristic-based initialization algorithm and a Weighted Euclidean Distance (WED) algorithm are introduced into SOM to speed up the training process and improve model quality. Meanwhile, a neighborhood-based searching algorithm is presented to accelerate the detection time by taking into account the large scale and high dynamic features of virtual machines on cloud platform. To demonstrate the effectiveness, experiments on a common benchmark KDD Cup dataset and a real dataset have been performed. Results suggest that IISOM has advantages in accuracy and convergence velocity of anomaly detection for virtual machines on cloud platform. PMID- 29117243 TI - Virome analysis of two sympatric bat species (Desmodus rotundus and Molossus molossus) in French Guiana. AB - Environmental disturbances in the Neotropics (e.g., deforestation, agriculture intensification, urbanization) contribute to an increasing risk of cross-species transmission of microorganisms and to disease outbreaks due to changing ecosystems of reservoir hosts. Although Amazonia encompasses the greatest diversity of reservoir species, the outsized viral population diversity (virome) has yet to be investigated. Here, through a metagenomic approach, we identified 10,991 viral sequences in the saliva and feces of two bat species, Desmodus rotundus (hematophagous), trapped in two different caves surrounded by primary lowland forest, and Molossus molossus (insectivorous), trapped in forest and urban habitats. These sequences are related to 51 viral families known to infect a wide range of hosts (i.e., bacteria, plants, insects and vertebrates). Most viruses detected reflected the diet of bat species, with a high proportion of plant and insect-related viral families for M. molossus and a high proportion of vertebrate-related viral families for D. rotundus, highlighting its influence in shaping the viral diversity of bats. Lastly, we reconstructed the phylogenetic relationships for five vertebrate-related viral families (Nairoviridae, Circoviridae, Retroviridae, Herpesviridae, Papillomaviridae). The results showed highly supported clustering with other viral sequences of the same viral family hosted by other bat species, highlighting the potential association of viral diversity with the host's diet. These findings provide significant insight into viral bat diversity in French Guiana belonging to the Amazonian biome and emphasize that habitats and the host's dietary ecology may drive the viral diversity in the bat communities investigated. PMID- 29117244 TI - Re-establishing safer medical-circumcision-integrated initiation ceremonies for HIV prevention in a rural setting in Papua New Guinea. A multi-method acceptability study. AB - BACKGROUND: Efforts to stem the spread of Human Immunodeficiency Virus (HIV) in Papua New Guinea (PNG) are hampered by multiple interrelated factors including limited health services, extreme diversities in culture and language and highly prevalent gender inequity, domestic violence and poverty. In the rural district of Yangoru-Saussia, a revival of previously ceased male initiation ceremonies (MICs) is being considered for a comprehensive approach to HIV prevention. In this study, we explore the local acceptability of this undertaking including replacing traditional penile cutting practices with medical male circumcision (MMC). METHODS: A multi-method study comprising three phases. Phase one, focus group discussions with male elders to explore locally appropriate approaches to HIV prevention; Phase two, interviews and a cross-sectional survey with community men and women to assess views on MICs that include MMC for HIV prevention; Phase three, interviews with cultural leaders and a cross sectional survey to assess the acceptability of replacing traditional penile bleeding with MMC. RESULTS: Cultural leaders expressed that re-establishing MICs was locally appropriate for HIV prevention given the focus on character building and cultural preservation. Most surveyed participants (81.5%) supported re-establishing MICs and 92.2% supported adapting MICs with MMC. Changes to penile bleeding emerged as a contentious and contested issue given its cultural significance in symbolizing initiates' transition from childhood to adulthood. Participants were concerned about potential clash with modern education, introduced religious beliefs and limited government support in leadership and funding. CONCLUSIONS: Most people in this study in Yangoru-Saussia support re-establishing MICs and replacing traditional penile bleeding with MMC. This culturally-sensitive alignment of MMC (and HIV prevention) with revived MICs responds to a national health priority in PNG and acts as an example of providing culturally-sensitive male circumcision for HIV prevention recommended by WHO/UNAIDS. However, the implementation of this undertaking will require considerable effort, especially when modern pursuits in education and religion must be factored and when there is expectation for local authorities to lead and provide funding. PMID- 29117246 TI - Is there a problem with quantum models of psychological measurements? AB - This article presents the results of an experiment, called the ABA experiment, designed to test a fundamental prediction of quantum probability theory when applied to human judgments and decisions. The prediction concerns the effect of one measurement on another when the measurements are incompatible (i.e., the answers to the measurements depend on the order of these measurements). After an initial measurement of an opinion on an issue, A, the answer to a second measurement on the same issue A immediately afterwards will certainly be the same as the first. However, according to the uncertainty principle, if a measurement of opinion on issue A is followed by an incompatible measurement on another issue, B, then the answer to a second measurement on issue A will become uncertain. This prediction was tested with 325 participants on a wide range of 12 different set of issues that were previously shown to be incompatible. Contrary to previous claims published in this journal, the empirical findings support the prediction of quantum probability theory applied to human judgments. PMID- 29117247 TI - A mobile loop near the active site acts as a switch between the dual activities of a viral protease/deubiquitinase. AB - The positive-strand RNA virus Turnip yellow mosaic virus (TYMV) encodes an ovarian tumor (OTU)-like protease/deubiquitinase (PRO/DUB) protein domain involved both in proteolytic processing of the viral polyprotein through its PRO activity, and in removal of ubiquitin chains from ubiquitylated substrates through its DUB activity. Here, the crystal structures of TYMV PRO/DUB mutants and molecular dynamics simulations reveal that an idiosyncratic mobile loop participates in reversibly constricting its unusual catalytic site by adopting "open", "intermediate" or "closed" conformations. The two cis-prolines of the loop form a rigid flap that in the most closed conformation zips up against the other side of the catalytic cleft. The intermediate and closed conformations also correlate with a reordering of the TYMV PRO/DUB catalytic dyad, that then assumes a classical, yet still unusually mobile, OTU DUB alignment. Further structure based mutants designed to interfere with the loop's mobility were assessed for enzymatic activity in vitro and in vivo, and were shown to display reduced DUB activity while retaining PRO activity. This indicates that control of the switching between the dual PRO/DUB activities resides prominently within this loop next to the active site. Introduction of mutations into the viral genome revealed that the DUB activity contributes to the extent of viral RNA accumulation both in single cells and in whole plants. In addition, the conformation of the mobile flap was also found to influence symptoms severity in planta. Such mutants now provide powerful tools with which to study the specific roles of reversible ubiquitylation in viral infection. PMID- 29117248 TI - Medial knee loading is altered in subjects with early osteoarthritis during gait but not during step-up-and-over task. AB - This study evaluates knee joint loading during gait and step-up-and-over tasks in control subjects, subjects with early knee OA and those with established knee OA. Thirty-seven subjects with varying degrees of medial compartment knee OA severity (eighteen with early OA and sixteen with established OA), and nineteen healthy controls performed gait and step-up-and-over tasks. Knee joint moments, contact forces (KCF), the magnitude of contact pressures and center of pressure (CoP) location were analyzed for the three groups for both activities using a multi body knee model with articular cartilage contact, 14 ligaments, and six degrees of freedom tibiofemoral and patellofemoral joints. During gait, the first peak of the medial KCF was significantly higher for patients with early knee OA (p = 0.048) and established knee OA (p = 0.001) compared to control subjects. Furthermore, the medial contact pressure magnitudes and CoP location were significantly different in both groups of patients compared to controls. Knee rotation moments (KRMs) and external rotation angles were significantly higher during early stance in both patient groups (p < 0.0001) compared to controls. During step-up-and-over, there was a high variability between the participants and no significant differences in KCF were observed between the groups. Knee joint loading and kinematics were found to be altered in patients with early knee OA only during gait. This is an indication that an excessive medial KCF and altered loading location, observed in these patients, is a contributor to early progression of knee OA. PMID- 29117249 TI - Multimodel inference applied to oxygen recovery kinetics after 6-min walk tests in patients with chronic obstructive pulmonary disease. AB - 6-min walk tests (6MWT) are routinely performed in patients with chronic obstructive pulmonary disease (COPD). Oxygen uptake ([Formula: see text]) kinetics during 6MWT can be modeled and derived parameters provide indicators of patients' exercise capacity. Post-exercise [Formula: see text] recovery also provides important parameters of patients' fitness which has not been extensively investigated in COPD. Several nonlinear regression models with different underlying biological assumptions may be suitable for describing recovery kinetics. Multimodel inference (model averaging) can then be used to capture the uncertainty in considering several models. Our aim was to apply multimodel inference in order to better understand the physiological underpinnings of [Formula: see text] recovery after 6MWT in patients with COPD. 61 patients with COPD (stages 2 to 4) were included in this study. Oxygen kinetics during 6MWT were modeled using nonlinear regression. Three statistical approaches (mixed effects, meta-analysis and weighted regression) were compared in order to summarize estimates obtained from multiple kinetics. The recovery phase was modeled using 3 distinct equations (log-logistic, Weibull 1 and Weibull 2). Three models were fitted to the set of 61 kinetics. A significant model-averaged difference of 40.39 sec (SE = 17.1) in the time to half decrease of [Formula: see text] level ([Formula: see text]) was found between stage 2 and 4 (p = 0.0178). In addition, the Weibull 1 model characterized by a steeper decrease at the beginning of the recovery phase showed some improvement of goodness of fit when fitted to the kinetics of patients with stage 2 COPD in comparison with the 2 other models. Multimodel inference was successfully used to model [Formula: see text] recovery after 6MWT in patients with COPD. Significant model-averaged differences in [Formula: see text] were found between moderate and very severe COPD patients. Furthermore, specific patterns of [Formula: see text] recovery could be identified across COPD stages. PMID- 29117250 TI - Effect of nitrogen levels and nitrogen ratios on lodging resistance and yield potential of winter wheat (Triticum aestivum L.). AB - Lodging is one of the constraints that limit wheat yields and quality due to the unexpected bending or breaking stems on wheat (Triticum aestivum L.) production worldwide. In addition to choosing lodging resistance varieties, husbandry practices also have a significant effect on lodging. Nitrogen management is one of the most common and efficient methods. A field experiment with Yangmai 20 as research material (a widely-used variety) was conducted to study the effects of different nitrogen levels and ratios on culm morphological, anatomical characters and chemical components and to explore the nitrogen application techniques for lodging tolerance and high yield. Results showed that some index of basal internodes, such as stem wall thickness, filling degree, lignin content, cellulose content, water-soluble carbohydrate (WSC) and WSC/N ratio, were positively and significantly correlated with culm lodging-resistant index (CLRI). As the increase of nitrogen level and basal nitrogen ratio, the basal internodes became slender and fragile with the thick stem wall, while filling degree, chemical components and the strength of the stem decreased gradually, which significantly increased the lodging risk. The response of grain yield to nitrogen doses was quadratic and grain yield reached the highest at the nitrogen ratio of 50%:10%:20%:20% (the ratio of nitrogen amount applied before sowing, at tillering stage, jointing stage and booting stage respectively, abbreviated as 5:1:2:2). These results suggested that for Yangmai 20, the planting density of 180*104ha-1, nitrogen level of 225 kg ha-1, and the ratio of 5: 1: 2: 2 effectively increased lodging resistance and grain yield. This combination of planting density and nitrogen level and ratio could effectively relieve the contradiction between high yielding and anti-lodging. PMID- 29117251 TI - The CXCL12/CXCR7 signaling axis, isoforms, circadian rhythms, and tumor cellular composition dictate gradients in tissue. AB - Chemokine CXCL12 gradients drive chemotaxis in a CXCR4-dependent mechanism and have been implicated in cancer metastasis. While CXCL12 gradients are typically studied in organized, defined environments, the tumor microenvironment is disorganized. In vivo, CXCL12 gradients depend on many factors: the number and arrangement of cells secreting and degrading CXCL12, isoform-dependent binding to the extracellular matrix, diffusion, and circadian fluctuations. We developed a computational model of the tumor microenvironment to simulate CXCL12 gradient dynamics in disorganized tissue. There are four major findings from the model. First, CXCL12-beta and -gamma form higher magnitude (steeper) gradients compared to CXCL12-alpha. Second, endothelial CXCR7+ cells regulate CXCL12 gradient direction by controlling concentrations near but not far from the vasculature. Third, the magnitude and direction of CXCL12 gradients are dependent on the local composition of secreting and scavenging cells within the tumor. We theorize that "micro-regions" of cellular heterogeneity within the tumor are responsible for forming strong gradients directed into the blood. Fourth, CXCL12 circadian fluctuations influence gradient magnitude but not direction. Our simulations provide predictions for future experiments in animal models. Understanding the generation of CXCL12 gradients is crucial to inhibiting cancer metastasis. PMID- 29117252 TI - Preclinical 4D-flow magnetic resonance phase contrast imaging of the murine aortic arch. AB - PURPOSE: Cardiovascular diseases remain the number one death cause worldwide. Preclinical 4D flow phase contrast magnetic resonance imaging can provide substantial insights in the analysis of aortic pathophysiologies in various animal models. These insights may allow a better understanding of pathophysiologies, therapy monitoring, and can possibly be translated to humans. This study provides a framework to acquire the velocity field within the aortic arch. It analyses important flow values at different locations within the aortic arch. Imaging parameters with high temporal and spatial resolution are provided, that still allow combining this time-consuming method with other necessary imaging-protocols. METHODS: A new setup was established where a prospectively gated 4D phase contrast sequence is combined with a highly sensitive cryogenic coil on a preclinical magnetic resonance scanner. The sequence was redesigned to maintain a close to steady state condition of the longitudinal magnetization and hence to overcome steady state artifacts. Imaging parameters were optimized to provide high spatial and temporal resolution. Pathline visualizations were generated from the acquired velocity data in order to display complex flow patterns. RESULTS: Our setup allows data acquisition with at least two times the rate than that of previous publications based on Cartesian encoding, at an improved image quality. The "steady state" sequence reduces observed artifacts and provides uniform image intensity over the heart cycle. This made possible quantification of blood speed and wall shear stress (WSS) within the aorta and its branches. The highest velocities were observed in the ascending aorta with 137.5 +/- 8 cm/s. Peak velocity values in the Brachiocephalic trunk were 57 +/- 12 cm/s. Quantification showed that the peak flow occurs around 20 ms post R-wave in the ascending aorta. The highest mean axial wall shear stress was observed in the analysis plane between the left common carotid artery (LCCA) and the left subclavian artery. A stable image quality allows visualizing complex flow patterns by means of streamlines and for the first time, to the best of our knowledge, pathline visualizations from 4D flow MRI in mice. CONCLUSION: The described setup allows analyzing pathophysiologies in mouse models of cardiovascular diseases in the aorta and its branches with better image quality and higher spatial and temporal resolution than previous Cartesian publications. Pathlines provide an advanced analysis of complex flow patterns in the murine aorta. An imaging protocol is provided that offers the possibility to acquire the aortic arch at sufficiently high resolution in less than one hour. This allows the combination of the flow assessment with other multifunctional imaging protocols. PMID- 29117253 TI - The physiological determinants of drug-induced lysosomal stress resistance. AB - Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs. PMID- 29117254 TI - Link-N: The missing link towards intervertebral disc repair is species-specific. AB - INTRODUCTION: Degeneration of the intervertebral disc (IVD) is a frequent cause for back pain in humans and dogs. Link-N stabilizes proteoglycan aggregates in cartilaginous tissues and exerts growth factor-like effects. The human variant of Link-N facilitates IVD regeneration in several species in vitro by inducing Smad1 signaling, but it is not clear whether this is species specific. Dogs with IVD disease could possibly benefit from Link-N treatment, but Link-N has not been tested on canine IVD cells. If Link-N appears to be effective in canines, this would facilitate translation of Link-N into the clinic using the dog as an in vivo large animal model for human IVD degeneration. MATERIALS AND METHODS: This study's objective was to determine the effect of the human and canine variant of Link-N and short (s) Link-N on canine chondrocyte-like cells (CLCs) and compare this to those on already studied species, i.e. human and bovine CLCs. Extracellular matrix (ECM) production was determined by measuring glycosaminoglycan (GAG) content and histological evaluation. Additionally, the micro-aggregates' DNA content was measured. Phosphorylated (p) Smad1 and -2 levels were determined using ELISA. RESULTS: Human (s)Link-N induced GAG deposition in human and bovine CLCs, as expected. In contrast, canine (s)Link-N did not affect ECM production in human CLCs, while it mainly induced collagen type I and II deposition in bovine CLCs. In canine CLCs, both canine and human (s)Link-N induced negligible GAG deposition. Surprisingly, human and canine (s)Link-N did not induce Smad signaling in human and bovine CLCs. Human and canine (s)Link-N only mildly increased pSmad1 and Smad2 levels in canine CLCs. CONCLUSIONS: Human and canine (s)Link-N exerted species-specific effects on CLCs from early degenerated IVDs. Both variants, however, lacked the potency as canine IVD regeneration agent. While these studies demonstrate the challenges of translational studies in large animal models, (s)Link-N still holds a regenerative potential for humans. PMID- 29117255 TI - Utilization of urea and expression profiles of related genes in the dinoflagellate Prorocentrum donghaiense. AB - Urea has been shown to contribute more than half of total nitrogen (N) required by phytoplankton in some estuaries and coastal waters and to provide a substantial portion of the N demand for many harmful algal blooms (HABs) of dinoflagellates. In this study, we investigated the physiological and transcriptional responses in Prorocentrum donghaiense to changes in nitrate and urea availability. We found that this species could efficiently utilize urea as sole N source and achieve comparable growth rate and photosynthesis capability as it did under nitrate. These physiological parameters were markedly lower in cultures grown under nitrate- or urea-limited conditions. P. donghaiense N content was similarly low under nitrate- or urea-limited culture condition, but was markedly higher under urea-replete condition than under nitrate-replete condition. Carbon (C) content was consistently elevated under N-limited condition. Consequently, the C:N ratio was as high as 21:1 under nitrate- or urea limitation, but 7:1 under urea-replete condition and 9:1 to 10:1 under nitrate replete condition. Using quantitative reverse transcription PCR, we investigated the expression pattern for four genes involved in N transport and assimilation. The results indicated that genes encoding nitrate transport, urea hydrolysis, and nickel transporter gene were sensitive to changes in general N nutrient availability whereas the urea transporter gene responded much more strongly to changes in urea concentration. Taken together, our study shows the high bioavailability of urea, its impact on C:N stoichiometry, and the sensitivity of urea transporter gene expression to urea availability. PMID- 29117256 TI - MRI-defined paraspinal muscle morphology in Japanese population: The Wakayama Spine Study. AB - OBJECTIVE: This study aimed to establish sex- and age-dependent distributions of the cross sectional area and fatty infiltration ratio of paraspinal muscles, and to examine the correlation between paraspinal muscle degeneration and low back pain in the Japanese population. METHODS: In this cross-sectional study, data from 796 participants (241 men, 555 women; mean age, 63.5 years) were analyzed. The measurement of the cross sectional area and fatty infiltration ratio of the erector spinae and multifidus from the level of T12/L1 to L4/5 and psoas major at the level of T12/L1 was performed using axial T2-weighted magnetic resonance imaging. Multivariate logistic regression analysis was used to estimate the association between fatty infiltration of the paraspinal muscles and the prevalence of low back pain. RESULTS: The cross sectional area was larger in men than women, and tended to decrease with age, with the exception of the erector spinae at T12/L1 and L1/2 in women. The fatty infiltration ratio was lower in men than women, except for multifidus at T12/L1 in 70-79 year-olds and psoas major in those less than 50 years-old, and tended to increase with age. Logistic regression analysis adjusted for age, sex, and body mass index showed that the fatty infiltration ratio of the erector spinae at L1/2 and L2/3 was significantly associated with low back pain (L1/2 level: odds ratio, 1.05; 95% confidence interval, 1.005-1.104; L2/3 level: odds ratio, 1.05; 95% confidence interval, 1.001-1.113). CONCLUSION: This study measured the cross sectional area and fatty infiltration ratio of paraspinal muscles in the Japanese population using magnetic resonance imaging, and demonstrated that the fatty infiltration ratio of the erector spinae in the upper lumbar spine was significantly associated with the presence of low back pain. The measurements could be used as reference values, which are important for future comparative studies. PMID- 29117257 TI - Feeling younger and identifying with older adults: Testing two routes to maintaining well-being in the face of age discrimination. AB - Integrating the social identity and aging literatures, this work tested the hypothesis that there are two independent, but simultaneous, responses by which adults transitioning into old age can buffer themselves against age discrimination: an individual response, which entails adopting a younger subjective age when facing discrimination, and a collective response, which involves increasing identification with the group of older adults. In three experimental studies with a total number of 488 older adults (50 to 75 years of age), we manipulated age discrimination in a job application scenario and measured the effects of both responses on perceived health and self-esteem. Statistical analyses include individual study results as well as a meta-analysis on the combined results of the three studies. Findings show consistent evidence only for the individual response, which was in turn associated with well-being. Furthermore, challenging previous research, the two responses (adopting a younger subjective age and increasing group identification) were not only theoretically, but also empirically distinct. This research complements prior research by signaling the value of considering both responses to discrimination as complementary rather than mutually exclusive. PMID- 29117258 TI - Lung epithelial response to cigarette smoke and modulation by the nicotinic alpha 7 receptor. AB - Cigarette smoking (CS) is a principal contributor to a spectrum of devastating lung diseases whose occurrence and severity may vary between individuals and not appear for decades after prolonged use. One explanation for the variability and delay in disease onset is that nicotine, the addictive component of CS, acts through the ionotropic nicotinic acetylcholine receptor (nAChR) alpha7 (alpha7) to modulate anti-inflammatory protection. In this study we measured the impact alpha7 signaling has on the mouse distal lung response to side-stream CS exposure for mice of the control genotype (alpha7G) and those in which the alpha7-receptor signaling mechanisms are restricted by point mutation (alpha7E260A:G). Flow cytometry results show that after CS there is an increase in a subset of CD11c (CD11chi) alveolar macrophages (AMs) and histology reveals an increase in these cells within the alveolar space in both genotypes although the alpha7E260A:G AMs tend to accumulate into large aggregates rather than more widely distributed solitary cells common to the alpha7G lung after CS. Changes to lung morphology with CS in both genotypes included increased tissue cavitation due to alveolar expansion and bronchial epithelium dysplasia in part associated with altered club cell morphology. RNA-Seq analysis revealed changes in epithelium gene expression after CS are largely independent of the alpha7-genotype. However, the alpha7E260A:G genotype did reveal some unique variations to transcript expression of gene sets associated with immune responsiveness and macrophage recruitment, hypoxia, genes encoding mitochondrial respiration complex I and extracellular fibrillary matrix proteins (including alterations to fibrotic deposits in the alpha7G proximal airway bronchioles after CS). These results suggest alpha7 has a central role in modulating the response to chronic CS that could include altering susceptibility to associated lung diseases including fibrosis and cancer. PMID- 29117259 TI - Community structure of the metabolically active rumen bacterial and archaeal communities of dairy cows over the transition period. AB - Dairy cows experience dramatic changes in host physiology from gestation to lactation period and dietary switch from high-forage prepartum diet to high concentrate postpartum diet over the transition period (parturition +/- three weeks). Understanding the community structure and activity of the rumen microbiota and its associative patterns over the transition period may provide insight for e.g. improving animal health and production. In the present study, rumen samples from ten primiparous Holstein dairy cows were collected over seven weeks spanning the transition period. Total RNA was extracted from the rumen samples and cDNA thereof was subsequently used for characterizing the metabolically active bacterial (16S rRNA transcript amplicon sequencing) and archaeal (qPCR, T-RFLP and mcrA and 16S rRNA transcript amplicon sequencing) communities. The metabolically active bacterial community was dominated by three phyla, showing significant changes in relative abundance range over the transition period: Firmicutes (from prepartum 57% to postpartum 35%), Bacteroidetes (from prepartum 22% to postpartum 18%) and Proteobacteria (from prepartum 7% to postpartum 32%). For the archaea, qPCR analysis of 16S rRNA transcript number, revealed a significant prepartum to postpartum increase in Methanobacteriales, in accordance with an observed increase (from prepartum 80% to postpartum 89%) in relative abundance of 16S rRNA transcript amplicons allocated to this order. On the other hand, a significant prepartum to postpartum decrease (from 15% to 2%) was observed in relative abundance of Methanomassiliicoccales 16S rRNA transcripts. In contrast to qPCR analysis of the 16S rRNA transcripts, quantification of mcrA transcripts revealed no change in total abundance of metabolically active methanogens over the transition period. According to T-RFLP analysis of the mcrA transcripts, two Methanobacteriales genera, Methanobrevibacter and Methanosphaera (represented by the T-RFs 39 and 267 bp), represented more than 70% of the metabolically active methanogens, showing no significant changes over the transition period; minor T-RFs, likely to represent members of the order Methanomassiliicoccales and with a relative abundance below 5% in total, decreased significantly over the transition period. In accordance with the T-RFLP analysis, the mcrA transcript amplicon sequencing revealed Methanobacteriales to cover 99% of the total reads, dominated by the genera Methanobrevibacter (75%) and Methanosphaera (24%), whereas the Methanomassiliicoccales order covered only 0.2% of the total reads. In conclusion, the present study showed that the structure of the metabolically active bacterial and archaeal rumen communities changed over the transition period, likely in response to the dramatic changes in physiology and nutritional factors like dry matter intake and feed composition. It should be noted however that for the methanogens, the observed community changes were influenced by the analyzed gene (mcrA or 16S rRNA). PMID- 29117260 TI - The association of visual memory with hippocampal volume. AB - BACKGROUND: In this study we investigated the role of hippocampal volume (HV) in visual memory. METHODS: Participants were a subsample of older adults (> = 70 years) from the Einstein Aging Study. Visual performance was measured using the Complex Figure (CF) copy and delayed recall tasks from the Repeatable Battery for the Assessment of Neuropsychological Status. Linear regressions were fitted to study associations between HV and visual tasks. RESULTS: Participants' (n = 113, mean age = 78.9 years) average scores on the CF copy and delayed recall were 17.4 and 11.6, respectively. CF delayed recall was associated with total (beta = .031, p = 0.001) and left (beta = 0.031, p = 0.001) and right HVs (beta = 0.24, p = 0.012). CF delayed recall remained significantly associated with left HV even after we also included right HV (beta = 0.27, p = 0.025) and the CF copy task (beta = 0.30, p = 0.009) in the model. CF copy did not show any significant associations with HV. CONCLUSION: Our results suggest that left HV contributes in retrieval of visual memory in older adults. PMID- 29117261 TI - Diagnostic accuracy of the ROCHE Septifast PCR system for the rapid detection of blood pathogens in neonatal sepsis-A prospective clinical trial. AB - INTRODUCTION: Diagnosis of neonatal sepsis remains a major challenge in neonatology. Most molecular-based methods are not customized for neonatal requirements. The aim of the present study was to assess the diagnostic accuracy of a modified multiplex PCR protocol for the detection of neonatal sepsis using small blood volumes. METHODS: 212 episodes of suspected neonatal late onset sepsis were analyzed prospectively using the Roche SeptiFast(r) MGRADE PCR with a modified DNA extraction protocol and software-handling tool. Results were compared to blood culture, laboratory biomarkers and clinical signs of sepsis. RESULTS: Of 212 episodes, 85 (40.1%) were categorized as "not infected". Among these episodes, 1 was false positive by blood culture (1.2%) and 23 were false positive by PCR (27.1%). Of 51 (24.1%) episodes diagnosed as "culture proven sepsis", the same pathogen was detected by blood culture and PCR in 39 episodes (76.5%). In 8 episodes, more pathogens were detected by PCR compared to blood culture, and in 4 episodes the pathogen detected by blood culture was not found by PCR. One of these episodes was caused by Bacillus cereus, a pathogen not included in the PCR panel. In 76/212 (35.8%) episodes, clinical sepsis was diagnosed. Among these, PCR yielded positive results in 39.5% of episodes (30/76 episodes). For culture-positive sepsis, PCR showed a sensitivity of 90.2% (95%CI 86.2-94.2%) and a specificity of 72.9% (95%CI 67.0-79.0%). CONCLUSION: The Roche SeptiFast(r) MGRADE PCR using a modified DNA extraction protocol showed acceptable results for rapid detection of neonatal sepsis in addition to conventional blood culture. The benefit of rapid pathogen detection has to be balanced against the considerable risk of contamination, loss of information on antibiotic sensitivity pattern and increased costs. PMID- 29117262 TI - Benthic colonization in newly ice-free soft-bottom areas in an Antarctic fjord. AB - Extended glacier retreat is among the main consequences of the rapid warming of the West Antarctic Peninsula. Particularly, in the inner part of Potter Cove (South Shetland Islands, Antarctica) large areas are now exposed to open sea conditions owing to the retreat of Fourcade glacier. During the 2010 austral summer, underwater photographic surveys were undertaken by SCUBA diving up to 30 m in these new ice-free areas 80 m from the glacier front. Our main aim was to investigate colonization and early succession of the benthic assemblages on soft bottom areas. Here, we reported a total of 1,146 animals belonging to 13 taxa. Filter-feeders comprised the largest trophic group and sessile fauna showed much higher coverages and densities than mobile fauna at all depths. The most abundant groups were ascidians and bryozoans, which together comprised ~90% of all taxa documented. In a region where most of marine-terminating glaciers are in retreat, these results are an important contribution to improve our knowledge on colonization in the newly ice-free areas. PMID- 29117263 TI - Genetic health and population monitoring of two small black bear (Ursus americanus) populations in Alabama, with a regional perspective of genetic diversity and exchange. AB - One of the major concerns in conservation today is the loss of genetic diversity which is a frequent consequence of population isolation and small population sizes. Fragmentation of populations and persecution of carnivores has posed a substantial threat to the persistence of free ranging carnivores in North America since the arrival of European settlers. Black bears have seen significant reductions in range size from their historic extent, which is most pronounced in the southeastern United States and even more starkly in Alabama where until recently bears were reduced to a single geographically isolated population in the Mobile River Basin. Recently a second population has naturally re-established itself in northeastern Alabama. We sought to determine size, genetic diversity and genetic connectivity for these two populations in relation to other regional populations. Both populations of black bears in Alabama had small population sizes and had moderate to low genetic diversity, but showed different levels of connectivity to surrounding populations of bears. The Mobile River Basin population had a small population size at only 86 individuals (76-124, 95% C.I.), the lowest genetic diversity of compared populations (richness = 2.33, Ho and He = 0.33), and showed near complete genetic isolation from surrounding populations across multiple tests. The newly recolonizing population in northeastern Alabama had a small but growing population doubling in 3 years (34 individuals 26-43, 95% C.I.), relatively moderate genetic diversity compared to surrounding populations (richness = 3.32, Ho = 0.53, He = 0.65), and showed a high level of genetic connectivity with surrounding populations. PMID- 29117264 TI - Obesity and the burden of health risks among the elderly in Ghana: A population study. AB - BACKGROUND: The causes and health risks associated with obesity in young people have been extensively documented, but elderly obesity is less well understood, especially in sub-Saharan Africa. This study examines the relationship between obesity and the risk of chronic diseases, cognitive impairment, and functional disability among the elderly in Ghana. It highlights the social and cultural dimensions of elderly obesity and discusses the implications of related health risks using a socio-ecological model. METHODOLOGY: We used data from wave 1 of the Ghana Study on Global Ageing and Adult Health (SAGE) survey-2007/8, with a restricted sample of 2,091 for those 65 years and older. Using random effects multinomial, ordered, and binary logit models, we examined the relationship between obesity and the risk of stage 1 and stage 2 hypertension, arthritis, difficulties with recall and learning new tasks, and deficiencies with activities of daily living and instrumental activities of daily living. FINDINGS: Elderly Ghanaians who were overweight and obese had a higher risk of stage 1 and stage 2 hypertension, and were more likely to be diagnosed with arthritis and report severe deficiencies with instrumental activities of daily living. Those who were underweight were 1.71 times more likely to report severe difficulties with activities of daily living. A sub analysis using waist circumference as a measure of body fat showed elderly females with abdominal adiposity were relatively more likely to have stage 2 hypertension. CONCLUSIONS: These findings call for urgent policy initiatives geared towards reducing obesity among working adults given the potentially detrimental consequences in late adulthood. Future research should explore the gendered pathways leading to health disadvantages among Ghanaian women in late adulthood. PMID- 29117265 TI - Genomic sequencing identifies a few mutations driving the independent origin of primary liver tumors in a chronic hepatitis murine model. AB - With the development of high-throughput genomic analysis, sequencing a mouse primary cancer model provides a new opportunity to understand fundamental mechanisms of tumorigenesis and progression. Here, we characterized the genomic variations in a hepatitis-related primary hepatocellular carcinoma (HCC) mouse model. A total of 12 tumor sections and four adjacent non-tumor tissues from four mice were used for whole exome and/or whole genome sequencing and validation of genotyping. The functions of the mutated genes in tumorigenesis were studied by analyzing their mutation frequency and expression in clinical HCC samples. A total of 46 single nucleotide variations (SNVs) were detected within coding regions. All SNVs were only validated in the sequencing samples, except the Hras mutation, which was shared by three tumors in the M1 mouse. However, the mutated allele frequency varied from high (0.4) to low (0.1), and low frequency (0.1-0.2) mutations existed in almost every tumor. Together with a diploid karyotype and an equal distribution pattern of these SNVs within the tumor, these results suggest the existence of subclones within tumors. A total of 26 mutated genes were mapped to 17 terms describing different molecular and cellular functions. All 41 human homologs of the mutated genes were mutated in the clinical samples, and some mutations were associated with clinical outcomes, suggesting a high probability of cancer driver genes in the spontaneous tumors of the mouse model. Genomic sequencing shows that a few mutations can drive the independent origin of primary liver tumors and reveals high heterogeneity among tumors in the early stage of hepatitis-related primary hepatocellular carcinoma. PMID- 29117266 TI - A screen for E3 ubiquitination ligases that genetically interact with the adaptor protein Cindr during Drosophila eye patterning. AB - Ubiquitination is a crucial post-translational modification that can target proteins for degradation. The E3 ubiquitin ligases are responsible for recognizing substrate proteins for ubiquitination, hence providing specificity to the process of protein degradation. Here, we describe a genetic modifier screen that identified E3 ligases that modified the rough-eye phenotype generated by expression of cindrRNAi transgenes during Drosophila eye development. In total, we identified 36 E3 ligases, as well as 4 Cullins, that modified the mild cindrRNA mis-patterning phenotype. This indicates possible roles for these E3s/Cullins in processes that require Cindr function, including cytoskeletal regulation, cell adhesion, cell signaling and cell survival. Three E3 ligases identified in our screen had previously been linked to regulating JNK signaling. PMID- 29117267 TI - The impact of cannabis use on patients enrolled in opioid agonist therapy in Ontario, Canada. AB - BACKGROUND: With the Canadian government legalizing cannabis in the year 2018, the potential harms to certain populations-including those with opioid use disorder-must be investigated. Cannabis is one of the most commonly used substances by patients who are engaged in medication-assisted treatment for opioid use disorder, the effects of which are largely unknown. In this study, we examine the impact of baseline and ongoing cannabis use, and whether these are impacted differentially by gender. METHODS: We conducted a retrospective cohort study using anonymized electronic medical records from 58 clinics offering opioid agonist therapy in Ontario, Canada. One-year treatment retention was the primary outcome of interest and was measured for patients who did and did not have a cannabis positive urine sample in their first month of treatment, and as a function of the proportion of cannabis-positive urine samples throughout treatment. RESULTS: Our cohort consisted of 644 patients, 328 of which were considered baseline cannabis users and 256 considered heavy users. Patients with baseline cannabis use and heavy cannabis use were at increased risk of dropout (38.9% and 48.1%, respectively). When evaluating these trends by gender, only female baseline users and male heavy users are at increased risk of premature dropout. INTERPRETATION: Both baseline and heavy cannabis use are predictive of decreased treatment retention, and differences do exist between genders. With cannabis being legalized in the near future, physicians should closely monitor cannabis-using patients and provide education surrounding the potential harms of using cannabis while receiving treatment for opioid use disorder. PMID- 29117269 TI - Assessing reporting quality of randomized controlled trial abstracts in psychiatry: Adherence to CONSORT for abstracts: A systematic review. AB - BACKGROUND: Reporting quality of randomized controlled trial (RCT) abstracts is important as readers often make their first judgments based on the abstracts. This study aims to assess the reporting quality of psychiatry RCT abstracts published before and after the release of Consolidated Standards of Reporting Trials for Abstracts (CONSORT-A) guidelines. METHODS: MEDLINE/PubMed search was conducted to identify psychiatric RCTs published during 2005-2007 (pre-CONSORT) and 2012-2014 (post-CONSORT). Two independent reviewers assessed abstracts using a 18-point overall quality score (OQS) based on the CONSORT-A guidelines. Linear regression analysis was conducted to analyze factors associated with reporting quality. RESULTS: Among 1,927 relevant articles, 285 pre-CONSORT and 214 post CONSORT psychiatric RCT abstracts were included for analysis. The mean OQS improved from 6.9 (range: 3-13; 95% confidence interval (CI): 6.7-7.2) to 8.2 (range: 4-16; 95% CI: 7.8-8.5) after the CONSORT-A guidelines. Despite improvement, methods of randomization, allocation concealment, and funding source remained to be insufficiently reported (<5%) even after the release of CONSORT-A. High-impact general medical journals, multicenter design, positive outcome, and structured abstracts were associated with better reporting quality. CONCLUSIONS: The reporting quality in psychiatric RCT abstracts, although improved, remains suboptimal. To improve reporting quality of psychiatry RCT abstracts, greater efforts by both investigators and journal editors are required to enhance better adherence to the CONSORT-A guidelines. PMID- 29117268 TI - General response of Salmonella enterica serovar Typhimurium to desiccation: A new role for the virulence factors sopD and sseD in survival. AB - Salmonella can survive for long periods under extreme desiccation conditions. This stress tolerance poses a risk for food safety, but relatively little is known about the molecular and cellular regulation of this adaptation mechanism. To determine the genetic components involved in Salmonella's cellular response to desiccation, we performed a global transcriptomic analysis comparing S. enterica serovar Typhimurium cells equilibrated to low water activity (aw 0.11) and cells equilibrated to high water activity (aw 1.0). The analysis revealed that 719 genes were differentially regulated between the two conditions, of which 290 genes were up-regulated at aw 0.11. Most of these genes were involved in metabolic pathways, transporter regulation, DNA replication/repair, transcription and translation, and, more importantly, virulence genes. Among these, we decided to focus on the role of sopD and sseD. Deletion mutants were created and their ability to survive desiccation and exposure to aw 0.11 was compared to the wild type strain and to an E. coli O157:H7 strain. The sopD and sseD mutants exhibited significant cell viability reductions of 2.5 and 1.3 Log (CFU/g), respectively, compared to the wild-type after desiccation for 4 days on glass beads. Additional viability differences of the mutants were observed after exposure to aw 0.11 for 7 days. E. coli O157:H7 lost viability similarly to the mutants. Scanning electron microscopy showed that both mutants displayed a different morphology compared to the wild-type and differences in production of the extracellular matrix under the same conditions. These findings suggested that sopD and sseD are required for Salmonella's survival during desiccation. PMID- 29117270 TI - Screening for the presence of mcr-1/mcr-2 genes in Shiga toxin-producing Escherichia coli recovered from a major produce-production region in California. AB - The rapid spreading of polymyxin E (colistin) resistance among bacterial strains through the horizontally transmissible mcr-1 and mcr-2 plasmids has become a serious concern. The emergence of these genes in Shiga toxin-producing Escherichia coli (STEC), a group of human pathogenic bacteria was even more worrisome, urging us to investigate the prevalence of mcr genes among STEC isolates. A total of 1000 STEC isolates, recovered from livestock, wildlife, produce and other environmental sources in a major production region for leafy vegetables in California during 2006-2014, were screened by PCR for the presence of plasmid-borne mcr-1 and mcr-2. All isolates tested yielded negative results, indicating if any, the occurrence rate of mcr-1/mcr-2 among STEC was very low in this agricultural region. This study provides valuable information such as sample size needed and methodologies for future surveillance programs of antimicrobial resistance. PMID- 29117271 TI - Nurses' professional competency and organizational commitment: Is it important for human resource management? AB - BACKGROUND: Professional competency is a fundamental concept in nursing, which has a direct relationship with quality improvement of patient care and public health. Organizational commitment as a kind of affective attachment or sense of loyalty to the organization is an effective factor for professional competency. OBJECTIVE: This study was conducted to evaluate the nurses' professional competency and their organizational commitment as well as the relationship between these two concepts. METHODS AND MATERIALS: This descriptive-analytic study was conducted at the hospitals affiliated with a University of Medical Sciences, in the southeast of Iran in 2016. The sample included 230 nurses who were selected using stratified random sampling. Data were gathered by three questionnaires including socio-demographic information, competency inventory for registered nurse (CIRN) and Allen Meyer's organizational commitment. RESULTS: Results showed that professional competency (Mean+/-SD: 2.82+/-0.53, range: 1.56 4.00) and organizational commitment (Mean+/-SD: 72.80+/-4.95, range: 58-81) of the nurses were at moderate levels. There was no statistically significant correlation between professional competency and organizational commitment (rho = 0.02; p = 0.74). There were significant differences in professional competency based on marital status (p = 0.03) and work experience (p<0.001). CONCLUSION: The results highlighted that the nurses needed to be more competent and committed to their organizations. Developing professional competency and organizational commitment is vital, but not easy. This study suggests that human resource managers should pursue appropriate strategies to enhance the professional competency and organizational commitment of their nursing staff. It is necessary to conduct more comprehensive studies for exploring the status and gaps in the human resource management of healthcare in different cultures and contexts. PMID- 29117272 TI - Risks Associated With Primary and Redo Carotid Endarterectomy in the Endovascular Era. PMID- 29117274 TI - I Have High Blood Pressure: What Do I Need to Know? PMID- 29117273 TI - Coronary Artery Calcium Score for Long-term Risk Classification in Individuals With Type 2 Diabetes and Metabolic Syndrome From the Multi-Ethnic Study of Atherosclerosis. AB - Importance: Although the risk of type 2 diabetes is considered to be equivalent to coronary heart disease (CHD) risk, there is considerable heterogeneity among individuals for CHD and atherosclerotic cardiovascular disease (ASCVD) risk. It is not known whether coronary artery calcium (CAC) assessment at baseline in individuals with established metabolic syndrome (MetS) or diabetes identifies CHD and ASCVD prognostic indicators during a long follow-up period. Objective: To compare improvement in long-term prognostication of incident CHD and ASCVD using CAC scores among those with diabetes, MetS, or neither condition. Design, Setting, and Participants: This study included participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of 6814 males and females aged 45 to 84 years without known CVD from 4 race/ethnicity groups (white [38.5%], African American [27.5%], Hispanic [22.1%], and Chinese [11.9%]) recruited from 6 US communities from July 2000 through August 2002. Follow-up for each participant extended to the first occurrence of an incident event, other death, loss to follow-up, or the last follow-up call through December 31, 2013. Data analysis was performed from June 1, 2016, to September 12, 2017. Cox proportional hazards regression models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve and net reclassification improvement were used to compare incremental contributions of CAC score when added to the Framingham risk score, ethnicity/race, and socioeconomic status. Main Outcomes and Measures: CHD events, including myocardial infarction, resuscitated cardiac arrest, or CHD death. Results: Of 6814 MESA participants, 6751 had complete risk factor and follow-up data and were included in this study (mean [SD] age, 62.2 [10.2] years; 3186 [47.2%] male). A total of 881 (13.0%) had diabetes, 1738 (25.7%) had MetS, and 4132 (61.2%) had neither condition. After 11.1 mean years of follow-up, CHD events occurred in 84 participants with diabetes (135 ASCVD events), 115 with MetS (175 ASCVD events), and 157 with neither (250 ASCVD events). The CAC score was independently associated with incident CHD in multivariable analyses in those with diabetes (HR, 1.30; 95% CI, 1.19-1.43), MetS (HR, 1.30; 95% CI, 1.20-1.41), and neither condition (HR, 1.37; 95% CI, 1.27-1.47). For incident CHD, net reclassification improvement with addition of CAC score was 0.23 (95% CI, 0.10-0.37) in those with diabetes, 0.22 (95% CI, 0.09-0.35) in those with MetS, and 0.25 (95% CI, 0.15-0.35) in those with neither condition. The CAC score was also a prognostic indicator of CHD and ASCVD after controlling for diabetes duration of 10 years or longer at baseline, insulin use, and glycemic control. Conclusions and Relevance: In a large multiethnic cohort, the addition of CAC score to global risk assessment was associated with significantly improved risk classification in those with MetS and diabetes, even if diabetes duration was longer than a decade, suggesting a role for the CAC score in risk assessment in such patients. PMID- 29117275 TI - Effectiveness of Online Collaborative Care for Treating Mood and Anxiety Disorders in Primary Care: A Randomized Clinical Trial. AB - Importance: Collaborative care for depression and anxiety is superior to usual care from primary care physicians for these conditions; however, challenges limit its provision in routine practice and at scale. Advances in technology may overcome these barriers but have yet to be tested. Objective: To examine the effectiveness of combining an internet support group (ISG) with an online computerized cognitive behavioral therapy (CCBT) provided via a collaborative care program for treating depression and anxiety vs CCBT alone and whether providing CCBT in this manner is more effective than usual care. Design, Setting, and Participants: In this 3-arm randomized clinical trial with blinded outcome assessments, primary care physicians from 26 primary care practices in Pittsburgh, Pennsylvania, referred 2884 patients aged 18 to 75 years in response to an electronic medical record prompt from August 2012 to September 2014. Overall, 704 patients (24.4%) met all eligibility criteria and were randomized to CCBT alone (n = 301), CCBT+ISG (n = 302), or usual care (n = 101). Intent-to treat analyses were conducted November 2015 to January 2017. Interventions: Six months of guided access to an 8-session CCBT program provided by care managers who informed primary care physicians of their patients' progress and promoted patient engagement with our online programs. Main Outcomes and Measures: Mental health-related quality of life (12-Item Short-Form Health Survey Mental Health Composite Scale) and depression and anxiety symptoms (Patient-Reported Outcomes Measurement Information System) at 6-month follow-up, with treatment durability assessed 6 months later. Results: Of the 704 randomized patients, 562 patients (79.8%) were female, and the mean (SD) age was 42.7 (14.3) years. A total of 604 patients (85.8%) completed our primary 6-month outcome assessment. At 6-month assessment, 254 of 301 patients (84.4%) receiving CCBT alone started the program (mean [SD] sessions completed, 5.4 [2.8]), and 228 of 302 patients (75.5%) in the CCBT+ISG cohort logged into the ISG at least once, of whom 141 (61.8%) provided 1 or more comments or posts (mean, 10.5; median [range], 3 [1-306]). Patients receiving CCBT+ISG reported similar 6-month improvements in mental health-related quality of life, mood, and anxiety symptoms compared with patients receiving CCBT alone. However, compared with patients receiving usual care, patients in the CCBT alone cohort reported significant 6-month effect size improvements in mood (effect size, 0.31; 95% CI, 0.09-0.53) and anxiety (effect size, 0.26; 95% CI, 0.05-0.48) that persisted 6 months later, and completing more CCBT sessions produced greater effect size improvements in mental health-related quality of life and symptoms. Conclusions and Relevance: While providing moderated access to an ISG provided no additional benefit over guided CCBT at improving mental health related quality of life, mood, and anxiety symptoms, guided CCBT alone is more effective than usual care for these conditions. Trial Registration: clinicaltrials.gov Identifier: NCT01482806. PMID- 29117276 TI - Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial. AB - Importance: Current guidelines for atherosclerotic cardiovascular disease focus on high-intensity statins and targeting or using a threshold low-density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dL for the highest-risk patients. Whether further reduction of LDL-C beyond these boundaries would be beneficial is unknown. Objective: To compare outcomes of evolocumab vs placebo in patients with stable atherosclerotic cardiovascular disease and a baseline LDL-C of less than 70 mg/dL and in those receiving background treatment with a maximal potency statin. Design, Setting, and Participants: This secondary ad hoc analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial compared randomized treatments in 2 subgroups of patients with stable atherosclerotic cardiovascular disease currently receiving statin. Patients were classified by a baseline LDL-C of less than 70 or at least 70 mg/dL and by statin intensity (maximal: atorvastatin calcium, 80 mg/d, or rosuvastatin, 40 mg/d; submaximal: all other dosages). Patients with baseline LDL of less than 70 mg/dL either had a final screening LDL-C of at least 70 mg/dL or a final screening non-high-density lipoprotein cholesterol level of at least 100 mg/dL. Data were retrieved from 2013 to 2016 and analyzed in 2017 based on intention to treat. Main Outcomes and Measures: The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The secondary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. Safety outcomes included adverse events and events of interest identified in the FOURIER trial. Interaction testing was used to assess the consistency of results in patients who did vs did not satisfy the above criteria. Results: A total of 27 564 patients (75.4% men and 24.6% women; mean [SD] age, 62.5 [9.0] years) were included in the analysis. Of 2034 patients (7.4%) who had a baseline LDL-C of less than 70 mg/dL, evolocumab reduced the risk for the primary endpoint (hazard ratio [HR], 0.80; 95% CI, 0.60-1.07) to a similar degree as in the 25 529 patients who had baseline LDL-C of at least 70 mg/dL (HR 0.86; 95% CI, 0.79-0.92; P = .65 for interaction; 1 patient was missing baseline LDL-C data). Of 7533 patients (27.3%) receiving maximal-potency statins, evolocumab significantly reduced the primary endpoint (HR, 0.86; 95% CI, 0.75 0.98) to a similar degree as in the 20 031 patients not receiving a maximal potency statin (HR, 0.85; 95% CI, 0.78-0.93; P = .88 for interaction). The key secondary endpoint was reduced to a similar degree in both analyses. No major safety concerns were identified. Conclusions and Relevance: Evolocumab was equally effective in reducing cardiovascular events in patients with stable atherosclerotic cardiovascular disease regardless of whether the baseline LDL-C was less than 70 or at least 70 mg/dL and whether the background statin was of maximal or submaximal potency. PMID- 29117277 TI - Naringenin Eye Drops Inhibit Corneal Neovascularization by Anti-Inflammatory and Antioxidant Mechanisms. AB - Purpose: To investigate the effect of naringenin eye drops in corneal neovascularization induced by alkali (1 N NaOH) burn in mice. Methods: Corneal neovascularization in the right eye of male Swiss mice was induced by alkali. Treatment with naringenin eye drops (0.08-80 MUg; 8 MUL of 0.01-10 g/L solution) or vehicle (saline) started 2 days before corneal neovascularization was induced and was performed twice a day. Mice were treated up until the time animals were euthanized and cornea tissue was collected for testing, which was 2, 4, and 6 hours after alkali stimulus for cytokine and antioxidant capacity measurements, and 3 and/or 7 days after alkali stimulus for the assessment of corneal epithelial thickness and neovascularization, neutrophil, and macrophage recruitment, and vascular endothelial growth factor (Vegf), platelet-derived growth factor (Pdgf), matrix metalloproteinase-14 (Mmp14), and pigment epithelium derived factor (Pedf) mRNA expression. Results: Naringenin eye drops inhibited alkali burn-induced neutrophil (myeloperoxidase activity and recruitment of Lysm GFP+ cells) and macrophage (N-acetyl-beta-D glucosaminidase activity) recruitment into the eye, decrease in epithelial thickness, and neovascularization in the cornea. Further, naringenin inhibited alkali-induced cytokine (IL-1beta and IL-6) production, Vegf, Pdgf, and Mmp14 mRNA expression, and the reduction of ferric reducing antioxidant power and Azinobis-(3-Ethylbenzothiazoline 6-Sulfonic acid) radical scavenging capacity as well as increased the reduced glutathione and protein-bound sulfhydryl groups levels. Conclusions: Collectively, these results indicate that naringenin eye drops are protective in alkali-induced corneal burn by inhibiting leukocyte recruitment, the proangiogenic factor expression, inflammatory cytokine production, and loss of antioxidant defenses. PMID- 29117279 TI - Overlapping Surgery-Opportunities in Neurosurgery Based on New Research. PMID- 29117278 TI - Diurnal Variations in the Morphology of Schlemm's Canal and Intraocular Pressure in Healthy Chinese: An SS-OCT Study. AB - Purpose: To characterize the diurnal variations in the dimensions of the Schlemm's canal (SC) and its association with intraocular pressure (IOP) using swept-source optical coherence tomography (SS-OCT). Methods: The temporal, nasal, inferior, and superior limbus of 102 eyes of 51 healthy subjects were imaged in vivo by SS-COT at 5 time points of 8 AM, 11 AM, 2 PM, 5 PM, and 8 PM. IOP was measured at the same time by Goldmann applanation tonometry (GAT). The diameter and the cross-sectional area of the SC were measured in ImageJ. The associations between changes in the SC parameters, IOP, and other biometric parameters were determined using a general estimating equations model. The temporal and inferior limbus of 94 eyes of 47 healthy subjects were also imaged before and during the Valsalva maneuver (VM) at 8 PM. Results: Mean IOPs at different time points were 13.37, 12.89, 11.9, 12.02, and 12.36 mm Hg. Of all four quadrants, the detectable rate of SC was highest in the superior quadrant (85.3%) and lowest in the inferior quadrant (75.5%). We found that changes in the SC area and diameter were negatively associated with IOP changes only in the inferior quadrant (P = 0.0046 and P = 0.0332, respectively), after adjusting for age, sex, eye, spherical equivalent, and axial length. The mean SC area and diameter during the VM were significantly higher than prior to the VM (P < 0.001). Conclusions: The changes in the SC parameters were negatively associated with IOP changes only in the inferior quadrant. The VM could expand the SC in healthy subjects. Imaging of the SC may be a useful method to discover the reason why IOP fluctuates, and how SC changes morphologically during the daytime in the future. PMID- 29117280 TI - Physical Activity to Prevent Cardiovascular Disease: A Simple, Low-Cost, and Widely Applicable Approach for All Populations. PMID- 29117281 TI - Defining Osteopathic Continuing Medical Education. PMID- 29117282 TI - Association of Genetic Risk for Schizophrenia and Bipolar Disorder With Infant Neuromotor Development. PMID- 29117283 TI - Resuscitating Cardiovascular Drug Development. PMID- 29117284 TI - What Constitutes Experience in Surgical Treatment of Valve Disease and How Important Is It? PMID- 29117286 TI - The Imminent Demise of Cardiovascular Drug Development. PMID- 29117285 TI - Topical Timolol for Paronychia and Pseudopyogenic Granuloma in Patients Treated With Epidermal Growth Factor Receptor Inhibitors and Capecitabine. PMID- 29117287 TI - Are Cholesterol Treatment Targets a Deterrent to Optimal Lipid-Lowering Therapy? PMID- 29117288 TI - Dynamic Network Communication in the Human Functional Connectome Predicts Perceptual Variability in Visual Illusion. AB - Ubiquitous variability between individuals in visual perception is difficult to standardize and has thus essentially been ignored. Here we construct a quantitative psychophysical measure of illusory rotary motion based on the Pinna Brelstaff figure (PBF) in 73 healthy volunteers and investigate the neural circuit mechanisms underlying perceptual variation using functional magnetic resonance imaging (fMRI). We acquired fMRI data from a subset of 42 subjects during spontaneous and 3 stimulus conditions: expanding PBF, expanding modified PBF (illusion-free) and expanding modified-PBF with physical rotation. Brain-wide graph analysis of stimulus-evoked functional connectivity patterns yielded a functionally segregated architecture containing 3 discrete hierarchical networks, commonly shared between rest and stimulation conditions. Strikingly, communication efficiency and strength between 2 networks predominantly located in visual areas robustly predicted individual perceptual differences solely in the illusory stimulus condition. These unprecedented findings demonstrate that stimulus-dependent, not spontaneous, dynamic functional integration between distributed brain networks contributes to perceptual variability in humans. PMID- 29117289 TI - CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. PMID- 29117291 TI - Does Botulinum Toxin Injection into Masseter Muscles Affect Subcutaneous Thickness? AB - Background: Botulinum toxin (BoNT) is widely used to treat masseter muscle hypertrophy. Changes in the muscle thickness have been found in many studies, but there has been no report on changes in the thickness from the skin surface to the masseter muscle. Objectives: We aimed to use ultrasonography to measure not only changes in the muscle thickness but also changes in subcutaneous thickness. Methods: This study enrolled 20 volunteer patients: 10 were assigned to an experimental group (injected with each side 25 U of botulinum toxin into both masseter muscles) and 10 to a control group (injected with normal saline). The thicknesses were measured before the injection and at 4, 8, and 12 weeks after the injection both at rest and during maximum muscle contraction. Results: The subcutaneous thickness did not differ significantly over time either at rest (P = 0.063) or during maximal contraction (P = 0.392), or between the experimental and control groups at rest (P = 0.392) or during maximum contraction (P = 0.259). The muscle thickness in the experimental group differed significantly over time. Conclusions: Botulinum toxin injection only changes the muscle thickness and does not affect the subcutaneous thickness from the skin surface to the masseter muscle. PMID- 29117290 TI - The DNA Methyltransferase 1 (DNMT1) Controls the Shape and Dynamics of Migrating POA-Derived Interneurons Fated for the Murine Cerebral Cortex. AB - The proliferative niches in the subpallium generate a rich cellular variety fated for diverse telencephalic regions. The embryonic preoptic area (POA) represents one of these domains giving rise to the pool of cortical GABAergic interneurons and glial cells, in addition to striatal and residual POA cells. The migration from sites of origin within the subpallium to the distant targets like the cerebral cortex, accomplished by the adoption and maintenance of a particular migratory morphology, is a critical step during interneuron development. To identify factors orchestrating this process, we performed single-cell transcriptome analysis and detected Dnmt1 expression in murine migratory GABAergic POA-derived cells. Deletion of Dnmt1 in postmitotic immature cells of the POA caused defective migration and severely diminished adult cortical interneuron numbers. We found that DNA methyltransferase 1 (DNMT1) preserves the migratory shape in part through negative regulation of Pak6, which stimulates neuritogenesis at postmigratory stages. Our data underline the importance of DNMT1 for the migration of POA-derived cells including cortical interneurons. PMID- 29117292 TI - Cell-based cardiac regeneration. PMID- 29117293 TI - Patient Satisfaction With an Early Smartphone-Based Cosmetic Surgery Postoperative Follow-Up. AB - Background: While prevalent in everyday life, smartphones are also finding increasing use as a medical care adjunct. The use of smartphone technology as a postoperative cosmetic surgery adjunct for care has received little attention in the literature. Objectives: The purpose of this effort was to assess the potential efficacy of a smartphone-based cosmetic surgery early postoperative follow-up program. Specifically, could smartphone photography provided by the patient to the plastic surgeon in the first few days after surgery allay patient's concerns, improve the postoperative experience and, possibly, detect early complications? Methods: From August 2015 to March 2016 a smartphone-based postoperative protocol was established for patients undergoing cosmetic procedures. At the time of discharge, the plastic surgeon sent a text to the patient with instructions for the patient to forward a postoperative photograph of the operated area within 48 to 72 hours. The plastic surgeon then made a return call/text that same day to review the patient's progress. A postoperative questionnaire evaluated the patients' postoperative experience and satisfaction with the program. Results: A total of 57 patients were included in the study. Fifty-two patients responded to the survey. A total of 50 (96.2%) patients reported that the process improved the quality of their postoperative experience. The protocol allowed to detect early complications in 3 cases. The physician was able to address and treat the complications the following day prior to the scheduled clinic follow up. Conclusions: The smartphone can be effectively utilized by the surgeon to both enhance the patient's postoperative experience and alert the surgeon to early postoperative problems. Level of Evidence: 4. PMID- 29117294 TI - Computer-Assisted Planning and 3D Printing-Assisted Modeling for Chin Augmentation. AB - Background: Patients are frequently not satisfied with the outcome of chin augmentation. Objectives: We report the use of three-dimensional (3D) imaging and printing to design custom fit porous polyethylene chin implants. Methods: Patients requesting chin augmentation received 3D computed tomography (CT) imaging of the facial area. Patients could select the chin contour they desired by viewing 3D images of their face and chin. A 3D mandible replicate was printed from the CT data, and used to sculpt the inner surface of the implant to match the shape of the mandible, and the outer surface to match the contour the patient desired. Implants were placed with a 2 cm mucosal incision. The primary outcome was patient satisfaction with the cosmetic result at 6 months postoperatively. Results: From April 2014 to March 2015, 107 females and 22 males (mean age, 29.7 years) received chin augmentation using 3D imaging and printing to create a custom fit porous polyethylene implant. No major complications (eg, infection, nerve injury) occurred. At 1 month, five of the 124 patients who returned for follow up were not satisfied; however, became satisfied after a minor adjustment procedure. All of the 78 patients that returned for the 6 month follow up were satisfied with the cosmetic result. No implant displacement, skin numbness, or infection was noted during the 6 months of follow up. Conclusions: Three dimensional imaging and printing can be used to produce custom fit porous polyethylene chin implants that results in minimal complications and a very high satisfaction rate. Level of Evidence: 4. PMID- 29117297 TI - Breast Mass in a Man. PMID- 29117295 TI - Hand Rejuvenation by Targeted Volume Restoration of the Dorsal Fat Compartments. AB - Background: Recent anatomic findings suggest aging-related changes of the complex fat distribution in the hand. Objectives: To rejuvenate the aging hand, we developed a targeted fat grafting technique based on the physiologic fat distribution of the hand. Methods: The dorsum of both hands was examined in 30 healthy volunteers of different age utilizing B-mode ultrasound to determine physiological changes of the aging hand. Additional anatomic dissection was performed in 10 hands of five fresh cadavers to establish the anatomic basis for the targeted restoration technique. A total of 17 patients were treated for hand rejuvenation utilizing this technique and followed up for at least 6 months. The posttreatment outcome was assessed through B-mode ultrasound, 3-dimensional (3D) topography scanning, and a patient satisfaction survey. Results: According to the fat distribution of the dorsum, hand aging was divided into three grades: (1) mild atrophy with rhytides; (2) moderate atrophy with exposed veins; and (3) serious atrophy with exposed tendons. Anatomic findings showed the existence of distinct superficial and deep fat compartments. The average fat grafting volume was 25.5 ml per hand dorsum administered in one or two procedures. Patients were monitored for 8.3 +/- 2.6 months. After 6 months, a volume gain was found in all patients. The degree of aging was significantly reduced. The majority of patients (94.1%) were satisfied with their results. Conclusions: This study provides the anatomic and clinical basis for targeted restoration of the physiological fat volume in the hand dorsum with high satisfaction rates. Level of Evidence: 4. PMID- 29117298 TI - Long-Term Quality-of-Life Outcomes After Body Contouring Surgery: Phase IV Results for the Body-QoL(r) Cohort. AB - Background: Body contouring surgery (BCS) is becoming increasing popular for aesthetic and reconstructive purposes, particularly among patients with massive weight loss (MWL). However, data on quality of life (QoL) following the surgery are limited, especially long-term QoL. Objectives: The authors evaluated the effect of BCS on QoL and the durability of this effect over time. Methods: QoL was measured with the Body-QoL(r) instrument at 3 time points among consecutively treated patients: the day before BCS, 1 to 9 months postoperatively (short term), and 1 to 2.7 years postoperatively (long term). Total Body-QoL scores were compiled, as were scores for the instrument's main domains: body satisfaction, sex life, self-esteem and social performance, and physical symptoms. Scores were examined for the entire study population and separately for the cosmetic and MWL cohorts. Results: Fifty-seven of the 112 patients participated in the short-term assessment and 84 in the long-term assessment. Total Body-QoL scores increased significantly (P < 0.0001), from 44.0 +/- 14.1 preoperatively to 85.5 +/- 17.5 short-term postoperatively and to 84.4 +/- 12.7 long-term postoperatively. Scores for the 2 postoperative assessments did not differ significantly. Similar results were observed for scores on each separate domain. Although preoperative scores were lower for the MWL cohort than the cosmetic cohort (33.9 +/- 15.6 vs 46.1 +/- 12.8; P = 0.0002), they improved substantially after BCS, approaching scores for the cosmetic cohort. Conclusions: QoL increases significantly after BCS. This favorable outcome remained stable throughout long-term follow-up and was true for the cosmetic and MWL cohorts. Level of Evidence 4: PMID- 29117296 TI - Polygenic Risk of Spasmodic Dysphonia is Associated With Vulnerable Sensorimotor Connectivity. AB - Spasmodic dysphonia (SD), or laryngeal dystonia, is an isolated task-specific dystonia of unknown causes and pathophysiology that selectively affects speech production. Using next-generation whole-exome sequencing in SD patients, we computed polygenic risk score from 1804 genetic markers based on a genome-wide association study in another form of similar task-specific focal dystonia, musician's dystonia. We further examined the associations between the polygenic risk score, resting-state functional connectivity abnormalities within the sensorimotor network, and SD clinical characteristics. We found that the polygenic risk of dystonia was significantly associated with decreased functional connectivity in the left premotor/primary sensorimotor and inferior parietal cortices in SD patients. Reduced connectivity of the inferior parietal cortex was correlated with the age of SD onset. The polygenic risk score contained a significant number of genetic variants lying near genes related to synaptic transmission and neural development. Our study identified a polygenic contribution to the overall genetic risk of dystonia in the cohort of SD patients. Associations between the polygenic risk and reduced functional connectivity of the sensorimotor and inferior parietal cortices likely represent an endophenotypic imaging marker of SD, while genes involved in synaptic transmission and neuron development may be linked to the molecular pathophysiology of this disorder. PMID- 29117299 TI - High- vs Low-Dose Corticosteroid Injection in the Treatment of Adhesive Capsulitis with Severe Pain: A Randomized Controlled Double-Blind Study. AB - Objective: To compare the degree of pain relief between high-dose (40 mg of triamcinolone acetonide) and low-dose (20 mg of triamcinolone acetonide) corticosteroid injections in patients with severe pain due to adhesive capsulitis. Design: A prospective, randomized, double-blind, dose-comparative study. Subjects: A total of 32 patients who were diagnosed with adhesive capsulitis and who expressed severe pain intensity, 8 or more points on a numeric rating scale (NRS). Methods: Patients received injections of high- or low-dose triamcinolone acetonide under ultrasound guidance. NRS, Shoulder Pain and Disability Index (SPADI), and the passive range of motion (PROM) in four directions were evaluated before and three weeks after the injection. Results: NRS scores showed significant improvement three weeks after the injection in both groups (P = 0.01 in both the low-dose group and high-dose group), but there was no statistically significant difference between the two groups (P = 0.63). SPADI score significantly improved at three weeks after the injection in both groups (P = 0.02 in the low-dose group and P < 0.01 in the high-dose group), but group difference was not observed (P = 0.06). The change of PROM in four directions after the injection did not show any significant difference between the low- and high-dose groups. Conclusions: Injection of 20 mg of triamcinolone acetonide is sufficient to elicit symptom relief in patients with severe adhesive capsulitis; hence, 20 mg of triamcinolone acetonide can be recommended in patients with adhesive capsulitis with severe pain. PMID- 29117302 TI - Nathaniel Hawthorne's "The Birthmark". PMID- 29117303 TI - Robert Chesebrough and the Dermatologic Wonder of Petroleum Jelly. PMID- 29117300 TI - Association of Resilience With Depression and Health-Related Quality of Life for Patients With Hidradenitis Suppurativa. AB - Importance: Hidradenitis suppurativa (HS) places a significant burden on the health-related quality of life (HRQOL) of patients, many of whom have depression. Resilience can play a role in mitigating the negative stressors, such as the symptoms of HS, on patients' mental health. Objective: To investigate the correlation among resilience, depression, and HRQOL for patients with HS. Design, Setting, and Participants: This cross-sectional survey study of 154 patients from 2 referral centers in the United States and in Denmark was conducted from June 1, 2016, to March 31, 2017. Patients were considered eligible if they were 18 years or older and had a visit for HS at 1 of the 2 referral centers in the past 2 years (from January 1, 2014, through December 31, 2016). Patients were excluded if they declined to participate, could not read or write in English or Danish, or had a cognitive disability that would preclude their understanding of the survey questions. Main Outcomes and Measures: The survey instrument included 4 questionnaires: (1) a sociodemographic and clinical characteristics questionnaire, (2) the Brief Resilient Coping Scale, (3) the Hospital Anxiety and Depression Scale, and (4) the Dermatology Life Quality Index. The main outcome of interest was the HRQOL as measured by the Dermatology Life Quality Index. Results: All 154 patients submitted a completed survey. The mean (SD) age of the participants was 40.93 (13.5) years; most participants were women (130 [84.4%]), and most participants self-identified as white (139 [90.2%]). The rate of depression among the patients in this study was comparable to those reported in previous studies; 55 patients (35.7%) were classified as having depression, and 32 patients (20.8%) had borderline depressive symptoms. Patient-rated HS severity and the depression score each independently estimated 27% and 10% of variation in HRQOL, respectively. The interaction term for resilience and depression was significant, indicating that resilience moderates depression. Analysis of the mediation effects of resilience was not significant, indicating that resilience did not mediate the association between depressive symptoms and HRQOL. The resilience score was significantly associated with depressive symptoms (regression coefficient a = -0.21; P < .001), and the depressive symptoms score (c = 0.637; P < .001) was significantly associated with lower HRQOL (c' = 0.644; P < .001). However, both the direct association (b = 0.033; P = .86) and the indirect association (a * b = 0.007; P = .87) of resilience with HRQOL were not significant. Conclusions and Relevance: Patients with higher resilience levels experienced a smaller decrease in HRQOL as depressive symptoms increased. Because the findings suggest that resilience can be taught, there is an opportunity to develop a resiliency training program and investigate its role in stress levels and depressive symptoms, as well as in HRQOL and disease activity. PMID- 29117304 TI - Delusions of Parasitosis as an Overvalent Idea. PMID- 29117305 TI - The Evolution of Human Skin Color. PMID- 29117306 TI - Frontal Fibrosing Alopecia-The Fashion of the Renaissance. PMID- 29117307 TI - The Black Panther, From Politics to Popular Culture. PMID- 29117309 TI - Effect of Oral Administration of a Mixture of Probiotic Strains on SCORAD Index and Use of Topical Steroids in Young Patients With Moderate Atopic Dermatitis: A Randomized Clinical Trial. AB - Importance: Oral intake of new probiotic formulations may improve the course of atopic dermatitis (AD) in a young population. Objective: To determine whether a mixture of oral probiotics is safe and effective in the treatment of AD symptoms and to evaluate its influence on the use of topical steroids in a young population. Design, Setting, and Participants: A 12-week randomized, double blind, placebo-controlled intervention trial, from March to June 2016, at the outpatient hospital Centro Dermatologico Estetico de Alicante, Alicante, Spain. Observers were blinded to patient groupings. Participants were children aged 4 to 17 years with moderate atopic dermatitis. The groups were stratified and block randomized according to sex, age, and age of onset. Patients were ineligible if they had used systemic immunosuppressive drugs in the previous 3 months or antibiotics in the previous 2 weeks or had a concomitant diagnosis of intestinal bowel disease or signs of bacterial infection. Interventions: Twelve weeks with a daily capsule containing freeze-dried powder with 109 total colony-forming units of the probiotic strains Bifidobacterium lactis CECT 8145, B longum CECT 7347, and Lactobacillus casei CECT 9104 and maltodextrin as a carrier, or placebo (maltodextrin-only capsules). Main Outcomes and Measures: SCORAD index score and days of topical steroid use were analyzed. Results: Fifty children (26 [50%] female; mean [SD] age, 9.2 [3.7] years) participated. After 12 weeks of follow up, the mean reduction in the SCORAD index in the probiotic group was 19.2 points greater than in the control group (mean difference, -19.2; 95% CI, -15.0 to 23.4). In relative terms, we observed a change of -83% (95% CI, -95% to -70%) in the probiotic group and -24% (95% CI, -36% to -11%) in the placebo group (P < .001). We found a significant reduction in the use of topical steroids to treat flares in the probiotic arm (161 of 2084 patient-days [7.7%]) compared with the control arm (220 of 2032 patient-days [10.8%]; odds ratio, 0.63; 95% CI, 0.51 to 0.78). Conclusions and Relevance: The mixture of probiotics was effective in reducing SCORAD index and reducing the use of topical steroids in patients with moderate AD. Trial Registration: clinicaltrials.gov Identifier: NCT02585986. PMID- 29117311 TI - Ketamine Minus the Trip: New Hope for Treatment-Resistant Depression. PMID- 29117310 TI - Sequencing and phasing cancer mutations in lung cancers using a long-read portable sequencer. AB - Here, we employed cDNA amplicon sequencing using a long-read portable sequencer, MinION, to characterize various types of mutations in cancer-related genes, namely, EGFR, KRAS, NRAS and NF1. For homozygous SNVs, the precision and recall rates were 87.5% and 91.3%, respectively. For previously reported hotspot mutations, the precision and recall rates reached 100%. The precise junctions of EML4-ALK, CCDC6-RET and five other gene fusions were also detected. Taking advantages of long-read sequencing, we conducted phasing of EGFR mutations and elucidated the mutational allelic backgrounds of anti-tumor drug-sensitive and resistant mutations, which could provide useful information for selecting therapeutic approaches. In the H1975 cells, 72% of the reads harbored both L858R and T790M mutations, and 22% of the reads harbored neither mutation. To ensure that the clinical requirements can be met in potentially low cancer cell populations, we further conducted a serial dilution analysis of the template for EGFR mutations. Several percent of the mutant alleles could be detected depending on the yield and quality of the sequencing data. Finally, we characterized the mutation genotypes in eight clinical samples. This method could be a convenient long-read sequencing-based analytical approach and thus may change the current approaches used for cancer genome sequencing. PMID- 29117313 TI - Outcomes in Asymptomatic Redo Carotid Endartectomy: A Word of Caution. PMID- 29117312 TI - Association of Overlapping Surgery With Patient Outcomes in a Large Series of Neurosurgical Cases. AB - Importance: Overlapping surgery (OS) is common. However, there is a dearth of evidence to support or refute the safety of this practice. Objective: To determine whether OS is associated with worsened morbidity and mortality in a large series of neurosurgical cases. Design, Setting, and Participants: A retrospective cohort study was completed for patients who underwent neurosurgical procedures at Emory University Hospital, a large academic referral hospital, between January 1, 2014, and December 31, 2015. Patients were operated on for pathologies across the spectrum of neurosurgical disorders. Propensity score weighting and logistic regression models were executed to compare outcomes for patients who received nonoverlapping surgery and OS. Investigators were blinded to study cohorts during data collection and analysis. Main Outcomes and Measures: The primary outcome measures were 90-day postoperative mortality, morbidity, and functional status. Results: In this cohort of 2275 patients who underwent neurosurgery, 1259 (55.3%) were female, and the mean (SD) age was 52.1 (16.4) years. A total of 972 surgeries (42.7%) were nonoverlapping while 1303 (57.3%) were overlapping. The distribution of American Society of Anesthesiologists score was similar between nonoverlapping surgery and OS cohorts. Median surgical times were significantly longer for patients in the OS cohort vs the nonoverlapping surgery cohort (in-room time, 219 vs 188 minutes; skin-to-skin time, 141 vs 113 minutes; both P < .001). Overlapping surgery was more frequently elective (93% vs 87%; P < .001). Regression analysis failed to demonstrate an association between OS and complications, such as mortality, morbidity, or worsened functional status. Measures of baseline severity of illness, such as admission to the intensive care unit and increased length of stay, were associated with mortality (intensive care unit: odds ratio [OR], 25.5; 95% CI, 6.22-104.67; length of stay: OR, 1.03; 95% CI, 1.00-1.05), morbidity (intensive care unit: OR, 1.85; 95% CI, 1.43-2.40; length of stay: OR, 1.06; 95% CI, 1.04-1.08), and unfavorable functional status (length of stay: OR, 1.03; 95% CI, 1.02-1.05). Conclusions and Relevance: These data suggest that OS can be safely performed if appropriate precautions and patient selection are followed. Data such as these will help determine health care policy to maximize patient safety. PMID- 29117314 TI - Assessment of Fluorodeoxyglucose F18-Labeled Positron Emission Tomography for Diagnosis of High-Risk Lung Nodules. AB - Importance: Clinicians rely heavily on fluorodeoxyglucose F18-labeled positron emission tomography (FDG-PET) imaging to evaluate lung nodules suspicious for cancer. We evaluated the performance of FDG-PET for the diagnosis of malignancy in differing populations with varying cancer prevalence. Objective: To determine the performance of FDG-PET/computed tomography (CT) in diagnosing lung malignancy across different populations with varying cancer prevalence. Design, Setting, and Participants: Multicenter retrospective cohort study at 6 academic medical centers and 1 Veterans Affairs facility that comprised a total of 1188 patients with known or suspected lung cancer from 7 different cohorts from 2005 to 2015. Exposures: 18F fluorodeoxyglucose PET/CT imaging. Main Outcome and Measures: Final diagnosis of cancer or benign disease was determined by pathological tissue diagnosis or at least 18 months of stable radiographic follow-up. Results: Most patients were male smokers older than 60 years. Overall cancer prevalence was 81% (range by cohort, 50%-95%). The median nodule size was 22 mm (interquartile range, 15-33 mm). Positron emission tomography/CT sensitivity and specificity were 90.1% (95% CI, 88.1%-91.9%) and 39.8% (95% CI, 33.4%-46.5%), respectively. False-positive PET scans occurred in 136 of 1188 patients. Positive predictive value and negative predictive value were 86.4% (95% CI, 84.2%-88.5%) and 48.7% (95% CI, 41.3%-56.1%), respectively. On logistic regression, larger nodule size and higher population cancer prevalence were both significantly associated with PET accuracy (odds ratio, 1.027; 95% CI, 1.015-1.040 and odds ratio, 1.030; 95% CI, 1.021-1.040, respectively). As the Mayo Clinic model-predicted probability of cancer increased, the sensitivity and positive predictive value of PET/CT imaging increased, whereas the specificity and negative predictive value dropped. Conclusions and Relevance: High false-positive rates were observed across a range of cancer prevalence. Normal PET/CT scans were not found to be reliable indicators of the absence of disease in patients with a high probability of lung cancer. In this population, aggressive tissue acquisition should be prioritized using a comprehensive lung nodule program that emphasizes advanced tissue acquisition techniques such as CT-guided fine-needle aspiration, navigational bronchoscopy, and endobronchial ultrasonography. PMID- 29117315 TI - Interdisciplinary Perspectives on Sun Safety. AB - Overexposure to the sun is associated with an increased risk of melanoma and nonmelanoma skin cancer, but indications of improvements in sun protection behavior are poor. Attempts to identify emerging themes in skin cancer control have largely been driven by groups of experts from a single field. In December 2016, 19 experts from various disciplines convened for Interdisciplinary Perspectives on Skin Cancer, a 2-day meeting hosted by the National Academy of Sciences. The group discussed knowledge gaps, perspectives on sun exposure, implications for skin cancer risk and other health outcomes, and new directions. Five themes emerged from the discussion: (1) The definition of risk must be expanded, and categories for skin physiology must be refined to incorporate population diversities. (2) Risky sun exposure often co-occurs with other health related behaviors. (3) Messages must be nuanced to target at-risk populations. (4) Persons at risk for tanning disorder must be recognized and treated. (5) Sun safety interventions must be scalable. Efficient use of technologies will be required to sharpen messages to specific populations and to integrate them within multilevel interventions. Further interdisciplinary research should address these emerging themes to build effective and sustainable approaches to large-scale behavior change. PMID- 29117316 TI - Vitreous Fibronectin and Fibrinogen Expression Increased in Eyes With Proliferative Diabetic Retinopathy After Intravitreal Anti-VEGF Therapy. AB - Purpose: To evaluate vitreous humor (VH) protein expression profiles in patients with proliferative diabetic retinopathy (PDR), with and without intravitreal injection (IVI) of anti-vascular endothelial growth factor (anti-VEGF) before vitrectomy. Methods: We enrolled consecutive PDR patients who needed pars plana vitrectomy (PPV) with or without IVI or pan-retinal photocoagulation (PRP). Visual acuity, duration, and treatment of diabetes mellitus, ocular treatment history, and fundus examinations were recorded. VH samples were collected without artificial humor infusion. Label-free quantitative proteomics analysis was performed to determine the protein expression profiles of VH samples. Enzyme linked immunosorbent assays were performed to validate the proteomics results. Results: PDR patients who underwent IVI at a mean of 5.8 days (range, 3-8 days) before PPV (IVI group, n = 12) were younger than PDR patients with a history of PRP (PRP group, n = 29) and untreated PDR patients (control group, n = 21). The duration of diabetes mellitus was similar in the three groups. Label-free quantitative proteomics analysis showed that the signal intensities for fibronectin, fibrinogen alpha chain, fibrinogen beta chain, fibrinogen gamma chain, VEGF receptor 1 (VEGFR1), and VEGFR2 were significantly greater in the IVI group than in the other two groups. Enzyme-linked immunosorbent assays validated the results for fibronectin and fibrinogens, but found no significant differences in VEGF or VEGFR2 concentrations. VEGFR1 expression was significantly greater in the IVI and PRP groups than in the control group. Conclusions: VH fibronectin and fibrinogen concentrations were highest in the IVI patients, which may promote fibrin-fibronectin complexation and fibrosis in eyes with PDR. PMID- 29117317 TI - Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates. AB - Purpose: To investigate shedding and biodistribution characteristics of recombinant adeno-associated virus serotype 8 (rAAV8) after single-dose subretinal or intravitreal injection in nonhuman primates (NHP, Macaca fascicularis) as a surrogate for environmental hazard and patient safety. Methods: In a study for regulatory submission, 22 NHP were divided into four cohorts receiving either single subretinal injections of vehicle or clinical grade rAAV8 (1 * 1011 or 1 * 1012 vector genomes [vg]) versus single intravitreal application of 1 * 1012 vg. Viral shedding and biodistribution were monitored in biofluids for up to 91 days, followed by necropsy and tissue harvesting of all major organs, the visual pathway, and lymphatic tissue. Quantification of vector genomes was done by quantitative (q)PCR. Results: Shedding occurred in a dose dependent manner in all biofluids and persisted for a maximum of 7 days. Intravitreal delivery led to increased and persistent (up to 13 weeks) distribution of vector genomes in blood and draining lymphatic tissue, increased off-target deposition, and inefficient gene transfer to the retina. No vector targeting of the germ line was observed in any cohort. Conclusions: These data illustrate that subretinal application of rAAV8 leads to a more favorable biodistribution profile compared to intravitreal injections. Extraocular biodistribution is limited after subretinal delivery, while intravitreal injection leads to both greater and more persistent systemic exposure, evident in blood and lymphatic tissues. With the knowledge on the dynamics of shedding in a setting mimicking clinical application, guidelines can be developed to refine clinical trial protocols to reduce the risk for trial subjects and their environment. PMID- 29117318 TI - Lamin Cleavage: A Reliable Marker for Studying Staurosporine-Induced Apoptosis in Corneal Tissue. AB - Purpose: The aims of this study were to identify a robust apoptosis marker suitable for both quantification and back-to-back analyses of programmed cell death and to define specific upstream targets for apoptosis in corneal cells. Methods: Apoptotic cleavage of initiator caspases and their downstream targets such as lamins and poly-ADP ribose polymerase was investigated in human corneal endothelial cells (HCEC-12), keratocytes (HCK), epithelial cells (HCEp), and full thickness corneas using Western blotting and confocal microscopy following apoptosis induction with staurosporine. We specifically focused on nuclear lamins, which have important structural and regulatory functions in the cell nucleus. Results: The cleavage of lamin A in HCEC-12 was significantly increased following apoptotic induction compared with HCK. More importantly, lamin A cleavage was detected in a dose-dependent manner in full-thickness corneal tissue by both Western blot analysis and fluorescence microscopy. Our study also demonstrates that HCEp show approximately three-fold increase in caspase 6 cleavage compared with endothelial cells or keratocytes. The presence of cleaved caspase 9 was lower in endothelial cells compared with epithelial cells and keratocytes. Conclusions: We successfully established lamin A cleavage as a quantifiable marker of apoptosis in both corneal cells and tissue. Quantification of lamin A cleavage by Western blotting followed by a back-to-back analysis with fluorescence microscopy was studied for the first time in the experimental (donor) corneal tissue. Screening of downstream apoptosis proteins and establishing cell type-specific protocols allowed us to identify possible targets (caspases, Apaf-1, etc.) for protective therapeutic approaches. PMID- 29117319 TI - Role of Hospital Volumes in Identifying Low-Performing and High-Performing Aortic and Mitral Valve Surgical Centers in the United States. AB - Importance: Identifying high-performing surgical valve centers with the best surgical outcomes is challenging. Hospital surgical volume is a frequently used surrogate for outcomes. However, its ability to distinguish low-performing and high-performing hospitals remains unknown. Objective: To examine the association of hospital procedure volume with hospital performance for aortic and mitral valve (MV) surgical procedures. Design, Setting, and Participants: Within an all payer nationally representative data set of inpatient hospitalizations, this study identified 682 unique hospitals performing surgical aortic valve replacement (SAVR) and MV replacement and repair with or without coronary artery bypass grafting (CABG) between 2007 and 2011. Procedural outcomes were further assessed for a 10-year period (2005-2014) to assess representativeness of study period. Main Outcomes and Measures: In-hospital risk-standardized mortality rate (RSMR) calculated using hierarchical models and an empirical bayesian approach with volume-based shrinkage that allowed for reliability adjustment. Results: At 682 US hospitals, 70 295 SAVR, 19 913 MV replacement, and 17 037 MV repair procedures were performed between 2007 and 2011, with a median annual volume of 43 (interquartile range [IQR], 23-76) SAVR, 13 (IQR, 6-22) MV replacement, and 9 (IQR, 4-19) MV repair procedures. Of 225 SAVR hospitals in the highest-volume tertile, 34.7% and 36.0% were in the highest-RSMR tertile for SAVR + CABG and isolated SAVR procedures, respectively, while 21.5% and 17.5% of the 228 SAVR hospitals in the lowest-volume tertile were in the lowest respective RSMR tertile. Similarly, 36.8% and 43.5% of hospitals in the highest tertile of volume for MV replacement and repair, respectively, were in the corresponding highest RSMR tertile, and 17.4% and 11.2% of the low-volume hospitals were in the lowest RSMR tertile for MV replacement and repair, respectively. There was limited correlation between outcomes for SAVR and MV procedures at an institution. If solely volume-based tertiles were used to categorize hospitals for quality, 44.7% of all valve hospitals would be misclassified (as either low performing or high performing) when assessing performance based on tertiles of RSMR. Conclusions and Relevance: Hospital procedure volume alone frequently misclassifies hospital performance with regard to risk-standardized outcomes after aortic and MV surgical procedures. Valve surgery quality improvement endeavors should focus on a more comprehensive assessment that includes risk-adjusted outcomes rather than hospital volume alone. PMID- 29117321 TI - The International Glossary on Infertility and Fertility Care, 2017. AB - STUDY QUESTION: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A. PMID- 29117320 TI - Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives. AB - STUDY QUESTION: What progress has been made in fertility preservation (FP) over the last decade? SUMMARY ANSWER: FP techniques have been widely adopted over the last decade and therefore the establishment of international registries on their short- and long-term outcomes is strongly recommended. WHAT IS KNOWN ALREADY: FP is a fundamental issue for both males and females whose future fertility may be compromised. Reproductive capacity may be seriously affected by age, different medical conditions and also by treatments, especially those with gonadal toxicity. There is general consensus on the need to provide counselling about currently available FP options to all individuals wishing to preserve their fertility. STUDY DESIGN, SIZE, DURATION: An international meeting with representatives from expert scientific societies involved in FP was held in Barcelona, Spain, in June 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty international FP experts belonging to the American Society of Reproductive Medicine, ESHRE and the International Society of Fertility Preservation reviewed the literature up to June 2015 to be discussed at the meeting, and approved the final manuscript. At the time this manuscript was being written, new evidence considered relevant for the debated topics was published, and was consequently included. MAIN RESULTS AND THE ROLE OF CHANCE: Several oncological and non oncological diseases may affect current or future fertility, either caused by the disease itself or the gonadotoxic treatment, and need an adequate FP approach. Women wishing to postpone maternity and transgender individuals before starting hormone therapy or undergoing surgery to remove/alter their reproductive organs should also be counselled accordingly. Embryo and oocyte cryopreservation are first-line FP methods in post-pubertal women. Metaphase II oocyte cryopreservation (vitrification) is the preferred option. Cumulative evidence of restoration of ovarian function and spontaneous pregnancies after ART following orthotopic transplantation of cryopreserved ovarian tissue supports its future consideration as an open clinical application. Semen cryopreservation is the only established method for FP in men. Testicular tissue cryopreservation should be recommended in pre-pubertal boys even though fertility restoration strategies by autotransplantation of cryopreserved testicular tissue have not yet been tested for safe clinical use in humans. The establishment of international registries on the short- and long-term outcomes of FP techniques is strongly recommended. LIMITATIONS, REASONS FOR CAUTION: Given the lack of studies in large cohorts or with a randomized design, the level of evidence for most of the evidence reviewed was three or below. WIDER IMPLICATIONS OF THE FINDINGS: Further high quality studies are needed to study the long-term outcomes of FP techniques. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A. PMID- 29117322 TI - Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses. AB - Background: There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciencias da Saude, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly >=28 weeks' gestation or >=1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets. Results: We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0-2%) of all stillbirths in developed countries and 4% (95% CI, 2%-6%) in Africa were associated with GBS. Conclusions: GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination. PMID- 29117323 TI - Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children: Why, What, and How to Undertake Estimates? AB - Improving maternal, newborn, and child health is central to Sustainable Development Goal targets for 2030, requiring acceleration especially to prevent 5.6 million deaths around the time of birth. Infections contribute to this burden, but etiological data are limited. Group B Streptococcus (GBS) is an important perinatal pathogen, although previously focus has been primarily on liveborn children, especially early-onset disease. In this first of an 11-article supplement, we discuss the following: (1) Why estimate the worldwide burden of GBS disease? (2) What outcomes of GBS in pregnancy should be included? (3) What data and epidemiological parameters are required? (4) What methods and models can be used to transparently estimate this burden of GBS? (5) What are the challenges with available data? and (6) How can estimates address data gaps to better inform GBS interventions including maternal immunization? We review all available GBS data worldwide, including maternal GBS colonization, risk of neonatal disease (with/without intrapartum antibiotic prophylaxis), maternal GBS disease, neonatal/infant GBS disease, and subsequent impairment, plus GBS-associated stillbirth, preterm birth, and neonatal encephalopathy. We summarize our methods for searches, meta-analyses, and modeling including a compartmental model. Our approach is consistent with the World Health Organization (WHO) Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER), published in The Lancet and the Public Library of Science (PLoS). We aim to address priority epidemiological gaps highlighted by WHO to inform potential maternal vaccination. PMID- 29117324 TI - Intrapartum Antibiotic Chemoprophylaxis Policies for the Prevention of Group B Streptococcal Disease Worldwide: Systematic Review. AB - Background: Intrapartum antibiotic chemoprophylaxis (IAP) prevents most early onset group B streptococcal (GBS) disease. However, there is no description of how IAP is used around the world. This article is the sixth in a series estimating the burden of GBS disease. Here we aimed to review GBS screening policies and IAP implementation worldwide. Methods: We identified data through (1) systematic literature reviews (PubMed/Medline, Embase, Literature in the Health Sciences in Latin America and the Caribbean [LILACS], World Health Organization library database [WHOLIS], and Scopus) and unpublished data from professional societies and (2) an online survey and searches of policies from medical societies and professionals. We included data on whether an IAP policy was in use, and if so whether it was based on microbiological or clinical risk factors and how these were applied, as well as the estimated coverage (percentage of women receiving IAP where indicated). Results: We received policy information from 95 of 195 (49%) countries. Of these, 60 of 95 (63%) had an IAP policy; 35 of 60 (58%) used microbiological screening, 25 of 60 (42%) used clinical risk factors. Two of 15 (13%) low-income, 4 of 16 (25%) lower-middle-income, 14 of 20 (70%) upper-middle-income, and 40 of 44 (91%) high-income countries had any IAP policy. The remaining 35 of 95 (37%) had no national policy (25/33 from low income and lower-middle-income countries). Coverage varied considerably; for microbiological screening, median coverage was 80% (range, 20%-95%); for clinical risk factor-based screening, coverage was 29% (range, 10%-50%). Although there were differences in the microbiological screening methods employed, the individual clinical risk factors used were similar. Conclusions: There is considerable heterogeneity in IAP screening policies and coverage worldwide. Alternative global strategies, such as maternal vaccination, are needed to enhance the scope of global prevention of GBS disease. PMID- 29117325 TI - Risk of Early-Onset Neonatal Group B Streptococcal Disease With Maternal Colonization Worldwide: Systematic Review and Meta-analyses. AB - Background: Early-onset group B streptococcal disease (EOGBS) occurs in neonates (days 0-6) born to pregnant women who are rectovaginally colonized with group B Streptococcus (GBS), but the risk of EOGBS from vertical transmission has not been systematically reviewed. This article, the seventh in a series on the burden of GBS disease, aims to estimate this risk and how it varies with coverage of intrapartum antibiotic prophylaxis (IAP), used to reduce the incidence of EOGBS. Methods: We conducted systematic reviews (Pubmed/Medline, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups on maternal GBS colonization and neonatal outcomes. We included articles with >=200 GBS colonized pregnant women that reported IAP coverage. We did meta-analyses to determine pooled estimates of risk of EOGBS, and examined the association in risk of EOGBS with IAP coverage. Results: We identified 30 articles including 20328 GBS-colonized pregnant women for inclusion. The risk of EOGBS in settings without an IAP policy was 1.1% (95% confidence interval [CI], .6%-1.5%). As IAP increased, the risk of EOGBS decreased, with a linear association. Based on linear regression, the risk of EOGBS in settings with 80% IAP coverage was predicted to be 0.3% (95% CI, 0-.9). Conclusions: The risk of EOGBS among GBS-colonized pregnant women, from this first systematic review, is consistent with previous estimates from single studies (1%-2%). Increasing IAP coverage was linearly associated with decreased risk of EOGBS disease. PMID- 29117326 TI - Infant Group B Streptococcal Disease Incidence and Serotypes Worldwide: Systematic Review and Meta-analyses. AB - Background: Group B Streptococcus (GBS) remains a leading cause of neonatal sepsis in high-income contexts, despite declines due to intrapartum antibiotic prophylaxis (IAP). Recent evidence suggests higher incidence in Africa, where IAP is rare. We investigated the global incidence of infant invasive GBS disease and the associated serotypes, updating previous estimates. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data regarding invasive GBS disease in infants aged 0-89 days. We conducted random-effects meta analyses of incidence, case fatality risk (CFR), and serotype prevalence. Results: We identified 135 studies with data on incidence (n = 90), CFR (n = 64), or serotype (n = 45). The pooled incidence of invasive GBS disease in infants was 0.49 per 1000 live births (95% confidence interval [CI], .43-.56), and was highest in Africa (1.12) and lowest in Asia (0.30). Early-onset disease incidence was 0.41 (95% CI, .36-.47); late-onset disease incidence was 0.26 (95% CI, .21 .30). CFR was 8.4% (95% CI, 6.6%-10.2%). Serotype III (61.5%) dominated, with 97% of cases caused by serotypes Ia, Ib, II, III, and V. Conclusions: The incidence of infant GBS disease remains high in some regions, particularly Africa. We likely underestimated incidence in some contexts, due to limitations in case ascertainment and specimen collection and processing. Burden in Asia requires further investigation. PMID- 29117327 TI - Maternal Colonization With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses. AB - Background: Maternal rectovaginal colonization with group B Streptococcus (GBS) is the most common pathway for GBS disease in mother, fetus, and newborn. This article, the second in a series estimating the burden of GBS, aims to determine the prevalence and serotype distribution of GBS colonizing pregnant women worldwide. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus), organized Chinese language searches, and sought unpublished data from investigator groups. We applied broad inclusion criteria to maximize data inputs, particularly from low- and middle-income contexts, and then applied new meta-analyses to adjust for studies with less-sensitive sampling and laboratory techniques. We undertook meta analyses to derive pooled estimates of maternal GBS colonization prevalence at national and regional levels. Results: The dataset regarding colonization included 390 articles, 85 countries, and a total of 299924 pregnant women. Our adjusted estimate for maternal GBS colonization worldwide was 18% (95% confidence interval [CI], 17%-19%), with regional variation (11%-35%), and lower prevalence in Southern Asia (12.5% [95% CI, 10%-15%]) and Eastern Asia (11% [95% CI, 10% 12%]). Bacterial serotypes I-V account for 98% of identified colonizing GBS isolates worldwide. Serotype III, associated with invasive disease, accounts for 25% (95% CI, 23%-28%), but is less frequent in some South American and Asian countries. Serotypes VI-IX are more common in Asia. Conclusions: GBS colonizes pregnant women worldwide, but prevalence and serotype distribution vary, even after adjusting for laboratory methods. Lower GBS maternal colonization prevalence, with less serotype III, may help to explain lower GBS disease incidence in regions such as Asia. High prevalence worldwide, and more serotype data, are relevant to prevention efforts. PMID- 29117328 TI - Maternal Disease With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses. AB - Background: Infections such as group B Streptococcus (GBS) are an important cause of maternal sepsis, yet limited data on epidemiology exist. This article, the third of 11, estimates the incidence of maternal GBS disease worldwide. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on invasive GBS disease in women pregnant or within 42 days postpartum. We undertook meta-analyses to derive pooled estimates of the incidence of maternal GBS disease. We examined maternal and perinatal outcomes and GBS serotypes. Results: Fifteen studies and 1 unpublished dataset were identified, all from United Nations-defined developed regions. From a single study with pregnancies as the denominator, the incidence of maternal GBS disease was 0.38 (95% confidence interval [CI], .28-.48) per 1000 pregnancies. From 3 studies reporting cases by the number of maternities (pregnancies resulting in live/still birth), the incidence was 0.23 (95% CI, .09-.37). Five studies reported serotypes, with Ia being the most common (31%). Most maternal GBS disease was detected at or after delivery. Conclusions: Incidence data on maternal GBS disease in developing regions are lacking. In developed regions the incidence is low, as are the sequelae for the mother, but the risk to the fetus and newborn is substantial. The timing of GBS disease suggests that a maternal vaccine given in the late second or early third trimester of pregnancy would prevent most maternal cases. PMID- 29117329 TI - Preterm Birth Associated With Group B Streptococcus Maternal Colonization Worldwide: Systematic Review and Meta-analyses. AB - Background: Preterm birth complications are the leading cause of deaths among children <5 years of age. Studies have suggested that group B Streptococcus (GBS) maternal rectovaginal colonization during pregnancy may be a risk factor for preterm delivery. This article is the fifth of 11 in a series. We aimed to assess the association between GBS maternal colonization and preterm birth in order to inform estimates of the burden of GBS. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups on the association of preterm birth (<37 weeks' gestation) and maternal GBS colonization (GBS isolation from vaginal, cervical, and/or rectal swabs; with separate subanalysis on GBS bacteriuria). We did meta-analyses to derive pooled estimates of the risk and odds ratios (according to study design), with sensitivity analyses to investigate potential biases. Results: We identified 45 studies for inclusion. We estimated the risk ratio (RR) for preterm birth with maternal GBS colonization to be 1.21 (95% confidence interval [CI], .99-1.48; P = .061) in cohort and cross-sectional studies, and the odds ratio to be 1.85 (95% CI, 1.24-2.77; P = .003) in case-control studies. Preterm birth was associated with GBS bacteriuria in cohort studies (RR, 1.98 [95% CI, 1.45-2.69]; P < .001). Conclusions: From this review, there is evidence to suggest that preterm birth is associated with maternal GBS colonization, especially where there is evidence of ascending infection (bacteriuria). Several biases reduce the chance of detecting an effect. Equally, however, results, including evidence for the association, may be due to confounding, which is rarely addressed in studies. Assessment of any effect on preterm delivery should be included in future maternal GBS vaccine trials. PMID- 29117330 TI - Neonatal Encephalopathy With Group B Streptococcal Disease Worldwide: Systematic Review, Investigator Group Datasets, and Meta-analysis. AB - Background: Neonatal encephalopathy (NE) is a leading cause of child mortality and longer-term impairment. Infection can sensitize the newborn brain to injury; however, the role of group B streptococcal (GBS) disease has not been reviewed. This paper is the ninth in an 11-article series estimating the burden of GBS disease; here we aim to assess the proportion of GBS in NE cases. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups reporting GBS-associated NE. Meta-analyses estimated the proportion of GBS disease in NE and mortality risk. UK population-level data estimated the incidence of GBS-associated NE. Results: Four published and 25 unpublished datasets were identified from 13 countries (N = 10436). The proportion of NE associated with GBS was 0.58% (95% confidence interval [CI], 0.18%-.98%). Mortality was significantly increased in GBS-associated NE vs NE alone (risk ratio, 2.07 [95% CI, 1.47-2.91]). This equates to a UK incidence of GBS-associated NE of 0.019 per 1000 live births. Conclusions: The consistent increased proportion of GBS disease in NE and significant increased risk of mortality provides evidence that GBS infection contributes to NE. Increased information regarding this and other organisms is important to inform interventions, especially in low- and middle-resource contexts. PMID- 29117331 TI - Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses. AB - Background: Survivors of infant group B streptococcal (GBS) disease are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified. This is the 10th of 11 articles estimating the burden of GBS disease. Here we aimed to estimate NDI in survivors of infant GBS disease. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on the risk of NDI after invasive GBS disease in infants <90 days of age. We did meta-analyses to derive pooled estimates of the percentage of infants with NDI following GBS meningitis. Results: We identified 6127 studies, of which 18 met eligibility criteria, all from middle- or high-income contexts. All 18 studies followed up survivors of GBS meningitis; only 5 of these studies also followed up survivors of GBS sepsis and were too few to pool in a meta-analysis. Of meningitis survivors, 32% (95% CI, 25%-38%) had NDI at 18 months of follow-up, including 18% (95% CI, 13%-22%) with moderate to severe NDI. Conclusions: GBS meningitis is an important risk factor for moderate to severe NDI, affecting around 1 in 5 survivors. However, data are limited, and we were unable to estimate NDI after GBS sepsis. Comparability of studies is difficult due to methodological differences including variability in timing of clinical reviews and assessment tools. Follow-up of clinical cases and standardization of methods are essential to fully quantify the total burden of NDI associated with GBS disease, and inform program priorities. PMID- 29117333 TI - Oleic acid stimulation of motility of human extravillous trophoblast cells is mediated by stearoyl-CoA desaturase-1 activity. AB - STUDY QUESTION: Do fatty acids regulate development and motility of human extravillous trophoblast cells (EVTs)? SUMMARY ANSWER: Oleic acid is a promising lipid molecule that has beneficial effects on motility and development of human EVTs. WHAT IS KNOWN ALREADY: Fatty acid uptake into trophoblast cells is important for maintaining cellular events during pregnancy, but the molecular mechanisms of action of various fatty acids, including trans fatty acids, saturated fatty acids and monounsaturated fatty acids, in EVT cell lines are not clear. STUDY DESIGN, SIZE, DURATION: Effects of oleic acid, elaidic acid, palmitic acid and stearic acid on HTR8/SVneo cells were assessed in diverse assays in a dose- and time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Effects of fatty acids on cell proliferation, migration, invasion and apoptosis (Annexin V expression, propidium iodide staining, TUNEL and invasion assays) of HTR8/SVneo cells were determined. Signal transduction pathways in HTR8/SVneo cells in response to fatty acids were determined by Western blot analyses. Regulation of fatty acids on oxidative conditions in EVTs were determined and validated by measurement of production of cellular reactive oxygen species, intracellular concentrations of free Ca2+and lipid peroxidation assays. MAIN RESULTS AND THE ROLE OF CHANCE: In present study, we confirmed different effects of oleic acid and elaidic acid on migration, invasion, proliferation and apoptosis of the EVT cell line, HTR8/SVneo. We also investigated stearoyl-CoA desaturase-1 (SCD1) to determine if its activity contributed to oleic acid induced migration of HTR8/SVneo cells. Next, we analyzed cell signaling molecules mediated by oleic acid and elaidic acid treatment, including MAPK and PI3K/AKT pathways in HTR8/SVneo cells. We further established whether selective inhibition of signaling molecules altered the ability of fatty acids to cause changes in migration and proliferation of HTR8/SVneo cells. Last, we examined the regulatory effects of oleic acid and SCD1 on oxidative stress in HTR8/SVneo cells. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The lack of in vivo animal studies is a major limitation of this research. Effectiveness of oleic acid to stimulate migration of human EVT cells requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that oleic acid can play an important role in promoting invasion of human EVT cell lines while both trans fatty acids and saturated fatty acids are not conducive to normal placentation. This may have implications for the prevention of pre-eclampsia and intrauterine growth restriction. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810) awarded to G.S. and (No. HI17C0929) awarded to W.L. There are no conflicts of interest. PMID- 29117334 TI - Remote monitoring for heart failure: the story moves on. PMID- 29117332 TI - Estimates of the Burden of Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children. AB - Background: We aimed to provide the first comprehensive estimates of the burden of group B Streptococcus (GBS), including invasive disease in pregnant and postpartum women, fetal infection/stillbirth, and infants. Intrapartum antibiotic prophylaxis is the current mainstay of prevention, reducing early-onset infant disease in high-income contexts. Maternal GBS vaccines are in development. Methods: For 2015 live births, we used a compartmental model to estimate (1) exposure to maternal GBS colonization, (2) cases of infant invasive GBS disease, (3) deaths, and (4) disabilities. We applied incidence or prevalence data to estimate cases of maternal and fetal infection/stillbirth, and infants with invasive GBS disease presenting with neonatal encephalopathy. We applied risk ratios to estimate numbers of preterm births attributable to GBS. Uncertainty was also estimated. Results: Worldwide in 2015, we estimated 205000 (uncertainty range [UR], 101000-327000) infants with early-onset disease and 114000 (UR, 44000 326000) with late-onset disease, of whom a minimum of 7000 (UR, 0-19000) presented with neonatal encephalopathy. There were 90000 (UR, 36000-169000) deaths in infants <3 months age, and, at least 10000 (UR, 3000-27000) children with disability each year. There were 33000 (UR, 13000-52000) cases of invasive GBS disease in pregnant or postpartum women, and 57000 (UR, 12000-104000) fetal infections/stillbirths. Up to 3.5 million preterm births may be attributable to GBS. Africa accounted for 54% of estimated cases and 65% of all fetal/infant deaths. A maternal vaccine with 80% efficacy and 90% coverage could prevent 107000 (UR, 20000-198000) stillbirths and infant deaths. Conclusions: Our conservative estimates suggest that GBS is a leading contributor to adverse maternal and newborn outcomes, with at least 409000 (UR, 144000-573000) maternal/fetal/infant cases and 147000 (UR, 47000-273000) stillbirths and infant deaths annually. An effective GBS vaccine could reduce disease in the mother, the fetus, and the infant. PMID- 29117338 TI - Error in End Matter. PMID- 29117336 TI - Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial. AB - Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. Patients and methods: Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. Results: Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (kappa = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. Conclusions: There was significant discordance between patient- and clinician reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy. PMID- 29117337 TI - sEEG is a Safe Procedure for a Comprehensive Anatomic Exploration of the Insula: A Retrospective Study of 108 Procedures Representing 254 Transopercular Insular Electrodes. AB - BACKGROUND: The exploration of the insula in pre-surgical evaluation of epilepsy is considered to be associated with a high vascular risk resulting in an incomplete exploration of the insular cortex. OBJECTIVE: To report a retrospective observational study of insular exploration using stereoelectroencephalography (sEEG) with transopercular and parasagittal oblique intracerebral electrodes from January 2008 to January 2016. The first purpose of this study was to evaluate the surgical risks of insular cortex sEEG exploration. The second purpose was to define the ability of placing intracerebral contacts in the whole insular cortex. METHODS: Ninety-nine patients underwent 108 magnetic resonance imaging (MRI)-guided stereotactic implantations of intracerebral electrodes in the context of preoperative assessment of drug-resistant epilepsy, including at least 1 electrode placed in the insular cortex. On postoperative computed tomography images co-registered with MRI, followed by MRI segmentation and application of a transformation matrix, intracerebral contact coordinates of the insular electrodes' contacts were anatomically localized in the Talairach space. Finally, dispersion and clustering analysis was performed. RESULTS: There was no morbidity, in particular hemorrhagic complications, or mortality related to insular electrodes. Statistical comparison of intracerebral contact positions demonstrated that whole insula exploration is possible on the left and right sides. In addition, the clustering analysis showed the homogeneous distribution of the electrodes within the insular cortex. CONCLUSION: In the presurgical evaluation of drug-resistant epilepsy, the insular cortex can be explored safely and comprehensively using transopercular sEEG electrodes. Parasagittal oblique trajectories may also be associated to achieve an optimal exploration. PMID- 29117335 TI - Improved survival using specialized multidisciplinary board in sarcoma patients. AB - Background: Sarcomas are rare but aggressive diseases. Specialized multidisciplinary management is not implemented for all patients in most countries. We investigated the impact of a multidisciplinary tumor board (MDTB) presentation before treatment in a nationwide study over 5 years. Patients and methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized MDTB, funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma patients in France. Patients' characteristics and follow-up are collected in a database regularly monitored and updated. The management and survival of patients presented to these MDTB before versus after initial treatment were analyzed. Results: Out of the 12 528 patients aged >=15 years, with a first diagnosis of soft tissue and visceral sarcoma obtained between 1 January 2010 and 31 December 2014, 5281 (42.2%) and 7247 (57.8%) were presented to the MDTB before and after the initiation of treatment, respectively. The former group had generally worse prognostic characteristics. Presentation to a MDTB before treatment was associated with a better compliance to clinical practice guidelines, for example, biopsy before surgery, imaging, quality of initial surgery, and less reoperations (all P < 0.001). Local relapse free survival and relapse-free survival were significantly better in patients presented to a MDTB before initiation of treatment, both in univariate and multivariate analysis. Conclusion: The compliance to clinical practice guidelines and relapse-free survival of sarcoma patients are significantly better when the initial treatment is guided by a pre-therapeutic specialized MDTB. PMID- 29117339 TI - Incidence and Predictors of Venous Thromboembolism in Abdominoplasty. AB - Background: The prevention of venous thromboembolism (VTE) is a high priority in aesthetic surgery. Abdominoplasty is the aesthetic procedure most commonly associated with VTE, yet the mechanisms for the development of VTE associated with this procedure are unclear. Objectives: The purpose of this study was to analyze the incidence and predictors of VTE in patients undergoing abdominoplasty procedures in outpatient surgery centers using data from the Internet Based Quality Assurance Program (IBQAP). Methods: IBQAP data from 2001 to 2011 were queried retrospectively to identify abdominoplasty cases and VTE cases. Patient- and procedure-specific variables were analyzed to identify potential predictors of VTE in abdominoplasty. Results: Among all outpatient aesthetic surgery cases entered from 2001 to 2011, 414 resulted in VTE, representing a VTE incidence of 0.02%. Of these, 240 (58%) occurred in abdominoplasty cases. Predictors of VTE were age greater than 40 years and BMI greater than 25 kg/m2. Patient sex, duration of anesthesia and surgery, type of anesthesia, type of additional procedure, and number of procedures did not appear to influence the risk of VTE. Importantly, 95.5% of the VTEs identified for this study occurred in patients whose Caprini risk assessment model score was between 2 and 8, which would not be an indication for chemoprophylaxis according to current recommendations. Conclusions: Many factors must be considered when determining the true incidence of VTE in abdominoplasty. Research is needed to discover the reason abdominoplasty carries a greater risk compared with other aesthetic surgery procedures so that appropriate steps can be taken to prevent its occurrence and improve the safety of the procedure. PMID- 29117340 TI - Race and Ethnicity Do Not Clinically Associate with Quality of Life Among Patients with Chronic Severe Pain in a Federally Qualified Health Center. AB - Objective: Previous research suggests that race/ethnicity predicts health-related quality of life (HRQL) in chronic pain populations but has not examined this in community settings. This study evaluated this association in 522 community dwelling patients with chronic pain treated at a Federally Qualified Health Center (FQHC). Design: Cross-sectional secondary analysis. Setting: Six practice sites of an FQHC in New York. Subjects: One hundred forty-two non-Hispanic blacks, 121 non-Hispanic whites, 219 Hispanics, and 40 classified as "other" with severe chronic pain. Methods: Patients with chronic severe pain (three or more months with worst pain >= 4/10 or T-score > 60.5 on the Patient-Reported Outcomes Measurement Information System pain interference tool) were interviewed as part of a clinical trial. Race/ethnicity and other potential predictors of HRQL were assessed. Results: Mean age was 53.0 years, and 70.1% were women; 62.8% earned less than $10,000 per year, and 22.8% were Spanish-speaking with low acculturation. Mean worst pain during the past week was 8.6/10, and 39.6% used opioids. In multivariate analyses, race/ethnicity was not significantly associated with mental HRQL. Hispanics had significantly lower physical HRQL than non-Hispanic whites or blacks, but this difference was not clinically meaningful (mean T-scores = 33.9 [Hispanics], 35.8 [non-Hispanic whites], and 35.6 [non Hispanic blacks]). Mental HRQL was predicted by depression, anxiety, pain disability, income, and physical HRQL; physical HRQL was predicted by race/ethnicity, anxiety, pain disability, age, care satisfaction, and mental HRQL. Conclusions: Race/ethnicity does not explain important variation in HRQL reported by diverse patients with chronic pain. Psychological distress, pain disability, age, and socioeconomic status predicted this health outcome. Future studies may clarify modifiers of these associations to guide treatment in FQHC populations. PMID- 29117341 TI - Association of Physical Activity With Risk of Major Cardiovascular Diseases in Chinese Men and Women. AB - Importance: In China, the patterns and levels of physical activity differed from those in high-income countries. Substantial uncertainty remains about the relevance, both qualitatively and quantitatively, of domain-specific physical activity for cardiovascular disease (CVD) subtypes in Chinese adults. Objective: To assess the shape and strength of the associations of total, occupational, and nonoccupational physical activity with CVD subtypes in Chinese men and women. Design, Setting, and Participants: This population-based prospective cohort study in 10 (5 urban, 5 rural) areas across China included 487 334 adults who were aged 30 to 79 (mean 51) years with no prior CVD history when enrolled from June 2004 to July 2008. Exposures: Self-reported total, occupational, and nonoccupational physical activity, quantified as metabolic equivalent of task hours per day (MET h/d) based on the type, frequency, and duration of specific activities. Main Outcomes and Measures: Major vascular events (n = 36 184) and their components, including major coronary events (n = 5082), ischemic stroke (n = 25 647), intracerebral hemorrhage (n = 5252), and CVD death (n = 8437). Cox regression yielded adjusted hazard ratios for each disease that was associated with physical activity. Results: Of the 487 334 study participants, 287 527 (59%) were women and the mean (SD) age was 51 (10.5) years. The overall mean (SD) total physical activity was 21.5 (12.8) MET-h/d, mainly from occupational activity, especially among men (75% vs 50% in women). Total physical activity was inversely associated with the risk of major vascular events, with the adjusted hazard ratio that compared the top vs bottom quintiles of physical activity being 0.77 (95% CI, 0.74-0.80). Throughout the range of total physical activity studied, the association with CVD with each 4 MET-h/d higher usual total physical activity (approximately 1 hour of brisk walking per day) associated with a 6% (95% CI, 5% 7%) lower risk of major vascular events, and a 9%, 5%, 6%, and 12% lower risk of major coronary events, ischemic stroke, intracerebral hemorrhage, and CVD death, respectively. The strength of the associations was similar and independent of each other for occupational and nonoccupational physical activity. However, for occupational physical activity, the associations with CVD subtypes were greatly attenuated above 20 MET-h/d, especially for intracerebral hemorrhage. The associations of total physical activity with major vascular events were similar among men and women and across different levels of sedentary leisure time but were much weaker among individuals with high blood pressure. Conclusions and Relevance: Among Chinese adults, higher occupational or nonoccupational physical activity was associated with significantly lower risks of major CVD. PMID- 29117343 TI - Finding the Missing Tuberculosis Patients. PMID- 29117344 TI - Patient-Centered Tuberculosis Programs Are Necessary to End the Epidemic. PMID- 29117342 TI - The South African Tuberculosis Care Cascade: Estimated Losses and Methodological Challenges. AB - Background: While tuberculosis incidence and mortality are declining in South Africa, meeting the goals of the End TB Strategy requires an invigorated programmatic response informed by accurate data. Enumerating the losses at each step in the care cascade enables appropriate targeting of interventions and resources. Methods: We estimated the tuberculosis burden; the number and proportion of individuals with tuberculosis who accessed tests, had tuberculosis diagnosed, initiated treatment, and successfully completed treatment for all tuberculosis cases, for those with drug-susceptible tuberculosis (including human immunodeficiency virus (HIV)-coinfected cases) and rifampicin-resistant tuberculosis. Estimates were derived from national electronic tuberculosis register data, laboratory data, and published studies. Results: The overall tuberculosis burden was estimated to be 532005 cases (range, 333760-764480 cases), with successful completion of treatment in 53% of cases. Losses occurred at multiple steps: 5% at test access, 13% at diagnosis, 12% at treatment initiation, and 17% at successful treatment completion. Overall losses were similar among all drug-susceptible cases and those with HIV coinfection (54% and 52%, respectively, successfully completed treatment). Losses were substantially higher among rifampicin- resistant cases, with only 22% successfully completing treatment. Conclusion: Although the vast majority of individuals with tuberculosis engaged the public health system, just over half were successfully treated. Urgent efforts are required to improve implementation of existing policies and protocols to close gaps in tuberculosis diagnosis, treatment initiation, and successful treatment completion. PMID- 29117345 TI - Harnessing the Power of Data to Guide Local Action and End Tuberculosis. PMID- 29117346 TI - Increasing Access to Tuberculosis Services in Ethiopia: Findings From a Patient Pathway Analysis. AB - Background: In Ethiopia, extensive scale-up of the availability of health extension workers (HEWs) at the community level has been credited with increased identification and referral of patients with presumptive tuberculosis, which has contributed to increased tuberculosis case notification and better treatment outcomes. However, nearly 30% of Ethiopia's estimated 191000 patients with tuberculosis remained unnotified in 2015. A better understanding of patient care seeking practices may inform future government action to reach all patients with tuberculosis. Methods: A patient-pathway analysis was completed to assess the alignment between patient care initiation and the availability of diagnostic and treatment services at the national level. Results: More than one third of patients initiated care with HEWs, who refer patients to health centers for diagnosis. An additional one third of patients initiated care at health centers. Of those health centers, >80% had microscopy services, but few had access to Xpert. Despite an extensive microscopy and radiography network at middle levels of the health system, a quarter of all notified patients with tuberculosis had no bacteriological confirmation of disease. While 30% of patients reported receiving some form of care from the private sector, private-sector facilities, especially pharmacies, were not widely accessed for tuberculosis diagnosis. Discussion: The availability of HEWs can increase access to tuberculosis diagnostic and treatment support services, particularly for rural populations. Continued strengthening of referral systems from HEWs and health posts are needed to enable consistent and timely access to Xpert as an initial diagnostic test and to drug resistance screening. PMID- 29117347 TI - Quality Tuberculosis Care in Indonesia: Using Patient Pathway Analysis to Optimize Public-Private Collaboration. AB - Background: Tuberculosis (TB) is the fourth leading cause of death in Indonesia. In 2015, the World Health Organization estimated that nearly two-thirds of the TB patients in Indonesia had not been notified, and the status of their care remained unknown. As such, Indonesia is home to nearly 20% of the world's "missing" TB patients. Understanding where patients go for care may enable strategic planning of services to better reach them. Methods: A patient pathway analysis (PPA) was conducted to assess the alignment between patient care seeking and the availability of TB diagnostic and treatment services at the national and subnational level in Indonesia. Results: The PPA results revealed that only 20% of patients encountered diagnostic capacity at the location where they first sought care. Most initial care seeking occurred in the private sector and case notification lagged behind diagnostic confirmation in the public sector. Conclusions: The PPA results emphasize the role that the private sector plays in TB patient care seeking and suggested a need for differentiated approaches, by province, to respond to variances in care-seeking patterns and the capacities of public and private providers. PMID- 29117348 TI - Delivering Patient-Centered Care in a Fragile State: Using Patient-Pathway Analysis to Understand Tuberculosis-Related Care Seeking in Pakistan. AB - Background: Pakistan has the sixth largest population in the world and boasts the fifth greatest burden of tuberculosis. The Government of Pakistan has set the ambitious goal of zero deaths due to tuberculosis and universal access to tuberculosis care by 2020. Successfully reaching these goals is dependent on the country's capacity to diagnose and successfully treat an estimated 200000 unnotified or missing patients with tuberculosis. Methods: A patient-pathway analysis (PPA) was conducted at the national level, as well as for each of the 4 provinces, to assess the alignment between patient care seeking and the availability of tuberculosis diagnostic and treatment services. Results: Almost 90% of patients initiated care in the private sector, which accounts for only 15% of facilities with the capacity for tuberculosis diagnosis and treatment. Across the country, nearly 50% of tuberculosis microscopy laboratories were located in public-sector-basic health units and regional health centers. However, very few patients initiated care in these facilities. Overall, tuberculosis case detection was high given the low likelihood of patients reaching facilities with the capacity for tuberculosis service delivery during their first visit. Discussion: Improving the engagement of the informal sector and lower-level clinicians will improve the efficiency and timeliness of tuberculosis diagnosis for patients in Pakistan. Concurrently, the apparent strength of the referral networks connecting community-level workers and private clinicians to the public sector for tuberculosis diagnosis and treatment suggests that strengthening the capacity of the public sector could be valuable. PMID- 29117349 TI - Using Patient-Pathway Analysis to Inform a Differentiated Program Response to Tuberculosis: The Case of Kenya. AB - Background: A recent tuberculosis prevalence survey in Kenya found that the country is home to nearly twice as many patients with tuberculosis as previously estimated. Kenya has prioritized identifying and treating the unnotified or missing cases of tuberculosis. This requires a better understanding of patient care seeking and system weaknesses. Methods: A patient-pathway analysis (PPA) was completed to assess the alignment between patient care seeking and the availability of tuberculosis diagnostic and treatment services at the national level and for all 47 counties at the subnational level in Kenya. Results: It was estimated that more than half of patients initiate care in the public sector. Nationally, just under half of patients encountered tuberculosis diagnostic and treatment capacity where they initiated care. Overall, there was distinct variation in diagnostic and treatment availability across counties and facility levels. Discussion: The PPA results emphasized the need for a differentiated approach to tuberculosis care, by county, and the distinct need for better referral systems. The majority of Kenyans actively sought care; improving diagnostic and treatment capacity in the formal and informal private sector, as well as in the public sector, could help identify the majority of missing cases. PMID- 29117350 TI - Conducting Patient-Pathway Analysis to Inform Programming of Tuberculosis Services: Methods. AB - Patient-centered care is a central pillar of the World Health Organization's End TB Strategy. Understanding where patients access health services is a first step to planning for the placement of services to meet patient needs and preferences. The patient-pathway analysis (PPA) methodology detailed in this article was developed to better understand the alignment between patient care seeking and tuberculosis service availability. A PPA describes the steps that people with tuberculosis take from the initial care visit to cure. The results of a PPA reveal programmatic gaps in care seeking, diagnosis, treatment initiation, and continuity of care. They can be used as inputs to an evidence-based process of identifying and developing interventions to address the gaps in patient care. This paper summarizes the steps to conduct a PPA and serves as the basis for understanding country case studies that profile the use of PPA. PMID- 29117351 TI - Finding the Missing Patients With Tuberculosis: Lessons Learned From Patient Pathway Analyses in 5 Countries. AB - Background: Despite significant progress in diagnosis and treatment of tuberculosis over the past 2 decades, millions of patients with tuberculosis go unreported every year. The patient-pathway analysis (PPA) is designed to assess the alignment between tuberculosis care-seeking patterns and the availability of tuberculosis services. The PPA can help programs understand where they might find the missing patients with tuberculosis. Methods: This analysis aggregates and compares the PPAs from case studies in Kenya, Ethiopia, Indonesia, the Philippines, and Pakistan. Results: Across the 5 countries, 24% of patients with tuberculosis initiated care seeking in a facility with tuberculosis diagnostic capacity. Forty-two percent of patients sought care at level 0 facilities, where there was generally no tuberculosis diagnostic capacity; another 42% of patients sought care at level 1 facilities, of which 39% had diagnostic capacity. Sixty six percent of patients initially sought care in private facilities, which had considerably less tuberculosis diagnostic capacity than public facilities; only 7% of notified cases were from the private sector. The GeneXpert system was available in 14%-41% of level 2 facilities in the 3 countries for which there were data. Tuberculosis treatment capacity tracked closely with the availability of diagnostic capacity. There were substantial subnational differences in care seeking patterns and service availability. Discussion: The PPA can be a valuable planning and programming tool to ensure that diagnostic and treatment services are available to patients where they seek care. Patient-centered care will require closing the diagnostic gap and engaging the private sector. Extensive subnational differences in patient pathways to care call for differentiated approaches to patient-centered care. PMID- 29117352 TI - Using Patient Pathway Analysis to Design Patient-centered Referral Networks for Diagnosis and Treatment of Tuberculosis: The Case of the Philippines. AB - Background: Tuberculosis (TB) is the 8th leading cause of death in the Philippines. A recent prevalence survey found that there were nearly 70% more cases of tuberculosis than previously estimated. Given these new data, the National TB Program (NTP), operating through a decentralized health system, identified about 58% of the estimated new drug-sensitive (DS) TB patients in 2016. However, the NTP only identified and commenced treatment for around 17% of estimated new drug-resistant patients. In order to reach the remaining 42% of drug-sensitive patients and 83% of drug-resistant patients, it is necessary to develop a better understanding of where patients seek care. Methods: National and regional patient pathway analyses (PPAs) were undertaken using existing national survey and NTP data. The PPA assessed the alignment between patient care seeking and the availability of TB diagnostic and treatment services. Results: Systemic referral networks from the community-level Barangay Health Stations (BHSs) to diagnostic facilities have enabled more efficient detection of drug-sensitive tuberculosis in the public sector. Approximately 36% of patients initiated care in the private sector, where there is limited coverage of appropriate diagnostic technologies. Important differences in the alignment between care seeking patterns and diagnostic and treatment availability were found between regions. Conclusions: The PPA identified opportunities for strengthening access to care for all forms of tuberculosis and for accelerating the time to diagnosis by aligning services to where patients initiate care. Geographic variations in care seeking may guide prioritization of some regions for intensified engagement with the private sector. PMID- 29117353 TI - Quantifying Overdiagnosis in Cancer Screening: A Systematic Review to Evaluate the Methodology. AB - Background: Overdiagnosis is the main harm of cancer screening programs but is difficult to quantify. This review aims to evaluate existing approaches to estimate the magnitude of overdiagnosis in cancer screening in order to gain insight into the strengths and limitations of these approaches and to provide researchers with guidance to obtain reliable estimates of overdiagnosis in cancer screening. Methods: A systematic review was done of primary research studies in PubMed that were published before January 1, 2016, and quantified overdiagnosis in breast cancer screening. The studies meeting inclusion criteria were then categorized by their methods to adjust for lead time and to obtain an unscreened reference population. For each approach, we provide an overview of the data required, assumptions made, limitations, and strengths. Results: A total of 442 studies were identified in the initial search. Forty studies met the inclusion criteria for the qualitative review. We grouped the approaches to adjust for lead time in two main categories: the lead time approach and the excess incidence approach. The lead time approach was further subdivided into the mean lead time approach, lead time distribution approach, and natural history modeling. The excess incidence approach was subdivided into the cumulative incidence approach and early vs late-stage cancer approach. The approaches used to obtain an unscreened reference population were grouped into the following categories: control group of a randomized controlled trial, nonattenders, control region, extrapolation of a prescreening trend, uninvited groups, adjustment for the effect of screening, and natural history modeling. Conclusions: Each approach to adjust for lead time and obtain an unscreened reference population has its own strengths and limitations, which should be taken into consideration when estimating overdiagnosis. PMID- 29117354 TI - Editorial: Challenges in Quantifying Overdiagnosis. PMID- 29117355 TI - Current Gaps in Ovarian Cancer Epidemiology: The Need for New Population-Based Research. AB - With recent ovarian cancer screening studies showing no clinically significant mortality benefit, preventing this disease, identifying high-risk populations, and extending survival remain priorities. However, several challenges are impeding progress in ovarian cancer research. With most studies capturing exposure information from 10 or more years ago, evaluation of how changing patterns of exposures, such as new oral contraceptive formulations and increased intrauterine device use, might influence ovarian cancer risk and survival is difficult. Risk factors for ovarian cancer should be evaluated in the context of tumor histotypes, which have unique molecular features and cells of origin; this is a task that requires large collaborative studies to achieve meaningful sample sizes. Importantly, identification of novel modifiable risk factors, in addition to those currently known to reduce risk (eg, childbearing, tubal ligation, oral contraceptive use), is needed; this is not feasibly implemented at a population level. In this Commentary, we describe important gaps in knowledge and propose new approaches to advance epidemiologic research to improve ovarian cancer prevention and survival, including updated classification of tumors, collection of data on changing and novel exposures, longer follow-up on existing studies, evaluation of diverse populations, development of better risk prediction models, and collaborating prospectively with consortia to develop protocols for new studies that will allow seamless integration for future pooled analyses. PMID- 29117356 TI - Spatio-Temporal Genomic Heterogeneity, Phylogeny, and Metastatic Evolution in Salivary Adenoid Cystic Carcinoma. AB - Background: Adenoid cystic carcinoma (ACC), an uncommon and indolent salivary gland malignancy, is characterized by varied morphologic and clinical manifestations. Molecular genetic studies of ACC identified certain structural and mutational alterations that may play a driver role in tumor development. The evolution and regional consistency of these events in ACC development progression are uncertain. Methods: To investigate the spatial and temporal clonal landscape of ACC, whole-genome sequencing and variant analyses were performed on 34 regionally sampled primary tumors and their concurrent and metachronous metastatic deposits from eight patients. Results: The average mutation rate per case (primary and metastasis) was 0.32 per million base pairs, and the average incidence of shared mutations in primary and metastatic specimens in each case was 21.9% (range = 0%-44.4%). The analyses revealed considerable spatial clonal differences within and between primary tumors and metastatic disease. Phylogeny formation displayed branching evolution with a main trunk and two distinct mono splits in all cases. One of the main branches represented intratumor subclonal diversity, and the other delineated metastatic departure and progression. All metastatic tumors shared clonal linkage to their matching primary in concordance with parallel dissemination of metastasis. Synchronous metastases were genomically more similar to their primary than metachronous metastatic disease. Truncal genetic alterations included somatic mutations in the NOTCH pathway genes (NOTCH1 and SPEN) and t(6;9) associated gene fusions. Conclusions: Our study delineated clonal and subclonal phylogeny for primary and metastatic ACC, defined early genetic drivers, and provides a conceptual framework for a rational strategy to integrate heterogeneity in clinical assessment. PMID- 29117358 TI - RE: Post-traumatic Stress as the Primary Cause for Cognitive Decline-Not the Whole Story, and Perhaps No Story at All. PMID- 29117357 TI - Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma. AB - To investigate genetic predispositions for MYCN-amplified neuroblastoma, we performed a meta-analysis of three genome-wide association studies totaling 615 MYCN-amplified high-risk neuroblastoma cases and 1869 MYCN-nonamplified non-high risk neuroblastoma cases as controls using a fixed-effects model with inverse variance weighting. All statistical tests were two-sided. We identified a novel locus at 3p21.31 indexed by the single nucleotide polymorphism (SNP) rs80059929 (odds ratio [OR] = 2.95, 95% confidence interval [CI] = 2.17 to 4.02, Pmeta = 6.47 * 10-12) associated with MYCN-amplified neuroblastoma, which was replicated in 127 MYCN-amplified cases and 254 non-high-risk controls (OR = 2.30, 95% CI = 1.12 to 4.69, Preplication = .02). To confirm this signal is exclusive to MYCN amplified tumors, we performed a second meta-analysis comparing 728 MYCN nonamplified high-risk patients to identical controls. rs80059929 was not statistically significant in MYCN-nonamplified high-risk patients (OR = 1.24, 95% CI = 0.90 to 1.71, Pmeta = .19). SNP rs80059929 is within intron 16 in the KIF15 gene. Additionally, the previously reported LMO1 neuroblastoma risk locus was statistically significant only in patients with MYCN-nonamplified high-risk tumors (OR = 0.63, 95% CI = 0.53 to 0.75, Pmeta = 1.51 * 10-8; Pmeta = .95). Our results indicate that common genetic variation predisposes to different neuroblastoma genotypes, including the likelihood of somatic MYCN-amplification. PMID- 29117359 TI - Co-occurring Genomic Alterations and Association With Progression-Free Survival in BRAFV600-Mutated Nonmelanoma Tumors. AB - BRAFV600 mutations occur in multiple nonmelanoma tumors, but no US Food and Drug Administration-approved BRAF-targeted therapies exist for these cancers. BRAF inhibitor vemurafenib was recently found to demonstrate activity across various BRAF-mutated nonmelanoma cancer types. However, most tumors ultimately become resistant to BRAF-targeted monotherapy. To identify whether co-occurring genomic alterations drive resistance to BRAF-targeted therapies, we analyzed next generation sequencing data from 30 advanced BRAF-mutated nonmelanoma cancers treated with BRAF inhibitor monotherapy. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. All statistical tests were two-sided. We identified a strong association between co-occurring PI3K-mTOR pathway aberrations and primary resistance to BRAF-targeted therapy. PI3K-mTOR pathway aberrations were associated with a statistically significant reduction in progression-free survival (HR = 15.0, 95% CI = 3.6 to 63.0, P < .001) and overall survival (HR = 19.2, 95% CI = 3.7 to 100.0, P < .001). This suggests that co occurring genomic alterations may predict response and resistance to BRAF inhibitor therapy and identify subgroups of BRAF-mutated nonmelanomas cancers. PMID- 29117361 TI - RE: Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial. PMID- 29117360 TI - Racial and Ethnic Disparities in the Incidence of Pediatric Extracranial Embryonal Tumors. AB - Background: Few studies have comparatively assessed differences in the incidence of childhood cancer by race and ethnicity that could inform etiologic research. We aimed to identify disparities in the incidence of pediatric extracranial embryonal tumors by race and ethnicity in the United States using a population based cancer registry. Methods: Cases of extracranial embryonal tumors among children age 0 to 19 years diagnosed between 2000 and 2010 were retrieved from the Surveillance, Epidemiology, and End Results Program 18 (n = 8188). Age standardized incidence rates and incidence rate ratios (IRRs) were obtained by race/ethnicity. Whites were the reference group. The percentage of families living below the poverty line by county was used to stratify by socioeconomic status (SES). Results: All minority groups had a lower incidence of neuroblastoma (Hispanics: IRR = 0.53, 95% confidence interval [CI] = 0.47 to 0.59; blacks: IRR = 0.70, 95% CI = 0.61 to 0.81; Native-Hawaiian/Asian-Pacific-Islander (API): IRR = 0.56, 95% CI = 0.46 to 0.67; and American Indian/Alaska Native (AI/AN): IRR = 0.28, 95% CI = 0.15 to 0.48) while Hispanics had a higher incidence of retinoblastoma (IRR = 1.26, 95% CI = 1.07 to 1.48). Incidence of nephroblastoma was lower among Hispanics (IRR = 0.80, 95% CI = 0.71 to 0.91) and API (IRR = 0.43, 95% CI = 0.33 to 0.56) while equivalent for blacks. Similarly, incidence of rhabdomyosarcoma was low among Hispanics (IRR = 0.85, 95% CI = 0.74 to 0.98) and API (IRR = 0.61, 95% CI = 0.47 to 0.79) while equivalent for blacks. However, incidence of hepatoblastoma was low among blacks (IRR = 0.44, 95% CI = 0.28 to 0.68) while equivalent for Hispanics and API. Incidence of germ cell tumors was higher among Hispanics (IRR = 1.30, 95% CI = 1.19 to 1.42) and lower among blacks (IRR = 0.52, 95% CI = 0.44 to 0.61) and API (IRR = 0.79, 95% CI = 0.67 to 0.93). No effect modification by SES was observed. Conclusions: Unique incidence patterns of childhood extracranial embryonal tumors exist by race and ethnicity in the United States. The interplay between race/ethnicity and genetics, epigenetics, and gene-environment interactions in the causation of these cancers deserves further investigation. PMID- 29117362 TI - Cancer Groups Outline Research Needs To Address Health Care Disparities. PMID- 29117363 TI - New Gene-Editing Tool Slowly Advances Into the Clinic. PMID- 29117364 TI - Gadolinium Presence Within Cutaneous Sclerotic Bodies Confirmed by Laser Ablation Inductively Coupled Plasma Mass Spectrometry. PMID- 29117365 TI - Pediatric Exclusivity and Regulatory Authority: Implications of Amgen v HHS. PMID- 29117366 TI - 2017 Pathobiology for Investigators, Students, and Academicians (PISA) Meeting. PMID- 29117367 TI - Clinically Oriented Software for Facial Symmetry, Morphology, and Aesthetic Analysis. PMID- 29117368 TI - Considering health equity when moving from evidence-based guideline recommendations to implementation: a case study from an uppermiddle income country on the GRADE approach. PMID- 29117369 TI - Maternal Blood Pressure Rise During Pregnancy and Offspring Obesity Risk at 4 to 7 Years Old: The Jiaxing Birth Cohort. AB - Context: Maternal hypertensive disorders during pregnancy are suggested to affect obesity risk in offspring. However, little is known about the prospective association of rise in maternal blood pressure within normal range during pregnancy with this risk for obesity. Objective: To clarify the associations of diastolic and systolic blood pressure during pregnancy among normotensive women with the risk for obesity in offspring. Design: Prospective cohort study. Setting: Southeast China. Participants: Up to 2013, a total of 88,406 mother child pairs with anthropometric measurements of offspring age 4 to 7 years were included in the present analysis. Main Outcome Measures: Overweight/obesity risk in offspring. Results: Among normotensive women, second- and third-trimester diastolic and systolic blood pressures were positively associated with risk for overweight/obesity in offspring: odds ratios per 10-mm Hg higher second- and third-trimester diastolic blood pressure were 1.05 [95% confidence interval (CI), 1.01 to 1.09] and 1.05 (95% CI, 1.02 to 1.10), respectively, and for systolic blood pressure were 1.08 (95% CI, 1.05 to 1.11) and 1.06 (95% CI, 1.03 to 1.09). Each 10-mm Hg greater rise in blood pressure between first and third trimesters was associated with a higher risk for offspring overweight/obesity: diastolic, 1.06 (95% CI, 1.01 to 1.10); systolic, 1.05 (95% CI, 1.02 to 1.07). Among all women (combining normotensive and hypertensive women), maternal hypertension in the second and third trimesters was associated with 49% and 14% higher risks for overweight/obesity in offspring, respectively. Conclusions: These results suggest that rise in maternal blood pressure during pregnancy and hypertension during pregnancy, independent of maternal body size before pregnancy, are risk factors for offspring childhood obesity. PMID- 29117370 TI - Molecular Confirmation of Frogs (Anura) as Hosts of Corethrellidae (Diptera) in the Southeastern United States. AB - Flies in the family Corethrellidae Edwards 1932 (Diptera) are known to be attracted to the mating calls of male frogs. For the first time, the hosts of corethrellids were identified to species by analyzing bloodmeals taken from resting female flies. A portion of the cytochrome b gene was amplified and sequenced from blood-engorged flies using vertebrate-specific primers. The flies were collected over 6 yr at two locations in the southeastern United States from resting boxes and natural resting sites (rodent burrows). Potential host abundance focused on frog surveillance, and estimation relied on visual encounters, passive trapping (artificial refugia), and call surveys. This study confirms that corethrellids take blood from tree frogs (Hylidae); however, it was found that true frogs (Lithobates Fitzinger 1843 (Ranidae: Anura) sp.) were the principal host selected by Corethrella brakeleyi (Coquillett 1902) (~73% of identified bloodmeals). These preliminary data suggest that host selection of Corethrella Freeman 1962 sp. is not necessarily correlated with host calling abundance. PMID- 29117371 TI - Influence of the Neonicotinoid Insecticide Thiamethoxam on miRNA Expression in the Honey Bee (Hymenoptera: Apidae). AB - MicroRNAs (miRNAs) are small endogenous noncoding single-stranded RNAs regulating gene expression in eukaryotes. They play important roles in regulating caste differentiation, behavior development, and immune defences in the honey bee, Apis mellifera (Linnaeus) (Hymenoptera: Apidae). In this study, we explored the effect of the neonicotinoid insecticide, thiamethoxam, on miRNA expression in this species using deep small RNA sequencing. The results showed that seven miRNAs were significantly differentially expressed (q-value <0.01 and |log2(fold change)| >1) upon exposure to 10 ppb thiamethoxam over 10 d. Some candidate target genes were related to behavior, immunity, and neural function. Several miRNAs, including ame-miR-124, ame-miR-981, ame-miR-3791, and ame-miR-6038, were selected and further validated using real-time quantitative PCR analysis. The findings expand our understanding of the effects of neonicotinoid insecticides on honey bees at the molecular level. PMID- 29117372 TI - Silkworm: A Promising Model Organism in Life Science. AB - As an important economic insect, silkworm Bombyx mori (L.) (Lepidoptera: Bombycidae) has numerous advantages in life science, such as low breeding cost, large progeny size, short generation time, and clear genetic background. Additionally, there are rich genetic resources associated with silkworms. The completion of the silkworm genome has further accelerated it to be a modern model organism in life science. Genomic studies showed that some silkworm genes are highly homologous to certain genes related to human hereditary disease and, therefore, are a candidate model for studying human disease. In this article, we provided a review of silkworm as an important model in various research areas, including human disease, screening of antimicrobial agents, environmental safety monitoring, and antitumor studies. In addition, the application potentiality of silkworm model in life sciences was discussed. PMID- 29117373 TI - Seasonal Terpene Variation in Needles of Pinus radiata (Pinales: Pinaceae) Trees Attacked by Tomicus piniperda (Coleoptera: Scolytinae) and the Effect of Limonene on Beetle Aggregation. AB - Concentrations of four monoterpenes were determined in needles of Pinus radiata (D.Don) (Pinales: Pinaceae) trees that were attacked or nonattacked by Tomicus piniperda (L.) (Coleoptera: Scolytinae). Compounds were identified and quantified by gas chromatography-mass spectrometry. The mean ambient temperature was obtained using climate-recording data loggers. The effect of limonene on field aggregation was also evaluated at three limonene release rates using Lindgren attractant-baited traps and trap logs. Attacked trees produced less alpha-pinene in March, July, and November than nonattacked trees, less beta-pinene in July and November, and less limonene from May to November. Limonene reduced the attraction of T. piniperda to attractant-baited traps and trap logs. Results were linked to better responses to high temperatures, with respect to terpene contents, by the nonattacked trees after the spring attack. PMID- 29117374 TI - New Pyrethroids for Use Against Tuta Absoluta (Lepidoptera: Gelechiidae): Their Toxicity and Control Speed. AB - Insect pests are responsible for major losses in crop productivity, and insecticides are the main tools used to control these organisms. There is increasing demand for new products for pest management. Therefore, the aim of this study was to assess the toxicity of pyrethroids with acid moiety modifications to measure the insecticidal activity of these compounds on Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae). First, we synthesized E/Z mixtures of five pyrethroids: [9], [10], [11], [12], and [13]. Then, we separated the cis and trans pyrethroid isomers of [9], [10], [11], and [12]. We assessed the toxicity of these compounds against T. absoluta. The E/Z mixtures of the five pyrethroids (30 ug of substance per mg-1 of insect) caused high (100%) and rapid (<12 h) tomato borer mortality. The cis isomer of pyrethroid [10] was the most toxic to T. absoluta, causing mortality similar to permethrin. The other isomers were less powerful than permethrin. PMID- 29117375 TI - Fumigant Toxicity and Sublethal Effects of Artemisia khorassanica and Artemisia sieberi on Sitotroga cerealella (Lepidoptera: Gelechiidae). AB - Fumigant toxicity and sublethal effects of essential oils from Artemisia khorassanica Podl. and Artemisia sieberi Bess were investigated against adults of Sitotroga cerealella Olivier. To assess the sublethal effects, adult moths were exposed to the LC30 of each essential oil, and life table parameters of the surviving S. cerealella were studied. Higher fumigant toxicity of A. khorassanica (LC50: 7.38 ul/liter air) than A. sieberi (LC50: 9.26 ul/liter air) was observed against S. cerealella. Also, the insecticidal effects of A. khorassanica (LT50: 9.01 h) were faster than A. sieberi (LT50: 14.37 h). A significant extension was observed in the developmental time (egg to adult) of S. cerealella treated with the essential oils. In addition, fecundity of S. cerealella reduced by 25.29 and 35.78% following exposure to sublethal concentrations of A. sieberi and A. khorassanica, respectively. Both tested essential oils caused a significant reduction in the gross and net reproductive rates, intrinsic rate of increase (rm), and finite rate of increase of S. cerealella. The rm values following exposure to A. sieberi, A. khorassanica, and control were 0.098, 0.094, and 0.107 d-1, respectively. The results of this study suggest that tested essential oils have a good potential to apply in integrated pest management of S. cerealella. PMID- 29117377 TI - Molecular Detection of Chilo infuscatellus. AB - The Chilo infuscatellus (Snellen; Lepidoptera: Pyralidae) is the main pest of sugarcane in China. The shortage of easily distinguishable morphological characters especially in early stage make it challenging to diagnosed and promptly take steps for pest management. In the present study, we described a PCR method for the molecular identification of based on barcode region of COI sequences between C. infuscatellus and four other sugarcane borer species. A 285bp fragment was successfully amplified from all life stages and different geographical populations. Sensitivity tests revealed that diagnostic bands were generated as low as the DNA template concentration of 5 ng/ul. Our work demonstrated a rapid and accurate way for the molecular diagnosis of C. infuscatellus. PMID- 29117376 TI - Comparative Genomic Analysis for Genetic Variation in Sacbrood Virus of Apis cerana and Apis mellifera Honeybees From Different Regions of Vietnam. AB - Sacbrood virus (SBV) is one of the most common viral infections of honeybees. The entire genome sequence for nine SBV infecting honeybees, Apis cerana and Apis mellifera, in Vietnam, namely AcSBV-Viet1, AcSBV-Viet2, AcSBV-Viet3, AmSBV-Viet4, AcSBV-Viet5, AmSBV-Viet6, AcSBV-Viet7, AcSBV-Viet8, and AcSBV-Viet9, was determined. These sequences were aligned with seven previously reported complete genome sequences of SBV from other countries, and various genomic regions were compared. The Vietnamese SBVs (VN-SBVs) shared 91-99% identity with each other, and shared 89-94% identity with strains from other countries. The open reading frames (ORFs) of the VN-SBV genomes differed greatly from those of SBVs from other countries, especially in their VP1 sequences. The AmSBV-Viet6 and AcSBV Viet9 genome encodes 17 more amino acids within this region than the other VN SBVs. In a phylogenetic analysis, the strains AmSBV-Viet4, AcSBV-Viet2, and AcSBV Viet3 were clustered in group with AmSBV-UK, AmSBV-Kor21, and AmSBV-Kor19 strains. Whereas, the strains AmSBV-Viet6 and AcSBV-Viet7 clustered separately with the AcSBV strains from Korea and AcSBV-VietSBM2. And the strains AcSBV Viet8, AcSBV-Viet1, AcSBV-Viet5, and AcSBV-Viet9 clustered with the AcSBV-India, AcSBV-Kor and AcSBV-VietSBM2. In a Simplot graph, the VN-SBVs diverged stronger in their ORF regions than in their 5' or 3' untranslated regions. The VN-SBVs possess genetic characteristics which are more similar to the Asian AcSBV strains than to AmSBV-UK strain. Taken together, our data indicate that host specificity, geographic distance, and viral cross-infections between different bee species may explain the genetic diversity among the VN-SBVs in A. cerana and A. mellifera and other SBV strains. PMID- 29117378 TI - Insecticidal activities of constituents of Litsea cubeba fruit extracts effective against the maize weevil (Coleoptera: Curculionidae). AB - In this study, we investigated the insecticidal activities, including contact toxicity, fumigant toxicity, and repellent activity, of Litsea cubeba fruit extracts against Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae). The extracts, obtained by liquid-liquid extraction in n-hexane, ethyl acetate, chloroform, and water were analyzed by gas chromatography-mass spectrometry. Among the different extract types, chloroform extracts exhibited the strongest repellent, contact, and fumigant activities against S. zeamais. The main components of the chloroform extracts were identified as laurine (21.15%) and 2,6 diisopropyl aniline (16.14%), followed by chlorobutanol (10.54%), 3-O-methyl-N acetyl-d-glucosamine (10.03%), and 6-methyl-5-hepten-2-one (8.33%). Among the identified components of the chloroform extracts, chlorobutanol showed the strongest fumigant toxicity (LD50 = 21.91 mg/liter), contact toxicity (LD50 = 54.25 ug/adult), and repellent activity against S. zeamais. These results indicate that L. cubeba fruit extracts possess natural insecticide-like activities against S. zeamais. PMID- 29117379 TI - Inhibitory effect of indole analogs against Paenibacillus larvae, the causal agent of American foulbrood disease. AB - Paenibacillus larvae, a Gram-positive bacterium, causes American foulbrood (AFB) in honey bee larvae (Apis mellifera Linnaeus [Hymenoptera: Apidae]). P. larvae spores exit dormancy in the gut of bee larvae, the germinated cells proliferate, and ultimately bacteremia kills the host. Hence, spore germination is a required step for establishing AFB disease. We previously found that P. larvae spores germinate in response to l-tyrosine plus uric acid in vitro. Additionally, we determined that indole and phenol blocked spore germination. In this work, we evaluated the antagonistic effect of 35 indole and phenol analogs and identified strong inhibitors of P. larvae spore germination in vitro. We further tested the most promising candidate, 5-chloroindole, and found that it significantly reduced bacterial proliferation. Finally, feeding artificial worker jelly containing anti germination compounds to AFB-exposed larvae significantly decreased AFB infection in laboratory-reared honey bee larvae. Together, these results suggest that inhibitors of P. larvae spore germination could provide another method to control AFB. PMID- 29117380 TI - Wild Silkworm Cocoon Contains More Metabolites Than Domestic Silkworm Cocoon to Improve Its Protection. AB - The silk of silkworm consists of fibroin fiber coated by sericins. In addition, some nonprotein components were also identified in the sericin fraction. The presence of nonprotein components in the silk has not been well explained. In the present study, methods based on gas chromatography-mass spectrometry were used to identify the metabolites in the cocoon silk from a wild silkworm and two domestic silkworm strains. In total, 45 metabolites were in the cocoon silk, including organic acids, fatty acids, carbohydrates, amino acids, and hydrocarbons. Comparative analyses revealed that 17 metabolites were significant more in the wild silkworm cocoon than in the domestic silkworm cocoon, including three organic acids, three fatty acids, three aldoses, four sugar alcohols, three hydrocarbons, and pyridine. Of them, citric acid in the wild silkworm cocoon is more than 40 times that in the domestic silkworm cocoon, which may have protective value against microbes. The carbohydrate, lipid, and the long-chain hydrocarbons may act as water repellent to make the pupa survive longer in the dry environment. Many metabolites in the cocoon silk may play roles to improve the silk resistance. Lots of nonprotein components were identified in the silk for the first time, providing useful data for understanding the biological function of the cocoon silk. PMID- 29117381 TI - Assessment of Feeding Acceptance and Injury of Kerman Pistachios, Pistacia vera, by Brown Marmorated Stink Bug (Hemiptera: Pentatomidae). AB - In the United States, California (CA) is the primary commercial producer of pistachio nuts, Pistacia vera L. (Anacardiaceae). The brown marmorated stink bug (BMSB), Halyomorpha halys (Stal) (Hemiptera: Pentatomidae), an invasive and polyphagous insect pest from Asia, has established in urban areas in several pistachio-growing counties in CA. Breeding BMSB populations have not been detected in commercial pistachio acreage. However, the detection of BMSB in Kern and Fresno counties, major Kerman pistachio producing areas in CA, underscored key knowledge gaps on BMSB ecology in CA and motivated investigations on the susceptibility of pistachio nuts to BMSB feeding. Laboratory feeding trials conducted in quarantine under permit indicated that adult BMSB stylets can penetrate developing pistachio shells and associated feeding was correlated with kernel necrosis for nuts collected mid to late season (June to August 2016). Feeding damage estimates indicated that higher levels of kernel injury were associated with female BMSB when compared to feeding by male BMSB. These results suggest that there is probable risk of feeding damage to field grown pistachios from BMSB. The implications of this study for BMSB pest management in the CA pistachio system and future research directions are discussed. PMID- 29117383 TI - Assisted reproductive technology in Europe, 2013: results generated from European registers by ESHRE. AB - STUDY QUESTION: Are there any changes in the treatments involving ART and IUI initiated in Europe during 2013 compared with previous years? SUMMARY ANSWER: An increase in the overall number of ART cycles resulting from a higher number of countries reporting data was evident, the pregnancy rates (PRs) in 2013 remained stable compared with those reported in 2012, the number of transfers with multiple embryos (3+) was lower than ever before yet the multiple delivery rates (DRs) remained unchanged, and IUI activity and success rates were similar to those of last years. WHAT IS KNOWN ALREADY: Since 1997, ART data in Europe have been collected and reported in 16 manuscripts, published in Human Reproduction. STUDY DESIGN, SIZE, DURATION: Retrospective data collection of European ART data by the European IVF-monitoring Consortium for ESHRE. Data for cycles between 1 January and 31 December 2013 were collected from National Registers, when existing, or on a voluntary basis by personal information. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: From 38 countries (+4 compared with 2012), 1169 clinics reported 686 271 treatment cycles including 144 299 of IVF, 330 367 of ICSI, 154 712 of frozen embryo replacement (FER), 40 244 of egg donation (ED), 247 of IVM, 9791 of PGD/PGS and 6611 of frozen oocyte replacements. European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1095 IUI labs in 22 countries. A total of 175 467 IUI-H and 43 785 IUI-D cycles were included. MAIN RESULTS AND THE ROLE OF CHANCE: In 17 countries where all clinics reported to their ART register, a total of 374 177 ART cycles were performed in a population of around 310 million inhabitants, corresponding to 1175 cycles per million inhabitants (range, 235-2703 cycles per million inhabitants). For all IVF cycles, the clinical PRs per aspiration and per transfer were stable with 29.6% (29.4% in 2012) and 34.5% (33.8% in 2012), respectively. For ICSI, the corresponding rates also were stable with 27.8% (27.8% in 2012) and 32.9% (32.3% in 2012). In FER cycles, the PR per thawing/warming increased to 27.0% (23.1% in 2012). In ED cycles, the PR per fresh transfer increased to 49.8% (48.4% in 2012), to 38.5% (35.9% in 2012) per thawed transfer, and to 46.4% for transfers after FOR (45.1% in 2012). The DRs after IUI remained stable at 8.6% (8.5% in 2012) after IUI-H and was slightly lower after IUI-D (11.1% versus 12.0% in 2012). In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 31.4, 56.3, 11.5, and 1.0% of the cycles, respectively (corresponding numbers were 30.2, 55.4, 13.3 and 1.1% in 2012). The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 82., 17.5 and 0.5%, respectively, resulting in a total multiple DR of 18.0% compared to 17.9% in 2012. In FER-cycles, the multiple DR was 12.8% (12.5% twins and 0.3% triplets), nearly the same as in 2012 (12.5, 12.2 and 0.3% respectively). Twin and triplet DRs associated with IUI cycles were 9.5%/0.6% and 7.5%/0.3%, following treatment with husband/donor semen, respectively. LIMITATIONS, REASONS FOR CAUTION: The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, the results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The 17th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 685 000 cycles reported in 2013 and an increasing contribution to birth rate in many countries. However, the need to improve and standardize the national registries, and to establish validation methodologies, remains manifest. STUDY FUNDING/COMPETING INTEREST(S): The study has no external funding; all costs are covered by ESHRE. There are no competing interests. PMID- 29117382 TI - City-Dwellers and Country Folks: Lack of Population Differentiation Along an Urban-Rural Gradient in the Mosquito Culex pipiens (Diptera: Culicidae). AB - Mosquitoes (Diptera, Culicidae) occur in natural, urban, and peri-urban areas throughout the globe. Although the characteristics of urban and peri-urban habitats differ from those of natural habitats in many ways (e.g., fragmentation, pollution, noise, and light), few studies have examined the population connectivity of mosquitoes in urban areas. To obtain an overview of the species composition, we sampled mosquitoes from 23 sites in and around the city of Berlin, Germany. Of 23 species, five occurred in urban, 10 in peri-urban, and 20 in rural areas. Culex pipiens Linnaeus (Diptera: Culicidae) was the most common species collected (75% of all individuals) and occurred in all habitats. Hence this species was selected to be analysed at 10 microsatellite markers. There was no significant differentiation (FST = 0.016, P = 0.9) or isolation by distance (P = 0.06) among Cx. pipiens populations along an urban-rural gradient. The only significant differences detected were between Cx. pipiens and a laboratory population of Cx. pipiens f. molestus (pairwise FST = 0.114-0.148, P <= 0.001 in all comparisons), suggesting that the markers chosen were suitable for the identification of population differentiation. Our results indicate that Cx. pipiens gene flow is widespread within and among urban, peri-urban, and rural areas and that urban habitat does not necessarily impede or enhance gene flow among these populations. PMID- 29117384 TI - ESHRE PGD Consortium data collection XIV-XV: cycles from January 2011 to December 2012 with pregnancy follow-up to October 2013. AB - STUDY QUESTION: How does the data collection XIV-XV of the European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium compare with the cumulative data for data collections I-XIII? SUMMARY ANSWER: The 14th and 15th retrospective collection represents valuable data on PGD/PGS cycles, pregnancies and children: the main trend observed is the increased application of array technology at the cost of FISH testing in PGS cycles and in PGD cycles for chromosomal abnormalities. WHAT IS KNOWN ALREADY: Since 1999, the PGD Consortium has collected, analysed and published 13 previous data sets and an overview of the first 10 years of data collections. STUDY DESIGN, SIZE, DURATION: Data were collected from each participating centre using a FileMaker Pro database (versions 5-12). Separate predesigned FileMaker Pro files were used for the cycles, pregnancies and baby records. The study documented cycles performed during the calendar years 2011 and 2012 and follow-up of the pregnancies and babies born which resulted from these cycles (until October 2013). PARTICIPANTS/MATERIALS, SETTINGS, METHOD: Data were submitted by 71 centres (full PGD Consortium members). Records with incomplete or inconsistent data were excluded from the calculations. Corrections, calculations and tables were made by expert co authors. MAIN RESULTS AND THE ROLE OF CHANCE: For data collection XIV-XV, 71 centres reported data for 11 637 cycles with oocyte retrieval (OR), along with details of the follow-up on 2147 pregnancies and 1755 babies born. A total of 1953 cycles to OR were reported for chromosomal abnormalities, 144 cycles to OR for sexing for X-linked diseases, 3445 cycles to OR for monogenic diseases, 6095 cycles to OR for PGS and 38 cycles to OR for social sexing. From 2010 until 2012, the use of arrays for genetic testing increased from 4% to 20% in PGS and from 6% to 13% in PGD cycles for chromosomal abnormalities; the uptake of biopsy at the blastocyst stage (from <1% up to 7%) was only observed in cycles for structural chromosomal abnormalities, alongside the application of array comparative genomic hybridization. LIMITATIONS, REASONS FOR CAUTION: The findings apply to the 71 participating centres and may not represent worldwide trends in PGD. WIDER IMPLICATIONS OF THE FINDINGS: The annual data collections provide an important resource for data mining and for following trends in PGD/PGS practice. STUDY FUNDING/COMPETING INTEREST(S): None. PMID- 29117386 TI - Editorial: When Is Correlation Causation? PMID- 29117385 TI - Meta-Analysis of the Association Between Phosphodiesterase Inhibitors (PDE5Is) and Risk of Melanoma. AB - The US Food and Drug Administration recently announced the need to evaluate the association between PDE5is and melanoma. We performed a meta-analysis on the association between PDE5i and melanoma using random effects models and examined whether it met Hill's criteria for causality. A systematic search of Medline, EMBASE, and the Cochrane Library from 1998 to 2016 identified three case-control studies and two cohort studies, including a total of 866 049 men, of whom 41 874 were diagnosed with melanoma. We found a summary estimate indicating an increased risk of melanoma in PDE5i users (relative risk = 1.11, 95% confidence interval = 1.02 to 1.22). However, the association was only statistically significant among men with low PDE5i exposure (not high exposure) and with low-stage melanoma (not high stage), indicating a lack of dose response and biological gradient. PDE5i use was also associated with basal cell cancer, suggesting a lack of specificity and likely confounding by ultraviolet exposure. Thus, although this meta-analysis found a statistically significant association between PDE5i and melanoma, it did not satisfy Hill's criteria for causality. PMID- 29117388 TI - Neurofibromatosis Type 1-Associated MPNST State of the Science: Outlining a Research Agenda for the Future. AB - Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma for which the only effective therapy is surgery. In 2016, an international meeting entitled "MPNST State of the Science: Outlining a Research Agenda for the Future" was convened to establish short- and long-term research priorities. Key recommendations included the: 1) development of standardized, cost-efficient fluorodeoxyglucose positron emission tomography and whole-body magnetic resonance imaging guidelines to evaluate masses concerning for MPNST; 2) development of better understanding and histologic criteria for the transformation of a plexiform neurofibroma to MPNST; 3) establishment of a centralized database to collect genetic, genomic, histologic, immunohistochemical, molecular, radiographic, treatment, and related clinical data from MPNST subspecialty centers in a standardized manner; 4) creation of accurate mouse models to study the plexiform neurofibroma-to-MPNST transition, MPNST metastasis, and drug resistance; 5) use of trial designs that minimize regulatory requirements, maximize availability to patients, consider novel secondary end points, and study patients with newly diagnosed disease. Lastly, in order to minimize delays in developing novel therapies and promote the most efficient use of research resources and patient samples, data sharing should be incentivized. PMID- 29117389 TI - Response. PMID- 29117390 TI - RE: Colorectal Cancer Incidence Patterns in the United States, 1974-2013. PMID- 29117387 TI - Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry. AB - Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 * 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 * 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk. PMID- 29117391 TI - RE: Colorectal Cancer Incidence Patterns in the United States, 1974-2013. PMID- 29117392 TI - Africa's Neglected Epidemic. PMID- 29117393 TI - Patient Consent: Defining Control of Genetic Information. PMID- 29117394 TI - New Initiative Takes Fresh Approach To Increase Value in Cancer Care. PMID- 29117395 TI - Monthly and Median Costs of Cancer Drugs at the Time of FDA Approval 1965-2016. PMID- 29117396 TI - Orthogonal Catheter Access for Stent Assisted Coiling of Posterior Cerebral Artery Aneurysm. PMID- 29117397 TI - Challenges and Opportunities in Implementation: The AAALAC International Perspective. AB - In spite of the increasing trend for local authorities and international organization to follow the same ethical principles, the regulatory framework on the protection, care, and use of research animals is still heterogeneous. Differences across geopolitical areas exist not only at the legal level but, more important, also at the level of implementation of the existing regulations. In this diverse landscape, AAALAC International uses performance standards to assure harmonization of accredited animal care and use programs globally. Accredited programs must first comply with applicable legislation, which may establish different baseline levels, on top of which performance standards are to be applied for the different animal care and use program areas. To achieve this goal, AAALAC International has given its Council on Accreditation an international composition and perspective that allows better interpretation of the different scenarios. There are a number of challenges and opportunities that may impact the implementation of existing legislation and the accreditation of animal care and use programs across countries. Challenges may relate to financial constraints, administrative burden, or differences between compliance and best practices. Opportunites may be represented by other fields of animal research, the level of development of research in some countries, or increasing interinstitutional collaborations. A description of these challenges and opportunities in North America, Europe, and the Pacific Rim from the AAALAC International perspective is discussed in this article. PMID- 29117398 TI - Australian Regulation of Animal Use in Science and Education: A Critical Appraisal. AB - One of the touchstone principles in Australia's regulation of the use of animals for scientific and educational purposes is reduction, refinement and replacement (3Rs). However, the use of animals for scientific and educational purposes is increasing in Australia, raising concerns about the effectiveness of the current regulatory framework in achieving the objectives of the 3Rs. This article critically evaluates the current regulatory framework in Australia. Several strengths are identified. However, 4 recommendations to improve the regulatory environment are proposed to bring Australia in line with international best practice. Specifically, Australian regulation governing the use of animals for scientific or educational purposes could be improved through greater transparency, higher standards of competency, the development of a central regulatory authority, and greater incentives to encourage research and development into nonanimal alternatives. PMID- 29117399 TI - Gaps in US Animal Welfare Law for Laboratory Animals: Perspectives From an Animal Law Attorney. AB - The use of animals in biomedical, toxicological, and basic research has been common practice, and a tool for scientists and researchers, for many years. And yet, serious conflict continues to exist between those who believe that the use of animals in research will yield scientific results that benefit humans and those who believe such practices are unethical regardless of use or outcome. High profile undercover cases have further raised public awareness and have put the entire industry under pressure to be transparent, accountable, and aggressive in its adoption of reduction, refinement, and replacement (3R) principles. Many animal law attorneys are deeply frustrated by what they see as weak US laws that are unevenly enforced, especially when compared with legal advances in other countries and regions. This article (1) explores those gaps in US animal welfare laws with an emphasis on the Animal Welfare Act, (2) argues in favor of stronger laws and rigorous enforcement, and (3) suggests steps to advance these goals. These steps include (1) expanding the definition of "animal" in the Animal Welfare Act (AWA), (2) improving and expanding minimum care requirements in USDA regulations, (3) instituting mandatory reporting requirements, improving Institutional Animal Care and Use Committees, and allowing easier accessibility to laboratory reports and plans, (4) adding a citizen suit provision to the AWA, and (5) continuing education about the emotional and social capacities of animals and a stronger commitment to 3R principles. PMID- 29117400 TI - Laboratory Animal Legislation in Latin America. AB - A review of existing legislation covering laboratory animals in Latin America is presented. The region presents a spectrum of economic development, political stability, and cultural diversity. With the exception of a few nations, there is a lack of regulations as well as minimal enforcement of existing laws pertaining to laboratory animals. Brazil, Mexico, and Uruguay stand out as the only nations in this region with specific legislation regulating laboratory animal care and use; the history and current status of regulations in these three nations is reviewed. PMID- 29117401 TI - Laboratory Animal Laws, Regulations, Guidelines and Standards in China Mainland, Japan, and Korea. AB - China, Japan, and Korea have spent decades developing and amending laws, regulations, and guidelines to address the humane care and use of laboratory animals. This process began in 1983 in China, 1973 in Japan, and 1991 in Korea and has continued to the present. The governmental oversight of research varies between these countries, ranging from regulations by multiple levels of government in China to self-regulation under multiple government guidelines in Japan. Common to all is incorporation of the internationally recognized principles of the 3Rs: replacement, reduction and refinement. This paper reviews how the framework of laws, regulations, and guidelines evolved in each of these countries, their current status, and the expectation that they will continue to evolve. PMID- 29117402 TI - Can TTIP Improve Laboratory Animal Welfare in Safety Testing and 3Rs? AB - In the context of the current negotiations between the European Union (EU) and the United States under the Transatlantic Trade Investment Partnership (TTIP), there is the opportunity to look at both legislative frameworks to better pinpoint convergences, synergies, and gaps when it comes to use of laboratory animals for scientific purposes and bring together the best of both worlds. The objectives in this article are to indicate what are the current EU pieces of legislation that are relevant under TTIP regarding the uses of laboratory animals for scientific purposes under the regulations about cosmetics and chemicals, among others. The same approach will be taken to look at the relevant American legal frameworks, that is, the Food and Cosmetics Act and the Toxic Safety Control Act as well as its most recent reauthorization. In conclusion, the authors will identify future frameworks that can contribute to the harmonization of regulatory standards and further steps where TTIP negotiators should strengthen regulatory cooperation. PMID- 29117403 TI - Protecting Animals and Enabling Research in the European Union: An Overview of Development and Implementation of Directive 2010/63/EU. AB - In 1986, European Directive 86/609/EEC, regulating the use of animals in research, was one of the first examples of common legislation to set standards for animal protection across the Member States of the former European Economic Community, now the European Union, with the aim of securing a level European playing field. Starting in 2002, a process of revising European animal experimentation legislation was undertaken, with one of its key aims being to ensure high standards of welfare for laboratory animals across Europe. This resulted in Directive 2010/63/EU, which has regulated this activity in Europe since 2013. Since this is a European Union Directive, transposition into national legislation is a necessary and important part of the implementation of the new legislation. This paper gives an overview of the transposition process followed by an analysis of the potential to reach the different objectives of the directive, particularly with a focus on securing the same high standards of animal protection across member countries. The analysis focuses on three separate issues: (1) minimum standards for laboratory animal housing and care, (2) restrictions on the use of certain animal species, and (3) project review and authorization. PMID- 29117404 TI - The Governance of Animal Care and Use for Scientific Purposes in Africa and the Middle East. AB - Animals are commonly used for scientific purposes in Africa and the Middle East. However, this field is often inadequately regulated, with many countries lacking national legislation, policies, or guidelines for the care and use of animals used for research, testing, or education. This results in an essentially uncontrolled system where scientific quality and animal wellbeing cannot robustly be guaranteed, which may hinder acceptance (i.e., publication) of results by the scientific community and limit public confidence. Though accepted international guidelines and best practice recommendations exist that could be adopted or adapted to meet local needs, the responsible conduct of research and animal welfare may not be prioritized in regions that are affected by instability, poverty, disease, or malnutrition. Some notable exceptions do, however, exist in individual countries or institutions where ethical review processes, oversight of animal health and welfare, the competence of personnel, and other scientific standards are appropriately regulated and implemented. These countries and institutions represent nodes of expertise that could act as platforms of support for surrounding regions in terms of the provision of education, training, and sharing of experience and resources. To make such regional capacity-strengthening efforts sustainable will require regional cooperation, the establishment of regional networks, harmonization of policies, pooled resources, and long-term investment in education, training, and infrastructure. An overarching system is needed to oversee the efficient promotion of scientific and ethical standards and the dissemination of information on laboratory animal science in Africa and the Middle East, while each country should remain able to maintain a system of oversight that reflects its own cultures, traditions, religions, laws, and regulations. This article provides an overview of the governance of the care and use of animals for scientific purposes in different regions of Africa and the Middle East as a foundation for coordinated future advancement. PMID- 29117405 TI - Ten Fundamental Legal Terms and Concepts That Are Useful in Understanding Laboratory Animal Law Across Nations. AB - Almost all researchers, veterinarians, technicians, and students who work with laboratory animals are familiar with the laws, regulations, and policies governing the use of animals in their jurisdictions. This knowledge can be learned in an academic setting, but is often gained by "on the job" training conducted by facilities and institutions where these professionals work. In addition, these laws and regulations exist along a continuum; some countries have detailed and expansive animal law regimes, while others have few, if any laws. Accordingly, those who carry out research involving animals know local laws and regulations, but might not be aware of the laws, regulations, and policies of other jurisdictions.As scientific research becomes increasingly globalized, there is a growing need to gain an understanding of the laws and regulations of other countries. This article seeks to help bridge this gap in knowledge by defining 10 fundamental legal terms and concepts that are important in understanding the similarities and differences among the legal traditions of different nations and international agreements that impact laboratory animal research. The article focuses on Western law terms and concepts, because many laboratory animal statutes that have been enacted in these countries and international treaties and protocols can be viewed through a Western legal lens. PMID- 29117406 TI - Comparison of the Canadian and US Laws, Regulations, Policies, and Systems of Oversight for Animals in Research. AB - The Canadian and United States' approaches to oversight of animals in research are both based on the "3Rs" principles outlined in Russell and Burch's classic text, The Principles of Humane Experimental Technique. Each country seeks to protect the welfare of animals, while permitting the legitimate goals of scientific research to be attained according to the legal principles, cultures, and strengths and constraints of their jurisprudential and societal traditions. Canada is one of the most decentralized federations in the world, and regulation of activities is based to a great extent on custom and practice. The United States is more hierarchical and, at least with respect to laws governing animal research, more centralized. Accordingly, the Canadian approach is rooted in the concepts of social contracts, with a greater emphasis on guidance and policy and less reliance on legislation. No federal (national) direct legislation of laboratory animal welfare exists, although the federal government uses its criminal and spending authorities to shape behavior. The central feature of the Canadian system is the Canadian Council on Animal Care, which was formed to support universities and government departments involved in animal-based science. Animal care committees play a central role in implementing the guidelines and policies in facilities that carry out animal research. The United States has enacted two federal (national) laws applicable to animals in research. The Animal Welfare Act is a more traditional, command-and-control law that gives authority to the US Department of Agriculture to promulgate regulations, inspect facilities, and enforce violations. The Health Research Extension Act, which amended the US Public Health Services (PHS) Act, applies to any activity conducted or supported by the PHS, including research efforts supported by the US National Institutes of Health. It is largely nonregulatory and establishes a system of assurances and policies that covered research facilities must follow. States play only a minor role in animal research protection. As in Canada, institutional animal care and use committees are tasked with self-regulation of activities that use animals for research. PMID- 29117407 TI - Laws, Regulations, Guidelines and Standards for Animal Care and Use for Scientific Purposes in the Countries of Singapore, Thailand, Indonesia, Malaysia, and India. AB - The laws, regulations, guidelines, and standards on animal care and use for scientific purposes in the countries of Singapore, Thailand, Indonesia, and Malaysia, and India are described in this manuscript. For each of these five countries, a brief introduction is provided on the history of how the need for animal welfare in research, education, training, and testing came to being. This is followed by some background information leading to the current status of regulations and guidelines in each of the five countries. There is also a description of the responsibilities and functions of institutional animal welfare and ethics oversight bodies, enforcement agencies, penalties, and organizations supporting the industry. Finally, a conclusion with insights into the future of laboratory animal welfare and science in each of these five countries in Asia is provided. PMID- 29117408 TI - Introduction: Global Laws, Regulations, and Standards for Animals in Research. AB - This issue contains a collection of papers describing the state of animal laws, regulations, and standards in counties worldwide, grouped by geographic regions (i.e., North America, South America, Pacific Rim, Africa, and the Middle East). An overview of the US and Canadian legal requirements for animal welfare is provided, along with consideration of potential gaps in the US Animal Welfare Act. The EU Directive on the protection of animals used for scientific purposes and its transposition is discussed, and challenges facing laboratory animal protection regimes in Latin America and the Pacific Rim are examined. Legislation for laboratory animal use has been enacted in India and Australia, while animal protection regimes have not yet been enacted in the Middle East and Africa. International harmonization is a particularly important challenge for the global scientific community and private accreditation by organizations such as AAALAC International, plays a key role in promoting high standards for animal care and use programs globally. This article highlights three future trends. First, international efforts at harmonization will continue, and seek to keep pace with the globalization of science. Second, nations that have not yet developed robust legal systems applicable to laboratory animal welfare will seek out the expertise of those nations that have well established regimes. Third, for countries with mature animal protection systems, animal use in research will continue to be of societal concern, and efforts to change existing laws will not abate. The opportunity to use animals in laboratory research is not an entitlement. It is a privilege accorded by society to certain members of the scientific community and along with it comes the responsibility to adhere to, and seek improvement in, applicable laws, regulations, policies and standards. PMID- 29117409 TI - Development of a Perfusion-Based Cadaveric Simulation Model Integrated into Neurosurgical Training: Feasibility Based On Reconstitution of Vascular and Cerebrospinal Fluid Systems. AB - BACKGROUND: Novel methodologies providing realistic simulation of the neurosurgical operating room environment are currently needed, particularly for highly subspecialized operations with steep learning curves, high-risk profiles, and demands for advanced psychomotor skills. OBJECTIVE: To describe the development of a curriculum for using perfusion-based cadaveric simulation models in a "Mock Operating Room" for neurosurgical procedures. METHODS: At the USC Keck School of Medicine Fresh Tissue Dissection Laboratory between 2012 and 2016, 43 cadaveric specimens underwent cannulation of the femoral or carotid artery and artificial perfusion of the arterial system, and/or cannulation of the intradural cervical spine for intrathecal reconstitution of the cerebrospinal fluid (CSF) system. Models were used to train neurosurgical residents in various procedures. Self-assessment of pre- and postprocedure trainee confidence (Likert) scores was compared for each module. RESULTS: The following novel procedural training methodologies were successfully established: management of an injury to the carotid artery during an endoscopic endonasal approach (n = 12), endoscopic endonasal CSF leak repair (n = 6) with fluorescein perfusion, carotid endarterectomy (n = 4), extracranial-to-intracranial bypass (n = 2), insertion of ventriculostomy catheter (n = 7), spinal laminectomy with durotomy repair (n = 9), and intraventricular neuro-endoscopy with septum pellucidotomy and third ventriculostomy (n = 12). In all instances, trainees reported improvement in their postprocedural confidence scores, with mean pre- and postprocedural Likert scores being 2.85 +/- 1.09 and 4.14 +/- 0.93 (P < .05). CONCLUSION: Augmentation of fresh cadaveric specimens via reconstitution of vascular and CSF pathways is a feasible methodology for complimenting surgical training in numerous neurosurgical procedures, and may hold implications in the future of neurosurgical resident education. PMID- 29117410 TI - Corneal Cross-Linking (CXL): Standardizing Terminology and Protocol Nomenclature. PMID- 29117411 TI - Assessing the Likely Effect of Posterior Corneal Curvature on Toric IOL Calculation for IOLs of 2.50 D or Greater Cylinder Power. AB - PURPOSE: To establish whether average refractive overcorrection or undercorrection of corneal astigmatism based on the orientation (rule) of the astigmatism occurs if toric intraocular lenses (IOLs) are calculated on the basis of anterior corneal measurements in eyes requiring toric IOL cylinder power of 2.50 diopters (D) or greater. METHODS: One hundred thirteen consecutive eyes with anterior corneal keratometric astigmatism requiring IOL cylinder power of 2.50 D or greater underwent phacoemulsification with IOL powers calculated using anterior corneal curvature data alone. Eyes were grouped as either "with-the rule" (WTR) or "against-the-rule" (ATR) on the basis of the steep anterior corneal meridian. Targeted and achieved astigmatic outcomes were compared. The main outcome measure was the postoperative refractive astigmatic prediction error. RESULTS: A mean overcorrection occurred in anterior WTR eyes of 0.16 +/- 0.57 D and a mean undercorrection of ATR eyes of -0.14 +/- 0.53 D. These were significantly different from the ideal value of zero (WTR: P = .04, ATR: P = .05). Although statistically significant, the effect sizes of these prediction errors were 0.40 for WTR and 0.36 for ATR and the error values fell below a clinically significant value of 0.25 D. CONCLUSIONS: In eyes requiring toric IOLs of cylinder power 2.50 D or greater, an overcorrection occurs in anterior WTR eyes and an undercorrection in ATR eyes. This probable posterior corneal astigmatism effect is not clinically significant. IOL cylinder powers are sufficiently accurately calculated using unadjusted anterior keratometry values in these eyes. [J Refract Surg. 2017;33(11):730-734.]. PMID- 29117412 TI - In Vivo Measurement of Longitudinal Chromatic Aberration in Patients Implanted With Trifocal Diffractive Intraocular Lenses. AB - PURPOSE: To measure the longitudinal chromatic aberration (LCA) by both psychophysical methods and in vivo double-pass retinal imaging in patients bilaterally implanted with trifocal diffractive intraocular lenses (IOLs). METHODS: Measurements were performed with a polychromatic adaptive optics system provided with a supercontinuum laser, a Hartmann-Shack wavefront sensor, a deformable mirror, a motorized Badal system, a pupil monitoring system, a double pass retinal imaging channel, and a psychophysical channel with monochromatically illuminated stimuli. Ten patients (20 eyes) bilaterally implanted with hydrophilic trifocal diffractive IOLs (POD F [FINeVision]; PhysIOL, Liege, Belgium) participated in the study. Measurements were performed in both eyes at three different viewing distances (0.00, +1.75, and +3.50 diopters [D]). Subjective best focus of monochromatic stimuli at five wavelengths (480 to 700 nm) was obtained using the Badal system. Best focused images of through-focus double-pass image series were obtained at three wavelengths (480 to 700 nm). LCA was computed from chromatic difference of focus curves (objective and subjective) as the difference between 480 and 700 nm at near, intermediate, and far. RESULTS: The average subjective LCA was 0.82 +/- 0.05 D for far, 0.27 +/- 0.15 D for intermediate, and 0.15 +/- 0.15 D for near. The average objective LCA was 0.72 +/ 0.10 D for far, 0.19 +/- 0.15 D for intermediate, and 0.07 +/- 0.17 D for near. CONCLUSIONS: Objective LCA was lower than subjective LCA, which was in agreement with previous studies on patients with phakic and monofocal IOLs. In vivo measurements of LCA enable understanding of the relative contribution of refractive and diffractive LCA and will eventually optimize IOL designs to improve polychromatic image quality. [J Refract Surg. 2017;33(11):736-742.]. PMID- 29117413 TI - Comparison of Wound Sealability Between Femtosecond Laser-Constructed and Manual Clear Corneal Incisions in Patients Undergoing Cataract Surgery: A Pilot Study. AB - PURPOSE: To compare the sealability of femtosecond laser-constructed and manual clear corneal incisions (CCIs) in patients undergoing cataract surgery. METHODS: This prospective, randomized study included 62 eyes of 62 patients with cataract grade 1 to 2 (LOCS scale). The patients were randomly assigned (1:1) for creation of either manual CCI (with a 2.4-mm keratome) or femtosecond laser-assisted CCI (LENSAR, Inc., Orlando, FL) (31 eyes in each group) before undergoing femtosecond laser-assisted cataract surgery. Wound sealability was assessed as grade 1, 2, or 3 (1: need to reform anterior chamber and hydrate wound at end of surgery; 2: need to reform anterior chamber only; 3: formed anterior chamber, no hydration or anterior chamber reformation necessary). RESULTS: The nuclear sclerosis grade, cumulative dissipated energy and phacoemulsification time were comparable between the two groups. No complications were experienced in any of the patients. The mean wound sealability for the femtosecond laser group (2.35 +/- 0.84) was statistically significantly better in comparison to the manual group (1.32 +/- 0.65) (P < .001). At the end of the surgery, 22.6% (n = 7) of eyes in the femtosecond laser group needed reformation of the anterior chamber and hydration of the wound compared to 77.4% (n = 24) of eyes in the manual group. Conversely, 58.1% (n = 18) of eyes in the femtosecond laser group compared to 9.7% (n = 3) of eyes in the manual group were observed to have a formed anterior chamber. CONCLUSIONS: Femtosecond laser-created CCIs had significantly better wound sealability compared to those created with a metal keratome. [J Refract Surg. 2017;33(11):744-748.]. PMID- 29117414 TI - Monovision LASIK Versus Presbyopia-Correcting IOLs: Comparison of Clinical and Patient-Reported Outcomes. AB - PURPOSE: To compare clinical and quality of life outcomes between patients who underwent monovision LASIK and refractive lens exchange. METHODS: The study comprised 590 patients with refractive lens exchange and 608 patients with monovision LASIK available for 3-month postoperative clinical visits. All patients with refractive lens exchange had a Tecnis Symfony lens (Johnson & Johnson Vision Care, Inc., Santa Ana, CA) in at least one eye. Patients were divided into four refractive categories: moderate to high myopia, low myopia, plano presbyopia, and hyperopia. Three-month postoperative data were compared between monovision LASIK and refractive lens exchange for each group. RESULTS: Postoperatively, the percentage of patients with binocular uncorrected distance visual acuity of 20/20 or better, for monovision LASIK and refractive lens exchange, respectively, was as follows: moderate to high myopia: 84.7% vs 90.7% (P = .31), low myopia: 89.4% vs 85.2% (P = .45), plano presbyopia: 90.5% vs 89.9% (P = .90), and hyperopia: 77.5% vs 84.2% (P = .03). For near vision, the percentage with binocular near visual acuity of 20/40 or better (J5) at 40 cm was as follows: moderate to high myopia: 98.9% vs 90.7% (P < .01), low myopia: 100% vs 98.1% (P = .17), plano presbyopia: 96.8% vs 95.8% (P = .34), and hyperopia: 95.6% vs 95.7% (P = .96). There was a statistically significant difference in patient satisfaction in favor of monovision LASIK for moderate to high myopia (94.3% for monovision LASIK vs 79.1% for refractive lens exchange, P <.01). For all other refractive categories, there was no significant difference in patient satisfaction. All myopic patients with refractive lens exchange experienced more postoperative visual phenomena than patients with monovision LASIK. The plano presbyopia group had comparable visual phenomena between the two procedures. CONCLUSIONS: Monovision LASIK and refractive lens exchange are both reasonable options for presbyopic patients. [J Refract Surg. 2017;33(11):749-758.]. PMID- 29117415 TI - Risk Factors for Opaque Bubble Layer in Small Incision Lenticule Extraction (SMILE). AB - PURPOSE: To assess the independent effect of myopia and astigmatism on the risk of the occurrence of opaque bubble layer (OBL) in small incision lenticule extraction (SMILE) and further investigate the relationship between scanning depth and OBL. METHODS: Twenty-two cases and 317 controls were included in a case control study from the database of Tianjin Eye Hospital from April 2015 to July 2016. Baseline characteristics were recorded and all of the eyes were manually reviewed by two different observers masked to preoperative refractive status. Multiple regression analysis was used to assess the independent relationship between the attempted correction in diopters and the risk of OBL and to further analyze the association between scanning depth and the risk. RESULTS: The risk of OBL significantly decreased with increasing myopia (diopters) (odds ratio [OR] = 0.44; 95% confidence interval [CI]: 0.30 to 0.64; P < .0001). The risk of OBL also significantly decreased with increasing astigmatism (diopters) (OR = 0.10; 95% CI: 0.02 to 0.42; P = .0017). Lenticular thickness changed by 14.86 MUm per diopter for myopia (beta =14.86; 95% CI = 14.56 to 15.15; P < .0001) and 15.10 MUm per diopter for astigmatism (beta = 15.10; 95% CI = 13.96 to 16.24; P < .0001), respectively. CONCLUSIONS: A low correction was a significant independent risk factor for OBL during SMILE and the effect of astigmatism on OBL was greater than that of myopia. Deepening the photodisruption plane appropriately may reduce the risk of OBL. [J Refract Surg. 2017;33(11):759-764.]. PMID- 29117416 TI - Accuracy of Visual Estimation of LASIK Flap Thickness. AB - PURPOSE: To assess the accuracy of surgeons' visual estimation of LASIK flap thickness when created by a femtosecond laser by comparing it to ultrasound measurements. METHODS: Surgeons were asked to visually estimate the thickness of a femtosecond flap during the procedure. Total corneal thickness was measured by ultrasound pachymetry prior to the procedure and the stromal bed was similarly measured after flap lifting. The estimates from three experienced surgeons (cornea fellowship trained and more than 5 years in practice) were compared to those of three cornea fellows, with each surgeon evaluating 20 eyes (120 total). Surgeons were not told the thickness of the flaps unless required for safety reasons. RESULTS: The average difference between visual and ultrasonic estimation of LASIK flap thickness was 15.20 MUm. The flap was 10 MUm thicker than estimated in 37% of eyes, 20 MUm thicker in 17% of eyes, and 30 MUm thicker in 10% of eyes. The largest deviation was 53 MUm. There was no statistically significant difference between the accuracy of experienced surgeons and fellows (P = .51). CONCLUSIONS: There are significant differences between surgeons' visual estimates and ultrasonic measurements of LASIK flap thickness. Relying on these visual estimates may lead to deeper excimer laser ablation than intended. This could lead to thinner residual stromal beds and higher percent tissue altered than planned. The authors recommend that surgeons measure flaps intraoperatively to maximize accuracy and safety. [J Refract Surg. 2017;33(11):765-767.]. PMID- 29117417 TI - Repeatability of a Commercially Available Adaptive Optics Visual Simulator and Aberrometer in Normal and Keratoconic Eyes. AB - PURPOSE: To evaluate the repeatability of aberration measurement obtained by a Hartmann-Shack aberrometer combined with a visual adaptive optics simulator in normal and keratoconic eyes. METHODS: One hundred fifteen normal eyes and 92 eyes with grade I and II keratoconus, as per the Amsler-Krumeich classification, were included in the study. To evaluate the repeatability, three consecutive measurements of ocular aberrations were obtained by a single operator. Zernike analyses up to the 5th order for a pupil size of 4.5 mm were performed. Statistical analyses included the intraclass correlation coefficient (ICC) and within-subject standard deviation (SD). RESULTS: For intrasession repeatability, the ICC value for sphere and cylinder was 0.94 and 0.93 in normal eyes and 0.98 and 0.97 in keratoconic eyes, respectively. The ICC for root mean square of higher order aberrations (HOARMS) was 0.82 in normal and 0.98 in keratoconic eyes. For 3rd order aberrations (trefoil and coma), the ICC values were greater than 0.87 for normal eyes and greater than 0.92 for keratoconic eyes. The ICC for spherical aberration was 0.92 and 0.90 in normal and keratoconic eyes, respectively. CONCLUSIONS: Visual adaptive optics provided repeatable aberrometry data in both normal and keratoconic eyes. For most of the parameters, the repeatability in eyes with early keratoconus was somewhat better than that for normal eyes. The repeatability of the Zernike terms was acceptable for 3rd order (trefoil and coma) and spherical aberrations. Therefore, visual adaptive optics was a suitable tool to perform repeatable aberrometric measurements. [J Refract Surg. 2017;33(11):769-772.]. PMID- 29117419 TI - Secondary Lenticule Remnant Removal After SMILE. AB - PURPOSE: The authors report four cases of residual intrastromal lenticule after seemingly uneventful small incision lenticule extraction (SMILE) surgery and the outcome after a secondary procedure to remove the lenticule remnant. METHODS: Case reports. RESULTS: All four cases presented with suboptimal corrected distance visual acuity (CDVA) and refractive surprise. Irregularities in the corneal curvature and elevation were detected on corneal topography and tomography. Careful review of the intraoperative video showed an incomplete removal of the SMILE lenticule. All four cases underwent a secondary surgical procedure to remove the residual lenticule remnant. All cases had improvements in the CDVA, refraction, and topography, with the CDVA returning to the preoperative value (20/20) in all cases. CONCLUSIONS: Performing an early, secondary lenticular remnant removal operation is feasible, safe, and can result in improvement in both refraction and visual acuity. During the original SMILE surgery, surgeons should routinely examine the removed lenticule for completeness. [J Refract Surg. 2017;33(11):779-782.]. PMID- 29117418 TI - Keratoconus Screening With Dynamic Biomechanical In Vivo Scheimpflug Analyses: A Proof-of-Concept Study. AB - PURPOSE: This proof-of-concept study was designed to analyze the ability of in vivo biomechanical corneal analyses with the corneal visualization Scheimpflug technology (CorvisST; Oculus Optikgerate, Wetzlar, Germany) to differentiate between normal eyes and eyes with manifest keratoconus after strictly eliminating the potential confounding factors intraocular pressure (IOP) and central corneal thickness (CCT). METHODS: In this retrospective, cross-sectional study, after pairwise matching for CCT and IOP, 29 normal eyes and 29 keratoconic eyes (one eye from each patient) were selected as study population. Older CorvisST parameters and the new Corvis Biomechanical Index (CBI), including several biomechanical and one tomographic parameter, as well as an adjusted CBI (aCBI) (including only biomechanical parameters), were compared regarding their discriminative ability between both groups. RESULTS: None of the CorvisST parameters of the former software version demonstrated statistically significant differences between normal and keratoconic eyes. On the other hand, the CBI and aCBI reached accuracies of 0.91 and 0.93, respectively, to discriminate between CCT- and IOP-matched normal and keratoconic eyes (CBI: [AUC/sensitivity/specificity]: 0.961/0.90/0.93; aCBI: [AUC/sensitivity/specificity]: 0.986/0.93/0.93). CONCLUSIONS: This study demonstrated that the concept of keratoconus screening with the CorvisST is effective in differentiating keratoconic from non-keratoconic eyes. The next steps will be testing the indices in subclinical keratoconus cases and hopefully combining biomechanical analyses with already established topography and tomography indices to further improve current keratoconus screening. [J Refract Surg. 2017;33(11):773-778.]. PMID- 29117421 TI - Erratum for "Intracorneal Ring Segments Implantation for Corneal Ectasia". PMID- 29117422 TI - Erratum for "Mathematical Model to Compare the Relative Tensile Strength of the Cornea After PRK, LASIK, and Small Incision Lenticule Extraction". PMID- 29117420 TI - Intraoperative Optical Coherence Tomography-Guided Management of Cap-Lenticule Adhesion During SMILE. AB - PURPOSE: To report successful lenticule extraction using intraoperative optical coherence tomography (OCT) in a case of cap-lenticule adhesion during small incision lenticule extraction (SMILE). METHODS: Case report. RESULTS: A 22-year old patient with a refractive error of -5.00 -0.50 * 120 degrees and -5.00 -0.75 * 60 degrees in the right and left eyes, respectively, was scheduled for SMILE. The lenticule was created using the VisuMax femtosecond laser system (Carl Zeiss Meditec, Jena, Germany). The surgeon experienced difficulty while extracting the lenticule in the right eye. The patient was immediately shifted under the surgical microscope integrated with intraoperative OCT. The lenticule was found to be adherent to the anterior stromal cap, which was seen as hyperreflective spikes in the posterior plane, in contrast to the anterior plane, which showed minimal reflectivity, suggesting an inadvertent posterior plane entry. The peripheral edge of the lenticule was lifted from the anterior stromal cap under direct visualization of intraoperative feedback images provided by intraoperative OCT. The edge of the lenticule, which was freed, was then grasped with microforceps and extracted in toto using the continuous curvilinear lenticulerrhexis technique. At the end of surgery, the intrastromal pocket was screened under intraoperative OCT for any lenticule remnants. One week after surgery, the uncorrected distance visual acuity was 20/20 with smooth, regular interface on anterior segment optical coherence tomography. CONCLUSIONS: Intraoperative OCT is useful in cases of difficult lenticule extraction during SMILE because it provides real-time visualization of the lenticule and helps in discerning its relation with the anterior stromal cap and the underlying stromal bed. By using intraoperative OCT and the continuous curvilinear lenticulerrhexis technique, satisfactory anatomical and visual outcomes were obtained. [J Refract Surg. 2017;33(11):783-786.]. PMID- 29117423 TI - Bridging the Gap With Peer Support: Patricia's Recovery Story. PMID- 29117424 TI - For the Love of the Game: Game- Versus Lecture-Based Learning With Generation Z Patients. AB - The current study evaluated adolescent patients' enjoyment of and knowledge gained from game-based learning compared with an interactive lecture format on the topic of mood disorders. It was hypothesized that game-based learning would be statistically more effective than a lecture in knowledge acquisition and satisfaction scores. A pre-post design was implemented in which a convenience sample of 160 adolescent patients were randomized to either a lecture (n = 80) or game-based (n = 80) group. Both groups completed a pretest/posttest and satisfaction survey. Results showed that both groups had significant improvement in knowledge from pretest compared to posttest. Game-based learning was statistically more effective than the interactive lecture in knowledge achievement and satisfaction scores. This finding supports the contention that game-based learning is an active technique that may be used with patient education. [Journal of Psychosocial Nursing and Mental Health Services, 56(2), 29 36.]. PMID- 29117425 TI - Effect of Psychiatric Symptoms on Employment Outcomes for Individuals Receiving Supported Employment Services: A Preliminary Study. AB - Psychiatric symptoms are often cited by community-based providers as barriers to employment for individuals with mental health conditions. The current study assessed whether psychiatric symptoms and hospitalization in the past year predicted employment outcomes for participants receiving supported employment (SE) services. A total of 105 participants enrolled in SE services were assessed on their level of psychiatric symptoms, hospitalization in the past year, and employment outcomes. Simultaneous logistic regression was used. Eighty-two participants met for the 6-month follow up. Findings indicate that higher overall scores on the 6-month Brief Symptom Inventory (BSI) are predictive of an employment outcome, and suggest that psychiatric symptoms were not a barrier to employment. Participants with higher overall scores on the BSI, thus suggesting greater symptoms, were more likely to gain employment than individuals with lower BSI scores. [Journal of Psychosocial Nursing and Mental Health Services, 56(3), 33-38.]. PMID- 29117426 TI - Get on Board: Realizing Full Partnerships in Health Care. AB - Psychiatric-mental health nurses (PMHNs) have a strong leadership history, but challenges (e.g., subordinate roles to physicians) to presenting a professional persona have made it difficult to actualize nursing leadership and realize full partnership in health care reform. Physicians outnumber nurses approximately four to one on hospital and other boards, and data suggest this gap is widening. Time, preparation, desire to serve, lack of a unified voice, and being viewed as employees versus professionals are barriers to optimal nursing leadership. Nursing's perspective is crucial to improving outcomes given the complex and shifting landscape of health care, including mental and physical health integration. Nurses can optimize their leadership skills and prepare for full partnerships on boards and beyond through self-reflection, leadership development, use of the Oregon Nurses on Boards Toolkit, and active engagement and collaborations with professional associations. PMHNs are well positioned for this work. [Journal of Psychosocial Nursing and Mental Health Services, 56(3), 39 44.]. PMID- 29117427 TI - Impact of a Nursing in Psychiatry Course on Students' Attitudes Toward Mental Health Disorders. AB - Negative attitudes toward patients with mental illnesses are not uncommon among health professionals, and lead to poorer quality and outcomes of care. Because attitudes are formed early in life, the current study aimed to investigate if teaching psychiatry in secondary school nursing students (i.e., adolescents) changes attitudes toward three prevalent psychiatric disorders: schizophrenia, posttraumatic stress disorder (PTSD), and depression. A pilot quasi-experimental study was conducted with 51 fourth-year students in secondary nursing school who completed a questionnaire regarding attitudes toward these disorders on the first and last day of their Nursing in Psychiatry course. Results show that the stigma attached to all three disorders was significantly reduced after students completed the course. Students attached greater stigma to schizophrenia than PTSD, and to PTSD than depression, before and after the course. The study indicates that education in psychiatry helps reduce negative attitudes toward PTSD, schizophrenia, and depression. [Journal of Psychosocial Nursing and Mental Health Services, 56(3), 45-51.]. PMID- 29117428 TI - Change in knee flexor torque after fatiguing exercise identifies previous hamstring injury in football players. AB - Muscular fatigue and interlimb strength asymmetry are factors known to influence hamstring injury risk; however, limb-specific exacerbation of knee flexor (hamstrings) torque production after fatiguing exercise has previously been ignored. To investigate changes in muscular force production before and after sport-specific (repeated-sprint) and non-specific (knee extension-flexion) fatiguing exercise, and explore the sensitivity and specificity of isokinetic endurance (ie, muscle-specific) and single-leg vertical jump (ie, whole limb) tests to identify previous hamstring injury. Twenty Western Australia State League footballers with previous unilateral hamstring injury and 20 players without participated. Peak concentric knee extensor and flexor (180 degrees ?s-1 ) torques were assessed throughout an isokinetic endurance test, which was then repeated alongside a single-leg vertical jump test before and after maximal repeated-sprint exercise. Greater reductions in isokinetic knee flexor torque ( 16%) and the concentric hamstring:quadriceps peak torque ratio (-15%) were observed after repeated-sprint running only in the injured (kicking) leg and only in the previously injured subjects. Changes in (1) peak knee flexor torque after repeated-sprint exercise, and (2) the decline in knee flexor torque during the isokinetic endurance test measured after repeated-sprint exercise, correctly identified the injured legs (N = 20) within the cohort (N = 80) with 100% specificity and sensitivity. Decreases in peak knee flexor torque and the knee flexor torque during an isokinetic endurance test after repeated-sprint exercise identified previous hamstring injury with 100% accuracy. Changes in knee flexor torque, but not SLVJ, should be tested to determine its prospective ability to predict hamstring injury in competitive football players. PMID- 29117429 TI - Old meets new: most probable number validation of metagenomic and metatranscriptomic datasets in soil. AB - : Metagenomics and metatranscriptomics provide insights into biological processes in complex substrates such as soil, but linking the presence and expression of genes with functions can be difficult. Here, we obtain traditional most probable number estimates (MPN) of Rhizobium abundance in soil as a form of sample validation. Our work shows that in the Highfield experiment at Rothamsted, which has three contrasting conditions (>50 years continual bare fallow, wheat and grassland), MPN based on host plant nodulation assays corroborate metagenomic and metatranscriptomic estimates for Rhizobium leguminosarum sv. trifolii abundance. This validation is important to legitimize soil metagenomics and metatranscriptomics for the study of complex relationships between gene function and phylogeny. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has demonstrated for the first time a functional assay validation of metagenomic and metatranscriptomic datasets by utilizing the clover and Rhizobium leguminosarum sv. trifolii mutualism. The results show that the Most Probable Number results corroborate the results of the 'omics approaches and gives confidence to the study of other biological systems where such a cross-check is not available. PMID- 29117430 TI - Biological false-positive venereal disease research laboratory test in cerebrospinal fluid in the diagnosis of neurosyphilis - a case-control study. AB - BACKGROUND: There is no clear consensus on the diagnosis of neurosyphilis. The Venereal Disease Research Laboratory (VDRL) test from cerebrospinal fluid (CSF) has traditionally been considered the gold standard for diagnosing neurosyphilis but is widely known to be insensitive. OBJECTIVE: In this study, we compared the clinical and laboratory characteristics of true-positive VDRL-CSF cases with biological false-positive VDRL-CSF cases. METHODS: We retrospectively identified cases of true and false-positive VDRL-CSF across a 3-year period received by the Immunology and Serology Laboratory, Singapore General Hospital. A biological false-positive VDRL-CSF is defined as a reactive VDRL-CSF with a non-reactive Treponema pallidum particle agglutination (TPPA)-CSF and/or negative Line Immuno Assay (LIA)-CSF IgG. A true-positive VDRL-CSF is a reactive VDRL-CSF with a concordant reactive TPPA-CSF and/or positive LIA-CSF IgG. RESULTS: During the study period, a total of 1254 specimens underwent VDRL-CSF examination. Amongst these, 60 specimens from 53 patients tested positive for VDRL-CSF. Of the 53 patients, 42 (79.2%) were true-positive cases and 11 (20.8%) were false-positive cases. In our setting, a positive non-treponemal serology has 97.6% sensitivity, 100% specificity, 100% positive predictive value and 91.7% negative predictive value for a true-positive VDRL-CSF based on our laboratory definition. HIV seropositivity was an independent predictor of a true-positive VDRL-CSF. CONCLUSION: Biological false-positive VDRL-CSF is common in a setting where patients are tested without first establishing a serological diagnosis of syphilis. Serological testing should be performed prior to CSF evaluation for neurosyphilis. PMID- 29117432 TI - Gas Chromatography Mass Spectrometry (GC-MS) for Identification of Designer Stimulants Including 2C Amines, NBOMe Compounds, and Cathinones in Urine. AB - Phenethylamine derivatives are being increasingly exploited for recreational use as "designer" stimulants designed to mimic psychostimulant properties of amphetamine or other illicit substances like 3,4-methylenedioxymethamphetamine (MDMA [ecstasy]). Clandestine operations meticulously design phenethylamines so the user can bypass legal action when detected, as many of these are yet to be regulated by government authorities. Substituted phenethylamines or 2C amines, N methoxybenzyl derivatives of the corresponding 2C amines commonly known as NBOMe compounds, and cathinones are among the most commonly abused phenethylamines. Current FDA-approved assays used in screening for illicit drug use lack the sensitivity needed to detect designer stimulants making it challenging for toxicologists to accurately identify these compounds. Gas chromatography mass spectrometry (GC-MS) is a sensitive method for identifying designer stimulants. This unit describes and compares two qualitative GC-MS methods for identifying 2C amines, NBOMe compounds, and cathinones in urine. (c) 2017 by John Wiley & Sons, Inc. PMID- 29117431 TI - Food allergy and atopic dermatitis: Prediction, progression, and prevention. AB - The rising burden of allergic diseases in childhood requires a compelling need to identify individuals at risk for atopy very early in life or even predict the onset of food allergy and atopic dermatitis since pregnancy. The development and clinical phenotypes of atopic diseases in childhood depend on a complex interaction between genetic and environmental factors, such as allergen exposure, air pollution, and infections. Preventive strategies may include avoidance measures, diet supplements, and early complementary food introduction. Overall, the management of allergic diseases has been improving to date toward a patient's tailored approach. This review will cover the current understanding of risk factors, prediction, and management of food allergy and atopic dermatitis in childhood and discuss how these may contribute to the modification of the natural history of food allergy and atopic dermatitis. PMID- 29117433 TI - Inter-and Intra-Laboratory Standardization of TUNEL Assay for Assessment of Sperm DNA Fragmentation. AB - The functional aspects of sperm activity such as sperm chromatin integrity and ability to fertilize cannot be characterized by routine semen parameters. Men with unexplained infertility and idiopathic infertility, as well as men with normozoospermic semen profiles, show high DNA fragmentation. Molecular anomalies in the sperm can be detected by a sperm DNA fragmentation (SDF) assay which can be used in adjunct to conventional semen analysis. While the sperm chromatin structure assay (SCSA) remains the "gold standard," the TUNEL assay using flow cytometry is becoming popular among the different tests that are currently available to measure sperm DNA fragmentation. In this unit, we describe the inter laboratory and intra-laboratory standardization of the TUNEL assay using a benchtop cytometer. The article also provides a step-by-step protocol for measuring sperm DNA fragmentation using the TUNEL assay and a bench-top flow cytometer, and also points out the inherent challenges with this test. (c) 2017 by John Wiley & Sons, Inc. PMID- 29117435 TI - Overview of Neurotoxicology. AB - The nervous system has a central and primary function in the body, and its relevance and complexity make it a target for a large number of toxic substances. The most common forms of neurotoxicity are the death of neurons (neuronopathy), the degeneration of axons (axonopathy), damage to glial cells (e.g., myelinopathy), and interference with the axonal membrane or neurotransmission. Important neurotoxicants are found among pesticides, metals, solvents, natural substances, and industrial chemicals. Environmental chemicals may also contribute to the etiopathogenesis of neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Specific testing guidelines exist to assess potential neurotoxicity and developmental neurotoxicity in particular, and novel alternative testing approaches are being developed. (c) 2017 by John Wiley & Sons, Inc. PMID- 29117434 TI - Co-Culture of Neurons and Microglia. AB - Microglia, the resident immune cells of the brain, have been implicated in numerous neurodegenerative and neurodevelopmental diseases. Activation of microglia by a variety of stimuli induces the release of factors, including pro- and anti-inflammatory cytokines and reactive oxygen species, that contribute to modulating neuro-inflammation and oxidative stress, two crucial processes linked to disorders of the central nervous system. The in vitro techniques described here will provide a set of protocols for the isolation and plating of primary cerebellar granule neurons, primary cortical microglia from a mixed glia culture, and methods for co-culturing both cell types. These methods allow the study of how microglia and the factors they release in this shared environment mediate the effects of toxicants on neuronal function and survival. The protocols presented here allow for flexibility in experimental design, the study of numerous toxicological endpoints, and the opportunity to explore neuroprotective strategies. (c) 2017 by John Wiley & Sons, Inc. PMID- 29117437 TI - Measuring beta-Galactosidase Activity in Gram-Positive Bacteria Using a Whole Cell Assay with MUG as a Fluorescent Reporter. AB - The use of beta-galactosidase enzyme as a biomarker has the potential to determine activity levels of the microbiome of a variety of organisms due to its common presence in both eukaryotes and prokaryotes. Completing the assay in a whole-cell format facilitates the monitoring of beta-galactosidase activity in its actual cellular environment. This unit describes an optimized fluorescent assay for beta-galactosidase that has enough sensitivity to detect the enzymatic activity despite the thick gram-positive bacterial cellular membrane. The use of a smaller fluorometric substrate, namely 4-methylumbelliferyl beta-D galactopyranoside (MUG), has facilitated its penetration into the cells as well as its direct detection without any extra steps. This assay provides an improved technique for measuring a well-studied reporter enzyme and offers new avenues for using beta-galactosidase as a biomarker. (c) 2017 by John Wiley & Sons, Inc. PMID- 29117436 TI - Isolation, Cryopreservation, and Immunophenotyping of Human Peripheral Blood Mononuclear Cells. AB - This unit describes procedures for the isolation, cryopreservation, and thawing of human peripheral blood mononuclear cells (HPBMC) and analysis of cell surface markers (CSM) for immunophenotyping using polychromatic flow cytometry. This methodology can be used to ensure that cell integrity and phenotype stability are not altered through cryopreservation and extended storage. For this analysis, HPBMC were isolated from 7 healthy individuals, and 11-color flow cytometry was performed on freshly isolated samples as well as samples cryopreserved for short- and long-term periods. There is no significant difference in the percentage of cells expressing the CSM CD3, CD4, CD8, CD45RO, CD16, CD19, or CD56 between freshly isolated and cryopreserved HPBMC. Hence, cryopreservation of HPBMC does not influence the phenotype of distinct cellular subsets in isolated mononuclear cells. This protocol for HPBMC isolation, cryopreservation, and thawing of HPBMC is intended for long-term studies of large cohorts requiring sample shipment and subsequent batch analysis. (c) 2017 by John Wiley & Sons, Inc. PMID- 29117438 TI - Metallic Nano-Composite Toxicity Evaluation by Zebrafish Embryo Toxicity Test with Identification of Specific Exposure Biomarkers. AB - Nanomaterials (NM) have different shapes and can be composed of different materials such as carbon, silicon, and some metals like gold, silver, and titanium. They are used as fillers, catalysts, semiconductors, cosmetics, drug carriers in medicine, energy storage systems, and antifriction coatings. NM are the parent compounds of nanoparticles (NPs), which may be divided into two groups: fullerenes and engineered nanoparticles (ENPs). After crossing the cell membrane, NPs may be stored in vesicles, mitochondria, and additional organelles within epithelial cells. They may generate reactive oxygen species, oxidative stress, and cytotoxicity, as well as denaturation of proteins, apoptosis, and necrosis. Nowadays, new toxicological data are required to assess the potential exposure of the environment and human beings to pollutants. The aim of the present investigation is to evaluate the toxicity of the metallic nano-composite by the zebrafish embryo toxicity test (ZFET). The methods described here can be easily adapted to other nanocomposites or nanomaterials with some variations. (c) 2017 by John Wiley & Sons, Inc. PMID- 29117440 TI - The utility of monitoring trimellitic anhydride (TMA)-specific IgG to predict IgE mediated sensitization in an immunosurveillance program. AB - BACKGROUND: Workplace exposure to trimellitic anhydride (TMA) can elicit TMA specific IgE (sIgE), which may lead to occupational asthma (OA). An occupational immunosurveillance program (OISP) has been implemented to monitor TMA exposure and immunologic outcomes. The purpose of this study was to determine whether TMA specific IgG (sIgG) responses can discriminate between TMA-exposed workers with and without sIgE responses. METHODS: Serum TMA-specific antibody (IgG, IgG4, and IgE) levels were estimated longitudinally (years 2006 to 2014) in TMA-exposed workers recruited in low, medium, and high exposure areas. sIgG and sIgE titers plotted against exposure duration were compared between workers with (a) sIgG only and (b) with sIgG who developed sIgE. RESULTS: Among 92 TMA-exposed workers continuously monitored for sIgG and sIgE, 38 developed sIgG; 11 developed a sIgE response 342.38 +/- 186.03 days posthire and were removed from exposure. The average detection time of sIgG in removed workers (159 +/- 92 days) was significantly shorter than for actively exposed workers with only sIgG (346 +/- 187 days). Workers with earlier sIgG responses of higher titer (mean value 42.25 MUg/mL) compared to delayed responders with lower sIgG titers (mean value 14.79 MUg/mL) more frequently developed sIgE responses. Hierarchical clustering showed the initial magnitude and exposure time required for detectable sIgG production discriminated between workers with only sIgG from workers who subsequently produced sIgE. CONCLUSIONS: This study demonstrates the utility of longitudinally monitoring TMA-specific antibodies in an OISP as exposed workers with early sIgG responses and of higher magnitude are more likely to develop TMA sIgE sensitization. PMID- 29117441 TI - Actinic keratosis area and severity index (AKASI) is associated with the incidence of squamous cell carcinoma. AB - BACKGROUND: Actinic keratoses (AKs) are commonly diagnosed clinically. Actinic keratosis area and severity index (AKASI) is a new easy-to-use tool to assess the severity of AKs on the head. OBJECTIVES: To determine the association between chronically UV-induced tumours such as basal cell carcinomas (BCC) or squamous cell carcinomas (SCC) and AKASI. METHODS: We performed a retrospective analysis of patients who had undergone oncological surgery due to UV-induced tumours and who were assessed for AKASI and Physician's global assessment (PGA) prior to surgery. Statistical analysis was performed to evaluate correlation between AKASI, PGA and invasive carcinomas. RESULTS: Of the 210 patients included, 26 patients had histologically diagnosed SCCs and presented with a median (range) AKASI of 6.9 (0-13.0) and PGA of 2 (0-4). In contrast, the 82 patients with BCCs showed a median (range) AKASI of 3.3 (0-15.2) and PGA of 1 (0-4). The Mann Whitney U-test showed significant differences (P = 0.0018) between AKASI of patients with SCC and BCC. In addition, we found a significantly higher AKASI in patients with SCC compared to patients with non-invasive lesions like AK and Bowen disease (BD) (P = 0.0275). Spearman's coefficient of rank correlation between AKASI and PGA indicates that these measures of AK severity were strongly correlated (P < 0.0001; r = 0.90; 95% CI 0.865-0.920). CONCLUSIONS: Patients with SCC show significantly higher AKASI than patients with BCC or patients without invasive tumours. Hence, AKASI may be used to stratify risk for developing invasive SCC. PMID- 29117439 TI - The Female Self-Advocacy in Cancer Survivorship Scale: A validation study. AB - AIM: To develop and psychometrically test the validity of the Female Self Advocacy in Cancer Survivorship Scale. BACKGROUND: Female cancer survivors need to self-advocate to overcome challenges associated with cancer yet no valid measure of self-advocacy exists. DESIGN: Instrument development. Mixed-mode cross sectional survey design. PARTICIPANTS: We recruited adult females (18+ years; N = 317) with a history of invasive cancer from local and national tumour registries and advocacy organizations to complete online or paper questionnaires. METHODS: Between July 2014 - March 2015 to evaluate the construct validity based on evidence of the scale's: (1) internal structure consistent with the underlying model of self-advocacy; (2) sensitivity to differences between groups known to differ in self-advocacy skills; (3) relationships between self-advocacy and key potential predictors (openness and conscientiousness; information engagement; social support) and outcomes (symptom burden and healthcare utilization); (4) relationships between self-advocacy and related concepts (patient activation; self-advocacy within another patient population); and (5) relationships between self-advocacy and criterion measures. Analyses included an exploratory factor analysis, t tests, and bivariate correlations using validated, reliable measures for constructs. RESULTS: Evidence from all five hypotheses supported the construct validity of the Female Self-Advocacy in Cancer Survivorship Scale. The factor analysis confirmed the three underlying dimensions of self-advocacy resulting in a 20-item measure with strong internal consistency that explained almost half of response variance. CONCLUSION: The Female Self-Advocacy in Cancer Survivorship Scale is a valid, reliable measure of how well adult female cancer survivors can get their needs met in the face of adversity. PMID- 29117442 TI - Neuromuscular adaptations induced by adjacent joint training. AB - Effects of resistance training are well known to be specific to tasks that are involved during training. However, it remains unclear whether neuromuscular adaptations are induced after adjacent joint training. This study examined the effects of hip flexion training on maximal and explosive knee extension strength and neuromuscular performance of the rectus femoris (RF, hip flexor, and knee extensor) compared with the effects of knee extension training. Thirty-seven untrained young men were randomly assigned to hip flexion training, knee extension training, or a control group. Participants in the training groups completed 4 weeks of isometric hip flexion or knee extension training. Standardized differences in the mean change between the training groups and control group were interpreted as an effect size, and the substantial effect was assumed to be >=0.20 of the between-participant standard deviation at baseline. Both types of training resulted in substantial increases in maximal (hip flexion training group: 6.2% +/- 10.1%, effect size = 0.25; knee extension training group: 20.8% +/- 9.9%, effect size = 1.11) and explosive isometric knee extension torques and muscle thickness of the RF in the proximal and distal regions. Improvements in strength were accompanied by substantial enhancements in voluntary activation, which was determined using the twitch interpolation technique and RF activation. Differences in training effects on explosive torques and neural variables between the two training groups were trivial. Our findings indicate that hip flexion training results in substantial neuromuscular adaptations during knee extensions similar to those induced by knee extension training. PMID- 29117443 TI - Changes in muscle size via MRI and ultrasound: Are they equivalent? PMID- 29117444 TI - Mediating role of psychological well-being in the relationship between organizational support and nurses' outcomes: A cross-sectional study. AB - AIM: To examine the relationship between organizational support for nursing practice and nurse-assessed quality of care and nurses' job satisfaction in hospital settings and to investigate the mediating role of psychological well being in the aforementioned relationships. BACKGROUND: There has been growing concern about quality of care in healthcare organizations. The past research has documented the effect of nurse practice environment on nurses' quality of care and job satisfaction. However, little is known about the underlying mechanism behind these associations. DESIGN: A cross-sectional survey was undertaken. METHODS: Data were collected from two large public hospitals in Iran between February - March 2017. A sample of 345 nurses participated in the study. Data were analysed using descriptive statistics and partial least squared-structural equation modelling. RESULTS: The results showed that nurses' perception of organizational support was related to their quality of care, job satisfaction and psychological well-being. Also, there was a positive relationship between nurses' psychological well-being and their quality of care and job satisfaction. Moreover, psychological well-being partially mediated the relationship between organizational support with nurse-assessed quality of care and nurses' job satisfaction. CONCLUSION: The findings suggest that organizational support for nursing practice and psychological well-being are two factors that contribute to caring behaviour of nurses and their job satisfaction. Also, positively perceived organizational support generates favourable psychological well-being which in turn enhances nurses' quality of care and job satisfaction. The findings highlight the importance of establishing a supportive nurse practice environment and paying attention to the nurses' psychological well-being in healthcare sectors. PMID- 29117445 TI - Intrapartum glycaemic control and neonatal hypoglycaemia in pregnancies complicated by diabetes: a systematic review. AB - AIMS: To examine whether, in neonates of mothers with Type 1, Type 2 and gestational diabetes, in-target intrapartum glycaemic control was associated with a lower risk of neonatal hypoglycaemia compared with out-of-target glycaemic control. METHODS: We searched PubMed and EMBASE for all available publications, regardless of year, based on a published protocol (PROSPERO CRD42016052439). Studies were excluded if they did not report original data or were animal studies. Data were extracted from published reports in duplicate using a prespecified data extraction form. The main outcome of interest was the association between in-target intrapartum glycaemic control and neonatal hypoglycaemia. RESULTS: We screened 2846 records for potential study inclusion; 23 studies, including approximately 2835 women with diabetes, were included in the systematic review. Only two of those studies specifically examined in-target vs out-of-target intrapartum glycaemic control. Of the studies included, six showed a relationship between intrapartum glucose and neonatal hypoglycaemia, five others showed a relationship in at least one of the analyses performed and 12 did not find a significant relationship. Only one study was identified as having a low risk of bias. CONCLUSIONS: There is a paucity of high-quality data supporting the association of glucose during labour and delivery with neonatal hypoglycaemia in pregnancies complicated by diabetes. Further studies are required to examine the impact of tight glycaemic targets in labour. PMID- 29117446 TI - Challenging rules, creating values: Park's sweet spot theory-driven central 'optimum nurse staffing zone'. PMID- 29117447 TI - Toxic reagents and expensive equipment: are they really necessary for the extraction of good quality fungal DNA? AB - : The aim of this work was to evaluate a fungal DNA extraction procedure with the lowest inputs in terms of time as well as of expensive and toxic chemicals, but able to consistently produce genomic DNA of good quality for PCR purposes. Two types of fungal biological material were tested - mycelium and conidia - combined with two protocols for DNA extraction using Sodium Dodecyl Sulphate (SDS) and Cetyl Trimethyl Ammonium Bromide as extraction buffers and glass beads for mechanical disruption of cell walls. Our results showed that conidia and SDS buffer was the combination that lead to the best DNA quality and yield, with the lowest variation between samples. This study clearly demonstrates that it is possible to obtain high yield and pure DNA from pigmented conidia without the use of strong cell disrupting procedures and of toxic reagents. SIGNIFICANCE AND IMPACT OF THE STUDY: There are numerous methods for DNA extraction from fungi. Some rely on expensive commercial kits and/or equipments, unavailable for many laboratories, or make use of toxic chemicals such as chloroform, phenol and mercaptoethanol. This study clearly demonstrates that it is possible to obtain high yields of pure DNA from pigmented conidia without the use of strong and expensive cell disrupting procedures and of toxic reagents. The method herein described is simultaneously inexpensive and adequate to DNA extraction from several different types of fungi. PMID- 29117449 TI - Better uptake of technology and improved outcomes in Type 1 diabetes. PMID- 29117448 TI - An exploratory study of safety culture, biological risk management and hand hygiene of healthcare professionals. AB - AIMS: The objectives of the study were to: (1) examine the relationships between three different qualitative perceptions of safety culture and the Canadian Patient Safety Climate Survey factors; (2) determine whether these perceptions are associated with different hand hygiene practices. BACKGROUND: Healthcare associated infections and safety cultures are a worldwide issue. During the A/H1N1 Influenza pandemic, Europe and North America did not have the same responses. Importantly, healthcare professionals' perceptions can influence patient safety through infection prevention practices like hand hygiene. DESIGN: A cross-sectional design was used with data collected in 2015. METHODS: The Canadian Patient Safety Culture Survey and hand hygiene observations were gathered from three healthcare centres (two Canadian and one European). Descriptive analyses and ANOVAs were conducted to explore healthcare professionals' safety perceptions and practices. RESULTS: The rates of hand hygiene practices varied widely between the three sites, ranging from 35-77%. One site (Site 3) was found to have the highest scores of management follow-up, feedback about incidents, supervisory leadership for safety, unit learning culture and senior leadership support for safety, and the highest levels of overall patient safety grades for the unit and organization. CONCLUSION: The quantitative results of this study support the previously described model based on qualitative results: individual culture, blaming culture and collaborative culture. Differences between continents emerged regarding infection prevention practices and the way we qualify infections. The results raise concerns about infection practices and about safety cultures and challenges worldwide. PMID- 29117450 TI - Nutrition strategies before and during ultra-endurance event: A significant gap between science and practice. AB - The purpose of this study was to investigate and assess the nutritional practices of open-water swimmers, during the preparation period and the competition, as well as their implications on performance and anthropometric parameters according to their age. Twenty-four (n = 24) men open-water swimmers, twelve young (26.3 +/ 4.9 years) and twelve older athletes (45.8 +/- 9.7 years), participated in this study. Nutritional behavior-energy intake consumption, and anthropometric characteristics were evaluated prior to the Toroneos Gulf crossing (26 km). In addition, nutritional intakes during the race and anthropometrics after the race were also evaluated. Significant differences between the two groups were found for Toroneos Gulf crossing performance, BMI, and all variables of body composition at the preparation period (P < .05). The results involving energy consumption, in both preparation period and during the race, displayed significant differences between the two groups, while both groups exhibited significantly negative energy balances. During the race, significant differences were found also for the energy expenditure, relative energy intake, negative energy balance, relative consumption of carbohydrates per hour, and relative protein intake (P < .05). In both groups, lower intakes than the recommended were observed for macronutrient-micronutrient elements at any time point. Significant correlations were found between selected variables of body composition, nutritional intakes during the preparation period and the competition, and athletes' performance. In summary, this study provides strong evidence about the malnutrition of ultra-endurance swimmers prior and during their competition, with potential dangers for their health and performance as certain deficiencies in both macro- and micronutrient contents are present. PMID- 29117451 TI - Factors predicting Registered Nurses' intentions to leave their organization and profession: A job demands-resources framework. AB - AIMS: To develop a comprehensive model of nursing turnover intention by examining the effects of job demands, job resources, personal demands and personal resources on burnout and work engagement and subsequently on the intention to leave the organization and profession. BACKGROUND: The ageing population and a growing prevalence of multimorbidity are placing increasing strain on an ageing nursing workforce. Solutions that address the anticipated nursing shortage should focus on reducing burnout and enhancing the engagement of Registered Nurses (RNs) to improve retention. DESIGN: A cross-sectional survey design. METHOD: Data were collected in 2014-2015 via an e-survey from 2,876 RNs working in New Zealand. Data were analysed with structural equation modelling. RESULTS: Higher engagement results in lower intention to leave the organization and profession. Burnout has significant effects on intentions to leave through lower engagement. While most of the demands and resources' variables (except professional development) have effects on intentions to leave, greater workload and greater work-life interference result in higher burnout and are the strongest predictors of intentions to leave. Greater emotional demands (challenges) and greater self efficacy also have strong effects in lowering intentions to leave through higher engagement. CONCLUSIONS: Employee burnout and work engagement play an important role in transmitting the impacts of job demands, job resources, personal demands and personal resources into RN intention to leave the organization and profession. Work-life interference and high workloads are major threats to nursing retention while challenge demands and higher levels of self-efficacy support better retention. PMID- 29117452 TI - Influence of population size, density, and proximity to talent clubs on the likelihood of becoming elite youth athlete. AB - Previous studies have found significant differences in the likelihood of becoming an elite athlete depending on community population sizes and densities, an effect known as the place of early development, or birthplace effect. However, the results have not been consistent between sports or European countries. As both professional and voluntary clubs are vital to the talent development systems in Europe, the proximity of an athlete's place of early development to the location of talent clubs may be an important predictor of the likelihood of becoming an elite athlete. Therefore, the primary purpose of this study was to investigate the place of early development effect and the effect of proximity to talent clubs. The samples included elite youth league athletes (579 football and 311 handball) and national youth athletes (85 football and 80 handball) and a comparison group of 147 221 football and 26 290 handball youth athletes. Odds ratios showed variations in the optimal community size and density across sports. Geospatial analyses of proximity to talent clubs highlighted a trend indicating that most national and elite youth league athletes in both sports had their place of early development in their sport near a talent club. The results suggest that proximity is an important predictor in the development of expertise across sports, but future studies need to clarify if proximity is important in other countries and sports. PMID- 29117453 TI - Data handling in NMR facilities and assignment of NMR spectra in synthetic chemistry labs: Why electronic structure validation should become part of the routine. PMID- 29117454 TI - Factors affecting quality of nurse shift handover in the emergency department. AB - AIM: The aim of this study was to explore and test factors hypothesized to influence quality of Emergency Department nurse-to-nurse shift handover communication. BACKGROUND: Nurse-to-nurse shift handover communication includes the transfer of information and responsibility for patients at shift change. The unique environment of the Emergency Department, where there is a high degree of patient unpredictability, increased patient volumes and rapid patient turnover, can create challenges for high quality handover communication. There is considerable literature addressing handover communication and factors that influence quality or effectiveness. However, few studies have empirically tested those factors. DESIGN: A quantitative, cross-sectional design was used to test a conceptual model of factors hypothesized to influence quality of handover communication. METHODS: In 2014, data were gathered using surveys mailed to Emergency Department nurses across Ontario, Canada. RESULTS: The final eligible sample was 231 of 576 for an overall response rate of 40.1%. Analysis was performed using backwards elimination stepwise multiple linear regression. Four statistically significant explanatory variables were retained in the final multiple regression model, explaining 34% (p < .0001) of variance in handover quality. Handover quality was increased when patients flowed smoothly through triage, when nurses experienced positive intrusions, in the presence of a positive safety climate and when there were positive relationships between incoming and outgoing nurses. CONCLUSIONS: By understanding those factors that contribute to handover quality, it is possible to develop targeted interventions aimed at improving the quality of Emergency Department nurse-to-nurse shift handover. PMID- 29117455 TI - Response to the letter to editor by Dankel et al. 2017 "Changes in muscle size via MRI and ultrasound: Are they equivalent?" PMID- 29117456 TI - Testing hypotheses for maternal effects in Daphnia magna. AB - Maternal effects are widely observed, but their adaptive nature remains difficult to describe and interpret. We investigated adaptive maternal effects in a clone of the crustacean Daphnia magna, experimentally varying both maternal age and maternal food and subsequently varying food available to offspring. We had two main predictions: that offspring in a food environment matched to their mothers should fare better than offspring in unmatched environments, and that offspring of older mothers would fare better in low food environments. We detected numerous maternal effects, for example offspring of poorly fed mothers were large, whereas offspring of older mothers were both large and showed an earlier age at first reproduction. However, these maternal effects did not clearly translate into the predicted differences in reproduction. Thus, our predictions about adaptive maternal effects in response to food variation were not met in this genotype of Daphnia magna. PMID- 29117458 TI - Telephone-based CBT and the therapeutic relationship: The views and experiences of IAPT practitioners in a low-intensity service. AB - WHAT IS KNOWN ON THE SUBJECT: There is a move towards the use of new ways of delivering mental health care, particularly via an increased use of telephone therapies. Although some studies have noted the advantages of telephone-delivered therapies (e.g., removing access barriers) and reported on equivalent therapeutic effects when compared to face-to-face, there are concerns about how telephone based therapy adversely affects the therapeutic relationship. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: It contributes new knowledge regarding psychological practitioners' experience and views about using telephone-based therapies and how this affects the therapeutic relationship. WHAT ARE THE IMPLICATIONS FOR PRACTICE: This paper provides data about the new practitioner workforce (IAPT Psychological Wellbeing Practitioners) and adds to a growing area of research regarding their clinical role. It has relevance for mental health nursing, because health services internationally and across the professions are exploring how telehealth can improve health care. This paper suggests that mental health services need to focus on what type of therapeutic relationship their practice facilitates and on offering transparency to service users. It concludes that telephone work in IAPT can accommodate a working alliance, but not other types of therapeutic relationship, which practitioners and service users hoped for. Services need to focus on what facilitates and inhibits deeper therapeutic closeness and connection. ABSTRACT: Introduction Over-the-telephone (OTT) delivered psychological therapies as an alternative method to face-to-face (F2F) are becoming more prevalent in mental health care. Research suggests a range of benefits of OTT use in therapy, but there are growing concerns about its consequences for the therapeutic relationship. This paper presents new knowledge regarding psychological practitioners' experience and views of OTT work and its potential effects on the therapeutic relationship in the context of the UK's Increasing Access to Psychological Therapy (IAPT) programme. Aim This paper presents IAPT practitioners' experiences and views of OTT work and its potential effects on the therapeutic relationship. Methods Completed questionnaires (exploring OTT versus F2F work) which were distributed to IAPT practitioners revealed a concern about the therapeutic relationship in OTT. To explore this further, nine in-depth semi-structured interviews with PWPs were conducted and the findings from this qualitative study are reported here. Results Practitioners noted OTT use facilitated access and flexibility for service users; however, they expressed some concern over the adverse effect of OTT on the therapeutic relationship. Discussion Although a working alliance was possible OTT, this research suggests the type of therapeutic relationship formed OTT in a "low contact-high volume" service such as IAPT needs to be better defined. By addressing this, dissonance which might arise between practitioner aims and the aims of IAPT can be reduced. This research also contributes to wider debates regarding mental health care and its provision in the UK. Implications for practice This paper concludes that mental health services need to focus on what type of therapeutic relationship their practice facilitates and to offer transparency to service users. The findings suggest that telephone work in IAPT can accommodate a working alliance, but not other types of therapeutic relationship, which practitioners and service users hoped for. Services need to offer a more nuanced understanding of the concept of a therapeutic relationship and focus on what facilitates and inhibits deeper therapeutic closeness and connection. PMID- 29117457 TI - Diurnal and photoperiodic changes in thyrotrophin-stimulating hormone beta expression and associated regulation of deiodinase enzymes (DIO2, DIO3) in the female juvenile chicken hypothalamus. AB - Increased thyrotrophin-stimulating hormone beta (TSHbeta) expression in the pars tuberalis is assumed to be an early step in the neuroendocrine mechanism transducing photoperiodic information. The present study aimed to determine the relationship between long-photoperiod (LP) and diurnal TSHbeta gene expression in the juvenile chicken by comparing LP-photostimulated birds with groups kept on a short photoperiod (SP) for 1 or 12 days. TSHbeta expression increased by 3- and 23-fold after 1 and 12 days of LP-photostimulation both during the day and at night. Under both SP and LP conditions, TSHbeta expression was between 3- and 14 fold higher at night than in the day, suggesting that TSHbeta expression cycles in a diurnal pattern irrespective of photoperiod. The ratio of DIO2/3 was decreased on LPs, consequent to changes in DIO3 expression, although there was no evidence of any diurnal effect on DIO2 or DIO3 expression. Plasma prolactin concentrations revealed both an effect of LPs and time-of-day. Thus, TSHbeta expression changes in a dynamic fashion both diurnally and in response to photoperiod. PMID- 29117459 TI - Receptor homodimerization plays a critical role in a novel dominant negative P2RY12 variant identified in a family with severe bleeding. AB - : Essentials Three dominant variants for the autosomal recessive bleeding disorder type-8 have been described. To date, there has been no phenotype/genotype correlation explaining their dominant transmission. Proline plays an important role in P2Y12R ligand binding and signaling defects. P2Y12R homodimer formation is critical for the receptor function and signaling. SUMMARY: Background Although inherited platelet disorders are still underdiagnosed worldwide, advances in molecular techniques are improving disease diagnosis and patient management. Objective To identify and characterize the mechanism underlying the bleeding phenotype in a Caucasian family with an autosomal dominant P2RY12 variant. Methods Full blood counts, platelet aggregometry, flow cytometry and western blotting were performed before next-generation sequencing (NGS). Detailed molecular analysis of the identified variant of the P2Y12 receptor (P2Y12R) was subsequently performed in mammalian cells overexpressing receptor constructs. Results All three referred individuals had markedly impaired ADP-induced platelet aggregation with primary wave only, despite normal total and surface P2Y12R expression. By NGS, a single P2RY12:c.G794C substitution (p.R265P) was identified in all affected individuals, and this was confirmed by Sanger sequencing. Mammalian cell experiments with the R265P-P2Y12R variant showed normal receptor surface expression versus wild-type (WT) P2Y12R. Agonist stimulated R265P-P2Y12R function (both signaling and surface receptor loss) was reduced versus WT P2Y12R. Critically, R265P-P2Y12R acted in a dominant negative manner, with agonist-stimulated WT P2Y12R activity being reduced by variant coexpression, suggesting dramatic loss of WT homodimers. Importantly, platelet P2RY12 cDNA cloning and sequencing in two affected individuals also revealed three-fold mutant mRNA overexpression, decreasing even further the likelihood of WT homodimer formation. R265 located within extracellular loop 3 (EL3) is one of four residues that are important for receptor functional integrity, maintaining the binding pocket conformation and allowing rotation following ligand binding. Conclusion This novel dominant negative variant confirms the important role of R265 in EL3 in the functional integrity of P2Y12R, and suggests that pathologic heterodimer formation may underlie this family bleeding phenotype. PMID- 29117460 TI - Maternal folic acid use during pregnancy, methylenetetrahydrofolate reductase gene polymorphism, and child's lung function and asthma. AB - BACKGROUND: Folic acid supplement use during pregnancy might affect childhood respiratory health, potentially mediated by methylenetetrahydrofolate reductase polymorphism C677T (MTHFR-C677T) carriership. OBJECTIVES: We examined the associations of maternal folic acid supplement use and folate, vitamin B12 and homocysteine concentrations during pregnancy with childhood lung function and asthma. METHODS: This study was embedded in a population-based prospective cohort study among 5653 children. Folic acid supplement use was assessed by questionnaires. Folate, vitamin B12 and homocysteine plasma concentrations were measured in early pregnancy and at birth. At age 10 years, forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), FEV1 /FVC, forced expiratory flow between 25% and 75% (FEF25-75 ), at 75% of FVC (FEF75 ), and asthma were examined. RESULTS: Maternal folic acid supplement use during pregnancy was associated with higher childhood FEV1 and FVC and with a lower FEV1 /FVC, compared with no folic acid supplement use. Among mothers carrying MTHFR C677T variants, preconceptional start of folic acid supplement use was associated with lower FEV1 /FVC (-0.17 [-0.32, -0.02]) and FEF25-75 (-0.24 [-0.40, -0.07]). Among children carrying MTHFR-C677T wild-type, a higher vitamin B12 level at birth was associated with a lower FEV1 (-0.07 [-0.12, -0.01]) and FVC (-0.09 [ 0.15, -0.04]). Folate and homocysteine concentrations were not consistently associated with lower childhood lung function or asthma. CONCLUSIONS: Preconceptional start of maternal folic acid supplement use and higher vitamin B12 concentrations at birth might adversely affect childhood lung function depending on MTHFR-C677T carriership. The clinical implications need to be evaluated. PMID- 29117461 TI - Atrial natriuretic peptide reduces inflammation and enhances apoptosis in rat acute pancreatitis. AB - AIM: We previously reported that atrial natriuretic peptide (ANP) reduces serum amylase and intrapancreatic trypsinogen activation in the onset of acute pancreatitis whereas secretin increases them. In the present work, we sought to establish the effect of ANP and secretin on the inflammatory response and cell death in experimental acute pancreatitis. METHODS: The expression and activity of key inflammatory mediators and apoptosis were evaluated in the presence or absence of the atrial peptide, secretin or both in cerulein-induced acute pancreatitis in rats. Also, ultrastructural changes in pancreatic acinar cells were assessed by transmission electron microscopy. RESULTS: ANP significantly reduced NF-kappaB activation and TNF-alpha intrapancreatic levels. Furthermore, it decreased inducible nitric oxide synthase and cyclooxygenase 2 expression and activity while it diminished myeloperoxidase activity. ANP also stimulated apoptosis as shown by caspase-3 expression and activation as well as TUNEL assay. These findings correlated well with the ultrastructural changes observed in the exocrine pancreas. Although secretin reduced various inflammatory markers, it also diminished caspase-3 activation and the overall response was the aggravation of the disease as reflected by the ultrastructural alterations of pancreatic acinar cells. In the presence of ANP, various effects evoked by secretin were antagonized. CONCLUSION: Present findings show that ANP significantly attenuated the severity of acute pancreatitis in the rat by inducing apoptosis and reducing the inflammatory response and further suggest that ANP may have eventual therapeutic implications in the disease and/or in medical interventions at risk of its developing like endoscopic retrograde cholangiopancreatography. PMID- 29117462 TI - Gaining Access to Bacteria through (Reversible) Control of Lipophilicity. AB - The development of antimicrobial photodynamic therapy (aPDT) is highly dependent on the development of suitable photosensitizers (PSs); ideally, affinity of a PS towards bacterial cells should be much higher than that towards mammalian cells. A cationic charge on a PS may lead to its selective binding to bacteria mediated through electrostatic interaction; however, the photodynamic outcome is highly dependent on the lipophilicity of the PS. Herein, we report the aPDT effect of silicon(IV) phthalocyanine derivatives bearing four positive charges and methyl, phenyl, or naphthyl substituents at the periphery of the macrocycle. We show that through modulation of lipophilicity, it is possible to find a therapeutic window in which bacteria, but not mammalian cells, are effectively killed. The photobiological activity of these PSs was significantly lower when they were deployed as host-guest complexes with cucurbit[7]uril (CB[7]). CB[7] blocks the hydrophobic part of the PS and reduces its lipophilicity, indicating that a hydrophobic interaction with the outer membrane of bacterial cells is essential for aPDT activity. The efficacies of the obtained PSs have been evaluated by using different uropathogenic E. coli isolates and human kidney epithelial carcinoma cells. PMID- 29117463 TI - Vasculitis and IgA monoclonal gammopathy of cutaneous significance. PMID- 29117465 TI - More SPRINT controversy. PMID- 29117464 TI - Salivary scintigraphy for Sjogren's syndrome in patients with xerostomia: A retrospective study. AB - OBJECTIVES: The value of salivary gland scintigraphy in the diagnosis of Sjogren's syndrome remains controversial. The primary aim of this study was to estimate the diagnostic accuracy of salivary gland scintigraphy in the diagnosis of Sjogren's syndrome among 237 patients with xerostomia. METHODS: We retrospectively compared eight scintigraphy parameters between 106 Sjogren patients and 131 non-Sjogren patients. RESULTS: Seven of the eight parameters were significantly decreased in patients with Sjogren; however, their diagnostic accuracy was low, with areas under the curves (AUCs) ranging from 0.58 (95% CI 0.50-0.65) to 0.63 (95% CI: 0.55-0.70). The prestimulatory oral activity index allowed discrimination between primary and secondary Sjogren's syndrome (AUC 0.73, 95% CI: 0.62-0.84), and the secretion velocity for parotid glands allowed discrimination between patients with Sjogren and burning mouth syndrome (AUC 0.71, 95% CI 0.59-0.82). CONCLUSION: The accuracy of scintigraphy parameters for the diagnosis of Sjogren's syndrome among patients with xerostomia was low; however, some functional indices appeared to assist discrimination between primary and secondary SS patients and between subgroups of patients with different causes of xerostomia. PMID- 29117467 TI - Non-steroidal anti-inflammatory drugs may blunt more than pain. PMID- 29117466 TI - Dental properties, ultrastructure, and pulp cells associated with a novel DSPP mutation. AB - OBJECTIVE: To investigate physical characteristics and behaviours of dental pulp cells of teeth isolated from a dentinogenesis imperfecta (DGI) patient with a novel dentin sialophosphoprotein (DSPP) mutation. SUBJECTS AND METHODS: Whole exome and Sanger sequencing were employed to identify mutations. Physical characteristics of the teeth were examined. Pulp cells' behaviours including cell proliferation, colony-forming unit, osteogenic differentiation, pluripotent markers, and mesenchymal stem cell markers were investigated. RESULTS: The proband had opalescent brown primary teeth with extensive loss of enamel. Mutation analysis revealed a novel heterozygous 4-bp deletion, c.1915_1918delAAGT (p.K639QfsX674), in exon 5 of the DSPP associated with DGI. Analysis of the extracted primary incisor demonstrated a decrease in brightness but an increase in yellow and red chroma. The dentin showed reduced mineral density. The dentinal tubules were present in the predentin, but progressively collapsed in the dentin. The pulp cells exhibited markedly reduced CD105 expression, decreased cell proliferation, and smaller colony-forming units. CONCLUSIONS: We identified a novel mutation in the DSPP gene which disturbed dentin characteristics and pulp cells' behaviours. Our study expands the mutation spectrum and understanding of pathologic dentin phenotypes related to the frameshift deletion in the dentin phosphoprotein (DPP) region of the DSPP gene. PMID- 29117468 TI - Zoonotic helminth exposure and risk of allergic diseases: A study of two generations in Norway. AB - BACKGROUND: Animal and human studies indicate that definitive host helminth infections may confer protection from allergies. However, zoonotic helminths, such as Toxocara species (spp.), have been associated with increased allergies. OBJECTIVE: We describe the prevalence of Toxocara spp. and Ascaris spp. seropositivity and associations with allergic diseases and sensitization, in 2 generations in Bergen, Norway. METHODS: Serum levels of total IgG4, anti-Toxocara spp. IgG4 and Ascaris spp. IgG4 were established by ELISA in 2 cohorts: parents born 1945-1972 (n = 171) and their offspring born 1969-2003 (n = 264). Allergic outcomes and covariates were recorded through interviews and clinical examinations including serum IgEs and skin prick tests. RESULTS: Anti-Ascaris spp. IgG4 was detected in 29.2% of parents and 10.3% of offspring, and anti Toxocara spp. IgG4 in 17.5% and 8.0% of parents and offspring, respectively. Among offspring, anti-Toxocara spp. IgG4 was associated with pet keeping before age 15 (OR = 6.15; 95% CI = 1.37-27.5) and increasing BMI (1.16[1.06-1.25] per kg/m2 ). Toxocara spp. seropositivity was associated with wheeze (2.97[1.45- 7.76]), hayfever (4.03[1.63-9.95]), eczema (2.89[1.08-7.76]) and cat sensitization (5.65[1.92-16.6]) among offspring, but was not associated with allergic outcomes among parents. Adjustment for childhood or current pet keeping did not alter associations with allergies. Parental Toxocara spp. seropositivity was associated with increased offspring allergies following a sex-specific pattern. CONCLUSIONS & CLINICAL RELEVANCE: Zoonotic helminth exposure in Norway was less frequent in offspring than parents; however, Toxocara spp. seropositivity was associated with increased risk of allergic manifestations in the offspring generation, but not among parents. Changes in response to helminth exposure may provide insights into the increase in allergy incidence in affluent countries. PMID- 29117470 TI - One hundred thousand US Dollars to battle scientific logorrhoea. PMID- 29117469 TI - Optimal extent of surgery for early gallbladder cancer with regard to long-term survival: a meta-analysis. AB - BACKGROUND: The optimal surgical extent for T1 gallbladder cancer (GBC) remains controversial. Simple cholecystectomy is routinely performed for T1 GBC while several guidelines recommend extended cholecystectomy for T1b GBC. However, evidence regarding the optimal surgical extent for T1 GBC is lacking. This study aims to systematically evaluate the optimal surgical extent for early GBC with regard to long-term survival. METHODS: A comprehensive literature search in MEDLINE was performed to identify studies with histologically proven GBC and survival data. A total of 22 articles with a total of 2,578 patients were included in the final analysis. Dichotomous data regarding cancer-related death in all T1, T1a, and T1b GBC cases were extracted. Risk ratios, risk differences, and 95% confidence intervals (CIs) were pooled. RESULTS: The risk ratio between simple and extended cholecystectomy in T1 GBC patients was 1.06 (95% CI 0.97 1.16); T1a, 0.82 (95% CI 0.70-0.96); and T1b, 1.06 (95% CI 0.93-1.22). No significant difference was found according to the extent of surgery in all T1 or T1b GBC cases (P = 0.17 and P = 0.36, respectively). Simple cholecystectomy had significantly lower cancer-related death in T1a GBC patients (P = 0.01). CONCLUSION: Simple and extended cholecystectomy showed comparable survival outcomes in T1 GBC patients. PMID- 29117472 TI - Text messaging approach improves weight loss in patients with nonalcoholic fatty liver disease: A randomized study. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease. The only effective treatment is 7%-10% weight loss. Mobile technology is increasingly used in weight management. This study was performed to evaluate the effects of text messaging intervention on weight loss in patients with NAFLD. METHODS: Thirty well-defined NAFLD patients (mean age 52 years, 67% females, mean BMI 38) were randomized 1:1 to control group: counselling on healthy diet and exercise, or intervention group: text messages in addition to healthy life style counselling. NAFLD text messaging program sent weekly messages for 22 weeks on healthy life style education. Primary outcome was change in weight. Secondary outcomes were changes in liver enzymes and lipid profile. RESULTS: Intervention group lost an average of 6.9 lbs. (P = .03) compared to gain of 1.8 lbs. in the control group (P = .45). Intervention group also showed a decrease in ALT level (-12.5 IU/L, P = .035) and improvement in serum triglycerides (-28 mg/dL, P = .048). There were no changes in the control group on serum ALT level (-6.1 IU/L, P = .46) and on serum triglycerides (-20.3 mg/dL P = .27). Using one-way analysis of variance, change in outcomes in intervention group compared to control group was significant for weight (P = .02) and BMI (P = .02). CONCLUSIONS: Text messaging on healthy life style is associated with reduction in weight in NAFLD patients. Larger studies are suggested to examine benefits on liver histology, and assess long-term impact of this approach in patients with NAFLD. PMID- 29117471 TI - Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma. AB - Currently, molecular markers are not used when determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). In the present study, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT) and adjacent non-malignant tissues (AT) typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients. The workflow integrated differentially expressed gene selection, gene ontology enrichment, computational classification, survival predictions, image analysis and experimental validation methods. We developed a 24-ribosomal gene-based HCC classifier (RGC), which is prognostically significant in both PT and AT. The RGC gene overexpression in PT was associated with a poor prognosis in the training (hazard ratio = 8.2, P = 9.4 * 10-6 ) and cross-cohort validation (hazard ratio = 2.63, P = 0.004) datasets. The multivariate survival analysis demonstrated the significant and independent prognostic value of the RGC. The RGC displayed a significant prognostic value in AT of the training (hazard ratio = 5.0, P = 0.03) and cross-validation (hazard ratio = 1.9, P = 0.03) HCC groups, confirming the accuracy and robustness of the RGC. Our experimental and bioinformatics analyses suggested a key role for c-MYC in the pro-oncogenic pattern of ribosomal biogenesis co-regulation in PT and AT. Microarray, quantitative RT-PCR and quantitative immunohistochemical studies of the PT showed that DKK1 in PT is the perspective biomarker for poor HCC outcomes. The common co-transcriptional pattern of ribosome biogenesis genes in PT and AT from HCC patients suggests a new scalable prognostic system, as supported by the model of tumor-like metabolic redirection/assimilation in non-malignant AT. The RGC, comprising 24 ribosomal genes, is introduced as a robust and reproducible prognostic model for stratifying HCC patient risks. The adjacent non-malignant liver tissue alone, or in combination with HCC tissue biopsy, could be an important target for developing predictive and monitoring strategies, as well as evidence-based therapeutic interventions, that aim to reduce the risk of post surgery relapse in HCC patients. PMID- 29117473 TI - Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure-Activity Relationships. AB - Since the time of its identification, the natural compound largazole rapidly caught the attention of the medicinal chemistry community for its impressive potency as an inhibitor of histone deacetylases (HDACs) and its strong antiproliferative activity against a broad panel of cancer cell lines. The design of largazole analogues is an expanding field of study, due to their remarkable potential as novel anticancer therapeutics. At present, a large ensemble of largazole analogues has been reported, allowing the identification of important structure-activity relationships (SAR) that can guide the design of novel compounds with improved HDAC inhibitory profiles, anticancer activity, and pharmacokinetic properties. The aim of this review is to concisely summarize the information obtained by biological evaluations of the various largazole analogues reported to date, with particular attention given to the latest analogues, as well as to analyze the various SAR obtained from this data, with the purpose of providing useful guidelines for the development of novel potent and selective HDAC inhibitors to be used as anticancer agents. PMID- 29117474 TI - The Role of Science in the Opioid Crisis. PMID- 29117475 TI - Comparison of Cormack Lehane Grading System and Intubation Difficulty Score in Patients Intubated by D-Blade Video and Direct Macintosh Laryngoscope: A Randomized Controlled Study AB - D-blade is a relatively new device in the field of videolaryngoscopy, designed forairway management by enabling indirectoscopic glottic view. In our study, we investigated efficiencyof D-blade in comparison with direct Macintosh laryngoscope (gold standard). Fifty-two adultpatients with normal airway scheduled for elective surgery in general anesthesia were randomly assignedin D blade video or direct Macintosh group. In the first video group, patients were laryngo-scopedand intubated by D-blade, and in the second group laryngoscopy and intubation were performedby Macintosh laryngoscope. Glottic view was evaluated according to Cormack Lehane gradingsystem (C-L), while duration of intubation and easiness of intubation were evaluated according tothe intubation difficulty score (IDS). Additionally, hemodynamic parameters were recorded beforeand after induction. There were no statistically significant between-group differences in time to intubation,easiness of endotracheal tube insertion, C-L, and IDS. In comparison with direct Macintoshlaryngoscope, D-blade showed similar but still favorable characteristics. In our opinion, D-blade is auseful device in airway management and should be used in daily anesthesiologist work. PMID- 29117476 TI - N,N'-Bisoxalamides Enhance the Catalytic Activity in Cu-Catalyzed Coupling of (Hetero)Aryl Bromides with Anilines and Secondary Amines. AB - N,N'-Bis(furan-2-ylmethyl)oxalamide (BFMO), an inexpensive and conveniently available bidentate ligand, is very effective for promoting Cu-catalyzed N arylation of anilines and cyclic secondary amines. The method enables coupling of a broad range of (hetero)aryl bromides with various (hetero)aryl amines and cyclic secondary amines at 0.5-5 mol % catalyst loadings at relatively low temperatures. For coupling with more sterically hindered acyclic secondary amines, using N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide (BTMPO) as a ligand gives the better results. Additionally, high selectivity is achieved in CuI/BFMO catalyzed direct monoarylation of piperazine with (hetero)aryl bromides to afford pharmaceutically important building blocks. PMID- 29117477 TI - 1-Butyl-3-methylimidazol-2-ylidene Borane: A Readily Available, Liquid N Heterocyclic Carbene Borane Reagent. AB - 1-Butyl-3-methylimidazol-2-ylidene borane has been synthesized directly from two inexpensive commercial reagents: 1-butyl-3-methylimidazolium bromide and sodium borohydride. This NHC-borane reagent is a stable, free-flowing liquid that shows promise for use in radical, ionic, and metal-catalyzed reactions. PMID- 29117478 TI - Design, Synthesis, and Self-Assembly of Polymers with Tailored Graft Distributions. AB - Grafting density and graft distribution impact the chain dimensions and physical properties of polymers. However, achieving precise control over these structural parameters presents long-standing synthetic challenges. In this report, we introduce a versatile strategy to synthesize polymers with tailored architectures via grafting-through ring-opening metathesis polymerization (ROMP). One-pot copolymerization of an omega-norbornenyl macromonomer and a discrete norbornenyl comonomer (diluent) provides opportunities to control the backbone sequence and therefore the side chain distribution. Toward sequence control, the homopolymerization kinetics of 23 diluents were studied, representing diverse variations in the stereochemistry, anchor groups, and substituents. These modifications tuned the homopolymerization rate constants over 2 orders of magnitude (0.36 M-1 s-1 < khomo < 82 M-1 s-1). Rate trends were identified and elucidated by complementary mechanistic and density functional theory (DFT) studies. Building on this foundation, complex architectures were achieved through copolymerizations of selected diluents with a poly(d,l-lactide) (PLA), polydimethylsiloxane (PDMS), or polystyrene (PS) macromonomer. The cross propagation rate constants were obtained by nonlinear least-squares fitting of the instantaneous comonomer concentrations according to the Mayo-Lewis terminal model. In-depth kinetic analyses indicate a wide range of accessible macromonomer/diluent reactivity ratios (0.08 < r1/r2 < 20), corresponding to blocky, gradient, or random backbone sequences. We further demonstrated the versatility of this copolymerization approach by synthesizing AB graft diblock polymers with tapered, uniform, and inverse-tapered molecular "shapes." Small angle X-ray scattering analysis of the self-assembled structures illustrates effects of the graft distribution on the domain spacing and backbone conformation. Collectively, the insights provided herein into the ROMP mechanism, monomer design, and homo- and copolymerization rate trends offer a general strategy for the design and synthesis of graft polymers with arbitrary architectures. Controlled copolymerization therefore expands the parameter space for molecular and materials design. PMID- 29117480 TI - Mass Administration of Ivermectin in Areas Where Loa loa Is Endemic. PMID- 29117479 TI - Effect of treatment with an internal teat sealant at drying-off in cows wintered on forage crops in New Zealand on clinical mastitis and somatic cell counts. AB - AIMS: To determine the impact of treatment with internal teat sealant (ITS) compared to no treatment at drying-off on the incidence of clinical mastitis (CM) during the dry period and 84 days after calving, and the prevalence of cows with somatic cell counts (SCC) >=200,000 cells/mL at the first lactation herd test, for cows wintered on forage crops. METHODS: In four dairy herds in the South Island of New Zealand, cows with no history of CM or individual SCC >100,000 cells/mL during the 2015-16 season were randomly assigned to treatment with ITS in each quarter (ITS group) at drying-off or no treatment (Control group). Cows were otherwise treated similarly, wintered on forage crops and transferred to pasture for calving and lactation. Cows were monitored over the dry period and for 84 days after calving, and any case of CM recorded. Individual SCC were recorded at the first herd test after calving. RESULTS: Between drying-off and 84 days after calving 36/470 (7.7%) cows in the ITS groups and 73/442 (16.5%) cows in the Control group were diagnosed with CM (RR=0.46; 95% CI=0.26-0.73). The final multivariable logistic regression model included an interaction between treatment group and length of dry period. For a Friesian/Jersey cow, aged 4-8 years, with a dry period of 30-80 days, dried off without ITS, the probability of CM in the study period was 0.12 (95% CI=0.09-0.16), and for such a cow treated with ITS the probability was 0.07 (95% CI=0.05-0.10). For an equivalent cow, with a dry period of 81-140 days, which was untreated, the probability was 0.21 (95% CI=0.14-0.29), and for such a cow treated with ITS it was 0.05 (95% CI=0.02 0.11). At the first herd test after calving 77/383 (20.1%) cows in the Control group and 57/425 (13.4%) cows in the ITS group had SCC >=200,000 cells/mL (RR=1.51; 95% CI=1.10-2.06). CONCLUSIONS AND CLINICAL RELEVANCE: For these farms, treatment of cows with no history of elevated SCC or CM with ITS at drying-off halved the incidence of CM between drying-off and 84 days after calving, and reduced by 33% the proportion of cows with SCC>=200,000 at the first herd test after calving, compared with untreated cows. Treatment with ITS reduced the risk of CM proportionally more for cows with a dry period of 81-140 days than for cows with a shorter dry period. PMID- 29117481 TI - Advanced Diffusion-weighted Imaging Modeling for Prostate Cancer Characterization: Correlation with Quantitative Histopathologic Tumor Tissue Composition-A Hypothesis-generating Study. AB - Purpose To correlate quantitative diffusion-weighted imaging (DWI) parameters derived from conventional monoexponential DWI, stretched exponential DWI, diffusion kurtosis imaging (DKI), and diffusion-tensor imaging (DTI) with quantitative histopathologic tumor tissue composition in prostate cancer in a preliminary hypothesis-generating study. Materials and Methods This retrospective institutional review board-approved study included 24 patients with prostate cancer (mean age, 63 years) who underwent magnetic resonance (MR) imaging, including high-b-value DWI and DTI at 3.0 T, before prostatectomy. The following parameters were calculated in index tumors and nontumoral peripheral zone (PZ): apparent diffusion coefficient (ADC) obtained with monoexponential fit (ADCME), ADC obtained with stretched exponential modeling (ADCSE), anomalous exponent (alpha) obtained at stretched exponential DWI, ADC obtained with DKI modeling (ADCDKI), kurtosis with DKI, ADC obtained with DTI (ADCDTI), and fractional anisotropy (FA) at DTI. Parameters in prostate cancer and PZ were compared by using paired Student t tests. Pearson correlations between tumor DWI and quantitative histologic parameters (nuclear, cytoplasmic, cellular, stromal, luminal fractions) were determined. Results All DWI parameters were significantly different between prostate cancer and PZ (P < .012). ADCME, ADCSE, and ADCDKI all showed significant negative correlation with cytoplasmic and cellular fractions (r = -0.546 to -0.435; P < .034) and positive correlation with stromal fractions (r = 0.619-0.669; P < .001). ADCDTI and FA showed correlation only with stromal fraction (r = 0.512 and -0.413, respectively; P < .045). alpha did not correlate with histologic parameters, whereas kurtosis showed significant correlations with histopathologic parameters (r = 0.487, 0.485, -0.422 for cytoplasmic, cellular, and stromal fractions, respectively; P < .040). Conclusion Advanced DWI methods showed significant correlations with histopathologic tissue composition in prostate cancer. These findings should be validated in a larger study. (c) RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on November 10, 2017. PMID- 29117482 TI - Technical Developments: Zero Echo Time Imaging of the Shoulder: Enhanced Osseous Detail by Using MR Imaging. AB - Purpose To determine the intermodality agreement of morphologic grading and clinically relevant quantitative measurements between computed tomography (CT) and zero echo time (ZTE) magnetic resonance (MR) imaging of the shoulder. The primary objective was to demonstrate the clinical applicability of ZTE in osseous shoulder imaging. Materials and Methods Thirty-four patients undergoing standard of-care (SOC) MR imaging with concomitant CT were enrolled in this institutional review board-approved study. ZTE images were acquired after SOC MR imaging. Glenoid morphology (version, vault depth, erosion), injury or disease (osteoarthritis, Bankart and Hill-Sachs lesions, subchondral cysts), and evidence of prior surgery were graded or measured. kappa Values, intraclass correlation coefficients (ICCs), and Bland-Altman limits of agreement were used to establish agreement. Qualitative comparison of osseous findings was performed between ZTE and SOC MR imaging. Results Binary classification and nominal/ordinal grades showed substantial or better agreement between raters and modalities (kappa or ICC > 0.6). Continuous measurements exhibited strong correlation between raters and modalities, although not universally. Bankart ICCs were not significant, owing to low prevalence. ZTE exhibited greater conspicuity of enthesopathic cysts and marrow edema. In 21 of 34 cases, ZTE imaging of osseous features exceeded SOC MR imaging. Conclusion ZTE MR imaging provides "CT-like" contrast for bone. The results of this study demonstrate strong intermodality agreement between measurements and grades from CT and ZTE images in a cohort of patients undergoing imaging with both modalities. A majority of ZTE image sets provided superior visualization of osseous features when compared with SOC MR image sets. This superiority coupled with strong quantitative agreement with CT suggests that ZTE may be used clinically in lieu of CT in some cases. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29117485 TI - Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass. PMID- 29117484 TI - Carotid Intraplaque Hemorrhage Imaging with Quantitative Vessel Wall T1 Mapping: Technical Development and Initial Experience. AB - Purpose To develop a three-dimensional (3D) high-spatial-resolution time efficient sequence for use in quantitative vessel wall T1 mapping. Materials and Methods A previously described sequence, simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) imaging, was extended by introducing 3D golden angle radial k-space sampling (GOAL-SNAP). Sliding window reconstruction was adopted to reconstruct images at different inversion delay times (different T1 contrasts) for voxelwise T1 fitting. Phantom studies were performed to test the accuracy of T1 mapping with GOAL-SNAP against a two-dimensional inversion recovery (IR) spin-echo (SE) sequence. In vivo studies were performed in six healthy volunteers (mean age, 27.8 years +/- 3.0 [standard deviation]; age range, 24-32 years; five male) and five patients with atherosclerosis (mean age, 66.4 years +/- 5.5; range, 60-73 years; five male) to compare T1 measurements between vessel wall sections (five per artery) with and without intraplaque hemorrhage (IPH). Statistical analyses included Pearson correlation coefficient, Bland Altman analysis, and Wilcoxon rank-sum test with data permutation by subject. Results Phantom T1 measurements with GOAL-SNAP and IR SE sequences showed excellent correlation (R2 = 0.99), with a mean bias of -25.8 msec +/- 43.6 and a mean percentage error of 4.3% +/- 2.5. Minimum T1 was significantly different between sections with IPH and those without it (mean, 371 msec +/- 93 vs 944 msec +/- 120; P = .01). Estimated T1 of normal vessel wall and muscle were 1195 msec +/- 136 and 1117 msec +/- 153, respectively. Conclusion High-spatial-resolution (0.8 mm isotropic) time-efficient (5 minutes) vessel wall T1 mapping is achieved by using the GOAL-SNAP sequence. This sequence may yield more quantitative reproducible biomarkers with which to characterize IPH and monitor its progression. (c) RSNA, 2017. PMID- 29117483 TI - A Manganese-based Alternative to Gadolinium: Contrast-enhanced MR Angiography, Excretion, Pharmacokinetics, and Metabolism. AB - Purpose To compare intravascular contrast enhancement produced by the manganese based magnetic resonance (MR) imaging contrast agent manganese-N-picolyl-N,N',N' trans-1,2-cyclohexenediaminetriacetate (Mn-PyC3A) to gadopentetate dimeglumine (Gd-DTPA) and to evaluate the excretion, pharmacokinetics, and metabolism of Mn PyC3A. Materials and Methods Contrast material-enhanced MR angiography was performed in baboons (Papio anubis; n = 4) by using Mn-PyC3A and Gd-DTPA. Dynamic imaging was performed for 60 minutes following Mn-PyC3A injection to monitor distribution and elimination. Serial blood sampling was performed to quantify manganese and gadolinium plasma clearance by using inductively coupled plasma mass spectrometry and to characterize Mn-PyC3A metabolism by using high performance liquid chromatography. Intravascular contrast enhancement in the abdominal aorta and brachiocephalic artery was quantified by measuring contrast to-noise ratios (CNRs) versus muscle at 9 seconds following Mn-PyC3A or Gd-DTPA injection. Plasma pharmacokinetics were modeled with a biexponential function, and data were compared with a paired t test. Results Aorta versus muscle CNR (mean +/- standard deviation) with Mn-PyC3A and Gd-DTPA was 476 +/- 77 and 538 +/ 120, respectively (P = .11). Brachiocephalic artery versus muscle CNR was 524 +/ 55 versus 518 +/- 140, respectively (P = .95). Mn-PyC3A was eliminated via renal and hepatobiliary excretion with similar pharmacokinetics to Gd-DTPA (area under the curve between 0 and 30 minutes, 20.2 +/- 3.1 and 17.0 +/- 2.4, respectively; P = .23). High-performance liquid chromatography revealed no evidence of Mn-PyC3A biotransformation. Conclusion Mn-PyC3A enables contrast-enhanced MR angiography with comparable contrast enhancement to gadolinium-based agents and may overcome concerns regarding gadolinium-associated toxicity and retention. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29117486 TI - Midostaurin in FLT3-Mutated Acute Myeloid Leukemia. PMID- 29117487 TI - Adjuvant Melanoma Therapy - Head-Spinning Progress. PMID- 29117488 TI - Gold Thread Acupuncture for Rheumatoid Arthritis. PMID- 29117489 TI - Case 34-2017. A 76-Year-Old Man with Fever, Weight Loss, and Weakness. PMID- 29117490 TI - Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement. AB - BACKGROUND: In patients undergoing aortic-valve or mitral-valve replacement, either a mechanical or biologic prosthesis is used. Biologic prostheses have been increasingly favored despite limited evidence supporting this practice. METHODS: We compared long-term mortality and rates of reoperation, stroke, and bleeding between inverse-probability-weighted cohorts of patients who underwent primary aortic-valve replacement or mitral-valve replacement with a mechanical or biologic prosthesis in California in the period from 1996 through 2013. Patients were stratified into different age groups on the basis of valve position (aortic vs. mitral valve). RESULTS: From 1996 through 2013, the use of biologic prostheses increased substantially for aortic-valve and mitral-valve replacement, from 11.5% to 51.6% for aortic-valve replacement and from 16.8% to 53.7% for mitral-valve replacement. Among patients who underwent aortic-valve replacement, receipt of a biologic prosthesis was associated with significantly higher 15-year mortality than receipt of a mechanical prosthesis among patients 45 to 54 years of age (30.6% vs. 26.4% at 15 years; hazard ratio, 1.23; 95% confidence interval [CI], 1.02 to 1.48; P=0.03) but not among patients 55 to 64 years of age. Among patients who underwent mitral-valve replacement, receipt of a biologic prosthesis was associated with significantly higher mortality than receipt of a mechanical prosthesis among patients 40 to 49 years of age (44.1% vs. 27.1%; hazard ratio, 1.88; 95% CI, 1.35 to 2.63; P<0.001) and among those 50 to 69 years of age (50.0% vs. 45.3%; hazard ratio, 1.16; 95% CI, 1.04 to 1.30; P=0.01). The incidence of reoperation was significantly higher among recipients of a biologic prosthesis than among recipients of a mechanical prosthesis. Patients who received mechanical valves had a higher cumulative incidence of bleeding and, in some age groups, stroke than did recipients of a biologic prosthesis. CONCLUSIONS: The long-term mortality benefit that was associated with a mechanical prosthesis, as compared with a biologic prosthesis, persisted until 70 years of age among patients undergoing mitral-valve replacement and until 55 years of age among those undergoing aortic-valve replacement. (Funded by the National Institutes of Health and the Agency for Healthcare Research and Quality.). PMID- 29117491 TI - Monogenic Diseases of DNA Repair. PMID- 29117492 TI - Acute Respiratory Distress Syndrome. PMID- 29117493 TI - Levosimendan in Cardiac Surgery. PMID- 29117494 TI - Explaining Sluggish Savings under Accountable Care. PMID- 29117495 TI - Compartment Syndrome. PMID- 29117496 TI - Coronary-Artery Aneurysm in Tocilizumab-Treated Children with Kawasaki's Disease. PMID- 29117497 TI - Paving the Path toward Porcine Organs for Transplantation. PMID- 29117499 TI - Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis. AB - In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and childhood disability. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. While studies show CHORIO contributes to preterm CNS injury and is also a common independent risk factor for brain injury in term infants, the molecular mechanisms mediating inflammation in the placental-fetal-brain axis that result in PBI remain a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been clinically implicated in CHORIO and in mature CNS injury, although their specific role in PBI pathophysiology is poorly defined. Given CXCL1/CXCR2 signaling is essential to neural cell development and neutrophil recruitment, a key pathological hallmark of CHORIO, we hypothesized CHORIO would upregulate CXCL1/CXCR2 expression in the placenta and fetal circulation, concomitant with increased CXCL1/CXCR2 signaling in the developing brain, immune cell activation, neutrophilia, and microstructural PBI. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague Dawley rats to induce CHORIO. Specifically, uterine arteries were occluded for 60min to induce placental transient systemic hypoxia-ischemia (TSHI), followed by intra-amniotic injection of lipopolysaccharide (LPS). Pups were born at E22. Placentae, serum and brain were collected along an extended time course from E19 to postnatal day (P)15 and analyzed using multiplex electrochemiluminescence (MECI), Western blot, qPCR, flow cytometry (FC) and diffusion tensor imaging (DTI). Results demonstrate that compared to sham, CHORIO increases placental CXCL1 and CXCR2 mRNA levels, concomitant with increased CXCR2+ neutrophils. Interestingly, pup serum CXCL1 expression in CHORIO parallels this increase, with sustained elevation through P15. Analyses of CHORIO brains reveal similarly increased CXCL1/CXCR2 expression through P7, together with increased neutrophilia, microgliosis and peripheral macrophages. Similar to the placenta, cerebral neutrophilia was defined by increased CXCR2 surface expression and elevated myeloperoxidase expression (MPO), consistent with immune cell activation. Evaluation of microstructural brain injury at P15 with DTI reveals aberrant microstructural integrity in the callosal and capsular white matter, with reduced fractional anisotropy in superficial and deep layers of overlying cortex. In summary, using an established model of CHORIO that exhibits mature CNS deficits mimicking those of preterm survivors, we show CHORIO induces injury throughout the placental-fetal-brain axis with a CXCL1/CXCR2 inflammatory signature, neutrophilia, and microstructural abnormalities. These data are concomitant with abnormal cerebral CXCL1/CXCR2 expression, and support temporal aberrations in CXCL1/CXCR2 and neutrophil dynamics in the placental-fetal-brain axis following CHORIO. These investigations define novel targets for directed therapies for infants at high risk for PBI. PMID- 29117500 TI - Development and ultrastructure of the rigid dorsal and flexible ventral cuticles of the elytron of the red flour beetle, Tribolium castaneum. AB - Insect exoskeletons are composed of the cuticle, a biomaterial primarily formed from the linear and relatively rigid polysaccharide, chitin, and structural proteins. This extracellular material serves both as a skin and skeleton, protecting insects from environmental stresses and mechanical damage. Despite its rather limited compositional palette, cuticles in different anatomical regions or developmental stages exhibit remarkably diverse physicochemical and mechanical properties because of differences in chemical composition, molecular interactions and morphological architecture of the various layers and sublayers throughout the cuticle including the envelope, epicuticle and procuticle (exocuticle and endocuticle). Even though the ultrastructure of the arthropod cuticle has been studied rather extensively, its temporal developmental pattern, in particular, the synchronous development of the functional layers in different cuticles during a molt, is not well understood. The beetle elytron, which is a highly modified and sclerotized forewing, offers excellent advantages for such a study because it can be easily isolated at precise time points during development. In this study, we describe the morphogenesis of the dorsal and ventral cuticles of the elytron of the red flour beetle, Tribolium castaneum, during the period from the 0 d-old pupa to the 9 d-old adult. The deposition of exocuticle and mesocuticle is substantially different in the two cuticles. The dorsal cuticle is four-fold thicker than the ventral. Unlike the ventral cuticle, the dorsal contains a thicker exocuticle consisting of a large number of horizontal laminae and vertical pore canals with pore canal fibers and rib-like veins and bristles as well as a mesocuticle, lying right above the enodcuticle. The degree of sclerotization appears to be much greater in the dorsal cuticle. All of these differences result in a relatively thick and tanned rigid dorsal cuticle and a much thinner and less pigmented membrane-like ventral cuticle. PMID- 29117501 TI - Mitral Valve-in-Valve/Ring and Other Percutaneous Treatments of Surgical Failures. AB - Re-do mitral valve surgery is associated with high morbidity and mortality. In recent years a variety of percutaneous repair techniques of surgical failures have emerged as safe and effective treatment options for several post-surgical problems including bioprosthetic mitral valve failure, prosthetic regurgitation or stenosis following annuloplasty, and periprosthetic regurgitation. This review will cover the indications, techniques and outcomes of these novel percutaneous therapies. PMID- 29117502 TI - Mitral Valve Repair in Degenerative Mitral Regurgitation: State of the Art. AB - In industrialized countries, the most common etiology of mitral regurgitation (MR) is degenerative mitral valve (MV) disease. The natural history of severe degenerative MR is poor. However, its appropriate and timely correction is associated with a life expectancy similar to that of the normal population. Surgical MV repair is the gold standard treatment. This review will focus on the most recent evidence with a specific emphasis on surgical indications, timing of treatment, contemporary surgical techniques, Heart Teams and Centers of Excellence. PMID- 29117503 TI - Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs. AB - Poorly water-soluble drugs are a significant and ongoing issue for the pharmaceutical industry. An overview of recent developments for the preparation of spray-dried delivery systems is presented. Examples include amorphous solid dispersions, spray dried dispersions, microparticles, nanoparticles, surfactant systems and self-emulsifying drug delivery systems. Several aspects of formulation are considered, such as pre-screening, choosing excipient(s), the effect of polymer structure on performance, formulation optimisation, ternary dispersions, fixed-dose combinations, solvent selection and component miscibility. Process optimisation techniques including nozzle selection are discussed. Comparisons are drawn with other preparation techniques such as hot melt extrusion, freeze drying, milling, electro spinning and film casting. Novel analytical and dissolution techniques for the characterization of amorphous solid dispersions are included. Progress in understanding of amorphous supersaturation or recrystallisation from solution gathered from mechanistic studies is discussed. Aspects of powder flow and compression are considered in a section on downstream processing. Overall, spray drying has a bright future due to its versatility, efficiency and the driving force of poorly soluble drugs. PMID- 29117504 TI - Experimentally designed lyophilized dry emulsion tablets for enhancing the antihyperlipidemic activity of atorvastatin calcium: Preparation, in-vitro evaluation and in-vivo assessment. AB - This article presents the development of lyophilized orally disintegrating tablets prepared with the dry emulsion technique to enhance the in-vitro dissolution and in-vivo performance of the poorly bioavailable drug atorvastatin calcium (ATV). Tablets were fabricated by freeze-drying o/w emulsions of ATV. The Emulsions were prepared using a matrix former solution (alginate or gelatin, 2 or 4%) containing a sugar alcohol (mannitol) and a collapse protectant (glycine) as the water phase and Labrafac(r) as the oil phase in the presence of surfactant (synperonic(r) PE/P 84 or synperonic(r) F108) under proper homogenization. The influence of formulation parameters on friability of the prepared tablets, disintegration time and in-vitro dissolution of the drug from these tablets were investigated. Results showed the significant influence of the matrix former and emulsifier type on the disintegration time. In-vitro dissolution study revealed the enhanced dissolution rate of ATV from the lyophilized dry emulsion tablets (LDET) compared to the plain drug. DSC and XRD studies of the optimized ATV loaded LDET proved the presence of the drug in the amorphous form. SEM images showed the intact, porous and non-collapsible structure of the prepared LDET with complete loss of ATV crystallinity. Administration of ATV-loaded LDET to high fat diet-induced hyperlipidemic rats demonstrated a significant decrease (p<0.05) in the serum and tissue levels of the tested parameters compared to the market product used. The obtained results suggest a promising, easy-to-manufacture and effective dosage form for the treatment of hyperlipidemia. PMID- 29117506 TI - Changes in body mass index and incidence of diabetes: A longitudinal study of Alberta's Tomorrow Project Cohort. AB - Although obesity is a known risk factor for diabetes, the impact of body mass index (BMI) changes over time, especially BMI reduction, on diabetes development is less than clear. The objective of this study is to characterize the association between BMI changes over time and incidence of diabetes in a cohort of adults in Alberta. From 2000 to 2008, Alberta's Tomorrow Project (ATP) enrolled participants aged 35-69 to a population-based prospective cohort study. BMI was calculated from self-reported height and weight; change in BMI (?BMI) was calculated as the difference between baseline and follow-up measurements. Diabetes cases were identified using the Canadian National Diabetes Surveillance System algorithm applied to linked administrative data (2000-2015). Multivariable Cox regression was used to examine the association between ?BMI and incidence of diabetes. In a subset of the ATP cohort (n=19,164), 1168 incident cases of diabetes were identified during 198,853person-years of follow-up. Overall, BMI increase was associated with increased risk and BMI reduction was associated with reduced risk of diabetes. Particularly, compared to minimal BMI change (+/-5%), moderate (5%-10%) reduction in BMI was associated with 34% (95% CI: 12%-51%) reduction in risk of diabetes in participants with obesity; whereas 10% or greater increase in BMI was associated with an increased risk of diabetes of 64% or more in participants with overweight and obesity; in participants with normal and underweight, BMI changes was not apparently associated with risk of diabetes. Public health programs promoting weight loss, even at a moderate extent, would reduce risk of diabetes. PMID- 29117505 TI - Changes in behavior and brain immediate early gene expression in male threespined sticklebacks as they become fathers. AB - Motherhood is a period of intense behavioral and brain activity. However, we know less about the neural and molecular mechanisms associated with the demands of fatherhood. Here, we report the results of two experiments designed to track changes in behavior and brain activation associated with fatherhood in male threespined stickleback fish (Gasterosteus aculeatus), a species in which fathers are the sole providers of parental care. In experiment 1, we tested whether males' behavioral reactions to different social stimuli depends on parental status, i.e. whether they were providing parental care. Parental males visited their nest more in response to social stimuli compared to nonparental males. Rates of courtship behavior were high in non-parental males but low in parental males. In experiment 2, we used a quantitative in situ hybridization method to compare the expression of an immediate early gene (Egr-1) across the breeding cycle - from establishing a territory to caring for offspring. Egr-1 expression peaked when the activities associated with fatherhood were greatest (when they were providing care to fry), and then returned to baseline levels once offspring were independent. The medial dorsal telencephalon (basolateral amygdala), lateral part of dorsal telencephalon (hippocampus) and anterior tuberal nucleus (ventral medial hypothalamus) exhibited high levels of Egr-1 expression during the breeding cycle. These results help to define the neural circuitry associated with fatherhood in fishes, and are consistent with the hypothesis that fatherhood - like motherhood - is a period of intense behavioral and neural activity. PMID- 29117507 TI - Zingerone protects keratinocyte stem cells from UVB-induced damage. AB - The epidermis, the outermost layer of the skin, is a stratified epithelium that protects the body from the external environment. Keratinocyte stem cells (KSCs) are involved in epidermis homeostasis by maintaining epidermal integrity through a process of constant regeneration. Ultraviolet B (UVB) radiation is a major inducer of cellular damage in the epidermis. In this study, we investigated the effects of zingerone (a phenolic compound derived from spices) on UVB-induced cellular damage in KSCs. We found that zingerone significantly inhibited cellular senescence of KSCs in response to UVB irradiation. These effects were confirmed by the senescence-associated beta-galactosidase and comet assays. Zingerone decreased the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in UVB-irradiated KSCs. Moreover, UVB-induced expression of p21, a cell cycle arrest-related gene, was reduced by zingerone treatment, whereas zingerone upregulated the expression of proliferation-related genes such as proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF), in addition to anti-senescence-related genes including telomerase reverse transcriptase (TERT), histone deacetylase 1 (HDAC1), and DNA (cytosine-5) methyltransferase 1 (DNMT1). The UVB-protective effects of zingerone were mediated by inhibition of p42/44 MAPK and p38 MAPK. Therefore, zingerone could potentially be used to protect the epidermis from UVB-induced damage. PMID- 29117508 TI - Oral pathogenesis of Aggregatibacter actinomycetemcomitans. AB - Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is a Gram negative, facultative anaerobic bacillus that causes periodontal diseases such as localized aggressive periodontitis (LAP) and. consequently. bone resorption. The potential virulence factors of this organism are powerful leukotoxin, lipopolysaccharide (LPS), cell surface-associated materials, enzymes, and less well-defined virulence factors that will modulate the activity of the host defenses. This organism can induce bone resorption by various virulence factors in periodontal disease. In this review article, we reviewed the pathogenic roles of A. actinomycetemcomitans in periodontal disease and the mechanism which can induce bone resorption. Findings from several studies indicate that the interaction between virulence factors and the host immune system's response often progress bone resorption in periodontal disease. In this organism, GroEL, DnaK, HtpG, LTX, CDT, LPS, and cell surface-associated materials produce cytokines when exposed to the immune system. The produced cytokines are the main cause of tissue destruction and bone resorption in A. actinomycetemcomitans inflammation in periodontal disease. PMID- 29117509 TI - Heart rate variability mediates the link between rumination and depressive symptoms: A longitudinal study. AB - Ruminative thinking about negative feelings has been prospectively associated with increases in depressive symptoms and heightened risk for new onsets of major depression. One putative pathophysiological mechanism underlying this link might be represented by autonomic nervous system dysfunction. The objective of this longitudinal study was to evaluate the interplay between rumination, autonomic function (as revealed by heart rate variability (HRV) analysis), and depressive symptoms in healthy young subjects, over a three-year period. Rumination and depressive symptoms were evaluated in twenty-two women and twenty men at three assessment points (Time 0, 1 and 2) by the score on the Ruminative Response Scale, and the Center for Epidemiological Studies Depression Scale, respectively. Vagally-mediated HRV was assessed in a laboratory session (Time 0) and in two ambulatory sessions at Time 1 and Time 2 (~13 and 34months after Time 0, respectively). Ruminative thinking was found to be (i) a stable trait characteristic, (ii) more prevalent in women than men, and (iii) positively correlated with depressive symptoms. Moreover, resting HRV was negatively correlated with both rumination and depressive symptoms. Finally, HRV at Time 1 mediated the relationship between rumination at Time 0 and depressive symptoms at Time 2. We conclude that autonomic dysfunction, specifically low vagal tone, may be prospectively implicated in the generation of depressive symptoms in a non clinical setting. PMID- 29117510 TI - MEMS devices for drug delivery. AB - Novel drug delivery systems based on microtechnology have advanced tremendously, but yet face some technological and societal hurdles to fully achieve their potential. The novel drug delivery systems aim to deliver drugs in a spatiotemporal- and dosage-controlled manner with a goal to address the unmet medical needs from oral delivery and hypodermic injection. The unmet needs include effective delivery of new types of drug candidates that are otherwise insoluble and unstable, targeted delivery to areas protected by barriers (e.g. brain and posterior eye segment), localized delivery of potent drugs, and improved patient compliance. After scrutinizing the design considerations and challenges associated with delivery to areas that cannot be efficiently targeted through standard drug delivery (e.g. brain, posterior eye segment, and gastrointestinal tract), this review provides a summary of recent advances that addressed these challenges and summarizes yet unresolved problems in each target area. The opportunities for innovation in devising the novel drug delivery systems are still high; with integration of advanced microtechnology, advanced fabrication of biomaterials, and biotechnology, the novel drug delivery is poised to be a promising alternative to the oral administration and hypodermic injection for a large spectrum of drug candidates. PMID- 29117511 TI - The role of mucus as an invisible cloak to transepithelial drug delivery by nanoparticles. AB - Mucosal administration of drugs and drug delivery systems has gained increasing interest. However, nanoparticles intended to protect and deliver drugs to epithelial surfaces require transport through the surface-lining mucus. Translation from bench to bedside is particularly challenging for mucosal administration since a variety of parameters will influence the specific barrier properties of the mucus including the luminal fluids, the microbiota, the mucus composition and clearance rate, and the condition of the underlying epithelia. Besides, after administration, nanoparticles interact with the mucosal components, forming a biomolecular corona that modulates their behavior and fate after mucosal administration. These interactions are greatly influenced by the nanoparticle properties, and therefore different designs and surface-engineering strategies have been proposed. Overall, it is essential to evaluate these biomolecule-nanoparticle interactions by complementary techniques using complex and relevant mucus barrier matrices. PMID- 29117512 TI - Mucus models to evaluate the diffusion of drugs and particles. AB - Mucus is a complex hydrogel that acts as a natural barrier to drug delivery at different mucosal surfaces including the respiratory, gastrointestinal, and vaginal tracts. To elucidate the role mucus plays in drug delivery, different in vitro, in vivo, and ex vivo mucus models and techniques have been utilized. Drug and drug carrier diffusion can be studied using various techniques in either isolated mucus gels or mucus present on cell cultures and tissues. The species, age, and potential disease state of the animal from which mucus is derived can all impact mucus composition and structure, and therefore impact drug and drug carrier diffusion. This review provides an overview of the techniques used to characterize drug and drug carrier diffusion, and discusses the advantages and disadvantages of the different models available to highlight the information they can afford. PMID- 29117513 TI - Mechanisms of dietary flavonoid action in neuronal function and neuroinflammation. AB - Flavonoids are a class of plant-derived dietary polyphenols that have attracted attention for their pro-cognitive and anti-inflammatory effects. The diversity of flavonoids and their extensive in vivo metabolism suggest that a variety of cellular targets in the brain are likely to be impacted by flavonoid consumption. Initially characterized as antioxidants, flavonoids are now believed to act directly on neurons and glia via the interaction with major signal transduction cascades, as well as indirectly via interaction with the blood-brain barrier and cerebral vasculature. This review discusses potential mechanisms of flavonoid action in the brain, with a focus on two critical transcription factors: cAMP response element-binding protein (CREB) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB). To advance beyond current understanding of cellular targets, critical bioavailability studies need to be performed to verify the identity and concentration of flavonoid metabolites reaching the brain after ingestion and to validate that these metabolites are produced not just in rodent models but also in humans. Recent advances in human induced pluripotent stem cell (iPSC) differentiation protocols to generate human neuronal and glial cell types could also provide a unique tool for clinically relevant in vitro investigation of the mechanisms of action of bioavailable flavonoid metabolites in humans. PMID- 29117514 TI - Investigating cascade impactor performance using a modified 3D printed induction port. AB - Based on a computer tomographic scan of a human trachea, a modified induction port (mIP), for use with the Next Generation Cascade Impactor, was manufactured using 3D printing technology. Standard United States Pharmacopoeia IP (USPIP) was compared to the mIP and a 3D printed version of the USPIP (USP3DIP) by analyzing different types of commercial salbutamol formulations for inhalation. Increased retention of particles in the mIP was found analyzing a pMDI formulation, leading to a decrease in the FPF from 28.8+/-2.0% to 14.2+/-1.2%, which correlates better to in vivo deposition data from literature. Increased deposition was found to be based on geometrical factors only. The impact of surface related effects was investigated by (a) comparing results obtained with the USPIP and USP3DIP (all formulations) and (b) generating another model IP (USP3DSEIP) with a surface area equivalent to the mIP but maintaining the geometry of the USPIP (pMDI only). USPIP, USP3DIP, and USP3DSEIP were found to perform equivalently. The impact of different geometries on airflow velocities in the USPIP and mIP was assessed using a computational fluid dynamics (CFD) model. Conclusively, this study shows that replacing the USP IP by the mIP can provide additional information in formulation assessment and in in vitro/in vivo correlation, when applied on pMDI formulations. PMID- 29117515 TI - Metformin and epothilone A treatment up regulate pro-apoptotic PARP-1, Casp-3 and H2AX genes and decrease of AKT kinase level to control cell death of human hepatocellular carcinoma and ovary adenocarcinoma cells. AB - High mortality rates in ovarian and liver cancer are largely a result of resistance to currently used chemotherapy. Here, we investigated genotoxic and pro-oxidant effects of metformin (MET) and epothilone A (A) in combination with respect to apoptosis in HepG2 and SKOV-3 cancer cells. Reactive oxygen species (ROS) was studied using 2',7'-dichlorodihydrofluoresein diacetate, and samples were analyzed for the presence and absence of the N-acetylcysteine (NAC). Expression of genes involved in programmed cell death, oxidative and alkylating DNA damage was measured. Probes were analyzed in the presence of Akt or nuclear factor-kappaB inhibitor. Compared to either drug alone, combination of epothilone A and metformin was more potent; decreased Akt level; and elevated percentage of apoptotic cells, induced cell cycle arrest at G1 phase and elevated the sub-G1 cell population by increasing the mRNA level of caspase-3, poly (ADP-ribose) polymerase-1 and H2AX. The anticancer effect of the drug combination was partially reversed by NAC supplementation, suggesting that ROS generation is required to induce apoptosis. The present study demonstrates that novel combination such as epothilone A and MET show promise in expanding ovarian and liver cancer therapy. PMID- 29117498 TI - 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. AB - BACKGROUND: The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. METHODS: In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan-Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients' outcomes during the period from 5 to 20 years. RESULTS: Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1-3), and 34% with four to nine nodes involved (T1N4-9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1-3, and 41% with T2N4-9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. CONCLUSIONS: After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.). PMID- 29117516 TI - Resolution Optimization Based on Fluorophore Photophysics in Single-Molecule Localization Microscopy. PMID- 29117517 TI - Role of Disulfide Bonds on DNA Packaging Forces in Bull Sperm Chromatin. AB - Short arginine-rich proteins called protamines mediate the near crystalline DNA packaging in most vertebrate sperm cells. Protamines are synthesized during spermiogenesis and condense the paternal genome into a transcriptionally inactive state in late-stage spermatids. Protamines from eutherian mammals, including bulls and humans, also contain multiple cysteine residues that form intra- and interprotamine sulfur-sulfur bonds during the final stages of sperm maturation. Although the cross-linked protamine network is known to stabilize the resulting nucleoprotamine structure, little is known about the role of disulfide bonds on DNA condensation in the mammalian sperm. Using small angle x-ray scattering, we show that isolated bull nuclei achieve slightly lower DNA packing densities compared to salmon nuclei despite salmon protamine lacking cysteine residues. Surprisingly, reduction of the intermolecular sulfur-sulfur bonds of bull protamine results in tighter DNA packing. Complete reduction of the intraprotamine disulfide bonds ultimately leads to decondensation, suggesting that disulfide-mediated secondary structure is also critical for proper protamine function. Lastly, comparison of multiple bull collections showed some to have aberrant x-ray scattering profiles consistent with incorrect disulfide bond formation. Together, these observations shed light on the biological functions of disulfide linkages for in vivo DNA packaging in sperm chromatin. PMID- 29117518 TI - Protein Sequence and Membrane Lipid Roles in the Activation Kinetics of Bovine and Human Rhodopsins. AB - Rhodopsin is a G protein-coupled receptor found in the rod outer segments in the retina, which triggers a visual response under dim light conditions. Recently, a study of the late, microsecond-to-millisecond kinetics of photointermediates of the human and bovine rhodopsins in their native membranes revealed a complex, double-square mechanism of rhodopsin activation. In this kinetic scheme, the human rhodopsin exhibited more Schiff base deprotonation than bovine rhodopsin, which could arise from the ~7% sequence difference between the two proteins, or from the difference between their membrane lipid environments. To differentiate between the effects of membrane and protein structure on the kinetics, the human and bovine rhodopsins were inserted into 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine lipid nanodiscs and the kinetics of activation at 15 degrees C and pH 8.7 was investigated by time-resolved absorption spectroscopy and global kinetic analysis. For both proteins, the kinetics in nanodiscs shows the characteristics observed in the native membranes, and is described by a multisquare model with Schiff base deprotonation at the lumirhodopsin I intermediate stage. The results indicate that the protein sequence controls the extent of Schiff base deprotonation and accumulation of intermediates, and thus plays the main role in the different activation kinetics observed between human and bovine rhodopsins. The membrane lipid does have a minor role by modulating the timing of the kinetics, with the nanodisc environment leading to an earlier Schiff base deprotonation. PMID- 29117519 TI - High Tensile Strength of Engineered beta-Solenoid Fibrils via Sonication and Pulling. AB - We present estimates of ultimate tensile strength (UTS) for two engineered beta solenoid protein mutant fibril structures (spruce budworm and Rhagium inquisitor antifreeze proteins) derived from sonication-based measurements and from force pulling molecular dynamics simulations, both in water. Sonication experiments generate limiting scissioned fibrils with a well-defined length-to-width correlation for the mutant spruce budworm protein and the resultant UTS estimate is 0.66 +/- 0.08 GPa. For fibrils formed from engineered R. inquisitor antifreeze protein, depending upon geometry, we estimate UTSs of 3.5 +/- 3.2-5.5 +/- 5.1 GPa for proteins with interfacial disulfide bonds, and 1.6 +/- 1.5-2.5 +/- 2.3 GPa for the reduced form. The large error bars for the R. inquisitor structures are intrinsic to the broad distribution of limiting scission lengths. Simulations provide pulling velocity-dependent UTSs increasing from 0.2 to 1 GPa in the available speed range, and 1.5 GPa extrapolated to the speeds expected in the sonication experiments. Simulations yield low-velocity values for the Young's modulus of 6.0 GPa. Without protein optimization, these mechanical parameters are similar to those of spider silk and Kevlar, but in contrast to spider silk, these proteins have a precisely known sequence-structure relationship. PMID- 29117520 TI - Phosphorylated Calmodulin Promotes PI3K Activation by Binding to the SH2 Domains. AB - How calmodulin (CaM) acts in KRAS-driven cancers is a vastly important question. CaM binds to and stimulates PI3Kalpha/Akt signaling, promoting cell growth and proliferation. Phosphorylation of CaM at Tyr99 (pY99) enhances PI3Kalpha activation. PI3Kalpha is a lipid kinase. It phosphorylates PIP2 to produce PIP3, to which Akt binds. PI3Kalpha has two subunits: the regulatory p85 and the catalytic p110. Here, exploiting explicit-solvent MD simulations we unveil key interactions between phosphorylated CaM (pCaM) and the two SH2 domains in the p85 subunit, confirm experimental observations, and uncover PI3Kalpha's mechanism of activation. pCaMs form strong and stable interactions with both nSH2 and cSH2 domains, with pY99 being the dominant contributor. Despite the high structural similarity between the two SH2 domains, we observe that nSH2 prefers an extended CaM conformation, whereas cSH2 prefers a collapsed conformation. Notably, collapsed CaM is observed after binding of an extended CaM to K-Ras4B. Thus, the more populated extended pCaM conformation targets nSH2 to release its autoinhibition of p110 catalytic sites. This executes the key activation step of PI3Kalpha. Independently, K-Ras4B allosterically activates p110. These events are at the cell membrane, which contributes to tighten the PI3Kalpha Ras binding domain/K-Ras4B interaction, to accomplish K-Ras4B allosteric activation, with a minor contribution from cSH2. PMID- 29117521 TI - Sparse Labeling PELDOR Spectroscopy on Multimeric Mechanosensitive Membrane Channels. AB - Pulse electron paramagnetic resonance (EPR) is being applied to ever more complex biological systems comprising multiple subunits. Membrane channel proteins are of great interest as pulse EPR reports on functionally significant but distinct conformational states in a native environment without the need for crystallization. Pulse EPR, in the form of pulsed electron-electron double resonance (PELDOR), using site-directed spin labeling, is most commonly employed to accurately determine distances (in the nanometer range) between different regions of the structure. However, PELDOR data analysis is more challenging in systems containing more than two spins (e.g., homomultimers) due to distorting multispin effects. Without suppression of these effects, much of the information contained in PELDOR data cannot be reliably retrieved. Thus, it is of utmost importance for future PELDOR applications in structural biology to develop suitable approaches that can overcome the multispin problem. Here, two different approaches for suppressing multispin effects in PELDOR, sparse labeling of the protein (reducing the labeling efficiency f) and reducing the excitation probability of spins (lambda), are compared on two distinct bacterial mechanosensitive channels. For both the pentameric channel of large conductance (MscL) and the heptameric channel of small conductance (MscS) of Escherichia coli, mutants containing a spin label in the cytosolic or the transmembrane region were tested. Data demonstrate that distance distributions can be significantly improved with either approach compared to the standard PELDOR measurement, and confirm that lambda < 1/(n-1) is needed to sufficiently suppress multispin effects (with n being the number of spins in the system). A clear advantage of the sparse labeling approach is demonstrated for the cytosolic mutants due to a significantly smaller loss in sensitivity. For the transmembrane mutants, this advantage is less pronounced but still useful for MscS, but performance is inferior for MscL possibly due to structural perturbations by the bulkier diamagnetic spin label analog. PMID- 29117522 TI - The Fast Component of hERG Gating Charge: An Interaction between D411 in the S1 and S4 Residues. AB - Kv11.1 (hERG) is a voltage-gated potassium channel that shows very slow ionic current activation kinetics, and an unusual underlying biphasic gating charge movement with fast and slow components that differ greatly in time course. The structural basis and role of the fast component of gating charge (Qfast) is unclear, and its relationship to the slow activation of hERG channels is not understood. In this study we have used the cut-open oocyte voltage-clamp technique to investigate the relationship of fast gating charge movement-to residue interactions between D411 at the bottom of the S1, and lower S4 domain charged and uncharged residues. Neutralization of D411 or K538 and V535A prevented Qfast and greatly accelerated overall charge movement. Voltage-clamp fluorometry showed a loss of a fast component of S4 fluorescence in D411N, V535A, and K538Q upon depolarization, whereas [2-(trimethyl ammonium) ethyl] methanethiosulfonate chloride modification of I521C in the outer S4 was enhanced at more negative potentials and at earlier times in these same mutants. A functional interaction between these regions during activation was suggested by DeltaDeltaGo values >4.2 kJ/mol obtained from double mutant cycle analysis. The data indicate that interactions of S1 residue D411 with lower S4 residues stabilizes early closed states of the channel, and that disruption of these interactions results in both faster rates of activation gating and an elimination of the fast component of gating charge movement and of fluorescence. We propose that the Qfast charge movement during activation accompanies transitions through early closed states of the hERG activation pathway, and that the weak voltage dependence of these transitions limits the overall activation rate of hERG channels. Disruption of the D411-S4 interactions destabilizes these early closed states, leaving hERG channels able to activate at a rate similar to conventional potassium channels. PMID- 29117523 TI - FRET Analysis of the Promiscuous yet Specific Interactions of the HIV-1 Vpu Transmembrane Domain. AB - The Vpu protein of HIV-1 functions to downregulate cell surface localization of host proteins involved in the innate immune response to viral infection. For several target proteins, including the NTB-A and PVR receptors and the host restriction factor tetherin, this antagonism is carried out via direct interactions between the transmembrane domains (TMDs) of Vpu and the target. The Vpu TMD also modulates homooligomerization of this protein, and the tetherin TMD forms homodimers. The mechanism through which a single transmembrane helix is able to recognize and interact with a wide range of select targets that do not share known interaction motifs is poorly understood. Here we use Forster resonance energy transfer to characterize the energetics of homo- and heterooligomer interactions between the Vpu TMD and several target proteins. Our data show that target TMDs compete for interaction with Vpu, and that formation of each heterooligomer has a similar dissociation constant (Kd) and free energy of association to the Vpu homooligomer. This leads to a model in which Vpu monomers, Vpu homooligomers, and Vpu-target heterooligomers coexist, and suggests that the conserved binding surface of Vpu TMD has been selected for weak binding to multiple targets. PMID- 29117525 TI - Membrane Cholesterol Reduces Polymyxin B Nephrotoxicity in Renal Membrane Analogs. AB - Polymyxin B (PmB) is a "last-line" antibiotic scarcely used due to its nephrotoxicity. However, the molecular basis for antibiotic nephrotoxicity is not clearly understood. We prepared kidney membrane analogs of detergent-susceptible membranes, depleted of cholesterol, and cholesterol enriched, resistant membranes. In both analogs, PmB led to membrane damage. By combining x-ray diffraction, molecular dynamics simulations, and electrochemistry, we present evidence for two populations of PmB molecules: peptides that lie flat on the membranes, and an inserted state. In cholesterol depleted membranes, PmB forms clusters on the membranes leading to an indentation of the bilayers and increase in water permeation. The inserted peptides formed aggregates in the membrane core leading to further structural instabilities and increased water intake. The presence of cholesterol in the resistant membrane analogs led to a significant decrease in membrane damage. Although cholesterol did not inhibit peptide insertion, it minimized peptide clustering and water intake through stabilization of the bilayer structure and suppression of lipid and peptide mobility. PMID- 29117524 TI - Cholesterol Promotes Protein Binding by Affecting Membrane Electrostatics and Solvation Properties. AB - Binding of the retroviral structural protein Gag to the cellular plasma membrane is mediated by the protein's matrix (MA) domain. Prominent among MA-PM interactions is electrostatic attraction between the positively charged MA domain and the negatively charged plasma membrane inner leaflet. Previously, we reported that membrane association of HIV-1 Gag, as well as purified Rous sarcoma virus (RSV) MA and Gag, depends strongly on the presence of acidic lipids and is enhanced by cholesterol (Chol). The mechanism underlying this enhancement was unclear. Here, using a broad set of in vitro and in silico techniques we addressed molecular mechanisms of association between RSV MA and model membranes, and investigated how Chol enhances this association. In neutron scattering experiments with liposomes in the presence or absence of Chol, MA preferentially interacted with preexisting POPS-rich clusters formed by nonideal lipid mixing, binding peripherally to the lipid headgroups with minimal perturbation to the bilayer structure. Molecular dynamics simulations showed a stronger MA-bilayer interaction in the presence of Chol, and a large Chol-driven increase in lipid packing and membrane surface charge density. Although in vitro MA-liposome association is influenced by disparate variables, including ionic strength and concentrations of Chol and charged lipids, continuum electrostatic theory revealed an underlying dependence on membrane surface potential. Together, these results conclusively show that Chol affects RSV MA-membrane association by making the electrostatic potential at the membrane surface more negative, while decreasing the penalty for lipid headgroup desolvation. The presented approach can be applied to other viral and nonviral proteins. PMID- 29117526 TI - Lysenin Toxin Membrane Insertion Is pH-Dependent but Independent of Neighboring Lysenins. AB - Pore-forming toxins form a family of proteins that act as virulence factors of pathogenic bacteria, but similar proteins are found in all kingdoms of life, including the vertebrate immune system. They are secreted as soluble monomers that oligomerize on target membranes in the so-called prepore state; after activation, they insert into the membrane and adopt the pore state. Lysenin is a pore-forming toxin from the earthworm Eisenida foetida, of which both the soluble and membrane-inserted structures are solved. However, the activation and membrane insertion mechanisms have remained elusive. Here, we used high-speed atomic force microscopy to directly visualize the membrane-insertion mechanism. Changing the environmental pH from pH 7.5 to below pH 6.0 favored membrane insertion. We detected a short alpha-helix in the soluble structure that comprised three glutamic acids (Glu92, Glu94, and Glu97) that we hypothesized may represent a pH sensor (as in similar toxins, e.g., Listeriolysin). Mutant lysenin still can form pores, but mutating these glutamic acids to glutamines rendered the toxin pH insensitive. On the other hand, toxins in the pore state did not favor insertion of neighboring prepores; indeed, pore insertion breaks the hexagonal ordered domains of prepores and separates from neighboring molecules in the membrane. pH dependent activation of toxins may represent a common feature of pore-forming toxins. High-speed atomic force microscopy with single-molecule resolution at high temporal resolution and the possibility of exchanging buffers during the experiments presents itself as a unique tool for the study of toxin-state conversion. PMID- 29117527 TI - The Role of Probe Photophysics in Localization-Based Superresolution Microscopy. AB - Fluorescent proteins are used extensively for biological imaging applications; photoactivatable and photoconvertible fluorescent proteins (PAFPs) are used widely in superresolution localization microscopy methods such as fluorescence photoactivation localization microscopy and photoactivated localization microscopy. However, their optimal use depends on knowledge of not only their bulk fluorescence properties, but also their photophysical properties at the single molecule level. We have used fluorescence correlation spectroscopy and cross-correlation spectroscopy to quantify the diffusion, photobleaching, fluorescence intermittency, and photoconversion dynamics of Dendra2, a well-known PAFP used in localization microscopy. Numerous dark states of Dendra2 are observed both in inactive (green fluorescent) and active (orange fluorescent) forms; the interconversion rates are both light- and pH-dependent, as observed for other PAFPs. The dark states limit the detected count rate per molecule, which is a crucial parameter for localization microscopy. We then developed, to our knowledge, a new mathematical estimate for the resolution in localization microscopy as a function of the measured photophysical parameters of the probe such as photobleaching quantum yield, count rate per molecule, and intensity of saturation. The model was used to predict the dependence of resolution on acquisition parameters such as illumination intensity and time per frame, demonstrating an optimal set of acquisition parameters for a given probe for a variety of measures of resolution. The best possible resolution was then compared for Dendra2 and other widely used probes, including Alexa dyes and quantum dots. This work establishes a framework for determination of the best possible resolution using a localization microscope to image a particular fluorophore, and suggests that development of probes for use in superresolution localization microscopy must consider the count rate per molecule, the saturation intensity, the photobleaching yield, and, crucially, management of bright/dark state transitions, to optimize image resolution. PMID- 29117528 TI - Ensembles of Bidirectional Kinesin Cin8 Produce Additive Forces in Both Directions of Movement. AB - Most kinesin motors move in only one direction along microtubules. Members of the kinesin-5 subfamily were initially described as unidirectional plus-end-directed motors and shown to produce piconewton forces. However, some fungal kinesin-5 motors are bidirectional. The force production of a bidirectional kinesin-5 has not yet been measured. Therefore, it remains unknown whether the mechanism of the unconventional minus-end-directed motility differs fundamentally from that of plus-end-directed stepping. Using force spectroscopy, we have measured here the forces that ensembles of purified budding yeast kinesin-5 Cin8 produce in microtubule gliding assays in both plus- and minus-end direction. Correlation analysis of pause forces demonstrated that individual Cin8 molecules produce additive forces in both directions of movement. In ensembles, Cin8 motors were able to produce single-motor forces up to a magnitude of ~1.5 pN. Hence, these properties appear to be conserved within the kinesin-5 subfamily. Force production was largely independent of the directionality of movement, indicating similarities between the motility mechanisms for both directions. These results provide constraints for the development of models for the bidirectional motility mechanism of fission yeast kinesin-5 and provide insight into the function of this mitotic motor. PMID- 29117529 TI - Arabidopsis Leaf Trichomes as Acoustic Antennae. AB - The much studied plant Arabidopsis thaliana has been reported recently to react to the sounds of caterpillars of Pieris rapae chewing on its leaves by promoting synthesis of toxins that can deter herbivory. Identifying participating receptor cells-potential "ears"-of Arabidopsis is critical to understanding and harnessing this response. Motivated in part by other recent observations that Arabidopsis trichomes (hair cells) respond to mechanical stimuli such as pressing or brushing by initiating potential signaling factors in themselves and in the neighboring skirt of cells, we analyzed the vibrational responses of Arabidopsis trichomes to test the hypothesis that trichomes can respond acoustically to vibrations associated with feeding caterpillars. We found that these trichomes have vibrational modes in the frequency range of the sounds of feeding caterpillars, encouraging further experimentation to determine whether trichomes serve as mechanical antennae. PMID- 29117530 TI - Cytoplasmic Flow and Mixing Due to Deformation of Motile Cells. AB - The cytoplasm of a living cell is a dynamic environment through which intracellular components must move and mix. In motile, rapidly deforming cells such as human neutrophils, bulk cytoplasmic flow couples cell deformation to the transport and dispersion of cytoplasmic particles. Using particle-tracking measurements in live neutrophil-like cells, we demonstrate that fluid flow associated with the cell deformation contributes to the motion of small acidic organelles, dominating over diffusion on timescales above a few seconds. We then use a general physical model of particle dispersion in a deforming fluid domain to show that transport of organelle-sized particles between the cell periphery and the bulk can be enhanced by dynamic deformation comparable to that observed in neutrophils. Our results implicate an important mechanism contributing to organelle transport in these motile cells: cytoplasmic flow driven by cell shape deformation. PMID- 29117531 TI - Charge Influences Substrate Recognition and Self-Assembly of Hydrophobic FG Sequences. AB - The nuclear pore complex controls the passage of molecules via hydrophobic phenylalanine-glycine (FG) domains on nucleoporins. Such FG domains consist of repeating units of FxFG, FG, or GLFG sequences, many of which are interspersed with highly charged amino acid sequences. Despite the high density of charge in certain FG domains, if and how charge influences FG-domain self-assembly and selective binding of nuclear transport receptors is largely unexplored. Using rationally designed short peptide sequences, we determined that the charge type and identity of amino acids surrounding FG sequences impact the structure and selectivity of FG-based gels. Moreover, we showed that spatial localization of the charged amino acids with respect to the FG sequence determines the degree to which charge influences hydrophobic interactions. Taken together, our study highlights that charge type and placement of amino acids regulate FG-sequence function and are important considerations when studying the mechanism of nuclear pore complex transport in vivo. PMID- 29117532 TI - Structure, Mechanics, and Instability of Fibrin Clot Infected with Staphylococcus epidermidis. AB - Health care-associated infection, over half of which can be attributed to indwelling medical devices, is a strong risk factor for thromboembolism. Although most experimental models of medical device infection draw upon isolated bacterial biofilms, in fact there is no infection without host protein contribution. Here we study, to our knowledge, a new model for medical device infection-that of an infected fibrin clot-and show that the common blood-borne pathogen Staphylococcus epidermidis influences this in vitro model of a blood clot mechanically and structurally on both microscopic and macroscopic scales. Bacteria present during clot formation produce a visibly disorganized microstructure that increases clot stiffness and triggers mechanical instability over time. Our results provide insight into the observed correlation between medical device infection and thromboembolism; the increase in model clot heterogeneity shows that S. epidermidis can rupture a fibrin clot. The resultant embolization of the infected clot can contribute to the systemic dissemination of the pathogen. PMID- 29117533 TI - Late-Arriving Signals Contribute Less to Cell-Fate Decisions. AB - Gene regulatory networks are largely responsible for cellular decision-making. These networks sense diverse external signals and respond by adjusting gene expression, enabling cells to reach environment-dependent decisions crucial for their survival or reproduction. However, information-carrying signals may arrive at variable times. Besides the intrinsic strength of these signals, their arrival time (timing) may also carry information about the environment and can influence cellular decision-making in ways that are poorly understood. For example, it is unclear how the timing of individual phage infections affects the lysis-lysogeny decision of bacteriophage lambda despite variable infection times being likely in the wild and even in laboratory conditions. In this work, we combine mathematical modeling with experimentation to address this question. We develop an experimentally testable theory, which reveals that late-infecting phages contribute less to cellular decision-making. This implies that infection delays lower the probability of lysogeny compared to simultaneous infections. Furthermore, we show that infection delays reduce lysogenization by providing insufficient CII for threshold crossing during the critical decision-making period. We find evidence for a cutoff time after which subsequent infections cannot influence the cellular decision. We derive an intuitive formula that approximates the probability of lysogeny for variable infection times by a time weighted average of probabilities for simultaneous infections. We validate these theoretical predictions experimentally. Similar concepts and simplifying modeling approaches may help elucidate the mechanisms underlying other cellular decisions. PMID- 29117535 TI - Rescuing infusion of miRNA-1 prevents cardiac remodeling in a heart-selective miRNA deficient mouse. AB - OBJECTIVE: The decreased expression of muscle-specific microRNA-1 (miR-1) has been found in many cardiovascular diseases and is considered to contribute to heart failure (HF). Here we investigated the role of miR-1 in myocardium protection by infusion of miR-1 in a cardiac global miRNA-deficient mouse. METHODS: We generated a cardiac-selective miRNA-deficient mouse by crossing Dicerflox/flox mice with mice expressing tamoxifen-inducible Cre recombinase under the control of a mouse alphaMHC promoter. When Dicer gene was removed following tamoxifen injection, the mice were treated with micrONTM mmu-miR-1a-3p agomir (agomir-1). The mice were subjected to echocardiography measurement, and the heart tissue specimens were stained with hematoxylin and eosin (H&E) and Sirius red. Terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling assay and Ki67 immunofluorescence were used to determine apoptosis and proliferation. RESULTS: Dicer deletion resulted in extensive decrease in cardiac miRNAs in the mice. In echocardiography, the mice developed rapid and dramatic left ventricular enlargement. In histology, apparent cardiomyocyte hypertrophy, myofiber disarray, ventricular fibrosis, inflammatory infiltration, and severe ventricular remodeling were exhibited. When the mice were treated with agomir-1, they did not show any significant abnormalities in heart structure and histology in response to Dicer ablation. CONCLUSION: The proper expression of miRNAs plays vital roles in the maintenance of heart histology and function. Among these miRNAs, miR-1 is critical to inhibit myocyte hypertrophy and extracellular matrix deposition, thereby preventing cardiac remodeling in cardiac-selective Dicer deficient mice. PMID- 29117536 TI - Long noncoding RNA FTX regulates cardiomyocyte apoptosis by targeting miR-29b-1 5p and Bcl2l2. AB - Cardiomyocyte apoptosis correlates with the pathogenesis of heart disease. Long noncoding RNA (LncRNA) emerges as a class of noncoding RNAs that regulate gene expression and participate in various cellular processes. However, the role of lncRNAs in cardiomyocyte apoptosis remains to be elucidated. In our study, we found that lncRNA FTX is significantly down-regulated upon ischemia/reperfusion injury and hydrogen peroxide treatment. Enhanced expression of FTX inhibits cardiomyocyte apoptosis induced by hydrogen peroxide. miR-29b-1-5p was found to interact with FTX and regulate the expression of Bcl2l2. Inhibition of miR-29b-1 5p attenuated cardiomyocyte apoptosis upon hydrogen peroxide treatment. We then found that FTX functions as endogenous sponge for miR-29b-1-5p and regulates the activity of miR-29b-1-5p. The results demonstrate that FTX regulates cardiomyocyte apoptosis through modulating the expression of Bcl2l2 which is mediated by miR-29b-1-5p. Our findings reveal a novel regulatory model which is composed of FTX, miR-29b-1-5p and Bcl2l2. Manipulating of their levels may become a new approach to tackling cardiomyocyte apoptosis related heart diseases. PMID- 29117534 TI - Building Predictive Models of Genetic Circuits Using the Principle of Maximum Caliber. AB - Learning the underlying details of a gene network is a major challenge in cellular and synthetic biology. We address this challenge by building a chemical kinetic model that utilizes information encoded in the stochastic protein expression trajectories typically measured in experiments. The applicability of the proposed method is demonstrated in an auto-activating genetic circuit, a common motif in natural and synthetic gene networks. Our approach is based on the principle of maximum caliber (MaxCal)-a dynamical analog of the principle of maximum entropy-and builds a minimal model using only three constraints: 1) protein synthesis, 2) protein degradation, and 3) positive feedback. The MaxCal generated model (described with four parameters) was benchmarked against synthetic data generated using a Gillespie algorithm on a known reaction network (with seven parameters). MaxCal accurately predicts underlying rate parameters of protein synthesis and degradation as well as experimental observables such as protein number and dwell-time distributions. Furthermore, MaxCal yields an effective feedback parameter that can be useful for circuit design. We also extend our methodology and demonstrate how to analyze trajectories that are not in protein numbers but in arbitrary fluorescence units, a more typical condition in experiments. This "top-down" methodology based on minimal information-in contrast to traditional "bottom-up" approaches that require ad hoc knowledge of circuit details-provides a powerful tool to accurately infer underlying details of feedback circuits that are not otherwise visible in experiments and to help guide circuit design. PMID- 29117537 TI - Antioxidant effects of epigallocatechin-3-gallate on the aTC1-6 pancreatic alpha cell line. AB - Hypoglycemia is a major barrier to achieving stable metabolic control in patients with diabetes which is a serious clinical concern. With progression of diabetes, the ability of pancreatic alpha-cells which respond to hypoglycemia becomes impaired; However, it is not clear whether the dysfunctional responses of alpha cells during hypoglycemia are related with oxidative stress. In the present study, we investigated whether epigallocatechin-3-gallate (EGCG) has antioxidant potential on pancreatic alpha TC1-6 (alphaTC1-6) cell lines and protect the normal function of alpha-cells from H2O2 induced oxidative stress. ROS production, cell viability, glucagon secretion, and cell apoptosis were assessed. EGCG reduced ROS production and cell apoptosis, while restored cell viability and glucagon secretion within a particular concentration range. Moreover, EGCG activated Akt signaling and inhibited P38 as well as JNK mitogen-activated protein kinase (MAPK) pathway. Taken together, EGCG prevented alphaTC1-6 cells from H2O2 induced oxidative stress, restored dysfunction of glucagon secretion and inhibited cell apoptosis via the activation of Akt signaling and suppression of P38 and JNK pathway. These results provide rationale for combining the conventional anti-hyperglycemia therapy and antioxidant therapy in order to avert hypoglycemia in clinical treatment of diabetes. PMID- 29117538 TI - LncRNA COL1A2-AS1 inhibits the scar fibroblasts proliferation via regulating miR 21/Smad7 pathway. AB - lncRNA COL1A2-AS1 (COL1A2 antisense RNA 1), a lncRNA overexpressed in hypertrophic scar, has been demonstrated to be involved in the hypertrophic scar formation. However, the mechanisms of lncRNA COL1A2-AS1 inhibiting the scar fibroblasts proliferation remains not well understood. In this study, we demonstrated that lncRNA COL1A2-AS1 was upregulated in hypertrophic scar tissue and fibroblasts, and suppressed fibroblasts proliferation by promoting Smad7 expression. Furthermore, we found that miR-21 was involved in lncRNA COL1A2-AS1 induced expression of Smad7, by which COL1A2-AS1 acted as endogenous sponge to adsorb miR-21 and in turn regulated Smad7 and a cascade of molecular to play a protective role in hypertrophic scar. In addition, overexpression of miR-21 attenuated COL1A2-AS1-mediated proliferation suppression of hypertrophic scar fibroblasts. In conclusion, our study demonstrated that COL1A2-AS1/miR-21/Smad pathway plays an important role in inhibiting hypertrophic scar formation, and suggested this novel pathway may be a new target for hypertrophic scar treatment. PMID- 29117540 TI - A Weak Spot in Multiple Protozoan Parasites. AB - Eukaryotic protozoan parasites, including the etiological agents of malaria, toxoplasmosis, and leishmaniasis, collectively cause significant mortality in humans. In a recent issue of Structure,Jain et al. (2017) identify a set of quinazolinone-based derivatives targeting the parasitic prolyl-tRNA synthetase enzyme as promising drugs for the clearance of diverse parasites. PMID- 29117539 TI - Hsa_circ_0009910 promotes carcinogenesis by promoting the expression of miR-449a target IL6R in osteosarcoma. AB - Circular RNAs (circRNAs) have recently shown capabilities as gene regulators in mammals. Some of them interact with microRNAs (miRNAs) and function as sponges to affect related miRNAs' activities. In this study, the molecular function of circRNA_0009910 and its potential downstream miRNA targets were explored. The expression levels of hsa_circ_0009910 were found to be overexpressed in osteosarcoma (OS) cells. Knockdown of circ_0009910 induced cell proliferation inhibition, cell cycle arrest, and apoptosis in OS cells. The target miRNA was predicted to be miR-449a, whose expression was downregulated in OS cells. Inhibition of miR-449a abolished the effect of circ_0009910 knockdown on cell growth and apoptosis. The expression of miR-449a were found to be negatively correlated with that of circ_0009910 in OS tissues. Direct interaction of circ_0009910 and miR-449a was confirmed through dual-luciferase assays. Moreover, IL6R was predicted as a potential target of miR-449a. Overexpression of miR-449a decreased the mRNA and protein levels of IL6R. Restoration of IL6R impaired the miR-449a induced inhibition of cell proliferation, cell cycle arrest, and apoptosis. The mRNA expression of IL6R was inversely correlated with miR-449a in OS tissues. In addition, JAK1/STAT3 signaling pathway was regulated by circ_0009910/miR-449a/IL6R axis. Taken together, we suggested that circ_0009910 acted as a sponge of miR-449a and upregulated miR-449a functional target IL6R, thereby contributed to carcinogenesis of OS. PMID- 29117541 TI - Dealing with Consequences of Irreproducibility and Modifying the Published Literature: Retractions versus Revisions. AB - One of the barriers to revising the literature when new data are produced, demonstrating the lack of reproducibility of particular published findings, is the stigma associated with the current tools available, most notably the use of retractions. We suggest an additional tool: revisions, which could be linked to prior manuscripts by the original authors and by others (upon peer review). We hope new approaches such as the ability to revise prior reports will help to keep the literature up-to-date and representative of the most complete understanding of an issue. PMID- 29117542 TI - What Ignites UCP1? AB - We thought we knew how the heat-producing uncoupling protein 1 in brown adipose tissue was activated: by fatty acids released upon lipid droplet breakdown in the brown adipocytes. However, two studies in this issue (Schreiber et al., 2017; Shin et al., 2017) imply that this classical model may not be valid: heat can be produced in brown fat without intracellular lipolysis. PMID- 29117543 TI - NFIL-trating the Host Circadian Rhythm-Microbes Fine-Tune the Epithelial Clock. AB - The diurnal activities of the intestinal microbiota and its host are closely connected, but the nature of their circadian communication pathways remains obscure. Wang et al. (2017) have described a signaling circuit linking microbial sensing by the immune system to the epithelial clock, thereby orchestrating local and systemic lipid metabolism. PMID- 29117544 TI - Glial Cell Evolution: The Origins of a Lipid Store. AB - In Drosophila, neuronal mitochondria that lack OXPHOS generate ROS-protective fatty acids and lipid droplets in associated glia. In this issue, Liu et al. (2017) demonstrate that neuronal lipid synthesis is driven by the glial lactate shuttle. This lipoprotein-dependent deposition of lipids may be at the origin of glial specializations evolving in vertebrates. PMID- 29117545 TI - Resistance Is Futile: Targeting Mitochondrial Energetics and Metabolism to Overcome Drug Resistance in Cancer Treatment. AB - Metabolism is a key regulator of cancer biology; however, its role in therapeutic resistance has remained largely unresolved. Several new studies disclose that mitochondrial metabolism and oxidative phosphorylation at least in part drive chemoresistance in cancer and thus have important implications for targeted and more effective chemotherapies. PMID- 29117546 TI - Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota. PMID- 29117547 TI - A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13. AB - Prostate cancer (PCa) is the leading cancer among men in the United States, with genetic factors contributing to ~42% of the susceptibility to PCa. We analyzed a PCa risk region located at 7p15.2 to gain insight into the mechanisms by which this noncoding region may affect gene regulation and contribute to PCa risk. We performed Hi-C analysis and demonstrated that this region has long-range interactions with the HOXA locus, located ~873 kb away. Using the CRISPR/Cas9 system, we deleted a 4-kb region encompassing several PCa risk-associated SNPs and performed RNA-seq to investigate transcriptomic changes in prostate cells lacking the regulatory element. Our results suggest that the risk element affects the expression of HOXA13 and HOTTIP, but not other genes in the HOXA locus, via a repressive loop. Forced expression of HOXA13 was performed to gain further insight into the mechanisms by which this risk element affects PCa risk. PMID- 29117548 TI - Multiplexing Visual Signals in the Suprachiasmatic Nuclei. AB - The suprachiasmatic nuclei (SCN), the site of the mammalian circadian (daily) pacemaker, contains thousands of interconnected neurons, some of which receive direct retinal input. Here, we study the fast (<1 s) responses of SCN neurons to visual stimuli with a large-scale mathematical model tracking the ionic currents and voltage of all SCN neurons. We reconstruct the SCN network connectivity and reject 99.99% of theoretically possible SCN networks by requiring that the model reproduces experimentally determined receptive fields of SCN neurons. The model shows how the SCN neuronal network can enhance circadian entrainment by sensitizing a population of neurons in the ventral SCN to irradiance. This SCN network also increases the spatial acuity of neurons and increases the accuracy of a simulated subconscious spatial visual task. We hypothesize that much of the fast electrical activity within the SCN is related to the processing of spatial information. PMID- 29117549 TI - Prefrontal Cortex Drives Distinct Projection Neurons in the Basolateral Amygdala. AB - The prefrontal cortex (PFC) regulates emotional behavior via top-down control of the basolateral amygdala (BLA). However, the influence of PFC inputs on the different projection pathways within the BLA remains largely unexplored. Here, we combine whole-cell recordings and optogenetics to study these cell-type specific connections in mouse BLA. We characterize PFC inputs onto three distinct populations of BLA neurons that project to the PFC, ventral hippocampus, or nucleus accumbens. We find that PFC-evoked synaptic responses are strongest at amygdala-cortical and amygdala-hippocampal neurons and much weaker at amygdala striatal neurons. We assess the mechanisms for this targeting and conclude that it reflects fewer connections onto amygdala-striatal neurons. Given the similar intrinsic properties of these cells, this connectivity allows the PFC to preferentially activate amygdala-cortical and amygdala-hippocampal neurons. Together, our findings reveal how PFC inputs to the BLA selectively drive feedback projections to the PFC and feedforward projections to the hippocampus. PMID- 29117550 TI - MicroRNA Regulation of nAChR Expression and Nicotine-Dependent Behavior in C. elegans. AB - Chronic exposure to nicotine upregulates nicotinic acetylcholine receptors (nAChRs), and such upregulation is critical for the development of nicotine dependence in humans and animal models. However, how nicotine upregulates nAChRs is not well understood. Here, we identify a key role for microRNA in regulating nicotine-dependent behavior by modulating nAChR expression in C. elegans. We show that the nAChR gene acr-19 and alg-1, a key Argonaute-family member in the microRNA machinery, are specifically required for nicotine withdrawal response following chronic nicotine treatment. Chronic exposure to nicotine downregulates alg-1, leading to upregulation of acr-19. This effect is mediated by the microRNA miR-238 that recognizes the 3' UTR of acr-19 transcript. Our results unveil a previously unrecognized role for microRNA in nicotine signaling, providing insights into how chronic nicotine administration leads to upregulation of nAChR and ultimately nicotine dependence. PMID- 29117551 TI - Distinct Roles of Sensory Neurons in Mediating Pathogen Avoidance and Neuropeptide-Dependent Immune Regulation. AB - Increasing evidence implies an extensive and universal interaction between the immune system and the nervous system. Previous studies showed that OCTR-1, a neuronal G-protein-coupled receptor (GPCR) analogous to human norepinephrine receptors, functions in sensory neurons to control the gene expression of both microbial killing pathways and the unfolded protein response (UPR) in Caenorhabditis elegans. Here, we found that OCTR-1-expressing neurons, ASH, are involved in controlling innate immune pathways. In contrast, another group of OCTR-1-expressing neurons, ASI, was shown to promote pathogen avoidance behavior. We also identified neuropeptide NLP-20 and AIA interneurons, which are responsible for the integration of conflicting cues and behaviors, as downstream components of the ASH/ASI neural circuit. These findings provide insights into a neuronal network involved in regulating pathogen defense mechanisms in C. elegans and might have broad implications for the strategies utilized by metazoans to balance the energy-costly immune activation and behavioral response. PMID- 29117552 TI - Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production. AB - Glucagon is secreted from pancreatic alpha cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1 61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in beta cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion. PMID- 29117553 TI - Drosophila Embryonic Hemocytes Produce Laminins to Strengthen Migratory Response. AB - The most prominent developmental function attributed to the extracellular matrix (ECM) is cell migration. While cells in culture can produce ECM to migrate, the role of ECM in regulating developmental cell migration is classically viewed as an exogenous matrix presented to the moving cells. In contrast to this view, we show here that Drosophila embryonic hemocytes deposit their own laminins in streak-like structures to migrate efficiently throughout the embryo. With the help of transplantation experiments, live microscopy, and image quantification, we demonstrate that autocrine-produced laminin regulates hemocyte migration by controlling lamellipodia dynamics, stability, and persistence. Proper laminin deposition is regulated by the RabGTPase Rab8, which is highly expressed and required in hemocytes for lamellipodia dynamics and migration. Our results thus support a model in which, during embryogenesis, the Rab8-regulated autocrine deposition of laminin reinforces directional and effective migration by stabilizing cellular protrusions and strengthening otherwise transient adhesion states. PMID- 29117554 TI - Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan. AB - Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age associated pathologies. However, the "anti-aging" factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging. Genetic or pharmacological abrogation of apln signaling also induces cellular senescence mediated, in part, by the activation of senescence-promoting transcription factors. Conversely, restoration of apln in 15-month-old wild-type mice reduces cardiac hypertrophy and exercise-induced hypertensive response. Additionally, apln-restored mice exhibit enhanced vigor and rejuvenated behavioral and circadian phenotypes. Hence, a declining apelinergic axis promotes aging, whereas its restoration extends the murine healthspan. PMID- 29117555 TI - Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging. AB - In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target genes. This resulted in a robust restoration of cytoplasmic proteostasis and increased vitality later in life, without detrimental effects on fecundity. We propose that low levels of mitochondrial stress regulate cytoplasmic proteostasis and healthspan during aging by coordinating the long-term activity of HSF-1 with conditions preclusive to optimal fitness. PMID- 29117556 TI - CDK8 Kinase Activity Promotes Glycolysis. AB - Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancerous tissues. Despite its importance in cancer development, our understanding of mechanisms driving this form of metabolic reprogramming is incomplete. We report here an analysis of colorectal cancer cells engineered to carry a single point mutation in the active site of the Mediator-associated kinase CDK8, creating hypomorphic alleles sensitive to bulky ATP analogs. Transcriptome analysis revealed that CDK8 kinase activity is required for the expression of many components of the glycolytic cascade. CDK8 inhibition impairs glucose transporter expression, glucose uptake, glycolytic capacity and reserve, as well as cell proliferation and anchorage-independent growth, both in normoxia and hypoxia. Importantly, CDK8 impairment sensitizes cells to pharmacological glycolysis inhibition, a result reproduced with Senexin A, a dual inhibitor of CDK8/CDK19. Altogether, these results contribute to our understanding of CDK8 as an oncogene, and they justify investigations to target CDK8 in highly glycolytic tumors. PMID- 29117558 TI - Dietary Uncoupling of Gut Microbiota and Energy Harvesting from Obesity and Glucose Tolerance in Mice. AB - Evidence suggests that altered gut microbiota composition may be involved in the development of obesity. Studies using mice made obese with refined high-fat diets have supported this; however, these have commonly used chow as a control diet, introducing confounding factors from differences in dietary composition that have a key role in shaping microbiota composition. We compared the effects of feeding a refined high-fat diet with those of feeding either a refined low-fat diet or a chow diet on gut microbiota composition and host physiology. Feeding both refined low- or high-fat diets resulted in large alterations in the gut microbiota composition, intestinal fermentation, and gut morphology, compared to a chow diet. However, body weight, body fat, and glucose intolerance only increased in mice fed the refined high-fat diet. The choice of control diet can dissociate broad changes in microbiota composition from obesity, raising questions about the previously proposed relationship between gut microbiota and obesity. PMID- 29117557 TI - The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co expression Networks. AB - Regular endurance training improves muscle oxidative capacity and reduces the risk of age-related disorders. Understanding the molecular networks underlying this phenomenon is crucial. Here, by exploiting the power of computational modeling, we show that endurance training induces profound changes in gene regulatory networks linking signaling and selective control of translation to energy metabolism and tissue remodeling. We discovered that knockdown of the mTOR independent factor Eif6, which we predicted to be a key regulator of this process, affects mitochondrial respiration efficiency, ROS production, and exercise performance. Our work demonstrates the validity of a data-driven approach to understanding muscle homeostasis. PMID- 29117560 TI - Timed Synaptic Inhibition Shapes NMDA Spikes, Influencing Local Dendritic Processing and Global I/O Properties of Cortical Neurons. AB - The NMDA spike is a long-lasting nonlinear phenomenon initiated locally in the dendritic branches of a variety of cortical neurons. It plays a key role in synaptic plasticity and in single-neuron computations. Combining dynamic system theory and computational approaches, we now explore how the timing of synaptic inhibition affects the NMDA spike and its associated membrane current. When impinging on its early phase, individual inhibitory synapses strongly, but transiently, dampen the NMDA spike; later inhibition prematurely terminates it. A single inhibitory synapse reduces the NMDA-mediated Ca2+ current, a key player in plasticity, by up to 45%. NMDA spikes in distal dendritic branches/spines are longer-lasting and more resilient to inhibition, enhancing synaptic plasticity at these branches. We conclude that NMDA spikes are highly sensitive to dendritic inhibition; sparse weak inhibition can finely tune synaptic plasticity both locally at the dendritic branch level and globally at the level of the neuron's output. PMID- 29117559 TI - An Eye Organoid Approach Identifies Six3 Suppression of R-spondin 2 as a Critical Step in Mouse Neuroretina Differentiation. AB - Recent advances in self-organizing, 3-dimensional tissue cultures of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provided an in vitro model that recapitulates many aspects of the in vivo developmental steps. Using Rax-GFP-expressing ESCs, newly generated Six3-/- iPSCs, and conditional null Six3delta/f;Rax-Cre ESCs, we identified Six3 repression of R-spondin 2 (Rspo2) as a required step during optic vesicle morphogenesis and neuroretina differentiation. We validated these results in vivo by showing that transient ectopic expression of Rspo2 in the anterior neural plate of transgenic mouse embryos was sufficient to inhibit neuroretina differentiation. Additionally, using a chimeric eye organoid assay, we determined that Six3 null cells exert a non-cell-autonomous repressive effect during optic vesicle formation and neuroretina differentiation. Our results further validate the organoid culture system as a reliable and fast alternative to identify and evaluate genes involved in eye morphogenesis and neuroretina differentiation in vivo. PMID- 29117561 TI - Ronin Governs Early Heart Development by Controlling Core Gene Expression Programs. AB - Ronin (THAP11), a DNA-binding protein that evolved from a primordial DNA transposon by molecular domestication, recognizes a hyperconserved promoter sequence to control developmentally and metabolically essential genes in pluripotent stem cells. However, it remains unclear whether Ronin or related THAP proteins perform similar functions in development. Here, we present evidence that Ronin functions within the nascent heart as it arises from the mesoderm and forms a four-chambered organ. We show that Ronin is vital for cardiogenesis during midgestation by controlling a set of critical genes. The activity of Ronin coincided with the recruitment of its cofactor, Hcf-1, and the elevation of H3K4me3 levels at specific target genes, suggesting the involvement of an epigenetic mechanism. On the strength of these findings, we propose that Ronin activity during cardiogenesis offers a template to understand how important gene programs are sustained across different cell types within a developing organ such as the heart. PMID- 29117562 TI - Primer-Independent DNA Synthesis by a Family B DNA Polymerase from Self Replicating Mobile Genetic Elements. AB - Family B DNA polymerases (PolBs) play a central role during replication of viral and cellular chromosomes. Here, we report the discovery of a third major group of PolBs, which we denote primer-independent PolB (piPolB), that might be a link between the previously known protein-primed and RNA/DNA-primed PolBs. PiPolBs are encoded by highly diverse mobile genetic elements, pipolins, integrated in the genomes of diverse bacteria and also present as circular plasmids in mitochondria. Biochemical characterization showed that piPolB displays efficient DNA polymerization activity that can use undamaged and damaged templates and is endowed with proofreading and strand displacement capacities. Remarkably, the protein is also capable of template-dependent de novo DNA synthesis, i.e., DNA priming activity, thereby breaking the long-standing dogma that replicative DNA polymerases require a pre-existing primer for DNA synthesis. We suggest that piPolBs are involved in self-replication of pipolins and may also contribute to bacterial DNA damage tolerance. PMID- 29117563 TI - Outcomes of Congenital Zika Disease Depend on Timing of Infection and Maternal Fetal Interferon Action. AB - Zika virus (ZIKV) infection during pregnancy in humans results in intrauterine growth restriction, spontaneous abortion, and microcephaly. Here, we found that fetus-derived type I interferon (IFN-I) signaling can enhance anti-ZIKV responses and provide clinical benefits to the fetus. Because IFN-lambda shares signaling cascades and antiviral functions with IFN-I, we investigated the in vivo effects of IFN-lambda in ZIKV-infected pregnant mice. IFN-lambda administration during mid-pregnancy reduced ZIKV burden in maternal and fetal organs and alleviated placental injuries and fetal demise. In addition, prophylactic and therapeutic treatment of IFN-lambda1 in a human trophoblast line, as well as in primary human amniotic epithelial cells, greatly reduced the ZIKV burden. Our data highlight IFN-lambda1 as a potential therapeutic useful for women at risk for congenital Zika disease. PMID- 29117565 TI - The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I. AB - Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5) and RIG-I, are crucial for host recognition of non-self RNAs, especially viral RNA. Thus, the expression and activation of RLRs play fundamental roles in eliminating the invading RNA viruses and maintaining immune homeostasis. However, how RLR expression is tightly regulated remains to be further investigated. In this study, we identified a major histocompatibility complex (MHC)-encoded gene, tripartite interaction motif 40 (TRIM40), as a suppressor of RLR signaling by directly targeting MDA5 and RIG I. TRIM40 binds to MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination via its E3 ligase activity, leading to their proteasomal degradation. TRIM40 deficiency enhances RLR-triggered signaling. Consequently, TRIM40 deficiency greatly enhances antiviral immune responses and decreases viral replication in vivo. Thus, we demonstrate that TRIM40 limits RLR-triggered innate activation, suggesting TRIM40 as a potential therapeutic target for the control of viral infection. PMID- 29117566 TI - Cytosolic Recognition of RNA Drives the Immune Response to Heterologous Erythrocytes. AB - The archetypal T cell-dependent antigen is sheep red blood cells (SRBCs), which have defined much of what we know about humoral immunity. Early studies using solubilized or sonicated SRBCs argued that the intact structure of SRBCs was important for optimal antibody responses. However, the reason for the requirement of intact SRBCs for the response to polyvalent protein antigen remained unknown. Here, we report that the immune response to SRBCs is driven by cytosolic recognition of SRBC RNA through the RIG-I-like receptor (RLR)-mitochondrial anti viral signaling adaptor (MAVS) pathway. Following the uptake of SRBCs by antigen presenting cells, the MAVS signaling complex governs the differentiation of both T follicular cells and antibody-producing B cells. Importantly, the involvement of the RLR-MAVS pathway precedes that of endosomal Toll-like receptor pathways, yet both are required for optimal effect. PMID- 29117564 TI - An IRF-3-, IRF-5-, and IRF-7-Independent Pathway of Dengue Viral Resistance Utilizes IRF-1 to Stimulate Type I and II Interferon Responses. AB - Interferon-regulatory factors (IRFs) are a family of transcription factors (TFs) that translate viral recognition into antiviral responses, including type I interferon (IFN) production. Dengue virus (DENV) and other clinically important flaviviruses are suppressed by type I IFN. While mice lacking the type I IFN receptor (Ifnar1-/-) succumb to DENV infection, we found that mice deficient in three transcription factors controlling type I IFN production (Irf3-/-Irf5-/-Irf7 /- triple knockout [TKO]) survive DENV challenge. DENV infection of TKO mice resulted in minimal type I IFN production but a robust type II IFN (IFN-gamma) response. Using loss-of-function approaches for various molecules, we demonstrate that the IRF-3-, IRF-5-, IRF-7-independent pathway predominantly utilizes IFN gamma and, to a lesser degree, type I IFNs. This pathway signals via IRF-1 to stimulate interleukin-12 (IL-12) production and IFN-gamma response. These results reveal a key antiviral role for IRF-1 by activating both type I and II IFN responses during DENV infection. PMID- 29117567 TI - The Host Protein Reticulon 3.1A Is Utilized by Flaviviruses to Facilitate Membrane Remodelling. AB - Flaviviruses are enveloped, positive-sensed single-stranded RNA viruses that remodel host membranes, incorporating both viral and host factors facilitating viral replication. In this study, we identified a key role for the membrane bending host protein Reticulon 3.1 (RTN3.1A) during the replication cycle of three flaviviruses: West Nile virus (WNV), Dengue virus (DENV), and Zika virus (ZIKV). We observed that, during infection, RTN3.1A is redistributed and recruited to the viral replication complex, a recruitment facilitated via the WNV NS4A protein, however, not DENV or ZIKV NS4A. Critically, small interfering RNA (siRNA)-mediated knockdown of RTN3.1A expression attenuated WNV, DENV, and ZIKV replication and severely affected the stability and abundance of the NS4A protein, coinciding with a significant alternation and reduction of viral membrane structures in the endoplasmic reticulum. These observations identified a crucial role of RTN3.1A for the viral remodelling of host membranes during efficient flavivirus replication and the stabilization of viral proteins within the endoplasmic reticulum. PMID- 29117568 TI - PTEN Regulates Glucose Transporter Recycling by Impairing SNX27 Retromer Assembly. AB - The tumor suppressor PTEN executes cellular functions predominantly through its phosphatase activity. Here we identified a phosphatase-independent role for PTEN during vesicular trafficking of the glucose transporter GLUT1. PTEN physically interacts with SNX27, a component of the retromer complex that recycles transmembrane receptors such as GLUT1 from endosomes to the plasma membrane. PTEN binding with SNX27 prevents GLUT1 accumulation at the plasma membrane because of defective recycling and thus reduces cellular glucose uptake. Mechanistically, PTEN blocks the association of SNX27 with VPS26 and thereby hinders assembly of a functional retromer complex during the receptor recycling process. Importantly, we found a PTEN somatic mutation (T401I) that is defective in disrupting the association between SNX27 and VPS26, suggesting a critical role for PTEN in controlling optimal GLUT1 levels at the membrane to prevent tumor progression. Together, our results reveal a fundamental role of PTEN in the regulation of the SNX27 retromer pathway, which governs glucose transport and might contribute to PTEN tumor suppressor function. PMID- 29117569 TI - ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak. AB - Mitochondrial distribution and motility are recognized as central to many cellular functions, but their regulation by signaling mechanisms remains to be elucidated. Here, we report that reactive oxygen species (ROS), either derived from an extracellular source or intracellularly generated, control mitochondrial distribution and function by dose-dependently, specifically, and reversibly decreasing mitochondrial motility in both rat hippocampal primary cultured neurons and cell lines. ROS decrease motility independently of cytoplasmic [Ca2+], mitochondrial membrane potential, or permeability transition pore opening, known effectors of oxidative stress. However, multiple lines of genetic and pharmacological evidence support that a ROS-activated mitogen-activated protein kinase (MAPK), p38alpha, is required for the motility inhibition. Furthermore, anchoring mitochondria directly to kinesins without involvement of the physiological adaptors between the organelles and the motor protein prevents the H2O2-induced decrease in mitochondrial motility. Thus, ROS engage p38alpha and the motor adaptor complex to exert changes in mitochondrial motility, which likely has both physiological and pathophysiological relevance. PMID- 29117570 TI - Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1. AB - Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization. PMID- 29117572 TI - Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function. PMID- 29117571 TI - Single-Cell Virology: On-Chip Investigation of Viral Infection Dynamics. AB - We have developed a high-throughput, microfluidics-based platform to perform kinetic analysis of viral infections in individual cells. We have analyzed thousands of individual poliovirus infections while varying experimental parameters, including multiplicity of infection, cell cycle, viral genotype, and presence of a drug. We make several unexpected observations masked by population based experiments: (1) viral and cellular factors contribute uniquely and independently to viral infection kinetics; (2) cellular factors cause wide variation in replication start times; and (3) infections frequently begin later and replication occurs faster than predicted by population measurements. We show that mutational load impairs interaction of the viral population with the host, delaying replication start times and explaining the attenuated phenotype of a mutator virus. We show that an antiviral drug can selectively extinguish the most fit members of the viral population. Single-cell virology facilitates discovery and characterization of virulence determinants and elucidation of mechanisms of drug action eluded by population methods. PMID- 29117573 TI - Conducting Quantitative Medical Education Research: From Design to Dissemination. AB - Rigorous medical education research is critical to effectively develop and evaluate the training we provide our learners. Yet many clinical medical educators lack the training and skills needed to conduct high-quality medical education research. We offer guidance on conducting sound quantitative medical education research. Our aim is to equip readers with the key skills and strategies necessary to conduct successful research projects, highlighting new concepts and controversies in the field. We utilize Glassick's criteria for scholarship as a framework to discuss strategies to ensure that the research question of interest is worthy of further study and how to use existing literature and conceptual frameworks to strengthen a research study. Through discussions of the strengths and limitations of commonly used study designs, we expose the reader to particular nuances of these decisions in medical education research and discuss outcomes generally focused on, as well as strategies for determining the significance of consequent findings. We conclude with information on critiquing research findings and preparing results for dissemination to a broad audience. Practical planning worksheets and comprehensive tables illustrating key concepts are provided in order to guide researchers through each step of the process. Medical education research provides wonderful opportunities to improve how we teach our learners, to satisfy our own intellectual curiosity, and ultimately to enhance the care provided to patients. PMID- 29117574 TI - An astrocyte derived extracellular matrix coating reduces astrogliosis surrounding chronically implanted microelectrode arrays in rat cortex. AB - Available evidence suggests that the magnitude of the foreign body response (FBR) to implants placed in cortical brain tissue is affected by the extent of vasculature damage following device insertion and the magnitude of the ensuing macrophage response. Since the extracellular matrix (ECM) serves as a natural hemostatic and immunomodulatory agent, we examined the ability of an FDA-approved neurosurgical hemostatic coating and an ECM coating derived from primary rat astrocytes to reduce the FBR surrounding a penetrating microelectrode array chronically implanted in rat cortex. Using quantitative methods, we examined various components of the FBR in vitro and after implantation. In vitro assays showed that both coatings accelerated coagulation in a similar fashion but only the astrocyte-derived material suppressed macrophage activation. In addition, the ECM coating derived from astrocytes, also decreased the astrogliotic response 8 weeks after implantation. Neither coating had a significant influence on the intensity or spatial distribution of FBR biomarkers 1 week after implantation or on degree of macrophage activation or neuronal survival at the later time point. The results show that microelectrode coatings with similar hemostatic properties but different immunomodulatory characteristics differentially affect the FBR to an anchored, single-shank, silicon microelectrode array. The results also support the concept that divergent biological pathways affect the various components of the FBR in the CNS and suggests that decreasing its impact will require a multifaceted approach. PMID- 29117575 TI - Self-assembling peptide hydrogel enables instant epicardial coating of the heart with mesenchymal stromal cells for the treatment of heart failure. AB - Transplantation of mesenchymal stromal cells (MSCs) is an emerging therapy for the treatment of heart failure. However, the delivery method of MSC is currently suboptimal. The use of self-assembling peptide hydrogels, including PuraMatrix(r) (PM; 3-D Matrix, Ltd), has been reported for clinical hemostasis and in research models. This study demonstrates the feasibility and efficacy of an advanced approach for MSC-therapy, that is coating of the epicardium with the instantly produced PM hydrogel incorporating MSCs (epicardial PM-MSC therapy). We optimized the conditions/procedure to produce "instant" 2PM-MSC complexes. After spreading on the epicardium by easy pipetting, the PM-MSC complex promptly and stably adhere to the beating heart. Of note, this treatment achieved more extensive improvement of cardiac function, with greater initial retention and survival of donor MSCs, compared to intramyocardial MSC injection in rat heart failure models. This enhanced efficacy was underpinned by amplified myocardial upregulation of a group of tissue repair-related genes, which led to enhanced repair of the damaged myocardium, i.e. augmented microvascular formation and reduced interstitial fibrosis. These data suggest a potential for epicardial PM MSC therapy to be a widely-adopted treatment of heart failure. This approach may also be useful for treating diseases in other organs than the heart. PMID- 29117577 TI - Diterpenoids from Croton crassifolius include a novel skeleton possibly generated via an intramolecular [2+2]-photocycloaddition reaction. AB - Five previously undescribed terpenoids (cracrosons D-H), including three clerodane diterpenoids, together with 16 known diterpenoids were isolated from Croton crassifolius (Euphorbiaceae). Cracroson D features a previously undescribed carbon skeleton with an unprecedented cyclobutane ring. Their structures, including their absolute configurations, were elucidated using spectroscopic and single-crystal X-ray diffraction analyses along with CD calculations. A plausible biogenetic pathway for cracroson D is also proposed, which was supported by the experimental results. Additionally, all of the compounds were evaluated in vitro for cytotoxicity against T24 and A549 cells using the CCK-8 method. PMID- 29117576 TI - The utility of anti-Mullerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer. AB - AIM: Chemotherapy results in permanent loss of ovarian function in some premenopausal women. Accurate identification in women with hormone-sensitive early breast cancer (eBC) would allow optimisation of subsequent endocrine treatment. We sought to assess whether analysis of anti-Mullerian hormone (AMH) using a sensitive automated assay could identify women who would not regain ovarian function after chemotherapy. METHODS: Data from women in the Ovarian Protection Trial in Premenopausal Breast Cancer Patients (OPTION) trial of goserelin (a gonadotrophin-releasing hormone (GnRH) analogue) for ovarian protection were analysed. Women were assessed for premature ovarian insufficiency (POI: amenorrhoea with elevated follicle-stimulating hormone (FSH)) at 24 months after diagnosis. The accuracy of AMH for the diagnosis of POI and its prediction from measurement at the end of chemotherapy was calculated. RESULTS: AMH below the level of detection showed good diagnostic accuracy for POI at 24 months (n = 73) with receiver operating characteristic (ROC) area under the curve of 0.86, sensitivity 1.0 and specificity 0.73 at the assay limit of detection. In women aged >40 at diagnosis who did not receive goserelin, AMH measured at end of chemotherapy also gave good prediction of POI at 24 months (area under the curve (AUC) 0.89 95% CI 0.75-1.0, n = 32), with sensitivity 0.91, specificity 0.82, diagnostic odds ratio (DOR) 42.8. FSH gave slightly lower AUC, and specificity was low at 0.55. Age but not tamoxifen impacted on AMH levels. CONCLUSION: Using this sensitive AMH assay, the finding of an undetectable AMH level in women aged >40 at the end of chemotherapy for eBC gave a good prediction that ovarian function would not return. This may allow alterations in post-chemotherapy endocrine management. PMID- 29117578 TI - Practical issues in implementing whole-genome-sequencing in routine diagnostic microbiology. AB - BACKGROUND: Next generation sequencing (NGS) is increasingly being used in clinical microbiology. Like every new technology adopted in microbiology, the integration of NGS into clinical and routine workflows must be carefully managed. AIM: To review the practical aspects of implementing bacterial whole genome sequencing (WGS) in routine diagnostic laboratories. SOURCES: Review of the literature and expert opinion. CONTENT: In this review, we discuss when and how to integrate whole genome sequencing (WGS) in the routine workflow of the clinical laboratory. In addition, as the microbiology laboratories have to adhere to various national and international regulations and criteria for their accreditation, we deliberate on quality control issues for using WGS in microbiology, including the importance of proficiency testing. Furthermore, the current and future place of this technology in the diagnostic hierarchy of microbiology is described as well as the necessity of maintaining backwards compatibility with already established methods. Finally, we speculate on the question of whether WGS can entirely replace routine microbiology in the future and the tension between the fact that most sequencers are designed to process multiple samples in parallel whereas for optimal diagnosis a one-by-one processing of the samples is preferred. Special reference is made to the cost and turnaround time of WGS in diagnostic laboratories. IMPLICATIONS: Further development is required to improve the workflow for WGS, in particular to shorten the turnaround time, reduce costs, and streamline downstream data analyses. Only when these processes reach maturity will reliance on WGS for routine patient management and infection control management become feasible, enabling the transformation of clinical microbiology into a genome-based and personalized diagnostic field. PMID- 29117579 TI - The involvement of alpha oscillations in voluntary attention directed towards encoding episodic memories. AB - Forming episodic memories is often driven by top-down processes of allocating attention towards voluntarily remembering the details of an episode. This attention orientation is needed to make sure that information is encoded for later remembering. Here we designed an episodic long-term memory (LTM) EEG experiment where we examined brain oscillatory activity associated with attention allocation towards the temporal link between an item and its context. The remembering of this temporal conjunction is crucial for item-context binding and hence for the formation of episodic memories. Participants saw a background picture and a word in a central position on a computer screen and were instructed to memorise (a) the picture only, (b) the word, (c) both individually (i.e. ignoring their co-occurrence) and (d) both with them being presented together. Attention allocation towards item-context binding was associated with oscillatory alpha desynchronization in the upper alpha band (10-13 Hz) over dominantly left posterior brain areas. The results highlight the role of alpha desynchronization in voluntary attention allocation towards the temporal conjunction of item and its context in episodic binding and the involvement of posterior brain areas. The pattern of results suggest that they most likely reflect additional visual processes recruited by attentional mechanisms and do not tap into neural processes of item-context binding per se. Moreover, it indicates that the involvement of alpha oscillations in cognitive processes may be more complex. PMID- 29117581 TI - Collective sparse symmetric non-negative matrix factorization for identifying overlapping communities in resting-state brain functional networks. AB - Resting-state functional magnetic resonance imaging (rs-fMRI) provides a valuable tool to study spontaneous brain activity. Using rs-fMRI, researchers have extensively studied the organization of the brain functional network and found several consistent communities consisting of functionally connected but spatially separated brain regions across subjects. However, increasing evidence in many disciplines has shown that most realistic complex networks have overlapping community structure. Only recently has the overlapping community structure drawn increasing interest in the domain of brain network studies. Another issue is that the inter-subject variability is often not directly reflected in the process of community detection at the group level. In this paper, we propose a novel method called collective sparse symmetric non-negative matrix factorization (cssNMF) to address these issues. The cssNMF approach identifies the group-level overlapping communities across subjects and in the meantime preserves the information of individual variation in brain functional network organization. To comprehensively validate cssNMF, a simulated fMRI dataset with ground-truth, a real rs-fMRI dataset with two repeated sessions and another different real rs-fMRI dataset have been used for performance comparison in the experiment. Experimental results show that the proposed cssNMF method accurately and stably identifies group-level overlapping communities across subjects as well as individual differences in network organization with neurophysiologically meaningful interpretations. This research extends our understanding of the common underlying community structures and individual differences in community strengths in brain functional network organization. PMID- 29117580 TI - Discovery and visualization of structural biomarkers from MRI using transport based morphometry. AB - Disease in the brain is often associated with subtle, spatially diffuse, or complex tissue changes that may lie beneath the level of gross visual inspection, even on magnetic resonance imaging (MRI). Unfortunately, current computer assisted approaches that examine pre-specified features, whether anatomically defined (i.e. thalamic volume, cortical thickness) or based on pixelwise comparison (i.e. deformation-based methods), are prone to missing a vast array of physical changes that are not well-encapsulated by these metrics. In this paper, we have developed a technique for automated pattern analysis that can fully determine the relationship between brain structure and observable phenotype without requiring any a priori features. Our technique, called transport-based morphometry (TBM), is an image transformation that maps brain images losslessly to a domain where they become much more separable. The new approach is validated on structural brain images of healthy older adult subjects where even linear models for discrimination, regression, and blind source separation enable TBM to independently discover the characteristic changes of aging and highlight potential mechanisms by which aerobic fitness may mediate brain health later in life. TBM is a generative approach that can provide visualization of physically meaningful shifts in tissue distribution through inverse transformation. The proposed framework is a powerful technique that can potentially elucidate genotype-structural-behavioral associations in myriad diseases. PMID- 29117582 TI - Rational dose of insecticide chlorantraniliprole displays a transient impact on the microbial metabolic functions and bacterial community in a silty-loam paddy soil. AB - Chlorantraniliprole (CAP) is a newly developed insecticide widely used in rice fields in China. There have been few studies regarding its effects on soil microbial functional diversity and bacterial community composition. An 85-day microcosm experiment was performed to reveal the dissipation dynamics of CAP under different application doses in a silty-loam paddy soil in subtropical China. The half-life of CAP was 51.3 and 62.5d for low (1mgkg-1) and high (10mgkg 1) application dose, respectively. We used a combination of community level physiological profile (CLPP) and 16S rRNA gene sequencing analysis to get insights into the soil microbial features responded to CAP during the experiment. Non-metric multidimensional scaling (NMDS) performed on CLPP and the sequence results indicated that the soil microbial functional diversity and bacterial community composition were significantly changed by CAP application at day 14, and recovered to the similar level as no CAP treatment (CK) under low dose of CAP at day 36. However, high dose of CAP imposed longer effect on these soil microbial features, and was still significantly different from CK at day 36. Mcrobial taxa analysis at phylum level showed that high dose of CAP decreased the relative abundance of Nitrospirae at day 14, while increased Bacteroidetes and decreased Actinobacteria, Nitrospirae, and Firmicutes at day 36 in relative to CK. Low dose of CAP only increased Crenarchaeota and decreased Nitrospirae at day 14. The response ratio (RR) analysis was used to quantify significant responses of OTUs to different doses of CAP and found that CAP significantly affected the microbes involving the N transformation. This study provides a basic information to aid in the development of application regulations regarding the safe use of CAP in soil and inspire us to apply CAP at rational dose to minimize its ecotoxicity on soil microbes. PMID- 29117583 TI - Identifying climate risk perceptions, information needs, and barriers to information exchange among public land managers. AB - Meeting ecosystem management challenges posed by climate change requires building effective communication channels among researchers, planners and practitioners to focus research on management issues requiring new knowledge. We surveyed resource managers within two regions of the western United States regions to better understand perceived risks and vulnerabilities associated with climate change and barriers to obtaining and using relevant climate science information in making ecosystem management decisions. We sought to understand what types of climate science information resource managers find most valuable, and the formats in which they prefer to receive climate science information. We found broad concern among natural resource managers in federal agencies that climate change will make it more difficult for them to achieve their management goals. Primary barriers to incorporating climate science into planning are distributed among challenges identifying, receiving, and interpreting appropriate science and a lack of direction provided by agency leadership needed to meaningfully use this emerging science in resource planning. PMID- 29117584 TI - Environmental and health effects of the herbicide glyphosate. AB - The herbicide glyphosate, N-(phosphonomethyl) glycine, has been used extensively in the past 40years, under the assumption that side effects were minimal. However, in recent years, concerns have increased worldwide about the potential wide ranging direct and indirect health effects of the large scale use of glyphosate. In 2015, the World Health Organization reclassified glyphosate as probably carcinogenic to humans. A detailed overview is given of the scientific literature on the movement and residues of glyphosate and its breakdown product aminomethyl phosphonic acid (AMPA) in soil and water, their toxicity to macro- and microorganisms, their effects on microbial compositions and potential indirect effects on plant, animal and human health. Although the acute toxic effects of glyphosate and AMPA on mammals are low, there are animal data raising the possibility of health effects associated with chronic, ultra-low doses related to accumulation of these compounds in the environment. Intensive glyphosate use has led to the selection of glyphosate-resistant weeds and microorganisms. Shifts in microbial compositions due to selective pressure by glyphosate may have contributed to the proliferation of plant and animal pathogens. Research on a link between glyphosate and antibiotic resistance is still scarce but we hypothesize that the selection pressure for glyphosate resistance in bacteria could lead to shifts in microbiome composition and increases in antibiotic resistance to clinically important antimicrobial agents. We recommend interdisciplinary research on the associations between low level chronic glyphosate exposure, distortions in microbial communities, expansion of antibiotic resistance and the emergence of animal, human and plant diseases. Independent research is needed to revisit the tolerance thresholds for glyphosate residues in water, food and animal feed taking all possible health risks into account. PMID- 29117585 TI - Metagenomics profiling for assessing microbial diversity in both active and closed landfills. AB - The municipal landfill is an example of human-made environment that harbours some complex diversity of microorganism communities. To evaluate this complexity, the structures of bacterial communities in active (operational) and closed (non operational) landfills in Malaysia were analysed with culture independent metagenomics approaches. Several points of soil samples were collected from 0 to 20cm depth and were subjected to physicochemical test, such as temperature, pH, and moisture content. In addition, the heavy metal contamination was determined by using ICPMS. The bacterial enumeration was examined on nutrient agar (NA) plates aerobically at 30 degrees C. The soil DNA was extracted, purified and amplified prior to sequence the 16S rRNA gene for statistical and bioinformatics analyses. As a result, the average of bacteria for the closed landfill was higher compared to that for the active landfill at 9.16*107 and 1.50*107, respectively. The higher bacterial OTUs sequenced was also recorded in closed landfills compared to active landfill i.e. 6625 and 4552 OTUs respectively. The data from both landfills showed that the predominant phyla belonged to Proteobacteria (55.7%). On average, Bacteroidetes was the second highest phylum followed by Firmicutes for the active landfill. While the phyla for communities in closed landfill were dominated by phyla from Acidobacteria and Actinobacteria. There was also Euryarchaeota (Archaea) which became a minor phylum that was detected in active landfill, but almost completely absent in closed landfill. As such, the composition of bacterial communities suggests some variances between the bacterial communities found in active and closed landfills. Thus, this study offers new clues pertaining to bacterial diversity pattern between the varied types of landfills studied. PMID- 29117587 TI - Potent removal of cyanobacteria with controlled release of toxic secondary metabolites by a titanium xerogel coagulant. AB - Cyanobacteria blooming is a serious environmental issue throughout the world. Removal of cyanobacterial cells from surface water with controlled release of cyanobacterial organic matter (COM), especially toxic microcystins (MCs), would potentially reduce the processing burden in follow-up water treatment. Coagulation is a key technique in water treatment. Herein, the potential application of a novel titanium xerogel coagulant (TXC) was evaluated for the treatment of cyanobacteria-laden water in terms of cyanobacteria removal efficiency, variation of cell viability, the release and evolution of COM in the floc accumulation and storage process. Under acidic to neutral conditions, TXC showed a higher removal efficiency of approximately 99% for cyanobacteria and a lower residual Ti concentration than the widely-used commercial polyferric sulfate (PFS) and polyaluminum chloride (PAC). Another advantage of TXC was the reduced MCs concentration caused by the released acetylacetone (AcAc) from the hydrolysis of TXC. Under solar irradiation, AcAc degraded the extracellular MCs from an initial concentration of 40 MUg/L to a residual concentration of 7 MUg/L during a 16-day floc storage process. The low residual Ti concentration (< 0.04 mg/L) and the efficient removal of COM/MCs following TXC coagulation reduced the toxicity to photobacteria. The results demonstrate that TXC is a promising dual effect coagulant for treatment of cyanobacteria-laden water. PMID- 29117586 TI - Stable long-term operation of an upflow anammox sludge bed reactor at mainstream conditions. AB - The efforts for implementing the anammox process at mainstream conditions with high nitrogen removal rates have gained much attention in the race for achieving an energy-positive urban wastewater treatment plant. Here, the successful and stable long-term operation of an Upflow Anammox Sludge Bed (UAnSB) reactor treating a low-strength synthetic influent amended with ammonium and nitrite for 420 days, and a nitrite-amended pre-treated real urban wastewater for 110 days at temperatures as low as 11 degrees C is presented. The short and long-term effects of temperature on anammox activity were assessed when the synthetic influent was treated, and the UAnSB reactor was demonstrated to be a robust reactor to confront low temperatures, typically found at mainstream conditions. In fact, a nitrogen loading rate as high as 1.8 +/- 0.1 g N L-1 d-1 with 82 +/- 4% of nitrogen removal was achieved at 11 degrees C treating the low-strength synthetic influent. Furthermore, the effect of treating a nitrite-amended pre treated real urban wastewater at 11 degrees C at long-term in the UAnSB reactor was evaluated, and a stable operation was achieved with a high average nitrogen removal rate (1.2 +/- 0.5 g N L-1 d-1). The relative abundance of anammox bacteria was maintained higher than 70% according to fluorescence in situ hybridization during the whole operation, being Candidatus Brocadia anammoxidans the predominant microbial species. The presence of heterotrophs in the sludge bed was surmised through heterotrophic batch tests, but anammox activity was demonstrated to be higher than heterotrophic activity, even when the synthetic influent was replaced by the nitrite-amended pre-treated real wastewater. The feasibility of operating an enriched anammox reactor at high nitrogen removal rate at long-term at mainstream conditions was demonstrated in this study. PMID- 29117588 TI - Metabolic profiling on the effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in MCF-7 cells. AB - Polybrominated diphenyl ethers (PBDEs) are commonly used to prevent the development of fire in various factory products. Due to the adverse effects on human health and the bio-accumulation capacity, PBDEs are considered as one kind of persistent organic pollutants (POPs). BDE-47 is one of the most frequently detected PBDEs congeners in human samples. Although numerous studies have shown the close connection between BDE-47 and human health, few reports were related to breast carcinoma. In the present study, the toxicity mechanism of BDE-47 was investigated by using MCF-7 breast cancer cells. Metabolomics analysis was conducted by using ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Results showed that the toxicity to MCF-7 cells gradually increased when the concentration of BDE-47 exceeded 1 MUM in the medium with 1% fetal bovine serum (FBS). It was found that pyrimidine metabolism, purine metabolism and pentose phosphate pathway (PPP) were the most influenced metabolic pathways, and the metabolites in the three metabolic pathways were significantly downregulated. Moreover, the increase of reactive oxygen species (ROS) was detected by using the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining method. The obtained results suggested that the BDE-47 induced oxidative stress by downregulating the NADPH generation in PPP. The pyrimidine metabolism and purine metabolism might be downregulated by the downregulation of mRNA transcripts. Therefore, BDE-47 could induce oxidative stress by inhibiting PPP and disorder the metabolism of the entire cell subsequently. This research provided evidence for investigating mechanism of the adverse effect of BDE-47 on human health. PMID- 29117589 TI - Chronic exposure of nanomolar MC-LR caused oxidative stress and inflammatory responses in HepG2 cells. AB - Low dose but long-term exposure of microcystin-LR (MC-LR) could induce human hepatitis and promote liver cancer according to epidemiological investigation results, but the exact mechanism has not been completely elucidated. In the present study, a chronic toxicity test of MC-LR exposure on HepG2 cells at 0.1-30 nM for 83 d was conducted under laboratory conditions. The western blot assay result revealed that MC-LR entered HepG2 cells, even at the concentration of 0.1 nM, after 83 d of exposure, but no cytotoxicity was observed in the HepG2 cells, as determined by the CCK-8 and LDH tests. However, the results of the DCF fluorescence assay showed that the intracellular ROS level in the 30 nM MC-LR treated cells was significantly higher than that of the control cells, and 5 and 10 nM of MC-LR exposure totally increased the activity of SOD in HepG2 cells. These results indicate that MC-LR exposure at low concentration also induced excessive ROS in HepG2 cells. Additionally, long-term exposure of MC-LR at low concentration remarkably promoted the expression of NF-kappaB p65, COX-2, iNOS, TNF-alpha, IL-1beta, and IL-6 in the cells, suggesting that long-term MC-LR exposure at low concentration can induce inflammatory reaction to HepG2 cells, which might account for MC-induced human hepatitis. Thus, we hypothesized that the pathogenesis of human hepatitis and hepatocarcinoma caused by MCs might be closely associated with oxidative stress and inflammation. PMID- 29117590 TI - Phosphate solubilization and chromium (VI) remediation potential of Klebsiella sp. strain CPSB4 isolated from the chromium contaminated agricultural soil. AB - In this study, an effort was made to identify an efficient phosphate solubilizing bacterial strain from chromium contaminated agricultural soils. Based on the formation of a solubilized halo around the colonies on Pikovskaya's agar amended with chromium (VI), 10 strains were initially screened out. Out of 10, strain CPSB4, which showed significantly high solubilization zone at different chromium concentrations, was selected for further study. The strain CPSB4 showed significant plant growth promotion traits with chromium (VI) stress under in vitro conditions in broth. The plant growth promotion activities of the strain decreased regularly, but were not completely lost with the increase in concentration of chromium up to 200 mg L-1. On subjected to FT-IR analysis, the presence of the functional group, indicating the organic acid aiding in phosphate solubilization was identified. At an optimal temperature of 30 degrees C and pH 7.0, the strain showed around 93% chromium (VI) reduction under in-vitro conditions in broth study. In soil condition, the maximum chromium (VI) reduction obtained was 95% under in-vitro conditions. The strain CPSB4 was identified as Klebsiella sp. on the basis of morphological, biochemical and 16S rRNA gene sequencing. This study shows that the diverse role of the bacterial strain CPSB4 would be useful in the chromium contaminated soil as a good bioremediation and plant growth promoting agent as well. PMID- 29117591 TI - Effects of salinity and COD/N on denitrification and bacterial community in dicyclic-type electrode based biofilm reactor. AB - A dicyclic-type electrode based biofilm electrode reactor (BER) was developed for advanced nitrate removal from saline municipal wastewater. The denitrification efficiency was evaluated with a synthetic feed (NO3--N, 20 mg L-1) under different salinity and COD to nitrogen ratios (COD/N). As the salinity increased from 0% to 1.0%, the denitrification performance of both the traditional biofilm reactor (BR) and BER was inhibited; however, the BER showed better adaptation and ability to recover. The BER achieved a high nitrate removal efficiency (>=90%) at a salinity of 1.0% and a low COD/N of 2.5 (theoretical stoichiometric 2.86 ignoring microbial growth). The abundance of Methylotenera mobilis in BR and Clostridium sticklandii in BER was higher than in the initial sludge sample used as inoculum. Likewise, the abundance of napA, nirS and nosZ genes increased as the COD/N further decreased. Under high salinity stress, the BER had a higher denitrification efficiency and the consumption of the organic carbon source (i.e., methanol) was reduced compared to BR. The cooperation between heterotrophic and autotrophic denitrifiers in the BER system provides a more efficient and feasible solution for nitrate removal from saline municipal wastewater. PMID- 29117592 TI - NK-lysin from Oreochromis niloticus improves antimicrobial defence against bacterial pathogens. AB - NK-lysin, an effector of cytotoxic T cells and natural killer cells, is a potent antimicrobial peptide widely distributed in mammals. Homologues of NK-lysin have been discovered in several teleost species, but only several of their natural functions was recorded so far. Here we identified an NK-lysin from Nile tilapia (Oreochromis niloticus), On-NKL, and analysed its expression model and biological effects on pathogen infection. The open reading frame of On-NKL sequence spans 432 bp, codes for 143 amino acids and shares 27%-62% overall sequence identities with NK-lysin of other species. The deduced mature peptide of On-NKL possesses a saposin B domain and six well-conserved cysteine residues that essential for antimicrobial activity by forming three intrachain disulphide bonds. The results of qRT-PCR showed that On-NKL expression was observed in multiple tissues and head kidney leucocytes and nonspecific cytotoxic cells (NCCs) and is most abundant in gills. After bacterial challenge, On-NKL expression significantly varied in different tissues and NCCs. Following bacterial infection, On-NKL overexpressing fish featured significantly lower pathogen loads in tissues than control fish. On-NKL-overexpressing fish also exhibited 33.3% relative percent survival compare with control groups. Findings suggested that On-NKL could be the potential effector of NCCs and act as immune-related gene that enhances antimicrobial defence. PMID- 29117593 TI - Spirulina (Arthrospira platensis) supplementation improves growth performance, feed utilization, immune response, and relieves oxidative stress in Nile tilapia (Oreochromis niloticus) challenged with Pseudomonas fluorescens. AB - One hundred and eighty Nile tilapia fish were used in eighty-three-day growth trial. Fish were divided into three treatment groups. The first group T0 was given the basal diet without any supplementation and served as the control group. The second group T1 was given the basal diet supplemented by 1% Spirulina. The third group T2 was given the basal diet supplemented by 2% Spirulina. At the end of the growth performance trial, a challenge trial was conducted using virulent strain of Pseudomonas fluorescens. Clinical signs, mortalities, postmortem lesions and histopathological alterations were recorded. Hematological, biochemical, oxidative stress and immunological parameters were measured after challenge with Pseudomonas fluorescens. Growth performance was non significantly improved in tilapia fed the diet with 1% Spirulina supplementation (T1). There were neither signs nor mortalities among fishes belonging to 1% Spirulina challenged group. The results showed that Spirulina has a positive effect on hematological, biochemical parameters, MDA, SOD and CAT at T1 (1% spirulia) rather than T2 (2%spirulia). Moreover, the results indicate that Spirulina 1% enhanced bactericidal, phagocytic and lysozyme activities conferring protection against infection. Our results demonstrated a significant up-regulation of pro inflammatory cytokine (IL-1beta and TNF-alpha) and a down-regulation of anti inflammatory cytokine (IL-10). We concluded that 1% Spirulina supplementation significantly improved immunity of Nile tilapia against Pseudomonas fluorescence than 2% Spirulina supplementation. PMID- 29117599 TI - Unilateral Tongue Fasciculation Associated with Genetic Paraganglioma Syndrome. PMID- 29117594 TI - Histones and chymotrypsin-like elastases play significant roles in the antimicrobial activity of tongue sole neutrophil extracellular traps. AB - Neutrophil extracellular traps (NETs) are a form of extracellular antimicrobial structure of neutrophils observed in higher and lower vertebrates, the latter including the teleost fish tongue sole Cynoglossus semilaevis. However, the antimicrobial mechanism of fish NETs is unknown. In the present study, we examined the potential contribution of histones and elastases to the antibacterial effect of tongue sole NETs. For this purpose, two histones (CsH2B and CsH4) and two elastases (CsEla1 and CsEla2) of tongue sole were investigated. The histones and elastases possess the conserved domain structures characteristic of that of histones H2B/H4 and trypsin-like serine protease, respectively. Recombinant CsH2B, CsH4, CsEla1, and CsEla2 bound a wide range of Gram-negative and Gram-positive bacteria, and some of the bound bacteria were inhibited in growth by the bound histones/elastases. CsH2B, CsH4, CsEla1, and CsEla2 were all localized in NETs induced by various stimuli including bacterial pathogen. Treatment of NETs with antibodies targeting CsH2B, CsH4, CsEla1, and CsEla2 significantly reduced the antimicrobial effect of NETs. These results indicate that histones and chymotrypsin-like elastases are fundamental components of teleost NETs that play important roles in the antimicrobial activity of NETs. PMID- 29117601 TI - Immune Pathobiology of Schwannomas: A Concise Review. AB - Schwannomas are benign tumors treatable with neurosurgery or radiosurgery, yet a small subset may exhibit aggressive growth. Hence illuminating their immune features can help develop better treatments. A tumor-promoting inflammation exists in schwannomas. Transcription factor NF-kappaB triggers synthesis of inflammatory cytokines and chemokines. NF-kappaB is suppressed by NF2/merlin, yet it is mutated or repressed in schwannomas, and therefore MCP-1/CCL2, MIP 1alpha/CCL3, CXCL16, and CXCR6/Bonzo are likely expressed in these tumors. CD68+ and CD163+ macrophages may infiltrate schwannomas and promote their growth. Anti inflammatory salicylates inhibit schwannomas in cell culture and clinically. Schwannomas that cannot be completely removed by neurosurgery or controlled by radiosurgery may be suitable targets of pharmacologic interventions focusing on immune mechanisms. PMID- 29117602 TI - [Low-intensity Psychiatric Expert Monitoring and Counseling of Unemployed: Presentation of the Gutersloh Pilot Project]. AB - Objective Psychological problems are highly prevalent in unemployed people and can lead to impairments in several areas of life. Programs to support and assist those affected, especially the long-term unemployed, are scarce. Reservations by those affected present an additional barrier with respect to health care utilisation. The authors designed a collaborative care cooperation project between a local job center and a psychiatric clinic with the aims of counselling unemployed people with psychological distress as well as offering continuing psychosocial care if required. Method This paper presents the methodological design, clinical procedure as well as a preliminary evaluation of the pilot phase. Results Within the first 12 months of the pilot phase, 57 long-term unemployed were enrolled in the project. Subjective psychological distress in the sample was comparable with other studies reporting high rates of psychological problems in the unemployed. The psychosocial intervention was well accepted not only by the unemployed but also by case managers and led to high re-assignment rates (n=37) to complementary services within the psychosocial health care system. Conclusion Unemployment and psychological distress should be addressed together within collaborative care projects that can positively affect the negative interaction between unemployment and psychological distress. Low intensity psychological interventions are well suited to address barriers that hinder health care utilization and to offer person-centered, psychological assistance. PMID- 29117603 TI - [Clinical tests for symptom validity assessment]. AB - Assessing symptom validity is essential both in the clinical and medicolegal contexts. If neurological symptoms are demonstrated and/or a patient complains of pain that is not or cannot be fully explained by an underlying disease, it is necessary to recognize reliably a possible psychological cause in order to avoid further unnecessary examinations. In the medicolegal context, malingering or exaggeration of complaints for obtaining financial benefit is to be differentiated in a further step. The present overview contains a summary of clinical observations and tests for neurologists and psychiatrists used for symptom validity assessment of sensorimotor symptoms, tremor, gait, equilibrium and visual disturbances as well as pain. PMID- 29117604 TI - [In-depth analysis of cost structure for electroconvulsive therapy in a performance-based hospital budget]. AB - Objective New medical guideline recommendations for the treatment of major depressive disorders and regulative changes in the payment system of the German mental health care system warrant a revision of the framework in which electroconvulsive therapies (ECT) are offered. Methods A cost structure analysis of the clinical resources essential for the ECT procedure was conducted and economically validated, exemplified at a German inpatient ECT treatment center. Results The identification of directly attributable costs to the ECT intervention presupposes an accurate assessment of personnel engagement time and material consumption as well as an inclusion of overhead costs for the operational readiness of the hospital. Conclusion The increasing importance of ECT in the clinical portfolio of therapy options demands an adequate refunding to support the expansion of this highly effective treatment. For the calculation of an appropriate reimbursement for ECT and ascertaining an acceptable contribution, a detailed knowledge of personnel costs and infrastructure settings of the respective hospitals is required. PMID- 29117606 TI - [The Dawn of Modernity: Giovanni Boccaccio's "The Decameron" and the Tradition of Genetic Understanding]. AB - "The Decameron" by Giovanni Boccaccio is a work which stands between the Middle Ages and Modernity. There are theories which postulate that concepts of identity and individuality, which arose with the dawn of Modernity, have an influence on mental illness. We chose a hermeneutic approach towards "The Decameron" to analyse the depiction of a changing society, of love, mental suffering and the role of therapeutic interventions. We conclude that Boccaccio showed an interest in intrapsychic mechanisms, an idea pertaining to Modernity, and discuss this idea in light of today's psychiatry and Karl Jaspers' concept of "genetic understanding". PMID- 29117605 TI - [New oral anticoagulants (NOAC) in stroke treatment]. AB - Since 2011, new oral anticoagulants (NOAC) can be prescribed for prevention of cardio-embolic ischemic strokes in addition to vitamin K antagonists. NOAC are indicated in patients with non-valvular atrial fibrillation. Although its use is a matter of debate in Germany, the neurological and cardiological societies recommend the use of NOAC over and above vitamin K antagonists due to a better benefit-to-risk ratio attributed to it, especially because of the lower risk of intracranial hemorrhage in NOAC use. A specific antidote is commercially available for the direct thrombin inhibitor dabigatran only. For the factor Xa inhibitors, an antidote is being investigated in clinical trials. To our best knowledge, there are no direct head-to-head studies between the NOACs. Therefore, none of them can be assumed to be superior and the decision for a specific NOAC should be based on the available scientific data from the NOAC trials considering the individual patient's characteristics and comorbidities. PMID- 29117607 TI - [Choroidal Osteoma in a Male Patient - Multimodal Imaging]. PMID- 29117608 TI - [Assessment of Cyclofusion Capabilities of Normal Subjects with 3D Dynamic Random Dot Stereograms]. AB - BACKGROUND: Evaluation of a new method for cyclofusion measurement. PATIENTS AND METHODS: The maximal incyclofusion and excyclofusion tolerated of 20 normal subjects (15 females, mean age 36 +/- 9.9 years) were measured by computer generated dynamic random-dot stereograms (DRDS). Subjects had to detect the orientation of only binocularly visible Landolt C stimuli randomly presented with a 3-D monitor. Both eyes were separately stimulated with shutter glasses. The DRDS-pattern projected to the left and right eye were rotated in the opposite direction in 0.5 degrees steps. In 10 subjects, cyclofusion measurements were repeated. RESULTS: Incylofusional amplitudes were between 2.5 degrees and 6 degrees , excyclofusional amplitudes measured between 3 degrees and 5.5 degrees . Mean incyclofusion was 3.71 degrees (SD 0.82) and mean excyclofusion measured 4.24 degrees (SD 0.73). Repeated measurements of incyclofusion and excyclofusion in the same subject demonstrated a difference of about 0.5 degrees (0.55 degrees for incyclofusion, 0.45 degrees for excyclofusion). CONCLUSIONS: The DRDS Landolt C method provided a reliable assessment with good reproducibility of cyclofusion in healthy subjects with only binocularly perceivable objects. Our cyclofusional capabilities were slightly higher than those received with dissociating 2D measurements. PMID- 29117609 TI - [In Vitro Evaluation of the Optical Quality of Segmental Refractive Multifocal Intraocular Lenses]. AB - OBJECTIVES: In customised patient care, it is important to know the optical quality of different intraocular lenses (IOL). In this study, the optical quality of three segmental intraocular lenses were compared. MATERIALS AND METHODS: The LENTIS Comfort LS-313 MF15, LENTIS Mplus X LS-313 MF30 and LENTIS High Add IOL LS 313 MF80 (Oculentis, Berlin, Germany) with a far power of + 21 D were analysed at the optical bench OptiSpheric IOL PRO (Trioptics GmbH, Wedel, Germany). The lenses have almost the same optical design but differ in the power of the near segment. The MF15 has a + 1.5 D addition to improve vision in intermediate distances, the MF30 has a near addition of + 3 D and the MF80 has a near addition of + 8 D. The modulation transfer function area (MTFa) and the Strehl ratio were examined for apertures of 3 mm (photopic) and 4.5 mm (mesopic). RESULTS: The MTFa values for the far focus are 33.34/30.80/51.53 (MF15/MF30/MF80) with an aperture of 3 mm and 25.38/22.52/43.15 for 4.5 mm. The MTFa values for the intermediate focus are 29.85/16.21/6.25 for a 3 mm aperture and 23.92/8.05/3.08 for 4.5 mm. The MTFa values for the near focus are 9.75/21.49/33.12 for an aperture of 3 mm and 4.95/22.70/31.68 for 4.5 mm. The Strehl ratio of the far focus is 0.34/0.30/0.52 for an aperture of 3 mm and 0.24/0.22/0.43 for 4.5 mm. For the intermediate focus, the Strehl ratio is 0.30/0.17/0.07 for an aperture of 3 mm and 0.24/0.08/0.03 for 4.5 mm. The Strehl ratio of the near focus is 0.10/0.22/0.33 for an aperture of 3 mm and 0.05/0.23/0.32 for 4.5 mm. CONCLUSION: We confirmed that the addition influences the optical quality of segmental bifocal intraocular lenses. For the far focus, the results of the MF15 and MF30 are similar. In intermediate distances, the MF15 achieves the best results. For near distances, the MF30 achieves better optical values than the MF15. The lens MF80, which has been designed for patients with maculopathies, achieves good results for far and near distances. PMID- 29117610 TI - [Evaluation of Ophthalmic Follow-up Care of Former Pre-term and Full-term Infants Aged from 4 to 10 Years in Germany - Results of the Wiesbaden Prematurity Study (WPS)]. AB - BACKGROUND: The purpose of this investigation was to analyse the ophthalmic follow-up care of former pre-term and full-term born infants aged 4 to 10 years in the clinical practice and the comparison to the recommendations of the national ophthalmic guidelines. METHODS: For the prospective Wiesbaden Prematurity Study (WPS), 503 infants were examined: 239 former pre-term infants (PT) with gestational age (GA) <= 32 weeks and 264 former full-term born infants (FT) with a GA >= 37 weeks aged 4 to 10 years. Ophthalmic examination was performed including refractive measurements and orthoptic examination. Anisometropia was defined as a difference of >= 1 D spherical equivalent. Data was assessed if an ophthalmological examination was performed after hospital discharge, and how many times the ophthalmologist was contacted within the last 12 months. RESULTS: Overall, strabismus and anisometropia were present in 18 and 10% of all PT, and in 2 and 5% of all FT infants, respectively. In infants aged 4 to 6 years, 65% of all former PT and 42% of all former FT had ophthalmological contacts within the last year (p = 0.002). 15% of the pre-term infants with strabismus did not have an ophthalmological examination within the last year. The parents of three former pre-term infants reported that they never had an ophthalmologic examination after hospital discharge. CONCLUSION: Two-thirds of the former pre-term infants participated in a screening examination at the age of 4 to 6 years in the last year according to their parents, which is recommended by the guidelines for the care of former pre-term infants. There is still room for improvement to provide best ophthalmological care for this vulnerable population that have high risk for strabismus and amblyopia. PMID- 29117611 TI - [The Use of a Microsensor in Therapy of Amblyopia]. AB - Amblyopia is one of the most common visual disorders in children. Current therapy of amblyopia is an occlusion therapy of the stronger eye with an occlusion patch until the best corrected visual acuity is achieved. The success of occlusion therapy essentially depends on the compliance of the children and their parents. There is a commercially available 8 * 12 mm small TheraMon microsensor (TheraMon(r)-Chip, MC Technology GmbH). This sensor allows a simple objective documentation of the therapy compliance of patches and glasses. It samples the surrounding temperature in regular intervals. Due to the specific temperatures, it is possible to detect the time of application and, therefore, the compliance. Therefore, TheraMon microsensor could be a study-related approach for monitoring the compliance and further leading to possible improvement of application time protocols in amblyopia therapy. PMID- 29117612 TI - Effect of Diabetes on the Assessment Role of 2-Oxoglutarate to the Severity of Chronic Heart Failure. AB - BACKGROUND: Serum 2-oxoglutarate can reflect the severity of chronic heart failure (CHF) in patients without diabetes. Whether this predictive role persists in type 2 diabetes mellitus (T2DM) patients is unclear. In this study, we investigated this predictive role in T2DM patients and whether 2-oxoglutarate can indicate the diastolic or systolic function of left ventricle. METHODS: One hundred eighty CHF patients (76 with T2DM) and 66 healthy controls were studied. 2-Oxoglutarate was assayed by liquid chromatography-mass spectrometry/mass spectrometry. Echocardiographic parameters, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and other parameters were measured. RESULTS: 2-Oxoglutarate was increased in CHF patients with or without T2DM compared with controls (both P<0.01). Patients with a lower left ventricular ejection fraction or a higher NT proBNP or left ventricular end-diastolic volume index had higher levels of 2 oxoglutarate (median, 18.77 MUg/mL versus 11.25 MUg/mL; median, 14.06 ug/ml versus 9.39 ug/ml; median, 18.06 ug/mL versus 11.60 ug/mL, all P<0.05) in nondiabetic patients but not in T2DM patients. In multiple logistic regression analysis, NT-proBNP (OR=3.445, 95% CI=1.098 to 10.816, P=0.034) and left ventricular end-diastolic diameter (OR=2.544, 95% CI=1.033 to 6.268, P=0.042) were independently associated with increased 2-oxoglutarate in nondiabetic patients. CONCLUSIONS: The levels of 2-oxoglutarate can reflect the clinical severity of CHF in nondiabetic patients but not in those with T2DM, and it can be used as a potential indicator of the systolic dysfunction of the left ventricle. PMID- 29117613 TI - Evaluation of the Relation Between Omentin-1 and Vitamin D in Postmenopausal Women With or Without Osteoporosis. AB - INTRODUCTION: Crosstalk between bone and adipose tissues is implicated in several pathologic conditions related to bone metabolism. Omentin-1, a 34-kD protein, is released from omental adipose tissue. A few studies indicated the effect of omentin-1 on bone health and bone mineral density (BMD) and the interaction of omentin-1 with vitamin D. Therefore, this study aimed to investigate the relationship between omentin-1, vitamin D, and BMD in postmenopausal women with osteoporosis compared with non-osteoporotic counterparts. MATERIALS AND METHODS: Forty postmenopausal women with osteoporosis (OP), 40 counterparts without OP, and 30 premenopausal women were enrolled. Dual-energy X-ray Absorptiometry results, body mass index, and some demographic and biochemical data were recorded. Vitamin D (25-hydroxyvitamin D3) levels were measured using liquid chromatography-tandem mass spectrometry. Serum omentin-1 was determined using an enzyme-linked immunosorbent assay. RESULTS: Omentin-1 levels tended to increase in both postmenopausal women groups compared with the control group, but this increase was significant only in women with osteoporosis. Vitamin D levels were not different between the groups. When women were categorized according to vitamin D levels, women with normal vitamin D levels had significantly higher omentin-1 levels. A positive correlation was found between omentin-1 and vitamin D levels in all groups (r=0.197, p=0.041, n=110). CONCLUSION: The tendency to an increase in omentin-1 levels in postmenopausal women with osteoporosis may be due to a physiologic compensation against bone loss after menopause. The linear relationship between omentin-1 and vitamin D suggests that adipose tissue is one of the target tissues for the vitamin D effect. PMID- 29117614 TI - The Effect of Hypolipidemic Agents on Thyroid Autoimmunity in Women with Hashimoto's Thyroiditis Treated with Levothyroxine and Selenomethionine. AB - BACKGROUND: Levothyroxine and selenomethionine were found to reduce thyroid antibody titers in patients with Hashimoto's thyroiditis. The same effect was produced by intensive statin therapy. The aim of the present study was to assess whether hypolipidemic agents modulate the impact of thyroid hormone supplementation and selenomethionine on thyroid autoimmunity. METHODS: The study included 62 women with Hashimoto's thyroiditis treated for at least 6 months with levothyroxine and selenomethionine. On the basis of plasma lipids, women were divided into three groups: women with isolated hypercholesterolemia (group A; n=20), women with isolated hypertriglyceridemia (group B; n=17), and women with normal plasma lipids (group C; n=25). Group A were then treated with atorvastatin (20 mg daily), while group B received micronized fenofibrate (200 mg daily). Serum titers of thyroid peroxidase and thyroglobulin antibodies, as well as serum levels of thyrotropin, free thyroxine and free triiodothyronine were measured at the beginning of the study and 6 months later. RESULTS: Fenofibrate decreased triglycerides and increased HDL cholesterol, while simvastatin decreased total and LDL cholesterol. Fenofibrate reduced titers of thyroid peroxidase and, to a lesser extent, thyroglobulin antibodies. Atorvastatin tended to increase thyroid peroxidase antibodies. No changes in thyrotropin, free thyroxine and free triiodothyronine were observed in any treatment group. Fenofibrate-induced changes in thyroid antibody titers correlated with baseline antibody titers, as well as with treatment-induced changes in HDL cholesterol and insulin sensitivity. CONCLUSIONS: The obtained results indicate that only fibrates may potentiate the effect of selenomethionine and levothyroxine on thyroid autoimmunity in women. PMID- 29117615 TI - Safety of Metformin Therapy in Patients with Type 2 Diabetes Living on an Oxygen Deficient Plateau, Tibet, China. AB - BACKGROUND: In the general population, the absolute risk of lactic acidosis in patients treated with metformin appears to be low. However, in the Tibetan plateau, an extreme oxygen-deficient environment, there are no data available concerning the safety of metformin. The aim of our study is to assess the safety of metformin in people of the plateau area. METHODS: We conducted an observational cross-sectional study in Tibet. All the 166 subjects were divided into two groups: T2DM+metformin group and T2DM group. Clinical characteristics as well as lactate levels were measured in all subjects. The association between lactate, metformin use, FBG, HbA1c, eGFR, and other potential predictors was evaluated. RESULTS: A total of 166 subjects were enrolled in this study. Average age was 51.7+/-12.3 years, and the percentage of male participants was 67%. The median level of lactate was 1.89 (1.35-2.91) mmol/L in all the subjects. The mean (+/-SD) lactate concentration in patients treated with metformin, versus those who were not, was 2.35+/-1.42 vs 2.29+/-1.65 mmol/L, respectively (mean difference 0.06 mmol/L, 95% CI: -0.48-0.60, P=0.556). FBG was significantly higher in the high lactate group than in the low lactate group (12.1+/-4.1 vs. 10.5+/-4.0 mmol/L, P=0.018). Similarly, HbA1c level was also significantly higher in the high lactate group than in the low lactate group (12.3+/-2.6 vs. 11.0+/ 3.0%, P=0.008). CONCLUSIONS: In the oxygen-deficient Tibetan plateau, lactate concentration among patients on metformin was not significantly different from patients without metformin. The level of lactate was significantly associated with FBG and HbA1c levels. PMID- 29117616 TI - Invasive Pituitary Adenoma-Derived Tumor-Associated Fibroblasts Promote Tumor Progression both In Vitro and In Vivo. AB - Tumor-associated fibroblasts are the most abundant population in tumor stroma and impact on tumor initiation and progression. However, the biological function of tumor-associated fibroblasts in pituitary adenomas has not been fully elucidated to date. So, this study aims to clarify the function and significance of primary cultured pituitary adenoma-derived tumor-associated fibroblasts on rat pituitary adenoma cells. We identified primary cultured tumor-associated fibroblasts and normal fibroblasts based on the expression of alpha-smooth muscle actin as well as morphology. Furthermore, we investigated cell biological influences on rat pituitary adenoma cells through indirectly co-culturing tumor-associated fibroblasts with GH3 cells and subcutaneous xenograft model. All sorts of fibroblasts showed positive staining for alpha-smooth muscle actin. But alpha smooth muscle actin and vascular endothelial growth factor highly expressed in invasive pituitary adenoma-derived tumor-associated fibroblasts compared to non invasive pituitary adenoma-derived tumor-associated fibroblasts and normal fibroblasts. Besides, invasive pituitary adenoma-derived tumor-associated fibroblasts promoted the proliferation of GH3 cells in vitro as well as tumor growth in vivo. Finally, vascular endothelial growth factor was highly expressed in tumor specimens co-injected with invasive pituitary adenoma-derived tumor associated fibroblasts. Our results suggested that invasive pituitary adenoma derived tumor-associated fibroblasts displayed apparent growth promotion effects on rat pituitary cells both in vitro and in vivo accompanied by over-expression of vascular endothelial growth factor in invasive pituitary adenoma-derived tumor associated fibroblasts and tumor specimens. PMID- 29117617 TI - Plasma Free Fatty Acids Metabolic Profile Among Uyghurs and Kazaks With or Without Type 2 Diabetes Based on GC-MS. AB - Free fatty acids (FFAs) participate in a variety of physiological functions. FFAs are associated with the development of type 2 diabetes mellitus (T2DM). Uyghurs and Kazaks have a different prevalence of T2DM, which cannot be explained by traditional risk factors. This study aimed to examine FFAs as potential biomarkers to distinguish between healthy and T2DM Uyghurs and Kazaks. This was a prospective study conducted at the Xianjiang Medical University from 01/2007 to 06/2010 in Uyghurs and Kazaks. The subjects were grouped as T2DM patients (Uyghurs: n=39; Kazaks, n=21) and controls (Uyghurs: n=35; Kazaks, n=40). Gas chromatography-mass spectrometry (GC-MS) and partial least squares discriminant analysis (PLS-DA) models were used to study the FFA profiles between Uyghurs and Kazaks with T2DM. PLS-DA analysis showed that among Kazaks, T2DM patients had lower C22:6, C18:3 n-6, and C20:3 n-6, but higher C22:0 levels compared with controls. Among Uyghurs, the most important variables to discriminate T2DM patients from controls were higher C22:6 and C20:4 n-6, and lower C22:0, C14:1, C18:3 n6, and C20:3 n6. Kazaks and Uyghurs displayed different FFA profiles between patients with T2DM and controls. These results suggest different risk factors and pathogenesis of T2DM between Kazaks and Uyghurs. PMID- 29117619 TI - Development of Obesity-Associated Comorbidities Post Bariatric Surgery with a Special Focus on Diabetes Remission and Short-Term Relapse. AB - PURPOSE: The purpose of this study is to study a heterogeneous group of obese patients undergoing Bariatric surgery(BS) and its impact on glycemic control. Secondary endpoints include changes in lipid profile and albuminuria. BS has shown to effectively reduce body-weight. However, the impact on obesity-related comorbidities varies strongly between individuals. Especially postoperative short and long-term improvement of Diabetes is an active area of investigation. METHODS: We conducted a retrospective analysis from baseline to 24 months post bariatric surgery in our interdisciplinary obesity outpatient-clinic. Follow-up data was collected from 215 patients who had undergone either Roux-en-Y gastric bypass or Sleeve Gastrectomy. The prevalence of and changes in the major obesity related comorbidities and concurrent medication were assessed. RESULTS: Standard parameters of diabetic control showed a U-shaped curve with initial improvement after six months, but with a gradual worsening after the first year of follow-up. Weight loss resulted in dose reduction of oral antidiabetic medication and insulin in 85% and 100% of patients, respectively. With weight loss, a significant improvement in lipid profile one year after surgery was seen. Subgroup analysis demonstrated gender- and age-dependent differences in overall benefit. CONCLUSIONS: Current data on diabetes remission might be too optimistic and close follow-up should be provided to prevent gradual worsening of glucose metabolism after BS. PMID- 29117618 TI - The Effects of Flaxseed Oil Omega-3 Fatty Acids Supplementation on Metabolic Status of Patients with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVE: This study was conducted to evaluate the effects of flaxseed oil omega 3 fatty acids supplementation on metabolic status of patients with polycystic ovary syndrome (PCOS). METHODS: This randomized double-blind, placebo-controlled trial was conducted on 60 women with PCOS according to the Rotterdam criteria aged 18-40 years old. Participants were randomly assigned into two groups to receive either 1,000 mg flaxseed oil omega-3 fatty acids (n=30) or placebo (n=30) twice a day for 12 weeks. Metabolic, endocrine, inflammatory factors were quantified at baseline and after the 12-week intervention. RESULTS: After the 12 week intervention, compared to the placebo, flaxseed oil omega-3 supplementation significantly decreased insulin values (-2.6+/-7.7 vs.+1.3+/-3.9 uIU/mL, P=0.01), homeostasis model of assessment-estimated insulin resistance (-0.7+/-1.7 vs.+0.3+/-0.9, P=0.01), mF-G scores (-1.2+/-1.7 vs. -0.1+/-0.4, P=0.001), and increased quantitative insulin sensitivity check index (+0.01+/-0.02 vs. -0.01+/ 0.02, P=0.01). In addition, supplementation with flaxseed oil omega-3 resulted in significant decreases in serum triglycerides (-5.1+/-20.9 vs.+9.7+/-26.1 mg/dL, P=0.01), VLDL-cholesterol (-1.0+/-4.2 vs.+1.9+/-5.2 mg/dL, P=0.01) and high sensitivity C-reactive protein (hs-CRP) (-1.6+/-3.1 vs.+0.2+/-1.5 mg/L, P=0.004) compared to the placebo. We did not see any significant effect of flaxseed oil omega-3 supplementation on hormonal and other lipid profiles, and plasma nitric oxide levels. CONCLUSIONS: Overall, flaxseed oil omega-3 supplementation for 12 weeks in women with PCOS had beneficial effects on insulin metabolism, mF-G scores, serum triglycerides, VLDL-cholesterol and hs-CRP levels, but did not affect hormonal and other lipid profiles, and plasma nitric oxide levels. PMID- 29117620 TI - The Effects of a Modified High-carbohydrate High-fat Diet on Metabolic Syndrome Parameters in Male Rats. AB - Metabolic syndrome is a cluster of metabolic abnormalities including central obesity, hyperglycemia, hypertension, and dyslipidemia. A previous study has established that high-carbohydrate high-fat diet (HCHF) can induce MetS in rats. In this study, we modified components of the diet so that it resembled the diet of Southeast Asians. This study aimed to determine the effects of this modified HCHF diet on metabolic parameters in rats. Male Wistar rats (n=14) were randomised into two groups. The normal group was given standard rat chow. The MetS group was given the HCHF diet, comprises of fructose, sweetened condensed milk, ghee, Hubble Mendel and Wakeman salt mixture, and powdered rat food. The diet regimen was assigned for a period of 16 weeks. Metabolic syndrome parameters (abdominal circumference, blood glucose, blood pressure, and lipid profile) were measured at week 0, 8, 12, and 16 of the study. The measurement of whole body composition (fat mass, lean mass, and percentage of fat) was performed using dual energy X-ray absorptiometry at week 0, 8, and 16. Our results indicated that the components of MetS were partially developed after 8 weeks of HCHF diet. Systolic blood pressure, triglyceride, low density lipoprotein cholesterol, fat content, and percentage of fat was significantly higher in the HCHF group compared to normal group (p<0.05). After 12 weeks of HCHF diet, the rats showed significant increases in abdominal circumference, blood pressure, glucose intolerance, and dyslipidemia compared to normal control (p<0.05). In conclusion, MetS is successfully established in male rats induced by the modified HCHF diet after 12 weeks. PMID- 29117621 TI - Gender Differences in Cardiometabolic Risk Factors in Metabolically Healthy Normal Weight Adults with Central Obesity. AB - We investigated whether metabolically healthy normal weight adults with central obesity display worse cardiometabolic profile compared with their centrally lean counterparts. This retrospective, cross-sectional study, comprised 1 135 subjects (64% females) aged 18-to-81 years, presenting <=2 components of metabolic syndrome. They were classified as centrally lean (waist-to-height ratio (WHtR)<0.5 and waist circumference<80 cm in females and<94 cm in males) or presenting central obesity (WHtR >=0.5, regardless of waist circumference). Data on blood pressure, glucose homeostasis, lipid profile, renal function, high sensitive C-reactive protein (hsCRP), uric acid, adiponectin, leptin, and soluble receptor for advanced glycation end products were compared between the groups, separately in males and females. 5.7% of males and 6.9% of females presented WHtR >=0.5. Compared with centrally lean subjects, those with central obesity had higher BMI-adjusted fasting plasma glucose (p<0.001), and leptin levels (p<0.05); females also presented higher blood pressure (p<0.001), while males had higher hsCRP concentrations (p=0.021). These changes associated with significantly higher BMI-adjusted odds to present fasting plasma glucose >5.6 mmol/l in both genders, higher odds to present hsCRP >3 mg/l in males, and those to present elevated blood pressure in females. Our analysis suggests that in metabolically healthy normal weight subjects WHtR >=0.5 might indicate "early increased health risk". PMID- 29117622 TI - Visceral Adiposity Index was a useful Predictor of Prediabetes. AB - AIM: To study the relationship of visceral adiposity index (VAI) and prediabetes and the power of which in predicting of prediabetes. METHODS: A cross-sectional epidemiological survey was conducted. All participants were divided into four groups: VAI and WC (both are normal), VAI? and WC (postcritical VAI and normal WC), VAI and WC? (Normal VAI and postcritical WC), and VAI? and WC? (postcritical VAI and postcritical WC). A multivariate logistic analysis was used to analyze the relationship between the four groups and prediabetes, and diabetes. A receiver operating characteristic (ROC) curve analysis was used to evaluate the accuracy of predictions for prediabetes and diabetes. RESULTS: Both VAI and WC were independent risk factors of Prediabetes. The ORs for Prediabetes in the VAI?&WC group were 1.641 (95%CI 1.146-2.349), P=0.007, in males, in Model 2. The ORs for Prediabetes in the VAI&WC? group were 1.454 (95%CI 1.055-2.005), P=0.022, in males, in Model 2. The ORs for Prediabetes in the VAI?&WC group were 2.305 (95%CI 1.623-3.273), P=0.000, in females, in Model 2. The ORs for Prediabetes in the VAI&WC? group were 1.997 (95%CI 1.529-2.608), P=0.000, in females, in Model 2. The AUC value of VAI were 0.601 (95%CI 0.568-0.634), P=0.000, in prediabetes of men; which were 0.645 (95%CI 0.618-0.672), P=0.000, in prediabetes women. WC had the highest AUC value of 0.605 (95%CI 0.571-0.638), P=0.000, in prediabetes of men, also had the highest of AUC value of 0.673 (95%CI 0.648-0.697), P=0.000, in prediabetes of women. CONCLUSION: VAI was positively associated with prediabetes, and also a usefulindicator of prediabetes. PMID- 29117623 TI - Comments to the Editor Concerning the Paper Entitled "Mitochondrial Dysfunction in Diabetic Cardiomyopathy: Effect of Mesenchymal Stem Cell with PPAR-gamma Agonist or Exendin-4" Mohamed Abd Elaziz Wassef et al. PMID- 29117624 TI - The Role of Lipids in the Pathogenesis of Metabolic Syndrome in Adolescents. AB - The increasing prevalence of childhood obesity is a driving force behind the increase in adolescent's metabolic syndrome (MetS). Although there is no clear consensus about the pediatric definition for MetS, this syndrome is becoming very common among adolescents. It is characterized by insulin resistance (IR), dyslipidemia, abdominal obesity and hypertension, and is associated with a high risk of type 2 diabetes mellitus and CVD in adulthood. Due to the increasing prevalence of obesity, there is strong incentive to reduce the impact of the adverse health effects associated with MetS. We explored the etiological role of nutrient-derived metabolic stressors, especially fatty acids, in the development of obesity and MetS. We also reviewed the evidence that pro-inflammatory stressors may predispose to obesity-induced insulin resistance. This article presents the opinion that reducing the impact of metabolic and inflammatory stressors may reduce the adverse health effects of obesity, and slow the progression towards MetS and CVD in adolescents. Evidence so far is limited from pediatric dietary epidemiological and interventional studies investigating the potential preventive and therapeutic effects of dietary fatty acid modification. This review will further investigate our understanding of the interaction between fatty acids in the pathogenesis and progression of MetS in adolescents. PMID- 29117625 TI - NMR, MP2, and DFT study of thiophenoxyketenimines (o-thio-Schiff bases): Determination of the preferred form. AB - Five new thiophenoxyketinimines have been synthesized. 1 H and 13 C NMR spectra as well as deuterium isotope effects on 13 C chemical shifts are determined, and spectra are assigned. DFT and MP2 calculations of both structures, chemical shifts, and isotope effects on chemical shifts are done. The combined analysis reveals that the compounds are primarily on a zwitterionic form with an NH+ and a S- group and with a little of the neutral form mixed in. Very strong intramolecular hydrogen bonding is found and very high NH chemical shifts are observed. The theoretical calculations show that calculations at the MP2 level are best to obtain correct "C?S" chemical shifts. PMID- 29117626 TI - Unravelling the roles of innate lymphoid cells in cerebral malaria pathogenesis. AB - Cerebral malaria (CM) is one complication of Plasmodium parasite infection that can lead to strong inflammatory immune responses in the central nervous system (CNS), accompanied by lung inflammation and anaemia. Here, we focus on the role of the innate immune response in experimental cerebral malaria (ECM) caused by blood-stage murine Plasmodium berghei ANKA infection. While T cells are important for ECM pathogenesis, the role of innate lymphoid cells (ILCs) is only emerging. The role of ILCs and non-lymphoid cells, such as neutrophils and platelets, contributing to the host immune response and leading to ECM and human cerebral malaria (HCM) is reviewed. PMID- 29117627 TI - Unusual type of partial anomalous pulmonary venous connection: Three pulmonary veins connected to the coronary sinus. PMID- 29117628 TI - Blood eosinophils: The forgotten man of inhaled steroid dose titration. PMID- 29117629 TI - Medical and dietary interventions for preventing recurrent urinary stones in children. AB - BACKGROUND: Nephrolithiasis, or urinary stone disease, in children causes significant morbidity, and is increasing in prevalence in the North American population. Therefore, medical and dietary interventions (MDI) for recurrent urinary stones in children are poised to gain increasing importance in the clinical armamentarium. OBJECTIVES: To assess the effects of medical and dietary interventions (MDI) for the prevention of idiopathic urinary stones in children aged from one to 18 years. SEARCH METHODS: We searched multiple databases using search terms relevant to this review, including studies identified from the Cochrane Central Register of Controlled Trials (CENTRAL, 2017, Issue 1), MEDLINE OvidSP (1946 to 14 February 2017), Embase OvidSP (1980 to 14 February 2017), International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Additionally, we handsearched renal-related journals and the proceedings of major renal conferences, and reviewed weekly current awareness alerts for selected renal journals. The date of the last search was 14 February 2017. There were no language restrictions. SELECTION CRITERIA: Randomized controlled trials of at least one year of MDI versus control for prevention of recurrent idiopathic (non-syndromic) nephrolithiasis in children. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. Titles and abstracts were identified by search criteria and then screened for relevance, and then data extraction and risk of bias assessment were carried out. We assessed the quality of evidence using GRADE. MAIN RESULTS: The search identified one study of 125 children (72 boys and 53 girls) with calcium containing idiopathic nephrolithiasis and normal renal morphology following initial treatment with shockwave lithotripsy (SWL). Patients were randomized to oral potassium citrate 1 mEq/kg per day for 12 months versus no specific medication or preventive measure with results reported for a total of 96 patients (48 per group). This included children who were stone-free (n = 52) or had residual stone fragments (n = 44) following SWL. Primary outcomes:Medical therapy may lower rates of stone recurrence with a risk ratio (RR) of 0.19 (95% confidence interval (CI) 0.06 to 0.60; low quality evidence). This corresponds to 270 fewer stone recurrences per 1000 (133 fewer to 313 fewer) children. We downgraded the quality of evidence by two levels for very serious study limitations related to unclear allocation concealment (selection bias) and a high risk of performance, detection and attrition bias. While the data for adverse events were incomplete, they reported that six of 48 (12.5%) children receiving potassium citrate left the trial because of adverse effects. This corresponds to a RR of 13.0 (95% CI 0.75 to 224.53; very low quality evidence); an absolute effect size estimate could not be generated. We downgraded the quality of evidence for study limitations and imprecision.We found no information on retreatment rates. SECONDARY OUTCOMES: We found no evidence on serum electrolytes, 24-hour urine collection parameters or time to new stone formation.We were unable to perform any preplanned secondary analyses. AUTHORS' CONCLUSIONS: Oral potassium citrate supplementation may reduce recurrent calcium urinary stone formation in children following SWL; however, our confidence in this finding is limited. A substantial number of children stopped the medication due to adverse events. There is no trial evidence on retreatment rates. There is a critical need for additional well-designed trials in children with nephrolithiasis. PMID- 29117630 TI - Biophysical properties of microvascular endothelium: Requirements for initiating and conducting electrical signals. AB - OBJECTIVE: Electrical signaling along the endothelium underlies spreading vasodilation and blood flow control. We use mathematical modeling to determine the electrical properties of the endothelium and gain insight into the biophysical determinants of electrical conduction. METHODS: Electrical conduction data along endothelial tubes (40 MUm wide, 2.5 mm long) isolated from mouse skeletal muscle resistance arteries were analyzed using cable equations and a multicellular computational model. RESULTS: Responses to intracellular current injection attenuate with an axial length constant (lambda) of 1.2-1.4 mm. Data were fitted to estimate the axial (ra ; 10.7 MOmega/mm) and membrane (rm ; 14.5 MOmega?mm) resistivities, EC membrane resistance (Rm ; 12 GOmega), and EC-EC coupling resistance (Rgj ; 4.5 MOmega) and predict that stimulation of >=30 neighboring ECs is required to elicit 1 mV of hyperpolarization at distance = 2.5 mm. Opening Ca2+ -activated K+ channels (KCa ) along the endothelium reduced lambda by up to 55%. CONCLUSIONS: High Rm makes the endothelium sensitive to electrical stimuli and able to conduct these signals effectively. Whereas the activation of a group of ECs is required to initiate physiologically relevant hyperpolarization, this requirement is increased by myoendothelial coupling and KCa activation along the endothelium inhibits conduction by dissipating electrical signals. PMID- 29117631 TI - Astrocyte elevated gene-1 promotes invasion and epithelial-mesenchymal transition in bladder cancer cells through activation of signal transducer and activator of transcription 3. AB - OBJECTIVES: To determine the impact of astrocyte elevated gene-1 on the invasion and epithelial-mesenchymal transition of bladder cancer cells in vitro and metastasis in vivo. METHODS: Gain- and loss-of-function studies were carried out to investigate the biological roles of astrocyte elevated gene-1 in bladder cancer cell invasion, epithelial-mesenchymal transition and lung metastasis. The mechanism underlying the activity of astrocyte elevated gene-1 was examined. RESULTS: Overexpression of astrocyte elevated gene-1 led to a significant increase in the invasive ability of UMUC3 and T24 bladder cancer cells in Matrigel invasion assays. In contrast, silencing of astrocyte elevated gene-1 restrained bladder cancer cell invasion. Overexpression of astrocyte elevated gene-1 downregulated E-cadherin and upregulated vimentin and Twist1, while silencing of astrocyte elevated gene-1 exerted an opposite effect. Mechanistically, astrocyte elevated gene-1 overexpression promoted the phosphorylation of signal transducer and activator of transcription 3 in bladder cancer cells. Treatment with WP1066, a specific signal transducer and activator of transcription 3 inhibitor, significantly abolished astrocyte elevated gene-1 induced invasion and epithelial-mesenchymal transition in UMUC3 cells. In vivo studies showed that astrocyte elevated gene-1 overexpression stimulated the growth of UMUC3 xenograft tumors and lung metastasis. CONCLUSIONS: Astrocyte elevated gene-1 shows the ability to promote bladder cancer metastasis, which is causally linked to induction of signal transducer and activator of transcription 3 activation and epithelial-mesenchymal transition. Therefore, targeting astrocyte elevated gene-1 might offer therapeutic benefits in treating metastatic bladder cancer. PMID- 29117632 TI - Living quarters of a living fossil-Uncovering the current distribution pattern of the rediscovered Hula painted frog (Latonia nigriventer) using environmental DNA. AB - One of the greatest challenges of effective conservation measures is the correct identification of sites where rare and elusive organisms reside. The recently rediscovered Hula painted frog (Latonia nigriventer) has not been seen for many decades and was therefore categorized extinct. Since its rediscovery in 2011, individuals from the critically endangered species have been found, with great effort, only in four restricted sites. We applied the environmental DNA (eDNA) approach to search for new populations of the Hula painted frog in suitable aquatic habitats. We further used the eDNA data to classify the landscape factors associated with the species distribution and to predict its suitable habitats. We sampled 52 aquatic sites in the Hula Valley during the spring of 2015 and 2016 and amplified the samples with a species-specific qPCR assay. DNA of the Hula painted frog was detected in 22 of the sites, all of which clustered within three main areas. A boosting classification model showed that soil type, vegetation cover and the current and former habitats are all key predictors of the frog's current distribution. Intriguingly, the habitat suitability models reveal a high affinity of the species to its long-lost habitat of the historical wetlands. Our findings encourage a series of informed searches for new populations of this threatened frog and provide guidance for future conservation management programmes. In the era of global conservation crisis of amphibians, developing the eDNA approach, a reliable detection method for many critically endangered and elusive amphibians, is of particular importance. PMID- 29117633 TI - Ancient symbiosis confers desiccation resistance to stored grain pest beetles. AB - Microbial symbionts of insects provide a range of ecological traits to their hosts that are beneficial in the context of biotic interactions. However, little is known about insect symbiont-mediated adaptation to the abiotic environment, for example, temperature and humidity. Here, we report on an ancient clade of intracellular, bacteriome-located Bacteroidetes symbionts that are associated with grain and wood pest beetles of the phylogenetically distant families Silvanidae and Bostrichidae. In the saw-toothed grain beetle Oryzaephilus surinamensis, we demonstrate that the symbionts affect cuticle thickness, melanization and hydrocarbon profile, enhancing desiccation resistance and thereby strongly improving fitness under dry conditions. Together with earlier observations on symbiont contributions to cuticle biosynthesis in weevils, our findings indicate that convergent acquisitions of bacterial mutualists represented key adaptations enabling diverse pest beetle groups to survive and proliferate under the low ambient humidity that characterizes dry grain storage facilities. PMID- 29117634 TI - Spatial variability of marine bacterial and archaeal communities along the particulate matter continuum. AB - Biotic and abiotic particles shape the microspatial architecture that defines the microbial aquatic habitat, being particles highly variable in size and quality along oceanic horizontal and vertical gradients. We analysed the prokaryotic (bacterial and archaeal) diversity and community composition present in six distinct particle size classes ranging from the pico- to the microscale (0.2 to 200 MUm). Further, we studied their variations along oceanographic horizontal (from the coast to open oceanic waters) and vertical (from the ocean surface into the meso- and bathypelagic ocean) gradients. In general, prokaryotic community composition was more variable with depth than in the transition from the coast to the open ocean. Comparing the six size-fractions, distinct prokaryotic communities were detected in each size-fraction, and whereas bacteria were more diverse in the larger size-fractions, archaea were more diverse in the smaller size-fractions. Comparison of prokaryotic community composition among particle size-fractions showed that most, but not all, taxonomic groups have a preference for a certain size-fraction sustained with depth. Species sorting, or the presence of diverse ecotypes with distinct size-fraction preferences, may explain why this trend is not conserved in all taxa. PMID- 29117635 TI - Evaluation of the Influence of Three Newly Developed Bispyridinium Anti-nicotinic Compounds (MB408, MB442, MB444) on the Efficacy of Antidotal Treatment of Nerve Agent Poisoning in Mice. AB - The influence of three newly developed bispyridinium antinicotinic compounds (the non-oximes MB408, MB442 and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with an oxime) of acute poisoning by the organophosphorus nerve agents tabun and soman was studied in mice. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-oximes was evaluated by determination of the LD50 values of the nerve agents and measurement of the survival time after supralethal poisoning. Addition of all the tested non-oximes increased significantly the therapeutic efficacy of atropine in combination with an oxime against tabun poisoning. They also positively influenced the number of surviving mice 6 hr after supralethal poisoning with tabun. However, they were only slightly effective for the treatment of soman poisoning. The benefit of the tested bispyridinium non-oximes was dose-dependent. To conclude, the addition of bispyridinium non-oximes to the standard antidotal treatment of acute poisoning with tabun was beneficial regardless of the chosen non-oxime, but only slightly beneficial in the case of soman poisoning. PMID- 29117636 TI - Chlamydia trachomatis regulates growth and development in response to host cell fatty acid availability in the absence of lipid droplets. AB - Chlamydia trachomatis (Ct) is a Gram-negative obligate intracellular pathogen of humans that causes significant morbidity from sexually transmitted and ocular diseases globally. Ct acquires host fatty acids (FA) to meet the metabolic and growth requirements of the organism. Lipid droplets (LDs) are storehouses of FAs in host cells and have been proposed to be a source of FAs for the parasitophorous vacuole, termed inclusion, in which Ct replicates. Previously, cells devoid of LDs were shown to produce reduced infectious progeny at 24 hr postinfection (hpi). Here, although we also found reduced progeny at 24 hpi, there were significantly more progeny at 48 hpi in the absence of LDs compared to the control wild-type (WT) cells. These findings were confirmed using transmission electron microscopy where cells without LDs were shown to have significantly more metabolically active reticulate bodies at 24 hpi and significantly more infectious but metabolically inert elementary bodies at 48 hpi than WT cells. Furthermore, by measuring basal oxygen consumption rates (OCR) using extracellular flux analysis, Ct infected cells without LDs had higher OCRs at 24 hpi than cells with LDs, confirming ongoing metabolic activity in the absence of LDs. Although the FA oleic acid is a major source of phospholipids for Ct and stimulates LD synthesis, treatment with oleic acid, but not other FAs, enhanced growth and led to an increase in basal OCR in both LD depleted and WT cells, indicating that FA transport to the inclusion is not affected by the loss of LDs. Our results show that Ct regulates inclusion metabolic activity and growth in response to host FA availability in the absence of LDs. PMID- 29117637 TI - Secondary ion mass spectrometry imaging and multivariate data analysis reveal co aggregation patterns of Populus trichocarpa leaf surface compounds on a micrometer scale. AB - Spatially resolved analysis of a multitude of compound classes has become feasible with the rapid advancement in mass spectrometry imaging strategies. In this study, we present a protocol that combines high lateral resolution time-of flight secondary ion mass spectrometry (TOF-SIMS) imaging with a multivariate data analysis (MVA) approach to probe the complex leaf surface chemistry of Populus trichocarpa. Here, epicuticular waxes (EWs) found on the adaxial leaf surface of P. trichocarpa were blotted on silicon wafers and imaged using TOF SIMS at 10 MUm and 1 MUm lateral resolution. Intense M+? and M-? molecular ions were clearly visible, which made it possible to resolve the individual compound classes present in EWs. Series of long-chain aliphatic saturated alcohols (C21 C30 ), hydrocarbons (C25 -C33 ) and wax esters (WEs; C44 -C48 ) were clearly observed. These data correlated with the 7 Li-chelation matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis, which yielded mostly molecular adduct ions of the analyzed compounds. Subsequently, MVA was used to interrogate the TOF-SIMS dataset for identifying hidden patterns on the leaf's surface based on its chemical profile. After the application of principal component analysis (PCA), a small number of principal components (PCs) were found to be sufficient to explain maximum variance in the data. To further confirm the contributions from pure components, a five-factor multivariate curve resolution (MCR) model was applied. Two distinct patterns of small islets, here termed 'crystals', were apparent from the resulting score plots. Based on PCA and MCR results, the crystals were found to be formed by C23 or C29 alcohols. Other less obvious patterns observed in the PCs revealed that the adaxial leaf surface is coated with a relatively homogenous layer of alcohols, hydrocarbons and WEs. The ultra-high-resolution TOF-SIMS imaging combined with the MVA approach helped to highlight the diverse patterns underlying the leaf's surface. Currently, the methods available to analyze the surface chemistry of waxes in conjunction with the spatial information related to the distribution of compounds are limited. This study uses tools that may provide important biological insights into the composition of the wax layer, how this layer is repaired after mechanical damage or insect feeding, and which transport mechanisms are involved in deploying wax constituents to specific regions on the leaf surface. PMID- 29117638 TI - Renal transplant outcomes in primary FSGS compared with other recipients and risk factors for recurrence: A national review of the Irish Transplant Registry. AB - INTRODUCTION: Primary focal segmental glomerular sclerosis (p-FSGS) is commonly complicated by recurrence (r-FSGS) post-transplantation. Our objective was to describe Irish outcomes for transplantation after end-stage renal disease (ESRD) due to p-FSGS, specifically rates of, and treatments for, r-FSGS. PATIENTS AND METHODS: Irish patients with biopsy-proven FSGS were identified from the Irish National Kidney Transplant database (1982-2015). Medical record review was performed to identify predictors of r-FSGS and treatments for r-FSGS. Transplant outcomes were compared to outcomes in all renal transplants performed during the same time period using registry data. Demographic and clinical predictors of r FSGS were identified. Statistical analysis was performed using Stata (version 13, College Station, TX, USA). RESULTS: Thirty-eight transplant recipients had biopsy proven p-FSGS, 16 received a second transplant. A total of 3846 transplants formed the comparator group. r-FSGS complicated 60.5% (23/38) of first transplants. Eighty-six percent (10/12) of patients with previous r-FSGS developed recurrent disease after further transplantation. Patients with p-FSGS receiving a first renal transplant had higher rate of graft failure than those with another cause of ESRD (HR 1.9, 95% CI 1.152-3.139). Sixteen patients received immunotherapy for r-FSGS; 12 (86%) had at least partial response, but two (14%) developed significant complications. DISCUSSION: We demonstrate high rates of r-FSGS and describe modest success from with treatments for r-FSGS. PMID- 29117639 TI - Comparison of surgical outcomes between open and robot-assisted minimally invasive pancreaticoduodenectomy. AB - BACKGROUND: Robot surgery is a new method that maintains advantages and overcomes disadvantages of conventional methods, even in pancreatic surgery. This study aimed to evaluate safety and benefits of robot-assisted minimally invasive pancreaticoduodenectomy (robot PD). METHODS: This study included 237 patients who underwent PD between 2015 and 2017. Demographics and surgical outcomes were evaluated. RESULTS: Fifty-one patients underwent robot PD and 186 underwent open PD. Robot PD group had younger age (60.7 vs. 65.4 years, P = 0.006) and lower body mass index (22.7 vs. 24.0, P = 0.007). Robot PD group had lower proportion of patients with firm or hard pancreatic texture (15.7% vs. 38.2%, P = 0.004) and smaller pancreatic duct size (2.3 vs. 3.3 mm, P = 0.002). Two groups had similar operation time (robot vs. open: 335.6 vs. 330.1 min) and complications (15.7% vs. 21.0%), including postoperative pancreatic fistula rate (6.0% vs. 12.0%). Robot PD group had lower postoperative pain score (3.7 vs. 4.1 points, P = 0.008), and shorter postoperative stay (10.6 vs. 15.3 days, P = 0.001). CONCLUSION: Robot PD is comparable to open PD in early outcomes. Robot PD is safe and feasible and enables early recovery; indication for robot PD is expected to expand in the near future. PMID- 29117640 TI - Functional Characterization of 22 CYP3A4 Protein Variants to Metabolize Ibrutinib In Vitro. AB - Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested that CYP3A4 genetic polymorphisms may influence the rate of the metabolism and elimination of CYP3A4 substrates in human beings. Ibrutinib is an anticancer drug and primarily metabolized by CYP3A4. The aim of this study was to systematically investigate the effects of 22 CYP3A4 protein variants on the metabolism of ibrutinib in vitro. When compared with wild-type CYP3A4.1, two variants (CYP3A4.17 and CYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4.10, .11, .18, .23 and .33) exhibited no significant differences; another five variants (CYP3A4.3, .4, .9, .19 and .34) showed increased intrinsic clearance values, while the remaining nine variants (CYP3A4.2, .5, .14, .15, .16, .28, .29, .31 and .32) displayed decreased enzymatic activities in different degrees. As the first study of 22 CYP3A4 protein variants in ibrutinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism and elimination of ibrutinib and also offer a reference to the personalized treatment of ibrutinib in clinic. PMID- 29117641 TI - Increasing workplace violence in an Australian adult emergency department. AB - OBJECTIVE: Workplace violence (WPV) is an increasingly concerning occupational hazard within the ED. The aim of the present study was to evaluate the incidence and characteristics of WPV in an adult ED. METHODS: A retrospective cohort study was conducted to identify the incidence of ED WPV in an adult metropolitan ED. Data were obtained from the activity records of security staff from 1 January 2013 to 31 December 2015 for all incidents of patient-perpetrated violence. Data on patients identified from these records as requiring security staff intervention for violence in the ED were collected through an explicit chart review. Data on patient illicit drug or alcohol exposure and acute psychiatric diagnoses were also collected. RESULTS: There were 1853 episodes of patient perpetrated WPV identified over the study period. The incidence of WPV over the 3 years was 103 (95% CI: 98-108) per 10 000 of the presenting population, with a significant increase from 2013 to 2015 (IRR 1.07; 95% CI: 1.04-1.10; P < 0.01). Drug and/or alcohol exposure was observed in 1145 (61.8%) patients. Among the drug- and/or alcohol-affected violent population, three quarters (840/1145 = 73.4%) did not have a concurrent psychiatric diagnosis that required assessment during the violent presentation. CONCLUSION: The rate of WPV was increasing within this Australian ED during the study period. The majority of violent patients were affected by drugs and/or alcohol in the absence of a psychiatric diagnosis. Interventions to reduce access to and misuse of alcohol and illicit drugs could have a substantial impact on the concerning increase of violence in the ED. PMID- 29117642 TI - Policy Change and the National Essential Medicines List Development Process in Brazil between 2000 and 2014: Has the Essential Medicine Concept been Abandoned? AB - Brazil has had a National Essential Medicines List (EML) since 1964. From 2000 to 2010, five consecutive evidence-based editions were produced, building on the essential medicine concept. In 2012, the government changed course to establish a new paradigm, introducing adoption of new medicines as the main aim within the recommendation process. The objective of the article was to report efforts to develop Brazil's national EML, policy changes from 2000 to 2014, discussing results, challenges and perspectives. Brazilian EML history and development process were collected from legislation, minutes, reports and legal ordinances, from 2000 to 2014. The Brazilian EML and the WHO Model Lists were compared using the Anatomical Therapeutic Chemical system. Overlap between lists was verified, and linear trends were produced. Type of membership, inclusion criteria, procedures, flow and listed medicines varied greatly between the selection committees acting before and after 2012. Paradigm-changing legislation aiming at linking list compliance to public financing in 2012 produced (i) greater importance given to political and administrative stakeholders, (ii) increasing trends in number of medicines over the years, (iii) decrease in use of WHO Model List as a reference and (iv) substitution of an essential medicines list review and update process by an adoption decision output. Other issues remained unchanged. Insufficient efforts for list implementation, such as lack of physician education, presented consequences to the health system. Substantial efforts were made to produce and update the list from 2000 to 2014. However, continuous and intense health litigation disproves process outcome effectiveness. PMID- 29117643 TI - Advanced Electrocardiogram Analysis in the Amitriptyline-poisoned Pig Treated with Activated Charcoal Haemoperfusion. AB - Coated activated charcoal haemoperfusion (CAC-HP) does not reduce the plasma concentration in amitriptyline (AT)-poisoned pigs. The aim of this non-blinded, randomized, controlled animal trial was to determine if CAC-HP reduces the pathological ECG changes caused by AT poisoning. Fourteen female Danish Landrace pigs (mean weight 27.7 kg, range 20-35 kg (CAC-HP) and 24.4 kg, range 18-30 kg (control group, CG), n = 7 in each group) were included. After randomization, the pigs were anaesthetized and intravenously poisoned with AT. The intervention group underwent 4 hr of CAC-HP plus standard care (oral activated charcoal). Intervention was compared to standard care alone. From each pig, a 12-lead ECG and haemodynamic variables were obtained at baseline, at full AT loading dose, before and during CAC-HP. Baseline ECG variables (RR, PR, QRS, QTc, QTp, QTe, TpTe and TpTe/QT) for lead II, v2 and v5 were not significantly different (F = 0.035-0.297, p-values 0.421-0.919). Differences within groups over time and between groups were tested by anova repeated measures. For all variables, the time-plus-group level of significance revealed a p-value > 0.05. Severe cardiovascular arrhythmias occurred in both groups with 3 in the CAC-HP group versus 1 incident with premature death in the CG. The attenuating effect of CAC HP to orally instilled activated charcoal alone on AT-induced ECG alterations did not differ significantly. We conclude that the use of modern CAC-HP as an adjunctive treatment modality in AT-poisoned pigs is inadequate. PMID- 29117646 TI - Lipids from yeasts and fungi: physiology, production and analytical considerations. AB - The last years there has been a significant rise in the number of publications in the international literature that deal with the production of lipids by microbial sources (the 'single cell oils; SCOs' that are produced by the so-called 'oleaginous' micro-organisms). In the first part of the present review article, a general overview of the oleaginous micro-organisms (mostly yeasts, algae and fungi) and their potential upon the production of SCOs is presented. Thereafter, physiological and kinetic events related with the production of, mostly, yeast and fungal lipids when sugars and related substrates like polysaccharides, glycerol, etc. (the de novo lipid accumulation process) or hydrophobic substrates like oils and fats (the ex novo lipid accumulation process) were employed as microbial carbon sources, are presented and critically discussed. Considerations related with the degradation of storage lipid that had been previously accumulated inside the cells, are also presented. The interplay of the synthesis of yeast and fungal lipids with other intracellular (i.e. endopolysaccharides) or extracellular (i.e. citric acid) secondary metabolites synthesized is also presented. Finally, aspects related with the lipid extraction and lipidome analysis of the oleaginous micro-organisms are presented and critically discussed. PMID- 29117644 TI - Respectful care during childbirth in health facilities globally: a qualitative evidence synthesis. AB - BACKGROUND: What constitutes respectful maternity care (RMC) operationally in research and programme implementation is often variable. OBJECTIVES: To develop a conceptualisation of RMC. SEARCH STRATEGY: Key databases, including PubMed, CINAHL, EMBASE, Global Health Library, grey literature, and reference lists of relevant studies. SELECTION CRITERIA: Primary qualitative studies focusing on care occurring during labour, childbirth, and/or immediately postpartum in health facilities, without any restrictions on locations or publication date. DATA COLLECTION AND ANALYSIS: A combined inductive and deductive approach was used to synthesise the data; the GRADE CERQual approach was used to assess the level of confidence in review findings. MAIN RESULTS: Sixty-seven studies from 32 countries met our inclusion criteria. Twelve domains of RMC were synthesised: being free from harm and mistreatment; maintaining privacy and confidentiality; preserving women's dignity; prospective provision of information and seeking of informed consent; ensuring continuous access to family and community support; enhancing quality of physical environment and resources; providing equitable maternity care; engaging with effective communication; respecting women's choices that strengthen their capabilities to give birth; availability of competent and motivated human resources; provision of efficient and effective care; and continuity of care. Globally, women's perspectives of what constitutes RMC are quite consistent. CONCLUSIONS: This review presents an evidence-based typology of RMC in health facilities globally, and demonstrates that the concept is broader than a reduction of disrespectful care or mistreatment of women during childbirth. Innovative approaches should be developed and tested to integrate RMC as a routine component of quality maternal and newborn care programmes. TWEETABLE ABSTRACT: Understanding respectful maternity care - synthesis of evidence from 67 qualitative studies. PMID- 29117645 TI - Proteomic profiling of TGFBI-null mouse corneas reveals only minor changes in matrix composition supportive of TGFBI knockdown as therapy against TGFBI-linked corneal dystrophies. AB - TGFBIp is a constituent of the extracellular matrix in many human tissues including the cornea, where it is one of the most abundant proteins expressed. TGFBIp interacts with Type I, II, IV, VI, and XII collagens as well as several members of the integrin family, suggesting it plays an important role in maintaining structural integrity and possibly corneal transparency as well. Significantly, more than 60 point mutations within the TGFBI gene have been reported to result in aberrant TGFBIp folding and aggregation in the cornea, resulting in severe visual impairment and blindness. Several studies have focused on targeting TGFBIp in the cornea as a therapeutic approach to treat TGFBI-linked corneal dystrophies, but the effect of this approach on corneal homeostasis and matrix integrity remained unknown. In the current study, we evaluated the histological and proteomic profiles of corneas from TGFBI-deficient mice as well as potential redundant functions of the paralogous protein POSTN. The absence of TGFBIp in mouse corneas did not grossly affect the collagen scaffold, and POSTN is unable to compensate for loss of TGFBIp. Proteomic comparison of wild-type and TGFBI-/- mice revealed 11 proteins were differentially regulated, including Type VI and XII collagens. However, as these alterations did not manifest at the macroscopic and behavioral levels, these data support partial or complete TGFBI knockdown as a potential therapy against TGFBI-linked corneal dystrophies. Lastly, in situ hybridization verified TGFBI mRNA in the epithelial cells but not in other cell types, supportive of a therapy directed specifically at this lineage. PMID- 29117647 TI - Personality Changes Following Brain Artery Aneurysm Surgery AB - Neuropsychological testing of patients in the course of their recovery from braininjuries enables analysis of cognitive deficiencies and/or emotional changes. The principle study objectivewas to define organic and/or reactive personality changes and the course of these changes in thefunction of the time span following brain artery aneurysm surgery in both female and male patients.The study was carried out at the Clinical Department of Neurosurgery, Zagreb University HospitalCenter in Zagreb. The data refer to the period from 1989 to 2012 collected in two time intervals, i.e.11 months and 12-48 months following brain artery aneurysm surgery. Of 72 patients included in thestudy, there were 28 male and 44 female patients. Neuropsychological testing consisted of clinical interview,clinical assessment of frontal lobe syndrome, Cornell personality questionnaire and EmotionalProfile Index. Study results showed evidence of frontal lobe syndrome in 32% of patients on firsttesting and significant recovery on retesting, when only 17% of patients presented with frontal lobesyndrome. The reactive personality changes found in both testing intervals indicated increased neuroticism.In the first testing period, asthenic syndrome occurred most often, followed by conversionand aggressive-antisocial syndromes, while in the second testing interval asthenic syndrome was mostpronounced and conversion and antisocial syndromes showed the same level of expression. The resultsalso showed higher depressive and disorganizing states, which were even more pronounced in thesecond testing interval. As regards sex differences, the inclination toward cardiovascular somatizationand destructiveness was more expressed in females than in males, showing a tendency of aggravationwith increasing the time span following surgery. It may be concluded that the study has contributedto better understanding of organic and/or reactive personality changes in patients undergoing brainartery aneurysm surgery. PMID- 29117648 TI - Serum Neuron-Specific Enolase as a Marker of Brain Ischemia-Reperfusion Injury in Patients Undergoing Carotid Endarterectomy AB - In patients with atherosclerotic stenosis of the extracranial segment of internalcarotid artery, surgical intervention is an effective method to prevent cerebral ischemic stroke. However,this surgical procedure may cause vascular brain damage. The aim of the study was to investigateconsequential brain ischemia reperfusion injury by measuring the cerebral specific marker, neuron specific(NSE), in serum of patients having undergone internal carotid endarterectomy (CEA).The study involved 25 patients that underwent CEA due to internal carotid artery stenosis. Bloodsamples were obtained from each patient on three occasions: within 24 h prior to surgery, 12 h aftersurgery, and 48 h after surgery. Serum NSE levels were measured by a commercially available enzyme linkedimmunosorbent assay. The study showed that serum NSE level was statistically significantlyincreased 48 h after CEA as compared with the level 12 h after surgery and the level before surgery(p<0.05). Difference in serum NSE between the level before surgery and 12 h after CEA was notstatistically significant (p>0.05). Data from our study showed CEA to affect serum NSE in patientswith significant internal carotid artery stenosis. Thus, serum NSE may be used as a biochemical markerof brain ischemia-reperfusion injury following CEA. PMID- 29117649 TI - Use of Alternative and Complementary Medicine in Patients with Malignant Diseases in High-Volume Cancer Center and Future Aspects AB - Usage of complementary and alternative medicine (CAM) is steadily increasingover the last decades, gaining medical, economic and sociological importance. The aim of the presentstudy was to assess the use of complementary and alternative therapies in cancer patients. A cross-sectional,descriptive survey design was used to collect data through an anonymous questionnaire. Atotal of 267 patients were included in the study. The prevalence of CAM use among cancer patients inthis study was 60.3%. It was found that 61 heterogeneous CAM therapies were used, the most popularamong patients being naturopathy/folk medicine. In multivariate logistic regression analysis, independentpredictors of CAM use were high income, divorced status, female sex and younger age. Inconclusion, considering the fact that a large proportion of patients used at least one CAM approach,we need to continue our efforts to improve the patient-oncologist communication in order to delivermost reliable information to patients and to better understand the possible standard medicine-CAMinteractions. According to results of the latest studies, CAM therapies that help manage pain, nausea,fatigue, anxiety, and other symptoms should be integrated into the patient overall care. PMID- 29117650 TI - Sensitivity and Specificity of Fenyo-Lindberg and Teicher Scores in the Diagnosis of Acute Appendicitis in Women AB - The aim of the study was to assess diagnostic accuracy (sensitivity and specificity)of Fenyo-Lindberg and Teicher scores for distinguishing patients that need immediate surgical treatmentfrom the others, in a female population from an urban setting. The study prospectively included130 female patients admitted to the emergency department with abdominal pain indicating acuteappendicitis. The scores and parameters of validity were calculated and compared to definitive diagnosis.For Fenyo-Lindberg score of -17 or less, 84.5% sensitivity, 55.6% specificity, 87.9% positive predictivevalue (PPV) and 48.4% negative predictive value (NPV) were recorded. For cut-off value greateror equal to -2, there was 59.2% sensitivity, 77.8% specificity, 91% PPV and 33.3% NPV. The ReceiverOperating Characteristic (ROC) curve analysis of Fenyo-Lindberg score showed that the best singlecut-off value for discriminating acute appendicitis in the study population was -15. For Teicher score,values greater than -3 yielded 89.3% sensitivity and 22.2% specificity, 81.4% PPV and 35.3% NPV. Inconclusion, Fenyo-Lindberg score could be used as an additional tool to exclude appendicitis andavoid unnecessary appendectomies. Teicher score may help in recognizing patients with appendicitis.None of the two scores can indicate or decline appendectomy in all cases. Scoring systems may beuseful for pointing to important clinical signs and symptoms in specific subpopulations. PMID- 29117651 TI - Comparison of Psychomotor Development Screening Test and Clinical Assessment of Psychomotor Development AB - Numerous adverse factors are acting in the prenatal, perinatal and postnatal periodof life and may be the cause of later mild or severe deviations from normal psychomotor development.Therefore, it is crucial to identify infants with neurological risk factors and infants that already have adelay from orderly development, in order to immediately initiate the rehabilitation process. The aim ofthis study was to determine whether there is difference in the assessment of psychomotor developmentin neurological risk children based on the psychomotor development test (Croatian, Razvojpsihomotorike, RPM test) and clinical evaluation of neuromotor development. RPM test is designedfor rough estimate of psychomotor development in children in the first two years of life. The studyincluded 15 full term children (8 male and 7 female) with clinical diagnosis of mild paraparesis andmild deviation from normal psychological and social development, and 15 full term children (8 maleand 7 female) without neurological risk factors and deviations from normal psychomotor development,all at the age of 12-24 months. Of the 15 children diagnosed with mild paraparesis, none haddelayed psychomotor development, 6.7% had suspect development and 93.3% had normal developmenton RPM test. All children in the control group had normal development on RPM test. Accordingto the results, the RPM test is not sensitive enough to detect mild neurodevelopmental disorders. PMID- 29117652 TI - Microhardness of Bulk-Fill Composite Materials AB - The aim of the study was to determine microhardness of high- and low viscositybulk-fill composite resins and compare it with conventional composite materials. Four materialsof high-viscosity were tested, including three bulk fills: QuiXfi l (QF), x-tra fi l (XTF) and TetricEvoCeram Bulk Fill (TEBCF), while nanohybrid composite GrandioSO (GSO) served as control.The other four were low-viscosity composites, three bulk-fill materials: Smart Dentin Replacement(SDR), Venus Bulk Fill (VBF) and x-tra base (XB), and conventional control material X-Flow (XF).Composite samples (n=5) were polymerized for 20 s with Bluephase G2 curing unit. Vickers hardnesswas used to determine microhardness of each material at the surface, and at 2-mm and 4-mm depth.GSO on average recorded significantly higher microhardness values than bulk-fill materials (p<0.001).The low-viscosity composite XF revealed similar microhardness values as SDR, but significantly lowerthan XB (p<0.001) and significantly higher than VBF (p<0.001). Microhardness of high-viscositybulk-fill materials was lower than microhardness of the conventional composite material (GSO).Surface microhardness of low-viscosity materials was generally even lower. The microhardness of alltested materials at 4 mm was not different from their surface values. However, additional cappinglayer was a necessity for low-viscosity bulk fill materials due to their low microhardness. PMID- 29117653 TI - Effect of Delivery and Episiotomy on the Emergence of Urinary Incontinence in Women: Review of Literature AB - Episiotomy is obstetric procedure during which the incision extends the vestibuleof the vagina during the second stage of labor. Episiotomy was extensively spread with gradual increaseof rates in the first half of the 20th century and was performed medio-laterally in all nulliparouswomen with the idea to protect fetal head from trauma and pelvic floor from injuries. However, reportsclaiming that episiotomy had no such benefits were published. It was shown that routine medio-lateralepisiotomy did not protect against the appearance of urinary incontinence after vaginal delivery,while the risk of anal incontinence could be increased. The role of episiotomy in development of pelvicfloor dysfunction remains quite unclear. Due to the mentioned reason, restricted episiotomy approachshould be accepted. The origin of stress incontinence during pregnancy is controversial and not definitelyscientifically proven. Pregnancy per se and older age at first delivery may have impact on theonset of pelvic floor dysfunction. Urinary incontinence in pregnancy increases the risk of later urinaryincontinence, both postpartum and later in life. Vaginal delivery is just one of the potential risk factorsfor development of urinary incontinence. Mechanical pressure by fetus on the pelvic floor structures,limited denervation of the pelvic floor and soft tissue damage during delivery are some of explanationsfor the onset of stress urinary incontinence. On the other hand, cesarean delivery might not be protectiveagainst emergence of urinary incontinence. Further research in this field is needed. PMID- 29117654 TI - Diagnostic Value of Fine Needle Aspiration Cytology for Breast Tumors AB - Breast cancer is the most frequently diagnosed cancer and the leading cause ofdeath from cancer in women. The accuracy of diagnosis can be increased with a combination of clinicalexamination, imaging diagnostics, and fi ne needle aspiration cytology (FNAC) or core needle biopsy,also known as triple test. The aim of the study was to evaluate the sensitivity and specificity ofFNAC in the diagnosis of breast tumors in our institution by correlating it with histopathology findings.We assessed the accuracy of 124 FNAC findings by comparing cytological diagnosis of breastmasses with the diagnoses from histopathology reports obtained by surgery. Statistical analysis showed95.1% accuracy, 97.7% sensitivity, 89.1% specificity, 95.5% positive predictive value and 94.2%negative predictive value of FNAC. Study results indicated that FNAC could be used as a highlyreliable tool in the differential diagnosis of breast tumors, in combination with clinical and imagingfindings, especially in developing countries with limited financial resources. PMID- 29117655 TI - Genetic Etiology of Primary Premature Ovarian Insufficiency AB - Primary premature ovarian insufficiency (PPOI) is characterized by hypergonadotropicamenorrhea and hypoestrogenism in women under 40 years of age. PPOI incidence is 1:10,000in women aged 18-25, 1:1000 in women aged 25-30 and 1:100 in women aged 35-40. In 10%-28% ofcases, PPOI causes primary and in 4%-18% secondary amenorrhea. The process is a consequence ofaccelerated oocyte atresia, diminished number of germinated cells, and central nervous system aging.Specific genes are responsible for the control of oocyte number undergoing the ovulation process andthe time to cessation of the reproductive function. A positive family history of PPOI is found in 15%of women with PPOI, indicating the existing genetic etiology. Primary POI comprises genetic aberrationslinked to chromosome X (monosomy, trisomy, translocation, deletion) or to autosomal chromosome.Secondary POI implies surgical removal of ovaries, chemotherapy and radiotherapy, andinfections. Diagnostic criteria include follicle stimulating hormone level >40 IU/L and estradiol level<50 pmol/L. PMID- 29117656 TI - Knowledge, Attitudes and Habits Regarding Oral Health in First- and Final-Year Dental Students AB - The purpose of the research was to compare oral health behavior and plaque indicesbetween Croatian first-year and final-year dental students. Therefore, 46.9% of first-year and 47%of final-year dental students were surveyed using the Hiroshima University Dental Behavior Inventory(HU-DBI) questionnaire and had their plaque indices determined. Descriptive statistics analysis,nonparametric tests, and correlation analysis were performed (p<0.05). Sixth-year students had a significantly better mean HU-DBI score (8.06) than first-year students (6.45). Significantly more first-yearstudents thought that they could not help having false teeth at their old age (p=0.007), had neverbeen taught professionally how to brush (p=0.019), and used a toothbrush with hard bristles (p=0.001).Significantly more final-year students brushed each of their teeth carefully (p=0.008), thought theycould clean their teeth well without using tooth paste (p=0.000), used a dye to see how clean theirteeth were (p=0.002), and had their dentist telling them they brushed very well (p=0.028). Plaqueindex values were significantly lower (p<0.05) among first-year (7.94+/-0.72) than among final year(9.13+/-0.77) students. With advancement in dental training, oral health attitudes improved, but thelevel of dental students' oral hygiene decreased. PMID- 29117657 TI - 'Plug Free' Connector Placement Modification of a Bilayer Patch Device in Male Indirect Inguinal Hernioplasty AB - The bilayer patch device (Ethicon, Prolen Hernia System(r)) for inguinal herniarepair has a connector that acts as a ,plug' in the internal inguinal ring. The position of this ,plug' componentmay be responsible for higher incidence of chronic pain and intestinal damage. We assumedthat changing the position of the connector of a bilayer patch device (PHS(r)) and placing it mediallyin Hesselbach triangle would contribute to lower incidence of chronic pain and would not result inintestinal damage, with good clinical outcome following indirect inguinal hernioplasty. This retrospectivestudy included 73 patients with 76 indirect inguinal hernias, who underwent the procedure ofmodifying the position of the bilayer patch device in the 2005-2015 period. The mean age of the patientswas 57 years. Three patients had early postoperative complications (3.95%), two of which hadpostoperative seroma and one had postoperative pain. Three patients (3.95%) had late postoperativecomplications. One patient (1.32%) had chronic pain. There was one recurrence (1.32%) and one patient(1.32%) needed the mesh removed due to discomfort. The 'plug free' position of the connector ofa bilayer patch device in patients with indirect inguinal hernioplasty is a safe procedure with low rateof chronic pain, no intestinal damage, and standard low recurrence. PMID- 29117658 TI - Treatment of Postherpetic Neuralgia with 5% Topical Lidocaine Plaster - Experience from a Small County Hospital: Case Report AB - Postherpetic neuralgia (PHN) characterized by chronic neuropathic pain is a commoncomplication of herpes zoster. We investigated the efficacy, safety and cost of treating refractorychronic neuropathic pain with 5% topical lidocaine plaster (TLP) in a female patient attending painunit at a small county hospital. An 80-year-old female diagnosed with PHN presented with severe leftintercostal allodynia and hyperalgesia up to the root of the fourth to tenth thoracic dermatome. Weadministered the well established first- and second-line specific medications for PHN, but treatmentregimens were not efficient. Then we introduced TLP and analyzed data from initial assessment andthroughout follow up of 1313 days. The efficacy of treatment was based on pain severity that wasassessed using the Short-Form McGill Pain Questionnaire and the related visual analog scale. In thelast two years of observation, significant reduction was recorded in healthcare resource utilization(changes correlated with substantial reduction in direct cost (2012-2013: -425.90 ?; and 2013-2014:-1,435 ?) and clinically relevant reduction in pain severity. No unusual side effects were observed. Inconclusion, treatment of PHN with 5% lidocaine plaster demonstrated efficacy in reducing pain severityand cost of medical care with a satisfactory safety profile. A starting point for future studies shouldbe comparison of different treatment protocols and upgrading the knowledge, especially related to thecost of PHN treatment. PMID- 29117659 TI - Combined Treatment of Ruptured Middle Cerebral Artery Aneurysm Followed by Subarachnoid Hemorrhage and Acute Subdural Hematoma in Multiple Aneurysm Disease of Cerebral Blood Vessels: Case Report AB - Aneurysms of blood vessels at the base of the brain are pathological focal out pouchings,usually found at the branching points of the arteries. Aneurysm can remain silent for life.Clinical presentation is due to rupture and bleeding. In only 1.3% of cases it results in subdural hematoma,which is associated with direct interaction of the aneurysm with the basal arachnoid membrane.Multiple aneurysms are present in 15% to 33% of cases with subarachnoid hemorrhage. Assessmentof these patients is more complicated, as there are no specific signs to pinpoint/detect the aneurysmthat has ruptured. This report presents a 44-year old female patient suffering from multiple cerebralaneurysm disease, who was urgently treated after rupture by both endovascular (for multiple aneurysms)and surgical (for acute subdural hematoma) approach in the same act under general anesthesia,which resulted in complete recovery of the patient. PMID- 29117660 TI - Nebivolol Induced Hyperkalemia: Case Report AB - In this article, we document a conclusive case of nebivolol-induced hyperkalemiafor the first time in the known medical literature. Hyperkalemia is associated with serious conditionssuch as cardiac arrhythmias and sudden cardiac death. Nebivolol was not known to cause hyperkalemia,and this event is not listed in its summary of product characteristics (SmPC). For older betablockers, hyperkalemia is recognized as a rare adverse event linked to cytochrome P450 2D6 (CYP2D6)polymorphism and poor drug degradation. Our patient, a 47-year-old woman taking nebivolol forhypertension developed persistent hyperkalemia, with serum potassium levels up to 6.4 mmol/L.After extensive diagnostic evaluation and exclusion of other known conditions leading to hyperkalemia,its cause remained occult. Since hyperkalemia coincided with increased doses of nebivolol, dosereduction and discontinuation were attempted, resulting in normalized serum potassium. Poor drugmetabolism could not explain this adverse effect, since pharmacogenetic testing showed no relevantaberrations. In conclusion, hyperkalemia is a harmful adverse event with possible lethal outcome, andit may be caused by nebivolol. Therefore, medical professionals have to be aware of this side effect andhyperkalemia should be listed as an adverse event in nebivolol SmPC. PMID- 29117661 TI - A Rare Case of Infectious Multifocal Serpiginoid Choroiditis AB - Multifocal serpiginoid choroiditis is an infectious variety of serpiginous choroiditis.The disease is characterized by infectious etiology and overlapping clinical features in an intermediaryform of acute posterior multifocal placoid pigment epitheliopathy and serpiginous choroiditis.In a 33-year-old patient, bilateral multiple placoid partially confluent chorioretinal lesions were diagnosedafter a febrile flu-like episode. On the right eye, there was a progressive decrease in visual acuity.Later, the lesions had a prolonged progressive devastating clinical course and widespread distributionof placoid lesions, and took the form of serpiginoid choroiditis. We conducted extensive laboratorywork-up and ancillary investigation for granulomatous diseases such as tuberculosis and sarcoidosis,and the results were not consistent with these entities. Systemic medical work-up revealed a history ofexposure to the human immunodeficiency virus, herpes simplex virus 1, varicella zoster virus and cytomegalovirus.The titer of Mycoplasma pneumoniae IgM antibodies was positive. After serologicalanalysis positive for Mycoplasma pneumoniae, systemic antibiotic therapy and anti-inflammatory dosesof corticosteroids were administered. Improvement of visual acuity after the introduction of causalantibiotic therapy in combination with anti-inflammatory therapy confirmed our suspicion that Mycoplasmapneumoniae was the etiologic cause of multifocal serpiginoid choroiditis. PMID- 29117662 TI - Acute Gallbladder Torsion with Gangrene and Cholelithiasis - A Rare Condition AB - We report a case of a 75-year-old female with acute torsion of the gallbladder withgangrene and cholelithiasis. On admission, the patient underwent physical examination, laboratoryblood analysis, abdominal ultrasound and plain abdominal x ray. Due to the signs of acute abdomenand poor general condition of the patient, urgent surgical procedure was indicated. Intraoperatively,the gallbladder was found to be greatly enlarged, gangrenous and greatly distended with 360 degrees clockwisetorsion around its mesentery. Cholecystectomy was performed. Gallbladder torsion is a rare surgicalemergency which physicians should bear in mind when encountering patients with symptoms ofacute cholecystitis. The only treatment for this condition is urgent cholecystectomy with prior detorsion.The mortality rate in patients not undergoing surgery is 100%. PMID- 29117663 TI - HISTORICAL REVIEW. PMID- 29117664 TI - Pituitary Abscess with Unusual Clinical Course AB - The aim is to present unusual clinical course and magnetic resonance imaging(MRI) features of pituitary abscess. A 59-year-old man presented with fever, polyuria, polydipsia andmarked weight loss within the last two months. Basic endocrinology tests revealed the presence ofanterior pituitary dysfunction, associated with central diabetes insipidus and increased levels of inflammatorymarkers. The presence of expansile sellar lesion, showing restricted diffusion signal patterncompatible with acute pituitary pyogenic abscess was found on MRI. Regression of pituitary abscesswas obvious during the next few weeks of parenteral antibiotic treatment. Adequate substitution treatmentwith L thyroxine, hydrocortisone, testosterone and desmopressin was achieved. Seventeenmonths later, clinical deterioration associated with recurrent pituitary abscess was confirmed on MRI.Abscess regression was obvious again after conservative treatment. However, control MRI study performedthree years after initial scanning revealed the presence of pituitary tumor, most consistent withmacroadenoma. Surgical intervention was ordered. Histologic evaluation indicated the presence offibrotic changes, associated with granulation tissue and rare cellular elements, compatible with chronicinflammation. To the best of our knowledge, there are no studies in the literature describing such apattern of chronic evolution of pyogenic pituitary abscess with consequent chronic inflammatorychanges with granulation tissue proliferation, mimicking macroadenoma. PMID- 29117665 TI - Application of therapeutic plasma exchange in patients having severe fever with thrombocytopenia syndrome. AB - Background/Aims: Severe fever with thrombocytopenia syndrome (SFTS) is a viral hemorrhagic fever with a high fatality rate. However, effective treatments for SFTS cases not responded to supportive therapy have not been established. Herein, we introduced the therapeutic plasma exchange (TPE) in SFTS patients in a tertiary hospital between 2013 and 2015. Methods: TPE was performed in patients with rapidly progressing SFTS. Clinical, laboratory, and virological parameters were compared before and after TPE. Results: Among 27 confirmed SFTS patients, two patients were treated with TPE and ribavirin combination in May 2013, then, 14 patients with rapidly progressing SFTS patients were treated with only TPE from June 2013 to September 2015: their median age was 58 years (interquartile range, 50 to 70) and eight (57.1%) were male. Body temperature, pressure-adjusted heart rate, white blood cell and platelet counts, coagulation profile, serum creatinine, and multiple organ dysfunction score improved immediately after TPE. In addition, the mean cyclic threshold value of real-time reverse transcriptase polymerase chain reaction for SFTS virus after TPE (mean +/- standard deviation, 31.3 +/- 2.9) was significantly higher than that before TPE (26.5 +/- 2.9; p < 0.001), indicating that serum viral loads decreased after TPE. Finally, 13 of 14 TPE-treated patients (92.8%) recovered from rapidly progressing SFTS without sequelae. Conclusions: SFTS patients treated with TPE showed improvements in clinical, laboratory, and virological parameters. These results suggest that TPE would be a therapeutic modality as rescue therapy in patients with rapidly progressing SFTS. PMID- 29117666 TI - Prognostic significance of non-chest pain symptoms in patients with non-ST segment elevation myocardial infarction. AB - BACKGROUND/AIMS: Chest pain is an essential symptom in the diagnosis of acute coronary syndrome (ACS). One-third of patients with ACS present atypically, which can influence their receiving timely lifesaving therapy. METHODS: A total of 617 NSTEMI patients from the Korea Acute MI Registry (KAMIR) and the Korea Working Group on MI (KorMI) databases were analyzed. The study population was divided into two groups by symptoms at presentation (typical symptoms group, 128; atypical symptoms groups, 128). RESULTS: In this study population, 23% of patients presented without chest pain. After propensity score matching, the contact-to-device time (2,618 +/- 381 minutes vs. 1,739 +/- 241 minutes, p = 0.050), the symptoms-to-balloon time (3,426 +/- 389 minutes vs. 2,366 +/- 255 minutes, p = 0.024), and the door-to-balloon time (2,339 +/- 380 minutes vs. 1,544 +/- 244 minutes, p = 0.002) were significantly higher in the patients with atypical symptoms than in those with typical symptoms, respectively. Atypical symptoms were an independent predictor for 1-year mortality (hazard ratio, 2.820; 95% confidence interval, 1.058 to 7.515; p = 0.038). The Kaplan-Meier estimates showed higher risk for 12-month mortality in patients with atypical symptoms (p = 0.048) and no significant difference for 12-month major adverse cardiac events (p = 0.487). CONCLUSION: Acute myocardial infarction patients with atypical symptoms were not rare in clinical practice and showed a high risk of delayed reperfusion therapy. After imbalance between the groups was minimized by use of propensity score matching, patients who presented atypically had a high mortality rate. PMID- 29117667 TI - Association of a genetic polymorphism of IL1RN with risk of acute pancreatitis in a Korean ethnic group. AB - BACKGROUND/AIMS: Several epidemiological studies have validated the association of interleukin gene polymorphisms with acute pancreatitis (AP) in different populations. However, there have been few studies in Asian ethnic groups. We aimed to investigate the relationships between inflammatory cytokine polymorphisms and AP as pilot research in a Korean ethnic group. METHODS: Patients who had been diagnosed with AP were prospectively enrolled. DNA was extracted from whole blood, and DNA sequencing was subsequently performed. Single nucleotide polymorphisms (SNPs) of the interleukin 1beta (IL1B), interleukin 1 receptor antagonist (IL1RN), and tumor necrosis factor alpha (TNFA) genes of patients with AP were compared to those of normal controls. RESULTS: Between January 2011 and January 2013, a total of 65 subjects were enrolled (40 patients with AP vs. 25 healthy controls). One intronic SNP (IL1RN -1129T>C, rs4251961) was significantly associated with the risk of AP (odds ratio, 0.304; 95% confidence interval, 0.095 to 0.967; p = 0.043). However, in our study, AP was not found to be associated with polymorphisms in the promoter regions of inflammatory cytokine genes, including IL1B (-118C>T, c47+242C>T, +3954C/T, and 598T>C) and TNFA (-1211T>C, -1043C>A, -1037C>T, -488G>A, and -418G>A). CONCLUSION: IL1RN -1129T>C (rs4251961) genotypes might be associated with a significant increase of AP risk in a Korean ethnic group. PMID- 29117668 TI - Outcomes of patients treated with Sengstaken-Blakemore tube for uncontrolled variceal hemorrhage. AB - Background/Aims: The aim of this study was to investigate the mortality, bleeding control rate, and their associated predictors in patients treated with Sengstaken Blakemore (SB) tube for uncontrolled variceal hemorrhage associated with hemodynamic instability or failure of endoscopic treatment. METHODS: The clinical data of 66 consecutive patients with uncontrolled variceal hemorrhage treated with SB tube at Gyeongsang National University Hospital from October 2010 to October 2015 were retrospectively analyzed. RESULTS: The overall success rate of initial hemostasis with SB tube was 75.8%, and the independent factors associated with hemostasis were non-intubated state before SB tube (odds ratio, 8.50; p = 0.007) and Child-Pugh score < 11 (odds ratio, 15.65; p = 0.022). Rebleeding rate after successful initial hemostasis with SB tube was 22.0%, and esophageal rupture occurred in 6.1%. Mortality within 30 days was 42.4%, and the related independent factors with mortality were failure of initial hemostasis with SB tube (hazard ratio, 6.24; p < 0.001) and endotracheal intubation before SB tube (hazard ratio, 2.81; p = 0.018). Conclusions: Since the era of endoscopic band ligation, SB tube might be a beneficial option as a temporary salvage treatment for uncontrolled variceal hemorrhage. However, rescue therapy had a high incidence of fatal complication and rebleeding. PMID- 29117669 TI - Late diagnosis of influenza in adult patients during a seasonal outbreak. AB - BACKGROUND/AIMS: Due to advances in diagnostic techniques, clinicians are more frequently performing influenza diagnostic tests and referring to their test results ahead of the administration of neuraminidase inhibitors (NAIs). To investigate the clinical significance of the time from symptom onset to laboratory diagnosis, we reviewed the clinical characteristics of adult patients with influenza who had an early laboratory diagnosis (ED) or a late laboratory diagnosis (LD) at one of four tertiary care centers during a seasonal outbreak of influenza. METHODS: Clinical data were collected from 1,405 adults during the 2013 to 2014 influenza season. A patient was regarded as receiving an ED or LD if he/she received an influenza diagnostic test at 0 to 1 or 4 to 7 days after symptom onset, respectively. Early NAI therapy and late NAI therapy were defined as the administration of NAI <= 2 or > 2 days after symptom onset, respectively. RESULTS: Nearly half of the patients (47.0%) received an ED (n = 661), whereas 13.5% (n = 190) received a LD. Patients with a LD had initial symptoms of cough, sputum production, and dyspnea and experienced pneumonia, antibiotic therapy, hospitalization, and admission to the intensive care unit more often than those with an ED. NAI therapy and early NAI therapy were less frequent in patients with a LD than those with an ED. Of the analyzed baseline characteristics, age >= 50 years, influenza B infection, and diagnosis using a polymerase chain reaction test were significantly associated with a LD. CONCLUSIONS: LD was associated with inappropriate antiviral therapy and complicated presenting features in adult patients with seasonal influenza. ED of influenza should be emphasized, especially for older adults. PMID- 29117670 TI - Association between dietary intake and postlaparoscopic cholecystectomic symptoms in patients with gallbladder disease. AB - Background/Aims: After cholecystectomy, patients have reported postcholecystectomic syndromes such as abdominal symptoms, dyspepsia, and diarrhea, which suggest a relationship between cholecystectomic symptoms and diet, although the details of this association remain unclear. The present study investigated the hypothesis that dietary intake of nutrients and foods was significantly associated with postcholecystectomic syndromes. METHODS: Gallstone patients (n = 59) who underwent laparoscopic cholecystectomy were enrolled, and dietary intake and clinical parameters were assessed immediately postcholecystectomy and 3 months later. RESULTS: There were no significant differences in biochemical measurements or characteristics between symptomatic and asymptomatic patients. Immediately postcholecystectomy, there were no significant differences in consumption of nutrients or foods between symptomatic and asymptomatic patients. However, 3 months after cholecystectomy, symptomatic patients consumed more animal protein, cholesterol, and eggs, and fewer vegetables than did asymptomatic patients. Multivariable-adjusted regression analyses also indicated that the risk for symptoms was positively associated with intake of animal protein, cholesterol, and eggs, but negatively associated with intake of vegetables after adjusting for confounders. In addition, symptomatic patients consumed more bread-based breakfast foods, while asymptomatic patients consumed more rice. Conclusions: Postcholecystectomic syndromes were positively associated with intake of cholesterol, animal protein, and eggs, and negatively associated with intake of vegetables, suggesting that diet was plays a role in postcholecystectomic syndromes. PMID- 29117671 TI - Changing trends in clinical characteristics and antibiotic susceptibility of Klebsiella pneumoniae bacteremia. AB - BACKGROUND/AIMS: Klebsiella pneumoniae is second most common organism of gram negative bacteremia in Korea and one of the most common cause of urinary tract infection, and intra-abdominal infection. METHODS: We compared clinical and microbiological characteristics about K. pneumoniae bacteremia in a tertiary hospital between 10 years. Group A is who had K. pneumoniae bacteremia at least one time from January 2004 to December 2005. Group B is from January 2012 to December 2013. We also analyzed antibiotic resistance, clinical manifestation of the K. pneumoniae bacteremia divided into community-acquired infections, healthcare associated infections, and nosocomial infections. RESULTS: The resistance for ampicillin, aztreonam, cefazolin, and cefotaxime significantly increased compared to 10 years ago. Extended spectrum beta-lactamase positivity surged from 4.3% to 19.6%. Ten years ago, 1st, 2nd cephalosporin, and aminoglycoside were used more as empirical antibiotics. But these days, empirical antibiotics were broad spectrum such as 3rd and 4th cephalosporin. In treatment outcome, acute kidney injury decreased from 47.5% to 28.7%, and mortality decreased from 48.9% to 33.2%. In community-acquired infections, there was similar in antimicrobial resistance and mortality. In healthcare-associated and nosocomial infections, there was significantly increasing in antibiotic resistance, decreasing in mortality, and acute kidney injury. CONCLUSIONS: In community-acquired infections, broader antibiotics were more used than 10 years ago despite of similar antimicrobial resistance. When K. pneumoniae bacteremia is suspected, we recommend to use the narrow spectrum antibiotics as initial therapy if there are no healthcare-associated risk factors, because the antibiotic resistance is similar to 10 years ago in community-acquired infections. PMID- 29117672 TI - Synchronous diffuse large B-cell lymphoma of the small intestine and adenocarcinoma of the colon. PMID- 29117673 TI - Unusual isolated extramedullary relapse of acute lymphoblastic leukemia in the breast despite complete donor hematopoietic chimerism after allogeneic hematopoietic stem cell transplantation. PMID- 29117674 TI - Dominant Pathways of Adenosyl Radical-Induced DNA Damage Revealed by QM/MM Metadynamics. AB - Brominated nucleobases sensitize double stranded DNA to hydrated electrons, one of the dominant genotoxic species produced in hypoxic cancer cells during radiotherapy. Such radiosensitizers can therefore be administered locally to enhance treatment efficiency within the solid tumor while protecting the neighboring tissue. When a solvated electron attaches to 8-bromoadenosine, a potential sensitizer, the dissociation of bromide leads to a reactive C8 adenosyl radical known to generate a range of DNA lesions. In the current work, we propose a multiscale computational approach to elucidate the mechanism by which this unstable radical causes further damage in genomic DNA. We employed a combination of classical molecular dynamics conformational sampling and QM/MM metadynamics to study the thermodynamics and kinetics of plausible reaction pathways in a realistic model, bridging between different time scales of the key processes and accounting for the spatial constraints in DNA. The obtained data allowed us to build a kinetic model that correctly predicts the products predominantly observed in experimental settings-cyclopurine and beta-elimination (single strand break) lesions-with their ratio and yield dependent on the effective lifetime of the radical species. To date, our study provides the most complete description of purine radical reactivity in double stranded DNA, explaining the radiosensitizing action of electrophilic purines in molecular detail as well as providing a conceptual framework for the computational modeling of competing reaction pathways in biomolecules. PMID- 29117675 TI - Many-Body Coarse-Grained Interactions Using Gaussian Approximation Potentials. AB - We introduce a computational framework that is able to describe general many-body coarse-grained (CG) interactions of molecules and use it to model the free energy surface of molecular liquids as a cluster expansion in terms of monomer, dimer, and trimer terms. The contributions to the free energy due to these terms are inferred from all-atom molecular dynamics (MD) data using Gaussian Approximation Potentials, a type of machine-learning model that employs Gaussian process regression. The resulting CG model is much more accurate than those possible using pair potentials. Though slower than the latter, our model can still be faster than all-atom simulations for solvent-free CG models commonly used in biomolecular simulations. PMID- 29117676 TI - Diastereodivergent Asymmetric Carboamination/Annulation of Cyclopropenes with Aminoalkenes by Chiral Lanthanum Catalysts. AB - Stereodivergent asymmetric catalysis is an important technology that can allow efficient access to various stereoisomers of a given product with multiple stereocenters from the same set of starting materials, but its application to the synthesis of a highly strained cyclopropane compound has remained unexplored to date. We report here the first diastereodivergent enantioselective synthesis of bicyclic aminocyclopropanes by lanthanum-catalyzed asymmetric carboamination/annulation of cyclopropenes with aminoalkenes. This protocol features 100% atom efficiency, good yield (up to 90%), and high chemo- (up to >20:1) and stereoselectivity (up to >20:1 dr and 99% ee), constituting a unique route for the efficient synthesis of two different diastereoisomers of a given chiral bicyclic aminocyclopropane compound. PMID- 29117677 TI - Phase Behavior of a New Class of Anthraquinone-Based Discotic Liquid Crystals. AB - Five novel columnar liquid crystalline compounds (4.1-4.5) consisting of a central anthraquinone core carrying four alkoxy chains (R = n-C6H13, n-C8H17, n C10H21, n-C12H25, and 3,7-dimethyl octyl) with two diagonally opposite 1-ethynyl 4-pentylbenzene units were synthesized, and their phase transitions were investigated between changes in the molecular structure and their self-assembly into the columnar mesophases. Small and wide-angle X-ray scattering (SAXS/WAXS) studies were performed to deduce the exact nature of the mesophases, and their corresponding electron density maps were derived from the intensities of the peaks observed in the diffraction patterns. A comparison of compounds with different alkoxy chains indicated that the soft crystal columnar rectangular (Crcolrec) phase was stable at lower temperature for the shortest peripheral alkoxy chain (4.1; R = n-C6H13) and was found to exhibit the columnar hexagonal (Colh) phase and then the discotic nematic (ND) phase with increasing temperature. In contrast, increasing the peripheral chain length to n-C8H17 or the branched one (4.2 and 4.5) stabilized the Colh phase at lower temperature and showed the ND phase at higher temperature. Further increase in chain length (4.3 and 4.4; n-C10H21, n-C12H25) demonstrated the formation of the ND phase. Conductivity measurement in the Colh mesophase was found to be almost 10 times higher in magnitude than the corresponding Crcolrec phase. The HOMO-LUMO band gap of all the compounds was found to be in the range from 2.79 to 2.82 eV, which is quite less and comparable with the optical energy band gap. PMID- 29117678 TI - Peroxide Activation Regulated by Hydrogen Bonds within Artificial Cu Proteins. AB - Copper-hydroperoxido species (CuII-OOH) have been proposed to be key intermediates in biological and synthetic oxidations. Using biotin-streptavidin (Sav) technology, artificial copper proteins have been developed to stabilize a CuII-OOH complex in solution and in crystallo. Stability is achieved because the Sav host provides a local environment around the Cu-OOH that includes a network of hydrogen bonds to the hydroperoxido ligand. Systematic deletions of individual hydrogen bonds to the Cu-OOH complex were accomplished using different Sav variants and demonstrated that stability is achieved with a single hydrogen bond to the proximal O-atom of the hydroperoxido ligand: changing this interaction to only include the distal O-atom produced a reactive variant that oxidized an external substrate. PMID- 29117679 TI - Interplay between Localized and Free Charge Carriers Can Explain Hot Fluorescence in the CH3NH3PbBr3 Perovskite: Time-Domain Ab Initio Analysis. AB - Delayed high-energy fluorescence observed experimentally in methylammonium lead bromine CH3NH3PbBr3 (MAPbBr3) demonstrates long-lived energetic charge carriers with extremely high mobilities that can be used to enhance photon-to-electron conversion efficiency of perovskite solar cells. It has been suggested that hot fluorescence is associated with reorientational motions of the MA molecules. We support this hypothesis by time-domain ab initio quantum dynamics calculations showing that reorientation of the MA molecules can affect strongly the perovskite emission energy and lifetime. We demonstrate MAPbBr3 structures differing in the MA orientations and exhibiting the same emission properties as in the experiments. The higher bandgap structures responsible for hot fluorescence support delocalized wave functions that can be interpreted as free charge carriers. The lower energy structures exhibit localized polaron-like electrons and holes, and a significantly longer electron-hole recombination time, in agreement with experiment. The fluorescence lifetimes differ owing to variation in the nonadiabatic coupling between the emitting and ground states, stemming from charge carrier localization. Loss of coherence due to elastic electron phonon scattering is similar in the two cases. The simulations provide a detailed atomistic understanding of excited-state dynamics in MAPbBr3 and show how structural transformations can rationalize the experimentally reported hot fluorescence in MAPbBr3. Other localized structures involving inorganic lattice distortions, defects, domain boundaries, ion diffusion, electric ordering, etc., can be invoked with the proposed two-emitter interpretation of hot and regular luminescence. PMID- 29117680 TI - Molecular Determinants and Bottlenecks in the Dissociation Dynamics of Biotin Streptavidin. AB - Biotin-streptavidin is a very popular system used to gain insight into protein ligand interactions. In its tetrameric form, it is well-known for its exceptionally high kinetic stability, being one of the strongest known noncovalent interactions in nature, and it is heavily used across the biotechnological industry. In this work, we gain understanding of the molecular determinants and bottlenecks in the dissociation of the dimeric biotin streptavidin system in wild type and with a point mutation. Using recently proposed enhanced sampling methods with full atomistic resolution, we reproduce the experimentally reported effect of the mutation on the dissociation rate. We also answer a longstanding question regarding cause/effect in the coupled events of bond stretching and bond hydration during dissociation and establish that in this system, it is the bond stretching and not hydration which forms the bottleneck in the early parts of the dissociation process. We believe these calculations represent a step forward in the use of atomistic simulations to study pharmacokinetics. An improved understanding of biotin-streptavidin dissociation dynamics should also have direct benefits in biotechnological and nanobiotechnological applications. PMID- 29117681 TI - Kinetics of the CH3 + C5H5 Reaction: A Theoretical Study. AB - Formation of fulvene and benzene through the reaction of cyclopentadienyl (C5H5) with methyl radical (CH3) and consequent dissociation of its primary C6H7 products has been studied using ab initio and theoretical kinetics calculations. The potential energies and geometries of all involved species have been computed at the CCSD(T)-F12/cc-pVTZ-f12//B2PLYPD3/aug-cc-pVDZ level theory. Multichannel/multiwell RRKM-Master Equation calculations have been utilized to produce phenomenological pressure- and temperature-dependent absolute and individual-channel rate constants for various reactions at the C6H8 and C6H7 potential energy surfaces. The kinetic scheme combining the primary and secondary reactions has been used to generate the overall rate constants for the production of fulvene and benzene and their branching ratios. Analyses of the kinetic data revealed that at low pressures (0.01 atm) benzene formation prevails, with branching ratios exceeding 60%, whereas at the highest pressure (100 atm) fulvene formation is prevalent, with the branching ratio of benzene being lower than 40%. At intermediate pressures (1 and 10 atm) the two product channels compete and fulvene formation is preferable at temperatures above 1600 K. The results demonstrate that a five-member ring can be efficiently transformed into an aromatic six-member ring by methylation and corroborate the potentially important role of the methyl radical in the mechanism of PAH growth where CH3 additions alternate with H abstractions and acetylene additions. PMID- 29117683 TI - Not Physical Chemistry (in the Eyes of the Journal of Physical Chemistry). PMID- 29117684 TI - Communication: The Al + CO2 -> AlO + CO reaction: Experiment vs. theory. AB - Based on their highly sophisticated crossed-beam experimental studies of the Al + CO2 -> AlO + CO reaction, Honma and Hirata have directly challenged the results of earlier theoretical studies of this system. We report high level theoretical studies of this system. It is shown that, consistent with Honma-Hirata experimental conclusions, the previous theoretical prediction of a substantial barrier height for this reaction was incorrect. However, for the structures of the possible intermediates, in agreement with the 1992 theoretical study of Sakai, we find striking disagreement with the experimental conclusion that the O C-O moiety is nearly linear. The energies of the three entrance channel intermediates lie 14.4, 15.2, and 16.4 kcal mol-1 below separated Al + CO2. PMID- 29117685 TI - Relativistic effects on the NMR parameters of Si, Ge, Sn, and Pb alkynyl compounds: Scalar versus spin-orbit effects. AB - The NMR chemical shifts and indirect spin-spin coupling constants of 12 molecules containing 29Si, 73Ge, 119Sn, and 207Pb [X(CCMe)4, Me2X(CCMe)2, and Me3XCCH] are presented. The results are obtained from non-relativistic as well as two- and four-component relativistic density functional theory (DFT) calculations. The scalar and spin-orbit relativistic contributions as well as the total relativistic corrections are determined. The main relativistic effect in these molecules is not due to spin-orbit coupling but rather to the scalar relativistic contraction of the s-shells. The correlation between the calculated and experimental indirect spin-spin coupling constants showed that the four-component relativistic density functional theory (DFT) approach using the Perdew's hybrid scheme exchange-correlation functional (PBE0; using the Perdew-Burke-Ernzerhof exchange and correlation functionals) gives results in good agreement with experimental values. The indirect spin-spin coupling constants calculated using the spin-orbit zeroth order regular approximation together with the hybrid PBE0 functional and the specially designed J-coupling (JCPL) basis sets are in good agreement with the results obtained from the four-component relativistic calculations. For the coupling constants involving the heavy atoms, the relativistic corrections are of the same order of magnitude compared to the non relativistically calculated results. Based on the comparisons of the calculated results with available experimental values, the best results for all the chemical shifts and non-existing indirect spin-spin coupling constants for all the molecules are reported, hoping that these accurate results will be used to benchmark future DFT calculations. The present study also demonstrates that the four-component relativistic DFT method has reached a level of maturity that makes it a convenient and accurate tool to calculate indirect spin-spin coupling constants of "large" molecular systems involving heavy atoms. PMID- 29117682 TI - Constant pH Molecular Dynamics Reveals How Proton Release Drives the Conformational Transition of a Transmembrane Efflux Pump. AB - AcrB is the inner-membrane transporter of an E. coli AcrAB-TolC tripartite efflux complex, which plays a major role in the intrinsic resistance to clinically important antibiotics. AcrB pumps a wide range of toxic substrates by utilizing the proton gradient between periplasm and cytoplasm. Crystal structures of AcrB revealed three distinct conformational states of the transport cycle, substrate access, binding, and extrusion or loose (L), tight (T), and open (O) states. However, the specific residue(s) responsible for proton binding/release and the mechanism of proton-coupled conformational cycling remain controversial. Here we use the newly developed membrane hybrid-solvent continuous constant pH molecular dynamics technique to explore the protonation states and conformational dynamics of the transmembrane domain of AcrB. Simulations show that both Asp407 and Asp408 are deprotonated in the L/T states, while only Asp408 is protonated in the O state. Remarkably, release of a proton from Asp408 in the O state results in large conformational changes, such as the lateral and vertical movement of transmembrane helices as well as the salt-bridge formation between Asp408 and Lys940 and other side chain rearrangements among essential residues. Consistent with the crystallographic differences between the O and L protomers, simulations offer dynamic details of how proton release drives the O-to-L transition in AcrB and address the controversy regarding the proton/drug stoichiometry. This work offers a significant step toward characterizing the complete cycle of proton coupled drug transport in AcrB and further validates the membrane hybrid-solvent CpHMD technique for studies of proton-coupled transmembrane proteins which are currently poorly understood. PMID- 29117686 TI - Correlated electron dynamics in strong-field nonsequential double ionization of Mg. AB - Using the classical ensemble model, we systematically investigate strong-field nonsequential double ionization (NSDI) of Mg by intense elliptically polarized laser pulses with different wavelengths. Different from the noble atoms, NSDI occurs for Mg driven by elliptically and circularly polarized laser fields. Our results show that in elliptically and circularly polarized laser fields, the NSDI yield is sharply suppressed as the wavelength increases. Interestingly, the correlated behavior in the electron momentum spectra depends sensitively on the wavelengths. The corresponding electron dynamics is revealed by back tracing the classical trajectory. PMID- 29117687 TI - Performing SELEX experiments in silico. AB - Due to the sequence-dependent nature of the elasticity of DNA, many protein-DNA complexes and other systems in which DNA molecules must be deformed have preferences for the type of DNA sequence they interact with. SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments and similar sequence selection experiments have been used extensively to examine the (indirect readout) sequence preferences of, e.g., nucleosomes (protein spools around which DNA is wound for compactification) and DNA rings. We show how recently developed computational and theoretical tools can be used to emulate such experiments in silico. Opening up this possibility comes with several benefits. First, it allows us a better understanding of our models and systems, specifically about the roles played by the simulation temperature and the selection pressure on the sequences. Second, it allows us to compare the predictions made by the model of choice with experimental results. We find agreement on important features between predictions of the rigid base-pair model and experimental results for DNA rings and interesting differences that point out open questions in the field. Finally, our simulations allow application of the SELEX methodology to systems that are experimentally difficult to realize because they come with high energetic costs and are therefore unlikely to form spontaneously, such as very short or overwound DNA rings. PMID- 29117688 TI - MnNiO3 revisited with modern theoretical and experimental methods. AB - MnNiO3 is a strongly correlated transition metal oxide that has recently been investigated theoretically for its potential application as an oxygen-evolution photocatalyst. However, there is no experimental report on critical quantities such as the band gap or bulk modulus. Recent theoretical predictions with standard functionals such as LDA+U and HSE show large discrepancies in the band gaps (about 1.23 eV), depending on the nature of the functional used. Hence there is clearly a need for an accurate quantitative prediction of the band gap to gauge its utility as a photocatalyst. In this work, we present a diffusion quantum Monte Carlo study of the bulk properties of MnNiO3 and revisit the synthesis and experimental properties of the compound. We predict quasiparticle band gaps of 2.0(5) eV and 3.8(6) eV for the majority and minority spin channels, respectively, and an equilibrium volume of 92.8 A3, which compares well to the experimental value of 94.4 A3. A bulk modulus of 217 GPa is predicted for MnNiO3. We rationalize the difficulty for the formation of ordered ilmenite-type structure with specific sites for Ni and Mn to be potentially due to the formation of antisite defects that form during synthesis, which ultimately affects the physical properties of MnNiO3. PMID- 29117689 TI - A lattice model for the impact of volume fraction fluctuations upon percolation by cylinders. AB - A lattice model for continuum percolation by cylindrical rods is generalized to account for inhomogeneities in the volume fraction that are indicative of particle clustering or aggregation. The percolation threshold is evaluated from a formalism that uses two different categories of occupied sites (denoting particles) with different occupation probabilities that represent large and small local volume fractions. Our modeling framework enables independent variations in (i) the strength of the correlation that adjacent particles experience high (or low) effective volume fractions, (ii) the disparity between the macroscopically averaged volume fraction and (say) the volume fraction characterizing the regions with high effective particle concentrations, and (iii) the overall proportion of particles that are located in regions with either high or low volume fraction. Calculations performed for monodisperse cylinders show that enhancement in each of the above factors leads to reduction in the macroscopically averaged volume fraction at the percolation threshold. PMID- 29117690 TI - Similarity transformed equation of motion coupled-cluster theory based on an unrestricted Hartree-Fock reference for applications to high-spin open-shell systems. AB - The similarity transformed equation of motion coupled-cluster approach is extended for applications to high-spin open-shell systems, within the unrestricted Hartree-Fock (UHF) formalism. An automatic active space selection scheme has also been implemented such that calculations can be performed in a black-box fashion. It is observed that both the canonical and automatic active space selecting similarity transformed equation of motion (STEOM) approaches perform about as well as the more expensive equation of motion coupled-cluster singles doubles (EOM-CCSD) method for the calculation of the excitation energies of doublet radicals. The automatic active space selecting UHF STEOM approach can therefore be employed as a viable, lower scaling alternative to UHF EOM-CCSD for the calculation of excited states in high-spin open-shell systems. PMID- 29117691 TI - Theory of molecular nonadiabatic electron dynamics in condensed phases. AB - In light of the rapid progress of ultrafast chemical dynamics driven by the pulse lasers having width as short as several tens of attoseconds, we herein develop a theory of nonadiabatic electron wavepacket dynamics in condensed phases, with which to directly track the dynamics of electronic-state mixing such as electron transfer in liquid solvents. Toward this goal, we combine a theory of path branching representation for nonadiabatic electron wavepacket dynamics in vacuum {a mixed quantum-classical representation, Yonehara and Takatsuka [J. Chem. Phys. 129, 134109 (2008)]} and a theory of entropy functional to treat chemical dynamics in condensed phases {a mixed dynamical-statistical representation, Takatsuka and Matsumoto [Phys. Chem. Chem. Phys. 18, 1771 (2016)]}. Difficulty and complexity in the present theoretical procedure arise in embedding the Schrodinger equation into classically treated statistical environment. Nevertheless, the resultant equations of motion for electronic-state mixing due to the intrinsic nonadiabatic interactions and solute-solvent interactions, along with the force matrix that drives nuclear branching paths, both turn out to be clear enough to make it possible to comprehend the physical meanings behind. We also discuss briefly the nonvalidness of naive application of the notion of nonadiabatic transition dynamics among free energy surfaces. PMID- 29117692 TI - Delayed Slater determinant update algorithms for high efficiency quantum Monte Carlo. AB - Within ab initio Quantum Monte Carlo simulations, the leading numerical cost for large systems is the computation of the values of the Slater determinants in the trial wavefunction. Each Monte Carlo step requires finding the determinant of a dense matrix. This is most commonly iteratively evaluated using a rank-1 Sherman Morrison updating scheme to avoid repeated explicit calculation of the inverse. The overall computational cost is, therefore, formally cubic in the number of electrons or matrix size. To improve the numerical efficiency of this procedure, we propose a novel multiple rank delayed update scheme. This strategy enables probability evaluation with an application of accepted moves to the matrices delayed until after a predetermined number of moves, K. The accepted events are then applied to the matrices en bloc with enhanced arithmetic intensity and computational efficiency via matrix-matrix operations instead of matrix-vector operations. This procedure does not change the underlying Monte Carlo sampling or its statistical efficiency. For calculations on large systems and algorithms such as diffusion Monte Carlo, where the acceptance ratio is high, order of magnitude improvements in the update time can be obtained on both multi-core central processing units and graphical processing units. PMID- 29117693 TI - Non-constant link tension coefficient in the tumbling-snake model subjected to simple shear. AB - The authors of the present study have recently presented evidence that the tumbling-snake model for polymeric systems has the necessary capacity to predict the appearance of pronounced undershoots in the time-dependent shear viscosity as well as an absence of equally pronounced undershoots in the transient two normal stress coefficients. The undershoots were found to appear due to the tumbling behavior of the director u when a rotational Brownian diffusion term is considered within the equation of motion of polymer segments, and a theoretical basis concerning the use of a link tension coefficient given through the nematic order parameter had been provided. The current work elaborates on the quantitative predictions of the tumbling-snake model to demonstrate its capacity to predict undershoots in the time-dependent shear viscosity. These predictions are shown to compare favorably with experimental rheological data for both polymer melts and solutions, help us to clarify the microscopic origin of the observed phenomena, and demonstrate in detail why a constant link tension coefficient has to be abandoned. PMID- 29117694 TI - Benchmark CCSD-SAPT study of rare gas dimers with comparison to MP-SAPT and DFT SAPT. AB - Symmetry-adapted perturbation theory (SAPT) based on coupled cluster approach with single and double excitations (CCSD) treatment of intramonomer electron correlation effects was applied to study rare gas homodimers from He2 to Kr2. The obtained benchmark CCSD-SAPT energies, including cumulant contributions to first order exchange and second-order exchange-induction terms, were then compared to their counterparts found using other methods-Moller-Plesset-SAPT based on many body Moller-Plesset perturbation theory and DFT-SAPT based on density functional theory. The SAPT terms up to the second-order were calculated with the basis sets close to the complete basis set at the large range of interatomic distances R. It was shown that overestimation of the binding energies De found with DFT-SAPT reported in the work of Shirkov and Makarewicz [J. Chem. Phys. 142, 064102 (2015)] for Ar2 and Kr2 is mostly due to underestimation of the exchange energy Eexch(1) when comparing to the CCSD-SAPT benchmark. The CCSD-SAPT potentials were found to give the following values of the dissociation energies D0: 0.0006 cm-1 for He2, 16.71 cm-1 for Ne2, 85.03 cm-1 for Ar2, and 129.81 cm-1 for Kr2, which agree well with the values found from previously reported highly accurate ab initio supermolecular potentials and experimental data. The long-range dispersion coefficients C2n up to n = 6 that give the dispersion energy asymptotically equivalent to its SAPT counterpart were calculated from dynamic multipole polarizabilities at different levels of theory. PMID- 29117695 TI - A study on the plasticity of soda-lime silica glass via molecular dynamics simulations. AB - Molecular dynamics (MD) simulations were applied to construct a plasticity model, which enables one to simulate deformations of soda-lime silica glass (SLSG) by using continuum methods. To model the plasticity, stress induced by uniaxial and a variety of biaxial deformations was measured by MD simulations. We found that the surfaces of yield and maximum stresses, which are evaluated from the equivalent stress-strain curves, are reasonably represented by the Mohr-Coulomb ellipsoid. Comparing a finite element model using the constructed plasticity model to a large scale atomistic model on a nanoindentation simulation of SLSG reveals that the empirical method is accurate enough to evaluate the SLSG mechanical responses. Furthermore, the effect of ion-exchange on the SLSG plasticity was examined by using MD simulations. As a result, it was demonstrated that the effects of the initial compressive stress on the yield and maximum stresses are anisotropic contrary to our expectations. PMID- 29117696 TI - Going beyond the standard line tension: Size-dependent contact angles of water nanodroplets. AB - The dependence of the contact angle on the size of a nanoscopic droplet residing on a flat substrate is traditionally ascribed solely to line tension. Other contributions, stemming from the droplet geometry dependence of the surface tension and line tension, are typically ignored. Here, we perform molecular dynamics simulations of water droplets of cylindrical morphology on surfaces of a wide range of polarities. In the cylindrical geometry, where the line tension is not operative directly, we find significant contact angle dependence on the droplet size. The effect is most pronounced on hydrophilic surfaces, with the contact angle increase of up to 10 degrees with a decreasing droplet size. On hydrophobic surfaces, the trend is reversed and considerably weaker. Our analysis suggests that these effects can be attributed to the Tolman correction due to the curved water-vapor interface and to a generalized line tension that possesses a contact angle dependence. The latter is operative also in the cylindrical geometry and yields a comparable contribution to the contact angle as the line tension itself in case of spherical droplets. PMID- 29117697 TI - Non-orthogonal internally contracted multi-configurational perturbation theory (NICPT): Dynamic electron correlation for large, compact active spaces. AB - A computational method is presented for systems that require high-level treatments of static and dynamic electron correlation but cannot be treated using conventional complete active space self-consistent field-based methods due to the required size of the active space. Our method introduces an efficient algorithm for perturbative dynamic correlation corrections for compact non-orthogonal MCSCF calculations. In the algorithm, biorthonormal expansions of orbitals and CI-wave functions are used to reduce the scaling of the performance determining step from quadratic to linear in the number of configurations. We describe a hierarchy of configuration spaces that can be chosen for the active space. Potential curves for the nitrogen molecule and the chromium dimer are compared for different configuration spaces. Already the most compact spaces yield qualitatively correct potentials that with increasing size of configuration spaces systematically approach complete active space results. PMID- 29117698 TI - Note: MSM lag time cannot be used for variational model selection. AB - The variational principle for conformational dynamics has enabled the systematic construction of Markov state models through the optimization of hyperparameters by approximating the transfer operator. In this note, we discuss why the lag time of the operator being approximated must be held constant in the variational approach. PMID- 29117699 TI - The accretion of the new ice layer on the surface of hexagonal ice crystal and the influence of the local electric field on this process. AB - The process of creation of a new layer of ice on the basal plane and on the prism plane of a hexagonal ice crystal is analyzed. It is demonstrated that the ordering of water molecules in the already existing crystal affects the freezing. On the basal plane, when the orientations of water molecules in the ice block are random, the arrangement of the new layer in a cubic manner is observed more frequently-approximately 1.7 times more often than in a hexagonal manner. When the water molecules in the ice block are more ordered, it results in the predominance of the oxygen atoms or the hydrogen atoms on the most outer part of the surface of the ice block. In this case, the hexagonal structure is formed more frequently when the supercooling of water exceeds 10 K. This phenomenon is explained by the influence of the oriented electric field, present as a consequence of the ordering of the dipoles of water molecules in the ice block. This field modifies the structure of solvation water (i.e., the layer of water in the immediate vicinity of the ice surface). We showed that the structure of solvation water predetermines the kind of the newly created layer of ice. This effect is temperature-dependent: when the temperature draws nearer to the melting point, the cubic structure becomes the prevailing form. The temperature at which the cubic and the hexagonal structures are formed with the same probabilities is equal to about 260 K. In the case of the prism plane, the new layer that is formed is always the hexagonal one, which is independent of the arrangement of water molecules in the ice block and is in agreement with previous literature data. For the basal plane, as well as for the prism plane, no evident dependence on the ordering of water molecules that constitute the ice block on the rate of crystallization can be observed. PMID- 29117701 TI - Retention of contaminants Cd and Hg adsorbed and intercalated in aluminosilicate clays: A first principles study. AB - Layered clay materials have been used to incorporate transition metal (TM) contaminants. Based on first-principles calculations, we have examined the energetic stability and the electronic properties due to the incorporation of Cd and Hg in layered clay materials, kaolinite (KAO) and pyrophyllite (PYR). The TM can be (i) adsorbed on the clay surface as well as (ii) intercalated between the clay layers. For the intercalated case, the contaminant incorporation rate can be optimized by controlling the interlayer spacing of the clay, namely, pillared clays. Our total energy results reveal that the incorporation of the TMs can be maximized through a suitable tuning of vertical distance between the clay layers. Based on the calculated TM/clay binding energies and the Langmuir absorption model, we estimate the concentrations of the TMs. Further kinetic properties have been examined by calculating the activation energies, where we found energy barriers of ~20 and ~130 meV for adsorbed and intercalated cases, respectively. The adsorption and intercalation of ionized TM adatoms were also considered within the deprotonated KAO surface. This also leads to an optimal interlayer distance which maximizes the TM incorporation rate. By mapping the total charge transfers at the TM/clay interface, we identify a net electronic charge transfer from the TM adatoms to the topmost clay surface layer. The effect of such a charge transfer on the electronic structure of the clay (host) has been examined through a set of X-ray absorption near edge structure (XANES) simulations, characterizing the changes of the XANES spectra upon the presence of the contaminants. Finally, for the pillared clays, we quantify the Cd and Hg K-edge energy shifts of the TMs as a function of the interlayer distance between the clay layers and the Al K-edge spectra for the pristine and pillared clays. PMID- 29117700 TI - Optimal updating magnitude in adaptive flat-distribution sampling. AB - We present a study on the optimization of the updating magnitude for a class of free energy methods based on flat-distribution sampling, including the Wang Landau (WL) algorithm and metadynamics. These methods rely on adaptive construction of a bias potential that offsets the potential of mean force by histogram-based updates. The convergence of the bias potential can be improved by decreasing the updating magnitude with an optimal schedule. We show that while the asymptotically optimal schedule for the single-bin updating scheme (commonly used in the WL algorithm) is given by the known inverse-time formula, that for the Gaussian updating scheme (commonly used in metadynamics) is often more complex. We further show that the single-bin updating scheme is optimal for very long simulations, and it can be generalized to a class of bandpass updating schemes that are similarly optimal. These bandpass updating schemes target only a few long-range distribution modes and their optimal schedule is also given by the inverse-time formula. Constructed from orthogonal polynomials, the bandpass updating schemes generalize the WL and Langfeld-Lucini-Rago algorithms as an automatic parameter tuning scheme for umbrella sampling. PMID- 29117702 TI - Charge-regularized swelling kinetics of polyelectrolyte gels: Elasticity and diffusion. AB - We apply a recently developed method [S. Sen and A. Kundagrami, J. Chem. Phys. 143, 224904 (2015)], using a phenomenological expression of osmotic stress, as a function of polymer and charge densities, hydrophobicity, and network elasticity for the swelling of spherical polyelectrolyte (PE) gels with fixed and variable charges in a salt-free solvent. This expression of stress is used in the equation of motion of swelling kinetics of spherical PE gels to numerically calculate the spatial profiles for the polymer and free ion densities at different time steps and the time evolution of the size of the gel. We compare the profiles of the same variables obtained from the classical linear theory of elasticity and quantitatively estimate the bulk modulus of the PE gel. Further, we obtain an analytical expression of the elastic modulus from the linearized expression of stress (in the small deformation limit). We find that the estimated bulk modulus of the PE gel decreases with the increase of its effective charge for a fixed degree of deformation during swelling. Finally, we match the gel-front locations with the experimental data, taken from the measurements of charged reversible addition-fragmentation chain transfer gels to show an increase in gel-size with charge and also match the same for PNIPAM (uncharged) and imidazolium-based (charged) minigels, which specifically confirms the decrease of the gel modulus value with the increase of the charge. The agreement between experimental and theoretical results confirms general diffusive behaviour for swelling of PE gels with a decreasing bulk modulus with increasing degree of ionization (charge). The new formalism captures large deformations as well with a significant variation of charge content of the gel. It is found that PE gels with large deformation but same initial size swell faster with a higher charge. PMID- 29117703 TI - Demixing of active particles in the presence of external fields. AB - Self-propelled active particles are inherently out of equilibrium as they collect energy from their surroundings and transform it into directed motion. A recent theoretical study suggests that binary mixtures of active particles with distinct effective diffusion coefficients exhibit dynamical demixing when their diffusion coefficients differ by more than one order of magnitude. Here, we show that this difference may be reduced drastically in the presence of external fields even when the response to the field is the same for both species. We investigate this demixing as a function of the ratio of the diffusion coefficients and discuss the implications of the results for active systems. PMID- 29117704 TI - An Integrated Approach to Bias in a Longitudinal Survey in the United Kingdom: Assessing Construct, Method, and Item Bias in the General Health Questionnaire (GHQ-12). AB - Construct, method, and item bias are three levels of measurement bias (i.e., internal bias) essential for valid group comparisons. While many studies often focus on only one level of bias, an integrated perspective on bias is still missing, especially in longitudinal designs. The aim of this study is to address bias in an integrated manner, using four waves of data in the U.K. Longitudinal Household Panel Survey. Responses to the General Health Questionnaire (GHQ-12) from natives and two generations of immigrants were used to analyze the three levels of bias. While the basic structure of the GHQ-12 was stable across groups and time, item and method bias decreased with repeated administrations. Results were confirmed with a sensitivity test. The integrated results allowed for a distinction between temporal sources of bias that became smaller over time and sources affecting valid comparisons persistently. We discuss the implications for mental health assessment. PMID- 29117705 TI - Personality Inventory for DSM-5-Short Form (PID-5-SF): Reliability, Factorial Structure, and Relationship With Functional Impairment in Dual Diagnosis Patients. AB - Section III of the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition ( DSM-5) has generated a personality paradigm consisting of 25 personality facets identified in five domains. The developed assessment instrument Personality Inventory for DSM-5 (PID-5) has showed good psychometric properties, but the potential for certain improvements still remain. In this article, a sample of 282 dual diagnosis patients is used to provide evidence of the psychometric properties of the PID-5-Short Form. The mean value of Cronbach's alpha coefficients reached .73 on the facets and .84 for domains and test-retest values ranged between .57 to .83 for facets and .70 to .87 for the domains. Confirmatory factor analyses conducted showed good fit on both models tested: the five correlated factor structure and hierarchical structure of personality traits. The WHODAS 2.0 domains of understanding and communicating, and participating in society, appear to show the strongest relationship with personality facets. In general, the PID-5-Short Form shows adequate psychometric properties for use in dual diagnosis patients. PMID- 29117706 TI - The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease. AB - SIGNIFICANCE: Great attention has been placed on the link between metabolism and immune function giving rise to the term "immunometabolism." It is widely accepted that inflammation and oxidative stress are key processes that underlie metabolic complications during obesity, diabetes, and atherosclerosis. Therefore, identifying the mechanisms and mediators that are involved in the regulation of both inflammation and metabolic homeostasis is of high scientific and therapeutic interest. Recent Advances: G protein-coupled receptors (GPCRs) that signal in response to metabolites have emerged as attractive therapeutic targets in inflammatory disease. Critical Issues and Future Directions: In this review, we discuss recent findings about the physiological role of the main metabolite sensing GPCRs, their implication in immunometabolic disorders, their principal endogenous and synthetic ligands, and their potential as drug targets in inflammation and metabolic disease. Antioxid. Redox Signal. 29, 237-256. PMID- 29117707 TI - Susceptibility of iodine concentration map of dual-energy contrast-enhanced digital mammography for quantitative and tumor enhancement assessment. AB - Background Dual-energy (DE) contrast-enhanced digital mammography (DE-CEDM) provides additional information on tumor angiogenesis. Purpose To investigate the susceptibility of reconstructing color-coded iodine concentration maps on the basis of quantitative calibrations of the iodine concentration and contrast-to noise ratio (CNR) in DE-CEDM applications. Material and Methods A custom-made phantom filled with iodine concentrations in the range of 0.1-10 mg/cm2 was used in calibrations. All DE images were acquired using the GE Senographe Essential system. From DE subtraction images, the image contrast and CNR were obtained, and the quantitative relationship between these two metrics and the iodine concentration at each phantom thickness was investigated. The quantitative CNR calibration curves were applied to reconstruct color-coded iodine maps on a pixel by-pixel basis. Results Both the mean contrast and mean CNR increased linearly with the iodine concentration. The iodine concentration estimated from the iodine map reconstructed from quantitative CNR calibrations was highly consistent with the desired iodine concentration (R2 = 0.989), and smaller relative errors (in the range of 3.0-19.5%) were observed with iodine concentrations not less than 1 mg/cm2. Conclusion An iodine concentration map could be reconstructed based on the linear relationship between the CNR and iodine concentration. From the color coded iodine concentration map, the contrast medium enhancement phenomenon could be further estimated quantitatively, and tumor enhancement patterns could be easily observed. PMID- 29117708 TI - How to Identify Narcissism With 13 Items? Validation of the German Narcissistic Personality Inventory-13 (G-NPI-13). AB - Four studies investigated the construct validity of the brief version of the German Narcissistic Personality Inventory-13 (G-NPI-13). Study 1 ( N = 603) confirmed the three-factor structure of the G-NPI-13 and its associations with the NPI-40 and the NPI-16. In Study 2 ( N = 438), the convergent and discriminant validity of the G-NPI-13 was analyzed by investigating its relationships with the "Big Five," self-esteem, and mental health variables (depression, anxiety, stress symptoms; life satisfaction, happiness, social support). Study 3 ( N = 118) provided further support for the convergence between the G-NPI-13 and the NPI-40 by investigating their associations with vulnerable narcissism, self-monitoring, and mental health. In Study 4 ( N = 82), the 1-year test-retest reliability (three measurement time points) of the G-NPI-13 was investigated. Taken together, the G-NPI-13 is a valid, reliable, and economical instrument for measuring the personality trait narcissism. Possible practical applications and limitations of the G-NPI-13 are discussed. PMID- 29117709 TI - Detecting Perfusion Pattern Based on the Background Low-Frequency Fluctuation in Resting-State Functional Magnetic Resonance Imaging Data and Its Influence on Resting-State Networks: An Iterative Postprocessing Approach. AB - Resting-state functional magnetic resonance imaging (RS-fMRI) is based on the assumption that the vascular response and the blood oxygenation level-dependent response are homogenous across the entire brain. However, this a priori hypothesis is not consistent with the well-known variability of cerebral vascular territories. To explore whether the RS networks are influenced by varied vascular speed in different vascular territories, we assessed the time-shift maps that give an estimate of the local timing of the vascular response and checked whether local differences in this timing have an impact on the estimates of RS networks. Two hundred seventeen elderly (>=60 years), healthy participants (73.74 +/- 4.41 years, 143 females, 203 right handed) underwent one MRI examination, including an RS-fMRI session. After preprocessing, statistical analyses included time-shift analyses and RS-fMRI analyses using as regressor the delay maps obtained from the time-shift analyses. The functional connectivity map of default mode network (DMN) of each participant was then calculated by using the seed-to-voxel analysis in the REST toolbox. Faster cerebrovascular responses were notably present in the primary motor and somatosensory and peri-insular cortex, while slower responses were present in various regions, including notably the posterior cingulate cortex (PCC). Moreover, significant changes notably in the DMN, including medial prefrontal cortex (t = 11.95), PCC (t = 11.52), right middle temporal lobe (t = 10.72), and right angular gyrus (t = 10.88), were observed also taking into account the cerebrovascular delayed maps. As the most prominent example of the RS networks, DMN activation patterns change as a function of the cerebrovascular delay. These data suggest that a group correction for vascular maps in RS-fMRI measurements is essential to correctly depict functional differences and exclude potential confounding effects, notably in the elderly with increasing prevalence of vascular comorbidity. PMID- 29117710 TI - Psychometric Properties of the Frost Multidimensional Perfectionism Scale in Spanish Children and Adolescents. AB - The Frost Multidimensional Perfectionism Scale (FMPS) is one of the most used instruments to assess perfectionism. The FMPS assesses six dimensions: Concern over Mistakes (CM), Parental Expectations (EP), Parental Criticism (PC), Doubts about Actions (DA), Organization (OR), and Personal Standards (PS). CM, PE, PC, and DA are facets of a more general dimension considered Maladaptive Perfectionism. PS is frequently considered Adaptive Perfectionism. FMPS psychometric properties have been studied in adults but scarcely in children. We adapted the FMPS for Spanish children and adolescents and studied these properties in a sample of 1,648 Spanish young people (mean age = 13.36; SD = 2.28). Multigroup confirmatory factor analyses were used to test whether the FMPS dimensions found in adults are applicable to children. Results supported this hypothesis. The FMPS dimensional structure was invariant across gender and age. FMPS subscales showed good internal consistency (Cronbach's alpha: .71-.92) and test-retest reliability (intraclass correlations: .70-.85). Moderate and high correlations with measures of dysfunctional beliefs, anxiety, and depression supported the validity of the FMPS scores. Results from regression equations showed that the relationship of perfectionism with anxiety and depression is mostly due to Maladaptive Perfectionism. PMID- 29117712 TI - Systematic Review of Differential Reinforcement of Alternative Behavior Without Extinction for Individuals With Autism. AB - The purpose of this article is to review the literature on differential reinforcement of alternative behavior procedures without extinction for individuals with autism. Using predetermined inclusion criteria, a total of 10 studies were included and summarized in terms of the following: (a) participant characteristics (e.g., sex, age, and diagnosis), (b) treatment setting, (c) problem behavior, (d) function, (e) alternative behavior, (f) intervention, (g) outcomes, and (h) conclusiveness of evidence. Of the 10 studies, nine demonstrated positive effects and one mixed effects. Five studies successfully reduced problem behavior by manipulating different reinforcement parameters (magnitude, immediacy, and quality) and four manipulated the schedule of reinforcement. One study had mixed results with two of the three participants requiring extinction. The findings of this review suggest that variations of differential reinforcement of alternative behavior interventions without an extinction component may be considered promising practices for the treatment of challenging behavior in individuals with autism. PMID- 29117711 TI - Acetylation Regulates Thioredoxin Reductase Oligomerization and Activity. AB - AIMS: Thioredoxin reductase 1 (TrxR1) is a cancer target and essential selenoprotein that defends the cell against reactive oxygen species and regulates cellular signaling and redox pathways. Previous cell-based studies correlated TrxR1 acetylation with modulated cellular reduction activity, yet the function of specific acetylation sites on TrxR1 remains unknown. INNOVATION: We produced site specifically acetylated TrxR1 variants that also contain selenocysteine (Sec). We demonstrated efficient high-fidelity protein synthesis with 22 different amino acids by simultaneous UAG codon reassignment to NE-acetyl-lysine and UGA codon recoding to Sec. RESULTS: We characterized TrxR1 variants acetylated at physiologically relevant sites and found that single acetylation sites increased TrxR1 activity, enhancing the apparent catalytic rate up to 2.7-fold. The activity increase in acetylated TrxR1 (acTrxR1) is reversible and is reduced following deacetylation with histone deacetylase. CONCLUSION: Here we present a novel mechanism through which acetylation increases TrxR1 activity by destabilizing low-activity TrxR1 multimers, increasing the population of active dimeric TrxR1. Antioxid. Redox Signal. 29, 377-388. PMID- 29117713 TI - Is the HIV epidemic changing views on marriage aspirations? Perspectives of university students in Durban, South Africa. AB - Marriage rates in South Africa have dropped to approximately 37% in recent years. This is particularly marked in the Black African population compared to other race groups. In tandem, the prevalence of HIV in this country has risen to 12.7%, with the highest prevalence among Black Africans. However, no data associates marriage decline with high HIV prevalence. We bridge this gap in knowledge by investigating young students' aspirations to marry in the context of high national HIV rates. A cross-sectional study was conducted among university students (n = 384) in KwaZulu-Natal, South Africa, between October and November 2014. Quantitative data were collected through self-administered questionnaires. Data was analysed by Likert scale analysis, Chi square test, Fisher's exact test, multivariate regression modelling and calculation of odds ratios. Majority of respondents (85.8%, n = 331) indicated that they wished to get married but more than half (53%, n = 205, p < 0.001) indicated that the high prevalence of HIV has had a negative impact on their marriage aspirations. Students indicated that considering a partner's HIV status prior to marriage was important (p < 0.001), marriage did not offer protection from HIV (p < 0.001), and testing for HIV prior to marriage was imperative (p < 0.001). Considering a partner's HIV status before marriage is important and associated with increased odds (OR = 5.62, 95%CI: 1.57 20.05) of wanting to get married. There was a significant relationship between respondents wanting to get married and the future marriage partner being HIV negative (p = 0.003). Furthermore, the HIV epidemic has decreased the odds of wanting to get married (OR = 0.21; 95%CI: 0.08-0.58). We conclude that while the majority of young students have marriage aspirations, the high prevalence of HIV has resulted in a negative perception of marriage. Although HIV testing prior to marriage is considered important, students recognize that they may not be protected from infection during marriage. PMID- 29117714 TI - Potassium Fluctuations Are Associated With Inhospital Mortality From Acute Myocardial Infarction. Soroka Acute Myocardial Infarction II (SAMI-II) Project. AB - Potassium levels (K, mEq/L) fluctuate in patients with acute myocardial infarction (AMI). Potassium was reported to be associated with prognosis in patients with AMI; however, studies evaluating the prognostic value of K fluctuations in this setting are scarce. We retrospectively analyzed patients with AMI hospitalized in a tertiary medical center, through 2002 to 2012. Patients on chronic dialysis or mechanical ventilation were excluded. Based on all K values during hospitalization, minimal, maximal, and fluctuation (gap between 2 consecutive K) were recorded. Primary outcome was inhospital all-cause mortality. Overall, 10 032 patients were studied (age 68.1 +/- 14.3 years, 65.4% males, 44.2% ST-segment elevation MI), of which 507 (3.7%) died in hospital. Potassium decreased during the first 2 to 3 days ( P for trend <.001), followed by stabilization ( P for trend = .807). Potassium in the extreme categories (<3.8 and >=4.7) and absolute fluctuations >0.1 mEq/L were more common among nonsurvivors than survivors ( P < .001 each). In a multivariate analysis, combinations of minimal K <3.8 with maximal K >=4.7 (odds ratio [OR] = 18.1), K >=4.4 with fluctuation >=0.1 (OR = 1.74), or <-0.1 (OR = 2.6) and minimal K after the first 2 admission days (OR = 2.07) were associated with increased risk of mortality ( P < .001 each). Potassium fluctuations, peak and nadir K, and its timing independently predict inhospital mortality in patients with AMI. PMID- 29117716 TI - Artificial Intelligence-Magic? / L'intelligence artificielle : de la magie? PMID- 29117715 TI - Iso-osmolar contrast media and adverse renal and cardiac events after percutaneous cardiovascular intervention. AB - AIM: To assess the relationship between type of contrast media (CM), iso-osmolar contrast media (IOCM) or low-osmolar contrast media (LOCM), and major adverse renal and cardiovascular events (MARCE). MATERIALS & METHODS: Coronary or peripheral angioplasty visits were stratified into CM cohorts: IOCM or LOCM. Multivariable regression analysis used hospital fixed effects to assess the relationship between MARCE events and type of CM. RESULTS: Among 333,533 visits (357 hospitals), the incidence of MARCE was 7.41%. After controlling for observable and unobservable time invariant within-hospital characteristics, administration of IOCM versus LOCM was associated with a 0.69% absolute and 9.32% relative risk reduction in MARCE rate. CONCLUSION: Our study indicates that as compared with LOCM, IOCM may be associated with reduction of MARCE events in coronary or peripheral angioplasty patients. PMID- 29117717 TI - Ulcerative Pearly Plaque of the Ear in an Elderly Man Mimicking Squamous Cell Carcinoma. PMID- 29117718 TI - Deep Tissue Sequencing Using Augmented Intelligence to Probe Melanocytic Lesions. PMID- 29117719 TI - Introducing a "Workplace Prescription" to Facilitate Return to Work for Workers With Occupational Contact Dermatitis. PMID- 29117720 TI - Examining College Students' Social Environment, Normative Beliefs, and Attitudes in Subsequent Initiation of Electronic Nicotine Delivery Systems. AB - BACKGROUND: Although use of Electronic Nicotine Delivery Systems (ENDS) is increasingly prevalent among young adults, little is known about predictors of ENDS initiation among this population. AIMS: We examined the roles of the social environment (i.e., peer ENDS use and household ENDS use), normative beliefs (i.e., social acceptability of ENDS use), and attitudes (i.e., inclination to date someone who uses ENDS) in prospectively predicting initiation of ENDS over a 1-year period among 18- to 29-year-old college students. METHOD: Participants were 2,110 (18- to 29-year-old) students ( M = 20.27, SD = 2.17) from 24 colleges in Texas who participated in a three-wave online survey, with 6 months between each wave. All participants reported never using ENDS at baseline. A multivariable, multilevel logistic regression model, accounting for clustering of students within colleges, was used to assess if students' social environment, normative beliefs, and attitudes predicted subsequent initiation of ENDS up to 1 year later, adjusting for various sociodemographic factors and number of other tobacco products used. RESULTS: In all, 329 college students (16%) initiated ENDS within 1 year. Results from the logistic regression indicated that college students who were younger (18-24 years old), ever used other tobacco products, indicated a more dense peer network of ENDS users, and had a higher inclination to date someone who uses ENDS had higher odds of initiating ENDS than their peers. CONCLUSION: Preventing ENDS initiation should be included in college health promotion programs, which should highlight the roles of students' social environment and attitudes regarding ENDS use. PMID- 29117721 TI - Enhanced sciatic nerve regeneration by human endometrial stem cells in an electrospun poly (epsilon-caprolactone)/collagen/NBG nerve conduit in rat. AB - In recent years, for neurodegenerative diseases therapy, research has focused on the stem cells therapy. Due to promising findings in stem cell therapy, there are various sources of stem cells for transplantation in human. The aim of this study was to evaluate sciatic nerve regeneration in the rat after nerve transaction followed by human endometrial stem cells (hEnSCs) treatment into poly (e caprolactone)/collagen/nanobioglass (PCL/collagen/NBG) nanofibrous conduits. After treatment of animals, the performance in motor and sensory tests, showed significant improvement in rats treated with hEnSCs as an autograft. H&E images provided from cross-sectional and, longitudinal-sections of the harvested regenerative nerve as well as immunohistochemistry results indicated that regenerative nerve fibres had been formed and accompanied with new blood vessels in the conduit cell group. Due to the advantage of high surface area for cell attachment, it is reported that this electrospun nerve conduit could find more application in cell therapy for nerve regeneration in future, to further improve the functional regeneration outcome, especially for longer nerve defect restoration. In conclusion, our results suggest that the PCL/collagen/NBG nanofibrous conduit filled with hEnSCs is a suitable strategy to improve nerve regeneration after a nerve transaction in rat. PMID- 29117722 TI - Endoscopic ultrasound-guided pancreatic fluid collections' transmural drainage outcomes in 100 consecutive cases of pseudocysts and walled off necrosis: a single-centre experience from the United Kingdom. AB - BACKGROUND AND AIM: Endoscopic ultrasound-guided drainage is a minimally invasive first-line modality for the drainage of pancreatic fluid collection (PFC) resulting in a shorter hospital stay and less morbidity compared with surgical cystogastrostomy. Our aim is to evaluate potential differences in the outcomes of endoscopic ultrasound (EUS) guided transmural drainage (EUS-TD) drainage of pancreatic pseudocyst (PP) and walled-off necrosis (WON). METHOD: We retrospectively reviewed 100 consecutive EUS-guided drainages of PFC utilising EUS reports; clinical notes and imaging with follow-up (FU) to 12 months. All procedures were undertaken under conscious sedation with EUS guidance alone (without fluoroscopy) and placement of plastic double pigtail stents. RESULTS: In these 100 sequential cases, there were 78 cases of PP and 22 cases of WON. All 22/22(100%) cases of WON had successful EUS-guided stent placement. In 2/22(9%), there was little or no clinical improvement. These two patients required further computed tomography (CT)-guided drainage and one of these patients (1/22) (4.5%) developed recurrence within 12 months FU after removal of stents. In case of PP, overall stent placement was successful in 76/78 (97%) patients, but 6/78(8%) required 2nd EUS procedure after failure to show clinical improvement; 3/78(2.5%) required further CT-guided drainage. The overall complication rate was 9%(9/100) with 4%(4/100) requiring endoscopic or CT-guided intervention with no overall 30 day mortality. CONCLUSION: This is the largest series from a single UK centre demonstrating that EUS-guided cystogastrostomy of PFC drainage using plastic double pigtail stents is sufficient in majority of cases with PFC including that of WON, with or without infection. PMID- 29117723 TI - Cardiovascular Disease Risk Predicts Health Perception in Prison Inmates. AB - We hypothesized that risk factors for cardiovascular disease (CVD) would be associated with worse health perceptions in prison inmates. This study included 362 inmates recruited from four medium security prisons in Kentucky. Framingham Risk Score was used to estimate the risk of developing CVD within the next 10 years. A single item on self-rated health from the Medical Outcomes Survey-Short Form 36 was used to measure health perception. Multinomial logistic regression showed that for every 1-unit increase in Framingham Risk Score, inmates were 23% more likely to have rated their health as fair/poor and 11% more likely to rate their health as good rather than very good/excellent. These findings demonstrate that worse health perceptions may serve as a starting point for discussing cardiovascular risk factors and prevention with inmates. PMID- 29117724 TI - Reference intervals for absolute and percentage immature platelet fraction using the Sysmex XN-10 automated haematology analyser in a UK population. AB - BACKGROUND: Immature platelet fraction (IPF) estimation is a non-invasive and sensitive test that is available on recently introduced Sysmex XN-series of automated haematology analysers. It is a direct cellular indicator of thrombopoiesis. The aim of this study was to establish reference intervals for IPF, for both absolute (A-IPF) and percentage (%-IPF) measurements. MATERIAL AND METHODS: A total of 2366 samples that met the inclusion criteria were assayed for full blood count on the Sysmex XN-10 and a non-parametric percentile method was used for calculating the reference intervals. RESULTS: After the outliers were excluded, the reference interval for %-IPF and A-IPF on Sysmex XN-10 were 1.6 10.1% and 4.37-23.21 * 109/L in total individuals, respectively. There was a statistical significance noted between the sexes (p = .004) for %-IPF, therefore a sex-specific reference interval was established, which was 1.8-10.0% for the males and 1.5-10.1% for females. No significant difference in sex status for A IPF and age status for both %-IPF and A-IPF was observed. A very poor correlation was estimated between age versus %-IPF, rho = 0.0156, and age versus A-IPF, rho = -0.0023, indicating that there is no overall biological relationship between age and these parameters. As expected, a strong correlation between %-IPF and A-IPF was noted which could be attributed to their inter-relatedness. CONCLUSIONS: This large-scale study showed comparable reference intervals with the previous studies for %-IPF and A-IPF in a UK population. It found the need to establish sex specific reference intervals for %-IPF, but not for A-IPF, whereas reference intervals were found to be stable across the age range. PMID- 29117725 TI - Experiencing Financial Hardship Associated With Medical Bills and Its Effects on Health Care Behavior: A 2-Year Panel Study. AB - Using 2-year panel data, this study examined (1) whether experiencing financial hardship associated with out-of-pocket medical expenditures affected delaying/missing necessary health care in the following year; (2) whether such financial hardship mediated the effects of predisposing, enabling, and need characteristics on timely health care access (i.e., significant indirect effects); and (3)whether such mediating effects are different by chronic health status (i.e., moderated mediation) among U.S. adults. The 2011 National Health Interview Survey was linked to the 2012 Medical Expenditure Panel Survey. The sample includes 8,993 adults aged between 26 and 64 years. Among them, 1,089 reported having at least one chronic health condition that had caused activity limitations. Multiple-group path analysis was conducted using Mplus 7.2. Approximately 35% experienced financial difficulties paying medical bills, including 28% who were currently paying off medical debts. Almost 14% of the respondents reported delayed/missed necessary medical treatments. In addition to direct effects, predisposing, enabling, and need factors affected access to care indirectly via financial hardship, although significant moderated mediation was found by chronic health status. However, different from the Andersen's behavioral model of health service utilization, the effect of financial hardship due to medical bills as a barrier to the timely use of necessary health services was not smaller among adults with chronic health conditions. Policy alternatives should be explored to provide affordable financing programs and adequate safety net health services to reduce the financial burden of health care for those who are financially vulnerable, especially those suffering from chronic health conditions. PMID- 29117726 TI - Construct validity of the Eating Assessment Tool (EAT-10). AB - PURPOSE: We aimed to evaluate the construct validity of the Eating Assessment Tool (EAT-10) by determining its dimensionality, rating scale integrity, item person match, precision and relationship with the degree of airway invasion and functional oral intake. METHODS: We conducted a retrospective analysis of patients' EAT-10 scores. We used the Rasch rating scale model. We investigated correlations between the EAT-10 and scores on the Penetration-Aspiration Scale (PAS) and Functional Oral Intake Scale (FOIS). RESULTS: The median score of the EAT-10 from 127 patients was 16 of 40 (range 0-40). Confirmatory factor analysis supported unidimensionality. The 5-point rating scale categories met published criteria. Two items misfit the Rasch model and two other items displayed differential item functioning. Rasch person reliability was 0.79. Our patient cohort was divided into three person-strata. Correlations between the EAT-10 and the PAS and FOIS were weak to moderate in strength (respectively: r = 0.26, p = 0.0036; r = -0.27, p = 0.0027). CONCLUSIONS: Our analyses identified deficits in the construct validity of the EAT-10 suggestive of a need to improve the EAT-10 to support its frequent use in clinical practice and research. Implications for Rehabilitation Swallowing disorders are associated with severe complications, such as pneumonia and malnutrition, and impose both social and psychological burdens on patients. The Eating Assessment Tool is a self-report instrument developed to estimate initial dysphagia severity and monitor change in patient reported dysphagia symptoms as a response to treatment. This study shows that the Eating Assessment Tool has deficits in its construct validity and a need to improve the instrument to support its frequent use in clinical practice and research. PMID- 29117727 TI - Crispoic acid, a new compound from Laelia marginata (Orchidaceae), and biological evaluations against parasites, human cancer cell lines and Zika virus. AB - The phytochemical study of Laelia marginata (Lindl.) L. O. Williams (Orchidaceae) led to the isolation of a new natural product named crispoic acid (1), together with six other known compounds (2-7). The new natural product was identified as a dimer of eucomic acid and was structurally characterised based upon 1D and 2D NMR and HRMS data. Biological assays with plant crude extract, fractions and isolated compounds were performed against two human cancer cell lines (Hela and Siha), and the tropical parasites Trypanosoma cruzi and Leishmania (Leishmania) amazonensis. The phenantrenoid 9,10-dihydro-4-methoxyphenanthren-2,7-diol 2 was active against Hela and Siha cells (CC50 5.86 +/- 0.19 and 20.78 +/- 2.72 MUg/mL, respectively). Sub-lethal concentrations of the flavone rhamnazin 4 were not able to rescue the viability of the Vero cells infected by Zika virus. PMID- 29117728 TI - Different pattern of risk factors for post-ERCP pancreatitis in patients with biliary stricture. AB - OBJECTIVE: To identify possible risk factors associated with post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in biliary stricture (BS), common bile duct stone (CBDS) and unselected patients. MATERIALS AND METHODS: Consecutive ERCP patients with native papilla from January 2010 to December 2014 in Xijing Hospital were eligible. Patient-related and procedure related parameters were collected retrospectively. The primary outcome was PEP. Univariate and multivariate logistic regression were used for data analysis. RESULTS: Totally 3133 unselected patients were included. 695 (22.2%) had BS alone and 1893 (60.4%) had CBDS alone. PEP incidence was higher in BS group compared with CBDS group (6.8% vs. 3.8%, p = .001). Among patient-related factors, duodenal stenosis (OR, 2.74; 95%CI, 1.14-6.59) and hilar stricture (OR, 2.59; 95%CI, 1.41-4.77) were found to be independently associated with PEP in BS group. While female gender (OR, 2.11; 95%CI, 1.20-3.73) and normal total bilirubin (OR, 1.93; 95%CI, 1.13-3.32) were related to PEP in CBDS group. Among procedure related factors, cannulation time >= 5 min (OR, 2.38; 95%CI, 1.06-5.33) and precut (OR, 3.20; 95%CI, 1.35-7.59) was respectively the only independent risk factor for PEP in BS and CBDS group. CONCLUSIONS: Patients with BS and CBDS had different patterns of patient-related and procedure-related risk factors for PEP. The prophylaxis of PEP may need to be individualized based on different indications. PMID- 29117729 TI - Chemical composition and antiproliferative activity of Croton campestris A.St. Hil. essential oil. AB - Herein, the antiproliferative potential of the essential oil obtained from fresh leaves of Croton campestris against human tumour cell lines was investigated for the first time. Furthermore, the essential oil obtained by hydrodistillation had the composition determined by gas chromatography-mass spectrometry (GC/MS). Ten major components were identified that comprised 91.59% of the total content, with 23.8% consisting of (Z)-caryophyllene and 16.08% consisting of gamma-elemene as main components. The cytotoxic activity was observed mainly for breast (MCF-7) and colon (HT-29) human tumour cell lines, with GI50 (50% growth inhibition) concentration of 8.61 and 9.94 MUg/mL, respectively. The results of this study showed that the essential oil obtained from Croton campestris A.St.-Hil. represents a potential source for the search of new antitumour agents. PMID- 29117730 TI - Difficulty and independence in shopping among older Americans: more than just leaving the house. AB - BACKGROUND: The built, social and economic environments are associated with disability, but knowledge of how these environmental characteristics simultaneously influence older adults' ability to shop independently is limited. OBJECTIVE: We investigated cross-sectional associations between the outdoor home, local neighborhood and macrosocioeconomic levels of the environment and shopping difficulty and interactions between environmental factors and shopping difficulty. METHODS: Using nationally representative data from a study of Medicare-eligible adults, we conducted a cross-sectional secondary data analysis to examine associations between the environment and difficulty shopping (N = 5504). RESULTS: Sidewalk conditions, broken steps, neighborhood social cohesion and neighborhood socioeconomic disadvantage were associated with more difficulty shopping, although health factors partially accounted for associations between broken steps and disadvantage and shopping difficulty. The association between social cohesion and shopping difficulty also depended on the degree of socioeconomic disadvantage in the neighborhood. CONCLUSIONS: Overall, results suggest that factors in the outdoor and local neighborhood environment influence the ability to shop independently for older adults, but that it also may depend on the socioeconomic context of the neighborhood. Interventions aimed at improving the built environment directly outside of older adults' homes and helping increase social cohesion among neighbors, has the potential to reduce difficulty in carrying out this important activity. Implications for rehabilitation Built features of the outdoor home environment including sidewalks and broken steps influence whether older adults are able to safely leave their home to conduct daily activities such as shopping, so it is important that clinicians and rehabilitation professionals are aware of these challenges when helping their patients resume daily activities such as shopping. The physical condition and safety of the immediate outdoor home and neighborhood environment is critical for maintaining independence and well-being for older adults, which is critical for physical rehabilitation as well as maintenance of essential activities such as shopping. Living in more socially cohesive neighborhoods may aid in physical rehabilitation efforts by helping older adults feel more comfortable and able to shop independently in neighborhoods with social and economic disadvantages. PMID- 29117731 TI - Anti-inflammatory activity of compounds isolated from Swertia mussotii. AB - Six compounds were isolated from an ethanol extract of Swertia mussotii and identified as 2-phenylethyl-beta-D-glucoside (1), amaroswerin (2), 1,3,7,8 tetrahydroxyxanthone (3), swertiamarine (4), 1,3,8-trihydroxy-5-methoxyxanthone (5) and methylswertianin (6). Compounds 1, 2 and 6 were isolated from S. mussotii for the first time. The anti-inflammatory activities of the compounds were evaluated by determining their effect on the production of NO by LPS-stimulated RAW264.7 cells. Amaroswerin was the most potent inhibitor of NO release, with an IC50 value of 5.42 MUg/mL. Treatment with amaroswerin inhibited expression of iNOS at both protein and mRNA levels. Amaroswerin also dose-dependently suppressed production of TNF-alpha, IL-6 and IL-1beta and reduced expression of mRNA for these LPS-stimulated pro-inflammatory mediators. Amaroswerin thus inhibits the expression of iNOS, TNF-alpha, IL-6 and IL-1beta by downregulating transcription in LPS-induced RAW264.7 macrophage cells, indicating that amaroswerin may be a valuable therapeutic agent for the treatment of inflammatory diseases. PMID- 29117732 TI - Phytochemical constituents from dietary plant Citrus hystrix. AB - Chemical investigation of the fruit peel of dietary plant Citrus hystrix offered two new flavones 5,6,4'-trihydroxypyranoflavone I and 5,4'-dimethyl-6 prenylpyranoflavone XIII besides 11 known compounds. The structures of all compounds were elucidated with the aid of suitable analytical methods like 1D, 2D NMR, mass and single crystal X-ray analysis. An X-ray crystal study of compound II was done for the first time and the compounds I-VI, XI and XII are hitherto not reported from this plant. Biological studies revealed that compound I found to have a good antidiabetic and antiacetylcholinesterase activities meanwhile compounds II, III and V showed a significant free radical scavenging ability as well as antioxidant capacity. In addition, compounds I, IV, V and VI showed cytotoxicity against U87, A549 and MCF-7 cells. Overall, the new compound I showed valuable bioactive properties. Due to insufficient quantity of compound XIII, biological studies were not done. PMID- 29117733 TI - Analysis of 17 polyphenolic compounds in organic and conventional legumes by high performance liquid chromatography-diode array detection (HPLC-DAD) and evaluation of their antioxidant activity. AB - Consumption of legumes has become popular among health-conscious consumers due to the high levels of nutrients such as proteins, dietary fibres, minerals, vitamins and micronutrients like polyphenols. Ten legumes cultivars organically and conventionally grown were compared regarding their chemical profiles in terms of total phenolic content (TPC), total anthocyanin content (TAC), total flavonoid content (TFC) and their antioxidant capacity. The chemical profiles (i.e. free phenolics and anthocyanins) were determined with aid of new high-performance liquid chromatography-diode array detection (HPLC-DAD) method able to identify two individual anthocyanins and 15 polyphenols. Results showed that phenolic acids, namely gallic acid, caffeic acid, syringic acid and ferulic acid, are mainly significantly higher in the organic samples with respect to the conventional ones. All organic legumes showed a higher antioxidant capacity with respect to conventional samples with the exception of red and yellow dehulled lentils. PMID- 29117734 TI - Risk factors for a delay in medical education: Results of an online survey among four German medical schools. AB - BACKGROUND: Delayed study progress in medical school is a challenging issue for the tax paying community, the faculty and the medical students themselves. Reasons for a delay might be different from known risk factors for academic difficulties. METHODS: An online survey regarding delays in the study progress and including a personality test (BFI-10) was presented to medical students from four German medical schools after completion of their 3rd year of study. RESULTS: Of 617 students, 51.2% reported a mean delay of 2.1 +/- 1.5 semesters. Frequent risk factors were secondary employment (69.5%, odds ratio (OR) 1.7, p = 0.004), female gender (69.8%, OR 1.6, p = 0.007), work or study abroad (35.9%, OR 1.5, p = 0.02), a late graduation (5.9%, OR 2.4, p = 0.02), as well as support through scholarship or mentoring (19.9%, OR 1.8, p = 0.004). "Working on doctoral thesis" (11.3%, OR 1.9, p = 0.03) and structural curricular issues (36.6%, OR 0.9, p = 0.7) were frequently identified as obstacles. "Support by friends/family" was considered helpful by 24.1% (OR 1.4, p = 0.09), as well as a high intrinsic motivation (19.1%, OR 0.5, p = 0.01). In the BFI-10, students with study delay were more prone to openness and agreeableness. CONCLUSIONS: Risk factors for delay are not identical to those for academic difficulties. To decrease the risk for delays, firm curricular structures should be identified and alleviated. Intrinsic motivation is a strong impetus of study progress and additionally might be strengthened by curricular changes. PMID- 29117735 TI - Antioxidant and alpha-glucosidase inhibitory ingredients identified from Jerusalem artichoke flowers. AB - Jerusalem artichoke (JA, Helianthus tuberosus L.) has been researched extensively due to its wide range of uses, but there are limited studies on its flowers. In this study, we report the first detailed phytochemical study on JA flowers, which yielded 21 compounds. Compound 4 was identified as a major water-soluble yellow pigment of JA flowers. In addition, the methanol extract of JA flowers and the isolates were evaluated for their antioxidant and alpha-glucosidase inhibitory activities. Among the tested compounds, compound 13 showed the strongest ABTS+ free radical scavenging activity with SC50 value of 2.30 +/- 0.13 MUg/mL, and compound 6 showed most potent alpha-glucosidase inhibitory activity with inhibition rate of 60.0% +/- 10.3% at a concentration of 250 MUg/mL. Results showed that methanol extract of JA flowers exhibited antioxidant and alpha glucosidase inhibitory activities which could be attributed to its phenolic ingredients including chlorogenic acid derivatives, flavonoids and phenols. PMID- 29117736 TI - A new bischromanone from the stems of Semecarpus caudata. AB - From an CHCl3-soluble fraction of the stems of Semecarpus caudata, one new bischromanone named semecarpanone (1), together with 5 known flavonoids (2-6) were isolated. Their structures were elucidated based on interpretation of spectroscopic data. The stereo-configuration of 1 was identified based on the calculated and experimental coupling constants. Compounds 4-6 showed potent tyrosinase inhibitory activity with the IC50 values ranging from 15.0 to 76.3 MUM. PMID- 29117737 TI - Iodine Status of Taiwanese Population in 2013: 10 Years After Changing From Mandatory to Voluntary Salt Iodization. AB - BACKGROUND: In 2003, Taiwan's iodine policy changed from mandatory to voluntary. The Nutrition and Health Survey in Taiwan (NAHSIT) 2001-2002 for schoolchildren showed adequate iodine nutrition, while NAHSIT 2005-2008 for adults showed the iodine status was at borderline adequacy. OBJECTIVE: To investigate the iodine status of the Taiwanese population from schoolchildren to adulthood 10 years after the change of the salt iodization policy. METHOD: Urinary iodine was measured in samples from subjects in NAHSIT 2013. RESULTS: The median urinary iodine concentration (UIC) of the Taiwanese population aged 6 years and above in 2013 was 96 MUg/L, indicating mild iodine deficiency. The median UIC of 6- to 12 year-old schoolchildren was 124 MUg/L (interquartile range [IQR]: 92-213 MUg/L), and 115 MUg/L (IQR: 80-166 MUg/L), 125 MUg/L (IQR: 74-161 MUg/L), 73 MUg/L (IQR: 52-131 MUg/L), and 78 MUg/L (IQR: 52-132 MUg/L) in populations aged 13 to 18 years, 19 to 44 years, 45 to 64 years, and >=65 years, respectively. Declining iodine nutrition in age groups >=45 years old was noted that the median UIC of populations aged 45 to 64 years and >=65 years was 99 and 88 MUg/L, respectively, in NAHSIT 2005-2008. The median UIC of schoolchildren was not lower than that during the mandatory salt fortification period, but the distribution of urinary iodine levels signified a dietary pattern change. CONCLUSION: Wide-ranging variation in iodine nutrition levels was observed in different age groups. Universal salt iodization, as suggested by the World Health Organization, should be the best strategy to achieve adequate iodine nutrition. PMID- 29117738 TI - Adding high-frequency transcutaneous electrical nerve stimulation to the first phase of post anterior cruciate ligament reconstruction rehabilitation does not improve pain and function in young male athletes more than exercise alone: a randomized single-blind clinical trial. AB - PURPOSE: Knee ligamentous trauma and the following pain is one of the most prevalent athletic injuries. Transcutaneous electrical nerve stimulation is one of the conservative approaches in controlling pain which is low cost, noninvasive, and safe with low complications. Our purpose was to study whether transcutaneous electrical nerve stimulation (TENS) could help athletes perform better during the first phase of rehabilitation (0-4 weeks) after anterior cruciate ligament (ACL) reconstruction surgery and until the follow-up. METHODS: This randomized single blind (exercise instructor and assessor) clinical trial was performed on 70 male athletes, undergone ACL surgery. After the surgery, patients were randomly divided into two groups: the first group received semi supervised exercise plus high-frequency TENSTENS for 35 min a day and the second group only performed exercises. Treatment duration continued for 20 sessions, 4 weeks. The visual analog scale (VAS) score (100 mm), International Knee Documentation Committee (IKDC) questionnaire and knee flexion Range of motion (ROM) were evaluated for all patients after the surgery (before commencing the rehabilitation program), after 4 weeks and 14 weeks from the surgery. RESULTS: Mixed ANOVA was used to explore the interaction effects of time and group on outcome measures and post hoc additional tests were performed on the data. The VAS, IKDC questionnaire score and knee flexion ROM increased in both groups over time, but the amount of improvement did not differ between the two groups, implying no additional improvement in the group receiving TENS along with exercises. CONCLUSION: The findings of the present trial shows that adding TENS to a specific protocol of semi-supervised exercise in the first phase of rehabilitation after ACL reconstruction is not efficient on improving knee function and pain more than exercise alone. Implications for Rehabilitation Injury to the anterior cruciate ligament of the knee is a common injury specifically in athletes. Incorporating effective pain relieving strategies during the post anterior cruciate ligament reconstruction surgery rehabilitation could lead to improvement in regaining the range of motion and function of the knee which is of crucial importance after the surgery. Applying transcutaneous electrical nerve stimulation alongside a specific protocol of semi-supervised exercise in the first phase of rehabilitation after anterior cruciate ligament reconstruction did not have any additional effect to exercise alone. PMID- 29117739 TI - Cardiac autonomic denervation and expression of neurotrophins (NGF and BDNF) and their receptors during experimental Chagas disease. AB - Although cardiac dysautonomia is a distinctive feature of Chagas disease, its clinical and functional significance is still being speculated. Neurotrophic factors are potentially involved; however, studies of their effect in this infection are rare. Ultrastructural abnormalities in autonomic varicosities, levels of both nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF), as well as the expression of their receptors, were analysed in the heart of a rat model of Trypanosoma infection. Predominantly, at the early stage of the infection, cardiac autonomic varicosities displayed several signs of degeneration parallel to the elevation of cardiac levels of NGF, as well as expression of the receptors TrkA and p75NTR. For BDNF and TrkB, the changes were less conspicuous. Data obtained here can contribute to further clarify the factors related to the autonomic nervous system's adaptive changes that could determine the evolution of different clinical forms of Chagas disease; mainly, the cardiac form. PMID- 29117740 TI - Regional Variations of Medicare Physician Payments for Hand Surgery Procedures in the United States. AB - BACKGROUND: Medicare reimbursement is known to exhibit geographic variation for inpatient orthopedic procedures. This study determined whether US geographic variations also exist for commonly performed hand surgeries. METHODS: Using the Medicare Provider Utilization and Payment Data (2012-2013) from Centers for Medicare & Medicaid Services, we analyzed regional physician charges/payments for common outpatient hand surgeries. RESULTS: The most commonly performed procedures in the United States were open carpal tunnel release (n = 21 944), trigger finger release (n = 15 345), endoscopic carpal tunnel release (n = 7106), and basal joint arthroplasty/ligament reconstruction and tendon interposition (n = 2408). A range of average Medicare physician reimbursements existed based on geographic region for basal joint arthroplasty ($669-$571), endoscopic carpal tunnel release ($400-$317), open carpal tunnel release ($325-$261), and trigger finger release ($215-$167). The latter three exhibited statistically significant variation across geographic regions with regard to both charges and physician reimbursement. However, the overall percentage physician reimbursement (70%-79%) to charges was similar across all geographic regions. CONCLUSIONS: In conclusion, further research is warranted to determine why regional or geographic variations in physician payments exist in the United States for commonly performed hand surgeries. PMID- 29117741 TI - beta-Thromboglobulin may not reflect platelet activation during haemodialysis with the HeprAN membrane. AB - BACKGROUND: When blood passes through the extracorporeal circuit during haemodialysis (HD) undesirable effects including platelet degranulation and coagulation activation take place. beta-thromboglobulin (beta-TG) is a sensitive marker of platelet activation. The aim of this study was to investigate platelet degranulation and coagulation activation during HD with the heparin-coated dialysis membrane HeprAN. METHODS: Four HD sessions were evaluated in each of 12 chronic HD patients. None of the patients used oral warfarin, other anticoagulants or antiplatelet drugs. In the first session the HeprAN membrane or a conventional polyflux membrane was used in a randomized manner and thereafter alternately in a cross-over design, and 50% of the conventional dalteparin dose was given at start of HD. Prothrombin fragment 1 + 2 (PF1 + 2), beta-TG and anti factor Xa activity were measured repeatedly. RESULTS: No dialysis sessions were terminated early due to clotting of the extracorporeal system. Activation of intravascular coagulation as assessed by change in PF1 + 2 during 4 hours of HD was the same with the two membranes. beta-TG concentration decreased significantly during 4 hours of HD with the HeprAN membrane but remained stable with the polyflux membrane. CONCLUSION: There were no differences in clotting scores or coagulation activation with the two membranes. The decrease in beta-TG during HD with the HeprAN membrane suggests beta-TG to be an inferior marker of platelet degranulation when using a heparin-coated dialysis membrane. A possible mechanism for the decline in beta-TG concentration may be adherence of this heparin-binding protein to the heparin-coated dialysis membrane. PMID- 29117742 TI - Dereplication and targeted isolation of bioactive sulphur compound from bacteria isolated from a hydrothermal field. AB - Marine micro-organisms in the deep-sea hydrothermal vent systems are considered as potential sources of bioactive natural products. Sixteen bacterial strains were isolated from a deep-sea hydrothermal field and screened for bioactive metabolism studies. After the strains were subjected to bioactive testing at different culture media, chemical dereplication by HPLC coupled to high resolution mass spectrometer was performed to analyse or determine the main secondary metabolisms in those strains. Strain 06204 was large-scale fermented with relative optimal media, for isolating the desired sulphur compound. Butyrolactone I 3-sulphate was isolated and structurally identified from the extract, guided by dereplication and showed moderate antivirus activities against H3N2 and EV71 viruses. Our study suggests that deep-sea hydrothermal bacteria are good sources of sulphur natural products. Meanwhile, the described approach, mainly bioactive screening, dereplication and targeted isolation, is effective and efficient to discover interesting bioactive compounds in hydrothermal bacteria. PMID- 29117743 TI - Neurological Manifestations of Primary Immunodeficiency Diseases. PMID- 29117745 TI - Antihyperglycemic, antihyperlipidemic and antioxidative evaluation of compounds from Senna sophera (L.) Roxb in streptozotocin-induced diabetic rats. AB - Senna sophera (L.) Roxb (Common name: Kasunda, Baner) (Leguminosae) is used as traditional medicine in Africa and Asia. The compounds were isolated from methanolic extract of leaves of Senna sophera (MFCS). Compound A was identified as Hexahydroxy diphenic acid and Compound B as Kaempferol. MFCS administration to diabetic rats exhibited significant reduction in the blood sugar level and showed gain in body weight. After the treatment of 100 mg/kg of MFCS, the blood sugar level was reduced to 52.33 +/- 2.83 mg/dl in comparison to the blood sugar level of vehicle control 76.66 +/- 3.17 mg/dl, whereas treatment with 50 mg/kg of MFCS reduced the blood sugar level slightly (72.33 +/- 2.42 mg/dl). The daily continuous administration of MFCS for a period of 21 days normalised the serum lipid levels confirming the effect of MFCS on diabetic hyperlipidemia. Treatment with MFCS also reversed the activities of antioxidants, which could be a result of decreased lipid peroxidation. PMID- 29117744 TI - Twelve tips to promote successful development of a learner performance dashboard within a medical education program. AB - Easily accessible and interpretable performance data constitute critical feedback for learners that facilitate informed self-assessment and learning planning. To provide this feedback, there has been a proliferation of educational dashboards in recent years. An educational (learner) dashboard systematically delivers timely and continuous feedback on performance and can provide easily visualized and interpreted performance data. In this paper, we provide practical tips for developing a functional, user-friendly individual learner performance dashboard and literature review of dashboard development, assessment theory, and users' perspectives. Considering key design principles and maximizing current technological advances in data visualization techniques can increase dashboard utility and enhance the user experience. By bridging current technology with assessment strategies that support learning, educators can continue to improve the field of learning analytics and design of information management tools such as dashboards in support of improved learning outcomes. PMID- 29117746 TI - In vitro evaluation of the amoebicidal activity of rosemary (Rosmarinus officinalis L.) and cloves (Syzygium aromaticum L. Merr. & Perry) essential oils against Acanthamoeba polyphaga trophozoites. AB - Several species of the genus Acanthamoeba cause human diseases. Treatment of infections involves various problems, emphasising the need to develop alternative antiprotozoal agents. We studied the anti-amoebic activity of Essential Oils (EOs), derived from rosemary (Rosmarinus officinalis L.) and cloves (Syzygium aromaticum L. Merr. & Perry), against Acanthamoeba polyphaga strain. The amoebicidal activity of cloves and rosemary EOs was preliminary demonstrated by the morphology change (modifications in the cell shape, the presence of precipitates in the cytoplasm, autophagic vesicles, membrane blends) of the treated trophozoites. The cell-counts, carried out after staining trophozoites with a Trypan blue solution, revealed that both EOs were active in a dose dependent manner and in relation to the exposure time. This activity was evident after few hours, with encouraging results obtained in particular with cloves EO, able to act at the lower concentrations and after 1 h, probably for its high eugenol content (65.30%). PMID- 29117747 TI - Substance use among Danish psychiatric patients: a cross-sectional study. AB - BACKGROUND: Patients with psychiatric disorders have a greater risk of mortality than the general population. Use or abuse of substances, including alcohol, play a crucial part in this context. Moreover, it is well known that drug use can worsen psychopathology and reduce treatment compliance. However, the magnitude of these problems among Danish psychiatric patients has not been studied previously. AIMS: The aim of this study is to investigate substance use among psychiatric patients in the Capital Region of Denmark. METHODS: Outpatients from five psychiatric units were asked to complete a questionnaire regarding their use of alcohol and other drugs of abuse. The questionnaire was based on the Alcohol Use Disorder Identification Test (AUDIT), supplemented by questions regarding use of tobacco and illicit drugs. The results were compared with those uses in the general population. RESULTS: In total, 412 psychiatric patients participated in the study, and 33% had an AUDIT-score >=8, indicating problematic alcohol use according to the AUDIT guidelines. The mean weekly alcohol intake was 9.7 +/- 28.3 standard drinks, and 47% were current smokers with a mean daily use of 19.9 +/- 13.8 cigarette equivalents. Compared to the general population, the psychiatric patients had higher odds of being current smokers and having used illicit drugs within the past month. Women with psychiatric disorders were twice as likely to binge drink on a monthly basis. No significant difference was found in the patients' AUDIT scores compared to the general population. CONCLUSIONS: Our findings demonstrate a substantial and problematic use of tobacco and illicit drugs among Danish psychiatric patients, greater than in the general population. PMID- 29117748 TI - Ward round simulation in final year medical students: Does it promote students learning? AB - INTRODUCTION: Ward round skills are essential for doctors in hospital settings. Literature shows medical students' deficiencies in these skills. Simulation has been used to train these skills. However, exposing learners to simulation at an early stage may be associated with a high cognitive load and limited learning. This study aims to determine how students experience this load and its interplay with performance and which factors promote and impair learning. METHODS: Fifty six final year medical students participated in a simulated ward round training exercise. Both students' performance and cognitive load were measured to determine if there was any correlation and interviews were carried out to understand which factors support and impair learning. RESULTS: Performance scores revealed deficiencies in ward round skills. Students experienced a cognitive load that weakly correlated with performance. Qualitative findings provided important insights into simulated ward-based learning. It is clear that well-designed clinical scenarios, prioritization tasks, teamwork and feedback support students' learning process whereas distractions impair learning. CONCLUSIONS: WRS proved to be a good teaching method to improve clinical skills at this stage as the cognitive load is not too high to impair learning. Hence, including tasks in the simulation design can enhance the learning process. PMID- 29117749 TI - Comments on "The pillars of well-constructed simulated patient programs: A qualitative study with experienced educators". PMID- 29117750 TI - Comparison of faculty assessment and students' self-assessment of performance during clinical case discussions in a pharmacotherapy capstone course. AB - OBJECTIVES: The primary objective of this study was to compare faculty assessment and third year students' self-assessment of performance in clinical case discussions. The secondary objective was to evaluate if student characteristics influence self-assessments. METHODS: This retrospective analysis compared faculty and student self-assessment scores for two clinical case discussions using Spearman's correlation and Wilcoxon's signed ranks test. Chi-squared test was used to compare frequency of faculty and student self-assessments indicating the highest possible rating for the pooled score and for each individual component. The pooled score included three individual components: level of engagement, quality of contribution, and professionalism. RESULTS: Pooled faculty and student self-assessments correlated for both the first (r = 0.41, p < 0.001) and second (r = 0.35; p < 0.001) clinical case discussions. The frequency that faculty and student self-assessment ratings were the highest possible pooled score was similar for both the first (51.3% vs. 44.7%, respectively, p = 0.25) and second (58.6% vs. 47.4%, p = 0.05) clinical case discussions. Student characteristics (age, gender, and grade point average at graduation) did not influence self assessments. CONCLUSIONS: Students' self-assessment correlated with faculty assessment of performance during clinical case discussions. Increased use of self assessments for professional development in pharmacy and other healthcare professional curricula should be considered. PMID- 29117751 TI - Phenotypic and mtDNA variation in Philippine Kappaphycus cottonii (Gigartinales, Rhodophyta). AB - Members of the carrageenan-producing seaweeds of the genus Kappapphycus have a complicated taxonomic history particularly with regard to species identification. Many taxonomic challenges in this group have been currently addressed with the use of mtDNA sequences. The phylogenetic status and genetic diversity of one of the lesser known species, Kappaphycus cottonii, have repeatedly come into question. This study explored the genetic variation in Philippine K. cottonii using the mtDNA COI-5P gene and cox2-3 spacer sequences. The six phenotypic forms in K. cottonii did not correspond to the observed genetic variability; hinting at the greater involvement of environmental factors in determining changes to the morphology of this alga. Our results revealed that the Philippine K. cottonii has the richest number of haplotypes that have been detected, so far, for any Kappaphycus species. Our inferred phylogenetic trees suggested two lineages: a lineage, which exclusively includes K. cottonii and another lineage comprising the four known Kappaphycus species: K. alvarezii, K. inermis, K. malesianus, and K. striatus. The dichotomy supports the apparent synamorphy for each of these lineages (the strictly terete thalli, lack of protuberances, and the presence of a hyphal central core in the latter group, while the opposite of these morphologies in K. cottonii). These findings shed new light on understanding the evolutionary history of the genus. Assessing the breadth of the phenotypic and genetic variation in K. cottonii has implications for the conservation and management of the overall Kappaphycus genetic resources, especially in the Philippines. PMID- 29117752 TI - The Criminogenic and Noncriminogenic Treatment Needs of Intimate Partner Violence Offenders. AB - The criminogenic needs of general offenders have been empirically studied, but the criminogenic treatment needs of intimate partner violence (IPV) offenders, or how they compare with other violent or nonviolent offenders, have not been as thoroughly explored. Therefore, we examined and compared the criminogenic and noncriminogenic needs of 99 IPV offenders, 233 non-IPV violent offenders, and 103 nonviolent offenders, all of whom were men who had undergone institutional forensic assessment. Results indicated that IPV offenders had more treatment needs than the other two offender groups, including the Central Eight criminogenic needs. These findings support a focus on criminogenic treatment needs in batterer intervention programs for men, consistent with the principles of effective intervention for offenders. PMID- 29117753 TI - A Comparative Analysis of Domestic Violence Shelter Staff Perceptions Regarding Barriers to Services in Bosnia and Herzegovina and the United States. AB - Service provision for domestic violence (DV) survivors has been a long-standing staple of shelters in the United States. Although shelter services provide numerous benefits for survivors, barriers tied to acquisition remain a pressing concern when combatting DV. Nevertheless, there has been minimal research exploring barriers to service acquisition on a cross-national level. As such, the current research cross-nationally examines perceptions of shelter staff regarding acquisition barriers as well as the effectiveness of local agencies to meet survivor needs and differences in populations served in the United States (specifically Texas) as well as in Bosnia and Herzegovina. Data collection stemmed from self-report surveys originally constructed in English and translated into Bosnian/Serbian/Croatian. Results underscored differences between populations served, perceptions of local agencies assisting survivors of DV, and barriers tied to cultural and financial concerns. Implications, limitations, and future directions are also discussed. PMID- 29117754 TI - Generation and characterization of new alleles of quiver (qvr) that encodes an extracellular modulator of the Shaker potassium channel. AB - Our earlier genetic screen uncovered a paraquat-sensitive leg-shaking mutant quiver1 (qvr1), whose gene product interacts with the Shaker (Sh) K+ channel. We also mapped the qvr locus to EY04063 and noticed altered day-night activity patterns in these mutants. Such circadian behavioral defects were independently reported by another group, who employed the qvr1 allele we supplied them, and attributed the extreme restless phenotype of EY04063 to the qvr gene. However, their report adopted a new noncanonical gene name sleepless (sss) for qvr. In addition to qvr1 and qvrEY, our continuous effort since the early 2000s generated a number of novel recessive qvr alleles, including ethyl methanesulfonate (EMS) induced mutations qvr2 and qvr3, and P-element excision lines qvrip6 (imprecise jumpout), qvrrv7, and qvrrv9 (revertants) derived from qvrEY. Distinct from the original intron-located qvr1 allele that generates abnormal-sized mRNAs, qvr2, and qvr3 had their lesion sites in exons 6 and 7, respectively, producing nearly normal-sized mRNA products. A set of RNA-editing sites are nearby the lesion sites of qvr3 and qvrEY on exon 7. Except for the revertants, all qvr alleles display a clear ether-induced leg-shaking phenotype just like Sh, and weakened climbing abilities to varying degrees. Unlike Sh, all shaking qvr alleles (except for qvrf01257) displayed a unique activity-dependent enhancement in excitatory junction potentials (EJPs) at larval neuromuscular junctions (NMJs) at very low stimulus frequencies, with qvrEY displaying the largest EJP and more significant NMJ overgrowth than other alleles. Our detailed characterization of a collection of qvr alleles helps to establish links between novel molecular lesions and different behavioral and physiological consequences, revealing how modifications of the qvr gene lead to a wide spectrum of phenotypes, including neuromuscular hyperexcitability, defective motor ability and activity-rest cycles. PMID- 29117756 TI - Long-term postpartum effect of severe maternal morbidity on sexual function. AB - There was limited knowledge on the sexual function in women who have survived severe obstetric complications. The aim of this study was to compare the level of sexual functioning among women with and without severe morbidity at six months postpartum and to identify the factors associated with sexual function scores of women. A prospective double-cohort study design was applied at two tertiary hospitals over a six-month period. Postpartum women with and without severe maternal morbidity were selected as the exposed and the non-exposed group, respectively. The study included 145 exposed and 187 non-exposed women. Those with severe maternal morbidity were significantly ( P < 0.001) older (mean (SD): 31.6 years (6.26) vs. 29.2 years (5.65)) and had longer hospital stays (mean (SD): 5.9 days (3.79) vs. 3.6 days (2.23)). They were also more likely to have delivered preterm (75.9 vs. 93.0) and to have had a caesarean section (80.7 vs. 67.9) than those without severe maternal morbidity. After adjusting for age and mental health, there was no significant difference in Female Sexual Function Index scores ( P = 0.895) between the two groups. Both groups showed the highest sexual dysfunction in pain and the lowest dysfunction in orgasm. Linear regression analyses showed no association between Female Sexual Function Index scores and sociodemographic characteristics, reproductive history, or quality of life. Sexual function in women with severe maternal morbidity did not differ from that in women without severe maternal morbidity. In-depth qualitative studies of women who have experienced potentially life-threatening conditions may improve the understanding of their sexual function. PMID- 29117755 TI - Contribution of oxidative stress in acute intestinal mucositis induced by 5 fluorouracil (5-FU) and its pro-drug capecitabine in rats. AB - This study was designed to examine the contribution of oxidative stress in gastrointestinal disorders after an intraperitoneal administration of 5 fluorouracil (5-FU; 100 mg/kg of body weight (b.w.)) and capecitabine oral administration (500 mg/kg b.w.). The animals were divided into three groups: Group A (NaCl,10 ml/kg of b.w.) considered as control group, group B was intoxicated by 5-FU and group C was the group of animals treated with capecitabine (CAP). To evaluate the secretory and enteropooling effects, we used magnesium sulfate (MgSO4), 1 ml/100 g of b.w. as a hypersecretion agent . The mucosal gastro-intestinal specimens were scraped and examined for biological markers of oxidative stress and intracellular mediators. These anticancer drugs caused many intestinal damages manifested by an elevation of fluid accumulation and imbalance in electrolytes secretion. The intestinal tissues from treated rats not only showed a significant increase in malondialdehyde (MDA), protein carbonylation and hydrogen peroxide (H2O2) production. but also showed a significant depletion of enzymatic and non-enzymatic antioxidant, such as, glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and sulfhydryl groups (-SH). These effects were related with histopathological damage and a perturbation of intracellular mediators. As expected, these disturbances were observed in the group of rats poisoned by the MgSO4. Data suggest the contribution of oxidative stress in chemotherapy-induced many disorders in intestinal tract. PMID- 29117757 TI - The effect of prenatal vaginal progesterone on cervical length in nonselected twin pregnancies. AB - PURPOSE: The aim of this study was to investigate the influence of vaginal progesterone on cervical length (CL) in asymptomatic nonselected twin gestations. METHODS: This was a secondary analysis of a randomized, double-blind, placebo controlled trial of twin pregnancies exposed to vaginal progesterone or placebo. The CL was examined at six different time periods: 18-21+6 weeks (T1), 21-23+6 weeks (T2), 24-26+6 weeks (T3), 27-29+6 weeks (T4), 30-32+6 weeks (T5) and 33 34+6 weeks (T6). The rate of cervical shortening per week and the percent cervical shortening were compared between the groups, with analyses of the entire cohort and of those who delivered spontaneously according to gestational age at birth. RESULTS: The final analysis included 184 women in the progesterone group and 188 women in the placebo group. The baseline characteristics were similar in both groups. No differences in cervical shortening in terms of absolute value or percent shortening were observed between the groups at each time period or throughout gestation. Furthermore, no difference was found in cervical shortening for those who delivered spontaneously. CONCLUSION: Cervical shortening in asymptomatic nonselected twin pregnancies occurred at a similar rate, regardless of vaginal progesterone treatment. PMID- 29117758 TI - Primary tumor volume measurements in Ewing sarcoma: MRI inter- and intraobserver variability and comparison with FDG-PET. AB - BACKGROUND: Primary tumor volume is as an important and independent prognostic factor in Ewing sarcoma. However, the observer variability of magnetic resonance imaging (MRI)-based primary tumor volume measurements in newly diagnosed Ewing sarcoma has never been investigated. Furthermore, it is unclear how MRI-based volume measurements compare to 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)-based volume measurements. This study aimed to determine the observer variability of simplified MRI-based primary tumor volume measurements in newly diagnosed treatment-naive Ewing sarcoma and to compare them to the actual primary tumor volume at MRI and the FDG-PET-based metabolically active tumor volume (MATV). MATERIAL AND METHODS: Twenty-nine newly diagnosed Ewing sarcoma patients with pretreatment MRI (of whom 11 also underwent FDG-PET) were included. Both exact and dichotomized (according to the proposed threshold of 200 mL) primary tumor volume measurements were analyzed. RESULTS: Mean inter- and intraobserver differences of MRI-based simplified tumor volume +/- limits of agreement varied between 15-42 +/- 155-204 mL and between 9-16 +/- 64-250 mL, respectively. Inter- and intraobserver agreements of dichotomized MRI-based simplified tumor volume measurements was very good (kappa = 0.827-1.000). Mean difference between simplified and actual tumor volumes at MRI +/- limits of agreement was 60 +/- 381 mL. Agreement between dichotomized simplified and actual tumor volumes at MRI was very good (kappa = 0.839). Mean difference between MRI based simplified tumor volume and MATV +/- limits of agreement was 181 +/- 549 mL and almost significantly different (p = .0581). Agreement between dichotomized MRI-based simplified tumor volume and MATV was moderate (kappa = 0.560). CONCLUSIONS: Exact MRI-based simplified primary tumor volume measurements in Ewing sarcoma suffer from considerable observer variability, but observer agreement of dichotomized measurements (<=200 mL vs. >200 mL) is very good and generally matches MRI-based actual volume measurements. MRI-based primary tumor volume measurements poorly-moderately agree with and tend to be higher than the MATV. PMID- 29117759 TI - Sustaining Engagement in Longitudinal Research With Vulnerable Families: A Mixed Methods Study of Attrition. AB - The aim of this mixed-methods study was to investigate attrition at the age 10 year follow-up in a study of vulnerable children and their families living with low income following a two-generation preschool program in Calgary, Alberta, Canada. Quantitative factors associated with attrition included: (a) food bank use; (b) unstable housing; (c) child welfare involvement; (d) unpartnered status; and (e) caregiver noncompletion of high school. Qualitative themes related to attrition included: (a) income and employment; (b) health; (c) unstable housing; (d) change of guardianship; (e) domestic violence; (f) work and time management challenges; and (g) negative caregiver-child relationships. Triangulation of quantitative and qualitative results occurred using Maslow's Hierarchy of Needs; families with unmet physiological, safety, belongingness and love needs, and esteem needs were more likely to attrite. Attrition in longitudinal studies with vulnerable families is complex, affected by frequently changing life circumstances, and struggles to access necessities of life. Strategies for retaining vulnerable families in longitudinal research are offered. PMID- 29117760 TI - The benefits of trauma simulation for medical students - experiences from the University Of Bristol. PMID- 29117761 TI - Full-driving soft robotic colonoscope in compliant colon tissue. AB - Robotic colonoscopy is an efficient examination method for finding malignant tumour in its early stage. This research developed a novel robotic endoscope with 13 mm diameter, 105 mm length and 22.3 g weight. A contact biomechanical model is proposed to increase the locomotion safety and efficiency in the soft tissue. The model shows that the friction difference between the robot and the tissue is a key factor to locomotion capability. A soft, full bellow with excellent compatibility was designed to package the robot body. The bellow increased the static friction and decreased the kinetic friction given the change in the contact state. The bellow is divided into three segments. Each segment is composed of a linear locomotor with micromotor, turbine-worm and wire wrapping sliding mechanism. The robot is tested in in vivo pig colon, which revealed an excellent locomotion capability and safety in soft tissues. PMID- 29117762 TI - A Time Limit for Initiating Anti-Inflammatory Treatment for Improved Olfactory Function after Head Injury. AB - We previously reported that treatment with an anti-inflammatory drug, specifically a steroid, is effective in improving recovery during the acute phase of head injury. Clinically, however, patients with head injury usually become aware of their olfactory loss several weeks or months after the injury, which may be a critical factor in poor recovery from olfactory dysfunction. This raises an important question: When should steroid administration begin in order to achieve optimum improvement of olfactory dysfunction? The present study was designed to reveal the time limit for starting anti-inflammatory treatment for better improvement of post-traumatic olfactory dysfunction. Olfactory nerve transection (NTx) was performed in olfactory marker protein (OMP)-tau-lacZ mice and subcutaneous injections of dexamethasone sodium phosphate for 5 consecutive days was started at 7, 14, 28, and 42 days after the NTx (7-, 14-, 28-, and 42-day time-points). Histological assessment of olfactory nerve recovery in the olfactory bulb was made at 5, 14, and 42 days after the start of drug treatment. Olfactory function assessments using both an olfactory avoidance behavioral test and evoked potential testing also were performed. Animals treated at 7 days post injury had less injury-associated tissue with fewer astrocytes and macrophages and better histological and functional nerve recovery, compared with control mice. However, those treated at 14, 28, or 42 days post-injury did not show significant histological or functional differences between saline control and treatment groups. These findings suggest that an anti-inflammatory treatment using steroids for traumatic olfactory dysfunction may be effective if started at least by 7 days, but may be ineffective at 14 days or later after head injury. PMID- 29117763 TI - Pilose antler peptide attenuates high-fat-diet-induced liver injury. AB - This study was performed to investigate the action of pilose antler peptide (PAP) on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) in rats. Animals were randomly divided into five groups: control group, model group receiving high-fat diet (HFD), atorvastatin group receiving high-fat diet (HFD) + atorvastatin (20 mg/kg), PAP-L group receiving HFD + PAP (50 mg/kg) and PAP-H group receiving HFD + DB (100 mg/kg). PAP administration significantly reduced the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), with improvement in liver histopathological examination. To further investigate the molecular mechanism of the effect of PAP on NAFLD, expression levels of AMP activated protein kinase (AMPK)/NF-kappaB pathway in the liver were determined by western blot analysis, respectively. These results suggested that PAP administration was beneficial to treatments of NAFLD in rats fed HFD by modulating the expression levels of AMPK/NF-kappaB pathway. PMID- 29117764 TI - Counseling and in-advance provision of levonorgestrel emergency contraceptive pills decrease the rate of unplanned pregnancy during breastfeeding: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of counseling and in-advance provision of levonorgestrel emergency contraceptive pills (LNG-ECPs) during postpartum counseling on the incidence of occurrence of unplanned pregnancy during breastfeeding. MATERIALS AND METHODS: The current study is an open-label, parallel, randomized controlled trial carried out in a university hospital in Egypt. All women who delivered and planning to birth-space and breastfeed for at least 1 year were approached for participation during a postpartum hospital stay. Eligible participants were randomly allocated to receive adequate lactational amenorrhea method (LAM) counseling Group 1 (LAM-only) or the above LAM counseling in addition to counseling and in advance provision of one packet of 0.75-mg LNG ECPs Group 2 (LAM + EC). The two study groups were followed 6 months and the primary outcome was the unplanned pregnancy rate. RESULTS: The study included 2708 women randomized into two groups; LAM-only and LAM + EC groups. Demographic characteristics were homogenous between the groups at the time of recruitment. Unplanned pregnancy was significantly higher in LAM-only group 70 (5.3%) as compared with 5 (0.4%) in LAM-EC group (p = .0001). Also, 619 women (46.6%) used LNG-ECPs with minor side effects like nausea in 175 (28.3%) women, headache in 94 (15.2%) women, vomiting in 24 (3.9%) women. CONCLUSION: In-advance counseling and provision of LNG-ECPs for those opt to use LAM during postpartum family planning counseling can decrease the rate of unplanned pregnancy during breastfeeding and increase the initiation of long-term use of contraception. PMID- 29117765 TI - Imaging-Guided Preoperative Localization of Intra-Abdominal Local Recurrences of Colorectal Cancer Using the Harpoon Technique. AB - BACKGROUND AND AIMS: Intra-abdominal local recurrences of colorectal cancer can be difficult to localize and excise because they are not easily visible or palpable. MATERIALS AND METHODS: We report on our experience using the computed tomography-guided harpoon technique to locate and resect these nodules in seven patients. RESULTS: No complications were recorded during the procedures. Six nodes were malignant and all margins were tumor free. CONCLUSIONS: Harpoon placement for intra-abdominal local recurrences of colorectal cancer is a feasible and useful technique that provides direct localization and complete excision of lesions. PMID- 29117766 TI - Mothers Coping With Bereavement in the 2008 China Earthquake: A Dual Process Model Analysis. AB - The purpose of this study is to explore the grief experiences of mothers after they lost their children in the 2008 China earthquake. Informed by the Dual Process Model, this study conducted in-depth interviews to explore how six bereaved mothers coped with such grief over a 2-year period. Right after the earthquake, these mothers suffered from intensive grief. They primarily coped with loss-oriented stressors. As time passed, these mothers began to focus on restoration-oriented stressors to face changes in life. This coping trajectory was a dynamic and integral process, which bereaved mothers oscillated between loss- and restoration-oriented stressors. This study offers insight in extending the existing empirical evidence of the Dual Process Model. PMID- 29117767 TI - Unspoken barriers to change in the medical learning environment. PMID- 29117768 TI - Wavelet-based feature extraction for classification of epileptic seizure EEG signal. AB - Electroencephalogram (EEG) signal-processing techniques are the prominent role in the detection and prediction of epileptic seizures. The detection of epileptic activity is cumbersome and needs a detailed analysis of the EEG data. Therefore, an efficient method for classifying EEG data is required. In this work, a constructive pattern recognition strategy for analysing EEG data as normal and epileptic seizure has been proposed. With this strategy, the signals were decomposed into frequency sub-bands using discrete wavelet transform (DWT). principal component analysis (PCA) and linear discriminant analysis (LDA) are applied to reduce the dimensionality of EEG data. These reduced features were used as input to Naive Bayes and K-Nearest Neighbour Classifier to classify normal or epileptic seizure signal. The performance of classifier was evaluated in terms of accuracy, sensitivity and specificity. The experimental results show that PCA with Naive Bayes classifier provides 98.6% accuracy and LDA with Naive Bayes classifier attains improved result of 99.8% accuracy. Also, the result shows that PCA, LDA with K-NN achieves 98.5% and 100% accuracy. This evaluation is used to propose a reliable, practical epilepsy detection method to enhance the patient's care and quality of life. PMID- 29117769 TI - Psychophysiological Reactivity Profiles of Partner-Violent Men With Borderline or Psychopathic Personality Features: The Role of Empathy. AB - Borderline and psychopathic features have been linked to unique psychophysiological reactivity profiles. Studies have suggested that levels of psychophysiological reactivity for partner-violent men cannot be attributed to personality features alone. This study tested cognitive and affective empathy as moderators of relations between borderline personality, Factor 1 psychopathy, and psychophysiological reactivity using a community sample of 135 male participants and their female partners. Cognitive empathy moderated the relation between borderline personality features and heart rate reactivity. Affective empathy moderated the relation between Factor 1 psychopathy features and heart rate reactivity. However, directions of these interactions were contrary to original predictions. Understanding unique empathy deficits may be beneficial for identifying ways to minimize relationship conflict, manage arousal, and decrease violence. PMID- 29117770 TI - The role of the medical student: To learn or to provide a service? PMID- 29117771 TI - The interaction of correctness of and certainty in MCQ responses. PMID- 29117772 TI - Initial neonatal resuscitation: skill retention after the implementation of the novel 24/7 HybridLab(r) learning system. AB - BACKGROUND: Ensuring long-term retention of the acquired practical skills is one of the major aims of a medical school. This depends on the application of training techniques and their combinations. In order to standardize the teaching process, to acquire and maintain a broad array of technical, professional, and interpersonal skills and competencies, and to improve the retention of practical skills, we developed a new training technique - the HybridLab(r) learning method. It consists of an e-learning platform, hands-on simulation, carefully elaborated learning algorithms (DRAKON), peer-to-peer teaching, and assessment and feedback by peers, and later - by a remote instructor. Summary of the work: The subjects of the study were fifth-year students of the Lithuanian University of Health Sciences Medical Academy who during 2014-2015 were studying the obstetrics and gynecology module in the neonatology cycle. We analyzed the retention of practical skills in the initial neonatal resuscitation among students who were training with the use of our developed HybridLab(r) technique at 6 and 12 months after the completion of the cycle. SUMMARY OF RESULTS: After 6 and 12 months, mean changes in the subjects' evaluation scores (percentage drop-off between the first and the second total score) dropped by, respectively, 31.8% (SD: 27.5) and 7.7% (SD: 25.6), and did not differ statistically significantly (p = .2). In the group of subjects who were not given a possibility to remember the skills and the course of initial neonatal resuscitation, the mean change between the first and the second total evaluation scores was 42.5% (SD: 26.7). In students who were given such possibility, the mean change between the first and the second total evaluation scores was significantly smaller -12.7% (SD: 13.8) (p < .001). Changes in the evaluation scores of individual skills (first steps, mouth-to-mouth ventilation, and chest compressions) between the first and the second evaluation also differed statistically significantly and were smaller in the group of students who were given a possibility to remember their skills (p < .001). DISCUSSION: The HybridLab(r) learning method is a novel technique, and thus more studies are required to evaluate the significance of the HybridLab(r) technique for long-time retention of practical skills. CONCLUSION: As a result of the application of the HybridLab(r) training technique, practical skill retention among medical students after 6 and 12 months dropped by only about 13%. A recall system significantly improved practical skill retention. PMID- 29117773 TI - Taxonomic characterization of Tanakia species (Acheilognathidae) using DNA barcoding analyses. AB - Tanakia is a bitterling genus with six species found in Far East Asia. Our aim was to construct the standard DNA barcode database available for the identification of six Tanakia species by comparing the range of intra- and inter specific genetic distances, identifying the phylogenetic placement of each Tanakia species and providing the unique barcode characteristics that are specific to each species, using cytochrome oxidase I (COI) and cytochrome b (cyt b). Both loci failed to create a perfect barcoding gap between the ranges of inter- and intra-specific genetic distances, though interspecific COI distances were sufficiently greater than intraspecific values with only a few exceptions. In our phylogenetic analyses, T. koreensis and T. signifer did not form a monophyletic cluster of haplotypes in both loci. COI provided clear nucleotide characteristics that distinguish each species, whereas relatively fewer informative sites were found within the range of cyt b. Overall, COI could be regarded as appropriate species identification solution in Tanakia. Our analyses yielded some taxonomic issues that need the further investigation, and are expected to be helpful in the examination for the conservation status of Tanakia species that are on the verge of being endangered. PMID- 29117774 TI - Multi-Image Pinhole Viewer Using a Biscuit. AB - A camera obscura-type viewer based on pinhole optics, with the apertures being the holes in a commercial snack biscuit (or cracker), produces interesting and easily obtainable projected images, as demonstrated during the 2017 solar eclipse. PMID- 29117775 TI - Stereoscopic Slant Contrast and the Perception of Inducer Slant at Brief Stimulus Presentations. AB - Slant contrast refers to a stereoscopic phenomenon in which the perceived slant of a test object is affected by the disparity of a surrounding inducer object. Slant contrast has been proposed to involve cue conflict, but it is unclear whether this idea is useful in explaining slant contrast at short stimulus presentations (<1 s). We measured both slant contrast and perceived inducer slant while varying the presentation duration (100-800 ms) of stereograms with several spatial configurations. In three psychophysical experiments, we found that (a) both slant contrast and perceived inducer slant increased as a function of stimulus duration, and (b) slant contrast was relatively stable across different test and inducer shapes at each short stimulus duration, whereas perceived inducer slant increased when cue conflict was reduced. These results suggest that at brief, not long stimulus presentations, the cue conflict between disparity and perspective plays a smaller role in slant contrast than other depth cues. PMID- 29117776 TI - The effect of nurses' ethical leadership and ethical climate perceptions on job satisfaction. AB - BACKGROUND: The development of ethical leadership approaches plays an important role in achieving better patient care. Although studies that analyze the impact of ethical leadership on ethical climate and job satisfaction have gained importance in recent years, there is no study on ethical leadership and its relation to ethical climate and job satisfaction in our country. OBJECTIVES: This descriptive and cross-sectional study aimed to determine the effect of nurses' ethical leadership and ethical climate perceptions on their job satisfaction. METHODS: The study sample is composed of 285 nurses who agreed to participate in this research and who work at the internal, surgical, and intensive care units of a university hospital and a training and research hospital in Izmir, Turkey. Data were collected using Ethical Leadership Scale, Hospital Ethical Climate Scale, and Minnesota Satisfaction Scale. While the independent sample t-test, analysis of variance, Mann-Whitney U test, and Kruskal-Wallis test were used to analyze the data, the correlation analysis was used to determine the relationship between the scales. Ethical considerations: The study proposal was approved by the ethics committee of the Faculty of Medicine, Dokuz Eylul University. FINDINGS: The nurses' mean scores were 59.05 +/- 14.78 for the ethical leadership, 92.62 +/- 17 for the ethical climate, and 62.15 +/- 13.46 for the job satisfaction. The correlation between the nurses' ethical leadership and ethical climate mean scores was moderately positive and statistically significant (r = +0.625, p = 0.000), was weak but statistically significant between their ethical leadership and job satisfaction mean scores (r = +0.461, p = 0.000), and was moderately positive and statistically significant between their ethical climate and job satisfaction mean scores (r = +0.603, p = 0.000). CONCLUSION: The nurses' ethical leadership, ethical climate, and job satisfaction levels are moderate, and there is a positive relationship between them. The nurses' perceptions of ethical leadership are influenced by their educational status, workplace, and length of service. PMID- 29117777 TI - "Testing, Testing": Multiple HIV-Positive Tests among Patients Initiating Antiretroviral Therapy in Ethiopia. AB - Repeat HIV testing after receiving a positive result has never been studied systematically and may give insight into reasons for delayed linkage to care. Among 831 adults in 6 secondary facilities in Oromia, Ethiopia, who completed an interviewer-administered structured questionnaire within 2 weeks of initiating antiretroviral therapy in 2012 to 2013, 110 (13.2%) reported having retested after an HIV-positive result. The odds of repeat (versus single) HIV-positive testing were higher among those who had doubted their HIV status (adjusted odds ratio [AOR]ref=nodoubt = 6.5; 95% confidence interval [CI]: 3.7-11.4) and those who initially tested at another facility, whether another secondary facility (AOR ref=studyfacility = 22.7; 95% CI: 11.0-46.9) or a lower-level facility (AORref=studyfacility = 19.1; 95% CI: 10.5-34.5). The odds of repeat (versus single) HIV-positive testing were lower among those who initially tested because of symptoms (AORref=not a reason = 0.40; 95% CI: 0.24-0.66). Median time between initial diagnosis and enrollment in care was 12.3 versus 1.0 month for repeat and single HIV-positive testers, respectively ( P < .001). Repeat HIV-positive testing-not a rare occurrence-appears to stem from doubt, seeking care at a facility other than where diagnosed, and testing for a reason other than having symptoms. Because repeat HIV-positive testing is associated with delay in linkage to care, providers should be aware of this potential when counseling those who test HIV positive. PMID- 29117778 TI - Serotonin: A mediator of the gut-brain axis in multiple sclerosis. AB - BACKGROUND: The significance of the gut microbiome for the pathogenesis of multiple sclerosis (MS) has been established, although the underlying signaling mechanisms of this interaction have not been sufficiently explored. OBJECTIVES: We address this point and use serotonin (5-hydroxytryptamine (5-HT))-a microbial modulated neurotransmitter (NT) as a showcase to demonstrate that NTs regulated by the gut microbiome are potent candidates for mediators of the gut-brain axis in demyelinating disorders. Methods, Results, and Conclusion: Our comprehensive overview of literature provides evidence that 5-HT levels in the gut are controlled by the microbiome, both via secretion and through regulation of metabolites. In addition, we demonstrate that the gut microbiome can influence the formation of the serotonergic system (SS) in the brain. We also show that SS alterations have been related to MS directly-altered expression of 5-HT transporters in central nervous system (CNS) and indirectly-beneficial effects of 5-HT modulating drugs on the course of the disease and higher prevalence of depression in patients with MS. Finally, we discuss briefly the role of other microbiome-modulated NTs such as gamma-aminobutyric acid and dopamine in MS to highlight a new direction for future research aiming to relate microbiome regulated NTs to demyelinating disorders. PMID- 29117779 TI - Refractory chronic lupus peritonitis resolved by multitargeted therapy. PMID- 29117780 TI - Adjustment for treatment changes in epilepsy trials: A comparison of causal methods for time-to-event outcomes. AB - Background When trials are subject to departures from randomised treatment, simple statistical methods that aim to estimate treatment efficacy, such as per protocol or as treated analyses, typically introduce selection bias. More appropriate methods to adjust for departure from randomised treatment are rarely employed, primarily due to their complexity and unfamiliarity. We demonstrate the use of causal methodologies for the production of estimands with valid causal interpretation for time-to-event outcomes in the analysis of a complex epilepsy trial, as an example to guide non-specialist analysts undertaking similar analyses. Methods Two causal methods, the structural failure time model and inverse probability of censoring weighting, are adapted to allow for skewed time varying confounders, competing reasons for treatment changes and a complicated time to remission outcome. We demonstrate the impact of various factors: choice of method (structural failure time model versus inverse probability of censoring weighting), model for inverse probability of censoring weighting (pooled logistic regression versus Cox models), time interval (for creating panel data for time varying confounders and outcome), choice of confounders and (in pooled logistic regression) use of splines to estimate underlying risk. Results The structural failure time model could adjust for switches between trial treatments but had limited ability to adjust for the other treatment changes that occurred in this epilepsy trial. Inverse probability of censoring weighting was able to adjust for all treatment changes and demonstrated very similar results with Cox and pooled logistic regression models. Accounting for increasing numbers of time-varying confounders and reasons for treatment change suggested a more pronounced advantage of the control treatment than that obtained using intention to treat. Conclusions In a complex trial featuring a remission outcome, underlying assumptions of the structural failure time model are likely to be violated, and inverse probability of censoring weighting may provide the most useful option, assuming availability of appropriate data and sufficient sample sizes. Recommendations are provided for analysts when considering which of these methods should be applied in a given trial setting. PMID- 29117781 TI - A joint model for multivariate hierarchical semicontinuous data with replications. AB - Longitudinal data are often collected in biomedical applications in such a way that measurements on more than one response are taken from a given subject repeatedly overtime. For some problems, these multiple profiles need to be modeled jointly to get insight on the joint evolution and/or association of these responses over time. In practice, such longitudinal outcomes may have many zeros that need to be accounted for in the analysis. For example, in dietary intake studies, as we focus on in this paper, some food components are eaten daily by almost all subjects, while others are consumed episodically, where individuals have time periods where they do not eat these components followed by periods where they do. These episodically consumed foods need to be adequately modeled to account for the many zeros that are encountered. In this paper, we propose a joint model to analyze multivariate hierarchical semicontinuous data characterized by many zeros and more than one replicate observations at each measurement occasion. This approach allows for different probability mechanisms for describing the zero behavior as compared with the mean intake given that the individual consumes the food. To deal with the potentially large number of multivariate profiles, we use a pairwise model fitting approach that was developed in the context of multivariate Gaussian random effects models with large number of multivariate components. The novelty of the proposed approach is that it incorporates: (1) multivariate, possibly correlated, response variables; (2) within subject correlation resulting from repeated measurements taken from each subject; (3) many zero observations; (4) overdispersion; and (5) replicate measurements at each visit time. PMID- 29117782 TI - A Proteomic Network for Symbiotic Nitrogen Fixation Efficiency in Bradyrhizobium elkanii. AB - Rhizobia colonize legumes and reduce N2 to NH3 in root nodules. The current model is that symbiotic rhizobia bacteroids avoid assimilating this NH3. Instead, host legume cells form glutamine from NH3, and the nitrogen is returned to the bacteroid as dicarboxylates, peptides, and amino acids. In soybean cells surrounding bacteroids, glutamine also is converted to ureides. One problem for soybean cultivation is inefficiency in symbiotic N2 fixation, the biochemical basis of which is unknown. Here, the proteomes of bacteroids of Bradyrhizobium elkanii USDA76 isolated from N2 fixation-efficient Peking and -inefficient Williams 82 soybean nodules were analyzed by mass spectrometry. Nearly half of the encoded bacterial proteins were quantified. Efficient bacteroids produced greater amounts of enzymes to form Nod factors and had increased amounts of signaling proteins, transporters, and enzymes needed to generate ATP to power nitrogenase and to acquire resources. Parallel investigation of nodule proteins revealed that Peking had no significantly greater accumulation of enzymes needed to assimilate NH3 than Williams 82. Instead, efficient bacteroids had increased amounts of enzymes to produce amino acids, including glutamine, and to form ureide precursors. These results support a model for efficient symbiotic N2 fixation in soybean where the bacteroid assimilates NH3 for itself. PMID- 29117783 TI - Research Priorities. PMID- 29117784 TI - Lucky, Competent, or Just a Cheat? Interactive Effects of Honesty-Humility and Moral Cues on Cheating Behavior. AB - Despite substantial research on cheating, how and when individual predispositions figure into cheating behavior remains unclear. In Study 1, we investigated to what extent Honesty-Humility predicted cheating behavior. As expected, individuals high on Honesty-Humility were less likely to cheat than were individuals low on this trait. In Study 2, integrating arguments from personality research about traits with arguments from behavioral ethics about moral primes, we examined how Honesty-Humility and situational primes interacted to affect cheating. We found an interaction indicating that individuals high on Honesty Humility consistently did not cheat much across situational primes, whereas individuals low on Honesty-Humility cheated more when exposed to immoral primes than when exposed to moral primes. Our research invites reflection about the interplay of individual differences in Honesty-Humility and situational cues in predicting cheating, including the design of anti-cheating systems and the context in which these person and situation factors interact. PMID- 29117785 TI - Notch1 regulates tongue cancer cells proliferation, apoptosis and invasion. AB - OBJECTIVES: Notch1 regulates tumor biology in a complex, context-dependent manner. The roles of Notch1 in tongue cancer are still controversial. The aim of this study is to investigate the roles of Notch1 in tongue cancer. MATERIALS AND METHODS: The expression of Notch1 was tested between tongue cancer and normal samples by using immunohistochemistry. Tongue cancer cells were transfected with siRNA or plasmid, respectively. Cell proliferation, apoptosis, migration and invasion ability were tested in appropriate ways. The subcutaneous tumor model was established to observe the tumor growth. RESULTS: Notch1 was upregulated in tongue carcinoma tissues and the expression of Notch1 was related with tumor stage and differentiation. Overexpression of Notch1 could increase tongue cancer cells proliferation, invasion and migration. But inhibited the expression of Notch1 could decrease cells proliferation, invasion and migration and promote cell apoptosis in vitro and in vivo. CONCLUSION: Our results prove that the oncogenic role of Notch1 in tongue cancer and provide the direction of targeted therapy of tongue cancer. PMID- 29117786 TI - Molecular Characterization and Functional Analysis of PR-1-Like Proteins Identified from the Wheat Head Blight Fungus Fusarium graminearum. AB - The group 1 pathogenesis-related (PR-1) proteins originally identified from plants and their homologs are also found in other eukaryotic kingdoms. Studies on nonplant PR-1-like (PR-1L) proteins have been pursued widely in humans and animals but rarely in filamentous ascomycetes. Here, we report the characterization of four PR-1L proteins identified from the ascomycete fungus Fusarium graminearum, the primary cause of Fusarium head blight of wheat and barley (designated FgPR-1L). Molecular cloning revealed that the four FgPR-1L proteins are all encoded by small open reading frames (612 to 909 bp) that are often interrupted by introns, in contrast to plant PR-1 genes that lack introns. Sequence analysis indicated that all FgPR-1L proteins contain the PR-1-specific three-dimensional structure, and one of them features a C-terminal transmembrane (TM) domain that has not been reported for any stand-alone PR-1 proteins. Transcriptional analysis revealed that the four FgPR-1L genes are expressed in axenic cultures and in planta with different spatial or temporal expression patterns. Phylogenetic analysis indicated that fungal PR-1L proteins fall into three major groups, one of which harbors FgPR-1L-2-related TM-containing proteins from both phytopathogenic and human-pathogenic ascomycetes. Low-temperature sodium dodecyl sulfate polyacrylamide gel electrophoresis and proteolytic assays indicated that the recombinant FgPR-1L-4 protein exists as a monomer and is resistant to subtilisin of the serine protease family. Functional analysis confirmed that deletion of the FgPR-1L-4 gene from the fungal genome results in significantly reduced virulence on susceptible wheat. This study provides the first example that the F. graminearum-wheat interaction involves a pathogen derived PR-1L protein that affects fungal virulence on the host. PMID- 29117788 TI - Recurrent Admissions for Hypothermia From Concomitant Topiramate and Phenobarbital: A Case Report. AB - INTRODUCTION: This article presents an additional case of concomitant topiramate and phenobarbital administration that resulted in 8 hospital admissions for hypothermia that resolved after discontinuation of phenobarbital. CASE: A 56-year old white female with cerebral palsy and quadriplegia, epilepsy, and hypothyroidism was admitted to a community teaching hospital multiple times with documented hypothermia. These admissions followed a subsequent dose increase of topiramate in December 2014. In February 2015, the patient was admitted with 35 degrees C rectal temperature. Her 2 admissions in April were for hypothermia with temperatures of 34.6 degrees C and 33.6 degrees C, respectively. The patient had 5 other admissions with hypothermia through December 2015. All other causes of hypothermia were ruled out. The hypothermia resolved when phenobarbital was discontinued. DISCUSSION: A recent case series noted an association between phenobarbital and topiramate causing hypothermia. The patient's hypothermia developed while on concomitant phenobarbital and topiramate but only after an increase in topiramate. No other causes for hypothermia were found based upon physical examination or lab work. The Naranjo nomogram noted a probable causation. CONCLUSION: This case report points to an association of hypothermia with concomitant topiramate and phenobarbital with resolution after phenobarbital discontinuation. Improvement after discontinuation of phenobarbital seems to support a drug-effect relationship. PMID- 29117789 TI - NLRP3 polymorphisms and response to interferon-beta in multiple sclerosis patients. AB - We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical radiological criteria after 1 year of IFNbeta treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNbeta and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNbeta in MS patients. PMID- 29117787 TI - Reprogramming of Adult Peripheral Blood Cells into Human Induced Pluripotent Stem Cells as a Safe and Accessible Source of Endothelial Cells. AB - New approaches in regenerative medicine and vasculogenesis have generated a demand for sufficient numbers of human endothelial cells (ECs). ECs and their progenitors reside on the interior surface of blood and lymphatic vessels or circulate in peripheral blood; however, their numbers are limited, and they are difficult to expand after isolation. Recent advances in human induced pluripotent stem cell (hiPSC) research have opened possible avenues to generate unlimited numbers of ECs from easily accessible cell sources, such as the peripheral blood. In this study, we reprogrammed peripheral blood mononuclear cells, human umbilical vein endothelial cells (HUVECs), and human saphenous vein endothelial cells (HSVECs) into hiPSCs and differentiated them into ECs. The phenotype profiles, functionality, and genome stability of all hiPSC-derived ECs were assessed and compared with HUVECs and HSVECs. hiPSC-derived ECs resembled their natural EC counterparts, as shown by the expression of the endothelial surface markers CD31 and CD144 and the results of the functional analysis. Higher expression of endothelial progenitor markers CD34 and kinase insert domain receptor (KDR) was measured in hiPSC-derived ECs. An analysis of phosphorylated histone H2AX (gammaH2AX) foci revealed that an increased number of DNA double strand breaks upon reprogramming into pluripotent cells. However, differentiation into ECs restored a normal number of gammaH2AX foci. Our hiPSCs retained a normal karyotype, with the exception of the HSVEC-derived hiPSC line, which displayed mosaicism due to a gain of chromosome 1. Peripheral blood from adult donors is a suitable source for the unlimited production of patient-specific ECs through the hiPSC interstage. hiPSC-derived ECs are fully functional and comparable to natural ECs. The protocol is eligible for clinical applications in regenerative medicine, if the genomic stability of the pluripotent cell stage is closely monitored. PMID- 29117790 TI - Body Mass Index and Acute Ischemic Stroke Outcomes. AB - Background The impact of body mass index on acute ischemic stroke outcomes is unclear. Aims and/or hypothesis We sought to determine the effect of body mass index on short-term (90 days) acute ischemic stroke outcomes. Methods Data were extracted for patients with acute ischemic stroke and records of body mass index at baseline from the Virtual International Stroke Trials Archive database. Multivariate logistic regression and Cox proportional hazard analysis were used to analyze effect of body mass index on poor functional outcome (modified Rankin Scale >2) and mortality, respectively, within 90 days of stroke's onset. Results Of the 4811 patients (mean age 68.8 +/- 12.2 years) included in the study, 2002 (41.6%) were overweight, and 1095 (22.8%) were obese. Overweight (body mass index 25-29.9 kg/m2) was associated with decreased mortality (hazard ratios 0.59; 95% confidence interval 0.51-0.68; P < 0.01) and decrease in poor functional outcome (odds ratio 0.74; 95% confidence interval 0.64-0.85; P < 0.01) following acute ischemic stroke. The association of body mass index with stroke outcomes was dependent on age, gender, and use of thrombolytic therapy. Conclusions Being overweight or obese is associated with a better functional outcome and reduced mortality in patients of acute ischemic stroke. However, the definition of an 'optimal' body mass index, in relation to stroke outcomes, may be affected by age, gender, and use of thrombolytic therapy. PMID- 29117793 TI - IJS Editorial, S Davis 24Th July 2012. PMID- 29117791 TI - Implementing Generalized Additive Models to Estimate the Expected Value of Sample Information in a Microsimulation Model: Results of Three Case Studies. AB - BACKGROUND: The expected value of sample information (EVSI) can help prioritize research but its application is hampered by computational infeasibility, especially for complex models. We investigated an approach by Strong and colleagues to estimate EVSI by applying generalized additive models (GAM) to results generated from a probabilistic sensitivity analysis (PSA). METHODS: For 3 potential HIV prevention and treatment strategies, we estimated life expectancy and lifetime costs using the Cost-effectiveness of Preventing AIDS Complications (CEPAC) model, a complex patient-level microsimulation model of HIV progression. We fitted a GAM-a flexible regression model that estimates the functional form as part of the model fitting process-to the incremental net monetary benefits obtained from the CEPAC PSA. For each case study, we calculated the expected value of partial perfect information (EVPPI) using both the conventional nested Monte Carlo approach and the GAM approach. EVSI was calculated using the GAM approach. RESULTS: For all 3 case studies, the GAM approach consistently gave similar estimates of EVPPI compared with the conventional approach. The EVSI behaved as expected: it increased and converged to EVPPI for larger sample sizes. For each case study, generating the PSA results for the GAM approach required 3 to 4 days on a shared cluster, after which EVPPI and EVSI across a range of sample sizes were evaluated in minutes. The conventional approach required approximately 5 weeks for the EVPPI calculation alone. CONCLUSION: Estimating EVSI using the GAM approach with results from a PSA dramatically reduced the time required to conduct a computationally intense project, which would otherwise have been impractical. Using the GAM approach, we can efficiently provide policy makers with EVSI estimates, even for complex patient-level microsimulation models. PMID- 29117792 TI - Mortality After Elective and Ruptured Abdominal Aortic Aneurysm Surgical Repair: 12-Year Single-Center Experience of Estonia. AB - BACKGROUND AND AIMS: Abdominal aortic aneurysm is a degenerative vascular pathology with high mortality due to its rupture, which is why timely treatment is crucial. The current single-center retrospective study was undertaken to analyze short- and long-term all-cause mortality after operative treatment of abdominal aortic aneurysm and to examine the factors that influence outcome. MATERIAL AND METHODS: The data of all abdominal aortic aneurysm patients treated with open repair or endovascular aneurysm repair in 2004-2015 were retrospectively retrieved from the clinical database of Tartu University Hospital. The primary endpoint was 30-day, 90-day, and 5-year all-cause mortality. The secondary endpoint was determination of the risk factors for mortality. RESULTS AND CONCLUSION: Elective abdominal aortic aneurysm repair was performed on 228 patients (mean age 71.8 years), of whom 178 (78%) were treated with open repair and 50 (22%) with endovascular aneurysm repair. A total of 48 patients with ruptured abdominal aortic aneurysm were treated with open repair (mean age 73.8 years) at the Department of Vascular Surgery, Tartu University Hospital, Estonia. Mean follow-up period was 4.2 +/- 3.3 years. In patients with elective abdominal aortic aneurysm, 30-day, 90-day, and 5-year all-cause mortality rates were 0.9%, 2.6%, and 32%, respectively. In multivariate analysis, the main predictors for 5-year mortality were preoperative creatinine value and age (p < 0.05). In patients with ruptured abdominal aortic aneurysm, 30-day, 90 day, and 5-year all-cause mortality rates were 22.9%, 33.3%, and 55.1%, respectively. In multivariate analysis, the risk factors for 30-day mortality in ruptured abdominal aortic aneurysm were perioperative hemoglobin and lactate levels (p < 0.05). According to this study, the all-cause mortality rates of elective abdominal aortic aneurysm and ruptured abdominal aortic aneurysm at our hospital were comparable to those at other centers worldwide. Even though some variables were identified as potential predictors of survival, the mortality rates after ruptured abdominal aortic aneurysm remain high. Early diagnosis, timely treatment, and detection of the risk factors for abdominal aortic aneurysm progression would improve survival in patients with abdominal aortic aneurysm. PMID- 29117794 TI - Cognitive telerehabilitation in mild cognitive impairment, Alzheimer's disease and frontotemporal dementia: A systematic review. AB - Introduction Given the limited effectiveness of pharmacological treatments, non pharmacological interventions in neurodegenerative diseases have gained increasing attention in recent years and telerehabilitation has been proposed as a cognitive rehabilitation strategy. The purpose of this systematic review is to examine the evidence for the efficacy of cognitive telerehabilitation interventions compared with face-to-face rehabilitation in patients with mild cognitive impairment, Alzheimer's disease and frontotemporal dementia. Methods In accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines, a systematic search of the Medline database was conducted. Out of 14 articles assessed for eligibility, five studies were identified, three in participants with mild cognitive impairment or Alzheimer's disease, two in patients with primary progressive aphasia. Results The Physiotherapy Evidence Database scale was used to assess the methodological quality of four out of five studies included in this systematic review, with only one report receiving a high-quality rating. Effect-size analysis evidenced positive effects of telerehabilitation interventions, comparable with those reported for face-to-face rehabilitation. Discussion The available evidence for the effectiveness of cognitive telerehabilitation is limited, and the quality of the evidence needs to be improved. The systematic review provides preliminary evidence suggesting that cognitive telerehabilitation for neurodegenerative disease may have comparable effects as conventional in-person cognitive rehabilitation. PMID- 29117795 TI - High-sensitivity cardiac troponin T in obstructive sleep apnea patients without cardiovascular diseases: Efficacy of CPAP treatment. AB - The aims of this article were to determine the levels of serum high-sensitivity cardiac troponin T (hs-cTnT) in obstructive sleep apnea (OSA) patients without cardiovascular disease (CVD) and to assess the efficacy of continuous positive airway pressure (CPAP). Snorers referred for polysomnography (PSG) for the investigation of OSA were eligible and hs-cTnT levels measured in our pilot study. Hs-cTnT was measured again after 3 months of CPAP treatment in participants with severe OSA. A total of 93 participants recruited after PSG. When compared with simple snoring group, severe OSA group had comparable higher hs-cTnT (7.5 +/- 3.0 vs. 5.0 +/- 2.1; p < 0.05). Hs-cTnT was positively correlated with apnea hypopnea index, and oxygen desaturation index ( r = 0.283, 0.282; p = 0.006, 0.006, respectively). Hs-cTnT levels were not significantly altered in 28 individuals who received 3 months of CPAP treatment (8.4 +/- 2.4 vs.7.6 +/- 2.1; p = 0.064). Elevated hs-cTnT levels were observed in severe OSA patients without CVD, and CPAP treatment had no influence on this levels. PMID- 29117796 TI - Effects of varenicline therapy in combination with advanced behavioral support on smoking cessation and quality of life in inpatients with acute exacerbation of COPD, bronchial asthma, or community-acquired pneumonia: A prospective, open label, preference-based, 52-week, follow-up trial. AB - Quitting smoking is the most important element in the therapeutic management of chronic respiratory diseases. Combining pharmacotherapy with behavioral support increases smoking cessation success rates. In addition, hospitalized smokers have increased motivation to quit. We investigated the efficacy on smoking cessation, of varenicline in combination with behavioral support, in smokers hospitalized due to (a) acute exacerbation of chronic obstructive pulmonary disease (COPD), or (b) bronchial asthma attack, or (c) community-acquired pneumonia (CAP). The method used is prospective, open-label, preference-based, parallel group, 52-week trial. Patients chose the smoking cessation intervention they preferred: a standard regimen of varenicline combined with post-discharge advanced behavioral support (group A) or one private consultation session during hospitalization (group B). Follow-up phone calls were scheduled in weeks 1, 2, and 4 and months 3, 6, and 9. The final hospital visit was performed in week 52. Primary outcome was success rate defined as the percentage (%) of smoking abstinence at week 52 and secondary outcomes were (a) changes in quality of life (QoL) indicated by the scores on the Short Form 36 (SF36) questionnaire and (b) predictors of smoking abstinence investigated with multiple binary logistic regression. One hundred one patients were enrolled, 44 (43.6%) in group A and 57 (56.4%) in group B. Respective abstinence rates were 54.5% and 15.8% at week 12 and 52.3% and 14.0% at week 52. Scores on SF36 were statistically significantly increased in both groups. Predictors of smoking abstinence were varenicline (odds ratio (OR) 7.29; 95% confidence interval (CI) 2.15, 24.77; p = 0.001), age (OR 1.07; 95%CI 1.00, 1.15; p = 0.042), Fagerstrom score (OR 0.37; 95%CI 0.20, 0.68; p = 0.001), SF36 domains "vitality" (OR 1.12; 95%CI 1.04, 1.21; p = 0.003), and "social functioning" (OR 0.95; 95%CI 0.90, 1.00; p = 0.041). Varenicline in combination with behavioral support resulted in high abstinence rates inpatients hospitalized for exacerbation of COPD, asthma attack, or CAP, and improved QoL. PMID- 29117797 TI - Obesity and metabolic syndrome in COPD: Is exercise the answer? AB - Approximately half of all patients with chronic obstructive pulmonary disease (COPD) attending pulmonary rehabilitation (PR) programmes are overweight or obese which negatively impacts upon dyspnoea and exercise tolerance particularly when walking. Within the obese population (without COPD), the observed heterogeneity in prognosis is in part explained by the variability in the risk of developing cardiovascular disease or diabetes (cardiometabolic risk) leading to the description of metabolic syndrome. In obesity alone, high-intensity aerobic training can support healthy weight loss and improve the constituent components of metabolic syndrome. Those with COPD, obesity and/or metabolic syndrome undergoing PR appear to do as well in traditional outcomes as their normal-weight metabolically healthy peers in terms of improvement of symptoms, health-related quality of life and exercise performance, and should therefore not be excluded. To broaden the benefit of PR, for this complex population, we should learn from the extensive literature examining the effects of exercise in obesity and metabolic syndrome discussed in this review and optimize the exercise strategy to improve these co-morbid conditions. Standard PR outcomes could be expanded to include cardiometabolic risk reduction to lower future morbidity and mortality; to this end exercise may well be the answer. PMID- 29117798 TI - Inflammatory biomarkers and radiologic measurements in never-smokers with COPD: A cross-sectional study from the CODA cohort. AB - Various biomarkers have emerged as potential surrogates to represent various subgroups of chronic obstructive pulmonary disease (COPD), which manifest with different phenotypes. However, the biomarkers representing never-smokers with COPD have not yet been well elucidated. The aim of this study was to evaluate the associations of certain serum and radiological biomarkers with the presence of COPD in never-smokers. To explore the associations of serum and radiological biomarkers with the presence of COPD in never-smokers, we conducted a cross sectional patient cohort study composed of never-smokers from the COPD in Dusty Areas (CODA) cohort, consisting of subjects living in dusty areas near cement plants in South Korea. Of the 131 never-smokers in the cohort, 77 (58.8%) had COPD. There were no significant differences in the number of subjects with high levels of inflammatory biomarkers (>90th percentile of never-smokers without COPD), including white blood cell count, total bilirubin, interleukin (IL)-6, IL 8, and C-reactive protein, or radiologic measurements (including emphysema index and mean wall area percentage) between never-smokers with COPD and those without COPD. However, the number of subjects with high uric acid was significantly higher in never-smokers with COPD than never-smokers without COPD (31.2% (24/77) vs. 11.1% (6/54); p = 0.013). In addition, multivariate analysis revealed that high uric acid was significantly associated with the presence of COPD in never smokers (adjusted relative risk: 1.63; 95% confidence interval: 1.21, 2.18; p = 0.001). Our study suggests that high serum levels of uric acid might be a potential biomarker for assessing the presence of COPD in never-smokers. PMID- 29117800 TI - Corrigendum. PMID- 29117801 TI - Conference Diary. PMID- 29117802 TI - Reply. PMID- 29117799 TI - Subclinical executive function impairment in children with asymptomatic, treated phenylketonuria: A comparison with children with immunodeficiency virus. AB - In this study we compared the neuropsychological profile of phenylketonuria (PKU) and human immunodeficiency virus (HIV) to examine the specificity of the executive function (EF) impairment reported in these two patologies. A total of 55 age-matched children and adolescents were assessed, including 11 patients with PKU, 16 patients with HIV and 28 healthy controls, underwent a neuropsychological assessment. Although neither the PKU nor the HIV group scored below the normative ranges, both groups showed lower scores in neuropsychological tests engaging EFs than controls. In addition, compared to patients with PKU the HIV group performed significantly worse in the Trail-Making Test A, Corsi Span and Verbal Fluency. These findings suggest that EF impairments in PKU (a) are limited to EFs (i.e., working memory and attentional shifting), (b) are not simply due to generalized processing speed deficits and PMID- 29117805 TI - Author Reply. PMID- 29117804 TI - A Systematic Review of Occupational Health and Safety Business Cases. AB - Business cases are arguments developed to secure management commitment and approval for investment in an intervention. This systematic review evaluated 12 experimental and quasi-experimental studies on occupational health and safety interventions (OHSI) in various settings. The search engines used in this systematic review include PubMed, CINAHL, and Scopus. A cost and benefit analysis of OHSI was completed at the organizational level in these studies. The focus of this analysis included sample, design, theoretical framework, interventional strategies, and threats to validity and outcomes. Positive returns on investment of OHSI outcomes were shown in 10 of the studies. The other two studies concluded that their chosen OHSI were not cost-effective. PMID- 29117806 TI - The International Journal of Stroke Welcomes Associate Editor Jong S. Kim. PMID- 29117808 TI - Conference Diary. PMID- 29117807 TI - Six Years and Still Moving Forward. PMID- 29117809 TI - The International Journal of Stroke Welcomes Professor Patrick Lyden as Associate Editor. PMID- 29117810 TI - Conference Diary. PMID- 29117811 TI - A new endovascular technique for the treatment of dialysis-associated steal syndrome. AB - Background Dialysis access-associated steal syndrome is a major complication of arteriovenous fistula creation whereby the low-resistance venous conduit shunts arterial inflow through the anastomosis, resulting in clinically significant distal artery insufficiency. Herein, we describe a case of severe steal phenomenon with gangrene of a digit following placement of an arteriovenous fistula that was treated with a novel, entirely endovascular technique. To our knowledge, this was the first totally endovascular approach to dialysis access associated steal syndrome. Methods Catheterization of the right subclavian, axillary, and brachial arteries was performed. A short 5-Fr sheath was exchanged for a long destination 6-Fr sheath and placed in the proximal brachial artery. An arteriogram showed no stenosis of the arterial system, but did show substantial steal phenomenon with inflow to the arteriovenous fistula, instead of the forearm. We placed a stent graft in the brachial artery across the anastomosis such that the graft covered 3/4 of the length of the opening of the anastomosis. Results Immediately after placement of the stent graft the clinical picture improved dramatically. Patient was followed for 15 months after this procedure until her demise for unrelated causes without ever experiencing dialysis access associated steal syndrome and with a patent and functional arteriovenous fistula. Conclusion We present a patient with severe dialysis access-associated steal syndrome complicated by third fingertip gangrene, which was successfully treated using a completely endovascular technique. This novel endovascular approach enabled a high-risk patient to avoid open surgery, preserve her limb, and maintain the function of her arteriovenous fistula. PMID- 29117812 TI - Author Response to Social Marketing and the FAST Campaign. PMID- 29117813 TI - Conference Diary. PMID- 29117814 TI - As One Door Closes, Another Opens. PMID- 29117816 TI - AAOHN Member Opinions on Demonstrating Value: A Closer Look at the Findings. AB - An assessment was conducted to update a tool kit published by the American Association of Occupational Health Nurses (AAOHN) in 1998. The original document, Success Tool for Measuring and Articulating Value, had been a respected resource. Although the AAOHN guide, Demonstrating Value, is a tool with steps and examples for demonstrating value, the intention of this article is to explore the rich data collected during the assessment process, which included interviews with occupational health nurse leaders and an AAOHN member survey. Findings were summarized including data responses compared with occupational health nurses' tenure in the profession, size of company, job title, and clinic setting (i.e., single- vs. multi-nurse or corporate clinic). In addition, key advice from occupational health nurse leaders was summarized. Justifying services and demonstrating value were viewed by all respondents as essential to the profession as well as for ensuring the quality of occupational health nursing services. A gap was identified between more experienced occupational health nurses and those new to the field, as well as between occupational health nursing settings related to the importance of, and involvement in, demonstrating value. PMID- 29117815 TI - Health Risk Appraisals With Aging Adults: An Integrative Review. AB - Identification of risk factors unique to the aging experience is vital to support health promotion efforts and prevent loss of independence for the increasing aging population. Health risk appraisals are tools capable of identifying a broad range of factors that affect health; however, these tools were designed for use with predominantly healthy working-age adults. The purpose of this integrative review was to describe uses and adaptations of health risk appraisals with aging adults. A total of 43 articles met inclusion criteria, identifying multiple adaptations necessary to effectively identify the risks faced by aging adults, including those related to activities of daily living, pain, depression, social support/network, vision, hearing, and cognitive status. Uses included support for health promotion efforts and to determine risk for depression, falls, and loss of independence. Further research needs to be done to evaluate impact when used as a health promotion and prevention tool for aging adults. PMID- 29117817 TI - Roadmap for creating an accelerated three-year medical education program. AB - : Medical education is undergoing significant transformation. Many medical schools are moving away from the concept of seat time to competency-based education and introducing flexibility in the curriculum that allows individualization. In response to rising student debt and the anticipated physician shortage, 35% of US medical schools are considering the development of accelerated pathways. The roadmap described in this paper is grounded in the experiences of the Consortium of Accelerated Medical Pathway Programs (CAMPP) members in the development, implementation, and evaluation of one type of accelerated pathway: the three-year MD program. Strategies include developing a mission that guides curricular development - meeting regulatory requirements, attaining institutional buy-in and resources necessary to support the programs, including student assessment and mentoring - and program evaluation. Accelerated programs offer opportunities to innovate and integrate a mission benefitting students and the public. ABBREVIATIONS: CAMPP: Consortium of accelerated medical pathway programs; GME: Graduate medical education; LCME: Liaison committee on medical education; NRMP: National residency matching program; UME: Undergraduate medical education. PMID- 29117819 TI - Role of ultrasound in confirmation of endotracheal tube in neonates: a review. AB - Tracheal intubation (TI) is a commonly done procedure in neonatal intensive care unit and delivery room during resuscitation. The confirmation of endotracheal tube (ETT) position should be done quickly as tube malposition is associated with various serious adverse outcomes like hypoxemia, right upper lobe collapse, atelectasis, air leak syndromes and esophageal intubation. ETT position can be confirmed by various methods like clinical sign, chest radiography, capnography, external digital tracheal palpation, ultrasonography (USG), respiratory function monitor, video-laryngoscope and fiberoptic devices. The current gold standard test to confirm ETT position is a chest radiograph, but it has many fallacies thus presently there is the need for a modality that helps in detection of endotracheal intubation and tube position with minimal complications. USG has been used in adult and pediatric population for detecting ETT position but there are very less studies in neonates. In this review, we analyze all the published studies, case reports and personal experiences that have sought the use of USG in neonatal population for detection of ETT position. PMID- 29117818 TI - One-Year Outcomes Following Directional Atherectomy of Popliteal Artery Lesions: Subgroup Analysis of the Prospective, Multicenter DEFINITIVE LE Trial. AB - PURPOSE: To report the effectiveness of directional atherectomy for the treatment of popliteal artery occlusive disease. METHODS: This subset of the prospective, multicenter, single-arm DEFINITIVE LE trial included 158 patients (mean age 72.0+/-10.9 years; 82 men) who underwent directional atherectomy in 162 popliteal artery lesions between 2009 and 2011. Forty-eight (30.4%) patients were suffering from critical limb ischemia (CLI). The mean lesion length was 5.8+/-3.9 cm; 38 (23.5%) arteries were occluded. The primary outcome measure for patients with intermittent claudication (IC) was duplex ultrasound-defined primary patency at 1 year; the outcome for subjects with CLI was freedom from major amputation of the target limb at 1 year. Outcomes and adverse events were independently assessed. RESULTS: Procedure success (<=30% residual stenosis) was achieved in 84.4% of treated lesions; adjunctive stenting was required in 6 (3.7%) of the 162 lesions. The 1-year primary patency rate was 75.0% (IC patients 78.2% and CLI patients 67.5%, p=0.118). The freedom from major amputation in both cohorts was 100%. In both IC and CLI patients, significant improvements were demonstrated at 1 year in the Rutherford category, walking distance, and quality of life in comparison to baseline. CONCLUSION: This study indicates that directional atherectomy in popliteal arteries leads to favorable technical and clinical results at 1 year for claudicant as well as CLI patients. PMID- 29117820 TI - Carpal Tunnel Syndrome and Trigger Wrist Caused by Localized Amyloidosis: A Case Report. AB - We report a case of carpal tunnel syndrome and trigger wrist caused by localized amyloidosis. A 37-year-old man, who worked as a manufacturer, presented with a 5 month history of tingling sensation in the three radial fingers of the left hand and a painful click at the volar aspect of the wrist during digital motion. We divided the transverse carpal ligament and detected diffuse tenosynovitis that was especially severe around the flexor digitorum profundus tendons. Histological findings led to a diagnosis of amyloidosis. Localized amyloidosis could thus be a cause of trigger wrist. Systemic amyloidosis may develop in patients with localized amyloidosis; therefore, patients with trigger wrist caused by flexor tenosynovitis should be investigated for the existence of localized amyloidosis, with biopsy of the flexor tenosynovium. PMID- 29117821 TI - Assessment of Usefulness of Anthropometric Data for Predicting the Scaphoid and the Screw Length: A New Technique. AB - BACKGROUND: Headless screw is frequently used for scaphoid fracture fixation. Aim of the study was to assess the correlation between the axial length of the scaphoid and the axial length of the middle phalanx of index, middle, ring and little finger so as to provide an indirect method to assess the length of the scaphoid and thereby the length of the screw. METHODS: Thirty five fresh frozen cadavers with seventy wrists and hands were dissected. The age, sex and side were recorded. The axial length of the scaphoid, axial length of the middle phalanx of index, middle, ring and little finger were recorded and a correlation was assessed. Five cadavers were randomly selected and radiographs of the hand were done. Pearson coefficient correlation was assessed between the axial length of the middle phalanx of ring finger on a radiograph and actual length of middle phalanx. RESULTS: A significant positive correlation was noted between the axial length of the scaphoid and the axial length of the middle phalanx of ring finger (r = 0.646), also a positive correlation between the axial length of middle phalanx of ring finger on a radiograph and the axial length of the scaphoid measured by vernier caliper (r = 0.91). CONCLUSIONS: A preoperative radiograph of the wrist with hand will help us indirectly assess the axial length of the scaphoid by measuring the axial length of the middle phalanx of ring finger. PMID- 29117822 TI - Patient-Reported Outcome Following Ulnotriquetral Ligament Split Tear Repair. AB - BACKGROUND: While the clinical presentation and mechanism of injury of ulnotriquetral (UT) ligament split tear had been well described, there has been no other studies that has reported on the outcome of a UT ligament repair. This study aims to look at the patient-reported outcomes following UT ligament split tear repair. METHODS: 18 wrists (13 right and 5 left) in 17 patients (12 males and 5 females, mean age 25.0 +/- 8.4 years, range 16-50 years) who had UT ligament split tear and undergone surgical repair between November 2007 and December 2013 were retrospectively analysed. Patient-reported outcome of resolution of pain, and objective measurements such as improvement in grip strength and range of movement of the wrist were recorded. Patients were followed up until the pain was completely resolved or the last documented consultation. The mean follow-up duration was 16.2 months. RESULTS: 94% reported improvements post-surgery, of which 63% reported complete resolution of pain. 6% reported no improvement in pain post-operatively. No patient reported worsening of pain after the surgery. There was significant improvement in grip strength from a mean of 23.5 kg to 27.1 kg. There was no significant change in range of motion of the wrist. CONCLUSIONS: The majority of patients reported resolution or improvement of pain after surgical repair. In addition, there was statistically significant improvement in grip strength recorded. PMID- 29117823 TI - Feasibility and Advantages of Full Thickness Skin Graft from the Anterolateral Thigh. AB - BACKGROUND: Full thickness skin graft (FTSG) gives better outcomes than split thickness skin graft (STSG), but it has the drawback of limited donor sites. Anterolateral thigh (ALT), a popular donor site of STSG, is also a popular donor site of perforator flaps. This area has the advantage of large flap size available with primary closure. Based on this we harvested FTSG instead of STSG from the ALT. METHODS: We retrospectively reviewed 10 cases of FTSG from the ALT, with the recipient site of foot in 3, ankle in 2, lower leg in 2, forearm in 2, and wrist in 1 patient. In all cases elliptical full thickness skin was harvested from the ALT, and the donor site was closed primarily. The skin was defatted and placed onto the defect with vacuum-assisted closure (VAC). The skin size ranged 7 30 cm in length and 3-12 cm in width. Mean follow up period was 7 months (range, 3-13). RESULTS: FTSG from the ALT provided durable wound coverage, with excellent color and texture matching. Partial (< 20%) graft failure was observed in 1 case, but no additional surgery was necessary. No patient reported donor site pain at postoperative 2 weeks. No donor site complications were encountered. No patient complained a feeling of tension in the thigh at final follow-up. CONCLUSIONS: FTSG from the ALT is feasible with the aid of VAC. Considering the skin quality, large skin size available, early pain relief, and little donor site morbidity, the ALT should be revisited as a donor site of FTSG. PMID- 29117824 TI - Ancient Schwannoma of Radial Nerve: A Report of Two Cases. AB - Ancient schwannoma is a rare variant of schwannoma associated with a longstanding course. They differ from classical schwannomas in the long duration for this subtype of schwannoma to develop and also by demonstrating haemorrhagic and degenerative changes with nuclear atypia. It is because of these histologic hallmarks that they are frequently misdiagnosed as malignant tumours. They usually involve the major nerves of flexor surfaces in upper extremity such as the ulnar and median nerve but schwannomas of the radial nerve are a rare entity. We report two cases of ancient schwannoma involving the radial nerve at mid arm and dorsum of the hand. The differential diagnoses included atypical soft tissue sarcomas and tumours of neural origin. Imaging and histopathology are crucial in diagnoses of these tumours. PMID- 29117825 TI - Acute Compartment Syndrome of Upper Extremities with Tendon Ruptures. AB - BACKGROUND: It is well known that acute compartment syndrome is associated with fracture of the forearm, while involvement of soft tissue injury including musculotendinous injury remains unclear. The purpose of this study was to evaluate the soft tissue involvement, including musculotendinous ruptures, in acute compartment syndrome of the upper limb. METHODS: We retrospectively enrolled 16 patients who underwent surgical treatment for acute compartment syndrome of the upper extremity. The average age of the patients was 47 years (range, 14 to 79) and the mean follow-up period after the surgery was 15 months (range, 12 to 29). Complications included at least one presentation at the final follow up of sensory disturbances or motor disturbances. We examined the presence of musculotendinous injury mechanism of injury, presence of fracture, the performance of skin grafting, and complications. RESULTS: Mechanism of injury of "caught in a machine" was found in six cases. Three of these patients had musculotendinous ruptures and all muscle tears were revealed by intraoperative findings. No patients had muscle ruptures with other injury mechanisms. Seven out of 16 patients (44%) developed complications at final follow-up. Skin grafting was performed in six patients, and five of these patients developed complications. Only one of the nine patients without complications underwent skin grafting. CONCLUSIONS: In cases of high-energy injuries, the surgeon should suspect the presence of a musculotendinous injury prior to surgery. PMID- 29117826 TI - An Anatomic Variant of Persistent Median Artery in Association with Carpal Tunnel Syndrome: Case Report and Review of the Literature. AB - The persistent median artery can be a rare cause of carpal tunnel syndrome. We present an anatomic variant of this artery. A 47-year-old female patient with bilateral carpal tunnel syndrome was found to have bilateral patent, functional persistent median arteries (PMA) upon operative exploration. Unlike previous reports, the PMAs were not located dorsal to the flexor retinaculum (FR). Rather, the PMAs were interposed between the palmar aponeurosis and the FR. Accompanied by two venae comitantes, the aberrant arteries were positioned directly in line with our carpal tunnel incisions on both hands. Although rare, it is important for the surgeon to be aware of this anatomic variant to prevent inadvertent injury to what may be an important vascular supply to the distal median nerve. PMID- 29117827 TI - Tuberculosis of the Elbow Region in Pediatric Age Group - Experiences from a Single Centre. AB - BACKGROUND: Clinical series of tuberculosis of elbow region in children are few. The purpose of our study was to retrospectively review the presentation, healing response and functional results of 30 children. METHODS: The pretreatment disease presentation was studied from patient's case records. Serial radiographs of the patients were studied to see remineralization and healing of radiological lesions. For elbow's functional evaluation, pain, range of motion and recurrence were observed at final follow up. RESULTS: The mean patient age was 8.2 years. The mean duration of symptoms before presentation was 47 days. A discharging sinus was present in 6 patients. Multifocal presentation was found in 7 patients. The lesion was most commonly localized in proximal ulna or lower humerus. The classical 'ice cream scoop' appearance of proximal ulnar metaphysis was noted in 5 elbows. Most elbows were in Martini stage 2 (70%) at the time of presentation. All patients were treated non-operatively. Average follow up after completion of antitubercular therapy was 18.97 months. The resolution of regional osteopenia, sclerosis of lytic lesions, reappearance of bony trabeculae and decrease in size of cavities was the usual sequence of radiological healing. End average elbow flexion arc deteriorated with increasing Martini stage. 'Ice cream scoop lesions' resulted in a worse functional outcome with formation of an irregular proximal ulnar articular surface. CONCLUSIONS: Restriction of elbow range of motion, early discharging sinus formation and radiological 'ice cream scoop' appearance indicated a tubercular pathology. Late presentation with advanced disease, total joint involvement, and 'ice cream scoop appearance' resulted in decreased elbow flexion arc. PMID- 29117828 TI - Dual Plating Technique for Volar Rim Fracture of the Distal Radius Using DePuy Synthes 2.0 m and 2.4 mm Locking Plates. AB - BACKGROUND: To assess the surgical results of distal radius fractures with the involvement of a volar rim fragment using the DePuy-Synthes 2.0 mm and 2.4 mm locking plates. METHODS: Subjects were six women and one man of average age 57 years (range, 31-83 y) and a mean follow-up period of 9 months (range, 5-19 mo) with AO B3 (volar shearing) distal radius fractures. Time of the procedure, physical examination of wrist range of motion, grip strength compared with the contralateral healthy wrist, and radiographic evaluation (volar tilt, radial inclination, and ulnar variance) were evaluated. The Visual Analog Scale (VAS: 0 points represents no pain, 100 points represents the worst pain possible) and the Quick Disability of the Arm, Shoulder, and Hand questionnaire (QuickDASH, 0 = no disability, 100 = extreme disability) were completed by patients at the final follow-up. RESULTS: The average time of the procedure was 74 min. There were no perioperative complications. Average radiographic measures were: volar tilt, 8 degrees ; radial inclination, 23 degrees , and ulnar variance, 0 mm. Wrist range of motion averaged 63 degrees in wrist extension (range, 55-80 degrees ) and 55 degrees in wrist flexion (range, 45-65 degrees ). Grip strength averaged 81% of the contralateral side at final evaluation (range, 67-100%). The mean QuickDASH score was 3.0 points (range, 0-9.1 points) and the mean VAS for pain was 9.3 at final follow-up. CONCLUSIONS: Open reduction internal fixation with the DePuy Synthes 2.0 mm and 2.4 mm locking plates is an effective means of fixing a distal radius fracture that includes a volar rim fragment without interfering with flexor tendon gliding. PMID- 29117829 TI - Chronic Compartment Syndrome of the Mobile Wad: A Case Report. AB - A case of chronic compartment syndrome of the mobile wad in a 15-year-old female amateur tennis player is described. She presented with a 7-month history of radial forearm pain and tenderness with mild swelling, and was unable to swing the tennis racket. MRI showed high intensity within the brachioradialis muscle. Endoscopic fasciotomy showed degeneration of the brachioradialis muscle belly. Complete pain relief was obtained 4 months after the fasciotomy. PMID- 29117830 TI - In Vitro Evaluation of Human Hand Tendon Ingrowth into A Synthetic Scaffold. AB - BACKGROUND: Synthetic scaffold has been used for tissue approximation and reconstructing damaged and torn ligaments. This study explores the ability of tendon ingrowth into a synthetic scaffold in vitro, evaluate growth characteristics, morphology and deposition of collagen matrix into a synthetic scaffold. METHODS: Upper limb tendons were harvested with consent from patients with crush injuries and non-replantable amputations. These tendons (both extensor and flexor) measuring 1 cm are sutured to either side of a 0.5 cm synthetic tendon strip and cultured in growth medium. At 2, 4, 6 and 8 weeks, samples were fixed into paraffin blocks, cut and stained with haematoxylin-eosin (H&E) and Masson's trichrome. RESULTS: Minimal tendon ingrowth were seen in the first 2 weeks of incubation. However at 4 weeks, the cell ingrowth were seen migrating towards the junction between the tendon and the synthetic scaffold. This ingrowth continued to expand at 6 weeks and up to 8 weeks. At this point, the demarcation between human tendon and synthetic scaffold was indistinct. CONCLUSIONS: We conclude that tendon ingrowth composed of collagen matrix were able to proliferate into a synthetic scaffold in vitro. PMID- 29117831 TI - Age-Dependent Schwann Cell Phenotype Regulation Following Peripheral Nerve Injury. AB - BACKGROUND: Schwann cells are integral to the regenerative capacity of the peripheral nervous system, which declines after adolescence. The mechanisms underlying this decline are poorly understood. This study sought to compare the protein expression of Notch, c-Jun, and Krox-20 after nerve crush injury in adolescent and young adult rats. We hypothesized that these Schwann cell myelinating regulatory factors are down-regulated after nerve injury in an age dependent fashion. METHODS: Adolescent (2 months old) and young adult (12 months old) rats (n = 48) underwent sciatic nerve crush injury. Protein expression of Notch, c-Jun, and Krox-20 was quantified by Western blot analysis at 1, 3, and 7 days post-injury. Functional recovery was assessed in a separate group of animals (n = 8) by gait analysis (sciatic functional index) and electromyography (compound motor action potential) over an 8-week post-injury period. RESULTS: Young adult rats demonstrated a trend of delayed onset of the dedifferentiating regulatory factors, Notch and c-Jun, corresponding to the delayed functional recovery observed in young adult rats compared to adolescent rats. Compound motor action potential area was significantly greater in adolescent rats relative to young adult rats, while amplitude and velocity trended toward statistical significance. CONCLUSIONS: The process of Schwann cell dedifferentiation following peripheral nerve injury shows different trends with age. These trends of delayed onset of key regulatory factors responsible for Schwann cell myelination may be one of many possible factors mediating the significant differences in functional recovery between adolescent and young adult rats following peripheral nerve injury. PMID- 29117832 TI - Prevalence of Absence of Palmaris Longus and Its Association with Gender, Hand Dominance and Absence of FDS Tendon to Little Finger Among Malay Population. AB - BACKGROUND: Palmaris Longus is being widely used in reconstructive, plastic and cosmetic surgeries due to its long tendon. It is the most readily available source for tendon grafting. The objective of this study was to determine the prevalence of absence of Palmaris Longus and its association with gender, hand dominance and absence of FDS (flexor digitorum superficialis) tendon to little finger among Malay population. METHODS: An analytical cross sectional study design was used and a self-administered proforma was distributed for data collection. 1239 Malay secondary school children in Putrajaya were tested for absence of Palmaris Longus using Schaffer's test. 4 additional tests namely Thompson's test, Mishra's test I, Mishra's test II and Pushpakumar's 'two-finger sign' method were used to confirm its absence in respondents with negative Schaffer's test. Function of Flexor Digitorum Superficialis tendon to little finger was determined by flexing PIP of little finger while hyperextend the other fingers. RESULTS: The prevalence of absence of Palmaris Longus was 11.7%. Left side absence of Palmaris Longus was much common. There was a significant association between absence of Palmaris Longus with gender in which female had higher prevalence of absence of Palmaris Longus than male. CONCLUSIONS: In conclusion, the prevalence of absence of Palmaris Longus in Malay population was lower than Indian but higher than Chinese population. Females had higher prevalence of absence of Palmaris Longus and no association can be found with hand dominance and absence of Flexor Digitorum Superficialis tendon to little finger. PMID- 29117833 TI - Management of the Pediatric Patient Following Upper Extremity Replantation or Revascularization: A Suggested Protocol. AB - BACKGROUND: Traumatic pediatric amputations of the hand and upper extremity can have long-term financial, psychological, developmental, and functional consequences that readily extend beyond the realm of that which is normally encountered in comparatively injured adults. These factors, along with a paucity of medical comorbidities, have guided a more liberal and aggressive approach to treating pediatric amputations in hopes of optimizing psychosocial, aesthetic, and developmental outcomes. Furthermore, advances in pharmacology and microsurgical replantation techniques have allowed what were otherwise exceedingly rare surgeries to become commonplace in hospitals all over the world. Despite these gains, vascular thrombosis remains the leading cause of failure in microvascular surgeries. A recent survey showed that 96% of reconstructive surgeons use some form of anticoagulation therapy in their treatment, but no consensus regarding pharmacologic agents, dosing, or efficacy exists. The risk of thrombosis is further complicated by the dynamic nature of vasculature in response to stressors such as sympathetic tone, decreased intravascular volume, and response to external temperature. Given the lack of a higher-level evidence to guide the replantation surgeon in postoperative orders, we created an inclusive protocol, outlining complete and proper management of the pediatric patient following revascularization or replantation surgery. METHODS: We reviewed the methods employed by our microvascular surgeons and consulted with board certified pediatricians to produce a final document that was adopted ubiquitously among our providers. RESULTS: We do not have head-to-head data demonstrating improved outcomes with use of the protocol. Nonetheless, the original document has been modified and reproduced here for your consideration and use. CONCLUSIONS: Since initiating the protocol, we feel it has helped standardize our practice, avoid instances of incomplete or missed order sets, and facilitate interdisciplinary management through decreased gaps in communication, especially in those surgeries terminating in the middle of the night. PMID- 29117834 TI - Open Wedge Osteotomy with Ulnar Shortening for Madelung Deformity Using a Computer-Generated Template. AB - A variety of osteotomies have been reported to correct Madelung deformity using plain radiographs. However, evaluation of the deformity using 2-dimensional plain radiography is difficult because of its complex 3-dimensional nature. Therefore, we performed corrective osteotomy using recently developed 3D simulation technology on an adult woman with Madelung deformity, and achieved an excellent outcome. In this study, we calculated the amount of parallel displacement as well as the rotational angle for more precise correction, and performed open wedge osteotomy. Furthermore, we performed concurrent ulnar shortening. An exaggerated radial inclination was observed in the posteroanterior radiograph. A palmar shift of the carpus and dorsal dislocation of the ulnar head were observed in the lateral radiograph. In the preoperative findings, radial inclination (RI), volar tilt (VT), and ulnar variance (UV) were 35 degrees , 40 degrees , and 12 mm, respectively. The wrist showed improvement, with an RI of 25 degrees , VT of 14 degrees , and UV of 0 mm. At present, 14 months after surgery, there has been no loss of correction, instability of the ulnar head, or pain on the ulnar side. The procedure resulted in improvements in the protrusion and pain in the ulnar portion of the patient's wrist. Based on this result, we believe that accurate corrective osteotomy with ulnar shortening should be performed for Madelung deformity. PMID- 29117835 TI - Spontaneous Rupture of the Extensor Pollicis Longus with the Extensor Pollicis Brevis Deformity. AB - This paper examines three cases of spontaneous ruptures of the extensor pollicis longus (EPL) with the extensor pollicis brevis (EPB) deformity. The patients ranged from 39 to 71 years old. Non-dominant hands were involved in all three cases. There were no trauma nor pathological cause of EPL ruptures. A tendon transfer using the extensor indicis proprius was performed in each case. Intraoperative findings showed hypoplastic EPB in one case and EPB defects in two cases. A weak or defective EPB puts an excessive load on the EPL, which might be one of the causes of spontaneous EPL rupture. PMID- 29117837 TI - Extensor Digitorum Communis (EDC) Anchor and Interposition Arthroplasty for the Metacarpo-Phalangeal Joint (MCPJ). AB - Replacing a destroyed MCPJ has always been a challenge. Few operations have resulted in consistent satisfactory results. Also, anchoring a subluxed EDC tendon from the metacarpal head has produced numerous corrective procedures, again indicating the difficulty to keep the extensor tendon aligned. The EDC anchor and interposition arthroplasty procedure addresses both these challenging problems. PMID- 29117836 TI - Compressive Ulnar Neuropathy Caused by Olecranon Bursitis and Concomitant Epidermal Cyst: A Case Report. AB - Epidermal cyst is a dermal or subcutaneous epithelial cyst that contains keratin and is lined by true epidermis. Although extremely rare, it can cause pathology including nerve compression syndrome. We report a rare case of ulnar nerve compression in the elbow that was caused by olecranon bursitis and concomitant epidermal cyst in a 67-year-old man. The ulnar nerve was immediately adjacent to the olecranon bursa and was significantly compressed. There was no connection between the tumor and the ulnar nerve. Pain, numbness, and weakness in his ring and little fingers disappeared after resection of the cyst and bursa. PMID- 29117839 TI - Fight Bite Injuries: Aggressive Tendencies Associated with Smaller Second to Fourth Digit Ratio. AB - BACKGROUND: Fight bite injuries are typically sustained by young, combative males and are the direct consequence of an aggressive act. Second to fourth digit ratios (2D:4D) are dependent on prenatal androgen exposure and lower ratios have been shown to be linked to various psychological and physical traits, including aggression. The aim of this study was to examine the 2D:4D ratios in a cohort of patients with fight bite injuries and compare these to an age and gender-matched control group. METHODS: The 2D:4D ratios were calculated using plain films of the hand from 133 patients (122 males, 11 females) with fight bite injuries. A further 133 radiographs were obtained from patients that did not have fight bite injuries and digit ratios were calculated in the same fashion. Statistical analysis was then carried out to compare the 2D:4D ratios between the different groups. RESULTS: The 2D:4D ratios for male fight bite patients was significantly smaller than the male control group (p < 0.05). No significant difference was observed between the female fight bite patients and the female control group (p > 0.05). CONCLUSIONS: Fight bite injuries are usually sustained as a result of aggression. 2D:4D ratios are reflect intrauterine androgen exposure and low ratios have been linked to aggressive tendencies. We have demonstrated that male patients who sustained fight bite injuries have a lower 2D:4D ratio then the general population, thereby suggesting that exposure to prenatal androgens can lead to aggressive tendencies in adulthood. This suggests that lower ratios may predict a predisposition to acts of aggression, and as such result in an increased likelihood of sustaining an injury such as a fight bite. PMID- 29117838 TI - The 'Te' Technique for Restoring Fingertip Stability Post Traumatic Acro Osteolysis - A Report and Review of Management Options. AB - BACKGROUND: Fractures of the distal phalanx can result in bony non-union, resulting in acro-osteolysis and subsequent fingertip instability due to soft tissue dissociation from bone. Conventional methods of treating this involve osseous fixation, but do not address the laxity and lack of soft tissue stability with bone. Current techniques also do not address the management of such conditions if bony fragments are too small to reduce. We present a novel method that addresses both soft tissue and bony deformity in this condition. METHODS: A review of current techniques in the literature is provided as well as an in depth description of our technique using a representative case. RESULTS: Follow-up results and photographs are presented in this article. Functional assessment is also provided in the article as part of the follow-up. CONCLUSIONS: This technique is applicable for cases where severe resorption of distal phalanx has occurred, leaving little or no purchase for bony fixation. Hence, the technique can not only be applied post traumatic acro-osteolysis, but also other conditions where secondary soft tissue lengthening occurs and fingertip instability is formed as a result. PMID- 29117840 TI - Very Distal Radius Wedge Osteotomy for Kienbock's Disease: Case Series. AB - BACKGROUND: Radius osteotomy is one of the standard surgical procedures for the treatment of Kienbock's disease. Unfortunately, radius osteotomy can result in an incongruous distal radio-ulnar joint (DRUj) postoperatively, because the procedure is performed proximal to the DRUj. METHODS: A very distal radius wedge osteotomy was performed as a 15-degree lateral closing wedge osteotomy with the apex of the wedge distal to that of conventional lateral closing wedge osteotomy; this procedure was developed to avoid postoperative incongruous DRUj. We performed this procedure on 6 patients (stage III-A: 1, stage III-B: 5) with a mean age of 49 years. Clinical and radiographic evaluations were performed at a mean follow-up of 32 months. RESULTS: Wrist pain disappeared in all patients. Mean grip strength improved from 35% to 87% of the contralateral side (p = 0.0255). Mean range of motion, measured as flexion-extension arc, improved from 93 to 128 degrees. Nakamura's score was good in all patient. Mean lunate covering ratio increased from 61% to 90% (p = 0.0151) and mean sigmoid notch inclination angle, a radiographic parameter of DRUj congruency, was not significantly different between pre-operative and final follow-up evaluation. No clinical or radiographic DRUj osteoarthritis findings were observed. CONCLUSIONS: Our procedure of very distal radius wedge osteotomy provided satisfactory clinical results without an incongruous DRUj. This technique might prevent the occurrence of postoperative DRUj osteoarthritis. PMID- 29117841 TI - Metallic Mercury Injection in the Hand Caused by A Broken Mercury Thermometer: A Case Report. AB - Incorrect usage of or accidents related to metallic mercury can be hazardous. Herein, we present a case of subcutaneous metallic mercury injection in the hand caused by a broken thermometer and surgical tips for this injury. A 43-year-old female patient visited our hospital due to mercurial injection injury at the left hand suffered 4 weeks previously. On gross findings, the mercury deposition was limited to the subcutaneous layer and enveloped by granulation tissue. The blood mercury level, which had been abnormally elevated, fortunately decreased to within normal levels within five months. Nonetheless, this initial elevation indicates the possibility of systemic complications after local absorption of mercury droplets into the general circulation. In conclusion, we recommend prompt and complete excision of mercury material to prevent local and systemic complications, and excising the granulation tissue in its entirety, while retaining the mercury droplets within, is recommended. PMID- 29117842 TI - Distraction Arthroplasty in an Osteochondral Defect of the Middle Finger in a Juvenile Patient. AB - A 13-year-old female patient visited our hospital with a painful distal interphalangeal joint and deformity on her right middle finger. Initial plain radiographs uncovered ulnar-sided subluxation of the distal interphalangeal joint of the right middle finger, and an osteochondral defect was also noted at the articular surface of the distal and middle phalanges. We decided to attempt distraction arthroplasty with an external fixator. Finally postoperative 12-month follow-up plain radiographs showed complete osteochondral regeneration and phalangeal alignment. To our knowledge, this is the first report to assess the use of a distraction arthroplasty concept for treating an osteochondral defect in the finger. PMID- 29117843 TI - Outcome of Hook Plate Fixation of Mallet Fractures. AB - BACKGROUND: Hook plate fixation of closed mallet fractures was first described in 2007, but there has subsequently been a lack of studies examining the outcomes and complications of this technique. METHODS: This paper aims to assess the clinical outcomes of hook plate fixation of closed mallet fractures by retrospectively reviewing 31 closed, bony mallet injuries that were surgically fixed with a hook plate between 2002-2011. RESULTS: Patients who underwent hook plate fixation had a median time to radiographic union of 83 days. Pre-operative median distal interphalangeal joint (DIPJ) extensor lag was 20 degrees , with a post-operative extensor lag of 0 degrees . Median DIPJ flexion was 60 degrees , with 58% of all cases achieving greater than 50 degrees of DIPJ flexion. There were 4 instances of minor complications (i.e. transient nail deformity and marginal skin flap ischaemia), with 3 cases of major complications (i.e. fracture redisplacement). CONCLUSIONS: Our results show that the hook plate technique has satisfactory functional outcomes and an acceptable complications rate compared to other treatment modalities in the existing literature. Nevertheless, the outcomes of this technique in our sample population were not as excellent as initially reported. LEVEL OF EVIDENCE: Level IV: Retrospective case series, Therapeutic Studies. PMID- 29117844 TI - Early Results of the ARPE Arthroplasty Versus Trapeziectomy for the Treatment of Thumb Carpometacarpal Joint Osteoarthritis. AB - BACKGROUND: Thumb carpometacarpal joint arthroplasty for osteoarthritis may hold advantages over trapeziectomy by preserving range of motion, whilst providing stability and preventing thumb shortening. METHODS: We compare functional and satisfaction outcomes scores, radiological shortening and complication rates between patients treated with trapeziectomy and those receiving the ARPE thumb CMCJ arthroplasty. RESULTS: Seventy-five trapeziectomies and one hundred and ten ARPE arthroplasties were performed over the study period. Both treatments resulted in significant improvements in functional scores. When matching patients according to pre-operative function, patients receiving the ARPE arthroplasty had better post-operative function (Quick DASH: trapeziectomy = 25.1, ARPE = 16.8). More patients receiving the ARPE arthroplasty were satisfied with their treatment (trapeziectomy = 7.8/10, ARPE = 8.7/10) and would have the same treatment again (trapeziectomy = 76%, ARPE = 89%). The ARPE also resulted in less thumb shortening. However the ARPE arthroplasty is associated with a higher complication rate, with 14% of patients requiring further surgery at a mean of 2 years follow up (95% implant survival). CONCLUSIONS: Both trapeziectomy and the ARPE CMCJ arthroplasty are effective treatment options for thumb CMCJ osteoarthritis. Arthroplasty may offer potential advantages in terms of post operative function and patient satisfaction. However the risk of complications and requirement for further surgery is greater and must be carefully considered during patient selection and pre-operative counselling. PMID- 29117845 TI - Restoration of the Active Forearm Rotation Using Vascularized Free Fibular Graft and Radial Head Arthroplasty for a Wide Defect of the Proximal Radius. AB - In this report we present a case of re-stabilization of the proximal radius using vascularized free fibular graft combined with anconeus arthroplasty to stabilize the transplanted fibula in a patient with large loss of the proximal radius due to Ewing's sarcoma. A 20-year-old woman had Ewing's sarcoma in the proximal three fourths of the radius. The resection of large part of the radius containing radial head were necessary for removal of the sarcoma. Reconstruction of the proximal radius was performed using vascularized free fibular graft and the transplanted fibula was stabilized by attaching the anconeus to the proximal edge of the fibula. 2 years after surgery, she had neither recurrence nor metastasis, and achieved functional recovery. The combination anconeus arthroplasty with vascularized free fibular graft can be a good technique for re-stabilization of the elbow and recovery of the forearm function. PMID- 29117846 TI - Lunotriquetral Ligament Reconstruction Utilizing a Palmaris Longus Autograft. AB - Injury to the lunotriquetral ligament can result in midcarpal instability, with resultant alterations in normal wrist kinematics and subsequent arthrosis. We performed a previously undescribed technique of lunotriquetral ligament reconstruction in two patients utilizing a palmaris longus tendon autograft. Average age at presentation was 24 years old with a mean follow up of 10 months. Average range of motion was 62.5 degrees of flexion and 57.5 degrees of extension. Total arc of motion was 83% of the contralateral uninvolved extremity. Average grip strength was 31 kg which was 91% of the contralateral extremity. Average Quick Disability of Arm, Shoulder and Hand score was 12.5 and Modern Activity Subjective Survey of 2007 was 1.5. No complications were noted. PMID- 29117848 TI - We Thank Our Reviewers. PMID- 29117847 TI - The Impact of School Visits on Siblings of Children With Cancer. AB - BACKGROUND: Childhood cancer affects the entire family. Siblings experience similar stress to that of the ill child, including anger, depression, jealousy, guilt, and social isolation. School reentry programs are shown to be positive interventions for patients, it is hypothesized that similar outcomes exist for siblings. OBJECTIVE: To examine the feasibility of studying the impact of the Ontario Oncology Nurse School Visitation Program on the well-being and school adjustment of siblings of pediatric cancer patients. METHODS: Fourteen sibling participants and parents completed a semistructured interview and the PedsQL(r) questionnaire before and after a nurse school visit. School attendance was also compared and data were collected for logistics of study procedures. RESULTS: The mode of data collection was agreeable and easy to plan and execute. School attendance showed a reduction of days missed; there was no significant impact on PedsQL results but the interviews yielded positive feedback. CONCLUSIONS: The outlook for siblings improves with the support of family members and health care professionals. This pilot study provides hypotheses and design for future research. PMID- 29117849 TI - Seeking Ways to Inform the Uninformed: Improving the Informed Consent Process in Online Social Science Research. AB - Participants often do not read consent forms in social science research. This is not surprising, especially for online studies, given they do not typically offer greater risk than what is encountered in daily life. However, if no one is reading, are participants really informed? This study used previous research to craft experimentally manipulated consent forms utilizing different visual presentations (e.g., greater use of line spacing, bullets, bolding, diagrams). Participants ( n = 547) were randomly exposed to one of seven form variations. Results found no significant differences between forms in reading or comprehension. Open-ended questions asked participants why they do not read consent forms and what would influence them to read the forms. Participants most frequently stated forms need to be shorter, and important information needs to be highlighted. We suggest improvements to informed consent forms, including removing much of the information that is constant across forms, and only including unique aspects of studies. PMID- 29117850 TI - A stochastic estimation procedure for intermittently-observed semi-Markov multistate models with back transitions. AB - Multistate models provide an important method for analyzing a wide range of life history processes including disease progression and patient recovery following medical intervention. Panel data consisting of the states occupied by an individual at a series of discrete time points are often used to estimate transition intensities of the underlying continuous-time process. When transition intensities depend on the time elapsed in the current state and back transitions between states are possible, this intermittent observation process presents difficulties in estimation due to intractability of the likelihood function. In this manuscript, we present an iterative stochastic expectation-maximization algorithm that relies on a simulation-based approximation to the likelihood function and implement this algorithm using rejection sampling. In a simulation study, we demonstrate the feasibility and performance of the proposed procedure. We then demonstrate application of the algorithm to a study of dementia, the Nun Study, consisting of intermittently-observed elderly subjects in one of four possible states corresponding to intact cognition, impaired cognition, dementia, and death. We show that the proposed stochastic expectation-maximization algorithm substantially reduces bias in model parameter estimates compared to an alternative approach used in the literature, minimal path estimation. We conclude that in estimating intermittently observed semi-Markov models, the proposed approach is a computationally feasible and accurate estimation procedure that leads to substantial improvements in back transition estimates. PMID- 29117851 TI - Estimating individual benefits of medical or behavioral treatments in severely ill patients. AB - There is a need for statistical methods appropriate for the analysis of clinical trials from a personalized-medicine viewpoint as opposed to the common statistical practice that simply examines average treatment effects. This article proposes an approach to quantifying, reporting and analyzing individual benefits of medical or behavioral treatments to severely ill patients with chronic conditions, using data from clinical trials. The approach is a new development of a published framework for measuring the severity of a chronic disease and the benefits treatments provide to individuals, which utilizes regression models with random coefficients. Here, a patient is considered to be severely ill if the patient's basal severity is close to one. This allows the derivation of a very flexible family of probability distributions of individual benefits that depend on treatment duration and the covariates included in the regression model. Our approach may enrich the statistical analysis of clinical trials of severely ill patients because it allows investigating the probability distribution of individual benefits in the patient population and the variables that influence it, and we can also measure the benefits achieved in specific patients including new patients. We illustrate our approach using data from a clinical trial of the anti-depressant imipramine. PMID- 29117852 TI - The resignation of Sir William Charles Ellis. AB - Sir William Ellis (1780-1839) was superintendent of the West Riding Pauper Lunatic Asylum and Hanwell Asylum. He was a practitioner of moral therapy and non restraint. He added his own religious aspects to his treatment based on his personal experiences. These interventions were novel and benefitted his patients. However, he is less well known in the present day than his contemporaries who also championed non-restraint. In 1838, he left Hanwell Asylum, as he disagreed with plans to expand patient capacity. The resurgence of Whig politics at the time also played its part in his resignation. Ellis died one year later, his contributions to modern psychiatry remaining in relative obscurity. This paper seeks to shed light on Ellis and analyse his resignation as an example of how politics can affect healthcare. PMID- 29117853 TI - Lest we forget: Captain Noel Chavasse (1884-1917) VC and Bar, MC, RAMC. PMID- 29117854 TI - Nodal Factors Predictive of Recurrence After Thyroidectomy and Neck Dissection for Papillary Thyroid Carcinoma. AB - BACKGROUND: Lymph node (LN) yield and ratio are considered important predictors of post-treatment outcomes for several human cancers. This study examined the association between nodal factors, including the LN yield and ratio, with recurrence after thyroidectomy plus central compartment neck dissection (ND) for papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: This retrospective study involved 2384 consecutive patients who underwent a thyroidectomy plus central compartment ND combined with (n = 440) or without lateral compartment ND at the authors' tertiary referral center between 2006 and 2012. The number of harvested LNs, as well as other tumor and nodal findings, were carefully reviewed. Univariable and multivariable Cox proportional hazards regression models were conducted to predict recurrence and its association with clinicopathologic variables. RESULTS: All nodal factors, including the positive number of LNs, ratio, and extranodal extension, were significantly associated with nodal and any-site recurrence after thyroidectomy, as well as the tumor size and multifocality (p < 0.01). The multivariable analysis showed that tumor size, multifocality, LN ratio, and extranodal extension were independent factors predictive of post-treatment recurrence (p < 0.05). The LN yield was higher in patients with nodal recurrence but did not significantly affect the nodal recurrence. Patients with a LN ratio >0.3 exhibited a 1.7-fold higher risk of post-treatment nodal recurrence than their counterparts (p < 0.01). CONCLUSIONS: LN ratio is an independent determinant predictive of nodal and any-site recurrence following thyroidectomy for PTC. PMID- 29117855 TI - Evaluating Effective Leadership and Governance in a Midwestern Agricultural Safety and Health Coalition. AB - Agricultural Centers are a coalition of organizations and individual members with a common purpose: to improve the health and safety of the agricultural community. Successful leadership and governance are essential in accomplishing these goals. This article examined the effectiveness of a midwestern Agricultural Health and Safety Center (Ag Center) leadership and governance structure. The Internal Coalition Outcomes Hierarchy (ICOH) framework and the Internal Coalition Effectiveness (ICE(c)) instrument were used, with field visit interviews conducted to gain further insight. Combined comparative findings from both research methods showed that scores in each of the categories increased. Adjustments led to stronger collaborative leadership, vital to successful population health improvement programs. This study showcases coalition qualities in a broader environment, capturing a clearer depiction of leadership and member interaction. Field visit interviews confirmed that this midwestern Ag Center continued to have strong levels of effectiveness in each of the conceptual constructs of a coalition. PMID- 29117856 TI - Conference Diary. PMID- 29117857 TI - Editorial: Multiple Myeloma Immunotherapies. PMID- 29117858 TI - Measuring improvement in knowledge of drug policy reforms following a police education program in Tijuana, Mexico. AB - BACKGROUND: Mexico's 2009 "narcomenudeo reform" decriminalized small amounts of drugs, shifting some drug law enforcement to the states and mandating drug treatment diversion instead of incarceration. Data from Tijuana suggested limited implementation of this harm reduction-oriented policy. We studied whether a police education program (PEP) improved officers' drug and syringe policy knowledge, and aimed to identify participant characteristics associated with improvement of drug policy knowledge. METHODS: Pre- and post-training surveys were self-administered by municipal police officers to measure legal knowledge. Training impact was assessed through matched paired nominal data using McNemar's tests. Multivariable logistic regression was used to identify predictors of improved legal knowledge, as measured by officers' ability to identify conceptual legal provisions related to syringe possession and thresholds of drugs covered under the reform. RESULTS: Of 1750 respondents comparing pre- versus post training, officers reported significant improvement (p < 0.001) in their technical understanding of syringe possession (56 to 91%) and drug amounts decriminalized, including marijuana (9 to 52%), heroin (8 to 71%), and methamphetamine (7 to 70%). The training was associated with even greater success in improving conceptual legal knowledge for syringe possession (67 to 96%) (p < 0.001), marijuana (16 to 91%), heroin (11 to 91%), and methamphetamine (11 to 89%). In multivariable modeling, those with at least a high school education were more likely to exhibit improvement of conceptual legal knowledge of syringe possession (adjusted odds ratio [aOR] 2.6, 95% CI 1.4-3.2) and decriminalization for heroin (aOR 2.7, 95% CI 1.3-4.3), methamphetamine (aOR 2.2, 95% CI 1.4-3.2), and marijuana (aOR 2.5, 95% CI 1.6-4). CONCLUSIONS: Drug policy reform is often necessary, but not sufficient to achieve public health goals because of gaps in translating formal laws to policing practice. To close such gaps, PEP initiatives bundling occupational safety information with relevant legal content demonstrate clear promise. Our findings underscore additional efforts needed to raise technical knowledge of the law among personnel tasked with its enforcement. Police professionalization, including minimum educational standards, appear critical for aligning policing with harm reduction goals. PMID- 29117861 TI - Correction to: "Non alcoholic fatty liver disease and eNOS dysfunction in humans". AB - After publication of the original article [1], it was noticed that one of the affiliations of author Carmine Vecchione was missing. PMID- 29117859 TI - A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D-culture methods for hepatocellular carcinoma. AB - BACKGROUND: Patients suffering from advanced stage hepatocellular carcinoma (HCC) often exhibit a poor prognosis or dismal clinical outcomes due to ineffective chemotherapy or a multi-drug resistance (MDR) process. Thus, it is urgent to develop a new chemotherapeutic sensitivity testing system for HCC treatment. The presence study investigated the potential application of a novel chemotherapeutic sensitivity-testing system based on a collagen gel droplet embedded 3D-culture system (CD-DST). METHODS: Primary cells were separating from surgical resection specimens and then tested by CD-DST. To identify whether HCC cell lines or cells separating from clinical specimens contain MDR features, the cells were treated with an IC 50 (half maximal inhibitory concentration) or IC max (maximal inhibitory concentration) concentration of antitumor agents, e.g., 5 furuolouracil (5-FU), paclitaxel (PAC), cisplatin (CDDP), epirubicin (EPI), or oxaliplatin (L-OHP), and the inhibitory rates (IRs) were calculated. RESULTS: HepG2 cells were sensitive to 5-FU, PAC, CDDP, EPI, or L-OHP; the IC 50 value is 0.83 +/- 0.45 MUg/ml, 0.03 +/- 0.02 MUg/ml, 1.15 +/- 0.75 MUg/ml, 0.09 +/- 0.03 MUg/ml, or 1.76 +/- 0.44 MUg/ml, respectively. Only eight (8/26), nine (9/26), or five (5/26) patients were sensitive to the IC max concentration of CDDP, EPI, or L-OHP; whereas only three (3/26), four (4/26), or two (2/26) patients were sensitive to the IC 50 concentration of CDDP, EPI, or L-OHP. No patients were sensitive to 5-FU or PAC. CONCLUSIONS: The in vitro drug sensitivity exanimation revealed the MDR features of HCC and examined the sensitivity of HCC cells from clinical specimens to anti-tumor agents. CD-DST may be a useful method to predict the potential clinical benefits of anticancer agents for HCC patients. PMID- 29117860 TI - Erv1 of Arabidopsis thaliana can directly oxidize mitochondrial intermembrane space proteins in the absence of redox-active Mia40. AB - BACKGROUND: Many proteins of the mitochondrial intermembrane space (IMS) contain structural disulfide bonds formed by the mitochondrial disulfide relay. In fungi and animals, the sulfhydryl oxidase Erv1 'generates' disulfide bonds that are passed on to the oxidoreductase Mia40, which oxidizes substrate proteins. A different structural organization of plant Erv1 proteins compared to that of animal and fungal orthologs was proposed to explain its inability to complement the corresponding yeast mutant. RESULTS: Herein, we have revisited the biochemical and functional properties of Arabidopsis thaliana Erv1 by both in vitro reconstituted activity assays and complementation of erv1 and mia40 yeast mutants. These mutants were viable, however, they showed severe defects in the biogenesis of IMS proteins. The plant Erv1 was unable to oxidize yeast Mia40 and rather even blocked its activity. Nevertheless, it was able to mediate the import and folding of mitochondrial proteins. CONCLUSIONS: We observed that plant Erv1, unlike its homologs in fungi and animals, can promote protein import and oxidative protein folding in the IMS independently of the oxidoreductase Mia40. In accordance to the absence of Mia40 in many protists, our study suggests that the mitochondrial disulfide relay evolved in a stepwise reaction from an Erv1 only system to which Mia40 was added in order to improve substrate specificity. Graphical Abstract The mitochondrial disulfide relay evolved in a step-wise manner from an Erv1-only system. PMID- 29117862 TI - Successful medical management of acute mesenteric ischemia due to superior mesenteric and portal vein thrombosis in a 27-year-old man with protein S deficiency: a case report. AB - BACKGROUND: Acute mesenteric ischemia poses a diagnostic challenge due to nonspecific clinical clues and lack of awareness owing to its rarity. Ischemia due to mesenteric venous thrombosis has a good prognosis compared to arterial cause and can be managed conservatively with early diagnosis. The portomesenteric venous system is an unusual site of thrombosis in patients with protein S deficiency, and its thrombosis is an uncommon cause of acute mesenteric ischemia. CASE PRESENTATION: We present a case of a 27-year-old Mongolian man who presented with acute abdominal pain increasing in severity, and refractory to repeated attempts at treatment with a misdiagnosis of acute peptic ulcer disease. Contrast enhanced computed tomography of his abdomen detected complete occlusion of the superior mesenteric vein, an extension of acute thrombus into the portal vein, and ischemic mid-jejunal loops. Early diagnosis and immediate anticoagulation with continuous intravenous infusion of unfractionated heparin prevented subsequent consequences. On further workup, our patient was diagnosed with isolated protein S deficiency. We started lifelong thromboprophylaxis with warfarin to prevent recurrence and our patient was asymptomatic on the latest follow-up 5 months after discharge. CONCLUSION: Despite accurate detection of acute mesenteric ischemia by contrast-enhanced computed tomography, high index of suspicion is indispensable for its early diagnosis. Early diagnosis and immediate anticoagulation will prevent subsequent complications and need for surgical intervention. Young patients without known risk factors presenting with venous thrombosis in atypical sites should be investigated for prothrombotic diseases. PMID- 29117864 TI - Correction to: Ideas, actors and institutions: lessons from South Australian Health in All Policies on what encourages other sectors' involvement. AB - After publication of the article [1], it has been brought to our attention that Table 1 has been formatted poorly in the original version so that the columns are not aligned with their corresponding information. The correct version of the table is presented below. The original version of the article has now been revised. PMID- 29117865 TI - Correction to: Improved plan quality with automated radiotherapy planning for whole brain with hippocampus sparing: a comparison to the RTOG 0933 trial. AB - In the original publication [1] figure legends 2 and 4 have been swapped. The original article was updated to rectify this error. PMID- 29117863 TI - RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. AB - BACKGROUND: TRIM25 is a novel RNA-binding protein and a member of the Tripartite Motif (TRIM) family of E3 ubiquitin ligases, which plays a pivotal role in the innate immune response. However, there is scarce knowledge about its RNA-related roles in cell biology. Furthermore, its RNA-binding domain has not been characterized. RESULTS: Here, we reveal that the RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain, which we postulate to be a novel RNA-binding domain. Using CLIP-seq and SILAC-based co-immunoprecipitation assays, we uncover TRIM25's endogenous RNA targets and protein binding partners. We demonstrate that TRIM25 controls the levels of Zinc Finger Antiviral Protein (ZAP). Finally, we show that the RNA-binding activity of TRIM25 is important for its ubiquitin ligase activity towards itself (autoubiquitination) and its physiologically relevant target ZAP. CONCLUSIONS: Our results suggest that many other proteins with the PRY/SPRY domain could have yet uncharacterized RNA-binding potential. Together, our data reveal new insights into the molecular roles and characteristics of RNA-binding E3 ubiquitin ligases and demonstrate that RNA could be an essential factor in their enzymatic activity. PMID- 29117866 TI - Ambulatory systolic blood pressure and obesity are independently associated with left ventricular hypertrophic remodeling in children. AB - BACKGROUND: Children with obesity have hypertrophic cardiac remodeling. Hypertension is common in pediatric obesity, and may independently contribute to hypertrophy. We hypothesized that both the degree of obesity and ambulatory blood pressure (ABP) would independently associate with measures of hypertrophic cardiac remodeling in children. METHODS: Children, aged 8-17 years, prospectively underwent cardiovascular magnetic resonance (CMR) and ABP monitoring. Left ventricular (LV) mass indexed to height2.7 (LVMI), myocardial thickness and end diastolic volume were quantified from a 3D LV model reconstructed from cine balanced steady state free precession images. Categories of remodeling were determined based on cutoff values for LVMI and mass/volume. Principal component analysis was used to define a "hypertrophy score" to study the continuous relationship between concentric hypertrophy and ABP. RESULTS: Seventy-two children were recruited, and 68 of those (37 healthy weight and 31 obese/overweight) completed both CMR and ABP monitoring. Obese/overweight children had increased LVMI (27 +/- 4 vs 22 +/- 3 g/m2.7, p < 0.001), myocardial thickness (5.6 +/- 0.9 vs 4.9 +/- 0.7 mm, p < 0.001), mass/volume (0.69 +/- 0.1 vs 0.61 +/- 0.06, p < 0.001), and hypertrophy score (1.1 +/- 2.2 vs -0.96 +/- 1.1, p < 0.001). Thirty-five percent of obese/overweight children had concentric hypertrophy. Ambulatory hypertension was observed in 26% of the obese/overweight children and none of the controls while masked hypertension was observed in 32% of the obese/overweight children and 16% of the controls. Univariate linear regression showed that BMI z-score, systolic BP (24 h, day and night), and systolic load correlated with LVMI, thickness, mass/volume and hypertrophy score, while 24 h and nighttime diastolic BP and load also correlated with thickness and mass/volume. Multivariate analysis showed body mass index z-score and systolic blood pressure were both independently associated with left ventricular mass index (beta=0.54 [p < 0.001] and 0.22 [p = 0.03]), thickness (beta=0.34 [p < 0.001] and 0.26 [p = 0.001]) and hypertrophy score (beta=0.47 and 0.36, both p < 0.001). CONCLUSIONS: In children, both the degree of obesity and ambulatory blood pressures are independently associated with measures of cardiac hypertrophic remodeling, however the correlations were generally stronger for the degree of obesity. This suggests that interventions targeted at weight loss or obesity associated co-morbidities including hypertension may be effective in reversing or preventing cardiac remodeling in obese children. PMID- 29117867 TI - Epicardial left ventricular leads via minimally invasive technique: a role of steroid eluting leads. AB - BACKGROUND: We retrospectively assessed two types of sutureless screw-in left ventricular (LV) leads (steroid eluting vs. non-steroid eluting) in cardiac resynchronization therapy (CRT) implantation with regards to their electrical performance. METHODS: Between March 2008 and May 2014 an epicardial LV lead was implanted in 32 patients after failed transvenous LV lead placement using a left sided lateral minithoracotomy or video-assisted thoracoscopy (mean age 64 +/- 9 years). Patients were divided into two groups according to the type of implanted lead. Steroid eluting (SE) group: 21 patients (MyodexTM 1084 T; St. Jude Medical) and non-steroid eluting (NSE) group: 11 patients (MyoPore(r) 511,212; Greatbatch Medical). RESULTS: All epicardial leads could be placed successfully, without any intraoperative complications or mortality. With regard to the implanted lead following results were observed: sensing (mV): SE 8.8 +/- 6.1 vs. NSE 10.1 +/- 5.3 (p = 0.380); pacing threshold (V@0.5 ms): SE 1.0 +/- 0.5 vs. NSE 0.9 +/- 0.5 (p = 0.668); impedance (ohms): SE 687 +/- 236 vs. NSE 790 +/- 331 (p = 0.162). At the follow-up (2.6 +/- 1.9 years) the following results were seen: sensing (mV): SE 8.7 +/- 5.0 vs. NSE 11.2 +/- 6.6 (p = 0.241), pacing threshold (V@0.5 ms): SE 1.4 +/- 0.5 vs. NSE 1.0 +/- 0.3 (p = 0.035), impedance (ohms): SE 381 +/- 95 vs. NSE 434 +/- 88 (p = 0.129). CONCLUSIONS: Based on the results no strong differences have been found between the both types of epicardial LV leads (steroid eluting vs. non-steroid eluting) in CRT implantation in short- and midterm. PMID- 29117868 TI - Correction to: Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis. AB - Upon publication of the original article [1], it was noted that references 11 and 22 were miscited in the reference list. PMID- 29117869 TI - Frequency of use of the International Classification of Diseases ICD-10 diagnostic categories for mental and behavioural disorders across world regions. AB - AIMS: The study aimed to examine variations in the use of International Classification of Diseases, Tenth Edition (ICD-10) diagnostic categories for mental and behavioural disorders across countries, regions and income levels using data from the online World Psychiatric Association (WPA)-World Health Organization (WHO) Global Survey that examined the attitudes of psychiatrists towards the classification of mental disorders. METHODS: A survey was sent to 46 psychiatric societies which are members of WPA. A total of 4887 psychiatrists participated in the survey, which asked about their use of classification, their preferred system and the categories that were used most frequently. RESULTS: The majority (70.1%) of participating psychiatrists (out of 4887 psychiatrists) reported using the ICD-10 the most and using at least one diagnostic category once a week. Nine out of 44 diagnostic categories were considerably variable in terms of frequency of use across countries. These were: emotionally unstable personality disorder, borderline type; dissociative (conversion) disorder; somatoform disorders; obsessive-compulsive disorder (OCD); mental and behavioural disorders due to the use of alcohol; adjustment disorder; mental and behavioural disorders due to the use of cannabinoids; dementia in Alzheimer's disease; and acute and transient psychotic disorder. The frequency of use for these nine categories was examined across WHO regions and income levels. The most striking differences across WHO regions were found for five out of these nine categories. For dissociative (conversion) disorder, use was highest for the WHO Eastern Mediterranean Region (EMRO) and non-existent for the WHO African Region. For mental and behavioural disorders due to the use of alcohol, use was lowest for EMRO. For mental and behavioural disorders due to the use of cannabinoids, use was lowest for the WHO European Region and the WHO Western Pacific Region. For OCD and somatoform disorders, use was lowest for EMRO and the WHO Southeast Asian Region. Differences in the frequency of use across income levels were statistically significant for all categories except for mental and behavioural disorders due to the use of alcohol. The most striking variations were found for acute and transient psychotic disorder, which was reported to be more commonly used among psychiatrists from countries with lower income levels. CONCLUSIONS: The differences in frequency of use reported in the current study show that cross cultural variations in psychiatric practice exist. However, whether these differences are due to the variations in prevalence, treatment-seeking behaviour and other factors, such as psychiatrist and patient characteristics as a result of culture, cannot be determined based on the findings of the study. Further research is needed to examine whether these variations are culturally determined and how that would affect the cross-cultural applicability of ICD-10 diagnostic categories. PMID- 29117870 TI - Is there enough "interest in and pleasure in" the concept of depression? The development of the Leuven Affect and Pleasure Scale (LAPS). AB - OBJECTIVE: Presence of negative mood (depressed mood) and anhedonia (lack of interest and pleasure) are considered core symptoms of depression, while absence of positive mood is not taken into account. It is therefore remarkable that the depression scales routinely used to assess changes during antidepressant treatment (Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS]) do not really take into account anhedonia. Several scales were developed to assess positive mood and hedonic tone, but they only partially cover the multidimensional concept. Therefore we developed a new 16-item questionnaire, the Leuven Affect and Pleasure Scale (LAPS), to assess negative affect, positive affect, and hedonic tone. METHODS: This first article on the LAPS questionnaire reports on the correlations between the different items, on the factor analysis, and on the differences found in 3 groups of subjects : healthy college students (N=138), depressed but still functioning college students (N=27), and severely depressed inpatients (N=38). These differences were calculated using univariate general linear models with Bonferroni post-hoc testing, and effect sizes were expressed in eta2. RESULTS: Negative and positive affect were only moderately correlated, and the 4 independent variables (cognitive functioning, overall functioning, meaningful life, and happiness) had stronger correlations with positive affect than with negative affect. The major difference in negative affect was between healthy college students and depressed college students, positive affect was different between the 3 groups, and the major difference for hedonic tone was between depressed college students and depressed inpatients. Affiliative positive affect and the affiliative hedonic function were well preserved, even in depressed inpatients. CONCLUSIONS: This preliminary report suggests that the LAPS offers a comprehensive assessment of negative and positive affect, of hedonic tone, and of independent variables (cognitive functioning, overall functioning, meaningful life, and happiness). Clinically relevant differences in subscores were found in 3 groups of subjects with variable levels of depression (healthy subjects, mildly depressed subjects, and severely depressed inpatients). PMID- 29117871 TI - Language difficulties and internalizing problems: Bidirectional associations from 18 months to 8 years among boys and girls. AB - Studies have shown that early language difficulties are associated with later internalizing problems. Less is known about the nature of the association: the bidirectional relationship over time, the role of different types of language difficulties, and gender differences. The present study examined bidirectional longitudinal associations between parent-rated language difficulties and internalizing problems in a four-wave cross-lagged model from 18 months to 8 years. Data from the Norwegian Mother and Child Cohort Study were used (N = 114,000). Gender-specific dichotomized language variables were created, and associations were investigated uniquely for boys and girls. Logistic regression analyses showed that all cross-lagged associations from 18 months to 5 years were significant for girls (odds ratios [ORs] = 1.48-1.94). For boys, only internalizing problems at 3 years predicted change in language difficulties (OR = 2.33). From 5 to 8 years, the cross-lagged associations between semantic language difficulties and internalizing problems were significant and strong for girls (ORs = 1.92-2.97) and nonsignificant for boys. The results suggest that the associations between language difficulties and internalizing problems are bidirectional from an early age, and that girls are especially vulnerable for developing co-occurring language difficulties and internalizing problems during the years of transition to school. PMID- 29117872 TI - How do drugs for psychiatric disorders work? PMID- 29117873 TI - Implementation of an emergency department atrial fibrillation and flutter pathway improves rates of appropriate anticoagulation, reduces length of stay and thirty day revisit rates for congestive heart failure. AB - OBJECTIVES: An evidence-based emergency department (ED) atrial fibrillation and flutter (AFF) pathway was developed to improve care. The primary objective was to measure rates of new anticoagulation (AC) on ED discharge for AFF patients who were not AC correctly upon presentation. METHODS: This is a pre-post evaluation from April to December 2013 measuring the impact of our pathway on rates of new AC and other performance measures in patients with uncomplicated AFF solely managed by emergency physicians. A standardized chart review identified demographics, comorbidities, and ED treatments. The primary outcome was the rate of new AC. Secondary outcomes were ED length of stay (LOS), referrals to AFF clinic, ED revisit rates, and 30-day rates of return visits for congestive heart failure (CHF), stroke, major bleeding, and death. RESULTS: ED AFF patients totalling 301 (129 pre-pathway [PRE]; 172 post-pathway [POST]) were included; baseline demographics were similar between groups. The rates of AC at ED presentation were 18.6% (PRE) and 19.7% (POST). The rates of new AC on ED discharge were 48.6 % PRE (95% confidence interval [CI] 42.1%-55.1%) and 70.2% POST (62.1%-78.3%) (20.6% [p<0.01; 15.1-26.3]). Median ED LOS decreased from 262 to 218 minutes (44 minutes [p<0.03; 36.2-51.8]). Thirty-day rates of ED revisits for CHF decreased from 13.2% to 2.3% (10.9%; p<0.01; 8.1%-13.7%), and rates of other measures were similar. CONCLUSIONS: The evidence-based pathway led to an improvement in the rate of patients with new AC upon discharge, a reduction in ED LOS, and decreased revisit rates for CHF. PMID- 29117875 TI - Intradural Hematoma and Arachnoid Cyst Following Lumbar Spinal Surgery: A Case Report. PMID- 29117874 TI - Estimated incidence and number of outpatient visits for seasonal influenza in 2015-2016 in Beijing, China. AB - Information on morbidity burden of seasonal influenza in China is limited. A multiplier model was used to estimate the incidence and number of outpatient visits for seasonal influenza by age group for the 2015-2016 season in Beijing, the capital of China, based on reported numbers of influenza-like illness consultations and proportions of positive cases from influenza surveillance systems in Beijing, general consultation rates and other parameters from previous studies, surveys and surveillance systems. An estimated total of 1 190 200 (95% confidence interval (CI) 830 400-1 549 900) cases of influenza virus infections occurred in Beijing, 2015-2016 season, with an attack rate of 5.5% (95% CI 3.9 7.2%). These infections resulted in an estimated 468 280 (95% CI 70 700-606 800) outpatient visits, with an attack rate of 2.2% (95% CI 0.3-2.8%). The attack rate of influenza virus infections was highest among children aged 0-4 years (31.9% (95% CI 21.9-41.9%)), followed by children aged 5-14 years (18.7% (95% CI 12.9 24.5%)). Our study demonstrated a substantial influenza-related morbidity in Beijing, China, especially among the preschool- and school-aged children. This suggests that development or modification of seasonal influenza targeted vaccination strategies need to recognize that incidence is highest in children. PMID- 29117876 TI - The role of gender and anxiety in the association between somatic diseases and depression: findings from three combined epidemiological studies in primary care. AB - AIMS: Although associations between various somatic diseases and depression are well established, findings concerning the role of gender and anxiety disorders for these associations remain fragmented and partly inconsistent. Combining data from three large-scaled epidemiological studies in primary care, we aim to investigate interactions of somatic diseases with gender and anxiety disorders in the association with depression. METHODS: Self-reported depression according to the International Classification of Diseases, Tenth Edition (ICD-10) was assessed in n = 83 737 patients from three independent studies [DETECT (Diabetes Cardiovascular Risk Evaluation: Targets and Essential Data for Commitment of Treatment), Depression-2000 and Generalized Anxiety and Depression in Primary Care (GAD-P)] using the Depression Screening Questionnaire (DSQ). Diagnoses of depression, anxiety disorders and somatic diseases were obtained from treating physicians via standardised clinical appraisal forms. RESULTS: In logistic regressions, adjusted for gender, age group and study, each somatic disease except for arterial hypertension and endocrine diseases was associated with self reported depression (odds ratio, OR 1.3-2.6) and each somatic disease was associated with physician-diagnosed depression (OR 1.1-2.4). Most of these associations remained significant after additional adjustment for anxiety disorders and other somatic diseases. The associations with depression increased with a higher number of somatic diseases. Cardiovascular diseases (OR 0.8), diabetes mellitus (OR 0.8) and neurological diseases (OR 0.8) interacted with gender in the association with self-reported depression, while endocrine diseases (OR 0.8) interacted with gender in the association with physician-diagnosed depression. That is, the associations between respective somatic diseases and depression were less pronounced in females v. males. Moreover, cardiovascular diseases (OR 0.7), arterial hypertension (OR 0.8), gastrointestinal diseases (OR 0.7) and neurological diseases (OR 0.6) interacted with anxiety disorders in the association with self-reported depression, and each somatic disease interacted with anxiety disorders in the association with physician-diagnosed depression (OR 0.6-0.8). That is, the associations between respective somatic diseases and depression were less pronounced in patients with v. without anxiety disorders; arterial hypertension was negatively associated with self-reported depression only in patients with anxiety disorders, but not in patients without anxiety disorders. CONCLUSIONS: A range of somatic diseases as well as anxiety disorders are linked to depression - and especially patients with co-/multi-morbidity are affected. However, interactions with gender and anxiety disorders are noteworthy and of relevance to potentially improve recognition and treatment of depression by physicians. Somatic diseases are associated more strongly with depression in males v. females as well as in patients without v. with anxiety disorders, primarily because women and patients with anxiety disorders per se are characterised by considerably increased depression prevalence that only marginally changes in the presence of somatic comorbidity. PMID- 29117877 TI - Post-Traumatic Symptomatology and Compulsions as Potential Mediators of the Relation Between Child Sexual Abuse and Auditory Verbal Hallucinations. AB - BACKGROUND: Whilst evidence is mounting that childhood sexual abuse (CSA) can be a cause of auditory verbal hallucinations (AVH), it is unclear what factors mediate this relation. Recent evidence suggests that post-traumatic symptomatology may mediate the CSA-AVH relation in clinical populations, although this hypothesis has not yet been tested in the general population. There is also reason to believe that obsessive ideation could mediate the CSA-AVH relation. AIMS: To test for evidence to falsify the hypotheses that post-traumatic symptomatology, obsessions, compulsions, anxiety and depression mediate the relation between CSA and AVH in a general population sample. METHOD: Indirect effects of CSA on AVH via potential mediators were tested for, using a regression based approach employing data from the 2007 Adult Psychiatric Morbidity Survey (n = 5788). RESULTS: After controlling for demographics, IQ and child physical abuse, it was found that CSA, IQ, post-traumatic symptomatology and compulsions predicted lifetime experience of AVH. Mediation analyses found significant indirect effects of CSA on AVH via post-traumatic symptomatology [odds ratio (OR): 1.11; 95% confidence interval (CI):1.00-1.29] and compulsions (OR: 1.10, 95% CI: 1.01-1.28). CONCLUSIONS: These findings offer further support for the hypothesis that post-traumatic symptomatology is a mediator of the CSA-AVH relation. Although no evidence was found for obsessional thoughts as a mediating variable, a potential mediating role for compulsions is theoretically intriguing. This study's findings reiterate the need to ask about experiences of childhood adversity and post-traumatic symptomology in people with AVH, as well as the likely therapeutic importance of trauma-informed and trauma-based interventions for this population. PMID- 29117878 TI - Genetic diversity and evolution of Pneumocystis fungi infecting wild Southeast Asian murid rodents. AB - Pneumocystis organisms are airborne-transmitted fungal parasites that infect the lungs of numerous mammalian species with strong host specificity. In this study, we investigated the genetic diversity and host specificity of Pneumocystis organisms infecting Southeast Asian murid rodents through PCR amplification of two mitochondrial genes and tested the co-phylogeny hypothesis among these fungi and their rodent hosts. Pneumocystis DNA was detected in 215 of 445 wild rodents belonging to 18 Southeast Asian murid species. Three of the Pneumocystis lineages retrieved in our phylogenetic trees correspond to known Pneumocystis species, but some of the remaining lineages may correspond to new undescribed species. Most of these Pneumocystis species infect several rodent species or genera and some sequence types are shared among several host species and genera. These results indicated a weaker host specificity of Pneumocystis species infecting rodents than previously thought. Our co-phylogenetic analyses revealed a complex evolutionary history among Pneumocystis and their rodent hosts. Even if a significant global signal of co-speciation has been detected, co-speciation alone is not sufficient to explain the observed co-phylogenetic pattern and several host switches are inferred. These findings conflict with the traditional view of a prolonged process of co-evolution and co-speciation of Pneumocystis and their hosts. PMID- 29117879 TI - Human parasitology worldwide research. AB - In this article, the trends in human parasitology have been studied through the analysis of the number of publications in this area. The parameters studied were: number of articles, language, countries and institutions with the highest number of publications, and keywords with greater presence in the articles of human parasitology. The results of the analysis confirm the growing interest in this area, observing an exponential growth in the number of publications in the last decades. We also verified that the main country in terms of scientific production is the USA, although among the most important institutions, we find non-US centres such as the Oswaldo Cruz Foundation and the London School of Hygiene and Tropical Medicine. For observing the relative importance of the journals that publish articles in this specific topic, an index has been created based on the h index of the journal with publications related to human parasitology and divided by every 100 items. This rank is led fist by 'Journal of Medical Entomology' closely followed by 'Parasitology'. The analysis of the keywords allows to draw conclusions about the great importance of malaria in the current world research. A change in analytical methodology is also observed, and molecular techniques are now being imposed. These techniques, in the near future, have to influence in an improvement in the treatments and prevention of the diseases caused by parasites. Finally, it can be seen that diseases traditionally studied as helminthiasis and amebiasis are currently as well studied as others such as toxoplasmosis or leishmaniasis. PMID- 29117880 TI - Use of benzodiazepines and cognitive performance in primary care patients with first cognitive complaints. AB - ABSTRACTThe aim of the present study is to investigate the impact of benzodiazepine use on cognitive performance in primary care patients with first cognitive complaints. The association between the exposition to benzodiazepines (short and long half-life) and cognitive performance, evaluated through the Mini Mental State Examination (MMSE), was tested through analysis of the covariance and logistic regression models. Within the 4,249 participants (mean age 77.0 +/- 8.2, 66.4% women), 732 (17%) were on benzodiazepines. When compared with non users, short- and long-acting benzodiazepine users presented overlapping adjusted MMSE mean scores (respectively, mean MMSE score: 25.3, 95%CI 25.2-25.5; 25.4, 95%CI 25.1-25.7, and 25.9, 95%CI 25.3-26.4; p = 0.156). When tested according to the logistical regression model, after adjusting for potential confounders, no association was found between short and long acting benzodiazepine use and a MMSE < 24 (respectively, OR 0.9, 95%CI 0.7-1.2; OR 0.8, 95%CI 0.7-1.3) as compared with non-users. In conclusion, according to the results of our study, benzodiazepine use seems not to impact on cognitive performance- as assessed with the MMSE- of primary care patients referring to GPs for first cognitive complaints. PMID- 29117881 TI - Downregulated Trophinin-Associated Protein Plays a Critical Role in Human Hepatocellular Carcinoma Through Upregulation of Tumor Cell Growth and Migration. AB - Trophinin-associated protein (TROAP) was a protein first identified to mediate the process of embryo transplantation and later found to be involved in microtubule regulation. However, little is known about the role of TROAP in hepatocellular carcinoma (HCC). In the present study, we reported that both TROAP mRNA and protein expressions were downregulated in human HCC samples as well as cell lines. A high level of TROAP was associated with small tumor size (p < 0.05), minor tumor nodules (p < 0.01), and mild vein invasion (p < 0.05). We further constructed in vitro TROAP depletion and overexpression HCC cell models. TROAP depletion significantly enhanced the proliferation and colony formation abilities, whereas TROAP overexpression had an inhibitory effect on the growth of HCC cells. The G1/S phase arrest by TROAP overexpression correlated with increased cell cycle inhibitors p21 and p27, and declined cell cycle promoting kinase complex CDK6/cyclin D1. Depressed TROAP expression enhanced the migration ability, while the opposite influence was observed in TROAP-overexpressed HCC cells. Taken together, these results indicate that TROAP suppresses cellular growth and migration in HCC. This discovery will further our understanding of the pathogenic mechanisms of human HCC. PMID- 29117882 TI - Excessive Daytime Sleepiness in Acute Ischemic Stroke: Association With Restless Legs Syndrome, Diabetes Mellitus, Obesity, and Sleep-Disordered Breathing. AB - STUDY OBJECTIVES: Sleep disorders are frequent in stroke patients. The prevalence of sleep-disordered breathing (SDB), excessive daytime sleepiness (EDS), and restless legs syndrome (RLS) among stroke survivors is up to 91%, 72%, and 15%, respectively. Although the relationship between EDS and SDB is well described, there are insufficient data regarding the association of EDS with RLS. The aim of this study was to explore the association between EDS, SDB, and RLS in acute ischemic stroke. METHODS: We enrolled 152 patients with acute ischemic stroke. Epworth Sleepiness Scale (ESS) was used to assess EDS. SDB was assessed using standard overnight polysomnography. All patients filled in a questionnaire focused on RLS. Clinical characteristics and medication were recorded on admission. RESULTS: EDS was present in 16 (10.5%), SDB in 90 (59.2%) and RLS in 23 patients (15.1%). EDS was significantly more frequent in patients with RLS in comparison with the patients without RLS (26.1% versus 7.8%, P = .008). ESS was significantly higher in the population with RLS compared to the population without RLS (7 [0-14] versus 3 [0-12], P = .032). We failed to find any significant difference in the frequency of EDS and values of ESS in the population with SDB compared to the population without SDB. Presence of RLS (beta = 0.209; P = .009), diabetes mellitus (beta = 0.193; P = .023), and body mass index (beta = 0.171; P = .042) were the only independent variables significantly associated with ESS in multiple linear regression analysis. CONCLUSIONS: Our results suggest a significant association of ESS with RLS, diabetes mellitus, and obesity in patients with acute ischemic stroke. PMID- 29117884 TI - Improving Sleep for Hospitalized Antepartum Patients: A Non-Randomized Controlled Pilot Study. AB - STUDY OBJECTIVES: To evaluate feasibility and efficacy of a hospital-based protocol for improving sleep in high- risk antepartum patients. METHODS: Sleep measures were compared during 1 week of hospitalization before and after implementing a Sleep Improvement Protocol for Antepartum Patients (SIP-AP). A non randomized convenience sample of usual care controls was compared to a subsequent intervention sample after the protocol was implemented. Women were eligible if they spoke English, were medically stable, pregnant for at least 20 weeks, and hospitalized at least 24 hours; 25 pregnant women had sufficient data for analyses (11 controls, 14 intervention). Sleep was assessed in 3 ways: the Pittsburgh Sleep Quality Index was completed after obtaining consent to estimate sleep quality prior to hospital admission; sleep diary completed each hospital day; and General Sleep Disturbance Scale completed at 7 days or prior to hospital discharge. Symptoms that could affect sleep were assessed with the Memorial Symptom Assessment Scale. RESULTS: Both groups recorded similar sleep duration (7 hours) but the intervention group had fewer symptoms and significantly (P = .015) lower sleep disturbance scores (53.1 +/- 14.5) than controls (71.9 +/- 18.8). Participant feedback about the intervention was positive, although adherence to components of the intervention protocol was variable. CONCLUSIONS: This pilot study provides evidence of the feasibility and preliminary efficacy of the SIP-AP intervention for reducing symptoms and improving sleep of antepartum patients during hospitalization. Further detailed evaluation of specific components of this protocol is warranted, and other types of hospitalized patients may benefit from unit-based modifications to this SIP-AP protocol. PMID- 29117883 TI - Admission Criteria for Children With Obstructive Sleep Apnea After Adenotonsillectomy: Considerations for Cost. AB - STUDY OBJECTIVES: Postoperative respiratory complications (PRCs) are common among children with obstructive sleep apnea (OSA) after adenotonsillectomy. We analyzed postoperative admission guidelines to determine which optimally balanced patient safety and cost. METHODS: Retrospective study of children aged 12 years or younger undergoing adenotonsillectomy for OSA after polysomnography at a tertiary academic care center over 2 years. Demographics, medical History, and hospital course were collected. Advanced Excel modeling was used to assess the number of children with PRCs identified with guideline admission criteria and to validate the significance of these findings in our patient population with logistic regression. RESULTS: Six hundred thirty children were included; 116 had documented PRCs. Children with PRCs were younger (P = .024) and more frequently male (P = .012). There were no significant differences in race (P = .411) or obesity (P = .265). More children with PRCs had an apnea-hypopnea index (AHI) > 24 events/h (P < .001). Following guidelines from the American Academy of Pediatrics, American Academy of Otolaryngology - Head and Neck Surgery, and Nationwide Children's Hospital, 82%, 87%, and 99% of children with PRCs would be identified, costing $535,962, $647,165, and $1,053,694 for admission, respectively. Using a non-validated, forced model to refine predictors described in published guidelines, our model would have identified 95% of children with one or more PRCs, with a moderate cost. CONCLUSIONS: Current admission guidelines attempt to identify children with OSA at high risk for PRCs after adenotonsillectomy; however, none consider the economic cost to the health care system. We present a comparison of the number of patients identified with PRCs after adenotonsillectomy and the cost of expected admissions using currently published guidelines. COMMENTARY: A commentary on this article appears in this issue on page 1371. PMID- 29117885 TI - Functional Evaluation of Small Fiber Pathways in Primary Restless Legs Syndrome: Adelta Pathway Study. AB - STUDY OBJECTIVES: The aim of this study was to provide a neurophysiological evaluation of the function of large and small fibers, particularly the peripheral part of the thermonociceptive Adelta pathway in patients with primary restless legs syndrome (RLS). METHODS: The main evaluation was based on an analysis of the parameters of laser-evoked potentials (LEPs), N2 and P2 components, and an assessment of thermonociceptive thresholds (pain thresholds; PThs). Routine nerve conduction studies (NCS) were also performed. RESULTS: No essential or important differences of clinical significance were observed in the parameters of large fiber conduction between the study and the control groups. Prolonged latencies of N2 and P2 potentials were obtained during foot stimulation in patients with primary RLS when compared to controls (N2, P2-lower right limb, and N2-lower left limb). We also observed higher amplitudes of LEPs evaluated as P2 and N2-P2 potentials in patients with primary RLS in comparison with the control group. Significantly higher (normal distribution P < .05) thermonociceptive thresholds in both lower and upper limbs were found in the RLS group. CONCLUSIONS: On the basis of the analysis of LEPs and their comparison with the respective results from the control group, the presence of functional disability of the thermonociceptive Adelta pathway was confirmed in patients with primary RLS. The results indicated the presence of changes in the conduction of small fiber pathways in the pathomechanism of idiopathic RLS. PMID- 29117886 TI - A Longitudinal Follow-Up Study on Multiple Sleep Latency Test and Body Mass Index of Patients With Narcolepsy Type 1 in Korea. AB - STUDY OBJECTIVES: Narcolepsy is a chronic disorder with numerous adverse long term consequences including increased obesity, high mortality rates, and decreased quality of life. With emerging attention to the long-term course of the disorder and importance of accurate diagnosis, the diagnostic stability of the Multiple Sleep Latency Test (MSLT)-the mostly frequently used test to identify narcolepsy-is often challenged. METHODS: In this study, we compared the baseline and follow-up demographic characteristics and body mass index (BMI) of patients with narcolepsy type 1. Moreover, MSLT results from repeated tests conducted on 48 patients with narcolepsy type 1 were compared, with mean follow-up of approximately 10 years. RESULTS: BMI from the baseline to the follow-up visit was significantly increased in the participants. There were no significantly different parameter changes in MSLT results. CONCLUSIONS: MSLT has good test retest validity in patients with narcolepsy type 1. Close surveillance for the detection and management of obesity is warranted in clinical settings. PMID- 29117887 TI - Correlates to Problem Behaviors in Pediatric Narcolepsy: A Pilot Study. AB - STUDY OBJECTIVE: Excessive daytime sleepiness, the hallmark of narcolepsy, predisposes patients to serious performance decrements in multiple areas of function. Psychosocial dysfunction has been demonstrated in adults and children with narcolepsy. Several factors could influence psychosocial functioning in children. The objective of this study was to examine neurobehavioral problems in children with narcolepsy and to define associations with these problem behaviors. METHODS: A cross-sectional study was performed where the Child Behavior Checklist (CBCL) was completed by guardians of children (age 18 years or younger) in whom narcolepsy with or without cataplexy was diagnosed (based on the International Classification of Sleep Disorders, Second Edition) between July 2008 and October 2014. Spearman correlations (continuous variables) and Wilcoxon rank-sum tests (categorical variables) were performed for the CBCL findings and narcolepsy factors previously shown to influence psychosocial functioning. RESULTS: The participants' current age correlated significantly with multiple CBCL scales. Caregivers of younger participants reported higher total psychosocial problems and externalizing problems. In addition, caregivers of younger participants reported higher scores on indices measuring inattention, withdrawal, thought problems, aggression, and rule-breaking behaviors. Values of P < .001 were found for total psychosocial problems, externalizing behaviors, and thought problems (negative correlations of 0.66, 0.65, and 0.64, respectively). CONCLUSIONS: Patients with pediatric narcolepsy have high rates of attention and emotional/behavior problems. These problems strongly correlated with age. Younger children expressed higher emotional, behavioral, and attention problems. Sleep physicians need to be aware of and assess the mental and behavioral health of their pediatric patients with narcolepsy. PMID- 29117888 TI - The REM Sleep Behavior Disorder Screening Questionnaire: Validation Study of the Korean Version (RBDQ-KR). AB - STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is a parasomnia that is commonly associated with neurodegenerative disorders. We aimed to validate the Hong Kong version of the self-reported RBD questionnaire (RBDQ-HK) with the Korean version (RBDQ-KR) and to investigate its clinical usefulness. METHODS: One hundred five patients with RBD and 105 age- and sex-matched controls were enrolled. Thirty were randomly selected for a retest with the questionnaire after 2 to 4 weeks without any treatment. Receiver operating characteristic curve and exploratory factor analysis were used to evaluate the scale, which had a score ranging from 0 to 100. RESULTS: There was no difference in mean age and sex in patients with RBD and control subjects. Patients with RBD had a significantly higher total RBDQ-KR score than the control group (P < .001). The RBDQ-KR demonstrated high sensitivity (93.3%), specificity (89.5%), positive predictive value (89.9%), and negative predictive value (93.1%). Cronbach alpha coefficient for internal consistency of the total score of the RBDQ-KR was 0.9, which shows high reliability. Exploratory factor analysis showed two components, dream related and behavioral factors, consistent with the main clinical features of RBD. Based on the results, the best cutoff for the total score ranging from 0 to 100 was at 18/19 and for factor 2 ranging from 0 to 75 was at 11. CONCLUSIONS: This study showed RBDQ-KR is a valid and reliable questionnaire for RBD symptoms and severity in Korea. It serves as an effective tool to identify patients with RBD and to facilitate future clinical and research studies. PMID- 29117889 TI - Confusing Signals During a Positive Airway Pressure Titration. PMID- 29117890 TI - Yogic Pranayama and PAP Therapy: Is There a Connection? PMID- 29117891 TI - Recurrent Hypersomnia and Autonomic Dysregulation in Posttraumatic Stress Disorder. PMID- 29117892 TI - Emergency department referral patterns of Australian general practitioner registrars: a cross-sectional analysis of prevalence, nature and associations. AB - Objective Limited international evidence suggests general practice registrars' emergency department (ED) referral rates exceed those of established general practitioners (GPs). The aim of the present study was to fill an evidence gap by establishing the prevalence, nature and associations of Australian GP registrar ED referrals.Methods A cross-sectional analysis was performed of the Registrar Clinical Encounters in Training (ReCEnT) cohort study of GP registrars' consultation experiences, between 2010 and 2015. The outcome factor in logistic regression analysis was referral to an ED. Independent variables included patient level, registrar-level, practice-level and consultation-level factors.Results In all, 1161 GP registrars (response rate 95.5%) contributed data from 166966 consultations, comprising 258381 individual problems. Based on responses, 0.5% of problems resulted in ED referral, of which nearly 25% comprised chest pain, abdominal pain and fractures. Significant (P < 0.05) associations of ED referral included patient age <15 and >34 years, the patient being new to the registrar, one particular regional training provider (RTP), in-consultation information or assistance being sought and learning goals being generated. Outer regional-, remote- or very remote-based registrars made significantly fewer ED referrals than more urban registrars. Of the problems referred to the ED, 45.5% involved the seeking of in-consultation information or assistance, predominantly from supervisors.Conclusions Registrars' ED referral rates are nearly twice those of established GPs. The findings of the present study suggest acute illnesses or injuries present registrars with clinical challenges and real learning opportunities, and highlight the importance of continuity of care, even for acute presentations.What is known about the topic? A GP's decision concerning continued community- versus hospital-based management of acute presentations demands careful consideration of a suite of factors, including implications for patient care and resource expenditure. General practice vocational training is a critical period for the development of GP registrars' long-term patterns of practice. Although limited international evidence suggests GP registrars and early career GPs refer patients to the ED at a higher rate than their more experienced peers, these studies involved small subject numbers and did not investigate associations of registrars making an ED referral. Relevant Australian studies focusing on GP registrars' ED referral patterns are lacking.What does this paper add? The present ongoing cohort study is the first to establish the patterns of ED referrals made by Australian GP registrars, encompassing five general practice RTPs across five states, with participating registrars practising in urban, rural, remote and very remote practices. Several significant associations were found with GP registrars making ED referrals, including patient age, continuity of care, the registrar's RTP, assistance sought by the registrar and rurality of the registrar's practice.What are the implications for practitioners? The higher likelihood of GP registrars seeing acute presentations than their more established practice colleagues, coupled with a demonstrated association of registrars seeking in-consultation assistance for such presentations, highlights the importance of GP supervisor accessibility in facilitating ED referral appropriateness and in the development of registrars' safe clinical practice. PMID- 29117893 TI - What's in a name? An overview of organisational health literacy terminology. AB - Organisational health literacy (OHL) is a relatively new concept and its role in improving population health outcomes is gaining recognition. There are several terms being used in relation to OHL but there is no consensus about the definition of OHL nor agreement on a single approach to its application within health services. This contested space continues to create discussion and debate between health literacy researchers worldwide. Increasingly, health service accreditation standards are moving towards including OHL and so services need to clearly define their roles and responsibilities in this area. Inherent in this is the need to develop and validate quantifiable measures of OHL change. This is not to say it needs a 'one-size-fits-all' approach but rather that terminology needs to be fit for purpose. This paper reviews the literature on OHL, describing and contrasting OHL terminology to assist practitioners seeking OHL information and health services clarifying their roles and responsibilities in this area. PMID- 29117895 TI - Response. PMID- 29117894 TI - Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling. AB - Toddler/Apela/Elabela is a conserved secreted peptide that regulates mesendoderm development during zebrafish gastrulation. Two non-exclusive models have been proposed to explain Toddler function. The 'specification model' postulates that Toddler signaling enhances Nodal signaling to properly specify endoderm, whereas the 'migration model' posits that Toddler signaling regulates mesendodermal cell migration downstream of Nodal signaling. Here, we test key predictions of both models. We find that in toddler mutants Nodal signaling is initially normal and increasing endoderm specification does not rescue mesendodermal cell migration. Mesodermal cell migration defects in toddler mutants result from a decrease in animal pole-directed migration and are independent of endoderm. Conversely, endodermal cell migration defects are dependent on a Cxcr4a-regulated tether of the endoderm to mesoderm. These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling. PMID- 29117897 TI - Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents. AB - Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists. PMID- 29117898 TI - The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. AB - Osteosarcoma is a rare primary bone cancer characterized by cancer cells producing calcified osteoid extracellular matrix and inducing lung metastases with a high frequency. The local microenvironment defined several tumor niches controlling the tumor growth and cell extravasation. The immune infiltrate composes one of these niches. The immune environment of osteosarcoma is mainly composed by T-lymphocytes and macrophages but also contains other subpopulations including B-lymphocytes and mast cells. Osteosarcoma cells control the recruitment and differentiation of immune infiltrating cells and establish a local immune tolerant environment favorable to the tumor growth, drug resistance and the occurrence of metastases. Osteosarcoma cells are able to affect the balance between M1 and M2 macrophage subtypes and so could control the T lymphocyte responses via the PD-1/PDL-1 system. In addition, mesenchymal stem cells may also contribute to this immune tolerance and strengthen the immune evasion. The present review gives a brief overview of the immune components of osteosarcoma and their most recent therapeutic interests. PMID- 29117896 TI - Discovery of a head-to-tail cyclic peptide as the Keap1-Nrf2 protein-protein interaction inhibitor with high cell potency. AB - Directly disrupting Keap1-Nrf2 protein-protein interaction (PPI) has emerged as a novel way to activate Nrf2. Peptide Keap1-Nrf2 PPI inhibitors have been reported with high Keap1 binding affinity. However, these peptide inhibitors show weak activity in cells. In this study, the head-to-tail cyclic strategy was applied in the development of peptide inhibitors. The privileged residue sequence with minimal acidic residues was used as the template for the cyclic peptide, and the appropriate conjugation method was designed based on the peptide-Keap1 binding mode. The glycine was introduced as the linker to connect both sides, which can avoid the terminal charge, enhance the peptide stability and constrain the binding conformation simultaneously. The obtained novel cyclic peptide 3 showed high binding affinity with Keap1 and possessed high potency in Nrf2 activation at cellular level. We also showed that peptide 3 exhibited effective anti inflammatory effects in mouse RAW 264.7 cells by activating the Nrf2-regulated defense system and enhancing the antioxidant capacity. This study proved that the head-to-tail cyclic strategy is quite useful in improving the cell potency of peptide Keap1-Nrf2 inhibitors and provided a possible way to develop drug-like peptides as therapeutic Nrf2 activators. PMID- 29117899 TI - Editorial: Volume-outcome relationship in adrenal surgery. PMID- 29117900 TI - Gestalt for shock and mortality in the emergency department: A prospective study. AB - OBJECTIVE: The diagnosis of shock in patients presenting to the emergency department (ED) is often challenging. We aimed to compare the accuracy of experienced emergency physician gestalt against Li's pragmatic shock (LiPS) tool for predicting the likelihood of shock in the emergency department, using 30-day mortality as an objective standard. METHOD: In a prospective observational study conducted in an urban, academic ED in Hong Kong, adult patients aged 18years or older admitted to the resuscitation room or high dependency unit were recruited. Eligible patients had a standard ED workup for shock. The emergency physician treating the patient was asked whether he or she considered shock to be probable, and this was compared with LiPS. The proxy 'gold' or reference standard was 30 day mortality. The area under the receiver operating curve (AUROC) was used to predict prognosis. The primary outcome measure was 30-day mortality. RESULTS: A total of 220 patients fulfilled the inclusion criteria and were included in the analysis. The AUROC for LiPS (0.722; sensitivity=0.733, specificity=0.711, P<0.0001) was greater than emergency physician gestalt (0.620, sensitivity=0.467, specificity=0.774, P=0.0137) for diagnosing shock using 30-day mortality as a proxy (difference P=0.0229). LiPS shock patients were 6.750 times (95%CI=2.834 16.076, P<0.0001) more likely to die within 30-days compared with non-shock patients. Patients diagnosed by emergency physicians were 2.991 times (95%CI=1.353-6.615, P=0.007) more likely to die compared with the same reference. CONCLUSIONS: LiPS has a higher diagnostic accuracy than emergency physician gestalt for shock when compared against an outcome of 30-day mortality. PMID- 29117901 TI - A patient with midventricular takotsubo: any attenuation in the amplitude of the QRS complexes in subsequent electrocardiograms? PMID- 29117902 TI - Editorial: Approaches of the treatment of DCIS. PMID- 29117904 TI - The past, present, and the promise of the future of nuclear medicine and biology. PMID- 29117903 TI - Histopathological and Immunohistochemical Analysis of the Use of Collagen Dressing as a Reinforcement of Esophagic Anastomosis in a Rat Experimental Model. AB - INTRODUCTION: One of the most severe complications after esophaguectomy is anastomotic dehiscence. The use of collagen sponges could be an effective way to resolve this complication. Our objective was to perform an experimental model of esophageal anastomosis in rats to study these mechanisms. METHODS: A total of 50 Sprague-Dawley rats were used divided into 2 groups, Tachosil(r) group (n=25) and control group (n=25). After the section of the abdominal esophagus a single-layer esophago-gastric anastomosis was performed reinforced with 1cm of Tachosil(r) wrapping the anastomosis in group 1. A functional study was performed using manometry as well as histopathological and immunohistochemical studies for angiogenic, fibrogenic and growth factors. RESULTS: The mortality in our series was 8% in the collagen dressing group, compared to 36% in the control group. When esophageal manometry was performed, the dehiscence pressure was higher in the reinforced anastomosis, On microscopical analysis, in the collagen dressing group a profuse inflammatory reaction with abundant neutrophils and macrophages surrounded by a connective matrix with fibroblasts and blood vessels was observed, The expression of VEGF, FGF1 and FGF2 was noticeably higher in the collagen dressing group. CONCLUSIONS: These results show that the application of collagen dressing facilitates tissue reparation phenomena, and therefore could be very useful as a reinforcement of esophago-gastric anastomosis to prevent dehiscence. PMID- 29117905 TI - [Marie Curie and medicine]. PMID- 29117906 TI - Molecular characterization of macrophyte-derived dissolved organic matters and their implications for lakes. AB - Chemical properties of whole organic matter (OM) and its dissolved organic matter (DOM) extracted from three types of dominant macrophytes in Lake Dianchi were comparatively characterized using elemental analysis, UV, 3D-EEM and 13C NMR spectroscopy and their implications for lakes were discussed. Ratios of C/N and C/P were least in the floating water hyacinth and submerged sago pondweed, while total dissolved nitrogen (TDN) and phosphorus (TDP), dissolved organic nitrogen (DON) and phosphorus (DOP) were greatest in those species. In emergent species, C/N, C/P, DON and DON/TDN were less in leaves than in their corresponding shoots. The specific UV absorbance at 254nm (SUVA254) and 280nm (SUVA280) of extracts were in the range of 0.50-1.96L/mgC.m and 0.40-1.48L/mgC.m. Both SUVA values were greater in leaves than those in shoots. 3D-EEM spectra showed only a single fulvic-like fluorescence in leaves of emergent macrophytes. In contrast, protein like peak were observed in spectra of floating and submerged species, as well as the shoot DOM of emergent species. Solid-state 13C NMR demonstrated that leaves had greater percentage of recalcitrant alkyl C and aromatic C, while shoots were rich in labile carbohydrates. The overall characterization works suggested that macrophyte-derived DOM has less aromatic constituents than do DOM in natural waters and soil leachates. Also OM and DOM derived from shoots had greater contents of protein-like and carbohydrate materials, while leaves were rich in aromatics. Floating and submerged plants possessed potential to not only accumulate excess N and P, but also for returning them to the lake. Shoots of riparian and emergent species were also an important source of nutrients. Thus, macrophyte biomass should be a great concern in nutrient regulation in Lake Dianchi. PMID- 29117907 TI - The prognostic value of the combined use of QRS distortion and fragmented QRS in patients with acute STEMI undergoing primary percutaneous coronary intervention. AB - BACKGROUND: No study has investigated the prognostic importance of the combined use of QRS distortion and fragmented QRS (fQRS) for risk stratification in acute ST segment elevation myocardial infarction (STEMI). OBJECTIVE: To determine the prognostic value of the combined use of QRS distortion and fQRS in patients with acute STEMI undergoing primary percutaneous coronary intervention (pPCI). METHODS: A total of 454 patients with first STEMI who underwent pPCI were included in this study. Patients were categorized into three groups according to the presence of QRS distortion and fQRS on admission electrocardiography. Group I was defined as fQRS (-) and QRS distortion (-), group 2 was defined as fQRS (+) and QRS distortion (-), or fQRS (-) and QRS distortion (+), and group 3 was defined as both fQRS (+) and QRS distortion (+). RESULTS: Patients in group III had a significantly higher in-hospital mortality rate compared with patients in groups I and II. These patients also had lower left ventricular ejection fraction and ST resolution ratios, higher maximum troponin, and higher frequency of three vessel disease. Multivariate analysis indicated that group III (OR: 8.84, 95% CI: 2.73-28.62, p<0.001) was an independent predictors of in-hospital mortality. CONCLUSION: The combined use of QRS distortion and fQRS provides additional prognostic value compared with the presence of QRS distortion or fQRS alone for early risk stratification in patients with STEMI treated with pPCI. PMID- 29117908 TI - Clinical characteristics of primary psychotic disorders with concurrent substance abuse and substance-induced psychotic disorders: A systematic review. AB - BACKGROUND: Distinguishing between a primary psychotic disorder with concurrent substance abuse (PPD+SA) and a substance-induced psychotic disorder (SIPD) can be diagnostically challenging. We aimed to determine if these two diagnoses are clinically distinct, particularly in relation to psychopathology. In addition, we aimed to examine the specific clinical features of cannabis-induced psychotic disorder (CIPD) as compared to primary psychotic disorder with concurrent cannabis abuse (PPD+CA) and also to SIPD associated with any substance. METHODS: A systematic review of SIPD literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Using strict inclusion criteria, a total of six studies examining SIPD were included in the review (two of which only considered psychosis induced by cannabis alone). The findings did not reveal many consistent differences in psychopathology. However, we did find that that compared to PPD+SA, individuals with SIPD have a weaker family history of psychotic disorder; a greater degree of insight; fewer positive symptoms and fewer negative symptoms; more depression (only in CIPD) and more anxiety. CONCLUSION: There remains a striking paucity of information on the psychopathology, clinical characteristics and outcome of SIPD. Our review highlights the need for further research in this area. PMID- 29117909 TI - A history of obstetric complications is associated with the risk of progression from an at risk mental state to psychosis. AB - OBJECTIVE: Clinical criteria for diagnosing Clinical High Risk for psychosis are now available. However, an understanding of the factors modulating the risk of subsequent development of frank psychosis in "at risk" individuals remains elusive. The aim of the study was to identify associations between obstetric history and the development of psychotic disorders in individuals with an At Risk Mental State (ARMS). METHODS: Obstetric data was obtained from the medical records of 82 individuals meeting ARMS criteria. The participants were followed up for a mean period of 42.3 (+/-28.3) months for transition to psychosis. RESULTS: A history of at least one obstetric complication (OC) endorsed as definite on the Lewis and Murray Obstetric Complications Scale was found to be associated with increased risk of transition to schizophrenia (OR: 6.57, 95% CI:1.89-22.85). The number of definite OCs was found to be positively correlated with the proportion of converters (p<0.0001). The probability of conversion to schizophrenia was found to increase with a decrease of Apgar-1 and Apgar-5 scores (ORs: 0.40, 95% CI:0.22-0.74 and 0.25, 95% CI:0.10-0.63, respectively). CONCLUSIONS: The findings emphasise the potential value of including obstetric data in algorithms estimating the likelihood of transition of an ARMS to full blown psychosis. PMID- 29117910 TI - Increased resting-state global functional connectivity density of default mode network in schizophrenia subjects treated with electroconvulsive therapy. AB - Modified electroconvulsive therapy (MECT) has been widely applied to help treat schizophrenia patients who are treatment-resistant to pharmaceutical therapy. Although the technique is increasingly prevalent, the underlying neural mechanisms have not been well clarified. We conducted a longitudinal study to investigate the alteration of global functional connectivity density (gFCD) in schizophrenia patients undergoing MECT using resting state fMRI (functional magnetic resonance imaging). Two groups of schizophrenia inpatients were recruited. One group received a four-week MECT together with antipsychotic drugs (ECT+Drug, n=21); the other group only received antipsychotic drugs (Drug, n=21). Both groups were compared to a sample of healthy controls (HC, n=23). fMRI scans were obtained from the schizophrenia patients twice at baseline (t1) and after 4 week treatment (t2), and from healthy controls at baseline. gFCD was computed using resting state fMRI. Repeated ANCOVA showed a significant interaction effect of group*time in the schizophrenia patients in left precuneus (Pcu), ventral medial prefrontal cortex (vMPFC), and dorsal medial prefrontal cortex (dMPFC) (GRF-corrected P<0.05), which are mainly located within the default mode network (DMN). Post-hoc analysis revealed that compared with baseline (t1), an increased gFCD was found in the ECT+Drug group in the dMPFC (t=3.87, p=0.00095), vMPFC (t=3.95, p=0.00079) and left Pcu (t=3.33, p=0.0034), but no significant effect was identified in the Drug group. The results suggested that increased global functional connectivity density within the DMN might be one important neural mechanism of MECT in schizophrenia. PMID- 29117911 TI - Insights on insight. PMID- 29117912 TI - Measurement of physical activity in the pre- and early post-operative period after total knee arthroplasty for Osteoarthritis using a Fitbit Flex device. AB - Total knee arthroplasty (TKA) is a standard treatment for patients with end stage knee Osteoarthritis (OA) to reduce pain and restore function. The aim of this study was to assess pre- and early post-operative physical activity (PA) with Fitbit Flex devices for patients with OA undergoing TKA and determine any benchmarks for expected post-operative activity. Significant correlations of pre operative step count, post-operative step count, Body Mass Index (BMI) and Short Form 12 Physical Component Summaries (SF-12 PCS) were found. Mean step counts varied by 3,203 steps per day between obese and healthy weight patients, and 3,786 steps per day between those with higher and lower SF-12 PCS scores, suggesting the need for benchmarks for recovery that vary by patient pre operative factors. A backwards stepwise regression model developed to provide patient specific step count predictions at 6 weeks had an R2 of 0.754, providing a robust patient specific benchmark for post-operative recovery, while population means from BMI and SF-12 subgroups provide a clinically practical alternative. PMID- 29117913 TI - Two Interventions for Patients with Major Depression and Severe Chronic Obstructive Pulmonary Disease: Impact on Dyspnea-Related Disability. AB - OBJECTIVE: The Personalized Intervention for Depressed Patients with Chronic Obstructive Pulmonary Disease (PID-C) is an intervention aiming to help patients adhere to their rehabilitation and care. This study tested the hypothesis that the Problem-Solving Adherence (PSA) intervention, which integrates problem solving into adherence enhancement procedures, reduces dyspnea-related disability more than PID-C. Exploratory analyses sought to identify patients with distinct dyspnea-related disability trajectories and to compare their clinical profiles. METHODS: In this randomized controlled trial in an acute inpatient rehabilitation and community, 101 participants diagnosed with chronic obstructive pulmonary disease (COPD) and major depression were included after screening 633 consecutive admissions for acute inpatient rehabilitation. Participants underwent 14 sessions of PID-C versus PSA over 26 weeks using the Pulmonary Functional Status and Dyspnea Questionnaire. RESULTS: The study hypothesis was not supported. Exploratory latent class growth modeling identified two distinct disability trajectories. Dyspnea-related disability improved in 39% of patients and remained unchanged in the rest. Patients whose dyspnea-related disability improved had more severe disability and less sense of control over their condition at baseline. CONCLUSION: Improvement or no worsening of disability was noted in both treatment groups. This is a favorable course for depressed patients with a severe, deteriorating medical illness. PID-C is compatible with the expertise of clinicians working in community-based rehabilitation programs, and after further testing in the community, it can be integrated in the care of depressed COPD patients. PMID- 29117914 TI - Enhancing Quality of Life and Caregiver Interactions for Persons with Dementia Using TimeSlips Group Storytelling: A 6-Month Longitudinal Study. PMID- 29117915 TI - DRG migration: A novel measure of inefficient surgical care in a value-based world. AB - BACKGROUND: Diagnosis-Related Group (DRG) migration, DRG 331 to 330, is defined by the assignment to a higher cost DRG due only to post admission comorbidity or complications (CC). METHODS: We assessed the 5% national Medicare data set (2011 2014) for colectomy (DRG's 331/330), excluding present on admission CC's and selecting patients with one or more CC's post-admission to define the impact on payments, cost, and length of stay (LOS). RESULTS: The incidence of DRG migration was 14.2%. This was associated with statistically significant increases in payments, hospital cost, and LOS compared to DRG 331 patients. CONCLUSIONS: When DRG migration rate was extrapolated to the entire at risk population, the results were an increase of Centers for Medicare and Medicaid Services (CMS) cost by $98 million, hospital cost by $418 million, and excess hospital days equaling 68,669 days. These negative outcomes represent potentially unnecessary variations in the processes of care, and therefore a unique economic concept defining inefficient surgical care. PMID- 29117916 TI - Technical skill improvement with surgical preparatory courses: What advantages are reflected in residency? AB - INTRODUCTION: Sustainability of skill acquisition gained from graduating medical student (GMS) preparatory courses remains uncertain. GMS skills were assessed before (T1) and after a preparatory course (T2) and then again 2 (T3) and 4 (T4) months into residency and compared to surgical interns without such a course. METHODS: In April, GMS took the preparatory course. In July-August all interns participated in a basic skills curriculum. Learners completed four technical exercises pre/post each course. Three surgeons scored performances. GMS scores were compared across the 4 time points. Control interns were compared at T3 and T4. RESULTS: Thirty-two interns completed all pre/post course assessments (T3 and T4); seven of those were GMSs. GMS scores increased from 74.5%(T1) to 94.2%(T2) (p < 0.001), and were maintained into residency. Control interns also improved (65.8%(T3) to 91.8%(T4), p < 0.001). GMS-interns scored higher starting residency compared to control interns (T3, 89.08% vs 65.03%, p < 0.001). CONCLUSIONS: These findings support existing literature and demonstrate that students maintain their skills into residency. Preparatory courses provide a head start. Without such course, interns require a steep learning curve. PMID- 29117918 TI - Lack of soluble circulating cardiodepressant factors in takotsubo cardiomyopathy. AB - Circulating cardiodepressant factors were found to mediate cardiac dysfunction in patients with sepsis and acute systolic heart failure. To investigate the presence of circulating cardiodepressant factors in patients with Takotsubo Cardiomyopathy (TC), plasma samples were collected from 4 patients with TC, 3 with septic shock, 5 with acute systolic heart failure and 4 healthy controls and injected intraperitoneally in mice. The cardiodepressant effects are measured with transthoracic echocardiography. Plasma injection from control and TC subjects had no effects on left ventricle ejection fraction (LVEF) whereas plasma from the other two groups induced a significant reduction in LVEF. At difference than sepsis and acute heart failure, TC is not characterized by the presence of soluble cardiodepressant factors. Myocardial dysfunction in TC may be mediated by a neurocardiogenic mechanism. PMID- 29117919 TI - GuideLiner extension catheter-facilitated side strut stenting technique for the treatment of right coronary artery ostial in-stent restenosis. AB - Percutaneous coronary intervention (PCI) for the treatment of right coronary artery (RCA) ostial in-stent restenosis (ISR) can be challenging. The technical difficulties are compounded by excessive stent protrusion into the aorta, preventing coaxial engagement of the guiding catheter and wiring through the central stent lumen. Through this review, we aim to highlight the practical challenges encountered during the treatment of ostial RCA ISR through PCI and evaluate the various interventional techniques that have been used. We describe the first reported case of a GuideLiner extension catheter-facilitated side-strut stenting for the treatment of ostial RCA ISR and demonstrate the safety and feasibility of this novel technique. PMID- 29117917 TI - Antagonistic endophytic bacteria associated with nodules of soybean (Glycine max L.) and plant growth-promoting properties. AB - A total of 276 endophytic bacteria were isolated from the root nodules of soybean (Glycine max L.) grown in 14 sites in Henan Province, China. The inhibitory activity of these bacteria against pathogenic fungus Phytophthora sojae 01 was screened in vitro. Six strains with more than 63% inhibitory activities were further characterized through optical epifluorescence microscopic observation, sequencing, and phylogenetic analysis of 16S rRNA gene, potential plant growth promoting properties analysis, and plant inoculation assay. On the basis of the phylogeny of 16S rRNA genes, the six endophytic antagonists were identified as belonging to five genera: Enterobacter, Acinetobacter, Pseudomonas, Ochrobactrum, and Bacillus. The strain Acinetobacter calcoaceticus DD161 had the strongest inhibitory activity (71.14%) against the P. sojae 01, which caused morphological abnormal changes of fungal mycelia; such changes include fracture, lysis, formation of a protoplast ball at the end of hyphae, and split ends. Except for Ochrobactrum haematophilum DD234, other antagonistic strains showed the capacity to produce siderophore, indole acetic acid, and nitrogen fixation activity. Regression analysis suggested a significant positive correlation between siderophore production and inhibition ratio against P. sojae 01. This study demonstrated that nodule endophytic bacteria are important resources for searching for inhibitors specific to the fungi and for promoting effects for soybean seedlings. PMID- 29117920 TI - Orbital atherectomy treatment of severely calcified native coronary lesions in patients with prior coronary artery bypass grafting: Acute and one-year outcomes from the ORBIT II trial. AB - AIMS: Patients undergoing percutaneous coronary intervention (PCI), with a history of coronary artery bypass grafting (CABG), may be at increased risk for mortality and repeat revascularization, compared with patients without prior CABG. In this post-hoc analysis of the ORBIT II trial, safety and efficacy of coronary orbital atherectomy (OA) to modify severe coronary artery calcium, prior to stent placement, was evaluated in subjects based on history of CABG. METHODS AND RESULTS: Comorbidities: diabetes, dyslipidemia, hypertension, and history of myocardial infarction (MI) were more prevalent in the CABG group. The in-hospital major adverse cardiac event (MACE) rate, defined as a composite of cardiac death, MI (CK-MB>3* ULN), and target vessel revascularization (TVR), was higher in the CABG group (16.9% vs. 8.5%, p=0.04), driven primarily by a higher incidence of MI (16.9% vs. 8.0%, p=0.03); however, Q-wave rates were low at 1.5% vs 0.5%, (p=0.38). There was no significant difference in rates of cardiac death (6.2% vs. 2.7%, p=0.17) and TVR (7.9% vs. 5.5%, p=0.47). CONCLUSIONS: Low rates of TVR, cardiac death, and Q-wave MI, suggest OA treatment to facilitate stent delivery is successful and provides durable outcomes in subjects with and without prior CABG. CONDENSED ABSTRACT: Patients with history of CABG have extensive coronary artery disease. Those who undergo PCI may be at increased risk for mortality and repeat revascularization, compared with patients without prior CABG. This post hoc analysis of ORBIT II trial evaluated safety and efficacy of coronary OA to modify severe coronary artery calcium, prior to stent placement, based on subject history of CABG. The MACE rate was higher in the CABG group, driven by higher incidence of MI; however, Q-wave rates were low. OA treatment to facilitate stent delivery is successful, but higher incidence of non-Q-wave MI in CABG patients warrants further study. PMID- 29117921 TI - Intralabyrinthine sporadic endolymphatic sac tumour. AB - INTRODUCTION: Endolymphatic sac tumours are benign, slowly growing tumours that invade the temporal bone, and present clinically in the form of unilateral hearing loss. They can be sporadic or occur in the context of Von Hippel-Lindau disease (VHL). CASE SUMMARY: The authors report a case of endolymphatic sac tumour arising in the utricle presenting histological and immunohistochemical features corresponding to endolymphatic sac tumour in a patient without VHL. DISCUSSION: Endolymphatic sac tumours invade the posterior part of the petrous temporal bone. According to two studies concerning patients with Von Hippel Lindau disease, endolymphatic sac tumours arise from the endolymphatic duct. This case of intralabyrinthine sporadic endolymphatic sac tumour supports this hypothesis for sporadic forms, indicating the need for labyrinthectomy associated with tumour resection to avoid recurrence. PMID- 29117922 TI - Depression, anxiety, and post-traumatic stress disorder among youth in low and middle income countries: A review of prevalence and treatment interventions. AB - BACKGROUND: Low and middle income countries (LMICs) not only have the majority of the world's population but also the largest proportion of youth. Poverty, civil conflict and environmental stressors tend to be endemic in these countries and contribute to significant psychiatric morbidity, including depression, anxiety and post-traumatic stress disorder (PTSD). However, mental health data from LMICs is scarce, particularly data on youth. Evaluation of such information is crucial for planning services and reducing the burden of disability. This paper reviews the published data on the prevalence and randomized trials of interventions for depression, anxiety and PTSD in youth in LMICs. METHODS: PubMed and Google Scholar were searched for articles published in English up to January 2017, using the keywords: Low/middle income country, depression, anxiety, post-traumatic stress disorder, child, youth, adolescent, prevalence, treatment, intervention, and outcomes. RESULTS: The few prevalence studies in LMICs reported rates of up to 28% for significant symptoms of depression or anxiety among youth, and up to 87% for symptoms of PTSD among youth exposed to traumatic experienences, though these rates varied widely depending on several factors, including the assessments tools used. Most rigorous interventions employed some form or variation of CBT, with mixed results. Studies using other forms of psychosocial interventions appear to be heterogeneous and less rigorous. CONCLUSIONS: The mental health burden due to depression and anxiety disorders in youth is substantial in LMICs, with high needs but inadequate services. Youth specific services for early detection and cost-effective interventions are needed. PMID- 29117924 TI - Red flags in epilepsy surgery: Identifying the patients who pay a high cognitive price for an unsuccessful surgical outcome. AB - Preoperative estimates of cognitive and seizure outcome must be as accurate as possible if the candidate is to make an informed decision about epilepsy surgery. Significant declines in memory function are reported in approximately 30% of temporal lobe surgery patients. The percentage varies according to the ways in which a postoperative deterioration is defined but since the majority of outcome studies do not take into account the patient's capacity to deteriorate if they are functioning at or close to the floor of a memory test prior to surgery, the published percentages may be an underrepresentation of the true extent of memory decline following epilepsy surgery. We examined the cognitive 'cost' of epilepsy surgery in a consecutive series of 474 patients who underwent elective surgery for medically intractable epilepsy. All patients underwent a presurgical assessment prior to and 1year after the surgery. Reliable change indices were used to identify significant postoperative memory decline. Postoperative outcome was dichotomized using the ILAE 2008 classification. All patients in class one were classified as seizure-free (67.5% of the sample). Excluding patients already functioning at or below the 2nd percentile on standardized memory tests, 37.8% experienced a significant postoperative decline in memory function. Twelve percent experienced the 'double hit' of significant postoperative memory decline and ongoing seizures following surgery. Patients with pathologies other than hippocampal sclerosis and with signs of limited cognitive reserve, both in terms of memory function and overall intellectual ability were most likely to suffer a double hit. Our results indicate that caution should be exercised when operating on these patients and preoperative counseling should be tailored to reflect the likely risk/benefit ratio of a temporal lobe resection for medically intractable epilepsy in this group. PMID- 29117923 TI - Genital injuries acute evaluation and management. AB - Genital trauma may result in external injuries to the labia, vulva or vagina, urethra and anus and internal injuries to the bony pelvis, bladder, bowels and reproductive organs. Worldwide, the most common cause of genital trauma in reproductive age women is injury sustained during childbirth, but in this chapter we will focus on accidental genital injuries as well as those arising from sexual violence, and female genital mutilation. While genital injuries alone rarely result in death; if not properly managed, chronic discomfort, dyspareunia, infertility, or fistula formation may result. Clinicians need to be able to recognize these injuries and provide initial management, and assure that the patient's mental, emotional and physical needs are addressed. PMID- 29117925 TI - Frequency and predictors of psychological distress after a diagnosis of epilepsy: A community-based study: Methodological issues. PMID- 29117926 TI - [Maternal deaths due to hypertensive disorders. Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Between 2010 and 2012, the rate of maternal death caused by hypertensive disorders (0,5/100,000 living birth) was reduced by 50% compared to the 2007-2009 period. Hypertensive disorders were responsible from 5% of maternal deaths and from 10% of direct maternal mortality. Eleven deaths happened during the postpartum period but 9 hypertensive complications began before delivery. Seventy percent of these deaths seem to be avoidable. The main causes of suboptimal management were: unappropriated or insufficient obstetrical and anesthetic treatments, undiagnosed HELLP syndrome and subcapsular liver hematoma, delayed treatment. The analysis of these maternal deaths gave the opportunity to stress some major lessons to optimize medical management in case of hypertensive diseases during pregnancy: abdominal symptoms during third trimester of pregnancy lead to search hypertensive disorders; HELLP syndrome with severe anemia indicate to carry out abdominal ultrasound. PMID- 29117927 TI - Sexual Health and the Internet: Cross-Sectional Study of Online Preferences Among Adolescents. AB - BACKGROUND: The Internet is widely used by adolescents for sexual health information and bears the potential to increase knowledge and positively affect behavior. OBJECTIVE: The objective of this study is to assess students' preferences when looking for sexual health information online. METHODS: We conducted a cross-sectional survey among ninth grade students in a convenience sample of 13 secondary schools in Berlin, Germany. During a regular school period, participants were requested to rate the importance they attribute to nine aspects of sexual health websites in a paper-based questionnaire. Bivariate and multivariable analyses were used to assess awareness and preferences by gender, age, migrant background, and school type. RESULTS: Of 1190 eligible students, 1177 (98.91%) students with a mean age of 14.6 (SD 0.7) years participated, 52.52% (605/1152) were male, and 52.94% (612/1156) had at least one parent born abroad. Participant numbers were spread equally across three types of secondary schools in Berlin. Website aspects most frequently cited as important were easily comprehensible wording (88.33%, 961/1088), clear information layout (80.57%, 871/1081), and reliability of the website's publisher (79.28%, 857/1081), whereas the visual style of a website was deemed important by the lowest number of students (35.13%, 378/1076). There was a marked gender difference in the importance students attached to website publisher reliability. Although 437/515 (84.9%) of female participants regarded this as important, only 420/566 (74.2%) of male participants did likewise (P<.001). In multivariable analyses, demographic differences were also particularly visible in the importance of publisher reliability: male participants were significantly less likely to find this aspect important (OR 0.50, 95% CI 0.37-0.69). The odds ratio for students with migrant background was 0.64 (95% CI 0.50-0.81, reference=no migrant background) and OR 2.04 (95% CI 1.03-4.03) for students in the most academic school type (reference=least academic). CONCLUSIONS: Students prefer easily understandable online resources. Setting up sexual health websites according to the explicit preferences of the target audience might encourage usage, especially by those subpopulations less likely to critically assess information validity: male adolescents, children of immigrants, and the academically disadvantaged. PMID- 29117929 TI - A Fully Automated Web-Based Program Improves Lifestyle Habits and HbA1c in Patients With Type 2 Diabetes and Abdominal Obesity: Randomized Trial of Patient E-Coaching Nutritional Support (The ANODE Study). AB - BACKGROUND: The prevalence of abdominal obesity and type 2 diabetes mellitus (T2DM) is a public health challenge. New solutions need to be developed to help patients implement lifestyle changes. OBJECTIVE: The objective of the study was to evaluate a fully automated Web-based intervention designed to help users improve their dietary habits and increase their physical activity. METHODS: The Accompagnement Nutritionnel de l'Obesite et du Diabete par E-coaching (ANODE) study was a 16-week, 1:1 parallel-arm, open-label randomized clinical trial. Patients with T2DM and abdominal obesity (n=120, aged 18-75 years) were recruited. Patients in the intervention arm (n=60) had access to a fully automated program (ANODE) to improve their lifestyle. Patients were asked to log on at least once per week. Human contact was limited to hotline support in cases of technical issues. The dietetic tool provided personalized menus and a shopping list for the day or the week. Stepwise physical activity was prescribed. The control arm (n=60) received general nutritional advice. The primary outcome was the change of the dietary score (International Diet Quality Index; DQI-I) between baseline and the end of the study. Secondary endpoints included changes in body weight, waist circumference, hemoglobin A1c (HbA1c) and measured maximum oxygen consumption (VO2 max). RESULTS: The mean age of the participants was 57 years (standard deviation [SD] 9), mean body mass index was 33 kg/m2 (SD 4), mean HbA1c was 7.2% (SD 1.1), and 66.7% (80/120) of participants were women. Using an intention-to-treat analysis, the DQI-I score (54.0, SD 5.7 in the ANODE arm; 52.8, SD 6.2 in the control arm; P=.28) increased significantly in the ANODE arm compared to the control arm (+4.55, SD 5.91 vs -1.68, SD 5.18; between arms P<.001). Body weight, waist circumference, and HbA1c changes improved significantly in the intervention. CONCLUSIONS: Among patients with T2DM and abdominal obesity, the use of a fully automated Web-based program resulted in a significant improvement in dietary habits and favorable clinical and laboratory changes. The sustainability of these effects remains to be determined. TRIAL REGISTRATION: ClinicalTrials.gov NCT02343107; http://clinicaltrials.gov/ct2/show/NCT02343107 (Archived by WebCite at http://www.webcitation.org/6uVMKPRzs). PMID- 29117928 TI - Brain Activation in Response to Personalized Behavioral and Physiological Feedback From Self-Monitoring Technology: Pilot Study. AB - BACKGROUND: The recent surge in commercially available wearable technology has allowed real-time self-monitoring of behavior (eg, physical activity) and physiology (eg, glucose levels). However, there is limited neuroimaging work (ie, functional magnetic resonance imaging [fMRI]) to identify how people's brains respond to receiving this personalized health feedback and how this impacts subsequent behavior. OBJECTIVE: Identify regions of the brain activated and examine associations between activation and behavior. METHODS: This was a pilot study to assess physical activity, sedentary time, and glucose levels over 14 days in 33 adults (aged 30 to 60 years). Extracted accelerometry, inclinometry, and interstitial glucose data informed the construction of personalized feedback messages (eg, average number of steps per day). These messages were subsequently presented visually to participants during fMRI. Participant physical activity levels and sedentary time were assessed again for 8 days following exposure to this personalized feedback. RESULTS: Independent tests identified significant activations within the prefrontal cortex in response to glucose feedback compared with behavioral feedback (P<.001). Reductions in mean sedentary time (589.0 vs 560.0 minutes per day, P=.014) were observed. Activation in the subgyral area had a moderate correlation with minutes of moderate-to-vigorous physical activity (r=0.392, P=.043). CONCLUSION: Presenting personalized glucose feedback resulted in significantly more brain activation when compared with behavior. Participants reduced time spent sedentary at follow-up. Research on deploying behavioral and physiological feedback warrants further investigation. PMID- 29117930 TI - Psychometric Evaluation of a Patient-Reported Symptom Index for Nonmuscle Invasive Bladder Cancer: Field Testing Protocol. AB - BACKGROUND: Nonmuscle invasive bladder cancer (NMIBC) is a chronic condition requiring intensive follow-up, repeated endoscopic examinations, tumor resections, and intravesical treatments that can occur every 3 months for life. In this clinical context, patient-reported outcomes (PROs) are a critical concern for patients and their managing clinicians. PROs have enormous potential to be integral to treatment assessment and recommendations for NMIBC; however, current PRO measures are inadequate for NMIBC because they lack key NMIBC-specific symptoms and side effects associated with contemporary treatments. OBJECTIVE: The overarching aim of this study was to develop and evaluate a patient-reported symptom index (SI) for individuals with NMIBC (the NMIBC-SI) that is acceptable to patients; reliable, valid, and responsive to differences between contemporary treatments for NMIBC; and fit for purpose as an endpoint in clinical trials. METHODS: The NMIBC-SI will be evaluated in 2 field tests across a total of 3 years. Field test 1 is a cross-sectional study design involving 225 adult NMIBC patients recruited while undergoing active treatment or those who completed final treatment within the past week. Data collected include patient demographics, clinical features of the tumor, risk category, treatment type, comorbidity, and PROs. Field test 2 is a prospective longitudinal study involving 225 newly diagnosed NMIBC-SI patients. Clinical data and patient-completed questionnaires will be collected at 4 time points during treatment: before tumor resection, 1 week after resection, end-of-induction intravesical therapy, and 1-year follow up. Standard psychometric tests will be performed to assess the reliability, validity, responsiveness, and clinical utility of the NMIBC-SI. RESULTS: Participant recruitment to field test 1 commenced in February 2017. Recruitment for field test 2 is planned to commence in January 2018. Final results are expected to be published in 2019. The NMIBC-SI will be freely available for use via registration. CONCLUSIONS: This study protocol contains detailed methods that will be used across multiple international sites. Phase 2 in the development of the NMIBC-SI will enable a comprehensive evaluation of its reliability, validity, and responsiveness to ensure that the NMIBC-SI is fit for purpose in clinical research and provides an evidence base for the ongoing improvement of future therapies for NMIBC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03091764; http://clinicaltrials.gov/ct2/showNCT03091764 (Archived by WebCite at http://www.webcitation.org/6umBhQeNX). PMID- 29117931 TI - Electronic Brief Intervention and Text Messaging for Marijuana Use During Pregnancy: Initial Acceptability of Patients and Providers. AB - BACKGROUND: Marijuana is the most widely used illicit substance during pregnancy. Technology-delivered brief interventions and text messaging have shown promise in general and pregnant samples but have not yet been applied to marijuana use in pregnancy. OBJECTIVE: The objective of the study was to evaluate, among pregnant women and prenatal care providers, the acceptability of an electronic brief intervention and text messaging plan for marijuana use in pregnancy. METHODS: Participants included patients (n=10) and medical staff (n=12) from an urban prenatal clinic. Patient-participants were recruited directly during a prenatal care visit. Those who were eligible reviewed the interventions individually and provided quantitative and qualitative feedback regarding software acceptability and helpfulness during a one-on-one interview with research staff. Provider participants took part in focus groups in which the intervention materials were reviewed and discussed. Qualitative and focus group feedback was transcribed, coded manually, and classified by category and theme. RESULTS: Patient participants provided high ratings for satisfaction, with mean ratings for respectfulness, interest, ease of use, and helpfulness ranging between 4.4 and 4.7 on a 5-point Likert scale. Of the 10 participants, 5 reported that they preferred working with the program versus their doctor, and 9 of 10 said the intervention made them more likely to reduce their marijuana use. Provider participants received the program favorably, stating the information presented was both relevant and important for their patient population. CONCLUSIONS: The findings support the acceptability of electronic brief intervention and text messaging for marijuana use during pregnancy. This, combined with their ease of use and low barrier to initiation, suggests that further evaluation in a randomized trial is appropriate. PMID- 29117933 TI - A Web-Based Study of Dog Ownership and Depression Among People Living With HIV. AB - BACKGROUND: People living with human immunodeficiency virus (PLHIV) are approximately twice as likely to be depressed compared with HIV-negative individuals. Depression is consistently associated with low antiretroviral therapy (ART) adherence, an important step within the HIV care continuum related to HIV disease progression and overall health. One factor that may have positive psychosocial benefits and promote ART adherence is dog ownership. Research indicates that dog ownership is associated with lower depression, and initial evidence suggests its positive impact on psychosocial outcomes for PLHIV. OBJECTIVE: The aim of our study was to expand the existing research by examining the relationship between current dog ownership and depression for a sample of PLHIV while controlling for demographic characteristics and other potential confounders. METHODS: Participants aged 18 years or older and who self-reported an HIV diagnosis were recruited via social media into When Dogs Heal, a cross sectional Web-based survey to collect data among adult PLHIV. The research visit was conducted via a Web-based survey, and there was no in-person interaction with the participant. Primary outcome measures included demographic questions (age, race, ethnicity, gender, and sexual orientation), pet ownership (type of pet owned and current dog ownership), depression (Center for Epidemiologic Studies Depression Scale, 10 items), and resilience (Resilience Research Centre Adult Resilience Measure, 28 items). RESULTS: A total of 252 participants were enrolled into the study in January 2016, with a final analytic sample of 199 participants. Mean age was 49 years, 86.4% (172/199) of participants were male, and 80.4% (160/199) were white. Current dog ownership was prevalent among the sample (68.3%, 136/199). Bivariate analysis indicated that there was no significant relationship between depression and demographic characteristics (age, race, ethnicity, gender, and sexual orientation), with P>.05. The multivariate logistic regression, including age, race, ethnicity, gender, resilience, and current dog ownership, was significant, with P<.001. Of the 6 predictor variables, only 2 were statistically significant: dog ownership and resilience. Noncurrent dog owners had 3 times higher odds of depression in comparison with current dog owners: odds ratio 3.01; 95% CI 1.54-6.21. CONCLUSIONS: Growing evidence suggests that dog ownership reduces the likelihood of depression and, therefore, may confer long-term health benefits on PLHIV. Future studies should explore whether dog-specific interventions are a feasible and efficacious intervention to improve outcomes among PLHIV. PMID- 29117932 TI - Patient Transfers and Risk of Back Injury: Protocol for a Prospective Cohort Study With Technical Measurements of Exposure. AB - BACKGROUND: More than one third of nurses experience musculoskeletal pain several times during a normal work week. Consistent use of assistive devices during patient transfers is associated with a lower risk of occupational back injuries and low back pain (LBP). While uncertainties exist regarding which type of assistive devices most efficiently prevent LBP, exposure assessments using technological advancements allow for quantification of muscle load and body positions during common work tasks. OBJECTIVE: The main objectives of this study are (1) to quantify low back and neck/shoulder muscle load in Danish nurses during patient transfers performed with different types of assistive devices, and (2) to combine the exposure profile for each type of assistive device with fortnightly questionnaires to identify the importance of muscle load (intensity and frequency of transfers) and body position (degree of back inclination and frequency) on LBP intensity and risk of back injury during a patient transfer. METHODS: A combination of technical measurements (n=50) and a prospective study design (n=2000) will be applied on a cohort of female nurses in Danish hospitals. The technical measurements will be comprised of surface electromyography and accelerometers, with the aim of quantifying muscle load and body positions during various patient transfers, including different types of assistive devices throughout a workday. The study will thereby gather measurements during real-life working conditions. The prospective cohort study will consist of questionnaires at baseline and 1-year follow-up, as well as follow-up via email every other week for one year on questions regarding the frequency of patient transfers, use of assistive devices, intensity of LBP, and back injuries related to patient transfers. The objective measurements on muscle load and body positions during patient handlings will be applied to the fortnightly replies regarding frequency of patient transfer and use of different assistive devices, in order to identify risk factors for back injuries related to patient transfers and intensity of LBP. RESULTS: Data collection is scheduled to commence during the winter of 2017. CONCLUSIONS: The design of this study is novel in its combination of technical measurements applied on a prospective cohort, and the results will provide important information about which assistive devices are associated with intensity of LBP and risk of back injury related to patient transfers. Furthermore, this study will shed light on the dose-response relationship between intensity, duration, and frequency of patient transfers and the intensity of LPB in Danish nurses, and will thereby help to guide and improve electronic health practices among this population. PMID- 29117934 TI - Uses of Mobile Device Digital Photography of Dermatologic Conditions in Primary Care. AB - BACKGROUND: PhotoExam is a mobile app that incorporates digital photographs into the electronic health record (EHR) using iPhone operating system (iOS, Apple Inc) based mobile devices. OBJECTIVE: The aim of this study was to describe usage patterns of PhotoExam in primary care and to assess clinician-level factors that influence the use of the PhotoExam app for teledermatology (TD) purposes. METHODS: Retrospective record review of primary care patients who had one or more photos taken with the PhotoExam app between February 16, 2015 to February 29, 2016 were reviewed for 30-day outcomes for rates of dermatology consult request, mode of dermatology consultation (curbside phone consult, eConsult, and in-person consult), specialty and training level of clinician using the app, performance of skin biopsy, and final pathological diagnosis (benign vs malignant). RESULTS: During the study period, there were 1139 photo sessions on 1059 unique patients. Of the 1139 sessions, 395 (34.68%) sessions documented dermatologist input in the EHR via dermatology curbside consultation, eConsult, and in-person dermatology consult. Clinicians utilized curbside phone consults preferentially over eConsults for TD. By clinician type, nurse practitioners (NPs) and physician assistants (PAs) were more likely to utilize the PhotoExam for TD as compared with physicians. By specialty type, pediatric clinicians were more likely to utilize the PhotoExam for TD as compared with family medicine and internal medicine clinicians. A total of 108 (9.5%) photo sessions had a biopsy performed of the photographed site. Of these, 46 biopsies (42.6%) were performed by a primary care clinician, and 27 (25.0%) biopsies were interpreted as a malignancy. Of the 27 biopsies that revealed malignant findings, 6 (22%) had a TD consultation before biopsy, and 10 (37%) of these biopsies were obtained by primary care clinicians. CONCLUSIONS: Clinicians primarily used the PhotoExam for non-TD purposes. Nurse practitioners and PAs utilized the app for TD purposes more than physicians. Primary care clinicians requested curbside dermatology consults more frequently than dermatology eConsults. PMID- 29117935 TI - Maternal mental health: Handle with care. PMID- 29117936 TI - Wanted: clinicians to avert NHS transformation failure. PMID- 29117938 TI - Functional characterization of AVPR2 mutants found in Turkish patients with nephrogenic diabetes insipidus. AB - Diabetes insipidus is a rare disorder characterized by an impairment in water balance because of the inability to concentrate urine. While central diabetes insipidus is caused by mutations in the AVP, the reason for genetically determined nephrogenic diabetes insipidus can be mutations in AQP2 or AVPR2 After release of AVP from posterior pituitary into blood stream, it binds to AVPR2, which is one of the receptors for AVP and is mainly expressed in principal cells of collecting ducts of kidney. Receptor activation increases cAMP levels in principal cells, resulting in the incorporation of AQP2 into the membrane, finally increasing water reabsorption. This pathway can be altered by mutations in AVPR2 causing nephrogenic diabetes insipidus. In this study, we functionally characterize four mutations (R68W, DeltaR67-G69/G107W, V162A and T273M) in AVPR2, which were found in Turkish patients. Upon AVP stimulation, R68W, DeltaR67 G69/G107W and T273M showed a significantly reduced maximum in cAMP response compared to wild-type receptor. All mutant receptor proteins were expressed at the protein level; however, R68W, DeltaR67-G69/G107W and T273M were partially retained in the cellular interior. Immunofluorescence studies showed that these mutant receptors were trapped in ER and Golgi apparatus. The function of V162A was indistinguishable from the indicating other defects causing disease. The results are important for understanding the influence of mutations on receptor function and cellular trafficking. Therefore, characterization of these mutations provides useful information for further studies addressing treatment of intracellularly trapped receptors with cell-permeable antagonists to restore receptor function in patients with nephrogenic diabetes insipidus. PMID- 29117939 TI - A Novel Signaling Complex between TROY and EGFR Mediates Glioblastoma Cell Invasion. AB - Glioblastoma is the most frequent primary brain tumor in adults and a highly lethal malignancy with a median survival of about 15 months. The aggressive invasion of the surrounding normal brain makes complete surgical resection impossible, increases the resistance to radiation and chemotherapy, and assures tumor recurrence. Thus, there is an urgent need to develop innovative therapeutics to target the invasive tumor cells for improved treatment outcomes of this disease. Expression of TROY (TNFRSF19), a member of the tumor necrosis factor (TNF) receptor family, increases with increasing glial tumor grade and inversely correlates with patient survival. Increased expression of TROY stimulates glioblastoma cell invasion in vitro and in vivo and increases resistance to temozolomide and radiation therapy. Conversely, silencing TROY expression inhibits glioblastoma cell invasion, increases temozolomide sensitivity, and prolongs survival in an intracranial xenograft model. Here, a novel complex is identified between TROY and EGFR, which is mediated predominantly by the cysteine-rich CRD3 domain of TROY. Glioblastoma tumors with elevated TROY expression have a statistically positive correlation with increased EGFR expression. TROY expression significantly increases the capacity of EGF to stimulate glioblastoma cell invasion, whereas depletion of TROY expression blocks EGF stimulation of glioblastoma cell invasion. Mechanistically, TROY expression modulates EGFR signaling by facilitating EGFR activation and delaying EGFR receptor internalization. Moreover, the association of EGFR with TROY increases TROY-induced NF-kappaB activation. These findings substantiate a critical role for the TROY-EGFR complex in regulation of glioblastoma cell invasion.Implications: The TROY-EGFR signaling complex emerges as a potential therapeutic target to inhibit glioblastoma cell invasion. Mol Cancer Res; 16(2); 322-32. (c)2017 AACR. PMID- 29117941 TI - Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU. AB - Thymidylate synthase (TS) inhibitors including fluoropyrimidines [e.g., 5 Fluorouracil (5-FU) and 5-Fluorodeoxyuridine (5-FdU, floxuridine)] and antifolates (e.g., pemetrexed) are widely used against solid tumors. Previously, we reported that shRNA-mediated knockdown (KD) of uracil DNA glycosylase (UDG) sensitized cancer cells to 5-FdU. Because p53 has also been shown as a critical determinant of the sensitivity to TS inhibitors, we further interrogated 5-FdU cytotoxicity after UDG depletion with regard to p53 status. By analyzing a panel of human cancer cells with known p53 status, it was determined that p53-mutated or -deficient cells are highly resistant to 5-FdU. UDG depletion resensitizes 5 FdU in p53-mutant and -deficient cells, whereas p53 wild-type (WT) cells are not affected under similar conditions. Utilizing paired HCT116 p53 WT and p53 knockout (KO) cells, it was shown that loss of p53 improves cell survival after 5 FdU, and UDG depletion only significantly sensitizes p53 KO cells. This sensitization can also be recapitulated by UDG depletion in cells with p53 KD by shRNAs. In addition, sensitization is also observed with pemetrexed in p53 KO cells, but not with 5-FU, most likely due to RNA incorporation. Importantly, in p53 WT cells, the apoptosis pathway induced by 5-FdU is activated independent of UDG status. However, in p53 KO cells, apoptosis is compromised in UDG-expressing cells, but dramatically elevated in UDG-depleted cells. Collectively, these results provide evidence that loss of UDG catalyzes significant cell death signals only in cancer cells mutant or deficient in p53.Implications: This study reveals that UDG depletion restores sensitivity to TS inhibitors and has chemotherapeutic potential in the context of mutant or deficient p53. Mol Cancer Res; 16(2); 212-21. (c)2017 AACR. PMID- 29117940 TI - ETV4 Facilitates Cell-Cycle Progression in Pancreatic Cells through Transcriptional Regulation of Cyclin D1. AB - The ETS family transcription factor ETV4 is aberrantly expressed in a variety of human tumors and plays an important role in carcinogenesis through upregulation of relevant target gene expression. Here, it is demonstrated that ETV4 is overexpressed in pancreatic cancer tissues as compared with the normal pancreas, and is associated with enhanced growth and rapid cell-cycle progression of pancreatic cancer cells. ETV4 expression was silenced through stable expression of a specific short hairpin RNA (shRNA) in two pancreatic cancer cell lines (ASPC1 and Colo357), while it was ectopically expressed in BXPC3 cells. Silencing of ETV4 in ASPC1 and Colo357 cells reduced the growth by 55.3% and 38.9%, respectively, while forced expression of ETV4 in BXPC3 cells increased the growth by 46.8% in comparison with respective control cells. Furthermore, ETV4-induced cell growth was facilitated by rapid transition of cells from G1- to S-phase of the cell cycle. Mechanistic studies revealed that ETV4 directly regulates the expression of Cyclin D1 CCND1, a protein crucial for cell-cycle progression from G1- to S-phase. These effects on the growth and cell cycle were reversed by the forced expression of Cyclin D1 in ETV4-silenced pancreatic cancer cells. Altogether, these data provide the first experimental evidence for a functional role of ETV4 in pancreatic cancer growth and cell-cycle progression.Implications: The functional and mechanistic data presented here regarding ETV4 in pancreatic cancer growth and cell-cycle progression suggest that ETV4 could serve as a potential biomarker and novel target for pancreatic cancer therapy. Mol Cancer Res; 16(2); 187-96. (c)2017 AACR. PMID- 29117942 TI - ERbeta Sensitizes NSCLC to Chemotherapy by Regulating DNA Damage Response. AB - The expression of wild-type estrogen receptor beta (ESR2/ERbeta1) correlates with clinical outcome in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanism that accounts for this association is currently poorly understood. ERbeta1 was previously linked to chemotherapy response in patients with breast cancer and in breast cancer cells. The effect of the receptor in NSCLC cells after chemotherapy treatment, a common remedy for advanced NSCLC, has not been studied. Here, upregulation of ERbeta1 increases the sensitivity of NSCLC cells to treatment with doxorubicin and etoposide. This effect was primarily observed in p53-defecient NSCLC cells. In these cells, ERbeta1 either enhanced G2-M cell-cycle arrest by activating the checkpoint kinase 1 (Chk1) and altering downstream signaling or induced apoptosis. The expression of p63 target genes that control G2-M checkpoint activation was altered by ERbeta1 suggesting an ERbeta1-p63 transcriptional cooperation in lung cancer cells that affects DNA damage response (DDR). These results suggest involvement of ERbeta1 in the mechanism that regulates DNA damage response in NSCLC cells and support the potential predictive and therapeutic value of the receptor in clinical management of the disease.Implications: This study demonstrating the impact of ERbeta1 on chemosensitivity of NSCLC cells suggests the predictive value of the receptor for successful response of tumors to chemotherapy and the potential benefit of chemotherapy-treated patients from the use of ER ligands. Mol Cancer Res; 16(2); 233-42. (c)2017 AACR. PMID- 29117943 TI - FBXO31 Suppresses Gastric Cancer EMT by Targeting Snail1 for Proteasomal Degradation. AB - The F-box protein FBXO31, a component of the Skp1/Cul1/F-box (SCF) E3 ubiquitin ligase complex, plays an important regulatory role in neuronal development, stress response, and tumorigenesis. Our recent report indicates that FBXO31 functions as a tumor suppressor in gastric cancer, and the loss of FBXO31 protein is associated with a higher malignant phenotype and poorer prognosis. However, little is known about the underlying mechanism. In this study, FBXO31 inhibits gastric cancer progression by suppressing the epithelial-mesenchymal transition (EMT). FBXO31 overexpression decreases, whereas its inhibition increases, the protein level of the EMT transcription factor Snail1 (SNAI1), respectively. Further evidence demonstrates that FBXO31 interacts with Snail1 and mediates the ubiquitin- and proteasome-dependent degradation of Snail1 in gastric cancer. The F-box domain of FBXO31 and the phosphorylation of Snail1 are necessary for the molecular interaction between FBXO31 and Snail1. Mouse modeling experiments reveal that FBXO31 overexpression inhibits in vivo colonization of gastric cancer cells. Furthermore, a highly significant negative correlation between FBXO31 and Snail1 is validated in human gastric cancer clinical specimens. Taken together, these findings identify Snail1 as a new target protein of FBXO31 in gastric cancer and substantiate a novel regulatory role of FBXO31 on gastric cancer progression and metastasis.Implication: These findings demonstrate that FBXO31 exerts the tumor-inhibitory role in gastric cancer by ubiquitin-mediated degradation of Snail1, which represents a viable strategy of FBXO31 activators in the prevention and therapy of gastric cancer. Mol Cancer Res; 16(2); 286-95. (c)2017 AACR. PMID- 29117944 TI - Small-Molecule Sigma1 Modulator Induces Autophagic Degradation of PD-L1. AB - Emerging evidence suggests that Sigma1 (SIGMAR1, also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small-molecule modulators of Sigma1 alter endoplasmic reticulum (ER)-associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type I integral membrane glycoprotein that is cotranslationally inserted into the ER and is processed and transported through the secretory pathway. Once at the surface of cancer cells, PD-L1 acts as a T-cell inhibitory checkpoint molecule and suppresses antitumor immunity. Here, we demonstrate that in Sigma1 expressing triple-negative breast and androgen-independent prostate cancer cells, PD-L1 protein levels were suppressed by RNAi knockdown of Sigma1 and by small molecule inhibition of Sigma1. Sigma1-mediated action was confirmed by pharmacologic competition between Sigma1-selective inhibitor and activator ligands. When administered alone, the Sigma1 inhibitor decreased cell surface PD L1 expression and suppressed functional interaction of PD-1 and PD-L1 in a coculture of T cells and cancer cells. Conversely, the Sigma1 activator increased PD-L1 cell surface expression, demonstrating the ability to positively and negatively modulate Sigma1 associated PD-L1 processing. We discovered that the Sigma1 inhibitor induced degradation of PD-L1 via autophagy, by a mechanism distinct from bulk macroautophagy or general ER stress-associated autophagy. Finally, the Sigma1 inhibitor suppressed IFNgamma-induced PD-L1. Our data demonstrate that small-molecule Sigma1 modulators can be used to regulate PD-L1 in cancer cells and trigger its degradation by selective autophagy.Implications: Sigma1 modulators sequester and eliminate PD-L1 by autophagy, thus preventing functional PD-L1 expression at the cell surface. This posits Sigma1 modulators as novel therapeutic agents in PD-L1/PD-1 blockade strategies that regulate the tumor immune microenvironment.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/2/243/F1.large.jpg Mol Cancer Res; 16(2); 243-55. (c)2017 AACR. PMID- 29117946 TI - Increasing access to contraceptive implants in the postnatal period via a home insertion service by community midwives. PMID- 29117945 TI - Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin. AB - Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME). Intracellular daunorubicin concentrations were evaluated using fluorescence. Daunorubicin and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of daunorubicin-metabolizing enzymes, aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3), in human adipose tissue, were queried using public databases and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized daunorubicin to daunorubicinol, reducing its antileukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of daunorubicin to daunorubicinol in vivo Adipocytes expressed high levels of AKR and CBR isoenzymes that deactivate anthracyclines. Indeed, adipocyte protein levels of AKR1C1, AKR1C2, and AKR1C3 are higher than all other human noncancerous cell types. To our knowledge, this is the first demonstration that adipocytes metabolize and inactivate a therapeutic drug. Adipocyte-mediated daunorubicin metabolism reduces active drug concentration in the TME. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow. As AKR and CBR enzymes metabolize several drugs, and can be expressed at higher levels in obese individuals, this proof-of-principle finding has important implications across many diseases.Implications: Adipocyte absorption and metabolism of chemotherapies can reduce cytotoxicity in cancer microenvironments, potentially contributing to poorer survival outcomes. Mol Cancer Res; 15(12); 1704-13. (c)2017 AACR. PMID- 29117947 TI - Adolescent Hearing Loss: Rising or Not, It Remains a Concern. PMID- 29117948 TI - Mortality in Infants Affected by Preterm Birth and Severe Small-for-Gestational Age Birth Weight. AB - BACKGROUND: Few researchers have evaluated neonatal mortality in the combined presence of preterm birth (PTB) and small-for-gestational age (SGA) birth weight. None differentiated between infants with and without anomalies, considered births starting at 23 weeks' gestation, or defined SGA at a more pathologic cutpoint less than the fifth percentile. METHODS: We completed a population-based cohort study within the province of Ontario, Canada, from 2002 to 2015. Included were 1 676 110 singleton hospital live births of 23 to 42 weeks' gestation. Modified Poisson regression compared rates and relative risks of neonatal mortality among those with (1) preterm birth at 23 to 36 weeks' gestation and concomitant severe small for gestational age (PTB-SGA), (2) PTB at 23 to 36 weeks' gestation without severe SGA, (3) term birth with severe SGA, and each relative to (4) neither. Relative risks were adjusted for maternal age and stratified by several demographic variables. RESULTS: Relative to a neonatal mortality rate of 0.6 per 1000 term infants without severe SGA, the rate was 2.8 per 1000 among term births with severe SGA (adjusted relative risk [aRR] 4.6; 95% confidence interval [CI] 4.0-5.4), 22.9 per 1000 for PTB without severe SGA (aRR 38.3; 95% CI 35.4-41.4) and 60.0 per 1000 for PTB-SGA (aRR 96.7; 95% CI 85.4-109.5). Stratification by demographic factors showed a persistence of this pattern of neonatal death. Restricting the sample to births at >=24 weeks' gestation, or newborns without a congenital or chromosomal anomaly, also demonstrated the same pattern. CONCLUSIONS: Methods to detect or prevent PTB or SGA should focus on PTB-SGA, which serves as a useful perinatal surveillance indicator. PMID- 29117949 TI - Trends in Hearing Loss Among Adolescents. AB - OBJECTIVES: Our aim with this article is to evaluate whether the prevalence of hearing loss is increasing among adolescents living in the United States. METHODS: All available data about hearing loss among adolescents from the large, federally funded National Health and Nutrition Examination Survey (NHANES) were analyzed. By using the 4 data releases between 1994 and 2010 (a total of 6891 adolescents), the prevalence of adolescent hearing loss >15 and >=25 dB at low frequencies (0.5, 1, and 2 kHz) and high frequencies (3, 4, 6, and 8 kHz) for bilateral, unilateral, and any loss were calculated. RESULTS: Only 13 of 90 comparisons of prevalence across combinations of degree, frequency, and laterality of hearing loss revealed a statistically significant increase at P < .05. Among the 18 subgroups of degree, frequency, and laterality, 61% had a lower prevalence of hearing loss in 2010 than in 1994, and 100% of the subgroups had a lower prevalence in 2010 than in 2006. CONCLUSIONS: With previous analyses of NHANES data from 1994 to 2006, researchers showed that hearing loss among US adolescents was increasing. Based on the NHANES data from 1994 to 2010 that are now available, there is no consistent evidence that hearing loss among adolescents in the United States is increasing. Results reveal that conclusions about trends using data from 2 time points can be misleading. NHANES should resume collecting audiometric data as part of their data collection protocol so that trends in the prevalence of childhood hearing loss can be documented. PMID- 29117950 TI - Epilepsy in multiple sclerosis: A nationwide population-based register study. AB - OBJECTIVE: To determine the cumulative incidence of epilepsy in a population based cohort of patients with multiple sclerosis (MS) and to investigate the association between epilepsy and clinical features of MS. METHODS: All available patients in the Swedish MS register (n = 14,545) and 3 age- and sex-matched controls per patient randomly selected from the population register (n = 43,635) were included. Data on clinical features of MS were retrieved from the Swedish MS register, and data on epilepsy and death were retrieved from comprehensive patient registers. RESULTS: The cumulative incidence of epilepsy was 3.5% (95% confidence interval [CI] 3.17-3.76) in patients with MS and 1.4% (95% CI 1.30 1.52) in controls (risk ratio 2.5, 95% CI 2.19-2.76). In a Cox proportional model, MS increased the risk of epilepsy (hazard ratio 3.2, 95% CI 2.64-3.94). Patients with relapsing-remitting MS had a cumulative incidence of epilepsy of 2.2% (95% CI 1.88-2.50), whereas patients with progressive disease had a cumulative incidence of 5.5% (95% CI 4.89-6.09). The cumulative incidence rose continuously with increasing disease duration to 5.9% (95% CI 4.90-7.20) in patients with disease duration >=34 years. Patients with an Expanded Disability Status Scale (EDSS) score >=7 had a cumulative incidence of epilepsy of 5.3% (95% CI 3.95-7.00). Disease duration and EDSS score were associated with epilepsy after multiple logistic regression (odds ratio [OR] 1.03, 95% CI 1.01-1.04 per year, p = 0.001; and OR 1.2, 95% CI 1.09-1.26 per EDSS step, p < 0.0001). CONCLUSIONS: Epilepsy is more common among patients with MS than in the general population, and a diagnosis of MS increases the risk of epilepsy. Our data suggest a direct link between severity of MS and epilepsy. PMID- 29117952 TI - Preventing cognitive decline in sickle cell disease: A good night's sleep. PMID- 29117951 TI - Long-term benefit of enzyme replacement therapy in Pompe disease: A 5-year prospective study. AB - OBJECTIVE: To determine the effect of enzyme replacement therapy (ERT) after 5 years and to identify predictors for a favorable response because few data are available on the long-term efficacy of ERT in Pompe disease. METHODS: We included 102 adult patients with Pompe disease in a nationwide, prospective cohort study. We assessed muscle strength (manual muscle testing with Medical Research Council [MRC] grading, handheld dynamometry [HHD]), muscle function (6-minute walk test, Quick Motor Function Test), daily life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale), and pulmonary function (forced vital capacity [FVC] in upright and supine positions, maximum inspiratory and expiratory pressures) at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements. RESULTS: Median follow-up duration was 6.1 years (range 0.4-7.9 years), of which 5.0 years (range 0.2-7.3 years) were during ERT. Treated patients had better muscle strength (MRC sum score +6.6 percentage points [pp]; HHD sum score +9.6 pp, both p < 0.0001), activity levels (R-PAct +10.8 pp, p < 0.002), and pulmonary function (FVC upright +7.3 pp, FVC supine +7.6 pp, both p < 0.0003) than expected for their untreated disease course. Walking distance improved (416 vs 376 m at baseline, p = 0.03). The largest increase was seen during the first 2 to 3 years of treatment. Response to treatment was similar between groups regardless of sex, age, or disease duration. CONCLUSIONS: Long-term ERT positively affects muscle strength, pulmonary function, and daily life activities in adult patients with Pompe disease, with a peak effect at ~2 to 3 years of treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with Pompe disease, long-term ERT positively affects muscle strength, pulmonary function, and daily life activities. PMID- 29117953 TI - Brain microbleeds, anticoagulation, and hemorrhage risk: Meta-analysis in stroke patients with AF. AB - OBJECTIVES: To assess the association between cerebral microbleeds (CMBs) and future spontaneous intracerebral hemorrhage (ICH) risk in ischemic stroke patients with nonvalvular atrial fibrillation (AF) taking oral anticoagulants. METHODS: This was a meta-analysis of cohort studies with >50 patients with recent ischemic stroke and documented AF, brain MRI at baseline, long-term oral anticoagulation treatment, and >=6 months of follow-up. Authors provided summary level data on stroke outcomes stratified by CMB status. We estimated pooled annualized ICH and ischemic stroke rates from Poisson regression. We calculated odds ratios (ORs) of ICH by CMB presence/absence, >=5 CMBs, and CMB topography (strictly lobar, mixed, and strictly deep) using random-effects models. RESULTS: We established an international collaboration and pooled data from 8 centers including 1,552 patients. The crude CMB prevalence was 30% and 7% for >=5 CMBs. Baseline CMB presence (vs no CMB) was associated with ICH during follow-up (OR 2.68, 95% confidence interval [CI] 1.19-6.01, p = 0.017). Presence of >=5 CMB was related to higher future ICH risk (OR 5.50, 95% CI 2.07-14.66, p = 0.001). The pooled annual ICH incidence increased from 0.30% (95% CI 0.04-0.55) among CMB negative patients to 0.81% (95% CI 0.17-1.45) in CMB-positive patients (p = 0.01) and 2.48% (95% CI 1.2-6.2) in patients with >=5 CMBs (p = 0.001). There was no association between CMBs and recurrent ischemic stroke. CONCLUSIONS: The presence of CMB on MRI and the dichotomized cutoff of >=5 CMBs might identify subgroups of ischemic stroke patients with AF with high ICH risk and after further validation could help in risk stratification, in anticoagulation decisions, and in guiding randomized trials and ongoing large observational studies. PMID- 29117954 TI - Blood pressure from mid- to late life and risk of incident dementia. AB - OBJECTIVE: To determine the association between blood pressure during midlife (40 64 years) to late life (>=65 years) and risk of incident dementia. METHODS: This study included 1,440 (758 women, mean age 69 +/- 6 years) Framingham Offspring participants who were free of dementia and attended 5 consecutive examinations at 4-year intervals starting at midlife (1983-1987, mean age 55 years) until late life (1998-2001, mean 69 years) and subsequently were followed up for incident dementia (mean 8 years). We determined the effect of midlife hypertension (>=140/90 mm Hg), late life hypertension, lower late life blood pressure (<100/70 mm Hg), persistence of hypertension during mid- to late life, and steep decline in blood pressure from mid- to late life over an 18-year exposure period. RESULTS: During the follow-up period, 107 participants (71 women) developed dementia. Using multivariable Cox proportional hazards models, we found that midlife systolic hypertension (hazard ratio [HR] 1.57, 95% confidence interval [CI] 1.05-2.35) and persistence of systolic hypertension into late life (HR 1.96, 95% CI 1.25-3.09) were associated with an elevated risk of incident dementia. However, in individuals with low to normal blood pressure (<=140/90 mm Hg) at midlife, a steep decline in systolic blood pressure during mid- to late life was also associated with a >2-fold increase in dementia risk (HR 2.40, 95% CI 1.39 4.15). CONCLUSIONS: Elevated blood pressure during midlife, persistence of elevated blood pressure into late life, and, among nonhypertensives, a steep decline in blood pressure during mid- to late life were associated with an increased dementia risk in a community-based cohort. Our data highlight the potential sustained cognitive benefits of lower blood pressures in midlife but also suggest that declining blood pressure in older adults with prehypertension or normotension, but not in those with hypertension, may be a risk marker for dementia. PMID- 29117955 TI - Alzheimer's Disease-Related Dementias Summit 2016: National research priorities. AB - Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature. PMID- 29117956 TI - SNPs in Abeta clearance proteins: Lower CSF Abeta1-42 levels and earlier onset of dementia in PD. AB - OBJECTIVE: To evaluate whether genetic variants in beta-amyloid (Abeta) clearance proteins are associated with CSF levels of Abeta1-42 on a biological level and the onset of dementia on a clinical level in Parkinson disease (PD). METHODS: We analyzed genetic variants known to be involved in Abeta clearance in a PD group comprising 456 patients, 103 of them with dementia. Single nucleotide polymorphisms in the genes APOE, cystatin C (CST), and membrane metalloendopeptidase (MME) were evaluated in relation to demographic variables, clinical phenotypes, and CSF Abeta1-42 levels using a cross-sectional approach. RESULTS: Risk variants in the genes APOE and CST were associated with lower CSF Abeta1-42 levels. Clinically, patients with 2 risk alleles in CST tended to show a shorter interval from age at onset of PD to age at onset of dementia. CONCLUSIONS: This study suggests that genetic variants associated with Abeta clearance are involved in the pathogenesis of dementia in PD and possibly influence the onset of dementia. PMID- 29117958 TI - Stroke after trauma in children and young adults: Some opportunity for primary prevention. PMID- 29117957 TI - Nocturnal oxyhemoglobin desaturation and arteriopathy in a pediatric sickle cell disease cohort. AB - OBJECTIVE: The purpose of this study of sickle cell disease (SCD) was to determine whether arteriopathy, measurable as intracranial vessel signal loss on magnetic resonance angiography (MRA), was associated with low nocturnal hemoglobin oxygen saturation (SpO2) or hemolytic rate, measurable as reticulocytosis or unconjugated hyperbilirubinemia. METHODS: Ninety-five East London children with SCD without prior stroke had overnight pulse oximetry, of whom 47 (26 boys, 39 hemoglobin SS; mean age 9.1 +/- 3.1 years) also had MRA, transcranial Doppler (TCD), steady-state hemoglobin, and reticulocytes within 34 months. Two radiologists blinded to the other data graded arteriopathy on MRA as 0 (none) or as increasing severity grades 1, 2, or 3. RESULTS: Grades 2 or 3 arteriopathy (n = 24; 2 with abnormal TCD) predicted stroke/TIA compared with grades 0 and 1 (log-rank chi2 [1, n = 47] = 8.1, p = 0.004). Mean overnight SpO2 correlated negatively with reticulocyte percentage (r = -0.387; p = 0.007). Despite no significant differences across the degrees of arteriopathy in genotype, mean overnight SpO2 was higher (p < 0.01) in those with grade 0 (97.0% +/- 1.6%) than those with grades 2 (93.9 +/- 3.7%) or 3 (93.5% +/- 3.0%) arteriopathy. Unconjugated bilirubin was not associated but reticulocyte percentage was lower (p < 0.001) in those with grade 0 than those with grades 2 and 3 arteriopathy. In multivariable logistic regression, lower mean overnight SpO2 (odds ratio 0.50, 95% confidence interval 0.26-0.96; p < 0.01) predicted arteriopathy independent of reticulocyte percentage (odds ratio 1.47, 95% confidence interval 1.15-1.87; p = 0.003). CONCLUSION: Low nocturnal SpO2 and reticulocytosis are associated with intracranial arteriopathy in children with SCD. Preventative strategies might reduce stroke risk. PMID- 29117960 TI - Comment: beta-Amyloid pathology and Parkinson disease. PMID- 29117961 TI - Comorbidity increases the risk of relapse in multiple sclerosis: A prospective study. AB - OBJECTIVE: To evaluate the association between comorbidity and relapse rate in individuals with multiple sclerosis (MS). METHODS: We recruited individuals with prevalent relapsing-onset MS from 4 Canadian MS Clinics to participate in a 2 year prospective multicenter cohort study involving cross-sectional assessment of comorbidities and relapses. Comorbidities were recorded using questionnaires, and relapses were captured from medical records at each visit. The association between comorbidities at baseline and relapse rate over the subsequent 2-year follow-up period was examined using Poisson regression, adjusting for age, sex, disability, disease duration, and treatment status. RESULTS: Of 885 participants, 678 (76.6%) were women, averaging age 48.2 years at baseline. Anxiety (40.2%), depression (21.1%), hypertension (17.7%), migraine (18.1%), and hyperlipidemia (11.9%) were the most prevalent comorbidities. The frequency of participants experiencing relapses remained constant at 14.9% and 13.2% in years 1 and 2 post baseline. After adjustment, participants reporting >=3 baseline comorbidities (relative to none) had a higher relapse rate over the subsequent 2 years (adjusted rate ratio 1.45, 95% confidence interval [CI] 1.00-2.08). Migraine and hyperlipidemia were associated with increased relapse rate (adjusted rate ratio 1.38; 95% CI 1.01-1.89 and 1.67; 95% CI 1.07-2.61, respectively). CONCLUSIONS: Individuals with migraine, hyperlipidemia, or a high comorbidity burden (3 or more conditions) had an increased relapse rate over 2 years. These findings have potential implications for understanding the pathophysiology of MS relapses, and suggest that closer monitoring of individuals with specific or multiple comorbidities may be needed. Future research is needed to understand if the presence of comorbidity warrants a tailored approach to MS management. PMID- 29117959 TI - Barriers and facilitators to provide quality TIA care in the Veterans Healthcare Administration. AB - OBJECTIVE: To identify key barriers and facilitators to the delivery of guideline based care of patients with TIA in the national Veterans Health Administration (VHA). METHODS: We conducted a cross-sectional, observational study of 70 audiotaped interviews of multidisciplinary clinical staff involved in TIA care at 14 VHA hospitals. We de-identified and analyzed all transcribed interviews. We identified emergent themes and patterns of barriers to providing TIA care and of facilitators applied to overcome these barriers. RESULTS: Identified barriers to providing timely acute and follow-up TIA care included difficulties accessing brain imaging, a constantly rotating pool of housestaff, lack of care coordination, resource constraints, and inadequate staff education. Key informants revealed that both stroke nurse coordinators and system-level factors facilitated the provision of TIA care. Few facilities had specific TIA protocols. However, stroke nurse coordinators often expanded upon their role to include TIA. They facilitated TIA care by (1) coordinating patient care across services, communicating across service lines, and educating clinical staff about facility policies and evidence-based practices; (2) tracking individual patients from emergency departments to inpatient settings and to discharge for timely follow-up care; (3) providing and referring TIA patients to risk factor management programs; and (4) performing regular audit and feedback of quality performance data. System-level facilitators included clinical service leadership engagement and use of electronic tools for continuous care across services. CONCLUSIONS: The local organization within a health care facility may be targeted to cultivate internal facilitators and a systemic infrastructure to provide evidence-based TIA care. PMID- 29117964 TI - Clinical characteristics of children evaluated for suspected pulmonary embolism with D-dimer testing. AB - BACKGROUND: We sought to determine clinical variables in children tested for suspected pulmonary embolism (PE) that predict PE+ outcome for the development of paediatric PE prediction rule. METHODS: Data were collected by query of a laboratory database for D-dimer from January 2004 to December 2014 for a large multicentre hospital system and the radiology database for pulmonary vascular imaging in children aged 5-17. Using explicit, predefined methods, trained abstractors, determined if D-dimer was sent in the evaluation of PE and then recorded predictor data which was tested for association with PE+ outcome using univariate techniques. RESULTS: D-dimer was ordered in 526 children for clinical suspicion of PE. Thirty-four of 526 were PE+ (6.4%, 95% CI 4.3% to 8.7%). The radiology database identified 17 additional patients with PE (n=51 PE+ total). Children evaluated for PE were primarily in the ED setting (80%), teenagers (88%) and 2:1 female:male. Children with PE had higher mean heart and higher respiratory rate and a lower pulse oximetry and haemoglobin concentration. On univariate analysis, five conditions were more frequent in PE+ compared with no PE: surgery, central line, limb immobility, prior PE or deep vein thrombosis and cancer. CONCLUSIONS: The rate of PE diagnosis in children with D-dimer was 6.4%, similar to that seen in adults; most children with PE are over 13 years and had clinical predictors known to increase probability of PE in symptomatic adults. Future studies should use these criteria to develop a clinical decision rule for PE in children. PMID- 29117962 TI - Lower cardiac index levels relate to lower cerebral blood flow in older adults. AB - OBJECTIVE: To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults. METHODS: Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 +/- 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo continuous arterial spin-labeling MRI. Linear regressions with ordinary least square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), APOE epsilon4 status, cognitive diagnosis, and regional tissue volume. RESULTS: Lower cardiac index corresponded to lower resting CBF in the left (beta = 2.4, p = 0.001) and right (beta = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe beta = 2.3, p = 0.003; right temporal lobe beta = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index * cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes. CONCLUSIONS: Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR. PMID- 29117965 TI - Diagnostic accuracy of the D-dimer in children. AB - BACKGROUND: We sought to measure the diagnostic accuracy of D-dimer in children with suspected pulmonary embolism (PE). METHODS: We queried our electronic medical record for quantitative D-dimer values obtained in all children ages 5-17 over 10 years in our 10-hospital system. Patients who had a D-dimer obtained in the evaluation of PE underwent supervised chart review to extract baseline demographics (age, sex, ethnicity), medical history, laboratory data and imaging results. PE was confirmed by imaging positive for deep vein thrombosis (DVT) or PE and excluded by imaging or no DVT or PE diagnosis within 90 days. RESULTS: Over a 10-year period, we identified 13 792 orders for D-dimer testing in 2554 unique patients. Chart review indicated that 526 (20.6%) unique patients had D dimer testing performed in the evaluation of PE (Cohen's kappa=0.95, 95% CI 0.85 to 1.0). Most D-dimers (465/526, 88%) were ordered in children aged >12 years. Of these 526 children, 34 (6.4%, 95% CI) had a criterion standard positive for new or recurrent PE. The mean D-dimer value was 2104+/-1394 ng/mL in the 34/34 PE+ children and 586+/-962 ng/mL in PE- children with a sensitivity of 34/34 (100%, 89% to 100%) and a specificity of 290/492 (58%, 54% to 63%). The area under the receiver operating characteristic curve was 0.90 ((0.9)87-0.94). CONCLUSIONS: D dimer is currently ordered in children for suspected PE in the emergency care setting, mostly in teenagers. The observed lower limit 95% CIs of 89% and 54% for diagnostic sensitivity and the specificity, respectively, suggest if used in patients with low-clinical probability, a normal D-dimer can safely exclude PE in children. PMID- 29117969 TI - Why might the finding of a new genetic association with inflammatory bowel disease be of potential value in disease control? PMID- 29117968 TI - Muscling out from under the yolk of the egg's "bad" reputation. PMID- 29117972 TI - Antibiotics or NSAIDs for uncomplicated urinary tract infection? PMID- 29117963 TI - Population-based study of ischemic stroke risk after trauma in children and young adults. AB - OBJECTIVE: To quantify the incidence, timing, and risk of ischemic stroke after trauma in a population-based young cohort. METHODS: We electronically identified trauma patients (<50 years old) from a population enrolled in a Northern Californian integrated health care delivery system (1997-2011). Within this cohort, we identified cases of arterial ischemic stroke within 4 weeks of trauma and 3 controls per case. A physician panel reviewed medical records, confirmed cases, and adjudicated whether the stroke was related to trauma. We calculated the 4-week stroke incidence and estimated stroke odds ratios (OR) by injury location using logistic regression. RESULTS: From 1,308,009 trauma encounters, we confirmed 52 trauma-related ischemic strokes. The 4-week stroke incidence was 4.0 per 100,000 encounters (95% confidence interval [CI] 3.0-5.2). Trauma was multisystem in 26 (50%). In 19 (37%), the stroke occurred on the day of trauma, and all occurred within 15 days. In 7/28 cases with cerebrovascular angiography at the time of trauma, no abnormalities were detected. In unadjusted analyses, head, neck, chest, back, and abdominal injuries increased stroke risk. Only head (OR 4.1, CI 1.1-14.9) and neck (OR 5.6, CI 1.03-30.9) injuries remained associated with stroke after adjusting for demographics and trauma severity markers (multisystem trauma, motor vehicle collision, arrival by ambulance, intubation). CONCLUSIONS: Stroke risk is elevated for 2 weeks after trauma. Onset is frequently delayed, providing an opportunity for stroke prevention during this period. However, in one-quarter of stroke cases with cerebrovascular angiography at the time of trauma, no vascular abnormality was detected. PMID- 29117966 TI - Early psychosis for the non-specialist doctor. PMID- 29117967 TI - Updated systematic review and meta-analysis of acupuncture for chronic knee pain. AB - OBJECTIVE: To assess the effectiveness and safety of acupuncture for the treatment of chronic knee pain (CKP). METHODS: We searched the MEDLINE, EMBASE, Cochrane CENTERAL, CINAHL and four Chinese medical databases from their inception to June 2017. We included randomised controlled trials of acupuncture as the sole treatment or as an adjunctive treatment for CKP. The primary outcome was pain intensity measured by visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and 11-point numeric rating scale. Secondary outcome measurements included the 36-Item Short Form Health Survey and adverse events. The quality of all included studies was evaluated using the Cochrane risk-of-bias criteria and the STRICTA (Standards for Reporting Interventions in Controlled Trials of Acupuncture) checklist. RESULTS: Nineteen trials were included in this systematic review. Of these, data from 17 studies were available for analysis. Regarding the effectiveness of acupuncture alone or combined with other treatment, the results of the meta-analysis showed that acupuncture was associated with significantly reduced CKP at 12 weeks on WOMAC pain subscale (mean difference (MD) -1.12, 95% confidence interval (CI) 1.98 to -0.26, I2=62%, 3 trials, 608 participants) and VAS (MD -10.56, 95% CI 17.69 to -3.44, I2=0%, 2 trials, 145 patients). As for safety, no difference was found between the acupuncture and control groups (risk ratio 1.08, 95% CI 0.54 to 2.17, I2=29%). CONCLUSION: From this systematic review, we conclude that acupuncture may be effective at relieving CKP 12 weeks after acupuncture administration, based on the current evidence and our protocol. However, given the heterogeneity and methodological limitations of the included trials, we are currently unable to draw any strong conclusions regarding the effectiveness of acupuncture for chronic knee pain. In addition, we found that acupuncture appears to have a satisfactory safety profile, although further studies with larger numbers of participants are needed to confirm the safety of this technique. STRENGTHS: Systematic review without language restrictions. LIMITATIONS: Only a few high-quality and consistent trials could be included in this review. PMID- 29117974 TI - David Oliver: An argument against more NHS funding? I don't buy it. PMID- 29117973 TI - How to approach psychotic symptoms in a non-specialist setting. PMID- 29117975 TI - Deanna Attai: Operation Chocolate. PMID- 29117976 TI - Doctors are less likely to be struck off for dishonesty than other health workers. PMID- 29117977 TI - US doctors voice concern over plans to raid public health fund to pay for children's healthcare. PMID- 29117978 TI - How are junior doctors supposed to learn without the opportunity? PMID- 29117980 TI - Treating Recurrent Glioma with Toca 511. AB - Findings from a phase I study suggest that delivering high concentrations of the chemotherapy 5-FU directly to brain tumors via the retroviral vector vocimagene amiretrorepvec, or Toca 511, may benefit patients with recurrent high-grade glioma. This investigational treatment was well tolerated and induced robust, durable responses lasting a median of 3 years. PMID- 29117979 TI - Faltering growth in children: improving early detection of cleft palate. PMID- 29117981 TI - Delhi fights for air under toxic smog. PMID- 29117983 TI - GPs lose millions from mis-sold financial products. PMID- 29117982 TI - Menopause Characteristics, Total Reproductive Years, and Risk of Cardiovascular Disease Among Chinese Women. AB - BACKGROUND: Previous studies, mostly of Western women, have reported inconsistent findings on the association of menopause characteristics (status, age, and time since menopause) and total reproductive years with risk of cardiovascular disease (CVD). METHODS AND RESULTS: The China Kadoorie Biobank recruited 302 632 women in 2004 to 2008 from 10 regions across China. During 9-year follow-up, 19 393 incident cases of stroke, 18 611 of ischemic heart disease, and 4978 CVD deaths occurred. Cox regression yielded adjusted hazard ratios relating each menopause characteristic and total reproductive years to CVD risk. Among 274 233 women with no prior CVD at baseline, 134 010 were naturally postmenopausal women (mean [SD] age at menopause of 48.6 [4.0] years and total reproductive years 32.7 [4.4]). Compared with premenopausal women, naturally peri- or postmenopausal women were at a higher risk of either fatal or nonfatal CVD. Among women who had had menopause, inverse associations were observed between age at menopause and risks of CVD mortality, incident ischemic heart disease, stroke, and subtypes of stroke, with 1.5% higher risk of CVD death (P<0.001), 0.7% for incident ischemic heart disease (P=0.002), and 0.5% for incident stroke (P=0.02) for every 1 year lower age at menopause. Compared with women who had menopause at age 48 to 50 years, lower age at menopause (ie, <43 years) was associated with 14% higher risk of CVD death and 6% higher risks of both incident ischemic heart disease and stroke. Higher risks of both fatal and nonfatal CVD were also found in women with 5 to 10, 10 to 15, 15 to 20, or >20 years since menopause compared with <5 years since menopause. Total reproductive years were inversely associated with risks of both fatal and nonfatal CVD, with 1.4% lower risk of CVD death per additional reproductive year (P<0.001). CONCLUSIONS: Women with younger age at menopause, longer time since menopause, or fewer total reproductive years had a higher risk of CVD. PMID- 29117984 TI - Sixty seconds on . . . the tampon tax. PMID- 29117985 TI - "Weekend effect" is not reduced by clinical standards designed to tackle it, study finds. PMID- 29117986 TI - Uncertain overseas recruitment is threatening care, NHS leaders warn. PMID- 29117987 TI - The global abortion policies database: knowledge as a health intervention. PMID- 29117988 TI - An overlooked case of pacemaker-related heart failure. AB - : This case describes an iatrogenic cause of heart failure: the pacemaker syndrome. The diagnosis was initially overlooked but in retrospect could have easily been made by reviewing the rhythm strip recorded during the echocardiogram. The patient eventually received the correct treatment to restore atrioventricular synchrony and experienced rapid resolution to her disabling symptoms. LEARNING POINTS: New-onset heart failure following a pacemaker implant should be evaluated with an echocardiogram.Alongside pacing-induced left ventricular systolic dysfunction and pacing wire-related cardiac valve disruption, pacemaker syndrome should be considered.Interpreting a good-quality (showing both P waves and QRS complexes) rhythm strip can greatly aid in the diagnosis of pacemaker syndrome. PMID- 29117989 TI - Elevated mortality among weekend hospital admissions is not associated with adoption of seven day clinical standards. AB - INTRODUCTION: Patients admitted to hospital in an emergency at weekends have been found to experience higher mortality rates than those admitted during the week. The National Health Service (NHS) in England has introduced four priority clinical standards for emergency hospital care with the objective of reducing deaths associated with this 'weekend effect'. This study aimed to determine whether adoption of these clinical standards is associated with the extent to which weekend mortality is elevated. METHODS: We used publicly available data on performance against the four priority clinical standards in 2015 and estimates of Trusts' weekend effects between 2013/2014 and 2015/2016 for 123 NHS Trusts in England. We examined whether adoption of the priority clinical standards was associated with the extent to which weekend mortality was elevated, and changes over a 3 year period in the extent to which mortality was elevated. RESULTS: Levels of achievement of two of the four clinical standards (ongoing review and access to diagnostic services) had small positive associations with the magnitude of the weekend effect in 2015/2016. Levels of achievement of the remaining two standards (time to first consultant review and access to consultant directed interventions) had small negative associations with the magnitude of the weekend effect in 2015/2016. No association was statistically significant. The same pattern was observed in the associations between achievement of the standards and changes in the magnitudes of the weekend effect between 2013/2014 and 2015/2016. DISCUSSION: We found no association between Trusts' performance against any of the four standards and the current magnitude of their weekend effects, or the change in their weekend effects over the past 3 years. These findings cast doubt on whether adoption of seven day clinical standards in the delivery of emergency hospital services will be successful in reducing the weekend effect. PMID- 29117991 TI - Availability of naloxone in Canadian pharmacies:a population-based survey. AB - BACKGROUND: Naloxone is life-saving when administered after opioid overdose. In March 2016, the Canadian government made the antidote available without prescription, but anecdotal reports suggest members of the public have difficulty in procuring it. We examined the availability of naloxone in community pharmacies across Canada. METHODS: We identified community pharmacies in Canada (n = 10 296) and randomly selected 506, stratified using proportionate allocation by population size. We excluded pharmacies in Alberta and Manitoba because these provinces released data indicating which pharmacies made naloxone available to the public during the data collection phase of the study. We contacted pharmacies by telephone during working hours and used a standardized survey to enquire about the availability of naloxone, the associated cost and the need for a prescription. When a pharmacy did not have naloxone available, we ascertained if it could be procured within 7 days. RESULTS: We contacted 429 community pharmacies. Of these, 103 (24.0%) had naloxone available. Availability was highest in British Columbia (33 of 65; 50.8%), followed by the Maritimes (12 of 35; 34.3%), Ontario (52 of 193; 26.9%) and central and northern Canada (5 of 21; 23.8%). In Quebec, 1 of 115 (0.9%) pharmacies had naloxone available. Of pharmacies without naloxone, fewer than 1 in 5 anticipated being able to provide it within 1 week (63 of 326; 19.3%). INTERPRETATION: Most community pharmacies in Canada did not have naloxone on hand and in those without naloxone available, fewer than 1 in 5 anticipated being able to provide it within 1 week. Our findings emphasize the need for increased availability of naloxone in pharmacies across Canada. PMID- 29117990 TI - Simultaneous Physiologically Based Pharmacokinetic (PBPK) Modeling of Parent and Active Metabolites to Investigate Complex CYP3A4 Drug-Drug Interaction Potential: A Case Example of Midostaurin. AB - Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by CYP3A4 to form two major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or advSM. The model reasonably predicted changes in midostaurin exposure after single-dose administration with ketoconazole (a 5.8-fold predicted versus 6.1-fold observed increase) and rifampicin (90% predicted versus 94% observed reduction) as well as changes in midazolam exposure (1.0 predicted versus 1.2 observed ratio) after daily dosing of midostaurin for 4 days. The qualified model was then applied to predict the DDI effect with other CYP3A4 inhibitors or inducers and the DDI potential with midazolam under steady-state conditions. The simulated midazolam area under the curve ratio of 0.54 and an accompanying observed 1.9-fold increase in the CYP3A4 activity of biomarker 4beta-hydroxycholesterol indicated a weak-to-moderate CYP3A4 induction by midostaurin and its metabolites at steady state in patients with advSM. In conclusion, a simultaneous parent-and-active-metabolite modeling approach allowed predictions under steady-state conditions that were not possible to achieve in healthy subjects. Furthermore, endogenous biomarker data enabled evaluation of the net effect of midostaurin and its metabolites on CYP3A4 activity at steady state and increased confidence in DDI predictions. PMID- 29117992 TI - Naltrexone/bupropion for obesity. AB - Naltrexone/bupropion (Mysimba - Orexigen Therapeutics Ireland Limited) is a fixed dose combination product for the treatment of adults who are obese or overweight with at least one weight-related comorbidity, as an adjunct to diet and lifestyle modifications. Originally licensed by the European Medicines Agency (EMA) in 2015, it has recently been launched in the UK. Here, we review the evidence for its efficacy and safety and consider its place in therapy. PMID- 29117993 TI - An update on the bleeding risks associated with DOACs. AB - The direct oral anticoagulants (DOACs), also referred to as novel (or non-vitamin K antagonist) oral anticoagulants (NOACs), represent a major development in anticoagulation therapy due to their rapid onset of action, predictable dose response with fixed doses and limited interactions with food and drugs.1,2 However, these agents have been in widespread clinical use for less than a decade and, compared with extensive experience with warfarin, there is uncertainty relating to optimal laboratory monitoring of anticoagulation, perioperative management and treatment of bleeding.3 In addition, there is currently only one drug licensed in the UK for rapid reversal of the anticoagulant effect of a DOAC. Here, we review DOAC-related bleeding and the role of drugs to reverse the anticoagulant action of DOACs. PMID- 29117994 TI - The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis. AB - Sepsis and acute kidney injury (AKI) synergistically increase morbidity and mortality in the ICU. How sepsis reduces glomerular filtration rate (GFR) and causes AKI is poorly understood; one proposed mechanism includes tubuloglomerular feedback (TGF). When sodium reabsorption by the proximal tubules is reduced in normal animals, the macula densa senses increased luminal sodium chloride, and then adenosine-1a receptor (A1aR) signaling triggers tubuloglomerular feedback, reducing GFR through afferent arteriole vasoconstriction. We measured GFR and systemic hemodynamics early during cecal ligation and puncture-induced sepsis in wild-type and A1aR-knockout mice. A miniaturized fluorometer was attached to the back of each mouse and recorded the clearance of FITC-sinistrin via transcutaneous fluorescence to monitor GFR. Clinical organ injury markers and cytokines were measured and hemodynamics monitored using implantable transducer telemetry devices. In wild-type mice, GFR was stable within 1 h after surgery, declined by 43% in the next hour, and then fell to less than 10% of baseline after 2 h and 45 min. In contrast, in A1aR-knockout mice GFR was 37% below baseline immediately after surgery and then gradually declined over 4 h. A1aR knockout mice had similar organ injury and inflammatory responses, albeit with lower heart rate. We conclude that transcutaneous fluorescence can accurately monitor GFR and detect changes rapidly during sepsis. Tubuloglomerular feedback plays a complex role in sepsis; initially, TGF helps maintain GFR in the 1st hour, and over the subsequent 3 h, TGF causes GFR to plummet. By 18 h, TGF has no cumulative effect on renal or extrarenal organ damage. PMID- 29117996 TI - Effect of isolated ultrafiltration and isovolemic dialysis on myocardial perfusion and left ventricular function assessed with 13N-NH3 positron emission tomography and echocardiography. AB - Hemodialysis is associated with a fall in myocardial perfusion and may induce regional left ventricular (LV) systolic dysfunction. The pathophysiology of this entity is incompletely understood, and the contribution of ultrafiltration and diffusive dialysis has not been studied. We investigated the effect of isolated ultrafiltration and isovolemic dialysis on myocardial perfusion and LV function. Eight patients (7 male, aged 55 +/- 18 yr) underwent 60 min of isolated ultrafiltration and 60 min of isovolemic dialysis in randomized order. Myocardial perfusion was assessed by 13N-NH3 positron emission tomography before and at the end of treatment. LV systolic function was assessed by echocardiography. Regional LV systolic dysfunction was defined as an increase in wall motion score in >=2 segments. Isolated ultrafiltration (ultrafiltration rate 13.6 +/- 3.9 ml.kg-1.h 1) induced hypovolemia, whereas isovolemic dialysis did not (blood volume change 6.4 +/- 2.2 vs. +1.3 +/- 3.6%). Courses of blood pressure, heart rate, and tympanic temperature were comparable for both treatments. Global and regional myocardial perfusion did not change significantly during either isolated ultrafiltration or isovolemic dialysis and did not differ between treatments. LV ejection fraction and the wall motion score index did not change significantly during either treatment. Regional LV systolic dysfunction developed in one patient during isolated ultrafiltration and in three patients during isovolemic dialysis. In conclusion, global and regional myocardial perfusion was not compromised by 60 min of isolated ultrafiltration or isovolemic dialysis. Regional LV systolic dysfunction developed during isolated ultrafiltration and isovolemic dialysis, suggesting that, besides hypovolemia, dialysis-associated factors may be involved in the pathogenesis of hemodialysis-induced regional LV dysfunction. PMID- 29117995 TI - Role of mitochondria-derived reactive oxygen species in microvascular dysfunction in chronic kidney disease. AB - Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3-5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 +/- 13 yr; estimated glomerular filtration rate (eGFR) 46 +/- 13 ml.kg-1.1.73 m-2] and 11 matched healthy participants (58 +/- 2 yr; eGFR >90 ml.kg-1.1.73 m-2). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42 degrees C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43 degrees C. Urinary isofuran/F2-isoprostane ratios were assessed by gas chromatography mass spectroscopy. Isofuran-to-F2-isoprostane ratios were increased in CKD patients (3.08 +/- 0.32 vs. 1.69 +/- 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 +/- 1 vs. 92 +/- 1%CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 +/- 1 vs. 93 +/- 1%CVCmax; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction. PMID- 29117997 TI - Metformin: an antiproliferative agent and methylation regulator in treating prostatic disease? AB - Existing drugs that have been used in clinical practice for other purposes can prove useful for reutilization, since much of the safety profile and pharmacokinetics have been completed. Therefore, the drugs can enter clinical practice for a variety of causes with less regulatory burden. Metformin may prove to be such a drug; it may have a role in other diseases, besides the management of diabetes. In this perspective, we provide our findings and understanding of metformin as an alternative way to treat urological abnormal proliferation. We propose the potential mechanisms into two hallmarks: direct antiproliferative function via insulin-like growth factor (IGF) signaling pathway and epigenetic modulating via adjusting DNA methylation. These specific hallmarks may ultimately contribute to a better understanding of metformin in treating prostatic diseases. PMID- 29117999 TI - NHS will have workforce plan for first time in 17 years, Hunt announces. PMID- 29117998 TI - Ocrelizumab appears to reduce relapse and disability in multiple sclerosis but quality of evidence is moderate. PMID- 29118003 TI - NHS should be "first port of call" for potential Brexit savings, says Hunt. PMID- 29118000 TI - Ca2+/calmodulin binding to PSD-95 mediates homeostatic synaptic scaling down. AB - Postsynaptic density protein-95 (PSD-95) localizes AMPA-type glutamate receptors (AMPARs) to postsynaptic sites of glutamatergic synapses. Its postsynaptic displacement is necessary for loss of AMPARs during homeostatic scaling down of synapses. Here, we demonstrate that upon Ca2+ influx, Ca2+/calmodulin (Ca2+/CaM) binding to the N-terminus of PSD-95 mediates postsynaptic loss of PSD-95 and AMPARs during homeostatic scaling down. Our NMR structural analysis identified E17 within the PSD-95 N-terminus as important for binding to Ca2+/CaM by interacting with R126 on CaM. Mutating E17 to R prevented homeostatic scaling down in primary hippocampal neurons, which is rescued via charge inversion by ectopic expression of CaMR126E, as determined by analysis of miniature excitatory postsynaptic currents. Accordingly, increased binding of Ca2+/CaM to PSD-95 induced by a chronic increase in Ca2+ influx is a critical molecular event in homeostatic downscaling of glutamatergic synaptic transmission. PMID- 29118001 TI - Real-time detection of condensin-driven DNA compaction reveals a multistep binding mechanism. AB - Condensin, a conserved member of the SMC protein family of ring-shaped multi subunit protein complexes, is essential for structuring and compacting chromosomes. Despite its key role, its molecular mechanism has remained largely unknown. Here, we employ single-molecule magnetic tweezers to measure, in real time, the compaction of individual DNA molecules by the budding yeast condensin complex. We show that compaction can proceed in large steps, driving DNA molecules into a fully condensed state against forces of up to 2 pN. Compaction can be reversed by applying high forces or adding buffer of high ionic strength. While condensin can stably bind DNA in the absence of ATP, ATP hydrolysis by the SMC subunits is required for rendering the association salt insensitive and for the subsequent compaction process. Our results indicate that the condensin reaction cycle involves two distinct steps, where condensin first binds DNA through electrostatic interactions before using ATP hydrolysis to encircle the DNA topologically within its ring structure, which initiates DNA compaction. The finding that both binding modes are essential for its DNA compaction activity has important implications for understanding the mechanism of chromosome compaction. PMID- 29118002 TI - Prevalence and risk factor for injury in sub-Saharan Africa: a multicountry study. AB - INTRODUCTION: Injury-related morbidity is a neglected health concern in many low income and middle-income countries. Most injury data in Africa have been collected from hospital-based studies, and few studies have occurred across multiple countries. Using data from a novel cohort, we examined the prevalence and incidence of serious injuries and associated risk factors across five sites in sub-Saharan Africa (SSA). METHODS: A common baseline and follow-up survey was administered to participants. The study population included 1316 persons at baseline and 904 persons at follow-up. Frequencies were calculated, and logistic regression models were used to assess risk factors for injury. RESULTS: A total of 233 (17.7%) persons reported a serious injury at baseline and 60 (6.6%) reported a serious injury 6 months later at follow-up. Sixty-nine per cent of participants responded to the follow-up questionnaire. At baseline and follow-up, the most common cause of serious injury at urban sites was transport related, followed by poison/overdose. In rural Uganda, sharp instruments injuries were most common, followed by transport-related injuries. Living at an urban site was associated with an increased odds for serious injury compared with those at the rural site (OR: 1.83, 95% CI 1.15 to 2.90). Participants who consumed above a moderate amount of alcohol were at a higher risk of serious injury compared with those who did not consume alcohol (OR: 1.86, 95% CI 1.02 to 3.41). High level of education was an important risk factor for injury. CONCLUSION: At baseline and follow-up, common causes of serious injury were transport related, sharp instrument and poison/overdose. Alcohol consumption, urban location and education are important risk factors for injury. It is feasible to collect longitudinal injury data using a standardised questionnaire across multiples sites in SSA. Longitudinal data collection should be leveraged to obtain robust data on risk factors for injury in SSA. PMID- 29118004 TI - Introduction to a review series on therapeutic antibodies. PMID- 29118006 TI - The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. AB - In recent years, monoclonal antibodies (mAbs) able to reinvigorate antitumor T cell immunity have heralded a paradigm shift in cancer treatment. The most high profile of these mAbs block the inhibitory checkpoint receptors PD-1 and CTLA-4 and have improved life expectancy for patients across a range of tumor types. However, it is becoming increasingly clear that failure of some patients to respond to checkpoint inhibition is attributable to inadequate T-cell priming. For full T-cell activation, 2 signals must be received, and ligands providing the second of these signals, termed costimulation, are often lacking in tumors. Members of the TNF receptor superfamily (TNFRSF) are key costimulators of T cells during infection, and there has been an increasing interest in harnessing these receptors to augment tumor immunity. We here review the immunobiology of 2 particularly promising TNFRSF target receptors, CD27 and OX40, and their respective ligands, CD70 and OX40L, focusing on their role within a tumor setting. We describe the influence of CD27 and OX40 on human T cells based on in vitro studies and on the phenotypes of several recently described individuals exhibiting natural deficiencies in CD27/CD70 and OX40. Finally, we review key literature describing progress in elucidating the efficacy and mode of action of OX40- and CD27-targeting mAbs in preclinical models and provide an overview of current clinical trials targeting these promising receptor/ligand pairings in cancer. PMID- 29118005 TI - Redirecting T cells to hematological malignancies with bispecific antibodies. AB - There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need, because it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibodies (BsAbs) is an attractive strategy. BsAbs are an "off-the-shelf" product that is easily scalable in contrast to adoptive T cell therapies. Among these, the bispecific T-cell engager blinatumomab has emerged as the most successful BsAb to date. It consists of 2 single-chain variable fragments specific for CD19 present on B-cell malignancies and CD3 expressed on almost all T cells. Blinatumomab has shown potent antitumor activity as a single agent, particularly for acute lymphoblastic leukemia, resulting in its US Food and Drug Administration approval. However, although successful in inducing remissions, these are normally short-lived, with median response durations of <1 year. Nevertheless, the success of blinatumomab has reinvigorated the BsAb field, which is bustling with preclinical and clinical studies for not only B-cell-derived lymphoblastic leukemia and lymphoma but also acute myeloid leukemia and multiple myeloma. Here, we will review the successes and challenges of T-cell-targeted BsAbs for the immunotherapy of hematological malignancies with special focus on conducted clinical studies and strategies to improve their efficacy. PMID- 29118009 TI - Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. AB - 4-1BB (CD137, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4 1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Agonistic monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. Preclinical results in a variety of induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies can lead to tumor clearance and durable antitumor immunity. Clinical trials of 2 agonist antibodies, urelumab and utomilumab, are ongoing. Despite initial signs of efficacy, clinical development of urelumab has been hampered by inflammatory liver toxicity at doses >1 mg/kg. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist relative to urelumab. Both antibodies have demonstrated promising results in patients with lymphoma and are being tested in combination therapy trials with other immunomodulatory agents. In an effort to optimally leverage 4-1BB-mediated immune activation, the next generation of 4-1BB targeting strategies attempts to decouple the observed antitumor efficacy from the on-target liver toxicity. Multiple therapeutics that attempt to restrict 4 1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. 4-1BB is a compelling target for cancer immunotherapy and future agents show great promise for achieving potent immune activation while avoiding limiting immune-related adverse events. PMID- 29118008 TI - CTLA-4: a moving target in immunotherapy. AB - CD28 and CTLA-4 are members of a family of immunoglobulin-related receptors that are responsible for various aspects of T-cell immune regulation. The family includes CD28, CTLA-4, and ICOS as well as other proteins, including PD-1, BTLA, and TIGIT. These receptors have both stimulatory (CD28, ICOS) and inhibitory roles (CTLA-4, PD-1, BTLA, and TIGIT) in T-cell function. Increasingly, these pathways are targeted as part of immune modulatory strategies to treat cancers, referred to generically as immune checkpoint blockade, and conversely to treat autoimmunity and CTLA-4 deficiency. Here, we focus on the biology of the CD28/CTLA-4 pathway as a framework for understanding the impacts of therapeutic manipulation of this pathway. PMID- 29118010 TI - CD38 antibodies in multiple myeloma: back to the future. AB - CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ~30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors. PMID- 29118007 TI - PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. AB - Programmed cell death protein 1 (PD-1) blockade targeting the PD-1 immune checkpoint has demonstrated unprecedented clinical efficacy in the treatment of advanced cancers including hematologic malignancies. This article reviews the landscape of PD-1/programmed death-ligand 1 (PD-L1) expression and current PD-1 blockade immunotherapy trials in B-cell lymphomas. Most notably, in relapsed/refractory classical Hodgkin lymphoma, which frequently has increased PD 1+ tumor-infiltrating T cells, 9p24.1 genetic alteration, and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORRs) of 65% to 87% and durable disease control in phase 1/2 clinical trials. The median duration of response was 16 months in a phase 2 trial. PD-1 blockade has also shown promise in a phase 1 trial of nivolumab in relapsed/refractory B-cell non-Hodgkin lymphomas, including follicular lymphoma, which often displays abundant PD-1 expression on intratumoral T cells, and diffuse large B-cell lymphoma, which variably expresses PD-1 and PD-L1. In primary mediastinal large B-cell lymphoma, which frequently has 9p24.1 alterations, the ORR was 35% in a phase 2 trial of pembrolizumab. In contrast, the ORR with pembrolizumab was 0% in relapsed chronic lymphocytic leukemia (CLL) and 44% in CLL with Richter transformation in a phase 2 trial. T cells from CLL patients have elevated PD-1 expression; CLL PD-1+ T cells can exhibit a pseudo exhaustion or a replicative senescence phenotype. PD-1 expression was also found in marginal zone lymphoma but not in mantle cell lymphoma, although currently anti-PD-1 clinical trial data are not available. Mechanisms and predictive biomarkers for PD-1 blockade immunotherapy, treatment-related adverse events, hyperprogression, and combination therapies are discussed in the context of B cell lymphomas. PMID- 29118012 TI - Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats. AB - In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFalpha, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats. PMID- 29118013 TI - Restricting glycolysis impairs brown adipocyte glucose and oxygen consumption. AB - During thermogenic activation, brown adipocytes take up large amounts of glucose. In addition, cold stimulation leads to an upregulation of glycolytic enzymes. Here we have investigated the importance of glycolysis for brown adipocyte glucose consumption and thermogenesis. Using siRNA-mediated knockdown in mature adipocytes, we explored the effect of glucose transporters and glycolytic enzymes on brown adipocyte functions such as consumption of glucose and oxygen. Basal oxygen consumption in brown adipocytes was equally dependent on glucose and fatty acid oxidation, whereas isoproterenol (ISO)-stimulated respiration was fueled mainly by fatty acids, with a significant contribution from glucose oxidation. Knockdown of glucose transporters in brown adipocytes not only impaired ISO stimulated glycolytic flux but also oxygen consumption. Diminishing glycolytic flux by knockdown of the first and final enzyme of glycolysis, i.e., hexokinase 2 (HK2) and pyruvate kinase M (PKM), respectively, decreased glucose uptake and ISO stimulated oxygen consumption. HK2 knockdown had a more severe effect, which, in contrast to PKM knockdown, could not be rescued by supplementation with pyruvate. Hence, brown adipocytes rely on glucose consumption and glycolytic flux to achieve maximum thermogenic output, with glycolysis likely supporting thermogenesis not only by pyruvate formation but also by supplying intermediates for efferent metabolic pathways. PMID- 29118014 TI - Exercise training reduces intrahepatic lipid content in people with and people without nonalcoholic fatty liver. AB - Exercise training reduces intrahepatic lipid (IHL) content in people with elevated liver fat content. It is unclear, however, whether exercise training reduces IHL content in people with normal liver fat content. Here, we measured the effect of exercise training on IHL content in people with and people without nonalcohol fatty liver. We further measured changes in insulin sensitivity and hepatic energy metabolism. Eleven males with nonalcoholic fatty liver (NAFL) and 11 body mass index-matched individuals without nonalcoholic fatty liver (CON) completed a 12-wk supervised exercise training program. IHL content (proton magnetic resonance spectroscopy), maximal oxidative capacity (Vo2max, spiroergometry), total muscle strength, body composition, insulin sensitivity (hyperinsulinemic-euglycemic clamp), hepatic ATP-to-total phosphorus ratio, and the hepatic phosphomonoester-to-phosphodiester (PME/PDE) ratio (phosphorus magnetic resonance spectroscopy) were determined. IHL content reduced with exercise training ( P = 0.014) in the whole study population. The relative reduction in IHL content was comparable in NAFL (-34.5 +/- 54.0%) and CON (-28.3 +/- 60.1%) individuals ( P = 0.800). Vo2max ( P < 0.001), total muscle strength ( P < 0.001), and skeletal muscle insulin sensitivity ( P = 0.004) increased, whereas adipose tissue ( P = 0.246) and hepatic ( P = 0.086) insulin sensitivity did not increase significantly. Hepatic ATP-to-total phosphorus ratio ( P = 0.987) and PME/PDE ratio ( P = 0.792) did not change. Changes in IHL content correlated with changes in body weight ( r = 0.451, P = 0.035) and changes in hepatic PME/PDE ratio ( r = 0.569, P = 0.019). In conclusion, exercise training reduced intrahepatic lipid content in people with nonalcoholic fatty liver and in people with normal intrahepatic lipid content, and the percent reduction in intrahepatic lipid content was similar in both groups. PMID- 29118015 TI - ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications. AB - noncoding RNAs (lncRNAs) have gained widespread interest due to their prevailing presence in various diseases. lncRNA ANRIL (a. k. a. CDKN2B-AS1) is located on human chromosome 9 (p21.3) and transcribed in opposite direction to the INK4b-ARF INK4a gene cluster. It has been identified as a highly susceptible region for diseases such as coronary artery diseases and type 2 diabetes. Here, we explored its regulatory role in diabetic nephropathy (DN) and diabetic cardiomyopathy (DCM) in association with epigenetic modifiers p300 and polycomb repressive complex 2 (PRC2) complex. We used an ANRIL-knockout (ANRILKO) mouse model for this study. The wild-type and ANRILKO animals with or without streptozotocin induced diabetes were monitored for 2 min. At the end of the time point, urine and tissues were collected. The tissues were measured for fibronectin (FN), type IV collagen (Col1alpha4), and VEGF mRNA and protein expressions. Renal function was determined by the measurement of 24-h urine volume and albumin/creatinine ratio at euthanasia. Renal and cardiac structures were investigated using periodic acid-Schiff stain and/or immunohistochemical analysis. Elevated expressions of extracellular matrix (ECM) proteins were prevented in ANRILKO diabetic animals. Furthermore, ANRILKO had a protective effect on diabetic mouse kidneys, as evidenced by lowering of urine volume and urine albumin levels in comparison with the wild-type diabetic animals. These alterations regulated by ANRIL may be mediated by p300 and enhancer of zeste 2 (EZH2) of the PRC2 complex. Our study concludes that ANRIL regulates functional and structural alterations in the kidneys and hearts in diabetes through controlling the expressions of ECM proteins and VEGF. PMID- 29118011 TI - Comparative genome analysis of programmed DNA elimination in nematodes. AB - Programmed DNA elimination is a developmentally regulated process leading to the reproducible loss of specific genomic sequences. DNA elimination occurs in unicellular ciliates and a variety of metazoans, including invertebrates and vertebrates. In metazoa, DNA elimination typically occurs in somatic cells during early development, leaving the germline genome intact. Reference genomes for metazoa that undergo DNA elimination are not available. Here, we generated germline and somatic reference genome sequences of the DNA eliminating pig parasitic nematode Ascaris suum and the horse parasite Parascaris univalens. In addition, we carried out in-depth analyses of DNA elimination in the parasitic nematode of humans, Ascaris lumbricoides, and the parasitic nematode of dogs, Toxocara canis. Our analysis of nematode DNA elimination reveals that in all species, repetitive sequences (that differ among the genera) and germline expressed genes (approximately 1000-2000 or 5%-10% of the genes) are eliminated. Thirty-five percent of these eliminated genes are conserved among these nematodes, defining a core set of eliminated genes that are preferentially expressed during spermatogenesis. Our analysis supports the view that DNA elimination in nematodes silences germline-expressed genes. Over half of the chromosome break sites are conserved between Ascaris and Parascaris, whereas only 10% are conserved in the more divergent T. canis. Analysis of the chromosomal breakage regions suggests a sequence-independent mechanism for DNA breakage followed by telomere healing, with the formation of more accessible chromatin in the break regions prior to DNA elimination. Our genome assemblies and annotations also provide comprehensive resources for analysis of DNA elimination, parasitology research, and comparative nematode genome and epigenome studies. PMID- 29118016 TI - Modeling insulin resistance in rodents by alterations in diet: what have high-fat and high-calorie diets revealed? AB - For over half a century, researchers have been feeding different diets to rodents to examine the effects of macronutrients on whole body and tissue insulin action. During this period, the number of different diets and the source of macronutrients employed have grown dramatically. Because of the large heterogeneity in both the source and percentage of different macronutrients used for studies, it is not surprising that different high-calorie diets do not produce the same changes in insulin action. Despite this, diverse high-calorie diets continue to be employed in an attempt to generate a "generic" insulin resistance. The high-fat diet in particular varies greatly between studies with regard to the source, complexity, and ratio of dietary fat, carbohydrate, and protein. This review examines the range of rodent dietary models and methods for assessing insulin action. In almost all studies reviewed, rodents fed diets that had more than 45% of dietary energy as fat or simple carbohydrates had reduced whole body insulin action compared with chow. However, different high-calorie diets produced significantly different effects in liver, muscle, and whole body insulin action when insulin action was measured by the hyperinsulinemic euglycemic clamp method. Rodent dietary models remain an important tool for exploring potential mechanisms of insulin resistance, but more attention needs to be given to the total macronutrient content and composition when interpreting dietary effects on insulin action. PMID- 29118017 TI - Role of immune factors in angiotensin II-induced hypertension and renal damage in Dahl salt-sensitive rats. AB - The present study assessed the importance of immunity in angiotensin (ANG) II (5 ng.kg-1.min-1 iv)-mediated hypertension in Dahl salt-sensitive (SS) rats and SS rats deficient in T and B lymphocytes (SSRag1-/-) fed a 0.4% NaCl diet. Baseline mean arterial blood pressure (MAP) was not different between groups. ANG II infusion significantly increased MAP in both groups, although MAP increased more rapidly in SS rats, and the maximal MAP achieved was significantly greater in SS than SSRag1-/- rats (190 +/- 3 vs. 177 +/- 3 mmHg) after 12 days. Renal damage, as assessed by albumin excretion rate, was significantly increased after 12 days of ANG lI infusion in SS (from 32 +/- 4 to 81 +/- 9 mg/day) and SSRag1-/- (from 12 +/- 2 to 51 +/- 8 mg/day) rats; albumin excretion rate was significantly different between SS and SSRag1-/- rats at all points measured. After 9 days of recovery from ANG II, MAP was decreased to a greater extent in SSRag1-/- than SS rats (143 +/- 5 vs. 157 +/- 8 mmHg) compared with the peak MAP during ANG II infusion. At this same time point, albumin excretion rate was significantly lower in SSRag1-/- than SS rats (42 +/- 8 vs. 66 +/- 7 mg/day). Further studies demonstrated an increase in CD45+ total leukocytes, CD11b/c+ macrophages/monocytes, and CD3+ T cells in kidneys of ANG II- compared with vehicle-treated SS rats. The present data suggest that infiltrating T cells in the kidney exacerbate renal damage in ANG II-induced hypertension in SS rats maintained on a 0.4% NaCl diet, similar to results observed with a salt stimulus in SS rats. PMID- 29118018 TI - Th17 cells contribute to pulmonary fibrosis and inflammation during chronic kidney disease progression after acute ischemia. AB - Acute kidney injury (AKI) is associated with high mortality rates and predisposes development of chronic kidney disease (CKD). Distant organ damage, particularly in the lung, may contribute to mortality in AKI patients. Animal models of AKI demonstrate an increase in pulmonary infiltration of lymphocytes and reveal an acute compromise of lung function, but the chronic effects of AKI on pulmonary inflammation are unknown. We hypothesized that in response to renal ischemia/reperfusion (I/R), there is a persistent systemic increase in Th17 cells with potential effects on pulmonary structure and function. Renal I/R injury was performed on rats, and CKD progression was hastened by unilateral nephrectomy and exposure to 4.0% sodium diet between 35 and 63 days post-I/R. Th17 cells in peripheral blood showed a progressive increase up to 63 days after recovery from I/R injury. Infiltration of leukocytes including Th17 cells was also elevated in bronchiolar lavage (BAL) fluid 7 days after I/R and remained elevated for up to 63 days. Lung histology demonstrated an increase in alveolar cellularity and a significant increase in picrosirius red staining. Suppression of lymphocytes with mycophenolate mofetil (MMF) or an IL-17 antagonist significantly reduced Th17 cell infiltration and fibrosis in lung. In addition, tracheal smooth muscle contraction to acetylcholine was significantly enhanced 63-days after I/R relative to sham-operated controls. These data suggest that AKI is associated with a persistent increase in circulating and lung Th17 cells which may promote pulmonary fibrosis and the potential alteration in airway contractility. PMID- 29118020 TI - Viscerosensory input drives angiotensin II type 1A receptor-expressing neurons in the solitary tract nucleus. AB - Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (ANG II) is known to modulate peripheral visceral reflexes, in part, by activating ANG II type 1A receptors (AT1AR) in the NTS. AT1AR-expressing NTS neurons occur throughout the NTS with a defined subnuclear distribution, and most of these neurons are depolarized by ANG II. In this study we determined whether AT1AR-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by ANG II. Using AT1AR-GFP mice to make targeted whole cell recordings from AT1AR-expressing NTS neurons, we demonstrate that two thirds (37 of 56) of AT1AR-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT1AR expressing neurons can receive either C- or A-fiber-mediated input. Application of ANG II to a subset of second-order AT1AR-expressing neurons did not affect spontaneous, evoked, or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT1AR-expressing viscerosensory neurons terminate on AT1AR-expressing NTS neurons. Our data suggest that ANG II is likely to modulate multiple visceral sensory modalities by altering the excitability of second-order AT1AR-expressing NTS neurons. PMID- 29118019 TI - Acyloxyacyl hydrolase modulates pelvic pain severity. AB - Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2CxB progeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC. PMID- 29118021 TI - Venous collapse regulates intracranial pressure in upright body positions. AB - Recent interest in intracranial pressure (ICP) in the upright posture has revealed that the mechanisms regulating postural changes in ICP are not fully understood. We have suggested an explanatory model where the postural changes in ICP depend on well-established hydrostatic effects in the venous system and where these effects are interrupted by collapse of the internal jugular veins (IJVs) in more upright positions. The aim of this study was to investigate this relationship by simultaneous invasive measurements of ICP, venous pressure, and IJV collapse in healthy volunteers. ICP (monitored via the lumbar route), central venous pressure (peripherally inserted central catheter line), and IJV cross sectional area (ultrasound) were measured in 11 healthy volunteers (47 +/- 10 yr, mean +/- SD) in 7 positions, from supine to sitting (0-69 degrees ). Venous pressure and anatomical distances were used to predict ICP in accordance with the explanatory model, and IJV area was used to assess IJV collapse. The hypothesis was tested by comparing measured ICP with predicted ICP. Our model accurately described the general behavior of the observed postural ICP changes (mean difference, -0.03 +/- 2.7 mmHg). No difference was found between predicted and measured ICP for any tilt angle ( P values, 0.65-0.94). The results support the hypothesis that postural ICP changes are governed by hydrostatic effects in the venous system and IJV collapse. This improved understanding of postural ICP regulation may have important implications for the development of better treatments for neurological and neurosurgical conditions affecting ICP. PMID- 29118022 TI - Tonic aortic depressor nerve stimulation does not impede baroreflex dynamic characteristics concomitantly mediated by the stimulated nerve. AB - Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 +/- 70.9 vs. 247.3 +/- 47.2 arbitrary units, P < 0.01) and mean AP (98.4 +/- 7.8 vs. 89.2 +/- 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 +/- 1.0 vs. 14.7 +/- 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy. PMID- 29118023 TI - The orchestration of autonomous and behavioral thermoregulation. PMID- 29118024 TI - Arsenic exposure induces glucose intolerance and alters global energy metabolism. AB - Environmental pollutants acting as endocrine-disrupting chemicals (EDCs) are recognized as potential contributors to metabolic disease pathogenesis. One such pollutant, arsenic, contaminates the drinking water of ~100 million people globally and has been associated with insulin resistance and diabetes in epidemiological studies. Despite these observations, the precise metabolic derangements induced by arsenic remain incompletely characterized. In the present study, the impact of arsenic on in vivo metabolic physiology was examined in 8-wk old male C57BL/6J mice exposed to 50 mg/l inorganic arsenite in their drinking water for 8 wk. Glucose metabolism was assessed via in vivo metabolic testing, and feeding behavior was analyzed using indirect calorimetry in metabolic cages. Pancreatic islet composition was assessed via immunofluorescence microscopy. Arsenic-exposed mice exhibited impaired glucose tolerance compared with controls; however, no difference in peripheral insulin resistance was noted between groups. Instead, early insulin release during glucose challenge was attenuated relative to the rise in glycemia. Despite decreased insulin secretion, pancreatic beta cell mass was not altered, suggesting that arsenic primarily disrupts beta-cell function. Finally, metabolic cage analyses revealed that arsenic exposure induced novel alterations in the diurnal rhythm of food intake and energy metabolism. Taken together, these data suggest that arsenic exposure impairs glucose tolerance through functional impairments in insulin secretion from beta-cells rather than by augmenting peripheral insulin resistance. Further elucidation of the mechanisms underlying arsenic-induced behavioral and beta-cell-specific metabolic disruptions will inform future intervention strategies to address this ubiquitous environmental contaminant and novel diabetes risk factor. PMID- 29118025 TI - Specialized ribosomes and specific ribosomal protein paralogs control translation of mitochondrial proteins. AB - Genome duplication in eukaryotes created paralog pairs of ribosomal proteins (RPs) that show high sequence similarity/identity. However, individual paralogs can confer vastly different effects upon cellular processes, e.g., specific yeast paralogs regulate actin organization, bud site selection, and mRNA localization, although how specificity is conferred is unknown. Changes in the RP composition of ribosomes might allow for specialized translation of different subsets of mRNAs, yet it is unclear whether specialized ribosomes exist and if paralog specificity controls translation. Using translatome analyses, we show that the translation of mitochondrial proteins is highly down-regulated in yeast lacking RP paralogs required for normal mitochondrial function (e.g., RPL1b). Although RPL1a and RPL1b encode identical proteins, Rpl1b-containing ribosomes confer more efficient translation of respiration-related proteins. Thus, ribosomes varying in RP composition may confer specialized functions, and RP paralog specificity defines a novel means of translational control. PMID- 29118027 TI - Heterogeneity of signal transduction by Na-K-ATPase alpha-isoforms: role of Src interaction. AB - Of the four Na-K-ATPase alpha-isoforms, the ubiquitous alpha1 Na-K-ATPase possesses both ion transport and Src-dependent signaling functions. Mechanistically, we have identified two putative pairs of domain interactions between alpha1 Na-K-ATPase and Src that are critical for alpha1 signaling function. Our subsequent report that alpha2 Na-K-ATPase lacks these putative Src binding sites and fails to carry on Src-dependent signaling further supported our proposed model of direct interaction between alpha1 Na-K-ATPase and Src but fell short of providing evidence for a causative role. This hypothesis was specifically tested here by introducing key residues of the two putative Src interacting domains present on alpha1 but not alpha2 sequence into the alpha2 polypeptide, generating stable cell lines expressing this mutant, and comparing its signaling properties to those of alpha2-expressing cells. The mutant alpha2 was fully functional as a Na-K-ATPase. In contrast to wild-type alpha2, the mutant gained alpha1-like signaling function, capable of Src interaction and regulation. Consistently, the expression of mutant alpha2 redistributed Src into caveolin-1-enriched fractions and allowed ouabain to activate Src-mediated signaling cascades, unlike wild-type alpha2 cells. Finally, mutant alpha2 cells exhibited a growth phenotype similar to that of the alpha1 cells and proliferated much faster than wild-type alpha2 cells. These findings reveal the structural requirements for the Na-K-ATPase to function as a Src-dependent receptor and provide strong evidence of isoform-specific Src interaction involving the identified key amino acids. The sequences surrounding the putative Src-binding sites in alpha2 are highly conserved across species, suggesting that the lack of Src binding may play a physiologically important and isoform-specific role. PMID- 29118026 TI - Carbon monoxide in lung cell physiology and disease. AB - Carbon monoxide (CO) is an endogenously produced gas that has gained recognition as a biological signal transduction effector with properties similar, but not identical, to that of nitric oxide (NO). CO, which binds primarily to heme iron, may activate the hemoprotein guanylate cyclase, although with lower potency than NO. Furthermore, CO can modulate the activities of several cellular signaling molecules such as p38 MAPK, ERK1/2, JNK, Akt, NF-kappaB, and others. Emerging studies suggest that mitochondria, the energy-generating organelle of cells, represent a key target of CO action in eukaryotes. Dose-dependent modulation of mitochondrial function by CO can result in alteration of mitochondrial membrane potential, mitochondrial reactive oxygen species production, release of proapoptotic and proinflammatory mediators, as well as the inhibition of respiration at high concentration. CO, through modulation of signaling pathways, can impact key biological processes including autophagy, mitochondrial biogenesis, programmed cell death (apoptosis), cellular proliferation, inflammation, and innate immune responses. Inhaled CO is widely known as an inhalation hazard due to its rapid complexation with hemoglobin, resulting in impaired oxygen delivery to tissues and hypoxemia. Despite systemic and cellular toxicity at high concentrations, CO has demonstrated cyto- and tissue-protective effects at low concentration in animal models of organ injury and disease. These include models of acute lung injury (e.g., hyperoxia, hypoxia, ischemia reperfusion, mechanical ventilation, bleomycin) and sepsis. The success of CO as a candidate therapeutic in preclinical models suggests potential clinical application in inflammatory and proliferative disorders, which is currently under evaluation in clinical trials. PMID- 29118028 TI - Dynamic functional contribution of the water channel AQP5 to the water permeability of peripheral lens fiber cells. AB - Although the functionality of the lens water channels aquaporin 1 (AQP1; epithelium) and AQP0 (fiber cells) is well established, less is known about the role of AQP5 in the lens. Since in other tissues AQP5 functions as a regulated water channel with a water permeability (PH2O) some 20 times higher than AQP0, AQP5 could function to modulate PH2O in lens fiber cells. To test this possibility, a fluorescence dye dilution assay was used to calculate the relative PH2O of epithelial cells and fiber membrane vesicles isolated from either the mouse or rat lens, in the absence and presence of HgCl2, an inhibitor of AQP1 and AQP5. Immunolabeling of lens sections and fiber membrane vesicles from mouse and rat lenses revealed differences in the subcellular distributions of AQP5 in the outer cortex between species, with AQP5 being predominantly membranous in the mouse but predominantly cytoplasmic in the rat. In contrast, AQP0 labeling was always membranous in both species. This species-specific heterogeneity in AQP5 membrane localization was mirrored in measurements of PH2O, with only fiber membrane vesicles isolated from the mouse lens, exhibiting a significant Hg2+ sensitive contribution to PH2O. When rat lenses were first organ cultured, immunolabeling revealed an insertion of AQP5 into cortical fiber cells, and a significant increase in Hg2+-sensitive PH2O was detected in membrane vesicles. Our results show that AQP5 forms functional water channels in the rodent lens, and they suggest that dynamic membrane insertion of AQP5 may regulate water fluxes in the lens by modulating PH2O in the outer cortex. PMID- 29118029 TI - Graphical Interpretation and Analysis of Proteins and their Ontologies (GiaPronto): A One-Click Graph Visualization Software for Proteomics Data Sets. AB - Here we present a free interactive web tool to process and visualize proteomics data sets with a single click. GiaPronto can process all proteomics quantification methods, i.e. label-free, SILAC and isobaric labeling, and analyze post-translational modifications (PTMs). The software performs normalization and statistics, assists determination of regulated proteins, biomarkers and Gene Ontology (GO) enrichment, and provides high resolution images and tables for further data analysis. We foresee that GiaPronto will become the most rapid and simple tool for assessing data quality and determining most relevant features of proteomic data sets. GiaPronto is available at giapronto.diskinlab.org. PMID- 29118030 TI - Large-Scale Low-Cost NGS Library Preparation Using a Robust Tn5 Purification and Tagmentation Protocol. AB - Efficient preparation of high-quality sequencing libraries that well represent the biological sample is a key step for using next-generation sequencing in research. Tn5 enables fast, robust, and highly efficient processing of limited input material while scaling to the parallel processing of hundreds of samples. Here, we present a robust Tn5 transposase purification strategy based on an N terminal His6-Sumo3 tag. We demonstrate that libraries prepared with our in-house Tn5 are of the same quality as those processed with a commercially available kit (Nextera XT), while they dramatically reduce the cost of large-scale experiments. We introduce improved purification strategies for two versions of the Tn5 enzyme. The first version carries the previously reported point mutations E54K and L372P, and stably produces libraries of constant fragment size distribution, even if the Tn5-to-input molecule ratio varies. The second Tn5 construct carries an additional point mutation (R27S) in the DNA-binding domain. This construct allows for adjustment of the fragment size distribution based on enzyme concentration during tagmentation, a feature that opens new opportunities for use of Tn5 in customized experimental designs. We demonstrate the versatility of our Tn5 enzymes in different experimental settings, including a novel single-cell polyadenylation site mapping protocol as well as ultralow input DNA sequencing. PMID- 29118032 TI - Impact of Nonoptimal Intakes of Saturated, Polyunsaturated, and Trans Fat on Global Burdens of Coronary Heart Disease. PMID- 29118033 TI - Trimethylamine-N-Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3-SOD2-mtROS Signaling Pathway. PMID- 29118031 TI - Neurohormonal Blockade and Circulating Cardiovascular Biomarkers During Anthracycline Therapy in Breast Cancer Patients: Results From the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study. AB - BACKGROUND: Anthracyclines are associated with cardiotoxic effects. Cardiovascular biomarkers may reflect myocardial injury, dysfunction, inflammation, and fibrosis and may precede and predict the development of left ventricular impairment. The aim of this study was to assess: (1) longitudinal change in circulating cardiovascular biomarkers, (2) the effect of metoprolol succinate and candesartan cilexetil on the biomarker response, and (3) the associations between on-treatment changes in biomarker concentrations and subsequent left ventricular dysfunction in patients with early breast cancer receiving anthracyclines. METHODS AND RESULTS: This report encompasses 121 women included in the 2*2 factorial, placebo-controlled, double-blind PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial with metoprolol and candesartan given concomitantly with anticancer therapy containing the anthracycline, epirubicin (total cumulative dose, 240-400 mg/m2). Cardiovascular magnetic resonance, echocardiography images, and circulating levels of biomarkers were obtained before and after anthracycline treatment. Cardiac troponins I and T, B-type natriuretic peptide, N-terminal pro-B-type natriuretic peptide, C-reactive protein, and galectin-3 increased during anthracycline therapy (all P<0.05). The troponin response was attenuated by metoprolol (P<0.05), but not candesartan. There was no association between change in biomarker concentrations and change in cardiac function during anthracycline therapy. CONCLUSIONS: Treatment with contemporary anthracycline doses for early breast cancer is associated with increase in circulating cardiovascular biomarkers. This increase is, however, not associated with early decline in ventricular function. Beta-blockade may attenuate early myocardial injury, but whether this attenuation translates into reduced risk of developing ventricular dysfunction in the long term remains unclear. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrial.gov. Unique identifier: NCT01434134. PMID- 29118035 TI - Single Channel Analysis of Isoflurane and Ethanol Enhancement of Taurine Activated Glycine Receptors. AB - The amino acid taurine is an endogenous ligand acting on glycine receptors (GlyRs), which is released by astrocytes in many brain regions, such as the nucleus accumbens and prefrontal cortex. Taurine is a partial agonist with an efficacy significantly lower than that of glycine. Allosteric modulators such as ethanol and isoflurane produce leftward shifts of glycine concentration-response curves but have no effects at saturating glycine concentrations. In contrast, in whole-cell electrophysiology studies these modulators increase the effects of saturating taurine concentrations. A number of possible mechanisms may explain these enhancing effects, including modulator effects on conductance, channel open times, or channel closed times. We used outside-out patch-clamp single channel electrophysiology to investigate the mechanism of action of 200 mM ethanol and 0.55 mM isoflurane in enhancing the effects of a saturating concentration of taurine. Neither modulator enhanced taurine-mediated conductance. Isoflurane increased the probability of channel opening. Isoflurane also increased the lifetimes of the two shortest open dwell times while both agents decreased the likelihood of occurrence of the longest-lived intracluster channel-closing events. The mechanism of enhancement of GlyR functioning by these modulators is dependent on the efficacy of the agonist activating the receptor and the concentration of agonist tested. PMID- 29118034 TI - Cardiovascular Effects of Long-Term Exposure to Air Pollution: A Population-Based Study With 900 845 Person-Years of Follow-up. AB - BACKGROUND: Studies have shown that long-term exposure to air pollution such as fine particulate matter (<=2.5 MUm in aerodynamic diameter [PM2.5]) increases the risk of all-cause and cardiovascular mortality. To date, however, there are limited data on the impact of air pollution on specific cardiovascular diseases. This study aimed to evaluate cardiovascular effects of long-term exposure to air pollution among residents of Seoul, Korea. METHODS AND RESULTS: Healthy participants with no previous history of cardiovascular disease were evaluated between 2007 and 2013. Exposure to air pollutants was estimated by linking the location of outdoor monitors to the ZIP code of each participant's residence. Crude and adjusted analyses were performed using Cox regression models to evaluate the risk for composite cardiovascular events including cardiovascular mortality, acute myocardial infarction, congestive heart failure, and stroke. A total of 136 094 participants were followed for a median of 7.0 years (900 845 person-years). The risk of major cardiovascular events increased with higher mean concentrations of PM2.5 in a linear relationship, with a hazard ratio of 1.36 (95% confidence interval, 1.29-1.43) per 1 MUg/m3 PM2.5. Other pollutants including PM2.5-10 of CO, SO2, and NO2, but not O3, were significantly associated with increased risk of cardiovascular events. The burden from air pollution was comparable to that from hypertension and diabetes mellitus. CONCLUSIONS: This large-scale population-based study demonstrated that long-term exposure to air pollution including PM2.5 increases the risk of major cardiovascular disease and mortality. Air pollution should be considered an important modifiable environmental cardiovascular risk factor. PMID- 29118036 TI - Zellmer lecturer provides insights into future of healthcare, opportunities for pharmacists. PMID- 29118037 TI - Nursing home evacuation turns medication reconciliation into emergency. PMID- 29118038 TI - Outpatient pharmacy steps in when community pharmacies shut down. PMID- 29118040 TI - Special patient populations needed special attention during hurricane. PMID- 29118041 TI - Marijuana legalization: A continuing conundrum. PMID- 29118042 TI - Videoconferencing for residency interviews during the Phase II Match. PMID- 29118043 TI - Feasibility of measuring QT intervals with a portable device. PMID- 29118044 TI - A practical guide to conducting and writing medical record review studies. AB - PURPOSE: A practical guide to conducting and reporting medical record review studies, including instruction and insights on topics ranging from idea conception to manuscript submission, is provided. SUMMARY: Research based on the retrospective collection and analysis of data from medical records is often the first type of research conducted by new investigators; such research can be particularly useful in high-acuity populations and is often more feasible and cost-effective than prospective studies. The research process begins with formulating a valid hypothesis-driven or exploratory research question and refining it into one that is testable; this can be facilitated by incorporating information from various sources (e.g., relevant literature, consultation with experts, observations of practice). Accurate sample size calculations are important in ensuring study feasibility (i.e., the estimated sample sizes required can be obtained). Appropriate data collection methods are particularly crucial in medical record review studies; key considerations include pertinent variables, systematic subject identification, standardized data collection instruments, training of data collectors to minimize interrater variability, processes to ensure the accuracy and reliability of data, and blinded collection of the outcome variable. Checklists are provided to guide investigators in retrospective data collection, manuscript preparation, and decisions regarding authorship eligibility and sequencing. CONCLUSION: The quality of medical record review studies and the likelihood of their acceptance for publication can be improved through adherence to recommended standards of research design, data collection and analysis, ethical authorship, and manuscript preparation. PMID- 29118045 TI - Measurement of selected preventable adverse drug events in electronic health records: Toward developing a complexity score. AB - PURPOSE: The defining of a select number of high-priority preventable adverse drug events (pADEs) for measurement in the electronic health record (EHR) and the estimation of pADE incidences in two tertiary care facilities are described. METHODS: This study was part of a larger effort aimed at developing an automated electronic health record (EHR)-based complexity-score (C-score) that ranks hospitalized patients according to their risk for pADEs for clinical intervention. We developed measures for 16 high-priority pADEs often deemed preventable using discrete clinical and administrative EHR data. For each pADE we specified inclusion and exclusion criteria that were used to define risk populations for each specific pADE. The incidence of each type of pADE was then measured during a designated follow-up period considering all adult admissions to 2 large academic tertiary care hospitals, who were eligible for the pADE-specific risk populations during any of their first 5 hospital days. RESULTS: Utilizing the data from 83,787 admissions who were at risk for at least one pADE during at least one of their first five hospital days, we found that 27,193 admissions (32.5%) developed at least one pADE. Uncontrolled postsurgical pain, uncontrolled pneumonia, and drug-associated hypotension had the highest incidences with the following number of days with pADE per number of patients at risk: 13,484 of 19,640; 527 of 1,530; and 13,394 of 43,630, while drug-associated falls (446 of 75,036), drug-associated acute mental status changes (262 of 66,875) and venous thromboembolism (214 of 74,283) had the lowest incidence rates. CONCLUSION: EHR based definitions of clinically important pADEs were developed, and the incidence of the pADEs was estimated. These definitions will be advanced for the creation of prediction models to develop a C-score for identifying patients at risk for pADEs to prioritize pharmacist intervention. PMID- 29118046 TI - Stability of busulfan solutions in polypropylene syringes and infusion bags as determined with an original assay. AB - PURPOSE: The stability of busulfan solution in 0.9% sodium chloride and stored in polypropylene syringes or infusion bags was evaluated. METHODS: Busulfan solutions (0.54 mg/mL) were prepared and transferred to 50-mL polypropylene syringes and 100- and 500-mL polypropylene infusion bags and stored at 2-8 and 23 27 degrees C. Chemical stability was measured using a stability-indicating, ultrahigh performance liquid chromatography coupled to mass spectrometry method. The stability of busulfan was assessed by measuring the percentage of the initial concentration remaining at the end of each time point of analysis. The initial busulfan concentration was defined as 100%. Stability was defined as retention of at least 90% of the initial busulfan concentration. A visual inspection of the samples for particulate matter, clarity, and color without instrumentation of magnification was conducted at each time point of analysis. RESULTS: The visual inspection demonstrated no influence of the storage container when busulfan infusions diluted in 0.9% sodium chloride injection were stored at 23-27 degrees C. No color change or precipitate was observed at this temperature; however, a rapid decrease of the busulfan content in all containers stored at room temperature was observed. Busulfan in syringes was chemically stable for 12 hours, while busulfan in infusion bags (100 and 500 mL) was stable only for 3 hours at 23-27 degrees C. CONCLUSION: Busulfan 0.54-mg/mL solution in 0.9% sodium chloride injection was physically and chemically stable for 30 hours when stored in 50-mL polypropylene syringes at 2-8 degrees C and protected from light. PMID- 29118047 TI - Interprofessional development and implementation of a pharmacist professional advancement and recognition program. AB - PURPOSE: The interprofessional development, implementation, and outcomes of a pharmacist professional advancement and recognition program (PARP) at an academic medical center are described. SUMMARY: Limitations of the legacy advancement program, in combination with low rates of employee engagement in peer recognition and professional development, at the UW Health department of pharmacy led to the creation of a task force comprising pharmacists from all practice areas to develop a new pharmacist PARP. Senior leadership within the organization expanded the scope of the project to include an interprofessional work group tasked to develop guidelines and core principles that other professional staff could use to reduce variation across advancement and recognition programs. Key program design elements included a triennial review of performance against advancement standards and the use of peer review to supplement advancement decisions. The primary objective was to meaningfully improve pharmacists' engagement as measured through employee engagement surveys. Secondary outcomes of interest included the results of pharmacist and management satisfaction surveys and the program's impact on the volume and mix of pharmacist professional development activities. Of the 126 eligible pharmacists, 93 participated in the new program. The majority of pharmacists was satisfied with the program. For pharmacists who were advanced as part of the program, meaningful increases in employee engagement scores were observed, and a mean of 95 hours of professional development and quality improvement activities was documented. CONCLUSION: Implementation of a PARP helped increase pharmacist engagement through participation in quality improvement and professional development activities. The program also led to the creation of organizationwide interprofessional guidelines for advancement programs within various healthcare disciplines. PMID- 29118048 TI - RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer. AB - Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRasG12D in mouse lung epithelial cells markedly impairs the progression of KRasG12D -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRasG12D -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer. PMID- 29118051 TI - Chronic inflammation is a feature of Achilles tendinopathy and rupture. AB - BACKGROUND: Recent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture. METHODS: We studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers. RESULTS: Tendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-kappaB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increased PTGS2 and interleukin-8 expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells. CONCLUSIONS: Tissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease. PMID- 29118052 TI - Why not consider a sex factor within the ISO 11088 ski binding setting standard? PMID- 29118053 TI - International variations in primary care physician consultation time: a systematic review of 67 countries. AB - OBJECTIVE: To describe the average primary care physician consultation length in economically developed and low-income/middle-income countries, and to examine the relationship between consultation length and organisational-level economic, and health outcomes. DESIGN AND OUTCOME MEASURES: This is a systematic review of published and grey literature in English, Chinese, Japanese, Spanish, Portuguese and Russian languages from 1946 to 2016, for articles reporting on primary care physician consultation lengths. Data were extracted and analysed for quality, and linear regression models were constructed to examine the relationship between consultation length and health service outcomes. RESULTS: One hundred and seventy nine studies were identified from 111 publications covering 28 570 712 consultations in 67 countries. Average consultation length differed across the world, ranging from 48 s in Bangladesh to 22.5 min in Sweden. We found that 18 countries representing about 50% of the global population spend 5 min or less with their primary care physicians. We also found significant associations between consultation length and healthcare spending per capita, admissions to hospital with ambulatory sensitive conditions such as diabetes, primary care physician density, physician efficiency and physician satisfaction. CONCLUSION: There are international variations in consultation length, and it is concerning that a large proportion of the global population have only a few minutes with their primary care physicians. Such a short consultation length is likely to adversely affect patient healthcare and physician workload and stress. PMID- 29118054 TI - Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England. AB - OBJECTIVE: Severe vitamin D deficiency is a recognised cause of skeletal muscle fatigue and myopathy. The aim of this study was to examine whether chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with altered circulating vitamin D metabolites. DESIGN: Cohort study. SETTING: UK university hospital, recruiting from April 2014 to April 2015. PARTICIPANTS: Ninety-two patients with CFS/ME and 94 age-matched healthy controls (HCs). MAIN OUTCOME MEASURES: The presence of a significant association between CFS/ME, fatigue and vitamin D measures. RESULTS: No evidence of a deficiency in serum total 25(OH) vitamin D (25(OH)D2 and 25(OH)D3 metabolites) was evident in individuals with CFS/ME. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis revealed that total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively). Analysis of food/supplement diaries with WinDiets revealed that the higher total 25(OH) vitamin D concentrations observed in the CFS/ME group were associated with increased vitamin D intake through use of supplements compared with the control group. Analysis of Chalder Fatigue Questionnaire data revealed no association between perceived fatigue and vitamin D levels. CONCLUSIONS: Low serum concentrations of total 25(OH)D do not appear to be a contributing factor to the level of fatigue of CFS/ME. PMID- 29118055 TI - Trump's promises on opioids not backed by funds. PMID- 29118057 TI - GP is suspended for three months after "improper relationship" with patient. PMID- 29118058 TI - Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair Than iPSCs. AB - RATIONALE: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs. OBJECTIVE: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo. METHODS AND RESULTS: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV-treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. CONCLUSIONS: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage. PMID- 29118062 TI - Wearables for Promoting Physical Activity. AB - BACKGROUND: The rapid expansion and popularity of consumer-wearable physical activity monitors (WPAMs) has enabled the integration of technology into physical activity (PA) intervention, deployment, and evaluation. This brief review reports on the accuracy of consumer-WPAMs, considers the intervention effects of using consumer-WPAMs, and offers future considerations as the proliferation of this area of product development and consumer use continues to escalate. CONTENT: The studies reviewed document the utility for consumer-WPAMs to objectively assess PA, with output metrics similar to research-grade activity monitors. Early intervention efficacy for the use of consumer-WPAMs to increase PA holds considerable promise. Substantial increases in moderate- to vigorous-intensity PA (MVPA) have been reported across different research study designs and populations in which consumer-WPAMs have been used in isolation or in conjunction with other behavioral change strategies. The utility of consumer-WPAMs is currently being investigated in clinical populations, notably showing increases in PA in individuals at risk for cancer or post cancer survivors, in those with chronic obstructive pulmonary disease, and in postsurgical patients. There has been a proliferation of registered trials at clinicaltrials.gov, and an increase of disseminated works regarding the use of consumer-WPAMs is expected. SUMMARY: There are many research studies documenting the validity and intervention effectiveness of consumer-WPAMs; evidence is emerging on the health benefits linked to use of such devices. Future work on the long-term effects of consumer WPAMs on behavior and health is warranted, and prospects appear exciting as wearable technology advances and adoption increases. PMID- 29118060 TI - Association Between Inflammatory Markers and Progression to Kidney Dysfunction: Examining Different Assessment Windows in Patients With Type 1 Diabetes. AB - OBJECTIVE: To determine whether biomarkers of inflammation and endothelial dysfunction are associated with the development of kidney dysfunction and the time frame of their association. RESEARCH DESIGN AND METHODS: Biomarkers were measured at four time points during 28 years of treatment and follow-up in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. In addition to traditional biomarkers of inflammation (C-reactive protein and fibrinogen), we measured interleukin-6 (IL-6) and soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1/2), markers of endothelial dysfunction (soluble intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E selectin [sE-selectin]), and fibrinolysis (total and active plasminogen activator inhibitor-1 [PAI-1]). Renal outcomes were defined as progression to incident chronic kidney disease (stage 3 or more severe) or macroalbuminuria (albumin excretion rate >=300 mg/24 h). Prospective multivariate event-time analyses were used to determine the association of each biomarker with each subsequent event within prespecified intervals (3-year and 10-year windows). RESULTS: Multivariate event-time models indicated that several markers of inflammation (sTNFR-1/2), endothelial dysfunction (sE-selectin), and clotting/fibrinolysis (fibrinogen and PAI-1) are significantly associated with subsequent development of kidney dysfunction. Although some markers showed variations in the associations between the follow-up windows examined, the results indicate that biomarkers (sTNFR-1/2, sE-selectin, PAI-1, and fibrinogen) are associated with progression to chronic kidney disease in both the 3-year and the 10-year windows. CONCLUSIONS: Plasma markers of inflammation, endothelial dysfunction, and clotting/fibrinolysis are associated with progression to kidney dysfunction in type 1 diabetes during both short-term and long-term follow-up. PMID- 29118063 TI - Dietary Fat: Friend or Foe? PMID- 29118059 TI - Diabetes Care Disparities in Long-standing Type 1 Diabetes in Canada and the U.S.: A Cross-sectional Comparison. AB - OBJECTIVE: To assess national differences in diabetes care and quality of life (QOL) between individuals with long-standing type 1 diabetes (>=50 years) in Canada and the U.S. RESEARCH DESIGN AND METHODS: Cross-sectional data from identical surveys administered in the Canadian Study of Longevity in Diabetes and the Joslin Medalist Study, collected in 2013-2016 and 2005-2011, respectively, were compared. Laboratory values and ophthalmic examination were completed by clinical care physicians for Canadians and the Joslin Clinic for Americans. Univariate comparisons and multivariable regression for HbA1c, QOL, insulin pump use, and coronary artery disease (CAD) were performed. Nephropathy, CAD, and peripheral arterial disease (PAD) were self-reported; neuropathy was defined by a Michigan Neuropathy Screening Instrument (Questionnaire component) score >=3, and proliferative retinopathy was documented from ophthalmic examination. QOL was self-reported on an ordinal scale. RESULTS: Three hundred sixty-one Canadians and 668 Americans had similar ages (mean 65.78 years [SD 8.67] vs. 66.38 years [7.66], P = 0.27) and durations of diabetes (median 53.00 years [interquartile range 51.00, 58.00] vs. 53.00 years [51.00, 57.00], P = 0.51). Canadians had higher HbA1c (mean 7.53% [SD 1.03] [59 mmol/mol] vs. 7.22% [0.98] [55 mmol/mol], P < 0.0001), lower QOL (36.9% vs. 48.7% with "excellent" QOL, P = 0.0002), and less CAD (29.7% vs. 41.2%, P = 0.0003) and insulin pump use (43.3% vs. 55.6%, P = 0.0002). Other complication rates were similar. Residual differences for Canadians compared with Americans remained after adjustment for age, sex, CAD, PAD, education, and relevant a priori selected variables: 0.28% higher HbA1c (P = 0.0004); and odds ratios of 0.68 (95% CI 0.51, 0.90), 0.46 (0.31, 0.68), and 0.71 (0.52, 0.96) for higher QOL, CAD, and insulin pump use, respectively. CONCLUSIONS: Although Canadians and Americans have similar rates of complications other than CAD, further research is required to understand why Canadians have higher HbA1c levels, lower QOL, and less insulin pump use. PMID- 29118061 TI - Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression. AB - Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets.Experimental Design: We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC.Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs.Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. Clin Cancer Res; 24(2); 360-9. (c)2017 AACR. PMID- 29118065 TI - Rejection Hurts! PMID- 29118064 TI - Leukocyte Counts Based on DNA Methylation at Individual Cytosines. AB - BACKGROUND: White blood cell counts are routinely measured with automated hematology analyzers, by flow cytometry, or by manual counting. Here, we introduce an alternative approach based on DNA methylation (DNAm) at individual CG dinucleotides (CpGs). METHODS: We identified candidate CpGs that were nonmethylated in specific leukocyte subsets. DNAm levels (ranging from 0% to 100%) were analyzed by pyrosequencing and implemented into deconvolution algorithms to determine the relative composition of leukocytes. For absolute quantification of cell numbers, samples were supplemented with a nonmethylated reference DNA. RESULTS: Conventional blood counts correlated with DNAm at individual CpGs for granulocytes (r = -0.91), lymphocytes (r = -0.91), monocytes (r = -0.74), natural killer (NK) cells (r = -0.30), T cells (r = -0.73), CD4+ T cells (r = -0.41), CD8+ T cells (r = -0.88), and B cells (r = -0.66). Combination of these DNAm measurements into the "Epi-Blood-Count" provided similar precision as conventional methods in various independent validation sets. The method was also applicable to blood samples that were stored at 4 degrees C for 7 days or at -20 degrees C for 3 months. Furthermore, absolute cell numbers could be determined in frozen blood samples upon addition of a reference DNA, and the results correlated with measurements of automated analyzers in fresh aliquots (r = 0.84). CONCLUSIONS: White blood cell counts can be reliably determined by site specific DNAm analysis. This approach is applicable to very small blood volumes and frozen samples, and it allows for more standardized and cost-effective analysis in clinical application. PMID- 29118066 TI - Use of a Self-Instructional Radiographic Anatomy Module for Dental Hygiene Faculty Calibration. AB - Purpose: Dental hygiene educators often provide inconsistent instruction in clinical settings and various attempts to address the lack of consistency have been reported in the literature. The purpose of this pilot study was to determine if the use of a use of a self-instructional, radiographic anatomy (SIRA) module improved DH faculty calibration regarding the identifica-tion of normal intraoral and extraoral radiographic anatomy and whether its effect could be sustained over a period of four months.Methods: A convenience sample consisting of all dental hygiene faculty members involved in clinical instruction (N=23) at the University of North Carolina (UNC) was invited to complete the four parts of this online pilot study: a pre-test, review of the SIRA module, an immediate post-test, and a four-month follow-up post-test. Descriptive analyses, the Friedman's ANOVA, and the exact form of the Wilcoxon-Signed-Rank test were used to an-alyze the data. Level of significance was set at 0.05. Participants who did not complete all parts of the study were omitted from data analysis comparing the pre to post-test performance.Results: The pre-test response rate was 73.9% (N=17), and 88.2% (N=15) of those initial participants completed both the immediate and follow-up post-tests. Faculty completing all parts of the study consisted of: 5 full-time faculty, 5 part-time faculty, and 5 graduate teaching assistants. The Friedman's ANOVA revealed no statistically significant difference (P=0.179) in percentages of correct responses between the three tests (pre, post and follow-up). The exact form of the Wilcoxon-Signed-Rank test revealed marginal significance when comparing percent of correct responses at pre-test and immediate post-test (P=0.054), and no statistically significant difference when comparing percent of correct responses at immediate post-test and the follow-up post-test four months later (P=0.106).Conclusions: Use of a SIRA module did not significantly affect DH faculty test performance. Lack of statistical significance in the percentages of correct responses between the three tests may have been affected by the small number of participants completing all four parts of the study (N=15). Additional research is needed to identify and improve methods for faculty calibration. PMID- 29118049 TI - The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota. AB - The human gut microbiota is engaged in multiple interactions affecting host health during the host's entire life span. Microbes colonize the neonatal gut immediately following birth. The establishment and interactive development of this early gut microbiota are believed to be (at least partially) driven and modulated by specific compounds present in human milk. It has been shown that certain genomes of infant gut commensals, in particular those of bifidobacterial species, are genetically adapted to utilize specific glycans of this human secretory fluid, thus representing a very intriguing example of host-microbe coevolution, where both partners are believed to benefit. In recent years, various metagenomic studies have tried to dissect the composition and functionality of the infant gut microbiome and to explore the distribution across the different ecological niches of the infant gut biogeography of the corresponding microbial consortia, including those corresponding to bacteria and viruses, in healthy and ill subjects. Such analyses have linked certain features of the microbiota/microbiome, such as reduced diversity or aberrant composition, to intestinal illnesses in infants or disease states that are manifested at later stages of life, including asthma, inflammatory bowel disease, and metabolic disorders. Thus, a growing number of studies have reported on how the early human gut microbiota composition/development may affect risk factors related to adult health conditions. This concept has fueled the development of strategies to shape the infant microbiota composition based on various functional food products. In this review, we describe the infant microbiota, the mechanisms that drive its establishment and composition, and how microbial consortia may be molded by natural or artificial interventions. Finally, we discuss the relevance of key microbial players of the infant gut microbiota, in particular bifidobacteria, with respect to their role in health and disease. PMID- 29118067 TI - A Comparison of Cognitive Presence in Asynchronous and Synchronous Discussions in an Online Dental Hygiene Course. AB - Purpose: Many dental hygiene degree completion (34) and graduate (14) programs offer the majority or all of their course offerings online. While the concept of real-time video web-conferencing has been realized through advances in technology, only 5% of dental hygiene programs report utilizing real-time technologies. The purpose of this study was to use the Community of Inquiry Framework to observe and compare the development of cognitive presence and critical thinking between two different methods of online discussion; asynchronous discussion boards and synchronous video web-conferences.Methods: Students in one online course were divided into two groups. Each week one group completed the course discussion questions through an asynchronous discussion board while the other group completed the same discussion questions via a synchronous video web-conference. Data were recorded and analyzed to compare total indicators of cognitive presence during the two discussion sessions, as well as comparing the various levels of cognitive presence.Results: A total of 117 messages were recorded in the asynchronous discussion sessions and 260 messages in the synchronous discussion sessions. The synchronous video web conferences achieved significantly more total cognitive presence than the asynchronous discussions (p=0.005). Furthermore, the synchronous discussions reached the highest phase of cognitive presence, the resolution phase, in 10.19% of the messages, while the asynchronous discussions reached the resolution phase significantly less often at 0.85% (p=0.005).Conclusions: This study suggests that synchronous video web-conference in online discussions may create higher levels of cognitive presence in an online course. Higher levels of cognitive presence found in synchronous video web-conferencing may foster critical thinking skills in degree completion and graduate dental hygiene online courses. PMID- 29118068 TI - The Impact of Community Rotations on the Cultural Competence of Dental Hygiene Students in the State of Texas. AB - Purpose: Culturally competent health care providers understand cultural attitudes, values, beliefs and practices and are able to use this knowledge to guide patient care. Rising oral health disparities among racial and ethnic minorities require that dental educators emphasize the attainment of cultural competence in order to prepare students to effectively care for patients with backgrounds different from their own. This study investigated the role of community rotations on the cultural competence of second-year Texas dental hygiene students.Methods: A modified version of the validated self-assessing Clinical Cultural Competency Questionnaire (CCCQ) was given to students at twelve Texas dental hygiene programs with a 100% response rate (239/239). Data analysis was performed using the Kendall tau correlation for associations and Kruskal Wallis and Mann-Whitney U tests for differences among and between groups.Results: Students scored highest in attitude (86th percentile). Time spent in community rotations (p=0.009), number of community rotations (p=0.028), racial/ethnic diversity of program clinic patients (p=0.042), and training hours (p=0.044) were associated with increased cultural competence scores. Students with over 50 community rotation hours (p=0.006) scored significantly higher than students with less than 50 hours. Generally, those with four rotations (p=0.002) scored highest. Those with public clinic (p=0.049) and school (p=0.044) rotations scored significantly higher than those without these experiences. Those with nursing home (p=0.009) and hospital (p=0.026) experience scored lower than those without these experiences. Students seeing the most racially/ethnically diverse patients in program clinics scored higher (p=0.014) than students seeing less diverse patients. Those with 6-10 training hours scored higher (p=0.013) than those with other training levels. Hispanics scored significantly higher than whites in skill and overall cultural competence (p<= 0.005).Conclusion: Dental hygiene programs should invest time in cultural competence training and choose a robust program of community rotations, while considering the diversity of the student body and clinic patient pool to enhance graduates' cultural competence. PMID- 29118069 TI - Public Health Dental Hygienists in Massachusetts: A Qualitative Study. AB - Purpose: The aim of this qualitative, phenomenological study was to explore the attitudes and perceptions of public health dental hygienists on providing preventive care to underserved populations in Massachusetts.Methods: Non probability purposive sampling was used for initial participant recruitment, and snowball sampling occurred thereafter. Data collection occurred through semi structured interviews. Qualitative analysis was conducted using Pitney and Parker's eight-step CREATIVE process.Results: Data saturation occurred with 10 participants (n=10), one-third of the public health dental hygienists who are practicing in Massachusetts. The majority of practice settings included school based programs (70%), while programs for children with special needs (10%) were the least common. Two major themes emerged from the data; (a) the opportunity to be an oral health change agent and (b) barriers to practice. Six subcategories emerged from the data and are reviewed within the context of their associated themes. Additionally, career satisfaction emerged as an unintended theme, and was reported as the driving force for the majority of participants.Conclusion: This study revealed a better understanding of the public health dental hygiene workforce model in Massachusetts. Public health dental hygienists in Massachusetts perceive themselves as change agents within the health care profession, and although barriers to practice are plentiful, these oral health care professionals are committed to improving access to dental care. PMID- 29118070 TI - Perceptions of Oral Cancer Screenings as Compared to Other Cancer Screenings: A pilot study. AB - Purpose: The purpose of this pilot study was to compare public perceptions of Idaho adults regarding oral cancer (OC) screening with other common cancer screenings including breast cancer (BC), prostate cancer (PC), and colon cancer (CC) screenings.Methods: This study utilized a convenience sample (N=100) of Idaho residents. A self-designed, validated interview-administered questionnaire was administered by a data collection service using computer-assisted telephone interview software to assess consumer perceptions about cancer screenings. Data were analyzed using descriptive statistics, frequencies, and Pearson's Chi-Square tests.Results: Participants were predominantly white (90%) with a mean age of 52.7 years with some post-high school education (80%) and the majority had received OC screenings (54%).The majority of participants perceived benefits of each specific cancer screening as very helpful: (a) OC screening (60%), (b) BC screening (79.2% females), (c) PC screening (63.8% males), and (d) CC screening (84%), and also reported no perceived risks regarding OC (80%), BC (60.4%), PC (66%) screening. Only 11% reported fear of finding cancer with an OC screening. The study findings supported significant associations (p<0.05) between consumer perceptions of cost and time as barriers to accessing all of the selected cancer screenings.Conclusion: This study identified associations between consumer perceptions of OC screening when compared with BC, PC, and CC. Concerns about cost and time for cancer screenings may reflect low consumer awareness regarding differences between OC and other cancer screenings. Future studies including larger samples representing more diverse populations are recommended to further explore the basis of participants' perceptions of cancer screenings and to identify ways to minimize barriers to cancer screenings. PMID- 29118071 TI - Effects of Instrument Handle Design on Dental Hygienists' Forearm Muscle Activity During Scaling. AB - Purpose: The purpose of this study was to determine the effects of 4 different commercially available instrument handle designs (A. 16 grams and 12.7 mm diameter, B. 23 grams and 11.1 mm diameter, C. 21 grams and 7.9 mm diameter and D. 18 grams and 6.35 mm diameter) on the muscle activity of four forearm muscles during a simulated scaling experience.Methods: A convenience sample of 27 (n=27) dental hygienists used a Columbia 13/14 curet with four different instrument handles to scale artificial calculus from typodont teeth. Each participant's muscle activity was measured using surface electromyography (sEMG).Results: Similar muscle activity was generated when scaling with instruments at 16, 18, and 21 grams with varying diameter handles. Instrument B generated significantly more muscle activity when compared to each of the other instrument handle designs (p=0.001, p=0.002, p=0.039). The lower left quadrant displayed significantly less muscle activity during scaling than the upper and lower right quadrants (p=0.026, p=0.000), although no significant interaction effect was found with instruments within quadrants. Most participants (62.96%) preferred instrument A, which was rated more comfortable based on weight when compared to the other instruments tested.Conclusions: Instrument handle design has an effect on forearm muscle activity when scaling in a simulated environment. The heaviest instrument with a relatively large diameter (B 11.1 mm and 23 g) generated significantly more overall mean muscle activity compared to the other three instruments. Similar amounts of muscle activity were produced by instruments weighing between 16 and 21 g. Participants' instrument preferences were more affected by handle diameter than weight. Results support the need for further research to determine the impact of these findings on muscle load related to risk of musculoskeletal disorders in a real-world setting. PMID- 29118072 TI - Child Care Providers' Knowledge About Dental Injury First Aid in Preschool-age Children. AB - Purpose: The aim of this study was to assess child care providers' level of knowledge of first aid management and attitudes towards dental injuries among preschool-age children within Fairfield County, Connecticut and Boston, Massachusetts.Methods: This descriptive cross-sectional study used a web-based, validated questionnaire adapted from several studies with permission from authors. A panel of 5 dental experts determined the relevance of the questions and overall content (I-CVI range 0.8-1; S-CVI = 0.95). The 28 question survey included demographics, level of knowledge, attitudes about traumatic dental injuries, emergency management, and 2 case study questions on management of luxation and tooth fracture. Survey data was coded and analyzed for associations and trends using STATA(r) statistics/data analysis software v. 11.2.Results: A total of 100 child care providers completed the online questionnaire. Eighty-four percent self-reported little to no knowledge about dental injury management. Sixty percent of child care providers agreed that they are responsible for managing dental injuries. Approximately two-thirds of child care providers reported not feeling adequately informed about dental injuries, with 77% expressing interest in receiving more information.Conclusions: The majority of child care providers' do not have the knowledge to perform adequate first aid following a dental injury. Professional development on first aid for dental injuries is recommended among this workforce population. PMID- 29118073 TI - Regulation of ATP utilization during metastatic cell migration by collagen architecture. AB - Cell migration in a three-dimensional matrix requires that cells either remodel the surrounding matrix fibers and/or squeeze between the fibers to move. Matrix degradation, matrix remodeling, and changes in cell shape each require cells to expend energy. While significant research has been performed to understand the cellular and molecular mechanisms guiding metastatic migration, less is known about cellular energy regulation and utilization during three-dimensional cancer cell migration. Here we introduce the use of the genetically encoded fluorescent biomarkers, PercevalHR and pHRed, to quantitatively assess ATP, ADP, and pH levels in MDA-MB-231 metastatic cancer cells as a function of the local collagen microenvironment. We find that the use of the probe is an effective tool for exploring the thermodynamics of cancer cell migration and invasion. Specifically, we find that the ATP:ADP ratio increases in cells in denser matrices, where migration is impaired, and it decreases in cells in aligned collagen matrices, where migration is facilitated. When migration is pharmacologically inhibited, the ATP:ADP ratio decreases. Together, our data indicate that matrix architecture alters cellular energetics and that intracellular ATP:ADP ratio is related to the ability of cancer cells to effectively migrate. PMID- 29118074 TI - Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing. AB - The secretory pathway is a major determinant of cellular homoeostasis. While research into secretory stress signaling has so far mostly focused on the endoplasmic reticulum (ER), emerging data suggest that the Golgi itself serves as an important signaling hub capable of initiating stress responses. To systematically identify novel Golgi stress mediators, we performed a transcriptomic analysis of cells exposed to three different pharmacological compounds known to elicit Golgi fragmentation: brefeldin A, golgicide A, and monensin. Subsequent gene-set enrichment analysis revealed a significant contribution of the ETS family transcription factors ELK1, GABPA/B, and ETS1 to the control of gene expression following compound treatment. Induction of Golgi stress leads to a late activation of the ETS upstream kinases MEK1/2 and ERK1/2, resulting in enhanced ETS factor activity and the transcription of ETS family target genes related to spliceosome function and cell death induction via alternate MCL1 splicing. Further genetic analyses using loss-of-function and gain of-function experiments suggest that these transcription factors operate in parallel. PMID- 29118075 TI - Translational control of a human CDKN1A mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes. AB - In response to sublethal ultraviolet B (UVB) irradiation, human keratinocytes transiently block progression of the cell cycle to allow ample time for DNA repair and cell fate determination. These cellular activities are important for avoiding the initiation of carcinogenesis in skin. Central to these processes is the repression of initiation of mRNA translation through GCN2 phosphorylation of eIF2alpha (eIF2alpha-P). Concurrent with reduced global protein synthesis, eIF2alpha-P and the accompanying integrated stress response (ISR) selectively enhance translation of mRNAs involved in stress adaptation. In this study, we elucidated a mechanism for eIF2alpha-P cytoprotection in response to UVB in human keratinocytes. Loss of eIF2alpha-P induced by UVB diminished G1 arrest, DNA repair, and cellular senescence coincident with enhanced cell death in human keratinocytes. Genome-wide analysis of translation revealed that the mechanism for these critical adaptive responses by eIF2alpha-P involved induced expression of CDKN1A encoding the p21 (CIP1/WAF1) protein. We further show that human CDKN1A mRNA splice variant 4 is preferentially translated following stress-induced eIF2alpha-P by a mechanism mediated in part by upstream ORFs situated in the 5' leader of CDKN1A mRNA. We conclude that eIF2alpha-P is cytoprotective in response to UVB by a mechanism featuring translation of a specific splice variant of CDKN1A that facilitates G1 arrest and subsequent DNA repair. PMID- 29118077 TI - Supporting Our Communities of Scholars. PMID- 29118078 TI - Exploring Interprofessional Relationships Between Dental Hygienists and Health Professionals in Rural Canadian Communities. AB - Purpose: For most Canadians living in rural communities, limited access to dental care can negatively impact oral and general health. This narrative, tertiary review of the literature explores the outcomes of interprofessional relationships between dental hygienists and other health professionals on individuals residing in rural communities in Canada. Themes addressed include: implementing interprofessional education experiences in entry-to-practice health programs, interprofessional dynamics in primary health care teams, health perceptions in rural communities, and barriers and enablers to interprofessional relationships.Conclusion: Findings from this review suggest that the development of interprofessional relationships between health care professionals is complex and dynamic. Interprofessional collaboration should first be implemented at the educational level to help develop trust and understanding of each profession's role in health care. Alternative models of health care delivery, such as interprofessional collaborative practice, have the potential to reduce overall health care costs and improve access of comprehensive health care services to Canadians residing in rural communities. PMID- 29118076 TI - The meiosis-specific Cdc20 family-member Ama1 promotes binding of the Ssp2 activator to the Smk1 MAP kinase. AB - Smk1 is a meiosis-specific MAP kinase (MAPK) in budding yeast that is required for spore formation. It is localized to prospore membranes (PSMs), the structures that engulf haploid cells during meiosis II (MII). Similar to canonically activated MAPKs, Smk1 is controlled by phosphorylation of its activation-loop threonine (T) and tyrosine (Y). However, activation loop phosphorylation occurs via a noncanonical two-step mechanism in which 1) the cyclin-dependent kinase activating kinase Cak1 phosphorylaytes T207 during MI, and 2) Smk1 autophosphorylates Y209 as MII draws to a close. Autophosphorylation of Y209 and catalytic activity for substrates require Ssp2, a meiosis-specific protein that is translationally repressed until anaphase of MII. Ama1 is a meiosis-specific targeting subunit of the anaphase-promoting complex/cyclosome that regulates multiple steps in meiotic development, including exit from MII. Here, we show that Ama1 activates autophosphorylation of Smk1 on Y209 by promoting formation of the Ssp2/Smk1 complex at PSMs. These findings link meiotic exit to Smk1 activation and spore wall assembly. PMID- 29118079 TI - Experiences of the Kansas Extended Care Permit Providers: A descriptive study. AB - Purpose: A total of 40 states to date have expanded the role of dental hygienists with the goal of improving access to basic oral health services for underserved populations. In Kansas, legislative changes have resulted in the Extended Care Permit (ECP) designation. The purpose of this study is to describe the experiences of registered dental hygienists in Kansas holding ECP certificates (ECP RDH) as of July of 2014.Methods: Secondary data analysis was performed utilizing data collected from a survey conducted in 2014 by Oral Health Kansas. All registered ECP RDH's were sent the 32-item survey via Survey Monkey(r). Descriptive statistical analyses consisted of frequency distributions, and measures of central tendency. Inferential analyses using t-tests and ANOVA were conducted to compare groups.Results: A total of 73 responses were received from the (n= 176) surveys that were e-mailed for a 41% response rate. Of the clinicians who responded, 80%, worked at least part-time and in school settings. The most consistent barriers to providing care were the inability to directly bill insurance (52%), financial sustainability (42%) and physical requirements (42%). Follow-up tests found significant differencs between clinician groups when examining barriers.Conclusion: Although the ECP legislation appears to be expanding access to care for citizens in Kansas, significant barriers still exist in making this a viable model for oral healthcare delivery. PMID- 29118080 TI - Perceptions of Program Directors and Educators Regarding the Adequacy of Oral Health Education in Nursing Assistant Curricula. AB - Purpose: National data indicate that the oral health status of the aging population in long term care facilities (LTCF) is poor in the majority of cases. Nursing assistants are considered to be the primary caregivers of oral health care to elders residing in LTCF's. The aim of this research was to explore the perspectives among nursing educators and program directors on the adequacy of oral health education in nursing assistant curricula.Methods: This exploratory, cross-sectional study utilized a web-based questionnaire adapted, with permission, from a prior study conducted in 2009. The 17- question survey regarding the adequacy of oral health education, was e-mailed to 253 nursing educators and program directors in 71 locations in the New England area with an explanation of the study and a link to SurveyMonkey(r).Results: Of the 253 surveys e-mailed, 100 surveys (n=100) were returned giving an overall response rate of 40%. Fourteen respondents (n=14) indicated that their program did not include oral health education in their curriculum and were excluded from the study. The remaining 86 participants (program directors n=26 and educators n=60) indicated that oral health education was included in their nursing assistant curricula. Respondents who reported spending more time on both didactic (P<0.001) and clinical instruction in oral health (P<0.001) were more likely to agree that the oral health care education provided in their program was adequate (P<0.001).Conclusion: The results indicate that the perception of nursing educators and program directors is that the level of oral health education within the nursing assistant curricula is adequate in preparing students with the skills and knowledge needed to provide oral health care to patients. PMID- 29118081 TI - Perceptions of Dental Hygienists and Dentists about Preventing Early Childhood Caries: A Qualitative Study. AB - Purpose: The objective of this qualitative pilot study was to gain an in-depth understanding of dental hygienists and dentists perspectives regarding children's oral health and what needs to be done to prevent early childhood caries (ECC), the most frequent chronic disease of childhood.Methods: A skilled facilitator conducted four focus groups and four phone interviews with 20 dental hygienists and 17 dentists practicing in a variety of locations within the state of Maryland. The interview guide was based on results from previous state-wide surveys of dental hygienists and dentists. Sessions were recorded, transcribed, and reviewed by the PI and facilitator. Qualitative content analysis was used to identify and manually code themes.Results: Focus groups and interviews provided rich and insightful information for strategies to help solve the ECC problem in Maryland, which supplemented the earlier quantitative mail survey data. Three key themes emerged: challenges to preventing ECC among low-income families; necessary educational methods and practices; and, the need for inter-professional collaboration. Discussions focused on issues related to educating parents with low oral health literacy about how to prevent ECC and the value of including non dental health care providers, such as pediatricians and school nurses, in the caries prevention process.Conclusions: Current approaches to educating low-income adults about caries prevention are insufficient to prevent ECC and dental care providers cannot accomplish this goal alone. Ensuring that all dental care providers have a science-based understanding of caries prevention is critical. Integrating science-based oral health preventive care into medical and nursing undergraduate programs could increase providers' knowledge and confidence towards incorporating oral health into patient care plans; improve the oral health literacy of providers and patients; and improve patient oral health outcomes. PMID- 29118082 TI - Health Literacy Approaches to Improving Communication between Dental Hygienists and Patients for HPV-Related Oral Cancer Prevention. AB - Purpose: Human Papillomavirus (HPV) has been identified as a causal agent for oropharyngeal cancers, suggesting a new role for dental hygienists in HPV-related cancer prevention strategies. Health literacy assessment is an approach that can be used to understand providers' informational assets and needs for educating and discussing HPV prevention with patients. This study aimed to understand dental hygienists' level of health literacy regarding HPV-related oropharyngeal cancers.Methods: Four focus group sessions with dental hygienists (n=48) were conducted at a national conference. The constant comparison method, with a priori codes for health literacy competencies (i.e., access/understand/appraise/apply), was utilized for this qualitative study.Results: Participants mentioned a variety of modes (e.g., magazines, journals) for accessing HPV-information; however, descriptions of understanding HPV and its relationship to oropharyngeal cancer varied. Participants considered patients' personal characteristics, the dental practice environment, and professional factors to appraise HPV-related information. Additionally, participants self-described themselves as being "prevention specialists." These factors influenced how dental hygienists applied primary and secondary prevention of HPV-related care issues with their patients (e.g., education and oral-cancer screenings).Conclusions: Dental hygienists recognized the importance of HPV and oropharyngeal cancer prevention efforts, including oral-cancer screenings and promotion of the HPV vaccine. The study findings identified opportunities for intervention focusing on primary prevention. PMID- 29118083 TI - The Effect of Magnification Loupes on Dental Hygienists' Posture while Exploring. AB - Purpose: The purpose of this study was to determine the effects of dental magnification loupes on posture during instrumentation.Methods: A convenience sample of 27 right-handed dental hygienists, with no prior history of injuries or disabilities of the head, neck, or trunk region, enrolled in the study. Baseline posture calibration was taken and tri-axial accelerometers were placed on four locations of the head and trunk (occipital region of head; cervical vertebrae C5; thoracic vertebrae T5; lumbar vertebrae L1) to measure acceleration and the orientation of the body to gravity. Participants were randomly assigned to wear self-supplied magnification loupes during either the first or second half of the session. Dental chair mounted typodonts, prepared with artificial calculus, were used to represent a simulated oral environment. Participants were asked to explore all areas of the mouth using an ODU 11/12 explorer. Mean accelerations of the three axes were used to compute average forward/backward (AP) and side to side (ML) tilt of each accelerometer recorded during the instrumentation sessions. An end-user opinion survey was completed by each participant at the conclusion of the session.Results: No statistically significant differences in posture were revealed between the sessions with the participants wearing their loupes and not wearing loupes. However, data from the end-user survey indicate that 74% of all the participants strongly agreed that magnification loupes made exploring easier and 67% strongly agreed that they felt that magnification loupes improved their posture.Conclusion: While the majority of participants perceived that their magnification loupes enhanced their posture and made exploring easier, data from this study provided little evidence to suggest that wearing loupes leads to improved body orientation. Future research needs to examine the declination angle of ergonomic loupes and its relationship to neck and trunk flexion. PMID- 29118084 TI - Perceptions of Registered Dental Hygienists in Alternative Practice Regarding Silver Diamine Fluoride. AB - Purpose: Silver diamine fluoride (SDF) is an inexpensive, non-invasive, antimicrobial liquid used to treat carious lesions and decrease sensitivity. The purpose of this study was to assess the perceptions of registered dental hygienists in alternative practice (RDHAP) regarding the use of SDF to treat dental caries.Methods: A 16-item survey designed to evaluate RDHAP's familiarity and perceptions of SDF was electronically distributed to 222 RDHAPs practicing in the state of California. A survey research software program collected and tabulated responses, calculated response frequencies for each survey item, and determined statistical relationships among variables, using cross tabulation analysis.Results: The response rate was 46% (n=103). Over half the respondents, 54%, were unfamiliar with SDF. After describing SDF's properties and uses, 78% of respondents agreed that applying SDF to treat dental caries would be within the scope of practice of a RDHAP. Respondents agreed that patients or parents of patients would be interested in using SDF because it provides an alternative to removing tooth structure with a dental drill in order to place restorative material (82%), less expensive than restorative treatment (82%), applied like a varnish and time efficient (86%), and utilized without local anesthesia (91%). Over 56% of the respondents agreed that many patients or guardians of patients would object to the permanent black staining of the carious lesion treated with SDF. The respondents' employment/practice settings were related statistically (p<0.01) to their agreement that SDF is within the RDHAP scope of practice and their disagreement the question that patients would not accept SDF treatment due to the black staining (p=0.03). Eighty-eight percent of the respondents felt that the advantages of SDF outweigh the disadvantages for their patient populations.Conclusions: SDF would be a useful therapeutic agent for the treatment of dental caries for RDHAP practitioners treating underserved populations. PMID- 29118086 TI - CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis. AB - Glucagon-like peptide 1 (GLP-1) is a major incretin that controls glucose homeostasis. The secretion of mature GLP-1 is regulated via GPCRs, including bile acid receptor G protein-coupled bile acid receptor 1, which uses cAMP signaling to enhance the exocytosis of GLP-1-containing vesicles. However, the role of cAMP mediated transcription has not been clearly demonstrated to date. In this study, we explored the role of cAMP response element-binding protein/CREB-regulated transcription coactivator 2 (CREB/CRTC2)-dependent transcription on GLP-1 secretion in the L cells. We found that the reduced CREB/CRTC2 activity impaired the cAMP-dependent increase in GLP-1 secretion, whereas expression of constitutively active CRTC2 increased GLP-1 exocytosis from the L cells. Close investigation revealed that expression of not only proglucagon but also PC1/3, an endopeptidase for GLP-1 maturation, is transcriptionally regulated by CREB/CRTC2. Furthermore, expression of peroxisome proliferator-activating receptor coactivator 1 alpha is also reduced upon depletion of CRTC2, leading to the decreased expression of oxidative phosphorylation (OxPhos) genes, reduced ATP levels, and calcium concentrations in the L cells. Finally, we observed that intestine-specific CRTC2 knockout mice displayed reduced GLP-1 expression, leading to the lower plasma GLP-1 levels, impaired glucose tolerance, and decreased insulin-containing beta cells in pancreatic islets. Our data show that the CREB/CRTC2-dependent transcriptional pathway is critical for regulating glucose homeostasis by controlling production of GLP-1 from the L cells at the level of transcription, maturation, and exocytosis.-Lee, J.-H., Wen, X., Cho, H., Koo, S.-H. CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis. PMID- 29118087 TI - Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease. AB - The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5-24.9 kg/m2; reference; n=192), overweight (25.0-29.9 kg/m2; n=168), or obese (>=30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean+/-SD age was 37+/-8 years, annual percent change in TKV was 7.4%+/-5.1%, and BMI was 26.3+/-4.9 kg/m2 The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%+/-4.7%, overweight: 7.9%+/-4.8%, obese: 9.4%+/-6.2%; P<0.001). In the fully adjusted model, higher BMI associated with greater annual percent change in TKV (beta=0.79; 95% confidence interval [95% CI], 0.18 to 1.39, per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change in TKV >=7% compared with <5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76; 95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal weight (fully adjusted beta =-0.08; 95% CI, -0.15 to -0.02). In conclusion, overweight and, particularly, obesity are strongly and independently associated with rate of progression in early-stage ADPKD. PMID- 29118088 TI - IDO Immune Status after Chemoradiation May Predict Survival in Lung Cancer Patients. AB - Host immunity influences the impact of radiotherapy (RT) in cancer, but mechanistic connections remain obscure. In this study, we investigated the relationship of indoleamine 2,3-dioxygenase (IDO) systemic activity on clinical outcomes in RT-treated non-small cell lung cancer (NSCLC). IDO-mediated production of kynurenine and the kynurenine:tryptophan ratio in patient blood serum were determined for stage III NSCLC patients at times before, during, and after RT administration and then correlated to overall survival (OS), progression free survival, and disease progression rate in patients. We found the impact of RT on these serum IDO markers to be heterogeneous in patients. On average, kynurenine:tryptophan ratios were reduced during RT but restored after RT. Notably, both baseline levels of kynurenine:tryptophan and changes in the levels of kynurenine after RT were significantly associated with OS. When combined, favorable change and favorable baseline corresponded with very long-term OS (median OS was not reached after 57 months of median follow-up). Favorable change combined with unfavorable baseline still corresponded with a lack of distant metastases. Our results suggest that RT alters IDO-mediated immune status in NSCLC patients and that changes in this serum biomarker may be useful to predict outcomes and perhaps personalize RT dosage to improve survival.Significance: Radiotherapy appears to influence systemic IDO activity and to exert a significant impact on metastatic risk and overall survival, with possible implications for defining a biomarker to optimize radiation dose in patients to improve outcomes. Cancer Res; 78(3); 809-16. (c)2017 AACR. PMID- 29118089 TI - Oncolytic Virotherapy Blockade by Microglia and Macrophages Requires STAT1/3. AB - The first oncolytic virotherapy employing HSV-1 (oHSV-1) was approved recently by the FDA to treat cancer, but further improvements in efficacy are needed to eradicate challenging refractory tumors, such as glioblastomas (GBM). Microglia/macrophages comprising approximately 40% of a GBM tumor may limit virotherapeutic efficacy. Here, we show these cells suppress oHSV-1 growth in gliomas by internalizing the virus through phagocytosis. Internalized virus remained capable of expressing reporter genes while viral replication was blocked. Macrophage/microglia formed a nonpermissive OV barrier, preventing dissemination of oHSV-1 in the glioma mass. The deficiency in viral replication in microglial cells was associated with silencing of particular viral genes. Phosphorylation of STAT1/3 was determined to be responsible for suppressing oHSV 1 replication in macrophages/microglia. Treatment with the oxindole/imidazole derivative C16 rescued oHSV-1 replication in microglia/macrophages by inhibiting STAT1/3 activity. In the U87 xenograft model of GBM, C16 treatment overcame the microglia/macrophage barrier, thereby facilitating tumor regression without causing a spread of the virus to normal organs. Collectively, our results suggest a strategy to relieve a STAT1/3-dependent therapeutic barrier and enhance oHSV-1 oncolytic activity in GBM.Significance: These findings suggest a strategy to enhance the therapeutic efficacy of oncolytic virotherapy in glioblastoma. Cancer Res; 78(3); 718-30. (c)2017 AACR. PMID- 29118090 TI - Complement Activation via a C3a Receptor Pathway Alters CD4+ T Lymphocytes and Mediates Lung Cancer Progression. AB - The complement cascade is a part of the innate immune system that acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFNgamma+/TNFalpha+/IL10+ CD4+ and CD8+ T cells. Immunodepletion of CD4+ but not CD8+ T cells in tumor bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway.Significance: This provocative study suggests that inhibiting complement activation may heighten immunotherapeutic responses in lung cancer, offering findings with immediate implications, given the existing clinical availability of complement antagonists. Cancer Res; 78(1); 143-56. (c)2017 AACR. PMID- 29118091 TI - Structure-based drug design: aiming for a perfect fit. AB - Knowledge of the three-dimensional structure of therapeutically relevant targets has informed drug discovery since the first protein structures were determined using X-ray crystallography in the 1950s and 1960s. In this editorial we provide a brief overview of the powerful impact of structure-based drug design (SBDD), which has its roots in computational and structural biology, with major contributions from both academia and industry. We describe advances in the application of SBDD for integral membrane protein targets that have traditionally proved very challenging. We emphasize the major progress made in fragment-based approaches for which success has been exemplified by over 30 clinical drug candidates and importantly three FDA-approved drugs in oncology. We summarize the articles in this issue that provide an excellent snapshot of the current state of the field of SBDD and fragment-based drug design and which offer key insights into exciting new developments, such as the X-ray free-electron laser technology, cryo-electron microscopy, open science approaches and targeted protein degradation. We stress the value of SBDD in the design of high-quality chemical tools that are used to interrogate biology and disease pathology, and to inform target validation. We emphasize the need to maintain the scientific rigour that has been traditionally associated with structural biology and extend this to other methods used in drug discovery. This is particularly important because the quality and robustness of any form of contributory data determines its usefulness in accelerating drug design, and therefore ultimately in providing patient benefit. PMID- 29118092 TI - Structure-based discovery of cyclin-dependent protein kinase inhibitors. AB - The cell fate-determining roles played by members of the cyclin-dependent protein kinase (CDK) family explain why their dysregulation can promote proliferative diseases, and identify them as potential targets for drug discovery in oncology and beyond. After many years of research, the first efficacious CDK inhibitors have now been registered for clinical use in a defined segment of breast cancer. Research is underway to identify inhibitors with appropriate CDK-inhibitory profiles to recapitulate this success in other disease settings. Here, we review the structural data that illustrate the interactions and properties that confer upon inhibitors affinity and/or selectivity toward different CDK family members. We conclude that where CDK inhibitors display selectivity, that selectivity derives from exploiting active site sequence peculiarities and/or from the capacity of the target CDK(s) to access conformations compatible with optimizing inhibitor-target interactions. PMID- 29118094 TI - Fragment-based drug discovery and its application to challenging drug targets. AB - Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein-fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein-protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2. PMID- 29118095 TI - NMR in structure-based drug design. AB - NMR spectroscopy is a powerful technique that can provide valuable structural information for drug discovery endeavors. Here, we discuss the strengths (and limitations) of NMR applications to structure-based drug discovery, highlighting the different levels of resolution and throughput obtainable. Additionally, the emerging field of paramagnetic NMR in drug discovery and recent developments in approaches to speed up and automate protein-observed NMR data collection and analysis are discussed. PMID- 29118093 TI - Current perspectives in fragment-based lead discovery (FBLD). AB - It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery - generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients. In addition, we discuss some of the more recent applications of the methods in chemical biology - providing chemical tools to investigate biological molecules, mechanisms and systems. PMID- 29118096 TI - The SGC beyond structural genomics: redefining the role of 3D structures by coupling genomic stratification with fragment-based discovery. AB - The ongoing explosion in genomics data has long since outpaced the capacity of conventional biochemical methodology to verify the large number of hypotheses that emerge from the analysis of such data. In contrast, it is still a gold standard for early phenotypic validation towards small-molecule drug discovery to use probe molecules (or tool compounds), notwithstanding the difficulty and cost of generating them. Rational structure-based approaches to ligand discovery have long promised the efficiencies needed to close this divergence; in practice, however, this promise remains largely unfulfilled, for a host of well-rehearsed reasons and despite the huge technical advances spearheaded by the structural genomics initiatives of the noughties. Therefore the current, fourth funding phase of the Structural Genomics Consortium (SGC), building on its extensive experience in structural biology of novel targets and design of protein inhibitors, seeks to redefine what it means to do structural biology for drug discovery. We developed the concept of a Target Enabling Package (TEP) that provides, through reagents, assays and data, the missing link between genetic disease linkage and the development of usefully potent compounds. There are multiple prongs to the ambition: rigorously assessing targets' genetic disease linkages through crowdsourcing to a network of collaborating experts; establishing a systematic approach to generate the protocols and data that comprise each target's TEP; developing new, X-ray-based fragment technologies for generating high quality chemical matter quickly and cheaply; and exploiting a stringently open access model to build multidisciplinary partnerships throughout academia and industry. By learning how to scale these approaches, the SGC aims to make structures finally serve genomics, as originally intended, and demonstrate how 3D structures systematically allow new modes of druggability to be discovered for whole classes of targets. PMID- 29118098 TI - X-ray free electron laser: opportunities for drug discovery. AB - Past decades have shown the impact of structural information derived from complexes of drug candidates with their protein targets to facilitate the discovery of safe and effective medicines. Despite recent developments in single particle cryo-electron microscopy, X-ray crystallography has been the main method to derive structural information. The unique properties of X-ray free electron laser (XFEL) with unmet peak brilliance and beam focus allow X-ray diffraction data recording and successful structure determination from smaller and weaker diffracting crystals shortening timelines in crystal optimization. To further capitalize on the XFEL advantage, innovations in crystal sample delivery for the X-ray experiment, data collection and processing methods are required. This development was a key contributor to serial crystallography allowing structure determination at room temperature yielding physiologically more relevant structures. Adding the time resolution provided by the femtosecond X-ray pulse will enable monitoring and capturing of dynamic processes of ligand binding and associated conformational changes with great impact to the design of candidate drug compounds. PMID- 29118097 TI - Molecular recognition of ternary complexes: a new dimension in the structure guided design of chemical degraders. AB - Molecular glues and bivalent inducers of protein degradation (also known as PROTACs) represent a fascinating new modality in pharmacotherapeutics: the potential to knockdown previously thought 'undruggable' targets at sub stoichiometric concentrations in ways not possible using conventional inhibitors. Mounting evidence suggests these chemical agents, in concert with their target proteins, can be modelled as three-body binding equilibria that can exhibit significant cooperativity as a result of specific ligand-induced molecular recognition. Despite this, many existing drug design and optimization regimens still fixate on binary target engagement, in part due to limited structural data on ternary complexes. Recent crystal structures of protein complexes mediated by degrader molecules, including the first PROTAC ternary complex, underscore the importance of protein-protein interactions and intramolecular contacts to the mode of action of this class of compounds. These discoveries have opened the door to a new paradigm for structure-guided drug design: borrowing surface area and molecular recognition from nature to elicit cellular signalling. PMID- 29118099 TI - The potential of cryo-electron microscopy for structure-based drug design. AB - Structure-based drug design plays a central role in therapeutic development. Until recently, protein crystallography and NMR have dominated experimental approaches to obtain structural information of biological molecules. However, in recent years rapid technical developments in single particle cryo-electron microscopy (cryo-EM) have enabled the determination to near-atomic resolution of macromolecules ranging from large multi-subunit molecular machines to proteins as small as 64 kDa. These advances have revolutionized structural biology by hugely expanding both the range of macromolecules whose structures can be determined, and by providing a description of macromolecular dynamics. Cryo-EM is now poised to similarly transform the discipline of structure-based drug discovery. This article reviews the potential of cryo-EM for drug discovery with reference to protein ligand complex structures determined using this technique. PMID- 29118100 TI - 'Difficult Conversations': evaluation of multiprofessional training. AB - OBJECTIVES: Evidence-based communication skills training for health and social care professionals is essential to improve the care of seriously ill patients and their families. We aimed to evaluate the self-reported impact of 'Difficult Conversations', a multidisciplinary half-day interactive workshop, and gain feedback to inform future development and evaluation. METHODS: Service evaluation using questionnaire data collected before and immediately after workshops from February 2015 to August 2016 regarding participant self-assessed confidence, knowledge and skills. Qualitative free-text comments provided feedback about the workshop and were subjected to content analysis. RESULTS: Of 886 workshop participants, 655 completed baseline questionnaires and 714 postworkshop questionnaires; 550 were matched pairs. Participants were qualified or trainee general practitioners (34%), community nurses and care coordinators (32%), social care professionals (7%), care home staff (6%), advanced practice/specialist nurses (5%), care workers (5%) and allied health professionals (3%). All groups demonstrated significant increases in mean self-assessed confidence (2.46, 95% CI 2.41 to 2.51; to 3.20, 95% CI 3.17 to 3.24; P<0.001), knowledge (2.22, 95% CI 2.17 to 2.27; to 3.18, 95% CI 3.14 to 3.22; P<0.001) and skills (2.37, 95% CI 2.32 to 2.42; to 3.09, 95% CI 3.05 to 3.12; P<0.001). Qualitative findings showed participants valued role play, the communication framework acronym and opportunities for discussion. They commended workshop facilitators' skills, the safe atmosphere and interprofessional learning. Suggested improvements included more prepared role play and greater coverage of the taught topics. CONCLUSIONS: 'Difficult Conversations' workshops were associated with improvements in participants' self-assessed confidence, knowledge, and skills. Our findings identify workshop characteristics that are acceptable to multidisciplinary trainees. Further testing is warranted to determine effectiveness and accurately identify workshop components leading to change. PMID- 29118101 TI - Japanese physicians' experiences of terminally ill patients voluntarily stopping eating and drinking: a national survey. AB - OBJECTIVES: Voluntarily stopping eating and drinking (VSED) could be regarded as a patients' own non-treatment decision that hastens death, which involves patients voluntarily forgoing food and liquid until death. The aims of this study were to investigate the experience of home hospice physicians and palliative care specialists who care for patients during VSED in Japan, and their opinions on continuous deep sedation (CDS) as a means to relieve patient symptoms during VSED. METHODS: 219 home hospice physicians and 695 palliative care specialists across Japan were surveyed by mail questionnaire in 2016. RESULTS: A total of 571 (62%) responses were analysed. A total of 185 (32%) had experience of patients who selected VSED. In response to questions about CDS to provide relief to patients during VSED, the number of physicians who replied that CDS was acceptable was 88 (15%). CONCLUSIONS: In Japan, 32% of physicians surveyed replied that they had experience of caring for patients during VSED in a clinical setting and 15% considered CDS acceptable. PMID- 29118103 TI - Familiar But Unexpected: Effects of Sound Context Statistics on Auditory Responses in the Songbird Forebrain. AB - Rapid discrimination of salient acoustic signals in the noisy natural environment may depend, not only on specific stimulus features, but also on previous experience that generates expectations about upcoming events. We studied the neural correlates of expectation in the songbird forebrain by using natural vocalizations as stimuli and manipulating the category and familiarity of context sounds. In our paradigm, we recorded bilaterally from auditory neurons in awake adult male zebra finches with multiple microelectrodes during repeated playback of a conspecific song, followed by further playback of this test song in different interleaved sequences with other conspecific or heterospecific songs. Significant enhancement in the auditory response to the test song was seen when its acoustic features differed from the statistical distribution of context song features, but not when it shared the same distribution. Enhancement was also seen when the time of occurrence of the test song was uncertain. These results show that auditory forebrain responses in awake animals in the passive hearing state are modulated dynamically by previous auditory experience and imply that the auditory system can identify the category of a sound based on the global features of the acoustic context. Furthermore, this probability-dependent enhancement in responses to surprising stimuli is independent of stimulus-specific adaptation, which tracks familiarity, suggesting that the two processes could coexist in auditory processing. These findings establish the songbird as a model system for studying these phenomena and contribute to our understanding of statistical learning and the origin of human ERP phenomena to unexpected stimuli.SIGNIFICANCE STATEMENT Traditional auditory neurophysiology has mapped acoustic features of sounds to the response properties of neurons; however, growing evidence suggests that neurons can also encode the probability of sounds. We recorded responses of songbird auditory neurons in a novel paradigm that presented a familiar test stimulus in a sequence with similar or dissimilar sounds. The responses encode, not only stimulus familiarity, but also the expectation for a class of sounds based on the recent statistics of varying sounds in the acoustic context. Our approach thus provides a model system that uses a controlled stimulus paradigm to understand the mechanisms by which top-down processes (expectation and memory) and bottom-up processes (based on stimulus features) interact in sensory coding. PMID- 29118102 TI - Phencyclidine Discoordinates Hippocampal Network Activity But Not Place Fields. AB - We used the psychotomimetic phencyclidine (PCP) to investigate the relationships among cognitive behavior, coordinated neural network function, and information processing within the hippocampus place cell system. We report in rats that PCP (5 mg/kg, i.p.) impairs a well learned, hippocampus-dependent place avoidance behavior in rats that requires cognitive control even when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium-freguency gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive impairment caused by systemic PCP administration. PCP discoordinates theta modulated medium-frequency and slow gamma oscillations in CA1 LFPs such that medium-frequency gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell firing fields are preserved under PCP, but the drug discoordinates the subsecond temporal organization of discharge among place cells. This discoordination causes place cell ensemble representations of a familiar space to cease resembling pre-PCP representations despite preserved place fields. These findings point to the cognitive impairments caused by PCP arising from neural discoordination. PCP disrupts the timing of discharge with respect to the subsecond timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as the root of PCP induced cognitive impairment.SIGNIFICANCE STATEMENT Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma oscillations in the LFP and the discharge of a subset of pyramidal neurons called "place cells" is spatially organized such that discharge is restricted to locations called a cell's "place field." Because this temporal coordination and spatial discharge organization is thought to represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt cognitive behavior and assess the importance of neural coordination and place fields for spatial cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal discharge without disrupting firing fields. These findings dissociate place fields from spatial cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial cognition. PMID- 29118104 TI - Conditional Deletion of Ric-8b in Olfactory Sensory Neurons Leads to Olfactory Impairment. AB - The olfactory system can discriminate a vast number of odorants. This ability derives from the existence of a large family of odorant receptors expressed in the cilia of the olfactory sensory neurons. Odorant receptors signal through the olfactory-specific G-protein subunit, Galphaolf. Ric-8b, a guanine nucleotide exchange factor, interacts with Galphaolf and can amplify odorant receptor signal transduction in vitro To explore the function of Ric-8b in vivo, we generated a tissue specific knock-out mouse by crossing OMP-Cre transgenic mice to Ric-8b floxed mice. We found that olfactory-specific Ric-8b knock-out mice of mixed sex do not express the Galphaolf protein in the olfactory epithelium. We also found that in these mice, the mature olfactory sensory neuron layer is reduced, and that olfactory sensory neurons show increased rate of cell death compared with wild-type mice. Finally, behavioral tests showed that the olfactory-specific Ric 8b knock-out mice show an impaired sense of smell, even though their motivation and mobility behaviors remain normal.SIGNIFICANCE STATEMENT Ric-8b is a guanine nucleotide exchange factor (GEF) expressed in the olfactory epithelium and in the striatum. Ric-8b interacts with the olfactory Galphaolf subunit, and can amplify odorant signaling through odorant receptors in vitro However, the functional significance of this GEF in the olfactory neurons in vivo remains unknown. We report that deletion of Ric-8b in olfactory sensory neurons prevents stable expression of Galphaolf. In addition, we demonstrate that olfactory neurons lacking Ric-8b (and consequently Galphaolf) are more susceptible to cell death. Ric-8b conditional knock-out mice display impaired olfactory guided behavior. Our results reveal that Ric-8b is essential for olfactory function, and suggest that it may also be essential for Galphaolf-dependent functions in the brain. PMID- 29118105 TI - Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis. AB - Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system. PMID- 29118106 TI - Sleep in Humans Stabilizes Pattern Separation Performance. AB - Replay of hippocampal neural representations during sleep is thought to promote systems consolidation of declarative memory. How this reprocessing of memory during sleep affects the hippocampal representation itself, is unclear. Here we tested hippocampal stimulus processing (i.e., pattern separation) before and after periods of sleep and wakefulness in humans (female and male participants). Pattern separation deteriorated across the wake period but remained stable across sleep (p = 0.013) with this sleep-wake difference being most pronounced for stimuli with low similarity to targets (p = 0.006). Stimuli with the highest similarity showed a reversed pattern with reduced pattern separation performance after sleep (p = 0.038). Pattern separation performance was positively correlated with sleep spindle density, slow oscillation density, and theta power phase locked to slow oscillations. Sleep, presumably by neural memory replay, shapes hippocampal representations and enhances computations of pattern separation to subsequent presentation of similar stimuli.SIGNIFICANCE STATEMENT The consolidation of hippocampus-dependent memories is causally related to reactivation during sleep of previously encoded representations. Here, we show that reactivation-based consolidation processes during sleep shape the hippocampal representation itself. We studied the effect of sleep and wakefulness on pattern separation (i.e., orthogonalization of similar representations) and completion performance (i.e., recall of a memory in light of noisy input) that are essential cognitive elements of encoding and retrieval of information by the hippocampus. Our results demonstrate that pattern separation was stabilized after sleep but diminished after wakefulness. We further showed that pattern separation was related to EEG oscillatory parameters of non-REM sleep serving as markers of sleep-dependent memory consolidation and hippocampal reactivation. PMID- 29118107 TI - Morphological Constraints on Cerebellar Granule Cell Combinatorial Diversity. AB - Combinatorial expansion by the cerebellar granule cell layer (GCL) is fundamental to theories of cerebellar contributions to motor control and learning. Granule cells (GrCs) sample approximately four mossy fiber inputs and are thought to form a combinatorial code useful for pattern separation and learning. We constructed a spatially realistic model of the cerebellar GCL and examined how GCL architecture contributes to GrC combinatorial diversity. We found that GrC combinatorial diversity saturates quickly as mossy fiber input diversity increases, and that this saturation is in part a consequence of short dendrites, which limit access to diverse inputs and favor dense sampling of local inputs. This local sampling also produced GrCs that were combinatorially redundant, even when input diversity was extremely high. In addition, we found that mossy fiber clustering, which is a common anatomical pattern, also led to increased redundancy of GrC input combinations. We related this redundancy to hypothesized roles of temporal expansion of GrC information encoding in service of learned timing, and we show that GCL architecture produces GrC populations that support both temporal and combinatorial expansion. Finally, we used novel anatomical measurements from mice of either sex to inform modeling of sparse and filopodia-bearing mossy fibers, finding that these circuit features uniquely contribute to enhancing GrC diversification and redundancy. Our results complement information theoretic studies of granule layer structure and provide insight into the contributions of granule layer anatomical features to afferent mixing.SIGNIFICANCE STATEMENT Cerebellar granule cells are among the simplest neurons, with tiny somata and, on average, just four dendrites. These characteristics, along with their dense organization, inspired influential theoretical work on the granule cell layer as a combinatorial expander, where each granule cell represents a unique combination of inputs. Despite the centrality of these theories to cerebellar physiology, the degree of expansion supported by anatomically realistic patterns of inputs is unknown. Using modeling and anatomy, we show that realistic input patterns constrain combinatorial diversity by producing redundant combinations, which nevertheless could support temporal diversification of like combinations, suitable for learned timing. Our study suggests a neural substrate for producing high levels of both combinatorial and temporal diversity in the granule cell layer. PMID- 29118109 TI - Activation of gamma-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1. AB - gamma-Secretase is an intramembrane cleaving protease that is responsible for the generation of amyloid-beta peptides, which are linked to the pathogenesis of Alzheimer disease. Recently, gamma-secretase modulators (GSMs) have been shown to specifically decrease production of the aggregation-prone and toxic longer Abeta species, and concomitantly increase the levels of shorter Abeta. We previously found that phenylimidazole-type GSMs bind to presenilin 1 (PS1), the catalytic subunit of the gamma-secretase, and allosterically modulate gamma-secretase activity. However, the precise conformational alterations in PS1 remained unclear. Here we mapped the amino acid residues in PS1 that is crucial for the binding and pharmacological actions of E2012, a phenylimidazole-type GSM, using photoaffinity labeling and the substituted cysteine accessibility method. We also demonstrated that a piston-like vertical motion of transmembrane domain (TMD) 1 occurs during modulation of Abeta production. Taking these results together, we propose a model for the molecular mechanism of phenylimidazole-type GSMs, in which the trimming activity of gamma-secretase is modulated by the position of the TMD1 of PS1 in the lipid bilayer.SIGNIFICANCE STATEMENT Reduction of the toxic longer amyloid-beta peptide is one of the therapeutic approaches for Alzheimer disease. A subset of small compounds called gamma-secretase modulators specifically decreases the longer amyloid-beta production, although its mechanistic action remains unclear. Here we found that the modulator compound E2012 targets to the hydrophilic loop 1 of presenilin 1, which is a catalytic subunit of the gamma-secretase. Moreover, E2012 triggers the piston movement of the transmembrane domain 1 of presenilin 1, which impacts on the gamma-secretase activity. These results illuminate how gamma-secretase modulators allosterically affect the proteolytic activity, and highlight the importance of the structural dynamics of presenilin 1 in the complexed process of the intramembrane cleavage. PMID- 29118108 TI - Network Configurations in the Human Brain Reflect Choice Bias during Rapid Face Processing. AB - Network interactions are likely to be instrumental in processes underlying rapid perception and cognition. Specifically, high-level and perceptual regions must interact to balance pre-existing models of the environment with new incoming stimuli. Simultaneous electroencephalography (EEG) and fMRI (EEG/fMRI) enables temporal characterization of brain-network interactions combined with improved anatomical localization of regional activity. In this paper, we use simultaneous EEG/fMRI and multivariate dynamical systems (MDS) analysis to characterize network relationships between constitute brain areas that reflect a subject's choice for a face versus nonface categorization task. Our simultaneous EEG and fMRI analysis on 21 human subjects (12 males, 9 females) identifies early perceptual and late frontal subsystems that are selective to the categorical choice of faces versus nonfaces. We analyze the interactions between these subsystems using an MDS in the space of the BOLD signal. Our main findings show that differences between face-choice and house-choice networks are seen in the network interactions between the early and late subsystems, and that the magnitude of the difference in network interaction positively correlates with the behavioral false-positive rate of face choices. We interpret this to reflect the role of saliency and expectations likely encoded in frontal "late" regions on perceptual processes occurring in "early" perceptual regions.SIGNIFICANCE STATEMENT Our choices are affected by our biases. In visual perception and cognition such biases can be commonplace and quite curious-e.g., we see a human face when staring up at a cloud formation or down at a piece of toast at the breakfast table. Here we use multimodal neuroimaging and dynamical systems analysis to measure whole-brain spatiotemporal dynamics while subjects make decisions regarding the type of object they see in rapidly flashed images. We find that the degree of interaction in these networks accounts for a substantial fraction of our bias to see faces. In general, our findings illustrate how the properties of spatiotemporal networks yield insight into the mechanisms of how we form decisions. PMID- 29118110 TI - Cellular Functions of the Autism Risk Factor PTCHD1 in Mice. AB - The gene patched domain containing 1 (PTCHD1) is mutated in patients with autism spectrum disorders and intellectual disabilities and has been hypothesized to contribute to Sonic hedgehog (Shh) signaling and synapse formation. We identify a panel of Ptchd1-interacting proteins that include postsynaptic density proteins and the retromer complex, revealing a link to critical regulators of dendritic and postsynaptic trafficking. Ptchd1 knock-out (KO) male mice exhibit cognitive alterations, including defects in a novel object recognition task. To test whether Ptchd1 is required for Shh-dependent signaling, we examined two Shh dependent cell populations that express high levels of Ptchd1 mRNA: cerebellar granule cell precursors and dentate granule cells in the hippocampus. We found that proliferation of these neuronal precursors was not altered significantly in Ptchd1 KO male mice. We used whole-cell electrophysiology and anatomical methods to assess synaptic function in Ptchd1-deficient dentate granule cells. In the absence of Ptchd1, we observed profound disruption in excitatory/inhibitory balance despite normal dendritic spine density on dentate granule cells. These findings support a critical role of the Ptchd1 protein in the dentate gyrus, but indicate that it is not required for structural synapse formation in dentate granule cells or for Shh-dependent neuronal precursor proliferation.SIGNIFICANCE STATEMENT The mechanisms underlying neuronal and cellular alterations resulting from patched domain containing 1 (Ptchd1) gene mutations are unknown. The results from this study support an association with dendritic trafficking complexes of Ptchd1. Loss-of-function experiments do not support a role in sonic hedgehog dependent signaling, but reveal a disruption of synaptic transmission in the mouse dentate gyrus. The findings will help to guide ongoing efforts to understand the etiology of neurodevelopmental disorders arising from Ptchd1 deficiency. PMID- 29118111 TI - Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension. AB - The embryonic lineage of intramural cells, microstructural organization of the extracellular matrix, local luminal and wall geometry, and haemodynamic loads vary along the length of the aorta. Yet, it remains unclear why certain diseases manifest differentially along the aorta. Toward this end, myriad animal models provide insight into diverse disease conditions-including fibrosis, aneurysm and dissection-but inherent differences across models impede general interpretations. We examined region-specific cellular, matrix, and biomechanical changes in a single experimental model of hypertension and atherosclerosis, which commonly coexist. Our findings suggest that (i) intramural cells within the ascending aorta are unable to maintain the intrinsic material stiffness of the wall, which ultimately drives aneurysmal dilatation, (ii) a mechanical stress-initiated, inflammation-driven remodelling within the descending aorta results in excessive fibrosis, and (iii) a transient loss of adventitial collagen within the suprarenal aorta contributes to dissection propensity. Smooth muscle contractility helps to control wall stress in the infrarenal aorta, which maintains mechanical properties near homeostatic levels despite elevated blood pressure. This early mechanoadaptation of the infrarenal aorta does not preclude subsequent acceleration of neointimal formation, however. Because region-specific conditions may be interdependent, as, for example, diffuse central arterial stiffening can increase cyclic haemodynamic loads on an aneurysm that is developing proximally, there is a clear need for more systematic assessments of aortic disease progression, not simply a singular focus on a particular region or condition. PMID- 29118113 TI - Measurement of micro-scale soil deformation around roots using four-dimensional synchrotron tomography and image correlation. AB - This study applied time lapse (four-dimensional) synchrotron X-ray computed tomography to observe micro-scale interactions between plant roots and soil. Functionally contrasting maize root tips were repeatedly imaged during ingress into soil columns of varying water content and compaction. This yielded sequences of three-dimensional densiometric data, representing time-resolved geometric soil and root configurations at the micronmetre scale. These data were used as inputs for two full-field kinematic quantification methods, which enabled the analysis of three-dimensional soil deformation around elongating roots. Discrete object tracking was used to track rigid mineral grains, while continuum digital volume correlation was used to track grey-level patterns within local sub-volumes. These techniques both allowed full-field soil displacements to be quantified at an intra-rhizosphere spatial sampling scale of less than 300 um. Significant differences in deformation mechanisms were identified around different phenotypes under different soil conditions. A uniquely strong contrast was observed between intact and de-capped roots grown in dry, compacted soil. This provides evidence that functional traits of the root cap significantly reduce the amount of soil disturbance per unit of root elongation, with this effect being particularly significant in drier soil. PMID- 29118112 TI - The biology and mathematical modelling of glioma invasion: a review. AB - Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion. PMID- 29118114 TI - A chemo-mechano-biological formulation for the effects of biochemical alterations on arterial mechanics: the role of molecular transport and multiscale tissue remodelling. AB - This paper presents a chemo-mechano-biological framework for arterial physiopathology. The model accounts for the fine remodelling in the multiscale hierarchical arrangement of tissue constituents and for the diffusion of molecular species involved in cell-cell signalling pathways. Effects in terms of alterations in arterial compliance are obtained. A simple instructive example is introduced. Although oversimplified with respect to realistic case studies, the proposed application mimics the biochemical activity of matrix metalloproteinases, transforming growth factors beta and interleukins on tissue remodelling. Effects of macrophage infiltration, of intimal thickening and of a healing phase are investigated, highlighting the corresponding influence on arterial compliance. The obtained results show that the present approach is able to capture changes in arterial mechanics as a consequence of the alterations in tissue biochemical environment and cellular activity, as well as to incorporate the protective role of both autoimmune responses and pharmacological treatments. PMID- 29118115 TI - Computational tools for clinical support: a multi-scale compliant model for haemodynamic simulations in an aortic dissection based on multi-modal imaging data. AB - Aortic dissection (AD) is a vascular condition with high morbidity and mortality rates. Computational fluid dynamics (CFD) can provide insight into the progression of AD and aid clinical decisions; however, oversimplified modelling assumptions and high computational cost compromise the accuracy of the information and impede clinical translation. To overcome these limitations, a patient-specific CFD multi-scale approach coupled to Windkessel boundary conditions and accounting for wall compliance was developed and used to study a patient with AD. A new moving boundary algorithm was implemented to capture wall displacement and a rich in vivo clinical dataset was used to tune model parameters and for validation. Comparisons between in silico and in vivo data showed that this approach successfully captures flow and pressure waves for the patient-specific AD and is able to predict the pressure in the false lumen (FL), a critical variable for the clinical management of the condition. Results showed regions of low and oscillatory wall shear stress which, together with higher diastolic pressures predicted in the FL, may indicate risk of expansion. This study, at the interface of engineering and medicine, demonstrates a relatively simple and computationally efficient approach to account for arterial deformation and wave propagation phenomena in a three-dimensional model of AD, representing a step forward in the use of CFD as a potential tool for AD management and clinical support. PMID- 29118116 TI - Adaptive control of turbulence intensity is accelerated by frugal flow sampling. AB - The aerodynamic performance of vehicles and animals, as well as the productivity of turbines and energy harvesters, depends on the turbulence intensity of the incoming flow. Previous studies have pointed at the potential benefits of active closed-loop turbulence control. However, it is unclear what the minimal sensory and algorithmic requirements are for realizing this control. Here we show that very low-bandwidth anemometers record sufficient information for an adaptive control algorithm to converge quickly. Our online Newton-Raphson algorithm tunes the turbulence in a recirculating wind tunnel by taking readings from an anemometer in the test section. After starting at 9% turbulence intensity, the algorithm converges on values ranging from 10% to 45% in less than 12 iterations within 1% accuracy. By down-sampling our measurements, we show that very-low bandwidth anemometers record sufficient information for convergence. Furthermore, down-sampling accelerates convergence by smoothing gradients in turbulence intensity. Our results explain why low-bandwidth anemometers in engineering and mechanoreceptors in biology may be sufficient for adaptive control of turbulence intensity. Finally, our analysis suggests that, if certain turbulent eddy sizes are more important to control than others, frugal adaptive control schemes can be particularly computationally effective for improving performance. PMID- 29118117 TI - A Y161F Hemagglutinin Substitution Increases Thermostability and Improves Yields of 2009 H1N1 Influenza A Virus in Cells. AB - Vaccination is the primary strategy for influenza prevention and control. However, egg-based vaccines, the predominant production platform, have several disadvantages, including the emergence of viral antigenic variants that can be induced during egg passage. These limitations have prompted the development of cell-based vaccines, which themselves are not without issue. Most importantly, vaccine seed viruses often do not grow efficiently in mammalian cell lines. Here we aimed to identify novel high-yield signatures for influenza viruses in continuous Madin-Darby canine kidney (MDCK) and Vero cells. Using influenza A(H1N1)pdm09 virus as the testing platform and an integrating error-prone PCR based mutagenesis strategy, we identified a Y161F mutation in hemagglutinin (HA) that not only enhanced the infectivity of the resultant virus by more than 300 fold but also increased its thermostability without changing its original antigenic properties. The vaccine produced from the Y161F mutant fully protected mice against lethal challenge with wild-type A(H1N1)pdm09. Compared with A(H1N1)pdm09, the Y161F mutant had significantly higher avidity for avian-like and human-like receptor analogs. Of note, the introduction of the Y161F mutation into HA of seasonal H3N2 influenza A virus (IAV) and canine H3N8 IAV also increased yields and thermostability in MDCK cells and chicken embryotic eggs. Thus, residue F161 plays an important role in determining viral growth and thermostability, which could be harnessed to optimize IAV vaccine seed viruses.IMPORTANCE Although a promising complement to current egg-based influenza vaccines, cell-based vaccines have one large challenge: high-yield vaccine seeds for production. In this study, we identified a molecular signature, Y161F, in hemagglutinin (HA) that resulted in increased virus growth in Madin-Darby canine kidney and Vero cells, two cell lines commonly used for influenza vaccine manufacturing. This Y161F mutation not only increased HA thermostability but also enhanced its binding affinity for alpha2,6- and alpha2,3-linked Neu5Ac. These results suggest that a vaccine strain bearing the Y161F mutation in HA could potentially increase vaccine yields in mammalian cell culture systems. PMID- 29118118 TI - N-Myc Downstream-Regulated Gene 1 Restricts Hepatitis C Virus Propagation by Regulating Lipid Droplet Biogenesis and Viral Assembly. AB - Host cells harbor various intrinsic mechanisms to restrict viral infections as a first line of antiviral defense. Viruses have evolved various countermeasures against these antiviral mechanisms. Here we show that N-Myc downstream-regulated gene 1 (NDRG1) limits productive hepatitis C virus (HCV) infection by inhibiting viral assembly. Interestingly, HCV infection downregulates NDRG1 protein and mRNA expression. The loss of NDRG1 increases the size and number of lipid droplets, which are the sites of HCV assembly. HCV suppresses NDRG1 expression by upregulating MYC, which directly inhibits the transcription of NDRG1 The upregulation of MYC also leads to the reduced expression of the NDRG1-specific kinase serum/glucocorticoid-regulated kinase 1 (SGK1), resulting in a markedly diminished phosphorylation of NDRG1. The knockdown of MYC during HCV infection rescues NDRG1 expression and phosphorylation, suggesting that MYC regulates NDRG1 at both the transcriptional and posttranslational levels. Overall, our results suggest that NDRG1 restricts HCV assembly by limiting lipid droplet formation. HCV counteracts this intrinsic antiviral mechanism by downregulating NDRG1 via a MYC-dependent mechanism.IMPORTANCE Hepatitis C virus (HCV) is an enveloped single stranded RNA virus that targets hepatocytes in the liver. HCV is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, and estimates suggest a global prevalence of 2.35%. Up to 80% of acutely infected individuals will develop chronic infection, and as many as 5% eventually progress to liver cancer. An understanding of the mechanisms behind virus-host interactions and viral carcinogenesis is still lacking. The significance of our research is that it identifies a previously unknown relationship between HCV and a known tumor-associated gene. Furthermore, our data point to a new role for this gene in the liver and in lipid metabolism. Thus, HCV infection serves as a great biological model to advance our knowledge of liver functions and the development of liver cancer. PMID- 29118119 TI - A Mechanism for Priming and Realignment during Influenza A Virus Replication. AB - The influenza A virus genome consists of eight segments of single-stranded RNA. These segments are replicated and transcribed by a viral RNA-dependent RNA polymerase (RdRp) that is made up of the influenza virus proteins PB1, PB2, and PA. To copy the viral RNA (vRNA) genome segments and the cRNA segments, the replicative intermediate of viral replication, the RdRp must use two promoters and two different de novo initiation mechanisms. On the vRNA promoter, the RdRp initiates on the 3' terminus, while on the cRNA promoter, the RdRp initiates internally and subsequently realigns the nascent vRNA product to ensure that the template is copied in full. In particular, the latter process, which is also used by other RNA viruses, is not understood. Here we provide mechanistic insight into priming and realignment during influenza virus replication and show that it is controlled by the priming loop and a helix-loop-helix motif of the PB1 subunit of the RdRp. Overall, these observations advance our understanding of how the influenza A virus initiates viral replication and amplifies the genome correctly.IMPORTANCE Influenza A viruses cause severe disease in humans and are considered a major threat to our economy and health. The viruses replicate and transcribe their genome by using an enzyme called the RNA polymerases. To ensure that the genome is amplified faithfully and that abundant viral mRNAs are made for viral protein synthesis, the RNA polymerase must work correctly. In this report, we provide insight into the mechanism that the RNA polymerase employs to ensure that the viral genome is copied correctly. PMID- 29118120 TI - Analyses of the Kroon Virus Major Capsid Gene and Its Transcript Highlight a Distinct Pattern of Gene Evolution and Splicing among Mimiviruses. AB - The inclusion of Mimiviridae members in the putative monophyletic nucleocytoplasmic large DNA virus (NCLDV) group is based on genomic and phylogenomic patterns. This shows that, along with other viral families, they share a set of genes known as core or "hallmark genes," including the gene for the major capsid protein (MCP). Although previous studies have suggested that the maturation of mimivirus MCP transcripts is dependent on splicing, there is little information about the processing of this transcript in other mimivirus isolates. Here we report the characterization of a new mimivirus isolate, called Kroon virus (KV) mimivirus. Analysis of the structure, synteny, and phylogenetic relationships of the MCP genes in many mimivirus isolates revealed a remarkable variation at position and types of intronic and exonic regions, even for mimiviruses belonging to the same lineage. In addition, sequencing of KV and Acanthamoeba polyphaga mimivirus (APMV) MCP transcripts has shown that inside the family, even related giant viruses may present different ways to process the MCP mRNA. These results contribute to the understanding of the genetic organization and evolution of the MCP gene in mimiviruses.IMPORTANCE Mimivirus isolates have been obtained by prospecting studies since 2003. Based on genomic and phylogenomic studies of conserved genes, these viruses have been clustered together with members of six other viral families. Although the major capsid protein (MCP) gene is an important member of the so-called "hallmark genes," there is little information about the processing and structure of this gene in many mimivirus isolates. In this work, we have analyzed the structure, synteny, and phylogenetic relationships of the MCP genes in many mimivirus isolates; these genes showed remarkable variation at position and types of intronic and exonic regions, even for mimiviruses belonging to the same lineage. These results contribute to the understanding of the genetic organization and evolution of the MCP gene in mimiviruses. PMID- 29118122 TI - Unique Directional Motility of Influenza C Virus Controlled by Its Filamentous Morphology and Short-Range Motions. AB - Influenza virus motility is based on cooperation between two viral spike proteins, hemagglutinin (HA) and neuraminidase (NA), and is a major determinant of virus infectivity. To translocate a virus particle on the cell surface, HA molecules exchange viral receptors and NA molecules accelerate the receptor exchange of HA. This type of virus motility was recently identified in influenza A virus (IAV). To determine if other influenza virus types have a similar receptor exchange mechanism-driven motility, we investigated influenza C virus (ICV) motility on a receptor-fixed glass surface. This system excludes receptor mobility, which makes it more desirable than a cell surface for demonstrating virus motility by receptor exchange. Like IAV, ICV was observed to move across the receptor-fixed surface. However, in contrast to the random movement of IAV, a filamentous ICV strain, Ann Arbor/1/50 (AA), moved in a straight line, in a directed manner, and at a constant rate, whereas a spherical ICV strain, Taylor/1233/47 (Taylor), moved randomly, similar to IAV. The AA and Taylor viruses each moved with a combination of gradual (crawling) and rapid (gliding) motions, but the distances of crawling and gliding for the AA virus were shorter than those of the Taylor virus. Our findings indicate that like IAV, ICV also has a motility that is driven by the receptor exchange mechanism. However, compared with IAV movement, filamentous ICV movement is highly regulated in both direction and speed. Control of ICV movement is based on its specific motility employing short crawling and gliding motions as well as its own filamentous morphology.IMPORTANCE Influenza virus enters into a host cell for infection via cellular endocytosis. Human influenza virus infects epithelial cells of the respiratory tract, the surfaces of which are hidden by abundant cilia that are inactive in endocytosis. An open question is the manner by which the virus migrates to endocytosis-active domains. In analyzing individual virus behaviors through single-virus tracking, we identified a novel function of the hemagglutinin and esterase of influenza C virus (ICV) as the motility machinery. Hemagglutinin iteratively exchanges a viral receptor, causing virus movement. Esterase degrades the receptors along the trajectory traveled by the virus and prevents the virus from moving backward, causing directional movement. We propose that ICV has a unique motile machinery directionally controlled via hemagglutinin sensing the receptor density manipulated by esterase. PMID- 29118121 TI - HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded. AB - HIV-1 R5 variants exploit CCR5 as a coreceptor to infect both T cells and macrophages. R5 viruses that are transmitted or derived from immune tissue and peripheral blood are mainly inefficient at mediating infection of macrophages. In contrast, highly macrophage-tropic (mac-tropic) R5 viruses predominate in brain tissue and can be detected in cerebrospinal fluid but are infrequent in immune tissue or blood even in late disease. These mac-tropic R5 variants carry envelope glycoproteins (Envs) adapted to exploit low levels of CD4 on macrophages to induce infection. However, it is unclear whether this adaptation is conferred by an increased affinity of the Env trimer for CD4 or is mediated by postbinding structural rearrangements in the trimer that enhance the exposure of the coreceptor binding site and facilitate events leading to fusion and virus entry. In this study, we investigated CD4 binding to mac-tropic and non-mac-tropic Env trimers and showed that CD4-IgG binds efficiently to mac-tropic R5 Env trimers, while binding to non-mac-tropic trimers was undetectable. Our data indicated that the CD4 binding site (CD4bs) is highly occluded on Env trimers of non-mac-tropic R5 viruses. Such viruses may therefore infect T cells via viral synapses where Env and CD4 become highly concentrated. This environment will enable high-avidity interactions that overcome extremely low Env-CD4 affinities.IMPORTANCE HIV R5 variants bind to CD4 and CCR5 receptors on T cells and macrophages to initiate infection. Transmitted HIV variants infect T cells but not macrophages, and these viral strains persist in immune tissue even in late disease. Here we show that the binding site for CD4 present on HIV's envelope protein is occluded on viruses replicating in immune tissue. This occlusion likely prevents antibody binding to this site and neutralization of the virus, but it makes it difficult for virus CD4 interactions to occur. Such viruses probably pass from T cell to T cell via cell contacts where CD4 is highly concentrated and allows infection via inefficient envelope-CD4 binding. Our data are highly relevant for vaccines that aim to induce antibodies targeting the CD4 binding site on the envelope protein. PMID- 29118123 TI - Estimating Initial Viral Levels during Simian Immunodeficiency Virus/Human Immunodeficiency Virus Reactivation from Latency. AB - Human immunodeficiency virus (HIV) viremia rebounds rapidly after treatment interruption, and a variety of strategies are being explored to reduce or control viral reactivation posttreatment. This viral rebound arises from reactivation of individual latently infected cells, which spread during ongoing rounds of productive infection. The level of virus produced by the initial individual reactivating cells is not known, although it may have major implications for the ability of different immune interventions to control viral rebound. Here we use data from both HIV and simian immunodeficiency virus (SIV) treatment interruption studies to estimate the initial viral load postinterruption and thereby the initial individual reactivation event. Using a barcoded virus (SIVmac239M) to track reactivation from individual latent cells, we use the observed viral growth rates and frequency of reactivation to model the dynamics of reactivation to estimate that a single reactivated latent cell can produce an average viral load equivalent to ~0.1 to 0.5 viral RNA (vRNA) copies/ml. Modeling of treatment interruption in HIV suggests an initial viral load equivalent of ~0.6 to 1 vRNA copies/ml. These low viral loads immediately following latent cell reactivation provide a window of opportunity for viral control by host immunity, before further replication allows viral spread. This work shows the initial levels of viral production that must be controlled in order to successfully suppress HIV reactivation following treatment interruption.IMPORTANCE Current treatment for HIV is able to suppress viral replication and prevent disease progression. However, treatment cannot eradicate infection, because the virus lies silent within latently infected cells. If treatment is stopped, the virus usually rebounds above the level of detection within a few weeks. There are a number of approaches being tested aimed at either eradicating latently infected cells or controlling the virus if it returns. Studying both the small pool of latently infected cells and the early events during viral reactivation is difficult, because these involve very small levels of virus that are difficult to measure directly. Here, we combine experimental data and mathematical modeling to understand the very early events during viral reactivation from latency in both HIV infection of humans and SIV infection of monkeys. We find that the initial levels of virus are low, which may help in designing therapies to control early viral reactivation. PMID- 29118124 TI - c-Myc Represses Transcription of Epstein-Barr Virus Latent Membrane Protein 1 Early after Primary B Cell Infection. AB - Recent evidence has shown that the Epstein-Barr virus (EBV) oncogene LMP1 is not expressed at high levels early after EBV infection of primary B cells, despite its being essential for the long-term outgrowth of immortalized lymphoblastoid cell lines (LCLs). In this study, we found that expression of LMP1 increased 50 fold between 7 days postinfection and the LCL state. Metabolic labeling of nascent transcribed mRNA indicated that this was primarily a transcription mediated event. EBNA2, the key viral transcription factor regulating LMP1, and CTCF, an important chromatin insulator, were recruited to the LMP1 locus similarly early and late after infection. However, the activating histone H3K9Ac mark was enriched at the LMP1 promoter in LCLs relative to that in infected B cells early after infection. We found that high c-Myc activity in EBV-infected lymphoma cells as well as overexpression of c-Myc in an LCL model system repressed LMP1 transcription. Finally, we found that chemical inhibition of c-Myc both in LCLs and early after primary B cell infection increased LMP1 expression. These data support a model in which high levels of endogenous c-Myc activity induced early after primary B cell infection directly repress LMP1 transcription.IMPORTANCE EBV is a highly successful pathogen that latently infects more than 90% of adults worldwide and is also causally associated with a number of B cell malignancies. During the latent life cycle, EBV expresses a set of viral oncoproteins and noncoding RNAs with the potential to promote cancer. Critical among these is the viral latent membrane protein LMP1. Prior work suggests that LMP1 is essential for EBV to immortalize B cells, but our recent work indicates that LMP1 is not produced at high levels during the first few weeks after infection. Here we show that transcription of the LMP1 gene can be negatively regulated by a host transcription factor, c-Myc. Ultimately, understanding the regulation of EBV oncogenes will allow us to better treat cancers that rely on these viral products for survival. PMID- 29118125 TI - ALT-803 Transiently Reduces Simian Immunodeficiency Virus Replication in the Absence of Antiretroviral Treatment. AB - Developing biological interventions to control human immunodeficiency virus (HIV) replication in the absence of antiretroviral therapy (ART) could contribute to the development of a functional cure. As a potential alternative to ART, the interleukin-15 (IL-15) superagonist ALT-803 has been shown to boost the number and function of HIV-specific CD8+ T and NK cell populations in vitro Four simian immunodeficiency virus (SIV)-positive rhesus macaques, three of whom possessed major histocompatibility complex alleles associated with control of SIV and all of whom had received SIV vaccine vectors that had the potential to elicit CD8+ T cell responses, were given ALT-803 in three treatment cycles. The first and second cycles of treatment were separated by 2 weeks, while the third cycle was administered after a 29-week break. ALT-803 transiently elevated the total CD8+ effector and central memory T cell and NK cell populations in peripheral blood, while viral loads transiently decreased by ~2 logs in all animals. Virus suppression was not sustained as T cells became less responsive to ALT-803 and waned in numbers. No effect on viral loads was observed in the second cycle of ALT-803, concurrent with downregulation of the IL-2/15 common gammaC and beta chain receptors on both CD8+ T cells and NK cells. Furthermore, populations of immunosuppressive T cells increased during the second cycle of ALT-803 treatment. During the third treatment cycle, responsiveness to ALT-803 was restored. CD8+ T cells and NK cells increased again 3- to 5-fold, and viral loads transiently decreased again by 1 to 2 logs.IMPORTANCE Overall, our data show that ALT-803 has the potential to be used as an immunomodulatory agent to elicit effective immune control of HIV/SIV replication. We identify mechanisms to explain why virus control is transient, so that this model can be used to define a clinically appropriate treatment regimen. PMID- 29118126 TI - Respiratory Syncytial Virus: Targeting the G Protein Provides a New Approach for an Old Problem. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the United States <5 years old. In the elderly (>65 years old), RSV results in ~175,000 hospitalizations annually in the United States with a worldwide incidence of ~34 million. There is no approved RSV vaccine, and treatments are limited. Recently, a phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely, prevention of moderate-to-severe RSV associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in preterm infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (MAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has reemerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human MAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This MAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab. PMID- 29118128 TI - A valence-free definition of sociality as any violation of inter-individual independence. AB - Well over 90% of studies in biomedical sciences are performed on single animals. While knowledge of the genetics, development and physiology of single individuals accrues, an understanding of the biological mechanisms by which individuals interact has barely budged. Yet many of society's greatest problems derive from an inability of humans to get along with each other. Studies in social neuroscience are primarily observational and rarely employ subjects who physically interact. Thus, social interaction represents a largely unexplored frontier of biology. The neuroscience that underlies social behaviour and interactions can and should be studied using the scientific method. However, a workable and objective definitional framework of sociality is needed for scientific progress in this field. Here we propose a definition that uses a test of independence from the presence of others. The null hypothesis is that a behaviour is independent from the influence of others. Rejection of this null hypothesis means that the actions of an individual depend on the actions of one or more other individuals. This definition has the advantages of not being contaminated by moral judgements or biases in favour of pro-social behaviour, and of being applicable to a wide range of physiological processes. The definition of a social behaviour proposed here says nothing regarding the valence of the behaviour with respect to others. Thus, a behaviour that is influenced by the presence of others may benefit, harm, or have no effect on others. It is hoped that this definitional framework for sociality will facilitate our understanding of the origins and mechanisms of social behaviour among animals including humans as well as offer efficacious approaches to social disorders such as autism. PMID- 29118127 TI - Peripheral Blood Biomarkers of Disease Outcome in a Monkey Model of Rift Valley Fever Encephalitis. AB - Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and humans. Although the disease is caused by a mosquito-borne virus, humans are infected through contact with, or inhalation of, virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis, resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus, animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness. To understand the disease process and identify biomarkers of lethality, two groups of 5 AGM were infected by inhalation with either a lethal or a sublethal dose of RVFV. Divergence between lethal and sublethal infections occurred as early as 2 days postinfection (dpi), at which point CD8+ T cells from lethally infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of major histocompatibility complex (MHC) class II molecules, in contrast to surviving animals. At 4 dpi, lethally infected animals failed to demonstrate proliferation of total CD4+ and CD8+ T cells, in contrast to survivors. These marked changes in peripheral blood cells occur much earlier than more-established indicators of severe RVF disease, such as granulocytosis and fever. In addition, an early proinflammatory (gamma interferon [IFN-gamma], interleukin 6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1]) and antiviral (IFN-alpha) response was seen in survivors, while very late cytokine expression was found in animals with lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow the testing of therapeutics and vaccines in the AGM model.IMPORTANCE Rift Valley Fever (RVF) is an important emerging viral disease for which we lack both an effective human vaccine and treatment. Encephalitis and neurological disease resulting from RVF lead to death or significant long-term disability for infected people. African green monkeys (AGM) develop lethal neurological disease when infected with RVF virus by inhalation. Here we report the similarities in disease course between infected AGM and humans. For the first time, we examine the peripheral immune response during the course of infection in AGM and show that there are very early differences in the immune response between animals that survive infection and those that succumb. We conclude that AGM are a novel and suitable monkey model for studying the neuropathogenesis of RVF and for testing vaccines and therapeutics against this emerging viral pathogen. PMID- 29118129 TI - Admixture mapping in a hybrid zone reveals loci associated with avian feather coloration. AB - Identifying the genetic bases for colour patterns has provided important insights into the control and expression of pigmentation and how these characteristics influence fitness. However, much more is known about the genetic bases for traits based on melanin pigments than for traits based on another major class of pigments, carotenoids. Here, we use natural admixture in a hybrid zone between Audubon's and myrtle warblers (Setophaga coronata auduboni/S. c. coronata) to identify genomic regions associated with both types of pigmentation. Warblers are known for rapid speciation and dramatic differences in plumage. For each of five plumage coloration traits, we found highly significant associations with multiple single-nucleotide polymorphisms (SNPs) across the genome and these were clustered in discrete regions. Regions near significantly associated SNPs were enriched for genes associated with keratin filaments, fibrils that make up feathers. A carotenoid-based trait that differs between the taxa-throat colour-had more than a dozen genomic regions of association. One cluster of SNPs for this trait overlaps the Scavenger Receptor Class F Member 2 (SCARF2) gene. Other scavenger receptors are presumed to be expressed at target tissues and involved in the selective movement of carotenoids into the target cells, making SCARF2 a plausible new candidate for carotenoid processing. In addition, two melanin-based plumage traits-colours of the eye line and eye spot-show very strong associations with a single genomic region mapping to chromosome 20 in the zebra finch. These findings indicate that only a subset of the genomic regions differentiated between these two warblers are associated with the plumage differences between them and demonstrate the utility of reduced-representation genomic scans in hybrid zones. PMID- 29118130 TI - What have humans done for evolutionary biology? Contributions from genes to populations. AB - Many fundamental concepts in evolutionary biology were discovered using non-human study systems. Humans are poorly suited to key study designs used to advance this field, and are subject to cultural, technological, and medical influences often considered to restrict the pertinence of human studies to other species and general contexts. Whether studies using current and recent human populations provide insights that have broader biological relevance in evolutionary biology is, therefore, frequently questioned. We first surveyed researchers in evolutionary biology and related fields on their opinions regarding whether studies on contemporary humans can advance evolutionary biology. Almost all 442 participants agreed that humans still evolve, but fewer agreed that this occurs through natural selection. Most agreed that human studies made valuable contributions to evolutionary biology, although those less exposed to human studies expressed more negative views. With a series of examples, we discuss strengths and limitations of evolutionary studies on contemporary humans. These show that human studies provide fundamental insights into evolutionary processes, improve understanding of the biology of many other species, and will make valuable contributions to evolutionary biology in the future. PMID- 29118131 TI - Humans as a model species for sexual selection research. AB - Ever since Darwin, questions about humans have driven sexual selection research. While studies of other organisms are often justified as useful for improving understanding of humans, humans themselves can be useful models. Although humans present some drawbacks as model organisms (complicated societies, slow reproduction and strong ethical constraints on experimental options), humans nonetheless offer many advantages (being abundant, accessible and having detailed historical records for some populations). As an additional challenge, humans exhibit a rather puzzling combination of traits. Some traits (pair-bonding, biparental care and modest sexual dimorphism in body size) suggest selection for monogamous mating, while other traits (including sexual dimorphism in body composition and appearance) suggest selection for polygyny. Such puzzles have motivated research on other species, resulting in a rich set of comparative data that provides insights into humans and other species. Recent studies of visual trait dimorphism suggest that human appearance reflects adaptation for multi level societies, rather than high levels of polygyny. In addition to biological traits, human cultural traits have undergone rapid evolution. Changes in subsistence strategies profoundly affect opportunities for sexual selection. The enormous variability of human behaviour and ecology provides abundant opportunities to test key hypotheses, and poses challenging puzzles for future research. PMID- 29118132 TI - Physical trade-offs shape the evolution of buoyancy control in sharks. AB - Buoyancy control is a fundamental aspect of aquatic life that has major implications for locomotor performance and ecological niche. Unlike terrestrial animals, the densities of aquatic animals are similar to the supporting fluid, thus even small changes in body density may have profound effects on locomotion. Here, we analysed the body composition (lipid versus lean tissue) of 32 shark species to study the evolution of buoyancy. Our comparative phylogenetic analyses indicate that although lean tissue displays minor positive allometry, liver volume exhibits pronounced positive allometry, suggesting that larger sharks evolved bulkier body compositions by adding lipid tissue to lean tissue rather than substituting lean for lipid tissue, particularly in the liver. We revealed a continuum of buoyancy control strategies that ranged from more buoyant sharks with larger livers in deeper ecosystems to relatively denser sharks with small livers in epipelagic habitats. Across this eco-morphological spectrum, our hydrodynamic modelling suggests that neutral buoyancy yields lower drag and more efficient steady swimming, whereas negative buoyancy may be more efficient during accelerated movements. The evolution of buoyancy control in sharks suggests that ecological and physiological factors mediate the selective pressures acting on these traits along two major gradients, body size and habitat depth. PMID- 29118133 TI - Climate change and bird reproduction: warmer springs benefit breeding success in boreal forest grouse. AB - Global warming is predicted to adversely affect the reproduction of birds, especially in northern latitudes. A recent study in Finland inferred that declining populations of black grouse, Tetrao tetrix, could be attributed to advancement of the time of mating and chicks hatching too early-supporting the mismatch hypothesis. Here, we examine the breeding success of sympatric capercaillie, T. urogallus, and black grouse over a 38-year period in southeast Norway. Breeding season temperatures increased, being most pronounced in April. Although the onset of spring advanced nearly three weeks, the peak of mating advanced only 4-5 days. In contrast to the result of the Finnish study, breeding success increased markedly in both species (capercaillie: 62%, black grouse: 38%). Both brood frequency and brood size increased during the study period, but significantly so only for brood frequency in capercaillie. Whereas the frequency of capercaillie broods was positively affected by rising temperatures, especially during the pre-hatching period, this was not the case in black grouse. Brood size, on the other hand, increased with increasing post-hatching temperatures in both species. Contrary to the prediction that global warming will adversely affect reproduction in boreal forest grouse, our study shows that breeding success was enhanced in warmer springs. PMID- 29118134 TI - Temperature effects on life-history trade-offs, germline maintenance and mutation rate under simulated climate warming. AB - Mutation has a fundamental influence over evolutionary processes, but how evolutionary processes shape mutation rate remains less clear. In asexual unicellular organism, increased mutation rates have been observed in stressful environments and the reigning paradigm ascribes this increase to selection for evolvability. However, this explanation does not apply in sexually reproducing species, where little is known about how the environment affects mutation rate. Here we challenged experimental lines of seed beetle, evolved at ancestral temperature or under simulated climate warming, to repair induced mutations at ancestral and stressful temperature. Results show that temperature stress causes individuals to pass on a greater mutation load to their grand-offspring. This suggests that stress-induced mutation rates, in unicellular and multicellular organisms alike, can result from compromised germline DNA repair in low condition individuals. Moreover, lines adapted to simulated climate warming had evolved increased longevity at the cost of reproduction, and this allocation decision improved germline repair. These results suggest that mutation rates can be modulated by resource allocation trade-offs encompassing life-history traits and the germline and have important implications for rates of adaptation and extinction as well as our understanding of genetic diversity in multicellular organisms. PMID- 29118135 TI - Mass extinction in tetraodontiform fishes linked to the Palaeocene-Eocene thermal maximum. AB - Integrative evolutionary analyses based upon fossil and extant species provide a powerful approach for understanding past diversification events and for assessing the tempo of evolution across the Tree of Life. Herein, we demonstrate the importance of integrating fossil and extant species for inferring patterns of lineage diversification that would otherwise be masked in analyses that examine only one source of evidence. We infer the phylogeny and macroevolutionary history of the Tetraodontiformes (triggerfishes, pufferfishes and allies), a group with one of the most extensive fossil records among fishes. Our analyses combine molecular and morphological data, based on an expanded matrix that adds newly coded fossil species and character states. Beyond confidently resolving the relationships and divergence times of tetraodontiforms, our diversification analyses detect a major mass-extinction event during the Palaeocene-Eocene Thermal Maximum (PETM), followed by a marked increase in speciation rates. This pattern is consistently obtained when fossil and extant species are integrated, whereas examination of the fossil occurrences alone failed to detect major diversification changes during the PETM. When taking into account non-homogeneous models, our analyses also detect a rapid lineage diversification increase in one of the groups (tetraodontoids) during the middle Miocene, which is considered a key period in the evolution of reef fishes associated with trophic changes and ecological opportunity. In summary, our analyses show distinct diversification dynamics estimated from phylogenies and the fossil record, suggesting that different episodes shaped the evolution of tetraodontiforms during the Cenozoic. PMID- 29118136 TI - Variably hungry caterpillars: predictive models and foliar chemistry suggest how to eat a rainforest. AB - A long-term goal in evolutionary ecology is to explain the incredible diversity of insect herbivores and patterns of host plant use in speciose groups like tropical Lepidoptera. Here, we used standardized food-web data, multigene phylogenies of both trophic levels and plant chemistry data to model interactions between Lepidoptera larvae (caterpillars) from two lineages (Geometridae and Pyraloidea) and plants in a species-rich lowland rainforest in New Guinea. Model parameters were used to make and test blind predictions for two hectares of an exhaustively sampled forest. For pyraloids, we relied on phylogeny alone and predicted 54% of species-level interactions, translating to 79% of all trophic links for individual insects, by sampling insects from only 15% of local woody plant diversity. The phylogenetic distribution of host-plant associations in polyphagous geometrids was less conserved, reducing accuracy. In a truly quantitative food web, only 40% of pair-wise interactions were described correctly in geometrids. Polyphenol oxidative activity (but not protein precipitation capacity) was important for understanding the occurrence of geometrids (but not pyraloids) across their hosts. When both foliar chemistry and plant phylogeny were included, we predicted geometrid-plant occurrence with 89% concordance. Such models help to test macroevolutionary hypotheses at the community level. PMID- 29118137 TI - Defector clustering is linked to cooperation in a pathogenic bacterium. AB - Spatial clustering is thought to favour the evolution of cooperation because it puts cooperators in a position to help each other. However, clustering also increases competition. The fate of cooperation may depend on how much cooperators cluster relative to defectors, but these clustering differences have not been the focus of previous models and experiments. By competing siderophore-producing cooperator and defector strains of the opportunistic pathogen Pseudomonas aeruginosa in experimental microhabitats, we found that at the spatial scale of individual interactions, cooperator clustering lowers cooperation, but defector clustering favours cooperation. A theoretical model and individual-based simulations show these counterintuitive effects can arise when competition and cooperation occur at a single resource-determined scale, with population dynamics crucially allowing cooperators and defectors to cluster differently. The results suggest that cooperation relies on the regulation of sufficient defector clustering relative to cooperator clustering, which may be important in bacteria, social amoeba and cancer inhibition. PMID- 29118138 TI - Macroecological factors shape local-scale spatial patterns in agriculturalist settlements. AB - Macro-scale patterns of human systems ranging from population distribution to linguistic diversity have attracted recent attention, giving rise to the suggestion that macroecological rules shape the assembly of human societies. However, in which aspects the geography of our own species is shaped by macroecological factors remains poorly understood. Here, we provide a first demonstration that macroecological factors shape strong local-scale spatial patterns in human settlement systems, through an analysis of spatial patterns in agriculturalist settlements in eastern mainland China based on high-resolution Google Earth images. We used spatial point pattern analysis to show that settlement spatial patterns are characterized by over-dispersion at fine spatial scales (0.05-1.4 km), consistent with territory segregation, and clumping at coarser spatial scales beyond the over-dispersion signals, indicating territorial clustering. Statistical modelling shows that, at macroscales, potential evapotranspiration and topographic heterogeneity have negative effects on territory size, but positive effects on territorial clustering. These relationships are in line with predictions from territory theory for hunter gatherers as well as for many animal species. Our results help to disentangle the complex interactions between intrinsic spatial processes in agriculturalist societies and external forcing by macroecological factors. While one may speculate that humans can escape ecological constraints because of unique abilities for environmental modification and globalized resource transportation, our work highlights that universal macroecological principles still shape the geography of current human agricultural societies. PMID- 29118140 TI - Correction to 'The growth of finfish in global open-ocean aquaculture under climate change'. PMID- 29118139 TI - Anticipatory flexibility: larval population density in moths determines male investment in antennae, wings and testes. AB - Developmental plasticity provides individuals with a distinct advantage when the reproductive environment changes dramatically. Variation in population density, in particular, can have profound effects on male reproductive success. Females may be easier to locate in dense populations, but there may be a greater risk of sperm competition. Thus, males should invest in traits that enhance fertilization success over traits that enhance mate location. Conversely, males in less dense populations should invest more in structures that will facilitate mate location. In Lepidoptera, this may result in the development of larger antennae to increase the likelihood of detecting female sex pheromones, and larger wings to fly more efficiently. We explored the effects of larval density on adult morphology in the gum-leaf skeletonizer moth, Uraba lugens, by manipulating both the number of larvae and the size of the rearing container. This experimental arrangement allowed us to reveal the cues used by larvae to assess whether absolute number or density influences adult responses. Male investment in testes size depended on the number of individuals, while male investment in wings and antennae depended upon larval density. By contrast, the size of female antennae and wings were influenced by an interaction of larval number and container size. This study demonstrates that male larvae are sensitive to cues that may reveal adult population density, and adjust investment in traits associated with fertilization success and mate detection accordingly. PMID- 29118141 TI - Midbrain adaptation may set the stage for the perception of musical beat. AB - The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat. PMID- 29118142 TI - How social information can improve estimation accuracy in human groups. AB - In our digital and connected societies, the development of social networks, online shopping, and reputation systems raises the questions of how individuals use social information and how it affects their decisions. We report experiments performed in France and Japan, in which subjects could update their estimates after having received information from other subjects. We measure and model the impact of this social information at individual and collective scales. We observe and justify that, when individuals have little prior knowledge about a quantity, the distribution of the logarithm of their estimates is close to a Cauchy distribution. We find that social influence helps the group improve its properly defined collective accuracy. We quantify the improvement of the group estimation when additional controlled and reliable information is provided, unbeknownst to the subjects. We show that subjects' sensitivity to social influence permits us to define five robust behavioral traits and increases with the difference between personal and group estimates. We then use our data to build and calibrate a model of collective estimation to analyze the impact on the group performance of the quantity and quality of information received by individuals. The model quantitatively reproduces the distributions of estimates and the improvement of collective performance and accuracy observed in our experiments. Finally, our model predicts that providing a moderate amount of incorrect information to individuals can counterbalance the human cognitive bias to systematically underestimate quantities and thereby improve collective performance. PMID- 29118144 TI - Growth, Change....and Gratitude! PMID- 29118145 TI - Access to Oral Health Care: A National Crisis and Call for Reform. AB - Purpose: According to the report Healthy People 2020, oral health is integral to overall health and access to dental services is essential to promoting and maintaining good oral health. Yet, those who need dental care the most are often the least likely to receive it. The dental hygiene profession is poised to play a pivotal role in the resolution of oral health disparities. The purpose of this manuscript is to examine the critical issue of access to oral health care in the United States from various perspectives and consider potential implications for dental professionals and the oral health care system. This report focuses on major underserved and vulnerable populations and highlights several barriers that significantly affect the ability to access and navigate the oral health care system. These include low socioeconomic status; the shortage and maldistribution of dentists; a lack of professional training regarding current evidence-based oral health guidelines; deficient continuity of care due to inadequate interdisciplinary collaboration; low oral health literacy; and patient perceptions and misconceptions about preventive dental care. This report also contains an update on provider participation in Medicaid; the state of children's oral health; and emerging workforce models, state initiatives, and legislative reforms. Recommendations increasing access to care require local, state, and federal stakeholders to combine forces that take advantage of the existing dental hygiene workforce, utilize innovative delivery models, improve license reciprocity, reduce prohibitive supervision, and expand the dental hygiene scope of practice. The major focus of future research will be on the implementation of mid-level oral health care providers. Dental hygienists are an integral part of the access to care solution and have a great opportunity to lead the call to action and fulfill the American Dental Hygienists' Association's mandate that oral health care is the right of all people. PMID- 29118143 TI - Structural basis for arginine methylation-independent recognition of PIWIL1 by TDRD2. AB - The P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) pathway plays a central role in transposon silencing and genome protection in the animal germline. A family of Tudor domain proteins regulates the piRNA pathway through direct Tudor domain-PIWI interactions. Tudor domains are known to fulfill this function by binding to methylated PIWI proteins in an arginine methylation dependent manner. Here, we report a mechanism of methylation-independent Tudor domain-PIWI interaction. Unlike most other Tudor domains, the extended Tudor domain of mammalian Tudor domain-containing protein 2 (TDRD2) preferentially recognizes an unmethylated arginine-rich sequence from PIWI-like protein 1 (PIWIL1). Structural studies reveal an unexpected Tudor domain-binding mode for the PIWIL1 sequence in which the interface of Tudor and staphylococcal nuclease domains is primarily responsible for PIWIL1 peptide recognition. Mutations disrupting the TDRD2-PIWIL1 interaction compromise piRNA maturation via 3'-end trimming in vitro. Our work presented here reveals the molecular divergence of the interactions between different Tudor domain proteins and PIWI proteins. PMID- 29118146 TI - Dental Hygiene Students' Perceptions of Importance and Confidence in Applying Motivational Interviewing During Patient Care. AB - Purpose: Motivational Interviewing (MI) is an evidence-based, patient-centered counseling approach for eliciting behavior change. In 2012, the University of Michigan (U-M) Dental Hygiene Program significantly enhanced their behavior change curriculum by reinforcing and building upon the Motivational Interviewing segment. The purpose of this study was to examine students' perceptions of the importance of MI and their confidence in applying it during patient care.Methods: A convenience sample of 22 U-M Class of 2015 dental hygiene students who had received an enhanced curriculum participated in this study, utilizing a retrospective, pre-test/post-test design.Results: A Wilcoxon signed rank test was used to compare the differences in average ranks between T1 (Retrospective Pre Test) and T4 (Post-Test 3) for the importance and confidence questions at each time point for the Class of 2015. Students' perceptions of importance increased with statistical significance in five out of eight MI strategies. Perceptions in confidence increased in seven out of eight strategies. Effect size ranged from .00 to .55. Assessment of qualitative data provided additional insight on student experiences.Conclusion: Student perceptions of importance of using MI and their confidence in applying MI increased in a majority of the strategy categories. Successes with patient health behavior change and challenges with time to integrate this in practice were noted. Research on the longitudinal impact and faculty feedback calibration is recommended. PMID- 29118147 TI - Admissions Criteria that Influence Dental Hygiene Students' Performance on Board Examinations. AB - Purpose: The purpose of the study is to assess which dental hygiene program admission variables contribute to the selection of students who are successful in passing the National Board Dental Hygiene Examination (NBDHE) and a clinical dental hygiene board examination.Methods: A retrospective study was conducted by investigating 121 educational records and application forms from graduates through the years 2008 to 2011 from one educational institution. Predictor variables included re-application status, student GPA, age, race/ethnicity, type of school attended for pre-requisite coursework, number of times the pre requisite courses needed to be retaken, course load while taking the pre requisites, previous degrees obtained, American College Test (ACT) scores and student participation in the university's lower division (LD) or upper pre placement (UPP) program. Graduate success is defined by NBDHE scores and clinical board scores.Results: The data was analyzed using univariate analyses and multivariate regression statistical techniques. Univariate analyses did not identify any predictor variables to be significantly associated with the dental hygiene student's clinical board score. However, the variables of ACT scores and type of student, specifically the UPP students, demonstrated a significant relationship with NBDHE scores.Conclusion: ACT scores are a variable that is positively associated with higher NBDHE results. Results indicate that UPP students benefit from participating in supportive educational services while fulfilling requirements for admissions in the dental hygiene program. Results also indicate that there were no significant variables identified to predict clinical board scores. PMID- 29118148 TI - The Prevalence of Dental Anxiety in Dental Practice Settings. AB - Purpose: The purpose of this study was to assess the prevalence of dental anxiety and missed dental appointments due to dental anxiety among patients within three types of private dental offices.Methods: This descriptive, cross-sectional study utilized the Modified Dental Anxiety Scale (MDAS). The MDAS consists of five questions to assess dental anxiety. Demographics and an open-ended question about missed dental appointments due to dental anxiety were included. Linear and logistic regression models were used to analyze anxiety scores as related to gender and age. Participants' responses to the open-ended question were compiled according to themes.Results: Three hundred and eight (n=308) dental patients participated in the study. Using the MDAS cut-off scores of 15 and 19, the prevalence estimates of moderate to high and high dental anxiety within the total study population was 19% and 6.82% respectively. Females had an MDAS score 2.12 times higher than males (p<0.05). For every one unit increase in age, the MDAS score was 0.08 units lower (p<0.05). Out of the 308 participants, 26 (8.4%) responded to missing a dental appointment due to dental anxiety. Five common themes were coded as the source of dental anxiety: fear of dental experience, previous negative dental experience, cost of treatment, gag reflex, and fear of bad news.Conclusions: Moderate to high dental anxiety was present in 19% of the population sampled. Awareness of patients' dental anxiety level and the utilization of anxiety reducing measures during treatment may encourage routine care. PMID- 29118149 TI - Perceptions Related to Use of Electronic Cigarettes among California College Students. AB - Purpose: To assess electronic cigarette (e-cigarette) use, factors associated with use, and exposure to e-cigarette-related information from health professionals in a sample of college students attending a public university in northern California, using a web-based survey.Methods: In this quantitative cross sectional study, survey items assessed e-cigarette use, perceived risks and benefits, and exposure to e-cigarette-related information from health professionals and were pilot tested for feasibility and acceptability. Participants were recruited from three courses taught at a northern California public university and were given an electronic link to the survey with informed consent information. Frequency distributions and cross-tabulations were calculated for survey responses. The Mann-Whitney U-test was used to compare differences in perceived risks, benefits, and social consequences between ever users and never-users.Results: Ninety-one individuals completed the web-based survey. Among respondents, 89% were aware of e-cigarettes, 49% were ever-users, and 10% were current (past-30 day) e-cigarette users. Compared to e-cigarette ever-users, never-users perceived a higher chance of experiencing 5 out of 8 physical and social risks from e-cigarette use (P<0.05). E-cigarettes, marijuana, and hookah were perceived to be less harmful to health than cigarettes. Few participants reported receiving counseling regarding e-cigarettes from health professionals, including dental hygienists. Counseling about the adverse health effects of cigarettes was more common in this study population.Conclusion: Dental hygienists must stay current with the scientific evidence related to e-cigarette use and incorporate such information into their client tobacco-related counseling. Addressing the perceived physical and social risks associated with e cigarette use when counseling college students may deter them from initiating or continuing e-cigarette use. PMID- 29118150 TI - Gastroesophageal Reflux Disease Symptom Screening in a Dental Setting. AB - Purpose: Gastroesophageal Reflux Disease (GERD) is a chronic health condition in which the symptoms often go unnoticed. Oral problems accompanying GERD may include non-specific burning sensation, mucosa ulceration and erosion, erythema of the soft/hard palate mucosa and uvula, loss of taste and either xerostomia or increased salivary flow with potential long-term complications such as difficulty swallowing, trouble breathing, esophagitis and potential development of esophageal adenocarcinoma (EAC). The purpose of this study was to assess the feasibility of using a GERD screening in the dental clinic setting to identify and refer patients.Methods: This was a descriptive survey design utilizing a convenience sample of patients (n=227) from two dental hygiene clinics. Students and faculty were calibrated to administer a previously validated, GERD diagnostic screening questionnaire.Results: The prevalence of GERD in the study population was 8.7%; with 10.1% of female reporting symptoms verses 7.0% of male. There were no statistically significant differences in the study population demographics and GERD prevalence.Conclusion: Screening for GERD symptoms should be a routine procedure for oral health care providers, as is oral cancer screening. GERD screening has the potential to identify those at risk and enable referral to medical care in order to decrease the serious complications associated with GERD. PMID- 29118151 TI - Vietnamese Oral Health Beliefs and Practices: Impact on the Utilization of Western Preventive Oral Health Care. AB - Purpose: Infrequent use of the Western health care by the Vietnamese may be explained by deeply-rooted traditional oral health beliefs and practices unique to the Asian culture. This study investigated Vietnamese oral health beliefs and practices and their relationship to the utilization of Western preventive oral health care services among Vietnamese-Americans.Methods: An exploratory, cross sectional survey design with a convenience sample of 140 par-ticipants (n = 140) was used for this study. Participants were recruited on site of a Vietnamese owned business, with questionnaires consisting of 28 questions that were distributed in hard copy by the principal investigator (PI) on multiple occasions and at various times of the day.Results: Spearman Rank Correlations tests showed participants who agreed with the statement, "Regular dental visits will help prevent dental problems," were more likely to utilize medical health services (p< 0.05) and visit a dentist if their "gums were bleeding" (p< 0.05). However, only 22.86% of the participants would visit a dentist if experiencing a toothache. Despite results showing a strong association between the use of medical health care services and the belief that dental visits can prevent future dental health problems, participants did not believe in seeking Western oral health care for all dental health issues. No statistical significance was found between age, gender, pri-mary language, years spent in the United States, education level, religion and the Vietnamese survey participants' individual oral beliefs and practices.Conclusion: The results suggest that Vietnamese Americans holding the belief that dental visits help prevent oral health problems, were more likely to utilize Western health care services. The study also supports existing literature that Vietnamese oral health beliefs and practices impact the use of Western health care services. PMID- 29118153 TI - The Impact of Leadership and Research on Decision Making. PMID- 29118154 TI - Perceptions and Attitudes of Dental Hygiene Educators About the Establishment of Doctoral Education Programs in Dental Hygiene. AB - Purpose: To assess the perceptions and attitudes of dental hygiene (DH) educators at selected colleges and universities regarding the establishment of doctoral educational programs in DH in the United States.Methods: An online survey of DH educators at the 58 U.S. schools offering baccalaureate or master's degree programs was used to assess participants' perceptions and attitudes regarding the following: need to establish doctoral programs in DH, interests in supporting their development, potential barriers and facilitators, and goals/motivators of potential enrollees. Percentages of respondents selecting each response were calculated for each survey item and responses of selected items analyzed for significant differences.Results: Of 608 potential participants, 203 completed the survey for a 33% response rate. More than half the respondents strongly agreed and a quarter more agreed that a DH doctoral program was needed to relate equitably with doctoral graduates of other health-related disciplines and to expand the DH body of knowledge by conducting discipline-specific research. A majority indicated likely interest in supporting the development of both clinically oriented and research-based doctoral programs. Significantly (p<0.01) more respondents with doctorates were interested in developing doctoral programs than those with a master's degree as their terminal degree. Respondents identified shortages of qualified educators and interested enrollees as primary barriers. Facilitators included support from the American Dental Education Association and the American Dental Hygienists' Association. Becoming a better researcher and an institutional administrator were perceived as chief motivations.Conclusion: The majority of DH educators perceived that doctoral educational programs in DH are needed to advance the DH profession. PMID- 29118155 TI - Detection of Early-Stage Oral Cancer Lesions: A Survey of California Dental Hygienists. AB - Purpose: To assess dental hygienists' knowledge of early-stage oral cancer lesions and their practices, attitudes, barriers, and facilitators related to early detection.Methods: A 20-item survey containing images of oral lesions and related multiple-choice questions was distributed electronically by the California Dental Hygienists' Association to all dental hygienists whose email addresses were in their database. Response frequencies were calculated per survey item. Logistic regression analysis was used to explore associations.Results: Seven hundred fifty-one dental hygienists responded, yielding a 12% response rate. Respondents' correct identification of the six images of oral lesions varied from 40%-97%. Most respondents reported conducting oral cancer examinations (OCE) at every dental hygiene appointment and performing palpation during OCE. Regions of the mouth varied regarding the frequency of palpation. Lymph node palpation was considered the most commonly omitted step. Those who conducted palpations were 3.3 (95% CI: 1.4 to 7.9, p=0.006) times more likely to report that they knew someone with oral cancer and had detected oral cancer lesions than those who did not. Knowing a person with a history of oral cancer and previously detecting a cancerous lesion were also reported as factors encouraging respondents to bring suspicious lesions to the attention of the dentist. Discouraging factors were mostly related to the dentist' behavior, such as not referring a suspicious lesion for biopsy that the respondent identified.Conclusion: Detection of early-stage oral cancer lesions by dental hygienists may be enhanced through more extensive education of visual appearances of lesions and the importance of palpation in a comprehensive OCE. PMID- 29118156 TI - Distribution of Bacteria in Dental Offices and the Impact of Hydrogen Peroxide Disinfecting Wipes. AB - Purpose: The purpose of this study was to characterize the occurrence of heterotrophic plate count bacteria (HPCs), fecal bacterial indicators, and methicillin-resistant Staphylococcus aureus (MRSA) on hard, nonporous surfaces (fomites) commonly found in dental offices, and to assess the impact of a hygienic disinfection intervention on the reduction of these bacteria in the office setting.Methods: Samples of various fomites were collected from dental offices located in Arizona (6) and Illinois (4) and assayed for HPCs, total coliforms, Escherichia coli, and MRSA in order to establish baseline bacterial levels. Dental office personnel were then provided with disposable disinfectant wipes containing hydrogen peroxide to use in the office, and the surfaces were subsequently resampled to assess their impact on the specified bacterial populations.Results: The greatest numbers of HPCs were found on the patients' arm rest and office phones, with dental tool handles and the dentist examination lights yielding the lowest levels. Coliform bacteria and E. coli were also detected on those surfaces demonstrating the highest HPCs, and were cultured from other fomites as well. MRSA was also isolated from 5% of the fomites tested. The use of disinfectant wipes significantly reduced the numbers of HPC bacteria detected on fomites (p=0.002). No total coliforms, E. coli, or MRSA were cultured from disinfected fomites following the hygienic intervention.Conclusion: The use of hydrogen peroxide-impregnated towelettes reduced total bacterial numbers on fomites commonly located in dental offices. Total coliforms, E. coli, and MRSA were reduced to levels below detection. PMID- 29118157 TI - Program Evaluation of a Distance Master's Degree Dental Hygiene Program: A Program Effectiveness Study. AB - Purpose: The purpose of this study was to conduct a program evaluation of the University of Missouri-Kansas City Master of Science in Dental Hygiene Education Program (MSDH). This evaluation examined long-term outcomes in the context of stakeholders (the profession, the student, and the degree-granting institution).Methods: A mixed-methods approach was used to gather data from the 28 graduates from the MSDH program. An electronic questionnaire included both open- and closed-ended questions including demographic and practice data, and data related to alumni preparedness to reach their career goals. Virtual focus groups provided valuable insight into whether the program has achieved its goals, and prepared the graduates to meet their program competencies and future goals.Results: Out of a total of 28 individuals who have successfully completed the distance program (2001-2011), 19 participated in an online survey (67.8%). The majority of the participants (73.7%) participated in one of 3 focus groups. Sixty-three percent of the graduates are currently employed in dental hygiene education. Eighty-four percent of the respondents have published their research conducted while in the program, thereby contributing to the dental hygiene body of knowledge. Sixty-eight percent indicated that had the distance option not existed, they would not have been able to obtain their advanced degree in dental hygiene. Twenty-one percent of the respondents report either being currently enrolled in a doctoral program, or having completed a doctoral degree.Conclusion: These results suggest that the University of Missouri-Kansas City Master of Science in Dental Hygiene Education Program is meeting its goals from the perspective of all stakeholders and providing its graduates with access to education and educational resources to meet the program competencies and ultimately achieve their career goals. PMID- 29118158 TI - Dental Hygienists' Attitudes Toward the Obese Population. AB - Purpose: To explore dental hygienists' attitudes toward the obese population and to determine whether there are differences in attitudes among those with different self-reported body images.Methods: The study population was dental hygienists whose email addresses were in the database of the California Dental Hygienists' Association (CDHA). CDHA distributed the electronic message containing study information, informed consent, and a link to the survey. The survey consisted of 14 items from the Fat Phobia Scale, 13 items from the Anti fat Attitudes Questionnaire (AFAQ), 3 demographic questions, and 1 question on body image. Frequencies of responses for each survey item were calculated, and Likert-like scale responses from the AFAQ were analyzed to determine significant differences among self-reported body images.Results: Of the 6,248 email addresses in the CDHA database, 518 hygienists or 8% responded. Mild fat phobia was indicated by 57% of the word pair scores on the Fat Phobia Scale being higher than 2.50. On the AFAQ, 84% agreed to the statement, "People who weigh too much could lose at least some part of their weight through a little exercise." Significantly (p<0.05) more respondents who self-reported as overweight than underweight agreed to "I feel disgusted with myself when I gain weight" and "I worry about becoming fat," while more in the overweight than underweight category significantly (p<0.05) disagreed with "Fat people make me somewhat uncomfortable."Conclusion: Dental hygienists exhibited mildly negative attitudes toward the obese population. Curricula specific to the role of the dental hygienist in addressing the health effects of obesity are recommended. PMID- 29118159 TI - A Comparison of Attrition Rates in Dental Hygiene Programs Using Selective and Nonselective Admissions. AB - Purpose: The purpose of this study was to determine if there is a difference between attrition rates for dental hygiene programs that use selective admissions and nonselective admissions. Admissions to dental hygiene programs is based on a predetermined class size; therefore, applicants must meet the criteria to be considered for selection. Dental hygiene programs want to retain their enrolled students and maximize their student successes; therefore, it is imperative to validate current admissions practices that help reduce attrition rates.Methods: An online survey consisting of forced choice and open-ended questions was sent to the directors of accredited dental hygiene programs in the United States. Surveys were analyzed using descriptive statistics and frequency distributions. Open ended questions were analyzed using the constant comparative method to identify recurring themes.Results: Ninety-nine surveys were returned for a 30% response rate. There was no statistical difference in attrition rates when selective or nonselective admissions criteria was used in dental hygiene programs (year 2011 p=.435 and year 2012 p=.784). Results of this study also showed baccalaureate degree dental hygiene programs have significantly higher completion rates than associate degree dental hygiene programs (2011 p=.002 and 2012 p=.005).Conclusion: Evidence from this study suggests there is no difference between attrition rates for dental hygiene programs that use selective admissions versus nonselective admissions. Additionally, this study determined that baccalaureate degree dental hygiene programs have less attrition compared to associate degree dental hygiene programs. PMID- 29118160 TI - A Dental Radiography Checklist as a Tool for Quality Improvement. AB - Purpose: A checklist intervention was applied to the dental radiographic acquisition process to determine its effectiveness in improving the diagnostic value of bitewing images and reducing patient exposure to unnecessary radiation.Methods: A mixed-method, nonrandomized research design using two dental hygiene program cohorts (n=33) as control and intervention groups was used to assess the effect of a radiographic checklist on the number and type of radiographic imaging errors. The relationship between perceived value of the checklist and willingness to continue its use was examined and analyzed using descriptive statistics. The effect of previous radiography experience, type and number of acquisition errors, and number of retake exposures were analyzed using Fisher's Exact test, chi-square analysis, Spearman's rho, ANOVA, Cronbach's alpha, Breslow-Day, and Pearson correlation coefficient test.Results: Checklist use did not contribute to an improvement in the diagnostic value of radiographs, nor did the intervention reduce patient exposure to unnecessary radiation. Additionally, analysis did not reveal a statistically significant difference between types of radiographic errors and previous radiography experience. A positive correlation was found between perceived value and willingness to continue checklist use.Conclusion: Similarities between the professions of medicine and dentistry suggest that dental procedures may also benefit from application of checklists. Although a positive association between checklist use and error and retake rate was not realized in this study, checklist use may help to improve the quality of radiographic exposures, thereby impacting patient safety by limiting unnecessary exposure to radiation. Additional research is needed to continue to evaluate the effects of checklist use on dental radiographs. As the body of knowledge related to checklist development and use continues to grow, dental hygienists can look for additional ways to incorporate checklists into practice. PMID- 29118161 TI - Dietary Nutrient Intake, Ethnicity, and Epigenetic Silencing of Lung Cancer Genes Detected in Sputum in New Mexican Smokers. AB - Lung cancer gene methylation detected in sputum assesses field cancerization and predicts lung cancer incidence. Hispanic smokers have higher lung cancer susceptibility compared with non-Hispanic whites (NHW). We aimed to identify novel dietary nutrients affecting lung cancer gene methylation and determine the degree of ethnic disparity in methylation explained by diet. Dietary intakes of 139 nutrients were assessed using a validated Harvard food frequency questionnaire in 327 Hispanics and 1,502 NHWs from the Lovelace Smokers Cohort. Promoter methylation of 12 lung cancer genes was assessed in sputum DNA. A global association was identified between dietary intake and gene methylation (Ppermutation = 0.003). Seventeen nutrient measurements were identified with magnitude of association with methylation greater than that seen for folate. A stepwise approach identified B12, manganese, sodium, and saturated fat as the minimally correlated set of nutrients whose optimal intakes could reduce the methylation by 36% (Ppermutation < 0.001). Six protective nutrients included vitamin D, B12, manganese, magnesium, niacin, and folate. Approximately 42% of ethnic disparity in methylation was explained by insufficient intake of protective nutrients in Hispanics compared with NHWs. Functional validation of protective nutrients showed an enhanced DNA repair capacity toward double-strand DNA breaks, a mechanistic biomarker strongly linked to acquisition of lung cancer gene methylation in smokers. Dietary intake is a major modifiable factor for preventing promoter methylation of lung cancer genes in smokers' lungs. Complex dietary supplements could be developed on the basis of these protective nutrients for lung cancer chemoprevention in smokers. Hispanic smokers may benefit the most from this complex for reducing their lung cancer susceptibility. Cancer Prev Res; 11(2); 93-102. (c)2017 AACR. PMID- 29118162 TI - Does Mutated K-RAS Oncogene Attenuate the Effect of Sulindac in Colon Cancer Chemoprevention? AB - The NSAID sulindac has been successfully used alone or in combination with other agents to suppress colon tumorigenesis in patients with genetic predisposition and also showed its efficacy in prevention of sporadic colon adenomas. At the same time, some experimental and clinical reports suggest that a mutant K-RAS oncogene may negate sulindac antitumor efficacy. To directly assess sulindac activity at suppressing premalignant lesions carrying K-RAS mutation, we utilized a novel mouse model with an inducible colon-specific expression of the mutant K ras oncogene (K-rasG12D ). Tumor development and treatment effects were monitored by minimally invasive endoscopic Optical coherence tomography. Expression of the mutant K-ras allele accelerated azoxymethane (AOM)-induced colon carcinogenesis in C57BL/6 mice, a strain otherwise resistant to this carcinogen. Sulindac completely prevented AOM-induced tumor formation in K-ras wild-type (K-ras wt) animals. In K-rasG12D -mutant mice, a 38% reduction in tumor number, an 83% reduction in tumor volume (P <= 0.01) and an increase in the number of adenoma free mice (P = 0.04) were observed. The partial response of K-RasG12D animals to sulindac treatment was evident by the decrease in mucosal thickness (P < 0.01) and delay in progression of the precancerous aberrant crypt foci to adenomas. Molecular analyses showed significant induction in cyclooxygenase 2 (COX-2), cleaved caspase-3 (CC3), and Ki-67 expression by AOM, but not sulindac treatment, in all genotypes. Our data underscore the importance of screening for K-RAS mutations in individuals with colon polyps to provide more personalized interventions targeting mutant K-RAS signaling pathways. Cancer Prev Res; 11(1); 16-26. (c)2017 AACR. PMID- 29118163 TI - Assessment of Chronic Wasting Disease Prion Shedding in Deer Saliva with Occupancy Modeling. AB - The detection of prions is difficult due to the peculiarity of the pathogen, which is a misfolded form of a normal protein. The specificity and sensitivity of detection methods are imperfect in complex samples, including in excreta. Here, we combined optimized prion amplification procedures with a statistical method that accounts for false-positive and false-negative errors to test deer saliva for chronic wasting disease (CWD) prions. This approach enabled us to discriminate the shedding of prions in saliva and the detection of prions in saliva-a distinction crucial to understanding the role of prion shedding in disease transmission and for diagnosis. We found that assay sensitivity and specificity were indeed imperfect, and we were able to draw several conclusions pertinent to CWD biology from our analyses: (i) the shedding of prions in saliva increases with time postinoculation, but is common throughout the preclinical phase of disease; (ii) the shedding propensity is influenced neither by sex nor by prion protein genotype at codon 96; and (iii) the source of prion-containing inoculum used to infect deer affects the likelihood of prion shedding in saliva; oral inoculation of deer with CWD-positive saliva resulted in 2.77 times the likelihood of prion shedding in saliva compared to that from inoculation with CWD positive brain. These results are pertinent to horizontal CWD transmission in wild cervids. Moreover, the approach described is applicable to other diagnostic assays with imperfect detection. PMID- 29118164 TI - Evaluation of In-House and Commercial Serological Tests for Diagnosis of Human Tularemia. AB - Tularemia is a zoonosis caused by the bacterium Francisella tularensis Its specific diagnosis remains based on serological methods, while F. tularensis is rarely detected in clinical samples by culture or PCR. The aim of the present study was to evaluate the performance of the Serion enzyme-linked immunosorbent assay (ELISA) classic Francisella tularensis IgG and IgM tests (Virion/Serion GmbH Institute, Wurzburg, Germany) and the VIRapid tularemia immunochromatographic test (ICT) (Vircell, Granada, Spain) compared to that of the in-house microagglutination test (MAT) and indirect immunofluorescence assay (IFA) currently used at the French National Reference Center for Francisella We evaluated 256 consecutive sera from 208 patients, including 51 confirmed and 23 probable tularemia cases, and 134 control patients not infected with F. tularensis The IFA tests displayed 72.5% sensitivity for IgM (cutoff titer >=80) and 74.5% for IgG (cutoff titer >=160), and 99.3% specificity for both IgM and IgG. Using cutoffs advocated by the manufacturer, the Serion ELISAs displayed 88.2% sensitivity for IgM and 86.3% for IgG antibodies; specificity was 94.8% for IgM and 95.5% for IgG. Compared to MAT and IFA tests, the Serion ELISAs allowed earlier detection of specific antibodies (1 to 2 weeks versus 2 to 3 weeks after the onset of symptoms). The ICT sensitivity and specificity were 90% and 83.6%, respectively, when considering the cutoff advocated by the manufacturer. In conclusion, the Serion ELISAs are useful as screening tests for tularemia diagnosis, but additional confirmatory tests (such as MAT and IFA) are needed, especially in areas of low endemicity. PMID- 29118165 TI - Multicenter Evaluation of the Xpert MRSA NxG Assay for Detection of Methicillin Resistant Staphylococcus aureus in Nasal Swabs. AB - Health care-associated methicillin-resistant Staphylococcus aureus (MRSA) infections are a burden on the health care system. Clinical laboratories play a key role in reducing this burden, as the timely identification of MRSA colonization or infection facilitates infection control practices that are effective at limiting invasive MRSA infections. The Xpert MRSA NxG assay recently received FDA clearance for the direct detection of MRSA from nasal swabs. This multicenter study evaluated the clinical performance characteristics of the Xpert MRSA NxG assay with prospectively collected rayon nasal swabs (n = 1,103) and flocked swab (ESwab) nasal specimens (n = 846). Culture-based identification methods and antimicrobial susceptibility testing were used as the reference standards for comparison. According to the reference method, the positivity rates for MRSA in the population evaluated were 11.1% (122/1,103) for rayon swabs and 11.6% (98/846) for flocked swabs. The overall sensitivity and specificity of the rayon swabs were 91.0% (95% confidence interval [CI], 84.6 to 94.9%) and 96.9% (95% CI, 95.7 to 97.8%), respectively, across eight testing sites. The flocked swab specimens were 92.9% sensitive (95% CI, 86.0 to 96.5%) and 97.6% specific (95% CI, 96.2 to 98.5%) for MRSA detection across six testing sites. The sensitivity and specificity of the combined flocked and rayon swab data were 91.8% (95% CI, 87.4 to 94.8%) and 97.2% (95% CI, 96.3 to 97.9%), respectively. The positive predictive value (PPV) for rayon swabs was 78.7%, versus 83.5% for ESwabs. The negative predictive values (NPVs) for rayon swabs and ESwab specimens were 98.9% and 99.1%, respectively. In conclusion, the Xpert MRSA NxG assay is a sensitive and specific assay for the direct detection of MRSA from nasal swab specimens. PMID- 29118166 TI - Laboratory Focus on Improving the Culture of Biosafety: Statewide Risk Assessment of Clinical Laboratories That Process Specimens for Microbiologic Analysis. AB - The Wisconsin State Laboratory of Hygiene challenged Wisconsin laboratories to examine their biosafety practices and improve their culture of biosafety. One hundred three clinical and public health laboratories completed a questionnaire based, microbiology-focused biosafety risk assessment. Greater than 96% of the respondents performed activities related to specimen processing, direct microscopic examination, and rapid nonmolecular testing, while approximately 60% performed culture interpretation. Although they are important to the assessment of risk, data specific to patient occupation, symptoms, and travel history were often unavailable to the laboratory and, therefore, less contributory to a microbiology-focused biosafety risk assessment than information on the specimen source and test requisition. Over 88% of the respondents complied with more than three-quarters of the mitigation control measures listed in the survey. Facility assessment revealed that subsets of laboratories that claim biosafety level 1, 2, or 3 status did not possess all of the biosafety elements considered minimally standard for their respective classifications. Many laboratories reported being able to quickly correct the minor deficiencies identified. Task assessment identified deficiencies that trended higher within the general (not microbiology specific) laboratory for core activities, such as packaging and shipping, direct microscopic examination, and culture modalities solely involving screens for organism growth. For traditional microbiology departments, opportunities for improvement in the cultivation and management of highly infectious agents, such as acid-fast bacilli and systemic fungi, were revealed. These results derived from a survey of a large cohort of small- and large-scale laboratories suggest the necessity for continued microbiology-based understanding of biosafety practices, vigilance toward biosafety, and enforcement of biosafety practices throughout the laboratory setting. PMID- 29118167 TI - Invasive Disease Caused Simultaneously by Dual Serotypes of Streptococcus pneumoniae. AB - There are at least 98 known pneumococcal serotypes. Invasive pneumococcal disease (IPD) is usually caused by a single serotype, and dual-serotype IPD is rare. To assess factors associated with dual-serotype IPD, patient information obtained through laboratory-based surveillance for IPD from 2005 through 2014 in South Africa was reviewed. Genomes of isolate pairs from coinfected individuals were sequenced to determine their molecular characteristics. For 30 (91%) of 33 patients with dual serotypes, one or both isolates were a pneumococcal conjugate vaccine (PCV13) serotype. Dual-serotype IPD was associated with children <5 years of age (adjusted odds ratio [aOR], 4.7; 95% confidence interval [95% CI], 1.8 to 11.7), underlying illness (other than HIV) (aOR, 2.8; 95% CI, 1.1 to 6.6) and death (aOR, 2.5; 95% CI, 1.08 to 6.09). For each coinfecting pair, isolates were genotypically unrelated, and their genotypes were common among isolates of the same serotype in South Africa. Of 701 accessory genes identified among dual serotype IPD isolates, four were common between isolate pairs. Coinfecting isolate pairs had different genotypic backgrounds. The association of dual serotypes with death warrants increased awareness of IPD coinfection caused by two or more serotypes. PMID- 29118168 TI - Use of the Accelerate Pheno System for Identification and Antimicrobial Susceptibility Testing of Pathogens in Positive Blood Cultures and Impact on Time to Results and Workflow. AB - The Accelerate Pheno system uses automated fluorescence in situ hybridization technology with morphokinetic cellular analysis to provide rapid species identification (ID) and antimicrobial susceptibility testing (AST) results for the most commonly identified organisms in bloodstream infections. The objective was to evaluate the accuracy and workflow of bacterial and yeast ID and bacterial AST using the Accelerate Pheno system in the clinical microbiology laboratory. The consecutive fresh blood cultures received in the laboratory were analyzed by the Accelerate Pheno system within 0 to 8 h of growth detection. ID/AST performance, the average times to results, and workflow were compared to those of the routine standard of care. Of the 232 blood cultures evaluated (223 monomicrobial and 9 polymicrobial) comprising 241 organisms, the overall sensitivity and specificity for the identification of organisms were 95.6% and 99.5%, respectively. For antimicrobial susceptibility, the overall essential agreement was 95.1% and categorical agreement was 95.5% compared to routine methods. There was one very major error and 3 major errors. The time to identification and the time to susceptibility using the Accelerate Pheno system were decreased by 23.47 and 41.86 h, respectively, compared to those for the standard of care. The reduction in hands on time was 25.5 min per culture. The Accelerate Pheno system provides rapid and accurate ID/AST results for most of the organisms found routinely in blood cultures. It is easy to use, reduces hands on time for ID/AST of common blood pathogens, and enables clinically actionable results to be released much earlier than with the current standard of care. PMID- 29118169 TI - The Complexities of Nocardia Taxonomy and Identification. AB - Nocardia species are a complex group of organisms considered to belong to the aerobic actinomycetes. Of the validly described species, many have been implicated as the cause of serious human infections, especially in immunocompromised patients. The genus has a complicated taxonomic history; this is especially true for Nocardia asteroides, the type species of the genus and previously the most frequently reported nocardial taxon from human specimens. We provide background on the current taxonomy of Nocardia, with a focus on clinically relevant species, and discuss the currently available methods used to accurately identify isolates to the species, complex, or group level. PMID- 29118170 TI - lytA Quantitative PCR on Sputum and Nasopharyngeal Swab Samples for Detection of Pneumococcal Pneumonia among the Elderly. AB - Real-time quantitative PCR (qPCR) assay of sputum or nasopharyngeal specimens has shown promising results in the detection of pneumococcal community-acquired pneumonia (PncCAP). We applied qPCR for the autolysin gene (lytA) and compared sputum and nasopharyngeal swab (NPS) pneumococcal loads in elderly patients with community-acquired pneumonia (CAP), and specifically in patients with PncCAP, to those in patient groups with other respiratory diseases. We studied patients aged >=65 years with radiologically confirmed CAP, clinical CAP not retrospectively radiologically confirmed, other acute respiratory infections, or stable chronic lung disease. Pneumococcal etiology of CAP was ascertained by using a combination of multiple diagnostic methods. We analyzed sputum and NPS specimens by lytA qPCR with 104 pneumococcal genome equivalents (GE)/ml as a cutoff for positivity. Among PncCAP patients, lytA qPCR detected pneumococci in 94% of the sputum samples and in large quantities (mean, 6.82 +/- 1.02 log10 GE/ml) but less frequently in NPS (44%) and in smaller quantities (5.55 +/- 0.92 log10 GE/ml). In all other patient groups, <=10% of the sputum samples and <5% of the NPS samples were lytA qPCR positive; but when they were positive, the sputum pneumococcal loads were similar to those in the PncCAP patients, suggesting a pneumococcal etiology in these patients. This was supported by other pneumococcal assay results. Overall, sputum lytA qPCR positivity was more common in PncCAP patients than in the other patient groups, but the quantitative results were mainly similar. NPS lytA qPCR was less sensitive than sputum lytA qPCR in detecting PncCAP. PMID- 29118171 TI - Total Laboratory Automation and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Improve Turnaround Times in the Clinical Microbiology Laboratory: a Retrospective Analysis. AB - Technological advances have changed the practice of clinical microbiology. We implemented Bruker matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and BD Kiestra total laboratory automation (TLA) 4 and 3 years ago, respectively. To assess the impact of these new technologies, we compared turnaround times (TATs) for positive and negative urine cultures before and after implementation. In comparison I, TATs for 61,157 urine cultures were extracted for two periods corresponding to pre-TLA and post-TLA, both using MALDI-TOF MS for organism identification. In comparison II, time to organism identification (ID) and antimicrobial susceptibility (AST) reports were calculated for 5,402 positive culture reports representing four different periods: (i) manual plating and conventional biochemical identification (CONV), (ii) manual plating and MALDI-TOF MS identification (MALDI), (iii) MALDI-TOF MS identification and early phase implementation of TLA (TLA1), and (iv) MALDI-TOF MS identification and late phase implementation of TLA (TLA2). By the comparison I results, median pre- and post-TLA TATs to organism IDs (18.5 to 16.9 h), AST results (41.8 to 40.8 h), and preliminary results for negative cultures (17.7 to 13.6 h), including interquartile ranges for all comparisons, were significantly decreased post-TLA (P < 0.001). By the comparison II results, MALDI significantly improved TAT to organism ID compared to CONV (21.3 to 18 h). TLA further improved overall TAT to ID (18 to 16.5 h) and AST (42.3 to 40.7 h) results compared to MALDI (P < 0.001). In summary, TLA significantly improved TAT to organism ID, AST report, and preliminary negative results. MALDI-TOF MS significantly improved TAT for organism ID. Use of MALDI-TOF MS and TLA individually and together results in significant decreases in microbiology report TATs. PMID- 29118173 TI - mecC-Harboring Methicillin-Resistant Staphylococcus aureus: Hiding in Plain Sight. AB - Previously there was scant data on the performance of laboratory testing to detect mecC-mediated beta-lactam resistance in Staphylococcus aureus Kriegeskorte and colleagues (J Clin Microbiol 56:e00826-17, 2018, https://doi.org/10.1128/JCM.00826-17) report the performance of various clinical tests for the detection of mecC-harboring methicillin-resistant S. aureus (MRSA), which failed to identify from 0 to 41% of tested mecC-harboring MRSA isolates. Changes in practice and new test development are necessary to address the challenge of mecC-harboring MRSA. PMID- 29118172 TI - Multicenter Evaluation of the Modified Carbapenem Inactivation Method and the Carba NP for Detection of Carbapenemase-Producing Pseudomonas aeruginosa and Acinetobacter baumannii. AB - The purpose of this study was to develop the modified carbapenem inactivation method (mCIM) for the detection of carbapenemase-producing Pseudomonas aeruginosa (CP-PA) and carbapenemase-producing Acinetobacter baumannii (CP-AB) and perform a multicenter evaluation of the mCIM and Carba NP tests for these nonfermenters. Thirty P. aeruginosa and 30 A. baumannii isolates previously characterized by whole-genome sequencing from the CDC-FDA Antibiotic Resistance Isolate Bank were evaluated, including CP isolates (Ambler class A, B, and D), non-carbapenemase producing (non-CP) carbapenem-resistant isolates, and carbapenem-susceptible isolates. Initial comparison of a 1-MUl versus 10-MUl loop inoculum for the mCIM was performed by two testing sites and showed that 10 MUl was required for reliable detection of carbapenemase production among P. aeruginosa and A. baumannii Ten testing sites then evaluated the mCIM using a 10-MUl loop inoculum. Overall, the mean sensitivity and specificity of the mCIM for detection of CP-PA across all 10 sites were 98.0% (95% confidence interval [CI], 94.3 to 99.6; range, 86.7 to 100) and 95% (95% CI, 89.8 to 97.7; range, 93.3 to 100), whereas the mean sensitivity and specificity among CP-AB were 79.8% (95% CI, 74.0 to 84.9; range, 36.3 to 95.7) and 52.9% (95% CI, 40.6 to 64.9; range, 28.6 to 100), respectively. At three sites that evaluated the performance of the Carba NP test using the same set of isolates, the mean sensitivity and specificity of the Carba NP test were 97.8% (95% CI, 88.2 to 99.9; range, 93.3 to 100) and 97.8% (95% CI, 88.2 to 99.9; range, 93.3 to 100) for P. aeruginosa and 18.8% (95% CI, 10.4 to 30.1; range, 8.7 to 26.1) and 100% (95% CI, 83.9 to 100; range, 100) for A. baumannii Overall, we found both the mCIM and the Carba NP test to be accurate for detection of carbapenemase production among P. aeruginosa isolates and less reliable for use with A. baumannii isolates. PMID- 29118174 TI - FDA-CDC Antimicrobial Resistance Isolate Bank: a Publicly Available Resource To Support Research, Development, and Regulatory Requirements. AB - The FDA-CDC Antimicrobial Resistance Isolate Bank was created in July 2015 as a publicly available resource to combat antimicrobial resistance. It is a curated repository of bacterial isolates with an assortment of clinically important resistance mechanisms that have been phenotypically and genotypically characterized. In the first 2 years of operation, the bank offered 14 panels comprising 496 unique isolates and had filled 486 orders from 394 institutions throughout the United States. New panels are being added. PMID- 29118175 TI - Predicting Invasive Aspergillosis in Hematology Patients by Combining Clinical and Genetic Risk Factors with Early Diagnostic Biomarkers. AB - Personalized medicine provides a strategic approach to the management of IA. The incidence of IA in high-risk hematology populations is relatively low (<10%), despite unavoidable Aspergillus exposure in patients with a potentially similar clinical risk. Nonclinical variables, including genetic mutations that increase susceptibility to IA, could explain why only certain patients develop the disease. This study screened for mutations in 322 hematology patients classified according to IA status and developed a predictive model based on genetic risk, established clinical risk factors, and diagnostic biomarkers. Genetic markers were determined by real-time PCR and, with clinical risk factors and Aspergillus PCR results, subjected to multilogistic regression analysis to identify a best fit model for predicting IA. The probability of IA was calculated, and an optimal threshold was determined. Mutations in dectin-1 (rs7309123) and DC-SIGN (rs11465384 and rs7248637), allogeneic stem cell transplantation, respiratory virus infection, and Aspergillus PCR positivity were all significant risk factors for developing IA and were combined in a predictive model. An optimal threshold requiring three positive factors generated a mean sensitivity/specificity of 70.4%/89.2% and a probability of developing IA of 56.7%. In patients with no risk factors, the probability of developing IA was 2.4%, compared to >79.1% in patients with four or more factors. Using a risk threshold of 50%, preemptive therapy would have been prescribed for 8.4% of the population. This pilot study shows that patients can be stratified according to risk of IA, providing personalized medicine based on strategic evidence for the management of IA. Further studies are required to confirm this approach. PMID- 29118178 TI - The Impact of Leadership and Research on Decision Making: Forming Collaborations and Shared Partnerships. PMID- 29118176 TI - Highly Sensitive Detection of Isoniazid Heteroresistance in Mycobacterium tuberculosis by DeepMelt Assay. AB - Detection of heteroresistance of Mycobacterium tuberculosis remains challenging using current genotypic drug susceptibility testing methods. Here, we described a melting curve analysis-based approach, termed DeepMelt, that can detect less abundant mutants through selective clamping of the wild type in mixed populations. The singleplex DeepMelt assay detected 0.01% katG S315T in 105M. tuberculosis genomes/MUl. The multiplex DeepMelt TB/INH detected 1% of mutant species in the four loci associated with isoniazid resistance in 104M. tuberculosis genomes/MUl. The DeepMelt TB/INH assay was tested on a panel of DNA extracted from 602 precharacterized clinical isolates. Using the 1% proportion method as the gold standard, the sensitivity was found to be increased from 93.6% (176/188, 95% confidence interval [CI] = 89.2 to 96.3%) to 95.7% (180/188, 95% CI = 91.8 to 97.8%) compared to the MeltPro TB/INH assay. Further evaluation of 109 smear-positive sputum specimens increased the sensitivity from 83.3% (20/24, 95% CI = 64.2 to 93.3%) to 91.7% (22/24, 95% CI = 74.2 to 97.7%). In both cases, the specificity remained nearly unchanged. All heteroresistant samples newly identified by the DeepMelt TB/INH assay were confirmed by DNA sequencing and even partially by digital PCR. The DeepMelt assay may fill the gap between current genotypic and phenotypic drug susceptibility testing for detecting drug-resistant tuberculosis patients. PMID- 29118177 TI - Direct Detection of Shigella in Stool Specimens by Use of a Metagenomic Approach. AB - The underestimation of Shigella species as a cause of childhood diarrhea disease has become increasingly apparent with quantitative PCR (qPCR)-based diagnostic methods versus culture. We sought to confirm qPCR-based detection of Shigella via a metagenomics approach. Three groups of samples were selected from diarrheal cases from the Global Enteric Multicenter Study: nine Shigella culture-positive and qPCR-positive (culture+ qPCR+) samples, nine culture-negative but qPCR positive (culture- qPCR+) samples, and nine culture-negative and qPCR-negative (culture- qPCR-) samples. Fecal DNA was sequenced using paired-end Illumina HiSeq, whereby 3.26 * 108 +/- 5.6 * 107 high-quality reads were generated for each sample. We used Kraken software to compare the read counts specific to "Shigella" among the three groups. The proportions of Shigella-specific nonhuman sequence reads between culture+ qPCR+ (0.65 +/- 0.42%) and culture- qPCR+ (0.55 +/- 0.31%) samples were similar (Mann-Whitney U test, P = 0.627) and distinct from the culture- qPCR- group (0.17 +/- 0.15%, P < 0.05). The read counts of sequences previously targeted by Shigella/enteroinvasive Escherichia coli (EIEC) qPCR assays, namely, ipaH, virA, virG, ial, ShET2, and ipaH3, were also similar between the culture+ qPCR+ and culture- qPCR+ groups and distinct from the culture- qPCR- groups (P < 0.001). Kraken performed well versus other methods: its precision and recall of Shigella were excellent at the genus level but variable at the species level. In summary, metagenomic sequencing indicates that Shigella/EIEC qPCR-positive samples are similar to those of Shigella culture positive samples in Shigella sequence composition, thus supporting qPCR as an accurate method for detecting Shigella. PMID- 29118179 TI - Public Opinions Regarding Advanced Dental Hygiene Practitioners in a High-Need State. AB - Purpose: The new Advanced Dental Hygiene Practitioner (ADHP) profession is expected to increase access to oral health care for the general population, particularly in rural and underserved areas. In order for this strategy to be successful, the public must feel comfortable with the care provided by ADHPs and seek out their services, yet consumer receptivity has been overlooked in the literature. The current study explores comfort with ADHPs for one high-need state: Kentucky.Methods: Consumer receptivity to the ADHP was assessed using a large, random sample telephone survey. As a point of comparison, respondents were first asked about their comfort with care provided by two other advanced practice clinicians already licensed in the state: advanced practice registered nurses (APRN) and physician assistants (PA).Results: After hearing a brief description of the profession, nearly 3 in 4 Kentucky adults said they would be somewhat (35.4%) or very (38.2%) comfortable seeing an ADHP for routine dental care. The total proportion of Kentucky adults who were comfortable seeking care from an ADHP (73.6%) was slightly less than the proportion indicating comfort seeing an APRN (79.7%) or PA (81.3%).Conclusion: Overall, this study demonstrates that adults are receptive to new models of care delivery and report high levels of comfort with ADHPs. Consumer concerns are unlikely to be a barrier to expanded licensure for dental hygienists in high-need areas like Kentucky. PMID- 29118180 TI - Perceptions of California Dental Hygienists Regarding Mandatory Continued Competence Requirements as a Condition of License Renewal. AB - Purpose: To determine the perceptions of California dental hygienists (DHs) regarding mandatory continued competence requirements (MCCRs) as a condition for license renewal.Methods: A quantitative cross-sectional survey was distributed through email by the California Dental Hygienists' Association (CDHA). The CDHA agreed to send a link to the survey and informed consent information to DHs whose email addresses were in the CDHA database. The online survey consisted of 19 items. All survey responses were analyzed using frequency distributions for categorical variables and means for continuous variables. Chi-square tests assessed associations between variables and differences between groups. The Wilcoxon signed rank test assessed relationships between perceptions and support of MCCRs for license renewal.Results: Almost all (93%) believed that they have remained competent to deliver care since licensure. Over half agreed that continued competence should be verified throughout ones' professional career (53%). Most (81%) agreed that continued competence is important for patient safety and well-being. Less than half (47%) supported MCCRs as a condition of license renewal; however, 51% of those who agreed that competence is important for patient safety and well-being and 67% of those who agreed with verification of competence were in support of MCCRs.Conclusion: While California DHs agreed that continued competence is important for patient safety and well-being and verification of competence is important, less than half supported MCCRs. Prior to instituting mandate for license renewal in California, continued competence and methods to ensure continued competence throughout ones' career should be defined. PMID- 29118181 TI - Oral Health Care Providers' Knowledge and Attitudes About Intimate Partner Violence. AB - Introduction: Given its high prevalence, intimate partner violence (IPV) is an important public health issue. Oral health care providers (OHCPs) often encounter victims of intimate partner abuse in dental settings, but there is a lack of existing literature regarding OHCPs' attitudes toward and knowledge of IPV.Purpose: This study assessed OHCPs' knowledge and perception of preparedness in assessment and management for IPV.Methods: Using a validated survey tool called PREMIS, this study assessed a convenience sample of OHCPs' knowledge and attitudes about the identification, assessment, and management of IPV.Results: The survey results obtained from 117 OHCPs indicated 92% had had some form of IPV education, but 45% felt they did not have sufficient training to assist individuals who were victims of IPV. Other areas in which the respondents felt ill-prepared included identifying victims of IPV (61.5%) and appropriate referrals to social services (64%). Only 7 to 9% screen new patients or those with abuse indicators on the history or exam.Conclusion: This study explored OHCPs' attitudes and knowledge of IPV and provided insight into IPV screening practices and management in dental care settings. Because injuries to the head, neck, and face are very common in IPV, OHCPs have the opportunity to play a key role in managing "the silent epidemic" of domestic violence by routinely including screening of new and returning patients and having a referral resources available. PMID- 29118182 TI - Senior Dental Students' Knowledge and Attitudes Toward Dental Hygienists' Contributions to Comprehensive Patient Care. AB - Purpose: To assess senior dental students' knowledge and attitudes toward dental hygienists' contributions to comprehensive patient care and to compare the responses of students from two dental schools, one with a dental hygiene (DH) program, and one without a DH program.Methods: Senior dental students from one school with DH (n=363) and one without DH (n=111) were requested to complete a 15 item survey assessing knowledge of clinical duties of licensed dental hygienists, attitudes regarding outcomes of collaborating with hygienists, and demographic characteristics. Responses were collated, and frequencies of responses for each item were analyzed by Qualtrics software program. The chi-square test was used to compare responses of the two groups of dental students.Results: The response rate was 27%. More respondents from the school with DH than those from the school without DH significantly agreed to these statements: "collaborating with DH students in school, has given, or would have given me, a better understanding of the value a dental hygienist brings to my future dental practice" (p=0.02) and "having a DH program at a dental school leads to patients receiving more comprehensive preventive care" (p=0.01). The likelihood of employing a dental hygienist was not significantly different between the two groups of students. The perceived high financial cost was the most frequent reason not to employ a hygienist.Conclusion: Collaboration of dental and DH students in entry-level education results in dental students' greater understanding and support of the dental hygienists' contributions to comprehensive patient care. PMID- 29118183 TI - The Importance of Developing Communication Skills: Perceptions of Dental Hygiene Students. AB - Purpose: The purpose of this study was to gather data from first- and second-year dental hygiene students concerning their perceptions of the benefits and possible impediments to effective patient communication. Additionally, the students were asked to theorize as to the impact emerging communication technologies could have on oral health promotion, practice administration and patient/provider communication.Methods: A self-administered questionnaire of 6 open-ended queries was employed. Thematic analysis was conducted to reveal themes related to their perceived ability to effectively communicate, perceived barriers to communication, possible solutions to lessen or eliminate these barriers, and the impact of emerging technologies on interpersonal communication.Results: The questionnaire was completed by 63 of 68 students (93%). Patient apathy and patient unwillingness to change detrimental health-related habits were the most frequently cited barriers to effective communication. Of the students having patient contact, many stated that they were less sure of their ability to communicate effectively if the patient differed from themselves, such as being elderly or being from another culture. While most of the students believed their fundamental communication skills were good, many noted that improving their higher-order skills, such as conveying empathy or displaying a nonjudgmental attitude, were essential to being more effective communicators. Many students felt emerging technologies such as universal translators could potentially assist them in overcoming some of their perceived deficiencies.Conclusion: While perceived inadequacies will likely diminish as the students gain more experience in school and later in private practice, dental hygiene programs may wish to consider implementing additional structured educational experiences to better prepare students to address patient apathy and to effectively convey a sense of personal compassion. Promoting student involvement in community outreach activities and providing a variety of service learning opportunities, including foreign travel, may broaden student experiences and deepen their awareness and appreciation of verbal and nonverbal communications displayed by differing cultures. PMID- 29118184 TI - Disaster Preparedness and Response: A Survey of U.S. Dental Hygienists. AB - Purpose: The purpose of this study was to assess dental hygienists' interests, current involvement, formal education, views, comfort levels, and intentions for involvement with disaster preparedness and response.Methods: Dental hygienists (n=400) were asked to respond to a 21-item online survey. Data was analyzed using descriptive statistics, chi-square goodness-of-fit tests, and a paired-samples t test. Common themes were identified and categorized from open-ended questions.Results: A response rate of 84% (n=334) was obtained. Most respondents (97%) reported no involvement with disaster preparedness and response; however, a majority (86%) reported interest. Of those who indicated an interest in disaster preparedness and response, 92% had intentions for becoming involved. A majority of dental hygienists (93%) had not received formal education in disaster preparedness and response; yet, 95% shared the view that dental hygienists could have a vital role in this specialty area. Although results indicated a mean difference of 9% increased comfort with activities not requiring physical contact with human remains, dental hygienists were relatively comfortable with activities requiring contact: taking photographs (76%, n=254), taking radiographs (83%, n=273), resecting the mandible (55%, n=184), cleaning skeletonized remains (67%, n=221).Conclusion: Dental hygienists view themselves as professionals who could have a vital role in disaster preparedness and response. Efforts should be made to increase dental hygiene formal education in disaster preparedness and response with needed curriculum models and competencies for best outcomes when dental hygienists are serving their communities. PMID- 29118185 TI - Implications for Improving Oral Health Care Among Female Prisoners in Georgia's Correctional System. AB - Georgia has the eighth-highest state rate of incarceration and fourth-highest number of prisoners in the country. Aside from receiving a dental examination at intake to assess oral health needs, there are no efforts to determine the barriers and determinants that contribute to the presenting oral health status of Georgia's state prisoners. Also, there is no prerelease planning to establish a health care home for prisoners being released back into the community to continue oral health care services in an effort to support successful reentry.This study assessed the barriers that impact N=98 female inmates' access to oral health care, prior to incarceration, within Georgia's prison system using a 21-item survey developed by a division of an academic institution and administered by the staff of a state department. Majority of the survey respondents reported that they do not have a regular dental provider (83%), lack insurance coverage (66%), and had their last dental visit more than a year ago because they did not have money for service or treatment (64%). The data collected from this study will be utilized to inform future project efforts to both reduce costs and increase access to oral health care for Georgia's uninsured and underinsured, and especially the incarcerated and reentry populations. PMID- 29118186 TI - Identification of phlebovirus and arenavirus RNA sequences that stall and repress the exoribonuclease XRN1. AB - Regulated mRNA decay plays a vital role in determining both the level and quality of cellular gene expression. Viral RNAs must successfully evade this host RNA decay machinery to establish a productive infection. One way for RNA viruses to accomplish this is to target the cellular exoribonuclease XRN1, because this enzyme is accessible in the cytoplasm and plays a major role in mRNA decay. Members of the Flaviviridae use RNA structures in their 5'- or 3'-untranslated regions to stall and repress XRN1, effectively stabilizing viral RNAs while also causing significant dysregulation of host cell mRNA stability. Here, we use a series of biochemical assays to demonstrate that the 3'-terminal portion of the nucleocapsid (N) mRNA of Rift Valley fever virus, a phlebovirus of the Bunyaviridae family, also can effectively stall and repress XRN1. The region responsible for impeding XRN1 includes a G-rich portion that likely forms a G quadruplex structure. The 3'-terminal portions of ambisense-derived transcripts of multiple arenaviruses also stalled XRN1. Therefore, we conclude that RNAs from two additional families of mammalian RNA viruses stall and repress XRN1. This observation. emphasizes the importance and commonality of this viral strategy to interfere with the 5'-to-3'-exoribonuclease component of the cytoplasmic RNA decay machinery. PMID- 29118187 TI - JNK2 up-regulates hypoxia-inducible factors and contributes to hypoxia-induced erythropoiesis and pulmonary hypertension. AB - The hypoxic response is a stress response triggered by low oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive. Here, using genetic knockout cells and/or mice, we show that JNK2, but not JNK1, up-regulates the expression of HIF-1alpha and HIF-2alpha and contributes to hypoxia-induced PH and polycythemia. Knockout or silencing of JNK2, but not JNK1, prevented the accumulation of HIF-1alpha in hypoxia-treated cells. Loss of JNK2 resulted in a decrease in HIF-1alpha and HIF-2alpha mRNA levels under resting conditions and in response to hypoxia. Consequently, hypoxia treated Jnk2-/- mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (Epo). Jnk2-/- mice were also protected from hypoxia-induced PH, as indicated by lower right ventricular systolic pressure, a process that depends on HIF. Taken together, our results suggest that JNK2 is a positive regulator of HIFs and therefore may contribute to HIF-dependent pathologies. PMID- 29118188 TI - Structure and monomer/dimer equilibrium for the guanylyl cyclase domain of the optogenetics protein RhoGC. AB - RhoGC is a fusion protein from the aquatic fungus Blastocladiella emersonii, combining a type I rhodopsin domain with a guanylyl cyclase domain. It has generated excitement as an optogenetics tool for the manipulation of cyclic nucleotide signaling pathways. To investigate the regulation of the cyclase activity, we isolated the guanylyl cyclase domain from Escherichia coli with (GCwCCRho) and without (GCRho) the coiled-coil linker. Both constructs were constitutively active but were monomeric as determined by size-exclusion chromatography and analytical ultracentrifugation, whereas other class III nucleotidyl cyclases are functional dimers. We also observed that crystals of GCRho have only a monomer in an asymmetric unit. Dimers formed when crystals were grown in the presence of the non-cyclizable substrate analog 2',3' dideoxyguanosine-5'-triphosphate, MnCl2, and tartrate, but their quaternary structure did not conform to the canonical pairing expected for class III enzymes. Moreover, the structure contained a disulfide bond formed with an active site Cys residue required for activity. We consider it unlikely that the disulfide would form under intracellular reducing conditions, raising the possibility that this unusual dimer might have a biologically relevant role in the regulation of full-length RhoGC. Although we did not observe it with direct methods, a functional dimer was identified as the active state by following the dependence of activity on total enzyme concentration. The low affinity observed for GCRho monomers is unusual for this enzyme class and suggests that dimer formation may contribute to light activation of the full-length protein. PMID- 29118189 TI - The peptidyl-prolyl isomerase PIN1 relieves cyclin-dependent kinase 2 (CDK2) inhibition by the CDK inhibitor p27. AB - PIN1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans isomerization of peptide bonds between proline and phosphorylated serine/threonine residues. By changing the conformation of its protein substrates, PIN1 increases the activities of key proteins that promote cell cycle progression and oncogenesis. Moreover, it has been shown that PIN1 stabilizes and increases the level of the cyclin-dependent kinase (CDK) inhibitor p27, which inhibits cell cycle progression by binding cyclin A- and cyclin E-CDK2. Notwithstanding the associated increase in the p27 level, PIN1 expression promotes rather than retards cell proliferation. To explain the paradoxical effects of PIN1 on p27 levels and cell cycle progression, we hypothesized that PIN1 relieves CDK2 inhibition by suppressing the CDK inhibitory activity of p27. Here, we confirmed that PIN1-expressing cells exhibit higher p27 levels but have increased CDK2 activities and higher proliferation rates in the S-phase compared with Pin1-null fibroblasts or PIN1-depleted hepatoma cells. Using co-immunoprecipitation and CDK kinase activity assays, we found that PIN1 binds the phosphorylated Thr187-Pro motif in p27 and reduces p27's interaction with cyclin A- or cyclin E-CDK2, leading to increased CDK2 kinase activity. In conclusion, our results indicate that although PIN1 increases p27 levels, it also attenuates p27's inhibitory activity on CDK2 and thereby contributes to increased G1-S phase transitions and cell proliferation. PMID- 29118191 TI - Effects of muscle action type on corticospinal excitability and triceps surae muscle-tendon mechanics. AB - This study investigated whether the specific motor control strategy reported for eccentric muscle actions is dependent on muscle mechanical behavior. Motor evoked potentials, Hoffman reflex (H-reflex), fascicle length, pennation angle, and fascicle velocity of soleus muscle were compared between isometric and two eccentric conditions. Ten volunteers performed maximal plantarflexion trials in isometric, slow eccentric (25 degrees /s), and fast eccentric (100 degrees /s) conditions, each in a different randomized testing session. H-reflex normalized by the preceding M wave (H/M) was depressed in both eccentric conditions compared with isometric ( P < 0.001), while no differences in fascicle length and pennation angle were found among conditions. Furthermore, although the fast eccentric condition had greater fascicle velocity than slow eccentric ( P = 0.001), there were no differences in H/M. There were no differences in motor evoked potential size between conditions, and silent period was shorter for both eccentric conditions compared with isometric ( P = 0.009). Taken together, the present results corroborate the hypothesis that the central nervous system has an unique activation strategy during eccentric muscle actions and suggest that sensory feedback does not play an important role in modulating these muscle actions. NEW & NOTEWORTHY The present study provides new insight into the motor control of eccentric muscle actions. It was demonstrated that task-dependent corticospinal excitability modulation does not seem to depend on sensory information processing. These findings support the hypothesis that the central nervous system has a unique activation strategy during eccentric muscle actions. PMID- 29118190 TI - Juvenile hormone and 20-hydroxyecdysone coordinately control the developmental timing of matrix metalloproteinase-induced fat body cell dissociation. AB - Tissue remodeling is a crucial process in animal development and disease progression. Coordinately controlled by the two main insect hormones, juvenile hormone (JH) and 20-hydroxyecdysone (20E), tissues are remodeled context specifically during insect metamorphosis. We previously discovered that two matrix metalloproteinases (Mmps) cooperatively induce fat body cell dissociation in Drosophila However, the molecular events involved in this Mmp-mediated dissociation are unclear. Here we report that JH and 20E coordinately and precisely control the developmental timing of Mmp-induced fat body cell dissociation. We found that during the larval-prepupal transition, the anti metamorphic factor Kr-h1 transduces JH signaling, which directly inhibited Mmp expression and activated expression of tissue inhibitor of metalloproteinases (timp) and thereby suppressed Mmp-induced fat body cell dissociation. We also noted that upon a decline in the JH titer, a prepupal peak of 20E suppresses Mmp induced fat body cell dissociation through the 20E primary-response genes, E75 and Blimp-1, which inhibited expression of the nuclear receptor and competence factor betaftz-F1 Moreover, upon a decline in the 20E titer, betaftz-F1 expression was induced by the 20E early-late response gene DHR3, and then betaftz F1 directly activated Mmp expression and inhibited timp expression, causing Mmp induced fat body cell dissociation during 6-12 h after puparium formation. In conclusion, coordinated signaling via JH and 20E finely tunes the developmental timing of Mmp-induced fat body cell dissociation. Our findings shed critical light on hormonal regulation of insect metamorphosis. PMID- 29118192 TI - Endocannabinoid-mediated potentiation of nonnociceptive synapses contributes to behavioral sensitization. AB - Endocannabinoids, such as 2-arachidonoyl glycerol (2-AG) and anandamide, can elicit long-term depression of both excitatory and inhibitory synapses. This latter effect will result in disinhibition and would therefore be expected to produce an increase in neural circuit output. However, there have been no examples directly linking endocannabinoid-mediated disinhibition to a change in a functional neurobehavioral circuit. The present study uses the well-characterized central nervous system of the medicinal leech, Hirudo verbana, to examine the functional/behavioral relevance of endocannabinoid modulation of an identified afferent synapse. Bath application of 2-AG potentiates synaptic transmission by pressure-sensitive sensory neurons (P cells) as well as the magnitude of the defensive shortening reflex elicited by P-cell stimulation. This potentiation requires activation of TRPV-like channels. Endocannabinoid/TRPV signaling was found to produce sensitization of the shortening reflex elicited by either direct stimulation of nearby nociceptive afferents (N cells) or noxious stimulation applied to skin several segments away. In both cases, heterosynaptic potentiation of P-cell synapses was observed in parallel with an increase in the magnitude of elicited shortening and both synaptic and behavioral effects were blocked by pharmacological inhibition of 2-AG synthesis or TRPV-like channel activation. Serotonin (5-HT) is known to play a critical role in sensitization in Hirudo and other animals, and the 5-HT2 receptor antagonist ritanserin also blocked behavioral sensitization and the accompanying synaptic potentiation. These findings suggest a novel, endocannabinoid-mediated contribution to behavioral sensitization that may interact with known 5-HT-dependent modulatory processes. NEW & NOTEWORTHY There is considerable interest in the analgesic potential of cannabinoids. However, there is evidence that the cannabinoid system can have both pro- and antinociceptive effects. This study examines how an endogenous cannabinoid transmitter can potentiate nonnociceptive synapses and enhance their capacity to elicit a nocifensive behavioral response. PMID- 29118193 TI - Duration analysis using matching pursuit algorithm reveals longer bouts of gamma rhythm. AB - The gamma rhythm (30-80 Hz), often associated with high-level cortical functions, is believed to provide a temporal reference frame for spiking activity, for which it should have a stable center frequency and linear phase for an extended duration. However, recent studies that have estimated the power and phase of gamma as a function of time suggest that gamma occurs in short bursts and lacks the temporal structure required to act as a reference frame. Here, we show that the bursty appearance of gamma arises from the variability in the spectral estimator used in these studies. To overcome this problem, we use another duration estimator based on a matching pursuit algorithm that robustly estimates the duration of gamma in simulated data. Applying this algorithm to gamma oscillations recorded from implanted microelectrodes in the primary visual cortex of awake monkeys, we show that the median gamma duration is greater than 300 ms, which is three times longer than previously reported values. NEW & NOTEWORTHY Gamma oscillations (30-80 Hz) have been hypothesized to provide a temporal reference frame for coordination of spiking activity, but recent studies have shown that gamma occurs in very short bursts. We show that existing techniques have severely underestimated the rhythm duration, use a technique based on the Matching Pursuit algorithm, which provides a robust estimate of the duration, and show that the median duration of gamma is greater than 300 ms, much longer than previous estimates. PMID- 29118194 TI - Optimal use of limb mechanics distributes control during bimanual tasks. AB - Bimanual tasks involve the coordination of both arms, which often offers redundancy in the ways a task can be completed. The distribution of control across limbs is often considered from the perspective of handedness. In this context, although there are differences across dominant and nondominant arms during reaching control ( Sainburg 2002 ), previous studies have shown that the brain tends to favor the dominant arm when performing bimanual tasks ( Salimpour and Shadmehr 2014 ). However, biomechanical factors known to influence planning and control in unimanual tasks may also generate limb asymmetries in force generation, but their influence on bimanual control has remained unexplored. We investigated this issue in a series of experiments in which participants were instructed to generate a 20-N force with both arms, with or without perturbation of the target force during the trial. We modeled the task in the framework of optimal feedback control of a two-link model with six human-like muscles groups. The biomechanical model predicted a differential contribution of each arm dependent on the orientation of the target force and joint configuration that was quantitatively matched by the participants' behavior, regardless of handedness. Responses to visual perturbations were strongly influenced by the perturbation direction, such that online corrections also reflected an optimal use of limb biomechanics. These results show that the nervous system takes biomechanical constraints into account when optimizing the distribution of forces generated across limbs during both movement planning and feedback control of a bimanual task. NEW & NOTEWORTHY Here, we studied a bimanual force production task to examine the effects of biomechanical constraints on the distribution of control across limbs. Our findings show that the central nervous system optimizes the distribution of force across the two arms according to the joint configuration of the upper limbs. We further show that the underlying mechanisms influence both movement planning and online corrective responses to sudden changes in the target force. PMID- 29118195 TI - Binocular deprivation induces both age-dependent and age-independent forms of plasticity in parvalbumin inhibitory neuron visual response properties. AB - Activity of cortical inhibitory interneurons is rapidly reduced in response to monocular deprivation during the critical period for ocular dominance plasticity and in response to salient events encountered during learning. In the case of primary sensory cortex, a decrease in mean evoked firing rate of parvalbumin positive (PV) inhibitory neurons is causally linked to a reorganization of excitatory networks following sensory perturbation. Converging evidence indicates that it is deprivation, and not an imbalance between open- and closed-eye inputs, that triggers rapid plasticity in PV neurons. However, this has not been directly tested in vivo. Using two-photon guided cell-attached recording, we examined the impact of closing both eyes for 24 h on PV neuron response properties in mouse primary visual cortex. We found that binocular deprivation induces a 30% reduction in stimulus-evoked mean firing rate and that this reduction is specific to critical period-aged mice. The number of PV neurons showing detectable tuning to orientation increased after 24 h of deprivation, and this effect was also specific to critical period-aged mice. In contrast to evoked mean firing rate and orientation tuning, measurements of trial-to-trial variability revealed that stimulus-driven decreases in variability are significantly dampened by deprivation during both the critical period and the postcritical period. These data establish that open-eye inputs are not required to drive deprivation-induced weakening of PV neuron evoked activity and that other aspects of in vivo PV neuron activity are malleable throughout life. NEW & NOTEWORTHY Parvalbumin positive (PV) neurons in sensory cortex are generally considered to be mediators of experience-dependent plasticity, and their plasticity is restricted to the critical period. However, in regions outside of sensory cortex, accumulating evidence demonstrates that PV neurons are plastic in adults, raising the possibility that aspects of PV response properties may be plastic throughout life. Here we identify a feature of in vivo PV neuron activity that remains plastic past the critical period. PMID- 29118196 TI - Involvement of N-methyl-d-aspartate receptors in plasticity induced by paired corticospinal-motoneuronal stimulation in humans. AB - Plasticity can be induced at human corticospinal-motoneuronal synapses by delivery of repeated, paired stimuli to corticospinal axons and motoneurons in a technique called paired corticospinal-motoneuronal stimulation (PCMS). To date, the mechanisms of the induced plasticity are unknown. To determine whether PCMS induced plasticity is dependent on N-methyl-d-aspartate receptors (NMDARs), the effect of the noncompetitive NMDAR antagonist dextromethorphan on PCMS-induced facilitation was assessed in a 2-day, double-blind, placebo-controlled experiment. PCMS consisted of 100 pairs of stimuli, delivered at an interstimulus interval that produces facilitation at corticospinal-motoneuronal synapses that excite biceps brachii motoneurons. Transcranial magnetic stimulation elicited corticospinal volleys, which were timed to arrive at corticospinal-motoneuronal synapses just before antidromic potentials elicited in motoneurons with electrical brachial plexus stimulation. To measure changes in the corticospinal pathway at a spinal level, biceps responses to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were measured before and for 30 min after PCMS. Individuals who displayed a >=10% increase in CMEP size after PCMS on screening were eligible to take part in the 2-day experiment. After PCMS, there was a significant difference in CMEP area between placebo and dextromethorphan days ( P = 0.014). On the placebo day PCMS increased average CMEP areas to 127 +/- 46% of baseline, whereas on the dextromethorphan day CMEP area was decreased to 86 +/- 33% of baseline (mean +/- SD; placebo: n = 11, dextromethorphan: n = 10). Therefore, dextromethorphan suppressed the facilitation of CMEPs after PCMS. This indicates that plasticity induced at synapses in the human spinal cord by PCMS may be dependent on NMDARs. NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation can strengthen the synaptic connections between corticospinal axons and motoneurons at a spinal level in humans. The mechanism of the induced plasticity is unknown. In our 2 day, double-blind, placebo-controlled study we show that the N-methyl-d-aspartate receptor (NMDAR) antagonist dextromethorphan suppressed plasticity induced by paired corticospinal-motoneuronal stimulation, suggesting that an NMDAR-dependent mechanism is involved. PMID- 29118197 TI - Control of saccadic latency in a dynamic environment: allocation of saccades in time follows the matching law. AB - When exploring the visual environment, one uses saccades to shift gaze and fixation to gather spatially and temporally localized information. We propose that the temporal structure of our environment should constrain the temporal allocation of saccades. Here we probe the possibility of learning to control saccadic latencies in a choice paradigm. Six participants made saccades within 80 300 ms following a target horizontally stepping by 10 degrees between two fixed locations. For each participant we constructed two classes of latencies, "short" and "long," using the first and last quartiles of the individual baseline distribution (e.g., [80;152] ms and [185;300] ms, respectively). We then concurrently reinforced each class in three blocked conditions across ~60 experimental sessions per participant, using different reinforcement probabilities such that the relative ratio of reinforcement rates for short vs. long latencies was 9/1, 1/9, or 1/1. Latency distributions followed the reinforcement conditions: distributions shifted toward the shorter or longer values or became strongly bimodal. Moreover, the relative rates of short over long latencies matched the relative rates of reinforcers earned for the corresponding latencies (slope up to 0.95), which reveals the ability to choose when to saccade. Our results reveal that learned contingencies considerably affect the allocation of saccades in time and are in line with recent studies on the temporal adjustment of behavior to dynamic environments. This study provides strong evidence for fine operant control of saccadic latency, supporting the hypothesis of a cost-benefit control of saccade latencies. NEW & NOTEWORTHY Saccades may be regarded as an information-foraging behavior mostly concerned with the spatial localization of objects, yet our world is dynamic and environmental temporal regularities should also affect saccade decisions. We present behavioral data from a choice task establishing that humans can learn to choose their saccadic latencies depending on the reinforcement contingencies. This suggests a cost-benefit-based policy that takes into account the learned temporal properties of the environmental contingencies for controlling saccade triggering. PMID- 29118198 TI - A fast, invariant representation for human action in the visual system. AB - Humans can effortlessly recognize others' actions in the presence of complex transformations, such as changes in viewpoint. Several studies have located the regions in the brain involved in invariant action recognition; however, the underlying neural computations remain poorly understood. We use magnetoencephalography decoding and a data set of well-controlled, naturalistic videos of five actions (run, walk, jump, eat, drink) performed by different actors at different viewpoints to study the computational steps used to recognize actions across complex transformations. In particular, we ask when the brain discriminates between different actions, and when it does so in a manner that is invariant to changes in 3D viewpoint. We measure the latency difference between invariant and noninvariant action decoding when subjects view full videos as well as form-depleted and motion-depleted stimuli. We were unable to detect a difference in decoding latency or temporal profile between invariant and noninvariant action recognition in full videos. However, when either form or motion information is removed from the stimulus set, we observe a decrease and delay in invariant action decoding. Our results suggest that the brain recognizes actions and builds invariance to complex transformations at the same time and that both form and motion information are crucial for fast, invariant action recognition. NEW & NOTEWORTHY The human brain can quickly recognize actions despite transformations that change their visual appearance. We use neural timing data to uncover the computations underlying this ability. We find that within 200 ms action can be read out of magnetoencephalography data and that this representation is invariant to changes in viewpoint. We find form and motion are needed for this fast action decoding, suggesting that the brain quickly integrates complex spatiotemporal features to form invariant action representations. PMID- 29118199 TI - Rapid feedback responses are flexibly coordinated across arm muscles to support goal-directed reaching. AB - A transcortical pathway helps support goal-directed reaching by processing somatosensory information to produce rapid feedback responses across multiple joints and muscles. Here, we tested whether such feedback responses can account for changes in arm configuration and for arbitrary visuomotor transformations-two manipulations that alter how muscles at the elbow and wrist need to be coordinated to achieve task success. Participants used a planar three degree-of freedom exoskeleton robot to move a cursor to a target following a mechanical perturbation that flexed the elbow. In our first experiment, the cursor was mapped to the veridical position of the robot handle, but participants grasped the handle with two different hand orientations (thumb pointing upward or thumb pointing downward). We found that large rapid feedback responses were evoked in wrist extensor muscles when wrist extension helped move the cursor to the target (i.e., thumb upward), and in wrist flexor muscles when wrist flexion helped move the cursor to the target (i.e., thumb downward). In our second experiment, participants grasped the robot handle with their thumb pointing upward, but the cursor's movement was either veridical or was mirrored such that flexing the wrist moved the cursor as if the participant extended their wrist, and vice versa. After extensive practice, we found that rapid feedback responses were appropriately tuned to the wrist muscles that supported moving the cursor to the target when the cursor was mapped to the mirrored movement of the wrist, but were not tuned to the appropriate wrist muscles when the cursor was remapped to the wrist's veridical movement. NEW & NOTEWORTHY We show that rapid feedback responses were evoked in different wrist muscles depending on the arm's orientation, and this muscle activity was appropriate to generate the wrist motion that supported a reaching action. Notably, we also show that these rapid feedback responses can be evoked in wrist muscles that are detrimental to a reaching action if a nonveridical mapping between wrist and hand motion is extensively learned. PMID- 29118200 TI - Vestibular short-latency evoked potential abolished by low-frequency noise exposure in rats. AB - The vestibular system plays a critical role in detection of head movements and is essential for normal postural control. Because of their anatomical proximity to the cochlea, the otolith organs are selectively exposed to sound pressure and are at risk for noise overstimulation. Clinical reports suggest a link between noise exposure and balance problems, but the structural and physiological basis for this linkage is not well understood. The goal of this study was to determine the effects of low-frequency noise (LFN) on the otolith organs by correlating changes in vestibular short-latency evoked potentials (VsEPs) with changes in saccular afferent endings following noise exposure. LFN exposure transiently abolished the VsEP and reduced the number of stained calyces within the sacculus. Although some recovery of the VsEP waveform could be observed within 3 days after noise, at 3 wk recovery was only partial in most animals, consistent with a reduced number of afferents with calyceal endings. These data show that a single intense noise exposure is capable of causing a vestibular deficit that appears to mirror the synaptic deficit associated with hidden hearing loss after noise-induced cochlear injury. NEW & NOTEWORTHY This is the first study to explore the effects of low frequency high-intensity noise on vestibular short-latency evoked potential (VsEP) responses, which shows a linkage between attenuated noise-induced VsEPs and pathological changes to otolith organ afferents. This finding suggests a potential limitation of the VsEP for evaluation of vestibular dysfunction, since the VsEP measurement may assess the activity of a specific class rather than all afferents. PMID- 29118201 TI - Inflow of oxygen and glucose in brain tissue induced by intravenous norepinephrine: relationships with central metabolic and peripheral vascular responses. AB - As an essential part of sympathetic activation that prepares the organism for "fight or flight," peripheral norepinephrine (NE) plays an important role in regulating cardiac activity and the tone of blood vessels, increasing blood flow to the heart and the brain and decreasing blood flow to the organs not as necessary for immediate survival. To assess whether this effect is applicable to the brain, we used high-speed amperometry to measure the changes in nucleus accumbens (NAc) levels of oxygen and glucose induced by intravenous injections of NE in awake freely moving rats. We found that NE at low doses (2-18 MUg/kg) induces correlative increases in NAc oxygen and glucose, suggesting local vasodilation and enhanced entry of these substances in brain tissue from the arterial blood. By using temperature recordings from the NAc, temporal muscle, and skin, we show that this central effect is associated with strong skin vasoconstriction and phasic increases in intrabrain heat production, indicative of metabolic neural activation. A tight direct correlation between NE-induced changes in metabolic activity and NAc levels of oxygen and glucose levels suggests that local cerebral vasodilation is triggered via a neurovascular coupling mechanism. Our data suggest that NE, by changing vascular tone and cardiac activity, triggers a visceral sensory signal that rapidly reaches the central nervous system via sensory nerves and induces neural activation. This neural activation leads to a chain of neurovascular events that promote entry of oxygen and glucose in brain tissue, thus preventing any possible metabolic deficit during functional activation. NEW & NOTEWORTHY Using high-speed amperometry and thermorecording in freely moving rats, we demonstrate that intravenous norepinephrine at physiological doses induces rapid correlative increases in nucleus accumbens oxygen and glucose levels coupled with increased intrabrain heat production. Although norepinephrine cannot cross the blood-brain barrier, by changing cardiac activity and vascular tone, it creates a sensory signal that reaches the central nervous system via sensory nerves, induces neural activation, and triggers a chain of neurovascular events that promotes intrabrain entry of oxygen and glucose. PMID- 29118202 TI - Bayesian optimal adaptation explains age-related human sensorimotor changes. AB - The brain uses information from different sensory systems to guide motor behavior, and aging is associated with simultaneous decline in the quality of sensory information provided to the brain and deterioration in motor control. Correlations between age-dependent decline in sensory anatomical structures and behavior have been demonstrated in many sensorimotor systems, and it has recently been suggested that a Bayesian framework could explain these relationships. Here we show that age-dependent changes in a human sensorimotor reflex, the vestibuloocular reflex, are explained by a Bayesian optimal adaptation in the brain occurring in response to death of motion-sensing hair cells. Specifically, we found that the temporal dynamics of the reflex as a function of age emerge from ( r = 0.93, P < 0.001) a Kalman filter model that determines the optimal behavioral output when the sensory signal-to-noise characteristics are degraded by death of the transducers. These findings demonstrate that the aging brain is capable of generating the ideal and statistically optimal behavioral response when provided with deteriorating sensory information. While the Bayesian framework has been shown to be a general neural principle for multimodal sensory integration and dynamic sensory estimation, these findings provide evidence of longitudinal Bayesian processing over the human life span. These results illuminate how the aging brain strives to optimize motor behavior when faced with deterioration in the peripheral and central nervous systems and have implications in the field of vestibular and balance disorders, as they will likely provide guidance for physical therapy and for prosthetic aids that aim to reduce falls in the elderly. NEW & NOTEWORTHY We showed that age-dependent changes in the vestibuloocular reflex are explained by a Bayesian optimal adaptation in the brain that occurs in response to age-dependent sensory anatomical changes. This demonstrates that the brain can longitudinally respond to age-related sensory loss in an ideal and statistically optimal way. This has implications for understanding and treating vestibular disorders caused by aging and provides insight into the structure-function relationship during aging. PMID- 29118204 TI - Mitotic Chromosome Assembly In Vitro: Functional Cross Talk between Nucleosomes and Condensins. AB - The mitotic chromosome is a macromolecular assembly that ensures error-free transmission of the genome during cell division. It has long been a big mystery how long stretches of DNA might be folded into rod-shaped chromosomes or how such an elaborate process might be accomplished at a mechanistic level. Cell-free extracts made from frog eggs offer a unique opportunity to address these questions by enabling mitotic chromosomes to be assembled in a test tube. Moreover, the core part of the chromosome assembly reaction can now be reconstituted with a limited number of purified factors. A combination of these in vitro assays makes it possible not only to prepare a complete list of proteins required for chromosome assembly but also to dissect functions of individual proteins and their cooperation with unparalleled clarity. Emerging lines of evidence underscore the paramount importance of condensins in building mitotic chromosomes and shed new light on the functional cross talk between nucleosomes and condensins in this process. PMID- 29118203 TI - Condom use behaviour among people living with HIV: a seven-country community based participatory research in the Asia-Pacific region. AB - OBJECTIVES: We examined the prevalence of inconsistent condom use and its correlates among people living with HIV (PLHIV) in the Asia-Pacific region. METHODS: Between 1 October 2012 and 31 May 2013, a total of 7843 PLHIV aged 18-50 years were recruited using targeted and venue-based sampling in Bangladesh, Indonesia, Lao People's Democratic Republic (PDR), Nepal, Pakistan, Philippines and Vietnam. Logistic regression was used to explore the association between condom use behaviour and demographics, social support, stigma and discrimination and various health-related variables. RESULTS: Overall, 43% of 3827 PLHIV practised inconsistent condom use at sexual intercourse with their regular partner. An even higher proportion, 46% of 2044 PLHIV admitted that they practised unprotected sex with a casual partner. Participants from Lao PDR reported the lowest prevalence of inconsistent condom use for both regular and casual partners, while participants from the Philippines had the highest risk behaviour. Inconsistent condom use was significantly associated with belonging to a key population (drug user, sex worker or refugee subpopulation), not knowing that condoms are still needed if both partners are HIV positive, having a regular partner whose HIV status was either positive or unknown, having experienced physical assault and not receiving antiretroviral treatment. CONCLUSIONS: This large seven-country study highlights a high prevalence of inconsistent condom use among PLHIV in the Asia-Pacific region. In addition to knowledge-imparting interventions, the adoption and expansion of the 'Test and Treat' strategy could help to maximise the prevention benefits of antiretroviral treatment. PMID- 29118205 TI - Epigenetic Etiology of Intellectual Disability. AB - Intellectual disability (ID) is a prevailing neurodevelopmental condition associated with impaired cognitive and adaptive behaviors. Many chromatin modifying enzymes and other epigenetic regulators have been genetically associated with ID disorders (IDDs). Here we review how alterations in the function of histone modifiers, chromatin remodelers, and methyl-DNA binding proteins contribute to neurodevelopmental defects and altered brain plasticity. We also discuss how progress in human genetics has led to the generation of mouse models that unveil the molecular etiology of ID, and outline the direction in which this field is moving to identify therapeutic strategies for IDDs. Importantly, because the chromatin regulators linked to IDDs often target common downstream genes and cellular processes, the impact of research in individual syndromes goes well beyond each syndrome and can also contribute to the understanding and therapy of other IDDs. Furthermore, the investigation of these disorders helps us to understand the role of chromatin regulators in brain development, plasticity, and gene expression, thereby answering fundamental questions in neurobiology. PMID- 29118206 TI - Social Origins of Developmental Risk for Mental and Physical Illness. AB - Adversity in early childhood exerts an enduring impact on mental and physical health, academic achievement, lifetime productivity, and the probability of interfacing with the criminal justice system. More science is needed to understand how the brain is affected by early life stress (ELS), which produces excessive activation of stress response systems broadly throughout the child's body (toxic stress). Our research examines the importance of sex, timing and type of stress exposure, and critical periods for intervention in various brain systems across species. Neglect (the absence of sensitive and responsive caregiving) or disrupted interaction with offspring induces robust, lasting consequences in mice, monkeys, and humans. Complementary assessment of internalizing disorders and brain imaging in children suggests that early adversity can interfere with white matter development in key brain regions, which may increase risk for emotional difficulties in the long term. Neural circuits that are most plastic during ELS exposure in monkeys sustain the greatest change in gene expression, offering a mechanism whereby stress timing might lead to markedly different long-term behaviors. Rodent models reveal that disrupted maternal-infant interactions yield metabolic and behavioral outcomes often differing by sex. Moreover, ELS may further accelerate or delay critical periods of development, which reflect GABA circuit maturation, BDNF, and circadian Clock genes. Such factors are associated with several mental disorders and may contribute to a premature closure of plastic windows for intervention following ELS. Together, complementary cross-species studies are elucidating principles of adaptation to adversity in early childhood with molecular, cellular, and whole organism resolution. PMID- 29118207 TI - Emerging Mechanisms Underlying Dynamics of GABAergic Synapses. AB - Inhibitory circuits are diverse, yet with a poorly understood cell biology. Functional characterization of distinct inhibitory neuron subtypes has not been sufficient to explain how GABAergic neurotransmission sculpts principal cell activity in a relevant fashion. Our Mini-Symposium brings together several emerging mechanisms that modulate GABAergic neurotransmission dynamically from either the presynaptic or the postsynaptic site. The first two talks discuss novel developmental and neuronal subtype-specific contributions to the excitatory/inhibitory balance and circuit maturation. The next three talks examine how interactions between cellular pathways, lateral diffusion of proteins between synapses, and chloride transporter function at excitatory and inhibitory synapses and facilitate inhibitory synapse adaptations. Finally, we address functional differences within GABAergic interneurons to highlight the importance of diverse, flexible, and versatile inputs that shape network function. Together, the selection of topics demonstrates how developmental and activity-dependent mechanisms coordinate inhibition in relation to the excitatory inputs and vice versa. PMID- 29118208 TI - Unconventional NMDA Receptor Signaling. AB - In the classical view, NMDA receptors (NMDARs) are stably expressed at the postsynaptic membrane, where they act via Ca2+ to signal coincidence detection in Hebbian plasticity. More recently, it has been established that NMDAR-mediated transmission can be dynamically regulated by neural activity. In addition, NMDARs have been found presynaptically, where they cannot act as conventional coincidence detectors. Unexpectedly, NMDARs have also been shown to signal metabotropically, without the need for Ca2+ This review highlights novel findings concerning these unconventional modes of NMDAR action. PMID- 29118209 TI - In Vivo Imaging of CNS Injury and Disease. AB - In vivo optical imaging has emerged as a powerful tool with which to study cellular responses to injury and disease in the mammalian CNS. Important new insights have emerged regarding axonal degeneration and regeneration, glial responses and neuroinflammation, changes in the neurovascular unit, and, more recently, neural transplantations. Accompanying a 2017 SfN Mini-Symposium, here, we discuss selected recent advances in understanding the neuronal, glial, and other cellular responses to CNS injury and disease with in vivo imaging of the rodent brain or spinal cord. We anticipate that in vivo optical imaging will continue to be at the forefront of breakthrough discoveries of fundamental mechanisms and therapies for CNS injury and disease. PMID- 29118210 TI - Illuminating Neural Circuits: From Molecules to MRI. AB - Neurological disease drives symptoms through pathological changes to circuit functions. Therefore, understanding circuit mechanisms that drive behavioral dysfunction is of critical importance for quantitative diagnosis and systematic treatment of neurological disease. Here, we describe key technologies that enable measurement and manipulation of neural activity and neural circuits. Applying these approaches led to the discovery of circuit mechanisms underlying pathological motor behavior, arousal regulation, and protein accumulation. Finally, we discuss how optogenetic functional magnetic resonance imaging reveals global scale circuit mechanisms, and how circuit manipulations could lead to new treatments of neurological diseases. PMID- 29118212 TI - Delineating the Diversity of Spinal Interneurons in Locomotor Circuits. AB - Locomotion is common to all animals and is essential for survival. Neural circuits located in the spinal cord have been shown to be necessary and sufficient for the generation and control of the basic locomotor rhythm by activating muscles on either side of the body in a specific sequence. Activity in these neural circuits determines the speed, gait pattern, and direction of movement, so the specific locomotor pattern generated relies on the diversity of the neurons within spinal locomotor circuits. Here, we review findings demonstrating that developmental genetics can be used to identify populations of neurons that comprise these circuits and focus on recent work indicating that many of these populations can be further subdivided into distinct subtypes, with each likely to play complementary functions during locomotion. Finally, we discuss data describing the manner in which these populations interact with each other to produce efficient, task-dependent locomotion. PMID- 29118211 TI - Sensation during Active Behaviors. AB - A substantial portion of our sensory experience happens during active behaviors such as walking around or paying attention. How do sensory systems work during such behaviors? Neural processing in sensory systems can be shaped by behavior in multiple ways ranging from a modulation of responsiveness or sharpening of tuning to a dynamic change of response properties or functional connectivity. Here, we review recent findings on the modulation of sensory processing during active behaviors in different systems: insect vision, rodent thalamus, and rodent sensory cortices. We discuss the circuit-level mechanisms that might lead to these modulations and their potential role in sensory function. Finally, we highlight the open questions and future perspectives of this exciting new field. PMID- 29118213 TI - Volition and Action in the Human Brain: Processes, Pathologies, and Reasons. AB - Humans seem to decide for themselves what to do, and when to do it. This distinctive capacity may emerge from an ability, shared with other animals, to make decisions for action that are related to future goals, or at least free from the constraints of immediate environmental inputs. Studying such volitional acts proves a major challenge for neuroscience. This review highlights key mechanisms in the generation of voluntary, as opposed to stimulus-driven actions, and highlights three issues. The first part focuses on the apparent spontaneity of voluntary action. The second part focuses on one of the most distinctive, but elusive, features of volition, namely, its link to conscious experience, and reviews stimulation and patient studies of the cortical basis of conscious volition down to the single-neuron level. Finally, we consider the goal directedness of voluntary action, and discuss how internal generation of action can be linked to goals and reasons. PMID- 29118214 TI - Central Network Dynamics Regulating Visceral and Humoral Functions. AB - The brain processes information from the periphery and regulates visceral and immune activity to maintain internal homeostasis, optimally respond to a dynamic external environment, and integrate these functions with ongoing behavior. In addition to its relevance for survival, this integration underlies pathology as evidenced by diseases exhibiting comorbid visceral and psychiatric symptoms. Advances in neuroanatomical mapping, genetically specific neuronal manipulation, and neural network recording are overcoming the challenges of dissecting complex circuits that underlie this integration and deciphering their function. Here we focus on reciprocal communication between the brain and urological, gastrointestinal, and immune systems. These studies are revealing how autonomic activity becomes integrated into behavior as part of a social strategy, how the brain regulates innate immunity in response to stress, and how drugs impact emotion and gastrointestinal function. These examples highlight the power of the functional organization of circuits at the interface of the brain and periphery. PMID- 29118215 TI - Adolescence and Reward: Making Sense of Neural and Behavioral Changes Amid the Chaos. AB - Adolescence is a time of significant neural and behavioral change with remarkable development in social, emotional, and cognitive skills. It is also a time of increased exploration and risk-taking (e.g., drug use). Many of these changes are thought to be the result of increased reward-value coupled with an underdeveloped inhibitory control, and thus a hypersensitivity to reward. Perturbations during adolescence can alter the developmental trajectory of the brain, resulting in long-term alterations in reward-associated behaviors. This review highlights recent developments in our understanding of how neural circuits, pubertal hormones, and environmental factors contribute to adolescent-typical reward associated behaviors with a particular focus on sex differences, the medial prefrontal cortex, social reward, social isolation, and drug use. We then introduce a new approach that makes use of natural adaptations of seasonally breeding species to investigate the role of pubertal hormones in adolescent development. This research has only begun to parse out contributions of the many neural, endocrine, and environmental changes to the heightened reward sensitivity and increased vulnerability to mental health disorders that characterize this life stage. PMID- 29118216 TI - Circuit and Synaptic Plasticity Mechanisms of Drug Relapse. AB - High rates of relapse to drug use during abstinence is a defining feature of human drug addiction. This clinical scenario has been studied at the preclinical level using different animal models in which relapse to drug seeking is assessed after cessation of operant drug self-administration in rodents and monkeys. In our Society for Neuroscience (SFN) session entitled "Circuit and Synaptic Plasticity Mechanisms of Drug Relapse," we will discuss new developments of our understanding of circuits and synaptic plasticity mechanisms of drug relapse from studies combining established and novel animal models with state-of-the-art cellular, electrophysiology, anatomical, chemogenetic, and optogenetic methods. We will also discuss the translational implications of these new developments. In the mini-review that introduces our SFN session, we summarize results from our laboratories on behavioral, cellular, and circuit mechanisms of drug relapse within the context of our session. PMID- 29118217 TI - New Breakthroughs in Understanding the Role of Functional Interactions between the Neocortex and the Claustrum. AB - Almost all areas of the neocortex are connected with the claustrum, a nucleus located between the neocortex and the striatum, yet the functions of corticoclaustral and claustrocortical connections remain largely obscure. As major efforts to model the neocortex are currently underway, it has become increasingly important to incorporate the corticoclaustral system into theories of cortical function. This Mini-Symposium was motivated by a series of recent studies which have sparked new hypotheses regarding the function of claustral circuits. Anatomical, ultrastructural, and functional studies indicate that the claustrum is most highly interconnected with prefrontal cortex, suggesting important roles in higher cognitive processing, and that the organization of the corticoclaustral system is distinct from the driver/modulator framework often used to describe the corticothalamic system. Recent findings supporting roles in detecting novel sensory stimuli, directing attention and setting behavioral states, were the subject of the Mini-Symposium at the 2017 Society for Neuroscience Annual Meeting. PMID- 29118220 TI - Who's Watching the Kids? PMID- 29118221 TI - Letter to the Editor: Defining "Standard of Care". PMID- 29118218 TI - Consciousness Regained: Disentangling Mechanisms, Brain Systems, and Behavioral Responses. AB - How consciousness (experience) arises from and relates to material brain processes (the "mind-body problem") has been pondered by thinkers for centuries, and is regarded as among the deepest unsolved problems in science, with wide ranging theoretical, clinical, and ethical implications. Until the last few decades, this was largely seen as a philosophical topic, but not widely accepted in mainstream neuroscience. Since the 1980s, however, novel methods and theoretical advances have yielded remarkable results, opening up the field for scientific and clinical progress. Since a seminal paper by Crick and Koch (1998) claimed that a science of consciousness should first search for its neural correlates (NCC), a variety of correlates have been suggested, including both content-specific NCCs, determining particular phenomenal components within an experience, and the full NCC, the neural substrates supporting entire conscious experiences. In this review, we present recent progress on theoretical, experimental, and clinical issues. Specifically, we (1) review methodological advances that are important for dissociating conscious experience from related enabling and executive functions, (2) suggest how critically reconsidering the role of the frontal cortex may further delineate NCCs, (3) advocate the need for general, objective, brain-based measures of the capacity for consciousness that are independent of sensory processing and executive functions, and (4) show how animal studies can reveal population and network phenomena of relevance for understanding mechanisms of consciousness. PMID- 29118222 TI - Sexual Health Is Paramount in the Counseling of Women at Risk for Breast or Ovarian Cancer Undergoing Risk-Reducing Surgery. PMID- 29118223 TI - Time to Change: Supporting Sexual and Gender Minority People-An Underserved, Understudied Cancer Risk Population. PMID- 29118219 TI - Nonhuman Primate Optogenetics: Recent Advances and Future Directions. AB - Optogenetics is the use of genetically coded, light-gated ion channels or pumps (opsins) for millisecond resolution control of neural activity. By targeting opsin expression to specific cell types and neuronal pathways, optogenetics can expand our understanding of the neural basis of normal and pathological behavior. To maximize the potential of optogenetics to study human cognition and behavior, optogenetics should be applied to the study of nonhuman primates (NHPs). The homology between NHPs and humans makes these animals the best experimental model for understanding human brain function and dysfunction. Moreover, for genetic tools to have translational promise, their use must be demonstrated effectively in large, wild-type animals such as Rhesus macaques. Here, we review recent advances in primate optogenetics. We highlight the technical hurdles that have been cleared, challenges that remain, and summarize how optogenetic experiments are expanding our understanding of primate brain function. PMID- 29118224 TI - Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation. AB - mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors. PMID- 29118225 TI - Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer. AB - Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important. PMID- 29118226 TI - NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017. AB - For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas. PMID- 29118227 TI - Nonadherence to Statins and Antihypertensives and Hospitalizations Among Elderly Medicare Beneficiaries With Incident Cancer. AB - Background: Incident cancer diagnosis may increase the risk of coronary artery disease (CAD)-related hospitalizations, especially in older individuals. Adherence to statins and/or angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs)/beta-blockers reduces CAD-related hospitalizations. This study examined the relationship between medication adherence and CAD-related hospitalizations immediately following cancer diagnosis. Patients and Methods: A retrospective observational longitudinal study was conducted using SEER-Medicare data. Elderly Medicare fee-for-service beneficiaries with preexisting CAD and incident breast, colorectal, or prostate cancer (N=12,096) were observed for 12 months before and after cancer diagnosis. Hospitalizations measured every 120 days were categorized into CAD-related hospitalization, other hospitalization, and no hospitalization. Medication adherence was categorized into 5 mutually exclusive groups: adherent to both statins and ACEIs/ARBs/beta-blockers (reference group), not adherent to both statins and ACEIs/ARBs/beta-blockers, adherent to either statins or ACEIs/ARBs/beta-blockers, use of one medication class and adherent to that class, and use of one medication class and not adherent to that class. The relationship between medication adherence and hospitalization was analyzed using repeated measures multinomial logistic regressions. Inverse probability treatment weights were used to control for observed group differences among medication adherence categories. Results: Adherence to both statins and ACEIs/ARBs/beta-blockers was estimated at 31.2% during the 120-day period immediately following cancer diagnosis; 13.7% were not adherent to both medication classes during the same period, and 27.4% had CAD-related hospitalizations immediately after cancer diagnosis, which declined to 10.6% during the last 4 months of the postdiagnosis period. In the adjusted analyses, those not adherent to both statins and ACEIs/ARBs/beta-blockers were more likely to have CAD-related hospitalization compared with those adherent to both medication classes (adjusted odds ratio, 1.82; 95% CI, 1.72-1.92; P<.0001). Conclusions: Given the complexity of interaction between CAD and cancer, it is important to routinely monitor medication adherence in general clinical practice and to provide linkages to support services that can increase medication adherence. PMID- 29118228 TI - Do Published Data in Trials Assessing Cancer Drugs Reflect the Real Picture of Efficacy and Safety? AB - Background: The reporting quality of publications is of vital importance to ensure accurate evidence dissemination. This study aimed to compare the consistency of results reporting between the ClinicalTrials.gov results database and the respective matching publications. Methods: We identified 323 phase III/IV cancer drug trials with a randomized controlled design and searched PubMed for publications in a 50% random sample (n=160). Data were extracted independently from ClinicalTrials.gov and publications. A scoring system was applied to determine characteristics associated with reporting quality. Results: Of 117 reviewed trials with publications, result reporting was significantly more complete in ClinicalTrials.gov for efficacy measurement (92.3% vs 90.6%), serious adverse events (SAEs; 100% vs 43.6%), and other adverse events (OAEs; 100% vs 62.4%). For trials with both posted and published results for design information (n=117), efficacy measurements (n=98), SAEs (n=51), and OAEs (n=73), discrepancies were found in 16 (13.7%), 38 (38.8%), 26 (51.0%), and 54 (74.0%) trials, respectively. Overreporting of treatment effects (7 trials) and alteration of primary end points favoring statistically significant outcomes (11 trials) were the major discrepancies in efficacy reporting; incomplete (66 trials) and underreporting (20 trials) of SAEs were the predominant issues in benefit/risk reporting. Median quality score was 21 (range, 14-28). Trials that had parallel assignment, were phase IV, had primary funding by industry, were completed after 2009, and had earlier results posted possessed better reporting quality. Conclusions: Although most trials showed reasonable completeness and consistency, some discrepancies are prevalent and persistent, jeopardizing evidence-based decision-making. Our findings highlight the need to consult results systematically from both ClinicalTrials.gov and publications. PMID- 29118229 TI - Sexual and Gender Minority Issues Across NCCN Guidelines: Results From a National Survey. AB - Background: The lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ) population is at higher risk for multiple types of cancers compared with the heterosexual population. Expert NCCN panels lead the nation in establishing clinical practice guidelines addressing cancer prevention, early detection, and treatment of cancer sites and populations. Given the emergence of new data identifying cancer disparities in the LGBTQ population, this study examined the inclusion of medical and/or psychosocial criteria unique to LGBTQ within NCCN Guidelines. Methods: Data were collected for 32 of the 50 NCCN Guidelines. Results: NCCN panel members reported that neither sexual orientation (84%) nor gender identity (94%) were relevant to the focus of their guidelines; 77% responded that their panels currently do not address LGBTQ issues, with no plans to address them in the future. Conclusions: Greater consideration should be given to the needs of LGBTQ patients across the cancer care continuum. Given that research concerning LGBTQ and cancer is in its infancy, additional empirical and evidence-based data are needed to bolster further integration of LGBTQ-specific criteria into clinical care guidelines. PMID- 29118230 TI - Addition of Definitive Radiotherapy to Chemotherapy in Patients With Newly Diagnosed Metastatic Nasopharyngeal Cancer. AB - Background: Management of metastatic (M1) nasopharyngeal cancer (NPC) is controversial; data suggest high overall survival (OS) rates with definitive chemoradiotherapy (CRT). Herein, we evaluated OS in patients with M1 NPC undergoing chemotherapy alone versus CRT. Methods: The National Cancer Data Base was queried for M1 NPC cases. Patients undergoing no/unknown chemotherapy and/or with unknown/nondefinitive radiotherapy (RT) doses (<60 Gy) were excluded. Logistic regression analysis ascertained clinical factors associated with RT administration. Kaplan-Meier analysis evaluated OS between both cohorts; Cox proportional hazards modeling assessed factors associated with OS. Survival was then evaluated between matched populations using inverse-probability-weighted regression adjustment. OS between groups was also measured in patients surviving >=1 and >=3 years to address bias from poor-prognostic subsets (eg, widely disseminated disease), and those receiving CRT <=30 and <=60 days of each other (surrogates for concurrent CRT) versus >30 and >60 days (sequential) of each other. Results: Of 555 patients, 296 (53%) received chemotherapy alone and 259 (47%) underwent CRT. Patients undergoing CRT more often had private insurance (P=.001) and lived in areas with higher education levels (P=.028). Median OS in the chemotherapy-only and CRT cohorts were 13.7 and 25.8 months, respectively (P<.001); differences persisted between matched populations (P<.001). On multivariate analysis, receipt of additional RT independently predicted for improved OS (P<.001). OS differences between cohorts remained apparent when evaluating patients surviving for >=1 (P<.001) and >=3 (P=.002) years. Patients who received concurrent or sequential CRT displayed improved OS over those receiving chemotherapy alone, for both the 30-day (P<.001) and 60-day cutoffs (P<.001). Conclusions: Patients with M1 NPC undergoing definitive RT and chemotherapy experienced higher survival than those receiving chemotherapy alone. Risk stratification and patient selection for such combined modality interventions is critical. PMID- 29118231 TI - Apoyo con Carino: Strategies to Promote Recruiting, Enrolling, and Retaining Latinos in a Cancer Clinical Trial. AB - Background: We present and describe tailored strategies to address known barriers to minority participation in clinical trial research. The strategies used allowed our team to engage communities and successfully recruit, enroll, and retain a diverse underserved population of Latinos with advanced cancer for this clinical trial. Methods: Participants were recruited from 3 urban and 7 rural sites. We identified 4 critical barriers to recruitment for this underserved population: (1) mistrust; (2) language and communication barriers; (3) lack of access to academic cancer center; and (4) inability to participate due to transportation, childcare, or work responsibilities. We developed tailored strategies to engage referring sites and patients to participate in the clinical trial. Results: We identified 318 potentially eligible participants; 34 were found to be ineligible, and 223 consented to participate in the study, representing a 79.0% enrollment rate. All patients (100%) self-identified as Latino, and 47.5% spoke Spanish as their primary language. Patients were socioeconomically disadvantaged: 53.6% had an annual income <$15,000 USD, and 50.2% had less than a high school education. A total of 177 participants completed the 3-month follow-up; 26 died before the 3 month follow interview, and 20 did not complete the follow-up evaluation (9% withdrawal rate). Conclusions: Our community-informed strategies were highly effective for recruiting, enrolling, and retaining an underserved diverse population of Latinos. The barriers we identified and the strategies we used have the potential to inform research to increase minority participation in cancer clinical trials. ClinicalTrials.gov identifier: NCT01695382. PMID- 29118232 TI - Healthcare Utilization and Costs During the Initial Phase of Care Among Elderly Women With Breast Cancer. AB - Background: Understanding the patterns of healthcare utilization and costs during the initial phase of care (12 months after breast cancer [BC] diagnosis) in older women (aged >=65 years) is crucial in the allocation of Medicare resources. The objective of this study was to determine healthcare utilization and costs during the initial phase of care in older, female, Medicare fee-for-service beneficiaries diagnosed with BC, and to determine the factors associated with higher costs. Methods: A retrospective observational study using the SEER Medicare linked database was conducted in 69,307 women aged >=66 years diagnosed with primary incident BC in 2003-2009 to determine healthcare utilization, average costs, and costs for specific services during the initial phase of care. Generalized linear model regression was conducted to identify the factors associated with higher costs in a multivariate framework. Results: A total of 96% of women were treated with surgery during the initial phase of BC care, whereas 21% and 54% underwent chemotherapy and radiotherapy, respectively. Costs during the initial phase of care totalled $28,075 in 2012 USD, comprising $13,344 for physician services and $7,456 for outpatient services. Factors associated with higher costs during the initial phase of care were younger age (66-69 years), African American race, higher household income, advanced stages of BC, initial BC treatment, higher number of primary care physician visits, and presence of comorbidities and/or a mental condition. Conclusions: The economic burden of BC is substantial during the initial phase of care. Physician and outpatient services accounted for the highest proportion of costs. Predisposing factors, need-related factors, healthcare use, and external environmental healthcare factors significantly predicted costs during the initial phase of care. PMID- 29118233 TI - Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. AB - Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL. PMID- 29118234 TI - Emerging Role of CAR T Cells in Non-Hodgkin's Lymphoma. AB - Adoptive T-cell therapy with chimeric antigen receptor T cells (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies, and several groups have published positive results using anti-CD19 CAR-Ts for the treatment of B-cell acute lymphoblastic leukemia. Recently, new data from clinical trials have demonstrated the benefits of CAR-T therapy in the non Hodgkin's lymphoma (NHL) setting. This review describes some of the most recent and promising advances in engineered T-cell therapy, with particular emphasis on the clinical benefits of NHL treatment. PMID- 29118235 TI - Truth in Advertising: Do Clinical Trial Publications Tell It All? PMID- 29118237 TI - Weapon damage is associated with contest dynamics but not mating success in fallow deer (Dama dama). AB - Antlers function as primary weapons during fights for many species of ungulate. We examined the association between antler damage and (i) contest dynamics: the behavioural tactics used during fighting including fight duration, and (ii) mating success, fighting rate and dominance. Structural damage of the antlers was associated with contest dynamics: damage was negatively associated with jump clash attacks by individuals with damaged antlers, whereas opponents were more likely to physically displace individuals with damaged antlers during fighting. We found a positive association between dominance and damage indicating that high ranking individuals were likely to have breaks to their antlers. We found no evidence that damage was associated with either mating success or the number of fights individuals engaged in. Our study provides a new perspective on understanding the association between contest dynamics and weapon structure, while also showing that damage has limited fitness consequences for individuals. PMID- 29118238 TI - Correction to 'O brother, where art thou? Investment in siblings for inclusive fitness benefits, not father absence, predicts earlier age at menarche'. PMID- 29118239 TI - A positive genetic correlation between hypoxia tolerance and heat tolerance supports a controversial theory of heat stress. AB - We used quantitative genetics to test a controversial theory of heat stress, in which animals overheat when the demand for oxygen exceeds the supply. This theory, referred to as oxygen- and capacity-limited thermal tolerance, predicts a positive genetic correlation between hypoxia tolerance and heat tolerance. We demonstrate the first genetic correlation of this kind in a model organism, Drosophila melanogaster Genotypes more likely to fly under hypoxic stress (12% O2) were also more likely to fly under heat stress (39 degrees C). This finding prompts new questions about mechanisms and limits of adaptation to heat stress. PMID- 29118240 TI - Birdsong signals individual diversity at the major histocompatibility complex. AB - The major histocompatibility complex (MHC) plays a key role in vertebrate immunity, and pathogen-mediated selection often favours certain allelic combinations. Assessing potential mates' MHC profiles may provide receivers with genetic benefits (identifying MHC-compatible mates and producing optimally diverse offspring) and/or material benefits (identifying optimally diverse mates capable of high parental investment). Oscine songbirds learn songs during early life, such that song repertoire content can reflect population of origin while song complexity can reflect early life condition. Thus birdsong may advertise the singer's genetic dissimilarity to others in the population (and, presumably, compatibility with potential mates), or individual genetic diversity (and thus condition-dependent material benefits). We tested whether song repertoire content and/or complexity signal MHC class IIbeta dissimilarity and/or diversity in male song sparrows (Melospiza melodia). Pairwise dissimilarity in repertoire content did not predict MHC dissimilarity between males, suggesting that locally rare songs do not signal rare MHC profiles. Thus, geographical variation in song may not facilitate MHC-mediated inbreeding or outbreeding. Larger repertoires were associated with intermediate MHC diversity, suggesting intermediate rather than maximal MHC diversity is optimal. This could reflect trade-offs between resisting infection and autoimmune disorders. Song complexity may advertise optimal MHC diversity, a trait affecting disease resistance and capacity for parental care. PMID- 29118241 TI - Temporal shifts in intraguild predation pressure between beluga whales and Greenland halibut in a changing Arctic. AB - Asymmetrical intraguild predation (AIGP), which combines both predation and competition between predator species, is pervasive in nature with relative strengths varying by prey availability. But with species redistributions associated with climate change, the response by endemic predators within an AIGP context to changing biotic-abiotic conditions over time (i.e. seasonal and decadal) has yet to be quantified. Furthermore, little is known on AIGP dynamics in ecosystems undergoing rapid directional change such as the Arctic. Here, we investigate the flexibility of AIGP among two predators in the same trophic guild: beluga (Delphinapterus leucas) and Greenland halibut (Reinhardtius hippoglossoides), by season and over 30 years in Cumberland Sound-a system where forage fish capelin (Mallotus villosus) have recently become more available. Using stable isotopes, we illustrate different predator responses to temporal shifts in forage fish availability. On a seasonal cycle, beluga consumed less Greenland halibut and increased consumption of forage fish during summer, contrasting a constant consumption rate of forage fish by Greenland halibut year round leading to decreased AIGP pressure between predators. Over a decadal scale (1982-2012), annual consumption of forage fish by beluga increased with a concomitant decline in the consumption of Greenland halibut, thereby indicating decreased AIGP pressure between predators in concordance with increased forage fish availability. The long-term changes of AIGP pressure between endemic predators illustrated here highlights climate-driven environmental alterations to interspecific intraguild interactions in the Arctic. PMID- 29118242 TI - The loneliness of the long-distance toad: invasion history and social attraction in cane toads (Rhinella marina). AB - Individuals at the leading edge of a biological invasion constantly encounter novel environments. These pioneers may benefit from increased social attraction, because low population densities reduce competition and risks of pathogen transfer, and increase benefits of information transfer. In standardized trials, cane toads (Rhinella marina) from invasion-front populations approached conspecifics more often, and spent more time close to them, than did conspecifics from high-density, long-colonized populations. PMID- 29118243 TI - Widespread co-occurrence of two distantly related mitochondrial genomes in individuals of the leaf beetle Gonioctena intermedia. AB - Mitochondrial genome heteroplasmy-the presence of more than one genomic variant in individuals-is considered only occasional in animals, and most often involves molecules differing only by a few recent mutations. Thanks to new sequencing technologies, a large number of DNA fragments from a single individual can now be sequenced and visualized separately, allowing new insights into intra-individual mitochondrial genome variation. Here, we report evidence from both (i) massive parallel sequencing (MPS) of genomic extracts and (ii) Sanger sequencing of PCR products, for the widespread co-occurrence of two distantly related (greater than 1% nucleotide divergence, excluding the control region) mitochondrial genomes in individuals of a natural population of the leaf beetle Gonioctena intermedia Sanger sequencing of PCR products using universal primers previously failed to identify heteroplasmy in this population. Its occurrence was detected with MPS data and may have important implications for evolutionary studies. It suggests the need to re-evaluate, using MPS techniques, the proportion of animal species displaying heteroplasmy. PMID- 29118245 TI - Mer Receptor Tyrosine Kinase Signaling Prevents Self-Ligand Sensing and Aberrant Selection in Germinal Centers. AB - Mer tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells (ACs) and inducing immunoregulatory signals. We previously showed that Mer-deficient mice (Mer-/-) have increased germinal center (GC) responses, T cell activation, and AC accumulation within GCs. Accumulated ACs in GCs can undergo necrosis and release self-ligands, which may influence the outcome of a GC response and selection. In this study, we generated Mer-/- mice with a global MyD88, TLR7, or TLR9 deficiency and cell type-specific MyD88 deficiency to study the functional correlation between Mer and TLRs in the development of GC responses and autoimmunity. We found that GC B cell-intrinsic sensing of self RNA, but not self-DNA, released from dead cells accumulated in GCs drives enhanced GC responses in Mer-/- mice. Although self-ligands directly affect GC B cell responses, the loss of Mer in dendritic cells promotes enhanced T cell activation and proinflammatory cytokine production. To study the impact of Mer deficiency on the development of autoimmunity, we generated autoimmune-prone B6.Sle1b mice deficient in Mer (Sle1bMer-/-). We observed accelerated autoimmunity development even under conditions where Sle1bMer-/- mice did not exhibit increased AC accumulation in GCs compared with B6.Sle1b mice, indicating that Mer immunoregulatory signaling in APCs regulates B cell selection and autoimmunity. We further found significant expansion, retention, and class switching of autoreactive B cells in GCs under conditions where ACs accumulated in GCs of Sle1bMer-/- mice. Altogether, both the phagocytic and immunomodulatory functions of Mer regulate GC responses to prevent the development of autoimmunity. PMID- 29118244 TI - Isolation and Characterization of Antigen-Specific Plasmablasts Using a Novel Flow Cytometry-Based Ig Capture Assay. AB - We report the development of a novel flow cytometry-based Ig capture assay (ICA) for the identification and sorting of individual Ab-secreting cells based on their Ag reactivity. The ICA represents a fast and versatile tool for single-cell sorting of peripheral plasmablasts, streamlining subsequent Ab analysis, and cloning. We demonstrate the utility of the assay by isolating Ag-reactive plasmablasts from cryopreserved PBMC obtained from volunteers vaccinated with a recombinant HIV envelope protein. To show the specificity of the ICA, we produced Ag-specific Abs from these cells and subsequently verified their Ag reactivity via ELISA. Furthermore, we used the ICA to track Ag-specific plasmablast responses in HIV-vaccine recipients over a period of 42 d and performed a head-to head comparison with a conventional B cell ELISpot. Results were highly comparable, highlighting that this assay is a viable alternative for monitoring Ag-specific plasmablast responses at early time points after infection or vaccination. The ICA provides important added benefits in that phenotypic information can be obtained from the identified Ag-specific cells that can then be captured for downstream applications such as B cell sequencing and/or Ab cloning. We envisage the ICA as being a useful tool in Ab repertoire analysis for future clinical trials. PMID- 29118246 TI - Serum IgA Immune Complexes Promote Proinflammatory Cytokine Production by Human Macrophages, Monocytes, and Kupffer Cells through FcalphaRI-TLR Cross-Talk. AB - IgA is predominantly recognized to play an important role in host defense at mucosal sites, where it prevents invasion of pathogens by neutralization. Although it has recently become clear that IgA also mediates other immunological processes, little remains known about the potential of IgA to actively contribute to induction of inflammation, particularly in nonmucosal organs and tissues. In this article, we provide evidence that immune complex formation of serum IgA plays an important role in orchestration of inflammation in response to pathogens at various nonmucosal sites by eliciting proinflammatory cytokines by human macrophages, monocytes, and Kupffer cells. We show that opsonization of bacteria with serum IgA induced cross-talk between FcalphaRI and different TLRs, leading to cell type-specific amplification of proinflammatory cytokines, such as TNF alpha, IL-1beta, IL-6, and IL-23. Furthermore, we demonstrate that the increased protein production of cytokines was regulated at the level of gene transcription, which was dependent on activation of kinases Syk and PI3K. Taken together, these data demonstrate that the immunological function of IgA is substantially more extensive than previously considered and suggest that serum IgA-induced inflammation plays an important role in orchestrating host defense by different cell types in nonmucosal tissues, including the liver, skin, and peripheral blood. PMID- 29118247 TI - Regulation of Root Traits for Internal Aeration and Tolerance to Soil Waterlogging-Flooding Stress. PMID- 29118248 TI - A Tonoplast Sugar Transporter Underlies a Sugar Accumulation QTL in Watermelon. AB - How sugar transporters regulate sugar accumulation in fruits is poorly understood and particularly so for species storing high-concentration Suc. Accumulation of soluble sugars in watermelon (Citrullus lanatus) fruit, a major quality trait, had been selected during domestication. Still, the molecular mechanisms controlling this quantitative trait are unknown. We resequenced 96 recombinant inbred lines, derived from crossing sweet and unsweet accessions, to narrow down the size of a previously described sugar content quantitative trait locus, which contains a putative Tonoplast Sugar Transporter gene (ClTST2). Molecular and biochemical analyses indicated that ClTST2 encodes a vacuolar membrane protein, whose expression is associated with tonoplast uptake and accumulation of sugars in watermelon fruit flesh cells. We measured fruit sugar content and resequenced the genomic region surrounding ClTST2 in 400 watermelon accessions and associated the most sugar-related significant single-nucleotide polymorphisms (SNPs) to the ClTST2 promoter. Large-scale population analyses strongly suggest increased expression of ClTST2 as a major molecular event in watermelon domestication associated with a selection sweep around the ClTST2 promoter. Further molecular analyses explored the binding of a sugar-induced transcription factor (SUSIWM1) to a sugar-responsive cis-element within the ClTST2 promoter, which contains the quantitative trait locus (QTL) causal SNP. The functional characterization of ClTST2 and its expression regulation by SUSIWM1 provide novel tools to increase sugar sink potency in watermelon and possibly in other vegetable and fruit crops. PMID- 29118249 TI - Reduction in Root Secondary Growth as a Strategy for Phosphorus Acquisition. AB - We tested the hypothesis that reduced root secondary growth of dicotyledonous species improves phosphorus acquisition. Functional-structural modeling in SimRoot indicates that, in common bean (Phaseolus vulgaris), reduced root secondary growth reduces root metabolic costs, increases root length, improves phosphorus capture, and increases shoot biomass in low-phosphorus soil. Observations from the field and greenhouse confirm that, under phosphorus stress, resource allocation is shifted from secondary to primary root growth, genetic variation exists for this response, and reduced secondary growth improves phosphorus capture from low-phosphorus soil. Under low phosphorus in greenhouse mesocosms, genotypes with reduced secondary growth had 39% smaller root cross sectional area, 60% less root respiration, 27% greater root length, 78% greater shoot phosphorus content, and 68% greater shoot mass than genotypes with advanced secondary growth. In the field under low phosphorus, these genotypes had 43% smaller root cross-sectional area, 32% greater root length, 58% greater shoot phosphorus content, and 80% greater shoot mass than genotypes with advanced secondary growth. Secondary growth eliminated arbuscular mycorrhizal associations as cortical tissue was destroyed. These results support the hypothesis that reduced root secondary growth is an adaptive response to low phosphorus availability and merits investigation as a potential breeding target. PMID- 29118250 TI - Defining the Dental Hygienist's Role in Improving Population Health through Interprofessional Collaboration. PMID- 29118251 TI - Interprofessional Education in Dental Hygiene Programs and CODA Standards: Dental Hygiene Program Directors' Perspectives. AB - Purpose: The Patient Protection and Affordable Care Act changed the paradigm of health care delivery by addressing interprofessional education (IPE) and care (IPC). These considerations, combined with evolving dental hygiene (DH) workforce models, challenge DH educators and clinicians alike to embrace IPE and IPC. The objectives of this study were to determine DH program directors' perceptions of the importance of IPE, to assess current and planned activities related to Commission on Dental Accreditation (CODA) standards that imply competency in IPE, and assessment of outcomes.Methods: Email addresses of the 322 entry-level, DH program directors in the United States were obtained from the American Dental Hygienists' Association and a web-based survey was developed based on the American Dental Education Association Team Study Group on Interprofessional Education. Descriptive statistics were computed for the responses to the closed ended questions and answers to open-ended questions were transcribed and thematically coded.Results: A response rate of 30% (N = 102) was obtained from the DH program directors. While the respondents indicated that they personally considered IPE to be important, one-third reported that IPE was not a priority for their academic institution. The majority of current IPE activities related to the 2014 CODA Standards 2-17, 2-26 and 2-19 were clinic-based (Standards 2-17 and 2-19: N=49; Standard 2-19: N=64). Fewer classroom-based activities were reported (N=12 vs. N=25). The respondents planned 27 clinic-based, 9 classroom-based and 51 other future IPE-related activities. Competency assessment was mostly determined with clinic-based activities (N=43) and other activities such as rubrics (N=16) and the development of IPE assessment tools (N=10). Thirty-three respondents named positive aspects of IPE and 13 saw IPE as relevant for the dental hygiene profession.Conclusion: Accountable accreditation standards have been identified as the driver of change for incorporating IPE, making an explicit IPE standard for dental hygiene education an important agenda item for the profession. PMID- 29118252 TI - Effects of Yoga on Musculoskeletal Pain. AB - Purpose: Musculoskeletal pain has been associated with work stress and a shortened career in the dental hygiene profession. The purpose of this study was to determine if participating in two yoga sessions per week would reduce the musculoskeletal pain reported by dental hygiene students and or impact body composition.Methods: A convenience sample of 77 dental hygiene students self selected into treatment (yoga) and control groups. Students in the yoga group participated in bi-weekly, 60-minute yoga sessions for 13 consecutive weeks. Students completed a questionnaire and a Comparative Pain Scale evaluation prior to and immediately following the study period to assess musculoskeletal pain. Additionally, the Omron HBF-514C Full Body Composition Sensing Monitor and Scale was used to measure body mass index (BMI), body fat, and muscle prior to and upon completion of the study. Paired sample t-tests and independent t-tests were used to analyze the data.Results: Thirty-eight dental hygiene students, with an average age of 23.9 years, participated in the yoga group and 39 were assigned to the control group. The majority of the participants were Caucasian (63.6%) females (90.9%). Participants in both groups were of similar age, ethnicity, and had comparable pre-study Harich Comparative Pain Scale scores. After participating in the yoga sessions, the treatment group reported a significant decrease in musculoskeletal pain (p<0.001), while the control group reported no significant decrease in musculoskeletal pain (p=0.881). The yoga sessions did not significantly impact the BMI scores for the yoga treatment group (p=.984) or the control group (p=.901).Conclusion: This research supports the practice of bi weekly yoga sessions as beneficial in decreasing musculoskeletal pain in dental hygiene students. Yoga can be considered a viable complementary health approach to incorporate into student schedules as a means of increasing the health and longevity of a dental hygiene career. PMID- 29118253 TI - Student Preparation for the National Board Dental Hygiene Examination: A national survey of dental hygiene program directors. AB - Purpose: Dental hygiene students nearing completion of their educational programs are required to take written and clinical examinations in order to be eligible for licensure. The written licensure exam, the National Board Dental Hygiene Examination (NBDHE), is administered by the Joint Commission of National Dental Examinations (JCNDE). Failing a licensing examination is a costly experience for students and has the potential for a negative impact on a program's accreditation status. Nursing programs have published extensively on strategies used to prepare students for licensure examinations. However, there appears to be a gap in the literature as to how dental hygiene programs prepare their students to take the NBDHE. The purpose of this study was to conduct a national survey of U.S. dental hygiene program directors to determine what strategies their programs employ to prepare students to take the NBDHE and to explore the viewpoints of dental hygiene program directors regarding student preparation methods for the NBDHE.Methods: An survey instrument was developed, pilot tested, revised and mailed to directors of the 335 CODA accredited U.S. dental hygiene programs. The survey consisted of a combination of response formats including forced choice, multiple allowable answered, and open-ended written comments.Results: A total of 154 surveys were returned, yielding an overall response rate of 45% (154/341). The vast majority of directors (93%) reported they use specific methods and practices to prepare students for the NBDHE. The top two strategies identified were dental hygiene review texts (84%) and a board review course (83%). The majority of directors (84%) reported supporting student participation in non mandatory, commercial review courses. In regard to mock board exams, directors "agreed/strongly agreed" (75%) that the mock board exam is a useful coaching tool in the overall process of NBDHE preparations. A majority (65%) indicated they were not concerned with failure rates, and 43% reported failure rates do reflect on the program.Conclusion: These results suggest that the majority of dental hygiene programs are utilizing strategies to prepare students for the NBDHE with board review textbooks and board review courses named as the top two strategies. PMID- 29118254 TI - Comparison of two Manual Toothbrushes in Effectiveness of Plaque Removal: A pilot study. AB - Purpose: This pilot study compared the effectiveness of plaque removal of two manual toothbrushes; a novel toothbrush design and a control reference toothbrush.Methods: Thirty-eight individuals meeting specific criteria consented to participate and were randomly assigned to one of two groups. Subjects were given both study toothbrushes eight days prior to data collection to use on alternate days for two minutes twice daily for familiarization. Subjects refrained from any oral hygiene procedures for twenty-four hours prior to data collection at which time a baseline plaque score was recorded using the O'Leary Plaque Control Record. Following the baseline plaque score recording, timed brushing was supervised by a research assistant, using a split mouth design, followed by a post-brushing plaque score. All plaque scores were recorded by the same examiner blinded to group assignment. Pre- and post-brushing scores were compared using t-tests and analysis of variance (ANOVA) to determine differences. Subjects also completed a qualitative survey on the two brushes.Results: When compared to overall plaque scores, no significant differences were shown between the two brushes or when compared to all interproximal surfaces, all smooth surfaces and left vs. right sides. Both brushes performed better on the left side. The control brush was slightly more effective than the novel brush in the mandible (p=0.0222) and on lingual (p=0.0169) surfaces. Results of the survey showed that the subjects significantly favored the novel brush.Conclusion: Both brushes were effective, although the reference brush was slightly more effective in plaque removal than the novel design brush in the mandible and on lingual surfaces; however, the novel brush was preferred by participants. PMID- 29118255 TI - The Effect of Stainless Steel and Silicone Instruments on Hand Comfort and Strength: A pilot study. AB - Purpose: Many dental hygienists experience musculoskeletal pain during the course of their careers, often as a result of the sustained grips on instruments and repetitive movements employed during clinical practice. Current research suggests that lighter instruments with a larger diameter reduce force and load on the hand during scaling procedures; therefore, the texture and weight of silicone handles is designed to decrease the strain placed on the hand and fingers. The purpose of this research is to investigate and compare the effect of silicone instrument handles and traditional stainless steel instrument handles on hand comfort and strength.Methods: This pilot study used a comparative cross-sectional study design. A convenience sample of dental hygiene students (n= 23) participated in two simulated scaling sessions for 30 minutes, one week apart. During the first session, students were required to use traditional stainless steel instruments (10mm diameter and 21-26g weight), while during the second session students used instruments with silicone handles. Students were required to complete a Hand Health Profile and perform hand strength tests following each session. Paired t tests were used to determine significant differences between the grip strength, pinch strength and hand health profiles scores after using stainless steel and silicone instrument handles.Results: The data analyses revealed a statistically significant improvement in grip strength (p<0.02), key pinch strength (p<0.05) and overall hand comfort (p<0.001).Conclusions: This study suggests that the use of silicone instrument handles may improve hand comfort and reduce hand fatigue. These findings should prompt further investigation on ergonomic instrument design. PMID- 29118256 TI - Survey of Knowledge, Beliefs, and Behaviors of Migrant Vietnamese Parents Regarding Young Children's Oral Health. AB - Purpose: The purpose of this study was to investigate the oral health knowledge, beliefs, and behaviors of migrant Vietnamese parents of 1-5 year-olds in San Jose, California.Method: A verbally-administered survey was conducted with a convenience sample of 45 Vietnamese parents recruited at San Jose public libraries. Following preliminary screening, written informed consent was obtained from eligible individuals. A pre-tested, structured 94-item questionnaire was used to collect information regarding parent demographics, and the parent's knowledge, beliefs, and behaviors about children's oral health. Simple descriptive statistics were used to analyze the data.Results: Vietnamese parents acknowledged a number of basic concepts regarding early childhood caries (ECC), such as influences of sugar consumption, oral hygiene, and bottle use. Unlike other groups, they reported some familiarity with the role of bacteria in caries etiology. Oral health knowledge and beliefs, however, were not reflected in parental oral health behaviors such as supervision of children's brushing. Knowledge about the preventive role of fluoride was limited and varied among the population. Parental knowledge and behaviors did not vary by education level or length of residence in US.Conclusion: Vietnamese parents demonstrated reasonably good oral health knowledge, but poor behavioral guidance of their children's oral health, indicating the need for continued parental education emphasizing age appropriate oral care and the preventative role of fluoride. PMID- 29118258 TI - Adha Annual Conference Research Posters. PMID- 29118257 TI - Bone Loss in Furcation-involved Mandibular Molars: A Retrospective Analysis. AB - Purpose: The purpose of this retrospective study was to determine whether teeth with furcation involvement lose significantly more bone in furcation sites over time than interproximal sites of the same tooth.Methods: Existing radiographs were analyzed to compare the rate of bone loss between furcation and interproximal sites of the same tooth. Selection criteria included mandibular molars with furcation involvement and a minimum follow-up of 5 years. Using ImageJ software, anatomical landmarks were located and measured corono apically.Results: Bone level change over time averaged 4.22 % +/- 2.49 for interproximal sites and 4.55% +/- 2.84 for furcation sites. Significant difference in bone loss was noted in furcation sites between compliant (a minimum of one periodontal maintenance appointments per year) and non-compliant (fewer than one periodontal maintenance appointments per year) sub-groups. No other sub group variables were associated with significant bone loss.Conclusion: There were no significant differences in bone loss between furcation sites and interproximal sites of the same tooth. Compliant patients lost significantly less bone in furcation sites than non-compliant patients. Periodontal maintenance therapy may provide more effective debridement for mandibular molars that exhibit radiographic furcation bone loss than previously thought. Clinicians are encouraged to expand and explore a non-surgical approach for maintaining multi rooted teeth with furcation involvement. PMID- 29118259 TI - Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events. AB - Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)-super-affinity peptide derived from placenta growth factor-2 (PlGF 2123-144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123-144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123-144-anti CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123-144-anti-PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123-144-Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade. PMID- 29118261 TI - Erratum for the Research Article: "Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism" by I. Vujkovic-Cvijin, R. M. Dunham, S. Iwai, M. C. Maher, R. G. Albright, M. J. Broadhurst, R. D. Hernandez, M. M. Lederman, Y. Huang, M. Somsouk, S. G. Deeks, P. W. Hunt, S. V. Lynch, J. M. McCune. PMID- 29118260 TI - Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing. AB - Fibroblasts are primary cellular protagonists of wound healing. They also exhibit circadian timekeeping, which imparts an approximately 24-hour rhythm to their biological function. We interrogated the functional consequences of the cell autonomous clockwork in fibroblasts using a proteome-wide screen for rhythmically expressed proteins. We observed temporal coordination of actin regulators that drives cell-intrinsic rhythms in actin dynamics. In consequence, the cellular clock modulates the efficiency of actin-dependent processes such as cell migration and adhesion, which ultimately affect the efficacy of wound healing. Accordingly, skin wounds incurred during a mouse's active phase exhibited increased fibroblast invasion in vivo and ex vivo, as well as in cultured fibroblasts and keratinocytes. Our experimental results correlate with the observation that the time of injury significantly affects healing after burns in humans, with daytime wounds healing ~60% faster than nighttime wounds. We suggest that circadian regulation of the cytoskeleton influences wound-healing efficacy from the cellular to the organismal scale. PMID- 29118263 TI - RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration. AB - Advanced genetic approaches have accelerated the identification of causative genes linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the disease-related proteins encoded by these genes form aggregates in the cellular machineries that regulate RNA and protein quality control in cells. Cross-talk among the signaling pathways governing these machineries leads to pathological cascades mediated by the accumulation of mutant RNA binding proteins. We outline the molecular basis of ALS and FTD pathogenesis and discuss the prospects for therapeutic strategies to treat these diseases. PMID- 29118264 TI - Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH. AB - In response to heart failure (HF), the heart reacts by repressing adult genes and expressing fetal genes, thereby returning to a more fetal-like gene profile. To identify genes involved in this process, we carried out transcriptional analysis on murine hearts at different stages of development and on hearts from adult mice with HF. Our screen identified Oplah, encoding for 5-oxoprolinase, a member of the gamma-glutamyl cycle that functions by scavenging 5-oxoproline. OPLAH depletion occurred as a result of cardiac injury, leading to elevated 5 oxoproline and oxidative stress, whereas OPLAH overexpression improved cardiac function after ischemic injury. In HF patients, we observed elevated plasma 5 oxoproline, which was associated with a worse clinical outcome. Understanding and modulating fetal-like genes in the failing heart may lead to potential diagnostic, prognostic, and therapeutic options in HF. PMID- 29118262 TI - Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with beta-blockers. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mediated by T790M-independent mechanisms remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). We identified a targetable mechanism of EGFR inhibitor resistance whereby stress hormones activate beta2 adrenergic receptors (beta2-ARs) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce interleukin-6 (IL-6) expression. We show that stress and beta2-AR activation promote tumor growth and EGFR inhibitor resistance, which can be abrogated with beta-blockers or IL-6 inhibition. IL-6 was associated with a worse outcome in EGFR TKI-treated NSCLC patients, and beta blocker use was associated with lower IL-6 concentrations and improved benefit from EGFR inhibitors. These findings provide evidence that chronic stress hormones promote EGFR TKI resistance via beta2-AR signaling by an LKB1/CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein)/IL-6 dependent mechanism and suggest that combinations of beta-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance. PMID- 29118265 TI - A Systematic Review of Health-Related Quality of Life Reporting in Ovarian Cancer Phase III Clinical Trials: Room to Improve. AB - BACKGROUND: Epithelial ovarian cancer (OC) remains a significant cause of morbidity and mortality for women worldwide. Patients may experience a multitude of disease- and treatment-related symptoms that can impact quality of life (QOL) and should be measured and reported in clinical trials. This systematic review investigated the adequacy of reporting of QOL in randomized phase III trials in OC in both the first-line and recurrent disease setting. MATERIALS AND METHODS: A systematic review of MEDLINE and EMBASE identified randomized clinical trials of systemic therapy in OC from 1980 to 2014. The adequacy of reporting QOL was evaluated with respect to adherence to established guidelines on reporting QOL in clinical trials and the recent recommendations on the inclusion of patient reported outcomes in clinical trials from the Fifth Ovarian Cancer Consensus Conference. RESULTS: Of 3,247 abstracts, 35 studies, including 24,664 patients, met inclusion criteria. Twenty-two trials (63%) were in the first-line setting, with 13 (37%) in the recurrent setting. The inclusion of QOL assessments increased from 2% (1980s) to 62% (2010+). Quality of life was a co-primary endpoint in only one trial.Minimal clinically important differences in QOL were defined in eight trials (23%), with results included in the abstract in 37% and article in 86%. Compliance was reported in 26 trials (74%), with 13 trials (37%) reporting specifically how they dealt with missing data. Only seven trials reported the reasons for missing data (20%).Group results were published in 29 trials (83%), with 6 (17%) reporting individual patient results. Results were more commonly reported as a mean overall score (21 trials; 60%), with specific domain scores in only 9 trials (26%). No studies reported QOL beyond progression or included predefined context-specific endpoints based on objectives of treatment (i.e., palliation/cure/maintenance) and the patient population. Duration of benefit of palliative chemotherapy was reported in only one study. CONCLUSION: Inclusion and reporting of QOL as a trial endpoint has improved in phase III trials in OC, but there are still significant shortfalls that need to be addressed in future trials. IMPLICATIONS FOR PRACTICE: The impact of treatment on quality of life (QOL) is an important consideration in patients with ovarian cancer for whom treatment is often given with palliative intent. Both the disease and treatment impact a patient's QOL and require careful evaluation in clinical trials. Matching the QOL questions to the patient population of interest is critical. Similar rigor to that used to assess progression-based endpoints is essential to guide clinical decisions. This systematic review demonstrated that although the inclusion and reporting of QOL as a trial endpoint has improved in phase III trials there are still significant shortfalls that need to be addressed in future trials. PMID- 29118266 TI - The Effect of Message Content and Clinical Outcome on Patients' Perception of Physician Compassion: A Randomized Controlled Trial. AB - BACKGROUND: In a previous randomized crossover study, patients perceived a physician delivering a more optimistic message (MO) as more compassionate and professional. However, the impact of the clinical outcome of the patient on patient's perception of physician's level of compassion and professionalism has not been previously studied. Our aim was to determine if the reported clinical outcome modified the patient's perception of physician compassion, professionalism, impression, and preference for physician. MATERIALS AND METHODS: One hundred twenty-eight advanced cancer patients in an outpatient Supportive Care Center were randomized to complete validated questionnaires about patients' perception of physician's level of compassion, professionalism, impression, and preference of physician for themselves and their family after watching scripted videos depicting a physician delivering an MO versus a less optimistic (LO) message followed by a clinical vignette depicting a worse outcome. RESULTS: Median age was 61 years and 55% were female. There was no difference in compassion score after the vignette in the MO and LO groups. However, there were significantly worse overall impression and professionalism scores in both the MO and LO groups after the vignette. In the MO group, preference for the physician for themselves and their family significantly decreased after the vignette. CONCLUSION: Seeing a worse clinical outcome did not change the patients' appraisal of an inappropriately optimistic physician. However, it reduced the overall impression of both physicians that conveyed an MO or an LO message and it also resulted in less likelihood of choosing the MO physician for themselves and their family. IMPLICATIONS FOR PRACTICE: The study found that a patient's perception of a physician's compassion did not change after reading a vignette describing a negative clinical outcome, regardless of whether the physician had given a more or a less optimistic message to the patient. However, the results suggested that patients perceived worse professionalism and overall physician impression scores for both more and less optimistic physicians and lower likelihood to choose the more optimistic physician for themselves and their family. PMID- 29118267 TI - Clinical Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography in the Diagnostic Algorithm of Advanced Entero-Pancreatic Neuroendocrine Neoplasms. AB - BACKGROUND: The role of 18F-fluorodeoxyglucose positron emission tomography (18F FDG PET) in the diagnostic algorithm of entero-pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F-FDG PET to identify patients with more aggressive disease among those with advanced EP NENs. Subjects, Materials, and Methods . Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F-FDG PET and computed tomography scans during a time frame of 1 month, were included. RESULTS: A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F-FDG PET, whereas 18F-FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F-FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F-FDG PET was significantly associated with PD at the time of study entry (p < .0001 at multivariate analysis). Although a higher proportion of 18F FDG PET-positive examinations were observed in patients with higher tumor grade (p = .01), 53.8% of patients with grade 1 neuroendocrine tumors (NETs) had positive 18F-FDG PET, and 37.5% of patients with grade 2 NETs had negative 18F FDG PET. Overall survival was significantly shorter in 18F-FDG PET-positive patients (median: 60 months) in comparison with 18F-FDG PET-negative patients (median not reached; p = .008). CONCLUSION: 18F-FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F-FDG PET is clinically useful. IMPLICATIONS FOR PRACTICE: The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F-fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome. PMID- 29118268 TI - Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies. AB - BACKGROUND: After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. MATERIALS AND METHODS: We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). RESULTS: Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of >=6 azacitidine treatment cycles was significantly predictive of response. CONCLUSION: Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. IMPLICATIONS FOR PRACTICE: Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by anemia. After erythropoiesis stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta-analysis of 233 azacitidine-treated red blood cell (RBC) transfusion-dependent patients with LR MDS (92.3% non-del[5q]) from 7 studies showed 38.9% became RBC transfusion independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non-del(5q) LR-MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR-MDS patients. PMID- 29118269 TI - Genetic architecture and regulatory impact on hepatic microRNA expression linked to immune and metabolic traits. AB - Regulation of microRNA (miRNA) expression contributes to a wide range of target gene expression and phenotypes. The miRNA expression in the liver, the central metabolic organ, was examined in 209 pigs, and integrated with haematological and clinical biomarkers of metabolic and overall health, mRNA-target expression levels and single-nucleotide polymorphism (SNP) genotypes. The expression levels of 426 miRNA species correlated with plasma haematological or biochemical traits (r2 = |0.19-0.45|, false discovery rate < 5%). Pairs of these miRNAs and their predicted target mRNAs showing expressing levels associated with the identical traits were examined to understand how immune and metabolic traits are affected by miRNA-mediated regulatory networks derived by mapping miRNA abundance as an expression quantitative trait. In total, 221 miRNA-expression-QTL correspond to 164 SNPs and 108 miRNAs, including miR-34a, miR-30e, miR-148-3p, miR-204, miR-181 5p, miR-143-5p and let-7 g that also correlate with the biomarkers. Sixty-one SNPs were simultaneously associated with 29 miRNA and 41 mRNA species. The expression levels of 13 out of 29 miRNA were correlated with one of the biochemical or haematological traits. For example, the expression levels of miR 34a were correlated with serum phosphorus and cholesterin levels; miR-204, miR 15a and miR-16b were correlated with triglyceride. For haematological traits, the expression levels of miR-652 and miR-204 were correlated with the mean corpuscular haemoglobin concentration, and the expression of miR-143 was correlated with plateletcrit. Pleiotropic association analyses revealed genetic links between mRNA and miRNA on SSC6 for miR-34a, SSC9 for miR-708 and SSC14 for miR-652. Our analysis of miRNA and mRNA transcript profiles, their correlation with clinically important plasma parameters of hepatic functions as well as information on their genetic regulation provide novel regulatory networks and potential new biomarkers for immune and metabolic traits. PMID- 29118270 TI - Upregulation of PIR gene expression induced by human papillomavirus E6 and E7 in epithelial oral and cervical cells. AB - The hallmark of high-risk human papillomavirus (HR-HPV)-related carcinogenesis is E6 and E7 oncogene overexpression. The aim of this work was to characterize epithelial oral and cervical cancer cells that express HR-HPV E6 and E7 oncoproteins. Transcriptomic assay using DNA microarrays revealed that PIR gene expression was detected in oral cells in an HR-HPV E6/E7-dependent manner. In addition, PIR was overexpressed in HPV-positive SiHa and Ca Ski cells, whereas it was undetectable in HPV-negative C33A cells. The PIR expression was dependent on functional HR-HPV E6 and E7 oncoproteins even though the E7 oncoprotein had higher activity to induce PIR overexpression in comparison with E6. In addition, using an siRNA for PIR silencing in oral cells ectopically expressing HR-HPV E6/E7, there was a significant increase in E-cadherin transcripts and a decrease in Vimentin, Slug, Zeb and Snail transcripts, suggesting that HR-HPV-induced PIR overexpression is involved in epithelial-mesenchymal transition. Furthermore, migration of PIR-silenced cells was significantly decreased. Finally, using inhibitors of some specific pathways, it was found that EGFR/ERK and PI3 K/AKT signalling pathways are important for E7-mediated PIR overexpression. It can be concluded that PIR gene expression is highly dependent on the expression of HR HPV oncoproteins and is important for EMT regulation. PMID- 29118271 TI - Heparin-bound chemokine CXCL8 monomer and dimer are impaired for CXCR1 and CXCR2 activation: implications for gradients and neutrophil trafficking. AB - Chemokine CXCL8 plays a pivotal role in host immune response by recruiting neutrophils to the infection site. CXCL8 exists as monomers and dimers, and mediates recruitment by interacting with glycosaminoglycans (GAGs) and activating CXCR1 and CXCR2 receptors. How CXCL8 monomer and dimer interactions with both receptors and GAGs mediate trafficking is poorly understood. In particular, both haptotactic (mediated by GAG-bound chemokine) and chemotactic (mediated by soluble chemokine) gradients have been implicated, and whether it is the free or the GAG-bound CXCL8 monomer and/or dimer that activates the receptor remains unknown. Using solution NMR spectroscopy, we have now characterized the binding of heparin-bound CXCL8 monomer and dimer to CXCR1 and CXCR2 receptor N-domains. Our data provide compelling evidence that heparin-bound monomers and dimers are unable to bind either of the receptors. Cellular assays also indicate that heparin-bound CXCL8 is impaired for receptor activity. Considering dimer binds GAGs with higher affinity, dimers will exist predominantly in the GAG-bound form and the monomer in the free form. We conclude that GAG interactions determine the levels of free CXCL8, and that it is the free, and not GAG-bound, CXCL8 that activates the receptors and mediates recruitment of blood neutrophils to the infected tissue. PMID- 29118274 TI - The Role of the Dental Hygiene Profession: Reducing the Risk of Obesity, One Sweetened Beverage at a Time. PMID- 29118273 TI - Correction to 'Interactions of the Bacillus subtilis DnaE polymerase with replisomal proteins modulate its activity and fidelity'. PMID- 29118275 TI - A Mid-Level Dental Provider in Oregon: Dental hygienists' perceptions. AB - Purpose: Many states are exploring alternative provider models and examining the role of the dental hygienist to address access to care challenges as the United States continues to face increasing demands for oral healthcare services. The purpose of this study was to assess dental hygienists' opinions in the state of Oregon regarding the current limitations of dental hygienists' scope of practice, perceived need for a mid-level provider in Oregon, and personal interest in becoming a mid-level provider.Methods: In December 2013 a survey was mailed to a sample of 1,231 dental hygienists registered in Oregon representing 30% of the licentiates. All licentiates holding expanded practice permits (EPP) were included in the sample (n=351). The following categories were included in the 32 question survey: scope of practice, mid-level provider, current practice, and demographics.Results: A total of 440 surveys were returned for a response rate of 36%. Of the EPP holders, 51% responded to the survey. Over half of respondents (59%) believe that a mid-level provider is needed in the state. Respondents holding membership in the American Dental Hygienists' Association, as well as EPP holders, were significantly more likely to respond that a mid-level dental provider was needed in the state (p<0.0001). Ninety-one percent (n=400) of respondents agreed or strongly agreed that if a mid-level provider was introduced in Oregon, the new provider should be a registered dental hygienist model. Forty three percent (n=186) of respondents were interested in becoming mid-level providers and 47% (n=203) of respondents believed that the minimum education for a mid-level provider should be a bachelor's degree. The majority, 74% (n=137), of those interested in becoming a mid-level provider indicated a preference in completing their education through online teaching combined with a clinical internship.Conclusion: There is strong support from dental hygienists in Oregon that a need exists for a mid-level dental provider and that this provider model should be dental hygiene based. Individuals interested in developing a curriculum for a mid-level provider should consider including online teaching components with a clinical internship component. PMID- 29118272 TI - Beyond cancer genes: colorectal cancer as robust intrinsic states formed by molecular interactions. AB - Colorectal cancer (CRC) has complex pathological features that defy the linear additive reasoning prevailing in current biomedicine studies. In pursuing a mechanistic understanding behind such complexity, we constructed a core molecular cellular interaction network underlying CRC and investigated its nonlinear dynamical properties. The hypothesis and modelling method has been developed previously and tested in various cancer studies. The network dynamics reveal a landscape of several attractive basins corresponding to both normal intestinal phenotype and robust tumour subtypes, identified by their different molecular signatures. Comparison between the modelling results and gene expression profiles from patients collected at the second affiliated hospital of Zhejiang University is presented as validation. The numerical 'driving' experiment suggests that CRC pathogenesis may depend on pathways involved in gastrointestinal track development and molecules associated with mesenchymal lineage differentiation, such as Stat5, BMP, retinoic acid signalling pathways, Runx and Hox transcription families. We show that the multi-faceted response to immune stimulation and therapies, as well as different carcinogenesis and metastasis routes, can be straightforwardly understood and analysed under such a framework. PMID- 29118276 TI - Factors Associated with the Economic Sustainability of the Registered Dental Hygienist in Alternative Practice. AB - Purpose: The purpose of this study was to investigate key factors associated with the economic sustainability of the Registered Dental Hygienist in Alternative Practice (RDHAP).Methods: An invitation to participate in a 38-question electronic survey was sent via postal mail to 440 RDHAP licentiate addressees obtained through the Dental Hygiene Committee of California (DHCC). Legal restrictions did not allow for obtaining the RDHAP licentiate email addresses from the DHCC. The survey was disseminated via email to the 254 RDHAPs who were members of the California Dental Hygienists' Association. Additional invitations to participate were made via flyer distribution at an RDHAP symposium, and on RDHAP only social media sites.Results: The response rate was an estimated 16%. While 44% of the RDHAPs reported some employment in a traditional dental practice, given the opportunity, 61% of these respondents indicated that they would practice exclusively as an RDHAP. With regard to practice strategic planning and alliances, 31% felt that dentists lacked knowledge of the RDHAP, and 25% indicated dentists were resistant to this workforce model. Regarding RDHAP practice staffing patterns, 75% indicated not having any employees. When asked about business systems, 64% had solo, portable practices and 16% had standalone practices. Economic sustainability challenges included practice business/equipment expenses (29%), insurance/reimbursement issues (21%), patient flow (19%) and RDHAP visibility (14%).Conclusions: RDHAP practices face challenges including the need for strategic planning and intra- and inter professional alliances, efficient and effective patient flow, optimal staffing patterns and effective business systems. Focus on enhancing RDHAP visibility within the dental and medical communities should be a priority. In addition, further research should explore RDHAPs aligning with community-based clinics, Federally Qualified Health Centers and Dental Support Organizations (DSOs) with a commitment to disease prevention in addition to the financial resources and staff to manage practice business systems. PMID- 29118277 TI - Impact of State Workforce Policies on Underserved Patients' Access to Dental Care: A longitudinal study. AB - Purpose: Dental diseases are almost entirely preventable, but discrepancies in access to oral healthcare limit the effectiveness of preventive interventions. Dental hygienists are strategically positioned to improve access to preventive dental procedures; however, state workforce policies determine their permitted clinical tasks.Methods: This study cross-referenced oral healthcare service use at Federally Qualified Health Centers (FQHCs) between 2004 and 2012 with the Dental Hygiene Professional Practice Index (DHPPI), which quantifies the various aspects of state policy environments for the dental hygiene workforce. More specifically, the study used generalized linear mixed-effects models to examine the influence of state policy environment on access to dental care at 958 FQHC grantees.Results: States with "favorable" policy environments consistently reported the highest proportion of FQHC patients accessing dental care services (18%), whereas states with "restrictive" environments reported the lowest proportion (12%).Conclusion: A smaller proportion of FQHC patients' receive dental examinations in states with restrictive state workforce policies; state lawmakers should frame workforce policies to protect public safety without limiting the oral health workforce's ability to provide important oral health services to underserved people. PMID- 29118278 TI - Oral Health Status of Independent Older Adults in Texas: An observational study comparing urban and rural areas. AB - Purpose: The purpose of this study was to assess the oral health needs of community-dwelling older adults participating in congregate meal centers and to determine whether differences exist in the oral health needs of older adult populations residing in urban versus rural communities in the state of Texas.Methods: Study participants were recruited at 6 congregate meal centers located in identified rural and urban communities in the greater metropolitan area of Austin, Texas. (N=78) Participants completed a validated, modified questionnaire containing 20 items on the following topics: self-reported oral health, tooth loss, dental insurance, frequency of dental visits, time since last dental visit, access to dental care, dry mouth, and oral cancer screening. Each participant received an oral health screening based on the Association of State and Territorial Dental Directors Basic Screening Survey for Older Adults. The examiners received hands-on training prior to the study to ensure the validity of their findings and to test for inter-examiner reliability.The chi-square test of independence was performed to analyze the participants' responses on the Basic Screening Survey to identify any relationships between the variables.Results: There were no significant differences in oral health conditions of older adults residing in urban versus rural communities. Over 50% of the participants (64.9% urban; 56.1% rural) reported incomes below $15,000 and lacked dental insurance to cover all or a portion of their oral health care needs. Eighty-seven percent of the participants reported tooth loss due to dental caries, 35% required periodontal care, and 37% reported occasional and 43% reported frequent oral pain over the last 12 months.Conclusions: Oral health promotion and disease prevention is an emergent need for older adult populations residing in urban and rural communities of the state of Texas. Analysis revealed that the majority of the older adult populations in both settings to have financial and socioeconomic barriers to access preventative and restorative dental care services. PMID- 29118279 TI - Measuring the Impact of Cultural Competence Training for Dental Hygiene Students. AB - Purpose: The purpose of this study was to measure the change in levels of knowledge of providing culturally competent care and self-assessed cultural competence of senior level dental hygiene students after the implementation of an online cultural competence training module.Methods: Twenty-eight members of the senior class of 31 dental hygiene students (N=28) volunteered to participate in this IRB approved study at the Ohio State University School of Dentistry. The students took the online Inventory for Assessing the Process of Cultural Competence- Student Version (IAPCC-SV), to assess their self-perceived cultural competence. Upon completion of the pre-test, students then completed the United States Department of Health and Human Services (HHS) Office of Minority Health (OMH) Cultural Competency Program for Oral Health Professionals; a three-module online training program designed to measure increased knowledge of cultural competence. Three weeks following the initial pre-test and upon completion of the Cultural Competency Program for Oral Health Professionals online learning modules, students re-took the IAPCC-SV.Results: Twenty-eight senior dental hygiene students completed the IAPCC-SV pre-test, the OMH e-learning modules and the IAPCC-SV post-test. The average score on the pre-test was 55.14+/-7.54 and the average score on the post-test was 61.33+/-7.86. There was a significant difference in pre-test and post-test scores (p<0.001). There were also significant differences in the constructs of knowledge of cultural competence (p<0.001) and skill (p<0.001).Conclusion: The HHS OMH Cultural Competency Program for Oral Health Professionals was effective for increasing dental hygiene students' levels of knowledge of cultural competence. PMID- 29118280 TI - Association Between Social Anxiety with Oral Hygiene Status and Tongue Coating among Patients with Subjective Halitosis. AB - Purpose: Halitosis is a universal affliction suffered by many individuals irrespective of age, sex and social status. Concern about oral malodor can significantly impede an individual's personal, professional and public life which can lead to the development of social anxiety. The present study was undertaken to assess the association between social anxiety with oral hygiene status and tongue coating among patients with subjective halitosis.Methods: A total of 321(n=321) subjects were self-recruited to participate in this IRB approved study. A 24- item Liebowitz Social Anxiety Scale, Self-Report version (LSAS-SR) was distributed and completed by the participants; followed by oral examination using Simpified Oral Hygiene Index and Tongue Coating Record (TCR). ANOVA, t-test and Mann Whitney U test was used for comparison among variables. Correlation was performed using Karl Pearson's correlation coefficient method. The level of significance was set as p<0.05.Results: The total LSAS for the study population of 321 was 61.41+/-24.09; with females having significantly higher scores (64.64+/-24.95; p=0.01*). Comparison of clinical oral parameters between the genders revealed that poor oral hygiene (2.45+/-1.06) with a higher tongue coating score (71.38+/-18.24) was observed among male participants. However, these scores were statistically insignificant. A significant correlation between total LSAS, majority of its subscales and the oral parameters among females and subjects with high school education was also reported.Conclusion: This study revealed that social anxiety, poor oral hygiene and tongue coating were associated with subjective halitosis. Hence, maintenance of good oral health along with the use of appropriate tongue cleaning methods is of critical importance in reducing oral malodor. In some cases, comprehensive treatment of halitosis may require a multidisciplinary approach including dental, psychology and counselling professionals. PMID- 29118281 TI - A Comparison of Efficiency and Material Wear of Diamond-Plated versus Ceramic Sharpening Stones. AB - Purpose: The purpose of this study was to compare sharpening efficiency and metal (carbon steel) removal from scalers using two types of synthetic sharpening stones: ceramic and diamond-plated. Previous research used scanning electron microscopy alone to measure instrument sharpness. Additionally, no research has been reported on the use of diamond-plated sharpening stones.Methods: Fifteen threaded, double-ended H6/H7 scalers were randomly divided into three groups of ten: control, ceramic stone, and diamond-plated stone. All cutting edges were dulled by scaling the surfaces of extracted molars. The cutting edges were then sharpened by a blinded examiner with the assigned stone until optimal sharpness was achieved using a test stick between sharpening strokes. The number of strokes needed to reach sharpness for each cutting edge was recorded. Four hundred sharpening strokes were then applied on each end using the assigned stone. The scaler ends were weighed before and after sharpening to determine amount of material loss in milligrams. Statistical analysis was performed using ANOVA followed by a Tukey-Kramer post-hoc test.Results: The diamond-plated sharpening stone removed significantly more metal (7.62 mg +/-0.38) than the ceramic stone (0.69 mg +/-0.06) (p<0.001), while there was no significant difference between the ceramic sharpening stone and the control. There was no significant difference between diamond-plated and ceramic stones in the number of strokes needed to sharpen scalers.Conclusion: While a similar number of strokes was needed to sharpen scalers with the diamond-plated or ceramic stone, the diamond-plated stone removed nearly 7 mg more metal than the ceramic stone using a standardized number of sharpening strokes, suggesting greater scaler longevity when using a ceramic sharpening stone. PMID- 29118282 TI - The Role of Bile Acids in Glucose Metabolism and Their Relation with Diabetes. AB - Bile acids (BAs), the end products of cholesterol catabolism, are essential for the absorption of lipids and fat-soluble vitamins; but they have also emerged as novel signaling molecules that act as metabolic regulators. It has been well described that the enterohepatic circulation, a nuclear (FXR) and a cytoplasmic (TGR5/M-BAR) receptor aid in controlling hepatic bile acid synthesis. Modulating bile acid synthesis greatly impacts in metabolism, because these receptors also are implicated in glucose, lipid, and energy expenditure. Recent studies had revealed the way these receptors participate in regulating gluconeogenesis, peripheral insulin sensitivity, glycogen synthesis, glucagon like peptide 1 (GLP 1) and insulin secretion. Nowadays, it is demonstrated that enhancing bile acid signaling in the intestine contributes to the metabolic benefits of bile acid sequestrants and bariatric surgery on glucose homeostasis. This paper discusses the role of bile acid as regulators of glucose metabolism and their potential as therapeutic targets for diabetes. PMID- 29118283 TI - [Maturation-related phenotypic changes in the adult hippocampal neurons by electrocovulsive treatment]. PMID- 29118284 TI - [An in vitro model system for studying the stress-induced memory disorder]. PMID- 29118285 TI - [Memantine improves cognitive function via KATP channel inhibition]. PMID- 29118286 TI - [Effects of reactive oxygen species on synaptic plasticity in CNS in relation to aging]. PMID- 29118287 TI - [Mouse model of febrile seizures]. PMID- 29118288 TI - [Research and development of therapy for advanced heart failure by utilizing pluripotent stem cell-derived cardiomyocytes]. PMID- 29118289 TI - [Pharmacological properties and clinical findings of new drugs for the treatment of HIV-1, FTC/TAF 200/10 and 200/25 mg (Descovy(r) Combination Tablet LT and HT)]. PMID- 29118290 TI - [Neural circuits regulating stress resilience]. PMID- 29118291 TI - [Outcomes of Pharmaceutical Faculty-focused Introduction to Nursing Education for Pharmacy Students: A Questionnaire Survey]. AB - The scope of pharmaceutical education in Japan has been expanding, and with it an awareness of the importance of team medical care. However, pharmaceutical education still gives little attention to the psychosocial aspects of care, instead focusing on the structures and functions of drugs. In contrast, nursing education emphasizes the fact that medical care involves patients' family and significant others as much as the patients themselves, and thus nursing students are taught the basic needs and developmental stages of those people requiring care alongside their practical nursing skills. In this study, we examined the effect of incorporating certain aspects of introductory nursing education into pharmaceutical education on the self-efficacy of pharmaceutical students. We thus ran an introduction to nursing education course for fourth-year pharmaceutical students (n=86). After the course had finished, we surveyed students about the course. Approximately 94.2% of the students became more interested in team medical care and nearly all (98.8%) thought that what they had learned in the course would be useful in their career. The results indicated that the introduction to nursing education course offered students an opportunity to acquire different viewpoints on clinical situations because the lectures were given by a pharmacist with a nurse license and they were based on his clinical experiences. We therefore propose that more facets of introductory nursing education be incorporated into pharmaceutical education to help students develop their ability to consider patients' psychosocial backgrounds. PMID- 29118292 TI - [Impact of frailty and metabolic syndrome on the incidence of loss of independence in community-dwelling older Japanese: the Kusatsu-town study]. AB - Objectives To investigate the relationship between frailty, metabolic syndrome (MetS), and loss of independence leading to the onset of disability or death among community-dwelling older Japanese.Methods Between 2002 and 2011, we conducted a 7-year prospective study involving 1,453 residents aged 65 years and over, initially free of disability, who underwent a comprehensive geriatric assessment in Kusatsu town. Statistical analysis was conducted for those with complete values, resulting in a variable number of subjects for each data point. Frailty was defined for 1,335 subjects as three or more of the following criteria: weight loss (>2-3 kg in the past six months), weakness (grip strength was <26 kg for men and <18 kg for women), exhaustion (answer of "no" to the question "Do you feel full of energy?" on the Geriatric Depression Scale), slowness (usual gait speed<1.0 m/s), and low physical activity (answer of "less than once a week" to the question "How often do you usually go outdoors?"). MetS was defined for 1,450 subjects from the Japanese definition. The Cox proportional hazard regression model was used to estimate hazard ratio (HR) of loss of independence for 1,217 subjects.Results During the follow-up, 494 cases of loss of independence, including 376 disabilities and 118 deaths were identified. In men and women, the incidence of the loss of independence showed a significant linear trend according to the severity classification of frailty. By contrast, there was no relationship between MetS and the loss of independence. Subjects classified as prefrail and frail had an increased risk of loss of independence compared with robust participants, with sex- and age-adjusted HRs (95% CIs) of 1.5 (1.2-1.9) and 2.4 (1.8-3.3), respectively. After adjusting for sex, age, the presence of MetS, low serum total cholesterol, chronic kidney disease, anemia, low serum albumin, cognitive impairment, and past history of stroke, the respective multivariable HRs (95% CIs) of loss of independence were 1.5 (1.2-1.9) and 2.1 (1.5-2.9). The magnitude of the risk of loss of independence incidence for frailty was greater among the subjects aged 65-74 years than those aged >=75 years.Conclusions Frailty was significantly associated with incident loss of independence among elderly Japanese. The presence of MetS had no effect on subsequent onset of disability and mortality in elderly Japanese. Our findings suggest screening and intervention for frailty in the early stage of aging are beneficial to prolong healthy life expectancy of elderly Japanese. PMID- 29118293 TI - [Structure and characteristics of technical support that psychiatric social workers of prefectural governments provide for municipalities]. AB - Objectives The support to municipalities by prefectural governments has become necessary in the fields of mental health and welfare. Therefore, psychiatric social workers (PSW) ordered from the prefectural governor has been providing technical support (TS) that promote community activities of the municipality and improve staff support for persons with mental disabilities. The purpose of this study was to identify empirical structure and characteristics of TS that PSW provide for municipality staff.Method Semi-structured interviews were conducted with seven certified PSW randomly selected from the membership list of the National Psychiatric Social Worker Organization. Inclusion criteria required participants to have more than 10 years of experience at the prefectural government and experience providing TS in the last five years. Interviews focused on two situations: a casework and a project related to mental health. Interview data were analyzed using a qualitative content method, setting a framework for the consultation process.Results The analysis included five categories < > and 15 subcategories [ ], which consisted of 37 concepts. In category with municipalities consisted of [complementary relationship] and [partnership]. The category included two subcategories, [analyze/judgment from the conditions spread in front of] and [analyze/judgment be the accumulated skills and knowledge in person]. In category , six policies were considered as important, including [problem solving and promoting action], [fostering person centered care perspective], [promoting the understanding of residents], [provide psychological support to the staff], [clarify responsibility as the municipal officials], and [coordinate to improve the environment]. Category consisted of both [support indirectly] and [support cooperatively]. The last category, included three subcategories, [lead to the maintenance and improvement of the system], [have the staff pleasure/contribute to the community], and [consider whether it can be applied to other regions]. The results showed that the characteristics of TS had a consultation function, and the support function utilized complementarity and collaboration between prefecture and municipality providing services to residents.Conclusion This study has clarified the characteristics of TS, which have not been clarified in previous research. We should accumulate the knowledge and establish a method for spreading through various regions. PMID- 29118294 TI - [Changes in the average interval since last visit and the number of repeat outpatients in the Patient Survey of Japan]. AB - Objectives The Patient Survey provides basic information on disease and injury statistics of patients in Japan, and an estimation of the number of patients by disease and injury can be made using this survey. In this survey, the number of outpatients with repeat visits affects the survey results. The average interval since last visit (AILV) and a correction factor are used to estimate the number of repeat outpatients. Patients with AILV > 30 days are not included in the survey. However, in the last years, AILV exceeded 30 days in many cases, suggesting that the current 30-day threshold is no longer suitable. Thus, this study investigated the AILV in the current patient population and the effect of the increase in AILV on the number of repeat outpatients.Methods Patients Survey data of 1996-2011 were used to estimate the effect of changing the AILV threshold on the number of repeat outpatients.Results AILV increased for patients with most diseases and injuries. Using the current 30-day threshold, the overall outpatient coverage rate decreased from 91% in 1996 to 78% in 2011. A higher AILV threshold was necessary to maintain the overall outpatient coverage rate. For example, a threshold of 90 days increased the coverage rate in 2011 to 96%. However, raising the threshold markedly increased the number of repeat outpatients. For example, the overall number of repeat outpatients in 2011 increased from 43.01 million with the current 30-day threshold to 71.03 million using the 90-day threshold. The peak of the AILV of outpatients was observed on the next day after the first visit and the peak of the AILV of outpatients was observed every other week.Conclusion AILV increased over time and changing the AILV threshold markedly increased the number of repeat outpatients and total patients, indicating that there is a need to raise the AILV threshold. PMID- 29118295 TI - [Self-evaluation and worries of regional inclusive elderly-support centers and expected roles of prefectures]. PMID- 29118296 TI - Mismatch between fetal sexing and birth phenotype: a case of complete androgen insensitivity syndrome. AB - With advancing maternal age, the number of prenatal genetic tests is increasing in many countries. Prenatal genetic tests, such as amniocentesis, chorionic villus sampling and non-invasive prenatal testing, can disclose fetal chromosomal sex, although these tests were originally designed to prenatally diagnose chromosomal aneuploidies, such as trisomy 21, 18 and 13. Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder caused by an androgen receptor dysfunction leading to hormone resistance. The affected individuals are genetic males as shown by 46,XY but present complete female external genitalia and normal breast development at puberty albeit without menstruation. CAIS is commonly diagnosed in adolescence based on primary amenorrhea or in childhood based on inguinal hernia or testis-like masses in the inguinal region. In the present report, we describe a baby in whom CAIS was diagnosed immediately after birth based on a mismatch between the fetal karyotype detected by amniocentesis and the external genitalia phenotype at birth. We speculate that the increase in the number of prenatal genetic tests is contributing to the early detection of 46,XY disorders of sex development, especially those previously called complete sex reversal, which is supposedly diagnosed during childhood or adolescence. Hence, it is necessary to understand the disease-specific hormone profile at each developmental stage for accurate diagnosis. PMID- 29118297 TI - Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a DTNA Mutation. AB - DTNA encoding dystrobrevin-alpha (alpha-DB) is a putative causal gene associated with left ventricular noncompaction cardiomyopathy (LVNC). The aim of the study was to investigate the causal role of DTNA in LVNC using a transgenic mouse model.A missense mutation (c.146A > G, p.N49S) of DTNA was identified in a patient with LVNC by Sanger sequencing. Six independent lines of transgenic mice expressing the mutant DTNA under a myosin heavy chain 6 (Myh6) promoter were generated (Myh6:DtnaN49S). Phenotypic characteristics of DTNA-p.N49S mutations were evaluated by echocardiography, histological observation, and immunoblotting. Multiple trabeculation and a higher ratio of non-compacted to compact myocardial layer were found in the Myh6:DtnaN49S mice compared to the controls. The transgenic mice also showed left ventricular (LV) dilation and cardiac systolic dysfunction. In conclusion, overexpression of the DTNA-p.N49S mutation in a mouse heart can be responsible for the phenotype of deep trabeculation, dilated cardiomyopathy, and cardiac dysfunction, which resembles the phenotype of LVNC. PMID- 29118298 TI - More than 50 Years after Konno's Development of the Endomyocardial Biopsy. AB - The endomyocardial biopsy (EMB) method was first developed by Japan's Dr. Souji Konno in 1962. Since then, this technique has been used worldwide in clinical cardiology for the recognition and diagnosis of cardiomyopathies, arrhythmias, and other heart conditions. Many studies relating to the EMB have been published at the global level, including a large review by Cooper, et al.,1) wherein a limited selection of Japanese papers were cited despite considerable pioneering work on the EMB having been done in Japan. Following this, the Cardiac Biopsy Conference (CABIC) organization, which was founded in Japan in 1979, conducted a nationwide survey of the English language literature on the EMB. Among the collection of 500 studies compiled, approximately 40 abstracts have been selected by the co-editors in CABIC for further discussion. This report aims to supplement Cooper's work and bring to light other prominent contributions of Japanese researchers on the EMB. PMID- 29118299 TI - The Effect of Cilostazol on the Angiographic Outcome of Drug-Eluting Coronary Stents Angiographic Analysis of the CILON-T (Influence of CILostazol-Based Triple Antiplatelet Therapy ON Ischemi Complication after Drug-Eluting StenT Implantation) Trial. AB - It is not clear if anti-restonotic effect of cilostazol is consistent for different types of drug-eluting stents (DES).The purpose of this study was to compare the anti-proliferative effect of cilostazol between DAT and TAT with consideration of confounding influences of DES type.Nine hundred and fifteen patients were randomized to either dual antiplatelet therapy (DAT; aspirin and clopidogrel) or triple antiplatelet therapy (TAT; aspirin, clopidogrel, and cilostazol) in the previous CILON-T trial. After excluding 70 patients who received both or neither stents, we analyzed 845 patients who received exclusively PES or ZES, and compared in-stent late loss at 6 months between both antiplatelet regimens (DAT versus TAT).Baseline angiographic and clinical characteristics were similar between the DAT (656 lesions in 425 patients) and the TAT group (600 lesions in 420 patients). The 6-month follow-up angiography was completed in 745 patients (88.2%). Quantitative coronary angiography showed that TAT significantly reduced in-stent late loss (DAT 0.62 +/- 0.62 mm versus TAT 0.54 +/- 0.49 mm, P = 0.015). Stent type, diabetes or lesion length did not interact with difference of late loss. However, reduction of late loss by cilostazol did not lead to a significant reduction in the rate of target lesion revascularization (TLR) (DAT 7.8% versus TAT 6.9%, P = 0.69) due to a nonlinear relationship found between late loss and TLR.The TAT group showed less in-stent late loss as compared to the DAT group. This was consistently observed regardless of DES type, lesion length, or diabetic status. However, reduction of late loss by cilostazol did not lead to a significant reduction in TLR. PMID- 29118300 TI - Improvement of Left Ventricular Ejection Fraction by Baroreflex Activation Therapy in a Young Man with Dilated Cardiomyopathy. AB - The progression of heart failure with reduced ejection fraction is promoted by sympathovagal imbalance. Baroreflex activation therapy (BAT) by the electrical stimulation of baroreceptors at the carotid sinus significantly improved exercise capacity and NT-proBNP levels in a randomized trial; however, no significant difference in left ventricular ejection fraction (LV-EF) between groups was found. Here, we report the case of a 30-year-old man with a long history of dilated cardiomyopathy and severely reduced LV-EF despite optimal medical therapy, who was treated with BAT since October 2014 and showed a remarkable improvement in both symptoms and LV-EF under this treatment. PMID- 29118301 TI - Two-Incision Totally Thoracoscopic Approach for Mitral Valve Replacement. AB - Totally thoracosopic mitral valve replacement (MVR) has been applied to mitral stenosis for many years. Three working ports are usually necessary, among which the longest port ranges from 6 to 8 cm. This study aimed to determine the safety and feasibility of the two-incision totally thoracoscopic approach for MVR, with the longest incision of 3 cm.From January 2014 to February 2016, 90 patients with mitral valve stenosis were retrospectively analyzed. Thirty-six (40%) patients were included in the two-incision group and 54 patients were operated on using the sternotomy approach. Perioperative variables and postoperative 3-month follow up data were analyzed.All patients underwent MVR. Tricuspid valvuloplasty was performed in 23 (25.5%) patients with the Kay technique. The mean total surgery time, cardiopulmonary bypass, and cross-clamp times were longer in the two incision group (266 +/- 42 versus 200 +/- 38 minutes; 156 +/- 23 versus 121 +/- 21 minutes; 100 +/- 17 versus 80 +/- 17 minutes, respectively) (P < 0.05). The mean postoperative mechanical ventilation time was shorter in the two-incision group (8.6 +/- 2.5 versus 11.2 +/- 2.6 hours, respectively) (P < 0.05). The mean volume of blood drainage was less in the two-incision group (497 +/- 120 versus 730 +/- 198 mL, respectively) (P < 0.05). Reopening occurred in one (sternotomy group, 1.8%) patient. No deaths, perivalvular leakage, infectious endocarditis, atelectasis of the lungs, or moderate tricuspid regurgitation were found at the 3 month follow-up.The two-incision totally thoracoscopic approach for MVR is safe and feasible. Concomitant tricuspid valvuloplasty can be conveniently performed. However, further clinical data are needed in future studies. PMID- 29118302 TI - Impact of the Relationship between the Defibrillation Threshold (DFT) and Clinical Outcomes in Recipients of Modern Era Implantable Cardioverter Defibrillator (ICD). AB - Defibrillation threshold (DFT) testing during implantable cardioverter defibrillator (ICD) implantations is considered necessary for appropriate shock therapy and to measure the safety margin. However, the relationship between the DFT with modern era devices and the clinical outcome, including the total mortality is limited, which may lead to DFT testing itself being questioned. This study aimed to evaluate the relationship between the DFT and clinical outcome in ICD recipients.We enrolled 81 consecutive patients (66 males, aged 64.6 +/- 13.8 years) who received an ICD implantation and underwent DFT testing. The DFT was measured with a step-by-step method in the patients upon implant. Further, we evaluated the relationship between the DFT and the clinical outcome, which included major cardiac adverse events and any cause of death.The mean DFT was 11.6 +/- 9.24J in total. In 40 patients (49.4%), VF was terminated by a low output (5J), whereas 11 patients (13.6%) had a high DFT. The rates of atrial fibrillation were significantly higher in the high DFT group (63.6% versus 24.2%, P = 0.007). During the observational period (median 432 days; range from 151 days to 1146 days), the incidence of clinical events occurred in 22 patients (27.2%) in total. In a multivariate analysis, a high DFT was the only predictive factor for the incidence of the clinical outcome (OR 4.54, 95% CI 1.03-21.9, P = 0.045). PMID- 29118303 TI - Primary Left Atrial Osteosarcoma. AB - Primary cardiac osteosarcomas are rare entities, mostly arising from the left atrium. Because of their rarity, few reports have described this uncommon lesion. We herein report a case of primary cardiac osteosarcoma originating from the left atrium in a 34-year-old woman, who underwent tumor debulking surgery and died 3 months after being diagnosed. PMID- 29118304 TI - Pediatric Optic Pathway/Hypothalamic Glioma. AB - Optic pathway/hypothalamic gliomas (OP/HGs) are rare astrocytic tumors that appear more commonly among young children and often are unresectable. They comprise approximately 2% of all central nervous system tumors and account for 3 5% of pediatric intracranial tumors. Initial manifestations are often visual disturbances, endocrinopathies and hypothalamic dysfunction such as the diencephalic syndrome, and sometimes hydrocephalus due to cerebrospinal fluid (CSF) outflow obstruction. In many cases, the tumors are diagnosed late in the clinical course because they silently enlarge. These tumors consist mostly of histologically benign, World Health Organization (WHO) grade I tumors represented by pilocytic astrocytomas (PA), the rest being pilomyxoid astrocytomas (PXA) - WHO grade II tumors. In young pediatric patients, however, can be seen PXA that show aggressive clinical course such as CSF dissemination. Our small series of 14 non-Neurofibromatosis type 1 (NF-1) OP/HGs PA patients underwent extended resection without any adjuvant treatments. The median age at initial treatment was 11.5 +/- 6.90 years (range, 1-25 years) and median follow up 85.5 +/- 25.0 months. Surgical resection for OP/HGs results in acceptable middle-term survival, tumor control and functional outcome equivalent to chemotherapy. There is, however, no longer doubt that chemotherapy with or without biopsy and as-needed debulking surgery remains the golden standard in management of OP/H. Clinical conditions and treatment plans for OP/HGs vary depending on their structure of origin. PMID- 29118305 TI - Association of Age at Menarche With Left Ventricular Diastolic Dysfunction in Middle-Aged Women. AB - BACKGROUND: There is sparse research on whether if early menarche is related to left ventricular (LV) diastolic dysfunction. The present study examined this relationship in Korean women.Methods and Results:In a cross-sectional study we analyzed the records of 18,910 Korean women (>=30 years) who underwent echocardiography as part of a comprehensive health examination. Age at menarche was assessed using standardized, self-administered questionnaires. Presence of LV diastolic dysfunction was determined from the echocardiographic findings. Of the 18,910 women, 3,449 had LV diastolic dysfunction. Age at menarche was inversely associated with prevalence of LV diastolic dysfunction. In a multivariable adjusted model, odds ratios (95% confidence interval) for LV diastolic dysfunction comparing menarche age to menarche at 15-18 years were 1.77 (1.38 2.27) for <12 years, 1.31 (1.11-1.54) for 12 years, 1.26 (1.11-1.43) for 13 years, and 1.03 (0.91-1.15) for 14 years (P for trend <0.001). Adjusting for body mass index or percent fat mass partially reduced these associations. CONCLUSIONS: This large study found an inverse relationship between menarche age and LV diastolic dysfunction. Future prospective studies are needed to investigate potential causal relationships. PMID- 29118306 TI - Quantitation Error in 1H MRS Caused by B1 Inhomogeneity and Chemical Shift Displacement. AB - PURPOSE: The quantitation accuracy in proton magnetic resonance spectroscopy (1H MRS) improves at higher B0 field. However, a larger chemical shift displacement (CSD) and stronger B1 inhomogeneity exist. In this work, we evaluate the quantitation accuracy for the spectra of metabolite mixtures in phantom experiments at 4.7T. We demonstrate a position-dependent error in quantitation and propose a correction method by measuring water signals. MATERIALS AND METHODS: All experiments were conducted on a whole-body 4.7T MR system with a quadrature volume coil for transmission and reception. We arranged three bottles filled with metabolite solutions of N-acetyl aspartate (NAA) and creatine (Cr) in a vertical row inside a cylindrical phantom filled with water. Peak areas of three singlets of NAA and Cr were measured on three 1H spectra at three volume of interests (VOIs) inside three bottles. We also measured a series of water spectra with a shifted carrier frequency and measured a reception sensitivity map. RESULTS: The ratios of NAA and Cr at 3.92 ppm to Cr at 3.01 ppm differed amongst the three VOIs in peak area, which leads to a position-dependent error. The nature of slope depicting the relationship between peak areas and the shifted values of frequency was like that between the reception sensitivities and displacement at every VOI. CONCLUSION: CSD and inhomogeneity of reception sensitivity cause amplitude modulation along the direction of chemical shift on the spectra, resulting in a quantitation error. This error may be more significant at higher B0 field where CSD and B1 inhomogeneity are more severe. This error may also occur in reception using a surface coil having inhomogeneous B1. Since this type of error is around a few percent, the data should be analyzed with greater attention while discussing small differences in the studies of 1H MRS. PMID- 29118308 TI - Synthesis, Molecular Docking and Biological Evaluation of Quinolone Derivatives as Novel Anticancer Agents. AB - A series of novel quinolone derivatives (8a-j) were synthesized, and their anticancer activities were tested in human cancer cell lines, human lung carcinoma cell (A549), human promyelocytic leukemia cell (HL-60), and human cervical cancer cell (Hela). Compound 8i was found to be 5-times more potent in cell-killing activity for cell lines A549, HL-60, and Hela than the positive control irinotecan or cisplatin, with IC50 of 0.009, 0.008 and 0.010 uM, respectively. The docking study revealed that compound 8i might have strong interactions with the active site of DNA-topoisomerase I. PMID- 29118307 TI - Prevention of Pulmonary Edema after Minimally Invasive Cardiac Surgery with Mini Thoracotomy Using Neutrophil Elastase Inhibitor. AB - PURPOSE: Unilateral re-expansion pulmonary edema (RPE) is a rare but one of the most critical complications that may occur after re-expansion of a collapsed lung after minimally invasive cardiac surgery (MICS) with mini-thoracotomy. METHODS: We performed a total of 40 consecutive patients with MICS by right mini thoracotomy with single-lung ventilation between January 2013 and June 2016. We divided the patients into control group (n = 13) and neutrophil elastase inhibitor group (n = 27). Neutrophil elastase inhibitor group received continuous intravenous infusion of neutrophil elastase inhibitor at 0.2-0.25 mg/kg per hour from the start of anesthesia until extubation during the perioperative period. RESULTS: There were no relations with operative time, cardiopulmonary bypass (CPB) time, aortic clamp time, and intraoperative water valances for postoperative mechanical ventilation support time. Compared with the neutrophil elastase inhibitor group, the control group had significantly higher initial alveolar-arterial oxygen gradient and significantly lower initial ratio of partial pressure of arterial oxygen to fraction of inspired oxygen at the intensive care unit (ICU). The control group had significantly longer postoperative mechanical ventilation support time and hospital stay compared with the neutrophil elastase inhibitor group. CONCLUSIONS: Neutrophil elastase inhibitor may have beneficial effects against RPE after MICS with mini thoracotomy. PMID- 29118309 TI - Cyprotuoside C and Cyprotuoside D, Two New Cycloartane Glycosides from the Rhizomes of Cyperus rotundus. AB - Cyprotuoside C (1) and cyprotuoside D (2), two new cycloartane glycosides were isolated from the ethanol extract of the rhizomes of Cyperus rotundus. Their structures were identified as 24R-9,10-seco-cycloartan-1(10),9(11)-dien 3beta,7beta,24,25-tetraol 3-O-beta-D-xylopyranosyl-(1->4)-[alpha-L arabinopyranosyl-(1->6)]-beta-D-glucopyranosyl-25-O-beta-D-glucuronide (1) and 9,10-seco-cycloartan-1(10),9(11),23(24)-trien-3beta,7beta,25-triol 3-O-beta-D xylopyranosyl-(1->4)-{alpha-L-arabinopyranosyl-(1->6)-[alpha-L-rhamnopyranosyl-(1 >2)]}-beta-D-glucopyranosyl-25-O-beta-D-glucuronide (2) by spectroscopic methods. PMID- 29118310 TI - Manifestation of Coronary Atherosclerosis in Klang Valley, Malaysia: An Autopsy Study. AB - AIMS: The present study aimed to determine the epidemiological aspects of medico legal autopsies and manifestation of coronary atherosclerosis. METHODS: This was a cross sectional study involving 222 cases recruited from National Institute of Forensic Medicine (NIFM) Hospital Kuala Lumpur (HKL) and Department of Forensic Medicine Hospital Sungai Buloh (HSgB) for a period of 15 months, from December 2012 to April 2014. Sociodemographic and autopsy findings, including the cause and manner of death were documented. RESULTS: Male and female subjects aged 18-70 years were recruited. Males contributed to 86% of the total subjects and comprised 61% of young adults. Road traffic accidents were the primary cause of death, contributing almost 50% of the subjects. One third of the cases comprised of death due to natural causes, wherein almost 75% of the subjects within this category succumbed to sudden cardiac death. Coronary artery disease (CAD) contributed to 60% of the sudden cardiac death (SCD). Single and double-vessel diseases were the most common pattern of atherosclerosis. In almost 80% of CAD cases, atherosclerosis affected the left anterior descending artery (LAD). CONCLUSION: Cardiovascular diseases were the most significant natural cause of sudden death with a staggering figure of 75%. CAD was the single most commonly encountered pathology within the SCD. Most cases presented with single and double vessel diseases, observed in all subjects, as well as the young adult population. PMID- 29118311 TI - Factors Associated with Intima-Media Complex Thickness of the Common Carotid Artery in Japanese Noncardioembolic Stroke Patients with Hyperlipidemia: The J STARS Echo Study. AB - AIMS: There may be ethnic differences in carotid atherosclerosis and its contributing factors between Asian and other populations. The purpose of this study was to examine intima-media complex thickness (IMT) of the carotid artery and associated clinical factors in Japanese stroke patients with hyperlipidemia from a cohort of the Japan Statin Treatment Against Recurrent Stroke Echo Study. METHODS: Patients with hyperlipidemia, not on statins, who developed noncardioembolic ischemic stroke were included in this study. Mean IMT and maximum IMT of the distal wall of the common carotid artery were centrally measured using carotid ultrasonography. Significant factors related to mean IMT and maximum IMT were examined using multivariable analysis. RESULTS: In 793 studied patients, mean IMT was 0.89+/-0.15 mm and maximum IMT was 1.19+/-0.32 mm.Age (per 10 years, parameter estimate=0.044, p<0.001), smoking (0.022, p=0.004), category of blood pressure (0.022, p=0.006), HDL cholesterol (per 10 mg/dl, -0.009, p=0.008), and diabetes mellitus (0.033, p=0.010) were independently associated with mean IMT. Age (per 10 years, 0.076, p<0.001), smoking (0.053, p=0.001), HDL cholesterol (-0.016, p=0.036), and diabetes mellitus (0.084, p=0.002) were independently associated with maximum IMT. CONCLUSION: Baseline mean and maximum values of carotid IMT in Japanese noncardioembolic stroke patients with hyperlipidemia were 0.89+/-0.15 mm and 1.19+/-0.32 mm, respectively, which were similar to those previously reported from Western countries. Age, smoking, hypertension, HDL cholesterol, and diabetes mellitus were associated with mean IMT, and those, except for hypertension, were associated with maximum IMT. PMID- 29118312 TI - Dynamics of liver enzymes in rabbits experimentally infected with Fasciola sp. (Intermediate form from Japan). AB - Dynamics of serum liver enzymes in rabbits experimentally infected with metacercariae of Fasciola sp. (intermediate form between Fasciola hepatica and F. gigantica) were monitored. Gradual increase of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed from 3 weeks post inoculation (WPI) and peaked at 6 WPI, which corresponded well to the period of migration and development of juvenile fluke in the liver parenchyma and the time when the young adult flukes migrated to the bile duct. However, no significant increase in serum gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) were observed. This could reflect reduced or minimal injury of bile ducts and biliary epithelia as the flukes had reached the adult stage. Alpha- fetoprotein (AFP) and carcinoembryonic antigen (CEA) were not detected in the infected rabbit during the course of the experiment. Serum liver enzymes monitoring might be useful for understanding the host-parasite relationship in fascioliasis. PMID- 29118313 TI - Feline coronavirus antibody titer in cerebrospinal fluid from cats with neurological signs. AB - To investigate the utility of cerebrospinal fluid (CSF) anti-feline coronavirus (FCoV) antibody test for diagnosis of feline infectious peritonitis (FIP), the antibody titers were tested in CSF and sera from 271 FIP-suspected neurological cats. CSF antibody was detected in 28 cats, which were divided into 2 groups; 15 with CSF titer of 1:80 or lower and 13 with CSF titer of 1:640 or higher. In the latter group, reciprocal serum titer/reciprocal CSF titer was 8 or lower, which is extremely lower than normal range (256-2048), and FCoV RNA was detected in all of 11 CSF samples assayed by RT-PCR. Our findings indicate that CSF titer of 1:640 or higher may be served as a candidate for the index for diagnosing FIP. PMID- 29118314 TI - Association of Immune Factors with Drug-Resistant Tuberculosis: A Case-Control Study. AB - BACKGROUND Presently, studies of factors associated with drug-resistant tuberculosis (TB) focus on patients' socio-demographic characteristics and living habits, to the exclusion of biochemical indicators, especially immune factors. This study was carried out to determine whether immune factors are associated with drug-resistant TB. MATERIAL AND METHODS A total of 227 drug-resistant pulmonary TB patients and 225 drug-susceptible pulmonary TB patients were enrolled in this study. Information on socio-demographic characteristics and biochemical indicators were obtained through their clinical records. Non conditional logistic regression was used to analyze the association of these indicators with drug-resistant TB. RESULTS There were significant differences in re-treatment, marital status, alanine aminotransferase (ALT), blood uric acid (BUA), carcino-embryonic antigen (CEA), T-spot, and CD3 and CD4 counts between the 2 groups. In multivariable analysis, re-treatment [Odds Ratio (OR)=5.290, 95% Confidence Interval [CI]=2.652-10.551); CD3 (OR=1.034, 95% CI=1.001-1.068); CD4 (OR=1.035, 95% CI =1.001-1.070) and IgM (OR=1.845, 95% CI=1.153-2.952) were associated with drug-resistant TB. CONCLUSIONS These results suggest the need for greater attention to re-treatment cases and immune function when treating drug resistant TB. PMID- 29118315 TI - Balancing Medical and Non-Accidental Causes of Multiple Fractures in a Child with Progressive Familial Intrahepatic Cholestasis. AB - BACKGROUND All medical practitioners must be vigilant for child abuse and neglect (CAN) so that opportunities to intervene, prevent, and improve outcomes are not missed. However, child abuse is often overlooked in practice, and no sign or pattern of presentation of fractures is absolutely specific for child abuse. CASE REPORT Here, we present the case of a 22-month-old girl with progressive familial intrahepatic cholestasis (PFIC) type 2 who presented with "red flag" fractures indicative of child abuse. Biochemistry showed vitamin D deficiency and a skeletal survey revealed rickets and multiple pathological fractures. However, her age, number of differently-aged fractures and their circumstances, and differential diagnosis of CAN prompted adherence to joint Royal College of Radiologists and Royal College of Paediatrics and Child Health guidelines for non accidental injury. CONCLUSIONS This case highlights some important considerations in management of suspected CAN in the context of the pathophysiology of a rare hereditary disorder that can result in pathological fractures. PMID- 29118317 TI - Strain-shear coupling in bilayer MoS2. AB - Layered materials such as graphite and transition metal dichalcogenides have extremely anisotropic mechanical properties owing to orders of magnitude difference between in-plane and out-of-plane interatomic interaction strengths. Although effects of mechanical perturbations on either intralayer or interlayer interactions have been extensively investigated, mutual correlations between them have rarely been addressed. Here, we show that layered materials have an inevitable coupling between in-plane uniaxial strain and interlayer shear. Because of this, the uniaxial in-plane strain induces an anomalous splitting of the degenerate interlayer shear phonon modes such that the split shear mode along the tensile strain is not softened but hardened contrary to the case of intralayer phonon modes. We confirm the effect by measuring Raman shifts of shear modes of bilayer MoS2 under strain. Moreover, by analyzing the splitting, we obtain an unexplored off-diagonal elastic constant, demonstrating that Raman spectroscopy can determine almost all mechanical constants of layered materials. PMID- 29118316 TI - Distinct Campylobacter fetus lineages adapted as livestock pathogens and human pathobionts in the intestinal microbiota. AB - Campylobacter fetus is a venereal pathogen of cattle and sheep, and an opportunistic human pathogen. It is often assumed that C. fetus infection occurs in humans as a zoonosis through food chain transmission. Here we show that mammalian C. fetus consists of distinct evolutionary lineages, primarily associated with either human or bovine hosts. We use whole-genome phylogenetics on 182 strains from 17 countries to provide evidence that C. fetus may have originated in humans around 10,500 years ago and may have "jumped" into cattle during the livestock domestication period. We detect C. fetus genomes in 8% of healthy human fecal metagenomes, where the human-associated lineages are the dominant type (78%). Thus, our work suggests that C. fetus is an unappreciated human intestinal pathobiont likely spread by human to human transmission. This genome-based evolutionary framework will facilitate C. fetus epidemiology research and the development of improved molecular diagnostics and prevention schemes for this neglected pathogen. PMID- 29118318 TI - Rapid termination of the African Humid Period triggered by northern high-latitude cooling. AB - The rapidity and synchrony of the African Humid Period (AHP) termination at around 5.5 ka are debated, and it is unclear what caused a rapid hydroclimate response. Here we analysed the hydrogen isotopic composition of sedimentary leaf waxes (deltaDwax) from the Gulf of Guinea, a proxy for regional precipitation in Cameroon and the central Sahel-Sahara. Our record indicates high precipitation during the AHP followed by a rapid decrease at 5.8-4.8 ka. The similarity with a deltaDwax record from northern East Africa suggests a large-scale atmospheric mechanism. We show that northern high- and mid-latitude cooling weakened the Tropical Easterly Jet and, through feedbacks, strengthened the African Easterly Jet. The associated decrease in precipitation triggered the AHP termination and combined with biogeophysical feedbacks to result in aridification. Our findings suggest that extratropical temperature changes, albeit smaller than during the glacial and deglacial, were important in triggering rapid African aridification during the Holocene. PMID- 29118319 TI - Cortisol responses enhance negative valence perception for ambiguous facial expressions. AB - Stress exposure elicits a prolonged neuroendocrine response, marked by cortisol release, which can influence important forms of affective decision-making. Identifying how stress reactivity shapes subjective biases in decisions about emotional ambiguity (i.e., valence bias) provides insight into the role stress plays in basic affective processing for healthy and clinical populations alike. Here, we sought to examine how stress reactivity affects valence decisions about emotional ambiguity. Given that stress prioritizes automatic emotional processing which, in the context of valence bias, is associated with increased negativity, we tested how individual differences in acute stress responses influence valence bias and how this decision process evolves over time. Participants provided baseline ratings of clear (happy, angry) and ambiguous (surprised) facial expressions, then re-rated similar stimuli after undergoing an acute stress or control manipulation a week later; salivary cortisol was measured throughout to assay stress reactivity. Elevations in cortisol were associated with more negative ratings of surprised faces, and with more direct response trajectories toward negative ratings (i.e., less response competition). These effects were selectively driven by the stress group, evidencing that increased stress reactivity is associated with a stronger negativity bias during ambiguous affective decision-making. PMID- 29118321 TI - Reconstruction of Complex Network based on the Noise via QR Decomposition and Compressed Sensing. AB - It is generally known that the states of network nodes are stable and have strong correlations in a linear network system. We find that without the control input, the method of compressed sensing can not succeed in reconstructing complex networks in which the states of nodes are generated through the linear network system. However, noise can drive the dynamics between nodes to break the stability of the system state. Therefore, a new method integrating QR decomposition and compressed sensing is proposed to solve the reconstruction problem of complex networks under the assistance of the input noise. The state matrix of the system is decomposed by QR decomposition. We construct the measurement matrix with the aid of Gaussian noise so that the sparse input matrix can be reconstructed by compressed sensing. We also discover that noise can build a bridge between the dynamics and the topological structure. Experiments are presented to show that the proposed method is more accurate and more efficient to reconstruct four model networks and six real networks by the comparisons between the proposed method and only compressed sensing. In addition, the proposed method can reconstruct not only the sparse complex networks, but also the dense complex networks. PMID- 29118320 TI - Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. AB - Maternal overnutrition increases the risk of long-term metabolic dysfunction in offspring. Exercise improves metabolism partly by upregulating mitochondrial biogenesis or function, via increased levels of nicotinamide adenine dinucleotide (NAD+). We have shown that the NAD+ precursor, nicotinamide mononucleotide (NMN) can reverse some of the negative consequences of high fat diet (HFD) consumption. To investigate whether NMN can impact developmentally-set metabolic deficits, we compared treadmill exercise and NMN injection in offspring of obese mothers. Five week old lean and obese female C57BL6/J mice were mated with chow fed males. Female offspring weaned onto HFD were given treadmill exercise for 9 weeks, or NMN injection daily for 18 days. Maternal obesity programmed increased adiposity and liver triglycerides, with decreased glucose tolerance, liver NAD+ levels and citrate synthase activity in offspring. Both interventions reduced adiposity, and showed a modest improvement in glucose tolerance and improved markers of mitochondrial function. NMN appeared to have stronger effects on liver fat catabolism (Hadh) and synthesis (Fasn) than exercise. The interventions appeared to exert the most global benefit in mice that were most metabolically challenged (HFD-consuming offspring of obese mothers). This work encourages further study to confirm the suitability of NMN for use in reversing metabolic dysfunction linked to programming by maternal obesity. PMID- 29118322 TI - Conduction-band effective mass and bandgap of ZnSnN2 earth-abundant solar absorber. AB - Pseudo III-V nitride ZnSnN2 is an earth-abundant semiconductor with a high optical absorption coefficient in the solar spectrum. Its bandgap can be tuned by controlling the cation sublattice disorder. Thus, it is a potential candidate for photovoltaic absorber materials. However, its important basic properties such as the intrinsic bandgap and effective mass have not yet been quantitatively determined. This paper presents a detailed optical absorption analysis of disordered ZnSnN2 degenerately doped with oxygen (ZnSnN2-x O x ) in the ultraviolet to infrared region to determine the conduction-band effective mass (m c*) and intrinsic bandgap (E g). ZnSnN2-x O x epilayers are n-type degenerate semiconductors, which exhibit clear free-electron absorption in the infrared region. By analysing the free-electron absorption using the Drude model, m c* was determined to be (0.37 +/- 0.05)m 0 (m 0 denotes the free electron mass). The fundamental absorption edge in the visible to ultraviolet region shows a blue shift with increasing electron density. The analysis of the blue shift in the framework of the Burstein-Moss effect gives the E g value of 0.94 +/- 0.02 eV. We believe that the findings of this study will provide important information to establish this material as a photovoltaic absorber. PMID- 29118323 TI - Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation. AB - Although efficacy of combined histone deacetylase (HDAC) inhibitors and conventional photon radiotherapy is being tested in clinical trials, their combined effect with proton beam radiotherapy has yet to be determined. Here, we compared combined effect of valproic acid (VPA), a class I and II HDAC inhibitor and antiepileptic drug with proton and photon irradiation in hepatocellular carcinoma (HCC) cells in vitro and in vivo. We found that VPA sensitized more Hep3B cells to proton than to photon irradiation. VPA prolonged proton-induced DNA damage and augmented proton-induced apoptosis. In addition, VPA further increased proton-induced production of intracellular reactive oxygen species and suppressed expression of nuclear factor erythroid-2-related factor 2 (NRF2), a key transcription factor regulating antioxidant response. Downregulation of NRF2 by siRNA transfection increased proton-induced apoptotic cell death, supporting NRF2 as a target of VPA in radiosensitization. In Hep3B tumor xenograft models, VPA significantly enhanced proton-induced tumor growth delay with increased apoptosis and decreased NRF2 expression in vivo. Collectively, our study highlights a proton radiosensitizing effect of VPA in HCC cells. As NRF2 is an emerging prognostic marker contributing to radioresistance in HCC, targeting NRF2 pathway may impact clinical outcome of proton beam radiotherapy. PMID- 29118324 TI - Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine. AB - The combination of platinum and gemcitabine is one of the standard regimens in the treatment of advanced lung squamous carcinoma (LSC). Resistance to gemcitabine is main barrier to the successful treatment of LSC. In this study, we showed that suppression of the Fanconi anemia (FA) pathway increased the sensitivity of two LSC cell lines SK-MES-1 and KLN205 to gemcitabine. Moreover, we found that the CHK1 pathway and the FA pathway are functionally compensatory in the repair of DNA damage in the LSC cell lines. Inactivation of one of the two pathways led to DNA damage, triggering compensatory activation of other pathway. Furthermore, we demonstrated that FANCD2 depletion combined with CHK1 inhibitor MK-8776 significantly potentiated the cytotoxicity of gemcitabine to the two LSC cell lines, compared to individual FANCD2 depletion or MK-8776 treatment. The enhanced effect of gemcitabine-chemosensitization was accompanied by loss of DNA repair function and accumulation of DNA single strand breaks and double strand breaks, in parallel with obvious increase of caspase-3 dependent apoptosis. Our results indicate that the enhancement effect of FANCD2 depletion combined with CHK1 inhibitor in sensitizing the LCS cells to gemcitabine supports the FA pathway and CHK1 as two therapeutic targets for improvement of anti-tumor regimens in treatment of LSC. PMID- 29118325 TI - The Mammalian Target of Rapamycin and DNA methyltransferase 1 axis mediates vascular endothelial dysfunction in response to disturbed flow. AB - The earliest atherosclerotic lesions preferentially develop in arterial regions experienced disturbed blood flow, which induces endothelial expression of pro atherogenic genes and the subsequent endothelial dysfunction. Our previous study has demonstrated an up-regulation of DNA methyltransferase 1 (DNMT1) and a global hypermethylation in vascular endothelium subjected to disturbed flow. Here, we determined that DNMT1-specific inhibition in arterial wall ameliorates the disturbed flow-induced atherosclerosis through, at least in part, targeting cell cycle regulator cyclin A and connective tissue growth factor (CTGF). We identified the signaling pathways mediating the flow-induction of DNMT1. Inhibition of the mammalian target of rapamycin (mTOR) suppressed the DNMT1 up regulation both in vitro and in vivo. Together, our results demonstrate that disturbed flow influences endothelial function and induces atherosclerosis in an mTOR/DNMT1-dependent manner. The conclusions obtained from this study might facilitate further evaluation of the epigenetic regulation of endothelial function during the pathological development of atherosclerosis and offer novel prevention and therapeutic targets of this disease. PMID- 29118326 TI - Incidence, Predictors and Outcome of Prosthesis-Patient Mismatch after Transcatheter Aortic Valve Replacement: a Systematic Review and Meta-analysis. AB - The aim of this study was to investigate the incidence, predictors and outcome of prosthesis-patient mismatch (PPM) following transcatheter aortic valve replacement (TAVR). A total of 30 articles incorporating 4,691 patients were identified. The pooled incidences of overall, moderate and severe PPM following TAVR were 33.0%, 25.0% and 11.0% respectively. Medtronic CoreValve (MCV) had lower incidence of overall (32% vs: 40%, P < 0.0001) and moderate (23% vs 32%, P < 0.0001) than Edwards Sapien (ESV). PPM was associated with a younger age, smaller annulus diameter and lower left ventricular ejection fraction in comparison with those patients without PPM. Post-dilation (OR, 0.51, 95% CI, 0.38 to 0.68, p < 0.001) during TAVR would decrease the incidence of PPM. Although PPM was common after TAVR, no significant differences were observed both in short- and mid-term all-cause mortality (30 day: OR: 1.1, 95% CI, 0.70 to 1.73 and 2 year: OR: 1.01, 95% CI, 0.74 to 1.38) between patients with PPM and those without PPM. In conclusion, despite being common after TAVR, the incidence of PPM was lower than that of surgical aortic valve replacement (SAVR) and decreased with the experience accumulating, and PPM was not seen to impact on short- and mid term survival, regardless of its magnitude. PMID- 29118327 TI - Creating nanoscale emulsions using condensation. AB - Nanoscale emulsions are essential components in numerous products, ranging from processed foods to novel drug delivery systems. Existing emulsification methods rely either on the breakup of larger droplets or solvent exchange/inversion. Here we report a simple, scalable method of creating nanoscale water-in-oil emulsions by condensing water vapor onto a subcooled oil-surfactant solution. Our technique enables a bottom-up approach to forming small-scale emulsions. Nanoscale water droplets nucleate at the oil/air interface and spontaneously disperse within the oil, due to the spreading dynamics of oil on water. Oil-soluble surfactants stabilize the resulting emulsions. We find that the oil-surfactant concentration controls the spreading behavior of oil on water, as well as the peak size, polydispersity, and stability of the resulting emulsions. Using condensation, we form emulsions with peak radii around 100 nm and polydispersities around 10%. This emulsion formation technique may open different routes to creating emulsions, colloidal systems, and emulsion-based materials. PMID- 29118328 TI - Decreased absolute numbers of CD3+ T cells and CD8+ T cells during aging in herpes zoster patients. AB - Herpes zoster (HZ) is an infectious dermatosis with high incidence worldwide. Age is a key risk factor for HZ, and postherpetic neuralgia (PHN) is the main sequelae. Until now, no index has been available to predict the pathogenesis of PHN, and rare reports have focused on the immune response during aging and PHN. In this study, we selected immunoglobulin and complement proteins as markers for humoral immunity, while T lymphocyte subsets and natural killer (NK) cells were selected as markers for cell immunity, to systematically study the characteristics of immune responses in the peripheral blood of HZ patients. Our data showed that the absolute number of CD3+ T cells and CD8+ T cells decreased during aging and PHN. This implies that more attention should be paid to prevent the occurrence of PHN, especially in the aged population. PMID- 29118329 TI - Aortic stiffness improves the prediction of both diagnosis and severity of coronary artery disease. AB - Elective coronography has low diagnostic yield for obstructive coronary artery disease (CAD). We aim to determine whether non-invasive aortic stiffness assessment improves diagnostic accuracy of CAD screening by reducing the number of false-positive results from the cardiac stress test. A cross-sectional study was conducted from January 2013 to September 2014 in our medical center. Electrocardiogram (ECG) stress test coupled with nuclear imaging was performed in 367 consecutive patients routinely followed for myocardial ischemia screening. Aortic pulse wave velocity (PWV) was assessed by applanation tonometry in the overall population. Forty-two patients underwent elective coronography because of ischemia. Theoretical PWV was calculated according to age, blood pressure and gender. The results were expressed as an index ((measured PWV-theoretical PWV)/theoretical PWV) for each patient. Ten patients presented with obstructive CAD, 16 patients had non-obstructive CAD and 16 patients had normal coronary angiography. PWV index and severity of CAD were positively correlated (P=0.001). All patients with obstructive CAD had a positive PWV index. When considering the PWV index retrospectively, the false positive results of cardiac stress test were significantly reduced (P<0.001). Twenty-three procedures may have been avoided in the present study cohort. The salient finding of this study was that in patients with known or suspected CAD, routinely followed aortic PWV index may be considered clinically useful for reducing the rate of unnecessary invasive angiographies. The clinical relevance of this individualized decision approach should be confirmed in a large-scale study. Prospective studies have the potential to evaluate the PWV index as a marker of CAD. PMID- 29118330 TI - Molecular spectrum of secretome regulates the relative hepatogenic potential of mesenchymal stem cells from bone marrow and dental tissue. AB - Liver regeneration is a spontaneous process that occurs after liver injury, but acute liver failure is a complex and fatal disease which is difficult to treat. Cell-based therapies are promising alternative therapeutic approach for liver failure and different cell sources have been tested in this regard. We investigated the comparative hepatogenic potential of human bone marrow stem cells (BMSC) with stem cells derived from human dental pulp (DPSC), apical papilla (SCAP) and follicle (DFSC) during this study. Hepatogenic potential of stem cells was assessed by functional assays at both genetic and protein level. We observed higher expression of most of the hepatic markers post differentiation in DPSCs compared to other cell types. LC-MS/MS analysis of stem cell secretome revealed the presence of different proteins related to hepatogenic lineage like growth arrest specific protein 6, oncostatin M, hepatocyte growth factor receptor etc. Interactome and Reactome pathway analysis revealed the interaction of DPSC/SCAP secretome proteins and these proteins were found to be associated with various pathways involved in lipid transport and metabolism. To the best of our knowledge, this is the first study regarding detailed investigation of hepatogenic potential of BMSCs v/s DMSCs (DPSC, SCAP & DFSC) along-with secretome characterization. PMID- 29118331 TI - Room temperature magnetization switching in topological insulator-ferromagnet heterostructures by spin-orbit torques. AB - Topological insulators with spin-momentum-locked topological surface states are expected to exhibit a giant spin-orbit torque in the topological insulator/ferromagnet systems. To date, the topological insulator spin-orbit torque-driven magnetization switching is solely reported in a Cr-doped topological insulator at 1.9 K. Here we directly show giant spin-orbit torque driven magnetization switching in a Bi2Se3/NiFe heterostructure at room temperature captured using a magneto-optic Kerr effect microscope. We identify a large charge-to-spin conversion efficiency of ~1-1.75 in the thin Bi2Se3 films, where the topological surface states are dominant. In addition, we find the current density required for the magnetization switching is extremely low, ~6 * 105 A cm-2, which is one to two orders of magnitude smaller than that with heavy metals. Our demonstration of room temperature magnetization switching of a conventional 3d ferromagnet using Bi2Se3 may lead to potential innovations in topological insulator-based spintronic applications. PMID- 29118332 TI - Poly-beta-hydroxybutyrate administration during early life: effects on performance, immunity and microbial community of European sea bass yolk-sac larvae. AB - The reliable production of marine fish larvae is one of the major bottlenecks in aquaculture due to high mortalities mainly caused by infectious diseases. To evaluate if the compound poly-beta-hydroxybutyrate (PHB) might be a suitable immunoprophylactic measure in fish larviculture, its capacity to improve immunity and performance in European sea bass (Dicentrarchus labrax) yolk-sac larvae was explored. PHB was applied from mouth opening onwards to stimulate the developing larval immune system at the earliest possible point in time. Larval survival, growth, microbiota composition, gene expression profiles and disease resistance were assessed. PHB administration improved larval survival and, furthermore, altered the larva-associated microbiota composition. The bacterial challenge test using pathogenic Vibrio anguillarum revealed that the larval disease resistance was not influenced by PHB. The expression profiles of 26 genes involved e.g. in the immune response showed that PHB affected the expression of the antimicrobial peptides ferritin (fer) and dicentracin (dic), however, the response to PHB was inconsistent and weaker than previously demonstrated for sea bass post-larvae. Hence, the present study highlights the need for more research focusing on the immunostimulation of different early developmental stages for gaining a more comprehensive picture and advancing a sustainable production of high quality fry. PMID- 29118333 TI - Global mapping of stratigraphy of an old-master painting using sparsity-based terahertz reflectometry. AB - The process by which art paintings are produced typically involves the successive applications of preparatory and paint layers to a canvas or other support; however, there is an absence of nondestructive modalities to provide a global mapping of the stratigraphy, information that is crucial for evaluation of its authenticity and attribution, for insights into historical or artist-specific techniques, as well as for conservation. We demonstrate sparsity-based terahertz reflectometry can be applied to extract a detailed 3D mapping of the layer structure of the 17th century easel painting Madonna in Preghiera by the workshop of Giovanni Battista Salvi da Sassoferrato, in which the structure of the canvas support, the ground, imprimatura, underpainting, pictorial, and varnish layers are identified quantitatively. In addition, a hitherto unidentified restoration of the varnish has been found. Our approach unlocks the full promise of terahertz reflectometry to provide a global and detailed account of an easel painting's stratigraphy by exploiting the sparse deconvolution, without which terahertz reflectometry in the past has only provided a meager tool for the characterization of paintings with paint-layer thicknesses smaller than 50 MUm. The proposed modality can also be employed across a broad range of applications in nondestructive testing and biomedical imaging. PMID- 29118334 TI - Temporal and spatial expression of genes involved in DNA methylation during reproductive development of sexual and apomictic Eragrostis curvula. AB - Recent reports in model plant species have highlighted a role for DNA methylation pathways in the regulation of the somatic-to-reproductive transition in the ovule, suggesting that apomixis (asexual reproduction through seeds) likely relies on RdDM downregulation. Our aim was therefore to explore this hypothesis by characterizing genes involved in DNA methylation in the apomictic grass Eragrostis curvula. We explored floral transcriptomes to identify homologs of three candidate genes, for which mutations in Arabidopsis and maize mimic apomixis (AtAGO9/ZmAGO104, AtCMT3/ZmDMT102/ZmDMT105, and AtDDM1/ZmCHR106), and compared both their spatial and temporal expression patterns during reproduction in sexual and apomictic genotypes. Quantitative expression analyses revealed contrasting expression patterns for the three genes in apomictic vs sexual plants. In situ hybridization corroborated these results for two candidates, EcAGO104 and EcDMT102, and revealed an unexpected ectopic pattern for the AGO gene during germ line differentiation in apomicts. Although our data partially support previous results obtained in sexual plant models, they suggest that rather than an RdDM breakdown in the ovule, altered localization of AtAGO9/ZmAGO104 expression is required for achieving diplospory in E. curvula. The differences in the RdDM machinery acquired during plant evolution might have promoted the emergence of the numerous apomictic paths observed in plants. PMID- 29118335 TI - ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT. AB - Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT. PMID- 29118336 TI - Self-assembling dipeptide antibacterial nanostructures with membrane disrupting activity. AB - Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, specifically in drug delivery and tissue regeneration. However, the intrinsic antibacterial capabilities of these assemblies have been largely overlooked. The recent identification of common characteristics shared by antibacterial and self-assembling peptides provides a paradigm shift towards development of antibacterial agents. Here we present the antibacterial activity of self-assembled diphenylalanine, which emerges as the minimal model for antibacterial supramolecular polymers. The diphenylalanine nano assemblies completely inhibit bacterial growth, trigger upregulation of stress response regulons, induce substantial disruption to bacterial morphology, and cause membrane permeation and depolarization. We demonstrate the specificity of these membrane interactions and the development of antibacterial materials by integration of the peptide assemblies into tissue scaffolds. This study provides important insights into the significance of the interplay between self-assembly and antimicrobial activity and establishes innovative design principles toward the development of antimicrobial agents and materials. PMID- 29118337 TI - Short-term effects of non-grazing on plants, soil biota and aboveground belowground links in Atlantic mountain grasslands. AB - Mountain grasslands in the Iberian Peninsula are the result of extensive grazing. However, a progressive abandonment of grazing activity is currently observed in the study region. The objective of this work was to evaluate the short-term (2 years) effects of non-grazing on the diversity and composition of plants, soil microorganisms (prokaryotes, fungi, arbuscular mycorrhiza), mesofauna, macrofauna and aboveground-belowground links, through the study of 16 grazed vs. non-grazed areas in Atlantic grasslands located in the Basque Country (Spain). Sites were divided between 4 habitat types with different elevation, pasture productivity, vegetation type and parent material. Herbivores appeared to influence plant community composition, contributing to increase aboveground diversity, while having unequal effects on belowground communities depending on the organisms analysed. This may be explained by the different habitat and trophic level of each soil organism, which may be more or less affected by the predominating negative effects of grazing, such as soil compaction, and only partially compensated by other positive effects. Finally, habitat type appeared to be the strongest influence on both above- and belowground communities, also influencing the effect of the absence of grazing. PMID- 29118338 TI - Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model. AB - Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-beta1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-beta1, forming what appears to be a sialidase - TGF-beta1 - sialidase positive feedback loop. Monocyte-derived cells called fibrocytes also activate fibroblasts, and we found that sialidases potentiate fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-beta1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis. PMID- 29118339 TI - Action Categorization in Rhesus Monkeys: discrimination of grasping from non grasping manual motor acts. AB - The ability to recognize others' actions is an important aspect of social behavior. While neurophysiological and behavioral research in monkeys has offered a better understanding of how the primate brain processes this type of information, further insight with respect to the neural correlates of action recognition requires tasks that allow recording of brain activity or perturbing brain regions while monkeys simultaneously make behavioral judgements about certain aspects of observed actions. Here we investigated whether rhesus monkeys could actively discriminate videos showing grasping or non-grasping manual motor acts in a two-alternative categorization task. After monkeys became proficient in this task, we tested their ability to generalize to a number of untrained, novel videos depicting grasps or other manual motor acts. Monkeys generalized to a wide range of novel human or conspecific grasping and non-grasping motor acts. They failed, however, for videos showing unfamiliar actions such as a non-biological effector performing a grasp, or a human hand touching an object with the back of the hand. This study shows the feasibility of training monkeys to perform active judgements about certain aspects of observed actions, instrumental for causal investigations into the neural correlates of action recognition. PMID- 29118340 TI - The liquid-glass-jamming transition in disordered ionic nanoemulsions. AB - In quenched disordered out-of-equilibrium many-body colloidal systems, there are important distinctions between the glass transition, which is related to the onset of nonergodicity and loss of low-frequency relaxations caused by crowding, and the jamming transition, which is related to the dramatic increase in elasticity of the system caused by the deformation of constituent objects. For softer repulsive interaction potentials, these two transitions become increasingly smeared together, so measuring a clear distinction between where the glass ends and where jamming begins becomes very difficult or even impossible. Here, we investigate droplet dynamics in concentrated silicone oil-in-water nanoemulsions using light scattering. For zero or low NaCl electrolyte concentrations, interfacial repulsions are soft and longer in range, this transition sets in at lower concentrations, and the glass and the jamming regimes are smeared. However, at higher electrolyte concentrations the interactions are stiffer, and the characteristics of the glass-jamming transition resemble more closely the situation of disordered elastic spheres having sharp interfaces, so the glass and jamming regimes can be distinguished more clearly. PMID- 29118341 TI - Novel serotonin transporter regulators: Natural aristolane- and nardosinane- types of sesquiterpenoids from Nardostachys chinensis Batal. AB - Serotonin transporter (SERT) is a classic target of drug discovery for neuropsychiatric and digestive disorders, and against those disorders, plants of Nardostachys genus have been valued for centuries in the systems of Traditional Chinese Medicine, Ayurvedic and Unani. Herein, chemical investigation on the roots and rhizomes of Nardostachys chinensis Batal. led to the isolation of forty sesquiterpenoids including six new aristolane-type sesquiterpenoids and six new nardosinane-type sesquiterprenoids. Their structures were elucidated by extensive spectroscopic methods, combined with analyses of circular dichroism and single crystal X-ray diffraction data. To explore natural product scaffolds with SERT regulating activity, a high-content assay for measurement of SERT function in vitro was conducted to evaluate the SERT regulating properties of these isolates. In conclusion, eleven compounds could be potential natural product scaffolds for developing drug candidates targeting SERT. Among which, kanshone C of aristolane type sesquiterpenoid inhibited SERT most strongly, while desoxo-nachinol A of nardosinane-type sesquiterpenoid instead enhanced SERT potently. PMID- 29118342 TI - Physical understanding of the tropical cyclone wind-pressure relationship. AB - The relationship between the two common measures of tropical cyclone intensity, the central pressure deficit and the peak near-surface wind speed, is a long standing problem in tropical meteorology that has been approximated empirically yet lacks physical understanding. Here we provide theoretical grounding for this relationship. We first demonstrate that the central pressure deficit is highly predictable from the low-level wind field via gradient wind balance. We then show that this relationship reduces to a dependence on two velocity scales: the maximum azimuthal-mean azimuthal wind speed and half the product of the Coriolis parameter and outer storm size. This simple theory is found to hold across a hierarchy of models spanning reduced-complexity and Earth-like global simulations and observations. Thus, the central pressure deficit is an intensity measure that combines maximum wind speed, storm size, and background rotation rate. This work has significant implications for both fundamental understanding and risk analysis, including why the central pressure better explains historical economic damages than does maximum wind speed. PMID- 29118343 TI - EXOSC10/Rrp6 is post-translationally regulated in male germ cells and controls the onset of spermatogenesis. AB - EXOSC10 is a catalytic subunit of the exosome that processes biologically active transcripts, degrades aberrant mRNAs and targets certain long non-coding RNAs (lncRNAs). The yeast orthologue Rrp6 is required for efficient growth and gametogenesis, and becomes unstable during meiosis. However, nothing is known about the localization, stability and function of EXOSC10 in the rodent male germline. We detect the protein in nucleoli and the cytoplasm of mitotic and meiotic germ cells, and find that it transiently associates with the XY body, a structure targeted by meiotic sex chromosome inactivation (MSCI). Finally, EXOSC10 becomes unstable at later stages of gamete development. To determine Exosc10's meiotic function, we inactivated the gene specifically in male germ cells using cre recombinase controlled by Stra8 or Ddx4/Vasa promoters. Mutant mice have small testes, show impaired germ cell differentiation and are subfertile. Our results demonstrate that EXOSC10 is post-translationally regulated in germ cells, associate the protein with epigenetic chromosome silencing, and reveal its essential role in germ cell growth and development. PMID- 29118344 TI - Delivery of Native Proteins into C. elegans Using a Transduction Protocol Based on Lipid Vesicles. AB - The nematode worm Caenorhabditis elegans (C. elegans) is a versatile and widely used animal model for in vivo studies of a broad range of human diseases, in particular for understanding their genetic origins and for screening drug candidates. Nevertheless, the challenges associated with the administration of native proteins to C. elegans have limited the range of applications of this animal model in protein-based drug discovery programs. Here, we describe a readily usable protocol for the transduction of native proteins in C. elegans, which is based on the encapsulation of the proteins of interest within cationic lipid vesicles, prior to their administration to worms. This procedure limits the degradation of the proteins in the guts of the animals, and promotes their adsorption into body tissues. To illustrate the efficacy of this approach we apply it to deliver an antibody designed to inhibit alpha-synuclein aggregation, and show that it can lead to the rescue of the disease phenotype in a C. elegans model of Parkinson's disease. As this transduction protocol is fast and inexpensive, we anticipate that it will be readily applicable to protein-based drug discovery studies that utilize C. elegans as a model organism. PMID- 29118345 TI - Paradoxes in leaky microbial trade. AB - Microbes produce metabolic resources that are important for cell growth yet leak into the environment. Other microbes can use these resources, adjust their own metabolic production accordingly, and alter the resources available for others. We analyze a model in which metabolite concentrations, production regulation, and population frequencies coevolve in the simple case of two cell types producing two metabolites. We identify three paradoxes where changes that should intuitively benefit a cell type actually harm it. For example, a cell type can become more efficient at producing a metabolite and its relative frequency can decrease-or alternatively the total population growth rate can decrease. Another paradox occurs when a cell type manipulates its counterpart's production so as to maximize its own instantaneous growth rate, only to achieve a lower final growth rate than had it not manipulated. These paradoxes highlight the complex and counterintuitive dynamics that emerge in simple microbial economies. PMID- 29118347 TI - In-situ synthesis of amorphous silver silicate/carbonate composites for selective visible-light photocatalytic decomposition. AB - Coupling two different semiconductors to form composite photocatalysts is an extremely significant technique for environmental remediation. Here, a one-step in-situ precipitation method has been developed to prepare amorphous silver silicate/carbonate (AgSiO/Ag2CO3) nanoparticles (NPs) composites, which are well dispersed sphere-like particles with the sizes of around ~50-100 nm. The high efficiency photocatalytic activities under visible light (VL) have been carefully evaluated, and the AgSiO/Ag2CO3 NPs composites exhibit selective photocatalytic degradations on Methylene Blue (MB) and Rhodamine B (RhB). The maximum degradation rate for MB can reach ~99.1% within ~40 min under VL irradiation, much higher than that of RhB (~12%) in the same condition, which can be ascribed to (I) the smaller molecule size of MB than that of RhB, (II) the fast charge separation between AgSiO NPs and Ag2CO3 NPs, abundant heterojunction interfaces as well as fully exposed reactive sites. These composites are proposed to be an example for the preparation of other silicate composite photocatalysts for practical applications in environmental remediation. PMID- 29118349 TI - Diabetes: Anti-PCSK9 antibodies - beneficial or inducers of diabetes? PMID- 29118348 TI - Frontal theta activation during motor synchronization in autism. AB - Autism is characterized by two primary characteristics: deficits in social interaction and repetitive behavioral patterns. Because interpersonal communication is extremely complicated, its underlying brain mechanisms remain unclear. Here we showed that both characteristics can be explained by a unifying underlying mechanism related to difficulties with irregularities. To address the issues, we measured electroencephalographm during a cooperative tapping task, which required participants to tap a key alternately and synchronously with constant rhythmic a PC program, a variable rhythmic PC program, or a human partner. We found that people with autism had great difficulty synchronizing tapping behavior with others, and exhibited greater than normal theta-wave (6 Hz) activity in the frontal cortex during the task, especially when their partner behaved somewhat irregularly (i.e. a variable rhythmic PC program or a human partner). Importantly, the higher theta-wave activity was related to the severity of autism, not the performance on the task. This indicates that people with autism need to use intense cognition when trying to adapt to irregular behavior and can easily become overtaxed. Difficulty adapting to irregular behavior in others is likely related to their own tendencies for repetitive and regular behaviors. Thus, while the two characteristics of autism have been comprehended separately, our unifying theory makes understanding the condition and developing therapeutic strategies more tractable. PMID- 29118350 TI - Ageing: Improvement in age-related cognitive functions and life expectancy by ketogenic diets. PMID- 29118351 TI - Diabetes: A new hope for insulin-sensitizing drugs. PMID- 29118346 TI - Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head. AB - Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH. PMID- 29118352 TI - Thyroid cancer: Lenvatinib - beyond trials. PMID- 29118353 TI - Obesity: The myth of innocent obesity. PMID- 29118354 TI - Apolipoprotein M mediates sphingosine-1-phosphate efflux from erythrocytes. AB - Sphingosine-1-phosphate (S1P) is a bioactive lipid implicated in e.g. angiogenesis, lymphocyte trafficking, and endothelial barrier function. Erythrocytes are a main source of plasma S1P together with platelets and endothelial cells. Apolipoprotein M (apoM) in HDL carries 70% of plasma S1P, whereas 30% is carried by albumin. The current aim was to investigate the role of apoM in export of S1P from human erythrocytes. Erythrocytes exported S1P more efficiently to HDL than to albumin, particularly when apoM was present in HDL. In contrast, export of sphingosine to HDL was unaffected by the presence of apoM. The specific ability of apoM to promote export of S1P was independent of apoM being bound in HDL particles. Treatment with MK-571, an inhibitor of the ABCC1 transporter, effectively reduced export of S1P from human erythrocytes to apoM, whereas the export was unaffected by inhibitors of ABCB1 or ATPase. Thus, ABCC1 could be involved in export of S1P from erythrocytes to apoM. PMID- 29118355 TI - Decoy Wnt receptor (sLRP6E1E2)-expressing adenovirus induces anti-fibrotic effect via inhibition of Wnt and TGF-beta signaling. AB - Aberrant activation of the canonical Wingless type (Wnt) signaling pathway plays a key role in the development of hypertrophic scars and keloids, and this aberrant activation of Wnt pathway can be a potential target for the development of novel anti-fibrotic agents. In this study, we evaluated the anti-fibrotic potential of a soluble Wnt decoy receptor (sLRP6E1E2)-expressing non-replicating adenovirus (Ad; dE1-k35/sLRP6E1E2) on human dermal fibroblasts (HDFs), keloid fibroblasts (KFs), and keloid tissue explants. Higher Wnt3a and beta-catenin expression was observed in the keloid region compared to the adjacent normal tissues. The activity of beta-catenin and mRNA expression of type-I and -III collagen were significantly decreased following treatment with dE1-k35/sLRP6E1E2 in HDFs and KFs. The expression of LRP6, beta-catenin, phosphorylated glycogen synthase kinase 3 beta, Smad 2/3 complex, and TGF-beta1 were decreased in Wnt3a- or TGF-beta1-activated HDFs, following administration of dE1-k35/sLRP6E1E2. Moreover, dE1-k35/sLRP6E1E2 markedly inhibited nuclear translocation of both beta catenin and Smad 2/3 complex. The expression levels of type-I and -III collagen, fibronectin, and elastin were also significantly reduced in keloid tissue explants after treatment with dE1-k35/sLRP6E1E2. These results indicate that Wnt decoy receptor-expressing Ad can degrade extracellular matrix in HDFs, KFs, and primary keloid tissue explants, and thus it may be beneficial for treatment of keloids. PMID- 29118356 TI - Anaerobic digestion of pig manure supernatant at high ammonia concentrations characterized by high abundances of Methanosaeta and non-euryarchaeotal archaea. AB - We examined the effect of ammonium and temperature on methane production in high rate upflow anaerobic sludge bed reactors treating pig manure supernatant. We operated four reactors at two ammonium concentrations ('low' at 1.9, 'high' at 3.7 g L-1, termed LA and HA reactors, respectively) and at variable temperatures over 358 days. Archaeal and bacterial communities were characterized by Illumina sequencing of 16S rRNA amplicons. Ammonium was a major selective factor for bacterial and archaeal community structure. After ~200 days of adaptation to high ammonium levels, acetate and propionate removal and methane production improved substantially in HA reactors. Aceticlastic Methanosaeta was abundant and positively correlated to methane yield in the HA reactors, whereas Methanosarcina was more abundant in LA reactors. Furthermore, a group of monophyletic OTUs that was related to Thaumarchaeota in phylogenetic analysis was highly abundant in the archaeal communities, particularly in the HA reactors. The most abundant bacterial OTU in LA reactors, representing Syntrophomonadaceae, was also positively correlated to methane yield in the HA reactors, indicating its importance in methane production under ammonia stress. In conclusion, efficient methane production, involving aceticlastic methanogenesis by Methanosaeta took place in the reactors at free ammonia concentrations as high as 1 g L-1. PMID- 29118357 TI - Pumilio-dependent localization of mRNAs at the cell front coordinates multiple pathways required for chemotaxis. AB - Chemotaxis is a specialized form of directed cell migration important for normal development, wound healing, and cancer metastasis. In the social amoeba Dictyostelium discoideum, four signaling pathways act synergistically to maintain directional cell migration. However, it is unknown how these pathways are coordinated in space and time to achieve persistent chemotaxis. Here, we show that the mRNAs and proteins of these four chemotaxis pathways and actin are preferentially enriched at the cell front during dynamic cell migration, which requires the Pumilio-related RNA-binding protein Puf118. Significantly, disruption of the Pumilio-binding sequence in chemotaxis pathway mRNAs, or mislocalization of Puf118 and its target mRNAs to the cell rear perturbs efficient chemotaxis in shallow cAMP gradients, without affecting the abundance of the mRNAs or encoded proteins. Thus, the polarized localization of Puf118 bound mRNAs coordinates the distribution of different chemotaxis pathway proteins in time and space, leading to cell polarization and persistent chemotaxis. PMID- 29118358 TI - Spatial Distribution of Carbon Stored in Forests of the Democratic Republic of Congo. AB - National forest inventories in tropical regions are sparse and have large uncertainty in capturing the physiographical variations of forest carbon across landscapes. Here, we produce for the first time the spatial patterns of carbon stored in forests of Democratic Republic of Congo (DRC) by using airborne LiDAR inventory of more than 432,000 ha of forests based on a designed probability sampling methodology. The LiDAR mean top canopy height measurements were trained to develop an unbiased carbon estimator by using 92 1-ha ground plots distributed across key forest types in DRC. LiDAR samples provided estimates of mean and uncertainty of aboveground carbon density at provincial scales and were combined with optical and radar satellite imagery in a machine learning algorithm to map forest height and carbon density over the entire country. By using the forest definition of DRC, we found a total of 23.3 +/- 1.6 GtC carbon with a mean carbon density of 140 +/- 9 MgC ha-1 in the aboveground and belowground live trees. The probability based LiDAR samples capture variations of structure and carbon across edaphic and climate conditions, and provide an alternative approach to national ground inventory for efficient and precise assessment of forest carbon resources for emission reduction (ER) programs. PMID- 29118359 TI - Visualization and quantification of injury to the ciliated epithelium using quantitative flow imaging and speckle variance optical coherence tomography. AB - Mucociliary flow is an important defense mechanism in the lung to remove inhaled pathogens and pollutants. Disruption of ciliary flow can lead to respiratory infections. Multiple factors, from drugs to disease can cause an alteration in ciliary flow. However, less attention has been given to injury of the ciliated epithelium. In this study, we show how optical coherence tomography (OCT) can be used to investigate injury to the ciliated epithelium in a multi-contrast setting. We used particle tracking velocimetry (PTV-OCT) to investigate the cilia driven flow field and 3D speckle variance imaging to investigate size and extent of injury caused to the skin of Xenopus embryos. Two types of injuries are investigated, focal injury caused by mechanical damage and diffuse injury by a calcium chloride shock. We additionally investigate injury and regeneration of cilia to calcium chloride on ex vivo mouse trachea. This work describes how OCT can be used as a tool to investigate injury and regeneration in ciliated epithelium. PMID- 29118360 TI - Visible and UV photo-detection in ZnO nanostructured thin films via simple tuning of solution method. AB - This study demonstrates significant visible light photo-detection capability of pristine ZnO nanostructure thin films possessing substantially high percentage of oxygen vacancies [Formula: see text] and zinc interstitials [Formula: see text], introduced by simple tuning of economical solution method. The demonstrated visible light photo-detection capability, in addition to the inherent UV light detection ability of ZnO, shows great dependency of [Formula: see text] and [Formula: see text] with the nanostructure morphology. The dependency was evaluated by analyzing the presence/percentage of [Formula: see text] and [Formula: see text] using photoluminescence (PL) and X-ray photoelectron spectroscopy (XPS) measurements. Morphologies of ZnO viz. nanoparticles (NPs), nanosheets (NSs) and nanoflowers (NFs), as a result of tuning of synthesis method contended different concentrations of defects, demonstrated different photo detection capabilities in the form of a thin film photodetector. The photo detection capability was investigated under different light excitations (UV; 380~420 nm, white ; lambda > 420 nm and green; 490~570 nm). The as fabricated NSs photodetector possessing comparatively intermediate percentage of [Formula: see text] ~ 47.7% and [Formula: see text] ~ 13.8% exhibited superior performance than that of NPs and NFs photodetectors, and ever reported photodetectors fabricated by using pristine ZnO nanostructures in thin film architecture. The adopted low cost and simplest approach makes the pristine ZnO-NSs applicable for wide wavelength applications in optoelectronic devices. PMID- 29118361 TI - Behavioral changes after nicotine challenge are associated with alpha7 nicotinic acetylcholine receptor-stimulated glutamate release in the rat dorsal striatum. AB - Neurochemical alterations associated with behavioral responses induced by re exposure to nicotine have not been sufficiently characterized in the dorsal striatum. Herein, we report on changes in glutamate concentrations in the rat dorsal striatum associated with behavioral alterations after nicotine challenge. Nicotine challenge (0.4 mg/kg/day, subcutaneous) significantly increased extracellular glutamate concentrations up to the level observed with repeated nicotine administration. This increase occurred in parallel with an increase in behavioral changes in locomotor and rearing activities. In contrast, acute nicotine administration and nicotine withdrawal on days 1 and 6 did not alter glutamate levels or behavioral changes. Blockade of alpha7 nicotinic acetylcholine receptors (nAChRs) significantly decreased the nicotine challenge induced increases in extracellular glutamate concentrations and locomotor and rearing activities. These findings suggest that behavioral changes in locomotor and rearing activities after re-exposure to nicotine are closely associated with hyperactivation of the glutamate response by stimulating alpha7 nAChRs in the rat dorsal striatum. PMID- 29118362 TI - Deconstructing atypical eye gaze perception in autism spectrum disorder. AB - The ability to discern the target of another person's gaze is critical for social and linguistic development, but functions atypically in autism spectrum disorder (ASD). A multi-pronged approach allowed us to deconstruct this complex ability, to uncover the fundamental bases of this impairment. We analyzed performance on a novel gaze perception task with classical psychophysical metrics (precision and accuracy), principal component analysis (in the analysis of spatial biases), and Bayesian computational modeling (in the analysis of individual subjects' use of contextual salience cues). Compared to controls, adults with ASD were less precise and less accurate in their judgments of gaze direction. Further, although nearly all controls exhibited a prototypical pattern of spatial bias in their judgments, this spatial prior was severely disrupted among a large subset of ASD participants. By contrast, Bayesian computational modeling revealed that both groups exploited contextual salience cues in their gaze judgments, and that the average strength of this contextual prior was similar for both groups. This comprehensive study revealed that although most ASD participants performed atypically in at least one aspect of gaze perception, the particular aspects disrupted varied idiosyncratically across individuals. Impairment in gaze perception in ASD likely arises via heterogeneous underlying mechanisms. PMID- 29118363 TI - Influence of hydrocarbon oil structure on adjuvanticity and autoimmunity. AB - Mineral oils are extensively used in our daily life, in food, cosmetics, biomedicine, vaccines and in different industrial applications. However, exposure to these mineral oils has been associated with immune adjuvant effects and the development of autoimmune diseases. Here we investigate the structural impacts of the hydrocarbon oil molecules on their adjuvanticity and autoimmunity. First, we showed that hydrocarbon oil molecules with small atomic differences could result in experimental arthritis in DA rats differing in disease severity, incidence, weight change and serum levels of acute phase proteins. Injection of these hydrocarbon oils resulted in the activation, proliferation and elevated expression of Th1 and especially Th17 cytokines by the T cells, which correlate with the arthritogenicity of the T cells. Furthermore, the more arthritogenic hydrocarbon oils resulted in an increased production of autoantibodies against cartilage joint specific, triple-helical type II collagen epitopes. When injected together with ovalbumin, the more arthritogenic hydrocarbon oils resulted in an increased production of alphabeta T cell-dependent anti-ovalbumin antibodies. This study shows the arthritogenicity of hydrocarbon oils is associated with their adjuvant properties with implications to not only arthritis research but also other diseases and medical applications such as vaccines in which oil adjuvants are involved. PMID- 29118364 TI - Experimental throughfall reduction barely affects soil carbon dynamics in a warm temperate oak forest, central China. AB - Changing precipitation patterns could affect soil carbon (C) cycling in China's forests. A throughfall reduction (TFR) experiment was conducted in a warm temperate oak forest in central China to examine effects of reduced precipitation on total soil respiration (SR), heterotrophic soil respiration (HR), autotrophic soil respiration (AR), soil microbial biomass, and fine root biomass from 2013 to 2016. Rain-out shelters, excluding ~50% of throughfall, were applied between May and September, thereby simulating a ~30% reduction in annual precipitation. Although soil moisture was significantly reduced during TFR, microbial biomass and HR remained unaffected. SR, AR, as well as fine root biomass increased during TFR in a comparable dry year, but remained unaffected during all other years. Annual rates of SR, HR, and AR were all unaffected by TFR. Our results indicate that a mild, steady, reduction in growing season precipitation does not affect soil organic matter decomposition in the oak forest ecosystem studied. Low SR rates during a natural dry-spell indicate that SR can be significantly decreased under more severe drought than imposed by the TFR treatment. Our data suggest a low soil moisture threshold of about 10 vol% for SR in the studied soil. PMID- 29118365 TI - Impaired development of the cerebral cortex in infants with congenital heart disease is correlated to reduced cerebral oxygen delivery. AB - Neurodevelopmental impairment is the most common comorbidity associated with complex congenital heart disease (CHD), while the underlying biological mechanism remains unclear. We hypothesised that impaired cerebral oxygen delivery in infants with CHD is a cause of impaired cortical development, and predicted that cardiac lesions most associated with reduced cerebral oxygen delivery would demonstrate the greatest impairment of cortical development. We compared 30 newborns with complex CHD prior to surgery and 30 age-matched healthy controls using brain MRI. The cortex was assessed using high resolution, motion-corrected T2-weighted images in natural sleep, analysed using an automated pipeline. Cerebral oxygen delivery was calculated using phase contrast angiography and pre ductal pulse oximetry, while regional cerebral oxygen saturation was estimated using near-infrared spectroscopy. We found that impaired cortical grey matter volume and gyrification index in newborns with complex CHD was linearly related to reduced cerebral oxygen delivery, and that cardiac lesions associated with the lowest cerebral oxygen delivery were associated with the greatest impairment of cortical development. These findings suggest that strategies to improve cerebral oxygen delivery may help reduce brain dysmaturation in newborns with CHD, and may be most relevant for children with CHD whose cardiac defects remain unrepaired for prolonged periods after birth. PMID- 29118366 TI - BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination. AB - The ATPase activity of NLRP3 has pivotal role in inflammasome activation and is recognized as a good target for the development of the NLRP3 inflammasome specific inhibitor. However, signals in the vicinity of the ATPase activity of NLRP3 have not been fully elucidated. Here, we demonstrate NLRP3 inflammasome specific action of a benzoxathiole derivative, BOT-4-one. BOT-4-one exhibited an inhibition of NLRP3 inflammasome activation, which was attributable to its alkylating capability to NLRP3. In particular, the NLRP3 alkylation by BOT-4-one led to an impaired ATPase activity of NLRP3, thereby obstructing the assembly of the NLRP3 inflammasome. Additionally, we found that NLRP3 alkylators, including BOT-4-one, enhance the ubiquitination level of NLRP3, which might also contribute to the inhibition of NLRP3 inflammasome activation. Finally, BOT-4-one appeared to be superior to other known NLRP3 alkylators in inhibiting the functionality of the NLRP3 inflammasome and its resulting anti-inflammatory activity was confirmed in vivo using a monosodium urate-induced peritonitis mouse model. Collectively, the results suggest that NLRP3 alkylators function by inhibiting ATPase activity and increasing the ubiquitination level of NLRP3, and BOT-4-one could be the type of NLRP3 inhibitor that may be potentially useful for the novel development of a therapeutic agent in controlling NLRP3 inflammasome-related diseases. PMID- 29118368 TI - Functional Group Effects on the Photoelectronic Properties of MXene (Sc2CT2, T = O, F, OH) and Their Possible Photocatalytic Activities. AB - In view of the diverse functional groups left on the MXene during the etching process, we computationally investigated the effects of surface-group types on the structural, electronic and optical properties of Sc2CT2 (T = -O, -OH, -F) MXenes. For all geometries of the Sc2CT2 MXenes, the geometry I of Sc2CT2, which has the functional groups locating above the opposite-side Sc atoms, are lowest energy structure. Accordingly, the energetically favorable Sc2CF2-I, Sc2CO2-I and Sc2C(OH)2-I were selected for further evaluation of the photocatalytic activities. We found that the Sc2CO2-I is metallic, while Sc2CF2-I and Sc2C(OH)2 are semiconductors with visible-light absorptions and promising carrier mobilities. Compared with the Sc2C(OH)2-I, the Sc2CF2-I has not only more suitable band gap (1.91 eV), but also the higher redox capability of photo activated carriers, which should have better photocatalytic performance. PMID- 29118367 TI - Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability. AB - Mutations in the HECT, UBA and WWE domain-containing 1 (HUWE1) E3 ubiquitin ligase cause neurodevelopmental disorder X-linked intellectual disability (XLID). HUWE1 regulates essential processes such as genome integrity maintenance. Alterations in the genome integrity and accumulation of mutations have been tightly associated with the onset of neurodevelopmental disorders. Though HUWE1 mutations are clearly implicated in XLID and HUWE1 regulatory functions well explored, currently much is unknown about the molecular basis of HUWE1-promoted XLID. Here we showed that the HUWE1 expression is altered and mutation frequency increased in three different XLID individual (HUWE1 p.R2981H, p.R4187C and HUWE1 duplication) cell lines. The effect was most prominent in HUWE1 p.R4187C XLID cells and was accompanied with decreased DNA repair capacity and hypersensitivity to oxidative stress. Analysis of HUWE1 substrates revealed XLID-specific down regulation of oxidative stress response DNA polymerase (Pol) lambda caused by hyperactive HUWE1 p.R4187C. The subsequent restoration of Pollambda levels counteracted the oxidative hypersensitivity. The observed alterations in the genome integrity maintenance may be particularly relevant in the cortical progenitor zones of human brain, as suggested by HUWE1 immunofluorescence analysis of cerebral organoids. These results provide evidence that impairments of the fundamental cellular processes, like genome integrity maintenance, characterize HUWE1-promoted XLID. PMID- 29118369 TI - Influence of non-thermal plasma on structural and electrical properties of globular and nanostructured conductive polymer polypyrrole in water suspension. AB - Non-thermal plasma has proved its benefits in medicine, plasma assisted polymerization, food industry and many other fields. Even though, the ability of non-thermal plasma to modify surface properties of various materials is generally known, only limited attention has been given to exploitations of this treatment on conductive polymers. Here, we show study of non-thermal plasma treatment on properties of globular and nanostructured polypyrrole in the distilled water. We observe that plasma presence over the suspension level doesn't change morphology of the polymer (shape), but significantly influences its elemental composition and physical properties. After 60 min of treatment, the relative concentration of chloride counter ions decreased approximately 3 and 4 times for nanostructured and globular form, respectively and concentration of oxygen increased approximately 3 times for both forms. Simultaneously, conductivity decrease (14 times for globular and 2 times for nanostructured one) and changes in zeta potential characteristics of both samples were observed. The modification evolution was dominated by multi-exponential function with time constants having values approximately 1 and 10 min for both samples. It is expected that these time constants are related to two modification processes connected to direct presence of the spark and to long-lived species generated by the plasma. PMID- 29118370 TI - All-Materials-Inclusive Flash Spark Plasma Sintering. AB - A new flash (ultra-rapid) spark plasma sintering method applicable to various materials systems, regardless of their electrical resistivity, is developed. A number of powders ranging from metals to electrically insulative ceramics have been successfully densified resulting in homogeneous microstructures within sintering times of 8-35 s. A finite element simulation reveals that the developed method, providing an extraordinary fast and homogeneous heating concentrated in the sample's volume and punches, is applicable to all the different samples tested. The utilized uniquely controllable flash phenomenon is enabled by the combination of the electric current concentration around the sample and the confinement of the heat generated in this area by the lateral thermal contact resistance. The presented new method allows: extending flash sintering to nearly all materials, controlling sample shape by an added graphite die, and an energy efficient mass production of small and intermediate size objects. This approach represents also a potential venue for future investigations of flash sintering of complex shapes. PMID- 29118371 TI - Genetic association analysis of microRNA137 and its target complex 1 with schizophrenia in Han Chinese. AB - Recent genome-wide association studies (GWAS) have identified a strong association signal of microRNA137 host gene (MIR137) with schizophrenia. MIR137 dysfunction results in downregulation of presynaptic target gene complexin 1 (CPLX1) and impairs synaptic plasticity in the hippocampus. In this study, we aimed to investigate whether the variants of MIR137 and CPLX1 confer susceptibility to schizophrenia in Han Chinese. This study employed 736 patients with schizophrenia patients and 751 well-matched healthy subjects for genetic analysis, and genotyped 12 SNPs within MIR137 and CPLX1. SZDB database was used to performed brain eQTL analysis. There were no significant differences of CPLX1 expression in hippocampus, prefrontal cortex or stratum between the schizophrenia patients and control subjects. No significant differences were observed in allele and genotype frequencies in studied SNPs between the case and control groups. Gene interaction analysis showed that MIR137 SNP rs1625579 did not affect schizophrenia susceptibility in interaction with the CPLX1 polymorphic variants. Our findings do not support MIR137 and CPLX1 conferring susceptibility to schizophrenia in Han Chinese. PMID- 29118372 TI - Human single chain-transbodies that bound to domain-I of non-structural protein 5A (NS5A) of hepatitis C virus. AB - A safe and broadly effective direct acting anti-hepatitis C virus (HCV) agent that can withstand the viral mutation is needed. In this study, human single chain antibody variable fragments (HuscFvs) to conserved non-structural protein 5A (NS5A) of HCV were produced by phage display technology. Recombinant NS5A was used as bait for fishing-out the protein bound-phages from the HuscFv-phage display library. NS5A-bound HuscFvs produced by five phage transfected-E. coli clones were linked molecularly to nonaarginine (R9) for making them cell penetrable (become transbodies). The human monoclonal transbodies inhibited HCV replication in the HCVcc infected human hepatic cells and also rescued the cellular antiviral immune response from the viral suppression. Computerized simulation verified by immunoassays indicated that the transbodies used several residues in their multiple complementarity determining regions (CDRs) to form contact interface with many residues of the NS5A domain-I which is important for HCV replication complex formation and RNA binding as well as for interacting with several host proteins for viral immune evasion and regulation of cellular physiology. The human monoclonal transbodies have high potential for testing further as a new ramification of direct acting anti-HCV agent, either alone or in combination with their cognates that target other HCV proteins. PMID- 29118373 TI - Establishing zebrafish as a model to study the anxiolytic effects of scopolamine. AB - Scopolamine (hyoscine) is a muscarinic acetylcholine receptor antagonist that has traditionally been used to treat motion sickness in humans. However, studies investigating depressed and bipolar populations have found that scopolamine is also effective at reducing depression and anxiety symptoms. The potential anxiety reducing (anxiolytic) effects of scopolamine could have great clinical implications for humans; however, rats and mice administered scopolamine showed increased anxiety in standard behavioural tests. This is in direct contrast to findings in humans, and complicates studies to elucidate the specific mechanisms of scopolamine action. The aim of this study was to assess the suitability of zebrafish as a model system to test anxiety-like compounds using scopolamine. Similar to humans, scopolamine acted as an anxiolytic in individual behavioural tests (novel approach test and novel tank diving test). The anxiolytic effect of scopolamine was dose dependent and biphasic, reaching maximum effect at 800 uM. Scopolamine (800 uM) also had an anxiolytic effect in a group behavioural test, as it significantly decreased their tendency to shoal. These results establish zebrafish as a model organism for studying the anxiolytic effects of scopolamine, its mechanisms of action and side effects. PMID- 29118374 TI - The Bacillus BioBrick Box 2.0: expanding the genetic toolbox for the standardized work with Bacillus subtilis. AB - Standardized and well-characterized genetic building blocks allow the convenient assembly of novel genetic modules and devices, ensuring reusability of parts and reproducibility of experiments. In the first Bacillus subtilis-specific toolbox using the BioBrick standard, we presented integrative vectors, promoters, reporter genes and epitope tags for this Gram-positive model bacterium. With the Bacillus BioBrick Box 2.0, we significantly expand the range of our toolbox by providing new integrative vectors, introducing novel tools for fine-tuning protein expression, and carefully evaluating codon-adapted fluorescence proteins in B. subtilis, which cover the whole spectrum of visible light. Moreover, we developed new reporter systems to allow evaluating the strength of promoters and ribosome binding sites. This well-evaluated extension of our BioBrick-based toolbox increases the accessibility of B. subtilis and will therefore promote the use of this model bacterium and biotechnological workhorse as a host for fundamental and applied Synthetic Biology projects. PMID- 29118375 TI - The lipid raft-dwelling protein US9 can be manipulated to target APP compartmentalization, APP processing, and neurodegenerative disease pathogenesis. AB - The trafficking behavior of the lipid raft-dwelling US9 protein from Herpes Simplex Virus strikingly overlaps with that of the amyloid precursor protein (APP). Both US9 and APP processing machinery rely on their ability to shuttle between endosomes and plasma membranes, as well as on their lateral accumulation in lipid rafts. Therefore, repurposing US9 to track/modify these molecular events represents a valid approach to investigate pathological states including Alzheimer's disease and HIV-associated neurocognitive disorders where APP misprocessing to amyloid beta formation has been observed. Accordingly, we investigated the cellular localization of US9-driven cargo in neurons and created a US9-driven functional assay based on the exogenous enzymatic activity of Tobacco Etch Virus Protease. Our results demonstrate that US9 can direct and control cleavage of recombinant proteins exposed on the luminal leaflet of transport vesicles. Furthermore, we confirmed that US9 is associated with lipid rafts and can target functional enzymes to membrane microdomains where pathologic APP-processing is thought to occur. Overall, our results suggest strongly that US9 can serve as a molecular driver that targets functional cargos to the APP machinery and can be used as a tool to study the contribution of lipid rafts to neurodegenerative disease conditions where amyloidogenesis has been implicated. PMID- 29118376 TI - Novel Plasmodium antigens identified via genome-based antibody screen induce protection associated with polyfunctional T cell responses. AB - The development of vaccines against complex intracellular pathogens, such as Plasmodium spp., where protection is likely mediated by cellular immune responses, has proven elusive. The availability of whole genome, proteome and transcriptome data has the potential to advance rational vaccine development but yet there are no licensed vaccines against malaria based on antigens identified from genomic data. Here, we show that the Plasmodium yoelii orthologs of four Plasmodium falciparum proteins identified by an antibody-based genome-wide screening strategy induce a high degree of sterile infection-blocking protection against sporozoite challenge in a stringent rodent malaria model. Protection increased in multi-antigen formulations. Importantly, protection was highly correlated with the induction of multifunctional triple-positive T cells expressing high amounts of IFN-gamma, IL-2 and TNF. These data demonstrate that antigens identified by serological screening are targets of multifunctional cellular immune responses that correlate with protection. Our results provide experimental validation for the concept of rational vaccine design from genomic sequence data. PMID- 29118377 TI - Gender composition mediates social facilitation effect in co-action condition. AB - Working with co-actors is a common work-organization mode. Whether the presence of opposite-sex co-actors (OCs) can induce social facilitation effect and how an actor's performance is influenced by the gender composition of co-actors remain unknown. The present study aims to examine the influence of the gender composition of co-actors on the intensity of the social facilitation effect. In Experiment 1, participants performed visual search tasks alone and in six co action conditions with varying gender compositions. In Experiment 2, the participants performed modular arithmetic tasks in three conditions with electroencephalogram activity recorded and salivary cortisol measured: alone, with a same-sex co-actor (SC), and with an OC. Results indicated that the social facilitation effect was stronger in the presence of OCs than in the presence of only SCs. The intensities of social facilitation effect resulting from the varying gender composition of co-actors were obtained and compared. A participant's power of alpha band was lower, whereas power of beta band and normalised cortisol level were higher in the presence of an OC than in the presence of an SC. These findings provide insights into the influencing mechanisms of gender composition on the intensity of the social facilitation effect in the co-action condition. PMID- 29118378 TI - The Association between Galectin-3 and hs-CRP and the Clinical Outcome after Non ST-Elevation Myocardial Infarction with Preexisting Atrial Fibrillation. AB - Increased galectin-3 plasma concentration has been linked to an unfavorable outcome in patients with heart failure or atrial fibrillation (AF). There are no published data about the prognostic utility of galectin-3 and high-sensitivity C reactive protein (hs-CRP) for long-term clinical outcome in the Non-ST elevation acute myocardial infarction (NSTEMI) patients with preexisting AF. Thirty-two patients with the first acute NSTEMI and preexisting AF and 22 patients without preexisting AF, were prospectively followed for fifteen months. Patients with AF had significantly higher galectin-3 plasma levels (p < 0.05) and hs-CRP concentration (p < 0.01), compared with patients without AF. Galectin-3 plasma concentration was not a significant covariate of the composite outcomes (p = 0.913). Patients with high hs-CRP (above 4.55 mg/L) showed 2.5 times increased risk (p < 0.05) of the composite outcome occurrence (p < 0.05). Besides, three vessel coronary artery disease, creatinine serum level, and creatinine clearance were significant covariates (p < 0.05; p < 0.05; p < 0.01) of the composite outcome, respectively. Creatinine clearance, solely, has been shown to be an independent predictor of unfavorable prognosis after a 15-month follow-up. Galectin-3 and hs-CRP plasma levels were elevated in NSTEMI patients with AF, but with differential predictive value for an unfavorable clinical outcome. Only hs CRP was associated with increased risk of composite outcome occurrence. PMID- 29118379 TI - A new antagonist for CCR4 attenuates allergic lung inflammation in a mouse model of asthma. AB - CCR4 is highly expressed on Th2 cells. CCR4 ligands include CCL22 and CCL17. Chemokine-like factor 1 can also mediate chemotaxis via CCR4. We designed and synthetized novel CCR4 antagonists, which were piperazinyl pyridine derivatives, for disrupting the interaction between three ligands and CCR4. We also determined whether these novel CCR4 antagonists could alleviate allergic asthma in a mouse. For identifying the potent compounds in vitro, we used chemotaxis inhibition and competition binding assays induced by CCL22, CCL17 and one of CKLF1's C-terminal peptides, C27. We found compound 8a which showed excellent potency in blocking the interaction of CCR4 and its three ligands. For studying the specificity of compounds, we chose chemotaxis inhibition assays with different receptors and ligands. We found compound 8a had excellent receptor specificity and exerted few influence on the interaction of other receptors and their ligands. In the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, compound 8a had no obvious cytotoxicity till the higher concentration (16 MUM). For determining the potency of compounds in blocking the interaction of CCR4 in vivo, we used the ovalbumin induced allergic asthma model in mice. Our study demonstrated that CCR4 blockaded by compound 8a effectively attenuated airway hyperresponsiveness, airway eosinophilia and Th2 cytokines. PMID- 29118380 TI - Delivery of the gene encoding the tumor suppressor Sef into prostate tumors by therapeutic-ultrasound inhibits both tumor angiogenesis and growth. AB - Carcinomas constitute over 80% of all human cancer types with no effective therapy for metastatic disease. Here, we demonstrate, for the first time, the efficacy of therapeutic-ultrasound (TUS) to deliver a human tumor suppressor gene, hSef-b, to prostate tumors in vivo. Sef is downregulated in various human carcinomas, in a manner correlating with tumor aggressiveness. In vitro, hSef-b inhibited proliferation of TRAMP C2 cells and attenuated activation of ERK/MAPK and the master transcription factor NF-kappaB in response to FGF and IL-1/TNF, respectively. In vivo, transfection efficiency of a plasmid co-expressing hSef b/eGFP into TRAMP C2 tumors was 14.7 +/- 2.5% following a single TUS application. Repeated TUS treatments with hSef-b plasmid, significantly suppressed prostate tumor growth (60%) through inhibition of cell proliferation (60%), and reduction in blood vessel density (56%). In accordance, repeated TUS-treatments with hSef-b significantly inhibited in vivo expression of FGF2 and MMP-9. FGF2 is a known mitogen, and both FGF2/MMP-9 are proangiogenic factors. Taken together our results strongly suggest that hSef-b acts in a cell autonomous as well as non cell autonomous manner. Moreover, the study demonstrates the efficacy of non viral TUS-based hSef-b gene delivery approach for the treatment of prostate cancer tumors, and possibly other carcinomas where Sef is downregulated. PMID- 29118382 TI - Quantifying the potential for bursting bubbles to damage suspended cells. AB - Bubbles that rise to the surface of a cell suspension can damage cells when they pop. This phenomenon is particularly problematic in the biotechnology industry, as production scale bioreactors require continuous injection of oxygen bubbles to maintain cell growth. Previous studies have linked cell damage to high energy dissipation rates (EDR) and have predicted that for small bubbles the EDR could exceed values that would kill many cells used in bioreactors, including Chinese Hamster Ovary (CHO) cells. However, it's unclear how many cells would be damaged by a particular bursting bubble, or more precisely how much volume around the bubble experiences these large energy dissipation rates. Here we quantify these volumes using numerical simulations and demonstrate that even though the volume exceeding a particular EDR increases with bubble size, on a volume-to-volume basis smaller bubbles have a more significant impact. We validate our model with high-speed experiments and present our results in a non-dimensionalized framework, enabling predictions for a variety of liquids and bubble sizes. The results are not restricted to bubbles in bioreactors and may be relevant to a variety of applications ranging from fermentation processes to characterizing the stress levels experienced by microorganisms within the sea surface microlayer. PMID- 29118381 TI - A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. AB - Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field. PMID- 29118383 TI - Impact of Lactobacillus reuteri colonization on gut microbiota, inflammation, and crying time in infant colic. AB - Infant colic is a distressing condition of unknown etiology. An aberrant gastrointestinal microbiota has been associated, and Lactobacillus reuteri supplementation has been shown to reduce crying and/or fussing time ('crying time') in some infants with colic. The relationship between L. reuteri gut colonization and crying time has not been examined. We investigated the relationship between L. reuteri colonization and fecal microbiota (microbial diversity and Escherichia coli), intestinal inflammation, and crying time in infants with colic, using a subset of 65 infants from the Baby Biotics trial, which randomized healthy term infants aged <13 weeks with infant colic to receive probiotic L. reuteri DSM 17938 (1 * 108 colony forming units) or placebo daily for 28 days. We observed an overall reduction in median crying time, regardless of L. reuteri colonization status (n = 14 colonized). There were no differences in E. coli colonization rates or densities, microbial diversity or intestinal inflammation by L. reuteri colonization status. We found that L. reuteri density positively correlated with crying time, and E. coli density negatively correlated with microbial diversity. As density of L. reuteri was associated with increased crying time, L. reuteri supplementation may not be an appropriate treatment for all infants with colic. PMID- 29118384 TI - The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation. AB - Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma. To more fully characterize the genomic landscape of this tumor type, we performed next generation sequencing studies for mutational and copy number analysis. We analyzed whole exome sequencing data from 12 MPNST and SNP arrays for a subset of these. We additionally conducted a literature review of prior next generation sequencing studies in this disease and compared to the current study. We report recurrent mutations in NF1, SUZ12, EED, TP53 and CDKN2A in our study cohort. Combined with prior studies, we calculate the disease specific incidence of mutation in these genes to be: NF1 (56/64 = 87.5%). SUZ12 (69/123 = 56.1%), EED (40/123 = 32.5%), TP53 (29/72 = 40.3%), and CDKN2A (54/72 = 75.0%). Notably, we also identified frequent Ras pathway activating somatic mutations outside of these previously reported recurrently mutated genes. Five of the 12 MPNST in our cohort (42%) contained such a mutation. In conclusion, our study adds to the growing understanding of the genomic complexity of MPNST. We report a previously underappreciated frequency and variety of secondary or tertiary Ras pathway activating mutations, though not highly recurrent in a single gene. PMID- 29118385 TI - Enhanced physicochemical properties of polydimethylsiloxane based microfluidic devices and thin films by incorporating synthetic micro-diamond. AB - Synthetic micro-diamond-polydimethylsiloxane (PDMS) composite microfluidic chips and thin films were produced using indirect 3D printing and spin coating fabrication techniques. Microfluidic chips containing up to 60 wt% micro-diamond were successfully cast and bonded. Physicochemical properties, including the dispersion pattern, hydrophobicity, chemical structure, elasticity and thermal characteristics of both chip and films were investigated. Scanning electron microscopy indicated that the micro-diamond particles were embedded and interconnected within the bulk material of the cast microfluidic chip, whereas in the case of thin films their increased presence at the polymer surface resulted in a reduced hydrophobicity of the composite. The elastic modulus increased from 1.28 for a PDMS control, to 4.42 MPa for the 60 wt% composite, along with a three fold increase in thermal conductivity, from 0.15 to 0.45 W m-1 K-1. Within the fluidic chips, micro-diamond incorporation enhanced heat dissipation by efficient transfer of heat from within the channels to the surrounding substrate. At a flow rate of 1000 MUL/min, the gradient achieved for the 60 wt% composite chip equalled a 9.8 degrees C drop across a 3 cm long channel, more than twice that observed with the PDMS control chip. PMID- 29118386 TI - Code-modulated visual evoked potentials using fast stimulus presentation and spatiotemporal beamformer decoding. AB - When encoding visual targets using various lagged versions of a pseudorandom binary sequence of luminance changes, the EEG signal recorded over the viewer's occipital pole exhibits so-called code-modulated visual evoked potentials (cVEPs), the phase lags of which can be tied to these targets. The cVEP paradigm has enjoyed interest in the brain-computer interfacing (BCI) community for the reported high information transfer rates (ITR, in bits/min). In this study, we introduce a novel decoding algorithm based on spatiotemporal beamforming, and show that this algorithm is able to accurately identify the gazed target. Especially for a small number of repetitions of the coding sequence, our beamforming approach significantly outperforms an optimised support vector machine (SVM)-based classifier, which is considered state-of-the-art in cVEP based BCI. In addition to the traditional 60 Hz stimulus presentation rate for the coding sequence, we also explore the 120 Hz rate, and show that the latter enables faster communication, with a maximal median ITR of 172.87 bits/min. Finally, we also report on a transition effect in the EEG signal following the onset of the stimulus sequence, and recommend to exclude the first 150 ms of the trials from decoding when relying on a single presentation of the stimulus sequence. PMID- 29118387 TI - Flat-band light dynamics in Stub photonic lattices. AB - We experimentally study a Stub photonic lattice and excite their localized linear states originated from an isolated Flat Band at the center of the linear spectrum. By exciting these modes in different regions of the lattice, we observe that they do not diffract across the system and remain well trapped after propagating along the crystal. By using their wave nature, we are able to combine - in phase and out of phase - two neighbor states into a coherent superposition. These observations allow us to propose a novel setup for performing three different all-optical logical operations such as OR, AND, and XOR, positioning Flat Band systems as key setups to perform all-optical operations at any level of power. PMID- 29118392 TI - Control of evaporation by geometry in capillary structures. From confined pillar arrays in a gap radial gradient to phyllotaxy-inspired geometry. AB - Evaporation is a key phenomenon in the natural environment and in many technological systems involving capillary structures. Understanding the evaporation front dynamics enables the evaporation rate from microfluidic devices and porous media to be finely controlled. Of particular interest is the ability to control the position of the front through suitable design of the capillary structure. Here, we show how to design model capillary structures in microfluidic devices so as to control the drying kinetics. This is achieved by acting on the spatial organization of the constrictions that influence the invasion of the structure by the gas phase. Two types of control are demonstrated. The first is intended to control the sequence of primary invasions through the pore space, while the second aims to control the secondary liquid structures: films, bridges, etc., that can form in the region of pore space invaded by the gas phase. It is shown how the latter can be obtained from phyllotaxy-inspired geometry. Our study thus opens up a route toward the control of the evaporation kinetics by means of tailored capillary structures. PMID- 29118388 TI - Near infrared light decreases synaptic vulnerability to amyloid beta oligomers. AB - Synaptic dysfunction due to the disrupting binding of amyloid beta (Abeta) and tau oligomers is one of the earliest impairments in Alzheimer's Disease (AD), driving initial cognitive deficits and clinical manifestation. Consequently, there is ample consensus that preventing early synaptic dysfunction would be an effective therapeutic strategy for AD. With this goal in mind, we investigated the effect of a treatment of mice with near infrared (NIR) light on synaptic vulnerability to Abeta oligomers. We found that Abeta oligomer binding to CNS synaptosomes isolated from wild type (wt) mice treated with NIR light was significantly reduced and the resulting suppression of long term potentiation (LTP) by Abeta oligomers was prevented. Similarly, APP transgenic mice treated with NIR showed a significant reduction of endogenous Abeta at CNS synapses. We further found that these phenomena were accompanied by increased synaptic mitochondrial membrane potential in both wt and Tg2576 mice. This study provides evidence that NIR light can effectively reduce synaptic vulnerability to damaging Abeta oligomers, thus furthering NIR light therapy as a viable treatment for AD. PMID- 29118393 TI - Birth of an oceanic spreading center at a magma-poor rift system. AB - Oceanic crust is continuously created at mid-oceanic ridges and seafloor spreading represents one of the main processes of plate tectonics. However, if oceanic crust architecture, composition and formation at present-day oceanic ridges are largely described, the processes governing the birth of a spreading center remain enigmatic. Understanding the transition between inherited continental and new oceanic domains is a prerequisite to constrain one of the last major unsolved problems of plate tectonics, namely the formation of a stable divergent plate boundary. In this paper, we present newly released high resolution seismic reflection profiles that image the complete transition from unambiguous continental to oceanic crusts in the Gulf of Guinea. Based on these high-resolution seismic sections we show that onset of oceanic seafloor spreading is associated with the formation of a hybrid crust in which thinned continental crust and/or exhumed mantle is sandwiched between magmatic intrusive and extrusive bodies. This crust results from a polyphase evolution showing a gradual transition from tectonic-driven to magmatic-driven processes. The results presented in this paper provide a characterization of the domain in which lithospheric breakup occurs and enable to define the processes controlling formation of a new plate boundary. PMID- 29118394 TI - An apelin receptor antagonist prevents pathological retinal angiogenesis with ischemic retinopathy in mice. AB - Pathological retinal angiogenesis is caused by the progression of ischemic retinal diseases and can result in retinal detachment and irreversible blindness. This neovascularization is initiated from the retinal veins and their associated capillaries and involves the overgrowth of vascular endothelial cells. Since expression of the apelin receptor (APJ) is restricted to the veins and proliferative endothelial cells during physiological retinal angiogenesis, in the present study, we investigated the effect of APJ inhibition on pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). In vitro experiments revealed that ML221, an APJ antagonist, suppressed cultured endothelial cell proliferation in a dose-dependent manner. Intraperitoneal administration of ML221 inhibited pathological angiogenesis but enhanced the recovery of normal vessels into the ischemic regions in the retina of the OIR model mice. ML221 did not affect the expression levels of vascular endothelial growth factor (VEGF) and its receptor (VEGFR2) in the retina. APJ was highly expressed in the endothelial cells within abnormal vessels but was only detected in small amounts in morphologically normal vessels. These results suggest that APJ inhibitors selectively prevent pathological retinal angiogenesis and that the drugs targeting APJ may be new a candidate for treating ischemic retinopathy. PMID- 29118395 TI - Anisotropic attosecond charge carrier dynamics and layer decoupling in quasi-2D layered SnS2. AB - Strong quantum confinement effects lead to striking new physics in two dimensional materials such as graphene or transition metal dichalcogenides. While spectroscopic fingerprints of such quantum confinement have been demonstrated widely, the consequences for carrier dynamics are at present less clear, particularly on ultrafast timescales. This is important for tailoring, probing, and understanding spin and electron dynamics in layered and two-dimensional materials even in cases where the desired bandgap engineering has been achieved. Here we show by means of core-hole clock spectroscopy that SnS2 exhibits spin dependent attosecond charge delocalization times (tau deloc) for carriers confined within a layer, tau deloc < 400 as, whereas interlayer charge delocalization is dynamically quenched in excess of a factor of 10, tau deloc > 2.7 fs. These layer decoupling dynamics are a direct consequence of strongly anisotropic screening established within attoseconds, and demonstrate that important two-dimensional characteristics are also present in bulk crystals of van der Waals-layered materials, at least on ultrafast timescales. PMID- 29118396 TI - Engineering Saccharomyces cerevisiae for geranylgeraniol overproduction by combinatorial design. AB - Combinatorial design is an effective strategy to acquire the optimal solution in complex systems. In this study, the combined effects of pathway combination, promoters' strength fine-tuning, copy numbers and integration locus variations caused by delta-integration were explored in Saccharomyces cerevisiae using geranylgeraniol (GGOH) production as an example. Two GGOH biosynthetic pathway branches were constructed. In branch 1, GGOH was converted from isopentenyl pyrophosphate (IPP) and farnesyl diphosphate (FPP). In branch 2, GGOH was derived directly from IPP and dimethylallyl pyrophosphate (DMAPP). Regulated by 10 combinations of 11 diverse promoters, a fusion gene BTS1-ERG20, a heterologous geranylgeranyl diphosphate synthase from Sulfolobus acidocaldarius (GGPPSsa) and an endogenous N-terminal truncated gene 3-hydroxyl-3-methylglutaryl-CoA reductase isoenzyme 1 (tHMGR), were incorporated into yeast by delta-integration, leading to a series of GGOH producing strains with yields ranging from 18.45 mg/L to 161.82 mg/L. The yield was further increased to 437.52 mg/L by optimizing the fermentation medium. Consequently, the GGOH yield reached 1315.44 mg/L in a 5-L fermenter under carbon restriction strategy. Our study not only opens large opportunities for downstream diterpenes overproductions, but also demonstrates that pathway optimization based on combinatorial design is a promising strategy to engineer microbes for overproducing natural products with complex structure. PMID- 29118398 TI - Updating the Geologic Barcodes for South China: Discovery of Late Archean Banded Iron Formations in the Yangtze Craton. AB - Banded iron formations (BIFs) in Archean cratons provide important "geologic barcodes" for the global correlation of Precambrian sedimentary records. Here we report the first finding of late Archean BIFs from the Yangtze Craton, one of largest Precambrian blocks in East Asia with an evolutionary history of over 3.3 Ga. The Yingshan iron deposit at the northeastern margin of the Yangtze Craton, displays typical features of BIF, including: (i) alternating Si-rich and Fe-rich bands at sub-mm to meter scales; (ii) high SiO2 + Fe2O3total contents (average 90.6 wt.%) and Fe/Ti ratios (average 489); (iii) relative enrichment of heavy rare earth elements and positive Eu anomalies (average 1.42); (iv) and sedimentary Fe isotope compositions (delta56FeIRMM-014 as low as -0.360/00). The depositional age of the BIF is constrained at ~2464 +/- 24 Ma based on U-Pb dating of zircon grains from a migmatite sample of a volcanic protolith that conformably overlied the Yingshan BIF. The BIF was intruded by Neoproterozoic (805.9 +/- 4.7 Ma) granitoids that are unique in the Yangtze Craton but absent in the North China Craton to the north. The discovery of the Yingshan BIF provides new constraints for the tectonic evolution of the Yangtze Craton and has important implications in the reconstruction of Pre-Nuna/Columbia supercontinent configurations. PMID- 29118397 TI - The Kunitz Domain I of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cells. AB - Dysregulation of pericellular proteolysis is often required for tumor invasion and cancer progression. It has been shown that down-regulation of hepatocyte growth factor activator inhibitor-2 (HAI-2) results in activation of matriptase (a membrane-anchored serine protease), human prostate cancer cell motility and tumor growth. In this study, we further characterized if HAI-2 was a cognate inhibitor for matriptase and identified which Kunitz domain of HAI-2 was required for inhibiting matriptase and human prostate cancer cell motility. Our results show that HAI-2 overexpression suppressed matriptase-induced prostate cancer cell motility. We demonstrate that HAI-2 interacts with matriptase on cell surface and inhibits matriptase proteolytic activity. Moreover, cellular HAI-2 harnesses its Kunitz domain 1 (KD1) to inhibit matriptase activation and prostate cancer cell motility although recombinant KD1 and KD2 of HAI-2 both show an inhibitory activity and interaction with matriptase protease domain. The results together indicate that HAI-2 is a cognate inhibitor of matriptase, and KD1 of HAI-2 plays a major role in the inhibition of cellular matritptase activation as well as human prostate cancer invasion. PMID- 29118399 TI - Gravitational Field effects on the Decoherence Process and the Quantum Speed Limit. AB - In this paper we use spinor transformations under local Lorentz transformations to investigate the curvature effect on the quantum-to-classical transition, described in terms of the decoherence process and of the quantum speed limit. We find that gravitational fields (introduced adopting the Schwarzschild and anti-de Sitter geometries) affect both the decoherence process and the quantum speed limit of a quantum particle with spin-1/2. In addition, as a tangible example, we study the effect of the Earth's gravitational field, characterized by the Rindler space-time, on the same particle. We find that the effect of the Earth's gravitational field on the decoherence process and quantum speed limit is very small, except when the mean speed of the quantum particle is comparable to the speed of light. PMID- 29118401 TI - Slow waves in locally resonant metamaterials line defect waveguides. AB - Many efforts have been devoted to wave slowing, as it is essential, for instance, in analog signal computing and is one prerequisite for increased wave/matter interactions. Despite the interest of many communities, researches have mostly been conducted in optics, where wavelength-scaled structured composite media are promising candidates for compact slow light components. Yet their structural scale prevents them from being transposed to lower frequencies. Here, we propose to overcome this limitation using the deep sub-wavelength scale of locally resonant metamaterials. We experimentally show, in the microwave regime, that introducing coupled resonant defects in such metamaterials creates sub-wavelength waveguides in which wave propagation exhibit reduced group velocities. We qualitatively explain the mechanism underlying this slow wave propagation and demonstrate how it can be used to tune the velocity, achieving group indices as high as 227. We conclude by highlighting the three beneficial consequences of our line defect slow wave waveguides: (1) the sub-wavelength scale making it a compact platform for low frequencies (2) the large group indices that together with the extreme field confinement enables efficient wave/matter interactions and (3) the fact that, contrarily to other approaches, slow wave propagation does not occur at the expense of drastic bandwidth reductions. PMID- 29118400 TI - Differential transcriptome regulation by 3,5-T2 and 3',3,5-T3 in brain and liver uncovers novel roles for thyroid hormones in tilapia. AB - Although 3,5,3'-triiodothyronine (T3) is considered to be the primary bioactive thyroid hormone (TH) due to its high affinity for TH nuclear receptors (TRs), new data suggest that 3,5-diiodothyronine (T2) can also regulate transcriptional networks. To determine the functional relevance of these bioactive THs, RNA-seq analysis was conducted in the cerebellum, thalamus-pituitary and liver of tilapia treated with equimolar doses of T2 or T3. We identified a total of 169, 154 and 2863 genes that were TH-responsive (FDR < 0.05) in the tilapia cerebellum, thalamus-pituitary and liver, respectively. Among these, 130, 96 and 349 genes were uniquely regulated by T3, whereas 22, 40 and 929 were exclusively regulated by T2 under our experimental paradigm. The expression profiles in response to TH treatment were tissue-specific, and the diversity of regulated genes also resulted in a variety of different pathways being affected by T2 and T3. T2 regulated gene networks associated with cell signalling and transcriptional pathways, while T3 regulated pathways related to cell signalling, the immune system, and lipid metabolism. Overall, the present work highlights the relevance of T2 as a key bioactive hormone, and reveals some of the different functional strategies that underpin TH pleiotropy. PMID- 29118402 TI - Influences of anthropogenic land use on microbial community structure and functional potentials of stream benthic biofilms. AB - Stream ecosystems are the primary receivers of nutrient and organic carbon exported from terrestrial ecosystems and are profoundly influenced by the land use of the surrounding landscape. The aquatic impacts of anthropogenic land use are often first observed in stream benthic biofilms. We studied the benthic biofilms in streams flowing through forest (upstream) and anthropogenic land use (downstream) areas in southwestern China. The results showed that anthropogenic land use increased nutrient and organic carbon in both stream water and benthic biofilms, which are closely related to the differences in the microbial communities. The taxonomic dissimilarity of the communities was significantly correlated with the functional gene dissimilarity, and the upstream sites had more distinct functional genes. Network analysis showed that upstream sites had more highly connected microbial networks. Furthermore, downstream sites had higher relative abundances of anammox and denitrification suggesting stronger nitrogen removal than upstream sites. Increased nutrients in both the stream water and biofilms caused by anthropogenic land use had severe impacts on the nitrogen cycle in stream ecosystems. Downstream sites also had stronger carbon metabolism than upstream sites. This study provides insights into the influences of anthropogenic land use on microbial community structure and functions of stream benthic biofilms. PMID- 29118403 TI - Quantitative text feature analysis of autobiographical interview data: prediction of episodic details, semantic details and temporal discounting. AB - Autobiographical memory and episodic future thinking (i.e. the capacity to project oneself into an imaginary future) are typically assessed using the Autobiographical Interview (AI). In the AI, subjects are provided with verbal cues (e.g. "your wedding day") and are asked to freely recall (or imagine) the cued past (or future) event. Narratives are recorded, transcribed and analyzed using an established manual scoring procedure (Levine et al., 2002). Here we applied automatic text feature extraction methods to a relatively large (n = 86) set of AI data. In a first proof-of-concept approach, we used regression models to predict internal (episodic) and semantic detail sum scores from low-level linguistic features. Across a range of different regression methods, prediction accuracy averaged at about 0.5 standard deviations. Given the known association of episodic future thinking with temporal discounting behavior, i.e. the preference for smaller-sooner over larger-later rewards, we also ran models predicting temporal discounting directly from linguistic features of AI narratives. Here, prediction accuracy was much lower, but involved the same text feature components as prediction of internal (episodic) details. Our findings highlight the potential feasibility of using tools from quantitative text analysis to analyze AI datasets, and we discuss potential future applications of this approach. PMID- 29118405 TI - Extreme behavioural shifts by baboons exploiting risky, resource-rich, human modified environments. AB - A range of species exploit anthropogenic food resources in behaviour known as 'raiding'. Such behavioural flexibility is considered a central component of a species' ability to cope with human-induced environmental changes. Here, we study the behavioural processes by which raiding male chacma baboons (Papio ursinus) exploit the opportunities and mitigate the risks presented by raiding in the suburbs of Cape Town, South Africa. Ecological sampling and interviews conducted with 'rangers' (employed to manage the baboons' space use) revealed that baboons are at risk of being herded out of urban spaces that contain high-energy anthropogenic food sources. Baboon-attached motion/GPS tracking collars showed that raiding male baboons spent almost all of their time at the urban edge, engaging in short, high-activity forays into the urban space. Moreover, activity levels were increased where the likelihood of deterrence by rangers was greater. Overall, these raiding baboons display a time-activity balance that is drastically altered in comparison to individuals living in more remote regions. We suggest our methods can be used to obtain precise estimates of management impact for this and other species in conflict with people. PMID- 29118404 TI - A POCS super resolution restoration algorithm based on BM3D. AB - The inherent shortcoming of POCS (Projection Onto Convex Sets) is its sensitiveness to noise. The restoration quality of POCS based super resolution will severely decline when the noise is larger. In practical applications, the low resolution images generally include some kinds of noise, such as camera internal noise, transmission system noise and coherent noise. Therefore POCS cannot be used directly in super-resolution restoration for observed low resolution images. In order to solve the noise sensitive problem of the traditional POCS restoration algorithm, we firstly propose to optimize the BM3D (Block-Matching 3D) filtering by mean pre-screening of image blocks and limiting the number of image blocks. Then we combine the optimized BM3D filtering with POCS restoration in this paper. Experimental results show that the proposed POCS super resolution restoration algorithm based on BM3D can achieve better restoration effect when the low resolution images contain noise. Furthermore no noise can be perceived in the restored high resolution image basically. PMID- 29118406 TI - Single-cell Co-expression Subnetwork Analysis. AB - Single-cell transcriptomic data have rapidly become very popular in genomic science. Genomic science also has a long history of using network models to understand the way in which genes work together to carry out specific biological functions. However, working with single-cell data presents major challenges, such as zero inflation and technical noise. These challenges require methods to be specifically adapted to the context of single-cell data. Recently, much effort has been made to develop the theory behind statistical network models. This has lead to many new models being proposed, and has provided a thorough understanding of the properties of existing models. However, a large amount of this work assumes binary-valued relationships between network nodes, whereas genomic network analysis is traditionally based on continuous-valued correlations between genes. In this paper, we assess several established methods for genomic network analysis, we compare ways that these methods can be adapted to the single-cell context, and we use mixture-models to infer binary-valued relationships based on gene-gene correlations. Based on these binary relationships, we find that excellent results can be achieved by using subnetwork analysis methodology popular amongst network statisticians. This methodology thereby allows detection of functional subnetwork modules within these single-cell genomic networks. PMID- 29118408 TI - High Energy Conversion Efficiency with 3-D Micro-Patterned Photoanode for Enhancement Diffusivity and Modification of Photon Distribution in Dye-Sensitized Solar Cells. AB - Dye sensitize solar cells (DSSCs) have been considered as the promising alternatives silicon based solar cell with their characteristics including high efficiency under weak illumination and insensitive power output to incident angle. Therefore, many researches have been studied to improve the energy conversion efficiency of DSSCs. However the efficiency of DSSCs are still trapped at the around 10%. In this study, micro-scale hexagonal shape patterned photoanode have proposed to modify light distribution of photon. In the patterned electrode, the appearance efficiency have been obtained from 7.1% to 7.8% considered active area and the efficiency of 12.7% have been obtained based on the photoanode area. Enhancing diffusion of electrons and modification of photon distribution utilizing the morphology of the electrode are major factors to improving the performance of patterned electrode. Also, finite element method analyses of photon distributions were conducted to estimate morphological effect that influence on the photon distribution and current density. From our proposed study, it is expecting that patterned electrode is one of the solution to overcome the stagnant efficiency and one of the optimized geometry of electrode to modify photon distribution. Process of inter-patterning in photoanode has been minimized. PMID- 29118407 TI - Transparent, abrasion-insensitive superhydrophobic coatings for real-world applications. AB - Superhydrophobic surfaces and surface coatings are of high interest for many applications in everyday life including non-wetting and low-friction coatings as well as functional clothing. Manufacturing of these surfaces is intricate since superhydrophobicity requires structuring of surfaces on a nano- to microscale. This delicate surface structuring makes most superhydrophobic surfaces very sensitive to abrasion and renders them impractical for real-life applications. In this paper we present a transparent fluorinated polymer foam that is synthesized by a simple one-step photoinitiated radical polymerization. We term this material "Fluoropor". It possesses an inherent nano-/microstructure throughout the whole bulk material and is thus insensitive to abrasion as its superhydrophobic properties are not merely due to a thin-layer surface-effect. Due to its foam like structure with pore sizes below the wavelength of visible light Fluoropor appears optically transparent. We determined contact angles, surface energy, wear resistance and Vickers hardness to highlight Fluoropor's applicability for real word applications. PMID- 29118409 TI - Engineering DNA Backbone Interactions Results in TALE Scaffolds with Enhanced 5 Methylcytosine Selectivity. AB - Transcription activator-like effectors (TALEs) are DNA major-groove binding proteins widely used for genome targeting. TALEs contain an N-terminal region (NTR) and a central repeat domain (CRD). Repeats of the CRD selectively recognize each one DNA nucleobase, offering programmability. Moreover, repeats with selectivity for 5-methylcytosine (5mC) and its oxidized derivatives can be designed for analytical applications. However, both TALE domains also nonspecifically interact with DNA phosphates via basic amino acids. To enhance the 5mC selectivity of TALEs, we aimed to decrease the nonselective binding energy of TALEs. We substituted basic amino acids with alanine in the NTR and identified TALE mutants with increased selectivity. We then analysed conserved, DNA phosphate-binding KQ diresidues in CRD repeats and identified further improved mutants. Combination of mutations in the NTR and CRD was highly synergetic and resulted in TALE scaffolds with up to 4.3-fold increased selectivity in genomic 5mC analysis via affinity enrichment. Moreover, transcriptional activation in HEK293T cells by a TALE-VP64 construct based on this scaffold design exhibited a 3.5-fold increased 5mC selectivity. This provides perspectives for improved 5mC analysis and for the 5mC-conditional control of TALE-based editing constructs in vivo. PMID- 29118410 TI - The microbiological characteristics and risk factors for PICC-related bloodstream infections in intensive care unit. AB - The study was aimed to investigate the pathogens distribution and risk factors for PICC-related bloodstream infection in intensive care unit (ICU) patients. 402 patients placed with PICC in ICU were recruited in the study. The microbiological characteristics of PICC-related infection were investigated by Vitek 2 Compact automated microbial system. Antibiotics sensitivity was performed with disk diffusion and minimum inhibitory concentration (MIC) methods. Multivariate logistic and cox analyses were performed to identify the risk factors for PICC related infection in ICU patients. 38 PICC-related infection cases were observed, and its morbidity was 9.45%. The morbidity was significantly higher in power PICC cases than that in common PICC cases. Gram-positive bacteria might be responsible for the major infection cases, followed by gram-negative bacteria, and fungi. Drug sensitivity analyses indicated that gram-negative bacteria showed low resistance to carbapenems antibiotics, and Cefperazone/sulbactam. The gram positive bacterial exhibited sensitive to Teicoplanin and Vancomycin. The isolated fungi showed low resistance to the commonly used antifungal antibiotics. Multivariate analyses demonstrated that power PICC, high Charison scores, diabetes mellitus, double lumens triple lumens were risk factors for PICC-related infections among ICU patients. Power PICC, high Charison scores, diabetes mellitus, multi-lumens are risk factors for PICC-related bloodstream infection in ICU patients. PMID- 29118411 TI - Gut remediation: a potential approach to reducing chromium accumulation using Lactobacillus plantarum TW1-1. AB - Some lactobacilli have protective effects against some heavy metals in mammals, but the underlying mechanism is not fully understood. To evaluate the remediation potency and the mechanism of Lactobacillus against chromium (Cr) in mice, Lactobacillus plantarum TW1-1 was orally administrated to Kunming mice for 7 weeks during exposure to 1 mM K2Cr2O7 in drinking water. Results showed that TW1 1 helped to decrease Cr accumulation in tissues and increase Cr excretion in feces, and may also attenuate alterations in oxidative stress and histopathological changes caused by Cr exposure. Moreover, the chromate reduction ability of fecal bacteria doubled after administration of TW1-1 upon Cr induction. MiSeq sequencing of fecal bacterial 16S rRNA genes revealed that the overall structures of gut microbiota was shifted by Cr exposure and partially restored by TW1-1. The abundances of 49 of the 79 operational taxonomic units altered by Cr were reversed by TW1-1. Based on these, we proposed a working model of TW1-1 against Cr: TW1-1 helps to remove Cr from the host and meanwhile acts as a regulator of gut microbiota, which aids in chromate reduction and provide protection against Cr. We call this process of remediation of heavy metal in the gut "gut remediation". PMID- 29118412 TI - Investigation on thermodynamics of ion-slicing of GaN and heterogeneously integrating high-quality GaN films on CMOS compatible Si(100) substrates. AB - Die-to-wafer heterogeneous integration of single-crystalline GaN film with CMOS compatible Si(100) substrate using the ion-cutting technique has been demonstrated. The thermodynamics of GaN surface blistering is in-situ investigated via a thermal-stage optical microscopy, which indicates that the large activation energy (2.5 eV) and low H ions utilization ratio (~6%) might result in the extremely high H fluence required for the ion-slicing of GaN. The crystalline quality, surface topography and the microstructure of the GaN films are characterized in detail. The full width at half maximum (FWHM) for GaN (002) X-ray rocking curves is as low as 163 arcsec, corresponding to a density of threading dislocation of 5 * 107 cm-2. Different evolution of the implantation induced damage was observed and a relationship between the damage evolution and implantation-induced damage is demonstrated. This work would be beneficial to understand the mechanism of ion-slicing of GaN and to provide a platform for the hybrid integration of GaN devices with standard Si CMOS process. PMID- 29118413 TI - Fabrication of Subnanometer-Precision Nanopores in Hexagonal Boron Nitride. AB - We demonstrate the fabrication of individual nanopores in hexagonal boron nitride (h-BN) with atomically precise control of the pore shape and size. Previous methods of pore production in other 2D materials typically create pores with irregular geometry and imprecise diameters. In contrast, other studies have shown that with careful control of electron irradiation, defects in h-BN grow with pristine zig-zag edges at quantized triangular sizes, but they have failed to demonstrate production and control of isolated defects. In this work, we combine these techniques to yield a method in which we can create individual size quantized triangular nanopores through an h-BN sheet. The pores are created using the electron beam of a conventional transmission electron microscope; which can strip away multiple layers of h-BN exposing single-layer regions, introduce single vacancies, and preferentially grow vacancies only in the single-layer region. We further demonstrate how the geometry of these pores can be altered beyond triangular by changing beam conditions. Precisely size- and geometry-tuned nanopores could find application in molecular sensing, DNA sequencing, water desalination, and molecular separation. PMID- 29118414 TI - Cellular information dynamics through transmembrane flow of ions. AB - We propose cells generate large transmembrane ion gradients to form information circuits that detect, process, and respond to environmental perturbations or signals. In this model, the specialized gates of transmembrane ion channels function as information detectors that communicate to the cell through rapid and (usually) local pulses of ions. Information in the ion "puffs" is received and processed by the cell through resulting changes in charge density and/or mobile cation (and/or anion) concentrations alter the localization and function of peripheral membrane proteins. The subsequent changes in protein binding to the membrane or activation of K+, Ca2+ or Mg2+-dependent enzymes then constitute a cellular response to the perturbation. To test this hypothesis we analyzed ion based signal transmission as a communication channel operating with coded inputs and decoded outputs. By minimizing the Kullback-Leibler cross entropy [Formula: see text] between concentrations of the ion species inside [Formula: see text] and outside [Formula: see text] the cell membrane, we find signal transmission through transmembrane ion flow forms an optimal Shannon information channel that minimizes information loss and maximizes transmission speed. We demonstrate the ion dynamics in neuronal action potentials described by Hodgkin and Huxley (including the equations themselves) represent a special case of these general information principles. PMID- 29118415 TI - Demonstration of measuring sea fog with an SNSPD-based Lidar system. AB - The monitor of sea fogs become more important with the rapid development of marine activities. Remote sensing through laser is an effective tool for monitoring sea fogs, but still challengeable for large distance. We demonstrated a Long-distance Lidar for sea fog with superconducting nanowire single-photon detector (SNSPD), which extended the ranging area to a 180-km diameter area. The system, which was verified by using a benchmark distance measurement of a known island, is applied to the Mie scattering weather prediction Lidar system. The fog echo signal distribution in the range of 42.3~63.5 km and 53.2~74.2 km was obtained by the Lidar system. Then the fog concentration and the velocity of the fog were deduced from the distribution, which is consistent with the weather prediction. The height of the sea fog is about two hundred meter while the visibility at this height is about 90 km due to the Earth's radius of curvature. Therefore, the capability of this SNSPD-based Lidar was close to the theoretical limit for sea fog measurements for extremely high signal-to-noise ratio of SNSPD. PMID- 29118416 TI - Protein nutrition governs within-host race of honey bee pathogens. AB - Multiple infections are common in honey bees, Apis mellifera, but the possible role of nutrition in this regard is poorly understood. Microsporidian infections, which are promoted by protein-fed, can negatively correlate with virus infections, but the role of protein nutrition for the microsporidian-virus interface is unknown. Here, we challenged naturally deformed wing virus - B (DWV B) infected adult honey bee workers fed with or without pollen ( = protein) in hoarding cages, with the microsporidian Nosema ceranae. Bee mortality was recorded for 14 days and N. ceranae spore loads and DWV-B titers were quantified. Amongst the groups inoculated with N. ceranae, more spores were counted in protein-fed bees. However, N. ceranae infected bees without protein-diet had reduced longevity compared to all other groups. N. ceranae infection had no effect on protein-fed bee's longevity, whereas bees supplied only with sugar water showed reduced survival. Our data also support that protein-feeding can have a significant negative impact on virus infections in insects. The negative correlation between N. ceranae spore loads and DWV-B titers was stronger expressed in protein-fed hosts. Proteins not only enhance survival of infected hosts, but also significantly shape the microsporidian-virus interface, probably due to increased spore production and enhanced host immunity. PMID- 29118417 TI - Brain activation induced by chronic psychosocial stress in mice. AB - Chronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of ?FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of ?FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans. PMID- 29118418 TI - Cascading Failures in Interdependent Networks with Multiple Supply-Demand Links and Functionality Thresholds. AB - Various social, financial, biological and technological systems can be modeled by interdependent networks. It has been assumed that in order to remain functional, nodes in one network must receive the support from nodes belonging to different networks. So far these models have been limited to the case in which the failure propagates across networks only if the nodes lose all their supply nodes. In this paper we develop a more realistic model for two interdependent networks in which each node has its own supply threshold, i.e., they need the support of a minimum number of supply nodes to remain functional. In addition, we analyze different conditions of internal node failure due to disconnection from nodes within its own network. We show that several local internal failure conditions lead to similar nontrivial results. When there are no internal failures the model is equivalent to a bipartite system, which can be useful to model a financial market. We explore the rich behaviors of these models that include discontinuous and continuous phase transitions. Using the generating functions formalism, we analytically solve all the models in the limit of infinitely large networks and find an excellent agreement with the stochastic simulations. PMID- 29118419 TI - Melatonin promotes triacylglycerol accumulation via MT2 receptor during differentiation in bovine intramuscular preadipocytes. AB - Melatonin (N-acetyl-5-methoxytryptamine) is a derivative of tryptophan which is produced and secreted mainly by the pineal gland and regulates a variety of important central and peripheral actions. To examine the potential effects of melatonin on the proliferation and differentiation of bovine intramuscular preadipocytes (BIPs), BIPs were incubated with different concentrations of melatonin. Melatonin supplementation at 1 mM significantly increased peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein (C/EBP) beta, and C/EBPalpha expression and promoted the differentiation of BIPs into adipocytes with large lipid droplets and high cellular triacylglycerol (TAG) levels. Melatonin also significantly enhanced lipolysis and up-regulated the expression of lipolytic genes and proteins, including hormone sensitive lipase (HSL), adipocyte triglyceride lipase (ATGL), and perilipin 1 (PLIN1). Moreover, melatonin reduced intracellular reactive oxygen species (ROS) levels by increasing the expression levels and activities of superoxide dismutase 1 (SOD1) and glutathione peroxidase 4 (GPX4). Finally, the positive effects of melatonin on adipogenesis, lipolysis, and redox status were reversed by treatment with luzindole, anantagonist of nonspecific melatonin receptors 1 (MT1) and 2 (MT2), and 4-phenyl-2-propionamidotetraline (4P-PDOT), a selective MT2 antagonist. These results reveal that melatonin promotes TAG accumulation via MT2 receptor during differentiation in BIPs. PMID- 29118420 TI - AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease. AB - Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD. We treated 1-month-old PD mice with an AAV2.9-MCK-TFEB vector. An animal cohort was analyzed at 3 months for muscle and heart pathology. A second cohort was followed at different timepoints for functional analysis. In muscles from TFEB-treated mice we observed reduced PAS staining and improved ultrastructure, with reduced number and increased translucency of lysosomes, while total glycogen content remained unchanged. We also observed statistically significant improvements in rotarod performance in treated animals compared to AAV2.9-MCK-eGFP-treated mice at 5 and 8 months. Cardiac echography showed significant reduction in left-ventricular diameters. These results show that TFEB overexpression and modulation of autophagy result in improvements of muscle pathology and of functional performance in the PD murine model, with delayed disease progression. PMID- 29118421 TI - Navigability of temporal networks in hyperbolic space. AB - Information routing is one of the main tasks in many complex networks with a communication function. Maps produced by embedding the networks in hyperbolic space can assist this task enabling the implementation of efficient navigation strategies. However, only static maps have been considered so far, while navigation in more realistic situations, where the network structure may vary in time, remains largely unexplored. Here, we analyze the navigability of real networks by using greedy routing in hyperbolic space, where the nodes are subject to a stochastic activation-inactivation dynamics. We find that such dynamics enhances navigability with respect to the static case. Interestingly, there exists an optimal intermediate activation value, which ensures the best trade-off between the increase in the number of successful paths and a limited growth of their length. Contrary to expectations, the enhanced navigability is robust even when the most connected nodes inactivate with very high probability. Finally, our results indicate that some real networks are ultranavigable and remain highly navigable even if the network structure is extremely unsteady. These findings have important implications for the design and evaluation of efficient routing protocols that account for the temporal nature of real complex networks. PMID- 29118422 TI - River-bed armouring as a granular segregation phenomenon. AB - River bed-load transport is a kind of dense granular flow, and such flows are known to segregate grains. While gravel-river beds typically have an "armoured" layer of coarse grains on the surface, which acts to protect finer particles underneath from erosion, the contribution of granular physics to river-bed armouring has not yet been investigated. Here we examine these connections in a laboratory river with bimodal sediment size, by tracking the motion of particles from the surface to deep inside the bed, and find that armour develops by two distinct mechanisms. Bed-load transport in the near-surface layer drives rapid, shear rate-dependent advective segregation. Creeping grains beneath the bed-load layer give rise to slow but persistent diffusion-dominated segregation. We verify these findings with a continuum phenomenological model and discrete element method simulations. Our experiments suggest that some river-bed armouring may be due to granular segregation from below-rather than fluid-driven sorting from above-while also providing new insights on the mechanics of segregation that are relevant to a wide range of granular flows. PMID- 29118423 TI - Tolerogenic dendritic cells are efficiently generated using minocycline and dexamethasone. AB - Tolerogenic dendritic cells (tDCs) represent a promising tool for cellular therapy against autoimmune diseases, allergies, and transplantation rejection. Numerous pharmacological agents are known to induce tDC generation. Minocycline, which has long been used as a broad-spectrum antibiotic, was recently shown to significantly increase the generation of DCs with regulatory properties. Here, we examined the effect of the combination of minocycline with dexamethasone, rapamycin, vitamin D3, and interleukin (IL)-10, which are all known inducers of tDC generation. The highest number of tDCs was generated when minocycline and dexamethasone were used together with granulocyte colony-stimulating factor (GM SCF) and IL-4. The tolerogenicity of the minocycline/dexamethasone-conditioned tDCs was much better than or at least equal to those of the tDCs generated with either one of these agents, as assessed through in vitro phenotypic and functional assays. In addition, pretreatment with MOG35-55 peptide-pulsed minocycline/dexamethasone-conditioned tDCs significantly ameliorated the clinical signs of experimental autoimmune encephalitis induced by MOG peptide injection in a murine model. These results confirmed that tDCs with potent tolerogenic properties could be efficiently generated by the combined use of minocycline and dexamethasone, along with GM-CSF and IL-4. Our results would help in the development of ex vivo tDC-based immunotherapies. PMID- 29118424 TI - Methods for Scarless, Selection-Free Generation of Human Cells and Allele Specific Functional Analysis of Disease-Associated SNPs and Variants of Uncertain Significance. AB - With the continued emergence of risk loci from Genome-Wide Association studies and variants of uncertain significance identified from patient sequencing, better methods are required to translate these human genetic findings into improvements in public health. Here we combine CRISPR/Cas9 gene editing with an innovative high-throughput genotyping pipeline utilizing KASP (Kompetitive Allele-Specific PCR) genotyping technology to create scarless isogenic cell models of cancer variants in ~1 month. We successfully modeled two novel variants previously identified by our lab in the PALB2 gene in HEK239 cells, resulting in isogenic cells representing all three genotypes for both variants. We also modeled a known functional risk SNP of colorectal cancer, rs6983267, in HCT-116 cells. Cells with extremely low levels of gene editing could still be identified and isolated using this approach. We also introduce a novel molecular assay, ChIPnQASO (Chromatin Immunoprecipitation and Quantitative Allele-Specific Occupation), which uses the same technology to reveal allele-specific function of these variants at the DNA protein interaction level. We demonstrated preferential binding of the transcription factor TCF7L2 to the rs6983267 risk allele over the non-risk. Our pipeline provides a platform for functional variant discovery and validation that is accessible and broadly applicable for the progression of efforts towards precision medicine. PMID- 29118425 TI - The study on the association between Beijing genotype family and drug susceptibility phenotypes of Mycobacterium tuberculosis in Beijing. AB - The predominant prevalent Mycobacterium tuberculosis (M. tb) lineage was the Beijing genotype family in Beijing. There has been no systematic study on the association between drug resistance and Beijing genotype. Here we collected 268 M. tb strains, analyzed the background information and the bacteriological characteristics. The mean age of the cases was 40.12 years; male patients were almost three times than female patients. After genotyping analyzation, 81.7% (219/268) strains were categorized as Beijing genotype; no significant difference was observed between Beijing and non-Beijing genotype in gender, age and treatment history. Drug susceptibility testing (DST) analyzation demonstrated that 172 (64.2%) strains were fully sensitive to all drugs (Isoniazid, Rifampin, Streptomycin, and Ethambutol), while 96 (35.8%) strains were resistant to at least one of the drugs. Beijing genotype strains exhibited a significantly higher clustering rate. However, no significant association relationship was observed between drug resistance and Beijing genotype family. The study provided insights into the genotype diversity and revealed that the frequencies of drug-resistance of Beijing genotype strains.It would be helpful for the establishment of the efficient tuberculosis (TB) prevention and control strategy in Beijing. PMID- 29118426 TI - Maximum temperature drove snow cover expansion from the Arctic, 2000-2008. AB - Investigating annual phenology of snow cover around the circumpolar Arctic is of significance for better grasping the effect of environment variation on global climate change, and previous studies found that temperature is the kernel climate feature interlinking with snow onset. However, how temperature closely drives snow cover expansion has not been fully exploited. Our analysis based on the Special Sensor Microwave Imager (SSM/I) and Special Sensor Microwave Imager Sounder (SSMIS) (i.e., SSM/I-SSMIS) data during 2000-2008 showed that the snow onset date (Do) was primarily driven by the maximum temperature approximately at the 22nd day in advance (termed as the optimal period, OP) in the Northern Hemisphere. Specifically, the spatial patterns of the Do trends are similar with the previous finding, e.g., east Europe and west Asia exhibiting the most notable Do delay, and the OP days in latitude show the principal trend of first decreasing and then increasing. These characteristics can be attributed to the variation of the maximum temperature feature in latitude. Overall, the derivation of the statistical rules of temperature driving snow cover expansion from the Arctic facilitates predicting the occurrence of snow and understanding various terrestrial processes. PMID- 29118427 TI - A fast fabrication of copper nanowire transparent conductive electrodes by using pulsed laser irradiation. AB - Copper nanowires have shown promise for use in next-generation conducting materials for transparent electrodes owing to their low sheet resistance, natural abundance, and high transmittance properties. Additionally, copper nanowires can be easily synthesized via low-cost solution-based processes. However, copper requires a uniform film to coat the nanowires on the substrate and removing film former residue in the post-treatment process remains a challenge. This lead to the high cost and complexity of fabricating transparent electrode. In this study, we demonstrate a simple, time-saving production method using a combination of laser irradiation and acid dipping to fabricate high-quality copper nanowire transparent electrodes. Preparation of electrodes was achieved by scanning pulsed laser on a copper nanowire film and then dipping in glacial acetic acid. The electrode exhibited excellent properties and the film former was totally erased from the electrode surface. Moreover, to demonstrate their capability, the as fabricated electrodes were applied in touch-sensor fabrication. PMID- 29118428 TI - A Thermodynamic Model of Diameter- and Temperature-dependent Semiconductor Nanowire Growth. AB - Creating and manipulating nanowires (NWs) with controllable growth direction and crystal orientation is important to meeting the urgent demands of emerging applications with designed properties. Revealing the underlying mechanisms of the experimentally demonstrated effects of NW diameter and growth temperature on growth direction is crucial for applications. Here, we establish a thermodynamic model to clarify the dependence of NW growth direction on diameter and temperature via the vapor-liquid-solid growth mechanism, enabling analysis of NW critical length between unstable and stable states. At a small critical length, NWs with a large diameter or grown at low temperature tend to grow along the <111> direction, while at a large critical length, NWs with a small diameter or grown at high temperature favor the <110> direction. Specific growth parameters of ZnSe NW have been obtained which can guide the design of functional NWs for applications. PMID- 29118429 TI - Mesenchymal stem cells internalize Mycobacterium tuberculosis through scavenger receptors and restrict bacterial growth through autophagy. AB - Human mesenchymal stem cells (MSCs) express scavenger receptors that internalize lipids, including oxidized low-density lipoprotein (oxLDL). We report that MSCs phagocytose Mycobacterium tuberculosis (Mtb) through two types of scavenger receptors (SRs; MARCO and SR-B1), as blockade of the receptors with antibodies or siRNA knockdown decreased the uptake of Mtb. MSCs also expressed mannose receptor (MR) that was found to endocytose rhodamine-labeled mannosylated BSA (rMBSA), though the receptor was not involved in the uptake of Mtb. Dil-oxLDL and rMBSA taken up into MSC endosomes colocalized with Mtb phagosomes, thus suggesting that the latter were fusion competent. Phagocytosed Mtb did not replicate within MSCs, thus suggesting an intrinsic control of bacterial growth. Indeed, MSCs exhibited intrinsic autophagy, which was up-regulated after activation with rapamycin. SiRNA knockdown of autophagy initiator beclin-1 enhanced Mtb survival, whereas rapamycin-induced autophagy increased intracellular killing of Mtb. In addition, MSCs secreted nitric oxide after Mtb infection, and inhibition of NO by N(G) monomethyl-L-arginine enhanced intracellular survival of Mtb. MSCs can be grown in large numbers in vitro, and autologous MSCs transfused into tuberculosis patients have been found to be safe and improve lung immunity. Thus, MSCs are novel phagocytic cells with a potential for immunotherapy in treating multidrug resistant tuberculosis. PMID- 29118430 TI - Inter-individual variation in genes governing human hippocampal progenitor differentiation in vitro is associated with hippocampal volume in adulthood. AB - Hippocampal volumes are smaller in psychiatric disorder patients and lower levels of hippocampal neurogenesis are the hypothesized cause. Understanding which molecular processes regulate hippocampal progenitor differentiation might aid in the identification of novel drug targets that can promote larger hippocampal volumes. Here we use a unique human cell line to assay genome-wide expression changes when hippocampal progenitor cells differentiate. RNA was extracted from proliferating cells versus differentiated neural cells and applied to Illumina Human HT-12 v4 Expression BeadChips. Linear regressions were used to determine the effect of differentiation on probe expression and we assessed enrichment for gene ontology (GO) terms. Genetic pathway analysis (MAGMA) was used to evaluate the relationship between hippocampal progenitor cell differentiation and adult hippocampal volume, using results from the imaging genomics consortium, ENIGMA. Downregulated transcripts were enriched for mitotic processes and upregulated transcripts were enriched for cell differentiation. Upregulated (differentiation) transcripts specifically, were also predictive of adult hippocampal volume; with Early growth response protein 2 identified as a hub transcription factor within the top GO term, and a potential drug target. Our results suggest that genes governing differentiation, rather than mitosis, have an impact on adult hippocampal volume and that these genes represent important drug targets. PMID- 29118431 TI - Mechanotransduction of matrix stiffness in regulation of focal adhesion size and number: reciprocal regulation of caveolin-1 and beta1 integrin. AB - Focal adhesion (FA) assembly, mediated by integrin activation, responds to matrix stiffness; however, the underlying mechanisms are unclear. Here, we showed that beta1 integrin and caveolin-1 (Cav1) levels were decreased with declining matrix stiffness. Soft matrix selectively downregulated beta1 integrin by endocytosis and subsequent lysosomal degradation. Disruption of lipid rafts with methyl-beta cyclodextrin or nystatin, or knockdown of Cav1 by siRNA decreased cell spreading, FA assembly, and beta1 integrin protein levels in cells cultured on stiff matrix. Overexpression of Cav1, particularly the phospho-mimetic mutant Cav1-Y14D, averted soft matrix-induced decreases in beta1 integrin protein levels, cell spreading, and FA assembly in NMuMG cells. Interestingly, overexpression of an auto-clustering beta1 integrin hindered soft matrix-induced reduction of Cav1 and cell spreading, which suggests a reciprocal regulation between beta1 integrin and Cav1. Finally, co-expression of this auto-clustering beta1 integrin and Cav1-Y14D synergistically enhanced cell spreading, and FA assembly in HEK293T cells cultured on either stiff ( > G Pa) or soft (0.2 kPa) matrices. Collectively, these results suggest that matrix stiffness governs the expression of beta1 integrin and Cav1, which reciprocally control each other, and subsequently determine FA assembly and turnover. PMID- 29118432 TI - Novel method for rapid fluorescence in-situ hybridization of ALK rearrangement using non-contact alternating current electric field mixing. AB - Echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) rearrangement is a key driver mutation in non-small cell lung cancer (NSCLC). Although Break-Apart ALK fluorescence in situ hybridization (FISH) is a reliable diagnostic method for detecting ALK gene rearrangement, it is too costly and time-consuming for use as a routine screening test. Our aim was to evaluate the clinical utility of a novel rapid FISH (RaFISH) method developed to facilitate hybridization. RaFISH takes advantage of the non-contact mixing effect of an alternating current (AC) electric field. Eighty-five specimens were used from patients diagnosed with NSCLC identified immunohistochemically as ALK 0, (1/2+) or (3+). With RaFISH, the ALK test was completed within 4.5 h, as compared to 20 h needed for the standard FISH. Although RaFISH produced results more promptly, the staining and accuracy of the ALK evaluation with RaFISH was equal to the standard. We found 97.6% agreement between FISH and RaFISH based on the status of the ALK signals. These results suggest RaFISH could be used as a clinical tool to promptly determine ALK status. PMID- 29118433 TI - Visualization of lipid directed dynamics of perilipin 1 in human primary adipocytes. AB - Perilipin 1 is a lipid droplet coating protein known to regulate lipid metabolism in adipocytes by serving as a physical barrier as well as a recruitment site for lipases to the lipid droplet. Phosphorylation of perilipin 1 by protein kinase A rapidly initiates lipolysis, but the detailed mechanism on how perilipin 1 controls lipolysis is unknown. Here, we identify specific lipid binding properties of perilipin 1 that regulate the dynamics of lipolysis in human primary adipocytes. Cellular imaging combined with biochemical and biophysical analyses demonstrate that perilipin 1 specifically binds to cholesteryl esters, and that their dynamic properties direct segregation of perilipin 1 into topologically distinct micro domains on the lipid droplet. Together, our data points to a simple unifying mechanism that lipid assembly and segregation control lipolysis in human primary adipocytes. PMID- 29118434 TI - Supernatural Belief Is Not Modulated by Intuitive Thinking Style or Cognitive Inhibition. AB - According to the Intuitive Belief Hypothesis, supernatural belief relies heavily on intuitive thinking-and decreases when analytic thinking is engaged. After pointing out various limitations in prior attempts to support this Intuitive Belief Hypothesis, we test it across three new studies using a variety of paradigms, ranging from a pilgrimage field study to a neurostimulation experiment. In all three studies, we found no relationship between intuitive or analytical thinking and supernatural belief. We conclude that it is premature to explain belief in gods as 'intuitive', and that other factors, such as socio cultural upbringing, are likely to play a greater role in the emergence and maintenance of supernatural belief than cognitive style. PMID- 29118435 TI - Disordered Nanohole Patterns in Metal-Insulator Multilayer for Ultra-broadband Light Absorption: Atomic Layer Deposition for Lithography Free Highly repeatable Large Scale Multilayer Growth. AB - In this paper, we demonstrate a facile, lithography free, and large scale compatible fabrication route to synthesize an ultra-broadband wide angle perfect absorber based on metal-insulator-metal-insulator (MIMI) stack design. We first conduct a simulation and theoretical modeling approach to study the impact of different geometries in overall stack absorption. Then, a Pt-Al2O3 multilayer is fabricated using a single atomic layer deposition (ALD) step that offers high repeatability and simplicity in the fabrication step. In the best case, we get an absorption bandwidth (BW) of 600 nm covering a range of 400 nm-1000 nm. A substantial improvement in the absorption BW is attained by incorporating a plasmonic design into the middle Pt layer. Our characterization results demonstrate that the best configuration can have absorption over 0.9 covering a wavelength span of 400 nm-1490 nm with a BW that is 1.8 times broader compared to that of planar design. On the other side, the proposed structure retains its absorption high at angles as wide as 70 degrees . The results presented here can serve as a beacon for future performance enhanced multilayer designs where a simple fabrication step can boost the overall device response without changing its overall thickness and fabrication simplicity. PMID- 29118436 TI - Combining membrane proteomics and computational three-way pathway analysis revealed signalling pathways preferentially regulated in human iPSCs and human ESCs. AB - Owing to the clinical potential of human induced pluripotent stem cells (hiPSCs) in regenerative medicine, a thorough examination of the similarities and differences between hiPSCs and human embryonic stem cells (hESCs) has become indispensable. Moreover, as the important roles of membrane proteins in biological signalling, functional analyses of membrane proteome are therefore promising. In this study, a pathway analysis by the bioinformatics tool GSEA was first performed to identify significant pathways associated with the three comparative membrane proteomics experiments: hiPSCs versus precursor human foreskin fibroblasts (HFF), hESCs versus precursor HFF, and hiPSCs versus hESCs. A following three-way pathway comparison was conducted to identify the differentially regulated pathways that may contribute to the differences between hiPSCs and hESCs. Our results revealed that pathways related to oxidative phosphorylation and focal adhesion may undergo incomplete regulations during the reprogramming process. This hypothesis was supported by another public proteomics dataset to a certain degree. The identified pathways and their core enriched proteins could serve as the starting point to explore the possible ways to make hiPSCs closer to hESCs. PMID- 29118437 TI - The relation between gallstone disease and cardiovascular disease. AB - Gallstone disease (GD) is a common digestive disorder that shares many risk factors with cardiovascular disease (CVD). CVD is an important public health issue that encompasses a large percentage of overall mortality. Several recent studies have suggested an association between GD and CVD, while others have not. In this report, we present a meta-analysis of cohort studies to assess the association between GD and CVD. We included eight studies published from 1980 to 2017, including nearly one million participants. The pooled relative risk (RR, 95% confidence interval [CI]) from the random-effects model associates with GD is 1.23 (95% CI: 1.17-1.30) for fatal and nonfatal CVD events. The pooled RR from the random-effects model of CVD events in female patients with GD is 1.24 (95% CI: 1.16-1.32). In male GD patients, the pooled RR from the random-effects model for CVD is 1.18 (95% CI: 1.06-1.31). Our meta-analysis demonstrates a substantially increased risk of fatal and nonfatal CVD events among patients with a medical history of GD. We suggest that interested investigators should further pursue the subject. In addition, both male and female patients with GD have a risk of CVD, and women have a higher risk than men. PMID- 29118438 TI - Substrate Specificity and Allosteric Regulation of a D-Lactate Dehydrogenase from a Unicellular Cyanobacterium are Altered by an Amino Acid Substitution. AB - Lactate/lactic acid is an important chemical compound for the manufacturing of bioplastics. The unicellular cyanobacterium Synechocystis sp. PCC 6803 can produce lactate from carbon dioxide and possesses D-lactate dehydrogenase (Ddh). Here, we performed a biochemical analysis of the Ddh from this cyanobacterium (SyDdh) using recombinant proteins. SyDdh was classified into a cyanobacterial clade similar to those from Gram-negative bacteria, although it was distinct from them. SyDdh can use both pyruvate and oxaloacetate as a substrate and is activated by fructose-1,6-bisphosphate and repressed by divalent cations. An amino acid substitution based on multiple sequence alignment data revealed that the glutamine at position 14 and serine at position 234 are important for the allosteric regulation by Mg2+ and substrate specificity of SyDdh, respectively. These results reveal the characteristic biochemical properties of Ddh in a unicellular cyanobacterium, which are different from those of other bacterial Ddhs. PMID- 29118441 TI - Vasculitis syndromes: NET production complements endothelial damage. PMID- 29118439 TI - Preventing progression from arthralgia to arthritis: targeting the right patients. AB - Early treatment is associated with improved outcomes in patients with rheumatoid arthritis (RA), suggesting that a 'window of opportunity', in which the disease is most susceptible to disease-modifying treatment, exists. Autoantibodies and markers of systemic inflammation can be present long before clinical arthritis, and maturation of the immune response seems to coincide with the development of RA. The pre-arthritis phase associated with symptoms such as as joint pain without clinical arthritis (athralgia) is now hypothesized to fall within the aforementioned window of opportunity. Consequently, disease modulation in this phase might prevent the occurrence of clinically apparent arthritis, which would result in a persistent disease course if untreated. Several ongoing proof-of concept trials are now testing this hypothesis. This Review highlights the importance of adequate risk prediction for the correct design, execution and interpretation of results of these prevention trials, as well as considerations when translating these findings into clinical practice. The patients' perspectives are discussed, and the accuracy with which RA development can be predicted in patients presenting with arthralgia is evaluated. Currently, the best starting position for preventive studies is proposed to be the inclusion of patients with an increased risk of RA, such as those identified as fulfilling the EULAR definition of 'arthralgia suspicious for progression to RA'. PMID- 29118440 TI - Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. AB - The role of native (not culture-expanded) joint-resident mesenchymal stem cells (MSCs) in the repair of joint damage in osteoarthritis (OA) is poorly understood. MSCs differ from bone marrow-residing haematopoietic stem cells in that they are present in multiple niches in the joint, including subchondral bone, cartilage, synovial fluid, synovium and adipose tissue. Research in experimental models suggests that the migration of MSCs adjacent to the joint cavity is crucial for chonodrogenesis during embryogenesis, and also shows that synovium-derived MSCs might be the primary drivers of cartilage repair in adulthood. In this Review, the available data is synthesized to produce a proposed model in which joint resident MSCs with access to superficial cartilage are key cells in adult cartilage repair and represent important targets for manipulation in 'chondrogenic' OA, especially in the context of biomechanical correction of joints in early disease. Growing evidence links the expression of CD271, a nerve growth factor (NGF) receptor by native bone marrow-resident MSCs to a wider role for neurotrophins in OA pathobiology, the implications of which require exploration since anti-NGF therapy might worsen OA. Recognizing that joint resident MSCs are comparatively abundant in vivo and occupy multiple niches will enable the optimization of single-stage therapeutic interventions for OA. PMID- 29118443 TI - Oxygen drives benthic-pelagic decomposition pathways in shallow wetlands. AB - Oxygen availability is perceived as an important environmental factor limiting POM decomposition. In shallow wetlands, however, the impact of commonly observed anoxic conditions in the benthic layer on the relative contribution of microbes and invertebrates to POM decomposition remains largely unknown. Therefore, the aim of this study was to determine if dissolved oxygen drives benthic-pelagic decomposition pathways in shallow wetlands. Dissolved oxygen concentration, invertebrate community composition, microbial decomposition and invertebrate consumption were measured in the benthic and pelagic layer of 15 permanent drainage ditches. We showed that an increased duration of anoxic conditions in the benthic layer of the ditches was related to increased microbial decomposition in this layer, while invertebrate consumption decreased in the benthic layer and increased in the pelagic layer. The increased invertebrate consumption in the pelagic layer was related to the presence of amphipods. We concluded that anoxic conditions in the benthic layer of shallow wetlands relate to an increase in microbial decomposition and a decrease in invertebrate consumption, as detritivorous invertebrates move to the pelagic layer to consume particulate organic matter. This illustrates that environmental conditions, such as dissolved oxygen, may drive the relative importance of aquatic organisms to ecosystem functioning. PMID- 29118442 TI - Serology reflects a decline in the prevalence of trachoma in two regions of The Gambia. AB - Trachoma is caused by Chlamydia trachomatis (Ct). It is targeted for global elimination as a public health problem. In 2014, a population-based cross sectional study was performed in two previously trachoma-endemic areas of The Gambia. Participants of all ages from Lower River Region (LRR) (N = 1028) and Upper River Region (URR) (N = 840) underwent examination for trachoma and had blood collected for detection of antibodies against the Ct antigen Pgp3, by ELISA. Overall, 30 (1.6%) individuals had active trachoma; the prevalence in children aged 1-9 years was 3.4% (25/742) with no statistically significant difference in prevalence between the regions. There was a significant difference in overall seroprevalence by region: 26.2% in LRR and 17.1% in URR (p < 0.0001). In children 1-9 years old, seroprevalence was 4.4% in LRR and 3.9% in URR. Reversible catalytic models using information on age-specific seroprevalence demonstrated a decrease in the transmission of Ct infection in both regions, possibly reflecting the impact of improved access to water, health and sanitation as well as mass drug administration campaigns. Serological testing for antibodies to Ct antigens is potentially useful for trachoma programmes, but consideration should be given to the co-endemicity of sexually transmitted Ct infections. PMID- 29118445 TI - Large area imaging of forensic evidence with MA-XRF. AB - This study introduces the use of macroscopic X-ray fluorescence (MA-XRF) for the detection, classification and imaging of forensic traces over large object areas such as entire pieces of clothing and wall paneling. MA-XRF was sufficiently sensitive and selective to detect human biological traces like blood, semen, saliva, sweat and urine on fabric on the basis of Fe, Zn, K, Cl and Ca elemental signatures. With MA-XRF a new chemical contrast is introduced for human stain detection and this can provide a valuable alternative when the evidence item is challenging for conventional techniques. MA-XRF was also successfully employed for the chemical imaging and classification of gunshot residues (GSR). The full and non-invasive elemental mapping (Pb, Ba, Sr, K and Cl) of intact pieces of clothing allows for a detailed shooting incident reconstruction linking firearms and ammunition to point of impact and providing information on the shooting angle. In high resolution mode MA-XRF can even be used to provide information on the shooting order of different ammunition types. Finally, by using the surface penetration of X-rays we demonstrate that the lead signature of a bullet impact can be easily detected even if covered by multiple layers of wall paint or human blood. PMID- 29118444 TI - Vanillin Affects Amyloid Aggregation and Non-Enzymatic Glycation in Human Insulin. AB - Curcumin is known for its anti-inflammatory, antioxidant and anticancer activity, as well as for its ability to interfere with amyloid aggregation and non enzymatic glycation reaction, that makes it an attractive potential drug. However, curcumin therapeutic use is limited because of its low systemic bioavailability and chemical stability as it undergoes rapid hydrolysis in physiological conditions. Recently, much attention has been paid to the biological properties of curcumin degradation products as potential bioactive molecules. Between them, vanillin, a natural vanilla extract, is a stable degradation product of curcumin that could be responsible for mediating its beneficial effects. We have analyzed the effect of vanillin, in comparison with curcumin, in the amyloid aggregation process of insulin as well as its ability to prevent the formation of the advanced glycation end products (AGEs). Employing biophysical, biochemical and cell based assays, we show that vanillin and curcumin similarly affect insulin amyloid aggregation promoting the formation of harmless fibrils. Moreover, vanillin restrains AGE formation and protects from AGE-induced cytotoxicity. Our novel findings not only suggest that the main health benefits observed for curcumin can be ascribed to its degradation product vanillin, but also open new avenues for developing therapeutic applications of curcumin degradation products. PMID- 29118446 TI - Imaging cellulose synthase motility during primary cell wall synthesis in the grass Brachypodium distachyon. AB - The mechanism of cellulose synthesis has been studied by characterizing the motility of cellulose synthase complexes tagged with a fluorescent protein; however, this approach has been used exclusively on the hypocotyl of Arabidopsis thaliana. Here we characterize cellulose synthase motility in the model grass, Brachypodium distachyon. We generated lines in which mEGFP is fused N-terminal to BdCESA3 or BdCESA6 and which grew indistinguishably from the wild type (Bd21-3) and had dense fluorescent puncta at or near the plasma membrane. Measured with a particle tracking algorithm, the average speed of GFP-BdCESA3 particles in the mesocotyl was 164 +/- 78 nm min-1 (error gives standard deviation [SD], n = 1451 particles). Mean speed in the root appeared similar. For comparison, average speed in the A. thaliana hypocotyl expressing GFP-AtCESA6 was 184 +/- 86 nm min-1 (n = 2755). For B. distachyon, we quantified root diameter and elongation rate in response to inhibitors of cellulose (dichlorobenylnitrile; DCB), microtubules (oryzalin), or actin (latrunculin B). Neither oryzalin nor latrunculin affected the speed of CESA complexes; whereas, DCB reduced average speed by about 50% in B. distachyon and by about 35% in A. thaliana. Evidently, between these species, CESA motility is well conserved. PMID- 29118447 TI - Influenza virus segment 5 (+)RNA - secondary structure and new targets for antiviral strategies. AB - Influenza A virus is a threat for humans due to seasonal epidemics and occasional pandemics. This virus can generate new strains that are dangerous through nucleotide/amino acid changes or through segmental recombination of the viral RNA genome. It is important to gain wider knowledge about influenza virus RNA to create new strategies for drugs that will inhibit its spread. Here, we present the experimentally determined secondary structure of the influenza segment 5 (+)RNA. Two RNAs were studied: the full-length segment 5 (+)RNA and a shorter construct containing only the coding region. Chemical mapping data combined with thermodynamic energy minimization were used in secondary structure prediction. Sequence/structure analysis showed that the determined secondary structure of segment 5 (+)RNA is mostly conserved between influenza virus type A strains. Microarray mapping and RNase H cleavage identified accessible sites for oligonucleotides in the revealed secondary structure of segment 5 (+)RNA. Antisense oligonucleotides were designed based on the secondary structure model and tested against influenza virus in cell culture. Inhibition of influenza virus proliferation was noticed, identifying good targets for antisense strategies. Effective target sites fall within two domains, which are conserved in sequence/structure indicating their importance to the virus. PMID- 29118448 TI - Epigenetics: Leaving a lasting mark. PMID- 29118450 TI - Neural circuits: Shock signals. PMID- 29118449 TI - Axo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system. AB - It is widely recognized that myelination of axons greatly enhances the speed of signal transmission. An exciting new finding is the dynamic communication between axons and their myelin-forming oligodendrocytes, including activity-dependent signalling from axon to myelin. The oligodendrocyte-myelin complex may in turn respond by providing metabolic support or alter subtle myelin properties to modulate action potential propagation. In this Opinion, we discuss what is known regarding the molecular physiology of this novel, synapse-like communication and speculate on potential roles in disease states including multiple sclerosis, schizophrenia and Alzheimer disease. An emerging appreciation of the contribution of white-matter perturbations to neurological dysfunction identifies the axo myelinic synapse as a potential novel therapeutic target. PMID- 29118451 TI - Measurements of ultrafast spin-profiles and spin-diffusion properties in the domain wall area at a metal/ferromagnetic film interface. AB - Exciting a ferromagnetic material with an ultrashort IR laser pulse is known to induce spin dynamics by heating the spin system and by ultrafast spin diffusion processes. Here, we report on measurements of spin-profiles and spin diffusion properties in the vicinity of domain walls in the interface region between a metallic Al layer and a ferromagnetic Co/Pd thin film upon IR excitation. We followed the ultrafast temporal evolution by means of an ultrafast resonant magnetic scattering experiment in surface scattering geometry, which enables us to exploit the evolution of the domain network within a 1/e distance of 3 nm to 5 nm from the Al/FM film interface. We observe a magnetization-reversal close to the domain wall boundaries that becomes more pronounced closer to the Al/FM film interface. This magnetization-reversal is driven by the different transport properties of majority and minority carriers through a magnetically disordered domain network. Its finite lateral extension has allowed us to measure the ultrafast spin-diffusion coefficients and ultrafast spin velocities for majority and minority carriers upon IR excitation. PMID- 29118452 TI - Magnesium homeostasis protects Salmonella against nitrooxidative stress. AB - The PhoPQ two-component regulatory system coordinates the response of Salmonella enterica serovar Typhimurium to diverse environmental challenges encountered during infection of hosts, including changes in Mg2+ concentrations, pH, and antimicrobial peptides. Moreover, PhoPQ-dependent regulation of gene expression promotes intracellular survival of Salmonella in macrophages, and contributes to the resistance of this pathogen to reactive nitrogen species (RNS) generated from the nitric oxide produced by the inducible nitric oxide (NO) synthase of macrophages. We report here that Salmonella strains with mutations of phoPQ are hypersensitive to killing by RNS generated in vitro. The increased susceptibility of ?phoQ Salmonella to RNS requires molecular O2 and coincides with the nitrotyrosine formation, the oxidation of [4Fe-4S] clusters of dehydratases, and DNA damage. Mutations of respiratory NADH dehydrogenases prevent nitrotyrosine formation and abrogate the cytotoxicity of RNS against ?phoQ Salmonella, presumably by limiting the formation of peroxynitrite (ONOO-) arising from the diffusion-limited reaction of exogenous NO and endogenous superoxide (O2*-) produced in the electron transport chain. The mechanism underlying PhoPQ-mediated resistance to RNS is linked to the coordination of Mg2+ homeostasis through the PhoPQ-regulated MgtA transporter. Collectively, our investigations are consistent with a model in which PhoPQ-dependent Mg2+ homeostasis protects Salmonella against nitrooxidative stress. PMID- 29118453 TI - Prediction of Visual Field Progression in Patients with Primary Open-Angle Glaucoma, Mainly Including Normal Tension Glaucoma. AB - An objective method to predict individual visual field progression will contribute to realise personalised medication. The purpose of this study was to establish a predictive formula for glaucomatous visual field progression in patients with Primary open-angle glaucoma, mainly including normal tension glaucoma. This study was a large-scale, longitudinal and retrospective study including 498 eyes of 312 patients visiting from June 2009 to May 2015. In this analysis, 191 eyes of 191 patients meeting all eligible criteria were used. A predictive formula to calculate the rate of glaucomatous visual field progression (mean deviation slope) was obtained through multivariate linear regression analysis by adopting "Angle of Retinal Nerve Fibre Layer Defect" at the baseline, "Vertical Cup-Disc ratio" at the baseline, "Presence or absence of Disc Haemorrhage" during the follow-up period, and "Mean IOP change (%)" during the follow-up period as predictors. Coefficient of determination of the formula was 0.20. The discriminative ability of the formula was evaluated as moderate performance using receiver operating characteristic analysis, and the area under the curve was approximately 0.75 at all cut-off values. Internal validity was confirmed by bootstrapping. The predictive formula established by this type of approach might be useful for personalised medication. PMID- 29118454 TI - Production and Purification of Filovirus Glycoproteins in Insect and Mammalian Cell Lines. AB - Filoviruses are highly virulent pathogens capable of causing severe disease. The glycoproteins of filoviruses are the only virally expressed proteins on the virion surface and are required for receptor binding. As such, they are the main candidate vaccine antigen. Despite their virulence, most filoviruses are not comprehensively characterized, and relatively few commercially produced reagents are available for their study. Here, we describe two methods for production and purification of filovirus glycoproteins in insect and mammalian cell lines. Considerations of expression vector choice, modifications to sequence, troubleshooting of purification method, and glycosylation differences are all important for successful expression of filovirus glycoproteins in cell lines. Given the scarcity of commercially available filovirus glycoproteins, we hope our experiences with possible difficulties in purification of the proteins will facilitate other researchers to produce and purify filovirus glycoproteins rapidly. PMID- 29118455 TI - Acoustic frequency filter based on anisotropic topological phononic crystals. AB - We present a design of acoustic frequency filter based on a two-dimensional anisotropic phononic crystal. The anisotropic band structure exhibits either a directional or a combined (global + directional) bandgap at certain frequency regions, depending on the geometry. When the time-reversal symmetry is broken, it may introduce a topologically nontrivial bandgap. The induced nontrivial bandgap and the original directional bandgap result in various interesting wave propagation behaviors, such as frequency filter. We develop a tight-binding model to characterize the effective Hamiltonian of the system, from which the contribution of anisotropy is explicitly shown. Different from the isotropic cases, the Zeeman-type splitting is not linear and the anisotropic bandgap makes it possible to achieve anisotropic propagation characteristics along different directions and at different frequencies. PMID- 29118456 TI - Expanding the Pipeline: The New York University School of Medicine-University of Ghana School of Medicine and Dentistry Psychiatric Education Initiative. AB - As many low- and middle-income countries (LAMICs), Ghana is affected by a severe shortage of mental health specialists: there are 11 practicing psychiatrists for a population of 25 million. The pipeline for Ghanaian psychiatrists remains restricted for the foreseeable future given the low expressed interest in the field by junior medical trainees. The few senior psychiatric specialists are overextended with clinical and professional duties leaving them with minimal time to teach and mentor trainees. This limits opportunities for mentorship, modeling, teaching, and curricular development, leaving trainees with little exposure to psychiatric practice, and therefore, little motivation to enter a highly stigmatized and underresourced field. To support the training of Ghanaian medical students in psychiatry, the New York University School of Medicine-University of Ghana School of Medicine and Dentistry (NYUSOM-UGSMD) Psychiatric Education Initiative, and the NYU Global Mental Health Elective were formed (1) to provide educational support to medical students and residents at UGSMD and (2) to provide a sustainable international experience for NYUSOM residents with a strong interest in leadership in global mental health and underserved populations. PMID- 29118457 TI - A Case Series of Family-Based Therapy for Weight Restoration in Young Adults with Anorexia Nervosa. AB - This case series aims to examine the preliminary efficacy, acceptability and feasibility of Family-Based Treatment to promote weight restoration in young adults with anorexia nervosa. Four young adults with sub/threshold anorexia nervosa were provided 11-20 sessions of Family-Based Treatment for young adults with pre-, post- and follow-up assessments. At post- and follow-up, 3/4 participants were in the normal weight range, 3/4 were in the non-clinical range on the Eating Disorders Examination and reported being not/mildly depressed. At post-treatment, 2/4 were in the good psychosocial functioning range and by follow up, 3/4 were in this range. These results suggest that Family-Based Treatment for young adults with anorexia nervosa is a promising treatment. PMID- 29118458 TI - Maternal Stress and Child Outcomes: Evidence from Siblings. AB - We study how maternal stress affects offspring outcomes. We find that in-utero exposure to elevated levels of the stress hormone cortisol negatively affects offspring cognition, health and educational attainment. These findings are based on comparisons between siblings which limits variation to short-lived shocks and controls for unobserved differences between mothers that could bias estimates. Our results are consistent with recent experimental results in the neurobiological literature linking exogenous exposure to stress hormones in-utero with declines in offspring cognitive, behavioral and motor development. Moreover, we find that not only are mothers with low levels of human capital characterized by higher and more variable cortisol levels, but that the negative impact of elevated cortisol on their offspring is greater. These results suggest that maternal stress may play a role in the intergenerational persistence of poverty. PMID- 29118459 TI - Model-based functional neuroimaging using dynamic neural fields: An integrative cognitive neuroscience approach. AB - A fundamental challenge in cognitive neuroscience is to develop theoretical frameworks that effectively span the gap between brain and behavior, between neuroscience and psychology. Here, we attempt to bridge this divide by formalizing an integrative cognitive neuroscience approach using dynamic field theory (DFT). We begin by providing an overview of how DFT seeks to understand the neural population dynamics that underlie cognitive processes through previous applications and comparisons to other modeling approaches. We then use previously published behavioral and neural data from a response selection Go/Nogo task as a case study for model simulations. Results from this study served as the 'standard' for comparisons with a model-based fMRI approach using dynamic neural fields (DNF). The tutorial explains the rationale and hypotheses involved in the process of creating the DNF architecture and fitting model parameters. Two DNF models, with similar structure and parameter sets, are then compared. Both models effectively simulated reaction times from the task as we varied the number of stimulus-response mappings and the proportion of Go trials. Next, we directly simulated hemodynamic predictions from the neural activation patterns from each model. These predictions were tested using general linear models (GLMs). Results showed that the DNF model that was created by tuning parameters to capture simultaneously trends in neural activation and behavioral data quantitatively outperformed a Standard GLM analysis of the same dataset. Further, by using the GLM results to assign functional roles to particular clusters in the brain, we illustrate how DNF models shed new light on the neural populations' dynamics within particular brain regions. Thus, the present study illustrates how an interactive cognitive neuroscience model can be used in practice to bridge the gap between brain and behavior. PMID- 29118460 TI - Migration in the 1930s: Beyond the Dust Bowl. AB - This paper analyzes in detail the role of environmental and economic shocks in the migration of the 1930s. The 1940 U.S. Census of Population asked every inhabitant where they lived five years earlier, a unique source for understanding migration flows and networks. Earlier research documented migrant origins and destinations, but we will show how short term and annual weather conditions at sending locations in the 1930s explain those flows, and how they operated through agricultural success. Beyond demographic data, we use data about temperature and precipitation, plus data about agricultural production from the agricultural census. The widely known migration literature for the 1930s describes an era of relatively low migration, with much of the migration that did occur outward from the Dust Bowl region and the cotton South. Our work about the complete U.S. will provide a fuller examination of migration in this socially and economically important era. PMID- 29118461 TI - Relationship between rs854560 PON1 Gene Polymorphism and Tobacco Smoking with Coronary Artery Disease. AB - Paraoxonase-1 (PON1) is the antioxidant marker of high-density lipoproteins protecting against atherosclerosis and coronary artery disease (CAD) phenotype. The purpose of the present study was to determine whether the PON1 gene rs854560 polymorphism (163T>A) is associated with CAD in Polish population. rs854560 was genotyped in 494 subjects: 248 patients with premature CAD and 246 blood donors as a control. We found that the risk of CAD was significantly higher in TT homozygotes than in A allele carriers (OR = 1.87, p = 0.041). The synergistic effect between the TT genotype and cigarette smoking was observed (SIM = 9.81; SI = 14.70). The relative increase in risk from interaction between factors was over 37 (RERI = 36.13). The PON1 polymorphism did not modulate the risk of CAD in response to exposure to other traditional risk factors. In conclusion, the rs854560 polymorphism may modulate the risk of CAD in response to cigarette smoking in Polish population. Carriers of TT genotype seem to be particularly at risk of CAD, when exposed to cigarette smoking. PMID- 29118463 TI - Automatic Identification of Character Types from Film Dialogs. AB - We study the detection of character types from fictional dialog texts such as screenplays. As approaches based on the analysis of utterances' linguistic properties are not sufficient to identify all fictional character types, we develop an integrative approach that complements linguistic analysis with interactive and communication characteristics, and show that it can improve the identification performance. The interactive characteristics of fictional characters are captured by the descriptive analysis of semantic graphs weighted by linguistic markers of expressivity and social role. For this approach, we introduce a new data set of action movie character types with their corresponding sequences of dialogs. The evaluation results demonstrate that the integrated approach outperforms baseline approaches on the presented data set. Comparative in-depth analysis of a single screenplay leads on to the discussion of possible limitations of this approach and to directions for future research. PMID- 29118462 TI - Predictive Role of F2-Isoprostanes as Biomarkers for Brain Damage after Neonatal Surgery. AB - Objective: Neonates have a high risk of oxidative stress during anesthetic procedures. The predictive role of oxidative stress biomarkers on the occurrence of brain injury in the perioperative period has not been reported before. Methods: A prospective cohort study of patients requiring major surgery in the neonatal period was conducted. Biomarker levels of nonprotein-bound iron (NPBI) in plasma and F2-isoprostane in plasma and urine before and after surgical intervention were determined. Brain injury was assessed using postoperative MRI. Results: In total, 61 neonates were included, median gestational age at 39 weeks (range 31-42) and weight at 3000 grams (1400-4400). Mild to moderate brain lesions were found in 66%. Logistic regression analysis showed a significant difference between plasma NPBI in patients with nonparenchymal injury versus no brain injury: 1.34 umol/L was identified as correlation threshold for nonparenchymal injury (sensitivity 67%, specificity 91%). In the multivariable analysis, correcting for GA, no other significant relation was found with the oxidative stress biomarkers and risk factors. Conclusion: Oxidative stress seems to occur during anaesthesia in this cohort of neonates. Plasma nonprotein-bound iron showed to be associated with nonparenchymal injury after surgery, with values of 1.34 umol/L or higher. Risk factors should be elucidated in a more homogeneous patient group. PMID- 29118464 TI - Eocene squalomorph sharks (Chondrichthyes, Elasmobranchii) from Antarctica. AB - Rare remains of predominantly deep-water sharks of the families Hexanchidae, Squalidae, Dalatiidae, Centrophoridae, and Squatinidae are described from the Eocene La Meseta Formation, Seymour Island, Antarctic Peninsula, which has yielded the most abundant chondrichthyan assemblage from the Southern Hemisphere to date. Previously described representatives of Hexanchus sp., Squalus weltoni, Squalus woodburnei, Centrophorus sp., and Squatina sp. are confirmed and dental variations are documented. Although the teeth of Squatina sp. differ from other Palaeogene squatinid species, we refrain from introducing a new species. A new dalatiid taxon, Eodalatias austrinalis gen. et sp. nov. is described. This new material not only increases the diversity of Eocene Antarctic elasmobranchs but also allows assuming that favourable deep-water habitats were available in the Eocene Antarctic Ocean off Antarctica in the Eocene. The occurrences of deep water inhabitants in shallow, near-coastal waters of the Antarctic Peninsula agrees well with extant distribution patterns. PMID- 29118465 TI - Antioxidant and Anti-Inflammatory Activities in Extracts from Minke Whale (Balaenoptera acutorostrata) Blubber. AB - Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-PUFA) is commonly recognized to reduce cardiovascular disease (CVD). In previous studies, cold pressed whale oil (CWO) and cod liver oil (CLO) were given as a dietary supplement to healthy volunteers. Even though CWO contains less than half the amount of LC-n3-PUFA of CLO, CWO supplement resulted in beneficial effects on anti-inflammatory and CVD risk markers compared to CLO. In the present study, we prepared virtually lipid-free extracts from CWO and CLO and evaluated the antioxidative capacity (AOC) and anti-inflammatory effects. Oxygen radical absorbance capacity (ORAC) and ferric reducing antioxidant power (FRAP) assays were used to test the AOC, and the results indicated high levels of antioxidants present in all extracts. The anti-inflammatory effects of the extracts were tested with lipopolysaccharide- (LPS-) treated THP-1 cells, measuring its ability to reduce cytokine and chemokine secretion. Several CWO extracts displayed anti inflammatory activity, and a butyl alcohol extract of CWO most effectively reduced TNF-alpha (50%, p < 0.05) and MCP-1 (85%, p < 0.001) secretion. This extract maintained a stable effect of reducing MCP-1 secretion (60%, p < 0.05) even after long-term storage. In conclusion, CWO has antioxidant and anti inflammatory activities that may act in addition to its well-known LC-n3-PUFA effects. PMID- 29118466 TI - Associations of Functional MicroRNA Binding Site Polymorphisms in IL23/Th17 Inflammatory Pathway Genes with Gastric Cancer Risk. AB - IL23/Th17 axis acts as an inflammatory pathway in gastric carcinogenesis. MicroRNA- (miRNA-) binding site single-nucleotide polymorphisms (SNPs) of inflammatory genes may alter gastric cancer (GC) susceptibility. In this study, four miRNA binding site SNPs (rs3748067 of IL17A, rs887796, rs1468488 of IL17RA, and rs10889677 of IL23R) were genotyped from 500 patients and 500 controls. Unconditional logistic regression analyses and multifactor dimensionality reduction software were used to evaluate the relationships of SNPs with GC and gene-environment interactions, respectively. Quantitative real-time PCR, Western blot analysis, and luciferase report gene assay were applied for function verification. We found that CT (ORadj = 0.59; 95% CI: 0.44-0.79), CT + TT (ORadj = 0.58; 95% CI: 0.43-0.77) genotypes, and T allele (ORadj = 0.77; 95% CI: 0.47 0.80) of rs3748067 reduced GC risk; the rs10889677 CC genotype (ORadj = 2.22; 95% CI: 1.27-3.87) and C allele (ORadj = 1.24; 95% CI: 1.02-1.52) increased GC risk. A meaningful interaction among ever smoked, family history of GC, and rs3748068 could intensify GC risk by 2.25-fold. Functional tests demonstrated the inhibitory effect of miR-10a-3p on IL17A expression in SGC-7901 cells. These results suggested that miRNA binding site SNPs within IL23/Th17 inflammatory pathway genes and their interactions with environmental factors could be associated with GC risk. PMID- 29118469 TI - Welsh Women's Industrial Fiction 1880-1910. AB - From the beginning of the genre, women writers have made a major contribution to the development of industrial writing. Although prevented from gaining first-hand experience of the coalface, Welsh women writers were amongst the first to try to fictionalize those heavy industries-coal and metal in the south, and slate in the north-which dominated the lives of the majority of the late nineteenth-century Welsh population. Treatment of industrial matter is generally fragmentary in this early women's writing; industrial imagery and metaphor may be used in novels that are not primarily "about" industry at all. Yet from c. 1880-1910, Welsh women writers made a significant-and hitherto critically neglected-attempt to make sense in literature of contemporary industrial Wales in powerful and innovative ways. This essay maps their contribution and considers anglophone Welsh women writers' adaptations and innovations of form (particularly romance) as they try to find a way of representing industrial landscapes, communities and the daily realities of industrial labour. It identifies the genesis in women's writing of tropes that would become central to later industrial fiction, including depictions of industrial accident, injury, death and disability. And it explores the representation of social relations (class, gender, ethnicity, sexuality) and conflict on this tumultuous, dangerous new stage. PMID- 29118467 TI - The Light and Shadow of Senescence and Inflammation in Cardiovascular Pathology and Regenerative Medicine. AB - Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation. PMID- 29118470 TI - Diagnostic Utility and Pitfalls of Tzanck Smear Cytology in Diagnosis of Various Cutaneous Lesions. AB - Aims: Tzanck smear is an old but useful test for diagnosis of cutaneous dermatoses. The aim of this study was to highlight the potential usefulness and diagnostic pitfalls of Tzanck smear for diagnosis of cutaneous dermatoses and infections. Materials and Methods: This hospital based cross-sectional study was carried out on all Tzanck smears received for a period of twenty months (January 2014-August 2015). The smears were assessed to establish the utility of Tzanck smears in corroborating or excluding a diagnosis of immunobullous lesion or herpetic infection. Cases with discrepant diagnosis on histopathology were reviewed to identify additional cytomorphological features. Results: A total of 57 Tzanck smears were performed during the study period. Out of the 18 clinically suspected cases of immunobullous disorders, Tzanck smear findings corroborated the clinical diagnosis in 7/18 cases, one case was diagnosed as cutaneous candidiasis, and diagnosis of immunobullous lesions could be excluded in 5/18 cases. Out of the 19 suspected cases of herpetic infections, viral cytopathic effect was observed in 8/19 cases. Besides immunobullous lesions and herpetic infections, acantholytic cells were also observed in spongiotic dermatitis and genodermatosis. Dyskeratotic keratinocytes seen in vacuolar interface dermatitis were not easily distinguishable from acantholytic cells on Tzanck smear. Conclusions: Tzanck smear test is an inexpensive and useful diagnostic tool for certain skin diseases. It can aid in establishing a rapid clinical diagnosis and can serve as a useful adjunct to routine histological examination. We recommend the use of Tzanck smear as a first-line investigation for vesiculobullous, erosive, and pustular lesions. PMID- 29118468 TI - The Intricate Link among Gut "Immunological Niche," Microbiota, and Xenobiotics in Intestinal Pathology. AB - Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut "immunological niche." Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies. PMID- 29118471 TI - Cytomorphologic Diversity of Papillary Thyroid Carcinoma. AB - Introduction: Cytologic features of papillary thyroid carcinoma (PTC) have been extensively documented in literature. However, PTC variants can prove to be diagnostically challenging on fine needle aspiration cytology (FNAC). Aims: To study the FNAC features of PTC and its variants and explore the causes for misdiagnosis. Materials and Methods: This is a retrospective study. All cases of histopathologically (HP) confirmed cases of PTC during a 2-year period (January 2012 to December 2013) with presurgical FNAC were included. The cytologic findings and FNAC diagnosis of each case were documented and compared with the HP report. The misdiagnosed cases were reviewed to look for any cytological clues and reasons for misdiagnosis. Results: A total of 58 cases were included. The overall diagnostic accuracy was 55.6% which improved to 64.8% on including suspicious for PTC cases. Follicular variant was the most misdiagnosed variant; 41.2% of the cases were called follicular neoplasm. Oncocytic variant showed cells with abundant eosinophilic cytoplasm along with bizarre giant cells. Warthin tumor-like variant showed cells with moderate eosinophilic cytoplasm with close apposition of lymphocytes in a background of reactive lymphocytes and lymphoid tangles. Cystic variant was paucicellular. Columnar cell variant showed tall columnar cells with nuclear stratification. Cribriform-morular variant showed syncytial sheets of cells and hyaline globules. Conclusions: PTC variants have distinct cytomorphological features. In some variants (follicular, columnar cell), nuclear grooves and inclusions may not be apparent, contributing to the diagnostic confusion. Benign nodule adjacent to the tumor can dominate the FNAC smear and lead to misdiagnosis. PMID- 29118472 TI - Comparison of Conventional Ziehl-Neelsen Method of Acid Fast Bacilli with Modified Bleach Method in Tuberculous Lymphadenitis. AB - Introduction: Tuberculosis caused by Mycobacterium tuberculosis is a chronic infectious disease and a major health problem in developing countries, with lymphadenopathy being the most common presentation. Tuberculous lymphadenitis can be diagnosed on fine needle aspiration cytology of lymph node. Conventional Ziehl Neelsen method for acid fast bacilli plays a key role in the diagnosis and monitoring of treatment for tuberculosis, however, with low sensitivity. Present study emphasizes the role of bleach concentration method in fine needle aspiration cytology of lymph nodes over conventional direct smear microscopy. Materials and Methods: The study included 75 patients with clinically suspected tuberculous lymphadenopathy who were referred to the Department of Pathology in a tertiary care hospital, Faridabad. Data regarding age, sex, duration and site of swelling, nature of aspirate, and cytomorphological diagnosis were documented for each patient. Results: Of the total 75 cases, 15 were positive both in conventional Ziehl-Neelsen method and bleach concentration method. By bleach concentration method, additional 34 cases showed positivity that were not revealed by conventional Ziehl-Neelsen method. Thus, a total 49 cases were positive for acid fast bacilli. Conclusion: There are problems in arriving at an absolute diagnosis in certain cases of tuberculous lymphadenitis when the aspirate shows polymorphous picture with occasional epithelioid cells and absence of typical Langhans giant cell or caseous necrosis. In the present study, acid fast bacilli positivity was established in 65.33% of the cases with the bleach method. Bleach method for detection of tubercle bacilli has a high case detection rate than that of the conventional Ziehl-Neelsen method. PMID- 29118473 TI - Validating Micronucleus Score in Effusion Fluids. AB - Background: Identifying malignant cells in effusion fluid is vital in staging and management of cancers. Differentiating reactive mesothelial cells from malignant cells in effusion fluid is a challenging task and there is an ongoing need for simpler and cost effective tool to aid the diagnosis. Micronucleus is an additional smaller nucleus in the cytoplasm, formed by chromosomes or chromosomal fragments formed during cell division. Aims: The aim of this study was to assess the significance of micronucleated cell in effusion fluids to distinguish adenocarcinomatous from reactive mesothelial effusions. Materials and Methods: Thirty cases of unequivocal malignant effusion fluids and 30 benign cases with reactive mesothelial cells as control were studied. Number of microucleated cells present per1000 well-preserved cells in Leishman-stained smears were counted. Results: Mean (+/-SD) micronucleated score in malignant and benign effusions were 15.77 +/- 9.78 and 1.87 +/- 1.78, respectively. The median scores were 13 and 2, respectively. Mann-Whitney test showed that this difference was statistically significant (P < 0.001). This study revealed that there was a significant difference in micronucleus scoring between benign and malignant effusions. Conclusions: Micronucleus score can be used as an additional biomarker in the interpretation of routinely stained cytosmears. PMID- 29118474 TI - Cytological Evaluation of Thyroid Lesions by Nuclear Morphology and Nuclear Morphometry. AB - Introduction: Fine needle aspiration (FNA) of the thyroid gland is an effective diagnostic method. The Bethesda system for reporting thyroid cytopathology classifies them into six categories and gives implied risk for malignancy and management protocol in each category. Though the system gives specific criteria, diagnostic dilemma still exists. Using nuclear morphometry, we can quantify the number of parameters, such as those related to nuclear size and shape. The evaluation of nuclear morphometry is not well established in thyroid cytology. Objective: To classify thyroid lesions on fine needle aspiration cytology (FNAC) using Bethesda system and to evaluate the significance of nuclear parameters in improving the prediction of thyroid malignancy. Materials and Methods: In the present study, 120 FNAC cases of thyroid lesions with histological diagnosis were included. Computerized nuclear morphometry was done on 81 cases which had confirmed cytohistological correlation, using Aperio computer software. One hundred nuclei from each case were outlined and eight nuclear parameters were analyzed. Results: In the present study, thyroid lesions were common in female with M: F ratio of 1:5 and most commonly in 40-60 yrs. Under Bethesda system, 73 (60.83%) were category II; 14 (11.6%) were category III, 3 (2.5%) were category IV, 8 (6.6%) were category V, and 22 (18.3%) were category VI, which were malignant on histopathological correlation. Sensitivity, specificity, and diagnostic accuracy of Bethesda reporting system are 62.5, 84.38, and 74.16%, respectively. Minimal nuclear diameter, maximal nuclear diameter, nuclear perimeter, and nuclear area were higher in malignant group compared to nonneoplastic and benign group. Conclusion: The Bethesda system is a useful standardized system of reporting thyroid cytopathology. It gives implied risk of malignancy. Nuclear morphometry by computerized image analysis can be utilized as an additional diagnostic tool. PMID- 29118475 TI - Histological Follow-Up in Patients with Atypical Glandular Cells on Pap Smears. AB - Context: Atypical glandular cells (AGCs) result in the Papanicolaou (Pap) smear may be associated with significant genital and nongenital neoplastic processes. Aims: To evaluate the underlying histopathology in women who had AGCs on Pap smears. Settings and Design: Retrospective cross-sectional study. Patients and Methods: Clinicopathological data of patients who had AGC on Pap smears and underwent histological workup between January 2004 and December 2014 were retrieved from the computerized database of a tertiary care center. Patients with a prior history of cervical intraepithelial neoplasia or gynecological cancer were excluded. Statistical Analysis Used: Chi-square test or Fisher's exact tests were used as appropriate. Results: Cytological examination of the uterine cervix was carried out in 117,560 patients. We identified 107 patients (0.09%) with AGC and 80 of those with histological follow-up were included in the study. The median age at diagnosis was 47 years (range, 18-79), and 32 women (40%) were postmenopausal, while 56 (70%) had gynecological symptoms. Significant preinvasive or invasive lesions on pathological examination were detected in 27 (33.8%) patients, including 12 endometrial adenocarcinomas (15%), 8 cervical carcinomas (10%), 3 cervical intraepithelial neoplasia II/III (3.75%), 2 ovarian adenocarcinomas (2.5%), and 2 metastatic tumors (2.5%). Univariate analysis showed that postmenopausal status (P < 0.001), age >50 years old (P < 0.001), having symptoms at the time of admission (P = 0.041), and AGC "favor neoplasia" smear results (P = 0.041) were the clinical factors associated with significant pathological outcome. Conclusions: Patients with AGC on Pap smears should be evaluated vigilantly with histological workup, especially if they are postmenopausal or symptomatic. PMID- 29118476 TI - Age and Pattern of Pap Smear Abnormalities: Implications for Cervical Cancer Control in a Developing Country. AB - Aim: To characterize the age and pattern of Pap smear abnormalities in a major teaching hospital in Southwestern Nigeria. Design: This is a review of medical records of patients that came for cervical cancer screening. Materials and Methods: The Pap smear results of women between May 2013 and April 2015 were retrieved. A total of 2048 Pap smear results were retrieved during the study period and analyzed with Statistical Package for Social Sciences (SPSS) version 20. A total of 252 (12.3%) samples were excluded from the analysis. Results: The mean age of the women was 45.77 +/- 9.9 years and the mode was 50 years. Normal Pap smear result was reported in 728 (40.6%) women. Only 20 women has had more than one more than one Pap smear done. The most common abnormality was inflammatory smear result as this was reported in 613 (29.9%) women. Atypical squamous cell of undetermined significance, low-grade squamous intraepithelial lesion (LGSIL), and high-grade squamous intraepithelial lesion (HGSIL) were reported in 117 (5.7%), 209 (10.2%), and 111 (5.4%) women, respectively. Atypical glandular cell and squamous cell carcinoma were reported in 12 (6.0%) and 3 (1.0%), respectively. Conclusion: There is a high incidence of abnormal Pap smear in this environment and women start cervical cancer screening late in their reproductive life, past the age at which cervical premalignant lesions peak. This may be a contributing factor to the high burden of cervical cancer in developing countries. PMID- 29118477 TI - Evaluation of the Efficacy of Post Prostatic Massage Urine Cytology in Diagnosis of Various Prostatic Lesions with Cytohistological and Clinical Correlation. AB - Background: Elderly men are at high risk of various prostatic diseases carrying high morbidity and mortality rates. For screening large populations, there is a need for a simple, reliable, and noninvasive test with high sensitivity and specificity. Exfoliated prostatic cancer cells can be harvested by prostatic massage and subjected to cytologic examination and molecular tests. Aims: This study was undertaken to evaluate the morphology of various prostatic lesions on post prostatic massage urine cytology and correlate cytologic, histologic, and clinical findings. It was further proposed to establish the diagnostic accuracy of post prostatic massage urine cytology in different prostatic lesions. Materials and Methods: Totally, 100 cases including 50 cases each from study group and control group were subjected to post prostatic massage urine cytology and correlated with clinical and histological findings. Results: Five out of 50 cases were diagnosed as prostatic carcinoma, of which 60% were clinically detected. Diagnostic accuracy by histology and cytology independently was 80%, and 20% remained false negative by each technique. On combining both the techniques, diagnostic accuracy was 100%. For nine cases each of prostatitis and nodular hyperplasia diagnosed clinically, the diagnostic accuracy by cytology was 100 and 66.6%, respectively. 62% (31) cases were diagnosed as nodular hyperplasia including 22 (44%) cases of nodular hyperplasia with prostatitis. Conclusion: Collection of urinary specimens after prostatic massage provides adequate samples for cytological examination and carries great importance in establishing the preoperative morphologic diagnosis in cases of malignancy, prostatitis, and prostatic calculi. PMID- 29118478 TI - Intraoperative Squash Smear Cytology in CNS Lesions: A Study of 150 Pediatric Cases. AB - Background: Tumors of the central nervous system in the pediatric age group occur relatively frequently during the early years of life. Brain tumors are the most common solid malignancies of childhood and only second to acute childhood leukemia. Squash cytology is an indispensable diagnostic aid to central nervous system (CNS) lesions. The definitive diagnosis of brain lesions is confirmed by histological examination. Aim: To study the cytology of CNS lesions in pediatric population and correlate it with histopathology. Materials and Methods: One hundred and fifty cases of CNS lesions in pediatric patients were studied over a period of 2 years. Intraoperative squash smears were prepared, stained with hematoxylin and eosin, and examined. Remaining sample was subjected to histopathological examination. Results: Medulloblastoma (24.0%) was the most frequently encountered tumor followed by pilocyctic astrocytoma (21.33%) and ependymoma (13.33%). Diagnostic accuracy of squash smear technique was 94.67% when compared with histological diagnosis. Conclusion: Smear cytology is a fairly accurate tool for intraoperative CNS consultations. PMID- 29118479 TI - Intraparotid Schwannoma Masquerading as Primary Spindle Cell Tumour of Parotid: A Diagnostic Pitfall. AB - A middle-aged female presented with a painless, slowly growing mass in the left parotid region; fine needle aspiration cytology from the mass showed uniform spindle cells in a fibrillary background with some cells showing palisading. A cytodiagnosis of schwannoma was given, which was further confirmed on biopsy. PMID- 29118480 TI - Cytological Profile of a Case of Malignant Mesothelioma of Pleura with Supraclavicular Lymph Node Metastasis. AB - Malignant mesothelioma of pleura is a locally aggressive rare neoplasm of mesothelial cells, which produces distant metastasis in advanced stages of its course. It is exceptional for patients to present with metastasis prior to the detection of primary tumor in the pleura. Here, we report a case of malignant mesothelioma of pleura in a 65-year-old quarry worker where the initial diagnosis was offered by fine needle aspiration of an enlarged supraclavicular lymph node. Subsequent pleural fine needle aspiration cytology (FNAC), tumor biopsy, and immunohistochemical analysis confirmed the diagnosis. PMID- 29118481 TI - Role of Cytology in Early Diagnosis of Cerebrotendinous Xanthomas. AB - Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disease characterized by widespread tissue deposition of two neutral sterols, cholestenol and cholesterol, resulting in tendinous xanthomas, juvenile cataracts, progressive neurological defects, and premature death from arteriosclerosis. Because it is a treatable cause of cerebellar ataxia and dementia, its early diagnosis is desirable. Here, we have reported the case of an 11-year-old boy with this disorder who was diagnosed based on the cytological findings of fine needle aspiration and clinical features. PMID- 29118482 TI - Cyto-Histo Correlation of a Very Rare Tumor: Superficial Angiomyxoma. AB - Superficial angiomyxoma (SA) is one of the superficially located myxoid soft tissue tumor. Because of the rarity of this tumor, there is paucity of fine needle aspiration cytology (FNAC) findings. Here, we present a case of SA in a 14 year-old girl who presented with a left leg swelling. The cytology of the lesion along with the histopathologic correlation is presented. PMID- 29118483 TI - Unusual Contaminants: Arthropod in Pap Smear. PMID- 29118484 TI - Open Access and Other Challenges of Present Day Journal Publishing. PMID- 29118485 TI - Classification of retinoblastoma: Evolution with time and the need for uniformity. PMID- 29118486 TI - Choroidal melanoma: A short review with an Indian perspective. AB - Choroidal melanoma (CM), the most common intraocular tumor in adults, is still a rarity in Asia. Having a high propensity for metastasis with a poor survival, recognizing it early is essential. Although it has typical clinical features, there are instances of simulating lesions. Fine-needle aspiration biopsy can be a valuable tool not only to confirm our clinical suspicion but also aid in prognosticating it. From days of histopathological prognostic markers, we are moving on to genetic markers which are reliably providing insights, helping us in providing a better care for our patients. Eye preservation has taken an all new important meaning in CM with many centers opting for different modalities of radiation. Herein, we try to provide a short synopsis of CM looking into its epidemiology, clinical features, diagnosis, and management. We also look briefly into the role of fine-needle biopsy in managing CM. Being a tertiary referral ocular center in India, we do come across CM; we have shared the preliminary reports of our analysis of managing CM over a 9-year period. PMID- 29118487 TI - Long-term use of 0.003% tacrolimus suspension for treatment of vernal keratoconjunctivitis. AB - PURPOSE: To evaluate the safety and efficacy of 0.003% tacrolimus suspension for the treatment of refractory vernal keratoconjunctivitis (VKC). MATERIALS AND METHODS: This prospective study included 40 eyes of 20 patients with severe VKC. After discontinuing all other medications, patients were treated with varying doses of 0.003% tacrolimus suspension. All were followed for at least 24 months. Changes in signs and symptoms after treatment were evaluated; adverse events were assessed. The clinical response to the treatment was the most important measurement to achieve the conclusion. RESULTS: The mean age of the patients was 15.7 +/- 1.4 years. Two patients discontinued treatment due to severe burning sensation and were excluded from the study. Significant improvements in all signs and symptoms, including itching, foreign body sensation, papillae, and Trantas dots, were seen in all patients 6 weeks after starting topical tacrolimus. Itching was the first symptom to improve. Treatment was gradually reduced, and intervals were increasing between applications. Recurrence occurred in all patients who attempted to discontinue treatment. No additional medications were required to provide relief, and no significant changes in visual acuity or refraction were seen. CONCLUSIONS: The safety and efficacy of 0.003% Tacrolimus suspension treatment for refractory VKC were achieved and it can be considered a useful option instead of steroids, despite the poor compliance in few patients due its adverse effects. PMID- 29118488 TI - The role of trabeculectomy in enhancing glaucoma patient's quality of life. AB - PURPOSE: Is to control intraocular pressure (IOP) (up to 21 mmHg), to decrease medical treatment after trabeculectomy and to slow down or stop progression and deterioration in visual fields in glaucoma patients. METHODS: A retrospective study. The charts of all trabeculectomies done in the Department of Ophthalmology at the Skane University Hospital, Sweden during 2010 were retrospectively evaluated. The study was performed during fall 2012, so the longest follow-up is almost 2 years. RESULTS: In total, 38 patients (21 males and 17 females) underwent trabeculectomy. The IOP was measured in both visits (pre- and post operative); with a difference of -15.49 mmHg (-50.09%) respectively, showing a very highly statistical significance (P < 0.001). The amount of antiglaucoma drops was measured before and after the trabeculectomy, of average 3.5 drops and 1.2 drops, respectively. Showing a -2.30 difference (-66.41%), illustrating a very highly statistical significant value (P < 0.001). From 36 patients, 17 patients (45%) took Diamox before trabeculectomy, whereas 19 patients (50%) did not. After the trabeculectomy, only 1 patient (3%) took Diamox and 35 patients (92%) stopped taking Diamox, showing a very highly significant statistical value (P < 0.001). The visual field was measured for 13 patients showing a difference of -13.22 (-21.86%) before and after the trabeculectomy. CONCLUSION: Trabeculectomy showed very high statistical significant results regarding IOP reduction and decrease in the amount of topical and systemic antiglaucoma medications. PMID- 29118489 TI - Minimal duration cataract surgery with oblique limbal stab incision technique. AB - PURPOSE: Small incision cataract surgery (SICS) and phacoemulsification with oblique limbal stab incision technique were studied and compared. SETTING: The study was conducted in the Department of Ophthalmology, Indira Gandhi Medical College, Shimla, for 1 year. DESIGN: This was a prospective randomized study. METHODS: One hundred patients undergoing SICS (6-7 mm) were compared with another age- and sex-matched 100 patients undergoing phaco (2.8 mm) surgery with oblique limbal stab incision technique. These two groups were further subdivided into two groups of 50 each. Patients with traumatic cataract, corneal diseases, and preoperative astigmatism >1.5 D were excluded from the study. The patients were subjected to standard preoperative evaluation. Follow-up was done at 1, 2, 4, 6, and 12 weeks. RESULTS: Mean surgically induced astigmatism at 12 weeks was <1 D in both groups (+0.62 D +/- 0.34 in Group A and +0.46 D +/- 0.39 in Group B) (statistically significant P < 0.0010). Mean surgical duration was 690.09 s in SICS and 792.29 s in phacoemulsification (statistically significant, P < 0.0010). Visual outcome was between 6/6 and 6/9 in 86% of the patients in Group A and 97% of patients in Group B at 12 weeks. CONCLUSION: SICS and phacoemulsification with this technique yield lesser astigmatism than clear corneal and scleral incisions, with the advantage of extension without suturing in complicated cases of phaco and in patients with rigid intraocular lens phacoemulsification gives better BCVA in a larger proportion of patients at 12 weeks. PMID- 29118490 TI - Corneal epithelial defect after pars plana vitrectomy. AB - AIM: This study aims to study the incidence of corneal epithelial defect (CED) after pars plana vitrectomy (PPV) and associated patient-related risk factors. The incidence of other immediate postoperative complications was also in the scope of this study. DESIGN: Retrospective descriptive case series study. METHODS: Review of electronic medical records of all patients who underwent PPV alone or combined with cataract surgery and/or scleral buckle in a tertiary hospital by one retinal surgeon. All demographic data, surgery notes, and immediate postoperative findings were obtained for all patients. RESULTS: The cohort of the included cases was composed of a total of 168 procedures that were performed in 121 eyes of 106 patients over 5 years. CEDs occurred in 19 eyes (15.7%) of 19 patients (17.9%). Males were affected more than females (90% vs. 10%). Patients with postoperative CED were found to have longer duration of surgery when compared to patients without postoperative CED (P = 0.0038). All cases of CED had a complete resolution of the defects after supportive therapy. Immediate intraocular hypertension (IOH) was found in 30 eyes (24.8%). IOH was controlled in all cases with medical therapy only. Post-PPV immediate complications, other than CED and IOH, occurred in 10.7% of the eyes. These included vitreous hemorrhage, choroidal detachment, corneal edema, anterior chamber fibrin, and hyphema. CONCLUSION: Development of CED is not uncommon after PPV. This complication is more common in males and may be related to prolonged duration of surgery. It also develops more in older patients. CED after PPV can be managed with conservative treatment with good outcome. PMID- 29118491 TI - Retinopathy of prematurity like retinopathy in full-term infants. AB - PURPOSE: The purpose of this study is to assess clinical characteristics, risk factors, and management outcomes of retinal changes similar to retinopathy of prematurity (ROP), seen in full-term infants. PATIENTS AND METHODS: This is a retrospective review of 46 eyes of 23 patients, born at full term or near full term and diagnosed to have active ROP-like retinopathy or sequelae of ROP-like retinopathy. RESULTS: Mean birth weight (BW) and gestational age (GA) were 2342 +/- 923 g (range, 1200-4160 g) and 38.5 +/- 1.85 weeks (range, 37-40 weeks). Mean age at the time of diagnosis was 3.5 +/- 8.75 years (range, 1 month-16 years). Stage 1 and 2 of retinopathy was seen in 10 eyes (21.7%), threshold disease with plus disease in 12 eyes (26%) and Stage 4 or 5 in 14 eyes (30.4%). Involutional sequelae were noted in 10 eyes (21.7%). Twenty-one eyes (45.6%) underwent appropriate treatment in the form of laser, cryotherapy, or retinal detachment surgery. Eight eyes (17.4%) with advanced sequelae such as total closed funnel retinal detachment and macular fold were not treated. Mean follow-up was 3 years (range, 1 month to 12 years). At the last follow-up, 29 eyes (63%) had a favorable structural outcome (P < 0.001). Among the patients in whom visual acuity could be assessed (16 eyes), favorable visual outcome was noted in 9 eyes (56.2%). Low BW (P = 0.038), multiple births (P = 0.013), respiratory distress syndrome (RDS) (P = 0.001), phototherapy (P = 0.001), and oxygen administration (P < 0.001) were significantly associated with the development of ROP-like retinopathy in these full-term infants. CONCLUSIONS: ROP-like retinopathy can occur in full-term and near full-term infants and can potentially lead to permanent visual impairment. Screening of infants with risk factors such as oxygen administration, RDS, multiple births, and low BW, regardless of GA, may reduce visual impairment. PMID- 29118492 TI - Association of ocular findings and outcome in cerebral venous thrombosis. AB - BACKGROUND: Cerebral venous thrombosis (CVT) is a potentially life-threatening underdiagnosed disease. Headache is a common but nonspecific finding in CVT. Other features such as ocular finding can assist to correct diagnosis, but their frequency in CVT has not been previously evaluated. The aim of this study is to evaluate the ocular symptoms and signs in CVT and their association with outcome. METHODS: The demographic, clinical, laboratory, radiological, and outcome data were collected and analyzed from patients referred to a tertiary hospital during 6 years. Based on delay from symptom onset to hospital admission, mode of onset was categorized as acute (<2 days), subacute (2-14 days), or chronic (>14 days). RESULTS: Fifty-three patients were identified with a mean age of 33.7 years (17 60 years). Ocular symptoms and signs were the most frequent clinical presentations (77.4%) following headache (83%). Papilledema and diplopia were the main findings in chronic CVTs (P = 0.003 and 0.002, respectively). Proptosis was significantly associated with thrombosis in cavernous sinus (P = 0.00). Otherwise, there was no relationship between any specific ocular findings and the type or number of thrombosed sinus or hemorrhagic infarction. Mortality rate and recurrence in our patients were 3.8% and 5.7%. Absence of proptosis and vision loss was associated with favorable outcome (P = 0.001 and 0.003, respectively). CONCLUSION: Ocular features were among the most common presentation of CVT in every three phases of CVT and could be the sole finding of CVT. Patients who do not have vision loss and proptosis might have a better outcome in CVT. PMID- 29118493 TI - Experience of intravitreal triamcinolone acetonide for treatment of diabetic macular edema among Omani population. AB - PURPOSE: The purpose of this study was to evaluate the outcome of intravitreal (IVT) triamcinolone in diabetic macular edema (DME). MATERIALS AND METHODS: A retrospective study of 42 eyes diagnosed clinically and supported with optical coherence tomography (OCT), with DME of more than 300 MUm in thickness. All eyes were injected with a single IVT injection of preservative free triamcinolone acetonide (TA) with dose of 4 mg. Patients were subjected to visual acuity (VA) and OCT on each follow-up visit which was continued for 6 months. The total number of IVT injections given was 48. Six eyes had a repeat injection. None of the eyes had any other IVT injection within 6 weeks of TA. Twenty-one eyes were pseudophakic. RESULTS: Mean age of the patients was 58.8 years. The mean central subfield thickness (CST) at baseline was 504.6 MUm. At 6 weeks, the mean CST dropped by 183.6 MUm (P < 0.00001). At 6-month follow-up, the mean CST had increased by 74.6 MUm from 6 weeks level; however, the 6-month mean CST was 109 MU less than mean baseline thickness (P < 0.0005). The mean baseline VA was 0.80 LogMAR units. At 6 weeks, the mean VA dropped by 0.01 LogMAR. At 6 months, VA improved by 0.02 LogMAR units from baseline. Overall, VA improved in 47% eyes, dropped from baseline in 35% eyes, and remained unchanged in 18% eyes. CONCLUSION: Triamcinolone acetonide is a safe, effective, and promising therapy in DME. PMID- 29118494 TI - Comparison between Ologen implant and different concentrations of Mitomycin C as an adjuvant to trabeculectomy surgery. AB - CONTEXT: Trabeculectomy is the most common surgical procedure for treatment of glaucoma. To improve success rates, adjuvants were utilized as Mitomycin C (MMC) and Ologen implant. AIMS: This study aims to establish efficacy and safety of Ologen implant versus MMC in trabeculectomy. SETTING AND DESIGN: A prospective, comparative clinical study was conducted at the Department of Ophthalmology, Assiut University, between December 2014 and April 2016. SUBJECTS AND METHODS: Patients with primary open-angle glaucoma (OAG), primary narrow-angle glaucoma and secondary OAG were assigned equally to trabeculectomy with Ologen, 0.4 mg/mL or 0.2 mg/mL MMC. The study outcome measures were reduction in intra-ocular pressure (IOP), success rates, survival analysis, and rate of complications. STATISTICAL ANALYSIS USED: SPSS software Version 17.0 (SPSS, Inc., IL, USA) was utilized. RESULTS: Thirty eyes were included in the study. Mean baseline IOP in Ologen, MMC 0.4 and MMC 0.2 groups were 27.43 +/- 2.97, 28.4 +/- 3.24, and 27.56 +/- 2.69 mmHg, respectively. At week 24 follow-up, mean IOP in Ologen, MMC 0.4 and MMC 0.2 groups were 18.55 +/- 3.18, 16.2 +/- 3.22, and 16.93 +/- 3.04 mmHg, respectively. No significant inter-group difference was noticed at any visits. Complete success was achieved in 10%, 40%, and 30%, whereas incomplete success in 70%, 50%, and 60%, respectively in Ologen, MMC 0.4 and MMC 0.2 groups. No treatment group difference was reported by Kaplan-Meier analysis. Shallow anterior chamber occurred more in Ologen and MMC 0.4 groups. A single case of serous choroidal effusion had occurred in MMC 0.4 group. CONCLUSION: Ologen implant is a promising alternative to MMC for improving the success rate of trabeculectomy. PMID- 29118495 TI - Emergency visits after corneal transplantation in Yemen. AB - PURPOSE: Awareness of symptoms and signs of possible complications after corneal transplantation is very important. Early presentation can enhance long-term survival of the cornea. This study evaluates the reasons for emergency presentation and management of postcorneal transplantation complications. PATIENTS AND METHODS: This retrospective study included a total of 134 postkeratoplasty patients at the cornea unit in Yemen Magrabi Eye Hospital in Sana'a between 2008 and 2010. RESULTS: The most common indication for keratoplasty was keratoconus in 103 patients (76.9%) followed by bullous keratopathy (4.5%) and corneal dystrophy (4.5%). 80 (59.7%) patients presented for emergency visits. Pain and foreign body sensation were the main presenting symptoms. Loose irritating sutures (29.9%) and graft rejection (10.4%) were the most common diagnoses. Twelve patients (8.9%) were admitted to the hospital for re-suturing. CONCLUSION: Proper postoperative care is critical for a successful keratoplasty; early intervention of sight-threatening complications increases the chance of graft survival and best-obtained vision. In our corneal transplantation service, all patients are routinely instructed to arrange a same day emergency visit if they experience any symptom in eyes that have undergone keratoplasty. PMID- 29118496 TI - Visual outcome and complications of various techniques of secondary intraocular lens. AB - BACKGROUND/AIMS: The purpose of this study was to compare and evaluate the visual outcome and complications of various techniques of secondary intraocular lens (IOL) (i.e., anterior chamber IOL [ACIOL], suture-fixated posterior chamber IOL [PCIOL], and glue-fixated PCIOL). STUDY DESIGN AND SETTING: This was a randomized, prospective, interventional, comparative, clinical trial study. SUBJECTS AND METHODS: Patients of either sex having aphakia and lacking posterior capsular support were included in the study, and patients having corneal or scleral pathology, optic atrophy, uncontrolled glaucoma, retinal detachment, and other retinal pathology were excluded from the study. The patients were divided into three groups after comprehensive ophthalmological examination - Group A (secondary ACIOL) included 44 patients, Group B (secondary scleral-fixated sutured PCIOL) included 32 patients, and Group C (fibrin glue-fixated sutured PCIOL) included 34 patients. RESULTS: A total of 110 patients were included in this study, of which 59 (53.63%) were males and 51 (46.37%) were females. The best-corrected visual acuity (VA) after 6 weeks was in the range of 20/60-20/40 in 36.4% of Group A and 40.6% of Group B patients. In Group C, 52.9% of patients had best-corrected VA in the range of 20/30-20/20. The overall complications were less in glued PCIOL group. CONCLUSION: It can be concluded that fibrin glue assisted PCIOL implantation provides better visual outcome with minimal complications in eyes with deficient capsular support. PMID- 29118497 TI - Comparing ganglion cell-inner plexiform layer thickness with focal and global responses on multifocal electroretinogram in glaucoma. AB - BACKGROUND: The aim of this study was to evaluate responses on multifocal electroretinogram (mfERG) with ganglion cell-inner plexiform layer (GCIPL) thickness on cirrus spectral-domain optical coherence tomography (SD-OCT) in glaucoma. METHODS: All diagnosed glaucoma patients attending glaucoma services at our institute from November 2012 to April 2013 were screened for this observational hospital-based study. Controls included patients attending our outpatient services for general eye checkup. Structural parameters on SD-OCT including GCIPL and retinal nerve fiber layer (RNFL) thickness were compared with functional parameters on mfERG in early (mean deviation <-6 dB), moderate (-6 to 12 dB), and controls. RESULTS: A total of 54 cases and 33 controls fulfilling inclusion criteria were recruited for the study. The average and minimum GCIPL thickness did not vary significantly between early and control eyes while moderate glaucoma eyes had marginally lower GCIPL thickness than early glaucoma eyes. The GCIPL minimum thickness on univariate regression was found to be influenced by N2 amplitudes (beta = -0.5, P = 0.012) and global N2P1amplitudes (beta =0.6, P = 0.01) in moderate glaucoma. In early glaucoma, these were influenced only by RNFL parameters with no association with functional mfERG responses. Multivariate logistic regression identified global N2P1 amplitude to be significantly influencing GCIPL average and minimum thickness (P = 0.01 and 0.02, R2 = 47.8% and 52.3%, respectively) in moderate glaucoma. Maximum area under the curve was found for GCIPL minimum (95% confidence interval [CI] 0.53 0.81) and N2P1 amplitude (95% CI 0.55-0.80). CONCLUSIONS: The second order responses N2P1 and N2 amplitude on mfERG predict function that correlated with structural GCIPL thickness in moderate glaucoma. Early glaucoma may be best predicted by RNFL thickness rather than on mfERG responses. PMID- 29118498 TI - Comparison of clinical outcome between 23-G and 25-G vitrectomy in diabetic patients. AB - PURPOSE: To compare the clinical outcomes and complications between 23-G and 25-G vitrectomy in patients with diabetic vitreous hemorrhage (VH). MATERIALS AND METHODS: A retrospective comparative study comprising 69 eyes (36 eyes in 23-G group and 33 eyes in 25-G group) of 65 patients who underwent vitrectomy with air tamponade for diabetic vitreous hemorrhage (VH) with at least 6 months of follow up was conducted. RESULTS: There were no significant differences between the two groups in age, gender, bilaterality, type of diabetes, presence of hypertension, lens status, and previous argon laser photocoagulation state (P > 0.05). Best corrected visual acuity (BCVA) of both groups at postoperative 1 month logarithm of the minimum angle of resolution (logMAR) (1.06 +/- 0.99, 0.90 +/- 0.96), 3 months logMAR (1.07 +/- 0.93, 0.83 +/- 0.85), and 6 months logMAR (1.03 +/- 0.89, 0.83 +/- 0.85) significantly improved from the preoperative BCVA logMAR (2.03 +/- 0.83, 2.15 +/- 0.99) for 23-G group, 25-G group, respectively (P < 0.0001). There was no significant difference in BCVA between the two groups preoperatively and at 1, 3, and 6 months postoperatively (P = 0.566, 0.506, 0.333, and 0.445, respectively), incidence of intraoperative wound suturing (21.4%, 15.2%), postoperative hypotony (0.0%, 0.0%), early postoperative VH (POVH) (11.1%, 15.2%), late POVH (5.6%, 0.0%), retinal detachment (2.8%, 6.1%), neovascular glaucoma (92.8%, 9.1%), and endophthalmitis (0.0%, 0.0%) for 23-G group, 25-G group, respectively (P > 0.05). CONCLUSION: 25-G vitrectomy is as effective for PDR as 23-G vitrectomy. PMID- 29118499 TI - Causes and management of small pupil in patients with cataract. AB - BACKGROUND: The purpose of the study was to present the causes and management of small pupil (<6 mm) in Greek patients with cataract. METHODS: About 1144 consecutive patients with cataract comprised the study group. The pupil size was measured after maximal dilation by means of Rosenbaum cards and Colvard pupillometer. Dilation regimen included phenylephrine 10%, tropicamide 1%, cyclopentolate 1%, and ketorolac trometamol 0.5% administered 3 times at 5 min intervals starting 1 h before surgery. The presence of possible risk factors for small pupil was recorded. The need of additional maneuvers and devices to dilate the pupil during cataract surgery was examined, and the complication rate in cases with small pupils was recorded. RESULTS: Small pupil was observed in 78 out of 1144 eyes (6.8%, 95% confidence interval = 5.2%-8.8%). Nine eyes had pupil size <4 mm (0.78%) preoperatively. Six cases (0.52%) developed intraoperative pupillary miosis. The major cause of small pupil was pseudoexfoliation (PEX) in 47.4% (37/78) of patients. No significant associations were observed regarding age, gender, history of diabetes mellitus, the maturity of cataract, and phacodonesis. Techniques for small pupil management included pupil stretching in 14 cases (17.9%), use of iris hooks in 6 cases (7.7%), iris sphincter cuts in 2 cases (2.6%), and placement of a Malyugin Ring in 4 cases (5.1%). Seven eyes (9%) with small pupil had capsular rupture versus 16 eyes (1.5%) with normal dilation (P < 0.001). CONCLUSIONS: Small pupil is not very common in Greek population, is mostly caused by PEX, and it is associated with increased complication rate. PMID- 29118500 TI - Iridoplasty of fixed-dilated pupil (Urrets-Zavalia syndrome) after deep anterior lamellar keratoplasty. AB - A 38-year-old woman with advanced keratoconus initially developed Urrets-Zavalia Syndrome (UZS) in the left eye after deep anterior lamellar keratoplasty. During the uneventful surgery, a 7-mm-wide pupil unresponsive to light was noticed. On the first postoperative day, intraocular pressure (IOP) was elevated up to 45 mmHg with shallow anterior chamber (AC). A peripheral iridotomy in 2 o'clock position was conducted and a fixed combination of brinzolamide 1% and timolol 0.5% was administered topically. In the subsequent postoperative period, IOP was successfully reduced, but the patient reported severe photophobia, glare, and decreased vision. Twelve months after surgery, her best-corrected visual acuity (BCVA) was 20/200, the fixed-dilated pupil persisted, iris was atrophic, and lens opacities were detected. She was submitted for phacoemulsification cataract surgery combined with iridoplasty using the closed chamber slipping suture technique. Three months after surgery, her BCVA was 20/25, pupil diameter remained stable at 4 mm, and glare symptoms were significantly reduced. A very adequate cosmetic outcome was also achieved. Iridoplasty in postkeratoplasty patient with unilateral UZS was effective in improving patient's visual function disability and restoring residual anisocoria. This technique can be applied as a single procedure or combined with another one for the management of UZS. PMID- 29118501 TI - Novel PDE6A mutation in an Emirati patient with retinitis pigmentosa. AB - Mutations in the PDE6A gene are known to cause a form of retinitis pigmentosa (RP43), characterized by progressive retinal degeneration. We describe an Emirati patient with RP caused by a novel mutation in PDE6A. Clinical diagnosis of RP was made based on clinical evaluation and electroretinograms. The molecular analysis involved performing whole-exome sequencing, which enabled the identification of a homozygous 2-bp deletion (c.1358_1359delAT) in PDE6A, which was predicted to result in a frameshift and premature termination (p.Ile452Serfs*7). The mutation completely removed the catalytic PDEase domain in the protein. The parents were found to be heterozygous carriers of the variant. We thus report the first known case of a pathological variant in the PDE6A gene from the Arabian Peninsula. PMID- 29118502 TI - Bilateral sensorineural hearing loss secondary to sympathetic ophthalmia in a human leukocyte antigen-A2 positive patient. AB - We report a case of sympathetic ophthalmia 1 month following trauma in a 71-year old immunocompetent female patient of Indian origin. The patient was hospitalized with signs and symptoms of meningism, ataxia, and neurosensory deafness. We explore and provide further clinical evidence in supporting the hypothesis of antigen cross-reactivity derived from tissues with common neural crest embryological background such as the uvea and cells of the labyrinth. The patient was human leukocyte antigen-A2 positive and treatment with oral steroids and cyclosporine has managed to have favorable results and control the inflammation. PMID- 29118503 TI - Inadvertent intralenticular dexamethasone implant: 1-year follow-up and management. AB - We report the case of a 72-year-old female who developed macular edema (ME) due to hemicentral retinal vein occlusion in her right eye. A dexamethasone implant was inadvertently injected into the crystalline lens. The patient was followed without repositioning of the dexamethasone implant during the 12 months. Besides, the posterior subcapsular cataract and ME had progressed significantly; hence, cataract extraction and intravitreal ranibizumab injection were performed in the same session. A three-piece intraocular lens was implanted in the sulcus with optic captured, and then intravitreal ranibizumab injection was performed. The patient had an uncomplicated postoperative recovery. At 2 months, best-corrected visual acuity was 0.7, and the macula was dry. PMID- 29118504 TI - Bilateral early capsular block syndrome following implantation of the new trifocal toric lens. AB - A young patient underwent phacoemulsification with endocapsular implantation of trifocal toric lens in both eyes (AT LISA tri toric 939 MP, Carl-Zeiss, Germany). One-week postsurgery, he developed capsular block syndrome (CBS) in both eyes. There was deterioration of uncorrected visual acuity at 1-week postsurgery, with a myopic shift of 2.5 diopters (D) in the right eye and 2.0 D in the left eye. The intraocular pressure was only elevated in the left eye. Neodymium: yttrium aluminum-garnet laser posterior capsulotomy resolved the block successfully in both eyes. A thick lens with a plate haptic design may have contributed to the early CBS. PMID- 29118505 TI - Descemet's membrane macroperforation during interface irrigation in big bubble deep anterior lamellar keratoplasty. AB - This report describes the macroperforation of descemet's membrane (DM) during irrigation of the interface following successful removal of stromal tissue in big bubble (BB) deep anterior lamellar keratoplasty (DALK). A 42-year-old woman with keratoconus underwent a BB DALK procedure. After successful formation of Type 2 bubble and removal of stromal tissue, interface irrigation was performed to remove residual viscoelastic. This led to a macroperforation of DM, and the case was converted to penetrating keratoplasty. To the best of our knowledge, this is the first report of such a complication in the literature. Recognition of a 2 bubble formation during pneumodissection should alert the surgeon to a high risk of DM rupture. We advise against the removal of DM from the donor in such cases as an added measure of safety. PMID- 29118506 TI - Localized retinal degeneration secondary to Waldenstrom's macroglobulinemia. AB - A 52-year-old man, treated for Waldenstrom's macroglobulinemia (WM), continued to experience decreased vision even after 24 months. He was evaluated using multimodal imaging and electroretinography. The retina did not show any hyperviscosity changes but revealed a yellow lesion at macula with atrophic changes causing a pattern on fluorescein angiography similar to a leopard's skin. Optical coherence tomographic imaging revealed uniformly reflective material deposited in the outer retina with degeneration of outer retinal layers. Full field electroretinography was normal, but multifocal electroretinography revealed reduced foveal responses. This case highlights the degenerative effects of long standing immunogammopathy maculopathy in WM. PMID- 29118507 TI - Periventricular leukomalacia with -16 DS high myopia in a 21/2 months old infant: A rare case presentation. AB - Periventricular leukomalacia (PVL) is coagulation necrosis of white matter seen in preterm, low birth weight (LBW) infants and associated with a range of ocular manifestations. We report a case of 21/2 months old (47 weeks gestational age) female infant with PVL associated with bilateral high myopia (-16 DS). On examination, child had difficulty in tracking objects and inferior field defect with preference for superior gaze. She was prescribed spectacles and visual stimulation exercises to preserve existing vision and prevent amblyopia. Periventricular leukomalacia can affect full-term infants although it is more common in preterm and LBW infants. All preterm, LBW infants, and those with positive neuroradiological findings must be assessed by an ophthalmologist as early as possible to detect the associated ocular manifestations. PMID- 29118508 TI - Treatment of unilateral zone I cytomegalovirus retinitis in acute lymphoblastic leukemia with oral valganciclovir and intravitreal ganciclovir. AB - Cytomegalovirus retinitis (CMVR) is an opportunistic infection seen in immunocompromised patients, especially suffering from acquired immune deficiency syndrome. It is uncommonly seen in hematological malignancies and in patients on immunosuppressants. The authors present a 12-year-old girl with unilateral CMVR who was on maintenance phase therapy for mixed phenotype (B/myeloid) leukemia. Serology for human immunodeficiency virus was negative. The child was successfully treated with oral valganciclovir and repeated intravitreal ganciclovir injections. CMVR in pediatric population with leukemia can be successfully treated with oral valganciclovir and intravitreal ganciclovir injections. PMID- 29118509 TI - Epiretinal membrane development after submacular perfluorocarbon liquid removal. AB - Optical coherence tomography of submacular perfluorocarbon liquid and its safe removal with a small gauge cannula have been presented in the report. This case was complicated by development of an epiretinal membrane, though visual acuity was preserved. PMID- 29118510 TI - Foveal neovascularization in a patient with Type 2 diabetes mellitus. AB - Retinal neovascularization in Diabetes mellitus (DM) is commonly seen at the optic disc and mid-periphery. It is rare at the fovea as the fovea is an avascular zone and there are very few case reports of foveal neovascularization in Type 1 DM. We report a case of unilateral foveal neovascularization in Type 2 DM. PMID- 29118511 TI - Pigmented ciliary body medulloepithelioma in a newborn infant. AB - Ciliary body medulloepithelioma is a nonpigmented tumor which presents during the first decade of life. It is rarely seen in newborn infants. We report a pigmented medulloepithelioma in a newborn infant, which showed a rapid growth. Ciliary body medulloepithelioma should be considered in the differential diagnosis in a newborn infant presenting with leukocoria. PMID- 29118512 TI - Multiple white dots on posterior capsule. AB - A 38 years old female patient presented with unilateral cataract without known predisposing factors. During cataract extraction, the surgeon noticed multiple white dots scattered over inner surface of the posterior capsule. These dots were of uniform size and shape. They were distributed uniformly and involved all the areas of the posterior capsule and extended up to equator. The surgeon decided to implant IOL and tackle the opacities in a later setup. In spite of the extensive opacities, the patient's Uncorrected Corrected Visual Acuity (UCVA) at six weeks was 6/9, Best Corrected Visual Acuity(BCVA) was 6/6 and near vision with correction was N6. The other eye was normal. This case is reported for the peculiar appearance and distribution of the capsular opacities and good visual outcome in spite of this. PMID- 29118513 TI - The shining eye. PMID- 29118514 TI - Progressive visual loss with systemic symptoms in an adult. PMID- 29118515 TI - Two brothers with reduced vision. PMID- 29118516 TI - Retrobulbar alcohol injection for phantom eye pain syndrome in bilateral eviscerated orbit. PMID- 29118517 TI - Dissecting Cellulitis of the Scalp Early Diagnosed by Color Doppler Ultrasound. AB - Dissecting cellulitis of the scalp (DC) is a chronic inflammatory condition of the scalp that ultimately leads to scarring alopecia. A healthy 19-year-old male presented with a solitary, soft, alopecic nodule that had appeared 1 year before. A color Doppler ultrasound examination showed a hypodermal anechoic fluid collection in the left parietotemporal region of the scalp, connected to the base of widened hair follicles, and presented inner echoes suggestive of debris, as well as several fragments of hair tracts. A diagnosis of DC was made and an epidermal or trichilemmal cyst was ruled out. This case shows the importance of color Doppler ultrasound for supporting the diagnosis at an early stage or with an unusual presentation of DC. PMID- 29118518 TI - Insignificant Correlation between Thyroid Hormone and Antithyroid Peroxidase Antibodies in Alopecia Areata Patients in Northern Rajasthan. AB - Background: Alopecia areata (AA) is a common, recurrent form of nonscarring alopecia which often presents as circumscribed patches of spontaneous hair loss. The global prevalence of this disease varies from 0.1% to 0.2% in general population and 7-30 cases per 1000 dermatological patients. The etiology of AA still remains uncertain; however, genetic or environmental factor and autoimmunity are claimed responsible for it. Various autoimmune diseases, such as Hashimoto's thyroiditis, diabetes mellitus, vitiligo, and lupus erythematosus, have been reported in association with AA. Aim: The index study was aimed at estimation of serum T3, T4, thyroid-stimulating hormone, and antithyroid peroxidase (TPO) antibodies. Material and Methods: Similar age/sex-matched AA patients and controls (110 in each group). Enhanced chemiluminescence immunoassay for thyroid profile and anti-TPO antibody level estimation in veinous blood sample. Observations: The mean/standard deviation (SD) of T3 was 3.30 +/- 0.84 pg/ml in AA while 3.27 +/- 0.67 pg/ml in controls (P = 0.302). Serum mean/SD of T4 level was1.23 +/- 0.76 ng/dl in AA patients while 1.17 +/- 0.34 ng/dl in controls (P = 0.522). The mean/SD of anti-TPO levels in AA patients was 21.52 +/- 35.09 while 56.43 +/- 140.72 in controls (P = 0.136). Limitation: The limitation of this study was moderate number of AA patients and different genotype of study population. Conclusion: Occurrence of thyroid dysfunction and evidence of anti TPO antibodies in AA is rare event in this study population. PMID- 29118519 TI - Detection of Tumor Necrosis Factor-alpha in Nonlesional Tissues of Alopecia Areata Patients: A Prove for a Systemic Disease. AB - Introduction: The pathogenesis of alopecia areata (AA) remains incompletely understood. Different cytokines may play a role in AA. Tumor necrosis factor alpha (TNF-alpha) has been shown to be inhibitory to hair follicle growth in in vitro studies suggesting that it may play an important role in AA. This study was conducted to assess the presence of TNF-alpha in lesional and nonlesional skin of AA, to review its possible role in AA, and to show whether AA is a systemic or localized disease by comparing the level of TNF-alpha between lesional and nonlesional skin biopsies of the patients. Materials and Methods: Thirty patients with AA and thirty age- and sex-matched healthy controls were included in the study. A 4 mm punch skin biopsy was taken from lesional and nonlesional skin of every patient, as well as from the normal skin of each individual in the control group for immunohistochemical analysis of TNF-alpha. Results: The level of TNF alpha in lesional skin biopsies was significantly higher than in nonlesional skin biopsies of patients as well as controls' biopsies. Furthermore, TNF-alpha level in nonlesional biopsies of patients was significantly higher than the level in controls' biopsies. Conclusions: We concluded that skin of AA has a high level of TNF-alpha (a normal inhibitor of hair follicle growth in vitro). This high level may point to the important role of TNF-alpha in AA. Further studies should be conducted to detect the level of TNF-alpha in long-standing AA and the more severe cases of AA. PMID- 29118520 TI - Utilization of Mental Health Resources and Complementary and Alternative Therapies for Alopecia Areata: A U.S. Survey. AB - Background: The efficacy of traditional medical treatments for alopecia areata (AA) is limited, leading some to pursue alternative treatments. The utilization and nature of these treatments are unclear. Objective: To assess the extent to which patients with AA pursue alternative treatments and to characterize these treatments. Methods: A 13-item electronic survey was E-mailed by the National Alopecia Areata Foundation (NAAF) to their patient database and shared on the NAAF social media to individuals with AA. Results: Of 1083 respondents, 78.1% of patients were very or somewhat unsatisfied, compared to 7.7% who were very or somewhat satisfied with the current medical treatments for AA. Approximately a third of patients pursued therapy-related mental health services (31.2%) and attended support groups (29.0%). Patients were more likely to pursue a mental health-related therapy if they had long-standing alopecia, or if they were young, female, or white. Limitations: This was a convenience sample of patients recruited online and via the NAAF AA registry. Conclusion: Many patients with AA are dissatisfied with current treatments and are seeking mental health treatment for AA. While the efficacy of alternative therapies is unknown, further research is needed to determine their role in the treatment of AA. PMID- 29118521 TI - A Proposal of an Effective Platelet-rich Plasma Protocol for the Treatment of Androgenetic Alopecia. AB - Background: Platelet-rich plasma (PRP) has emerged as a promising treatment for androgenetic alopecia (AGA). In spite of the several studies previously reported, to date, a standardized protocol for PRP preparation and application, as well as a standard method for evaluating results has not been established. Aims: The aim of this study is to propose a standardized method for preparation and application of PRP for male AGA (MAGA) and female AGA (FAGA) and assess its safety and efficacy as a co-adjuvant therapy. Materials and Methods: Seventy-eight patients, 19 men and 59 women with AGA Grades II-IV in Ebling's scale, currently on treatment with topical minoxidil and/or oral finasteride for more than a year without improvement, were included in this study. PRP was prepared using a single spin method, and injected in affected areas for 3 monthly sessions, followed by 3 bimonthly sessions. A decrease of at least one grade in Ebling's scale was considered a successful result. Results: After the 6 degrees session, 71.4% of MAGA and 73.4% of FAGA patients reached a successful outcome while 21.4% and 16.3%, respectively, remained without changes. Only 7.1% of MAGA and 10.2% of FAGA presented worsening of their condition. Conclusions: PRP together with a periodical application protocol can be considered effective as a coadjuvant therapy in patients who no longer respond to pharmacological treatments. Ebling's scale was a practical and reliable parameter to allow a better evaluation in both MAGA and FAGA. PMID- 29118522 TI - Association of Leukotrichia in Vitiligo and Asp148Glu Polymorphism of Apurinic/Apyrimidinic Endonuclease 1. AB - Background: Oxidative stress and increased DNA damage have been implicated in the etiopathogenesis of vitiligo. Oxidative DNA damage is mainly repaired by the base excision repair (BER) pathway. Aim: We sought to determine whether polymorphisms in DNA repair genes may have a role in the pathogenesis of vitiligo. Materials and Methods: We conducted a study including 100 patients with vitiligo and age- and sex-matched 193 control subjects to examine the role of single-nucleotide polymorphisms of BER genes, human 8-oxoG DNA N-glycosylase 1 (codon 326), apurinic/apyrimidinic endonuclease 1 (APE1) (codon 148), and X-ray repair cross complementing group 1 (codon 399) as risk factors for vitiligo. These polymorphisms were determined by quantitative real-time polymerase chain reaction and melting curve analysis. Results: No significant association was observed between the variant alleles of studied genes and vitiligo. Conclusion: However, we showed that the presence of APE1 148Glu variant allele is associated with leukotrichia. This preliminary study suggests that APE1 (codon 148) polymorphism may play a role in vitiligo pathogenesis. PMID- 29118523 TI - Three Cases of Hair Loss Analyzed by the Point of View of the Analytical Psychology. AB - Psychotrichology is the science, which covers the psychosomatics applied to hair problems, i.e., body-psyche phenomena involving scalp and hair disorders. The approaches involving psychotricology are varied and may include psychiatric,[1] psychoanalytical,[23] and those involving knowledge related to analytical psychology.[4] An analysis from the analytical psychology point of view, a theory developed by the physician Carl Gustav Jung, favors a symbolic view to the disease, providing it attributions and meanings that go beyond those related to physical body signs and symptoms only. This paper aims to describe and analyze, under the analytical psychology view, three cases the psychic and clinical demonstrations of which relate to symbolic and historic aspects concerning life of patients as possibilities of cause and maintenance of hair problems. The first of them is related to an 8-year-old girl who witnessed a scene of physical aggression by her father against her mother and developed a case of total alopecia. The second case is related to a 43-year-old woman who developed self inflicted scalp dermatitis due to severe anxiety; and at last, the case of a telogen effluvium in a 23-year-old woman who developed hyperprolactinemia after the death of her mother, having to substitute her in the care about her husband and brothers. Looking at the clinical history and symbolic matters of scalp and hair diseases enabled, in the aforementioned cases, a better understanding of patients' psychoemotional disorders that may be related to the beginning and maintenance of clinical cases presented by them. PMID- 29118524 TI - Collision Tumor between Trichofolliculoma and Melanocytic Nevus. AB - Trichofolliculoma (TF) is a hamartomatous hair follicle-related tumor, clinically described as a dome-shaped papule with a central pore crossed by one or more silky white hairs. Histologically, it described as a cystic cavity containing keratinous debris, hair shaft fragments, and numerous hair follicles arising from its linings. Collision or compound tumors are a coexistence of two or more identifiable tumors in the same lesion. We present a case of a 47-year-old man with a lesion on his left cheek clinically characterized as a TF. However, the histopathological study reveals a collision tumor involving a TF and a melanocytic nevus. Collision tumors involving melanocytic nevi and hair follicle related tumors have been previously reported, such as desmoplastic trichoepithelioma, epidermoid cyst, folliculosebaceous cystic hamartoma, and trichoadenoma. PMID- 29118525 TI - Cytodiagnosis of Eccrine Porocarcinoma of the Scalp. AB - Eccrine porocarcinoma is a rare, malignant adnexal tumor of the duct of eccrine sweat gland. Cytology of eccrine porocarcinoma has been described in very few previous literature. Here, we present a case of fine needle aspiration cytology (FNAC) of eccrine porocarcinoma of the scalp, which is subsequently confirmed by histology. Accurate diagnosis of eccrine porocarcinoma by FNAC is very difficult, but determining the malignant nature of the lesion is crucial for curative surgery. FNAC can be a convenient, safe, and effective approach to solve difficult diagnostic dilemma. PMID- 29118526 TI - Panfolliculoma: A Clinical Case Report. AB - Panfolliculoma is a benign neoplasm of follicular differentiation, and its morphological characteristics are similar to those of trichoblastoma, but it shows greater follicular differentiation. A 55-year-old female patient, visited for a dermatological consultation, presented comedo-like lesions on the eyelids, which were accompanied by moderate pruritus that spread gradually. On examination, the patient had localized dermatosis on the face, which symmetrically affected both upper eyelids and to a lesser extent the lower eyelids. The lesions consisted of papulonodular neoformations, comedones, and redundant skin, and a biopsy was performed. The histopathological report mainly described the presence of atrophic epidermis and dermis that was occupied entirely by a neoplasm of epithelial strain, comprising cystic structures that were surrounded by infundibular epithelium of an internal radicular sheath. Panfolliculoma is a rare benign neoplasm of follicular differentiation, and its morphological characteristics are similar to those of trichoblastoma, the pathologist must perform the clinicopathological correlation to establish the correct diagnosis. PMID- 29118527 TI - Unusual Pattern of Whitening of Eyebrows Following Sunitinib Therapy: A Case Report with Brief Review of Literature. AB - Sunitinib is a vascular endothelial growth factor receptor inhibitor which has shown high activity in metastatic renal cell carcinoma (mRCC) patients and is now widely used for the same. It is generally well tolerated, but sometimes, it exhibits a distinct pattern of novel side effects that require monitoring and management. Important known side effect of sunitinib includes fatigue, diarrhea, anorexia, skin toxicity, and hypertension which need special mention. Considering its effectiveness in first-line setting in mRCC and paucity of other good options, utmost efforts are made to continue it with identification of side effects which may require only slight dose modification or no dose alteration. We report here a 38-year-old male who was diagnosed as a case of mRCC and started on sunitinib at the diagnosis and developed whitish discoloration of eyebrows and body hairs after 3 months of starting sunitinib. In view of good overall response to treatment and no other significant toxicity, sunitinib was continued with good tolerability. PMID- 29118528 TI - Adult testicular cancer: Two decades of Saudi national data. AB - There is a paucity of data regarding testicular cancer among Saudis as well as the nonexistent of published national data. Furthermore, a substantial increase of the incidence of testicular cancer among Saudis was lately noted. The aim of the study is to determine the trends and patterns of testicular cancer among adult Saudis using national data over a period of 20 years. The national database of the Saudi Cancer Registry (SCR) on testicular cancer over the last two decades was studied including epidemiological and histological patterns. The 1004 cases of testicular cancer among adult Saudis reported by the SCR will be the subject of this study. From 1994 to 2013, 1004 cases of testicular cancer among adult Saudis were reported to the SCR, with a steadily significant increase in incidence rate reaching an annual rate of 94 cases in 2013. Age of the patients ranged 15-93 years with a mean of 34.5 years. The most affected age group was 20 34 years, where 51% of all testicular cancer accumulated. Around 85% of testicular cancer is germ cell tumors, while paratesticular and gonadal stromal tumors represent 15%. Of all testicular cancer, seminomas were seen in 40.7%, nonseminomas in 44.6%. Notably, 70.4% of the cases in the first decade were seminomas, while in the second decade 65.9% of the cases were nonseminomas. The subtypes of the nonseminomas were a mixed tumor in 51.6%, embryonal carcinoma in 19.9%, yolk sac tumor in 12.3%, germinomas in 6.7%, teratomas in 6%, and choriocarcinomas in 3.6%. Lymphomas (34.7%) and rhabdomyosarcomas (23.6%) are on the top of the paratesticular tumor group. The Surveillance Epidemiology and End Results summary stage of seminomas was localized in 61.6%, regional in 19.8%, and distant in 12.6%, while of nonseminomas was 48%, 15.5%, and 28.5%, respectively. Localized and distant status of seminomas improved over the studied period by 12% and 4% respectively, while this trend was not seen in nonseminomas. The incidence rate is on rising with doubling observed during the last decade. The most affected age group was 20-34 years. Noteworthy was the dominance of the seminomas in the first decade and of the nonseminomas in the second decade. Paratesticular tumors rate is high, third of which were lymphomas. Compared to data from Western countries, notably, there is a high rate of yolk sac tumors and germinomas and a low incidence of choriocarcinomas and embryonal carcinomas. In general, late presentation of all testicular cancer was noted, although a modest stage improvement over the studied period was observed in seminomas, not in nonseminomas. PMID- 29118529 TI - Pediatric testicular cancer: Two decades of Saudi national data. AB - Pediatric testicular cancer is exceedingly rare. There are no data available touching Saudi children. The aim of the study is to determine the trends and patterns of testicular cancer among Saudi children over a period of 20 years. The national database of the Saudi Cancer Registry (SCR) on pediatric testicular cancer over the last two decades was examined including epidemiological and histological patterns. From 1994 to 2013, 82 cases of testicular cancer among Saudi children aged 1-14 years were accumulated at the SCR. The annual percentage change rate was 3.3%. Of all cases, 62% appeared within the first 2 years of life. Seminomas were seen in 39%, nonseminomas in 40.3%, and paratesticular tumors in 20.7%. No gonadal stromal tumors observed. About 91% of the seminomas accrued in the first decade (1994-2003), while all nonseminomas fell in the last decade (2004-2013). The most common subtypes of the nonseminomas were yolk sac tumors and mixed tumors. More than 80% of the paratesticular tumors were rhabdomyosarcomas and lymphomas. The SEER summary stage of seminomas was localized in 56%, regional in 22%, and distant in 16%, while of nonseminomas was 56%, 16%, and 28%, respectively, and no stage improvement over the studied period was noted. No temporal trend in incidence rate was observed. The most affected age group was the first 2 years of life. Noteworthy was the high incidence of seminoma and the low rate of teratomas and stromal tumors, when compared to Western data. Notable was the dominance of the seminomas in the first decade and of the nonseminomas in the second decade. At the time of diagnosis, nonseminomas were more advanced than seminomas. No stage improvement noted over the studied period. PMID- 29118530 TI - Prognostic impact of Bacillus Calmette-Guerin interruption at the time of induction and consolidation. AB - Context: Intravesical Bacillus Calmette-Guerin (BCG) is a cause of bladder and systemic toxicity that is difficult to prevent and is responsible for treatment drop out in bladder cancer patients. More recently, BCG shortage has become the main cause of incomplete treatment. Aims: The aim of this study was to examine the impact on long-term prognosis of bladder cancer patients following discontinuation of BCG instillations. Settings and Design: In this retrospective study, data were examined from 333 consecutive nonmuscle invasive bladder cancer patients treated from 2005 to 2015 by transurethral resection (TUR) and had undergone adjuvant BCG therapy after TUR. Subjects and Methods: Rate of complete cure, the reason for the interruption, toxicity, and the associations between discontinuance of BCG therapy, tumor characteristics, association with carcinoma in situ and tumor recurrence or progression were analyzed. Statistical Analysis Used: Recurrence and progression-free survival rate curves were estimated using the Kaplan-Meier method and were compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Differences among groups were considered as statistically significant when P < 0.05. Results: Overall, 303 patients were eligible for analysis. Median follow up was 36 (confidence interval: 7-120) months. A total of 55 (18.1%) had <6 installations (Group I); 87 (28.7%) completed induction and 1-year maintenance (Group III); and 161 (53.1%) completed the induction course, but not the 1-year maintenance (Group II). Grade III-IV toxicity rates were significantly higher in Group I than Group II and III. Interruption for BCG shortage was the main cause of interrupting BCG in Group II. Multivariate analysis showed that discontinuation of BCG induction therapy was an independent predictor for tumor recurrence (P < 0.001) and 1-year BCG maintenance therapy for tumor progression (P = 0.005). Conclusions: Discontinuation of BCG therapy has a significantly deleterious effect on tumor recurrence and progression rates. Although BCG toxicity is a major cause of drop out, BCG shortage became a major cause of discontinuation. All effort must be done today to restore normal production of BCG worldwide. PMID- 29118531 TI - Preliminary report on the effect of urethral diverticulum magnetic resonance imaging configuration on the incidence of new onset urodynamic stress urinary incontinence following excision. AB - Context: Excision of urethral diverticulum in females has been reported to be associated with new onset urodynamic stress urinary incontinence (USUI) in up to 49%. Aims: We have assessed the incidence of new onset USUI in all patients having urethral diverticulum excision with Martius fat pad interposition under the care of a single surgeon between May 1, 2007, and December 1, 2011. The incidence of new onset USUI has been correlated with the preoperative magnetic resonance imaging (MRI) appearance of the urethral diverticulum. Patients and Methods: All 33 patients (mean age 42) having urethral diverticulum with Martius fat pad interposition had prospective data tabulated on demographics, preoperative MRI appearance, and pre- and post-operative videocystometrogram. Statistical Analysis Used: Statistical analysis was performed by Chi-squared and Fisher's exact. Results: Of the 33 patients, 10 (30%) had preoperative USUI and have been excluded from this study. Other preoperative urodynamic findings included idiopathic detrusor overactivity in ten (30%) and bladder outflow obstruction in five (16%). Two (10%) of the patients had a simple diverticulum, 16 (73%) had a horseshoe diverticulum, and 5 (17%) had a circumferential diverticulum. The rate of new onset USUI was 0% for simple, 6% for saddle, and 20% for circumferential. Conclusions: New onset USUI occurs in 9% of patients having excision of urethral diverticulum with Martius fat pad interposition. The incidence appears to increase with increasing complexity of urethral diverticulum on preoperative MRI - rising from 0% following simple urethral diverticulum excision to 20% following circumferential diverticulum excision. PMID- 29118532 TI - Transperitoneal laparoscopic repair of retrocaval ureter: Our experience and review of literature. AB - Context and Aim: Retrocaval ureter (RCU), also known as circumcaval ureter, occurs due to anomalous development of inferior vena cava (IVC) and not ureter. The surgical approach for this entity has shifted from open to laparoscopic and robotic surgery. This is a relatively new line of management with very few case reports. Herein, we describe the etiopathology, our experience with six cases of transperitoneal laparoscopic repair of RCU operated at tertiary care center in India and have reviewed different management options. Methods: From 2013 to 2016, we operated total six cases of transperitoneal laparoscopic repair of RCU. All were male patients with average age of 29.6 years (14-50). Pain was their only complaint with normal renal function and no complications. After diagnosis with CT Urography, they underwent radionuclide scan and were operated on. Postoperative follow-up was done with ultrasonography every 3 months and repeat radionuclide scan at 6 months. The maximum follow-up was for 2.5 years. Results: All cases were completed laparoscopically. Average operating time was 163.2 min. Blood loss varied from 50 to 100 cc. Ureteroureterostomy was done in all patients. None developed urinary leak or recurrent obstruction postoperatively. Maximum time for the requirement of external drainage was for 4 days (2-4 days). Average postoperative time for hospitalization was 3.8 days. Follow-up ultrasound and renal scan showed unobstructed drainage. Conclusions: Transperitoneal or retroperitoneal approach can be considered equivalent as parameters like operative time, results are comparable for these two modalities. We preferred transperitoneal approach as it provides good working space for intracorporeal suturing. PMID- 29118533 TI - Pathological nature of renal tumors - does size matter? AB - Introduction: We examined the relationship between the size and nature of renal masses in term of malignant potential, histological grading, pathological staging and presence of necrosis and sarcomatoid changes. Materials and Methods: Retrospectively, we reviewed 323 consecutive nephrectomies between 2000 and 2010. Final pathology was correlated with tumour size. The renal tumours were stratified into three groups according to the largest diameter, defined as 4 cm or smaller, greater than 4 cm to 7 cm, and greater than 7 cm. We recorded the proportion of benign tumours, tumour grade and stage, presence of necrosis and sarcomatoid change. Results: Small renal masses <=4 cm (SRMs) were more likely to be localised to the kidney (90%) and of lower histological grade (75%). The proportion of benign tumours in SRMs (15%) was higher than other two groups with the majority of benign tumours being oncocytomas. There was a statistically significant trend with greater necrosis and sarcomatoid change for the large size group. Conclusions: SRMs are likely to be low grade and organ confined with little or no adverse pathological features. There is increased likelihood of benignity in SRTs with the majority of benign tumours being oncocytomas. PMID- 29118535 TI - Rapid versus gradual bladder decompression in acute urinary retention. AB - Objective: To demonstrate a benefit in diminished adverse events such as hypotension and hematuria with gradual drainage of the bladder when compared to rapid decompression in patients with acute urinary retention (AUR) due to benign prostatic hyperplasia in a case-control study. Methods: Sixty-two patients matched our selection criteria presenting with AUR. They were divided into two groups - the first was managed by rapid drainage of the bladder, the second was managed by gradual drainage through a urethral catheter (The first 100 mL immediately evacuated, then the rest evacuated gradually over 2 h). Results: The mean age was 64.4 and 63.2 years in the first and second group, respectively. Diagnosed cause was benign hyperplasia of the prostate. Hematuria occurred in two patients in the first group and none in the second group. The two cases of hematuria were mild and treated conservatively. After the relief of the obstruction, the mean blood pressure was noticed to decrease by 15 mmHg and 10 mmHg in the first and second group, respectively, however, no one developed significant hypotension. Pain relief was achieved after complete drainage in the first group and after the evacuation of 100 mL in the second group. Conclusions: We conclude that there is no significant difference between rapid and gradual decompression of the bladder in patients with AUR. Hematuria and hypotension may occur after rapid decompression of the obstructed urinary bladder, but these complications are rarely clinically significant. PMID- 29118534 TI - Pure retroperitoneoscopic donor nephrectomy in duplication of inferior vena cava: A series of four cases. AB - Aim: Complex vascular anatomy poses a major challenge to the donor surgeon. Here, we have described the technical nuances in retroperitoneoscopic living donor nephrectomy for the left kidney in the situations of a rare vascular anomaly of duplication of inferior vena. Materials and Methods: Between September 2005 and June 2016, 1460 retroperitoneoscopic living donor nephrectomy were carried out in single surgical unit of our institution. Out of these four donors were found to have duplication of inferior vena cava (IVC). We retrospectively analyzed the prospectively collected data of these donors and studied the operative details for managing the duplicated limb of the IVC. Results: The mean age of the donors was 42.5 (range 30-54) years. Mean body mass index was 26.9 (range 25.2-28.6) kg/m2. Mean operative time (defined as between giving skin incision to the skin closure [O. T]), was 230 (range 185-310 min). Mean Warm ischemia time (defined from clamping of the renal artery to the starting of the cold HTK perfusion, [WIT]) was 136 s (range 105-178 s). In two cases, the renal vein could be controlled distal to the duplicated limb. In one case, the duplicated limb was clipped while in another a stapler was used to take a cuff of IVC. Conclusion: Retroperitoneoscopic donor nephrectomy can be performed safely in cases of duplication of IVC. Preoperative computerized tomography angiography with vascular reconstruction and surgical expertise is desirable in carrying out the procedure. PMID- 29118536 TI - Characteristics of bladder neoplasms in the young population of Saudi Arabia. AB - Context: Bladder neoplasms are a well-studied subject in medicine. However, the evidence of bladder neoplasms in children and the young adult population (<=40 years), particularly in Saudi Arabia, is lacking. Aims: The aims of this study were to identify histopathological characteristics as well as clinical features, prognosis, and treatment of bladder neoplasms in this age group in a single tertiary referral center, Riyadh, Saudi Arabia. Settings and Design: A retrospective cohort study. Materials and Methods: Children and young adults (<=40 years) diagnosed with epithelial and mesenchymal bladder neoplasms from 1994 to 2017. Statistical Analysis Used: Descriptive data are presented as mean (standard deviation) or median (interquartile range) for continuous variables and n (%) for categorical variables. Statistical Package for Social Sciences version 23 was used. Results: Thirty-eight cases were identified. The majority, 71.1% (n = 27) were male. The median age of diagnosis was 33 years ranging from 1 to 40 years. Nearly 45% (n = 17) were smokers. Macroscopic hematuria was present in 57.8% (n = 22). The most common histopathology was papillary urothelial carcinoma (n = 18, 58%). All mesenchymal neoplasms accounted for 18.4% (n = 7). Of all malignancies, 63.2% (n = 24) and 44.7% (n = 17) were low stage and low grade, respectively. Transurethral resection of bladder tumor (TURBT) was conducted for 81.6% (n = 31). The mean length of follow-up was 36.05 months (+/-39.4 months). Recurrence occurred in 15.8% (n = 6) and 7.9% (n = 3) had progression. Distant metastasis was reported in 5.3% (n = 2). Nearly 8% (n = 3) died during their follow-up. Conclusions: Bladder malignancies at the early fourth decade of life tend to be a low stage and low grade. The most common histopathology was papillary urothelial carcinoma. Management should be based on the clinical and histopathological features. However, most of the patient underwent TURBT. PMID- 29118537 TI - Choosing an ideal vascular cover for Snodgrass repair. AB - Aim: The aim of this study is to compare tunica vaginalis (TV), dorsal dartos, and ventral dartos flap as a second layer vascular cover during Snodgrass repair. Materials and Methods: Data of 83 patients who underwent primary hypospadias repair with Snodgrass technique (age range: 1.6-12 years) were retrospectively collected and compared. They were divided into three groups. Group A (26 patients) included cases using TV flap, Group B (36 patients) included those where dorsal dartos from prepuce was used as second cover, and Group C (21 patients) included those with ventral dartos as cover. Results: In Group A, no complications recorded. Mild scrotal edema was present in 5 patients which was conservatively managed. In Group B, there were 8 fistulas, 2 glans breakdown, and 1 meatal stenosis. In Group C, there were 3 fistulas and 1 glans breakdown. Conclusion: TV flap is better than dorsal dartos and ventral dartos as vascular cover for primary hypospadias repair with Snodgrass technique. PMID- 29118538 TI - Utilization of penile prosthesis and male incontinence prosthetics in Saudi Arabia. AB - Background: Erectile dysfunction is a prevalent disease affecting over 50% of men between the ages of 40 and 70 years. Penile prosthesis represents the end of the line treatment when other less invasive therapies fail or are contraindicated. Male stress urinary incontinence can significantly diminish quality of life and lead to embarrassment and social withdrawal. Surgical therapies, such as male urethral slings and artificial urinary sphincters (AUS), are considered effective and safe treatments for male stress incontinence. No data exist on the utilization of penile prosthesis or male incontinence surgical treatment in Saudi Arabia. Generally, urological prosthetic surgery is performed either in private hospitals or in government hospitals. Our aim was to assess the trend of penile prosthesis and male incontinence device utilization in Saudi Arabia. Materials and Methods: We utilized sales' data of penile prosthetics, male slings, and AUS from the only two companies selling these devices in Saudi Arabia (AMS(r) and Coloplast(r)), from January 2013 to December 2016. Results: There were 2599 penile prosthesis implantation procedures done in the study period, with 67% of them performed in private institutions. There was a progressively increased use of penile prosthetics which nearly doubled from 2013 to 2016. The main type of prosthesis utilized was the semirigid type 70% versus 11% of the 2-piece inflatable and 17% of the 3-piece inflatable device. Only 10 slings and 31 AUS were inserted during the same study period. Conclusions: There is an increased utilization of penile prosthetics in Saudi Arabia. The private sector performs the majority of penile prosthesis procedures, and most of them are of the semirigid type. The governmental sector is more likely to perform inflatable penile prosthesis and male incontinence device procedures. Male incontinence prosthetics' use is very limited in Saudi Arabia. PMID- 29118539 TI - Laparoscopic heminephrectomy in horseshoe kidneys: A single center experience. AB - Introduction: Laparoscopic approach in horseshoe kidney (HSK) is a challenge because of the aberrant vessels, the renal isthmus and the renal ectopia are all unique features of this anomaly encountered during the surgery. We report our single center experience with this technique in managing three patients with HSK. Methods: A total of 15 cases (9 males and 6 females) were operated between June 2011 and December 2016 for various indications. Of these four patients were managed laparoscopically, two patients with HSK had non-functioning renal moiety underwent transperitoneal heminephrectomy. The third patient with a mass in right moiety with thin fibrous isthmus was successfully managed with laparoscopic heminephrectomy. Fourth patient with pelvi-ureteric junction obstruction with multiple renal calculi was managed with pyeloplasty and complete clearance of all calyceal the stones. Result: Mean operating time was 140 +/- 1.8 (100-180) min, and estimated blood loss was 131 +/- 12.6 (30-320) ml. The mean hospital stay was 2.3 +/- 1.4 (1-5) days. There were no major intra- and post-operative complications except minimal postoperative discomfort. Conclusion: Laparoscopic nephrectomy is technically feasible, safe, and reliable for benign and malignant diseases in a HK with mainly three factors posing challenges during the surgery are the abnormal vasculature, division of the isthmus, and lower location of the kidney. PMID- 29118540 TI - Total endoscopic and anal irrigation management approach to noncompliant neuropathic bladder and bowel in children: A long-term follow-up. AB - Purpose: To evaluate the long-term efficacy and durability of combined intradetrusor botulinum-A toxin (BTX-A), endoscopic treatment of vesicouerteral reflux and anal irrigation for stool incontinence (SI) via a total endoscopic and anal irrigation management (TEAM(r)) approach in patients with myelomeningocele and neuropathic bladder and bowel who did not respond to conservative measures. Materials and Methods: Fourteen myelomeningocele patients with at least 3 years follow-up were included in the study. All patients have urinary and SI not responded to conservative management. All patients received a cystoscopic intradetrusor injection of 12 U/kg (maximum 300 U) BTX-A. There was vesicoureteral reflux in 22 ureters, and a Deflux(r) injection was completed during the same procedure. SI was managed using trans-anal irrigation, either with a fleet enema or Peristeen(r) system regularly. Results: After at least 3 years of follow-up, mean maximum bladder capacity increased significantly from 78 +/- 36 ml to 200 +/- 76 ml (P < 0.0001) and the maximum detrusor pressure decreased from 56 +/- 12 cm H2O to 29 +/- 7 cm H2O (P < 0.001). Twenty-one refluxing ureters (95%) showed complete resolution and one persisted. Ten patients (72%) achieved complete dryness between catheterizations. Four patients (28%) went for augmentation cystoplasty, due to progressive hydronephrosis and/or persistent urinary incontinence. Thirteen patients achieved complete stool continence. Conclusions: Over long-term follow-up, major reconstruction surgery can be avoidable or delayable; the TEAM(r) approach is a minimally invasive, safe, simple, and effective way to achieve upper urinary tract protection and provide urinary and stool continence. PMID- 29118541 TI - Hypospadias repair during adulthood: Case series. AB - Purpose: We report our complications and success rate in adult hypospadias repair. Patients and Methods: This was a retrospective study of patients aged >=17 years who underwent hypospadias repair during 2006-2014. We analyzed two groups, one with primary repair and the other that had secondary repair after failed childhood hypospadias surgery. Outcome was compared between the two groups and among different surgical procedures. Descriptive statistics and Fisher's exact test were used and significance level was set at P < 0.05. Results: Forty patients were included, of which 26 presented for a secondary repair and 14 for primary repair. The meatus was distal in 15 patients, mid-penile in 16, and penoscrotal in 9. The median age of patients at the time of surgery was 21 years (standard deviation [SD] =4, range 17-30). The median follow-up period was 37 months (SD = 8, range 5-75). In the primary repair group, the success rate was 71% (10/14), whereas in the secondary repair group, the success rate was 55% (14/26). The overall complication rate was 60%. Following a subsequent repair, the overall success rate reached 95% (38/40). There was no significant difference in success or complications between patients who presented with primary or secondary hypospadias or between methods of repair. Conclusion: Delayed hypospadias repair in adults is associated with a high success rate of 95% with no difference between primary and secondary repair. Secondary repair however may require more than one procedure most of the time. PMID- 29118542 TI - The role of the endothelin axis in promoting epithelial to mesenchymal transition and lymph node metastasis in prostate adenocarcinoma. AB - Introduction: Aberrant activation of endothelin (ET) axis has been identified as a key player in tumor growth and metastasis in several tumor types. However, little is known about the possible interaction of the ET with epithelial to mesenchymal transition (EMT), a process that transforms tumor cells in a motile, resistant to apoptosis phenotype prone to invasion and metastasis. The aim of this study was to investigate the activation of the ET axis in prostate adenocarcinoma and examine possible associations with EMT markers, lymph node (LN) metastasis, and other clinicopathological parameters. Materials and Methods: We immunohistochemically evaluated the expression of ET-1 and its receptors A and B (ET-A, ET-B) in 64 N0 and 23 N1 prostate adenocarcinoma cases. EMT markers E cadherin, N-cadherin, and beta-catenin and the transcriptional factor SNAIL were evaluated. We examined possible correlations of ET pathway members with EMT markers, LN status, Gleason grade, and T stage. Results: Our results revealed increased expression of ET-1 and ET-A (but not ET-B) in prostate carcinoma; both ET-1 and ET-A were associated with lymph metastasis and T stage but not with Gleason grade. We observed E-cadherin and beta-catenin decrease/relocalization and increased N-cadherin expression. SNAIL also showed increased expression in tumor tissue and was associated with LN metastasis (Mann-Whitney test, P = 0.0032). Expression of ET-1 and ET-A correlated well with SNAIL expression (Spearman r, P = 0.0002 and P = 0.0176, respectively). Conclusions: These findings indicate that activation of the ET pathway may induce EMT through SNAIL activation and correlates with increased metastatic potential. PMID- 29118543 TI - Laser-induced synlabia, cryptomenorrhea, and urine retention: A case report and literature review. AB - Cosmetic laser use has many pros and cons. The worldwide use of laser for body hair removal has led to many medical complications. Unsupervised use of the laser for hair removal in vulva may result in many problems and can merely damage the vulva, although rarely, affecting the body image. This rare and novel case report is a 21 year old virgin who presented with acute urinary retention and cryptomenorrhea due to complete synlabia secondary to unsupervised vulval laser hair removal. The urinary retention was relieved by suprapubic catheterization initially. During examination under anesthesia, the fused labia were separated by a surgical incision with drainage of hematocolpos and then, a Foley's urethral catheter was inserted. She had an uneventful recovery. We report this case to emphasize on the supervised use of laser by trained and qualified personnel for hair removal in vulva to minimize its complications. PMID- 29118544 TI - The rarest phenomenon of flexible ureterolithotripsy: Kidney stone in supernumerary type combination with a horseshoe kidney. AB - The horseshoe kidney (HSK) is common and supernumerary kidney is the rarest developmental anomaly of the urogenital system. The supernumerary kidney in a HSK conjunction is extremely rare, and prevalence of it is unknown. A review of literature, there have been a few case reports about the supernumerary and HSK combination, however, none of which also had a concomitant kidney stone and obstructive pathology. Our case indicated that patient referred to flank pain and visible hematuria to our clinic, and further investigations demonstrate supernumerary kidney in a horseshoe configuration and kidney stone. Kidney stone could not be found at the first attempt because of the anatomical malformation. Retrograde pyelography showed ureteral branching and helps to define the placement of stone. This stone was fragmented with flexible ureteroscopy in the lower pole of the middle kidney in the second session. There was no stone fragments absence at the 1st-month control. This exceedingly rare type case should be evaluated meticulously on preoperative duration otherwise can be a challenge for surgeons. Visualize pelvicalyceal system under the fluoroscope is a vital step in this regard to being guidance during the procedure. PMID- 29118546 TI - Migration of malleable penile prosthesis. AB - Penile prosthesis migration is rare. Most reported cases are migration of inflatable penile prosthesis reservoirs. We reported a case of rectal migration of malleable penile prosthesis passed out as hard bowel motion without patient recognition. PMID- 29118545 TI - Imaging modalities for an uncommon inguinal scrotal pathology: A case report and literature review. AB - Inguinal scrotal swelling is a common presentation to surgical clinic with various differential diagnoses. In most circumstances, a good clinical assessment is sufficient to identify the diagnosis. Imaging is necessary when diagnostic difficulty was encountered. The choice of imaging study could affect the management and outcome. A 60-year-old male presented with an enlarging right inguinal scrotal swelling for 5 years. Clinical examination showed a swelling extended from the right inguinal region down to the right scrotum, firm, not reducible, and not separable from the right testis. Differential diagnoses range from the malignant testicular tumor, irreducible inguinal hernia to the soft tissue tumor. Ultrasonography and computed tomography scan were unable to conclude the origin of the tumor and involvement of the right testis. Inguinal exploration with potential radical orchiectomy was planned and caused much distress to the patient, resulted in delay in surgery. Intraoperatively, the mass was separated from the testis and spermatic cord, and thus, excision biopsy was performed sparing the testis and spermatic cord. Histopathological examination showed cellular angiofibroma. The right choice of imaging modality is important to provide a precise diagnosis and better treatment plan. This could avoid the unnecessary distress to the patient for potential organ lost. A review through the literature showed the ability of magnetic resonance imaging to better delineate the anatomy of inguinal scrotal soft-tissue mass and thus should have been the imaging modality of choice. PMID- 29118547 TI - Benign testicular neoplasm in a human immunodeficiency virus-positive patient masquerading as testicular cancer. AB - Inflammatory myofibroblastic tumor (IMT) is a rare, benign neoplasm comprising spindle myoepithelial cells in the background of inflammatory cells. It can involve multiple anatomic sites in the body but rarely involves the testis. We report a case of 52-year-old male patient with a history of human immunodeficiency virus who presented with a painless, testicular mass for 2 months. Despite being treated with prolonged antibiotics and nonsteroidal anti inflammatory drugs, scrotal ultrasound demonstrated an increase in the size of the lesion. With a presumed diagnosis of testicular germ cell tumor, a right radical inguinal orchiectomy was performed. Microscopic and immunohistochemical features were consistent with testicular IMT, a benign neoplastic process. PMID- 29118548 TI - Epithelioid hemangioma of penis mimicking malignancy: A rare case. AB - Penile epithelioid hemangioma (EH) is a rare vascular neoplasm with no definite etiology. Herein, we report a case of EH of the penis in a 64-year-old man presenting with painless, bleeding mass on the glans penis. The patient underwent local excision, and on histopathological examination, a diagnosis of EH was made. Immunohistochemistry revealed positivity for CD31, smooth muscle antigen, and negative expression of cytokeratin. The present case highlights the importance of histopathology in conjunction with immunohistochemistry to reach a definitive diagnosis of this rare benign entity and differentiating it from the close malignant mimics, thereby avoiding aggressive management of the patients. PMID- 29118549 TI - Bladder endocervicosis - A rare diagnosis with a silent presentation. AB - Bladder endocervicosis is a benign disease, characterized by the presence of ectopic endocervical tissue in the bladder wall, with few cases described in the literature. A case of bladder endocervicosis in a 35-year-old female, with the previous history of cesarean section, subtotal hysterectomy, and right oophorectomy is reported here. The patient was asymptomatic and the bladder lesion was detected on pelvic ultrasonography. Transurethral bladder resection was performed and the histopathological analysis revealed bladder endocervicosis. 12 months of follow-up have passed without evidence of clinical or radiological recurrence. Clinical presentation, pathological features, and treatment are discussed. PMID- 29118550 TI - "Horrendoplasty" - A case of total perineal destruction by agricultural implement. AB - Although posterior urethral injury occurs almost always in association with pelvic fracture, it may result from severe trauma to the perineum with its associated potential lethality and severe morbidity. Early primary endoscopic realignment over a urethral catheter can be attempted, although an immediate suprapubic tube placement remains the standard of care. Definitive treatment consists of elective open posterior anastomotic urethroplasty through a perineal approach. The authors present a 53-year-old man who sustained total, massive perineal destruction resulting from work accident with an agricultural implement. Immediate suprapubic tube placement was performed followed by delayed elective transperineal anastomotic posterior urethroplasty. A major multidisciplinary approach was necessary in the management strategy, including orthopedic, general, plastic, vascular surgeries, and reconstructive urology teams. At a later stage, with the patient stabilized and recovered from major, life-threatening lesions dealt with by a multidisciplinary team, urethral reconstruction can be undertaken with ultimate good functional outcomes. PMID- 29118551 TI - Importance of lower pole nephrectomy during ureterocalicostomy. AB - Ureterocalicostomy is usually a salvage procedure for recurrent pelvi-ureteric junction (PUJ) stricture or upper ureteric injury. It requires meticulous dissection of the upper ureter, and lower pole nephrectomy is considered an essential step to achieve a wide funneled and dependent ureterocaliceal anastomosis. We, hereby, highlight the importance of guillotine lower pole nephrectomy through a case report of recurrent PUJ stricture managed with ureterocalicostomy that failed due to the omission of lower pole nephrectomy. PMID- 29118552 TI - Drugs for improving esophageal mucosa defense: where are we now and where are we going? AB - In the past, the attention of physiologists and doctors has been mainly focused on the key role of acid in the pathogenesis of gastroesophageal reflux disease (GERD), but increasing evidence that 20-40% of reflux patients respond not at all or only partially to proton pump inhibitors (PPIs) has underlined the concept that factors other than acid are implicated in its development and the elicitation of symptoms. Among these, impaired mucosal integrity, particularly in most patients with non-erosive reflux disease, has recently been reincluded and the reinforcement of defensive mechanisms and/or its protection has been reappointed as a renewed therapeutic target for the management of GERD patients. In this review we will summarize the existing knowledge of the old and novel compounds able to produce this therapeutic effect, including sucralfate, alginate based drugs, and a new medical device consisting of hyaluronic acid and chondroitin sulfate dispersed in a bioadhesive carrier, together with the potential indications for their use. It is to be stressed, however, that, although these compounds may represent a real alternative to PPI therapy in GERD, the combination of mucosal protection with acid suppression may help manage many cases with a partial or unsatisfactory response to PPIs alone. PMID- 29118553 TI - Endoscopic management of colorectal adenomas. AB - Colorectal adenomas are well known precursors of invasive adenocarcinoma. Colonoscopy is the gold standard for adenoma detection. Colonoscopy is far more than a diagnostic tool, as it allows effective treatment of colorectal adenomas. Endoscopic resection of colorectal adenomas has been shown to reduce the incidence and mortality of colorectal cancer. Difficult resection techniques are available, such as endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic full-thickness resection. This review aims to provide an overview of the different endoscopic resection techniques and their indications, and summarizes the current recommendations in the recently published guideline of the European Society of Gastrointestinal Endoscopy. PMID- 29118555 TI - Current and future biomarkers in colorectal cancer. AB - Colorectal cancer (CRC), one of the leading causes of death among cancer patients, is a heterogeneous disease and is characterized by diversions in multiple molecular pathways throughout its evolutionary process. To date, specific mutations in RAS and RAF genes are tested in everyday clinical practice along with mismatch repair gene deficiency, serving either as prognostic or predictive biomarkers, providing information for patient risk stratification and the choice of appropriate therapy. However, ongoing studies are focusing on the potential role of recently discovered genetic and epigenetic alterations in the management of CRC patients and their potential prognostic or predictive value. To overcome the problem of tumor heterogeneity as well as the practical obstacles of access to tumor tissue, and to achieve real-time monitoring of disease and therapy efficacy, liquid biopsies constitute a novel technology worth exploring. CRC screening and management is entering a new era where molecular testing will be applied to genomic material extracted from easily accessible bodily fluids. PMID- 29118554 TI - Risk factors for postoperative recurrence of Crohn's disease with emphasis on surgical predictors. AB - Intestinal resection for Crohn's disease is not curative and postoperative recurrence rates remain high. Early detection of indices associated with recurrence and risk stratification are fundamental for the postoperative management of patients. Early endoscopy at 6-12 months is the "gold standard" procedure, whereas other modalities such as fecal calprotectin and imaging techniques can contribute to the diagnosis of recurrence. The purpose of this review is to summarize current data regarding risk factors correlated with postoperative relapse. Smoking is a well-established, modifiable risk factor. There are sufficient data that correlate penetrating disease, perianal involvement, extensive resections, prior surgery, histological features (plexitis and granulomas), and improper management after resection with high rates for recurrence. The literature provides conflicting data for other possible predictors, such as age, sex, family history of inflammatory bowel disease, location of disease, strictureplasties, blood transfusions, and postoperative complications, necessitating further evidence. On the other hand, surgical factors such as anastomotic configuration, open or laparoscopic approach, and microscopic disease at specimen margins when macroscopic disease is resected, seem not to be related with an increased risk of recurrence. Further recognition of histological features as well as gene-related factors are promising fields for research. PMID- 29118557 TI - Effects of probiotic-containing products on stool frequency and intestinal transit in constipated adults: systematic review and meta-analysis of randomized controlled trials. AB - Background: Probiotics are commonly recommended for the alleviation of constipation symptoms. The aim of this research was to determine the effects of probiotic-containing products on stool frequency and intestinal transit time (ITT) in constipated adults and to determine the factors that influence the efficacy of these products. Methods: We conducted a systematic review of randomized controlled trials that measured weekly stool frequency or ITT in constipated adults receiving probiotic-containing supplements. A random effects meta-analysis was performed; stool frequency was summarized by the mean difference statistic and ITT was summarized by the standardized mean difference (SMD) statistic. Meta-regression and diagnostic model performance testing were used to identify publication bias and sources of heterogeneity. Results: A total of 21 studies (23 comparisons) comprising 2656 subjects were included. All studies utilized probiotics containing Lactobacillus or Bifidobacterium species. Probiotic-containing products resulted in a mean increase in weekly stool frequency of 0.83 (95% confidence interval [CI] 0.53-1.14, P<0.001). There was high heterogeneity among the studies (I2=85%, P<0.001) and evidence of significant publication bias (Egger's P-value <0.01). After adjustment for publication bias, the mean difference in weekly stool frequency was reduced from 0.83 to 0.30. The effects on stool frequency were greater in studies where functional constipation was diagnosed using Rome III (P<0.01), or Rome II or III criteria (P<0.05), compared to non-Rome diagnosis techniques. Probiotic containing products were also efficacious in reducing ITT (SMD=0.65, 95%CI 0.33 0.97, P<0.001). There was high heterogeneity among studies (I2=66%, P<0.01), but no evidence of publication bias (Egger's P-value=0.52). A larger total sample size was associated with greater efficacy as regards ITT (P=0.03). The probiotic species, the number of probiotic strains and the daily probiotic dosage had no influence on the outcomes. Conclusion: Supplementation with products containing Lactobacillus or Bifidobacterium species increases stool frequency and reduces ITT in constipated adults. However, since significant heterogeneity in outcomes was detected among the studies analyzed, the results should be interpreted with caution. PMID- 29118556 TI - Long non-coding RNA in pancreatic adenocarcinoma and pancreatic neuroendocrine tumors. AB - Interest in non-coding regions of DNA has been increasing since the mapping of the human genome revealed that human DNA contains far fewer genes encoding proteins than previously expected. However, analysis of the derivatives of DNA transcription (transcriptomics) revealed that the majority of the genetic material is transcribed into non-coding RNA (ncRNA), indicating that these molecules probably provide the functional diversity and complexity of the physiology of the human body that cannot be attributed to the proteins. Of these ncRNA, long ncRNA (lncRNA) have a length greater than 200 nucleotides and share many common components with the coding messenger RNA (mRNA): They are transcribed by RNA polymerase II, comprised of multiple exons and subjected to normal RNA splicing giving RNA products of several kilobases. Scientific data reveal the regulatory role of lncRNA in the control of gene expression during cell development and homeostasis. However, to date, very few lncRNAs have been characterized in depth, and lncRNAs are thought to have a wide range of functions in cellular and developmental processes. These molecules will have the possibility to be used as biomarkers and contribute to the development of targeted therapies. Concerning pancreatic cancer, there are limited data in the literature that correlate the growth of these tumors with deregulation of various lncRNA. We herein review the literature regarding the role of lncRNA as a diagnostic and prognostic biomarker and possible therapeutic target in the neoplasms of the pancreas, particularly pancreatic adenocarcinoma and pancreatic neuroendocrine tumors. PMID- 29118559 TI - Long-term efficacy of vacuum-assisted therapy (Endo-SPONGE(r)) in large anastomotic leakages following anterior rectal resection. AB - Background: The aim of our study was to test the long-term efficacy of Endo SPONGE(r) therapy in a group of patients treated in our center with vacuum assisted therapy because of anastomotic leakages after colorectal surgery. Methods: Eleven patients [male: 6; mean age: 71 (range: 44-82) years] who had anastomotic leakage treated with Endo-SPONGE(r) placement were included in the study. Patient records were examined retrospectively. All patients with documented anastomotic leakage on abdominal computed tomography following an anterior resection of the rectum for rectal cancer underwent sigmoidoscopy to determine the extent of the anastomotic defect and the size of the presacral abscess. Results: Ten of the 11 patients (90.9%) showed closure of the anastomotic leakage after a mean of 16 sponge changes. During follow up [mean: 29 (range: 6-64) months], we observed two cases of anastomotic stricture. Treatment failure was observed in one patient who presented an increased size of dehiscence after 23 sessions of endoscopic treatment, despite an initial good response. Conclusions: Our study substantially confirms previous conclusions and reaffirms that Endo-SPONGE(r) treatment for colorectal anastomotic leakages, performed in suitable patients, represents a successful and safe approach. The reduction in wound closure time, mild-to-moderate discomfort and possibly shorter hospitalization suggest that Endo-SPONGE(r) treatment can be a prominent therapeutic regimen with adequate patient acceptance. PMID- 29118558 TI - Cap-assisted colonoscopy versus standard colonoscopy: is the cap beneficial? A meta-analysis of randomized controlled trials. AB - Background: In an effort to improve visualization during colonoscopy, a transparent plastic cap or hood may be placed on the end of the colonoscope. Cap assisted colonoscopy (CAC) has been studied and is thought to improve polyp detection. Numerous studies have been conducted comparing pertinent clinical outcomes between CAC and standard colonoscopy (SC) with inconsistent results. Methods: Numerous databases were searched in November 2016. Only randomized controlled trials (RCTs) involving adult subjects that compared CAC to SC were included. Outcomes of total colonoscopy time, time to cecum, cecal intubation rate, terminal ileum intubation rate, polyp detection rate (PDR), and adenoma detection rate (ADR) were analyzed in terms of odds ratio (OR) or mean difference (MD) with fixed effect and random effects models. Results: Five hundred eighty nine articles and abstracts were discovered. Of these, 23 RCTs (n=12,947) were included in the analysis. CAC showed statistically significant superiority in total colonoscopy time (MD -1.51 min; 95% confidence interval [CI] -2.67 to 0.34; P<0.01) and time to cecum (MD -0.82 min; 95%CI -1.20 to -0.44; P<0.01) compared to SC. CAC also showed better PDR (OR 1.17; 95%CI 1.06-1.29; P<0.01) but not ADR (OR 1.11; 95%CI 0.95-1.30; P=0.20). In contrast, on sensitivity analysis, ADR was better with CAC. Terminal ileum intubation and cecal intubation rates demonstrated no significant difference between the two groups (P=0.11 and P=0.73, respectively). Conclusions: The use of a transparent cap during colonoscopy improves PDR while reducing procedure times. ADR may improve in cap-assisted colonoscopy but further studies are required to confirm this. PMID- 29118560 TI - The effectiveness of intravenous iron for iron deficiency anemia in gastrointestinal cancer patients: a retrospective study. AB - Background: Knowledge of the role of intravenous iron without the use of additional erythropoietic stimulating agents in anemic cancer patients is limited. This study evaluated the effect of ferric carboxymaltose (FCM) in a group of digestive oncology (DIO) patients and aimed to differentiate therapy response according to different types of iron deficiency (ID) anemia. Methods: In this retrospective study, we identified DIO patients who were receiving FCM and had eligible baseline and follow-up hemoglobin (Hb) levels that did not require red blood cell transfusion. Subgroup analyses examined adequately versus inadequately treated patients and low (<100 ug/L) vs. high (>100 ug/L) baseline ferritin levels. Inadequate treatment was defined as administration of an insufficient dose of FCM, based on the modified Ganzoni formula. Results: A total of 414 patients were receiving FCM, of whom 41 were excluded because of transfusion and another 70 because of unknown or inadequate baseline iron status. Thus, the study group consisted of 303 patients. Follow-up serum levels were evaluated after a median of 4 weeks. Overall, the median change between baseline and follow-up Hb was 0.5 (interquartile range [IQR]: -0.1-1.6) g/dL. No significant difference in this change was found between the adequately and inadequately dosed groups. The median change in Hb was significantly greater in the low baseline ferritin group than in the high baseline ferritin group: 1.2 (IQR: 0.3-2.2) vs. 0.4 (IQR: -0.3-1.4) g/dL, respectively; P=0.004. Conclusions: Intravenous administration of iron in DIO patients with ID anemia leads to a significant increase in Hb. Moreover, differentiating between the types of ID anemia based on ferritin levels could be applied to predict therapy response, although better biomarkers are needed. PMID- 29118561 TI - Pilot study of the prevalence of binge eating disorder in non-alcoholic fatty liver disease patients. AB - Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States. Binge eating disorder (BED) is the most common form of eating disorder. NAFLD and BED have similar risk factors, including obesity, insulin resistance, and metabolic syndrome. The aim of our study was to examine prevalence of BED in NAFLD patients. Methods: We administered the Binge Eating Scale (BES), a questionnaire validated to screen for BED, to NAFLD patients at our Fatty Liver Center. Demographics were retrieved retrospectively from our electronic medical record. Results: Of the total 95 NAFLD patients screened, 22 (23.1%) had binge eating tendencies; 6 of the 22 (6.3%) scored 27 or more points, suggestive of severe binge eating. Patient demographics included 59 females and 36 males (14 females and 8 males positive for BED). Liver disease severity and of metabolic syndrome presence were similar in both groups: 45 patients had steatosis, 25 steatohepatitis, and 24 cirrhosis, of which 10 steatosis, 5 steatohepatitis, and 7 cirrhosis patients screened positive for BED. Of the NAFLD patients with BED, 50.0% had insulin resistance, 68.2% hypertension, and 50.0% hyperlipidemia, whereas among non-BED NAFLD patients 58.9% had insulin resistance, 63.0% hypertension, and 67.1% hyperlipidemia. Conclusions: This pilot study suggests that BED may have a higher prevalence among NAFLD patients than in the general population. Based on these preliminary results, further study into the prevalence of BED is recommended. More data is need to identify effects of BED on the progression of NAFLD and role of BED treatment. PMID- 29118562 TI - Obstetricians' and gynecologists' knowledge, education, and practices regarding chronic hepatitis B in pregnancy. AB - Background: In pregnant women with high viral loads, third-trimester initiation of antiviral agents can reduce the risk of vertical transmission. We aimed to assess obstetricians' and gynecologists' (OB-GYN) knowledge and clinical practice when treating pregnant women with chronic hepatitis B virus (HBV). Methods: All program directors (PDs) from 250 US OB-GYN residency programs were invited to anonymously complete an 18-item questionnaire. Descriptive statistics were calculated and analyzed. Results: A total of 323 participants responded, including both PDs (n=51, response rate 21%) and residents (n=272, response rate 11%). Responding PDs (62% university-based vs. 32% community-based) came from various practice types. All PDs and 95.2% of residents reported screening for chronic HBV in pregnant patients on the first prenatal visit. A majority of PDs (85.5%) and residents (85%) correctly interpreted HBV serologies. Referral patterns showed that 66.7% of PDs and 65.5% of residents refer to a specialist regardless of viral load. A minority of respondents (19.6% PDs and 12.6% residents) knew that third-trimester antiviral therapy is recommended for women with high viral loads (>200,000 IU/mL). Few respondents had prescribed HBV antivirals (9.8% PDs and 6.0% residents), with residents more commonly prescribing tenofovir and less frequently lamivudine. Half the PDs believed trainees from their programs were comfortable managing HBV in pregnancy, but only 41.8% of residents reported being comfortable managing pregnant patients with HBV. Conclusion: OB-GYNs report screening almost all pregnant patients for chronic HBV, though significant gaps still exist in practitioner comfort and training regarding the management of HBV during pregnancy. PMID- 29118563 TI - Cardiac dysfunction as an early predictor of portal hypertension in chronic hepatitis C. AB - Background: Cirrhotic cardiomyopathy is characterized by a set of cardiovascular modifications observed in advanced chronic liver disease. The aim of this study was to investigate cardiovascular alterations in chronic liver disease with different stages of fibrosis and to correlate cardiac involvement with endoscopic complications of portal hypertension. Methods: Seventy patients with chronic hepatitis C-related chronic liver disease and 20 sex- and age-matched controls underwent clinical evaluation, hepatic transient elastography, and echocardiography. Forty-nine of the 70 patients underwent an esophagogastroduodenoscopy for screening of esophageal and gastric varices. Results: According to the value of liver stiffness (LS), patients were divided in 2 groups: non-cirrhotics (LS<12.5 kPa; n=30; median LS=8.1 kPa, 95% confidence interval [CI] 6.4-9.2 kPa) and cirrhotics (LS>12.5 kPa; n=40; median LS=19.4 kPa, 95%CI 17-22 kPa). Compared to non-cirrhotics, cirrhotics showed a significant dilatation of the left atrium (P=0.007 and P=0.003 for area and volume index, respectively). In patients with chronic liver disease, peak systolic wave velocity (Sc) measured by tissue Doppler imaging (TDI) was lower (P=0.004), but ejection fraction was not reduced. Left atrial volume, left ventricular mass index and TDI Sc-wave velocity, but not liver stiffness, correlated with endoscopic signs of portal hypertension. Conclusions: Left atrial enlargement and peak Sc-wave systolic velocities are echocardiographic markers of diastolic and systolic dysfunction in liver cirrhosis. Cardiac alterations closely correlate to endoscopic portal hypertension; further studies could elucidate the potential role of echocardiography in the early identification of cirrhotic patients at higher risk for endoscopic complications of portal hypertension. PMID- 29118564 TI - Sex-related differences in predicting choledocholithiasis using current American Society of Gastrointestinal Endoscopy risk criteria. AB - Background: American Society of Gastrointestinal Endoscopy (ASGE) criteria is widely used to predict probability of choledocholithiasis among patients with symptomatic gallstone disease but does not take sex into consideration. Methods: The cohort study included patients who underwent either endoscopic retrograde cholangiopancreatography or intraoperative cholangiography for suspected choledocholithiasis at our medical center. Clinical, laboratory and radiological data were collected for each patient and used to stratify them based on the ASGE risk criteria for choledocholithiasis. Results: A total of 646 patients composed the final study cohort. The composite incidence rate of choledocholithiasis for male and female groups was 47.5% and 46.2% respectively. Total bilirubin (>4 mg/dL), cholangitis, abnormal liver function tests (transaminitis), dilation of the common bile duct (>6 mm) on ultrasound examination, and biliary pancreatitis were individually associated with choledocholithiasis in 73.5%, 68.4%, 61.1%, 60.0%, and 51.7% of males, respectively. Total bilirubin >4 mg/dL and 1.8-4 mg/dL, cholangitis, and transaminitis were individually associated with choledocholithiasis in 82.6%, 64.0%, 58.2%, and 50.0% of females, respectively. The distribution in probability group/incidence of choledocholithiasis was as follows: for males, low probability 3.3%/0%, intermediate probability 56.7%/33.8%), high probability 40%/77.8%; and for females, low probability 5.3%/14.3%, intermediate probability 70.2%/39.6%, high probability 24.5%/72.1%. Conclusions: The composite incidence for choledocholithiasis was similar across male and female patients. A significantly higher proportion of females compared to males were in the intermediate probability group. Better sex stratification can help improve the positive and negative predictive values of ASGE risk stratification criteria. Improve patient outcomes and reduce associated healthcare cost. PMID- 29118565 TI - Is complete mesocolic excision oncologically superior to conventional surgery for colon cancer? A retrospective comparative study. AB - Background: During the last decade, many efforts have been made in order to improve the oncologic outcomes following colonic resection. Complete mesocolic excision (CME) has proved to provide high rates of disease-free and overall survival rates in patients undergoing resection for colonic malignancies. The aim of our study was to further investigate the role of CME in colonic surgery through comparison with a series of conventional resections. Methods: All data regarding resections for colonic cancer since 2006 were obtained prospectively from two surgical departments. Retrieved data from 290 patients were analyzed and compared between those who underwent CME and those who had conventional surgery. Results: The CME group presented a higher rate of postoperative morbidity and readmissions. Histopathological features were in favor of CME surgery compared with the conventional group, in terms of both resected bowel length (33 vs. 20 cm) and lymph node harvest (27 vs. 18). Although CME was associated with better disease-free and overall survival times, only tumor differentiation, adjuvant chemotherapy and age had a statistically significant affect on those outcome values (P<0.05). Conclusion: CME improves histopathologic features, but without presenting oncologic superiority. Larger prospective studies following adequate surgical training are needed to prove the technique's advantages in oncologic outcomes. PMID- 29118566 TI - Successful endoscopic treatment for gastric mural abscess due to fish bone migration. PMID- 29118567 TI - Endoscopic submucosal dissection with double-tunnel technique for en bloc resection of large rectal laterally spreading tumor. PMID- 29118568 TI - A unique appendiceal orifice: a striking foreign body in the cecum. PMID- 29118569 TI - Embolia cutis medicamentosa: an unusual adverse reaction to terlipressin. AB - Terlipressin is a synthetic long-acting analog of vasopressin widely used to control variceal bleeding by lowering portal venous pressure. We report an unusual adverse reaction to terlipressin in a 78-year-old patient with esophageal variceal bleeding who developed skin necrosis soon after treatment initiation. Skin biopsy revealed embolia cutis medicamentosa. PMID- 29118570 TI - Helicobacter pylori best treatment approach: should a national consensus be the best consensus? PMID- 29118571 TI - Crashworthiness Design for Bionic Bumper Structures Inspired by Cattail and Bamboo. AB - Many materials in nature exhibit excellent mechanical properties. In this study, we evaluated the bionic bumper structure models by using nonlinear finite element (FE) simulations for their crashworthiness under full-size impact loading. The structure contained the structural characteristics of cattail and bamboo. The results indicated that the bionic design enhances the specific energy absorption (SEA) of the bumper. The numerical results showed that the bionic cross-beam and bionic box of the bionic bumper have a significant effect on the crashworthiness of the structure. The crush deformation of bionic cross-beam and box bumper model was reduced by 33.33%, and the total weight was reduced by 44.44%. As the energy absorption capacity under lateral impact, the bionic design can be used in the future bumper body. PMID- 29118572 TI - Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate loaded implants on sarcoma 180 tumor-bearing mice. AB - Purpose: Methotrexate is widely used in chemotherapy for a variety of malignancies. However, severe toxicity, poor pharmacokinetics, and narrow safety margin of methotrexate limit its clinical application. The aim of this study was to develop sustained-release methotrexate-loaded implants and evaluate antitumor activity of the implants after intratumoral implantation. Materials and methods: We prepared the implants containing methotrexate, poly(D,L-lactide-co-glycolide), and polyethylene glycol 4000 with the melt-molding technique. The implants were characterized with regards to drug content, morphology, in vitro, and in vivo release profiles. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were carried out to investigate the physicochemical properties of the implants. Furthermore, the antitumor activity of the implants was tested in a sarcoma 180 mouse model. Results: The implants were prepared as solid rods. Scanning electron microscopy images showed a smooth surface of the implant, suggesting that methotrexate was homogeneously dispersed in the polymeric matrix. The results of DSC and FTIR indicated that no significant interaction between methotrexate and the polymer was observed in the implants. Both in vitro and in vivo release profiles of the implants were characterized by burst release followed by sustained release of methotrexate. Intratumoral implantation of methotrexate-loaded implants could efficiently delay tumor growth. Moreover, an increase in the dose of implants led to a higher tumor suppression rate without additional systemic toxicity. Conclusion: These results demonstrate that methotrexate-loaded implants had significant antitumor efficacy in a sarcoma 180 mouse model without dose-limiting side effects, and suggest that the implants could be potentially applied as an intratumoral delivery system to treat cancer. PMID- 29118573 TI - Development and utilization of the Medicines Use Review patient satisfaction questionnaire. AB - The Medicines Use Review is a community pharmacy service funded in the United Kingdom to improve patients' adherence to medication and reduce medicines waste. The objective was to develop, pilot, and utilize a new Medicines Use Review patient satisfaction questionnaire. A questionnaire for patient self-completion was developed using a published framework of patient satisfaction with the Medicines Use Review service. The questions were validated using the content validity index and the questionnaire piloted through three pharmacies (February April 2016). The revised questionnaire contained 12 questions with responses on a 5-point Likert scale, and a comments box. The questionnaire was distributed to patients following a Medicines Use Review consultation via community pharmacies (June-October 2016). Exploratory factor analysis and Cronbach's alpha were performed to investigate the relationships between the items and to examine structural validity. The survey results were examined for patients' reported satisfaction with Medicines Use Reviews, while the handwritten comments were thematically analyzed and mapped against the questionnaire items. An estimated 2,151 questionnaires were handed out, and a total of 505 responses were received indicating a 24% response rate. Exploratory factor analysis revealed two factors with a cumulative variance of 68.8%, and Cronbach's alpha showed high internal consistency for each factor (alpha=0.90 and alpha=0.89, respectively). The survey results demonstrated that patients could show a high degree of overall satisfaction with the service, even if initially reluctant to take part in a Medicines Use Review. The results support the Medicines Use Review patient satisfaction questionnaire as a suitable tool for measuring patient satisfaction with the Medicines Use Review service. A wider study is needed to confirm the findings about this community pharmacy-based adherence service. PMID- 29118574 TI - How is adult patient adherence recorded in orthodontists' clinical notes? A mixed method case-note study. AB - Background: Patient adherence in orthodontic treatment is extremely important as it is linked with better treatment outcomes. Despite its importance, however, there is no shared definition of the concept. This makes the recording of adherence-related behaviors in patient notes difficult. The current study explored how, and to what extent adherence is recorded in adult patients' medical records by orthodontists working in a large National Health Service (NHS) London hospital. Materials and methods: A mixed-methods approach was used. A total of 17 clinicians with a mean age of 31 years (SD =4.87) provided N=20 case notes spanning N=324 appointments with patients they judged to be non-adherent. The notes were inspected for evidence of recording of patient adherence using adherence indicators identified in the literature. Results: The term "adherence" did not feature in any notes. The quantitative analysis showed that the three most frequent adherence-related behaviors recorded in notes were "oral hygiene," "appointment attendance" and "breakages of appliances." Qualitative analysis not only confirmed these factors but also showed that 1) the clinical aspects of treatment, 2) clinician-patient interaction factors and 3) patient attitudes also featured. This part of the analysis also highlighted inconsistencies across case notes in terms of the amount of information being recorded. Conclusion: Adherence as a term does not feature in the clinical case notes of clinician-identified non adherent adult patients, while predictors of adherence are recorded with varying degrees of consistency. PMID- 29118575 TI - Adherence to fingolimod in multiple sclerosis: an investigator-initiated, prospective, observational, single-center cohort study. AB - Objectives: Adherence to multiple sclerosis (MS) treatment is essential to optimize the likelihood of full treatment effect. This prospective, observational, single-center cohort study investigated adherence to fingolimod over the 2 years following treatment initiation. Two facets of adherence - implementation and persistence - were examined and compared between new and experienced users of disease-modifying treatments (DMTs). Materials and methods: Implementation rates were based on the proportion of days covered and calculated as percentages per half-yearly visits and over 2 years, captured through refill data, pill count, and self-report. Nonadherence was defined as taking less than 85.8% of prescribed pills. Implementation rates were classified as nonadherent (<85.8%), suboptimally adherent (>=85.8% but <96.2%), and optimally adherent (>=96.2%), including perfectly adherent (100%). Persistence, ie, time until discontinuation, was analyzed by Kaplan-Meier analysis. Reasons for discontinuation were recorded. Results: The cohort included 98 patients with relapsing MS, all of whom received a dedicated education session about their medication. Of these 80% were women, 31.6% had fingolimod as first DMT, and 68.4% had switched from other DMTs. The mean implementation rate over 2 years was 98.6% (IQR1-3 98.51%-98.7%) and did not change significantly over time; 89% of measurements were in the optimally adherent category, 45.6% in the perfectly adherent category. There was one single occurrence of nonadherence. New users of DMTs were 1.29 times more likely to be adherent than experienced users (OR 1.29, 95% CI 1.11-1.51; P<0.001), but not more persistent. Nineteen of 98 patients discontinued fingolimod. Conclusion: The very high implementation rates displayed in this sample of MS patients suggest that facilitation by health care professionals in preserving adherence behavior may be sufficient for the majority of patients. Targeted interventions should focus on patients who are nonadherent or who stop treatment without intention to reinitiate. PMID- 29118576 TI - Psychosocial therapy for Parkinson's-related dementia: intervention development. AB - Background: Group-based psychosocial therapy, such as group Cognitive Stimulation Therapy, improves cognition and quality of life in people living with dementia. Neuropsychiatric symptoms and restricted mobility are common complications for people with Parkinson's-related dementia (PRD) and may limit access to, and participation in, group activities. This study describes the development of a condition-specific, home-based psychosocial therapy for people with PRD ready to be trialled in a clinical population. Methods: By means of a multistage process, a draft therapy manual was developed in an iterative manner through collaboration with medical experts, researchers and Patient and Public Involvement (PPI) representatives. In stage 1, an extensive literature search of psychosocial therapies for dementia with potential relevance for Parkinson's disease (PD) was undertaken to select a candidate therapy for adaptation. In stage 2, qualitative feedback from stakeholders and intelligence regarding existing nonpharmacological therapies for cognitive impairment in PD was combined to produce a prototype therapy manual. In stage 3, the manual was field tested in: 1) a home-setting using a 25-item assessment tool; and 2) at a local PD support group with PPI representatives. Based on the feedback from this phase, final design modifications were implemented and a draft therapy manual produced. Results: The manual was developed in an iterative manner. Interview and focus group transcripts identified three enduring themes: manual form and content, therapy acceptability by people with PRD, and companion guidance and support. Major adaptations included: removal of discrete levels of task complexity, removal of images that were potentially hallucinogenic or lacked clarity, and updating of the content. Conclusion: We have successfully developed a Cognitive Stimulation Therapy-based psychosocial therapy specifically adapted for people with PRD. The therapy is ready to trial in a pilot randomized controlled study. PMID- 29118578 TI - Changes in definition lead to changes in the clinical characteristics across COPD categories according to GOLD 2017: a national cross-sectional survey in China. AB - Purpose: To investigate how the changes of definition in assessment of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stratification 2017 lead to changes of chronic obstructive pulmonary disease (COPD) patient clinical characteristics across categories in China. Patients and methods: COPD patients from 11 medical centers in China were stratified into old and new groups A-D twice according to the GOLD 2011 and 2017 comprehensive assessment. Demography and clinical characteristics were compared between old and new groups A-D. Results: In 1,532 COPD patients, the distribution from group A to D was 330 (21.5%), 132 (8.6%), 411 (26.8%), 659 (43.0%) and 557 (36.4%), 405 (26.4%), 184 (12.0%), 386 (25.2%), respectively according to GOLD 2011 and 2017. 46.7% (500/1,070) patients in high-risk groups were regrouped to low-risk groups. Compared to the old groups A and B, the new groups A and B had a higher proportion of males, lower body mass index, higher modified Medical Research Council (mMRC) grade, poor pulmonary function, more patients with chronic bronchitis, and fewer patients with coronary heart disease and hypertension disease. Compared to the old groups C and D, the new groups C and D had older patients, fewer men, better pulmonary functions, frequent acute exacerbations in the previous year, and more patients with chronic bronchitis, coronary heart disease, or diabetes mellitus. The new group D had more patients with stroke than the old group D. Conclusion: In China, GOLD 2017 shifted the overall COPD comprehensive assessments distribution to more low-risk groups. The new high-risk groups had more characteristics associated with high risk of acute exacerbation and mortality. Some of the changes in demography and clinical characteristics of the new low-risk groups were associated with high risk of acute exacerbation and/or mortality. PMID- 29118577 TI - Associations between occupational inhalation risks and FeNO levels in airway obstruction patients: results from the National Health and Nutrition Examination Survey, 2007-2012. AB - Purpose: To investigate associations between occupational inhalation risks and fractional exhaled nitric oxide (FeNO) levels in patients with chronic obstructive pulmonary disease (COPD). Patients and methods: Data of 16,486 subjects who had undergone spirometry with pre-bronchodilator and post bronchodilator lung function assessment were retrieved from the National Health and Nutrition Examination Survey, 2007-2012 database. After excluding 2,638 subjects with missing spirometry values, data of 13,336 subjects were included for analysis. Factors associated with occupational inhalation, FeNO levels and COPD were analyzed using logistic regression analysis. Results: COPD was associated with occupational exposures to mineral dusts, organic dusts, exhaust fumes, other fumes, and second-hand smoking (P<0.05). Long-term exposure to these occupational hazards carried significantly higher risk for subjects with COPD than for controls (crude odds ratios [ORs]: mineral dusts: 2.364, organic dusts: 2.427, exhaust fumes: 2.728, other fumes: 2.144). In subgroup analysis, COPD correlated positively with long-term exposures to organic dusts and exhaust fumes in subjects with FeNO <=50 ppb (ORs 1.361 and 1.314, respectively); conversely, COPD correlated negatively with intermediate to long-term exposures to organic dusts and exhaust fumes in those with FeNO >50 ppb (ORs 0.058 and 0.210, respectively). Conclusion: Occupational exposures to airborne pollutants carries higher risk of COPD than non-exposure and the risk is higher the longer the duration of exposure. Exposure-response relationships are inconsistent in subjects with suspected asthmatic airway inflammation (FeNO >=50 ppb). More careful risk assessment is needed in occupational inhalation exposure, since COPD with asthmatic airway inflammation, or asthma-COPD overlapping syndrome, may have the distinguishing features of both COPD and asthma. PMID- 29118579 TI - Surface modification of vascular endothelial growth factor-loaded silk fibroin to improve biological performance of ultra-high-molecular-weight polyethylene via promoting angiogenesis. AB - Ultra-high-molecular-weight polyethylene (UHMWPE) has been applied in orthopedics, as the materials of joint prosthesis, artificial ligaments, and sutures due to its advantages such as high tensile strength, good wear resistance, and chemical stability. However, postoperative osteolysis induced by UHMWPE wear particles and poor bone-implant healing interface due to scarcity of osseointegration is a significant problem and should be solved imperatively. In order to enhance its affinity to bone tissue, vascular endothelial growth factor (VEGF) was loaded on the surface of materials, the loading was performed by silk fibroin (SF) coating to achieve a controlled-release delivery. Several techniques including field emission scanning electron microscopy (FESEM) and attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) and water contact angle measurement were used to validate the effectiveness of introduction of SF/VEGF. The result of ELISA demonstrated that the release of VEGF was well maintained up to 4 weeks. The modified UHMWPE was evaluated by both in vitro and in vivo experiments. According to the results of FESEM and cell counting kit-8 (CCK-8) assay, bone marrow mesenchymal stem cells cultured on the UHMWPE coated with SF/VEGF and SF exhibited a better proliferation performance than that of the pristine UHMWPE. The model rabbit of anterior cruciate ligament reconstruction was used to observe the graft-bone healing process in vivo. The results of histological evaluation, microcomputed tomography (micro-CT) analysis, and biomechanical tests performed at 6 and 12 weeks after surgery demonstrated that graft-bone healing could be significantly improved due to the effect of VEGF on angiogenesis, which was loaded on the surface by SF coating. This study showed that the method loading VEGF on UHMWPE by SF coating played an effective role on the biological performance of UHMWPE and displayed a great potential application for anterior cruciate ligament reconstruction. PMID- 29118580 TI - Supercritical carbon dioxide-developed silk fibroin nanoplatform for smart colon cancer therapy. AB - Purpose: To deliver insoluble natural compounds into colon cancer cells in a controlled fashion. Materials and methods: Curcumin (CM)-silk fibroin (SF) nanoparticles (NPs) were prepared by solution-enhanced dispersion by supercritical CO2 (SEDS) (20 MPa pressure, 1:2 CM:SF ratio, 1% concentration), and their physicochemical properties, intracellular uptake efficiency, in vitro anticancer effect, toxicity, and mechanisms were evaluated and analyzed. Results: CM-SF NPs (<100 nm) with controllable particle size were prepared by SEDS. CM-SF NPs had a time-dependent intracellular uptake ability, which led to an improved inhibition effect on colon cancer cells. Interestingly, the anticancer effect of CM-SF NPs was improved, while the side effect on normal human colon mucosal epithelial cells was reduced by a concentration of ~10 MUg/mL. The anticancer mechanism involves cell-cycle arrest in the G0/G1 and G2/M phases in association with inducing apoptotic cells. Conclusion: The natural compound-loaded SF nanoplatform prepared by SEDS indicates promising colon cancer-therapy potential. PMID- 29118581 TI - Complexity and wide range of neuromyelitis optica spectrum disorders: more than typical manifestations. AB - Neuromyelitis optica (NMO), considered to be mediated by autoantibodies, often cause severely disabling disorders of the central nervous system, and predominantly cause optic nerve damage and longitudinally extensive transverse myelitis. Remarkable progress has been made in deciphering NMO pathogenesis during the past decade. In 2015, the International Panel for NMO Diagnosis proposed the unifying term "NMO spectrum disorders" (NMOSD) and the updated NMOSD criteria reflects a wide range of disease and maintains reasonable specificity. Moreover, cumulative findings have indicated that NMOSD are frequently associated with multiple autoimmune diseases, thereby presenting complex clinical symptoms that make this disease more difficult to recognize. Notably, most neurologists do not heed these symptoms or comorbid conditions in patients with NMOSD. Whereas previous reviews have focused on pathogenesis, treatment, and prognosis in NMOSD, we summarize the present knowledge with particular emphasis on atypical manifestations and autoimmune comorbidities in patients with NMOSD. Furthermore, we emphasized the identification of these atypical characteristics to enable a broader and better understanding of NMOSD, and improve early accurate diagnosis and therapeutic decision making. PMID- 29118583 TI - The association of serum vitamin D concentration and ventricular dysfunction among patients with acute coronary syndrome. AB - Objective: To determine if vitamin D deficiency was associated with higher odds of left ventricular dysfunction among patients with acute coronary syndrome (ACS) and, if so, to determine whether this association was mediated by increased inflammation as measured by C-reactive protein (CRP) and white blood cell count (WBC). Methods: This was a cross-sectional study of 170 participants with ACS. Multiple logistic regression was used to examine the association between the outcome of ventricular performance and serum vitamin D concentrations. We also determined whether CRP and WBC meet standard criteria as the mediators between left ventricular ejection fraction and vitamin D deficiency. Results: Participants with vitamin D deficiency were more likely to have ventricular dysfunction (OR: 2.12, 95% CI: 1.2-5.23). WBC counts did not meet one of the criteria for mediation. However, the WBC was an effect modifier such that the association of vitamin D deficiency and ventricular dysfunction was only present among participants with WBC more than 11,000. Conclusion: This study found that vitamin D deficiency was associated with higher odds of ventricular dysfunction. Further longitudinal and experimental studies are necessary to confirm this finding and to determine if there is a role for vitamin D supplementation therapy in preventing ventricular dysfunction in select patient populations. PMID- 29118582 TI - Association of TNF-alpha G-308A gene polymorphism with depression: a meta analysis. AB - Background: Although many studies have investigated the association of a single nucleotide polymorphism in TNF-alpha G-308A gene with depression, their association is still controversial. To clarify this, we performed a meta analysis. Method: Studies related to TNF-alpha G-308A and depression were retrieved from PubMed, Medline, Embase, and Scopus (up to April 18, 2017). The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in the models of allele comparison (G vs A), homozygote comparison (GG vs AA), dominant (GG vs GA + AA), and recessive (GG + GA vs AA) to estimate the strength of the associations. Results: A total of 10 case-control studies were included in this meta-analysis. Overall, no significant association between TNF-alpha G-308A and depression was found (G vs A: OR [95% CI] =1.09 [0.92, 1.29]; GG vs AA: 1.24 [0.71, 2.15]; GG vs GA + AA: 1.01 [0.76, 1.35]; GG + GA vs AA: 1.22 [0.70, 2.13]). In subgroup analyses by ethnicity or age group, no statistically significant association between TNF-alpha G-308A polymorphisms and depression was shown. Conclusion: This meta-analysis revealed that TNF-alpha G-308A polymorphism is not associated with susceptibility to depression. PMID- 29118584 TI - Developing a novel dual PI3K-mTOR inhibitor from the prodrug of a metabolite. AB - This study presents a process of developing a novel PI3K-mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1) was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2) was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2) instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3) was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3) did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future. PMID- 29118585 TI - Pain management, prescription opioid mortality, and the CDC: is the devil in the data? PMID- 29118586 TI - Successful Surgical Resection of Iatrogenic Antecubital Venous Pseudoaneurysm Following Venipuncture: A 2-Case Report. AB - Iatrogenic venous pseudoaneurysm (VP) formation after venipuncture is rare. This report showed 2 cases of VP following venipuncture, and VPs were resected surgically. A 58-year-old woman and a 56-year-old woman developed a soft antecubital mass after blood sampling from the basilic veins. One patient had the sensory disturbance of forearm. The mass was diagnosed as a VP with thrombus by duplex ultrasound and magnetic resonance imaging. The aneurysm was resected completely, and the sensory disturbance of the patient was improved. Surgical resection was the most appropriate treatment for the relief of symptoms due to compression. PMID- 29118587 TI - Consequences of Different Corticosteroids on Serum Potassium and Prostate Specific Antigen in Patients Receiving Abiraterone for Castration-Resistant Prostate Cancer: A Retrospective Observational Study. AB - Background: Abiraterone acetate is an androgen synthesis inhibitor approved for the treatment of castration-resistant prostate cancer (CRPC). Although co administration of either prednisone or prednisolone at 10 mg/d has been recommended to reduce the risk of abiraterone-induced hyperaldosteronism (notably hypokalemia) and to give adjunctive pain relief effects, whether these glucocorticoids can be substituted by dexamethasone remains unknown. Methods: We performed a retrospective review of medical records of patients who were given abiraterone for the treatment of CRPC with either prednisolone (ABI/PSL) 10 mg/d or dexamethasone (ABI/DEX) 0.5 or 1 mg/d between 2014 and 2017 in Juntendo University Nerima Hospital. Demographic and biochemical data including prostate specific antigen (PSA) level were retrieved from the electronic medical records. Results: Fifty-three eligible patients (27 in ABI/PSL group and 26 in ABI/DEX group) were extracted from the records. Both groups showed no significant changes in serum potassium level before and after starting treatment. In the ABI/PSL group, 12 patients (46%) showed elevations of PSA and 7 patients (27%) discontinued treatment within 3 months. In contrast, in the ABI/DEX group, only 6 patients (25%) showed elevations of PSA and 3 patients (13%, all were given dexamethasone 1 mg/d) discontinued treatment. Conclusions: Dexamethasone and prednisolone may be equally effective in preventing abiraterone-induced hypokalemia. PMID- 29118588 TI - Professionalism among paramedic students: achieving the measure or missing the mark? AB - Background: Professionalism is a pillar of paramedicine. Internationally paramedic curricula emphasize valid assessment of three domains: cognitive, psychomotor, and affective domains (professionalism). Little is reported on competency measures for professionalism specific to paramedicine. Literature suggests that paramedic students, paramedic practitioners, medical directors, and patients believe that professional attributes should have an increased focus. Objective: The objective of this scoping review is to outline valid and reliable assessments that evaluate professional behaviors. Method: This review used Arksey and O'Malley's six-stage scoping methodology. In September 2016, five databases were searched for articles of relevance; these were MEDLINE, Scopus, Google Scholar, PsycINFO/APA, and EMBASE. Results: A total of 1587 articles were identified after removal of 468 duplicates. Five articles met the inclusion criteria, two of the articles were from the US and three from UK. The studies range from 2004 to 2014. Three different scales were identified but only two were recommended for use. A US-based scale is composed of 11 items and one generic form of professionalism. The UK scale has 77 items and identified 11 factors within 68 items. Conclusions: This scoping review serves to describe valid and reliable measures for professionalism among paramedicine by outlining the quantity of instruments evident in the literature. The scoping review aimed to report the scales supporting evidence of validity and reliability. Three scales were identified in a total of five different studies that specifically measured professional attributes in paramedicine. Currently, two scales are available: an evaluation with 11 items and a self-reported questionnaire with 77 items. PMID- 29118590 TI - Contribution to the knowledge of Neanurinae of Vietnam with description of three new species (Collembola, Neanuridae). AB - Detailed and illustrated descriptions of three new species belonging to the tribe Lobellini from Vietnam are given. Lobellina weineraesp. n. is the most similar to L. minuta (Lee, 1980) and L. musangensis Yosii, 1976, but differs from them in chaetotaxic details and the number of mandibular teeth. Lobellina pomorskiisp. n. differs from L. perfusionides (Stach, 1965) in chaetotaxic details and the number of tubercles on Abd.V. Yuukianura deharvengisp. n. is superficially similar to Y. halophila Yosii, 1955, but it differs in the build of the maxilla, the size of eyes and an inner tooth on the claw, and in chaetotaxic details. Furthermore, some remarks on the characteristics and the peculiarity of the Vietnamese fauna of the subfamily, and the key to all species from the country, are included. PMID- 29118589 TI - The complete mitochondrial DNA sequence of the pantropical earthworm Pontoscolex corethrurus (Rhinodrilidae, Clitellata): Mitogenome characterization and phylogenetic positioning. AB - Pontoscolex corethrurus (Muller, 1857) plays an important role in tropical soil ecosystems and has been widely used as an animal model for a large variety of ecological studies in particular due to its common presence and generally high abundance in human-disturbed tropical soils. In this study we describe the complete mitochondrial genome of the peregrine earthworm P. corethrurus. This is the first record of a mitochondrial genome within the Rhinodrilidae family. Its mitochondrial genome is 14 835 bp in length containing 37 genes (13 protein coding genes (PCG) 2 rRNA genes and 22 tRNA genes). It has the same gene content and structure as in other sequenced earthworms but unusual among invertebrates it hasseveral overlapping open reading frames. All genes are encoded on the same strand. Most of the PCGs use ATG as the start codon except for ND3 which uses GTG as the start codon. The A+T content of the mitochondrial genome is 59.9% (31.8% A 28.1% T 14.6% G and 25.6% for C). The annotated genome sequence has been deposited in GenBank under the accession number KT988053. PMID- 29118591 TI - Description of a new species of Lamellothyrea Krikken (Coleoptera, Scarabaeidae, Cetoniinae) from the iSimangaliso Wetland Park, KwaZulu-Natal (South Africa). AB - Recent data and material obtained from northern KwaZulu-Natal (South Africa) and Maputo Bay (Mozambique) have provided support for the description of a new species of the genus Lamellothyrea Krikken, 1980. The genus previously included only one species, L. descarpentriesi, with uncertain and poorly defined type locality, i.e. "Transvaal". It is now evident that two different species are actually involved, L. descarpentriesi with currently known distribution limited to the coastal area north of Maputo, and L. isimangalisosp. n. with a known distribution range virtually restricted to the iSimangaliso Wetland Park, in north-eastern KwaZulu-Natal. The two species appear to be separated by a substantial discontinuity in southern Mozambique and can be easily separated on the basis of their clypeal structure, extent of white dorsal tomentum and shape of aedeagal parameres. Both species appear to be restricted to the coastal belt, with L. isimangaliso sp. n. occupying almost exclusively dune forest habitats. In this species, adult activity depends on rainfall and shows two peaks, one at the onset of summer and the second in autumn. PMID- 29118592 TI - A review of the genus Lordiphosa Basden in India, with descriptions of four new species from the Himalayan region (Diptera, Drosophilidae). AB - All Indian species of the genus Lordiphosa Basden are reviewed, with descriptions of four new species, L. curva Fartyal & Toda, sp. n. of the denticeps species group and L. ayarpathaensis Kandpal & Singh, sp. n., L. makaibarensis Pradhan & Chatterjee, sp. n. and L. srinagarensis Sati & Fartyal, sp. n. of the nigricolor species group. Two of the new species, L. ayarpathaensis and L. makaibarensis, were found visiting flowers of Hedychium spicatum and Datura suaveolens, respectively. This is the first record of flower visitation in Lordiphosa flies. In addition, L. parantillaria (Kumar & Gupta, 1990), syn. n. is synonymized with L. antillaria (Okada, 1984). Supplementary and revised descriptions for L. antillaria and L. neokurokawai (Singh & Gupta, 1981) and a key to all Indian species of Lordiphosa are provided. PMID- 29118593 TI - Stranding survey as a framework to investigate rare cetacean records of the north and north-eastern Brazilian coasts. AB - Marine mammal stranding events are used as an important tool for understanding cetacean biology worldwide. Nonetheless, there are vast gaps of knowledge to be filled in for a wide range of species. Reputable information is required regarding species from large baleen whales to sperm and beaked whales, as well as pelagic dolphins. This paper describes new cetacean records from north and north eastern Brazil, which are both the least surveyed areas regarding aquatic mammals. Regular beach surveys were conducted to recover cetacean carcasses along the coast of Para beginning November 2005. At the coasts of the Maranhao and Piaui states, the surveys were conducted between 2003 and 2013. From 2003 to 2014, 34 strandings of cetaceans were registered. The study provides four additional species records' in the area based on strandings (Balaenoptera borealis, Balaenoptera physalus, Peponocephala electra, and Pseudorca crassidens). A mass stranding of Guiana dolphins (Sotalia guianensis, N = 12), the most common species for the region, was reported for the first time. The records presented herein are of special concern, since they expand the knowledge on cetaceans from the Brazilian coast. In addition, this study conducted an analysis to verify the similarity between cetacean compositions described for north and north-eastern Brazil and the southern Caribbean region. The results showed a high similarity between these regions, proving the connection with the Caribbean cetacean fauna. PMID- 29118594 TI - Reinstatement of Eschatoporiini Blaisdell, 1906, a unique tribe of blind cavernicolous Tenebrionidae from California, with a new species from Napa County (Coleoptera, Tenebrionidae, Lagriinae). AB - The tribe Eschatoporini Blaisdell, 1906 is reinstated, based on molecular and morphological data, and the spelling corrected as Eschatoporiini. The tribe currently includes only the cave-dwelling genus Eschatoporis Blaisdell, 1906 from California, which is associated with underground aquifers. A second species of Eschatoporis is described from a cave in Napa County, California. The phylogenetic placement of Eschatoporiini within the Lagriinae is examined, and notes on the biology of Eschatoporis are provided. PMID- 29118595 TI - A taxonomic review of the Selenophori group (Coleoptera, Carabidae, Harpalini) in the West Indies, with descriptions of new species and notes about classification and biogeography. AB - Primarily a taxonomic review of the West Indian elements of the selenophorine Harpalini, this paper includes a classification, a key, descriptions and illustrations of taxa, re-rankings, and new synonymies. In total, 45 species and subspecies are treated, six of which are described as new. A new genus and new species are as follows, with type localities in parentheses: Paraulacoryssusgen. n., (type species Selenophorus puertoricensis Mutchler, 1934); Neodiachipteryx davidsonisp. n., (Zamba, Dominican Republic); Selenophorus spinosussp. n., seriatoporus species group (Benjamin Constant, state of Amazonas, Brazil); Selenophorus obtusoidessp. n., parumpunctatus species group (near Soroa, Pinar del Rio Province, Cuba); Selenophorus ivieisp. n., nonseriatus species group (Big River, Montserrat, 16 degrees 45.719N', 62 degrees 11.335W'); Selenophorus irecsp. n., nonseriatus species group (Vernou, Guadeloupe, Lesser Antilles); and Selenophorus fabriciisp. n., opalinus species group (Cabo Rojo, Pedernales Province, Dominican Republic). This last species was misidentified as Selenophorus integer (Fabricius). In turn, that species was misidentified as Selenophorus chalybeus Dejean. Selenophorus chalybeus Dejean is a junior synonym of Selenophorus integer Fabricius, syn. n.; and Isopleurus macleayi Kirby is a junior synonym of Selenophorus pyritosus Dejean, syn. n. Biogeographically, log of land area plotted against log of number of species shows that the equilibrium theory of biogeography applies to the West Indian selenophorine fauna. Taxonomically, the selenophorine taxa of the West Indies are arranged in eight genera. The 30 species/subspecies of Selenophorus (sensu stricto) are arranged in 10 species groups. Geographically, the major sources of the selenophorines are the Bahamas, the Greater Antilles and Lesser Antilles. The West Indian islands probably have been invaded by 26 taxa. Of the currently extant taxa, 11 are classified as immigrant, meaning that they are represented both in the islands and on the mainland (South America or Middle America and southern Florida). Thirty three taxa are classified as precinctive, meaning that they originated where they are now living, the implication being that they have descended from immigrants, thus older in the islands than the current-day immigrants. It is postulated that the West Indian taxa represent three age groups: oldest, ancestors having reached the proto-Antilles by a landspan known as GAARlandia; a middle-age group (Neogene period), their ancestors having reached the islands by dispersal over water, between islands; and a young group of extant taxa, no older than the Pleistocene, also having reached the islands over water. PMID- 29118596 TI - Revision of torrent mites (Parasitengona, Torrenticolidae, Torrenticola) of the United States and Canada: 90 descriptions, molecular phylogenetics, and a key to species. AB - The descriptive biology of torrent mites (Parasitengona: Torrenticolidae: Torrenticola) of North America (north of Mexico) is investigated using integrative methods. Material examined includes approximately 2,300 specimens from nearly 500 localities across the United States and Canada, and a few collections in Mexico and Central America. Species hypotheses are derived from a phylogenetic analysis of the barcoding region of cytochrome c oxidase subunit 1 (COI) for 476 specimens and supported with morphology and biogeography. Relationships between species are examined with a combined analysis of COI and two expansion regions (D2-3) of the large ribosomal subunit (28S rDNA) for 57 specimens. All previously described species from the US and Canada are examined. Our results indicate the need to synonymize four species: T. mercedensis (Marshall, 1943) is a junior synonym of T. sierrensis (Marshall, 1943); T. rectiforma Habeeb, 1974 is a junior synonym of T. ellipsoidalis (Marshall, 1943); T. neoconnexa Habeeb, 1957 is a junior synonym of T. magnexa Habeeb, 1955; and T. esbelta Cramer, 1992 is a junior synonym of T. boettgeri KO Viets, 1977. We describe 66 new species and re-describe all previously described regional species. Our findings indicate that total diversity of Torrenticola in the United States and Canada comprises 90 species, 57 known from the east and 33 from the west. We organize these species into four species complexes that include 13 identification groups. An additional 13 species do not fit within an identification group. The southern Appalachians are suspected to contain the highest concentration of remaining undescribed diversity. A key is provided to all known species in the US and Canada. PMID- 29118597 TI - Comments on the recent changes in taxonomy of pygmy unicorns, with description of a new species of Metopomystrum from Brazil (Insecta, Tetrigidae, Cleostratini, Miriatrini). AB - The tribe Cleostratini Bolivar, 1887 sensu Storozhenko, 2016 does not represent a monophyletic taxon because it gathers various Tetrigidae genera with various types of horn and prolongation of frons or vertex. Prolongation of these structures is present in morphologically and biogeographically distant groups. We do not regard Miriatrini Cadena-Castaneda & Cardona, 2015 synonymous with Cleostratini because the genus Miriatra Bolivar, 1906 belongs to a group of genera distant from Cleostratus Stal, 1877. There is no adequate diagnosis for proposed groups of genera forming tribes Cleostratini or Miriatrini. Miriatrini stat. resurr. are monotypic and include only Miriatra, Cleostratini are monotypic as well. Apteromystrum Storozhenko, 2016 syn. n. is regarded synonymous with Metopomystrum, M. apterumcomb. resurr., M. amazoniensiscomb. resurr. and Miriatra brevifastigiata (Cadena-Castaneda & Cardona, 2015), comb. n. are not Metopomystrum member. Herein a new species of pygmy unicorn, Metopomystrum muriciense Silva & Skejo, sp. n., is described from Atlantic Forest remnants in northeast of Brazil, collected on the Estacao Serra do Ouro (municipality of Murici, Alagoas state). Distribution data, morphological characterization, and an identification key to Metopomystrum species are also presented. PMID- 29118598 TI - First record of Thecturota tenuissima Casey from Canada (Coleoptera, Staphylinidae, Aleocharinae). AB - Thecturota tenuissima Casey, is reported for the first time from Canada, based on records from Ontario and Quebec. It was originally described from Rhode Island, USA, and no other records of this species in North America were published since that time. The specimens from Canada were captured by car netting. We provide here a redescription of this species and never before published images of habitus, tergite, and sternite VIII of both sexes, median lobe of aedeagus and spermatheca. The features distinguishing T. tenuissima from T. capito Casey (=pusio (Casey)), the only other species reported in Canada, are provided and illustrated. PMID- 29118599 TI - Revision of Hemiquedius Casey (Staphylinidae, Staphylininae) and a review of beetles dependent on beavers and muskrats in North America. AB - Based on newly discovered characters on the male genitalia, external morphology and an accumulation of ecological data, we revise the single member of the genus Hemiquedius. Two new species, H. infinitus Brunke & Smetana, sp. n. and H. castoris Brunke & Smetana, sp. n., from eastern North America are described, and H. ferox (LeConte), restricted to peninsular Florida, is re-described. Hemiquedius castoris is strongly associated with the microhabitats provided by nest materials of the North American beaver and muskrat. A key to the three species of Hemiquedius is provided and diagnostic characters are illustrated. We also review the beetles known to be obligate associates of beavers and muskrats, and discuss the potential role of these keystone vertebrates in beetle evolution and distribution. Based on nest-associated beetles and their closest living relatives, beaver and muskrat lodges may extend distributions northward by moderating winters, promote sympatric speciation and act as refugia against extinction of lineages on a broader timescale. Further research into these potential impacts by ecologists and evolutionary biologists is encouraged. PMID- 29118600 TI - A revision of Meladema diving beetles (Coleoptera, Dytiscidae), with the description of a new species from the central Mediterranean based on molecules and morphology. AB - Meladema Laporte, 1835 are relatively large, stream-dwelling diving beetles, distributed widely in the Western Palaearctic, from the Atlantic Islands to Turkey, and from southern France and the Balkans to the central Sahara. In addition to the three previously recognised taxa (M. coriacea Laporte, 1835, M. imbricata (Wollaston, 1871) and M. lanio (Fabricius, 1775)) we describe a new, cryptic, species from the central Mediterranean area, which can be distinguished from M. coriacea on both DNA sequence data and morphology, and provide a key to known species of the genus. Based on the study of genotyped material, both recent and archival, as well as the examination of a large number of museum specimens, we show that M. lepidopterasp. n. occurs to the apparent exclusion of M. coriacea on Corsica, Sardinia and islands of the Tuscan Archipelago, but that both taxa are found in peninsular Italy, where they may occasionally hybridize. In the absence of the original type series, we designate a neotype for M. coriacea, and take the opportunity to designate a lectotype for M. lanio. Morphological variation in Meladema species is discussed, including that seen in known and presumed hybrids. Our study highlights the incomplete state of knowledge of Mediterranean biodiversity, even in relatively large, supposedly well-studied taxa. PMID- 29118601 TI - Two new species of the Phanaeus endymion species group (Coleoptera, Scarabaeidae, Scarabaeinae). AB - Phanaeus bravoensissp. n. is described from the coniferous-oak forests in the state of Guerrero, and P. huicholsp. n. from coniferous-oak forests and cloud forests in Jalisco and Nayarit. The new species are closely related to P. halffterorum and P. zoque respectively. Morphological trait combination, geographic distribution, and trophic habits show important differences among the studied species. A distribution map and an updated key to separate the species are included. PMID- 29118602 TI - First checklist of the fruit flies of Morocco, including new records (Diptera, Tephritidae). AB - The first checklist of the Tephritidae of Morocco, containing 59 species, is presented here. Out of 38 species collected during the present project, three (Campiglossa martii (Becker, 1908), Tephritis divisa (Rondani, 1871), and Terellia sp. near longicauda) present new records for North Africa, and ten (Carpomya incompleta (Becker, 1903), Chaetorellia conjuncta (Becker, 1913), Chetostoma curvinerve Rondani, 1856, Dacus frontalis (Becker, 1922), D. longistylus (Wiedemann, 1830), Dioxyna sororcula (Wiedemann, 1830), Ensina sonchi (Linnaeus, 1767), Myopites inulaedyssentericae Blot, 1827, M. stylatus Fabricius, 1794, and Tephritis vespertina (Loew, 1844)) are new for Morocco. PMID- 29118603 TI - Echiniscidae from the Sierra Nevada de Santa Marta, Colombia, new records and a new species of Bryodelphax Thulin, 1928 (Tardigrada). AB - Three species of Echiniscus are recorded for the first time from Colombia: Echiniscus dariae, Echiniscus kofordi, and Echiniscus perarmatus. In addition, the description of the new species Bryodelphax kristensenisp. n., is mainly based on the presence of ten paired plus two unpaired granularly sculptured ventral plates, the dorsal plate ornamentation with superficial irregular pores, no spine on the anterior legs, and the hind legs without papillae or dentate collar. PMID- 29118604 TI - Taxonomy of North European Lumbricillus (Clitellata, Enchytraeidae). AB - Lumbricillus is a genus of clitellate worms with about 80 described species that inhabit marine and limnic habitats. This study follows a recent analysis of the phylogeny of the genus based on 24 species of Lumbricillus collected mainly in Norway and Sweden. We provide the illustrated taxonomic descriptions of all these species and describe two of them as new; Lumbricillus latithecatussp. n. and L. scandicussp. n. Using the recent phylogeny, we informally divide Lumbricillus into five distinct morphological groups, into which we also tentatively place the Lumbricillus species not included in this study. Furthermore, we establish Claparedrilusgen. n., with the type species C. semifuscoidessp. n., and transfer Pachydrilus semifuscus Claparede, 1861 (previously referred to Lumbricillus) into said genus. PMID- 29118605 TI - A new species of Tridactylogonus Jeekel, 1982 from South Australia (Diplopoda, Polydesmida, Paradoxosomatidae). AB - Tridactylogonus warrenbenensissp. n. is described from Warrenben Conservation Park at the southern end of the Yorke Peninsula in South Australia. Like T. obscurus Jeekel, 1982 and T. rugosissimus Jeekel, 2002, the new species has prominent cellular sculpturing on the prozonites and granulose sculpturing on parts of the metazonites. Unlike its congeners and most species in the subfamily Australiosomatinae, the new species lacks a femoral process or tubercle on male leg 1. PMID- 29118606 TI - Callosa gen. n., a new troglobitic genus from southwest China (Araneae, Linyphiidae). AB - A new linyphiid genus Callosagen. n., with two new species Callosa ciliatasp. n. (??, type species) and Callosa baiseensissp. n. (??), from southwest China are described. Detailed description of genitalic characters and somatic features is provided, as well as light microscopy and SEM micrographs of each species. Callosagen. n. was found in caves in Yunnan and Guangxi, and its copulatory organs are similar to those of Bathyphantes and Porrhomma, but differ greatly in details. The monophyly and placement of Callosagen. n. are supported by the results of molecular analysis. PMID- 29118607 TI - New records of Sarcophagidae from Turkey (Diptera). AB - Faunistic records of 68 flesh fly species are presented, and altogether, 22 species are recorded from Turkey for the first time. A further 46 species were recorded for the first time in at least one Turkish province. This paper presents the first locality data for four additional species, which were previously mentioned only generically in catalogues. One new synonym has been established, Servaisia (s. str.) rybaltschenkoi (Verves, 1977) = Blaesoxipha ataturkia Lehrer, 2008, syn. n. Two new combinations are proposed: Helicophagella (Parabellieria) dreyfusi (Lehrer, 1994), comb. n. and Helicophagella (s. str.) bellae (Lehrer, 2000), comb. n. PMID- 29118608 TI - A revision of the family Ameroseiidae (Acari, Mesostigmata), with some data on Slovak fauna. AB - The family Ameroseiidae Evans, 1961 (Acari: Mesostigmata) includes a total of 12 valid and adequately described genera, namely Afrocypholaelaps Elsen, 1972, Ameroseiella Bregetova, 1977, Ameroseius Berlese, 1904, Asperolaelaps Womersley, 1956, Brontispalaelaps Womersley, 1956, Epicriopsis Berlese, 1916, Hattena Domrow, 1963, Kleemannia Oudemans, 1930, Neocypholaelaps Vitzthum, 1942, Pseudoameroseiusgen. n., Sertitympanum Elsen & Whitaker, 1985 and Sinoseius Bai & Gu, 1995. One of these genera includes subgenera, namely Kleemannia (Primoseius) Womersley, 1956. All genera are reviewed and re-diagnosed, and a dichotomous key is provided for their identification. Ameroseius (50 species), Kleemannia (28 species) and Neocypholaelaps (22 species) are the largest genera in the family. Ameroseiella, Kleemannia, Kleemannia (Primoseius) and Sinoseius are considered to be valid taxa and, in presented systematic classification, they are removed from synonymy with Ameroseius. The genus Pseudoameroseiusgen. n., with type species Ameroseius michaelangeli Moraza, 2006 (from Canary Islands), is newly erected to further refine broad primary concept of Ameroseius as understood by some former authors (Karg, Bregetova). Asperolaelaps is removed from synonymy with Neocypholaelaps. Three new species are here described, namely Ameroseius renataesp. n. (based on specimens from Slovakia), Kleemannia dolichochaetasp. n. (from Spain) and Kleemannia mirandasp. n. (from U.S.A.). The following new junior synonymies are proposed: Ameroseius apodius Karg, 1971 = Ameroseiella macrochelae (Westerboer, 1963); Ameroseius bregetovae Livshits & Mitrofanov, 1975 = Neocypholaelaps favus Ishikawa, 1968; Ameroseius chinensis Khalili-Moghadam & Saboori, 2016 = Ameroseius guyimingi Ma, 1997; Ameroseius crassisetosus Ye & Ma, 1993, Ameroseius qinghaiensis Li & Yang, 2000 and Ameroseius norvegicus Narita, Abduch & Moraes, 2015 = Ameroseius corbiculus (Sowerby, 1806); Ameroseius dubitatus Berlese, 1918 = Kleemannia plumosa (Oudemans, 1902); Ameroseius eumorphus Bregetova, 1977 and Kleemannia potchefstroomensis Kruger & Loots, 1980 = Kleemannia pseudoplumosa (Rack, 1972); Ameroseius gilarovi Petrova, 1986 = Kleemannia plumigera Oudemans, 1930; Ameroseius imparsetosus Westerboer, 1963 = Ameroseius georgei (Turk, 1943); Ameroseius lanatus Solomon, 1969 and Ameroseius fimetorum Karg, 1971 = Kleemannia tenella (Berlese, 1916); Ameroseius lanceosetis Livshits & Mitrofanov, 1975 = Kleemannia pavida (C. L. Koch, 1839); Ameroseius marginalis Fan & Li, 1993 and Ameroseius sichuanensis Fan & Li, 1993 = Kleemannia insignis (Bernhard, 1963); Ameroseius pseudofurcatus Livshits & Mitrofanov, 1975 = Ameroseius furcatus Karg, 1971; Ameroseius stramenis Karg, 1976 and Lasioseius (Lasioseius) gracilis Halbert, 1923 = Kleemannia delicata (Berlese, 1918); Epicriopsis langei Livshits & Mitrofanov, 1975 and Epicriopsis baloghi Kandil, 1978 = Epicriopsis palustris Karg, 1971; Epicriopsis rivus Karg, 1971 = Epicriopsis mirabilis Willmann, 1956; Neocypholaelaps ewae Haitlinger, 1987 = Neocypholaelaps indicus Evans, 1963; Neocypholaelaps lindquisti Prasad, 1968, Afrocypholaelaps ranomafanaensis Haitlinger, 1987 and Afrocypholaelaps analicullus Ho, Ma, Wang & Severinghaus, 2010 = Afrocypholaelaps africanus (Evans, 1963); Sinoseius pinnatus Huhta & Karg, 2010 = Sinoseius lobatus Bai, Gu & Fang, 1995. Ameroseius womersleyi Masan, is a replacement name proposed for Ameroseius ornatus Womersley, 1956, a junior secondary homonym of Cornubia ornata Turk, 1943 [= Ameroseius corbiculus (Sowerby, 1806)]. Cornubia georgei Turk, 1943 is removed from synonymy with Ameroseius corbiculus (Sowerby, 1806). An annotated catalogue of the world species of Ameroseiidae is provided, partly based on type (in more than 60 species) and non-type specimens from various museum deposits and personal collections, including new or revised material from Slovakia. It contains 206 named species (138 valid species, 37 synonyms, nine unrecognizable species, 15 species previously excluded from Ameroseiidae, and seven "nomina nuda"), with details of their authorship, synonyms, nomenclatural and bibliographic details, generic placement, and morphology. Altogether 23 new combinations are proposed. The genus Sertitympanum with Sertitympanum nodosum (Sheals, 1962) and two further species, namely Kleemannia kosi El-Badry, Nasr & Hafez, 1979 and Kleemannia parplumosa Nasr & Abou-Awad, 1986, are reported from Europe for the first time. New keys are given for identification of 37 species belonging to eight genera which have been found in Europe to date (Ameroseiella, Ameroseius, Epicriopsis, Kleemannia, Neocypholaelaps, Pseudoameroseiusgen. n., Sertitympanum and Sinoseius). All of these genera except Pseudoameroseius gen. nov. and Sertitympanum occur in Slovakia. So, the fauna of Slovakia includes six genera and 27 species, including ten first reports for the country. PMID- 29118609 TI - A new large tellinid species of the genus Pharaonella from the Ryukyu Archipelago, Japan (Mollusca, Bivalvia). AB - A new tellinid species, Pharaonella amanyusp. n., is described from sand banks around Amami Islands, the Ryukyu Archipelago, in southern Japan. A molecular phylogenetic analysis suggests that this new species is closely related to P. sieboldii. This species has long siphons and lives buried deep in well-sorted white sand syntopically with Tonganaella tongana. These rare, large tellinid species are indicators of unspoiled tidal/subtidal sand flats, which should receive the highest priority conservation in the Ryukyu Archipelago. PMID- 29118610 TI - A new terrestrial talitrid genus, Myanmarorchestia, with two new species from Myanmar (Crustacea, Amphipoda, Talitridae). AB - Myanmarorchestia Hou, gen. n. with two new species is described from terrestrial habitats in Myanmar. This new genus is characterised by 4-dentate lacinia on left mandible, simple gnathopod I in both sexes, weakly chelate gnathopod II in male, simplidactylate pereopods and complex and lobed gills. Myanmarorchestia peterjaegeri Hou, sp. n. closely resembles M. seabri Hou, sp. n. in gnathopod II merus and carpus protuberant on posterior margin; however, the former is distinguished from the latter by palp of maxilla I with two articles, coxal gills convoluted, and telson with nicks on surface. Additionally, DNA barcodes of the new species are obtained to confirm their distinctiveness. PMID- 29118612 TI - Distributional records of Antarctic and sub-Antarctic Ophiuroidea from samples curated at the Italian National Antarctic Museum (MNA): check-list update of the group in the Terra Nova Bay area (Ross Sea) and launch of the MNA 3D model 'virtual gallery'. AB - The distributional records of Ophiuroidea stored at the Italian National Antarctic Museum (MNA, Section of Genoa) are presented, corresponding to 1595 individuals that belong to 35 species and 17 genera. Specimens were collected in 106 different sampling stations at depths ranging from 21 to 1652 m in the framework of 14 Antarctic expeditions to the Ross Sea, one to the Antarctic Peninsula, and one to the Falkland Islands (Islas Malvinas). Three species, Amphiura joubini Koehler, 1912, Amphiura (Amphiura) angularis Lyman, 1879, and Ophiura flexibilis (Koehler, 1911), are reported as new records for the Terra Nova Bay area, whose check-list of species increases from 15 to 18 species. The determination of these three new records was based both on morphological identification and molecular analyses (COI barcoding). Some of the genetically characterised specimens were also documented through photogrammetry and micro computed tomography and represent the first bulk of 3D models that will be available through the MNA and Sketchfab websites, both for research and educational purposes. PMID- 29118611 TI - Complete mitochondrial genomes from two species of Chinese freshwater crabs of the genus Sinopotamon recovered using next-generation sequencing reveal a novel gene order (Brachyura, Potamidae). AB - Recent morphological and molecular evidence has challenged classical interpretations of eubrachyuran phylogeny and evolution. Complete mitochondrial genomes of two species of potamid freshwater crabs, Sinopotamon yaanense and Sinopotamon yangtsekiense were obtained using next-generation sequencing. The results revealed a novel gene order with translocations of a five-gene block and a tRNA gene in comparison to available brachyuran mitochondrial genomes. DNA sequence comparisons position the Potamidae, a primary freshwater crab family, outside of the clade for the traditional heterotreme families, and closer to the clade that includes the thoracotreme families of grapsoid and ocypodoid crabs. Mitogenomic comparisons using rapid next-generation sequencing and a much wider taxonomic sample are required for a high-resolution examination of the phylogenetic relationships within the Eubrachyura. PMID- 29118613 TI - A new species of Stigmatomma from Taiwan (Hymenoptera, Formicidae, Amblyoponinae). AB - Stigmatomma is the most speciose ant genus in the subfamily Amblyoponinae. In the present paper, the worker caste of a new species is described, S. luyiaesp. n., which was collected from a soil sample in a subtropical evergreen broad-leaved forest in Taiwan. An identification key to the females of Stigmatomma species with 11 antennomeres occurring in Asia is also provided. PMID- 29118614 TI - The genus Braunsia Kriechbaumer, 1894 from China with description of two new species (Hymenoptera, Braconidae, Agathidinae). AB - The species of Braunsia Kriechbaumer, 1894 (Hymenoptera, Braconidae, Doryctinae) from China are revised and ten species are recognized. Two new species, B. guangdongensissp. n. and B. shenyangensissp. n., are described and illustrated. B. fumipennis (Cameron, 1899), B. pilosa Belokobylskij, 1986, B. postfurcalis Watanabe, 1937, and B. smithii (Dalla Torre, 1898), are recorded from China for the first time. A key to the Chinese species of the genus Braunsia is provided. PMID- 29118615 TI - Revision of the Neotropical water scavenger beetle genus Quadriops Hansen, 1999 (Coleoptera, Hydrophilidae, Acidocerinae). AB - The genus Quadriops Hansen, 1999 is revised and redescribed. The genus is found to contain six species, including two that are here described as new: Quadriops clusiasp. n. (Brazil, Guyana, Suriname) and Q. acroreiussp. n. (Suriname, French Guiana). Two species are found to be junior subjective synonyms of Q. depressus Hansen, 1999: Q. amazonensis Garcia, 2000, syn. n. and Q. politus Hansen, 1999, syn. n. The male of Q. similaris Hansen, 1999 is described for the first time. New records are provided for Q. dentatus Hansen, 1999, Q. reticulatus Hansen, 1999, and Q. similaris. All species are described and illustrated in detail. Most species are confirmed as having a terrestrial way of life, with several species being found in rotten fruits, sap flows, and dead wood. Furthermore, we discuss ecological trends of the species given their collecting information. PMID- 29118617 TI - A sea anemone of many names: a review of the taxonomy and distribution of the invasive actiniarian Diadumene lineata (Diadumenidae), with records of its reappearance on the Texas coast. AB - Diadumene lineata (Actiniaria: Diadumenidae) is a prolific invader of coastal environments around the world. First described from Asia, this sea anemone has only been reported once from the western Gulf of Mexico at Port Aransas, Texas. No subsequent sampling has located this species at this locality. The first record of the reappearance of D. lineata on the Texas coast from three locations in the Galveston Bay area is provided, and its geographic distribution and taxonomic history reviewed. PMID- 29118616 TI - Phylogeography and population structure of - grypotus (Richardson, 1846) as revealed by mitochondrial control region sequences. AB - The 137 individuals of Johnius grypotus were collected from seven localities from the Bohai Sea to the East China Sea. A 549 base pair (bp) fragment of the hypervariable region of the mtDNA control region was sequenced to examine genetic diversity and population structure. The populations of J. grypotus showed high haplotype diversity (h) with a range from 0.7500 to 0.9740 and low nucleotide diversity (pi) with a range from 0.0024 to 0.0067. Low and non-significant genetic differentiation was estimated among populations except for North Yellow Sea population, which has a significant genetic difference with other populations. The demographic history examined by mismatch distribution analyses and Bayesian skyline plot (BSP) analyses revealed that a sudden population expansion occurred almost 20 to 40 thousand years before. Relatively recent population expansion in the last glacial period, large dispersal of eggs or larvae carried by coastal current, and the homogeneity of living environment may have an important influence on the population genetic pattern. PMID- 29118618 TI - Aroui minusetosus, a new species of Scopelocheiridae from Korea (Crustacea, Amphipoda, Lysianassoidea). AB - A new species, Aroui minusetosussp. n., is recorded from Korean waters with detailed description and illustrations. A new key to all known Aroui is provided. The Korean material of this scopelocheirid is readily assigned to the genus Aroui by the presence of long and distally barbed setae on the outer plate of maxilla 2. This new species is distinguished from congeners by ventrally smooth coxae 1-3 and a setose posteroventral margin of coxa 4, the subchelate gnathopod 2 having a row of four robust setae on its posterior margin (including an elongate single locking seta), and the setation of all appendages which is less dense than in other species. This is the first record of scopelocheirid amphipods from Korean waters. PMID- 29118619 TI - Revision of the family Carabodidae (Acari, Oribatida) XII. Yoshiobodes camerunensis sp. n. and Rugocepheus costaricensis sp. n. AB - Yoshiobodes camerunensissp. n., collected in Cameroon, is the first species of this genus reported from the Afrotropical region. Diagnostic characters include lamellae terminating in a bridge and not in lamellar tips; cup-shaped bothridia, bothridial ring present; rostral setae cochleariform, smooth; lamellar setae slightly lanceolate, barbate; fifteen pairs of notogastral setae; c3 lanceolate, rounded end, with longitudinal shallow grooves; other notogastral setae curved lanceolate-cochleariform. Rugocepheus costaricensissp. n. is the third species of the genus to be described, and the first collected outside the African region. Prodorsum presents a Y-shaped structure; elevated interlamellar process, superior flat zone; lamellae lacking lamellar tips; fourteen pairs of notogastral setae; four notogastral furrows, and an unpaired elevated central area devoid of setae. Both species are described and illustrated based on adult specimens, studied by means of optical and SEM microscopy. PMID- 29118621 TI - A new species of Trachymyrmex (Hymenoptera, Formicidae) fungus-growing ant from the Sierra Madre Oriental of northeastern Mexico. AB - Here we describe a new species of Trachymyrmex, T. pakawasp. n., from the Gran Sierra Plegada range of the Sierra Madre Oriental, in the states of Coahuila and Nuevo Leon, northeastern Mexico. Trachymyrmex pakawa is a large-sized species compared to other North American Trachymyrmex. Its geographic distribution includes the piedmont of the Gran Sierra Plegada at La Estanzuela, Monterrey, as well as peripheral mountains segregated from the Sierra Madre Oriental (Cerro de las Mitras, Sierra de Zapaliname, Canon de San Lorenzo, Cerro de las Letras). The preferred habitats of T. pakawa include oak-pine forest at La Estanzuela, xeric oak forest at Zapaliname and mesic Chihuahuan desert scrub with sotol (Dasylirion) at other sites. All localities are on slopes, on very rocky, shallow lithosols overlaying large boulders. This species nests under and between large boulders and rocks. It has not been observed on alluvial or better developed, deeper soils, and it is absent from sites with human activity (urban, disturbed, and landscaped areas). It is closely related to and morphologically similar to Trachymyrmex smithi. The known distribution ranges of T. pakawa and T. smithi almost overlap in Saltillo, Coahuila state. The main character that distinguishes the new species from T. smithi is longer antennal scapes in T. pakawa; also, different nesting habits (rocky slopes vs. alluvial sites or deep sand in T. smithi), and geographic distribution. Phylogenetic analysis of DNA sequences from the mitochondrial marker cytochrome c oxidase subunit I (COI) and the first intron of the F1 copy of the nuclear protein-coding gene Elongation Factor 1- alpha (EF1-alpha-F1) confirm a sister-species relationship between T. pakawa and T. smithi. Bayesian coalescent analyses indicate a divergence time of about 8.00 million years before present (95% confidence interval: 4.8-11.5 mya) between T. pakawa and T. smithi. The divergence of the lineages of T. pakawa and T. smithi could have been driven by the Pliocene-Holocene desertification of southwestern North America. This process resulted in isolated mesic refugia and forests in the Madrean ranges and piedmonts of northeastern Mexico (the current habitat of T. pakawa) while T. smithi adapted to the deeper, often sandy soils on the drier desert plains of Coahuila and Chihuahua states in Mexico, and New Mexico and Texas in the USA. Within the Nearctic species of the Trachymyrmex septentrionalis species group, T. pakawa is the species that is closest (by geographical distribution) to Neotropical species of Trachymyrmex like T. saussurei. PMID- 29118620 TI - DNA barcoding and morphological analysis for rapid identification of most economically important crop-infesting Sunn pests belonging to Eurygaster Laporte, 1833 (Hemiptera, Scutelleridae). AB - The genus Eurygaster Laporte, 1833 includes ten species five of which inhabit the European part of Russia. The harmful species of the genus is E. integriceps. Eurygaster species identification based on the morphological traits is very difficult, while that of the species at the egg or larval stages is extremely difficult or impossible. Eurygaster integriceps, E. maura, and E. testudinaria differ only slightly between each other morphologically, E. maura and E. testudinaria being almost indiscernible. DNA barcoding based on COI sequences have shown that E. integriceps differs significantly from these closely related species, which enables its rapid and accurate identification. Based on COI nucleotide sequences, three species of Sunn pests, E. maura, E. testudinarius, E. dilaticollis, could not be differentiated from each other through DNA barcoding. The difference in the DNA sequences between the COI gene of E. integriceps and COI genes of E. maura and E. testudinarius was more than 4%. In the present study DNA barcoding of two Eurygaster species was performed for the first time on E. integriceps, the most dangerous pest in the genus, and E. dilaticollis that only inhabits natural ecosystems. The PCR-RFLP method was developed in this work for the rapid identification of E. integriceps. PMID- 29118622 TI - Omoglymmius (s. str.) wukong sp. n., a new species from Xizang, China (Coleoptera, Rhysodidae, Omoglymmiini). AB - Omoglymmius (s. str.) wukongsp. n. (Coleoptera: Rhysodidae: Omoglymmiini) is described from Xizang, China. Relevant morphological characters of the new species are illustrated with colour plates, and known distribution of the subgenus Omoglymmius in the Himalayan region is mapped. PMID- 29118623 TI - Pseudaspidimerus palatus, a new species of the genus Pseudaspidimerus Kapur, 1948 from the Malay Peninsula (Coleoptera, Coccinellidae). AB - A new species of the genus Pseudaspidimerus Kapur, 1948 (Coleoptera: Coccinellidae), Pseudaspidimerus palatus Huo & Wang, sp. n. from the Malay Peninsula is described with illustrations and a distribution map. The genus Pseudaspidimerus is recorded for the first time from Malaysia and Singapore. PMID- 29118624 TI - A species checklist of the subgenus Culicoides (Avaritia) in China, with a description of a new species (Diptera, Ceratopogonidae). AB - A checklist of the subgenus Culicoides (Avaritia Fox) (Diptera: Ceratopogonidae: Culicoides) in China, currently including 57 species, is provided. Their full citations, more detailed locations of the type locality, and distribution of each species by province, and/or state of each species are also provided. Culicoides (Avaritia) fenggangensis Liu & Hou, sp. n. is described and illustrated, based on both male and female specimens from China. The new species is compared with its similar congeners, C. (A.) comparis Liu & Yu, 2005 and C. (A.) dentiformis McDonald & Lu, 1972. PMID- 29118625 TI - A new species of Scinax from the Purus-Madeira interfluve, Brazilian Amazonia (Anura, Hylidae). AB - A new tree frog species of the genus Scinax from the interfluve between the Purus and Madeira rivers, Brazilian Amazonia, is described and illustrated. The new species is diagnosed by medium body size, snout truncate in dorsal view, ulnar and tarsal tubercles absent, nuptial pads poorly developed, skin on dorsum shagreen, dorsum light brown with dark brown spots and markings, white groin with black spots, anterior and posterior surfaces of thighs black, and iris bright orange. The advertisement call consists of a single short note, with 16-18 pulses and dominant frequency at 1572-1594 Hz. Tadpoles are characterized by body ovoid in dorsal view and triangular in lateral view, tail higher than body, oral disc located anteroventrally and laterally emarginated, dorsum of body uniformly grey brown with dark brown eye-snout stripe in preservative, fins translucent with small to large irregular diffuse dark brown spots. PMID- 29118626 TI - Abyssal fauna of the UK-1 polymetallic nodule exploration area, Clarion Clipperton Zone, central Pacific Ocean: Mollusca. AB - We present the first DNA taxonomy publication on abyssal Mollusca from the Clarion-Clipperton Zone (CCZ), central Pacific ocean, using material collected as part of the Abyssal Baseline (ABYSSLINE) environmental survey cruise 'AB01' to the UK Seabed Resources Ltd (UKSRL) polymetallic-nodule exploration area 'UK-1' in the eastern CCZ. This is the third paper in a series to provide regional taxonomic data for a region that is undergoing intense deep-sea mineral exploration for high-grade polymetallic nodules. Taxonomic data are presented for 21 species from 42 records identified by a combination of morphological and genetic data, including molecular phylogenetic analyses. These included 3 heterodont bivalves, 5 protobranch bivalves, 4 pteriomorph bivalves, 1 caudofoveate, 1 monoplacophoran, 1 polyplacophoran, 4 scaphopods and 2 solenogastres. Gastropoda were recovered but will be the subject of a future study. Seven taxa matched published morphological descriptions for species with deep Pacific type localities, and our sequences provide the first genetic data for these taxa. One taxon morphologically matched a known cosmopolitan species but with a type locality in a different ocean basin and was assigned the open nomenclature 'cf' as a precautionary approach in taxon assignments to avoid over estimating species ranges. One taxon is here described as a new species, Ledella knudseni sp. n. For the remaining 12 taxa, we have determined them to be potentially new species, for which we make the raw data, imagery and vouchers available for future taxonomic study. The Clarion-Clipperton Zone is a region undergoing intense exploration for potential deep-sea mineral extraction. We present these data to facilitate future taxonomic and environmental impact study by making both data and voucher materials available through curated and accessible biological collections. PMID- 29118627 TI - A new species of the water mite genus Sperchon Kramer, 1877 from China, with identifying Sperchon rostratus Lundblad, 1969 through DNA barcoding (Acari, Hydrachnidia, Sperchontidae). AB - A new species of the water mite genus Sperchon Kramer, 1877 from China, Sperchon fuxiensis Zhang, sp. n., is described and illustrated in this article. DNA barcoding for the new species is documented for future use. Descriptions of both male and female of Sperchon rostratus Lundblad, 1969 are given in the present study, and DNA barcoding for identifying S. rostratus is also discussed. PMID- 29118628 TI - Two new species of the rare Neotropical caddisfly genus Amphoropsyche Holzenthal (Trichoptera, Leptoceridae). AB - Two new species in the rare, endemic Neotropical caddisfly genus Amphoropsyche Holzenthal, 1985 are described from Ecuador (A. carchisp. n.) and Peru (A. matsigenkasp. n.) bringing to 17 the number of species known in the genus. Almost all species are known from only a few individuals and from even fewer localities. The new species belong to a group of 10 other species that have tergum X in the male genitalia divided into a mesal process and a pair of lateral processes. Amphoropsyche carchi can be separated from those species by the rounded mesal concavity, the short mesobasal lobe, and the short 2nd article of the inferior appendage, while A. matsigenka can be diagnosed by the very slender and straight inferior appendage, which bears a pair of spine-like mesoventral projections. We also present a new record for Amphoropsyche tandayapa Holzenthal & Razuri Gonzales, 2011, from Ecuador, previously known only from the male holotype. PMID- 29118629 TI - Austromonticola, a new genus of broad-nosed weevil (Coleoptera, Curculionidae, Entiminae) from montane areas of New Zealand. AB - Austromonticolagen. n. is proposed for a group of eight New Zealand alpine broad nosed weevil species, all of which are here described: A. atriariussp. n. (type locality: Umbrella Mountains, Central Otago), A. caelibatussp. n. (type locality: Ohau Range, Mackenzie), A. furcatussp. n. (type locality: Old Man Range, Central Otago), A. inflatussp. n. (type locality: Hawkdun Range, Central Otago), A. planulatussp. n. (type locality: St Marys Range, Central Otago), A. postinventussp. n. (type locality: Kirkliston Range, South Canterbury), A. mataurasp. n. (type locality: Mt Dick, Otago Lakes) and A. rotundussp. n. (type locality: Old Man Range, Central Otago). All species occur exclusively above 1000 m elevation in the mountains of Central Otago and South Canterbury in the South Island. A phylogeny of the genus, including six outgroups, was inferred from 33 morphological characters. It resolved the genus as monophyletic, and revealed two strongly supported clades within Austromonticola. DNA sequences of four gene regions were obtained from five species. Of these, the 3' end of COI proved to be the most suitable for the identification of specimens. Females of all species have diagnostic secondary sexual structures on the elytra and ventrites. These structures are hypothesised to have evolved to assist with oviposition in and beside cushion plants or by selection for structures to mitigate the costs to females of prolonged mating. PMID- 29118630 TI - Herpetofaunal assemblages of a lowland broadleaf forest, an overgrown orchard forest and a lime orchard in Stann Creek, Belize. AB - Understanding and monitoring ecological impacts of the expanding agricultural industry in Belize is an important step in conservation action. To compare possible alterations in herpetofaunal communities due to these anthropogenic changes, trapping arrays were set in a manicured orchard, a reclaimed orchard and a lowland broadleaf forest in Stann Creek district at Toucan Ridge Ecology and Education Society (TREES). Trapping efforts were carried out during the rainy season, from June to September, 2016, during which time the study site was hit by a category one hurricane between sampling sessions. Trapping yielded 197 individual herpetofauna and 40 different species overall; 108 reptile captures (30 species) and 88 amphibian captures (ten species). Reptiles and amphibians were more abundant in the lowland broadleaf forest and the manicured orchard area. Amphibian species diversity was relatively similar in each habitat type. Reptile captures were most diverse in the Overgrown Orchard Forest (OGF) and Overgrown Orchard Riparian Forest (OGR) and least diverse in the Lowland Broadleaf Forest (LBF). The findings of this study suggest that reptile and amphibian sensitivity to anthropogenically altered areas is minimal when enveloped by natural habitat buffers, and additionally, that extreme weather events have little impact on herpetofauna communities in the area. PMID- 29118631 TI - A new genus and species of bristle worm from Beibu Gulf, South China Sea (Annelida, Polychaeta, Amphinomidae). AB - Alleurythoe, a new genus with type species Alleurythoe tenuichaetasp. n., is described and illustrated based on material from Beibu Gulf, northwestern South China Sea. The new genus is distinguished from all genera within Amphinomidae by a combination of characters: caruncle trilobed, conspicuous, attached to and confluent with the posterior prostomial lobe, which is free from the body wall and has 6-7 folds on each of the lateral lobes; both noto- and neuropodial aciculae are spinose, extending beyond the chaetal lobe. Alleurythoe tenuichaetasp. n. is characterized by having branchiae present from chaetiger 4 and a bifurcate neurochaetae capillary. A key distinguishing the genera of Amphinominae is provided. PMID- 29118632 TI - The millipede genus Stemmiulus Gervais, 1844 in Cameroon, with descriptions of three new species (Diplopoda, Stemmiulida, Stemmiulidae). AB - The large pantropical millipede genus Stemmiulus, which currently encompasses more than 150 species, i.e. the bulk of the species diversity of the family Stemmiulidae and entire order Stemmiulida, is shown to comprise seven species in Cameroon, including three new ones: S. ongot Nzoko Fiemapong & VandenSpiegel, sp. n., S. uncus Nzoko Fiemapong & VandenSpiegel, sp. n., and S. mbalmayoensis Nzoko Fiemapong & VandenSpiegel, sp. n. In addition, S. beroni Mauries, 1989, previously known only from the type locality in Nigeria, is recorded from Cameroon for the first time, also being redescribed based on new samples. A key is given to all species of the genus encountered in the country, based on male gonopodal conformation, except for S. camerunensis (Silvestri, 1916), which was described only from female and juvenile material. PMID- 29118634 TI - The collection of birds from Mozambique at the Instituto de Investigacao Cientifica Tropical of the University of Lisbon (Portugal). AB - The Instituto de Investigacao Cientifica Tropical of the University of Lisbon, which resulted from the recent merger (in 2015) of the former state laboratory Instituto de Investigacao Cientifica Tropical in the University of Lisbon, holds an important collection of bird skins from the Portuguese-speaking African Countries (Angola, Mozambique, Sao Tome and Principe, Guinea Bissau and Cape Verde), gathered as a result of several scientific expeditions made during the colonial period. In this paper, the subset from Mozambique is described, which was taxonomically revised and georeferenced. It contains 1585 specimens belonging to 412 taxa, collected between 1932 and 1971, but mainly in 1948 (43% of specimens) and 1955 (30% of specimens). The collection covers all eleven provinces of the country, although areas south of the Zambezi River are better represented than those north of the river. The provinces with the highest number of specimens were Maputo, Sofala, and Gaza. Although it is a relatively small collection with a patchy coverage, it adds significantly to Global Biodiversity Information Facility, with 15% of all records available before and during the collecting period (1830-1971) being the second largest dataset for that period for Mozambique. PMID- 29118635 TI - A new species of Monstrillopsis (Crustacea, Copepoda, Monstrilloida) from the lower Northwest Passage of the Canadian Arctic. AB - A new species of monstrilloid copepod, Monstrillopsis planifronssp. n., is described from an adult female that was collected beneath snow-covered sea ice during the 2014 Ice Covered Ecosystem - CAMbridge bay Process Study (ICE-CAMPS) in Dease Strait of the Canadian Arctic Archipelago. Currently, up to six species of this order are known to occur in polar latitudes. The new species described herein shares similarities with Monstrillopsis dubia (Scott, 1904) but differs in its body proportions and cephalothorax ornamentation; the cephalothorax is covered by minute scattered papillae on dorsal and ventral surfaces; this species has a reduced fifth leg endopod, fifth leg exopod armed with three setae, antennule with fused segments 3-4, and the genital double-somite bears unique posterolateral processes. This is the second species of this genus recorded in the Arctic, after Monstrillopsis ferrarii (Suarez-Morales & Ivanenko, 2004), described from the White Sea, and is the first record of Monstrillopsis in Canadian waters. With the addition of this new species and the recognition of Monstrillopsis bernardensis comb. nov. as a member of this genus, the number of nominal species is now 15. Overall, this genus has a tendency to be distributed in temperate and cold waters, while only three species have been found in tropical and subtropical latitudes. PMID- 29118633 TI - Checklist of the freshwater fishes of Colombia: a Darwin Core alternative to the updating problem. AB - The present work is part of a process to create a Catalogue of the Freshwater Fishes of Colombia and consisted in the depuration and updating of the taxonomic and geographic components of the checklist of the freshwater fishes of Colombia. An exhaustive revision of the 1435 species recorded in 2008 was necessary to: 1. Add new species described since 2009 and species originally described from Colombia but inadvertently omitted in 2008; 2. Add new records of already described species; 3. Delete species whose presence in Colombia was not supported by voucher specimens in ichthyological collections; and 4. Revise the geographic distribution of the species listed in 2008. This process resulted in the following numbers: 1. Total number of freshwater fish species in Colombia: 1494; 2. Number of species recorded by hydrographic region - Amazon: 706, Orinoco: 663, Caribbean: 223, Magdalena-Cauca: 220, Pacific: 130; and 3. Number of endemic species: 374 (76% from the trans-Andean region). Updating the current checklist is a fundamental requirement to ensure its incorporation in the decision-making process with regard to the conservation of Colombian aquatic species and ecosystems, which are facing transformation processes as a result of activities such as mining, construction of hydroelectric plants, expansion of the agricultural frontier and subsequent deforestation, industrial and domestic pollution, development of waterways, introduction of exotic species, and climate change. PMID- 29118636 TI - A study of the genus Paraputo Laing, 1929 of China, with description of two new species (Hemiptera, Sternorrhyncha, Coccomorpha). AB - A study of the genus Paraputo Laing, 1929 (Coccomorpha: Pseudococcidae) from China is provided. Eight Paraputo species are recognized in China, of which two species, P. platanisp. n. and P. yunnanensissp. n., are described as new and P. banzigeri Williams, 2004 is recorded from China for the first time. Two new combinations are introduced, involving transfer of P. citricola Tang, 1992 and P. sinensis Borchsenius, 1962 to the genus Formicococcus Takahashi, 1928. A key to the Paraputo species of China is provided. PMID- 29118637 TI - Revision of the genus Limobius, with the description of a new species (Coleoptera, Curculionidae, Hyperini). AB - The new species, Limobius winkelmannisp. n. is described, keyed, and illustrated. This enigmatic new species has seven desmomeres as other Hyperini-species, but according to shape of elytra and aedeagus, which are typical for representatives of Limobius, it is treated in this genus. The actualised key and check-list of Limobius is presented. The taxonomical position and status of the genus Limobius within the tribe Hyperini is also discussed here. PMID- 29118638 TI - New records of the soldier flies of Morocco with a bibliographical inventory of the North African fauna (Diptera, Stratiomyidae). AB - A checklist of soldier flies species recorded from the North African countries of Morocco, Algeria, Tunisia, Libya, and Egypt is based on both literature records and material newly collected in Morocco. Four subfamilies (Stratiomyinae, Sarginae, Nemotelinae, and Pachygasterinae), and twelve species from five genera have been collected and are recognized in Morocco. Pachygaster atra (Panzer, 1798), Oxycera pardalina (Meigen, 1822), Nemotelus danielssoni (Mason, 1989), and Oxycera terminata (Meigen, 1822) are newly recorded to the North African fauna. Nemotelus atriceps (Loew, 1856) and Nemotelus maculiventris (Bigot, 1861) are reported for the first time in Morocco. The present number of soldier flies known from Morocco is 33. PMID- 29118639 TI - Roa rumsfeldi, a new butterflyfish (Teleostei, Chaetodontidae) from mesophotic coral ecosystems of the Philippines. AB - A new species of the butterflyfish genus Roa is herein described from the Verde Island Passage in the Philippines, West Pacific Ocean. Roa rumsfeldisp. n. was found on mesophotic coral ecosystems at Puerto Galera and Batangas, and sampled through technical mixed-gas rebreather diving at 100-130 m depth. This represents the fifth known species of Roa. The main differences between Roa rumsfeldisp. n. and its congeners are the lower number of pored scales in the lateral line, longer snout, longer caudal peduncle, shorter caudal fin, pelvic fin color (dark first spine vs. white in all other Roa), and genetics (8.4% divergence from its closest relative Roa modesta in the mitochondrial COI gene). Roa spp. are usually seen in pairs, but the two specimens we collected were solitary individuals. We have kept one of the specimens alive in the California Academy of Sciences' Twilight Zone exhibit for more than one year, where it thrives and is feeding on a variety of dried and fresh food. PMID- 29118640 TI - Checklist of the tidal pool fishes of Jeju Island, Korea. AB - Seventy-six species of fishes, representing 60 genera and 34 families, were recorded from tidal pools on Jeju Island, southern Korea. The major families in terms of species were the Gobiidae (11 species), Pomacentridae (8 species), Blenniidae (6 species), and Labridae (5 species). Thirty-nine species were classified as tropical, 26 as temperate and 11 as subtropical. PMID- 29118641 TI - Corrigenda: Jiao TY, Yao QY, Xiao H (2017) Review of Dibrachys Forster from China (Hymenoptera, Chalcidoidea, Pteromalidae). ZooKeys 656: 123-149. AB - [This corrects the article DOI: 10.3897/zookeys.656.11373.]. PMID- 29118642 TI - A new species of Mongolodiaptomus Kiefer, 1938 from northeast Thailand and a key to the species (Crustacea, Copepoda, Calanoida, Diaptomidae). AB - This study describes the new species Mongolodiaptomus loeiensissp. n. collected from a temporary pond nearby a cave located in Loei Province, in northeastern Thailand. Mongolodiaptomus loeiensissp. n. is similar to M. calcarus (Shen & Tai, 1965) in the male but can be distinguished from its congeners by the following unique characteristics in the males: (1) the right caudal ramus has 3 ventral chitinous prominences; (2) intercoxal plate of P5 is produced into 2 spine-like lobes on distal margin; (3) the basis of right P5 has a subglobular chitinous prominence on mid-distal caudal surface; and (4) the principal lateral spine on the right Exp-2 P5 is extremely bent at its tip. The occurrence of diaptomid copepods in the study area is discussed and an identification key to worldwide species of the genus Mongolodiaptomus Kiefer, 1938 is presented herein. PMID- 29118643 TI - An Early Miocene bumble bee from northern Bohemia (Hymenoptera, Apidae). AB - A new species of fossil bumble bee (Apinae: Bombini) is described and figured from Early Miocene (Burdigalian) deposits of the Most Basin at the Bilina Mine, Czech Republic. Bombus trophoniussp. n., is placed within the subgenus Cullumanobombus Vogt and distinguished from the several species groups therein. The species is apparently most similar to the Nearctic B. (Cullumanobombus) rufocinctus Cresson, the earliest-diverging species within the clade and the two may be related only by symplesiomorphies. The age of the fossil is in rough accordance with divergence estimations for Cullumanobombus. PMID- 29118644 TI - Morphology of the limbs in the semi-fossorial desert rodent species of Tympanoctomys (Octodontidae, Rodentia). AB - Here, a detailed description of the forelimbs and hindlimbs of all living species of the genus Tympanoctomys are presented. These rodents, highly adapted to desert environments, are semi-fossorial with capacity to move on the surface as well as to build burrows. The shape, structure, and size of the limbs are described. Contrary to what was expected for scratch digging semi-fossorial species, Tympanoctomys have slender humerus, radius and ulna; with narrow epicondyles of the humerus and short olecranon of the ulna with poorly developed processes. Following our descriptions, no intrageneric morphological variation regarding to the configuration of the limbs was detected, probably due to phylogenetic proximity, and not related to specific variations in response to different use of substrates or habits. The obtained results constitute a source of previously unpublished information as well as an important base for future analysis in different studies, such as morphometric, morpho-functional, or phylogenetic researches. PMID- 29118645 TI - New species of Ipomoea (Convolvulaceae) from South America. AB - The importance of discovering, describing and cataloguing poorly known species in herbarium collections is discussed. It is a spur to efforts at rediscovery and consequent conservation efforts. The problems faced in describing species from limited material are discussed and our methods and criteria in making a decision are described. Prospects for future novelties are briefly assessed. Fifteen new species are described and illustrated with line drawings and distribution maps: Ipomoea attenuata J.R.I. Wood & Scotland, I. cuscoensis J.R.I. Wood & P. Munoz, I. dasycarpa J.R.I. Wood & Scotland, I. dolichopoda J.R.I. Wood & R. Degen, I. ensiformis J.R.I.Wood & Scotland, I. fasciculata J.R.I. Wood & Scotland, I. graminifolia J.R.I. Wood & Scotland, I. kraholandica J.R.I. Wood & Scotland, I. longirostra J.R.I. Wood & Scotland, I. revoluta J.R.I. Wood & Scotland, I. scopulina J.R.I. Wood &. Scotland, I. uninervis J.R.I. Wood & Scotland, I. veadeirosii J.R.I. Wood & Scotland, I. velutinifolia J.R.I. Wood & Scotland, I. walteri J.R.I. Wood & Scotland. All species are narrow endemics except I. velutinifolia which is found in Brazil and Peru; of the others, 12 are found in Brazil and one each in Paraguay and Peru. PMID- 29118646 TI - Epilithic diatom communities of selected streams from the Lerma-Chapala Basin, Central Mexico, with the description of two new species. AB - The Lerma-Chapala Basin, in Central Mexico, is geologically heterogeneous, climatically diverse and boasts high biodiversity, lying within two Biodiversity Hotspots, namely Mesoamerica and the Madrean Pine-Oak Woodlands. Epilithon and water samples were collected in the basin from 14 sampling sites three times each, two sampling campaigns during the rainy season and one in the dry season. A total of 274 infrageneric taxa in 48 genera were recorded. The taxonomic composition observed was dominated by taxa from the genera Nitzschia, Gomphonema, Pinnularia, Navicula, Sellaphora and Eunotia. About a third of the taxa found could not be identified to the species level. From those unidentified morphodemes, two are described as new species, namely Brachysira altepetlensis and Sellaphora queretana. Furthermore, Eolimna rhombica is transferred to Sellaphora. Canonical Correspondence Analysis (CCA) revealed that specific conductivity and pH were the main environmental factors driving the community composition observed. Three groups of samples were identified after the CCA: 1) characterized by acidic waters and low conductivity; 2) with circumneutral waters, low specific conductivity and high temperature and phosphorous concentrations; and 3) characterized by circumneutral waters, high conductivity and low nitrogen concentrations. The indicator value method (IndVal), based on the relative abundance and relative frequency of the most abundant taxa was calculated based on the groups observed in the CCA, identifying the characteristic taxa for each of the three groups. PMID- 29118647 TI - The Mosses of Crocker Range Park, Malaysian Borneo. AB - This paper reports the mosses from Crocker Range Park (CRP) in Sabah, Malaysian Borneo. In total, 293 species, three subspecies and eight varieties belonging to 118 genera and 36 families are reported. This represents about 40% and 47% of the species and infra-specific taxa reported from Borneo and Sabah, respectively. Out of these, six species are new records for Borneo, namely Barbella horridula, Chaetomitrium lancifolium, Distichophyllum leiopogon, Rhaphidostichum luzonense, Rosulabryum capillare and Taxiphyllum taxirameum and 12 species and one variety are new to Sabah. With these additions, the current number of mosses in Sabah and Borneo are 651 and 766, respectively. The largest family of mosses is Calymperaceae with 35 species and one subspecies, followed by Sematophyllaceae with 32 species and two varieties and Pylaisiadelphaceae with 21 species and one variety. In conclusion, CRP has a very high species richness of mosses which is the second highest in Borneo, after Mount Kinabalu. PMID- 29118648 TI - Data Release: DNA barcodes of plant species collected for the Global Genome Initiative for Gardens Program, National Museum of Natural History, Smithsonian Institution. AB - The Global Genome Initiative has sequenced and released 1961 DNA barcodes for genetic samples obtained as part of the Global Genome Initiative for Gardens Program. The dataset includes barcodes for 29 plant families and 309 genera that did not have sequences flagged as barcodes in GenBank and sequences from officially recognized barcoding genetic markers meet the data standard of the Consortium for the Barcode of Life. The genetic samples were deposited in the Smithsonian Institution's National Museum of Natural History Biorepository and their records were made public through the Global Genome Biodiversity Network's portal. The DNA barcodes are now available on GenBank. PMID- 29118649 TI - Morphological phylogeny of Tradescantia L. (Commelinaceae) sheds light on a new infrageneric classification for the genus and novelties on the systematics of subtribe Tradescantiinae. AB - Throughout the years, three infrageneric classifications were proposed for Tradescantia along with several informal groups and species complexes. The current infrageneric classification accepts 12 sections - with T. sect. Tradescantia being further divided into four series - and assimilates many concepts adopted by previous authors. Recent molecular-based phylogenetic studies indicate that the currently accepted sections might not represent monophyletic groups within Tradescantia. Based on newly gathered morphological data on the group, complemented with available micromorphological, cytological and phytochemical data, I present the first morphology-based evolutionary hypothesis for Tradescantia. Furthermore, I reduce subtribe Thyrsantheminae to a synonym of subtribe Tradescantiinae, and propose a new infrageneric classification for Tradescantia, based on the total evidence of the present morphological phylogeny, in accordance to the previously published molecular data. PMID- 29118650 TI - A new species of Raputia (Rutaceae) from the Selva Central of Peru. AB - Raputia codo-pozuzoensis Rob. Fernandez & Arteaga, sp. nov. (Galipeinae, Rutaceae), a new species endemic to the Huanuco region, in the Selva Central of Peru, is described and illustrated here. The new species differs from other species of Raputia by the combination of 5-7-foliolate leaves (a new characteristic for the genus) and longer petioles. A key to the four Peruvian species of Raputia is presented. PMID- 29118651 TI - Asplenium merapohense (Aspleniaceae), a new species from the Peninsular Malaysia. AB - A new species of Asplenium is described from two collections made on limestone hills in Peninsular Malaysia. Conspicuous by its extremely narrow pinnae, it is probably allied to A. salignum but differs in sufficient characters (scale size, size and shape of lamina, venation and sorus length, position and orientation) to be a species in its own right. PMID- 29118652 TI - Isoetes nana, a new species from the coastal mountains of southeastern Brazil. AB - Isoetes nana, a new species from the coastal mountains of southeastern Brazil (Serra de Itatiaia), is described, illustrated and compared to similar species. This species can be distinguished from similar species by a set of characters that include 5-15 small erect leaves reaching only up to 3.5cm long, megaspores rugulate (rarely laevigate or obscurely cristate) and microspores sparsely echinate. We include a key to identify this new species and spore images for all species that are discussed in this study. Isoetes nana is known only from the type locality, where it was reported to occur in small ponds on rocky outcrops at high elevations. We suggest it should be classified as a data deficient species based on the IUCN criteria. PMID- 29118654 TI - Overview of PacELF-the Pacific Programme for the Elimination of Lymphatic Filariasis. PMID- 29118653 TI - A combined human case of Dirofilaria ursi infection in dorsal subcutaneous tissue and Anisakis simplex sensu stricto (s.s.) infection in ventral subcutaneous tissue. AB - Background: Dirofilaria ursi is a filarial nematode that parasitizes the subcutaneous tissues of the American black bear (Ursus americanus) and Japanese black bear (Ursus thiabetanus japonicus). D. ursi that has parasitized black bears has the potential to subsequently infect humans. In addition, extra gastrointestinal anisakiasis is less common in Japan. Case presentation: We report a case of ventral subcutaneous anisakiasis and dorsal subcutaneous dirofilariasis that was acquired in Fukushima, in the northern part of Japan. The patient was an 83-year-old Japanese female, and subcutaneous parasitic granulomas were present on her left abdomen (near the navel) and left scapula. A pathological examination of the surgically dissected tissue sections from each region demonstrated eosinophilic granulomas containing different species of parasites. To enable the morphological and molecular identification of these parasites, DNA was extracted from paraffin-embedded sections using DEXPAT reagent, and the cytochrome oxidase 2 (COX2), internal transcribed spacer 1 (ITS1), 5.8S and ITS2 regions of the Anisakis larvae, and the 5S rRNA region of the male Dirofilaria were sequenced. The PCR products were examined and compared with DNA databases. Molecular analysis of the COX2 and 5S rRNA sequences of each worm revealed that the nematode found in the ventral region belonged to Anisakis simplex sensu stricto (s.s.) and the male Dirofilaria found in the dorsal region was classified as D. ursi. Conclusion: The present case showed a combined human case of D. ursi and A. simplex s.s. infections in subcutaneous tissues. The results of this study will contribute to the identification of unknown parasites in histological sections. PMID- 29118655 TI - The burden of dengue, source reduction measures, and serotype patterns in Myanmar, 2011 to 2015-R2. AB - Background: Myanmar is currently classified as a high burden dengue country in the Asian Pacific region. The Myanmar vector-borne diseases control (VBDC) program has collected data on dengue and source reduction measures since 1970, and there is a pressing need to collate, analyze, and interpret this information. The aim of this study was to describe the burden of hospital-based dengue disease, dengue control measures, and serotype patterns in Myanmar between 2011 and 2015. Methods: This was a cross-sectional study using annual records from the Dengue Fever/Dengue Hemorrhagic Fever Prevention and Control Project in Myanmar. Results: Between 2011 and 2015, there were a total of 89,832 cases and 393 deaths in hospitals, with 97% of cases being in children. In 2013 and 2015, there was an increased number of cases, respectively at 21,942 and 42,913, while during the other 3 years, numbers ranged from 4738 to 13,806. The distribution of dengue deaths each year mirrored the distribution of cases. Most cases (84%) occurred in the wet season and 54% occurred in the delta/lowlands. Case fatality rate (CFR) was highest in 2014 at 7 per 1000 dengue cases, while in the other years, it ranged from 3 to 5 per 1000 cases. High CFR per 1000 were also observed in infants < 1 year (CFR = 8), adults >= 15 years (CFR = 7), those with disease severity grade IV (CFR = 17), and those residing in hilly regions (CFR = 9). Implementation and coverage of dengue source reduction measures, including larval control, space spraying, and health education, all increased between 2012 and 2015, although there was low coverage of these interventions in households and schools and for water containers. In the 2013 outbreak, dengue virus serotype 1 predominated, while in the 2015 outbreak, serotypes 1, 2, and 4 were those mainly in circulation. Conclusion: Dengue is a serious public health disease burden in Myanmar. More attention is needed to improve monitoring, recording, and reporting of cases, deaths, and vector control activities, and more investment is needed for programmatic research. PMID- 29118656 TI - 'A matter of commonsense': the Coventry poliomyelitis epidemic 1957 and the British public. AB - In 1956, the British Ministry of Health instituted a vaccination programme against poliomyelitis, but run into myriad supply and administrative issues. When Coventry experienced an epidemic in 1957, it came to symbolise these problems. Throughout, it was claimed that the government lacked 'common sense'. This article explores how and why 'common sense' was used as a rhetorical weapon in the debates over policy at the local and national level. While those claiming 'common sense' were often at odds with medical and administrative authorities, the arguments were often informed by deeply held beliefs about vaccination and disease. PMID- 29118657 TI - Critical ignition conditions in exothermically reacting systems: first-order reactions. AB - In this paper, the comparative analysis of the thermal explosion (TE) critical conditions on the planes temperature-conversion degree and temperature-time was conducted. It was established that the ignition criteria are almost identical only at relatively small values of Todes parameter. Otherwise, the results of critical conditions analysis on the plane temperature-conversion degree may be wrong. The asymptotic method of critical conditions calculation for the first order reactions was proposed (taking into account the reactant consumption). The degeneration conditions of TE were determined. The calculation of critical conditions for specific first-order reaction was made. The comparison of the analytical results obtained with the results of numerical calculations and experimental data showed that they are in good agreement. PMID- 29118658 TI - Extended lubrication theory: improved estimates of flow in channels with variable geometry. AB - Lubrication theory is broadly applicable to the flow characterization of thin fluid films and the motion of particles near surfaces. We offer an extension to lubrication theory by starting with Stokes equations and considering higher-order terms in a systematic perturbation expansion to describe the fluid flow in a channel with features of a modest aspect ratio. Experimental results qualitatively confirm the higher-order analytical solutions, while numerical results are in very good agreement with the higher-order analytical results. We show that the extended lubrication theory is a robust tool for an accurate estimate of pressure drop in channels with shape changes on the order of the channel height, accounting for both smooth and sharp changes in geometry. PMID- 29118659 TI - Modelling wave-induced sea ice break-up in the marginal ice zone. AB - A model of ice floe break-up under ocean wave forcing in the marginal ice zone (MIZ) is proposed to investigate how floe size distribution (FSD) evolves under repeated wave break-up events. A three-dimensional linear model of ocean wave scattering by a finite array of compliant circular ice floes is coupled to a flexural failure model, which breaks a floe into two floes provided the two dimensional stress field satisfies a break-up criterion. A closed-feedback loop algorithm is devised, which (i) solves the wave-scattering problem for a given FSD under time-harmonic plane wave forcing, (ii) computes the stress field in all the floes, (iii) fractures the floes satisfying the break-up criterion, and (iv) generates an updated FSD, initializing the geometry for the next iteration of the loop. The FSD after 50 break-up events is unimodal and near normal, or bimodal, suggesting waves alone do not govern the power law observed in some field studies. Multiple scattering is found to enhance break-up for long waves and thin ice, but to reduce break-up for short waves and thick ice. A break-up front marches forward in the latter regime, as wave-induced fracture weakens the ice cover, allowing waves to travel deeper into the MIZ. PMID- 29118660 TI - On three-dimensional misorientation spaces. AB - Determining the local orientation of crystals in engineering and geological materials has become routine with the advent of modern crystallographic mapping techniques. These techniques enable many thousands of orientation measurements to be made, directing attention towards how such orientation data are best studied. Here, we provide a guide to the visualization of misorientation data in three dimensional vector spaces, reduced by crystal symmetry, to reveal crystallographic orientation relationships. Domains for all point group symmetries are presented and an analysis methodology is developed and applied to identify crystallographic relationships, indicated by clusters in the misorientation space, in examples from materials science and geology. This analysis aids the determination of active deformation mechanisms and evaluation of cluster centres and spread enables more accurate description of transformation processes supporting arguments regarding provenance. PMID- 29118661 TI - A Fokker-Planck reaction model for the epitaxial growth and shape transition of quantum dots. AB - We construct a Fokker-Planck reaction (FPR) model to investigate the dynamics of the coupled epitaxial growth and shape transition process of an array of quantum dots (QDs). The FPR model is based on a coupled system of Fokker-Planck equations wherein the distribution of each island type is governed by its own Fokker-Planck equation for growth, with reaction terms describing the shape transitions between islands of different types including asymmetric shapes. The reaction terms for the shape transitions depend on the island size and are determined from explicit calculations of the lowest barrier pathway for each shape transition. This mean field model enables us to consider the kinetics of asymmetric shape transitions and study the evolution of island shape distributions during the coupled growth and transition process. Asymmetric metastable shapes play a crucial role in the dynamics, with asymmetric QDs comprising up to 10% of the population, and with up to 100% of the shape transitions passing through asymmetric shapes. Moreover, we find that the characteristic multimodal distribution of pyramid/dome QD coarsening can be eliminated at sufficiently high temperature and deposition rate. PMID- 29118662 TI - Indentation of a floating elastic sheet: geometry versus applied tension. AB - The localized loading of an elastic sheet floating on a liquid bath occurs at scales from a frog sitting on a lily pad to a volcano supported by the Earth's tectonic plates. The load is supported by a combination of the stresses within the sheet (which may include applied tensions from, for example, surface tension) and the hydrostatic pressure in the liquid. At the same time, the sheet deforms, and may wrinkle, because of the load. We study this problem in terms of the (relatively weak) applied tension and the indentation depth. For small indentation depths, we find that the force-indentation curve is linear with a stiffness that we characterize in terms of the applied tension and bending stiffness of the sheet. At larger indentations, the force-indentation curve becomes nonlinear and the sheet is subject to a wrinkling instability. We study this wrinkling instability close to the buckling threshold and calculate both the number of wrinkles at onset and the indentation depth at onset, comparing our theoretical results with experiments. Finally, we contrast our results with those previously reported for very thin, highly bendable membranes. PMID- 29118663 TI - Nonlinear mechanics of non-rigid origami: an efficient computational approach. AB - Origami-inspired designs possess attractive applications to science and engineering (e.g. deployable, self-assembling, adaptable systems). The special geometric arrangement of panels and creases gives rise to unique mechanical properties of origami, such as reconfigurability, making origami designs well suited for tunable structures. Although often being ignored, origami structures exhibit additional soft modes beyond rigid folding due to the flexibility of thin sheets that further influence their behaviour. Actual behaviour of origami structures usually involves significant geometric nonlinearity, which amplifies the influence of additional soft modes. To investigate the nonlinear mechanics of origami structures with deformable panels, we present a structural engineering approach for simulating the nonlinear response of non-rigid origami structures. In this paper, we propose a fully nonlinear, displacement-based implicit formulation for performing static/quasi-static analyses of non-rigid origami structures based on 'bar-and-hinge' models. The formulation itself leads to an efficient and robust numerical implementation. Agreement between real models and numerical simulations demonstrates the ability of the proposed approach to capture key features of origami behaviour. PMID- 29118664 TI - Kinematic dynamos in spheroidal geometries. AB - The kinematic dynamo problem is solved numerically for a spheroidal conducting fluid of possibly large aspect ratio with an insulating exterior. The solution method uses solenoidal representations of the magnetic field and the velocity by spheroidal toroidal and poloidal fields in a non-orthogonal coordinate system. Scaling of coordinates and fields to a spherical geometry leads to a modified form of the kinematic dynamo problem with a geometric anisotropic diffusion and an anisotropic current-free condition in the exterior, which is solved explicitly. The scaling allows the use of well-developed spherical harmonic techniques in angle. Dynamo solutions are found for three axisymmetric flows in oblate spheroids with semi-axis ratios 1<=a/c<=25. For larger aspect ratios strong magnetic fields may occur in any region of the spheroid, depending on the flow, but the external fields for all three flows are weak and concentrated near the axis or periphery of the spheroid. PMID- 29118666 TI - The motion of a vortex on a closed surface of constant negative curvature. AB - The purpose of this work is to present an algorithm to determine the motion of a single hydrodynamic vortex on a closed surface of constant curvature and of genus greater than one. The algorithm is based on a relation between the Laplace Beltrami Green function and the heat kernel. The algorithm is used to compute the motion of a vortex on the Bolza surface. This is the first determination of the orbits of a vortex on a closed surface of genus greater than one. The numerical results show that all the 46 vortex equilibria can be explicitly computed using the symmetries of the Bolza surface. Some of these equilibria allow for the construction of the first two examples of infinite vortex crystals on the hyperbolic disc. The following theorem is proved: 'a Weierstrass point of a hyperellitic surface of constant curvature is always a vortex equilibrium'. PMID- 29118665 TI - Nonlinear graphene plasmonics. AB - The rapid development of graphene has opened up exciting new fields in graphene plasmonics and nonlinear optics. Graphene's unique two-dimensional band structure provides extraordinary linear and nonlinear optical properties, which have led to extreme optical confinement in graphene plasmonics and ultrahigh nonlinear optical coefficients, respectively. The synergy between graphene's linear and nonlinear optical properties gave rise to nonlinear graphene plasmonics, which greatly augments graphene-based nonlinear device performance beyond a billion fold. This nascent field of research will eventually find far-reaching revolutionary technological applications that require device miniaturization, low power consumption and a broad range of operating wavelengths approaching the far infrared, such as optical computing, medical instrumentation and security applications. PMID- 29118667 TI - Twistor theory at fifty: from contour integrals to twistor strings. AB - We review aspects of twistor theory, its aims and achievements spanning the last five decades. In the twistor approach, space-time is secondary with events being derived objects that correspond to compact holomorphic curves in a complex threefold-the twistor space. After giving an elementary construction of this space, we demonstrate how solutions to linear and nonlinear equations of mathematical physics-anti-self-duality equations on Yang-Mills or conformal curvature-can be encoded into twistor cohomology. These twistor correspondences yield explicit examples of Yang-Mills and gravitational instantons, which we review. They also underlie the twistor approach to integrability: the solitonic systems arise as symmetry reductions of anti-self-dual (ASD) Yang-Mills equations, and Einstein-Weyl dispersionless systems are reductions of ASD conformal equations. We then review the holomorphic string theories in twistor and ambitwistor spaces, and explain how these theories give rise to remarkable new formulae for the computation of quantum scattering amplitudes. Finally, we discuss the Newtonian limit of twistor theory and its possible role in Penrose's proposal for a role of gravity in quantum collapse of a wave function. PMID- 29118668 TI - A bioinspired study on the compressive resistance of helicoidal fibre structures. AB - Helicoidal fibre structures are widely observed in natural materials. In this paper, an integrated experimental and analytical approach was used to investigate the compressive resistance of helicoidal fibre structures. First, helicoidal fibre-reinforced composites were created using three-dimensionally printed helicoids and polymeric matrices, including plain, ring-reinforced and helix reinforced helicoids. Then, load-displacement curves under monotonic compression tests were collected to measure the compressive strengths of helicoidal fibre composites. Fractographic characterization was performed using an X-ray microtomographer and scanning electron microscope, through which crack propagations in helicoidal structures were illustrated. Finally, mathematical modelling was performed to reveal the essential fibre architectures in the compressive resistance of helicoidal fibre structures. This work reveals that fibre-matrix ratios, helix pitch angles and interlayer rotary angles are critical to the compressive resistance of helicoidal structures. PMID- 29118669 TI - Glomangiomyoma of the neck in a child in Nepal: a rare case report and literature review. AB - Background: Glomangiomyoma is a rare histological variant of glomus tumour. Clinically, it mimicks as a haemangioma and is challenging to diagnose. Its occurrence in the neck of a child has not been previously described. Case presentation: A 3 year old girl presented with the complaints of painless progressive neck swelling in the right side for one and half year. Sonography, computed tomography (CT), magnetic resonance imaging (MRI), CT neck angiography and fine needle aspiration cytology (FNAC) were suggestive of vacular malformation i.e. giant haemangioma or arteriovenous malformation. The mass was removed in toto under general anaesthesia without postoperative complications. The histopathology confirmed it to be glomangiomyoma with haemangiopericytoma like features. Conclusion: It's an extremely rare variant of glomus tumour and may be the first report of a glomangiomyoma in the neck of a child. Despite a rare entity, it should be borne in mind during differential diagnosis. PMID- 29118670 TI - An overview of the role of platelets in angiogenesis, apoptosis and autophagy in chronic myeloid leukaemia. AB - Amongst males, leukaemia is the most common cause of cancer-related death in individuals younger than 40 years of age whereas in female children and adolescents, leukaemia is the most common cause of cancer-related death. Chronic myeloid leukaemia (CML) is a chronic leukaemia of the haematopoietic stem cells affecting mostly adults. The disease results from a translocation of the Philadelphia chromosome in stem cells of the bone marrow. CML patients usually present with mild to moderate anaemia and with decreased, normal, or increased platelet counts. CML represents 0.5% of all new cancer cases in the United States (2016). In 2016, an estimated 1070 people would die of this disease in the United States. Platelets serve as a means for tumours to increase growth and to provide physical- and mechanical support to elude the immune system and to metastasize. Currently there is no literature available on the role that platelets play in CML progression, despite literature reporting the fact that platelet count and size are affected. Resistance to CML treatment with tyrosine kinase inhibitors can be as a result of acquired resistance ensuing from mutations in the tyrosine kinase domains, loss of response or poor tolerance. In CML this resistance has recently become linked to bone marrow (BM) angiogenesis which aids in the growth and survival of leukaemia cells. The discovery of the lungs as a site of haematopoietic progenitors, suggests that CML resistance is not localized to the bone marrow and that the mutations leading to the disease and resistance to treatment may also occur in the haematopoietic progenitors in the lungs. In conclusion, platelets are significantly affected during CML progression and treatment. Investigation into the role that platelets play in CML progression is vital including how treatment affects the cell death mechanisms of platelets. PMID- 29118672 TI - Correction to: The role of ppargamma and autophagy in ros production, lipid droplets biogenesis and its involvement with colorectal cancer cells modulation. AB - [This corrects the article DOI: 10.1186/s12935-017-0451-5.]. PMID- 29118671 TI - miR-422a inhibits cell proliferation in colorectal cancer by targeting AKT1 and MAPK1. AB - Background: miRNAs are regarded as molecular biomarkers and therapeutic targets for colorectal cancer (CRC), a series of miRNAs have been proven to involve into CRC carcinogenesis, invasion and metastasis. Aberrant miR-422a expression and its roles have been reported in some cancers. However, the function and underlying mechanism of miR-422a in the progression of CRC remain largely unknown. Methods: Real-time PCR were used to quantify miR-422a expression in CRC tissues. Both vivo and vitro functional assays showed miR-422a inhibits CRC cell proliferation. Target prediction program (miRBase) and luciferase reporter assays were conducted to confirm the target genes AKT1 and MAPK1 of miR-422a. Specimens from 50 patients with CRC were analyzed for the correlation between the expression of miR 422a and the expression of the target genes AKT1 and MAPK1 by real-time PCR. Results: MiR-422a was down-regulated in CRC tissues and cell lines. Ectopic expression of miR-422a inhibited cell proliferation and tumor growth ability; inhibition of endogenous miR-422a, by contrast, promoted cell proliferation and tumor growth ability of CRC cells. MiR-422a directly targets 3'-UTR of the AKT1 and MAPK1, down-regulation of miR-422a led to the activation of Raf/MEK/ERK and PI3K/AKT signaling pathways to promote cell proliferation in CRC. In addition, miR-422a expression was negatively correlated with the expressions of AKT1 and MAPK1 in CRC tissues. Conclusion: miR-422a inhibits cell proliferation in colorectal cancer by targeting AKT1 and MAPK1. PMID- 29118673 TI - MiR-20a-5p represses the multi-drug resistance of osteosarcoma by targeting the SDC2 gene. AB - Background: As one of the hallmarks of cancer, chemoresistance hinders curative cancer chemotherapy in osteosarcoma (OS). MicroRNAs (miRNAs) act as key regulators of gene expression in diverse biological processes including the multi chemoresistance of cancers. Methods: Based on the CCK8 experiments, we performed an RNA-seq-based miR-omic analysis of osteosarcoma (OS) cells (a multi chemosensitive OS cell line G-292 and a multi-chemoresistant OS cell line SJSA-1) to detect the levels of miR-20a-5p. We predicted Homo sapiens syndecan 2 (SDC2) as one of the target genes of miR-20a-5p via several websites, which was further validated by detecting their expression of both mRNA and protein level in both the miR-20a-5p-mimic transfected G-292 and miR-20a-5p-antagomiR transfected SJSA 1 cells. The involvement of SDC2 with OS chemoresistance was checked by siRNA mediated repression or overexpression of SDC2 gene. Cell viability was assessed by CCK8 assay. Results: We found that the miR-20a-5p level was higher in G-292 cells than in SJSA-1 cells. Forced expression of miR-20a-5p counteracted OS chemoresistance in both cell culture and tumor xenografts in nude mice. As one of miR-20a-5p's targets, SDC2 was found to mediate the miR-20a-5p-induced repression of OS chemoresistance. Conclusions: Our results suggest that miR-20a-5p and SDC2 contribute to OS chemoresistance. The key players in the miR-20a-5p/SDC2 axis may be a potential diagnostic biomarker and therapeutic target for OS patients. PMID- 29118674 TI - High frequency of IgE sensitization towards kiwi seed storage proteins among peanut allergic individuals also reporting allergy to kiwi. AB - Background: IgE sensitization to storage proteins from nuts and seed is often related to severe allergic symptoms. There is a risk of immunological IgE cross reactivity between storage proteins from different species. The potential clinical implication of such cross-reactivity is that allergens other than the known sensitizer can cause allergic symptoms. Previous studies have suggested that kiwi seed storage proteins may constitute hidden food allergens causing cross-reactive IgE-binding with peanut and other tree nut homologs, thereby mediating a potential risk of causing allergy symptoms among peanut ant tree nut allergic individuals. The objective of this study was to investigate the degree of sensitization towards kiwi fruit seed storage proteins in a cohort of peanut allergic individuals. Methods: A cohort of 59 adolescents and adults with peanut allergy was studied, and self reported allergies to a number of additional foods were collected. Quantitative IgE measurements to seed storage proteins from kiwi and peanut were performed. Results: In the cohort, 23 out of the 59 individuals were reporting kiwi fruit allergy (39%). The frequency of IgE sensitization to kiwi fruit and to any kiwi seed storage protein was higher among peanut allergic individuals also reporting kiwi fruit allergy (P = 0.0001 and P = 0.01). A positive relationship was found between IgE levels to 11S globulin (r = 0.65) and 7S globulin (r = 0.48) allergens from kiwi and peanut, but IgE levels to 2S albumin homologs did not correlate. Patients reporting kiwi fruit allergy also reported allergy to hazelnut (P = 0.015), soy (P < 0.0001), pea (P = 0.0002) and almond (P = 0.016) to a higher extent than peanut allergic individuals without kiwi allergy. Conclusions: Thirty-nine percent of the peanut allergic patients in this cohort also reported kiwi fruit allergy, they displayed a higher degree of sensitization to kiwi storage proteins from both kiwi and peanut, and they also reported a higher extent of allergy to other nuts and legumes. On the molecular level, there was a correlation between IgE levels to 11S and 7S storage proteins from kiwi and peanut. Taken together, reported symptoms and serological findings to kiwi in this cohort of patients with concurrent allergy to peanut and kiwi fruit, could be explained by a combination of cross-reactivity between the 11S and 7S globulins and co-sensitization to the 2S albumin Act d 13. PMID- 29118675 TI - Selecting optimal second-generation antihistamines for allergic rhinitis and urticaria in Asia. AB - Background: Allergic diseases are on the rise in many parts of the world, including the Asia-Pacific (APAC) region. Second-generation antihistamines are the first-line treatment option in the management of allergic rhinitis and urticaria. International guidelines describe the management of these conditions; however, clinicians perceive the additional need to tailor treatment according to patient profiles. This study serves as a consensus of experts from several countries in APAC (Hong Kong, Malaysia, the Philippines, Singapore, Thailand, Vietnam), which aims to describe the unmet needs, practical considerations, challenges, and key decision factors when determining optimal second-generation antihistamines for patients with allergic rhinitis and/or urticaria. Methods: Specialists from allergology, dermatology, and otorhinolaryngology were surveyed on practical considerations and key decision points when treating patients with allergic rhinitis and/or urticaria. Results: Clinicians felt the need for additional tools for diagnosis of these diseases and a single drug with all preferred features of an antihistamine. Challenges in treatment include lack of clinician and patient awareness and compliance, financial constraints, and treatment for special patient populations such as those with concomitant disease. Selection of optimal second-generation antihistamines depends on many factors, particularly drug safety and efficacy, impact on psychomotor abilities, and sedation. Country-specific considerations include drug availability and cost effectiveness. Survey results reveal bilastine as a preferred choice due to its high efficacy and safety, suitability for special patient populations, and the lack of sedative effects. Conclusions: Compliance to the international guidelines is present among allergists, dermatologists and otorhinolaryngologists; however, this is lower amongst general practitioners (GPs). To increase awareness, allergy education programs targeted at GPs and patients may be beneficial. Updates to the existing international guidelines are suggested in APAC to reflect appropriate management for different patient profiles and varying symptoms of allergic rhinitis and urticaria. PMID- 29118677 TI - Article Watch: December 2017. AB - This column highlights recently published articles that are of interest to the readership of this publication. We encourage ABRF members to forward information on articles they feel are important and useful to Clive Slaughter, MCG-UGA Medical Partnership, 1425 Prince Ave., Athens, GA 30606, USA. Tel: (706) 713 2216; Fax: (706) 713-2221; E-mail: cslaught@uga.edu, or to any member of the editorial board. Article summaries reflect the reviewer's opinions and not necessarily those of the association. PMID- 29118678 TI - Cerebellum Tissue Segmentation with Ensemble Sparse Learning. PMID- 29118676 TI - Host responses to concurrent combined injuries in non-human primates. AB - Background: Multi-organ failure (MOF) following trauma remains a significant cause of morbidity and mortality related to a poorly understood abnormal inflammatory response. We characterized the inflammatory response in a non-human primate soft tissue injury and closed abdomen hemorrhage and sepsis model developed to assess realistic injury patterns and induce MOF. Methods: Adult male Mauritan Cynomolgus Macaques underwent laparoscopy to create a cecal perforation and non-anatomic liver resection along with a full-thickness flank soft tissue injury. Treatment consisted of a pre-hospital phase followed by a hospital phase after 120 minutes. Blood counts, chemistries, and cytokines/chemokines were measured throughout the study. Lung tissue inflammation/apoptosis was confirmed by mRNA quantitative real-time PCR (qPCR), H&E, myeloperoxidase (MPO) and TUNEL staining was performed comparing age-matched uninjured controls to experimental animals. Results: Twenty-one animals underwent the protocol. Mean percent hepatectomy was 64.4 +/- 5.6; percent blood loss was 69.0 +/- 12.1. Clinical evidence of end-organ damage was reflected by a significant elevation in creatinine (1.1 +/- 0.03 vs. 1.9 +/- 0.4, p=0.026). Significant increases in systemic levels of IL-10, IL-1ra, IL-6, G-CSF, and MCP-1 occurred (11-2986-fold) by 240 minutes. Excessive pulmonary inflammation was evidenced by alveolar edema, congestion, and wall thickening (H&E staining). Concordantly, amplified accumulation of MPO leukocytes and significant pulmonary inflammation and pneumocyte apoptosis (TUNEL) was confirmed using qRT-PCR. Conclusion: We created a clinically relevant large animal multi-trauma model using laparoscopy that resulted in a significant systemic inflammatory response and MOF. With this model, we anticipate studying systemic inflammation and testing innovative therapeutic options. PMID- 29118679 TI - An Electronic Health Record Data-driven Model for Identifying Older Adults at Risk of Unintentional Falls. AB - Screening for risk of unintentional falls remains low in the primary care setting because of the time constraints of brief office visits. National studies suggest that physicians caring for older adults provide recommended fall risk screening only 30 to 37 percent of the time. Given prior success in developing methods for repurposing electronic health record data for the identification of fall risk, this study involves building a model in which electronic health record data could be applied for use in clinical decision support to bolster screening by proactively identifying patients for whom screening would be beneficial and targeting efforts specifically to those patients. The final model, consisting of priority and extended measures, demonstrates moderate discriminatory power, indicating that it could prove useful in a clinical setting for identifying patients at risk of falls. Focus group discussions reveal important contextual issues involving the use of fall-related data and provide direction for the development of health systems-level innovations for the use of electronic health record data for fall risk identification. PMID- 29118680 TI - Mapping of Standards to Facilitate Immunization Information Exchange through Two Dimensional Bar Coding of Vaccine Products. AB - Purpose: A two-dimensional barcode that includes both static information (vaccine identifier) and variable information (expiration date and lot number) can facilitate streamlined documentation and sharing of vaccine administration. We sought to identify how vaccine tracking information in the two-dimensional barcode is represented in systems that are used by pharmacies, providers, and public health agencies. Methods: We identified and reviewed relevant information technology standards that govern data storage and exchange for providers, pharmacy systems, billing systems, and manufacturers to identify how each system codes the vaccine identifier, expiration date, and lot number. We selected standards commonly used by manufacturers, providers, and pharmacies and mapped the critical vaccine data elements across them. We shared the mapping with stakeholders to identify areas of alignment across standards and discussed how to address misalignment going forward. Results: Data elements were not consistently formatted in each type of information system. The vaccine lot number and expiration date were consistent, which would facilitate sharing across information systems. However, the way to identify a given vaccine is not consistent in each standard and would require manual entry. This inconsistency is related to the segmentation of the National Drug Code into three components. Therefore, vaccine identification methods differ across the systems governed by different standards. Conclusion: Patient safety can be enhanced by automated verification of the vaccine ordered versus the vaccine administered. Immunizers' back-end systems would benefit from automated documentation and reporting. PMID- 29118681 TI - National Survey on Doctoral-Level Education in Health Information Management: Perceptions and Rationale. AB - Objective: The purpose of this survey was to understand the perceptions and educational goals of the health information management (HIM) workforce in regard to pursuing doctoral-level degrees. Method: Survey data were collected from members of the American Health Information Management Association (AHIMA) to gain further insight into their interest in pursuing a doctoral degree, their reasons for obtaining such a degree, their methods of learning, and their financial support for an advanced degree. Descriptive characteristics were collected from AHIMA profile information. Results: A total of 13,020 surveys were electronically sent to selected AHIMA members, of which 1,453 were returned, for an 11 percent response rate. Of the 651 respondents who indicated that they were interested in obtaining a doctoral-level degree, close to half would like to start their doctoral-level study in the next one to five years. Discussion: This research points to recommendations for efforts to increase student funding opportunities, to increase the number of accredited HIM schools/programs, to create opportunities for doctoral-level study in HIM, to offer options for blended online learning, and to increase the number of doctorally prepared and qualified HIM faculty. PMID- 29118682 TI - Mobile Robotic Telepresence Solutions for the Education of Hospitalized Children. AB - Hospitalization affects children's school attendance, resulting in poor academic and sociodevelopmental outcomes. The increasing ubiquity of mobile and tablet technology in educational and healthcare environments, and the growth of the mobile robotic telepresence (MRT) industry, offer opportunities for the use of MRT to connect hospitalized children to their school environments. This article describes an approach at one rural healthcare center in collaboration with local school districts with the aim of describing strategies and limitations of MRT use. Future research is needed on MRT implementation, from user experiences to operational strategies, and outcome metrics need to be developed to measure academic and socioemotional outcomes. By partnering with educational systems and using this technology, hospital information technology personnel can help hospitalized children engage with their school environments to maintain connections with peers and access academic instruction. PMID- 29118683 TI - The E-health Literacy Demands of Australia's My Health Record: A Heuristic Evaluation of Usability. AB - Background: My Health Record is Australia's electronic personal health record system, which was introduced in July 2012. As of August 2017, approximately 21 percent of Australia's total population was registered to use My Health Record. Internationally, usability issues have been shown to negatively influence the uptake and use of electronic health record systems, and this scenario may particularly affect people who have low e-health literacy. It is likely that usability issues are negatively affecting the uptake and use of My Health Record in Australia. Objective: To identify potential e-health literacy-related usability issues within My Health Record through a heuristic evaluation method. Methods: Between September 14 and October 12, 2016, three of the authors conducted a heuristic evaluation of the two consumer-facing components of My Health Record-the information website and the electronic health record itself. These two components were evaluated against two sets of heuristics-the Health Literacy Online checklist and the Monkman Heuristics. The Health Literacy Online checklist and Monkman Heuristics are evidence-based checklists of web design elements with a focus on design for audiences with low health literacy. During this heuristic evaluation, the investigators individually navigated through the consumer-facing components of My Health Record, recording instances where the My Health Record did not conform to the checklist criteria. After the individual evaluations were completed, the investigators conferred and aggregated their results. From this process, a list of usability violations was constructed. Results: When evaluated against the Health Literacy Online Checklist, the information website demonstrated violations in 12 of 35 criteria, and the electronic health record demonstrated violations in 16 of 35 criteria. When evaluated against the Monkman Heuristics, the information website demonstrated violations in 7 of 11 criteria, and the electronic health record demonstrated violations in 9 of 11 criteria. The identified violations included usability issues with the reading levels used within My Health Record, the graphic design elements, the layout of web pages, and a lack of images and audiovisual tools to support learning. Other important usability issues included a lack of translated resources, difficulty using accessibility tools, and complexity of the registration processes. Conclusion: My Health Record is an important piece of technology that has the potential to facilitate better communication between consumers and their health providers. However, this heuristic evaluation demonstrated that many usability-related elements of My Health Record cater poorly to users at risk of having low e-health literacy. Usability issues have been identified as an important barrier to use of personal health records internationally, and the findings of this heuristic evaluation demonstrate that usability issues may be substantial barriers to the uptake and use of My Health Record. PMID- 29118684 TI - A Pilot Study Investigating Employee Utilization of Corporate Telehealth Services. AB - In line with the vision of the University of Mississippi Medical Center (UMMC) to improve health outcomes and eliminate healthcare disparities in Mississippi, a corporate telehealth program was initiated beginning May 2014. A descriptive study was performed to discover common characteristics among enrolled employee users who took advantage of UMMC's corporate telehealth services offered in their workplace throughout the program's first year of operation. This pilot study examined the number of videoconference visits (e-visits) throughout the first year of operation, from May 2014 through April 2015. This examination of common user traits may help identify characteristics that indicate an employee's likelihood of using corporate telehealth. The study revealed the highest use among employees between the ages of 30 and 49 years and among those who attended a formal orientation session including both the employer's human resources personnel and a UMMC corporate telehealth representative. Corporations may find that offering corporate telehealth serves as an effective means to reduce overall healthcare costs and productivity loss. Furthermore, the identification of common variables in this study may help the UMMC corporate telehealth program develop additional methods to reach and assist employees who may not otherwise seek medical treatment. PMID- 29118685 TI - A Rare Thermophilic Bug in Complicated Diverticular Abscess. AB - Actinomycosis is a form of painful abscess in the gastrointestinal tract or in deep tissue caused by actinomyces species. They are one of the commensal bacteria in the oral cavity and gastrointestinal tract of humans but can opportunistically cause infection in immunosuppressive hosts through invasion of breached mucosa or necrotic tissue while mimicking malignancy, gastrointestinal tuberculosis, and inflammatory bowel disease. Actinomyces israelii is, by far, the major and most common human pathogen throughout literatures. By virtue of rarity and diagnostic confusion with masquerading malignancies, only 10% of the cases have been diagnosed preoperatively, so as to be able to verge patients from undergoing unnecessary surgical intervention. Herein, we present a rare case of complicated diverticular abscess manifested by Actinomyces meyeri after postoperative tissue diagnosis. PMID- 29118686 TI - Hepatectomy for Hilar Cholangiocarcinoma with Right-Sided Ligamentum Teres Using a Hepatectomy Simulation System. AB - Right-sided ligamentum teres (RSLT) is a rare congenital anomaly often accompanied by variation of the hepatic vasculature. We herein report a surgical case of a hilar cholangiocarcinoma with RSLT in whom preoperative hepatectomy simulation proved useful for understanding the anatomical structure of the liver. A 78-year-old male with obstructive jaundice was referred to our department for further examination. The patient was suspected of having a hilar cholangiocarcinoma originating from the left hepatic bile duct by contrast enhanced computed tomography (CT), and CT also showed right umbilical portion (RUP). Three-dimensional images of the hepatic vasculature and biliary system reconstructed using a hepatectomy simulation system suggested that all portal branches ramified from RUP were right paramedian branches, and three leftward portal branches from these ran parallel to the peripheral bile ducts confluent with the left hepatic bile duct, where the tumor was present. Hepatic resection of part of the ventral area of the right paramedian sector and left hemiliver was performed along the demarcation line drawn after clamping the portal branches; the ratio of estimated liver resection volume was 28.9%. After the operation, bile leakage occurred. However, the leakage was treated with percutaneous drainage alone, and the patient was discharged 77 days after the operation. The patient is doing well without any signs of recurrence 21 months after the operation. The vascular and biliary anatomy in patients with RSLT is complicated and should be evaluated in detail preoperatively using a hepatectomy simulation system. PMID- 29118687 TI - Renoportal Anastomosis in Left Lateral Lobe Living Donor Liver Transplantation: A Pediatric Case. AB - In adult liver transplantation, renoportal anastomosis (RPA) has been introduced as a useful technique for patients with grade 4 portal vein thrombosis and a splenorenal shunt. Here, we report a pediatric case in which RPA allowed a left lateral lobe living donor liver transplantation (LDLT) despite portal vein thrombosis and a large splenorenal shunt. At 36 days old, the patient underwent a Kasai operation for biliary atresia. At 17 months old, she underwent LDLT because of repetitive cholangitis. Pretransplant examinations revealed a large splenorenal shunt and portal vein thrombosis. Simple end-to-end portal reconstruction and clamping of the collateral route after removing the thrombosis were unsuccessful. Thus, RPA was performed using a donor superficial femoral vein as an interpositional graft. The portal vein pressure was 20 mm Hg after arterial reperfusion. Ligation of the splenic artery reduced the portal vein pressure. Although she developed severe acute cellular rejection and chylous ascites, there were no signs of portal vein complications. She was discharged 73 days after transplantation without any signs of renal dysfunction. The patient's condition was good at her last follow-up, 22 months after transplantation. To our knowledge, this is the youngest case of RPA in pediatric left lateral lobe LDLT. Additionally, this is the first case of RPA with splenic artery ligation and using the donor's superficial femoral vein as the venous graft for RPA. Although long-term follow-up is necessary, RPA could be a salvage option in LDLT in infants if other methods are unsuccessful. PMID- 29118688 TI - A Tale of Two Lymphomas. AB - We present a patient with coeliac disease who developed refractory coeliac disease II, which was complicated by the development of metachronous lymphomas. PMID- 29118689 TI - Postpolypectomy Intramural Colonic Hematoma: The Conservative Management of a Potentially Fatal Complication. AB - Most medical professionals consider colonoscopy to be a safe procedure with a low rate of severe complications such as bowel perforation, gastrointestinal tract bleeding, or mortality. Bowel wall hematoma is a rare complication associated with colonoscopy that can result in significant morbidity and even mortality. We present a case of postpolypectomy hematoma diagnosed with CT imaging and successfully managed in a conservative fashion. PMID- 29118690 TI - Pneumoperitoneum after Endoscopic Retrograde Cholangiopancreatography due to Rupture of Intrahepatic Bile Ducts and Glisson's Capsule in Hepatic Metastasis: A Case Report and Review of Literature. AB - Introduction: Endoscopic retrograde cholangiopancreatography (ERCP) has been proven to be a safe and effective method for diagnosis and treatment of biliary and pancreatic disorders. Major complications of ERCP include pancreatitis, hemorrhage, cholangitis, and duodenal perforation. We report a third case in literature of pneumoperitoneum after ERCP due to rupture of intrahepatic bile ducts and Glisson's capsule in a peripheral hepatic lesion. Case Report: A 50 year-old male with a history of metastatic pancreatic neuroendocrine tumor and who had a partially covered metallic stent placed in the biliary tree 1 year ago presented to the oncology clinic with fatigue, abdominal pain, and hypotension. He was planned for ERCP for possible cholangitis secondary to obstructed previously placed biliary stent. However, the duodenoscope could not be advanced to the level of the major papilla because of narrowed pylorus and severely strictured duodenal sweep. Forward-view gastroscope was then passed with careful manipulation to the severely narrowed second part of the duodenum where the previously placed metallic stent was visualized. Balloon sweeping of stenting was done. Cholangiography did not show any leak. Following the procedure, the patient underwent CT scan of the abdomen that showed pneumoperitoneum which was communicating with pneumobilia through a loculated air collection in necrotic hepatic metastasis perforating Glisson's capsule. The patient was managed conservatively. Conclusion: In our case, pneumoperitoneum resulted from rupture of intrahepatic bile ducts and Glisson's capsule in hepatic metastasis. This case emphasizes the need for close clinical and radiological observation of patients with hepatic masses (primary or metastatic) subjected to ERCP. PMID- 29118691 TI - Vanishing Tumor in a Liver Graft from a Hepatitis B Virus Surface Antigen Positive Donor. AB - We report a case of vanishing tumor considered as inflammatory pseudotumor (IPT) found in the liver after living donor liver transplantation (LDLT) from a hepatitis B virus surface antigen-positive donor. The radiological findings were similar to those of hepatocellular carcinoma (HCC). However, the tumor disappeared completely within several months and was suggested to have been an IPT. IPT is known to be associated with biliary duct operation or biliary infection, and it can show various enhancement patterns in radiological studies, sometimes resembling HCC. It should be considered in the differential diagnosis of a liver tumor in patients with LDLT. PMID- 29118693 TI - Design of a Soft Robotic Elbow Sleeve with Passive and Intent-Controlled Actuation. AB - The provision of continuous passive, and intent-based assisted movements for neuromuscular training can be incorporated into a robotic elbow sleeve. The objective of this study is to propose the design and test the functionality of a soft robotic elbow sleeve in assisting flexion and extension of the elbow, both passively and using intent-based motion reinforcement. First, the elbow sleeve was developed, using elastomeric and fabric-based pneumatic actuators, which are soft and lightweight, in order to address issues of non-portability and poor alignment with joints that conventional robotic rehabilitation devices are faced with. Second, the control system was developed to allow for: (i) continuous passive actuation, in which the actuators will be activated in cycles, alternating between flexion and extension; and (ii) an intent-based actuation, in which user intent is detected by surface electromyography (sEMG) sensors attached to the biceps and triceps, and passed through a logic sequence to allow for flexion or extension of the elbow. Using this setup, the elbow sleeve was tested on six healthy subjects to assess the functionality of the device, in terms of the range of motion afforded by the device while in the continuous passive actuation. The results showed that the elbow sleeve is capable of achieving approximately 50% of the full range of motion of the elbow joint among all subjects. Next, further experiments were conducted to test the efficacy of the intent-based actuation on these healthy subjects. The results showed that all subjects were capable of achieving electromyography (EMG) control of the elbow sleeve. These preliminary results show that the elbow sleeve is capable of carrying out continuous passive and intent-based assisted movements. Further investigation of the clinical implementation of the elbow sleeve for the neuromuscular training of neurologically-impaired persons, such as stroke survivors, is needed. PMID- 29118692 TI - Statistical Image Properties in Large Subsets of Traditional Art, Bad Art, and Abstract Art. AB - Several statistical image properties have been associated with large subsets of traditional visual artworks. Here, we investigate some of these properties in three categories of art that differ in artistic claim and prestige: (1) Traditional art of different cultural origin from established museums and art collections (oil paintings and graphic art of Western provenance, Islamic book illustration and Chinese paintings), (2) Bad Art from two museums that collect contemporary artworks of lesser importance ((c) Museum Of Bad Art [MOBA], Somerville, and Official Bad Art Museum of Art [OBAMA], Seattle), and (3) twentieth century abstract art of Western provenance from two prestigious museums (Tate Gallery and Kunstsammlung Nordrhein-Westfalen). We measured the following four statistical image properties: the fractal dimension (a measure relating to subjective complexity); self-similarity (a measure of how much the sections of an image resemble the image as a whole), 1st-order entropy of edge orientations (a measure of how uniformly different orientations are represented in an image); and 2nd-order entropy of edge orientations (a measure of how independent edge orientations are across an image). As shown previously, traditional artworks of different styles share similar values for these measures. The values for Bad Art and twentieth century abstract art show a considerable overlap with those of traditional art, but we also identified numerous examples of Bad Art and abstract art that deviate from traditional art. By measuring statistical image properties, we quantify such differences in image composition for the first time. PMID- 29118694 TI - Implications of Schwann Cells Biomechanics and Mechanosensitivity for Peripheral Nervous System Physiology and Pathophysiology. AB - The presence of bones around the central nervous system (CNS) provides it with highly effective physiologically crucial mechanical protection. The peripheral nervous system (PNS), in contrast, lacks this barrier. Consequently, the long held belief is that the PNS is mechanically vulnerable. On the other hand, the PNS is exposed to a variety of physiological mechanical stresses during regular daily activities. This fact prompts us to question the dogma of PNS mechanical vulnerability. As a matter of fact, impaired mechanics of PNS nerves is associated with neuropathies with the liability to mechanical stresses paralleled by significant impairment of PNS physiological functions. Our recent biomechanical integrity investigations on nerve fibers from wild-type and neuropathic mice lend strong support in favor of natural mechanical protection of the PNS and demonstrate a key role of Schwann cells (SCs) therein. Moreover, recent works point out that SCs can sense mechanical properties of their microenvironment and the evidence is growing that SCs mechanosensitivity is important for PNS development and myelination. Hence, SCs exhibit mechanical strength necessary for PNS mechanoprotection as well as mechanosensitivity necessary for PNS development and myelination. This mini review reflects on the intriguing dual ability of SCs and implications for PNS physiology and pathophysiology. PMID- 29118695 TI - Synapse Innervation and Associative Memory Cell Are Recruited for Integrative Storage of Whisker and Odor Signals in the Barrel Cortex through miRNA-Mediated Processes. AB - Associative learning is a common way for information acquisition, and the integrative storage of multiple associated signals is essential for associative thinking and logical reasoning. In terms of the cellular mechanism for associative memory, our studies by behavioral task and cellular imaging demonstrate that paired whisker and odor stimulations lead to odorant-induced whisker motion and associative memory cell recruitment in the barrel cortex (BC), which is driven presumably by synapse innervation from co-activated sensory cortices. To confirm these associative memory cells and synapse innervations essential for associative memory and to examine their potential mechanisms, we studied a causal relationship between epigenetic process and memory cell/synapse recruitment by manipulating miRNAs and observing the changes from the recruitments of associative memory cells and synapse innervations to associative memory. Anti-miRNA-324 and anti-miRNA-133a in the BC significantly downregulate new synapse innervation, associative memory cell recruitment and odorant-induced whisker motion, where Tau-tubulin kinase-1 expression is increased. Therefore, the upregulated miRNA-324 in associative learning knocks down Ttbk1-mediated Tau phosphorylation and microtubule depolymerization, which drives the balance between polymerization and depolymerization toward the axon prolongation and spine stabilization to initiate new synapse innervations and to recruit associative memory cells. PMID- 29118696 TI - A Theory of How Columns in the Neocortex Enable Learning the Structure of the World. AB - Neocortical regions are organized into columns and layers. Connections between layers run mostly perpendicular to the surface suggesting a columnar functional organization. Some layers have long-range excitatory lateral connections suggesting interactions between columns. Similar patterns of connectivity exist in all regions but their exact role remain a mystery. In this paper, we propose a network model composed of columns and layers that performs robust object learning and recognition. Each column integrates its changing input over time to learn complete predictive models of observed objects. Excitatory lateral connections across columns allow the network to more rapidly infer objects based on the partial knowledge of adjacent columns. Because columns integrate input over time and space, the network learns models of complex objects that extend well beyond the receptive field of individual cells. Our network model introduces a new feature to cortical columns. We propose that a representation of location relative to the object being sensed is calculated within the sub-granular layers of each column. The location signal is provided as an input to the network, where it is combined with sensory data. Our model contains two layers and one or more columns. Simulations show that using Hebbian-like learning rules small single column networks can learn to recognize hundreds of objects, with each object containing tens of features. Multi-column networks recognize objects with significantly fewer movements of the sensory receptors. Given the ubiquity of columnar and laminar connectivity patterns throughout the neocortex, we propose that columns and regions have more powerful recognition and modeling capabilities than previously assumed. PMID- 29118697 TI - Reliable and Reproducible GABA Measurements Using Automated Spectral Prescription at Ultra-High Field. AB - Purpose: To evaluate spectral acquisition processes important for obtaining reliable and reproducible gamma-aminobutyric acid (GABA) signals from volunteers in brain regions that are frequently used for neuroimaging studies [anterior cingulate cortex (ACC), superior temporal gyrus, and caudate] at ultra-high field. Methods: Ten healthy volunteers were studied using a single-voxel Point RESolved Spectrosocpy (PRESS) sequence with band selective inversion with gradient dephasing pulses (BASING). The editing pulse was designed to be symmetrically placed at 2.0 and 1.4 ppm in the two cycles to reduce the co editing of macro-molecules (MM). Spectral data were obtained with phase encoding matrix 8 * 8 * 1 and two editing cycles or 1 * 1 * 1 and 64 editing/64 non editing. The total acquisition time was approximately 4.5 min for each acquisition. An automated MRS prescription method was utilized for the placement of the GABA scan location in 5/10 subjects. Three regions of interest were predefined in the MNI152 space and then registered and transformed to subject space. These volunteers also had repeat scans to examine between-session reproducibility. Results: The placement of editing pulses symmetrically at 1.7 ppm reduced the effect of MM contributions and provided more accurate GABA estimation. Chemical shift misregistration errors caused by classic PRESS localization sequence are more significant at ultra-high field strength. Therefore, a large over-excitation factor was needed to reduce this error. Furthermore, the inefficiency of saturation bands and unspoiled coherence could also interfere with the quality of the data. Reliable recovery of metabolite signals resulted from the implementation of 8 * 8 * 1 phase encoding that successfully removed artifacts and errors, without compromising the total acquisition time. Between successive scans on the same subject, dice overlap ratios of the excited spectral volume between the two scans were in the range of 92-95%. Within subject variability of metabolites between two repeat scans was smaller in the ACC and left superior temporal gyrus when compared to that in the right caudate, with averaged coefficients of variation being 3.6, 6.0, and 16.9%, respectively. Conclusion: This study demonstrated the feasibility of obtaining reliable and reproducible GABA measurements at ultra-high field. PMID- 29118699 TI - Performance and Usability of Various Robotic Arm Control Modes from Human Force Signals. AB - Elaborating an efficient and usable mapping between input commands and output movements is still a key challenge for the design of robotic arm prostheses. In order to address this issue, we present and compare three different control modes, by assessing them in terms of performance as well as general usability. Using an isometric force transducer as the command device, these modes convert the force input signal into either a position or a velocity vector, whose magnitude is linearly or quadratically related to force input magnitude. With the robotic arm from the open source 3D-printed Poppy Humanoid platform simulating a mobile prosthesis, an experiment was carried out with eighteen able-bodied subjects performing a 3-D target-reaching task using each of the three modes. The subjects were given questionnaires to evaluate the quality of their experience with each mode, providing an assessment of their global usability in the context of the task. According to performance metrics and questionnaire results, velocity control modes were found to perform better than position control mode in terms of accuracy and quality of control as well as user satisfaction and comfort. Subjects also seemed to favor quadratic velocity control over linear (proportional) velocity control, even if these two modes did not clearly distinguish from one another when it comes to performance and usability assessment. These results highlight the need to take into account user experience as one of the key criteria for the design of control modes intended to operate limb prostheses. PMID- 29118698 TI - An Acute Exposure to Muscle Vibration Decreases Knee Extensors Force Production and Modulates Associated Central Nervous System Excitability. AB - Local vibration (LV) has been recently validated as an efficient training method to improve muscle strength. Understanding the acute effects may help elucidate the mechanism(s). This study aimed to investigate the effects of a single bout of prolonged LV on knee extensor force production and corticospinal responsiveness of vastus lateralis (VL) and rectus femoris (RF) muscles in healthy young and old adults. Across two visits, 23 adult subjects (20-75 years old) performed pre- and post-test measurements, separated by 30-min of either rest (control; CON) or LV. Maximal voluntary contraction (MVC) force was assessed and transcranial magnetic stimulation (TMS) was used to evaluate cortical voluntary activation (VATMS) as well as the motor evoked potential (MEP) and silent period (SP). In 11 young adults, thoracic electrical stimulation was used to assess the thoracic motor evoked potential (TMEP). Although MVC decreased after both CON (-6.3 +/- 4.4%, p = 0.01) and LV (-12.9 +/- 7.7%, p < 0.001), the MVC loss was greater after LV (p = 0.001). Normalized maximal electromyographic (EMG) activity decreased after LV for both VL (-25.1 +/- 10.7%) and RF (-20.9 +/- 16.5%; p < 0.001), while it was unchanged after CON (p = 0.32). For RF, the TMEP and MEP/TMEP ratio decreased (p = 0.01) and increased (p = 0.01) after LV, respectively. Both measures were unchanged for VL (p = 0.27 and p = 0.15, respectively). No changes were reported for TMS-related parameters. These results confirm our hypothesis that modulations within the central nervous system would accompany the significant reduction of maximal voluntary force. A reduced motoneuron excitability seems to explain the decreased MVC after prolonged LV, as suggested by reductions in maximal EMG (all subjects) and TMEP area (data from 11 young subjects). A concomitant increased cortical excitability seems to compensate for lower excitability at the spinal level. PMID- 29118700 TI - Looking Beyond the Cyclosporine "Swish and Spit" Technique in a Recalcitrant Case of Erosive Lichen Planus Involving the Tongue. AB - Oral lichen planus is a relatively common autoimmune disease affecting the middle aged population. Although no treatment is necessary for a benign asymptomatic case, in case of erosive lichen planus, topical corticosteroids form the mainstay of treatment. In case of failure, apart from tacrolimus, cyclosporine, using the "swish and spit" technique, is a valid therapeutic intervention. In our case, though, this therapeutic option had to be replaced by the systemic use of cyclosporine with gratifying results. PMID- 29118701 TI - Nevus Comedonicus: Case Report. AB - Nevus comedonicus is a rare cutaneous anomaly, characterized by the clustering of papules with firm, blackened horny buffers. It in general has a zosteriform pattern and affects both genders equally. In some patients, there is formation of cysts, abscesses, and fistulas, aggravating its psychosocial impact. The association with extracutaneous lesions characterizes the nevus comedonicus syndrome. Despite several therapeutic options, the result is unsatisfactory in most cases. We report the case of a man with an exuberant congenital lesion, affecting the left suprascapular region, arm, and forearm. PMID- 29118702 TI - Plaque-Type Syringoma: A Case Report. AB - Syringomas are benign appendageal tumors originated from eccrine ducts. The lesions usually present as multiple small, firm papules at lower eyelids and cheeks of women. Plaque-type syringoma is an infrequent form of syringoma and to date, 12 cases have been reported. Pathology demonstrated benign proliferation of eccrine ductal structures in the dermis with surrounding fibrotic stroma. We report the case of a 40-year-old Thai male with plaque-type syringomas at infraorbital areas. PMID- 29118703 TI - Transplant-Ineligible Symptomatic but Indolent Multiple Myeloma Shows Better Prognosis with Conventional Agents. AB - The survival of multiple myeloma patients has improved significantly over the last several decades. However, the median overall survival of these patients remains less than 5 years. In this report, we discuss 4 cases of multiple myeloma patients that showed long survival. Interestingly, these patients had severe organ damage at diagnosis, used only conventional agents, and did not always show deep response. Although current guidelines recommend novel agents to achieve deep response, the current cases suggest that some multiple myeloma patients may not need intensive treatment. Here, we discuss 4 cases of symptomatic but indolent transplant-ineligible myeloma. PMID- 29118704 TI - Spontaneous Remission of Severe Systemic Langerhans Cell Histiocytosis with Bladder Involvement: A Case Study. AB - Background: The clinical presentation of Langerhans cell histiocytosis (LCH) is heterogeneous ranging from single-organ involvement to systemic disease causing substantial morbidity and mortality. We describe an unusual course of severe multisystem LCH with spontaneous remission. Case Presentation: We report on a 45 year-old Caucasian woman with cervical cancer, FIGO stage IVB. Five months after the end of combined radiochemotherapy and brachytherapy, the patient was readmitted because of severe dysuria. Sterile leukocyturia was seen, and cystoscopy revealed only 3 unspecific small mucosal lesions compatible with postradiation cystitis. Incidentally, a computed tomography (CT) scan of the body showed diffuse micronodular and cystic lesions in lungs and hypodense lesions in the liver. Biopsies revealed infiltrations of CD1a and Langerin (CD207)-positive histiocytes in the lung, liver, and bladder. Additionally, positron emission tomography-CT (PET-CT) was compatible with bone involvement. Retrospective analysis revealed that the increase in alkaline phosphatase might have been a surrogate of bone marrow infiltration with osseous activity. Repeated pneumothoraces occurred, and only one course of vinblastine-prednisolone could be applied. Despite ongoing tobacco consumption and without further therapy, PET-CT showed considerable remission 2 months later. However, despite stable remission, documented by serial PET and conventional CT scans, persistent infiltration of the bladder by Langerhans histiocytes could still be demonstrated 17 months later. Unfortunately, cervical cancer recurred and progressed. Conclusion: Multisystem LCH may rapidly occur, may be oligosymptomatic and, even in high-risk cases, remission without specific therapy might occur. Whether alkaline phosphatase might be a surrogate to monitor osseous disease activity has to be further explored. PMID- 29118705 TI - Oxaliplatin-Induced Hyperammonemic Encephalopathy in a Patient with Metastatic Pancreatic Cancer: A Case Report. AB - Oxaliplatin-based chemotherapy is widely used to treat advanced cancer. Oxaliplatin-induced hyperammonemic encephalopathy is rarely reported. Here, we report a case of oxaliplatin-induced hyperammonemic encephalopathy occurring after gemcitabine plus oxaliplatin (GEMOX) chemotherapy in a patient with pancreatic cancer. A 76-year-old man received GEMOX regimen as first-line treatment for pancreatic adenocarcinoma with peritoneal dissemination. GEMOX consists of gemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) on day 1, repeated every 2 weeks. The second cycle of GEMOX was administered as planned. However, he appeared to have difficulties with daily activities. Two days later, he visited the emergency room complaining of drowsiness. On examination, the patient had a Glasgow Coma Scale (GCS) score of 14 (E4V4M6), and asterixis was not present. Blood examination revealed a serum ammonia level of 202 ug/dL. The levels of serum hepatic enzymes were only mildly elevated, and the hemoglobin level was typical for this patient. Computed tomography, magnetic resonance imaging, lumbar puncture test, and blood culture showed no abnormality. Based on these results, he was diagnosed with oxaliplatin-induced hyperammonemia. One day after hospitalization, GCS score had significantly decreased to 6 (E1V1M4). His consciousness disorder improved after administration of a nutritional supplement containing a high concentration of branched-chain amino acids for 5 days, and the level of serum ammonia improved to 79 ug/dL. He stated that he could not remember the episode. The findings of this case suggest the importance of examining serum ammonia levels in patients receiving an oxaliplatin-containing regimen who develop disordered consciousness. PMID- 29118706 TI - Recurrent Diabetic Macular Edema: What to Do. AB - Diabetic macular edema (DME) is a leading cause of blindness in the working population. Herein, we report the case of a patient with recurrent DME for about 6 years, uncontrolled by several medical and surgical treatments, that was successfully treated with a single sustained-release fluocinolone acetonide intravitreal implant in her right eye. The affected eye had presented a visual acuity of 2/10 and a central macular thickness of 488 um prior to the injection. After treatment with the fluocinolone acetonide intravitreal implant, the patient's right eye presented an improvement in best corrected visual acuity to 6/10 and a reduction of central macular thickness to 198 um. These functional and anatomical results were continuous and sustained during a follow-up period of more than 12 months, and with an acceptable and manageable safety profile. These results show that fluocinolone acetonide intravitreal implantation is an effective treatment option in DME and should be considered in the DME treatment pathway. PMID- 29118707 TI - Bullous Exudative Retinal Detachment after Retinal Pattern Scan Laser Photocoagulation in Diabetic Retinopathy. AB - Laser retinal photocoagulation is the gold standard treatment for diabetic retinopathy. We describe 3 cases in which bullous exudative retinal detachment (ERD) developed after pattern scan laser photocoagulation (PASCAL) in diabetic retinopathy. ERD spontaneously resolved in all 3 cases with various visual courses. This case series highlights 2 key points: first, ERD can occur regardless of gender, age, glycemic control, or vitreous status and despite a moderate number of laser shots, even with PASCAL; second, ERD in nonvitrectomized eyes may cause irreversible visual loss, even if the ERD resolves within 1 month. PMID- 29118708 TI - Corneal Collagen Cross-Linking Combined with an Artiflex Iris-Fixated Anterior Chamber Phakic Intraocular Lens Implantation in a Patient with Progressive Keratoconus. AB - We present here the case of a 24-year-old male who experienced progressive keratoconus and vision loss which adversely affected his ability to carry out everyday tasks. This landed him in the Hashmanis Hospital for consultation. He had a preoperative best corrected visual acuity of 6/12. He underwent multiple Oculus Pentacam examinations, which showed progressive keratoconus. Corneal collagen cross-linking (CXL) was performed to stabilize his cornea and, subsequently, an Artiflex anterior chamber iris-fixated phakic intraocular lens (ACIF-PIOL) was implanted to alleviate his refractive errors. The patient achieved a postoperative uncorrected visual acuity of 6/12. This report shows that CXL combined with ACIF-PIOL can be safe and effective in those with progressive keratoconus. PMID- 29118709 TI - Piccolo Promotes Vesicle Replenishment at a Fast Central Auditory Synapse. AB - Piccolo and Bassoon are the two largest cytomatrix of the active zone (CAZ) proteins involved in scaffolding and regulating neurotransmitter release at presynaptic active zones (AZs), but have long been discussed as being functionally redundant. We employed genetic manipulation to bring forth and segregate the role of Piccolo from that of Bassoon at central auditory synapses of the cochlear nucleus-the endbulbs of Held. These synapses specialize in high frequency synaptic transmission, ideally poised to reveal even subtle deficits in the regulation of neurotransmitter release upon molecular perturbation. Combining semi-quantitative immunohistochemistry, electron microscopy, and in vitro and in vivo electrophysiology we first studied signal transmission in Piccolo-deficient mice. Our analysis was not confounded by a cochlear deficit, as a short isoform of Piccolo ("Piccolino") present at the upstream ribbon synapses of cochlear inner hair cells (IHC), is unaffected by the mutation. Disruption of Piccolo increased the abundance of Bassoon at the AZs of endbulbs, while that of RIM1 was reduced and other CAZ proteins remained unaltered. Presynaptic fiber stimulation revealed smaller amplitude of the evoked excitatory postsynaptic currents (eEPSC), while eEPSC kinetics as well as miniature EPSCs (mEPSCs) remained unchanged. Cumulative analysis of eEPSC trains indicated that the reduced eEPSC amplitude of Piccolo-deficient endbulb synapses is primarily due to a reduced readily releasable pool (RRP) of synaptic vesicles (SV), as was corroborated by a reduction of vesicles at the AZ found on an ultrastructural level. Release probability seemed largely unaltered. Recovery from short-term depression was slowed. We then performed a physiological analysis of endbulb synapses from mice which, in addition to Piccolo deficiency, lacked one functional allele of the Bassoon gene. Analysis of the double-mutant endbulbs revealed an increase in release probability, while the synapses still exhibited the reduced RRP, and the impairment in SV replenishment was exacerbated. We propose additive roles of Piccolo and Bassoon in SV replenishment which in turn influences the organization and size of the RRP, and an additional role of Bassoon in regulation of release probability. PMID- 29118711 TI - Commentary: The Relationship of Bilingualism Compared to Monolingualism to the Risk of Cognitive Decline or Dementia: A Systematic Review and Meta-Analysis. PMID- 29118710 TI - Cognitive Vulnerability in Aging May Be Modulated by Education and Reserve in Healthy People. AB - Aging is related to a deterioration of cognitive performance and to multiple alterations in the brain. Even before the beginning of a noticeable cognitive decline, the framework which holds cognitive function experiences these alterations. From a system-vulnerability point of view of cognition, the deterioration associated with age would be the collection of repercussions during a life. Brain function and structure are modified in a multidimensional way, which could concern different aspects like structural integrity, functional activity, connectivity, or glucose metabolism. From this point of view, the effects of aging could affect the most brain systems and their functional activity. In this study, we analyze the functional development of three cognitive domains in relation to aging, educational level, and cognitive reserve (CR). A total of 172 healthy subjects were divided into two age groups (young and old), and completed a battery of classic neuropsychological tests. The tests were organized and analyzed according to three cognitive domains: working memory and flexibility, visuoconstructive functions, and declarative memory. Subjects also completed a questionnaire on CR. Results showed that the performance in all cognitive domains decreased with age. In particular, tests related to working memory, flexibility, and visuoconstructive abilities were influenced by age. Nevertheless, this effect was attenuated by effects of education, mainly in visuoconstructive domain. Surprisingly, visual as well as verbal memory tests were not affected either by aging, education, or CR. Brain plasticity plays a prominent role in the aging process, but, as other studies have shown, the plasticity mechanism is quite different in healthy vs. pathological brains. Moreover, this plasticity brain mechanism could be modulated by education and CR. Specially, cognitive domains as working memory, some executive functions and the visuoconstructive abilities seem to be modulated by education. Therefore, it seems to be crucial, to propose mechanisms of maintenance of a healthy and enriched brain, since it promotes auto-regulatory mechanisms of well-aging. PMID- 29118712 TI - Comparative Long-Term Effect of Three Anti-P2Y12 Drugs after Percutaneous Angioplasty: An Observational Study Based on Electronic Drug Adherence Monitoring. AB - Aims: Dual platelet inhibition using anti-P2Y12 drugs and aspirin is the standard of care in patients after percutaneous coronary interventions (PCI). Prasugrel and ticagrelor have been shown to be more potent than clopidogrel with less high on-treatment platelet reactivity. Whether differences in long-term adherence to these drugs can partly explain different antiplatelet efficacy has not been studied so far. The objective was to compare the long-term P2Y12 receptor inhibition and drug adherence to different anti-P2Y12 drugs, and to assess the impact of adherence on the pharmacodynamic effect. Methods: Monocentric, prospective, observational study. Stable outpatients treated with clopidogrel 75 mg once daily, prasugrel 10 mg once daily or ticagrelor 90 mg twice daily after PCI with stent implantation were included. Drug adherence was recorded during 6 months using electronic monitoring. Platelet responsiveness was assessed with the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI) at inclusion, 3 and 6 months. Results: 120 patients had VASP-PRI and adherence data available. At 6-months, mean VASP-PRI (+/-SD) was 17.7 +/- 11.0% with ticagrelor, 29.2 +/- 15.5% with prasugrel and 47.2 +/- 17.6% with clopidogrel (ANOVA, P < 0.0001). Median [IQR] taking adherence was 96 [82-100]% with ticagrelor, 100 [97 101]% with prasugrel and 100 [99-101]% with clopidogrel (p = 0.0001). Median [IQR] correct dosing was 88 [73-95]% with ticagrelor, 97 [92.5-98]% with prasugrel and 98 [96-99]% with clopidogrel (p = 0.0001). Anti-P2Y12 drug (p <= 0.001) and diabetes (p = 0.014) emerged as predictors of poor antiplatelet response after adjusting for age, BMI, sex, and CYP2C19*2 carriers status. Conclusion: Drug adherence to anti-P2Y12 drugs assessed with electronic monitoring was very high. However, anti-P2Y12 drugs showed significant differences in antiplatelet activity, with newer anti-P2Y12 drugs ticagrelor and prasugrel exerting a stronger P2Y12 receptor inhibition. These data suggest that pharmacokinetic-pharmacodynamic differences between oral anti-P2Y12 drugs are more important than adherence in determining antiplatelet efficacy when adherence to prescription is high. The study was registered (Current Controlled Trials ISRCTN85949729). PMID- 29118713 TI - Corticotropin Releasing Factor in the Bed Nucleus of the Stria Terminalis in Socially Defeated and Non-stressed Mice with a History of Chronic Alcohol Intake. AB - Stress exposure has been identified as one risk factor for alcohol abuse that may facilitate the transition from social or regulated use to the development of alcohol dependence. Preclinical studies have shown that dysregulation of the corticotropin releasing factor (CRF) neurotransmission has been implicated in stress-related psychopathologies such as depression and anxiety, and may affect alcohol consumption. The bed nucleus of the stria terminalis (BNST) contains CRF producing neurons which seem to be sensitive to stress. In this study, adult male C57BL/6 mice previously defeated in resident-intruder confrontations were evaluated in the elevated plus-maze and tail suspension test. Mice were also tested for sweet solution intake before and after social stress. After having had continuous access to ethanol (20% weight/volume) for 4 weeks, control and stressed mice had CRF type 1 (CRFR1) or type 2 (CRFR2) receptor antagonists infused into the BNST and then had access to ethanol for 24 h. In separate cohorts of control and stressed mice, we assessed mRNA levels of BNST CRF, CRFR1 and CRFR2. Stressed mice increased their intake of sweet solution after ten sessions of social defeat and showed reduced activity in the open arms of the elevated plus-maze. When tested for ethanol consumption, stressed mice persistently drank significantly more than controls during the 4 weeks of access. Also, social stress induced higher BNST CRF mRNA levels. The selective blockade of BNST CRFR1 with CP376,395 effectively reduced alcohol drinking in non-stressed mice, whereas the selective CRFR2 antagonist astressin2B produced a dose dependent increase in ethanol consumption in both non-stressed controls and stressed mice. The 10-day episodic defeat stress used here elicited anxiety- but not depressive-like behaviors, and promoted an increase in ethanol drinking. CRF CRFR1 signaling in the BNST seems to underlie ethanol intake in non-stressed mice, whereas CRFR2 modulates alcohol consumption in both socially defeated and non-stressed mice with a history of chronic intake. PMID- 29118714 TI - Advances in Roles of miR-132 in the Nervous System. AB - miR-132 is an endogenous small RNA and controls post-transcriptional regulation of gene expression via controlled degradation of mRNA or transcription inhibition. In the nervous system, miR-132 is significant for regulating neuronal differentiation, maturation and functioning, and widely participates in axon growth, neural migration, and plasticity. The miR-132 is affected by factors like mRNA expression, functional redundancy, and signaling cascades. It targets multiple downstream molecules to influence physiological and pathological neuronal activities. MiR-132 can influence the pathogenesis of many diseases, especially in the nervous system. The dysregulation of miR-132 results in the occurrence and exacerbation of neural developmental, degenerative diseases, like Alzheimer's disease, Parkinson's disease and epilepsy, neural infection and psychiatric disorders including disturbance of consciousness, cognition and memory, depression and schizophrenia. Regulation of miR-132 expression relieves symptoms, alleviates severity and finally effects a cure. This review aims to discuss the clinical potentials of miR-132 in the nervous system. PMID- 29118715 TI - Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non thyoidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice. AB - Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/Slc16a2 and MCT10/Slc16a10), metabolism (Dio1, Dio2, and Dio3) and action (Thra and Thrb) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T4) and triiodothyronine (T3), expression of Dio1, Thra, Slc16a2, and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra, and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models. PMID- 29118716 TI - Etiology and Recovery of Neuromuscular Fatigue following Competitive Soccer Match Play. AB - Aim: Previous research into the etiology of neuromuscular fatigue following competitive soccer match-play has primarily focused on peripheral perturbations, with limited research assessing central nervous system function in the days post match. The aim of the present study was to examine the contribution and time course of recovery of central and peripheral factors toward neuromuscular fatigue following competitive soccer match-play. Methods: Sixteen male semi-professional soccer players completed a 90-min soccer match. Pre-, post- and at 24, 48, and 72 h participants completed a battery of neuromuscular, physical, and perceptual tests. Maximal voluntary contraction force (MVC) and twitch responses to electrical (femoral nerve) and transcranial magnetic stimulation (TMS) of the motor cortex during isometric knee-extension and at rest were measured to assess central nervous system (voluntary activation, VA) and muscle contractile (potentiated twitch force, Qtw, pot) function. Electromyography responses of the rectus femoris to single- and paired-pulse TMS were used to assess corticospinal excitability and short-interval intracortical inhibition (SICI), respectively. Fatigue and perceptions of muscle soreness were assessed via visual analog scales, and physical function was assessed through measures of jump (countermovement jump height and reactive strength index) and sprint performance. Results: Competitive match-play elicited significant post-match declines in MVC force (-14%, P < 0.001) that persisted for 48 h (-4%, P = 0.01), before recovering by 72 h post-exercise. VA (motor point stimulation) was reduced immediately post-match (-8%, P < 0.001), and remained depressed at 24 h (-5%, P = 0.01) before recovering by 48 h post-exercise. Qtw,pot was reduced post-match ( 14%, P < 0.001), remained depressed at 24 h (-6%, P = 0.01), before recovering by 48 h post-exercise. No changes were evident in corticospinal excitability or SICI. Jump performance took 48 h to recover, while perceptions of fatigue persisted at 72 h. Conclusion: Competitive soccer match-play elicits substantial impairments in central nervous system and muscle function, requiring up to 48 h to resolve. The results of the study could have important implications for fixture scheduling, the optimal management of the training process, squad rotation during congested competitive schedules, and the implementation of appropriate recovery interventions. PMID- 29118717 TI - Identification of Intracellular beta-Barrel Residues Involved in Ion Selectivity in the Mechanosensitive Channel of Thermoanaerobacter tengcongensis. AB - The mechanosensitive channel of small conductance (MscS) is a bacterial membrane pore that senses membrane tension and protects cells from lysis by releasing osmolytes. MscS is a homoheptameric channel with a cytoplasmic domain with seven portals and a beta-barrel opening to the cytoplasm. TtMscS, an MscS channel from Thermoanaerobacter tengcongensis, is an anion-selective channel. A previous study from our laboratory has defined the crucial role of beta-barrel in the anion selectivity of TtMscS (Zhang et al., 2012). However, the mechanistic details by which the beta-barrel determines anion selectivity remain unclear. Here, using mutagenesis and patch-clamp recordings, we investigated the function and structural correlations between beta-barrels and the anion selectivity of TtMscS at the atomic level. Our results indicated that mutation of V274, a residue at the center of the inner wall of the beta-barrel in TtMscS, caused the anion selectivity of TtMscS reverse to cation selectivity. Moreover, the electrostatic potential (T272) and physical size (L276) of residues in the inner wall of beta barrel also determine the anion selectivity of TtMscS. In summary, the present study confirmed that the beta-barrel region of TtMscS acts as a "selective filter" that renders TtMscS anion selectivity. PMID- 29118718 TI - The Practice of Physical Activity in the Setting of Lower-Extremities Sarcomas: A First Step toward Clinical Optimization. AB - Lower-extremities sarcoma patients, with bone tumor and soft-tissue sarcoma, are a unique population at high risk of physical dysfunction and chronic heart diseases. Thus, providing an adequate physical activity (PA) program constitutes a primary part of the adjuvant treatment, aiming to improve patients' quality of life. The main goal of this paper is to offer clear suggestions for clinicians regarding PA around the time between diagnosis and offered treatments. These preliminary recommendations reflect our interpretation of the clinical and preclinical data published on this topic, after a systematic search on the PubMed database. Accordingly, patients could be advised to (1) start sessions of supportive rehabilitation and low-intensity PA after surgery and (2) increase PA intensities progressively during home stay. The usefulness of PA during the preoperative period remains largely unknown but emerging preclinical data on mice bearing intramuscular sarcoma are most likely discouraging. However, efforts are still needed to in-depth elucidate the impact of PA before surgery completion. PA should be age-, sex-, and treatment-adapted, as young/adolescent, women and patients receiving platinum-based chemotherapy are more susceptible to physical quality deterioration. Concerning PA intensity, the practice of moderate intensity resistance and endurance exercises (30-60 min/day) are safe after surgery, even when receiving adjuvant chemo/radiotherapy. The general PA recommendations for cancer patients, 150 min/week of combined moderate-intensity endurance/resistance exercises, could be feasible after 18-24 months of rehabilitation. We believe that these suggestions will help clinicians to design a low-risk and useful PA program. PMID- 29118719 TI - The Origins and Functions of Tissue-Resident Macrophages in Kidney Development. AB - The adult kidney hosts tissue-resident macrophages that can cause, prevent, and/or repair renal damage. Most of these macrophages derive from embryonic progenitors that colonize the kidney during its development and proliferate in situ throughout adulthood. Although the precise origins of kidney macrophages remain controversial, recent studies have revealed that embryonic macrophage progenitors initially migrate from the yolk sac, and later from the fetal liver, into the developing kidney. Once in the kidney, tissue-specific transcriptional regulators specify macrophage progenitors into dedicated kidney macrophages. Studies suggest that kidney macrophages facilitate many processes during renal organogenesis, such as branching morphogenesis and the clearance of cellular debris; however, little is known about how the origins and specification of kidney macrophages dictate their function. Here, we review significant new findings about the origins, specification, and developmental functions of kidney macrophages. PMID- 29118720 TI - Altered Right Ventricular Mechanical Properties Are Afterload Dependent in a Rodent Model of Bronchopulmonary Dysplasia. AB - Infants born premature are at increased risk for development of bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), and ultimately right ventricular (RV) dysfunction, which together carry a high risk of neonatal mortality. However, the role alveolar simplification and abnormal pulmonary microvascular development in BPD affects RV contractile properties is unknown. We used a rat model of BPD to examine the effect of hyperoxia-induced PH on RV contractile properties. We measured in vivo RV pressure as well as passive force, maximum Ca2+ activated force, calcium sensitivity of force (pCa50) and rate of force redevelopment (ktr) in RV skinned trabeculae isolated from hearts of 21-and 35 day old rats pre-exposed to 21% oxygen (normoxia) or 85% oxygen (hyperoxia) for 14 days after birth. Systolic and diastolic RV pressure were significantly higher at day 21 in hyperoxia exposed rats compared to normoxia control rats, but normalized by 35 days of age. Passive force, maximum Ca2+ activated force, and calcium sensitivity of force were elevated and cross-bridge cycling kinetics depressed in 21-day old hyperoxic trabeculae, whereas no differences between normoxic and hyperoxic trabeculae were seen at 35 days. Myofibrillar protein analysis revealed that 21-day old hyperoxic trabeculae had increased levels of beta-myosin heavy chain (beta-MHC), atrial myosin light chain 1 (aMLC1; often referred to as essential light chain), and slow skeletal troponin I (ssTnI) compared to age matched normoxic trabeculae. On the other hand, 35-day old normoxic and hyperoxic trabeculae expressed similar level of alpha- and beta-MHC, ventricular MLC1 and predominantly cTnI. These results suggest that neonatal exposure to hyperoxia increases RV afterload and affect both the steady state and dynamic contractile properties of the RV, likely as a result of hyperoxia-induced expression of beta-MHC, delayed transition of slow skeletal TnI to cardiac TnI, and expression of atrial MLC1. These hyperoxia-induced changes in contractile properties are reversible and accompany the resolution of PH with further developmental age, underscoring the importance of reducing RV afterload to allow for normalization of RV function in both animal models and humans with BPD. PMID- 29118722 TI - Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway. AB - Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Kruppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation. PMID- 29118721 TI - Gut-Brain Axis in Regulation of Blood Pressure. AB - Hypertension (HTN) is an escalating health issue worldwide. It is estimated that 1.56 billion people will suffer from high blood pressure (BP) by 2025. Recent studies reported an association between gut dysbiosis and HTN, thus proposing interesting avenues for novel treatments of this condition. The sympathetic nervous system (SNS) and the immune system (IS) play a recognized role in the onset and progression of HTN, while reciprocal communication between gut microbiota and the brain can regulate BP by modulating the interplay between the IS and SNS. This review presents the current state of the science implicating brain-gut connection in HTN, highlighting potential pathways of their interaction in control of BP. PMID- 29118723 TI - Inflammation, Stress Response, and Redox Dysregulation Biomarkers: Clinical Outcomes and Pharmacological Implications for Psychosis. AB - In recent years, several studies claiming the finding of a specific biomarker for the identification of the "high-risk state" to develop psychosis, first psychotic episode, as well as the prediction of the individual response to antipsychotics have been published. Together with genetic reports, numerous publications in this field have been focused on inflammation and stress response blood biomarkers, as well as on indicators of redox dysregulation. In this review, we focus on human studies found in PubMed from January 1st 2010 to January 31st 2017, describing the clinical use of these biomarkers to detect the "premorbid" psychotic state and early phases of the disease. Their pharmacological implications in predicting and monitoring the individual response to antipsychotic medication is also discussed. PMID- 29118724 TI - Alternations of White Matter Structural Networks in First Episode Untreated Major Depressive Disorder with Short Duration. AB - It is crucial to explore the pathogenesis of major depressive disorder (MDD) at the early stage for the better diagnostic and treatment strategies. It was suggested that MDD might be involving in functional or structural alternations at the brain network level. However, at the onset of MDD, whether the whole brain white matter (WM) alterations at network level are already evident still remains unclear. In the present study, diffusion MRI scanning was adopt to depict the unique WM structural network topology across the entire brain at the early stage of MDD. Twenty-one first episode, short duration (<1 year) and drug-naive depression patients, and 25 healthy control (HC) subjects were recruited. To construct the WM structural network, atlas-based brain regions were used for nodes, and the value of multiplying fiber number by the mean fractional anisotropy along the fiber bundles connected a pair of brain regions were used for edges. The structural network was analyzed by graph theoretic and network based statistic methods. Pearson partial correlation analysis was also performed to evaluate their correlation with the clinical variables. Compared with HCs, the MDD patients had a significant decrease in the small-worldness (sigma). Meanwhile, the MDD patients presented a significantly decreased subnetwork, which mainly involved in the frontal-subcortical and limbic regions. Our results suggested that the abnormal structural network of the orbitofrontal cortex and thalamus, involving the imbalance with the limbic system, might be a key pathology in early stage drug-naive depression. And the structural network analysis might be potential in early detection and diagnosis of MDD. PMID- 29118726 TI - The Relationship between Syntactic Satiation and Syntactic Priming: A First Look. AB - Syntactic satiation is the phenomenon where some sentences that initially seem ungrammatical appear more acceptable after repeated exposures (Snyder, 2000). We investigated satiation by manipulating two factors known to affect syntactic priming, a phenomenon where recent exposure to a grammatical structure facilitates subsequent processing of that structure (Bock, 1986). Specifically, we manipulated (i) Proximity of exposure (number of sentences between primes and targets) and (ii) Lexical repetition (type of phrase repeated across primes and targets). Experiment 1 investigated whether acceptability ratings of Complex-NP Constraint (CNPC) and Subject islands improve as consequence of these variables. If so, priming and satiation may be linked. When primes were separated from targets by one sentence, CNPC islands' acceptability was improved by a preceding island of the same type, but Subject islands' acceptability was not. When prime target pairs were separated by five sentences, we found no improvement for either island type. Experiment 2 asked whether improvements in Experiment 1 reflected online processing or offline end-of-sentence effects. We used a self-paced reading paradigm to diagnose online structure-building and processing facilitation (Ivanova et al., 2012a) during processing. We found priming for Subject islands when primes and targets were close together, but not when they were further apart. No effects were detected when CNPC islands were close together, but there was a localized effect when sentences were further apart. The disjunction between Experiments 1 and 2 suggests repetition of the structure in Subject islands facilitated online processing but did not 'spill over' to acceptability ratings. Meanwhile, results for CNPC islands suggest that acceptability rating improvements in Experiment 1 may be driven by factors distinct from online processing facilitation. Together, our experiments show that satiation may not be a one-size-fit-all phenomenon but, instead, appears to manifest itself differently for different types of structures. Priming is possible and may be linked to satiation in some purportedly "unbuildable" structures (e.g., Subject islands), but not for all types (e.g., CNPC islands). Despite this, it appears that while the types of mechanisms targeting different island types are distinct, they are nevertheless similarly sensitive to the proximity between individual exposures. PMID- 29118725 TI - Cognitive and Neural Correlates of Mathematical Giftedness in Adults and Children: A Review. AB - Most mathematical cognition research has focused on understanding normal adult function and child development as well as mildly and moderately impaired mathematical skill, often labeled developmental dyscalculia and/or mathematical learning disability. In contrast, much less research is available on cognitive and neural correlates of gifted/excellent mathematical knowledge in adults and children. In order to facilitate further inquiry into this area, here we review 40 available studies, which examine the cognitive and neural basis of gifted mathematics. Studies associated a large number of cognitive factors with gifted mathematics, with spatial processing and working memory being the most frequently identified contributors. However, the current literature suffers from low statistical power, which most probably contributes to variability across findings. Other major shortcomings include failing to establish domain and stimulus specificity of findings, suggesting causation without sufficient evidence and the frequent use of invalid backward inference in neuro-imaging studies. Future studies must increase statistical power and neuro-imaging studies must rely on supporting behavioral data when interpreting findings. Studies should investigate the factors shown to correlate with math giftedness in a more specific manner and determine exactly how individual factors may contribute to gifted math ability. PMID- 29118727 TI - Huggable Communication Medium Maintains Level of Trust during Conversation Game. AB - There have been several attempts in recent years to develop a remote communication device using sensory modalities other than speech that would induce a user's positive experience with his/her conversation partner. Specifically, Hugvie is a human-shaped pillow as well as a remote communication device enabling users to combine a hugging experience with telecommunication to improve the quality of remote communication. The present research is based on the hypothesis that using Hugvie maintains users' level of trust toward their conversation partners in situations prone to suspicion. The level of trust felt toward other remote game players was compared between participants using Hugvie and those using a basic communication device while playing a modified version of Werewolf, a conversation-based game, designed to evaluate trust. Although there are always winners and losers in the regular version of Werewolf, the rules were modified to generate a possible scenario in which no enemy was present among the players and all players would win if they trusted each other. We examined the effect of using Hugvie while playing Werewolf on players' level of trust toward each other and our results demonstrated that in those using Hugvie, the level of trust toward other players was maintained. PMID- 29118729 TI - Employees' Perceived Opportunities to Craft and In-Role Performance: The Mediating Role of Job Crafting and Work Engagement. AB - The present study was designed to gain knowledge of the relationship between employees' perceived opportunities to craft, their actual job crafting behavior and, in line with JD-R theory, subsequently their work engagement and performance. Although scholars have suggested that employees' perceived opportunities to craft their job may predict their actual job crafting behavior, which may have consequences for their well-being and performance, no study has examined the relationships between these variables. We collected data among a heterogeneous group of Dutch employees (N = 2090). Participants of the study reported their perceived opportunities to craft, job crafting behavior, work engagement and performance. Results indicated that individuals who experience a high level of opportunities to craft reported higher levels of job crafting behavior. In turn, perceived opportunities to craft and job crafting behavior related to higher levels of work engagement and subsequently performance. We discuss the implications of these findings for theory and practice. PMID- 29118728 TI - Mutual Influence of Reward Anticipation and Emotion on Brain Activity during Memory Retrieval. AB - Previous studies on the joint effect of reward motivation and emotion on memory retrieval have obtained inconsistent results. Furthermore, whether and how any such joint effect might vary over time remains unclear too. Accordingly, using the event-related potential (ERP) measurement of high temporal resolution, our study investigates the cognitive and brain mechanisms of monetary reward and emotion affecting the retrieval processes of episodic memory. Twenty undergraduate and graduate students participated in the research, and our study's behavioral results indicated that reward (relative to no reward) and negative emotion (relative to positive and neutral emotion) significantly improved recognition performance. The ERP results showed that there were significant interactions between monetary reward and emotion on memory retrieval, and the reward effects of positive, neutral, and negative memory occurred at varied intervals in mean amplitude. The reward effect of positive memory appeared relatively early, at 260-330 ms after the stimulus onset in the frontal frontocentral area, at 260-500 ms in the centroparietal-parietal area and at 500 700 ms in the frontocentral area. However, the reward effects of neutral and negative memory occurred relatively later, and that of negative memory appeared at 500-700 ms in the frontocentral and centroparietal area and that of neutral memory was at 500-700 ms in the frontocentral and centroparietal-parietal area. Meanwhile, significant FN400 old/new effects were observed in the negative and rewarded positive items, and the old/new effects of negative items appeared earlier at FN400 than positive items. Also, significant late positive component (LPC) old/new effects were found in the positive, negative, and rewarded neutral items. These results suggest that, monetary reward and negative emotion significantly improved recognition performance, and there was a mutual influence between reward and emotion on brain activity during memory retrieval. PMID- 29118730 TI - Color Image Norms in Mandarin Chinese. AB - The present study comprises two parts, an object picture naming task and rating tasks, and reports naming latencies and norms for 435 color images in Mandarin Chinese. These norms include name agreement (%), H-value, concept agreement, familiarity, visual complexity, age of acquisition (AOA) based on adult ratings, object agreement, viewpoint agreement, word frequency, and word length. We examined correlations between the norms and explored the internal structure among these correlative variables by a factor analysis. Four factors were extracted, which accounted for 74.86% of the total variance. These data were analyzed to identify variables with significant contributions to naming latencies using multiple regression analysis, including norms of name agreement (%), familiarity, word frequency, concept agreement, AOA, and object agreement. These variables explained 54.70% of the total variance of naming latencies. This work presents a new set of photo stimuli and a large set of normalized variables. We expect that this study will provide useful materials for further researches. PMID- 29118731 TI - The Indirect Effect of Emotion Regulation on Minority Stress and Problematic Substance Use in Lesbian, Gay, and Bisexual Individuals. AB - Lesbian, gay, and bisexual (LGB) individuals report higher levels of problematic alcohol and substance use than their heterosexual peers. This disparity is linked to the experience of LGB-specific stressors, termed minority stress. Additionally, bisexual individuals show increased rates of psychopathology, including problematic alcohol and substance use, above and beyond lesbian and gay individuals. However, not everyone experiencing minority stress reports increased rates of alcohol and substance misuse. Emotion regulation (ER), which plays a critical role in psychopathology in general, is theorized to modulate the link between minority stress and psychopathology. However, it remains largely unknown whether ER plays a role in linking instances of minority stress with substance and alcohol use outcomes. To address the gap, the current study assessed 305 LGB individuals' instances of minority stress, ER, and substance and alcohol use outcomes. We assessed the role of ER in problematic alcohol and substance use among LGB individuals using moderated mediation, where sexual minority status was entered as the moderator, and ER difficulties was entered as the mediator. The results indicated significant indirect effects of minority stress, through ER difficulties, on both problematic alcohol and substance use. However, there was no significant interaction with sexual orientation status, suggesting that ER may be important for all LGB individuals in predicting problematic alcohol and substance use. These results highlight the important role that ER plays between instances of minority stress and substance and alcohol use in LGB individuals, suggesting that ER skills may serve as a novel target for intervention. PMID- 29118732 TI - Editorial: Brain-Mind-Body Practice and Health. PMID- 29118734 TI - Editorial: Mental Health Challenges in Elite Sport: Balancing Risk with Reward. PMID- 29118733 TI - Testing Measurement Invariance across Groups of Children with and without Attention-Deficit/ Hyperactivity Disorder: Applications for Word Recognition and Spelling Tasks. AB - Although studies have consistently demonstrated that children with attention deficit/hyperactivity disorder (ADHD) perform significantly lower than controls on word recognition and spelling tests, such studies rely on the assumption that those groups are comparable in these measures. This study investigates comparability of word recognition and spelling tests based on diagnostic status for ADHD through measurement invariance methods. The participants (n = 1,935; 47% female; 11% ADHD) were children aged 6-15 with normal IQ (>=70). Measurement invariance was investigated through Confirmatory Factor Analysis and Multiple Indicators Multiple Causes models. Measurement invariance was attested in both methods, demonstrating the direct comparability of the groups. Children with ADHD were 0.51 SD lower in word recognition and 0.33 SD lower in spelling tests than controls. Results suggest that differences in performance on word recognition and spelling tests are related to true mean differences based on ADHD diagnostic status. Implications for clinical practice and research are discussed. PMID- 29118735 TI - Divergent Thinking in Parkinsonism: A Case-Control Study. AB - Background: Creativity is a multidimensional phenomenon and an important component of human capacities. This ability is characterized by the involvement of several cognitive functions particularly linked to the prefrontal cortex. We compared divergent thinking, a measure of creativity, in patients affected by progressive supranuclear palsy (PSP), other parkinsonian syndromes, and healthy controls (HCs). Methods: Creativity features were evaluated using the Abbreviated Torrance Test for Adults (ATTA). Consecutive PSP outpatients were screened for inclusion. Then, patients with multiple system atrophy (MSA) and Parkinson's disease (PD) and a group of HC were studied. All groups have preserved cognitive functions and were matched for gender, education, disease duration, and age at onset with exception of PD patients who were matched by disease severity rather than disease duration. Results: PSP patients were characterized by lower values in total ATTA and all subscales than HC and both MSA and PD patients. No differences were found comparing HC versus both MSA and PD patients. PSP patients were characterized by more impaired frontal functioning [assessed by means of Frontal Assessment Battery (FAB)] than HC and both PD and MSA patients. Conclusion: In the present study, ATTA was significantly lower in PSP patients than in the other study groups. The worst performance in ATTA-total score and the lower score in FAB in PSP patients support the role of frontal function in creative processes. PMID- 29118737 TI - A Case Series of Adult-Onset Rasmussen's Encephalitis: Diagnostic and Therapeutic Challenges. AB - Rasmussen's encephalitis (RE) is a rare neurologic disorder characterized by progressive cerebral hemiatrophy and medically refractory epilepsy. The majority of current literature on this topic is focused on the pediatric population. In this case series, we will review three cases of adult-onset RE, as defined by fulfillment of the 2005 Bien criteria. The diagnostic challenge of characterizing this rare disease will be highlighted by the extensive serum, CSF, and pathologic sampling in all three patients. MR imaging and EEG data will be examined over time to characterize hallmark findings as well as progression. In addition, we will review the various forms of therapy attempted in these three patients, namely anti-epileptic drug therapy and immunomodulatory therapy. We will also utilize this case series to critically evaluate the broader context of atypical presentations of this disease and the value of current diagnostic criteria. PMID- 29118738 TI - Monitoring of Dual CRISPR/Cas9-Mediated Steroidogenic Acute Regulatory Protein Gene Deletion and Cholesterol Accumulation Using High-Resolution Fluorescence In Situ Hybridization in a Single Cell. AB - Recent advances in fluorescence microscopy, coupled with CRISPR/Cas9 gene editing technology, provide opportunities for understanding gene regulation at the single cell level. The application of direct imaging shown here provides an in situ side by-side comparison of CRISPR/Cas9-edited cells and adjacent unedited cells. We apply this methodology to the steroidogenic acute regulatory protein (StAR) gene in Y-1 adrenal cells and MA-10 testis cells. StAR is a gatekeeper protein that controls the access of cholesterol from the cytoplasm to the inner mitochondria. The loss of this mitochondrial cholesterol transfer mediator rapidly increases lipid droplets in cells, as seen in StAR-/- mice. Here, we describe a dual CRISPR/Cas9 strategy marked by GFP/mCherry expression that deletes StAR activity within 12 h. We used single-molecule fluorescence in situ hybridization (sm-FISH) imaging to directly monitor the time course of gene editing in single cells. We achieved StAR gene deletion at high efficiency dual gRNA targeting to the proximal promoter and exon 2. Seventy percent of transfected cells showed a slow DNA deletion as measured by PCR, and loss of Br-cAMP stimulated transcription. This DNA deletion was seen by sm-FISH in both loci of individual cells relative to non-target Cyp11a1 and StAR exon 7. sm-FISH also distinguishes two effects on stimulated StAR expression without this deletion. Br-cAMP stimulation of primary and spliced StAR RNA at the gene loci were removed within 4 h in this dual CRISPR/Cas9 strategy before any effect on cytoplasmic mRNA and protein occurred. StAR mRNA disappeared between 12 and 24 h in parallel with this deletion, while cholesterol ester droplets increased fourfold. These alternative changes match distinct StAR expression processes. This dual gRNA and sm-FISH approach to CRISPR/Cas9 editing facilitates rapid testing of editing strategies and immediate assessment of single-cell adaptation responses without the perturbation of clonal expansion procedures. PMID- 29118739 TI - Resolving Species Level Changes in a Representative Soil Bacterial Community Using Microfluidic Quantitative PCR. AB - Rapid advances in genome sequencing technologies enable determination of relative bacterial abundances and community composition, yet, changes at the species level remain difficult to detect despite importance for certain ecological inferences. We present a method for extraction and direct quantification of species composition of a predefined multispecies bacterial community using microfluidic based quantitative real-time PCR (qPCR). We employ a nested PCR approach based on universal 16S rRNA gene pre-amplification followed by detection and quantification of absolute abundance of bacterial species using microfluidic array of parallel singleplex qPCR reactions. Present microfluidic qPCR supports 2,304 simultaneous reactions on a single chip, while automatic distribution of samples and reactants minimizes pipetting errors and technical variations. The utility of the method is illustrated using a synthetic soil bacterial community grown in two contrasting environments - sand microcosms and batch cultures. The protocol entails extraction of total nucleic acid, preparation of genomic DNA, and steps for qPCR assessment of bacterial community composition. This method provides specific and sensitive quantification of bacterial species requiring only 2 ng of community DNA. Optimized extraction protocol and preamplification step allow for rapid, quantitative, and simultaneous detection of candidate species with high throughput. The proposed method offers a simple and accurate alternative to present sequencing methods especially when absolute values of species abundance are required. Quantification of changes at the species level contributes to the mechanistic understanding of the roles of particular species in a bacterial community functioning. PMID- 29118740 TI - Response to Trypanosoma cruzi by Human Blood Cells Enriched with Dentritic Cells Is Controlled by Cyclooxygenase-2 Pathway. AB - Chagas disease (Cd) or American human trypanosomiasis is caused by Trypanosoma cruzi and affects ~7 million people, mostly in Latin America. The infective trypomastigote forms of the parasite can invade several human blood cell populations, including monocytes and dendritic cells (DC). Although these cells display a wide functional diversity, their interactions with T. cruzi via cyclooxygenase (COX) and cyclic adenosine monophosphate (cAMP) dependent pathways have not been analyzed. To exploiting this mechanism, DC-enriched peripheral human blood mononuclear cell populations (DC-PBMC) were used as our model. Our results showed that the treatment of these cell populations with celecoxib (CEL), a cyclooxygenase-2 selective inhibitor or SQ 22,536, an adenilate cyclase inhibitor, significantly caused marked inhibition of T. cruzi infection. In contrast, aspirin (ASA, a non-selective COX-1 and COX-2 inhibitor) treatment did not inhibit the infection of the cells by the parasite and was independent of nitric oxide (NO) production. The expression of co-stimulatory molecules CD80 and CD86 were similar on cells treated or not with both COX-inhibitors. The infection stimulated the release of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10 production by infected cells. Treatment with ASA or CEL did not affect TNF-alpha, IL-6, IL 8, IL-10, and NO production by infected cells, but increased IL-1beta production by them. Our results suggest a key role of COX-2 and cAMP pathways in T. cruzi invasion process of human blood cells and these pathways may represent targets of new therapeutic options for Cd. PMID- 29118736 TI - Perception of Upright: Multisensory Convergence and the Role of Temporo-Parietal Cortex. AB - We inherently maintain a stable perception of the world despite frequent changes in the head, eye, and body positions. Such "orientation constancy" is a prerequisite for coherent spatial perception and sensorimotor planning. As a multimodal sensory reference, perception of upright represents neural processes that subserve orientation constancy through integration of sensory information encoding the eye, head, and body positions. Although perception of upright is distinct from perception of body orientation, they share similar neural substrates within the cerebral cortical networks involved in perception of spatial orientation. These cortical networks, mainly within the temporo-parietal junction, are crucial for multisensory processing and integration that generate sensory reference frames for coherent perception of self-position and extrapersonal space transformations. In this review, we focus on these neural mechanisms and discuss (i) neurobehavioral aspects of orientation constancy, (ii) sensory models that address the neurophysiology underlying perception of upright, and (iii) the current evidence for the role of cerebral cortex in perception of upright and orientation constancy, including findings from the neurological disorders that affect cortical function. PMID- 29118741 TI - Analysis of the Germination of Individual Clostridium sporogenes Spores with and without Germinant Receptors and Cortex-Lytic Enzymes. AB - The Gram-positive spore-forming anaerobe Clostridium sporogenes is a significant cause of food spoilage, and it is also used as a surrogate for C. botulinum spores for testing the efficacy of commercial sterilization. C. sporogenes spores have also been proposed as a vector to deliver drugs to tumor cells for cancer treatments. Such an application of C. sporogenes spores requires their germination and return to life. In this study, Raman spectroscopy and differential interference contrast (DIC) microscopy were used to analyze the germination kinetics of multiple individual C. sporogenes wild-type and germination mutant spores. Most individual C. sporogenes spores germinated with L alanine began slow leakage of ~5% of their large Ca-dipicolinic acid (CaDPA) depot at T1, all transitioned to rapid CaDPA release at Tlag1, completed CaDPA release at Trelease, and finished peptidoglycan cortex hydrolysis at Tlys. T1, Tlag1, Trelease, and Tlys times for individual spores were heterogeneous, but DeltaTrelease (Trelease - Tlag1) periods were relatively constant. However, variability in T1 (or Tlag1) times appeared to be the major reason for the heterogeneity between individual spores in their germination times. After Trelease, some spores also displayed another lag in rate of change in DIC image intensity before the start of a second obvious DIC image intensity decline of 25 30% at Tlag2 prior to Tlys. This has not been seen with spores of other species. Almost all C. sporogenes spores lacking the cortex-lytic enzyme (CLE) CwlJ spores exhibited a Tlag2 in L-alanine germination. Sublethal heat treatment potentiated C. sporogenes spore germination with L-alanine, primarily by shortening T1 times. Spores without the CLEs SleB or CwlJ exhibited greatly slowed germination with L alanine, but spores lacking all germinant receptor proteins did not germinate with L-alanine. The absence of these various germination proteins also decreased but did not abolish germination with the non-GR-dependent germinants dodecylamine and CaDPA, but spores without CwlJ exhibited no germination with CaDPA. Finally, C. sporogenes spores displayed commitment in germination, but memory in GR dependent germination was small, and less than the memory in Bacillus spore germination. PMID- 29118742 TI - Diets Alter the Gut Microbiome of Crocodile Lizards. AB - The crocodile lizard is a critically endangered reptile, and serious diseases have been found in this species in recent years, especially in captive lizards. Whether these diseases are caused by changes in the gut microbiota and the effect of captivity on disease remains to be determined. Here, we examined the relationship between the gut microbiota and diet and disease by comparing the fecal microbiota of wild lizards with those of sick and healthy lizards in captivity. The gut microbiota in wild crocodile lizards was consistently dominated by Proteobacteria (~56.4%) and Bacteroidetes (~19.1%). However, the abundance of Firmicutes (~2.6%) in the intestine of the wild crocodile lizards was distinctly lower than that in other vertebrates. In addition, the wild samples from Guangdong Luokeng Shinisaurus crocodilurus National Nature Reserve also had a high abundance of Deinococcus-Thermus while the wild samples from Guangxi Daguishan Crocodile Lizard National Nature Reserve had a high abundance of Tenericutes. The gut microbial community in loach-fed crocodile lizards was significantly different from the gut microbial community in the earthworm-fed and wild lizards. In addition, significant differences in specific bacteria were detected among groups. Notably, in the gut microbiota, the captive lizards fed earthworms resulted in enrichment of Fusobacterium, and the captive lizards fed loaches had higher abundances of Elizabethkingia, Halomonas, Morganella, and Salmonella, all of which are pathogens or opportunistic pathogens in human or other animals. However, there is no sufficient evidence that the gut microbiota contributes to either disease A or disease B. These results provide a reference for the conservation of endangered crocodile lizards and the first insight into the relationship between disease and the gut microbiota in lizards. PMID- 29118743 TI - Salinity-Based Toxicity of CuO Nanoparticles, CuO-Bulk and Cu Ion to Vibrio anguillarum. AB - Bacteria are used in ecotoxicology for their important role in marine ecosystems and their quick, reproducible responses. Here we applied a recently proposed method to assess the ecotoxicity of nanomaterials on the ubiquitous marine bacterium Vibrio anguillarum, as representative of brackish and marine ecosystems. The test allows the determination of 6-h EC50 in a wide range of salinity, by assessing the reduction of bacteria actively replicating and forming colonies. The toxicity of copper oxide nanoparticles (CuO NPs) at different salinities (5-20-35 0/00) was evaluated. CuSO4 5H2O and CuO bulk were used as reference toxicants (solubility and size control, respectively). Aggregation and stability of CuO NP in final testing dispersions were characterized; Cu2+ dissolution and the physical interactions between Vibrio and CuO NPs were also investigated. All the chemical forms of copper showed a clear dose-response relationship, although their toxicity was different. The order of decreasing toxicity was: CuSO4 5H2O > CuO NP > CuO bulk. As expected, the size of CuO NP aggregates increased with salinity and, concurrently, their toxicity decreased. Results confirmed the intrinsic toxicity of CuO NPs, showing modest Cu2+ dissolution and no evidence of CuO NP internalization or induction of bacterial morphological alterations. This study showed the V. anguillarum bioassay as an effective tool for the risk assessment of nanomaterials in marine and brackish environments. PMID- 29118745 TI - Biofilm Structures in a Mono-Associated Mouse Model of Clostridium difficile Infection. AB - Clostridium difficile infection (CDI) is a major healthcare-associated disease with high recurrence rates. Host colonization is critical for the infectious process, both in first episodes and in recurrent disease, with biofilm formation playing a key role. The ability of C. difficile to form a biofilm on abiotic surfaces is established, but has not yet been confirmed in the intestinal tract. Here, four different isolates of C. difficile, which are in vitro biofilm producers, were studied for their ability to colonize germ-free mice. The level of colonization achieved was similar for all isolates in the different parts of the murine gastrointestinal tract, but pathogen burden was higher in the cecum and colon. Confocal laser scanning microscopy revealed that C. difficile bacteria were distributed heterogeneously over the intestinal tissue, without contact with epithelial cells. The R20291 strain, which belongs to the Ribotype 027 lineage, displayed a unique behavior compared to the other strains by forming numerous aggregates. By immunochemistry analyses, we showed that bacteria were localized inside and outside the mucus layer, irrespective of the strains tested. Most bacteria were entrapped in 3-D structures overlaying the mucus layer. For the R20291 strain, the cell-wall associated polysaccharide PS-II was detected in large amounts in the 3-D structure. As this component has been detected in the extrapolymeric matrix of in vitro C. difficile biofilms, our data suggest strongly that at least the R20291 strain is organized in the mono-associated mouse model in glycan-rich biofilm architecture, which sustainably maintains bacteria outside the mucus layer. PMID- 29118744 TI - Two Lactobacillus Species Inhibit the Growth and alpha-Toxin Production of Clostridium perfringens and Induced Proinflammatory Factors in Chicken Intestinal Epithelial Cells in Vitro. AB - Clostridium perfringens is the causative pathogen of avian necrotic enteritis. Lactobacillus spp. are well-characterized probiotics with anti-microbial and immune-modulatory activities. In the present study, we investigated the effects of L. acidophilus and L. fermentum on the growth, alpha-toxin production and inflammatory responses of C. perfringens. In in vitro culture experiments, both lactobacilli inhibited the growth of C. perfringens (P < 0.01), accompanied with a decrease in pH (P < 0.01). Supernatants from lactobacilli cultures also suppressed the growth of C. perfringens during 24 h of incubation (P < 0.01), but this inhibitory effect disappeared after 48 h. Both lactobacilli decreased the alpha-toxin production of C. perfringens (P < 0.01) without influencing its biomass, and even degraded the established alpha-toxin (P < 0.01). Lower environmental pH reduced the alpha-toxin production as well (P < 0.01). Preincubation with L. acidophilus decreased the attachment of C. perfringens to cells (P < 0.01) with the cell cytotoxicity being unaffected. Both lactobacilli pretreatment reduced the up-regulation of proinflammatory factors, peptidoglycan (PGN) receptors and nuclear factor kappa B (NF-kappaB) p65 in C. perfringens challenged chicken intestinal epithelial cells (P < 0.05). In conclusion, L. acidophilus and L. fermentum inhibited the pathological effects of C. perfringens in vitro conditions. PMID- 29118746 TI - The Use of Mixed Populations of Saccharomyces cerevisiae and S. kudriavzevii to Reduce Ethanol Content in Wine: Limited Aeration, Inoculum Proportions, and Sequential Inoculation. AB - Saccharomyces cerevisiae is the most widespread microorganism responsible for wine alcoholic fermentation. Nevertheless, the wine industry is currently facing new challenges, some of them associate with climate change, which have a negative effect on ethanol content and wine quality. Numerous and varied strategies have been carried out to overcome these concerns. From a biotechnological point of view, the use of alternative non-Saccharomyces yeasts, yielding lower ethanol concentrations and sometimes giving rise to new and interesting aroma, is one of the trendiest approaches. However, S. cerevisiae usually outcompetes other Saccharomyces species due to its better adaptation to the fermentative environment. For this reason, we studied for the first time the use of a Saccharomyces kudriavzevii strain, CR85, for co-inoculations at increasing proportions and sequential inoculations, as well as the effect of aeration, to improve its fermentation performance in order to obtain wines with an ethanol yield reduction. An enhanced competitive performance of S. kudriavzevii CR85 was observed when it represented 90% of the cells present in the inoculum. Furthermore, airflow supply of 20 VVH to the fermentation synergistically improved CR85 endurance and, interestingly, a significant ethanol concentration reduction was achieved. PMID- 29118747 TI - Emerging Targets for Developing T Cell-Mediated Vaccines for Human Immunodeficiency Virus (HIV)-1. AB - Human immunodeficiency virus (HIV)-1 has infected >75 million individuals globally, and, according to the UN, is responsible for ~2.1 million new infections and 1.1 million deaths each year. Currently, there are ~37 million individuals with HIV infection and the epidemic has already resulted in 35 million deaths. Despite the advances of anti-retroviral therapy (ART), a cost effective vaccine remains the best long-term solution to end the HIV-1 epidemic especially given that the vast majority of infected individuals live in poor socio-economic regions of the world such as Sub-Saharan Africa which limits their accessibility to ART. The modest efficacy of the RV144 Thai trial provides hope that a vaccine for HIV-1 is possible, but as markers for sterilizing immunity are unknown, the design of an effective vaccine is empirical, although broadly cross reactive neutralizing antibodies (bNAb) that can neutralize various quasispecies of HIV-1 are considered crucial. Since HIV-1 transmission often occurs at the genito-rectal mucosa and is cell-associated, there is a need to develop vaccines that can elicit CD8+ T cell immunity with the capacity to kill virus infected cells at the genito-rectal mucosa and the gut. Here we discuss the recent progress made in developing T cell-mediated vaccines for HIV-1 and emphasize the need to elicit mucosal tissue-resident memory CD8+ T (CD8+ Trm) cells. CD8+ Trm cells will likely form a robust front-line defense against HIV-1 and eliminate transmitter/founder virus-infected cells which are responsible for propagating HIV-1 infections following transmission in vast majority of cases. PMID- 29118748 TI - Remarkable Diversity of Escherichia coli Carrying mcr-1 from Hospital Sewage with the Identification of Two New mcr-1 Variants. AB - The plasmid-borne colistin-resistant gene mcr-1 has rapidly become a worldwide public health concern. This study aims to determine the host bacterial strains, plasmids, and genetic contexts of mcr-1 in hospital sewage. A 1-ml hospital sewage sample was cultured. Colistin-resistant bacterial colonies were selected on agar plates and were subjected to whole genome sequencing and subsequent analysis. The transfer of mcr-1 between bacterial strains was tested using conjugation. New variants of mcr-1 were cloned to test the impact of variations on the function of mcr-1. Plasmids carrying mcr-1 were retrieved from GenBank for comparison based on concatenated backbone genes. In the sewage sample, we observed that mcr-1 was located in various genetic contexts on the chromosome, or plasmids of four different replicon types (IncHI2, IncI2, IncP, and IncX4), in Klebsiella pneumoniae, Kluyvera spp. and seven Escherichia coli strains of six different sequence types (ST10, ST34, ST48, ST1196, ST7086, and ST7087). We also identified two new variants of mcr-1, mcr-1.4 and mcr-1.7, both of which encode an amino acid variation from mcr-1. mcr-1-carrying IncX4 plasmids, which have a global distribution across the Enterobacteriaceae, are the result of global dissemination of a single common plasmid, while IncI2 mcr-1 plasmids appear to acquire mcr-1 in multiple events. In conclusion, the unprecedented remarkable diversity of species, strains, plasmids, and genetic contexts carrying mcr-1 present in a single sewage sample from a single healthcare site highlights the continued evolution and dynamic transmission of mcr-1 in healthcare-associated environments. PMID- 29118749 TI - Hoisting-Loop in Bacterial Multidrug Exporter AcrB Is a Highly Flexible Hinge That Enables the Large Motion of the Subdomains. AB - The overexpression of RND-type exporters is one of the main causes of multidrug resistance (MDR) in Gram-negative pathogens. In RND transporters, such as Escherichia coli's main efflux pump AcrB, drug efflux occurs in the porter domain, while protons flow through the transmembrane domain: remote conformational coupling. At the border of a transmembrane helix (TM8) and subdomain PC2, there is a loop which makes a hoisting movement by a random-coil to-alpha-helix change, and opens and closes a drug channel entrance. This loop is supposed to play a key role in the allosteric conformational coupling between the transmembrane and porter domain. Here we show the results of a series of flexibility loop-mutants of AcrB. We determined the crystal structure of a three amino acid truncated loop mutant, which is still a functional transporter, and show that the short alpha-helix between Cbeta15 and the loop unwinds to a random coil in the access and binding monomers and in the extrusion monomer it makes a partially stretched coil-to-helix change. The loop has undergone compensatory conformational changes and still facilitates the opening and closing of the channel. In addition, more flexible mutated loops (proline mutated and significantly elongated) can still function during export. The flexibility in this region is however limited, as an even more truncated mutant (six amino acid deletion) becomes mostly inactive. We found that the hoisting-loop is a highly flexible hinge that enables the conformational energy transmission passively. PMID- 29118750 TI - An RNA Virome Associated to the Golden Orb-Weaver Spider Nephila clavipes. AB - The golden orb-weaver spider Nephila clavipes, known for its sexual size dimorphism, is abundant and widespread in the New World. The first annotated genome of orb-weaver spiders, exploring N. clavipes, has recently been reported. The study, focused primarily on the diversity of silk specific genes, shed light into the complex evolutionary history of spiders. Furthermore, a robust transcriptome analysis provided a massive resource for N. clavipes RNA survey. Here, I present evidence of viral sequences corresponding to the first 10 extant virus species associated to N. clavipes and indeed, nephilids. The putatively new species are linked to ssRNA positive-strand viruses, such as Picornavirales, and to ssRNA negative-strand and dsRNA viruses. In addition, I detected sequence data of new strains of two recently reported arthropod viruses, which complemented and extended the corresponding sequence references. The identified viruses appear to be complete, potentially functional, and presenting the typical architecture and consistent viral domains. The intrinsic nature of the detected sequences and their absence in the recently generated genome assembly, suggest that they correspond to bona fide RNA virus sequences. The available RNA data allowed for the first time to address a tissue/organ specific analysis of virus loads/presence in spiders, suggesting a complex spatial and differential distribution of the tentative viruses, encompassing the spider brain and also silk and venom glands. Until recently, the virus landscape associated to spiders remained elusive. The discovered viruses described here provide only a fragmented glimpse of the potential magnitude of the Aranea virosphere. Future studies should focus not only on complementing and expanding these findings, but also on addressing the potential ecological role of these viruses, which might influence the biology of these outstanding arthropod species. PMID- 29118751 TI - Cyanobacteria and Alphaproteobacteria May Facilitate Cooperative Interactions in Niche Communities. AB - Hypoliths, microbial assemblages found below translucent rocks, provide important ecosystem services in deserts. While several studies have assessed microbial diversity of hot desert hypoliths and whether these communities are metabolically active, the interactions among taxa remain unclear. Here, we assessed the structure, diversity, and co-occurrence patterns of hypolithic communities from the hyperarid Namib Desert by comparing total (DNA) and potentially active (RNA) communities. The potentially active and total hypolithic communities differed in their composition and diversity, with significantly higher levels of Cyanobacteria and Alphaproteobacteria in potentially active hypoliths. Several phyla known to be abundant in total hypolithic communities were metabolically inactive, indicating that some hypolithic taxa may be dormant or dead. The potentially active hypolith network was highly modular in structure with almost exclusively positive co-occurrences (>95% of the total) between taxa. Members of the Cyanobacteria and Alphaproteobacteria were identified as potential keystone taxa, and exhibited numerous positive co-occurrences with other microbes, suggesting that these groups might have important roles in maintaining network topological structure despite their low abundance. PMID- 29118752 TI - Role of the Human Breast Milk-Associated Microbiota on the Newborns' Immune System: A Mini Review. AB - The human milk is fundamental for a correct development of newborns, as it is a source not only of vitamins and nutrients, but also of commensal bacteria. The microbiota associated to the human breast milk contributes to create the "initial" intestinal microbiota of infants, having also a pivotal role in modulating and influencing the newborns' immune system. Indeed, the transient gut microbiota is responsible for the initial change from an intrauterine Th2 prevailing response to a Th1/Th2 balanced one. Bacteria located in both colostrum and mature milk can stimulate the anti-inflammatory response, by stimulating the production of specific cytokines, reducing the risk of developing a broad range of inflammatory diseases and preventing the expression of immune-mediated pathologies, such as asthma and atopic dermatitis. The aim of the present Mini Review is to elucidate the specific immunologic role of the human milk-associated microbiota and its impact on the newborn's health and life, highlighting the importance to properly study the biological interactions in a bacterial population and between the microbiota and the host. The Auto Contractive Map, for instance, is a promising analytical methodology based on artificial neural network that can elucidate the specific role of bacteria contained in the breast milk in modulating the infants' immunological response. PMID- 29118754 TI - Critical Role of Plasmacytoid Dendritic Cells in Regulating Gene Expression and Innate Immune Responses to Human Rhinovirus-16. AB - Though human rhinoviruses (HRVs) are usually innocuous viruses, they can trigger serious consequences in certain individuals, especially in the setting of impaired interferon (IFN) synthesis. Plasmacytoid dendritic cells (pDCs) are key IFN producing cells, though we know little about the role of pDC in HRV-induced immune responses. Herein, we used gene expression microarrays to examine HRV activated peripheral blood mononuclear cells (PBMCs) from healthy people, in combination with pDC depletion, to assess whether observed gene expression patterns were pDC dependent. As expected, pDC depletion led to a major reduction in IFN-alpha release. This was associated with profound differences in gene expression between intact PBMC and pDC-depleted PBMC, and major changes in upstream regulators: 70-80% of the HRV activated genes appeared to be pDC dependent. Real-time PCR confirmed key changes in gene expression, in which the following selected genes were shown to be highly pDC dependent: the transcription factor IRF7, both IL-27 chains (IL-27p28 and EBI3), the alpha chain of the IL-15 receptor (IL-15RA) and the IFN-related gene IFI27. HRV-induced IL-6, IFN-gamma, and IL-27 protein synthesis were also highly pDC dependent. Supplementing pDC depleted cultures with recombinant IL-15, IFN-gamma, IL-27, or IL-6 was able to restore the IFN-alpha response, thereby compensating for the absence of pDC. Though pDC comprise only a minority population of migratory leukocytes, our findings highlight the profound extent to which these cells contribute to the immune response to HRV. PMID- 29118753 TI - Intestinal Epithelial Cell Endoplasmic Reticulum Stress and Inflammatory Bowel Disease Pathogenesis: An Update Review. AB - The intestinal epithelial cells serve essential roles in maintaining intestinal homeostasis, which relies on appropriate endoplasmic reticulum (ER) function for proper protein folding, modification, and secretion. Exogenous or endogenous risk factors with an ability to disturb the ER function can impair the intestinal barrier function and activate inflammatory responses in the host. The last decade has witnessed considerable progress in the understanding of the functional role of ER stress and unfolded protein response (UPR) in the gut homeostasis and its significant contribution to the pathogenesis of inflammatory bowel disease (IBD). Herein, we review recent evidence supporting the viewpoint that deregulation of ER stress and UPR signaling in the intestinal epithelium, including the absorptive cells, Paneth cells, goblet cells, and enteroendocrine cells, mediates the action of genetic or environmental factors driving colitis in experimental animals and IBD patients. In addition, we highlight pharmacologic application of chaperones or small molecules that enhance protein folding and modification capacity or improve the function of the ER. These molecules represent potential therapeutic strategies in the prevention or treatment of IBD through restoring ER homeostasis in intestinal epithelial cells. PMID- 29118756 TI - TH17 Cell and Epithelial Cell Crosstalk during Inflammatory Bowel Disease and Carcinogenesis. AB - The intestine is colonized by hundreds of different species of commensal bacteria, viruses, and fungi. Therefore, the intestinal immune system is constantly being challenged by foreign antigens. The immune system, the commensal microbiota, and the intestinal epithelial surface have to maintain a tight balance to guarantee defense against potential pathogens and to prevent chronic inflammatory conditions at the same time. Failure of these mechanisms can lead to a vicious cycle in which a perpetual tissue damage/repair process results in a pathological reorganization of the normal mucosal surface. This dysregulation of the intestine is considered to be one of the underlying causes for both inflammatory bowel disease (IBD) and colorectal cancer. TH17 cells have been associated with immune-mediated diseases, such as IBD, since their discovery in 2005. Upon mucosal damage, these cells are induced by a combination of different cytokines, such as IL-6, TGF-beta, and IL-1beta. TH17 cells are crucial players in the defense against extracellular pathogens and have various mechanisms to fulfill their function. They can activate and attract phagocytic cells. Additionally, TH17 cells can induce the release of anti-microbial peptides from non-immune cells, such as epithelial cells. The flip side of the coin is the strong potential of TH17 cells to be pro-inflammatory and promote pathogenicity. TH17 cells have been linked to both mucosal regeneration and inflammation. In turn, these cells and their cytokines emerged as potential therapeutic targets both for inflammatory diseases and cancer. This review will summarize the current knowledge regarding the TH17 cell-enterocyte crosstalk and give an overview of its clinical implications. PMID- 29118757 TI - Decreased Immunity to Varicella Zoster Virus in Giant Cell Arteritis. AB - Introduction: Herpes zoster, which can have a major impact on quality of life, results from reactivation of a latent varicella zoster virus (VZV) infection. We hypothesized that giant cell arteritis (GCA) patients are at increased risk of herpes zoster because of treatment with high-dose glucocorticoids and advanced age. Aim of the study, therefore, was to determine cell-mediated and humoral immunity to VZV in patients with GCA, patients with closely related disease polymyalgia rheumatica (PMR; treated with lower doses of glucocorticoids) and healthy controls (HCs). Methods: Cell-mediated immunity to VZV was determined by performing interferon-gamma (IFNgamma) enzyme-linked immunospot and intracellular cytokine flow cytometry measurements in 11 GCA and 15 PMR patients and in 26 age/sex-matched HCs. Immunoglobulin G antibodies to VZV glycoprotein (VZV-IgG) were measured in serum samples of 35 GCA and 26 PMR patients at different times of follow-up and in 58 age and sex-matched HCs by an enzyme-linked immunosorbent assay. Results: The number of VZV-specific IFNgamma spot-forming cells was significantly lower in GCA patients on treatment, than in age-matched HCs (p = 0.029), but was not different in PMR patients on treatment. Similar levels of VZV IgG were found in GCA and PMR patients at baseline, compared to HCs. Conclusion: The finding of a decreased cell-mediated immunity to VZV, known to be of great importance in defense to the virus, indicates an increased herpes zoster risk in GCA patients compared to an already at-risk elderly population. Herpes zoster vaccination is, therefore, of special importance in GCA patients, and would ideally be administered at time of diagnosis. Interestingly, as VZV was suggested to be the trigger in GCA pathogenesis, similar levels of VZV-IgG were found in GCA patients at time of diagnosis and age-matched HCs, indicating that GCA patients did not experience herpes zoster substantially more often in the months preceding diagnosis than controls. PMID- 29118755 TI - Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells. AB - Inefficient and abnormal clearance of apoptotic cells (efferocytosis) contributes to systemic autoimmune disease in humans and mice, and inefficient chromosomal DNA degradation by DNAse II leads to systemic polyarthritis and a cytokine storm. By contrast, efficient clearance allows immune homeostasis, generally leads to a non-inflammatory state for both macrophages and dendritic cells (DCs), and contributes to maintenance of peripheral tolerance. As many as 3 * 108 cells undergo apoptosis every hour in our bodies, and one of the primary "eat me" signals expressed by apoptotic cells is phosphatidylserine (PtdSer). Apoptotic cells themselves are major contributors to the "anti-inflammatory" nature of the engulfment process, some by secreting thrombospondin-1 (TSP-1) or adenosine monophosphate and possibly other immune modulating "calm-down" signals that interact with macrophages and DCs. Apoptotic cells also produce "find me" and "tolerate me" signals to attract and immune modulate macrophages and DCs that express specific receptors for some of these signals. Neither macrophages nor DCs are uniform, and each cell type may variably express membrane proteins that function as receptors for PtdSer or for opsonins like complement or opsonins that bind to PtdSer, such as protein S and growth arrest-specific 6. Macrophages and DCs also express scavenger receptors, CD36, and integrins that function via bridging molecules such as TSP-1 or milk fat globule-EGF factor 8 protein and that differentially engage in various multi-ligand interactions between apoptotic cells and phagocytes. In this review, we describe the anti-inflammatory and pro homeostatic nature of apoptotic cell interaction with the immune system. We do not review some forms of immunogenic cell death. We summarize the known apoptotic cell signaling events in macrophages and DCs that are related to toll-like receptors, nuclear factor kappa B, inflammasome, the lipid-activated nuclear receptors, Tyro3, Axl, and Mertk receptors, as well as induction of signal transducer and activator of transcription 1 and suppressor of cytokine signaling that lead to immune system silencing and DC tolerance. These properties of apoptotic cells are the mechanisms that enable their successful use as therapeutic modalities in mice and humans in various autoimmune diseases, organ transplantation, graft-versus-host disease, and sepsis. PMID- 29118758 TI - Combining Vgamma9Vdelta2 T Cells with a Lipophilic Bisphosphonate Efficiently Kills Activated Hepatic Stellate Cells. AB - Activated hepatic stellate cells (aHSCs) are now established as a central driver of fibrosis in human liver injury. In the presence of chronic or repeated injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) can occur, so there is interest in down-regulating aHSCs activity in order to treat these diseases. Here, we report that Vgamma9Vdelta2 T cells are reduced in patients with liver cirrhosis, stimulating us to investigate possible interactions between Vgamma9Vdelta2 T cells and aHSCs. We find that Vgamma9Vdelta2 T cells kill aHSCs and killing is enhanced when aHSCs are pretreated with BPH-1236, a lipophilic analog of the bone resorption drug zoledronate. Cytotoxicity is mediated by direct cell-to-cell contact as shown by Transwell experiments and atomic force microscopy, with BPH-1236 increasing the adhesion between aHSCs and Vgamma9Vdelta2 T cells. Mechanistically, BPH-1236 functions by inhibiting farnesyl diphosphate synthase, leading to accumulation of the phosphoantigen isopentenyl diphosphate and recognition by Vgamma9Vdelta2 T cells. The cytolytic process is largely dependent on the perforin/granzyme B pathway. In a Rag2-/ gammac-/- immune-deficient mouse model, we find that Vgamma9Vdelta2 T cells home in to the liver, and when accompanied by BPH-1236, kill not only orthotopic aHSCs but also orthotopic HCC tumors. Collectively, our results provide the first proof of-concept of a novel immunotherapeutic strategy for the treatment of fibrosis cirrhosis-HCC diseases using adoptively transferred Vgamma9Vdelta2 T cells, combined with a lipophilic bisphosphonate. PMID- 29118759 TI - B Cells Are Indispensable for a Novel Mouse Model of Primary Sjogren's Syndrome. AB - Primary Sjogren's syndrome (pSS) is characterized by a panel of autoantibodies, while it is not clear whether B cells and autoantibodies play an essential role in pathogenesis of the disease. Here, we report a novel mouse model for pSS which is induced by immunization with the Ro60_316-335 peptide containing a predominant T cell epitope. After immunization, mice developed several symptoms mimicking pSS, including a decreased secretion of tears, lymphocytic infiltration into the lacrimal glands, autoantibodies, and increased levels of inflammatory cytokines. Disease susceptibility to this novel mouse model varies among strains, where C3H/HeJ (H2-k) and C3H/HeN (H2-k) are susceptible while DBA/1 (H2-q) and C57BL/6 (H2-b) are resistant. Depletion of B cells using anti-CD20 monoclonal antibodies prevented C3H/HeN mice from development of the pSS-like disease. In addition, HLA DRB1*0803, a pSS risk allele, was predicted to bind to the hRo60_308-328 which contains a predominant T cell epitope of human Ro60. Therefore, this study provides a novel mouse model for pSS and reveals an indispensable role of B cells in this model. Moreover, it suggests that T cell epitope within Ro60 antigen is potentially pathogenic for pSS. PMID- 29118760 TI - Septic Shock and the Aging Process: A Molecular Comparison. AB - Aging is a continuous process promoted by both intrinsic and extrinsic factors that each trigger a multitude of molecular events. Increasing evidence supports a central role for inflammation in this progression. Here, we discuss how the low grade chronic inflammation that characterizes aging is tightly interconnected with other important aspects of this process, such as DNA damage, mitochondrial dysfunction, and epigenetic changes. Similarly, inflammation also plays a critical role in many morbid conditions that affect patients who are admitted to Intensive Care. Although the inflammatory response is low grade and persistent in healthy aging while it is acute and severe in critically ill states, we hypothesize that both situations have important interconnections. Here, we performed an extensive review of the literature to investigate this potential link. Because sepsis is the most extensively studied disease and is the leading cause of death in Critical Care, we focus our discussion on comparing the inflammatory profile of healthy older people with that of patients in septic shock to explain why we believe that both situations have synergistic effects, leading to critically ill aged patients having a worse prognosis when compared with critically ill young patients. PMID- 29118761 TI - Immunological and Clinical Effect of Diet Modulation of the Gut Microbiome in Multiple Sclerosis Patients: A Pilot Study. AB - Pathogenesis of autoimmune disorders, including multiple sclerosis (MS), has been linked to an alteration of the resident microbial commensal community and of the interplay between the microbiota and the immune system. Dietary components such as fiber, acting on microbiota composition, could, in principle, result in immune modulation and, thus, could be used to obtain beneficial outcomes for patients. We verified this hypothesis in a pilot study involving two groups of clinically similar relapsing-remitting (RR) MS patients who had undergone either a high vegetable/low-protein diet (HV/LP diet group; N = 10) or a "Western Diet" (WD group; N = 10) for at least 12 months. Gut microbiota composition, analyzed by 16 S V4 rRNA gene sequencing and immunological profiles, was examined after a minimum of 12 months of diet. Results showed that, in the HV/LP diet group compared to the WD group: (1) Lachnospiraceae family was significantly more abundant; (2) IL-17-producing T CD4+ lymphocytes (p = 0.04) and PD-1 expressing T CD4+ lymphocytes (p = 0.0004) were significantly decreased; and (3) PD-L1 expressing monocytes (p = 0.009) were significantly increased. In the HV/LP diet group, positive correlations between Lachnospiraceae and both CD14+/IL-10+ and CD14+/TGFbeta+monocytes (RSp = 0.707, p = 0.05, and RSp = 0.73, p = 0.04, respectively), as well as between Lachnospiraceae and CD4+/CD25+/FoxP3+ T lymphocytes (RSp = 0.68, p = 0.02) were observed. Evaluation of clinical parameters showed that in the HV/LP diet group alone the relapse rate during the 12 months follow-up period and the Expanded Disability Status Scale score at the end of the study period were significantly reduced. Diet modulates dysbiosis and improves clinical parameters in MS patients by increasing anti-inflammatory circuits. Because Lachnospiraceae favor Treg differentiation as well as TGFbeta and IL-10 production this effect could be associated with an increase of these bacteria in the microbiota. PMID- 29118762 TI - LC3-Associated Phagocytosis Is Required for Dendritic Cell Inflammatory Cytokine Response to Gut Commensal Yeast Saccharomyces cerevisiae. AB - The human fungal microbiota known as mycobiota is increasingly recognized as a critical factor in human gut health and disease. Non-pathogenic commensal yeasts such as Saccharomyces cerevisiae promote homeostasis in the gut, whereas dysbiosis of the gut mycobiota is associated with inflammation. Glycan-binding receptors (lectins) are key host factors in host-mycobiota interaction in the gut. They are expressed on immune cells such as dendritic cells (DCs) and recognize fungal polysaccharides. This interaction is imperative to mount appropriate immune responses for immune homeostasis in the gut as well as clearance of fungal pathogens. Recent studies demonstrate that microtubule associated protein light-chain 3 (LC3)-associated phagocytosis (LAP) is involved in lectin-fungi interactions. Yet, the biological impact of LAP on the lectin function remains largely elusive. In this report, we demonstrate that in mouse LAP is linked to dendritic cell-associated lectin 2 (Dectin-2), a C-type lectin specific to fungal alpha-mannan polysaccharide. We found that mouse Dectin-2 recognizes commensal yeast S. cerevisiae and Kazachstania unispora. Mouse bone marrow-derived DCs (BMDCs) produced inflammatory cytokines TNFalpha and IL-1beta in response to the yeasts in a Dectin-2 and spleen tyrosine kinase (Syk) dependent manner. We found that S. cerevisiae and K. unispora induced LAP in mouse BMDCs upon internalization. Furthermore, LC3 was activated by stimulation of BMDCs with the yeasts in a Dectin-2 and Syk-dependent manner. To address the biological impact of LAP on Dectin-2 yeast interaction, we established a knock-in mouse strain (Atg16L1E230, thereafter called E230), which BMDCs exhibit autophagy active and LAP-negative phenotypes. When stimulated with yeasts, E230 BMDCs produced significantly less amounts of TNFalpha and IL-1beta. Taken together, we revealed a novel link between Dectin-2 and LAP that enables host immune cells to respond to mycobiota. PMID- 29118763 TI - Induction of Antihuman C-C Chemokine Receptor Type 5 Antibodies by a Bovine Herpesvirus Type-4 Based Vector. AB - Bovine herpesvirus 4 (BoHV-4) is a promising vector for the delivery and intracellular expression of recombinant antigens and can thus be considered as a new prototype vaccine formulation system. An interesting, and actively pursued, antigen in the context of human immunodeficiency virus (HIV) infection prophylaxis (and therapy) is the C-C chemokine receptor type 5 (CCR5) co receptor, whose blockage by specific antibodies has been shown to inhibit both viral entry and cell-to-cell transmission of the virus. Building on our previous work on the BoHV-4 vector system, we have engineered and tested a replication competent derivative of BoHV-4 (BoHV-4-CMV-hCCR5DeltaTK) bearing a human CCR5 (hCCR5) expression cassette. We show here that CCR5 is indeed expressed at high levels in multiple types of BoHV-4-CMV-hCCR5DeltaTK-infected cells. More importantly, two intravenous inoculations of CCR5-expressing BoHV-4 virions into rabbits led to the production of anti-CCR5 antibodies capable of reacting with the CCR5 receptor exposed on the surface of HEK293T cells through specific recognition of the amino-terminal region (aa 14-34) of the protein. Given the growing interest for anti-CCR5 immunization as an HIV control strategy and the many advantages of virus-based immunogen formulations (especially for poorly immunogenic or self-antigens), the results reported in this study provide preliminary validation of BoHV-4 as a safe viral vector suitable for CCR5 vaccination. PMID- 29118764 TI - Folic Acid and Homocysteine in Chronic Kidney Disease and Cardiovascular Disease Progression: Which Comes First? AB - Background: Hyperhomocysteinemia (Hhcy) occurs in about 85% of chronic kidney disease (CKD) patients because of impaired renal metabolism and reduced renal excretion. Folic acid (FA), the synthetic form of vitamin B9, is critical in the conversion of homocysteine (Hcy) to methionine. If there is not enough intake of FA, there is not enough conversion, and Hcy levels are raised. Summary: Hhcy is regarded as an independent predictor of cardiovascular morbidity and mortality in end-stage renal disease. Hhcy exerts its pathogenic action on the main processes involved in the progression of vascular damage. Research has shown Hhcy suggests enhanced risks for inflammation and endothelial injury which lead to cardiovascular disease (CVD), stroke, and CKD. FA has also been shown to improve endothelial function without lowering Hcy, suggesting an alternative explanation for the effect of FA on endothelial function. Recently, the role of FA and Hhcy in CVD and in CKD progression was renewed in some randomized trials. Key Messages: In the general population and in CKD patients, it remains a topic of discussion whether any beneficial effects of FA therapy are to be referred to its direct effect or to a reduction of Hhcy. While waiting for the results of confirmatory trials, it is reasonable to consider FA with or without methylcobalamin supplementation as appropriate adjunctive therapy in patients with CKD. PMID- 29118765 TI - Urinary Liver-Type Fatty Acid-Binding Protein Level as a Predictive Biomarker of Acute Kidney Injury in Patients with Acute Decompensated Heart Failure. AB - Background: There are no biological markers to predict the onset of acute kidney injury (AKI) in patients with acute decompensated heart failure (ADHF). Liver type fatty acid-binding protein (L-FABP) levels are markedly upregulated in the proximal tubules after renal ischemia. We investigated whether urinary L-FABP is a suitable marker to predict AKI in ADHF patients. Methods: We examined 281 consecutive patients with ADHF. Serum creatinine (Cr) and L-FABP levels were measured at admission and 24 and 48 h after admission. Results: AKI developed in 104 patients (37%). Urinary L-FABP levels at admission were significantly higher in patients with AKI than in those without (33.0 vs. 5.2 MUg/g Cr; p < 0.001). Multivariate analysis showed that baseline urinary L-FABP level was an independent predictor of AKI in ADHF patients (odds ratio 1.08, 95% confidence interval 1.05-1.12; p < 0.001). Receiver operating characteristic analysis showed that baseline urinary L-FABP level exhibited 94.2% sensitivity and 87.0% specificity at a cutoff value of 12.5 MUg/g Cr. Conclusions: Urinary L-FABP level is useful for predicting the onset of AKI in patients with ADHF. The results of our study could help clinicians diagnose AKI in ADHF patients earlier, leading to possible improvements in the treatment of this group of patients. PMID- 29118766 TI - The Role of Endotoxin in the Setting of Cardiorenal Syndrome Type 5. AB - Lipopolysaccharide or endotoxin, the major cell wall component of gram-negative bacteria, plays a pivotal role in the pathogenesis of sepsis. It is able to activate the host defense system through the interaction with Toll-like receptor 4, thus triggering pro-inflammatory mechanisms. When the production of inflammatory mediators becomes uncontrolled and excessive, septic shock develops with multiple organ dysfunction, such as myocardial and renal impairment, which are hallmarks of cardiorenal syndrome type 5. In this review, we will analyze the role of endotoxin in the pathogenesis of sepsis, its effects on cardiac and renal interactions in the setting of cardiorenal syndrome type 5 and the possible use of extracorporeal therapies in this clinical condition. PMID- 29118767 TI - Long-Term Progression of Coronary Artery Calcification Is Independent of Classical Risk Factors, C-Reactive Protein, and Parathyroid Hormone in Renal Transplant Patients. AB - Aims: Compared to the general population, mortality is significantly increased in renal transplant recipients. In the general population, coronary artery calcification (CAC) and its evolution over time are associated with cardiovascular and all-cause mortality, and the study of this biomarker could provide useful information for describing the long-term progression of coronary heart disease in renal transplant recipients. Methods: We followed up a cohort of 113 renal transplant patients by performing three multi-detector computed tomography studies over 83.6 +/- 6.8 months. Data analysis was performed by logistic regression analysis and by mixed linear modelling. Results: Progression was observed in 34.5% of patients. Baseline CAC and time-to-transplantation were the sole variables that predicted CAC evolution over time. Neither classical nor nontraditional risk factors, biomarkers of renal function (GFR) and kidney damage (albuminuria) or biomarkers of bone mineral disorder (BMD), such as serum phosphorus, calcium, and PTH, were associated with the long-term progression of coronary calcification. Serum triglycerides predicted CAC progression only in logistic regression analysis, while in addition to baseline CAC, time to transplantation was the sole variable predicting CAC progression when the data were analyzed by mixed linear modelling. These data suggested that, in addition to the background calcification burden, other unmeasured factors play major roles in promoting the evolution of coronary calcification in the transplant population. Conclusion: CAC progression continued over the long-term follow-up of renal transplant patients. This phenomenon was unaccounted for by classical and nontraditional risk factors, as well as by biomarkers of renal dysfunction and renal damage. PMID- 29118768 TI - The Relationship between Hypertriglyceridemic Waist Phenotype and Early Diabetic Nephropathy in Type 2 Diabetes. AB - Background/Aims: The aim of this study was to explore the relationship between hypertriglyceridemic waist (HW) phenotype and early diabetic nephropathy in type 2 diabetes. Methods: A cross-sectional study was conducted on 538 type 2 diabetes patients in Qinhuangdao. The HW phenotype was defined as serum triglyceride concentrations >=1.7 mmol/L and waist circumference >=90 cm (males) and >=85 cm (females). Results: The prevalence of the HW phenotype was 34.9%. The prevalence of early diabetic nephropathy was 10.6% in type 2 diabetes patients with normal waist circumference and triglycerides and 24.5% in type 2 diabetes patients with HW phenotype. After adjustment for sex, age, body mass index, hypertension, history of diabetes, and glycosylated hemoglobin A1c, the prevalence of early diabetic nephropathy among type 2 diabetes patients with the HW phenotype was 2.81 (95% confidence interval 1.36-5.80, p = 0.005) times higher than that among type 2 diabetes patients with normal waist circumference and triglycerides. Conclusion: There was a significant correlation between HW phenotype and early diabetic nephropathy in type 2 diabetes. PMID- 29118769 TI - Clinical Usefulness of Urinary Liver Fatty Acid-Binding Protein Excretion for Predicting Acute Kidney Injury during the First 7 Days and the Short-Term Prognosis in Acute Heart Failure Patients with Non-Chronic Kidney Disease. AB - Background: The clinical significance of urinary liver fatty acid-binding protein (u-LFABP) in acute heart failure (AHF) patients remains unclear. Methods and Results: The u-LFABP levels on admission of 293 AHF patients were analyzed. The patients were divided into 2 groups according to the u-LFABP quartiles (Q1, Q2, and Q3 = low u-LFABP [L] group vs. Q4 = high u-LFABP [H] group). We evaluated the diagnostic and prognostic value of u-LFABP and compared the findings between the chronic kidney disease (CKD; n = 165) and non-CKD patients (n = 128). Acute kidney injury (AKI) during the first 7 days was evaluated based on the RIFLE criteria. In the non-CKD group, the number of AKI patients during the first 7 days was significantly greater in the H group (70.0%) than in the L group (45.6%). A multivariate logistic regression model indicated that the H group (odds ratio: 3.850, 95% confidence interval [CI] 1.128-13.140) was independently associated with AKI during the first 7 days. The sensitivity and specificity of u LFABP for predicting AKI were 63.6 and 59.7% (area under the ROC curve 0.631) at 41.9 ng/mg * cre. A Cox regression model identified the H group (hazard ratio: 13.494, 95% CI 1.512-120.415) as an independent predictor of the 60-day mortality. A Kaplan-Meier curve, including all-cause death within 60 days, showed a significantly poorer survival rate in the H group than in the L group (p = 0.036). Conclusions: The u-LFABP level is an effective biomarker for predicting AKI during the first 7 days of hospitalization and an adverse outcome in AHF patients with non-CKD. PMID- 29118770 TI - Contrast-Induced Nephropathy Is Less Common in Patients with Good Coronary Collateral Circulation. AB - Background/Aims: Contrast-induced nephropathy (CIN) is a typically reversible type of acute renal failure that develops after exposure to contrast agents; underlying endothelial dysfunction is thought to be an important risk factor for CIN. Although the mechanism of coronary collateral circulation (CCC) is not fully understood, a pivotal role of the endothelium has been reported in many studies. The aim of this study was to investigate whether there is a relationship between CCC and CIN. Methods: Patients with at least one occluded major coronary artery and blood creatinine analyses performed before and on the second day after angiography were included in the study. CIN was defined as a 25% or greater elevation of creatinine on the second day after exposure to the contrast agent. Collateral grading was performed according to the Rentrop classification. Patients were grouped according to whether they developed CIN or not, i.e., CIN( ) and CIN(+) group. Results: A total of 214 patients who met the inclusion criteria were included in the study. CIN was diagnosed in 43 patients (20.1%) in the study population. Good CCC was identified in 112 patients (65.5%) in the CIN( ) group, whereas it was identified in 13 patients (30.2%) in the CIN(+) group. In the CIN(-) group, good CCC was significantly more frequent (p < 0.001). Furthermore, collateral circulation was an independent predictor of CIN. Conclusion: Good collateral circulation was associated with a lower frequency of CIN, and poor collateral circulation was an independent predictor of CIN. PMID- 29118771 TI - A Profile of Renal Function in Northern Cameroonians with Essential Hypertension. AB - Background/Aim: The two-way cause and effect relationship existing between high blood pressure and kidney dysfunction is currently a well-documented phenomenon with patients in either category being almost equally predisposed to the other pathology. Our goal was to assess the renal function capacity of hypertensive patients in our setting. Methods: This cross-sectional descriptive study involved the determination of blood pressure levels and the collection of blood and urine samples for the measurement of renal function markers. Hypertensive patients who came for medical follow-up constituted the study participants, and were enrolled consecutively into the study from February to May 2015. Data analysis was performed using the SPSS 20.0 software, and significant differences were determined at p < 0.05. Results: The prevalence of elevated creatinine and urea levels were 35 and 27%. Eighty percent of the participants had a decreased glomerular filtration rate (<=90 mL/min/1.73 m3), with at least 36% recording less than 60 mL/min/1.73 m3. Proteinuria and glucosuria were recorded in 15% and 8% of the participants, respectively. The mean diastolic pressure was observed to be significantly higher in participants with proteinuria (p = 0.016), and participants' weight directly correlated with systolic blood pressure (p = 0.015). Furthermore, the mean estimated glomerular filtration rate was relatively lower in participants >60 years compared to those <60 years (p < 0.001). Conclusion: Renal function is often perturbed in hypertensive patients, and good blood pressure control may reduce the progression of renal impairment. Thus, a systematic evaluation of renal function in addition to blood pressure control in hypertensive patients is indispensable towards effectively reducing the occurrence of renal events and preventing end-stage renal disease. PMID- 29118772 TI - One-Year Conservative Care Using Sodium Bicarbonate Supplementation Is Associated with a Decrease in Electronegative LDL in Chronic Kidney Disease Patients: A Pilot Study. AB - Background: Chronic kidney disease (CKD) patients develop metabolic acidosis when approaching stages 3 and 4, a period in which accelerated atherogenesis may ensue. Studies in vitro show that low pH may increase low-density lipoprotein (LDL) oxidation, suggesting a role for chronic metabolic acidosis in atherosclerosis. The present study attempted to evaluate the effects of conservative care using oral sodium bicarbonate (NaHCO3) supplementation on the electronegative LDL [LDL(-)], a minimally oxidized LDL, plasma levels in CKD patients. Methods: Thirty-one CKD patients were followed by a multidisciplinary team during 15 months of care in which 1.0 mmol/kg/day oral NaHCO3 supplementation was first given in the third month. Blood samples were collected 3 months before the initiation of oral NaHCO3 supplementation (T1), at the time of the beginning of supplementation (T2), and thereafter, each 4 months (T3, T4 and T5) until month 15 of care. Blood parameters and LDL(-) were measured from these collections. Results: After 12 months of conservative care, creatinine clearance (MDRD) was kept stable, and serum bicarbonate (HCO3-) increased from 20.5 +/- 2.9 to 22.6 +/- 1.1 mM (p < 0.003). LDL(-) plasma levels declined from 4.5 +/- 3.3 to 2.1 +/- 0.9 U/L (p < 0.007) after reaching mean serum HCO3- levels of 22.6 +/- 1.1 mM. Conclusions: Conservative care using oral NaHCO3 supplementation was able to stabilize renal function and decrease serum levels of LDL(-), a modified proatherogenic lipoprotein, only when mean serum HCO3- levels approached 22 mM. This study constitutes evidence that alkali therapy, in addition to its beneficial effect on renal disease progression, might serve as a preventive strategy to attenuate atherogenesis in CKD patients. PMID- 29118773 TI - Host-Multi-Pathogen Warfare: Pathogen Interactions in Co-infected Plants. AB - Studies of plant-pathogen interactions have historically focused on simple models of infection involving single host-single disease systems. However, plant infections often involve multiple species and/or genotypes and exhibit complexities not captured in single host-single disease systems. Here, we review recent insights into co-infection systems focusing on the dynamics of host-multi pathogen interactions and the implications for host susceptibility/resistance. In co-infection systems, pathogen interactions include: (i) Competition, in which competing pathogens develop physical barriers or utilize toxins to exclude competitors from resource-dense niches; (ii) Cooperation, whereby pathogens beneficially interact, by providing mutual biochemical signals essential for pathogenesis, or through functional complementation via the exchange of resources necessary for survival; (iii) Coexistence, whereby pathogens can stably coexist through niche specialization. Furthermore, hosts are also able to, actively or passively, modulate niche competition through defense responses that target at least one pathogen. Typically, however, virulent pathogens subvert host defenses to facilitate infection, and responses elicited by one pathogen may be modified in the presence of another pathogen. Evidence also exists, albeit rare, of pathogens incorporating foreign genes that broaden niche adaptation and improve virulence. Throughout this review, we draw upon examples of co-infection systems from a range of pathogen types and identify outstanding questions for future innovation in disease control strategies. PMID- 29118775 TI - Accumulation Profiles of Embryonic Salt-Soluble Proteins in Maize Hybrids and Parental Lines Indicate Matroclinous Inheritance: A Proteomic Analysis. AB - Maize is one of the most widely cultivated crops. It accumulates a large quantity of seed storage proteins, which are important for seed development and germination, and contribute to the nutritional quality of seeds. Based on solubility, the storage proteins are divided into albumins (water-soluble), globulins (salt-soluble), prolamins (alcohol-soluble), and glutelins (acid- or alkali-soluble). Maize hybrids are cultivated due to the superior performance of F1 hybrids than that of their parents, a phenomenon known as heterosis. However, the accumulation patterns of seed storage proteins in maize embryos between the hybrids and their parental inbred lines have not been compared. In the present study, two elite inbred lines of China, Zheng 58 and Chang 7-2, and their reciprocal hybrids (Zheng 58 * Chang 7-2 and Chang 7-2 * Zheng 58) were used to explore parental influences on the accumulation patterns of seed storage proteins in maize embryos. For this purpose, we focused on seed salt-soluble proteins (SSPs) in our experiments. The SSPs were selectively extracted from maize mature embryos after extensive removal of water-soluble albumin and separated using two dimensional gel electrophoresis (2-DE), followed by mass spectrometry analysis. Our results indicated that the 2-DE SSP profiles of hybrids closely resembled those of their maternal parent rather than the paternal parent. In other words, 2 DE SSP profiles of Zheng 58 * Chang 7-2 were more similar those of Zheng 58 whereas such profiles of Chang 7-2 * Zheng 58 were more similar to those of Chang 7-2 although the 2-DE profiles of all four maize types were quite similar. In total, 12 relatively abundant SSPs spots representing five kinds of proteins were identified, of which nine protein spots displayed non-additive accumulation in at least one hybrid. This study provided additional data on dominance and partial dominance effects on maize hybrids embryos. Besides, earlier studies on accumulation profiles of globulin-1 (also known as vicilin), which is one of the most abundant globulins in maize embryos, also support the above results. This study would be helpful in revealing the mechanisms underlying SSPs accumulation patterns in the hybrids. PMID- 29118774 TI - Genome-Wide Identification and Expression, Protein-Protein Interaction and Evolutionary Analysis of the Seed Plant-Specific BIG GRAIN and BIG GRAIN LIKE Gene Family. AB - BIG GRAIN1 (BG1) is an auxin-regulated gene which functions in auxin pathway and positively regulates biomass, grain size and yield in rice. However, the evolutionary origin and divergence of these genes are still unknown. In this study, we found that BG genes are probably originated in seed plants. We also identified that seed plants evolved a class of BIG GRAIN LIKE (BGL) genes which share conserved middle and C-terminal motifs with BG. The BG genes were present in all monocot and eudicot species analyzed; however, the BGL genes were absent in few monocot lineages. Both BG and BGL were found to be serine-rich proteins; however, differences in expansion and rates of retention after whole genome duplication events were observed. Promoters of BG and BGL genes were found to be enriched with auxin-responsive elements and the Arabidopsis thaliana BG and BGL genes were found to be auxin-regulated. The auxin-induced expression of AthBG2 was found to be dependent on the conserved ARF17/19 module. Protein-protein interaction analysis identified that AthBG2 interact with regulators of splicing, transcription and chromatin remodeling. Taken together, this study provides interesting insights about BG and BGL genes and incentivizes future work in this gene family which has the potential to be used for crop manipulation. PMID- 29118776 TI - Design of a Custom RT-qPCR Array for Assignment of Abiotic Stress Tolerance in Traditional Portuguese Grapevine Varieties. AB - Widespread agricultural losses attributed to drought, often combined with high temperatures, frequently occur in the field, namely in Mediterranean climate areas, where the existing scenarios for climate change indicate an increase in the frequency of heat waves and severe drought events in summer. Grapevine (Vitis vinifera L.) is the most cultivated fruit species in the world and the most valuable one and is a traditional Mediterranean species. Currently, viticulture must adjust to impending climate changes that are already pushing vine-growers toward the use of ancient and resilient varieties. Portugal is very rich in grapevine biodiversity, however, currently, 90% of the total producing area is planted with only 16 varieties. There is a pressing need to understand the existing genetic diversity and the physiological potential of the varieties/genotypes available to be able to respond to climate changes. With the above scenario in mind, an assembly of 65 differentially expresses genes (DEGs) previously identified as responsive to abiotic stresses in two well studied genotypes, 'Touriga Nacional' and 'Trincadeira,' was designed to scan the gene expression of leaf samples from 10 traditional Portuguese varieties growing in two regions with distinct environmental conditions. Forty-five of those DEGs proved to be associated to "abiotic stress" and were chosen to build a custom qPCR array to identify uncharacterized genotypes as sensitive or tolerant to abiotic stress. According to the experimental set-up behind the array design these DEGs can also be used as indicators of the main abiotic stress that the plant is subjected and responding to (drought, heat, or excess light). PMID- 29118777 TI - Capparis spinosa L. in A Systematic Review: A Xerophilous Species of Multi Values and Promising Potentialities for Agrosystems under the Threat of Global Warming. AB - Caper (Capparis spinosa L.) is a xerophytic shrub with a remarkable adaptability to harsh environments. This plant species is of great interest for its medicinal/pharmacological properties and its culinary uses. Its phytochemical importance relies on many bioactive components present in different organs and its cultivation can be of considerable economic value. Moreover, taxonomic identification of C. spinosa L. has been difficult due to its wide heterogeneity, and many authors fell into confusion due to the scarcity of genetic studies. The present review summarizes information concerning C. spinosa L. including agronomic performance, botanical description, taxonomical approaches, traditional pharmacological uses, phytochemical evaluation and genetic studies. This knowledge represents an important tool for further research studies and agronomic development on this indigenous species with respect to the emerging climatic change in the Eastern Mediterranean countries. Indeed, this world region is particularly under the threat of global warming and it appears necessary to rethink agricultural systems to adapt them to current and futures challenging environmental conditions. Capparis spinosa L. could be a part of this approach. So, this review presents a state of the art considering caper as a potential interesting crop under arid or semi-arid regions (such as Eastern Mediterranean countries) within the climate change context. The aim is to raise awareness in the scientific community (geneticists, physiologists, ecophysiologists, agronomists, ...) about the caper strengths and interest to the development of this shrub as a crop. PMID- 29118778 TI - Advanced Backcross QTL Analysis of Fiber Strength and Fineness in a Cross between Gossypium hirsutum and G. mustelinum. AB - The molecular genetic basis of cotton fiber strength and fineness in crosses between Gossypium mustelinum and Gossypium hirsutum (Upland cotton) was dissected using 21 BC3F2 and 12 corresponding BC3F2:3 and BC3F2:4 families. The BC3F2 families were genotyped with simple sequence repeat markers from a G. hirsutum by G. mustelinum linkage map, and the three generations of BC3-derived families were phenotyped for fiber strength (STR) and fineness (Micronaire, MIC). A total of 42 quantitative trait loci (QTLs) were identified through one-way analysis of variance, including 15 QTLs for STR and 27 for MIC, with the percentage of variance explained by individual loci averaging 13.86 and 14.06%, respectively. Eighteen of the 42 QTLs were detected at least twice near the same markers in different generations/families or near linked markers in the same family, and 28 of the 42 QTLs were identified in both mixed model-based composite interval mapping and one-way variance analyses. Alleles from G. mustelinum increased STR for eight of 15 and reduced MIC for 15 of 27 QTLs. Significant among-family genotypic effects (P < 0.001) were detected in 13 and 10 loci for STR and MIC respectively, and five loci showed significant (P < 0.001) genotype * family interaction for MIC. These results support the hypothesis that fiber quality improvement for Upland cotton could be realized by introgressing G. mustelinum alleles although complexities due to the different effects of genetic background on introgressed chromatin might be faced. Building on prior work with G. barbadense, G. tomentosum, and G. darwinii, QTL mapping involving introgression of G. mustelinum alleles offers new allelic variation to Upland cotton germplasm. PMID- 29118780 TI - Editorial: Role of Silicon in Plants. PMID- 29118779 TI - Development of Chloroplast Genomic Resources for Oryza Species Discrimination. AB - Rice is the most important crop in the world as the staple food for over half of the population. The wild species of Oryza represent an enormous gene pool for genetic improvement of rice cultivars. Accurate and rapid identification of these species is critical for effective utilization of the wild rice germplasm. In this study, we developed valuable chloroplast molecular markers by comparing the chloroplast genomes for species identification. Four chloroplast genomes of Oryza were newly sequenced on the Illumina HiSeq platform and other 14 Oryza species chloroplast genomes from Genbank were simultaneously taken into consideration for comparative analyses. Among 18 Oryza chloroplast genomes, five variable regions (rps16-trnQ, trnTEYD, psbE-petL, rpoC2 and rbcL-accD) were detected for DNA barcodes, in addition to differences in simple sequence repeats (SSR) and repeat sequences. The highest species resolution (72.22%) was provided by rpoC2 and rbcL accD with distance-based methods. Three-marker combinations (rps16-trnQ + trnTEYD + rbcL-accD, rps16-trnQ + trnTEYD + rpoC2 and rpoC2 + trnTEYD + psbE-petL) showed the best species resolution (100%). Phylogenetic analysis based on the chloroplast genome provided the best resolution of Oryza. In the comparison of chloroplast genomes in this study, identification of the most variable regions and assessment of the focal regions of divergence were efficient in developing species-specific DNA barcodes. Based on evaluation of the chloroplast genomic resources, we conclude that chloroplast genome sequences are a reliable and valuable molecular marker for exploring the wild rice genetic resource in rice improvement. PMID- 29118781 TI - Belowground Plant-Herbivore Interactions Vary among Climate-Driven Range Expanding Plant Species with Different Degrees of Novel Chemistry. AB - An increasing number of studies report plant range expansions to higher latitudes and altitudes in response to global warming. However, consequences for interactions with other species in the novel ranges are poorly understood. Here, we examine how range-expanding plant species interact with root-feeding nematodes from the new range. Root-feeding nematodes are ubiquitous belowground herbivores that may impact the structure and composition of natural vegetation. Because of their ecological novelty, we hypothesized that range-expanding plant species will be less suitable hosts for root-feeding nematodes than native congeneric plant species. In greenhouse and lab trials we compared nematode preference and performance of two root-feeding nematode species between range-expanding plant species and their congeneric natives. In order to understand differences in nematode preferences, we compared root volatile profiles of all range-expanders and congeneric natives. Nematode preferences and performances differed substantially among the pairs of range-expanders and natives. The range-expander that had the most unique volatile profile compared to its related native was unattractive and a poor host for nematodes. Other range-expanding plant species that differed less in root chemistry from native congeners, also differed less in nematode attraction and performance. We conclude that the three climate-driven range-expanding plant species studied varied considerably in their chemical novelty compared to their congeneric natives, and therefore affected native root feeding nematodes in species-specific ways. Our data suggest that through variation in chemical novelty, range-expanding plant species may vary in their impacts on belowground herbivores in the new range. PMID- 29118783 TI - Cerebrospinal Fluid Phosphate in Delirium after Hip Fracture. AB - Aims: Phosphate is essential for neuronal activity. We aimed to investigate whether delirium is associated with altered phosphate concentrations in cerebrospinal fluid (CSF) and serum. Methods: Seventy-seven patients with hip fracture were assessed for delirium before and after acute surgery. Prefracture dementia was diagnosed by an expert panel. Phosphate was measured in CSF obtained immediately before spinal anesthesia (n = 77) and in serum (n = 47). CSF from 23 cognitively healthy elderly patients undergoing spinal anesthesia was also analyzed. Results: Hip fracture patients with prevalent delirium had higher CSF phosphate concentrations than those without delirium (median 0.63 vs. 0.55 mmol/L, p = 0.001). In analyses stratified on dementia status, this difference was only significant in patients with dementia. Serum phosphate was ~1 mmol/L; there was no association between serum phosphate concentration and delirium status. CSF phosphate did not correlate with serum levels. Conclusion: Patients with delirium superimposed on dementia have elevated phosphate levels. PMID- 29118782 TI - Influence of Mild Cognitive Impairment, Depression, and Anxiety on the Quality of Life of Patients with Parkinson Disease. AB - Background: Neuropsychiatric symptoms (NPS) and mild cognitive impairment (MCI) are common in Parkinson disease (PD) and have a negative impact on the patient's quality of life (QoL). We aim to describe the effect of NPS and MCI on each other and on QoL. Methods: Sixteen MCI and 37 non-MCI PD patients completed different self-assessment questionnaires including the Parkinson's Disease Questionnaire (PDQ-39), the Beck Depression Inventory (BD), the Beck Anxiety Inventory (BAI), and the Self-Report Manic Inventory (SRMI). Linear regression with stepwise elimination was used to select the significant predictors of QoL and to control for confounding factors. Results: The significant linear regression model (R2 = 0.68, p <= 0.01) revealed significant effects of MCI (p = 0.03), BDI (p <= 0.01), BAI (p <= 0.01), age (p = 0.03), a trend of SRMI (p = 0.06), and disease duration (p = 0.08) on QoL. Conclusions: MCI, anxiety, depression, and age decrease QoL in patients with PD. NPS has the main influence in the prediction of QoL in patients with PD, whereas MCI is only of minor importance. PMID- 29118784 TI - Montreal Cognitive Assessment in a 63- to 65-year-old Norwegian Cohort from the General Population: Data from the Akershus Cardiac Examination 1950 Study. AB - Aims: To investigate Montreal Cognitive Assessment (MoCA) test scores in a cohort aged 63-65 years from a general population in relation to the proposed cut-off score of 26 for mild cognitive impairment (MCI) and to explore the impact of education. Methods: MoCA scores were assessed in the Akershus Cardiac Examination 1950 Study, a cross-sectional cohort study of all men and women born in 1950 living in Akershus County, Norway. The participants were aged 63-65 at the time of data collection. Results: MoCA scores were available in 3,413 participants, of which 47% had higher education (>12 years). The mean MoCA score was 25.3 (95% confidence interval [CI] 25.2-25.4), and 49% had a score below the suggested cut off of 26 points. Those with higher education had significantly higher scores (mean 26.2, 95% CI 26.1-26.3 vs. 24.4, 95% CI 24.3-24.6, p < 0.001). Conclusions: Approximately 50% scored below the cut-off score of 26 points, suggesting that the cut-off score may have been set too high to distinguish normal cognitive function from MCI. Educational level had a significant impact on MoCA scores. PMID- 29118785 TI - Advance Directives as Support of Autonomy for Persons with Dementia? A Pilot Study among Persons with Dementia and Their Informal Caregivers. AB - Background: Advance directives could be an important instrument to support a person's will once he/she is not able to consent anymore - if composed competently. A survey was conducted to identify the level of knowledge concerning possibilities and limits of advance directives. Methods: The study was conducted as part of the Bavarian Dementia Survey (BayDem). Data were collected from January 2014 to December 2015 by structured face-to-face interviews. Study participants were persons with dementia and their informal caregivers (n = 74). Results: In total, 66% reported having written an advance directive. Concerning the participants' knowledge about possibilities and limitations of advance directives, a lack of knowledge was noted about the possibility to revoke an advance directive. Furthermore, 70% of informal caregivers and 56% of persons with dementia were not aware of the possibility to include dementia-specific terms in the advance directive. Conclusion: It is necessary to optimize structures for public information and education concerning the topic of advance directives for persons with dementia. PMID- 29118786 TI - The Cognitive Telephone Screening Instrument (COGTEL): A Brief, Reliable, and Valid Tool for Capturing Interindividual Differences in Cognitive Functioning in Epidemiological and Aging Studies. AB - Aims: The present study set out to evaluate the psychometric properties of the Cognitive Telephone Screening Instrument (COGTEL) in 2 different samples of older adults. Methods: We assessed COGTEL in 116 older adults, with retest after 7 days to evaluate the test-retest reliability. Moreover, we assessed COGTEL in 868 older adults to evaluate convergent validity to the Mini-Mental State Examination (MMSE). Results: Test-retest reliability of the COGTEL total score was good at 0.85 (p < 0.001). Latent variable analyses revealed that COGTEL and MMSE correlated by 0.93 (p < 0.001), indicating convergent validity of the COGTEL. Conclusion: The present analyses suggest COGTEL as a brief, reliable, and valid instrument for capturing interindividual differences in cognitive functioning in epidemiological and aging studies, with the advantage of covering more cognitive domains than traditional screening tools such as the MMSE, as well as differentiating between individual performance levels, in healthy older adults. PMID- 29118787 TI - Radiation Exposure during Neurointerventional Procedures in Modern Biplane Angiographic Systems: A Single-Site Experience. AB - Background and Purpose: Per the ALARA principle, reducing the dose delivered to both patients and staff must be a priority for endovascular therapists, who should monitor their own practice. We evaluated patient exposure to radiation during common neurointerventions performed with a recent flat-panel detector angiographic system and compared our results with those of recently published studies. Methods: All consecutive patients who underwent a diagnostic cerebral angiography or intervention on 2 modern flat-panel detector angiographic biplane systems (Innova IGS 630, GE Healthcare, Chalfont St Giles, UK) from February to November 2015 were retrospectively analyzed. Dose-area product (DAP), cumulative air kerma (CAK) per plane, fluoroscopy time (FT), and total number of digital subtraction angiography (DSA) frames were collected, reported as median (interquartile range), and compared with the previously published literature. Results: A total of 755 consecutive cases were assessed in our institution during the study period, including 398 diagnostic cerebral angiographies and 357 interventions. The DAP (Gy * cm2), fontal and lateral CAK (Gy), FT (min), and total number of DSA frames were as follows: 43 (33-60), 0.26 (0.19-0.33), 0.09 (0.07-0.13), 5.6 (4.2-7.5), and 245 (193-314) for diagnostic cerebral angiographies, and 66 (41-110), 0.46 (0.25-0.80), 0.18 (0.10-0.30), 18.3 (9.1 30.2), and 281 (184-427) for interventions. Conclusion: Our diagnostic cerebral angiography group had a lower median and was in the 75th percentile of DAP and FT when compared with the published literature. For interventions, both DAP and number of DSA frames were significantly lower than the values reported in the literature, despite a higher FT. Subgroup analysis by procedure type also revealed a lower or comparable DAP. PMID- 29118788 TI - Mechanical Thrombectomy for M2 Occlusions: A Single-Centre Experience. AB - Background: The recent success of several mechanical thrombectomy trials has resulted in a significant change in the management of patients presenting with stroke. However, questions still remain as to whether certain groups will benefit from mechanical thrombectomy. In particular, it is still uncertain whether mechanical thrombectomy should be performed in the M2 branches and, more generally, in the distal vasculature. Methods: We retrospectively analysed our prospectively maintained database of all patients undergoing mechanical thrombectomy between January 2008 and August 2016. We collected demographic, radiological, procedural and outcome data. Results: We identified 106 patients that met our inclusion criteria. The mean age of the patients was 68 +/- 13.8 years, and there were 58 (54.7%) male patients. Associated medical conditions were common with hypertension seen in 71% of the patients. The average Alberta Stroke Program Early CT (ASPECT) score on admission was 8.5 +/- 1.7. The mean National Institutes of Health Stroke Scale score was 11.8 +/- 7.02. The mean duration of the procedure was 103 +/- 3.4 min, and the average number of thrombectomy attempts required was 1.8 (range 1-8). Angiographically, Thrombolysis in Cerebral Infarction Scale (TICI) >=2b was obtained in 90.5% of the patients. Five patients (4.7%) had symptomatic intracranial haemorrhage on follow-up. At 90-day follow-up, 54.6% of the patients had a modified Rankin Scale (mRS) score 0-2, and 71.5% had an mRS score <=3. There were 15 deaths at 90 days (14.1%). Conclusion: Mechanical thrombectomy in patients with solitary M2 clots is technically possible and carries a high degree of success with a good safety profile. Patients with confirmed M2 occlusion should be considered for mechanical thrombectomy. PMID- 29118789 TI - Anterior Communicating Artery Aneurysm Treatment with the Pipeline Embolization Device: A Single-Center Experience with Long-Term Follow-Up. AB - Introduction: The pipeline embolization device (PED) is increasingly used in the endovascular management of cerebral aneurysms. Longitudinal data regarding safety and benefit of the PED in anterior communicating (ACOM) artery aneurysms are limited and particularly lacking in residual ACOM artery aneurysms. We report the use of the PED in 3 patients with ACOM artery aneurysms who were previously coiled. Methods: Three patients with ACOM artery aneurysms, all previously treated with coiling and with recurrence of the aneurysm neck, were treated with the PED. All obtained follow-up diagnostic cerebral angiograms at either 3 or 6 months. Results: Mean age of patients was 59 years. All patients received cerebral angiograms at a minimum of 3 months after treatment with the PED. Follow up angiography was performed up to a mean of 10 months at which time point all cases demonstrated complete aneurysm occlusion, without any stenosis in the parent artery. Conclusion: The PED can be safely used for the treatment of ACOM artery aneurysms. Complete aneurysm obliteration can be achieved in cases refractory to endovascular coiling. These findings warrant replication in a larger data set. PMID- 29118790 TI - Rescue Treatment with Pipeline Embolization for Postsurgical Clipping Recurrences of Anterior Communicating Artery Region Aneurysms. AB - Background: Postsurgical clipping aneurysm recurrences or residuals can be difficult to manage with either traditional open microsurgical approaches or endosaccular coiling. Endoluminal parent vessel reconstruction with flow diversion may be an ideal method for treating these recurrences by avoiding reoperative surgery or intraprocedural aneurysm rupture with aneurysm access. Method: We retrospectively reviewed a single-center aneurysm database identifying all anterior communicating artery (ACom) region aneurysms with recurrences after microsurgical clipping. Cases subsequently treated with Pipeline embolization device (PED) were identified for analysis. Results: Nine PED neurointerventions were performed for the treatment of 6 ACom region recurrent aneurysms after surgical clipping (ACom, n = 4 and A1-A2 junction, n = 2). Of the 6 aneurysms treated, 4 were previously ruptured. Mean patient age was 59.5 +/- 6.9 years (range 50-67 years). Mean aneurysm size was 5.1 +/- 2.2 mm (range 3-9 mm). Mean fluoroscopy time was 44.1 +/- 12.4 min. A single PED, deployed from ipsilateral A2 to ipsilateral A1, was used in 6 cases. No instances of periprocedural complications were encountered. Angiographic follow-up was available in all aneurysms; 5 of these 6 (83%) demonstrated complete aneurysm occlusion. Conclusion: Flow diversion with PED can be a safe and efficacious treatment approach for recurrent ACom region aneurysms after surgical clipping. PMID- 29118791 TI - Utilizing CT with Maximum Intensity Projection Reconstruction Bypassing CTA Improves Time to Groin Puncture in Large Vessel Occlusion Stroke Thrombectomy. AB - Background and Purpose: Prior to thrombectomy for proximal anterior circulation large vessel occlusion (LVO) stroke, recent trials have utilized CT angiography (CTA) for vascular imaging immediately following noncontrast CT (NCCT) for decision-making, but thin-section NCCT with automated maximum intensity projection (MIP) reconstruction also has high accuracy in demonstrating the site of an occluding thrombus. We hypothesized that performing thin-section NCCT with MIP alone prior to thrombectomy improves the time to groin puncture (GP) compared to performing CTA after NCCT. Materials and Methods: We performed a retrospective cohort study of anterior circulation LVO thrombectomy at our tertiary care academic medical center. All stroke patients evaluated with thin-section NCCT (0.625 mm) with automated MIP reconstructions alone and those who had additional CTA were included. We excluded transfer patients, in-hospital strokes, posterior circulation strokes, and patients that were evaluated with stroke imaging other than NCCT or CTA prior to thrombectomy. The study groups were compared for duration from NCCT to GP and total stroke imaging duration. Results: From March 2008 through August 2015, 34 thrombectomy patients met the inclusion/exclusion criteria - 13 in the NCCT and 20 in the NCCT+CTA group. The total stroke imaging duration was shorter in the NCCT group than in the NCCT+CTA group (2 min [1-6] vs. 28 min [23-65]; p < 0.001). The NCCT-only group had a shorter time from NCCT to GP (68 min [32-99] vs. 104 min [79-128]; p = 0.030). Conclusion: Avoiding advanced imaging for patients with anterior circulation LVO in whom thin-section NCCT with MIPs reveals a hyperdense sign significantly shortens the imaging-to-GP time. PMID- 29118792 TI - Anchoring Pipeline Flow Diverter Construct in the Treatment of Traumatic Distal Cervical Carotid Artery Injury. AB - Background: Traumatic extracranial internal carotid artery (ICA) dissections are uncommon and can be difficult to treat. Thinning of adventitia and dilatation may occur following arterial dissection, thus resulting in a fusiform pseudoaneurysm, which can subsequently cause bleeding, expanding, or pulsatile hematoma. Currently, medical management with anticoagulation remains the first line of treatment and yields good outcomes in 75% of cases with a mortality rate of 3-4%. Endovascular intervention is indicated with failure of medical therapy, progressive enlargement of a traumatic pseudoaneurysm, acute flow-related infarcts due to vessel occlusion, or when anticoagulation is contraindicated due to risk of pseudoaneurysm rupture and hemorrhage. Recognized interventional treatments include parent artery occlusion with or without revascularization, endovascular coil embolization, and covered stenting. Summary: A wide variety of endovascular stents are available that are capable of opening a stenosed vessel while obliterating the associated false lumen and providing a scaffold for embolization of the pseudoaneurysm. The use of the Pipeline Embolization Device (PED) in the management of traumatic intracranial pseudoaneurysms has been described. However, there are few reports on the usage of the PED for treating traumatic extracranial ICA dissection and/or pseudoaneurysms. However, a potential complication of the use of PED in the extracranial ICA is a hypothetical tendency to migrate in a mobile vessel. Thus, the risk of migration of the PED has encouraged practitioners to adopt strategies to limit this risk. Key Messages: We describe different techniques employed to anchor the flow diverting construct within tortuous, mobile vessels. PMID- 29118793 TI - Feasibility of Real-Time Angiographic Perfusion Imaging in the Treatment of Cerebral Vasospasm. AB - Background: Objective assessment and quantification of the severity of cerebral vasospasm following aneurysmal subarachnoid hemorrhage is not routinely utilized. We investigated the feasibility of angiographic perfusion imaging derived from digital subtraction angiography (DSA) following endovascular vasospasm treatment procedures. Methodology: Real-time blood flow analysis was performed using parametric color coding on pre- and postintervention DSA. Semiquantitative parenchymal perfusion parameters (arrival time [AT] of contrast, time to peak [TTP] opacification, and mean transit time [MTT] of contrast) were calculated across 3 vascular territories (anterior cerebral artery [ACA], middle cerebral artery [MCA], and lenticulostriate arteries) using standard 2-D angiographic perfusion software. The pre- and postintervention arterial vessel diameters were compared. Results: Twelve endovascular vasospasm treatments in 6 patients were performed. All patients received intra-arterial vasodilator therapy with either nimodipine, milrinone, or both. Following intra-arterial intervention, parenchymal flow analysis showed improvement in TTP and MTT across all vascular territories (p < 0.002) and improvement in AT in the ACA and MCA territories (p < 0.03). Improvement in parenchymal perfusion parameters was associated with improvement in vessel diameters in all territories following treatment (p < 0.05). Conclusion: Real-time parenchymal perfusion imaging during endovascular vasospasm treatment procedures is feasible and provides reliable semiquantitative measurement of angiographic treatment response. PMID- 29118794 TI - Safety and Efficacy of Low-Profile, Self-Expandable Stents for Treatment of Intracranial Aneurysms: Initial and Midterm Results - A Systematic Review and Meta-Analysis. AB - Low-profile stents seem to be associated with a higher incidence of thromboembolic events compared with preexisting stents. We conducted a systematic review of 11 eligible reports and a meta-analysis of 7 reports with respect to the clinical efficacy and safety of low-profile stents. There were 217 intracranial aneurysms reported; 22% were ruptured aneurysms. In all, 72% were treated using single stenting, 19% were treated using overlapping stenting, and 6% were treated using balloon angioplasty followed by stenting; 3% were used to assess the flow diverter effect in a dissecting aneurysm or were treated using unexpected subtotal coil packing. On immediate postprocedural angiographic results, Raymond class I and II obliteration was obtained in 87% of the aneurysms. On angiographic results at 3-6 months, Raymond class I and II obliteration or stability was obtained in 79% of the aneurysms, and Raymond class III obliteration was obtained in 3% of the aneurysms. The recurrence rate on follow-up of intracranial aneurysms was 6.5% (5.7% with LEO Baby and 1.3% with LVIS Jr). The periprocedural complication rate was 12.4%. Periprocedural thromboembolism occurred in 6.5% of the cases. The rate of in-stent stenosis on follow-up of intracranial aneurysms was 10%. In the midterm result, the recurrence rate with use of low-profile, self-expandable stents was relatively low compared to that with use of other self-expandable stents. In the meta analysis comparing LEO Baby with LVIS Jr, the obliteration rate at 6 months was not significantly different, but the periprocedural complication rate was relatively low with LVIS Jr. PMID- 29118795 TI - Cost Analysis of the Addition of Hyperacute Magnetic Resonance Imaging for Selection of Patients for Endovascular Stroke Therapy. AB - Background and Purpose: Patient selection is important to determine the best candidates for endovascular stroke therapy. In application of a hyperacute magnetic resonance imaging (MRI) protocol for patient selection, we have shown decreased utilization with improved outcomes. A cost analysis comparing the pre- and post-MRI protocol time periods was performed to determine if the previous findings translated into cost opportunities. Materials and Methods: We retrospectively identified individuals considered for endovascular stroke therapy from January 2008 to August 2012 who were <=8 h from stroke symptoms onset. Patients prior to April 30, 2010 were selected based on results of the computed tomography/computed tomography angiography alone (pre-hyperacute), whereas patients after April 30, 2010 were selected based on results of MRI (post hyperacute MRI). Demographic, outcome, and financial information was collected. Log-transformed average daily direct costs were regressed on time period. The regression model included demographic and clinical covariates as potential confounders. Multiple imputation was used to account for missing data. Results: We identified 267 patients in our database (88 patients in pre-hyperacute MRI period, 179 in hyperacute MRI protocol period). Patient length of stay was not significantly different in the hyperacute MRI protocol period as compared to the pre-hyperacute MRI period (10.6 vs. 9.9 days, p < 0.42). The median of average daily direct costs was reduced by 24.5% (95% confidence interval 14.1-33.7%, p < 0.001). Conclusions: Use of the hyperacute MRI protocol translated into reduced costs, in addition to reduced utilization and better outcomes. MRI selection of patients is an effective strategy, both for patients and hospital systems. PMID- 29118796 TI - A Comparison of Mechanical Thrombectomy in the M1 and M2 Segments of the Middle Cerebral Artery: A Review of 585 Consecutive Patients. AB - Background: Mechanical thrombectomy for anterior-circulation large-vessel occlusion has shown benefit; however, the question of whether this technique is safe and effective in the distal vasculature remains unanswered. We sought to compare the outcome data from mechanical thrombectomy of the M2 branches of the middle cerebral artery (MCA) with those of the M1 segment. Methods: We performed a retrospective analysis of prospectively collected data of patients with acute ischaemic stroke undergoing mechanical thrombectomy of isolated M1 or M2 branches of the MCA between August 2008 and August 2016. Results: We identified 585 patients, 479 with M1 occlusions and 106 with M2 occlusions. The average age was 72 +/- 12.8 and 68 +/- 13.8 years, respectively (p = 0.007). The baseline Alberta Stroke Program Early Computed Tomographic (ASPECT) score was similar in both cohorts, but patients with M1 occlusions presented with higher mean National Institutes of Health Stroke Scale (NIHSS) scores of 15.7 compared to 11.8 (p < 0.001). There was no significant difference in the average procedure time for each cohort; fewer thrombectomy attempts were required in the M2 cohort (2.3 vs. 1.8, p = 0.0004), but the overall time to recanalization was longer in the M2 cohort (353 vs. 399 min, p < 0.001). Similar rates of successful reperfusion (Thrombolysis in Ischaemic Stroke score [TICI] >=2b 88.5 vs. 90.5%, p = 0.612) were seen, but food outcome (modified Rankin Scale <=2) was lower in M1 occlusions (37.2 vs. 54.3%, p < 0.001). Rates of symptomatic intracranial haemorrhage were similar. Conclusion: Good clinical outcomes can be achieved for both groups with no significant differences in procedure length, final TICI recanalization rates or intracranial haemorrhage between the M1 and M2 cohorts. PMID- 29118797 TI - Comparison of Vacuum Pressures and Forces Generated by Different Catheters and Pumps for Aspiration Thrombectomy in Acute Ischemic Stroke. AB - Background: Direct aspiration thrombectomy is an increasingly utilized technique in endovascular stroke treatment that relies on vacuum and suction force to remove the clot. This report assesses the pressures and forces generated by different catheters and pumps. Methods: Vacuum pressures were measured using a vacuum gauge for several catheters (Stryker Catalyst6, Penumbra Ace 064, Medtronic Arc 061, and Penumbra 041) and pumps (Penumbra pump, 60-mL syringe, and the ASPIRE device). Suction forces were calculated based on pressure and catheter tip size (force = area * pressure). Vacuum pressures and forces were also assessed with a coaxial microcatheter (Rebar 18; inner diameter = 0.021 inches), mimicking a combined aspiration and stent retriever approach. Results: All catheters transmitted similar vacuum pressures, but suction force was proportionate to catheter tip area. Pump vacuum pressures were also similar, although the Penumbra pump (mean -25.63 inches Hg [inHg]) was slightly weaker than the syringe and the ASPIRE device (-27.04 and -27.58 inHg, respectively; p < 0.001, two-way ANOVA). A coaxial microcatheter lowered the mean vacuum pressure by only 1.2 inHg (p = 0.005), though it would theoretically create a very significant reduction in suction force if partially blocking the aspiration catheter tip area. Conclusions: All catheters transmit similar vacuum pressure, but the suction force on the clot is stronger with larger catheter tips. Coaxial microcatheters will have a minimal impact on suction force as long as they are proximal to the aspiration catheter tip. Currently available thrombectomy suction devices, including the Penumbra pump, the ASPIRE handheld pump, and the 60-mL syringe, all develop similar vacuum pressures. PMID- 29118798 TI - Internal Carotid Artery and the Proximal M1 Segment Are Optimal Targets for Mechanical Thrombectomy. AB - Background and Purpose: Mechanical thrombectomy (MT) is an established treatment of acute anterior circulation stroke caused by large vessel occlusion (LVO). We compared the clinical outcome (3-month modified Rankin Scale, mRS) in hyperacute (<3h from the onset of symptoms) ischemic stroke between an MT and an intravenous thrombolysis (IVT) cohort in proximal (ICA and the proximal M1 segment of the middle cerebral artery) and distal (the distal M1 and the M2 segment) LVOs. Methods: We prospectively reviewed 67 patients who underwent MT with newer generation stent retrievers. The IVT cohort consisted of 98 patients who received IVT without MT. We recorded baseline clinical, procedural and imaging variables, technical outcome, 24-h imaging outcome, and the clinical outcome. Differences between the groups were studied with theoretically appropriate statistical tests and binary logistic regression analysis. Results: The proportion of patients who had a proximal LVO and experienced good (mRS <=2) or excellent (mRS <=1) clinical outcome was significantly larger in the MT group (62 vs. 7%, p < 0.001; 47 vs. 3%, p < 0.001, respectively). In a regression model including relevant confounding variables, good clinical outcome was seen significantly more often among patients with proximal occlusions (OR = 6.0, CI 95% 1.9-18.3, p = 0.002). In a similar model, no statistically significant differences were observed in patients with more distal occlusions. Conclusions: MT is superior to IVT in achieving good clinical outcome in hyperacute anterior circulation stroke in the most proximal occlusions (ICA and proximal M1 segment). In the distal M1 and M2 segments neither of these therapies clearly outperforms the other. PMID- 29118799 TI - Optional Endovascular Therapy of Dissecting Posterior Cerebral Artery Aneurysm. AB - BACKGROUND: Posterior cerebral artery aneurysms are uncommon, with an occurrence rate of less than 1% of intracranial aneurysms. They have various shapes, including saccular and fusiform. Dissecting aneurysms may occur in distal posterior cerebral artery and they may affect the whole artery. Endovascular therapy is considered as a safe method of treatment and there are different techniques for endovascular therapy. SUMMARY: Posterior cerebral artery aneurysms are uncommon. Endovascular therapy is considered as a safe method of treatment and there are different techniques for endovascular therapy. We present here three cases collected from Maison Blanche Hospital (Intervention Neuroradiology Department, CHU Reims, France) during 2011-2012; they were females, at a young age and the affected side was on the right. The first case was affected at the P2 P3 segment, the aneurysm was fusiform in shape and she presented with ischemic stroke, while the second and third cases were affected at the P2 segment, the aneurysms being saccular in shape; one of them presented with subarachnoid hemorrhage with a history of migraine and the other patient presented with ischemic stroke. All of them had no history of trauma, hypertension or other diseases. One patient was treated by coiling and sacrificing the parent artery, the second patient was treated with stent-assisted coils, and the third one was treated by coiling without sacrificing the parent artery. PMID- 29118800 TI - Septoplasty: Scepter Balloon Angioplasty for Vasospasm after Aneurysmal Subarachnoid Hemorrhage. AB - Introduction: Balloon angioplasty can be a requisite approach for the treatment of symptomatic and/or severe vasospasm. Dual-lumen microcatheter balloons have multiple potential advantages for this indication including accommodating a 0.014 inch wire and the potential to deliver superselective vasodilators directly via the microcatheter prior to angioplasty. Methods: The authors reviewed a 3-year institutional experience with the Scepter XC balloon (Microvention, Tustin, CA, USA) in the treatment of postaneurysmal subarachnoid hemorrhage vasospasm, focusing on treatment methods, angiographic, and clinical results. Results: Sixty four vessels were treated in 18 patients. Fifteen cases were performed under intravenous (i.v.) conscious sedation (83%). The mean pretreatment stenosis was 59% (range 40-80), and the mean post-treatment stenosis was 12% (range 0-40). Five vessels in 3 patients were subsequently retreated via angioplasty for recurrent vasospasm (8%). There were no complications related to the passage of the balloon microcatheter or inflation of the balloon such as dissection or vessel rupture. Of 14 patients with delayed cerebral ischemia, 7 had complete symptomatic resolution after treatment, and 3 had significant symptomatic improvement. Four patients did not improve after treatment though 3 already had confirmed infarcts on imaging prior to angiography. Conclusion: The Scepter XC is a safe and effective balloon microcatheter for angioplasty of cerebral vasospasm after subarachnoid hemorrhage, allowing for superselective delivery of a vasodilator. Its ease of deliverability and visibility often allows for the performance of the procedure under i.v. conscious sedation. PMID- 29118801 TI - Trends in Endovascular Treatment of Aneurysmal Subarachnoid Hemorrhages. AB - Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) accounts for 5% of all strokes; 30-day mortality is as high as 40%. We sought to evaluate outcomes of aSAH patients treated 2004-2014 by endovascular therapy (EVT), to demonstrate associated trends, and to evaluate angioplasty use for aSAH-related cerebral vasospasm. Methods: The Nationwide Inpatient Sample (NIS) database 2004-2014 was used to derive a study cohort using ICD-9 codes. Survey procedures were used to adjust for stratified cluster design of NIS. NIS trend weights were used to generate national estimates. Mortality during hospitalization and use of angioplasty for aSAH-induced cerebral vasospasm trends were evaluated with multivariate regression analysis. Results: We identified n = 10,822 (weighted n = 52,062) EVT-treated aSAH hospitalizations. Increasing years independently predicted decreased mortality (odds ratio [OR] 0.926, 95% confidence interval [CI] 0.905-0.948, p < 0.0001), decreased utilization of angioplasty (age >=50 years [OR 0.916, 95% CI 0.867-0.968, p = 0.0019] and age <50 years [OR 0.922, 95% CI 0.879-0.967, p = 0.0009]) after controlling for increasing age, Charlson comorbidity index, and external ventricular drain placement. Angioplasty rates were higher in age <50 years compared to age >=50 years (5 vs. 3.63%, p < 0.001). Conclusion: It is notable that EVT for aSAH management will be an integral and increasingly useful tool for initial aneurysm management. Advances in procedural techniques, operator experience, and periprocedural management could be significant contributors of decreasing mortality and reducing the need for angioplasty for cerebral vasospasm in patients admitted with aSAH. PMID- 29118802 TI - Mechanical Thrombectomy for Middle Cerebral Artery Division Occlusions: A Systematic Review and Meta-Analysis. AB - Background: Middle cerebral artery division (M2) occlusion was significantly underrepresented in recent mechanical thrombectomy (MT) randomized controlled trials, and the approach to this disease remains heterogeneous. Objective: To conduct a systematic review and meta-analysis of outcomes at 90 days among patients undergoing MT for M2 middle cerebral artery (MCA) occlusions. Methods: Five clinical databases were searched from inception through September 2016. Observational studies reporting 90-day modified Rankin Scale scores for patients undergoing MT for M2 MCA occlusions with an M1 MCA control group were selected. The primary outcome of interest was good clinical outcome 90 days after MT of an M1 or M2 MCA occlusion. Secondary outcomes of interest included mortality and excellent clinical outcome, recanalization rates, significant intracerebral hemorrhage, and procedural complications. Results: A total of 323 publications were identified, and 237 potentially relevant articles were screened. Six studies were included in the analysis (M1 = 1,203, M2 = 258; total n = 1,461). We found no significant differences in good clinical outcomes (1.10 [95% CI, 0.83-1.44]), excellent clinical outcomes (1.07 [0.65-1.79]), mortality at 3 months (0.85 [0.58 1.24]), recanalization rates (1.06 [0.32-3.48]), and significant intracranial hemorrhage (1.19 [0.61-2.30]). Conclusions: MT of M2 MCA occlusions is as safe as that of main trunk MCA occlusions, and comparable in terms of clinical outcomes and hemorrhagic complications. Randomized clinical trials are needed to assess the impact of MT in patients with M2 occlusions, given that M1 MCA occlusions have different natural histories than M2 occlusions. PMID- 29118803 TI - Multimodal Therapy for Non-Superacute Vertebral Basilar Artery Occlusion. AB - Objective: The aim of this study was to evaluate the feasibility and safety of multimodal therapy for patients with non-superacute vertebral basilar artery occlusion. Method: We performed a retrospective analysis of multimodal therapy for patients with vertebral basilar artery occlusion. All patients who were beyond the time window to receive intravenous thrombolysis and who had deterioration of symptoms after drug treatment received small-balloon dilatation of the occlusive artery to estimate vascular occlusion aetiology. Thrombectomy with a Solitaire AB system was applied to the thrombus, and angioplasty with intracranial stents was used to treat stenosis. During the 3-month follow-up, National Institute of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) scores were recorded regularly. Results: We included 12 patients with a mean age of 60.4 (SD: 12.9) years. The average score on the NIHSS was 16.6 (SD: 11.6), and the average time from onset to admission was 95 h (SD: 121). The arteries were recanalized for all patients, but the degree of residual stenosis in the parent artery was 17.5% (SD: 20.1). During the follow-up period, one patient died of pulmonary haemorrhage and infection, and another patient died from haemorrhage related to high perfusion. After 3 months of follow-up, the 10 surviving patients showed an average NIHSS score of 7.9 (SD: 8.7) and an average mRS score below 2 (1.3 +/- 1.4). Conclusion: For patients with posterior circulation stroke due to basilar artery or vertebral artery occlusion who present to the hospital 6 h after symptom onset and who exhibit deterioration of symptoms after drug treatment, multimodal recanalization of the occluded artery may be a feasible and safe therapy. PMID- 29118804 TI - Hybrid Retrograde-Antegrade Recanalization of Acute Basilar Artery Occlusion. AB - Acute basilar artery (BA) occlusion has a very poor prognosis. Recanalization can be challenged by bilateral vertebral artery (VA) occlusions, arterial dissection, or advanced atherosclerotic disease. We describe a case in whom the BA was accessed and recanalized through a retrograde-antegrade approach from the anterior circulation using a large posterior communicating artery (PCOM). Once the BA had been crossed retrogradely through the PCOM, another microcatheter was advanced antegradely through the VA into the BA and right posterior cerebral artery using the "buddy-wire" technique. In this way the BA was recanalized and reconstructed with stents. This technical note demonstrates a new approach to BA treatment when the antegrade access is hampered by advanced VA/BA disease or dissection. PMID- 29118805 TI - Novel Distal Emboli Protection Technology: The EmboTrap. AB - Background: Over the course of the thrombectomy procedure, clot fragments may become dislodged and lead to downstream emboli due to manipulation of an endovascular device. The EmboTrap thrombectomy system features an inner stent channel with an outer stent trap design that may potentially reduce the risk of distal clot fragmentation during clot removal. We tested the hypothesis that distal emboli to both the same and new territory generated during mechanical thrombectomy are a function of device design. Methods: EmboTrap and Solitaire thrombectomy were conducted in an in vitro model system that mimicked a middle cerebral artery (MCA) occlusion within a complete circle of Willis vascular replica and a contrast-enhanced clot analog. Emboli generated during the procedure with a size >1,000 MUm were collected and measured with calipers. The Coulter principle was used to characterize emboli with a size between 200 and 1,000 um. Results: EmboTrap thrombectomy resulted in a significant reduction in the risk of large emboli (>1,000 MUm) formation as compared to first-generation stent retriever thrombectomy (p = 0.031, Fisher exact test). The majority of emboli >1,000 MUm (~80%) were found in the MCA, regardless of device type. There was no significant difference between the EmboTrap and Solitaire in 200 to 1,000 MUm emboli formation (p = 0.89, Mann-Whitney test). When combining all emboli in the most dangerous range (>200 MUm), EmboTrap offered a size reduction of emboli (p = 0.022). Conclusion: The risk of distal embolization can be altered with improved stent retriever design. When encountering fragment-prone clots, EmboTrap thrombectomy may lower the risk of distal embolization. PMID- 29118806 TI - Computer-Aided Cobb Measurement Based on Automatic Detection of Vertebral Slopes Using Deep Neural Network. AB - Objective: To develop a computer-aided method that reduces the variability of Cobb angle measurement for scoliosis assessment. Methods: A deep neural network (DNN) was trained with vertebral patches extracted from spinal model radiographs. The Cobb angle of the spinal curve was calculated automatically from the vertebral slopes predicted by the DNN. Sixty-five in vivo radiographs and 40 model radiographs were analyzed. An experienced surgeon performed manual measurements on the aforementioned radiographs. Two examiners used both the proposed and the manual measurement methods to analyze the aforementioned radiographs. Results: For model radiographs, the intraclass correlation coefficients were greater than 0.98, and the mean absolute differences were less than 3 degrees . This indicates that the proposed system showed high repeatability for measurements of model radiographs. For the in vivo radiographs, the reliabilities were lower than those from the model radiographs, and the differences between the computer-aided measurement and the manual measurement by the surgeon were higher than 5 degrees . Conclusion: The variability of Cobb angle measurements can be reduced if the DNN system is trained with enough vertebral patches. Training data of in vivo radiographs must be included to improve the performance of DNN. Significance: Vertebral slopes can be predicted by DNN. The computer-aided system can be used to perform automatic measurements of Cobb angle, which is used to make reliable and objective assessments of scoliosis. PMID- 29118807 TI - A Novel Active Semisupervised Convolutional Neural Network Algorithm for SAR Image Recognition. AB - Convolutional neural network (CNN) can be applied in synthetic aperture radar (SAR) object recognition for achieving good performance. However, it requires a large number of the labelled samples in its training phase, and therefore its performance could decrease dramatically when the labelled samples are insufficient. To solve this problem, in this paper, we present a novel active semisupervised CNN algorithm. First, the active learning is used to query the most informative and reliable samples in the unlabelled samples to extend the initial training dataset. Next, a semisupervised method is developed by adding a new regularization term into the loss function of CNN. As a result, the class probability information contained in the unlabelled samples can be maximally utilized. The experimental results on the MSTAR database demonstrate the effectiveness of the proposed algorithm despite the lack of the initial labelled samples. PMID- 29118808 TI - Pathological Brain Detection Using Weiner Filtering, 2D-Discrete Wavelet Transform, Probabilistic PCA, and Random Subspace Ensemble Classifier. AB - Accurate diagnosis of pathological brain images is important for patient care, particularly in the early phase of the disease. Although numerous studies have used machine-learning techniques for the computer-aided diagnosis (CAD) of pathological brain, previous methods encountered challenges in terms of the diagnostic efficiency owing to deficiencies in the choice of proper filtering techniques, neuroimaging biomarkers, and limited learning models. Magnetic resonance imaging (MRI) is capable of providing enhanced information regarding the soft tissues, and therefore MR images are included in the proposed approach. In this study, we propose a new model that includes Wiener filtering for noise reduction, 2D-discrete wavelet transform (2D-DWT) for feature extraction, probabilistic principal component analysis (PPCA) for dimensionality reduction, and a random subspace ensemble (RSE) classifier along with the K-nearest neighbors (KNN) algorithm as a base classifier to classify brain images as pathological or normal ones. The proposed methods provide a significant improvement in classification results when compared to other studies. Based on 5 * 5 cross-validation (CV), the proposed method outperforms 21 state-of-the-art algorithms in terms of classification accuracy, sensitivity, and specificity for all four datasets used in the study. PMID- 29118809 TI - Nonintrusive Load Monitoring Based on Advanced Deep Learning and Novel Signature. AB - Monitoring electricity consumption in the home is an important way to help reduce energy usage. Nonintrusive Load Monitoring (NILM) is existing technique which helps us monitor electricity consumption effectively and costly. NILM is a promising approach to obtain estimates of the electrical power consumption of individual appliances from aggregate measurements of voltage and/or current in the distribution system. Among the previous studies, Hidden Markov Model (HMM) based models have been studied very much. However, increasing appliances, multistate of appliances, and similar power consumption of appliances are three big issues in NILM recently. In this paper, we address these problems through providing our contributions as follows. First, we proposed state-of-the-art energy disaggregation based on Long Short-Term Memory Recurrent Neural Network (LSTM-RNN) model and additional advanced deep learning. Second, we proposed a novel signature to improve classification performance of the proposed model in multistate appliance case. We applied the proposed model on two datasets such as UK-DALE and REDD. Via our experimental results, we have confirmed that our model outperforms the advanced model. Thus, we show that our combination between advanced deep learning and novel signature can be a robust solution to overcome NILM's issues and improve the performance of load identification. PMID- 29118810 TI - The Differential Role of Human Cationic Trypsinogen (PRSS1) p.R122H Mutation in Hereditary and Nonhereditary Chronic Pancreatitis: A Systematic Review and Meta Analysis. AB - Background: Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The PRSS1 p.R122H mutation was the first discovered to affect hereditary CP, with 80% penetrance. We performed here a systematic review and meta-analysis to evaluate the associations of PRSS1 p.R122H mutation with CP of diverse etiology. Methods: The PubMed, EMBASE, and MEDLINE database were reviewed. The pooled odds ratio (OR) with 95% confidence intervals was used to evaluate the association of p.R122H mutation with CP. Initial analysis was conducted with all etiologies of CP, followed by a subgroup analysis for hereditary and nonhereditary CP, including alcoholic or idiopathic CP. Results: A total of eight case-control studies (1733 cases and 2415 controls) were identified and included. Overall, PRSS1 p.R122H mutation was significantly associated with an increased risk of CP (OR = 4.78[1.13-20.20]). Further analysis showed p.R122H mutation strongly associated with the increased risk of hereditary CP (OR = 65.52[9.09-472.48]) but not with nonhereditary CP, both alcoholic and idiopathic CP. Conclusions: Our study showing the differential role of p.R122H mutation in various etiologies of CP indicates that this complex disorder is likely influenced by multiple genetic factors as well as environmental factors. PMID- 29118811 TI - Obese Children with Metabolic Syndrome Have 3 Times Higher Risk to Have Nonalcoholic Fatty Liver Disease Compared with Those without Metabolic Syndrome. AB - Background: The aim of this study was to investigate the relationship between metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD) in obese children. One hundred and twenty-five subjects aged 11-12 years old participated in the study. Methods: Anthropometric and biochemical indices were measured, including lipid and liver profile, blood glucose, serum insulin, and liver ultrasound. Results: Forty-four children (58.6%) were found to have MS. Insulin resistance was present in 78 (62.4%) children. Patients with MS were more likely to have NAFLD (P < 0.001). Children with NAFLD had significantly higher body mass index, waist circumference, triglycerides, fasting insulin, and lower high density lipoprotein compared to patients with normal livers (P < 0.001). Insulin resistance was significantly higher in children with NAFLD (P < 0.001). Obese children presenting with MS were 3.01 (2.87-3.57, P < 0.002) times more likely to develop NAFLD compared to those without metabolic syndrome after adjustment of cofounders. Conclusions: Obese children with MS have a higher risk of developing NAFLD. Weight management and early prevention should be the first line of treatment to prevent any possible health issues later on. PMID- 29118812 TI - PDE5 Overexpression in Well-Differentiated Thyroid Carcinomas Is Associated with Lymph Node Metastasis. AB - Overexpression of PDE5 is observed in certain human cancers, but PDE5 expression in well-differentiated thyroid carcinoma (WDTC) is unknown. We therefore examined PDE5 expression and its relationship with the clinicopathological features of WDTC. Real-time qPCR and Western blotting were performed to analyze the expression of PDE5 mRNA and protein in paired WDTC tumor and adjacent nontumor tissues. Immunohistochemistry was used to analyze the expression of PDE5 in paraffin-embedded tissues obtained from 103 cases of WDTC. Statistical analyses were performed to examine the correlation between PDE5 expression and clinicopathological features. The expression of PDE5 mRNA and protein was upregulated in WDTC lesions compared to their paired noncancerous tissues. The expression of PDE5 was significantly correlated with age (P = 0.032), regional lymph node status (P = 0.004), and the presence of distant metastasis (P = 0.020). High PDE5 expression was more closely associated with lymph node involvement in patients over 45 years (OR = 15.60, P <= 0.05). Thus, PDE5 may be a potential biomarker in WDTC, particularly in patients with regional lymph node metastasis, which is associated with disease recurrence, treatment failure, and morbidity. PDE5 expression may also help predict the prognosis and recurrence of WDTC after surgery. PMID- 29118813 TI - The Leukemic Stem Cell Niche: Adaptation to "Hypoxia" versus Oncogene Addiction. AB - Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern the maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC). The physiological oxygen concentration in tissues ranges between 0.1 and 5.0%. Stem cell niches (SCN) are placed in tissue areas at the lower end of this range ("hypoxic" SCN), to which stem cells are metabolically adapted and where they are selectively hosted. The data reported here indicated that driver oncogenic proteins of several leukemias are suppressed following cell incubation at oxygen concentration compatible with SCN physiology. This suppression is likely to represent a key positive regulator of LSC survival and maintenance (self-renewal) within the SCN. On the other hand, LSC committed to differentiation, unable to stand suppression because of addiction to oncogenic signalling, would be unfit to home in SCN. The loss of oncogene addiction in SCN adapted LSC has a consequence of crucial practical relevance: the refractoriness to inhibitors of the biological activity of oncogenic protein due to the lack of their molecular target. Thus, LSC hosted in SCN are suited to sustain the long term maintenance of therapy-resistant minimal residual disease. PMID- 29118815 TI - Response to case report: Airway autoimmune responses in severe eosinophilic asthma following low-dose Mepolizumab therapy. PMID- 29118814 TI - TGF-beta1-induced epithelial-mesenchymal transition in lung cancer cells involves upregulation of miR-9 and downregulation of its target, E-cadherin. AB - Background: TGF-beta1 plays an important role in the epithelial-mesenchymal transition (EMT) of epithelial cancers, including non-small cell lung cancer (NSCLC). While the full underlying mechanism remains unclear, miR-9 is known to play a critical role in the regulation of NSCLC cell invasion. We tested whether miR-9 targets E-cadherin and thus affects TGF-beta1-induced EMT in NSCLC cells by assessing the expression levels of miR-9 and E-cadherin for NSCLC patients and then verifying the targeting of E-cadherin by miR-9 using the dual luciferase reporter system. Results: MiR-9 was significantly upregulated in NSCLC tissues compared with its level in adjacent normal tissues. The expression of E-cadherin in NSCLC tissues was significantly decreased. In addition, we found that TGF beta1 significantly upregulated the expression of miR-9 and downregulated the expression of E-cadherin. E-cadherin was confirmed as a direct target gene of miR 9. Using an miR-9 inhibitor reversed the TGF-beta1-mediated inhibition of E cadherin expression and upregulation of the mesenchymal marker alpha-SMA. TGF beta1 significantly induced cell invasion, and this effect was significantly inhibited by miR-9 inhibitors. Conclusions: TGF-beta1 induced EMT in NSCLC cells by upregulating miR-9 and downregulating miR-9's target, E-cadherin. PMID- 29118816 TI - Synthesis of Novel Fluorene Bisamide Derivatives via Ugi Reaction and Evaluation their Biological Activity against Mycobacterium species. AB - A series of new fluorene bisamide derivatives were synthesized through multi component Ugi reaction and tested for their in-vitro anti-mycobacterial activity. The structures of the products 5a-w were deduced from their IR, 1H NMR, and 13C NMR spectra. Elemental analyses (CHN) for novel compounds (5a, 5d, 5f, 5h, 5k, 5l, 5p, 5s, 5t, 5v, 5w) was done. These compounds were evaluated as anti bacterial agents against Mycobacterium bovis and M. tuberculosis, while their activity expressed as the minimum inhibitory concentration (MIC) in MUg/mL. Among the twenty-three synthesized compounds, 5a was found to be the most active compound in vitro with MIC of 1.95 MUg/mL against Mycobactrium bovis and compound 5k showed greatest potency against sensitive and resistant strains of M.tuberculosis (H37Rv, IHMT149/09, HPV115/08, and HPV65/08). PMID- 29118817 TI - Maternal high-fat diet impairs glucose metabolism, beta-cell function and proliferation in the second generation of offspring rats. AB - Background: This study aimed to assess the impact of perinatal high-fat (HF) diet in female Sprague-Dawley rats (F0) on glucose metabolism and islet function in their early life of second-generation of offspring (F2). Methods: F0 rats were fed with a standard chow (SC) or HF diet for 8 weeks before mating, up to termination of lactation for their first-generation of offspring (F1-SC and F1 HF). F1 females were mated with normal males at the age of week 11, and producing F2 offspring (F2-SC, F2-HF). All the offspring were fed SC diet after weaning for 3 weeks. The glucose level and islet function of F2 offspring were assessed at the age of week 3 and 12. Results: The F2-HF offspring had a high birth weight and maintained a higher body mass at the age of week 3 and 12, along with an impaired glucose tolerance and lower serum insulin levels compared with the F2 SC. beta-cell proliferation was also impaired in the islets of F2-HF rats at the age of week 3 and 12. The pancreatic and duodenal homeobox factor-1 (Pdx1) and Neurogenic differentiation 1 (NeuroD1) expressions were decreased in the islet of F2-HF rats at the age of week 12. Conclusions: Maternal HF diet during pre gestation, gestation, and lactation in rats could result in the increased body weight and glucose intolerance in their early life of F2 offspring due to impaired beta-cell function and proliferation. PMID- 29118818 TI - Folic acid prevents cardiac dysfunction and reduces myocardial fibrosis in a mouse model of high-fat diet-induced obesity. AB - Background: Folic acid (FA) is an antioxidant that can reduce reactive oxygen species generation and can blunt cardiac dysfunction during ischemia. We hypothesized that FA supplementation prevents cardiac fibrosis and cardiac dysfunction induced by obesity. Methods: Six-week-old C57BL6/J mice were fed a high-fat diet (HFD), normal diet (ND), or an HFD supplemented with folic acid (FAD) for 14 weeks. Cardiac function was measured using a transthoracic echocardiographic exam. Phenotypic analysis included measurements of body and heart weight, blood glucose and tissue homocysteine (Hcy) content, and heart oxidative stress status. Results: HFD consumption elevated fasting blood glucose levels and caused obesity and heart enlargement. FA supplementation in HFD-fed mice resulted in reduced fasting blood glucose, heart weight, and heart tissue Hcy content. We also observed a significant cardiac systolic dysfunction when mice were subjected to HFD feeding as indicated by a reduction in the left ventricular ejection fraction and fractional shortening. However, FAD treatment improved cardiac function. FA supplementation protected against cardiac fibrosis induced by HFD. In addition, HFD increased malondialdehyde concentration of the heart tissue and reduced the levels of antioxidant enzyme, glutathione, and catalase. HFD consumption induced myocardial oxidant stress with amelioration by FA treatment. Conclusion: FA supplementation significantly lowers blood glucose levels and heart tissue Hcy content and reverses cardiac dysfunction induced by HFD in mice. These functional improvements of the heart may be mediated by the alleviation of oxidative stress and myocardial fibrosis. PMID- 29118819 TI - A method for automatic segmentation and splitting of hyperspectral images of raspberry plants collected in field conditions. AB - Hyperspectral imaging is a technology that can be used to monitor plant responses to stress. Hyperspectral images have a full spectrum for each pixel in the image, 400-2500 nm in this case, giving detailed information about the spectral reflectance of the plant. Although this technology has been used in laboratory based controlled lighting conditions for early detection of plant disease, the transfer of such technology to imaging plants in field conditions presents a number of challenges. These include problems caused by varying light levels and difficulties of separating the target plant from its background. Here we present an automated method that has been developed to segment raspberry plants from the background using a selected spectral ratio combined with edge detection. Graph theory was used to minimise a cost function to detect the continuous boundary between uninteresting plants and the area of interest. The method includes automatic detection of a known reflectance tile which was kept constantly within the field of view for all image scans. A method to split images containing rows of multiple raspberry plants into individual plants was also developed. Validation was carried out by comparison of plant height and density measurements with manually scored values. A reasonable correlation was found between these manual scores and measurements taken from the images (r2 = 0.75 for plant height). These preliminary steps are an essential requirement before detailed spectral analysis of the plants can be achieved. PMID- 29118820 TI - Non-destructive, high-content analysis of wheat grain traits using X-ray micro computed tomography. AB - Background: Wheat is one of the most widely grown crop in temperate climates for food and animal feed. In order to meet the demands of the predicted population increase in an ever-changing climate, wheat production needs to dramatically increase. Spike and grain traits are critical determinants of final yield and grain uniformity a commercially desired trait, but their analysis is laborious and often requires destructive harvest. One of the current challenges is to develop an accurate, non-destructive method for spike and grain trait analysis capable of handling large populations. Results: In this study we describe the development of a robust method for the accurate extraction and measurement of spike and grain morphometric parameters from images acquired by X-ray micro computed tomography (MUCT). The image analysis pipeline developed automatically identifies plant material of interest in MUCT images, performs image analysis, and extracts morphometric data. As a proof of principle, this integrated methodology was used to analyse the spikes from a population of wheat plants subjected to high temperatures under two different water regimes. Temperature has a negative effect on spike height and grain number with the middle of the spike being the most affected region. The data also confirmed that increased grain volume was correlated with the decrease in grain number under mild stress. Conclusions: Being able to quickly measure plant phenotypes in a non-destructive manner is crucial to advance our understanding of gene function and the effects of the environment. We report on the development of an image analysis pipeline capable of accurately and reliably extracting spike and grain traits from crops without the loss of positional information. This methodology was applied to the analysis of wheat spikes can be readily applied to other economically important crop species. PMID- 29118821 TI - TasselNet: counting maize tassels in the wild via local counts regression network. AB - Background: Accurately counting maize tassels is important for monitoring the growth status of maize plants. This tedious task, however, is still mainly done by manual efforts. In the context of modern plant phenotyping, automating this task is required to meet the need of large-scale analysis of genotype and phenotype. In recent years, computer vision technologies have experienced a significant breakthrough due to the emergence of large-scale datasets and increased computational resources. Naturally image-based approaches have also received much attention in plant-related studies. Yet a fact is that most image based systems for plant phenotyping are deployed under controlled laboratory environment. When transferring the application scenario to unconstrained in-field conditions, intrinsic and extrinsic variations in the wild pose great challenges for accurate counting of maize tassels, which goes beyond the ability of conventional image processing techniques. This calls for further robust computer vision approaches to address in-field variations. Results: This paper studies the in-field counting problem of maize tassels. To our knowledge, this is the first time that a plant-related counting problem is considered using computer vision technologies under unconstrained field-based environment. With 361 field images collected in four experimental fields across China between 2010 and 2015 and corresponding manually-labelled dotted annotations, a novel Maize Tassels Counting (MTC) dataset is created and will be released with this paper. To alleviate the in-field challenges, a deep convolutional neural network-based approach termed TasselNet is proposed. TasselNet can achieve good adaptability to in-field variations via modelling the local visual characteristics of field images and regressing the local counts of maize tassels. Extensive results on the MTC dataset demonstrate that TasselNet outperforms other state-of-the-art approaches by large margins and achieves the overall best counting performance, with a mean absolute error of 6.6 and a mean squared error of 9.6 averaged over 8 test sequences. Conclusions: TasselNet can achieve robust in-field counting of maize tassels with a relatively high degree of accuracy. Our experimental evaluations also suggest several good practices for practitioners working on maize-tassel-like counting problems. It is worth noting that, though the counting errors have been greatly reduced by TasselNet, in-field counting of maize tassels remains an open and unsolved problem. PMID- 29118822 TI - Histological quantification of maize stem sections from FASGA-stained images. AB - Background: Crop species are of increasing interest both for cattle feeding and for bioethanol production. The degradability of the plant material largely depends on the lignification of the tissues, but it also depends on histological features such as the cellular morphology or the relative amount of each tissue fraction. There is therefore a need for high-throughput phenotyping systems that quantify the histology of plant sections. Results: We developed custom image processing and an analysis procedure for quantifying the histology of maize stem sections coloured with FASGA staining and digitalised with whole microscopy slide scanners. The procedure results in an automated segmentation of the input images into distinct tissue regions. The size and the fraction area of each tissue region can be quantified, as well as the average coloration within each region. The measured features can discriminate contrasted genotypes and identify changes in histology induced by environmental factors such as water deficit. Conclusions: The simplicity and the availability of the software will facilitate the elucidation of the relationships between the chemical composition of the tissues and changes in plant histology. The tool is expected to be useful for the study of large genetic populations, and to better understand the impact of environmental factors on plant histology. PMID- 29118823 TI - Sequence analysis of cultivated strawberry (Fragaria * ananassa Duch.) using microdissected single somatic chromosomes. AB - Background: Cultivated strawberry (Fragaria * ananassa Duch.) has homoeologous chromosomes because of allo-octoploidy. For example, two homoeologous chromosomes that belong to different sub-genome of allopolyploids have similar base sequences. Thus, when conducting de novo assembly of DNA sequences, it is difficult to determine whether these sequences are derived from the same chromosome. To avoid the difficulties associated with homoeologous chromosomes and demonstrate the possibility of sequencing allopolyploids using single chromosomes, we conducted sequence analysis using microdissected single somatic chromosomes of cultivated strawberry. Results: Three hundred and ten somatic chromosomes of the Japanese octoploid strawberry 'Reiko' were individually selected under a light microscope using a microdissection system. DNA from 288 of the dissected chromosomes was successfully amplified using a DNA amplification kit. Using next-generation sequencing, we decoded the base sequences of the amplified DNA segments, and on the basis of mapping, we identified DNA sequences from 144 samples that were best matched to the reference genomes of the octoploid strawberry, F. * ananassa, and the diploid strawberry, F. vesca. The 144 samples were classified into seven pseudo-molecules of F. vesca. The coverage rates of the DNA sequences from the single chromosome onto all pseudo-molecular sequences varied from 3 to 29.9%. Conclusion: We demonstrated an efficient method for sequence analysis of allopolyploid plants using microdissected single chromosomes. On the basis of our results, we believe that whole-genome analysis of allopolyploid plants can be enhanced using methodology that employs microdissected single chromosomes. PMID- 29118824 TI - Experience from the First Live-Birth Derived From Oocyte Nuclear Transfer as a Treatment Strategy for Mitochondrial Diseases. PMID- 29118825 TI - Hemoglobin-Dilution Method: Effect of Measurement Errors on Vascular Volume Estimation. AB - The hemoglobin-dilution method (HDM) has been used to estimate changes in vascular volumes in patients because direct measurements with radioisotopes are time-consuming and not practical in many facilities. The HDM requires an assumption of initial blood volume, repeated measurements of plasma hemoglobin concentration, and the calculation of the ratio of hemoglobin measurements. The statistics of these ratio distributions resulting from measurement error are ill defined even when the errors are normally distributed. This study uses a "Monte Carlo" approach to determine the distribution of these errors. The finding was that these errors could be closely approximated with a log-normal distribution that can be parameterized by a geometric mean (X) and a dispersion factor (S). When the ratio of successive Hb concentrations is used to estimate blood volume, normally distributed hemoglobin measurement errors tend to produce exponentially higher values of X and S as the SD of the measurement error increases. The longer tail of the distribution to the right could produce much greater overestimations than would be expected from the SD values of the measurement error; however, it was found that averaging duplicate and triplicate hemoglobin measurements on a blood sample greatly improved the accuracy. PMID- 29118826 TI - Prevalence of HPV infection in hypopharyngeal and laryngeal squamous cell carcinoma at Thailand's largest tertiary referral center. AB - Background: Following the well-established relationship between human papillomavirus (HPV) and cervical carcinoma, the carcinogenicity of this virus has also been confirmed in subsets of head and neck carcinoma (HNCA), but mainly in the oropharynx. Other subsites of HNCA with less known association to HPV have never been studied in Thailand. Accordingly, the aim of this study was to investigate the prevalence of HPV DNA in hypopharyngeal and laryngeal squamous cell carcinoma in Thai population. Methods: This cross-sectional study included hypopharyngeal and laryngeal squamous cell carcinoma patients diagnosed and treated at the Department of Otorhinolaryngology, Siriraj Hospital during the September 2011-December 2013 study period. Presence of HPV genome was confirmed by polymerase chain reaction from pathologically-confirmed fresh specimens. Demographic data and risk factors of HPV infection were evaluated. Results: Eighty patients were included, and 95% of those were male. Only one patient was noted with positive HPV-62 serotype. Most patients consumed tobacco and/or alcohol. Five patients had no risk factors for cancer development. Risk of HPV infection was evaluated by self-reporting questionnaire. The mean age of sexual debut was 20.17 years. Forty-eight patients had multiple sexual partners. Sixteen and seven patients had history of sexually transmitted disease infection and habitual oral sex contact, respectively. Conclusion: There was no oncogenic HPV DNA detected within pathologic specimens of laryngeal and hypopharyngeal cancers in this study. Compared to rates reported from developed countries, the prevalence of HPV-related HNCA in Thailand is very low. PMID- 29118827 TI - This month in JICS. PMID- 29118828 TI - LocSSIPs - The quest to improve patient safety. PMID- 29118829 TI - Evaluating the safety and efficacy of regional citrate compared to systemic heparin as anticoagulation for continuous renal replacement therapy in critically ill patients: A service evaluation following a change in practice. AB - Following the implementation of citrate anticoagulation for continuous renal replacement therapy, we evaluate its first year of use and compare it to the previously used heparin, to assess whether our patients benefit from the recently reported advantages of citrate. We retrospectively analysed 2 years of data to compare the safety and efficacy of citrate versus heparin. The results have shown that 43 patients received continuous renal replacement therapy with heparin, 37 patients with citrate. We found no significant difference in metabolic control of pH, urea and creatinine after 72 h. Filters anticoagulated with citrate had significantly longer median lifespan (33 h vs 17 h; p = 0.001), shorter downtime (0 h vs 5 h; p = 0.015) and less filter sets per patient day (0.37 vs 0.67; p = 0.002). Filters anticoagulated with heparin were commonly interrupted due to clotting (50% vs 16.4%), whereas filters anticoagulated with citrate were often stopped electively (53.4% vs 24.6%). Patients on heparin filters had significantly higher APPTs, some at potentially dangerous levels (>180 s), whilst patients on citrate filters had significantly higher levels of bicarbonate. Therefore, we conclude that citrate is superior in terms of safety and efficacy, with longer filter lifespan. It has become our first line anticoagulant for continuous renal replacement therapy. PMID- 29118830 TI - A multicentre prospective evaluation of alcohol-related admissions to intensive care units in Wales. AB - Purpose: We conducted a prospective multicentre study in 13 Welsh intensive care units to assess what proportion of intensive care admissions relate to alcohol, and how outcomes among these patients compare with non-alcohol related admissions. Materials and methods: Data were prospectively collected for one month between June and July 2015. Every intensive care admission was screened for alcohol associations based on ICD-10 criteria, using a pre-designed pro-forma. Follow-up data were collected at 60 days using a pre-existing database (WardWatcher; Critical Care Audit Ltd, England). Outcomes included: lengths of mechanical ventilation, intensive care units and hospital stay; intensive care units and hospital mortality. Results: Alcohol contributed directly to 10% of all ICU admissions and to 11% of unplanned admissions. These patients were younger (52 vs. 66, p = 0.0011), more likely to be male (68% vs. 52%, p = 0.014) and had more prolonged ventilation (p = 0.019) There was no significant difference between the groups with respect to length of stay or mortality. Conclusions: Alcohol contributes to a significant proportion of ICU admissions in Wales, a Western European country with a relatively low number of ICU beds per capita. Strategies to address this impact should be explored. PMID- 29118831 TI - Basic critical care echocardiography: How many studies equate to competence? A pilot study using high fidelity echocardiography simulation. AB - Background: Assessment of competence in basic critical care echocardiography is complex. Competence relies on not only imaging accuracy but also interpretation and appropriate management decisions. The experience to achieve these skills, real-time, is likely more than required for imaging accuracy alone. We aimed to assess the feasibility of using simulation to assess number of studies required to attain competence in basic critical care echocardiography. Methods: This is a prospective pilot study recruiting trainees at various degrees of experience in basic critical care echocardiography using experts as reference standard. We used high fidelity simulation to assess speed and accuracy using total time taken, total position difference and total angle difference across the basic acoustic windows. Interpretation and clinical application skills were assessed using a clinical scenario. 'Cut-off' values for number of studies required for competence were estimated. Results: Twenty-seven trainees and eight experts were included. The subcostal view was achieved quickest by trainees (median 23 s, IQR 19-37). Eighty-seven percent of trainees did not achieve accuracy across all views; 81% achieved accuracy with the parasternal long axis and the least accurate was the parasternal short axis (44% of trainees). Fewer studies were required to be considered competent with imaging acquisition compared with competence in correct interpretation and integration (15 vs. 40 vs. 50, respectively). Discussion: The use of echocardiography simulation to determine competence in basic critical care echocardiography is feasible. Competence in image acquisition appears to be achieved with less experience than correct interpretation and correct management decisions. Further studies are required. PMID- 29118832 TI - The impact of focused echocardiography using the Focused Intensive Care Echo protocol on the management of critically ill patients, and comparison with full echocardiographic studies by BSE-accredited sonographers. AB - Introduction: Focused echocardiography is widely used to assist clinical decision making in critically ill patients. In the UK, the Focused Intensive Care Echo protocol is recommended by the Intensive Care Society to ensure consistency of approach and guarantee training standards. Concerns remain about the reliability of information attained by non-expert clinicians in focused echocardiography, particularly when this is used to alter clinical management. Methods: A prospective, observational evaluation of 60 consecutive patients undergoing Focused Intensive Care Echo studies in a single ICU. Results: A complete Focused Intensive Care Echo study was possible in 43/60 scans (72%) and new diagnostic information obtained following 41/60 scans (68%), which lead to a change of clinical management in 28/60 (47%) of cases. In 24/60 (40%) of cases, a full transthoracic study was subsequently undertaken by a fully accredited sonographer. There were no cases where the results from the full study contradicted those from the limited Focused Intensive Care Echo study; additional diagnostic information was attained following 68% of full studies. Conclusion: Focused echocardiography using the Focused Intensive Care Echo protocol is feasible and clinically useful in a high proportion of ICU patients. However, many still require additional expert echocardiographic assessment. Focused echocardiography delivered by non-experts is clinically useful in this setting but its limitations must be understood and access to expert assessment should be available. PMID- 29118834 TI - The microcirculation and its measurement in sepsis. AB - The microcirculation describes the smallest elements of the cardiovascular conducting system and is pivotal in the maintenance of homeostasis. Microcirculatory dysfunction is present early in the pathophysiology of sepsis, with the extent of microcirculatory derangement relating to disease severity and prognosis in ICU patients. However, at present microcirculatory function is not routinely monitored at the bedside. This article describes the pathophysiology of microcirculatory derangements in sepsis, methods of its measurement and evidence to support their clinical use. PMID- 29118833 TI - In-patient physiotherapy for adults on veno-venous extracorporeal membrane oxygenation - United Kingdom ECMO Physiotherapy Network: A consensus agreement for best practice. AB - Clinical specialist physiotherapists from the five severe respiratory failure centres in England where respiratory extracorporeal membrane oxygenation (ECMO) is practiced have established this consensus agreement for physiotherapy best practice. The severe respiratory failure centres are Wythenshawe Hospital, Manchester; Glenfield Hospital, Leicester; Papworth Hospital, Cambridge; Guy's and St Thomas' Hospital, London and The Royal Brompton Hospital, London. Although research into physiotherapy and ECMO is increasing, there is not a sufficient amount to write evidence-based guidelines; hence the development of a consensus document, using knowledge and experience of the specialist physiotherapists working with patients receiving ECMO. The document outlines safety aspects, practicalities and additional treatment considerations for physiotherapists conducting respiratory care and physical rehabilitation. PMID- 29118835 TI - Classic cases revisited - Oxygen in court and the problem of therapeutic illusion. AB - Medical science attempts to inform clinical practice. Law is concerned with causality. Intersection of law and medicine at times highlights the shortcomings in the medical approach to causality. Evidence-based medicine is only as good as the process of gathering evidence and this is inherently imperfect as suggested by philosophers. There is a risk of attributing a causal relationship when there is none, which can result in a false belief about an intervention. False beliefs can become entrenched forming a dogma. An application of treatment and a subsequent observation of clinical improvement may create a therapeutic illusion of benefit. It is possible that oxygen is used in this way. We cannot safely infer based on harm associated with its deprivation that supplementation of oxygen is beneficial in all patients. Evidence of benefit of oxygen therapy versus harm is not overwhelmingly convincing. The case of oxygen serves to illustrate a potential for a wider problem in science and medicine where potentially harmful treatments are administered based on beliefs rather than evidence and on the extrapolations from population-wide observations and without considering particulars of each case. Current application of oxygen is possibly inappropriate and efforts should be made to reappraise its use. PMID- 29118836 TI - The life and work of Rudolf Virchow 1821-1902: "Cell theory, thrombosis and the sausage duel". PMID- 29118837 TI - Trial of decompressive craniectomy for traumatic intracranial hypertension. PMID- 29118838 TI - A complex obstetric case. AB - A 33-year-old primigravida presented with severe sepsis, severe pre-eclampsia, peripartum cardiomyopathy and the haemolysis, elevated liver enzymes and low platelets syndrome manifesting over the course of 24 h causing a diagnostic conundrum and a difficult sequence of physiological problems to overcome. We describe a previously unreported sequence of events involving a pre-eclamptic, septic parturient to improve anaesthetic and intensive care physician awareness of confounding factors that complicate assessment and management of these patients. PMID- 29118839 TI - Acute angle closure glaucoma - A potential blind spot in critical care. AB - We report a case of a 69-year-old gentleman who developed an acutely painful eye with loss of visual acuity whilst on the critical care unit. He was admitted three days previously with an infective exacerbation of chronic obstructive pulmonary disease requiring invasive mechanical ventilation. In addition, he received intravenous antibiotics, steroids, nebulised bronchodilators and intravenous aminophylline, together with noradrenaline for blood pressure support. On development of visual symptoms, an emergency ophthalmology review diagnosed acute angle closure glaucoma. Treatment with pilocarpine eye drops, intravenous acetazolamide and bilateral YAG laser iridotomies provided immediate symptom relief and he went on to make an excellent recovery. Acute angle closure glaucoma is a potentially devastating ophthalmic emergency. Critical care patients are at particular risk for the development of this condition due to the use of predisposing medications, such as sympathomimetics and beta agonists. Sedated patients also run a risk of delayed diagnosis so a high index of suspicion is required. PMID- 29118840 TI - Too many pills to swallow: A case of a mixed overdose. AB - Propranolol is a highly lipid-soluble beta-receptor antagonist. We describe a case of mixed overdose, including propranolol, amlodipine and olanzapine, resulting in severe resistant hypotension which was successfully treated. A 21 year-old student ingested 6.4 g of propranolol, 280 mg of amlodipine and 560 mg of olanzapine. The patient was brought to the emergency department and exhibited signs of severe systemic toxicity - profound hypotension and circulatory collapse, respiratory depression and coma. The patient had conventional therapy but failed to respond to this and was therefore commenced on IntraLipid infusion, high-dose insulin infusion and inotrope infusion. An endoscopy was performed in intensive care which revealed a large drug beozar - this was removed. We believe that this combination of infusions with early endoscopy could be beneficial in treating similar patients in the future and present the first case of a propranolol drug bezoar. PMID- 29118841 TI - Management of severe dehydration. AB - The presented case is one of severe dehydration and acute kidney injury with significant resultant complications that required considerable fluid and electrolyte replacement. Approaches to fluid resuscitation in the context of hypernatraemia and the hyperosmolar state were considered and then judiciously combined to manage a complex case with a successful outcome. Conflicting guidance in this domain is discussed with recommendations for a future management strategy that is tailored to individual patients. PMID- 29118842 TI - Inaccuracies in calculating predicted body weight and its impact on safe ventilator settings (Journal of the Intensive Care Society 2016; 17: 191-195). PMID- 29118843 TI - The balance of accuracy and reliability in estimating tidal volume from height. PMID- 29118844 TI - Ultrasound probe grip: the afternoon tea technique. AB - Background: Globally, ultrasound is being used to assist in central venous and difficult peripheral intravenous access in a variety of emergency and non emergency clinical settings. Context: After reading Flood's paper on safe central venous access and noting the difficulties clinicians find in probe stabilisation whilst performing dynamic intravenous access, we decided to share our teaching technique. Innovation: The purpose of this correspondence is to highlight the 'afternoon tea technique' as a potential teaching method for probe stabilisation. Implications: It is hoped that this technique will improve the image quality in dynamic procedures and increase the success rate of ultrasound-guided intravenous access in clinical practice. PMID- 29118845 TI - Association between intravascular thermoregulation devices and the development of venous thrombo-embolic phenomenon. PMID- 29118846 TI - Ventilator-associated events ... perhaps not the answer. PMID- 29118847 TI - Starvation ketoacidosis: Treatment pitfalls. PMID- 29118848 TI - Lost youth. PMID- 29118849 TI - Examining the need & potential for biomedical engineering to strengthen health care delivery for displaced populations & victims of conflict. AB - Conflict and the subsequent displacement of populations creates unique challenges in the delivery of quality health care to the affected population. Equitable access to quality care demands a multi-pronged strategy with a growing need, and role, for technological innovation to address these challenges. While there have been significant contributions towards alleviating the burden of conflict via data informatics and analytics, communication technology, and geographic information systems, little has been done within biomedical engineering. This article elaborates on the causes for gaps in biomedical innovation for refugee populations affected by conflict, tackles preconceived notions, takes stock of recent developments in promising technologies to address these challenges, and identifies tangible action items to create a stronger and sustainable pipeline for biomedical technological innovation to improve the health and well-being of an increasing group of vulnerable people around the world. PMID- 29118850 TI - Study of in vitro transcriptional binding effects and noise using constitutive promoters combined with UP element sequences in Escherichia coli. AB - Background: UP elements (upstream element) are DNA sequences upstream of a promoter that interact with the alpha-subunit of RNA polymerase (RNAP) and can affect transcription by altering the binding RNAP to DNA. However, details of UP element and binding affinity effects on transcriptional strength are unclear. Results: Here, we investigated the effects of UP element sequences on gene transcription, binding affinity, and gene expression noise. Addition of UP elements resulted in increased gene expression (maximum 95.7-fold increase) and reduced gene expression noise (8.51-fold reduction). Half UP element sequences at the proximal subsite has little effect on transcriptional strength despite increasing binding affinity by 2.28-fold. In vitro binding assays were used to determine dissociation constants (Kd) and in the in vitro system, the full range of gene expression occurs in a small range of dissociation constants (25 nM < Kd < 45 nM) indicating that transcriptional strength is highly sensitive to small changes in binding affinity. Conclusions: These results demonstrate the utility of UP elements and provide mechanistic insight into the functional relationship between binding affinity and transcription. Given the centrality of gene expression via transcription to biology, additional insight into transcriptional mechanisms can foster both fundamental and applied research. In particular, knowledge of the DNA sequence-specific effects on expression strength can aid in promoter engineering for different organisms and for metabolic engineering to balance pathway fluxes. PMID- 29118851 TI - Targeted metatranscriptomics of compost-derived consortia reveals a GH11 exerting an unusual exo-1,4-beta-xylanase activity. AB - Background: Using globally abundant crop residues as a carbon source for energy generation and renewable chemicals production stand out as a promising solution to reduce current dependency on fossil fuels. In nature, such as in compost habitats, microbial communities efficiently degrade the available plant biomass using a diverse set of synergistic enzymes. However, deconstruction of lignocellulose remains a challenge for industry due to recalcitrant nature of the substrate and the inefficiency of the enzyme systems available, making the economic production of lignocellulosic biofuels difficult. Metatranscriptomic studies of microbial communities can unveil the metabolic functions employed by lignocellulolytic consortia and identify novel biocatalysts that could improve industrial lignocellulose conversion. Results: In this study, a microbial community from compost was grown in minimal medium with sugarcane bagasse sugarcane bagasse as the sole carbon source. Solid-state nuclear magnetic resonance was used to monitor lignocellulose degradation; analysis of metatranscriptomic data led to the selection and functional characterization of several target genes, revealing the first glycoside hydrolase from Carbohydrate Active Enzyme family 11 with exo-1,4-beta-xylanase activity. The xylanase crystal structure was resolved at 1.76 A revealing the structural basis of exo-xylanase activity. Supplementation of a commercial cellulolytic enzyme cocktail with the xylanase showed improvement in Avicel hydrolysis in the presence of inhibitory xylooligomers. Conclusions: This study demonstrated that composting microbiomes continue to be an excellent source of biotechnologically important enzymes by unveiling the diversity of enzymes involved in in situ lignocellulose degradation. PMID- 29118852 TI - Prevalence of overweight and obesity in United Arab Emirates Expatriates: the UAE National Diabetes and Lifestyle Study. AB - Objective: To describe current prevalence of obesity and related non-communicable diseases (NCDs) in expatriates living in the United Arab Emirates (UAE). Methods: We used data from the cross-sectional UAE National Diabetes and Lifestyle Study (UAEDIAB), which surveyed adult expatriates living in the UAE for at least 4 years. We report crude prevalence of overweight and obesity, indicated by gender and ethnicity-specific body mass index (BMI), waist circumference (WC) and waist to-hip ratio (WHR) cut-offs, by lifestyle and biomedical characteristics, as well as age and sex-adjusted odds ratios. Results: Out of a total of 3064 recruited expatriates (response rate 68%), 2724 had completed all stages of the UAEDIAB study. Expatriates were; 81% men, mean age 38 years (range 18-80), 71% South East Asians, and 36% university graduates. In this sample, the prevalence of overweight and obesity, by BMI, were 43.0 and 32.3%, respectively. 52.4 and 56.5% of participants were at a substantially increased risk according to WC and WHR, respectively. The prevalence of diabetes, hypertension and hypercholesterolemia were 15.5, 31.8, and 51.7%, respectively, with the prevalence of each being higher in those with obesity. Conclusion: Prevalence of obesity and associated NCDs are extremely high in UAE expatriates. Without comprehensive prevention and management, levels of disease will continue to increase and productivity will fall. PMID- 29118853 TI - Identification of a novel HERV-K(HML10): comprehensive characterization and comparative analysis in non-human primates provide insights about HML10 proviruses structure and diffusion. AB - Background: About half of the human genome is constituted of transposable elements, including human endogenous retroviruses (HERV). HERV sequences represent the 8% of our genetic material, deriving from exogenous infections occurred millions of years ago in the germ line cells and being inherited by the offspring in a Mendelian fashion. HERV-K elements (classified as HML1-10) are among the most studied HERV groups, especially due to their possible correlation with human diseases. In particular, the HML10 group was reported to be upregulated in persistent HIV-1 infected cells as well as in tumor cells and samples, and proposed to have a role in the control of host genes expression. An individual HERV-K(HML10) member within the major histocompatibility complex C4 gene has even been studied for its possible contribution to type 1 diabetes susceptibility. Following a first characterization of the HML10 group at the genomic level, performed with the innovative software RetroTector, we have characterized in detail the 8 previously identified HML10 sequences present in the human genome, and an additional HML10 partial provirus in chromosome 1p22.2 that is reported here for the first time. Results: Using a combined approach based on RetroTector software and a traditional Genome Browser Blat search, we identified a novel HERV-K(HML10) sequence in addition to the eight previously reported in the human genome GRCh37/hg19 assembly. We fully characterized the nine HML10 sequences at the genomic level, including their classification in two types based on both structural and phylogenetic characteristics, a detailed analysis of each HML10 nucleotide sequence, the first description of the presence of an Env Rec domain in the type II HML10, the estimated time of integration of individual members and the comparative map of the HML10 proviruses in non-human primates. Conclusions: We performed an unambiguous and exhaustive analysis of the nine HML10 sequences present in GRCh37/hg19 assembly, useful to increase the knowledge of the group's contribution to the human genome and laying the foundation for a better understanding of the potential physiological effects and the tentative correlation of these sequences with human pathogenesis. PMID- 29118854 TI - Saudi lung cancer management guidelines 2017: Improving lung cancer care in Saudi region. PMID- 29118856 TI - Sleep disturbances and memory impairment among pregnant women consuming khat: An under-recognized problem. AB - Khat (Catha edulis) is a evergreen flowering shrub that is cultivated at high altitudes, especially in East Africa and the southwest of the Arabian Peninsula. The plant contains alkaloids, of which cathinone and cathine have structural similarity and pharmacological action similar to amphetamines. The leaves are, therefore, consumed in some regions as a psychoactive stimulant due to cultural beliefs and misperceptions on the health benefits of khat consumption. This resulted in a growing prevalence of khat consumption among pregnant women. The myriad of physiological changes associated with pregnancy impairs sleep and memory. Moreover, khat has also been shown to have adverse effects on memory and sleep. Therefore, its use during pregnancy may further aggravate those impairments. The purpose of this mini-review is to summarize the changes in sleep and memory during pregnancy and the evidence supporting a relationship between khat consumption and neurocognitive deficits and sleep dysfunctions. The misperceptions of beneficial effects of khat, the high prevalence of consumption among pregnant women, and the possibility of under-reporting of khat abuse do necessitate the development of alternative methodologies to identify cases of unreported khat abuse in pregnant women. It is proposed that screening for sleep problems and memory deficits may help identify under-reported cases of khat abuse in pregnant women. PMID- 29118855 TI - Saudi lung cancer management guidelines 2017. AB - BACKGROUND: Lung cancer management is getting more complex due to the rapid advances in all aspects of diagnostic and therapeutic options. Developing guidelines is critical to help practitioners provide standard of care. METHODS: The Saudi Lung Cancer Guidelines Committee (SLCGC) multidisciplinary members from different specialties and from various regions and healthcare sectors of the country reviewed and updated all lung cancer guidelines with appropriate labeling of level of evidence. Supporting documents to help healthcare professionals were developed. RESULTS: Detailed lung cancer management guidelines were finalized with appropriate resources for systemic therapy and short reviews highlighting important issues. Stage based disease management recommendation were included. A summary explanation for complex topics were included in addition to tables of approved systemic therapy. CONCLUSION: A multidisciplinary lung cancer guidelines was developed and will be disseminated across the country. PMID- 29118857 TI - Analysis of predictive parameters for the development of radiation-induced pneumonitis. AB - INTRODUCTION: Prevention and effective treatment of radiation-induced pneumonitis (RP) could facilitate greater use of radiation therapy (RT) for lung cancer. The purpose of this study was to determine clinical parameters useful for early prediction of RP. METHODS: Blood sampling, pulmonary function testing, chest computed tomography, and bronchoalveolar lavage (BAL) were performed in patients with pathologically confirmed lung cancer who had completed >=60 Gy of RT, at baseline, shortly after RT, and at 1 month posttreatment. RESULTS: By 3 months post-RT, 11 patients developed RP (RP group) and the remaining 11 patients did not (NRP group). RT significantly increased total cell counts and alveolar macrophages in BAL of the NRP group, whereas lymphocyte count was increased in both groups. Matrix metallopeptidase-9 (MMP-9) increased and vascular endothelial growth factor decreased significantly in the BAL fluid (BALF) of the RP group following RT. Serum surfactant protein D (SP-D) increased significantly in the NRP group. SP-D in BALF from the RP group increased significantly with a subsequent increase in serum SP-D. Pulmonary dilution decreased similarly in both groups of patients. CONCLUSIONS: Increased SP-D in BALF, rather than that in serum, could be useful biomarkers in predicting RP. The MMP-9 in BALF might play a role in the pathogenesis of RP. Pulmonary dilution test may not be predictive of the development of RP. PMID- 29118858 TI - Characteristics and predictors of mortality of patients with hematologic malignancies requiring invasive mechanical ventilation. AB - RATIONALE: Acute respiratory failure (ARF) may complicate the course of hematologic malignancies (HMs). Our objective was to study the characteristics, outcomes and predictors of mortality of patients with HMs who required intubation for ARF. METHODS: This retrospective cohort study evaluated all patients with HMs who were admitted to the Intensive Care Unit (ICU) of King Abdul-Aziz Medical City-Riyadh between 2008 and 2013 and required invasive mechanical ventilation. We noted their baseline characteristics, treatments and different outcomes. Multivariable logistic regression analysis was performed to evaluate predictors of hospital mortality. RESULTS: During the 6-year period, 190 patients with HMs were admitted to the ICU and 122 (64.2%) required intubation for ARF. These patients had mean age of 57.2 +/- 19.3 years and Acute Physiology and Chronic Health Evaluation II score of 28.0 +/- 7.8 and were predominantly males (63.4%). Lymphoma (44.3%) and acute leukemia (38.5%) were the most common hematologic malignancy. Noninvasive ventilation (NIV) was tried in 22 patients (18.0%) but failed. The code status was changed to "Do-Not-Resuscitate" for 39 patients (32.0%) during ICU stay. Hospital mortality was 70.5% and most deaths (81.4%) occurred in the ICU. The mortality of patients with "Do-Not-Resuscitate" status was 97.4%. On multivariable logistic regression analysis, male gender (odds ratio (OR), 6.74; 95% confidence interval (CI), 2.24-20.30), septic shock (OR, 6.61; 95% CI, 1.93-22.66) were independent mortality predictors. Remission status, non NIV failure and chemotherapy during ICU stay were not associated with mortality. CONCLUSIONS: Patients with HMs requiring intubation had high mortality (70.5%). Male gender and presence of septic shock were independent predictors of mortality. PMID- 29118859 TI - Pleuropulmonary manifestation in patients with rheumatoid arthritis in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Pleuropulmonary (PP) involvement in rheumatoid arthritis (RA) is associated with high morbidity and mortality. Nevertheless, limited data are available regarding lung complications in the Middle East, especially in Saudi Arabia. The objectives of the current study were to determine the prevalence of PP manifestations and to identify the associated risk factors. METHODS: This was a retrospective study involving 419 patients diagnosed at a tertiary center over a 12.5-year period. The frequency of pulmonary manifestations was recorded based on combined results from chest X-rays, pulmonary function tests, and high-resolution computed tomography scan of the chest. RESULTS: The overall frequency of lung involvement was 25.8%. Pneumonia, bronchiectasis, and interstitial lung disease were the most common abnormalities (36%, 35%, and 23%, respectively). The presence of comorbid illness (odds ratio [OR]: 3.19; 95% confidence interval [CI]: 2.02-5.1), male gender (OR: 2.4; 95% CI: 1.3-4.24), and the presence of extra-articular manifestations of RA (ExRA) (OR: 2.35; 95% CI: 0.4-4.01) were predictive of lung involvement. CONCLUSIONS: Pneumonia, bronchiectasis, and interstitial lung disease were the most common abnormalities seen in RA patients. The presence of comorbidity, male gender, and ExRA was significantly associated with lung involvement. PMID- 29118860 TI - Coronary flow reserve is impaired in patients with obstructive sleep apnea. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is common in adult populations. Accumulating data indicate that it is independently associated with a variety of cardiovascular diseases and has prognostic importance in affected cases. In this study, we aimed to evaluate coronary flow reserve (CFR) in patients with OSA and controls. METHODS: Sixty-one patients undergoing an overnight polysomnography were enrolled in this study. Patients with an apnea-hypopnea index (AHI) >5 were accepted as OSA group (n = 45) and those with an AHI <5 were taken as controls (n = 16). Using Doppler echocardiography at baseline and following dipyridamole infusion, coronary peak flow velocities were obtained. CFR was calculated as the ratio of peak diastolic flow to baseline diastolic flow. A CFR value <2 was accepted as impaired coronary microvascular function. RESULTS: The mean age was 50.8 +/- 10.8 years, of which 16 (26.2%) were female. Both groups had similar features with regard to demographic and clinical variables. The mean value of CFR was significantly lower in patients with OSA compared to those controls (2.24 +/- 0.46 vs. 2.74 +/- 0.62, respectively, P = 0.001). An abnormal CFR value was observed in 12 (26.7%) patients with OSA and in 1 (6.3%) participant in control group. CONCLUSIONS: The findings of this study indicate that CFR, an indicator of coronary microvascular function, is significantly impaired in patients with OSA. Coronary microvascular function, an early sign of atherosclerosis, can be evaluated noninvasively in these patients might be used as a predictor of cardiovascular risk. PMID- 29118861 TI - Lung granuloma: A clinicopathologic study of 158 cases. AB - BACKGROUND AND AIMS: A granuloma is a common pathological diagnosis in lung biopsies and is caused by a variety of etiologies. The aim of this study was to assess the etiology and frequency of different cases of lung granulomas. METHODS: The medical records of all patients who had lung granulomas between 2005 and 2013 were retrospectively reviewed. Based on the histological features of the granulomas, along with the clinical, laboratory, and radiological findings, an attempt was made to identify the etiology of the granuloma in each case. RESULTS: A total of 158 patients with lung biopsy specimens showing lung granulomas were identified. The histological findings revealed necrotizing granulomas in 92 (58%) of the cases and nonnecrotizing granulomas in 66 (42%). A definite etiology was determined in 133 cases (84%), whereas in 26 cases (16%), the etiology could not be identified despite an extensive workup. Infection was the most frequent cause of granuloma, accounting for 105 cases (66%). Mycobacterial tuberculosis (TB) was the type of infection that caused the largest number of granulomas, and was responsible for 100 cases (63%). Among the noninfectious etiologies of lung granuloma, sarcoidosis was the most common cause, accounting for 20 (13%) of the cases. CONCLUSIONS: Mycobacterial TB and sarcoidosis are the most common causes of lung granulomas in our region. In a substantial proportion of cases, the cause may not be identified despite an extensive workup. PMID- 29118862 TI - Thromboprophylaxis and mortality among patients who developed venous thromboembolism in seven major hospitals in Saudi Arabia. AB - INTRODUCTION: Venous thromboembolism (VTE) during hospitalization is a serious and potentially fatal condition. Despite its effectiveness, evidence-based thromboprophylaxis is still underutilized in many countries including Saudi Arabia. OBJECTIVE OF THE STUDY: Our objectives were to determine how often hospital-acquired VTE patients received appropriate thromboprophylaxis, VTE associated mortality, and the percentage of patients given anticoagulant therapy and adherence to it after discharged. METHODS: This study was conducted in seven major hospitals in Saudi Arabia. From July 1, 2009, till June 30, 2010, all recorded deep vein thrombosis (DVT) and pulmonary embolism (PE) cases were noted. Only patients with confirmed VTE diagnosis were included in the analysis. RESULTS: A total of 1241 confirmed VTE cases occurred during the 12-month period. Most (58.3%) of them were DVT only, 21.7% were PE, and 20% were both DVT and PE. 21.4% and 78.6% of confirmed VTE occurred in surgical and medical patients, respectively. Only 40.9% of VTE cases received appropriate prophylaxis (63.2% for surgical patients and 34.8% for medical patients; P < 0.001). The mortality rate was 14.3% which represented 1.6% of total hospital deaths. Mortality was 13.5% for surgical patients and 14.5% for medical patients (P > 0.05). Appropriate thromboprophylaxis was associated with 4.11% absolute risk reduction in mortality (95% confidence interval: 0.24%-7.97%). Most (89.4%) of the survived patients received anticoagulation therapy at discharge and 71.7% of them were adherent to it on follow-up. CONCLUSION: Thromboprophylaxis was underutilized in major Saudi hospitals denoting a gap between guideline and practice. This gap was more marked in medical than surgical patients. Hospital-acquired VTE was associated with significant mortality. Efforts to improve thromboprophylaxis utilization are warranted. PMID- 29118863 TI - A novel cystic fibrosis gene mutation c.2490insT in a Palestinian patient: A case report and review of the literature. AB - We report the case of a 19-year-old male patient of Palestinian descent, who presented with a 1-year history of recurrent Pseudomonas aeruginosa respiratory infections, weight loss, chronic diarrhea, and a normal chloride sweat test. A panel for common cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations test was also negative. Cystic fibrosis (CF) was still clinically suspected thus, full CFTR gene sequencing was performed, which revealed a homozygous unreported mutation c.2490insT (GenBank accession number: BankIt2019289 seq1 MF167456). Both parents were also found to be heterozygous for this mutation. This case highlights the importance of clinical evaluation and the need for extensive genetic investigation when dealing with a genetic disease with wide variability in a clinical presentation such as CF. PMID- 29118864 TI - Rituximab treatment in patients with systemic sclerosis and interstitial lung disease. AB - There is increasing interest in rituximab (RTX) as an alternative to cyclophosphamide for the treatment of interstitial lung diseases (ILDs) associated with systemic sclerosis (SSc). However, no report has addressed its efficacy in Saudi patients with SSc-ILD. To assess the efficacy of RTX treatment in Saudi patients with SSc-ILD, hospital records were reviewed between 2013 and 2016. Four female patients received at least 4 cycles of RTX (I cycle, consisting of two infusions of 1000 mg 2 weeks apart). Pulmonary function tests (PFTs) and chest high-resolution computed tomography (HRCT) were performed before and after treatment to assess the response. HRCT revealed improvement in one patient, stable disease in two patients, and worsening in one patient. Moreover, RTX prevented the further decline of forced vital capacity significantly in PFT. These results provide further evidence that RTX is an effective treatment for SSc ILD. PMID- 29118865 TI - Protective effects of tea polyphenols and beta-carotene against gamma-radiation induced mutation and oxidative stress in Drosophila melanogaster. AB - Background: The commonly consumed antioxidants beta-carotene and tea polyphenols were used to assess their protective effects against gamma-radiation induced sex linked recessive lethal (SLRL) mutation and oxidative stress in Drosophila melanogaster. Third instar larvae and adult males of wild-type Oregon-K (ORK) were fed on test agents for 24 and 72 h respectively before exposure to 10Gy gamma-irradiation. The treated/control flies were used to assess the induction of SLRLs. We also evaluated antioxidant properties of these phytochemicals in the third instar larvae. Results: Different stages of spermatogenesis in adult males showed a decrease in gamma-radiation induced SLRL frequencies upon co-treatment with test agents. A similar trend was observed in larvae. Furthermore, a significant increase in antioxidant enzymatic activities with a decrease in malondialdehyde content was observed. Conclusion: beta-carotene and tea polyphenols have exerted antigenotoxic and antioxidant effects in Drosophila. This study demonstrated the suitability of Drosophila as an alternative to mammalian testing for evaluating the antigenotoxic and antioxidant activity of natural products. PMID- 29118866 TI - Estimation of the effects of heavy Asian dust on respiratory function by definition type. AB - Background: The adverse effects of Asian dust (AD) on health have been demonstrated in earlier studies, but there is no standardized definition for heavy-AD. This study aimed to examine which definition of heavy-AD has the most adverse effect on respiratory function. Methods: One-hundred-and-thirty-seven adults with asthma, and 384 school children self-measured their morning peak expiratory flow (PEF). The four definitions of heavy-AD are: (1) the definition provided by the Japan Meteorological Agency (JMA), (2) daily median AD particle level >= 0.07 km-1, obtained through light detection and ranging (LIDAR) (3) hourly AD particle level >= 0.1 km-1, and (4) hourly level >= 0.07 km-1. Linear mixed models were used to estimate the effects of heavy-AD, by definition type, on daily PEF values. Results: In adults with asthma, as per the JMA's definition, significantly reduced PEF were observed on heavy-AD days (lag 0), lag 0-1, and lag 0-3. In school children, after a heavy-AD event, as defined by the JMA, PEF significantly decreased on lag 0-1, lag 0-2, and lag 0-3. However, as per the other definitions, there was no significant decrease in the PEF in the adults and children. Conclusion: The associations between heavy-AD and respiratory function differed between these definitions. PMID- 29118868 TI - Efficacy of Video Capsule Endoscopy in the Management of Suspected Small Bowel Bleeding in Patients With Continuous Flow Left Ventricular Assist Devices. AB - Background: Continuous flow left ventricular assist device (CF-LVAD) patients have a high prevalence of gastrointestinal bleeding from the small bowel. Video capsule endoscopy (VCE) is often used for diagnosis in these patients, but efficacy has yet to be determined. In this study, we evaluated the efficacy of VCE in the management of CF-LVAD patients with suspected small bowel bleeding by comparing to a non-VCE CF-LVAD control group. Methods: We retrospectively reviewed the charts of all patients with CF-LVADs implanted at Stanford Hospital from January 2010 to October 2015. Patients were included in the study if there was a clinical suspicion of small bowel bleeding and either a negative upper endoscopy or colonoscopy. Results: A total of 26 patients met inclusion criteria for a total of 15 encounters where VCE was done, and 25 where VCE was not done. There were no statistical differences when comparing these groups in terms of medical therapy use (thalidomide or octreotide), enteroscopy use (double-balloon or push), intervention on lesions, or any 30-day outcomes. There was no advantage to VCE with regard to the composite endpoint time to re-bleed or death related to re-bleeding (median 114 vs. 161 days, P = 0.15) after removing patients who did not get a VCE due to death or critical illness. Conclusions: We did not find VCE changed management or outcomes in CF-LVAD patients with suspected small bowel bleeding at our institution when compared to a non-VCE control group. Our experience is small and single center, and larger, multi-center studies could further elucidate the utility of VCE in this patient population. PMID- 29118867 TI - Non-Alcoholic Fatty Liver Disease in Africa and Middle East: An Attempt to Predict the Present and Future Implications on the Healthcare System. AB - Non-alcoholic fatty liver disease (NAFLD) encompasses a group of hepatic diseases that range in severity. NAFLD is increasingly recognized as an epidemic among different populations, including those in Africa and the Middle East. The objective of this narrative review is to document the prevalence of and risk factors for NAFLD in Africa and the Middle East and the potential implications on the healthcare systems. An in-depth search on Google Scholar, Medline and PubMed was conducted using the terms "non-alcoholic fatty liver disease" and "non alcoholic steatohepatitis", in addition to "prevalence and risk factors for NAFLD", with special emphasis on Africa and the Middle East countries. There were three types of epidemiological studies that included prevalence, risk factors and management/complications of NAFLD. There was noticeable variation in the prevalence of NAFLD among different countries, based on the variation in the prevalence of risk factors (type 2 diabetes, obesity, metabolic syndrome and dyslipidemia) and the diagnostic tool used in the study. However, the highest prevalence rate was reported in some Middle East countries. In Africa, there were few studies about NAFLD and most reported variable prevalence rates. There is an increasing prevalence of NAFLD as a result of the increasing risk factors, particularly in the Middle East, while in Africa, the situation is still unclear. Health providers in these regions are faced with many challenges that need urgent plans. PMID- 29118869 TI - Proton Pump Inhibitor Use Is Associated With an Increased Frequency of Hospitalization in Patients With Cystic Fibrosis. AB - Background: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications in clinical practice. PPI use has been associated with the development of community-acquired pneumonia. With a reported prevalence of gastroesophageal reflux disease (GERD) and PPI use that is higher than the general population, patients with cystic fibrosis (CF) are particularly vulnerable to PPI adverse effects. We sought to explore whether PPI use was associated with a higher number of hospitalizations for CF pulmonary exacerbation. Methods: We conducted a longitudinal retrospective review in an academic outpatient setting. Patients > 18 years of age with a diagnosis of CF and at least 1 year of follow-up were eligible for inclusion. Baseline characteristics, PPI use, and details of hospitalization through 1 year of follow up were collected. Results: One hundred fourteen patients met inclusion criteria. Fifty-nine patients (51.7%) were hospitalized at least once in the follow-up year, mean number of hospitalizations was 2.17 (+/- 1.9). At least 6 months of PPI use was observed in 59 patients (51.7%). In univariate analysis, PPI use was associated with a significantly higher mean number of hospitalizations (0.9 vs. 1.4, P = 0.009). In a multi-variable regression model, PPI use remained significantly associated with a higher number of hospitalizations (P = 0.03), while controlling for risk factors traditionally associated with increased pulmonary exacerbations. Conclusion: PPI use is highly prevalent in CF patients. Exposure to PPI therapy is independently associated with a higher number of hospitalizations for pulmonary exacerbation in CF patients. PMID- 29118870 TI - Risk Factors for Gastroesophageal Reflux Disease in Saudi Arabia. AB - Background: Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal tract diseases worldwide. GERD has an effect on the patients' quality of life as well as the health care system that can be prevented by identifying its risk factors among the population. Hence, we applied this study to assess the GERD's risk factors in Saudi Arabia. Methods: A cross-sectional study was designed to assess the GERD's risk factors among the community of Saudi Arabia. The sample was collected randomly during the period from November to December 2016. Through a self-administered validated GERD questionnaire (GerdQ), GERD was diagnosed. Then, the GERD's risk factors were assessed among all participants. The data were analyzed using Statistical Package for Social Sciences version 21.0; the Student's t-test was used to assess the association of GERD and risk factors. Results: A total of 2,043 subjects participated in the study. The characteristics and behaviors of participants statistically significant with GERD were positive family history (39.3%), obese (body mass index > 30 kg/m2) (39.4%), not performing weekly regular physical activities >= 30 min (31.1%) and smoking (39.3%). GERD was commonly noticed in participants on analgesics (38.4%), not taking fibers (37.4%), drinking tea (33.4%), eating greasy (31.2%) and fast food (32.7%), and these were statistically significant with GERD (P <= 0.05). Conclusion: The characteristics and behaviors associated with GERD in Saudi population are family history of GERD, obesity, sedentary lifestyle and smoking. Other common risk factors correlated with GERD are analgesics intake, no fibers intake, drinking tea, greasy and fast food intake. PMID- 29118871 TI - Gastroesophageal Reflux Disease Associated With Anxiety: Efficacy and Safety of Fixed Dose Combination of Amitriptyline and Pantoprazole. AB - Background: The aim of the study was to evaluate the efficacy and tolerability of fixed dose combination of amitriptyline and pantoprazole in gastroesophageal reflux disease (GERD) associated with anxiety. Methods: A non-randomized, open labeled, non-comparative, multi-center study was conducted in a total of 99 patients (77 men and 22 women, mean age 44.16 +/- 11.53 years). Each patient was administered a fixed dose combination of amitriptyline 10 mg and pantoprazole 40 mg once a day, for 4 weeks. GERD questionnaire, hospital anxiety and depression score (HADS) and SF-8 questionnaire (short-form health survey) were performed at baseline and at the end of study as assessment tools. Results: At the end of study, data were extractable only in 96 patients because three patients were dropped out due to loss of follow-up at week 4. GERD symptoms and anxiety score reduced significantly (P < 0.0001) at week 4 compared to baseline. SF-8 score also improved significantly (P < 0.0001) at week 4. There were no adverse events reported. Conclusion: Amitriptyline and pantoprazole combination was found to be effective and safe for management in GERD patients with coexisting anxiety. PMID- 29118872 TI - Demographic, Endoscopic and Histopathologic Features Among Stool H. pylori Positive and Stool H. pylori Negative Patients With Dyspepsia. AB - Background: Dyspepsia is a common presentation for many patients in gastroenterology clinics. Helicobacter pylori (H. pylori) infection is endemic in many countries around the world and its relation to dyspepsia has long been questioned. This study aimed at comparing demographic, endoscopic and histologic features among dyspeptic patients with and without stool H. pylori antigen positivity. Methods: One hundred and fifty-one consecutive patients with dyspepsia were divided into group I (n = 80) and group II (n = 71) according to positive or negative H. pylori stool antigen testing, respectively. All patients were subjected to history taking, clinical examination, laboratory investigations, abdominal ultrasonography, H. pylori stool antigen detection, and upper gastrointestinal tract endoscopy with four gastric mucosal biopsies for histopathologic examination. Results: Stool H. pylori antigen negative group included more smokers and consumed much more fast and spicy food than the positive group. The most common endoscopic findings of both groups were gastritis, reflux esophagitis, gastric erosions, peptic ulcer, mucosal nodularity and hiatus hernia and were encountered in 100%, 74.2%, 23.2%, 15.2%, 13.9%, and 13.2% respectively with non-significant difference between both groups except for gastric erosions that were significantly higher in stool H. pylori negative group (P < 0.001). Histologic evidence of gastritis was reported in 100% and 92.9% of patients in group I and group II, respectively. Chronic active gastritis with neutrophil infiltration was significantly higher in group I (P < 0.001). H. pylori bacilli were histologically detected in 83.7% and 47.9% of patients in group I and group II, respectively (P < 0.001). Conclusion: All patients with dyspepsia in this study had endoscopic evidence of gastritis. Most of these patients had histologic evidence of gastric mucosal inflammation. Consequently, it may be advisable to perform endoscopy on these patients and obtain gastric mucosal biopsies. PMID- 29118873 TI - Concurrent Primary Gastric and Pulmonary Diffuse Large B-Cell Lymphoma: A Case Report and Literature Review. AB - The primary pulmonary diffuse large B-cell lymphoma (PPDLBCL), a kind of non Hodgkin's lymphomas, itself is a rare entity. Its association with primary B-cell gastric lymphoma has not been established yet. Herein we present a case of PPDLBCL along with a literature review. This case is special and extremely rare as it has concurrent primary gastric B-cell lymphoma. PMID- 29118874 TI - Pharmacobezoar: An Unusual Cause of Large Bowel Obstruction. AB - Large bowel obstruction (LBO) is an abdominal emergency with high morbidity and mortality rates if left untreated. LBO is four to five times less frequent than small bowel obstruction (SBO) and the causes of LBO and SBO differ substantially. Colonic malignancy remains the most common cause of LBO (> 60%). Additional causes of LBO include entities such as diverticulitis, colonic volvulus, and adhesion. Herein we present a case of acute LBO caused by pharmacobezoar. PMID- 29118875 TI - A Fatal Case of Intra-Abdominal Hemorrhage Following Diagnostic Blind Percutaneous Liver Biopsy in a Patient With Peliosis Hepatis. AB - Peliosis hepatis (PH) is a rare vascular condition of the liver characterized by the presence of cystic blood filled cavities distributed randomly throughout the liver parenchyma. We describe a case of a 42-year-old previously healthy male patient, airlifted to us in a state of hemorrhagic shock after undergoing percutaneous diagnostic liver biopsy for lesions seen on CT scan. Repeat CT scan with IV contrast on presentation in our hospital showed intraperitoneal bleeding. Hepatic angiography failed to identify any specific bleeding source. A diagnostic laparoscopy was performed and approximate 9 L of hemoperitoneum was evacuated. The postoperative course was complicated with rapid hemodynamic deterioration, associated with acute hepatic failure progressively leading to multiorgan failure and death in spite of aggressive intensive care support. We suggest that PH should be considered as differential diagnosis of hypervascular hepatic lesions. It potentially can cause fatal acute non-traumatic liver hemorrhage. PMID- 29118876 TI - Large Dermoid Cyst Presenting as Recurrent Pancreatitis. AB - Pancreatic dermoid cysts are rare and benign congenital abnormalities of germ cell origin. They occur equally in males and females without age predilection. Though radiographic imaging aids in the diagnosis, most times they are inconclusive and require fine-needle aspiration cytology for confirmation. We report the first case of a dermoid cyst presenting as recurrent pancreatitis in a 49-year-old male. Computed tomography scan, followed by magnetic resonance imaging, showed a complex cystic mass lesion adjacent to the pancreatic tail. Endoscopic ultrasound noted a large heterogeneous cystic lesion with hypoechoic wall layers in the tail of the pancreas without invading surrounding structures. Fine-needle aspiration cytology revealed numerous mature squamous cells consistent with a pancreatic dermoid cyst. We discuss the history, clinical presentation, diagnosis, and treatment of pancreatic dermoid cysts. PMID- 29118877 TI - Eosinophilic Colitis Masquerading as Malignancy of Colon. AB - Eosinophilic colitis (EC) is a rare part of spectrum of diseases called eosinophilic gastrointestinal disease (EGID). It was found to have bimodal distribution involving neonates and adults in age groups of 30 - 50 with male preponderance. We present this case of a 78-year-old woman who came to the hospital with abdominal pain, hematochezia and unintentional weight loss, and was found to have EC. This case was very unique given the age at presentation and the radiological findings mimicking malignancy. We reviewed the possible etiologies, clinical features, pathology, and treatment of EC along with the review of the literature. PMID- 29118878 TI - Pathophysiology and Current Evidence for Detection of Dyssynchrony. PMID- 29118879 TI - Prevalence and Risk Factors for Acute Coronary Syndrome Among Sudanese Individuals With Diabetes: A Population-Based Study. AB - Background: Acute coronary syndrome (ACS) is common with diabetes. The aim of this study was to establish prevalence and risk factors for ACS among Sudanese individuals with diabetes mellitus (DM). Methods: A descriptive cross-sectional study was conducted in Khartoum State and Atabra (North of Sudan). The data collection was performed through pretested questionnaire, in addition to measurement of lipid profile and HbA1c. Results: Among the 496 respondents, 234 (48.4%) were males and only 15 of them had ACS, while 255 (51.6%) were females and 12 had ACS. Therefore, the prevalence of ACS was 5.44% (95% confidence interval (CI): 3.45-7.44%). The unadjusted risk factors for ACS were age (P = 0.0008864), duration of DM (P = 0.01105) and presence of hypertension (P = 0.0006021). The presence of albuminuria, gender, and body mass index (BMI) was not associated with ACS. In addition, parameters like HbA1c, high-density lipoprotein (HDL), triglyceride and low-density cholesterol (LDL) were also not associated with ACS. Logistic regression analysis showed that duration of diabetes (odds ratio (OR) for below 5 years' history of DM = 0.175 (95% CI for OR: 0.180 - 0.835), P = 0.04051) and hypertension (OR = 2.462 (95% CI for OR: 1.007 - 6.500), P = 0.039) were absolute risk factors for ACS. Conclusion: The prevalence of ACS is estimated to be 5.44%. ACS in Sudanese individuals with DM was associated with hypertension, increase in age and increase in duration of DM. PMID- 29118880 TI - Occurrence and Impact of Time Delay to Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction. AB - Background: The aim of the study was to evaluate the occurrence, duration and impact of time delays to primary percutaneous coronary intervention (pPCI) in ST segment elevation myocardial infarction (STEMI). Methods: A total of 357 consecutive STEMI patients enrolled in the prospective Special Program University Medicine ACS (SPUM-ACS) cohort were included. In order to identify the causes behind a possible treatment delay, we constructed four different time points which included: 1) symptom onset to hospital arrival, 2) hospital arrival to arrival in the catheterization laboratory, 3) hospital arrival to first balloon inflation, and 4) time from arrival in the catheterization laboratory to first balloon inflation in addition to total ischemic time. Patients were stratified according to a delay > 3 h, > 30 min, > 90 min and > 1 h, respectively and major adverse events at 0, 30 and 365 days were analyzed. Results: Resuscitated STEMI patients (23 patients) and STEMI patients presenting at weekends (101 patients) and to lesser extent at night hours (100 patients) experienced more time delays than stable patients and those presenting at office hours. Median door-to-balloon time averaged 93 min in resuscitated, but 65 min in stable patients. Median door to-balloon time at weekends and public holidays was 89 min, but 68 min at office hours. Median time from hospital arrival to cathlab arrival at weekends and public holidays was 30 min, but 15 min during office hours. Corresponding times for resuscitated patients was 45 and 15 min in stable patients. Of note, resuscitated patients were late presenters as regards time from symptoms onset to hospital arrival with a median time of 180 min compared to 155 min in stable patients. Median total ischemic time was 225 min for all patients, 223 min at day hours, 239 at night hours, 244 min at weekends, 233 min at office days, 220 min in stable patients and 273 min in resuscitated patients. Patients with STEMI who arrived > 3 h after symptom onset had a higher rate of myocardial infarction (MI) at 1 year (1.6% vs. 9% in < 3 h; P = 0.008). Furthermore, STEMI patients who had a delay of > 1 h from cathlab arrival to first balloon inflation had a higher rate of in hospital reinfarction at 0 day (0.6% vs. 0% in < 1 h; P = 0.007), MI at 30 days (0.8% vs. 0% in < 1 h; P = 0.001) and MI at 1 year (1.4% vs. 1.1% in < 1 h; P = 0.012). Similarly, in these patients, cardiac deaths at 0 day (0.8% vs. 0.6% in < 1 h; P = 0.035) and at 30 days (0.8% vs. 0.6% in < 1 h; P = 0.035) were higher as were major adverse cardiovascular events (MACCE) at 0 day (1.4% vs. 0.8% in < 1 h; P = 0.004). Conclusion: Resuscitated STEMI patients and those presenting at weekends and to lesser extent at night hours experienced more time delays and longer ischemic time than stable patients and those presenting at office hours. In STEMI patients, any delay in treatment increased their risk of MACCE. Efforts should focus on improving patient's awareness along with minimizing in-hospital transfer to the catheterization laboratory especially at weekends and in resuscitated patients. PMID- 29118881 TI - In-Hospital Clinical Outcomes and Procedural Complications of Percutaneous Coronary Intervention in Elderly Patients. AB - Background: As population growth leads to an increase in the number of the elderly with coronary artery disease, an evaluation of the clinical outcomes of percutaneous coronary intervention (PCI) in the elderly patients seems to be essential. Methods: A prospective, observational cohort study was performed on 468 patients in two groups of elderly and non-elderly patients (mean age: 60.01 +/- 10.84 years; >= 70 years, 20.1%; men, 62%) who underwent PCI, to evaluate the procedural success and in-hospital major and minor adverse cardiovascular events in the elderly patients. Results: The procedural success rate was significantly lower (95.7% vs. 99.5%, P = 0.017) and the rates of in-hospital complications were significantly higher (10.6% vs. 0.8%, P < 0.0001) in elderly (+70) than in non-elderly patients. On the basis of a multivariate analysis, being elderly was not an independent predictor of procedural failure, but increased the chance of in-hospital complications to 8% higher (odds ratio: 0.08; 95% confidence interval: 0.01 - 0.39; P = 0.002). Conclusion: Regardless of the difference in the procedural success and in-hospital complication rates between our two study groups, aging is not an important predictor of them. Furthermore, PCI should not be refused in elderly patients if indicated. PMID- 29118882 TI - Association of Heart Rate Recovery With Microalbuminuria in Non-Obstructive Coronary Artery Disease. AB - Background: Non-obstructive coronary artery disease (CAD) is associated with significantly increased risk for myocardial infarction. Heart rate recovery (HRR), a measure of autonomic function, is a strong predictor of all-cause mortality. Microalbuminuria, a marker of early arterial disease, is an independent risk factor for cardiovascular disease and mortality. We aimed to investigate HRR and determine its relationship with microalbuminuria in patients with non-obstructive CAD. Methods: We prospectively studied 565 patients who underwent elective coronary angiography. All participants underwent urinary analysis and then an exercise test. Microalbuminuria was defined as an urinary albumin-to-creatinine ratio (UACR) of 30 - 299 mg/g. The HRR was abnormal if <= 12 beats/min during the first minute after exercise. First, all patients were divided into two groups, patients with microalbuminuria (n = 152) and patients without microalbuminuria (n = 413). Then, all patients were re-divided into two groups, those with lower HRR (<= 12 beats/min, n = 126) and those with higher HRR (> 12 beats/min, n = 439). Results: Patients with microalbuminuria had lower HRR and patients with lower HRR had higher UACR. While UACR was negatively correlated with HRR in patients with microalbuminuria (r = -0.424; P < 0.001) and in patients with lower HRR (r = -0.192; P= 0.042), there was no correlation of UACR with HRR in neither patients with normoalbuminuria nor patients with higher HRR, respectively. In the all study population, there was a significant inverse association between UACR and HRR (r = -0.445, P < 0.001), and UACR independently predicted the presence of lower HRR (P < 0.001). Conclusions: Our findings showed that there was a significant inverse association between UACR and HRR in patients especially with microalbuminuria, and that albuminuria might predict cardiac autonomic imbalance evaluated by HRR in patients with non-obstructive CAD. PMID- 29118883 TI - Assessment of Right Ventricular Function by Newer Imaging in Echocardiography in Idiopathic Pulmonary Arterial Hypertension. AB - Background: The aims of the study were to assess the right ventricular (RV) functions in patients with idiopathic pulmonary arterial hypertension (IPAH) with RV longitudinal strain (RVLS) in addition to conventional parameters, as well as its correlation with severity and prognosis in IPAH. Methods: Twenty-two IPAH patients were followed up for 1 year. ANOVA and Gabriel's pairwise comparison tests were used for comparison of RVLS with respect to WHO functional class status. Patients were divided into non-survival (group 1) and survival (group 2), and clinical and echocardiographic parameters of RV function were compared at baseline and at 6 months with t-test & Mann-Whitney test. Results: At baseline, with respect to WHO functional class, mean RVLS showed no significant interclass difference (P = 0.0781). Among the other conventional echocardiographic parameters, RV E/A showed significant difference at baseline (P = 0.004), but not at 6 months (P = 0.366); whereas tricuspid annular plane systolic excursion (TAPSE) which had no significant difference initially (P = 0.174) revealed a significance level at 6 months (P = 0.029) between the two groups. Fractional area change (FAC), RV index of myocardial performance (RIMP), and right atrial (RA) area displayed significant difference neither at baseline nor at 6 months. RVLS exhibited significant difference neither at baseline (P = 0.912) nor at 6 months (P = 0.181). None of the echocardiographic parameters including RVLS showed a significant average change with change in severity of PAH both at 6 and 12 months. Conclusion: RVLS was not proved to be a useful parameter for early detection of RV dysfunction and prognosis in patients with IPAH in comparison with the conventional echocardiographic parameters. PMID- 29118884 TI - Breast Arterial Calcifications on Mammography Do Not Predict Myocardial Ischemia on Myocardial Perfusion Single-Photon Emission Computed Tomography. AB - Background: The aim of this study was to determine if breast arterial calcification (BAC) on mammography predicts myocardial ischemia (MI) on stress myocardial perfusion single-photon emission computed tomography (MPS). BAC is a type of medial artery calcification that can be seen incidentally on mammography, but the relationship between coronary artery calcification and MI on MPS is yet unknown. Methods: A total of 435 consecutive women underwent mammography and stress MPS within 1 year of each other. BAC was quantitatively evaluated (0 - 13). Patients with known coronary artery diseases (CADs) such as coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), MI, positive coronary angiogram or positive MPS were excluded from the study. Risk factors for CAD were obtained from a chart review. Results: The mean age was 58 +/- 8 years. BAC was found in 258 (59%) of the study population. BAC-positive patients were significantly older than BAC-negative patients (P < 0.0001), there were strong associations between BAC and hypertension (P = 0.0309), chronic kidney disease (CKD) (P = 0.0001), and diabetes (P = 0.0309), but there were significant associations between BACV and hyperlipidemia, family history of CAD, and smoking (P = 0.6856, P = 0.9642, and P = 0.087, respectively). The mean score of BAC was 5 +/- 5 in patients with normal MPS and was 6 +/- 6 in patients with abnormal MPS. There were no associations between total BAC and MPS results (P = 0.2095), and between BAC categories and MPS result (P = 0.3069). Conclusions: Based on our study, the presence and severity of BAC on screening or diagnostic mammography do not predict MI on stress MPS, and further cardiac workup based on the presence of BAC is not warranted. BAC is very common in mammography up to 59% and associated with age, diabetes, CKD, and hypertension. In contrast, the prevalence of MI is only 13% in women with BAC and associated with age, diabetes, CKD, hyperlipidemia, and impaired left ventricular function. PMID- 29118885 TI - Mitral Annular Dynamics and Left Ventricular Diastole. AB - Background: Though diastolic interrogation of the mitral annulus (MA) using tissue Doppler imaging (TDI) has been quite useful in assessing left ventricular (LV) diastolic function, the relative contribution of the previous cycle MA systolic displacement or velocity components to subsequent LV diastole has not been previously investigated. We therefore sought to determine the association between MA systolic dynamics and LV diastolic function parameters. Methods: For this retrospective study, only complete echocardiograms having good endocardial border resolution of both left atrial (LA) and LV chambers with M-mode (MAPSE) and tissue Doppler of the lateral MA (MA TDI S') as well as complete Doppler data to perform assessment of LV diastole were included in our analysis. Results: Data from 100 patients (mean age 54 +/- 14) showed that both MA systolic displacement and velocity correlate with LV ejection fraction (P < 0.05). Only MA displacement was associated with age and LV mass. Most importantly no correlation was found between MAPSE and LV diastole. However, in sharp contrast MA TDI S' correlated with MA relaxation velocities during both early and late LV diastole. Conclusion: Even though MAPSE and MA TDI S' are surrogate measures of LV ejection fraction, only MA TDI S' correlates with diastolic MA velocities as no correlation was identified between MAPSE and measures of LV diastole. Additional studies are now warranted to explore whether a reduced MA TDI S' may affect the symptomatic profile or the overall prognosis of patients with LV diastolic dysfunction. PMID- 29118886 TI - Polymorphic Ventricular Tachycardia Secondary to Subarachnoid Haemorrhage: A Rare Occurrence in the Setting of Normal QTc. AB - Subarachnoid hemorrhage (SAH) is a neurologic emergency associated with high mortality rate. Polymorphic ventricular tachycardia (VT) is a rare arrhythmia. It can occur in any setting of a long QT interval and bradycardia. This may result from a cardiomyopathy (both ischemic and non-ischemic), acute coronary ischemia, congenital long QT syndrome, electrolyte disturbances and cerebrovascular diseases. We report a rare case of polymorphic VT of unclear etiology with a normal corrected QT, likely secondary to SAH. Reports associating ventricular arrhythmias and SAH have been described, yet the mechanism of this association remains unclear. Previous observations of VT seen in patients with SAH suggest a relationship with QT prolongation. The QT interval, however, remained normal in our patient, suggesting an alternative and unknown mechanism for the polymorphic VT. PMID- 29118887 TI - A Case of Early Prosthetic Valve Endocarditis Caused by Staphylococcus warneri in a Patient Presenting With Congestive Heart Failure. AB - Staphylococcus warneri, a coagulase negative staphylococcus, has been isolated in prosthetic device-related infections and has been reported as a rare cause of endocarditis. We report a case of prosthetic aortic valve S. warneri endocarditis, in which the patient lacked typical infectious signs and symptoms, instead presenting with congestive heart failure due to perforation of the valve. Providers should consider endocarditis with a low virulence pathogen such as S. warneri when a patient with a prosthetic valve presents with heart failure, even in the absence of fever, leukocytosis and other infectious symptoms. PMID- 29118888 TI - A Rare Cause of Dyspnea: Undifferentiated Pleomorphic Sarcoma in the Left Atrium. AB - Primary cardiac tumors are a rare entity. The presence of a mass in the left atrium suggests myxoma as a first differential diagnosis. Here we present a rare case of a woman with exertional dyspnea with a large tumor in the left atrium. The patient was extensively studied with echocardiography, cardiac MRI, coronary angiography and computed tomography. Extracardiac neoplastic involvement was ruled out. The patient underwent surgery, the mass was removed, and the final diagnosis was an undifferentiated pleomorphic sarcoma. PMID- 29118889 TI - Successful Treatment of Iatrogenic External Iliac Artery Perforation With Covered Stent: Case Report and Review of the Literature. AB - Retroperitoneal hemorrhage from iliac artery injury is a potentially serious complication of vascular interventional procedures leading to hemorrhagic shock and death if not diagnosed early and treated promptly. We report a 70-year-old male admitted to our facility with non-ST-elevation myocardial infarction, whose heart catheterization revealed left anterior descending artery (LAD) with 80% proximal, 95% mid and 100% distal disease. The left circumflex and right coronary arteries were 100% occluded proximally and received collaterals from the LAD. The patient declined coronary artery bypass surgery; therefore, the decision was made to perform high-risk percutaneous coronary intervention (PCI) of the LAD with Impella left ventricular assist device support. Left femoral artery angiogram revealed severely tortuous and calcified aorta, left external iliac and left common iliac arteries, and was accessed with 14-inch Impella sheath. He developed groin pain with mild hypotension thought to be due to sedation, which responded to intravenous fluids and dopamine. He underwent successful rotational atherectomy of the proximal and mid LAD with deployment of drug-eluting stents. Following PCI, he suffered acute profound hypotension necessitating intravenous fluids and vasopressor support with epinephrine. Emergency transthoracic echocardiogram did not reveal any pericardial effusion, and showed normal left ventricle and right ventricle systolic function. The Impella device was removed and selective left common iliac angiogram from the right femoral access revealed a vascular injury site with shift of the bladder to the right indicative of retroperitoneal hematoma. A digital subtraction angiogram revealed extravasation of blood at the vascular injury site. An 8.0 * 59 mm iCAST covered stent was deployed to the left external iliac artery with successful sealing of the perforation. The Impella device site was closed with two Perclose devices. The patient required 4 units of packed red blood cell transfusion. His hospital course was complicated by transient acute kidney injury, with return of his renal function to baseline at discharge 10 days later. This case underscores the importance of prompt recognition and treatment of vascular complications associated with interventional procedures, and highlights some of the risk predictors of such complications, which should be anticipated and planned for prior to intervention. PMID- 29118890 TI - A Novel Technique for the Administration of Sub-Ambient Oxygen in the Operating Room. AB - Hypoplastic left heart syndrome (HLHS) is a common form of congenital heart disease with abnormal development of left-sided structures of the heart. As excessive pulmonary blood flow is common prior to palliative surgical procedures, therapeutic maneuvers may be required to decrease pulmonary blood flow and augment systemic cardiac output. Respiratory manipulations to optimize the ratio of pulmonary to systemic blood flow may include techniques to induce hypercarbia or the delivery of sub-ambient concentrations of oxygen (FiO2 less than 0.21). We present a neonate with HLHS who required intraoperative care during a stage I hybrid procedure. Options for the intraoperative administration of a sub-ambient concentration of oxygen are presented. PMID- 29118891 TI - Systolic Anterior Motion of Mitral Valve Subchordal Apparatus: A Rare Echocardiographic Pattern in Non-Obstructive Hypertrophic Cardiomyopathy. AB - Systolic anterior motion (SAM) of the mitral valve or chordate is one characteristic seen in hypertrophic cardiomyopathy (HCM) either in obstructive or non-obstructive phenotypes. More often than not, the obstruction is caused by valvular rather than chordal SAM. We describe the role of echocardiography in identifying the actual anatomical location of the mitral valve apparatus involved in SAM and in assessing consequent left ventricular outflow tract (LVOT) obstruction in an otherwise asymptomatic patient. We report a case of a 29-year old male admitted for an elective non-cardiac surgery, presenting with a cardiac murmur and left axis deviation with biventricular hypertrophy on electrocardiogram. On 2D transthoracic echocardiography (TTE), an asymmetrically hypertrophied left ventricle with systolic motion of anterior mitral valve was incidentally seen. Continuous wave Doppler assessment across the LVOT showed some gradient of obstruction (peak gradient: 9 mm Hg). Transesophageal echocardiography (TEE) demonstrated a redundant anterior mitral valve with the subchordal apparatus mainly causing SAM and confirmed the gradient obtained on TTE, with a mild degree, yet non-significant, degree of LVOT obstruction (mean gradient: 10 mm Hg) documented. Because of this finding, patient was cleared for surgery. Management was deemed conservative with emphasis on close surveillance for signs and symptoms attributable to development of significant LVOT obstruction in patients with HCM. To our knowledge, this is the first reported case in our country of an echocardiographic pattern of systolic anterior motion primarily of the subchordal mitral valve apparatus causing some, though non significant, degree of LVOT obstruction in HCM. Echocardiographic features such as asymmetric left ventricular hypertrophy and presence of some LVOT obstruction caused primarily by subchordal apparatus could impact management in asymptomatic patients. PMID- 29118892 TI - Apical Hypertrophic Cardiomyopathy: A Case Report. AB - Apical hypertrophic cardiomyopathy (ApHCM) is a rare variant of hypertrophic cardiomyopathy, characterized by a spade-like left ventricular cavity. A 58-year old African-American female with past medical history of hypertension presented for evaluation of recurrent exertional chest tightness, palpitations and headache. Prior workup including multiple stress tests and angiogram was non conclusive. Electrocardiogram (EKG) showed characteristic marked T-waves inversions in inferior leads and left ventriculography revealed left ventricle apical hypertrophy with spade like left ventricular cavity that was typical of Yamaguchi syndrome. This case highlights the rare incidence of the disease among African American as well as the challenging diagnostic and presentation features of the disease. PMID- 29118893 TI - Content Analysis by the Crowd: Assessing the Usability of Crowdsourcing for Coding Latent Constructs. AB - Crowdsourcing platforms are commonly used for research in the humanities, social sciences and informatics, including the use of crowdworkers to annotate textual material or visuals. Utilizing two empirical studies, this article systematically assesses the potential of crowdcoding for less manifest contents of news texts, here focusing on political actor evaluations. Specifically, Study 1 compares the reliability and validity of crowdcoded data to that of manual content analyses; Study 2 proceeds to investigate the effects of material presentation, different types of coding instructions and answer option formats on data quality. We find that the performance of the crowd recommends crowdcoded data as a reliable and valid alternative to manually coded data, also for less manifest contents. While scale manipulations affected the results, minor modifications of the coding instructions or material presentation did not significantly influence data quality. In sum, crowdcoding appears a robust instrument to collect quantitative content data. PMID- 29118895 TI - Reduction Mammoplasty: Intraoperative Weight Versus Pathology Weight and Its Implications. AB - Background: Despite the efficacy of reduction mammoplasty and demonstration that resection weight does not predict symptomatic relief of macromastia, many insurers still rely on the Schnur scale or predetermined resection weight for reimbursement. Insurers review pathology reports to determine reimbursement. Tissue desiccation and handling decrease specimen weight prior to pathology evaluation. Surgeons often make judgments based on intraoperative weight. Our goal was to determine whether (1) discrepancies exist between intraoperative and pathology weights, and (2) how differences may impact reimbursement and medical practice. Methods: Medical records review was performed on 25 reduction mammoplasty cases performed between 2007 and 2010, yielding 48 specimens. Tumescent was never used. Weight of each specimen from operative and pathology reports was reviewed and compared. The 2-sample Kolmogorov-Smirnov test was used to compare sample weights. Results: Comparison of intraoperative versus pathology specimen weights revealed an average 7% weight decrease (range, +11% to -45%). Average and median specimen weight decrease from intraoperative to pathology weights was 48 g (SD = 71 g) and 31 g (interquartile range = 6.6-58 g), respectively. Average intraoperative specimen weight was 780.7 g (SD = 375.3 g; range, 290-2238 g). Average pathology specimen weight was 732.3 g (SD = 358.4 g; range, 265-2053.6 g) (P < .001) All but 2 samples weighed less in pathology. Conclusion: Desiccation and handling between intraoperative and pathology weighing decrease specimen weight. Weight discrepancies may have implications on coverage and reimbursement by insurers. Awareness of such discrepancies can help plastic surgeons and patients avoid unexpected coverage and reimbursement complications. PMID- 29118894 TI - An invisible threat: mutation-mediated resistance to triazole drugs in Aspergillus. AB - Aspergillosis has emerged as an important contributor to infection-related morbidity and mortality in susceptible populations. This comes at a time when we are also seeing an increase in the vulnerable populations themselves. At the same time, some parts of the world are reporting an increased incidence of aspergillosis refractory to triazole therapy. Resistance to triazole drugs may have major implications for aspergillosis management since our antifungal armamentarium is limited. This review gives an overview of populations at risk of developing aspergillosis and highlights resistance mechanisms that may contribute to morbidity and mortality in these vulnerable populations. PMID- 29118896 TI - New Insights into the Benefits of Physical Activity and Exercise for Aging and Chronic Disease. PMID- 29118898 TI - Power to the People: Data Citizens in the Age of Precision Medicine. AB - Twentieth-century bioethics celebrated individual autonomy but framed autonomy largely in terms of an individual's power to make decisions and act alone. The most pressing challenges of big data science in the twenty-first century can only be resolved through collective action and common purpose. This Article surveys some of these challenges and asks how common purpose can ever emerge on the present bioethical and regulatory landscape. The solution may lie in embracing a broader concept of autonomy that empowers individuals to protect their interests by exercising meaningful rights of data citizenship. This Article argues that twentieth-century bioethics was a paternalistic, top-down affair in which self proclaimed ethics experts set standards to protect research subjects portrayed as autonomous yet too vulnerable and disorganized to protect themselves. The time may be ripe for BioEXIT, a popular uprising of regular people seeking a meaningful voice in establishing citizen-led ethical and privacy standards to advance big-data science while addressing the concerns people feel about the privacy of their health data. PMID- 29118900 TI - Effect and mechanism of pyrroloquinoline quinone on anti-osteoporosis in Bmi-1 knockout mice-Anti-oxidant effect of pyrroloquinoline quinone. AB - Pyrroloquinoline quinone (PQQ), considered as an ROS scavenger,could protect mitochondrial activity from damage of oxidative stress. To determine the role of PQQ supplement in rescuing long bone osteoporosis in Bmi-1-/- mice. We fed Bmi-1 knockout mice a diet supplemented with PQQ (BKO+PQQ), BKO mice with normal diet (BKO) and wild type mice with normal diet (WT) as controls. We compared the differences of skeletal phenotype by means of imaging, histopathological and molecular biology methods in three groups of animals. Results showed that BKO+PQQ mice increased morphology of tibia, decreased X-ray transmittance, and increased bone density, thickness of cortical bone, width of growth plate and trabecular bone mass compared with BKO mice. Our study also investigated that, compared mice BKO, PCNA positive cells percentage of tibial growth plate areas significantly increased in BKO+PQQ mice, and TUNEL positive cells percentage was significantly decreased. To detect the effect of PQQ on osteoblast formation of tibiae. Our results showed, compared with BKO mice, osteogenic cell, osteoblast number areas, ALP, Col I and OCN positive areas significantly increased in tibia of BKO+PQQ mice. Further studies showed that supplemental PQQ played a role in anti osteoporosis by up-regulating antioxidant capacity, inhibiting oxidative stress and reducing DNA damage, down-regulating CDKI proteins levels, and decreasing cell apoptosis. This study not only reveals the mechanism of PQQ supplementation in anti-osteoporosis, but also provides the experimental and theoretical basis for the clinical application of PQQ in osteoporosis. PMID- 29118897 TI - Redox Regulation of Inflammatory Processes Is Enzymatically Controlled. AB - Redox regulation depends on the enzymatically controlled production and decay of redox active molecules. NADPH oxidases, superoxide dismutases, nitric oxide synthases, and others produce the redox active molecules superoxide, hydrogen peroxide, nitric oxide, and hydrogen sulfide. These react with target proteins inducing spatiotemporal modifications of cysteine residues within different signaling cascades. Thioredoxin family proteins are key regulators of the redox state of proteins. They regulate the formation and removal of oxidative modifications by specific thiol reduction and oxidation. All of these redox enzymes affect inflammatory processes and the innate and adaptive immune response. Interestingly, this regulation involves different mechanisms in different biological compartments and specialized cell types. The localization and activity of distinct proteins including, for instance, the transcription factor NFkappaB and the immune mediator HMGB1 are redox-regulated. The transmembrane protein ADAM17 releases proinflammatory mediators, such as TNFalpha, and is itself regulated by a thiol switch. Moreover, extracellular redox enzymes were shown to modulate the activity and migration behavior of various types of immune cells by acting as cytokines and/or chemokines. Within this review article, we will address the concept of redox signaling and the functions of both redox enzymes and redox active molecules in innate and adaptive immune responses. PMID- 29118901 TI - Impacts of berberine on oxidized LDL-induced proliferation of human umbilical vein endothelial cells. AB - Berberine (BBR), a Chinese medicine extracted from natural plant, has been demonstrated to improve lipid disorders. Oxidized low-density lipoprotein (oxLDL), a proatherogenic lipoprotein, has been shown to be involved in vascular endothelial cell dysfunction such as excessive or abnormal proliferation. The purpose of the present study was to investigate the impacts of BBR on cell proliferations as well as potential involving signal pathways. HUVECs were stimulated with oxLDL and co-cultured with BBR at a variety of concentrations in different time points. The data showed that oxLDL (10-100 MUg/ml) remarkably promoted human umbilical vein endothelial cells (HUVECs) proliferation assessed by Cell Counting Kit-8 (CCK-8) and EdU assay. The effects were found to be involved in up-regulation of proliferating cell nuclear antigen (PCNA), nuclear factor kB (NF-kB) and oxidized low density lipoprotein receptor 1 (LOX-1) and activation of phosphatidylinositol 3 kinase (PI3K)/Akt, ERK1/2 and p38 mitogen activated protein kinase (MAPK) signaling pathways evaluated by either real time polymerase chain reaction (PCR) or western blot analysis. Interestingly, HUVECs proliferation was significantly inhibited by BBR (5-25 MUg/ml), which down regulated the expression of PCNA, NF-kB and LOX-1 and reduced the phosphorylation of Akt, ERK1/2 and p38MAPK. Furthermore, the anti-proliferative effect of BBR on HUVECs was effectively abrogated by a PI3K inhibitor LY294002, an ERK1/2 inhibitor PD98059 and a p38 inhibitor SB202190 partly through the restoration of phosphorylation of Akt, ERK1/2 and p38MAPK. Taken together, our data suggested that BBR inhibited ox-LDL-induced HUVECs proliferation by decreasing the expression of PCNA, NF-kB and LOX-1 and suppressing the activation of PI3K/Akt, ERK1/2 and p38MAPK pathways, indicating a latent candidate for anti atherosclerosis clinically. PMID- 29118899 TI - Alterations in tendon microenvironment in response to mechanical load: potential molecular targets for treatment strategies. AB - Rotator cuff (RC) tendons could beinflicted in many ways with an eventual outcome of pain, weakness and disability, which represent a large burden on health care cost. However, optimal healing, either conservatively or with surgical intervention, remains an issue that needs further investigation. Disorders of the RC tendons may result from external factors like trauma, or internal factors through physiologic and metabolic derangement. Most RC tendon disorders may be asymptomatic and may result from an over-activity of the inflicted shoulder and its tendons. Such tendon disorders are poorly diagnosed since patients do not seek medical attention until pain or weakness ensue. Immunological and biochemical events in RC disorders due to mechanical intolerance have not been investigated. Generally, the mechanical load drives normal physiological properties of the tendon. But, mechanical overload/burden exerts stress on tenocytes, and disrupts the tendon microenvironment by triggering a multitude of signaling pathways leading to extracellular matrix remodeling, disorganization, alteration in collagen composition and apoptosis. These events result in weak tendon which is highly susceptible to rupture or tear. In this article, we critically reviewed the intrinsic signaling pathways that are excessively triggered by continuous mechanical load and the counteracting physiological responses and associated derangements. The elucidation of the molecular events underlying mechanical stress-induced symptomatic/asymptomatic tendinopathy could provide information on potential target sites for translational application in the management of rotator cuff disorders. PMID- 29118902 TI - Inhibitory effects of thalidomide on bleomycin-induced pulmonary fibrosis in rats via regulation of thioredoxin reductase and inflammations. AB - In this study, the potential clinical effects of thalidomide on bleomycin-induced pulmonary fibrosis were investigated. A Sprague-Dawley rats' model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin was adopted. The rats in thalidomide treated groups were intraperitoneally injected with thalidomide (10, 20, 50 mg/kg) daily for 28 days, while the rats in control and bleomycin treated groups were injected with a saline solution. The effects of thalidomide on pulmonary injury were evaluated by the lung wet/dry weight ratios, cell counts, and histopathological examination. Inflammation of lung tissues was assessed by measuring the levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta in bronchoalveolar lavage fluid (BALF). Oxidative stress was evaluated by detecting the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) in lung tissue. The results indicated that thalidomide treatment remarkably attenuated bleomycin-induced pulmonary fibrosis, oxidative stress and inflammation in rats' lung. The anti-inflammatory and anti-oxidative effects of thalidomide were also found in human lung fibroblasts. Thalidomide administration significantly stimulated the activity of thioredoxin reductase, while other enzymes or proteins involved in biologic oxidation-reduction equilibrium were not affected. Our findings indicate that thalidomide-mediated suppression of fibro-proliferation may contribute to the anti-fibrotic effect against bleomycin-induced pulmonary fibrosis. The mechanisms are related to the inhibition of oxidative stress and inflammatory response. In summary, these results may provide a rationale to explore clinical application of thalidomide for the prevention of pulmonary fibrosis. PMID- 29118903 TI - MiR-665 regulates VSMCs proliferation via targeting FGF9 and MEF2D and modulating activities of Wnt/beta-catenin signaling. AB - Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of cardiovascular diseases. Studies have showed the great impact of microRNAs (miRNAs) on the cell proliferation in VSMCs. This study examined the in vitro functional roles of miR-665 in the VSMCs and explored the underlying molecular mechanisms. The mRNA and protein expression levels were determined by qRT-PCR and western blot assays, respectively. CCK-8, transwell invasion and wound healing assays were performed to measure VSMCs proliferation, invasion and migration, respectively. The miR-665 targeted-3'UTR of fibroblast growth factor 9 (FGF9) and myocyte enhancer factor 2D (MEF2D) was confirmed by luciferase reporter assay. Platelet-derived growth factor-bb (PDGF-bb) and 20% serum promoted cell proliferation and suppressed the expression of miR-665 in VSMCs. In vitro functional assays demonstrated that miR-665 inhibited VSMCs proliferation, invasion and migration. Bioinformatics analysis showed that FGF9 and MEF2D were found to be downstream targets of miR-665. Luciferase report assay confirmed that FGF9 and MEF2D 3'UTRs are direct targets of miR-665, and miR-665 overexpression suppressed both the mRNA and protein expression levels of FGF9 and MEF2D. Furthermore, rescue experiments showed that enforced expression of FGF9 or MEF2D attenuated the inhibitory effects of miR-665 on VSMCs proliferation. More importantly, overexpression of miR-665 also suppressed the mRNA and protein expression levels of beta-catenin, c-myc and cyclin D1. In summary, miR-665 suppressed the VSMCs proliferation, invasion and migration via targeting FGF9 and MEF2D, and the in vitro effects of miR-665 on VSMCs may be associated with modulation of Wnt/beta-catenin signaling activities. PMID- 29118904 TI - Inhibiting post-translational core fucosylation protects against albumin-induced proximal tubular epithelial cell injury. AB - Albuminuria is an independent risk factor for renal interstitial fibrosis (RIF). Glomerular-filtered albumin in endocytic and non-endocytic pathways may injure proximal tubular epithelial cells (PTECs) via megalin and TGFbetaRII, respectively. Since megalin and TGFbetaRII are both modified by post translational core fucosylation, which plays a critical role in RIF. Thus, we sought to identify whether core fucosylation is a potential target for reducing albumin-induced injury to PTECs. We constructed a human PTEC-derived cell line (HK-2 cells) and established an in vitro model of bovine serum albumin (BSA) injury. RNAi was used to inhibit the expression of megalin, TGFbetaRII, and Fut8. Western blotting, immunostaining, ELISA, lectin blotting, and fluorescence activated cell sorting were used to identify BSA-induced endocytic and non endocytic damage in HK-2 cells. Fut8 is a core fucosylation-related gene, which is significantly increased in HK-2 cells following an incubation with BSA. Fut8 siRNA significantly reduced the core fucosylation of megalin and TGFbetaRII and also inhibited the activation of the TGFbeta/TGFbetaRII/Smad2/3 signaling pathway. Furthermore, Fut8 siRNA could reduce monocyte chemotactic protein-1, reactive oxygen species, and apoptosis, as well as significantly decrease the fibronectin and collagen I levels in BSA-overloaded HK-2 cells. Core fucosylation inhibition was more effective than inhibiting either megalin or TGFbetaRII for the prevention of albumin-induced injury to PTECs. Our findings indicate that post-translational core fucosylation is essential for the albumin-induced injury to PTECs. Thus, the inhibition of core fucosylation could effectively alleviate albumin-induced endocytic and non-endocytic injury to PTECs. Our study provides a potential therapeutic target for albuminuria-induced injury. PMID- 29118906 TI - RNAi-mediated silencing of NOX4 inhibited the invasion of gastric cancer cells through JAK2/STAT3 signaling. AB - NADPH oxidase 4 (NOX4) is a member of the NADPH oxidase (NOX) family of enzymes and has been found abnormally expressed in human cancers. However, its role in gastric cancer (GC) is still unclear. In the current study, we reported that NOX4 expression levels were significantly up-regulated in GC tissues compared to normal tissues (P<0.0001). Higher NOX4 expression was significantly associated with poorer overall survival in GC patients. Silencing NOX4 in two NOX4 high expression GC cell lines, MGC-803 and BGC-823 cells, did not affect cell proliferation, while inhibited cell adhesion and cell invasion of GC cells. Furthermore, Gene set enrichment analysis (GSEA) results indicated that NOX4 expression was strongly associated with cell migration, epithelial-mesenchymal transition (EMT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. More interestingly, Interleukin-6 (IL-6) increased the invasion ability and activation of JAK2/STAT3 of MGC-803 and BGC-823 cells. Such effects were attenuated by NOX4 silencing. Overexpression of NOX4 in one NOX4 low expression GC cell line, SGC-7901 cells, significantly promoted cell invasion, which was impaired by treatment of JAK2 inhibitor, AG490. AG490 inhibited STAT3 activation in SW1990 cells. NOX4 may exert its function through JAK2/STAT3 pathway. In summary, the findings of this study indicate that NOX4 may promote the development of GC, potentially representing a novel prognostic marker for overall survival in GC. PMID- 29118905 TI - Intramyocardial injection of thioredoxin 2-expressing lentivirus alleviates myocardial ischemia-reperfusion injury in rats. AB - The aim of this study is to explore the role of thioredoxin-2 (Trx2) in autophagy and apoptosis during myocardial ischemia-reperfusion (I/R) injury in vivo. In the study, adult male Sprague-Dawley rats were assigned to four groups at random and pretreated with normal saline (sham operation and I/R groups) and either a control lentivirus (Lv-GFP-N) or one expressing Trx2 (Lv-GFP-Trx2). Sevendays after pretreatment, rat MIRI models were produced via occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion for 6 h. Hearts and blood were harvested to assess efficiency of lentivirus transfection via immunofluorescence staining, quantitative RT-PCR and western blotting, oxidative stress via the malondialdehyde level and superoxide dismutase activity, myocardial damage via myocardial enzymelevels and histopathological staining, myocardial apoptosis via TUNEL assays and western blotting, and myocardial autophagy viawestern blotting. Our results showed thatthe delivery of Lv-GFP-Trx2 into the myocardium remarkably increased Trx2 expression. The upregulation of Trx2 contributed to alleviation of oxidative stress, attenuation of myocardial histological damage, reduced leakage of myocardial enzyme and decrease in infarct size. Moreover, the overexpression of Trx2 was significantly associated with thedecreased incidence of apoptosis via ASK1-dependent intrinsic mitochondrial apoptotic pathwayand autophagy via the mammalian target of rapamycin (mTOR) pathway. The study indicates that upregulation of Trx2 protectsthe myocardium from MIRI and isinvolved inthe inhibition of apoptosis and autophagy. Therefore, Trx2 isa promising therapeutic strategy for attenuating MIRI. PMID- 29118907 TI - NOVA1 acts as an oncogene in osteosarcoma. AB - Osteosarcoma is one of the most common bone tumors in young patients. NOVA1 (neuro-oncological ventral antigen 1) is a neuron-specific RNA binding-protein and belongs to the Nova family. Previous studies showed that NOVA1 played crucial roles in the development of several tumors. The objective of our study was to study the role of NOVA1 in the osteosarcoma. In our study, we showed that NOVA1 expression was upregulated in osteosarcoma cell lines and tissues. The expression of NOVA1 was upregulated in 22 (22/30; 73%) osteosarcoma cases compared to that in the adjacent tissues. Overexpression of NOVA1 promoted osteosarcoma cell viability, colony formation and invasion. Furthermore, knockdown of NOVA1 suppressed osteosarcoma cell viability, colony formation and invasion. These data suggested that NOVA1 acted as an oncogene in the development of osteosarcoma. PMID- 29118908 TI - miR-25 is upregulated before the occurrence of esophageal squamous cell carcinoma. AB - MicroRNAs (miRNAs) are potential biomarkers for cancer detection including esophageal squamous cell carcinoma (ESCC); however, little is known about their expression profile and diagnostic impact in esophageal squamous cell intraepithelial neoplasia, the pathological precancerous lesion of ESCC. In this study, we examined the expression levels of eight miRNAs that were reported to be deregulated in ESCC, including miR-25, let-7a, miR-100, miR-133a, miR-223, miR 375, miR-483-5p and miR-1322, in 30 pairs of esophageal squamous cell neoplasia lesion tissues and corresponding adjacent normal tissues using quantitative real time PCR (qRT-PCR). Differential expression of miRNAs was further examined by in situ hybridization. Furthermore, the deregulated miRNAs were also measured in serum and serum exosome samples of these patients. miR-25, an oncomir that had been reported to be upregulated in ESCC tissues, were found to be overexpressed in esophageal squamous cell intraepithelial neoplasia lesions (66.7%, 20/30) compared to adjacent normal tissues (P < 0.05), while the other seven miRNAs did not show a significant difference between the lesions and controls. The miR-25 signal was stronger in lesion tissues than in normal tissues according to in situ hybridization. The concentrations of miR-25 in both serum and exosome samples of patients were not significantly different from those of healthy individuals. These findings suggested that the overexpression of miR-25 in esophageal squamous cell intraepithelial neoplasia lesions might be a promising early biomarker candidate for the prediction of ESCC. PMID- 29118909 TI - Role of autophagy and its signaling pathways in ischemia/reperfusion injury. AB - This study was conducted to investigate the mechanism of autophagy and its signaling pathways in ischemia/reperfusion injury (IRI). Pulmonary microvascular endothelial cells (PMVECs) were used to construct I/R models. The cells were then treated with autophagy inhibitor 3-MA and infected with adenovirus expressing Beclin 1-shRNA. The expression of CD31, LC3-II, Bcl-2, Bax, LC3-II, Beclin 1, AKT, p-AKT, AMPK and p-AMPK, apoptosis, cell viability and migration ability were determined. Over 95% isolated PMVECs were positive for CD31. The expression of LC3-II and Beclin 1 was up-regulated in I/R cells. 3-MA and Beclin 1 knockdown inhibited the expression of LC3-II and Beclin 1 and autophagosome formation. Autophagy induced by hypoxia was antagonistic against apoptosis, which increased after treatment with 3-MA and knockdown of Beclin 1. 3-MA and Beclin 1 knockdown downregulated and upregulated the expression of Bcl-2 and Bax, respectively. Apoptosis mediated by hypoxia and reperfusion-induced autophagy was reduced by 3 MA and Beclin-1 knockdown, which increased and reduced the expression of Bcl-2 and Bax, respectively, leading to significant decreased Bax/Bcl-2 ratio. In these cells, expression of p-AKT, p-AMPK and p-mTOR was up-regulated. After treatment with 3-MA and Beclin 1 knockdown, expression of p-AKT and p-AMPK was significantly reduced. PMID- 29118910 TI - Feasibility of magnetic resonance redox imaging at low magnetic field: comparison at 1 T and 7 T. AB - The effect of different static magnetic field strengths, 1 T or 7 T, on the quality of nitroxyl radical-based magnetic resonance redox imaging (MRRI) was examined. A stable nitroxyl radical, 3-methoxycarbonyl-2,2,5,5 tetramethylpyrrolidine-N-oxyl (MC-PROXYL), was used as a T1 contrast agent. Phantoms and animals were scanned at 1 T and 7 T using a similar gradient echo sequence. The quality of T1-weighted images and susceptibility of T1-weighted signals were compared. The nitroxyl radical-based T1-weighted signal enhancement ratio was higher at 1 T compared with at 7 T when the identical phantom was scanned using a similar gradient echo sequence. The gradient echo scanning at 7 T was sensitive to movement and/or flux of the sample solution, which could result in the distortion of baseline T1-weighted signals. No such wobbling of the signal was observed when the experiment was done at 1 T. The detection at the lower field is less affected by voltex flow in the sample, much stable T1-weighted signal detection is available at the lower field. The visual characteristics of in vivo nitroxyl decay profiles were similar between the 1 T and 7 T experiments, except noises were large at 1 T. The correlation trends of in vivo decay constants among brain regions also similar between 1 T and 7 T experiments. Nitroxyl radical-based MRRI could be an adequate theranostic tool when performed on clinically popular low magnetic field MRI instruments. PMID- 29118911 TI - Fibroblast growth factor 21 delayed endothelial replicative senescence and protected cells from H2O2-induced premature senescence through SIRT1. AB - Vascular aging is an independent risk factor for age-related diseases, including atherosclerosis. Fibroblast growth factor 21 (FGF21) has been widely recognized as a metabolic regulator that is elevated in response to caloric and nutritional restrictions. Recent studies have demonstrated its emerging role as a pro longevity hormone, but its effects on the senescence of human umbilical vascular endothelial cells (HUVECs) remain unclear. In the present study, we explored the anti-senescence effects and underlying mechanism of FGF21 on HUVECs. Co cultivation of HUVECs with 5 ng/mL FGF21 significantly attenuated the phenotype changes of cells during in vitro subculture, including increased senescent population, decreased proliferation rate, decreased SIRT1 and elevated P53 and P21 protein levels. FGF21 also protected HUVECs from H2O2-induced cell damage, including premature cell senescence, intracellular accumulation of reactive oxygen species, increased DNA damage, decreased SIRT1 protein level and elevated protein levels of VCAM-1, ICAM-1, P53 and P21. Transient knockdown of SIRT1 in HUVECs significantly suppressed the protective effects of FGF21 for the rescue of H2O2-induced premature senescence and DNA damage, which suggests that the anti senescence effect of FGF21 on HUVECs is SIRT1-dependent. These results support the potential of FGF21 as a therapeutic target for postponing vascular aging and preventing age-related vascular diseases. PMID- 29118912 TI - High expression of Fibronectin 1 suppresses apoptosis through the NF-kappaB pathway and is associated with migration in nasopharyngeal carcinoma. AB - Fibronectin 1 (FN1) is a member of the glycoprotein family located on chromosome 2q35. It has been reported that FN1 is upregulated in many tumors, and its expression is negatively related to the prognosis and survival of cancer patients. Through data analysis, we found that FN1 is upregulated in nasopharyngeal carcinoma (NPC). This study aimed to investigate how FN1 expression affects NPC cell behavior. In this study, we downregulated FN1 in two NPC cell lines, 5-8F (EBV-) and C666-1 (EBV+), and evaluated invasion, migration and apoptosis. FN1 promoted migration and invasion by upregulating MMP9 and MMP2 expression; the NF-kappaB/P65 signaling pathway was also affected by FN1. FN1 suppressed apoptosis in NPC cells by upregulating BCL2 and increasing the nuclear localization of P65, both by inducing cytosolic accumulation and nuclear translocation, but FN1 expression was not reduced when the NF-kappaB/P65 pathway was inhibited in the negative control (NC) group. Compared with NC cells, shFN1 cells showed little change in apoptosis when the NF-kappaB/P65 pathway was activated by LPS. These results suggest that FN1 regulates apoptosis though P65 in the NF-kappaB pathway. Our results show that FN1 plays an important role in NPC cells and is a potential target for NPC treatment. PMID- 29118913 TI - Protease activated receptor 2 in diabetic nephropathy: a double edged sword. AB - Diabetic nephropathy is a major microvascular complication of diabetes mellitus, and the leading cause of end stage renal disease worldwide. The pathogenesis of diabetic nephropathy is complex, making the development of novel treatments that stop or reverse the progression of microalbuminuria into end stage renal disease a challenge. Protease activated receptor (PAR)-2 has recently been shown to aggravate disease progression in diabetic nephropathy based upon which it was suggested that PAR-2 would be a potential target for the treatment of diabetic nephropathy. To fully appreciate the translational potential of PAR-2 in diabetic nephropathy, we evaluated the effect of PAR-2 deficiency on the development of diabetic nephropathy in a streptozotocin-induced diabetes model characteristic of type 1 diabetes. Although diabetic PAR-2 deficient mice showed reduced albuminuria compared to diabetic wild type mice, an increase in mesangial expansion was evident in the PAR-2 deficient mice. No differences were observed in blood glucose levels, podocyte numbers or in glomerular vascular density. These results show that PAR-2 plays a dual role in the development of streptozotocin-induced diabetic nephropathy and may thus not be the eagerly awaited novel target to combat diabetic nephropathy. Targeting PAR-2 should consequently only be pursued with great care in a clinical setting. PMID- 29118914 TI - The neuroprotective effects of remifentanil on isoflurane-induced apoptosis in the neonatal rat brain. AB - Remifentanil is one of the most frequently prescribed opioids used in combination with inhalation anesthetics in clinical practice, but the effects of such combinations on the developing rat brain are unknown. In our study, we investigated first the potential neurotoxic effects of remifentanil on the developing brain and then the effects of remifentanil on isoflurane-induced apoptosis in the neonatal rat brain following exposure to a nociceptive stimulus. In the first experiment, postnatal day (P) 7 rats were randomly exposed to 30% oxygen, 1.5% isoflurane alone, 1.5% isoflurane and a plantar incision, normal saline, or remifentanil at a low (5 ug.kg-1.h-1), moderate (20 ug.kg-1.h-1) or high (80 ug.kg-1.h-1) dose for 4 h. In the second 4-h experiment, P7 rats were randomly exposed to 1.5% isoflurane, infused with different doses of remifentanil (5, 10, and 20 ug.kg-1.h-1), and subjected to a plantar incision. In both experiments, the number of apoptotic neurons in the cortex, hippocampus, and thalamus was assessed after two hours by cleaved caspase-3 or TUNEL staining. Our data showed that unlike 1.5% isoflurane, remifentanil at any dose did not cause significant neuronal apoptosis in any brain section. In addition, in response to a nociceptive stimulus, the infusion of 10 ug.kg-1.h-1 remifentanil reduced isoflurane-induced apoptosis in the hippocampus (P = 0.003 in CA1, P = 0.002 in CA3) but not in the cortex or thalamus. Our findings suggest that remifentanil does not induce apoptosis and reduces isoflurane-induced apoptosis in the developing brain. PMID- 29118915 TI - A novel culture system robustly maintained pluripotency of embryonic stem cells and accelerated somatic reprogramming by activating Wnt signaling. AB - Wnt signaling is intrinsic to embryonic stem cell self-renewal and mammalian development. However, the effects of wnts on ES cells self-renewal and iPS cells transduction was not clearly understood. In this study, L-Wnt3a cells that secreted activated Wnt3a protein into medium were used to produce Wnt3a condition medium (Wnt3a-CM) or feeder layer for ES cells cultivation and iPS cells transduction. The results showed that L-Wnt3a cells as feeder layer significantly promoted establishment of ES cell lines and generation of iPS cells. The ES cells robustly maintained pluripotency in Wnt3a-CM on feeder free condition. Moreover, we demonstrate that activated Wnt signaling by Wnt3a-CM at the early stage of reprogramming promoted generation of iPS cells by up-regulating Tcf3 and Tcf4, improving mesenchymal-to-epithelial transition (MET), promptly reactivating endogenous pluripotent genes, and regulating epigenetic remodeling. Taken together, L-Wnt3a cells and their condition medium could be a novel culture system to robustly maintained pluripotency of ES cells and accelerated somatic reprogramming by activating Wnt signaling. PMID- 29118916 TI - Knockdown of HOXA-AS2 suppresses proliferation and induces apoptosis in colorectal cancer. AB - Colorectal cancer (CRC) remains one of the most common cancers worldwide. Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes, including cell growth, differentiation, apoptosis, and cancer progression. However, the function of lncRNAs in the progression of CRC remains largely unknown. Here, we reported that HOXA cluster antisense RNA2 (HOXA-AS2) was upregulated in CRC. Increased HOXA-AS2 expression in CRC was associated with larger tumor size and higher clinical stage. In vitro experiments revealed that HOXA-AS2 knockdown significantly inhibited CRC cell proliferation by causing G1 arrest and promoting apoptosis, whereas HOXA-AS2 overexpression promoted cell proliferation. Further functional assays indicated that HOXA-AS2 overexpression significantly promoted cell migration and invasion by regulating the epithelial-mesenchymal transition (EMT). In conclusion, our study identifies HOXA-AS2C as a potential biomarker in CRC. PMID- 29118917 TI - Influence of renal function on the association between homocysteine level and risk of ischemic stroke. AB - We examined whether the association between total homocysteine (tHCY) and risk of ischemic stroke (IS) varies depending on renal function to gain insight into why tHCY-lowering vitamins do not reduce the incidence of cardiovascular disease in clinical trials. We analyzed data from 542 IS patients with large artery atherosclerosis (LAA) or small artery occlusion (SAO) after stratification by estimated glomerular filtration rate (eGFR) to evaluate renal function. We found that tHCY level was positively associated with the occurrence of IS in both LAA (OR: 1.159, 95% CI: 1.074-1.252, P<0.001) and SAO (OR: 1.143, 95% CI: 1.064 1.228, P<0.001) patients and in LAA (OR: 1.135, 95% CI: 1.047-1.230, P=0.002) and SAO (OR: 1.159, 95% CI: 1.060-1.268, P=0.001) subgroups with normal renal function but not in LAA or SAO subgroups with renal insufficiency. eGFR level was positively associated with IS in LAA (OR: 1.022, 95% CI: 1.010-1.034, P<0.001) and SAO (OR: 1.024, 1.012-1.037, P<0.001) subgroups with normal renal function but was negatively associated with IS in LAA (OR: 0.875, 95% CI: 0.829-0.925, P<0.001) and SAO (OR: 0.890, 95% CI: 0.850-0.932, P<0.001) subgroups with renal insufficiency. Folic acid level was negatively associated with IS in LAA (OR: 0.734, 95% CI: 0.606-0.889, P=0.002) and SAO (OR: 0.861, 95% CI: 0.767-0.967, P=0.012) subgroups with renal insufficiency. Therefore, renal function as evaluated by eGFR exerts a significant influence on the association between tHCY and risk of IS. PMID- 29118918 TI - Image-guided dendritic cell-based vaccine immunotherapy in murine carcinoma models. AB - In recent decades, immunotherapy has undergone extensive developments for oncologic therapy applications. Dendritic cells (DCs) plays a fundamental role in cell-based vaccination immunotherapy against various types of cancer. It involves stimulating innate and adaptive immunity, in particular cytotoxic T-cell mediated antitumor effects, against targeted tumors and has been studied in both preclinical and clinical settings. Nevertheless, clinical outcomes have been unsatisfying. The antitumor response requires sufficient migration of viable DCs from primary administration site to targeted tumors through related lymphatics. The dynamics and mechanisms of the DCs migration still need further investigation. Here, we briefly introduce the current clinically applicable methods for manufacturing DC-based cancer vaccines and their most commonly used non-invasive, real-time tracking approaches. Furthermore, we propose a hypothesis that intraperitoneal injection may improve the efficiency of DC-based cancer vaccine. PMID- 29118919 TI - Integrative analysis of BSG expression in NPC through immunohistochemistry and public high-throughput gene expression data. AB - BACKGROUND: Though basigin (BSG) was reported to be overexpressed in nasopharyngeal carcinoma (NPC) and correlate with the development of NPC, the molecular basis of BSG in NPC remained elusive. The aim of the research was to investigate BSG expression in NPC and the potential molecular mechanism underlying it. MATERIALS AND METHODS: BSG expression in NPC tissues was detected with immunohistochemistry. Chi-square test, Kruskal-Wallis test and Spearman correlation test were performed to examine the relationship between BSG expression and the clinico-pathological features as well as EGFR and P-53 expression in NPC. In addition, data from the Human Protein Atlas (HPA) database and oncomine were collected to validate BSG expression in NPC. Meta-analysis was conducted to investigate the association between BSG expression and the clinico pathological variables of NPC. The prognostic value and the alteration of BSG gene status were also analyzed with data from The Cancer Genome Atlas (TCGA). RESULTS: BSG presented notably higher expression in NPC tissues than in non cancer tissues. Moreover, IHC results showed that BSG expression was significantly correlated with tumor progression. A positive correlation was also found between BSG expression and EGFR, P53 expression. Meta-analysis confirmed that BSG was indicative of lymph node metastasis and TNM stage in NPC. Additionally, data from cBioPortal indicated that alteration of BSG gene existed in 5% of NPC cases and BSG correlative genes were obtained from the Co-expression Analysis in TCGA. CONCLUSION: BSG was overexpressed in NPC and might have an oncogenic effect on the tumorigenesis and progression of NPC. PMID- 29118920 TI - Combination therapy with extracorporeal shock wave and melatonin markedly attenuated neuropathic pain in rat. AB - This study tested the hypothesis that combination therapy using extracorporeal shock wave (ECSW)-melatonin (Mel) was superior to either alone at ameliorating neuropathic pain (NP). NP was induced by chronic constriction injury (CCI) to the left sciatic nerve in rats. Animals were categorized into sham control (group 1), CCI only (group 2), CCI-ECSW (group 3), CCI-Mel (group 4) and CCI-ECSW-Mel (group 5). By days 2 and 8 after CCI, the mechanical paw withdrawal threshold (MPWT)/thermal paw withdrawal latency (TPWL) were highest in group 2, lowest in group 1, significantly lower in group 5 than in groups 3 and 4 (all p<0.0001), and not significantly different between groups 3 and 4. The protein expressions of inflammatory (TNF-alpha/NF-kappaB/MMP-9/IL-1beta/GFAP/ox42), oxidative-stress (NOX-1/NOX-2/NOX-4/oxidized protein), DNA/mitochondrial-damaged (gamma H2AX/cytosolic mitochondria), apoptotic (cleaved capase-3/PARP), and MAPK family biomarkers (p-P38/p-JNK/p-ERK1/2) in dorsal root ganglia and spinal dorsal horn expressed a similar pattern of MPWT/TPWL among the five groups, except for significantly higher in group 4 than in group 3 (all p<0.0001). The protein expressions of Nav.1.3, Nav.1.8 and Nav.1.9 in sciatic nerve displayed an identical pattern to inflammation among the five groups (all p<0.001). Pain facilitated cellular expressions (p-P38+/peripherin+ cells, P38+/NF200+ cells) displayed an identical pattern to inflammation among the five groups (all p<0.0001). In conclusion, ECSW-Mel combination therapy markedly ameliorated NP induced by CCI. PMID- 29118921 TI - Resveratrol improves neuron protection and functional recovery through enhancement of autophagy after spinal cord injury in mice. AB - Resveratrol (Res), a natural phenolic compound, has been proven to have a wide variety of beneficial health effects. For example, resveratrol has neuroprotective effects in different central nervous system diseases. However, the mechanisms underlying resveratrol neuroprotection in spinal cord injury (SCI) remain unclear. In this study, we showed that resveratrol treatment improved the restoration of locomotor function, and decreased the degeneration of neurons in SCI mice, which was paralleled by a reduction of apoptosis. We further examined autophagy markers via western blot and immunofluorescence. Results showed that the beneficial effects of resveratrol were related to the promotion LC3II and beclin-1 expression. In addition, autophagy suppression with chloroquine (CQ) partially abolished apoptosis inhibition and locomotor functional improvement of Res on SCI, which indicated that the beneficial effect of resveratrol on SCI was through autophagy enhancement. In conclusion, these results illustrated that the neuroprotective effects of resveratrol in SCI are partially through autophagy stimulation, and implied that Res is a promising drug for SCI therapy. PMID- 29118922 TI - IL-6 increases SDCBP expression, cell proliferation, and cell invasion by activating JAK2/STAT3 in human glioma cells. AB - Syndecan-binding protein (SDCBP), which is induced by tumor necrosis factor-alpha and interferon-gamma, controls the proliferation and invasion of several different types of cancer cells. Interleukin-6 (IL-6) is known to play an important role in the glioma cell growth and invasion. The present study aimed to investigate the relationship between IL-6 and SDCBP in glioma cells. SDCBP expression was knocked down in two glioma cell lines (T98G and U87) by small interfering RNA (siRNA) transfection. Cell proliferation and invasion were significantly repressed following SDCBP knockdown, and there was a positive correlation between SDCBP and IL-6 expression levels in glioma tissues. IL-6 stimulation dose- and time-dependently induced SDCBP expression at both mRNA and protein levels. Furthermore, pre-treatment with the Janus kinase 2 (JAK2) inhibitor AG490 abolished the IL-6-induced SDCBP expression, suggesting that the effect of IL-6 on SDCBP transcription is dependent on JAK2/signal transducer and activator of transcription 3 (STAT3) signaling. Finally, IL-6 did not stimulate glioma cell growth or invasion when SDCBP expression was suppressed. In summary, our results suggest that IL-6 promotes glioma cell proliferation and invasion by inducing SDCBP expression, which is mediated by JAK2/STAT3 signaling. PMID- 29118923 TI - DDX3 binding with CK1epsilon was closely related to motor neuron degeneration of ALS by affecting neurite outgrowth. AB - Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by progressive degeneration of motor neurons. The pathogenesis of ALS remains largely unknown. RNA helicase DDX3 is a multifunctional protein involved in several steps of gene expression. Casein kinase 1epsilon (CK1epsilon) is an important signal molecule of Wnt signaling pathway and is closely related to neurite growth. However, the roles of DDX3 and CK1epsilon in the pathogenesis of ALS remain unclear. In this study, we first investigated the expression of DDX3 and CK1epsilon in the spinal cord of SOD1-G93A ALS transgenic mice using RT PCR, Western blot and immunohistochemical technique. Results showed that the altered expression of DDX3 and CK1epsilon was found in the spinal cord of ALS mice. DDX3 and CK1epsilon positive cells were mainly distributed in the anterior horn of spinal cord and co-localized with neurons not with glial cells, suggesting that the altered expression of DDX3 and CK1epsilon was closely related to motor neuron degeneration of ALS. Moreover, we selected NSC34 cell line and transfected pEGFP-G93A-SOD1 plasmid to further examine the mechanism. Knockdown of DDX3 that uses small interfering RNA (siRNA) decreased the mRNA and protein levels of CK1epsilon significantly and inhibited neurite outgrowth of SOD1 mutant NSC34 cells in vitro. Co-immunoprecipitation kit confirmed that DDX3 could band with CK1epsilon in vivo. Our data suggested that DDX3 binding with CK1epsilon was closely related to motor neuron degeneration of ALS by affecting neurite outgrowth. Thus, elucidating the underlying mechanisms of ALS is crucial for future development of ALS treatments. PMID- 29118924 TI - Effects of targeted CD97 immune epitopes small interference RNA on cellular biological behaviors in MDA-MB231 malignant breast cancer cell line. AB - Two CD97 immune epitopes, CD97EGF (epidermal growth factor domain) and CD97Stalk (stalk domain), have different distribution patterns in malignant epidermal tumors. However, little is known about the effect of CD97EGF and CD97Stalk immune epitopes in breast cancer metastasis. To explore the effects on cell proliferation, infiltration, apoptosis, and the cell cycle, we used small interfering RNA (siRNA) against CD97EGF and CD97Stalk immune epitopes to knock down CD97 in MDA-MB231 breast cancer cells. Compared with controls, CD97 knockdown caused decreased cell growth, proliferation, migration, infiltration, and altered distribution of the percentage of cells in G0/G1 and S phase. We suggest that the potential mechanism of CD97EGF and CD97Stalk immune epitopes on the biological behaviors of MDA-MB231 breast cancer cells may be related to the altered number of N-terminal glycosylation sites, which influence the stability and signaling intensity of CD97 heterodimers. PMID- 29118925 TI - Bardoxolone methyl (CDDO-Me or RTA402) induces cell cycle arrest, apoptosis and autophagy via PI3K/Akt/mTOR and p38 MAPK/Erk1/2 signaling pathways in K562 cells. AB - Chronic myeloid leukemia (CML) treatment remains a challenge due to drug resistance and severe side effect, rendering the need on the development of novel therapeutics. CDDO-Me (Bardoxolone methyl), a potent Nrf2 activator and NF-kappaB inhibitor, is a promising candidate for cancer treatment including leukemia. However, the underlying mechanism for CDDO-Me in CML treatment is unclear. This study aimed to evaluate the molecular interactome of CDDO-Me in K562 cells using the quantitative proteomics approach stable-isotope labeling by amino acids in cell culture (SILAC) and explore the underlying mechanisms using cell-based functional assays. A total of 1,555 proteins responded to CDDO-Me exposure, including FANCI, SRPK2, XPO5, HP1BP3, NELFCD, Na+,K+-ATPase 1, etc. in K562 cells. A total of 246 signaling pathways and 25 networks regulating cell survival and death, cellular function and maintenance, energy production, protein synthesis, response to oxidative stress, and nucleic acid metabolism were involved. Our verification experiments confirmed that CDDO-Me down-regulated Na+,K+-ATPase alpha1 in K562 cells, and significantly arrested cells in G2/M and S phases, accompanied by remarkable alterations in the expression of key cell cycle regulators. CDDO-Me caused mitochondria-, death receptor-dependent and ER stress-mediated apoptosis in K562 cells, also induced autophagy with the suppression of PI3K/Akt/mTOR signaling pathway. p38 MAPK/Erk1/2 signaling pathways contributed to both apoptosis- and autophagy-inducing effects of CDDO-Me in K562 cells. Taken together, these data demonstrate that CDDO-Me is a potential anti-cancer agent that targets cell cycle, apoptosis, and autophagy in the treatment of CML. PMID- 29118926 TI - GTS-21 attenuates LPS-induced renal injury via the cholinergic anti-inflammatory pathway in mice. AB - This study aimed to investigate the role of GTS-21 in cholinergic anti inflammatory pathway-mediated protection of LPS-induced septic renal injury in mice. C57BL/6 mice were used to construct septic injury models. The optimal duration of lipopolysaccharide (LPS) treatment was determined using HE staining and TUNEL assay. Mice injected with saline were used as blank control and with LPS (10 mg/kg) as model, which were further treated with alpha-bungarotoxin (BT LPS), GTS-21 (GTS-21-LPS) and BT and GTS-21 (BT-GTS-21-LPS). The pathological examinations were performed on HE stained renal tissues, apoptosis was determined using TUNEL assay, mRNA expression of NF-kB p65, Caspase-3, Caspase-8, Bcl-2, Bax, p53 and a7nACh was quantified using qRT-PCR, protein levels of IL-6, IL 1beta, TNF-alpha and phosphorylated STAT3 (p-STAT3) were analyzed using Western blots. HE staining and TUNEL assays showed that the optimal LPS treatment time for renal injury induction was 16 h. Compared with the blank control, mice in LPS group had significantly higher levels of NF-Kb p65, Caspase-3, Caspase-8, Bax, p53, IL-6, IL-1beta, TNF-alpha and p-STAT3, while alpha7nAChR and Bcl-2 levels were decreased significantly (P < 0.01); GTS-21 and BT significantly increased the expression of NF-Kb p65, Caspase-3, Caspase-8, Bax, p53, IL-6, IL-1beta, TNF alpha and p-STAT3, while alpha7nAChR and Bcl-2 levels were decreased significantly (P < 0.01). It is concluded that GTS-21 can effective alleviate the renal injury, while alpha7nAChR-specific blocker BT is antagonistic against the anti-inflammatory effect of GTS-21 on sepsis in mice. PMID- 29118927 TI - Topical insulin accelerates cutaneous wound healing in insulin-resistant diabetic rats. AB - Insulin signaling defects could lead to insulin resistance in insulin target organs: typically, in the muscler, liver, and adipose tissue. We have observed that insulin accelerated diabetic wound healing in our previous works; to further elucidate the mechanism, we investigated the expression and activation of insulin and insulin-like growth factor (IGF)-1 signaling, compared insulin sensitivity in skin tissue with that in liver tissue, and also observed the regulation of insulin on inflammatory response of wounds during the healing process. We found lower expression of insulin receptor, phos-AKT, IGF-1 in type II diabetic rat skin compared with that in normal rat skin. However, the level of phos-AKT in diabetic rat skin remarkably increased after systemic insulin injection, whereas no significant change of phos-AKT was observed in liver upon insulin stimulation. In insulin-treated wounds, we detected a significant increase in insulin signaling proteins and growth factor, as well as the phosphorylated insulin receptor substrate-1 and AKT. The increased Glut1 protein level and translocation of Glut1 from cytosol to cell membrane of the basal epidermal cells were also observed after insulin application. Insulin-treated wounds showed advanced infiltration and resolution of macrophages and a change pattern similar to that of inflammatory mediators, including TNF-alpha and IL-6. Our findings support that insulin is a valid agent for diabetic wound healing because of its effect on ameliorating defective insulin action and regulating inflammation response. Our results indicate the presence of subtle insulin responsiveness in diabetic skin tissue, regardless of the presence of impaired insulin sensitivity, which could be the cellular and molecular mechanism of insulin accelerating diabetic wound healing. PMID- 29118928 TI - MiR-5100 targets TOB2 to drive epithelial-mesenchymal transition associated with activating smad2/3 in lung epithelial cells. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating disease and the pathogenesis of IPF remains unclear. Our previous study indicated that miR-5100 promotes the proliferation and metastasis of lung epithelial cells. In this study, we investigated the effect and mechanism of miR-5100 on bleomycin (BLM)-induced mouse lung fibrosis and transforming growth factor beta (TGF-beta1) or epidermal growth factor (EGF) induced EMT-model in A549 and Beas-2B cells. The elevated level of miR-5100 was observed in both the mouse lung fibrosis tissues and EMT cell model. Furthermore, the exogenous expression of miR-5100 promoted the EMT related changes, enhanced TGF-beta1 or EGF-induced EMT and activated the smad2/3 in lung epithelial cells, while silencing miR-5100 had the converse effects. In addition, transwell assay showed that miR-5100 can enhance cell migration. Using target prediction software and luciferase reporter assays, we identified TOB2 as a specific target of miR-5100 and miR-5100 can decrease the accumulation of endogenous TOB2 in A549 and Beas-2B cells. Moreover, the exogenous expression of TOB2 relieves the promotion of miR-5100 on EMT process and migration ability. Taken together, our results indicate that miR-5100 promotes the EMT process by targeting TOB2 associated with activating smad2/3 in lung epithlium cells. Our findings may provide novel insights into the pathogenesis of IPF. PMID- 29118929 TI - Cestrum strigilatum (Ruiz & Pavon, 1799) B chromosome shares repetitive DNA sequences with A chromosomes of different Cestrum (Linnaeus, 1753) species. AB - Species of Cestrum (Linnaeus, 1753) have shown large diversity in the accumulation and distribution of repetitive DNA families, and B chromosomes have been described in seven species. Some types of repetitive DNA were identified in A and B chromosomes in species of this plant group, such as AT-rich SSR, 35S and 5S rDNA, C-Giemsa and C-CMA/DAPI bands and retrotransposons. To increase our understanding of the relationships of A and B chromosomes, the B of C. strigilatum Ruiz & Pavon, 1799 was microdissected, amplified and hybridized in situ against chromosomes of this species, and in six other species of this genus. FISH signals were observed in whole the B of C. strigilatum, including stretches of A chromosomes, as well as in some A chromosomes of all tested species. A strong FISH signal was seen adjacent to the 5S rDNA in the proximal region of pair 8 of all species and, due to this, we have searched for 5S rDNA fragments in the microdissected B chromosome. PCR and sequencing data evidenced 5S rDNA deletion along evolutionary pathways of the B of C. strigilatum. Although A and B chromosomes displayed redundancy in the repetitive DNA families in different species, the B of C. strigilatum seemed to differ from those Bs of other Cestrum species by the loss of rDNA fractions. A possible origin of Bs in Cestrum was discussed. PMID- 29118931 TI - Outcome of breath tests in adult patients with suspected small intestinal bacterial overgrowth. AB - Aim: The aim was to investigate breath test outcomes in patients with suspected SIBO and indicative symptoms of SIBO, diagnosed by breath testing. Background: Breath testing is used to detect small intestinal bacterial overgrowth (SIBO) by measuring hydrogen and methane produced by intestinal bacteria. Methods: This retrospective cross sectional study included 311 patients with gastrointestinal symptoms who underwent the breath test for evaluation of SIBO at Celiac Disease Center at Columbia University, New York, in 2014-2015. The patients were divided into two groups based on the physician's choice: lactulose breath test group (72%) and glucose breath test group (28%). Among them, 38% had a history of celiac disease or non-celiac gluten sensitivity. Results: In total, 46% had a positive breath test: 18% were positive for methane, 24 % positive for hydrogen and 4% positive for both gases (p=0.014). Also, 50% had a positive lactulose breath result and 37% had a positive glucose breath result (p=0.036). The most common symptom for performing the breath test was bloating and the only clinical symptom that significantly showed a positive glucose breath test was increased gas (p=0.028). Conclusion: Lactulose breath test was more often positive than glucose breath test. Positivity for hydrogen was more common than methane. Bloating was the most frequently perceived symptom of the patients undergoing the breath test but the only statistically significant clinical symptom for a positive glucose breath test was increased gas. Furthermore, the results showed that there was no significant association between positive breath test result and gender, age, non-celiac gluten sensitivity or celiac disease. PMID- 29118930 TI - Biomarkers in inflammatory bowel diseases: insight into diagnosis, prognosis and treatment. AB - Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology which mostly involves the intestine and requires a personalized approach for treatment. IBD represents a heterogeneous group of patients with inherently variable disease courses. Hence, the heterogeneity of patient populations may delay the diagnosis, clinical practice and initiation of appropriate treatment. Use of biomarkers for diagnosis and management of IBD is still necessary. Descriptions of the immunological pathway abnormalities in IBD improve assessment to identify the patient's disease status, and relative risk of progression to complicated disease behaviors, and this information may ultimately influence therapeutic decisions. In this study, we try to explain the role of biomarkers in early diagnosis, estimating prognosis, and target agents for correct managements of IBD's patients. This information might be important to provide insight into emerging panels of multiple IBD biomarkers and highlighting the essential role of personalizes panel for each patient. PMID- 29118932 TI - Results of liver transplantation with donors older than 80 years: a case control study. AB - Aim: The inclusion of elderly donors can increase the pool of organs available for transplant. Background: To compare clinical outcomes and survival rates in patients who received livers from donors aged >= 80 years vs. younger donors. Methods: We considered all liver transplantations performed in our unit between January 2006 and January 2015. Twelve patients received liver from a cadaveric donor aged >= 80 years (study group) and their outcomes were compared with those of patients who received liver from a younger donor (control group). This study was carried out to analyze the characteristics of donors and recipients, as well as the clinical course and survival of recipients. Results: Statistically significant differences were observed in donors' age (55.6 +/- 14.4 vs. 82.7 +/- 2.7 years, p < 0.001), donors' ICU stay (p = 0.008), donors' ALT levels (p = 0.009) and donors' AST levels (p = 0.01). Statistically significant differences were found in ischemia time (p < 0.05). In total, 8.3% of the recipients of liver from a donor aged < 80 required retransplantation vs. 25% of recipients of donor's >= 80 years. Patient survival at one, three and five years was 89%, 78.6% and 74.5%, respectively vs. 83.4%, 79.4% and 59.6% for the study group. Conclusion: Livers from older donors can be safely used for transplantation with acceptable patient survival rates. However, graft survival rates are lower for recipients of livers from older donors as compared to younger donors, and survival only increased with retransplantation. PMID- 29118933 TI - Prevalence of cytotoxin-associated genes of Helicobacter pylori among Iranian GERD patients. AB - Aim: Since the impact of H. pylori and its virulence is not clear in GERD, this study aimed to evaluate the prevalence of cag A and cag E gens of H. pylori among Iranian GERD patients. Background: Gastroesophageal reflux disease (GERD) is defined as a condition of reflux the stomach juice by low pH causes tissue damage. Helicobacter pylori may or may not influence the GERD; however, it is unclear. Methods: This study was a case-control study performed on patients with GERD who underwent upper gastrointestinal endoscopy at Taleghani Hospital of Tehran, Iran. Prevalence of H. pylori and presence of the cag A and cag E genes in GERD and control group was investigated. Results: H. pylori was detected in 54% and 62% of GERD and control groups respectively. Prevalence of cag A gene among GERD patients was 44.4% whereas among the control group it was 87%. Prevalence of the cag E among GERD patients and control group was 44.4% and 64% respectively. Coexistence of cag A and cag E in GERD patients was 25.7% and in the control patients it was 54.8%. Conclusion: We did not find correlation between H. pylori existence in GERD patients in comparison to the control group. Similar to other Asian studies, the presence of the cag A in control group was more than GERD patients significantly. The co-existence of cag A and cag E was also more in control group significantly. PMID- 29118934 TI - Exploring conserved mRNA-miRNA interactions in colon and lung cancers. AB - Aim: The main goal of this analysis was prioritization of co-expressed genes and miRNAs that are thought to have important influences in the pathogenesis of colon and lung cancers. Background: MicroRNAs (miRNAs) as small and endogenous noncoding RNAs which regulate gene expression by repressing mRNA translation or decreasing stability of mRNAs; they have proven pivotal roles in different types of cancers. Accumulating evidence indicates the role of miRNAs in a wide range of biological processes from oncogenesis and tumor suppressors to contribution to tumor progression. Colon and lung cancers are frequently encountered challenging types of cancers; therefore, exploring trade-off among underlying biological units such as miRNA with mRNAs will probably lead to identification of promising biomarkers involved in these malignancies. Methods: Colon cancer and lung cancer expression data were downloaded from Firehose and TCGA databases and varied genes extracted by DCGL software were subjected to build two gene regulatory networks by parmigene R package. Afterwards, a network-driven integrative analysis was performed to explore prognosticates genes, miRNAs and underlying pathways. Results: A total of 192 differentially expressed miRNAs and their target genes within gene regulatory networks were derived by ARACNE algorithm. BTF3, TP53, MYC, CALR, NEM2, miR-29b-3p and miR-145 were identified as bottleneck nodes and enriched via biological gene ontology (GO) terms and pathways chiefly in biosynthesis and signaling pathways by further screening. Conclusion: Our study uncovered correlated alterations in gene expression that may relate with colon and lung cancers and highlighted the potent common biomarker candidates for the two diseases. PMID- 29118935 TI - A systems biology analysis protein-protein interaction of NASH and IBD based on comprehensive gene information. AB - Aim: Analysis reconstruction networks from two diseases, IBD and NASH and their relationship, based on systems biology methods. Background: IBD and NASH are two complex diseases, with progressive prevalence and high cost for countries. There are some reports on co-existence of these two diseases. In addition, they have some similar risk factors such as age, obesity, and insulin resistance. Therefore, systems biology approach can help to discover their relationship. Methods: DisGeNET and STRING databases were sources of disease genes and constructing networks. Three plugins of Cytoscape software, including ClusterONE, ClueGO and CluePedia, were used to analyze and cluster networks and enrichment of pathways. Based on degree and Betweenness, hubs and bottleneck nodes were defined. Results: Common genes between IBD and NASH construct a network with 99 nodes. Common genes between IBD and NASH were extracted and imported to STRING database to construct PPI network. The resulting network contained 99 nodes and 333 edges. Five genes were selected as hubs: JAK2, TLR2, TP53, TLR4 and STAT3 and five genes were selected as bottleneck including: JAK2, TP53, AGT, CYP3A4 and TLR4. These genes were hubs in analysis network that was constructed from hubs of NASH and IBD networks. Conclusion: Systems biology methods, specifically PPI networks, can be useful for analyzing complicated related diseases. Finding Hub and bottleneck proteins should be the goal of drug designing and introducing disease markers. PMID- 29118936 TI - Regulation of HSVtk gene by endogenous microRNA-122a in liver cell lines as suicide gene therapy. AB - Aim: Here, we use miR-122a that exhibits liver-specific expression for developing a post-transcriptional regulative system mediated by microRNAs. Background: Gene therapy with adenovirus (Ad) vectors that express herpes simplex virus thymidine kinase (HSVtk) and ganciclovir (GCV) have been suggested as a therapeutic strategy to cancer. However, Ad vectors injected into tumors are dispersed into the systemic circulation and transduce liver cells, resulting in severe hepatotoxicity. To be effective, the delivery and expression of suicide genes to cancer treatment ought to be specific to tumor cells, and avoid death of healthy cells. Researchers have demonstrated that expression of transgene could be suppressed in healthy cells with use of vectors that are reactive to microRNA regulation. Methods: We constructed an Ad vector carrying four tandem copies of target sequences of miR-122a that were incorporated into 3'-UTR of HSVtk gene. The expression level of miR-122a was quantified in HepG2 and Huh7 cell lines. Results: Quantitative RT- PCR analysis demonstrated that Huh7 cells express large amounts of miR-122a compared to HepG2 cells. The viability of Huh7 cells and HepG2 cells after infection by Ad-tk-122aT vector was 83% and 23.5%, respectively. The viability of Huh7 cells was not reduced in the presence of GCV after infection by Ad-tk-122a vector. In contrast, cytotoxicity of HSV-tk/GCV was similar in Huh7 cells and HepG2 cells by Ad-tk vector, with 35.3% and 27% viability, respectively. Conclusion: Inclusion of the miR-122a target sequences in the HSVtk expression cassette yielded a feasible strategy for reducing cytotoxicity of suicide gene in a liver cell line with high miR-122a expression. PMID- 29118937 TI - Isolation, differentiation, and characterization of mesenchymal stem cells from human bone marrow. AB - Aim: We describe the minimum requirements and a simplified method for isolation and characterization of mesenchymal stem cells (MSCs) from human bone marrow. Background: MSCs are well known adult stem cells present in many tissues such as adipocytes, chondrocytes, osteoblasts, and neurons. Many isolations and characterization methods have emerged to apply MSCs in the clinical applications, which many of them are expensive and time-consuming. Methods: MSC isolation was carried out from human bone marrow, and cultured in defined medium. Cultures were maintained at 370C in a humidified atmosphere containing 5% CO2 for 48h. The medium was exchanged every 3-4 days. Adherent cells were characterized according to main criteria defined by ISCT, such as differentiation capability to adipocyte and osteoblast using specific differentiation mediums; also, flow cytometry verified MSC specific markers. Results: Isolated MSCs had a fibroblastic-like appearance with adherent property to the culture plate. Differentiation function was proved with the formation of lipid drops and calcium oxalates on the differentiated MSCs and finally, purified MSCs from bone marrow were positive for cell surface markers, CD73, CD90, and CD105 while being negative for CD34 and CD45. Conclusion: These findings confirm that the represented method is capable of isolating MSCs from bone marrow with proven results according to all minimum criteria defined by the International Society for Cellular Therapy (ISCT). PMID- 29118938 TI - Association between TNF-alpha rs1799964 and RAF1 rs1051208 MicroRNA binding site SNP and gastric cancer susceptibility in an Iranian population. AB - Aim: The aim of this study was to find the relationship between rs1799964 in TNF alpha gene as well as rs1051208 of RAF1 gene SNPs on GC in an Iranian population. Background: Gastric cancer (GC) is the second leading cause of cancer-related death worldwide after lung cancer. Tumor necrosis factor (TNF) is one of the most important factors in the pathogenesis of this cancer. Single nucleotide polymorphisms have a principle role in gene expression of TNF-alpha and miRNAs which may lead to gastric cancer. Methods: In a case-control study, we investigated the risk of GC in 198 Iranians. For this purpose, 5 mL of peripheral blood was collected in EDTA -containing tube and genomic DNA was isolated. Genotyping of SNPs was also performed by PCR-RFLP; to approve the outcome, 10% of genotyping results with RFLP were sequenced. Results: The comparison between case and control groups revealed a significant association between the rs1051208 C allele of RAF1 gene and GC (P = 0.04). We did not observe any remarkable association between TNF-alpha -1031 in gastric cancer patients and the healthy control group. Conclusion: The results indicated that C allele in RAF1 gene plays a role in susceptibility to gastric cancer. Therefore, SNPs are among notable biomarkers for predicting susceptibility to dreadful diseases, especially cancers. PMID- 29118939 TI - Escherichia coli pathotypes and Shigella sero-groups in diarrheic children in Nairobi city, Kenya. AB - Aim: In the present study, we investigated the prevalence of E. coli pathotypes and Shigella sero-groups and their antimicrobial profiles among diarrheic children in Nairobi city, Kenya. Background: Although diarrheagenic E. coli pathotypes and Shigella sero-groups are leading causes of diarrhea in children under five years in developing countries, their distribution and antimicrobial resistance vary from place to place and over time in a given region. Methods: In a cross-sectional study, we enrolled diarrheic children (n=354) under five years seeking treatment at Mbagathi Hospital, Nairobi city, Kenya,. Stool samples were collected from all children for bacterial culture. Bacterial isolation and identification was performed by conventional microbiological methods. Polymerase chain amplification was used to detect aspU, aggR, andpcvd432 for EAEC, est and elt for ETEC, eae for EPEC, stx for EHEC, and ipaH for EIEC and Shigella species. Antimicrobial profile was determined by disk diffusion method. Results: The prevalence of EAEC, ETEC, EPEC (eae), EIEC (ipaH) was 21.2%, 10.5%, 4.5%, and 0.6%, respectively, while that of mixed infection was 0.6%for ETEC/EAEC and 0.3%for EAEC/EPEC/ETEC. No EHEC strain was isolated. Pathogenetic analysis for EAEC showed that5.9% carried aspU,8.2% possessed both aspU and aggR and 7.1% had a combination of aspU, aggR andpcvd432 while that of ETEC was 2.3% for elt, 6.5% for both elt and est and 1.7% for est. The combination of aspU with aggR, elt and est, and pcvd432 with aggR, aspU and est was 0.3% for each case of ETEC/EAEC mixed infection. The aspU gene co-existed with aggR, pcvd432, eae and elt in the EAEC/EPEC/ETEC mixed infection. The prevalence of S. boydii, S. dysenteriae, S. flexneriand,S. sonnei was 0.8%, 0.6%, 1.7%, and 0.8%, respectively. No E. coli pathotype and shigella co-infection was detected. In addition, both E. coli pathotypes and Shigella species were resistant to ampicillin, trimethoprim/sulfamethoxazole, streptomycin, chloramphenicol and tetracycline while gentamycin and kanamycin resistance occurred in diarrheagenic E. coli. Conclusion: E. coli pathotypes and Shigella sero-groups harboring virulent genes are important causes of diarrhea in children in Kenya. The increasing spectrum of antibiotic resistance in diarrheagenic E. coli and Shigella species necessitates the development of antimicrobial stewardship education-programs to influence prescribing behavior as well as optimizing the use of effective antimicrobials in Kenya. PMID- 29118940 TI - Frequency of antibiotic associated diarrhea caused by Clostridium difficile among hospitalized patients in intensive care unit, Kerman, Iran. AB - Aim: This study evaluated the frequency of C. difficile and CDAD in the ICU of Shahid Bahonhar Hospital, Kerman, Iran. Background: Clostridium difficile (C. difficile) is the most important antibiotic associated diarrhea agent in intensive care unit (ICU) patients. Based on its toxin producing ability, C .difficile is divided to toxigenic and non-toxigenic strains. Methods: A total of 233 diarrheal samples were collected from ICU patients. The samples were cultured on Clostridium difficile medium with 5% defibrinated sheep blood containing cycloserine (500 mg/L), cefoxitin (16 mg/L) and lysozyme (5mg/L). The isolates were confirmed as C. difficile by polymerase chain reaction (PCR) of 16s rRNA gene and the presence of toxins genes (tcdA, tcdB, cdtA and cdtB) was also confirmed. Then, the toxin production of isolates was evaluated using ELISA. Results: C. difficile was isolated from 49 (21%) out of 233 samples. The total isolates fell into the A-/B-/CDT- (48.97%), A+/B-/CDT- (28%), A+/B+/CDT- (20.4%) and A+/B+/CDT+ (2%) types. Both types of C.difficile, A-/B-/CDT- and A+/B-/CDT-, which account for 77.5% of all isolates, were unable to produce the toxin (nontoxigenic). On the other hand, A+/B+/CDT+ and A+/B+/CDT- (22.5%), were able to produce toxin or were toxigenic. Conclusion: The frequency of C. difficile was about 21% and only 22.4% of C. difficile isolates were able to produce toxins. It is expected that C. difficile A+/B+/CDT+/- are toxigenic and related to C. difficile associated diarrhea (CDAD). Additionally, about 4.7% of hospitalized patients in ICU suffered from CDAD, which is higher than the rates reported from industrialized countries. Notably, 28% of isolates were C. difficile A+/B-/CDT- which only carries tcdA genes without toxin production. PMID- 29118942 TI - Could Helicobacter pylori cause an abnormal immune response? PMID- 29118941 TI - Prevalence and subtype identification of Blastocystis isolated from humans in Ahvaz, Southwestern Iran. AB - Aim: The aim of the present study was to determine the prevalence and subtype distribution of Blastocystis and its relation with demographic data and symptoms in humans referred to medical centers in Ahvaz 2014-2015. Background: Infections with intestinal parasites are one of the most important threats to human health worldwide, especially in tropical and subtropical areas. Blastocystis sp. is a common parasite of humans with a vast variety of non-human hosts. We aimed to study the prevalence and subtypes of Blastocystis sp. in individuals referred to medical laboratories in Ahvaz city, southwest Iran. Methods: From September 2014 to September 2015, 618 stool samples were collected from 16 medical laboratories in Ahvaz, and examined using direct wet mount, formalin-ether concentration, a modified version of the Ziehl-Neelsen staining technique, and cultivation in xenic HSr + S medium. Subtypes of positive Blastocysts sp. were obtained using the "barcoding" method. The results were analyzed using SPSS software, version 16, with Chi-square and Fisher's exact test. Results: Totally, 325 (52.6%) of the referred individuals were men and 293 (47.4%) were women. Blastocystis sp. was observed in 146 (23.6%) samples. Co-infections with other intestinal parasites were found in 32 (5.17%) cases. Out of the 146 positive isolates, 20.83%, 20.83% and 58.34% belonged to ST1, ST2, ST3 respectively. Conclusion: Blastocystis sp. was quite common in the study population, with a carrier rate corresponding to nearly one in every four individuals. The subtype distribution identified in the present study was largely identical to that reported from other studies in Iran, with ST3 being the most common. PMID- 29118943 TI - Novel therapies for perioperative respiratory complications. AB - Postoperative respiratory complications are of paramount clinical importance as they prolong the hospitalization, increase the costs of treatment and contribute to the perioperative mortality. Obesity, preexisting pulmonary disease and advanced age are known risk factors for developing postoperative respiratory complications, which affect exceeding number of patients. Hereby, we present a review on the pathogenesis of post-operative respiratory complications particularly in obese and older patients. We further focus on the standard management and emerging therapies for the post-operative respiratory complications. PMID- 29118944 TI - Cardiac progenitor cells application in cardiovascular disease. AB - Stem cells (SCs) have special potency to differentiate into different types of cells, especially cardiomyocytes. In order to demonstrate the therapeutic applications of these cells, various investigations are recently being developed. Cardiac progenitor cells are endogenous cardiac SCs that found to express tyrosine kinase receptors, c-Kit and other stemness features in adult heart, contributing to the regeneration of cardiac tissue after injury. This lineage is able to efficiently trans-differentiate into different cell types such as cardiomyocytes, endothelial cells, and smooth muscle cells. Noticeably, several cardiac progenitor cells have been identified until yet. The therapeutic applications of cardiac SCs have been studied previously, which could introduce a novel therapeutic approach in the treatment of cardiac disorders. The current review enlightens the potency of cardiac progenitor cells features and differentiation capacity, with current applications in cardiovascular field. PMID- 29118945 TI - The role of cholesterol-enriched diet and paraoxonase 1 inhibition in atherosclerosis progression. AB - Introduction: Atherosclerosis could be deemed as a chronic, progressive, and inflammatory disease. It has been well-documented that high-density lipoprotein (HDL) can reduce the risk of the atherosclerosis occurrence through exerting some anti-atherogenic mechanisms. In recent years, the strong evidence has suggested that paraoxonase 1 (PON1) may contribute to antioxidant properties of HDL. In the present study, the impact of a diet enriched with cholesterol and also the PON1 inhibition on atheroma formation and lipid profile has been investigated. Methods: In this study, 24 New Zealand rabbits were randomly assigned to three groups receiving standard diet, atherogenic diet, and atherogenic diet plus once daily intramuscular injection of nandrolone decanoate as the PON1 inhibitor. Triglyceride, cholesterol, HDL, and low-density lipoprotein (LDL) were determined and both cholesterol accumulation in aorta and fatty streak formation were evaluated. Results: The comparison of the results in three groups reveals that cholesterol level in the group received cholesterol-enriched diet plus once daily injection of PON1 inhibitor was higher than the groups received standard diet or atherogenic diet without PON1 inhibitor (P < 0.05). Furthermore, the percentage of atheroma with type-I lesions was equal to 75% compared with the group received atherogenic diet plus nandrolone at 30%. Additionally, the differences in fatty streak formation in aorta, as well as the right and left coronary arteries in three groups given show that the difference between groups receiving atherogenic diet and standard diet was significantly lower (P < 0.05) than the difference between groups receiving atherogenic diet plus PON1 inhibitor and standard diet. Conclusion: It can be concluded that lack of paraoxanase1 or even reduced the activity of this enzyme could accelerate the progression of fatty streak lesions toward advanced atherosclerotic lesions. PMID- 29118946 TI - Association of birth weight with abdominal obesity and weight disorders in children and adolescents: the weight disorder survey of the CASPIAN-IV Study. AB - Introduction: This study aims to evaluate the association of birth weight (BW) with weight disorders in a national sample of Iranian pediatric population. Methods: This nationwide survey was conducted among 25000 student's aged 6-18 year-old students, who were selected using multistage cluster random sampling from 30 provinces of Iran in 2011-2012. Anthropometric measures were measured under standard protocols by using calibrated instruments. Abdominal obesity was defined based on waist circumference (WC) >=90th percentile value for age and sex. The WHO criterion was used to categorize BMI. Students' BW was asked from parents using validate questionnaire and was categorized as low BW (LBW) (BW <2500 g), normal BW (NBW) (BW: 2500-4000 g) and high BW (HBW) (BW>4000 g). Results: This national survey was conducted among 23043 school students (participation rate: 92.6%). The mean age of participants (50.8% boys) was 12.54 +/- 3.31 years. Results of multivariate logistic regression show that LBW increased odds of underweight (OR [odds ratio]: 1.61; 95% CI: 1.37, 1.89) and students with HBW had decreased odds of underweight (OR: 0.74; 95% CI: 0.58, 0.93) compared to students with NBW. Students with LBW compared to student with NBW had decreased odds of overweight (OR: 0.83; 95% CI: 0.69, 0.98) and general obesity (OR: 0.73; 95% CI: 0.56, 0.95). On the other hand, HBW increased odd of overweight (OR: 1.28; 95% CI: 1.09, 1.50), generalized obesity (OR: 1.59; 95% CI: 1.29, 1.96) and abdominal obesity (OR: 1.29; 95% CI: 1.11, 1.49) compared to NBW group. Conclusion: BW is a determinant of weight disorders and abdominal obesity in childhood and adolescence. This finding underscores the importance of prenatal care as well as close monitoring of the growth pattern of children born with low or high BW. PMID- 29118947 TI - In-Hospital and long term results of primary angioplasty and medical therapy in nonagenarian patients with acute myocardial infarction. AB - Introduction: Although percutaneous coronary intervention is an accepted "first line" therapy in acute ST elevation myocardial infarction (STEMI) in general population, few data are available on the short- and long-term outcomes of very old patients (age >90 years). Our aim is to evaluate and compare the short and long-term outcomes after primary percutaneous coronary intervention (PPCI) or medical therapy in nonagenarian patients with STEMI. Methods: We retrospectively identified patients older than 90 years old in our clinic, with acute STEMI who presented within 12 hours after symptoms onset, either underwent PPCI or medically treated. In hospital events and long-term results analyzed subsequently. Results: From January 2005 to December 2014, 73 patients with STEMI either underwent PPCI (PPCI group n = 42) or had only medical treatment (Non-PPCI group n = 31). Mean age was 92.4 +/- 3.1 (90-106). Patients were followed 26.5 +/ 20.1 months. Recurrent myocardial infarction during hospitalization was not observed in both groups. In-hospital mortality, cerebrovascular events and acute renal failure rate were similar between two groups (respectively P = 0.797 and P = 1.000, P = 0.288), whereas arrhythmia was significantly higher in the PPCI group ( 0; 21.4%, P = 0.009). Results show re-infarction was similar in both groups (respectively 3.2%; 11.9%, P = 0.382) but mortality in long-term was significantly lower in the PPCI group (respectively 40.9%; 12.9%, P = 0.02). Conclusion: In nonagenarian patients, with STEMI mortality is very high. Although; in-hospital events were similar, the long-term mortality rate was significantly lower in patients treated with PPCI. PMID- 29118948 TI - Transcatheter heart valve in valve implantation with Edwards SAPIEN bioprosthetic valve for different degenerated bioprosthetic valve positions (First Iranian ViV report with mid-term follow up). AB - Introduction: After early successful experience with transcatheter aortic valve replacement (TAVR), concept of transcatheter implantation of a new valve within a failing bioprosthetic valve emerged. Valve-in-valve (ViV) implantation seems to be a simpler option for high risk surgical patients. Methods: We performed five ViV procedures in different valve positions. We included patients with failing bioprosthetic valves with high surgical risk due to concomitant comorbidities. We performed 2 transapical ViV procedures for failing mitral bioprosthetic valves, 1 transfemoral procedure for failing pulmonary valve and 2 transfemoral ViV implantation for failing tricuspid bioprosthetic valves. Results: The procedures were successfully completed in all 5 cases with initial excellent fluoroscopic and echocardiographic verification. There was no valve embolization or paravalvular leakage in any of the cases. Transcatheter valve function was appropriate with echocardiography. Post procedural clinical adverse events like pleural effusion and transient ischemic attack were managed successfully. In midterm follow up all cases remained in appropriate functional class except from the transcatheter pulmonary valve which became moderately stenotic and regurgitant. Conclusion: As the first Iranian all-comers case series with midterm follow up for ViV implantation, we had no mortality. Interestingly none of our patients had neurologic sequelae after the procedure. Midterm follow up for our patients was acceptable with good functional class and appropriate echocardiographic findings. Due to high surgical risk of the redo procedure after failing of a bioprosthetic valve especially in elderly patients with comorbidities, ViV implantation would be a good alternative to surgery for this high risk group. PMID- 29118949 TI - Cardiovascular disease events and its predictors in women: Isfahan Cohort Study (ICS). AB - Introduction: As a lack of validated data about cardiovascular (CV) events and its risk factors (RFs) in women of Eastern Mediterranean region, we aimed to evaluate common predictors of CV events among Iranian women. Methods: Isfahan cohort study (ICS) is a prospective cohort that followed 6323 residents (51.3% women, aged 35-75 years) from three counties and their rural districts in central Iran. Common cardiovascular disease (CVD) RFs namely hypertension (HTN), diabetes mellitus, dyslipidemia, abdominal obesity, smoking, low apolipoproteins A ( apo A) and high apolipoprotein B (apo-B) were evaluated. End points (CV events) were defined as fatal and nonfatal myocardial infarction, sudden cardiac death (SCD), unstable angina and stroke. Results: After 9 years of follow-up, 265 CV events were detected. The mean age of women with CV event was 57.6+/-10.9; about 8 years older than those without event. All CV RFs were significantly more prevalent in women with CV event except for low HDL cholesterol, overweight and low apo-A. HTN, diabetes, high triglyceride (TG), high LDL-C and obesity were significantly associated with CV events after adjustment for age, smoking and menopausal status (hazard ratios [95% CI]: 2.56 [1.93, 3.95], 2.43 [1.76, 3.35], 2.02 [1.49, 2.74], 1.59 [1.20, 2.11] and 1.49 [1.16-1.92], respectively), while low HDL cholesterol and abdominal obesity were not predictors for CV events (hazard ratios [95% CI]: 1.26 [0.96, 1.65], 1.71 [0.99, 2.96], respectively). Conclusion: In ICS, HTN, diabetes mellitus and high triglyceride are strong predictors for CV events in Iranian women. As almost all strong risk markers of CVD events are preventable, health policy makers have to give urgent consideration to make preventive public health strategies. PMID- 29118950 TI - Quality of surgical scrub in a heart hospital: Do not take it for granted. AB - Introduction: The role of scrub in the prevention of post-surgery infections is well-known. This study aimed to investigate the inputs and process of surgical scrub in operating rooms of the largest heart hospital of northwest Iran. Methods: This study took place with a before-after design as a clinical audit in 2014. A check list developed based on national and international standards of surgical hand scrub was used as the study instrument. Checklists were completed by observation of surgical team scrubbing in real situation. Descriptive statistics and graphs were used to describe the results. Results: A compliance degree with the standards for prerequisites, equipment, general items, process and time of scrub was observed as 58%, 55%, 33%, 68% and 22%, respectively. The compliance degree after the intervention was 72%, 66%, 66%, 85% and 61%, respectively. Improvement was observed in all studied aspects of scrub. The total score of compliance with the standards changed from 47% to 70%. The main issues were incorrect order of scrubbing the areas of the hands, incorrect way of scrubbing the arms, insufficient scrubbing the arms (not above elbow), and lack of awareness about hospital's policy on scrub time. Conclusion: The results showed defects in the surgical scrub of the studied hospital and that the compliance with the standards can be improved by simple interventions. Periodical audit and observation of the scrub and then feedback is recommended. PMID- 29118951 TI - Association of the rs555172 polymorphism in SENCR long non-coding RNA and atherosclerotic coronary artery disease. AB - Introduction: Variants in long non-coding RNAs (lncRNAs) have been implicated as potential biomarkers in prediction of complex disorders such as coronary artery disease (CAD). Studies considering the impact of the SENCR antisense lncRNAs on CAD have not established yet in Iranian population. This study aimed to investigate the association between SENCR rs555172 polymorphism and CAD in south Iranian population. Methods: Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was performed to determine the allele and the genotype distribution of SENCR lncRNA polymorphism in 150 patients with CAD compared with 149 healthy controls through this hospital-based case-control study. Results: The frequency of AA, AG, and GG genotypes in cases were 32.7%, 44.7%, and 22.6%, and in controls were 26.8%, 49%, and 24.2%, respectively. Association was not found with any of the genotypes in comparison of cases and controls. The allelic frequencies did not differ between cases and controls. Cross-tabulating the population based on the gender, the frequency of the GG genotype was significantly higher among women of the case group compared to men. The difference was not seen in the control group between two sexes. Conclusion: The results suggested that the SENCR gene polymorphism did not confer susceptibility to CAD. PMID- 29118952 TI - 24-Hour survival after cardiopulmonary resuscitation is reduced in patients with diabetes mellitus. AB - Introduction: Diabetes mellitus is a risk factor for cardiovascular disease. Some recent studies have shown an association between diabetes and out-of-hospital cardiac arrest incidence and survival. We aimed to investigate whether there is an association between the presence of diabetes mellitus and survival after cardiopulmonary resuscitation (CPR) in patients with an in-hospital cardiac arrest. Methods: A cross-sectional study was conducted during the period of January to February 2014, among 80 cases of cardiopulmonary arrest in patients at Qaem hospital of Mashhad, Iran. A code 99 was announced after a cardiac arrest was identified, and CPR was performed by the cardiac arrest team. Twenty four hour survival was compared in diabetic and non-diabetic patients who had a return to spontaneous circulation after CPR. We used SPSS statistics for Windows version 16 for data analysis. Results: The return to spontaneous circulation in the diabetic group was not significantly lower than for the non-diabetic group (42.9% versus 61.0% [P = 0.15]). However, the 24-hour survival in the diabetic group was significantly lower than for the non-diabetic group (19.0% versus 44.1% [P = 0.04]). Conclusion: The presence of diabetes mellitus is associated with a significantly lower rate of survival after CPR. PMID- 29118953 TI - The role of preoperative sildenafil therapy in controlling of postoperative pulmonary hypertension in children with ventricular septal defects. AB - Introduction: Most of the ventricular septal defects (VSD) are complicated with pulmonary arterial hypertension (PAH) which is the major cause of pulmonary hypertensive crisis and right ventricular failure. Methods: We reviewed clinical outcomes of 63 infants who underwent cardiac surgery and were divided into three groups. Control group (n=20) did not received sildenafil while group A (n = 22) received drug (0.3 mg/kg) before and after surgery. Group B (n=21) received drug at the initiation of surgery. Demographic data, preoperative and postoperative variables were compared among the patients. Results: Patients in the group A had lower preoperative pulmonary arterial pressure (PAP) compared to other groups (P < 0.001). Also, patients in control group had longer cardiopulmonary bypass time (P < 0.05). Postoperative PAP in patients of group A and B decreased significantly compared to control group (P < 0.001). Also, pre- and postoperative PVR (pulmonary vascular resistance) showed a significant decrease in group A compared with control and group B (P < 0.001). The intubation time in patients of the control group was significantly more prolonged compared with patients of group A and B (P < 0.001). Moreover, the length of ICU stay was significantly longer in patients of control group compared with group A and B (P < 0.001). Conclusion: Preoperative sildenafil therapy seems to be effective and safe to prevent postoperative PAH and pulmonary hypertensive crisis in children with ventricular septal defects and has a positive impact on postoperative care. PMID- 29118954 TI - Measuring system and method of determining the Adaptive Force. AB - The term Adaptive Force (AF) describes the capability of adaptation of the nerve muscle-system to externally applied forces during isometric and eccentric muscle action. This ability plays an important role in real life motions as well as in sports. The focus of this paper is on the specific measurement method of this neuromuscular action, which can be seen as innovative. A measuring system based on the use of compressed air was constructed and evaluated for this neuromuscular function. It depends on the physical conditions of the subject, at which force level it deviates from the quasi isometric position and merges into eccentric muscle action. The device enables - in contrast to the isokinetic systems - a measure of strength without forced motion. Evaluation of the scientific quality criteria of the devices was done by measurements regarding the intra- and interrater-, the test-retest-reliability and fatiguing measurements. Comparisons of the pneumatic device with a dynamometer were also done. Looking at the mechanical evaluation, the results show a high level of consistency (r2=0.94 to 0.96). The parallel test reliability delivers a very high and significant correlation (rho=0.976; p=0.000). Including the biological system, the concordance of three different raters is very high (p=0.001, Cronbachs alpha alpha=0.987). The test retest with 4 subjects over five weeks speaks for the reliability of the device in showing no statistically significant differences. These evaluations indicate that the scientific evaluation criteria are fulfilled. The specific feature of this system is that an isometric position can be maintained while the externally impacting force rises. Moreover, the device can capture concentric, static and eccentric strength values. Fields of application are performance diagnostics in sports and medicine. PMID- 29118956 TI - The Vienna FES Interview Protocol - A mixed-methods protocol to elucidate the opinions of various individuals responsible for the provision of FES exercise. AB - Functional Electrical Stimulation (FES) is the production of electrically elicited muscle contractions to perform a function or task. It has been used as a method to regain lost body functions or support weak body functions, and as such, has been clinically available since the early seventies. Some methods are applied routinely while others have not been translated to the bedside, or are still largely restricted to laboratory use. Progress in this field might be achieved by a strong cooperation of patients, clinicians, therapists and engineers. A better insight into multiple perspectives may help in understanding the shortcomings of current FES technology. This will help direct future research efforts into design of systems and potential application in relevant populations. In addition, these findings can assist with the translation of FES technology into a community context. We outline an interview protocol designed for use at the 12th Vienna International Workshop on Functional Electrical Stimulation where the mentioned experts from the field of FES met. PMID- 29118955 TI - Effect of electrical stimulation on motor nerve regeneration in sciatic nerve ligated-mice. AB - The purpose of this study was to investigate the effect of electrical stimulation on sciatic nerve regeneration and functional recovery of target muscles. Mice were randomly divided into 3 groups: ligated without electrical stimulation, ligated with electrical stimulation and control (non-ligated). The unilateral peripheral mononeuropathy was produced on the right hind limb. Sciatic nerve was then electrically stimulated daily for a period of 2 weeks (duration: 0.2 msec, frequency: 100Hz, amplitude: 15mA). Evoked surface EMG was recorded from biceps femoris (BF) and gluteus maximus (GM) muscles on the 3rd, 7th, 10th and 14th day after sciatic nerve ligation. Muscle force and sensitivity was determined by processing of the recorded EMG signals in time and frequency domains respectively. The results showed electrical stimulation (ES) produced a significant increase in the EMG response of BF, and muscle force significantly increased on the 14th day (p<0.001), however no significant difference was found in GM muscle force between experimental groups. This may be due to possible innervation by inferior gluteal nerve. Frequency analysis of BF signals indicates that hyperalgesia remained after 14 days in both ligated groups. On the 14th day no difference in GM muscle sensitivity was found between groups. In conclusion, the results of this study have shown that the electrical stimulation of sciatic nerve accelerates nerve repair and indirectly improves BF muscle force to a comparable level with control without effect on muscle sensitivity. However, ES had no effect on GM muscle force and sensitivity. PMID- 29118957 TI - Morphological peculiarities of neuromuscular junctions among different fiber types: Effect of exercise. AB - The aim of our research was to examine whether there are differences in the morphology of neuromuscular junctions of different types of muscle fibers in rodents, and after their adaptation to six weeks endurance exercise training. After 5-day acclimation, Wistar rats were subjected to run with the speed 35 m/min during 6 week, 5 days per week and the training volume reached 60 min per day. Muscle samples for ultrastructural studies were fixed, dehydrated and embedded in Epon-812. Ultra-thin sections were cut from longitudinally and transversely oriented blocs, using 4 blocks from each animal. The area of axon terminals on fast- twitch fibers is 1.5 time large (p<0.001) and the perimeter of terminals is 1.7 time large in comparison with slow- twitch oxidative fibers (p<0.001) in control group. There are correlation between cross-sectional area of different muscle fibers and length of axon terminals (r=0.72), between cross sectional area and with of axon terminal (r=-0.62), and between turnover rate of contractile proteins and length of axon terminal (r=0.75). Fast remodeling of synapse on oxidative and oxidative-glycolytic muscle fibers during endurance training seems to guarantees the intensive renewal of the structures of muscle fibers with higher oxidative capacity. PMID- 29118958 TI - Treatment of chronic pain associated with bruxism through Myofunctional therapy. AB - Temporomandibular disorders such as bruxism may cause painful clinical conditions and over time lead to chronic facial pain. A combination of therapeutic strategies that are usually undertaken by dentists and gnathologists to reduce bruxism episodes and consequently pain, are myofunctional therapy, pharmacological treatment, intraoral interventions and behavioural treatments. The aim of this work was to understand if myofuntional therapy alone can be a useful therapy for the reduction of chronic facial pain. 24 patients, 9 male and 15 female, age ranging between 25 and 45, were treated with a myofunctional therapy for 9 month. Each patient was evaluated through a numeric pain intensity scale ranging from 0 to 10 and the number of bruxism episodes/hour per patient were also recorded; electromyographic examinations of the temporal, masseter, sternocleidomastoid and digastric muscles were performed to evaluate muscle activation. Each patient was tested before (T0) and after (T1) the treatment period. Pain intensity decreased from T0 to T1 (8.13+/-0.39 vs. 1.75+/-2.43, respectively, p<0.01). The number of bruxism episodes also significatively decreased between T0 and T1 (24 vs. 9, p<0.01). Electromyographic assessment showed a decrease in the tonic activity of the masseter muscle (T0: 1.88+/-0.31 vs. T1: 1.4+/-0.25 MUV; p<0.05) and a reduction of the electric activity of the temporal and digastric muscles during serration of the mandible (T0: 167.9+/-19.6 MUV Vs T1: 144.6+16.43 MUV; p<0.05 and T0: 58.97+8.38 MUV Vs T1: 52.79+7.44 MUV; p<0.05, respectively). Myofunctional therapy could be used to reduce facial pain as a consequence of bruxism episodes. PMID- 29118959 TI - Congenital Myasthenic Syndrome due to DOK7 mutations in a family from Chile. AB - : Congenital myasthenic syndromes (CMS) are neuromuscular transmission disorders caused by mutations in genes encoding neuromuscular junction proteins. A 61-year old female and her older sister showed bilateral ptosis, facial and proximal limb weakness, and scoliosis since childhood. Another female sibling had milder signs, while other family members were asymptomatic. Facial nerve repetitive stimulation in the proband showed decrement of muscle responses. Single fiber EMG revealed increased jitter and blocking. Muscle biopsy showed type 2-fiber atrophy, without tubular aggregates. Mutational analysis in the three affected siblings revealed two compound heterozygous mutations in DOK7: c.1457delC, that predicts p.Pro486Argfs*13 and truncates the protein C-terminal domain, and c.473G>A, that predicts p.Arg158Gln and disruption of the dok7-MuSK interaction in the phosphotyrosine binding (PTB) domain. Unaffected family members carried only one or neither mutation. Discussion: Two of the affected sisters showed marked improvement with salbutamol treatment, which illustrates the benefits of a correct diagnosis and treatment of DOK7-CMS. PMID- 29118960 TI - From the Padua Muscle Days, the Basic and Applied Myology and the European Journal of Translational Myology to the A&CM Carraro Foundation for Translational Myology. AB - As a young researched I had the option to work on skeletal muscle at the University of Padova, Italy. Introduced to the study of muscle denervation/reinnervation, I started a project on long term denervated muscle that still is my primary interest and took me from rodents' models of chronic muscle denervation to human spinal cord injury-related muscle denervation and its managements. On the way, I organized a series of conferences in Euganei Hills, Padua, Italy and an international journal, the Basic and Applied Myology. From 2010 this journal changed name to European Journal of Translational Myology, whose contents are focused on Myology, though they have important implications in aging, several neurological disorders and cancer cachexia. A relatively large community of Basic Biologists, Clinicians and Biomedical Technologists (usually meeting separately in very different specialty Conferences) recognized the need of a Meeting Series focused on Translational Myology. Thus the Padua Muscle Days (PMD) started more than 25 years ago. The next events of the PMD Series will be in Autumn 2017 an one-day Seminar on Easy Aging and a three-day event: The 2017 Fall Padua Experts' Meeting. During the 2018Spring PMD, the Giovanni Salviati Memorial will be organized to honor a beloved friend and excellent scientist, who abruptly disappeared twenty years ago at the peak of his research activities. Many friends and still-active pupils accepted invitation and will provide the backbone of the Program of the 2018Spring PaduaMuscleDay to be held, March 14-16, 2018 in Euganei Hills and Padua (Italy). All these events will be sponsored by the Interdepartmental Research Centre of Myology of the University of Padova and by the A&CM Carraro Foundation for Translational Myology. PMID- 29118962 TI - Epileptic MEG Spike Detection Using Statistical Features and Genetic Programming with KNN. AB - Epilepsy is a neurological disorder that affects millions of people worldwide. Monitoring the brain activities and identifying the seizure source which starts with spike detection are important steps for epilepsy treatment. Magnetoencephalography (MEG) is an emerging epileptic diagnostic tool with high density sensors; this makes manual analysis a challenging task due to the vast amount of MEG data. This paper explores the use of eight statistical features and genetic programing (GP) with the K-nearest neighbor (KNN) for interictal spike detection. The proposed method is comprised of three stages: preprocessing, genetic programming-based feature generation, and classification. The effectiveness of the proposed approach has been evaluated using real MEG data obtained from 28 epileptic patients. It has achieved a 91.75% average sensitivity and 92.99% average specificity. PMID- 29118963 TI - Leveraging Multiactions to Improve Medical Personalized Ranking for Collaborative Filtering. AB - Nowadays, providing high-quality recommendation services to users is an essential component in web applications, including shopping, making friends, and healthcare. This can be regarded either as a problem of estimating users' preference by exploiting explicit feedbacks (numerical ratings), or as a problem of collaborative ranking with implicit feedback (e.g., purchases, views, and clicks). Previous works for solving this issue include pointwise regression methods and pairwise ranking methods. The emerging healthcare websites and online medical databases impose a new challenge for medical service recommendation. In this paper, we develop a model, MBPR (Medical Bayesian Personalized Ranking over multiple users' actions), based on the simple observation that users tend to assign higher ranks to some kind of healthcare services that are meanwhile preferred in users' other actions. Experimental results on the real-world datasets demonstrate that MBPR achieves more accurate recommendations than several state-of-the-art methods and shows its generality and scalability via experiments on the datasets from one mobile shopping app. PMID- 29118964 TI - Development of a Blood Pressure Measurement Instrument with Active Cuff Pressure Control Schemes. AB - This paper presents an oscillometric blood pressure (BP) measurement approach based on the active control schemes of cuff pressure. Compared with conventional electronic BP instruments, the novelty of the proposed BP measurement approach is to utilize a variable volume chamber which actively and stably alters the cuff pressure during inflating or deflating cycles. The variable volume chamber is operated with a closed-loop pressure control scheme, and it is activated by controlling the piston position of a single-acting cylinder driven by a screw motor. Therefore, the variable volume chamber could significantly eliminate the air turbulence disturbance during the air injection stage when compared to an air pump mechanism. Furthermore, the proposed active BP measurement approach is capable of measuring BP characteristics, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), during the inflating cycle. Two modes of air injection measurement (AIM) and accurate dual-way measurement (ADM) were proposed. According to the healthy subject experiment results, AIM reduced 34.21% and ADM reduced 15.78% of the measurement time when compared to a commercial BP monitor. Furthermore, the ADM performed much consistently (i.e., less standard deviation) in the measurements when compared to a commercial BP monitor. PMID- 29118965 TI - Digital Path Approach Despeckle Filter for Ultrasound Imaging and Video. AB - We propose a novel filtering technique capable of reducing the multiplicative noise in ultrasound images that is an extension of the denoising algorithms based on the concept of digital paths. In this approach, the filter weights are calculated taking into account the similarity between pixel intensities that belongs to the local neighborhood of the processed pixel, which is called a path. The output of the filter is estimated as the weighted average of pixels connected by the paths. The way of creating paths is pivotal and determines the effectiveness and computational complexity of the proposed filtering design. Such procedure can be effective for different types of noise but fail in the presence of multiplicative noise. To increase the filtering efficiency for this type of disturbances, we introduce some improvements of the basic concept and new classes of similarity functions and finally extend our techniques to a spatiotemporal domain. The experimental results prove that the proposed algorithm provides the comparable results with the state-of-the-art techniques for multiplicative noise removal in ultrasound images and it can be applied for real-time image enhancement of video streams. PMID- 29118966 TI - Gaussian Elimination-Based Novel Canonical Correlation Analysis Method for EEG Motion Artifact Removal. AB - The motion generated at the capturing time of electro-encephalography (EEG) signal leads to the artifacts, which may reduce the quality of obtained information. Existing artifact removal methods use canonical correlation analysis (CCA) for removing artifacts along with ensemble empirical mode decomposition (EEMD) and wavelet transform (WT). A new approach is proposed to further analyse and improve the filtering performance and reduce the filter computation time under highly noisy environment. This new approach of CCA is based on Gaussian elimination method which is used for calculating the correlation coefficients using backslash operation and is designed for EEG signal motion artifact removal. Gaussian elimination is used for solving linear equation to calculate Eigen values which reduces the computation cost of the CCA method. This novel proposed method is tested against currently available artifact removal techniques using EEMD-CCA and wavelet transform. The performance is tested on synthetic and real EEG signal data. The proposed artifact removal technique is evaluated using efficiency matrices such as del signal to noise ratio (DSNR), lambda (lambda), root mean square error (RMSE), elapsed time, and ROC parameters. The results indicate suitablity of the proposed algorithm for use as a supplement to algorithms currently in use. PMID- 29118967 TI - Cold-perfusion decellularization of whole-organ porcine pancreas supports human fetal pancreatic cell attachment and expression of endocrine and exocrine markers. AB - Despite progress in the field of decellularization and recellularization, the outcome for pancreas has not been adequate. This might be due to the challenging dual nature of pancreas with both endocrine and exocrine tissues. We aimed to develop a novel and efficient cold-perfusion method for decellularization of porcine pancreas and recellularize acellular scaffolds with human fetal pancreatic stem cells. Decellularization of whole porcine pancreas at 4 degrees C with sodium deoxycholate, Triton X-100 and DNase efficiently removed cellular material, while preserving the extracellular matrix structure. Furthermore, recellularization of acellular pieces with human fetal pancreatic stem cells for 14 days showed attached and proliferating cells. Both endocrine (C-peptide and PDX1) and exocrine (glucagon and alpha-amylase) markers were expressed in recellularized tissues. Thus, cold-perfusion can successfully decellularize porcine pancreas, which when recellularized with human fetal pancreatic stem cells shows relevant endocrine and exocrine phenotypes. Decellularized pancreas is a promising biomaterial and might translate to clinical relevance for treatment of diabetes. PMID- 29118968 TI - Combination of EZH2 inhibitor and BET inhibitor for treatment of diffuse intrinsic pontine glioma. AB - Background: Diffuse intrinsic pontine glioma is an infiltrative, often high-grade glioma of the brainstem that is not amenable to surgical resection. The current treatment of DIPG by radiation therapy showed dramatically improvement of patient's condition, however, the tumor recurs rapidly. More and more studies are focused on the genetic and epigenetic drivers of DIPGs, which may provide more and more novel therapy target for DIPG. EZH2 has been proved to be a potential therapeutic target for H3K27M-mutant pediatric gliomas recently. Meanwhile, BET family protein is a hot target in many different types of cancers, including DIPG. In this study, we performed the treatment of both EZH2 and BET inhibitor for DIPG cells. Results: The combination of these two inhibitors exhibited better inhibition of the tumor growth both in vitro and in vivo compared to use the inhibitor individually. This inhibition was performed by blocking the proliferation and promoting the cell apoptosis. Meanwhile, combination treatment of these two inhibitors would also affect the epigenetic markers which were abnormal in the tumors of the certain set of genes. Conclusion: Thus we provided a novel therapy strategy for clinical treatment of DIPG. PMID- 29118969 TI - Differential regulation of IFNalpha, IFNbeta and IFNepsilon gene expression in human cervical epithelial cells. AB - Interferonepsilon (IFNepsilon) is a unique type I IFN that has distinct functions from IFNalpha/beta. IFNepsilon is constitutively expressed at mucosal tissues, including the female genital mucosa, and is reported to be modulated by estrogen and seminal plasma. However, its regulation by cytokines, including TNFalpha, IL 1beta, IL-6, IL-8, IL-17, IL-22 and IFNalpha, which are commonly present in the female genital mucosa, is not well documented in freshly isolated primary cervical cells from tissues. We determined the effect of these cytokines on gene expression of type I IFNs in an immortalized endocervical epithelial cell line (A2EN) and in primary cervical epithelial cells. Several pro-inflammatory cytokines were found to induce IFNepsilon, and TNFalpha induced the strongest response in both cell types. Pretreatment of cells with the IkappaB inhibitor, which blocks the NF-kappaB pathway, suppressed TNFalpha-mediated IFNepsilon gene induction and promoter activation. Expression of IFNalpha, IFNbeta, and IFNepsilon was differentially regulated in response to various cytokines. Taken together, our results show that regulation of these IFNs depends on cell type, cytokine concentration, and incubation time, highlighting the complexity of the cytokine network in the cervical epithelium. PMID- 29118971 TI - Local allergic rhinitis: evolution of concepts. AB - The discovery of an exclusive local production of IgE antibodies dates back to the 1970s, but only recently the pathophysiology of such phenomenon was deeply investigated, leading to the concept of local allergic rhinitis (LAR). Currently, LAR is defined by the occurrence, in patients with symptoms clearly suggesting allergic rhinitis but with negative results to common allergy testing, of allergen specific IgE in the nasal mucosa. Most studies investigating LAR were based on the development of rhinitis symptoms following nasal provocation test (NPT) with the suspected allergens, but such test may be performed by a number of options, none of them being as yet acknowledged and recommended in consensus document. On the other hand, also the mere detection of IgE in the nasal mucosa indicates, as for IgE measurement in blood or other tissues, allergic sensitization but cannot give the certainty of clinical allergy. Therefore, the combination of IgE detection in nasal mucosa and a positive result of NPT should be used to diagnose LAR. Recent data on the use for in vitro testing of molecular allergy diagnostics in place of whole allergen extracts suggest that this method could improve the sensitivity and specificity of laboratory tests, and an appraisal of the basophil activation test as a third level technique, to be implemented when the results of local IgE testing and NPT are uncertain, is currently ongoing. PMID- 29118970 TI - 14-3-3zeta loss leads to neonatal lethality by microRNA-126 downregulation mediated developmental defects in lung vasculature. AB - Background: The 14-3-3 family of proteins have been reported to play an important role in development in various mouse models, but the context specific developmental functions of 14-3-3zeta remain to be determined. In this study, we identified a context specific developmental function of 14-3-3zeta. Results: Targeted deletion of 14-3-3zeta in the C57Bl/6J murine genetic background led to neonatal lethality due to respiratory distress and could be rescued by out breeding to the CD-1 or backcrossing to the FVB/NJ congenic background. Histological analysis of lung sections from 18.5 days post coitum embryos (dpc) showed that 14-3-3zeta-/- lung development is arrested at the pseudoglandular stage and exhibits vascular defects. The expression of miR-126, an endothelial specific miRNA known to regulate lung vascular integrity was down-regulated in the lungs of the 14-3-3zeta-/- embryos in the C57Bl/6J background as compared to their wild-type counterparts. Loss of 14-3-3zeta in endothelial cells inhibited the angiogenic capability of the endothelial cells as determined by both trans well migration assays and tube formation assays and these defects could be rescued by re-expressing miR-126. Mechanistically, loss of 14-3-3zeta led to reduced Erk1/2 phosphorylation resulting in attenuated binding of the transcription factor Ets2 on the miR-126 promoter which ultimately reduced expression of miR-126. Conclusion: Our data demonstrates that miR-126 is an important angiogenesis regulator that functions downstream of 14-3-3zeta and downregulation of miR-126 plays a critical role in 14-3-3zeta-loss induced defects in lung vasculature in the C57Bl/6J genetic background. PMID- 29118972 TI - What is chiropractic? AB - While in some jurisdictions chiropractic is fully integrated in public and insurance funded health care systems, in others it is outside and considered as complementary or alternative health care. There is a paucity of data and rigorous scientific studies regarding most aspects of chiropractic practice although research activity has been increasing in recent years. We call for papers for a thematic series in Chiropractic and Manual Therapies that can help define chiropractic better to stakeholders inside and outside the profession under the theme What is Chiropractic? PMID- 29118973 TI - The 2017 Bioinformatics Open Source Conference (BOSC). AB - The Bioinformatics Open Source Conference (BOSC) is a meeting organized by the Open Bioinformatics Foundation (OBF), a non-profit group dedicated to promoting the practice and philosophy of Open Source software development and Open Science within the biological research community. The 18th annual BOSC ( http://www.open bio.org/wiki/BOSC_2017) took place in Prague, Czech Republic in July 2017. The conference brought together nearly 250 bioinformatics researchers, developers and users of open source software to interact and share ideas about standards, bioinformatics software development, open and reproducible science, and this year's theme, open data. As in previous years, the conference was preceded by a two-day collaborative coding event open to the bioinformatics community, called the OBF Codefest. PMID- 29093809 TI - Gender differences in the prevalence of nonalcoholic fatty liver disease in the Northeast of Thailand: A population-based cross-sectional study. AB - Background. Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. A large number of studies have strongly described larger proportions of men being afflicted with NAFLD than women; however, recent studies investigating the role of gender and NAFLD have exposed the contrary. Methods. This cross-sectional study utilized data from the baseline survey of an ongoing cohort study called the Cholangiocarcinoma Screening and Care Program (CASCAP), conducted in the northeastern region of Thailand between March 2013 and September 2015. Information regarding socio-demographic, including gender, was collected using a standardized self-administered questionnaire. NAFLD was diagnosed with ultrasonography by board-certified radiologists. A binomial regression was used for estimating the prevalence differences, odds ratios (OR) and the 95% confidence intervals (CI) of NAFLD between men and women. Results. A total of 34,709 participants (27,073 females and 7,636 males) were recruited. The prevalence of NAFLD in women was 22.9% (95% CI: 22.5 to 23.5), whereas it was only 18.3% (95% CI: 17.4 to 19.2) in men. After adjusting for age and presence of diabetes mellitus and other underlying diseases, the prevalence was significantly higher in women, with adjusted prevalence difference of 4.2% (95% CI: 3.2 to 5.2) and adjusted OR of 1.3 (95% CI: 1.2 to 1.4). Women had a higher prevalence of NAFLD than men in all age groups and the largest difference was found in those aged 56-60 years (prevalence = 27.4% versus 21.2%; adjusted prevalence difference = 9.4%; 95% CI: 7.9 to 10.9; adjusted OR = 1.8; 95% CI: 1.8 to 2.0). Conclusion. NAFLD is more likely to affect women more than men, in particular, among the population 56-60 years of age, which is the post-menopausal transitional period. Therefore, post-menopausal women should be the target for interventions or further investigation for NAFLD. PMID- 29118975 TI - Interfacial microscopic examination and chemical analysis of resin-dentin interface of self-adhering flowable resin composite. AB - Background: The newly introduced self-adhering flowable resin-composites decrease the required time for application by incorporation of an acidic adhesive monomer, thus reducing the number of the steps, but its bonding is still uncertain. The aim of this study was to evaluate the interfacial microscopic examination and chemical analysis at the resin-dentin interface of a self-adhering flowable resin composite (Vertise-Flow) versus a total-etch (Te-Econom Plus) resin composite, using an etching agent (Eco-Etch gel) and bonding agent (Single Bond Universal). Methods: Sixteen freshly extracted sound human posterior teeth were used. The teeth were randomly divided into two groups: 8 specimens per type of composite. Standard-shaped class V cavities were prepared on the buccal surface. One group was restored by Te-Econom Plus resin composite by total-etch technique using Eco Etch gel, which was applied to dentine for 15 seconds, followed by rinsing, drying and bonding agent application (Single Bond Universal). The other group restored directly with self-adhering resin composite (Vertise-Flow) without application of etch or bond. Curing was done for 20 seconds using a light emitting diode light curing unit. Evaluation of the resin-dentin interface was done microscopically by examination of marginal gap distance in MUm using scanning electron microscope (SEM), and chemical analysis of silver particles was observed using SEM with energy-dispersive X-ray spectrometry after 24 hours of specimen storage in ammoniacal silver nitrate. Results: Regarding marginal gap distance (um) and silver atomic % mean values, teeth restored with self-adhering resin composite (Vertise-Flow) showed significantly higher mean values than the multi-step etch and rinse resin composite group (5.2 vs 0; 12.2 vs 8.2, respectively). Conclusions: Resin-dentin bonding using total-etch resin composite technique was more effective than self-adhering flowable resin composite (Vertise Flow) regarding marginal gap formation and penetration of silver particles. Further studies for bond strength could be performed. PMID- 29118976 TI - Impact of hormonal modulation at proestrus on ovarian responses and uterine gene expression of suckled anestrous beef cows. AB - Background: This study evaluated the impact of hormonal modulation at the onset of proestrus on ovarian response and uterine gene expression of beef cows. Methods: A total of 172 anestrous beef cows were assigned to one of four groups according to the treatment with estradiol cypionate (ECP) and/or equine chorionic gonadotropin (eCG) [CON (n = 43), ECP (n = 43), eCG (n = 44) and ECP + eCG (n = 42)]. Results: ECP-treated cows (ECP and ECP + eCG groups) presented greater occurrence of estrus (44.6% vs. 65.4%; P = 0.01) and pregnancy per AI [47.1% vs. 33.3%; P = 0.07], but similar progesterone (P4) concentration at subsequent diestrus than cows not treated with ECP (CON and eCG groups). Nonetheless, eCG treated cows (eCG and ECP + eCG groups) presented larger follicle at timed AI (12.6 +/- 0.3 vs. 13.5 +/- 0.3 mm; P = 0.03), greater ovulation rate (96.5% vs. 82.6%; P = 0.008) and greater P4 concentration at d 6 (3.9 +/- 0.2 vs. 4.8 +/- 0.2 ng/mL; P = 0.001) than cows not treated with eCG (CON and ECP groups). Next, cows with a new corpus luteum 6 d after TAI were submitted to uterine biopsy procedure. Uterine fragments [CON (n = 6), ECP (n = 6)] were analyzed by RNA-Seq and a total of 135 transcripts were differentially expressed between groups (73 genes up-regulated by ECP treatment). Subsequently, uterine samples were analyzed by qPCR (genes associated with cell proliferation). ECP treatment induced greater abundance of PTCH2 (P = 0.07) and COL4A1 (P = 0.02), whereas suppressed EGFR (P = 0.09) expression. Conversely, eCG treatment increased abundance of HB-EGF (P = 0.06), ESR2 (P = 0.09), and ITGB3 (P = 0.05), whereas it reduced transcription of ESR1 (P = 0.05). Collectively, supplementation with ECP or eCG at the onset of proestrous of anestrous beef cows influenced ovarian responses, global and specific endometrial gene expression. Conclusion: Proestrus estradiol regulate the endometrial transcriptome, particularly stimulating proliferative activity in the endometrium. PMID- 29118977 TI - Mycotoxin binder improves growth rate in piglets associated with reduction of toll-like receptor-4 and increase of tight junction protein gene expression in gut mucosa. AB - Background: Deoxynivalenol (DON) is a mycotoxin produced by Fusarium species in the field, commonly found in cereal grains, which negatively affects performances and health of animals. Mycotoxin binders are supposed to reduce the toxicity of mycotoxins. Method: The effect of a mycotoxin binder (containing acid-activated bentonite, clinoptilolite, yeast cell walls and organic acids) on growth performance and gut health was studied. Hundred and twenty weaning piglets were allocated to 4 treatments, with 5 pens of 6 piglets each, arranged in a 2 * 2 factorial design: control diet; control diet with 1 kg/t binder; control diet with DON; and control diet with DON and 1 kg/t binder. From d0-14, the diet of DON-challenged groups was artificially contaminated with a mixture of DON (2.6 mg/kg), 3-acetyl-deoxynivalenol (0.1 mg/kg) and 15-acetyl-deoxynivalenol (0.3 mg/kg), after which the total contamination level was reduced to 1 mg/kg, until d37. On d14, one pig from each pen was euthanized and distal small intestinal mucosa samples were collected for the assessment of intestinal permeability, and gene expression of tight junction proteins, toll-like receptor 4, inflammatory cytokines and intestinal alkaline phosphatase. Results: After 37 d, there were no differences in growth performance between control and DON-challenged groups (P > 0.05). Nevertheless, groups that received diets with binder had a significantly higher average daily gain (ADG) and average daily feed intake (ADFI) for the first 14 d as well as for the whole period, compared to groups without binder (P <= 0.05). Groups with binder in the diet also exhibited lower expression of toll like receptor 4 in distal small intestinal mucosa at d14, compared to groups without binder (P <= 0.05). Interestingly, comparing the two DON treatments, piglets fed DON and binder had significantly higher ADFI and ADG compared to those with only DON for the first 14-d (P <= 0.05). Addition of binder to DON contaminated diets, also down-regulated the gene expression of toll-like receptor 4 (P <= 0.05) and increased mRNA level zona occludens 1 (P <= 0.10) as compared to DON. Conclusions: The present data provide evidence that the binder improves growth rate in piglets associated with reduction of toll-like receptor-4 and increase of tight junction protein gene expression. However, the current study does not allow to assess whether the effects of the binder are mediated by alterations in the toxicokinetics of the mycotoxin. PMID- 29118978 TI - Systematic analysis of feeding behaviors and their effects on feed efficiency in Pekin ducks. AB - Background: Feeding behavior study is important for animal husbandry and production. However, few studies were conducted on the feeding behavior and their relationship with feeding efficiency in Pekin ducks. In order to investigate the feeding behavior and their relationship with feed efficiency and other economic traits in Pekin ducks, we selected 358 male Pekin ducks and recorded feeding information between 3 to 6 wk of age using automatic electronic feeders, and compared the feeding behavior under different residual feed intake (RFI) levels. Results: We observed that total feed time, daily feed intake and feed intake per meal had strong positive correlations with feed efficiency traits; moreover, strong correlation between feed intake per meal and body weight was found (R=0.32, 0.36). Daily feeding rate meal and meal duration had weak correlations with feed efficiency (R=0.14~0.15). The phenotypic correlation of between-meal pauses, with feed efficiency was not observed. When daily changes were analyzed, high RFI ducks had the highest feed consumption over all times, and obvious differences in daily visits were found among different RFI level animals during the middle period; these differences were magnified with age, but there was no difference in daily meal number. Moreover, our data indicate that high RFI birds mainly take their meals at the edge of the population enclosure, where they are more susceptible to environmental interference. Conclusions: Overall, this study suggests that the general feeding behaviors can be accurately measured using automatic electronic feeders and certain feeding behaviors in Pekin ducks are associated with improved feed efficiency. PMID- 29118979 TI - The effects of starter microbiota and the early life feeding of medium chain triglycerides on the gastric transcriptome profile of 2- or 3-week-old cesarean delivered piglets. AB - Background: The stomach is an underestimated key interface between the ingesta and the digestive system, affecting the digestion and playing an important role in several endocrine functions. The quality of starter microbiota and the early life feeding of medium chain triglycerides may affect porcine gastric maturation. Two trials (T1, T2) were carried out on 12 and 24 cesarean-delivered piglets (birth, d0), divided over two microbiota treatments, but slaughtered and sampled at two or three weeks of age, respectively. All piglets were fed orally: sow serum (T1) or pasteurized sow colostrum (T2) on d0; simple starter microbiota (Lactobacillus amylovorus, Clostridium glycolicum and Parabacteroides spp.) (d1 d3); complex microbiota inoculum (sow diluted feces, CA) or a placebo (simple association, SA) (d3-d4) and milk replacer ad libitum (d0-d4). The The T1 piglets and half of the T2 piglets were then fed a moist diet (CTRL); the remaining half of the T2 piglets were fed the CTRL diet fortified with medium chain triglycerides and 7% coconut oil (MCT). Total mRNA from the oxyntic mucosa was analyzed using Affymetrix(c)Porcine Gene array strips. Exploratory functional analysis of the resulting values was carried out using Gene Set Enrichment Analysis. Results: Complex microbiota upregulated 11 gene sets in piglets of each age group vs. SA. Of these sets, 6 were upregulated at both ages, including the set of gene markers of oxyntic mucosa. In comparison with the piglets receiving SA, the CA enriched the genes in the sets related to interferon response when the CTRL diet was given while the same sets were impoverished by CA with the MCT diet. Conclusions: Early colonization with a complex starter microbiota promoted the functional maturation of the oxyntic mucosa in an age-dependent manner. The dietary fatty acid source may have affected the recruitment and the maturation of the immune cells, particularly when the piglets were early associated with a simplified starter microbiota. PMID- 29118981 TI - Zika virus disease, microcephaly and Guillain-Barre syndrome in Colombia: epidemiological situation during 21 months of the Zika virus outbreak, 2015-2017. AB - Background: The Zika virus disease (ZVD) has had a huge impact on public health in Colombia for the numbers of people affected and the presentation of Guillain Barre syndrome (GBS) and microcephaly cases associated to ZVD. Methods: A retrospective descriptive study was carried out, we analyze the epidemiological situation of ZVD and its association with microcephaly and GBS during a 21-month period, from October 2015 to June 2017. The variables studied were: (i) ZVD cases, (ii) ZVD cases in pregnant women, (iii) laboratory-confirmed ZVD in pregnant women, (iv) ZVD cases associated with microcephaly, (v) laboratory confirmed ZVD associated with microcephaly, and (vi) ZVD associated to GBS cases. Average number of cases, attack rates (AR) and proportions were also calculated. The studied variables were plotted by epidemiological weeks and months. The distribution of ZVD cases in Colombia was mapped across the time using Kernel density estimator and QGIS software; we adopted Kernel Ridge Regression (KRR) and the Gaussian Kernel to estimate the number of Guillain Barre cases given the number of ZVD cases. Results: One hundred eight thousand eighty-seven ZVD cases had been reported in Colombia, including 19,963 (18.5%) in pregnant women, 710 (0.66%) associated with microcephaly (AR, 4.87 cases per 10,000 live births) and 453 (0.42%) ZVD associated to GBS cases (AR, 41.9 GBS cases per 10,000 ZVD cases). It appears the cases of GBS increased in parallel with the cases of ZVD, cases of microcephaly appeared 5 months after recognition of the outbreak. The kernel density map shows that throughout the study period, the states most affected by the Zika outbreak in Colombia were mainly San Andres and Providencia islands, Casanare, Norte de Santander, Arauca and Huila. The KRR shows that there is no proportional relationship between the number of GBS and ZVD cases. During the cross validation, the RMSE achieved for the second order polynomial kernel, the linear kernel, the sigmoid kernel, and the Gaussian kernel are 9.15, 9.2, 10.7, and 7.2 respectively. Conclusions: This study updates the epidemiological analysis of the ZVD situation in Colombia describes the geographical distribution of ZVD and shows the functional relationship between ZVD cases and GBS. PMID- 29118980 TI - SIRT1-dependent modulation of methylation and acetylation of histone H3 on lysine 9 (H3K9) in the zygotic pronuclei improves porcine embryo development. AB - Background: The histone code is an established epigenetic regulator of early embryonic development in mammals. The lysine residue K9 of histone H3 (H3K9) is a prime target of SIRT1, a member of NAD+-dependent histone deacetylase family of enzymes targeting both histone and non-histone substrates. At present, little is known about SIRT1-modulation of H3K9 in zygotic pronuclei and its association with the success of preimplantation embryo development. Therefore, we evaluated the effect of SIRT1 activity on H3K9 methylation and acetylation in porcine zygotes and the significance of H3K9 modifications for early embryonic development. Results: Our results show that SIRT1 activators resveratrol and BML 278 increased H3K9 methylation and suppressed H3K9 acetylation in both the paternal and maternal pronucleus. Inversely, SIRT1 inhibitors nicotinamide and sirtinol suppressed methylation and increased acetylation of pronuclear H3K9. Evaluation of early embryonic development confirmed positive effect of selective SIRT1 activation on blastocyst formation rate (5.2 +/- 2.9% versus 32.9 +/- 8.1% in vehicle control and BML-278 group, respectively; P <= 0.05). Stimulation of SIRT1 activity coincided with fluorometric signal intensity of ooplasmic ubiquitin ligase MDM2, a known substrate of SIRT1 and known limiting factor of epigenome remodeling. Conclusions: We conclude that SIRT1 modulates zygotic histone code, obviously through direct deacetylation and via non-histone targets resulting in increased H3K9me3. These changes in zygotes lead to more successful pre-implantation embryonic development and, indeed, the specific SIRT1 activation due to BML-278 is beneficial for in vitro embryo production and blastocyst achievement. PMID- 29118982 TI - Uneven distribution of professors and instructors in medical disciplines dealing with the four main chronic non-communicable diseases: the case of the Italian Universities. AB - Background: Chronic (non-communicable) diseases (NCD) -- principally cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes -- are leading causes of death and disability. There is the need to adopt a core University curriculum which let students be taught by teachers who are experts of the four main NCD, for reaching the public health goals proposed by the UN and the WHO. Methods: Our aim was to assess whether all medical students, regardless of the Italian university of enrolment, have an equal opportunity to be educated by an expert teacher in each of the four NCD. We have used the search engine http://cercauniversita.cineca.it/php5/docenti/cerca.php. Results: In January 2016, for each of the 43 universities with a school of medicine, we have assessed the presence of professors / instructors for each of the four academic disciplines corresponding to the four NCD: a) Respiratory medicine; b) Cardiovascular medicine; c) Oncology; d) Endocrinology. Comparing university personnel between Respiratory medicine and each of the other NCD academic sectors, there were negative differences, much wider with the sector Cardiovascular medicine, regarding individual (number of professors/instructors) and collective indicators (number of Universities with various kinds of professors/instructors). Conclusions: Both national societies and ERS should promote periodic analyses of the academic situation of respiratory medicine in the European countries for advocating the EU in order to have recommendations/suggestions for the Member States to get the proper recognition of respiratory medicine, at the same level as the other disciplines involved in preventing and managing the four main NCD. PMID- 29118983 TI - Identifying fundamental criteria for eating disorder recovery: a systematic review and qualitative meta-analysis. AB - Background: Outcome studies for eating disorders regularly measure pathology change or remission as the only outcome. Researchers, patients and recovered individuals highlight the importance of using additional criteria for measuring eating disorder recovery. There is no clear consensus on which additional criteria are most fundamental. Studies focusing on the perspectives of recovered patients show criteria which are closely related to dimensions of positive functioning as conceptualized in the complete mental health model. The aim of this study was to identify fundamental criteria for eating disorder recovery according to recovered individuals. Methods: A systematic review and a qualitative meta-analytic approach were used. Eighteen studies with recovered individuals and meeting various quality criteria were included. The result sections of the included papers were searched for themes that were stated as criteria for recovery or 'being recovered'. All themes were analyzed using a meta summary technique. Themes were labeled into criteria for recovery and the frequency of the found criteria was examined. Results: In addition to the remission of eating disorder pathology, dimensions of psychological well-being and self-adaptability/resilience were found to be fundamental criteria for eating disorder recovery. The most frequently mentioned criteria were: self-acceptance, positive relationships, personal growth, decrease in eating disorder behavior/cognitions, self-adaptability/resilience and autonomy. Conclusions: People who have recovered rate psychological well-being as a central criterion for ED recovery in addition to the remission of eating disorder symptoms. Supplementary criteria, besides symptom remission, are needed to measure recovery. We recommend including measurements of psychological well-being and self-adaptability/resilience in future research, such as outcome studies and in routine outcome measurement. PMID- 29118984 TI - Clinical trial protocol for TARDOX: a phase I study to investigate the feasibility of targeted release of lyso-thermosensitive liposomal doxorubicin (ThermoDox(r)) using focused ultrasound in patients with liver tumours. AB - Background: TARDOX is a Phase I single center study of ultrasound triggered targeted drug delivery in adult oncology patients with incurable liver tumours. This proof of concept study is designed to demonstrate the safety and feasibility of targeted drug release and enhanced delivery of doxorubicin from thermally sensitive liposomes (ThermoDox(r)) triggered by mild hyperthermia induced by focused ultrasound in liver tumours. A key feature of the study is the direct quantification of the doxorubicin concentration before and after ultrasound exposure from tumour biopsies, using high performance liquid chromatography (HPLC). Methods/Design: The study is conducted in two parts: Part 1 includes minimally-invasive thermometry via a thermistor or thermocouple implanted through the biopsy co-axial needle core, to confirm ultrasound-mediated hyperthermia, whilst Part 2 is carried out without invasive thermometry, to more closely mimic the ultimately intended clinical implementation of the technique. Whilst under a general anaesthetic, adult patients with incurable confirmed hepatic primary or secondary (metastatic) tumours receive a single cycle of ThermoDox(r), immediately followed by ultrasound-mediated hyperthermia in a single target liver tumour. For each patient in Part 1, the HPLC-derived total doxorubicin concentration in the ultrasound-treated tumour is directly compared to the concentration before ultrasound exposure in that same tumour. For each patient in Part 2, as the tumour biopsy taken before ultrasound exposure is not available, the mean of those Part 1 tumour concentrations is used as the comparator. Success of the study requires at least a two-fold increase in the total intratumoural doxorubicin concentration, or final concentrations over 10 MUg/g, in at least 50% of all patients receiving the drug, where tissue samples are evaluable by HPLC. Secondary outcome measures evaluate safety and feasibility of the intervention. Radiological response in the target tumour and control liver tumours are analysed as a tertiary outcome measure, in addition to plasma pharmacokinetics, fluorescence microscopy and immunohistochemistry of the biopsy samples. Discussion: If this early phase study can demonstrate that ultrasound-mediated hyperthermia can effectively enhance the delivery and penetration of chemotherapy agents intratumorally, it could enable application of the technique to enhance therapeutic outcomes across a broad range of drug classes to treat solid tumours. Trial registration: ClinicalTrials.gov Identifier: NCT02181075, Edura-CT Identifier: 2014-000514-61.Ethics Number: 14/NE/0124. PMID- 29118985 TI - Acute development of Cushing syndrome in an HIV-infected child on atazanavir/ritonavir based antiretroviral therapy. AB - : An 11-year-old male with perinatally acquired human immune deficiency virus (HIV) infection on antiretroviral regimen, which included abacavir plus lamivudine (Epzicom), didanosine, ritonavir and atazanavir presented with bilateral axillary striae, increased appetite, fatigue, facial swelling and acute weight gain. Two months prior to presentation, the patient had received a diagnostic and therapeutic intra-articular triamcinolone injection in the knee for pain relief and subsequently became progressively swollen in the face, developed striae bilaterally at the axillae, experienced increased appetite, fatigue and an 8 pound weight gain. During the endocrine workup, suspicion for adrenal insufficiency prompted 24-h urine collection for free cortisol, which was found to be undetectable (below LLQ of 1.0 ug/L). This prompted further evaluation of the hypothalamic-pituitary axis (HPA) by standard dose adrenocorticotropic hormone (ACTH) stimulation test. A 250 ug cosyntropin stimulation test was performed and confirmed HPA axis suppression. Baseline cortisol level was <1 ug/dL and stimulated cortisol level at 30 min was 3.8 ug/dL. The patient was diagnosed with iatrogenic Cushing syndrome and suppression of HPA axis secondary to the drug interaction between ritonavir (RTV) and intra articular triamcinolone injection. Following endocrine evaluation and workup, the patient was admitted for planned orthopaedic procedure including elective left hamstring lengthening, distal femoral osteotomy and patellar tendon advancement. Taking into consideration the diagnosis of iatrogenic Cushing syndrome, at the start of the surgical procedure, 100 mg IV stress dose of hydrocortisone followed by 50 mg hydrocortisone every 8 h for 24 h was administered. Stress dosing was discontinued 24 h after the procedure. Throughout the hospitalization and upon discharge, the patient continued his ART. From initial presentation, patient has remained clinically stable throughout surgery and postoperative period. Learning points: Drug-drug interaction between ritonavir and triamcinolone can cause Cushing syndrome.Although triamcinolone has a half-life of 3 h, an intra articular injection may be systematically absorbed for 3 weeks after injection, and adrenal suppression may last as long as 30 days.Co-administration of ritonavir and corticosteroids may result in an increase of plasma levels of corticosteroids levels, as they are both eliminated by CYP3A metabolism, and this interaction has the potential to prolong the half-life of triamcinolone several fold.No specific guidelines are available for the management of iatrogenic Cushing syndrome secondary to ritonavir and corticosteroids.One treatment option includes replacing ritonavir with a non-protease inhibitor-based regimen.Initiating hydrocortisone replacement therapy to prevent an adrenal crisis is also an alternate option. PMID- 29118986 TI - Sensor-augmented CSII therapy with predictive low-glucose suspend following total pancreatectomy. AB - : Pancreatogenic diabetes is characterised by recurrent severe hypoglycaemia due to changes in both endocrine and exocrine functions. There are no guidelines to manage these individuals. Herein, we describe the post-operative management of two people who developed pancreatogenic diabetes following total pancreatectomy for neuroendocrine malignancy. In both individuals, diabetes was managed using sensor-augmented predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII). We demonstrate the benefit of sensor-augmented CSII in averting hypoglycaemia whilst optimising glycaemic control. Expected rates of severe hypoglycaemia in individuals with pancreatogenic diabetes can be averted with the use of continuous glucose monitoring (CGM) technology, optimising quality of life and reducing the risk of diabetes-related complications. Learning points: There are no clear guidelines to manage people with pancreatogenic diabetes.We describe the use of CGM with predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII) in the management of two individuals post pancreatectomy.Predictive low-glucose suspend technology can achieve excellent glycaemic control whilst avoiding recurrent and severe hypoglycaemia in people with pancreatogenic diabetes.Predictive low-glucose suspend CGM should be considered as an effective therapeutic option for the management of pancreatogenic diabetes. PMID- 29118987 TI - Massive adrenal incidentalomas and late diagnosis of congenital adrenal hyperplasia in prostate cancer. AB - : In a 61-year-old Caucasian male with prostate cancer, leuprolide and bicalutamide failed to suppress the androgens. He presented to endocrinology with persistently normal testosterone and incidental massive (up to 18 cm) bilateral adrenal myelolipomas on CT scan. Blood test did not reveal metanephrine excess. The patient was noted to have short stature (151 cm) and primary infertility. Elementary school photographs demonstrated precocious puberty. Physical examination revealed palpable abdominal (adrenal) masses. Abiraterone and glucocorticoid treatment was commenced with excellent suppression of testosterone. Genetic testing revealed a mutation in CYP21A2 confirming 21 hydroxylase-deficient congenital adrenal hyperplasia (CAH). Association of large myelolipomas with CAH has been reported in the literature. Our case highlights the importance of considering CAH in patients with non-suppressed testosterone despite androgen deprivation therapy. Large myelolipomas should raise the suspicion of congenital adrenal hyperplasia. Learning points: Adrenal myelolipomas are rare benign lesions that are more common in patients with longstanding untreated congenital adrenal hyperplasia thought to be due to ACTH stimulation.Consider undiagnosed congenital adrenal hyperplasia in patients with adrenal myelolipoma.Glucocorticoid replacement may be an efficacious treatment for patients with prostate cancer and CAH. Abiraterone therapy has a risk of adrenal crisis if glucocorticoids are not replaced. PMID- 29118988 TI - Atypical manifestation of parathyroid carcinoma with late-onset distant metastases. AB - : Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 * 3 * 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment. Learning points: Metastases can develop many years after parathyroid cancer diagnosis.Surgery is the only curative treatment for parathyroid carcinoma.Chemotherapy and radiotherapy prove to be ineffective in parathyroid cancer treatment.Patient registering is required in order to delineate underlining pathology and offer specific treatment. PMID- 29118989 TI - Patients with papillary thyroid carcinoma associated with high stimulated serum calcitonin levels. AB - : Among various substances produced by C-cells, the most important one is calcitonin (CT) that is used for detection, post-operative follow-up and evaluation of individuals at risk of developing medullary thyroid carcinoma (MTC). However, the role of serum CT measurement in the evaluation of thyroid nodules has been widely discussed, and there is still no consensus about the role of CT in the initial evaluation of all thyroid nodules. Two patients with thyroid nodules whose fine-needle aspiration results were compatible with benign cytology besides having mildly elevated basal serum calcitonin levels were reported. Calcitonin responses (peak levels were 313 and 229 pg/mL, respectively) to calcium stimulation test were compatible with the possible diagnosis of MTC. However, the final diagnosis was papillary thyroid carcinoma of the thyroid gland. There are limited numbers of case reports showing such an increased serum calcitonin responses to calcium stimulation test associated with papillary or follicular thyroid carcinoma of the thyroid. We suggest to measure serum CT level once and in case of normal levels, no further CT measurement is necessary. Physicians should keep in mind that thyroid carcinomas other than MTCs may also be associated with high serum CT levels. Learning points: Although serum calcitonin is a valuable tumor marker for MTC, it is well known that mild elevations may be seen in some other diseases such as Hashimoto thyroiditis, neuroendocrine tumors or due to medications such as proton pump inhibitors, calcium salts, beta blockers and glucocorticoids.Those two cases indicate that high calcitonin responses to calcium stimulation test, mimicking MTC, may also be seen in patients with papillary thyroid carcinoma although the mechanism is not clear. PMID- 29118990 TI - Expanding HIV/AIDS care service sites: a cross sectional survey of community pharmacists' views in South-East, Nigeria. AB - Background: Community pharmacists are very accessible to most patients yet; they have been underutilized in the aspect of providing HIV care and services. The World Health Organisation recently recommended expanding community pharmacists' roles to address the increasing complexity of antiretroviral agents and co infection drug regimen. This study therefore was designed to assess the readiness and willingness of community pharmacists in Nigeria to participate in the care of people living with HIV/AIDS and the possible inclusion of their pharmacy premises as sites for HIV care services. Methods: A descriptive cross sectional survey was carried out among 205 community pharmacists in south east, Nigeria between October, 2016 and February, 2017. Two hundred and five self-administered questionnaires were distributed to conveniently selected community pharmacists in the region. Data collected were analysed using SPSS version 23. Descriptive statistics was conducted for the demographics and percentage mean scores for each domain were computed. The variables in each domain were categorised into groups and simple percentages were used to show the percentage distribution of the variables. Cross tabulation was also carried out to show the relationship between the variables and groups' differences were explored using analysis of variance and P-values <0.05 were considered significant. Results: All distributed questionnaires were filled and retrieved. The overall knowledge of HIV among the surveyed pharmacists was seen to be high (70.41%). Although the percentage attitude score of the respondents towards HIV care services was on the average (57%), they were highly willing and ready to use their premise to offer HIV services with a percentage mean readiness score of 87.32%. However, their perceived skills in carrying out these services were observed to be low. Conclusion: Community pharmacists in the south eastern part of Nigeria have high knowledge of HIV and a somewhat attitude towards HIV care services with high willingness and readiness to be involved in HIV care and services. Despite efforts to engage community pharmacists in HIV services more is needed in the aspect of making adequate policies to further empower more community pharmacists in this aspect of care. PMID- 29118991 TI - Factors increasing the risk for psychosocial stress among Korean adults living in rural areas: using generalized estimating equations and mixed models. AB - Background: This study was conducted to analyze the distribution of the psychosocial well-being index among adults living in two rural communities in Korea and to examine its correlation with lifestyle variables such as sleep duration, regular exercise, and sedentary time. Methods: Using the cohort data of the Atherosclerosis Risk of a Rural Area Korean General Population, this study examined 3631 participants living in Wonju and Pyeongchang in Gangwon Province; their preliminary data were established from 2005 to 2007 while their follow-up data were collected 3 years later. This study investigated demographic characteristics, lifestyle habits, disease history, Psychosocial Well-being Index Short Form (PWI-SF) scores, sleep duration, regular exercise, and sedentary time during work. Using repeated measures ANOVA, this study examined how the variables and PWI-SF scores changed over the course of 3 years and identified the correlation between them based on mixed model analysis. Afterwards, using the generalized estimation equation, this study identified each variable's risk towards the PWI-SF high-risk group and performed a stratified analysis by occupation after dividing the participants into farmers and non-farmers. Results: The PWI-SF high-risk group was found to be 18.9% of the participants from preliminary data and 15.5% from follow-up data. The odds ratio towards the PWI-SF high-risk group was 1.503 (95% CI 1.241-1.821) in the short sleep duration group and 1.327 (95% CI 1.136-1.550) in the non-regular exercise group. A stratified analysis by occupation showed that middle and long sedentary time in the white collar group increased the risk toward the PWI-SF high-risk group. Conclusions: Short sleep duration, no regular exercise, and long sedentary time in the white collar group were identified as risk factors toward the PWI-SF high-risk group in the rural communities, and policy interventions are needed to address this issue. PMID- 29118992 TI - Identifying risk for type 2 diabetes in different age cohorts: does one size fit all? AB - Objective: To estimate age-specific risk equations for type 2 diabetes onset in young, middle-aged, and older US adults, and to compare the performance of simple equations based on readily available demographic information alone, against enhanced equations that require both demographic and clinical information (fasting plasma glucose, high-density lipoprotein, and triglyceride levels). Research design and methods: We estimated the probability of developing diabetes by age group using data from the Coronary Artery Risk Development in Young Adults (for ages 18-40 years), Atherosclerosis Risk in Communities (for ages 45-64 years), and the Cardiovascular Health Study (for ages 65 years and older). Simple and enhanced equations were estimated using logistic regression models, and performance was compared by age group. Thresholds based on these risk equations were evaluated using split-sample bootstraps and calibrating the constant of one age cohort to others. Results: Simple risk equations had an area under the receiver-operating curve (AUROC) of 0.72, 0.79, 0.75, and 0.69 for age groups 18 30, 28-40, 45-64, and 65 and older, respectively. The corresponding AUROCs for enhanced equations were 0.75, 0.85, 0.85, and 0.81. Risk equations based on younger populations, when applied to older cohorts, underpredict diabetes incidence and risk. Conversely, risk equations based on older populations overpredict the likelihood of diabetes in younger cohorts. Conclusions: In general, risk equations are more successful in middle-aged adults than in young and old populations. The results demonstrate the importance of applying age specific risk equations to identify target populations for intervention. While the predictive capacity of equations that include biomarkers is better than of those based solely on self-reported variables, biomarkers are more important in older populations than in younger ones. PMID- 29118993 TI - Cellular characteristics of keratin 19-positive canine hepatocellular tumours explain its aggressive behaviour. AB - The expression of the hepatic progenitor cell marker keratin 19 (K19) in canine hepatocellular carcinomas is linked with a poor prognosis. To better understand this aggressive behaviour, K19-positive hepatocellular carcinomas (n=5) and K19 negative hepatocellular adenomas (n=6) were immunohistochemically stained for proteins involved in malignant tumour development. The K19-positive carcinomas showed marked positivity for platelet-derived growth factor receptor alpha polypeptide (PDGFRalpha), laminin, integrin beta-1/CD29, B-cell-specific Moloney murine leukaemia virus Integration site 1, glypican-3 (GPC-3) and prominin 1/CD133, in contrast with K19-negative hepatocellular adenomas. Conversely, neurofibromatosis type 2 was highly expressed in the hepatocellular adenomas in contrast with the hepatocellular carcinomas. This expression pattern is clearly in line with the observed aggressive behaviour. The presence of the malignancy markers PDGFRalpha and GPC-3 might make it possible to develop specific strategies to intervene in tumour growth and to devise novel serological tests and personalised treatment methods for canine hepatocellular carcinomas. PMID- 29118994 TI - Interval mapping for red/green skin color in Asian pears using a modified QTL-seq method. AB - Pears with red skin are attractive to consumers and provide additional health benefits. Identification of the gene(s) responsible for skin coloration can benefit cultivar selection and breeding. The use of QTL-seq, a bulked segregant analysis method, can be problematic when heterozygous parents are involved. The present study modified the QTL-seq method by introducing a |Delta(SNP-index)| parameter to improve the accuracy of mapping the red skin trait in a group of highly heterozygous Asian pears. The analyses were based on mixed DNA pools composed of 28 red-skinned and 27 green-skinned pear lines derived from a cross between the 'Mantianhong' and 'Hongxiangsu' red-skinned cultivars. The 'Dangshansuli' cultivar genome was used as reference for sequence alignment. An average single-nucleotide polymorphism (SNP) index was calculated using a sliding window approach (200-kb windows, 20-kb increments). Nine scaffolds within the candidate QTL interval were in the fifth linkage group from 111.9 to 177.1 cM. There was a significant linkage between the insertions/deletions and simple sequence repeat markers designed from the candidate intervals and the red/green skin (R/G) locus, which was in a 582.5-kb candidate interval that contained 81 predicted protein-coding gene models and was composed of two subintervals at the bottom of the fifth chromosome. The ZFRI 130-16, In2130-12 and In2130-16 markers located near the R/G locus could potentially be used to identify the red skin trait in Asian pear populations. This study provides new insights into the genetics controlling the red skin phenotype in this fruit. PMID- 29118995 TI - Added fructose as a principal driver of non-alcoholic fatty liver disease: a public health crisis. AB - Fatty liver disease affects up to one out of every two adults in the western world. Data from animal and human studies implicate added sugars (eg, sucrose and high-fructose corn syrup) in the development of fatty liver disease and its consequences. Added fructose in particular, as a component of added sugars, may pose the greatest risk for fatty liver disease. Considering that there is no requirement for added sugars in the diet, dietary guidelines should recommend reducing the intake of added sugars to just 5% of total calories in order to decrease the prevalence of fatty liver disease and its related consequences. PMID- 29118996 TI - Predictors of risk for sudden death in childhood hypertrophic cardiomyopathy: the importance of the ECG risk score. AB - Objective: To establish which risk factors are predictive for sudden death in hypertrophic cardiomyopathy (HCM) diagnosed in childhood. Methods: A Swedish national cohort of patients with HCM diagnosed <19 years of age was collected between 1972 and 2014, consisting of 155 patients with available ECGs, with average follow-up of 10.9+/-(SD 9.0) years, out of whom 32 had suffered sudden death or cardiac arrest (SD/CA group). Previously proposed risk factors and clinical features, ECG and ultrasound measures were compared between SD/CA group and patients surviving >2 years (n=100), and features significantly more common in SD/CA group were further analysed with univariate and multivariate Cox hazard regression in the total cohort. Results: Ranked according to relative risk (RR) the ECG risk score >5 points had an RR of 46.5 (95% CI 6.6 to 331), sensitivity of 97% (83% to 100%) and specificity of 80% (71% to 88%) (p<0.0001), and was the best ECG predictor, predicting a 5-year risk of SD/CA of 30.6%. The following are other features with importantly raised RR: Detroit wall thickness Z-score >4.5: 9.9 (3.1 to 31.2); septal thickness >=190% of upper limit of normal for age (septum in % of 95th centile for age (SEPPER) >=190%): 7.9 (3.2 to 19.4); ventricular tachycardia: 9.1 (3.6 to 22.8); ventricular ectopics on exercise testing: 7.4 (2.7 to 20.2); and left ventricular outflow gradient (left ventricular outflow tract obstruction (LVOTO)) >50 mm Hg: 6.6 (4.0 to 11.0). Family history was non-significant. Multivariate Cox hazard analysis gives the following as early predictors: limb-lead QRS amplitude sum (p=0.020), SEPPER >=190% (p<0.001) and LVOTO at rest (p=0.054); and for late predictors: last ECG risk score (p=0.002) and last Detroit Z-score (p=0.001). Both early (p=0.028) and late (p=0.037) beta-blocker doses reduced risk in the models. Conclusions: ECG phenotype as assessed by ECG risk score is important for risk of sudden death and should be considered for inclusion in risk stratification of paediatric patients with HCM. PMID- 29118997 TI - Long and short of optimal stent design. AB - The ideal stent must fulfil a broad range of technical requirements. Stents must be securely crimped onto the delivery balloon and, in this form, must have a low profile and be sufficiently flexible to facilitate deliverability to the lesion site without distortion or displacement. Following expansion, stents must exert sufficient radial force on the vessel wall to overcome lesion resistance and elastic recoil. To achieve an optimal lumen diameter, the lesion must be uniformly and adequately scaffolded, with minimal tissue prolapse between struts but without compromising side-branch access. Furthermore, the deployed stent must conform to the vessel curvature to minimise vessel distortion, particularly at the stent edges. Radio-opacity is also important to guide safe positioning, adequate deployment and postdilataion and to permit assessment of optimal stent expansion. Equally though, the stent lumen must also be sufficiently visible to allow radiographic assessment of flow dynamics and restenosis. Efforts to optimise one characteristic of stent design may have detrimental effects on another. Thus, currently available stents all reflect a compromise between competing desirable features and have subtle differences in their performance characteristics. Striving to achieve stents with optimal deliverability, conformability and radial strength led to a reduction in longitudinal strength. The importance of this parameter was highlighted by complications occurring in the real-world setting where percutaneous coronary intervention is often undertaken in challenging anatomy. This review focuses on aspects of stent design relevant to longitudinal strength. PMID- 29118998 TI - Association of QT interval with mortality by kidney function: results from the National Health and Nutrition Examination Survey (NHANES). AB - Objective: Prolonged QT interval predisposes to ventricular arrhythmias and sudden cardiac death. However, the association between QT interval and mortality by the level of pre-existing kidney function has not been investigated. Methods: We followed 6565 participants from the National Health and Nutrition Examination Survey III for a median of 13.3 years. Sample divided according to corrected QT (QTc) interval was as follows: normal (QTc <450 ms for men and <460 ms for women) or prolonged. It was further categorised as follows: (1) no chronic kidney disease (CKD), that is, albumin to creatinine ratio (ACR) <30 mg/g and estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2; (2) CKD by eGFR only (eGFR <60 mL/min/1.73 m2, ACR <30 mg/g); (3) CKD by ACR only (ACR >30 mg/g, eGFR >60 mL/min/1.73 m2) and (4) CKD by both. Cox proportional hazards models were used. Results: CKD group had prolonged QTc than those without CKD (20.5%vs12.9%, p<0.0001). Both prolonged QTc and CKD are independently associated with increased risk of mortality. When combined, risk of mortality is higher in those with CKD by eGFR with prolonged QTc than normal QTc (HR 2.6 (1.7-3.9) and 3.1 (1.7-5.4) vs 1.4 (1.1-1.7) and 1.7 (1.3-2.1) for all-cause and CV mortality). There is no significant difference in risk in those with CKD by ACR when QTc is prolonged. There is significant improvement in risk prediction for all-cause and CV mortality when QTc is added to CKD beyond established CV risk factors (net reclassification index p<0.00001). Conclusion: A screening ECG in those with CKD may help in finer risk stratification and may be considered. PMID- 29118999 TI - Associates and predictors of pleurisy or pericarditis in SLE. AB - Background/Purpose: Serositis is one of both ACR and SLICC classification criteria for systemic lupus erythematosus (SLE) and a common type of extra renal flare. However, little is known about clinical or immunological associations of pleurisy or pericarditis. The aim of this study is to analyze associates and predictors of pleurisy versus pericarditis in Caucasians and African Americans with SLE. Methods: 2,390 SLE patients in the Hopkins Lupus Cohort were analyzed for demographic, clinical and serologic associates of pleurisy or pericarditis, defined using the SELENA revision of the SLE Disease Activity Index (SLEDAI). The cross-sectional and prospective study using either univariate or multivariate analysis were performed to evaluate the associates of serositis in SLE. We reported associates with a p-value of less than 0.05 for pleurisy or pericarditis. Results: 43% had pleurisy and 22% had pericarditis. African American ethnicity was a predictive factor for new pericarditis. Hemolytic anemia, proteinuria, lymphadenopathy and anti-Sm were predictive only of pericarditis, whereas pulmonary fibrosis and GI infarction were predictive only of pleurisy. Fever, Raynaud's syndrome, and anti-DNA were predictors for both pericarditis and pleurisy. Conclusion: Our study provides further insights into the associates of pleurisy and pericarditis in SLE. Predictors of pleurisy and pericarditis are shown for the first time. The long term consequences from the cross-sectional analysis gives a lesson that serositis in SLE should not be considered benign. PMID- 29119000 TI - Comparing the physiochemical parameters of three celluloses reveals new insights into substrate suitability for fungal enzyme production. AB - Background: The industrial applications of cellulases are mostly limited by the costs associated with their production. Optimized production pathways are therefore desirable. Based on their enzyme inducing capacity, celluloses are commonly used in fermentation media. However, the influence of their physiochemical characteristics on the production process is not well understood. In this study, we examined how physical, structural and chemical properties of celluloses influence cellulase and hemicellulase production in an industrially optimized and a non-engineered filamentous fungus: Trichoderma reesei RUT-C30 and Neurospora crassa. The performance was evaluated by quantifying gene induction, protein secretion and enzymatic activities. Results: Among the three investigated substrates, the powdered cellulose was found to be the most impure, and the residual hemicellulosic content was efficiently perceived by the fungi. It was furthermore found to be the least crystalline substrate and consequently was the most readily digested cellulose in vitro. In vivo however, only RUT-C30 was able to take full advantage of these factors. When comparing carbon catabolite repressed and de-repressed strains of T. reesei and N. crassa, we found that cre1/cre-1 is at least partially responsible for this observation, but that the different wiring of the molecular signaling networks is also relevant. Conclusions: Our findings indicate that crystallinity and hemicellulose content are major determinants of performance. Moreover, the genetic background between WT and modified strains greatly affects the ability to utilize the cellulosic substrate. By highlighting key factors to consider when choosing the optimal cellulosic product for enzyme production, this study has relevance for the optimization of a critical step in the biotechnological (hemi-) cellulase production process. PMID- 29119001 TI - A Swedish national adoption study of risk of irritable bowel syndrome (IBS). AB - Objectives: Irritable bowel syndrome (IBS) clusters in families, but the familial risk of IBS has not been determined in adoptees. Studying adoptees and their biological and adoptive parents is a strong study design for separating genetic from environmental causes of familial clustering. This nationwide study aimed to separate the biological (genetic) and familial environmental contribution to the familial transmission of IBS. Methods: We performed a family study for Swedish born adoptees born from 1951 until 1995, and their biological and adoptive parents. The Swedish Multigeneration Register was linked to the Hospital Register (inpatients and outpatients) for the period 1964-2012 and the Swedish Outpatient Care Register for 2001-2012, and the Swedish Primary Healthcare register for 1989 2012. ORs for IBS were calculated for adoptees with an affected biological parent with IBS compared with adoptees without a biological parent with IBS. The OR for IBS was also determined in adoptees with an adoptive parent with IBS compared with adoptees without an adoptive parent with IBS. Heritability h2 (+/-SE) was also determined. Results: The ORs for IBS were 1.67 in adoptees (95% CI 1.06 to 2.62) of biological parents diagnosed with IBS. The ORs for IBS were 0.88 in adoptees (95% CI 0.48 to 1.63) of adoptive parents diagnosed with IBS. The heritability was 19.5%+/-8.5%. Conclusions: The present study indicates that biological (genetic) factors are important for the familial clustering of IBS. The heritability calculated is in the range from twin studies and suggests that heritability may be estimated in adoptees. PMID- 29119002 TI - Mechanisms of liver disease in patients infected with HIV. AB - Objective: To describe the various mechanisms of liver disease in patients with HIV infection, and to link these mechanisms to disease states which may utilise them. Background: Non-AIDS causes of morbidity and mortality are becoming increasingly common in patients chronically infected with HIV. In particular, liver-related diseases have risen to become one of the leading causes of non-AIDS related death. A thorough understanding of the mechanisms driving the development of liver disease in these patients is essential when evaluating and caring for these patients. Methods: The literature regarding mechanisms of liver disease by which different disease entities may cause hepatic injury and fibrosis was reviewed and synthesised. Results: A number of discrete mechanisms of injury were identified, to include: oxidative stress, mitochondrial injury, lipotoxicity, immune-mediated injury, cytotoxicity, toxic metabolite accumulation, gut microbial translocation, systemic inflammation, senescence and nodular regenerative hyperplasia. Disease states may use any number of these mechanisms to exert their effect on the liver. Conclusions: The mechanisms by which liver injury may occur in patients with HIV infection are numerous. Most disease states use multiple mechanisms to cause hepatic injury and fibrosis. PMID- 29119003 TI - Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis. AB - Background: Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD. Methods: A cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea. Findings: Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (rs=-0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis. Interpretation: The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into potential metabolic causes. PMID- 29119004 TI - Physiotherapy and physical activity: a cross-sectional survey exploring physical activity promotion, knowledge of physical activity guidelines and the physical activity habits of UK physiotherapists. AB - Objective: Physical inactivity is a public health priority and embedding promotion of physical activity (PA) within healthcare systems is an important lever for change. Many factors influence PA promotion in routine healthcare practice; these include the PA habits of healthcare professionals and also their knowledge of the PA guidelines. Little is known about the extent to which PA is currently promoted in physiotherapy practice or the factors that influence it. Methods: Following ethical approval, a cross-sectional survey of UK physiotherapists was conducted. Findings were analysed and reported in accordance with STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines. Results: There were 522 respondents, 514 of whom were physiotherapists. Seventy-seven per cent of respondents routinely discussed PA with patients and 68% routinely delivered brief interventions. Assessment of PA status was not routine practice, neither was signposting to further sources of PA support. Only 16% of respondents correctly answered questions about the content of the PA guidelines. Only 38% of respondents met current PA recommendations. Clinicians' PA levels were not associated with PA promotion activity. Conclusion: Despite the promising finding that some form of PA promotion is integrated into most respondents' practice, we report a poor understanding of brief interventions and poor knowledge of the PA guidelines. Additionally, the majority of respondents were not sufficiently active to meet current PA recommendations. PMID- 29119005 TI - Differences in left ventricular functional adaptation to arterial stiffness and neurohormonal activation in patients with hypertension: a study with two dimensional layer-specific speckle tracking echocardiography. AB - Background: Arterial stiffness increases pressure load to the left ventricle (LV), leading to LV hypertrophy and subendocardial ischemia. Neurohormones stimulate myocardial fibrosis and LV dysfunction. We aimed to explore the associations of arterial stiffness and plasma aldosterone with multi-directional, layer-specific LV, and left atrial (LA) mechanical function in hypertensive patients. Methods: Layer-specific LV global longitudinal strain (GLS-trans, GLS endo, GLS-epi), global circumferential strain (GCS-trans, GCS-endo, GCS-epi), LV torsional parameters, and LA global longitudinal strain (LA GLS) were analyzed by two-dimensional speckle tracking echocardiography in 195 hypertensive patients (110 men, mean age 55 years). Pulse wave velocity (PWV) was analyzed as a measure of arterial stiffness, and plasma aldosterone was measured for evaluation of neurohormonal activation. Results: In a simple correlation, PWV significantly correlated with LV GLS-endo and LA GLS. Log aldosterone correlated with both LV GCS-endo and LV GCS-trans. Multiple regression analysis revealed that LV GLS-endo (beta = 0.223, p = 0.031) and LA GLS (beta = -0.311, p = 0.002) were independently correlated with PWV even after controlling for confounding factors. Conclusions: In hypertensive patients without clinically apparent target organ damage, LV GLS, especially endocardium, and LA GLS were more dominantly affected by arterial stiffness because, among the three myocardial layers, the endocardium is most susceptible to pressure overload. Two-dimensional layer-specific speckle tracking echocardiography sensitively detects LV mechanical dysfunction and provides pathophysiologic insights into LV mechanical adaptations in hypertension. PMID- 29119006 TI - Cost-utility of COBRA-light versus COBRA therapy in patients with early rheumatoid arthritis: the COBRA-light trial. AB - Objective: To evaluate if COmbinatie therapie Bij Reumatoide Artritis (COBRA) light therapy is cost-effective in treating patients with early rheumatoid arthritis (RA) compared with COBRA therapy. Methods: This economic evaluation was performed next to the open-label, randomised non-inferiority COBRA-light trial in 164 patients with early RA. Non-responders to COBRA or COBRA-light received etanercept (50 mg/week) for 3-6 months. The societal perspective analysis took medical direct, non-medical direct and indirect costs into account. Costs were measured with patient cost diaries for the follow-up period of 52 weeks. Bootstrapping techniques estimated uncertainty around the cost-effectiveness ratios, presented in cost-effectiveness planes. Results: 164 patients were randomised to either COBRA or COBRA-light strategy. At week 52, COBRA-light proved to be non-inferior to COBRA therapy on all clinical outcome measures. The results of the base-case cost-utility analysis (intention-to-treat analyses) revealed that COBRA-light strategy is more expensive (k?9.3 (SD 0.9) compared with COBRA (k?7.2 (SD 0.8)), but the difference in costs were not significant (k?2.0; 95% CI -0.3 to 4.4). Also, both strategies produced similar quality adjusted life-years (QALYs). The sensitivity analyses showed robustness of these results. In a per-protocol sensitivity analysis, in which costs of etanercept were assumed to be provided as prescribed according to protocol, both arms had much higher costs: COBRA-light: k?11.5 (8.3) compared with k?8.5 (6.8) for COBRA, and the difference in costs was significant (k?2.9; 0.6 to 5.3). Conclusions: In the base-case cost-utility analysis, the two strategies produced similar QALYs for similar costs. But it is anticipated that if protocol had been followed correctly, the COBRA-light strategy would have been more costly due to additional etanercept costs, for a limited health gain. Given the limited added benefit and high costs of starting etanercept in the presence of low disease activity in our trial, such a strategy needs better justification than is available now. Trial registration number: 55552928, Results. PMID- 29119007 TI - Endothelial dysfunction is associated with activation of the type I interferon system and platelets in patients with systemic lupus erythematosus. AB - Objectives: Endothelial dysfunction may be connected to cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Type I interferons (IFNs) are central in SLE pathogenesis and are suggested to induce both endothelial dysfunction and platelet activation. In this study, we investigated the interplay between endothelial dysfunction, platelets and type I IFN in SLE. Methods: We enrolled 148 patients with SLE and 79 sex-matched and age-matched healthy controls (HCs). Type I IFN activity was assessed with a reporter cell assay and platelet activation by flow cytometry. Endothelial dysfunction was assessed using surrogate markers of endothelial activation, soluble vascular cell adhesion molecule-1 (sVCAM-1) and endothelial microparticles (EMPs), and finger plethysmograph to determine Reactive Hyperaemia Index (RHI). Results: In patients with SLE, type I IFN activity was associated with endothelial activation, measured by high sVCAM-1 (OR 1.68, p<0.01) and elevated EMPs (OR 1.40, p=0.03). Patients with SLE with high type I IFN activity had lower RHI than HCs (OR 2.61, p=0.04), indicating endothelial dysfunction.Deposition of complement factors on platelets, a measure of platelet activation, was seen in patients with endothelial dysfunction. High levels of sVCAM-1 were associated with increased deposition of C4d (OR 4.57, p<0.01) and C1q (OR 4.10, p=0.04) on platelets. High levels of EMPs were associated with C4d deposition on platelets (OR 3.64, p=0.03). Conclusions: Endothelial dysfunction was associated with activation of platelets and the type I IFN system. We suggest that an interplay between the type I IFN system, injured endothelium and activated platelets may contribute to development of CVD in SLE. PMID- 29119008 TI - Discordant patient-physician assessments of disease activity and its persistence adversely impact quality of life and work productivity in US Hispanics with rheumatoid arthritis. AB - Objective: This study was designed to evaluate the determinants of patient and physician global assessments (PtGA and MDGA, respectively) of disease activity, their discordance and change over 2 years in Hispanics with rheumatoid arthritis (RA). We further examined the impact of discordance and its persistence on health related quality of life (HRQOL) and work productivity on final visit. Methods: We studied 536 Hispanics with established RA from a single centre. PtGA and MDGA were measured annually on 10 cm visual analogue scales and discordance was defined as absolute difference between them >=3 cm. Associations between predictors and outcomes of interest were evaluated using multivariable regression and analysis of covariance for cross-sectional and longitudinal data, respectively. Results: Independent predictors of baseline PtGA were pain, fatigue, depression, general health perceptions and tender joint count. MDGA was predicted by swollen joint count, tender joint count, erythrocyte sedimentation rate, fatigue and depression. Both PtGA and MDGA improved over time (all p<0.001). Discordance was observed in 43% at baseline, with fair stability over 2 years. Higher (worse) patient ratings were most prevalent; their presence at any time and increasing persistence predicted lower physical and mental HRQOL, decreased work productivity and more activity impairment at 2-year follow-up (all p<0.001). Conclusions: Determinants of PtGA, MDGA and changes over 2 years were disparate in Hispanics with RA yielding significant discordance. Higher patient ratings at any time contributed to worse HRQOL, work productivity and activity impairment on final visit. PMID- 29119009 TI - Parents' perceptions of reasons for excess weight loss in obese children: a peer researcher approach. AB - Background: This study reports on the process of conducting participatory research by training peer researchers to conduct interviews and analyse data collected with parents of overweight children. The methodology was chosen as a means of (a) encouraging participation among a hard-to-engage group (i.e., parents of overweight children), and (b) generating novel insights and challenging academic/health professional assumptions through the involvement of parents in the interpretation of findings. Methods: Four parents (all female) were recruited as peer researchers and trained in research processes, ethics, and interview skills over three half-day workshops. The intended interviewees were parents of children identified as obese through the National Child Measurement Programme (NCMP) at the start of primary school (age 4-5) but who had lost their excess weight by age 10-11; little is currently known about how this excess weight loss is achieved. Interviews were conducted by peer researchers, transcribed verbatim and analysed thematically by both peer- and university-based investigators. Results: The peer researchers felt confident to conduct interviews after three training sessions. Recruitment of interviewees was challenging, resulting in only four volunteers (all mothers) over a 5-month period; thus peer researchers were only able to conduct one interview each. All interviews were considered good quality in comparison to those conducted by Masters-level research assistants. The process of co-analysis resulted in a change in emphasis from that initially generated by the university research team; the role of health professionals in weight management was de-emphasised, and the importance of 'not singling out' overweight children accentuated. Given the limited number of interviews, the results of the study are only provisional but resulted in three themes: Whole Family Action, Support (and lack of support), and Protecting Childhood. Conclusions: Training peer researchers to conduct and analyse interviews was feasible within a short period of training. Peer researchers found the experience interesting, informative and worthwhile. Two of the four volunteered to be involved in a related study 12 months later. The different perspective brought through co-analysis suggests that this approach to conducting participatory research may be a useful means of working with the public to generate new ideas to tackle intransigent issues. PMID- 29119011 TI - Pulmonary metastasectomy: beyond the tip of the iceberg. PMID- 29119012 TI - Prognostic factors after pulmonary metastasectomy of colorectal cancers: a single center experience. AB - Background: Surgical resection has been widely admitted as the treatment of choice for pulmonary metastases of colorectal cancer (CRC). Nevertheless, this practice is not supported by high level of evidence and patients' eligibility remains controversial. Aim of this study was to evaluate long terms results and factors influencing survival after lung metastasectomy of CRC. Methods: A single center retrospective analysis of patients with pathologically proven colorectal metastasis, operated from 2004 to 2013, was performed. Patients were treated with a multidisciplinary approach and selected for surgery if complete resection was considered feasible. Results: Three hundred and six patients were considered for analysis. Mean number of lesions at CT scan was 2.6+/-2.3. Ratios of each largest resection type at first side surgery were: segmentectomy 20.6%, lobectomy 12.9%, bilobectomy 1.2%, pneumonectomy 1.2% and sub-lobar resection 64.1%, respectively. No in-hospital death occurred. At pathology, mean number of resected metastasis was 2.6+/-2.3, ranging from 1 to 12. Resection was complete in 92.5% of patients. Nodal involvement was proven in 40 (12.9%) patients. The initially planned complete resection could not be achieved in 23 (7.5%) cases. Mean follow-up was 3.06+/-2.36 years. Kaplan-Meier analysis revealed that recurrence-free survival (RFS) was 76.3% [95% confidence interval (95% CI), 71-80.7%], 38.9% (95% CI, 33 44.7%), 28.3% (95% CI, 22.5-34.4%) and 22.7% (95% CI, 16.5-29.5%) at 1, 3, 5 and 7 years, respectively. Overall survival (OS) estimates were 77.8% (95% CI, 72.7 82.7%), 59.0% (95% CI, 51.2-66.4%), and 56.9% (95% CI, 48.4-65.0%) at 3, 5 and 7 years, respectively. Multivariate analysis, including pT parameter of the primary tumor, number of lesions, one-sided versus bilateral lung disease, and body mass index (BMI) (all significant at univariate analysis), showed that bilateral disease (P<0.001) and pT4 primary (P=0.005) were independent pejorative predictors of OS, whereas BMI >=25 was protective (P=0.028). Conclusions: Bilateralism and primary tumor local extension influence the prognosis of patients surgically treated for pulmonary colorectal metastases. Specifically designed randomized trials are necessary. PMID- 29119013 TI - Lung metastasectomy following kidney tumors: outcomes and prognostic factors from a single-center experience. AB - Background: The lung is one of the sites most frequently affected by metastatic renal cell carcinoma (mRCC). Nonsurgical therapy for mRCC has limited efficacy, while the 5-year survival rates data published in literature after pulmonary surgery for metastasectomy, emphasize the role of surgery as the treatment that guarantees the best effectiveness in pulmonary resectable metastases. Methods: From January 2000 to March 2016, 27 patients underwent pulmonary metastasectomy for metastatic renal cancer was retrospectively reviewed. Primary renal cancer was controlled in all patients and there was no other metastatic site in addition to the lung, at the time of metastasectomy. The aim of the study was to identify outcomes and prognostic factors in association with survival after complete pulmonary resection of metastases in a subgroup of patients with isolated pulmonary metastases from RCC. Results: Five- and 10-year overall survival (OS) from first pulmonary metastasectomy was 75% and 59%, respectively. Independent prognostic factor influencing survival were: dimension of pulmonary metastases >=2 cm (3-year survival: 67% vs. 100%; P=0.014) and disease free interval (DFI) >=5 years (3-year survival: 94% vs. 28%; P=0.05). The only independent prognostic factors affecting DFI was the dimension of pulmonary metastases >=2 cm (5-year DFI: 67% vs. 89%; P=0.03) at univariate analysis. Conclusions: Considering the good results based on high long-term efficacy and low morbidity after metastases surgical resection, we always recommend metastasectomy in patients with technically resectable metastases, especially in case of long DFI and reduced dimension of pulmonary lesions. PMID- 29119010 TI - Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: a pregnane X receptor-centric view. AB - Despite the major advances in developing diagnostic techniques and effective treatments, atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. While considerable progress has been achieved to identify gene variations and environmental factors that contribute to CVD, much less is known about the role of "gene-environment interactions" in predisposing individuals to CVD. Our chemical environment has significantly changed in the last few decades, and there are more than 100,000 synthetic chemicals in the market. Recent large-scale human population studies have associated exposure to certain chemicals including many endocrine disrupting chemicals (EDCs) with increased CVD risk, and animal studies have also confirmed that some EDCs can cause aberrant lipid homeostasis and increase atherosclerosis. However, the underlying mechanisms of how exposure to those EDCs influences CVD risk remain elusive. Numerous EDCs can activate the nuclear receptor pregnane X receptor (PXR) that functions as a xenobiotic sensor to regulate host xenobiotic metabolism. Recent studies have demonstrated the novel functions of PXR in lipid homeostasis and atherosclerosis. In addition to directly regulating transcription, PXR has been implicated in the epigenetic regulation of gene transcription. Exposure to many EDCs can also induce epigenetic modifications, but little is known about how the changes relate to the onset or progression of CVD. In this review, we will discuss recent research on PXR and EDCs in the context of CVD and propose that PXR may play a previously unrealized role in EDC mediated epigenetic modifications that affect lipid homeostasis and atherosclerosis. PMID- 29119014 TI - Pulmonary metastasectomy in uterine malignancies: outcome and prognostic factors. AB - Background: This retrospective study is designed to evaluate factors affecting survival in a population of patients receiving pulmonary metastasectomy after gynecologic cancers. Methods: Nineteen patients with isolated lung metastases (one or two) were surgically treated with R0 resection. Four of them underwent lobectomies. Results: Six patients (31.6%) received adjuvant therapy and 11 (58%) experienced recurrences after metastasectomy. Five- and ten-year survival were 40.9% and 31.4%, respectively. Five-year survival in patients receiving adjuvant therapy was 52.4%. At multivariate analysis factors negatively influencing survival were a disease-free interval (DFI) of less than 24 months and recurrence after pulmonary metastasectomy. Conclusions: Pulmonary resection for metastatic gynecologic cancer is feasible and effective; adequate selection of patients is mandatory to achieve satisfactory results and long-term survival. PMID- 29119015 TI - Pulmonary metastasectomy for sarcoma-Essen experience. AB - Background: Pulmonary metastasectomy is an established treatment modality for patients with soft as well as bone tissue sarcomas. Aim of this study is to describe the Essen experience in the surgical management of patients with pulmonary sarcoma metastases. Methods: This is a retrospective single center analysis of perioperative outcome of patients undergoing pulmonary metastasectomy for sarcoma metastases from 1997-2017 and a summary of published papers on this topic. Results: During the observation period 327 patients (49.23% female) underwent pulmonary metastasectomy for metastases of extrathoracic sarcomas in curative intent. The number of resected metastases was 1-3 in 283 cases (86.54%), 4-9 in 31 cases (9.48%) and 10 or more lesions in 14 cases (4.28%). Wedge resections or precision excisions with laser or electrocautery were performed in 278 cases (85.02%), anatomical segmental resections in 16 patients (4.89%) and lobectomies in 33 patients (10.09%). Bilateral procedures were performed in 98 cases (29.96%). Lymphadenectomy was performed in 122 patients. Positive lymph nodes were found only in 6 cases. All of these cases were patients with soft tissue sarcoma as primary tumor. Preoperative neoadjuvant treatment was performed in 79 patients (24.15%) with chemotherapy, in 54 patients (16.51%) with radiochemotherapy and in 10 patients (3.05%) with radiotherapy. Major postoperative complications were observed in 2.75% of all patients. Thirty-day mortality was 0%. Conclusions: Pulmonary metastasectomy in sarcoma patients is a feasible and safe treatment strategy even in patients with bilateral metastases and multiple lesions. Thoracic lymph node metastases are rare and did not influence survival in our cohort. PMID- 29119016 TI - Pulmonary metastasectomy for colorectal cancer: analysis of prognostic factors affecting survival. AB - Background: Pulmonary metastasectomy is considered a standard procedure in the treatment of metastatic colorectal cancer (CRC). Different prognostic factors including multiple metastatic nodules, the presence of extra-pulmonary metastases and BRAF mutation status have been associated with poor survival. The aim of this study was to evaluate which factors influenced survival in CRC patients undergoing pulmonary metastasectomy by studying primary tumors and pulmonary metastases. Methods: All patients treated for primary CRC who presented pulmonary metastases in a 10-year period were considered (group A). A control group treated for primary CRC who did not develop any pulmonary or extra-pulmonary metastases was taken for comparison (group B). Different prognostic factors including gender, age, tumor location, histological type, inflammatory infiltrate, BRAF, CDX2 and extra-pulmonary metastases were analyzed. Overall survival (OS) and patients' survival after pulmonary metastasectomy were also considered. Results: Fifty-four patients were evaluated in group A and twenty-three in group B. In group A, BRAF immunohistochemistry did not significantly differ between primary tumors and pulmonary metastases; no difference of BRAF expression was found between group A and B. Even the expression of CDX2 was not significantly different in primary tumors and metastases. Similarly, in group B CDX2 did not significantly differ from primary CRC of group A. The most significant prognostic factor was the presence of extra-pulmonary metastases. Patients with extra pulmonary metastases experienced a significant shorter survival compared to patients with pulmonary metastases alone (P=0.001 with log-rank test vs. P=0.003 with univariate Cox regression). Interestingly, patients with right pulmonary metastases presented a significant longer survival than those with left pulmonary metastases (P=0.027 with log-rank test vs. 0.04 with univariate Cox regression). Conclusions: The main prognostic factor associated with poor survival after lung resection of CRC metastases is a history of extra-pulmonary metastases. BRAF and CDX2 did not have a significant role in this small series of patients. PMID- 29119017 TI - Pulmonary metastasectomy: an overview. AB - Metastasectomy is the most frequent surgical resection undertaken by thoracic surgeons, being the lung the second common site of metastases. The present oncological criteria for pulmonary metastasectomy are: (I) the primary cancer need to be controlled or controllable; (II) no extrathoracic metastasis-that is not controlled or controllable-exists; (III) all of the tumor must be resectable, with adequate pulmonary reserve; (IV) there are no alternative medical treatment options with lower morbidity. General favourable prognostic features in patients with pulmonary metastases are: (I) one or few metastases; (II) long disease free interval; (III) normal CEA levels in colorectal cancers. Negative predictive features in patients candidate to pulmonary metastasectomies are: (I) active primary cancer; (II) extrathoracic metastases; (III) inability to obtain surgical radicality; (IV) mediastinal lymphatic spread. The lack of controlled trials and studies limited by short follow-up and small cohorts did not allow to overcome some skepticism; moreover, the heterogeneity of these patients in terms of demographic, biologic and histologic characteristics represents a clear limit even in the largest series. On the basis of present knowledge, without results coming from on-going randomized trials, radical resection, histology, and disease free interval seem to be independent prognostic factors identifying a cohort of patients maximally benefitting from lung metastasectomy. PMID- 29119018 TI - Metastasectomy in pediatric patients: indications, technical tips and outcomes. AB - Pulmonary metastasectomy has become a standard procedure for pediatric patients with certain types of solid tumors. Surgeons, expert pediatric oncologists and radiation oncologists contribute with their different skills to the management of pulmonary metastases. Patients are usually scheduled for surgery in case of primary tumor control, in absence of metastases in other organs and when a complete resection is achievable. Nodules are removed through precision resections using electrocautery or laser methods in order to ensure radical surgery with adequate margins. With these techniques, it is possible to preserve the surrounding parenchyma and cause a limited volumetric distortion as compared with staplers. Anatomical resections (segmentectomy, lobectomy or pneumonectomy) should be reserved for selected cases, since major lung resection can only be justified if it leads to a real oncological advantage. Repeated thoracotomies are possible, since there is no theoretical limit to reinterventions. Surgery of lung metastases has a therapeutic and curative role for some histology with acceptable rate of complications but it finds its role only in an aggressive multimodality approach. Indications can be discussed case by case and exceptions can be evaluated also in presence of different evidences. Children affected by metastatic tumors need to be managed by expert multidisciplinary oncological team in referral center with large experience. PMID- 29119019 TI - Survival and prognostic factors following pulmonary metastasectomy for sarcoma. AB - Sarcomas are a heterogeneous group of malignancies with a marked propensity to metastasize to the lungs. Chemotherapy offers only a limited benefit in metastatic disease, whereas lung metastasectomy, in selected cases, can lead to long-term survival. Other local ablative techniques and hybrid therapies have been proposed. A multidisciplinary setting is of paramount importance for choosing the most appropriate treatment for each case. There is no randomized controlled trial providing formal evidence of the effectiveness of lung metastasectomy. Main areas of controversy concern the selection of surgical candidates, the operative approach and the role of chemotherapy. Five-year survival rates range from 15% to 50.9%, as reported mainly in retrospective case series in which several prognostic factors were identified. In this article, the authors review the surgical management of sarcoma metastases to the lung, with a particular focus on the outcomes and prognostic factors associated with long-term survival after resection. The role of chemotherapy and other adjunctive therapies is also discussed. PMID- 29119020 TI - Pulmonary metastasectomy in uterine malignancy: outcomes and prognostic factors. AB - Metastatic uterine cancer is a form of systemic disease. As for other solid tumours, it is advocated by some authors that in selected patients, lung metastasectomy may play a role in long-term disease control. The practice of lung metastasectomy is however open to criticism as there is lack of convincing evidence, and over-encouraging outcomes may be attributed to intrinsic selection bias. The case of metastatic uterine tumours is reviewed in the light of the available literature, in order to identify common patterns and prognostic factors that may influence and determine an individualised and informed patient decision. PMID- 29119021 TI - Comparison between the Correlations of Retinal Nerve Fiber Layer Thickness Measured by Spectral Domain Optical Coherence Tomography and Visual Field Defects in Standard Automated White-on-White Perimetry versus Pulsar Perimetry. AB - Purpose: To compare the structure-function relationships between retinal nerve fiber layer thickness (RNFLT) and visual field defects measured either by standard automated perimetry (SAP) or by Pulsar perimetry (PP). Materials and Methods: 263 eyes of 143 patients were prospectively included. Depending on the RNFLT, patients were assigned to the glaucoma group (group A: RNFL score 3-6) or the control group (group B: RNFL score 0-2). Structure-function relationships between RNFLT and mean sensitivity (MS) measured by SAP and PP were analyzed. Results: Throughout the entire group, the MS assessed by PP and SAP correlated significantly with RNFLT in all sectors. In the glaucoma group, there was no significant difference between the correlations RNFL-SAP and RNFL-PP, whereas a significant difference was found in the control group. Conclusions: In the control group, the correlation between structure and function based on the PP data was significantly stronger than that based on SAP. PMID- 29119022 TI - Bruch's Membrane Opening Minimum Rim Width Measurement with SD-OCT: A Method to Correct for the Opening Size of Bruch's Membrane. AB - A precise evaluation of the retinal nerve fiber layer thickness (RNFLT) is key for diagnosing and monitoring glaucoma. The Bruch's membrane opening minimum rim width (BMO-MRW) has been proposed as a reproducible assessment of the optic nerve. The BMO-MRW measures the minimum distance from the BMO to the internal limiting membrane. We propose an approach to correct the BMO-MRW using the BMO size for increased accuracy in interindividual comparisons in future studies. Eighty-one healthy patients received SPECTRALIS spectral domain optical coherence tomography measurements for the peripapillary RNFLT and BMO-MRW. We calculated a BMO size-corrected BMO-MRW using the mean BMO size of our cohort. BMO size was defined using the manufacturer-provided BMO area and manually measured BMO perimeter. We observed that the BMO-MRW correlated highly with the perimeter (r = -0.553, p < 0.0001) and the area of the BMO (r = -0.546, p < 0.0001). Using these parameters, we provided a corrected BMO size-adjusted BMO-MRW which was better correlated with the RNFLT compared to the noncorrected one (z = -3.3495, p = 0.0004). We demonstrated the dependency of the BMO-MRW on ONH size. Furthermore, we showed the superiority of the corrected BMO-MRW using either the manually measured optic nerve head perimeter or the automatically provided ONH for future studies. PMID- 29119023 TI - Improvement in Quality Metrics Outcomes and Patient and Family Satisfaction in a Neurosciences Intensive Care Unit after Creation of a Dedicated Neurocritical Care Team. AB - Introduction: Dedicated neurointensivists have been shown to improve outcome measurements in the neurosciences intensive care unit (NSICU). Quality outcome data in relation to patient and family satisfaction is lacking. This study evaluated the impact of newly appointed neurointensivists and creation of a neurocritical care team on quality outcome measures including patient satisfaction in a NSICU. Methods: This is a retrospective study of data over 36 months from a 14-bed NSICU evaluating quality outcome measures and anonymous patient satisfaction questionnaires before and after neurointensivists appointment. Results: After appointment of neurointensivists, patient acuity of the NSICU increased by 33.4% while LOS decreased by 3.5%. There was a decrease in neurosciences mortality (35.8%), catheter-associated urinary tract infection (50%), central line associated bloodstream infection (100%), and ventilator associated pneumonia (50%). During the same time, patient satisfaction increased by 28.3% on physicians/nurses consistency (p = 0.025), by 69.5% in confidence/trust in physicians (p < 0.0001), by 78.3% on physicians treated me with courtesy/respect (p < 0.0001), and by 46.4% on physicians' attentiveness (p < 0.0001). Ultimately, patients recommending the hospital to others increased by 67.5% (p < 0.0001). Conclusion: Dedicated neurointensivists and the subsequent development of a neurocritical care team positively impacted quality outcome metrics, particularly significantly improving patient satisfaction. PMID- 29119025 TI - Parachute-Like Mitral Valve Tuberculoma: A Rare Presentation. AB - There have been anecdotal reports of tuberculous cardiac involvement, mainly in cases of military tuberculosis or immune deficient individuals. The spectrum of clinical presentations of tuberculous cardiac involvements includes incidental detection of single and multiple well-circumscribed tuberculomas, symptomatic obstructive lesions, AV conduction abnormalities, and even sudden death. We present a case of cardiac tuberculoma in an immune-competent person who presented with worsening dyspnea. The unique morphology of this mass posed an imaging challenge that required 4-dimensional (4D) echocardiography and cardiac magnetic resonance (CMR) detail to differentiate the mass from an anterior mitral leaflet (AML) aneurysm. Histological examination after surgical resection confirmed its tuberculous etiology. PMID- 29119024 TI - Effects of Propofol Treatment in Neural Progenitors Derived from Human-Induced Pluripotent Stem Cells. AB - Propofol is an intravenous anesthetic that has been widely used in clinics. Besides its anesthetic effects, propofol has also been reported to influence the regulation of the autonomic system. Controversies exist with regard to whether propofol exposure is safe for pregnant women and young children. In this work, human-induced pluripotent stem cell- (hiPSC-) derived neural progenitor cells (NPCs) were treated with propofol at 20, 50, 100, or 300 MUM for 6 h or 24 h, and acute and subacute cell injury, cell proliferation, and apoptosis were evaluated. Comparison of genome-wide gene expression profiles was performed for treated and control iPSC-NPCs. Propofol treatment for 6 h at the clinically relevant concentration (20 or 50 MUM) did not affect cell viability, apoptosis, or proliferation, while propofol at higher concentration (100 or 300 MUM) decreased NPC viability and induced apoptosis. In addition, 20 MUM propofol treatment for 6 h did not alter global gene expression. In summary, propofol treatment at commonly practiced clinical doses for 6 h did not have adverse effects on hiPSC derived NPCs. In contrast, longer exposure and/or higher concentration could decrease NPC viability and induce apoptosis. PMID- 29119026 TI - Thiamine Deficiency Leading to Refractory Lactic Acidosis in a Pediatric Patient. AB - Thiamine plays a critical role in energy metabolism. Critically ill children and adults may develop thiamine deficiency with ultimately increased mortality due to potentially irreversible consequences of severe type B lactic acidosis. We report a case of an unvaccinated term neonate with malignant pertussis requiring extracorporeal membrane oxygenation and continuous renal replacement therapy, who developed profound lactic acidosis of unknown etiology. After countless evaluations for likely causes, the patient was ultimately determined to have thiamine deficiency and her acidosis resolved rapidly with vitamin supplementation. PMID- 29119027 TI - Dosing of Ertapenem in an Extreme Obesity: A Case Report of 250 kg Patient. AB - Limited available data for dosing in obesity of the medicines used in this case are discussed, with the emphasis on ertapenem. The case illustrates the difficulties in dosing medicines to morbidly overweight patients. The number of such patients is increasing but data on adequate doses of medicines are scarce. We demonstrate that ertapenem 1,5 g i.v. once daily provided adequate drug exposure for susceptible bacteria in a 250 kg patient with normal renal function. The case suggests the usefulness of therapeutic drug monitoring of antibiotics, especially in critically ill patients. PMID- 29119028 TI - Erosive Pustular Dermatosis of the Scalp with Urate-Like Crystals. AB - Follicular urate-like crystals were first described in Necrotizing Infundibular Crystalline Folliculitis (NICF), a rare cutaneous disorder with multiple waxy folliculocentric papules. Similar crystal accumulation may be seen within follicular infundibulae as an incidental finding. We describe a case showing identical crystals occurring within the horn-like crusts of a patient with erosive pustular dermatosis of the scalp (EPDS), a condition which due to its presentation can often be mistaken for nonmelanoma skin cancer. A brief overview of erosive pustular dermatosis of the scalp (EPDS) is presented in this paper. PMID- 29119029 TI - Rhabdomyolysis Induced by Coadministration of Fusidic Acid and Atorvastatin: A Case Report and Comprehensive Review of the Literature. AB - Statins are among the most widely prescribed medications worldwide. Acute rhabdomyolysis constitutes a potentially life-threatening side effect regardless of whether statins are administered alone or in combination. The potentially fatal combination of a statin and fusidic acid has been well described in the literature. Acute renal failure can be a direct consequence of this drug-drug interaction. We present a case of a 79-year-old woman who presented to our Emergency Department with a one-week history of limb weakness, myalgia, and inability to stand and walk. The patient had been given fusidic acid to treat Methicillin-Sensitive Staphylococcus Aureus (MSSA) positive dermatitis in the 3 weeks prior to admission, while she continued to take her complete therapeutic regimen, which included atorvastatin. Thus, she developed rhabdomyolysis due to the interaction between fusidic acid and atorvastatin. Herein, we report a life threatening complication of coadministration of fusidic acid and a statin, which is preventable and predictable. The exact mechanism of the interaction is not fully understood, but coadministration of these two medications must be avoided in clinical practice. PMID- 29119030 TI - Latanoprost Induced Iris Pigment Epithelial and Ciliary Body Cyst Formation in Hypermetropic Eyes. AB - Purpose: Latanoprost has become one of the most widely prescribed topical antihypertensive medications in recent years. Yet there have been few reports of secondary iris pigment epithelial (IPE) and ciliary body (CB) cyst formation to date and none, to our knowledge, reported in eyes predisposed to primary angle closure. Methods: We report the first documented case of bilateral IPE and CB cysts in a hypermetropic patient with prior laser peripheral iridotomies (LPIs) as a rare, delayed side effect of topical Latanoprost treatment. The cysts subsided with discontinuation of Latanoprost, thereby demonstrating a causal relationship. We discuss the pathogenesis of such cysts and advocate using of serial ultrasound biomicroscopic (UBM) images to monitor them. Results and Conclusions: Latanoprost may cause iris pigment epithelial and ciliary body cysts that remain clinically undetected. In eyes predisposed to angle closure, such cysts may become clinically detectable and masquerade as iris tumours. Prior laser peripheral iridotomies in these eyes may delay or prevent the detection of these cysts. Ultrasound biomicroscopy (UBM) imaging is therefore a valuable tool in diagnosing and monitoring these cysts. PMID- 29119031 TI - Pediatric Pulmonary Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Case Report and Review of the Literature. AB - Non-Hodgkin's lymphoma (NHL) is a common malignancy of childhood; however, a lung primary presentation is an uncommon finding, as is finding an association with the Epstein-Barr virus (EBV). We report the case of a 23-month-old female who developed EBV-associated diffuse large B-cell lymphoma (DLBCL) that was initially thought to be pneumonia. Extensive tissue necrosis, focal angioinvasion, and angiodestruction were observed. She was refractory to various therapy regimens, subsequently developed DLBCL in the central nervous system, and eventually expired. Although EBV+ DLBCL was initially considered to occur predominantly in elderly patients over 50 years of age, it is now increasingly recognized to occur in younger patients with primarily nodal involvement who have overall better prognoses. To our knowledge, this case is the first reported EBV+ DLBCL occurring in a patient below two years of age with lung involvement as the initial clinical presentation. PMID- 29119032 TI - Cytomegalovirus Associated Duodenal Ulcer and Duodenitis in a Malnourished Pediatric Patient. AB - Cytomegalovirus (CMV) duodenitis is a rare occurrence, especially in pediatric patients. A thirteen-month-old female presented to the Emergency Department for a febrile seizure. She was incidentally admitted for severe malnutrition with an initial workup remarkable for only a slight elevation in her ALT at 48. The patient was found to have an oral aversion requiring nasogastric tube feeds for adequate caloric intake. She continued to fail to gain weight and underwent an EGD that demonstrated a duodenal ulcer. She was consequently started on sucralfate and omeprazole. Post-EGD lab work demonstrated a pronounced increase in AST and ALT. Pathology from the EGD biopsies later demonstrated viral inclusion bodies consistent with CMV duodenitis. Apart from malnutrition, other causes of immune deficiency were eliminated from the differential diagnosis due to negative HIV PCR and normal immunoglobulins. While on antiviral treatment, her viral load of 1080 IU/mL trended to resolution and her liver enzymes normalized. The patient was ultimately discharged home demonstrating adequate weight gain via gastrostomy tube feeds. This case advocates for pediatricians to include immunodeficiency and infectious etiologies in their differential for malnourished patients in order to lead to earlier diagnosis and management of this treatable condition. PMID- 29119033 TI - The Utility of MRI in the Diagnosis of Takayasu Arteritis. AB - Takayasu Arteritis (TA) is an inflammatory disorder involving the thoracoabdominal aorta and its branches and the pulmonary arteries, with eventual vascular stenosis, occlusion, or aneurysm formation. Conventional angiography has been the reference imaging standard for diagnosis of TA. The purpose of this case report is to demonstrate the utility of MR imaging and MR angiography in the diagnosis of Takayasu Arteritis in a pediatric patient. The patient is a 15-year old female patient presenting with anemia, hypertension, and acute kidney injury. Initial chest CT demonstrated ectasia of the ascending and focal stenosis of the descending thoracic aorta, prompting further evaluation with MRI and MRA. MRI/MRA demonstrated mural thickening with luminal stenosis of the aorta and aortic branch vessels. These imaging findings were suggestive of a large vessel arteritis and along with the clinical presentation and laboratory abnormalities the diagnosis of Takayasu Arteritis was suggested. Several case series in adults have described the cross-sectional findings of TA. However, this case report demonstrates the utility of MRI/MRA in the evaluation of TA in children and in the course of follow-up, as it provides a noninvasive method for evaluating a child without ionizing radiation or iodinated contrast. PMID- 29119034 TI - A Unique Case of Testicular Compromise in a Patient with Ovotesticular Disorder of Sexual Development and a Solitary Testicle. AB - Ovotesticular disorder of sexual development (OT-DSD), previously true hermaphroditism, is a condition in which one or both gonads contain testicular and ovarian tissue. A 23-year-old OT-DSD male patient presented with continuous pain in his right testicle which had been previously intermittent over the past five days. The patient had a prior history of left ovotestis removal with prosthesis placement, a right undescended testicle with aberrant anatomy, and hypospadias repair, all of which were corrected shortly after birth. A lack of blood flow to the testicle on Doppler ultrasound warranted immediate surgical intervention. Intraoperatively, an aberrant tunica vaginalis space with a compressive hematoma secondary to epididymal abscess rupture was identified as the causation for testicular compromise. Return of vascular flow to the testicle was confirmed with intraoperative Doppler after hematoma and epididymis excision, and the testicle was left in situ. It is imperative to consider epididymal etiologies with acute testicular pain, especially in a patient with a medical history that carries an increased risk for gonadal anomalies. PMID- 29119035 TI - Discordant HIV Test Results: Implications on Perinatal and Haemotransfusion Screening for HIV Infection, Cape Coast, Ghana. AB - Screening results of 488 pregnant women aged 15-44 years whose blood samples had been tested on-site, using First Response(r) HIV 1/2, and confirmed with INNO LIATM HIV I/II Score were used. Of this total, 178 were reactive (HIV I, 154; HIV II, 2; and HIV I and HIV II, 22). Of the 154 HIV I-reactive samples, 104 were confirmed to be HIV I-positive and 2 were confirmed to be HIV II-positive, while 48 were confirmed to be negative [false positive rate = 17.44% (13.56-21.32)]. The two HIV II samples submitted were confirmed to be negative with the confirmatory test. For the 22 HIV I and HIV II samples, 7 were confirmed to be HIV I-positive and 1 was confirmed to be HIV I- and HIV II-positive, while 14 were confirmed to be negative. Of the 310 nonreactive samples, 6 were confirmed to be HIV I-positive and 1 was confirmed to be HIV II-positive [false negative rate = 5.79% (1.63-8.38)], while 303 were negative. False negative outcomes will remain unconfirmed, with no management options for the client. False negative rate of 5.79% requires attention, as its resultant implications on control of HIV/AIDS could be dire. PMID- 29119036 TI - Technology-Assisted Rehabilitation of Writing Skills in Parkinson's Disease: Visual Cueing versus Intelligent Feedback. AB - Recent research showed that visual cueing can have both beneficial and detrimental effects on handwriting of patients with Parkinson's disease (PD) and healthy controls depending on the circumstances. Hence, using other sensory modalities to deliver cueing or feedback may be a valuable alternative. Therefore, the current study compared the effects of short-term training with either continuous visual cues or intermittent intelligent verbal feedback. Ten PD patients and nine healthy controls were randomly assigned to one of these training modes. To assess transfer of learning, writing performance was assessed in the absence of cueing and feedback on both trained and untrained writing sequences. The feedback pen and a touch-sensitive writing tablet were used for testing. Both training types resulted in improved writing amplitudes for the trained and untrained sequences. In conclusion, these results suggest that the feedback pen is a valuable tool to implement writing training in a tailor-made fashion for people with PD. Future studies should include larger sample sizes and different subgroups of PD for long-term training with the feedback pen. PMID- 29119037 TI - Thermal Emission of Alkali Metal Ions from Al30-Pillared Montmorillonite Studied by Mass Spectrometric Method. AB - The thermal emission of alkali metal ions from Al30-pillared montmorillonite in comparison with its natural form was studied by mass spectrometry in the temperature range 770-930 K. The measurements were carried out on a magnetic mass spectrometer MI-1201. For natural montmorillonite, the densities of the emission currents (j) decrease in the mass spectrum in the following sequence (T = 805 K, A/cm2): K+ (4.55 . 10-14), Cs+ (9.72 . 10-15), Rb+ (1.13 . 10-15), Na+ (1.75 . 10 16), Li+ (3.37 . 10-17). For Al30-pillared montmorillonite, thermionic emission undergoes temperature-time changes. In the low-temperature section of the investigated range (770-805 K), the value of j increases substantially for all ions in comparison with natural montmorillonite (T = 805 K, A/cm2): Cs+ (6.47 . 10-13), K+ (9.44 . 10-14), Na+ (3.34 . 10-15), Rb+ (1.77 . 10-15), and Li+ (4.59 . 10-16). A reversible anomaly is observed in the temperature range 805-832 K: with increasing temperature, the value of j of alkaline ions falls abruptly. This effect increases with increasing ionic radius of M+. After a long heating-up period, this anomaly disappears and the lnj - 1/T dependence acquires a classical linear form. The results are interpreted from the point of view of the dependence of the efficiency of thermionic emission on the phase transformations of pillars. PMID- 29119038 TI - Visualization of phage DNA degradation by a type I CRISPR-Cas system at the single-cell level. AB - Background: The CRISPR-Cas system is a widespread prokaryotic defense system which targets and cleaves invasive nucleic acids, such as plasmids or viruses. So far, a great number of studies have focused on the components and mechanisms of this system, however, a direct visualization of CRISPR-Cas degrading invading DNA in real-time has not yet been studied at the single-cell level. Methods: In this study, we fluorescently label phage lambda DNA in vivo, and track the labeled DNA over time to characterize DNA degradation at the single-cell level. Results: At the bulk level, the lysogenization frequency of cells harboring CRISPR plasmids decreases significantly compared to cells with a non-CRISPR control. At the single-cell level, host cells with CRISPR activity are unperturbed by phage infection, maintaining normal growth like uninfected cells, where the efficiency of our anti-lambda CRISPR system is around 26%. During the course of time-lapse movies, the average fluorescence of invasive phage DNA in cells with CRISPR activity, decays more rapidly compared to cells without, and phage DNA is fully degraded by around 44 minutes on average. Moreover, the degradation appears to be independent of cell size or the phage DNA ejection site suggesting that Cas proteins are dispersed in sufficient quantities throughout the cell. Conclusions: With the CRISPR-Cas visualization system we developed, we are able to examine and characterize how a CRISPR system degrades invading phage DNA at the single-cell level. This work provides direct evidence and improves the current understanding on how CRISPR breaks down invading DNA. PMID- 29119039 TI - OsiriX software as a preoperative planning tool in cranial neurosurgery: A step by-step guide for neurosurgical residents. AB - Background: OsiriX (Pixmeo, Switzerland) is an open-source Digital Imaging and Communications in Medicine (DICOM) viewer that is gaining more and more attention in the neurosurgical community because of its user-friendly interface, powerful three-dimensional (3D) volumetric rendering capabilities, and various options for data integration. This paper presents in detail the use of OsiriX software as a preoperative planning tool in cranial neurosurgery. Methods: In January 2013, OsiriX software was introduced into our clinical practice as a preoperative planning tool. Its capabilities are being evaluated on an ongoing basis in routine elective cranial cases. Results: The program has proven to be highly effective at volumetrically representing data from radiological examinations in 3D. Among its benefits in preoperative planning are simulating the position and exact location of the lesion in 3D, tailoring the skin incision and craniotomy bone flap, enhancing the representation of normal and pathological anatomy, and aiding in planning the reconstruction of the affected area. Conclusion: OsiriX is a useful tool for preoperative planning and visualization in neurosurgery. The software greatly facilitates the surgeon's understanding of the relationship between normal and pathological anatomy and can be used as a teaching tool. PMID- 29119040 TI - Giant mucopyocele associated with intracranial hypertension: Case report and literature review. AB - Background: Mucoceles are epithelial lined sacs that contain mucous. Eventually, they can be infected and so called mucopyoceles, which are usually slow growing lesions with common bone destruction located in the facial sinus. Mucoceles show multivariate etiology and occur between the fourth and seventh decade of life. Case Description: Patient, 55-year-old, female, was referred unconscious with Cushing's triad to our department; she had fever since four days. The findings of skull computer tomography highlighted a large bifrontal lesion with an invasion of the rear wall of the frontal sinus, compression of the frontal lobes, and midline deviation. She was taken for an emergency surgery, which showed invasion of the dura and mucous infection. Postoperatively, there was a fast recovery of neurologic level and extubation on the second postoperative day. She took antibiotics for 14 days and was discharged from the hospital without neurologic deficits. Conclusions: Mucopyoceles are usually slow growing lesions that rarely increases rapidly. Our patient presented signs of intracranial hypertension; therefore, it was necessary to have quick surgical intervention. PMID- 29119041 TI - Malignant glioma-primitive neuroectodermal tumor recurring as PNET-like only subdural collection: Case report. AB - Background: Histologic variants of conventional glioblastoma are rare clinical entities. In recent years, an aggressive variant termed malignant glioma with primitive neuroectodermal tumor components (MG-PNET) has been described in adults. In addition to the rarity of supratentorial primitive neuroectdoermal tumors (sPNET) in adults, MG-PNET can present with unique radiographic features. Case Description: We report the case of a 42-year-old male who presented with headaches and vision changes. Magnetic resonance imaging (MRI) of the brain revealed a large right frontal lesion. He underwent craniotomy with pathology demonstrating glioblastoma WHO grade IV, with primitive neuroectodermal tumor like components (MG-PNET). Seven weeks later the patient represented with worsening headaches and left-hand weakness. MRI brain revealed a diffusion restricting subdural collection overlying the prior craniotomy site. Biopsy revealed PNET-like recurrence of the previously treated MG-PNET. Conclusion: In addition to histologic deviation, MG-PNET can present with variable radiographic findings on MRI and a clinical course distinctive from traditional glioblastoma. The hypercellular nature of this lesion can present as a diffusion-restricting lesion. PMID- 29119042 TI - Extradural hemangioma mimicking a dumbbell nerve sheath tumor in the thoracolumbar spine: Case report. AB - Background: Extradural hemangiomas are rare, have varied and challenging clinical presentations, and require special considerations from the management point of view. Case Description: A 70-year-old female presented with back pain that was ultimately attributed to a thoracolumbar extra-dural "dumbbell" hemangioma. Following surgical resection, the patient did well. Conclusion: Extradural hemangiomas may present as spinal extradural soft tissue masses that must be differentiated from dumbbell neurofibroma. PMID- 29119043 TI - Successful outcome after endovascular thrombolysis for acute ischemic stroke even after 24 h of symptoms onset? PMID- 29119044 TI - Nursing review of diagnosis and treatment of lumbar degenerative spondylolisthesis. AB - Background: In the lumbar spine, degenerative spondylolisthesis or degenerative (not traumatic) slippage of one vertebral body over another is divided into 4 grades - grade I (25%), grade II (50%), grade III (75%), and grade IV (100%). Dynamic X-rays, magnetic resonance (MR), and computed tomography (CT) scans document the slip secondary to arthritic changes of the facet joint plus stenosis, ossification of the yellow ligament, disc herniations, and synovial cysts. MR best demonstrates soft tissue pathology whereas CT better delineates ossific/calcified disease. Methods: Grade I degenerative spondylolisthesis, typically found at the L4-L5 level followed by L3-L4 and L5S1, is more common in females (ratio 2:1) over the age of 65. Symptoms include radiculopathy (root pain) and neurogenic claudication (e.g., pain with ambulation, requiring the patient to stop, rest, sit down). Symptoms/signs may include unilateral/bilateral radiculopathy and uni/multifocal motor, reflex, and sensory deficits in. Some may also present with a cauda equina syndrome (e.g., paraparesis/sphincter dysfunction). Results: Surgery for grade I-II spondylolisthesis may include laminectomy alone, laminectomy/noninstrumented fusion or with an instrumented fusion. Older patients with osteoporosis are more likely to have no fusion or a noninstrumented fusion. All fusions utilize autograft harvested from the laminectomy that may or may not be combined with a bone graft expander (to increase the fusion mass) combined with autogenous bone marrow aspirate. The fusion mass is placed over the transverse processes following decortication. Conclusions: Patients with multilevel spinal stenosis and degenerative spondylolisthesis may require decompressive lumbar laminectomies alone or in combination with noninstrumented or instrumented fusions. PMID- 29119045 TI - Lumbar stenosis surgery: Spine surgeons not insurance companies should decide when enough is better than too much. AB - Background: Lumbar surgery for spinal stenosis is the most common spine operation being performed in older patients. Nevertheless, every time we want to schedule surgery, we confront the insurance industry. More often than not they demand patients first undergo epidural steroid injections (ESI); clearly they are not aware of ESI's lack of long-term efficacy. Who put these insurance companies in charge anyway? We did. How? Through performing too many unnecessary or overly extensive spinal operations (e.g., interbody fusions and instrumented fusions) without sufficient clinical and/or radiographic indications. Methods: Patients with lumbar spinal stenosis with/without degenerative spondylolisthesis (DS) are being offered decompressions alone and/or unnecessarily extensive interbody and/or instrumented fusions. Furthermore, a cursory review of the literature largely demonstrates comparable outcomes for decompressions alone vs. decompressions/in situ fusions vs. interbody/instrumented fusions. Results: Too many older patients are being subjected to unnecessary lumbar spine surgery, some with additional interbody/non instrumented or instrumented fusions, without adequate clinical/neurodiagnostic indications. Conclusions: The decision to perform spine surgery for lumbar stenosis/DS, including decompression alone, decompression with non instrumented or instrumented fusion should be in the hands of competent spinal surgeons with their patients' best outcomes in mind. Presently, insurance companies have stepped into the "void" left by spinal surgeons' failing to regulate when, what type, and why spinal surgery is being offered to patients with spinal stenosis. Clearly, spine surgeons need to establish guidelines to maximize patient safety and outcomes for lumbar stenosis surgery. We need to remove insurance companies from their present roles as the "spinal police." PMID- 29119046 TI - Hemorrhagic intracranial follicular dendritic cell sarcoma: A case report. AB - Background: Follicular dendritic cell (FDC) sarcoma is an extremely rare neoplasm, which has only been reported once in the literature with an intracranial occurrence. Neither hemorrhagic presentation of an intracranial instance of FDC sarcoma nor its rapid recurrence has yet been published in the literature. Case Description: We report the case of a 61-year-old female who presented with confusion and headaches secondary to a right frontal hemorrhagic lesion, and her subsequent presentations for recurrence of the lesion and finding of a new intracranial lesion. Immunohistopathologic analysis confirmed the diagnosis based on immunoreactivity for clusterin and CD 35. Conclusion: As demonstrated in this case report, the presentation and progression of primary intracranial follicular dendritic cell sarcoma can often be misleading, and consideration for this rare entity should be made in cases of hemorrhagic dural based lesions without a primary source of malignancy. PMID- 29119047 TI - Infections in deep brain stimulation: Shaving versus not shaving. AB - Background: To report our experience of infections in deep brain stimulation (DBS) surgeries comparing shaving versus no shaving of cranial hair. Nonshaving is strongly preferred by patients due to aesthetic and psychological factors. Methods: This study is a prospective follow-up of the infection rate in 43 nonshaven DBS cases between April 2014 and December 2015 compared to our former infection rate with shaving in our center. Minimum follow-up was 6 months. All patients, except 7 epilepsy patients, received implantation of the electrodes together with the extension cables and internal pulse generator in one session. Results: In 43 nonshaven patients, a total of 81 electrodes were implanted or revised with a mean follow-up of 16 months. One patient (2.32%) developed an infection of the implanted DBS-hardware and was treated with antibiotics. Conclusion: In our experience nonshaving of cranial hair in DBS surgery does not lead to more infections when compared to shaving. We have changed our protocol to nonshaving based on these findings. PMID- 29119048 TI - Elucidating immunometabolic targets in glioblastoma. AB - Immunometabolism has recently emerged on the forefront of cancer research as a new avenue to potentially develop more effective and targeted treatment options. Several pathologically altered metabolic targets across various cancer types have been identified, including lactate in aerobic glycolysis; tryptophan in amino acid metabolism; and arginine in the urea cycle. Numerous advancements have improved our understanding of the dual function of these targets in influencing immune functions as an auxiliary function to their well-established metabolic role. This paper provides a comprehensive overview of immunometabolism research and attempts to provide insight into potential immunometabolic targets in glioblastoma for the purpose of future development and study of targeted therapies. PMID- 29119049 TI - miR19b-3p promotes the growth and metastasis of colorectal cancer via directly targeting ITGB8. AB - MicroRNAs (miRNAs) are widely up-regulated or down-regulated in a variety of tumors, including lung cancer, liver cancer, and colorectal cancer (CRC). Furthermore, miRNAs can function as tumor suppressors or proto-oncogenes by controlling the growth and metastasis of cancer cells. In the present study, we found a significant increase in miR19b-3p levels in CRC compared to tumor tissue and revealed the role of miR19b-3p in CRC growth and metastasis. The exogenous overexpression of miR19b-3p induced the proliferation, migration, and invasion of CRC cells in vitro. In addition, the nude mouse xenograft model showed that miR19b-3p overexpression promoted CRC growth and lung metastasis in vivo, whereas silencing miR19b-3p showed opposite results. Mechanistic studies have shown that the integrin beta-8 (ITGB8) transcript is one of the direct targets of miR19b-3p, and the expression of ITGB8 in CRC specimens was positively correlated with miR19b-3p. Finally, ectopic expression of ITGB8 rescued cell proliferation and invasion, which was inhibited by down-regulation of miR19b-3p. In addition, knockdown of ITGB8 neutralized the effects of miR19b-3p overexpression on cell growth and metastasis in CRC cells. Together, these results suggest that the miR19b-3p/ITGB8 axis plays an important role in the growth and metastasis of CRC. PMID- 29119050 TI - Long noncoding RNA NBAT1 negatively modulates growth and metastasis of osteosarcoma cells through suppression of miR-21. AB - Osteosarcoma (OS) is the most common primary bone malignancies. Long noncoding RNAs (lncRNAs) are key regulatory RNAs which takes part in several biological processes. LncRNA neuroblastoma associated transcript 1 (NBAT1) is a newly identified functional lncRNA. NBAT1 functions as a tumor suppressor in some cancers. However, the expression pattern, the biological function and the mechanisms of NBAT1 in OS progress have not been elucidated. In this study, for the first time, we found that NBAT1 expression is downregulated in OS tissues and cell lines and is associated with clinical stage, distant metastasis and poor prognosis. Loss- and gain-of-function assays showed that NBAT1 played a negative regulatory role in OS growth and metastasis in vitro and in vivo. Further investigation demonstrated that NBAT1 physically interacted with miR-21 and then suppressed its expression. NBAT1 also regulated downstream genes targeted by miR 21, including PTEN, PDCD4, TPM1 and RECK. These findings may extend the function of NBAT1 in tumor progression and provide a novel target for OS treatment. PMID- 29119051 TI - USP51 promotes deubiquitination and stabilization of ZEB1. AB - ZEB1 is a transcription factor that induces epithelial-mesenchymal transition, tumor metastasis, and therapy resistance. ZEB1 protein is subject to ubiquitination and degradation, but the mechanism by which ZEB1 is stabilized in cells remains unclear. By screening a human deubiquitinase library, we identified USP51 as a deubiquitinase that binds, deubiquitinates, and stabilizes ZEB1. Depletion of USP51 in mesenchymal-like breast cancer cells led to downregulation of ZEB1 protein and mesenchymal markers, upregulation of E-cadherin, and inhibition of cell invasion. Conversely, overexpression of USP51 in epithelial cells resulted in upregulation of ZEB1 and mesenchymal markers. In addition, USP51 is able to regulate the expression of ZEB1 target genes. Importantly, USP51 is overexpressed in breast cancer patients and correlates with poor survival. Taken together, our findings suggest that USP51 is a ZEB1 deubiquitinase that may serve as an alternative pathway for targeting the cancer-promoting transcriptional factor ZEB1. PMID- 29119052 TI - Synergistic anticancer activity of a novel oral chemotherapeutic agent containing trifluridine and tipiracil in combination with anti-PD-1 blockade in microsatellite stable-type murine colorectal cancer cells. AB - Trifluridine/tipiracil (FTD/TPI) is a combination of FTD, an antineoplastic thymidine-based nucleoside analog, and TPI, which acts to enhance the bioavailability of FTD in vivo. It is used to treat patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. We investigated the anticancer activity of FTD/TPI combined with anti-mouse programed cell death 1 (PD-1) monoclonal antibody (mAb) against CMT-93 cells, which are microsatellite stable (MSS)-type murine colorectal cancer cells. Tumor growth inhibition (TGI) after treatment with anti-mouse PD-1 mAb monotherapy (0.1 mg, i.p., days 1, 5, 9) and FTD/TPI monotherapy (150 mg/kg/day, p.o., days 1-14) were 86.7% and 52.7%, respectively, and that of the combination was 98.4%. The TGI of the combination therapy was significantly greater than that of each monotherapy (P<0.05). The combination therapy caused complete tumor regression in four out of five mice without body-weight reduction, but neither of the monotherapies resulted in complete tumor regression. Low dose FTD/TPI (75 and 100 mg/kg) combined with anti-mouse PD-1 mAb also showed significant antitumor activity against CMT-93 tumors. Flow cytometric analysis revealed that a higher CD8+ T cell ratio among total lymphocytes and a lower regulatory T cells (Tregs) ratio in CD4+ T cells in the combination group compared with that in the control group. These results suggested that the combination therapy induced a cytotoxic response from infiltrated cytotoxic CD8+ T cells and reduced immunosuppressive activity as indicated by decreased Tregs. In this study, the combination therapy was found to have synergistically greater antitumor activity against CMT-93 cells. These preclinical findings indicated that FTD/TPI and anti-mouse PD-1 mAb combination therapy may be a promising treatment option, even for MSS-type colorectal cancer. PMID- 29119053 TI - Enzalutamide as an androgen receptor inhibitor prevents urothelial tumorigenesis. AB - Emerging preclinical evidence suggests the critical role of androgen-mediated androgen receptor (AR) signals in the development of bladder cancer. However, little is known about the efficacy of enzalutamide, an AR signaling inhibitor, in androgen-induced urothelial tumorigenesis. We therefore aimed to assess the effects of enzalutamide on neoplastic transformation of urothelial cells. An immortalized normal urothelial cell line SVHUC stably expressing wild-type AR (SVHUC-AR) was exposed to a chemical carcinogen 3-methylcholanthrene (MCA) to induce neoplastic transformation, and subsequently cultured for 6 weeks in the presence of anti-androgens, including enzalutamide, hydroxyflutamide, and bicalutamide. Tumorigenesis was then monitored, using plate and soft agar colony formation assays as well as mouse xenograft models. In SVHUC-AR cells exposed to MCA, each anti-androgen inhibited AR-mediated transcriptional activity, but only enzalutamide prevented AR nuclear translocation. In vitro transformation showed that treatment with each anti-androgen during the process of neoplastic transformation reduced the efficiency of colony formation in vitro. Compared with mock treatment, culture with enzalutamide (P = 0.028), hydroxyflutamide (P = 0.033), or bicalutamide (P = 0.038) also resulted in prevention/retardation of tumor formation in male NOD-SCID mice. In addition, anti-androgens up-regulated the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and PTEN, and down-regulated that of several oncogenic genes, such as c-myc, cyclin D1, and cyclin E, in MCA-exposed SVHUC-AR cells. Thus, enzalutamide, flutamide, and bicalutamide were found to similarly prevent neoplastic transformation of urothelial cells. These findings offer a potential chemopreventive approach for urothelial tumors using AR antagonists. PMID- 29119054 TI - MiR-216b functions as a tumor suppressor by targeting HMGB1-mediated JAK2/STAT3 signaling way in colorectal cancer. AB - MiR-216b is implicated in the development of multiple types of cancers, however, a role for miR-216b in colorectal cancer (CRC) remains elusive. The present study aimed to investigate the function and underlying mechanism of miR-216b in human CRC. In this study, we found miR-216b in CRC tissues and cell lines was markedly decreased compared with corresponding adjacent normal tissues (ANTs) and colonic mucosal epithelial cell line (FHC), and was obviously associated with the TNM stage, lymph node metastases, differentiation and poor overall survival (OS) (P<0.05). Furthermore, we demonstrated that miR-216b inhibited cell proliferation, migration, invasion and angiogenesis by targeting HMGB1 which was highly expressed in CRC. Additionally, we proved that miR-216b promoted the development and progression of CRC, at least partially through HMGB1-mediated JAK2/STAT3 pathway. Lastly, we showed that plasma miR-216b expression was reduced in CRC when compared to healthy controls and might be a potential diagnostic biomarker for CRC. The findings indicated that miR-216b might function as a suppressor in CRC and could serve as a promising diagnostic and prognostic biomarker for CRC. PMID- 29119055 TI - MiR-488 suppresses cell proliferation and invasion by targeting ADAM9 and lncRNA HULC in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) have been identified as regulators of tumor proliferation, invasion, and metastasis in hepatocellular carcinoma (HCC). In the current study, we determined the clinical significance and biological role of miR-488 in HCC. Our results demonstrated that the expression of miR-488 was notably downregulated in HCC tissues compared with paired adjacent normal tissues. Lower miR-488 expression was positively associated with tumor size, vascular invasion, and shorter overall survival (OS) in HCC patients. Furthermore, gain-and-lost function assays showed that upregulation of miR-488 significantly inhibited cell proliferation, colony formation, cell invasion, and the epithelial-to-mesenchymal transition (EMT) process. We showed that ADAM9 served as a direct target for miR 488 and mediated lower miR-488 expression, thus inducing cell proliferation and invasion in HCC. Moreover, we found that lncRNA HULC is a target of miR-488 in HCC cells and miR-488 inhibited the expression of HULC by sponging to HULC in HCC. Thus, our results suggest that miR-488 functions as a tumor suppressor in HCC and may be a potential target for HCC treatment. PMID- 29119056 TI - Downregulation of cyclin-dependent kinase 8 by microRNA-148a suppresses proliferation and invasiveness of papillary thyroid carcinomas. AB - MicroRNAs (miRNAs) are important gene regulators that play key roles in tumor genesis. In this study, we investigate the role of miR-148a in the development of papillary thyroid cancer (PTC). Data from the cancer genome atlas (TCGA) indicate that miR-148a is downregulated in PTC tissues; we also find that miR-148a is downregulated in tissue samples from PTC patients and PTC cell lines. Overexpression of miR-148a significantly suppresses PTC cell proliferation, migration and invasiveness in vitro, and inhibits tumor growth in vivo as well. We have identified the cyclin-dependent kinase 8 (CDK8) gene as a direct target of miR-148a using the online software packages TargetScan and miRanda. Overexpression of miR-148a significantly represses CDK8 expression by directly targeting the 3'-untranslated region (3'-UTR) of the CDK8 gene in PTC tissues and cell lines; overexpression of CDK8 reverses the inhibitory effects of miR-148a on PTC cell growth, migration and invasiveness. Taken together, our results indicate that miR-148a functions as a tumor suppressor in PTC by repressing CDK8 expression. PMID- 29119057 TI - Dendritic cells based immunotherapy. AB - Dendritic cells (DCs) are the most potent antigen-presenting cells, and tumor antigen-loaded DCs (DC-vaccines) can activate tumor-specific cytotoxic T lymphocytes (CTLs) in lymphatic tissues. DC vaccination is a newly emerging and potent form of cancer immunotherapy and has clinically relevant mechanisms of action with great potential for the systemic treatment of cancers. However, clinical trials have demonstrated relatively poor therapeutic efficacy. The efficacy of DC-vaccines is strongly influenced by various techniques for the priming antigen loading onto DCs and their ability to migrate to the draining lymph nodes (LNs). Therefore, it is critical to improve DC-vaccines homing to draining LNs after administration in order to optimize DC-based therapy for individual patients. This review underlines 1) appropriate strategy to load tumor antigens onto DCs and 2) to optimize vaccine administration methods to ensure loaded DCs can migrate to LNs, in particular, Intraperitoneal (IP) injection. IP injection of DC-based vaccine may be a potential regimen for gastrointestinal tumors including hepatocellular carcinoma (HCC) and pancreatic adenocarcinoma (PDAC) since huge populations of LNs are present throughout the gastrointestinal track. Which might improve the subsequent migration to LNs. PMID- 29119058 TI - Next-generation in vivo optical imaging with short-wave infrared quantum dots. AB - For in vivo imaging, the short-wavelength infrared region (SWIR; 1000-2000 nm) provides several advantages over the visible and near-infrared regions: general lack of autofluorescence, low light absorption by blood and tissue, and reduced scattering. However, the lack of versatile and functional SWIR emitters has prevented the general adoption of SWIR imaging by the biomedical research community. Here, we introduce a class of high-quality SWIR-emissive indium arsenide-based quantum dots (QDs) that are readily modifiable for various functional imaging applications, and that exhibit narrow and size-tunable emission and a dramatically higher emission quantum yield than previously described SWIR probes. To demonstrate the unprecedented combination of deep penetration, high spatial resolution, multicolor imaging and fast-acquisition speed afforded by the SWIR QDs, we quantified, in mice, the metabolic turnover rates of lipoproteins in several organs simultaneously and in real time as well as heartbeat and breathing rates in awake and unrestrained animals, and generated detailed three-dimensional quantitative flow maps of the mouse brain vasculature. PMID- 29119059 TI - The bacteriological profile of the burned patients in the center of burns in CHU Mohamed VI Marrakech (about 123 cases). AB - The bacterial nosocomial infection is one of the leading causes of morbidity and mortality for burned patient; we conducted a retrospective study of 123 patients hospitalized in the burns center CHUMED VI of Marrakechover a period of 3 years, from January 1st, 2013 to December 31st, 2016. The criteria for nosocomial infection were those of the Center for Disease Control in Atlanta in 1988. Incidence rates were calculated. The bacterial ecology of the department was described as also antibiotype. The predominancy of the population was male. The cumulative incidence was 103 infections per 1000 days of treatment. Regarding the characteristics of bacterial infections, infected sites were skin (69%), blood (18%), urinary tract (12%) and lungs (1%). The main organisms were: Staphylococcus sp. (37.7%), Pseudomonas aeruginosa (19.8%), Enterococcus faecalis and Proteus mirabilis (18.5%). Staphylococci were resistant meticillo-in 22% of cases. Pseudomonas and Acinetobacter were multi-resistant (66%). The establishment of the bacterial ecology of the service, helped us set the right rules of prescription of antibiotics, which was based on the infected site, the type of organism, its sensitivity, the molecule used and the pharmacokinetics particular patient burned. The two main organisms being Staphylococcus and Pseudomonas aeruginosa, antibiotics used in the Service will then beta-lactams, glycopeptides, fluoroquinolones and aminoglycosides. Finally, to control the epidemic risk posed by the emergence of resistant organisms is necessary to combine the practice of good antibiotic therapy and prevention. PMID- 29119060 TI - Intra-abdominal hypertension in severe burns: prevalence, incidence and mortality in a sub-Saharan African hospital. AB - BACKGROUND: Severe burns have been shown to be a risk factor for developing intra abdominal hypertension (IAH). Fluid resuscitation practices used in burns management further predispose patients to intra-abdominal hypertension. The mortality associated with IAH in severe burns is estimated to be more than 74.5% once organ dysfunction occurs. Despite 95% of all burns occurring in Low and Middle income countries (LMIC), there is paucity of published data on this topic in sub-Saharan Africa. OBJECTIVES: To determine the prevalence, incidence, organ dysfunction and mortality of intra-abdominal hypertension among severe burns patients. METHODS: A prospective cohort study was conducted over a 6 months period in the Burns Unit of Mulago National Referral Hospital. Patients of all age groups with burns >=25% and 20% in adults and children respectively were recruited and followed up for 7 days or until death occurred. Patients with burns older than 48 hours were excluded. The outcome variables were intra-abdominal pressure, organ dysfunction and seven day mortality. RESULTS: Of all the 335 burns patients admitted, 64 patients met the inclusion criteria. The overall prevalence of IAH was 57.8% while the prevalence in the children and adults was 54.5% and 61.3% respectively. The incidence of IAH was 13.1 cases/100 person days with the incidence in adults being twice that of the children. The one week mortality of patients with IAH was 82.6% with the risk of dying being 3.34 (p=0.0035) and seven day survival being less than 50%. CONCLUSION: One in two patients with severe burns exceeding 20% or 25% in children or adults respectively developed IAH. Adults had a higher prevalence and incidence of IAH. Mortality associated with IAH exceeded 80%. PMID- 29119061 TI - EMLA anaesthetic cream for debridement of burns: a study of plasma concentrations of lidocaine and prilocaine and a review of the literature. AB - The lidocaine-prilocaine cream (EMLATM) effectively reduces the pain from debridement of chronic leg ulcers. Studies have demonstrated that when applied to leg ulcers, plasma concentrations of the local anaesthetics are well below the threshold for CNS toxicity. However, there are minimal pharmacokinetic data available from EMLA application to burn wounds. This study evaluated EMLA cream for debridement of burns with regard to plasma concentrations of lidocaine and prilocaine, and reviewed the published literature on safety and efficacy of lidocaine-prilocaine applied epicutaneously to burns. Eight patients aged 22-59 received 5 g of EMLA 5% cream applied to 25 cm2 large 2nd degree burn areas for 30 min. Venous blood samples drawn at set intervals up to 120 min after cream application were analyzed for total plasma concentrations of lidocaine and prilocaine. Pain from debridement was assessed on a 4-point verbal scale and a 100-mm visual analog scale (VAS) with the end points "no pain" and "severe pain". A literature search on the use of lidocaine-prilocaine cream on burn wounds was performed in PubMed. The results showed that six patients felt no pain and two patients mild pain. The median VAS score was 11 (range 2-59). Peak plasma concentrations of lidocaine (mean 205 ng/ml) and prilocaine (mean 97 ng/ml) were observed after 15-60 min. Two published studies and two case reports of overdose of lidocaine-prilocaine cream applied to burns in paediatric patients were retrieved. Peak plasma concentrations of lidocaine and prilocaine combined after application of 5 g EMLA to burns 25 cm2 large for 30 min in adults are far below those associated with toxicity. Bioavailability estimation suggests 5 to 30% of the prilocaine dose applied to burns is percutaneously absorbed. The analgesic efficacy appears satisfactory for debridement of 2nd degree burns. PMID- 29119062 TI - Xanthine oxidase contributes to sustained airway epithelial oxidative stress after scald burn. AB - Respiratory tract infections and pneumonia are major causes of morbidity and mortality in burn victims, however, limited studies have examined the effects of burn injury on airway epithelium. The current study examines the effect of scald burn injury on rat tracheal epithelium at 5 days after injury and tests the hypothesis that treatment with febuxostat (FBX), an inhibitor of xanthine oxidase (XO), can be protective of cell homeostasis. Sprague Dawley rats were randomly divided into uninjured (sham), injured (control) and injured and FBX treated groups, n = 8. Control and FBX treated groups received 60% total body surface area scald burn injury. The FBX group received an i. p. dose (1 mg/kg) at 1 hour after injury and every 24 hours. At 5 days after injury, the animals were sacrificed and tracheal epithelial cell lysates were collected. Malondialdehyde (MDA), ATP, and XO activity were measured. Formation of 8-OHdG in tracheal epithelium was determined using immunohistochemistry (IHC) and immunoreactivity was quantitated. MDA levels were significantly increased in injured control animals (24.8 +/- 2.3) compared to sham (7.93 +/- 1.2, p = 0.002). FBX treatment attenuated this response (12.6 +/- 2.7, p = 0.02). ATP levels were significantly decreased in control (0.7 +/- 0.16) compared to sham, (2 +/- 0.14, p = 0.01). ATP levels were increased with FBX treatment (1.8 +/- 0.1, p = 0.03) compared to controls. There was a significant increase in XO activity in control animals, 1.04 +/- 0.06 compared to sham (0.34 +/- 0.05, p = 0.03), and this response decreased with FBX treatment 0.46 +/- 0.07 (p = 0.04). Immunolabeling of 8-OHdG in control animals was significantly increased (25.1 +/- 0.7 compared to the sham group 5.5 +/- 1.9 (p = 0.01)), and was decreased with FBX treatment (7.0 +/- 2.3 compared to control (p = 0.03)). The current study indicates that lipid peroxidation and ATP depletion persist in tracheal epithelium for 5 days after injury along with increased XO activity and 8-OHdG. These effects were significantly attenuated by FBX treatment, suggesting that reactive oxygen species generated by XO contribute to airway epithelial injury following scald burn. PMID- 29119063 TI - A new model for studying deep partial-thickness burns in rats. AB - Burn injuries are one of the most devastating injuries in the world. A uniform burn wound is essential for burn research. The objective of this study was to describe a new model for inducing deep partial-thickness burns in rats. Burn wounds were performed on the dorsal part of Sprague-Dawley rats using a constructed heating device in our laboratory. Digital images of each animal were captured every day for macroscopic evaluation and for assessment of the wound contraction rate. Six animals were sacrificed on days 1, 3, 7, 11, 14, and 21 after onset of burn and their skin tissues were harvested for histological analysis. Uniform deep partial-thickness burns could be achieved in Sprague Dawley rats under the condition of a contact temperature of 70 degrees C, with the weight of heating devices of 300 g, and a duration of 10 s. Macroscopic evaluation recorded the general appearance of the deep partial-thickness burns. Evaluation of the wound contraction rate showed that the deep partial-thickness wound area was reduced by 90.39% of the original wound area by day 21 after burn. Microscopic evaluation by hematoxylin-eosin staining revealed the histological changes during the wound healing process. This is a standardized and reproducible model for inducing deep partial-thickness burns in Sprague-Dawley rats. PMID- 29119065 TI - Dynamic nanoindentation testing: is there an influence on a material's hardness? AB - Modern nanoindentation devices are capable of dynamic experimentations, which allow us to exploit instrumented hardness tests extensively. Beside the assets of recording mechanical properties continuously over displacement, there are ongoing debates whether the superimposed force alters the material's hardness. We will show for a broad range of materials that significant hardness differences are noted between dynamic and static tests, even for large displacements. Those mainly result from a changing indentation strain-rate during the hold segment at peak load. This fact must be implicitly considered in studies using static indentation tests to guarantee comparability of obtained nanoindentation hardness values and derived quantities. PMID- 29119064 TI - Administration of tranexamic acid in trauma patients under stricter inclusion criteria increases the treatment window for stabilization from 24 to 48 hours-a retrospective review. AB - BACKGROUND: Since 2010, the use of Tranexamic Acid (TXA) in trauma has been brought to the forefront of severe hemorrhage treatment. However, the mixed literature illustrates the need for additional proof of efficacy and determining which patients may benefit from TXA. The purpose of this retrospective study was to evaluate a more stringent TXA inclusion criterion (heart rate >= 120 beats per minute (BPM) with a systolic blood pressure (SBP) <= 90 mmHg) as compared to the standard CRASH-2 inclusion criteria. METHODS: From 2013-2016 a total of 115 patients (control, n = 62; TXA, n = 53) were included in the analysis. These patients adhered to the standard CRASH-2 and more stringent inclusion criteria; they also survived at least 8.5 hrs (minimum amount of time required for full TXA dose) from the initiation. Basic characteristics of the patients were summarized. The mortality rates between TXA and control groups were compared using two proportion z-tests. All p values <0.05 were considered statistically significant. RESULTS: There was no statistical significant difference in patient characteristics between the two treatment groups, making them more comparable (p value >0.05). This study found a significant reduction of percent mortality at the 24 hr time point against the control (p = 0.007). Additionally, utilizing the more strict inclusion criteria (BPM >= 120 and SBP <= 90) substantially extended time to stabilize patients to 48 hrs (p = 0.029). CONCLUSION: By imposing the more strict criteria, TXA appears to be a better treatment option in reducing mortality rates and potentially extends the treatment time-frame for stabilizing the patient up to 48 hours. PMID- 29119066 TI - Bipolar Radiofrequency Facet Ablation of the Lumbar Facet Capsule: An Adjunct to Conventional Radiofrequency Ablation for Pain Management. AB - Radiofrequency facet ablation (RFA) has been performed using the same technique for over 50 years. Except for variations in electrode size, tip shape, and change in radiofrequency (RF) stimulation parameters, using standard, pulsed, and cooled RF wavelengths, the target points have remained absolutely unchanged from the original work describing RFA for lumbar pain control. Degenerative changes in the facet joint and capsule are the primary location for the majority of lumbar segmental pathology and pain. Multiple studies show that the degenerated facet joint is richly innervated as a result of the inflammatory overgrowth of the synovium. The primary provocative clinical test to justify an RFA is to perform an injection with local anesthetic into the facet joint and the posterior capsule and confirm pain relief. However, after a positive response, the radiofrequency lesion is made not to the facet joint but to the more proximal fine nerve branches that innervate the joint. The accepted target points for the recurrent sensory branch ignore the characteristic rich innervation of the pathologic lumbar facet capsule and assume that lesioning of these recurrent branches is sufficient to denervate the painful pathologic facet joint. This report describes the additional targets and technical steps for further coagulation points along the posterior capsule of the lumbar facet joint and the physiologic studies of the advantage of the bipolar radiofrequency current in this location. Bipolar RF to the facet capsule is a simple, extra step that easily creates a large thermo coagulated lesion in this capsule region of the pathologic facet joint. Early studies demonstrate bipolar RF to the facet capsule can provide long-term pain relief when used alone for specific localized facet joint pain, to coagulate lumbar facet cysts to prevent recurrence, and to get more extensive pain control by combining it with traditional lumbar RFA, especially when RFA is repeated. PMID- 29119067 TI - Experience with Ambulatory Management of Pleural Pathologies Utilizing Small-Bore Indwelling Pleural Catheters. AB - Introduction Pleural effusion is the excess fluid that accumulates in the pleural space. Pneumothorax is the collection of free air in the pleural cavity, while empyema is the collection of pus in the pleural cavity. Such pleural pathologies pose a great challenge to patients and health care professionals alike. While multiple management options exist, the major portion of it is carried out in the inpatient setting. We sought to evaluate the ambulatory use of indwelling pleural catheters for pleural pathologies, including malignant pleural effusion, empyema, and primary spontaneous pneumothorax. Methods We conducted a prospective case series analysis of 15 patients with various pleural pathologies in which an indwelling pleural catheter was placed by interventional radiologists on an outpatient basis and subsequently followed-up in a pulmonary clinic. Results were analyzed on the basis of clinical, as well as radiological progress with parameters being complete, partial, or no resolution. We also obtained prospective data on the quality of life of these patients. Results Six out of seven patients with malignant pleural effusion reported clinical (complete or partial) resolution, while three reported radiological (complete or partial) resolution. Two of the three patients with nonmalignant pleural effusions reported complete clinical as well as radiological resolution. All three patients with empyema reported complete clinical resolution and partial radiological resolution, while both patients with primary spontaneous pneumothorax reported complete clinical and radiological resolution. Patients reported preserved or improved quality of life with the whole process managed on an outpatient basis. Conclusion We report a high rate of clinical and radiological resolution in various pleural pathologies in our study, which is first of its kind from this part of the world. It demonstrates the feasibility of ambulatory management of pleural pathologies with a multidisciplinary approach. PMID- 29119068 TI - Ischemic Stroke of Midbrain and Cerebellum Involving Reticular Activating System. AB - The reticular activating system is the part of the brain that maintains the sleep/wake cycle. Any damage to this region can cause hypersomnolence and drowsiness along with altered sensorium. This case presents a patient with cerebellar and midbrain stroke with infarct of the reticular activating system, leading to hypersomnolence, drowsiness, and altered sensorium. PMID- 29119069 TI - Targeting the Tumor: Assessing the Impact of Bladder Volume and Position on Accuracy of Radiation Delivery for Patients with Bladder Cancer. AB - Context Daily variations in bladder size and position can negatively impact the ability to accurately deliver radiation. Aims We attempted to quantify how bladder volumes and positions change over the course of radiotherapy for muscle invasive bladder cancer and the planning target volume (PTV) margins required to account for such changes. Methods and material Cone-beam computed tomography (CT) images of 28 patients during their first, second, and third fractions and weekly thereafter were acquired. Bladders were contoured and the volume, centre of mass, and the maximal positions were recorded and compared to the planning CT scan. Statistical analysis Bladder parameters were analysed using regression analysis examining for time trends and correlation to the patient, tumour, or treatment related factors. Results There was great variability in the mean bladder volumes during the radiotherapy courses (154.17 +/- 129.38 cm3). There were no statistically significant trends for volume changes. Deviations in bladder positions were seen but were small in magnitude. No patient factors were identified which could help predict bladder changes clinically. Bladder variability resulted in a high percentage of fractions (39.6%) in which part of the bladder was outside the PTV. Calculated PTV margins (for 90% of the population to receive 95% of the prescription dose) were 1.48 cm right, 1.15 cm left, 2.13 cm posterior, 1.52 cm anterior, 2.23 cm superior, and 0.52 cm inferior. Conclusions Because of random bladder changes, a significant number of fractions were treated in which the clinical target volume (CTV) fell outside of the PTV. Methods to minimize the amount of CTV that is missed on a fraction to fraction basis should be explored. PMID- 29119070 TI - Superior Ophthalmic Vein Access for Embolization of an Indirect Carotid Cavernous Fistula. AB - Carotid cavernous fistulae (CCF) are defined as abnormal connections between the carotid circulation and cavernous sinus. CCFs can be categorized as being direct or indirect. Direct CCFs are usually associated with trauma, whereas indirect CCFs are associated with revascularization following cavernous sinus thrombosis. We present a case of a 53-year-old male who presented with tinnitus, proptosis, conjunctivitis, and blurry vision. The patient had a recent endovascular transvenous embolization that was only partially successful, with a residual carotid cavernous fistula draining to the left superior ophthalmic vein and multiple cortical veins. A physical examination of the patient showed elevated intraocular pressures bilaterally. The patient had a high-flow indirect carotid cavernous fistula with bilateral superior ophthalmic vein (SOV) and retrograde cortical vein drainage. The SOV was punctured with a micropuncture needle and was used to successfully gain access to the cavernous sinus. Multiple coils were placed in the posterior aspect of the sinus until there was complete occlusion of venous flow. Coils were packed up to the posterior aspect of the orbit near the junction of the cavernous sinus with the SOV, and the embolization was successful. Indirect CCFs have gradual onset and are usually low-flow. Low-flow CCFs might improve with medical management.Some CCFs may cause ocular manifestations and can be symptomatically managed with prism therapy or ocular patching for diplopia, lubrication for keratopathy, or topical agents for elevated intraocular pressures. However, patients presenting with persistent ocular morbidity may require surgical or endovascular intervention. PMID- 29119071 TI - Sporadic Meningioangiomatosis: A Series of Three Pediatric Cases. AB - Meningioangiomatosis (MA) is a rare benign, hamartomatous lesion within the leptomeninges and cerebral cortex. Three percent of intractable epileptic patients with tumor develop MA. It may be accompanied with neurofibromatosis type II, or it may occur sporadically. Three patients, age range of 2-16 years old, presented with episodes of seizure. The patients demonstrated no family history or stigmata of neurofibromatosis type II. Electroencephalogram (EEG) was unremarkable for epileptiform activity. Magnetic resonance imaging (MRI) revealed enhancing lesions within the frontal gyrus, the anterior cingulate gyrus, and the parietal lobe. Incomplete resection led to recurrence in one patient, and later, intraoperative ultrasound was used to achieve total resection in another patient. Each patient was seizure free on follow-up, and managed with anti-epileptic medication. Resection is the only curative treatment in 85% of MA cases. Complete resection is necessary for symptomatic treatment in cases of MA, as recurrence has been documented in this lesion. Intraoperative ultrasound is an effective imaging modality to ensure gross total resection of MA. PMID- 29119072 TI - A Comparison of Visual Outcomes and Patient Satisfaction Between Photorefractive Keratectomy and Femtosecond Laser-Assisted In Situ Keratomileusis. AB - Purpose To compare visual outcomes and satisfaction among patients of photorefractive keratectomy (PRK; Wavelight EX 500, Alcon, Ft Worth, TX, USA) and femtosecond laser-assisted in situ keratomileusis (FAL; Wavelight FS 200 laser and Wavelight EX 500, Alcon, Ft Worth, TX, USA). Methods We performed a retrospective study of 409 eyes in 207 patients that underwent either PRK (n=90) or FAL (n=117) at the two centers of Hashmanis Hospital, Karachi, Pakistan. The included refractive outcomes were sphere diopters (D), cylinder D, and spherical equivalent D. Additionally, visual acuities were included. All of these were assessed preoperatively and at the one-month postoperative check-up. Patient satisfaction was gauged at the time of chart review by contacting the patient. Results When looking at the postoperative outcomes, we found all values to be statistically significant (p<0.001) with superior outcomes in the FAL cohort. Additionally, 90% and 15% of eyes achieved a postoperative uncorrected visual acuity (UCVA) of 20/20 in FAL and PRK, respectively. Furthermore, the efficacy indexes of the FAL and PRK arms were 1.00 and 0.82, respectively. The predictability of the procedures were 92.1% and 64.9%, respectively. Lastly, 93.3% of patients were satisfied with FAL and 95.7% with PRK. Conclusion Our study shows superior visual outcomes in patients undergoing FAL. However, we found a higher satisfaction rate in those that underwent PRK, perhaps due to the higher cost of FAL. PMID- 29119073 TI - Assigning responsibility to close the loop on radiology test results. AB - Failure to follow-up on test results represents a serious breakdown point in the diagnostic process which can lead to missed or delayed diagnoses and patient harm. Amidst discussions to ensure fail-safe test result follow-up, an important, yet under-discussed question emerges: how do we determine who is ultimately responsible for initiating follow-up action on the tests that are ordered? This seemingly simple question belies its true complexity. Although many of these complexities are also applicable to other diagnostic specialities, the field of medical imaging provides an ideal context to discuss the challenges of attributing responsibility of test result follow-up. In this review, we summarize several key concepts and challenges in the context of critical results, wet reads, and incidental findings to stimulate further discussion on responsibility issues in radiology. These discussions could help establish reliable closed-loop communication to ensure that every test result is sent, received, acknowledged and acted upon without failure. PMID- 29119074 TI - Case report on a defective antibody response against pneumococcal serotype 9V in a patient with a single episode of pneumonia. AB - Background: Patients with recurrent respiratory tract infections and an impaired response to pneumococcal polysaccharide vaccination are diagnosed with a specific antibody deficiency. In adult patients with pneumococcal pneumonia an impaired antibody response to the infecting pneumococcal serotype can sometimes be found. It is unknown whether these patients are unable to produce an adequate anti polysaccharide antibody response to pneumococcal vaccination after recovery. Case presentation: The authors describe a case of invasive pneumonia caused by Streptococcus pneumoniae serotype 9V in a previously healthy 35-year-old female. This patient did not produce serotype-specific antibodies against the infecting serotype during disease. After pneumococcal polysaccharide vaccination 3 months after recovery, she responded adequately to most other pneumococcal serotypes, but still had no response to the infecting serotype 9V. However, after 9 years (and prior to pneumococcal-conjugate vaccination) normal antibody levels against 9V were found. These antibody levels further increased after pneumococcal conjugate vaccination. Conclusion: The authors believe that this case is the first description of a temporary deficient response to the infecting pneumococcal serotype in adults, while other reports with similar observations all involved children. PMID- 29119075 TI - The Classification of Long Bone Osteomyelitis: A Systemic Review of the Literature. AB - Background: Osteomyelitis is a complex disease. Treatment involves a combination of bone resection, antimicrobials and soft-tissue coverage. There is a difficulty in unifying a classification system for long bone osteomyelitis that is generally accepted. Objectives: In this systematic review, we aim to investigate the classification systems for long bone osteomyelitis that have been presented within the literature. By doing this, we hope to elucidate the important variables that are required when classifying osteomyelitis. Methods: A complete search of the Medline, EMBASE, Cochrane and Ovid databases was undertaken. Following exclusion criteria, 13 classification systems for long-bone osteomyelitis were included for review. Results: The 13 classification systems that were included for review presented seven different variables that were used for classification. Ten of them used only one main variable, two used two variables and one used seven variables. The variables included bone involvement (used in 7 classification systems), acute versus chronic infection (used in 6), aetiopathogenesis (used in 3), host status (used in 3), soft tissue (used in 2), microbiology (used in 1) and location of infected bone (used in 1). The purpose of each classification system could be grouped as either descriptive (3 classification systems), prognostic (4) or for management (4). Two of the 13 classification systems were for both prognostic and management purposes. Conclusions: This systematic review has demonstrated a variety of variables used for classification of long bone osteomyelitis. While some variables are used to guide management and rehabilitation after surgery (e.g., bone defect, soft tissue coverage), others were postulated to provide prognostic information (e.g., host status). Finally, some variables were used for descriptive purposes only (aetiopathogenesis). In our view and from today's perspective, bone involvement, antimicrobial resistance patterns of causative micro-organisms, the need for soft tissue coverage and host status are important variables to include in a classification system. PMID- 29119076 TI - Are There Benefits In Early Diagnosis Of Prosthetic Joint Infection With Multiplex Polymerase Chain Reaction? AB - Purpose Identification of bacteria and susceptibility are fundamental in periprosthetic joint infection (PJI). Especially in the case of systemic inflammatory response syndrome (SIRS) rapid detection of pathogens is essential for proper therapy. Bacterial cultures are time consuming. The polymerase chain reaction (PCR) is a non-culture molecular method and is able to rapidly identify pathogens and their resistance genes. Multiplex PCR (mPCR) can amplify several different DNA sequences simultaneously. The aim of this study was to show the value of mPCR for early diagnosis of PJI. Methods 60 patients undergoing total hip or knee revisions were recruited in this prospective single-centre-study. Three groups were created: 26 patients with aseptic loosening (negative control), 26 patients with chronic PJI, and 8 patients with acute PJI/SIRS. We compared the results of joint aspirates obtained intraoperatively investigated by mPCR with the microbiology results of tissue specimens. Results The overall sensitivity of mPCR was 78.8% (95% CI, 61.1 - 91.0%), the specificity was 100% (95% CI, 87.2 - 100%), the negative predictive value was 79.4% (95% CI, 62.1 - 91.3%), the positive predictive value was 100% (95% CI, 86.8 - 100%), and the overall accuracy was 88.3% (95% CI, 77.4 - 95.2%). The overall accuracy in acute infections/SIRS (87.5%) was greater than in late chronic PJI (76.9%). In PJI the mPCR was able to provide the results within 5 hours whereas the mean time for cultures was 6.4 days. Conclusions Multiplex PCR is a reliable diagnostic tool in PJI management, especially in acute cases complicated with SIRS. Early diagnosis within several hours is possible, targeted antibiotic treatment can be started promptly. PMID- 29119077 TI - Osteomyelitis of the Pelvic Bones: A Multidisciplinary Approach to Treatment. AB - Background and Purpose: A case series review of chronic pelvic osteomyelitis treated with combined medical and surgical treatment by a multidisciplinary team. Methods: All patients treated with surgical excision of pelvic osteomyelitis at our tertiary referral centre between 2002 and 2014 were included. All received combined care from a clinical microbiologist, an orthopaedic surgeon and a plastic surgeon. The rate of recurrent infection, wound healing problems and post operative mortality was determined in all. Treatment failure was defined as reoperation involving further bone debridement, a requirement for the use of long term suppressive antibiotics or sinus recurrence. Results: Sixty-one adults (mean age 50.2 years, range 16.8-80.6) underwent surgery. According to the Cierny-Mader classification of osteomyelitis there were 19 type II, 35 type III and 7 type IV cases. The ischium was the most common site of infection. Osteomyelitis was usually the result of contiguous focus infection associated with decubitus ulcers, predominantly in patients with spinal or cerebral disorders. Most patients with positive microbiology had polymicrobial infection (52.5%). Thirty patients required soft tissue reconstruction with muscle or myocutaneous flaps. Twelve deaths occurred a mean of 2.8 years following surgery (range 7 days-7.4 years). Excluding these deaths the mean follow-up was 4.6 years (range 1.5-12.2 years). Recurrent infection occurred in seven (11.5%) a mean of 1.5 years post operatively (92 days - 5.3 years). After further treatment 58 cases (95.1%) were infection free at final follow-up. Interpretation: Patients in this series have many comorbidities and risk factors for poor surgical outcome. Nevertheless, the multidisciplinary approach allows successful treatment in the majority of cases. PMID- 29119078 TI - Treatment of Cavitary Bone Defects in Chronic Osteomyelitis: Biogactive glass S53P4 vs. Calcium Sulphate Antibiotic Beads. AB - : Aim: To evaluate the efficacy of bioglass (BAG-S53P4) in the treatment of patients with chronic osteomyelitis and compare the results with calcium sulphate antibiotic beads in one medical centre. Methods: Retrospective analysis of 25 cases. INCLUSION CRITERIA: patients diagnosed clinically and radiographically of osteomyelitis and treated surgically (Group 1: cavitary bone defects treated with bioglass and Group 2: cavitary bone defects treated with calcium sulphate antibiotic beads) during the period of 2014 and 2015 in one medical centre. Results: Patients in group 1 (bioglass treatment): total of 12 patients (11 males and 1 female) with mean age: 50 years (30-86). Average length of hospital stay was 22 days and mean follow-up time: 23 months (16-33). Mean erythrocyte sedimentation rate (ESR) and mean c-reactive protein (CRP) before sugery: 55mm/hr and 54 mg/L, respectively. Mean ESR and mean CRP in last blood exam: 18 mm/hr and 8 mg/L, respectively. There were 2 postoperative complications: seroma formation and delayed wound healing. Only 1 patient had recurrence of infection. Patients in group 2 (calcium sulphate antibiotic beads treatment): total of 13 patients (9 males and 4 females) with mean age: 48 years (17-67). Average length of hospital stay was 21 days and mean follow-up time 22 months (16-29). Mean ESR and mean CRP before surgery: 51mm/hr and 41 mg/L, respectively. Mean ESR and mean CRP in last blood test: 15 mm/hr and 11 mg/L. 2 postoperative complications were registered: chronic expanding hematoma of the muscle flap donor site and seroma formation. 1 patient had recurrence of infection. Overall, there were no differences in recurrence of infection, p=0.740 and in complication rate, p=0.672. 11 (91,7%) patients in group 1 and 12 (92,3%) patients in group 2 showed no signs of recurrence of infection both clinically and radiologically at final follow-up. The most frequent cause of osteomyelitis in group 1 was post traumatic while a postsurgical aetiology was more frequent in group 2. The distal tibia was the most common location. The most frequent pathogen isolated in both groups was methicillin sensible staphylococcus aureus. Conclusions: An advance in treatment of patients with cavitary bone defects in chronic osteomyelitis is the use of synthetic bone substitutes although current evidence is low. In this study, we demonstrate how bioglass without local antibiotics and calcium sulphate antibiotic beads are both equally effective treatment options. Overall, there were no differences between groups in mean hospital stay, complication rates and recurrence of infection. PMID- 29119079 TI - Minimizing nocebo effect: Pragmatic approach. AB - The nocebo effect, the inverse of the placebo effect, is a well-established phenomenon, yet under-appreciated. It refers to nonpharmacological, harmful, or undesirable effects occurring after active or inactive therapy. The frequency of adverse events can dramatically increase by informing patients about the possible side effects of the treatment, and by negative expectations on the part of the patient. Patients who were told that they might experience sexual side effects after treatment with beta-blocker drugs reported these symptoms between three and four times more often than patients in a control group who were not informed about these symptoms. Nocebo effect has been reported in several neurological diseases such as migraine, epilepsy, multiple sclerosis, Parkinson's disease and neuropathic pain, and in patients with depression. The investigation of the biological and theoretical underpinning of the nocebo phenomenon is at an early stage, and more research is required. Physicians need to be aware of the influence of nocebo phenomenon and be able to recognize it and minimize its effects. PMID- 29119080 TI - Metastatic breast cancer: Endocrine therapy landscape reshaped. AB - Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus. Although still considered incurable by currently available treatment modalities, many patients with MBC nowadays enjoy several years of good quality life coupled with decent tumor control. The diversity of therapies and unusual pattern of side effects can be quite perplexing to the treating physician. The sequence of variable agents and management of side effects, in addition to the timing of initiation of cytotoxic chemotherapy, is among the challenges faced by oncologists. In this review, we shed a spotlight on mechanisms of resistance to ET, and provide a review of landmark studies that have recently reshaped the landscape of treatment options for patients with metastatic HR-positive, HER2 negative MBC. A suggested treatment strategy for newly diagnosed patients is also discussed herein. PMID- 29119081 TI - Adnexal masses in pregnancy: An updated review. AB - Adnexal masses in pregnancy are not commonly encountered. The majority of these masses are discovered incidentally during routine follow-up. However, some of these masses become symptomatic due to their size, location, and impingement of adjacent structures. Several diagnostic modalities can be utilized for the detection of adnexal masses with different sensitivity and specificity rates. The differential diagnosis of adnexal masses discovered during pregnancy is broad and includes both benign and malignant lesions. The management of such lesions has been a subject of debate for years with no consensus regarding the best management plan. Tumor size, site, and the trimester of mass detection are all crucial in management. In this account, we review adnexal masses discovered in pregnancy, the diagnostic modalities utilized for detecting these lesions, their differential diagnosis, and management strategies. PMID- 29119082 TI - Cardiac manifestations of Familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is autoinflammatory disorder characterized by sporadic attacks of fever, peritonitis, pleuritis, and arthritis. It is mainly seen in patients from Mediterranean origins, but it is now reported more frequently in Europe and North America due to immigration. To analyze the data on the cardiovascular manifestations in FMF patients, we searched PubMed using the terms "Familial Mediterranean Fever" or "FMF" in combination with other key words including "cardiovascular diseases" "pericardial diseases" "atherosclerosis" "coronary artery diseases" "cardiomyopathy" "pulmonary hypertension" or "valvular diseases." suggested several mechanisms to explain the cardiac involvements in FMF including the ongoing inflammation and the amyloid deposits in the heart and vessels' walls at the advanced stages of FMF. The course of these manifestations varies widely, but it can associate with poor prognosis in some cases such as with pulmonary hypertension. Interestingly, Colchicine, which is the cornerstone therapy of FMF, plays a vital role in treating and preventing some of these disorders. In this article, In this article, we will discuss the incidence, pathophysiology, and prognosis of the various cardiac manifestations affecting FMF patients. PMID- 29119083 TI - Awareness of health effects of exposure to secondhand smoke from cigarettes: A cross-sectional study of never-smoked adult primary care patients in Eastern Nigeria. AB - Background: Cigarette smoking whether actively or passively is a growing public health problem. Despite the wealth of information on the hazards of active cigarette smoking, awareness of the health effects of passive smoking on human population is often neglected in Nigeria. Aim: The study was aimed at describing the awareness of health effects of exposure to secondhand smoke from cigarettes among never-smoked adult primary care patients in Eastern Nigeria. Materials and Methods: A hospital-based study carried out on a cross-section of 500 adult patients in a primary care clinic in Nigeria. Data were collected using pretested, structured, and interviewer-administered questionnaire. Exposure to secondhand smoke was defined as exposure to cigarette smoke in a never-smoked adult patient in the previous 1 year. Data were analyzed using Statistical Package for Social Sciences version 21 for the calculation of percentages for categorical variables. Bivariate analysis involving Chi-square test was used to test for significance of association between categorical variables at P < 0.05. Results: The age of the respondents ranged from 18 to 74 years, with a mean age of 36 +/- 12.4 years. There were 180 (36.0%) males with 320 (64%) females, with a sex ratio of 1.8. Awareness of general health effects of secondhand smoke on adults, children, and pregnant women was 95.6%, 92.8%, and 65.2%, respectively. The most common specific health effects the respondents were aware for adults, children, and obstetric population were lung cancer (95.6%), precipitation of asthmatic condition (92.8%), and delivery of small babies (65.2%), respectively. The predominant source of awareness of information was radio (93.6%). Awareness of general health effects of exposure to secondhand smoke on adults (P = 0.041), children (P = 0.031), and obstetrics population (P = 0.02) was significantly associated with exposure status. Conclusion: The most common health effects of secondhand smoke the respondents had highest awareness were lung cancer, precipitation of asthmatic attacks, and delivery of small babies in adults, children, and obstetric population, respectively. Awareness of general health effects on adults, children, and obstetrics population was significantly associated with exposure status. The current level of awareness should be improved while effort should be intensified to address identified areas of low level of awareness. PMID- 29119084 TI - Gluten-free diet among school-age children in Olmsted County, Minnesota. AB - Objective: To assess the prevalence of gluten-free diet (GFD) among school-age children in Olmsted County, Minnesota, and compare it with the prevalence of celiac disease (CD) in the same age group. Methods: We performed a population based study in Olmsted County using a survey to collect information from the six school districts in the county for the academic year 2014-2015. The survey contained questions to (1) assess the prevalence of GFD among school-age children in the public schools of Olmsted County; (2) assess the prevalence of CD among school-age children in Olmsted County; and (3) determine the indications for GFD in these children. We used the infrastructure of the Rochester Epidemiology Project (REP) to calculate the prevalence of CD in children aged 4-18 years in December 2014. Results: Using the REP data, we identified sixty patients with CD in the county aged 4-18 years; the prevalence of CD among school students in 2014 was 193.6/100,000. The prevalence of GFD in Olmsted County children, however, was higher, at 265/100,000 according to the survey from the school districts. The prevalence of GFD was highest in Rochester, the largest city. GFD was more common among children in secondary schools. Conclusion: According to our study, there are more children on GFD than the actual cases of CD in Olmsted County during the study period. This finding could be related to an increased number of children without CD who are following GFD for other indications. PMID- 29119086 TI - Can acute-phase response biomarkers differentiate infection from inflammation postpediatric cardiac surgery? AB - Background: Infection is a common serious complication postpediatric cardiac surgery. Diagnosis of infection after cardiopulmonary bypass (CPB) is difficult in the presence of surgical stress, hemodynamic instability, and inflammatory reaction. Aim: The purpose of this study is to investigate the value of available inflammatory biomarkers and its validity to differentiate infection from inflammation postpediatric cardiac surgery and to find the trend and the change in the level of these biomarkers shortly after cardiac surgery. Methods: We conducted a prospective study that included all children who underwent cardiac surgery in Prince Sultan Cardiac Centre-Qassim from November 2013 to October 2015. C-reactive protein, erythrocyte sedimentation rate, white blood cell count, and neutrophil count were measured for all patients presurgery, 4 consecutive days postsurgery, and predischarge. Patients were divided into two groups (the infected and the noninfected group). We compared the level of biomarkers between both groups. Then, we further analyzed the effects of CPB and preoperative steroid on postoperative inflammatory biomarker levels. Collected data were then reviewed and analyzed. Results: There were 134 pediatric cardiac patients included during the study period. Group 1 (bacterial negative culture group) had 125 cases and Group 2 (bacterial positive culture group) had nine cases. We found no statistically significant difference in inflammatory biomarker elevation between both groups. Only Group 2 had higher (RACHS) Risk adjustment for congenital heart surgery score, more ventilator days, and more drop in platelet count on the 2nd and 3rd postoperative days in comparison with the noninfected group 1. Both groups of patients who were in on and off CPB had the same level of inflammatory biomarkers with no significant differences. Giving corticosteroid preoperatively did not affect the trend of biomarker elevation and made no difference when it was compared to the group of patients who did not receive corticosteroid before surgery. Conclusion: Common inflammatory biomarkers cannot differentiate between infection and inflammation within the first 5 days postpediatric cardiac surgery as these reflect the inflammatory process rather than infection. Trend is more important than single reading. PMID- 29119085 TI - Pediatric care during a short-term medical mission to a Syrian refugee camp in Northern Jordan. AB - Introduction: The Syrian refugee crisis, now in its 6th year, has displaced millions. Refugees depend on support from host nation governments and humanitarian organizations like the Syrian American Medical Society (SAMS). We describe the delivery of pediatric care during a SAMS short-term medical mission to a refugee camp in Northern Jordan. Methods: The medical mission team encompassed dozens of specialties. Teams visited many sites, including the Zaatari refugee camp near the Syrian border. For this study, we gathered quantitative data from one physician who provided pediatric care and anecdotes from multiple SAMS physicians who provided pediatric care in Zaatari during the same time period. The physician supplying the quantitative data recorded age, diagnoses, and prescriptions for each patient. Results: The physician saw an average of 69 patients per day. Many of these were children aged 0-4 years. At least one diagnosis was recorded for 73.9% of patients, and at least one prescription was recorded for 85.5% of patients. Discussion: Most presenting complaints involved acute infectious illnesses, but these seemed preventable and related to refugees' living situations. Mental health assessment was difficult. Referrals proved important for evaluation and management of both acute and chronic conditions. For the short term, we emphasize the importance of effective liaison with refugee camp authorities and outside health-care organizations. For the long term, we recommend increased health-care infrastructure development and more emphasis on preventative care. Conclusion: With this study, we provide new quantitative and qualitative insights into pediatric care during a short-term medical mission to a Syrian refugee camp in Northern Jordan. PMID- 29119087 TI - A new primary health-care system in the Syrian opposition territories: Good effort but far from being perfect. AB - Objectives: The primary health-care system in Syria has suffered a great deal of damage over the past 6 years. A large number of physicians and health-care providers have left the country. The objectives of this study are to describe our experience in establishing a primary health-care system in the opposition territories (OTs) in Syria and report the most common treated diseases. Methods: The administrative databases of ten primary care centers in the OT from January 2014 to December 2015 were reviewed. All patients' encounters, including children and adults, in these centers were included in the study. Results: Within the study period, the ten centers served 46,039 patients encounter per month (and average of 4600 patients encounters per center per month). A high number of communicable diseases were noted. Cutaneous leishmaniasis was the most common communicable disease (1170 cases a month). Tuberculosis was treated in 14 patients a month. Other infectious diseases that were almost eradicated before the crises were seen increasingly (29 mumps cases/month, 6 measles cases/month, and 34 cases of typhoid fever/month). Conclusion: The primary health-care system in Syria has been greatly damaged, and tremendous efforts are ongoing to provide access to various basic health-care services including primary care services. Despite these efforts, the current system is very vulnerable and not sustainable. This study summarizes basic health services provided by primary health-care centers in Syrian OTs. PMID- 29119089 TI - Evaluation of some microbiological and chemical parameters of Campania buffalo ricotta cheese. AB - Fresh ricotta (whey cheese), owing to its technological characteristics and intrinsic parameters (pH and aw), is an excellent substrate for the growth of spoilage and pathogenic microorganisms. On 19 July 2010, Campania buffalo ricotta cheese was assigned to the register of Protected Designations of Origin (PDO) by the European Commission, with EC Reg. 634/2010. It is mainly produced in the provinces of Caserta and Salerno around the rivers Garigliano and Volturno, the plain of the river Sele and the area of Cilento. This article reports the results of a 9-month monitoring (from May 2014 to January 2015) of ricotta samples aiming at evaluate the microbial status of some cheese factories, since ricotta is considered particularly suitable to judge the hygienic level of the dairy establishments. Four dairies were selected for sampling according to their different structural characteristics and the adequacy of both their premises and equipment. PMID- 29119090 TI - Evaluation of antibiotic usage in swine reproduction farms in Umbria region based on the quantitative analysis of antimicrobial consumption. AB - Antibiotic use in food-producing animals has considerable impact on public health, especially with respect to the development and spread of antibiotic resistance. Pigs represent one of the main species in which antibiotics are frequently used for different purposes. Surveillance of antibiotic consumption and dose appropriateness, through novel approaches based on defined daily doses, is strongly needed to assess farms' antibiotic risk, in terms of spread of antibiotic resistance and possibile presence of residues in meat. In this study, antibiotic consumption was monitored in 14 swine reproduction farms, together with managerial, structural, and health aspects. Most of the controlled farms (65%) were classified as at medium antibiotic risk, 21% at high antibiotic risk, and 14% at low antibiotic risk. Critical aspects of antibiotic administration concerned treatments for suckling and weaner piglets, oral antibiotic administration, treatment and diagnosis of gastroenteric infections, and use of critically important antimicrobials for human medicine, especially colistin. These aspects could be considered critical aspects of antibiotic use in from farrow-to-wean/finish swine farms in the Umbria region and must be controlled to minimize risks. Even though a small number of farms in Umbria region are at high antibiotic risk, the risk of antibiotic resistance should be minimized, and management and biosecurity of the farms should be improved by extending the use of antimicrobial susceptibility tests and optimizing the diagnostic methods for infectious diseases. Furthermore, farmers' and veterinarians' knowledge of antibiotic resistance should be improved and the prudent use of antibiotics encouraged to prevent the development and spread of resistant microorganisms. PMID- 29119091 TI - Alar width changes due to surgically-assisted rapid palatal expansion: A meta analysis. AB - A major objective of orthognatic surgery is the aesthetic outcome. Treatments only correcting for dentoskeletal deformities are not sufficient for optimal facial results because undesirable soft tissue changes may accompany skeletal manipulations. The primary objective of this study was to investigate alar base width (ABW) changes a minimum of 6 months following surgically-assisted rapid palatal expansion (SARPE). The following electronic databases and citation indices were searched: PubMed, Cochrane Library, Scopus, Web of Science, Embase, and Virtual Health Library. The search included articles published until September 2015 without language restriction. The intervention was SARPE with maxillary vestibular incision from first molar to contralateral first molar, a modified LeFort I osteotomy with or without pterygomaxillary disjunction, and a V Y closure. The primary outcome was the unstandardized mean difference between pre and postoperative ABW. A random effects meta-analysis was performed to combine study results, and included studies that were assessed for statistical heterogeneity using a Chi-square test for independence. The results of this meta analysis (N = 41) showed a significant + 1.74 mm, 95% CI [0.14, 3.34] ABW increase in patients submitted to SARPE. There was no statistical heterogeneity among included studies (chi2 = 0.03; df = 2; P = 0.98). ABW increases were observed despite including cinched patients in the analysis. None of the three included studies were completely free of bias. The most prominent flaws were measurement bias, limited sample size, and patient recruitment. PMID- 29119088 TI - Neurological Manifestations of Dengue Infection. AB - Dengue counts among the most commonly encountered arboviral diseases, representing the fastest spreading tropical illness in the world. It is prevalent in 128 countries, and each year >2.5 billion people are at risk of dengue virus infection worldwide. Neurological signs of dengue infection are increasingly reported. In this review, the main neurological complications of dengue virus infection, such as central nervous system (CNS), peripheral nervous system, and ophthalmic complications were discussed according to clinical features, treatment and possible pathogenesis. In addition, neurological complications in children were assessed due to their atypical clinical features. Finally, dengue infection and Japanese encephalitis were compared for pathogenesis and main clinical manifestations. PMID- 29119092 TI - Effect of malocclusion on the self-esteem of adolescents. AB - INTRODUCTION: Esthetics plays an essential role in orthodontic treatment. The psychological effects of malocclusion are an inspiration to improve one's esthetics and seek treatment. OBJECTIVES: This study aimed to assess relationships between self-esteem and malocclusion severity and type in adolescents using a self-esteem measurement scale and the index of treatment need (IOTN) and to investigate the influence of age, sex, and school type in these relationships. MATERIALS AND METHODS: Adolescent students aged 12-19 years randomly selected from four private and two governmental schools were enrolled for this study. After completing the self-esteem questionnaire, participants were examined by researchers to evaluate malocclusion severity and type using the IOTN. RESULTS: The sample consisted of 886 participants: 558 females (62.9%) and 328 males (37.1%) with a mean age of 16 years. Chi-square analysis showed that 17.1% of males and 31% of females showed low levels of self-esteem, with a statistically significant difference (P < 0.001). Cases with multiple malocclusions showed significantly lower self-esteem (P = 0.018) compared with single-category malocclusion. Anterior teeth spacing, crowding, and overjet malocclusion showed the highest percentages of low self-esteem. CONCLUSIONS: The present study supports that malocclusion has negative effects on self-esteem; multiple malocclusions with spacing, crowding, and overjet had the greatest effects. PMID- 29119093 TI - Surface modification for bonding between amalgam and orthodontic brackets. AB - OBJECTIVE: Testing of methods to enhance the shear bond strength (SBS) between orthodontic metal brackets and amalgam by sandblasting and different primers. MATERIALS AND METHODS: Three hundred samples of amalgam restorations (KerrAlloy(r)) were prepared in self-cured acrylic blocks, polished, and divided into two groups: nonsandblasted and sandblasted. Each group was divided into five subgroups with different primers used in surface treatment methods, with a control group of bonded brackets on human mandibular incisors. Following the surface treatments, mandibular incisor brackets (Unitek(r)) were bonded on the amalgam with adhesive resin (Transbond XT(r)). The SBS of the samples was tested. The adhesive remnant index (ARI) and failure modes were then determined under a stereo-microscope. Two-way analysis of variance, Chi-square, and Kruskal-Wallis tests were performed to calculate the correlations between and among the SBS and ARI values, the failure modes, and surface roughness results. RESULTS: There were statistically significant differences of SBS among the different adhesive primers and sandblasting methods (P < 0.05). The sandblasted amalgam with Assure Plus(r) showed the highest SBS (P < 0.001). Samples mainly showed an ARI score = 1 and mix-mode failure. There was a statistically significant difference of surface roughness between nonsandblasted amalgam and sandblasted amalgam (P < 0.05), but no significant differences among priming agents (P > 0.05). CONCLUSIONS: Using adhesive primers with sandblasting together effectively enhances the SBS between orthodontic metal brackets and amalgam. The two primers with the ingredient methacryloxydecyl dihydrogen phosphate (MDP) monomer, Alloy Primer(r) and Assure Plus(r), were the most effective. Including sandblasting in the treatment is essential to achieve the bonding strength required. PMID- 29119094 TI - A comparison of orthodontic elastic forces: Focus on reduced inventory. AB - OBJECTIVES: To compare orthodontic elastics with different force extension characteristics, thereby aiming to reduce the orthodontist's inventory for elastics. MATERIALS AND METHODS: Thirty nonextraction class I models were used to determine extension distances. Light, medium, and heavy forced Latex elastics of size 1/4 and 3/16 (from three manufacturers) were used. Thirty elastics from each pack were selected, for a total sample size of 540 elastics. Elastic force was measured at three extensions: three times the lumen (A), first molar to opposing canine (B), and second molar to opposing canine distance (C). Force values were compared with the analysis of variance followed by the post hoc Scheffe test. RESULTS: Mean distance for extensions B and C were 22.3 and 38.7 mm, respectively. There was a continuous but significant increase in the force of 1/4 elastics when stretched from A to extension C. A significant increase in the force level of 3/16 elastics was only noted when stretched from A to B. Overall, 1/4 elastics had a wider range of force coverage in the extensions used, compared to 3/16 elastics. CONCLUSIONS: The use of 1/4 elastics is sufficient to cover the range of forces in orthodontic treatment. PMID- 29119095 TI - Changes consequent to maxillary molar distalization with the bone-anchored pendulum appliance. AB - OBJECTIVES: This retrospective study aimed to evaluate the dentoalveolar, skeletal, and soft tissue effects obtained with bone-anchored pendulum appliance in patients with Class II malocclusion. MATERIALS AND METHODS: A total of 18 patients (4 male, 14 female) at a mean pretreatment age of 14.0 years (+1.08) were enrolled in this study. All patients were treated with the bone-anchored pendulum appliance for an average duration of 4.8 months. Only the active distalization period was evaluated with predistalization and postdistalization lateral cephalograms. Skeletal, dentoalveolar, and soft tissue variables were obtained. Based on these variables, the treatment effects were evaluated with dependent t-test. RESULTS: Correction of Class II molar relationship resulted from distal movement of 3.45 mm and tipping of 11.24 degrees of the first maxillary molars. The premolars were distalized accompanying the molars. CONCLUSIONS: The bone-anchored pendulum appliance proved to be an effective method for distalization of maxillary molars in cases that require maximum anchorage, avoiding reciprocal mesial movement of premolars and incisors. PMID- 29119096 TI - Severe skeletal Class II Division 1 malocclusion in postpubertal girl treated using Forsus with miniplate anchorage. AB - This case report outlines the treatment of a 17-year-old female with Class II Division 1 malocclusion with mandibular retrusion, deep bite, and convex facial profile. The Forsus fatigue resistance device with miniplate was used for this patient and it was very affecting tool in correcting both skeletal and dental parameters. The total active treatment time was 19 months. This method can serve as an alternate choice of treatment, especially those who refuse orthognathic surgery. Hence, Forsus with miniplate might be useful in both growing and postpubertal patients. PMID- 29119097 TI - Skeletal anchorage for intrusion of bimaxillary molars in a patient with skeletal open bite and temporomandibular disorders. AB - The treatment of severe skeletal anterior open bite is extremely difficult in adults, and orthognathic surgery is generally selected for its treatment. We report the case of an 18-year-old adult patient with skeletal anterior open bite and temporomandibular disorders who was successfully treated using temporary anchorage devices. She had an open bite of -2.0 mm and an increased facial height. Miniplates were implanted in both the maxilla and mandible, and molar intrusion resulted in counterclockwise rotation of the mandible over a period of 12 months. After active treatment, her upper and lower first molars were intruded by approximately 2 mm and her overbite became +2.5 mm. Her retrognathic profile improved with counterclockwise rotation of the mandible. Orthodontic treatment aided with skeletal anchorage is beneficial for intrusion of bimaxillary molars in patients with anterior open bite. PMID- 29119098 TI - Re-Emerging Vaccine-Preventable Diseases in War-Affected Peoples of the Eastern Mediterranean Region-An Update. AB - For the past few decades, the Eastern Mediterranean Region has been one area of the world profoundly shaped by war and political instability. On-going conflict and destruction have left the region struggling with innumerable health concerns that have claimed the lives of many. Wars, and the chaos they leave behind, often provide the optimal conditions for the growth and re-emergence of communicable diseases. In this article, we highlight a few of the major re-emerging vaccine preventable diseases in four countries of the Eastern Mediterranean Region that are currently affected by war leading to a migration crisis: Iraq, South Sudan, Syria, and Yemen. We will also describe the impact these infections have had on patients, societies, and national health care services. This article also describes the efforts, both local and international, which have been made to address these crises, as well as future endeavors that can be done to contain and control further devastation left by these diseases. PMID- 29119099 TI - Wnt and Hedgehog Signaling Regulate the Differentiation of F9 Cells into Extraembryonic Endoderm. AB - Mouse F9 cells differentiate into primitive extraembryonic endoderm (PrE) when treated with retinoic acid (RA), and this is accompanied by an up-regulation of Gata6. The role of the GATA6 network in PrE differentiation is known, and we have shown it directly activates Wnt6. Canonical Wnt/beta-catenin signaling is required by F9 cells to differentiate to PrE, and this, like most developmental processes, requires input from one or more additional pathways. We found both RA and Gata6 overexpression, can induce the expression of Indian Hedgehog (Ihh) and a subset of its target genes through Gli activation during PrE induction. Chemical activation of the Hh pathway using a Smoothened agonist (SAG) also increased Gli reporter activity, and as expected, when Hh signaling was blocked with a Smoothened antagonist, cyclopamine, this RA-induced reporter activity was reduced. Interestingly, SAG alone failed to induce markers of PrE differentiation, and had no effect on Wnt/beta-catenin-dependent TCF-LEF reporter activity. The expected increase in Wnt/beta-catenin-dependent TCF-LEF reporter activity and PrE markers induced by RA was, however, blocked by cyclopamine. Finally, inhibiting GSK3 activity with BIO increased both TCF-LEF and Gli reporter activities. Together, we demonstrate the involvement of Hh signaling in the RA-induced differentiation of F9 cells into PrE, and while the activation of the Hh pathway itself is not sufficient, it as well as active Wnt/beta-catenin are necessary for F9 cell differentiation. PMID- 29119100 TI - Motoric Cognitive Risk Syndrome: Predictor of Dementia and Age-Related Negative Outcomes. AB - Cognitive disorders represent a leading cause of disability in the aging population, of which dementia has the highest global burden. Early signs of dementia such as slow gait and memory complaints are known to present well before the overt manifestation of the disease. Motoric cognitive risk (MCR) syndrome characterized by the simultaneous presence of gait disturbances and memory complaints in older subjects has been proposed to study the close interactions between the physical and cognitive domains as well as a possible approach to identify individuals at increased risk of dementia. In addition, studies have shown MCR as a predictor of other negative outcomes in older adults, including disability, falls and death. However, the concept of MCR is still in its early stage and approach to the syndrome is still not well established. This review aims to put together the various aspects of MCR syndrome including its pathophysiology, diagnosis, epidemiology, and relationship with other geriatric conditions. PMID- 29119101 TI - Effect of Dual Infection with Eimeria tenella and Subgroup J Avian Leukosis Virus on the Cecal Microbiome in Specific-Pathogen-Free Chicks. AB - Understanding gut microflora alterations associated with gut parasites and other pathogens that drive these alterations may help to promote the understanding of intestinal flora's role in multiple-infected individuals. This study examined the effects of dual infection with Eimeria tenella and subgroup J avian leukosis virus (ALV-J) on the chick cecal microbiome. Specific-pathogen-free (SPF) chicks were infected with either ALV-J strain NX0101 at 1 day of age or E. tenella at 14 days of age, another group was infected with both pathogens. Cecal contents from chicks were extracted at the 21 days of age and examined using 16S rRNA genes illumina sequencing. A genus-level opportunistic pathogen enrichment and a decrease in possible resident probiotics were observed in response to all infection groups. Of note, E. tenella mainly induced a sharp decrease in the richness and diversity of cecal microflora from infected chicks because of the serious E. tenella-induced damage to intestinal tissues. ALV-J infection led to structural changes and increased the richness and diversity of the cecal microflora. As for E. tenella and ALV-J dual infected chicks, a marked enrichment of opportunistic pathogens in addition to some other bacteria that may play a role involving cecal microbiota carbohydrate transport and metabolic functions were also found compared to single pathogen-infected chicks. Overall, this study provides valuable insights into the SPF chick cecal microbial community, the modulations of this community in response to different pathogenic infections of single or dual infections, and the interactions between different pathogens and hosts from the perspective of intestinal microflora. PMID- 29119102 TI - The Transcriptional Network Structure of a Myeloid Cell: A Computational Approach. AB - Understanding the general principles underlying genetic regulation in eukaryotes is an incomplete and challenging endeavor. The lack of experimental information regarding the regulation of the whole set of transcription factors and their targets in different cell types is one of the main reasons to this incompleteness. So far, there is a small set of curated known interactions between transcription factors and their downstream genes. Here, we built a transcription factor network for human monocytic THP-1 myeloid cells based on the experimentally curated FANTOM4 database where nodes are genes and the experimental interactions correspond to links. We present the topological parameters which define the network as well as some global structural features and introduce a relative inuence parameter to quantify the relevance of a transcription factor in the context of induction of a phenotype. Genes like ZHX2, ADNP, or SMAD6 seem to be highly regulated to avoid an avalanche transcription event. We compare these results with those of RegulonDB, a highly curated transcriptional network for the prokaryotic organism E. coli, finding similarities between general hallmarks on both transcriptional programs. We believe that an approach, such as the one shown here, could help to understand the one regulation of transcription in eukaryotic cells. PMID- 29119103 TI - Evaluation of Catalytic Effects of Chymotrypsin and Cu2+ for Development of UV Spectroscopic Method for Gelatin-Source Differentiation. AB - The consumers interest in gelatin authentication is high due to allergic reactions and adoption of Halal and Kosher eating cultures. This research investigated browning development due to enzymatic hydrolysis and presence of Cu2+ during Maillard reaction of fish, porcine, and bovine gelatin. The rate of browning index samples showed two phases-rapid and slow-for all the gelatin samples and changes in browning index (DeltaBindex) were increased (>100%) in presence of Cu2+. DeltaBindex of enzymatic hydrolysates were different among the gelatin species. Fish gelatin hydrolyzate displayed > 400% increase in browning in the first six hours compared to gelatin hydrolyzates from porcine (200%) and bovine (140%). The variation in DeltaBindex of chymotrypsin digested gelatin in presence of Cu2+ could be valuable for the development of an efficient UV spectroscopic method for gelatin differentiation. PMID- 29119104 TI - Usefulness of Computed Tomography Image Processing by OsiriX Software in Detecting Wooden and Bamboo Foreign Bodies. AB - Objective: The aim of this study was to evaluate the usefulness of reconstructed computed tomography (CT) images using OsiriX software in detecting wooden and bamboo foreign bodies. Methods: Four sizes of wet and dry wooden and bamboo foreign bodies were selected to be analyzed. Those in the air and in the head of edible swine were scanned with a multidetector row CT scanner. The images were evaluated with OsiriX software in the bone and the abdomen window setting as unprocessed images. Three-dimensional rendered images assigned colors and opacity by a 16-bit color look-up table (CLUT) editor in OsiriX software were evaluated as processed images. Results: In the unprocessed images, dry and wet foreign bodies in the air were not detected except a part of wet wooden foreign bodies, and all the dry and wet foreign bodies in the swine's head mimicked air with linear shapes. In the processed images, all the dry and wet foreign bodies in the air were detected clearly, and all the wooden and some of the bamboo foreign bodies in the swine's head were detected clearly. Conclusions: CT images processed using OsiriX software, especially with a CLUT editor, were useful in detecting wooden and bamboo foreign bodies. PMID- 29119105 TI - A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers. AB - Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q)), segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating) domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147) with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported), highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers. PMID- 29119106 TI - Iterative Schemes to Solve Low-Dimensional Calibration Equations in Parallel MR Image Reconstruction with GRAPPA. AB - GRAPPA (Generalized Autocalibrating Partially Parallel Acquisition) is a widely used parallel MRI reconstruction technique. The processing of data from multichannel receiver coils may increase the storage and computational requirements of GRAPPA reconstruction. Random projection on GRAPPA (RP-GRAPPA) uses random projection (RP) method to overcome the computational overheads of solving large linear equations in the calibration phase of GRAPPA, saving reconstruction time. However, RP-GRAPPA compromises the reconstruction accuracy in case of large reductions in the dimensions of calibration equations. In this paper, we present the implementation of GRAPPA reconstruction method using potential iterative solvers to estimate the reconstruction coefficients from the randomly projected calibration equations. Experimental results show that the proposed methods withstand the reconstruction accuracy (visually and quantitatively) against large reductions in the dimension of linear equations, when compared with RP-GRAPPA reconstruction. Particularly, the proposed method using conjugate gradient for least squares (CGLS) demonstrates more savings in the computational time of GRAPPA, without significant loss in the reconstruction accuracy, when compared with RP-GRAPPA. It is also demonstrated that the proposed method using CGLS complements the channel compression method for reducing the computational complexities associated with higher channel count, thereby resulting in additional memory savings and speedup. PMID- 29119107 TI - Santamarine Inhibits NF-kappaB Activation and Induces Mitochondrial Apoptosis in A549 Lung Adenocarcinoma Cells via Oxidative Stress. AB - Santamarine (STM), a sesquiterpene lactone component of Magnolia grandiflora and Ambrosia confertiflora, has been shown to possess antimicrobial, antifungal, antibacterial, anti-inflammatory, and anticancer activities. However, no study has yet been conducted to investigate the molecular mechanism of STM-mediated anticancer activity. In the present study, we found that STM inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells through induction of oxidative stress. STM induces oxidative stress by promoting reactive oxygen species (ROS) generation, depleting intracellular glutathione (GSH), and inhibiting thioredoxin reductase (TrxR) activity in a dose-dependent manner. Further mechanistic study demonstrated that STM induces apoptosis by modulation of Bax/Bcl-2 expressions, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of PARP in a dose-dependent manner. Moreover, STM inhibited the constitutive and inducible translocation of NF kappaBp65 into the nucleus. IKK-16 (I-kappaB kinase inhibitor) augmented the STM induced apoptosis, indicating that STM induces apoptosis in A549 cells at least in part through NF-kappaB inhibition. Finally, STM-induced apoptosis and expressions of apoptosis regulators were effectively inhibited by thiol antioxidant N-acetyl-L-cysteine (NAC), indicating that STM exerts its anticancer effects mainly through oxidative stress. To the best of our knowledge, this is the first report providing evidence of anticancer activity and molecular mechanism of STM. PMID- 29119108 TI - Effect of Endocrown Restorations with Different CAD/CAM Materials: 3D Finite Element and Weibull Analyses. AB - The aim of this study was to evaluate the effects of two endocrown designs and computer aided design/manufacturing (CAD/CAM) materials on stress distribution and failure probability of restorations applied to severely damaged endodontically treated maxillary first premolar tooth (MFP). Two types of designs without and with 3 mm intraradicular extensions, endocrown (E) and modified endocrown (ME), were modeled on a 3D Finite element (FE) model of the MFP. Vitablocks Mark II (VMII), Vita Enamic (VE), and Lava Ultimate (LU) CAD/CAM materials were used for each type of design. von Mises and maximum principle values were evaluated and the Weibull function was incorporated with FE analysis to calculate the long term failure probability. Regarding the stresses that occurred in enamel, for each group of material, ME restoration design transmitted less stress than endocrown. During normal occlusal function, the overall failure probability was minimum for ME with VMII. ME restoration design with VE was the best restorative option for premolar teeth with extensive loss of coronal structure under high occlusal loads. Therefore, ME design could be a favorable treatment option for MFPs with missing palatal cusp. Among the CAD/CAM materials tested, VMII and VE were found to be more tooth-friendly than LU. PMID- 29119109 TI - All-Atom Four-Body Knowledge-Based Statistical Potentials to Distinguish Native Protein Structures from Nonnative Folds. AB - Recent advances in understanding protein folding have benefitted from coarse grained representations of protein structures. Empirical energy functions derived from these techniques occasionally succeed in distinguishing native structures from their corresponding ensembles of nonnative folds or decoys which display varying degrees of structural dissimilarity to the native proteins. Here we utilized atomic coordinates of single protein chains, comprising a large diverse training set, to develop and evaluate twelve all-atom four-body statistical potentials obtained by exploring alternative values for a pair of inherent parameters. Delaunay tessellation was performed on the atomic coordinates of each protein to objectively identify all quadruplets of interacting atoms, and atomic potentials were generated via statistical analysis of the data and implementation of the inverted Boltzmann principle. Our potentials were evaluated using benchmarking datasets from Decoys-'R'-Us, and comparisons were made with twelve other physics- and knowledge-based potentials. Ranking 3rd, our best potential tied CHARMM19 and surpassed AMBER force field potentials. We illustrate how a generalized version of our potential can be used to empirically calculate binding energies for target-ligand complexes, using HIV-1 protease-inhibitor complexes for a practical application. The combined results suggest an accurate and efficient atomic four-body statistical potential for protein structure prediction and assessment. PMID- 29119110 TI - A Randomized Controlled Trial Evaluating the Effects of Diosmin in the Treatment of Radicular Pain. AB - Diosmin has been widely used to treat patients with vascular pain for its potent anti-inflammatory and analgesic effects. To evaluate the therapeutic effects of Diosmin in the treatment of radicular pain, we conducted an investigator initiated, randomized, active-controlled noninferiority trial between January 1, 2009, and December 1, 2010. Diosmin (50 mg/kg/day) was orally administered to treat the radicular pain in 150 patients for one month. Another 150 patients with the same symptom were given 20% 250 ml mannitol (1 g/kg/day) for 7 days and dexamethasone (10 mg/day) for 3 days intravenously guttae. Short-term relief and long-term relief were measured. Secondary outcomes include improvement in functional and psychological status, return to work, and reduction in anti inflammatory analgesic drugs intake. Patients treated with oral Diosmin achieved reduction in radicular pain. The total satisfaction rate of Diosmin group was 84.7% [95% confidence interval (CI): 77.9%, 90.0%], and the complete satisfaction rate was 50.7% (95% CI: 42.4%, 58.9%). No statistically significant difference was found between the Diosmin group and the active-control group regarding patient satisfaction. No adverse effects were found during the study period. Our study suggests that clinical application of Diosmin with a dose of 50 mg/kg/day might reduce the radicular pain. This trial is registered with ISRCTN97157037. PMID- 29119111 TI - Recent Developments for Remediating Acidic Mine Waters Using Sulfidogenic Bacteria. AB - Acidic mine drainage (AMD) is regarded as a pollutant and considered as potential source of valuable metals. With diminishing metal resources and ever-increasing demand on industry, recovering AMD metals is a sustainable initiative, despite facing major challenges. AMD refers to effluents draining from abandoned mines and mine wastes usually highly acidic that contain a variety of dissolved metals (Fe, Mn, Cu, Ni, and Zn) in much greater concentration than what is found in natural water bodies. There are numerous remediation treatments including chemical (lime treatment) or biological methods (aerobic wetlands and compost bioreactors) used for metal precipitation and removal from AMD. However, controlled biomineralization and selective recovering of metals using sulfidogenic bacteria are advantageous, reducing costs and environmental risks of sludge disposal. The increased understanding of the microbiology of acid-tolerant sulfidogenic bacteria will lead to the development of novel approaches to AMD treatment. We present and discuss several important recent approaches using low sulfidogenic bioreactors to both remediate and selectively recover metal sulfides from AMD. This work also highlights the efficiency and drawbacks of these types of treatments for metal recovery and points to future research for enhancing the use of novel acidophilic and acid-tolerant sulfidogenic microorganisms in AMD treatment. PMID- 29119112 TI - Expression and Immunogenicity of Two Recombinant Fusion Proteins Comprising Foot and-Mouth Disease Virus Structural Protein VP1 and DC-SIGN-Binding Glycoproteins. AB - Improving vaccine immunogenicity by targeting antigens to dendritic cells has recently emerged as a new design strategy in vaccine development. In this study, the VP1 gene of foot-and-mouth disease virus (FMDV) serotype A was fused with the gene encoding human immunodeficiency virus (HIV) membrane glycoprotein gp120 or C2-V3 domain of hepatitis C virus (HCV) envelope glycoprotein E2, both of which are DC-SIGN-binding glycoproteins. After codon optimization, the VP1 protein and the two recombinant VP1-gp120 and VP1-E2 fusion proteins were expressed in Sf9 insect cells using the insect cell-baculovirus expression system. Western blotting showed that the VP1 protein and two recombinant VP1-gp120 and VP1-E2 fusion proteins were correctly expressed in the Sf9 insect cells and had good reactogenicity. Guinea pigs were then immunized with the purified proteins, and the resulting humoral and cellular immune responses were analyzed. The VP1-gp120 and VP1-E2 fusion proteins induced significantly higher specific anti-FMDV antibody levels than the VP1 protein and stronger cell-mediated immune responses. This study provides a new perspective for the development of novel FMDV subunit vaccines. PMID- 29119113 TI - Increased EGFR Phosphorylation Correlates with Higher Programmed Death Ligand-1 Expression: Analysis of TKI-Resistant Lung Cancer Cell Lines. AB - Despite the recent development of immunotherapies that target programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) treatment, these therapies are less effective in NSCLC patients with epidermal growth factor receptor (EGFR) mutations. However, the molecular mechanisms underlying this lower efficacy of immunotherapies in EGFR mutant lung cancers are still unclear. In this study, we analyzed PD-L1 protein expression in lung cancer cell lines with EGFR mutations prior to and after acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs). We found that parental lung cancer cell lines harboring EGFR mutations showed negative (PC9 and H3255 cells) and positive (HCC827 cells) staining for PD-L1 by immunohistochemistry. Comparing PD-L1 expression between EGFR-TKI resistant cell lines and their parental cells, we found that increased phosphorylation of EGFR was related to increased expression of PD-L1. Increased phosphorylation of EGFR was accompanied by the T790M secondary mutation. Acquired resistance cells with MET amplification or EGFR loss both showed decreased phosphorylation of EGFR and decreased PD-L1 expression. Our results indicate that lung cancer cell lines with EGFR mutations (parental cells) do not harbor high PD-L1 protein expression. In addition, EGFR phosphorylation affects PD-L1 expression after acquisition of resistance to EGFR-TKIs. PMID- 29119114 TI - Model Checking Temporal Logic Formulas Using Sticker Automata. AB - As an important complex problem, the temporal logic model checking problem is still far from being fully resolved under the circumstance of DNA computing, especially Computation Tree Logic (CTL), Interval Temporal Logic (ITL), and Projection Temporal Logic (PTL), because there is still a lack of approaches for DNA model checking. To address this challenge, a model checking method is proposed for checking the basic formulas in the above three temporal logic types with DNA molecules. First, one-type single-stranded DNA molecules are employed to encode the Finite State Automaton (FSA) model of the given basic formula so that a sticker automaton is obtained. On the other hand, other single-stranded DNA molecules are employed to encode the given system model so that the input strings of the sticker automaton are obtained. Next, a series of biochemical reactions are conducted between the above two types of single-stranded DNA molecules. It can then be decided whether the system satisfies the formula or not. As a result, we have developed a DNA-based approach for checking all the basic formulas of CTL, ITL, and PTL. The simulated results demonstrate the effectiveness of the new method. PMID- 29119115 TI - Optimization of the Time Window of Interest in Ovariectomized Imprinting Control Region Mice for Antiosteoporosis Research. AB - This study was performed to determine the optimal window of time during which the properties of osteoporosis are obvious and to explore the best region of interest for microstructural evaluation in antiosteoporosis research in an ovariectomized mouse model by examining changes in micro-computed tomography parameters and serum indices. Ovariectomized mice and sham-operated mice were randomly divided into five groups. At the end of the 4th, 8th, 12th, 16th, and 20th weeks after ovariectomy, the microstructure of the proximal tibia and distal femur was scanned by micro-computed tomography and blood samples were collected to detect serum biochemical indicators including alkaline phosphatase, osteocalcin, N terminal propeptide of type I procollagen (P1NP), and C-terminal telopeptide fragment of type I collagen (CTX1). The trabecular number and connectivity density decreased while the trabecular thickness and trabecular separation increased, indicating substantial changes in the trabecular microstructure of both the tibia and femur and significant changes in bone turnover after ovariectomy, as indicated by lower levels of serum alkaline phosphatase, osteocalcin, and P1NP and higher level of CTX1 in the ovariectomy than sham group. The proximal tibia from weeks 8 to 16 after ovariectomy was optimal for osteoporosis research in this model. PMID- 29119116 TI - Use of Limiting Dilution Method for Isolation of Nucleus Pulposus Mesenchymal Stem/Progenitor Cells and Effects of Plating Density on Biological Characteristics and Plasticity. AB - Objectives: To evaluate the effects of the limiting dilution method and plating density in rat nucleus pulposus mesenchymal stem/progenitor cells (NPMSCs). Materials and Methods: Nucleus pulposus tissues were isolated from 12-week-old male Sprague-Dawley rats and NPMSCs were isolated using limiting dilution method. Cells were then classified into 3 groups according to plating density. Cell morphologies were observed, and colony-forming units, migration abilities, proliferative capacities, cell cycle percentages, multilineage differentiation capacities, stem cell biomarker expression levels, and immunophenotyping were also examined in each group. Results: Low density group (LD) had higher morphological homogeneity, stronger colony-forming ability, higher cell proliferation capacity, and enhanced cell migration ability relative to the other two groups (p < 0.05). Moreover, LD had more cells entering S phase, with fewer cells arrested in G0/G1 phase (p < 0.05). While all three density groups showed a multilineage differentiation potential, LD showed a higher degree of observed and semiquantified lineage specific staining (p < 0.05). Furthermore, LD displayed higher expression levels of stem cell biomarkers (Nanog, Oct4, and Sox2) and showed higher percentages of CD29+, CD44+, and CD90+ cells (p < 0.05) following flow cytometry analysis. Conclusions: Limiting dilution method is suggested when isolating NPMSCs as a means of improving cell activity and plasticity. PMID- 29119117 TI - Blocking AGE-RAGE Signaling Improved Functional Disorders of Macrophages in Diabetic Wound. AB - Advanced glycosylation end products (AGEs) accumulate in diabetic wounds. Interactions between AGEs and their receptor (RAGE) leads to dermatologic problems in diabetes. Macrophage, which plays important roles in wound healing, highly expresses RAGE. Therefore, we investigated whether RAGE-expressing macrophages might be responsible for impaired wound healing on diabetes. We used anti-RAGE antibody applied topically on diabetic wounds. After confirming that wound healing was improved in anti-RAGE antibody group compared with normal mice, our results showed that macrophages appeared insufficient in the early stage and fading away slowly in the later proliferative phase compared with the control group, which was ameliorated in anti-RAGE antibody-applied wounds. Blocking AGE RAGE signaling also increased neutrophils phagocytized by macrophages and promoted the phenotypic switch of macrophages from proinflammatory to prohealing activities. In vitro, phagocytosis of THP-1 (M0) and lipopolysaccharide- (LPS-) induced (M1) macrophages was impaired by treatment with AGEs, while IL-4- and IL 13-induced (M2) macrophages was not. Finally, AGEs increased the proinflammatory response of M1 macrophages, while inhibiting the polarization and anti inflammatory functions of M2 macrophages. In conclusion, inhibition of AGE-RAGE signaling improved functional disorders of macrophages in the early inflammatory phase, which promoted the healing of wounds in diabetic mice. PMID- 29119118 TI - Diagnostic Accuracy of Monofilament Tests for Detecting Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis. AB - Objective: To systematically evaluate the diagnostic accuracy of monofilament tests for detecting diabetic peripheral neuropathy. Methods: We searched EMBASE (OvidSP), MEDLINE (OvidSP), the Cochrane Library, and Web of Science to identify diagnostic accuracy trials of monofilament tests for detecting diabetic peripheral neuropathy. We used a hierarchical summary receiver operating characteristics (HSROC) model to conduct the meta-analysis of diagnostic accuracy of monofilament tests for detecting diabetic peripheral neuropathy. Results: A total of 19 comparative trials met the inclusion criteria and were part of the qualitative synthesis. Eight trials using nerve conduction studies as the reference standard were selected for the meta-analysis. The pooled sensitivity and specificity of monofilament tests for detecting diabetic peripheral neuropathy were 0.53 (95% confidence interval (CI) 0.32 to 0.74) and 0.88 (95% CI 0.78 to 0.94), respectively. The pooled positive likelihood ratio and negative likelihood ratio were 4.56 (95% CI 2.93 to 7.10) and 0.53 (95% CI 0.35 to 0.81), respectively. Conclusions: Our review indicated that monofilament tests had limited sensitivity for screening diabetic peripheral neuropathy. The clinical use of the monofilament test in the evaluation of diabetic peripheral neuropathy cannot be encouraged based on currently available evidence. PMID- 29119119 TI - An Exploration of the Impact of Anticentromere Antibody on Early-Stage Embryo. AB - Background: Previously, we found women with positive anticentromere antibody showed impaired potential of oocyte maturation and embryo cleavage; the possible mechanism behind this phenomenon was still unknown. Objective: Thus, the present study aimed to preliminarily explore whether ACA could penetrate into the living embryos and impair their developmental potential via in vitro coculture with mouse embryos. Methods: Mouse embryos were collected and used for in vitro culture with polyclonal anticentromere protein A (CENP-A) antibody; then, immunofluorescence assay was performed to determine the penetration of antibody into embryos, and embryo development potential was observed. Results: All embryos cultured with anti-CENP-A antibody exhibited immunofluorescence on the nucleus, while none of the embryos from the control groups showed immunofluorescence. Additionally, embryos cultured with anti-CENP-A antibody experienced significant growth impairment compared with controls. Conclusion: Mouse embryos may be a direct target for ACA in vitro prior to implantation. However, the precise mechanism needs further clarification. PMID- 29119121 TI - Impact of Private Health Insurance on Lengths of Hospitalization and Healthcare Expenditure in India: Evidences from a Quasi-Experiment Study. AB - The health insurers administer retrospectively package rates for various inpatient procedures as a provider payment mechanism to empanelled hospitals in Indian healthcare market. This study analyzed the impact of private health insurance on healthcare utilization in terms of both lengths of hospitalization and per-day hospitalization expenditure in Indian healthcare market where package rates are retrospectively defined as healthcare provider payment mechanism. The claim records of 94443 insured individuals and the hospitalisation data of 32665 uninsured individuals were used. By applying stepwise and propensity score matching method, the sample of uninsured individual was matched with insured and 'average treatment effect on treated' (ATT) was estimated. Overall, the strategies of hospitals, insured and insurers for maximizing their utility were competing with each other. However, two aligning co-operative strategies between insurer and hospitals were significant with dominant role of hospitals. The hospitals maximize their utility by providing high cost healthcare in par with pre-defined package rates but align with the interest of insurers by reducing the number (length) of hospitalisation days. The empirical results show that private health insurance coverage leads to i) reduction in length of hospitalization, and ii) increase in per day hospital (health) expenditure. It is necessary to regulate and develop a competent healthcare market in the country with proper monitoring mechanism on healthcare utilization and benchmarks for pricing and provision of healthcare services. PMID- 29119120 TI - Computer-Aided Design of an Epitope-Based Vaccine against Epstein-Barr Virus. AB - Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt's lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble. PMID- 29119122 TI - Pediatric inhalation injury. AB - Smoke inhalation injury can cause severe physiologic perturbations. In pediatric patients, these perturbations cause profound changes in cardiac and pulmonary physiology. In this review, we examine the pathology, early management options, ventilator strategy, and long-term outcomes in pediatric patients who have suffered a smoke inhalation injury. PMID- 29119123 TI - Indication for Computed Tomography Scan in Shoulder Instability: Sensitivity and Specificity of Standard Radiographs to Predict Bone Defects After Traumatic Anterior Glenohumeral Instability. AB - Background: Quantifying glenohumeral bone loss is key in preoperative surgical planning for a successful Bankart repair. Hypothesis: Simple radiographs can accurately measure bone defects in cases of recurrent shoulder instability. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: A true anteroposterior (AP) view, alone and in combination with an axillary view, was used to evaluate the diagnostic properties of radiographs compared with computed tomography (CT) scan, the current gold standard, to predict significant bone defects in 70 patients. Sensitivity, specificity, and positive and negative predictive values were evaluated and compared. Results: Detection of glenoid bone loss on plain film radiographs, with and without axillary view, had a sensitivity of 86% for both views and a specificity of 73% and 64% with and without the axillary view, respectively. For detection of humeral bone loss, the sensitivity was 8% and 17% and the specificity was 98% and 91% with and without the axillary view, respectively. Regular radiographs would have missed 1 instance of significant bone loss on the glenoid side and 20 on the humeral side. Interobserver reliabilities were moderate for glenoid detection (kappa = 0.473 0.503) and poor for the humeral side (kappa = 0.278-0.336). Conclusion: Regular radiographs showed suboptimal sensitivity, specificity, and reliability. Therefore, CT scan should be considered in the treatment algorithm for accurate quantification of bone loss to prevent high rates of recurrent instability. PMID- 29119125 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2325967117727262.]. PMID- 29119126 TI - Phenotypic Heterogeneity of the m.14459G>A Mutation. PMID- 29119127 TI - Sensitive Assessment of Hippocampal Learning Using Temporally Dissociated Passive Avoidance Task. AB - The temporally dissociated passive avoidance (TDPA) paradigm is a variant of passive avoidance testing, and allows for more sensitive investigation of mild impairments in avoidance learning. Passive avoidance learning measures the latency to enter a "dark" context in which an aversive stimulus (foot shock) has been previously experienced using a light-dark box paradigm. Briefly, the animal is placed into the light side of the box and the time spent to cross into the dark side is measured. After entry into the dark chamber, the animal receives a mild (0.4-1.6 mA) footshock and is removed from the box. After a period of time, typically 24 h (note that this is entirely dependent on whether various levels of memory retention, e.g., short or long, are being measured), the animal is placed back into the box and cross-over latency is measured. Passive avoidance is learned after one trial and results in a robust increase in crossover latency. This behavior requires the association between a normally neutral environment and an aversive stimulus, and is dependent on hippocampal function (Stubley-Weatherly et al., 1996; Impey et al., 1998). TDPA extends this learning across multiple once-daily trials, producing a more graded and malleable latency score, and thus allows a more sensitive evaluation of changes in hippocampal function The task remains dependent on an intact hippocampus (Zhang et al., 2008), and subtle changes in hippocampal gene expression can result in robust alterations in TDPA latency scores (Eagle et al., 2015). We describe here a common method used to assess TDPA learning in mice. PMID- 29119124 TI - Spanish Consensus Statement: Clinical Management and Treatment of Tendinopathies in Sport. AB - On October 15, 2016, experts met at Clinica CEMTRO in Madrid, Spain, under the patronage of the Spanish Society for Sports Traumatology (SETRADE), the Spanish Society of Sports Medicine (SEMED), the Spanish Association of Medical Services for Football Clubs (AEMEF), the Spanish Association of Medical Services for Basketball Clubs (AEMB), F.C. Barcelona, and Clinica CEMTRO. The purpose was to consider the most appropriate clinical management and treatment of tendinopathies in sports, based on proven scientific data described in the medical literature as well as on each expert's experience. Prior to the meeting, each expert received a questionnaire regarding clinical management and treatment of tendinopathies in sports. The present consensus document summarizes the answers to the questionnaire and the resulting discussion and consensus regarding current concepts on tendinopathies in sports. PMID- 29119128 TI - Whole Mammary Gland Transplantation in Mice Protocol. AB - Whole Mammary Gland Transplantation involves transplanting an excised mammary gland into another, more suitable host. This method can be used to extend the life of a mammary gland past the mouse's life span by transplanting the mammary gland of an older mouse into a young healthy mouse. As you can see in the video below (Video 1), by attaching it to the abdomen of the mouse, the gland will receive a steady blood supply and both epithelial and stromal cells will remain viable for up to one year. Although this method is not used often, it has been part of several experiments including determining whether the stroma or epithelium is the primary target in chemically induced mouse mammary tumorigenesis (Medina and Kittrell, 2005). To monitor transplants, palpate every week for tumor formation. The transplanted mammary gland may also be passaged serially every 8-10 weeks. Keep transplanted gland in the same mouse for no longer than one year. PMID- 29119129 TI - Aging Partners Managing Chronic Illness Together: Introducing the Content Collection. AB - Prior literature on illness management within intimate relationships demonstrates a variety of benefits from supportive partnership. Indeed, much of the earliest research in this field engaged older adults with and without chronic conditions. However, this pioneering literature gave little consideration to relationships in which multiple partners were coping with chronic illness. By contrast, the majority of published manuscripts presented a "sick partner/well partner" model in which caregiving flowed only in one direction. Yet this idea makes little sense in the context of contemporaneous data on population aging and health as a majority of older adults now live with at least one chronic condition. Scholars still have not delved explicitly into the experiences of the vast population of older relationship partners who are managing chronic conditions simultaneously. We thus welcome Gerontology and Geriatric Medicine readers to this special content collection on Aging Partners Managing Chronic Illness Together. PMID- 29119130 TI - Addressing Pediatric Obesity in Clinic. AB - There is an epidemic of pediatric obesity in the United States. In most cases, there is an excess in the amount of calories consumed, compared with the amount of calories expended. Numerous body systems are affected by pediatric obesity, with complications varying between boys and girls. Behavioral, genetic, and environmental factors affect the ability of children to avoid becoming obese. Primary care physicians should screen for obesity in children as much as possible. Associated risk factors for obesity should be uncovered. Methods of preventing obesity should be discussed routinely with children and their families. Healthy dietary habits are key, and so are family-oriented interventions, such as eating together at dinnertime. One hour of moderate to vigorous activity daily is recommended for children and adolescents. While pediatric bariatric surgery is an option, there are also numerous nonpharmacological and pharmacological measures available as management for pediatric obesity. Family-based approaches, such as reducing screen time, have been very successful. Non-weight-bearing exercises also help children and adolescents expend calories without causing injury to themselves. Family availability, activity preference, and developmental levels should all be considerations when managing pediatric obesity. Motivational interviewing may also be helpful, especially when customized for each specific patient and family. Clinicians will play an increasing role in terms of identifying, treating, and preventing pediatric obesity; measures that can be done in the clinic should be considered more and more. PMID- 29119131 TI - Bedtime Use of Technology and Associated Sleep Problems in Children. AB - Children comprise one of the largest consumer groups of technology. Sleep is fundamental to optimal functioning during childhood, including health and behavior. The purpose of this study was to explore bedtime electronic use and its impact on 3 health consequences-sleep quantity and quality, inattention, and body mass index. Parents of 234 children, ages 8 to 17 years, were surveyed to quantify hours of technology use (computer, video games, cell phone, and television), hours of sleep, and inattentive behaviors. Using any device at bedtime was associated with a statically significant increased use of multiple forms of technology at bedtime and use in the middle of the night, reducing sleep quantity and quality. Little association was found between technology use and inattention. A statistically significant association was found between bedtime technology use and elevated body mass index. Clinicians should discuss the impact of technology at bedtime to prevent harmful effects of overexposure. PMID- 29119133 TI - Editorial: Improving the Way Science is Done, Evaluated, and Published. PMID- 29119132 TI - Addressing Unmet Sexual Health Needs among Black Adolescents with Mental Illnesses. AB - Despite advances in HIV epidemiologic and prevention research, adolescents with mental illnesses remain a historically underserved group with respect to human immunodeficiency virus (HIV)/sexually transmitted infection (STI) prevention resources. Black adolescents with mental illnesses in particular are a relatively underserved, hidden population in the field of sexual health. Strategies and guidelines are needed to account for underlying psychopathology among Black adolescents with mental illnesses in ways that current models have yet to address. In this paper, we propose several actionable mechanisms to better integrate HIV/STI and mental health related services and activities for sexual health promotion. PMID- 29119134 TI - Erratum: Author Correction: The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. AB - [This corrects the article DOI: 10.1038/s41523-017-0024-8.]. PMID- 29119135 TI - Ultrafast magnetization reversal by picosecond electrical pulses. AB - The field of spintronics involves the study of both spin and charge transport in solid-state devices. Ultrafast magnetism involves the use of femtosecond laser pulses to manipulate magnetic order on subpicosecond time scales. We unite these phenomena by using picosecond charge current pulses to rapidly excite conduction electrons in magnetic metals. We observe deterministic, repeatable ultrafast reversal of the magnetization of a GdFeCo thin film with a single sub-10-ps electrical pulse. The magnetization reverses in ~10 ps, which is more than one order of magnitude faster than any other electrically controlled magnetic switching, and demonstrates a fundamentally new electrical switching mechanism that does not require spin-polarized currents or spin-transfer/orbit torques. The energy density required for switching is low, projecting to only 4 fJ needed to switch a (20 nm)3 cell. This discovery introduces a new field of research into ultrafast charge current-driven spintronic phenomena and devices. PMID- 29119136 TI - K-Lambda crossover transition in the conduction band of monolayer MoS2 under hydrostatic pressure. AB - Monolayer MoS2 is a promising material for optoelectronics applications owing to its direct bandgap, enhanced Coulomb interaction, strong spin-orbit coupling, unique valley pseudospin degree of freedom, etc. It can also be implemented for novel spintronics and valleytronics devices at atomic scale. The band structure of monolayer MoS2 is well known to have a direct gap at K (K') point, whereas the second lowest conduction band minimum is located at Lambda point, which may interact with the valence band maximum at K point, to make an indirect optical bandgap transition. We experimentally demonstrate the direct-to-indirect bandgap transition by measuring the photoluminescence spectra of monolayer MoS2 under hydrostatic pressure at room temperature. With increasing pressure, the direct transition shifts at a rate of 49.4 meV/GPa, whereas the indirect transition shifts at a rate of -15.3 meV/GPa. We experimentally extract the critical transition point at the pressure of 1.9 GPa, in agreement with first-principles calculations. Combining our experimental observation with first-principles calculations, we confirm that this transition is caused by the K-Lambda crossover in the conduction band. PMID- 29119137 TI - Competitive chiral induction in a 2D molecular assembly: Intrinsic chirality versus coadsorber-induced chirality. AB - Noncovalently introducing stereogenic information is a promising approach to embed chirality in achiral molecular systems. However, the interplay of the noncovalently introduced chirality with the intrinsic chirality of molecules or molecular aggregations has rarely been addressed. We report a competitive chiral expression of the noncovalent interaction-mediated chirality induction and the intrinsic stereogenic center-controlled chirality induction in a two-dimensional (2D) molecular assembly at the liquid/solid interface. Two enantiomorphous honeycomb networks are formed by the coassembly of an achiral 5 (benzyloxy)isophthalic acid (BIC) derivative and 1-octanol at the liquid/solid interface. The preferential formation of the globally homochiral assembly can be achieved either by using the chiral analog of 1-octanol, (S)-6-methyl-1-octanol, as a chiral coadsorber to induce chirality to the BIC assembly via noncovalent hydrogen bonding or by covalently linking a chiral center in the side chain of BIC. Both the chiral coadsorber and the intrinsically chiral BIC derivative can act as a chiral seeds to induce a preferred handedness in the assembly of the achiral BIC derivatives. Furthermore, the noncovalent interaction-mediated chirality induction can restrain or even overrule the manifestation of the intrinsic chirality of the BIC molecule and dominate the handedness of the 2D molecular coassembly. This study provides insight into the interplay of intrinsically chiral centers and external chiral coadsorbers in the chiral induction, transfer, and amplification processes of 2D molecular assembly. PMID- 29119138 TI - Giant positive magnetoresistance in half-metallic double-perovskite Sr2CrWO6 thin films. AB - Magnetoresistance (MR) is the magnetic field-induced change of electrical resistance. The MR effect not only has wide applications in hard drivers and sensors but also is a long-standing scientific issue for complex interactions. Ferromagnetic/ferrimagnetic oxides generally show negative MR due to the magnetic field-induced spin order. We report the unusually giant positive MR up to 17,200% (at 2 K and 7 T) in 12-nm Sr2CrWO6 thin films, which show metallic behavior with high carrier density of up to 2.26 * 1028 m-3 and high mobility of 5.66 * 104 cm2 V-1 s-1. The possible mechanism is that the external magnetic field suppresses the long-range antiferromagnetic order to form short-range antiferromagnetic fluctuations, which enhance electronic scattering and lead to the giant positive MR. The high mobility may also have contributions to the positive MR. These results not only experimentally confirm that the giant positive MR can be realized in oxides but also open up new opportunities for developing and understanding the giant positive MR in oxides. PMID- 29119139 TI - A remote C-C bond cleavage-enabled skeletal reorganization: Access to medium /large-sized cyclic alkenes. AB - Although great success has been achieved in selective C-C bond cleavage via the intramolecular radical remote migration process of several carbon-based groups, the development of the radical-based remote vinyl migration process remains a formidable challenge because of the energetically unfavorable process. To address this problem, we report here, for the first time, a novel C-C bond reorganization strategy via an unprecedented radical 1,3-, 1,4-, or 1,5-vinyl migration triggered by various types of fluoroalkylation of alkenes for the efficient realization of 1,2-fluoroalkylalkenylation reaction. This strategy provides an expedient and broadly applicable platform to access skeletally and functionally diverse fluoroalkyl-containing medium- and large-sized cyclic alkenes with excellent chemo-, regio-, and stereoselectivity. The broad substrate scope, which covers distinctly electron-neutral or electron-deficient alkenyl migrating groups and various fluoroalkyl radical precursors, the excellent functional group tolerance, the remarkable selectivity, and the operational simplicity, as well as versatile transformations of the products, make this approach practical and attractive. PMID- 29119140 TI - The spin Nernst effect in tungsten. AB - The spin Hall effect allows the generation of spin current when charge current is passed along materials with large spin-orbit coupling. It has been recently predicted that heat current in a nonmagnetic metal can be converted into spin current via a process referred to as the spin Nernst effect. We report the observation of the spin Nernst effect in W. In W/CoFeB/MgO heterostructures, we find changes in the longitudinal and transverse voltages with magnetic field when temperature gradient is applied across the film. The field dependence of the voltage resembles that of the spin Hall magnetoresistance. A comparison of the temperature gradient-induced voltage and the spin Hall magnetoresistance allows direct estimation of the spin Nernst angle. We find the spin Nernst angle of W to be similar in magnitude but opposite in sign to its spin Hall angle. Under an open-circuit condition, this sign difference results in the spin current generation larger than otherwise. These results highlight the distinct characteristics of the spin Nernst and spin Hall effects, providing pathways to explore materials with unique band structures that may generate large spin current with high efficiency. PMID- 29119141 TI - Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases. AB - In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3alpha, 7beta-dihydroxy-5beta-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters. PMID- 29119142 TI - What constitutes successful commissioning of transition from children's to adults' services for young people with long-term conditions and what are the challenges? An interview study. AB - Objective: We explored what constitutes successful commissioning for transition and what challenges are associated with this. We aimed: (1) to identify explicit and implicit organisational structures, processes and relationships that drive commissioning around transition; (2) to identify challenges faced by commissioners; and (3) to develop a conceptual model. Design: A qualitative interview study. Setting: Commissioning and provider organisations across primary and secondary care and third sector in England, UK. Participants: Representatives (n=14) from clinical commissioning groups, health and well-being boards and local authorities that commission national health services (NHS) for transition from children's to adults' services in England; NHS directors, general practitioners and senior clinicians (n=9); and frontline NHS and third sector providers (n=6). Results: Both commissioners and providers thought successful transition is personalised, coordinated and collaborative with a focus on broad life outcomes and actualised through building pathways and universal services. A multitude of challenges were described, including inconsistent national guidance, fragmented resources, incompatible local processes, lack of clear outcomes and professional roles and relationships. No single specific process of commissioning for transition emerged-instead complex, multi-layered, interactive processes were described. Conclusions: The findings indicate a need to consider more explicitly the impact of national policies and funding streams on commissioning for transition. Commissioners need to require care pathways that enable integrated provision for this population and seek ways to ensure that generalist community providers engage with children with long-term conditions from early on. Future research is needed to identify a core set of specific, meaningful transition outcomes that can be commissioned, measured and monitored. PMID- 29119143 TI - Modified Controlled Encircling Scleral Buckle for Retinal Detachment. AB - During encircling scleral buckle placement, the ends of the element are tightened to achieve a shortened radius of the eye. The determining factor of the final buckle height is subjective using usually a combination of the buckle height visualized with the degree of scleral indentation and can be difficult to be taught early on to trainees. Here, we describe a case series in which a modified controlled encircling scleral buckle technique that simplifies and standardizes the achievement of reproducible buckle height of about a 1 mm is objective and easy to be taught. This novel encircling scleral buckling technique successfully achieves a good postoperative scleral buckle height in a reproducible and standardized fashion using objective measurements and it is easier to be taught to trainees. PMID- 29119144 TI - Dynamic Visualization and Comparative Analysis of Multiple Collinear Genomic Data. AB - We have developed a novel tool for visualizing and analyzing multiple collinear genomes. Unlike previous genome browsers and viewers, ours allows for simultaneous and comparative analysis. Our browser is web-based and provides intuitive selection and interactive navigation about features of interest. Dynamic visualizations adjust to scale and data content making analysis at variable resolutions and of multiple data sets more informative. Our tool illustrates genome-sequence similarity through a mosaic of intervals representing local phylogeny, subspecific origin, and haplotype identity. Comparative analysis is facilitated through reordering and clustering of tracks, which can vary throughout the genome. In addition, we provide local phylogenetic trees as an alternate visualization to assess local variations. We demonstrate our genome browser for an extensive set of genomic data sets composed of almost 200 distinct mouse strains. PMID- 29119145 TI - Extracting Adverse Drug Events from Text using Human Advice. AB - Adverse drug events (ADEs) are a major concern and point of emphasis for the medical profession, government, and society in general. When methods extract ADEs from observational data, there is a necessity to evaluate these methods. More precisely, it is important to know what is already known in the literature. Consequently, we employ a novel relation extraction technique based on a recently developed probabilistic logic learning algorithm that exploits human advice. We demonstrate on a standard adverse drug events data base that the proposed approach can successfully extract existing adverse drug events from limited amount of training data and compares favorably with state-of-the-art probabilistic logic learning methods. PMID- 29119146 TI - 4D Infant Cortical Surface Atlas Construction using Spherical Patch-based Sparse Representation. AB - The 4D infant cortical surface atlas with densely sampled time points is highly needed for neuroimaging analysis of early brain development. In this paper, we build the 4D infant cortical surface atlas firstly covering 6 postnatal years with 11 time points (i.e., 1, 3, 6, 9, 12, 18, 24, 36, 48, 60, and 72 months), based on 339 longitudinal MRI scans from 50 healthy infants. To build the 4D cortical surface atlas, first, we adopt a two-stage groupwise surface registration strategy to ensure both longitudinal consistency and unbiasedness. Second, instead of simply averaging over the co-registered surfaces, a spherical patch-based sparse representation is developed to overcome possible surface registration errors across different subjects. The central idea is that, for each local spherical patch in the atlas space, we build a dictionary, which includes the samples of current local patches and their spatially-neighboring patches of all co-registered surfaces, and then the current local patch in the atlas is sparsely represented using the built dictionary. Compared to the atlas built with the conventional methods, the 4D infant cortical surface atlas constructed by our method preserves more details of cortical folding patterns, thus leading to boosted accuracy in registration of new infant cortical surfaces. PMID- 29119147 TI - Betrixaban: a direct oral inhibitor of activated factor X for the prophylaxis of venous thromboembolism in patients hospitalized for acute medical illness. AB - Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a serious clinical and public health concern. Hospitalization is a major risk factor for developing VTE. Hospital-associated events account for more than 50% of all cases of VTE. Heparins have demonstrated to be efficacious in the prevention of VTE in medically ill patients. Despite the demonstrated efficacy and safety of the available direct oral anticoagulants in the prevention and treatment of different thromboembolic conditions, their net benefit in the prevention of VTE in hospitalized medically ill patients has not been fully confirmed. Betrixaban is an oral, specific and direct inhibitor of human coagulation factor Xa with demonstrated efficacy and safety for the prevention of VTE in patients undergoing total knee replacement and in patients with nonvalvular atrial fibrillation. Recent studies have successfully evaluated betrixaban 80 mg once daily in the prevention of VTE in acute medically ill patients in a large phase III trial. This review will address preclinical pharmacology and main aspects of the clinical development of betrixaban as an antithrombotic agent, with specific attention to recent studies on the prophylaxis of VTE in a specific population of patients hospitalized for acute medical illnesses. PMID- 29119148 TI - Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients. AB - Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. PMID- 29119149 TI - Sofosbuvir/ledipasvir fixed-dose combination for treatment of chronic hepatitis C virus infection in children. AB - The United States Food and Drug Administration recently approved sofosbuvir and the fixed-dose combination of ledipasvir/sofosbuvir for the treatment of hepatitis C virus (HCV) infection in children ages 12 to 17. These are the first direct-acting antiviral treatments approved for children and adolescents with HCV. Pharmacokinetic data confirm equivalent drug exposure in this population as that found in adults during clinical trials. The efficacy and safety of these drugs has been shown in clinical trials. PMID- 29119150 TI - Notable licensing deals in the biopharma industry in the second quarter of 2017. AB - During the second quarter of 2017, Cortellis Competitive Intelligence added 967 new licensing deals (excluding mergers and acquisition deals) as part of its ongoing coverage of pharmaceutical licensing activity. This meant an 8% decrease on the previous quarter (1,050) and a 3% decrease from the same quarter in 2016 (993). This quarter also showed a significant decline in the number of deals worth more than USD 0.5 billion from the last quarter (7 vs. 17). This article will highlight a number of the most valuable and notable deals forged during the quarter, as well as a selection of deals from some of the most prolific deal makers in the life sciences. An update on milestone, options and terminated deals of significance will also be presented, along with an early outlook on the next quarter's pharmaceutical licensing activity. PMID- 29119152 TI - Quantitative characterisation of conductive fibers by capacitive coupling. AB - This work presents a study on a capacitively coupled contactless conductivity detector (C4D) for micron-sized fibers. Following a previous report on the qualitative application of C4D for fibers, the present study provides a thorough analysis of the signal response to fiber conductivity. Using reduced graphene oxide (RGO) fibers, the detector response as a function of fiber length, cross sectional area and resistance has been investigated. To study the effect of insulating coatings, Parylene-coated RGO fibers were also investigated. In addition, measurements were performed in different coupling environments, such as in a capillary tube or air. The analysis of the measured data allowed the determination of the C4D conductivity of various RGO fibers, and the correlation with contact methods through empirical relationships to be determined. It was found that the detection limit and sensitivity of resistance measurements are mainly dependent on the sensor design, and also on the fiber properties. The detection threshold can be defined as the ratio of the coupling impedance to fiber resistance. In our case, the detection limit was found for impedance ratios equal to 14. This limit sets a functioning mode in C4D for fibers, which may be used as an area or resistance detector for the impedance ratio above or below the detection threshold. A semi-log linear response of the fiber resistance to the voltage output was found for impedance ratios between 2.66 and 0.63. These impedance ratios may serve as a reference for designing C4D, depending on the fibers to be tested and the analytical information needed. In summary, we suggest that C4D has the capacity to emerge as a new characterisation tool for micron sized fibers, due to its applicability to any conductive material, ease of use, and the contactless nature of the measurement. PMID- 29119153 TI - Effects of side chains of oxatub[4]arene on its conformational interconversion, molecular recognition and macroscopic self-assembly. AB - A series of oxatub[4]arenes with different alkyl side chains have been synthesized. The conformational interconversion, molecular recognition and macroscopic self-assembly behaviour of oxatub[4]arene derivatives were investigated. The difference in side chains slightly changes the binding affinities, but results in different self-assembly morphologies at the solid state. PMID- 29119154 TI - Terahertz spectroscopy for the isothermal detection of bacterial DNA by magnetic bead-based rolling circle amplification. AB - The demand for rapid and sensitive bacterial detection is continuously increasing due to the significant requirements of various applications. In this study, a terahertz (THz) biosensor based on rolling circle amplification (RCA) was developed for the isothermal detection of bacterial DNA. The synthetic bacterium specific sequence of 16S rDNA hybridized with a padlock probe (PLP) that contains a sequence fully complementary to the target sequence at the 5' and 3' ends. The linear PLP was circularized by ligation to form a circular PLP upon recognition of the target sequence; then the capture probe (CP) immobilized on magnetic beads (MBs) acted as a primer to initialize RCA. As DNA molecules are much less absorptive than water molecules in the THz range, the RCA products on the surface of the MBs cause a significant decrease in THz absorption, which can be sensitively probed by THz spectroscopy. Our results showed that 0.12 fmol of synthetic bacterial DNA and 0.05 ng MUL-1 of genomic DNA could be effectively detected using this assay. In addition, the specificity of this strategy was demonstrated by its low signal response to interfering bacteria. The proposed strategy not only represents a new method for the isothermal detection of the target bacterial DNA but also provides a general methodology for sensitive and specific DNA biosensing using THz spectroscopy. PMID- 29119155 TI - Cooperative bimetallic catalysis in asymmetric allylic substitution. AB - Synergistic catalysis is gaining increasing attention due to its advantages over traditional catalytic methodologies, such as improved catalytic activity, broader substrate scope, increased selectivity and lower cost. Methodologies involving the synergistic combination of metal catalysts and organocatalysts have been intensively studied. Given the clear benefits of bimetallic catalyst systems consisting of two distinct metal catalysts, cooperative bimetallic catalysis has proved to be successful for a number of difficult asymmetric transformations. This review highlights the recent advances in bimetallic systems for catalytic asymmetric allylic substitution reactions. Strategies using a chiral metal catalyst and the cooperative effect of a second achiral metal catalyst for asymmetric transformations are discussed. Additionally, several challenging asymmetric reactions realized by employing two different chiral metal catalysts in a synergistic manner are also covered. PMID- 29119156 TI - Sequential detection of Fe3+/2+ and pyrophosphate by a colorimetric chemosensor in a near-perfect aqueous solution. AB - A novel colorimetric chemosensor 1 was designed and synthesized for Fe3+/2+ and pyrophosphate. Sensor 1 showed a selective color change toward both Fe3+ and Fe2+ from yellow to brown in a near-perfect aqueous solution. The detection limits (0.36 MUM and 0.37 MUM) for Fe3+ and Fe2+ were much lower than the guideline (5.37 MUM) set by the Environmental Protection Agency (EPA) for iron in drinking water. Sensor 1 could be used to quantify Fe3+ in real water samples. Moreover, the resulting Fe3+-2.1 complex can detect pyrophosphate selectively over various anions especially including phosphate-based anions through a metal-complex displacement method. Based on UV-vis titrations, Job plot and ESI-mass spectrometry analyses, the sensing mechanisms of Fe3+, Fe2+ and PPi were proposed. PMID- 29119157 TI - Fluorine-free preparation of titanium carbide MXene quantum dots with high near infrared photothermal performances for cancer therapy. AB - Titanium carbide MXene quantum dots (QDs) were synthesized using an effective fluorine-free method as a biocompatible and highly efficient nanoagent for photothermal therapy (PTT) applications. In contrast to the traditional, hazardous and time-consuming process of HF pretreatment, our fluorine-free method is safe and simple. More importantly, abundant Al oxoanions were found to be modified on the MXene QD surface by the fluorine-free method, which endowed the QDs with strong and broad absorption in the NIR region. As a result, the as prepared MXene QDs exhibited an extinction coefficient as large as 52.8 Lg-1 cm-1 at 808 nm and a photothermal conversion efficiency as high as 52.2%. Both the values are among the best reported so far. The as-prepared MXene QDs achieved simultaneous photoacoustic (PA) imaging and the remarkable PTT effect of tumors. Moreover, MXene QDs showed great biocompatibility without causing noticeable toxicity in vitro and in vivo, indicating their high potential for clinical applications. PMID- 29119158 TI - Resonance Raman and IR spectroscopy of aligned carbon nanotube arrays with extremely narrow diameters prepared with molecular catalysts on steel substrates. AB - Carbon nanotubes (CNTs) are considered promising for a large range of emerging technologies ranging from advanced electronics to utilization as nanoreactors. Here we report a controlled facile synthesis of aligned carbon nanotubes with very small dimensions directly grown on steel grid substrates via two-step catalytic chemical vapor deposition (CCVD) of a molecular catalyst (ferrocene) with ethylene as the carbon source. The system is characterized by resonance Raman spectroscopy and the results show single walled carbon nanotube (SWCNT) arrays composed of 0.80 nm to 1.24 nm semiconducting CNTs, as analyzed using Kataura analysis, which is approaching the lowest diameters attainable for SWCNTs. The G+ and G- mode splitting, G- line shapes and ring breathing modes (RBMs) are analyzed to characterize the CNTs. The approach results in close packed and vertically aligned SWCNT bundles formed into hair shapes, with some contribution from multiwall CNTs (MWCNTs). IR spectroscopy is utilized to characterize the edge/defect states that have the ability to form esters and ether bonds in the as-prepared CNTs. The stepwise deposition of the catalyst followed by the carbon source gives control over the formation of small diameter single walled carbon nanotubes (SWCNTs). The utilization of molecular catalysts for narrow diameter growth directly on steel grid substrates forms a promising approach for producing cost-effective CNT substrates for a plethora of sensing and catalytic applications. PMID- 29119159 TI - Controlled multimodal hierarchically porous electrode self-assembly of electrochemically exfoliated graphene for fully solid-state flexible supercapacitor. AB - Supercapacitors constructed from three-dimensional (3D) graphene electrodes with high ion-accessible surface area and durable mechanical flexibility have great potential for wearable devices. For the development of a highly efficient graphene electrode for electrical double layer capacitors (EDLCs), proper control over not only the specific surface area but also the type of pore (macro-, meso- and micro-porous networks) adapted for an appropriate type of electrolyte is crucial to ensure an ideal performance in terms of both energy density and power delivery rate. However, there is still a lack of technology to create graphene structures that combine macro-, meso- and micro-pores by a one-step and facile method. In addition, the ion/electron transport of a solid state electrolyte among such multimodal pore structures is not fully investigated. Here, we report a novel cost-effective technique of concentration dependent self-assembly of electrochemically exfoliated graphene (EC-graphene) to obtain a 3D architecture with controllable macropores (0.39-4.99 MUm) and multimodal hierarchical meso- and micro-pores. The better performance of the 3D architecture is obtained due to its optimum micron-sized macropore diameter (~5 MUm) that serves as an ion buffering reservoir, followed by facile ion diffusion kinetics through the well modulated combination of macro-, meso- and micro-pores. The binder and conductive carbon additive free supercapacitor constructed from the 3D graphene electrode exhibited a specific capacitance of 45.40 F g-1 (6 M KOH) and 23.89 F g-1 (1 M H2SO4 gel electrolyte). A capacitance retention of above 90% (up to 180 degrees folding angle) after 50 bending-relaxing cycles is obtained, implying the superior durability of the device and the worthiness of the synthesis procedure. The method reported here may pave the way for the development of an environment friendly, large scale producible and controlled porous graphene-based architecture for the high performance next generation flexible, all-solid-state and binder-free energy storage devices. PMID- 29119161 TI - Facile solvothermal approach to pristine tetrahedrite nanostructures with unique multiply-voided morphology. AB - Tetrahedrite (Cu12Sb4S13) is a highly promising environmentally friendly material for energy conversion applications but its synthesis generally requires several days of heating at high temperature conditions. To fabricate tetrahedrite in a more rapid way and under milder conditions, solvothermal synthesis has been recently explored. However, a common problem faced when using this technique is the formation of significant amounts of other ternary Cu-Sb-S phases along with the desired tetrahedrite phase. Here, we present an optimized solvothermal procedure for synthesizing high-purity samples of tetrahedrite at moderate temperatures and reasonable heating times. The as-prepared samples are single crystalline nanometer-sized structures having multiple voids or pores. By modifying certain experimental parameters such as the reaction temperature and heating time, we have shown that we can alter the nanocrystal architecture. The formation mechanism was investigated and it was found that these porous tetrahedrite nanostructures are a product of the non-classical oriented aggregation growth process. Porosity in nanomaterials is known to improve material properties and is desirable in many important applications so the construction of void-containing tetrahedrite nanostructures will potentially extend the utility of tetrahedrite to a wider range of applications. In this work, we explore its possible use as a photothermal-responsive drug delivery vehicle. PMID- 29119162 TI - Intense red up-conversion luminescence and dynamical processes observed in Sc2O3:Yb3+,Er3+ nanostructures. AB - The intense red up-conversion luminescence in Sc2O3:Yb3+,Er3+ synthesized using a biphasic solvothermal (ST) method was observed upon laser diode pumping at 980 nm. Compared with that found in the bulk sample synthesized using a solid state (SS) reaction at the same sintering temperature (700 degrees C), the green and red up-conversion luminescence are enhanced by a factor of 19.7 and 23.4, respectively. The relative red intensity of the sample prepared using the ST method at 700 degrees C for 2 h was enhanced up to 6.6 times compared to that obtained by the SS reaction method at 1600 degrees C for 6 h. On analyzing the spectral distribution, power dependence and decay curves of Yb3+, we revealed that the red emission of the Er3+:4F9/2 level in Sc2O3:Yb3+,Er3+ was populated via three possible routes, i.e. excited-state absorption (ESA), two-step energy transfer up-conversion (ET) and non-multiphonon relaxation mechanism from the (2H11/2, 4S3/2) via cross-relaxation and energy back transfer (CRB). For the green up-conversion of the Er3+:(2H11/2, 4S3/2) level, a three-photon process described as Yb3+:2F5/2 + Er3+:4F9/2 -> Yb3+:2F7/2 + Er3+:2H9/2 occurs in the Sc2O3:Yb3+,Er3+ material. The results indicate that ST-Sc2O3:Yb3+,Er3+ can act as an efficient up-converting red light emitter and ST-Sc2O3 is an appropriate oxide host for up-conversion luminescence. PMID- 29119163 TI - Superhydrophobic inkjet printed flexible graphene circuits via direct-pulsed laser writing. AB - Solution-phase printing of exfoliated graphene flakes is emerging as a low-cost means to create flexible electronics for numerous applications. The electrical conductivity and electrochemical reactivity of printed graphene has been shown to improve with post-print processing methods such as thermal, photonic, and laser annealing. However, to date no reports have shown the manipulation of surface wettability via post-print processing of printed graphene. Herein, we demonstrate how the energy density of a direct-pulsed laser writing (DPLW) technique can be varied to tune the hydrophobicity and electrical conductivity of the inkjet printed graphene (IPG). Experimental results demonstrate that the DPLW process can convert the IPG surface from one that is initially hydrophilic (contact angle ~47.7 degrees ) and electrically resistive (sheet resistance ~21 MOmega ?-1) to one that is superhydrophobic (CA ~157.2 degrees ) and electrically conductive (sheet resistance ~1.1 kOmega ?-1). Molecular dynamic (MD) simulations reveal that both the nanoscale graphene flake orientation and surface chemistry of the IPG after DPLW processing induce these changes in surface wettability. Moreover, DPLW can be performed with IPG printed on thermally and chemically sensitive substrates such as flexible paper and polymers. Hence, the developed, flexible IPG electrodes treated with DPLW could be useful for a wide range of applications such as self-cleaning, wearable, or washable electronics. PMID- 29119164 TI - Enhanced photoelectrochemical water oxidation performance of a hematite photoanode by decorating with Au-Pt core-shell nanoparticles. AB - It is well known that bimetallic nanomaterials usually exhibit unique catalytic, optical, electric and magnetic properties due to the synergistic effect between different metals. In this work, we reported on a scalable method to fabricate an AuPt bimetallic core-shell nanoparticles loaded hematite (alpha-Fe2O3) photoanode for solar-driven photoelectrochemical water oxidation. Compared to single metal modified alpha-Fe2O3 photoanodes, the AuPt bimetallic core-shell nanoparticles loaded alpha-Fe2O3 photoanodes exhibited a synergistic effect for photoelectrochemical water oxidation. The photocurrent density of AuPt0.2/alpha Fe2O3 was boosted to 0.83 mA cm-2 at 1.23 V versus a reversible hydrogen electrode in a neutral electrolyte (0.5 M Na2SO4 aqueous solution) under 45 W xenon lamp irradiation. The incident photon-to-photocurrent efficiency value of optimum AuPt0.2/alpha-Fe2O3 was estimated to be 58%, which was significantly higher than the single metal-modified alpha-Fe2O3 and pristine alpha-Fe2O3 photoanodes (<10%). Electrochemical impedance spectroscopy and Mott-Schottky analysis confirmed that the Schottky junction formed by the AuPt bimetallic nanoparticles and alpha-Fe2O3 led to enhanced charge separation and band bending, resulting in a negative shift of onset potential. Based on the experimental and characterized results, a possible mechanism was proposed. This work provides an important reference for the design of other bimetallic-modified photoanodes for application in energy conversion. PMID- 29119165 TI - A photoredox-neutral Smiles rearrangement of 2-aryloxybenzoic acids. AB - We report on the use of visible light photoredox catalysis for the radical Smiles rearrangement of 2-aryloxybenzoic acids to obtain aryl salicylates. The method is free of noble metals and operationally simple and the reaction can be run under mild batch or flow conditions. Being a redox neutral process, no stoichiometric oxidants or reductants are needed. PMID- 29119166 TI - Pushing the photodelivery of nitric oxide to the visible: are {FeNO}7 complexes good candidates? AB - Photodelivery of NO requires stable compounds which can be made reactive by irradiation with (visible) light. Traditional {MNO}6 complexes require a substantial ligand design to shift their absorption spectra to the appropriate region of the electromagnetic spectrum. [Fe((CH2Py2)2Me[9]aneN3)(NO)](BF4)2 is a new {FeNO}7 octahedral coordination compound, which is thermally and air-stable in solution. Illumination with a 450 nm light source induces significant photodetachment of the coordinated NO (phiNO = 0.52 mol einstein-1), suggesting that {FeNO}7 compounds can be in fact suitable compounds for therapeutic NO photorelease. PMID- 29119167 TI - Correction: Controlled synthesis of lanthanide-doped Gd2O2S nanocrystals with novel excitation-dependent multicolor emissions. AB - Correction for 'Controlled synthesis of lanthanide-doped Gd2O2S nanocrystals with novel excitation-dependent multicolor emissions' by Lei Lei, et al., Nanoscale, 2017, 9, 5718-5724. PMID- 29119168 TI - Nanowire sensors monitor bacterial growth kinetics and response to antibiotics. AB - Miniaturized and cost-efficient methods aiming at high throughput analysis of microbes are of great importance for the surveillance and control of infectious diseases and the related issue of antimicrobial resistance. Here we demonstrate a miniature nanosensor based on a honeycomb-patterned silicon nanowire field effect transistor (FET) capable of detection of bacterial growth and antibiotic response in microbiologically relevant nutrient media. We determine the growth kinetics and metabolic state of Escherichia coli cells in undiluted media via the quantification of changes in the source-drain current caused by varying pH values. Furthermore, by measuring the time dependent profile of pH change for bacterial cultures treated with antibiotics, we demonstrate for the first time the possibility of electrically distinguishing between bacteriostatic and bactericidal drug effects. We believe that the use of such nanoscopic FET devices enables addressing parameters that are not easily accessible by conventional optical methods in a label-free format, i.e. monitoring of microbial metabolic activity or stress response. PMID- 29119169 TI - Histone-DNA interaction: an effective approach to improve the fluorescence intensity and stability of DNA-templated Cu nanoclusters. AB - The histone-DNA interaction is found to greatly improve the fluorescence intensity and stability of DNA-templated Cu nanoclusters (CuNCs), which would be highly beneficial for the application of CuNCs in biosensing/imaging. PMID- 29119170 TI - Bimetallic metal-organic framework derived Co3O4-CoFe2O4 composites with different Fe/Co molar ratios as anode materials for lithium ion batteries. AB - Developing high-performance electrode materials to replace a traditional graphite electrode is critical for the commercialization of lithium ion batteries, which however still remains a great challenge. Herein, we report a suitable method to synthesize a series of well-dispersed nanostructured Co3O4-CoFe2O4 composites (CCFs) from bimetallic metal-organic frameworks (BiMOFs) with varied Fe3+/Co2+ molar ratios. When used as anodes for lithium ion batteries, the CCF-12 composite exhibits a maximum initial discharge capacity of 1328 mA h g-1, a reversible capacity of 940 mA h g-1 at 100 mA g-1 after 80 cycles, and a better rate capability in comparison with those of pure Co3O4 and other CCF composites. The well-dispersed structure and small particle size are believed to mainly contribute to the outstanding electrochemical performance of CCF-12 electrodes. PMID- 29119171 TI - Ultra-fast vapor generation by a graphene nano-ratchet: a theoretical and simulation study. AB - Vapor generation is of prime importance for a broad range of applications: domestic water heating, desalination and wastewater treatment, etc. However, slow and inefficient evaporation limits its development. In this study, a nano ratchet, a multilayer graphene with cone-shaped nanopores (MGCN), to accelerate vapor generation has been proposed. By performing molecular dynamics simulation, we found that air molecules were spontaneously transported across MGCN and resulted in a remarkable pressure difference, 21 kPa, between the two sides of MGCN. We studied the dependence of the pressure difference on the ambient temperature and geometry of MGCN in detail. Through further analysis of the diffusive transport, we found that pressure difference depended on the competition between ratchet transport and Knudsen diffusion and it was further found that ratchet transport is dominant. The significant pressure difference could lead to a 15-fold or greater enhancement of vapor generation, which shows the wide applications of this nano-ratchet. PMID- 29119172 TI - Synthesis of amine-bridged bis(phenolate) rare-earth metal aryloxides and their catalytic performances for the ring-opening polymerization of l-lactic acid O carboxyanhydride and l-lactide. AB - A series of rare-earth metal complexes stabilized by different amine bridged bis(phenolate) ligands were synthesized and well characterized. Their catalytic performances for the ring-opening polymerization of l-lactic acid O carboxyanhydride (l-lacOCA) and l-lactide were explored. Sequential reactions of amine bridged bis(phenol) with (C5H5)3RE(THF) in a 1 : 1 molar ratio, followed by 1 equivalent of p-cresol gave the amine bridged bis(phenolate) rare-earth metal aryloxides {La[NNOO-R](OC6H4-4-CH3)(THF)}2 {[NNOO-R] = Me2NCH2CH2N}{CH2-(2-O-C6H2 R2-3,5)}2, R = Me (1), La[NNOO-R](OC6H4-4-CH3)(THF)2 [R = tBu (2); R = Cumyl (3)], Y[NNOO-R](OC6H4-4-CH3)(THF) [R = tBu (4)] and {Y[THFONOO-tBu](OC6H4-4 CH3)}2 {THFONOO-tBu = (CH2)3OCHCH2N[CH2-(2-O-C6H2-3,5-tBu2)]2} (5) in good isolated yields. Single-crystal structure determination revealed that complexes 1 and 5 have dimeric structures, whereas complexes 2 and 3 have monomeric structures in the solid state. It was found that these complexes are efficient initiators for the ring-opening polymerization of l-lacOCA, and the overall coordination environments around the metal centers and the ionic radii of the metal centers have an obvious influence on the catalytic performance. A comparative study on the polymerization kinetics of l-lacOCA and l-lactide initiated by complex 5 was carried out for the first time. The results obtained demonstrated that the polymerization of l-lacOCA and l-lactide is first order for the catalyst and monomer concentration in dichloromethane, respectively, and the Gibbs energy of activation of l-lacOCA and l-lactide is found to be essentially the same. Mechanistic studies revealed that l-lacOCA polymerization initiated by these rare-earth metal complexes proceeded via a coordination-insertion mechanism. PMID- 29119173 TI - Control of porphyrin interactions via structural changes of a peptoid scaffold. AB - Nature utilizes optimally organized pigments in light-harvesting complexes. To mimic the natural photosynthetic proteins, effective control over inter-pigment interactions is necessary to attain the desired photophysical properties. Previously, we developed porphyrin-peptoid conjugates (PPCamide) and displayed two porphyrins at defined positions on an alpha-helical peptoid using a flexible n-butyl linker. Herein, we synthesized new porphyrin-peptoid conjugates (PPCC-C), where porphyrins are conjugated through a rigid C-C linkage to the helical peptoid via the Suzuki-Miyaura cross-coupling reaction. With PPCC-C, we studied the effects of backbone conformation, inter-porphyrin distance, and the linker flexibility on porphyrin interactions. When the rigid C-C linkage was used, conformational homogeneity of the PPC increased, providing more effective intramolecular excitonic couplings between the porphyrins; however, the intermolecular porphyrin J-aggregation decreased. In PPCC-C with a nonameric peptoid backbone, the formation of a threaded loop conformation was observed, which could be switched back to a helical conformation by N-terminal acetylation or by the addition of a protic solvent. This threaded loop-to-helix conversion restored the intramolecular porphyrin interactions. Our results suggest that PPCs represent an excellent system for control over porphyrin interactions and therefore are useful as a model system to elucidate pigment interactions in nature or as a molecular construct with switchable photophysical properties. PMID- 29119175 TI - Protective effect of selenium supplementation following oxidative stress mediated by glucose on retinal pigment epithelium. AB - There are many conditions that affect the retina. However, diabetic retinopathy (RD) as a complication of Diabetes Mellitus continues to be the leading cause of blindness in working people globally. Diabetic retinopathy is an ocular complication of diabetes that is caused by the deterioration of the blood vessels that supply the retina, which has the consequence that the vision deteriorates irreversibly. The retina, and specifically the retinal pigment epithelium (RPE) is the only neural tissue that is exposed directly and frequently to light, which favors the oxidation of lipids that become extremely toxic to the cells of the retina. The RPE is a natural barrier playing an important role in the absorption of light and reduction of light scatter within the eye. In addition, the retina is the tissue that proportionally consumes more oxygen, which generates a high production of reactive oxygen species (ROS). The retina is particularly sensitive to hyperglycemia and oxidative stress. The eye tissues are enriched in certain antioxidants in the form of metabolic enzymes or small molecules. Since selenium is essential for regulating the activity of the enzymes involved in protection against oxidative stress, providing selenium to the ocular tissues could be useful for the treatment of different ocular pathologies. Thus, the aim of this study is to investigate the potential efficacy of selenium in human RPE against glucose-induced oxidative stress and its implications for GPx activity. Chromatographic techniques based on HPLC-ICP-MS will be applied in combination with isotope pattern deconvolution (IPD) to study the effects of selenium supplementation and hyperglycemia in an in vitro model of RPE cells. PMID- 29119176 TI - A novel microfluidic microelectrode chip for a significantly enhanced monitoring of NPY-receptor activation in live mode. AB - Lab-on-a-chip devices that combine, e.g. chemical synthesis with integrated on chip analytics and multi-compartment organ-on-a-chip approaches, are a fast and attractive evolving research area. While integration of appropriate cell models in microfluidic setups for monitoring the biological activity of synthesis products or test compounds is already in focus, the integration of label-free bioelectronic analysis techniques is still poorly realized. In this context, we investigated the capabilities of impedance spectroscopy as a non-destructive real time monitoring technique for adherent cell models in a microfluidic setup. While an initial adaptation of a microelectrode array (MEA) layout from a static setup revealed clear restrictions in the application of impedance spectroscopy in a microfluidic chip, we could demonstrate the advantage of a FEM simulation based rational MEA layout optimization for an optimum electrical field distribution within microfluidic structures. Furthermore, FEM simulation based analysis of shear stress and time-dependent test compound distribution led to identification of an optimal flow rate. Based on the simulation derived optimized microfluidic MEA, comparable impedance spectra characteristics were achieved for HEK293A cells cultured under microfluidic and static conditions. Furthermore, HEK293A cells expressing Y1 receptors were used to successfully demonstrate the capabilities of impedimetric monitoring of cellular alterations in the microfluidic setup. More strikingly, the maximum impedimetric signal for the receptor activation was significantly increased by a factor of 2.8. Detailed investigations of cell morphology and motility led to the conclusion that cultivation under microfluidic conditions could lead to an extended and stabilized cell-electrode interface. PMID- 29119177 TI - Physiological linkage of gender, bioavailable hydroxytyrosol derivatives, and their metabolites with systemic catecholamine metabolism. AB - Despite extensive characterization of hydroxytyrosol (HT), there is a gap in the knowledge about its capacity to modulate catecholamine pathways. This study deals with the evaluation of the effects of HT, hydroxytyrosol acetate (HTA), and 3,4 dihydroxyphenylacetic acid (DOPAC), as well as their microbial metabolites (homovanillyl alcohol and tyrosol), on the excretion of catecholamines by UHPLC ESI-QqQ-MS/MS upon administration at 1 and 5 mg kg-1 to male and female rats. The evaluation of urinary dopamine, norepinephrine, normetanephrine, and 3 methoxytyramine demonstrated 12.0- and 1.5-fold augmented excretions in males and females, respectively, due to the intake of HT derivatives. In addition, specific interconnections were identified between HT, HTA, DOPAC, and tyrosol and 3 methoxytyramine; between HTA and dopamine, norepinephrine, and normetanephrine; between HT, HTA, HVA, and tyrosol and dopamine, norepinephrine, and normetanephrine; and between HT, DOPAC, and HVA and dopamine and 3 methoxytyramine. Hence, a lack of linear relationships was observed between the oral administration of HT, HTA, and DOPAC and their plasma concentrations or urinary excretion levels after they were absorbed and distributed systemically. HT derivatives increase the synthesis of catecholamines in a derivative-, dosage , and gender-dependent way. PMID- 29119179 TI - Poly(acrylic acid) interpolymer complexes. AB - Interpolymer complex formation of poly(acrylic acid) with other macromolecules can occur via several mechanisms that vary depending on the pH. At low pH the protonated acid functional group can form bonds with both donor and acceptor moieties, resulting in desolvated structures consisting of two polymers. Complexes were formed in dilute solutions of PAA, functionalised with acenaphthylene, with a range of other polymers including: poly(NIPAM); poly(ethylene oxide) (PEO); poly(dimethylacrylamide) (PDMA); poly(diethyl acrylamide) (PDEAM) poly(vinyl alcohol) (PVA) and poly(vinyl pyrolidinone) (PVP). Fluorescence anisotropy was used to demonstrate complex formation in each case by monitoring the reductions in segmental motion of the chain as the complexes formed. Considerations of the molecular structures of the complexing moieties suggest that solvation energies and pKas play an important role in complex formation. PMID- 29119180 TI - Organically templated inorganic-organic hybrid metal (Zn and Cd) Sulfite-oxalates with layered and three-dimensional structures. AB - We report single crystal X-ray investigations of three d10 metal based oxalate sulfite inorganic-organic hybrid open framework materials, namely [Zn2(SO3)2(C2O4)0.5(C6N2H13)].(H2O)2, 1, [C4N2H12]0.5[Zn2(SO3)2(C2O4)0.5(H2O)2], 2 and [C4N2H12][Cd2(SO3)2(C2O4)(H2O)].H2O, 3 which show layered and three dimensional structures with different organic templates. These materials were synthesized under hydrothermal conditions and characterized by techniques such as single crystal X-ray diffraction, dipole moment calculations, FTIR, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The common feature for 1 and 2 is the interconnection of embedded zinc-sulfite chains via oxalate anions in the framework and in 3, cadmium-oxalate chains are interconnected via sulfite anions. The coordination geometries of metal(ii) ions vary significantly resulting in a ladder-like layered structure in the case of 1, a 3D framework in case of 2 and a layered structure with an embedded one-dimensional channel in 3. The observed structures can also be partly attributed to the influence exerted by the presence of different structure directing agents (SDA) in the lattice. The dipole moments for metal polyhedra 1, 2 and 3 were calculated from bond valence analyses and are 2.39 D for Zn(1)O4N polyhedra and 1.66 D for Zn(2)O4 polyhedra in 1, 24.90 D for Zn(1)O6 and 29.52 D for Zn(2)O4 in 2 and 5.82 D for Cd(1)O7 and 2.90 D for Cd(2)O6 in 3. PMID- 29119181 TI - Ligand directed structural diversity and magnetism in copper(ii)-azido assemblies with isomeric aminopyridines: synthesis, structure, magnetism and theoretical studies. AB - Four new copper complexes, viz. [{Cu(2-aminopyridine)(N3)2(H2O)}2]n (1), [Cu3(3 aminopyridine)2(N3)6]n (2), [{Cu(3-aminopyridine)(N3)2}2]n (3), and [Cu(4 aminopyridine)2(N3)2]n (4), have been synthesized with isomeric aminopyridines, viz. 2-aminopyridine (2-ap), 3-aminopyridine (3-ap), and 4-aminopyridine (4-ap), to probe the role of ligand and reactant molar ratios in directing the polynuclear assemblage and the associated magnetic properties. Ligand geometry is quite influential as can be seen through the versatile structures formed, viz. a hydrogen bonded layer of MU-1,1 azide bridged Cu dimers in 1; a network of two different types of dimers (Cu1-Cu2 & Cu3-Cu3') involving MU-1,1; MU-1,3; MU 1,1,3; & MU-1,1,3,3 azide bridges in 2; a ladder structure in which MU-1,1 azide bridges form the rungs and MU-1,3 azide bridges form the rails of the ladder in 3; and a 1-D polymer chain involving MU-1,1 azide bridges in 4. Consistent with the bridge geometry, compounds 1 & 2 display ferromagnetic interactions, while 3 & 4 display antiferromagnetic interactions. The rather unexpected antiferromagnetic interactions in 3, in spite of MU-1,1 azide bridged rungs may be due to the crossover near the bridge angle. The ferromagnetic interactions in 1 and 2 are supported by DFT calculations. PMID- 29119183 TI - The influence of thiolate ligands on the luminescence properties of cycloplatinated(ii) complexes. AB - Complexes [Pt(C^N)(PPh3)Cl] (C^N = bzq (7,8-benzoquinolinyl, A) and ppy (2 phenylpyridinyl, B)) were reacted with various thiolate ligands to afford complexes [Pt(C^N)(PPh3)(kappa1-S-SR)], C^N = bzq, R = SPh (thiophenolate, 1a); C^N = ppy, R = SPh (1b); C^N = bzq, R = Spy (pyridine-2-thiolate, 2a); C^N = ppy, R = Spy (2b); C^N = bzq, R = SpyN (pyrimidine-2-thiolate, 3a); C^N = ppy, R = SpyN (3b). Complexes 1-3 were characterized by NMR spectroscopy, and the solid state structures of 1a and 2a were determined by X-ray diffraction methods. Replacing a chloride ligand with electron-rich thiolates changes the lowest energy singlet and triplet excited states to the ones that feature charge transfer from the thiolate (mixed with some metal character) to the C^N ligand, which was supported by TD-DFT calculations. All complexes are emissive at 298 K in the solid state except 2b and 3b, which are emissive only at 77 K having a less rigid structure compared to others. The emission of 1a and 1b originates from a low-energy excited state of dPt/piSR -> pi*C^N while 3a exhibits a 3LC/3MLCT transition. For 1a and 1b, the radiative rate and the quantum efficiency are higher in a rigid environment such as a solid compared to a polymer and solution. Decreasing the rigidity of the environment leads to a flexibility of rotation of the -SR around the axis of the Pt-S bond. So the geometry can be easily changed after radiation and the lowest lying triplet excited state would have the effective contribution of the dd* transition, which opens a nonradiative pathway at room temperature. PMID- 29119184 TI - Highly efficient hydrogen evolution electrocatalysts based on coupled molybdenum phosphide and reduced graphene oxide derived from MOFs. AB - A coupled hybrid of molybdenum phosphide (MoP) and reduced graphene oxide has been prepared for the first time utilizing Mo-MOFs as precursors through a facile method. The nanocomposite exhibits superior electrocatalytic performance towards the HER, and is one of the best high-performance MoP-based electrocatalysts under acidic conditions reported so far. PMID- 29119185 TI - Polymer conformation during flow in porous media. AB - Molecular conformations of individual polymers during flow through porous media are directly observed by single-DNA imaging in microfluidics. As the Weissenberg number increases during flow (Wi > 1), we observe two types of elastic instabilities: (a) stationary dead-zone and (b) time-dependant dead-zone washing. When stretched polymer chains enter a dead-zone, they first re-coil and, once inside the dead-zone, they rotate and re-stretch again. The probability distribution of DNA chains under the stretched condition inside the dead-zone is found to be heterogeneous with a broad distribution. PMID- 29119186 TI - Ion dehydration controls adsorption at the micellar interface: hydrotropic ions. AB - The properties of ionic micelles depend on the nature of the counterion, and these effects become more evident as the ion adsorption at the interface increases. Prediction of the relative extent of ion adsorption is required for rational design of ionic micellar aggregates. Unlike the well understood adsorption of monatomic ions, the adsorption of polyatomic ions is not easily predicted. We combined experimental and computational methods to evaluate the affinity of hydrotropic ions, i.e., ions with polar and apolar regions, to the surface of positively charged micelles. We analyzed cationic micelles of dodecyltrimethylammonium and six hydrotropic counterions: methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, acetate, trifluoroacetate and benzoate. Our results demonstrated that the apolar region of hydrotropic ions had the largest influence on micellar properties. The dehydration of the apolar region of hydrotropic ions upon their adsorption at the micellar interface determined the ion adsorption extension, differently to what was expected based on Collins' law of matching affinities. These results may lead to more general models to describe the adsorption of ions, including polyatomic ions, at the micellar interface. PMID- 29119187 TI - Reaching for the limits in continuous-flow dielectrophoretic DNA analysis. AB - The efficient purification and analysis of topological DNA variants is mandatory for many state-of-the-art molecular medicine technologies, like gene- and cancer therapy as well as plasmid vaccination. In this work, we exploit dielectrophoresis (DEP) for a fast and efficient continuous-flow separation and analysis that goes beyond the standard methods of gel electrophoresis and capillary electrophoresis. The aim of this work was to reach for the limits in dielectrophoretic analysis of DNA regarding the size resolution and the topological conformation. A continuous-flow analytical separation of analyte mixtures of small linear DNA-fragments (10.0 kbp, 8.0 kbp, 6.0 kbp, and 5.0 kbp) and topological DNA variants (linear and supercoiled conformation) was investigated. We present a world record in the minimal size difference of 16.7% of DNA samples that can be resolved in a dielectrophoretic continuous-flow separation. Moreover, we demonstrate for the first time a microfluidic continuous flow separation of DNA molecules based on their topological conformation. Since dielectrophoresis is virtually label-free, it offers a fast in-process quality control with low consumption, e.g. for the production of gene vaccines. PMID- 29119188 TI - Catechol-TiO2 hybrids for photocatalytic H2 production and photocathode assembly. AB - Visible-light driven H2 evolution in water is achieved using catechol photosensitised TiO2 nanoparticles with a molecular nickel catalyst. Layer-by layer immobilisation of catechol-TiO2 onto tin-doped indium oxide electrodes generates photocathodic currents in the presence of an electron acceptor. This approach represents a new strategy for controlling photocurrent direction in dye sensitised photoelectrochemical applications. PMID- 29119189 TI - New lanthanide(iii) coordination polymers: synthesis, structural features, and catalytic activity in CO2 fixation. AB - A new series of lanthanide coordination polymers formulated as [Ln(MU-L)(MU3 L)(H2O)]nXn (Ln/X = Er/Cl (1), Er/Br (2), Tm/Cl (3), Tm/Br (4), Yb/Cl (5), and Yb/Br (6); L = 1,3-bis(4-carboxyphenyl) imidazolium carboxylate(1+)) were solvothermally generated and fully characterized. Single-crystal X-ray diffraction analysis shows that all products possess isomorphous structures that are composed of cationic 1D double chains with encapsulated halide anions. From a topological perspective, such 1D chains can be classified as a binodal 3,5 connected net with a unique topology defined by the point symbol of (3.42)(32.42.53.62.7). All products 1-6 feature a remarkable thermal stability and were applied as highly active heterogeneous catalysts for the coupling reactions between halogenated propylene oxides and CO2 to give the corresponding cyclic carbonates. The reaction conditions, substrate and catalyst scope, and mechanistic features of this catalytic transformation were investigated. High products yields (up to 98%), elevated TONs (up to 3920) or TOFs (up to 326 h-1) were attained under mild reaction conditions. In addition, catalyst 6 can be recycled at least eight times with no loss of catalytic activity. PMID- 29119190 TI - Reactivity and regioselectivity in Diels-Alder reactions of anion encapsulated fullerenes. AB - Encapsulation and surface chemical modification are methodologies to enhance the properties of fullerenes for various applications. Herein, density functional theory calculations are performed to study the Diels-Alder (DA) reactivity of anion encapsulated C60, including [X@C60]- (X = F, Cl, Br, or I), [S@C60]2-, and [N@C60]3-. Computational results reveal that encapsulated Cl-, Br-, I-, or S2- anions are located close to the center of the C60 molecule; however, encapsulated F- is displaced from the center. Encapsulated N3- bonds to the inner surface of the carbon cage, which leads to a negative charge transfer to the C60. In [N@C60]3-, C-C bonds near to the encapsulated N atom are more reactive. Our calculations reveal that encapsulated halogen or S anions decrease the DA reactivity because of the stronger closed-shell repulsion of the encapsulated anion. However, encapsulated N3- increases the DA reactivity. The higher distortion energy of the halogen- or S2--anion encapsulated C60 leads to lower reactivity of the 6-5 bond. Opposite regioselectivity of the DA reaction with [N@C60]3- is attributed to distortion energy of the cyclopentadiene (CPD) moiety. The asymmetrical transition state geometry leads to a lower distortion energy of the CPD moiety. PMID- 29119191 TI - Interfacial arrangement and phase transitions of PNiPAm microgels with different crosslinking densities. AB - Microgels are colloidal hydrogel particles that exhibit a pronounced softness, which arises from the swollen nature of the constituent polymer network. This softness leads to a substantial deformability of such particles at liquid interfaces, which, in turn translates into a complex phase behaviour that can exhibit a phase transition between a non-close packed and a close packed arrangement. Here, we explore how the degree of swellability and deformability - and therefore the softness of the particles - affects the phase behaviour of microgels at the air/water interface upon compression. We use precipitation polymerization to synthesize poly(N-isopropylacrylamide) microgels with similar hydrodynamic radii in the collapsed state and systematically vary the degree of swellability by changing the crosslinking density. We spread these microgels onto the air/water interface of a Langmuir trough and characterize their interfacial properties by surface pressure - area isotherms. Furthermore, we continuously transfer the interfacial microgel monolayer during compression onto a solid substrate, thus encoding the complete phase diagram of the microgels with increasing particle density as a function of the position on the solid substrate. We investigate the microgel arrangement by atomic force microscopy and scanning electron microscopy and use image analysis to extract quantitative information on the interparticle distance and degree of order. We find that the phase transition is very sensitive to the crosslinking density and occurs at much lower surface pressures for less deformable particles. The softest microgels do not undergo any phase transition. Instead, the system exhibits pronounced local conformation changes around point defects with local five- and sevenfold symmetries, indicating that the geometry of the assembled structure effectively controls the local pressure experienced by the microgels. PMID- 29119192 TI - Fluorescent probes for the simultaneous detection of multiple analytes in biology. AB - Many of the key questions facing cellular biology concern the location and concentration of chemical species, from signalling molecules to metabolites to exogenous toxins. Fluorescent sensors (probes) have revolutionised the understanding of biological systems through their exquisite sensitivity to specific analytes. Probe design has focussed on selective sensors for individual analytes, but many of the most pertinent biological questions are related to the interaction of more than one chemical species. While it is possible to simultaneously use multiple sensors for such applications, data interpretation will be confounded by the fact that sensors will have different uptake, localisation and metabolism profiles. An alternative solution is to instead use a single probe that responds to two analytes, termed a dual-responsive probe. Recent progress in this field has yielded exciting probes, some of which have demonstrated biological application. Here we review work that has been carried out to date, and suggest future research directions that will harness the considerable potential of dual-responsive fluorescent probes. PMID- 29119194 TI - Charles Richard Drew (1904-1950): Father of blood banking. PMID- 29119193 TI - Outpatient management of knee osteoarthritis. AB - Osteoarthritis of the knee is a common disease that causes significant disability. Most patients can be managed conservatively in the outpatient setting. A small minority require surgery. The cornerstones of treatment are weight loss, exercise and analgesia. Walking aids, medial patellar taping, acupuncture and transcutaneous electrical nerve stimulation are useful management adjuncts. Current evidence does not support routine prescription of glucosamine and chondroitin supplements. Early consultation with an orthopaedic surgeon should be made when conservative measures fail. PMID- 29119195 TI - Clinics in diagnostic imaging (180). Ductal carcinoma in situ (DCIS). AB - A 26-year-old woman presented with a slow-growing right breast lump. Excision biopsy of the lump showed invasive ductal carcinoma with adjacent ductal carcinoma in situ (DCIS). Preoperative imaging was performed to assess the extent of disease. Magnetic resonance (MR) imaging of the breasts showed an area of clustered ring enhancement deep to the biopsy site, which was representative of residual DCIS. DCIS is a common noninvasive malignancy that manifests as a primary breast tumour or in association with other lesions. The radiological features of DCIS are discussed herein, with special attention to the clustered ring enhancement pattern on MR imaging. PMID- 29119197 TI - [Correction: Chronic urticaria in childhood : Rational diagnostics and treatment]. PMID- 29119198 TI - [Segmental neurofibromatosis]. AB - Thirteen years ago, a 48-year-old man developed numerous neurofibromas in a circumscribed area on the right chest. At the same time, a bilateral seminoma was diagnosed and treated curatively. There was no evidence for other complications of neurofibromatosis. The family history was inconspicuous. The segmental neurofibromatosis (SN) presented in this patient is the result of a mosaic formation resulting from a mutation of the NF1 gene, a tumor suppressor gene. Concomitant, typical diseases of neurofibromatosis generalisata (NFG), including malignant neoplasms, are the exception to SN. PMID- 29119196 TI - [Optical coherence tomography in neuromyelitis optica spectrum disorders]. AB - Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing inflammatory conditions of the central nervous system (CNS). In 55% of the cases of NMOSD optic neuritis (ON) is the most frequent first manifestation and can cause severe damage to the afferent visual system and the retina with resultant severe visual impairment. In recent years, investigations of the retina as part of the CNS by optical coherence tomography (OCT) has been shown to be a valid and efficient method for diagnostics and evaluation of the disease course in NMOSD. In addition, OCT not only shows severe damage of the afferent visual system due to multiple bouts of ON but also reveals NMOSD-specific intraretinal pathologies. The latter could be just as important for future differential diagnostics as for the evaluation of potential therapeutic targets. This article briefly reviews the principles of the OCT technique and describes its relevance for the diagnostics and assessment of disease course in NMOSD. PMID- 29119199 TI - Speech audiometry and data logging in CI patients : Implications for adequate test levels. AB - BACKGROUND: As part of postoperative cochlear implant (CI) diagnostics, speech comprehension tests are performed to monitor audiological outcome. In recent years, a trend toward improved suprathreshold speech intelligibility in quiet and an extension of intelligibility to softer sounds has been observed. Parallel to audiometric data, analysis of the patients' acoustic environment can take place by means of data logging in modern CI systems. OBJECTIVES: Which speech test levels reflect the individual listening environment in a relevant manner and how can these be reflected in a clinical audiometric setting? PATIENTS AND METHODS: In a retrospective analysis, data logs of 263 adult CI patients were evaluated for sound level and the listening situation (quiet, speech in quiet, noise, speech in noise, music, and wind). Additionally, monosyllabic word comprehension in quiet was analyzed in experienced CI users at presentation levels of 40-80 dB. RESULTS: For the sound level in the acoustic environment of postlingually deafened adult CI users, data logging shows a maximum occurrence of speech signals in the range of 50-59 dB. This demonstrates the relevance of everyday speech comprehension at levels below 60 dB. CONCLUSION: Individual optimization of speech intelligibility with a CI speech processor should not be performed in the range of 65-70 dB only, but also at lower levels. Measurements at 50 dB currently seem to be a useful addition. PMID- 29119200 TI - [Possibilities of rehabilitation programmes for adult cancer survivors]. PMID- 29119201 TI - [Implants for genital prolapse : Contra mesh surgery]. AB - Alloplastic transvaginal meshes have become very popular in the surgery of pelvic organ prolapse (POP) as did alloplastic suburethral slings in female stress incontinence surgery, but without adequate supporting data. The simplicity of the mesh procedure facilitates its propagation with acceptance of higher revision and complication rates. Since attending physicians do more and more prolapse surgeries without practicing or teaching alternative techniques, expertise in these alternatives, which might be very useful in cases of recurrence, persistence or complications, is permanently lost. It is doubtful that proper and detailed information about alternatives, risks, and benefits of transvaginal alloplastic meshes is provided to every single prolapse patient according to the recommendations of the German POP guidelines, since the number of implanted meshes exceeds the number of properly indicated mesh candidates by far. Although there is no dissent internationally about the available mesh data, thousands of lawsuits in the USA, insolvency of companies due to claims for compensation and unambiguous warnings from foreign urological societies leave German urogynecologists still unimpressed. The existing literature in pelvic organ prolapse exclusively focusses on POP stage and improvement of that stage with surgical therapy. Instead, typical prolapse symptoms should trigger therapy and improvement of these symptoms should be the utmost treatment goal. It is strongly recommended for liability reasons to obtain specific written informed consent. PMID- 29119202 TI - [Janus kinase inhibitor baricitinib for rheumatoid arthritis : Randomized, double blind, placebo- and active-controlled, phase 3 study evaluating the efficacy and safety of baricitinib in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate therapy (RA-BEAM)]. PMID- 29119203 TI - Modeling Microbial Electrosynthesis. AB - Mathematical modeling is an overarching approach for assessing the complexity of microbial electrosynthesis (MES) and for complementing the relevant experimental research. By describing and linking compartments, components, and processes with appropriate mathematical equations, MES and the corresponding bioelectrodes and complete bioelectrochemical systems can be analyzed and predicted across several temporal and local scales. Thereby, insights into fundamental phenomena and mechanisms, in addition to process engineering and design can be obtained. However, a substantial lack of knowledge about extracellular electron transfer mechanisms and electrotrophic microorganisms presumably prevented the development of adequate models of MES, especially of biocathodes, so far. To propel efforts regarding this demanding task, this chapter provides a comprehensive overview of the relevant compartments, components and processes, appropriate model strategies, and a discussion on potential modeling pitfalls. By adapting an established approach to assessing the energetics of microorganism, an instruction for calculating stoichiometry, thermodynamics, and kinetics, with the example of electro-autotrophic growth at cathodes, is presented. Models of bioanodes and fundamental electrochemical equations are described to provided strategies for calculating cathodic electron-uptake reactions and connecting them to the microbial metabolism. Finally, differential equations are detailed for coupling the distinct compartments of a bioelectrochemical system. Although MES comprises anodic and cathodic reactions, the present chapter focuses on biocathodes representing a functional connection between cathode and electron-accepting microorganisms. PMID- 29119204 TI - Benzalkonium Chloride and Anticancer Drugs in Binary Mixtures: Reproductive Toxicity and Genotoxicity in the Freshwater Crustacean Ceriodaphnia dubia. AB - Benzalkonium chloride (BAC) is a cationic surfactant commonly used as a disinfectant. Its ubiquitous nature is the result of high usage and frequent discharge into the environment and evidence of interaction with numerous contaminants, such as pharmaceutical active compound residues. Anticancer drugs, among these compounds, are able to exert eco-genotoxic effects at sub ng-ug/L. The purpose of this study was to assess the reproductive toxicity and the genotoxicity of 5-fluorouracil (5-FU), cisplatin (CDDP), etoposide (ET), and imatinib mesylate (IM)-binary mixtures combined with BAC in Ceriodaphnia dubia. The effects of the mixtures were assessed under the assumption of independent action in experiments that applied two effect levels. The type of interaction was not the same over the range of effect sizes. The combined action experiment on reproduction showed an antagonistic effect at higher effect levels for all binary combinations, except for BAC/IM, whereas independent action was observed in all mixtures at a low effect level. The results of binary combinations on genotoxicity showed antagonistic effects for BAC + ET and BAC + CDDP, whereas independence was expressed in BAC + IM and BAC + 5-FU. The antagonistic interactions still led to higher effects than those observed after single exposures at the same doses in most cases. The effects of mixtures of drugs should be taken into account for environmental risk assessment. PMID- 29119206 TI - [Indices of Multiple Deprivation for the analysis of regional health disparities in Germany : Experiences from epidemiology and healthcare research]. AB - BACKGROUND: Deprivation indices allow material and social differences at the regional level to be described in a statistically efficient and concise manner and to use these in health analyses. Following the British example, Indices of Multiple Deprivation (IMDs) are now available for Germany, the German Index of Multiple Deprivation (GIMD) as well as its regional versions. In this study, empirical experiences based on the use of these indices in health studies will be presented. METHOD: The German IMDs consist of seven deprivation domains, which represent single aspects of deprivation (income, employment, and educational deprivation, municipal revenue deprivation, social capital deprivation, environment and security deprivation). Specific indicators were generated from data of official statistics and assigned to the deprivation domains. The weighted single domains were finally combined to an overall index. The German IMDs are available at a municipal level and at a district level. RESULTS: Analyses using the IMDs showed significant associations between regional deprivation and mortality, morbidity and aspects of health services research. Multilevel analyses showed significant associations with regional deprivation, independent of individual factors. CONCLUSIONS: The German IMDs are valid and efficient tools for the use in epidemiology and health services research, but also for health policy. When constructing deprivation indices, several methodological challenges have to be considered. PMID- 29119205 TI - Secretome profile analysis of multidrug-resistant, monodrug-resistant and drug susceptible Mycobacterium tuberculosis. AB - The emergence of drug-resistant tuberculosis has generated great concern in the control of tuberculosis and HIV/TB patients have established severe complications that are difficult to treat. Although, the gold standard of drug-susceptibility testing is highly accurate and efficient, it is time-consuming. Diagnostic biomarkers are, therefore, necessary in discriminating between infection from drug-resistant and drug-susceptible strains. One strategy that aids to effectively control tuberculosis is understanding the function of secreting proteins that mycobacteria use to manipulate the host cellular defenses. In this study, culture filtrate proteins from Mycobacterium tuberculosis H37Rv, isoniazid resistant, rifampicin-resistant and multidrug-resistant strains were gathered and profiled by shotgun-proteomics technique. Mass spectrometric analysis of the secreted proteome identified several proteins, of which 837, 892, 838 and 850 were found in M. tuberculosis H37Rv, isoniazid-resistant, rifampicin-resistant and multidrug-resistant strains, respectively. These proteins have been implicated in various cellular processes, including biological adhesion, biological regulation, developmental process, immune system process localization, cellular process, cellular component organization or biogenesis, metabolic process, and response to stimulus. Analysis based on STITCH database predicted the interaction of DNA topoisomerase I, 3-oxoacyl-(acyl-carrier protein) reductase, ESAT-6-like protein, putative prophage phiRv2 integrase, and 3 phosphoshikimate 1-carboxyvinyltransferase with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin, suggesting putative roles in controlling the anti-tuberculosis ability. However, several proteins with no interaction with all first-line anti-tuberculosis drugs might be used as markers for mycobacterial identification. PMID- 29119207 TI - Anesthesia in a child with suspected peroxisomal disorder. AB - We present the case of an 8-year-old female child with suspected peroxisomal disorder requiring general anesthesia for adenotomy, paracentesis and brainstem evoked response audiometry. Peroxisomes are small intracellular organelles that catalyse key metabolic reactions. Peroxisomal disorders are a heterogeneous group of rare genetic diseases. Anesthesia can be challenging as adrenal insufficiency, mental retardation, muscle weakness, risk of pulmonary aspiration, airway complications, seizure disorders and altered pharmacokinetics and pharmacodynamics can occur in these patients but guidelines for anesthesia do not exist due to the heterogeneity and rarity of these diseases and case reports are rare. Anesthesia was induced by sevoflurane via a face mask, followed by remifentanil and rocuronium for oral intubation after intravenous access was obtained. Anesthesia was maintained with sevoflurane and remifentanil. Dexamethasone was given for prophylaxis of postoperative nausea and vomiting as well as perioperative adrenal crises. Piritramide was given for postoperative analgesia. With this approach anesthesia was uneventful. The trachea was extubated with the patient awake and she was taken to the recovery room in a stable condition. The classification and breadth of clinical manifestations of peroxisomal disorders is complex and briefly summarized. Anesthesiologists should consider characteristics of their particular patient's form of peroxisomal disorder, as this may greatly influence procedural planning. PMID- 29119208 TI - Failures in adaptive locomotion: trial-and-error exploration to determine adequate foot elevation over obstacles. AB - Lifting the limb sufficiently to clear an obstacle seems like a straightforward task, yet trips are a common cause of falls across all ages. Examination of obstacle contacts in the lab revealed a progressive decrease in foot elevation with repeated exposures, ultimately resulting in failure (Heijnen et al. Exp Brain Res 23:219-231, 2012). The purpose of this study was to determine if the progressive decrease in foot elevation continued when knowledge of obstacle contact was removed. Twenty-one young adults (mean 20.0 +/- 1.0 years; 8 males) crossed a 20 cm obstacle in a 12 m walkway for 150 trials. The obstacle was covertly lowered between the lead and trail limb crossing of the obstacle, which eliminated obstacle contact with the trail limb if the limb was too low. The average failure rate was 8%, substantially higher than the 1-2% observed for stationary, visible obstacles. Therefore, tactile information from obstacle contact was instrumental for guiding the trail limb; visual information and joint angle information were insufficient for most participants. Foot elevation change over successive trials varied across participants, and was categorized as (1) asymptotic decrease (N = 11, 52%), with foot elevation converging to obstacle height, (2) linear decrease (N = 7, 33%), and (3) stable (N = 3, 14%). The asymptotic and stable groups appeared to have reasonable knowledge of obstacle height; the linear group did not. The asymptotic behavior is consistent with participants exploring the region above the obstacle through trial-and-error to determine appropriate foot elevation. PMID- 29119209 TI - Relationship between spasticity and spinal neural circuits in patients with chronic hemiparetic stroke. AB - Spasticity is a common problem in patients with stroke that contributes to motor dysfunction. However, the pathophysiological mechanisms underlying spasticity are not fully understood. The purpose of the present study was to explain the relationship between features of spinal neural circuits assessed using electrophysiological techniques and the clinical manifestations of stroke. The participants were 71 patients with chronic hemiparetic stroke. To assess spinal neural circuits, Hmax/Mmax of the forearm flexor muscles and reciprocal inhibition (RI) between forearm extensor and flexor muscles with the H reflex conditioning-test paradigm were measured. The relationships between electrophysiological parameters and clinical variables (age, time from stroke onset, upper extremity functional scores, and spasticity) were then analyzed. It was found that the third phase of RI (RI-3) correlated with the modified Ashworth scores of the wrist and finger flexors. No other correlations were found between electrophysiological and clinical measures. These results suggest that RI-3 is associated with spasticity and may be helpful to understand the basis of post stroke spasticity. PMID- 29119211 TI - Mitteilungen der DGKFO. PMID- 29119210 TI - [What could the pancreas have to do with shoulder pain?] PMID- 29119213 TI - ? PMID- 29119212 TI - ? PMID- 29119214 TI - Safety and Efficacy of Radiofrequency Catheter Ablation for Tachyarrhythmia in Children Weighing Less Than 10 kg. AB - An increasing number of children are undergoing radiofrequency catheter ablation (RFCA) for tachyarrhythmia. However, infants and toddlers undergoing RFCA are often resistant to medication or need to eliminate arrhythmia substrate, and the risks of RFCA complications are still high in infants and toddlers. From April 2008 and December 2016, 285 children who underwent radiofrequency catheter ablation (RFCA) were stratified according to body weight (group A, less than 10 kg, n = 22; group B, over 10 kg, n = 263) and the clinical features of RFCA were retrospectively reviewed in these groups. Indications for RFCA included drug refractory tachyarrhythmia or symptomatic tachycardia and tachycardia-induced cardiomyopathy. The acute success rate in this group was 90.9%, with a relatively low recurrence rate (15.0%) after 7.0 +/- 1.6 years follow-up. We performed RFCA using only 2-4 catheters in all cases. Major complications included complete right bundle branch block in one patient. No significant differences in rates of success, recurrence, or complications were noted between children weighing less and more than 10 kg. RFCA is safe and efficacious for tachyarrhythmia even in patients weighing less than 10 kg. PMID- 29119216 TI - Concentrations of Selected Elements in Liver Tissue of Grey Wolves (Canis lupus) from Serbia. AB - The grey wolf (Canis lupus) is a large carnivore species and a top predator in the ecosystems that it inhabits. Considering its role in food webs, wolves may be exposed to high concentrations of potentially harmful elements. Therefore liver samples from 28 legally hunted wolves were analyzed for concentrations of 16 elements using inductively coupled plasma optical emission spectrometry. The Mann Whitney U test showed a significant difference between the genders only for Li, and there were no differences between individuals caught in different years. The majority of statistically significant correlations between element levels were positive, except for three cases. Compliance with several criteria for suitable bioindicator organisms imply that wolves may serve for monitoring environmental contamination. PMID- 29119215 TI - Surgical Ligation Versus Percutaneous Closure of Patent Ductus Arteriosus in Very Low-Weight Preterm Infants: Which are the Real Benefits of the Percutaneous Approach? AB - Percutaneous treatment of patent ductus arteriosus (PDA) in extreme premature infants is technically difficult, and therefore, often not consider as an alternative to surgery. The main objective of our work was to compare respiratory status prior and post ductal closure and morbi-mortality, in our series of preterm infants with percutaneous PDA closure versus surgical ligation in the same time-period. Retrospective review of all premature infants submitted to percutaneous and surgical PDA closure from January 2011 to December 2016. All the antenatal, perinatal, and postnatal characteristics were collected. The main outcome was the assessment of the pulmonary status before and after ductal closure using a pulmonary score. Secondary outcomes included moderate-severe disability in neurodevelopment, death before discharge, moderate-severe chronic lung disease, and morbidity at discharge. 25 patients with a mean weight of 1330 g (+/- 280) underwent percutaneous closure of PDA with ADO-II-AS, and a total of 53 underwent surgical ligation. 28/53 with similar gestational age, birth weight, and procedure weight to those in the percutaneous group, were selected to perform the comparative study. Ductal closure (percutaneous and surgical) resulted in improved respiratory status. However, percutaneous group achieved a fastest respiratory improvement, than surgical group. The surgical closure group associated higher morbidity among survivors (HIV, number of sepsis, need, and duration of inotropics post-interventionism). The incidence of recurrent laryngeal nerve palsy among the surgical group was 17%. Percutaneous closure of PDA in carefully selected low-weight preterm infants is a safe and reliable alternative to surgical ligation. PMID- 29119217 TI - Psilocybin with psychological support for treatment-resistant depression: six month follow-up. AB - RATIONALE: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. OBJECTIVES: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. METHODS: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. RESULTS: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. CONCLUSIONS: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials. PMID- 29119219 TI - Cardiopulmonary resuscitation and intrathoracic renal ectopy. PMID- 29119218 TI - Odor cueing during slow-wave sleep benefits memory independently of low cholinergic tone. AB - RATIONALE: Sleep-dependent memory consolidation depends on the concerted reactivation of memories in the hippocampo-neocortical system. The communication of reactivated information from the hippocampus to the neocortex is assumed to be enabled by low levels of acetylcholine, particularly during slow-wave sleep (SWS). Recent studies suggest that the reactivation of memories does not only occur spontaneously but can also be externally triggered by re-presenting learning-associated cues during sleep. OBJECTIVES: Here we investigated whether the beneficial effect of cued memory reactivation during sleep depends on similar mechanisms as spontaneous reactivation, and specifically on low cholinergic tone. METHODS: In two experimental nights, healthy volunteers learned a visuo-spatial memory task in the presence of an odor before going to sleep for 40 min. In one night, subjects were presented with the odor again during SWS, whereas in the other night they received an odorless vehicle. In half of the subjects, the availability of acetylcholine during sleep was increased by administering the acetylcholine-esterase inhibitor physostigmine. RESULTS: Contrary to our hypothesis, increased cholinergic tone during sleep did not abolish the beneficial effect of odor cueing: memory performance was better after odor cueing compared to odorless vehicle, independent of physostigmine or placebo administration. CONCLUSIONS: This finding challenges the assumption that odor cued and spontaneous memory reactivation rely on the same neuropharmacological mechanisms. PMID- 29119220 TI - Biomarker-guided antifungal therapy in patients with suspected invasive candidiasis: Ready for prime time? PMID- 29119221 TI - Preparing Japanese surgeons for potential mass casualty situations will require innovative and systematic programs. AB - INTRODUCTION: The ongoing state of global geo-political instability means that it is prudent to prepare civilian surgeons to manage major military-type trauma. Japan has enjoyed a prolonged period of peace and consequently it is unlikely that surgeons will have been exposed to a sufficient volume of cases. This study reviews the state of trauma training and preparedness in Japan and reviews the trauma workload of a major Japanese emergency medical center and compared with a major South African trauma center with the intention of quantifying and comparing the time needed to gain adequate exposure to major trauma at the two centers. MATERIALS AND METHODS: The literature describing the surgical burden from a number of recent military missions was reviewed and the core surgical skills to manage military-type injuries were identified. We then went on to review all patients admitted to both Kurashiki Central Hospital (KCH) and Pietermaritzburg Metropolitan Trauma Service (PMTS) following trauma between the period September 2015 and August 2016. The burden of trauma at each center was quantified and the number of core surgical competencies or procedures performed at each center was then reviewed. These were then compared with the number of the core procedures which were performed on the reported military missions. RESULTS: Three reports on military surgical missions were reviewed. These came from the Dutch, French and British military surgical services. The average number of each core procedures performed on each reported military surgery mission are tabulated in the text. The most common procedures were wound debridement and orthopedic fixation, followed by trauma laparotomy, neck exploration and thoracotomy. During the 12 month study period, 309 trauma patients were admitted to KCH. Of which 206 (67%) were male, and the mean age was 57 years. There were 10 penetrating injuries and 299 blunt injuries. Of the penetrating injuries there were no gunshot wounds. The mechanisms of injury for blunt trauma were as follows: Road traffic accidents (RTAs); 141 (47%), fall; 136 (46%) and other injuries; 22 (7%). In the same period, 2887 trauma patients were admitted by the PMTS. There were 1244 cases (43%) of penetrating trauma and 1644 cases (57%) of blunt trauma in PMTS. The mechanisms of injury for penetrating trauma were as follows: stab wounds (SWs); 955 (77%), gunshot wounds (GSWs); 252 (20%), and other injuries; 37 (3%) and for blunt trauma were as follows: assault; 739 (45%), RTAs; 669 (41%), fall; 166 (10%), and other injuries; 70 (4%). The exposure to all the key competencies required to manage trauma is overwhelmingly greater in South Africa than in Japan. The length of time needed to obtain an equivalent trauma exposure to that achieved in South Africa, working in Japan is prohibitively long. CONCLUSION: Trauma training in Japan is hamstrung by a lack of clinical material as well as by systematic factors. Training a trauma surgeon is difficult. Developing a trauma system in the country may help address some of these deficits. South Africa in contrast has a huge burden of trauma and sufficient infrastructure to ensure that surgeons working there have adequate exposure to major trauma. Developing an academic exchange program between Japan and South Africa may allow for the transfer of trauma experience and skills between the two countries. PMID- 29119222 TI - The influence of an injury prevention program on young road users: a German experience. AB - PURPOSE: Trauma remains a leading cause of mortality and morbidity in youth. The Prevent Alcohol and Risk Related Trauma in Youth (P.A.R.T.Y.) program is an injury prevention program. The aim of the study was to analyze the influence on risk-taking behaviors and risk awareness on young road users by a pre-post questionnaire. METHODS: A pre-post intervention study was performed using a standardized questionnaire. The questionnaire contained three sections with different items (in total 22) to identify differences regarding students' risk behavior and risk awareness. Data were analyzed using the Wilcoxon signed-rank test with significance defined as p < 0.05. RESULTS: The study sample contains 193 students (age 14-17, 44% male). We found significant differences for asking if a student "fastens his/her helmet's chinstrap when driving a motorbike" (p = 0.001) and for the question "Do you wear a helmet when you go rollerblading" (p = 0.008). After attending the program, participants would decrease the use of a mobile phone while driving (p = 0.038) and the understanding of the risk "speeding" and "cycling without a helmet" significantly increased. CONCLUSIONS: The P.A.R.T.Y. program focuses on items like "use of helmet and mobile phones" and "alcohol/drug abuse". Evaluating the program helps to uncover vulnerabilities and to enhance important effects. Some of these items are addressed by the program, whereas some are not. It will be important to improve the program according to address topics that have not shown significant improvements, so that students learn more about the dangers and the right behavior in road traffic. PMID- 29119223 TI - [Acute myocardial infarction in patients with ST-segment elevation myocardial infarction : ESC guidelines 2017]. AB - This article gives an update on the management of acute ST-segment elevation myocardial infarction (STEMI) according to the recently released European Society of Cardiology guidelines 2017 and the modifications are compared to the previous STEMI guidelines from 2012. Primary percutaneous coronary intervention (PCI) remains the preferred reperfusion strategy. New guideline recommendations relate to the access site with a clear preference for the radial artery, use of drug eluting stents over bare metal stents, complete revascularization during the index hospitalization, and avoidance of routine thrombus aspiration. For periprocedural anticoagulation during PCI, bivalirudin has been downgraded. Oxygen treatment should be administered only if oxygen saturation is <90%. In cardiogenic shock, intra-aortic balloon pumps should no longer be used. New recommendations are in place with respect to the duration of dual antiplatelet therapy for patients without bleeding events during the first 12 months. Newly introduced sections cover myocardial infarction with no relevant stenosis of the coronary arteries (MINOCA), the introduction of new indicators for quality of care for myocardial infarction networks and new definitions for the time to reperfusion. PMID- 29119224 TI - Impact of repeated extracorporeal shock wave lithotripsy on prepubertal rat kidney. AB - This study aimed to investigate the effects of repeated extracorporeal shock wave lithotripsy (ESWL) on the kidneys of prepubertal and adult rats. Thirty rats were used: 15 were prepubertal (3 weeks of age) with an average body weight of 72.3 +/ 3.3 g, and 15 were adults with of 265 +/- 11.3 g. The prepubertal and adult rats were separately and randomly allocated to three groups, each consisting of five rats. Following anesthetization, the left kidney of each rat in each group received shock waves in one, two, or three sessions separated by 72 h. The rats in each group were killed 72 h after the last ESWL session, and both kidneys were harvested; the right kidney was used as the control. Renal injury was examined with histological analysis, immunohistochemistry, and Western blot to detecting the expression of heat-shock protein-70, tumor necrosis factor-alpha-alpha, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 as markers of renal damage. All of these markers were similarly increased with increased ESWL sessions in both age groups. Histological analysis revealed more serious fibrosis and inflammation in the ESWL-treated kidneys in both groups than in the controls, with the damage increasing with increasing numbers of sessions. ESWL on the kidney increased renal damage according to the number of sessions in both age groups of rats, and the effects of ESWL on renal injury were similar in the two groups. However, there were generally no significant differences in the effects of ESWL on molecular indicators of renal injury between prepubertal and adult rats. PMID- 29119226 TI - [Current developments in minimally invasive glaucoma surgery]. PMID- 29119225 TI - Piperlongumine inhibits the proliferation, migration and invasion of fibroblast like synoviocytes from patients with rheumatoid arthritis. AB - OBJECTIVES: Recent studies have indicated that piperlongumine (PLM) may exert anti-inflammatory effects. In the present study, we determined the effect of PLM on the proliferation, apoptosis, migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) (referred to herein as RA FLS). We further explored the mechanisms by which the studied compound inhibits the functions of RA FLS. METHODS: RA FLS viability and apoptosis were tested using MTT and Annexin V/PI assays, respectively. We performed an EDU assay to examine the proliferation of RA FLS. The migration and invasion of these cells were measured using a transwell chamber method and wound closure assay. The MMP-1, MMP-3, and MMP-13 levels in the culture supernatants of RA FLS were detected using a Luminex Assay kit. The intracellular ROS levels were detected using DCFH-DA. The expression levels of signal transduction proteins were measured using western blot. RESULTS: We found that PLM induced apoptosis in RA FLS at concentrations of 15 and 20 MUM. The proliferation of RA FLS was downregulated by PLM at concentrations of 1, 5 and 10 MUM. Migration and invasion of RA FLS were reduced by PLM at concentrations of 1, 5 and 10 MUM. PLM also inhibited cytoskeletal reorganization in migrating RA FLS and decreased TNF-alpha induced intracellular ROS production. Moreover, we demonstrated the inhibitory effect of PLM on activation of the p38, JNK, NF-kappaB and STAT3 pathways. CONCLUSIONS: Our findings suggest that PLM can inhibit proliferation, migration and invasion of RA FLS. Moreover, these data suggests that PLM might have therapeutic potential for the treatment of RA. PMID- 29119227 TI - [Hyaluronic acid gels for pressure regulation in glaucoma treatment]. AB - BACKGROUND: The increasing numbers of glaucoma patients and complications occuring during treatment, such as restenosis and hypotony, require new treatment options to prevent blindness in patients. Therefore, the abovementioned problems should be solved to prolong the lifetime of implants and to prevent repeated surgery. OBJECTIVE: Can a novel stent with hyaluronic acid hydrogels (HA gel) as a functional unit be used to regulate pressure in glaucoma therapy in the long term? MATERIAL AND METHODS: Model stents were filled with HA gels and it was investigated if these could regulate the pressure and what the underlying mechanism is. RESULTS: The results of the investigations showed that the HA gel inside the stent functions as a pressure valve. Under certain equilibrium pressures the HA gel closes the stent and therefore retains the fluid. At a certain overpressure the HA gel enables the fluid to be released and leads to a self-regulated adjustment of the equilibrium pressure. DISCUSSION: The next step will involve miniaturization of the stents. Experiments will then show if the valve function will also work in the dimensions necessary for an eye implant and if the current problem of hypotension in glaucoma therapy can be solved. PMID- 29119228 TI - Macropinocytosis, mTORC1 and cellular growth control. AB - The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth factor receptor signaling and the overall metabolic status of the cell are coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1 (mTORC1), which positively regulates protein synthesis and negatively regulates molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly binds to and activates mTORC1. Rag is activated by both lysosomal luminal and cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt, and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb converge at the lysosomal membrane, and several lines of evidence support the idea that growth factor-dependent endocytosis facilitates amino acid transfer into the lysosome leading to the activation of Rag. This review summarizes evidence that growth factor-stimulated macropinocytosis is essential for amino acid-dependent activation of mTORC1, and that increased solute accumulation by macropinocytosis in transformed cells supports unchecked cell growth. PMID- 29119230 TI - Re-evaluation of protein kinase CK2 pleiotropy: new insights provided by a phosphoproteomics analysis of CK2 knockout cells. AB - CK2 denotes a ubiquitous and pleiotropic protein kinase whose holoenzyme is composed of two catalytic (alpha and/or alpha') and two regulatory beta subunits. The CK2 consensus sequence, S/T-x-x-D/E/pS/pT is present in numerous phosphosites, but it is not clear how many of these are really generated by CK2. To gain information about this issue, advantage has been taken of C2C12 cells entirely deprived of both CK2 catalytic subunits by the CRISPR/Cas9 methodology. A comparative SILAC phosphoproteomics analysis reveals that, although about 30% of the quantified phosphosites do conform to the CK2 consensus, only one-third of these are substantially reduced in the CK2alpha/alpha'(-/-) cells, consistent with their generation by CK2. A parallel study with C2C12 cells deprived of the regulatory beta subunit discloses a role of this subunit in determining CK2 targeting. We also find that phosphosites notoriously generated by CK2 are not fully abrogated in CK2alpha/alpha'(-/-) cells, while some phosphosites unrelated to CK2 are significantly altered. Collectively taken our data allow to conclude that the phosphoproteome generated by CK2 is not as ample and rigidly pre determined as it was believed before. They also show that the lack of CK2 promotes phosphoproteomics perturbations attributable to kinases other than CK2. PMID- 29119231 TI - A valid method to determine the site of drowning. AB - The diatom test is considered a useful aid in determining the site of death from drowning. Nevertheless, there is disagreement within the scientific community concerning its reliability, and its findings have been challenged and sometimes overturned in courts of law. Using a model based on animal experimentation, we have developed a diatom test to discriminate between the locations of drowning sites from different aquatic systems. We carried out a complementary combination of quantitative and qualitative analyses together with a statistical analysis based on the Kullback-Leibler distance of the samples. A restrictive selection of exclusive diatom species from each reservoir was also made. This approach allowed us to validate the usefulness of the diatom test in determining the location of the site of drowning. PMID- 29119229 TI - The emerging role of galectins in high-fatality cancers. AB - Although we witnessed considerable progress in the prevention and treatment of cancer during the past few decades, a number of cancers remain difficult to treat. The main reasons for this are a lack of effective biomarkers necessary for an early detection and inefficient treatments for cancer that are diagnosed at late stages of the disease. Because of their alarmin-like properties and their protumorigenic role during cancer progression, members of the galectin family are uniquely positioned to provide information that could be used for the exploration of possible avenues for the treatment of high fatality cancer (HFC). A rapid overview of studies that examined the expressions and functions of galectins in cancer cells reveals that they play a central role in at least three major features that characterize HFCs: (1) induction of systemic and local immunosuppression, (2) chemoresistance of cancer cells, and (3) increased invasive behavior. Defining the galectinome in HFCs will also lead to a better understanding of tumor heterogeneity while providing critical information that could improve the accuracy of biomarker panels for a more personalized treatment of HFCs. In this review, we discuss the relevance of the galectinome in HFC and its possible contribution to providing potential solutions. PMID- 29119232 TI - Histopathological markers of treatment response and recurrence risk in ovarian cancers and borderline tumors. AB - Histopathology plays an important role in defining response to treatment for different tumor types. Histopathologic response criteria are currently used as reference standard in various types of cancer, including breast cancer, gastroesophageal cancer, and bone tumors. Since there were no generally accepted response criteria established for ovarian cancer, a systematic analysis of various features of tumor regression was performed. Patient survival served as the reference standard to validate the histopathologic features of tumor regression. In contrast to ovarian cancer, borderline ovarian tumors are epithelial ovarian neoplasms characterized by up-regulated cellular proliferation and cytologic atypia but without destructive stromal invasion. While borderline ovarian tumors generally have an excellent prognosis with a 5-year survival of > 95%, recurrences and malignant transformation occur in a small percentage of patients. Nevertheless, the identification of patients at increased risk for recurrence remains difficult. The aim of studying histopathological markers in ovarian cancers and borderline tumors was to evaluate whether histopathologic features including molecular pathologic alterations can predict patient outcome, particularly the risk of recurrence of serous and mucinous borderline tumors. PMID- 29119233 TI - Potential Outer Membrane Protein Candidates for Vaccine Development Against the Pathogen Vibrio anguillarum: A Reverse Vaccinology Based Identification. AB - Reverse vaccinology is a widely used approach that has facilitated the rapid identification of vaccine candidates suitable in vaccine development for pathogens. Vibrio anguillarum is a major pathogen responsible for vibriosis in fish and shellfish leading to huge economic losses to the aquaculture industry. Although commercial vaccines are available for fish against this bacterium they have their own limitations. In this study, we used the reverse vaccinology strategy to screen and identify V. anguillarum outer membrane proteins (OMPs) that could serve as vaccine candidates. Our analysis identified 23 antigenic outer membrane proteins which were highly conserved (>98% identity) across serovars of this bacterium. Of the 23, two were identified as outer membrane lipoproteins. Among the OMPs identified 18 were novel to this study and conserved across several Vibrio spp. with an identity of 21-93%. While the least (>48%) identity was observed for V. anguillarum ferrichrome-iron transporter protein, the highest identity (>80%) was seen for outer membrane proteins OmpK, BamA, OmpU, Fatty acid transporter, and two hypothetical proteins. These potential vaccine targets identified could contribute to the development of effective vaccine not only against V. anguillarum but also across other Vibrio spp. In addition, several B-cell and T-cell epitopes were predicted for the novel OMPs in this study which could aid in narrowing down peptide selection in designing a suitable epitope-based vaccine. PMID- 29119234 TI - Streptomyces lasii sp. nov., a Novel Actinomycete with Antifungal Activity Isolated from the Head of an Ant (Lasius flavus). AB - During a screening for novel and biotechnologically useful actinobacteria in insects, a novel actinobacteria with antifungal activity, designated strain 5H CA11T, was isolated from the head of an ant (Lasius flavus) and characterized using a polyphasic approach. The organism was found to have morphological and chemotaxonomic characteristics typical of members of the genus Streptomyces. 16S rRNA gene sequence analysis showed that strain 5H-CA11T is a member of the genus Streptomyces, with the highest sequence similarity to Streptomyces scabrisporus DSM 41855T (98.9%). Similarities to other type strains of the genus Streptomyces were lower than 96%. Phylogenetic analysis based on the 16S rRNA gene sequence also indicated that strain 5H-CA11T clusters with S. scabrisporus DSM 41855T using two tree-making algorithms. DNA-DNA hybridization between strain 5H-CA11T and S. scabrisporus JCM 11712T revealed 33.6% similarity, supporting the phenotypic and phylogenetic differences found between these two strains. Therefore, the strain is concluded to represent a novel species of the genus Streptomyces, for which the name Streptomyces lasii sp. nov. is proposed. The type strain is 5H-CA11T (=CGMCC 4.7303T = DSM 102043T). PMID- 29119236 TI - Imaging the multiple facets of immuno-oncology. PMID- 29119235 TI - Effect of probiotics and synbiotics consumption on serum concentrations of liver function test enzymes: a systematic review and meta-analysis. AB - PURPOSE: The gut-liver interaction suggests that modification of gut bacterial flora using probiotics and synbiotics may improve liver function. This systematic review and meta-analysis aimed to clarify the effect of probiotics and synbiotics consumption on the serum concentration of liver function enzymes. METHODS: PubMed (MEDLINE), Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library (Central) were searched from 1980 to August 2017 for studies where adults consumed probiotics and/or synbiotics in controlled trials and changes in liver function enzymes were examined. RESULTS: A total of 17 studies (19 trials) were included in the meta-analysis. Random effects meta-analyses were applied. Probiotics and synbiotics significantly reduced serum alanine aminotransferase [- 8.05 IU/L, 95% confidence interval (CI) - 13.07 to - 3.04; p = 0.002]; aspartate aminotransferase (- 7.79 IU/L, 95% CI: - 13.93 to - 1.65; p = 0.02) and gamma glutamyl transpeptidase (- 8.40 IU/L, 95% CI - 12.61 to - 4.20; p < 0.001). Changes in the serum concentration of alkaline phosphatase and albumin did not reach a statistically significant level. Changes to bilirubin levels were in favour of the control group (0.95 MUmol/L, 95% CI 0.48-1.42; p < 0.001). Subgroup analysis suggested the existence of liver disease at baseline, synbiotics supplementation and duration of supplementation >= 8 weeks resulted in more pronounced improvement in liver function enzymes than their counterparts. CONCLUSIONS: Probiotics and synbiotics may be suggested as supplements to improve serum concentration of liver enzymes, especially when synbiotics administered for a period >= 8 weeks and in individuals with liver disease. PMID- 29119237 TI - Impact of improved attenuation correction featuring a bone atlas and truncation correction on PET quantification in whole-body PET/MR. AB - PURPOSE: Recent studies have shown an excellent correlation between PET/MR and PET/CT hybrid imaging in detecting lesions. However, a systematic underestimation of PET quantification in PET/MR has been observed. This is attributable to two methodological challenges of MR-based attenuation correction (AC): (1) lack of bone information, and (2) truncation of the MR-based AC maps (MUmaps) along the patient arms. The aim of this study was to evaluate the impact of improved AC featuring a bone atlas and truncation correction on PET quantification in whole body PET/MR. METHODS: The MR-based Dixon method provides four-compartment MUmaps (background air, lungs, fat, soft tissue) which served as a reference for PET/MR AC in this study. A model-based bone atlas provided bone tissue as a fifth compartment, while the HUGE method provided truncation correction. The study population comprised 51 patients with oncological diseases, all of whom underwent a whole-body PET/MR examination. Each whole-body PET dataset was reconstructed four times using standard four-compartment MUmaps, five-compartment MUmaps, four compartment MUmaps + HUGE, and five-compartment MUmaps + HUGE. The SUVmax for each lesion was measured to assess the impact of each MUmap on PET quantification. RESULTS: All four MUmaps in each patient provided robust results for reconstruction of the AC PET data. Overall, SUVmax was quantified in 99 tumours and lesions. Compared to the reference four-compartment MUmap, the mean SUVmax of all 99 lesions increased by 1.4 +/- 2.5% when bone was added, by 2.1 +/ 3.5% when HUGE was added, and by 4.4 +/- 5.7% when bone + HUGE was added. Larger quantification bias of up to 35% was found for single lesions when bone and truncation correction were added to the MUmaps, depending on their individual location in the body. CONCLUSION: The novel AC method, featuring a bone model and truncation correction, improved PET quantification in whole-body PET/MR imaging. Short reconstruction times, straightforward reconstruction workflow, and robust AC quality justify further routine clinical application of this method. PMID- 29119238 TI - Correction to: Relative abundance of beta-thalassemia-related mutations in southern China correlates with geographical coordinates. AB - Figure 1c. is with numeric error. The error can not result in any change of discussion and conclusion. The proper figures corresponding to Fig 1c are in supplement file, see figure 5 and 6. PMID- 29119239 TI - Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in Chinese patients: randomized, sham-controlled, multicenter study. AB - PURPOSE: The purpose of this study was to evaluate the safety and efficacy of dexamethasone intravitreal implant 0.7 mg (DEX) for treatment of macular edema associated with retinal vein occlusion (RVO). METHODS: This study was a six month, randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial with a 2-month open-label study extension. Patients with branch or central RVO received DEX (n = 129) or sham procedure (n = 130) in the study eye at baseline; all patients who met re-treatment criteria received DEX at month 6. Efficacy measures included Early Treatment Diabetic Retinopathy Study (ETDRS), best-corrected visual acuity (BCVA), and central retinal thickness (CRT) on optical coherence tomography. RESULTS: Time to >=15-letter BCVA improvement from baseline during the first 6 months (primary endpoint) was earlier with DEX than sham (p < 0.001). At month 2 (peak effect), the percentage of patients with >=15 letter BCVA improvement from baseline was DEX: 35%, sham: 12%; mean BCVA change from baseline was DEX: +10.6 letters, sham: +1.7 letters; and mean CRT change from baseline was DEX: -407 MUm, sham: -62 MUm (all p < 0.001). Outcomes were better with DEX than sham in both branch and central RVO. The most common treatment-emergent adverse event was increased intraocular pressure (IOP). Increases in IOP generally were controlled with topical medication. Mean IOP normalized by month 4, and no patient required incisional glaucoma surgery. CONCLUSIONS: DEX had a favorable safety profile and provided clinically significant benefit in a Chinese patient population with RVO. Visual and anatomic outcomes were improved with DEX relative to sham for 3-4 months after a single implant. PMID- 29119240 TI - IVC filter placements in children: nationwide comparison of practice patterns at adult and children's hospitals using the Kids' Inpatient Database. AB - BACKGROUND: Inferior vena cava (IVC) filter placement in children has been described in literature, but there is variability with regard to their indications. No nationally representative study has been done to compare practice patterns of filter placements at adult and children's hospitals. OBJECTIVE: To perform a nationally representative comparison of IVC filter placement practices in children at adult and children's hospitals. MATERIALS AND METHODS: The 2012 Kids' Inpatient Database was searched for IVC filter placements in children <18 years of age. Using the International Classification of Diseases, 9th Revision (ICD-9) code for filter insertion (38.7), IVC filter placements were identified. A small number of children with congenital cardiovascular anomalies codes were excluded to improve specificity of the code used to identify filter placement. Filter placements were further classified by patient demographics, hospital type (children's and adult), United States geographic region, urban/rural location, and teaching status. Statistical significance of differences between children's or adult hospitals was determined using the Wilcoxon rank sum test. RESULTS: A total of 618 IVC filter placements were identified in children <18 years (367 males, 251 females, age range: 5-18 years) during 2012. The majority of placements occurred in adult hospitals (573/618, 92.7%). Significantly more filters were placed in the setting of venous thromboembolism in children's hospitals (40/44, 90%) compared to adult hospitals (246/573, 43%) (P<0.001). Prophylactic filters comprised 327/573 (57%) at adult hospitals, with trauma being the most common indication (301/327, 92%). The mean length of stay for patients receiving filters was 24.5 days in children's hospitals and 18.4 days in adult hospitals. CONCLUSION: The majority of IVC filters in children are placed in adult hospital settings. Children's hospitals are more likely to place therapeutic filters for venous thromboembolism, compared to adult hospitals where the prophylactic setting of trauma predominates. PMID- 29119241 TI - [Scientific misconduct-more frequent than previously thought]. PMID- 29119243 TI - Retraction Note to: L-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity. AB - In light of forensic evidence indicating duplication and/or manipulation of western blot images the Editor-in-Chief is retracting the article cited above. PMID- 29119242 TI - Dietary antioxidant capacity and risk of type 2 diabetes in the large prospective E3N-EPIC cohort. AB - AIMS/HYPOTHESIS: Recent evidence suggests that oxidative stress may contribute to the pathogenesis of type 2 diabetes. The diet, and especially fruit and vegetables, contains a variety of compounds with antioxidant activity, which may have cumulative/synergistic antioxidant effects. The total antioxidant capacity, an index derived from dietary intake, is a single estimate of antioxidant capacity from all dietary antioxidants. The main aim of this study was to investigate the relationship between total antioxidant capacity and risk of type 2 diabetes. METHODS: Among 64,223 women (mean age 52 +/- 7 years) from the French E3N-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 1751 women had validated type 2 diabetes during 15 years of follow-up. The total antioxidant capacity was estimated with the ferric ion-reducing antioxidant power (FRAP) method. Adjusted Cox proportional hazards regression models were used to calculate HRs and 95% CIs for the associations between total antioxidant capacity and type 2 diabetes risk, adjusted for potential confounders. RESULTS: In multivariable models, higher levels of total antioxidant capacity were associated with a lower risk of type 2 diabetes. Compared with women in the lowest quintile, women in the third, fourth and fifth quintiles for total antioxidant capacity had HRs of 0.74 (95% CI 0.63, 0.86), 0.70 (95% CI 0.59, 0.83) and 0.73 (95% CI 0.60, 0.89), respectively. The inverse association between total antioxidant capacity and risk of type 2 diabetes was linear up to values of 15 mmol/day, after which the effect reached a plateau. CONCLUSIONS/INTERPRETATION: Our findings suggest that the total antioxidant capacity may play an important role in reducing the risk of type 2 diabetes in middle-aged women. More studies are warranted to better understand the biological mechanisms underlying this inverse association. PMID- 29119244 TI - Enterovirus-associated changes in blood transcriptomic profiles of children with genetic susceptibility to type 1 diabetes. AB - AIMS/HYPOTHESIS: Enterovirus infections have been associated with the development of type 1 diabetes in multiple studies, but little is known about enterovirus induced responses in children at risk for developing type 1 diabetes. Our aim was to use genome-wide transcriptomics data to characterise enterovirus-associated changes in whole-blood samples from children with genetic susceptibility to type 1 diabetes. METHODS: Longitudinal whole-blood samples (356 samples in total) collected from 28 pairs of children at increased risk for developing type 1 diabetes were screened for the presence of enterovirus RNA. Seven of these samples were detected as enterovirus-positive, each of them collected from a different child, and transcriptomics data from these children were analysed to understand the individual-level responses associated with enterovirus infections. Transcript clusters with peaking or dropping expression at the time of enterovirus positivity were selected as the enterovirus-associated signals. RESULTS: Strong signs of activation of an interferon response were detected in four children at enterovirus positivity, while transcriptomic changes in the other three children indicated activation of adaptive immune responses. Additionally, a large proportion of the enterovirus-associated changes were specific to individuals. An enterovirus-induced signature was built using 339 genes peaking at enterovirus positivity in four of the children, and 77 of these genes were also upregulated in human peripheral blood mononuclear cells infected in vitro with different enteroviruses. These genes separated the four enterovirus positive samples clearly from the remaining 352 blood samples analysed. CONCLUSIONS/INTERPRETATION: We have, for the first time, identified enterovirus associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes. DATA AVAILABILITY: The datasets analysed during the current study are included in this published article and its supplementary information files ( www.btk.fi/research/computational-biomedicine/1234-2 ) or are available from the Gene Expression Omnibus (GEO) repository (accession GSE30211). PMID- 29119245 TI - Development and characterisation of a novel glucagon like peptide-1 receptor antibody. AB - AIMS/HYPOTHESIS: Glucagon like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion by binding to GLP-1 receptors (GLP1Rs) on pancreatic beta cells. GLP-1 mimetics are used in the clinic for the treatment of type 2 diabetes, but despite their therapeutic success, several clinical effects of GLP 1 remain unexplained at a mechanistic level, particularly in extrapancreatic tissues. The aim of this study was to generate and characterise a monoclonal antagonistic antibody for the GLP1R for use in vivo. METHODS: A naive phage display selection strategy was used to isolate single-chain variable fragments (ScFvs) that bound to GLP1R. The ScFv with the highest affinity, Glp1R0017, was converted into a human IgG1 and characterised further. In vitro antagonistic activity was assessed in a number of assays: a cAMP-based homogenous time resolved fluorescence assay in GLP1R-overexpressing cell lines, a live cell cAMP imaging assay and an insulin secretion assay in INS-1 832/3 cells. Glp1R0017 was further tested in immunostaining of mouse pancreas, and the ability of Glp1R0017 to block GLP1R in vivo was assessed by both IPGTT and OGTT in C57/Bl6 mice. RESULTS: Antibodies to GLP1R were selected from naive antibody phage display libraries. The monoclonal antibody Glp1R0017 antagonised mouse, human, rat, cynomolgus monkey and dog GLP1R. This antagonistic activity was specific to GLP1R; no antagonistic activity was found in cells overexpressing the glucose dependent insulinotropic peptide receptor (GIPR), glucagon like peptide-2 receptor or glucagon receptor. GLP-1-stimulated cAMP and insulin secretion was attenuated in INS-1 832/3 cells by Glp1R0017 incubation. Immunostaining of mouse pancreas tissue with Glp1R0017 showed specific staining in the islets of Langerhans, which was absent in Glp1r knockout tissue. In vivo, Glp1R0017 reversed the glucose-lowering effect of liraglutide during IPGTTs, and reduced glucose tolerance by blocking endogenous GLP-1 action in OGTTs. CONCLUSIONS/INTERPRETATION: Glp1R0017 is a monoclonal antagonistic antibody to the GLP1R that binds to GLP1R on pancreatic beta cells and blocks the actions of GLP-1 in vivo. This antibody holds the potential to be used in investigating the physiological importance of GLP1R signalling in extrapancreatic tissues where cellular targets and signalling pathways activated by GLP-1 are poorly understood. PMID- 29119247 TI - Wall following in Xenopus laevis is barrier-driven. AB - The tendency of animals to follow boundaries within their environment can serve as a strategy for spatial learning or defensive behaviour. We examined whether Xenopus laevis tadpoles and froglets employ such a strategy by characterizing their swimming pattern in a square tank with shallow water. Trajectories obtained from video recordings were analysed for proximity to the nearest wall. With the exception of young larvae, the vast majority of animals (both tadpoles and froglets) spent a disproportionately large amount of time near the wall. The total distance covered was not a confounding factor, but animals were stronger wall followers in smaller tanks. Wall following was also not influenced by whether the surrounding walls of the tank were black or white, illuminated by infrared light, or by the presence or absence of tentacles. When given a choice in a convex tank to swim straight and leave the wall or turn to follow the wall, the animals consistently left the wall, indicating that wall following in X. laevis is barrier-driven. This implies that wall following behaviour in Xenopus derives from constraints imposed by the environment (or the experimenter) and is unlikely a strategy for spatial learning or safety seeking. PMID- 29119248 TI - [Chronic pain: interaction between somatic and psychological factors (F45.41)]. PMID- 29119249 TI - Physical activity levels of patients with type 2 diabetes in hospital and at home. PMID- 29119246 TI - Skeletal muscle and performance adaptations to high-intensity training in elite male soccer players: speed endurance runs versus small-sided game training. AB - PURPOSE: To examine the skeletal muscle and performance responses across two different exercise training modalities which are highly applied in soccer training. METHODS: Using an RCT design, 39 well-trained male soccer players were randomized into either a speed endurance training (SET; n = 21) or a small-sided game group (SSG; n = 18). Over 4 weeks, thrice weekly, SET performed 6-10 * 30-s all-out runs with 3-min recovery, while SSG completed 2 * 7-9-min small-sided games with 2-min recovery. Muscle biopsies were obtained from m. vastus lateralis pre and post intervention and were subsequently analysed for metabolic enzyme activity and muscle protein expression. Moreover, the Yo-Yo Intermittent Recovery level 2 test (Yo-Yo IR2) was performed. RESULTS: Muscle CS maximal activity increased (P < 0.05) by 18% in SET only, demonstrating larger (P < 0.05) improvement than SSG, while HAD activity increased (P < 0.05) by 24% in both groups. Na+-K+ ATPase alpha1 subunit protein expression increased (P < 0.05) in SET and SSG (19 and 37%, respectively), while MCT4 protein expression rose (P < 0.05) by 30 and 61% in SET and SSG, respectively. SOD2 protein expression increased (P < 0.05) by 28 and 37% in SET and SSG, respectively, while GLUT-4 protein expression increased (P < 0.05) by 40% in SSG only. Finally, SET displayed 39% greater improvement (P < 0.05) in Yo-Yo IR2 performance than SSG. CONCLUSION: Speed endurance training improved muscle oxidative capacity and exercise performance more pronouncedly than small-sided game training, but comparable responses were in muscle ion transporters and antioxidative capacity in well-trained male soccer players. PMID- 29119250 TI - Microscopy-based high-throughput assays enable multi-parametric analysis to assess adverse effects of nanomaterials in various cell lines. AB - Manufactured nanomaterials (MNMs) selected from a library of over 120 different MNMs with varied compositions, sizes, and surface coatings were tested by four different laboratories for toxicity by high-throughput/-content (HT/C) techniques. The selected particles comprise 14 MNMs composed of CeO2, Ag, TiO2, ZnO and SiO2 with different coatings and surface characteristics at varying concentrations. The MNMs were tested in different mammalian cell lines at concentrations between 0.5 and 250 ug/mL to link physical-chemical properties to multiple adverse effects. The cell lines are derived from relevant organs such as liver, lung, colon and the immune system. Endpoints such as viable cell count, cell membrane permeability, apoptotic cell death, mitochondrial membrane potential, lysosomal acidification and steatosis have been studied. Soluble MNMs, Ag and ZnO, were toxic in all cell types. TiO2 and SiO2 MNMs also triggered toxicity in some, but not all, cell types and the cell type-specific effects were influenced by the specific coating and surface modification. CeO2 MNMs were nearly ineffective in our test systems. Differentiated liver cells appear to be most sensitive to MNMs, Whereas most of the investigated MNMs showed no acute toxicity, it became clear that some show adverse effects dependent on the assay and cell line. Hence, it is advised that future nanosafety studies utilise a multi-parametric approach such as HT/C screening to avoid missing signs of toxicity. Furthermore, some of the cell type-specific effects should be followed up in more detail and might also provide an incentive to address potential adverse effects in vivo in the relevant organ. PMID- 29119251 TI - Postoperative complications and long-term functional outcome in children operated for idiopathic rectal prolapse. AB - PURPOSE: The aim of the present study was to evaluate the postoperative complications and the long-term gastrointestinal functional outcome after surgical treatment for rectal prolapse on a strategy with stapled anopexy for short (< 5 cm) prolapse and Delormes procedure for longer (> 5 cm) rectal prolapse. METHODS: A total of 38 patients were included with a postoperative follow-up period ranging from 1 month to 9.1 years. Thirty patients (83%) completed the Rome III questionnaire on gastrointestinal function, with the follow-up period ranging from 2 months to 7 years. RESULTS: Thirty-five patients were treated with stapled anopexy as a primary surgical treatment. One minor complication with slight postoperative bleeding was observed, but the recurrence rate was 34.3%. Treatment of recurrence with re-stapling gave success rate of 44.4%. Ten patients (3 primary and 7 with recurrence after stapled anopexy) were treated with Delormes procedure with no observed complications or recurrence. Four out of nineteen patients treated with stapled anopexy fulfilled the criteria for functional gastrointestinal symptoms and in 3 out of 8 treated with Delormes procedure. No patients reported continence problems. CONCLUSION: The recurrence rate for stapled anopexy was high and none with Delormes procedure. The functional outcome was comparable with a healthy population of children. PMID- 29119252 TI - Image-based surgical risk factors for Wilms tumor. AB - PURPOSE: The standard treatment for Wilms tumor (WT) is primary resection. However, in cases with unresectable tumor or tumor spillage, which are considered to have high surgical risks, more intensive chemotherapy and radiotherapy are required. In the present study, we retrospectively analyzed preoperative image parameters to identify factors associated with surgical risks. METHODS: Twenty nine patients with WT were enrolled in this study. Data on various preoperative image parameters, such as tumor size, tumor volume, displacement of great vessels, and contralateral extension of the tumor were collected, and their relationship with surgical factors, including operative time, hemorrhage, tumor spillage, and unresectability were analyzed. RESULTS: Patients with unresectable tumor or with tumor spillage (surgical high-risk group) more frequently demonstrated displacement of great vessels and contralateral tumor extension. Operative time and blood loss were also significantly related to tumor size, area, volume, displacement of great vessels and contralateral extension. CONCLUSION: Besides tumor size, displacement of great vessels and contralateral extension were significantly associated with surgical risks. These factors are easily determined using CT images and are, therefore, useful to decide whether preoperative chemotherapy should be started instead of primary tumor resection for large localized WTs. PMID- 29119254 TI - Potential Pharmacological Chaperones for Cystathionine Beta-Synthase-Deficient Homocystinuria. AB - Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acid metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine beta-synthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form nonfunctional aggregates or to undergo proteasome-dependent degradation. Correction of CBS misfolding would represent an alternative therapeutic approach for HCU. In this review, we summarize the complex nature of CBS, its multi-domain architecture, the interplay between the three cofactors required for CBS function [heme, pyridoxal-5'-phosphate (PLP), and S-adenosylmethionine (SAM)], as well as the intricate allosteric regulatory mechanism only recently understood, thanks to advances in CBS crystallography. While roughly half of the patients respond to treatment with a PLP precursor pyridoxine, many studies suggested usefulness of small chemicals, such as chemical and pharmacological chaperones or proteasome inhibitors, rescuing mutant CBS activity in cellular and animal models of HCU. Non-specific chemical chaperones and proteasome inhibitors assist in mutant CBS folding process and/or prevent its rapid degradation, thus resulting in increased steady-state levels of the enzyme and CBS activity. Recent interest in the field and available structural information will hopefully yield CBS-specific compounds, by using high-throughput screening and computational modeling of novel ligands, improving folding, stability, and activity of CBS mutants. PMID- 29119253 TI - Higher expression of inhibitory CD158b and CD158e NK cell receptor and age predicts treatment response in children with chronic hepatitis C. AB - Treatment with pegylated interferon-alpha and ribavirin (PEG-IFN/RBV) is the only choice for chronic hepatitis C (CHC) in children. Natural killer (NK) cells were described to play a vital role in CHC. The aim of this study was to analyze the expression of peripheral blood NK cell receptors in their relation to PEG-IFN/RBV treatment response. Study included 26 children with CHC-13 boys, age range 13.42 +/- 3.28 years. Blood for biochemical, virological and cytometric testing was taken for evaluation prior to the antiviral treatment. NK cell receptors were detected by flow cytometry and the results were presented as proportion of cells and mean fluorescence intensity (MFI). Therapy consisted of PEG-IFNalpha-2b (60 MUg/m2 s.c 1*/week) and RBV (15 mg/kg p.o. daily). Treatment duration was response-related and varied from 12 to 72 weeks. Rapid virological response (RVR) was evaluated in the 4th week and sustained virological response (SVR) 6 months after completion of the therapy. RVR children were younger (11.67 +/- 3.74 vs 15.35 +/- 2.42; p = 0.001) and displayed higher CD158b (3.58 +/- 0.16 vs 3.45 +/- 0.13; p = 0.038) and CD158e expression (4.33 +/- 0.21 vs 4.03 +/- 0.16; p = 0.039). Density of CD158b (logMFI = 3.68 +/- 0.22 vs 3.36 +/- 0.16; p = 0.036) and CD158e expression was significantly higher (4.37 +/- 0.14 vs 4.12 +/- 0.21; p = 0.046) and NKG2D expression significantly lower (97.50 +/- 3.46 vs 94.92 +/- 5.93; p = 0.049) in SVR children. SVR children were also significantly younger (12.40 +/- 3.66 vs 15.13 +/- 2.83; p = 0.003). Significance of the age of patients, and expression of CD158b and CD158e were confirmed in univariate and multivariate analysis. Age of patients is negatively related to RVR and SVR. NK cell phenotype with higher expression density of CD158b and CD158e receptor was a positive predictor of SVR. PMID- 29119255 TI - Combining Raman and laser induced breakdown spectroscopy by double pulse lasing. AB - A new approach combining Raman spectrometry and laser induced breakdown spectrometry (LIBS) within a single laser event was suggested. A pulsed solid state Nd:YAG laser running in double pulse mode (two frequency-doubled sequential nanosecond laser pulses with dozens microseconds delay) was used to combine two spectrometry methods within a single instrument (Raman/LIBS spectrometer). First, a low-energy laser pulse (power density far below ablation threshold) was used for Raman measurements while a second powerful laser pulse created the plasma suitable for LIBS analysis. A short time delay between two successive pulses allows measuring LIBS and Raman spectra at different moments but within a single laser flash-lamp pumping. Principal advantages of the developed instrument include high quality Raman/LIBS spectra acquisition (due to optimal gating for Raman/LIBS independently) and absence of target thermal alteration during Raman measurements. A series of high quality Raman and LIBS spectra were acquired for inorganic salts (gypsum, anhydrite) as well as for pharmaceutical samples (acetylsalicylic acid). To the best of our knowledge, the quantitative analysis feasibility by combined Raman/LIBS instrument was demonstrated for the first time by calibration curves construction for acetylsalicylic acid (Raman) and copper (LIBS) in gypsum matrix. Combining ablation pulses and Raman measurements (LIBS/Raman measurements) within a single instrument makes it an efficient tool for identification of samples hidden by non-transparent covering or performing depth profiling analysis including remote sensing. Graphical abstract Combining Raman and laser induced breakdown spectroscopy by double pulse lasing. PMID- 29119256 TI - Gas chromatographic retention behavior of polycyclic aromatic hydrocarbons (PAHs) and alkyl-substituted PAHs on two stationary phases of different selectivity. AB - Retention indices (I) for 45 polycyclic aromatic hydrocarbons (PAHs) and 63 methyl-substituted PAHs were determined by gas chromatography - mass spectrometry (GC-MS) using two different stationary phases: a Rxi-PAH phase (a "higher phenyl content stationary phase") and a 50% (mole fraction) liquid crystalline dimethylpolysiloxane phase. Retention data were obtained for parent PAHs from molecular mass (MM) 128 g/mol (naphthalene) to 328 g/mol (benzo[c]picene) and for 12 sets of methyl-PAHs (methylfluorenes, methylanthracenes, methylphenanthrenes, methylfluoranthenes, methylpyrenes, methylbenz[a]anthracenes, methylbenzo[c]phenanthrenes, methylchrysenes, methyltriphenylenes, methylbenzo[a]pyrenes, methylperylenes, and methylpicenes). Molecular shape descriptors such as length-to-breath ratio (L/B) and thickness (T) were determined for all the PAHs studied. Correlation between I and L/B ratio was evaluated for both stationary phases with a better correlation observed for the 50% liquid crystalline phase (correlation coefficients ranging from 0.22 to 1.00). Graphical Abstract GC separation of six methylchrysene isomers (m/z 242) on two different stationary phases: 50 % phenyl-like methylpolysiloxane phase and 50 % liquid crystalline phase. Retention indices (I) are plotted as a function of L/B for both phases. The data marker numbers identify each isomer based on methyl substitution position. PMID- 29119257 TI - Risky decision-making and affective features of impulse control disorders in Parkinson's disease. AB - Impulse control disorders (ICDs) in Parkinson's disease (PD) are considered dopaminergic treatment side effects. Cognitive and affective factors may increase the risk of ICD in PD. The aim is to investigate risky decision-making and associated cognitive processes in PD patients with ICDs within a four-stage conceptual framework. Relationship between ICDs and affective factors was explored. Thirteen PD patients with ICD (ICD+), 12 PD patients without ICD (ICD ), and 17 healthy controls were recruited. Overall risky decision-making and negative feedback effect were examined with the Balloon Analogue Risk Task (BART). A cognitive battery dissected decision-making processes according to the four-stage conceptual framework. Affective and motivational factors were measured. ANOVA showed no effect of group on overall risky decision-making. However, there was a group * feedback interaction [F (2, 39) = 3.31, p = 0.047]. ICD+, unlike ICD- and healthy controls, failed to reduce risky behaviour following negative feedback. A main effect of group was found for anxiety and depression [F(2, 38) = 8.31, p = 0.001], with higher symptoms in ICD+ vs. healthy controls. Groups did not differ in cognitive outcomes or affective and motivational metrics. ICD+ may show relatively preserved cognitive function, but reduced sensitivity to negative feedback during risky decision-making and higher symptoms of depression and anxiety. PMID- 29119258 TI - In focus in HCB. PMID- 29119259 TI - Rheumatoid Arthritis-Associated Interstitial Lung Disease: Current Concepts. AB - PURPOSE OF REVIEW: Among the many extra-articular complications of rheumatoid arthritis (RA), interstitial lung disease (ILD) contributes significantly to morbidity and mortality. Prevalence estimates for RA-ILD vary widely depending on the specific clinical, radiographic, and functional criteria used to establish the diagnosis. A key unresolved issue is whether early, subclinical forms of RA ILD represent a precursor to end stage, fibrotic lung disease. Based on uncertainties surrounding the natural history of RA-ILD, incomplete understanding of underlying disease pathogenesis, and lack of controlled clinical trials, evidence-based therapeutic strategies remain largely undefined. RECENT FINDINGS: Correlative clinico-epidemiological studies have identified key risk factors for disease progression. Complementing these findings, the identification of specific molecular and serological markers of RA-ILD has improved our understanding of disease pathogenesis and established the foundation for predictive biomarker profiling. Experience from case series and cohort studies suggests that newer biological agents such as rituximab may be viable treatment options. RA-ILD continues to have a major impact on "disease intrinsic" morbidity and mortality. Increased understanding of disease pathogenesis and the natural history of subclinical RA-ILD will promote the development of more refined therapeutic strategies. PMID- 29119260 TI - Can positive affect attenuate (persistent) pain? State of the art and clinical implications. AB - PURPOSE OF REVIEW: Pain is an intense experience that can place a heavy burden on peoples' lives. The identification of psychosocial risk factors led to the development of effective pain treatments. However, effect sizes are modest. Accumulating evidence suggests that enhancing protective factors might also impact on (well-being despite) pain. Recent findings on positive affect (interventions) towards pain-related outcomes will be reviewed, and new avenues for treatment of persistent pain will be discussed. RECENT FINDINGS: Positive affect significantly attenuates the experience of pain in healthy and clinical populations. Positive affect interventions effectively reduce pain sensitivity and bolster well-being despite pain. Through both psychological and (neuro )biological pathways, but also through its effect on central treatment processes such as inhibitory learning, positive affect can optimize the efficacy of existing treatments. Comprehensive understanding of the unique roles and dynamic interplay of positive and negative affect in moderating pain may optimize the treatment of (persistent) pain. PMID- 29119261 TI - DNA and HSA interaction of Vanadium (IV), Copper (II), and Zinc (II) complexes derived from an asymmetric bidentate Schiff-base ligand: multi spectroscopic, viscosity measurements, molecular docking, and ONIOM studies. AB - The interaction of three complexes [Zn(II), Cu(II), and V(IV)] derived from an asymmetric bidentate Schiff-base ligand with DNA and HSA was studied using fluorescence quenching, UV-Vis spectroscopy, viscosity measurements, and computational methods [molecular docking and our Own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM)]. The obtained results revealed that the DNA and HSA affinities for binding of the synthesized compounds follow as V(IV) > Zn(II) > Cu(II) and Zn(II) > V(IV) > Cu(II), respectively. The distance between these compounds and HSA was obtained based on the Forster's theory of non-radiative energy transfer. Furthermore, computational molecular docking was carried out to investigate the DNA- and HSA-binding pose of the compounds. Molecular docking calculations showed that H-bond, hydrophobic, and pi cation interactions have dominant role in stability of the compound-HSA complexes. ONIOM method was utilized to investigate the HSA binding of the compounds more precisely in which molecular-mechanics method (UFF) and semi empirical method (PM6) were selected for the low layer and the high layer, respectively. The results show that the structural parameters of the compounds changed along with binding, indicating the strong interaction between the compounds with HSA and DNA. Viscosity measurements as well as computational docking data suggest that all metal complexes interact with DNA, presumably by groove-binding mechanism. PMID- 29119262 TI - Role of Cardiac PET in Clinical Practice. AB - OPINION STATEMENT: Early identification of atherosclerosis and at-risk lesions plays a critical role in reducing the burden of cardiovascular disease. While invasive coronary angiography serves as the gold standard for diagnosing coronary artery disease, non-invasive imaging techniques provide visualization of both anatomical and functional atherosclerotic processes prior to clinical presentation. The development of cardiac positron emission tomography (PET) has greatly enhanced our capability to diagnose and treat patients with early stages of atherosclerosis. Cardiac PET is a powerful, versatile non-invasive diagnostic tool with utility in the identification of high-risk plaques, myocardial perfusion defects, and viable myocardial tissue. Cardiac PET allows for comparisons of myocardial function both at time of rest and stress, providing accurate assessments of both myocardial perfusion and viability. Furthermore, novel PET techniques with unique radiotracers yield clinically relevant data on high-risk plaques in active progressive atherosclerosis. While PET exercise stress tests were previously difficult to perform given short radiotracer half life, the development of the novel radiotracer Flurpiridaz F-18 provides a promising future for PET exercise stress imaging. In addition, hybrid imaging with computed tomography angiography (CTA) and cardiac magnetic resonance (CMR) provides integration of cardiac function and structure. In this review article, we discuss the principles of cardiac PET, the clinical applications of PET in diagnosing and prognosticating patients at risk for future cardiovascular events, compare PET with other non-invasive cardiac imaging modalities, and discuss future applications of PET in CVD evaluation and management. PMID- 29119263 TI - Electronic properties of the polypyrrole-dopant anions ClO4- and MoO42-: a density functional theory study. AB - The conductive properties of polypyrrole chains doped with ClO4- or MoO42- anions and the existence of polarons and bipolarons in these doped polypyrrole chains were investigated by performing computational calculations based on density functional theory (DFT). Doping with these anions was found to decrease the band gap of the polypyrrole. Theoretical calculations revealed that changing the type of oxidative agent applied does not affect the conversion of polypyrrole into a conducting polymer, but the conductivity of the doped polypyrrole does depend on the ratio of oxidant to polypyrrole. PMID- 29119264 TI - Keap1-Nrf2 signaling pathway confers resilience versus susceptibility to inescapable electric stress. AB - The transcription factor Keap1-Nrf2 signaling plays a key role in the oxidative stress which is involved in psychiatric disorders. In the learned helplessness (LH) paradigm, protein levels of Keap1 and Nrf2 in the prefrontal cortex and dentate gyrus of hippocampus from LH (susceptible) rats were lower than control and non-LH (resilience) rats. Furthermore, protein expressions of Keap1 and Nrf2 in the parietal cortex from major depressive disorder, schizophrenia, and bipolar disorder were lower than controls. These results suggest that Keap1-Nrf2 signaling might contribute to stress resilience which plays a key role in the pathophysiology of psychiatric disorders. PMID- 29119265 TI - Postmortem studies indicate altered cell chemical composition of the suprachiasmatic nucleus in mood disorders. PMID- 29119267 TI - PpORS, an ancient type III polyketide synthase, is required for integrity of leaf cuticle and resistance to dehydration in the moss, Physcomitrella patens. AB - MAIN CONCLUSION: PpORS knockout mutants produced abnormal leaves with increased dye permeability and were more susceptible to dehydration, consistent with PpORS products being constituents of a cuticular structure in the moss. Type III polyketide synthases (PKSs) have co-evolved with terrestrial plants such that each taxon can generate a characteristic collection of polyketides, fine-tuned to its needs. 2'-Oxoalkylresorcinol synthase from Physcomitrella patens (PpORS) is basal to all plant type III PKSs in phylogenetic trees and may closely resemble their most recent common ancestor. To gain insight into the roles that ancestral plant type III PKSs might have played during early land plant evolution, we constructed and phenotypically characterized targeted knockouts of PpORS. Ors gametophores, unless submerged in water while they were developing, displayed various leaf malformations that included grossly misshapen leaves, missing or abnormal midribs, multicellular protuberances and localized necrosis. Ors leaves, particularly abnormal ones, showed increased permeability to the hydrophilic dye, toluidine blue. Ors gametophores lost water faster and were more susceptible to dehydration than those of the control strain. Our findings are consistent with ors leaves possessing a partially defective cuticle and implicate PpORS in synthesis of the intact cuticle. PpORS orthologs are present in a few moss species but have not been found in other plants. However, conceivably an ancestral ORS in early land plants may have contributed to their protection from dehydration. PMID- 29119266 TI - Civilians in World War II and DSM-IV mental disorders: results from the World Mental Health Survey Initiative. AB - PURPOSE: Understanding the effects of war on mental disorders is important for developing effective post-conflict recovery policies and programs. The current study uses cross-sectional, retrospectively reported data collected as part of the World Mental Health (WMH) Survey Initiative to examine the associations of being a civilian in a war zone/region of terror in World War II with a range of DSM-IV mental disorders. METHODS: Adults (n = 3370) who lived in countries directly involved in World War II in Europe and Japan were administered structured diagnostic interviews of lifetime DSM-IV mental disorders. The associations of war-related traumas with subsequent disorder onset-persistence were assessed with discrete-time survival analysis (lifetime prevalence) and conditional logistic regression (12-month prevalence). RESULTS: Respondents who were civilians in a war zone/region of terror had higher lifetime risks than other respondents of major depressive disorder (MDD; OR 1.5, 95% CI 1.1, 1.9) and anxiety disorder (OR 1.5, 95% CI 1.1, 2.0). The association of war exposure with MDD was strongest in the early years after the war, whereas the association with anxiety disorders increased over time. Among lifetime cases, war exposure was associated with lower past year risk of anxiety disorders (OR 0.4, 95% CI 0.2, 0.7). CONCLUSIONS: Exposure to war in World War II was associated with higher lifetime risk of some mental disorders. Whether comparable patterns will be found among civilians living through more recent wars remains to be seen, but should be recognized as a possibility by those projecting future needs for treatment of mental disorders. PMID- 29119268 TI - Gene structure, expression pattern and interaction of Nuclear Factor-Y family in castor bean (Ricinus communis). AB - MAIN CONCLUSION: Nuclear Factor-Y transcription factors, which function in regulating seed development (including storage reservoir accumulation) and responding to abiotic stresses, were identified and characterized in castor bean. Nuclear Factor-Y (NF-Y) transcription factors in plants contain three subunits (NF-YA, NF-YB and NF-YC), and function as a heterodimer or heterotrimer complex in regulating plant growth, development and response to stresses. Castor bean (Ricinus communis, Euphorbiaceae) one of the most economically important non edible oilseed crops, able to grow in diverse soil conditions and displays high tolerance to abiotic stresses. Due to increasing demands for its seed oils, it is necessary to elucidate the molecular mechanism underlying the regulation of growth and development. Based on the available genome data, we identified 25 RcNF Y members including six RcNF-YAs, 12 RcNF-YBs and seven RcNF-YCs, and characterized their gene structures. Yeast two-hybrid assays confirmed the protein-protein interactions among three subunits. Using transcriptomic data from different tissues, we found that six members were highly or specifically expressed in endosperms (in particular, two LEC1-type members RcNF-YB2 and RcNF YB12), implying their involvement in regulating seed development and storage reservoir accumulation. Further, we investigated the expression changes of RcNF-Y members in two-week-old seedlings under drought, cold, hot and salt stresses. We found that the expression levels of 20 RcNF-Y members tested were changed and three RcNF-Y members might function in response to abiotic stresses. This study is the first reported on genomic characterization of NF-Y transcription factors in the family Euphorbiaceae. Our results provide the basis for improved understanding of how NF-Y genes function in the regulation of seed development and responses to abiotic stresses in both castor bean and other plants in this family. PMID- 29119270 TI - Functional diversity in the pH signaling pathway: an overview of the pathway regulation in Neurospora crassa. AB - Microorganisms have the ability to adapt and respond to different environmental conditions, whether they are stressful or not. Although the detection and/or responding mechanisms are often unknown, a large number of proteins may participate in signal transduction pathways involved in environmental stimulus to induce physiological and cellular events. Here, we examine the important role in cell homeostasis that extracellular pH plays in different fungi, and summarize the recent data reported in distinct organisms, by comparing them to the well characterized mechanisms firstly described in Aspergillus and yeast. While most of the knowledge regarding the cellular processes triggered by the pH signaling pathway is based on the work in these two organisms, new data have been emerging in a diverse group of filamentous fungi, namely the involvement of this signaling pathway in metabolism and fungal pathogenicity. In this review, we present the major aspects of the pH signaling pathway in different model organisms, focusing on the protein components and the biological processes influenced by this pathway. In particular, we discuss novel cellular processes regulated by this pathway in the fungus Neurospora crassa. The diversity of functional processes that are affected under pH stress highlights how broadly this condition impacts on basic cellular processes in fungi and reveals how divergent fungal species are. PMID- 29119269 TI - Molecular regulation of aluminum resistance and sulfur nutrition during root growth. AB - MAIN CONCLUSION: Aluminum toxicity and sulfate deprivation both regulate microRNA395 expression, repressing its low-affinity sulfate transporter ( SULTR2;1 ) target. Sulfate deprivation also induces the high-affinity sulfate transporter gene ( SULTR12 ), allowing enhanced sulfate uptake. Few studies about the relationships between sulfate, a plant nutrient, and aluminum, a toxic ion, are available; hence, the molecular and physiological processes underpinning this interaction are poorly understood. The Al-sulfate interaction occurs in acidic soils, whereby relatively high concentrations of trivalent toxic aluminum (Al3+) may hamper root growth, limiting uptake of nutrients, including sulfur (S). On the other side, Al3+ may be detoxified by complexation with sulfate in the acid soil solution as well as in the root-cell vacuoles. In this review, we focus on recent insights into the mechanisms governing plant responses to Al toxicity and its relationship with sulfur nutrition, emphasizing the role of phytohormones, microRNAs, and ion transporters in higher plants. It is known that Al3+ disturbs gene expression and enzymes involved in biosynthesis of S-containing cysteine in root cells. On the other hand, Al3+ may induce ethylene biosynthesis, enhance reactive oxygen species production, alter phytohormone transport, trigger root growth inhibition and promote sulfate uptake under S deficiency. MicroRNA395, regulated by both Al toxicity and sulfate deprivation, represses its low-affinity Sulfate Transporter 2;1 (SULTR2;1) target. In addition, sulfate deprivation induces High Affinity Sulfate Transporters (HAST; SULTR1;2), improving sulfate uptake from low-sulfate soil solutions. Identification of new microRNAs and cloning of their target genes are necessary for a better understanding of the role of molecular regulation of plant resistance to Al stress and sulfate deprivation. PMID- 29119271 TI - Rnr1's role in telomere elongation cannot be replaced by Rnr3: a role beyond dNTPs? AB - Telomeres, the nucleoprotein complexes at the end of eukaryotic chromosomes, protect them from degradation and ensure the replicative capacity of cells. In most human tumors and in budding yeast, telomere length is maintained by the activity of telomerase, an enzyme that adds dNTPs according to an internal RNA template. The dNTPs are generated with the help of the ribonucleotide reductase (RNR) complex. We have recently generated strains lacking the large subunit of RNR, Rnr1, which were kept viable by the expression of RNR complexes containing the Rnr1 homolog, Rnr3. Interestingly, we found that these Rnr1-deficient strains have short telomeres that are stably maintained, but cannot become efficiently elongated by telomerase. Thus, a basic maintenance of short telomeres is possible under conditions, where Rnr1 activity is absent, but a sustained elongation of short telomeres fully depends on Rnr1 activity. We show that Rnr3 cannot compensate for this telomeric function of Rnr1 even when overall cellular dNTP values are restored. This suggests that Rnr1 plays a role in telomere elongation beyond increasing cellular dNTP levels. Furthermore, our data indicate that telomerase may act in two different modes, one that is capable of coping with the "end-replication problem" and is functional even in the absence of Rnr1 and another required for the sustained elongation of short telomeres, which fully depends on the presence of Rnr1. Supply of dNTPs for telomere elongation is provided by the Mec1ATR checkpoint, both during regular DNA replication and upon replication fork stalling. We discuss the implications of these results on telomere maintenance in yeast and cancer cells. PMID- 29119272 TI - Interaction of the Saccharomyces cerevisiae RING-domain protein Nse1 with Nse3 and the Smc5/6 complex is required for chromosome replication and stability. AB - Genomic stability is maintained by the concerted actions of numerous protein complexes that participate in chromosomal duplication, repair, and segregation. The Smc5/6 complex is an essential multi-subunit complex crucial for repair of DNA double-strand breaks. Two of its subunits, Nse1 and Nse3, are homologous to the RING-MAGE complexes recently described in human cells. We investigated the contribution of the budding yeast Nse1 RING-domain by isolating a mutant nse1-103 bearing substitutions in conserved Zinc-coordinating residues of the RING-domain that is hypersensitive to genotoxic stress and temperature. The nse1-103 mutant protein was defective in interaction with Nse3 and other Smc5/6 complex subunits, Nse4 and Smc5. Chromosome loss was enhanced, accompanied by a delay in the completion of replication and a modest defect in sister chromatid cohesion, in nse1-103. The nse1-103 mutant was synthetic sick with rrm3? (defective in fork passage through pause sites), this defect was rescued by inactivation of Tof1, a subunit of the fork protection complex that enforces pausing. The temperature sensitivity of nse1-103 was partially suppressed by deletion of MPH1, encoding a DNA-helicase. Homology modeling of the structure of the budding yeast Nse1-Nse3 heterodimer based on the human Nse1-MAGEG1 structure suggests a similar organization and indicates that perturbation of the Zn-coordinating cluster has the potential to allosterically alter structural elements at the Nse1/Nse3 interaction interface that may abrogate their association. Our findings demonstrate that the budding yeast Nse1 RING-domain organization is important for interaction with Nse3, which is crucial for completion of chromosomal replication, cohesion, and maintenance of chromosome stability. PMID- 29119273 TI - Immunohistochemical distribution of Ki67 in epidermis of thick glabrous skin of human digits. AB - The glabrous skin on the flexor sides of hands and feet, compared to other integument regions, has thicker epidermis and more complex pattern of epidermal ridges, wherefore in microscopy is denominated as thick skin. The epidermis of this skin type has individually unique and permanent superficial patterns, called dermatoglyphics, which are maintained by regenerative potential of deep epidermal rete ridges, that interdigitate with adjacent dermis. Using light microscopy, we analyzed cadaveric big toes thick skin samples, described histology of deep epidermal ridges (intermediate, limiting, and transverse), and quantitatively evidenced their pattern of proliferation by immunohistochemical assessment of Ki67. Immunohistochemical distribution of Ki67 was confined to basal and suprabasal layers, with pattern of distribution specific for intermediate, limiting and transverse ridges that gradually transform within epidermal height. Deep epidermal ridges, interdigitating with dermal papillae, participate in construction of intricate epidermal base, whose possible role in epidermal regeneration was also discussed. Having a prominent morphology, this type of epidermis offers the best morphological insight in complexities of skin organization, and its understanding could challenge and improve currently accepted models of epidermal organization. PMID- 29119274 TI - Quantification of pulmonary regurgitation and prediction of pulmonary valve replacement by echocardiography in patients with congenital heart defects in comparison to cardiac magnetic resonance imaging. AB - Pulmonary regurgitation (PR) is common in patients with congenital heart defects (CHD) and contributes to morbidity and mortality in the long-term. We investigated in this retrospective analysis whether readily accessible echocardiographic parameters are useful for quantification of PR and for predicting pulmonary valve replacement (PVR) in comparison to the gold-standard phase contrast (PC) flow measurements from cardiovascular magnetic resonance (CMR). Continuous wave (CW) Doppler and colour flow images in echocardiograms from 53 patients with CHD were analysed. Slope and jet-to-RVOT ratio correlated significantly with CMR-assessed regurgitation fraction (RF), whereas pressure half time (PHT) showed an inverse correlation. Patients with mild PR in CMR had significantly higher PHT, lower slope and jet-to-RVOT ratio than patients with moderate or severe regurgitation. The AUC regarding PR severity was 0.778 for PHT (95% CI, 0.649-0.907; P = 0.007 for CMR-RF <= 35%), 0.744 for slope (95% CI, 0.603-0.885; P = 0.017 for CMR-RF > 35%) and 0.652 for jet-to-RVOT ratio (95% CI, 0.473-0.860; P = 0.168 for CMR-RF > 35%). The optimal cut-off values calculated from ROC analysis were 95 ms for PHT and 4.9 m/s2 for slope. In logistic regression analysis, slope emerged as the most valuable parameter for predicting the indication for PVR (OR 12.9, 95% CI, 1.8-90.9, P = 0.010). In conclusion, echocardiographic assessment of PR was feasible. Both parameters, PHT and in particular slope, were predictors for PVR. Thus, echocardiography appears appropriate in the management of patients with PR. PMID- 29119276 TI - Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. AB - Background A single center phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) was conducted (NCT02331251). Methods PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS >= 70% received GNP until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months. Changes in tumor cell-free DNA copy number instability (CNI) was retrospectively evaluated. Results 17 pts. with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Grade 3 events occurred in 53% of patients. The phase II portion was completed for chemotherapy naive PDAC pts. Of the 11 evaluable chemotherapy naive PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 3 with PR on treatment for 8+, ~11, and 15 months; respectively. The primary endpoint of >15% complete response was not met. The median progression-free survival (PFS) and overall survival (OS) was 9.1 and 15.0 months for chemotherapy naive treated patients. Of 9 patients evaluable for CNI change, a greater reduction in CNI correlated with longer PFS and improved OS. Conclusions GNP can be safely given to chemotherapy naive PDAC patients. Efficacy appears to be slightly improved over previously reported results for standard weekly * 3 every 28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for OS. PMID- 29119275 TI - Comparison of effects of losartan and metoprolol on left ventricular and aortic function at rest and during exercise in chronic aortic regurgitation. AB - Aortic regurgitation (AR) increases the hemodynamic load on both the left ventricle (LV) and the aorta. Vasodilators and beta-blockers both reduce systemic blood pressure, but their relative effects on the LV and aortic function and aortic regurgitant fraction in chronic AR are uncertain. We aimed to compare short-term effects of losartan and metoprolol on LV and aortic function in asymptomatic patients with chronic moderate to severe AR, both at rest and during exercise, using cardiac magnetic resonance (CMR) imaging. 17 chronic AR patients were randomized to 4-6 weeks losartan followed by metoprolol, or vice versa, in a cross-over design. Aortic regurgitant fraction, aortic distensibility, pulse wave velocity and LV function were assessed at rest and after moderate exercise stress (29 +/- 7 W, heart rate increase 25 +/- 6 bpm) using CMR. Chronic AR patients on metoprolol had a significantly lower mean heart rate, cardiac power index and rate-pressure product, than on losartan (all p < 0.01). However, aortic regurgitant fraction was greater on metoprolol compared to losartan (by 7 +/- 11%, p = 0.02). Metoprolol was also associated with a greater reduction in aortic distensibility during exercise than losartan (- 2.4 +/- 1.5 * 10-3 vs - 1.7 +/- 2.1 * 10-3 mmHg-1 respectively, p = 0.04). End-diastolic volume index was higher on metoprolol than losartan at exercise (difference 6.6 +/- 7.8 ml/m2, p < 0.01), as was end-systolic volume index (difference 4.0 +/- 5.2 ml/m2, p < 0.01). Losartan and metoprolol have significantly different short-term effects on aortic regurgitation and LV and aortic function in chronic AR. Further research is required to determine the long-term clinical significance of these changes. PMID- 29119277 TI - Priority of lymph node dissection for proximal gastric cancer invading the greater curvature. AB - BACKGROUND: The therapeutic efficacy of dissection of the splenic hilar lymph nodes (#10) has not been fully evaluated in locally advanced proximal gastric cancer (LAGC) invading the greater curvature of the stomach. METHODS: Patients with LAGC invading the greater curvature who underwent D2 total gastrectomy with splenectomy between January 2000 and May 2015 were retrospectively examined. The therapeutic value index was calculated by multiplying the metastatic rate of a station and the 5-year survival of patients with metastasis to that station; the metastatic rate and the index of each lymph node station were then compared. RESULTS: In total, 82 patients were eligible for the present study. The most frequent metastatic node was #3, followed by #1, #4d and #7, #2, #4sa and #10, and #4sb and #9. These lymph nodes had a metastatic rate of more than 10%. The node station with the highest index was #3, followed by #7, #4d, #1, #4sb, #4sa, #2, and #9. The index of #10 was lower, but exceeded those of #8a and #11p. CONCLUSIONS: The metastatic rate of #10 was relatively high at 13%, and the therapeutic value index was as high as those of other suprapancreatic nodes. D2 dissection for proximal cancer located in the greater curvature should include removal of node #10. PMID- 29119278 TI - Development of endothermy in birds: patterns and mechanisms. AB - Endothermy is a conspicuous and important adaptation in birds. Even though juvenile and adult birds are endothermic and maintain a constant, high body temperature by means of internal heat production, they begin life expressing an ectothermic phenotype. Depending on where a species falls along a continuum of maturity at hatching, from precocial to altricial, they begin to express endothermic traits either close to the time of hatching or as nestlings over a period of 1-3 weeks. Developing endothermy requires attaining a high basal metabolic rate and associated aerobic scope to produce sufficient internal heat, insulation to retain the internally produced heat, and a thermostat that "turns on" heat production in response to cooling ambient temperatures. To support the high metabolic costs of endothermy, the animal must have the capacity to deliver sufficient oxygen and nutrients to the heat-generating tissues. In this review, we examine the development of physiological and morphological traits that are required for endothermy and discuss their potential to limit the development of endothermy. These include ventilatory and cardiovascular function, contribution of visceral organ masses, membrane lipid composition, substrate supply pathways, and skeletal muscle physiology. The developmental trajectories of each of these systems in precocial and altricial species can have significant effects on the development of an endothermic phenotype. PMID- 29119279 TI - Mechanical stress promotes matrix synthesis of mandibular condylar cartilage via the RKIP-ERK pathway. AB - Mandibular hypoplasia is a common jaw deformity that affects breathing, occlusal function and facial aesthetics. Stimulating mandibular condylar growing with functional appliances is an ordinary but controversial treatment method in orthodontics. Therefore, it is vital to clarify how functional appliances affect condylar growing. Raf-1 kinase inhibitor protein (RKIP), as an endogenous inhibitory molecule of the ERK signaling, is postulated to involve in stress induced response to articular cartilage. This study was to reveal the role of RKIP in regulating cartilage matrix synthesis with functional appliance treatment. Here, position rat mandibular forward simulating functional appliance effect to examine the stress-induced modification of mandibular condylar in vivo, meanwhile rat mandibular condylar chondrocytes (Mccs) were subjected to cyclic tensile stress (CTS, 16%, 1 HZ). The results showed that mandibular forward therapy enhanced condylar cartilage growth. The thicknesses of all layers of condylar cartilage were increased significantly. RKIP expression was also increased in the mature cartilage layer. In addition, CTS could enhance extracellular matrix formation and cartilage marker expression (aggrecan and collagen II), which shared a similar expression pattern with RKIP in Mccs. However, CTS induced up-regulation of collagen II and aggrecan was blocked by RKIP knockdown. Nuclear p-ERK, targeting downstream of RKIP, showed a decrease after CTS,which was disappeared in RKIP-knockdown Mccs. Taken together, physiological mechanical stimulation promotes cartilage growth modification by up regulating RKIP through inhibiting ERK signaling pathway. PMID- 29119280 TI - Cross-talk between high light stress and plant defence to the two-spotted spider mite in Arabidopsis thaliana. AB - Little is known about how plants deal with arthropod herbivores under the fluctuating light intensity and spectra which occur in natural environments. Moreover, the role of simultaneous stress such as excess light (EL) in the regulation of plant responses to herbivores is poorly characterized. In the current study, we focused on a mite-herbivore, specifically, the two-spotted spider mite (TSSM), which is one of the major agricultural pests worldwide. Our results showed that TSSM-induced leaf damage (visualized by trypan blue staining) and oviposition rate (measured as daily female fecundity) decreased after EL pre treatment in wild-type Arabidopsis plants, but the observed responses were not wavelength specific. Thus, we established that EL pre-treatment reduced Arabidopsis susceptibility to TSSM infestation. Due to the fact that a portion of EL energy is dissipated by plants as heat in the mechanism known as non photochemical quenching (NPQ) of chlorophyll fluorescence, we tested an Arabidopsis npq4-1 mutant impaired in NPQ. We showed that npq4-1 plants are significantly less susceptible to TSSM feeding activity, and this result was not dependent on light pre-treatment. Therefore, our findings strongly support the role of light in plant defence against TSSM, pointing to a key role for a photo protective mechanism such as NPQ in this regulation. We hypothesize that plants impaired in NPQ are constantly primed to mite attack, as this seems to be a universal evolutionarily conserved mechanism for herbivores. PMID- 29119282 TI - Could White Coat Ocular Hypertension Affect to the Accuracy of the Diagnosis of Glaucoma? Relationships Between Anxiety and Intraocular Pressure in a Simulated Clinical Setting. AB - Sixty-one healthy subjects participated in a laboratory study carried out in a simulated clinical setting. Anticipatory anxiety-state was assessed at the arrival and immediately after, with no brief phase of adaptation, measurements of intraocular pressure, heart rate, systolic and diastolic blood pressure were collected. At the end of the procedure, anxiety-trait was also assessed. Results suggest that high levels of both anxiety-state and anxiety-trait significantly predicted a clinically relevant increase of intraocular pressure. Anxiety-state mediated the relationship between anxiety-trait and intraocular pressure, which also was found to be related with heart rate but not related to both systolic and diastolic blood pressure. These results suggest a common mechanism of regulation underlying anxiogenic variability found on both intraocular pressure and heart rate. A reduction in parasympathetic activity appears as a possible mechanism underlying to this phenomenon. This anxiety-enhanced intraocular pressure could be considered a phenomenon analogous to white coat hypertension found in the measurement of blood pressure; therefore, it probably should be taken into account in the clinical context to prevent errors in the diagnosis of glaucoma. Further research on cognitive and emotional regulation of intraocular pressure is needed to best characterize this hypothetical phenomenon. PMID- 29119281 TI - "Swarm relaxation": Equilibrating a large ensemble of computer simulations?. AB - It is common practice in molecular dynamics and Monte Carlo computer simulations to run multiple, separately-initialized simulations in order to improve the sampling of independent microstates. Here we examine the utility of an extreme case of this strategy, in which we run a large ensemble of M independent simulations (a "swarm"), each of which is relaxed to equilibrium. We show that if M is of order [Formula: see text], we can monitor the swarm's relaxation to equilibrium, and confirm its attainment, within [Formula: see text], where [Formula: see text] is the equilibrium relaxation time. As soon as a swarm of this size attains equilibrium, the ensemble of M final microstates from each run is sufficient for the evaluation of most equilibrium properties without further sampling. This approach dramatically reduces the wall-clock time required, compared to a single long simulation, by a factor of several hundred, at the cost of an increase in the total computational effort by a small factor. It is also well suited to modern computing systems having thousands of processors, and is a viable strategy for simulation studies that need to produce high-precision results in a minimum of wall-clock time. We present results obtained by applying this approach to several test cases. PMID- 29119283 TI - Pudendal nerve injury is a relatively common but transient complication of hip arthroscopy. AB - PURPOSE: Hip arthroscopy is emerging as the standard of care for conditions involving the hip, and has a unique set of complications. The purpose of this review was to identify (1) the crude rate of pudendal nerve injury following hip arthroscopy and (2) the specific factors leading to pudendal nerve injury. METHODS: MEDLINE, EMBASE, and PubMed were searched from database inception to October 2016. Patient demographics, indications, surgical technique, complication rates, treatment approaches, and rehabilitation strategies were extracted. RESULTS: Twenty-four studies (n = 3405) were included, with the majority (66%) of studies being level IV evidence. The mean age was 33.9 +/- 9.7 years (range 12 78) and 48.2% were males. Average follow-up was 30.2 +/- 19.1 months. 62 patients were reported to have sustained pudendal nerve injury (1.8%) post-operatively, and all resolved within 6 weeks to 3 months. Of the seven studies that reported using a perineal post, 20 patients were diagnosed with pudendal nerve injury (4.3%), in contrast to two studies (189 patients) reporting only 0.5% pudendal nerve injury without the use of perineal post. Two studies commented on time of traction during surgical intervention with mean times of 98 and 68 min with complication rates of 10% and 6.6%, respectively. CONCLUSIONS: Pudendal nerve injury is not uncommon following hip arthroscopy, with a reported rate found in this review of 1.8%. Potential risk factors may include the use of a perineal post and long traction times. All reported cases resolved within 3 months. Patients should be informed of complications related to pudendal nerve injury, which include sexual and urinary dysfunction. LEVEL OF EVIDENCE: Level IV, systematic review of level I-IV studies. PMID- 29119284 TI - Unusual combined PCL and PLC pediatric multiligamentous knee injury treated with ligament repair procedure. PMID- 29119286 TI - No effect of topical application of tranexamic acid on articular cartilage. AB - PURPOSE: The objective of this study was to evaluate potential cytotoxicity of TXA on articular cartilage by assessing chondrocyte viability of osteochondral explants after exposure to different concentrations and durations of TXA. METHODS: Thirty-nine osteochondral plugs (OCPs) were harvested from three adult Yucatan minipigs immediately after their death. OCPs were divided into 13 groups exposed to different concentrations of TXA (1, 2 and 4 mg/ml in saline solution) for 1, 3 and 6 h. Negative controls were exposed to saline solution for 0, 1, 3 and 6 h. Chondrocyte viability was assessed by Live/Dead cell assay and calculated as the ratio of live cells (green fluorescence) to overall cells (green + red cells) for each concentration of TXA and time point in a 50-um scanned image. RESULTS: No correlation was found between chondrocyte viability, and TXA concentration and time of exposure. Overall, chondrocyte viability ranged from 90 to 99%. There was no statistical difference among control group, 1, 2 and 4 mg/ml TXA solutions at each time point [1 h (n.s.), 3 h (n.s.), 6 h (n.s.)]. Similarly, no statistical difference among groups was observed when comparing cell viability at 1, 3 and 6 h of TXA exposure, (Fig. 2) [1 mg/ml (n.s.), 2 mg/ml (n.s.), and 4 mg/ml (n.s.)]. CONCLUSIONS: In conclusion, doses of TXA approximating the current clinical protocols for topical use did not demonstrate any cytotoxic effects on cartilage explants in a Yucatan mini pig model. Thus, supporting the topical application for procedures with intact cartilage, such as partial knee replacement surgery and cartilage repair procedures. PMID- 29119285 TI - Lateral femoral notch depth is not associated with increased rotatory instability in ACL-injured knees: a quantitative pivot shift analysis. AB - PURPOSE: A deep lateral femoral notch (LFN) on lateral radiographs is indicative of ACL injury. Prior studies have suggested that a deep LFN may also be a sign of persistent rotatory instability and a concomitant lateral meniscus tear. Therefore, the purpose of this study was to evaluate the relationship between LFN depth and both quantitative measures of rotatory knee instability and the incidence of lateral meniscus tears. It was hypothesized that greater LFN depth would be correlated with increased rotatory instability, quantified by lateral compartment translation and tibial acceleration during a quantitative pivot shift test, and incidence of lateral meniscus tears. METHODS: ACL-injured patients enrolled in a prospective ACL registry from 2014 to 2016 were analyzed. To limit confounders, patients were only included if they had primary ACL tears, no concurrent ligamentous or bony injuries requiring operative treatment, and no previous knee injuries or surgeries to either knee. Eighty-four patients were included in the final analysis. A standardized quantitative pivot shift test was performed pre-operatively under anesthesia in both knees, and rotatory instability, specifically lateral compartment translation and tibial acceleration, was quantified using tablet image analysis software and accelerometer sensors. Standard lateral radiographs and sagittal magnetic resonance images (MRI) of the injured knee were evaluated for LFN depth. RESULTS: There were no significant correlations between LFN depth on either imaging modality and ipsilateral lateral compartment translation or tibial acceleration during a quantitative pivot shift test or side-to-side differences in these measurements. Patients with lateral meniscus tears were found to have significantly greater LFN depths than those without on conventional radiograph and MRI (1.0 vs. 0.6 mm, p < 0.05; 1.2 vs. 0.8 mm, p < 0.05, respectively). CONCLUSION: There was no correlation between lateral femoral notch depth on conventional radiographs or MRI and quantitative measures of rotatory instability. Concomitant lateral meniscus injury was associated with significantly greater LFN depth. Based on these findings, LFN depth should not be used as an indicator of excessive rotatory instability, but may be an indicator of lateral meniscus injury in ACL-injured patients. LEVEL OF EVIDENCE: Prognostic level IV. PMID- 29119287 TI - Smoking and obesity influence the risk of nonunion in lateral opening wedge, closing wedge and torsional distal femoral osteotomies. AB - PURPOSE: Lateral distal femoral osteotomies (DFO) have recently been performed more frequently. In addition to realignment for varus and valgus deformity, the indication was extended with the introduction of torsional osteotomies in patellofemoral instability. The purpose of this study was to assess the general and technical risk factors for nonunion in lateral opening, closing and torsional DFO. METHODS: A total of 150 lateral DFO [98 opening wedge (LOWDFO) and 52 closing wedge (LCWDFO)] were analyzed in regard to potential risk factors for nonunion until plate removal. Nonunion was defined as failure of osseous consolidation according to clinical and radiological evaluation. RESULTS: In LOWDFO, the nonunion rate was 2%, in LCWDFO the rate was higher with 9.6%. Nicotine abuse (p = 0.009) and a higher body mass index (p = 0.003) were significant risk factors. Patient's age and gender, the wedge height, hinge fractures, monoplanar versus biplanar osteotomy as well as additional torsional osteotomies were not significant in regard of nonunion. CONCLUSIONS: Lateral DFO have a low rate of complications and nonunion. Smoking and obesity were significantly associated with the risk of nonunion. Hinge fractures, monoplanar technique or complete bone cuts of the opposite hinge in torsional osteotomies did not negatively influence the nonunion rate in DFO. LEVEL OF EVIDENCE: Level IV. PMID- 29119288 TI - Renal Macrophages and Dendritic Cells in SLE Nephritis. AB - PURPOSE OF REVIEW: The purpose of the study was to review the characteristics of renal macrophages and dendritic cells during homeostasis and disease, with a particular focus on lupus nephritis. RECENT FINDINGS: Resident renal macrophages derive from embryonic sources and are long-lived and self-renewing; they are also replaced from the bone marrow with age. The unique characteristics of macrophages in each tissue are imposed by the microenvironment and reinforced by epigenetic modifications. In acute renal injury, inflammatory macrophages are rapidly recruited and then replaced by those with a wound healing/resolution phenotype. In lupus nephritis, dendritic cells infiltrate the kidneys and function to present antigen and organize tertiary lymphoid structures that amplify inflammation. In addition, both infiltrating and resident macrophages contribute to ongoing injury. These cells have a mixed inflammatory and alternatively activated phenotype that may reflect failed resolution, potentially leading to tissue fibrosis and irreversible damage. A further understanding of the renal inflammatory cells that mediate tissue injury and fibrosis should lead to new therapies to help preserve renal function in patients with lupus nephritis. PMID- 29119290 TI - A proposed severity classification system for hepatolithiasis based on an analysis of prognostic factors in a Japanese patient cohort. AB - BACKGROUND: Hepatolithiasis frequently results in severe complications. We conducted a cohort study to identify prognostic factors and to establish a hepatolithiasis severity classification system. METHODS: The study cohort comprised 396 patients who were identified through a 1998 nationwide survey and followed up for 18 years or until death. Cox regression analysis was used to identify prognostic factors. RESULTS: Median survival time of the patients was 308 (range 0-462) months. Of the 396 patients enrolled in the study, 118 (29.8%) died, most frequently from intrahepatic cholangiocarcinoma (25 patients, 21.2%). Age of >= 65 years at the time of initial diagnosis [hazard ratio (HR) 3.410], jaundice for >= 1 week during follow-up (HR 2.442), intrahepatic cholangiocarcinoma (HR 3.674), and liver cirrhosis (HR 5.061) were shown to be significant risk factors for death from any therapeutic course. The data led to a 3-grade disease severity classification system that incorporates intrahepatic cholangiocarcinoma and liver cirrhosis as major factors and age of >= 65 years and jaundice for >= 1 week during follow-up as minor factors. Survival rates differed significantly between grades. CONCLUSIONS: The proposed hepatolithiasis severity classification system can be used to assess prognosis and thereby improve patient outcomes. PMID- 29119289 TI - Local antibiotic decontamination to prevent anastomotic leakage short-term outcome in rectal cancer surgery. AB - PURPOSE: Anastomotic leakage still presents an issue in rectal cancer surgery with rates of about 11%. As bacteria play a critical role, there is the concept of perioperative local decontamination to prevent anastomotic leakage. METHODS: To ascertain the effectiveness of this treatment, we performed a retrospective analysis on 206 rectal resections with primary anastomosis and routine use of a selective decontamination of the digestive tract (SDD) regimen for local decontamination. SDD medication was administered every 8 h from the day before surgery to the seventh postoperative day. All patients were treated according to the fast-track protocol without mechanical bowel preparation; instead, a laxative was used. RESULTS: Overall morbidity was 30%, overall mortality 0.5%. In our data, overall rate of anastomotic leakage (AL) was 5.8%, with 3.9% in anterior rectal resection and 6.5% in low anterior rectal resection group. In 75% of cases, anastomotic leakage was grade "C" and needed re-laparotomy. Surgical site infection rate was 19.9%. No serious adverse events were related to decontamination. CONCLUSION: Local antibiotic decontamination appears to be safe and effective to decrease the rate of anastomotic leakage in rectal cancer surgery. Further focus should be on perioperative management including bowel preparation and choice of antimicrobial agents for local decontamination. PMID- 29119291 TI - Determination of histone epigenetic marks in Arabidopsis and tomato genes in the early response to Botrytis cinerea. AB - KEY MESSAGE: Determination of histone epigenetic marks in Arabidopsis and tomato genes in the early response to Botrytis cinerea may contribute to find biomarkers of the early detection of this devastating pathogen. Recent studies have linked epigenetic modifications with plant responses to biotic stresses. Information about specific histone marks upon necrotrophic pathogens is scarce. Here we wondered whether the altered responsiveness of specific genes in plants infected with Botrytis cinerea was associated with changes in chromatin structure. We performed a chromatin immunoprecipitation analysis that obtained differential epigenetic signature of activating marks H3K4me3, H3K9ac, and the repressor one H3K27me3 on both the promoter and the body of the highly induced PR1 in Arabidopsis plants infected with B. cinerea at 24 and 33 h after inoculation. We also determined the histone marks' profile in two differentially expressed genes in response to B. cinerea, as well as to oxidative stress, given its relevance in this infection. These are both the induced CYP71A13, which encodes a cytochrome P450 involved in camalexin synthesis, and is essential against this necrotroph and the repressed EXL7 (Exordium-like 1). We also adapted our protocol in tomato plants infected with B. cinerea. At 24 hpi, H3K4me3 level increased on the promoter and at different locations of the body of the genes induced upon B. cinerea, including DES (divinyl ethyl synthase), LoxD (lipoxygenase D), DOX1 (alpha-dioxygenase 1), PR2 (pathogenesis-related protein2), WRKY53 and WRKY33. The histone modifications determined herein will allow future studies on epigenetic marks and their transgenerational inheritance in plants infected with B. cinerea. In addition, the analyzed genes are potential biomarkers of B. cinerea infection that could contribute to its early detection in tomato and related crops. PMID- 29119292 TI - Population pharmacokinetics of nintedanib, an inhibitor of tyrosine kinases, in patients with non-small cell lung cancer or idiopathic pulmonary fibrosis. AB - PURPOSE: A population pharmacokinetic model was developed for nintedanib in patients with non-small cell lung cancer (NSCLC) or idiopathic pulmonary fibrosis (IPF). The effects of intrinsic and extrinsic patient factors on exposure of nintedanib and its main metabolite BIBF 1202 were studied. METHODS: Data from 1191 patients with NSCLC (n = 849) or IPF (n = 342) treated with oral nintedanib (once- or twice-daily, dose range 50-250 mg) in 4 Phase II or III studies were combined. Plasma concentrations of nintedanib (n = 5611) and BIBF 1202 (n = 5376) were analyzed using non-linear mixed-effects modeling. RESULTS: Pharmacokinetics of nintedanib were described by a one-compartment model with linear elimination, first-order absorption, and absorption lag time. For a typical patient, the absorption rate was 0.0827 h-1, apparent total clearance was 897 L/h, apparent volume of distribution at steady state was 465 L, and lag time was 25 min. Age, weight, smoking, and Asian race were statistically significant covariates influencing nintedanib exposure, but no individual covariate at extreme values (5th and 95th percentiles of baseline values for continuous covariates) resulted in a change of more than 33% relative to a typical patient. Pharmacokinetics and covariate effects for BIBF 1202 were similar to nintedanib. Mild or moderate renal impairment and mild hepatic impairment (classified by transaminase or bilirubin increase above the upper limit of normal) or underlying disease had no significant effects on nintedanib pharmacokinetics. CONCLUSIONS: This model adequately described the pharmacokinetic profile of nintedanib in NSCLC and IPF populations and can be used for simulations exploring covariate effects and exposure-response analyses. PMID- 29119293 TI - Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia. AB - Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to <= 120 MUmol/L in patients with relapsed or refractory (R/R) AML. Five patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply. All patients received Erwinaze at a dose of 25,000 IU/m2 intravenously three times weekly for 2 weeks. Median trough plasma Gln level at 48 h after initial Erwinaze administration was 27.6 MUmol/L, and 80% (lower limit of 1-sided 95% CI 34%) of patients achieved at least one undetectable plasma Gln value (< 12.5 MUmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1). No dose-limiting toxicities were identified. Two patients responded, one achieved partial remission and one achieved hematologic improvement after six doses of Erwinaze monotherapy. These data suggest asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and support more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML. PMID- 29119295 TI - Treatment of hip fracture of Pope Innocent XII by Marcello Malpighi with bed rest. AB - Marcello Malpighi (1628-1694), who is referred to as the father of microscopical anatomy, histology, physiology and embryology was an Italian biologist and physician, well known for his discoveries on microscopical anatomy of kidney, circulating and lymphatic systems. As well as being a brilliant anatomist, Malpighi was also a valued physician so far as to became the personal physician of Pope Innocent XII (1615-1700). On 23 August 1691, one month after his election, the Pope fell to the ground hitting his left hip. Malpighi, as his personal physician, was immediately called and diagnosed a hip fracture. At that time fractures were generally treated by surgeons, barbers and sawbones, while physicians were mainly concerned with internal diseases. Despite that, Marcello Malpighi cured Pope Innocent XII's hip fracture by applying some modern traumatologic concepts. This article analyses how Malpighi treated this hip fracture, comparing it with the current approach. PMID- 29119294 TI - Predictors of improvements in exercise capacity during cardiac rehabilitation in the recovery phase after coronary artery bypass graft surgery versus acute myocardial infarction. AB - This study aimed to elucidate the predictors of improvements in exercise capacity during cardiac rehabilitation (CR) in the recovery phase after coronary artery bypass graft surgery (CABG) versus acute myocardial infarction (AMI). We studied 152 patients (91 after AMI and 61 after CABG) who participated in a 3-month CR program. All patients underwent a cardiopulmonary exercise test, blood tests, maximal quadriceps isometric strength (QIS) measurement, and bioelectrical impedance body composition measurement at the beginning and end of the 3-month CR program. At baseline, the percentage of predicted peak oxygen uptake (%pred PVO2), maximal QIS, and hemoglobin (Hb) were significantly lower, while C reactive protein (CRP) was significantly higher, in the CABG than the AMI group. After the 3-month CR, %change in PVO2 (%DeltaPVO2) was significantly greater in the CABG than the AMI group (18 +/- 15% vs 11 +/- 12%, P < 0.01). At univariate analysis, baseline plasma brain natriuretic peptide (BNP), %change in maximal QIS after CR (%Delta maximal QIS), and change in plasma hemoglobin (DeltaHb) significantly correlated with %DeltaPVO2 in the CABG group, whereas only baseline %pred-PVO2 did so in the AMI group. Multiple regression analysis revealed that the same factors were independent and significant predictors of %DeltaPVO2 in the CABG and AMI groups. The predictors of improvements in exercise capacity after CR differed between patients after CABG or AMI. Specifically, in CABG patients both enhancing QIS and correcting anemia may contribute to greater improvements in exercise capacity after CR, while a more effective CR program should be designed for CABG patients with high baseline BNP. PMID- 29119296 TI - Comparison of dry needling and steroid injection in the treatment of plantar fasciitis: a single-blind randomized clinical trial. AB - INTRODUCTION: Plantar fasciitis is a common cause of heel pain. Considering different interventions which are applied for patients with plantar fasciitis, dry needling is proposed as a new modality of treatment recently. The aim of this study is to evaluate the effectiveness of dry needling versus steroid injection for plantar fasciitis. METHODS: Sixty-six patients were recruited to this single blind clinical trial study. Participants were randomly allocated to receive 1 ml (40 mg) of Depo-Medrol (methylprednisolone acetate) or dry needling. They were followed up for 12 months and monitored for total perception of pain using the visual analogue scale (VAS), with data obtained in baseline and at three weeks, six weeks, three months, six months and one year after treatment. RESULTS: Mean VAS score before treatment was 6.96 +/- 0.87 for the steroid group and 6.41 +/- 0.83 for the dry-needling group (P value = 0.54). Steroid injection reduced VAS scores rapidly until three weeks after treatment compared with dry needling (0.32 +/- 0.71 and 3.47 +/- 1.32, respectively; P value < 0.001). However, patients who were underwent dry needling reported lower VAS scores at the end of follow-up compared with the steroid group (0.69 +/- 0.93 and 2.09 +/- 1.58, respectively; P value = 0.004). Over the long term, 82.3% and 17.6% of changes in pain were contributed to time since treatment and treatment method, respectively (P values < 0.001). CONCLUSIONS: Steroid injection can palliate plantar heel pain rapidly but dry needling can provide more satisfactory results for patients with plantar fasciitis in the long term. PMID- 29119297 TI - Pyoderma gangrenosum after orthopaedic or traumatologic surgery: a systematic revue of the literature. AB - INTRODUCTION: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised by a painful ulceration mimicking infection of the operative site. To this day, there is still no general agreement on the medical and surgical treatment of PG. This systematic review of the literature aims to summarise recent studies about post-operative PG in orthopaedic surgery to improve its medical and surgical management. METHOD: In April 2017, we carried out an exhaustive review of the literature in MEDLINE, PubMed and Cochrane databases. Key words were pyoderma gangrenosum, orthopaedic surgery, and surgical wound infection. We identified 183 articles. After excluding articles reporting idiopathic PG, cases secondary to non-orthopaedic surgery, and cases about other subtypes of dermatosis, 30 studies were identified. We only included articles reporting PG after orthopaedic or trauma surgery. RESULTS: Thirty-one cases of PG have been reported, 58% (18) of which were in women, whose mean age was 56.5 years. Clinical signs were constant, the most frequently affected site was lower limbs [77.4% (24)] and delay of symptom onset was two to 17 days. Systemic corticosteroid therapy was systematic, polyvalent immunoglobulins were used in two cases and immunosuppressive drugs in one. Negative pressure therapy was used in seven cases and hyperbaric oxygen in three. DISCUSSION: Delayed diagnosis leads to one or more surgical revisions, which could have been avoided by using early and adapted medical treatment. Early onset of a painful and infected ulcer at the operating site in a patient at risk of PG is an indicator that dermatologist advice is recommended before surgical debridement. Surgical revision, outside the inflammatory phase and/or covered by a systemic corticosteroid therapy, does not lead to PG relapse. LEVEL OF EVIDENCE: IV: Systematic revue of the literature. PMID- 29119298 TI - Locking plates versus intramedullary nails in the management of displaced proximal humeral fractures: a systematic review and meta-analysis. AB - PURPOSE: To compare the clinical outcome and complications of locking plates versus intramedullary nails in patients with displaced proximal humeral fractures. Our hypothesis was that there would be no difference between these two implants with regard to clinical outcome and complications. METHODS: We performed a systemic review of PubMed, EMBASE, Clinical Trials Registry, Cochrane Central Register of Controlled Trials and Google Scholar to identify all relevant randomized controlled trials, prospective and retrospective comparative studies on April 26, 2017. The studies of locking plates compared to intramedullary nails in patients with displaced proximal humeral fractures were included. We conducted a meta-analysis of shoulder functional scores, range of motion, pain scores, and complications. RESULTS: This meta-analysis included 13 comparative studies with 958 patients (529 in the locking plate group and 429 in the intramedullary nail group). A significantly greater external rotation (MD = 9.67; 95% CI, 4.22-15.12; P = 0.0005) and a significantly higher penetration rate (RR = 1.75; 95% CI, 1.11 2.77; P = 0.02) were observed in the locking plate group compared with the intramedullary nail group. Constant-Murley scores, DASH scores and total complication rate were comparable between the two groups. Moreover, there were no significant differences in forward elevation, VAS scores, and other complications. CONCLUSIONS: Current evidence indicates that locking plates and intramedullary nails have similar performance in terms of the functional scores and total complication rate. No superior treatment was suggested between locking plates and intramedullary nails for displaced proximal humeral fractures. PMID- 29119299 TI - Enrolment of children in psychosocial care: problems upon entry, care received, and outcomes achieved. AB - Psychosocial care systems have been designed so that specific problems are treated by specific care types. There is insufficient evidence as to which problem types are actually presented to the various care types. This study assessed types and severity of problems among children and adolescents upon enrolment in psychosocial care, compared to children not enrolled; also outcomes after 3 and 12 months, overall and per care type. We obtained data on a cohort of 1382 Dutch children aged 4-18 years (response rate 56.6%), included upon enrolment in psychosocial care, and on 443 not-enrolled children (response rate 70.3%), all from one region. Results showed that enrolled children had more problems than children not enrolled in care. In child and adolescent mental healthcare (CAMH), relatively many children had internalizing problems, and in child and adolescent social care (CASC) relatively many children had externalizing, parenting, family and multiple problems. Regardless of the type of problem, care duration in preventive child healthcare (PCH) was relatively short; and in CASC and CAMH longer. After 3 and 12 months, rates of problem solution were highest in PCH. These rates were also substantial among children not in care. To conclude, our findings show that the system of psychosocial care functions as intended regarding the distribution of problems across care types. Extended demarcation of clients by problem type and severity towards type and contents of care may further improve the system. PMID- 29119300 TI - Longitudinal outcomes of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). AB - Little is known about the natural history of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). This study prospectively followed 33 children with PANDAS for up to 4.8 years (mean 3.3 +/- 0.7 years) after enrollment in a 24-week randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin (IVIG) (N = 35). Fourteen of eighteen children randomized to placebo received open label IVIG 6 weeks after the blinded infusion, so follow-up results reported below largely reflect outcomes in a population of children who received at least one dose of IVIG. Telephone interviews with the parents of participants found that at the time of phone follow-up, 29 (88%) were not experiencing clinically significant obsessive compulsive symptoms. During the interim period (6-57 months after entering the clinical trial), 24 (72%) had experienced at least one exacerbation of PANDAS symptoms, with a median of one exacerbation per child (range 1-12; interquartile range 0-3). A variety of treatment modalities, including antibiotics, IVIG, psychiatric medications, cognitive behavioral therapy, and others, were used to treat these exacerbations, and were often used in combination. The outcomes of this cohort are better than those previously reported for childhood-onset OCD, which may support conceptualization of PANDAS as a subacute illness similar to Sydenham chorea. However, some children developed a chronic course of illness, highlighting the need for research that identifies specific symptoms or biomarkers that can be used to predict the longitudinal course of symptoms in PANDAS. PMID- 29119301 TI - Whole body vibration added to treatment as usual is effective in adolescents with depression: a partly randomized, three-armed clinical trial in inpatients. AB - There is growing evidence for the effectiveness of exercise in the treatment of adult major depression. With regard to adolescents, clinical trials are scarce. Due to the inherent symptoms of depression (lack of energy, low motivation to exercise), endurance training forms could be too demanding especially in the first weeks of treatment. We hypothesized that an easy-to-perform passive muscular training on a whole body vibration (WBV) device has equal anti depressive effects compared to a cardiovascular training, both administered as add-ons to treatment as usual (TAU). Secondly, we presumed that both exercise interventions would be superior in their response, compared to TAU. In 2 years 64 medication-naive depressed inpatients aged 13-18, were included. Both exercise groups fulfilled a supervised vigorous training for 6 weeks. Depressive symptoms were assessed by self-report ("Depressions Inventar fur Kinder und Jugendliche" DIKJ) before intervention and after weeks 6, 14 and 26. Compared to TAU, both groups responded earlier and more strongly measured by DIKJ scores, showing a trend for the WBV group after week 6 (p = 0.082). The decrease became statistically significant for both intervention groups after week 26 (p = 0.037 for ergometer and p = 0.042 for WBV). Remission rates amounted to 39.7% after week 6 and 66% after week 26, compared to 25% after week 26 in TAU. These results provide qualified support for the effectiveness of exercise as add-on treatment for medication-naive depressed adolescents. The present results are limited by the not randomized control group. PMID- 29119302 TI - Goldfish, Carassius auratus, as an infection model for studying the pathogenesis of Edwardsiella piscicida. AB - This study demonstrates the feasibility of using goldfish as an infection model to investigate the pathogenesis of Edwardsiella piscicida. Goldfish were found to be susceptible to acute E. piscicida-induced disease and died in a dose-dependent manner. E. piscicida was further shown to replicate rapidly in the head kidneys and livers of infected goldfish from 1 d post-injection, and bacteria numbers were significantly decreased 5 d post-injection. Immune responses were successfully induced in goldfish injected with E. piscicida strains and 60% of goldfish inoculated with an attenuated E. piscicida strain were found to survive subsequent injection with a pathogenic strain. The results of differential leukocyte count experiments suggested that leukocytes were immediately recruited as an innate immune response against the infection. Thus, this well-characterized goldfish species is a suitable infection model for studying E. piscicida pathogenesis, and might be applicable to research on other fish diseases. PMID- 29119303 TI - Evolution of drug-resistant mutations in HBV genomes in patients with treatment failure during the past seven years (2010-2016). AB - The objective of this study was to analyze the prevalence of drug-resistant HBV mutants in patients with treatment failure during the past seven years (2010 2016). 4055 HBV-infected patients who underwent HBV polymerase gene mutation test from 2010 to 2016 were enrolled. The nucleos(t)ide analogues (NAs) resistance mutation positions, including rtL180, rtA181, rtT184, rtS202, rtM204, rtI233, rtN236, rtI169, rtV173, and rtM250 were analyzed. Genotypic resistance mutations were detected in 30.8% (1248/4055) of the patients with treatment failure. Rates of drug-resistant mutations associated with LAM, ADV, ETV, and multidrug were 27.23% (1104/4055), 9.67% (392/4055), 3.69% (150/4055), and 0.79% (32/4055). Among the primary NA-resistant mutations, rtM204I (13.44%, 545/4055) occurred more frequently, followed by rtM204V, rtN236T, rtA181T, and rtA181V. For single base mutations, rtL180M and rtA181V increased gradually during the past seven years, while rtM204I/V and rtN236T decreased after 2015. The development of drug resistant mutations positively correlated with the consumption of ETV (r = 0.964, P = 0.002), and weakly correlated with that of LAM (r = 0.679, P = 0.109) and ADV (r = 0.429, P = 0.354). Moreover, single-base mutation rtA181V and multi-base mutations (rtL180M + M204I and rtL180M + M204V + M204I) were more common in HBV genotype C than those in genotype B (1.94% vs. 0.66%, 1.84% vs. 0.16%, 1.02% vs. 0.16%, respectively). NA-related mutations in HBV RT region increased in the past seven years, especially for LAM. Frequencies of rtL180M and rtA181T/V increased gradually in the past seven years, to which we should pay more attention. PMID- 29119304 TI - Is thrombocytosis always an indicator of autosplenectomy in patients with systemic lupus erythematosus? AB - In systemic lupus erythematosus (SLE), the most commonly encountered finding related to platelets is thrombocytopenia whereas thrombocytosis is rarely reported. Our aim here was to reveal the type and the frequency of thrombocytosis in SLE patients along with its causes. Data of patients were evaluated retrospectively. Patients who had a platelet count of > 450,000/mm3 (> 450 * 109/L) in at least two subsequent counts and lasting more than 6 months during the follow-up were considered to have "persistent thrombocytosis". Peripheral smear results of patients with thrombocytosis were analyzed, and spleen imaging was performed for autosplenectomy/hyposplenism to patients with persistent thrombocytosis. A total of 205 patients with SLE were included in the study [196 (95.6%) female, mean age 41.5 years]. Out of 12 patients (5.9%) with thrombocytosis, 9 (4.3%) had transient thrombocytosis and 3 patients (1.4%) had persistent thrombocytosis. Of those with transient thrombocytosis, 5 were associated with iron deficiency anemia (IDA), 2 to polyarthritis, and the remaining 2 to digital ischemia and/or cutaneous vasculitis. Of three patients with persistent thrombocytosis, one was identified to have had splenectomy due to resistant immune thrombocytopenic purpura, and the other two (0.9%) patients had autosplenectomy. The only independent risk factor for the development of thrombocytosis was the presence of cutaneous vasculitis (OR 10.79 (95% CI 2.14 54.47), p = 0.0004). During the course of SLE, frequency of thrombocytosis is similar to that of the general population and the most common cause is reactive thrombocytosis. If the thrombocytosis was persistent, rheumatologist must consider that the patient may have autosplenectomy/asplenia/hyposplenism. PMID- 29119305 TI - The Development and Psychometric Properties of the Immigration Law Concerns Scale (ILCS) for HIV Testing. AB - To develop, pilot test, and conduct psychometric analyses of an innovative scale measuring the influence of perceived immigration laws on Latino migrants' HIV testing behavior. The Immigration Law Concerns Scale (ILCS) was developed in three phases: Phase 1 involved a review of law and literature, generation of scale items, consultation with project advisors, and subsequent revision of the scale. Phase 2 involved systematic translation- back translation and consensus based editorial processes conducted by members of a bilingual and multi-national study team. In Phase 3, 339 sexually active, HIV-negative Spanish-speaking, non citizen Latino migrant adults (both documented and undocumented) completed the scale via audio computer-assisted self-interview. The psychometric properties of the scale were tested with exploratory factor analysis and estimates of reliability coefficients were generated. Bivariate correlations were conducted to test the discriminant and predictive validity of identified factors. Exploratory factor analysis revealed a three-factor, 17-item scale. subscale reliability ranged from 0.72 to 0.79. There were significant associations between the ILCS and the HIV-testing behaviors of participants. Results of the pilot test and psychometric analysis of the ILCS are promising. The scale is reliable and significantly associated with the HIV-testing behaviors of participants. Subscales related to unwanted government attention and concerns about meeting moral character requirements should be refined. PMID- 29119306 TI - Interventions Aimed at Decreasing Obesity in Hispanic Children in the First 1000 Days: A Systematic Review. AB - The prevalence of obesity is higher among Hispanic children than among all other ethnicities, and recent efforts have been focused on addressing this growing disparity. The objective of this review was to examine the evidence for interventions designed to reduce obesity in Hispanic children in the first 1000 days of life and to assess and summarize the effectiveness of the interventions. A literature search was conducted using MEDLINE, Scopus, and PubMed. Included in the review were published studies that evaluated an intervention designed to prevent or reduce obesity in Hispanic children in the first 1000 days of life. Quality was assessed using the GRADE system. Out of 134 citations that were retrieved, 11 articles underwent full-text review, and 5 articles met study inclusion criteria. Only one study was of high quality, and the rest were of low or moderate quality. Three of the studies were lifestyle interventions, and two were educational interventions. Four out of the five interventions led to significant improvements in the outcome measures assessed. Very few published studies tested interventions in the population of Hispanic children ages 0-2 years. Limited evidence does suggest that these interventions may improve behaviors related to factors known to increase the risk for obesity. Future research should focus on designing interventions using common themes observed among successful studies. Further, these studies should also include clinical measures of obesity to further establish their effectiveness. PMID- 29119307 TI - Essential oils of Varronia curassavica accessions have different activity against white spot disease in freshwater fish. AB - The aim of this study was to evaluate the antiprotozoal activity of essential oils from Varronia curassavica accessions against different stages of Ichthyophthirius multifiliis. Essential oils from each accession were tested in vitro at the concentrations 0, 10, 25, 50, 75, 100, and 200 mg/L. The VCUR-001, VCUR-202, VCUR-509, and VCUR-601 accessions presented the major compounds alpha pinene, germacrene D-4-ol, (E)-caryophyllene and epiglobulol, and sabinene, respectively. These isolated compounds were tested in vitro at a concentration proportional to that found in the essential oil which caused 100% mortality of the parasite. The concentrations of 10 and 50 mg/L of the essential oil of accession VCUR-202 provided 100% mortality of trophonts and tomonts, respectively. For the accession VCUR-509, 100% mortality of trophonts and tomonts was observed at concentrations 75 and 200 mg/L of essential oil, respectively. The same mortality was observed at concentration 200 mg/L in both stages of the parasite for the other accessions. The major compounds alpha-pinene, sabinene, and the (E)-caryophyllene + epiglobulol mixture caused 100% mortality of trophonts and tomonts. The in vivo assay for white spot disease control was performed in a therapeutic bath of 1 h with the essential oil of accession VCUR 202 at concentrations of 0.5 and 2.0 mg/L. A significant reduction of about 30% of trophonts on infected fish was observed, independent of the oil concentration. The V. curassavica essential oil, especially the VCUR-202 accession, is a potential source of raw material for the formulation and commercialization of bioproducts to control freshwater white spot disease in fish. PMID- 29119309 TI - Localization and transport of indole-3-acetic acid during somatic embryogenesis in Coffea canephora. AB - Auxin and polar auxin transport have been implicated in controlling zygotic embryo development, but less is known about their role in the development of somatic embryos. The aim of this study was to determine if indole-3-acetic acid (IAA) and the PIN1 transporter participate in the induction of somatic embryogenesis (SE) and the development of somatic embryos. The results show that IAA levels gradually increase during pre-treatment and accumulate in the chloroplast. During pre-treatment and the globular stage of SE in C. canephora, auxin is distributed uniformly in all of the cells of the somatic embryo. During the subsequent stages of development, auxins are mobilized to the cells that will form the cotyledons and the root meristem. The location of the PIN transporters shifts from the plasmalemma of the protoderm cells during the globular stage to the plasmalemma of the cells that will give rise to the cotyledons and the vascular tissue in the late stages of somatic embryogenesis. The incubation of the explants in the presence of 2,3,5-triiodobenzoic acid (TIBA) produced aberrant somatic embryos, suggesting that PIN1 mediates the transport of IAA. PMID- 29119308 TI - Cryptic species Anopheles daciae (Diptera: Culicidae) found in the Czech Republic and Slovakia. AB - We report the distribution of mosquitoes of the maculipennis complex in two distinct areas of the Czech Republic (Bohemia and South Moravia) and in one locality of neighbouring Slovakia with emphasis on the detection of the newly described cryptic species Anopheles daciae (Linton, Nicolescu & Harbach, 2004). A total of 691 mosquitoes were analysed using a species-specific multiplex PCR assay to differentiate between the members of the maculipennis complex. In the Czech Republic, we found Anopheles maculipennis (with a prevalence rate of 1.4%), Anopheles messeae (49.0%) and Anopheles daciae (49.6%). In Slovakia, only An. messeae (52.1%) and An. daciae (47.9%) were detected. In this study, An. daciae was documented for the first time in the two countries where it represented a markedly higher proportion of maculipennis complex species (with an overall prevalence almost reaching 50%) in comparison to previous reports from Germany, Romania and Poland. The determination of the differential distribution of maculipennis complex species will contribute to assessing risks of mosquito-borne diseases such as malaria or dirofilariasis. PMID- 29119310 TI - On the regional variability of averaged cell area estimates for the human corneal endothelium in relation to the extent of polymegethism. AB - PURPOSE: To assess variability in the coefficient of variation (COV) in cell area estimates when using different numbers of cells for endothelial morphometry. METHODS: Using non-contact specular microscopy images of the corneal endothelium, 4 sets of 20 cases were selected that included 200 cells and had overall (global) COV values of less than 30 (group 1), 31-40 (group 2), 41-50 (group 3) and over 50% (group 4). Subjects could be normal, or had ophthalmic disease (such as diabetes), a history of rigid or soft contact lens wear or were assessed after cataract surgery. A step-wise analysis was undertaken, 20 cells at a time, of the variability in cell area estimates when using different numbers of cells for the calculations. RESULTS: Variability in the average cell area values was higher if only 20-60 cells were used in the calculations and then tended to decrease. The standard deviation values on these average cell area values and the calculated COV showed the same overall trends and were more than twice as large for endothelia with marked polymegethism. Using more than 100 cells/image in markedly polymegethous endothelia only increased the variability in the calculations. CONCLUSIONS: These analyses indicate that substantial region variability in cell area values can be expected in polymegethous endothelia. The analysis further confirm that using only small numbers of cells (e.g. less than 50/image) in such cases is likely to yield far less reliable estimates of COV. PMID- 29119311 TI - Cortical Processing of Level Cues for Spatial Hearing is Impaired in Children with Prelingual Deafness Despite Early Bilateral Access to Sound. AB - Bilateral cochlear implantation aims to restore binaural hearing, important for spatial hearing, to children who are deaf. Improvements over unilateral implant use are attributed largely to the detection of interaural level differences (ILDs) but emerging evidence of impaired sound localization and binaural fusion suggest that these binaural cues are abnormally coded by the auditory system. We used multichannel electroencephalography (EEG) to assess cortical responses to ILDs in two groups: 13 children who received early bilateral cochlear implants (CIs) simultaneously, known to protect the developing auditory cortices from unilaterally driven reorganization, and 15 age matched peers with normal hearing. EEG source analyses indicated a dominance of right auditory cortex in both groups. Expected reductions in activity to ipsilaterally weighted ILDs were evident in the right hemisphere of children with normal hearing. By contrast, cortical activity in children with CIs showed: (1) limited ILD sensitivity in either cortical hemisphere, (2) limited correlation with reliable behavioral right-left lateralization of ILDs (in 10/12 CI users), and (3) deficits in parieto-occipital areas and the cerebellum. Thus, expected cortical ILD coding develops with normal hearing but is affected by developmental deafness despite early and simultaneous bilateral implantation. Findings suggest that impoverished fidelity of ILDs in independently functioning CIs may be impeding development of cortical ILD sensitivity in children who are deaf but do not altogether limit benefits of listening with bilateral CIs. Future efforts to provide consistent/accurate ILDs through auditory prostheses including CIs could improve binaural hearing for children with hearing loss. PMID- 29119313 TI - The Effect of Emotional State on the Processing of Morphosyntactic and Semantic Reversal Anomalies in Japanese: Evidence from Event-Related Brain Potentials. AB - The present study examined the locus responsible for the effect of emotional state on sentence processing in healthy native speakers of Japanese, using event related brain potentials. The participants were induced into a happy, neutral, or sad mood and then subjected to electroencephalogram recording during which emotionally neutral sentences, including grammatical sentences (e.g. window-NOM close vi, 'The window closes.'), morphosyntactically-violated sentences (e.g. window-ACC close vi, Lit. 'Close the window.'), and semantically-reversed sentences (e.g. window-NOM close vt, 'The window closes pro.') were presented. The results of the ERP experiment demonstrated that while the P600 effect elicited by morphosyntactic violation was not modulated by mood, the P600 effect elicited by semantic reversal anomaly was observed only in participants previously induced into a happy mood. The LAN and N400 were not sensitive to the participants' transient emotional state. These results suggest intact memory access and impaired integration of syntactic and semantic information in individuals in a sad mood. PMID- 29119314 TI - Trait-specific long-term consequences of genomic selection in beef cattle. AB - Simulation studies allow addressing consequences of selection schemes, helping to identify effective strategies to enable genetic gain and maintain genetic diversity. The aim of this study was to evaluate the long-term impact of genomic selection (GS) in genetic progress and genetic diversity of beef cattle. Forward in-time simulation generated a population with pattern of linkage disequilibrium close to that previously reported for real beef cattle populations. Different scenarios of GS and traditional pedigree-based BLUP (PBLUP) selection were simulated for 15 generations, mimicking selection for female reproduction and meat quality. For GS scenarios, an alternative selection criterion was simulated (wGBLUP), intended to enhance long-term gains by attributing more weight to favorable alleles with low frequency. GS allowed genetic progress up to 40% greater than PBLUP, for female reproduction and meat quality. The alternative criterion wGBLUP did not increase long-term response, although allowed reducing inbreeding rates and loss of favorable alleles. The results suggest that GS outperforms PBLUP when the selected trait is under less polygenic background and that attributing more weight to low-frequency favorable alleles can reduce inbreeding rates and loss of favorable alleles in GS. PMID- 29119315 TI - Size-dependent Catalysis of Chlorovirus Population Growth by A Messy Feeding Predator. AB - Many chloroviruses replicate in endosymbiotic zoochlorellae that are protected from infection by their symbiotic host. To reach the high virus concentrations that often occur in natural systems, a mechanism is needed to release zoochlorellae from their hosts. We demonstrate that the ciliate predator Didinium nasutum foraging on zoochlorellae-bearing Paramecium bursaria can release live zoochlorellae from the ruptured prey cell that can then be infected by chloroviruses. The catalysis process is very effective, yielding roughly 95% of the theoretical infectious virus yield as determined by sonication of P. bursaria. Chlorovirus activation is more effective with smaller Didinia, as larger Didinia typically consume entire P. bursaria cells without rupturing them, precluding the release of zoochlorellae. We also show that the timing of Chlorovirus growth is tightly linked to the predator-prey cycle between Didinium and Paramecium, with the most rapid increase in chloroviruses temporally linked to the peak foraging rate of Didinium, supporting the idea that predator-prey cycles can drive cycles of Chlorovirus abundance. PMID- 29119312 TI - When signalling goes wrong: pathogenic variants in structural and signalling proteins causing cardiomyopathies. AB - Cardiomyopathies are a diverse group of cardiac disorders with distinct phenotypes, depending on the proteins and pathways affected. A substantial proportion of cardiomyopathies are inherited and those will be the focus of this review article. With the wide application of high-throughput sequencing in the practice of clinical genetics, the roles of novel genes in cardiomyopathies are recognised. Here, we focus on a subgroup of cardiomyopathy genes [TTN, FHL1, CSRP3, FLNC and PLN, coding for Titin, Four and a Half LIM domain 1, Muscle LIM Protein, Filamin C and Phospholamban, respectively], which, despite their diverse biological functions, all have important signalling functions in the heart, suggesting that disturbances in signalling networks can contribute to cardiomyopathies. PMID- 29119316 TI - Accessing the Hidden Microbial Diversity of Aphids: an Illustration of How Culture-Dependent Methods Can Be Used to Decipher the Insect Microbiota. AB - Microorganism communities that live inside insects can play critical roles in host development, nutrition, immunity, physiology, and behavior. Over the past decade, high-throughput sequencing reveals the extraordinary microbial diversity associated with various insect species and provides information independent of our ability to culture these microbes. However, their cultivation in the laboratory remains crucial for a deep understanding of their physiology and the roles they play in host insects. Aphids are insects that received specific attention because of their ability to form symbiotic associations with a wide range of endosymbionts that are considered as the core microbiome of these sap feeding insects. But, if the functional diversity of obligate and facultative endosymbionts has been extensively studied in aphids, the diversity of gut symbionts and other associated microorganisms received limited consideration. Herein, we present a culture-dependent method that allowed us to successfully isolate microorganisms from several aphid species. The isolated microorganisms were assigned to 24 bacterial genera from the Actinobacteria, Firmicutes, and Proteobacteria phyla and three fungal genera from the Ascomycota and Basidiomycota phyla. In our study, we succeeded in isolating already described bacteria found associated to aphids (e.g., the facultative symbiont Serratia symbiotica), as well as microorganisms that have never been described in aphids before. By unraveling a microbial community that so far has been ignored, our study expands our current knowledge on the microbial diversity associated with aphids and illustrates how fast and simple culture-dependent approaches can be applied to insects in order to capture their diverse microbiota members. PMID- 29119317 TI - Prodigiosin, Violacein, and Volatile Organic Compounds Produced by Widespread Cutaneous Bacteria of Amphibians Can Inhibit Two Batrachochytrium Fungal Pathogens. AB - Symbiotic bacteria can produce secondary metabolites and volatile compounds that contribute to amphibian skin defense. Some of these symbionts have been used as probiotics to treat or prevent the emerging disease chytridiomycosis. We examined 20 amphibian cutaneous bacteria for the production of prodigiosin or violacein, brightly colored defense compounds that pigment the bacteria and have characteristic spectroscopic properties making them readily detectable, and evaluated the antifungal activity of these compounds. We detected violacein from all six isolates of Janthinobacterium lividum on frogs from the USA, Switzerland, and on captive frogs originally from Panama. We detected prodigiosin from five isolates of Serratia plymuthica or S. marcescens, but not from four isolates of S. fonticola or S. liquefaciens. All J. lividum isolates produced violacein when visibly purple, while prodigiosin was only detected on visibly red Serratia isolates. When applied to cultures of chytrid fungi Batrachochytrium dendrobatidis (Bd) and B. salamandrivorans (Bsal), prodigiosin caused significant growth inhibition, with minimal inhibitory concentrations (MIC) of 10 and 50 MUM, respectively. Violacein showed a MIC of 15 MUM against both fungi and was slightly more active against Bsal than Bd at lower concentrations. Although neither violacein nor prodigiosin showed aerosol activity and is not considered a volatile organic compound (VOC), J. lividum and several Serratia isolates did produce antifungal VOCs. White Serratia isolates with undetectable prodigiosin levels could still inhibit Bd growth indicating additional antifungal compounds in their chemical arsenals. Similarly, J. lividum can produce antifungal compounds such as indole-3-carboxaldehyde in addition to violacein, and isolates are not always purple, or turn purple under certain growth conditions. When Serratia isolates were grown in the presence of cell-free supernatant (CFS) from the fungi, CFS from Bd inhibited growth of the prodigiosin-producing isolates, perhaps indicative of an evolutionary arms race; Bsal CFS did not inhibit bacterial growth. In contrast, growth of one J. lividum isolate was facilitated by CFS from both fungi. Isolates that grow and continue to produce antifungal compounds in the presence of pathogens may represent promising probiotics for amphibians infected or at risk of chytridiomycosis. In a global analysis, 89% of tested Serratia isolates and 82% of J. lividum isolates were capable of inhibiting Bd and these have been reported from anurans and caudates from five continents, indicating their widespread distribution and potential for host benefit. PMID- 29119319 TI - Olfactory stimulation may promote oral feeding in immature newborn: a randomized controlled trial. AB - Premature newborns have an increased mortality and morbidity due to respiratory immaturity and inefficient oral feeding performance. Transient assistance with feeding tubes until oral performance improves is required with consequent hospital admission. Based on a controlled and randomized study, we tested whether olfactory stimulation compared to odorless stimulation could accelerate the switch from feeding tube to satisfactory oral feeding. Fifty newborns were included and randomly assigned to either odorless or olfactory stimulation with anise or cinnamon. The main outcome measurement was the duration of the hospital stay. The odor-stimulated group could be discharged from hospital on average 3.4 days earlier than the control group (p = 0.12). When including only more mature newborns into the analysis (n = 39), the difference was statistically significant (p < 0.05). This trend emphasizes that olfaction may have its place in early feeding stimulation. PMID- 29119318 TI - Global oral health status of athletes with intellectual disabilities. AB - BACKGROUND: The aim of this study is to identify the oral health status and treatment needs of Special Olympics athletes with intellectual disabilities from 181 countries by the assessment of oral health parameters and differences between world regions. MATERIAL AND METHODS: Data were collected through interview and oral examinations within the Healthy Athletes Screening. These data were analysed with descriptive statistics of oral health parameters of athletes from Africa, Asia Pacific, East Asia, Europe/Eurasia, Latin America, Middle East North Africa (MENA) and North America. Mean differences of untreated visible dental caries, gingival signs and missing teeth were tested between regions by one-way ANOVA test and between age groups (8-11, 12-18, 19-39 and 40+) by chi-square tests for multiple comparisons with Hochberg-adjusted p value. The level of significance for all tests was set at a p value < 0.05. RESULTS: A total of 149,272 athletes with intellectual disabilities were screened. More than 80% of the athletes reported that they cleaned their mouths at least once a day. Athletes in Europe/Eurasia, Latin America, and MENA presented higher rates of signs of gingival disease than other regions. The prevalence of untreated dental caries was significantly higher in Latin America and the group of 8-11-year-olds from Latin America, Europe/Eurasia and Asia Pacific. CONCLUSIONS: The data provided by this study demonstrate that continuous efforts for preventive and restorative oral health care are needed for the oral health of these athletes with ID especially in Latin America, MENA and Europe/Eurasia regions. PMID- 29119320 TI - Total or subtotal glossectomy with laryngeal preservation: a national study of 29 patients. AB - Total glossectomy remains a controversial procedure as it often leads to notorious sequalae in swallowing and speaking functions. Disease entities indicating total glossectomy tend to have poor prognosis. We evaluated whether this type of surgery can be concidered justified based on our national series. We reviewed all total and subtotal glossectomies with laryngeal preservation performed in Finland between 2005 and 2014 in terms of overall survival (OS), disease-specific survival (DSS), locoregional control (LRC), and functional outcome as assessed by gastric tube or tracheostomy dependence and ability to produce intelligible speech. Of the 29 eligible patients, 15 had undergone total and 14 subtotal glossectomy with curative intent. In eight patients, total/subtotal glossectomy was performed as salvage procedure after the previous treatment. One-year estimates for OS, DSS, and LRC were 48, 59, and 66%, and corresponding 3-year estimates were 31, 46, and 46%, respectively. The gastrostomy and tracheostomy dependence rates at 1 year after operation were 77 and 15%, respectively. Fifty-nine percent of the patients were assessed to be able to communicate verbally. As in most other published studies, we found unsatisfactory survival figures after subtotal or total glossectomy and most patients remained dependent on gastrostomy tube. This surgery is, however, presumably the best and often only chance for cure in a selective patient population, and according to our opinion, it is indicated as a primary or salvage treatment provided that the reconstruction is planned optimally to guarantee a reasonable quality of life after surgery. PMID- 29119323 TI - Optimization of Bacillus subtilis natto growth parameters in glycerol-based medium for vitamin K (Menaquinone-7) production in biofilm reactors. AB - Menaquinone-7 (MK-7) is the key form of vitamin K used as a dietary supplement and its production revolves around Bacillus subtilis natto. Current fermentation strategies, which suggest static fermentations without aeration and agitation, can be problematic for large scale MK-7 production due to biofilm formation. The use of biofilm reactors, therefore, is proposed in the present study, which could utilize both agitation and aeration without interrupting MK-7 secretion. In this study, biofilm reactors were constructed using the selected plastic composite support (PCS) and B. subtilis natto strain for MK-7 production. Using response surface methodology (RSM), optimum growth parameters including temperature, pH, and agitation were determined in a glycerol-based medium. Results were presented in a statistical model (R 2 = 0.90), leading to optimum growth conditions of temperature (35 degrees C), agitation (200 rpm) and pH (6.58). Model-predicted MK-7 concentration was validated and MK-7 concentration of 12.09 mg/L was produced in the biofilm reactor. The obtained concentration was 58% higher as compared to the suspended-cell culture (7.67 mg/L). The results of this study will provide a critical step towards improved industrial scale production of MK 7. PMID- 29119322 TI - Studies on the scale-up of biomass production with Scenedesmus spp. in flat-plate gas-lift photobioreactors. AB - Microalgae are flagged as next-generation biomass feedstock for sustainable chemicals and fuels, because they actively metabolize the climate gas CO2, do not impact food production, and are not associated with land-use change. Scaling microalgae cultivation processes from lab to pilot scale is key to assessing their economic and ecologic viability. In this work, process performances of two different Scenedesmus species were studied using a 300 L flat-plate gas-lift photobioreactor system (14 m2 photosynthetically active area) equipped with a customized, broad-spectrum LED illumination system. Scaling up of batch processes from laboratory scale (1.8 L, 0.09 m2) to the geometrically equivalent pilot scale resulted in reduced volumetric biomass productivities of up to 11% and reduced areal biomass productivities of up to 7.5% at the pilot scale. Since biofilm formation was solely detected at pilot scale, biofilm most likely impaired scalability. Nevertheless, repeated addition of nutrients (BG-11) at pilot scale resulted in a 13.5 gCDW L-1 biomass concentration within a 15 day process time with S. obtusiusculus at constant incident-photon flux densities of 1400 umol photons m-2 s-1 and more than 19.5 gCDW L1 after 30 days with Scenedesmus ovalternus SAG 52.80 at constant incident-photon flux densities of 750 umol photons m-2 s-1. This resulted in areal biomass productivities of 14 gCDW m-2 day-1 (S. ovalternus) and 19 gCDW m-2 day-1 (S. obtusiusculus), respectively. PMID- 29119321 TI - Conservative treatment for advanced T3-T4 laryngeal cancer: meta-analysis of key oncological outcomes. AB - GOAL: Controversies exist regarding the treatment of advanced laryngeal carcinomas. The purpose of this systematic review was to evaluate the oncologic outcomes of both transoral laser and open partial laryngectomies for advanced (T3 T4) squamous cell laryngeal cancers management. INTRODUCTION: A systematic review of literature was led searching for articles mentioning the following terms: advanced (T3-T4) laryngeal cancer AND laser; AND open partial laryngectomy; AND transoral laser microsurgery; AND cordectomy; AND conservative surgery; AND tracheohyoidopexy or tracheohyoidoepiglottopexy; AND supratracheal partial laryngectomy; AND supracricoid partial laryngectomy; AND cricohyoidopexy or cricohyoidoepiglottopexy. Then a quantitative analysis was carried on papers published after 1980. DISCUSSION: The search identified 110 publications, and a total of 21 articles satisfied inclusion criteria and were selected for quantitative synthesis. 10 out of 21 studies had a good quality score, 10 were fair and only one rated a poor score. The pooled disease-free survival (DFS) was 79% (95% CI 74-85), and pooled overall survival (OS) was 71% (95% CI 64-78) at 5 years from all 1921 patients included in the study, with significant heterogeneity (I 2 = 89.7% and I 2 = 90.4%), respectively. Significant heterogeneity value (p = 0.118) was seen by comparing transoral laser and open partial laryngectomies in terms of DFS. CONCLUSION: The two surgical techniques are both valid conservative surgical options for advanced laryngeal cancer treatment. PMID- 29119324 TI - Image windowing mitigates edge effects in Differential Dynamic Microscopy. AB - Differential Dynamic Microscopy (DDM) analyzes traditional real-space microscope images to extract information on sample dynamics in a way akin to light scattering, by decomposing each image in a sequence into Fourier modes, and evaluating their time correlation properties. DDM has been applied in a number of soft-matter and colloidal systems. However, objects observed to move out of the microscope's captured field of view, intersecting the edges of the acquired images, can introduce spurious but significant errors in the subsequent analysis. Here we show that application of a spatial windowing filter to images in a sequence before they enter the standard DDM analysis can reduce these artifacts substantially. Moreover, windowing can increase significantly the accessible range of wave vectors probed by DDM, and may further yield unexpected information, such as the size polydispersity of a colloidal suspension. PMID- 29119325 TI - Major Mental Illness in Those Who Sexually Abuse. AB - PURPOSE OF REVIEW: There is evidence showing an increasing prevalence of mental illness in those in conflict with the law. However, there are many factors affecting the detection, treatment, and management of criminals who are mentally ill. RECENT FINDINGS: Sex offenders with major mental illness present many challenges to those providing treatment and management services. For example, it is important to consider whether sexually offensive behavior is the cause of criminal behavior or whether it is reflective of an antisocial orientation. Recent evidence suggests it may help better understand and inform risk assessment and management. This paper will review the literature on mental illness among sexual offenders, present a typology to aid in the assessment, treatment, and management of sexual offender with mental illness, and highlight important considerations when providing treatment to sexual offenders with mental illness. PMID- 29119327 TI - Pattern of protein expression in the epididymis of Oligoryzomys nigripes (Cricetidae, Sigmodontinae). AB - In the epididymis, epithelial cells work in a concerted manner to create a luminal environment for sperm maturation, transport, and storage. However, the cell functions may be affected by anthropogenic factors, causing negative impacts on male fertility. In our study, we describe the pattern of protein expression in the epithelium and luminal fluid from epididymis of Oligoryzomys nigripes, a South American sigmodontine rodent whose reproductive biology has been little studied. Nine animals were captured from a preserved area of Atlantic Forest, where the exposure to anthropogenic influences is minimal. Epididymides were processed for histological analysis under light and epifluorescence microscopy, in which we used cell-specific markers aquaporin 9 (AQP9), vacuolar H+-ATPase (V ATPase), and cytokeratin 5 (KRT5). Other samples were assessed for protein expression using shotgun proteomics. Similar to laboratory rodents, principal cells expressed AQP9 in their stereocilia. Basal cells, identified by KRT5 labeling, presented lateral body projections and a few axiopodia going toward the lumen. Clear cells expressed V-ATPase in their sub-apical vesicles and microplicae, and showed different shapes along the duct. Shotgun proteomics detected 51 proteins from epididymal supernatant. Most of them have been previously described in other species, indicating that they are well conserved. Twenty-three proteins detected in O. nigripes have not been described in epididymis from other South American sigmodontine rodents, confirming that the secretion pattern is species-specific. Our findings in O. nigripes from a protected area may help to create a baseline for studies investigating the effects of anthropogenic factors on functionality of the epididymal epithelium. PMID- 29119326 TI - Neurodegeneration and the ordered assembly of alpha-synuclein. AB - In 2017, it was 200 years since James Parkinson published 'An Essay on the Shaking Palsy' and 20 years since alpha-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here, we describe the work that led to the identification of alpha-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies. We also review some of the findings reported since 1997. PMID- 29119328 TI - Endoplasmic Reticulum Stress and Allergic Diseases. AB - PURPOSE OF REVIEW: In this review, we will integrate recent knowledge on endoplasmic reticulum (ER) stress and allergy, thereby highlighting the therapeutic potential of ER stress in the context of precision medicine for allergic diseases. RECENT FINDINGS: Emerging evidence suggests that allergic diseases are very heterogeneous having numerous endotypes. This leads to the new era of modern medicine, which assumes that a particular endotype-driven therapy, called precision medicine, would be more efficacious in a specific group of patients rather than in all patients. Currently, a dichotomy involving type 2/non type 2 immune response underlies most of the studies on inflammatory and immunologic mechanisms of allergic disorders. Whereas there are several approved or investigational endotype-driven therapeutic agents targeting type 2 immune responses, investigation of mechanisms and endotype-driven interventions regarding non-type 2 immune response lags far behind. Considering that non-type 2 immune response may represent a significant proportion of allergic disease, particularly corticosteroid-resistant severe disease, defining a novel concept of endotype-driven approach may be essential. Recently, stress responses originate from the endoplasmic reticulum (ER) and the associated inflammatory molecular platform has been suggested as a crucial player of immune and inflammatory responses. This implies that ER stress-related pathways may represent a new endotype-driven therapeutic strategy in the treatment of allergic diseases. PMID- 29119329 TI - A functional assessment of anatomical variants of the recurrent laryngeal nerve during thyroidectomies using neuromonitoring. AB - PURPOSE: The aim of the study was to assess the usefulness of intraoperative neuromonitoring (IONM) in identifying anatomical variants of the recurrent laryngeal nerve (RLN) during thyroidectomies, with emphasis on the nerve's relationship to the inferior thyroid artery (ITA), Zuckerkandl's tubercle, nonrecurrent laryngeal nerves (NRLNs), and extralaryngeal bifurcation. METHODS: A total of 128 subjects undergoing surgery for thyroid disorders were enrolled in the study, and the course and anatomical variants of RLN were assessed with IONM application. RESULTS: The standard relationship between RLN and ITA was that the artery and nerve intersect (100%). The right RLN was below the ITA in 76.67% of the patients, and the left RNL was below it in 75.81%. There were no statistically significant differences in the relationship between RLN and ITA on the two sides; and gender did not significantly influence the relationship between the RLN and ITA on either side. In one patient a nonrecurrent inferior laryngeal nerve was present on the right side (0.83%). RLN bifurcation was observed in 33.33% of the patients on the right and in 19.35% on the left side; the difference between sides was statistically significant (p < 0.05). Posterior tubercle (Zuckerkandl's tubercle) was observed on the right in 83% of the subjects and on the left in 69%. The age, thyroid volume and body mass index (BMI) did not influence the size of the tumor. CONCLUSIONS: The utilization of IONM of the RLN in thyroid surgery adds a new dimension to the standard of visual nerve identification allowing for functional nerve testing at the most vulnerable area of the dissection: at the level of Berry's ligament, posterior tubercle (Zuckerkandl's tubercle) and crossing of the RLN with the inferior thyroid artery. PMID- 29119330 TI - Analysis of factors controlling sediment phosphorus flux potential of wetlands in Hulun Buir grassland by principal component and path analysis method. AB - Phosphorus (P) flux potential can predict the trend of phosphorus release from wetland sediments to water and provide scientific parameters for further monitoring and management for phosphorus flux from wetland sediments to overlying water. Many studies have focused on factors affecting sediment P flux potential in sediment-water interface, but rarely on the relationship among these factors. In the present study, experiment on sediment P flux potential in sediment-water interface was conducted in six wetlands in Hulun Buir grassland, China and the relationships among sediment P flux potential in sediment-water interface, sediment physical properties, and sediment chemical characteristics were examined. Principal component analysis and path analysis were used to discuss these data in correlation coefficient, direct, and indirect effects on sediment P flux potential in sediment-water interface. Results indicated that the major factors affecting sediment P flux potential in sediment-water interface were amount of organophosphate-degradation bacterium in sediment, Ca-P content, and total phosphorus concentrations. The factors of direct influence sediment P flux potential were sediment Ca-P content, Olsen-P content, SOC content, and sediment Al-P content. The indirect influence sediment P flux potential in sediment-water interface was sediment Olsen-P content, sediment SOC content, sediment Ca-P content, and sediment Al-P content. And the standard multiple regression describing the relationship between sediment P flux potential in sediment-water interface and its major effect factors was Y = 5.849 - 1.025X 1 - 1.995X 2 + 0.188X 3 - 0.282X 4 (r = 0.9298, p < 0.01, n = 96), where Y is sediment P flux potential in sediment-water interface, X 1 is sediment Ca-P content, X 2 is sediment Olsen-P content, X 3 is sediment SOC content, and X 4 is sediment Al-P content. Therefore, future research will focus on these sediment properties to analyze the interrelation among sediment properties factors, main vegetable factors, and environment factors which influence the sediment P flux potential in sediment-water interface. PMID- 29119331 TI - Intestinal amino acid and peptide transporters in broiler are modulated by dietary amino acids and protein. AB - This study evaluated the effect of three levels of digestible amino acids (DAA; 100, 107 and 114% of Cobb recommendations) on mRNA abundance of peptide (PepT1) and amino acid (AA) transporters in 480-day-old broilers during prestarter period. Jejunal mRNA levels of the PepT1 and b0,+AT increased as DAA level increased from 100 to 114%. The expression of CAT1 mRNA in the jejunum was higher in birds fed 100% DAA diet. The transport systems B0AT and y+LAT1 were not affected by the dietary treatments. These results demonstrated that dietary content of protein and DAA differentially affected the expression of intestinal peptide and AA transporters to modulate absorption of peptide and AA in broilers. PMID- 29119332 TI - Therapeutic Effect of Vinorine on Sciatic Nerve Injured Rat. AB - Vinorine is a monoterpenoid indole alkaloid, a type of natural alkaloids. Growing reports exhibited the numerous pharmacology activities of vinorine such as anti inflammation, anti-bacterial and anti-tumor. In this study, the effect of vinorine injection (7.5, 15 and 30 mg/kg) on motor function, sensation and nerve regeneration in sciatic nerve crush injury rat was investigated. The results of behavioral analysis, electrophysiological analysis and muscle histological analysis suggested that vinorine promoted the motor function recovery after sciatic nerve injury. The results of mechanical withdrawal thresholds assay and hot plate test demonstrated that vinorine improved the sensation recovery after sciatic nerve injury. The results of Fluoro-gold retrograde labeling, transmission electron microscope assay, toluidine blue and HE staining showed that vinorine attenuated the nerve damage caused by sciatic nerve injury and promoted the nerve regeneration. Furthermore, nerve growth factor (NGF) and its downstream extracellular signal-regulated kinase (ERK) signaling pathway participated in the neuro-recovery effect of vinorine after crush. In conclusion, vinorine treatment accelerated the sciatic nerve regeneration, motor function recovery and sensation recovery after crush injury via regulation of NGF and ERK activity. These results suggested that vinorine is a promising agent for never injury therapy. PMID- 29119334 TI - Percutaneous endoscopic lumbar discectomy for high-grade down-migrated disc using a trans-facet process and pedicle-complex approach: a technical case series. AB - PURPOSE: The use of conventional percutaneous endoscopic lumbar discectomy (PELD) for high-grade down-migrated lumbar disc herniation medial to the pedicle via the transforaminal route can result in less favorable outcomes. We report a new PELD technique for the treatment of high-grade down-migrated lumbar disc herniation via a facet process and pedicle-complex approach. METHODS: Three patients with high-grade down-migrated L3-4 and L4-5 disc herniation presented to our hospital. Each underwent PELD via a facet process and pedicle complex approach to remove the herniated fragment and achieve complete decompression of the nerve root. RESULTS: Patients' symptoms were relieved. Postoperative magnetic resonance imaging showed root decompression. Follow-up 12-month computed tomography revealed no pedicle or facet fracture and healing of the pedicle complex and facet process bone tunnel. CONCLUSION: PELD via a facet process and pedicle complex approach may be an option for high-grade, down-migrated lumbar disc herniation with completely sequestrated nucleus pulposus. PMID- 29119333 TI - Physiologically Based Pharmacokinetic Modelling of Cytochrome P450 2C9-Related Tolbutamide Drug Interactions with Sulfaphenazole and Tasisulam. AB - BACKGROUND AND OBJECTIVES: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80-90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug-drug interactions (DDIs). This paper describes the development and verification of SimCYP(r)-based PBPK models that accurately describe the human pharmacokinetics of tolbutamide when dosed alone or in combination with the CYP2C9 inhibitors sulfaphenazole and tasisulam. METHODS: A PBPK model was optimized in SimCYP(r) for tolbutamide as a CYP2C9 substrate, based on published in vitro and clinical data. This model was verified to replicate the magnitude of DDI reported with sulfaphenazole and was further applied to simulate the DDI with tasisulam, a small molecule investigated for the treatment of cancer. A clinical study (CT registration # NCT01185548) was conducted in patients with cancer to assess the pharmacokinetic interaction of tasisulum with tolbutamide. A PBPK model was built for tasisulam, and the clinical study design was replicated using the optimized tolbutamide model. RESULTS: The optimized tolbutamide model accurately predicted the magnitude of tolbutamide AUC increase (5.3-6.2-fold) reported for sulfaphenazole. Furthermore, the PBPK simulations in a healthy volunteer population adequately predicted the increase in plasma exposure of tolbutamide in patients with cancer (predicted AUC ratio = 4.7-5.4; measured mean AUC ratio = 5.7). CONCLUSIONS: This optimized tolbutamide PBPK model was verified with two strong CYP2C9 inhibitors and can be applied to the prediction of CYP2C9 interactions for novel inhibitors. Furthermore, this work highlights the utility of mechanistic models in navigating the challenges in conducting clinical pharmacology studies in cancer patients. PMID- 29119335 TI - Unilateral vertebral artery injury in a patient with displaced upper cervical spine fractures: the treatment for one case of vertebral artery embolism. AB - PURPOSE: To report a novel treatment method for vertebral artery injury. Vertebral artery injuries may be caused during trauma by fracture and excessive motion with subluxation from C2 to C6 in spite of vertebral artery deeply seated and normally well protected inside the transverse foramen. Optimal medical management of the occluded vertebral artery has yet to be determined. METHODS: We report on a severely displaced C2-C3 fracture that was found to have a vertebral artery injury. Medical records and imaging were reviewed. RESULTS: A 50-year-old lady was hit by steel tube without loss of consciousness, but complaining of severe cervical and bilateral periscapular pain. Physical examination identified a neurologically intact patient with frontotemporal ecchymosis and posterior cervical tenderness. MRA and DSA showed an occluded left vertebral artery. After 3 days of observation, the patient showed no symptoms of brain ischemia or abnormal sensation and motor at four limbs. To ensure safety, we took the left vertebral artery embolism at the C2 and C5 levels before operation. CONCLUSIONS: To our knowledge, this is the first report of a displaced C2-C3 fracture in which transcatheter unilateral VAI embolization was used to prevent VAI bleeding during operation. PMID- 29119337 TI - Toxic metals in cigarettes and human health risk assessment associated with inhalation exposure. AB - This study evaluated the concentrations of cadmium (Cd), copper (Cu), iron (Fe), manganese (Mn), lead (Pb), and zinc (Zn) in 10 branded cigarettes commonly consumed in Nigeria. Chemical sequential extraction method and pseudo-total metal digestion procedure were used for extraction of metals from filler tobacco and filter samples. Samples were analyzed using flame atomic absorption spectrometry (FAAS). The filler tobacco of cigarettes had Cd, Cu, Fe, Mn, Pb, and Zn concentrations in the ranges of 5.90-7.94, 18.26-34.94, 192.61-3494.05, 44.67 297.69, 17.21-74.78, and 47.02-167.31 MUg/cigarette, respectively. The minimum and maximum concentrations in the filter samples were 8.67-12.34 MUg/g of Cd, 1.77-36.48 MUg/g of Cu, 1.83-15.27 MUg/g of Fe, 3.82-7.44 MUg/g of Mn, 4.09-13.78 MUg/g of Pb, and 30.07-46.70 MUg/g of Zn. The results of this study showed that the concentrations of heavy metals in the filler tobacco samples were consistently higher than those obtained for the cigarette filters except for Cd. Toxic metals were largely found in the most labile chemical fractions. Moderate to very high risks are found associated with potential exposure to Cd and Pb. The carcinogenic risks posed by Cd and Pb ranged between 1.87E-02 and 2.52E-02, 1.05E 03 and 4.76E-03, respectively, while the non-carcinogenic risk estimates for Cd and Pb were greater than 1.0 (HI > 1). Toxic metals in cigarette may have significant carcinogenic and non-carcinogenic health effects associated with inhalation exposure. Continuous monitoring and regulations of the ingredients of imported and locally produced tobacco products are advocated. PMID- 29119336 TI - Bariatric Surgery as an Efficient Treatment for Non-Alcoholic Fatty Liver Disease in a Prospective Study with 1-Year Follow-up : BariScan Study. AB - BACKGROUND: Bariatric surgery gains attention as a potential treatment for non alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate improvement of NAFLD after the two most common bariatric procedures with validated non-invasive instruments. MATERIAL AND METHODS: N = 100 patients scheduled for laparoscopic sleeve gastrectomy (LSG) or Roux-en-Y gastric bypass (RYGB) were included. NAFLD was evaluated preoperatively and postoperatively with liver stiffness measurement by transient elastography and laboratory-based fibrosis scores. Clinical data included body mass index (BMI), total weight loss (%TWL), excess weight loss (%EWL), age, gender, comorbidities, and the Edmonton obesity staging system (EOSS). RESULTS: There were significant improvements of BMI, %TWL, %EWL, and EOSS after bariatric surgery. Liver stiffness was significantly improved from pre- to postoperative (12.9 +/- 10.4 vs. 7.1 +/- 3.7 kPa, p < 0.001) at median follow-up of 12.5 months. Additionally, there were significant improvements of liver fibrosis scores (aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio 0.8 +/- 0.3 vs. 1.1 +/- 0.4, p < 0.001; NAFLD fibrosis score - 1.0 +/- 1.8 vs. - 1.7 +/- 1.3, p < 0.001; APRI score 0.3 +/- 0.2 vs. 0.3 +/- 0.1, p = 0.009; BARD score 2.3 +/- 1.2 vs. 2.8 +/- 1.1, p = 0.008) and laboratory parameters (ALT, AST, and GGT). After adjustment for baseline liver stiffness, RYGB showed higher improvements than LSG, and there was no gender difference. Improvement of liver stiffness was not correlated to improvement of BMI, %TWL, %EWL, or EOSS. CONCLUSIONS: NAFLD seems to be improved by bariatric surgery as measured by validated non-invasive instruments. Furthermore, it appears that RYGB is more effective than LSG. No correlation could be detected between NAFLD and weight loss. The present study highlights the potential of bariatric surgery for successful treatment of NAFLD. Further research is required to understand the exact mechanisms. PMID- 29119338 TI - Elevated Levels of ADMA Are Associated with Lower DDAH2 and Higher PRMT1 in LPS Induced Endometritis Rats. AB - Chronic endometritis is a continuous inflammation of uterine endometrium. Recent research has shown that higher asymmetric dimethylarginine (ADMA) levels contribute to endothelial dysfunction. In the present study, we tested whether there is a correlation between endometritis and ADMA in LPS-induced endometritis rat and the mechanisms involved. Thirty-six rats were divided into two groups: blank control group and rat model of endometritis group. The entire infused uterus were removed to observe the changes of histopathology, production of myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) 6, 8-isoprostane, and reactive oxygen species (ROS), and gene expression of dimethylarginine dimethylaminohydrolase 2 (DDAH2), protein-methyl transferase 1 (PRMT1), TNF-alpha, and IL-6. In endometritis rat group, characteristic histopathologic changes in uteri were observed. The uterine 8-isoprostane, ROS, MPO activity, IL-6 and TNF-alpha concentrations, PRMT1, IL-6, and TNF-alpha expressions were significantly elevated, and DDAH2 expression was notably reduced in endometritis group compared with control group. The present findings suggest that elevated levels of ADMA are associated with lower DDAH2 and higher PRMT1 in LPS-induced endometritis rat. PMID- 29119340 TI - Correction to: Charge Splitting In Situ Recorder (CSIR) for Real-Time Examination of Plasma Charging Effect in FinFET BEOL Processes. AB - CORRECTION: In the original publication [1] Fig. 3 was presented incorrect. The correct additional file has been included with this erratum and the original article has been updated to rectify this error. PMID- 29119339 TI - The prostate cancer screening clinic in the Bahamas: a model for low- and middle income countries. AB - PURPOSE: Grand Bahama (pop. 51,000) is an island within the Bahamas archipelago. A local chapter of International Us TOO Prostate Cancer Support Group (UTGB) has led an annual community-based prostate cancer screening clinic in Grand Bahama each September since 2009. Features of this initiative, characteristics of attendees, and a description of found cancers were summarized to determine the clinic's value and to guide improvements. METHOD: We analyzed the established clinic from 2012 to 2015, wherein UTGB attracted corporate funding, volunteers managed clinics, and health professionals provided healthcare services. An explicit algorithm was used to sort clients by age, comorbidities, and findings from digital rectal examinations, and prostate-specific antigen (PSA) values, to determine which clients would undergo secondary assessment and prostate biopsy. RESULTS: Overall, 1,844 males were registered (mean age 57.6 years), and only 149 men attended on more than one occasion for a total of 1,993 clinic visit. The urologist reviewed 315 men in secondary follow-up, for elevated PSA and/or an abnormal digital rectal examination. Of these, 45 men fulfilled criteria for trans-rectal ultrasound biopsy, and there were 40 found cases of prostate cancer, for a positive-predictive value of 89%. By D'Amico risk-stratification, these 40 cases were low (10%), intermediate (40%), and high risk (50%). The urologist counseled all 40 cases and facilitated access to standard care. CONCLUSION: This study suggests that low-resource countries can advance cost-effective screening clinics, apply policy guidelines, and provide services within acceptable standards of care. It is the expectation, with a sustained effort and community participation over the ensuing years, that earlier disease presentation will occur and, consequently, a concomitant decrease in the disease-specific mortality. PMID- 29119341 TI - Labyrinth. PMID- 29119342 TI - Last Two Inches. PMID- 29119345 TI - Impaired Face Perception in Individuals with Autism Spectrum Disorder: Insights on Diagnosis and Treatment. PMID- 29119343 TI - Long-term Survivors of Childhood Brain Tumors: Impact on General Health and Quality of Life. AB - PURPOSE OF REVIEW: We review and summarize the key issues affecting general health and quality of life (QOL) of pediatric long-term survivors of brain tumors. RECENT FINDINGS: Long-term survivors of brain tumors are at risk of considerable late morbidity and mortality. Lengthening survival in brain tumors has highlighted the deep impact of tumor and its treatment on the physical, psychological, functional, and social health and QOL of these survivors. Evolution in tumor therapy including surgery, radiotherapy, and systemic therapies, etc., has the potential to mitigate this impact to some extent. Sensitization of health staff, policy makers, and the primary designers of clinical trials towards integration of QOL end points while measuring survival in brain tumor patients is the need of the hour. New developments in tumor therapeutics must not only provide quantitative gain but also improve the quality of survival in these long-term survivors. While majority of the issues presented pertain to survivorship in pediatric brain tumor population, similar challenges are likely to exist in young adults surviving brain tumors as well. PMID- 29119346 TI - Structure, target-specificity and expression of PN_LNC_N13, a long non-coding RNA differentially expressed in apomictic and sexual Paspalum notatum. AB - KEY MESSAGE: ncRNA PN_LNC_N13 shows contrasting expression in reproductive organs of sexual and apomictic Paspalum notatum genotypes. Apomictic plants set genetically maternal seeds whose embryos derive by parthenogenesis from unreduced egg cells, giving rise to clonal offspring. Several Paspalum notatum apomixis related genes were identified in prior work by comparative transcriptome analyses. Here, one of these candidates (namely N13) was characterized. N13 belongs to a Paspalum gene family including 30-60 members, of which at least eight are expressed at moderate levels in florets. The sequences of these genes show no functional ORFs, but include segments of different protein coding genes. Particularly, N13 shows partial identity to maize gene BT068773 (RESPONSE REGULATOR 6). Secondary structure predictions as well as mature miRNA and target cleavage detection suggested that N13 is not a miRNA precursor. Moreover, N13 family members produce abundant 24-nucleotide small RNAs along extensive parts of their sequences. Surveys in the GREENC and CANTATA databases indicated similarity with plant long non-coding RNAs (lncRNAs) involved in splicing regulation; consequently, N13 was renamed as PN_LNC_N13. The Paspalum BT068773 predicted ortholog (N13TAR) originates floral transcript variants shorter than the canonical maize isoform and with possible structural differences between the apomictic and sexual types. PN_LNC_N13 is expressed only in apomictic plants and displays quantitative representation variation across reproductive developmental stages. However, PN_LNC_N13-like homologs and/or its derived sRNAs showed overall a higher representation in ovules of sexual plants at late premeiosis. Our results suggest the existence of a whole family of N13-like lncRNAs possibly involved in splicing regulation, with some members characterized by differential activity across reproductive types. PMID- 29119347 TI - N-glycan structures and downstream mannose-phosphorylation of plant recombinant human alpha-L-iduronidase: toward development of enzyme replacement therapy for mucopolysaccharidosis I. AB - KEY MESSAGE: Arabidopsis N-glycan processing mutants provide the basis for tailoring recombinant enzymes for use as replacement therapeutics to treat lysosomal storage diseases, including N-glycan mannose phosphorylation to ensure lysosomal trafficking and efficacy. Functional recombinant human alpha-L iduronidase (IDUA; EC 3.2.1.76) enzymes were generated in seeds of the Arabidopsis thaliana complex-glycan-deficient (cgl) C5 background, which is deficient in the activity of N-acetylglucosaminyl transferase I, and in seeds of the Arabidopsis gm1 mutant, which lacks Golgi alpha-mannosidase I (GM1) activity. Both strategies effectively prevented N-glycan maturation and the resultant N glycan structures on the consensus sites for N-glycosylation of the human enzyme revealed high-mannose N-glycans of predominantly Man5 (cgl-IDUA) or Man6-8 (gm1 IDUA) structures. Both forms of IDUA were equivalent with respect to their kinetic parameters characterized by cleavage of the artificial substrate 4 methylumbelliferyl-iduronide. Because recombinant lysosomal enzymes produced in plants require the addition of mannose-6-phosphate (M6P) in order to be suitable for lysosomal delivery in human cells, we characterized the two IDUA proteins for their amenability to downstream in vitro mannose phosphorylation mediated by a soluble form of the human phosphotransferase (UDP-GlcNAc: lysosomal enzyme N acetylglucosamine [GlcNAc]-1-phosphotransferase). Gm1-IDUA exhibited a slight advantage over the cgl-IDUA in the in vitro M6P-tagging process, with respect to having a better affinity (i.e. lower K m) for the soluble phosphotransferase. This may be due to the greater number of mannose residues comprising the high mannose N-glycans of gm1-IDUA. Our elite cgl- line produces IDUA at > 5.7% TSP (total soluble protein); screening of the gm1 lines showed a maximum yield of 1.5% TSP. Overall our findings demonstrate the relative advantages and disadvantages associated with the two platforms to create enzyme replacement therapeutics for lysosomal storage diseases. PMID- 29119348 TI - Implementing Evidence-Based Practices for Acute Stroke Care in Low- and Middle Income Countries. AB - PURPOSE OF REVIEW: Most strokes occur in low- and middle-income countries where resources to manage patients are limited. We explore the resources required to providing optimal acute stroke care and review barriers to implementing evidence based stroke care in settings with limited resources using the World Stroke Organization's Global Stroke Services Action Plan framework. RECENT FINDINGS: Major advances have been made during the past few decades in stroke prevention, treatment, and rehabilitation. These advances have been translated into practice in many high-income countries, but their uptake remains suboptimal in low- and middle-income countries. The review highlights the resources required to providing optimal acute stroke care in settings with limited resources. These resource levels were divided into minimal, essential, and advanced resources depending on the availability of stroke expertise, diagnostics, and facilities. Resources were described for the three stages of acute care: early diagnosis and management, acute management and prevention of complications, and early discharge and rehabilitation. Barriers to providing acute care at each of these stages in low- and middle-income countries are reviewed, explaining that some barriers persist in essential or advanced settings where some aspects of organized stroke units are available. PMID- 29119349 TI - Southern California neuroinvasive West Nile virus case series. AB - Approximately 80% of individuals infected with West Nile virus (WNV) are asymptomatic, and less than 1% suffer from neuroinvasion that can result in permanent neurological deficits or mortality. Our institution's location in southern California predisposes it to a sizable case volume of neuroinvasive WNV. A 2-year retrospective study was performed at the Olive View-UCLA Medical Center to identify patients with confirmed WNV infection with neuroinvasion. Patient demographics, neurological exam findings, and laboratory diagnostics were reviewed. Data were tabulated and are presented as percentage, mean +/- standard deviation, or median [range]. Twenty-two patients (36.4% female, age 50.2 +/- 10.6 years) were identified between 20 August 2012 and 24 September 2013. The most common positive findings on review of symptoms included fever (81.8%), nausea/vomiting (81.8%), and headache (68.2%). Thirteen patients (59.1%) presented with fever defined as >= 37.8 degrees C. Motor strength was reduced in nine patients (40.9%) and eight patients (36.4%) were hyporeflexive. Lumbar puncture was performed in all but three patients (cerebrospinal fluid [CSF] protein 76.8 +/- 29.6 mg/dL and glucose 71.0 +/- 18.8 mg/dL). Elevated CSF anti WNV IgM and IgG antibody was detected in 93.8% and 62.5% of the 16 tested cases, respectively. Elevated serum anti-WNV IgM and IgG antibody was detected in 100% and 72.2% of the 18 tested cases, respectively. Encephalitic presentations, with or without focal neurological deficits (e.g., motor weakness, hypotonia), dominated this series. In endemic areas, seasonal presentation of such symptoms should raise suspicion for WNV with neuroinvasion. PMID- 29119351 TI - Obituary: Toshio Fujita, QSAR pioneer. AB - This is the obituary for Toshio Fujita, pioneer of the quantitative structure activity relationship (QSAR) paradigm. PMID- 29119350 TI - Sustained high serum caspase-3 concentrations and mortality in septic patients. AB - Caspase-3 is the main executor of the apoptotic process. Higher serum caspase-3 concentrations in non-survivor compared to survivor septic patients have been found. The objectives of this work (with the increase of sample size to 308 patients, and the determination of serum caspase-3 concentrations also on days 4 and 8 of diagnosis of severe sepsis) were to know whether an association between serum caspase-3 concentrationss during the first week, degree of apoptosis, sepsis severity, and sepsis mortality exists. We collected serum samples of 308 patients with severe sepsis from eight intensive care units on days 1, 4 and 8 to measure concentrations of caspase-3 and caspase-cleaved cytokeratin (CCCK)-18 (to assess degree of apoptosis). End point was 30-day mortality. We found higher serum concentrations of caspase-3 and CCCK-18 in non-survivors compared to survivors on days 1 (p < 0.001), 4 (p < 0.001), and 8 (p < 0.001). We found an association between serum caspase-3 concentrations on days 1, 4 and 8 of severe sepsis diagnosis and serum CCCK-18 concentrations (p < 0.001), SOFA (p < 0.001), serum acid lactic concentrations (p < 0.001), and 30-day sepsis mortality (p < 0.001). The new findings of this work were that an association between serum caspase-3 concentrations during the first week, apoptosis degree, sepsis severity, and sepsis mortality exists. PMID- 29119353 TI - Impact of microinvasion on breast cancer mortality in women with ductal carcinoma in situ. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) is a neoplastic proliferation of epithelial cells which is confined within the basement membrane of the mammary ductal-lobular system. It is of interest to determine to what extent the potential to metastasize increases for DCIS patients when the basement membrane is breached (i.e. microinvasion is present). METHODS: We retrieved the records of 525,395 women who had either first primary DCIS or small (<= 2.0 cm) node negative invasive breast cancer in the Surveillance, Epidemiology and End Results (SEER) registries database (1990-2013). For each patient, we extracted information on year of diagnosis, age at diagnosis, tumour size, tumour grade, oestrogen receptor status, use of radiotherapy, type of surgery, cause of death and follow-up time. We classified patients into four groups, according to the size of the invasive component of the primary tumour. We estimated the actuarial rate of breast cancer-specific mortality at ten and 20 years for women in each size category. RESULTS: We identified 161,394 women with pure DCIS, 13,489 women with microinvasive carcinoma (<= 0.1 cm of invasion), 153,856 women with invasive cancer 0.2-1.0 cm in size and 196,656 women with invasive cancer 1.1-2.0 cm in size. The 20-year actuarial breast cancer-specific mortality rate was 3.8% for women with pure DCIS, was 6.9% for women with microinvasive carcinoma, was 6.8% for women with invasive cancer 0.2-1.0 cm in size and was 12.1% for women with invasive cancer 1.1-2.0 cm in size. The adjusted hazard ratio for death associated with microinvasive carcinoma (vs. pure DCIS) was 2.00 (95% CI 1.76 2.26; p < 0.0001). CONCLUSIONS: In terms of prognosis, microinvasive cancer more closely resembles small invasive cancer 0.2-1.0 cm) than pure DCIS. For invasive cancers under 1.0 cm, size has little impact on mortality. PMID- 29119352 TI - Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2. AB - Computer-aided drug design has become an integral part of drug discovery and development in the pharmaceutical and biotechnology industry, and is nowadays extensively used in the lead identification and lead optimization phases. The drug design data resource (D3R) organizes challenges against blinded experimental data to prospectively test computational methodologies as an opportunity for improved methods and algorithms to emerge. We participated in Grand Challenge 2 to predict the crystallographic poses of 36 Farnesoid X Receptor (FXR)-bound ligands and the relative binding affinities for two designated subsets of 18 and 15 FXR-bound ligands. Here, we present our methodology for pose and affinity predictions and its evaluation after the release of the experimental data. For predicting the crystallographic poses, we used docking and physics-based pose prediction methods guided by the binding poses of native ligands. For FXR ligands with known chemotypes in the PDB, we accurately predicted their binding modes, while for those with unknown chemotypes the predictions were more challenging. Our group ranked #1st (based on the median RMSD) out of 46 groups, which submitted complete entries for the binding pose prediction challenge. For the relative binding affinity prediction challenge, we performed free energy perturbation (FEP) calculations coupled with molecular dynamics (MD) simulations. FEP/MD calculations displayed a high success rate in identifying compounds with better or worse binding affinity than the reference (parent) compound. Our studies suggest that when ligands with chemical precedent are available in the literature, binding pose predictions using docking and physics-based methods are reliable; however, predictions are challenging for ligands with completely unknown chemotypes. We also show that FEP/MD calculations hold predictive value and can nowadays be used in a high throughput mode in a lead optimization project provided that crystal structures of sufficiently high quality are available. PMID- 29119354 TI - Characteristics and outcomes of breast cancer patients enrolled in the National Cancer Institute Cancer Therapy Evaluation Program sponsored phase I clinical trials. AB - PURPOSE: Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer-related death among women. Given the availability of approved therapies and abundance of phase II and III clinical trials, historically few BC patients have been referred for consideration of participation on a phase I trial. We were interested in determining whether clinical benefit rates differed in patients with BC from other patients enrolled in phase I trials. METHODS: We performed a retrospective analysis of all Cancer Therapy Evaluation Program (CTEP) sponsored phase I trials from 1993 to 2012. We report an analysis of demographic variables, rates of response to treatment, grade 4 toxicities, and treatment-related deaths. RESULTS: De-identified data from 8087 patients were analyzed, with 1,376 having a diagnosis of BC. The median time from initial cancer diagnosis to enrollment in a CTEP-sponsored phase I clinical trial was 614 days for all patients. Breast cancer patients were enrolled on average 790 days after initial diagnosis, while non-BC patients had a median enrollment time of 582 days (p < 0.001). Breast cancer patients had more clinical responses than non-BC patients (18.3% vs. 4.3%, respectively). Along with the higher rate of response, BC patients remained on phase I trials longer than non-BC patients with a median of 70 days while the latter were on trial for a median of 57 days. The overall rate of death related to the treatment drugs was 0.47%. CONCLUSIONS: Our data confirm our hypothesis that when compared to a general population of patients with cancer enrolled on phase I clinical trials, BC patients tend to derive clinical benefit from these therapies with similar toxicity profile. This evidence further supports enrollment of BC patients on phase I trials. PMID- 29119355 TI - Preparation of electrospun core-sheath yarn with enhanced bioproperties for biomedical materials. AB - OBJECTIVES: To create a multifunctional medical material that combines the advantages of both nanofibers and macroyarns. RESULTS: A novel electrospinning based approach was developed for creating polycaprolactone (PCL) nanofiber covered yarns (PCL-NCYs) in which polyglycolic acid multi-strand filaments (PGA MFs) were used as the core. BALB/3T3 (mouse embryonic fibroblast cell line) cells were cultured on the PCL-NCYs substrate and cell morphology and proliferation were determined by methylthiazol tetrazolium (MTT) assay. Compared with PGA-MFs, PCL-NCYs had a higher porosity and tensile strength of 88 +/- 8% and 348 +/- 16 MPa and in particular, the porosity was four times higher. BALB/3T3 cells attached more easily onto the nanofiber structure and proliferated along the direction of nanofibers, indicating that PCL-NCYs can achieve better cell differentiation and proliferation. CONCLUSIONS: PCL-NCYs can be created by combining electrospinning covering and textile twisting, and have better mechanical property and higher porosity, and can be used as a novel scaffold in tissue engineering. PMID- 29119357 TI - Citations and science. PMID- 29119356 TI - Test Performance Variation Between Settings and Populations. AB - The present paper is the third in a series on the evaluation of new tests designed to detect the disordered gambler. The present paper has two objectives. First, the observed variation in test performance between settings and populations is described in general terms and an explanation of the observed variation is presented in terms of what is referred to as spectrum effects. Second the expected variation in test performance between settings and populations is illustrated with several examples and the implications emphasized for the purpose of test evaluation. PMID- 29119358 TI - Hepatitis B, C and D virus genotypes detected in HBsAg- or anti-HCV-positive people from the Republic of Moldova. AB - In the Republic of Moldova, little is known about hepatitis B, C and D virus (HBV, HCV, HDV) genotypes, although the genetic variant may influence the course and outcome of disease. For HBV genotyping, 301 hepatitis B surface antigen (HBsAg)-positive sera collected in 2010 and 2011 from drug users, prison inmates, commercial sex workers, and the general population in different geographical regions were investigated. The 31 HBsAg-positive sera collected in 2011 were also tested for HDV. Eighty-eight anti-HCV-positive sera collected between 2010 and 2011 from the general population and health care workers were used for HCV genotyping. Phylogenetic analysis of 84 HBV sequences showed that most of the viruses belonged to genotype D (n = 82, 97.6%), predominantly to the subgenotype D1/D2 cluster (n = 75/82, 91.5%). One sequence (74110) clustered as an outlier to this cluster, and six sequences belonged to subgenotype D3. Only two subgenotype A2 sequences were found. Cloning of six samples with ambiguous sequence chromatogram signals showed no mixed infections. Phylogenetic analysis of HCV sequences from 66 patients showed a predominance of subtype 1b (n = 63, 95.5%). Two sequences belonged to subtype 3a, and one to subtype 2a. HDV RNA belonging to genotype 1 was found in two sera (2/31, 6.5%). Thus, genotypes prevalent in Europe were detected for all three hepatitis viruses. For both HBV and HCV, one genotype was dominant, while occasional other variants seem to be restricted to certain cohorts and/or transmission routes. PMID- 29119359 TI - Early HIV infection among persons referred for malaria parasite testing in Nigeria. AB - Persons in the early stages of HIV infection are the major drivers of new infections. These individuals may also develop renal dysfunctions at this time. Nigeria, as other African countries, has one of the highest prevalence of newly diagnosed HIV infections. Despite this, limited information exists on early HIV detection in the continent. This may be related to difficulties in providing early HIV diagnosis and treatment. Patients referred for malaria testing may provide a unique opportunity for early HIV detection. In this study, a method for identifying early HIV-infected individuals was assessed. HIV-1 subtype and renal function biomarkers were also analyzed in these persons. To identify early HIV infection, over a period of 18 months blood samples were collected from persons referred by clinicians for malaria parasite tests in Nigeria. A total of 671 samples were collected and analyzed for HIV antigen/antibody and subtypes. 101 of these samples were categorized into one of four groups: early HIV, chronic HIV, malaria infection and control groups for renal function analysis. 29% of HIV infected individuals were at the early stages of infection. The predominant subtype detected was CRF02_AG (57.14%). The early HIV group had the highest mean serum creatinine (95 umol/L) and urea (5.7 mmol/L) values across all groups with the difference significant at P < 0.05. There was no significant difference between the circulating subtype and the stage of HIV infection. Our results show the feasibility of screening persons referred for malaria tests for early HIV. This can be used to control new HIV infections in sub-Saharan Africa. PMID- 29119360 TI - Optimization of a magnetic capture RT-LAMP assay for fast and real-time detection of potato virus Y and differentiation of N and O serotypes. AB - Potato virus Y (PVY) infection has been a global challenge for potato production and the leading cause of downgrading and rejection of seed crops for certification. Accurate and timely diagnosis is a key for effective disease control. Here, we have optimized a reverse transcription loop-mediated amplification (RT-LAMP) assay to differentiate the PVY O and N serotypes. The RT LAMP assay is based on isothermal autocyclic strand displacement during DNA synthesis. The high specificity of this method relies heavily on the primer sets designed for the amplification of the targeted regions. We designed specific primer sets targeting a region within the coat protein gene that contains nucleotide signatures typical for O and N coat protein types, and these primers differ in their annealing temperature. Combining this assay with total RNA extraction by magnetic capture, we have established a highly sensitive, simplified and shortened RT-LAMP procedure as an alternative to conventional nucleic acid assays for diagnosis. This optimized procedure for virus detection may be used as a preliminary test for identifying the viral serotype prior to investing time and effort in multiplex RT-PCR tests when a specific strain is needed. PMID- 29119361 TI - Associated Factors of Self-Rated Mental Health Status in Southwestern Iran: Using SCAD Regression Model in a Population-Based Study. AB - This study aimed to investigate the association between self-rated mental health (SRMH) and current health status of an Iranian population. A cross-sectional study was conducted on 3400 individuals selected through random sampling in Shiraz, Iran between January 2014 and March 2015. Data were gathered through face to-face interviews. Statistical analyses were performed using the SPSS 19.0, and R.3.1.2 software was used for SCAD penalized logistic regression. The mean age of the participants was 38.5 (+/- 14.1 years). There were significant relationships between better SRMH and younger ages (p < 0.001), and between better SRMH and better self-rated physical health (p < 0.001). Individuals with poor SRMH were more likely to have signs and symptoms of medical diseases. SRMH, a component of self-rated health, was related to a variety of health problems in our study population. Therefore, paying attention to SRMH and mental well-being could be useful in making decision about implementation of preventive measures. PMID- 29119362 TI - Intergenerational Stability of Callous-Unemotional Traits. AB - This study investigated the stability of callous and unemotional (CU) traits across generations by assessing self-report assessments of psychopathy factors in parents and their relationship to children's CU traits in a clinical sample: 223 boys (M age = 7.65) and 83 girls (M = 7.35) referred for treatment of disruptive behavior disorders. First, we expanded previous findings showing a positive relationship between maternal psychopathy scores and CU traits in boys. Second, we tested whether parental psychopathy scores predicted CU traits in children over and above general indicators of mental health risk: parental psychopathology, parental warmth, and harsh parenting. Fathers' psychopathy factor 1 was uniquely related to CU traits. In contrast, the relationship between mothers' psychopathy factor 2 and children's CU traits disappeared when maternal warmth was included. Gender differences suggested these results are most applicable to boys. These findings support the intergenerational stability of psychopathy factor 1 between children and their fathers. PMID- 29119363 TI - The Effects of Visual Feedback Distortion with Unilateral Leg Loading on Gait Symmetry. AB - Our prior work provides evidence that visual feedback distortion drives an implicit adaptation; a gradual distortion of visual representation of step length modulated subjects' step lengths away from symmetry. To further explore the effect of the visual feedback distortion on unconscious change in step symmetry, we investigated whether such adaptation would occur even in the presence of altered limb mechanics by adding mass to one side of the leg. 26 subjects performed three 8-min trials (weight only, weight plus visual feedback, and weight plus visual feedback distortion) of treadmill walking. During the weight only trial, the subjects wore a 5 lb mass around the right ankle. The modification of limb inertia caused asymmetric gait. The visual feedback showing right and left step length information as bar graphs was displayed on a computer screen. To add visual feedback distortion, we increased the length of one side of the visual bars by 10% above the actual step length, and the visual distortion was implemented for the side that took longer in response to the added mass. We found that even when adjustments were made to unilateral loading, the subjects spontaneously changed their step symmetry in response to the visual distortion, which resulted in a more symmetric gait. This change may be characterized by sensory prediction errors, and our results suggest that visual feedback distortion has a significant impact on gait symmetry regardless of other conditions affecting limb mechanics. A rehabilitation program employing visual feedback distortion may provide an effective way to restore gait symmetry. PMID- 29119364 TI - Correction to: Diffusion coefficient in biomembrane critical pores. AB - The original version of this article unfortunately contained two mistakes. PMID- 29119365 TI - Pectin methylesterase inhibitor (PMEI) family can be related to male sterility in Chinese cabbage (Brassica rapa ssp. pekinensis). AB - Pectin-related genes play significant roles in pollen development and pollen tube growth, and their allelic variations are one of the major reasons for the abnormal development of male gametophyte. Currently, little is known about the role of the PMEI family in male sterility of plants. In this study, 97 putative PMEI genes were identified in Brassica rapa genome. By a phylogenetic analysis, the PMEI family was divided into 10 clades with highly conserved structural characteristics. The publically available RNA-seq data on different tissues of B. rapa accession Chiifu-401-42 revealed that 23 PMEI isoforms were flower-specific genes. We created a recessive genic male sterile mutant (ftms) in Chinese cabbage. This mutant was a doubled haploid line with stable inheritance, derived from Chinese cabbage 'FT' generated through a combination of radiation mutagenesis and isolated microspore culture. The transcriptome profiles of the floral buds of ftms and its wild-type line 'FT' were determined using RNA-seq. A total of 17 PMEI genes were found to be differentially expressed; all of them were down-regulated in ftms compared to their levels in 'FT'. Consistent with the transcriptome data, all these genes were observed to be highly expressed in the floral buds of 'FT' using qRT-PCR analysis. Of these, eight genes were specifically expressed in the floral buds of 'FT'; three of these (Bra019903, Bra014099, and Bra032239) were stamen-specific genes. The results contribute to further elucidation of the regulatory mechanisms underlying male sterility in Chinese cabbage. PMID- 29119368 TI - [Patient reported outcome measures in geriatric care: first experiences]. AB - BACKGROUND: There are difficulties in expressing the value of geriatric care in outcome measures such as recovery or mortality rates. Rather, the goal of geriatric care is to maintain quality of life and functionality. As such, patient reported outcome measures (PROMs) may be more effective in measuring the value healthcare creates in geriatric patients. In 2015 the Dutch Geriatrics Society asked their Committee Quality of Care Measurement to select a suitable PROM for the purpose of measuring the outcomes of geriatric hospital care. METHODS/RESULTS: The goal of this PROM is to measure outcomes of an hospital admission in the perspective of the elderly patient who was admitted to a geriatric ward. A group of caregivers in geriatric care identified four possible PROMs in the literature and based on selection criteria the TOPICS-MDS was chosen as most suitable. To increase the feasibility of implementation in daily practice, an item reduction study was performed and this resulted in a short form: TOPICS-SF. Two pilot studies in three hospitals took place on a geriatric ward. A response of 62% was observed during the first pilot with TOPICS-MDS and a response of 37% was observed during the second pilot with TOPICS-SF. The Katz-15 improved during hospital stay and during one month at home after discharge. CONCLUSION: The TOPICS-SF has been selected as PROM for the older patient receiving geriatric care and is feasible in practice. More research in different settings and with different moments of measurements is needed to evaluate the responsiveness of TOPICS-SF and the conditions for feasible implementation in daily practice. PMID- 29119366 TI - Fine-mapping and candidate gene analysis of the Brassica juncea white-flowered mutant Bjpc2 using the whole-genome resequencing. AB - Flower color in Brassica spp. is an important trait and considered a major visual signal for insect-pollinated plants. In previous study, we isolated and identified two genes (BjPC1 and BjPC2) that control the flower color in B. juncea, and mapped BjPC1 to a 0.13-cM region. In this study, we report the fine mapping and candidate analysis of BjPC2. We conducted whole-genome resequencing, using bulked segregant analysis (BSA) to determine the BjPC2 candidate intervals. Crossing, allelism testing, and repeated full-sib mating were used to generate XG3, a near isogenic line (NIL) population that segregated on the BjPC2 locus. Through a genome-wide comparison of single nucleotide polymorphism (SNP) profiles between the yellow- and white-flowered bulks, a candidate interval for BjPC2 was identified on chromosome B04 (2.45 Mb). The BjPC2 linkage map was constructed with the newly developed simple sequence repeat (SSR) markers in the candidate interval to narrow the candidate BjPC2 region to 31-kb. Expression profiling and RNA-seq analysis partially confirmed that the AtPES2 homolog, BjuB027334 is the most promising candidate gene for BjPC2. Furthermore, analyses with high pressure liquid chromatography and transmission electron microscopy demonstrated that BjPC2 might be important in xanthophyll esterification, a process that limits xanthophyll degradation and increases sequestration. Overall, we mapped the BjPC2 to a 31-kb region on the B04 in B. juncea and identified BjuB027334 as a valuable candidate gene. Our results provide a basis for understanding the molecular mechanisms underlying the white-flowered trait and for molecular marker-assisted selection of flower color in B. juncea breeding. PMID- 29119369 TI - Clinical Importance of Temporal Bone Features for the Efficacy of Contrast Enhanced Sonothrombolysis: a Retrospective Analysis of the NOR-SASS Trial. AB - Contrast-enhanced sonothrombolysis (CEST) seems to be a safe and promising treatment in acute ischemic stroke. It remains unknown if temporal bone features may influence the efficacy of CEST. We investigated the association between different temporal bone features on admission computed tomography (CT) scan and the outcome in acute ischemic stroke patients included in the randomized Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS). Patients diagnosed as stroke mimics and those with infratentorial stroke or with incorrect insonation were excluded. We retrospectively assessed temporal bone heterogeneity (presence of diploe), diploe ratio, thickness, and density on admission CT scans. National institute of Health Stroke Scale (NIHSS) at 24 h and modified Rankin Scale (mRS) at 3 months were correlated with CT findings both in CEST and sham CEST patients. A total of 99 patients were included of which 52 were assigned to CEST and 47 to sham CEST. Approximately 20% patients had a heterogeneous temporal bone in both the CEST and sham CEST group. All temporal bone CT features studied were associated with female sex. In the CEST group, temporal bone heterogeneity (p = 0.006) and higher temporal bone diploe ratio (p = 0.002) were associated with higher NIHSS at 24 h. There was no association between temporal bone features and mRS at 3 months. Approximately 20% of acute ischemic stroke patients have heterogeneous temporal bone and may be resistant to standard 2-MHz transcranial Doppler ultrasound treatment. Sonothrombolysis resistance may easily be predicted by admission CT for better selection. PMID- 29119370 TI - Vasoconstriction and Impairment of Neurovascular Coupling after Subarachnoid Hemorrhage: a Descriptive Analysis of Retinal Changes. AB - Impaired cerebral autoregulation and neurovascular coupling (NVC) contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Retinal vessel analysis (RVA) allows non-invasive assessment of vessel dimension and NVC hereby demonstrating a predictive value in the context of various neurovascular diseases. Using RVA as a translational approach, we aimed to assess the retinal vessels in patients with SAH. RVA was performed prospectively in 24 patients with acute SAH (group A: day 5-14), in 11 patients 3 months after ictus (group B: day 90 +/- 35), and in 35 age-matched healthy controls (group C). Data was acquired using a Retinal Vessel Analyzer (Imedos Systems UG, Jena) for examination of retinal vessel dimension and NVC using flicker-light excitation. Diameter of retinal vessels-central retinal arteriolar and venular equivalent-was significantly reduced in the acute phase (p < 0.001) with gradual improvement in group B (p < 0.05). Arterial NVC of group A was significantly impaired with diminished dilatation (p < 0.001) and reduced area under the curve (p < 0.01) when compared to group C. Group B showed persistent prolonged latency of arterial dilation (p < 0.05). Venous NVC was significantly delayed after SAH compared to group C (A p < 0.001; B p < 0.05). To our knowledge, this is the first clinical study to document retinal vasoconstriction and impairment of NVC in patients with SAH. Using non-invasive RVA as a translational approach, characteristic patterns of compromise were detected for the arterial and venous compartment of the neurovascular unit in a time-dependent fashion. Recruitment will continue to facilitate a correlation analysis with clinical course and outcome. PMID- 29119371 TI - Risk of revision and dislocation in single, dual mobility and large femoral head total hip arthroplasty: systematic review and network meta-analysis. AB - Postoperative dislocation is a challenging complication after total hip arthroplasty (THA) that affects patient outcome worldwide. Instability is one of the main complications with rates exceeding 20% in some series. Currently, alternative acetabular components are available with dual mobility (DMTHA) bearing surfaces and larger femoral head size that may reduce the risk of dislocation, yet provide the functional benefit of standard single mobility (STHA) bearing surface THA. However, whether STHA, big femoral head (BTHA) and DMTHA should be used is still controversial. This systematic review and meta analysis aim to compare postoperative dislocation and revision (aseptic loosening and infection) of BTHA, STHA and DMTHA in primary or revision THA. These clinical outcomes consist of postoperative dislocation and revision (aseptic loosening and infection). This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant studies were identified from Medline and Scopus from inception to June 8, 2017, that reported postoperative dislocation and revision (aseptic loosening and infection) of either implant THA. Eleven of 677 studies (nine comparative studies and two RCTs) (N = 4084 patients) were eligible; all 11 studies were included in pooling. Intervention included dual mobility THA (N = 1068 patients), standard THA (N = 2568 patients), big head THA (N = 378 patients) and constrain THA (N = 70 patients). A network meta-analysis showed that risk of revision and dislocation of DMTHA was significantly lower with RR of 2.19 (1.36, 3.53) and 4.19 (2.04, 8.62) when compared to STHA. While there was no statistically significant risk of having revision and dislocation of DMTHA when compared to BTHA and CTHA. The SUCRA probability of DM and BTHA was in the first and second rank with 46.5 and 44.8% in the risk of revision and 46.7 and 45.1% in the risk of dislocations. In short-term outcomes (5 years or less, with follow-up of 0-5 years), the best implant of choice that has lowest risk of revision and dislocation after THA is DMTHA follow by BTHA. We recommend using dual mobility and big head as an implant for safety in THA. However, there were only two studies that reported long-term survivorship (more than 5 years, with follow-up of 5-15 years). Further research that assesses long-term survivorship is necessary to further evaluate which implants are the best for THA. PMID- 29119372 TI - Anatomical considerations of C2 lamina for the placement of translaminar screw: a review of the literature. AB - PURPOSE: The thorough knowledge of C2 lamina anatomy is essential for the avoidance of complications during screw fixation. We performed a review of the literature, aiming to detect what was found about anatomical feasibility of C2 translaminar fixation in different populations, along with possible recommendations for the avoidance of complications, and to detect whether factors such as race or gender could influence axis lamina anatomy and fixation feasibility. METHODS: We performed a search in PubMed and Cochrane database of systematic reviews for studies which correlated axis lamina anatomy with fixation feasibility. We extracted data concerning measurements on C2 lamina, the methods and conclusions of the studies. RESULTS: Twenty-six studies met our inclusion criteria. The studies mainly focused on Asian populations. Male gender was generally related to larger anatomical parameters of C2 lamina. The use of a C2 translaminar screw with a diameter of 3.5 mm was generally feasible, even in children, but there was disagreement about risk of vertebral artery injury. Computed tomography was most frequently recommended preoperatively. Three dimensional reconstruction was suggested by some authors. CONCLUSION: C2 lamina anatomy generally permitted screw fixation in most studies, but there was disagreement about risk of vertebral artery injury. Preoperative computed tomography was generally recommended, while, according to some authors, three dimensional reconstruction could be essential. However, there is a relative lack of studies about non-Asian populations. More research could further illustrate the anatomy of C2 lamina, clarify the safety of axis fixation for more populations and perhaps modify preoperative imaging protocols. PMID- 29119373 TI - Additional value of systolic wall thickening in myocardial stunning evaluated by stress-rest gated perfusion SPECT. AB - AIM AND PATIENTS: The aim of the present study is to evaluate the additional value of systolic wall thickening to myocardial perfusion in diagnosing myocardial stunning in patients with angiography proven coronary artery disease. We selected 91 ischemic patients (82 males; mean age 59.7 +/- 10.3) with CAD documented by angiography. Ischemia was defined as a summed difference score >=5. All patients underwent a 2-day gated perfusion SPECT protocol. The patients received a dose of 740 MBq of 99mTc-tetrofosmin after stress and at rest. Treadmill maximal exercise tests were performed on all patients. RESULTS: The post-stress LVEF was significantly lower than rest LVEF (48.1% +/- 10.3% vs 50.3% +/- 10.7%; P = .0001). The wall thickening summed difference score was 4.44 +/- 4.13 (P = .0001). At a multivariate regression analysis, only WT-SDS as independent variable was significantly correlated with myocardial ischemia (SDS). We also divided patients according to SDS in those with mild (SDS < 8) and severe (SDS >= 8) ischemia. WT-SDS, but not ?LVEF, was significantly different between groups. CONCLUSIONS: WT-SDS, more than the depression in the global function (?LVEF) of the left ventricle, correlates with the degree of ischemia and better identifies, when present, the stunning phenomenon. PMID- 29119375 TI - The multiple fronts of conquering cancer. PMID- 29119374 TI - Review of cardiovascular imaging in the Journal of Nuclear Cardiology 2017. Part 1 of 2: Positron emission tomography, computed tomography, and magnetic resonance. AB - Several original articles and editorials have been published in the Journal of Nuclear Cardiology in 2017. It has become a tradition at the beginning of each year to summarize some of these key articles in 2 sister reviews. In this first part one, we will discuss some of the progress made in the field of heart failure (cardio-oncology, myocardial blood flow, viability, dyssynchrony, and risk stratification), inflammation, molecular and hybrid imaging using advancement in positron emission tomography, computed tomography, and magnetic resonance imaging. PMID- 29119376 TI - Regulatory effects of antitumor agent matrine on FOXO and PI3K-AKT pathway in castration-resistant prostate cancer cells. AB - We previously demonstrated that matrine could inhibit the proliferating, migrating, as well as invading processes of both PC-3 and DU145 cells. However, the underlying molecular mechanisms have not yet been clearly defined. In this study, using various techniques such as high throughput sequencing technology, bioinformatics, quantitative real-time PCR, and immunoblot analysis, we aimed to understand whether matrine serves as a novel regulator of FOXO and PI3K-AKT signaling pathway. DU145 and PC-3 cell lines were cultured for 24 h in vitro. Cells were treated with either matrine or control serum for 48 h, followed by extraction of total RNA. The RNA was sequenced using HiSeq 2500 high-throughput sequencing platform (Illumina). A gene library was established and quality analysis of read data carried out. Integrated database from the website DAVID was used to analyze Gene Ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway of differential genes was used for pathway analysis, screening for fold differences of more than two times. The FOXO and PI3K-AKT signaling pathways were screened, and expression levels of mRNA and core protein detected by real time PCR and immunoblotting, respectively. High throughput sequencing and GO analysis revealed that differentially expressed genes before and after treatment played an important role in cell metabolic process, growth process, anatomical structure formation, cellular component organization, and biological regulation. KEGG signal pathway analysis revealed that FOXO and PI3K-AKT signal pathways had a significant difference between before and after matrine-treated androgen independent prostate cancer cells PC-3 and DU145. Real-time PCR showed that matrine treatment led to a significant increase in the expression levels of FOXO1A, FOXO3A, FOXO4, and FOXO6 in DU145 and PC-3 cells (P<0.01 or P<0.05), whereas the PI3K expression levels decreased (P<0.01). Similarly, immunoblotting revealed a significant increase (P<0.05) in the expression levels of FOXO1A FOXO3A, FOXO4, and FOXO6 in both PC-3 and DU145 cells, whereas PI3K expression levels decreased (P<0.05). Matrine had a broad regulating effect on the mRNA expression profiles of both PC-3 and DU145 cells. Matrine may inhibit cell proliferation, migration, as well as invasion, and induce apoptosis in both PC-3 and DU145 cells through FOXO and PI3K-AKT signaling pathways. Matrine could therefore be used as a complementary drug to present chemotherapeutic agents, for treating androgen-independent prostate cancer. PMID- 29119377 TI - Meat retail conditions within the establishments of Kigali city (Rwanda): bacteriological quality and risk factors for Salmonella occurrence. AB - Meat constitutes one of the major vehicles for human foodborne infections. This study aimed to assess the retail conditions and to determine the microbiological quality and safety of meat retailed within the establishments of Kigali (Rwanda). A questionnaire survey was carried out in 150 retail outlets to characterise meat retail conditions. Additionally, 270 retail meat samples were analysed for the enumeration of hygiene indicator bacteria (total mesophilic bacteria and Escherichia coli) and for the qualitative detection of Salmonella, using conventional culture methods. The results revealed that beef was the predominant meat sold within the retail premises of Kigali city, while meat from non-bovine animal species was mainly sold in large establishments. Salmonella was detected in 19.6% of all the retailed meat samples evaluated, whereas the mean loads for total mesophilic bacteria and E. coli were 7.3 and 3.5 log cfu/g, respectively. Three factors, namely the temperature conditions of the meat under retail, the cleanability of the used meat cutting boards, and the training of personnel in hygienic meat handling practices, were found to be significantly (p <= 0.05) associated with the risk of Salmonella occurrence in the retailed meat. The findings from this study highlight the need for improvements in hygienic meat handling practices, particularly, in small and medium meat retail establishments in Kigali. PMID- 29119378 TI - Population genetic structure of Santa Ines sheep in Brazil. AB - This study aimed to describe the population genetic structure and evaluate the state of conservation of the genetic variability of Santa Ines sheep in Brazil. We used pedigree data of the Santa Ines breed available in electronic processing of the Brazilian Association of Sheep Breeders. A file with 20,206 records, which enabled the calculation of the genetic conservation index (GCI), individual inbreeding coefficient (F), change in inbreeding (DeltaF), effective population size (Ne), effective number of founders (fe), effective number of ancestors (falpha), generation interval (L), average relatedness coefficient of each individual (AR), and Wright's F-statistics (F IT, F IS, and F ST). For pedigree analysis and calculation of population parameters, the program ENDOG was used. The average inbreeding coefficient ([Formula: see text]) was 0.97% and the mean average relatedness ([Formula: see text]) 0.49%. The effective numbers of founders and ancestors were, respectively, 199 and 161. The average values of F and AR increased significantly over the years. The effective population size fluctuated over the years concurrently to oscillations in inbreeding rates, wherein N e reached just 68 in the year 2012. The mean average generation interval was 5.3 years. The Santa Ines breed in Brazil is under genetic drift process, with loss of genetic variation. It requires the implementation of a genetic management plan in the herd, for conservation and improvement of the breed. PMID- 29119380 TI - Chiral Symmetry Breaking in Peptide Systems During Formation of Life on Earth. AB - Chiral symmetry breaking in complex chemical systems with a large number of amino acids and a large number of similar reactions was considered. It was shown that effective averaging over similar reaction channels may result in very weak effective enantioselectivity of forward reactions, which does not allow most of the known models to result in chiral symmetry breaking during formation of life on Earth. Models with simple and catalytic synthesis of a single amino acid, formation of peptides up to length five, and sedimentation of insoluble pair of substances were considered. It was shown that depending on the model and the values of the parameters, chiral symmetry breaking may occur in up to about 10% out of all possible unique insoluble pair combinations even in the absence of any catalytic synthesis and that minimum total number of amino acids in the pair is 5. If weak enantioselective forward catalytic synthesis of amino acids is present, then the number of possible variants, in which chiral symmetry breaking may occur, increases substantially. It was shown that that the most interesting catalysts have zero or one amino acid of "incorrect" chirality. If the parameters of the model are adjusted in such a way to result in an increase of concentration of longer peptides, then catalysts with two amino acids of incorrect chirality start to appear at peptides of length five. Models of chiral symmetry breaking in the presence of epimerization were considered for peptides up to length three. It was shown that the range of parameters in which chiral symmetry breaking could occur significantly shrinks in comparison to previously considered models with peptides up to length two. An experiment of chiral symmetry breaking was proposed. The experiment consists of a three-step cycle: reversible catalytic synthesis of amino acids, reversible synthesis of peptides, and irreversible sedimentation of insoluble substances. PMID- 29119381 TI - Comparison of tenofovir plasma and tissue exposure using a population pharmacokinetic model and bootstrap: a simulation study from observed data. AB - Sparse tissue sampling with intensive plasma sampling creates a unique data analysis problem in determining drug exposure in clinically relevant tissues. Tissue exposure may govern drug efficacy, as many drugs exert their actions in tissues. We compared tissue area-under-the-curve (AUC) generated from bootstrapped noncompartmental analysis (NCA) methods and compartmental nonlinear mixed effect (NLME) modeling. A model of observed data after single-dose tenofovir disoproxil fumarate was used to simulate plasma and tissue concentrations for two destructive tissue sampling schemes. Two groups of 100 data sets with densely-sampled plasma and one tissue sample per individual were created. The bootstrapped NCA (SAS 9.3) used a trapezoidal method to calculate geometric mean tissue AUC per dataset. For NLME, individual post hoc estimates of tissue AUC were determined, and the geometric mean from each dataset calculated. Median normalized prediction error (NPE) and absolute normalized prediction error (ANPE) were calculated for each method from the true values of the modeled concentrations. Both methods produced similar tissue AUC estimates close to true values. Although the NLME-generated AUC estimates had larger NPEs, it had smaller ANPEs. Overall, NLME NPEs showed AUC under-prediction but improved precision and fewer outliers. The bootstrapped NCA method produced more accurate estimates but with some NPEs > 100%. In general, NLME is preferred, as it accommodates less intensive tissue sampling with reasonable results, and provides simulation capabilities for optimizing tissue distribution. However, if the main goal is an accurate AUC for the studied scenario, and relatively intense tissue sampling is feasible, the NCA bootstrap method is a reasonable, and potentially less time intensive solution. PMID- 29119383 TI - Determination of trace metal concentration in compost, DAP, and TSP fertilizers by neutron activation analysis (NAA) and insights from density functional theory calculations. AB - Leaching of toxic metals from fertilizers is a growing concern in an agricultural country like Bangladesh due to the serious consequences in health and food chain. Fertilizers used in farming fields and nurseries (plant sales outlet) in the mid southern part of Bangladesh were collected for the determination of toxic metals. This study employed the neutron activation method and a relative standardization approach. Three standard/certified reference materials, namely NIST coal fly ash 1633b, IAEA-Soil-7, and IAEA-SL-1 (lake sediment), were considered for elemental quantification. Concentration of As (2.63-16.73 mg/kg), Cr (40.93-261.77 mg/kg), Sb (0.47-63.58 mg/kg), Th (1.44-19.16 mg/kg), and U (1.90-209.41 mg/kg) were determined in fertilizers. High concentrations of Cr, Sb, and U were detected in some compost and phosphate fertilizers (TSP and diammonium phosphate (DAP)) in comparison with the IAEA/European market standard and other studies. Quantum mechanical calculations were performed to understand the molecular level interaction of CrO3, Sb2O3, and AsO3, with DAP by employing density functional theory with the B3LYP/SDD level of theory. Our results indicated that CrO3 and Sb2O3 have strong binding affinity with DAP compared to AsO3, which supports the experimental results. These compounds attached to the phosphate group through covalent-like bonding with oxygen. The frontier molecular orbital calculation indicated that HOMO-LUMO gap of the AsO3-DAP (5.46 eV) and Sb2O3-DAP (6.48 eV) complexes are relatively lower than the CrO3-DAP, which indicates that As and Sb oxides are chemically more prone to attach with the phosphate group of DAP fertilizer. PMID- 29119382 TI - Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia. AB - Brown adipose tissue (BAT) plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue (WAT), have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BATactivation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed. PMID- 29119384 TI - Tributyltin: Advancing the Science on Assessing Endocrine Disruption with an Unconventional Endocrine-Disrupting Compound. AB - Tributyltin (TBT) has been recognized as an endocrine disrupting chemical (EDC) for several decades. However, only in the last decade, was its primary endocrine mechanism of action (MeOA) elucidated-interactions with the nuclear retinoid-X receptor (RXR), peroxisome proliferator-activated receptor gamma (PPARgamma), and their heterodimers. This molecular initiating event (MIE) alters a range of reproductive, developmental, and metabolic pathways at the organism level. It is noteworthy that a variety of MeOAs have been proposed over the years for the observed endocrine-type effects of TBT; however, convincing data for the MIE was provided only recently and now several researchers have confirmed and refined the information on this MeOA. One of the most important lessons learned from years of research on TBT concerns apparent species sensitivity. Several aspects such as the rates of uptake and elimination, chemical potency, and metabolic capacity are all important for identifying the most sensitive species for a given chemical, including EDCs. For TBT, much of this was discovered by trial and error, hence important relationships and important sensitive taxa were not identified until several decades after its introduction to the environment. As recognized for many years, TBT-induced responses are known to occur at very low concentrations for molluscs, a fact that has more recently also been observed in fish species. This review explores the MeOA and effects of TBT in different species (aquatic molluscs and other invertebrates, fish, amphibians, birds, and mammals) according to the OECD Conceptual Framework for Endocrine Disruptor Testing and Assessment (CFEDTA). The information gathered on biological effects that are relevant for populations of aquatic animals was used to construct Species Sensitivity Distributions (SSDs) based on No Observed Effect Concentrations (NOECs) and Lowest Observed Effect Concentrations (LOECs). Fish appear at the lower end of these distributions, showing that they are as sensitive as molluscs, and for some species, even more sensitive. Concentrations in the range of 1 ng/L for water exposure (10 ng/g for whole-body burden) have been shown to elicit endocrine-type responses, whereas mortality occurs at water concentrations ten times higher. Current screening and assessment methodologies as compiled in the OECD CFEDTA are able to identify TBT as a potent endocrine disruptor with a high environmental risk for the original use pattern. If those approaches had been available when TBT was introduced to the market, it is likely that its use would have been regulated sooner, thus avoiding the detrimental effects on marine gastropod populations and communities as documented over several decades. PMID- 29119385 TI - Intestinal Permeability in Relapsing-Remitting Multiple Sclerosis. AB - Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care. PMID- 29119386 TI - Endovascular Ischemic Stroke Models in Nonhuman Primates. AB - To bridge the gap between rodent and human studies, the Stroke Therapy Academic Industry Roundtable committee suggests that nonhuman primates (NHPs) be used for preclinical, translational stroke studies. Owing to the fact that vast majority of ischemic strokes are caused by transient or permanent occlusion of a cerebral blood vessel eventually leading to brain infarction, ischemia induced by endovascular methods closely mimics thromboembolic or thrombotic cerebrovascular occlusion in patients. This review will make a thorough summary of transient or permanent occlusions of a cerebral blood vessel in NHPs using endovascular methods. Then, advantages and disadvantages, and potential applications will be analyzed for each kind of models. Additionally, we also make a further analysis based on different kinds of emboli, various occlusion sites, infract size, abnormal hemodynamics, and potential dysfunctions. Experimental models of ischemic stroke in NHPs are valuable tools to analyze specific facets of stroke in patients, especially those induced by endovascular methods. PMID- 29119388 TI - Potentialities of MicroRNA Diagnosis in Patients with Bladder Cancer. AB - Despite promising vista of the use of microRNA in molecular diagnosis of bladder cancer, there are few data on their expression profiles, which impedes assessment of diagnostic value of these marker molecules. In this study, suppression subtractive hybridization, on-chip hybridization, and high-throughput deep sequencing focused on profiling microRNA and assessing the diagnostic value of revealed marker molecules. PMID- 29119387 TI - A new ETV6-NTRK3 cell line model reveals MALAT1 as a novel therapeutic target - a short report. AB - BACKGROUND: Previously, the chromosomal translocation t(12;15)(p13;q25) has been found to recurrently occur in both solid tumors and leukemias. This translocation leads to ETV6-NTRK3 (EN) gene fusions resulting in ectopic expression of the NTRK3 neurotropic tyrosine receptor kinase moiety as well as oligomerization through the donated ETV6-sterile alpha motif domain. As yet, no in vitro cell line model carrying this anomaly is available. Here we genetically characterized the acute promyelocytic leukemia (APL) cell line AP-1060 and, by doing so, revealed the presence of a t(12;15)(p13;q25). Subsequently, we evaluated its suitability as a model for this important clinical entity. METHODS: Spectral karyotyping, fluorescence in situ hybridization (FISH), and genomic and transcriptomic microarray-based profiling were used to screen for the presence of EN fusions. qRT-PCR was used for quantitative expression analyses. Responses to AZ-23 (NTRK) and wortmannin (PI3K) inhibitors, as well as to arsenic trioxide (ATO), were assessed using colorimetric assays. An AZ-23 microarray screen was used to define the EN targetome, which was parsed bioinformatically. MAPK1 and MALAT1 activation were assayed using Western blotting and RNA-FISH, respectively, whereas an AML patient cohort was used to assess the clinical occurrence of MALAT1 activation. RESULTS: An EN fusion was detected in AP1060 cells which, accordingly, turned out to be hypersensitive to AZ-23. We also found that AZ-23 can potentiate the effect of ATO and inhibit the phosphorylation of its canonical target MAPK1. The AZ-23 microarray screen highlighted a novel EN target, MALAT1, which also proved sensitive to wortmannin. Finally, we found that MALAT1 was massively up-regulated in a subset of AML patients. CONCLUSIONS: From our data we conclude that AP-1060 may serve as a first publicly available preclinical model for EN. In addition, we conclude that these EN-positive cells are sensitive to the NTRK inhibitor AZ-23 and that this inhibitor may potentiate the therapeutic efficacy of ATO. Our data also highlight a novel AML EN target, MALAT1, which was so far only conspicuous in solid tumors. PMID- 29119389 TI - Balance of Fatty Acids and Their Correlations with Parameters of Lipid Metabolism and Markers of Inflammation in Men with Coronary Atherosclerosis. AB - We studied the balance of fatty acids and their correlation with parameters of lipid metabolism and inflammation markers in men with coronary atherosclerosis. In the blood of patients and healthy men, the content of myristic (C14:0), pentadecanoic (C15:0), palmitic (C16:0), stearic (C18:0), arachidic (C20:0) and docosanic (C22:0), TNFalpha, IL-1beta, IL-6, IL-8, C-reactive protein, cholesterol, triglycerides, HDL, and LPO intensity were measured. In patients with coronary atherosclerosis, increased concentrations of saturated fatty acids, triglycerides, LPO products, IL-6, IL-8, and C-reactive protein were found. Correlation analysis revealed multiple correlations between the studied fatty acids, correlation of C16:0, C18:0, and C20:0 with inflammation markers, C14:0, C16:0, and C18:0 with triglyceride level, C16:0, C18:0, and C20:0 with cholesterol. The contents of C14:0, C15:0, C16:0, and C18:0 correlated with the presence of coronary atherosclerosis. Lipid metabolism disturbances in coronary atherosclerosis were accompanied by changes in not only lipid spectrum and inflammation markers, but also fatty acids balance. PMID- 29119390 TI - Morphofunctional State of Erythrocytes in Rats with Walker-256 Carcinoma Treated with Docetaxel and Xymedon. AB - We compared the effect of xymedon (100 mg/kg) and Mexidol (50 mg/kg) on morphometric parameters of erythrocytes and oxygen-transporting function of hemoglobin in rats with Walker-256 carcinoma treated with docetaxel (15 mg/kg once intraperitoneally on day 11 after tumor cells transplantation). Xymedon and Mexidol were injected intramuscularly for 10 days starting from day 11 of the experiment. The studied parameters were evaluated on experimental days 14 and 22. Similar to Mexidol, xymedon prevented changes in the erythrocyte geometric parameters induced by docetaxel and neoplastic process, but increased hemoglobin packing density in erythrocytes (by 32%) more effectively than Mexidol. Optimization of oxygen-transporting function of hemoglobin and normalization of its structural and functional parameters changed by docetaxel treatment (content of oxyhemoglobin, hemoglobin affinity for oxygen and its ability to bind and release oxygen, intensity of symmetric and asymmetric vibrations of pyrrole rings) in rats receiving xymedon took longer time than in case of Mexidol treatment, but the effects were similar. PMID- 29119391 TI - Comparative Study of Toxicity of Alkoxyamines In Vitro and In Vivo. AB - Effect of alkoxyamines on normal and tumor cells was studied in vitro and in vivo. In vitro experiments showed that alkoxyamines produce a dose-dependent toxic effect on cells of human breast tumor MCF7 line. Transplantation of Krebs-2 ascites carcinoma cells preincubated with alkoxyamines to mice did not induce tumor growth. An opposite effect was observed in normal mouse cells: functional activity of peritoneal macrophages increased. The possibility of using alkoxyamines as theranostic agents is discussed. PMID- 29119392 TI - Results of Experimental Ligation of the Main Vein with the Use of Cell Technologies. AB - Autologous multipotent mesenchymal stromal cells (MMSC) of bone marrow origin with transfected GFP gene and additionally stained cell membranes were injected to rats through the skin in the projection of ligated femoral vein. The results were evaluated by fluorescent microscopy. No signs of MMSC incorporation into the wall of ligated vessel or reorganized collaterals were detected. Angiogenesis processes involving MMSC were detected in experimental rats within just 4 days and progressed until week 2 postinjection, mainly in granulations at the site of surgical intervention and the cicatrix forming there. Injected MMSC completely formed all tunics of the new vessels and incorporated in the vessels forming from the recipient cells. MMSC and the objects created from them were gradually eliminated with participation of macrophages and replaced by structures formed from the recipient cells. PMID- 29119393 TI - In Vitro Culturing and Storage of Campylobacter Genus Bacteria. AB - Experimental model for in vitro evaluation of Campylobacter genus bacteria growth kinetics, inhibition, or inactivation is proposed. The model allows quantitative evaluation of the sensitivity to various types of stress exposure and promotes detection of the regularities of their transformation into uncultivable forms. The model implies the use of 96-well plates for parallel culturing of several subpopulations of the test strain in media with various parameters. The proposed algorithm includes evaluation of the proportion of viable CFU to total level of planktonic and uncultivable cells in the population, which is estimated by the content of genomic DNA in the samples by quantitative PCR (or real-time PCR) with ciaB, cdtB, or 16S rRNA primers. The presence of biofilm matrix is detected by the intensity of staining of polystyrene plates. This model can be used for evaluation of the most significant types of exposure, including low-dose antibacterial treatment, promoting the formation of stable microorganism variants. The model has been used to study the effects of culturing conditions on the characteristics of C. jejuni populations. The most characteristic feature of C. jejuni is reduction of the count of viable cells up to complete disappearance of cultivable forms under favorable conditions of growth. The level of viable cells in the populations decreased 10-fold and more, on average, after 48-h incubation. Not all strains exhibit this property, some strains retain their viability, which is detected by the culturing method, and contributes to biofilm formation. PMID- 29119394 TI - Effects of Bone Marrow Multipotent Mesenchymal Stromal Cells and Their Secretion Products on the Cellular Composition of the Thymus and Spleen of Female Wistar Rats with Experimental Chronic Inflammation of the Internal Genitals. AB - The effects of bone marrow multipotent mesenchymal stromal cells and their secretion products on the subpopulation composition of thymic and splenic lymphocytes were studied in female Wistar rats with experimental chronic inflammatory process in the internal genitals. Stromal cells and medium conditioned by these cells in different administration routes (intravenous or lymphotropic injection) produces different modulating effect on blood leukocyte count and on subpopulation composition of the splenic and thymic lymphocytes. The most manifest anti-inflammatory effect was observed after lymphotropic injection of multipotent mesenchymal stromal cells creating a high concentration and long persistence of the factors produced by these cells in the focus of inflammation. PMID- 29119395 TI - Comparative Analysis of Quantitative Parameters of Expression of the Retinoic Acid Nuclear Receptor RARalpha Gene and APE1/YB-1/MDR1 Pattern Genes in Patients with Newly Detected Multiple Myeloma. AB - The expression of retinoic acid nuclear receptor gene RARalpha and its relationship with expression of APE1, YB-1, and MDR1 genes was studied in bone marrow aspiration biopsy specimens from 22 patients with newly detected multiple myeloma. The expression of RARalpha directly correlated with the expression of APE1/YB-1/MDR1 pattern genes. Groups differing by expression of RARalpha exhibited significant differences in the overall survival of patients; concordant and simultaneous changes in the expression of all genes of the APE1/YB-1/MDR1 pattern suggested the level of RARalpha gene expression as a potential prognostic factor in the pathogenesis of multiple myeloma. PMID- 29119396 TI - Functional and Biochemical Parameters of Erythrocytes during Mexicor Treatment in Posttraumatic Period after Experimental Blood Loss and Combined Traumatic Brain Injury. AB - Mexicor treatment (8 mg/kg body weight per day) during the posttraumatic period after concomitant traumatic brain injury and acute blood loss in rats increased electrophoretic mobility and concentration of 2,3-diphosphoglycerate, and reduced malondialdehyde content in erythrocytes. These changes improved hemodynamics and oxygen-transporting function of the blood. The most pronounced effects of Mexicor were observed at the early stages of posttraumatic period. PMID- 29119397 TI - Specific Features of Electrolyte Excretion at the Early Stages of Arterial Hypertension in SHR Rats. AB - Daytime and nighttime systolic and diastolic BP was recorded in 23-week-old SHR and Wistar rats by telemetric monitoring. Urine concentrations of sodium, potassium, and calcium were determined in SHR rats during of light (07.00-19.00 h) and dark hours (19.00-07.00 h) at the age of 18, 19, 20, 21, 22, and 23 week; 23-week-old Wistar rats were used as the control. At early stages of the experiment, urine sodium concentration was elevated in SHR rats both at daytime and at night. Thereafter, this value declined and by 22-23 week was significantly lower than in normotensive Wistar rats, but only during daytime. Daytime potassium concentration significantly surpassed the control level during weeks 18 19 of the experiment, but later, a tendency to a decrease in this parameter was observed. Daytime calcium content in SHR rats did not significantly differ from the control throughout the experiment. At night, this value exceeded the control level by more than 2 times during weeks 18-19, but then returned to the level observed in normotensive animals. PMID- 29119398 TI - Myocardial Protection against Ischemic and Reperfusion Injuries (Experimental Study). AB - The effects of hypoxic, hyperoxic, and hypoxic-hyperoxic preconditioning were examined in the prospective study on narcotized and artificially ventilated rabbits. Under artificial circulation, acute myocardial ischemia was modeled by ligation of anterior descending coronary artery, which was followed by reperfusion. The degree of ventricular arrhythmias was assessed, and the ischemic area was evaluated in percent of the area at risk. Microscopic characterization of the myocardium was employed to assess the cardioprotective effect of hypoxic and/or hyperoxic preconditioning. According to Kruskal-Wallis test, the greatest resistance of the myocardium to ischemic and reperfusion injury was observed after hypoxic-hyperoxic preconditioning (H=42.459; p=0.009). The rabbits subjected to this type of preconditioning demonstrated the least damaged myocardium in comparison with nonconditioned controls. PMID- 29119399 TI - Green Tea Extract Increases the Expression of Genes Responsible for Regulation of Calcium Balance in Rat Slow-Twitch Muscles under Conditions of Exhausting Exercise. AB - We studied the role of calcium-regulating structures of slow- (m. soleus, SOL) and fast-twitch (m. extensor digitorum longus, EDL) skeletal muscles of rats during adaptation to exhausting physical activity and the possibility of modulating this adaptation with decaffeinated green tea extract. It was established that EDL adaptation is mainly aimed at Sa2+ elimination from the sarcoplasm by Sa-ATPase and its retention in the reticulum by calsequestrin. Administration of green tea extract increased endurance due to involvement of slow-twitch muscles whose adaptation is associated with enhanced expression of all the studied genes responsible for the regulation of Ca2+ balance. PMID- 29119400 TI - Comparative Study of Fusogenic Activity of H1 and H5 Subtypes Influenza Virus Hemagglutinins. AB - Influenza virus hemagglutinins are surface proteins responsible for fusion of the viral and cellular membranes. Their capacity to mediate membrane fusion (fusogenic activity) is studied by various methods, including the syncytium formation and pseudovirus transduction methods. We constructed plasmids coding for genes of three H1 and one H5 hemagglutinins and compared their fusogenic activities. Hemagglutinin capacity to induce syncytium formation did not always correlate with the transduction activity of the respective pseudoviruses. Hemagglutinin H5 exhibited high fusogenic activity in studies by both methods, however, two of the studied H1 hemagglutinins induced the formation of syncytia, but did not mediate pseudovirus transduction. This could be due to different capsid sizes of influenza virus and vesicular stomatitis virus, which determines their different permeability through the fusion pore. PMID- 29119401 TI - Role of Endogenous Agonists of Opioid Receptors in the Regulation of Heart Resistance to Postischemic Reperfusion Injury. AB - Intravenous injection of nonselective antagonists of opioid receptors (OR) naltrexone (5 mg/kg) and naloxone methiodide (5 mg/kg), selective delta1-OR antagonist BNTX (0.7 mg/kg), selective delta2-OR blocker naltriben (0.3 mg/kg), selective kappa-OR antagonist norbinaltorphimine (2 mg/kg), and selective blocker of ORL1 opioid receptors JTC-801 (0.1 mg/kg) produced no effect on reperfusion injury to the heart in rats narcotized with alpha-chloralose. In contrast, selective MU-OR antagonist CTAP (1 mg/kg) limited the infarct size, although this effect was not observed at a lower CTAP concentration of 0.1 mg/kg. Probably, the myocardial infarct size-limiting effect of CTAP was associated with activation of the non-opioid receptors. It was hypothesized that endogenous OR agonists did not affect heart resistance to reperfusion injury in unadapted rats. PMID- 29119402 TI - A Third Case of Glycogen Storage Disease IB and Giant Cell Tumour of the Mandible: A Disease Association or Iatrogenic Complication of Therapy. AB - We report the third case of Glycogen Storage Disease type 1b (GSD 1b) with Giant Cell Tumour (GCT) of the mandible, associated with Granulocyte Colony Stimulating Factor (G-CSF) use. G-CSF in GSD 1b is indicated for persistent neutropaenia, sepsis, inflammatory bowel disease and severe diarrhoea. Our patient was 12 years old at GCT diagnosis and had been treated with G-CSF from 5 years of age. He underwent therapy with interferon followed by local resection which was successful in initial control of the disease. Histology demonstrated spindle shaped stromal cells together with numerous interspersed multinuclear osteoclastic giant cells. G-CSF has been hypothesized to induce osteoclastic differentiation and thus may be involved in the pathogenesis of GCT formation. At age 19 years he required a repeat operation for local recurrence. He currently continues on G-CSF and was commenced on denosumab for control of the GCT with no recurrence to date. A cause and effect relationship between G-CSF therapy and the development of GCT in GSD type 1b remains to be established. PMID- 29119403 TI - Evaluation of the Efficiency of Single-Inhaler Combination Therapy with Budesonide/Formoterol Fumarate in Patients with Bronchial Asthma in Daily Clinical Practice. AB - INTRODUCTION: The effectiveness of single-inhaler budesonide/formoterol fumarate combination therapy for asthma has been previously shown for the original product. The aim of this nonrandomized, open-label, postauthorization efficacy study (PAES) real-life clinical assessment was to evaluate the clinical effectiveness of a second product (Bufomix Easyhaler(r)) in the daily clinical practice of asthma therapy. METHODS: This multicenter PAES was conducted by 220 unselected allergologists and pulmonologists who enrolled 2200 adult outpatients (age 49.8 +/- 17.9 years) with asthma treated with Bufomix Easyhaler(r) for at least 14 days before enrolment. Asthma control was assessed during three subsequent visits with 8-12-week intervals on the basis of the Asthma Control Test (ACT). Adherence was assessed with the Medication Adherence Questionnaire. In addition, patient satisfaction with Bufomix Easyhaler(r) was scored, and adverse drug reactions were recorded. RESULTS: The percentage of patients with well-controlled asthma or total control of asthma (ACT score 20-25 points) increased from 46.6% at the first visit to 90.8% at the third visit (p < 0.001). In addition, the percentage of patients with poor control of asthma (ACT score less than 15 points) decreased from 14.9% to 1.2% (p < 0.001). The adherence rate increased from 88% at the first visit to 95.3% at the third visit. Patient satisfaction with the use of this dry powder inhaler increased with the duration of its use. Only one adverse drug reaction was reported. CONCLUSION: The results obtained confirm the effectiveness of Bufomix Easyhaler(r) in the treatment of asthma in outpatient adults in daily clinical practice. FUNDING: Orion Corporation. PMID- 29119404 TI - Predicting similarity judgments in intertemporal choice with machine learning. AB - Similarity models of intertemporal choice are heuristics that choose based on similarity judgments of the reward amounts and time delays. Yet, we do not know how these judgments are made. Here, we use machine-learning algorithms to assess what factors predict similarity judgments and whether decision trees capture the judgment outcomes and process. We find that combining small and large values into numerical differences and ratios and arranging them in tree-like structures can predict both similarity judgments and response times. Our results suggest that we can use machine learning to not only model decision outcomes but also model how decisions are made. Revealing how people make these important judgments may be useful in developing interventions to help them make better decisions. PMID- 29119406 TI - Increasing Valid Profiles in Phallometric Assessment of Sex Offenders with Child Victims: Combining the Strengths of Audio Stimuli and Synthetic Characters. AB - Penile plethysmography (PPG) is a measure of sexual interests that relies heavily on the stimuli it uses to generate valid results. Ethical considerations surrounding the use of real images in PPG have further limited the content admissible for these stimuli. To palliate this limitation, the current study aimed to combine audio and visual stimuli by incorporating computer-generated characters to create new stimuli capable of accurately classifying sex offenders with child victims, while also increasing the number of valid profiles. Three modalities (audio, visual, and audiovisual) were compared using two groups (15 sex offenders with child victims and 15 non-offenders). Both the new visual and audiovisual stimuli resulted in a 13% increase in the number of valid profiles at 2.5 mm, when compared to the standard audio stimuli. Furthermore, the new audiovisual stimuli generated a 34% increase in penile responses. All three modalities were able to discriminate between the two groups by their responses to the adult and child stimuli. Lastly, sexual interest indices for all three modalities could accurately classify participants in their appropriate groups, as demonstrated by ROC curve analysis (i.e., audio AUC = .81, 95% CI [.60, 1.00]; visual AUC = .84, 95% CI [.66, 1.00], and audiovisual AUC = .83, 95% CI [.63, 1.00]). Results suggest that computer-generated characters allow accurate discrimination of sex offenders with child victims and can be added to already validated stimuli to increase the number of valid profiles. The implications of audiovisual stimuli using computer-generated characters and their possible use in PPG evaluations are also discussed. PMID- 29119405 TI - Predictive joint-action model: A hierarchical predictive approach to human cooperation. AB - Research in a number of related fields has recently begun to focus on the perceptual, cognitive, and motor workings of cooperative behavior. There appears to be enough coherence in these efforts to refer to the study of the mechanisms underlying human cooperative behavior as the field of joint-action (Knoblich, Butterfill, & Sebanz, 2011; Sebanz, Bekkering, & Knoblich, 2006). Yet, the development of theory in this field has not kept pace with the proliferation of research findings. We propose a hierarchical predictive framework for the study of joint-action that we call the predictive joint-action model (PJAM). The presentation of this theoretical framework is organized into three sections. In the first section, we summarize hierarchical predictive principles and discuss their application to joint-action. In the second section, we juxtapose PJAM's assumptions with empirical evidence from the current literature on joint-action. In the third section, we discuss the overall success of the hierarchical predictive approach to account for the burgeoning empirical literature on joint action research. Finally, we consider the model's capacity to generate novel and testable hypotheses about joint-action. This is done with the larger goal of uncovering the empirical and theoretical pieces that are still missing in a comprehensive understanding of joint action. PMID- 29119407 TI - PD-L1 Testing in Guiding Patient Selection for PD-1/PD-L1 Inhibitor Therapy in Lung Cancer. AB - Immunotherapy with programmed death 1 (PD-1)- and programmed death-ligand 1 (PD L1)-targeted monoclonal antibodies has dramatically changed the therapeutic and prognostic landscape for several types of malignancy. PD-1 and PD-L1 are immune checkpoint proteins whose binding ultimately result in T cell exhaustion and self tolerance. Blocking this pathway 'releases the brakes' on the immune system and allows for attack of tumor cells that express PD-L1. The clinical trials that led to the US Food and Drug Administration (FDA) approval of these agents used different immunohistochemical (IHC) platforms with various PD-L1 antibodies to assess for PD-L1 expression on either tumor cells or tumor-infiltrating immune cells. There are four PD-L1 IHC assays registered with the FDA, using four different PD-L1 antibodies (22C3, 28-8, SP263, SP142), on two different IHC platforms (Dako and Ventana), each with their own scoring systems. Attempts at harmonization of PD-L1 IHC antibodies and staining platforms are underway. While PD-L1 IHC can be used to predict the likelihood of response to anti-PD-1 or anti PD-L1 therapy, a proportion of patients that are negative can have a response and identification of alternative biomarkers is critical to further refine selection of patients most likely to respond to these therapies. PMID- 29119408 TI - Pilot study of a new comprehensive radiology report categorization (RADCAT) system in the emergency department. AB - PURPOSE: The purpose of this study was to describe a new, broadly applicable radiology report categorization (RADCAT) system that was developed collaboratively between radiologists and emergency department (ED) physicians, and to establish its usability and performance by interobserver variation. METHODS: In collaboration with our ED colleagues, we developed the RADCAT system for all imaging studies performed in our level-1 trauma center, including five categories that span the spectrum of normal through emergent life-threatening findings. During a pilot phase, four radiologists used the system real-time to categorize a minimum of 400 reports in the ED. From this pool of categorized studies, 58 reports were then selected semi-randomly, de-identified, stripped of their original categorization, and recategorized based on the narrative radiology report by 12 individual reviewers (6 radiologists, and 6 ED physicians). Interobserver variation between all reviewers, radiologists only, and ED physicians only was calculated using Cohen's Kappa statistic and Kendall's coefficient of concordance. RESULTS: Altogether, agreement among radiologists and ED physicians was substantial (kappa = 0.73, p < 0.0001) and agreement for each category was substantial (all kappa > 0.60, p < 0.0001). The lowest agreement was observed with RADCAT-3 (kappa > 0.61, p < 0.0001) and the highest agreement with RADCAT-1 (kappa > 0.85, p < 0.0001). A high trend in agreement was observed for radiologists and ED physicians and their combination (all W > 0.90, p < 0.0001). CONCLUSIONS: Our RADCAT system is understandable between radiologists and ED physicians for categorizing a wide range of imaging studies, and warrants further assessment and validation. Based upon these pilot results, we plan to adopt this RADCAT scheme and further assess its performance. PMID- 29119409 TI - Recent Developments in ADC Technology: Preclinical Studies Signal Future Clinical Trends. AB - The antibody-drug conjugate (ADC) field is in a transitional period. Older approaches to conjugate composition and dosing regimens still dominate the ADC clinical pipeline, but preclinical work is driving a rapid evolution in how we strategize to improve efficacy and reduce toxicity towards better therapeutic outcomes. These advances are largely based upon a body of investigational studies that together offer a deeper understanding of the absorption, distribution, metabolism, and excretion (ADME) and drug metabolism and pharmacokinetics (DMPK) fates of both the intact conjugate and its small-molecule component. Knowing where the drug goes and how it is processed allows mechanistic connections to be drawn with commonly observed clinical toxicities. The field is also starting to consider ADC interactions with the immune system and potential synergistic therapeutic opportunities therein. In an indication of future directions for the field, antibody conjugates bearing non-cytotoxic small-molecule payloads are being developed to reduce side effects associated with treatment of chronic diseases. ADCs are not a magic bullet to cure disease. However, they will increasingly become valuable therapeutic tools to improve patient outcomes across a variety of indications. PMID- 29119410 TI - Africanizing Science in Post-colonial Kenya: Long-Term Field Research in the Amboseli Ecosystem, 1963-1989. AB - Following Kenya's independence in 1963, scientists converged on an ecologically sensitive area in southern Kenya on the northern slope of Mt. Kilimanjaro called Amboseli. This region is the homeland of the Ilkisongo Maasai who grazed this ecosystem along with the wildlife of interest to the scientists. Biologists saw opportunities to study this complex community, an environment rich in biological diversity. The Amboseli landscape proved to be fertile ground for testing new methods and lines of inquiry in the biological sciences that were generalizable and important for shaping natural resource management policies in Kenya. However, the local community was in the midst of its own transformation from a primarily transhumant lifestyle to a largely sedentary one, a complex political situation between local and national authorities, and the introduction of a newly educated generation. This article examines the intersection of African history and field science through the post-colonial Africanization of Kenyan politics, the broadening of scientific practices in Amboseli in previously Western-occupied spaces to include Kenyan participants, and an increasing awareness of the role of local African contexts in the results, methods, and implications of biological research. "Africanization" as an idea in the history of science is multifaceted encompassing not just Africans in the scientific process, but it needs an examination of the larger political and social context on both a local and national level. PMID- 29119412 TI - Association of Helicobacter pylori with the Risk of Hepatic Encephalopathy. AB - BACKGROUND/OBJECTIVES: Hepatic encephalopathy is the common manifestation of decompensated cirrhosis. The association between Helicobacter pylori (H. pylori) infection and hepatic encephalopathy has been shown in many epidemiologic studies. This meta-analysis was conducted to summarize all available studies to estimate the association between H. pylori infection and hepatic encephalopathy. METHODS: A comprehensive literature review was conducted using MEDLINE and EMBASE database through March 2017 to identify studies that reported the association between H. pylori infection and hepatic encephalopathy. Effect estimates from the individual study were extracted and combined using random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Of 15,233 studies, eleven studies (four cross-sectional, four case-control, and three cohort studies) met the eligibility criteria and were included in the meta-analysis. The pooled OR of hepatic encephalopathy in patients with H. pylori infection was 1.73 (95% CI 1.09 2.73) when compared with the patients without H. pylori infection. The association between H. pylori and hepatic encephalopathy was not statistically significant after the sensitivity analysis, excluding those using ELISA alone, with a pooled OR of 1.92 (95% CI 0.91-4.05, I 2 = 62%). There was no publication bias of overall included studies assessed by the funnel plots and Egger's regression asymmetry test. CONCLUSIONS: This study demonstrated a potential association between H. pylori infection and risk of hepatic encephalopathy. Future studies are required to assess the effect of chronicity of infection on the development of hepatic encephalopathy. PMID- 29119411 TI - Systematic Assessment of Research on Autism Spectrum Disorder (ASD) and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism Research. AB - Historically, entities with a vested interest in a product that critics have suggested is harmful have consistently used research to back their claims that the product is safe. Prominent examples are: tobacco, lead, bisphenol A, and atrazine. Research literature indicates that about 80-90% of studies with industry affiliation found no harm from the product, while only about 10-20% of studies without industry affiliation found no harm. In parallel to other historical debates, recent studies examining a possible relationship between mercury (Hg) exposure and autism spectrum disorder (ASD) show a similar dichotomy. Studies sponsored and supported by industry or entities with an apparent conflict of interest have most often shown no evidence of harm or no "consistent" evidence of harm, while studies without such affiliations report positive evidence of a Hg/autism association. The potentially causal relationship between Hg exposure and ASD differs from other toxic products since there is a broad coalition of entities for whom a conflict of interest arises. These include influential governmental public health entities, the pharmaceutical industry, and even the coal burning industry. This review includes a systematic literature search of original studies on the potential relationship between Hg and ASD from 1999 to August 2015, finding that of the studies with public health and/or industry affiliation, 86% reported no relationship between Hg and ASD. However, among studies without public health and/or industry affiliation, only 21% find no relationship between Hg and ASD. The discrepancy in these results suggests a bias indicative of a conflict of interest. PMID- 29119414 TI - A Fairy Tale with a Hairy Tail. PMID- 29119413 TI - Identification and Characterization of Fenofibrate-Induced Liver Injury. AB - BACKGROUND: Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended. AIMS: The aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate. METHODS: All cases of definite, very likely, and probable drug-induced liver injury (DILI) attributed to fenofibrate enrolled in the DILI Network study between 2004 and 2015 were reviewed. RESULTS: Among 1229 patients with confirmed DILI, 7 cases (0.6%) were attributed to fenofibrate. The median age was 43 (range 37-61) years, and latency to onset was short (5-8 weeks) in 4 patients but more prolonged (18-56 weeks) in the rest. Laboratory results at presentation showed hepatocellular, mixed, and cholestatic injury, but 6 cases presented with jaundice. No patient had undergone routine monitoring. Four patients required hospitalization and 2 in whom drug discontinuation was delayed had a severe outcome, 1 undergoing liver transplantation, and 1 developing chronic injury and death. Liver biopsy was available in 4 patients and showed diverse injury patterns. Genetic studies showed the presence of the rare HLA A*33:01 in 3 patients (43 vs. 1% in control populations). The causality scores were highly likely in 5 and probable in 2. CONCLUSIONS: Liver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Although most cases are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation. PMID- 29119415 TI - Clinical Trigonometry: Right Hepatic Trisegmentectomy After Radiation Trisegmentectomy for Hepatocellular Carcinoma. PMID- 29119416 TI - Inorganic benzenes as the noncovalent interaction donor: a study of the pi-hole interactions. AB - For inorganic benzenes C3N3X3 and B3O3X3 (X = H, F, CN), the positive electrostatic potentials (pi-hole) were discovered above and below the inorganic benzene ring center. Then, the pi-hole interactions between the inorganic benzenes and NCH have been designed and investigated by MP2/aug-cc-pVDZ calculations. In this paper, the termolecular complexes B3O3X3...NCH...NCH, C3N3X3...NCH...NCH (X = H, F, CN) were also designed to illustrate the enhancing effects of the H...N hydrogen bond on the pi-hole interactions. The pi-hole interaction energy was influenced by the strength of different electron withdrawing substituents of inorganic benzenes, gradually increasing in the order of X = H, F, CN. What's more, the pi electron densities account for 71~88% of the total electron densities, indicating the strength of interaction energy is mainly determined by pi-type electron densities. Graphical abstract The termolecular complexes B3O3X3...NCH...NCH, C3N3X3...NCH...NCH (X = H, F, CN) were designed to illustrate the enhancing effects of the H...N hydrogen bond on the pi-hole interactions. PMID- 29119417 TI - Effect of methylene blue-mediated antimicrobial photodynamic therapy on dentin caries microcosms. AB - Antimicrobial photodynamic therapy (aPDT) has been proposed as an adjuvant treatment of dental caries, although there are no well-defined protocols to its clinical application. This study aimed to evaluate the influence of aPDT on the viability of microorganisms, vitality of biofilms, and lactic acid production of dentin caries microcosms. Biofilms were grown on bovine dentin discs in anaerobic conditions at 37 degrees C for 5 days, inoculating infected carious dentin in modified McBain medium plus 1% sucrose. The biofilms were treated by the combination of deionized water or 100 mg L-1 methylene blue (MB) with 0, 37.5, or 75 J cm-2 LED at 630 nm. The counts of total microorganisms, total streptococci, mutans streptococci, and total lactobacilli were determined by colony-forming units (CFU). The vitality of microbial cells in intact biofilms was measured by confocal laser scanning microscope (CLSM). The lactic acid production was analyzed by enzymatic spectrophotometry at 340 nm. Statistical analysis was conducted by Kruskal-Wallis and post hoc Dunn's tests (P < 0.05). MB and 37.5 J cm-2 LED alone did not interfere in the viability of microorganisms, unlike 75 J cm-2 LED alone that decreased the total microorganism and lactobacillus counts. The combination of MB and 75 J cm-2 LED reduced the viability of all microorganisms and the vitality of intact biofilms. The production of lactic acid was statistically lower in all treatment groups in comparison with that of the control (no treatment), except for MB alone. Therefore, the MB-mediated aPDT was effective in controlling the viability, vitality and the acidogenicity of dentin caries microcosms. PMID- 29119418 TI - Low-level laser therapy improves the VO2 kinetics in competitive cyclists. AB - Some evidence supports that low-level laser therapy (LLLT) reduces neuromuscular fatigue, so incrementing sports performance. A previous randomized controlled trial of our group showed increased exercise tolerance in male competitive cyclists treated with three different LLLT doses (3, 6, and 9 J/diode; or 135, 270, and 405 J/thigh) before time-to-exhaustion cycling tests. Now, the present study was designed to evaluate the effects of these LLLT doses on the VO2 kinetics of athletes during cycling tests. Twenty male competitive cyclists (29 years) participated in a crossover, randomized, double-blind, and placebo controlled trial. On the first day, the participants performed an incremental cycling test to exhaustion to determine maximal oxygen uptake (VO2MAX) and maximal power output (POMAX), as well as a familiarization with the time-to exhaustion test. In the following days (2 to 5), all participants performed time to-exhaustion tests at POMAX. Before the exhaustion test, different doses of LLLT (3, 6, and 9 J/diode; or 135, 270, and 405 J/thigh, respectively) or placebo were applied bilaterally to the quadriceps muscle. All exhaustion tests were monitored online by an open-circuit spirometry system in order to analyze the VO2 amplitude, VO2 delay time, time constant (tau), and O2 deficit. Tau and O2 deficit were decreased with LLLT applications compared to the placebo condition (p < 0.05). No differences (p > 0.05) were found between the experimental conditions for VO2 amplitude and VO2 delay time. In conclusion, LLLT decreases tau and O2 deficit during time-to-exhaustion tests in competitive cyclists, and these changes in VO2 kinetics response can be one of the possible mechanisms to explain the ergogenic effect induced by LLLT. PMID- 29119419 TI - Screening of promoters from Arthrobacter sp. CGMCC 3584 using a green fluorescent protein reporter system. AB - Available molecular and genetic tools for the genetic manipulation of Arthrobacter species are limited until now. In gene engineering, a continuous set of promoters with various strengths are of importance for fine-tuning gene expression in metabolic optimization and control analysis. Here, for the first time, we constructed a promoter trap system using green fluorescence protein (GFP) as a reporter, for screening and characterizing functional Arthrobacter promoters. Twenty-three Arthrobacter transformants of various GFP fluorescence strengths were isolated and characterized through the analysis of DNA sequences. Among the 23 putative promoters, 2 were selected for deletion analysis of promoter elements. As a result, the deletion of the upstream of the putative promoter P8 and P13 caused a 43.8% decrease and a 29.1% increase in the fluorescence signals, respectively. Finally, we obtained the strongest promoter P13-3 which was 4.4 times more potent than the promoter of 6-hydroxyl-D-nicotine oxidase gene which was previously reported in Arthrobacter nicotinovorans, and the obtained promoter was used to improve the production of cyclic adenosine monophosphate in Arthrobacter sp. CGMCC 3584. The screening strategy together with obtained promoters in this study would contribute to the future engineering of Arthrobacter species. PMID- 29119421 TI - Synthesis of novel (E)-2-(4-(1H-1,2,4-triazol-1-yl)styryl)-4- (alkyl/arylmethyleneoxy)quinazoline derivatives as antimicrobial agents. AB - A series of novel (E)-2-(4-(1H-1,2,4-triazol-1-yl)styryl)-4 (alkyl/arylmethyleneoxy)quinazoline derivatives (4a-4s) were synthesized in good to excellent yields, and their structures were fully characterized by [Formula: see text] NMR, [Formula: see text] NMR, HRMS and IR spectra. The structure of compound 4b was further confirmed via single-crystal X-ray diffraction analysis. The bioassay results indicated that compounds 4s, 4q and 4n inhibit phytopathogenic bacterium Xanthomonas axonopodis pv. citri (Xac) more potently than commercial bactericide bismerthiazol. However, not a single compound can effectively inhibit three pathogenic fungi tested at 50 [Formula: see text]. PMID- 29119422 TI - Supported Decision-Making: Implications from Positive Psychology for Assessment and Intervention in Rehabilitation and Employment. AB - Purpose This article reviews existing literature on positive psychology, supported decision-making (SDM), employment, and disability. It examines interventions and assessments that have been empirically evaluated for the enhancement of decision-making and overall well-being of people with disabilities. Additionally, conceptual themes present in the literature were explored. Methods A systematic review was conducted across two databases (ERIC and PsychINFO) using various combination of keywords of 'disabilit*', work rehabilitation and employment terms, positive psychology terms, and SDM components. Seven database searches were conducted with diverse combinations of keywords, which identified 1425 results in total to be screened for relevance using their titles and abstracts. Database search was supplemented with hand searches of oft-cited journals, ancestral search, and supplemental search from grey literature. Results Only four studies were identified in the literature targeting SDM and positive psychology related constructs in the employment and job development context. Results across the studies indicated small to moderate impacts of the assessment and interventions on decision-making and engagement outcomes. Conceptually there are thematic areas of potential overlap, although they are limited in the explicit integration of theory in supported decision making, positive psychology, disability, and employment. Conclusion Results suggest a need for additional scholarship in this area that focuses on theory development and integration as well as empirical work. Such work should examine the potential utility of considering positive psychological interventions when planning for SDM in the context of career development activities to enhance positive outcomes related to decision-making, self-determination, and other positive psychological constructs. PMID- 29119423 TI - Meningioma and breast cancer: survival of patients with synchronous and metachronous meningioma and breast cancer. AB - The prognosis of the association between Breast Cancer (BC) and Meningioma (M) is unknown. To evaluate the survival impact of tumor exposure sequence in patients with both tumors. Patients were divided in groups according to the tumors sequence: BC before M (group 1), synchronous BC + M (group 2) and BC after M (group 3). The SEER database was used. Demographics, meningioma and breast cancer variables were analyzed. The primary outcome was oncological survival. A total of 1715 patients were included (median follow-up:84 months). Group 2 had the shortest survival (median:32 months) and group 1 the longest (median:110 months). On the unadjusted analysis, group 2 had the shortest survival (HR:3.13, 95% CI 1.62-6.04) and adjusted analysis confirmed this finding (HR 3.11, 95% CI 1.58 6.19), with no statistical difference between the metachronous tumors groups. Increasing age (HR:1.13, 95% CI 1.11-1.15, p < 0.005) and grade III meningioma (HR:4.51, 95% CI 1.90-10.69, p < 0.005) were related with lower survival. Meningioma treatment had no influence on the survival (p > 0.05). The association between surgery and radiotherapy in BC treatment improved the outcome (HR 0.37, 95% CI 0.23-0.93, p < 0.05). Grade III meningioma and receptor hormonal status influenced synchronous tumors (p < 0.05) but had no influence on metachronous tumors survival (p > 0.05) on stratified analysis. Synchronous tumors were associated with lower survival. Increasing age had a negative influence on patient survival. Although surgery and radiotherapy for breast cancer had a positive influence in the outcome, meningioma treatment was not related with survival. Grade III meningioma and hormonal receptor status only influenced synchronous tumors patient survival. PMID- 29119424 TI - Health literacy assessment in adults with neurofibromatosis: electronic and short form measurement using FCCHL and Health LiTT. AB - Determining health literacy level is an important prerequisite for effective patient education. We assessed multiple dimensions of health literacy and sociodemographic predictors of health literacy in patients with neurofibromatosis. In 86 individuals with a confirmed diagnosis of neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), or schwannomatosis, we assessed health literacy status using two HL tools-the adapted functional, communicative, and critical health literacy scale (adapted FCCHL) and health literacy assessment using talking touchscreen technology (Health LiTT). Factor analyses of the adapted FCCHL in NF patients showed factor structure and psychometric properties similar to pilot work in other patient populations. As a group, patients with NF had moderate scores on the Health LiTT and moderate to high scores on the adapted FCCHL, with the highest score on the functional health literacy subscale. Patients with NF1, those with lower education and those with learning disabilities had lower scores on Health LiTT; in multivariate analysis, learning disability and education remained significant predictors of HealthLiTT scores. Only lower education was associated with lower adapted FCCHL scores. Results suggest utilizing health literacy tools in NF patients is feasible and could provide physicians with valuable information to tailor health communication to subpopulations with lower health literacy levels. PMID- 29119425 TI - Correction to: Changes in transcranial motor evoked potentials during hemorrhage are associated with increased serum propofol concentrations. AB - In the original publication of the article, the corresponding author inadvertently omitted one of the co-authors in the author group. The corrected author group is given in this erratum. PMID- 29119426 TI - C-terminal residues of ferredoxin-NAD(P)+ reductase from Chlorobaculum tepidum are responsible for reaction dynamics in the hydride transfer and redox equilibria with NADP+/NADPH. AB - Ferredoxin-NAD(P)+ reductase ([EC 1.18.1.2], [EC 1.18.1.3]) from Chlorobaculum tepidum (CtFNR) is structurally homologous to the bacterial NADPH-thioredoxin reductase (TrxR), but possesses a unique C-terminal extension relative to TrxR that interacts with the isoalloxazine ring moiety of the flavin adenine dinucleotide prosthetic group. In this study, we introduce truncations to the C terminal residues to examine their role in the reactions of CtFNR with NADP+ and NADPH by spectroscopic and kinetic analyses. The truncation of the residues from Tyr326 to Glu360 (the whole C-terminal extension region), from Phe337 to Glu360 (omitting Phe337 on the re-face of the isoalloxazine ring) and from Ser338 to Glu360 (leaving Phe337 intact) resulted in a blue-shift of the flavin absorption bands. The truncations caused a slight increase in the dissociation constant toward NADP+ and a slight decrease in the Michaelis constant toward NADPH in steady-state assays. Pre-steady-state studies of the redox reaction with NADPH demonstrated that deletions of Tyr326-Glu360 decreased the hydride transfer rate, and the amount of reduced enzyme increased at equilibrium relative to wild-type CtFNR. In contrast, the deletions of Phe337-Glu360 and Ser338-Glu360 resulted in only slight changes in the reaction kinetics and redox equilibrium. These results suggest that the C-terminal region of CtFNR is responsible for the formation and stability of charge-transfer complexes, leading to changes in redox properties and reactivity toward NADP+/NADPH. PMID- 29119427 TI - Isolation of Bacteriophages for Fastidious Bacteria. AB - One of the most important factors for successful bacteriophage therapy is, undoubtedly, the isolation of excellent therapeutic candidate bacteriophages. There are only a few reports about active bacteriophages in the fastidious bacteria Helicobacter pylori. In this chapter, we describe a method for isolating and purifying KHP30-like bacteriophages in H. pylori, which have lytic and pseudolysogenic life cycles. PMID- 29119428 TI - Isolation of Bacteriophages of the Anaerobic Bacteria Bacteroides. AB - Here we describe the detection, enumeration, and isolation of bacteriophages infecting Bacteroides. The method is based on the infection of Bacteroides host strains and the production of visible plaques in a confluent lawn of the host strain using the double-layer agar method. This is a straightforward methodology that can be applied for the detection, enumeration and isolation of bacteriophages for other anaerobic bacteria, using an appropriate host strain and culture conditions. In the case of bacteriophages of Bacteroides the results can be obtained in less than 24 h, although the time could vary depending on the growth rate of the host strain. PMID- 29119429 TI - Isolation of Bacteriophages for Clinically Relevant Bacteria. AB - A number of bacteriophages deposited in different culture collections target clinically relevant bacterial hosts. In this chapter, we describe a method for isolating bacteriophage plaques for the most common bacteria involved in nosocomial infections. PMID- 29119430 TI - In Vitro Activity of Bacteriophages Against Planktonic and Biofilm Populations Assessed by Flow Cytometry. AB - The in vitro activity of bacteriophages against planktonic cultures and biofilms is commonly evaluated by culture methods. However, these methods can lead to an underestimation of total bacterial cells when they undergo different physiological states.This chapter describes the methodology used to assess the in vitro activity of bacteriophages against planktonic cultures of bacteria in different metabolic states and biofilm populations by flow cytometry. PMID- 29119431 TI - Observation of Bacteriophage Ultrastructure by Cryo-electron Microscopy. AB - Transmission Electron Microscopy (TEM) is an ideal method to observe and determine the structure of bacteriophages. From early studies by negative staining to the present atomic structure models derived from cryo-TEM, bacteriophage detection, classification, and structure determination has been mostly done by electron microscopy. Although embedding in metal salts has been a routine method for virus observation for many years, preservation of bacteriophages in a thin layer of fast frozen buffer has proven to be a most convenient preparation method for obtaining images using cryo-electron microscopy (cryo-EM). In this technique, frozen samples are observed at liquid nitrogen temperature and the images are acquired using different recording media. The incorporation of direct electron detectors has been a fundamental step to achieve atomic resolution images of a number of viruses. These projection images can be numerically combined using different approaches to render a three-dimensional model of the virus. For those viral components exhibiting any symmetry, averaging procedures help to render near-atomic resolution structures. PMID- 29119432 TI - Bacteriophage Taxonomy: An Evolving Discipline. AB - While taxonomy is an often-unappreciated branch of science it serves very important roles. Bacteriophage taxonomy has evolved from a mainly morphology based discipline, characterized by the work of David Bradley and Hans-Wolfgang Ackermann, to the holistic approach that is taken today. The Bacterial and Archaeal Viruses Subcommittee of the International Committee on Taxonomy of Viruses (ICTV) takes a comprehensive approach to classifying prokaryote viruses measuring overall DNA and protein identity and phylogeny before making decisions about the taxonomic position of a new virus. The huge number of complete genomes being deposited with NCBI and other public databases has resulted in a reassessment of the taxonomy of many viruses, and the future will see the introduction of new viral families and higher orders. PMID- 29119434 TI - Recovery and Characterization of Bacteria Resisting Infection by Lytic Bacteriophage. AB - Bacteria and bacteriophages coexist and coevolve, bacteriophages being obligatory predators exerting an evolutionary pressure on their prey. Mechanisms in action vary depending on the bacterial genomic content and on the regulation of the bacteriophage cycle. To assess the multiplicity of bacterial genes involved in resistance as well as the changes in the bacteriophage interactions with the bacteria, it is necessary to isolate and investigate large numbers of independent resistant variants. Here we describe protocols that have been applied to the study of Pseudomonas aeruginosa and four of its virulent bacteriophages belonging to the Podoviridae and Myoviridae bacteriophage families. Mutations are identified using whole genome sequencing of resistant variants. Phenotypic analyses are performed to describe the changes conferred by the mutations. PMID- 29119433 TI - Determination of the Bacteriophage Host Range: Culture-Based Approach. AB - The bacteriophage host range is one of the most practically important characteristics of each bacterial virus. Here the classical plate-culture-based approach for bacteriophage host range determination is described. The important considerations related to interpretation of the data and limitations of the methods are discussed. PMID- 29119435 TI - Guidelines to Compose an Ideal Bacteriophage Cocktail. AB - Correctly designed bacteriophage therapeutics are the cornerstone for a successful outcome of bacteriophage therapy. Here we overview strategies on how to choose bacteriophages and their bacterial hosts at different steps of a bacteriophage cocktail development in order to comply with all quality and safety requirements based on the already existing essentially empirical experience in bacteriophage therapy and current accomplishments in modern biomedical sciences. A modification of the classic Appelmans' method (1922) to assess stability of bacteriophage activity in liquid media is presented in order to improve the overall performance of therapeutic bacteriophages individually and collectively in the cocktail. PMID- 29119436 TI - Interaction of Bacteriophages with Mammalian Cells. AB - Natural bacteriophages (present in the microbiome) and those applied as therapeutic agents may interact with mammalian cells and tissues. Adhesion interactions may define bacteriophage pharmacokinetics and resulting efficiency of bacteriophage agents in therapeutic applications by shaping bacteriophage homing to tissues and organs. Here we propose protocols for testing direct adhesion of bacteriophages or bacteriophage proteins to mammalian cells (in vitro). We further propose an animal model for investigation of accumulation/homing of bacteriophages in tissues (in vivo). PMID- 29119437 TI - In Vivo Bacteriophage Biodistribution. AB - At the dawn of the renaissance of bacteriophage therapy, the full acceptation of bacteriophages as anti-bacterial agents requires the determination of their basic pharmacokinetic parameters. Such data, known for all conventional drugs used in human and veterinary medicine, allow optimizing dose regimens, efficacy, and help to limit toxicity. Here, we describe basic methods to experimentally obtain pharmacokinetic data and give also examples of data calculation to determine key parameters related to the biodistribution and elimination of bacteriophages in vivo. PMID- 29119438 TI - Interaction of Bacteriophages with the Immune System: Induction of Bacteriophage Specific Antibodies. AB - In all cases when a bacteriophage makes direct contact with a mammalian organism, it may challenge the mammalian immunological system. Its major consequence is production of antibodies specific to the bacteriophage. Here we present protocols applicable in studies of bacteriophage ability to induce specific antibodies. The protocols have been divided into three parts: purification, immunization, and detection (ELISA). PMID- 29119439 TI - Bacteriophage Treatment of Infected Diabetic Foot Ulcers. AB - Diabetic foot ulcers occur as a common complication of diabetes. Healing of the ulcers is largely delayed by the concomitant infection. Antibiotic treatment of infected ulcers is complicated by formation of microbial biofilms , which are often heterogeneous and resistant to antibiotics. Bacteriophage therapy is considered as an additional approach to the treatment of infected wounds. Here, we describe the basic method of application of bacteriophages for treatment of infected diabetic foot ulcers, including ones that are very large. PMID- 29119440 TI - Compassionate Use of Bacteriophage Therapy for Foot Ulcer Treatment as an Effective Step for Moving Toward Clinical Trials. AB - We here present detailed descriptions of successful treatment of a series of diabetic toe ulcers using the Eliava BioPreparations' commercial preparation of the very well-studied anti-staphylococcal bacteriophage Sb-1. This chapter outlines what we feel is an appropriate mechanism to speed movement toward full scale clinical trials with bacteriophage use to treat wound infections and to help address the crisis in antibiotic resistance. PMID- 29119441 TI - Bacteriophage Production in Bioreactors. AB - The optimal conditions for the production of virulent bacteriophages in bioreactors can vary greatly depending on the host-bacteriophage system used. We present a general method for the production of virulent bacteriophages in bioreactors that can be adapted to many host-bacteriophage systems and various operating conditions (reactor volume, medium composition, temperature, etc.). The procedures detail how to establish optimal initial infection conditions (infection load and initial multiplicity of infection (MOI)), prepare the host pre-culture and bioreactor, operate the bioreactor, and harvest the bacteriophage product. Batch operation is detailed but a short discussion addresses other modes of operation, namely two-stage continuous bioreactors and two-stage cycling bioreactors. PMID- 29119442 TI - Computational Modeling of Bacteriophage Production for Process Optimization. AB - Computational models can be used to optimize the production of bacteriophages. Here a model is described for production in a two-stage self-cycling process. Theoretical and practical considerations for modeling bacteriophage production are first introduced. The key experimental protocols required to estimate key kinetic parameters for the model, including determining variable infection rates as a function of substrate concentration, are described. ppSim is an open-source R-script that can simulate bacteriophage production to optimize productivity or minimize costs. The steps included to run the simulation using the experimentally determined infection parameters are described. An example is also presented, where a level sensor and cycle time are optimized to maximize bacteriophage productivity in two sequential 1-L bioreactors, resulting in a production rate of 4.46 * 1010 bacteriophage particles/hour. The protocols and programs described here will allow users to potentially optimize production of their own bacteriophage-bacteria pairing by effectively applying bacteriophage modeling. PMID- 29119443 TI - Methods for Bacteriophage Preservation. AB - In a view of growing interest in bacteriophages as the most abundant members of microbial communities and as antibacterial agents, reliable methods for bacteriophage long-term preservation, that warrant the access to original or mutant stocks of unchanged properties, have become of crucial importance. A storage method that retains the infectivity of any kind of bacteriophage virions, either in a cell lysate or in a purified suspension, does not exist, due to the enormous diversity of bacteriophages and hence the differentiation of their sensitivity to various storage conditions. Here, we describe a method of long term bacteriophage preservation, which is based on freezing of freshly infected susceptible bacteria at early stages of bacteriophage development. The infected bacteria release mature bacteriophages upon melting enabling the recovery of bacteriophage virions with high efficiency. The only limitation of this method is the sensitivity of bacteriophage host to deep-freezing, and thus it can be used for the long-term preservation of the vast majority of bacteriophages. PMID- 29119444 TI - Bacteriophage Production in Compliance with Regulatory Requirements. AB - In this chapter we review bacteriophage production requirements to help institutions, which wish to manufacture bacteriophage products for human use in compliance with the applicable regulatory expectancies, defining production processes and implementing relevant controls ensuring quality, safety, and efficacy of the final products. The information disclosed in this chapter can also serve as a basis for discussions with competent authorities regarding the development of expedited bacteriophage product development and licensing pathways, including relevant and pragmatic requirements, and allowing for the full exploitation of bacteriophages as natural controllers of bacterial populations. PMID- 29119445 TI - Guidelines for Bacteriophage Product Certification. AB - Following decades in the wilderness, bacteriophage therapy is now appearing as a credible antimicrobial strategy. However, this reemerging therapy does not rekindle without raising sensitive regulatory concerns. Indeed, whereas the European regulatory framework has been basically implemented to tackle ready-to use pharmaceuticals produced on a large scale, bacteriophage therapy relies on a dynamic approach requiring a regulation on personalized medicine, nonexistent at present. Because of this, no guideline are currently available for addressing the scientific and regulatory issues specifically related to phage therapy medicinal products (PTMP).Pending to the implementation of an appropriate regulatory framework and to the development of ensuing guidelines, several avenues which might lead to PTMP regulatory compliance are explored here. Insights might come from the multi-strain dossier approach set up for particular animal vaccines, from the homologous group concept developed for the allergen products or from the licensing process for veterinary autogenous vaccines. Depending on national legislations, customized preparations prescribed as magistral formulas or to be used on a named-patient basis are possible regulatory approaches to be considered. However, these schemes are not optimal and should thus be regarded as transitional. PMID- 29119446 TI - Nano/Micro Formulations for Bacteriophage Delivery. AB - Encapsulation methodologies allow the protection of bacteriophages for overcoming critical environmental conditions. Moreover, they improve the stability and the controlled delivery of bacteriophages which is of great innovative value in bacteriophage therapy. Here, two different encapsulation methodologies of bacteriophages are described using two biocompatible materials: a lipid cationic mixture and a combination of alginate with the antacid CaCO3. To perform bacteriophage encapsulation, a purified lysate highly concentrated (around 1010 1011 pfu/mL) is necessary, and to dispose of a specific equipment. Both methodologies have been successfully applied for encapsulating Salmonella bacteriophages with different morphologies. Also, the material employed does not modify the antibacterial action of bacteriophages. Moreover, both technologies can also be adapted to any bacteriophage and possibly to any delivery route for bacteriophage therapy. PMID- 29119447 TI - Synthetic Biology to Engineer Bacteriophage Genomes. AB - Recent advances in the synthetic biology field have enabled the development of new molecular biology techniques used to build specialized bacteriophages with new functionalities. Bacteriophages have been engineered towards a wide range of applications including pathogen control and detection, targeted drug delivery, or even assembly of new materials.In this chapter, two strategies that have been successfully used to genetically engineer bacteriophage genomes are addressed: a yeast-based platform and bacteriophage recombineering of electroporated DNA. PMID- 29119448 TI - Total aortic arch replacement using frozen elephant trunk technique with J Graft Open Stent Graft for distal aortic arch aneurysm. AB - OBJECTIVES: The J Graft Open Stent Graft, the first commercialized stent graft in Japan, has been available since February 2014, and we have used this new device as a frozen elephant trunk technique for distal aortic arch aneurysm. Here, we present our surgical method and result with this new device. METHODS: Between October 2014 and October 2016, 30 patients (26 males, mean age 74.3 +/- 9.7 years) underwent total aortic arch replacement using the frozen elephant trunk technique with the J Graft Open Stent Graft for distal aortic arch aneurysm. The follow-up period was 10 months. RESULTS: In-hospital mortality and 30-day mortality were 0%. Stroke occurred in three cases (10%), paraplegia in one case (3.3%), respiratory complication in two cases (6.7%), and renal failure in two cases (6.7%). During the follow-up period, there was no aorta- related death, and two patients needed an aortic operation (re-hemiarch replacement for pseudoaneurysm of proximal anastomotic site; axilloaxillary bypass for occlusion of the left subclavian artery), and two patients needed catheter embolization for type II endoleak for reopening of the left subclavian artery. CONCLUSION: Our short-term surgical results were acceptable. This new device is useful for distal aortic arch aneurysms. PMID- 29119449 TI - Successful coronary transfer for transposition of the great arteries with bilateral intramural coronary arteries from a single aortic sinus. AB - We experienced an arterial switch operation in a patient with d-transposition of the great arteries associated with bilateral intramural coronary arteries from a single coronary ostium. In performing the coronary transfer, intramural course of bilateral coronary arteries was unroofed and coronary ostium was separated into two coronary buttons. The two coronary buttons were translocated to the neo-aorta using modified trap-door technique. The angiogram performed 6 years after the operation revealed well-developed coronary arteries without stenosis, and the patient is doing well 8 years after the operation. PMID- 29119450 TI - Surgical treatment for adult congenital heart disease: consideration for indications and procedures. AB - The number of the adult patients with congenital heart diseases (ACHD) continues to grow owing to improvement of surgical results and medical management. Corrective surgery for complex CHD does not always mean complete cure. It is not rare that the patients will visit the cardiology institutes because of secondary lesions due to residua or sequela in adults. Some patients with CHD remain unrepairable with different degree of heart failure and pulmonary arterial hypertension. Association of arrhythmias is common in ACHD patients and sometimes critical. We experienced 265 surgical procedures for ACHD patients at our center between 1999 and 2015. Of these procedures, palliative surgery was performed in 3%, palliation to corrective surgery in 6%, primary repair in 57%, and redo surgery in 34%. Hospital mortality within 30 days in this period was 1.1%. Surgery for ACHD patients is safe, beneficial and low-risk treatment; however, tailored procedures for the individual patient are essential to obtain the optimal quality. A comprehensive multidisciplinary approach is required to fulfill this goal. PMID- 29119451 TI - Pristimerin Inhibits LPS-Triggered Neurotoxicity in BV-2 Microglia Cells Through Modulating IRAK1/TRAF6/TAK1-Mediated NF-kappaB and AP-1 Signaling Pathways In Vitro. AB - Microglia plays a prominent role in the brain's inflammatory response to injury or infection by migrating to affected locations and secreting inflammatory molecules. However, hyperactivated microglial is neurotoxic and plays critical roles in the pathogenesis of neurodegenerative diseases. Pristimerin, a naturally occurring triterpenoid, possesses antitumor, antioxidant, and anti-inflammatory activities. However, the effect and the molecular mechanism of pristimerin against lipopolysaccharide (LPS)-induced neurotoxicity in microglia remain to be revealed. In the present study, using BV-2 microglial cultures, we investigated whether pristimerin modifies neurotoxicity after LPS stimulation and which intracellular pathways are involved in the effect of pristimerin. Here we show that pristimerin markedly suppressed the release of Regulated on Activation, Normal T Expressed and Secreted (RANTES), transforming growth factor-beta1 (TGF beta1), IL-6, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO). Pristimerin also significantly inhibited migration of BV-2 microglia and alleviated the death of neuron-like PC12 cell induced by the conditioned medium from LPS-activated BV-2 microglial cells. Moreover, pristimerin reduced the expression and interaction of TNF Receptor-Associated Factor 6 (TRAF6) and Interleukin-1 Receptor-Associated Kinases (IRAK1), limiting TGF-beta activating kinase 1 (TAK1) activation, and resulting in an inhibition of IKKalpha/beta/NF kappaB and MKK7/JNK/AP-1 signaling pathway in LPS-activated BV-2 microglia. Taken together, the anti-neurotoxicity action of pristimerin is mediated through the inhibition of TRAF6/IRAK1/TAK1 interaction as well as the related pathways: IKKalpha/beta/NF-kappaB and MKK7/JNK/AP-1 signaling pathways. These findings may suggest that pristimerin might serve as a new therapeutic agent for treating hyperactivated microglial induced neurodegenerative diseases. PMID- 29119452 TI - Mental health, loneliness, and illness perception outcomes in quality of life among young breast cancer patients after mastectomy: the role of breast reconstruction. AB - PURPOSE: Tauomicron explore the relationship between mental health (depression, anxiety, and stress), loneliness, and illness perception with health-related quality of life (HRQoL) in young breast cancer patients, within a year after mastectomy, and to investigate the role of breast reconstruction. METHODS: Eighty one women with stage II breast cancer-35 with breast reconstruction and 46 without breast reconstruction-completed the Missoula-VITAS Quality of Life Index 15, the Depression Anxiety Stress Scale 21, the UCLA Loneliness Scale, the Brief Illness Perception Questionnaire, and a questionnaire with demographic and medical information. Statistical analysis was performed using IBM SPSS Statistics version 20. RESULTS: Breast reconstruction was a significant predictor of total HRQoL and its domains. Women with breast reconstruction had better HRQoL, significantly better mental health, less stress and anxiety levels but experienced more physical discomfort and perceived higher level of physical distress compared to the ones without breast reconstruction. On the contrary, patients without breast reconstruction had higher level of loneliness, which was found to be correlated with poor HRQoL and higher levels of anxiety. Negative illness perceptions were associated with poor HRQoL for both groups. CONCLUSIONS: Breast reconstruction is not a panacea for patients in improving HRQoL. PMID- 29119453 TI - Neighborhood structural differences and women's mental health: an empirical study in Accra, Ghana. AB - PURPOSE: This study explores the relationships between neighborhood structural differences such as socioeconomic status (SES), income inequality, and ethnic diversity on women's mental health in Accra, Ghana. METHODS: The study used secondary data from the 2009 Women Health Survey Accra II, linked with the 2010 sub-metro level census figures on income inequality. The analytical sample consists of 2814 women nested within 195 enumeration areas (clusters) in the Accra Metropolitan Area (AMA). Multilevel binary logit and complimentary log-log models were used to analyze the data. RESULTS: Results suggest that social capital and neighborhood socioeconomic structural factors such SES, ethnic diversity, and housing ownership were associated with depressive symptoms, feeling downhearted, and self-reported health. CONCLUSIONS: These findings suggest that policies and programs that improve the physical and economic conditions of deprived neighborhoods, as well as civic initiatives that improve social capital and cohesion, may be important for promoting collective actions and improving health outcomes in urban settings like Accra. PMID- 29119454 TI - New resilience instrument for patients with cancer. AB - OBJECTIVE: Resilience is an important concept in the cancer literature and is a salient indicator of cancer survivorship. The aim of this study is to develop and validate a new resilience instrument that is specific to patients with cancer diagnosis (RS-SC) in Mainland China. METHODS: First, a resilience framework was constructed for patients with cancer diagnosis. Second, items were formulated based on the framework to reflect different aspects of resilience. Third, two rounds of expert panel discussion were performed to select important and relevant items. Finally, two cross-sectional studies were conducted to evaluate the psychometric properties of this instrument. RESULTS: Fifty-one items were generated based on the resilience framework and the final 25-item RS-SC resulted in a five-factor solution including Generic Elements, Benefit Finding, Support and Coping, Hope for the Future and Meaning for Existence, accounting for 64.72% of the variance. The Cronbach's alpha of the RS-SC was 0.825 and the test-retest reliability was 0.874. CONCLUSION: The RS-SC is a brief and specific self-report resilience instrument for Chinese patients with cancer and shows sound psychometric properties in this study. The RS-SC has potential applications in both clinical practice and research with strength-based resiliency interventions. PMID- 29119455 TI - CT brain artefact due to air bubbles in the oil cooling system: characteristic band-like configuration on sagittal reformatted image. AB - PURPOSE: To retrospectively review the imaging characteristics of CT artefacts due to air bubbles within the oil cooling system of the X-ray tube housing. MATERIALS AND METHODS: Air bubbles were introduced into the oil cooling system of the X-ray tube housing during tube replacement in one of the CT scanners in the authors' institution. All 126 CT brain studies performed in this period were retrospectively reviewed. One hundred and four studies were negative for artefacts. Artefacts were confirmed in 5 and considered probable in 17 studies, respectively. The imaging characteristics of artefacts in these 22 cases were analysed. RESULTS: All artefacts manifested as ill-defined hypoattenuations in the periventricular/subcortical white matter of bilateral cerebral hemispheres with/without involvement of the internal capsule and basal ganglia. The posterior fossa was also involved in two (40%) confirmed and four (24%) probable studies. A band-like configuration of hypoattenuations on sagittal images was observed in five (100%) confirmed and eight (47%) probable studies. CONCLUSION: Air bubble artefacts manifested as hypoattenuations in the periventricular/subcortical white matter of the supratentorial brain. A characteristic band-like configuration was observed in the sagittal reformatted image, which is useful for differentiating it from periventricular small vessel disease. PMID- 29119456 TI - Heterogeneity of longitudinal and circumferential contraction in relation to late gadolinium enhancement in hypertrophic cardiomyopathy patients with preserved left ventricular ejection fraction. AB - PURPOSE: To evaluate heterogeneity of myocardial contraction in relation to extensive late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM) patients with preserved left ventricular ejection fraction, using fast strain encoded magnetic resonance imaging. MATERIALS AND METHODS: Twenty-two HCM patients and 24 age-matched control subjects were included in this retrospective study. The regional and global peak values of longitudinal and circumferential strain (LSregional, LSglobal, CSregional, CSglobal), and their regional heterogeneities were evaluated using coefficients of variation (LSCoV, CSCoV) in relation to LGE. Receiver operating characteristic curve analysis was performed to identify patients with a total left ventricular myocardial LGE >= 15%. RESULTS: LSglobal in HCM patients was significantly decreased compared to that in controls (- 14.4 +/- 2.4% vs - 17.2 +/- 2.0%; p = 0.0004), while CSglobal was not (p = 1.0). Negative LGE segments demonstrated decreased LSregional in HCM patients compared to in controls (p < 0.0001), while CSregional was not decreased. CSCoV demonstrated the largest area under the curve (AUC) (0.91), with high sensitivity (83%) and specificity (94%) for detection of HCM patients with extensive LGE, while the AUC of LSCoV was low (0.49). CONCLUSION: The heterogeneity in CSregional has a high diagnostic value for detection of HCM patients with extensive LGE. PMID- 29119457 TI - Dual energy computed tomography for the head. AB - Dual energy CT (DECT) is a promising technology that provides better diagnostic accuracy in several brain diseases. DECT can generate various types of CT images from a single acquisition data set at high kV and low kV based on material decomposition algorithms. The two-material decomposition algorithm can separate bone/calcification from iodine accurately. The three-material decomposition algorithm can generate a virtual non-contrast image, which helps to identify conditions such as brain hemorrhage. A virtual monochromatic image has the potential to eliminate metal artifacts by reducing beam-hardening effects. DECT also enables exploration of advanced imaging to make diagnosis easier. One such novel application of DECT is the X-Map, which helps to visualize ischemic stroke in the brain without using iodine contrast medium. PMID- 29119458 TI - Efficacy of radioiodine therapy for treating 20 patients with pulmonary metastases from differentiated thyroid cancer and a meta-analysis of the current literature. AB - BACKGROUND: Radioiodine therapy (RAI) after total or near-total thyroidectomy is a recommended treatment for patients with pulmonary metastasis from differentiated thyroid cancer (DTC). However, the total effective rate of iodine 131 therapy remains controversial. This study aimed to determine the efficacy of RAI for treating patients with pulmonary metastasis from DTC, and to identify independent predictors of its efficacy. METHODS: We conducted a retrospective study to evaluate 20 patients with pulmonary metastasis from DTC who underwent RAI at our center at first and performed a meta-analysis to evaluate relevant literature regarding the overall efficacy of RAI and subgroup-specific efficacies subsequently. RESULTS: The efficacy rate at our center was 40%, and no significant differences were observed according to sex, age, pathological type, metastasis state, or interval between the initial RAI and final surgery. The meta analysis revealed that the pooled overall efficacy rate was 58%, and significant differences were observed when we compared pulmonary metastasis versus pulmonary and other distant metastasis, age of < 40 years versus age of >= 40 years, papillary thyroid cancer versus follicular thyroid cancer and male patients versus female patients. CONCLUSIONS: These results suggest that RAI is an effective treatment for patients with pulmonary metastasis from DTC after surgical treatment. The efficacy of RAI was significantly predicted by the presence of papillary thyroid cancer, age of < 40 years, the absence of non-lung distant metastasis and female patients. PMID- 29119459 TI - Ethics and Epistemology of Big Data. AB - In this Symposium on the Ethics and Epistemology of Big Data, we present four perspectives on the ways in which the rapid growth in size of research databanks i.e. their shift into the realm of "big data"-has changed their moral, socio political, and epistemic status. While there is clearly something different about "big data" databanks, we encourage readers to place the arguments presented in this Symposium in the context of longstanding debates about the ethics, politics, and epistemology of biobank, database, genetic, and epidemiological research. PMID- 29119460 TI - Personal Genomic Testing, Genetic Inheritance, and Uncertainty. AB - The case outlined below is the basis for the In That Case section of the "Ethics and Epistemology of Big Data" symposium. Jordan receives reports from two separate personal genomic tests that provide intriguing data about ancestry and worrying but ambiguous data about the potential risk of developing Alzheimer's disease. What began as a personal curiosity about genetic inheritance turns into an alarming situation of medical uncertainty. Questions about Jordan's family tree are overshadowed by even more questions about Alzheimer's disease and healthy ageing. As a parent, Jordan is unsure whether to share these results and what it would mean for their children to learn about their genetic inheritance and potential future health. Furthermore, Jordan is unsure how to make sense of these reports in light of current knowledge of the risk factors for Alzheimer's disease and in the absence of effective treatments or robust preventative guidelines. PMID- 29119461 TI - The Future Emerges from the Past : Comment on "Personal Genomic Testing, Genetic Inheritance, and Uncertainty". AB - The case of Jordan (Mason 2017) highlights the gamble of connecting with the past through genomic testing. Unfortunately for Jordan, his genomic testing identified two variant genes which account for up to 75 per cent of early-onset Alzheimer's disease cases. Furthermore, his children were identified as having a 50 per cent risk of inheriting the gene which corresponds to the majority of early-onset Alzheimer's disease cases. Now Jordan is not only burdened with the foreknowledge that he will most likely develop Alzheimer's disease at a relatively young age but also burdened with the knowledge that his children may share his fate. Jordan was overwhelmed by his attempts to understand the genetic tests and experienced substantial distress. This response highlights the need for industry-wide regulations that adequately prepare individuals for the decision of whether to initiate genomic testing and require the results to be interpreted with genetic counsellors or other suitably skilled doctors. Furthermore, these industry-wide regulations need to be accountable to the same evidence-based standards that regulate the rest of the medical professions. PMID- 29119462 TI - Syncope in Pediatric Practice. AB - Syncope is defined as a sudden, self-limited loss of consciousness and postural tone followed by spontaneous and complete recovery without any neurological sequelae. It is one of the most common paroxysmal disorders in children and adolescents. The three major causes of syncope in children are neural, cardiovascular and other non-cardiovascular causes. The common unifying mechanism is transient global hypoperfusion of the brain. The diagnosis is primarily clinical and objective laboratory investigations add little to the diagnosis in children especially in neurocardiogenic subtype. Specific management depends on the underlying cause of syncope in children. For cardiac causes, management includes early referral to the pediatric cardiology specialist. When paroxysmal non-epileptic events are suspected, child psychology or psychiatry consultation should be sought to identify the stressors and counseling. For neurocardiogenic syncope, the main objective of treatment is to prevent recurrent events to improve the quality of life, psychological stress and school absenteeism by behavior and lifestyle modifications followed by drugs in refractory cases. The prognosis is excellent for neurocardiogenic syncope and is variable based on the underlying pathology in cardiogenic cases. As syncope is not a disease in itself but a symptom of an underlying disorder; hence, all children with syncope require assessment to exclude an underlying life-threatening cardiac or non-cardiac disorder. PMID- 29119463 TI - Socio-demographic Profile and Economic Burden of Treatment of Transfusion Dependent Thalassemia. AB - OBJECTIVE: To compile the socio-demographic profile and estimate the economic burden of transfusion dependent thalassemia. METHODS: This cross-sectional descriptive study was conducted at a tertiary care hospital in north India. Transfusion dependent thalassemia patients on regular blood transfusion for at least a year were selected. Thalassemia diagnosis was based on HPLC and/or mutation analysis results. Clinical and laboratory parameters were collected from electronic health records. Information regarding socio-economic profile and costs incurred, including indirect costs were collected by interviewing patients' guardians. The data was analyzed as a whole cohort and also in subgroups based on age. RESULTS: The data of 261 patients with a median age of 127 mo was collected. The median age at diagnosis was 9.8 mo. The total treatment expenses of a patient per year ranged from US$ 629 (INR 41,514) to US$ 2300 (INR 151,800), in the different age groups, at an average of US$ 1135 (INR 74,948). More than half (53%) of this was spent on medications. On an average, 38.8% of the family income was spent on the treatment of a thalassemia patient annually. Only 19 of 262 cases had an average pre-BT Hb >= 9 g/dl and serum ferritin <=1500 ng/dl. CONCLUSIONS: The treatment for transfusion dependent thalassemia is costly and mostly borne by the families in India. This study provides a realistic magnitude of this burden and will be useful in planning a thalassemia management program at the state or national level. PMID- 29119464 TI - Pediatric Cataract - Importance of Early Detection and Management. AB - Pediatric cataract is often diagnosed and managed late. This delay may be due to the ignorance on the part of the community, financial constraints, delay in the diagnosis and lack of tertiary care facilities. There is an urgent need to include rubella vaccination in the universal immunization program. A Simple Red Reflex test to detect a cataract and guiding the parent for early intervention will go a long way in achieving the target of eliminating cataract as a cause of childhood blindness. The importance of early detection and quick referral to a multispecialty center can save the child of lot many blind-years. These children have the potential to achieve the best possible visual acuity if managed early. PMID- 29119465 TI - Probiotic and Synbiotic Sorbets Produced with Jussara (Euterpe edulis) Pulp: Evaluation Throughout the Storage Period and Effect of the Matrix on Probiotics Exposed to Simulated Gastrointestinal Fluids. AB - The aims of the present study were to develop and evaluate different formulations of probiotic and synbiotic sorbets produced with jussara (Euterpe edulis) pulp, polydextrose, Lactobacillus acidophilus LA3, and Lactobacillus paracasei BGP1. The pasteurized jussara pulp presented high content of phenolic compounds, especially anthocyanins, which were not inhibitory to the probiotics used in this study. The levels of polyphenols and anthocyanins present in the sorbets were also high and kept stable for 120 days, as well as the populations of both probiotics. On the other hand, probiotic populations reduced ca. 4 log CFU/g when exposed to simulated gastrointestinal fluids. Altogether, the sorbets produced in this study showed interesting results, indicating the viability on producing functional foods with probiotics, prebiotics, and other components that are rich in polyphenols, such as jussara pulp. The combination of these elements can improve the health beneficial effects of these compounds and provide important advantages to the intestinal microbiota of consumers. PMID- 29119466 TI - A modified lightwand-guided approach for placement of a King Laryngeal TubeTM. PMID- 29119467 TI - Greenhouse gases: the choice of volatile anesthetic does matter. PMID- 29119468 TI - Clinical Decision Support and Optional Point of Care Testing of Renal Function for Safe Use of Antibiotics in Elderly Patients: A Retrospective Study in Community Pharmacy Practice. AB - OBJECTIVE: The aim was to investigate the management of drug therapy alerts on safe use of antibiotics in elderly patients with (potential) renal impairment and the contribution of optional creatinine point of care testing (PoCT) in community pharmacy practice. METHODS: Community pharmacists used a clinical decision support system (CDSS) for seven antibiotics. Alerts were generated during prescription processing in the case of previously registered renal impairment and when no information on renal function was available for patients aged 70 and over. Pharmacists could perform PoCT when renal function could not be retrieved from other health care professionals. Actions were registered in the CDSS. A retrospective descriptive analysis of alert management, performed PoCT and medication dispensing histories was performed. RESULTS: A total of 351 pharmacists registered the management of 88,391 alerts for 64,763 patients. For 68,721 alerts (77.7%), the pharmacist retrieved a renal function above the threshold for intervention. 1.7% of the alerts (n = 1532) led to a prescription modification because of renal impairment; in 3.0% of the alerts (n = 2631), the patient had renal impairment, but the pharmacist judged that no intervention was needed. Pharmacists performed 1988 PoCTs (2.2% of the alerts), which led to 15 prescription modifications (0.8% of the PoCT). CONCLUSION: Community pharmacists performed CDSS-based interventions to prevent potentially inappropriate (dosing of) antibiotics in elderly patients with renal impairment. Pharmacists were well able to retrieve information on renal function, using PoCT in a limited number of cases. The intervention rate could be greatly increased by better registration of information on renal function. Performing PoCT seems especially worthwhile in the highest age groups. PMID- 29119469 TI - Learning to prescribe intravenous fluids: A scoping review. AB - INTRODUCTION: Prescribing intravenous (IV) fluid therapy is a core skill expected of qualified doctors at the point of graduation, but medical graduates often feel ill-equipped to perform this task. This lack of preparedness contributes to treatment-related patient harm. This scoping review maps the current state of published evidence about how junior doctors prescribe IV fluid therapy and learn how to do it. METHODS: We searched five electronic databases and grey literature from 1994 until June 2016 for articles describing any aspect of IV fluid prescribing practice or its education. A total of 63 articles were selected for analysis. Using the WHO Guide to Good Prescribing to categorize the extracted findings, our review focuses on prescribing IV fluids in adult generalist settings. RESULTS: Most articles studied IV fluid prescribing from the perspective of the doctor. Junior clinicians struggled to conceptualize IV fluid prescribing as a 'whole task' in authentic work settings and lacked support. Educational interventions to improve IV fluid prescribing often focused on enhancing prescriber knowledge about fluid and electrolyte balance rather than execution of the prescribing task. CONCLUSIONS: Our understanding of IV fluid prescribing as a holistic integrated skill is patchy, as is its performance. Current IV fluid prescribing education appears insufficient to foster safe and effective practice. For education to achieve the ultimate goal of safer prescribing in workplaces, we need a clearer understanding of how healthcare professionals prescribe IV fluids in real world practice. PMID- 29119470 TI - Failure to flow: An exploration of learning and teaching in busy, multi-patient environments using an interpretive description method. AB - INTRODUCTION: As patient volumes continue to increase, more attention must be paid to skills that foster efficiency without sacrificing patient safety. The emergency department is a fertile ground for examining leadership and management skills, especially those that concern prioritization in multi-patient environments. We sought to understand the needs of emergency physicians (EPs) and emergency medicine junior trainees with regards to teaching and learning about how best to handle busy, multi-patient environments. METHOD: A cognitive task analysis was undertaken, using a qualitative approach to elicit knowledge of EPs and residents about handling busy emergency department situations. Ten experienced EPs and 10 junior emergency medicine residents were interviewed about their experiences in busy emergency departments. Transcripts of the interviews were analyzed inductively and iteratively by two independent coders using an interpretive description technique. RESULTS: EP teachers and junior residents differed in their perceptions of what makes an emergency department busy. Moreover, they focused on different aspects of patient care that contributed to their busyness: EP teachers tended to focus on volume of patients, junior residents tended to focus on the complexity of certain cases. The most important barrier to effective teaching and learning of managerial skills was thought to be the lack of faculty development in this skill set. CONCLUSIONS: This study presents qualitative data that helps us elucidate how patient volumes affect our learning environments, and how clinical teachers and residents operate within these environments. PMID- 29119471 TI - HIV Testing Among Men Who Have Sex with Men in the Northeastern United States. AB - Men who have sex with men (MSM) continue to be at especially high risk for HIV in the United States. Past studies have shown that rates of HIV testing differ across a number of demographic and behavioral factors, and this research may be helpful for targeting efforts to increase testing among certain subgroups of MSM. In this study, MSM were recruited from several online sources to complete a questionnaire on HIV testing. Generalized ordered logit models suggested that the odds of having tested within the last 12 months were higher among racial/ethnic minority MSM, those with a college degree, and those who engaged in more recent HIV-risk behavior. The odds of having tested within the last 12 months were also higher among those who reported having sex with a partner they met online in the last 12 months. Conversely, the odds of having tested in the last 12 months were lower among those who reported drinking alcohol heavily, when compared with more moderate drinkers, highlighting yet another potential impact of alcohol on HIV outcomes. PMID- 29119472 TI - MSM at Highest Risk for HIV Acquisition Express Greatest Interest and Preference for Injectable Antiretroviral PrEP Compared to Daily, Oral Medication. AB - Men who have sex with men (MSM) account for nearly 70% of new HIV diagnoses, with young black MSM at the highest risk for infection in the United States. Pre exposure prophylaxis (PrEP) can decrease HIV acquisition in at-risk individuals by over 90%. However, therapeutic efficacy requires a daily pill, posing adherence challenges. Experimental modalities, including injectable PrEP given once every 2 months, may improve adherence among those most in need. To assess interest in and preference for injectable PrEP, an online survey was mounted on two popular MSM sexual networking apps. Differences by age, race, and other characteristics were examined using multinomial logistic regressions. Of 4638 respondents, 73% expressed interest in injectable PrEP and 47% indicated they would prefer an injection (compared to 17% who prefer a daily pill and 36% who were unsure). Within this sample, interest in and preference for injectable PrEP was highest among MSM at highest risk for HIV infection (i.e., younger age groups, racial/ethnic minorities, those with risker sexual behavior). As a result, if proven effective in clinical trials, injectable PrEP has the potential to reduce social disparities in HIV transmission among MSM. PMID- 29119473 TI - Preference of Oral Tenofovir Disoproxil Fumarate/Emtricitabine Versus Rectal Tenofovir Reduced-Glycerin 1% Gel Regimens for HIV Prevention Among Cisgender Men and Transgender Women Who Engage in Receptive Anal Intercourse with Men. AB - Oral pre-exposure prophylaxis (PrEP) can prevent HIV transmission. Yet, some may prefer not to take systemic daily medication. MTN-017 was a 3-period, phase 2 safety and acceptability study of microbicide gel applied rectally either daily or before and after receptive anal intercourse (RAI), compared to daily oral tablet. At baseline, cisgender men and transgender women who reported RAI (N = 187) rated the daily oral regimen higher in overall liking, ease of use, and likelihood of future use than the gel regimens. After trying all three, 28% liked daily oral the least. Gel did not affect sexual enjoyment (88%) or improved it (7 8%). Most partners had no reaction to gel use. Ease of gel use improved significantly between the first and the last few times of daily use. A rectal gel used before and after RAI may constitute an attractive alternative to daily tablet. Experience with product use may increase acceptability. PMID- 29119475 TI - Comparative Cost-Effectiveness Analysis of Three Different Automated Medication Systems Implemented in a Danish Hospital Setting. AB - INTRODUCTION: Automated medication systems have been found to reduce errors in the medication process, but little is known about the cost-effectiveness of such systems. The objective of this study was to perform a model-based indirect cost effectiveness comparison of three different, real-world automated medication systems compared with current standard practice. METHODS: The considered automated medication systems were a patient-specific automated medication system (psAMS), a non-patient-specific automated medication system (npsAMS), and a complex automated medication system (cAMS). The economic evaluation used original effect and cost data from prospective, controlled, before-and-after studies of medication systems implemented at a Danish hematological ward and an acute medical unit. Effectiveness was described as the proportion of clinical and procedural error opportunities that were associated with one or more errors. An error was defined as a deviation from the electronic prescription, from standard hospital policy, or from written procedures. The cost assessment was based on 6 month standardization of observed cost data. The model-based comparative cost effectiveness analyses were conducted with system-specific assumptions of the effect size and costs in scenarios with consumptions of 15,000, 30,000, and 45,000 doses per 6-month period. RESULTS: With 30,000 doses the cost effectiveness model showed that the cost-effectiveness ratio expressed as the cost per avoided clinical error was ?24 for the psAMS, ?26 for the npsAMS, and ?386 for the cAMS. Comparison of the cost-effectiveness of the three systems in relation to different valuations of an avoided error showed that the psAMS was the most cost-effective system regardless of error type or valuation. CONCLUSION: The model-based indirect comparison against the conventional practice showed that psAMS and npsAMS were more cost-effective than the cAMS alternative, and that psAMS was more cost-effective than npsAMS. PMID- 29119474 TI - Food Insecurity is Associated with Poor HIV Outcomes Among Women in the United States. AB - Women in the general population experience more food insecurity than men. Few studies have examined food insecurity's impact on HIV treatment outcomes among women. We examined the association between food insecurity and HIV outcomes in a multi-site sample of HIV-infected women in the United States (n = 1154). Two fifths (40%) of participants reported food insecurity. In an adjusted multivariable Tobit regression model, food insecurity was associated with 2.08 times higher viral load (95% confidence interval (CI): 1.04, 4.15) and lower CD4+ counts (- 42.10, CI: - 81.16, - 3.03). Integration of food insecurity alleviation into HIV programs may improve HIV outcomes in women. PMID- 29119476 TI - Lessons Learned: Implementation of Pilot Universal Postpartum Nurse Home Visiting Program, Massachusetts 2013-2016. AB - Purpose Home visiting programs for new families in the United States have traditionally served high-risk families. In contrast, universal home visiting models serve all families regardless of income, age, risk or other criteria. They offer an entry point into a system of care for children and families, with the potential to improve population health. This paper describes lessons learned from the first three years of implementing a universal home visiting model. Description Welcome Family is a universal home visiting program in Massachusetts that offers a one-time visit by a nurse to new mothers up to eight weeks postpartum. The Massachusetts Department of Public Health (MDPH) is piloting Welcome Family in four communities with the goal of expanding statewide. Assessment Welcome Family served over 3000 families in its first three years. Program performance measures provided a framework to examine successes and challenges related to outreach and enrollment, program operations, and linkages with community resources. Early challenges included increasing referrals to a new program and limited capacity to serve all women giving birth. Local implementing agencies tested innovative strategies and MDPH made program modifications, such as developing quarterly data reports and establishing a learning collaborative, to address identified challenges. Conclusion MDPH is committed to the success of Welcome Family and uses continuous quality improvement to maximize the impact of the program on families and the system of care in Massachusetts. Lessons learned from the Massachusetts pilot can inform other states' efforts to enhance their early childhood systems of care through expanding universal home visiting. PMID- 29119477 TI - Pregnancy-Related Deaths, Florida, 1999-2012: Opportunities to Improve Maternal Outcomes. AB - Objectives To examine pregnancy-related deaths (PRDs) in Florida, to identify quality improvement (QI) opportunities, and to recommend strategies aimed at reducing maternal mortality. Methods The Florida Pregnancy-Associated Mortality Review (PAMR) Committee reviewed PRDs occurring between 1999 and 2012. The PAMR Committee determined causes of PRDs, identified contributing factors, and generated recommendations for prevention and quality improvement. Information from the PAMR data registry, and live births from Florida vital statistic data were used to calculate pregnancy-related mortality ratios (PRMR) and PRD univariate risk ratios (RR) with 95% confidence intervals (CI). Results Between 1999 and 2012, the PRMR fluctuated between 14.7 and 26.2 PRDs per 100,000 live births. The five leading causes of PRD were hypertensive disorders (15.5%), hemorrhage (15.2%), infection (12.7%), cardiomyopathy (11.1%), and thrombotic embolism (10.2%), which accounted for 65% of PRDs. Principal contributing factors were morbid obesity (RR = 7.0, 95% CI 4.9-10.0) and late/no prenatal care (RR = 4.2, 95% CI 3.1-5.6). The PRMR for black women was three-fold higher (RR = 3.3, 95% CI 2.7-4.0) than white women. Among the five leading causes of PRDs, 42.5% had at least one clinical care or health care system QI opportunity. Two-third of these were associated with clinical quality of care, which included standards of care, coordination, collaboration, and communication. The QI opportunities varied by PRD cause, but not by race/ethnicity. Conclusion Gaps in clinical care or health care systems were assessed as the primary factors in over 40% of PRDs leading the PAMR Committee to generate QI recommendations for clinical care and health care systems. PMID- 29119478 TI - After The Demonstration: What States Sustained After the End of Federal Grants to Improve Children's Health Care Quality. AB - Introduction Under the CHIPRA Quality Demonstration Grant Program, CMS awarded $100 million through 10 grants that 18 state Medicaid agencies implemented between 2010 and 2015. The program's legislatively-mandated purpose was to evaluate promising ideas for improving the quality of children's health care provided through Medicaid and CHIP. As part of the program's multifaceted evaluation, this study examined the extent to which states sustained key program activities after the demonstration ended. Methods We identified 115 potentially sustainable elements within states' CHIPRA demonstrations and analyzed data from grantee reports and key informant interviews to assess sustainment outcomes and key influential factors. We also assessed sustainment of the projects' intellectual capital. Results 56% of potentially sustainable elements were sustained. Sustainment varied by topic area: Elements related to quality measure reporting and practice facilitation were more likely to be sustained than others, such as parent advisors. Broad contextual factors, the state's Medicaid environment, implementation partners' resources, and characteristics of the demonstration itself all shaped sustainment outcomes. Discussion Assessing sustainment of key elements of states' CHIPRA quality demonstration projects provides insight into the fates of the "promising ideas" that the grant program was designed to examine. As a result of the federal government's investment in this grant program, many demonstration states are in a strong position to extend and spread specific strategies for improving the quality of care for children in Medicaid and CHIP. Our findings provide insights for policymakers and providers working to improve the quality of health care for low income children. PMID- 29119479 TI - Utility of CT imaging in differentiating sacroiliitis associated with spondyloarthritis from gouty sacroiliitis: a retrospective study. AB - Sacroiliitis is one of the criteria for classification as spondyloarthritis (SpA), though not unique to SpA. Other conditions including gout may be erroneously diagnosed as SpA due to sacroiliitis. The objective was to identify specific CT findings in sacroiliitis associated with SpA and gout. In this retrospective study, CT images of patients with sacroiliitis and clinical diagnosis of gout or SpA from 2010 to 2015 were independently reviewed by two radiologists, blinded to diagnosis. Axial and coronal oblique images were analyzed for characteristics of erosions. The receiver operator characteristic curve was constructed to analyze the discriminating ability of radiological findings. CT SI joint images of 11 patients with gout and 224 patients with SpA were re-analyzed. There was excellent agreement between the radiologists (ICC from 0.78 to 1). Erosions were more numerous in SpA. Erosions in gout were associated with tophi in 65.7% (73/111). Erosions in gout were para-articular and had sclerotic margins, overhanging edges, and multilobulated base (P < 0.0001 for all). Length and depth of erosions were more in gout as compared to SpA. AUCs for length, depth of erosions, and subchondral sclerosis were 0.665, 0.694, and 0.991, respectively. Subchondral sclerosis <= 4.5 mm had a sensitivity and specificity of 100 and 96%, respectively, for diagnosis of gout. In addition to known radiological features of gout, multilobulated base of erosions and absence of subchondral sclerosis could possibly distinguish sacroiliitis in SpA from gout. Our limited analysis suggests that CT imaging could help in differentiating the two. PMID- 29119480 TI - Rheumatoid factor false positivity in patients with ANCA-associated vasculitis not having medical conditions producing rheumatoid factor. AB - We investigated the rate of rheumatoid factor (RF) false positivity at diagnosis and its influence on clinical and prognostic features and rheumatoid arthritis (RA) development during the follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients without RA or other medical conditions triggering RF false positivity. We reviewed the medical records of 128 AAV patients. We divided patients with AAV and each variant into two groups according to RF positivity and compared variables between the two groups. Odds ratio and cumulative relapse-free survival rate were obtained by multivariate logistic regression analysis and the Kaplan-Meier survival analysis, respectively. The mean age at diagnosis was 53.6 years and 41 patients were male. Of 128 AAV patients, 69 patients (53.9%) were classified as microscopic polyangiitis (MPA), 29 (22.7%) as granulomatosis with polyangiitis (GPA) and 30 (23.4%) as eosinophilic GPA (EGPA). The rate of RF false positivity was 39.1% in AAV patients. On univariate analysis, general, cutaneous and mucous and ocular manifestations and myeloperoxidase (MPO)-ANCA (or perinuclear (P)-ANCA) positivity were associated with RF false positivity in patients with AAV. On multivariate analysis, cutaneous manifestation was the only independent predictor of RF false positivity in EGPA patients. RF false positivity had no influence on cumulative relapse-free survival rate of AAV or RA development during the follow up. RF false positivity rate was 39.1% in AAV patients and it was associated with cutaneous manifestation in EGPA patients at diagnosis, but not relapses of AAV or RA development during the follow-up. PMID- 29119481 TI - Prevalence of rheumatoid cachexia assessed by bioelectrical impedance vector analysis and its relation with physical function. AB - Rheumatoid arthritis (RA) patients frequently have changes in their body composition, with a decrease in muscle mass and an increase in fat mass, a syndrome that is termed rheumatoid cachexia (RC). The prevalence of this nutritional alteration is not well known; there is as yet no consensus, seeing as it depends on the methods, techniques, and cutoff points that are used for its diagnosis. The main aim of this study was to identify RC through assessment by bioelectrical impedance vector analysis (BIVA) and its association with metabolic causes, physical function, and the main disease status, among others. The prevalence of RC was identified in those subjects who fell outside the right lower quadrant of the reference curve of RXc graph of BIVA. Clinical, anthropometric, biochemical and physical activity, emotional status, and diet markers were also evaluated. Ninety-four patients were included (92.55% women). The prevalence of RC assessed by BIVA was 21.28%. BIVA-cachexia patients had a lesser value of handgrip strength vs. patients without BIVA-cachexia 10.2 kg (7.2 13.4) vs. 14.7 kg (9.6-19), p = 0.0062. Disability and folic acid with methotrexate consumption are related to BIVA-cachexia ((OR 4.69, 95% CI 1.33, 16.54, p = 0.016) and (OR 0.19, 95%CI 0.058, 0.651, p = 0.008), respectively). BIVA could represent a valuable tool to assess presence of RC. It is important that RA patients have physical therapy to improve their nutritional status. PMID- 29119482 TI - Patterns of comorbidity and disease characteristics among patients with ankylosing spondylitis-a cross-sectional study. AB - The knowledge of the development of comorbidities in patients with ankylosing spondylitis (AS) is limited. The aim of this study was to analyse associations between AS disease characteristics and comorbidity and to evaluate patterns of comorbidities in patients with AS. Patients with AS, fulfilling the modified New York Criteria, were identified (n = 346, mean age 56 +/- 15 years, 75% men, 99% HLA B27 positive). Through a review of the patient records, data on disease activity parameters, laboratory results, disease manifestations, and diagnoses of any clinically significant comorbidity was obtained. Four categories of comorbidities of interest were identified: A. arrhythmias, conduction disorders, and valvular heart disease; B. atherosclerosis and atherosclerotic CVD; C. spinal and non-spinal fractures; and D. obstructive sleep apnoea syndrome. Associations between AS disease characteristics and comorbidities in categories were assessed in logistic regression models. Differences in proportions of comorbidities was analysed using two-sided chi-square. Age was associated with all four categories of comorbidities, and male sex with arrhythmias, conduction disorders, valvular heart disease, and obstructive sleep apnoea syndrome. Early disease onset and long disease duration, respectively, were associated with arrhythmias, conduction disorders, and valvular heart disease. Obstructive sleep apnoea syndrome was associated with features of the metabolic syndrome. Patients with atherosclerotic cardiovascular disease had an increased risk of most other comorbidities, similar to, but more pronounced than patients with arrhythmias, conduction disorders and valvular heart disease. Comorbid conditions motivate clinical awareness among patients with AS. Longitudinal studies are needed to establish preventive measures. PMID- 29119484 TI - Clinically Amendable, Defined, and Rapid Induction of Human Brain Organoids from Induced Pluripotent Stem Cells. AB - Human brain organoids provide opportunities to produce three-dimensional (3D) brain-like tissues for biomedical research and translational drug discovery, toxicology, and tissue replacement. Here we describe a protocol for rapid and defined induction of brain organoids from human induced pluripotent stem cells (iPSCs), using commercially available culture and differentiation media and a cheap, easy to handle and clinically approved semisynthetic hydrogel. Importantly, the methodology is uncomplicated, well-defined, and reliable for reproducible and scalable organoid generation, and amendable to principles of current good laboratory practice (cGLP), with the potential for prospective adaptation to current good manufacturing practice (cGMP) toward clinical compliance. PMID- 29119483 TI - Low-level laser therapy for xerostomia in primary Sjogren's syndrome: a randomized trial. AB - To evaluate the effectiveness of low-level laser therapy (LLLT) in the treatment of xerostomia in primary Sjogren's syndrome (SS), a randomized clinical trial of patients with dry mouth symptoms associated with primary SS receiving care at a university hospital was conducted. Sixty-six patients were randomly assigned with a 1:1 allocation ratio to receive LLLT (laser group, n = 33) or placebo treatment (placebo group, n = 33). Patients in the laser group received LLLT twice a week for 6 weeks, for a total of 12 treatment sessions. Laser irradiation was performed with an aluminum-gallium-arsenide laser diode at a wavelength of 808 nm, 100-mW output power, and energy density of 4.0 J/cm2 per irradiation point per session. Placebo treatment was performed following the same protocol used for irradiated patients and using the same laser device to mimic a real irradiation, but with no active laser emission and the tip of the laser probe covered with aluminum foil. The outcomes of interest were xerostomia inventory scores, salivary flow rate, salivary beta-2 microglobulin levels, and salivary sodium and chlorine concentrations. Patients in both groups showed no improvement in xerostomia. Likewise, there was no significant improvement in xerostomia inventory scores (p = 0.301) or salivary flow rate (p = 0.643) in either group. There was no difference in salivary beta-2 microglobulin levels, sodium concentration, and chlorine concentration before and after intervention or between the two groups. The LLLT protocol used in this study effected no improvement in xerostomia or salivary flow rate in patients with primary SS. ClinicalTrials.gov Identifier: NCT02066896. PMID- 29119486 TI - Potentially Harmful Medication Use and Decline in Health-Related Quality of Life among Community-Dwelling Older Adults. AB - BACKGROUND: Several scales to quantify the impact of potentially harmful medications (PHMs) have been shown to predict mortality and functional decline; however, the effect of PHMs on quality of life (QoL) has not been well-studied. OBJECTIVE: The aims of this study were to investigate an association between PHM use and change in health-related QoL among community-dwelling older adults, and to compare the predictive capacity of PHM scales. METHODS: We conducted a retrospective cohort study using prescription claims data and survey responses. A total of 426 community-dwelling adults aged 65 years or older who visited senior centers and had received prescriptions through a statewide prescription drug subsidy program were included. Anticholinergic Cognitive Burden (ACB), Drug Burden Index-sedative component (DBI-Se), Drug Burden Index-anticholinergic component (DBI-ACh), and the number of regular medications and Beers list medications were calculated from the claims data between baseline and 12 months. In addition, change in the EuroQoL five-dimensions questionnaire (EQ-5D) between baseline and 6- and 12-month follow-up were measured as the main outcome. A linear mixed model was used for the analysis. RESULTS: After adjusting for covariates, both DBI-Se (coefficients - 0.076, 95% confidence interval [CI] - 0.131 to - 0.020) and DBI-Ach (coefficients - 0.095, 95% CI - 0.188 to - 0.002) significantly predicted a decline in EQ-5D index. The ACB, number of regular medications, and number of Beers medications did not have a significant association with EQ-5D changes. CONCLUSIONS: PHM measures incorporating dose revealed a better predictive capacity for QoL change. Reducing cumulative drug dose, as well as stopping medications, would be important for the well-being of this population. PMID- 29119487 TI - Exploring the Roles of Proline in Three-Dimensional Domain Swapping from Structure Analysis and Molecular Dynamics Simulations. AB - Three-dimensional (3D) domain swapping is a mechanism to form protein oligomers. It has been proposed that several factors, including proline residues in the hinge region, may affect the occurrence of 3D domain swapping. Although introducing prolines into the hinge region has been found to promote domain swapping for some proteins, the opposite effect has also been observed in several studies. So far, how proline affects 3D domain swapping remains elusive. In this work, based on a large set of 3D domain-swapped structures, we performed a systematic analysis to explore the correlation between the presence of proline in the hinge region and the occurrence of 3D domain swapping. We further analyzed the conformations of proline and pre-proline residues to investigate the roles of proline in 3D domain swapping. We found that more than 40% of the domain-swapped structures contained proline residues in the hinge region. Unexpectedly, conformational transitions of proline residues were rarely observed upon domain swapping. Our analyses showed that hinge regions containing proline residues preferred more extended conformations, which may be beneficial for the occurrence of domain swapping by facilitating opening of the exchanged segments. PMID- 29119488 TI - Combining hydrogen peroxide addition with sunlight regulation to control algal blooms. AB - The concentration, light conditions during treatment, and the number of hydrogen peroxide (H2O2) additions as well as the H2O2 treatment combined with subsequent shading to control algal blooms were studied in the field (Lake Dianchi, China). The cyanobacterial stress and injury due to H2O2 were dose dependent, and the control effectiveness and degradation of H2O2 were better and faster under full light than under shading. However, H2O2 was only able to control a bloom for a short time, so it may have promoted the recovery of algae and allowed the biomass to rebound due to the growth of eukaryotic algae. A second addition of H2O2 at the same dose had no obvious effect on algal control in the short term, suggesting that a higher concentration or a delayed addition should be considered, but these alternative strategies are not recommended so that the integrity of the aquatic ecosystem is maintained and algal growth is not promoted. Moreover, shading (85%) after H2O2 addition significantly reduced the algal biomass during the enclosure test, no restoration was observed for nearly a month, and the proportion of eukaryotic algae declined. It can be inferred that algal blooms can be controlled by applying a high degree of shading after treatment with H2O2. PMID- 29119489 TI - Sulfide influence on metal behavior in a polluted southern Mediterranean lagoon: implications for management. AB - The degree of pyritization and degree of trace metal pyritization (DTMP) were investigated in sediments from Ghar El Melh Lagoon (northern Tunisia) in order to study metal deposition. A sediment core and 28 samples were thus taken in summer 2008, and metals and sulfate were analyzed in pore water/pyrite. Acid-volatile sulfide and metals were simultaneously extracted from these two fractions and the role of pyrite in the metal cycling studied. To examine pyrite presence and mineralogical form in sediments, X-ray diffraction of the washed and decarbonated sediment was performed along with scanning electron microscopy. Results showed that pyrite is present in fromboidal and euhedral forms. Thermodynamic calculation highlighted the formation of metallic sulfides and the co precipitation of metals with iron sulfides. The DTMP increases with depth, indicating that these metals are either sequestered as sulfides or that they co precipitate with pyrite into the deep sediment. PMID- 29119490 TI - Influence of pyrolysis temperature and production unit on formation of selected PAHs, oxy-PAHs, N-PACs, PCDDs, and PCDFs in biochar-a screening study. AB - The influence of reactor type and operating conditions of the pyrolysis unit on the final concentration of toxic contaminants in biochar remains unclear. Therefore, we determined the concentrations of polycyclic aromatic hydrocarbons (PAHs), oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs), nitrogen containing polycyclic aromatic compounds (N-PACs), polychlorinated dibenzo-p dioxins (PCDDs), and dibenzofurans (PCDFs) in biochars produced from three different feedstocks (softwood, wheat straw, and anaerobic digestate). Different scaled pyrolysis units (one batch and two continuous units) at two different temperatures (550 and 700 degrees C) were considered. The results revealed that the type of biomass had a significant influence on the PAH, oxy-PAH, and N-PAC content of the biochars. The configuration and type of the pyrolysis unit influenced only the wheat straw pyrolyzed at 550 degrees C. PCDDs and PCDFs occurred at very low levels in the biochars. In terms of PAH, PCDD, and PCDF content, the biochars assessed in this study represent a low risk to the environment, regardless of the temperature and type and size of the pyrolysis unit. PMID- 29119491 TI - The mechanism of 2-chlorobiphenyl oxidative degradation by nanoscale zero-valent iron in the presence of dissolved oxygen. AB - It has recently been demonstrated that the addition of nanoscale zero-valent iron (nZVI) to oxygen-containing water or soil aquifers results in the oxidation of organic compounds. However, there has been little insight about the generation of the reactive oxygen species (ROS) that play a vital role in the transformation of contaminants in the presence of nZVI. This study investigated (i) the degradation of 2-chlorobiphenyl (2-CB) by nZVI; (ii) the generation and role of ROS in this process. Under anaerobic and aerobic conditions, the removal efficiency of 2-CB was 65.5 and 59.4%, respectively, after 4 h at a pH of 5.0. The results demonstrated that both the reductive and oxidative processes account for 2-CB degradation under aerobic conditions. Hydroxyl radicals (.OH) generated by nZVI at low pH could efficiently degrade 2-CB, the main reductive dechlorination product was biphenyl. Two other hydroxylation products (2-chlorophenol and 2 hydroxybiphenyl) were also examined. There was a higher degradation efficiency of 2-CB under acidic conditions than basic conditions because more .OH was generated by nZVI. The presence of natural organic matters (NOMs), including humic acid (HA), salicylic acid (SA), galic acid (GA), and tannic acid (TA), increased the degradation efficiency of 2-CB (k values ranged from 0.0041 to 0.0042 min-1), because NOMs can mediate the electron transfer from the nZVI surface to O2, and facilitate the production of Fe2+ and H2O2 that subsequently form .OH. The mechanisms of these processes have provided new insights into the role of nZVI in the transformation of organic compounds. PMID- 29119492 TI - A numerical study on the effect of various combustion bowl parameters on the performance, combustion, and emission behavior on a single cylinder diesel engine. AB - A numerical study was carried out to study the effect of various combustion bowl parameters on the performance behavior, combustion characteristics, and emission magnitude on a single cylinder diesel engine. A base combustion bowl and 11 different combustion bowls were created by varying the aspect ratio, reentrancy ratio, and bore to bowl ratio. The study was carried out at engine rated speed and a full throttle performance condition, without altering the compression ratio. The results revealed that the combustion bowl parameters could have a huge impact on the performance behavior, combustion characteristics, and emission magnitude of the engine. The bowl parameters, namely throat diameter and toroidal radius, played a crucial role in determining the performance behavior of the combustion bowls. It was observed that the combustion bowl parameters, namely central pip distance, throat diameter, and bowl depth, also could have an impact on the combustion characteristics. And throat diameter and toroidal radius, central pip distance, and toroidal corner radius could have a consequent effect on the emission magnitude of the engine. Of the different combustion bowls tested, combustion bowl 4 was preferable to others owing to the superior performance of 3% of higher indicated mean effective pressure and lower fuel consumption. Interestingly, trade-off for NO x emission was higher only by 2.85% compared with the base bowl. The sensitivity analysis proved that bowl depth, bowl diameter, toroidal radius, and throat diameter played a vital role in the fuel consumption parameter and emission characteristics even at the manufacturing tolerance variations. PMID- 29119493 TI - Liquid chromatography-mass spectrometry method for evaluating the dissipation dynamics of cyromazine and its metabolite in Agaricus bisporus and dietary risk assessment. AB - Providing guidance on the reasonable use of pesticide in agricultural production is of particular importance for ensuring food safety. In the present study, a field trial was performed to study the dissipation and accumulative pattern of cyromazine (CA) and its metabolite in Agaricus bisporus (A. bisporus) cultivation. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was first developed and validated for the determination of CA and melamine (MEL) in the casing soil and fruiting body. During the cultivation period, the dissipation rates of CA in the casing soil were between 51.57 and 63.48% at three dose groups. The fruiting body presented higher accumulation ability for MEL compared with CA. The terminal residues of MEL never exceeded the maximum residue limits (MRLs) in food. In addition, the intake health risk from the CA and MEL residues in the fruiting body were negligible to humans. This study will help to provide valuable guidance on the application strategies of CA in A. bisporus cultivation. PMID- 29119494 TI - The interface interaction behavior between E. coli and two kinds of fibrous minerals. AB - In the present, studies of interaction between human normal flora and fibrous mineral are still lacking. Batch experiments were performed to deal with the interaction of Escherichia coli and two fibrous minerals (brucite and palygorskite), and the interface and liquid phase characteristics in the short term interaction processes were discussed. The bacterial concentrations, the remnant glucose (GLU), pyruvic acid, and the activity of beta-galactosidase and six elements were measured, and the results show that the promoting effect of brucite on the growth of E. coli was more significant than that of palygorskite. FTIR and XRD analysis results also confirmed E. coli has obviously dissolved on brucite and damage effect on palygorskite silicon structure. SEM results show that the interfacial contact degree between E. coli cells and brucite fibers was higher than that of palygorskite. These may be due to the zeta potential difference between E. coli and palygorskite was 14.57-22.37 mV, while it of brucite was 44.04-64.24 mV. The elements dissolving of two fibrous minerals not only increased regularly to liquid EC but also had a good buffer effect to the decrease of liquid pH. Studies of short-term interaction between E. coli and brucite and palygorskite can help to understand the effect of fibrous minerals on microeubiosis of human normal flora and the contribution of microbial behaviors on the fibrous minerals weathering in the natural environment. PMID- 29119495 TI - Spatiotemporal characteristics of hydrochemistry in Asian arid inland basin-a case study of Shiyang River Basin. AB - Inland rivers play a key role in supplying water for domestic and agricultural purposes in Asian arid inland basin. This paper investigates the chemical composition of precipitation, river water, and groundwater, providing evidence for the influencing factors the water composition in the Shiyang River Basin. Water samples were collected and analyzed to determine the content of major cations (Ca2+, Mg2+, Na+, K+, and NH+ 4) and anions (HCO- 3, Cl-, NO- 3, NO- 2, F , and SO2-4), total solid solubility, and pH values. The results showed that precipitation, surface water, and groundwater were mildly alkaline. Ca2+ and SO2 4 were the predominant ions. The content of inorganic ions varied largely in the different seasons, with the highest ion concentration observed in spring and the lowest in summer. The seasonal variations in groundwater were less considerable than those in surface water. Furthermore, anion concentrations increased substantially from upstream to downstream. Regional weathering of carbonates and evaporation were established as the major sources of these ions. In addition, we discovered that anthropogenic inputs had led to light pollution of water in some residential districts. PMID- 29119496 TI - Photolytic degradation of ciprofloxacin in solid and aqueous environments: kinetics, phototransformation pathways, and byproducts. AB - Many lipophilic pharmaceuticals may be sorbed in solid phases, leading to different photochemical behaviors. This study investigated the photochemistry of ciprofloxacin in a solid-phase system and compared it to that in a water-phase system. Kaolinite was used as the model solid matrix. The photolysis of ciprofloxacin in kaolinite fits pseudo-first-order kinetics for thicknesses less than 199 MUm, and the rate constants k p decreased from 0.0154 to 0.0016 min-1 as the thickness of the layer increased. Unlike the aqueous phase, two-step degradation processes were observed for all kaolinite layer thicknesses (14-199 MUm), and the pseudo-first-order constant at the surface of the kaolinite layer was smaller than that in the water phase. Comparatively , a similar photolysis rate constant of ciprofloxacin in a kaolinite suspension was also observed, and it was an order of magnitude smaller than that of the direct photodegradation (0.035 min-1) in water. The results indicate that ciprofloxacin is likely more stable when it is adsorbed on kaolinite and that the half-lives of ciprofloxacin in kaolinite and a kaolinite suspension are 2-25 times longer than that in deionized water (20 min) under simulated sunlight. Direct photolysis is proposed to be the main photodegradation mechanism for ciprofloxacin in kaolinite, and the cleavage of a piperazine ring is the main degradation pathway. However, the interaction between ciprofloxacin and kaolinite reduces the direct photolysis and leads to a higher light stability. In association with the reduction in photolysis, the yields of norfloxacin and defluorinated byproduct decreased significantly. Consequently, the interaction increases the persistence of ciprofloxacin and thus the ecological risk to the environment. PMID- 29119497 TI - Deposition of absolute and relative airborne metals on eggshells: a field study. AB - A biomonitoring field study was conducted to test the deposition of airborne metals on chicken eggshell. The goal was to correlate PM2.5 particle concentration in air, absolute (metals in air) and relative (metals in PM2.5 particles) metals, and metal accumulation on eggshell. The PM2.5 sample was collected for 8 h at different air pollution sites as well as an unpolluted site with glass fiber filters via a fine particulate sampler (with and without addition of eggshell). The PM2.5 particle concentration was high at a cement factory site and low at a sugar factory site. The highest absolute total mass of metal (total mass of all metals in air) was found in the traffic site, and the highest relative total mass of metal (total mass of all metals in PM2.5 particles) was found at the tannery factory. The accumulation of Zn and Pb in eggshell was high at the tannery and sugar factory sites, and Fe was high in the other areas. Three common metals including Cd, As, and Pb were found with significant positive correlation between absolute and relative metals with the metals accumulated in eggshell. The results concluded that the eggshells might be useful tools for monitoring the airborne metals. PMID- 29119498 TI - Conceptual Challenges in the Theoretical Foundations of Systems Biology. AB - In the last decade, Systems Biology has emerged as a conceptual and explanatory alternative to reductionist-based approaches in molecular biology. However, the foundations of this new discipline need to be fleshed out more carefully. In this paper, we claim that a relational ontology is a necessary tool to ground both the conceptual and explanatory aspects of Systems Biology. A relational ontology holds that relations are prior-both conceptually and explanatory-to entities, and that in the biological realm entities are defined primarily by the context they are embedded within-and hence by the web of relations they are part of. PMID- 29119500 TI - Conceptual Challenges of the Systemic Approach in Understanding Cell Differentiation. AB - The cells of a multicellular organism are derived from a single zygote and genetically identical. Yet, they are phenotypically very different. This difference is the result of a process commonly called cell differentiation. How the phenotypic diversity emerges during ontogenesis or regeneration is a central and intensely studied but still unresolved issue in biology. Cell biology is facing conceptual challenges that are frequently confused with methodological difficulties. How to define a cell type? What stability or change means in the context of cell differentiation and how to deal with the ubiquitous molecular variations seen in the living cells? What are the driving forces of the change? We propose to reframe the problem of cell differentiation in a systemic way by incorporating different theoretical approaches. The new conceptual framework is able to capture the insights made at different levels of cellular organization and considered previously as contradictory. It also provides a formal strategy for further experimental studies. PMID- 29119499 TI - An Integrative Approach Toward Biology, Organisms, and Cancer. AB - Over the last two decades, we have challenged the hegemony of the somatic mutation theory of carcinogenesis (SMT) based on the lack of theoretical coherence of the premises adopted by its followers. We offered instead a theoretical alternative, the tissue organization field theory (TOFT), that is based on the premises that cancer is a tissue-based disease and that proliferation and motility is the default state of all cells. We went on to use a theory-neutral experimental protocol that simultaneously tested the TOFT and the SMT. The results of this test favored adopting the TOFT and rejecting the SMT. Recently, an analysis of the differences between the Physics of the inanimate and that of the living matter has led us to propose principles for the construction of a much needed theory of organisms. The three biological principles are (a) a default state, (b) a principle of variation, and (c) one of organization. The TOFT, defined as "development gone awry," fits well within the principles that we propose for a theory of organisms. This radical conceptual change opened up the possibility of anchoring mathematical modeling on genuine biological principles. By identifying constraints to the default state, multilevel biomechanical explanations become as legitimate as the molecular ones on which other modelers that adopt the SMT rely. Expanding research based on the premises of our theory of organisms will enrich a comprehensive understanding of normal development and of the one that goes awry. PMID- 29119501 TI - A Primer on Mathematical Modeling in the Study of Organisms and Their Parts. AB - Mathematical modeling is a very powerful tool for understanding natural phenomena. Such a tool carries its own assumptions and should always be used critically. In this chapter, we highlight the key ingredients and steps of modeling and focus on their biological interpretation. In particular, we discuss the role of theoretical principles in writing models. We also highlight the meaning and interpretation of equations. The main aim of this chapter is to facilitate the interaction between biologists and mathematical modelers. We focus on the case of cell proliferation and motility in the context of multicellular organisms. PMID- 29119502 TI - The Search for System's Parameters. AB - The analysis of biological data asks for a delicate balance of content-specific and procedural knowledge; this is why it is virtually impossible to apply standard mathematical and statistical recipes to systems biology.The separation of the important part of information from singular (and largely irrelevant) details implies a continuous interchange between biological and statistical knowledge. The generalization ability of the models must be the principal focus of system's parameter estimation, while the multi-scale character of biological regulation orients the modeling style toward data-driven strategies based on the correlation structure of the analyzed systems. PMID- 29119503 TI - Inverse Problems in Systems Biology: A Critical Review. AB - Systems Biology may be assimilated to a symbiotic cyclic interplaying between the forward and inverse problems. Computational models need to be continuously refined through experiments and in turn they help us to make limited experimental resources more efficient. Every time one does an experiment we know that there will be some noise that can disrupt our measurements. Despite the noise certainly is a problem, the inverse problems already involve the inference of missing information, even if the data is entirely reliable. So the addition of a certain limited noise does not fundamentally change the situation but can be used to solve the so-called ill-posed problem, as defined by Hadamard. It can be seen as an extra source of information. Recent studies have shown that complex systems, among others the systems biology, are poorly constrained and ill-conditioned because it is difficult to use experimental data to fully estimate their parameters. For these reasons was born the concept of sloppy models, a sequence of models of increasing complexity that become sloppy in the limit of microscopic accuracy. Furthermore the concept of sloppy models contains also the concept of un-identifiability, because the models are characterized by many parameters that are poorly constrained by experimental data. Then a strategy needs to be designed to infer, analyze, and understand biological systems. The aim of this work is to provide a critical review to the inverse problems in systems biology defining a strategy to determine the minimal set of information needed to overcome the problems arising from dynamic biological models that generally may have many unknown, non-measurable parameters. PMID- 29119504 TI - Systems Biology Approach and Mathematical Modeling for Analyzing Phase-Space Switch During Epithelial-Mesenchymal Transition. AB - In this report, we aim at presenting a viable strategy for the study of Epithelial-Mesenchymal Transition (EMT) and its opposite Mesenchymal-Epithelial Transition (MET) by means of a Systems Biology approach combined with a suitable Mathematical Modeling analysis. Precisely, it is shown how the presence of a metastable state, that is identified at a mesoscopic level of description, is crucial for making possible the appearance of a phase transition mechanism in the framework of fast-slow dynamics for Ordinary Differential Equations (ODEs). PMID- 29119505 TI - Parameters Estimation in Phase-Space Landscape Reconstruction of Cell Fate: A Systems Biology Approach. AB - The thermodynamical formalism of irreversible processes offers a theoretical framework appropriate to explain the complexity observed at the macroscopic level of dynamic systems. In this context, together with the theory of complex systems and systems biology, the thermodynamical formalism establishes an appropriate conceptual framework to address the study of biological systems, in particular cancer.The Chapter is organized as follows: In Subheading 1, an integrative view of these disciplines is offered, for the characterization of the emergence and evolution of cancer, seen as a self-organized dynamic system far from the thermodynamic equilibrium. Development of a thermodynamic framework, based on the entropy production rate, is presented in Subheading 2. Subheading 3 is dedicated to all tumor growth, as seen through a "phase transitions" far from equilibrium. Subheading 4 is devoted to complexity of cancer glycolysis. Finally, some concluding remarks are presented in Subheading 5. PMID- 29119506 TI - Complexity of Biochemical and Genetic Responses Reduced Using Simple Theoretical Models. AB - Living systems are known to behave in a complex and sometimes unpredictable manner. Humans, for a very long time, have been intrigued by nature, and have attempted to understand biological processes and mechanisms using numerous experimental and mathematical techniques. In this chapter, we will look at simple theoretical models, using both linear and nonlinear differential equations, that realistically capture complex biochemical and genetic responses of living cells. Even for cases where cellular behaviors are stochastic, as for single-cell responses, randomness added to well-defined deterministic models has elegantly been shown to be useful. The data collectively present evidence for further exploration of the self-organizing rules and laws of living matter. PMID- 29119507 TI - Systems Biology Modeling of Nonlinear Cancer Dynamics. AB - Systems Biology represents nowadays a promising standard framework for natural and human sciences to attack complicated problems involving Life. Here a particular application of such a program is discussed in the case of Cancer, by using a basic toy model for solid tumor spread for framing together two apparently different conceptual leading paradigms of Oncogenesis. PMID- 29119509 TI - A Network-Based Integrative Workflow to Unravel Mechanisms Underlying Disease Progression. AB - Unraveling mechanisms underlying diseases has motivated the development of systems biology approaches. The key challenges for the development of mathematical models and computational tool are (1) the size of molecular networks, (2) the nonlinear nature of spatio-temporal interactions, and (3) feedback loops in the structure of interaction networks. We here propose an integrative workflow that combines structural analyses of networks, high throughput data, and mechanistic modeling. As an illustration of the workflow, we use prostate cancer as a case study with the aim of identifying key functional components associated with primary to metastasis transitions. Analysis carried out by the workflow revealed that HOXD10, BCL2, and PGR are the most important factors affected in primary prostate samples, whereas, in the metastatic state, STAT3, JUN, and JUNB are playing a central role. The identified key elements of each network are validated using patient survival analysis. The workflow presented here allows experimentalists to use heterogeneous data sources for the identification of diagnostic and prognostic signatures. PMID- 29119508 TI - Endogenous Molecular-Cellular Network Cancer Theory: A Systems Biology Approach. AB - In light of ever apparent limitation of the current dominant cancer mutation theory, a quantitative hypothesis for cancer genesis and progression, endogenous molecular-cellular network hypothesis has been proposed from the systems biology perspective, now for more than 10 years. It was intended to include both the genetic and epigenetic causes to understand cancer. Its development enters the stage of meaningful interaction with experimental and clinical data and the limitation of the traditional cancer mutation theory becomes more evident. Under this endogenous network hypothesis, we established a core working network of hepatocellular carcinoma (HCC) according to the hypothesis and quantified the working network by a nonlinear dynamical system. We showed that the two stable states of the working network reproduce the main known features of normal liver and HCC at both the modular and molecular levels. Using endogenous network hypothesis and validated working network, we explored genetic mutation pattern in cancer and potential strategies to cure or relieve HCC from a totally new perspective. Patterns of genetic mutations have been traditionally analyzed by posteriori statistical association approaches in light of traditional cancer mutation theory. One may wonder the possibility of a priori determination of any mutation regularity. Here, we found that based on the endogenous network theory the features of genetic mutations in cancers may be predicted without any prior knowledge of mutation propensities. Normal hepatocyte and cancerous hepatocyte stable states, specified by distinct patterns of expressions or activities of proteins in the network, provide means to directly identify a set of most probable genetic mutations and their effects in HCC. As the key proteins and main interactions in the network are conserved through cell types in an organism, similar mutational features may also be found in other cancers. This analysis yielded straightforward and testable predictions on an accumulated and preferred mutation spectrum in normal tissue. The validation of predicted cancer state mutation patterns demonstrates the usefulness and potential of a causal dynamical framework to understand and predict genetic mutations in cancer. We also obtained the following implication related to HCC therapy, (1) specific positive feedback loops are responsible for the maintenance of normal liver and HCC; (2) inhibiting proliferation and inflammation-related positive feedback loops, and simultaneously inducing liver-specific positive feedback loop is predicated as the potential strategy to cure or relieve HCC; (3) the genesis and regression of HCC is asymmetric. In light of the characteristic property of the nonlinear dynamical system, we demonstrate that positive feedback loops must be existed as a simple and general molecular basis for the maintenance of phenotypes such as normal liver and HCC, and regulating the positive feedback loops directly or indirectly provides potential strategies to cure or relieve HCC. PMID- 29119510 TI - Spatiotemporal Fluctuation Analysis of Molecular Diffusion Laws in Live-Cell Membranes. AB - A present challenge of membrane biophysics is deciphering the dynamic behavior of molecules, such as lipids and proteins, within the natural environment of a living-cell membrane. Here, a fluorescence fluctuation-based approach will be described, which makes it possible to probe the "diffusion law" of molecules directly from imaging, in the form of a mean square displacement vs time-delay plot (iMSD), with no need for interpretative models. Of note, the presented approach does not require extraction of the molecular trajectories nor the use of bright fluorophores. Conversely, it can be used at high fluorophore density and with relatively dim fluorophores, such as GFP-tagged molecules transiently expressed within cells. The ability of this approach to resolve average molecular dynamic properties well below the diffraction limit will be discussed. Overall, this novel approach is proposed as a powerful tool for the determination of kinetic and thermodynamic parameters over wide spatial and temporal scales. PMID- 29119511 TI - A Method for Cross-Species Visualization and Analysis of RNA-Sequence Data. AB - In this methods article, I describe a computational workflow for cross-species visualization and comparison of mRNA-seq transcriptome profiling data. The workflow is based on gene set variation analysis (GSVA) and is illustrated using commands in the R programming language. I provide a complete step-by-step procedure for the workflow using mRNA-seq data sets from dog and human bladder cancer as an example. PMID- 29119512 TI - Multi-agent Simulations of Population Behavior: A Promising Tool for Systems Biology. AB - This contribution reports on the simulation of some dynamical events observed in the collective behavior of different kinds of populations, ranging from shape changing cells in a Petri dish to functionally correlated brain areas in vivo. The unifying methodological approach, based upon a Multi-Agent Simulation (MAS) paradigm as incorporated in the NetLogoTM interpreter, is a direct consequence of the cornerstone that simple, individual actions within a population of interacting agents often give rise to complex, collective behavior.The discussion will mainly focus on the emergence and spreading of synchronous activities within the population, as well as on the modulation of the collective behavior exerted by environmental force-fields. A relevant section of this contribution is dedicated to the extension of the MAS paradigm to Brain Network models. In such a general framework some recent applications taken from the direct experience of the author, and exploring the activation patterns characteristic of specific brain functional states, are described, and their impact on the Systems-Biology universe underlined. PMID- 29119513 TI - Metabolomics: Challenges and Opportunities in Systems Biology Studies. AB - Metabolomics has the capability of providing predisposition, diagnostic, prognostic, and therapeutic biomarker profiles of individual patients, since a large number of metabolites can be measured in an unbiased manner from biological samples. In this setting, 1H-Nuclear Magnetic Resonance (NMR) spectroscopy of biofluids such as plasma, urine, and fecal water offers the opportunity to identify patterns of biomarker changes that reflects the physiological or pathological status of an individual patient.In this chapter, we show as a metabolomics study can be used to diagnose a disease, classifying patients as healthy or as pathological taking into account individual variability. PMID- 29119514 TI - Systems Biology-Driven Hypotheses Tested In Vivo: The Need to Advancing Molecular Imaging Tools. AB - Processing and interpretation of biological images may provide invaluable insights on complex, living systems because images capture the overall dynamics as a "whole." Therefore, "extraction" of key, quantitative morphological parameters could be, at least in principle, helpful in building a reliable systems biology approach in understanding living objects. Molecular imaging tools for system biology models have attained widespread usage in modern experimental laboratories. Here, we provide an overview on advances in the computational technology and different instrumentations focused on molecular image processing and analysis. Quantitative data analysis through various open source software and algorithmic protocols will provide a novel approach for modeling the experimental research program. Besides this, we also highlight the predictable future trends regarding methods for automatically analyzing biological data. Such tools will be very useful to understand the detailed biological and mathematical expressions under in-silico system biology processes with modeling properties. PMID- 29119515 TI - The PROSECCO server for chemical shift predictions in ordered and disordered proteins. AB - The chemical shifts measured in solution-state and solid-state nuclear magnetic resonance (NMR) are powerful probes of the structure and dynamics of protein molecules. The exploitation of chemical shifts requires methods to correlate these data with the protein structures and sequences. We present here an approach to calculate accurate chemical shifts in both ordered and disordered proteins using exclusively the information contained in their sequences. Our sequence based approach, protein sequences and chemical shift correlations (PROSECCO), achieves the accuracy of the most advanced structure-based methods in the characterization of chemical shifts of folded proteins and improves the state of the art in the study of disordered proteins. Our analyses revealed fundamental insights on the structural information carried by NMR chemical shifts of structured and unstructured protein states. PMID- 29119516 TI - Protein-nucleotide contacts in motor proteins detected by DNP-enhanced solid state NMR. AB - DNP (dynamic nuclear polarization)-enhanced solid-state NMR is employed to directly detect protein-DNA and protein-ATP interactions and identify the residue type establishing the intermolecular contacts. While conventional solid-state NMR can detect protein-DNA interactions in large oligomeric protein assemblies in favorable cases, it typically suffers from low signal-to-noise ratios. We show here, for the oligomeric DnaB helicase from Helicobacter pylori complexed with ADP and single-stranded DNA, that this limitation can be overcome by using DNP enhanced spectroscopy. Interactions are established by DNP-enhanced 31P-13C polarization-transfer experiments followed by the recording of a 2D 13C-13C correlation experiment. The NMR spectra were obtained in less than 2 days and allowed the identification of residues of the motor protein involved in nucleotide binding. PMID- 29119517 TI - Effect of Application of Fe-Glycinate Chelate in Diet for Broiler Chickens in an Amount Covering 50 or 25% of the Requirement on Physical, Morphometric and Strength Parameters of Tibia Bones. AB - The purpose of the work was to check whether the application of Fe-glycinate chelate in mixtures fed to poultry in an amount covering 50 or 25% of the requirement would decrease the physical, morphometric and strength parameters of tibia bones in male Ross-308 broiler chickens in comparison to groups receiving Fe in an amount covering 100% of the requirement in the form of glycinate chelate or sulphate. It was found that the results for chickens from groups receiving Fe chelate covering 50 or 25% of the requirement were generally not lower than in the sulphate group and were higher than in the group receiving Fe in the amount covering 100% of the requirement. The presented results indicate that the standard requirement for Fe (40 mg kg-1 feed) as recommended by producers of Ross chickens may be too high if glycinate chelate is the source of Fe. This can be connected with the higher bioavailability of Fe from organic compounds in comparison to inorganic compounds. PMID- 29119518 TI - Cyclotron Phase-Coherent Ion Spatial Dispersion in a Non-Quadratic Trapping Potential is Responsible for FT-ICR MS at the Cyclotron Frequency. AB - Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) at the cyclotron frequency instead of the reduced cyclotron frequency has been experimentally demonstrated using narrow aperture detection electrode (NADEL) ICR cells. Here, based on the results of SIMION simulations, we provide the initial mechanistic insights into the cyclotron frequency regime generation in FT-ICR MS. The reason for cyclotron frequency regime is found to be a new type of a collective motion of ions with a certain dispersion in the initial characteristics, such as pre-excitation ion velocities, in a highly non-quadratic trapping potential as realized in NADEL ICR cells. During ion detection, ions of the same m/z move in phase for cyclotron ion motion but out of phase for magnetron (drift) ion motion destroying signals at the fundamental and high order harmonics that comprise reduced cyclotron frequency components. After an initial magnetron motion period, ion clouds distribute into a novel type of structures - ion slabs, elliptical cylinders, or star-like structures. These structures rotate at the Larmor (half-cyclotron) frequency on a plane orthogonal to the magnetic field, inducing signals at the true cyclotron frequency on each of the narrow aperture detection electrodes. To eliminate the reduced cyclotron frequency peak upon dipolar ion detection, a number of slabs or elliptical cylinders organizing a star-like configuration are formed. In a NADEL ICR cell with quadrupolar ion detection, a single slab or an elliptical cylinder is sufficient to minimize the intensity of the reduced cyclotron frequency components, particularly the second harmonic. Graphical Abstract ?. PMID- 29119519 TI - Brief Report: Physical Activity, Body Mass Index and Arterial Stiffness in Children with Autism Spectrum Disorder: Preliminary Findings. AB - We examined the association between physical activity (PA), body mass index (BMI) and novel measures of subclinical cardiovascular disease (CVD) in 15 children with autism spectrum disorder (ASD) (mean age 7 +/- 2 years, 2 girls). PA was objectively assessed using accelerometry as time spent in moderate-vigorous physical activity (MVPA). Arterial stiffness was measured via aortic pulse wave velocity (PWV) and taken as a marker of subclinical CVD risk. MVPA was inversely associated with aortic PWV (r = - 0.46, p < 0.05). BMI percentile was positively associated with aortic PWV (r = 0.61, p < 0.05). Overall findings suggest that reduced PA and higher body mass in children with ASD are associated with increased arterial stiffness which may have a detrimental impact on overall cardiovascular health. PMID- 29119520 TI - Connectivity-Based Parcellation of the Amygdala Predicts Social Skills in Adolescents with Autism Spectrum Disorder. AB - Amygdala dysfunction plays a role in the social impairments in autism spectrum disorders (ASD), but it is unclear which of its subregions are abnormal in ASD. This study compared the volume and functional connectivity (FC) strength of three FC-defined amygdala subregions between ASD and controls, and assessed their relation to social skills in ASD. A subregion associated with the social perception network was enlarged in ASD (F1 = 7.842, p = .008) and its volume correlated significantly with symptom severity (social skills: r = .548, p = .009). Posthoc analysis revealed that the enlargement was driven by the vmPFC amygdala network. These findings refine our understanding of abnormal amygdala connectivity in ASD and may inform future strategies for therapeutic interventions targeting the amygdalofrontal pathway. PMID- 29119521 TI - Attention Training in Autism as a Potential Approach to Improving Academic Performance: A School-Based Pilot Study. AB - This study assessed the effectiveness of an attention intervention program (Computerized Progressive Attentional Training; CPAT) in improving academic performance of children with ASD. Fifteen 6-10 year olds with ASD attending a mainstream and a special school were assigned to an experimental (CPAT; n = 8) and active control (computer games; n = 7) group. Children were assessed pre- and post-intervention on measures of behavioural symptoms, cognitive skills and academic performance. The intervention was conducted in school twice a week for 8 weeks. Children in the CPAT group showed cognitive and academic improvements over and above the active control group, while children in both groups showed improvements in behaviour. Results suggest that attention training is a feasible approach to improving academic performance in this population. PMID- 29119522 TI - Functional but Inefficient Kinesthetic Motor Imagery in Adolescents with Autism Spectrum Disorder. AB - Whether action representation in individuals with autism spectrum disorder (ASD) is deficient remains controversial, as previous studies of action observation or imitation report conflicting results. Here we investigated the characteristics of action representation in adolescents with ASD through motor imagery (MI) using a hand rotation and an object rotation task. Comparable with the typically developing group, the individuals with ASD were able to spontaneously use kinesthetic MI to perform the hand rotation task, as manifested by the significant biomechanical effects. However, the ASD group performed significantly slower only in the hand rotation task, but not in the object rotation task. The findings suggest that the adolescents with ASD showed inefficient but functional kinesthetic MI, implicating that their action representation might be preserved. PMID- 29119524 TI - Radiation dose exposure in patients affected by lymphoma undergoing repeat CT examinations: how to manage the radiation dose variability. AB - PURPOSE: To assess the variability of radiation dose exposure in patients affected by lymphoma undergoing repeat CT (computed tomography) examinations and to evaluate the influence of different scan parameters on the overall radiation dose. MATERIALS AND METHODS: A series of 34 patients (12 men and 22 women with a median age of 34.4 years) with lymphoma, after the initial staging CT underwent repeat follow-up CT examinations. For each patient and each repeat examination, age, sex, use of AEC system (Automated Exposure Control, i.e. current modulation), scan length, kV value, number of acquired scans (i.e. number of phases), abdominal size diameter and dose length product (DLP) were recorded. The radiation dose of just one venous phase was singled out from the DLP of the entire examination. All scan data were retrieved by our PACS (Picture Archiving and Communication System) by means of a dose monitoring software. RESULTS: Among the variables we considered, no significant difference of radiation dose was observed among patients of different ages nor concerning tube voltage. On the contrary the dose delivered to the patients varied depending on sex, scan length and usage of AEC. No significant difference was observed depending on the behaviour of technologists, while radiologists' choices had indirectly an impact on the radiation dose due to the different number of scans requested by each of them. CONCLUSIONS: Our results demonstrate that patients affected by lymphoma who undergo repeat whole body CT scanning may receive unnecessary overexposure. We quantified and analyzed the most relevant variables in order to provide a useful tool to manage properly CT dose variability, estimating the amount of additional radiation dose for every single significant variable. Additional scans, incorrect scan length and incorrect usage of AEC system are the most relevant cause of patient radiation exposure. PMID- 29119526 TI - Malignant Lymphoma of the Ileum Presenting as Ileocecal Intussusception. PMID- 29119525 TI - Haralick's texture features for the prediction of response to therapy in colorectal cancer: a preliminary study. AB - PURPOSE: Haralick features Texture analysis is a recent oncologic imaging biomarker used to assess quantitatively the heterogeneity within a tumor. The aim of this study is to evaluate which Haralick's features are the most feasible in predicting tumor response to neoadjuvant chemoradiotherapy (CRT) in colorectal cancer. MATERIALS AND METHODS: After MRI and histological assessment, eight patients were enrolled and divided into two groups based on response to neoadjuvant CRT in complete responders (CR) and non-responders (NR). Oblique Axial T2-weighted MRI sequences before CRT were analyzed by two radiologists in consensus drawing a ROI around the tumor. 14 over 192 Haralick's features were extrapolated from normalized gray-level co-occurrence matrix in four different directions. A dedicated statistical analysis was performed to evaluate distribution of the extracted Haralick's features computing mean and standard deviation. RESULTS: Pretreatment MRI examination showed significant value (p < 0.05) of 5 over 14 computed Haralick texture. In particular, the significant features are the following: concerning energy, contrast, correlation, entropy and inverse difference moment. CONCLUSIONS: Five Haralick's features showed significant relevance in the prediction of response to therapy in colorectal cancer and might be used as additional imaging biomarker in the oncologic management of colorectal patients. PMID- 29119527 TI - Multifocality in Small Bowel Neuroendocrine Tumors. AB - BACKGROUND: Neuroendocrine tumors (NETs) account for 30% of small bowel (SB) neoplasms. The objectives of this study were to evaluate the incidence of multifocality in primary small bowel neuroendocrine tumors (SBNETs) and to examine the associated outcomes. METHODS: Patients with multifocal SBNET were compared to those with a solitary lesion. Only patients who underwent diagnostic workup and surgical intervention at our institution were included in this study. The primary aim of our study was surgical outcomes and mortality and recurrence. The second aim of our study was to evaluate the utility of double-balloon enteroscopy (DBE) and capsule endoscopy. RESULTS: Of 178 patients with SBNETs during the study period, 85 met inclusion criteria. The mean age was 61.0 +/- 12.6 years and 44.7% were male. The ileum was the primary tumor site for 66 patients (77.7%). Of DBE patients, 28 (62.2%) had additional lesions identified, of which 23 (82.1%) had NET confirmed on pathology. Average tumor size was 1.8 cm and most were well differentiated (89.9%), with Ki-67 of >= 2% (65.8%); 74.4% had nodal metastases and 51% of patients had stage IV disease. Forty-six patients (54.1%) had multifocal disease, of whom 37 (80.5%) had an ileal primary. No differences in survival or recurrence were seen for multifocal versus solitary disease. CONCLUSIONS: SBNETs have a high incidence of multifocality. DBE can be used in the preoperative assessment to detect multifocal NET. Multifocality has no impact on survival or recurrence outcomes. PMID- 29119528 TI - Perioperative Factors Predicting Prolonged Postoperative Ileus After Major Abdominal Surgery. AB - BACKGROUND: Prolonged postoperative ileus (PPOI) is among the common complications adversely affecting postoperative outcomes. Predictors of PPOI after major abdominal surgery remain unclear, although various PPOI predictors have been reported in patients undergoing colorectal surgery. This study aimed to devise a model for stratifying the probability of PPOI in patients undergoing abdominal surgery. METHODS: Between 2012 and 2013, 841 patients underwent major abdominal surgery after excluding patients who underwent less-invasive abdominal surgery, ileus-associated surgery, and emergency surgery. Postoperative managements were generally based on enhanced recovery after surgery (ERAS) program. The definition of PPOI was based on nausea, no oral diet, flatus absence, abdominal distension, and radiographic findings. A nomogram was devised by evaluating predictive factors for PPOI. RESULTS: Of the 841 patients, 73 (8.8%) developed PPOI. Multivariable logistic regression analysis revealed smoking history (P = 0.025), colorectal surgery (P = 0.004), and an open surgical approach (P = 0.002) to all be independent predictive factors for PPOI. A nomogram was devised by employing these three significant predictive factors. The prediction model showed relatively good discrimination performance, the concordance index of which was 0.71 (95%CI 0.66-0.77). The probability of PPOI in patients with a smoking history who underwent open colorectal surgery was calculated to be 19.6%. CONCLUSIONS: Colorectal surgery, open abdominal surgery, and smoking history were found to be independent predictive factors for PPOI in patients who underwent major abdominal surgery. A nomogram based on these factors was shown to be useful for identifying patients with a high probability of developing PPOI. PMID- 29119529 TI - Better Late than Never? Adherence to Adjuvant Therapy Guidelines for Stage III Colon Cancer in an Underserved Region. AB - INTRODUCTION: In 2008, the American College of Surgeons Commission on Cancer (CoC) issued a quality guideline for stage III colon cancer (CC) recommending adjuvant chemotherapy (AC) within 120 days of diagnosis. We examined adherence in a healthcare system serving a region with disparities in CC outcomes. METHODS: In a retrospective analysis of patients (2005-2014) with stage III CC in a multi hospital healthcare system, the associations between adherence, clinicopathologic, demographic, geographic, and socioeconomic data and overall survival (OS) were examined. RESULTS: Of 1171 CC patients, 438 (37.4%) had stage III disease with 63% (n = 276) receiving AC and 37% (n = 162) not. AC conferred a 5-year OS advantage (62.4 vs. 42.5%, p < 0.0001). Younger age independently predicted AC receipt (OR = 0.95, p < 0.0001). Of 252 AC patients < 80 years, 75.8% were CoC guideline compliant (GC) whereas 24.2% were not (nGC). Although there was no OS difference between GC and nGC, both had superior survival (p < 0.0001) compared to non-AC patients. Surgical complications trended towards independent association with non-compliance (p = 0.07) CONCLUSION: Guideline compliance in our system (63%) is lower than the CoC Estimated Performance Rate (72.4%). Age influenced absolute receipt of AC while surgical complications may impact guideline compliance. Even when administered beyond 120 days, AC was associated with a survival benefit. PMID- 29119530 TI - Predictors of Futile Liver Resection for Patients with Barcelona Clinic Liver Cancer Stage B/C Hepatocellular Carcinoma. AB - BACKGROUND: There is little information concerning futile liver resection for patients with Barcelona Clinic Liver Cancer (BCLC) stage B/C hepatocellular carcinoma (HCC). This study aimed to establish a predictive model of futile liver resection for patients with BCLC stage B/C HCC. METHODS: The outcomes of 484 patients with BCLC stage B/C HCC who underwent liver resection at our centre between 2010 and 2016 were reviewed. Patients were randomised and divided 2:1 into training and validation sets. A novel risk-scoring model and prognostic nomogram were developed based on the results of multivariate analysis. RESULTS: Fifty-seven futile operations were observed. Multivariate analyses revealed tumour numbers > 3, Vp4 portal vein tumour thrombosis (PVTT) and alpha fetoprotein (AFP) > 400 ng/ml independently associated with futile liver resection. A risk-scoring model based on the above-mentioned factors was developed (predictive risk score = 1 * (if AFP > 400 ng/ml) + 2 * (if tumour number > 3) + 3 * (if with Vp4 PVTT)). The area under the receiver-operating characteristic curve of this model was 0.845, with a sensitivity of 60.0% and a specificity of 94.8%. A prognostic nomogram was also developed and achieved a C index of 0.831. The validation studies optically supported these results. CONCLUSION: A risk-scoring model and predictive nomogram for futile liver resection were developed in the present study. T'he BCLC stage B/C HCC patients with a high risk obtained no benefit from liver resection. PMID- 29119531 TI - The Non-operative Management of Asymptomatic Liver Hydatids: Ending Echinococcophobia. AB - BACKGROUND: Cystic echinococcosis is common in many countries and involves the liver in 75% of cases. The current belief is that all incidentally discovered asymptomatic liver hydatids must be subjected to some types of interventional treatments pre-emptively for fear of some presumably impending complications. We conducted this study to assess the prognosis of patients with liver hydatids without any surgical interventions. Furthermore, we tried to predict the outcome of the cyst using two radiological signs. METHODS: Of 434 asymptomatic patients with liver cysts who referred to our center, 297 were found eligible to be monitored at 1-3-year intervals by unenhanced computed tomography (CT) over a 20 year period. The patients were given the option of either having their cysts removed by open operation (the surgical group) or entering an open-ended "watch and-wait" program (the surveillance group). Using unenhanced CT, cyst size, laminated membrane detachment (LMD), and pericyst degenerative changes (PDCs) were evaluated every 1-3 years. If a complication happened or the cyst size increased during the follow-up period, the cyst outcome was considered "unfavorable"; otherwise, it was considered "favorable." RESULTS: Forty-three patients with 56 liver cysts were operated upon without morbidity or mortality. One hundred and twenty-seven patients with 137 cysts were followed. After a median follow-up of 6 (IQR 3 to 10) years, 111 (81.0%) had favorable outcome and 26 (19.0%) cysts had an unfavorable outcome. The size of 69 (50.4%) cysts with favorable outcome was not changed. It was decreased by a mean of 35.7% (SD 17.5%) in 34 (24.8%) cysts; 8 (5.8%) cysts disappeared. Of 26 cysts with unfavorable outcome, 8 (5.8%) developed complications (6 fistulas and 2 secondary infections) after a median follow-up of 6.5 (IQR 2.3 to 12.8) years. The size of the remaining 18 cysts increased by a mean of 42.2% (SD 29.5%). Albendazole administered at a dose of 400 mg, po, bid for 3 years, had a significant effect on hydatids. After adjustment for cyst size at diagnosis and patient's age and sex, logistic regression analysis showed that being univesicular (OR 6.00, 95% CI 1.32 to 27.29), having LMD (OR 5.51, 95% CI 1.03 to 29.43), and the presence of PDCs (OR 4.25, 95% CI 1.36 to 13.30) were independent predictors of a favorable outcome for a cyst. CONCLUSIONS: More than 80% of asymptomatic liver hydatids have a favorable outcome without pre-emptive surgical interventions. The presence of LMD at any stage and/or PDCs of any grade justifiably exempts asymptomatic univesicular liver hydatids from any treatments. Those without LMD or PDCs can be effectively managed with long-term albendazole, artificially inducing larval involution. PMID- 29119532 TI - Is Diversion with Ileostomy Non-inferior to Hartmann Resection for Left-sided Colorectal Anastomotic Leak? AB - BACKGROUND: Treatment of left-sided colorectal anastomotic leaks often requires fecal stream diversion for prevention of further septic complications. To manage anastomotic leak, it is unclear if diverting ileostomy provides similar outcomes to Hartmann resection with colostomy. METHODS: We identified all patients who developed anastomotic leak following left-sided colorectal resections from 1/2012 through 12/2014 using the American College of Surgeons National Surgical Quality Improvement Program. Then, we examined the risk of mortality and abdominal reoperation in patients treated with diverting ileostomy as compared to Hartmann resection. RESULTS: There were 1745 patients who experienced an anastomotic leak in a cohort of 63,748 patients (3.7%). Two hundred thirty-five patients had a reoperation for anastomotic leak involving the formation of a diverting ileostomy (n = 77) or Hartmann resection (n = 158). There was no difference in mortality or abdominal reoperation in patients treated with diverting ileostomy (3.9, 7.8%) versus Hartmann resection (3.8, 6.3%) (p = 0.8). CONCLUSION: There was no difference in the outcomes of mortality or need for second abdominal reoperation in patients treated with diverting ileostomy as compared to Hartmann resection for left-sided colorectal anastomotic leak. Thus, select patients with left-sided colorectal anastomotic leaks may be safely managed with diverting ileostomy. PMID- 29119533 TI - 18-Fluorodeoxyglucose Positron Emission Tomography Predicts Recurrence in Resected Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: We aimed to determine whether treatment should be stratified according to 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) maximum standardized uptake values (SUVmax) in pancreatic ductal adenocarcinoma. METHODS: Patients who underwent preoperative 18F-FDG PET/CT between 2006 and 2014 (n = 138) were stratified into high (>= 4.85) and low (< 4.85) PET groups. The clinicopathological characteristics and prognostic outcomes were analyzed retrospectively. RESULTS: The primary tumor SUVmax was positively correlated with preoperative CA19-9 levels (P < 0.001). The high PET group failed to achieve postoperative CA19-9 normalization (P = 0.014). Disease-specific (P < 0.001), recurrence-free (P < 0.001), liver recurrence-free (P < 0.001), and peritoneal recurrence-free (P = 0.020) survivals were significantly shorter in the high PET group. The primary tumor SUVmax was an independent predictive risk factor for liver metastasis (hazard ratio 3.46, 95% confidence interval 1.61-7.87; P = 0.001) and peritoneal recurrence (hazard ratio 3.36, 95% confidence interval 1.18-10.89; P = 0.023). CONCLUSIONS: Surgical resection failed to achieve CA19-9 normalization in the high PET group and distant recurrence was frequent. This suggests the potential for residual cancer at distant sites, even after curative resection. Stronger preoperative systemic chemotherapy is preferred for the high PET group patients. PMID- 29119534 TI - Angiotensin II Causes Neuronal Damage in Stretch-Injured Neurons: Protective Effects of Losartan, an Angiotensin T1 Receptor Blocker. AB - Angiotensin II (Ang II) is a mediator of oxidative stress via activation/induction of reactive oxygen and nitrogen species-generating enzymes, NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS). We investigated the hypothesis that overproduction of Ang II during traumatic brain injury (TBI) induces the activation of the oxidative stress, which triggers neuroinflammation and cell apoptosis in a cell culture model of neuronal stretch injury. We first established that stretch injury causes a rapid increase in the level of Ang II, which causes the release of pro-inflammatory cytokines, IL-1beta and TNF-alpha, via the induction of oxidative stress. Since angiotensin-converting enzyme (ACE) mediates the production of Ang II via the conversion of Ang I into Ang II, we analyzed the expression of ACE by western blotting. Further, we analyzed caspase 3-mediated apoptosis by TUNEL staining and annexin V western blotting. Angiotensin type I (AT1) receptor antagonist losartan attenuated Ang II-induced oxidative stress and associated neuroinflammation and cell death in cultured neurons. Remarkably, we noticed that the expression of Ang II type 1 receptor (AngT1R) upregulated in neuronal stretch injury; losartan mitigates this upregulation. Findings from this study significantly extend our understanding of the pathophysiology of TBI and may have significant implications for developing therapeutic strategies for TBI-associated brain dysfunctions. PMID- 29119535 TI - Mitochondria-Bound Hexokinase (mt-HK) Activity Differ in Cortical and Hypothalamic Synaptosomes: Differential Role of mt-HK in H2O2 Depuration. AB - Glucose and oxygen are vital for the brain, as these molecules provide energy and metabolic intermediates that are necessary for cell function. The glycolysis pathway and mitochondria play a pivotal role in cell energy metabolism, which is closely related to reactive oxygen species (ROS) production. Hexokinase (HK) is a key enzyme involved in glucose metabolism that modulates the level of brain mitochondrial ROS by recycling ADP for oxidative phosphorylation (OxPhos). Here, we hypothesize that the control of mitochondrial metabolism by hexokinase differs in distinct areas of the brain, such as the cortex and hypothalamus, in which ROS might function as signaling molecules. Thus, we investigated mitochondrial metabolism of synaptosomes derived from both brain regions. Cortical synaptosomes (CSy) show a predominance of glutamatergic synapses, while in the hypothalamic synaptosomes (HSy), the GABAergic synapses predominate. Significant differences of oxygen consumption and ROS production were related to higher mitochondrial complex II activity (succinate dehydrogenase-SDH) in CSy rather than to mitochondrial number. Mitochondrial HK (mt-HK) activity was higher in CSy than in HSy regardless the substrate added. Mitochondrial O2 consumption related to mt-HK activation by 2-deoxyglucose was also higher in CSy. In the presence of substrate for complex II, the activation of synaptosomal mt-HK promoted depuration of ROS in both HSy and CSy, while ROS depuration did not occur in HSy when substrate for complex I was used. The impact of the mt-HK inhibition by glucose-6-phosphate (G6P) was the same in synaptosomes from both areas. Together, the differences found between CSy and HSy indicate specific roles of mt-HK and SDH on the metabolism of each brain region, what probably depends on the main metabolic route that is used by the neurons. PMID- 29119537 TI - Second-Generation Outcomes of the Great Migration. AB - : The mass migration of African Americans out of the South during the first two thirds of the twentieth century represents one of the most significant internal migration flows in U.S. HISTORY: Those undertaking the Great Migration left the South in search of a better life, and their move transformed the cultural, social, and political dynamics of African American life specifically and U.S. society more generally. Recent research offers conflicting evidence regarding the migrants' success in translating their geographic mobility into economic mobility. Due in part to the lack of a large body of longitudinal data, almost all studies of the Great Migration have focused on the migrants themselves, usually over short periods of their working lives. Using longitudinally linked census data, we take a broader view, investigating the long-term economic and social effects of the Great Migration on the migrants' children. Our results reveal modest but statistically significant advantages in education, income, and poverty status for the African American children of the Great Migration relative to the children of southerners who remained in the South. In contrast, second generation white migrants experienced few benefits from migrating relative to southern or northern stayers. PMID- 29119536 TI - Turning Death to Growth: Hematopoietic Growth Factors Promote Neurite Outgrowth through MEK/ERK/p53 Pathway. AB - Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are the essential hematopoietic growth factors to control hematopoiesis. However, the role of SCF and G-CSF in the central nervous system remains poorly understood. Here, we have demonstrated the involvement of MEK/ERK/p53 signaling in SCF + G CSF-enhanced neurite extension. Cortical neurons dissected from embryonic rat brains were seeded onto the membranes of transwell inserts, and neurite outgrowth was determined by using both the neurite outgrowth quantification assay kit and immunostaining of beta III tubulin. Quantitative RT-PCR and western blotting were used for determining gene and protein expression of ERK and p53, respectively. p53 small interfering RNA (siRNAs) were introduced into neurons for examining the involvement of p53 in SCF + G-CSF-mediated neurite outgrowth. We observed that both SCF and G-CSF alone increased activation of MEK/ERK and gene expression of p53, while SCF + G-CSF synergistically activated the MEK/ERK signaling and upregulated p53 expression. MEK specific inhibitors (PD98059 and U0126) blocked the SCF + G-CSF-increased ERK phosphorylation and p53 gene and protein expression, and the MEK specific inhibitors also eliminated the SCF + G-CSF promoted neurite outgrowth. p53 siRNAs knocked down the SCF + G-CSF-elevated p53 protein and prevented the SCF + G-CSF-enhanced neurite outgrowth. These findings suggest that activation of MEK/ERK/p53 signaling is required for SCF + G-CSF promoted neurite outgrowth. Through the pro-apoptotic pathway of the MEK/ERK/p53, SCF + G-CSF turns neuronal fate from apoptotic commitment toward neural network generation. This observation provides novel insights into the putative role of SCF + G-CSF in supporting generation of neural connectivity during CNS development and in brain repair under pathological or neurodegenerative conditions. PMID- 29119538 TI - Safety and Effectiveness of Natalizumab: First Report of Interim Results of Post Marketing Surveillance in Japan. AB - INTRODUCTION: Natalizumab, a humanized anti-alpha4 integrin monoclonal antibody, received marketing approval in Japan in 2014 for the treatment of multiple sclerosis (MS). Because the previous large-scale clinical trials of natalizumab were mainly conducted in Europe and North American countries, and data in patients with MS from Japan were limited, we conducted an all-case post-marketing surveillance of natalizumab-treated MS patients from Japan to investigate the safety and effectiveness of natalizumab in a real-world clinical setting in Japan. Here, we report the results of an interim analysis. METHODS: During the observation period of 2 years, all patients who were treated with natalizumab subsequent to its approval in Japan were followed. The effectiveness of natalizumab was assessed by examining the changes in expanded disability status scale (EDSS) score and annualized relapse rate (ARR) from baseline. Safety was assessed by analyzing the incidence of adverse drug reactions (ADRs). RESULTS: The safety analysis included 106 patients (mean age 39.3 years; women 62.3%) whose data were collected until the data lock point (February 7, 2016). The effectiveness analysis included 75 patients. The majority of patients had relapsing-remitting MS (93/106 patients; 87.7%). The mean length of treatment exposure in the present study was 6.6 months. During the 2-year observation period, no significant change in the EDSS was observed, while the ARR decreased significantly from baseline (72.9% reduction, p = 0.001). ADRs and serious ADRs were observed in 11.3% and 3.8% of patients, respectively; however, no new safety concerns were detected. No patient had progressive multifocal leukoencephalopathy (PML) during the present study period. CONCLUSION: The safety and effectiveness of natalizumab were confirmed in Japanese patients with MS in clinical practice. Nevertheless, potential risks including PML require continuous, careful observation. FUNDING: Biogen Japan Ltd (Tokyo, Japan). PMID- 29119539 TI - Higher prevalence of unrecognized kidney disease at high altitude. AB - BACKGROUND: High altitude renal syndrome has been described in populations with excessive erythrocytosis. We evaluated whether high altitude (HA) dwellers might be at increased risk for kidney disease. METHODS: We performed a cross-sectional study to investigate differences in prevalence of kidney function and metabolic syndrome in healthy subjects living at HA vs. sea level (SL) without any known history of hypertension, diabetes or chronic kidney disease. RESULTS: We examined 293 subjects, aged 40 to 60 years: 125 SL (154 m) and 168 HA (3640 m) dwellers. HA dwellers had higher serum creatinine, lower estimated glomerular function rate (eGFR) (69.5 +/- 15.2 vs. 102.1 +/- 17.8 ml/min/1.73 m2, p < 0.0001), more proteinuria and higher hemoglobin concentrations compared to SL subjects. HA subjects had a lower prevalence of metabolic syndrome. Hemoglobin concentrations correlated inversely with eGFR in female (p = 0.001) and male (p = 0.03) HA dwellers. Using logistic regression analysis to compare subjects with eGFR < 90 vs. > 90 ml/min/1.73 m2, a lower eGFR was associated with female gender (odds ratio adjusted: 5.65 [95% confidence interval: 2.43-13.13]; p = 0.001), high altitude (14.78 [6.46-33.79]; p = 0.001), hemoglobin (1.68 [1.16-2.43]; p = 0.001) and uric acid (1.93 [1.36-2.72]; p = 0.001). CONCLUSIONS: Dwellers at high altitude who are considered healthy have worse kidney function, a higher prevalence of proteinuria and a lower prevalence of metabolic syndrome compared to people living at SL. PMID- 29119540 TI - Discrimination of stroke-related mild cognitive impairment and vascular dementia using EEG signal analysis. AB - Stroke survivors are more prone to developing cognitive impairment and dementia. Dementia detection is a challenge for supporting personalized healthcare. This study analyzes the electroencephalogram (EEG) background activity of 5 vascular dementia (VaD) patients, 15 stroke-related patients with mild cognitive impairment (MCI), and 15 control healthy subjects during a working memory (WM) task. The objective of this study is twofold. First, it aims to enhance the discrimination of VaD, stroke-related MCI patients, and control subjects using fuzzy neighborhood preserving analysis with QR-decomposition (FNPAQR); second, it aims to extract and investigate the spectral features that characterize the post stroke dementia patients compared to the control subjects. Nineteen channels were recorded and analyzed using the independent component analysis and wavelet analysis (ICA-WT) denoising technique. Using ANOVA, linear spectral power including relative powers (RP) and power ratio were calculated to test whether the EEG dominant frequencies were slowed down in VaD and stroke-related MCI patients. Non-linear features including permutation entropy (PerEn) and fractal dimension (FD) were used to test the degree of irregularity and complexity, which was significantly lower in patients with VaD and stroke-related MCI than that in control subjects (ANOVA; p ? 0.05). This study is the first to use fuzzy neighborhood preserving analysis with QR-decomposition (FNPAQR) dimensionality reduction technique with EEG background activity of dementia patients. The impairment of post-stroke patients was detected using support vector machine (SVM) and k-nearest neighbors (kNN) classifiers. A comparative study has been performed to check the effectiveness of using FNPAQR dimensionality reduction technique with the SVM and kNN classifiers. FNPAQR with SVM and kNN obtained 91.48 and 89.63% accuracy, respectively, whereas without using the FNPAQR exhibited 70 and 67.78% accuracy for SVM and kNN, respectively, in classifying VaD, stroke-related MCI, and control patients, respectively. Therefore, EEG could be a reliable index for inspecting concise markers that are sensitive to VaD and stroke-related MCI patients compared to control healthy subjects. PMID- 29119541 TI - Influence of implant number, length, and tilting degree on stress distribution in atrophic maxilla: a finite element study. AB - This study aims to evaluate the stress values, created in peri-implant region as a consequence of loading on fixed hybrid dentures that was planned with different implant numbers, lengths, or tilting angulations. Thirteen three-dimensional (3D) finite element analysis models were generated with four, five, or seven implants (group A, B, and C). Except the distal implants, all implants were modeled at 4.1 mm (diameter) and 11.5 mm (length) in size. Distal implants were configured to be in five different lengths (6, 8, 11.5, 13, and 16 mm) and three different implant inclination degrees (0 degrees , 30 degrees , and 45 degrees ). A 150-N load was applied vertically on prosthesis. Released stresses were evaluated comparatively. The lowest von Mises stress values were found in group C, in the 11.5-mm implant model. Tilting the distal implants 30 degrees caused higher stress values. In 45 degrees -tilting implant models, lower stress values were recorded according to the 30 degrees -tilting models. The ideal implant number is seven for an edentulous maxilla. Tilting the implants causes higher stress values. A 45 degrees inclination of implant causes lower stress values according to the 30 degrees models due to a shorter cantilever. The ideal implant length is 11.5 mm. PMID- 29119542 TI - How do we get there? Effects of cognitive aging on route memory. AB - Research into the effects of cognitive aging on route navigation usually focuses on differences in learning performance. In contrast, we investigated age-related differences in route knowledge after successful route learning. One young and two groups of older adults categorized using different cut-off scores on the Montreal Cognitive Assessment (MoCA), were trained until they could correctly recall short routes. During the test phase, they were asked to recall the sequence in which landmarks were encountered (Landmark Sequence Task), the sequence of turns (Direction Sequence Task), the direction of turn at each landmark (Landmark Direction Task), and to identify the learned routes from a map perspective (Perspective Taking Task). Comparing the young participant group with the older group that scored high on the MoCA, we found effects of typical aging in learning performance and in the Direction Sequence Task. Comparing the two older groups, we found effects of early signs of atypical aging in the Landmark Direction and the Perspective Taking Tasks. We found no differences between groups in the Landmark Sequence Task. Given that participants were able to recall routes after training, these results suggest that typical and early signs of atypical aging result in differential memory deficits for aspects of route knowledge. PMID- 29119543 TI - A type of anteroseptal left ventricular ballooning in a patient with Takotsubo cardiomyopathy. PMID- 29119544 TI - Nationwide claims data validated for quality assessments in acute myocardial infarction in the Netherlands. AB - INTRODUCTION: Since health insurance is compulsory in the Netherlands, the centrally registered medical claims data might pose a unique opportunity to evaluate quality of (cardiac) care on a national level without additional collection of data. However, validation of these claims data has not yet been assessed. DESIGN: Retrospective cohort study. METHODS: National claims data ('national registry') were compared with data collected by patient records reviews in four representative hospitals ('validation registry'). In both registries, we extracted the national diagnosis codes for ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction of 2012 and 2013. Additionally, data on medication use at one year after acute myocardial infarction (AMI) was extracted from the Dutch pharmacy information systems and also validated by local patient records reviews. The data were compared at three stages: 1) validation of diagnosis and treatment coding; 2) validation of the hospital where follow-up has taken place; 3) validation of follow-up medical treatment after 365 days. RESULTS: In total, 3,980 patients ('national registry') and 4,014 patients ('validation registry') were compared at baseline. After one year follow-up, 2,776 and 2,701 patients, respectively, were evaluated. Baseline characteristics, diagnosis and individual medication were comparable between the two registries. Of all 52,672 AMI patients in the Netherlands in 2012 and 2013, 81% used aspirin, 76% used P2Y12 inhibitors, 85% used statins, 82% used beta blockers and 74% angiotensin converting enzyme inhibitors/angiotensin II antagonists. Optimal medical treatment was achieved in 49% of the patients with AMI. CONCLUSION: Nationwide routinely collected claims data in patients with an acute myocardial infarction are highly accurate. This offers an opportunity for use in quality assessments of cardiac care. PMID- 29119546 TI - A systematic review of ectopic pregnancy after hysterectomy. AB - BACKGROUND: An ectopic pregnancy after hysterectomy is a rare but potentially life-threatening event. Women with this condition might not be appropriately investigated, resulting in delays in diagnosis and treatment. OBJECTIVES: To characterize cases of ectopic pregnancy occurring after hysterectomy. SEARCH STRATEGY: PubMed, Embase, Scopus, and Web of Science were searched using the terms "pregnancy, abdominal" or "pregnancy, tubal" or "pregnancy, ectopic" and "hysterectomy" or "post-hysterectomy" or "post hysterectomy." SELECTION CRITERIA: Case reports or case series published in English up to October 10, 2016, were included. Patients were included if the diagnosis was confirmed by definitive tests such as serum or urine beta-human chorionic gonadotropin (beta-hCG) testing, ultrasonography evidence of pregnancy, or histology. DATA COLLECTION AND ANALYSIS: Patient characteristics were extracted via a standard spreadsheet. MAIN RESULTS: A total of 57 patients were included in the analysis. Abdominal pain was the predominant symptom. Implantation in a remaining fallopian tube was common. Most patients were managed surgically. CONCLUSIONS: A high index of suspicion and a low threshold for performing a beta-hCG pregnancy test is recommended in all women presenting with clinical symptoms of ectopic pregnancy, regardless of the hysterectomy status. This could lead to earlier diagnosis and fewer complications. PMID- 29119545 TI - Mechanisms of nuclear pore complex assembly - two different ways of building one molecular machine. AB - The nuclear pore complex (NPC) mediates all macromolecular transport across the nuclear envelope. In higher eukaryotes that have an open mitosis, NPCs assemble at two points in the cell cycle: during nuclear assembly in late mitosis and during nuclear growth in interphase. How the NPC, the largest nonpolymeric protein complex in eukaryotic cells, self-assembles inside cells remained unclear. Recent studies have started to uncover the assembly process, and evidence has been accumulating that postmitotic and interphase NPC assembly use fundamentally different mechanisms; the duration, structural intermediates, and regulation by molecular players are different and different types of membrane deformation are involved. In this Review, we summarize the current understanding of these two modes of NPC assembly and discuss the structural and regulatory steps that might drive the assembly processes. We furthermore integrate understanding of NPC assembly with the mechanisms for rapid nuclear growth in embryos and, finally, speculate on the evolutionary origin of the NPC implied by the presence of two distinct assembly mechanisms. PMID- 29119547 TI - Interventions to improve access to cataract surgical services and their impact on equity in low- and middle-income countries. AB - BACKGROUND: Cataract is the leading cause of blindness in low- and middle-income countries (LMICs), and the prevalence is inequitably distributed between and within countries. Interventions have been undertaken to improve cataract surgical services, however, the effectiveness of these interventions on promoting equity is not known. OBJECTIVES: To assess the effects on equity of interventions to improve access to cataract services for populations with cataract blindness (and visual impairment) in LMICs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 3), MEDLINE Ovid (1946 to 12 April 2017), Embase Ovid (1980 to 12 April 2017), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 12 April 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 12 April 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 12 April 2017 and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 12 April 2017. We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We included studies that reported on strategies to improve access to cataract services in LMICs using the following study designs: randomised and quasi randomised controlled trials (RCTs), controlled before-and-after studies, and interrupted time series studies. Included studies were conducted in LMICs, and were targeted at disadvantaged populations, or disaggregated outcome data by 'PROGRESS-Plus' factors (Place of residence; Race/ethnicity/ culture/ language; Occupation; Gender/sex; Religion; Education; Socio-economic status; Social capital/networks. The 'Plus' component includes disability, sexual orientation and age). DATA COLLECTION AND ANALYSIS: Two authors (JR and JP) independently selected studies, extracted data and assessed them for risk of bias. Meta analysis was not possible, so included studies were synthesised in table and text. MAIN RESULTS: From a total of 2865 studies identified in the search, two met our eligibility criteria, both of which were cluster-RCTs conducted in rural China. The way in which the trials were conducted means that the risk of bias is unclear. In both studies, villages were randomised to be either an intervention or control group. Adults identified with vision-impairing cataract, following village-based vision and eye health assessment, either received an intervention to increase uptake of cataract surgery (if their village was an intervention group), or to receive 'standard care' (if their village was a control group).One study (n = 434), randomly allocated 26 villages or townships to the intervention, which involved watching an informational video and receiving counselling about cataract and cataract surgery, while the control group were advised that they had decreased vision due to cataract and it could be treated, without being shown the video or receiving counselling. There was low-certainty evidence that providing information and counselling had no effect on uptake of referral to the hospital (OR 1.03, 95% CI 0.63 to 1.67, 1 RCT, 434 participants) and little or no effect on the uptake of surgery (OR 1.11, 95% CI 0.67 to 1.84, 1 RCT, 434 participants). We assessed the level of evidence to be of low-certainty for both outcomes, due to indirectness of evidence and imprecision of results.The other study (n = 355, 24 towns randomised) included three intervention arms: free surgery; free surgery plus reimbursement of transport costs; and free surgery plus free transport to and from the hospital. These were compared to the control group, which was reminded to use the "low-cost" (~USD 38) surgical service. There was low certainty evidence that surgical fee waiver with/without transport provision or reimbursement increased uptake of surgery (RR 1.94, 95% CI 1.14 to 3.31, 1 RCT, 355 participants). We assessed the level of evidence to be of low-certainty due to indirectness of evidence and imprecision of results.Neither of the studies reported our primary outcome of change in prevalence of cataract blindness, or other outcomes such as cataract surgical coverage, surgical outcome, or adverse effects. Neither study disaggregated outcomes by social subgroups to enable further assessment of equity effects. We sought data from both studies and obtained data from one; the information video and counselling intervention did not have a differential effect across the PROGRESS-Plus categories with available data (place of residence, gender, education level, socioeconomic status and social capital). AUTHORS' CONCLUSIONS: Current evidence on the effect on equity of interventions to improve access to cataract services in LMICs is limited. We identified only two studies, both conducted in rural China. Assessment of equity effects will be improved if future studies disaggregate outcomes by relevant social subgroups. To assist with assessing generalisability of findings to other settings, robust data on contextual factors are also needed. PMID- 29119549 TI - A prototype small-bore ventilation catheter with a cuff: cuff inflation optimizes ventilation with the Ventrain. AB - BACKGROUND: Ventilation through small-diameter tubes typically precludes use of a cuff as this will impede the necessary passive outflow of gas alongside the tube's outer surface. Ventrain assists expiration and enables oxygenation and normoventilation through small-bore cannulas or catheters, particularly in obstructed airways. A small-bore ventilation catheter (SBVC; 40 cm long, 2.2 mm inner diameter) with a separate pressure monitoring lumen and a cuff was developed. Efficacy of oxygenation and ventilation with Ventrain through this catheter was investigated in sealed and open airways in a porcine cross-over study. METHODS: Six pigs were ventilated with Ventrain (15 l/min oxygen, frequency 30 breaths per min, I : E-ratio 1 : 1) through the SBVC, both with the cuff inflated and deflated. Prior to each test they were ventilated conventionally until steady state was achieved. RESULTS: With an inflated cuff, PaO2 rose instantly and remained elevated (median [range] PaO2 61 [52-69] kPa after 30 min; P = 0.027 compared to baseline). PaCO2 remained stable at 4.9 [4.2 6.2] kPa. After cuff deflation, PaO2 was significantly lower (9 [5-28] kPa at 10 min, P = 0.028) and interventional ventilation had to be stopped prematurely in five pigs as PaCO2 exceeded 10.6 kPa. Pulmonary artery pressures increased markedly in these pigs. Intratracheal pressures were kept between 5 and 20 cmH2 O with the cuff inflated, but never exceeded 2 cmH2 O after cuff deflation. CONCLUSION: The SBVC combines the benefits of a small diameter airway and a cuff. Cuff inflation optimizes oxygenation and ventilation with Ventrain. PMID- 29119548 TI - Association of total cholesterol, low-density lipoprotein cholesterol, and non high-density lipoprotein cholesterol with atherosclerotic cardiovascular disease and cancer in a Chinese male population. AB - This prospective study included 68,759 Chinese male adults from Kailuan cohort of China who had a standardized medical examination between 2006 and 2007 and were followed up for approximately 8 years until occurrence of ASCVD, cancer or death or until December 31, 2014. Subjects were divided into four categories based on the quartiles of TC, LDL-C and non-HDL-C. Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). During follow-up, 2,916 males developed ASCVD and 1,884 developed cancer. Compared with the lowest quartile, the upper-most quartiles of TC, LDL-C and non-HDL-C were all associated with increased ASCVD risk (HR 1.53; HR 1.16; HR 1.55); however, the upper-most quartiles of TC, LDL-C and non-HDL-C were all negatively associated with cancer (HR0.84; HR 0.82; HR 0.80) and these associations were present after exclusion of incident cancers during the first 4 years of follow-up. In a word, we report that high TC, LDL-C and non-HDL-C concentrations increased ASCVD incidence in a male population and that these lipid profiles were inversely associated with total cancer and several individual cancers. PMID- 29119550 TI - One Health, veterinarians and the nexus between disease and food security. AB - Achieving ecologically sustainable food systems for people and animals is one of the greatest challenges facing our world today. Four interdisciplinary approaches that promote a holistic, systems approach to disease prevention and food security are introduced. Current domestic and international initiatives that link disease prevention with food and nutrition security are presented, with an emphasis on animal-source food and examples from Australia, Tanzania and Timor-Leste. Veterinarians are uniquely placed to use their training in comparative physiology in support of the production of sustainable, nutritious, ethical and safe food delivered with minimal waste to promote human, animal and environmental health. PMID- 29119551 TI - Chimeric antigen receptor transduced T cells: Tuning up for the next generation. AB - Chimeric antigen receptor (CAR) T cell therapy has recently achieved impressive clinical outcome in patients with CD19-positive hematologic malignancies. Extrapolation of CAR T cell treatment to solid tumors, however, has not yet yielded similar results. This might be due to intrinsic causes, e.g. insufficient CAR T cell activation or CAR toxicity as well as extrinsic factors displaying an unfavorable tumor environment for CAR T cells by raising physical and chemical barriers. In this review, we discuss the advantages as well as major obstacles of CAR T cell therapy, particularly in the context of solid tumors, and focus on efforts and novel strategies in CAR T cell development. PMID- 29119553 TI - Innovation in the Design of Clinical Trials: Necessary for Innovation in Medicine. PMID- 29119556 TI - Estimands: A More Strategic Approach to Study Design and Analysis. AB - Do we always precisely define the treatment effects that our clinical trial will estimate? Our tenet is that this is not always done, or is done inadequately. This lack of clarity can result in a misalignment among trial objectives, trial design, and statistical methods. We will discuss these challenges and present an improved framework using estimands that is proposed in a draft International Council for Harmonization (ICH) E9 addendum. PMID- 29119557 TI - Understanding the role of parasites in food webs using the group model. AB - Parasites are ubiquitous and have been shown to influence macroscopic measures of ecological network structure, such as connectance and robustness, as well as local structure, such as subgraph frequencies. Nevertheless, they are often under represented in ecological studies due to their small size and often complex life cycles. We consider whether or not parasites play structurally unique roles in ecological networks; that is, can we distinguish parasites from other species using network structure alone? We partition the species in a community statistically using the group model, and we test whether or not parasites tend to cluster in their own groups, using a measure of "imbalance." We find that parasites form highly imbalanced groups, and that concomitant predation, in which a predator consumes a prey and its parasites, but not the number of interactions, improves the group model's ability to distinguish parasites from non-parasites. This work demonstrates that parasites and non-parasites interact in networks in statistically distinct ways, and that these differences are partly, but not entirely, due to the existence of concomitant predation. PMID- 29119558 TI - Panel Report, IPA Congress Buenos Aires, 2017: Transformations in the fear of intimacy. PMID- 29119559 TI - Preoperative methylprednisolone increases plasma Pentraxin 3 early after total knee arthroplasty: a randomized, double-blind, placebo-controlled trial. AB - Preoperative glucocorticoid administration reduces the systemic inflammatory response. Pentraxin 3 (PTX3) is a novel inflammatory marker belonging to the humoral arm of innate immunity exerting a potentially protective host response. This study evaluated PTX3 and other complement marker changes after preoperative methylprednisolone (MP) early after total knee arthroplasty (TKA). Seventy patients were randomized (1 : 1) to preoperative intravenous (i.v.) MP 125 mg (group MP) or isotonic saline i.v. (group C). The outcomes included change in plasma PTX3, mannose-binding lectin (MBL), ficolins (ficolin-1, -2 and -3), complement components (C4 and C3), terminal complement complex (TCC) and C reactive protein (CRP) concentrations. Blood samples were analysed at baseline and 2, 6, 24 and 48 h after surgery with complete sampling from 63 patients for analyses. MP resulted in an increase in circulating PTX3 compared to saline from baseline to 24 h postoperatively (P < 0.001), while MP reduced the systemic inflammatory response (CRP) 24 and 48 h postoperatively (P < 0.001). However, the small postoperative changes in MBL, ficolin-1, -2 and -3, C4, C3 and TCC concentrations did not differ between groups (P > 0.05). In conclusion, preoperative MP 125 mg increased circulating PTX3 and reduced the general inflammatory response (CRP) early after TKA, but did not affect other complement markers. PMID- 29119560 TI - Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis. AB - AIM: To assess the prevalence and risk factors for autism spectrum disorder (ASD) in epilepsy, and to better understand the relationship and comorbidity between these disorders. METHOD: PsychINFO and PubMed were searched for articles published in the past 15 years that examined the prevalence of ASD in individuals with epilepsy. RESULTS: A total of 19 studies were found with a pooled ASD prevalence of 6.3% in epilepsy. When divided by type, the risks of ASD for general epilepsy, infantile spasms, focal seizures, and Dravet syndrome were 4.7%, 19.9%, 41.9%, and 47.4% respectively. Studies with populations under 18 years showed a 13.2 times greater risk of ASD than study populations over 18 years, and samples with most (>50%) individuals with intellectual disability showed a greater risk 4.9 times higher than study populations with a minority of individuals with intellectual disability. The main risk factors for ASD reported in the 19 studies included presence of intellectual disability, sex, age, and symptomatic aetiology of epilepsy. INTERPRETATION: Current research supports a high prevalence of ASD in epilepsy. This study helps to define the clinical profile of patients with epilepsy who are at risk for ASD, which may help clinicians in early screening and diagnosis of ASD in this population. WHAT THIS PAPER ADDS: Critical evaluation of previous studies examining the prevalence of autism spectrum disorder (ASD) in individuals with epilepsy. A meta-analysis of 19 studies showed a pooled ASD prevalence of 6.3% in individuals with epilepsy. Studies that included a majority of individuals with intellectual disability or younger population age had a higher prevalence of autism. Risk factors reported in studies included presence of intellectual disability, sex, age, and symptomatic epilepsy origin. PMID- 29119561 TI - Panel Report, IPA Congress Buenos Aires 2017: Violation of intimacy and gender. PMID- 29119562 TI - Validating performance of TRISS, TARN and NORMIT survival prediction models in a Norwegian trauma population. AB - INTRODUCTION: Anatomic injury, physiological derangement, age, injury mechanism and pre-injury comorbidity are well-founded predictors of trauma outcome. Statistical prediction models may have poorer discrimination, calibration and accuracy when applied in new locations. We aimed to compare the TRISS, TARN and NORMIT survival prediction models in a Norwegian trauma population. METHODS: Consecutive patients admitted to Oslo University Hospital Ulleval within 24 h after injury, with Injury Severity Score >= 10, proximal penetrating injuries, or received by trauma team, were studied. Original NORMIT coefficients were updated in a derivation dataset (NORMIT 2; n = 5923; 2005-2009). TRISS, TARN and NORMIT prediction models were evaluated in the validation dataset (n = 6348; 2010-2013) using two different AIS editions for injury coding. Exclusion due to missing data was 0.26%. Outcome was 30-day mortality. Validation included AUROC, scaled Brier statistics, and calibration plots. RESULTS: The NORMIT models had significantly better discrimination, calibration, and overall fit than the TRISS 09, TARN 09 and TARN 12 models. The updated NORMIT 2 had higher numerical values of AUROC and scaled Brier than the original NORMIT, but with overlapping 95%CI. Overlapping 95%CI for AUROCs and Discrimination slopes indicated that the TARN and TRISS models performed similarly. Calibration plots showed tight and consistent predictions over all Ps strata for NORMIT 2 run on AIS'98 coded data, and only little deterioration when AIS'08 data was substituted. CONCLUSIONS: In a Norwegian trauma population, the updated Norwegian survival prediction model in trauma (NORMIT 2) performed better than well-established British and US alternatives. External validation of these three models in other Nordic populations is warranted. PMID- 29119563 TI - Impact of infrared treatment on quality and fungal decontamination of mung bean (Vigna radiata L.) inoculated with Aspergillus spp. AB - BACKGROUND: Mung bean is a rich source of protein, carbohydrates and fiber content. It also exhibits a high level of antioxidant activity due to the presence of phenolic compounds. Aspergillus flavus and A. niger are the two major fungal strains associated with stored mung bean that lead to post-harvest losses of grains and also cause serious health risks to human beings. Thus there is a need to explore an economical decontamination method that can be used without affecting the biochemical parameters of grains. RESULTS: It was observed that infrared (IR) treatment of mung bean surface up to 70 degrees C for 5 min at an intensity of 0.299 kW m-2 led to complete visible inhibition of fungal growth. Scanning electron microscopy revealed that surface irregularities and physical disruption of spores coat are the major reasons behind the inactivation of IR treated fungal spores. It was also reported that IR treatment up to 70 degrees C for 5 min does not cause any negative impact on the biochemical and physical properties of mung bean. CONCLUSION: From the results of the present study, it was concluded that IR treatment at 70 degrees C for 5 min using an IR source having an intensity of 0.299 kW m-2 can be successfully used as a method of fungal decontamination. The fungal spore population was reduced (approximately 5.3 log10 CFU g-1 reductions) without significantly altering the biochemical and physical properties of grains. (c) 2017 Society of Chemical Industry. PMID- 29119564 TI - Intracranial hemorrhages in neonates born from 32 weeks of gestation-low frequency of associated fetal and neonatal alloimmune thrombocytopenia: a register-based study. AB - BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare condition, with an estimated incidence of one in 1000 to 2000 live births. Predominantly, FNAIT is due to maternal alloantibodies that target paternally derived human platelet antigen (HPA) 1a. The most feared complication is an intracranial hemorrhage (ICH). The aim of this study was to determine the frequency of associated maternal platelet (PLT) alloimmunization in a population of neonates born from 32 weeks of gestation and diagnosed with an ICH. STUDY DESIGN AND METHODS: The Swedish Neonatal Quality (SNQ) register was used to identify neonates diagnosed with an ICH born between 2003 and 2012. Mothers were invited to donate peripheral blood, to investigate their HPA-1a antigen status, and test for anti-HPA and anti-HLA Class I alloantibodies. Clinical data for the neonates were retrieved from the SNQ register and available clinical records. RESULTS: Of 286 registered neonates, 278 mothers were contacted. Of 105 analyzed maternal samples, two (1.9%) were HPA-1a antigen negative. Antibody analyses revealed in total three (2.9%) mothers with anti-HPA: one mother (0.94%) with anti-HPA-1a and two mothers (1.9%) with anti-HPA-5b, of whom one had concurrent anti-HPA-15a. Twenty-four percent tested positive for anti-HLA Class I antibodies. A total of 8.5% of neonates (5/59) with PLT counts available in clinical records were severely thrombocytopenic, with PLT counts of less than 50 * 109 /L. CONCLUSIONS: This retrospective cohort revealed a wide range of factors associated with ICH in neonates born from 32 weeks of gestation and suggests PLT alloimmunization to be a less common contributor than anticipated. PMID- 29119566 TI - Numerical analysis for human perception of temperature rise on the fingertips during usage of a mobile device. PMID- 29119565 TI - Non-invasive methods for the assessment of brown adipose tissue in humans. AB - Brown adipose tissue (BAT) is a recently rediscovered tissue in people that has shown promise as a potential therapeutic target against obesity and its metabolic abnormalities. Reliable non-invasive assessment of BAT volume and activity is critical to allow its importance in metabolic control to be evaluated. Positron emission tomography/computed tomography (PET/CT) in combination with 2-deoxy-2 [18 F]fluoroglucose administration is currently the most frequently used and most established method for the detection and quantification of activated BAT in humans. However, it involves radiation exposure and can detect activated (e.g. after cold exposure), but not quiescent, BAT. Several alternative methods that overcome some of these limitations have been developed including different PET approaches, single-photon emission imaging, CT, magnetic resonance based approaches, contrast-enhanced ultrasound, near infrared spectroscopy, and temperature assessment of fat depots containing brown adipocytes. The purpose of this review is to summarize and critically evaluate the currently available methods that non-invasively probe various aspects of BAT biology in order to assess BAT volume and/or metabolism. Although several of these methods show promise for the non-invasive assessment of BAT volume and function, further research is needed to optimize them to enable an accurate, reproducible and practical means for the assessment of human BAT content and its metabolic function. PMID- 29119567 TI - Identification of a novel missense mutation in A allele in a Chinese individual. PMID- 29119569 TI - The use of fetal neurosonography and brain MRI in cases of cytomegalovirus infection during pregnancy: A retrospective analysis with outcome correlation. AB - OBJECTIVE: To analyze ultrasound (US) and magnetic resonance imaging (MRI) results and developmental outcome in cases of maternal primary cytomegalovirus (CMV) infection during pregnancy. METHODS: We retrospectively reviewed the results of fetal neurosonography and brain MRI of CMV-infected fetuses (Group 1). Cases of maternal infection in which the fetal status was unknown, and subsequently had a negative CMV postnatal urine analysis, were independently analyzed (Group 2). Imaging results were classified as follows: positive, negative, or inconclusive. Developmental landmarks were followed up. RESULTS: Eighty-one women were included in the study: 48 (59.2%) in Group 1 and 33 (40.8%) in Group 2. In Group 1, termination of pregnancy was performed in 8 cases (16.7%) following the diagnosis of brain abnormalities. Among the remaining cases, concordance rate between US and MRI was 78%. False negative rates for US and MRI were 5.5% and 6.4%, respectively (hearing deficits). For MRI, we found 17.5% of false positive/inconclusive results, while for the US, we found 5% of inconclusive results. In Group 2, false positive rates for US and MRI were 6.5% and 12.9%, respectively. CONCLUSIONS: Adding MRI in CMV-infected cases with a normal neurosonographic follow-up should be weighed against a nonnegligible rate of false positive and inconclusive findings. PMID- 29119568 TI - Unchanged mitochondrial phenotype, but accumulation of lipids in the myometrium in obese pregnant women. AB - KEY POINTS: Obesity during pregnancy and childbirth is associated with labour dystocia leading to instrumental or operative delivery, but the underlying pathophysiological mechanisms remain unclear and insufficient uterine contractility has been suggested. This study examined whether reduced myometrial mitochondrial capacity or quantity could contribute as a pathophysiological mechanism to labour dystocia. Data did not support reduced myometrial mitochondrial capacity or quantity in the myometrium at term in obese women, but a reduced myocyte density with increased triglyceride content was demonstrated, which could lead to poorer uterine contractility. These results add to the understanding of systemic effects of obesity, placing also the myometrium at term as an affected non-adipose tissue. ABSTRACT: Obesity is known to increase the risk of labour dystocia and insufficient energy supply, due to reduced mitochondrial capacity or quantity, could be a possible mechanism leading to reduced efficiency of uterine contractility during labour. In the present study of 36 women having an elective Caesarean section at term, obesity did not change mitochondrial phenotype in the myometrial myocyte obtained from uterine biopsies taken at delivery. Respiration rates in isolated mitochondria were unaffected by obesity. No indication of reduced content, investigated by quantification of the complexes of the respiratory chain, or altered regulation, examined by myometrial mRNA levels of genes related to mitochondrial biogenesis and inflammation, was detected. Yet we found increased myometrial triglyceride content in the obese group (2.39 +/- 0.26 vs. 1.56 +/- 0.20 mm, P = 0.024), while protein content and citrate synthase activity per gram wet weight myometrium were significantly lower in the obese (109.2 +/- 7.2 vs. 139.4 +/- 5.6 mg g-1 , P = 0.002, and 24.8 +/- 1.0 vs. 29.6 +/- 1.4 U g-1 wet wt, P = 0.008, respectively). These differences were substantiated by our histological findings where staining for nuclei, cytoplasm, glycogen and collagen supported the idea of a smaller muscle content in the myometrium in obese women. In conclusion no indication of myometrial mitochondrial dysfunction in the isolated state was found, but the observed increase of lipid content might play a role in the pathophysiological mechanisms behind labour dystocia in obese women. PMID- 29119570 TI - Timing of Intra-Aortic Balloon Pump Placement Before Off-Pump Coronary Artery Bypass Grafting and Clinical Outcomes. AB - We aimed to evaluate the timing of preoperative intra-aortic balloon pump (IABP) placement and outcomes in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Patients with prophylactic IABP placement before OPCAB presenting between January 1, 2010 and December 31, 2013 were included. Patients were categorized into two groups based on the timing of preoperative IABP placement: less than 2 h (Group A, n = 223) and more than 2 h (Group B, n = 94). According to the European System for Cardiac Operative Risk Evaluation (EuroSCORE), patients were divided into two subgroups: middle-low EuroSCORE (<6, Groups A1 and B1) and high EuroSCORE (>=6, Groups A2 and B2). Clinical data were compared between groups. Groups contained the following numbers of patients: Group A1, 163; Group A2, 60; Group B1, 60; and Group B2, 34. There was a significant difference in length of ICU and hospital stay between Group A and Group B, respectively (40.5 [22, 64] vs. 26.25 [18, 46.5] hours, P = 0.006; 16 [11, 22] vs. 11 [8, 14] days, P = 0.000). Duration of IABP support, ICU length of stay, hospital length of stay, and cost of hospitalization were significantly higher in Group A1 than in Group B1, respectively (73.69 +/- 44.12 vs. 64.03 +/- 40.93 h, P = 0.013; 36 [20, 56.5] vs. 25.5 [17, 43.75] hours, P = 0.035; 15(11,21) vs. 9(7.25, 12) days, P = 0.000; 109.53(101.20, 131.1) vs. 102.7(95.94, 115.32) thousands CNY, P = 0.009). The length of hospital stay was also significantly higher in Group A2 than in Group B2 (18(13, 26) vs. 13(11, 15) hours, P = 0.000). Preoperative placement of IABP greater than 2 h prior to OPCAB is of benefit, especially in those with high EuroSCORE. The optimal time for prophylactic IABP placement requires further study. PMID- 29119571 TI - Targeted exome sequencing defines novel and rare variants in complex blood group serology cases for a red blood cell reference laboratory setting. AB - BACKGROUND: We previously demonstrated that targeted exome sequencing accurately defined blood group genotypes for reference panel samples characterized by serology and single-nucleotide polymorphism (SNP) genotyping. Here we investigate the application of this approach to resolve problematic serology and SNP-typing cases. STUDY DESIGN AND METHODS: The TruSight One sequencing panel and MiSeq platform was used for sequencing. CLC Genomics Workbench software was used for data analysis of the blood group genes implicated in the serology and SNP-typing problem. Sequence variants were compared to public databases listing blood group alleles. The effect of predicted amino acid changes on protein function for novel alleles was assessed using SIFT and PolyPhen-2. RESULTS: Among 29 unresolved samples, sequencing defined SNPs in blood group genes consistent with serologic observation: 22 samples exhibited SNPs associated with varied but known blood group alleles and one sample exhibited a chimeric RH genotype. Three samples showed novel variants in the CROM, LAN, and RH systems, respectively, predicting respective amino acid changes with possible deleterious impact. Two samples harbored rare variants in the RH and FY systems, respectively, not previously associated with a blood group allele or phenotype. A final sample comprised a rare variant within the KLF1 transcription factor gene that may modulate DNA binding activity. CONCLUSION: Targeted exome sequencing resolved complex serology problems and defined both novel blood group alleles (CD55:c.203G>A, ABCB6:c.1118_1124delCGGATCG, ABCB6:c.1656-1G>A, and RHD:c.452G>A) and rare variants on blood group alleles associated with altered phenotypes. This study illustrates the utility of exome sequencing, in conjunction with serology, as an alternative approach to resolve complex cases. PMID- 29119572 TI - Use of skin stretchers for single-stage bilateral mastectomies in a dog and a cat. AB - OBJECTIVE: To describe the application of skin stretchers for closure of single stage bilateral mastectomies in a dog and a cat. STUDY DESIGN: Clinical case report. ANIMALS: A 12-year-old intact female Miniature Dachshund and a 13-year old spayed female domestic short-hair cat. METHODS: Skin stretchers were applied to the site of the skin adjacent to mammary glands for 2-4 days before surgery. Cable tension was adjusted every 6-8 hours to elongate the skin and to achieve primary closure of single-stage bilateral mastectomy without tension. RESULTS: Wound closure after single-stage bilateral mastectomy was achieved without tension or major complication in both animals. CONCLUSION: Use of skin stretchers allows primary closure of single-stage bilateral mastectomy in dogs and cats. PMID- 29119573 TI - Temperature cycling during platelet cold storage improves in vivo recovery and survival in healthy volunteers. AB - BACKGROUND: Room temperature (RT) storage of platelets (PLTs) can support bacterial proliferation in contaminated units, which can lead to transfusion transmitted septic reactions. Cold temperature storage of PLTs could reduce bacterial proliferation but cold exposure produces activation-like changes in PLTs and leads to their rapid clearance from circulation. Cold-induced changes are reversible by warming and periodic rewarming during cold storage (temperature cycling [TC]) has been proposed to alleviate cold-induced reduction in PLT circulation. STUDY DESIGN AND METHODS: A clinical trial in healthy human volunteers was designed to compare in vivo recovery, survival, and area under the curve (AUC) of radiolabeled autologous apheresis PLTs stored for 7 days at RT or under TC or cold conditions. Paired comparisons of RT versus TC and TC versus cold PLTs were conducted. RESULTS: Room temperature PLTs had in vivo recovery of 55.7 +/- 13.9%, survival of 161.3 +/- 28.8 hours, and AUC of 5031.2 +/- 1643.3. TC PLTs had recovery of 42.6 +/- 16.4%, survival of 48.1 +/- 14.4% hours, and AUC of 1331.3 +/- 910.2 (n = 12, p < 0.05). In a separate paired comparison, cold PLTs had recovery of 23.1 +/- 8.8%, survival of 33.7 +/- 14.7 hours, and AUC of 540.2 +/- 229.6 while TC PLTs had recovery of 36.5 +/- 12.9%, survival of 49.0 +/ 17.3 hours, and AUC of 1164.3 +/- 622.2 (n = 4, AUC had p < 0.05). CONCLUSION: TC storage for 7 days produced PLTs with better in vivo circulation kinetics than cold storage but is not equivalent to RT storage. PMID- 29119574 TI - Effects of EMF emissions from undersea electric cables on coral reef fish. AB - The objective of this study was to determine if electromagnetic field (EMF) emissions from undersea power cables impacted local marine life, with an emphasis on coral reef fish. The work was done at the South Florida Ocean Measurement Facility of Naval Surface Warfare Center in Broward County, Florida, which has a range of active undersea detection and data transmission cables. EMF emissions from a selected cable were created during non-destructive visual fish surveys on SCUBA. During surveys, the transmission of either alternating current (AC), direct current (DC), or none (OFF) was randomly initiated by the facility at a specified time. Visual surveys were conducted using standardized transect and point-count methods to acquire reef fish abundances and species richness prior to and immediately after a change in transmission frequency. The divers were also tasked to note the reaction of the reef fish to the immediate change in EMF during a power transition. In general, analysis of the data did not find statistical differences among power states and any variables. However, this may be a Type II error as there are strong indications of a potential difference of a higher abundance of reef fish at the sites when the power was off, and further study is warranted. Bioelectromagnetics. 39:35-52, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29119575 TI - Occurrence of hemolytic reactions on the same day as immune globulin product administrations during 2008 to 2014. AB - BACKGROUND: Hemolytic reactions (HRs) are rare serious adverse events after immune globulin (IG) use. Our large claims-based study evaluated occurrence of same-day hemolysis after administration of different IG products and potential risk factors, during the 2008 to 2014 study period. STUDY DESIGN AND METHODS: We conducted a retrospective cohort study using a large commercial administrative database. The study included individuals exposed to IG products as identified by procedure codes. HRs were ascertained using ICD-9-CM diagnosis codes. Unadjusted same-day hemolysis rates (per 1000 persons) were estimated overall, by age, sex, and IG products. Multivariable regression analyses were used to evaluate potential risk factors. RESULTS: Of 20,440 persons exposed, 211 (10.3 per 1000) had same-day HRs. The median numbers of doses for IG users with versus without same-day hemolysis were one and six, respectively. The unadjusted product specific HR rates ranged from 1.92 for subcutaneous product Hizentra to 17.99 for intravenous Octagam. The multivariable regression analyses showed significantly increased same-day HR risk in males and in IG users with histories of hemolysis, pneumonia, and hereditary hemolytic anemias. Compared to Gammagard Liquid, significantly elevated overall hemolysis risk was identified with Octagam (odds ratio, 2.36; 95% confidence interval, 1.04-5.35), using Firth's method to account for small sample size bias. CONCLUSION: The study showed variation in the same day IG-related hemolysis by age, sex, and IG products administered. The results suggest importance of underlying health conditions, especially prior hemolysis, and first IG product dose. Differences in HR occurrence may also be explained by product manufacturing processes, indications, routes, and rates of administration, which warrant further investigation. PMID- 29119576 TI - Natural Course of Fetal Axillary Lymphangioma Based on Prenatal Ultrasound Studies. AB - This series and literature review aimed to prenatally characterize the nature of axillary lymphangioma. A total of 30 cases, including our 5 cases, were analyzed. Insights gained from this review are as follows: Septate and nonseptate cysts seem to be different entities. The nonseptate type tends to be small and transient but more highly associated with aneuploidies. Septate cysts are very rarely associated with other abnormalities and hydrops fetalis, unlike cystic hygroma colli, but are more progressive with gestational age and associated with adverse outcomes. The cases with high flow have a higher risk of intralesional hemorrhage. Prenatal diagnosis is important for the route of timely delivery and possibly prenatal interventions. Shoulder dystocia is common and should always be taken into account for decisions on the route of delivery. PMID- 29119577 TI - Enhancing human aspects of care with young people with muscular dystrophy: Results from a participatory qualitative study with clinicians. AB - BACKGROUND: Most research into clinical care of Duchenne or Becker dystrophinopathies (MD) has focused on slowing progressive muscular weakness and extending lifespan. Scarce attention has been paid to the "human" aspects of care such as psychosocial health, living a fulfilling life, or dealing with disability stigma. This study partnered with clinicians to identify and address local and systemic barriers to these human aspects of care. METHODS: We employed a participatory qualitative design at a multidisciplinary MD clinic using 2 methods: (a) ethnographic observations over a 6-month period of clinic visits of children with MD and families, involving 12 clinicians, and (b) 3 "dialogues" (2 way discussions) with these clinicians to collaboratively analyze practices and co-produce recommendations for change. RESULTS: Our methods produced rich data that, when coanalyzed with clinicians and in consultation with a family advisor, provided deep insights into the practices and underlying assumptions of a neuromuscular clinic. Staff recognized the importance of the human aspects of care but, in reviewing the observational data, identified that it was given insufficient attention in (a) routine clinical processes, (b) clinician-family patterns of interaction, and (c) staffing allocations. CONCLUSION: Although the human aspects of care were important to clinicians in the MD clinic, the routines and nature of the clinic meant these were frequently sidelined for biomedical objectives. We present collaboratively produced practical recommendations toward addressing this disjunction between ideals and practice including developing flexibility to tailor appointment frequency, composition, and length; providing time and physical space for psychosocial aspects of care; and clinician skill building to support child/family expression of "negative" emotions; and discussion of sociopolitical aspects of MD such as living with disability stigma. The study offers a set of considerations that, taking into account individual differences, offer insights for similar clinics elsewhere. PMID- 29119578 TI - Carotid Flow Time Test Performance for the Detection of Dehydration in Children With Diarrhea. AB - OBJECTIVES: Unstructured clinical assessments of dehydration in children are inaccurate. Point-of-care ultrasound is a noninvasive diagnostic tool that can help evaluate the volume status; the corrected carotid artery flow time has been shown to predict volume depletion in adults. We sought to determine the ability of the corrected carotid artery flow time to identify dehydration in a population of children presenting with acute diarrhea in Dhaka, Bangladesh. METHODS: Children presenting with acute diarrhea were recruited and rehydrated according to hospital protocols. The corrected carotid artery flow time was measured at the time of presentation. The percentage of weight change with rehydration was used to categorize each child's dehydration as severe (>9%), some (3%-9%), or none (<3%). A receiver operating characteristic curve was constructed to test the performance of the corrected carotid artery flow time for detecting severe dehydration. Linear regression was used to model the relationship between the corrected carotid artery flow time and percentage of dehydration. RESULTS: A total of 350 children (0-60 months) were enrolled. The mean corrected carotid artery flow time was 326 milliseconds (interquartile range, 295-351 milliseconds). The area under the receiver operating characteristic curve for the detection of severe dehydration was 0.51 (95% confidence interval, 0.42, 0.61). Linear regression modeling showed a weak association between the flow time and dehydration. CONCLUSIONS: The corrected carotid artery flow time was a poor predictor of severe dehydration in this population of children with diarrhea. PMID- 29119579 TI - Objective measurement of spectacle wear with a temperature sensor data logger. AB - PURPOSE: This study seeks to establish the utility of the SmartButton Data Logger (www.acrsystems.com) to monitor spectacle wear for research and clinical applications. METHODS: Fifty adults wore a thermosensor on their spectacles for 2 weeks for each of two mount types while keeping wear-time logs. Temperatures during reported spectacle wear (ON) were compared to temperatures during non-wear (OFF) with repeated measures analysis of variance (ANOVA). In addition, two strategies to approximate spectacle wear from temperature data were evaluated: (1) Filtering data based on temperature ranges to identify spectacle wear (either group mean ON temperature, or an individual's mean ON temperature), and (2) Separate examiners inspecting temperature against time plots to identify spectacle wear. The success of these methods to approximate wear time was evaluated by per cent error with respect to subject reported wear time. RESULTS: Group mean ON (31.8 [0.6] degrees Celsius [ degrees C]) and OFF (24.7 [1.5] degrees C) temperatures differed significantly (F1,47 = 471.2, p < 0.001), but there was no difference in temperature between mounts (F1,47 = 1.9, p = 0.18). Median per cent error and first and third quartiles (Q1, Q3) of each technique used to approximate wear time were: group mean filtering = 8% (Q1 3%, Q3 18%), individual mean filtering = 7% (Q1 4%, Q3 19%), Examiner 1 = 6% (Q1 2%, Q3 14%), Examiner 2 = 7% (Q1 3%, Q3 12%). CONCLUSIONS: The SmartButton can monitor spectacle compliance in patients with all approximation methods evaluated providing less than 10% median per cent error in wear time. PMID- 29119580 TI - Comment on: Phenotypic Prenatal Diagnosis of Chronic Granulomatous Disease: A Useful Tool in the Absence of Molecular Diagnosis. PMID- 29119581 TI - Risk of tuberculosis comparison in new users of antitumour necrosis factor-alpha and with existing disease-modifying antirheumatic drug therapy. AB - WHAT IS KNOWN AND OBJECTIVE: Patients with rheumatic disease are at risk for infections. Evaluating antitumour necrosis factor (anti-TNF) drug-associated risk of infections requires justification of baseline risk in the population at high risk of infection. We examined the incidence of active tuberculosis (TB) and its risk factors in patients with rheumatic disease started with anti-TNF-alpha therapy or with existing disease-modifying antirheumatic drug (DMARD) therapy. METHODS: A retrospective cohort study of anti-TNF-alpha therapy new users (anti TNF-alpha group) and those starting with a DMARD after the failure of at least one other DMARD or who had added to existing DMARD treatment (DMARD group) for rheumatic disease in the largest medical setting in Taiwan from 1 January 2005 through 31 November 2013 was conducted to determine relative risk of TB between patient groups. Patients in the DMARD group were stratified into "mild" and "severe" disease severity as proxies for low and high background risk of infection. RESULTS AND DISCUSSION: A total of 3640 patients were enrolled (anti TNF: 955; DMARD: 2685). The incidence of TB was 903.9/100 000 patient-years for anti-TNF-alpha new users and 391.7/100 000 patient-years for DMARD switchers. In Cox regression model, adjusted HR for TB in the anti-TNF-alpha group was higher than for the entire DMARD group (aHR, 2.41; 95% confidence interval [CI], 1.2 4.85), subgroup with mild disease (2.91; 1.31-6.47) and subgroup with severe disease (1.65; 0.68-4.03). Significant independent risk factors for TB were being male, age >=60 years, history of respiratory disease, glucocorticoids dose >7.5 mg/d and living in a TB-prevalent region. WHAT IS NEW AND CONCLUSION: Anti-TNF alpha therapy was independently associated with increased risk of TB in patients with mild disease, but it was not significantly correlated in patients with severe disease after adjusting for confounders. PMID- 29119582 TI - Emotions and assessment: considerations for rater-based judgements of entrustment. AB - CONTEXT: Assessment is subject to increasing scrutiny as medical education transitions towards a competency-based medical education (CBME) model. Traditional perspectives on the roles of assessment emphasise high-stakes, summative assessment, whereas CBME argues for formative assessment. Revisiting conceptualisations about the roles and formats of assessment in medical education provides opportunities to examine understandings and expectations of the assessment of learners. The act of the rater generating scores might be considered as an exclusively cognitive exercise; however, current literature has drawn attention to the notion of raters as measurement instruments, thereby attributing additional factors to their decision-making processes, such as social considerations and intuition. However, the literature has not comprehensively examined the influence of raters' emotions during assessment. In this narrative review, we explore the influence of raters' emotions in the assessment of learners. METHODS: We summarise existing literature that describes the role of emotions in assessment broadly, and rater-based assessment specifically, across a variety of fields. The literature related to emotions and assessment is examined from different perspectives, including those of educational context, decision making and rater cognition. We use the concept of entrustable professional activities (EPAs) to contextualise a discussion of the ways in which raters' emotions may have meaningful impacts on the decisions they make in clinical settings. This review summarises findings from different perspectives and identifies areas for consideration for the role of emotion in rater-based assessment, and areas for future research. CONCLUSIONS: We identify and discuss three different interpretations of the influence of raters' emotions during assessments: (i) emotions lead to biased decision making; (ii) emotions contribute random noise to assessment, and (iii) emotions constitute legitimate sources of information that contribute to assessment decisions. We discuss these three interpretations in terms of areas for future research and implications for assessment. PMID- 29119583 TI - Hyperlipidemia is associated with an increased risk of clinical benign prostatic hyperplasia. AB - BACKGROUND: A high fat diet is associated with risk of benign prostatic hyperplasia (BPH). However, whether hyperlipidemia is associated with BPH remains unclear. This population-based cohort study elucidated whether hyperlipidemia is associated with an increased risk of BPH. METHODS: We used a new-exposure design and analyzed data retrieved from the Taiwan National Health Insurance Database between January 1, 2000 and December 31, 2013. The cohort of men with newly diagnosed hyperlipidemia and the age- and index-date-matched (1:3) nonhyperlipidemia cohort were tracked for incidence of BPH during a 1- to 14-year follow-up. Diagnosis of BPH using the International Classification of Diseases, Ninth Revision, Clinical Modification codes, and the occurrence of BPH diagnosis plus the use of alpha-blockers or 5-alpha reductase inhibitors or receipt of transurethral resection of the prostate were the primary and secondary endpoints, respectively. The confounders in this study were diabetes mellitus, hypertension, coronary heart disease, obesity, liver cirrhosis, nonsteroidal anti-inflammatory drugs, metformin, aspirin, and number of urologist visits. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards regression model adjusted for the propensity score. RESULTS: A total of 35 860 subjects (aged 40-99 years)-including the hyperlipidemia cohort (n = 8,965) and nonhyperlipidemia cohort (n = 26 895)-were identified. Our data revealed that the hyperlipidemia cohort had significantly higher incidences of developing BPH (24.6% vs 12.3%, P < 0.001) and treated BPH (13% vs 5.7%, P < 0.001) compared with the nonhyperlipidemia cohort. The risk of developing BPH in the hyperlipidemia cohort was significantly higher than that in the nonhyperlipidemia cohort (HR = 1.73, 95% CI = 1.63-1.83, P < 0.001) after adjustment for the propensity score. CONCLUSIONS: Hyperlipidemia is associated with an increased risk of clinical BPH. PMID- 29119584 TI - Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases. AB - AIMS: The aims of the present study were to analyse the usability of an immunohistochemical (IHC) analysis as compared with a frequently used mutation detection analysis, and to examine the extent of intratumour and intertumour heterogeneity of BRAF V600E in primary tumours and their corresponding metastases. In the development of intertumour heterogeneity between the primary tumour and the corresponding metastases, time as a factor was also investigated. METHODS AND RESULTS: In total, 227 samples from 224 melanoma patients were analysed with both the Cobas 4800 BRAF V600 Mutation Test and IHC anti-BRAF V600E staining. In 82 primary tumours and 224 corresponding metastases, the extents of intertumour and intratumour heterogeneity were investigated with IHC staining. In 15 cases, disagreement between IHC analysis and the Cobas test was seen. In all but one of the examined patients, homogeneity between the primary tumour and the corresponding metastasis was found. Except for this one case, no heterogeneity developed over longer periods. CONCLUSION: IHC analysis can be safely used as a BRAF pretreatment screening tool, and no additional test is needed when staining is positive. However, if stains are negative, additional tests are essential for detection of other BRAF mutations. We suggest that using primary melanoma tissues is just as safe as using metastatic tissue for detection of BRAF V600E, as BRAF intertumour heterogeneity is extremely rare. In addition, the time between diagnosis of the primary tumour and diagnosis of the corresponding metastasis seems not to increase the risk of intertumour heterogeneity. PMID- 29119585 TI - Effects of dopamine receptor antagonist antipsychotic therapy on blood pressure. AB - WHAT IS KNOWN AND OBJECTIVE: Hypertension, a major risk factor for adverse cardiovascular events, such as stroke and myocardial infarction, affects 80 million American adults. The aetiology of hypertension is multifaceted and difficult to identify. Dopamine receptors, especially those in the kidneys, play a role in blood pressure regulation, and alterations in their function can cause hypertension. The objective of this review was to investigate the association between the use of dopamine antagonists with hypertension focusing especially on second-generation antipsychotics, like clozapine that is D4 receptor antagonist. METHODS: A literature review was conducted using MEDLINE, Ovid, Science Direct, Web of Science and Cochrane Database of Systematic Reviews databases with keywords:hypertension, hypotension, renin-angiotensin-aldosterone system, dopaminergic receptors, blood pressure, antipsychotics. Inclusion criteria were human or animal studies, systematic reviews, meta-analyses, randomized controlled trials, case report/series, published in selected for inclusion. RESULTS AND DISCUSSION: All 5 dopamine receptor subtypes (ie D1, D2, D3, D4 and D5) regulate sodium excretion and BP. The D1, D3 and D4 receptors interact directly with the renin-angiotensin-aldosterone system, whereas D2 and D5 receptors directly interact with the sympathetic nervous system to regulate BP. Use of dopaminergic agonists or antagonists could therefore disturb the regulation of BP by dopamine receptors. WHAT IS NEW AND CONCLUSION: Based upon this review, individuals on antipsychotic agents, particularly clozapine, should be routinely monitored for hypertension, and addition of antihypertensive agents such as angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is indicated if hypertension occurs. PMID- 29119586 TI - Self-reported musculoskeletal disorder pain: The role of job hazards and work life interaction. AB - BACKGROUND: Previous research identified an association between work-family conflict and musculoskeletal pain. This study explores how the work-life interface might affect pain experienced by residential aged care staff. METHODS: A cross-sectional survey of 426 employees in residential aged care was analyzed to assess the impacts of workplace hazards, work-family conflict, and work-life balance on self-reported musculoskeletal pain. RESULTS: Work-family conflict acts as a mediator of the relationships between workplace hazards and the total number of body regions at which musculoskeletal pain was experienced. Work-life balance only acts as a mediator for particular hazards and only if work-family conflict is not taken into account. CONCLUSIONS: Addressing work-life interaction, and in particular work-family conflict, warrants further investigation as a legitimate means through which musculoskeletal disorder risk can be reduced. Policies and practices to improve work-life interaction and reduce work-family conflict should be considered as integral components of musculoskeletal disorder risk management strategies. PMID- 29119587 TI - Perceptions and Expected Immediate Reactions to Severe Storm Displays. AB - The National Weather Service has adopted warning polygons that more specifically indicate the risk area than its previous county-wide warnings. However, these polygons are not defined in terms of numerical strike probabilities (ps ). To better understand people's interpretations of warning polygons, 167 participants were shown 23 hypothetical scenarios in one of three information conditions polygon-only (Condition A), polygon + tornadic storm cell (Condition B), and polygon + tornadic storm cell + flanking nontornadic storm cells (Condition C). Participants judged each polygon's ps and reported the likelihood of taking nine different response actions. The polygon-only condition replicated the results of previous studies; ps was highest at the polygon's centroid and declined in all directions from there. The two conditions displaying storm cells differed from the polygon-only condition only in having ps just as high at the polygon's edge nearest the storm cell as at its centroid. Overall, ps values were positively correlated with expectations of continuing normal activities, seeking information from social sources, seeking shelter, and evacuating by car. These results indicate that participants make more appropriate ps judgments when polygons are presented in their natural context of radar displays than when they are presented in isolation. However, the fact that ps judgments had moderately positive correlations with both sheltering (a generally appropriate response) and evacuation (a generally inappropriate response) suggests that experiment participants experience the same ambivalence about these two protective actions as people threatened by actual tornadoes. PMID- 29119588 TI - An Early Pregnancy Unit in the United States: An Effective Method for Evaluating First-Trimester Pregnancy Complications. AB - In the United Kingdom, early pregnancy assessment clinics have existed since the early 1990s and have become the reference standard for evaluating and treating women with first-trimester pregnancy complications. These units have now been established in many countries and have been found to be effective and efficient, saving money and unnecessary emergency department visits and hospital admissions. To our knowledge, no such model has been described in the United States. A PubMed search using a combination of "early pregnancy unit," "early pregnancy assessment clinic," and "United States," "U.S.," and "America" on May 14, 2017, yielded no results. Denver Health, a safety net hospital in Denver, Colorado, has established the first known early pregnancy unit in the United States. Patients with positive urine pregnancy test results who are in their first trimester by best estimation, have not had a prior ultrasound examination, and present to their primary care providers with pain, bleeding, history of an ectopic pregnancy, history of a tubal ligation, or conception with an intrauterine device in place are eligible to be evaluated in the early pregnancy unit. This article describes our clinical setup, methods, and findings in the first 2 years of the unit's inception with the intention of serving as a model for the establishment of more early pregnancy units throughout the United States. PMID- 29119589 TI - Ultrasound Features of Breast Cancer for Predicting Axillary Lymph Node Metastasis. AB - OBJECTIVES: The purpose of this study was to assess the clinical value of ultrasound (US) features of breast lesions for predicting the risk of axillary lymph node metastasis in patients with breast cancer. METHODS: In this retrospective study, 425 patients with breast cancer were recruited, and their preoperative US features and postoperative pathologic results were collected. The association of these US features of breast cancer with axillary lymph node metastasis was determined by univariate and multivariate analyses. RESULTS: Among the 425 patients, 200 (47.1%) had axillary lymph node metastasis, and 225 (52.9%) did not. The parameters of tumor shape, color Doppler flow imaging grades, histologic grade, and E-cadherin level were significantly and independently associated with axillary lymph node metastasis (P < .05 for all). CONCLUSIONS: Axillary lymph node metastasis was prone to happen in patients with US features of an irregular tumor shape and higher color Doppler flow imaging grades. Ultrasound imaging provides a promising tool for predicting axillary lymph node metastasis in patients with breast cancer. PMID- 29119590 TI - Is an Isolated Aberrant Right Subclavian Artery an Easy-to-Diagnose Normal Variant? PMID- 29119591 TI - Widening participation in medicine? New insights from school students' aspirations. AB - OBJECTIVES: Students from lower socio-economic status backgrounds continue to be under-represented in medical education. Although various initiatives have been implemented by universities to widen participation, their effectiveness and their timing remain contentious. Prior studies have primarily focused on students already on a medical pathway, with little analytical attention given to the aspirations of primary and secondary school-aged students. The aim of this study was to identify the characteristics of students who express early interest in medicine and ascertain the degree to which diversification of the future medical student cohort is indicated. METHODS: As part of a longitudinal study of educational and occupational aspirations (2012-2015), students in Years 3-12 (n = 6492) from government schools in New South Wales, Australia, completed an annual online survey. Their individual responses were linked with prior academic achievement and demographic data. Logistic regression models were used to examine the significance of student- and school-related variables as predictors of interest in medicine. RESULTS: Significant predictors were: being in the early years of secondary school, possessing high cultural capital, coming from a language background other than English, being female, and perceiving oneself as 'well above average' relative to peers. Socio-economic status was a significant predictor when examined independently, but not when all variables were considered in the full regression model. CONCLUSIONS: For medical schools seeking to widen participation, this study underscores the importance of recognising the intersection of other factors with socio-economic status and how they contribute to students' aspirational biographies. If medical schools are to select from a more diverse range of applicants, recruitment strategies must take into account the discursive positioning of the discipline. Sustained outreach into primary and secondary schools may be critical to interrupting the current social reproduction of medical schooling. PMID- 29119592 TI - Orthopedic complications of linear morphea: Implications for early interdisciplinary care. AB - Linear morphea of the limb primarily affects children, and extracutaneous manifestations are common. Orthopedic surgeons are often essential in the care of patients with linear morphea, yet there are few reports outlining specific orthopedic complications in this population. We sought to improve the understanding of orthopedic complications in linear morphea of the limb. Between 1999 and 2014, 51 children were evaluated for linear morphea of an extremity. Twenty-six (51%) had documented orthopedic manifestations. Outcome measures included limb length discrepancy, angular malalignment, limb atrophy, and orthopedic surgical intervention. Joint contractures were most common, affecting 88% of patients, followed by limb atrophy, angular deformity, and limb length discrepancy; 14% required surgical intervention. Despite the use of systemic immunosuppressive therapy in many patients, approximately half of patients with linear morphea of an extremity have orthopedic disease. Early orthopedist involvement is crucial to improve limb alignment and preserve function. PMID- 29119594 TI - Uniform national guidelines do not prevent wide variations in the clinical application of phototherapy for neonatal jaundice. AB - AIM: This study compared the use of phototherapy for neonatal jaundice in all 21 Norwegian neonatal intensive care units (NICUs) from 2013-2014 to improve practice. METHODS: Information on all types of phototherapy devices was collected, and irradiance was measured from random units at 20 cm and 50 cm from the light source. We gathered information on local practice rules, including the use of single, double or triple phototherapy, how infants were positioned, the frequency of blood sampling, rules for using reflective surfaces and interrupting phototherapy. In every NICU, we asked one nurse with more than five years of experience and one with less than one year to set up phototherapy equipment, then measured the irradiance and distance. RESULTS: Photodiodes were the most common of the eight types of phototherapy devices used. Rules for the distance from the device to the infant varied from 10 to 40 cm and in practice they varied from 15 to 48 cm, with irradiance ranging from 11.1-56.1 W/m2 . There were significant variations between NICUs with regard to the overall treatment duration and duration in most birthweight categories. CONCLUSION: There were considerable variations in phototherapy practices among Norwegian NICUs. In particular, the significant variations in duration need to be addressed. PMID- 29119595 TI - Depolarization-induced synaptic vesicle hyperacidification: A new path regarding dopamine release. PMID- 29119593 TI - Prediction of cognitive worsening in de novo Parkinson's disease: Clinical use of biomarkers. AB - BACKGROUND: Cognitive impairment is a frequent and disabling feature of Parkinson's disease. Identifying the factors able to predict cognitive worsening since the early stage may improve disease management. The objective of this study was to define the best predictors of future cognitive worsening in a group of patients with newly diagnosed PD and to propose cutoff values potentially useful at the individual level. METHODS: Fifty-four consecutive drug-naive patients with de novo PD were prospectively evaluated by clinical and neuropsychological assessment, resting EEG, and 123 I-FP-CIT-SPECT and clinically classified into mainly motor, diffuse/malignant, and intermediate PD subtypes; they were then followed up for an average of 5 years. Cognitive outcome was defined by identifying cognitively stable or worsened patients. RESULTS: Step-wise logistic regression selected the posterior qEEG mean frequency and 123 I-FP-CIT-SPECT uptake at caudate level (P < 0.0001). The posterior qEEG mean frequency (cut point, 8.3 Hz) and the caudate 123 I-FP-CIT-SPECT uptake (cut point, 2.3, specific to nondisplaceable binding ratio) achieved 82% and 80% of accuracy, respectively, in predicting cognitive outcome. Survival analysis showed decreasing expected time to cognitive worsening associated with scores below the established thresholds for qEEG and 123 I-FP-CIT-SPECT and with the presence of a malignant clinical phenotype. CONCLUSIONS: Resting EEG and 123 I-FP-CIT-SPECT are good predictors of future cognitive worsening, in de novo drug-naive PD patients. Wherever available, these biomarkers could add valuable prognostic information to classification into different clinical phenotypes. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29119596 TI - Determination of tetracyclines in human urine samples by capillary electrophoresis in combination with field amplified sample injection. AB - A sensitive method using CZE-UV detection has been developed for the determination of five tetracycline antibiotics in human urine samples. To improve the sensitivity of the method, an on-line preconcentration strategy, named field amplified sample injection, has been developed, based on the electrokinetic injection of the sample, which requires only a 1:100 dilution with sample solvent before injection. Under optimum conditions, sensitivity enhancement factors ranged from 450 to 800 for the studied compounds. The applicability of the proposed method was demonstrated by the determination of these antibiotics in spiked urine samples. The limits of quantification were lower than 0.8 mg/L and the precision (intra- and inter-day), expressed as %RSD was below 14%. Recoveries ranged from 92.1 to 96.7%. Thus, the proposed procedure is a simple, fast and efficient strategy which could be used as therapeutic drug monitoring in human urine samples. PMID- 29119597 TI - Hispanic ethnicity as a risk factor for requiring glucarpidase rescue in pediatric patients receiving high-dose methotrexate. PMID- 29119598 TI - Opening/closing pattern of Trifecta and Freestyle valves versus native aortic valve: Are stentless valves more physiologic than a stented valve? AB - BACKGROUND: Stentless valves have long been considered the ideal valves in terms of hemodynamics. Recently, the Trifecta valve, a stented bioprosthesis with excellent fluid dynamic characteristics, has become available. The aim of the study was to compare the opening/closing pattern of the Freestyle stentless valve and the Trifecta valve with that of the native aortic valve. METHODS: A total of 12 patients with a Freestyle and 10 with a Trifecta valve were compared to normal native aortic valves in 12 control patients. Leaflet kinematics and hemodynamic parameters were obtained by echocardiographic M-mode and Doppler measurements. RESULTS: The control group displayed significantly longer Rapid Valve Opening Time (45 +/- 7 ms) and Rapid Valve Closing Time (42 +/- 9 ms) than Freestyle patients (Rapid Valve Opening Time: 32 +/- 7 ms; Rapid Valve Closing Time: 31 +/- 8 ms) and Trifecta patients (Rapid Valve Opening Time: 31 +/- 7 ms; Rapid Valve Closing Time: 30 +/- 8 ms) (P < 0.0001). The maximal leaflet displacement reached at the end of rapid valve opening was 16.7 +/- 3.2 mm, 17.7 +/- 2.3 mm, and 17.7 +/- 5.3 mm (P = 0.42) in the Freestyle, Trifecta, and control groups, respectively. The total opening time was shorter in the control group (223 +/- 25 ms) than in Freestyle (319 +/- 61 ms) and Trifecta (324 +/- 46 ms) patients (P < 0.0001). CONCLUSIONS: The Freestyle stentless valve was not superior to the Trifecta valve in terms of kinematics and functions more like a stented bioprosthesis. PMID- 29119599 TI - Clinical and neuropathological features of progressive supranuclear palsy in Leucine rich repeat kinase (LRRK2) G2019S mutation carriers. PMID- 29119600 TI - Tele-health for patients with deep brain stimulation: The experience of the Ontario Telemedicine Network. PMID- 29119602 TI - Closing the celebration of 200 years of Parkinson's Essay on the Shaking Palsy: Where do we go in the next 200 years? PMID- 29119601 TI - An integrative approach to assess X-chromosome inactivation using allele-specific expression with applications to epithelial ovarian cancer. AB - X-chromosome inactivation (XCI) epigenetically silences transcription of an X chromosome in females; patterns of XCI are thought to be aberrant in women's cancers, but are understudied due to statistical challenges. We develop a two stage statistical framework to assess skewed XCI and evaluate gene-level patterns of XCI for an individual sample by integration of RNA sequence, copy number alteration, and genotype data. Our method relies on allele-specific expression (ASE) to directly measure XCI and does not rely on male samples or paired normal tissue for comparison. We model ASE using a two-component mixture of beta distributions, allowing estimation for a given sample of the degree of skewness (based on a composite likelihood ratio test) and the posterior probability that a given gene escapes XCI (using a Bayesian beta-binomial mixture model). To illustrate the utility of our approach, we applied these methods to data from tumors of ovarian cancer patients. Among 99 patients, 45 tumors were informative for analysis and showed evidence of XCI skewed toward a particular parental chromosome. For 397 X-linked genes, we observed tumor XCI patterns largely consistent with previously identified consensus states based on multiple normal tissue types. However, 37 genes differed in XCI state between ovarian tumors and the consensus state; 17 genes aberrantly escaped XCI in ovarian tumors (including many oncogenes), whereas 20 genes were unexpectedly inactivated in ovarian tumors (including many tumor suppressor genes). These results provide evidence of the importance of XCI in ovarian cancer and demonstrate the utility of our two-stage analysis. PMID- 29119603 TI - Phototherapy is commonly used for neonatal jaundice but greater control is needed to avoid toxicity in the most vulnerable infants. AB - AIM: Limited information is available about how guidelines on phototherapy for neonatal jaundice are applied in practice and toxicity is a concern. We studied the use of phototherapy in relation to birthweight and gestational age (GA) in Norwegian neonatal intensive care units (NICUs). METHODS: The study population was all 5382 infants admitted to the 21 NICUs in Norway between September 1, 2013 and August 31, 2014. Data were recorded daily in the Norwegian Neonatal Network database and anonymised data on patient characteristics, diagnoses, duration, the ages at the start and discontinuation of phototherapy were analysed. RESULTS: More than a quarter (26.6%) of all infants admitted to Norwegian NICUs during the study period received phototherapy. The use of phototherapy was inversely related to GA and birthweight. More than 80% of the preterm infants under 28 weeks of GA received phototherapy. The duration was significantly longer in the lowest birthweight and GA groups and decreased with increasing birthweight and GA. CONCLUSION: Phototherapy is proved to be a strong candidate for the most common therapeutic modality in NICU infants. However, in the light of reported toxicity in the smallest, most vulnerable infants, we recommend increased emphasis on quality control. PMID- 29119604 TI - Anatomy and histology of the prostate and glands of Cowper in three species of neotropical bats. AB - The reproductive accessory glands (RAG) are essential components in reproduction because their secretion products ensure survival, viability, and sperm motility. The objective of this study was to characterize and compare the morphological and histological structure of the RAG in three species of bats of the genus Sturnira (S. erythromos, S. lilium, and S. oporaphilum). The RAG complex comprise a compact gland (prostate), which surrounds the urethra, and a pair of Glands of Cowper at the base of penis. Anatomical and histologically, the prostate are differentiated in two regions, ventral and dorsal. The dorsal region has tubuloalveolar glands with secretions fine granular or accumulations of a gel like substance with bubbles and the ventral region, has alveolar glands with secretory cells form a single-layer of small cells. The seminal vesicles are absent. The prostatic morphology of the three species is similar to that of other studied Stenodermatinae and Desmodontinae, but differs from other subfamilies of Phyllostomidae (Carollinae, Glossophaginae, and Phyllostominae) as that of Molossidae and Vespertilionidae. The RAG complex has no annual variation in relation to functionality or size, but it is variable depending on age (subadults and adults). This agrees with the annual reproductive pattern described for these species in these latitudes, where adult males are reproductively active throughout the year. PMID- 29119605 TI - The risk of venous thromboembolism in patients with clinically overt gastrointestinal bleeding. PMID- 29119606 TI - PKU-21: A Novel Layered Germanate Built from Ge7 and Ge10 Clusters for CO2 Separation. AB - The attractive properties of layered inorganic materials, which make them suitable for numerous applications in chemical industries and life sciences, originated from their crystalline framework structures. Here, we report a new layered germanate PKU-21, which was prepared by the hydrothermal synthesis method using 2-propanolamine (MIPA) as the structure-directing agent. The structure of PKU-21 was determined from synchrotron single-crystal X-ray diffraction and synchrotron powder X-ray diffraction data. It reveals a complicated framework structure containing 18 unique Ge atoms in the asymmetric unit. PKU-21 is the first layered germanate built from both Ge7 and Ge10 clusters, following the 3 dimensional germanate PKU-17. The preparation and structure of PKU-21 are discussed in comparison with PKU-17, which provides new insight into the formation mechanism of germanates. Gas sorption experiments indicate that the layered PKU-21 sample exhibits a better CO2 sorption selectivity over N2 and CH4 at 298 K than at 273 K, making it a promising candidate for CO2 separation. PMID- 29119607 TI - Impaired peripheral nerve regeneration in type-2 diabetic mouse model. AB - Peripheral neuropathy is one of the most common and serious complications of type 2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, that is, impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. This study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy. PMID- 29119609 TI - Conformational Bias by a Removable Silyl Group: Construction of Bicyclo[n.3.1]alkenes by Ring Closing Metathesis. AB - Herein, we report a novel strategy based on a conformationally controlled RCM by a removable silyl group, which allows the facile synthesis of various bicyclo[n.3.1]alkenes, especially a set of highly strained bicyclo[5.3.1]alkenes. Further derivatizations of the silyl group and the resultant double bond of bicyclo[5.3.1]undecene 2 f enabled a concise synthesis of A-B-C ring skeleton of taxol. Density functional theory (DFT) calculations suggest that the introduction of a bulky silyl group at C-5 position of the 1,3-dialkenylcyclohexanol substrates dramatically lowers the energy bias gap between diaxial conformers (to RCM) and diequatorial conformers (to cross metathesis), thereby favoring the expected RCM reaction to give the challenging bridged molecules. PMID- 29119608 TI - Synthetic AAV/CRISPR vectors for blocking HIV-1 expression in persistently infected astrocytes. AB - Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs. PMID- 29119611 TI - Task-dependent function of striatal cholinergic interneurons in behavioural flexibility. AB - Flexible switching of behaviours depends on integrative functioning through the neural circuit connecting the prefrontal cortex and the dorsomedial striatum (DMS). Although cholinergic interneurons modulate striatal outputs by diverse synaptic mechanisms, the roles of cholinergic interneurons in the DMS appear to vary among different models used to validate behavioural flexibility. Here, we conducted immunotoxin-mediated cell targeting of DMS cholinergic interneurons and examined the functions of these interneurons in behavioural flexibility, with the learning conditions differing in trial spacing and discrimination type in a modified T-maze. Elimination of the DMS cholinergic cell group normally spared reversal learning in place discrimination with an intertrial interval (ITI) of 15 s, but it impaired the reversal performance in response discrimination with the same ITI. In contrast, DMS cholinergic elimination resulted in enhanced reversal performance in both place and response discrimination tasks with a 10-min ITI and accelerated the reversal of response discrimination with a 20-min ITI. Our previous study also showed an enhanced influence of cholinergic targeting on place reversal learning with a 20-min ITI, and the present results demonstrate that DMS cholinergic interneurons act to inhibit both place and response reversal performance with a relatively longer ITI, whereas their functions differ between types of reversal performance in the tasks with a shorter ITI. These findings suggest distinct roles of the DMS cholinergic cell group in behavioural flexibility dependent on the trial spacing and discrimination type constituting the learning tasks. PMID- 29119610 TI - Association of vitamin E intake at early childhood with alanine aminotransferase levels at mid-childhood. AB - : The extent to which vitamin E (alpha-tocopherol) intake early in childhood is associated with alanine aminotransferase (ALT) level later in childhood is unknown. The objective of this research is to test the hypothesis that higher alpha-tocopherol intake during early childhood is associated with lower odds of elevated ALT levels during mid-childhood and to examine how body mass index (BMI) influences these relationships. We studied 528 children in Project Viva. Mothers reported child dietary intake at early childhood visits (median 3.1 years) using a validated food frequency questionnaire. At mid-childhood (median 7.6 years), we collected child blood and anthropometric data. The main outcome was elevated sex specific mid-childhood ALT level (>=22.1 U/L for female children and >=25.8 U/L for male children). In multivariable logistic regression models, we assessed the association of energy-adjusted alpha-tocopherol intake with ALT levels, adjusting for child age, sex, race/ethnicity, diet, and age-adjusted sex-specific BMI z score at mid-childhood. Among children in this study, 48% were female, 63% were non-Hispanic white, 19% were non-Hispanic black, and 4% were Hispanic/Latino. Mean alpha-tocopherol intake was 3.7 +/- 1.0 mg/day (range, 1.4-9.2) at early childhood. At mid-childhood, mean BMI z-score was 0.41 +/- 1.0 units and 22% had an elevated ALT level. In multivariable-adjusted logistic regression models, children with higher early childhood vitamin E intake had lower odds of elevated mid-childhood ALT (adjusted odds ratio [AOR], 0.62; 95% confidence interval [CI], 0.39, 0.99) for quartiles 2-4 compared with the lowest quartile of intake. Findings persisted after accounting for early childhood diet (AOR, 0.62; 95% CI, 0.36, 1.08) and were strengthened after additionally accounting for mid-childhood BMI z-score (AOR, 0.56; 95% CI, 0.32, 0.99). CONCLUSION: In this cohort, higher early childhood intake of alpha-tocopherol was associated with lower odds of elevated mid-childhood ALT level. (Hepatology 2018;67:1339-1347). PMID- 29119612 TI - Are you surprised to hear this? Longitudinal spectral speech exposure in older compared to middle-aged normal hearing adults. AB - Cognitive abilities such as attention or working memory can support older adults during speech perception. However, cognitive abilities as well as speech perception decline with age, leading to the expenditure of effort during speech processing. This longitudinal study therefore investigated age-related differences in electrophysiological processes during speech discrimination and assessed the extent of enhancement to such cognitive auditory processes through repeated auditory exposure. For that purpose, accuracy and reaction time were compared between 13 older adults (62-76 years) and 15 middle-aged (28-52 years) controls in an active oddball paradigm which was administered at three consecutive measurement time points at an interval of 2 wk, while EEG was recorded. As a standard stimulus, the nonsense syllable /'a:?a/was used, while the nonsense syllable /'a:sa/ and a morphing between /'a:?a/ and /'a:sa/ served as deviants. N2b and P3b ERP responses were evaluated as a function of age, deviant, and measurement time point using a data-driven topographical microstate analysis. From middle age to old age, age-related decline in attentive perception (as reflected in the N2b-related microstates) and in memory updating and attentional processes (as reflected in the P3b-related microstates) was found, as indicated by both lower neural responses and later onsets of the respective cortical networks, and in age-related changes in frontal activation during attentional stimulus processing. Importantly, N2b- and P3b-related microstates changed as a function of repeated stimulus exposure in both groups. This research therefore suggests that experience with auditory stimuli can support auditory neurocognitive processes in normal hearing adults into advanced age. PMID- 29119613 TI - MRI and US in the evaluation of fetal anomalies: The need to work together. AB - PURPOSE: Real-time virtual sonography (RVS) is a new technique that synchronizes real-time ultrasonography (US) and multiplanar reconstructed magnetic resonance imaging (MRI). The purpose of this study was to evaluate the feasibility and ability of RVS to assess the main pathologies in fetuses with suspected US anomalies. METHOD AND MATERIALS: Real-time virtual sonography (Hitachi, HI VISION Ascendus) was offered to 30 patients who had undergone fetal MRI. The acquired MRI image dataset was loaded into the fusion system and displayed together with the real-time US image. The ability of RVS to assess the main anatomical sites and fetal anomalies was evaluated. RESULTS: Real-time virtual sonography was technically possible in all cases. From a total of 30 patients, RVS helped the diagnosis in 10 cases. In 15 cases of encephalic pathology, fusion imaging improved the accuracy of the diagnosis; in the other 5 cases, MRI was superior to US even when using the RVS. CONCLUSION: This is a study on the feasibility and practical use of RVS. Thanks to information from both US and MRI, RVS allowed better identification of the fetal pathologies and improved the performance of the ultrasound examination. In our experience, it was really helpful in pathologies that would benefit from US follow-up. PMID- 29119614 TI - Magnetostructural Investigation of Orthogonal 1-Aryl-3-Phenyl-1,4 Dihydrobenzo[e][1,2,4]triazin-4-yl Derivatives. AB - 3-Phenyl-1,4-dihydrobenzo[e][1,2,4]triazinyl radicals with the N(1) position substituted with naphth-2-yl (1 b), naphth-1-yl (1 c), pyren-1-yl (1 d), anthracen-9-yl (1 e), 2-trifluoromethylphenyl (1 f), 3-trifluoromethylphenyl (1 g), and 2-iodophenyl (1 h) were characterized by using single-crystal X-ray diffraction, variable-temperature magnetic susceptibility, and DFT computational methods. The substituent at N(1) is essentially orthogonal to the heterocycle plane in 1 f and 1 h, and with a high torsion angle in 1 c and 1 d. Radicals 1 c and 1 h form unusual infinite chains with crisscrossing hetero-co-facial pi-pi interactions, whereas radical 1 d forms analogous homo-co-facial arrangements. Infinite chains of homo-co-facial pi-pi dimers are found in 1 b, 1 f and 1 g; in the latter the position of the CF3 group controls the slippage of the dimers in the chain. No pi-pi parallel arrangements were found in 1 e. Magnetic susceptibility measurements demonstrated strong antiferromagnetic interactions in 1 b (J=-264+/-4 cm-1 ) and 1 f (J=-134+/-1 cm-1 ), while weak intradimer ferromagnetic interactions were found in 1 g (J2 =+21+/-1 and J1 =-15+/-1 cm-1 ). Other derivatives exhibit typical weak antiferromagnetic exchange interactions in a range of -5 to -10 cm-1 . PMID- 29119615 TI - Deltamides and Croconamides: Expanding the Range of Dual H-bond Donors for Selective Anion Recognition. AB - Dual H-bond donors are widely used as recognition motifs in anion receptors. We report the synthesis of a library of dual H-bond receptors, incorporating the deltic and croconic acid derivatives, termed deltamides and croconamides, respectively, and a comparison of their anion binding affinities (for monovalent species) and Bronsted acidities to those of the well-established urea and squaramide dual H-bond donor motifs. For dual H-bonding cores with identical substituents, the trend in Bronsted acidity is croconamides>squaramides>deltamides>ureas, with the croconamides found to be 10 15 pKa units more acidic than the corresponding ureas. In contrast to the trends displayed by ureas, deltamides and squaramides, N,N'-dialkyl croconamides displayed higher binding affinity to chloride than the N,N'-diaryl derivatives, which was attributed to partial deprotonation of the N,N'-diaryl derivatives at neutral pH. A number of differences in anion binding selectivity were observed upon comparison of the dual H-bond cores. Whereas the squaramides display similar affinity for both chloride and acetate ions, the ureas have significantly higher affinity for acetate than chloride ions and the deltamides display higher affinity for dihydrogenphosphate ions than other oxoanions or halides. These inherent differences in binding affinity could be exploited in the design of anion receptors with improved ability to discriminate between monovalent anions. PMID- 29119616 TI - When I say ... gamification. PMID- 29119617 TI - Computer-aided design of human sialyltransferase inhibitors of hST8Sia III. AB - Sialyltransferase (ST) upregulation and the resultant hypersialylation of tumour cell surfaces is an established hallmark of many cancers including lung, breast, ovarian, pancreatic and prostate cancer. The role of ST enzymes in tumour cell growth and metastasis, as well as links to multi-drug resistance, has seen ST inhibition emerge as a target for potential antimetastatic cancer treatments. The most potent of these reported inhibitors are transition-state analogues. Although there are several examples of these in the literature, many have suspected poor pharmacokinetic properties and are not readily synthetically accessible. A proposed solution to these problems is the use of a neutral carbamate or 1,2,3 triazole linker instead of the more commonly used phosphodiester linker, and replacing the traditionally utilised cytidine nucleotide with uridine. Another issue in this area is the paucity of structural information of human ST enzymes. However, in late 2015 the structure of human ST8Sia III was reported (only the second human ST described so far), creating the opportunity for structure-based design of selective ST8 inhibitors for the first time. Herein, molecular docking and molecular dynamics simulations with the newly published crystal structure of hST8Sia III were performed for the first time with selected ST transition state analogues. Simulations showed that these compounds could participate in many of the key interactions common with the natural donor and acceptor substrates, and reveals some key insights into the synthesis of potentially selective ST inhibitors. PMID- 29119618 TI - Effects of chestnut tannins on intestinal morphology, barrier function, pro inflammatory cytokine expression, microflora and antioxidant capacity in heat stressed broilers. AB - A study was conducted to evaluate the effects of chestnut tannins (CT) on intestinal morphology, barrier function, pro-inflammatory cytokine expression, microflora and antioxidant capacity in heat-stressed broilers. Four hundred 28 day-old male Ross 308 broilers were randomly assigned into four groups, with 10 replicates per group and 10 broilers per replicate. The broilers in the normal (NOR) group were kept at 22 +/- 1 degrees C and fed the basal diet, and each of the other three groups were treated with cyclic heat (33 +/- 1 degrees C from 0800 to 1800 and 22 +/- 1 degrees C from 1800 to 0800) and fed the basal diet with 0 (HT), 1 (CT1) or 2 (CT2) g of CT/kg of diet. The experiment lasted for 14 days. Compared with the HT group, broilers in the NOR and CT2 groups had higher (p < .05) average daily gain and villus height in the jejunum and lower serum d lactate (p < .001) and diamine oxidase (p < .01) levels. The addition of 2 g CT/kg of diet increased the total antioxidant capacity (p < .001) and superoxide dismutase activities (p < .05) and zonula occludens-1 mRNA expression level (p < .05) and decreased the malondialdehyde concentration (p < .01) and mRNA expression levels of interleukin-6 (p < .001) and nuclear factor kappa B (p < .001) in the jejunal mucosa of heat-stressed broilers. The populations of Escherichia coli and Clostridium in the jejunum (p < .01) and caecum (p < .05) of broilers in the HT group were higher than those in the NOR and CT2 groups. In conclusion, the addition of 2 g CT/kg of diet seemed to be a feasible means of alleviating the negative effects of heat stress on the growth performance and intestinal function of broilers. PMID- 29119619 TI - Quantitative differentiation of whole smoke solution-induced mutagenicity in the mouse lymphoma assay. AB - In vitro genotoxicity dose-response data have been investigated for their utility in modeling and assessing potential differences in mutagenic responses between machine-generated whole smoke solutions (WSSs) from combusted cigarette tobacco products. Our previous study observed that potency ranking by benchmark dose (BMD) analysis was a useful modeling approach for quantitative assessment of differences between the mutagenicity of several structurally diverse chemical constituents of cigarette smoke. To follow-up on these observations, we used the mouse lymphoma assay (MLA) to evaluate the mutagenicity of WSSs prepared from two commercial cigarettes smoked under two different smoking machine regimens. L5178Y cells were exposed to >=5 concentrations of each WSS for 4 hr +/- S9 activation. S9 reduced the cytotoxicity and enhanced the mutagenicity of the WSSs. The resulting S9-mediated mutagenicity dose-responses were compared between test articles using BMD analysis, the lowest dose exceeding the Global Evaluation Factor, the no observed or lowest observed genotoxic effect level, and the mutagenic potency. The BMD10 , BMD50 , BMD100 , and BMD200 , indicating a 10%, 50%, 100%, or 200% increase in the background mutant frequency, respectively, were calculated using the PROAST software package. Overall, the quantitative approaches resulted in a similar rank order of mutagenic potency for the MLA tested WSSs, with potency increasing with the level of tar. The BMD approach using covariate analysis produced the most informative comparisons. Differences in potency were associated with the number of cigarettes smoked, the cigarette product smoked, and the smoking machine protocol used to prepare the sample. Under the conditions of this study, these results suggest that our hypothesis of modeling MLA data using the BMD approach to quantitatively discriminate between the mutagenic potential of WSSs from combustible cigarettes might be an useful method. Environ. Mol. Mutagen. 59:103-113, 2018. Published 2017. This article is a US Government work and is in the public domain in the USA. PMID- 29119620 TI - Identification of oestrogen, progesterone receptor and human epidermal growth factor receptor 2 expression in mediastinal metastases of breast cancer obtained by endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND: In breast cancer patients, the expression statuses of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are crucial in the choice of treatment. Receptor expression in metastatic lesions can differ from the primary tumour. The aim of our study was to analyse the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to obtain samples allowing the identification of ER, PR and HER2 expression in patients with mediastinal metastases of breast cancer. PATIENTS AND METHODS: The clinical files of all patients with a final diagnosis of breast cancer mediastinal metastases diagnosed by EBUS-TBNA in our institution were retrospectively analysed. The ability of EBUS-TBNA to obtain samples that allowed hormone receptor and HER2 expression analysis was calculated. RESULTS: Twenty-four patients were included. ER, PR and HER2 assessments could be performed in 22, 20 and 22 patients, respectively. In 20 of the 24 patients it was possible to investigate all three types of receptor expression. In the remaining four cases, where ER, PR or HER2 expression tests could not be performed, it was due to a lack of tissue. In cases with adequate results for EBUS-TBNA and the primary tumour agreement was greater for ER (16/19) and HER2 (12/14) than PR (8/17). Based on receptor status, there was a change in the choice of treatment for five patients. CONCLUSION: In patients with breast cancer mediastinal metastases, ER, PR and HER2 expression can be assessed in samples obtained by EBUS-TBNA whenever a sufficient tissue sample is collected. PMID- 29119621 TI - Evaluating the feasibility of the steady-state visual evoked potential (SSVEP) to study temporal attention. AB - Improvements in perceptual performance can be obtained when events in the environment are temporally predictable-and temporal predictability improves attention and sensory processing. The amplitude of the steady-state visual evoked potential (SSVEP) has been shown to correlate with attention paid to a flickering stimulus even if the flickering stimulus is irrelevant for the task. However, to our knowledge, the validity of the SSVEP to study temporal attention has not been established. Therefore, we designed an SSVEP temporal attention task to evaluate whether the SSVEP and its temporal dynamics can be used to study temporal attention. We used a forced-choice perceptual detection task while presenting task-irrelevant visual flicker at alpha (10 Hz) and two surrounding frequencies (6 or 15 Hz). Temporal predictability was manipulated by having the interstimulus intervals (ISI) be constant or variable. Behavioral results replicated previous studies confirming the benefits of temporal expectations on performance for trials with constant ISI. EEG analyses revealed robust SSVEP amplitudes for all flicker frequencies, although a main effect of temporal expectations on SSVEP amplitude was not significant. Additional analyses revealed temporal predictability-related modulations of SSVEP amplitude at 10 Hz and its second harmonic (20 Hz). The effect of temporal predictability was also observed for the 6 Hz flicker, but not for 15 Hz for any ISI condition. These results provide some evidence for the feasibility of the SSVEP technique to study temporal attention for stimuli with flicker frequencies around the alpha band. PMID- 29119622 TI - FzlA, an essential regulator of FtsZ filament curvature, controls constriction rate during Caulobacter division. AB - During bacterial division, polymers of the tubulin-like GTPase FtsZ assemble at midcell to form the cytokinetic Z-ring, which coordinates peptidoglycan (PG) remodeling and envelope constriction. Curvature of FtsZ filaments promotes membrane deformation in vitro, but its role in division in vivo remains undefined. Inside cells, FtsZ directs PG insertion at the division plane, though it is unclear how FtsZ structure and dynamics are mechanistically coupled to PG metabolism. Here we study FzlA, a division protein that stabilizes highly curved FtsZ filaments, as a tool for assessing the contribution of FtsZ filament curvature to constriction. We show that in Caulobacter crescentus, FzlA must bind to FtsZ for division to occur and that FzlA-mediated FtsZ curvature is correlated with efficient division. We observed that FzlA influences constriction rate, and that this activity is associated with its ability to bind and curve FtsZ polymers. Further, we found that a slowly constricting fzlA mutant strain develops 'pointy' poles, suggesting that FzlA influences the relative contributions of radial versus longitudinal PG insertion at the septum. These findings implicate FzlA as a critical coordinator of envelope constriction through its interaction with FtsZ and suggest a functional link between FtsZ curvature and efficient constriction in C. crescentus. PMID- 29119624 TI - From the Editors. PMID- 29119623 TI - Exponential Activation of Carbonic Anhydrase by Encapsulation in Dynameric Host Matrices with Chiral Discrimination. AB - Herein an unexpected exponential activation of bovine carbonic anhydrase (bCA) in aqueous solutions in the presence of dynameric host matrices is reported. Successive experiments confirmed the important role of dynamic imine exchange within the dynameric host structures for direct enzyme activation. This allows for optimal encapsulation of the guest enzyme, whereas the presence of external proton-sponge amino groups is less important. Non-exchanging polymeric sec-amine congeners formed from imine reduction of dynameric structures show no obvious activation on bCA. Although the dynamers synthesized from diamino chiral-pair precursors displayed similar activation constants toward bCA, different activation delay times were observed from these two dynamers of opposite optical activity. The circular dichroism (CD) spectra demonstrate selective structural changes in the secondary structure of bCA upon dynameric encapsulation in aqueous solution. The different interaction molds observed in CD spectra for the dynamers with opposite chirality explain the longer activation time required for one of the dynamers. PMID- 29119625 TI - Preparation and Characterization of P2 BCh Ring Systems (Ch=S, Se) and Their Reactivity with N-Heterocyclic Carbenes. AB - Four-membered rings with a P2 BCh core (Ch=S, Se) have been synthesized by the reaction of phosphinidene chalcogenide (Ar*P=Ch) and phosphaborene (Mes*P=BNR2 ). The mechanistic pathways towards these rings are explained by detailed computational work that confirmed the preference for the formation of P-P, not P B, bonded systems, which seems counterintuitive given that both phosphorus atoms contain bulky ligands. The reactivity of the newly synthesized heterocycles, as well as that of the known (RPCh)n rings (n=2, 3), was probed by the addition of N heterocyclic carbenes, which revealed that all investigated compounds can act as sources of low-coordinate phosphorus species. PMID- 29119626 TI - Construction of Zeolite-Like Cluster Organic Frameworks from 3 d-4 d/3 d-3 d Heterometallic Supertetrahedral Secondary Building Units: Syntheses, Structures, and Properties. AB - Two zeolite-like cluster organic frameworks based on Cd-Cu/Mn-Cu heterometallic supertetrahedral secondary building units have been successfully constructed under solvothermal conditions, namely, Cu[Cd4 Cu6 (L)4 (H2 O)18 ](Ac)9 ?DMA?3 H2 O (1), and Cu[Mn4 Cu6 (L)4 (Ac)3 (H2 O)12 ](Ac)6 ?CH3 CN?13 H2 O (2), where H3 L=2-(hydroxymethyl)-2-(pyridin-4-yl)-1,3-propanediol, Ac=CH3 COO- , DMA=N,N' dimethylacetamide. Single-crystal X-ray structural analysis reveals that both 1 and 2 exhibit 3-dimensional zeolite-like architectures with similar 4-connected components, but possess definitely different topologies of diamondoid (dia) and uncommon lonsdaleite (lon), respectively. 1 and 2 represent the first cases of zeolite-like cluster organic frameworks containing Cd-Cu/Mn-Cu heterometallic supertetrahedral secondary building units. Furthermore, the magnetic properties and porous nature of 1 and 2 were also studied. PMID- 29119628 TI - STAT3 Expression and Activity are Up-Regulated in Diffuse Large B Cell Lymphoma of Dogs. AB - BACKGROUND: The Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathways play important roles in the pathogenesis of diffuse large B cell lymphoma (DLBCL) in humans, and up-regulated STAT3 expression and activity are associated with worse clinical outcome in humans. No studies have evaluated the JAK-STAT signaling pathway in DLBCL of dogs. HYPOTHESIS: STAT3 pathway is deregulated in DLBCL in dogs. We aim to assess the expression, activation, and cellular localization of STAT3 and mitogen-activated protein kinase ERK1/2 in DLBCL of dogs. ANIMALS: Forty-three client-owned dogs diagnosed with DLBCL by histopathology METHODS: Retrospective analysis of DLBCL in dogs, including patient characteristics and treatment, immunohistochemistry, and protein expressions by Western blot. RESULTS: A higher percentage of STAT3 and p STAT3 immunolabelled cells were observed in DLBCL of dogs when compared to normal canine lymph nodes. In STAT3 immunolabelled cells, STAT3 has higher nuclear expression in lymphoma samples than in normal or reactive lymph nodes. In addition to up-regulated STAT3 expression and activation, mitogen-activated kinase ERK1/2 activation is up-regulated in DLBCL of dogs. CONCLUSION AND CLINICAL IMPORTANCE: Compared with the normal canine lymph node, DLBCL of dogs has up-regulated STAT3 pathway. Our results support future investigation of JAK inhibitors in the treatment of DLBCL in dogs. PMID- 29119627 TI - Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery. AB - To understand the molecular mechanism of rectal cancer and develop markers for disease prognostication, we generated and explored a dataset from 243 rectal cancer patients by gene expression microarray analysis of cancer samples and matched controls, and SNP-arrays of germline DNA. We found that two of the loci most strongly linked with colorectal cancer (CRC) risk, 8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), as well as 20q13 (in the intron of LAMA5), are tightly associated with the prognosis of rectal cancer patients. For SNPs on 18q21 (rs12953717 and rs4464148) and 20q13 (rs4925386), alleles that correlate with higher risk for the development of CRC are associated with shorter disease free survival (DFS). However, for rs6983267 on 8q24, the low risk allele is associated with a higher risk for recurrence and metastasis after surgery, and importantly, is strongly correlated with the resistance of CRC cell lines to chemoradiotherapy (CRT). We also found that although MYC expression is dramatically increased in cancer, patients with higher levels of MYC have a better prognosis. The expression of SMAD7 is weakly correlated with DFS. Notably, the presence of the 8q24 and 18q21 SNP alleles is not correlated with expression levels of MYC and SMAD7. rs4464148, and probably rs6983267 and rs4925386, are linked with overall survival time of patients. In conclusion, we show that several CRC risk SNPs detect subpopulations of rectal cancer patients with poor prognosis, and that rs6983267 probably affects prognosis through interfering with the resistance of cancer cells to CRT. PMID- 29119629 TI - Carbon-Heteroatom Bond Formation by an Ultrasonic Chemical Reaction for Energy Storage Systems. AB - The direct formation of C?N and C?O bonds from inert gases is essential for chemical/biological processes and energy storage systems. However, its application to carbon nanomaterials for improved energy storage remains technologically challenging. A simple and very fast method to form C?N and C?O bonds in reduced graphene oxide (RGO) and carbon nanotubes (CNTs) by an ultrasonic chemical reaction is described. Electrodes of nitrogen- or oxygen doped RGO (N-RGO or O-RGO, respectively) are fabricated via the fixation between N2 or O2 carrier gas molecules and ultrasonically activated RGO. The materials exhibit much higher capacitance after doping (133, 284, and 74 F g-1 for O-RGO, N RGO, and RGO, respectively). Furthermore, the doped 2D RGO and 1D CNT materials are prepared by layer-by-layer deposition using ultrasonic spray to form 3D porous electrodes. These electrodes demonstrate very high specific capacitances (62.8 mF cm-2 and 621 F g-1 at 10 mV s-1 for N-RGO/N-CNT at 1:1, v/v), high cycling stability, and structural flexibility. PMID- 29119630 TI - Mycobacterium tuberculosis Rv3651 is a triple sensor-domain protein. AB - The genome of the human pathogen Mycobacterium tuberculosis (Mtb) encodes ~4,400 proteins, but one third of them have unknown functions. We solved the crystal structure of Rv3651, a hypothetical protein with no discernible similarity to proteins with known function. Rv3651 has a three-domain architecture that combines one cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA (GAF) domain and two Per-ARNT-Sim (PAS) domains. GAF and PAS domains are sensor domains that are typically linked to signaling effector molecules. Unlike these sensor effector proteins, Rv3651 is an unusual sensor domain-only protein with highly divergent sequence. The structure suggests that Rv3651 integrates multiple different signals and serves as a scaffold to facilitate signal transfer. PMID- 29119631 TI - Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: A randomized controlled trial. AB - Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion-dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving <=6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to "early start deferiprone" (.ES-DFP) at a low dose (50 mg/kg/day) or to "delay chelation" (DC), and remained in the study until their serum ferritin (SF) level reached >=1000 MUg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 ug/L and TSAT > 70% compared with none in the ES-DFP group. LPI level > 0.6 uM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 ug/L was delayed by 6 months in the ES-DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES-DFP group. PMID- 29119632 TI - The effect of education of nurses on preventing catheter-associated urinary tract infections in patients who undergo hip fracture surgery. AB - AIMS AND OBJECTIVES: The aim of the study was to investigate the effect of educating nurses on preventing catheter-associated urinary tract infections in patients who undergo hip fracture surgery. BACKGROUND: Urinary tract infections after hip fracture surgery are observed at a rate of 12% to 61%, and the most important risk factor associated with urinary tract infection is considered to be the presence of urinary catheters. Nurse education about the use and management of urinary catheters is important to decrease the risk of urinary tract infections. DESIGN: The study was semi-experimental. METHODS: The study was conducted in an orthopedics and traumatology clinic of a training hospital between January 2014-December 2015. After a power analysis was performed, a total of 60 patients fulfilled the criteria to be included in the study, with n = 30 in the pre-education group and n = 30 in the posteducation group. Nurses who worked in the orthopedics and traumatology clinic of the military hospital were the target population, and 18 nurses who consented to join the study constituted the sample. The "Patient Monitoring Form," "Nurse Information Form" and "Daily Urinary Catheter Assessment Tool" were used as data collection tools. RESULTS: The mean pre-education knowledge score of the nurses was found to be 68.05 +/- 10.69, while the mean posteducation score was 95.13 +/- 6.27. The mean catheter duration decreased from 11.06 +/- 6.34 days-3.83 +/- 0.95 days after the education. The catheter-associated urinary tract infection rate decreased by 9.37 per thousand. CONCLUSION: Educating nurses on preventing catheter-associated urinary tract infections in patients who underwent hip fracture surgery significantly decreased the rate of catheter-associated urinary tract infections and the duration of catheterisation. RELEVANCE TO CLINICAL PRACTICE: The systematic and comprehensive education of all healthcare professionals and the development and practice of catheter removal protocols could contribute to the prevention of catheter-associated urinary tract infections. PMID- 29119633 TI - Antibody responses to GalC in severe and complicated childhood Guillain-Barre syndrome. PMID- 29119634 TI - The cerebral basis of Parkinsonian tremor: A network perspective. AB - Tremor in Parkinson's disease is a poorly understood sign. Although it is one of the clinical hallmarks of the disease, its pathophysiology remains unclear. It is clear that tremor involves different neural mechanisms than bradykinesia and rigidity, the other core motor signs of Parkinson's disease. In particular, the role of dopamine in tremor has been heavily debated given clinical observations that tremor has a variable response to dopaminergic medication. From a neuroscience perspective, tremor is also a special sign; unlike other motor signs, it has a clear electrophysiological signature (frequency, phase, and power). These unique features of tremor, and newly available neuroimaging methods, have sparked investigations into the pathophysiology of tremor. In this review, evidence will be discussed for the idea that parkinsonian tremor results from increased interactions between the basal ganglia and the cerebello-thalamo cortical circuit, driven by altered dopaminergic projections to nodes within both circuits, and modulated by context-dependent factors, such as psychological stress. Models that incorporate all of these features may help our understanding of the pathophysiology of tremor and interindividual differences between patients. One example that will be discussed in this article is the "dimmer switch" model. According to this model, cerebral activity related to parkinsonian tremor first arises in the basal ganglia and is then propagated to the cerebello thalamo-cortical circuit, where the tremor rhythm is maintained and amplified. In the future, detailed knowledge about the architecture of the tremor circuitry in individual patients ("tremor fingerprints") may provide new, mechanism-based treatments for this debilitating motor sign. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29119635 TI - The evolving role of the personal support worker in home care in Ontario, Canada. AB - To meet increasing demand for home care, the role of personal support workers (PSWs) is shifting from providing primarily personal and supportive care to include care activities previously provided by regulated health professionals (RHPs). Much of the research examining this shift focuses on specialty programmes, with few studies investigating the daily care being provided by PSWs, frequency of care activities being provided by PSWs, and characteristics of the population receiving more complex tasks. Between January and April 2015, a review of 517 home-care service user charts was undertaken in Ontario, Canada, to: (1) describe the range of tasks being performed by PSWs in home care, (2) identify tasks transferred by RHPs to PSWs, and (3) examine characteristics of service users receiving transferred care. Findings indicate that normally, PSWs provide personal and supportive care commensurate with their training. However, in approximately one quarter of care plans reviewed, PSWs also completed more complex care activities transferred to them by RHPs. Service users receiving transferred care were older and had higher levels of cognitive and functional impairment. Although there is potential for the expansion of home-care services through increased utilisation of PSWs, healthcare leadership must ensure that the right provider is being utilised at the right time and in the right place to ensure safe and effective quality care. Thus, several actions are recommended: PSW core competencies be clearly articulated, processes used to transfer care activities from RHPs to PSWs be standardised and a team-based approach to the delivery of home-care services be considered. Utilisation of a team-based model can help establish positive relationships among home-care providers, provide increased support for PSWs, allow for easier scheduling of initial training and ensure regular reassessments of PSW competence among PSWs providing added skills. PMID- 29119636 TI - Gastric accommodation in healthy subjects studied by ultrasound, manometry, and impedancemetry. AB - BACKGROUND: Gastric accommodation to a meal may be important in the pathogenesis of upper gastrointestinal disorders, but has been difficult to investigate in a minimally invasive fashion. METHODS: We studied gastric and lower esophageal physiology during food intake, combining transabdominal ultrasound, multichannel high-resolution impedance-manometry (HRIM) and a symptom questionnaire. A HRIM catheter was distally positioned at incisura angularis and 300 mL saline with 75 g glucose was ingested. Target variables were recorded for 30 min after fluid intake. KEY RESULTS: Fifteen healthy subjects' participated (11W/4M, median age 23.8 y) and all accepted the meal with few symptoms. At incisura angularis maximum change in pressure from pre-intake values was -7.4 mmHg after 60 s (P < .0001), rising to pre-intake values within 20 min. The corresponding area increased significantly from pre-intake values of 8.0 cm2 to 14.1 cm2 shortly after intake (P = .0012), peaked at 5 min and slowly decreased towards 30 min. The corresponding maximum change in stress from pre-intake pressure values was 59.2 mmHg shortly after (P < .0001), reaching pre-intake values within 20 min. Strain rose from 0 shortly before to 0.36 shortly after (P < .0001), peaking at 5 min. At incisura angularis, fullness was positively correlated with area and to strain, while fullness, area, and stress were negatively correlated with pressure. CONCLUSIONS & INFERENCES: The multimodal method enabled assessment of the gastric accommodation reflex, stress and strain in the stomach. It triggered few symptoms in healthy volunteers. We propose it to be a more physiological replacement of the barostat technique. PMID- 29119637 TI - Verbal responses, depressive symptoms, reminiscence functions and cognitive emotion regulation in older women receiving individual reminiscence therapy. AB - AIMS AND OBJECTIVES: To examine the effectiveness of individual reminiscence therapy in community-dwelling older women with depressive symptoms and to explore the characteristics of participants' verbalisation in the process. BACKGROUND: Previous studies have found reminiscence was related to depression and anxiety. Although reminiscence therapy is widely used to reduce depression, little is known about how it works, and the content of verbalisations might provide one explanation. DESIGN: The study employed a one-group pretest-post-test design. METHODS: Twenty-seven participants underwent 6-week interventions of individual reminiscence therapy at home that were conducted by one nurse and induced through seeing old photographs. The Geriatric Depression Scale, Zung Self-rating Anxiety Scale, Reminiscence Functions Scale and Cognitive Emotion Regulation Questionnaire were used to measure the emotional states, reminiscence functions and cognitive emotion regulation strategies. Participants' verbalisations were categorised using the Client Behavior System. RESULTS: Reminiscence therapy relieved depression and anxiety. Both the reminiscence function and cognitive emotion regulation became more favourable after interventions. Furthermore, higher frequencies of recounting, cognitive-behavioural exploration and affective exploration were noted in the process. Participants with more severe depressive symptoms tended to display a higher frequency of affective exploration. The reduction in depression, self-negative reminiscence and negative-focused emotion regulation were respectively associated with verbalisations. CONCLUSIONS: Individual reminiscence therapy might relieve negative emotion and improve reminiscence function and cognitive emotion regulation. The participants' verbalisation is worthy of our attention, due to its correlation with the severity of depression and its mitigating effects on the depression, anxiety, self-negative reminiscence and negative-focused regulation in older women. The results contribute to our understanding of the therapeutic procedure and suggest a need for more research on the therapeutic processes. RELEVANCE TO CLINICAL PRACTICE: Study on processes could help training novice clinical interveners so that reminiscence therapy can work better on emotional disorders in clinical practice. PMID- 29119638 TI - Biphasic papillary renal cell carcinoma is a rare morphological variant with frequent multifocality: a study of 28 cases. AB - AIMS: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC. METHODS AND RESULTS: We identified 28 tumours from multiple institutions. They typically showed two cell populations larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39 86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dube syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, alpha-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus <=1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34betaE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes). CONCLUSIONS: Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal. PMID- 29119639 TI - Perceptions of risk of coronary heart disease among people living with type 2 diabetes mellitus. AB - AIMS: Our aim is to assess perception of risk of developing coronary heart disease and to examine its associations with individuals' characteristics and health behaviours among Omani people with type 2 diabetes mellitus (T2DM). BACKGROUND: Evaluating perceptions of being at risk of developing a disease may give insight into health promotion behaviours. People with diabetes are at high risk of coronary heart disease. The management of diabetes mellitus should include prevention and control of coronary heart disease. DESIGN: A cross sectional correlational study was conducted. METHODS: A convenience sample of 160 adults with T2DM was invited to participate in this study between November 2014 and March 2015. Descriptive and regression analyses were performed to examine associations between study variables. RESULTS: Perception of risk of developing coronary heart disease was significantly associated with low educational level (beta = 0.191, P < .05), low income (beta = 0.201, P < .05), and high level of knowledge about diabetes mellitus (beta = 0.200, P < .05). People with T2DM who perceived coronary heart disease as having few moderate known outcomes and consequences reported consuming healthy diet more frequently. CONCLUSION: Teaching people with T2DM about the risk of developing coronary heart disease is essential as it could motivate them to perform health promotion behaviours, which may assist in controlling and reducing coronary heart disease. PMID- 29119640 TI - IL-23 Activated gammadelta T Cells Affect Th17 Cells and Regulatory T Cells by Secreting IL-21 in Children with Primary Nephrotic Syndrome. AB - This study (1) analysed the percentage of gammadelta T cells, gammadelta T cell subsets, Th17 cells and regulatory T cells (Treg cells) and (2) determined the role of IL-23 in primary nephrotic syndrome (PNS) patients with active disease and in remission. Eighty-four patients with PNS and 51 healthy age-matched controls were included in this study. The percentage of gammadelta T cells, gammadelta T cell subsets, Th17 cells and Treg cells in peripheral blood mononuclear cells (PBMCs) were analysed by fluorescence-activated cell sorting. PMBCs from PNS patients with active disease were cultured in the presence of IL 23, IL-23 and an IL-23 antagonist, or IL23 and an anti-IL-21 monoclonal antibody (mAb). The percentage of gammadelta T cells, IL-23R+ gammadelta T cells and IL 17+ gammadelta T cells were significantly increased in PNS patients with active disease. There was a positive correlation between the percentage of gammadelta T cells, IL-23R+ gammadelta T cells, IL-17+ gammadelta T cells and the Th17/Treg ratio. IL-23 increased the percentage of gammadelta T cells and Th17 cells and decreased the percentage of Treg cells in PBMCs isolated from PNS patients with active disease. Anti-IL-21 mAb reduced the percentage of gammadelta T cells and Th17 cells, but increased the percentage of Treg cells. gammadelta T cells, IL 17+ gammadelta T cells and IL-23R+ gammadelta T cells may be involved in the pathogenesis of paediatric PNS by modulating the balance of Th17/Treg cells. gammadelta T cells may cause an imbalance in Th17/Treg cells by secreting IL-21 in the presence of IL-23. PMID- 29119641 TI - Methods, metrics and research gaps around minimum data sets for nursing practice and fundamental care: A scoping literature review. AB - AIMS AND OBJECTIVES: To examine and map research on minimum data sets linked to nursing practice and the fundamentals of care. Another aim was to identify gaps in the evidence to suggest future research questions to highlight the need for standardisation of terminology around nursing practice and fundamental care. BACKGROUND: Addressing fundamental care has been highlighted internationally as a response to missed nursing care. Systematic performance measurements are needed to capture nursing practice outcomes. DESIGN: Overview of the literature framed by the scoping study methodology. METHOD: PubMed and CINAHL were searched using the following inclusion criteria: peer-reviewed empirical quantitative and qualitative studies related to minimum data sets and nursing practice published in English. No time restrictions were set. Exclusion criteria were as follows: no available full text, reviews and methodological and discursive studies. Data were categorised into one of the fundamentals of care elements. RESULTS: The review included 20 studies published in 1999-2016. Settings were mainly nursing homes or hospitals. Of 14 elements of the fundamentals of care, 11 were identified as measures in the included studies, but their frequency varied. The most commonly identified elements concerned safety, prevention and medication (n = 11), comfort (n = 6) and eating and drinking (n = 5). CONCLUSION: Studies have used minimum data sets and included variables linked to nursing practices and fundamentals of care. However, the relations of these variables to nursing practice were not always clearly described and the main purpose of the studies was seldom to measure the outcomes of nursing interventions. More robust studies focusing on nursing practice and patient outcomes are warranted. RELEVANCE TO CLINICAL PRACTICE: Using minimum data sets can highlight the nurses' work and what impact it has on direct patient care. Appropriate models, systems and standardised terminology are needed to facilitate the documentation of nursing activities. PMID- 29119642 TI - Protocol of a dose response trial of IV immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (DRIP study). AB - High peak levels of serum IgG may not be needed for maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with intravenous immunoglobulin (IVIg). More frequent dosing of IVIg leads to more stable IgG levels and higher trough levels which may be related with improved clinical efficacy. More frequent lower dosing leads to lower peak levels and may induce less systemic side-effects. The DRIP study is a double-blind randomized controlled cross-over intervention study. CIDP patients >=18 years old, proven IVIg dependent and receiving an individually established but stable maintenance dose and interval of IVIg (Kiovig) can be included. One group (A) will be treated with their normal dosage and interval of IVIg and receive a placebo (albumin 0.5%) infusion in between their regular IVIg infusions, for a total of four infusions. The other group (B) will be treated with half their normal IVIg dosage (with the same volume of placebo to maintain the total volume) at half their interval (double their frequency) for four infusions. After a wash-out phase (2 infusions), patients will cross-over to the other treatment group. During the study the total dose of IVIg administered will remain unchanged as before start of the trial. The main objective is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment as maintenance treatment for CIDP. Hand grip strength, as measured by the Martin Vigorimeter, will be used as the primary outcome measure. Secondary objective is to investigate whether high frequent low dosage of IVIg results in less adverse events compared to low frequent high dosage treatment. The DRIP study is currently ongoing and the protocol is presented. PMID- 29119643 TI - A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia. AB - Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a "3 + 3" design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1-14 and MEC days 4-8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1-10. The dose of lenalidomide was then escalated starting at 5 mg/d (5-10-25 50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1-10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21-50%); 30-day mortality was 6% and 60-day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12-month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T-cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1-10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC. PMID- 29119644 TI - Suicide amongst people with intellectual disability: An Australian online study of disability support staff experiences and perceptions. AB - BACKGROUND: Individuals with intellectual disability (ID) have a higher likelihood of exposure to identified risk factors for suicide when compared with the general community and have been recognised as being both capable of forming intent for suicide and acting on this intent. However, in spite of research outlining these concerns from the 1970s, there remains a dearth of studies that examine suicide amongst the population of people with ID. METHOD: An online cross sectional survey was purposively developed, with questions aimed at identifying both the experiences and current practices of support staff who assist people with ID in relation to suicide, suicidal behaviour and suicide assessment. It was undertaken across both rural and metropolitan areas in Australia. The survey was open for a period of 12 months. A total of 139 respondents (109 female/30 male), with a mean age of 41 and an average 12 years of experience in supporting people with ID, completed the tool. RESULTS: A total of nine suicides by people with ID were reported. Seventy-seven per cent of the respondents reported that they had individuals with ID display suicidal behaviours, and 76% noted that a person had specifically talked about wishing to end their life. Only four participants (3%) noted that they did not support individuals with a dual diagnosis of ID and mental health concern. Sixty per cent of participants reported that no one in their organisation had ever completed a suicide risk assessment, and only 28% reported that they would do a suicide risk assessment if an individual that they supported was diagnosed with a mental health issue. CONCLUSIONS: The current findings indicate that support staff recognise the capacity of people with ID to conceptualise suicide, note the existence of suicidal discussions and behaviours and report on actual suicides. This represents one of the few Australian studies that has specifically considered suicide amongst this cohort of people and reinforces the fact that suicide is not unknown in this population. The data indicate a possible divide between the reports of people with ID actively talking about and acting on suicidal thoughts and the lack of any proactive use of any tools to assess for this risk. PMID- 29119647 TI - MoB/g-C3 N4 Interface Materials as a Schottky Catalyst to Boost Hydrogen Evolution. AB - Proton adsorption on metallic catalysts is a prerequisite for efficient hydrogen evolution reaction (HER). However, tuning proton adsorption without perturbing metallicity remains a challenge. A Schottky catalyst based on metal-semiconductor junction principles is presented. With metallic MoB, the introduction of n-type semiconductive g-C3 N4 induces a vigorous charge transfer across the MoB/g-C3 N4 Schottky junction, and increases the local electron density in MoB surface, confirmed by multiple spectroscopic techniques. This Schottky catalyst exhibits a superior HER activity with a low Tafel slope of 46 mV dec-1 and a high exchange current density of 17 MUA cm-2 , which is far better than that of pristine MoB. First-principle calculations reveal that the Schottky contact dramatically lowers the kinetic barriers of both proton adsorption and reduction coordinates, therefore benefiting surface hydrogen generation. PMID- 29119645 TI - High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases. AB - Poorly differentiated chordomas (PDCs) represent a rare subset of notochordal neoplasms, affecting primarily children and associated with an aggressive outcome. In contrast to conventional chordomas, PDC show solid growth and increased cellularity, cytologic atypia, and mitotic activity. Recent studies have shown that PDCs are characterized by recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear SMARCB1 expression. Thus PDC joined the expanding family of SMARCB1-deficient tumors characterized by various SMARCB1 structural abnormalities, ranging from large homozygous deletions to small intragenic mutations. In the present study, we investigate the SMARCB1 abnormalities in a group of nine well-characterized PDCs and to establish the sensitivity of the FISH method in detecting these changes in the clinical setting. We further assessed the pathologic features and clinical behavior of this cohort managed at our referral center over a 20-year period. The mean age at diagnosis was 10 years-of-age. All except one case occurred in the cranial region. All demonstrated strong nuclear expression of brachyury and loss of SMARCB1 expression. FISH identified homozygous SMARCB1 deletions in all except one case; additionally two cases revealed a heterozygous EWSR1 locus co-deletion. Clinical follow-up information was available in five patients. Two patients presented with distant metastases at initial diagnosis. Two of the three remaining patients with primary disease failed both locally and distantly after multimodality therapy. We conclude that PDCs are highly aggressive tumors and the dominant mechanism of loss of SMARCB1 expression is through large, homozygous SMARCB1 deletions that can be readily detected by FISH. PMID- 29119648 TI - Genetic and environmental links between motor activity level and attention problems in early childhood. AB - Cross-lagged biometric models were used to examine genetic and environmental links between actigraph-assessed motor activity level (AL) and parent-rated attention problems (AP) in 314 same-sex twin pairs (MZ = 145, DZ = 169) at ages 2 and 3 years. At both ages, genetic correlations between AL and AP were moderate (ra2 = .35; ra3 = .39) indicating both overlap and specificity in genetic effects across the two domains. Within- and across-age phenotypic associations between AL and AP were entirely due to overlapping genetic influences. There was a unidirectional effect of AL at age 2 predicting later AP. For AP, genetic and environmental influences from age 2 were transmitted to age 3 via stability effects and from AL. For AL, across-age effects were transmitted only via stability. These results suggest that overactivity in late infancy may impact the later development of problems related to inattention, and that genetic factors explain the association between the two domains. PMID- 29119649 TI - PRospective Imaging of CErvical cancer and neoadjuvant treatment (PRICE) study: role of ultrasound to assess residual tumor in locally advanced cervical cancer patients undergoing chemoradiation and radical surgery. AB - OBJECTIVE: To determine the diagnostic performance of two-dimensional (2D) ultrasound parameters, three-dimensional (3D) power Doppler and contrast-enhanced indices in detecting residual disease in locally advanced cervical cancer patients triaged to neoadjuvant treatment followed by radical surgery. METHODS: Between October 2010 and June 2014, we screened 108 women with histologically documented locally advanced cervical cancer Stage IB2-IVA, of whom 88 were included in the final analysis. 2D ultrasound parameters, 3D power Doppler and contrast-ultrasound parameters were assessed 5 weeks after the end of neoadjuvant chemoradiation therapy. The pathological response was defined as complete (absence of any residual tumor after treatment) or partial (including microscopic and/or macroscopic residual tumor at pathology examination). The two response groups were compared and receiver-operating characteristics (ROC) curves generated to determine the best cut-off value of sonographic tumor diameter to predict residual disease. Histology was considered as reference. RESULTS: Complete pathological response to chemoradiation was observed in 40 (45.5%) patients and partial response in 48 (54.5%). The presence of residual disease, as confirmed at pathology examination, was detected by 2D grayscale ultrasound with a sensitivity of 64.6% and specificity of 65%. Color Doppler examination in the cases with lesions visualized on grayscale imaging detected the presence of residual disease, confirmed at pathology, with a sensitivity of 87.1% and specificity of 21.4%. The best area under the ROC curve (0.817) was for the detection of pathological residual disease of at least 6 mm in diameter, using a cut-off value of 12 mm for the largest tumor diameter assessed using 2D grayscale ultrasound (sensitivity, 95%; specificity, 70.6%). Neither 3D vascular indices nor contrast-ultrasound parameters obtained for lesions suspected at ultrasound following chemoradiation differed significantly between patients with histological complete and those with partial response. CONCLUSIONS: Our results show that grayscale and color Doppler ultrasound have a low level of diagnostic performance in detecting residual disease after neoadjuvant chemoradiation in patients with locally advanced cervical cancer. The best performance was achieved in detection of macroscopic (>= 6 mm) residual disease. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29119651 TI - Supramolecular Polymerization Controlled through Kinetic Trapping. AB - A method of controllable supramolecular polymerization through kinetic trapping is developed. To this end, two bifunctional monomers with cucurbit[7]uril (CB[7]) and adamantane end groups were synthesized. The CB[7]-containing monomer was presaturated with a pH-responsive competitive guest for kinetic control. Then, the kinetics of supramolecular polymerization of the two monomers was easily controlled through the modulation of pH. As a result, supramolecular polymerization was kinetically trapped at certain stages, and supramolecular polymers with different molecular weights were obtained. It is anticipated that this research will enrich the methods of controllable supramolecular polymerization. PMID- 29119650 TI - Thermally Activated Delayed Fluorescence in a Y3 N@C80 Endohedral Fullerene: Time Resolved Luminescence and EPR Studies. AB - The endohedral fullerene Y3 N@C80 exhibits luminescence with reasonable quantum yield and extraordinary long lifetime. By variable-temperature steady-state and time-resolved luminescence spectroscopy, it is demonstrated that above 60 K the Y3 N@C80 exhibits thermally activated delayed fluorescence with maximum emission at 120 K and a negligible prompt fluorescence. Below 60 K, a phosphorescence with a lifetime of 192+/-1 ms is observed. Spin distribution and dynamics in the triplet excited state is investigated with X- and W-band EPR and ENDOR spectroscopies and DFT computations. Finally, electroluminescence of the Y3 N@C80 /PFO film is demonstrated opening the possibility for red-emitting fullerene based organic light-emitting diodes (OLEDs). PMID- 29119652 TI - The novel language-systematic aphasia screening SAPS: screening-based therapy in combination with computerised home training. AB - BACKGROUND: SAPS-'Sprachsystematisches Aphasiescreening'-is a novel language systematic aphasia screening developed for the German language, which already had been positively evaluated. It offers a fast assessment of modality-specific psycholinguistic components at different levels of complexity and the derivation of impairment-based treatment foci from the individual performance profile. However, SAPS has not yet been evaluated in combination with the new SAPS-based treatment. AIMS: To replicate the practicality of SAPS and to investigate the effectiveness of a SAPS-based face-to-face therapy combined with computerised home training in a feasibility study. To examine the soundness of the treatment design, to determine treatment-induced changes in patient performance as measured by SAPS, to assess parallel changes in communicative abilities, and to differentiate therapy effects achieved by face-to-face therapy versus add-on effects achieved by later home training. METHODS & PROCEDURES: Sixteen participants with post-stroke aphasia (PWAs) were included into the study. They were administered the SAPS and communicative testing before and after the treatment regimen. Each PWA received one therapy session followed by home training per day, with the individual treatment foci being determined according to initial SAPS profile, and duration of treatment and possible change of focus dependent on performance assessed by continuous therapy monitoring. OUTCOMES & RESULTS: The combination of therapy and home training based on the SAPS was effective for all participants. We showed significant improvements for impairment based SAPS performance and, with high inter-individual variability, in everyday communication. These two main targets of speech and language therapy were correlated and SAPS improvements after therapy were significantly higher than after home training. CONCLUSIONS & IMPLICATIONS: SAPS offers the assessment of an individual performance profile in order to derive sufficiently diversified, well founded and specific treatment foci and to follow up changes in performance. The appending treatment regimen has shown to be effective for our participants. Thus, the study revealed feasibility of our approach. PMID- 29119653 TI - A social-ecological framework: A model for addressing ethical practice in nursing. AB - AIMS AND OBJECTIVES: To develop a framework to enable discussion, debate and the formulation of interventions to address ethical issues in nursing practice. BACKGROUND: Social, cultural, political and economic drivers are rapidly changing the landscape of health care in our local environments but also in a global context. Increasingly, nurses are faced with a range of ethical dilemmas in their work. This requires investigation into the culture of healthcare systems and organisations to identify the root causes and address the barriers and enablers of ethical practice. The increased medicalisation of health care; pressures for systemisation; efficiency and cost reduction; and an ageing population contribute to this complexity. Often, ethical issues in nursing are considered within the abstract and philosophical realm until a dilemma is encountered. Such an approach limits the capacity to tangibly embrace ethical values and frameworks as pathways to equitable, accessible, safe and quality health care and as a foundation for strengthening a supportive and enabling workplace for nurses and other healthcare workers. DESIGN: Conceptual framework development. METHODS: A comprehensive literature review was undertaken using the social-ecological framework as an organising construct. RESULTS: This framework views ethical practice as the outcome of interaction among a range of factors at eight levels: individual factors (patients and families); individual factors (nurses); relationships between healthcare professionals; relationships between patients and nurses; organisational healthcare context; professional and education regulation and standards; community; and social, political and economic. CONCLUSIONS: Considering these elements as discrete, yet interactive and intertwined forces can be useful in developing interventions to promote ethical practice. We consider this framework to have utility in policy, practice, education and research. RELEVANCE TO CLINICAL PRACTICE: Nurses face ethical challenges on a daily basis, considering these within a social-ecological framework can assist in developing strategies and resolutions. PMID- 29119654 TI - Carcass traits, meat quality, antioxidant status and antioxidant gene expression in muscle and liver of Hu lambs fed perilla seed. AB - The effects of perilla (Perilla frutescens L.) seed on carcass traits, meat quality, antioxidant status and antioxidant gene expression in the liver and muscle of Hu lambs were investigated in this study. Sixty Hu lambs (23.02 +/- 1.36 kg) were randomly divided into four experimental groups receiving diets containing 0%, 5%, 10% or 15% perilla seed (CD, 5%PFSD, 10%PFSD and 15%PFSD, respectively). The addition of perilla seed had no significant impacts on carcass traits (p > .05). There were no differences in pH, meat colour, drip loss, cooking loss or shear force among the four treatments (p > .05). Addition of perilla seed increased (p < .05) deposition of intramuscular lipids but had no effect on other chemical components in the longissimus dorsi (LD) (p > .05). The 15%PFSD diet decreased the total antioxidant capacity (T-AOC) and malondialdehyde (MDA) content in the liver (p < .05 for both) but increased the activity of these antioxidant enzymes in LD (p < .05 for both). Compared to CD, addition of perilla seed increased superoxide dismutase (SOD) and glutathione peroxidase (GPX) expression in the liver and LD (p < .05 for all). These results indicate that perilla seed supplementation in lambs' diets can increase deposition of intramuscular lipids and improve muscular oxidative status and meat quality. PMID- 29119655 TI - Targeting host mitochondria: A role for the Trypanosoma cruzi amastigote flagellum. AB - Trypanosoma cruzi is the kinetoplastid protozoan parasite that causes human Chagas disease, a chronic disease with complex outcomes including severe cardiomyopathy and sudden death. In mammalian hosts, T. cruzi colonises a wide range of tissues and cell types where it replicates within the host cell cytoplasm. Like all intracellular pathogens, T. cruzi amastigotes must interact with its immediate host cell environment in a manner that facilitates access to nutrients and promotes a suitable niche for replication and survival. Although potentially exploitable to devise strategies for pathogen control, fundamental knowledge of the host pathways co-opted by T. cruzi during infection is currently lacking. Here, we report that intracellular T. cruzi amastigotes establish close contact with host mitochondria via their single flagellum. Given the key bioenergetic and homeostatic roles of mitochondria, this striking finding suggests a functional role for host mitochondria in the infection process and points to the T. cruzi amastigote flagellum as an active participant in pathogenesis. Our study establishes the basis for future investigation of the molecular and functional consequences of this intriguing host-parasite interaction. PMID- 29119656 TI - Factors that lead to hospitalisation in patients with Parkinson disease-A systematic review. AB - OBJECTIVES: Parkinson disease (PD) frequently leads to acute hospitalisation resulting in increased cost to health care systems and reduced quality of life for patients. The objective of this review was to identify causes that lead to acute hospitalisation of patients with PD. METHODS: A systematic review of English language literature from 1997 to present. FINDINGS: The incidences of acute general medical or surgical problems that trigger acute hospitalisation in patients with PD are similar to those in the general population. However, falls, acute decompensation of PD symptoms and infections are far more common in PD patients and are responsible for more than 50% of the causes of hospitalisation in this patients' group. IMPLICATIONS: Preventive strategies to avoid decompensation of PD symptoms and early detection and treatment of infections are needed to reduce hospitalisation in patients with PD. PMID- 29119658 TI - Cytological identification of Schaumann bodies within granulomas clinches the diagnosis of sarcoidosis. PMID- 29119659 TI - GOx@ZIF-8(NiPd) Nanoflower: An Artificial Enzyme System for Tandem Catalysis. AB - We report a facile approach to prepare an artificial enzyme system for tandem catalysis. NiPd hollow nanoparticles and glucose oxidase (GOx) were simultaneously immobilized on the zeolitic imidazolate framework 8 (ZIF-8) via a co-precipitation method. The as-prepared GOx@ZIF-8(NiPd) nanoflower not only exhibited the peroxidase-like activity of NiPd hollow nanoparticles but also maintained the enzymatic activity of GOx. A colorimetric sensor for rapid detection of glucose was realized through the GOx@ZIF-8(NiPd) based multi-enzyme system. Moreover, the GOx@ZIF-8(NiPd) modified electrode showed good bioactivity of GOx and high electrocatalytic activity for the oxygen reduction reaction (ORR), which could also be used for electrochemical detection of glucose. PMID- 29119657 TI - Reduced neural responses to vocal fear: a potential biomarker for callous uncaring traits in early childhood. AB - OBJECTIVE: Callous-unemotional (CU) traits are characterized by a lack of guilt and empathy, and low responsiveness to distress and fear in others. Children with CU traits are at-risk for engaging in early and persistent conduct problems. Individuals showing CU traits have been shown to have reduced neural responses to others' distress (e.g., fear). However, the neural components of distress responses in children with CU traits have not been investigated in early childhood. In the current study, we examined neural responses that underlie the processing of emotionally valenced vocal stimuli using the event-related potential technique in a group of preschoolers. METHOD: Participants between 2 and 5 years old took part in an auditory oddball task containing English-based pseudowords spoken with either a fearful, happy, or a neutral prosody while electroencephalography data were collected. The mismatch negativity (MMN) component, an index of the automatic detection of deviant stimuli within a series of stimuli, was examined in association with two dimensions of CU traits (i.e., callousness-uncaring and unemotional dimensions) reported by primary caregivers. RESULTS: Findings suggest that the callousness-uncaring dimension of CU traits in early childhood is associated with reduced responses to fearful vocal stimuli. CONCLUSIONS: Reduced neural responses to vocal fear could be a biomarker for callous-uncaring traits in early childhood. These findings are relevant for clinicians and researchers attempting to identify risk factors for early callous uncaring traits. PMID- 29119660 TI - Metformin for the management of peri-operative hyperglycaemia. PMID- 29119663 TI - Polyglutamine inclusion body toxicity. PMID- 29119662 TI - Toxoplasma gondii infection shifts dendritic cells into an amoeboid rapid migration mode encompassing podosome dissolution, secretion of TIMP-1, and reduced proteolysis of extracellular matrix. AB - Dendritic cells (DCs) infected by Toxoplasma gondii rapidly acquire a hypermigratory phenotype that promotes systemic parasite dissemination by a "Trojan horse" mechanism in mice. Recent paradigms of leukocyte migration have identified the amoeboid migration mode of DCs as particularly suited for rapid locomotion in extracellular matrix and tissues. Here, we have developed a microscopy-based high-throughput approach to assess motility and matrix degradation by Toxoplasma-challenged murine and human DCs. DCs challenged with T. gondii exhibited dependency on metalloproteinase activity for hypermotility and transmigration but, strikingly, also dramatically reduced pericellular proteolysis. Toxoplasma-challenged DCs up-regulated expression and secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) and their supernatants impaired matrix degradation by naive DCs and by-stander DCs dose dependently. Gene silencing of TIMP-1 by short hairpin RNA restored matrix degradation activity in Toxoplasma-infected DCs. Additionally, dissolution of podosome structures in parasitised DCs coincided with abrogated matrix degradation. Toxoplasma lysates inhibited pericellular proteolysis in a MyD88-dependent fashion whereas abrogated proteolysis persevered in Toxoplasma-infected MyD88-deficient DCs. This indicated that both TLR/MyD88-dependent and TLR/MyD88-independent signalling pathways mediated podosome dissolution and the abrogated matrix degradation. We report that increased TIMP-1 secretion and cytoskeletal rearrangements encompassing podosome dissolution are features of Toxoplasma-induced hypermigration of DCs with an impact on matrix degradation. Jointly, the data highlight how an obligate intracellular parasite orchestrates key regulatory cellular processes consistent with non-proteolytic amoeboid migration of the vehicle cells that facilitate its dissemination. PMID- 29119661 TI - Development of the ability to combine visual and acoustic information in working memory. AB - Presentation of two kinds of materials in working memory (visual and acoustic), with the requirement to attend to one or both modalities, poses an interesting case for working memory development because competing predictions can be formulated. In two experiments, we assessed such predictions with children 7-13 years old and adults. With development, the ability to hold more information in the focus of attention could lead to an increase in the size of the trade-off between modalities; if attention can hold A items during unimodal-attention trials, then on average attention should hold A/2 of those same items during bimodal-attention trials. If A increases with age, so would the dual-task cost, A/2. The results clearly ruled out that possibility. It was the modality- or code specific components of working memory that improved with age and not the central component. We discuss various mechanisms that could have produced these results, including alternative attention-based mechanisms. The findings point to a rich field for continued research. PMID- 29119664 TI - Effects of body condition score (BCS) on steroid- and eicosanoid-metabolizing enzyme activity in various mare tissues during winter anoestrus. AB - The objective of this study was to determine the activity of steroid- and eicosanoid-metabolizing enzymes in horses with varying BCSs. The BCSs of twenty non-pregnant, anoestrous mares were determined prior to euthanasia, and tissue samples were collected from the liver, kidney, adrenal gland, ovary and endometrium. Cytochrome P450 1A (CYP1A), 2C (CYP2C), 3A (CYP3A) and uridine 5' diphospho-glucuronosyltransferase (UGT) activities were determined using luminogenic substrates. The MIXED procedure of SAS was used to test the effect of BCS on enzyme activity and differences between tissues. Activity of CYP1A in adrenals was increased (p <= .05) in BCS 5 versus BCSs 4 and 6. Activity of CYP1A in the liver was increased (p = .05) in BCS 4 versus BCSs 5 and 6. Activity of CYP1A was 100-fold greater (p < .0001) in the liver than in the adrenal, ovary and kidney. Activity of CYP2C was 100-fold greater (p < .0001) in the liver than in the adrenal, ovary and endometrium. Activity of CYP3A was only detectable in the liver. Activity of UGT in the kidney was decreased (p = .02) in BCS 4 versus BCSs 5 and 6. Activity of UGT was threefold greater (p < .0001) in the liver than in the kidney, whereas activity of UGT was ninefold greater (p < .0001) in the kidney than in the ovary and endometrium. In general, BCS did not alter the activity of steroid- and eicosanoid-metabolizing enzymes in horses. However, tissue differences in these enzymes indicated abundant hepatic metabolism in horses, which is similar to other livestock species. PMID- 29119665 TI - Adults who were born preterm with a very low birth weight reported a similar health-related quality of life to their term-born peers. PMID- 29119666 TI - Estimating and interpreting the pharmacokinetic profiles of individual patients with hemophilia A or B using a population pharmacokinetic approach: communication from the SSC of the ISTH. PMID- 29119667 TI - Electrochemiluminescence Bioassays with a Water-Soluble Luminol Derivative Can Outperform Fluorescence Assays. AB - The most efficient and commonly used electrochemiluminescence (ECL) emitters are luminol, [Ru(bpy)3 ]2+ , and derivatives thereof. Luminol stands out due to its low excitation potential, but applications are limited by its insolubility under physiological conditions. The water-soluble m-carboxy luminol was synthesized in 15 % yield and exhibited high solubility under physiological conditions and afforded a four-fold ECL signal increase (vs. luminol). Entrapment in DNA-tagged liposomes enabled a DNA assay with a detection limit of 3.2 pmol L-1 , which is 150 times lower than the corresponding fluorescence approach. This remarkable sensitivity gain and the low excitation potential establish m-carboxy luminol as a superior ECL probe with direct relevance to chemiluminescence and enzymatic bioanalytical approaches. PMID- 29119668 TI - Global improvement with cariprazine in the treatment of bipolar I disorder and schizophrenia: A pooled post hoc analysis. AB - INTRODUCTION: Global rating scale measures are useful for assessing the clinical relevance of patient change. Cariprazine, a dopamine D3 and D2 receptor partial agonist, is FDA-approved for the adult treatment of acute manic/mixed episodes of bipolar I disorder and schizophrenia. Post hoc evaluations of Clinical Global Impressions-Severity (CGI-S) scores from the cariprazine pivotal trials in both indications were conducted. METHODS: Data from 3 bipolar mania and 3 schizophrenia trials were pooled by indication (bipolar disorder = 1033; schizophrenia = 1466). Cariprazine- and placebo-treated patients were categorised by baseline CGI-S scores; the proportion of patients who improved from more severe categories at baseline to less severe categories at end-point was evaluated using a logistic regression model. Correlations between Young Mania Rating Scale and Positive and Negative Syndrome Scale total score changes and category shifts were also evaluated. RESULTS: In both disease states, more cariprazine- than placebo-treated patients had improved CGI-S scores at end point; more placebo-treated patients had worse end-point scores. More cariprazine vs placebo-treated patients shifted from the extremely/severely ill to mildly ill/better category (bipolar disorder = 55% vs 36%, odds ratio [OR] = 2.1; P = .09; schizophrenia = 42% vs 18%, OR = 3.4, P<.01). ORs was statistically significant in favour of cariprazine in shifts from marked and moderate illness to borderline/normal in both indications (P < .05). Correlations between rating scale improvement and category shift were greatest in patients with extreme/severe baseline illness for bipolar disorder (-0.853) and schizophrenia ( 0.677). CONCLUSIONS: Post hoc analyses showed that more cariprazine- than placebo treated patients with bipolar mania or schizophrenia had statistically significant and clinically meaningful CGI-S improvement. PMID- 29119670 TI - Open access: Is there a predator at the door? PMID- 29119669 TI - Sinusitis caused by Exserohilum rostratum after cord blood transplantation for myelodysplastic syndrome: A case report and literature review. AB - Invasive fungal disease is a serious infectious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Exserohilum rostratum is a species causing phaeohyphomycosis, which rarely causes invasive disease in humans. We treated a case of sinusitis caused by E. rostratum after cord blood transplantation (CBT). A 60-year-old man with myelodysplastic syndrome, who had a medical history of an operation to correct deviation of the nasal septum, developed sinusitis caused by E. rostratum under prolonged profound neutropenia after a second CBT because of the graft rejection of the first transplantation. Liposomal amphotericin B improved the sinusitis. A literature review revealed nine reported cases of sinusitis caused by E. rostratum, including our case. Although five cases had severe neutropenia at onset (HSCT recipients, n = 2; aplastic anemia, n = 3), the remaining four had no preexisting immunosuppressive conditions. However, three of the four patients had preexisting nasal diseases with or without a history of surgery, as in our case. Excluding our case, the outcome was fatal in five neutropenic patients, whereas the four patients without neutropenia recovered. Although sinusitis caused by E. rostratum is rare, E. rostratum should be recognized as a possible pathogen causing sinusitis in highly immunosuppressed patients such as HSCT recipients. Preexisting nasal disease and/or nasal surgery could be risks for this infection. PMID- 29119671 TI - A Microribbon Hybrid Structure of CoOx-MoC Encapsulated in N-Doped Carbon Nanowire Derived from MOF as Efficient Oxygen Evolution Electrocatalysts. AB - Developing highly efficient electrocatalysts for oxygen evolution is vital for renewable and sustainable energy production and storage. Herein, nitrogen-doped carbon encapsulated CoOx-MoC heterostructures are reported for the first time as high performance oxygen evolution electrocatalysts. The composition can be tuned by the addition of a Mo source to form a nanowire-assembled hierarchically porous microstructure, which can enlarge the specific surface area, thus exposing more active sites, facilitating mass transport and charge transfer. Moreover, it is demonstrated that the formation of CoOx-MoC heterostructures and the resulting synergistic effect between MoC and Co facilitate the reaction kinetics, leading to significantly improved oxygen evolution reaction (OER) activity with an onset overpotential of merely 290 mV, and a low overpotential of 330 mV to afford a current density of 10 mA cm-2 . The well-constructed microarchitecture contributes to superior long term stability electrochemical behaviors. This work provides a facile strategy via composition tuning and structure optimization for the development of next-generation nonprecious metal-based OER electrocatalysts. PMID- 29119672 TI - Self-compassion and psychological distress in parents of young people and adults with intellectual and developmental disabilities. AB - BACKGROUND: Parenting an individual with intellectual and developmental disabilities (IDD) can be challenging, particularly during adulthood. It is important to better understand ways of supporting families as individuals with IDD age. Self-compassion is a potential internal coping resource for parents, and is strongly linked to positive mental health outcomes, though research has yet to examine it in parents of adults with IDD. METHOD: The current study examines the association between self-compassion and measures of well-being for 56 parents of adults with IDD. RESULTS: Greater self-compassion was related to lower levels of stress and depression, even after accounting for other known stressors, such as economic disadvantage, having a child with an Autism Spectrum Disorder diagnosis, and high parent burden. CONCLUSIONS: Self-compassion may offer resiliency against these parenting challenges. PMID- 29119673 TI - Efficacy of antenatal corticosteroids in preterm twins: the EPIPAGE-2 cohort study. AB - OBJECTIVES: To investigate the efficacy of antenatal corticosteroid (ACS) therapy on short-term neonatal outcomes in preterm twins, and further document the influence of the ACS-to-delivery interval. DESIGN: EPIPAGE-2 is a nationwide observational multicentre prospective cohort study of neonates born between 22 and 34 completed weeks of gestation. SETTING: All French maternity units, except in a single administrative region, between March and December 2011. POPULATION: A total of 750 twin neonates born between 24 and 31 weeks of gestation. METHODS: Exposure to ACSs was examined in four groups: single complete course, with an ACS administration-to-delivery interval of <=7 days; single complete course, with an ACS-to-delivery interval of >7 days; repeated courses; or no ACS treatment. MAIN OUTCOME MEASURES: Neonatal outcomes analysed were severe bronchopulmonary dysplasia, periventricular leukomalacia or intraventricular haemorrhage grade III/IV, in-hospital mortality, and a composite indicator of severe outcomes. RESULTS: Compared with no ACSs, in multivariable analysis, a single course of ACSs with an administration-to-delivery interval of <=7 days was significantly associated with a reduced rate of periventricular leukomalacia or intraventricular haemorrhage grade III/IV (aOR 0.2; CI 95% 0.1-0.5), in-hospital mortality (0.3; 0.1-0.6), and the composite indicator (0.1; 0.1-0.3), whereas a single course of ACDs with an administration-to-delivery interval of >7 days did not significantly reduce the frequency of in-hospital mortality (0.7; 0.3-1.8). No significant differences in terms of benefit or risk were found when comparing repeated courses with a single complete course. CONCLUSION: In preterm twins, a single complete course of antenatal corticosteroids was associated with an improvement of severe neurological outcome, whereas reduced in-hospital mortality was seen only when the ACS-to-delivery interval was <=7 days. TWEETABLE ABSTRACT: A single complete course of antenatal steroids reduced severe neurological morbidity in preterm twins (24-31 weeks). PMID- 29119674 TI - Assessment of hydrogels for bioprinting of endothelial cells. AB - In tissue engineering applications, vascularization can be accomplished by coimplantation of tissue forming cells and endothelial cells (ECs), whereby the latter are able to form functional blood vessels. The use of three-dimensional (3D) bioprinting technologies has the potential to improve the classical tissue engineering approach because these will allow the generation of scaffolds with high spatial control of endothelial cell allocation. This study focuses on a side by side comparison of popular commercially available bioprinting hydrogels (Matrigel, fibrin, collagen, gelatin, agarose, Pluronic F-127, alginate, and alginate/gelatin) in the context of their physicochemical parameters, their swelling/degradation characteristics, their biological effects on vasculogenesis related EC parameters and their printability. The aim of this study was to identify the most suitable hydrogel or hydrogel combination for inkjet printing of ECs to build prevascularized tissue constructs. Most tested hydrogels displayed physicochemical characteristics suitable for inkjet printing. However, Pluronic F-127 and the alginate/gelatin blend were rapidly degraded when incubated in cell culture medium. Agarose, Pluronic F-127, alginate and alginate/gelatin hydrogels turned out to be unsuitable for bioprinting of ECs because of their non-adherent properties and/or their incapability to support EC proliferation. Gelatin was able to support EC proliferation and viability but was unable to support endothelial cell sprouting. Our experiments revealed fibrin and collagen to be most suitable for bioprinting of ECs, because these hydrogels showed acceptable swelling/degradation characteristics, supported vasculogenesis related EC parameters and showed good printability. Moreover, ECs in constructs of preformed spheroids survived the printing process and formed capillary-like cords. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 935-947, 2018. PMID- 29119675 TI - Tricalycoside, a New Cerebroside from Tricalysia coriacea (Rubiaceae). AB - A new cerebroside, named as tricalycoside (1), was isolated from the CH2 Cl2 /MeOH (1:1) extract of twigs and leaves of Tricalysia coriacea using repeated silica gel open column chromatography followed by preparative TLC and Sephadex LH 20, together with six known compounds (2 - 7). The structure of the new compound was determined by analysis of 1D- and 2D-NMR, MS data, chemical conversion, and by comparison of these data with those from the literature. Tricalycoside (1) possessed a weak antibacterial activity against Klebsiella pneumoniae (MIC = 75 MUg/mL). PMID- 29119676 TI - Need for reassurance in self-care of minor illnesses. AB - AIMS AND OBJECTIVES: This study describes people's need for reassurance in self care of minor illnesses. BACKGROUND: Self-care and active surveillance are advocated as important strategies to manage minor illnesses. Reassurance influences patient satisfaction and confidence in the practicing of self-care. DESIGN: This study is a descriptive and interpretive qualitative study. METHODS: Twelve persons with experience in self-care and receiving self-care advice were recruited, and data were collected using semi-structured interviews between September-December 2014. Data were analysed using qualitative content analyses. RESULTS: Having previous experience and the ability to actively manage symptoms using self-care interventions was described as reassuring. Participants became stressed and concerned when the symptoms persisted and interventions lacked the desired effect, which often resulted in a decision to consult. Participants wanted to feel that the nurse was an actual person, who was sympathetic, present and understanding, when they received self-care advice. The nurse's assessment and reasoning of the symptoms facilitated care-seekers' assessments of risk, and clear and concrete advice on how to manage the symptoms exerted a calming effect. Patients needed to trust that the nurse understood their situation to embrace the advice, and being invited to return created a feeling that the nurse had listened and taken them seriously. CONCLUSIONS: Reassurance has the potential to allay doubts and fears to build confidence, which influences self-care and consultation behaviour. Personal presence in the encounter, receiving an assessment and an explanation of the symptoms and precise advice are reassuring. RELEVANCE TO CLINICAL PRACTICE: The needs of nursing care may persist despite the absence of medical needs. The encounter between the nurse and care-seeker is a unique possibility for reassurance and confidence that a minor illness is self-limiting in its nature, and self-care interventions provide relief and comfort. PMID- 29119677 TI - Minimal mask immobilization with optical surface guidance for head and neck radiotherapy. AB - PURPOSE: Full face and neck thermoplastic masks provide standard-of-care immobilization for patients receiving H&N IMRT. However, these masks are uncomfortable and increase skin dose. The purpose of this pilot trial was to investigate the feasibility and setup accuracy of minimal face and neck mask immobilization with optical surface guidance. METHODS: Twenty patients enrolled onto this IRB-approved protocol. Patients were immobilized with masks securing only forehead and chin. Shoulder movement was restricted by either moldable cushion or hand held strap retractors. Positional information, including isocenter location and CT skin contours, were imported to a commercial surface image guidance system. Patients typically received standard-of-care IMRT to 60-70 Gy in 30-33 fractions. Patients were first set up to surface markings with optical image guidance referenced to regions of interest (ROIs) on simulation CT images. Positioning was confirmed by in-room CBCT. Following six-dimensional robotic couch correction, a new optical real-time surface image was acquired to track intrafraction motion and to serve as a reference surface for setup at the next treatment fraction. Therapists manually recorded total treatment time as well as couch shifts based on kV imaging. Intrafractional ROI motion tracking was automatically recorded by the optical image guidance system. Patient comfort was assessed by self-administered surveys. RESULTS: Setup error was measured as six dimensional shifts (vertical/longitudinal/lateral/rotation/pitch/roll). Mean error values were -0.51 +/- 2.42 mm, -0.49 +/- 3.30 mm, 0.23 +/- 2.58 mm, -0.15 +/- 1.01o , -0.02 +/- 1.19o , and 0.06 +/- 1.08o , respectively. Average treatment time was 21.6 +/- 8.4 mins). Subjective comfort during surface-guided treatment was confirmed on patient surveys. CONCLUSION: These pilot results confirm feasibility of minimal mask immobilization combined with commercially available optical image guidance. Patient acceptance of minimal mask immobilization has been encouraging. Follow-up validation, with direct comparison to standard mask immobilization, appears warranted. PMID- 29119678 TI - Clinical characteristics of ulcerative colitis-related colorectal cancer in Chinese patients. AB - OBJECTIVE: The prevalence of ulcerative colitis (UC) in China has been increasing, together with the incidence of ulcerative colitis-related colorectal cancer (UCRCC). In this study we aimed to investigate the clinical features of UCRCC in Chinese UC patients. METHODS: Clinical data of patients with UCRCC during January 2003 to December 2016 were retrieved from the Peking Union Medical College Hospital registration database and compared with that of sporadic colorectal cancer (CRC). RESULTS: During the study period, among the 10 110 patients with CRC 25 were found to have UCRCC, with an average age of 51 years and a median disease duration of 15 years. The cumulative prevalence of UCRCC was 0.25% in all CRC patients, with a significant increase from 2003-2007 to 2013 2016 (P < 0.01). Altogether 14 (56.0%) patients with UCRCC were men, and 5 (20.0%) had a family history of UC or cancer. Four (16.0%) patients had concurrent high-grade intraepithelial neoplasia with variable differentiated adenocarcinoma at other sites and 19 (59.4%) tumors were moderately or poorly differentiated. Twenty-three (92.0%) patients underwent surgery, of whom 10 (40%) were at stage III and IV according to the TNM staging system. Compared with the 10 085 patients with sporadic CRC, UCRCC patients were younger (P < 0.01) and were more likely to have descending colon involvement and multifocal lesions (P < 0.01). CONCLUSIONS: UCRCC patients have been increasing in recent years. Compared with patients with sporadic CRC, those with UCRCC are younger and are more likely to have descending colon involvement and multifocality. PMID- 29119679 TI - Noise-induced hearing loss - An examination of the methods of assessment in a cross-sectional study of 87 industrial workers. AB - OBJECTIVES: The surveillance of noise-induced hearing loss (NIHL) according to the Health and Safety Executive (HSE) differs from the medico-legal criteria used to assess NIHL. Our study compares the two systems and proposes a novel method of simplifying the medico-legal criteria and applying it to ascertain noise-induced hearing loss. DESIGN: The anonymised audiograms of a group of 87 industrial workers from a single site were analysed with both methods. RESULTS: The comparison showed approximately one-third of the workers assessed in this study had their noise-induced hearing loss underestimated by the HSE criteria. The majority of these individuals were over 40 years of age. CONCLUSIONS: The HSE criteria for noise-induced hearing loss need review and re-alignment with the medico-legal criteria to address the discrepancy between the two systems. PMID- 29119680 TI - Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho-kinase signalling in infarcted rats. AB - We have demonstrated that ATP-sensitive potassium (KATP ) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti-fibrotic effects of KATP channel agonists were mediated via regulating macrophage phenotype and fibroblast differentiation by a RhoA/RhoA-kinase dependent pathway. Wistar male rats after induction of myocardial infarction were randomized to either vehicle, nicorandil, an antagonist of KATP channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hrs after infarction. There were similar infarct sizes among the infarcted groups. At day 3 after infarction, post-infarction was associated with increased RhoA/ROCK activation, which can be inhibited by administering nicorandil. Nicorandil significantly increased myocardial IL-10 levels and the percentage of regulatory M2 macrophages assessed by immunohistochemical staining, Western blot, and RT-PCR compared with vehicle. An IL-10 receptor antibody increased myofibroblast infiltration compared with nicorandil alone. At day 28 after infarction, nicorandil was associated with attenuated cardiac fibrosis. These effects of nicorandil were functionally translated in improved echocardiographically derived cardiac performance. Fasudil showed similarly increased expression of M2 macrophages as nicorandil. The beneficial effects of nicorandil on fibroblast differentiation were blocked by adding glibenclamide. However, glibenclamide cannot abolish the attenuated fibrosis of fasudil, implying that RhoA/RhoA-kinase is a downstream effector of KATP channel activation. Nicorandil polarized macrophages into M2 phenotype by inhibiting RhoA/RhoA-kinase pathway, which leads to attenuated myofibroblast induced cardiac fibrosis after myocardial infarction. PMID- 29119681 TI - Weight Loss Success of Participants Residing in Rural and Urban Areas. AB - PURPOSE: Rural residents are significantly more likely to be overweight and obese than are urban residents. However, few data have compared weight control program responses in these population groups. Therefore, the primary aim of this study was to evaluate the weight loss outcomes of participants in a multisite, online behavioral intervention by residential location (rural vs urban) and, second, assess any possible differences in adherence to treatment goals. METHODS: A total of 492 adult participants (mean BMI = 35.7 kg/m2 ; 90% female; 24% minority) were categorized based on their home ZIP code and the 2010 US Census Urban and Rural Classification criteria (58.3% rural; 41.7% urban). Weight (kg) was measured in person at baseline and 6 months after participating in a behavioral weight control intervention. Adherence to physical activity and calorie and fat intake goals was assessed based on weekly self-monitoring journals. Weekly online chat attendance and completion of weekly online self-monitoring journals were recorded. Presence of obesogenic foods in the home was self-reported at baseline and 6 months. FINDINGS: There were no statistically significant differences in weight loss between rural and urban participants (-6.1 kg vs -5.3 kg, P = .16), nor were there differences in chat attendance, self-monitoring journals, self reported physical activity, calorie intake, or obesogenic foods reported in the household. CONCLUSIONS: Overall, there was no difference in weight loss and adherence to treatment goals for rural and urban participants. Further research on rural and urban residents is necessary to explore the factors responsible for the disparity in obesity prevalence. PMID- 29119682 TI - Molecular identification of tick-borne pathogens infecting cattle in Mymensingh district of Bangladesh reveals emerging species of Anaplasma and Babesia. AB - Tick-borne diseases are considered a major hindrance to the health and productive performance of cattle in Bangladesh. To elucidate the epidemiology of tick-borne pathogens (TBPs) in local cattle, a cross-sectional study was performed in the 12 subdistricts (Upazilas) of Mymensingh district in Bangladesh. Blood samples and ticks were collected from 384 clinically healthy cattle kept by 135 farmers from 96 randomly selected villages. DNA extracted from the blood samples was subsequently screened by polymerase chain reaction (PCR) and a Reverse Line Blot (RLB) hybridization assay using an in-house prepared chemiluminescence solution for the presence of Anaplasma, Ehrlichia, Rickettsia, Babesia and Theileria spp. A total of 2,287 ticks were collected from 232 infested cattle (60.4%, 232/384) and identified morphologically as Rhipicephalus (Boophilus) microplus (n = 1,432, 62.6%) and Haemaphysalis bispinosa (n = 855; 37.4%). The RLB results demonstrated that the majority of the cattle (62.2%) were infected with at least one TBP. Theileria orientalis infections were most common (212/384, 55.2%) followed by infections with Anaplasma bovis (137/384, 35.67%), Anaplasma marginale (16/384, 4.17%), Babesia bigemina (4/384, 1.04%) and Babesia bovis (2/384, 0.52%). A previously uncharacterized Anaplasma sp. (Anaplasma sp. Mymensingh) and Babesia sp. (Babesia sp. Mymensingh), which are genetically closely related to Anaplasma platys and B. bigemina, were detected in 50 of 384 (13.0%) and 1 of 384 (0.3%) of the blood samples, respectively. Key risk factors for the occurrence of T. orientalis, A. marginale and Anaplasma sp. Mymensingh were identified. In conclusion, this study revealed that cattle in Mymensingh district are mainly infested with R. microplus and H. bispinosa ticks and may carry multiple TBPs. In addition, two previously uncharacterized pathogens were detected in the bovine blood samples. The pathogenicity of these species remains to be determined. PMID- 29119683 TI - Poly-L-lactic acid for the Improvement of photodamage and rhytids of the decolletage. AB - BACKGROUND: Poly-L-lactic acid (PLLA) is a biostimulatory filler approved for use in HIV lipoatrophy as well as cosmetic improvement in facial folds and wrinkles in immunocompetent patients. Similar to the face and hands, the decolletage is commonly subject to photodamage and the resulting appearance of rhytids and crepiness, which could benefit from PLLA treatment. OBJECTIVES: The objective of the study was to assess the safety and efficacy of injected PLLA for the improvement in rhytids and crepiness of the decolletage. METHODS: In this open label, prospective, interventional study, 25 healthy female volunteers aged 40-to 70 years with moderate-to-severe crepiness and wrinkling of the decolletage were injected with 1 vial of PLLA at each of three treatments. The Fabi-Bolton 5-point chest wrinkling scale was used by both investigators and subjects to assign pretreatment and post-treatment follow-up scores at 1 month, 3 months, and 6 months. Adverse events were reported at each visit. RESULTS: All post-treatment mean scores had statistically significant improvement compared to the pretreatment baseline means as rated by both investigators and subjects. At 1 month following the last treatment, compared to baseline, investigators rated 83% of subjects had improved by at least one point on the scale. Subjects rated 74% of subjects improved by at least one point. At 6 months, 90% of subjects, as rated by the investigators, and 57% of subjects, as rated by the subjects, had improvement from baseline. CONCLUSION: PLLA is safe and effective for improvement in the rhytids and skin quality of the photodamaged decolletage. PMID- 29119684 TI - Use-dependent directional bias does not transfer to the untrained limb during bimanual contractions. AB - Skills learned through practice with one limb can often be transferred to the untrained limb. In the present report, we sought to determine whether movement direction biases, acquired through repeated movement with one limb, transfer to the untrained limb. In order to do so, we asked participants to perform synchronized bilateral contractions of muscles in both wrists, followed by the unilateral contraction of muscles in one wrist. In four experiments, we manipulated the position of the unilateral target to create use-dependent directional biases; changed the direction of the cursor in relation to the wrist movement to control for attentional biases; and sought to induce directional biases with both right and left unilateral movements. The results showed clear movement-related biases for the wrist that performed unilateral contractions, but no evidence that movement-related bias transferred to the opposite limb during bilateral action. Thus, motor preparation and execution of unilateral contractions does not affect the direction of movement made by the opposite limb during subsequent bilateral contractions. PMID- 29119685 TI - Fundamental care and knowledge interests: Implications for nursing science. AB - AIMS AND OBJECTIVES: To characterise the intratheoretical interests of knowledge in nursing science as an epistemological framework for fundamental care. BACKGROUND: For Jurgen Habermas, theory does not separate knowledge interests from life. All knowledge, understanding and human research is always interested. Habermas formulated the knowledge interests in empirical-analytical, historical hermeneutic and critical social sciences; but said nothing about health sciences and nursing science. DESIGN: Discursive paper. RESULTS: The article is organised into five sections that develop our argument about the implications of the Habermasian intratheoretical interests in nursing science and fundamental care: the persistence of a technical interest, the predominance of a practical interest, the importance of an emancipatory interest, "being there" to understand individuals' experience and an "existential crisis" that uncovers the individual's subjectivity. CONCLUSIONS: The nursing discipline can take on practical and emancipatory interests (together with a technical interest) as its fundamental knowledge interests. Nurses' privileged position in the delivery of fundamental care gives them the opportunity to gain a deep understanding of the patient's experience and illness process through physical contact and empathic communication. RELEVANCE TO CLINICAL PRACTICE AND NURSING RESEARCH: In clinical, academic and research environments, nurses should highlight the importance of fundamental care, showcasing the value of practical and emancipatory knowledge. This process could help to improve nursing science's leadership, social visibility and idiosyncrasy. PMID- 29119686 TI - Ketone body 3-hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina. AB - Calorie restriction (CR) being the most robust dietary intervention provides various health benefits. D-3-hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), were concomitantly preserved. Importantly, the upregulation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a regulator of G6PD, and elevation of the tricarboxylic acid cycle's Nrf2 activator, fumarate, were also shared. Together, our findings suggest that CR provides retinal antioxidative defense by 3HB through the antioxidant Nrf2 pathway via modification of a tricarboxylic acid cycle intermediate during 3HB metabolism. PMID- 29119687 TI - Combining biological and psychosocial baseline variables did not improve prediction of outcome of a very-low-energy diet in a clinic referral population. AB - Consistent, strong predictors of obesity treatment outcomes have not been identified. It has been suggested that broadening the range of predictor variables examined may be valuable. We explored methods to predict outcomes of a very-low-energy diet (VLED)-based programme in a clinically comparable setting, using a wide array of pre-intervention biological and psychosocial participant data. A total of 61 women and 39 men (mean +/- standard deviation [SD] body mass index: 39.8 +/- 7.3 kg/m2 ) underwent an 8-week VLED and 12-month follow-up. At baseline, participants underwent a blood test and assessment of psychological, social and behavioural factors previously associated with treatment outcomes. Logistic regression, linear discriminant analysis, decision trees and random forests were used to model outcomes from baseline variables. Of the 100 participants, 88 completed the VLED and 42 attended the Week 60 visit. Overall prediction rates for weight loss of >=10% at weeks 8 and 60, and attrition at Week 60, using combined data were between 77.8 and 87.6% for logistic regression, and lower for other methods. When logistic regression analyses included only baseline demographic and anthropometric variables, prediction rates were 76.2 86.1%. In this population, considering a wide range of biological and psychosocial data did not improve outcome prediction compared to simply-obtained baseline characteristics. PMID- 29119688 TI - Coarse and nano emulsions for effective delivery of the natural pest control agent pulegone for stored grain protection. AB - BACKGROUND: One of the most significant contributors to the global food crisis is grain loss during storage, mainly caused by pest insects. Currently, there are two main methods used for insect pest control: fumigation and grain protection using contact insecticides. As some chemical insecticides can harm humans and the environment, there is a global tendency to reduce their use by finding alternative eco-friendly approaches. RESULTS: In this study, the natural pest managing agent pulegone was encapsulated into coarse and nano emulsions. The emulsions were characterized using spectroscopic and microscopic methods and their stability and pulegone release ability were examined. The insecticidal activity of the prepared formulations against two stored product insects, rice weevil (Sitophilus oryzae L.) and red flour beetle (Tribolium castaneum Herbst), was demonstrated. The nano emulsion-based formulation offered significant advantages and provided powerful bioactivity, with high (> 90%) mortality rates for as long as 5 weeks for both insects, whereas coarse emulsions showed high efficacy for only 1 week. CONCLUSION: The developed pulegone-based nano emulsions could serve as a model for an effective alternative method for pest control. Although pulegone is from a natural source, toxicological studies should be performed before the widespread application of pulegone or pulegone-containing essential oils to dry food products. (c) 2017 Society of Chemical Industry. PMID- 29119689 TI - Decreased 5-HT2cR and GHSR1a interaction in antipsychotic drug-induced obesity. AB - Second generation antipsychotics (SGAs), notably atypical antipsychotics including olanzapine, clozapine and risperidone, can cause weight gain and obesity side effects. Antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling have been identified as a main cause of SGA induced obesity. Here we review the pivotal regulatory role of the 5-HT2cR in ghrelin-mediated appetite signalling. The 5-HT2cR dimerizes with GHSR1a to inhibit orexigenic signalling, while 5-HT2cR antagonism reduces dimerization and increases GHSR1a-induced food intake. Dimerization is specific to the unedited 5-HT2cR isoform. 5-HT2cR antagonism by SGAs may disrupt the normal inhibitory tone on the GHSR1a, increasing orexigenic signalling. The 5 HT2cR and its interaction with the GHSR1a could serve as the basis for discovering novel approaches to preventing and treating SGA-induced obesity. PMID- 29119690 TI - Experimental infection of sheep, goats and cattle with a bluetongue virus serotype 4 field strain from Bulgaria, 2014. AB - In 2014, a new bluetongue virus serotype 4 (BTV-4) strain was detected in southern Greece and spread rapidly throughout the Balkan Peninsula and adjacent countries. Within half a year, more than 7,068 outbreaks were reported in ruminants, particularly in sheep. However, the reported morbidity and case fatality rates in ruminants varied. The pathogenesis of a Bulgarian BTV-4 strain isolated from sheep during the BTV-4 epizootic was studied in different species. Therefore, four sheep, three goats and three cattle were experimentally infected with the isolate BTV-4/BUL2014/15 and monitored for clinical signs up to several weeks. Serum and whole-blood samples were collected at regular intervals and subjected to serological and virological analyses. In this context, BTV-4 specific real-time RT-PCR assays were developed. The infection kinetics were similar to those known for other traditional BTV serotypes, and only mild BT-like clinical signs were observed in goats and sheep. In cattle, no obvious clinical signs were observed, except a transient increase in body temperature. The study results contrast with the severe clinical signs reported in sheep experimentally infected with an African BTV-4 strain and with the reports of BT-like clinical signs in a considerable proportion of different ruminant species infected with BTV-4 in the Balkan region and Italy. The discrepancies between the results of these animal trials and observations of BTV-4 infection in the field may be explained by the influence of various factors on the manifestation of BT disease, such as animal breed, fitness and virus strain, as described previously. PMID- 29119691 TI - The detection of porcine circovirus 3 in Guangxi, China. AB - Porcine circovirus type 3 (PCV3) is a novel circovirus that was firstly detected in the USA. PCV3 is associated with porcine dermatitis and nephropathy syndrome (PDNS), reproductive failure and cardiac and multisystemic inflammation. Latterly, PCV3 was detected in Guangxi, China. Forty-one of 108 (37.96%) samples and nine of 47 (19.14%) samples were PCV3 positive in pig farms and pig slaughter houses, respectively. Three PCV3 strains were sequenced and designated PCV3 China/GX2016-1, PCV3-China/GX2016-2 and PCV3-China/GX2016-3. The complete genome of PCV3-China/GX2016-2 and PCV3-China/GX2016-3 is both 2,000 bp in length, while PCV3-China/GX2016-1 is of 1,999 bp and has a G deletion at position of 1,155 in its genome. The complete genome and capsid nucleotide of the three PCV3 strains identified in this study shared 97.5%-99.4% and 96.7%-99.1% identities with that of the other PCV3 strains available in NCBI, respectively. Phylogenetic analysis based on complete genome and capsid gene of 35 PCV3 strains showed that the three PCV3 sequences from Guangxi Province were divided into two clusters. The results of this study contribute to the understanding of PCV3 molecular epidemiology. PMID- 29119692 TI - Impact of same day vs day before pre-operative lymphoscintigraphy for sentinel lymph node biopsy for early breast cancer (local Australian experience). AB - INTRODUCTION: To assess the impact of delayed vs immediate pre-operative lymphoscintigraphy (LSG) for sentinel lymph node biopsy in a single Australian tertiary breast cancer centre. METHODS: Retrospective cohort study analysing patients with breast cancer or DCIS who underwent lumpectomy or mastectomy with pre-operative LSG and intra-operative sentinel lymph node biopsy from January 2015 to June 2016. RESULTS: A total of 182 LSG were performed. Group A patients had day before pre-operative LSG mapping (n = 79) and Group B had LSG mapping on the day of surgery (n = 103). The overall LSG localisation rate was 97.3% and no statistical difference was detected between the two groups. The overall sentinel lymph node biopsies (SLN) were identified in 99.6% of patients. The number of nodes excised was slightly higher in Group A (1.90 vs 1.72); however, this was not statistically significant. In addition, the number of nodes on histopathology and the incidence of second echelon nodal detection were also similar between the two groups without statistical significance. CONCLUSION: In conclusion, the 2-day LSG protocol had no impact on overall SLNB and LSG detection rates although slightly higher second tier nodes but this did not translate to any difference between the number of harvest nodes between the two groups. The 2-day LSG allows for greater flexibility in theatre planning and more efficient use of theatre time. We recommend a dose of 40 Mbq of Tc99 m pertechnetate-labelled colloid be given day prior to surgery within a 24-hour timeframe. PMID- 29119694 TI - Female urinary incontinence and obesity assessed by anthropometry and dual-energy X-ray absorptiometry: Analysis from the 2008-09 Korean National Health and Nutrition Examination Survey. AB - OBJECTIVE: In the present study we evaluated the association between obesity, assessed by dual energy X-ray absorptiometry (DEXA), and urinary incontinence (UI). METHODS: The study was performed on 5792 women who had taken part in the Korean National Health and Nutrition Examination Survey. UI was deemed to be present if a woman answered "yes" to the question "Do you have current UI?". Obesity was assessed using anthropometry and DEXA. Data were analyzed using Chi squared tests, t-tests, receiver operating characteristic curves, and logistic regression analysis. RESULTS: The UI group had significantly higher mean (+/-SD) waist circumference (78.5 +/- 10.0 vs, 82.4+/-9.1 kg) and body mass index (23.3 +/- 3.4 vs. 24.2 +/- 3.1 kg/m2 ) than the non-UI group. In addition, total fat mass (18.5 +/- 5.3 vs. 19.4 +/- 4.9 kg), trunk fat mass (9.3 +/- 3.4 vs. 10.1 +/- 3.2 kg), the trunk fat/leg fat (mass) ratio (1.58 +/- 0.54 vs. 1.73 +/- 0.50), total body fat percentage (32.3 +/- 5.4% vs. 33.0 +/- 5.0%), and trunk fat percentage (32.4 +/- 7.3% vs. 33.9 +/- 6.6%) were significantly higher in the UI group. Of these parameters, the trunk fat/leg fat ratio showed highest sensitivity (83.6%), with a cut-off value of 1.272. Before and after adjustment, trunk fat/leg fat ratio >1.272 was significantly related to UI and had the highest odds ratio (OR) among all DEXA parameters (adjusted OR 1.807; 95% confidence interval 1.343-2.431). CONCLUSION: Obesity parameters obtained using DEXA are closely related to UI. Of these parameters, the trunk fat/leg fat ratio is the strongest in predicting the presence of UI. In addition, the present study has found a novel trunk fat/leg fat ratio cut-off value for defining obesity related to the UI. PMID- 29119695 TI - Hierarchical classification of microorganisms based on high-dimensional phenotypic data. AB - The classification of microorganisms by high-dimensional phenotyping methods such as FTIR spectroscopy is often a complicated process due to the complexity of microbial phylogenetic taxonomy. A hierarchical structure developed for such data can often facilitate the classification analysis. The hierarchical tree structure can either be imposed to a given set of phenotypic data by integrating the phylogenetic taxonomic structure or set up by revealing the inherent clusters in the phenotypic data. In this study, we wanted to compare different approaches to hierarchical classification of microorganisms based on high-dimensional phenotypic data. A set of 19 different species of molds (filamentous fungi) obtained from the mycological strain collection of the Norwegian Veterinary Institute (Oslo, Norway) is used for the study. Hierarchical cluster analysis is performed for setting up the classification trees. Classification algorithms such as artificial neural networks (ANN), partial least-squared discriminant analysis and random forest (RF) are used and compared. The 2 methods ANN and RF outperformed all the other approaches even though they did not utilize predefined hierarchical structure. To our knowledge, the RF approach is used here for the first time to classify microorganisms by FTIR spectroscopy. PMID- 29119693 TI - The neural representation of social status in the extended face-processing network. AB - Social status is a salient cue that shapes our perceptions of other people and ultimately guides our social interactions. Despite the pervasive influence of status on social behavior, how information about the status of others is represented in the brain remains unclear. Here, we tested the hypothesis that social status information is embedded in our neural representations of other individuals. Participants learned to associate faces with names, job titles that varied in associated status, and explicit markers of reputational status (star ratings). Trained stimuli were presented in an functional magnetic resonance imaging experiment where participants performed a target detection task orthogonal to the variable of interest. A network of face-selective brain regions extending from the occipital lobe to the orbitofrontal cortex was localized and served as regions of interest. Using multivoxel pattern analysis, we found that face-selective voxels in the lateral orbitofrontal cortex - a region involved in social and nonsocial valuation, could decode faces based on their status. Similar effects were observed with two different status manipulations - one based on stored semantic knowledge (e.g., different careers) and one based on learned reputation (e.g., star ranking). These data suggest that a face-selective region of the lateral orbitofrontal cortex may contribute to the perception of social status, potentially underlying the preferential attention and favorable biases humans display toward high-status individuals. PMID- 29119696 TI - Antibacterial isoeugenol coating on stainless steel and polyethylene surfaces prevents biofilm growth. AB - AIMS: Pathogenic bacteria can spread between individuals or between food items via the surfaces they share. Limiting the survival of pathogens on surfaces, therefore, presents an opportunity to limit at least one route of how pathogens spread. In this study, we propose that a simple coating with the essential oil isoeugenol can be used to circumvent the problem of bacterial transfer via surfaces. METHODS AND RESULTS: Two commonly used materials, stainless steel and polyethylene, were coated by physical adsorption, and the coatings were characterized by Raman spectroscopy, atomic force microscopy and water contact angle measurements. We quantified and visualized the colonization of coated and uncoated surfaces by three bacteria: Staphylococcus aureus, Listeria monocytogenes and Pseudomonas fluorescens. No viable cells were detected on surfaces coated with isoeugenol. CONCLUSIONS: The isoeugenol coating prepared with simple adsorption proved effective in preventing biofilm formation on stainless steel and polyethylene surfaces. The result was caused by the antibacterial effect of isoeugenol, as the coating did not diminish the adhesive properties of the surface. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study demonstrates that a simple isoeugenol coating can prevent biofilm formation of S. aureus, L. monocytogenes and P. fluorescens on two commonly used surfaces. PMID- 29119697 TI - Presence of atypical porcine pestivirus (APPV) in Brazilian pigs. AB - Recently, a putative new pestivirus species, provisionally named as Atypical Porcine Pestivirus (APPV), was associated with the congenital tremor in piglets in North America and consequently in Europe and Asia. The present research aimed to describe the detection and characterization of APPV employing NS5B gene partial sequencing, gross pathology and histologic examination of piglets displaying congenital tremor from two different farms of Southern Brazil. No gross lesions were observed, and the histological findings revealed moderate vacuolization of the white matter of the cerebellum. RT-PCR followed by DNA sequencing and a phylogenetic analysis confirmed the presence of APPV in samples from the two farms, which the samples were distinct in nature. Phylogenetic reconstruction reinforced the high genetic variability within the APPVs previously reported. This is the first report of APPV in South America suggesting that this new group of viruses may be widespread in swine herds in other countries as it is in Brazil. PMID- 29119698 TI - Differences in ultrasound features of papillations in unilocular-solid adnexal cysts: a retrospective international multicenter study. AB - OBJECTIVES: To identify ultrasound features of papillations or of the cyst wall that can discriminate between benign and malignant unilocular-solid cysts with papillations but no other solid components. METHODS: From the International Ovarian Tumor Analysis (IOTA) database derived from seven ultrasound centers, we identified patients with an adnexal lesion described at ultrasonography as unilocular-solid with papillations but no other solid components. All patients had undergone transvaginal ultrasound between 1999 and 2007 or 2009 and 2012, by an experienced examiner following the IOTA research protocol. Information on four ultrasound features of papillations had been collected prospectively. Information on a further seven ultrasound features was collected retrospectively from electronic or paper ultrasound images of good quality. The histological diagnosis of the surgically removed adnexal lesion was considered the gold standard. RESULTS: Of 204 masses included, 131 (64.2%) were benign, 42 (20.6%) were borderline tumors, 30 (14.7%) were primary invasive tumors and one (0.5%) was a metastasis. Multivariate logistic regression analysis showed the following ultrasound features to be associated independently with malignancy: height of the largest papillation, presence of blood flow in papillations, papillation confluence or dissemination, and shadows behind papillations. Shadows decreased the odds of malignancy, while the other features increased them. CONCLUSION: We have identified ultrasound features that can help to discriminate between benign and malignant unilocular-solid cysts with papillations but no other solid components. Our results need to be confirmed in prospective studies. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29119699 TI - Effect of follistatin on pre-implantational development of pig parthenogenetic embryos. AB - The present study was designed to explore effects of follistatin (FST) on pre implantational development of parthenogenetically activated embryos (PAEs) in pigs. First, we investigated the FST messenger RNA expression level and dynamic FST protein expression patterns in porcine oocytes and PAEs. Then, PAEs were placed in embryo culture medium supplemented with 10 ng/mL of FST-288, FST-300, and FST-315. Next, PAEs were cultured with 0, 1, 10 and 100 ng/mL of FST-315 protein throughout the in vitro culture (IVC) duration. Further, 10 ng/mL of FST 300 was added from the start of IVC in which PAEs were treated for 30, 48 and 60 h. The results showed that 1 ng/mL FST-315 could significantly increase the total cell numbers of blastocyst and trophectoderm cell number in PAEs. Exogenous FST 300 supplementation could significantly promote the early cleavage divisions and improve the blastocyst formation rate of porcine embryos. FST-300 appeared to affect early embryonic development before activation of the embryonic genome. In all, the study confirmed for the first time that FST plays a role in promoting early embryonic development in pigs, which differed with different FST subtypes. FST-300 could facilitate the initial cleavage time and improve the blastocyst formation rate, and FST-315 could improve the blastocyst quality. PMID- 29119700 TI - Oral and written picture description in individuals with aphasia. AB - BACKGROUND: Aphasia is characterized by difficulties in connected speech/writing. AIMS: To explore the differences between the oral and written description of a picture in individuals with chronic aphasia (IWA) and healthy controls. Descriptions were controlled for productivity, efficiency, grammatical organization, substitution behaviour and discourse organization. METHODS & PROCEDURES: Fifty IWA and 50 healthy controls matched for age, gender and education provided an oral and written description of a black-and-white situational drawing from the Dutch version of the Comprehensive Aphasia Test. Between- and within-group analyses were carried out and the reliability of the test instrument was assessed. OUTCOMES & RESULTS: The language samples of the healthy controls were more elaborate, more efficient, syntactically richer, more coherent, and consisted of fewer spoken and written language errors than the samples of the IWA. Within-group comparisons showed that connected writing is more sensitive than connected speech to capture aphasic symptoms. CONCLUSIONS & IMPLICATIONS: The analysis of both modalities (speech and writing) at the discourse level allows one to assess simultaneously micro- and macro-linguistic skills and their potential interrelations in a given IWA. Connected writing appears to be more sensitive in discriminating IWA from healthy controls than connected speech. This method for analyzing language samples should, however, be used in conjunction with other assessment tools. PMID- 29119701 TI - Management of urethral stricture: High-pressure balloon dilation versus optical internal urethrotomy. AB - OBJECTIVE: Urethral stenosis is a disease in which the lumen of the urethra becomes constricted by fibrosis. Such stenoses have been treated by urethral dilation using a bougie and optical internal urethrotomy (OIU). Recently, high pressure balloon dilation (BD) has been developed as a new treatment method for urethral stenosis. The present study compared the effectiveness of urethral dilation by BD and OIU. METHODS: Twenty-two patients of urethral stenosis were treated at Yokohama City University Medical Center between 2005 and 2015. Of these, 13 underwent BD, whereas OIU was performed in 9. BD was performed at 30 atm twice for 5 min each time. In OIU, an endoscopic knife was used to cut out the stenotic lesion in 3 directions. The endpoint was set as restenosis, which required additional surgical treatment, including BD, OIU, and the use of a urethral bougie. RESULTS: The causes of urethral stricture were endoscopic surgery (n = 7; 31.8%), development after total prostatectomy (n = 4; 18.2%), iatrogenic reasons associated with catheter insertion (n = 5; 22.7%), development after a prostate needle biopsy (n = 3; 13.6%), and unknown (n = 3; 13.6%). The site of the stenotic lesion site was the anastomosis (n = 3; 13.6%), bladder neck (n = 6; 27.3%), prostatic urethra (n = 4; 18.2%), anterior urethra (n = 7; 31.8%), and membranous urethra (n = 2; 9.1%). The stenosis-free rate was 84% for those undergoing BD and 22% for those receiving OIU. The median stenosis-free time was significantly longer after BD than OIU (1675 vs. 244 days, respectively; P < .01). CONCLUSION: The stenosis-free time was significantly longer after BD than OIU. PMID- 29119702 TI - Bayesian sparse-based reconstruction in bioluminescence tomography improves localization accuracy and reduces computational time. AB - Bioluminescence tomography (BLT) provides fundamental insight into biological processes in vivo. To fully realize its potential, it is important to develop image reconstruction algorithms that accurately visualize and quantify the bioluminescence signals taking advantage of limited boundary measurements. In this study, a new 2-step reconstruction method for BLT is developed by taking advantage of the sparse a priori information of the light emission using multispectral measurements. The first step infers a wavelength-dependent prior by using all multi-wavelength measurements. The second step reconstructs the source distribution based on this developed prior. Simulation, phantom and in vivo results were performed to assess and compare the accuracy and the computational efficiency of this algorithm with conventional sparsity-promoting BLT reconstruction algorithms, and results indicate that the position errors are reduced from a few millimeters down to submillimeter, and reconstruction time is reduced by 3 orders of magnitude in most cases, to just under a few seconds. The recovery of single objects and multiple (2 and 3) small objects is simulated, and the recovery of images of a mouse phantom and an experimental animal with an existing luminescent source in the abdomen is demonstrated. Matlab code is available at https://github.com/jinchaofeng/code/tree/master. PMID- 29119703 TI - Rickettsia parkeri in free-ranging wild canids from Brazilian Pampa. AB - Spotted fevers are tick-borne diseases associated with various Rickettsia species. Rickettsia parkeri sensu stricto (s.s.) is the agent of an emerging eschar-associated rickettsiosis in humans from the USA and South American Pampa. Considering that R. parkeri s.s. is restricted to Americas and the potential role of dogs in the epidemiology of the disease, it is thus reasonable to hypothesize that wild canids could be involved in the enzootic cycle of this rickettsiosis. The aim of this work was to investigate the potential role of the wild canids from Pampa, Cerdocyon thous (crab-eating fox) and Lycalopex gymnocercus (Pampas fox), in the ecology of R. parkeri s.s. For that, 32 live-trapped free-ranging wild canids were sampled. Ticks were observed in 30 of the 32 foxes. Of the 292 ticks collected, 22 (7.5%) were positive by PCR for the presence of R. parkeri s.s. DNA. Also, 20 (62%) wild canids showed antibodies against R. parkeri. The results suggest that wild canids are involved in the enzootic cycle of R. parkeri s.s. in the Pampa biome and could be responsible for pathogen (and its vectors) dispersal. PMID- 29119704 TI - Pharmacokinetics of RP5063 Following Single Doses to Normal Healthy Volunteers and Multiple Doses Over 10 Days to Stable Schizophrenic Patients. AB - RP5063, a multimodal dopamine (D)-serotonin (5-HT) stabilizer, possesses high affinity for D2/3/4 and 5-HT1A/2A/2B/2C/6/7 receptors and moderate affinity for the serotonin transporter. Two phase I studies characterized the pharmacokinetics of a single dose (10 and 15 mg fasting, 15 mg fed/fasting) in healthy volunteers and multiple doses (10, 20, 50, and 100 mg fed) over 10 days in patients with stable schizophrenia. RP5063 displayed a dose-dependent Cmax at 4 to 6 h, linear dose proportionality for both Cmax and AUC, and a half-life between 40 and 71 h. In the single-dose study, food slightly increased the extent of drug absorption. In the multiple-dose study, steady-state was approached after 120 h of daily dosing. Pooled data in the single-dose study indicate that the pharmacokinetic profile appears to be comparable between Japanese and Caucasians. RP5063 appears to have a straightforward pharmacokinetic profile that supports for phase II and III evaluation as a once-daily oral administered agent. PMID- 29119705 TI - On-treatment changes of liver stiffness at week 26 could predict 2-year clinical outcomes in HBV-related compensated cirrhosis. AB - BACKGROUND & AIMS: It is unclear whether liver stiffness measurement (LSM) dynamic changes after anti-HBV treatment could predict the risk of liver-related events (LREs), particularly in patients with HBV-related compensated cirrhosis. METHODS: Treatment-naive patients with HBV-related compensated cirrhosis were enrolled. All patients were under entecavir-based antiviral therapy, and followed up every 26 weeks for 2 years. The association between LSM and LREs was analysed by Cox proportional hazard model and Harrell C-index analysis. RESULTS: A total of 438 patients were included in the study. At the follow-up of 104 weeks, LREs developed in 33/438 (7.8%) patients, including 16 episodes of decompensation, 18 HCC and 3 deaths. The median LSM remained high from 20.9, 18.6, 20.4 to 20.3 Kpa at week 0, 26, 52 and 78 among patients with LREs, whereas the LSM decreased from 17.8, 12.3, 10.6 to 10.2 Kpa in patients without LREs respectively. Percentage changes of LSM at 26 weeks from baseline were significantly associated with LREs (excluding 11 cases occurred within the first 26 weeks), with a crude hazard ratio of 2.94 (95% CI: 1.73-5.00) and an albumin-adjusted hazard ratio of 2.47 (95% CI: 1.49-4.11). The Harrell C-index of these 2 models for predicting 2-year LREs were 0.68 (95% CI: 0.56-0.80) and 0.75 (95% CI: 0.65-0.85) respectively. Nomograms were developed to identify individuals at high risk for point-of-care application. CONCLUSIONS: Dynamic changes of LSM alone, or combined with baseline albumin, could predict LREs in patients with HBV-related compensated cirrhosis during antiviral therapy. PMID- 29119706 TI - Insights on efficacious doses of PAMORAs for patients on chronic opioid therapy or opioid-naive patients. AB - BACKGROUND: Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naive subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naive subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users. METHODS: A PubMed search of MU-opioid antagonists to counter MU-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit. KEY RESULTS: The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naive subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naive subjects compared to chronic opioid users. Opioid-naive users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users. CONCLUSIONS & INFERENCES: Opioid-naive subjects require a higher dose of PAMORA than chronic opioid users to achieve MU-opioid antagonist effect. PMID- 29119707 TI - Impaired expression of CXCL5 and matrix metalloproteinases in the lungs of mice with high susceptibility to Streptococcus pneumoniae infection. AB - INTRODUCTION: Streptococcus pneumoniae colonizes the nasopharynx of healthy individuals establishing a commensal relationship with the host. In some conditions, bacteria invade the lower respiratory tract and innate immune responses are crucial to avoid diseases such as pneumonia, sepsis, or meningitis. METHODS: Here, we compared the susceptibility to pneumococcal respiratory infection of two outbred mouse lines, AIRmin and AIRmax, selected for low or high acute inflammatory responses, respectively. RESULTS: AIRmin mice showed increased susceptibility to infection with different pneumococcal serotypes, when compared to AIRmax. Significant higher numbers of alveolar macrophages expressing the CD206 mannose receptor were observed in AIRmin mice when compared to AIRmax mice. Despite this difference, secretion of several cytokines and chemokines in the respiratory tract of AIRmin and AIRmax mice, after infection, was similar. The only exception was CXCL5, which was highly induced after pneumococcal infection in AIRmax mice but not in AIRmin mice. Reduced expression of the matrix metalloproteinases (MMP) 2, 3, 8, and 9, as well as reduced activities of MMPs were also observed in the lungs of AIRmin mice, after infection. Such impaired responses may have contributed to the low influx of neutrophils observed in the airways of these mice. Finally, high percentages of macrophages and neutrophils in apoptosis or necrosis, at the site of infection, were also observed in AIRmin mice, suggesting that leukocyte functionality is also compromised. CONCLUSIONS: Our results indicate that CXCL5 and MMPs contribute to the resistance to pneumococcal infection in mice. PMID- 29119709 TI - Erratum. PMID- 29119708 TI - Eukaryotic Initiation Factor 5A2 Contributes to the Maintenance of CD133(+) Hepatocellular Carcinoma Cells via the c-Myc/microRNA-29b Axis. AB - Cancer stem cells (CSCs)/cancer-initiating cells (CICs) are suggested responsible for driving cancer resistance to conventional therapies and for cancer recurrence and/or metastasis. CD133 is served as a key biomarker to identify and characterize this subpopulation of cells in hepatocellular carcinoma (HCC). Our previous study indicated that overexpression of eukaryotic initiation factor 5A2 (EIF5A2) promotes HCC cell metastasis and angiogenesis. In this study, we demonstrated that EIF5A2 might play a crucial role in CSCs regulation and investigated its potential molecular mechanisms. Using quantitative real-time polymerase chain reaction assay, we observed that the expression of EIF5A2 positively correlated with CD133 levels in a cohort of cancerous and noncancerous liver tissues and cells. Next, HCC cells with high expression of EIF5A2 have a strong capacity to form undifferentiated tumor spheres in vitro and show elevated levels of stem cell-related genes, leading to an increased ability to develop tumors when subcutaneously injected into nude mice. Furthermore, differential microRNA expression was profiling between two EIF5A2-depleted HCC cell lines and their control one identified a decreased expression of miR-29b in EIF5A2-depleted cell lines. Further functional studies illustrated that downregulated miR-29b level is responsible for EIF5A2-maintained HCC cell stemness either in vitro or in vivo. Moreover, enforced expression of EIF5A2 in HCC cells largely enhanced the binding of c-Myc on the promoter of miR-29b and downregulation of miR-29b by EIF5A2 was dependent on c-Myc. Our findings, collectively, reveal that EIF5A2 contributes to the maintenance of CD133+ HCC cells via the c-Myc/miR-29b axis. Stem Cells 2018;36:180-191. PMID- 29119710 TI - Role of SDF-1:CXCR4 in Impaired Post-Myocardial Infarction Cardiac Repair in Diabetes. AB - Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF-1:CXCR4 expression is compromised in post-AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell-derived factor-1 (SDF-1). SDF-1 expression in control MSC and SDF-1-overexpressing MSC (SDF-1:MSC) were quantified using enzyme linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF-1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF-1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF-1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post-AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post-AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF-1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The SDF 1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of AMI. Over-express of SDF-1 expression in diabetes rescues cardiac function post AMI. Our results suggest that modulation of SDF-1 may improve post AMI cardiac repair in diabetes. Stem Cells Translational Medicine 2018;7:115-124. PMID- 29119711 TI - Bernard-Soulier syndrome in Pakistan: Biochemical and molecular analyses leading to identification of a novel mutation in GP1BA. PMID- 29119712 TI - Impact of delaying treatment intensification with a glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes uncontrolled on basal insulin: A longitudinal study of a US administrative claims database. AB - AIM: To evaluate the effect of delaying treatment intensification with a glucagon like peptide-1 receptor agonist (GLP-1 RA) on clinical and economic outcomes in patients with type 2 diabetes (T2D). METHODS: We conducted a retrospective observational claims study using IMPACT (Impact National Managed Care Benchmark Database) in adult patients with T2D who initiated basal insulin between January 1, 2005 and December 31, 2012, with or without OADs, who remained uncontrolled (glycated haemoglobin [HbA1c] >=7.0%). Patients were categorized into 3 groups: early, delayed, and no intensification with a GLP-1 RA. We evaluated changes from baseline to follow-up at 12 months for HbA1c level, rate of hypoglycaemic events, and healthcare costs, and we assessed the association between baseline patient characteristics and subsequent treatment intensification. RESULTS: A total of 139 patients (9.0% of 1552 eligible patients) met criteria for inclusion in the early intensification group, 588 patients (37.9%) met criteria for inclusion in the delayed intensification group, and 825 patients (53.2%) met criteria for inclusion in the no intensification group. Mean baseline HbA1c values were 9.16%, 9.07%, and 9.34%, respectively. At follow-up, delayed intensification was associated with significantly smaller decreases in HbA1c from baseline (-0.68%) compared with early intensification (-1.01%). Rates of overall hypoglycaemia were numerically greater in the delayed intensification group than in the early intensification group (0.26 vs 0.06 events/patient-years of exposure, respectively). Change in semi-annual total healthcare costs was greater in the no intensification group (+5266 USD) compared with the early intensification group ( 560 USD) and the delayed intensification group (+1943 USD). CONCLUSIONS: Timely addition of a GLP-1 RA to therapy for patients with T2D who were not adequately controlled with basal insulin is associated with better clinical and economic outcomes. PMID- 29119713 TI - Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival. AB - AIMS: To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose-lowering regimens with differing risks of hypoglycaemia. METHODS: Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent covariable. RESULTS: There were 6646 deaths in a total follow-up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (>=7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95-1.12); sulphonylurea, aHR 1.11 (95% CI 0.99-1.25); insulin, aHR 1.47 (95% CI 1.25-1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94-1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13-1.35) and including insulin, aHR 1.28 (95% CI 1.18-1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all-cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia. CONCLUSIONS: The pattern of mortality risk across the range of HbA1c differed by glucose-lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk. PMID- 29119714 TI - Cross-cultural adaptation and validation of the Spanish version of the Paediatric Throat Disorders Outcome Test (T-14). AB - OBJECTIVES: The Paediatric Throat Disorders Outcome Test (T-14) is a disease specific questionnaire that parents are requested to complete; it aimed to assess the quality of life related to tonsil and adenoid disease or its treatment in children with throat disorders. The aim of this study was to validate the Spanish adaptation of the T-14, thus allowing comparison across studies and facilitating international multicentre projects. DESIGN, SETTING AND PARTICIPANTS: This was a multicentre prospective instrument validation study. Guidelines for the cross cultural adaptation process from the original English-language scale into a Spanish-language version were followed. The psychometric properties (reproducibility, reliability, validity, responsiveness) of the Spanish version ("T-14-s" for "T-14-Spanish") were assessed in 50 consecutive children undergoing adeno/tonsillectomy (both before and 6 months after surgery) and in a separate cohort of 50 unaffected children in a comparable age range. MAIN OUTCOME MEASURES AND RESULTS: Test-retest reliability (gamma = 0.83) and internal consistency reliability (alpha = 0.94) were adequate. The T-14-s demonstrated satisfactory construct validity (r > 0.40). The instrument showed excellent between-group discrimination (P < .0001) and a high responsiveness to change (effect size = 2.09). CONCLUSIONS: The Spanish version of the T-14 (T-14-s) is a valid tool for measuring the subjective severity of throat disorders, and its use is recommended. PMID- 29119715 TI - Glabridin inhibits the activation of myofibroblasts in human fibrotic buccal mucosal fibroblasts through TGF-beta/smad signaling. AB - Oral submucous fibrosis (OSF) has been recognized as one of the oral potentially malignant disorders. Areca nut chewing is implicated in this pathological fibrosis, and it causes chronic inflammation and persistent activation of myofibroblasts. As yet, existing treatments only provide temporary symptomatic relief and there is a lack of an effective intervention to cure OSF. Therefore, development of approaches to ameliorate myofibroblast activities becomes a crucial objective to prevent the malignant progression of OSF. In this study, we examined the inhibitory effect of glabridin, an isoflavane extracted from licorice root, on the myofibroblast characteristics in human fibrotic buccal mucosal fibroblasts (fBMFs). Our results showed that myofibroblast activities, including collagen gel contractility, migration, invasion and wound healing abilities were reduced after exposure of glabridin in a dose-dependent manner. Most importantly, we demonstrated that the arecoline-induced myofiroblast activities were abolished by glabridin treatment. Additionally, the expression of the myofibroblast marker alpha-smooth muscle actin and other fibrogenic marker, type I collagen, in fBMFs were dose-dependently downregulated. Moreover, we showed that the production of TGF-beta was suppressed by glabridin in fBMFs and the protein expression of phospho-Smad2 was decreased as well. In summary, our data suggested that glabridin repressed the myofibroblast features in fBMFs via TGF-beta/Smad2 signaling pathway. Glabridin also prevented the arecoline increased myofibroblast activities, and could serve as a natural anti-fibrosis compound for OSF. PMID- 29119716 TI - Episodic memory retrieval in adolescents with and without developmental language disorder (DLD). AB - BACKGROUND: Two reasons may explain the discrepant findings regarding declarative memory in developmental language disorder (DLD) in the literature. First, standardized tests are one of the primary tools used to assess declarative memory in previous studies. It is possible they are not sensitive enough to subtle memory impairment. Second, the system underlying declarative memory is complex, and thus results may vary depending on the types of encoding and retrieval processes measured (e.g., item specific or relational) and/or task demands (e.g., recall or recognition during memory retrieval). AIMS: To adopt an experimental paradigm to examine episodic memory functioning in adolescents with and without DLD, with the focus on memory recognition of item-specific and relational information. METHODS & PROCEDURES: Two groups of adolescents, one with DLD (n = 23; mean age = 16.73 years) and the other without (n = 23; mean age = 16.75 years), participated in the study. The Relational and Item-Specific Encoding (RISE) paradigm was used to assess the effect of different encoding processes on episodic memory retrieval in DLD. The advantage of using the RISE task is that both item-specific and relational encoding/retrieval can be examined within the same learning paradigm. OUTCOMES & RESULTS: Adolescents with DLD and those with typical language development showed comparable engagement during the encoding phase. The DLD group showed significantly poorer item recognition than the comparison group. Associative recognition was not significantly different between the two groups; however, there was a non-significant trend for to be poorer in the DLD group than in the comparison group, suggesting a possible impairment in associative recognition in individuals with DLD, but to a lesser magnitude. CONCLUSIONS & IMPLICATIONS: These results indicate that adolescents with DLD have difficulty with episodic memory retrieval when stimuli are encoded and retrieved without support from contextual information. Associative recognition is relatively less affected than item recognition in adolescents with DLD. PMID- 29119717 TI - Enzymes as Enhancers for the Biodegradation of Synthetic Polymers in Wastewater. AB - Synthetic polyesters are today the second-largest class of ingredients in household products and are entering wastewater treatment plants (WWTPs) after product utilization. One approach to improve polymer biodegradation in wastewater would be to complement current processes with polyester-hydrolyzing enzymes and their microbial producers. In this study, the hydrolysis of poly(oxyethylene terephthalate) polymer by hydrolases from wastewater microorganisms was investigated in vitro and under realistic WWTP conditions. An esterase and a cutinase from Pseudomonas pseudoalcaligenes and a lipase from Pseudomonas pelagia were heterologously expressed in Escherichia coli BL21-Gold(DE3) and were purified by a C-terminal His6 tag. The hydrolases were proven to hydrolyze the polymer effectively, which is a prerequisite for further biodegradation. The hydrolases maintained high activity up to 50 % upon lowering the temperature from 28 to 15 degrees C to mimic WWTP conditions. The hydrolases were also not inhibited by the wastewater matrix. Polyester-hydrolyzing enzymes active under WWTP conditions and their microbial producers thus have the potential to improve biological treatment of wastewater rich in synthetic polymers. PMID- 29119718 TI - Glucocorticoids suppress brown adipose tissue function in humans: A double-blind placebo-controlled study. AB - AIM: To investigate the effect of glucocorticoids on brown adipose tissue (BAT) function in humans. MATERIALS AND METHODS: In a randomized double-blind cross over design, 13 healthy adults underwent 1 week of oral prednisolone treatment (15 mg/d) and placebo with an intervening 2-week wash-out period. BAT function was assessed in response to cooling (19 degrees C) and to a standardized meal, by measuring fluoro-deoxyglucose (FDG) uptake using positron emission tomography computed tomography and skin temperatures overlying the supraclavicular (SCL) BAT depots using infrared thermography. Postprandial energy and substrate metabolism was assessed by indirect calorimetry. RESULTS: During cooling, prednisolone significantly reduced BAT FDG uptake (standardized uptake value, SUVmax, 6.1 +/- 2.2 vs 3.7 +/- 1.2; P < .05) and SCL temperature (-0.45 +/- 0.1 vs -1.0 +/- 0.1 degrees C; P < .01) compared to placebo. Postprandially, prednisolone significantly blunted the rise in SCL temperature (+0.2 +/- 0.1 vs -0.3 +/- 0.1 degrees C; P < .05), enhanced energy production (+221 +/- 17 vs +283 +/- 27 kcal/d; P < .01) and lipid synthesis (+16.3 +/- 3.2 vs +23.6 +/- 4.9 mg/min; P < .05). The prednisolone-induced reduction in SCL temperature significantly correlated with the reduction in FDG uptake (r = 0.65, P < .05), while the increase in energy production significantly correlated with the increase in lipogenesis (r = 0.6, P < .05). CONCLUSION: Prolonged exposure to glucocorticoid suppresses the function of human BAT. The enhancement of energy production and lipogenesis in the face of reduced dissipation of energy as heat suggests that glucocorticoids channel energy towards fat storage after nutrient intake. This is a novel mechanism of glucocorticoid-induced obesity. PMID- 29119719 TI - A mHealth randomized controlled trial to reduce sugar-sweetened beverage intake in preschool-aged children. AB - BACKGROUND: Sugar-sweetened beverages and maternal weight are strong drivers of child obesity, but few studies have targeted these risk factors as an obesity prevention strategy in children. OBJECTIVE: The objective of this study was to test the efficacy of a smartphone-delivered intervention to reduce parent provided sugar-sweetened beverage and juice (SSB/juice) consumption among children ages 3-5 and maternal weight. METHODS: Mothers with overweight or obesity, who had a child ages 3-5 that consumed at least 12 fl. oz./day of SSB/juice (N = 51 dyads) were randomized to the Smart Moms group that received one group session, lessons on a mobile website, and text messages, or to a waitlist control group. Mothers self-monitored their children's beverages in addition to their own beverages, high-calorie foods, and weight. Assessments at baseline, 3, and 6 months included dietary recalls to measure SSB/juice intake and objectively measured maternal weight. RESULTS: Using linear mixed models controlling for baseline values, child age and race, there was a greater reduction in child SSB/juice in Smart Moms compared with control at 6 months ( 9.7 oz./day vs. 1.7 oz./day, p < .01). Mothers in Smart Moms lost 2.4 kg at 6 months compared with a 0.9-kg gain in the control group (p < .01). CONCLUSIONS: An intervention delivered using mHealth technologies can target mothers to change child dietary behaviours and improve maternal weight, which suggests a novel approach to family-based obesity prevention. PMID- 29119721 TI - Integrated Transmission Electron and Single-Molecule Fluorescence Microscopy Correlates Reactivity with Ultrastructure in a Single Catalyst Particle. AB - Establishing structure-activity relationships in complex, hierarchically structured nanomaterials, such as fluid catalytic cracking (FCC) catalysts, requires characterization with complementary, correlated analysis techniques. An integrated setup has been developed to perform transmission electron microscopy (TEM) and single-molecule fluorescence (SMF) microscopy on such nanostructured samples. Correlated structure-reactivity information was obtained for 100 nm thin, microtomed sections of a single FCC catalyst particle using this novel SMF TEM high-resolution combination. High reactivity in a thiophene oligomerization probe reaction correlated well with TEM-derived zeolite locations, while matrix components, such as clay and amorphous binder material, were found not to display activity. Differences in fluorescence intensity were also observed within and between distinct zeolite aggregate domains, indicating that not all zeolite domains are equally active. PMID- 29119720 TI - Phage Display on the Anti-infective Target 1-Deoxy-d-xylulose-5-phosphate Synthase Leads to an Acceptor-Substrate Competitive Peptidic Inhibitor. AB - Enzymes of the 2-C-methyl-d-erythritol-4-phosphate pathway for the biosynthesis of isoprenoid precursors are validated drug targets. By performing phage display on 1-deoxy-d-xylulose-5-phosphate synthase (DXS), which catalyzes the first step of this pathway, we discovered several peptide hits and recognized false-positive hits. The enriched peptide binder P12 emerged as a substrate (d-glyceraldehyde-3 phosphate)-competitive inhibitor of Deinococcus radiodurans DXS. The results indicate possible overlap of the cofactor- and acceptor-substrate-binding pockets and provide inspiration for the design of inhibitors of DXS with a unique and novel mechanism of inhibition. PMID- 29119722 TI - C-reactive protein as a predictor of low trough infliximab concentrations in patients who lose response to infliximab. AB - OBJECTIVE: Low serum infliximab concentrations are associated with an increased risk of loss of response in inflammatory bowel disease (IBD). The objective of this study was to evaluate the test characteristics of C-reactive protein (CRP) in identifying low serum infliximab concentrations in patients with IBD. METHODS: We measured serum infliximab concentrations and CRP levels in patients who experienced deteriorating symptoms while on infliximab (the reactive cohort). Receiver operating characteristic (ROC) curves were used to determine the CRP concentration threshold that identified an infliximab concentration <3 MUg/mL at the time of loss of response. These CRP thresholds for infliximab concentration <3 MUg/mL were then tested in a separate validation cohort. RESULTS: The reactive cohort contained 111 patients and the validation cohort contained 139 patients. In 41% of participants, serum infliximab concentration was <3 MUg/mL. In the reactive cohort, the area under the ROC curve for CRP to identify an infliximab concentration <3 MUg/mL was 0.70 (95% confidence interval [CI] 0.50-0.80, P = 0.02). A CRP level above 12 mg/L in the preceding 90 days provided a 90% specificity for the later detection of infliximab concentration <3 MUg/mL. These test characteristics were similar in the validation cohort. CONCLUSION: CRP levels over 12 mg/L exhibit a high specificity for identifying patients with an infliximab concentration <3 MUg/mL. CRP may be cost-effective for identifying patients with low concentrations of infliximab at the time of, or at risk of, loss of response. PMID- 29119724 TI - Evaluation of first-line bismuth-containing 7-day concomitant quintuple therapy for Helicobacter pylori eradication. AB - OBJECTIVE: Helicobacter pylori (H. pylori) infection is difficult to cure, mainly due to antibiotic resistance. This study aimed to determine the efficacy and safety of 7-day bismuth-containing concomitant quintuple regimen for H. pylori eradication. METHODS: Conducted from August 2015 to February 2016 at the First Affiliated Hospital of Nanchang University, this prospective trial enrolled 70 untreated patients who were positive for H. pylori. The patients received 7-day quintuple therapy consisting of bismuth subcitrate 220 mg, esomeprazole 20 mg, clarithromycin 500 mg, amoxicillin 1 g and metronidazole 400 mg, each was given twice daily. All patients underwent a 13 C-urea breath test at 4 weeks after treatment. RESULTS: A total of 70 patients at a mean age of 43.5 years, including 36 men, were included in this trial. One person who violated the protocol was further excluded. The treatment compliance rate was 99.6%. The overall eradication rates of the 7-day bismuth-containing concomitant quintuple therapy were 75.4% (intention-to-treat analysis) and 86.7% (per-protocol analysis). The prevalence of side effects was 31.9%, including a bitter taste (23.2%), nausea (4.3%), dizziness (2.9%), diarrhea (2.9%), limb asthenia (2.9%), skin rash (1.4%), numbness of the tip of the tongue (1.4%) and insomnia (1.4%). CONCLUSIONS: The 7-day bismuth-containing concomitant quintuple therapy may not be superior to traditionally widely accepted therapy due to its lack of acceptable efficacy and high rate of side effects. PMID- 29119723 TI - Tick attachment cement - reviewing the mysteries of a biological skin plug system. AB - The majority of ticks in the family Ixodidae secrete a substance anchoring their mouthparts to the host skin. This substance is termed cement. It has adhesive properties and seals the lesion during feeding. The particular chemical composition and the curing process of the cement are unclear. This review summarizes the literature, starting with a historical overview, briefly introducing the different hypotheses on the origin of the adhesive and how the tick salivary glands have been identified as its source. Details on the sequence of cement deposition, the curing process and detachment are provided. Other possible functions of the cement, such as protection from the host immune system and antimicrobial properties, are presented. Histochemical and ultrastructural data of the intracellular granules in the salivary gland cells, as well as the secreted cement, suggest that proteins constitute the main material, with biochemical data revealing glycine to be the dominant amino acid. Applied methods and their restrictions are discussed. Tick cement is compared with adhesives of other animals such as barnacles, mussels and sea urchins. Finally, we address the potential of tick cement for the field of biomaterial research and in particular for medical applications in future. PMID- 29119725 TI - Systematic review and meta-analysis: non-invasive detection of non-alcoholic fatty liver disease related fibrosis in the obese. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a significant disease burden in obesity. Liver fibrosis is an important prognostic factor in NAFLD, and detection is vital. The pathophysiological changes of obesity can alter the accuracy of non-invasive NAFLD tests. We aimed to review current evidence for common non-invasive tests for NAFLD-related fibrosis in obesity. METHODS: We systematically searched for studies assessing the diagnostic accuracy of 11 biomarker panels and elastography techniques for NAFLD-related fibrosis in obesity. Meta-analyses were performed where possible. RESULTS: Thirty-eight studies were identified assessing the selected tests in obese populations. Simple biomarker panels (e.g. NAFLD fibrosis score) were the most validated. Evidence showed better accuracy of complex biomarker panels (NAFLD fibrosis score: summary receiver operator characteristic [SROC] 0.795-0.813 vs. enhanced liver fibrosis: SROC 0.962); however, these were poorly validated in obesity. Elastography techniques were better studied and had high diagnostic accuracy (transient elastography: SROC 0.859; magnetic resonance elastography: SROC 0.965) but were limited by BMI-dependent failure. Limited evidence was found to validate the accuracy of any test in exclusively obese populations. CONCLUSION: In obese subjects, complex biomarker panels and elastography have been reasonable to good accuracy for NAFLD-related fibrosis; however, these methods have not been well validated. Further study in this high-risk population is needed. PMID- 29119726 TI - Cotrimoxazole prophylaxis was associated with enteric commensal bacterial resistance among HIV-exposed infants in a randomized controlled trial, Botswana. AB - INTRODUCTION: Despite declining risk of vertical HIV transmission, prophylactic cotrimoxazole (CTX) remains widely used to reduce morbidity and mortality in the event of HIV infection among exposed infants, with an inherent risk of conferring commensal antimicrobial resistance. Using data from a randomized, placebo controlled trial of infant CTX prophylaxis, we sought to quantify emergence of antibiotic resistance. METHODS: HIV-exposed uninfected infants enrolled in the Botswana Mpepu study were randomized to prophylactic CTX or placebo between 14 and 34 days of life and continued through 15 months. Stool samples were collected from a subset of participating infants at randomization, three, and six months, and stored at -70 degrees C prior to culture. Specimens that grew Escherichia coli (E. coli) or Klebsiella species (Klebsiella spp.) underwent antibiotic susceptibility testing by Kirby Bauer method using CTX (CTX 1.25/23.75 MUg) and Amoxicillin (10 MUg) in Mueller Hinton agar. Fisher's exact testing was used to compare prevalence of resistance by randomization arm (CTX/placebo). RESULTS AND DISCUSSION: A total of 381 stool samples from 220 infants were cultured: 118 at randomization, 151 at three months, and 112 at six-months. E. coli was isolated from 206 specimens and Klebsiella spp. from 138 specimens. Resistance to CTX was common in both E. coli and Klebsiella spp. at the randomization visit (52.2% and 37.7% respectively) and did not differ by study arm. E. Coli isolates from CTX recipients at three and six months had 94.9% and 84.2% CTX resistance, as compared with 51.4% and 57.5% CTX resistance in isolates from placebo recipients (p=0.01). Klebsiella spp. isolates from CTX recipients had 79.0% and 68.8% CTX resistance at three and six months, as compared with 19.1% and 14.3% in isolates from placebo recipients (p<0.01). CONCLUSIONS: HIV-exposed infants randomized to CTX prophylaxis had increased CTX-resistant commensal gastrointestinal bacteria compared with placebo recipients. Additional research is needed to determine the longer-term clinical, microbiologic, and public health consequences of antimicrobial resistance selected by infant CTX prophylaxis. PMID- 29119727 TI - Monosodium glutamate suppresses the female reproductive function by impairing the functions of ovary and uterus in rat. AB - The aim of the present study was to examine the effect of monosodium glutamate (MSG) on the functions of ovary and uterus in rat. Virgin female rats of Charles Foster strain (120 gms approximately) were administrated MSG by oral gavage at a dose level of 0.8, 1.6, 2.4 gm/kgBW/day, respectively for 30 and 40 days duration. We observed a significant decrease in the duration of proestrus, estrus and metestrus phases, and increase in the duration of diestrus phase and diestrus index compared to control. We found significant increase in the levels of serum LH, FSH and estradiol in test groups of rat. We also observed significant increase in the number of primary and primordial follicles, increase in the size of graafian follicle, and decrease in the size of corpus luteum. Further, we have seen significant increase in the activities SOD, CAT and GST, decrease in the activities GR and GPx, and decrease MDA level in MSG exposed groups. These results suggest that MSG impairs the functions of the ovary probably by augmenting the release of FSH, LH and estradiol; promoting the follicular maturation and improving the biochemical mechanism for antioxidant defense. We also observed significant potentiation of the force of contraction of uterus in estrus, metestrus and diestrus phases. This result suggests that MSG potentiates the contraction of uterus probably by stimulating the estradiol sensitivity to oxytocin. From the results it is concluded that MSG suppresses the female reproductive function in rat probably by impairing the functions of ovary and uterus. PMID- 29119728 TI - A framework for designing patient-specific bioprosthetic heart valves using immersogeometric fluid-structure interaction analysis. AB - Numerous studies have suggested that medical image derived computational mechanics models could be developed to reduce mortality and morbidity due to cardiovascular diseases by allowing for patient-specific surgical planning and customized medical device design. In this work, we present a novel framework for designing prosthetic heart valves using a parametric design platform and immersogeometric fluid-structure interaction (FSI) analysis. We parameterize the leaflet geometry using several key design parameters. This allows for generating various perturbations of the leaflet design for the patient-specific aortic root reconstructed from the medical image data. Each design is analyzed using our hybrid arbitrary Lagrangian-Eulerian/immersogeometric FSI methodology, which allows us to efficiently simulate the coupling of the deforming aortic root, the parametrically designed prosthetic valves, and the surrounding blood flow under physiological conditions. A parametric study is performed to investigate the influence of the geometry on heart valve performance, indicated by the effective orifice area and the coaptation area. Finally, the FSI simulation result of a design that balances effective orifice area and coaptation area reasonably well is compared with patient-specific phase contrast magnetic resonance imaging data to demonstrate the qualitative similarity of the flow patterns in the ascending aorta. PMID- 29119729 TI - Efficacy of statin delivery as an adjunct to scaling and root planing in the treatment of chronic periodontitis: A meta-analysis. AB - The action of statins in stimulating bone formation and having other pleiotropic effects, such as anti-inflammatory and immunomodulatory effects, has justified their use as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis (CP). The aim of the present study was to evaluate the efficacy of statin delivery as an adjunct to SRP in the treatment of CP. Electronic searches were conducted using the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register, up until July 2017. The primary outcome was probing depth (PD), while the secondary outcomes were changes in clinical attachment level (CAL) and bone defect (BD) fill. Eleven studies were included, and all showed significant PD reduction, CAL gain, and BD fill with adjunctive statin delivery compared to SRP alone. The meta-analysis showed significant improvement in periodontal parameters for atorvastatin (PD: weighted mean difference [WMD] = 1.84, -2.56 to -1.12, P < .001; CAL: WMD = -2.31, -3.58 to -1.03, P < .001; BD fill: WMD = 2.66, -3.92 to -1.39, P < .001), simvastatin (PD: WMD = -1.91, -2.27 to -1.55, P < .001; CAL: WMD = -1.91, -2.27 to -1.55, P = .001; BD: WMD = -1.52, 2.20 to -0.85, P < .001), and rosuvastatin (PD: WMD = -0.94, -1.32 to -0.55, P < .001; CAL: WMD = -1.00, -1.41 to -0.60, P < .001; BD fill: WMD = -1.30, -1.80 to 0.79, P < .001). Adjunctive statin delivery appears to be effective in reducing PD, CAL gain, and BD fill in CP, and therefore, these drugs could be a promising therapeutic option for periodontal regeneration in future. PMID- 29119731 TI - Development and current clinical application of ventricular assist devices in China. AB - Heart failure has become one of the biggest threats to human health. Transplantation remains the most effective therapy for heart failure, but because of the shortage of donors, it cannot meet the demand. Ventricular assist devices (VADs) were developed to treat heart failure, and have now been clinically applied worldwide. As the country with the largest population, China is also facing the threat of heart failure. However, the development of VADs in China is very slow and is seldom discussed. This paper first talks about the background for VAD development in China. Then several home-developed VADs in China are introduced. The current clinical application status of VADs in China is also presented. Finally the challenge and opportunity for VAD development in China are discussed. PMID- 29119730 TI - Nuclear magnetic resonance spectroscopy as a new approach for improvement of early diagnosis and risk stratification of prostate cancer. AB - Prostate cancer (PCa) is the second most common male cancer worldwide and the fifth leading cause of death from cancer in men. Early detection and risk stratification is the most effective way to improve the survival of PCa patients. Current PCa biomarkers lack sufficient sensitivity and specificity to cancer. Metabolite biomarkers are evolving as a new diagnostic tool. This review is aimed to evaluate the potential of metabolite biomarkers for early detection, risk assessment, and monitoring of PCa. Of the 154 identified publications, 27 and 38 were original papers on urine and serum metabolomics, respectively. Nuclear magnetic resonance (NMR) is a promising method for measuring concentrations of metabolites in complex samples with good reproducibility, high sensitivity, and simple sample processing. Especially urine-based NMR metabolomics has the potential to be a cost-efficient method for the early detection of PCa, risk stratification, and monitoring treatment efficacy. PMID- 29119732 TI - Metabolic benefits of rivaroxaban in non-valvular atrial fibrillation patients after radiofrequency catheter ablation. AB - BACKGROUND AND OBJECTIVE: Rivaroxaban is a new oral anticoagulant for stroke prevention in patients with non-valvular atrial fibrillation (NVAF), which has less drug-food interaction than warfarin. We conducted this prospective randomized study to evaluate the metabolic benefits as well as the safety and efficacy with rivaroxaban versus warfarin in patients with NVAF following radiofrequency catheter ablation (RFCA). METHODS: From April to July 2014, 60 patients with NVAF undergoing RFCA were prospectively enrolled in our study. Following RFCA, all patients were randomly assigned to receive rivaroxaban (Group R, n=30) or warfarin (Group W, n=30). Metabolic indices including serum total protein, albumin, globulin, and high-density lipoprotein (HDL) as well as bleeding, stroke, and systemic thromboembolism events were evaluated and compared during follow-up after 15, 30, 60, and 90 d of RFCA procedure. RESULTS: Serum total protein, albumin, globulin, and HDL levels were all significantly elevated at each follow-up stage in Group R when compared to the baseline (P<0.05 respectively). In Group W, the metabolic indices decreased at first and then had an increasing trend. There were no deaths or thromboembolic complications in each group. The prevalence of total bleeding complications was similar between Group R and Group W (11/30, 36.7% vs. 10/30, 33.3%, P=0.79). CONCLUSIONS: Patients with NVAF receiving rivaroxaban after RFCA procedures appear to benefit from a metabolic perspective compared with warfarin, providing practical clinical reference for the choice of the anticoagulant. Rivaroxaban seems to be as safe and effective in preventing thromboembolic events as warfarin for these patients. PMID- 29119733 TI - Administration of fentanyl via a slow intravenous fluid line compared with rapid bolus alleviates fentanyl-induced cough during general anesthesia induction. AB - OBJECTIVE: Fentanyl-induced cough (FIC) is a common complication with a reported incidence from 18.0% to 74.4% during general anesthesia induction. FIC increases the intrathoracic pressure and risks of postoperative nausea and vomiting, yet available treatments are limited. This study was designed to investigate whether administering fentanyl via a slow intravenous fluid line can effectively alleviate FIC during induction of total intravenous general anesthesia. METHODS: A total number of 1200 patients, aged 18-64 years, were enrolled, all of whom were American Society of Anesthesiologists (ASA) grade I or II undergoing scheduled surgeries. All patients received total intravenous general anesthesia, which was induced sequentially by midazolam, fentanyl, propofol, and cisatracurium injection. Patients were randomly assigned to receive fentanyl 3.5 MUg/kg via direct injection (control group) or via a slow intravenous fluid line. FIC incidence and the severity grades were analyzed with the Mann-Whitney test. Other adverse reactions, such as hypotension, hypertension, bradycardia, tachycardia, hypoxemia, vomiting, and aspiration, during induction were also observed. The online clinical registration number of this study was ChiCTR-IOR 16009025. RESULTS: Compared with the control group, the incidence of FIC was significantly lower in the slow intravenous fluid line group during induction (9.1%, 95% confidence interval (CI): 6.7%-11.4% vs. 55.9%, 95% CI: 51.8%-60.0%, P=0.000), as were the severity grades (P=0.000). There were no statistical differences between the two groups with regard to other adverse reactions (P>0.05). CONCLUSIONS: The administration of fentanyl via a slow intravenous fluid line can alleviate FIC and its severity during induction for total intravenous general anesthesia. This method is simple, safe, and reliable, and deserves clinical expansion. PMID- 29119734 TI - Tissue-engineered composite scaffold of poly(lactide-co-glycolide) and hydroxyapatite nanoparticles seeded with autologous mesenchymal stem cells for bone regeneration. AB - OBJECTIVE: A new therapeutic strategy using nanocomposite scaffolds of grafted hydroxyapatite (g-HA)/ poly(lactide-co-glycolide) (PLGA) carried with autologous mesenchymal stem cells (MSCs) and bone morphogenetic protein-2 (BMP-2) was assessed for the therapy of critical bone defects. At the same time, tissue response and in vivo mineralization of tissue-engineered implants were investigated. METHODS: A composite scaffold of PLGA and g-HA was fabricated by the solvent casting and particulate-leaching method. The tissue-engineered implants were prepared by seeding the scaffolds with autologous bone marrow MSCs in vitro. Then, mineralization and osteogenesis were observed by intramuscular implantation, as well as the repair of the critical radius defects in rabbits. RESULTS: After eight weeks post-surgery, scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) revealed that g-HA/PLGA had a better interface of tissue response and higher mineralization than PLGA. Apatite particles were formed and varied both in macropores and micropores of g-HA/PLGA. Computer radiographs and histological analysis revealed that there were more and more quickly formed new bone formations and better fusion in the bone defect areas of g-HA/PLGA at 2-8 weeks post-surgery. Typical bone synostosis between the implant and bone tissue was found in g-HA/PLGA, while only fibrous tissues formed in PLGA. CONCLUSIONS: The incorporation of g-HA mainly improved mineralization and bone formation compared with PLGA. The application of MSCs can enhance bone formation and mineralization in PLGA scaffolds compared with cell-free scaffolds. Furthermore, it can accelerate the absorption of scaffolds compared with composite scaffolds. PMID- 29119735 TI - Poly(D,L-lactic-co-glycolic acid)-based artesunate nanoparticles: formulation, antimalarial and toxicity assessments. AB - OBJECTIVE: The aim of this study was to formulate polymer-based artesunate nanoparticles for malaria treatment. METHODS: Artesunate was loaded with poly(D,L lactic-co-glycolic acid) (PLGA) by solvent evaporation from an oil-in-water single emulsion. Nanoparticles were characterized by X-ray diffraction and differential scanning calorimetry analyses. In vivo antimalarial studies at 4 mg/kg were performed on Swiss male albino mice infected with Plasmodium berghei. Hematological and hepatic toxicity assays were performed. In vitro cytotoxicity of free and encapsulated artesunate (Art-PLGA) to cell line RAW 264.7 was determined at concentrations of 7.8-1000 ug/ml. RESULTS: The particle size of the formulated drug was (329.3+/-21.7) nm and the entrapment efficiency was (38.4+/ 10.1)%. Art-PLGA nanoparticles showed higher parasite suppression (62.6%) compared to free artesunate (58.2%, P<0.05). Platelet counts were significantly higher in controls (305 000.00+/-148 492.40) than in mice treated with free artesunate (139 500.00+/-20 506.10) or Art-PLGA (163 500.00+/-3535.53) (P<0.05). There was no sign of hepatic toxicity following use of the tested drugs. The half maximal inhibitory concentration (IC50) of Art-PLGA (468.0 ug/ml) was significantly higher (P<0.05) than that of free artesunate (7.3 ug/ml) in the in vitro cytotoxicity assay. CONCLUSIONS: A simple treatment of PLGA-entrapped artesunate nanoparticles with dual advantages of low toxicity and better antiplasmodial efficacy has been developed. PMID- 29119736 TI - Yimu San improves obstetric ability of pregnant mice by increasing serum oxytocin levels and connexin 43 expression in uterine smooth muscle. AB - Prolonged farrowing remains one of the critical challenges in intensive pig farming. This study aims to explore the effects and mechanism of Yimu San (YMS), a Chinese veterinary medicine micro mist, on delivery ability with mouse models. Thirty-two pregnant mice were randomly divided into a control group and low-YMS, med-YMS, and high-YMS groups. The labor process time and stillbirth rate were recorded, the levels of serum oxytocin and prostaglandin E2 (PGE2) were measured with enzyme-linked immunosorbent assay (ELISA). Contractility measurements of the isolated uterus and the expression of connexin 43 (Cx43) in uterine smooth muscle were evaluated. The results showed that compared with the control group, the birth process time and stillbirth rate in the med-YMS and high-YMS groups were remarkably lower. The in vitro uterine contractions, levels of oxytocin, PGE2, and Cx43 in the med-YMS and high-YMS groups were significantly higher than those in the control group. The differences of the above measurements between the low YMS group and the control group were not obvious. It can be speculated that YMS could significantly promote labor in pregnant mice by enhancing the levels of oxytocin, Cx43, and PGE2. PMID- 29119737 TI - Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study. AB - Accumulating evidence indicates that endostatin inhibits fibrosis. However, the mechanism is yet to be clarified. The aim of this study is to evaluate the effect of endostatin on platelet-derived growth factor-BB (PDGF-BB)- or transforming growth factor beta1 (TGF-beta1)-induced fibrosis in cultured human skin fibroblasts, and to further examine the molecular mechanisms involved. Human dermal fibroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM) and serum-starved for 48 h before treatment. Cells were grouped as follows: "PDGF BB", "PDGF-BB+ endostatin", "TGF-beta1", "TGF-beta1+endostatin", "endostatin", and "blank control". The fibroblasts were stimulated with either TGF-beta1 or PDGF-BB for 72 h in order to set up the fibrosis model in vitro. The cells were co-cultured with either TGF-beta1 or PDGF-BB and endostatin and were used to check the inhibiting effect of endostatin. A blank control group and an endostatin group were used as negative control groups. The biomarkers of fibrosis, including the expression of collagen I, hydroxyproline, and alpha smooth muscle actin (alpha-SMA), were evaluated using an enzyme-linked immunosorbent assay (ELISA) and Western blot. The expression of phosphorylated PDGF receptor beta (p-PDGFRbeta), PDGFRbeta, phosphorylated extracellular signal regulated kinase (p-ERK), and ERK was detected using Western blot and immunofluorescent staining was used to explore the mechanisms. Both PDGF-BB and TGF-beta1 significantly up-regulated the expression of collagen I, hydroxyproline, and alpha-SMA. Endostatin significantly attenuated both the PDGF BB- and TGF-beta1-induced over-expression of collagen I, hydroxyproline, and alpha-SMA. PDGF-BB and TGF-beta1 both promoted the expression of PDGFR, ERK, and p-ERK. Endostatin inhibited the expression of PDGFR and p-ERK but did not affect the expression of total ERK. Endostatin inhibited hypertrophic scar by modulating the PDGFRbeta/ERK pathway. Endostatin could be a promising multi-target drug in future fibrosis therapy. PMID- 29119738 TI - Physiological characterization, transcriptomic profiling, and microsatellite marker mining of Lycium ruthenicum. AB - Lycium ruthenicum is a perennial shrub species that has attracted considerable interest in recent years owing to its nutritional value and ability to thrive in a harsh environment. However, only extremely limited transcriptomic and genomic data related to this species can be found in public databases, thereby limiting breeding research and molecular function analysis. In this study, we characterized the physiological and biochemical responses to saline-alkaline mixed stress by measuring photochemical efficiency, chlorophyll content, and protective enzyme activity. We performed global transcriptomic profiling analysis using the Illumina platform. After optimizing the assembly, a total of 68 063 unique transcript sequences with an average length of 877 bp were obtained. Among these sequences, 4096 unigenes were upregulated and 4381 unigenes were down regulated after saline-alkaline mixed treatment. The most abundant transcripts and over-represented items were assigned to gene ontology (GO) terms or Kyoto Encyclopedia of Genes and the Genomes (KEGG) categories for overall unigenes, and differentially expressed unigenes were analyzed in detail. Based on this set of RNA-sequencing data, a total of 9216 perfect potential simple sequence repeats (SSRs) were identified within 7940 unigenes with a frequency of 1/6.48 kb. A total of 77 primer pairs were synthesized and examined in wet-laboratory experiments, of which 68 loci (88.3%) were successfully amplified with specific products. Eleven pairs of polymorphic primers were verified in 225 individuals from nine populations. The inbreeding coefficient and the polymorphism information content value ranged from 0.011 to 0.179 and from 0.1112 to 0.6750, respectively. The observed and expected heterozygosities ranged from 0.064 to 0.840 and from 0.115 to 0.726, respectively. Nine populations were clustered into three groups based on a genetic diversity study using these novel markers. Our data will be useful for functional genomic investigations of L. ruthenicum and could be used as a basis for further research on the genetic diversity, genetic differentiation, and gene flow of L. ruthenicum and other closely related species. PMID- 29119739 TI - Fertility outcomes in infertile women with complex hyperplasia or complex atypical hyperplasia who received progestin therapy and in vitro fertilization. AB - This study aimed to evaluate fertility and oncologic outcomes in women with complex hyperplasia (CH) or complex atypical hyperplasia (CAH) who received fertility-sparing therapy and in vitro fertilization (IVF). Endometrial carcinoma is the most common carcinoma of the female genital tract, and is associated with endometrial hyperplasia (EH) resulting from long-term unopposed estrogenic stimulation of the endometrium. EH is characterized by non-physiological proliferation of endometrium that results in glands with irregular shapes and varying sizes. The World Health Organization (WHO) classified it into four types: simple or complex hyperplasia with or without atypia. CH is characterized by glands with irregular outlines that demonstrate marked structural complexity and back-to-back crowding. Atypical hyperplasia designates a proliferation of glands exhibiting cytologic atypia, in which varying degrees of nuclear atypia and loss of polarity are present. It has been reported that high-dose progestin is safe and efficient for CAH or early-stage low-grade carcinoma for young women who desire fertility-preserving treatment. However, few studies have reported the differences of pregnancy outcomes between patients with CAH and CH, while those patients take a great proportion in people suffered from infertility. More studies about the outcome of IVF are needed. Our aim is to evaluate fertility and oncological outcomes in women with CH or CAH who received fertility-sparing therapy. PMID- 29119740 TI - Breast metastasis of gastric signet-ring cell carcinoma. AB - Metastatic breast involvement from extra-mammary neoplasms is unusual with a low incidence of 0.5% to 1.2% in clinical practice, 2.7% in cytological series, and 1.7% to 6.6% in autopsy series of all breast malignancies. Nearly 500 cases have been reported in small series and case reports. Gastric carcinoma rarely metastasizes to the breast. There are only 38 cases reported in PubMed. In this study, we present a case report of a 49-year-old woman who was diagnosed with right breast metastasis from a gastric carcinoma and undertake a literature review to pay attention to the diagnosis, treatment, and the prognosis of the disease. PMID- 29119741 TI - Supervised toothbrushing programs in primary schools and early childhood settings: A scoping review. AB - OBJECTIVE: In this article we report the findings of a scoping review that aimed to identify and summarise the range of programs and guidelines available for toothbrushing programs in schools and early childhood settings. Dental caries is one of the most common preventable diseases affecting children worldwide. Untreated caries can impact on child health and wellbeing, development, socialisation and school attendance. Supervised toothbrushing programs in schools and other early childhood settings can be effective in improving the oral health of young children. There is limited understanding of the salient issues to consider when developing such programs or how they are best implemented in real world settings. METHODS: A scoping review methodology was utilised to provide a summary of the guidelines and programs available. Key search terms were developed, mapped and utilised to identify guidelines and programs across 6 databases and key search engines. RESULTS: We located 26 programs and guidelines that met the inclusion and exclusion criteria for the review. These were collated and summarised across key countries and critical aspects of program development and implementation were identified. Toothbrush type and storage, toothpaste strength and method of dispensing, toothbrush storage, staff training and parental consent are key considerations that varied widely. CONCLUSIONS AND RECOMMENDATIONS: Guidelines for supervised toothbrushing programs vary within and across countries due to differences in water fluoridation and availability of low fluoride toothpastes. The results of this review provide critical information to be considered when establishing and implementing toothbrushing programs in these settings. PMID- 29119742 TI - Super-resolution structured illumination in optically thick specimens without fluorescent tagging. AB - This research extends the work of Hoffman et al. to provide both sectioning and super-resolution using random patterns within thick specimens. Two methods of processing structured illumination in reflectance have been developed without the need for a priori knowledge of either the optical system or the modulation patterns. We explore the use of two deconvolution algorithms that assume either Gaussian or sparse priors. This paper will show that while both methods accomplish their intended objective, the sparse priors method provides superior resolution and contrast against all tested targets, providing anywhere from ~1.6* to ~2* resolution enhancement. The methods developed here can reasonably be implemented to work without a priori knowledge about the patterns or point spread function. Further, all experiments are run using an incoherent light source, unknown random modulation patterns, and without the use of fluorescent tagging. These additional modifications are challenging, but the generalization of these methods makes them prime candidates for clinical application, providing super resolved noninvasive sectioning in vivo. PMID- 29119743 TI - Managing chronic oedema and wet legs in the community: a service evaluation. AB - : Patients with chronic oedema and 'wet legs' are frequently seen in the community setting, with research indicating that more than half of community nurses' caseloads are patients with chronic oedema. However, a lack of nurse education and standardised care pathways for this condition has been identified. In June 2016, the Welsh Government supported the development of the On the Ground Education Project (OGEP), which aimed to raise community nurses' awareness and recognition of chronic oedema and wet legs, to improve the management of these conditions, and to support the efficient use of community nurses' time and resources. AIM: To investigate the potential economic benefits of the OGEP and its effects on patients' quality of life. METHOD: The OGEP was implemented between June 2016 and March 2017. During this time, 725 patients were assessed and chronic oedema was diagnosed in 426 (59%) of them. Of these, 100 patients were purposively recruited and 97 completed the pilot service evaluation. Data were collected observationally before and after the OGEP was implemented. Baseline measurements of resources, costs and outcomes were captured at the time the patients were initially identified and at a follow-up review three months later. The EQ-5D-5L tool was used to measure patients' health-related quality of life before and after the OGEP was implemented. Data were analysed using Microsoft Excel and SPSS Version 22. RESULTS: Following implementation of the OGEP, there was a significant decrease in the number of district nurse home visits, (P=<0.001), GP surgery appointments (P=0.003) and episodes of cellulitis (P=<0.001). The EQ-5D-5L utility scores showed that patients' quality of life improved after the OGEP was implemented, from a baseline of 0.401 (SD 0.254) to 0.537 (SD 0.231) at the three-month follow-up review. CONCLUSION: The OGEP may support the efficient use of community nurses' time and resources, reduce costs to the NHS, and improve the quality of life of patients with chronic oedema and wet legs. PMID- 29119744 TI - Cardiac monitoring and the use of a systematic approach in interpreting electrocardiogram rhythms. AB - Attaching a patient to a cardiac monitor and obtaining a clear electrocardiogram (ECG) trace may now be considered basic nursing skills. In line with the UK professional standards and code of conduct, healthcare practitioners are required to practise effectively and preserve patients' safety. Therefore, healthcare practitioners undertaking cardiac monitoring are required to have a basic understanding of normal sinus rhythms and some of the common types of cardiac arrhythmia. This will enable prompt recognition of early warning signs of potential and actual clinical conditions, and the timely initiation of treatment. This article reviews the clinical skill of attaching a patient to a three and five-lead cardiac monitor, discussing appropriate skin preparation and lead selection. It also outlines the identification of several of the common types of cardiac arrhythmia on an ECG rhythm strip using a systematic approach. PMID- 29119745 TI - [Aetiological studies, impact assessments, and epidemiology in the Court]. PMID- 29119746 TI - [Epidemiological studies and preventive impact assessments in contaminated areas]. PMID- 29119747 TI - [Restarting with prevention?] PMID- 29119748 TI - [The Country of fires. Fire emergency in Summer 2017 in Italy: impact on health and environment]. PMID- 29119749 TI - [Treating the mind is good for the heart]. PMID- 29119750 TI - [Acting to avoid post-truth]. PMID- 29119751 TI - [Mediterranean diet for everyone]. PMID- 29119752 TI - [The XLI Conference of the Italian Epidemiological Association. Epidemiology nowadays: evidence, communication, and participation]. PMID- 29119753 TI - [PFASs pollution in Veneto Region (Northern Italy). After USA, it is the turn of Italy]. PMID- 29119754 TI - [Epidemiological survey in Brindisi (Apulia Region, Southern Italy): informing citizens, making decisions, and acting is essential]. PMID- 29119755 TI - [We conduct studies, and then?] PMID- 29119756 TI - [The opponent you do not just imagine. The case of Falconara Marittima (Marche Region, Central Italy)]. AB - Falconara Marittima (Marche Region, Central Italy) is declared to be an area at high risk of environmental crisis, due to the presence of a refinery plant. In 2004, Marche Region funded an epidemiological survey to assess atmospheric risks linked to the refinery. This survey was conducted by the Italian National Cancer Institute of Milan, and citizens actively contributed. An excess for leukaemias and an increase in non-Hodgkin lymphomas were showed. These results were confirmed also by the Regional Environmental Protection Agency and the Regional Health Authority. But Marche Region and the Municipalities chose to not report the situation: the same Institutions, which at the beginning sided the citizens, became an opponent for health protection. PMID- 29119758 TI - [On vaccines, physicians, and expulsion from the college of physicians]. PMID- 29119757 TI - [Excess deaths for haematological tumours in Falconara Marittima (Marche Region, Central Italy): short story from the epidemiological survey up to now]. AB - API is a company refining petroleum products located in Falconara Marittima (Ancona Province, Marche Region, Central Italy). Thanks to the pressure made by citizens' committees, which considered the plant as a risk source for the population residing in the surroundings municipalities, Marche Region as institution asked for an epidemiological survey. This survey found a significative excess in deaths for haematological tumours in women and in a sub group of retired and elderly. The results were published in one report and two scientific journals, and were also presented during a public meeting. It was urgent to made public health intervention, which were called for, but up to now nothing has been done. Here, the reconstruction of this affair, from the start of the epidemiological survey up to the more recent development in terms of public health. PMID- 29119759 TI - [Admission test to the degree course in Medicine and Surgery and university career: the experience in the campuses of Piedmont Region (Northern Italy)]. AB - OBJECTIVES: to consider the admission test to the degree course in Medicine and Surgery in the three campus of Piedmont Region (Northern Italy) in order to discuss the ability of this test to predict the academic outcome of the students. DESIGN: cohort study considering all the students enrolled in the first year of medicine during the academic year 2014-2015. Their academic career is monitored during the period January 2015-February 2016. SETTING AND PARTICIPANTS: a total of 781 students is considered and divided into two groups: regular (registered after passing the admission test; n. 605) and TAR (registered after court decision and having won the case in tribunal; n. 176). MAIN OUTCOME MEASURES: the study is based on three indicators of performance: A1. at least one of the required exams in the first year passed; A2. at least half of the required exams in the first year passed; A3. all the exams required in the first year passed. Statistical analyses are based on: positive predictive value and relative 95% confidence interval; odds ratio and relative 95% confidence intervals, adjusted by sex, age, high school type, and vote estimated by logistic regression models. RESULTS: the results highlight the good prediction of the admission test that remains significant even after adjustment for the confounding factors considered. CONCLUSIONS: the major limits are the short period of observation and the restricted number of campus considered. However, this analysis confirms the importance of the admission test. In fact, students with low scores in the test could show serious disadvantages in passing the exams (in the appointed time) in the first year. PMID- 29119760 TI - [Tuberculosis in Prato (Tuscany Region, Central Italy) in the period 2007-2014]. AB - OBJECTIVES: a description of the epidemiology of tuberculosis in the province of Prato (Tuscany Region, Central Italy) during the period 2007-2014 and verify the latency time between the onset of symptoms and the start of therapy. DESIGN: descriptive, observational study. SETTING AND PARTICIPANTS: tuberculosis cases were identified for the period 2007-2014 through an analysis of the notification files available at the Hygiene and Public Health Service of the Local Health Unit of Prato and through the Information System on Infectious Diseases database. RESULTS: in the years 2007-2014, 619 cases of tuberculosis were reported in the province of Prato, of which 465 (75.12%) were cases of pulmonary TB. The annual rate ranges from 35.2 cases per 100.00 inhabitants in 2010 to 18.5 cases per 100.000 inhabitants in 2012. The median age of foreign-born patients was significantly lower than the one of Italian-born subjects (34 years; interquartile range - IQR: 28-41 vs. 63 years; IQR: 45-77; <0.0001). The rate of cases in patients above 64 years and below 64 years was significantly different between Italian and foreign subjects (<0.01); this dissimilarity remained significant even after stratification by gender. Males were the most affected, in line with regional and national data. The average delay between the date of onset of symptoms and the initiation of therapy was 59 days (IQR: 28-104). CONCLUSIONS: tuberculosis is a complex disease both from an epidemiological and a clinical point of view. This complexity is more relevant in areas where different ethnic groups live together. The data presented in this paper show the necessity of an intervention to improve access to healthcare facilities through a deep collaboration among who works in public health, in general medicine, and in the multidisciplinary integrated care of the considered area. PMID- 29119761 TI - [Mortality of immigrants in Tuscany Region (Central Italy), 1997-2013]. AB - OBJECTIVES: to evaluate mortality in immigrants dwelling in Tuscany Region (Central Italy) compared to mortality data relating to the Italian population residing in the same region. DESIGN: cross-sectional descriptive mortality study relying on a unique data source, i.e., the Regional Mortality Registry of Tuscany, for the period 1997-2013. SETTING AND PARTICIPANTS: in the analysis, immigrants residing in Tuscany were included; Italian residing in the same region were the comparison population. Immigrants were divided into two categories: immigrants from Countries at High Migration Rates (CHMRs) and immigrants from Developed Countries (DCs). MAIN OUTCOME MEASURES: proportional general and cause specific mortality by age and gender for the period 1997-2013; trends of standardized truncated (age 20-64) mortality rates for the Italian population, and for immigrants from CHMRs and from DCs for the period 2002-2013; standardized mortality ratios (SMRs) in people from CHMRs with confidence interval at 95% (95%CI) for all causes and cause-specific mortality. RESULTS: during 1997-2013, 4,681 deaths were recorded among immigrants, 3,005 of which were in immigrants from a CHMR. Both cause-specific and general mortality trends in Italians and in immigrants from DCs are lowering, while general mortality of immigrants from CHMRs seems to have risen in the last 5 years. Mortality of people from CHMRs for all causes, cardiovascular causes, and cancer is permanently lower than Italian population's mortality in the examined period, but the gap seems to progressively reduce. On the other hand, child mortality among immigrants from CHMRs, despite a declining trend, is consistently higher than Italian population's mortality. Following the SMR analysis, the only exceeding cause of mortality in people from CHMRs - compared to the Italian population - is homicide among men (SMR: 3.46; 95%CI 1.55-5.59). CONCLUSIONS: this study updates our knowledge on immigrants' mortality - and, indirectly, on their health status - in Tuscany. The gap between mortality of Italians and immigrants from CHMRs is reducing: this could be partially explained by a successful ongoing integration process. For future analyses, it would be important to obtain more complete data relative to non resident immigrants' mortality, as their number is constantly increasing. PMID- 29119762 TI - [Mortality study update of workers exposed to vinyl chloride in plants located in Ferrara and Ravenna (Emilia-Romagna Region, Northern Italy)]. AB - OBJECTIVES: to update the mortality study of subjects exposed to vinyl chloride in the phases of synthesis of the monomer and polymerization in the plants of Ferrara and Ravenna (Emilia-Romagna Region, Northern Italy). DESIGN: both for the whole cohort and for the two plants, standardized mortality ratios (SMRs), with 95% confidence intervals (95%CI), were calculated for different death causes, then stratified by duration and latency, periods of the beginning of work and cumulative exposure (ppm-years). SETTING AND PARTICIPANTS: the cohort includes 1,540 subjects (469 in Ferrara hired from 1953 to 1999; 1,071 in Ravenna hired from 1959 to 2000), with at least six months of work. RESULTS: by the end of the follow-up (31.12.2013), 348 deaths occurred. Overall observed mortality, contrasted to that expected based on Emilia-Romagna Region mortality rates, appeared to be lower than expected in the whole cohort (348 cases, SMR: 0.85; 95%CI 0.77-0.95) and in Ravenna (173 cases, SMR: 0.71; 95%CI 0.61-0.83). Mortality for all neoplasms was in excess in Ferrara (79 cases, SMR: 1.27; 95%CI 1.02-1.58), but lower than expected in Ravenna (83 cases, SMR: 0.80; 95%CI 0.64 0.99). An excess in mortality was observed in the whole cohort (16 cases, SMR: 1.74; 95%CI 1.07-2.85) and in Ferrara for liver cancer (7 cases, SMR: 2.12; 95%CI 1.02-4.46), and only in Ferrara for respiratory tract cancer (30 cases, SMR: 1.45; 95%CI 1.02-2.07) and larynx cancer (4 cases, SMR: 3.35; 95%CI 1.26-8.92). In the whole cohort, SMR for liver cancer was in excess since a cumulative exposure of 5,000 ppm-year and 12 cases belong to the job title of autoclave workers (12 cases, SMR 4.6; 95%CI 2.6-8.0), duration of work higher than 20 years (8 cases, SMR 2.4; 95%CI 1.2-4.9), and latency higher than 40 years (7 cases, SMR 2.5; 95%CI 1.2-5.2). The excess in mortality for lung cancer is statistically significant for and with cumulative exposure higher than 7,330 ppm-years (6 cases, SMR 3.2 95%CI 1.4-7.0). There are not excesses among subjects hired after 1971. CONCLUSIONS: the study findings confirm and expand the ones of previous studies. It was not possible to apply a best evidence approach to the study of liver cancer, and consequently it is not possible to distinguish between hepatic angiosarcoma and hepatocellular carcinoma. The evidence of a causal link between vinyl chloride exposure and liver cancer is anyhow confirmed. The causal link between vinyl chloride exposure and lung cancer must be further investigated. PMID- 29119764 TI - [Is burnout a syndrome or an occupational disease? Instructions for occupational physicians]. AB - Since Herbert Freudenberger described Burnout Syndrome (BOS) in 1974, thousands of scientific papers have been published on this syndrome and this trend does not seem to diminish. After being internationally known as a syndrome characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment in helping professions, its construct has been criticized, questioned, and subjected to profound modifications. To date, however, in Italy and in many other Countries it is not possible to diagnose this syndrome, because World Health Organization, in its last ICD-10, did not indicate any clinical criteria to diagnose it. Unfortunately, not even in the recent DSM- 5 by American Psychiatric Association, contrary to what was expected, BOS found room as a specific psychiatric disorder. As a consequence, framing this syndrome from a medical legal point of view is still widely debated from scholars. PMID- 29119765 TI - [Social inequalities in health: a topic of interest (at last)]. PMID- 29119763 TI - [Systematic review of safeness and therapeutic efficacy of cannabis in patients with multiple sclerosis, neuropathic pain, and in oncological patients treated with chemotherapy]. AB - BACKGROUND: medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. In the United States, 23 states and Washington DC (May 2015) have introduced laws to permit the medical use of cannabis. Within the European Union, medicinal cannabis laws and praxis vary wildly between Countries. OBJECTIVES: to provide evidence for benefits and harms of cannabis (including extracts and tinctures) treatment for adults in the following indications: control of spasticity and pain in patients with multiple sclerosis; control of pain in patients with chronic neuropathic pain; control of nausea and vomiting in adults with cancer receiving chemotherapy. METHODS: we searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE from inception to September 2016. We also searched for on-going studies via ClinicalTrials.gov and the World Health Organization and International Clinical Trials Registry Platform (ICTRP) search portal. All searches included also non English language literature. All relevant randomized controlled trials (RCTs) evaluating the safety and efficacy of cannabis (including extracts and tinctures) compared with placebo or other pharmacological agents were included. Three authors independently evaluated the titles and abstracts of studies identified in the literature searches for their eligibility. For studies considered eligible, we retrieved full texts. Three investigators independently extracted data. For the assessment of the quality of evidence, we used the standard methodological procedures recommended by Cochrane and GRADE working Group. RESULTS: 41 trials (4,550 participants) were included; 15 studies considered efficacy and safety of cannabis for patients with multiple sclerosis, 12 for patients with chronic pain, and 14 for patients with cancer receiving chemotherapy. The included studies were published between 1975 and 2015, and the majority of them were conducted in Europe. We judged almost 50% of these studies to be at low risk of bias. The large majority (80%) of the comparisons were with placebo; only 8 studies included patients with cancer receiving chemotherapy comparing cannabis with other antiemetic drugs. Concerning the efficacy of cannabis (compared with placebo) in patients with multiple sclerosis, confidence in the estimate was high in favour of cannabis for spasticity (numerical rating scale and visual analogue scale, but not the Ashworth scale) and pain. For chronic and neuropathic pain (compared with placebo), there was evidence of a small effect; however, confidence in the estimate is low and these results could not be considered conclusive. There is uncertainty whether cannabis, including extracts and tinctures, compared with placebo or other antiemetic drugs reduces nausea and vomiting in patients with cancer requiring chemotherapy, although the confidence in the estimate of the effect was low or very low. In the included studies, many adverse events were reported and none of the studies assessed the development of abuse or dependence. CONCLUSIONS: there is incomplete evidence of the efficacy and safety of medical use of cannabis in the clinical contexts considered in this review. Furthermore, for many of the outcomes considered, the confidence in the estimate of the effect was again low or very low. To give conclusive answers to the efficacy and safety of cannabis used for medical purposes in the clinical contexts considered, further studies are needed, with higher quality, larger sample sizes, and possibly using the same diagnostic tools for evaluating outcomes of interest. PMID- 29119766 TI - [Big data versus randomized clinical trials? Nobody benefits from the contrast]. PMID- 29119767 TI - [Our brain in an ageing world]. PMID- 29119768 TI - [Cancer and work: world's impact estimates]. PMID- 29119769 TI - [The decree on registries: new opportunities for evaluation in orthopaedics]. PMID- 29119770 TI - [A structural health reform: pay health, not disease. Aligning the interests of the main actors to the ethics and health of the community of citizens]. PMID- 29119771 TI - [The Crisis of Science and Democracy: a voyage to a destination not yet revealed]. PMID- 29119772 TI - [Homo faber fortunae suae?] PMID- 29119773 TI - [Which efficacy trials for drugs for rare diseases?] PMID- 29119774 TI - Adherence to the 24-Hour Movement Guidelines among 10- to 17-year-old Canadians. AB - INTRODUCTION: The Canadian 24-Hour Movement Guidelines for Children and Youth were released in 2016. They contain specific recommendations on the daily time that 5- to 17-year-olds should devote to moderate-to-vigorous physical activity, recreational screen time, and sleep. The objective of this study was to estimate the proportion of Canadians aged 10 to 17 years that meet the recommendations contained within the 24-Hour Movement Guidelines for Children and Youth. METHODS: A nationally representative sample of 22 115 young people was examined. Movement behaviour data were self-reported. Adherence to the guideline recommendations were based on the following: accumulation of at least 60 minutes per day of moderate-to-vigorous physical activity, no more than 2 hours per day of recreational screen time, and 9 to 11 hours/night of uninterrupted sleep for those aged 10 to 13 years or 8 to 10 hours/night for those aged 14 to 17 years. RESULTS: Only 3% of the sample met all three of the key recommendations contained in the guidelines. Twenty-five percent met two of the recommendations, 51% met one of the recommendations, and 21% met none of the three recommendations. More children and youth met recommendations for sleep duration (66%) than for moderate to-vigorous physical activity (35%) and screen time (8%). CONCLUSION: A small minority (< 3%) of Canadians aged 10 to 17 years met all three of the key recommendations contained in the 24-Hour Movement Guidelines for Children and Youth. PMID- 29119775 TI - Binge drinking and academic performance, engagement, aspirations, and expectations: a longitudinal analysis among secondary school students in the COMPASS study. AB - INTRODUCTION: The longitudinal relationship between binge drinking and academic engagement, performance, and future aspirations and expectations was examined among a cohort of secondary school students. METHODS: In separate multinomial generalized estimating equations models, linked data from Year 1 (Y1: 2012-2013), Year 2 (Y2: 2013-2014), and Year 3 (Y3: 2014-2015) of the COMPASS study (N = 27 112) were used to test the relative likelihood of responses to seven academic indices when binge drinking was initiated in varying frequencies, adjusting for gender, grade, race/ethnicity, tobacco use, and the individual mean of the predictor and all time-varying covariates. RESULTS: Among students who had never engaged in binge drinking at baseline, those who reported regular binge drinking at follow-up were relatively less likely to complete their homework, attend class, and value and achieve high grades, with more frequent binge drinking at follow-up generally resulting in larger relative risk ratios. Interestingly, shifting from "never" to "rare/sporadic" binge drinking one to two years later resulted in an increased relative risk of wanting to pursue all levels of postsecondary education. Beginning binge drinking on a "monthly" basis also increased the likelihood of college/ trade or bachelor degree ambitions, relative to high school, but not graduate/professional pathways; while degree aspirations were not associated with initiating weekly binge drinking. CONCLUSION: Results suggest students who initiate binge drinking have poor school performance and engagement, which may interfere with achieving their future academic goals. This study reinforces the reasons substance use prevention should be considered an academic priority, as such efforts may also prove beneficial for educational achievement. PMID- 29119777 TI - Release notice - Cancer in Young People in Canada: a report from the Enhanced Childhood Cancer Surveillance System. PMID- 29119776 TI - Between worst and best: developing criteria to identify promising practices in health promotion and disease prevention for the Canadian Best Practices Portal. AB - INTRODUCTION: In health promotion and chronic disease prevention, both best and promising practices can provide critical insights into what works for enhancing the healthrelated outcomes of individuals and communities, and how/why these practices work in different situations and contexts. METHODS: The promising practices criteria were developed using the Public Health Agency of Canada's (PHAC's) existing best practices criteria as the foundation. They were modified and pilot tested (three rounds) using published interventions. Theoretical and methodological issues and challenges were resolved via consultation and in-depth discussions with a working group. RESULTS: The team established a set of promising practices criteria, which differentiated from the best practices criteria via six specific measures. CONCLUSION: While a number of complex challenges emerged in the development of these criteria, they were thoroughly discussed, debated and resolved. The Canadian Best Practices Portal's screening criteria allow one to screen for both best and promising practices in the fields of public health, health promotion, chronic disease prevention, and potentially beyond. PMID- 29119778 TI - Correlation Between Concentration of Air Pollutants and Occurrence of Cardiac Arrhythmias in a Region with Humid Continental Climate AB - In this study, we investigated the correlation of air temperature, pressure and concentrationof air pollutants with the rate of admissions for cardiac arrhythmias at two clinical centersin the area with a humid continental climate. This retrospective study included 3749 patients witharrhythmias admitted to emergency department (ED). They were classified into four groups: supraventriculartachycardia (SVT), ventricular tachycardia (VT), atrial fibrillation/undulation (Afib/Aund),and palpitations (with no ECG changes, or with sinus tachycardia and extrasystoles). Thenumber of patients, values of meteorological parameters (average daily values of air temperature,pressure and relative humidity) and concentrations of air pollutants (particles of dimensions ~10micrometers or less (PM(10)), ozone (O(3)) and nitrogen dioxide (NO(2))) were collected during a two-yearperiod ( July 2008-June 2010). There were 1650 (44.0%), 1525 (40.7%), 451 (12.0%) and 123 (3.3%)patients with palpitations, Afib/Aund, SVT and VT, respectively. Spearman's correlation yieldedpositive correlation between the occurrence of arrhythmias and air humidity on the day (r=0.07), and1 (r=0.08), 2 (r=0.09) and 3 days before (r=0.09), and NO(2) particles on the day (r=0.08) of ED admission;palpitations and air humidity on the day (r=0.11), and 1 (r=0.09), 2 (r=0.07) and 3 days before(r=0.10), and PM(10) (r=0.11) and NO(2) (r=0.08) particles on the day of ED admission; and Afi b/Aundand air humidity 2 days before (r=0.08) ED admission (p<0.05 all). In conclusion, there was a veryweak positive correlation of the occurrence of cardiac arrhythmias with air humidity and concentrationof air pollutants in the region with a humid continental climate. PMID- 29119779 TI - Strategic Formulation of Graphene Oxide Sheets for Flexible Monoliths and Robust Polymeric Coatings Embedded with Durable Bioinspired Wettability ?. AB - Artificial bioinspired superhydrophobicity, which is generally developed through appropriate optimization of chemistry and hierarchical topography, is being recognized for its immense prospective applications related to environment and healthcare. Nevertheless, the weak interfacial interactions that are associated with the fabrication of such special interfaces often provide delicate biomimicked wettability, and the embedded antifouling property collapses on exposure to harsh and complex aqueous phases and also after regular physical deformations, including bending, creasing, etc. Eventually, such materials with potential antifouling property became less relevant for practical applications. Here, a facile, catalyst-free, and robust 1,4-conjugate addition reaction has been strategically exploited for appropriate covalent integration of modified graphene oxide to developing polymeric materials with (1) tunable mechanical properties and (2) durable antifouling property, which are capable of performing both in air and under oil. Furthermore, this approach provided a facile basis for (3) engineering a superhydrophobic monolith into arbitrary free-standing shapes and (4) decorating various flexible (metal, synthetic plastic, etc.) and rigid (glass, wood, etc.) substrates with thick and durable three-dimensional superhydrophobic coatings. The synthesized superhydrophobic monoliths and polymeric coatings with controlled mechanical properties are appropriate to withstand different physical insults, including twisting, creasing, and even physical erosion of the material, without compromising the embedded antiwetting property. The materials are also equally resistant to various harsh chemical environments, and the embedded antifouling property remained unperturbed even after continuous exposure to extremes of pH (pH 1 and pH 11), artificial sea water for a minimum of 30 days. These flexible and formable free-standing monoliths and stable polymeric coatings that are extremely water-repellent both in air and under oil, are of utmost importance owing to their suitability in practical circumstances and robust nature. PMID- 29119780 TI - Synergistic Effect of MoS2 Nanosheets and VS2 for the Hydrogen Evolution Reaction with Enhanced Humidity-Sensing Performance. AB - As a typical transition-metal dichalcogenides, MoS2 has been a hotspot of research in many fields. In this work, the MoS2 nanosheets were compounded on 1T VS2 nanoflowers (VS2@MoS2) successfully by a two-step hydrothermal method for the first time, and their hydrogen evolution properties were studied mainly. The higher charge-transfer efficiency benefiting from the metallicity of VS2 and the greater activity due to more exposed active edge sites of MoS2 improve the hydrogen evolution reaction performance of the nanocomposite electrocatalyst. Adsorption and transport of an intermediate hydrogen atom by VS2 also enhances the hydrogen evolution efficiency. The catalyst shows a low onset potential of 97 mV, a Tafel slope as low as 54.9 mV dec-1, and good stability. Combining the electric conductivity of VS2 with the physicochemical stability of MoS2, VS2@MoS2 also exhibits excellent humidity properties. PMID- 29119781 TI - Ultrahigh-Gain and Fast Photodetectors Built on Atomically Thin Bilayer Tungsten Disulfide Grown by Chemical Vapor Deposition. AB - The low responsivity observed in photodetectors based on monolayer transition metal dichalcogenides has encouraged the pursuit of approaches that can efficiently enhance the external quantum efficiency, which relies predominantly on the light absorption, the lifetime of the excess carriers, and the charge collection efficiency. Here, we demonstrate that phototransistors fabricated on large-area bilayer tungsten disulfide (WS2) grown by chemical vapor deposition exhibit remarkable performance with photoresponsivity, photogain, and detectivity of up to ~3 * 103 A/W, 1.4 * 104, and ~5 * 1012 Jones, respectively. These figures of merit of bilayer WS2 provide a significant advantage over monolayer WS2 due to the greatly improved carrier mobility and significantly reduced contact resistance. The photoresponsivity of bilayer WS2 phototransistor can be further improved to up to 1 * 104 A/W upon biasing a gate voltage of 60 V, without evident reduction in detectivity. Moreover, the bilayer WS2 phototransistor exhibits a high response speed of less than 100 MUs, large bandwidth of 4 kHz, high cycling reliability of over 105 cycles, and spatially homogeneous photoresponse. These outstanding figures of merit make WS2 bilayer a highly promising candidate for the design of high-performance optoelectronics in the visible regime. PMID- 29119782 TI - Intracellular Protein-Labeling Probes for Multicolor Single-Molecule Imaging of Immune Receptor-Adaptor Molecular Dynamics. AB - Single-molecule imaging (SMI) has been widely utilized to investigate biomolecular dynamics and protein-protein interactions in living cells. However, multicolor SMI of intracellular proteins is challenging because of high background signals and other limitations of current fluorescence labeling approaches. To achieve reproducible intracellular SMI, a labeling probe ensuring both efficient membrane permeability and minimal non-specific binding to cell components is essential. We developed near-infrared fluorescent probes for protein labeling that specifically bind to a mutant beta-lactamase tag. By structural fine-tuning of cell permeability and minimized non-specific binding, SiRcB4 enabled multicolor SMI in combination with a HaloTag-based red-fluorescent probe. Upon addition of both chemical probes at sub-nanomolar concentrations, single-molecule imaging revealed the dynamics of TLR4 and its adaptor protein, TIRAP, which are involved in the innate immune system. Statistical analysis of the quantitative properties and time-lapse changes in dynamics revealed a protein protein interaction in response to ligand stimulation. PMID- 29119783 TI - Dense Vertically Aligned Copper Nanowire Composites as High Performance Thermal Interface Materials. AB - Thermal interface materials (TIMs) are essential for managing heat in modern electronics, and nanocomposite TIMs can offer critical improvements. Here, we demonstrate thermally conductive, mechanically compliant TIMs based on dense, vertically aligned copper nanowires (CuNWs) embedded into polymer matrices. We evaluate the thermal and mechanical characteristics of 20-25% dense CuNW arrays with and without polydimethylsiloxane infiltration. The thermal resistance achieved is below 5 mm2 K W-1, over an order of magnitude lower than commercial heat sink compounds. Nanoindentation reveals that the nonlinear deformation mechanics of this TIM are influenced by both the CuNW morphology and the polymer matrix. We also implement a flip-chip bonding protocol to directly attach CuNW composites to copper surfaces, as required in many thermal architectures. Thus, we demonstrate a rational design strategy for nanocomposite TIMs that simultaneously retain the high thermal conductivity of aligned CuNWs and the mechanical compliance of a polymer. PMID- 29119784 TI - Hydroxymethylaniline Photocages for Carboxylic Acids and Alcohols. AB - ortho-, meta- and para-Hydroxymethylaniline methyl ethers 3-5-OMe and acetyl derivatives 3-5-OAc were investigated as potential photocages for alcohols and carboxylic acids, respectively. The measurements of photohydrolysis efficiency showed that the decaging from ortho- and meta-derivatives takes place efficiently in aqueous solution, but not for the para-derivatives. Contrary to previous reports, we show that the meta-derivatives are better photocages for alcohols, whereas ortho-derivatives are better protective groups for carboxylic acids. The observed differences were fully disclosed by mechanistic studies involving fluorescence measurements and laser flash photolysis (LFP). Photoheterolysis for the para-derivatives does not take place, whereas both meta- and ortho derivatives undergo heterolysis and afford the corresponding carbocations 3-C and 4-C. The ortho-carbocation 4-o-C was detected by LFP in aqueous solution (lambdamax = 410 nm, tau ~ 90 MUs). Moreover, spectroscopic measurements for the meta-acetyl derivative 3-m-OAC indicated the formation of cation in the excited state. The application of an ortho-aniline derivative as a protective group was demonstrated by synthesizing several derivatives of carboxylic acids. In all cases, the photochemical deprotection was accomplished in high yields (>80%). This mechanistic study fully rationalized the photochemistry of aniline photocages which is important for the design of new photocages and has potential for synthetic, biological, and medicinal applications. PMID- 29119785 TI - Plasmonic Near-Field Localization of Silver Core-Shell Nanoparticle Assemblies via Wet Chemistry Nanogap Engineering. AB - Silver nanoparticles are widely used in the field of plasmonics because of their unique optical properties. The wavelength-dependent surface plasmon resonance gives rise to a strongly enhanced electromagnetic field, especially at so-called hot spots located in the nanogap in-between metal nanoparticle assemblies. Therefore, the interparticle distance is a decisive factor in plasmonic applications, such as surface-enhanced Raman spectroscopy (SERS). In this study, the aim is to engineer this interparticle distance for silver nanospheres using a convenient wet-chemical approach and to predict and quantify the corresponding enhancement factor using both theoretical and experimental tools. This was done by building a tunable ultrathin polymer shell around the nanoparticles using the layer-by-layer method, in which the polymer shell acts as the separating interparticle spacer layer. Comparison of different theoretical approaches and corroborating the results with SERS analytical experiments using silver and silver-polymer core-shell nanoparticle clusters as SERS substrates was also done. Herewith, an approach is provided to estimate the extent of plasmonic near-field enhancement both theoretically as well as experimentally. PMID- 29119787 TI - Cysteine Linkages Accelerate Electron Flow through Tetra-Heme Protein STC. AB - Multi-heme proteins have attracted much attention recently due to their prominent role in mediating extracellular electron transport (ET), but one of their key fundamental properties, the rate constants for ET between the constituent heme groups, have so far evaded experimental determination. Here we report the set of heme-heme theoretical ET rate constants that define electron flow in the tetra heme protein STC by combining a novel projector-operator diabatization approach for electronic coupling calculation with molecular dynamics simulation of ET free energies. On the basis of our calculations, we find that the protein limited electron flux through STC in the thermodynamic downhill direction (heme 1->4) is ~3 * 106 s-1. We find that cysteine linkages inserting in the space between the two terminal heme pairs 1-2 and 3-4 significantly enhance the overall electron flow, by a factor of about 37, due to weak mixing of the sulfur 3p orbital with the Fe-heme d orbitals. While the packing density model, and to a higher degree, the pathway model of biological ET partly capture the predicted rate enhancements, our study highlights the importance of the atomistic and chemical nature of the tunneling medium at short biological tunneling distances. Cysteine linkages are likely to enhance electron flow also in the larger deca-heme proteins MtrC and MtrF, where heme-heme motifs with sub-optimal edge-to-edge distances are used to shuttle electrons in multiple directions. PMID- 29119786 TI - BODIPY-Bacteriochlorin Energy Transfer Arrays: Toward Near-IR Emitters with Broadly Tunable, Multiple Absorption Bands. AB - A series of energy transfer arrays, comprising a near-IR absorbing and emitting bacteriochlorin, and BODIPY derivatives with different absorption bands in the visible region (503-668 nm) have been synthesized. Absorption band of BODIPY was tuned by installation of 0, 1, or 2 styryl substituents [2-(2,4,6 trimethoxyphenyl)ethenyl], which leads to derivatives with absorption maxima at 503, 587, and 668 nm, respectively. Efficient energy transfer (>0.90) is observed for each dyad, which is manifested by nearly exclusive emission from bacteriochlorin moiety upon BODIPY excitation. Fluorescence quantum yield of each dyad in nonpolar solvent (toluene) is comparable with that observed for corresponding bacteriochlorin monomer, and is significantly reduced in solvent of high dielectric constants (DMF), most likely by photoinduced electron transfer. Given the availability of diverse BODIPY derivatives, with absorption between 500 700 nm, BODIPY-bacteriochlorin arrays should allow for construction of near-IR emitting agents with multiple and broadly tunable absorption bands. Solvent dielectric constant dependence of Phif in dyads gives an opportunity to construct environmentally sensitive fluorophores and probes. PMID- 29119788 TI - Radiochemical Determination of Long-Lived Radionuclides in Proton-Irradiated Heavy-Metal Targets: Part I-Tantalum. AB - In this study, distillation, precipitation, and ion-exchange methods were chosen for the separation of the long-lived beta-emitters 129I, 36Cl and the alpha emitters 154Dy, 148Gd, 150Gd, and 146Sm from Ta targets irradiated with protons up to 2.6 GeV to determine their production cross sections. Measurements of 129I/127I and 36Cl/35Cl ratios were performed with accelerator mass spectrometry. After separation of the lanthanides, the molecular plating technique was applied to prepare thin samples to obtain highly resolved alpha-spectra. Autoradiography and focused ion beam/scanning electron microscopy techniques were used to characterize the lanthanide deposited layer. Experimental cross-section data are compared with theoretical predictions obtained with INCL++ and ABLA07 code, and a satisfactory agreement is observed. PMID- 29119789 TI - Graphene Oxide Thin Film with Dual Function Integrated into a Nanosandwich Device for in Vivo Monitoring of Interleukin-6. AB - Graphene oxide (GO), with its exceptional physical and chemical properties and biocompatibility, holds a tremendous potential for sensing applications. In this study, GO, acting both as the electron-transfer bridge and the signal reporter, was attached on the interface to develop a label-free electrochemical nanosandwich device for detection of interleukin-6 (IL-6). First, a single layer of GO was covalently modified on gold electrodes, followed by attachment of anti IL-6 capture antibody to form the sensing interface. The 4-aminophenyl phosphorylcholine was further attached to the surface of GO to minimize nonspecific protein adsorption. For reporting the presence of analyte, the anti IL-6 detection antibody was covalently modified to the GO, which has been integrated with the redox probe Nile blue (NB). Finally, a nanosandwich assay was fabricated on gold surfaces for detection of IL-6 on the basis of the electrochemical signal of NB. The prepared nanosandwiches demonstrated high selectivity and stability for detection of IL-6 over the range of 1-300 pg mL-1 with the lowest detectable concentration of 1 pg mL-1. The device was successfully used for monitoring of IL-6 secretion in RAW cells and live mice. By tailoring the GO surface with functional components, such devices were able to detect the analyte in vivo without causing inflammatory response. PMID- 29119790 TI - Green Tea Polyphenols Decrease Strecker Aldehydes and Bind to Proteins in Lactose Hydrolyzed UHT Milk. AB - The effect of epigallocatechin gallate enriched green tea extract (GTE) on flavor, Maillard reactions and protein modifications in lactose-hydrolyzed (LH) ultrahigh temperature (UHT) processed milk was examined during storage at 40 degrees C for up to 42 days. Addition of GTE inhibited the formation of Strecker aldehydes by up to 95% compared to control milk, and the effect was similar when GTE was added either before or after UHT treatment. Release of free amino acids, caused by proteolysis, during storage was also decreased in GTE-added milk either before or after UHT treatment compared to control milk. Binding of polyphenols to milk proteins was observed in both fresh and stored milk samples. The inhibition of Strecker aldehyde formation by GTE may be explained by two different mechanisms; inhibition of proteolysis during storage by GTE or binding of amino acids and proteins to the GTE polyphenols. PMID- 29119792 TI - Synthesis of Au Nanoparticles with Benzoic Acid as Reductant and Surface Stabilizer Promoted Solely by UV Light. AB - Photoreductive synthesis of colloidal gold nanoparticles (AuNPs) from Au3+ is one important process for nanoprocessing. Several methods have been proposed; however, there is no report of a method capable of producing AuNPs with inexpensive reagents acting as both reductant and surface stabilizer, promoted solely under photoirradiation. We found that UV irradiation of water with Au3+ and benzoic acid successfully produces monodispersed AuNPs, where thermal reduction does not occur in the dark condition even at elevated temperatures. Photoexcitation of a benzoate-Au3+ complex reduces Au3+ while oxidizing benzoic acid. The benzoic acid molecules are adsorbed on the AuNPs and act as surface stabilizers. Change in light intensity and benzoic acid amount successfully creates AuNPs with controllable sizes. The obtained AuNPs can easily be redispersed in an organic solvent or loaded onto a solid support by simple treatments. PMID- 29119791 TI - Dynamic Optical Tuning of Interlayer Interactions in the Transition Metal Dichalcogenides. AB - Modulation of weak interlayer interactions between quasi-two-dimensional atomic planes in the transition metal dichalcogenides (TMDCs) provides avenues for tuning their functional properties. Here we show that above-gap optical excitation in the TMDCs leads to an unexpected large-amplitude, ultrafast compressive force between the two-dimensional layers, as probed by in situ measurements of the atomic layer spacing at femtosecond time resolution. We show that this compressive response arises from a dynamic modulation of the interlayer van der Waals interaction and that this represents the dominant light-induced stress at low excitation densities. A simple analytic model predicts the magnitude and carrier density dependence of the measured strains. This work establishes a new method for dynamic, nonequilibrium tuning of correlation-driven dispersive interactions and of the optomechanical functionality of TMDC quasi-two dimensional materials. PMID- 29119793 TI - A Comprehensive Approach to Assess Feathermeal as an Alternative Protein Source in Aquafeed. AB - The effect of partially replacing fishmeal in aquafeed with feathermeal (FTH) at three levels (0%: FTH0, 8%: FTH8, 24%: FTH24) and two extrusion temperatures (100 and 130 degrees C) was evaluated in rainbow trout (Oncorhynchus mykiss) with respect to growth performance, metabolism response, and oxidative status of the feed proteins. Multivariate data analyses revealed that FTH24 correlated positively with high levels of oxidation products, amino acids (AA) racemization, glucogenic AAs level in liver, feed intake (FI), specific growth rate (SGR), and feed conversion ratio (FCR); and low AAs digestibility. Both FI and SGR were significantly increased when 8 and 24% feathermeal was included in the feed extruded at 100 degrees C, while there was a negative effect on FCR in fish fed FTH24. In conclusion, higher oxidation levels in FTH24 may give rise to metabolic alterations while lower levels of FTH may be considered as fishmeal substitute in aquafeed for rainbow trout. PMID- 29119794 TI - Enzymatic Synthesis of a Novel Neuroprotective Hydroxytyrosyl Glycoside. AB - The eco-friendly synthesis of non-natural glycosides from different phenolic antioxidants was carried out using a fungal beta-xylosidase to evaluate changes in their bioactivities. Xylosides from hydroquinone and catechol were successfully formed, although the best results were obtained for hydroxytyrosol, the main antioxidant from olive oil. The formation of the new products was followed by thin-layer chromatography, liquid chromatography, and mass spectrometry. The hydroxytyrosyl xyloside was analyzed in more detail, to maximize its production and evaluate the effect of glycosylation on some hydroxytyrosol properties. The synthesis was optimized up to the highest production reported for a hydroxytyrosyl glycoside. The structure of this compound was solved by two-dimensional nuclear magnetic resonance and identified as 3,4-dihydroxyphenyl-ethyl-O-beta-d-xylopyranoside. Evaluation of its biological effect showed an enhancement of both its neuroprotective capacity and its ability to ameliorate intracellular levels of reactive oxygen species. PMID- 29119795 TI - Hydrogenation of CO to Methanol on Ni(110) through Subsurface Hydrogen. AB - We present a combined theoretical and experimental study of CO hydrogenation on a Ni(110) surface, including studies of the role of gas-phase atomic hydrogen, surface hydrogen, and subsurface hydrogen reacting with adsorbed CO. Reaction mechanisms leading both to methane and methanol are considered. In the reaction involving surface or subsurface hydrogen, we investigate four possible pathways, using density functional theory to characterize the relative energetics of each intermediate, including the importance of further hydrogenation versus C-O bond breaking, where the latter may lead to methane production. The most energetically favorable outcome is the production of methanol along a pathway involving the sequential hydrogenation of CO to a H3CO* intermediate, followed by a final hydrogenation to give methanol. In addition, we find that subsurface hydrogen noticeably alters reaction barriers, both passively and through the energy released by diffusion to the surface. Indeed, the effective reaction barriers are even lower than for CO methanolation on Cu(211) and Cu(111) than for Ni(110). In studies of gas-phase H atoms impinging on a CO-adsorbed Ni(110) surface, Born Oppenheimer molecular dynamics simulations show that direct impact of H is unlikely to result in hydrogenation of CO. This means that Eley-Rideal or hot atom mechanisms are not important; thus, thermal reactions involving subsurface hydrogen are the primary reaction mechanisms leading to methanol. Finally, we demonstrate experimentally for the first time the production of methanol and formaldehyde from CO hydrogenation on Ni(110) and confirm the role of subsurface hydrogen in the mechanism of this reaction. PMID- 29119796 TI - Supported Lipid Bilayers with Phosphatidylethanolamine as the Major Component. AB - Phosphatidylethanolamine (PE) is notoriously difficult to incorporate into model membrane systems, such as fluid supported lipid bilayers (SLBs), at high concentrations because of its intrinsic negative curvature. Using fluorescence based techniques, we demonstrate that having fewer sites of unsaturation in the lipid tails leads to high-quality SLBs because these lipids help to minimize the curvature. Moreover, shorter saturated chains can help maintain the membranes in the fluid phase. Using these two guidelines, we find that up to 70 mol % PE can be incorporated into SLBs at room temperature and up to 90 mol % PE can be incorporated at 37 degrees C. Curiously, conditions under which three dimensional tubules project outward from the planar surface as well as conditions under which domain formation occurs can be found. We have employed these model membrane systems to explore the ability of Ni2+ to bind to PE. It was found that this transition metal ion binds 1000-fold tighter to PE than to phosphatidylcholine lipids. In the future, this platform could be exploited to monitor the binding of other transition metal ions or the binding of antimicrobial peptides. It could also be employed to explore the physical properties of PE-containing membranes, such as phase domain behavior and intermolecular hydrogen bonding. PMID- 29119797 TI - Alexithymia predicts loss chasing for people at risk for problem gambling. AB - Background and aims The aim of this research was to investigate the relationship between alexithymia and loss-chasing behavior in people at risk and not at risk for problem gambling. Methods An opportunity sample of 58 (50 males and 8 females) participants completed the Problem Gambling Severity Index and the Toronto Alexithymia Scale (TAS-20). They then completed the Cambridge Gambling Task from which a measure of loss-chasing behavior was derived. Results Alexithymia and problem gambling risk were significantly positively correlated. Subgroups of non-alexithymic and at or near caseness for alexithymia by low risk and at risk for problem gambling were identified. The results show a clear difference for loss-chasing behavior for the two alexithymia conditions, but there was no evidence that low and at-risk problem gamblers were more likely to loss chase. The emotion-processing components of the TAS-20 were shown to correlate with loss chasing. Discussion and conclusion These findings suggest that loss-chasing behavior may be particularly prevalent in a subgroup of problem gamblers those who are high in alexithymia. PMID- 29119798 TI - A very low dose of rivastigmine-induced Pisa syndrome in a clozapine-treated patient. PMID- 29119799 TI - Testing our FAITHH: HIV stigma and knowledge after a faith-based HIV stigma reduction intervention in the Rural South. AB - Eliminating racial/ethnic HIV disparities requires HIV-related stigma reduction. African-American churches have a history of addressing community concerns, including health issues, but may also contribute to stigma. We developed and pilot tested a faith-based, anti-stigma intervention with 12 African-American churches in rural Alabama. We measured HIV-related stigma held by 199 adults who participated in the intervention (individual-level) and their perception of stigma among other congregants (congregational-level). Analyses of pre- and post assessments using a linear mixed model showed the anti-stigma intervention group reported a significant reduction in individual-level stigma compared with the control group (mean difference: -.70 intervention vs. -.16 control, adjusted p < .05). Findings suggest African-American churches may be poised to aid HIV stigma reduction efforts. PMID- 29119800 TI - Internet gaming disorder does not qualify as a mental disorder. PMID- 29119801 TI - Serum levels of Growth Arrest-Specific 6 protein and soluble AXL in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Serum soluble AXL (sAXL) and its ligand, Growth Arrest-Specific 6 protein (GAS6), intervene in tissue repair processes. AXL is increased in end stage heart failure, but the role of GAS6 and sAXL in ST-segment elevation myocardial infarction (STEMI) is unknown. OBJECTIVES: To study the association of sAXL and GAS6 acutely and six months following STEMI with heart failure and left ventricular remodelling. METHODS: GAS6 and sAXL were measured by enzyme-linked immunosorbent assay at one day, seven days and six months in 227 STEMI patients and 20 controls. Contrast-enhanced magnetic resonance was performed during admission and at six months to measure infarct size and left ventricular function. RESULTS: GAS6, but not sAXL, levels during admission were significantly lower in STEMI than in controls. AXL increased progressively over time ( p<0.01), while GAS6 increased only from day 7. GAS6 or sAXL did not correlate with brain natriuretic peptide or infarct size. However, patients with heart failure (Killip >1) had higher values of sAXL at day 1 (48.9+/-11.9 vs. 44.0+/-10.7 ng/ml; p<0.05) and at six months (63.3+/-15.4 vs. 55.9+/-13.7 ng/ml; p<0.05). GAS6 levels were not different among subjects with heart failure or left ventricular remodelling. By multivariate analysis including infarct size, Killip class and sAXL at seven days, only the last two were independent predictors of left ventricular remodelling (odds ratio 2.24 (95% confidence interval: 1.08-4.63) and odds ratio 1.04 (95% confidence interval: 1.00-1.08) respectively). CONCLUSION: sAXL levels increased following STEMI. Patients with heart failure and left ventricular remodelling have higher sAXL levels acutely and at six month follow up. These findings suggest a potential role of the GAS6-AXL system in the pathophysiology of left ventricular remodelling following STEMI. PMID- 29119802 TI - Using professional expertise in partnership with families: A new model of capacity building. AB - The first five years of parenting are critical to children's development. Parents are known to respond best to interventions with a partnership-based approach, yet child and family health nurses (CFHNs) report some tension between employing their expertise and maintaining a partnership relationship. This article identifies ways in which CFHNs skilfully use their professional expertise, underpinned by helping qualities and interpersonal skills, to assist families build confidence and capacity, and thus buffer against threats to parent and child well-being. It reports on an Australian ethnographic study of services for families with young children. Fifty-two interactions were observed between CFHNs and families in day-stay and home visiting services in Sydney. A new model is presented, based on four partnership activities and the fluid movement between them, to show how CFHNs use their expertise to identify strengths and foster resilience in families in the longer term, without undermining the principles of partnership. PMID- 29119803 TI - A study of the stressors and coping behaviors of parents of Chinese hemophilic children. AB - To understand the stressors experienced by parents of hemophiliac children in China and the coping behaviors utilized, semi-structured interviews were conducted with parents of 158 Chinese hemophiliac children. We administered the Coping Health Inventory for Parents to determine coping behaviors. Parents' main stressors were in the domains of children's illness and physical condition, economic problems, and so on. Parents engaged in various positive coping behaviors to manage these stressors. The helpfulness of these coping behaviors in maintaining a normal family life differed significantly by parents' education and income ( p < .01). Parents of hemophilic children in China face numerous stressors but engage in a number of coping behaviors to manage these stressors. While treating hemophilic children, Chinese medical workers should guide parents to adopt such positive coping behaviors. PMID- 29119804 TI - Longitudinal patterns of early development in Canadian late preterm infants: A prospective cohort study. AB - This prospective, longitudinal cohort study examined longitudinal patterns of early development in Canadian children born late preterm. A convenience sample of 82 mothers and their healthy, singleton, late preterm children participated. Mothers completed the Ages and Stages Questionnaires at 4, 8, and 18 months corrected age. Concerns were most commonly reported in the communication and gross motor domains, especially early in development. The proportion of children scoring below the referral cut-off in at least one domain at 4, 8, and 18 months was, respectively, 25.6, 25.6, and 14.6%. Only two children (2.4%) scored below referral cut-off in at least one domain at all three time points. At ages four and eight months, the late preterm sample had significantly lower communication and gross motor scores than the Ages and Stages Questionnaires normative sample. At age four months, there was also a significant difference on the fine motor domain. There were no significant differences at age 18 months. Healthy late preterm children appear to catch up to population norms by age 18 months corrected age. Longer term studies are needed to further clarify early indicators of delay in late preterm children and identity those who require close developmental monitoring. PMID- 29119805 TI - Sociocultural factors affecting uptake of home-based neonatal thermal care practices in Africa: A qualitative review. AB - Neonatal hypothermia is a major contributor to neonatal mortality in sub-Saharan Africa, often as a comorbidity of severe infections, preterm births or asphyxia. Simple, cost-effective thermal care practices (TCPs) immediately at birth and in the post-natal period are recommended in the World Health Organization 'warm chain'. Current practices are suboptimal in the home in low-resource settings, where approximately half of neonatal deaths occur. Several databases (PubMed, OVID SP, Web of Science, The Cochrane Library and Google Scholar) were searched for original research on home-based TCPs. Seventeen articles were identified, and the results were analysed using a 'thermal care behavioural model'. This review of the qualitative literature on home-based practices across Africa illuminates the sociocultural factors affecting the uptake of recommended practices and strategies for behaviour change. Findings from the review confirm that potentially harmful cultural norms and traditions influence the sequence of TCPs in different contexts across Africa. Furthermore, caregiver factors and contextual barriers or facilitating factors to TCPs and behaviour change exist. Hypothermia and home-based TCPs are areas for further research. Thermal care behaviour change interventions tailored to the sociocultural context are necessary to improve neonatal outcomes in Africa. PMID- 29119806 TI - Ethical dilemmas associated with clinicians' decisions about treatment in critically ill infants born in Cordoba, Argentina. AB - The objective of this article is to examine end of life decisions made by neonatologists of Cordoba, Argentina. An anonymous questionnaire was designed to investigate neonatologists' decisions on when to initiate or withdraw treatment in critical neonates. All neonatologists who take care of critically ill neonates in Cordoba participated in the survey. More than 75% of them would initiate treatment in preterm infants with uncertain prognosis based on the viability of the newborn. Because it is common to find that critically ill neonates lack sufficient diagnostic information at birth, this attitude seems to manifest a certain therapeutic activism. However, more than 80% of physicians withdraw futile treatments that do not produce benefits. Cordoban neonatologists initiate medical treatment based on the current clinical conditions of neonates, applying a certain degree of therapeutic activism. Doctors withdraw neonatal treatment when it is considered futile. PMID- 29119807 TI - Reliability and validity of the Beliefs About Medication Scale in pediatric inflammatory bowel disease. AB - Low adherence is a pervasive issue among youth with inflammatory bowel diseases (IBD), yet our understanding of perceived adherence barriers is hampered by a lack of validated instruments. This study sought to address this by evaluating the reliability and predictive validity of the Beliefs About Medication Scale (BAMS) among youth with IBD. Seventy-six youth (ages 11-18) with IBD who were prescribed a daily oral IBD medication completed baseline ratings of perceived adherence barriers via the BAMS. Parents provided information about patient demographic and disease factors. Subjective medication adherence was assessed via the medication adherence measure. Objective medication adherence was assessed via Medication Event Monitoring System (MEMS) Track Caps. BAMS subscales demonstrated adequate internal consistency ( alphas = .78-.90) and test-retest reliability ( rs = .64-.79). BAMS subscales reliably distinguished between adherent and low adherent groups, though intent to adhere (IA) was the only independent predictor of adherence status. The BAMS holds promise as a tool for assessing adherence barriers among adolescents with IBD. IA may be of particular value in identifying adolescents at risk for low adherence. PMID- 29119808 TI - Early warning- and track and trigger systems for newborn infants: A review. AB - Tools for clinical assessment and escalation of observation and treatment are insufficiently established in the newborn population. We aimed to provide an overview over early warning- and track and trigger systems for newborn infants and performed a nonsystematic review based on a search in Medline and Cinahl until November 2015. Search terms included 'infant, newborn', 'early warning score', and 'track and trigger'. Experts in the field were contacted for identification of unpublished systems. Outcome measures included reference values for physiological parameters including respiratory rate and heart rate, and ways of quantifying the extent of deviations from the reference. Only four neonatal early warning scores were published in full detail, and one system for infants with cardiac disease was considered as having a more general applicability. Temperature, respiratory rate, heart rate, SpO2, capillary refill time, and level of consciousness were parameters commonly included, but the definition and quantification of 'abnormal' varied slightly. The available scoring systems were designed for term and near-term infants in postpartum wards, not neonatal intensive care units. In conclusion, there is a limited availability of neonatal early warning scores. Scoring systems for high-risk neonates in neonatal intensive care units and preterm infants were not identified. PMID- 29119809 TI - Sleep in young children with asthma and their parents. AB - Sleep problems are common in healthy young children, as well as in older children and adolescents with asthma; yet little is known about the sleep patterns and sleep issues of young children with asthma. Further, when young children have sleep disruptions, parental sleep is also typically disrupted. The purpose of this study was to characterize sleep in young children (one to four years) with and without asthma and their parents. Parents of young children ( n = 364) from the general community completed measures of sleep patterns and sleep issues in their children and in themselves. Compared to children with well-controlled asthma or no asthma, children with poorly controlled asthma had poorer sleep patterns, more difficulty falling asleep, and more sleep disruptions (i.e. restless sleep, frequent apneas and gasping during sleep, and frequent sleep terrors). Parents of children with poorly controlled asthma indicated their own sleep was regularly disrupted, and they had frequent night awakenings due to attending to, and stress caused by, their child's health needs. Children with poorly controlled asthma and their parents demonstrated significant sleep issues. Clinical implications for working with young children with asthma and their parents are discussed. PMID- 29119810 TI - Changes in physical fitness of a home-based physical exercise program in childhood obesity: A quasi-experimental uncontrolled study. AB - Few studies have evaluated the changes in physical fitness (PF) of obese children and adolescents of a physical activity program for the treatment of obesity, and even fewer have explored the modality of home-based physical exercise. The objective of this study is to evaluate the changes in PF and body composition (BC) of a home-based physical exercise for treating childhood obesity. Thirty three overweight/obese children and adolescents participated for six months in a home-based intervention that combined aerobics and muscular strength exercises. The results were compared, before and after the intervention, for the different PF components (VO2max, abdominal muscle resistance strength, and lower body explosive strength) and BC (body mass index Z-score (BMI-Z), percentage of body fat, and fat-free mass) variables. A significant reduction was observed in the percentage of body fat (4.7%) and the BMI- Z score (.23), and there was an increase in the fat-free mass of 2.9 kg ( p < .001). In addition, the VO2max showed a significant increase ( p < .05). The results of the different strength tests also showed significant improvements ( p < .05). Our findings support the effectiveness of this program improving not only BC but also PF. However, our results should be interpreted with caution due to lack of control group. PMID- 29119811 TI - 22q11 deletion syndrome: Parents' and children's experiences of educational and healthcare provision in the United Kingdom. AB - 22q11 deletion syndrome (22q11DS) is a genetic syndrome, prevalence around 1:4000 1:6000 live births, with a complex array of associated features, impacting on healthcare and educational support. This study reports the perceptions of families and individuals with 22q11DS in relation to these needs. Individuals and families of those with 22q11DS were approached though two national charities - the Max Appeal and 22Crew. An initial observational survey design was used to gather views via questions probing access to healthcare and educational experiences. Thirty-four responses were received and the data subjected to descriptive analysis. Over half of the respondents were diagnosed before the age of 1. Ninety-one percent reported ongoing difficulties with learning at school, compounded by school attendance being compromised as a result of medical interventions. Individuals reported engaging heavily with educational support and a high number of health professions (mean 9.5; mode 10). Age of diagnosis of 22q11DS ranged from birth to nine years. Families had ongoing concerns about aspects of education and healthcare services, and lack of knowledge and awareness of the difficulties faced by individuals with 22q11DS was raised. Healthcare and education providers should be aware of the range of services individuals required on a regular basis so as to provide a more holistic approach to care. PMID- 29119812 TI - The nursing assessment of infants with bronchiolitis. AB - Bronchiolitis is the leading cause of morbidity and hospitalization in infants under the age of one year. Supportive treatments and regular assessment remain the mainstay of care for infants admitted to hospital. Nurses play an important role in the assessment of infants with bronchiolitis; however, this is not well described in the literature and consequently little is known about what strategies nurses employ in assessing infants with bronchiolitis. The aim of this study was to explore bronchiolitis assessment in the context of nursing practice. A naturalistic inquiry study was undertaken using think aloud and retrospective probing data collection methods. The results revealed that the information gathered by nurses in their assessment of infants with bronchiolitis was varied and the process of acquiring and evaluating this information was multifaceted and holistic in nature. A close partnership between the nurse and mother was identified, and the mother's expert knowledge and ability to identify subtle changes in the infant's clinical condition over time was essential to the assessment process. The assessment partnership with families provides nurses with the most comprehensive and holistic view of the infant's clinical condition and vital assessment information could be lost if this partnership does not occur. PMID- 29119813 TI - School-age children's perception of the hospital experience. AB - In order to determine the perception of hospital experiences among school-age children's (6-12 years), a descriptive and cross-sectional study was performed in 130 children hospitalized in a pediatric hospital with different diagnoses. Data were collected using a pediatric information form, questionnaire form, scale for attitudes towards hospital and healthcare personnel, and sources of anxiety generating thoughts scale (SAGTS). Children's expectations of the nurses were to be well treated (62%), to perform painless procedures (20%), to play games together (12%), to be capable of their job (10%), and to be cheerful (10%). Children's expectation of the hospital facilities was the availability of playgrounds and toys (19.2%), large and single rooms (15.4%), rooms with private bathroom (9.2%), and rooms with a television and Internet access (7.7%). A statistically significant, negative, and moderate linear relationship was found between the scale for attitudes towards hospital and healthcare personnel and SAGTS ( p < 0.05, r: -0.296). The present study was performed to define the children's hospital experiences, keeping in mind that the best opinion on this matter is the child's own opinion. The foundation of this understanding depends on admitting that the children can express their own opinions about the care they receive. PMID- 29119814 TI - Acceptability and feasibility of collecting psychosocial data from fathers of very low birth weight infants. AB - The aim of this study was to determine the feasibility and acceptability of collecting outcome data from parents of very low birth weight (VLBW) infants and to explore the psychological and social adaptation of fathers. Questionnaires were distributed to 38 parents of VLBW infants and 36 parents of term infants within a hospital Neonatal Intensive Care Unit. Field notes were also taken. Parents indicated collecting outcome data in this population was feasible and acceptable, but barriers and difficulties in data collection were identified, particularly for fathers. Furthermore, parents highlighted a lack of emotional support for fathers. In conclusion, research with parents of VLBW infants should happen with consultation, flexibility and measures designed specifically for this population. PMID- 29119815 TI - Improving transition to adult healthcare for young people with cystic fibrosis: A systematic review. AB - As survival increases worldwide, large numbers of young people will need to transition from child to adult cystic fibrosis (CF) services. Little is known about the best method for transitioning patients with CF and which transition programmes yield better outcomes. This paper provides a systematic review of the empirical literature on the outcomes and experiences of transition for young people with CF. Outcomes data were subject to a narrative synthesis and a thematic synthesis of experiences data. Structured transition programmes were associated with increased satisfaction, discussions about transition, self-care and self-advocacy skills, more independence, lower anxiety, and increased self management and parent management of physiotherapy and nutritional supplementation. Young people's concerns included leaving behind previous caregivers, differences in care provision and infection risks. Lack of preparation was a consistent theme. The two most useful aspects of transition programmes were meeting the adult doctors/CF specialist nurse/team and visiting the adult centre. Young people want education about the differences between services, implications of their condition and self-care management. Structured transition programmes appear to impact positively on experiences but the contribution of the different components of transition programmes is unclear. The absence of high-quality studies indicates the need for more well-designed research. PMID- 29119816 TI - An integrative review on parents' perceptions of their children's vaccinations. AB - An integrative literature review was conducted for studies published between January 2005 and January 2016 to obtain evidence on parents' experiences and perceptions of vaccinations. Considering the mandatory nature of vaccinations in many countries and the influences of parental experiences on the outcome of vaccinations, it is essential to understand the experiences and needs of parents regarding their children's vaccinations. CINAHL, PsycINFO, PubMed, Scopus and ScienceDirect were searched for data. In this review, 20 studies (10 quantitative and 10 qualitative) that related to parental perceptions regarding their child's vaccination were included. The parents had varied views on vaccination and they had many vaccination-related concerns and difficulties. Different factors influenced their vaccination decisions and they had varied support needs. This review found that exploring parental perceptions regarding their child's vaccination in terms of the attitudes and experiences of parents, how these affect vaccination decisions as well as the needs of parents regarding their children's vaccinations is important in multicultural societies. PMID- 29119817 TI - Factors affecting self-reported medication adherence and hypertension knowledge: A cross-sectional study in rural villages, Yogyakarta Province, Indonesia. AB - Objectives This study assessed medication adherence and hypertension knowledge, and their predictive factors, in people with hypertension, living in rural communities in Indonesia. Methods Data were acquired from 384 people living in eight rural villages via a researcher-administered questionnaire, a validated adherence scale, and a standardized hypertension knowledge survey. Multivariate analysis was used to identify the predictors of adherence and knowledge. Results Fifty-nine (15%) participants had good hypertension knowledge (score >= 8 out of 10). Compared to participants with poor knowledge, these participants had higher formal education (odds ratio = 2.7, 95% confidence interval = 1.5-4.7), and lived closer to a community health center (odds ratio = 1.8, 95% confidence interval = 1.0-3.3). Knowledge gaps about the need for long-term medication, hypertension complications, and the target blood pressure were identified. Good hypertension knowledge predicted good adherence to medication (odds ratio = 7.1, 95% confidence interval = 3.3-15.2). Only 42 (11%) participants were considered to have good adherence. Reasons for intentional nonadherence were beliefs that medicines should be taken only when symptoms are evident, limited access to healthcare services, and a preference using traditional medicines. Conclusion Strategies for addressing knowledge gaps and misconceptions about hypertension medication are needed, particularly for people with a low educational level and those living some distances from healthcare facilities. PMID- 29119818 TI - Profile of a national sample of Canadian children with participation and activity limitations. AB - Little is known about the nature of Canadian children with participation or activity limitations. Our objective was to profile a nationally representative sample of Canadian children with report of participation or activity limitation including identifying the major medical reasons attributed to these limitations and describe their sociodemographic and functional characteristics. We used data from the Canadian 2006 Participation and Activity Limitation Survey, a post census Statistics Canada national survey of adults and children whose everyday activities were limited because of a condition or health problem. Data were collected by telephone interview of children's (<15 years) parents. A sample of those who answered 'yes' to the 2006 Canada Census disability filter questions was chosen for follow-up. Functional ability was assessed using the Health Utility Index. Mental health (26.1%) was the most common reason reported for participation and activity limitations followed by respiratory (9.8%), neurological (5.5%), and congenital (4.6%) conditions. Having a comorbid condition was associated with each major reason for limitation. Mental health, neurological, and congenital conditions showed the highest risk of functional limitation. In conclusion, mental health conditions and those with multiple conditions should be a primary focus for interventions aimed at reducing the impact of health conditions. PMID- 29119819 TI - Stories of survival: Children's narratives of psychosocial well-being following paediatric critical illness or injury. AB - Survival from critical illness can expose children to an array of negative physical and psychological problems. While the perspective of parents and professionals have been well documented, there is limited understanding of how childhood critical care survivors make sense of their experiences in relation to psychosocial well-being. We aimed to explore long-term psychosocial well-being of childhood survivors of critical illness through their stories. A qualitative, exploratory study using serial in-depth interviews was employed. Nine children (aged 6-15 years) were recruited to the study, 6-14 months post-discharge from a paediatric intensive care unit. Qualitative art-based methods were used with a responsive interviewing technique and data were analysed using narrative psychological analysis. Four themes emerged: disrupted lives and stories; survivors revealed uncertainties in their stories as they recalled their critical care event, exposure to death and dying; talking about extreme physical vulnerability provoked anxieties, mediating between different social worlds and identities; revealed the dynamic nature of survival and getting on with life; the prospective outlook survivors had on their existence despite newly manifesting adversities. Childhood survivors' stories identify challenges and adversities that are faced when attempting to readjust to life following critical illness that both enhance and impair psychosocial well-being. PMID- 29119820 TI - Survey of adolescents' stress in school life in Thailand: Implications for school health. AB - Stress among adolescents is a widely discussed topic. This study examined stress levels, stress-related factors, and the possible correlation between stress and depression in adolescents at high schools in Thailand. The survey measuring stress (T-PSS-10) and depression (PHQ-9) was conducted on 15- to 19-year-olds in three public urban schools ( n = 168, response rate 90%). The data were analysed with descriptive statistics followed by the analysis of the background factors and their associations with adolescent stress levels using chi2 tests, or Pearson's correlation coefficient, while the mean differences between groups were tested with a T-test or analysis of variance. Adolescent stress levels ranged from 6 to 34 points, 17 being the most typical score (mean 15.95, SD 4.95, n = 164); the higher the score, the more the respondents perceived their lives to be stressful. There were no significant differences in stress levels among adolescents relating to age, gender, regular school attendance or which school attended. However, adolescents' high stress levels were associated with having a high number of depressive symptoms ( r = 0.69, p = < 0.001). Effective mechanisms and more studies need to be carried out in the school environment to monitor, identify and support adolescents' health and well-being. PMID- 29119821 TI - An exploration of Indonesian nurses' perceptions of barriers to paediatric pain management. AB - There is a dearth of research in Indonesia regarding pain management in children. Previous studies have identified that although a variety of research and clinical studies on all aspects of pain have been conducted in many countries, children continue to experience moderate to severe pain during hospitalization. Greater research efforts are needed to identify and explore the factors that impede effective pain management in children. To address this gap, the researchers conducted an exploratory descriptive qualitative study to capture Indonesian nurses' perceptions of barriers to paediatric pain management in two hospitals. Using purposive sampling, data were collected from 37 nurses through semi structured, in-depth interviews. Findings indicated that nurses working in Indonesian paediatric wards felt that they were not able to provide effective pain care to hospitalized children. Nurses identified several organizational structural and cultural factors that were thought to hinder their provision of effective pain care to paediatric patients. These factors are embedded in nurses' clinical practice. The study findings can assist to inform relevant initiatives and strategies to improve clinical nurses' performance and competency in providing effective pain care to paediatric patients. PMID- 29119822 TI - Co-producing a digital educational programme for registered children's nurses to improve care of children and young people admitted with self-harm. AB - Despite the increasing prevalence of hospital admissions for self-harm in children and young people (CYP), there is paucity of registered children's nurse (rCN) training or involvement of children to improve care for this often stigmatized patient group. This article describes a participatory approach towards using co-production with CYP and rCN to develop a digital educational programme to improve nurses' knowledge, attitudes and confidence in caring for CYP with self-harm injuries. A priority-setting workshop with rCNs was used to establish consensus of information needs. This was followed by an e-learning content development workshop undertaken with CYP whom had previously experienced hospital admissions for self-harm injuries. Findings from the nurse priority setting workshop identified three educational priorities: (1) knowledge of self harm, (2) effective communication and (3) risk management. The CYP subsequently developed these topic areas to ensure the contents and design of the e-learning resource had fidelity by reflecting the experiences of CYP and needs when cared for in hospital. This article illustrates that involving service users to co develop educational materials is a feasible and important step in designing educational resources and ensures the content is relevant, appropriate and sensitive to both the recipient of care and those responsible for its delivery. PMID- 29119823 TI - Maternal depressive symptoms and child nutritional status: A cross-sectional study in socially disadvantaged Pakistani community. AB - Malnutrition is a primary cause of child morbidity and mortality. The effects of maternal depressive symptoms on children's health, especially their nutritional status, have received less attention in developing countries but needs to be evaluated to understand the public health implications of maternal depression. The aim of the current study was to investigate the association between maternal depressive symptoms and children's nutritional status using data from low socioeconomic community in Pakistan. Maternal depressive symptoms defined as Aga Khan University Anxiety and Depression Scale score of 20 or greater was assessed for mothers with children under two years of age. Logistic regression models estimated the association between maternal depressive symptoms and stunting and underweight. Of 325 mothers, 40% scored positive on the depressive scale. The prevalence of stunting and underweight in children under two years was 36.6% and 35.4%, respectively. Maternal depressive symptoms were significantly associated with children being stunted and underweight. Mothers with depressive symptoms were more than three times likely to have stunted (odds ratio (OR) 3.15, 95% confidence interval (CI) 1.91-5.18, p value < .001) and underweight (OR 3.26, 95% CI 1.99-5.34, p value < .001) children compared to non-depressed mothers. Maternal-related factors such as poor education, unemployment, and low household income were found to be significantly associated with higher odds of children's short stature and underweight. PMID- 29119824 TI - An innovative health-care delivery model for children with medical complexity. AB - Children with medical complexity (CMC) account for a disproportionate share of pediatric health-care utilization and cost that is largely attributable to long hospitalizations, frequent hospital readmissions, and high use of emergency departments. In response, the Centers for Medicare and Medicaid Services Health Care Innovation Center supports the development and testing of innovative health care payment and service delivery models. The purpose of this article is to describe the CMS-funded coordinated health care for complex kids (CHECK) program, an innovative system of health-care delivery that provides improved, comprehensive, and well-coordinated services to CMC. The CHECK program uses a combination of high-tech and low-tech interventions to connect patients, stakeholders, and providers. It is anticipated that the investment in additional support services to CMC will result in improved quality of care that leads to a reduction in unnecessary inpatient hospitalizations, readmissions, and emergency department visits and a total cost savings. The CHECK program has the potential to inform future cost-effective health-care models aimed at improving the quality of life and care for CMC and their families. PMID- 29119825 TI - Why Chinese mothers stop breastfeeding: Mothers' self-reported reasons for stopping during the first six months. AB - The reasons why mothers in mainland China stop breastfeeding before their infants were six months old was investigated. Five hundred sixty-two mothers within two to three days after delivery in a hospital in Guangzhou, China, were followed up via telephone interview at one, four, and six months postpartum between January and August 2015 to assess their infant's feeding patterns and mother's reasons for breastfeeding cessation. Measures included the questionnaire about sociodemographic, psychosocial, and perinatal characteristics, the Breastfeeding Outcome Questionnaire and the Breastfeeding Self-efficacy Scale-Short Form. Compared with mothers who continued breastfeeding for at least six months, the mothers who stopped breastfeeding were less likely to have attended the perinatal classes, used more inhospital formula, and were less self-efficacious regarding breastfeeding and less intention to exclusive breastfeeding. The reasons that 180 mothers stopped breastfeeding before their infants were six months old were analyzed with content analysis. The reasons given for breastfeeding cessation were insufficient milk supply, medical reasons, lactational factors, and return to work. Lactational factors were nipple soreness and mastitis. In order to prolong breastfeeding, pregnant women should be encouraged to attend more prenatal classes. Attendance would enhance self-efficacy and intention to breastfeed longer. Strategies helping working mothers to continue breastfeeding are also needed. PMID- 29119826 TI - Comment to 'Regarding "Diabetes mellitus increases the risk of ruptured abdominal aortic aneurysms"'. AB - This publication is a commentary on the Letter to the Editor by Juliette Raffort and Fabien Lareyre. This article clarifies a number of concerns about the method of calculating the index of prevalence of ruptured abdominal aortic aneurysms (AAA). The method of qualifying patients for the study and the method of calculating the index of prevalence of ruptured AAA in cohorts of diabetic and non-diabetic patients was presented. Most researchers calculate the Index of Prevalence per 100,000 of the general population. This gives the misleading result that diabetes reduces the risk of AAA rupture.We used a method which calculated prevalence per 100,000 with diabetes mellitus and per 100,000 without diabetes mellitus. This method confirms that diabetes mellitus increases the risk of ruptured AAA. PMID- 29119827 TI - A two-week inpatient programme with a booster improved long-term management of severe chronic paediatric pain. AB - In the context of limited healthcare resources and increasing demands for more cost-effective healthcare solutions, this study assessed the short- and long-term clinical outcomes and resource utilization of a two-week inpatient, interdisciplinary, pain treatment (IIPT) including individual and group cognitive behavioural, occupational, physical and recreational therapy, education and family intervention and a booster in the chronic paediatric pain setting. Using a longitudinal design with a two-year follow-up, two-week IIPT resulted in sustainable improvements in mean and maximum pain intensity, physical functioning and internalization and reductions in the mean number of medical visits, school absence and frequency of pain medication at year 2 following IIPT. While pain related disability scores did not improve, problem-focused coping became more prevalent, and patient and parent-assessed satisfaction as well as pain experience continued to improve throughout the study. Our results demonstrate that a two-week IIPT with a booster confers meaningful short- and long-term improvements in clinical outcomes and resource utilization among paediatric patients with severe chronic pain. PMID- 29119829 TI - Self-determination theory and motivational interviewing interventions for type 2 diabetes prevention and treatment: A systematic review. AB - Treatment of those with obesity, prediabetes, and type 2 diabetes often yields initial health improvements, but gains erode over time. A systematic search of self-determination theory and motivational interviewing papers for the above populations was conducted, yielding 54 publications and 42 independent samples. Interventions to treat overweight and obesity ( n = 15), prediabetes ( n = 4), and type 2 diabetes ( n = 23) are summarized and evaluated using the Quality Rating Scale. While the results of these studies are mixed, the majority of the interventions resulted in health benefits. Suggestions for future research are discussed. PMID- 29119828 TI - A pilot study of children's physical activity levels during imagination-based mobile games. AB - This research looked at Biba: a suite of mobile games intended to get kids back out to playgrounds and engaging in more moderate to vigorous physical activity (MVPA). Year after year, annual national surveys report a general decline in physical activity amongst children and a corresponding increase in screen time. Further to this, time spent outside by children has been reported to be on the decline since the 1980s. Recent work has suggested that in order to 'maintain the outdoor recreation participation of children across America, park and recreation professionals may need to embrace the expanding role of technology'. This research tested Biba in precisely this regard, deploying a 20-subject within subject experimental design that compared Biba playground gameplay with typical free play playground sessions, measuring heart rate activity in them. The outcome demonstrated that Biba playground play results in greater amounts of MVPA with a difference in heart rate that was significantly higher in the Biba play session than in the free play session t(19) = 2.41, p < 0.05. PMID- 29119830 TI - Evaluating the construct validity of Stress Overload Scale-Short using exploratory structural equation modeling. AB - This study used exploratory structural equation modeling and confirmatory factor analysis to examine the construct validity of the Chinese version of Stress Overload Scale-Short, which included personal vulnerability and event load. The participants included 629 community residents and 495 university students. The results indicated a better goodness-of-fit using exploratory structural equation modeling compared with confirmatory factor analysis. The Stress Overload Scale Short performed well in distinguishing individuals with more negative emotion symptoms from the general population. A moderation analysis demonstrated that social support moderates the effect of personal vulnerability on negative emotion symptoms. These results facilitated the application of Stress Overload Scale Short in the current population. PMID- 29119831 TI - Lanostane triterpenoids and ergostane-type steroids from the cultured mycelia of Ganoderma capense. AB - Two new lanostane triterpenoids (1 and 2), two new ergostane-type steroids (3 and 4) together with two known lanostane triterpenoids (5 and 6) and one known steroid (7) were isolated from the cultured mycelia of Ganoderma capense (CGMCC 5.71). Their structures were determined on the basis of extensive spectroscopic (HRESIMS, 1D NMR, 2D NMR) data analyses. Compound 1 exhibited moderate cytotoxic activity against the human cancer cell line NCI-H1650 with an IC50 value of 22.3 MUM, and 7 displayed cytotoxic activity against the human cancer cell line HCT116 with an IC50 value of 17.4 MUM. In addition, compounds 2, 3, 5, and 6 displayed weak anti-HIV activity with IC50 values of 23.5, 46.7, 21.6, and 30.1 MUM, respectively. PMID- 29119832 TI - Fear of evaluation unpacked: day-to-day correlates of fear of negative and positive evaluation. AB - BACKGROUND AND OBJECTIVES: Social interactions inevitably go along with repeated evaluations. Some individuals are particularly sensitive to social evaluations: Psychometric studies suggest stable and distinct individual differences on fear of negative evaluations (FNE) and fear of positive evaluation (FPE). However, little is known about day-to-day correlates of FNE and FPE, particularly their respective contribution to positive/negative affect level and affect reactivity to different stressor types. DESIGN: Two studies naturalistically assessed the level of negative/positive affect and its reactivity to different stressor types (from distant or close social network, work and daily hassles, assessed daily) as a function of FNE/FPE. METHOD: Ecological Momentary Assessment employed five daily prompts during 12/10 days in convenience samples of 50/59 participants. RESULTS: FNE predicted lower positive affect level only in Study 2. Consistent across studies negative affect reactivity to stressors emanating from the distant social network was increased in individuals high in FNE or FPE. CONCLUSIONS: Results document the relevance of both types of evaluation fears (FNE/FPE) for day-to-day affect and stress reactivity. They further specify whose evaluations are well tolerated (close network) or feared (distant network), thereby refining current psycho-evolutionary accounts of FNE/FPE. PMID- 29119834 TI - Numerical study of intrathecal drug delivery to a permeable spinal cord: effect of catheter position and angle. AB - Intrathecal delivery is a procedure involving the release of therapeutic agents into the cerebrospinal fluid (CSF) hrough a catheter. It holds promise for treating high-impact central nervous system pathologies, for which systemic administration routes are ineffective. In this study we introduce a numerical model able to simultaneously account for solute transport in the fluid and in the spinal cord. Using a Discontinuous Galerkin method and a three-dimensional patient-specific geometry, we studied the effect of catheter position and angle on local spinal cord drug concentration. We considered twenty cardiac cycles to limit the computational cost of our approach, which resolves the physics both in space and time. We used clinically representative data for the drug injection speed and dose rate, and scaled drug diffusion/penetration properties to obtain observable effects during the considered simulation time. Based on our limited set of working parameters, lateral injection perpendicular to the cord turned out to be more effective than other configurations. Even if the adopted scaling does not allow for a direct clinical translation (a wider parametric assessment of the importance of CSF flow, geometry and diffusion properties is needed), it did not weaken our numerical approach, which can be used to systematically investigate multiple catheter, geometry and fluid/tissue properties configurations, thus paving the way for therapy control. PMID- 29119833 TI - Treatment of advanced basal cell carcinoma with sonidegib: perspective from the 30-month update of the BOLT trial. AB - Sonidegib, a hedgehog pathway inhibitor, was approved by the US FDA for the treatment of locally advanced basal cell carcinoma which cannot be readily treated with surgery or radiotherapy. The pharmacology and pharmacokinetics of sonidegib will be discussed in this review. Additionally, an in-depth analysis of the BOLT trial and data from the 30-month update will be included. This will serve as an update to a previously published article which reported the 12-month update of the BOLT trial. PMID- 29119835 TI - Incidental ethmoidal dural arteriovenous fistula coexisting with a pituitary adenoma exacerbating post-transsphenoidal epistaxis. AB - A 64 year-old man with pituitary adenoma developed massive epistaxis after an uneventful endoscopic transsphenoidal surgery. Angiography showed extravasation from the sphenopalatine artery, to which embolisation was performed. An incidentally coexisting ethmoidal dural arteriovenous fistula supplied by the ophthalmic artery aberrantly originated from the middle meningeal artery caused increased haemorrhage. PMID- 29119836 TI - The effects of tapering and artery wall stiffness on treatments for Coarctation of the Aorta. AB - Coarctation of the Aorta is a congenital narrowing of the aorta. Two commonly used treatments are resection and end-to-end anastomosis, and stent placements. We simulate blood flow through one-dimensional models of aortas. Different artery stiffnesses, due to treatments, are included in our model, and used to compare blood flow properties in the treated aortas. We expand our previously published model to include the natural tapering of aortas. We look at change in aorta wall radius, blood pressure and blood flow velocity, and find that, of the two treatments, the resection and end-to-end anastomosis treatment more closely matches healthy aortas. PMID- 29119837 TI - EPs 7630 is effective and safe in children under 6 years with acute respiratory tract infections: clinical studies revisited. AB - OBJECTIVE: Pelargonium sidoides preparation EPs 7630 has been proven safe and effective in acute respiratory tract infections (aRTIs), but data for young children have not been presented separately. This study reviewed clinical studies and presents an overview of known and newly analyzed data from children <6 years. METHODS: MEDLINE and EMBASE were searched for interventional and non interventional studies which investigated the effects of EPs 7630 in aRTIs and included children <6 years of age. Sub-group analyses for this age range were performed for symptom scales, global efficacy or effectiveness assessments, and safety outcomes. RESULTS: Seven studies with 1067 children <6 years exposed to EPs 7630 were identified. Efficacy of EPs 7630 was significantly superior to placebo in reducing symptom intensity and time until complete recovery in two randomized, double-blind trials in patients with acute bronchitis (AB). Similar symptom time courses were observed in two non-comparative observational studies in AB. One non-comparative, open-label study was identified in acute tonsillopharyngitis (ATP), and one in acute rhinosinusitis (ARS). In both indications, nearly all children showed complete recovery or major symptom improvements during the treatment period, with changes that were similar to those observed in controlled trials investigating older patient populations. The results were supported by an additional observational study including children with various diagnoses of aRTIs. EPs 7630 was safe and well-tolerated. CONCLUSIONS: EPs 7630 is efficacious in children <6 years suffering from AB. The analyses also support the effectiveness of the product in ATP and in ARS. No safety concerns were identified. PMID- 29119838 TI - Accelerated generation of (protonated) imines and quinoxalines by formation of C=N bonds in the microdroplets of a nebuliser. AB - Ions corresponding to protonated imines appear in the positive ion electrospray mass spectra of mixtures of the parent aromatic aldehyde and arylamine. The formation of these imine products occurs readily in the electrospray source nebuliser, even without the application of a spray potential. This accelerated formation of C=N bonds in the nebuliser has been extended to encompass the preparation of quinoxalines from a range of substituted phenylenediamines and benzils. The condensation may be induced either under conventional positive ion electrospray conditions (to give the protonated quinoxalines) or when the nebuliser is disconnected from the mass spectrometer (to give the neutral quinoxaline). Ions corresponding to intermediate adducts formed by condensation of the phenylenediamine component with the protonated benzil are observed in many cases when the condensation occurs in the mass spectrometer. This finding supports an interpretation based on nucleophilic addition in droplets generated by the nebuliser. PMID- 29119839 TI - Factors contributing to salivary human immunodeficiency virus type-1 levels measured by a Poisson distribution-based PCR method. AB - Objective To elucidate the mechanism underlying secretion of human immunodeficiency virus type 1 (HIV-1) into the oral cavity, by examining the relationships between various oral and systemic factors and the viral load in saliva. Methods Plasma and saliva samples from HIV-1 infected patients were assayed using the COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HIV-1 Test, version 1.0 and a Poisson distribution-based polymerase chain reaction (PCR) method for quantifying HIV-1 RNA and DNA. Results Forty-four pairs of samples were obtained from 18 patients. Salivary viral load was approximately 10% of the plasma viral load, but higher than the plasma load in two patients. The salivary viral DNA load was < 1% of the total HIV-1 nucleic acid load except in one patient who had more viral DNA than RNA. Multiple regression analysis showed that salivary viral load was significantly correlated with plasma viral load (partial correlation coefficient, 0.90) and the community periodontal index (-0.63). Conclusions The present results suggest that excretion through salivary glands, but not occult bleeding, may be a major pathway of HIV-1 into the oral cavity. PMID- 29119840 TI - Preparation of soft microcapsules containing multiple core materials with interfacial dehydration reaction using the (W/O)/W emulsion. AB - The soft microcapsules containing eucalyptus oil, ubiquinone and the fine water droplets could be prepared with interfacial dehydration reaction between hydroxy methyl cellulose and tannic acid using the water-in-oil-in-water type multiple (W/O)/W emulsion. The diameters of the microcapsules and the content and the microencapsulation efficiency of the core materials were significantly affected by the revolution velocity (Nr1) to form the (W/O) emulsion and the revolution velocity (Nr2) to form the (W/O)/W emulsion and the lecithin concentration. The mean diameters of the inner water droplets and those of the microcapsules were proportional to Nr1-1.25 and Nr1-0.11 for the revolution velocity (Nr1), respectively. With increasing the revolution velocity (Nr1), the content and the microencapsulation efficiency of the inner water droplets increased, while those of the oil phase decreased. The mean diameters of the microcapsules were proportional to Nr2-1.1. The content and the microencapsulation efficiency of the inner water droplets and those of the oil phase decreased with the revolution velocity (Nr1) and increased with the lecithin concentration. PMID- 29119841 TI - A state-of-art review of low intensity extracorporeal shock wave therapy and lithotripter machines for the treatment of erectile dysfunction. AB - INTRODUCTION: Current treatment for erectile dysfunction (ED) mostly attempts to improve erectile function with limited impact on altering the underlying pathophysiology of ED. Recent animal experiments have supported the notion that low intensity extracorporeal shockwave therapy (LIESWT) significantly improves penile hemodynamics and might induce structural changes that regenerate penile tissue. Areas covered: This review article provides an overview of the basic mechanics and clinical studies pertaining to LIESWT and its use in the field of ED. We identify several key aspects of LIESWT and compare contemporary LIESWT machines and their clinical outcomes. Expert commentary: There is emerging and strong literature to support the use of LIESWT in men with ED, with many clinical studies reported encouraging results in the use of LIESWT with improved erectile function, good safety records, and short-term durability. However, there is a need to define which subgroup of ED population is best suited and the LIESWT treatment protocol including LIESWT template, modality of shock waves energy, emission frequency, and total energy delivery. More stringent randomised controlled trials are warranted before there is widespread acceptance of this LIESWT technology as the standard of care in ED. PMID- 29119842 TI - Outcomes following front-line chemotherapy in peripheral T-cell lymphoma: 10-year experience at The Royal Marsden and The Christie Hospital. AB - We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age >60 years, International Prognostic Index (IPI) >= 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit. PMID- 29119843 TI - Statement of Retraction. PMID- 29119844 TI - Symptom relief and health-related quality of life in globus patients: a prospective study. AB - Globus may be a persistent symptom impairing patients' quality of life. Diagnostics and treatment are controversial but some globus patients may benefit from reassurance and attention. We investigated how globus symptoms change during a short-term follow-up without any treatment after an examination by an ear, nose and throat (ENT) physician and further diagnostic procedures. We also surveyed whether patients with persistent globus suffer from simultaneous voice problems. The study comprised 30 consecutive globus patients referred to Helsinki University Hospital, Department of Otorhinolaryngology - Head and Neck Surgery. We performed an ENT examination and scored patients' videolaryngostroboscopies using the Reflux Finding Score (RFS). Patients filled in three questionnaires: the Reflux Symptom Index (RSI), the Deglutition Handicap Index (DHI) and the 15 Dimensional Measure of Health-Related Quality of Life (15-D HRQoL). Patients underwent transnasal esophagoscopy, high-resolution manometry, and 24-hour multichannel intraluminal impedance and pH monitoring. After a four-month follow up, patients re-answered the same questionnaires and a speech and language pathologist (SLP) examined the patients. Baseline and follow-up questionnaires were available from 27 (90%) patients. According to the RSI (p = .001) and the DHI (p = .003), patients' symptoms diminished after four months. The 15-D showed improvement in one subscale measuring discomfort and symptoms (p = .023). The SLP examined 23 (77%) patients, finding functional voice problems in six (26%). The study showed that most globus patients felt their symptoms diminished without any treatment during four months. In some patients, coexisting voice problems may be associated with persistent globus. PMID- 29119845 TI - Corrigendum. PMID- 29119846 TI - Carbonate apatite nanoparticles carry siRNA(s) targeting growth factor receptor genes egfr1 and erbb2 to regress mouse breast tumor. AB - Cancer cells lose their control on cell cycle by numerous genetic and epigenetic alterations. In a tumor, these cells highly express growth factor receptors (GFRs), eliciting growth, and cell division. Among the GFRs, epidermal growth factor receptor-1 (EGFR1) (Her1/ERBB1) and epidermal growth factor receptor-2 (EGFR2) (Her2/ERBB2) from epidermal growth factor (EGF) family and insulin-like growth factor-1 receptor (IGF1R) are highly expressed on breast cancer cells, thus contributing to the aggressive growth and invasiveness, have been focused in this study. Moreover, overexpression of these receptors is related to suppression of cell death and conferring resistance against the classical drugs used to treat cancer nowadays. Therefore, silencing of these GFRs-encoding genes by using selective small interfering RNAs (siRNAs) could be a powerful approach to treat breast cancer. The inorganic pH sensitive carbonate apatite nanoparticles (NPs) were used as a nano-carrier to deliver siRNA(s) against single or multiple GFR genes in breast cancer cells as well as in a mouse model of breast carcinoma. Silencing of egfr1 and erbb2 simultaneously led to a reduction in cell viability with an increase in cell death signal in the cancer cells and regression of tumor growth in vivo. PMID- 29119847 TI - Myeloid/lymphoid neoplasms with FGFR1 rearrangement. AB - Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare entity. We present a multicenter experience of 17 patients with FISH-confirmed FGFR1 rearrangement. The clinical presentation at diagnosis included myeloproliferative neoplasm (MPN) in 4 (24%) patients, acute leukemia (AL) in 7 (41%), and concomitant MPN with AL in 6 (35%). The two most frequently observed cytogenetic abnormalities were t(8;13)(p11.2;q12)(partner gene ZMYM2) and t(8;22)(p11.2; q11.2)(BCR). Seventy eight percent of tested patients had a RUNX1 mutation, of whom all had AL. Overall response rate to frontline therapy was 69%, and 76% of patients subsequently received allogeneic stem cell transplant (ASCT). After a median follow-up of 11 months, median progression-free survival was 15 months and median overall survival was not reached. In conclusion, FGFR1-rearranged hematologic malignancies present with features of MPN and/or AL. FGFR1 and RUNX1 are therapeutic targets for ongoing and future clinical trials. PMID- 29119848 TI - Management of community-acquired pneumonia in immunocompetent adults: updated Swedish guidelines 2017. AB - Based on expert group work, Swedish recommendations for the management of community-acquired pneumonia in adults are here updated. The management of sepsis induced hypotension is addressed in detail, including monitoring and parenteral therapy. The importance of respiratory support in cases of acute respiratory failure is emphasized. Treatment with high-flow oxygen and non-invasive ventilation is recommended. The use of statins or steroids in general therapy is not found to be fully supported by evidence. In the management of pleural infection, new data show favourable effects of tissue plasminogen activator and deoxyribonuclease installation. Detailed recommendations for the vaccination of risk groups are afforded. PMID- 29119849 TI - Graphene oxide significantly inhibits cell growth at sublethal concentrations by causing extracellular iron deficiency. AB - Graphene oxide (GO)-based materials are increasingly being used in medical materials and consumer products. However, their sublethal effects on biological systems are poorly understood. Here, we report that GO (at 10 to 160 mg/L) induced significant inhibitory effects on the growth of different unicellular organisms, including eukaryotes (i.e. Saccharomyces cerevisiae, Candida albicans, and Komagataella pastoris) and prokaryotes (Pseudomonas fluorescens). Growth inhibition could not be explained by commonly reported cytotoxicity mechanisms such as plasma membrane damage or oxidative stress. Based on transcriptomic analysis and measurement of extra- and intracellular iron concentrations, we show that the inhibitory effect of GO was mainly attributable to iron deficiency caused by binding to the O-functional groups of GO, which sequestered iron and disrupted iron-related physiological and metabolic processes. This inhibitory mechanism was corroborated with supplementary experiments, where adding bathophenanthroline disulfonate-an iron chelating agent-to the culture medium exerted similar inhibition, whereas removing surface O-functional groups of GO decreased iron sequestration and significantly alleviated the inhibitory effect. These findings highlight a potential indirect detrimental effect of nanomaterials (i.e. scavenging of critical nutrients), and encourage research on potential biomedical applications of GO-based materials to sequester iron and enhance treatment of iron-dependent diseases such as cancer and some pathogenic infections. PMID- 29119850 TI - Dopamine induces platelet production from megakaryocytes via oxidative stress mediated signaling pathways. AB - Dopamine (DA), a catecholamine neurotransmitter, is known to for its diverse roles on hematopoiesis, yet its function in thrombopoiesis remains poorly understood. This study shows that DA stimulation can directly induce platelet production from megakaryocytes (MKs) in the final stages of thrombopoiesis via a reactive oxygen species (ROS)-dependent pathway. The mechanism was suggested by the results that DA treatment could significantly elevate the ROS levels in MKs, and time-dependently activate oxidative stress-mediated signaling, including p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, and caspase-3 signaling pathways, while the antioxidants N-acetylcysteine and L-glutathione could effectively inhibit the activation of these signaling pathways, as well as the ROS increase and platelet production triggered by DA. Therefore, our data revealed that the direct role and mechanism of DA in thrombopoiesis, which provides new insights into the function recognition of DA in hematopoiesis. PMID- 29119852 TI - Platelet-related indices in patients with lung cancer with nivolumab. PMID- 29119851 TI - Clinical characteristics of children infected with enterovirus D68 in an outpatient clinic and the association with bronchial asthma. AB - BACKGROUND: All reports of increases in severe respiratory disease associated with human enterovirus D68 (EV-D68) are from hospital settings. However, there are few reports describing clinical characteristics in less severely affected populations. METHODS: We conducted a retrospective observational study from January 2010 to December 2015 in Yamagata, Japan. Using regional passive surveillance, 5794 respiratory specimens were collected from children who initially presented to an outpatient clinic with acute respiratory symptoms. The collected samples were tested for EV-D68 by reverse transcription PCR. RESULTS: EV-D68 was detected in 79 specimens mainly during the two epidemic periods in August-October 2010 and August-October 2015, when detection rates were 10.2% (31 of 304 specimens) and 16.3% (46 of 282 specimens), respectively. Among the 69 EV D68-positive children, excluding those with viral coinfection, 39 (57%) had upper respiratory tract infections, 23 (33%) bronchiolitis or asthma attack, 5 (7%) bronchitis, 1 (1%) meningitis and 1 (1%) acute flaccid paralysis. In 23 children with wheezing, retraction was observed in 10 (43%), and six (26%) were diagnosed with asthma exacerbation. Six children required hospital admission, five (83%) because of asthma exacerbation. A history of asthma or wheezing was the most significant risk factor for the development of wheezing (odds ratio, 8.23; 95% CI, 2.65-25.50; p < .001). CONCLUSIONS: The low rate of hospitalization (9%, 6 of 69) indicates that most cases with EV-D68 infection were managed as outpatients. A history of asthma or wheezing was a potential risk factor for wheezing, resulting in hospitalization due to a severe asthma attack. PMID- 29119853 TI - High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. AB - Background and purpose - A better understanding of the patterns and variation in initiation and progression of osteoarthritis (OA) in the knee may influence the design of therapies to prevent or slow disease progression. By studying cartilage from the human lateral femoral condyle (LFC), we aimed to: (1) assess specimen distribution into early, mild, moderate, and severe OA as per the established histopathological scoring systems (HHGS and OARSI); and (2) evaluate whether these 2 scoring systems provide sufficient tools for characterizing all the features and variation in patterns of OA. Patients and methods - 2 LFC osteochondral specimens (4 x 4 x 8 mm) were collected from 50 patients with idiopathic OA varus knee and radiographically preserved lateral compartment joint space undergoing total knee arthroplasty. These were fixed, sectioned, and stained with HE and Safranin O-Fast Green (SafO). Results - The histopathological OA severity distribution of the 100 specimens was: 6 early, 62 mild, 30 moderate, and 2 severe. Overall, 45/100 specimens were successfully scored by both HHGS and OARSI: 12 displayed low OA score and 33 displayed cartilage surface changes associated with other histopathological features. However, 55/100 samples exhibited low surface structure scores, but were deemed to be inadequately scored by HHGS and OARSI because of anomalous features in the deeper zones not accounted for by these systems: 27 exhibited both SafO and tidemark abnormal features, 16 exhibited only SafO abnormal features, and 12 exhibited tidemark abnormal features. Interpretation - LFC specimens were scored as mild to moderate OA by HHGS and OARSI. Yet, several specimens exhibited deep zone anomalies while maintaining good surface structure, inconsistent with mild OA. Overall, a better classification of these anomalous histopathological features could help better understand idiopathic OA and potentially recognize different subgroups of disease. PMID- 29119854 TI - Sense or sensibility? Social sharers' evaluations of socio-affective vs. cognitive support in response to negative emotions. AB - When in emotional distress, people often turn to others for social support. A general distinction has been made between two types of support that are differentially effective: Whereas socio-affective support temporarily alleviates emotional distress, cognitive support may contribute to better long-term recovery. In the current studies, we examine what type of support individuals seek. We first confirmed in a pilot study that these two types of support can be reliably distinguished. Then, in Study 1, we experimentally tested participants' support evaluations in response to different emotional situations using a vignette methodology. Findings showed that individuals perceived any type of reaction that included socio-affective support as preferable. The evaluation of cognitive support, however, was dependent on the specific emotion: Unlike worry and regret, anger and sadness were characterised by a strong dislike for purely cognitive support. Using different materials, Study 2 replicated these findings. Taken together, the findings suggest that individuals evaluate different types of support in a way that is unlikely to benefit emotional recovery in the long run. PMID- 29119855 TI - Two novel variants of uncertain significance in GP9 associated with Bernard Soulier syndrome: Are they true mutations? AB - Bernard-Soulier syndrome (BSS) is an autosomal recessive major thrombocytopathy, the symptoms of which are mainly marked by mucocutaneous bleeding. This rare disease, initially described in the 1970s, is the result of an abnormal formation of the glycoprotein complex Ib-IX-V (GP Ib-IX-V), a platelet receptor of von Willebrand factor. A large number of mutations, sometimes involving the GP9 gene, have been described as possibly responsible for the disease. We report here the case of a BSS patient who presented with persistent thrombocytopenia (31x109/L) and decreased surface expression of GPIb-IX-V on large platelets with anisocytosis. Thorough molecular analyses disclosed two previously unreported GP9 variants, respectively c.230T>A (p.Leu77Gln) and c.255C>A (p.Asn85Lys). Both are likely to modify the conformation of GP-IX interactions with other glycoproteins of the Ib-IX-V complex and thus proper expression of this complex on the membrane of platelets. PMID- 29119856 TI - Radiological properties of healthy, carcinoma and equivalent breast tissues for photon and charged particle interactions. AB - PURPOSE: In this paper, the effective atomic numbers (Zeff), electron densities (Neff), exposure buildup factor (EBF) and energy absorption buildup factor (EABF) of healthy (H), carcinoma (C) and equivalent (E) breast tissues were investigated to quantify differences in radiological parameters between the tissues in the continuous energy region. For these purposes, Zeffs and Neffs, of healthy, carcinoma and equivalent (H-C-E) breast tissues were calculated for interaction of gamma rays and charged particles with selected tissues. EBFs and EABFs of the tissues were also calculated for gamma rays as well and were compared to each other for different photon energies (0.015-15 MeV) up to 40 mfp. METHOD: A well known interpolation procedure has been used for the calculation of Zeff using the mass stopping powers and mass attenuation coefficients for charged and uncharged radiations in the continuous energy region. And the buildup factors of the tissues were calculated by the well-known G-P fitting method based on the interpolation from the equivalent atomic number (Zeq). RESULTS: The variation of Zeffs, Neffs with energy and differences (%) in the Zeffs between the tissues were determined for photon, electron, proton and C ion, which is commonly used in hadron therapy in the relevant energy region 1 keV-400 MeV. Differences (%) between healthy and carcinoma tissues in Zeff were around 9%, >4%, >5%, >2.5% for C ion, photon, electron and proton interaction, respectively. The relative differences (RD %) in Zeff between healthy and equivalent tissues in the energy range 0.02-1 MeV were found to be less than 1% for photons and C ions. In addition differences (%) between healthy and carcinoma tissues in EABF and EBF were around 25%, but differences (%) between healthy and equivalent tissues were <6% and <4% (at 40 mfp) in the continuous energy region. CONCLUSIONS: From the results, BR12 was found the be available for an equivalent to healthy breast tissue in 0.02-1 MeV for photons and C ions due to RD (%) in Zeff between healthy and equivalent tissues (less than 1%). However, for electron interaction, the RD (%) in Zeff between healthy and equivalent tissues was always greater than 4% in the entire energy range, thus BR12 was found the worse an equivalent to healthy breast tissue in in the entire energy range for electron. Also the reported data in the study should be useful to choose best equivalence for photon, electron, proton and Carbon ion interactions. PMID- 29119857 TI - miR-638 Inhibits immature Sertoli cell growth by indirectly inactivating PI3K/AKT pathway via SPAG1 gene. AB - Numerous studies have demonstrated that microRNAs (miRNAs) play important roles in cell growth, apoptosis and spermatogenesis. Our previous study showed that miR 638 was differentially expressed in sexually immature and mature testes of Large White boars. Here we reported that sperm-associated antigen 1 (SPAG1) was a direct target gene of miR-638. Moreover, miR-638 inhibited cell proliferation and cell cycle, and promoted apoptosis of porcine immature Sertoli cells. Key genes including phosphorylated phosphatidylinositide 3-kinases (p-PI3K) and phosphorylated serine/ threonine kinase (p-AKT) in PI3K/AKT pathway as well as cell cycle factors including c-MYC, cyclin-D1 (CCND1), cyclin-E1 (CCNE1) and cyclin-dependent kinase 4 (CDK4) were all significantly down-regulated after overexpression of miR-638 or RNAi of SPAG1. Notably, mRNA levels of SRY-related HMG-box 2 (SOX2) and POU domain, class 5, transcription factor 1 (POU5F1) essential for spermatogonia proliferation were significantly suppressed in SPAG1 siRNA- transfected ST cells. This study suggests that miR-638 regulates immature Sertoli cell growth and apoptosis by targeting SPAG1 gene which can indirectly inactivate PI3K/AKT pathway, and plays roles in pig spermatogenesis. PMID- 29119858 TI - Eimeria taggarti N. Sp., a Novel Coccidian (Apicomplexa: Eimeriorina) in the Prostate of an Antechinus flavipes. AB - A novel coccidian species was discovered in the prostate of an Antechinus flavipes (yellow-footed antechinus) in South Australia during the period of postmating male antechinus immunosuppression and mortality. This novel coccidian is unusual because it develops extraintestinally and sporulates endogenously within the prostate gland of its mammalian host. Histological examination of prostatic tissue revealed dense aggregations of spherical and thin-walled tetrasporocystic, dizoic, sporulated coccidian oocysts within tubular lumina, with unsporulated oocysts and gamogonic stages within the cytoplasm of glandular epithelial cells. This coccidian was observed occurring concurrently with dasyurid gammaherpesvirus 1 infection of the antechinus' prostate. Eimeria specific 18S small-subunit ribosomal (r)DNA polymerase chain reaction amplification was used to obtain a partial 18S rDNA nucleotide sequence from the antechinus coccidian. Bayesian phylogenetic analysis based on 18S rDNA gene sequences revealed that the novel coccidian clusters with reptile-host coccidians, forming an ancestral basal lineage of the eimeriid clade. The species has been named Eimeria taggarti n. sp. on the basis of both sporulated oocyst morphology and molecular characterization. It is suspected that E. taggarti is sexually transmitted via excretion of sporulated oocysts or free sporocysts with prostatic secretions in semen. PMID- 29119859 TI - Novel genetic approaches to behavior in Drosophila. AB - The study of behavior requires manipulation of the controlling neural circuits. The fruit fly, Drosophila melanogaster, is an ideal model for studying behavior because of its relatively small brain and the numerous sophisticated genetic tools that have been developed for this animal. Relatively recent technical advances allow the manipulation of a small subset of neurons with temporal resolution in flies while they are subject to behavior assays. This review briefly describes the most important genetic techniques, reagents, and approaches that are available to study and manipulate the neural circuits involved in Drosophila behavior. We also describe some examples of these genetic tools in the study of the olfactory receptor system. PMID- 29119860 TI - Cost-effectiveness of bone-anchored prostheses using osseointegrated fixation: Myth or reality? AB - BACKGROUND: In principle, lower limb bone-anchored prostheses could alleviate expenditure associated with typical socket manufacturing and residuum treatments due to socket-suspended prostheses. OBJECTIVE: This study reports (a) the incremental costs and (b) heath gain as well as (c) cost-effectiveness of bone anchored prostheses compared to socket-suspended prostheses. STUDY DESIGN: Retrospective individual case-controlled observations and systematic review. METHODS: Actual costs were extracted from financial records and completed by typical costs when needed over 6-year time horizon for a cohort of 16 individuals. Health gains corresponding to quality-adjusted life-year were calculated using health-related quality-of-life data presented in the literature. RESULTS: The provision of bone-anchored prostheses costed 21% +/- 41% more but increased quality-adjusted life-years by 17% +/- 5% compared to socket-suspended prostheses. The incremental cost-effectiveness ratio ranged between -$25,700 per quality-adjusted life-year and $53,500 per quality-adjusted life-year with indicative incremental cost-effectiveness ratio of approximately $17,000 per quality-adjusted life-year. Bone-anchored prosthesis was cost-saving and cost effective for 19% and 88% of the participants, respectively. CONCLUSION: This study indicated that bone-anchored prostheses might be an acceptable alternative to socket-suspended prostheses at least from a prosthetic care perspective in Australian context. Altogether, this initial evidence-based economic evaluation provided a working approach for decision makers responsible for policies around care of individuals with lower limb amputation worldwide. Clinical relevance For the first time, this study provided evidence-based health economic benefits of lower limb bone-anchored prostheses compared to typical socket-suspended prostheses from a prosthetic care perspective that is essential to clinicians and decision makers responsible for policies. PMID- 29119861 TI - Carbohydrate and fat oxidation in persons with lower limb amputation during walking with different speeds. AB - BACKGROUND: Studies suggest that the energy expenditure of healthy persons (control) during walking with the preferred walking speed in steady-state conditions is dominated by fat oxidation. Conversely, carbohydrate and fat oxidation during walking is little investigated in transfemoral amputees. OBJECTIVES: To investigate carbohydrate and fat oxidation, energy cost of walking, and percent utilization of maximal aerobic capacity [Formula: see text]during walking. STUDY DESIGN: Eight transfemoral amputees and controls walked with their preferred walking speed and speeds 12.5% and 25% slower and faster than their preferred walking speed. METHODS: Energy expenditure and fuel utilization were measured using a portable metabolic analyzer. Metabolic values are means +/- standard deviation. RESULTS: For transfemoral amputees (37.0 +/- 10.9 years) and controls (39.0 +/- 12.3 years), fat utilization at the preferred walking speed was 44.8% +/- 7.2% and 45.0% +/- 7.2% of the total energy expenditure, respectively. The preferred walking speed of the transfemoral amputees and controls was close to a metabolic cross-over speed, which is the speed where carbohydrate utilization increases steeply and fat utilization decreases. When walking fast, at 90 m min-1 (preferred walking speed plus 25%), transfemoral amputees utilized 70.7% +/- 5.6% of their [Formula: see text], while the controls utilized 30.9% +/- 4.5% ( p < 0.001) at the matching speed (control preferred walking speed). At 90 m min-1, carbohydrate utilization was 78% +/- 4.7% and 55.2% +/- 7.2% of the total energy expenditure for the transfemoral amputees and controls, respectively ( p < 0.01). Compared to the control, energy cost of walking was higher for the transfemoral amputees at all speeds (all comparisons; p < 0.001). CONCLUSION: At the preferred walking speed, carbohydrate, not fat, dominates energy expenditure of both transfemoral amputees and controls. For the transfemoral amputees, consequences of fast walking are very high [Formula: see text] utilization and rate of carbohydrate oxidation. Clinical relevance Research on the relationships between physical effort and fuel partitioning during ambulation could provide important insights for exercise rehabilitation programs for lower limb amputees (LLA). Regular endurance exercise will improve maximal aerobic capacity and enable LLA to walk faster and at the same time expend less energy and improve fat utilization. PMID- 29119862 TI - Static and dynamic accuracy of a magnetic-inertial measurement unit used to provide racket swing kinematics. AB - Magnetic-inertial measurement units (MIMUs) are becoming more prevalent in sports biomechanics and may be a viable tool to evaluate kinematic parameters. This study examined the accuracy of a MIMU to estimate orientation angles under static conditions and dynamically from a squash racket during a forehand drive shot. A MIMU was mounted onto a goniometer and moved through 0-90 degrees , with static data collected at 10 degrees increments during 10 repetitions of all three axes. Typical error analyses showed the MIMU to be very reliable (TE <= 0.03 degrees ). MIMU accuracy was determined via intraclass correlation coefficients (ICC) (r > 0.999, p < 0.001). An ordinary least products regression showed no proportional bias and minimal fixed bias for all axes. Dynamic accuracy was assessed by comparing MIMU and optical motion capture data of squash racket swing kinematics. A MIMU was fixed onto a racket and 10 participants each hit 10 forehand shots. Mean orientation angle error at ball impact was <0.50 degrees and ICC showed very high correlations (r >= 0.988, p < 0.001) for all orientations. Swing phase root mean squared errors were <=2.20 degrees . These results indicate that a MIMU could be used to accurately and reliably estimate selected racket swing kinematics. PMID- 29119863 TI - Understanding uncertainty in young-onset Parkinson disease. AB - Objectives Individuals living with young-onset Parkinson's disease compose a rare subtype of a disease typically associated with older age. Situated within a large grounded theory study exploring information behavior, this paper describes the core category of the theory, i.e. uncertainty. Methods Data were collected with 39 individuals living with young-onset Parkinson's disease who took part in in depth interviews, focus groups and/or an online discussion board. Fourteen autobiographies written by individuals living with young-onset Parkinson's disease were also used as data sources. Results Through experiencing young-onset Parkinson's disease, participants were confronted with uncertainty along two main lines. First, they experienced uncertainty with respect to their identities as young- and middle-aged adults, deviating from the idealized age-graded life path marked out within their socio-cultural context. Second, they experienced uncertainty with respect to their functioning, as the heterogeneous nature of Parkinson's progression meant that it would not be possible to chart how their disease would change over time. This uncertainty was associated with feelings of lost control over their lives and increased grief. Discussion With a deeper appreciation for how uncertainty is experienced in the lives of those with young onset Parkinson's disease, health professionals may be better prepared to discuss these issues with patients and provide support and resources. PMID- 29119865 TI - Exercise and mental health of people living with HIV: A systematic review. AB - Objective Mental illness is highly prevalent among people living with HIV. Poor mental health is linked to HIV disease progression, making the treatment of mental illness alongside HIV essential. While the benefits of exercise on the physical health of people living with HIV are well established, the effect of exercise on mental health in this population is less examined. Therefore, this study aimed to conduct a systematic literature review of the effects of exercise on mental health in people living with HIV. Methods A search of electronic databases (PubMed, Web of Science, PsycINFO) through 30 November 2016 was completed. The methodological framework for scoping studies was used to conduct the review process. RISMA guidelines were used to report the results. Results The search resulted in 2273 articles and 52 were determined to be relevant. After review of the full text of potentially relevant studies, 24 studies were included for the analysis. Discussion Both aerobic and resistance exercise have independent and combined positive effects on various indicators of mental health in people living with HIV. Major limitations include high attrition rate, small sample size, and poor study designs. Higher quality studies with more diverse populations such as women, older adults, and transgender individuals are required. PMID- 29119864 TI - Associations between having an informal caregiver, social support, and self-care among low-income adults with poorly controlled diabetes. AB - Objective To determine whether the presence of an informal caregiver and the patient's level of social support are associated with better diabetes self-care among adults with poorly controlled diabetes. Methods Cross-sectional study using baseline data from 253 adults of age 30-70 with poorly controlled diabetes. Participants who reported receiving assistance with their diabetes from a friend or family member in the past month were classified as having a caregiver. We used multivariate linear and logistic regression models to evaluate the associations between having a caregiver and level of social support with five self-reported diabetes self-care behaviors: diet, foot checks, blood glucose monitoring, medications, and physical activity. Results Compared to participants with no informal caregiver, those with an informal caregiver were significantly more likely to report moderate or high medication adherence (OR = 1.93, 95% CI: 1.07 3.49, p = 0.028). When we included social support in the model, having a caregiver was no longer significantly associated with medication adherence (OR = 1.50, 95% CI: 0.80-2.82), but social support score was (OR = 1.22, 95% CI: 1.03 1.45, p = 0.023). Discussion Among low-income adults with poorly controlled diabetes, having both an informal caregiver and high social support for diabetes may have a beneficial effect on medication adherence, a key self-care target to improve diabetes control. PMID- 29119866 TI - Exploring service users', carers' and professionals' perspectives and experiences of current antipsychotic prescribing: A qualitative study. AB - Objectives Shared decision-making is the pinnacle of patient-centred care; mental health stakeholders value shared decision-making but find it difficult to enact. The objective was to compare and synthesise mental health stakeholder views on antipsychotic prescribing in one NHS Trust, to understand potential reasons for the difficult enactment of shared decision-making in practice. Methods We conducted 12 interviews and 5 focus groups with 33 mental health stakeholders, after obtaining their informed consent. They shared their experiences in and perceptions of antipsychotic prescribing and were recruited from Manchester Mental Health and Social Care Trust. Results Stakeholders agreed that successful shared decision-making demands a collaborative approach. We elucidated a striking divergence in views of the decision-making process and understanding of collaboration. Nurses, consultants and the pharmacist seemed most satisfied with the amount of collaboration but most pessimistic about the scope for it. Carers and most service users did not feel that there was any collaboration. Discussion Comparison of perspectives demonstrated the complexity of shared decision-making which is not addressed in current operational definitions or policy or nursing practice initiatives. The findings have the potential to progress initiatives in the mental health field from those that emphasise the need for shared decision making to those that develop tools to promote shared decision-making. PMID- 29119867 TI - Targeted macrophages delivery of rifampicin-loaded lipid nanoparticles to improve tuberculosis treatment. AB - AIM: This work aims to develop a mannosylated nanostructured lipid carrier (NLC) loaded with rifampicin to improve tuberculosis treatment. MATERIALS & METHODS: An active targeting strategy was used and the nanoparticles were characterized. Effects on cell viability and the antimycobacterial activity of the nanoformulations were evaluated. RESULTS: The nanoparticles developed exhibited a size of about 315 nm and polydispersity <0.2. The drug encapsulation efficiency was higher than 90% and its release was sensitive to pH. The mannosylated NLCs showed efficient uptake by bone marrow derived macrophages. Further, rifampicin loaded mannosylated NLCs were more efficient in inducing a decrease of intracellular growth of mycobacteria. CONCLUSION: The NLCs developed can be used as a promising carrier for safer and efficient management of tuberculosis. PMID- 29119868 TI - The contribution of disengagement to temporal discriminability. AB - The present study examines the idea that time-based forgetting of outdated information can lead to better memory of currently relevant information. This was done using the visual arrays task, along with a between-subjects manipulation of both the retention interval (1 s vs. 4 s) and the time between two trials (1 s vs. 4 s). Consistent with prior work [Shipstead, Z., & Engle, R. W. (2013). Interference within the focus of attention: Working memory tasks reflect more than temporary maintenance. Journal of Experimental Psychology: Learning, Memory, and Cognition, 39, 277-289; Experiment 1], longer retention intervals did not lead to diminished memory of currently relevant information. However, we did find that longer periods of time between two trials improved memory for currently relevant information. This replicates findings that indicate proactive interference affects visual arrays performance and extends previous findings to show that reduction of proactive interference can occur in a time-dependent manner. PMID- 29119869 TI - Information Structure Preferences in Focus-Sensitive Ellipsis: How Defaults Persist. AB - We compare the roles of overt accent and default focus marking in processing ellipsis structures headed by focus-sensitive coordinators (such as Danielle couldn't pass the quiz, let alone the final/Kayla). In a small auditory corpus study of radio transcripts, we establish that such structures overwhelmingly occur with contrastive pitch accents on the correlate and remnant ( the quiz and the final, or Danielle and Kayla), and that there is a strong bias to pair the remnant with the most local plausible correlate in production. In two auditory naturalness ratings experiments, we observe that marking a non-local correlate with contrastive pitch accent moderates, but does not fully overturn, the bias for local correlates in comprehension. We propose that the locality preference is due to a sentence-final default position for sentence accent, and that auditory processing is subject to "enduring focus," in which default positions for focus continue to influence the focus structure of the sentence even in the presence of overt accents. The importance of these results for models of auditory processing and of the processing of remnants in ellipsis structures is discussed. PMID- 29119871 TI - Missingness. PMID- 29119870 TI - Current and emerging global themes in the bioethics of regenerative medicine: the tangled web of stem cell translation. AB - Probably the most serious problem facing the field of regenerative medicine today is the challenge of effective translation and development of viable stem cell based therapies. Particular concerns have been raised over the growing market in unproven cell therapies. In this article, I explore recent developments in the stem cell therapy landscape and argue that while the sale of unproven therapies undoubtedly poses ethical concerns, it must be understood as part of a larger problem at the interface between biomedicine, healthcare, publics, policy and the market. Addressing this will require a broader perspective incorporating the shifting relationships between different stakeholder groups, the global politics of research and innovation, and the evolving role of publics and patients with respect to science. PMID- 29119872 TI - Adapting operational research training to the Rwandan context: the Intermediate Operational Research Training programme. AB - BACKGROUND: Promoting national health research agendas in low- and middle-income countries (LMICs) requires adequate numbers of individuals with skills to initiate and conduct research. Recently, non-governmental organizations (NGOs) have joined research capacity building efforts to increase research leadership by LMIC nationals. Partners In Health, an international NGO operating in Rwanda, implemented its first Intermediate Operational Research Training (IORT) course to cultivate Rwandan research talent and generate evidence to improve health care delivery. OBJECTIVE: This paper describes the implementation of IORT to share experiences with other organizations interested in developing similar training programmes. METHODS: The Intermediate Operational Research Training utilized a deliverable-driven training model, using learning-by-doing pedagogy with intensive hands-on mentorship to build research skills from protocol development to scientific publication. The course had short (two-day) but frequent training sessions (seven sessions over eight months). Trainees were clinical and programme staff working at the district level who were paired to jointly lead a research project. RESULTS: Of 10 trainees admitted to the course from a pool of 24 applicants, nine trainees completed the course with five research projects published in peer-reviewed journals. Strengths of the course included supportive national and institutional research capacity guidelines, building from a successful training model, and trainee commitment. Challenges included delays in ethical review, high mentorship workload of up to 250 hours of practicum mentorship, lack of access to literature in subscription journals and high costs of open access publication. CONCLUSIONS: The IORT course was an effective way to support the district-based government and NGO staff in gaining research skills, as well as answering research questions relevant to health service delivery at district hospitals. Other NGOs should build on successful programmes while adapting course elements to address context-specific challenges. Mentorship for LMIC trainees is critical for effectiveness of research capacity building initiatives. PMID- 29119873 TI - Possibilities for maintaining a strong self - a grounded theory study of relational experiences among Thai women in Sweden. AB - BACKGROUND: Due to increasing globalization and Internet communication, the number of international marriages has increased. In Sweden, 75% of the Thai population are women, among whom 80% are partnered with Swedish or other Scandinavian men. Previous studies have indicated that lack of autonomy, social isolation, and stigma are important risk factors for poor mental health for foreign-born women as well as for women in international marriages. OBJECTIVES: To explore what characterizes the processes, choices, challenges and relational conditions that Thai women, partnered with Swedish or Danish men, experience during their first years in Sweden. METHOD: A qualitative study using a Constructivist Grounded Theory approach based on fourteen individual interviews with Thai women partnered with Swedish or Danish men and residing in Sweden. RESULTS: The core category 'possibilities to maintain a strong self in Sweden' is linked to five categories characterizing the process that the women go through over time. The subcategories illustrate different paths taken even if there were possibilities to change paths along the way. The women had, for different reasons, reached a turning point that made them leave Thailand. In Sweden, they started in dependency and struggled in different ways to adjust to relational norms and handle prejudice. Toward the end of the timeline, differing ways of recognizing life choices depended on access to social networks and partners' attitudes. CONCLUSION: Our study showed the crucial role of economical, emotional and social support from partners and networks for Thai women's possibilities to maintain a strong self and good health after migration. This implies a need for supporting Thai women to be more independent by providing access to language education, employment and community involvement. The current requirement for becoming a permanent resident should also be reviewed not to jeopardize women international marriages possibilities' to leave unhealthy relationships. PMID- 29119874 TI - Using helping skills with Korean clients: The perspectives of Korean counselors. AB - OBJECTIVE: The purpose of this study was to investigate how Korean counselors modify the helping skills they learned during training in their work with Korean clients. METHOD: Thirteen practicing Korean therapists who had taken two master's level courses in the Hill helping skills model were interviewed about their experiences in applying the model in their work with clients. Data were analyzed using consensual qualitative research (CQR). RESULTS: Several characteristics were noted of Korean clients that might influence the appropriateness of the helping skills model (e.g., clients regard counseling as authorities and wise experts). Participants had a number of reactions to the overall helping skills model (e.g., noting that Korean counselors deliver empathy and genuineness more through non-verbal rather than verbal channels). Participants also noted needed modifications to specific stages or skills in the model (e.g., using the insight stage less than the exploration stage). DISCUSSION: Based on these findings, six guidelines are offered for modifying the Hill helping skills approach to fit the needs of Korean clients: Provide a pre-exploration stage to educate clients about approach, utilize indirect and non-verbal communication more than verbal communication, validate client's experiences, work cautiously with emotions, be cautious about using insight skills, and respond to clients' implicit communication when they ask for action. Clinical or methodological significance of this article: Psychotherapy models are typically transported to other cultures without sufficient attention to modifications needed for working with clients in that culture. In this paper, we begin to address how one particular model, the Hill Helping Skills Model, could be modified to make it responsive to Korean clients. Hopefully, by addressing implications for specific populations, we can begin to modify psychotherapy approaches to better fit clientele from diverse cultures. PMID- 29119875 TI - Effects of positive end-expiratory pressure on intraoperative core temperature in patients undergoing posterior spine surgery: prospective randomised trial. AB - Objective Positive end-expiratory pressure (PEEP) causes carotid baroreceptor unloading, which leads to thermoregulatory peripheral vasoconstriction. However, the effects of PEEP on intraoperative thermoregulation in the prone position remain unknown. Methods Thirty-seven patients undergoing spine surgery in the prone position were assigned at random to receive either 10 cmH2O PEEP (Group P) or no PEEP (Group Z). The primary endpoint was core temperature 180 minutes after intubation. Secondary endpoints were delta core temperature (difference in core temperature between 180 minutes and immediately after tracheal intubation), incidence of intraoperative hypothermia (core temperature of <36 degrees C), and peripheral vasoconstriction-related data. Results The median [interquartile range] core temperature 180 minutes after intubation was 36.1 degrees C [35.9 degrees C-36.2 degrees C] and 36.0 degrees C [35.9 degrees C-36.4 degrees C] in Groups Z and P, respectively. The delta core temperature and incidences of intraoperative hypothermia and peripheral vasoconstriction were not significantly different between the two groups. The peripheral vasoconstriction threshold (36.2 degrees C+/-0.5 degrees C vs. 36.7 degrees C+/-0.6 degrees C) was lower and the onset of peripheral vasoconstriction (66 [60-129] vs. 38 [28-70] minutes) was slower in Group Z than in Group P. Conclusions Intraoperative PEEP did not reduce the core temperature decrease in the prone position, although it resulted in an earlier onset and higher threshold of peripheral vasoconstriction. PMID- 29119876 TI - Endovascular treatment outcomes using the Stroke Triage Education, Procedure Standardization, and Technology (STEPS-T) program. AB - Background "Door to treatment" time affects outcomes of acute ischemic stroke (AIS) patients undergoing endovascular treatment (EVT). However, the correlation between staff education and accessible technology with stroke outcomes has not been demonstrated. Objective The objective of this paper is to demonstrate the five-year impact of the Stroke Triage Education, Procedure Standardization, and Technology (STEPS-T) program on time-to-treat and clinical outcomes. Methods The study analyzed a prospectively maintained database of AIS patients who benefited from EVT through implementation of STEPS-T. Demographics, clinical characteristics, and modified Rankin Score at three months were analyzed. Thrombolysis in Cerebral Infarction (TICI) scale was used to grade pre- and post procedure angiographic recanalization. Using electronic hemodynamic recording, stepwise workflow times were collected for door time (TD), entering angiography suite (TA), groin puncture (TG), first DSA (TDSA), microcatheter placement (TM), and final recanalization (TR). Median intervention time (TA to TR) and recanalization time (TG to TR) were compared through Year 1 to Year 5. Results A total of 230 individuals (age 74 +/- 12, between 30 to 95) were enrolled. Median intervention and recanalization times were significantly reduced, from 121 minutes to 52 minutes and from 83 minutes to 36 minutes respectively from Year 1 to Year 5, ( p < 0.001). Across the study period, annual recruitment went up from 12 to 66 patients, and modified Rankin Score between 0 and 2 increased from 36% to 59% ( p = 0.024). Conclusions STEPS-T improved time-to-treat in patients undergoing mechanical thrombectomy for AIS. During the observation period, clinical outcomes significantly improved. PMID- 29119877 TI - Direct puncture Onyx embolization of a large calvarial metastasis with intracranial extension: Case report. AB - We report a case of renal cell carcinoma (RCC) metastasis to the calvarium and describe a strategy for percutaneous embolization of hypervascular calvarial tumors with intracranial extension. An elderly patient with history of RCC presented with left-sided weakness. Imaging studies showed a large right frontoparietal calvarial mass with intra- and extracranial extension. The tumor was devascularized by direct puncture tumor embolization using Onyx 18, allowing subsequent operative resection without significant blood loss or the need for flap reconstruction of the scalp. Compared to more common endovascular approaches, direct-needle puncture embolization of transcalvarial masses may offer lower risk of injury to scalp vessels and underlying brain parenchyma. PMID- 29119878 TI - The technique of superselective ophthalmic artery chemotherapy for retinoblastoma: The Garrahan Hospital experience. AB - Background Superselective ophthalmic artery chemotherapy (SOAC) is a proven therapy for the treatment of retinoblastomas. We describe the technique, results and complications of SOAC performed in our hospital. Objective The aim of this article is to demonstrate that a seemingly complex technique can be carried out with a low morbidity rate. Methods A retrospective analysis of patients receiving SOAC in our department from November 2014 to April 2017 was performed. Data collected were age, gender, number of procedures, arteries approached, bilaterality of treatment, and complications. The procedure was performed using a 3F sheath and a flow-dependent 1.5F microcatheter that was navigated from the femoral artery to the ostium of the ophthalmic artery (OA). When the OA was too small or a stable position could not be achieved, the microcatheter was navigated in the external carotid artery to reach an anastomotic ramus (AR) of the middle meningeal artery (MMA) to the OA. The drugs were then injected through the microcatheter in a pulsatile way. Results Forty-one patients underwent SOAC. A total of 248 procedures were performed in 45 eyes, and 248 arteries were approached (205 OAs and 43 MMAs). Four patients underwent tandem therapy (both eyes treated in the same procedure). Complications were: hypotension and bradycardia during the procedure (five cases), transient thrombosis of the femoral artery (two cases), retinal hemorrhage (one case), alopecia (one case), and anaphylactic shock to carboplatin (one case). No patient showed adverse effects of radiation or ischemic stroke. Conclusion SOAC is a safe technique with a very low complication rate. PMID- 29119879 TI - Magnesium and zinc borate enhance osteoblastic differentiation of stem cells from human exfoliated deciduous teeth in vitro. AB - Various biocompatible and biodegradable scaffolds blended with biochemical signal molecules with adequate osteoinductive and osteoconductive properties have attracted significant interest in hard tissue engineering regeneration. We evaluated the distinct effects of magnesium borate, zinc borate, and boric acid blended into chitosan scaffold for osteogenic differentiation of stem cells from exfoliated deciduous teeth. Stem cells from exfoliated deciduous teeth cells are a potential source of functional osteoblasts for applications in bone tissue engineering, but the efficiency of osteoblastic differentiation is low, thereby significantly limiting their clinical applications. Divalent metal borates have potential function in bone remodeling because they can simulate bone formation and decrease bone resorption. These magnesium, zinc, and B ions can gradually be released into the culture medium from the scaffold and induce advanced osteoblastic differentiation from stem cells from exfoliated deciduous teeth. Stem cells from exfoliated deciduous teeth with magnesium borate or zinc borate as inducer demonstrated more osteoblastic differentiation after 21 days of culture. Differentiated cells exhibited activity of alkaline phosphatase, bone related gene expression of collagen type I, runt-related transcription factor 2, osteopontin, osteocalcin, vascular endothelial growth factor, and angiopoietin-1, as noted via real-time polymerase chain reaction analysis, as well as significant deposits of calcium minerals. Divalent mental magnesium and zinc and nonmetal boron can be an effective inducer of osteogenesis for stem cells from exfoliated deciduous teeth. This experiment might provide useful inducers for osteoblastic differentiation of stem cells from exfoliated deciduous teeth for tissue engineering and bone repair. PMID- 29119880 TI - Preparation and in vivo evaluation of a novel gel-based wound dressing using arginine-alginate surface-modified chitosan nanofibers. AB - The development of an effective wound dressing with the ability to induce skin wound healing is a great challenge in medicine. Nanofibers are highly attractive for wound dressing preparation due to their properties such as hemostasis induction, good absorption of wound exudates, and facilitation of cell growth. Chitosan nanofibers have attracted great attention for application in wound dressings due to their accelerating effects on wound healing. In this study, arginine surface-modified chitosan nanofibers were successfully prepared by attachment of arginine molecules on the surface of chitosan nanofibers using sodium alginate through electrostatic interaction. The effect of pH on the amount of attached arginine was evaluated at three different pH values; 5, 6, and 7. Fourier-transform infrared spectroscopy and zeta potential of chitosan nanofibers before and after surface modification suggested the occurrence of the attachment of arginine to chitosan nanofibers. Scanning electron microscope images showed the nanofibrous structure of arginine surface-modified chitosan nanofibers with an average diameter ranging from 100 nm to 150 nm. The release of arginine from arginine surface-modified chitosan nanofibers gel showed a sustained release manner. The suitable viscosity and spreadability of arginine surface-modified chitosan nanofibers gel verified its easy application at the wound site. Arginine surface-modified chitosan nanofibers gel significantly improved the wound healing process including wound closure when tested in vivo using rat model. Additionally, histological examination and immunohistochemical studies showed the significant enhancement of the re-epithelialization, collagen deposition, and angiogenesis in the skin of the animal group treated with arginine surface modified chitosan nanofibers gel compared with the other control groups. These results suggested that arginine surface-modified chitosan nanofibers gel could be introduced as an effective wound dressing. PMID- 29119881 TI - Anxiety and attitudes towards sex in women requesting emergency contraception. AB - : We performed an observational descriptive study on 89 women who requested for emergency contraception (EC) at the emergency units of two hospitals, Virgen de la Victoria Hospital, and Regional University Hospital in Malaga between October 2016 and April 2017. Both hospitals are on the Andalusian Public Health System. We evaluated a group of socio-demographic variables and others related to the beliefs and the knowledge about EC and contraception in general, sexual behavior, Eysenck's Inventory of Attitudes to Sex (satisfaction and promiscuity factors), and State-Trait Anxiety Inventory (STAI). RESULTS: State anxiety scores were low in 10.8% of the participants, middle in 25.7% and high in the 63.5%. On the other hand, the scores for trait anxiety were low in 13.5%, middle in 39.2% and high in 47.3%. The demand for EC resulted in a stressful situation for women, especially for youngest women. Also, married women with children and a history of pregnancy terminations showed higher anxiety scores. Regarding sexual attitudes, the highest levels of anxiety (state and trait) were found in women with less knowledge about EC, and in those who reported less satisfaction with their sex life. Best fit regression models for anxiety levels included beliefs that ECs are abortive, sexual dissatisfaction and women's age as predictive variables for STAI scores. In conclusion, women who requested EC showed high scores in anxiety-state and -trait, with those of younger age presenting more intense emotions. PMID- 29119882 TI - Current status of anti-inflammatory therapy for posttraumatic osteoarthritis. AB - Although there is ample evidence that intra-articular injuries are associated with the up-regulation of pro-inflammatory cytokines, the success of anti inflammatory, disease-modifying treatments to prevent posttraumatic osteoarthritis (PTOA) remain uncertain. To summarize the current status of anti inflammatory therapy for PTOA, we conducted a systematic review. 9 clinical studies in humans were identified applying anti-inflammatory agents to prevent or treat PTOA. A total of 347 patients aged an average 41 +/- 14 years were included in this review. 5 studies had comparable designs with randomized allocation. Those studies of course had a statistically significant higher Coleman Methodology Score (65 +/- 6) than the case-control studies (39 +/- 13, p = 0.013). The most frequently reported main outcome parameter was pain assessed by different scales (n = 7), the most examined joint the knee (n = 7). The majority of the analyses (n = 6) focused on the intra-articular (IA) application of hyaluronic acid (HA) reporting mainly positive effects. One study stated positive results following IA administration of Interleukin 1 receptor antagonist in patients presenting rupture of the anterior cruciate ligament. Platelet-rich plasma was also used to relieve symptoms following acute injury, but the study quality was too low to conclude any effects. Although the initial data, especially regarding IA HA injection, are encouraging, study designs differ substantially. Therefore, current data does not allow us to conclude that anti inflammatory therapy following acute injuries has beneficial effects on short- or long-term outcomes. PMID- 29119883 TI - A retrospective review of 345 patients with lumbar TDR in two years follow-up over 10 years of practice in one Belgian clinical center : Results. AB - Low back pain is one of the most common symptom with high cost for the public health. When conservative treatment fails, patients are heading to surgical treatment. Instead of lumbar arthrodesis, we can offer an alternative that will keep the intervertebral mobility : Total disc replacement (TDR) by prosthesis. Many studies have published good results rate over 80%, since first implantation in 1984. Believing in keeping the mobility, we promote TDR since 2002. This retrospective study review 345 patients with two years follow-up. The outcomes show 81% of good and really good results, according to gain of improvement on VAS and ODI scores. We report 6.88% of complications for the abdominal approach and 4.57% for the device, without harmful complication. Same results are obtained in case of postdiscectomy syndrome. PMID- 29119884 TI - Physicians versus surgeons. A pilot study on hand dexterity within a controlled population. AB - introduction : Hand dexterity is defined as the innate or acquired capacity of performing any given procedure with one's hands. This study seeks the role of regular hand training on hand dexterity over time. Materials and Methods : Pilot study composed by two independent groups with 28 subjects each (surgeons and physicians), stratified according to gender and age. Measurement of hand dexterity using Lafayette's Purdue Pegboard through the sum of the first three exercises as well as the assembly exercise. No difference was found between groups in regards of gender, age, time of practice and hand size (p = 0.415 ; p = 0.225 ; p = 0.267 ; p = 0.937). Statistical significance was assumed when p < 0.050. Results: Surgeons performed better but a statistically significant difference was not observed both on the -assembly score (p = 0.560) and three tests sum score (p = 0.244). The decay of dexterity over time happened in a homogeneous fashion in the surgeons' arm (p < 0.001 and p = 0.043) but not in the physicians' arm (p = 0.157 and p = 0.098). Discussion : Surgeons seem to perform better than physicians in regards of hand dexterity, although no definitive conclusion was possible given our small sample. It is well known that aging worsens hand -dexterity, but our study suggests it happens much more homogeneously within surgeons. PMID- 29119885 TI - RManagement of osteoporotic compression vertebral fractures. AB - Pathological vertebral fractures including osteoporotic compression fractures are common problems with an incidence which increases as the age of the population increases. The aim of this study is to evaluate the clinical outcome of percutaneous vertebroplasty in patients with refractory pathological fractures. It is a clinical prospective study conducted on 56 patients. The patients were assessed pre- and postoperatively with (VAS) with a 0 to 10 scaling. Local anesthesia was used in 51 patients and general anesthesia was used in 5 patients. Biplanar fluoroscopy was used. Unipedicular approach was used. 87.5% of patients experienced partial or complete pain relief within the first 24 hours after the procedure. The mean preoperative VAS was 8.4 +/- 1.6, which improved to 2.5 +/- 0.3 at four weeks after surgery. This mini-invasive procedure can immediately and significantly reduce pain and improve the quality of life of these patients. PMID- 29119886 TI - Paraspinal muscle volume in patients with Scheuermann's Kyphosis. AB - To measure the cross-sectional area (CSA) of para-spinal muscles in Scheuermann's kyphosis patients. Preoperative MRI images of 16 Scheuermann's kyphosis patients were analysed and compared to 16 patients with normal MRI images (control group). The CSAs were measured at L3-4 and L4-5. Both groups showed similar demographics and patient characteristics. The multifidus muscles CSA were found to be significantly smaller at L3/4 level in Scheuermann's kyphosis patients (p = 0.022 on the left and p = 0.016 on the right side compared to control group). There was no significant change in multifidus CSA found at L4/5. The mean CSA of the extensor spinae muscles group were significantly smaller at all levels in Scheuermann's kyphosis patients : p = 0.001 bilaterally at L3/4 and p = 0.015 right side and p = 0.009 left side at L4/5 level. This study shows that patients with Scheuermann's kyphosis deformity have significantly smaller CSA of lumbar multifidus and extensor spinae muscles. PMID- 29119887 TI - Aneurysmal bone cyst (ABC) : treatment options and proposal of a follow-up regime. AB - The aim of this study was to describe treatment -options and develop a follow-up regime for the -aneurysmal bone cyst, a neoplastic bone lesion with a noticeable recurrence rate. Reports of 28 patients and a mean follow-up of 42.2 months treated multidisciplinary were analysed. Data were complemented by a literature review including 790 patients. Patient age was from seven to 57 years, in line with the literature (1-69 years). Lesions most frequently affect long bones, spine and pelvis ; pain is the most common symptom. Treatment modalities vary, recurrences -occurred in 26.1% in our series, rates ranged from 0-60% in the literature, with the vast majority within 2 years. With regard to the findings we propose, irrespective of treatment, a follow-up regime including clinical survey and imaging, best with MRI, at 3 months, 6 months and at half-yearly intervals within the first two and yearly within the third to fifth year. PMID- 29119888 TI - Comparison between single stage and two stage bilateral total hip replacement- our results and review of literature. AB - Bilateral total hip replacement (THR) is a common procedure nowdays. Staging of surgery is still a -matter of debate. We performed a study to compare single stage and two stage bilateral THR and discuss the peri-operative and post operative advantages and complications. This was a retrospective study. 48 patients underwent single stage and 56 patients underwent two stage bilateral THR. The average follow up period was 64 months and 70 months respectively. The hospital stay was 5.6 days in single stage and 9.0 days in two stage bilateral THR. The total blood loss was 280 ml and 440 ml ; average blood trans-fusion was 1.6 units and 2.2 units and walk without support was started at 42 days and 58 days respectively. No difference in complication rate was seen. Single staged bilateral THR is a safe procedure. The definite benefits are short hospital stay, lower cost and early rehabilitation. PMID- 29119889 TI - Early clinical failure of the ACCIS(r) metal on metal hip arthroplasty system - A metal on metal hip with a difference. AB - The ACCIS hip system has been marketed with a unique bearing surface which the manufacturers claim to reduce wear below the level of other MoM bearings and consequently less metal ion release. The cobalt-chrome-molybdenum alloy is heat treated to reduce the number and size of block carbides and the surface is modified with titanium-niobium-nitride to create a ceramic-like surface. We present our experience with ACCIS. 148 surgical procedures were carried out in 126 patients using the ACCIS hip resurfacing (77) or large head MOM total hip replacement(71). Patients were followed up with regular clinical and radiological assessment. In addition, metal ion levels were obtained. There have been 27 revision procedures carried out for a variety of indications with a current revision rate of 18%. Seven failures could not be attributed to the prosthesis itself, still leaving a failure rate of 13.5%. The mean survival time of these is 33 months, ranging from 1 to 72 months. 13 revisions were -performed for pain and revision demonstrated poor cup integration. 7 were revised because of high ion levels but this was patient choice despite remaining asymptomatic. Whilst the testing phases indicated benefits in wear characteristics, this is not apparent in our group. We have demonstrated an unacceptably high revision rate due to unknown causes and have ceased implanting the ACCIS. PMID- 29119890 TI - Simultaneous versus staged bilateral direct anterior Total Hip Arthroplasty: Are early patient-centered outcomes equivalent? AB - While accumulating data on the direct anterior approach to total hip arthroplasty (THA) have demonstrated clinical benefit and durable results, there is little data that exists on patient-centered outcomes and satisfaction when comparing simultaneous bilateral procedures with staged arthroplasty. The aim of this study was to determine whether simultaneous bilateral THA and staged arthroplasty result in equivalent early (1) patient-centered outcomes and patient satisfaction; while maintaining acceptable rates of (2) objective clinical outcome scores, (2) complication rates; and (3) radiographic results. In retrospective review, 41 patients who underwent bilateral one-stage THA were compared to 44 patients who underwent staged bilateral THA during the same time period. The minimum clinical follow up was two years. Generic (EQ-VAS and EuroQoL 5D index) and condition-specific (Oxford Hip Score) instruments were used to assess patient-reported outcomes. Other variables included length of hospital stay (LOS), operative and anesthetic times, blood loss, intra- and post-operative (local and systemic) complications, and radiographic analysis. No significant differences between the two groups were found for patient-reported outcomes, complications, or radiographic assessment. The simultaneous THA group had shorter LOS and operative and anesthetic times, as well as less blood loss. PMID- 29119891 TI - The treatment of intertrochanteric fractures comparison of PFN and hemiarthroplasty 3-year mortality study. AB - Intertrochanteric fractures in elderly patients can increase mortality due to complications and negative functional results. The aim of this study is to retrospectively compare the follow-up and mortality rates among patients given a proximal femoral nail (PFN), the current routine treatment for these types of fractures, with those given hemiarthroplasty.The study retrospectively investigated 202 patients over the age of 60 who completed at least 3 years of follow-up after hemiarthroplasty or PFN for intertrochanteric fractures between 2007 and 2012. While 132 patients underwent cemented hemiarthroplasty, 70 had PFN.The monitoring duration for those with PFN surgery was 31.25+/-1.3 months while the duration of follow-up for those with hemiarthroplasty surgery was 20.0+/-1.2 months. At the end of 3 years of monitoring of the 202 patients, 99 were deceased. There was a statistically significant difference found in terms of patient life expectancy between those with PFN and those with hemiarthroplasty; Cox regression analysis identified that the mortality rate of those with hemiarthroplasty was 5.1 times greater.As a result, patients undergoing hemiarthroplasty should be carefully chosen and if possible, PFN should be preferred. PMID- 29119892 TI - Are there differences in Hip Biomechanics after hybrid and cementless resurfacing arthroplasty? AB - There is a paucity of information regarding the clinical performance of the fully cementless metal-on-metal hip resurfacing designs. We compared the biomechanical reconstruction between the two hips of a group of patients treated with a hybrid resurfacing design on one side and a new, fully cementless version of the same resurfacing design on the other side.We retrospectively identified 20 patients with a hybrid hip resurfacing on one side and a fully cementless device on the contralateral side. The cemented femoral components were implanted with a target angle stem to shaft angle of 140 degrees while the cementless femoral components were implanted with the aim to replicate the natural neck to shaft angle.No significant differences were observed post-operatively in femoral offset or leg length despite implantation with a larger metaphyseal stem to femoral shaft angle in the hybrid group. Both hybrid and cementless designs provide similar biomechanical reconstructions. PMID- 29119893 TI - Positive impacts of Patient Blood Management in total hip arthroplasty. Retrospective and prospective studies (N=700). AB - The study aimed to determine the impact of implementing a patient blood management (PBM) policy during total hip arthroplasty. Firstly, the authors collected retrospective data concerning blood consumption for all patients (N = 577) having undergone total hip arthroplasty between 2009 and 2011, other than for post-traumatic indications. During this period, no coherent blood management rules were in place. Based on the results obtained, a blood transfusion strategy called Patient Blood Management (PBM) was defined and implemented in our department for this type of surgical procedure beginning 2012. The impact of PBM was then analyzed after a 6-month prospective study during 2013/2014 on a cohort of 123 patients. These prospective data demonstrate that PBM significantly improved patient care and reduced the need for allogeneic labile blood transfusions. PMID- 29119894 TI - Debridement, antibiotics and implant retention in early periprosthetic joint infection after primary total hip arthroplasty : 88 percent survival after two years follow-up. AB - Treatment protocols and results of debridement, antibiotics, irrigation and retention of the prosthesis (DAIR) for early prosthetic joint infection (PJI) vary in literature. The purpose of this study was to analyze the results of DAIR with a multidisciplinary designed customized antibiotic protocol for early PJI after primary total hip replacement (THR). We retrospectively analyzed all patients with an early PJI between 2008 and 2012. When an infection was suspected, debridement of the prosthesis, and -collection of intraoperative cultures, was performed. -Patients were multidisciplinary discussed and treated with an appropriate antibiotic scheme for 12 weeks. Primary outcome was retention of the prosthesis after at least two years follow-up and without any signs of infection. We indentified 25 patients with early PJI. At a median follow-up time of 3.1 years (range 2.1-5.5 years), 88% had retention of the prosthesis and no signs of infection. This study suggests that DAIR with a multidisciplinary approach and an aimed antibiotic treatment for early PJI after THR is a reasonable treatment -option with 88% implant retention after two years follow up. PMID- 29119895 TI - Total hip Replacement in Crowe type IV dysplastic hips - average 5 year follow-up and literature review. AB - This is a retrospective study of 29 patients (34 hips) of Crowe grade IV dysplastic hips aged between 19 and 75 years who underwent THR for osteoarthritis secondary to DDH. The hips were evaluated radiologically for Sharp's acetabular angle, cup inclination, loosening, and ectopic bone formation. Clinically the results were evaluated by pre and postoperative -Harris hip scoring. The mean acetabular angle was 60.8 degrees (range, 45 degrees -68 degrees ) preoperatively. In 18 hips, subtrochanteric femoral osteotomy was performed. Pre operatively, the mean leg length discrepancy was 5 cm (range, 2-8 cm). Correction within 1 cm was possible in all patients -except in 4 patients. The mean Harris hip Score was 40.80 (32-45.90) preoperatively and 87.96 (74.78-94.72) at last follow-up. THR is successful in high dislocation dysplastic hips. Although there is no gold standard technique of THR in dysplastic hips and treatment of each patient should be individualized. Level of evidence : IV. PMID- 29119896 TI - Influence of pelvic postural angle change on acetabulum implantation in total hip arthroplasty. AB - The current study investigated the relationship between the implantation angle of the acetabular component and the change in the pelvic postural angle during hip arthroplasty surgery. One pelvis with a left lower limb prosthesis was used. Total hip arthroplasty on the left pelvis was simulated with the help of a computer-assisted navigation system. The pelvis revolved around the horizontal, longitudinal and sagittal axes at different angles, and the anteversion and abduction of the acetabular component were measured. The changing angle of the pelvis rotating around the horizontal and longitudinal axes greatly influenced acetabular component anteversion. The changing angle of the pelvis rotating around the sagittal axis had a relatively great influence on the acetabular component abduction angle. The change in the postural angle of the pelvis had a great influence on the installation angle of the acetabular component. It is important to standardize posture prior to the operation. PMID- 29119897 TI - Geometrical restoration and component positioning after hip arthroplasty for femoral neck fracture. AB - In this study, the restoration of leg length and global femoral offset and positioning of the femoral stem and acetabular cup of hemiartroplasty (HA) and total hip arthroplasty (THA) after femoral neck fracture (FNF) were compared at the postoperative radiographs between 181 hips operated using the direct lateral (DL) approach and 127 hips operated using the posterolateral (PL) approach. Regarding HA, the DL approach was associated with lengthening of the operated leg (5.7 mm vs. 2.1 mm), p = 0.001. The PL approach had more varus stem position (23% vs. 12%, p = 0.03) and the DL approach had more stems with C-position (58% vs. 32%, p = 0.001). Regarding THA, the DL approach showed increased cup anteversion (28 degrees vs. 21 degrees ), p = 0.016, and a decrease in FO (-5.9 mm vs. -2.0 mm, p = 0.04). Surgeons caring for FNF patients are to be aware of the differences in geometrical restroration and component positioning -between the two approaches. PMID- 29119898 TI - Constrained acetabular liners in hip revision surgery. A low-cost solution for senile patients. AB - The objective of this study was to analyze the results of a cemented polyethylene model that captures the hip prosthetic head. In a retrospective study we reviewed 36 cemented constrained acetabular liners implanted in patients older than 75 years (mean 83, SD : 4.4), of which 30 patients were aged 80-90 years and 26 were women. The average period of follow-up of our patients was 25.4 months (12-39 months, SD : 7.3). In 26 patients this model was implanted due to recurrent dislocation or instability, in 8 other cases this model was implanted during revision surgery for periprosthetic fractures, aseptic loosening of the acetabular component, wear of the polyethylene or replacement of the implant because of infection. There was a single case of recurrent dislocation (2.8%). Cemented acetabular constrained liners are a good option in revision surgery in senile patients in which the femoral stem is firmly fixed to the bone. PMID- 29119899 TI - Development of a lower limb arthroplasty service in a developing country : Lessons learned after the first 100 cases (joints). AB - There is emerging evidence that total hip arthroplasty (THR) can be safely practiced in developing countries but scant evidence of safety of total knee replacement (TKR). The purpose of this study is to evaluate the outcomes of these procedures focusing on procedure related complications. This is a retrospective study of the first 100 arthroplasties (92 patients) consisting of 58 TKR and 42 THR with a minimum follow-up of 26 months (range of 26 to 47 months). Major complications included deep infection in one TKR and dislocation of one THR and one TKR. Two patients died in the second post-operative week from cardiac events following TKR. Blood transfusion rate for hips and knees was 13.7% and 5.6% respectively. THR can be safely performed in less than ideal circumstances in developing countries in carefully selected patients. More importantly this study demonstrates that TKR can be safely practiced under the same circum-stances. PMID- 29119900 TI - GUse of provisional K wires instead of Poller screws for treatment of diametaphyseal fractures of the distal femur and proximal and distal tibia. AB - There are several important technical points that need to be observed when using an intramedullary nail to fix diametaphyseal fractures of femur and tibia. We aimed to describe a technique using 3.0-mm K wires, which act like Poller screws, in conjunction with intramedullary nails to obtain alignment of diametaphyseal fractures of the femur and tibia, and present our results. 7 distal femoral, 2 proximal tibial, and 4 distal tibial diametaphyseal fractures who were treated with this technique were identified. There was no case of nonunion at the last follow-up. In all, 12 of the 13 patients had postoperative fracture angulation that was less than 5 degrees degrees in the coronal and sagittal planes. K wires function essentially as a Poller screw for centralization of the nail and help to ensure reduction. Locking the nail in different directions, appropriate reduction can be maintained until the bone heals and there is no need for additional fixation material. PMID- 29119901 TI - Comparison of interfragmentary compression in conventional and locked plating of proximal unicondylar tibia fractures : A biomechanical cadaver study. AB - The extent of interfragmentary compression in intra-articular fractures treated with various fixation methods have not yet been reported. Lateral split fractures were created in six pairs of cadaver tibiae treated -using buttress plating with lag screws (group C) or locked buttress plating after clamp compression (group L). Interfragmentary compression and fracture displacement were continuously measured using pressure sensors and a stereoscopic 3-D image correlation system. Significantly larger interfragmentary compression was found initially after clamping the fragment (p < 0.05) in group C (median +/- SD ; 45.1 +/- 5.0 N/mm2) compared with group L (33.6 +/- 3.4 N/mm2), and a statistical trend towards larger compression was also found after cyclic loading (p = 0.05) in group C (45.3 +/- 8.6 N/mm2) compared with group L (28.7 +/- 5.8 N/mm2). These data indicate that conventional plating with lag screws achieves higher interfragmentary compression in this model compared with external clamp compression and locked plating. PMID- 29119902 TI - Use of tantalum cones in primary arthroplasty of acute proximal tibial fractures. AB - Metaphyseal tantalum cones in primary total knee arthroplasty and their functional outcome is described using 3 case reports over 6 years. 3 knees in 3 elderly individuals (mean age of 70.4 years), with pre-existing osteoarthritis and complex proximal tibial fractures, were operated on. Ambulation with walking frame was achieved from post-operation day 1, with weight-bearing as tolerated. Mean range of motion was 122 degrees and Mean Knee Society Score was 88. All showed improvement in pre-operative limb alignment. Radiological fracture union was achieved on an average of 3 months. All were independent ambulators and pain free at the latest follow-up. Our case series shows that tantalum cones are associated with significant improvements in clinical scores, patient symptoms, range of movement, early weight-bearing and low rates of complications in complex proximal tibial fractures with poor bone stock. PMID- 29119903 TI - Is acute compression and distraction superior to segmental bone transport techniques in chronic tibial osteomyelitis ? Comparison of Distraction Osteogenesis Techniques. AB - Treatment of tibial osteomyelitis with infected, necrotic, unstable bone segments (Cierny-Mader Type IV local osteomyelitis) includes debridement and segmental resection, which results in long bone defects. Reconstruction may be with distraction osteogenesis. Segmental bone transport and acute compression and distraction techniques are two main distraction osteogenesis techniques used in the treatment of Type IV local tibial osteomyelitis. In this retrospective, four center study we compared these two techniques during a 15-year period. 29 patients treated using segmental bone transport technique and 45 patients were treated using acute compression and distraction technique. The mean age (p= 0,34) and the mean bone loss with preoperative shortening (P=0,08) and the mean number of previous operation (p=0,06) were not different in these two groups. . At latest followup, functional and radiographic results were evaluated There was no difference between two technique on the Paley's scoring system ( p=0,33) and in the total number of complication(p=0,16). Mean external fixator index was lower in the second group ( p=0.02 ). Both techniques can be used safely; however, the acute compression distraction technique may provide greater patient satisfaction because of shorter external fixator index, although future studies will be needed to determine whether this is. PMID- 29119904 TI - Outcome of surgery for chronic patellar tendinopathy: A systematic review. AB - There is no consensus on how to best surgically treat chronic patellar tendinopathy. This systematic review investigates the surgical treatment for chronic patellar tendinopathy, and the outcomes. A database search was performed to identify all relevant articles, to which exclusion criteria were then applied. Data was extracted from 24 studies, and the outcomes were then systematically reviewed. The results showed that the success rate of surgery for patellar tendinopathy is generally over 77%. Return to sports rates are better for proximal tendon patients who undergo bony procedures. Patients return to sports faster if they undergo arthroscopic procedures, and fewer complications are described. Studies that did not involve any procedure on the proximal tendon did not produce a different result to studies where the tendon was operated on. We found no effect of post-operative immobilisation on outcome. Based on the included studies, surgery gives satisfactory results in the treatment of patellar tendinopathy. There is a lack of high-quality evidence on the effects of surgery and post-operative rehabilitation regime on chronic patellar tendinopathy, as well as lack of objective outcome measures. PMID- 29119905 TI - Tendon balancing in hallux valgus surgery. AB - Recurrent valgus of the hallux after hallux valgus surgery is an unpleasant complication. A possible cause is the imbalance and maltracking of particularly the extensor hallucis longus (EHL) and less frequently the flexor hallucis longus (FHL) or extensor hallucis brevis (EHB) tendon of the hallux. In patients with a tight achilles tendon, the EHL tendon can be recruited to aid dorsiflexion of the foot, creating imbalance. The literature on this subject is very scarce. In 10 patients with severe hallux valgus, a perioperative evaluation after performing the osteotomies and capsular closure showed tight extensor or flexor tendons of the hallux with residual valgus maltracking. A balancing of the tendons was performed with a -realignment -lengthening procedure. A good clinical result was obtained in all patients. No adverse effects were seen after tendon balancing. Strength in all tendons was at least 3+, except in one patient with multiple sclerosis. No weaknesses or -difficulties during walking were reported. Tendon balancing could play a role in prevention of hallux valgus recurrences and can be performed without loss of strength or compromising of walking ability. PMID- 29119906 TI - Reduced length of stay with minimally invasive repair of ruptured achilles tendon. AB - Minimally invasive techniques to repair ruptured achilles tendons have been developed to enhance recovery following tendon repair and decrease wound complications associated with open repair. We investigated outcomes of minimally invasive and open repair of acutely ruptured achilles tendons at our institution. We compared all cases of achilles tendon repair at our department, using open techniques and minimally invasive techniques with the Achillon device, over a two year period. Length of stay and operating time was recorded, as were any complication rates, including tendon re-rupture. Post-operatively functional outcome questionnaires were sent to all patients. In total 39 patients underwent open repair and 26 underwent minimally invasive repair. Length of stay was significantly shorter in the minimally invasive group, with 58% of minimally invasive cases performed as a day case, compared to 31.1% of open cases (p = 0.02). There was no difference in complication rates, including re-rupture, or functional outcome scores. Minimally invasive repair of ruptured achilles tendons results in reduced length of stay, compared to open repair. There is no evidence of weaker tendon repairs with minimally invasive techniques. Overall functional outcomes between both groups appear similar. Level of Evidence : III. PMID- 29119907 TI - Reversed shoulder arthroplasty as treatment for late or ancient chronic glenohumeral dislocation. AB - Chronic glenohumeral dislocation is a rare entity and several treatment options have been proposed. The aim of this study is to report the long-term follow-up of the reversed shoulder arthroplasty in patients with chronic glenohumeral dislocation. A retrospective analysis of all patients between January 2002 and December 2012 that were treated with a reversed shoulder arthroplasty for chronic anterior glenohumeral dislocations was performed. Pre-operative CT evaluation of the bone loss and fatty degeneration of the rotator cuff muscles was performed. Pre- and postoperative Constant-Murley score was evaluated. 6 patients (4 males and 2 females) with anterior glenohumeral dislocations were evaluated. Average age was 73 years (between 65-86 years). The average time of dislocation was 18 weeks (between 4 and 52 weeks). Average time of follow-up was 39 months (between 12 and 90 months). The CM improved from 33 (between 17 and 45) pre-op to 76 postop (between 55 and 89). No postoperative complications were observed. Reversed shoulder arthroplasty gives good results in case of chronic glenohumeral dislocation. PMID- 29119908 TI - Comorbidity in Dupuytren disease. AB - In this report, a possible association between Dupuytren's disease (DD) and other health problems was investigated. The health problems included in this study are : cardiac ischemia, hypertension, hyper-lipidemia, diabetes mellitus, epilepsy, gout, rheumatoid arthritis, malignancy, asthma and COPD. The data of 725 patients with DD were collected from -Intego, a database including all morbidity presented to the General Practitioners (GPs) in Flanders. The control group of 2900 age and sex matched non-DD patients was selected from the same database. A possible influence of severity of DD was evaluated by comparing the data of 333 patients operated for DD with the group of Integopatients with DD. This study showed a significant association of every single studied health condition with DD. Comparison of the -operated group with the group from Intego with DD, demonstrated only some significant associations, a difference which may be explained by the difference in data collection. PMID- 29119909 TI - Displaced distal end radius fractures in children treated with Kirschner wires - A systematic review. AB - The purpose was to analyse two reported risk factors on the outcome of Birmingham hip resurfacing (BHR). We reviewed consecutive BHR arthroplasties and found 1,476 cases eligible for analysis. The mean follow-up was 7.3 years. Patients were classified into groups according to their head size and body mass index (BMI). Statistical analysis examined the follow-up Oxford Hip Scores (OHS) and revision rates between groups. In the large head group (50mm and above) the OHS was 0.5 points higher (p=0.003) than the small head group. In the non-obese group (BMI <30) it was 0.3 points higher (p=0.007). No significant difference in the survival of the implants by either head size or by BMI was detected. BHR is a suitable option offering good survival and higher functional outcomes in non obese patients (BMI<30) with larger femoral head diameters (50 and above). Although results are statistically significant such a small difference in OHS will rarely show significant clinical difference. Therefore, despite. PMID- 29119910 TI - The pre-drilled hole method in the freehand technique for ulnar shortening osteotomy : a case series study. AB - Ulnar shortening is a common procedure for treating ulnar wrist pain of various causes. Many tools and devices had been reported in the literature to facilitate the procedure, but not all are universally available. Freehand technique is still useful in clinical practice. Here we present a pre-drilled hole method to improve the outcomes of the freehand technique. From 2008 to 2012, a total of 51 patients at our institution underwent ulnar shortening with this method, with an -average follow-up period of 24.4 months (range, 12-62 months). The average shortening length was 4.6 mm (range, 3-8.5 mm). All patients had uneventful union at an average of 9.8 weeks (range, 8-14 weeks) after the surgery. All had improved functional results. All patients returned to their previous full level of work and activities. The pre-drilled hole method for ulnar shortening is an easy assist to the freehand technique. Also, the union rate is high, and complications are uncommon. PMID- 29119911 TI - Adherence to infection control guidelines in surgery on MRSA positive patients : A cost analysis. AB - In surgical units, similar to other healthcare departments, guidelines are used to curb transmission of methicillin resistant Staphylococcus aureus (MRSA). The aim of this study was to calculate the extra costs for material and extra working hours for compliance to MRSA infection control guidelines in the operating rooms of a University Hospital. The study was based on observations of surgeries on MRSA positive patients. The average cost per surgery was calculated utilizing local information on unit costs. Robustness of the calculations was evaluated with a sensitivity analysis. The total extra costs of adherence to MRSA infection control guidelines averaged ? 340.46 per surgical procedure (range ? 207.76- ? 473.15). A sensitivity analysis based on a standardized operating room hourly rate reached a cost of ? 366.22. The extra costs of adherence to infection control guidelines are considerable. To reduce costs, the logistical planning of surgeries could be improved by for instance a dedicated room. PMID- 29119912 TI - The glutamate and the immune systems: new targets for the pharmacological treatment of OCD. AB - BACKGROUND: In the last decades the pharmacological treatment of obsessive compulsive disorder (OCD) has been significantly promoted by the effectiveness of selective serotonin (5-HT) reuptake inhibitors (SSRIs) and the subsequent development of the 5-HT hypothesis of OCD. However, since a large majority of patients (between 40% and 60 %) do not respond to SSRIs or strategies based on the modulation of the 5-HT system, it is now essential to search for other possible therapeutic targets. AIMS: The aim of this paper was to review current literature through a PubMed and Google Scholar search of novel hypotheses and related compounds for the treatment of OCD, with a special focus on the glutammate and the immune systems. DISCUSSION: The literature would indicate that glutamate, the main excitatory neurotransmitter, might play an important role in the pathophysiology of OCD. In addition, a series of clinical study would also support the potential efficacy of drugs modulating the glutamate system. The role of the immune system alterations in OCD in both children and adults needs to be more deeply elucidated. In children, it has been widely described a subtype of OCD resulting from infections driven by group A streptococcus beta-hemolitic and belonging to the so-called "pediatric autoimmune neuropsychiatric disorders associated with streptococcus" (PANDAS). In adults, available findings are meager and controversial, although interesting. CONCLUSIONS: The glutamate and the immune systems represent two intriguing topics of research that hold promises of development of open novel treatment strategies in OCD. PMID- 29119913 TI - The Growing Role of Electron Microscopy in Anti-parasitic Drug Discovery. AB - Parasitic diseases are a huge burden on human health causing significant morbidity and mortality. However, parasitic structure based drug discovery programmes have been hindered by a lack of high resolution structural information from parasitic derived proteins and have largely relied upon homology models from mammalian systems. The recent renaissance in electron microscopy (EM) has caused a dramatic rise in the number of structures being determined at high resolution and subsequently enabled it to be thought of as a tool in drug discovery. In this review, we discuss the challenges associated with the structural determination of parasitic proteins. We then discuss the reasons behind the resurgence in EM, how it may overcome some of these challenges and provide examples of EM derived parasitic protein structures. Finally, we discuss the challenges which EM needs to overcome before it is used as a mainstream technique in parasitic drug discovery. PMID- 29119914 TI - Obsessive-compulsive disorder with comorbid bipolar disorders: clinical features and treatment implications. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) symptoms within the context of a bipolar disorder (BD) have been described since the 19th century. Interestingly, the existence of a relevant overlap between the aforementioned psychiatric syndromes has been confirmed by a number of recent epidemiological and family studies. AIMS: The aim of the present paper is to review the clinical features and the therapeutic implications of the OCD-BD comorbidity. DISCUSSION: In the last two decades, the frequent association between OCD and BD has been earning a growing interest given its relevant nosological and therapeutic implications. Usually patients suffering from OCD-BD comorbidity show a peculiar clinical course, characterized by a larger number of concomitant depressive episodes and episodic course. In these cases, the treatment with antidepressants is more likely to elicit hypomanic or manic switches, while mood stabilizers improve significantly overall clinical picture. Moreover, OCD-BD patients are frequently comorbid with a number of other psychiatric disorders, in particular anxiety disorders, social phobia, and different substance abuses, such as alcohol, nicotine, caffeine and sedatives. CONCLUSIONS: BD-OCD comorbidity needs further investigations in order to provide more solid evidences to give patients a more precise clinical diagnosis and a more targeted therapeutic approach. PMID- 29119915 TI - An Update on Potential Molecular Mechanisms Underlying the Actions of Snake Venom L-amino Acid Oxidases (LAAOs). AB - BACKGROUND: LAAOs (EC 1.4.3.2) are found in concentrations that vary according to each species of snakes; Viperidae, Crotalidae and Elapidae contain 1-9% of this enzyme in their venoms. METHODS: This review focuses on an update on molecular mechanisms, platelet activities, antimicrobial, antiprotozoal, induction of apoptosis and inflammatory potential underlying the actions of SVLAAOs. RESULTS: Snake venom LAAOs (SV-LAAOs) have become an interesting subject for pharmacological, structural and molecular studies. CONCLUSION: Although the mechanisms of action of these enzymes are not well understood they are a subject of a variety of studies, because LAAOs are multifunctional enzymes exhibiting a wide range of pharmacological effects, including the inhibition or induction of platelet aggregation, hemolysis and hemorrhage, in addition to the stimulation of apoptosis, the activation of leukocytes and the formation of edema. Moreover, SV LAAOs play an important role in bactericidal, cytotoxic, anti-parasitic, anti tumor, and antiviral activities. PMID- 29119916 TI - Cytoprotective Polyphenols Against Chronological Skin Aging and Cutaneous Photodamage. AB - BACKGROUND: Skin aging is a complex biological process influenced by a combination of intrinsic and extrinsic factors, leading to cumulative alterations of skin structure, function and appearance. Polyphenols, which are secondary plant metabolites, represent one of the largest classes of compounds used in dermatology and nutricosmetics to combat skin aging. The main objective is to provide an overview of the existing literature linking skin aging and the ability of polyphenols as regulatory elements able to maintain skin homeostasis. METHODS: In this review, we discuss recent progress in understanding the molecular bases of skin aging, with specific emphasis on some well known and extensively studied polyphenols which have significant anti-aging influences and photoprotective effects. RESULTS: Although no relevant clinical data exist and standard delivery systems have not been established, promising results have been obtained in many in vitro and animal models. A wide variety of polyphenols may minimize mechanisms underlying the functional manifestations of photoaging and chronological skin aging. CONCLUSION: Polyphenols exert their influence mostly through their antioxidant and anti-inflammatory effects, thereby abrogating collagen degradation and/or increasing procollagen synthesis. PMID- 29119918 TI - New Strategies for the Prevention and Treatment of Bone Loss - From Mechanical Loading Point of View. AB - In contemporary society, a large number of adults experience more or less decrease in bone mass or bone density. It is known that bone, in response to mechanical loading, undergoes continuous remodeling throughout life, which helps in the growth and maintenance of the skeleton. Since mechanical loading acts as an important stimulus for bone growth and maintenance, it can be used as a strategy to prevent and treat the conditions of bone loss. This review summarizes the current knowledge about the effects of mechanical loading on bone, in the level of cells and tissue. PMID- 29119917 TI - Use of E. coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors. AB - BACKGROUND: The selective expression of non-human genes in tumor tissue to activate non-toxic compounds (Gene Directed Prodrug Enzyme Therapy, GDEPT) is a novel strategy designed for killing tumor cells in patients with little or no systemic toxicity. Numerous non-human genes have been evaluated, but none have yet been successful in the clinic. METHODS: Unlike human purine nucleoside phosphorylase (PNP), E. coli PNP accepts adenine containing nucleosides as substrates, and is therefore able to selectively activate non-toxic purine analogs in tumor tissue. Various in vitro and in vivo assays have been utilized to evaluate E. coli PNP as a potential activating enzyme. RESULTS: We and others have demonstrated excellent in vitro and in vivo anti-tumor activity with various GDEPT strategies utilizing E. coli PNP to activate purine nucleoside analogs. A phase I clinical trial utilizing recombinant adenoviral vector for delivery of E. coli PNP to solid tumors followed by systemic administration of fludarabine phosphate (NCT01310179; IND# 14271) has recently been completed. In this trial, significant anti-tumor activity was demonstrated with negligible toxicity related to the therapy. The mechanism of cell kill (inhibition of RNA and protein synthesis) is distinct from all currently used anticancer drugs and all experimental compounds under development. The approach has demonstrated excellent ability to kill neighboring tumor cells that do not express E. coli PNP, is active against non-proliferating and proliferating tumors cells (as well as tumor stem cells, stroma), and is therefore very effective against solid tumors with a low growth fraction. CONCLUSION: The unique attributes distinguish this approach from other GDEPT strategies and are precisely those required to mediate significant improvements in antitumor therapy. PMID- 29119919 TI - Polyphenols and Microvascular Function in Humans: A Systematic Review. AB - BACKGROUND: Polyphenol-rich dietary sources are acknowledged to have potential cardiovascular health benefits, particularly in reducing cardiovascular disease risk. METHODS: This systematic review sought to determine the effect of polyphenol-rich foods and beverages upon microvascular function, which is of considerable importance in its contribution towards the pathophysiology of microvascular-related complications but also in the future development of (macro vessel) cardiovascular disease. RESULTS: Overall, consumption of polyphenol-rich foods and beverages demonstrate improved microvascular function, although this is dependent upon the polyphenol source, the dose of the product, the duration of consumption and the population group studied. Most subgroups reviewed suggest an overall beneficial effect on microvascular function, particularly grape-derived products, cocoa, tea, pine bark and Rutaceae aurantiae. Other groups remain equivocal and require further study due to the limited research performed to date. CONCLUSION: Polyphenols are abundant in the human diet and this systematic review demonstrates that they are an inexpensive, non-pharmacological approach for improving cardiovascular health in currently healthy individuals and in populations with microvascular dysfunction. PMID- 29119920 TI - Polyphenols: Inflammation. AB - BACKGROUND: Polyphenols widely distributed in plants, fruits and vegetables have received considerable attention on account of their physiological functions, including their antioxidant and anti-inflammatory properties. Some antioxidant components of cacao liquor prepared from fermented and roasted cacao beans, which is a major ingredient of cocoa and chocolate products, have been characterized as flavan-3-ols and procyanidin oligomers. METHODS: This review focuses on a specific group of (-)-epicatechins and their oligomers, the procyanidins, in cacao products. Dietary polyphenols in cacao products have been shown to reduce hypertension, reduce platelet aggregation, improve serum lipids, and lower the incidence of atherosclerosis in animal studies and clinical trials. CONCLUSION: The intake of cacao products reduces hypertension and atherosclerosis on account of their physiological functions as antioxidants and anti-inflammation agents, indicating the mechanisms of prevention of hypertension and atherosclerosis by polyphenols. PMID- 29119921 TI - Design and Delivery of Therapeutic siRNAs: Application to MERS-Coronavirus. AB - BACKGROUND: The MERS-CoV is a novel human coronavirus causing respiratory syndrome since April 2012. The replication of MERS-CoV is mediated by ORF 1ab and viral gene activity can be modulated by RNAi approach. The inhibition of virus replication has been documented in cell culture against multiple viruses by RNAi approach. Currently, very few siRNA against MERS-CoV have been computationally designed and published. METHODS: In this review, we have discussed the computational designing and delivery of potential siRNAs. Potential siRNA can be designed to silence a desired gene by considering many factors like target site, specificity, length and nucleotide content of siRNA, removal of potential off target sites, toxicity and immunogenic responses. The efficient delivery of siRNAs into targeted cells faces many challenges like enzymatic degradation and quick clearance through renal system. The siRNA can be delivered using transfection, electroporation and viral gene transfer. Currently, siRNAs delivery has been improved by using advanced nanotechnology like lipid nanoparticles, inorganic nanoparticles and polymeric nanoparticles. CONCLUSION: The efficacy of siRNA-based therapeutics has been used not only against many viral diseases but also against non-viral diseases, cancer, dominant genetic disorders, and autoimmune disease. This innovative technology has attracted researchers, academia and pharmaceuticals industries towards designing and development of highly effective and targeted disease therapy. By using this technology, effective and potential siRNAs can be designed, delivered and their efficacy with toxic effects and immunogenic responses can be tested against MERS-CoV. PMID- 29119922 TI - Polyphenols: Anti-Platelet Nutraceutical? AB - BACKGROUND: Coronary artery disease (CAD) is a disease progressing over many years. Genetic factors, as well as the exposure to risk factors, are continuously leading to endothelial dysfunction, vascular alterations and, eventually, organ damage, major cardiovascular events and deaths. Oxidative stress, platelet hyperactivity and low-grade inflammation are important modulators in this context, contributing to plaque formation. Since platelet activation plays a critical role in the development and progression of atherothrombotic events, the inhibition of platelet hyperactivity may contribute to decreased atherothrombotic risk. The consumption of bioactive foods, and plant-derived polyphenols in particular, might impart anti-thrombotic and cardiovascular protective effects. METHODS: Aim of this work is to focus on the potential of dietary derived polyphenols to reduce platelet hyperactivity or hypercoagulability in addition to discussing their possible complementary anti-platelet therapeutic potential. All the relevant publications on this topic were systematically reviewed. RESULTS: Various studies demonstrated that polyphenol supplementation affects platelet aggregation and function in vitro and in vivo, mainly neutralizing free radicals, inhibiting platelet activation and related signal transduction pathways, blocking thromboxane A2 receptors and enhancing nitric oxide production. Experimental data concerning the effect of dietary polyphenols on platelet aggregation in vivo are poor, and results are often conflicting. Only flavanols clearly mirrored in vivo showed the efficacy in vitro in modulating platelet function. CONCLUSION: Dietary polyphenols, and above all flavanols contained in cocoa and berries, reduce platelet activation and aggregation via multiple pathways. However, more controlled interventional studies are required to establish which doses are required as well as what circulating concentrations are sufficient to induce functional antiplatelet effects. PMID- 29119923 TI - Drug-Induced Nephrotoxicity: Pathogenic Mechanisms, Biomarkers and Prevention Strategies. AB - BACKGROUND: Risk factors of drug-induced nephrotoxicity include drug overdose, drug-drug interactions and drug-related adverse effects. Since the usage of some nephrotoxic drugs is still unavoidable in the clinical setting, understanding the pathogenic mechanisms of their nephrotoxicities is critical to decrease the incidence of kidney injury. Early detection of drug-induced nephrotoxicity and reduction of the therapeutic side effects are realistic approaches to avoid the end stage of renal failure. METHOD: In this review, we summarized the mechanisms and prevention strategies for some drugs that were commonly used clinically and had the possibility of inducing acute and chronic kidney injuries. We discussed the advantages and drawbacks of currently available biomarkers for indicating kidney impairment. In vitro and pre-clinical in vivo models for assessing the nephrotoxicity during the drug developmental stages were also evaluated. RESULTS: Nowadays, an increasing number of biomarkers were discovered for the early diagnosis of kidney injury. In addition, various kinds of in vitro and pre clinical in vivo models were developed and utilized to minimize the potential nephrotoxicity during the drug development. CONCLUSION: The discovery of the early biomarkers and development of accurate diagnostic methods are effective prevention strategies for drug-induced kidney impairment. PMID- 29119924 TI - Deaths in the Lesbian, Gay, Bisexual and Transgender United Kingdom Communities Associated with GHB and Precursors. AB - BACKGROUND: Misuse of gammahydroxybutrate (GHB) and its prodrugs gammabutyrolactone (GBL) and 1,4 butanediol (1,4-BD) has increased greatly since the early 1990s, particularly amongst lesbian, gay, bisexual and transgender (LGBT) individuals in recreational and sexual settings, e.g. 'chemsex'. OBJECTIVE AND METHOD: This paper presents an overview of GHB pharmacotoxicology and provides analyses of cases in the LGBT population associated with the use of these substances extracted from the UK's National Programme on Substance Abuse Deaths database, to which notification is voluntary. RESULTS: From 1995 to September 2013, 21 GHB/GBL-associated fatalities were reported. None involved 1,4 BD. Typical victims were: Male (100%); White (67%), young (mean age 34 years); employed (90%); with a drug misuse history (81%). Most deaths were accidental (67%) or related to recreational drug use (19%), the remaining (potential) suicides. The majority of fatalities (83%) occurred in private residences, typically following recreational use; others occurred in specific 'gay'-oriented locales including clubs and saunas. Three London boroughs accounted for 62% of all notified deaths, reflecting the concentration of both resident and visiting 'gay' individuals. However, this may be an artefact of the voluntary nature of the data submission procedure in particular areas. GHB/GBL alone was implicated in 10% of fatalities. The following substances were implicated either alone or in combination in the remaining cases (percentages may add to more than 100%): cocaine (38%); alcohol (33%); amphetamines (29%); ecstasy (29%); diazepam (24%); ketamine (24%); mephedrone (24%). Post-mortem blood levels: mean 660 (range 22 - 2335; S.D. 726) mg/L. CONCLUSION: Significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, stimulants, and ketamine. Risk of death is increased due to their CNS-depressant properties. Of these, 'chemsex' drugs such as cocaine, mephedrone and ketamine are of note. More awareness is needed in the 'gay' community about risks associated with the consumption of such substances. PMID- 29119925 TI - Post-treatment with a Hydrogen Sulfide Donor Limits Neuronal Injury and Modulates Potassium Voltage-gated Channel Subfamily D Member 2 (Kv4.2) and Potassium Channel Interacting Protein 3 (KChIP3) During Transient Global Cerebral Ischemia. AB - BACKGROUND: Although the neuroprotective effect of sodium hydrosulfide (NaHS, a hydrogen sulfide donor) pretreatment has been revealed, the effect of NaHS post conditioning remains largely unknown. OBJECTIVE: We aimed to investigate the neuroprotective effect of NaHS post-conditioning against transient Global Cerebral Ischemia (tGCI)-induced hippocampal CA1 injury and its underlying molecular mechanism. METHODS: A tGCI rat model was established using the four vessel occlusion method for 15 min of ischemia. The survival of hippocampal neurons was determined by Nissl staining and NeuN immunostaining. Protein expression of potassium voltage-gated channel subfamily D member 2 (Kv4.2) and potassium channel interacting protein 3 (KChIP3) was assessed by Immunohistochemistry (IHC) and Western blot. RESULTS: Decreased concentrations (12 and 24 umol/kg) of NaHS post-conditioning significantly increased the numbers of survival neurons and NeuN-positive neurons in the hippocampal CA1 region at 7 days post-tGCI (all P<0.05). NaHS post-conditioning (24 umol/kg) at 12 and 24 hr posttGCI can achieve the best protective effect (both P<0.05). IHC data demonstrated that NaHS postconditioning (24 umol/kg) markedly attenuated tGCI induced down-regulation of Kv4.2 protein in the hippocampal CA1 region at 26 hr post-tGCI. Confocal images showed that Kv4.2 did not express in the neuronal nuclei but predominantly express in the neuronal dendrites. In addition, NaHS post-conditioning significantly up-regulated Kv4.2 and down-regulated KChIP3 in tGCI rats at 26 and 168 hr post- tGCI (all P<0.05). CONCLUSION: Decreased concentrations of NaHS post-conditioning at 12-24 hr post-tGCI effectively protected hippocampal CA1 neurons from tGCI-induced injury, which may be through regulating the expression of Kv4.2 and KChIP3. PMID- 29119926 TI - The role of CXCR3 in neurological diseases AB - Neurological diseases have become an obvious challenge due to insufficient therapeutic intervention. Therefore, novel drugs for various neurological disorders are in desperate need. Recently, compelling evidence has demonstrated that chemokine receptor CXCR3, which is a G protein-coupled receptor in the CXC chemokine receptor family, may play a pivotal role in the development of neurological diseases. The expression level of CXCR3 in T cells was significantly elevated in several neurological diseases, suggesting a potential therapeutic role of CXCR3 antagonists. In this review, we summarize the recent advances suggesting the involvement of CXCR3 in the pathogenesis of neurological diseases, including multiple sclerosis, glioma, Alzheimer's disease, chronic pain, human T lymphotropic virus type 1-associated myelopathy and bipolar disorder. The aim of this review is to provide evidence for the potential of CXCR3 as a therapeutic target for neurological diseases. PMID- 29119927 TI - Gene-environment Interactions in Late Life: Linking Psychosocial Stress with Brain Aging. AB - Gene-environment interactions (GxE) can have lasting consequences on brain structure and function, potentially contributing to diverse neuropsychiatric phenotypes. This has been extensively demonstrated by studies examining GxE in childhood and early adulthood, whereas much fewer studies have addressed this question in late life. The relative paucity of studies examining GxE in late life may stem from the working hypothesis that brains become less malleable to environmental inputs as life progresses. However, while some components of brain plasticity decline with increasing age, others are retained and may even become more pronounced in old ages. Moreover, the micro- and macro-structural brain changes that accrue as a result of aging-related morbidities are likely to accentuate the susceptibility of neural circuits to environmental stressors as life advances. Supporting this hypothesis, psychosocial stress can increase the risk for late-life neuropsychiatric syndromes, especially when afflicting genetically predisposed individuals. This article reviews evidence showing how gene-stress interactions can impact the aging brain and related phenotypes in late life, and it discusses the potential mechanisms underlying such GxE and their implications for the prevention and treatment of late-life neuropsychiatric syndromes. PMID- 29119930 TI - Anti-Oxidant Drugs: Novelties and Clinical Implications in Cerebellar Ataxias. AB - Background Hereditary cerebellar ataxias are a group of disorders characterized by heterogeneous clinical manifestations, progressive clinical course and diverse genetic causes. No disease modifying treatments are yet available for many of these disorders. Oxidative stress has been recurrently identified in different progressive cerebellar diseases, and it represents a widely investigated target for treatment. Objective To review the main aspects and new perspectives of antioxidant therapy in cerebellar ataxias ranging from bench to bedside Method This article is a summary of the state-of-the-art on the use of antioxidant molecules in cerebellar ataxia treatments. It also briefly summarizes aspects of oxidative stress production and general characteristics of antioxidant compounds. Results Antioxidants represent a vast category of compounds; old drugs have been extensively studied and modified in order to achieve better biological effects. Although the vast body of literature present on the use of antioxidants in cerebellar ataxias, for the majority of these disorders conclusive results on the efficacy are still missing. Conclusion Antioxidant therapy in cerebellar ataxias is a promising field of investigations. To achieve the success in identifying the correct treatment more work needs to be done. In particular, needed is a combined effort by basic scientists in developing more efficient molecules, and by clinical researchers together with patients communities, to run clinical trials in order to identify conclusive treatments strategies. PMID- 29119929 TI - Mean Diffusivity in the Dopaminergic System and Neural Differences Related to Dopaminergic System. AB - BACKGROUND: The mean diffusivity (MD) parameter obtained by diffusion tensor imaging provides a measure of how freely water molecules move in brain tissue. Greater tissue density conferred by closely arrayed cellular structures is assumed to lower MD by inhibiting the free diffusion of water molecules. METHODS: In this paper, we review studies showing MD variation among regions of the brain dopaminergic system (MDDS), especially subcortical structures such as the putamen, caudate nucleus, and globus pallidus, in different conditions with known associations to dopaminergic system function or dysfunction. The methodologies and background related to MD and MDDS are also discussed. RESULTS: Past studies indicate that MDDS is sensitive to pathological derangement of dopaminergic activity, neural changes caused by cognitive and pharmacological interventions that are known to affect the dopaminergic system, and individual character traits related to dopaminergic function. CONCLUSION: These results suggest that MDDS can be one useful tool to tap the neural differences related to the dopaminergic system. PMID- 29119928 TI - Rational Basis for Nutraceuticals in the Treatment of Glaucoma. AB - BACKGROUND: Glaucoma, the second leading cause of blindness worldwide, is a chronic optic neuropathy characterized by progressive retinal ganglion cell (RGC) axons degeneration and death. Primary open-angle glaucoma (OAG), the most common type, is often associated with increased intraocular pressure (IOP), however other factors have been recognized to partecipate to the patogenesis of the optic neuropathy. IOP-independent mechanisms that contribute to the glaucoma-related neurodegeneration include oxidative stress, excitotoxicity, neuroinflammation, and impaired ocular blood flow. The involvement of several and diverse factors is one of the reasons for the progression of glaucoma observed even under efficient IOP control with the currently available drugs. METHODS: Current research and online content related to the potential of nutritional supplements for limiting retinal damage and improving RGC survival is reviewed. RESULTS: Recent studies have suggested a link between dietary factors and glaucoma risk. Particularly, some nutrients have proven capable of lowering IOP, increase circulation to the optic nerve, modulate excitotoxicity and promote RGC survival. However, the lack of clinical trials limit their current therapeutic use. The appropriate use of nutraceuticals that may be able to modify the risk of glaucoma may provide insight into glaucoma pathogenesis and decrease the need for, and therefore the side effects from, conventional therapies. CONCLUSION: The effects of nutrients with anti-oxidant and neuroprotective properties are of great interest and nutraceuticals may offer some therapeutic potential although a further rigorous evaluation of nutraceuticals in the treatment of glaucoma is needed to determine their safety and efficacy. PMID- 29119931 TI - Extend, Pathomechanism and Clinical Consequences of Brain Volume Changes in Anorexia Nervosa. AB - INTRODUCTION: Brain volume deficits of grey matter (GM) and white matter (WM) are often found in patients with anorexia nervosa (AN). However, until recently, little was known about the influencing factors of these brain volume alterations, nor their exact quantification and rehabilitation. METHODS: This review addresses these open questions and further explores what is now known about the underlying pathobiology and the clinical consequences including human studies as well as animal studies mimicking anorexia nervosa in rodents. RESULTS: GM was reduced by 3.7% in adults and 7.6% in adolescents with AN. WM was reduced on average 2.2% in adult patients and 3.2% in adolescents. Most volume deficits in adults are reversible after long-term recovery; for adolescents, data are less clear. The main influencing factors for GM were absolute lowest weight at admission and illness duration. Cerebellar and WM reductions at admission predicted clinical outcome at one year follow-up. New studies found GABA receptor changes in GM and astrocyte loss in both GM and WM, as well as a possible role for oestrogen deficit. All three could partly explain clinical symptoms of anxiety, rigidity and learning impairments in patients with AN. CONCLUSION: Brain volume deficits in AN seem to play a causal role in the course and the prognosis of AN. A better understanding of these brain changes could lead to more targeted therapies for patients with AN, including astrocyte-directed approaches. PMID- 29119932 TI - Relevance of CYP2C9 Function in Valproate Therapy. AB - Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, co-medication) can transiently alter the enzyme expression and activities resulting in genotype-phenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways. CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions. The loss-of function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype. Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients' CYP2C9 status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children's anticonvulsant therapy. . PMID- 29119934 TI - Direct-acting Antivirals for HIV/HCV Co-infected Individuals: As Good as it Gets? AB - Although HIV/HCV co-infected individuals were historically considered a "difficult to treat" population in the era of Interferon (IFN)-based anti-HCV treatment, the introduction of directacting antivirals, characterized by excellent efficacy and good safety profile, has widely revolutionized the HCV treatment scenario. Recent real life studies reported excellent sustained virological response rates in HIV/HCV coinfected subjects, thus confirming data obtained in randomized clinical trials. However, certain issues have recently emerged in this population. In fact, high rates of acute HCV infection and reinfections were documented in several studies, particularly in HIV-positive men who have sex with men. Moreover, drug-drug interactions with ART or other co medications may require careful considerations as well as the management of HIV/HCV co-infected subjects with chronic kidney disease and advanced liver disease in the course of a DAA-based treatment. Hence, we aim to review DAA efficacy studies performed in HIV/HCV co-infected patients in both randomized clinical trials and real-world cohorts. In addition, current challenges and future perspectives are discussed in order to optimize management strategies for HIV/HCV co-infected subjects and their access to care in clinical practice. PMID- 29119933 TI - Pharmacological and Non-pharmacological Therapies of Cognitive Impairment in Multiple Sclerosis. AB - BACKGROUND: Cognitive impairment is one of the most important clinical features of neurodegenerative disorders including multiple sclerosis (MS). Conducted research shows that up to 65 percent of MS patients have cognitive deficits such as episodic memory, sustained attention, reduced verbal fluency; however, the cognitive MS domain is information processing speed. It is the first syndrome of cognitive dysfunction and the most widely affected in MS. Occasionally these impairments occur even before the appearance of physical symptoms. METHODS: Therefore, this review focused on the current status of our knowledge about possible methods of treatment cognitive impairment in MS patients including novel strategies. Research and online content was performed using Medline and EMBASE databases. RESULTS: The most recent research suggests that cognitive impairment is correlated with brain lesion volume and brain atrophy. The examination of the cognitive impairment is usually based on particular neuropsychological batteries. However, it can be not enough to make a precise diagnosis. This creates a demand to find markers that might be useful for identifying patients with risk of cognitive impairment at an early stage of the disease. Currently the most promising methods consist of neuroimaging indicators, such as diffusion tensor imaging, the magnetization transfer ratio, and N-acetyl aspartate levels. Diagnosis problems are strictly connected with treatment procedures. There are two main cognitive therapies: pharmacological (disease modifying drugs (DMD), symptomatic treatments) and non-pharmacological interventions that are focused on psychological and physical rehabilitation. Some trials have shown a positive association between physical activity and the cognitive function. CONCLUSION: This article is an overview of the current state of knowledge related to cognition impairment treatment in MS. Additionally, novel strategies for cognitive impairments such as cryostimulation and other complementary methods are presented. PMID- 29119935 TI - Perioperative Management of Hyperlipidemia Medications. AB - BACKGROUND: Coronary artery disease is a common comorbidity encountered during the perioperative period. Whether patients are scheduled for cardiac or noncardiac surgery, this cardiovascular disease must be addressed in the preoperative period to decrease the accompanying risks and potential postoperative problems. Lipid-lowering medications are often used to treat hyperlipidemia, a risk factor for the development of atherosclerosis and coronary artery disease. OBJECTIVE: To discuss the medications most commonly used to treat hyperlipidemia and to describe strategies for handling these treatment regimens in the perioperative period. METHOD: An online search of studies and review articles was conducted through PubMed and Medline that addressed pharmacology and perioperative management of hyperlipidemia medications. RESULTS: Statins are the most commonly prescribed lipid-lowering agents, with benefits that extend beyond correcting lipid levels. However, statins can have clinically significant adverse effects that may necessitate the use of other lipid-lowering medications with different mechanisms of action. Alternative medications such as nicotinic acid and omega-3 fatty acids should be withheld in the preoperative period because these agents have been associated with hypotension and increased bleeding. CONCLUSION: Clinicians must be familiar with the various lipid-lowering agents because it is very likely they will encounter such medications during preoperative visits. PMID- 29119936 TI - Recent Patents on Light-Based Anti-Infective Approaches. AB - BACKGROUND: Antibiotic resistance is one of the most serious health threats to modern medicine. The lack of potent antibiotics puts us at a disadvantage in the fight against infectious diseases, especially those caused by antibiotic resistant microbial strains. To this end, an urgent need to search for alternative antimicrobial approaches has arisen. In the last decade, light-based anti-infective therapy has made significant strides in this fight to combat antibiotic resistance among various microbial strains. This method includes utilizing antimicrobial blue light, antimicrobial photodynamic therapy, and germicidal ultraviolet irradiation, among others. Light-based therapy is advantageous over traditional antibiotics in that it eradicates microbial cells rapidly and the likelihood of light-resistance development by microbes is low. METHODS: This review highlights the patents on light-based therapy that were filed approximately within the last decade and are dedicated to eradicating pathogenic microorganisms. The primary database that was used for the search was Google Patents. The searches were performed using the keywords including blue light, antimicrobial photodynamic therapy, ultraviolet irradiation, antibiotic resistance, disinfection, bacterium, fungus, and virus. RESULTS: Forty-five patents were obtained in our search: 9 patents for the antimicrobial blue light approach, 21 for antimicrobial photodynamic therapy, 11 for UV irradiation, and lastly 4 for other light-based anti-infective approaches. The treatments and devices discussed in this review are interestingly enough able to be used in various different functions and settings, such as dental applications, certain eye diseases, skin and hard surface cleansing, decontamination of internal organs (e.g., the stomach), decontamination of apparel and equipment, eradication of pathogenic microorganisms from buildings and rooms, etc. Most of the devices and inventions introduce methods of destroying pathogenic bacteria and fungi without harming human cells and tissues. CONCLUSIONS: Light-based antimicrobial approaches hold great promise for the future in regards to treating antibiotic resistant infections and related diseases. PMID- 29119937 TI - Use of human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors in Autoimmune Diseases and New Perspectives in Cancer Therapy. AB - BACKGROUND: Human dihydroorotate dehydrogenase (hDHODH, EC 1.3.5.2), a flavindependent mitochondrial enzyme involved in de novo pyrimidine biosynthesis, is a validated therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. However, human DHODH inhibitors have also been investigated as treatment for cancer, parasite infections (i.e. malaria) and viruses as well as in the agrochemicals industry. OBJECTIVE: An overview of current knowledge of hDHODH inhibitors and their potential uses in diseases where hDHODH is involved. METHOD: This review focuses on recent advances in the development and application of hDHODH inhibitors, specifically covering the patent field, starting from a brief description of enzyme topography and of the strategies usually followed in designing its selective inhibitors. RESULTS: The most important and well-described novelty is the fact that the discovery, in the autumn of 2016, that hDHODH inhibitors are able to induce in vivo myeloid differentiation has led to the possibility of developing novel hDHODH based treatments for Acute Myelogenous Leukemia (AML). CONCLUSION: The review will describe a variety of specific inhibitor classes and conclude on recent and future therapeutic perspectives for this target. PMID- 29119938 TI - Adenosine Receptor Ligands on Cancer Therapy: A Review of Patent Literature. AB - BACKGROUND: Adenosine is a purine, with an adenine group and a ribose sugar, formed endogenously by ATP catabolism both intracellularly and extracellularly. Among the medicinal features of adenosine and its receptors (A1, A2A, A2B and A3), anticancer activity has been an intense field of research. The anticancer potential of adenosine receptor ligands has been brought to the forefront of research and evidenced in innumerous research articles and patents. OBJECTIVE: The present review focuses on the patent literature from 2002 onwards (2002-May 2017). METHODS: Patents were searched and downloaded from the open access patent data bases and are available online. RESULTS: A significant number of patents (65) have been published on adenosine receptor ligands claiming anticancer activity, or presenting new methods of preparation or treatment thereof, from 2002-2017 (May). From these, 35 were published highlighting the promising attributes of compounds/ methods to fight cancer. Most of the compounds act as adenosine A3 receptor agonists, while others act as antagonists for the other adenosine receptor subtypes. The signaling events triggered by activation of adenosine A3 receptor or by blockade of adenosine A1, A2A and A2B receptors can reverse an environment from being pro-cancer to an anti-cancer in the body. CONCLUSION: The promising anticancer effects mediated by adenosine receptor ligands put them in the forefront as new drug candidates. The present compilation can be worthy to medicinal chemists, pharmacologists, biochemists and other researchers focusing on the putative anticancer activity of adenosine receptor ligands. PMID- 29119939 TI - Mannose-Binding Lectin Protein Deficiency Among Patients with Primary Immunodeficiency Disease Receiving IVIG Therapy. AB - BACKGROUND: Primary immunodeficiencies (PIDs) are inherited disorders in which one or several components of the immune system are defective. Immunoglobulin replacement therapy is the mainstay of treatment for patients with impaired antibody production. However, recurrent infections would continue to occur in some patients due to the other high frequent concomitant defects, such as mannose binding lectin (MBL) deficiency. METHODS: A total of 51 PID patients participated in this cross-sectional study. A detailed questionnaire was completed by interviewing patients in order to record demographic, clinical and laboratory data. The levels of MBL were determined in the serums of patients by a sandwich enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: MBL deficiency was found in 29.4% of cases; 11.8% patients had mild, 3.9% patients had moderate and 13.7% patients had severe MBL deficiency. In patients with MBL deficiency, the rate of meningitis, sepsis, pneumonia, and otitis media was higher than patients with normal MBL levels. Immunoglobulin replacement therapy reduced the rate of infectious complications in PID patients; however, these reductions were more apparent in patients with normal MBL levels than patients with MBL deficiency. CONCLUSION: Antibody deficient patients with a concomitant immune defect in MBL production have higher rates of recurrent infections despite receiving Immunoglobulin replacement therapy. PMID- 29119940 TI - Development of Floating Delivery for Solid Self Micro-Emulsifying Drug Delivery System of Prochlorperazine Maleate. AB - BACKGROUND: Prochlorperazine maleate (PCM) is a phenothiazine antipsychotic used in the treatment of nausea, vomiting and vertigo. It is BCS class II drug with only 12.5% bioavailability. Patents data on PCM had shown work on conjugation and matrix formulation which suggested idea for the present work design. OBJECTIVE: The objective of this study was to enhance solubility of drug and to optimize gastro retentive floating capsule for controlled drug release at the targeted site for stipulated time. METHOD: The solubility of drug was determined in various vehicles like oils, surfactants and cosurfactants. Pseudo ternary phase diagrams were constructed to identify the efficient self emulsifying region. SMEDDS were tested for micro emulsifying properties. The resultant microemulsions were evaluated and were further selected for the floating drug delivery. Magnesium hydroxide was used as carrier to transform SMEDDS into Solid SMEDD (S SMEDD). Non-effervescent floating capsule containing S-SMEDD were optimized using factorial design with independent variable HPMC K4M and ethyl cellulose. RESULTS: SMEDD consists of PCM, isopropyl myristate, tween 80 and PEG 400 as a drug, oil, surfactant and co-surfactant (1:1 ratio). Optimized formulation F5 showed 10 hrs floating time and percent drug release 91.56+/-2.7% with controlled drug delivery in stomach. F5 followed Korsmeyer Peppas release kinetics where the drug followed Fickian diffusion transport mechanism due to swelling of polymers in controlled manner. CONCLUSION: It can be concluded that SMEDD enhanced the solubility of drug and floating capsule gave site specific drug release of PCM with the advantages of reduced dosing frequency and better compliance. PMID- 29119941 TI - Targeting of Inflammation for Radiation Protection and Mitigation. AB - BACKGROUND: Inflammation is the response of the immune system that guards the body against several harmful stimuli in normal conditions. However, in response to ionizing radiation that leads to a massive cell death and DNA aberrations, this phenomenon causes various side effects in normal tissues. Inflammation is involved in various side effects such as gastrointestinal toxicity, mucositis, skin reactions, nervous system damage, pneumonitis, fibrosis and so on. DISCUSSION: Observations have proposed that inflammatory mediators are involved in the toxic effect of ionizing radiation on non-irradiated cells via a phenomenon named bystander effect. Inflammation in both irradiated and non irradiated cells can trigger genomic instability, leading to increased risk of carcinogenesis. Targeting the inflammatory mediators has been an interesting idea for improving the therapeutic ratio throughout the reduction of normal tissue injury as well as an increase in tumor response to radiotherapy. CONCLUSION: So far, various targets have been proposed for the amelioration of radiation toxicity in radiotherapy. Of different targets, NF-kappaB, COX-2, some of NADPH Oxidase subfamilies, TGF-beta, p38 and the renin-angiotensin system have shown promising results. Interestingly, inhibition of these targets can help sensitize the tumor cells to the radiation treatment with some mechanisms such as suppression of angiogenesis and tumor growth as well as induction of apoptosis. In this review, we focus on recent advances on promising studies for targeting the inflammatory mediators in radiotherapy. PMID- 29119943 TI - An Appraisal on Various Methods of Nano Particulate Formulations. AB - BACKGROUND: Nanotechnology has immense significance in the field of medicine, agriculture, business, public health sector due to wide applicability of the nano products. Basically, nanotechnology is the incorporation of nanoscale structures into larger material components to improve the properties of constructed system. METHOD: Nanotechnology serves as an alternative drug delivery system to the liposomes drug delivery system as the stability of the product in biological fluids is the main problem associated with the liposomal drug delivery system. In the present review, nanoparticles, their applications, various techniques of preparation of nanoparticles and research update on nano particulate drug delivery system have been discussed. RESULTS: The main complication associated with biodegradable polymer is uncertainty in their absorption pathway in gastrointestinal tract. Sometimes, harmful by-products after metabolism are released. However, the polymeric nanoparticles (synthetic or semi-synthetic) have a defined structure therefore; get absorbed in intact form in gastrointestinal tract. CONCLUSION: Nano-particulate drug delivery system using natural/synthetic polymer may enhance the therapeutic activity of some anti-cancer drug by increasing the host's immune mechanism and antitumor role through improving the body's immune function. It has been observed that despite the technological challenges, nanoparticulate drug delivery system is the most promising drug delivery system in case of anticancer drugs because polymer based nanostructures enhance the bio-adhesiveness and as well as local accumulation of chemotherapeutic agent. PMID- 29119942 TI - 18F-FAZA PET/CT in the Preoperative Evaluation of NSCLC: Comparison with 18F-FDG and Immunohistochemistry. AB - PURPOSE: To assess the capability of 18F-FAZA PET/CT in identifying intratumoral hypoxic areas in early and locally advanced non-small cell lung cancer (NSCLC) patients and to compare 18FFAZA PET/CT with 18F-FDG PET/CT and histopathological biomarkers and to investigate whether the assessment of tumour to blood (T/B) and tumour to muscle (T/M) ratios provide comparable information regarding the hypoxic fractions of the tumour. MATERIALS AND METHODS: Seven patients with NSCLC were prospectively enrolled (3 men, 4 women; median age: 71 years; range 63-80). All patients underwent to 18F-FDG PET/CT and 18F-FAZA PET/CT before surgery. Maximum standardized uptake value (SUVmax) was used to evaluate 18FFDG PET/CT images, while 18F-FAZA PET/CT images have been interpreted by using tumour toblood (T/B) and tumour-to-muscle (T/M) ratio. Surgery was performed in all patients; immunohistochemical analysis for hypoxia biomarkers was performed on histologic tumor samples. RESULTS: All lung lesions showed intense 18F-FDG uptake (mean SUVmax: 7.35; range: 2.35-25.20). A faint 18F-FAZA uptake was observed in 6/7 patients (T/B < 1.2) while significant uptake was present in the remaining 1/7 (T/B and T/M=2.24). On both 2 and 4 h imaging after injection, no differences were observed between T/M and T/B (p=0.5), suggesting that both blood and muscle are equivalent in estimating the background activity for image analysis. Immunohisotchemical analysis showed low or absent staining for hypoxia biomarkers in 3 patients (CA-IX and GLUT-1: 0%; HIF-1alpha: mean 3.3%; range 0-10). Two patients showed staining for HIF-1alpha of 5%, with CA-IX being 60% and 30%, respectively and GLUT-1 being 30% and 80%, respectively; in 1/7 HIF-1alpha was 10%, CA-IX was 50% and GLUT-1 was 90%. In one patient a higher percentage of HIF 1alpha and CA-IX (20% and 70%, respectively) positive cells was present, with GLUT-1 being 30%. CONCLUSIONS: To the best of our knowledge, this is the first paper assessing hypoxia and glucose metabolism in comparison with immunohistochemistry in patients candidate to surgery for NSCLC. Although including a small number of patients, useful insight regarding correlation between imaging and immunohistochemistry are reported along with methodological suggestions for clinical practice. PMID- 29119944 TI - Immune responses and protection after DNA vaccination against Toxoplasma gondii calcium-dependent protein kinase 2 (TgCDPK2). AB - Toxoplasma gondii, an intracellular zoonotic protozoan parasite, is possibly the most widespread parasite of warm-blooded animals and can cause serious public health problems and economic losses worldwide. TgCDPK2, a member of the T. gondii calcium-dependent protein kinase family, was recently identified as an essential regulator for viable cyst development in T. gondii. In the present study, we evaluated the protective immunity induced by DNA vaccination based on a recombinant eukaryotic plasmid, pVAX-TgCDPK2, against acute toxoplasmosis in mice. BALB/c mice were intramuscularly immunized with pVAX-TgCDPK2 plasmid and then challenged by infection with the highly virulent RH strain of T. gondii. The specific immune responses and protective efficacy against T. gondii were analyzed by cytokine and serum antibody measurements, lymphocyte proliferation assays, flow cytometric on lymphocytes and the survival time of mice after challenge. Our results showed that mice immunized with pVAX-TgCDPK2 could elicit special humoral and cellular responses, with higher levels of IgG antibody, and increased levels of Th1-type cytokines IFN-gamma, IL-12(p70), and CD3 + CD4 + CD8 - and CD3 + CD8 + CD4 - T cells, and had a prolonged survival time (14.0 +/- 2.32 days) compared to control mice. These results demonstrate that pVAX-TgCDPK2 is a potential vaccine candidate against acute toxoplasmosis. PMID- 29119945 TI - Mechanical force induces mitochondrial fission. AB - Eukaryotic cells are densely packed with macromolecular complexes and intertwining organelles, continually transported and reshaped. Intriguingly, organelles avoid clashing and entangling with each other in such limited space. Mitochondria form extensive networks constantly remodeled by fission and fusion. Here, we show that mitochondrial fission is triggered by mechanical forces. Mechano-stimulation of mitochondria - via encounter with motile intracellular pathogens, via external pressure applied by an atomic force microscope, or via cell migration across uneven microsurfaces - results in the recruitment of the mitochondrial fission machinery, and subsequent division. We propose that MFF, owing to affinity for narrow mitochondria, acts as a membrane-bound force sensor to recruit the fission machinery to mechanically strained sites. Thus, mitochondria adapt to the environment by sensing and responding to biomechanical cues. Our findings that mechanical triggers can be coupled to biochemical responses in membrane dynamics may explain how organelles orderly cohabit in the crowded cytoplasm. PMID- 29119946 TI - Conversion of isotropic fluorescence into a long-range non-diverging beam. AB - Fluorescent samples typically emit isotropically in all directions. Large lenses and other optical components are needed to capture a significant fraction of the emission, and complex confocal microscopes are required for high resolution focal plane imaging. It is known that Bessel beams have remarkable properties of being able to travel over long distances, over 1000 times the wavelength, without diverging, and hence are called non-diffracting beams. In previous reports the Bessel beams were formed by an incident light source, typically with plane-wave illumination on a circular aperture. It was not known if Bessel beams could form from fluorescent light sources. We demonstrate transformation of the emission from fluorescent polystyrene spheres (FPS) into non-diverging beams which propagate up to 130 mm (13 cm) along the optical axis with a constant diameter. This is accomplished using a planar metal film, with no nanoscale features in the X-Y plane, using surface plasmon-coupled emission. Using samples which contain many FPS in the field-of-view, we demonstrate that an independent Bessel beam can be generated from any location on the metal film. The extremely long non diffracted propagation distances, and self-healing properties of Bessel beams, offer new opportunities in fluorescence sensing and imaging. PMID- 29119948 TI - Tailoring gas-phase CO2 electroreduction selectivity to hydrocarbons at Cu nanoparticles. AB - Copper-based surfaces appear as the most active catalysts for CO2 electroreduction to hydrocarbons, even though formation rates and efficiencies still need to be improved. The aim of the present work is to evaluate the continuous gas-phase CO2 electroreduction to hydrocarbons (i.e. ethylene and methane) at copper nanoparticulated-based surfaces, paying attention to particle size influence (ranging from 25-80 nm) on reaction productivity, selectivity, and Faraday efficiency (FE) for CO2 conversion. The effect of the current density and the presence of a microporous layer within the working electrode are then evaluated. Copper-based gas diffusion electrodes are prepared by airbrushing the catalytic ink onto carbon supports, which are then coupled to a cation exchange membrane (Nafion) in a membrane electrode assembly. The results show that the use of smaller copper nanoparticles (25 nm) leads to a higher ethylene production (1148 MUmol m-2 s-1) with a remarkable high FE (92.8%), at the same time, diminishing the competitive hydrogen evolution reaction in terms of FE. This work demonstrates the importance of nanoparticle size on reaction selectivity, which may be of help to design enhanced electrocatalytic materials for CO2 valorization to hydrocarbons. PMID- 29119947 TI - Visible to near-infrared photodetectors based on MoS2 vertical Schottky junctions. AB - Over the past few years, two-dimensional (2D) nanomaterials, such as MoS2, have been widely considered as the promising channel materials for next-generation high-performance phototransistors. However, their device performances still mostly suffer from slow photoresponse (e.g. with the time constant in the order of milliseconds) due to the relatively long channel length and the substantial surface defect induced carrier trapping, as well as the insufficient detectivity owing to the relatively large dark current. In this work, a simple multilayer MoS2 based photodetector employing vertical Schottky junctions of Au-MoS2-ITO is demonstrated. This unique device structure can significantly suppress the dark current down to 10-12 A and enable the fast photoresponse of 64 MUs, together with the stable responsivity of ~1 A W-1 and the high photocurrent to dark current ratio of ~106 at room temperature. This vertical-Schottky photodetector can also exhibit a wide detection range from visible to 1000 nm. All these results demonstrate clearly that the vertical Schottky structure is an effective configuration for achieving high-performance optoelectronic devices based on 2D materials. PMID- 29119949 TI - Balancing strength, hardness and ductility of Cu64Zr36 nanoglasses via embedded nanocrystals. AB - Superplasticity can be achieved in nanoglasses but at the expense of strength, and such a loss can be mitigated via embedding stronger nanocrystals, i.e., forming nanoglass/nanocrystal composites. As an illustrative case, we investigate plastic deformation of Cu64Zr36 nanoglass/nanocrystalline Cu composites during uniaxial tension and nanoindentation tests with molecular dynamics simulations. With increasing fraction of nanocrystalline grains, the tensile strength of the composite is enhanced, while its ductility decreases. The dominant interface type changes from glass-glass interface to glass-crystal interface to grain boundary, corresponding to a failure mode transition from superplastic flow to shear banding to brittle intercrystal fracture, respectively. Accordingly, the indentation hardness increases continuously and strain localization beneath the indenter is more and more severe. For an appropriate fraction of nanocrystalline grains, a good balance among strength, hardness and ductility can be realized, which is useful for the synthesis of novel nanograined glass/crystalline composites with high strength, high hardness and superior ductility. PMID- 29119950 TI - Bio-inspired composites with functionally graded platelets exhibit enhanced stiffness. AB - Unidirectional composites inspired from biological materials such as nacre are composed of stiff platelets arranged in a staggered manner within a soft matrix. Elaborate analyses have been conducted on the aforementioned composites and they are found to have excellent mechanical properties like stiffness, strength and fracture toughness. The superior properties exhibited by these composites have been proved to be the result of its unique structure. An emerging development in the field of composite structures is functionally graded composites, whose properties vary spatially and possess enhanced thermo-mechanical properties. In this paper, the platelets are functionally graded with its Young's modulus varying parabolically along the length. Two different models-namely, tension shear chain model and minimisation of complementary energy model have been employed to obtain the stiffness of the overall composite analytically. The effect of various parameters that define the composite model such as overlapping length between any two neighbouring platelets, different gradation parameters and platelet aspect ratio on the overall mechanical properties have been studied. Composites with functionally graded platelets are found to possess enhanced stiffness (upto [Formula: see text] higher) for certain values of these parameters. The obtained solutions have been validated using finite element analysis. Bio-inspired composites with functionally graded platelets can be engineered for structural applications, such as in automobile, aerospace and aircraft industries, where stiffness plays a crucial role. PMID- 29119951 TI - Reducing inhomogeneity in the dynamic properties of quantum dots via self-aligned plasmonic cavities. AB - A plasmonic cavity is shown to greatly reduce the inhomogeneity of dynamic optical properties such as quantum efficiency and radiative lifetime of InGaN quantum dots. By using an open-top plasmonic cavity structure, which exhibits a large Purcell factor and antenna quantum efficiency, the resulting quantum efficiency distribution for the quantum dots narrows and is no longer limited by the quantum dot inhomogeneity. The standard deviation of the quantum efficiency can be reduced to 2% while maintaining the overall quantum efficiency at 70%, making InGaN quantum dots a viable candidate for high-speed quantum cryptography and random number generation applications. PMID- 29119952 TI - Fluorescence lifetime components reveal kinetic intermediate states upon equilibrium denaturation of carbonic anhydrase II. AB - In most cases, intermediate states of multistage folding proteins are not 'visible' under equilibrium conditions but are revealed in kinetic experiments. Time-resolved fluorescence spectroscopy was used in equilibrium denaturation studies. The technique allows for detecting changes in the conformation and environment of tryptophan residues in different structural elements of carbonic anhydrase II which in its turn has made it possible to study the intermediate states of carbonic anhydrase II under equilibrium conditions. The results of equilibrium and kinetic experiments using wild-type bovine carbonic anhydrase II and its mutant form with the substitution of leucine for alanine at position 139 (L139A) were compared. The obtained lifetime components of intrinsic tryptophan fluorescence allowed for revealing that, the same as in kinetic experiments, under equilibrium conditions the unfolding of carbonic anhydrase II ensues through formation of intermediate states. PMID- 29119953 TI - [The influence of non-invasive electrical stimulation of the spinal cord on the locomotor function of patients presenting with movement disorders of central genesis]. AB - AIM: The objective of the present study was to evaluate the influence of non invasive (transcutaneous) electrical spinal cord stimulation on the locomotor function of the patients suffering from movement disorders. PATIENTS AND METHODS: The study involved 10 patients of both sexes at the age from 32 to 70 years (including 40% of men and 60% of women) presenting with the compromised locomotor function of varying severity associated with the disturbances of cerebral blood circulation caused either by an injury to the brain and spinal cord or by stroke. The transcutaneous electrical spinal cord stimulation was applied using different frequency regimes with the placement of the electrodes in the projection onto the region of TXI-TXII vertebrae. The active factors were bipolar electrical stimuli 0.5 ms in duration; the current strength was chosen for each patient on an individual basis taking into consideration its threshold level. Electromyograms and evoked motor responses of selected muscles, viz. m. rectus femoris, m.biceps femoris, m. tibialis anterior, and m.gastrocnemius were recorded with the use of the 'Neuro-MVP-8 eight-channel electromyography' ('Neurosoft', Russia). RESULTS: The data obtained give evidence that the stimulation of the spinal cord with a frequency of 1 Hz induces reflectory responses with monosynaptic and polysynaptic components in the muscles of the lower extremities, with the thresholds of these responses being significantly higher in the patients presenting with serious neurological problems. Stimulation with the frequencies of 5 and 30 Hz caused in the patients with paresis the involuntary movement of the legs the characteristics of which were similar to those of the locomotor movements. CONCLUSION: It has been demonstrated that the application of transcutaneous electrical spinal cord stimulation leads to increased excitability of the lumbar spinal neural structures of the patients. The study has shown the possibility of regulation of the locomotor functions in the patients presenting with movement disorders of central genesis by means of non-invasive electrical stimulation of the spinal cord. PMID- 29119955 TI - [The effectiveness of combined laser therapy for the treatment of the patients presenting with bronchial asthma and concomitant allergic rhinitis]. AB - A total of 137 patients suffering from bronchial asthma (BA) and concomitant allergic rhinitis (AR) were available for the examination at the stage of the rehabilitative treatment under conditions of the southern coast of the Crimea. All the patients were divided into three groups. The patients of group 1 underwent the standard complex of spa and health resort-based climatic therapy procedures (SCT), for those comprising group 2 SCT was supplemented by non invasive magnetic laser therapy (NMLT) while patients included in group 3 received SCT and the combination of NMLT with endonasal laser radiation (ENLR). The study has demonstrated that the combined application of physiotherapeutic procedures (NMLT and ENLR) enhances the effectiveness of SCT in comparison with either NMLT or SCT alone in terms of improvement of clinical manifestations of the disease, external respiratory function, laboratory characteristics, and immunological status of the patients suffering from bronchial asthma. PMID- 29119954 TI - [The role of dosed walking in the combination with elements of cognitive training in the comprehensive treatment of the patients presenting with Alzheimer's disease]. AB - AIM: The objective of the present study was to evaluate the effectiveness of dosed physical exercises for the combined treatment of the patients presenting with mild to moderate dementia associated with Alzheimer's disease (AD). MATERIAL AND METHODS: The comprehensive examination involved 41 patients (32 women and 9 men) with the confirmed diagnosis of 'probable' AD with stages 1 and 2 of dementia and 17 healthy volunteers comprising the group of comparison. In all the patients, the neurological examination was supplemented by neuropsychological testing. Two treatment modalities were applied, one being conventional therapy with the use of memantine at the average effective dose, the other with the combination of memantine and dosed physical exercises including elements of cognitive training. RESULTS: In the group of patients treated with memantine alone, changes in cognitive performances among the men did not suggest any statistically significant positive trendency whereas the results of estimation in the women based on the clock drawing test (CDT) and the Mini-Mental State Examination (MMSE) scores revealed the significant improvement of cognitive performances. The most pronounced effects were documented in the women who had received combined therapy with the inclusion of dosed physical exercises in the form of walking. The comparison of the results of the treatment with observations of the patients included in the comparison group demonstrated the improvement of frontal cognitive functioning in the patients of both sexes under the influence of the combined treatment which manifested itself as the absence of the statistically significant differences between the results of the evaluation based on the Frontal Assessment Battery (FAB) scale. CONCLUSION: The prescription of dosed physical exercises with elements of cognitive training to be applied for the treatment of the patients presenting with dementia of different severity associated with Alzheimer's disease makes it possible to optimize the outcome of the conventional medical treatment and thereby to improve the results of scoring assessments of cognitive performances based on the MMSE, FAB, and CDT scales. PMID- 29119956 TI - [A study of the 'effective' psychotherapist image and expectations about psychotherapy among the employees of hazardous occupations (policemen)]. AB - BACKGRAUND: The objective of the present study was to estimate the expectations about psychotherapy in terms of social and medical rehabilitation among the employees of hazardous occupations suffering from the consequences of a psychological trauma. MATERIAL AND METHODS: A total of 100 subjects employed by various departments of the Russian Ministry of Internal Affairs (MIA) were recruited to participate in the study. Their age varied from 19 to 35 (mean 25.8+/-3.6) years. The mean age of the 56 men and the 44 women was 25.8+/-3.7 years and 25.9+/-3.5 years respectively. The methods of research included a questionnaire study for the elucidation of psychotherapeutic expectations and psychotherapeutic experience, the diagnostic test for the assessment of the interpersonal relationships, and the NEO five-factor personality inventory (NEO FFI). RESULTS: The results of the questionnaire studies designed to obtain the profile of expectations about psychotherapy among the entire sample suggested the positive attitude of the responders toward the therapeutic interventions with no significant preferences given to their specific type providing that they proved efficient. However, the averaged estimates for the subscales that implied self exploration (e.g. inward orientation and catharsis) for the general sample proved somewhat lower than those for such subscales as outward orientation including advice, defensiveness, support, the development and practicing of concrete specific skills and techniques needed to facilitate dealing with particular problems and symptoms. Generally speaking, the participants of the present study positively evaluated the effectiveness of psychological aid designed to resolve the problems associated with psychic traumatization based on the relevant personal experience dictating the necessity to avoid factors and situations either reminiscent of those that had resulted in the psychotraumatic event or symbolizing it. Moreover, the patients exhibiting the signs of post-traumatic stress disorders (PTSD) suffere a number of abnormal changes in the cognitive and emotional spheres in the combination with enhanced physiological responsiveness. CONCLUSION: The results of the present study give evidence of the importance of taking into consideration the expectations of the patients suffering from the consequences of a psychological trauma as regards the results of psychotherapy as well as the mode of their personal interactions with the attending physicians which in its turn depend on the specific dynamics features of the disease and its overall clinical picture. In order to maintain a 'working alliance' between the patient of the given group and the psychotherapist, the latter should follow a certain pattern of interpersonal relationships with the patient which can be described by octants 2, 4-7 of the Interpersonal Relationship Diagnostics questionnaire. Also, the results obtained in the study can be used for the elaboration and implementation of the comprehensive psychotherapeutic and rehabilitative programs within the framework of health resort-based treatment programs for the employees of hazardous occupations who experience problems arising from the consequences of psychic trauma. PMID- 29119957 TI - [The psychological security in the framework of the system of factors responsible for the effectiveness of spa and health resort-based rehabilitation]. AB - AIM: The present work was designed to address the problem of ensuring the psychological security in the framework of organization of the rehabilitative treatment based at the spa and health resort facilities. MATERIAL AND METHODS: We undertook the questionnaire study for which 650 subjects were recruited among those attending spa and health resort facilities of the cities of Essentuki and Kislovodsk. The participants were asked to estimate the level of their personal security and the quality of the provided means for the rehabilitative treatment and general health improvement. RESULTS: It was found that as many as 43% of the respondents reported the moderate level of psychological security whereas about 30% of them estimated the level of their psychological security as low. Overall, the attitude toward the available means for health improvement and rehabilitation proved extremely variable. The factorial analysis has demonstrated the highly subjective opinions of the responders as regards the provided services categorized in terms of therapeutic (mineral water, preformed physical factors, peloid and dietary therapy), health improvement (herbal medicine, therapeutic physical training, therapy, bioclimatic therapy), and recreational (animation, excursion and touristic activities) factors. The value of these factors was perceived differently by the vacationers with different feelings of psychological security. Those reporting the high level of psychological security demonstrated the positive attitude toward all factors and circumstances available for the general improvement of the health status whereas the holidaymakers reporting the moderate level of personal psychological security exhibited the non-equivalent attitude toward the provided services; namely, they highly estimated the available therapeutic factors but either underestimated the value of the constituent components of the health improving and recreational factors or demonstrated the very selective attitude toward their assessment. Generally speaking, the feeling of personal psychological security in the participants of the study reflected their subjective approach to structuralization and differentiation of the factors underlying the effectiveness, final outcome, and psychological security of the spa and health resort-based rehabilitative treatment. CONCLUSION: The results of the present study give evidence of the paramount importance of personal psychological security as a most important factor contributing to the solution of problems facing the practice of the rehabilitation treatment based at the spa and health resort facilities. This work should be organized taking into consideration the necessity to ensure the feeling of personal security and psychological comfort in the holidaymakers as an indispensable prerequisite for the successful rehabilitative treatment of the vacationers and meeting the requirements of the holidaymakers. PMID- 29119958 TI - [The experience with the application of ozone therapy for the treatment of periodontitis in musicians-instrumentalists]. AB - : Playing various musical instruments is the cause of an additional load that affects the condition of dentition and of all organs and body systems at large. Each group of instruments is known to exert a specific impact on the health of the musicians including the undesirable influence on the state of thir oral cavity, such as a change of occlusion and irritation of oral mucosa. Taken together, these effects contribute to the development of periodontal disease, one of the most common dental disorders. AIM: The objective of the present study was to evaluate the effectiveness of ozone therapy conducted with the use of the generator producing ozone under effect of ultraviolet radiation for the treatment of periodontitis in musicians-instrumentalists. MATERIAL AND METHODS: The study included 42 musicians presenting with the diagnosis of periodontitis who were divided into two groups depending on the severity of the disease. Group 1 was comprised of the subjects with mild periodontitis while group 2 consisted of the musicians having periodontitis of moderate severity. All the participants in the study remained under observation over 6 months during which they were treated by ozone therapy. The results of the treatment were estimated immediately after the onset of therapy as well as within the next 3 and 6 months. The variance analysis with the use of Student's t-test was employed for the statistical treatment of the data obtained. RESULTS: The study has demonstrate that ozone therapy resulted in the reduction of inflammation and normalization of local blood circulation in the periodontal tissues; moreover, it extended and lengthened the periods of remission and stabilization of the process of recovery. CONCLUSION: The results of the study are of primary importance for the maintenance of oral cavity health in musicians-instrumentalists which is indispensable for the maintenance of their successful professional activity. PMID- 29119959 TI - [The potential of the non-pharmacological methods for the rehabilitation and prophylaxis in the patients suffering from with atopic dermatitis]. AB - This article was designed to discuss the therapeutic potential of various non pharmacological and physiotherapeutic methods for the treatment and rehabilitation of the patients presenting with atopic dermatitis (AD) during the inter-recurrence period of the disease. The particular emphasis is placed on the physical agents most frequently used for the purpose with special reference to the combined therapy of atopic dermatitis in the adults and children and to their rehabilitation in the inter-exacerbation periods. In addition, the data on the prospects for the use of various medications intended for tissue- and organotherapy of the patients suffering from atopic dermatitis are presented. The main traditional approaches to the management of the patients with atopic dermatitis under conditions of the spa and health resort facilities are considered based on the original experience of the authors including the application of various modes of ozone therapy regarded as a physiotherapeutic procedure for the treatment of atopic dermatitis in the children and adult patients, their rehabilitation, and the prevention of exacerbations of the pathological process based on the external and/or systemic application of the ozone-oxygen gaseous mixture. The selected modalities of ozone therapy used to treat various clinical forms and stages of the atopic dermatitis differing in severity are described in detail. The data on the influence of ozone therapy on a variety of pathogenetic factors of atopic dermatitis are presented as obtained by the investigations into dynamics of the characteristics of immunity, microcirculation, and the levels of free radical metabolites. The results of the study give evidence of the high effectiveness of ozone therapy as a method of physiotherapeutic treatment both in the capacity of a component of combined therapy during the acute phase of atopic dermatitis and as the means of secondary (post-exposure) prophylaxis of the exacerbations and relapses of this condition based at the medical and preventive treatment facilities of various specialization. PMID- 29119960 TI - [Scoliosis in the children: the new approaches to the treatment and rehabilitation]. AB - : Scoliosis is the most widespread orthopaedic condition affecting both the children and the adolescents. The electrostatic field is known to promote the development of vibrations of varying strength in the biological tissues and their penetration rather deep into their interior. AIM: The objective of the present study was to elucidate the possibilities and practicability of the application of a low-frequency electrostatic field for the conservative treatment of grade I and II scoliosis in the children and to develop the scientifically sound substantiation for the use of this technique in the clinical practice. MATERIAL AND METHODS: We examined and treated 94 children randomly divided into two groups (main and control) matched for the age and major clinical manifestation of the disease. All the patients received basic therapy. Those in the study group were additionally given low-frequency electrostatic therapy. RESULTS AND DISCUSSION: The comparative analysis of the results of the treatment gave evidence that the application of a low-frequency electrostatic field for the conservative treatment of grade I and II scoliosis in the children resulted in the well apparent positive changes in their health status. These changes manifested themselves in the favourable dynamics of both the clinical symptoms of the disease and as the improvement of the topographic and thermographic characteristics. Of special importance is the alleviation of the symptoms of scoliotic deformation of the vertebral column under effect of the low-frequency electrostatic field. CONCLUSION: The present study has demonstrated that the application of the low frequency electrostatic field significantly increases the effectiveness of the treatment of grade I and II scoliosis in the children and adolescents and promotes regression of this pathological condition. PMID- 29119961 TI - [The effectiveness of the improvement of health in the schoolchildren staying in a country summer camp]. AB - : Organization of recreational activities in the children's camps is inseparable from the assessment of their effectiveness. AIM: The objective of the present study was to estimate the influence of the pastime of the children in a summer camp under the habitual climatic conditions and the resulting improvement of their health status including the body component composition and the functional state of the organism. MATERIAL AND METHODS: The study included 44 schoolchildren at the age from 9 to12 years. The analysis of the effectiveness of recreational activities was carried out with the use of the method for the assessment of health improvement based at the children's summer camps. Alterations in the component composition of the body were evaluated from the results of bioimpedansometry. RESULTS: The physical development of the majority of the schoolchildren involved in the study both in the beginning and the end of the camp period was fairly well balanced. During the period of resting in the camp (14 days), changes in the body weight were largely attributable to the alteration in the lean body mass whereas the fat component remained rather stable. The cardio-respiratory system did not show any unambiguous signs of positive dynamics. The physical conditions of the children estimated based on the hand dynamometry index showed a negative change. The comprehensive assessment of the degree of health improvement with the use of a scoring system made it possible to demonstrated that half of the schoolchildren spending time in the summer camp under the moderate climate conditions markedly improved their somatic health, functional and physical state whereas the remaining half enjoyed only a slight improvement. CONCLUSION: We suppose that the main causes preventing manifestations of the maximal positive effect of the pastime in the summer camp on the health status of the children included the short period of stay in the camp and the irrational use of the available complex of recreational activities, such as the sound nutrition regimen, adequate physical loading including locomotor activity, and psychological comfort). Bioimpedansometry which objectively reflects any changes in the body component composition is recommended for the application as one of the additional instruments for the objective analysis of the changes in the body component composition of the children and of the effects exerted by the recreational activities in the summer camp on their health status. PMID- 29119962 TI - [The specific features of the development of metabolic and regenerative processes under the action of low-intensity electromagnetic radiation in radiation exposure conditions (an experimental study)]. AB - The experiments on male white rats with the use of biochemical, photo-optical, and electron-microscopic techniques have demonstrated that the use of low intensity electromagnetic radiation of ultrahigh frequency (EMR UHF) and low intensity low-frequency magnetic field (MF) during the post-irradiation period (within 21 days after exposure to radiation) enhanced the metabolic and regenerative processes in the testes and liver. It was shown that the application of MF largely intensified the antioxidant activity whereas EMR UHF preferentially stimulated the biosynthetic processes as well as the processes of cellular and intracellular regeneration. PMID- 29119963 TI - [What physiotherapeutic method for the treatment of post-mastectomy lymphedema is the most effective?] AB - We have undertaken the search for the publications of interest in the following databases: Scopus, Web of Science, MedLine, The Cochrane Library, CyberLeninka, and Russian science citation index. In addition, we evaluated the effectiveness of the physical agents and procedures having different mechanisms of action of the known factors responsible for the development of post-mastectomy lymphedema. Such agents and procedures include self-massage, manual lymphatic drainage, therapeutic physical exercises, compression bandaging, wearing elastic compression garments, Kinesio Tex taping, pneumatic compression, ultrasonic, electrostatic, extracorporeal shock wave therapy, electrical muscle stimulation, microcurrent and low-intensity laser therapy. These methods and products were used by the authors of selected publications either separately or in the combined modes taking into consideration the significant differences between effects of the application of individual techniques. The results of the treatment are presented for different time periods, either in absolute units (cm or ml) in the majority of the cases or in relative units (%) only in part of them without information concerning the statistical significance of the results obtained. There is thus far neither the universal classification of post-mastectomy lymphedema nor the generally accepted approaches to its diagnostics and treatment. Therefore, it is impossible to give an unambiguous answer as regards the effectiveness of one or another method for the diagnostics and treatment of this condition. The author of the present article observed 172 patients at the age of 56.8+/-9.7 years suffering from late grade I-IV lymphedema treated with the use of local low-intensity low-frequency electric and magnetic therapy in the combination with pneumatic compression applied during 15 days. The results of the treatment were evaluated using water and impedance plethysmography. Within 4 weeks after the onset of therapy, the volume of the upper limb decreased on the average for all stages of lymphedema by 37.7+/-9.3% under effect of pneumatic compression alone, by 49.5+/-10.7% under the influence of its combination with electrotherapy, by 59.9+/-5.4% under the action of the combination of pneumatic compression with magnetotherapy, and by 76.3+/-7.3% after the application of all the three techniques together (p<0.05). Electrical neurostimulation of the blood vessels and skeletal muscles proved especially effective for the treatment of I II grade lymphedema while magnetic therapy was most efficient for the management of grade III-IV lymphedema. The proposed method of combined physiotherapy looks very encouraging for the treatment of late lymphedema but does not completely solve all problems pertaining to the management of this pathological condition. PMID- 29119964 TI - Early improvement in food cravings are associated with long-term weight loss success in a large clinical sample. AB - This corrects the article DOI: 10.1038/ijo.2017.89. PMID- 29119966 TI - Cucurbitacin I inhibits STAT3, but enhances STAT1 signaling in human cancer cells in vitro through disrupting actin filaments. AB - STAT1 and STAT3 are two important members of the STAT (signal transducers and activators of transcription) protein family and play opposing roles in regulating cancer cell growth. Suppressing STAT3 and/or enhancing STAT1 signaling are considered to be attractive anticancer strategies. Cucurbitacin I (CuI) isolated from the cucurbitacin family was reported to be an inhibitor of STAT3 signaling and a disruptor of actin cytoskeleton. In this study we investigated the function and mechanisms of CuI in regulating STAT signaling in human cancer cells in vitro. CuI (0.1-10 mmol/L) dose-dependently inhibited the phosphorylation of STAT3, and enhanced the phosphorylation of STAT1 in lung adenocarcinoma A549 cells possibly through disrupting actin filaments. We further demonstrated that actin filaments physically associated with JAK2 and STAT3 in A549 cells and regulated their phosphorylation through two signaling complexes, the IL-6 receptor complex and the focal adhesion complex. Actin filaments also interacted with STAT1 in A549 cells and regulated its dephosphorylation. Taken together, this study reveals the molecular mechanisms of CuI in the regulation of STAT signaling and in a possible inhibition of human cancer cell growth. More importantly, this study uncovers a novel role of actin and actin-associated signaling complexes in regulating STAT signaling. PMID- 29119967 TI - Rhynchophylla total alkaloid rescues autophagy, decreases oxidative stress and improves endothelial vasodilation in spontaneous hypertensive rats. AB - Autophagy plays an important role in alleviating oxidative stress and stabilizing atherosclerotic plaques. However, the potential role of autophagy in endothelial vasodilation function has rarely been studied. This study aimed to investigate whether rhynchophylla total alkaloid (RTA) has a positive role in enhancing autophagy through decreasing oxidative stress, and improving endothelial vasodilation. In oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs), RTA (200 mg/L) significantly suppressed ox-LDL-induced oxidative stress through rescuing autophagy, and decreased cell apoptosis. In spontaneous hypertensive rats (SHR), administration of RTA (50 mg.kg-1.d-1, ip, for 6 weeks) improved endothelin-dependent vasodilation of thoracic aorta rings. Furthermore, RTA administration significantly increased the antioxidant capacity and alleviated oxidative stress through enhancing autophagy in SHR. In ox-LDL-treated HUVECs, we found that the promotion of autophagy by RTA resulted in activation of the AMP-activated protein kinase (AMPK) signaling pathway. Our results show that RTA treatment rescues the ox-LDL-induced autophagy impairment in HUVECs and improves endothelium-dependent vasodilation function in SHR. PMID- 29119968 TI - Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model. AB - Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto induction and time-dependent pharmacokinetics (pharmacokinetics with time dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid Emax equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an Emax equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies. PMID- 29119969 TI - Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-alpha. AB - BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-alpha (FAPalpha) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPalpha-based prodrug strategy to synthesize a dipeptide (Z-Gly-Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPalpha (rhFAPalpha) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPalpha-negative normal tissues, such as heart and kidney. In HCT-116 and MGC 803 cells with low levels of FAPalpha expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPalpha expression, the IC50 value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPalpha or tumor homogenate. In HCT-116 tumor bearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPalpha-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy. PMID- 29119971 TI - Paradoxical lack of increase in endothelin-1 levels in obese mice - possible role of endothelin-B receptors. PMID- 29119970 TI - Hispidulin mediates apoptosis in human renal cell carcinoma by inducing ceramide accumulation. AB - Hispidulin, a polyphenolic flavonoid extracted from the traditional Chinese medicinal plant S involucrata, exhibits anti-tumor effects in a wide array of human cancer cells, mainly through growth inhibition, apoptosis induction and cell cycle arrest. However, its precise anticancer mechanisms remain unclear. In this study, we investigated the molecular mechanisms that contribute to hispidulin-induced apoptosis of human clear-cell renal cell carcinoma (ccRCC) lines Caki-2 and ACHN. Hispidulin (10, 20 MUmol/L) decreased the viability of ccRCC cells in dose- and time-dependent manners without affecting that of normal tubular epithelial cells. Moreover, hispidulin treatment dose-dependently increased the levels of cleaved caspase-8 and caspase-9, but the inhibitors of caspase-8 and caspase-9 only partly abrogated hispidulin-induced apoptosis, suggesting that hispidulin triggered apoptosis via both extrinsic and intrinsic pathways. Moreover, hispidulin treatment significantly inhibited the activity of sphingosine kinase 1 (SphK1) and consequently promoted ceramide accumulation, thus leading to apoptosis of the cancer cells, whereas pretreatment with K6PC-5, an activator of SphK1, or overexpression of SphK1 significantly attenuated the anti-proliferative and pro-apoptotic effects of hispidulin. In addition, hispidulin treatment dose-dependently activated ROS/JNK signaling and led to cell apoptosis. We further demonstrated in Caki-2 xenograft nude mice that injection of hispidulin (20, 40 mg.kg-1.d-1, ip) dose-dependently suppressed tumor growth accompanied by decreased SphK1 activity and increased ceramide accumulation in tumor tissues. Our findings reveal a new explanation for the anti-tumor mechanisms of hispidulin, and suggest that SphK1 and ceramide may serve as potential therapeutic targets for the treatment of ccRCC. PMID- 29119973 TI - Anticoagulation therapy: Oral anticoagulants reduce dementia risk in patients with AF. PMID- 29119974 TI - Correction: Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. AB - [This corrects the article DOI: 10.1136/bmjdrc-2017-000438.]. PMID- 29119975 TI - Erratum: Microstructure of the Distal Radius and Its Relevance to Distal Radius Fractures. AB - [This corrects the article DOI: 10.1055/s-0037-1602849.]. PMID- 29119976 TI - Corrigenda: Caterino M, Vasquez-Velez L (2017) A revision of Prespelea Park (Staphylinidae, Pselaphinae). ZooKeys 685: 105-130. https://doi.org/10.3897/zookeys.685.13811. AB - [This corrects the article DOI: 10.3897/zookeys.685.13811.]. PMID- 29119977 TI - Laboratory spectroscopy of methoxymethanol in the millimeter-wave range. AB - Methoxymethanol, CH3OCH2OH is a very interesting candidate for detection in the interstellar medium since it can be formed in the recombination reaction between two radicals considered as intermediates in methanol formation: CH3O (already detected in the ISM) and CH2OH. It could also be formed by the addition of CH3O to formaldehyde (another abundant compound in the ISM) followed by abstraction of a hydrogen radical. In this study, we present the first spectroscopic characterization of methoxymethanol in the millimeter-wave range augmented by high level quantum chemical calculations. The analysis revealed three stable conformations all exhibiting different large amplitude motions (LAMs). For the analysis of the most stable conformation (I) we applied a model that accounts for hindered internal rotation of the methyl top. The analysis of conformation III was performed taking the interaction between the overall rotation and OH torsional motion into account. Conformation II was only tentatively assigned, as it exhibits several LAMs that significantly complicate the theoretical description. Accurate spectroscopic parameters obtained in this study provide a reliable basis for the detection of methoxymethanol in the ISM. PMID- 29119972 TI - Rotavirus infection. AB - Rotavirus infections are a leading cause of severe, dehydrating gastroenteritis in children <5 years of age. Despite the global introduction of vaccinations for rotavirus over a decade ago, rotavirus infections still result in >200,000 deaths annually, mostly in low-income countries. Rotavirus primarily infects enterocytes and induces diarrhoea through the destruction of absorptive enterocytes (leading to malabsorption), intestinal secretion stimulated by rotavirus non-structural protein 4 and activation of the enteric nervous system. In addition, rotavirus infections can lead to antigenaemia (which is associated with more severe manifestations of acute gastroenteritis) and viraemia, and rotavirus can replicate in systemic sites, although this is limited. Reinfections with rotavirus are common throughout life, although the disease severity is reduced with repeat infections. The immune correlates of protection against rotavirus reinfection and recovery from infection are poorly understood, although rotavirus specific immunoglobulin A has a role in both aspects. The management of rotavirus infection focuses on the prevention and treatment of dehydration, although the use of antiviral and anti-emetic drugs can be indicated in some cases. PMID- 29119978 TI - Demixing and ordering in Ni(Ti,Zr)(Sb,Sn) half-Heusler materials. AB - We employed density functional theory, Monte Carlo simulations and a mean field model to study phase separation in thermoelectric Ni(Ti,Zr)(Sb,Sn) half-Heusler materials, simultaneously alloyed in the (Ti,Zr)- and (Sb,Sn) sublattices. We found that the material shows demixing and ordering phenomena as the temperature is lowered. Below a critical temperature, which depends on the overall stoichiometry, demixing occurs within the sublattices. Typically, a strong demixing in the (Ti,Zr) sublattice is accompanied by a weaker demixing in the (Sb,Sn) sublattice stoichiometry. In the coexistence region, the Sb concentration in the Ti-rich phase is higher than that in the Zr-rich phase. For a Sn : Sb ratio of 1 : 3, we find a second phase separation in the Sb/Sn sublattice at about 200 K. Here, a phase without Sn coexists with a phase that has a 1 : 1 ratio of Sb and Sn. In the latter phase Sb and Sn alternate within the sublattice forming a highly ordered structure. The results provide new insights into the pattern formation in Ni(Ti,Zr)(Sb,Sn) which helps in creating nano-structuring strategies to improve the figure of merit in this class of thermoelectric materials. PMID- 29119979 TI - Enhanced delivery of lipophilic bioactives using emulsions: a review of major factors affecting vitamin, nutraceutical, and lipid bioaccessibility. AB - Many researchers are currently developing emulsion-based delivery systems to increase the bioavailability of lipophilic bioactive agents, such as oil-soluble vitamins, nutraceuticals, and lipids. Oil-in-water emulsions can be specifically designed to improve the bioavailability of these bioactives by altering their composition and structural organization. This article reviews recent progress in understanding the impact of emulsion properties on the bioaccessibility of lipophilic bioactive agents, including oil phase composition, aqueous phase composition, droplet size, emulsifier type, lipid physical state, and droplet aggregation state. This knowledge can be used to design emulsions that can enhance the bioavailability and efficacy of encapsulated hydrophobic bioactives. PMID- 29119980 TI - Ultrafast dynamics of UV-excited trans- and cis-ferulic acid in aqueous solutions. AB - The ultrafast UV-induced processes of the neutral, anionic and dianionic forms of trans- and cis-ferulic acid (FA) in aqueous solution were studied by static and femtosecond time-resolved emission and absorption spectroscopy combined with quantum chemical calculations. In all cases, initial excitation populates the first 1pipi* state. For the dianionic cis-isomer cFA2-, electronic deactivation takes place with a time constant of only 1.4 ps, whereas in all other cases, excited-state deactivation happens more than ten times slower, on a time scale of ~20 ps. The data suggest sequential de-excitation pathways, where initial sub picosecond solvent rearrangement and structural changes are followed by internal conversion to an intermediate excited electronic state from which deactivation to the ground state proceeds. Considering the time scales, barrierless excited-state pathways are suggested only in the case of cFA2-, where the observed formation of the isomerisation photoproduct tFA2- provides clear evidence for a cis ? trans isomerisation coordinate. In the other cases, pathways with an excited-state energy barrier, presumably along the same coordinate, are likely, given the longer excited-state lifetimes. PMID- 29119981 TI - Magnetic bead-based peptide extraction methodology for tissue imaging. AB - MALDI-TOF imaging mass spectrometry (IMS) is a common technique used for analyzing tissue samples, as it allows the user to detect multiple different analytes simultaneously. However, the detection and analysis of these analytes may sometimes be hampered due to the presence of contaminants in the tissue microenvironment, which leads to ion suppression. This challenge necessitates the development of an active extraction technique to selectively isolate analytes of interest without compromising their spatial localization within a tissue sample. This study proposes a magnetic bead-based active extraction approach to selectively sequester peptides of interest from tissue samples. The technique utilizes a heterobifunctional cross-linker to covalently bind peptides with free primary amine groups to functionalized magnetic beads. The cross-linked peptides can then be collected using a transfer magnet and imaged using MALDI-TOF IMS. We have established that this technique not only successfully isolates peptides both in-solution and on a solid surface, but also extracts peptides from a tissue section without significantly compromising their spatial localization. This novel method provides the means to detect a unique subset of peptides from tissue sections when compared to unextracted tryptically digested tissue, all while minimizing the presence of contaminants and maintaining spatial localization. PMID- 29119982 TI - Engineering n-p junction for photo-electrochemical hydrogen production. AB - The generation of hydrogen from water and sunlight offers a promising approach for producing scalable and sustainable carbon free fuels. One of the challenges of solar-to-fuel technology is the design of efficient, long-lasting and low-cost photocathodes, which are responsible for absorbing sunlight and driving catalytic hydrogen evolution. We report on the protection of a Cu/Cu2O/CuO photoelectrode against photocorrosion by a 200-300 nm-thick BaTiO3 perovskite layer, deposited using the sol-gel method. This photoelectrode mediates H2 production with a current density of ~3.1 mA cm-2 at 0 V versus RHE under 3 Sun irradiation and in a pH = 6 aqueous electrolyte. While the unprotected Cu/Cu2O/CuO photoelectrodes show a rapid decay of activity, the BaTiO3-protected photoelectrodes exhibit ~10% current decay over 20 min. PMID- 29119983 TI - Phosphorescent heterobimetallic complexes involving platinum(iv) and rhenium(vii) centers connected by an unsupported MU-oxido bridge. AB - Heterobimetallic compounds [(C^N)LMe2Pt(MU-O)ReO3] (C^N = ppy, L = PPh3, 2a; C^N = ppy, L = PMePh2, 2b; C^N = bhq, L = PPh3, 2c; C^N = bhq, L = PMePh2, 2d) containing a discrete unsupported Pt(iv)-O-Re(vii) bridge have been synthesized through a targeted synthesis route. The compounds have been prepared by a single pot synthesis in which the Pt(iv) precursor [PtMe2I(C^N)L] complexes are allowed to react easily with AgReO4 in which the iodide ligand of the starting Pt(iv) complex is replaced by an ReO4- anion. In these Pt-O-Re complexes, the Pt(iv) centers have an octahedral geometry, completed by a cyclometalated bidentate ligand (C^N), two methyl groups and a phosphine ligand, while the Re(vii) centers have a tetrahedral geometry. Elemental analysis, single crystal X-ray diffraction analysis and multinuclear NMR spectroscopy are used to establish their identities. The new complexes exhibit phosphorescence emission in the solid and solution states at 298 and 77 K, which is an uncommon property of platinum complexes with an oxidation state of +4. According to DFT calculations, we found that this emission behavior in the new complexes originates from ligand centered 3LC (C^N) character with a slight amount of metal to ligand charge transfer (3MLCT). The solid-state emission data of the corresponding cycloplatinated(iv) precursor complexes [PtMe2I(C^N)L], 1a-1d, pointed out that the replacement of I- by an ReO4- anion helps enhancing the emission efficiency besides shifting the emission wavelengths. PMID- 29119984 TI - Catalytic fixation of atmospheric carbon dioxide by copper(ii) complexes of bidentate ligands. AB - New copper(ii) complexes, [Cu(L1)2(H2O)](ClO4)2, 1 [L1 = 2-pyridin-2-yl quinoline], [Cu(L2)2(H2O)](ClO4)2, 2 [L2 = 2-pyridin-2-yl-quinoxaline], [Cu(L3)2(H2O)](ClO4)2, 3 [L3 = 6,7-dimethyl-2-pyridin-2-yl-quinoxaline], [Cu(L4)2(H2O)](ClO4)2, 4 [L4 = 4-phenyl-2-pyridin-2-yl-quinoline] and [Cu(L5)2(H2O)](ClO4)2, 5 [L5 = 4-phenyl-2-pyridin-2-yl-quinazoline], were synthesized and characterized as catalysts for selective fixation of atmospheric CO2. The molecular structure of 2 was determined by single-crystal X-ray studies and shown to have an unusual trigonal bipyramid geometry (tau, 0.936) around the copper(ii) center, with the coordination of two ligand units and a water molecule. The Cu-Nquin (2.040, 2.048 A) bonds are slightly longer than the Cu Npyr (1.987 A) bonds but shorter than the Cu-Owater bond (2.117 A). Well-defined Cu(ii)/Cu(i) redox potentials of around 0.352 to 0.401 V were observed for 1-5 in acetonitrile. The electronic absorption spectra of 1-5 showed ligand-based transitions at around 208-286 nm with a visible shoulder at around 342-370 nm. The d-d transitions appeared at around 750-800 and 930-955 nm in acetonitrile. The rhombic EPR spectra of 1-5 exhibited three different g values gx, 2.27-2.34; gy, 2.06-2.09; and gz, 1.95-1.98 at 70 K. Atmospheric CO2 was successfully fixed by 1-5 using Et3N as a sacrificial reducing agent, resulting in CO32--bound complexes of type [Cu(L)CO3(H2O)] that display an absorption band at around 614 673 nm and a nust at 1647 cm-1. This CO32--bound complex of 1 was crystallized from the reaction mixture and it displayed a distorted square pyramidal geometry (tau, 0.369) around the copper(ii) center via the coordination of only one ligand unit, a carbonate group, and water molecules. Furthermore, treatment of the carbonate-bound Cu(ii) complexes with one equivalent of H+ under N2 atmosphere resulted in the liberation of bicarbonate (HCO3-) and regenerated the parent complexes. These regenerated catalysts were active enough to fix CO2 in eight repeating cycles without any change in efficiency. The fixation of CO2 possibly occurs via the formation of Cu(i)-species, which is accompanied by the formation of an MLCT band at around 450-500 nm. The rates of Cu(i)-species formation, kobs, were determined and found to be 5.41-10.31 * 10-3 s-1 in the presence of Et3N in acetonitrile at 25 degrees C. Interestingly, the copper(i)-species of 3 has been successfully crystallized and displayed a distorted tetrahedral geometry through the coordination of two units of ligand L3. PMID- 29119986 TI - Chip-integrated plasmonic cavity-enhanced single nitrogen-vacancy center emission. AB - High temporal stability and spin dynamics of individual nitrogen-vacancy (NV) centers in diamond crystals make them one of the most promising quantum emitters operating at room temperature. We demonstrate a chip-integrated cavity-coupled emission into propagating surface plasmon polariton (SPP) modes narrowing the NV center's broad emission bandwidth with enhanced coupling efficiency. The cavity resonator consists of two distributed Bragg mirrors that are built at opposite sides of the coupled NV emitter and are integrated with a dielectric-loaded SPP waveguide (DLSPPW), using electron-beam lithography of hydrogen silsesquioxane resist deposited on silver-coated silicon substrates. A quality factor of ~70 for the cavity (full width at half maximum ~10 nm) with full tunability of the resonance wavelength is demonstrated. An up to 42-fold decay rate enhancement of the spontaneous emission at the cavity resonance is achieved, indicating high DLSPPW mode confinement. PMID- 29119985 TI - Phase formation of nanolaminated Mo2AuC and Mo2(Au1-xGax)2C by a substitutional reaction within Au-capped Mo2GaC and Mo2Ga2C thin films. AB - Au-containing nanolaminated carbides Mo2AuC and Mo2(Au1-xGax)2C were synthesized by a thermally induced substitutional reaction in Mo2GaC and Mo2Ga2C, respectively. The Au substitution of the Ga layers in the structures was observed using cross-sectional high-resolution scanning transmission electron microscopy. Expansion of c lattice parameters was also observed in the Au-containing phases compared to the original phases. Energy dispersive spectroscopy detected residual Ga in Au-substituted layers of both phases with a peculiar Ga in-plane ordering for Au : Ga = 9 : 1 ratio along the Au-Ga layers in Mo2(Au1-xGax)2C. These results indicate a generalization of the Au substitution reaction for the A elements in MAX phases. PMID- 29119988 TI - Di-isopropyl ether assisted crystallization of organic-inorganic perovskites for efficient and reproducible perovskite solar cells. AB - Organic-inorganic perovskite solar cells have emerged as a promising photovoltaic technology because of their advantages such as low cost, high efficiency, and solution processability. The performance of perovskite solar cells is highly dependent on the crystallinity and morphology of the perovskite films. Herein, we report a simple, one-step anti-solvent deposition process using di-isopropyl ether as a dripping solvent to obtain extremely uniform and highly crystalline CH3NH3PbI3 perovskite films. Compared to toluene, chlorobenzene, chloroform, or diethyl ether, di-isopropyl ether has proven to be a more suitable solvent for an anti-solvent deposition process. The perovskite solar cells fabricated by the anti-solvent deposition process using di-isopropyl ether treatment exhibit an average power conversion efficiency (PCE) of 17.67 +/- 0.54% and the highest PCE of 19.07%. Moreover, the higher boiling point of di-isopropyl ether makes the anti-solvent deposition process more tolerant to elevated ambient temperature, which can be carried out at ambient temperatures up to 40 degrees C. Our results demonstrate that di-isopropyl ether is an excellent dripping solvent in the anti solvent deposition process for efficient and reproducible perovskite solar cells. PMID- 29119991 TI - Templated self-assembly of one-dimensional CsPbX3 perovskite nanocrystal superlattices. AB - Ordered self-assembled arrays or superstructures of nanocrystals (NCs) have attracted intense research interest due to their ability to translate valuable nanoscale properties to larger length scales. Numerous techniques have been explored to induce self-assembly into various superstructures. Here we investigated a simple kinetic approach to form self-assembled one-dimensional perovskite CsPbX3 (X: halides) nanocrystal arrays templated inside a pod shaped inert lead sulfate (PbSO4) scaffold. Both the solvent effects, and the self assembly process and mechanism, are systematically studied based on a uniform procedure developed to generate CsPbX3 nanocrystal superlattices with different sizes and compositions. The formation of one-dimensional (1D) chains of NCs within a half-cylindrical pod of PbSO4 reflects a balance between solvophobicity and solvophilicity of the components. By reducing the size of NCs, we successfully realized 2D superlattices with two or three rows of close-packed CsPbBr3 NCs, in addition to single string-of-pearl type 1D assemblies. The superlattices can be assembled both inside and outside of the half-cylindrical shells by regulating the reaction conditions. The self-assembly behavior is reminiscent of the host-guest systems of organic molecular species where supramolecular recognition rules apply to give well-defined complexes. The current study opens a door for controlling self-assembled nanostructures of CsPbX3 NCs, and provides an attainable platform for future optoelectronic devices. PMID- 29119995 TI - Fabrication of tough photonic crystal patterns with vivid structural colors by direct handwriting. AB - Patterned photonic crystals (PCs) have attracted considerable attention due to their great potential in practical applications. Direct writing is an important and convenient method to fabricate patterned PCs. However, due to the limited interaction among spheres and the evaporation of ink, the obtained patterns usually suffer from poor structure strength, and non-uniform and unstable structural colors. In this work, an in situ embedding and locking strategy for fabricating tough PC patterns in one step was demonstrated. With properly dried polymer films as "paper" and dispersions of CdS spheres as "inks" to write on the "paper", the self-assembly of CdS spheres and locking of the PC structure can be achieved simultaneously, which gives rise to tough composite patterned PCs with uniform, stable and permanent structural colors. Based on this simple method, tough PC patterns can be easily and quickly created by direct hand writing or drawing without special treatment, equipment, masks or templates. The vivid structural colors of the tough PC patterns and this simple method show great potential for practical applications. PMID- 29119993 TI - A study of the reactivity of S(VI)-F containing warheads with nucleophilic amino acid side chains under physiological conditions. AB - Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related SVI F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5'-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present. PMID- 29119996 TI - Reversion of gold nanoparticle aggregates for the detection of Cu2+ and its application in immunoassays. AB - A high concentration of copper is a hazardous element to organisms and human health. Although various strategies have been reported for the sensitive detection of copper, a facile and rapid detection of aqueous copper has seldom been addressed to date. Here, we present an easy and accessible colorimetric method to detect Cu2+ using the redispersion of cysteamine-modified gold nanoparticles (CA-AuNPs). Initially, CA caused the aggregation of AuNPs due to the electrostatic interaction and aggregated AuNPs can be regenerated in basic medium. The subsequent addition of Cu2+ to the CA-AuNP dispersion could effectively trigger the aggregation of CA-AuNPs, resulting from the coordination reactivity between the deprotonated CA and Cu2+. This strategy resulted in a detection limit (LOD) of 1.52 MUM in drinking water, which is below the U.S. Environmental Protection Agency permissible limit (20 MUM). To demonstrate the broad application of CA-AuNPs, we further applied this method to plasmonic immunoassays based on the competitive interaction of Cu2+ between CA-AuNPs and enzymes. The LOD of the Down syndrome biomarker hyperglycosylated human chorionic gonadotropin (H-hCG) was 0.125 mIU mL-1, which is better than that of commercial immunoassays. Importantly, the determination of H-hCG in serum indicates its applicability for the measurement of real samples. Our assay agrees well with the current immunoassay systems and thus it can easily be expanded to a more common sensing platform for different types of biotargets by changing the corresponding antibodies. PMID- 29119997 TI - Dimeric camptothecin-loaded RGD-modified targeted cationic polypeptide-based micelles with high drug loading capacity and redox-responsive drug release capability. AB - Camptothecin (CPT) is a broad spectrum anticancer drug, but its application is limited due to the poor water solubility, lactone ring instability, and low drug loading potential. In this study, biocompatible cationic polypeptide-based micelles were developed to deliver dimeric CPT (DCPT) with the aim of overcoming the above-mentioned obstacles and achieving favorable therapeutic effects. Cationic polypeptide poly-lysine-block-poly-leucine (PLys-b-PLeu) was fabricated via the ring-opening polymerization of N-epsilon-carbobenzoxy-l-lysine (epsilon Lys(Z)) and l-leucine (Leu) and further grafted with polyethylene glycol (PEG) and an arginine-glycine-aspartic acid (RGD) peptide. DCPT was synthesized by reacting CPT and 2-hydroxyethyl disulfide, and micelles were prepared using a dialysis method. The obtained DCPT-loaded RGD-PEG-g-poly-l-lysine-b-poly-l leucine (DRPPP) micelles showed a high encapsulation efficiency of 89.7% and a high drug loading capacity of 46.1%. In addition, the DRPPP micelles remained stable under physiological conditions (PBS at a pH of 7.4) but showed rapid release when triggered by a reductive environment (PBS at a pH of 7.4 with 10 mM dithiothreitol). Compared to micelles without RGD decoration, the DRPPP micelles exhibited an increased cellular uptake through RGD targeting and were internalized into cells via caveolae-mediated endocytosis and macropinocytosis. Furthermore, the DRPPP micelles exerted an enhanced cytotoxicity against MDA-MB 231 cells compared to MCF-7 cells, which expressed less alphavbeta3 receptors. Besides, the DRPPP micelles induced cell apoptosis and caused a decrease of mitochondrial membrane potential. These results indicate that dimeric camptothecin-loaded cationic polypeptide-based micelle is a promising strategy for cancer therapy. PMID- 29119998 TI - Development of a computationally-designed polymeric adsorbent specific for mycotoxin patulin. AB - Patulin is a toxic compound which is found predominantly in apples affected by mould rot. Since apples and apple-containing products are a popular food for the elderly, children and babies, the monitoring of the toxin is crucial. This paper describes a development of a computationally-designed polymeric adsorbent for the solid-phase extraction of patulin, which provides an effective clean-up of the food samples and allows the detection and accurate quantification of patulin levels present in apple juice using conventional chromatography methods. The developed bespoke polymer demonstrates a quantitative binding towards the patulin present in undiluted apple juice. The polymer is inexpensive and easy to mass produce. The contributing factors to the function of the adsorbent is a combination of acidic and basic functional monomers producing a zwitterionic complex in the solution that formed stronger binding complexes with the patulin molecule. The protocols described in this paper provide a blueprint for the development of polymeric adsorbents for other toxins or different food matrices. PMID- 29119999 TI - Ion mobility-resolved collision-induced dissociation and electron transfer dissociation of N-glycopeptides: gathering orthogonal connectivity information from a single mass-selected precursor ion population. AB - Glycopeptide-level mass spectrometry (MS) and tandem mass spectrometry (MS/MS) analyses are commonly performed to establish site-specific protein glycosylation profiles that are of central importance to gaining structure-function insights on glycoproteins. Confoundingly, the complete characterization of glycopeptide connectivity usually requires the acquisition of multiple MS/MS fragmentation spectra. Complementary ion fragmentation techniques such as collision-induced dissociation (CID) and electron transfer dissociation (ETD) are often applied in concert to address this need. While structurally informative, the requirement for acquisition of two MS/MS spectra per analyte places considerable limitations upon the breadth and depth of large-scale glycoproteomic inquiry. Here, a previously developed method of multiplexing CID and ETD is applied to the study of glycopeptides for the first time. Integration of the two dissociation methods was accomplished through addition of an ion mobility (IM) dimension that disperses the two stages of MS/MS in time. This allows the two MS/MS spectra to be acquired within a few milliseconds of one another, and to be deconvoluted in post processing. Furthermore, the method allows both fragmentation readouts to be obtained from the same precursor ion packet, thus reducing the inefficiencies imposed by separate CID and ETD acquisitions and the relatively poor precursor ion to fragment ion conversion typical of ETD. N-Linked glycopeptide ions ranging in molecular weight from 1.8 to 6.5 kDa were generated from four model glycoproteins that collectively encompassed paucimannosidic, high mannose, and complex types of N-glycosylation. In each case, IM-resolved CID and ETD events provided complete coverage of the glycan topology and peptide sequence coverages ranging from 48.4% (over 32 amino acid residues) to 85.7% (over eight amino acid residues). The potential of this method for large-scale glycoproteomic analysis is discussed. PMID- 29120000 TI - Water-soluble and UV traceable isatoic anhydride-based reagents for bioconjugation. AB - Isatoic anhydride is elaborated to water soluble bioconjugation reagents that gives functionality and water solubility in one self-cleaning step. This new platform offers high atom economy with carbon dioxide being the only byproduct, and is shown to very quickly and efficiently label proteins in bicarbonate buffered solutions. PMID- 29120001 TI - Correction: Formation of beta-(1,3-1,6)-d-glucan-complexed [70]fullerene and its photodynamic activity towards macrophages. AB - Correction for 'Formation of beta-(1,3-1,6)-d-glucan-complexed [70]fullerene and its photodynamic activity towards macrophages' by Atsushi Ikeda et al., Org. Biomol. Chem., 2017, 15, 1990-1997. PMID- 29120002 TI - Size-dependent donor and acceptor states in codoped Si nanocrystals studied by scanning tunneling spectroscopy. AB - The electrical and optical properties of semiconductor nanocrystals (NCs) can be controlled, in addition to size and shape, by doping. However, such a process is not trivial in NCs due to the high formation energy of dopants there. Nevertheless, it has been shown theoretically that in the case of B and P (acceptor/donor) codoped Si-NCs the formation energy is reduced relative to that of single type doping. Previous comprehensive measurements on ensembles of such codoped Si-NCs have pointed to the presence of donor and acceptor states within the energy gap. However, such a conjecture has not been directly verified previously. Following that, we investigate here the electronic properties of B and P codoped Si-NCs via Scanning Tunneling Spectroscopy. We monitored the quantum confinement effect in this system, for which the energy gap changed from ~1.4 eV to ~1.8 eV with the decrease of NC diameter from 8.5 to 3.5 nm. Importantly, all spectra showed two in-gap band-states, one close to the conduction band edge and the other to the valence band edge, which we attribute to the P and B dopant levels, respectively. The energy separation between these dopants states decrease monotonically with increasing NC diameter, in parallel to the decrease of the conduction-to-valence bands separation. A fundamental quantity that is derived directly for these Si-NCs is the intrinsic like position of the Fermi energy, a non-trivial result that is very relevant for understanding the system. Following the above results we suggest an explanation for the character and the origin of the dopants bands. PMID- 29120003 TI - A Novel Method of Patient Positioning Using Shoulder Arthroscopy Equipment for Elbow Arthroscopy. AB - Indications for elbow arthroscopy are expanding; however, it is uncommon compared with shoulder arthroscopy. Elbow arthroscopy can be complicated by positioning, including the need to obtain specific arm holders required by most operating rooms. Surgery can be performed in the supine, prone, or lateral position. Arm traction allows for distraction of the joint space, full insufflation, and therefore visualization of intra-articular anatomy. This article outlines a new technique using previously available shoulder arthroscopy equipment to avoid increased cost incurred by procuring new, elbow-specific equipment. This technique is performed in the supine position using a hydraulic system and a shoulder 3-point distractor. [Orthopedics. 2018; 41(1):e158-e160.]. PMID- 29120004 TI - Nerve Traction Injury After Subacute Revision External Fixation of a Tibial Plateau Fracture. AB - Nerve traction injuries are common clinical entities that can be confused with nerve palsies secondary to alternate etiologies. Common mechanisms of nerve injury include direct laceration, crush injury, compression injury, elevated compartment pressures, or traction injury. Traction injuries commonly occur after trauma or aberrant patient positioning; however, traction injury following external fixation for lower extremity injury is rare. This case report describes a 42-year-old man who initially sustained a Schatzker VI tibial plateau fracture that required revision of external fixation for pin-site infection as soft tissues recovered from the initial trauma. Postoperatively, the patient experienced a nerve traction injury from lengthening after revision external fixation. Acute loss of common peroneal motor and sensory function was identified 1 hour postoperatively in the post-anesthesia care unit; this reversed on the immediate release of distraction from the external fixation construct. The patient's clinical course and the basic science principles underlying nerve traction injuries are discussed. Although traction injuries are rare after external fixation, orthopedic clinicians must understand them because early recognition can optimize outcomes. Knowledge of the biomechanical properties of peripheral nerves and their mechanisms of injury in such clinical settings may be useful for recognizing patients at risk for nerve traction injuries. [Orthopedics. 2018; 41(3):e434-e437.]. PMID- 29120005 TI - Peripheral Neuropathy Due to Recreational Use of Nitrous Oxide Presenting After an Ankle Sprain With Foot Drop. AB - A 22-year-old man was referred for orthopedic follow-up after an ankle injury. Initial evaluation in urgent care included radiographs with negative findings. After a delayed presentation, a course of functional treatment was recommended. Subsequently, he developed a deep venous thrombosis and pulmonary emboli. He was found to be factor V Leiden deficient and was fully anticoagulated on warfarin. Later reevaluation revealed a steppage gait and foot drop. Electrodiagnostic studies (ie, electromyography and nerve conduction studies) revealed a severe peripheral polyneuropathy. The patient admitted to engaging in high-volume recreational use of nitrous oxide. Neurological evaluation confirmed vitamin B12 deficiency consistent with the toxic effects of nitrous oxide. The patient's condition improved with vitamin B supplementation, bracing, and avoidance of nitrous oxide and similar neurotoxins. He participated in a 3-month physical rehabilitation program, and he displayed partial recovery at most recent follow up. [Orthopedics. 2018; 41(3):e432-e433.]. PMID- 29120006 TI - Manufactured Brace Modalities for Elbow Stiffness. AB - Multiple surgical and nonsurgical treatment options exist for patients with elbow stiffness. Many nonsurgical mobilization bracing options have been implemented to increase elbow range of motion. Three of the main bracing options for these patients are turnbuckle, static progressive stretch, and dynamic bracing. The purpose of this study was to review the current literature on turnbuckle, static progressive stretch, and dynamic bracing to provide information for practitioners and patients regarding which brace is more appropriate to use for elbow stiffness. Specifically, the authors compared the protocol and duration of splint use and changes in range of motion outcomes between static progressive and dynamic brace cohorts. A search of PubMed yielded 8 studies meeting inclusion criteria. Overall, although all 3 bracing options are available for patients, these studies found that, based on the evaluated metrics, the static progressive brace was a markedly superior option for patients with elbow stiffness. The time required to wear the static progressive stretch brace was 13 times less than that for the turnbuckle and 5 times less than that for the dynamic devices. Additionally, the high failure rate (10%) and low success rate (29%) of the dynamic brace, compared with the 63% regaining of functional range of motion in the static progressive stretch group, further highlight the benefits of the static progressive stretch brace. [Orthopedics. 2018; 41(1):e127-e135.]. PMID- 29120007 TI - Incidence of Heterotopic Ossification Following a Multimodal Pain Protocol in Total Hip Arthroplasty With the Posterior Approach. AB - Heterotopic ossification (HO) is prevalent after total hip arthroplasty (THA). Oral nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 (COX-2) inhibitors have reduced the incidence of HO; however, to the authors' knowledge, no studies have reported the incidence and severity of HO with a pain protocol highlighted by celecoxib in the pre- and postoperative period with a posterolateral approach. Between October 2014 and October 2015, a retrospective study was conducted of 687 consecutive primary THAs with minimum 1-year follow-up performed between January 2009 and December 2013. All patients underwent a posterolateral THA with a multimodal pain protocol consisting of preoperative celecoxib; local steroid infiltration intraoperatively; postoperative celecoxib, dexamethasone, and ketorolac; and aspirin or warfarin thromboprophylaxis. For all patients, pre- and postoperative radiographs were examined and classified for HO using the Brooker classification. Interobserver reliability was calculated for both incidence of HO and Brooker classification. Overall, HO was present around 98 (14.3%) THAs. The incidence of Brooker I, II, and III HO was 38 (5.5%), 47 (6.8%), and 12 (1.7%), respectively. No patients required surgical excision or had radiographic evidence of Brooker IV HO. Multivariate logistic regression identified male sex and hypertrophic osteoarthritis as significant risk factors. The use of aspirin for thromboprophylaxis significantly reduced the incidence of HO. This study found the overall incidence of HO when using celecoxib during a posterior THA to be 14.3%, which is similar to what others have reported with the direct lateral approach and with other COX-2 inhibitors for a posterior approach. Risk factors include male sex and preoperative hypertrophic osteoarthritis. [Orthopedics. 2018; 41(1):e92-e97.]. PMID- 29120008 TI - Three-Year Outcomes of a Highly Porous Acetabular Shell in Primary Total Hip Arthroplasty. AB - This multicenter study evaluated survivorship, functional outcomes, complications, and radiographic outcomes for patients who underwent total hip arthroplasty using a newly developed highly porous 3-dimensional titanium implant. Excellent aseptic (99.6%) and all-cause (98%) survivorship and functional outcomes were found at 3-year follow-up. This highly porous acetabular shell holds promise in total hip arthroplasty. [Orthopedics. 2018; 41(1):e154 e157.]. PMID- 29120009 TI - Challenges in interprofessionalism in Swiss health care: the practice of successful interprofessional collaboration as experienced by professionals. AB - The topic of interprofessional collaboration (IPC) between healthcare professionals has been widely discussed in recent years. Whereas the growing calls for more and better IPC can scarcely be ignored and a broad range of definitions and normative concepts have been proposed, it remains unclear what IPC actually means for practising professionals. This exploratory survey investigated the various ways in which successful IPC is understood in practice. As a main finding of the study, we were able to identify three distinct modes of collaboration between different professions in health care. Moreover, we provide evidence that whether and how IPC occurs strongly depends on the care contexts or settings in which these health professionals work. Explicit acknowledgement of and attention to these findings could improve the impact of initiatives to foster IPC. PMID- 29120010 TI - Innovative transition interventions to better align healthcare needs in hospitalised medical patients. AB - Understanding how best to manage the complex healthcare needs of hospitalised, mostly multimorbid medical patients is an international priority. Healthcare should be effective, safe and provide high quality at a reasonable cost. However, basic logistic and organisational issues of medical ward-based care have received less attention than the medical treatment of specific pathologies. Consequently, we still use old-fashioned care and transition procedures for medical inpatients. This contrasts with dynamic developments in other, non-healthcare industries, where process optimisation is a major part of innovation. Promising new approaches to better align healthcare needs of hospitalised medical patients from clinical trials will help to advance the field significantly. Healthcare costs attributable to the aging, multimorbid population are rising worldwide. One cost driver is the high resource use of in-hospital treatment. In view of the expected demographic evolution of an aging population, better resource allocation is important. As in other countries, the Swiss healthcare system is in the midst of transformation aiming to improve health outcomes of patients at an affordable cost. One important area of redesign is identifying the best setting for diagnosis, treatment and management of acute medical conditions with a shift of in-hospital to outpatient care. Also, safely reducing in-hospital length of stay of inpatient treatment is important, because inpatient care accounts for the largest share of total Swiss healthcare costs. Integration of new technology into these processes holds promises for optimisation. Use of electronic health record based tools has resulted in improved patient care and patient transitions. But evidence from clinical studies regarding the effect of inter-professional team care interventions on patient relevant outcomes, including activity of daily living, mortality and length of hospital stay, are inconsistent. Thus, there is room for improvement and a need for high quality trials providing evidence on how best to combine technology with innovative transition models for an ameliorated care of medical inpatients. We review in narrative form different transition interventions that have been evaluated for improved medical inpatient care and highlight important patient-centred outcome measures that were investigated. Further, we discuss a novel patient-management tool (In-HospiTOOL), which is currently being evaluated in an ongoing large Swiss multicentre study. PMID- 29120011 TI - Four-year long-term follow-up of diabetes patients after implementation of the Chronic Care Model in primary care: a cross-sectional study. AB - AIMS: Implementing the Chronic Care Model (CCM) via involvement of specially trained practice nurses improves cardiovascular risk profiles and perception of care among type 2 diabetes patients in small primary care practices (PCPs) in the short term. Little is known about the long-term effects of this intervention. METHODS: Cross-sectional survey among the participants of the cluster randomised controlled CARAT trial (30 PCPs, 303 diabetes patients), 3 years after its completion. OUTCOMES: Proportion of patients still treated according to the CCM, possible reasons for discontinuation, glycosylated haemoglobin (HbA1c), blood pressure, low density lipoprotein cholesterol, and accordance with CCM (assessed by means of PACIC [Patient Assessment of Chronic Illness Care]). RESULTS: Overall, 40.9% of practices (40.7% of patients) continued using the CCM. PCPs originally randomised to the intervention group were significantly more likely to be still using the CCM (11 PCPs / 88 patients vs 11 PCPs / 94 patients, p <0.001). Main reasons for discontinuation were organisational (40.9%) and financial aspects (18.1%), and the general practitioner refusing to transfer treatment responsibility (18.1%). HbA1c and PACIC development over the long term showed significant positive effects in favour of PCPs originally randomised to the intervention group and practices continuing to treat patients according to the CCM. CONCLUSIONS: Diabetes care according to the CCM, including the involvement of trained practice nurses, is a reasonable tool to improve care in the long-term. CCM training of the whole team is essential to overcome organisational challenges. Continuous team education, technical decision support, and recognition of the importance of these new structures in healthcare policy might improve the long-term clinical effect of the team approach. PMID- 29120012 TI - Hepatitis C virus dynamics among intravenous drug users suggest that an annual treatment uptake above 10% would eliminate the disease by 2030. AB - BACKGROUND AND AIMS: In Switzerland, the prevalence of hepatitis C virus (HCV) among people who inject drugs (PWID) has been decreasing owing to active harm reduction efforts and an aging population. Recent advances in HCV therapeutics may provide an opportunity to direct treatment to high-risk populations, with a goal of reducing HCV prevalence and preventing new infections. In order to guide these efforts, the current project was undertaken with the following aims: (1) to develop a simple model to estimate the number of new HCV infections using available data on PWID; (2) to examine the impact of intervention strategies (prevention and treatment) on new and total HCV infections among PWID. METHODS: A dynamic HCV transmission model was used to track HCV incidence and prevalence among active PWID according to their harm reduction status. The relative impact of treating 1, 5, 10 or 15% of HCV+ PWID with new oral direct acting antivirals was considered. RESULTS: In 2015, there were an estimated 10 160 active PWID in Switzerland, more than 85% of whom were engaged in harm reduction programmes. Approximately 42% of active PWID were HCV-RNA+, with 55 new viraemic infections occurring annually. By 2030, a 60% reduction in the HCV+ PWID population would be expected. In the absence of behavioural changes, the number of secondary infections would increase under all treatment scenarios. With high level treatment, the number of secondary infections would peak and then drop, corresponding to depletion of the viral pool. In Switzerland, 5% treatment of the 2015 HCV+ PWID population per year would result in a 95% reduction in total cases by 2030, whereas >=10% treatment would result in a >99% reduction. CONCLUSIONS: Timely treatment of hepatitis C virus among people who inject drugs is necessary to reduce the prevalence and prevent new infections in Switzerland. PMID- 29120013 TI - Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. AB - Primary polydipsia (PP) has been defined as excessive intake of fluids. However, the pathogenesis of PP remains unexplored. Different theories include a dysfunction in the thirst mechanism, involvement of the hippocampus, stress reducing behaviour and lesion occurrences in specific areas of the brain. Most studies have been performed in the psychiatric setting, indicating that PP coincides with schizophrenia, anxiety disorder and depression. However, an increasing number of case reports emphasise the incidence of PP in non psychiatric patients. As often recommended by healthcare professions and in life style programmes, the phenomenon of excessive fluid intake appears to be growing, especially in health-conscious and active people. PP is part of the polyuria polydipsia syndrome, so the differential diagnosis diabetes insipidus (central or nephrogenic) must be excluded. The gold standard when differentiating between these disorders has been the water deprivation test. However, new options for distinguishing between these entities have been proposed e.g., measurement of copeptin, a reliable surrogate marker of the hormone arginine vasopressin (AVP). The major risk of excessive drinking is the development of hyponatraemia and the ensuing complications. In patients with PP, factors reducing the renal excretory capacity of the kidney such as acute illness, medications or low solute intake may accumulate in hyponatraemia. Treatment options for PP remain scarce. Different medication and behavioural therapy have been investigated, but never on a large scale and rarely in non-psychiatric patients. This review provides an overview of the pathophysiology, characteristics, complications, and outcomes of patients with PP in the medical and psychiatric patient. PMID- 29120014 TI - Strong, generous support for medical research emerges from a large cohort of Swiss patients. PMID- 29120015 TI - Ascending aortic remodelling in Fabry disease after long-term enzyme replacement therapy. AB - BACKGROUND: Previous cross-sectional studies reported a high prevalence of ascending aorta dilations/aneurysms in male adults with Fabry disease, independently of cardiovascular risk factors. AIMS OF THE STUDY: To characterise the remodelling of the ascending aorta in classic Fabry disease under long-term enzyme replacement therapy. METHODS: Diameter of the ascending aorta was measured with magnetic resonance imaging at the sino-tubular junction (STJ), and proximal (pAsAo), and distal ascending aorta (dAsAo) at baseline, and after 5 and 10 years of enzyme replacement therapy in 15 adult Fabry patients (10 males; 5 females). RESULTS: Over a mean follow-up of 9.5 years, the annual expansion rates measured in 10 males with Fabry disease were 0.41 +/- 0.16, 0.36 +/- 0.25 and 0.41 +/- 0.26 mm/y at the STJ, pAsAo and dAsAo, respectively. Expansion rate at the pAsAo level in male patients was significantly higher than the expected expansion projected from theoretical normal values: 0.36 +/- 0.25 vs 0.13 +/- 0.05, p = 0.017. In 5 females, the annual expansion rates at the STJ, pAsAo and dAsAo were 0.14 +/- 0.11, 0.21 +/- 0.18 and 0.26 +/- 0.24 mm/y, respectively. There was no significant difference from the projected normal expansion rate at the level of the pAsAo: 0.21 +/- 0.18 vs 0.13 +/- 0.04, p = 0.39. CONCLUSION: Our data suggest that the remodelling of the ascending aorta is more pronounced in male patients with Fabry disease under long-term enzyme replacement therapy compared with the progression observed in a large population study. PMID- 29120016 TI - The subcutaneous implantable cardioverter defibrillator in daily clinical practice. AB - INTRODUCTION: In Switzerland, the first implantation of a subcutaneous implantable cardioverter-defibrillator (S-ICD) took place in November 2012. Up until the end of 2016, a total of 111 S-ICDs have been implanted. The aim of this study was to summarise the experience of a tertiary centre in Switzerland and to discuss the results in the context of international registries. METHODS: All patients in whom an S-ICD was implanted between November 2012 and the end of December 2016 at the University Heart Centre Zurich were included in this study. The clinical records of all patients were reviewed for retrospective collection of baseline characteristics as well as implantation and follow-up data. RESULTS: A total of 37 S-ICDs were implanted. The majority of patients (81%) were male, the mean age was 47 +/- 15 years. The most common underlying cardiac condition was coronary artery disease (30%), followed by hypertrophic cardiomyopathy (24%), inherited channelopathies (19%) and nonischaemic cardiomyopathy (11%). The median left ventricular ejection fraction was 44% (interquartile range 28-61%). There were four peri-interventional complications, all of which were pocket site related. There were no cases of systemic infection or perioperative death. During a median follow up of 3.7 months, there were three appropriate and successful ICD shocks (8.1%). Two patients (5.4%) experienced a total of three inappropriate shocks, all due to T-wave oversensing. CONCLUSION: This first large Swiss experience demonstrates results consistent with available international data. The S-ICD may hence represent an attractive alternative to conventional transvenous ICDs for a variety of patients. PMID- 29120017 TI - Review of maternal immunisation during pregnancy: focus on pertussis and influenza. AB - Seasonal influenza and pertussis infections are known to be significant causes of morbidity and mortality in neonates and infants worldwide. Influenza has also been associated with severe complications in pregnant women and after delivery. The most efficient and safe strategy to protect mothers and their offspring is maternal immunisation during pregnancy. The maternal antibodies thus acquired are transferred to the fetus as of the second trimester and confer passive immunity until the first infant immunisations. Therefore, it is strongly advised to administer booster doses of seasonal influenza and pertussis vaccines specifically during pregnancy. Influenza vaccines can be given at any time-point during pregnancy and pertussis vaccines after the first trimester. Both need a minimum interval of 14 days between immunisation and delivery and, especially for pertussis, early immunisation has been shown to increase neonatal antibody titres. Healthcare workers play a crucial role in vaccine uptake. This article aims to review the recommendations for maternal influenza and pertussis immunisation, and their physiological rationale, safety and benefit. PMID- 29120018 TI - RNA metabolism in Staphylococcus aureus virulence. AB - The opportunistic pathogen Staphylococcus aureus encounters a variety of host defence systems depending on its localisation during colonisation in the nares, systemic infections within the body, or persistent infections within cells or embedded in biofilms. To respond rapidly to these different environments, this bacterium has evolved, in its longstanding interaction with animal and human hosts, a variety of mechanisms to fine-tune its gene expression. RNA metabolism, including transcription, processing, translation into proteins and RNA decay, is a central player in this response and might in the future be used to treat this feared pathogen. PMID- 29120019 TI - Cellular protection mechanisms that minimise accumulation of mutations in intestinal tissue. AB - The epithelial lining of the intestine is constantly exposed to a hostile environment containing a mixture of gastric acids, consumed harmful substances and microbes. It is widely accepted that the intestine has multiple mechanisms to protect itself against tissue damage. Here, we review three cellular protection mechanisms that protect intestinal tissue against accumulation of somatic mutations: the conveyer belt-like structure, stem cell competition and crypt fusion. We highlight the events that can perturb these cellular protection mechanisms, and their impact on accumulation of new (oncogenic) mutations. Lastly, we review the potential of in-vitro and intravital microscopy techniques to study the dynamics of these protection processes. These studies may identify new targets that can be used to manipulate cellular protection mechanisms in such a way that accumulation of new mutations can be reduced. Importantly, reducing mutation accumulation has the potential to delay aging, and the initiation and progression of diseases such as colorectal cancer. PMID- 29120020 TI - Identification of a MAFB mutation in a patient with multicentric carpotarsal osteolysis. AB - Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant disease of the skeleton characterised by progressive destruction of carpal and tarsal bones. Recently, it has been demonstrated that this disease is caused by heterozygous mutations in the gene for the transcriptional repressor MAFB. We analysed genomic DNA and RNA from leucocytes of a female patient diagnosed with MCTO. We identified the mutation c.161C>T in the genomic sequence and in the expressed messenger RNA for MAFB. This is the second report of the c.161C>T mutation in a MCTO patient. Since the parents do not possess this mutation, the daughter must have acquired a de novo mutation. At the level of the gene, this mutation is found at a CpG dinucleotide sequence, suggesting that DNA methylation was involved in the occurrence of the DNA aberration. At the level of the protein, the mutation exchanges a serine with a leucine residue at a position on MAFB that can become phosphorylated in the wild-type protein. MAFB negatively regulates the RANKL-dependent differentiation of monocytes into osteoclasts. It is likely that the mutation will affect the phosphorylation status of the protein and its biological activity. When the activity of the transcriptional repressor is reduced, osteoclastogenesis will be increased, which might explain the carpotarsal bone destruction observed in the patient. PMID- 29120021 TI - Swiss Adult Congenital HEart disease Registry (SACHER) - rationale, design and first results. AB - BACKGROUND: In 2013, a prospective registry for adults with congenital heart disease (CHD) was established in Switzerland, providing detailed data on disease characteristics and outcomes: Swiss Adult Congenital HEart disease Registry (SACHER). Its aim is to improve the knowledge base of outcomes in adults with CHD. The registry design and baseline patient characteristics are reported. METHODS: All patients with structural congenital heart defects or hereditary aortopathies, followed-up at dedicated adult CHD clinics, are asked to participate in SACHER. Data of participants are pseudonymised and collected in an electronic, web-based, database (secuTrial(r)). Collected data include detailed diagnosis, type of repair procedures, previous complications and adverse outcomes during follow-up. RESULTS: From May 2014 to December 2016, 2836 patients (54% male, mean age 34 +/- 14 years), with a wide variety of congenital heart lesions, have been enrolled into SACHER. Most prevalent were valve lesions (25%), followed by shunt lesions (22%), cyanotic and other complex congenital heart disease (16%), diseases affecting the right heart, i.e., tetralogy of Fallot or Ebstein anomaly (15%), and diseases of the left ventricular outflow tract (13%); 337 patients (12%) had concomitant congenital syndromes. The majority had undergone previous repair procedures (71%), 47% of those had one or more reinterventions. CONCLUSION: SACHER collects multicentre data on adults with CHD. Its structure enables prospective data analysis to assess detailed, lesion-specific outcomes with the aim to finally improve long-term outcomes. PMID- 29120022 TI - Does interprofessionality work in Swiss ICUs and should it be encouraged? AB - A charter for the collaboration of healthcare specialists has recently been proposed by the Swiss Academy of Medical Sciences, to promote interprofessionality in daily clinical practice. This article reviews several aspects of this concept, from definition and basic principles to the potential benefit for the patients and caregivers, and it discusses the difficulties in implementing interprofessional teamwork in the daily practice of an intensive care unit (ICU). Although collaborative and interprofessional teamwork seems a logical approach in the care of critically ill patients, little published evidence shows that it really improves the level of care, meaning that this may be harder to implement than to promote. Eventually, some clues to achieve a successful realisation of interprofessional collaboration in the ICU are proposed. PMID- 29120023 TI - Role of liver magnetic resonance imaging in hyperferritinaemia and the diagnosis of iron overload. AB - Hyperferritinaemia is a frequent clinical problem. Elevated serum ferritin levels can be detected in different genetic and acquired diseases and can occur with or without anaemia. It is therefore important to determine whether hyperferritinaemia is due to iron overload or due to a secondary cause. The main causes of iron overload are intestinal iron hyperabsorption disorders and transfusion-dependent disorders. Iron homeostasis and iron overload are quantified by different diagnostic approaches. The evaluation of serum ferritin and transferrin saturation is the first diagnostic step to identify the cause of hyperferritinaemia. The assessment of liver iron concentration by liver biopsy or magnetic resonance imaging (MRI) may guide the further diagnostic and therapeutic workup. Liver biopsy is invasive and poorly accepted by patients and should only be carried out in selected patients with hereditary haemochromatosis. As a non invasive approach, MRI is considered the standard method to diagnose and to monitor both hepatic iron overload and the effectiveness of iron chelation therapy in many clinical conditions such as thalassaemia and myelodysplastic syndromes. Accurate evaluation and monitoring of iron overload has major implications regarding adherence, quality of life and prognosis. There are different technical MRI approaches to measuring the liver iron content. Of these, T2 and T2* relaxometry are considered the standard of care. MRI with cardiac T2* mapping is also suitable for the assessment of cardiac iron. Currently there is no consensus which technique should be preferred. The choice depends on local availability and patient population. However, it is important to use the same MRI technique in subsequent visits in the same patient to get comparable results. Signal intensity ratio may be a good adjunct to R2 and R2* methods as it allows easy visual estimation of the liver iron concentration. In this review a group of Swiss haematologists and radiologists give an overview of different conditions leading to primary or secondary iron overload and on diagnostic methods to assess hyperferritinaemia with a focus on the role of liver MRI. They summarise the standard practice in Switzerland on the use of liver iron concentration MRI as well as disease-specific guideline recommendations. PMID- 29120024 TI - Swiss Medical Weekly congratulates Jaco van Rheenen, recipient of the Dr Josef Steiner Cancer Research Foundation Award for 2017. PMID- 29120025 TI - Prevention and therapy of JC polyomavirus-mediated progressive multifocal leukoencephalopathy - a realistic possibility? AB - Progressive multifocal leukoencephalopathy (PML) is a serious opportunistic infection of the brain caused by the JC polyomavirus (JCPyV). PML occurs when immune control of persistent infection with JCPyV fails, the virus mutates and changes its cellular tropism, enters the brain and infects astrocytes, oligodendrocytes and, in particular cases, also neurones. Currently, there is no therapy for this often fatal disease. A number of approaches have failed, and only the restoration of protective immunity, if possible, can lead to clearance of the virus once PML has occurred. During the last two decades, investigators have attempted to understand the factors contributing to the development of PML, which immune mechanisms are involved in immune surveillance, and which in clearing JCPyV from the brain once PML has occurred. Recent data suggest that both CD4+ and CD8+ T cells of the cellular immune system, and also JCPyV-specific antibodies, are involved in protection against PML and in resolving the opportunistic infection. Based on the current immunological data, prophylactic and therapeutic vaccination strategies have been proposed, and first treatment attempts in PML patients have provided promising results that indicate therapeutic vaccination may be feasible. PMID- 29120026 TI - Risk factors for hypocalcaemia after completion hemithyroidectomy in thyroid cancer. AB - BACKGROUND: Hypocalcaemia (HC) is the most common complication after thyroid surgery in differentiated thyroid cancer and leads to a prolongation of the hospital stay. While risk factors for HC after total thyroidectomy (TE) are well investigated, only few studies have been published about HC risk factors after completion of thyroidectomy. Our aim was to identify potential risk factors for HC after completion of TE and to compare these incidences with figures from primary total TE. MATERIALS AND METHODS: A retrospective cohort study was undertaken including patients undergoing completion of TE between 2002 and 2013 in our tertiary care centre. Patients with hypocalcaemia (group 1) after undergoing second surgery were compared to normocalcaemia patients (group 2) with respect to gender, age, type of thyroid cancer, time interval between surgeries, pre/postoperative calcium and parathyroid hormone (PTH) levels, clinical hypocalcaemia signs and calcium substitution (intravenous, oral). Hypocalcaemia was defined as <2.10 mmol/l, hypoparathyroidism as <15pg/ml. RESULTS: 34 (25 female, 9 male) patients were included. A total of 12 patients (33%) developed a hypocalcaemia (group 1). Three patients out of these also presented with hypoparathyroidism. One patient in each group showed clinical signs of hypocalcaemia. Calcium substitution was necessary in six cases in group 1 and in one case in group 2. There was a significant difference between the groups concerning postoperative PTH (25.1 vs 37.6 pg/ml) and calcium levels (1.87 vs 2.27 mmol/l) (p <0.05). Group comparison shows no significant relationships between all other parameters (age, gender, type of thyroid cancer and duration of interval between surgeries). Logistic regression analysis identified a low preoperative serum calcium level as the only dominant factor indicating postoperative hypocalcaemia. CONCLUSIONS: A hypocalcaemia rate of 33% (12/34) and a hypoparathyroidism rate of 9% (3/34) after completion of thyroidectomy in our cohort is comparable to primary total thyroidectomy. A low preoperative calcium level is a significant risk factor for postoperative hypocalcaemia after completion of thyroidectomy. The prediction of hypocalcaemia still remains difficult since it has multifactorial causes. PMID- 29120027 TI - Humanised mouse models for haematopoiesis and infectious diseases. AB - "Humanised" mouse models have emerged over past years as powerful tools for investigating human haematopoiesis and immunity. They allowed the identification of key factors for the maintenance and function of normal and leukaemic human haematopoietic stem cells. These findings have been widely used to dissect the pathogenesis of multiple myeloid and lymphoid neoplasms, such as acute myeloid leukaemia and acute lymphoblastic leukaemia. Furthermore, these models can serve as a stepping-stone to clinical trials by testing novel drugs that target leukaemic stem cells. The investigation of human immunity in vivo is also of great interest in both the context of understanding the innate and adaptive immune system and responses to viral infections with exclusive human tropism, such as Epstein-Barr virus and human immunodeficiency virus. This review focuses on recent advances in the study of human haematopoiesis and immunity in humanised mouse models, underlining their relevance and limitations. PMID- 29120028 TI - Precision medicine for monogenic diabetes: from a survey to the development of a next-generation diagnostic panel. AB - Monogenic diabetes (MD) accounts for 1-2% of all diabetes cases. Because of its wide phenotypic spectrum, MD is often misdiagnosed as type 1 or type 2 diabetes. While clinical and biochemical parameters can suggest MD, a definitive diagnosis requires genetic analysis. We conducted a survey among clinicians specialising in diabetes to document the cases with MD. Of 74 clinically suspected MD patients, 46% had undergone genetic analysis, which was mostly conducted using Sanger's classical sequencing method. The most common recorded mutations were located in the GCK gene, followed by the mitochondrial genome (m.3243A>G mutation) and the HNF1B and HNF1A genes. The remaining 54% of patients only had a clinical diagnosis, mostly because genetic analysis was not easily accessible. Here, we designed a new diagnostic panel of 42 genes that was developed based on the survey. The panel was validated with an independent sample of nine known MD patients. Our survey confirms the need for a comprehensive analytical instrument for the diagnosis of MD, which will be met by the proposed panel. The diagnosis of MD is crucial because it dictates treatment and may improve metabolic control and reduce long-term complications as proposed by precision medicine. PMID- 29120029 TI - Safety and effectiveness of labour induction after caesarean section using balloon catheter or oxytocin. AB - AIMS OF THE STUDY: Induction of labour after previous caesarean section (CS) is a challenge for obstetricians due to the increased risk of uterine rupture. Common methods for labour induction are balloon catheters and oxytocin as they are considered safe. However, the effectiveness remains unclear as currently available data are limited. Therefore, we aimed to determine safety and effectiveness of balloon catheter or oxytocin for labour induction after CS. METHODS: We included 179 consecutive women with a previous CS and labour induction in this retrospective study. We performed labour induction using a balloon catheter in case of a Bishop score of <6 and intact membranes, or oxytocin in the case of a Bishop score of >6 and/or premature rupture of membranes. The primary outcome was the rate of successful vaginal deliveries. We adjusted for multiple factors that may have impacted on the rate of vaginal delivery as well. The secondary outcomes were the rate of maternal and neonatal morbidities. RESULTS: We detected a vaginal delivery success rate of 45.8% in the catheter and of 63.9% in the oxytocin group. We identified previous vaginal birth as an independent predictive factor for successful vaginal delivery in both groups. Induction using oxytocin was a negative predictive factor for neonatal admissions. Multivariate analysis showed that post-term pregnancy decreased the likelihood of vaginal delivery. We did not detect any factors predicting uterine rupture or uterine dehiscence, which occurred with similar frequency in both groups. Finally, the neonatal admission rate was less likely with higher gestational age and oxytocin as an induction method, whereas previous vaginal birth increased the risk. CONCLUSIONS: Our study indicates that induction of labour with balloon catheter or oxytocin seems to be safe in women with previous CS. Labour induction using a balloon catheter in women with previous CS and unfavourable cervix has a disappointingly low success rate. We identified factors influencing vaginal delivery success rates. Women with previous CS and indications for labour induction should be informed about vaginal birth success rates and the alternative of elective repeat CS needs to be discussed. PMID- 29120031 TI - Histopathological, immunohistochemical, and stereological analysis of the effect of Ginkgo biloba (Egb761) on the hippocampus of rats exposed to long-term cellphone radiation. AB - Cellular phones are major sources of electromagnetic radiation (EMR) that can penetrate the human body and pose serious health hazards. The increasingly widespread use of mobile communication systems has raised concerns about the effects of cellphone radiofrequency (RF) on the hippocampus because of its close proximity to radiation during cellphone use. The effects of cellphone EMR exposure on the hippocampus of rats and the possible counteractive effects of Ginkgo biloba (Egb761) were aimed to investigate. Rats were divided into three groups: Control, EMR, and EMR+Egb761. The EMR and EMR+Egb761 groups were exposed to cellphone EMR for one month. Egb761 was also administered to the EMR+Egb761 group. Specifically, we evaluated the effect of RF exposure on rat hippocampi at harmful EMR levels (0.96 W/kg specific absorption rate [SAR]) for one month and also investigated the possible impact of Ginkgo biloba (Egb761) using stereological, TUNEL-staining, and immunohistochemical methods. An increase in apoptotic proteins (Bax, Acas-3) and a decrease in anti-apoptotic protein (Bcl-2) immunoreactivity along with a decrease in the total granule and pyramidal cell count were noted in the EMR group. A decrease in Bax and Acas-3 and an increase in Bcl-2 immunoreactivity were observed in rats treated with Egb761 in addition to a decrease in TUNEL-stained apoptotic cells and a higher total viable cell number. In conclusion, chronic cellphone EMR exposure may affect hippocampal cell viability, and Egb761 may be used to mitigate some of the deleterious effects. PMID- 29120030 TI - Risk behaviours among native and immigrant youths in Switzerland: a cross sectional study. AB - QUESTION UNDER STUDY: Switzerland has been receiving migrants of various origins for more than 50 years. The adoption of risk-taking behaviours among migrant youths is unclear. Moreover, when studied, migrant youths are rarely analysed according to whether they are first or second generation, or just young people with mixed origins. The aim of this study was to assess whether there are any differences between first-and second-generation immigrants, youths of mixed origins and their native peers in Switzerland concerning their engagement in risk behaviours. METHODS: A total of 5834 youths from eleven post-mandatory schools in the canton of Fribourg (Switzerland) participated in the baseline survey of the GenerationFRee study, a longitudinal study to assess their lifestyle. Participants were divided by gender and by origin into: (a) natives: Swiss-born youths with Swiss-born parents, (b) first-generation migrants: foreign-born youths with foreign-born parents, (c) second-generation migrants: Swiss-born youths with foreign-born parents, (d) mixed-origin youths: Swiss-born youths with one Swiss-born parent and one foreign-born parent. Participants reported personal, family and school information, and attitudes towards eight risk behaviours. All significant variables at the bivariate level were included in a binary logistic regression. RESULTS: The logistic regression showed that, compared with natives, first-and second-generation migrant boys were less likely to misuse alcohol. Boys of mixed origins were similar to migrants, although at the bivariate level they were more exposed to risk behaviours than were migrants. First-and second-generation migrant girls were less likely to misuse alcohol but three times more likely to be excessive Internet users. Girls of mixed origin were more likely to have their parents not living together and reported antisocial behaviours almost twice more often. CONCLUSIONS: Our findings expose a lower engagement in risk behaviours among migrants. The migrant status in these two groups is clearly buffered if other control variables are considered. Thus, we can affirm that in the present study, migrants are not a high-risk population or not more at risk than the native group. Mixed origin youths showed higher risk behaviours than natives and migrants. Special attention should be given to this specific group, as they may be more vulnerable during adolescence. PMID- 29120032 TI - ORAL IRON PROPHYLAXIS DURING PREGNANCY-A COMPARATIVE STUDY ON DIFFERENT DOSAGE REGIMENS. AB - The effect of oral iron prophylaxis on haemoglobin concentration (Hb) and haematocrit (Hct) has been studied in 300 pregnant women. From the 3rd to 4th month of pregnancy and until term the women were randomly treated with 100 mg or 200 mg ferrous iron daily respectively as sustained-release tablets (Duroferon(r) Duretter(r) ) or 200 mg ferrous iron as rapidly disintegrating tablets. All three treatments gave the same effect on Hb and Hct. This was true irrespective of the initial Hb. It was concluded that even the 100 mg dose was sufficient to cover the increased iron demands during pregnancy and to give an increase in Hb in anemic patients. The frequency of side-effects was lower in the two groups receiving the sustained-release tablets. The changes in Hb with time during pregnancy in relation to the initial iron status are discussed and some practical conclusions concerning the interpretation of the effect of iron supplementation during pregnancy are drawn. PMID- 29120033 TI - A theoretical approach to the size-complexity rule. AB - The so-called size-complexity rule claims the existence of a positive correlation between organism size and number of cell types. In this spirit, here we address the relationship between organism size and number of potential tasks that can be performed. The modeling relies on the assumption that the states of the cells within the aggregates are such that the maximum fitness is realized, but also relies on the existence of tradeoffs among the distinct functions. For group sizes larger than the number of potential tasks, fitness maximization is attained when all cells in group specialize in a given task. Under this scenario, the number of potential tasks equals the number of cell types. We have found that the morphology and the topology of aggregates, as well as the developmental mode, strongly influence the dynamics of body formation. Particularly, it has been observed that more compact structures, such as sphere-like structures, are more likely to follow the claim of the size-complexity rule, whereas more fragile structures such as linear chains, which are more vulnerable to drastic changes due to division mechanisms, can, in a broad scenario, violate the size-complexity rule. PMID- 29120034 TI - Ultrasonographic Features of Eccrine Spiradenoma. AB - The purpose of this series was to evaluate the features of eccrine spiradenoma on ultrasonography (US). We reviewed the clinical data of 8 patients with eccrine spiradenoma who underwent preoperative US at 4 different medical institutions from 2004 to 2016 and analyzed the US features in terms of the tumor location, size, shape, margin, echo texture, echogenicity, posterior acoustic enhancement, calcification, septum, and color Doppler flow. There were 7 female patients and 1 male patient. The mean patient age was 45.6 years (range, 28-60 years). Most of the tumors were located primarily in the subcutaneous fat layer. The mean size of the tumors was 14.3 mm. The masses had a lobular appearance in 7 patients and had a tractlike structure in 3 patients. In 6 patients, the masses had a heterogeneous echo texture. Six cases showed hypoechogenicity with more hypoechoic foci in the masses, and 2 cases showed hypoechogenicity only. Color Doppler flow was evaluated in 7 patients; the blood flow was central and peripheral in 4 patients and only peripheral in 3 patients. All cases showed posterior acoustic enhancement and had well-defined margins. Calcification and septa were not seen in any cases. Eccrine spiradenoma is usually located in the subcutaneous fat layer, has a well-defined margin, a lobulated appearance, occasionally with a tractlike structure, a heterogeneous echo texture, a hypoechoic appearance with internal hypoechoic foci and posterior acoustic enhancement, and shows blood flow in the peripheral portion, with or without blood flow in the central portion. PMID- 29120035 TI - Effects of omega-3 polyunsaturated fatty acids and aspirin, alone and combined, on canine platelet function. AB - OBJECTIVES: To compare haemostatic function in healthy dogs after treatment with low-dose aspirin alone, fish oil alone or a combination of these two therapies. MATERIALS AND METHODS: Double-blinded randomised controlled clinical trial on 16 healthy client-owned dogs. Comprehensive haemostatic testing was performed at baseline and after 7 days of therapy with low-dose aspirin in all dogs. Following a 14-day washout, six dogs received fish oil, and nine dogs received combination therapy of aspirin plus fish oil; haemostatic testing was performed before and at 7 and 28 days after treatment initiation. RESULTS: Aspirin was associated with significantly decreased platelet function as measured by a collagen-epinephrine cartridge and inhibited arachidonic acid-induced whole-blood platelet aggregometry. Fish oil alone did not significantly affect any haemostatic tests. The combination of aspirin plus fish oil therapy caused a significantly greater inhibition of adenosine diphosphate and collagen-induced whole blood aggregometry compared to aspirin alone. CLINICAL SIGNIFICANCE: Fish oil added to aspirin therapy appears to augment inhibition of some measures of platelet function in healthy dogs. PMID- 29120036 TI - Rapid assessment with physical examination in dyspnoeic cats: the RAPID CAT study. AB - OBJECTIVES: To determine the underlying disease prevalence in acute feline dyspnoea and to examine whether historical and clinical examination findings can differentiate between acute cardiac and non-cardiac dyspnoea in cats in primary practice. MATERIALS AND METHODS: We prospectively enrolled cats presenting with dyspnoea for the first time to primary practice between June 1, 2011 and October 31, 2016. We collected signalment, historical and clinical data at presentation using a standard form. Cases were investigated by primary clinicians, and the final diagnosis was confirmed by the authors. Records lacking critical data were excluded. Relationships between historical or clinical variables and dyspnoea aetiology were examined. Diagnostic test performance analyses were used to find optimal cut-off values for select historical or clinical variables that could differentiate cardiac and non-cardiac dyspnoea. RESULTS: Participants included 108 cats. A definitive diagnosis was reached in 92 cases; 60 were cardiac (65%), 15 respiratory (16%), 10 neoplastic (11%) and 7 traumatic (8%). Of cats with cardiac dyspnoea, 25% had a history of cough. A gallop sound, rectal temperature less than 37.5 degrees C, heart rate of greater than 200 bpm and respiratory rate greater than 80 per minute were all useful to predict cardiac-associated dyspnoea. A triage algorithm using these findings in combination was designed to optimise the rapid diagnosis of probable cardiac dyspnoea. CLINICAL SIGNIFICANCE: Dyspnoeic cats presenting in practice with hypothermia, tachycardia, gallop sounds or profound tachypnoea are likely to have a cardiac cause underlying their dyspnoea. Although diagnosis requires confirmation, clinicians may be able to stratify risk and prioritise further investigation based on these findings. PMID- 29120037 TI - Independent recruitment of a novel seed dispersal system by camel crickets in achlorophyllous plants. AB - The seeds of most heterotrophic plants, commonly referred to as dust seeds, are typically dispersed in the air like dust particles. Therefore, little attention has been paid to how seeds of heterotrophic plants are dispersed, owing to the notion that wind dispersal is the dominant strategy. However, inconspicuous but fleshy, indehiscent fruit can be observed in distantly related plants that have independently evolved full heterotrophy. Here I investigated the seed dispersal system in three unrelated fully heterotrophic plants with fleshy, indehiscent fruits (Yoania amagiensis, Monotropastrum humile and Phacellanthus tubiflorus) by direct observation, a differential exclusion experiment of fruit feeders and investigation on seed viability through the digestive tract. The present study revealed that camel crickets are the major seed disperser in three achlorophyllous plants in the study population. This represents the first evidence of seed dispersal by camel crickets in any angiosperm species. These heterotrophic plants grow in the understorey of densely vegetated forests where wind is probably an ineffective seed dispersal agent. Life-history traits of the achlorophyllous plants associated with heterotrophic lifestyles, such as colonization of dark understorey habitats and dust seeds, could facilitate independent recruitment of the novel endozoochorous seed dispersal system by camel crickets. PMID- 29120039 TI - 15(S)15 METHYL PGF2alpha BY INTRAMUSCULAR ROUTE AT TWO HOURLY INTERVAL FOLLOWED BY THREE HOURLY FOR INDUCTION OF SECOND TRIMESTER ABORTION. AB - A multicentre trial of Prostin 15M in second trimester abortion in 322 patients of whom 115 were primigravidae was conducted during the period of six months. Intramuscular injection of Prostin 15M 250 ug was given two hourly till one centimeter dilatation of the cervix, followed by three hourly injections till abortion. The mean dose of Prostin 15M was 2.3 mg for primigravidae and 2.0 mg for the multigravidae. The mean induction abortion interval was 18.5 hours in primigravidae and 17 hours in multigravidae. Two hundred and seventy-six patients (85.7%) aborted with the treatment. There were 26 failures in primigravidae (22.6%) and 20 failures in the multigravidae (9.6%). Side effects of vomiting and diarrhoea were 3.0 and 4.1 episodes, respectively. In 53 cases where prophylactic antidiarrhoeal drug loperamide and antiemetic emidoxyn were given, the incidence of diarrhoea and vomiting was reduced to 1.6 and 1.7, respectively. There were no serious complications. In 50 cases the blood loss, as measured by alkaline hematin method was 25.4 ml (mean). PMID- 29120040 TI - INTRAMUSCULAR 15(S)15 METHYL PGF2alpha FOR PREOPERATIVE CERVICAL DILATATION DURING FIRST TRIMESTER. AB - The effect of single intramuscular injection of 15(S)15 methyl PGF2alpha . (Prostin 15M, Upjohn) on cervical dilatation was tried in women during first trimester pregnancy. Prostin 15M was given at a dose of 250 ug. Three hours later the cervical dilatation and uterine consistency were assessed and recorded, prior to vacuum aspiration. The control group consisted of women who did not receive any drugs for cervical dilatation. The mean cervical dilatation in Prostin 15M group was 9.7 +/- 2.3 (S.D.) mm compared to 3.4 +/- 1.5 (S.D.) mm in the control group. This difference was statistically significant (p <0.01). Vomiting was experienced by 18.6% and diarrhea by 20.9% of the patients. There was no significant difference in the blood loss between the Prostin 15M group and the control group. PMID- 29120038 TI - Functional diversification of Flowering Locus T homologs in soybean: GmFT1a and GmFT2a/5a have opposite roles in controlling flowering and maturation. AB - Soybean flowering and maturation are strictly regulated by photoperiod. Photoperiod-sensitive soybean varieties can undergo flowering reversion when switched from short-day (SD) to long-day (LD) conditions, suggesting the presence of a 'floral-inhibitor' under LD conditions. We combined gene expression profiling with a study of transgenic plants and confirmed that GmFT1a, soybean Flowering Locus T (FT) homolog, is a floral inhibitor. GmFT1a is expressed specifically in leaves, similar to the flowering-promoting FT homologs GmFT2a/5a. However, in Zigongdongdou (ZGDD), a model variety for studying flowering reversion, GmFT1a expression was induced by LD but inhibited by SD conditions. This was unexpected, as it is the complete opposite of the expression of flowering promoters GmFT2a/5a. Moreover, the key soybean maturity gene E1 may up regulate GmFT1a expression. It is also notable that GmFT1a expression was conspicuously high in late-flowering varieties. Transgenic overexpression of GmFT1a delayed flowering and maturation in soybean, confirming that GmFT1a functions as a flowering inhibitor. This discovery highlights the complex impacts of the functional diversification of the FT gene family in soybean, and implies that antagonism between flowering-inhibiting and flowering-promoting FT homologs in this highly photoperiod-sensitive plant may specify vegetative vs reproductive development. PMID- 29120041 TI - RANDOMIZED COMPARISON BETWEEN TWO-HOURLY AND THREE-HOURLY INTRAMUSCULAR TREATMENT WITH 15(S)15 METHYL PGF2alpha FOR TERMINATION OF SECOND TRIMESTER PREGNANCY. AB - In a multicentre trial, intramuscular 15(S)15 methyl PGF2alpha (Prostin 15M, Up john) was tried at 2-hourly and 3-hourly intervals for induction of second trimester abortion. The time schedule was assigned randomly. Eighty-eight patients for 2-hourly schedule and 89 patients for 3-hourly schedule were recruited. Of 2-hourly 83% and of 3-hourly schedule 88.8% of the patients aborted with the treatment. The induction abortion interval was 15.9 hours in 2-hourly and 17.2 hours in 3-hourly schedule. The dose of Prostin 15M was 2.2 mg and 1.7 mg respectively. The incidence of incomplete abortion was 21.9% in 2-hourly and 27.8% in the 3-hourly. The incidence of vomiting was less in the 3-hourly schedule, however, there was no difference in the incidence of diarrhoea. PMID- 29120042 TI - PROPHYLACTIC USE OF 15(S)15 METHYL PGF2alpha FOR CONTROL OF POSTPARTUM BLEEDING. AB - The efficacy of 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) was tested in controlling the bleeding during third stage of labour in women delivered at term. Prostin 15M was given in a dose of 125 ug by intramuscular route at the delivery of the anterior shoulder of the fetus. Prostin 15M significantly reduced the duration of third stage and blood loss to about a third of those who did not receive any oxytocic. The blood loss during 2 hours following delivery was also markedly reduced with Prostin 15M treatment. PMID- 29120043 TI - INDUCTION OF SECOND TRIMESTER ABORTION BY INTRAAMNIOTIC ADMINISTRATION OF 15(S)15 METHYL PGF2alpha. AB - In a multicentre trial 139 women between 15 and 20 weeks of gestation were treated with 2.5 mg intraamniotic administration of 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) for termination of pregnancy. Following treatment 97% of the primigravida and 94.5% of multigravida aborted. The induction abortion interval (Mean +/- S.E.M.) in the primigravida was 22.8 +/- 1.1 hours, while in the multigravida it was 18.3 +/- 1.0 hours. The mean number of episodes of vomiting was 1.4 and 0.9 in primigravidae and multigravidae, respectively. The mean number of episodes of diarrhoea was 0.7 in both groups. Of the primigravidae 10.9% and of the multigravidae 21.7% had incomplete abortions. No injuries to the genital tract were reported. PMID- 29120044 TI - STUDIES ON 15(S)15 METHYL PGF2alpha BY INTRAMUSCULAR ROUTE FOR SECOND TRIMESTER ABORTION (TWO HOURLY SCHEDULE). AB - A multicentre study was undertaken to study intramuscular 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) for induction of second trimester abortion. The patients were premedicated with Imodium and Perinorm to control the gastrointestinal side effects. The dose of Prostin 15M was 250 ug every two hours and the progress of the abortion was assessed before each injection. If there was no progress at the end of 10 injections the case was classified as a failure. Ninety-seven patients were recruited for the study, 39 were primigravidae and 58 multigravidae. Twenty-four out of 39 primigravidae and 52 out of 58 multigravidae aborted with the treatment. The mean induction abortion interval was 17.8 hours in the primigravidae and 14.5 hours in the multigravidae patients. The mean number of episodes of vomiting was 2.9 and diarrhoea 4.2 per patient per trial. The primigravidae had slightly higher incidence of gastrointestinal side effects. The overall incidence of incomplete abortion was 17.1%. PMID- 29120045 TI - STUDIES ON 15(S)15 METHYL PGF2alpha BY INTRAMUSCULAR ROUTE FOR SECOND TRIMESTER ABORTION (THREE HOURLY SCHEDULE). AB - A multicentre study was undertaken to study the intramuscular 15(S)-5 methyl PGF2alpha (Prostin 15M, Upjohn) for induction of second trimester abortion. The patients were premedicated with Imodium and Perinorm for control of gastrointestinal side effects. Prostin 15M was given 250 ug every three hours and the progress was assessed before each injection. If there was no progress at the end of 10 injections the case was classified as a failure. Sixty-two patients were recruited for the study, 24 were primigravidae and 38 multigravidae. Twenty three out of 24 primigravidae and 34 out of 38 multigravidae aborted with the treatment. The mean induction abortion interval in the primigravidae was 23.5 hours while it was 18.0 hours in the multigravidae. The mean number of vomitings was 2.9 and that of diarrhoea 5.0. The overall incidence of incomplete abortion was only 10.5%. PMID- 29120046 TI - PROPHYLACTIC USE OF 15(S)15 METHYL PGF2alpha BY INTRAMUSCULAR ROUTE FOR CONTROL OF POSTPARTUM BLEEDING - A COMPARATIVE TRIAL WITH METHYLERGOMETRINE. AB - In a multicentre trial (3 centres) the safety and efficacy of an intramuscular injection of 125 ug of 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) was compared with methylergometrine for prophylactic control of bleeding during the third stage of labour. Three hundred patients were recruited for the study - 150 to each treatment group. The duration of the third stage was shorter in the patients (4.4 minutes) treated with Prostin 15M compared to the methylergometrine group (8.6 minutes). Similarly the blood loss during the third stage was reduced by 50% of that observed in the methylergometrine group (72 ml vs 145 ml). Prostin 15M, when used prophylactically was better than methylergometrine in controlling the blood loss during the third stage of labour. PMID- 29120047 TI - MANAGEMENT OF INTRACTABLE POSTPARTUM HEMORRHAGE SECONDARY TO UTERINE ATONY WITH INTRAMUSCULAR 15(S)15 METHYL PGF2alpha. AB - In a multicentre trial the efficacy of 250 ug of intramuscular 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) was tested in controlling the postpartum hemorrhage following delivery at term. All patients included in this study did not respond to the conventional therapy of intravenous oxytocin infusion and methergin. Forty-eight patients were included in this analysis. Forty patients responded to therapy. The blood loss following Prostin 15M injection was significantly (p<0.01) reduced from 666 ml to 341 ml. The mean blood replacement was 833 ml. PMID- 29120048 TI - PROPHYLACTIC USE OF 15(S)15 METHYL PGF2alpha , BY INTRAMUSCULAR ROUTE - A CONTROLLED CLINICAL TRIAL. AB - In a multicentre study the safety and efficacy of 125 ug intramuscular injection of 15(S)15 methyl PGF2alpha , (Prostin 15M, Upjohn) was compared with ergometrine and controls who did not receive any oxytocic for prophylactic control of postpartum bleeding. The study included 441 patients. The duration of third stage was shortened to 6.1 minutes following ergometrine and to 3.5 minutes following Prostin 15M compared to 7.6 minutes in the control subjects. Similarly the blood loss during third stage was less (95.2 ml) in Prostin 15M treated group compared to the untreated control group (233.2 ml). Prostin 15M, when used prophylactically, was also better than ergometrine (154.0 ml) in controlling the blood loss during third stage of labour in normal vaginal delivery. PMID- 29120049 TI - ADJUNCTIVE USE OF LAMINARIA TENT WITH INTRAMUSCULAR 15(S)15 METHYL PGF2alpha FOR INDUCTION OF SECOND TRIMESTER ABORTION. AB - The adjunctive use of laminaria tent along with intramuscular 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) was studied for induction of second trimester abortion. Three hundred and two patients from eight centres were recruited for the study. Ninety-two were primigravidae and 210 were multigravidae. One to three laminaria tents were inserted overnight and they were removed before the start of treatment with 250 ug Prostin 15M administered intramuscularly every two hours till abortion. Of primigravida 81.5% and of the multigravidae 79.5% aborted within 24 hours of treatment. The induction abortion interval in the primigravida was 11.2 hours and in multigravidae it was 12.0 hours. The overall incomplete abortion rate was 31.0%. The pimigravidae had higher mean number of episodes of vomiting (2.5) and diarrhea (2.9) than the multigravidae (1.7 and 1.5, respectively). No other complications or injuries to genital tract were reported. PMID- 29120050 TI - INTRAMUSCULAR 15(S)15 METHYL PGF2alpha IN THE TREATMENT OF MISSED ABORTION. AB - Intramuscular 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) was used for induction of labour in cases of missed abortion and intra-uterine fetal death. The patients received premedication to control the gastrointestinal side effects. Prostin 15M was given at a dose of 250 ug every three hours and escalated whenever required. The trial was interrupted in two out of 83 patients. Altogether 75 patients (92.6%) expelled the fetus with the treatment. The mean induction abortion interval was 14.7 hours. The primigravidae had a longer (18.2 hrs) interval than the multigravidae (13.8 hrs). The mean number of episodes of vomiting was 2.9 and of diarrhoea 3.5 per patient and treatment. PMID- 29120051 TI - INTRAMUSCULAR 15(S)15 METHYL PGF2alpha FOR MENSTRUAL REGULATION. AB - A multicentre trial was carried out to find out the safety and efficacy of 15(S)15 methyl PGF2alpha (Prostin 15M, Upjohn) for induction of menses in early pregnancy (up to 49 days). Two hundred and eighty-four cases were recruited for the study. All patients received two doses of 0.5 mg (2.0 ml) Prostin 15M by the intramuscular route and antiemetic and antidiarrhoeal medication prior to the administration of the prostaglandin analogue. The overall success rate (complete abortion) at two weeks evaluation visit was 87.7%. The success rate was 92% up to 42 days and 100% up to 35 days of the last menstrual period. The side effects were mainly gastrointestinal and majority of the patients had less than three episodes of vomiting or diarrhoea. The duration of bleeding was prolonged (up to 7 days) with Prostin 15M treatment. Intramuscular Prostin 15M seems to be effective in inducing menses in early pregnancy especially if the duration of amenorrhea is up to 35 days. PMID- 29120052 TI - Nutrient-rich plants emit a less intense blend of volatile isoprenoids. AB - The emission of isoprenoids (e.g. isoprene and monoterpenes) by plants plays an important defensive role against biotic and abiotic stresses. Little is known, however, about the functional traits linked to species-specific variability in the types and rates of isoprenoids emitted and about possible co-evolution of functional traits with isoprenoid emission type (isoprene emitter, monoterpene emitter or both). We combined data for isoprene and monoterpene emission rates per unit dry mass with key functional traits (foliar nitrogen (N) and phosphorus (P) concentrations, and leaf mass per area) and climate for 113 plant species, covering the boreal, wet temperate, Mediterranean and tropical biomes. Foliar N was positively correlated with isoprene emission, and foliar P was negatively correlated with both isoprene and monoterpene emission rate. Nonemitting plants generally had the highest nutrient concentrations, and those storing monoterpenes had the lowest concentrations. Our phylogenetic analyses found that the type of isoprenoid emission followed an adaptive, rather than a random model of evolution. Evolution of isoprenoids may be linked to nutrient availability. Foliar N and P are good predictors of the type of isoprenoid emission and the rate at which monoterpenes, and to a lesser extent isoprene, are emitted. PMID- 29120054 TI - A PROSPECTIVE STUDY OF THE PLACENTAL WEIGHT AND CONTENT OF PROTEIN, RNA AND DNA. AB - An investigation was carried out of the placental weight and content of protein, RNA and DNA on 253 placentae. The material was prospectively selected from among mothers with a presumed optimal obstetric outcome, and randomized from 96.7% of the births in the County of Odense. After trimming, freezing and homogenization of the placentae, the content of protein, RNA and DNA were determined spectrophotometrically. It was found that the placental weight rose slightly, approximately 50 g from the 36th to 42nd week. This is not a statistically significant rise. The RNA and DNA ran a parallel course to that of the placental weight during this interval. It is concluded that there is probably no growth of the placenta after the 34th to 36th week, but continued connective tissue formation. The protein content increases throughout the whole pregnancy. After division of the material into primi- and multigravidae, it was found that the latter gave birth to 6% heavier infants, while the placental weight and nucleic acid content were increased by 7-10%. This would suggest that a "parity effect" is present in the mother and not in the placenta. A similar division according to the mother's pre-pregnant weight of more or less than 54 kg, showed that the heavier mothers gave birth to 5% heavier infants, but the difference with regard to the placental weight and content of RNA and DNA was less and non-significant. This would suggest that the heavy mothers deliver heavier infants for genetical reasons. The material was divided up according to the sex of the infants, and it was found that girls were 1% heavier (NS), while the placental weight of the girls was approximately 5% greater and the DNA content approximately 9% greater. This sex difference which only applies to the placenta is discussed. It was found, following division of the material into 12 parts according to the month of delivery, that the infant weight, placental weight and DNA content were lowest in May-June and highest in August-September. Arguments are put forward that the significant difference in the DNA content of approximately 29% could result from a deficiency of folic acid. PMID- 29120055 TI - THE SIGNIFICANCE OF DIFFERENT FORMS OF PLACENTITIS. AB - A blind histological examination of placentae, with regard to placentitis, was carried out of 2 prospective, selected materials. The first consisted of 283 placentae, which were selected with regard to optimal obstetric outcome. The second consisted of 160 placentae, randomized from all premature and low birth weight infants in the local area. Placentitis was sub-divided into: funisitis, chorionitis, villitis and hypercellular villi. Funisitis was found in premature infants only. Villitis resulted in the birth of significantly smaller infants and placentae, and must therefore, in contrast to funisitis and chorionitis, be considered chronic. Hypercellular villi are found to have no importance. Funisitis, chorionitis and villitis could possibly be explained by an infection in 10 of a total of 15 cases of placentitis. PMID- 29120056 TI - CIRCUMVALLATE PLACENTA AND INTRAUTERINE GROWTH RETARDATION. AB - A study has been made of a prospectively selected material of circumvallate placentae; the latter being defined as an elevated edge of more than 50% of the circumference. The material consists of 447 placentae from liveborn singleton infants, where 287 were from exemplary pregnancies, and 160 from births with a gestational age (GA) of less than 266 days and/or a birth weight of less than 2 750 g. The material was prospectively randomized. It was divided into clinical groups according to the GA and under-weight. Nineteen circumvallate placentae were found. Among these were more multigravidae and more with pre-gestational menstrual irregularity than expected. The number of antepartum haemorrhages was as expected. There were more premature infants, premature under-weight infants and under- weight infants than expected. Nine of the 20 premature under-weight infants in the material had circumvallate placenta. In relation to a previously published basic material, it was found that the birth weight, and placental content of RNA and DNA were significantly reduced. It is concluded that placentae with more than 50% circumvallation are associated with prematurity and under weight, as well as a placenta with fewer cells than normal. The genesis of the anomaly is discussed. PMID- 29120053 TI - Tumor conditions induce bone marrow expansion of granulocytic, but not monocytic, immunosuppressive leukocytes with increased CXCR2 expression in mice. AB - Myeloid-derived suppressor cells (MDSCs) promote tumor growth through, in part, inhibiting T-cell immunity. However, mechanisms underlying MDSC expansion and guidance of MDSCs toward the tumor microenvironment remain unclear. Employing Percoll density gradients, we separate bone marrow (BM) leukocytes from tumor bearing mice into four density-increasing bands with myeloid leukocytes enriched in bands III and IV. Band III comprises monocytes and low-density granulocytes, both confirmed to be M-MDSCs and G-MDSCs, respectively, by displaying potent inhibition of T-cell proliferation. However, monocytes act as M-MDSCs not only under tumor conditions but also the healthy condition. In contrast, band IV contains non-inhibitory, mature granulocytes. Only band III G-MDSCs display significant expansion in mice bearing B16 melanoma, Lewis lung carcinoma, or MC38 colon carcinoma. The expanded G-MDSCs also show increased CXCR2 expression, which guides egress out of BM, and produce arginase-1 and ROS upon encountering antigen activated T cells. Adoptive transfer assays demonstrate that both G-MDSCs and mature granulocytes infiltrate tumors, but only the former displays sustention and accumulation. Intratumoral administrations of granulocytes further demonstrate that G-MDSCs promote tumor growth, whereas mature granulocytes exert minimal effects, or execute powerful anti-tumor effects providing the presence of PMN activation mechanisms in the tumor microenvironment. PMID- 29120057 TI - INFARCTIONS AND INTERVILLOUS THROMBOSIS IN PLACENTA, AND THEIR ASSOCIATION WITH INTRAUTERINE GROWTH RETARDATION. AB - The number of infarctions and intervillous thromboses have been determined in a randomized, optimal obstetric material, consisting of 301 placentae. All the placentae were examined without knowledge of the pregnancies, deliveries or infants. They were examined macroscopically and histologically. The total content of protein, RNA and DNA were determined in a randomized sample of the 301 placentae. Fifty-two placentae had small infarctions, and the corresponding birth weights, placental weights and placental DNA were of the same magnitude as in the remainder of the material. There was the same frequency of infarctions among the placentae with intervillous thrombosis. There were 11 with intervillous thrombosis, and they had a significant reduction in infant birth weight and in placental content of DNA. A significant part of these (6) had asphyxia at birth. In neither of the groups was there proliferation of Langhans cells as a sign of longer lasting anoxia. The extent of villous fibrosis in the groups was the same as in the remainder of the material. It is concluded, that no evidence was found to support a theory that infarctions and intervillous thromboses have the same pathogenesis. PMID- 29120058 TI - THE RELATIONSHIP BETWEEN SOME DISORDERS OF THE UMBILICAL CORD AND INTRAUTERINE GROWTH RETARDATION. AB - Some disorders of the umbilical cord-Single umbilical artery, oedema of the cord, battledore insertion and velamentous insertion-have been examined in a prospectively randomized material. The material consists of 447 placentae from liveborn, singleton infants, where 287 were from exemplary pregnancies, and 160 from births with a gestational age of less than 266 days and/or a birth weight of less than 2750 g. The placentae were examined macroscopically and microscopically, and the total amount of protein, RNA, and DNA were determined in a randomized sample. Single umbilical artery was found to coincide with circumvallate placenta, suggesting a common fault in the placentation. Oedema of the umbilical cord was found to have no significance for the infant, but their placentae were significantly heavier, without signs of generalized oedema. The birth weight and placental weight were slightly and equally reduced in battledore insertion of the cord. The RNA/DNA ratio was increased, indicating tissue stress. This anomaly contrasted to the placentae, in which the cords were inserted velamentously. These had significantly reduced birth weights, and the weights of the placentae were slightly reduced. The incidences of complications during labour and congenital anomalies were increased. PMID- 29120059 TI - Source and sink mechanisms of nitrogen transport and use. AB - Contents Summary 35 I. Introduction 35 II. Nitrogen acquisition and assimilation 36 III. Root-to-shoot transport of nitrogen 38 IV. Nitrogen storage pools in vegetative tissues 39 V. Nitrogen transport from source leaf to sink 40 VI. Nitrogen import into sinks 42 VII. Relationship between source and sink nitrogen transport processes and metabolism 43 VIII. Regulation of nitrogen transport 43 IX. Strategies for crop improvement 44 X. Conclusions 46 Acknowledgements 47 References 47 SUMMARY: Nitrogen is an essential nutrient for plant growth. World wide, large quantities of nitrogenous fertilizer are applied to ensure maximum crop productivity. However, nitrogen fertilizer application is expensive and negatively affects the environment, and subsequently human health. A strategy to address this problem is the development of crops that are efficient in acquiring and using nitrogen and that can achieve high seed yields with reduced nitrogen input. This review integrates the current knowledge regarding inorganic and organic nitrogen management at the whole-plant level, spanning from nitrogen uptake to remobilization and utilization in source and sink organs. Plant partitioning and transient storage of inorganic and organic nitrogen forms are evaluated, as is how they affect nitrogen availability, metabolism and mobilization. Essential functions of nitrogen transporters in source and sink organs and their importance in regulating nitrogen movement in support of metabolism, and vegetative and reproductive growth are assessed. Finally, we discuss recent advances in plant engineering, demonstrating that nitrogen transporters are effective targets to improve crop productivity and nitrogen use efficiency. While inorganic and organic nitrogen transporters were examined separately in these studies, they provide valuable clues about how to successfully combine approaches for future crop engineering. PMID- 29120060 TI - Heterogeneity of intron presence/absence in Olifantiella sp. (Bacillariophyta) contributes to the understanding of intron loss. AB - Although hypotheses have been proposed and developed to interpret the origins and functions of introns, substantial controversies remain about the mechanism of intron evolution. The availability of introns in the intermediate state is quite helpful for resolving this debate. In this study, a new strain of diatom (denominated as DB21-1) was isolated and identified as Olifantiella sp., which possesses multiple types of 18S rDNAs (obtained from genomic DNA; lengths ranged from 2,056 bp to 2,988 bp). Based on alignments between 18S rDNAs and 18S rRNA (obtained from cDNA; 1,783 bp), seven intron insertion sites (IISs) located in the 18S rDNA were identified, each of which displayed the polymorphism of intron presence/absence. Specific primers around each IIS were designed to amplify the introns and the results indicated that introns in the same IIS varied in lengths, while terminal sequences were conserved. Our study showed that the process of intron loss happens via a series of successive steps, and each step could derive corresponding introns under intermediate states. Moreover, these results indicate that the mechanism of genomic deletion that occurs at DNA level can also lead to exact intron loss. PMID- 29120061 TI - Osteopathia striata with cranial sclerosis and Wilms tumor: Coincidence or consequence? PMID- 29120062 TI - Small patella syndrome: New clinical and molecular insights into a consistent phenotype. PMID- 29120063 TI - Systematic Sonography for Detection of Occult Wounds in Trauma. AB - Treating victims of penetrating trauma is challenging, especially in a mass casualty or resource-limited setting. The traditional focused assessment with sonography for trauma examination is a well-established clinical tool in the initial evaluation of trauma victims. This article describes a novel technique of systematic sonography of the abdomen to look for occult wounds, which is used in conjunction with the focused assessment with sonography for trauma examination to evaluate occult intraperitoneal injury and improve patient treatment and use of resources. The technique is highlighted in a case of a child injured in a conflict zone in northern Iraq. PMID- 29120064 TI - Size and Ultrasound Features Affecting Results of Ultrasound-Guided Fine-Needle Aspiration of Thyroid Nodules. AB - OBJECTIVES: Our goal was to assess the diagnostic efficacy of ultrasound (US) guided fine-needle aspiration (FNA) of thyroid nodules according to size and US features. METHODS: A retrospective correlation was made with 1745 whole thyroidectomy and hemithyroidectomy specimens with preoperative US-guided FNA results. All cases were divided into 5 groups according to nodule size (<=5, 5.1 10, 10.1-15, 15.1-20, and >20 mm). For target nodules, static images and cine clips of conventional US and color Doppler were obtained. Ultrasound images were reviewed and evaluated by two radiologists with at least 5 years US working experience without knowing the results of pathology, and then agreement was achieved. RESULTS: The Bethesda category I rate was higher in nodules larger than 15 mm (P < .05). The diagnostic accuracy was best in nodules of 5 to 10 mm in diameter. The sensitivity, accuracy, PPV, and LR for negative US-guided FNA results were better in nodules with a size range of 5 to 15 mm. The specificity, negative predictive value (NPV), and LR for positive results and the Youden index rose with increasing nodule size. Seventeen false-positive and 60 false-negative results were found in this study. The false-negative rate rose with increasing nodule size. However, the false-positive rate was highest in the group containing the smallest nodules. Nodules with circumscribed margins and those that were nonsolid and nonhypoechoic and had no microcalcifications correlated with Bethesda I FNA results. Nodules with circumscribed margins and those that were nonsolid, heterogeneous, and nonhypoechoic and had increased vascularity correlated with false-negative FNA results. Borders correlated with Bethesda I false-negative and false-positive FNA results. CONCLUSIONS: Tiny nodules (<=5 mm) with obscure borders tended to yield false-positive FNA results. Large nodules (>20 mm) with several US features tended to yield false-negative FNA results. PMID- 29120065 TI - Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa responsive infantile-onset Parkinsonism. AB - Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17 year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism. PMID- 29120066 TI - A novel nonsense variant in REEP6 is involved in a sporadic rod-cone dystrophy case. AB - Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is the most common form of progressive inherited retinal disorders secondary to photoreceptor degeneration. It is a genetically heterogeneous disease characterized by night blindness, followed by visual field constriction and, in most severe cases, total blindness. The aim of our study was to identify the underlying gene defect leading to severe RCD in a 60-year-old woman. The patient's DNA was investigated by targeted next generation sequencing followed by whole exome sequencing. A novel nonsense variant, c.267G>A p.(Trp89*), was identified at a homozygous state in the proband in REEP6 gene, recently reported mutated in 7 unrelated families with RCD. Further functional studies will help to understand the physiopathology associated with REEP6 mutations that may be linked to a protein trafficking defect. PMID- 29120067 TI - Review of patient decision-making factors and attitudes regarding preimplantation genetic diagnosis. AB - The increasing technical complexity and evolving options for repro-genetic testing have direct implications for information processing and decision making, yet the research among patients considering preimplantation genetic diagnosis (PGD) is narrowly focused. This review synthesizes the literature regarding patient PGD decision-making factors, and illuminates gaps for future research and clinical translation. Twenty-five articles met the inclusion criteria for evaluating experiences and attitudes of patients directly involved in PGD as an intervention or considering using PGD. Thirteen reports were focused exclusively on a specific disease or condition. Five themes emerged: (1) patients motivated by prospects of a healthy, genetic-variant-free child, (2) PGD requires a commitment of time, money, energy and emotions, (3) patients concerned about logistics and ethics of discarding embryos, (4) some patients feel sense of responsibility to use available technologies, and (5) PGD decisions are complex for individuals and couples. Patient research on PGD decision-making processes has very infrequently used validated instruments, and the data collected through both quantitative and qualitative designs have been inconsistent. Future research for improving clinical counseling is needed to fill many gaps remaining in the literature regarding this decision-making process, and suggestions are offered. PMID- 29120068 TI - Diagnosis and genetics of alacrima. AB - Alacrima, the lack of tears, is a rare clinical finding that has been reported as a feature of multiple genetic disorders and can serve as a diagnostic clue to some rare conditions. Causes of alacrima range from absence/hyposecretion of tears to agenesis or improper development of lacrimal gland ducts and associated structures. There are 13 known heritable disorders featuring varying degrees and causes of alacrima. Some manifest only the congenital absence of tears, while others affect multiple organ systems and may involve severe developmental delay, intellectual disability, and potentially life-threatening autonomic dysregulation. To aid in the diagnosis for patients manifesting alacrima, we review the major causes and the various genetic disorders associated with alacrima and provide a differential template for diagnosis. PMID- 29120069 TI - Effects of exposure to winter oilseed rape grown from thiamethoxam-treated seed on the red mason bee Osmia bicornis. AB - There has been increasing interest in the effects of neonicotinoid insecticides on wild bees. In solitary bee species the direct link between each individual female and reproductive success offers the opportunity to evaluate effects on individuals. The present study investigated effects of exposure to winter oilseed rape grown from thiamethoxam-treated seed on reproductive behavior and output of solitary red mason bees (Osmia bicornis) released in 6 pairs of fields over a 2 yr period and confined to tunnels in a single year. After adjustment to the number of females released, there was significantly lower production of cells and cocoons/female in tunnels than in open field conditions. This difference may be because of the lack of alternative forage within the tunnels. Under open field conditions, palynology of the pollen provisions within the nests demonstrated a maximum average of 31% oilseed rape pollen at any site, with Quercus (oak) contributing up to 86% of the pollen. There were no significant effects from exposure to oilseed rape grown from thiamethoxam-treated seed from nest establishment through cell production to emergence under tunnel or field conditions. Environ Toxicol Chem 2018;37:1071-1083. (c) 2017 SETAC. PMID- 29120070 TI - Cobalt-Catalyzed Asymmetric Allylation of Cyclic Ketimines. AB - A CoII /Box-catalyzed [Box=bis(oxazoline)] enantioselective addition of potassium allyltrifluoroborate to cyclic ketimines was developed, providing the corresponding chiral alpha-tertiary amines in high yields and with good enantioselectivity values. Alkoxycarbonyl- and alkyl-substituted saccharin derived ketimines are suitable substrates for this allylation reaction. The product can be converted to complex molecules over several simple steps, including a precursor of MK-0371, which is a kinesin spindle protein inhibitor. In addition, this catalytic system showed a strong positive nonlinear effect. PMID- 29120071 TI - Effects of vanadium supplementation on performance, some plasma metabolites and glucose metabolism in Mahabadi goat kids. AB - This experiment was conducted to investigate the effects of vanadium (V) supplementation on performance, some plasma metabolites (cholesterol and triglycerides) and glucose metabolism in Mahabadi goat kids. Twenty-eight male kids (15 +/- 2 kg body weight) were fed for 14 weeks in a completely randomized design with four treatments. Treatments were supplemented with 0 (control), 1, 2, and 3 mg V as vanadyl sulfate/animal/daily. On day 70, an intravenous glucose tolerance test (IVGTT) was conducted. Dry matter intake did not change by V supplementation, but adding V quadraticaly improved feed efficiency (p = .03) and tended to increase average daily gain (Quadratic, p = .09). Blood metabolites were unaffected by V supplementation, except for concentration of glucose in plasma, which decreased linearly as supplemental V level increased (p = .02). Plasma glucose concentrations at 15, 30, 45 and 60 min after glucose infusion were decreased in a quadratic fashion in response to increasing supplemental V level (p < .01). The IVGTT indicated that the kids supplemented with 2 mg V had higher glucose clearance rate (K) and lower glucose half-life (T1/2 ; p < .05). Glucose area under the response curve from 0 to 60 min and 0 to 180 min after glucose infusion were decreased linearly (p = .04) by supplemental V. The results suggested that moderate supplementation of V may improve glucose utilization and feed efficiency in fattening kids. PMID- 29120072 TI - RASA1 mutation in a family with capillary malformation-arteriovenous malformation syndrome: A discussion of the differential diagnosis. AB - We describe a family who presented with several scattered, vascular, cutaneous lesions and was found to have a novel mutation in RASA1, diagnostic of capillary malformation-arteriovenous malformation syndrome. Our patient was initially given a presumptive clinical diagnosis of hereditary hemorrhagic telangiectasia. Capillary malformation-arteriovenous malformation syndrome shares several features with hereditary hemorrhagic telangiectasia and hereditary benign telangiectasia, but it can be distinguished clinically according to its morphologic appearance and distribution of cutaneous vascular lesions, the presence of internal fast-flow lesions, and genetic analysis. PMID- 29120074 TI - A FRET Sensor to Monitor Bivalent SUMO-SIM Interactions in SUMO Chain Binding. AB - The small ubiquitin-like modifier (SUMO) can be assembled into polymeric chains as part of its diverse biochemical signal pattern upon conjugation to substrate proteins. SUMO chain recognition is facilitated by receptor proteins that contain at least two SUMO-interacting motifs (SIMs). Little is known about the structure of SUMO chains, both in an unliganded form and upon complexation with multi-SIM protein partners. A FRET sensor has been developed based on a linear dimer of human SUMO-2 as a minimal SUMO chain analogue. The synthetic acceptor and donor dyes were conjugated by maleimide and copper-catalyzed click chemistry to each of the two SUMO subunits. FRET changes were only observed in the presence of di- or multi-SIM ligands. Alteration of the short linker sequence between SIMs 2 and 3 of RNF4 showed a great tolerance, and hence, structural flexibility, of the SUMO dimer for bivalent binding of adjacent SIMs. The di-SUMO FRET sensor reports on the binding of SIM clusters of the proteins C5orf25 and SOBP; this suggest that these can bind to adjacent subunits of a SUMO chain. The developed FRET sensor will be a useful tool to study the importance of SIM and linker sequences, as well as biochemical and structural properties of SUMO chains and multi-SIM proteins. PMID- 29120073 TI - Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate glutamine cycle in the tree shrew visual cortex. AB - Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate-glutamine cycle (VNT ) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1 H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by -0.34 +/- 0.09 umol/g (p < 0.001), as well as a -9% +/- 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13 C MRS during [1,6-13 C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT , resulted in increased TCA cycle rates in neurons by 12% ( VTCAn, p < 0.001) and in astrocytes by 24% ( VTCAg, p = 0.007). We further observed linear relationships between VNT and both VTCAn and VTCAg. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes. PMID- 29120075 TI - Ultrasound findings in idiopathic facial aseptic granuloma: Case series and literature review. AB - Idiopathic facial aseptic granuloma is an inflammatory nodule commonly located on the cheeks and eyelids in young children. Despite its prolonged course, it tends toward spontaneous resolution, so invasive diagnostic procedures should be avoided. Cutaneous ultrasound is a noninvasive modality that has been found to improve the diagnostic accuracy of nodular skin lesions. We report five children with idiopathic facial aseptic granuloma in whom high-resolution ultrasound examination provided distinctive findings. PMID- 29120076 TI - Sequencing of uncertain significance. PMID- 29120077 TI - Self-Assembled Nanomicelles as MRI Blood-Pool Contrast Agent. AB - Gadolinium-loaded nanomicelles show promise as future magnetic resonance imaging (MRI) contrast agents (CAs). Their increased size and high gadolinium (Gd) loading gives them an edge in proton relaxivity over smaller molecular Gd complexes. Their size and stealth properties are fundamental for their long blood residence time, opening the possibility for use as blood-pool contrast agents. Using l-tyrosine as a three-functional scaffold we synthesized a nanostructure building block 8. The double C18 aliphatic chain on one side, Gd-1,4,7,10 tetraazacyclododecane-1-4-7-triacetic acid (Gd-DO3A) with access to bulk water in the center and 2 kDa PEG on the hydrophilic side gave the amphiphilic properties required for the core-shell nanomicellar architecture. The self-assembly into Gd loaded monodispersed 10-20 nm nanomicelles occurred spontaneously in water. These nanomicelles (Tyr-MRI) display very high relaxivity at 29 mm-1 s-1 at low field strength and low cytotoxicity. Good contrast enhancement of the blood vessels and the heart together with prolonged circulation time in vivo, makes Tyr-MRI an excellent candidate for a new supramolecular blood-pool MRI CA. PMID- 29120078 TI - High carbon dioxide concentration and elevated temperature impact the growth of weeds but do not change the efficacy of glyphosate. AB - BACKGROUND: Global climate changes may impact the growth and management of weed species. The aim of this work was to evaluate the impact of recent climate changes on the growth of weeds and herbicide efficacy. The effects of temperature, carbon dioxide (CO2 ), and herbicide on growth and control of Bromus tectorum L., Hordeum murinum L., and Lactuca serriola L. were studied. Treatments included: control or ambient environment (CO2 concentration 400-450 ppm; temperature 20/10 degrees C day/night); elevated temperature (CO2 concentration 400-450 ppm; temperature 25/15 degrees C day/night); high CO2 and elevated temperature (CO2 concentration 800-900 ppm; temperature 25/15 degrees C day/night); high CO2 (CO2 concentration 800-900 ppm; temperature 20/10 degrees C day/night). Glyphosate rates (active ingredient) used in the experiment were: 0 g ha-1 (untreated control); 360 g ha-1 ; 720 g ha-1 ; 1080 g ha-1 ; 1440 g ha-1 (recommended rate), and 2880 g ha-1 . RESULTS: High CO2 concentration and high CO2 concentration plus high temperature improved the biomass and growth parameters of weeds in the studies. In general, high temperature had a neutral, negative or slightly positive effect on the growth of weed species. Climatic conditions did not affect the activity of glyphosate; its application provided equal and effective weed control under both CO2 and temperature levels and their combinations. CONCLUSION: The positive effect of high CO2 concentration on the growth of weeds does not impact the activity of glyphosate. (c) 2017 Society of Chemical Industry. PMID- 29120079 TI - Complete Depolymerization and Repolymerization of a Sugar Poly(orthoester). AB - The capability of a polymer to depolymerize, regenerating its original monomer for further polymerization, is very attractive in terms of sustainability. Recently discovered sugar poly(orthoesters) are an important class of glycopolymer. The high sensitivity of the backbone orthoester linkage toward acidolysis provides a valuable model to study the depolymerization. Herein, a sugar poly(orthoester) is shown to be completely depolymerized under acidic conditions. Interestingly, instead of the original monomer, the depolymerization gave a stable cyclic product (1,6-anhydro glucopyranose) in most cases, which was kinetically and thermodynamically favored. However, this pathway could be inhibited by chemically deactivating a key intermediate and thus favoring the formation of the original monomer. Efficient repolymerizaton of the regenerated monomer is also demonstrated. PMID- 29120080 TI - Visible-Light Photoactive, Highly Efficient Triplet Sensitizers Based on Iodinated Aza-BODIPYs: Synthesis, Photophysics and Redox Properties. AB - A series of novel iodinated NO2 -substituted aza-BODIPYs have been synthesized and characterized. Highly desirable photophysical and photochemical properties were induced in NO2 -substituted aza-BODIPYs by iodination of the pyrrole rings. In particular, high values of singlet oxygen quantum yields (PhiDelta ) ranging from 0.79 to 0.85 were measured. The photooxygenation process proceeds via a Type II mechanism under the experimental conditions applied. The compounds studied exhibited an absorption band within the so-called "therapeutic window", with lambdamax located between 645 nm to 672 nm. They were non-fluorescent at room temperature with excited singlet-state lifetimes within the picosecond range as measured by femtosecond transient absorption. Nanosecond laser flash photolysis experiments revealed T1 ->Tn absorption spanning from ca. 400 nm to ca. 500 nm and allowed determination of the triplet-state lifetimes. The estimated triplet lifetimes (tauT ) in deaerated acetonitrile ranged between 2.74 MUs and 3.50 MUs. As estimated by CV/DPV measurements, all iodinated aza-BODIPYs studied exhibited one irreversible oxidation and two quasi-reversible reductions processes. Estimation of the EHOMO gave the value of -6.06 to -6.26 eV while the ELUMO was found to be located at ca. -4.6 eV. Thermogravimetric (TGA) analysis revealed that iodinated aza-BODIPYs were stable up to approximately 300 degrees C. All compounds studied exhibit high photostability in toluene solution. PMID- 29120081 TI - Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors. AB - As histone deacetylases (HDACs) play an important role in the treatment of cancer, their selective inhibition has been the subject of various studies. These continuous investigations have given rise to a large collection of pan- and selective HDAC inhibitors, containing diverse US Food and Drug Administration (FDA)-approved representatives. In previous studies, a class of alkyne-based HDAC inhibitors was presented. We modified this scaffold in two previously neglected regions and compared their cytotoxicity and affinity toward HDAC1, HDAC6, and HDAC8. We were able to show that R-configured propargylamines contribute to increased selectivity for HDAC6. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic portion by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance. PMID- 29120082 TI - Substantial differences in bias between single-digest and double-digest RAD-seq libraries: A case study. AB - The trade-offs of using single-digest vs. double-digest restriction site associated DNA sequencing (RAD-seq) protocols have been widely discussed. However, no direct empirical comparisons of the two methods have been conducted. Here, we sampled a single population of Gulf pipefish (Syngnathus scovelli) and genotyped 444 individuals using RAD-seq. Sixty individuals were subjected to single-digest RAD-seq (sdRAD-seq), and the remaining 384 individuals were genotyped using a double-digest RAD-seq (ddRAD-seq) protocol. We analysed the resulting Illumina sequencing data and compared the two genotyping methods when reads were analysed either together or separately. Coverage statistics, observed heterozygosity, and allele frequencies differed significantly between the two protocols, as did the results of selection components analysis. We also performed an in silico digestion of the Gulf pipefish genome and modelled five major sources of bias: PCR duplicates, polymorphic restriction sites, shearing bias, asymmetric sampling (i.e., genotyping fewer individuals with sdRAD-seq than with ddRAD-seq) and higher major allele frequencies. This combination of approaches allowed us to determine that polymorphic restriction sites, an asymmetric sampling scheme, mean allele frequencies and to some extent PCR duplicates all contribute to different estimates of allele frequencies between samples genotyped using sdRAD-seq versus ddRAD-seq. Our finding that sdRAD-seq and ddRAD-seq can result in different allele frequencies has implications for comparisons across studies and techniques that endeavour to identify genomewide signatures of evolutionary processes in natural populations. PMID- 29120084 TI - Excitation-Dependent Photoluminescence from Single-Carbon Dots. AB - Carbon dots (CDs) are carbon-based fluorescent nanoparticles that can exhibit excitation-dependent photoluminescence (PL) "tunable" throughout the entire visible range, interesting for optoelectronic and imaging applications. The mechanism underlying this tunable emission remains largely debated, most prominently being ascribed to dot-to-dot variations that ultimately lead to excitation-dependent ensemble properties. Here, single-dot spectroscopy is used to elucidate the origin of the excitation-dependent PL of CDs. It is demonstrated that already single CDs exhibit excitation-dependent PL spectra, similar to those of the CD ensemble. The single dots, produced by a facile one-step synthesis from chloroform and diethylamine, exhibit emission spectra with several characteristic peaks differing in emission peak position and spectral width and shape, indicating the presence of distinct emission sites on the CDs. Based on previous work, these emission sites are related to the sp2 subregions in the carbon core, as well as the functional groups on the surface. These results confirm that it is possible to integrate and engineer different types of electronic transitions at the nanoscale on a single CD, making these CDs even more versatile than organic dyes or inorganic quantum dots and opening up new routes toward light-emission engineering. PMID- 29120083 TI - Isolation and evolutionary analysis of Australasian topotype of bluetongue virus serotype 4 from India. AB - Bluetongue (BT) is a Culicoides-borne disease caused by several serotypes of bluetongue virus (BTV). Similar to other insect-borne viral diseases, distribution of BT is limited to distribution of Culicoides species competent to transmit BTV. In the tropics, vector activity is almost year long, and hence, the disease is endemic, with the circulation of several serotypes of BTV, whereas in temperate areas, seasonal incursions of a limited number of serotypes of BTV from neighbouring tropical areas are observed. Although BTV is endemic in all the three major tropical regions (parts of Africa, America and Asia) of the world, the distribution of serotypes is not alike. Apart from serological diversity, geography-based diversity of BTV genome has been observed, and this is the basis for proposal of topotypes. However, evolution of these topotypes is not well understood. In this study, we report the isolation and characterization of several BTV-4 isolates from India. These isolates are distinct from BTV-4 isolates from other geographical regions. Analysis of available BTV seg-2 sequences indicated that the Australasian BTV-4 diverged from African viruses around 3,500 years ago, whereas the American viruses diverged relatively recently (1,684 CE). Unlike Australasia and America, BTV-4 strains of the Mediterranean area evolved through several independent incursions. We speculate that independent evolution of BTV in different geographical areas over long periods of time might have led to the diversity observed in the current virus population. PMID- 29120085 TI - Novel Gold and Silver Carbene Complexes Exert Antitumor Effects Triggering the Reactive Oxygen Species Dependent Intrinsic Apoptotic Pathway. AB - Cisplatin and other platinum-based drugs are well-known valid anticancer drugs. However, during chemotherapy, the presence of numerous side effects and the onset of frequent phenomena of resistance has pushed many research groups to devise new metal-based compounds holding improved anticancer properties and fewer undesired effects. Amongst the variety of synthesized compounds, significant antiproliferative effects have been obtained by employing organometallic compounds, particularly those based on silver and gold. With this in mind, we synthesized four compounds, two silver complexes and two gold complexes, with good inhibitory effects on the in vitro proliferation of breast and ovarian cancer-cell models. The antitumor activity of the most active compound, that is, AuL4, was found to be ninefold higher than that of cisplatin, and this compound induced dramatic morphological changes in HeLa cells. AuL4 induced PARP-1 cleavage, caspases 3/7 and 9 activation, mitochondria disruption, cytochrome c release in cancer-cell cytoplasm, and the intracellular production of reactive oxygen species. Thus, AuL4 treatment caused cancer-cell death by the intrinsic apoptotic pathway, whereas no cytotoxic effects were recorded upon treating non tumor cell lines. The reported outcomes may be an important contribution to the expanding knowledge of medicinal bio-organometallic chemistry and enlarge the available anticancer toolbox, offering improved features, such as higher activity and/or selectivity, and opening the way to new discoveries and applications. PMID- 29120086 TI - How Effective is Plasmonic Enhancement of Colloidal Quantum Dots for Color Conversion Light-Emitting Devices? AB - Enhancing the fluorescence intensity of colloidal quantum dots (QDs) in case of color-conversion type QD light-emitting devices (LEDs) is very significant due to the large loss of QDs and their quantum yields during fabrication processes, such as patterning and spin-coating, and can therefore improve cost-effectiveness. Understanding the enhancement process is crucial for the design of metallic nanostructure substrates for enhancing the fluorescence of colloidal QDs. In this work, improved color conversion of colloidal green and red QDs coupled with aluminum (Al) and silver (Ag) nanodisk (ND) arrays designed by in-depth systematic finite-difference time domain simulations of excitation, spontaneous emission, and quantum efficiency enhancement is reported. Calculated results of the overall photoluminescence enhancement factor in the substrate of 500 * 500 um2 size are 2.37-fold and 2.82-fold for Al ND-green QD and Ag ND-red QD structures, respectively. Experimental results are in good agreement, showing 2.26-fold and 2.66-fold enhancements for Al ND and Ag ND structures. Possible uses of plasmonics in cases such as white LED and total color conversion for possible display applications are discussed. The theoretical treatments and experiments shown in this work are a proof of principle for future studies of plasmonic enhancement of various light-emitting materials. PMID- 29120087 TI - Histological evolution from primary lung adenocarcinoma harboring EGFR mutation to high-grade neuroendocrine carcinoma. AB - BACKGROUND: Although patients with EGFR mutated lung adenocarcinoma benefit greatly from tyrosine kinase inhibitors (TKIs), they inevitably develop acquired resistance after an average of 10-14 months of continuous treatment. METHODS: We retrospectively analyzed the clinical and histopathological data of eight patients with primary lung adenocarcinoma harboring EGFR mutations that transformed into high-grade neuroendocrine carcinoma after TKI therapy. Morphology scanning for neuroendocrine differentiation and immunohistochemistry for neuroendocrine markers CD56, chromogranin, and synaptophysin were performed on primary adenocarcinoma tissues and repeated biopsies. Mutations of EGFR exons 19-21 were reexamined using the amplification refractory mutation system. RESULTS: The carcinoma in seven patients transformed to small cell lung carcinoma; two of these patients enrolled in theAZD9291 study after acquiring a T790M missense mutation. The carcinoma in one patient transformed to large cell neuroendocrine carcinoma. None of the eight primary tumors exhibited neuroendocrine morphologic features and only one surgical specimen displayed a weak stain for neuroendocrine marker synaptophysin. Drug resistant high-grade neuroendocrine carcinomas retained their initial activating EGFR mutations. CONCLUSIONS: Lung adenocarcinoma in eight patients transformed into high-grade neuroendocrine carcinoma and retained the original activating EGFR mutations after targeted therapy by TKIs. Furthermore, the prognosis of the transformed carcinoma was worse than the original primary genetic and morphologic type. PMID- 29120088 TI - Assessment of chemotherapy on various biochemical markers in breast cancer patients. AB - Chemotherapy is a standard treatment method for the patients with locally advanced breast cancer. Lately, cyclophosphamide (CYP) and doxorubicin (DOX) are used as the major chemotherapeutic agents especially for the treatment of breast cancer. Till date, no serum biomarker has been able to provide an early diagnosis of breast cancer. This study aimed to assess inflammatory, cardiac, renal and hematological markers in 56 breast cancer patients (BCP) before, during and after termination of chemotherapy with CYP and DOX. Blood samples were collected from the patients at the each treatment stages mentioned above. These samples were assessed for interleukin 6 (IL-6), interleukin 10 (IL-10), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine, hemoglobin (Hb), leukocyte, platelet and Na+ /K+ -ATPase levels either by ELISA or colorimetric methods. The results suggest a significant increase in IL-6 level at all the stages in BCP as compared to control group. On the other hand, IL-10, CK and Na+ /K+ -ATPase levels were found to be significantly declined during all the stages. Moreover, the majority of hematological parameters remained unchanged throughout the treatment period with the exception of creatinine and Hb which showed slight modulation in their level at different stages. Based on the results, we conclude that breast cancer and co-treatment with CYP and DOX, interfere arious biological markers, thereby, showing the physiological imbalance. PMID- 29120089 TI - DNA damage in Arctic seabirds: Baseline, sensitivity to a genotoxic stressor, and association with organohalogen contaminants. AB - Environmental contaminants are found throughout Arctic marine ecosystems, and their presence in seabirds has been associated with toxicological responses. However, there are few studies of genotoxicity in Arctic avian wildlife. The purpose of the present study was to quantify deoxyribonucleic acid (DNA) damage in lymphocytes of selected seabird species and to examine whether accumulation of organohalogen contaminants (SigmaOHCs) affects DNA damage. Blood was sampled from common eider (Somateria mollissima), black guillemot (Cepphus grylle), black legged kittiwake (Rissa tridactyla), glaucous gull (Larus hyperboreus), arctic skua (Stercorarius parasiticus), and great skua (Stercorarius skua) in Kongsfjorden, Svalbard (Norway). Contaminant concentrations found in the 6 species differed, presumably because of foraging ecology and biomagnification. Despite large differences in contaminant concentrations, ranging from SigmaOHCs 3.3 ng/g wet weight in the common eider to SigmaOHCs 895 ng/g wet weight in the great skua, there was no strong difference among the species in baseline DNA damage or sensitivity to a genotoxic stressor (hydrogen peroxide). Baseline levels of DNA damage were low, with median values ranging from 1.7% in the common eider to 8.6% in the great skua. There were no associations between DNA damage and contaminants in the investigated species, suggesting that contaminant concentrations in Kongsfjorden are too low to evoke genotoxic effects, or possibly that lymphocytes are resistant to strand breakage. Clearly, genotoxicity is a topic for future studies of Arctic seabirds. Environ Toxicol Chem 2018;37:1084-1091. (c) 2017 SETAC. PMID- 29120090 TI - ednaoccupancy: An r package for multiscale occupancy modelling of environmental DNA data. AB - In this article, we describe ednaoccupancy, an r package for fitting Bayesian, multiscale occupancy models. These models are appropriate for occupancy surveys that include three nested levels of sampling: primary sample units within a study area, secondary sample units collected from each primary unit and replicates of each secondary sample unit. This design is commonly used in occupancy surveys of environmental DNA (eDNA). ednaoccupancy allows users to specify and fit multiscale occupancy models with or without covariates, to estimate posterior summaries of occurrence and detection probabilities, and to compare different models using Bayesian model-selection criteria. We illustrate these features by analysing two published data sets: eDNA surveys of a fungal pathogen of amphibians and eDNA surveys of an endangered fish species. PMID- 29120092 TI - Restoration of axon conduction and motor deficits by therapeutic treatment with glatiramer acetate. PMID- 29120091 TI - Running-wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post-transcriptional mechanism. AB - Loss of mitochondrial respiratory flux is a hallmark of skeletal muscle aging, contributing to a progressive decline of muscle strength. Endurance exercise alleviates the decrease in respiratory flux, both in humans and in rodents. Here, we dissect the underlying mechanism of mitochondrial flux decline by integrated analysis of the molecular network. Mice were given a lifelong ad libitum low-fat or high-fat sucrose diet and were further divided into sedentary and running wheel groups. At 6, 12, 18 and 24 months, muscle weight, triglyceride content and mitochondrial respiratory flux were analysed. Subsequently, transcriptome was measured by RNA-Seq and proteome by targeted LC-MS/MS analysis with 13 C-labelled standards. In the sedentary groups, mitochondrial respiratory flux declined with age. Voluntary running protected the mitochondrial respiratory flux until 18 months of age. Beyond this time point, all groups converged. Regulation Analysis of flux, proteome and transcriptome showed that the decline of flux was equally regulated at the proteomic and at the metabolic level, while regulation at the transcriptional level was marginal. Proteomic regulation was most prominent at the beginning and at the end of the pathway, namely at the pyruvate dehydrogenase complex and at the synthesis and transport of ATP. Further proteomic regulation was scattered across the entire pathway, revealing an effective multisite regulation. Finally, reactions regulated at the protein level were highly overlapping between the four experimental groups, suggesting a common, post transcriptional mechanism of muscle aging. PMID- 29120093 TI - Imbalanced Osteogenesis and Adipogenesis in Mice Deficient in the Chemokine Cxcl12/Sdf1 in the Bone Mesenchymal Stem/Progenitor Cells. AB - Bone and bone marrow serve as an imperative ecosystem to various types of cells participating in critical body functions. The chemokine Cxcl12, also known as stromal cell-derived factor 1 (Sdf1), is one of the communication factors in the marrow microenvironment that regulates hematopoietic stem/progenitor cell homeostasis. However, the function of Cxcl12 in other bone marrow cells in vivo is yet to be discovered. Here we report a novel function of Cxcl12 in postnatal bone development and homeostasis. Targeted deletion of Cxcl12 in Paired related homeobox 1 (Prx1)-expressing or osterix (Osx)-expressing mesenchymal stem/progenitor cells (MSPCs), but not in mature osteoblasts, resulted in marrow adiposity and reduced trabecular bone content. In vivo lineage tracing analysis revealed biased differentiation of MSPCs toward adipocytes. In contrast, adult stage deletion of Cxcl12 in Osx-expressing cells led to reduced bone content but not adiposity. Targeting the receptor Cxcr4 in the Prx1-expressing cells also resulted in reduced trabecular bone content but not adiposity. Our study reveals a previously unidentified role of the MSPC-secreting Cxcl12 that regulates its osteogenesis and adipogenesis through the cell-autonomous and non-autonomous mechanism, respectively; which could further influence the homeostatic control of the hematopoietic system. (c) 2017 American Society for Bone and Mineral Research. PMID- 29120094 TI - Visitor effect on the behavior of a group of spider monkeys (Ateles geoffroyi) maintained at an island in Lake Catemaco, Veracruz/Mexico. AB - We analyzed the effect of human visitors on the behavior of a group of spider monkeys (Ateles geoffroyi) kept on a small tourist island. Although the spider monkey is a common species in zoos, there are very few specific studies on visitor effects on these monkeys. We conducted behavioral observations on the group of spider monkeys to evaluate the effect of visitors. We also used actimetry devices to measure the variations in the spider monkeys' locomotor activity associated with human presence. With regard to the effect on behavior, we found an increase in self-directed behaviors and a decrease in vocalization, both associated with human presence. Moreover, our results suggest that when people feed monkeys, there is an increase in agonistic behaviors. On the other hand, we found that changes in activity levels in response to human presence vary among individuals. We conclude that changes in spider monkeys' behavior could provide evidence of the negative effect of visitors in our study conditions. Although we discuss the differences in activity levels due to differences in social position, further research is required this topic. Our results can be used to inform management plans for this species in captivity. Improving this relationship between humans and non-human primates through tourism education programs would benefit ecotourism and therefore species conservation programs. PMID- 29120095 TI - Technical Quality of Complete Dentures: Influence on Masticatory Efficiency and Quality of Life. AB - PURPOSE: To evaluate the effect of the technical quality of conventional complete dentures (CD) on masticatory efficiency and quality of life (QoL) of denture wearers during a 1-year follow-up. MATERIALS AND METHODS: A prospective clinical trial with 32 edentulous patients (mean age of 60.2 years) wearing mandibular and maxillary dentures was conducted. All patients were evaluated wearing their preexisting dentures and after 3, 6, and 12 months postinsertion of new dentures. A reproducible method for objective evaluation of the technical quality of CDs was employed. Masticatory efficiency was evaluated by the colorimetric method using beads as artificial testing food. The oral health impact on patient QoL was measured using the OHIP-EDENT (Oral Health Impact Profile in Edentulous Adults) questionnaire. The nonparametric Wilcoxon test was applied to reveal any differences in technical quality between the preexisting and new dentures. The Friedman test was used to detect differences in masticatory efficiency and oral health impact on QoL. Spearman's correlation was applied to reveal correlation between the variables. RESULTS: Comparing preexisting and new dentures, significant improvement was found in technical quality between the dentures (p < 0.001). There was no statistically significant difference in masticatory efficiency. A significant decrease was found in the total OHIP-EDENT scores after denture replacement. A positive correlation was found between technical quality and OHIP in the new denture wearers (p = 0.011). CONCLUSIONS: According to the results of this study, denture quality significantly improved patients' oral health-related QoL; however, insertion of new dentures did not influence masticatory efficiency. PMID- 29120096 TI - The association between oral health status and respiratory pathogen colonization with pneumonia risk in institutionalized adults. AB - OBJECTIVES: This study aimed to assess the oral health and the prevalence of pre existing oral colonization with respiratory pathogens in dependent elderly, and whether these factors influence pneumonia development. MATERIALS AND METHODS: Participants residing in a long-term care facility received bedside oral examinations, and information on their oral health (caries status, calculus index and debris index) was obtained. Samples from the tongue and teeth were collected at baseline and at time of pneumonia development. Sputum was collected at the time of pneumonia diagnosis. Samples were assessed for Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pneumoniae by polymerase chain reaction. RESULTS: This was a 1-year longitudinal study of 60 dependent elderly (mean age: 64.2 +/- 14.1 years). Seventeen patients (28.3%) developed pneumonia. The mean Decayed, Missing and Filled Teeth and Simplified Oral Hygiene Index were 22.8 +/- 9.2 and 4.0 +/- 1.0, respectively. At baseline, 48.3% were orally colonized with >=1 respiratory pathogens. The presence of H. influenzae (P = .002) and P. aeruginosa (P = .049) in the sputum was significantly associated with their colonization on the tongue at baseline. In the bivariate analyses, pneumonia development was associated with naso-gastric feeding tube (P = .0001), H. influenzae (P = .015) and P. aeruginosa (P = .003) tongue colonization at baseline and calculus index (P = .002). Multivariate analyses revealed that calculus index (P = .09) and the presence of tracheostomy (P = .037) were associated with pneumonia. CONCLUSIONS: The calculus amount and tongue colonization with respiratory pathogens are risk factors for pneumonia development. Oral hygiene measures to remove tongue biofilm and calculus may reduce pneumonia development. PMID- 29120098 TI - Functions at the junction - membrane proteins and myoblast fusion. AB - The fusion of myoblasts is an essential step in the formation of multinucleated muscle fibres and the molecular underpinnings of this process are being actively investigated. In this issue, Kim et al. report that the membrane protein Xkr8 plays a role in myotube fusion, adding another class of membrane proteins to the list of potential contributors to myoblast differentiation and fusion. PMID- 29120099 TI - Corrigendum. PMID- 29120101 TI - Inferring within-herd transmission parameters for African swine fever virus using mortality data from outbreaks in the Russian Federation. AB - Mortality data are routinely collected for many livestock and poultry species, and they are often used for epidemiological purposes, including estimating transmission parameters. In this study, we infer transmission rates for African swine fever virus (ASFV), an important transboundary disease of swine, using mortality data collected from nine pig herds in the Russian Federation with confirmed outbreaks of ASFV. Parameters in a stochastic model for the transmission of ASFV within a herd were estimated using approximate Bayesian computation. Estimates for the basic reproduction number varied amongst herds, ranging from 4.4 to 17.3. This was primarily a consequence of differences in transmission rate (range: 0.7-2.2), but also differences in the mean infectious period (range: 4.5-8.3 days). We also found differences amongst herds in the mean latent period (range: 5.8-9.7 days). Furthermore, our results suggest that ASFV could be circulating in a herd for several weeks before a substantial increase in mortality is observed in a herd, limiting the usefulness of mortality data as a means of early detection of an outbreak. However, our results also show that mortality data are a potential source of data from which to infer transmission parameters, at least for diseases which cause high mortality. PMID- 29120103 TI - Values on Paper, in the Head, and in Action: On Max Weber and Value Freedom Today. AB - This article starts out with a summary of Weber's views on value freedom, by emphasizing: (1) that value freedom constitutes a special constellation of values; and (2) that value freedom makes it possible for the social scientist to theorize on the basis of new and more extensive knowledge than if she had simply stated her own values and focused the analysis around these. The latter point emerges most clearly in Weber's instructions for how a social scientist should proceed when carrying out an analysis of her own preferred social policy. After the section on Weber's views on value freedom, an attempt is made to update his views. This is done by arguing that the impact of values (and value freedom) differs, depending on where these can be found: on paper, in the head of the social scientist, or in her actions. "Actions," in the context of value freedom, refer to the research process and especially to the element of theorizing. Value freedom helps to guide the research into new and fruitful directions and to steer it clear of propaganda. PMID- 29120102 TI - Deciphering lipid codes: K-Ras as a paradigm. AB - The cell plasma membrane (PM) is a highly dynamic and heterogeneous lipid environment, driven by complex hydrophobic and electrostatic interactions among the hundreds of types of lipid species. Although the biophysical processes governing lipid lateral segregation in the cell PM have been established in vitro, biological implications of lipid heterogeneity are poorly understood. Of particular interest is how membrane proteins potentially utilize transient spatial clustering of PM lipids to regulate function. This review focuses on a lipid-anchored small GTPase K-Ras as an example to explore how its C-terminal membrane-anchoring domain, consisting of a contiguous hexa-lysine polybasic domain and an adjacent farnesyl anchor, possesses a complex coding mechanism for highly selective lipid sorting on the PM. How this lipid specificity modulates K Ras signal transmission will also be discussed. PMID- 29120104 TI - Ethnicity and Effectively Maintained Inequality in BC Universities. AB - As Canadian postsecondary systems have expanded they have become more institutionally differentiated. In British Columbia, distinctions are made between research-intensive universities (RIUs) and teaching-intensive universities with respect to resources, programming, and perceived prestige value. We employ an effectively maintained inequality framework to examine the role played by ethnicity in the competition for admission to RIUs. Our findings indicate that, together with socioeconomic status and gender, ethnicity is significantly related to RIU attendance rates. Ethnic group differences were particularly marked-Chinese and Korean speakers being most likely and Tagalog speakers least likely to attend an RIU. High school grade point averages and English language proficiency scores moderated only some of these differences, raising questions about the efficacy of competitive admissions policies based solely on academic merit. PMID- 29120105 TI - An Essay on the Intrinsic Relationship between Social Facts and Moral Questions. AB - Value neutrality and science are often equated. This paper argues that the work of doing science and engaging in scientific practices with meaningful objects depend on social facts which have moral prerequisites and are not value neutral. PMID- 29120106 TI - Balancing the Scales: Negotiating Father's Parental Leave Use. AB - Studying couples who shared parental leave presents the opportunity to explore decision-making processes that may challenge conventional care arrangement typical of early parenthood. Interviews with 33 Canadian heterosexual couples indicate gendered sticking points in the division of official leave time. Whether fathers took leave because of their personal desires or material circumstances, this study finds that men and women did not enter negotiations on a level playing field. Strong cultural support for mothers'-but not fathers'-time with baby tipped the scales toward maternal care giving, even when couples wanted to share parental leave. Nevertheless, financial considerations such as a man's topped-up pay or woman's career could lessen the weight of mothers' moral entitlement to the leave time by presenting couples with an alternative logic on which to base their decision making. PMID- 29120107 TI - Foreword. PMID- 29120108 TI - Values within Reason. AB - The paper questions the assumptions that facts and values are always radically different, that objectivity and values do not mix, and that values are subjective and a-rational and should be excluded from social science. It argues (1) that such assumptions are underpinned by unnoticed slippages between different meanings of objectivity and by misunderstandings of the nature of values and normativity; (2) that evaluative judgments-often in the form of "thick ethical concepts" in which description and evaluation are fused-are necessary for objective description in social science; and (3) that framing the values issue in terms of the relations between is and ought misrepresents the place of normativity in social science and in everyday life. PMID- 29120109 TI - From Sinks to Webs: Critical Social Science after the Fact-Value Distinction. AB - The fact-value distinction is leaky. The problem is not just that values can color facts. The reverse is also true: facts are also entangled with values. Nor is that the end of the matter. The concepts of fact and value are not epistemologically or ethically neutral either. It is time to abandon the quest for axiological neutrality in favor of systematic attention to the complex relationship between the descriptive and the normative. Instead of attempting to be neutral, social scientists should strive to combine engagement with open mindedness. PMID- 29120110 TI - Observing Facts and Values: A Brief Theory and History. AB - Not acknowledging the history and metaphysics of the fact/value distinction has led to confusion about the difference between the normative and the cognitive, and disputes on whether there are ways to move from one side, facts, to the other, values. One solution is to recognize values as more "objective" than facts, and thus blur the common way of drawing this distinction. The origin of the distinction between facts and values appears in the space between them, when and where it is uncertain whether an observation becomes fact or value. Once values turn into subjective beliefs, the entire distinction collapses, and modernity begins to end. PMID- 29120111 TI - How Terrorism Affects Attitudes toward Democracy: Tunisia in 2015. AB - Tunisia is the only country that emerged from the Arab Spring as a democracy. However, Tunisian democracy is threatened by political divisions, economic problems, and the threat of terrorist attacks. We shed light on Tunisia's democratic prospects by examining (1) the degree to which major terrorist attacks in 2015 influenced Tunisian public opinion on democracy and (2) the extent to which preference for a democratic system affected opinions on the prospects for democracy in Tunisia. We use data from three waves of a nationwide survey conducted just before and just after Tunisia's first major terrorist attack, and just after the country's second major terrorist attack. We demonstrate that after the attacks the Tunisian public became less favourable toward democracy and less optimistic that Tunisia would soon be ready for it. Such scepticism was widespread, affecting people who preferred democracy as much as those who did not. We conclude that the prospects for Tunisian democracy are more precarious than is sometimes assumed. PMID- 29120112 TI - Sociology as Moral Philosophy (and Vice Versa). AB - In this article, I want to make an attempt to reconnect sociology to moral philosophy and moral philosophy to sociology. The thesis I want to defend is that sociology continues by other means the venerable tradition of practical and moral philosophy. Like its forebears, it stands and falls with a defense of "practical wisdom" (Aristotle) and "practical reason" (Kant). The development of a moral sociology presupposes, however, that one recognizes and rejects Max Weber's theory of axiological neutrality as an extremist position and that one carefully articulates prescriptive and descriptive, internal and external, as well as observer and actor positions. PMID- 29120113 TI - Hygiene practices in removable prosthodontics: A systematic review. AB - OBJECTIVE: To systematically review the recent scientific evidence about the hygiene practices of removable prostheses relative to the effectiveness, colour and dimensional stability. This review aimed also to identify patients' attitudes and habits towards denture hygiene. METHODS: Three electronic databases (MEDLINE/PubMed, Scopus and Cochrane Library) were screened, in English language, between January 1995 and December 2016. A supplementary hand search in the reference list of the identified articles was also performed. Controlled clinical trials (CCTs) involving patients with no clinical signs of denture stomatitis along with a comprehensive aim to assess the effectiveness of hygiene interventions and their impact on prosthesis colour and dimensional stability were eligible for inclusion. RESULTS: Following a thorough screening of titles/abstracts/full texts and consideration of the defined inclusion criteria, 21 CCTs examined the effectiveness of the hygiene approaches, 3 evaluated the colour stability of dentures subjected to hygiene practices, 2 examined the dimensional stability of dentures following microwave disinfection and 30 studies registered patients' attitudes and habits towards denture hygiene. CONCLUSIONS: Combined application of different hygiene interventions, including brushing or ultrasound vibration in conjunction with chemical agents, leads to more effective outcomes (reduction in denture biofilm percentage and/or number of microorganisms' colony-forming units). The dimensional stability seems to be unaltered, but the number of clinical trials was limited. Critical concentrations of cleansing solutions along with the duration of their implementation influence the serviceability of dentures regarding colour stability. Brushing represents the most commonly applied hygiene practice, while denture wearers' attitudes are not complied with the recommended guidelines considering the reported frequency of hygiene practices and the continuous denture wear. PMID- 29120114 TI - Molecular prevalence of Chlamydia and Chlamydia-like bacteria in Tunisian domestic ruminant farms and their influencing risk factors. AB - Chlamydia and Chlamydia-like bacteria are well known to infect several organisms and may cause a wide range of diseases, particularly in ruminants. To gain insight into the prevalence and diversity of these intracellular bacteria, we applied a pan-Chlamydiales real-time PCR to 1,134 veterinary samples taken from 130 Tunisian ruminant herds. The true adjusted animal population-level prevalence was 12.9% in cattle, against 8.7% in sheep. In addition, the true adjusted herd level prevalence of Chlamydiae was 80% in cattle and 25.5% in sheep. Chlamydiales from three family-level lineages were detected indicating a high biodiversity of Chlamydiales in ruminant herds. Our results showed that Parachlamydia acanthamoebae could be responsible for bovine and ovine chlamydiosis in central eastern Tunisia. Multivariable logistic regression analysis at the animal population level indicated that strata and digestive disorders variables were the important risk factors of bovine and ovine chlamydiosis. However, origin and age variables were found to be associated with bovine and ovine chlamydiosis, respectively. At the herd level, risk factors for Chlamydia positivity were as follows: abortion and herd size for cattle against breeding system, cleaning frequency, quarantine, use of disinfectant and floor type for sheep. Paying attention to these risk factors will help improvement of control programs against this harmful zoonotic disease. PMID- 29120115 TI - Quantitative determination of acidic hydrolysis products of Chemical Weapons Convention related chemicals from aqueous and soil samples using ion-pair solid phase extraction and in situ butylation. AB - Chemical warfare agents such as organophosphorus nerve agents, mustard agents, and psychotomimetic agent like 3-quinuclidinylbenzilate degrade in the environment and form acidic degradation products, the analysis of which is difficult under normal analytical conditions. In the present work, a simultaneous extraction and derivatization method in which the analytes are butylated followed by gas chromatography and mass spectrometric identification of the analytes from aqueous and soil samples was carried out. The extraction was carried out using ion-pair solid-phase extraction with tetrabutylammonium hydroxide followed by gas chromatography with mass spectrometry in the electron ionization mode. Various parameters such as optimum concentration of the ion-pair reagent, pH of the sample, extraction solvent, and type of ion-pair reagent were optimized. The method was validated for various parameters such as linearity, accuracy, precision, and limit of detection and quantification. The method was observed to be linear from 1 to 1000 ng/mL range in selected ion monitoring mode. The extraction recoveries were in the range of 85-110% from the matrixes with the limit of quantification for alkyl phosphonic acids at 1 ng/mL, thiodiglycolic acid at 20 ng/mL, and benzilic acid at 50 ng/mL with intra- and interday precisions below 15%. The developed method was applied for the samples prepared in the scenario of challenging inspection. PMID- 29120116 TI - Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass. PMID- 29120117 TI - Is Apolipoprotein E epsilon2 Associated with Delayed Onset of Non-Lesional Temporal Lobe Epilepsy? AB - The aim of the study was to evaluate the possible association between Apo E polymorphisms and age at seizure onset in patients with non-lesional temporal lobe epilepsy. Eighty patients with non-lesional temporal lobe epilepsy with or without bilateral tonic-clonic propagation were analyzed. Age at seizure onset was defined as age at the first unequivocal seizure (excluding febrile convulsions). ApoE alleles were determined by a procedure where genome DNA was amplified by chain reaction along with polymerase, using the LightCycler kit (Roche) for ApoE mutations on codons 112 and 158. There was a statistically significant difference between the groups of patients with ApoE epsilon2/3 and epsilon3/4 genotypes (p=0.03), but not between patients with ApoE, epsilon2/3 and epsilon3/3, and those with ApoE epsilon3/4 and epsilon3/3. In conclusion, the results of our study suggested positive association of a specific ApoE genotype and onset of non-lesional temporal lobe epilepsy. PMID- 29120118 TI - The Quantity and Quality of Life and the Evolution of World Inequality. AB - GDP per capita is usually used to proxy for the quality of life of individuals living in different countries. Welfare is also affected by quantity of life, however, as represented by longevity. This paper incorporates longevity into an overall assessment of the evolution of cross-country inequality and shows that it is quantitatively important. The absence of reduction in cross-country inequality up to the 1990s documented in previous work is in stark contrast to the reduction in inequality after incorporating gains in longevity. Throughout the post-World War II period, health contributed to reduce significantly welfare inequality across countries. This paper derives valuation formulas for infra-marginal changes in longevity and computes a "full" growth rate thatincorporates the gains in health experienced by 96 countries for the period between 1960 and 2000. Incorporating longevity gains changes traditional results; countries starting with lower income tended to grow faster than countries starting with higher income. We estimate an average yearly growth in "full income" of 4.1 percent for the poorest 50 percent of countries in 1960, of which 1.7 percentage points are due to health, as opposed to a growth of 2.6 percent for the richest 50 percent of countries, of which only 0.4 percentage points are due to health. Additionally, we decompose changes in life expectancy into changes attributable to 13 broad groups of causes of death and three age groups. We show that mortality from infectious, respiratory, and digestive diseases, congenital, perinatal, and "ill-defined" conditions, mostly concentrated before age 20 and between ages 20 and 50, is responsible for most of the reduction in life expectancy inequality. At the same time, the recent effect of AIDS, together with reductions in mortality after age 50--due to nervous system, senses organs, heart and circulatory diseases--contributed to increase health inequality across countries. PMID- 29120119 TI - Cyclin D1, Ret and P27 Expression in Papillary Thyroid Microcarcinoma AB - Th e aim of the study was to determine the influence of RET, p27 and cyclin D1on regional lymph node metastases in papillary microcarcinoma. The analysis included 70 patientswith papillary thyroid microcarcinoma that underwent surgery at Split University Hospital Centerbetween 1999 and 2001. Immunohistochemistry was performed on formalin-fixed, paraffin-embeddedtissue by the RET, p27 and cyclin D1 antibodies. Quantification was based on the intensity anddistribution of nuclear staining, dividing tumors into those that showed expression (expressors) andthose that showed no expression (non-expressors). Univariate analysis using chi2-test and Fisher exacttest was performed with the level of statistical significance set at p<0.05. There was no statisticallysignificant difference in the incidence of metastases according to the expression or non-expression ofRET mutation (chi2-test: p=0.459; Fisher exact test: p=0.672). Among 25 cases with cyclin D1 expression,6 had metastases, whereas only 2 of 45 cases with no cyclin D expression had metastases (chi2-test:p=0.014; Fisher exact test: p=0.021), indicating that the expression of cyclin D1 is not crucial for thedevelopment of metastases in lymph nodes. In contrast, analysis of p27 expression showed it to besignificantly associated with lymph node metastasis because 3 of 45 patients with p27 expression hadmetastases, indicating a statistically significant correlation between p27 expression and lymph nodemetastases (chi2-test: p=0.093; Fisher exact test: p=0.124). This study confirmed the importance of theevaluation of RET, p27 and cyclin D1 expression and demonstrated the validity of their application inthe assessment of microcarcinoma behavior. PMID- 29120120 TI - Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass. PMID- 29120121 TI - Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass. PMID- 29120122 TI - Vanishing Children: From High Unemployment to Low Fertility in Developed Countries. PMID- 29120123 TI - The Value of Multidetector Computed Tomography of Orbits in Globe Protrusion in Comparison to Hertel Exophthalmometry AB - The use of multidetector computed tomography (MDCT) is an integral part ofcontemporary diagnostics of Graves' orbitopathy. The aim of this study was to assess proptosis measurementby MDCT and to compare it to the current standard, Hertel exophthalmometry. A cross-sectionalstudy was conducted at the Clinical Centre of Serbia and included 91 patients (19 male and72 female) with verified Graves' orbitopathy. Globe protrusion measured by MDCT (globe protrusion,GPR) was correlated to Hertel measured protrusion (HR). There was no constant or any systematicbias between the two methods. GPR significantly correlated with the best-corrected visual acuity,while HR did not. Age, body mass index and duration of the disease did not influence proptosismeasurement by either method. Proptosis was significantly larger in males. According to our results,GPR compared to HR provides better assessment of the protrusion in Graves' disease. GPR measurementis simple and should always be part of the radiological assessment of orbits in Graves' disease. PMID- 29120124 TI - Levosimendan in Cardiac Surgery. PMID- 29120125 TI - Risk Factors Associated with Black Tooth Stain AB - The aim of the study was to show whether there is any influence of food, drink ordrug intake on the formation of tooth discoloration. A total of 500 patients aged 15-25 years wereexamined to take part in the study. Of these, 60 patients were selected and divided into two groups of30 patients each. Group 1 included patients with black pigmentation on vestibular/oral tooth surfaces.Group 2 included patients without discoloration (control). Data were recorded in a questionnaire.Atomic absorption spectrometry was used to determine elements in discoloration samples. The CariesRisk Test (CRT) buffer was used to assess buffer capacity of saliva, while CRT bacteria were used todetermine the presence of Streptococcus mutans and Lactobacillus spp. Statistically significant between groupdifferences were found for the intake of collard greens and beets (p<0.05), but not for othervegetables. As for drink consumption, patients with pigmentation reported less wine intake (p<0.05)than those without pigmentation. There was no difference according to drug intake between patientswith and without pigmentation. Patients with pigmentation were older, smoked and had lower salivapH with lower presence of Streptococcus mutans than those without pigmentation (p<0.05). In toothdiscoloration samples, there were traces of calcium, magnesium, iron, copper and zinc. The appearanceof tooth discoloration is influenced by many factors, among which diet and saliva seem to be veryimportant. Our study showed that patients with black pigmentation used to take more beets, whilepatients without pigmentation were taking more collard greens and red wine. PMID- 29120126 TI - Changes in Nursing Students' Attitudes Towards Nursing During Undergraduate Study AB - The aim of this study was to determine the attitudes of nursing students towardsnursing, and changes in their attitudes during the study. A quantitative study with pre-post survey wasconducted among nursing students enrolled in first study year in the academic year 2012/2013(N=115) and third study year in the academic year 2014/2015 (N=106). Students voluntarily andanonymously completed a questionnaire consisting of demographic information and the NursingImage Questionnaire, which includes 30 items that assess how an individual looks at the roles andtasks, values, social stereotypes of nursing, professionalism and performance of nurses. The resultsindicated that students had positive attitude towards nursing at the beginning and during the study.During the study, there was a positive change in attitudes in the majority of items of the questionnaire,whereas at the end of the study lower attitude was expressed in only four items. The study conductedamong nursing students indicated that students' attitudes changed during the study, influenced by theacquisition of knowledge and skills. During the study, students acquire a more realistic perception ofnursing, and adoption of professional values emerges. PMID- 29120127 TI - Levosimendan in Cardiac Surgery. PMID- 29120128 TI - Levosimendan in Cardiac Surgery. PMID- 29120129 TI - The Role of Electromyographic Blink Reflex in the Evaluation of Headache Incidence AB - Migraine and tension type headache are the most common disabling primaryheadache disorders. Epidemiological studies have documented their high prevalence and high socioeconomicand personal impacts. According to recent data, migraine ranks as the third most prevalentdisorder and seventh-highest specific cause of disability worldwide. Tension-type headache has lifetimeprevalence in the general population ranging between 30% and 78% in different studies. Accordingto the International Classification of Headache Disorders, 3rd edition, there also are many otherheadaches but their incidence in general population is lower than the previously mentioned headaches.Trigeminal nerve and upper cervical segments (C1 C3) are included in pain control of the head regionand often evaluated in headache studies in order to improve differential diagnosis and headache treatment.In our study, we evaluated the potential role of electromyographic (EMG) blink reflex in establishingdiagnosis of headache and evaluation of trigeminal nerve dysfunction as the possible underlyingpathomorphological headache mechanism. Our study included 60 patients with different types ofprimary headaches and 30 control subjects. Statistical analysis was performed by use of chi2-test andstatistical significance was set at p<0.001. Study results showed that patients with trigeminal dysfunctionin EMG blink reflex had a 5.6-fold higher risk of developing headache in comparison to subjectswith normal EMG blink reflex finding. PMID- 29120130 TI - Special Report: E-Waste Management in the United States and Public Health Implications. AB - Electronic waste (e-waste) generation is increasing worldwide, and its management becomes a significant challenge because of the many toxicants present in electronic devices. The U.S. is a major producer of e-waste, although its management practice and policy regulation are not sufficient to meet the challenge. We reviewed e-waste generation, current management practices and trends, policy challenges, potential health impact, and toxicant exposure prevention in the U.S. A large amount of toxic metals, flame retardants, and other persistent organic pollutants exist in e-waste or can be released from the disposal of e-waste (e.g., landfill, incineration, recycling). Landfill is still a major method used to dispose of obsolete electronic devices, and only about half of the states have initiated a landfill ban for e-waste. Recycling of e waste is an increasing trend in the past few years. There is potential, however, for workers to be exposed to a mixture of toxicants in e-waste and these exposures should be curtailed. Perspectives and recommendations are provided regarding managing e-waste in the U.S. to protect public health, including enacting federal legislation, discontinuing landfill disposal, protecting workers in recycling facilities from toxicant exposure, reducing toxicant release into the environment, and raising awareness of this growing environmental health issue among the public. PMID- 29120131 TI - In Vitro Effects of Selenium on Human Glioblastoma Multiforme Cell Lines: A Preliminary Study AB - Glioblastoma multiforme (GBM) is caused by the central nervous system derivedglial cells, and represents the most common (50%-60%) form of primary brain tumors. The aim of thisstudy was to investigate the in vitro effects of selenium on human GBM cells. In the present study,GMS-10 and DBTRG-05MG human GBM cell lines were used as a model to examine seleniumentering the cell, cell proliferation, cytotoxicity, DNA fragmentation and Ki-67 protein expression inselenomethionine treated and non-treated groups. Seleno-L-methionine (SeMet) as the organicsource of selenium exerted effects on cell proliferation and cytotoxicity, as assessed with WST-1 andlactate dehydrogenase (LDH) tests, respectively. Apoptosis was assessed by DNA fragmentation withan enzyme-linked immunosorbent assay. Ki-67 protein expression was determined by Western blotting,while selenium measurements were performed in the supernatants and lysates by using GraphiteFurnace Atomic Absorption Spectrometry. This is the first study to examine the effects of SeMet oncell proliferation and death in GMS 10 and DBTRG-05MG cells. Both GBM cell lines respondedto SeMet in a dose- and time-dependent manner. WST-1 test showed that low-dose SeMet treatment(50 and 100 MUM) increased cell proliferation. Analysis of intracellular SeMet levels by usingAAS showed results consistent with viability and cytotoxicity tests. SeMet treatment for 72h causedincreased DNA fragmentation in both cell lines. In conclusion, our results suggest that SeMet inducescell death at high doses, while increasing cell proliferation at low doses. In the view of the dataobtained in this investigation, further studies focusing on the possibility of using SeMet against differenttypes of GBM and in combination with prospect synergic compounds are considered to beworthwhile. PMID- 29120132 TI - Midostaurin in FLT3-Mutated Acute Myeloid Leukemia. PMID- 29120133 TI - Midostaurin in FLT3-Mutated Acute Myeloid Leukemia. PMID- 29120135 TI - Infertility Insurance Mandates and Fertility. PMID- 29120134 TI - Bone Mineral Density in Relation to Metabolic Syndrome Components in Postmenopausal Women With Diabetes Mellitus Type 2 AB - Diabetes mellitus type 2 is associated with greater bone mineral density (BMD)due to obesity, although rapid bone loss observed over time could be explained by elevated chronicinflammation. The objective of this study was to investigate the relationship between central adiposityand hyperinsulinemia, as well as inflammation markers with vertebral and femoral BMD and boneturnover markers in postmenopausal women with type 2 diabetes. Femoral and vertebral BMD,osteocalcin, pyrilinks D, beta-CrossLaps (B-CTx), insulin, C-reactive protein (CRP), fibrinogen andplasminogen activator inhibitor-1 (PAI-1) were measured in 114 postmenopausal female patientswith diabetes type 2. The patients of similar age, HbA1c levels and diabetes duration were divided into2 groups based on their body mass index (BMI) values: lower or equal to 27 kg/m(2) (31 patients) andhigher than 27 kg/m(2) (83 patients). Lower levels of osteocalcin (p=0.001), B-CTx (p=0.000007) andpyrilinks D (p=0.0365), and higher femoral BMD (p=0.00006), insulin level (p=0.0002), PAI-1(p=0.00000) and CRP (p=0.002) were found in the overweight group. There were no signifi cantdifferences in vertebral BMD and fibrinogen. Osteocalcin and B-CTx showed inverse correlation, andfemoral BMD positive correlation with waist circumference, insulin level and PAI-1. This suggeststhat abdominal obesity and hyperinsulinemia as components of the metabolic syndrome could increasefemoral BMD by lowering bone rate. In addition, the only inflammation marker linked withfemoral BMD was PAI-1, which is associated with increased mineralization of cortical bone in mouse. PMID- 29120137 TI - A Review of Promising Multicomponent Environmental Child Obesity Prevention Intervention Strategies by the Children's Healthy Living Program. AB - Childhood obesity has increased rapidly over the last three decades in the U.S. Individual-level interventions targeting healthy eating and physical activity have not significantly impacted clinical measures of obesity in children. Focusing "upstream" on physical, social, cultural, political, and economic environments may be more effective. The purpose of this qualitative review is to analyze published environmental interventions that effectively prevented or reduced obesity in children ages 2-10 years by working within their family, school, and/or community environment to increase physical activity, reduce sedentary behaviors, or improve healthy diet. Through an electronic database search, 590 original articles were identified and 33 were read in full. Using Brennan and co-authors' (2011) rating system, 18 were rated as effective intervention studies. This analysis showed that interventions targeting multiple environments (e.g., family, school, and community) show promise in reducing childhood obesity. Further research is needed to test interventions targeting multiple environments in different communities and populations. PMID- 29120136 TI - Postoperative Atrial Fibrillation Prophylaxis and Lung Resection - Our Experience with 608 Consecutive Patients AB - Postoperative atrial fibrillation is a common complication after lung resection. Itis burdened by increased mortality and morbidity, prolonged hospitalization, and higher resourceutilization in thoracic surgery patients. Therefore, some kind of pharmacological prophylaxis is recommended.In our patients, diltiazem, a calcium antagonist, is administered. We collected data on all 608patients having undergone lung resection (no less than lobectomy) between November 2012 and May2015. This period included patients having received diltiazem during their postoperative stay in ourIntensive Care Unit and surgical ward, and those that did not receive it. Patients having had atrialfibrillation before the surgery and patients with cardiac pacemaker were excluded from the trial. Otherpatients were divided into three groups: patients with some kind of antiarrhythmic therapy before andcontinued after the surgery; patients with diltiazem prophylaxis; and patients without any antiarrhythmicprophylaxis. The data collected were statistically analyzed. We found no statisticallysignificant difference in the incidence of postoperative atrial fibrillation among the groups (p<0.05). PMID- 29120138 TI - High Tumor Stroma Proportion is a Worse Prognostic Factor in Colorectal Cancer AB - High stroma proportion appears to be a very important prognostic factor inesophageal and breast cancer. Previous researches have shown that it might have a similar effect oncolorectal cancer. The aim of this study was to determine whether tumor stroma proportion influencedpatient survival. This retrospective study included 236 patients with colorectal cancer having undergonesurgery in 2006 and 2007 at Osijek University Hospital Center. Location with the higheststroma proportion at the site of deepest tumor invasion was determined. Patients were divided into thegroups with high stroma proportion (>50%) and low stroma proportion (<=50%). Stroma proportionshowed a statistically significant correlation with tumor stage. Kaplan-Meier survival curves yielded astatistically significant difference in patient overall survival (Cox ph model p=0.016) and progression-freesurvival (Cox ph model, p=0.0188) according to stroma proportion. Study results showed a statisticallysignificantly shorter overall survival and progression-free survival in patients with high stromaproportion. PMID- 29120139 TI - Coronary artery calcium and arterial ageing: further evidence to critically reappraise vitamin D for heart? PMID- 29120140 TI - Genetic aberration in solitary fibrous tumors and its clinical relevance. PMID- 29120141 TI - Acute Respiratory Distress Syndrome. PMID- 29120142 TI - Acute Respiratory Distress Syndrome. PMID- 29120143 TI - Restless Legs Syndrome in Multiple Sclerosis Patients - Patient Experience at Lipik Special Hospital for Medical Rehabilitation AB - The study included 60 patients with multiple sclerosis (MS) hospitalized atour institution from September 1 to December 31, 2014. The aim of the study was to assess theprevalence of restless legs syndrome (RLS) in MS patients and RLS relationship with patient age,sex, degree of disability, form of MS, time elapsed from MS diagnosis and use of antidepressants. Thediagnosis of RLS was made according to the criteria set by the International Restless Legs SyndromeStudy Group. Of the 60 patients, 24 (40%) met the criteria for the existence of RLS. In the group ofpatients with RLS, there was a significantly higher proportion of women and those that were takingantidepressants. There were no statistically significant between-group differences according to age,duration of illness, degree of disability and clinical course of MS. In the study, 37.5% of patients thatmet the criteria for RLS diagnosis had not informed the neurologists about their difficulties. Thehigh prevalence of RLS and the fact that a large proportion of patients did not inform the neurologistsabout their difficulties related to RLS point to the need of an active approach to diagnosis andtreatment. PMID- 29120144 TI - Charity Care, Risk Pooling, and the Decline in Private Health Insurance. PMID- 29120145 TI - Differences in Health-Promoting Lifestyle Profile Among Croatian Medical Students According to Gender and Year of Study AB - Increasing awareness of healthy lifestyle is important during the period of adolescencebecause habits are difficult to modify in adulthood. The aim of the study was to examine genderdifferences in health-promoting lifestyle among medical students and to analyze changes between thefirst and second year of the study. This cross sectional study was conducted on a sample of 1186 students(36% male). Data were collected by self-administered anonymous questionnaire, the Health-Promoting Lifestyle Profile [HPLP II] (Adult Version), and analyzed by descriptive statistics andnonparametric tests. The 941 HPLP II questionnaires were collected and analyzed (79% responserate). Both genders showed a medium level HPLP II total score (male M=2.68; IQR=2.42-2.92 vs.female M=2.65; IQR=2.46 2.90), without significant gender difference. A significantly higher scorewas observed in the subscales on health responsibility (p=0.027) and interpersonal relations (p<0.001)among female compared to male students, and a significantly higher score in the subscales on physicalactivity (p<0.001) and stress management (p=0.025) among male compared to female students. Consideringdifferences in the health-promoting lifestyle between study years, a significantly higher scorewas recorded among second-year students in the HPLP II total score (p=0.004) and the subscales onphysical activity (p=0.007), stress management (p=0.006) and spiritual growth (p=0.029). In conclusion,study results implied the need of organized health care and physical activity programs for universitystudents based on specific requirements and needs. PMID- 29120146 TI - Soil Lead Testing at a High Spatial Resolution in an Urban Community Garden: A Case Study in Relic Lead in Terre Haute, Indiana. AB - Industrial emissions, deteriorating or improperly removed lead paint, and the use of lead additives in fuel have left a substantial burden of heavy metals, such as lead, in urban soils. Much of this lead remains near the surface where it has the potential to impact human health. Exposure to lead, especially in children, can have lasting impacts on neurological development and academic achievement. Urban gardening, in particular, is an activity that could result in increased exposure to soil lead for many unsuspecting gardeners. During the summer of 2012, more than 1,061 surface soil samples were collected from an approximately 1.25 acre urban community garden in Terre Haute, Indiana. Samples were collected to evaluate the spatial distribution of lead across the community garden on the plot level. The results highlight the variability that can be seen within small areas of a former residential property, for example lead concentrations that are low (<200 parts per million [ppm]) within the same 10 x 10 foot garden plot as concentrations that are considered high (>600 ppm). Based on the results of this work, several areas of concern were identified and the community garden was reconfigured to reduce potential lead exposure to gardeners and the local community. PMID- 29120147 TI - The Association Between Retinol-Binding Protein 4 and Cardiovascular Risk Score is Mediated by Waist Circumference in Overweight/Obese Adolescent Girls AB - Retinol-binding protein 4 (RBP4) is an emerging risk factor for atheroscleroticdisease in adults. However, to our knowledge, there are no studies examining the relationship betweenRBP4 and cardiovascular risk in young population. Therefore, we aimed to estimate this potentialrelationship in overweight/obese adolescent girls. Seventy overweight/obese adolescent girls, meanage 17.6+/-1.20 years, were included. Anthropometric and biochemical parameters were measured.Cardiovascular risk score (CVRS) was calculated by adding points for each risk factor (e.g., sex,high-density lipoprotein cholesterol (HDL-c), non-HDL-c, smoking, blood pressure and fastingglycemia). According to the risk status, we divided adolescent girls into low, medium and high riskgroups (-2<= CVRS <=1, 2<= CVRS <=4 and CVRS >=5, respectively). We found significantly higher RBP4in the high risk group as compared with low risk group (p<0.001). However, multiple linear regressionanalysis showed waist circumference (beta=0.257, p=0.031) to be the only independent predictor ofhigher cardiovascular risk (adjusted R(2)=0.342, p<0.001). In conclusion, RBP4 may be associated withhigher cardiovascular risk in overweight/obese adolescent girls, but this association is mediated byabdominal obesity. PMID- 29120148 TI - The Consequences of the Growth of Health Insurance Premiums. PMID- 29120149 TI - Using Multiple Antibiotic Resistance Profiles of Coliforms as a Tool to Investigate Combined Sewer Overflow Contamination. AB - Studies have shown that fecal contamination can be determined by conducting multiple antibiotic resistance (MAR) analyses. The hypothesis is if bacteria exhibit resistance, they are likely to be derived from organisms exposed to antimicrobial agents. Therefore, this project seeks to apply MAR analysis to nonpoint source (NPS) and combined sewer overflow (CSO) areas along the Anacostia River in Washington, DC. Presumptive E. coli was isolated from NPS and CSO samples and tested with eight different antimicrobial agents to assess MAR indices. Isolates from CSO sources showed significantly greater resistance (p < .05) and higher MAR indices, with an average MAR index of 0.36 for CSO samples and 0.07 for NPS samples. It was also revealed that 96.9% of CSO isolates exhibited resistance, versus only 43.8% of NPS isolates. Our study on the Anacostia River using this approach clearly shows fecal coliforms are associated with CSO overflows, indicating that pollution-derived coliform levels are strongly linked to antimicrobial resistance. The implementation of this method as an index for water quality in the remediation of the Anacostia River has the ability to serve as a model and monitoring tool for the rehabilitation of urban watersheds. PMID- 29120150 TI - Incidence, Etiology and Outcome of Ventilator-Associated Pneumonia in Patients with Percutaneous Tracheotomy AB - Although the incidence of ventilator-associated pneumonia (VAP) is very high,there are still many uncertainties about clinical course of VAP among tracheotomized patients. Thegoal of the present study was to determine the impact of tracheotomy on VAP incidence and etiology,as well as outcome of VAP patients with tracheotomy. The study was conducted in a 15-bed Surgicaland Neurosurgical Intensive Care Unit (ICU), Sestre milosrdnice University Hospital Center inZagreb, Croatia. The study included all patients undergoing only percutaneous tracheotomy duringthe study period. According to our data, the incidence of VAP among percutaneous tracheotomizedpatients was 42%, not considering the time between tracheotomy and VAP onset. However, when onlypatients developing VAP after tracheotomy were taken into account, the incidence of VAP amongtracheotomized patients dropped to 8% only. The most commonly isolated bacterium was Staphylococcusaureus, accounting for 17 (37%) isolates, followed by Haemophilus influenzae, accounting foranother 10 (22%) isolates. The development of VAP among percutaneously tracheotomized patientswas associated with longer total ICU stay (regardless of whether VAP developed before or aftertracheotomy), while total duration of mechanical ventilation and mortality rate remained unaffected. PMID- 29120151 TI - Effects of Insurance Coverage on Use of Care and Health Outcomes for Nonpoor Young Women. PMID- 29120153 TI - Updated Drinking Water Advisory Communication Toolkit. PMID- 29120152 TI - First Aid Management in Emergency Care of Dental Injuries - Knowledge among Teachers in Rijeka, Croatia AB - The aim of the present cross-sectional study was to investigate the knowledge andattitude regarding emergency treatment of dental trauma among elementary school teachers in thecity of Rijeka, Croatia. A total of 144 teachers answered a four-part questionnaire which comprisedquestions regarding demographic data, role and responsibility at the working place, knowledge aboutdental trauma, and motivation for further education on the topic. Nearly half of the participants(47.2%) reported having seen at least one dental trauma in their professional careers. They chose tocontact the child's parent first (54.1%) and only 11.1% chose to contact a dentist instead. The majorityof teachers (81.9%) were not aware of the meaning of the term avulsio dentis. As to treatment ofavulsed tooth, 17.3% of teachers knew the appropriate management, while 14% of them would noteven touch it. With regard to transport of avulsed tooth or fractured tooth fragments, only 2%responded correctly. The majority of the responders (87.5%) had never been educated about dentaltrauma, but were willing to be informed through lectures (53.4%), basic life support courses (15.2%)and brochures (9.7%). Planning teachers' education through advanced training on the topic issuggested to be part of teachers' lifetime education. PMID- 29120155 TI - Sharing Is Caring: Nurturing the Tracking Network Through Multilevel Partnerships. PMID- 29120154 TI - Predisposing Factors Responsible for the Occurrence of Bacterial Purulent Meningoencephalitis AB - Bacterial purulent meningoencephalitis (BPME) is a life-threatening infectiousdisease caused by various pyogenic bacteria. The disease is defined as the inflammatory process ofleptomeninges (visceral layer, pia mater and arachnoid membrane) and brain parenchyma with exudatesin the subarachnoid space and surrounding brain structures. The aim of the study was to definethe predisposing factors responsible for the occurrence of BPME, as well as the possible correlationbetween the presence of predisposing factors and patient demographic characteristics, etiology andoutcome of the disease. This retrospective prospective study included 90 patients with BPME confirmed by clinical, neuroradiological and laboratory findings. Multivariate logistic regression modelswere fitted to analyze the impact of the predisposing factors on the disease outcomes. Predisposingfactors that were related to BPME were found in 61% of patients. Cranial trauma as the leading factorwas recorded in 23.3% of patients, followed by previous neurological disease in 14.4% of patients,while 13 patients were exposed to previous chemotherapy or long-term corticosteroid therapy. Cardiovasculardiseases were reported in 12.2% and diabetes in 7.8% of patients. The existence of cardiovasculardiseases significantly influenced unfavorable outcome of the disease, i.e. "deceased" in comparisonto "cured" (OR=8.418; 95% CI=1.007-76.270), independently of age and gender. None of theexamined predisposing factors was significantly related to the "recovered with sequels" outcome ascompared with "cured" outcome. Older age and presence of cardiovascular disease as a predisposingfactor significantly increased the odds of the BPME unfavorable outcome "deceased" as compared to"cured" outcome. PMID- 29120156 TI - Diabetic Macular Edema: Traditional and Novel Treatment AB - Diabetes is one of the leading public health problems worldwide. Diabetic macularedema (DME) is the main cause of vision loss in patients with diabetes. Ideal metabolic control ofdiabetes is the primary goal of treatment and the basic way of preventing and stopping the progressionof DME. Although laser photocoagulation has been the standard treatment of DME for nearly threedecades, superior outcomes can be achieved with novel, intravitreal anti-VEGF and steroid therapy.Novel treatment option for DME depends on visual acuity and location/extent of macular thickeningbased on optical coherence tomography scans. According to the International Clinical ClassificationScale, DME is divided into no center-involving DME and center-involving DME (CI-DME). Newguidelines recommend intravitreal treatment as the treatment of choice for patients with CI DMEand moderate visual impairment. Patients with no CI-DME and mild visual impairment should betreated with modified ETDRS laser photocoagulation and closely observed. Vitrectomy is the treatmentof choice for patients with a tractional component of DME. Nowadays, traditional treatmentgoal of preventing blindness in patients with DME has been changed by the new goal aiming torestore impaired vision, prevent further vision loss and improve visual function. Therefore, many trialsaddressing this new concept have been underway worldwide. PMID- 29120157 TI - Across the Country: What's Happening in Environmental Health. PMID- 29120159 TI - JEH Quiz #2: E-Waste Management in the United States and Public Health Implications. PMID- 29120160 TI - Preparation of Monodisperse Hydrophilic Quantum Dots with Amphiphilic Polymers. AB - Monodisperse hydrophilic quantum dots (QDs) are promising labeling materials for biomedical applications. However, the controllable preparation of monodisperse hydrophilic QDs with amphiphilic polymers remains a challenge. Herein, the molecular structures of amphiphilic polymers assembled on different-sized QDs are investigated. Both the experimental results and the molecular dynamics (MD) calculation suggest that the grafting ratio of amphiphilic polymers assembled on QDs increases as the size of QDs increases. Thus, the controllable preparation of different-sized monodisperse hydrophilic QDs can be achieved by simply varying the grafting ratio of amphiphilic molecules and applied in the simultaneous labeling of three tumor biomarkers. PMID- 29120161 TI - 2D Material Armors Showing Superior Impact Strength of Few Layers. AB - We study the ballistic properties of two-dimensional (2D) materials upon the hypervelocity impacts of C60 fullerene molecules combining ab initio density functional tight binding and finite element simulations. The critical penetration energy of monolayer membranes is determined using graphene and the 2D allotrope of boron nitride as case studies. Furthermore, the energy absorption scaling laws with a variable number of layers and interlayer spacing are investigated, for homogeneous or hybrid configurations (alternated stacking of graphene and boron nitride). At the nanolevel, a synergistic interaction between the layers emerges, not observed at the micro- and macro-scale for graphene armors. This size-scale transition in the impact behavior toward higher dimensional scales is rationalized in terms of scaling of the damaged volume and material strength. An optimal number of layers, between 5 and 10, emerges demonstrating that few layered 2D material armors possess impact strength even higher than their monolayer counterparts. These results provide fundamental understanding for the design of ultralightweight multilayer armors using enhanced 2D material-based nanocomposites. PMID- 29120162 TI - Y-Shaped DNA Duplex Structure-Triggered Gold Nanoparticle Dimers for Ultrasensitive Colorimetric Detection of Nucleic Acid with the Dark-Field Microscope. AB - Herein, we present a novel gold nanoparticle (AuNP) enumeration-based colorimetric aptamer biosensor for ultrasensitive detection of nucleic acid. This AuNP enumeration-based colorimetric method takes advantages of the distinctive and strong localized surface plasmon resonance light scattering with the dark field microscope. In our model system, first, cost-effective DNA1 instead of expensive 2-thioethyl ether acetic acid was capped on the surface of AuNPs to form a dense DNA1 layer. Then, two DNA strands (DNA2 and DNA3) in two different solutions were separately asymmetrically functionalized on the AuNPs capped dense DNA1 layer. The subsequent binding of the target DNA could trigger the formation of perfect complementary DNA with a Y shape and adjust the distance between nanoparticles to form AuNP dimers, accompanied by a color change from green to yellow as observed, and thereby modulated the performance of the sensor, which resulted in the ultrahigh sensitivity. With this design, a 43 aM limit of detection was obtained, which exhibited an increase of at least 5-9 orders of magnitude in sensitivity over other colorimetric sensors fabricated using conventional strategies. PMID- 29120163 TI - Tunable Synthesis of Yolk-Shell Porous Silicon@Carbon for Optimizing Si/C-Based Anode of Lithium-Ion Batteries. AB - Significant "breathing effect" calls for exploring efficient strategies to address the intrinsic issues of silicon anode of lithium-ion batteries (LIBs). We here report a controllable synthetic route to fabricate the silicon-carbon hybrids, in which porous silicon nanoparticles (p-SiNPs) are loaded in void carbon spheres by forming the yolk-shell p-SiNPs@hollow carbon (HC) nanohybrids tunable. A set of controlled experiments accompanying with systematic characterizations demonstrate that the void space and mass loading of Si can be adjusted in an effective way so that the nanostructure can be optimized with achieving improved electrochemical performance as anode of lithium-ion batteries (LIBs). The optimized p-SiNPs@HC nanohybrids show excellent performance as anode for Li-ion battery, delivering a capacity of more than 1400 mA h g-1 after 100 cycles at 0.2 A g-1 and 720 mA h g-1 at a high current density of 4 A g-1. The present work may provide us with an attractive and promising strategy for advancing Si-based anode materials due to advantages of tunable structure of silicon-carbon nanohybrids for optimizing electrochemical performance. PMID- 29120164 TI - Process-Function Data Mining for the Discovery of Solid-State Iron-Oxide PV. AB - Data mining tools have been known to be useful for analyzing large material data sets generated by high-throughput methods. Typically, the descriptors used for the analysis are structural descriptors, which can be difficult to obtain and to tune according to the results of the analysis. In this Research Article, we show the use of deposition process parameters as descriptors for analysis of a photovoltaics data set. To create a data set, solar cell libraries were fabricated using iron oxide as the absorber layer deposited using different deposition parameters, and the photovoltaic performance was measured. The data was then used to build models using genetic programing and stepwise regression. These models showed which deposition parameters should be used to get photovoltaic cells with higher performance. The iron oxide library fabricated based on the model predictions showed a higher performance than any of the previous libraries, which demonstrates that deposition process parameters can be used to model photovoltaic performance and lead to higher performing cells. This is a promising technique toward using data mining tools for discovery and fabrication of high performance photovoltaic materials. PMID- 29120165 TI - Efficient Planar Structured Perovskite Solar Cells with Enhanced Open-Circuit Voltage and Suppressed Charge Recombination Based on a Slow Grown Perovskite Layer from Lead Acetate Precursor. AB - For planar structured organic-inorganic hybrid perovskite solar cells (PerSCs) with the poly(3,4-ethylenedioxythiophene:polystyrene sulfonate) (PEDOT:PSS) hole transport layer, the open-circuit voltage (Voc) of the device is limited to be about 1.0 V, resulting in inferior performance in comparison with TiO2-based planar counterparts. Therefore, increasing Voc of the PEDOT:PSS-based planar device is an important way to enhance the efficiency of the PerSCs. Herein, we demonstrate a novel approach for perovskite film formation and the film is formed by slow growth from lead acetate precursor via a one-step spin-coating process without the thermal annealing (TA) process. Because the perovskite layer grows slowly and naturally, high-quality perovskite film can be achieved with larger crystalline particles, less defects, and smoother surface morphology. Ultraviolet absorption, X-ray diffraction, scanning electron microscopy, steady-state fluorescence spectroscopy (photoluminescence), and time-resolved fluorescence spectroscopy are used to clarify the crystallinity, morphology, and internal defects of perovskite thin films. The power conversion efficiency of p-i-n PerSCs based on slow-grown film (16.33%) shows greatly enhanced performance compared to that of the control device based on traditional thermally annealed perovskite film (14.33%). Furthermore, the Voc of the slow-growing device reaches 1.12 V, which is 0.1 V higher than that of the TA device. These findings indicate that slow growth of the perovskite layer from lead acetate precursor is a promising approach to achieve high-quality perovskite film for high-performance PerSCs. PMID- 29120166 TI - Aromatic Residues in the Fourth Transmembrane-Spanning Helix M4 Are Important for GABArho Receptor Function. AB - GABArho receptors are a subfamily of the GABAA receptor family of pentameric ligand-gated ion channels (pLGICs). Each of the five subunits has four transmembrane alpha-helices (M1-M4), with M4 most distant from the central pore. Aromatic residues in this M4 helix are important for receptor assembly in pLGICs and also may interact with adjacent lipids and/or residues in neighboring alpha helices and the extracellular domain to modify or enable channel gating. This study examines the role of M4 receptor aromatic residues in the GABArho receptor transmembrane domain using site-directed mutagenesis and subsequent expression in HEK293 cells, probing functional parameters using a fluorescent membrane potential-sensitive dye. The data indicate that many of the aromatic residues in M4 play a role in receptor function, as substitution with other residues can ablate and/or modify functional parameters. Modeling showed that these residues likely interact with residues in the adjacent M1 and M3 alpha-helices and/or residues in the Cys-loop in the extracellular domain. We suggest that many of these aromatic interactions contribute to an "aromatic zipper", which allows interactions between M4 and the rest of the receptor that are essential for function. Thus, the data support other studies showing that M4 does not play a passive role in "protecting" the other transmembrane helices from the lipid bilayer but is actively involved in the function of the protein. PMID- 29120167 TI - Understanding the Inflammatory Tissue Reaction to Brain Implants To Improve Neurochemical Sensing Performance. AB - Neurochemical sensing probes are a valuable diagnostic and therapeutic tool that can be used to study neurodegenerative diseases involving deficiencies in neurotransmitter signaling. However, implantation of these biosensors can elicit a harmful tissue response that alters the neurochemical environment within the brain. Transmission of chemical messengers via neurons is impeded by a barrier forming glial scar that occurs within weeks after insertion followed by progressive neurodegeneration, attenuating signal sensitivity. Emerging research reveals that non-neuronal cells also influence the neurochemical milieu following injury both directly and indirectly. The reactivity of both microglia and astrocytes to inserted probes have been extensively studied in the past yet there remains other glial subtypes in the brain, such as oligodendrocytes and their precursors, the myelin structures they form, as well as vascular-bound pericytes, that have the potential to contribute significantly to the inflammation due to their responsibility to maintain tissue homeostasis. A brief overview of how tissue injury alters the neurochemical makeup followed by alternative potential targets of investigation and novel strategies to enhance the chemical sensing abilities of implantable probes will be discussed. PMID- 29120168 TI - Organoarsonate Functionalization of Heteropolyoxotungstates. AB - Functionalization of the {P8W48} polyoxotungstate (POT) archetype with aromatic organoarsonates results in the first homometallic {P8W48} derivatives, with the general formula [(RAsVO)4PV8WVI48O184]32- [R = C6H5 (1) or p-(H2N)C6H4 (2)]. Short As-O bonds here induce unusual bending of the otherwise rigid {P8W48} macrocycle, breaking its D4h symmetry. The obtained species also represent the first lacunary POTs functionalized with organoarsonates and can potentially act as polyoxometalate precursors themselves. We elaborate solution stability in different aqueous media using 1H and 31P NMR spectroscopy and possible pathways for subsequent transformations in aqueous solutions of the functionalized polyanions. Recrystallization of the K+/Li+/dimethylammonium salt of 2 from 4 M LiCl solution yielded a further functionalized POT, [(H3NC6H4AsO)3P8W48O184Hx{WO2(H2O)2}0.4](30.2-x)- (3), revealing dissociation of the organoarsonate fragments in slightly acidic aqueous solutions followed by their rearrangement within the inner POT cavity. PMID- 29120169 TI - Characterizing Defects in a UiO-AZB Metal-Organic Framework. AB - Exploring defect sites in metal-organic framework materials has quickly become an interesting topic of discussion in the literature. With reports of the enhancement of material properties with increasing defect sites, we were interested in probing the defect nature of UiO-AZB (UiO = University of Oslo, AZB = 4,4'-azobenzenedicarboxylate) nanoparticles. In this report, we investigate the use of acetic, formic, and benzoic acids as the modulators to prepare UiO-AZB. The results of 1H NMR techniques and BET surface area analysis elucidate the extent of defects in our samples and are provided along with detailed discussions of the observed experimental trends. Interestingly, formic acid samples resulted in the most defected structure, reaching 36%. Additionally, for benzoic acid samples, with a 33% defect level, a drastic reduction in the accessible SA from 2682 m2/g to as low as 903 m2/g was observed, as the concentration of benzoic acid was increased. This was attributed to the creation of macropores in the individual crystallites and confirmed by average pore width analysis. PMID- 29120171 TI - Environmental Impacts of Future Urban Deployment of Electric Vehicles: Assessment Framework and Case Study of Copenhagen for 2016-2030. AB - To move toward environmentally sustainable transport systems, electric vehicles (EVs) are increasingly seen as viable alternatives to internal combustion vehicles (ICVs). To ensure effectiveness of such deployment, holistic assessments of environmental impacts can help decision-makers determine optimized urban strategies in a long-term perspective. However, explicit guidance and conduct of such assessments are currently missing. Here, we therefore propose a framework using life cycle assessment that enables the quantification of environmental impacts of a transport system at full urban scale from a fleet-based, foresight perspective. The analysis of the passenger car fleet development in the city of Copenhagen for the years 2016-2030 is used as a proof-of-concept. We modeled and compared five powertrain technologies, and we assessed four fleet-based scenarios for the entire city. Our results showed relative environmental benefits from range-extended and fuel-cell EVs over ICVs and standard EVs. These results were found to be sensitive to local settings, like electricity grid mix, which could alter the relative environmental performances across EV technologies. The comprehensive framework developed here can be applied to other geographic areas and contexts to assess the environmental sustainability of transport systems. PMID- 29120170 TI - Cationic Ti Complexes with Three [N,O]-Type Tetrazolyl Ligands: Ti<->Fe Transmetalation within Fe Metallascorpionate Complexes. AB - Herein, we report the synthesis of two novel ionic Ti complexes possessing three [N,O]-type bidentate ligands from the reaction of Fe metallascorpionate ligands possessing extended alcohol groups and TiCl4. The reaction of substituted hydroxyphenyl tetrazole and Fe(ClO4)3 in a molar ratio of 3:1 afforded iron scorpionate metalloligands possessing extended arms, which were characterized by IR spectroscopy and ESI-TOF-MS spectrometry. Their molecular structures were also confirmed as neutral Fe-centered scorpionate complexes by X-ray crystallography, in which the extended alcohol groups adopted a tripodal geometry. Moreover, two different crystals of iron scorpionate metalloligand grown from CH2Cl2 and CH3OH were studied, revealing that, in the latter crystal, the tripod arms are folded and aligned toward the C3-rotational axis of the molecule, whereas the tripod arms are unfolded and spread outward from the rotational axis in the former crystal. These metalloligands are solvatochromatic; a bathochromic shift was observed as the solvent polarity increased. From the reaction, the aforesaid Fe complexes were further reacted with TiCl4 in a molar ratio of 1:1 to produce ionic [TiL3]+[FeCl4]- (L = substituted hydroxyphenyl tetrazole) complexes from the transmetalation of Ti and Fe. The complexes were characterized by various analytical methods including UV/vis and IR spectroscopies, electrospray time-of flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography. PMID- 29120172 TI - Lupane-Type Triterpenes of Phoradendron vernicosum. AB - Three new lupane-type triterpenes, 3alpha,24-dihydroxylup-20(29)-en-28-oic acid (1), 3alpha,23-dihydroxy-30-oxolup-20(29)-en-28-oic acid (2), and 3alpha,23-O isopropylidenyl-3alpha,23-dihydroxylup-20(29)-en-28-oic acid (3), together with eight known compounds (4-11) were isolated from a methanol extract of Phoradendron vernicosum aerial parts. The chemical structures of 1-3 were determined on the basis of spectroscopic data interpretation. The isolated compounds were tested against seven human cancer cell lines and two normal cell lines. PMID- 29120173 TI - Elucidating the Mechanisms of the Tomato ovate Mutation in Regulating Fruit Quality Using Proteomics Analysis. AB - The ovate mutation has frequently been used to study changes in fruit shape but not fruit quality. A deterioration in fruit quality associated with the ovate mutation was discovered in this study. To elucidate how ovate influences the quality of fruit, we performed a proteomics analysis of the fruits of the ovate mutant (LA3543) and wild-type ("Ailsa Craig", LA2838A) using tandem mass tag analysis. The results indicated that the ovate mutation significantly influences fruit quality in a number of ways, including by reducing the expression of 1 aminocyclopropane-1-carboxylic acid oxidase 3 (ACO3) in ethylene biosynthesis, improving firmness by reducing the amount of pectinesterase and polygalacturonase, reducing sugar accumulation by downregulating the abundance of mannan endo-1,4-beta-mannosidase 4, beta-galactosidase, and beta-amylase, and reducing the malic acid content by downregulating the accumulation of malic enzymes and malate synthase. These findings could inform future improvements in fruit quality. PMID- 29120174 TI - One-Shot Multiple Borylation toward BN-Doped Nanographenes. AB - One-shot double, triple, and quadruple borylation reactions of triarylamines were developed through a judicious choice of boron source and Bronsted base. With the aid of borylation reactions, a variety of BN-doped nanographenes were synthesized in two steps from commercially available starting materials. An organic light emitting diode device employing BN-doped nanographene as an emitter exhibited deep pure-blue emission at 460 nm, with CIE coordinates of (0.13, 0.11), and an external quantum efficiency of 18.3%. PMID- 29120175 TI - N-Heterocyclic Carbene Boranes are Hydrogen Donors in Masamune-Bergman Reactions of Benzo[3,4]cyclodec-3-ene-1,5-diynes. AB - Thermal reactions of benzo[3,4]cyclodec-3-ene-1,5-diyne with N-heterocyclic carbene boranes (NHC-boranes) provided mixtures of 9-borylated 1,2,3,4 tetrahydroanthracenes along with 1,2,3,4-tetrahydroanthracene. These products indicate that NHC-boranes serve as hydrogen donors to a p-benzyne intermediate formed by the Masamune-Bergman reaction. Experimental results support a radical mechanism in nonpolar solvents, but suggest that ionic mechanisms compete in the production of 1,2,3,4-tetrahydroanthracene when the reaction is performed in a polar solvent. PMID- 29120177 TI - Zinc Complexes with Cyanoxime: Structural, Spectroscopic, and Catalysis Studies in the Pivaloylcyanoxime-Zn System. AB - Reaction of 2-hydroxyimino-4,4-dimethyl-3-oxo-pentanenitrile (common abbreviation HPiCO, pivaloyl-cyanoxime) with zinc sulfate in an aqueous solution results in the formation of the two new complexes: [Zn(PiCO){H(PiCO)2}(H2O)] (I) and tetranuclear Zn complex [Zn4(MU3-OH)2(PiCO)6 (H2O)4] (II). Both complexes were characterized by elemental analysis, IR- and UV-visible spectra, DSC/TGA studies, and X-ray analysis. In complex II, the PiCO- cyanoxime anion adopts three bidentate binding modes: O-monodentate, chelating (kappa2), and bridging (eta2) coordinations. Also, the ligand represents the mixture of two diasteromers (cis anti and cis-syn) that form five- and six-membered chelate rings with Zn atoms and cocrystallize in one unit cell at population of 0.57-0.43. There are two crystallographically different Zn-centers in the ASU, and two MU3-bridging hydroxo-groups arrange via inversion center the formation of an elegant tetranuclear complex. Each Zn atom has a molecule of coordinated water and is in the distorted octahedral environment. Because of the structural flexibility and multidentate propensity of the pivaloyl-cyanoxime, complex II may act as a structural model of naturally occurring Zn-containing enzymes. Indeed, compound I exhibits an efficient catalytic performance for transesterification reaction of various esters in ethanol under mild reaction conditions. Therefore, obtained results allow assignment of observed activity as green catalysis. PMID- 29120176 TI - Persistent Organic Pollutants in the East Antarctic Atmosphere: Inter-Annual Observations from 2010 to 2015 Using High-Flow-Through Passive Sampling. AB - In the first multiyear sampling effort for POPs in the eastern Antarctic atmosphere, 32 PCBs and 38 organochlorine pesticides were targeted in air collected with a high-flow-through passive sampler. Agricultural chemicals were found to dominate atmospheric profiles, in particular HCB and endosulfan-I, with average concentrations of 12 600 and 550 fg/m3, respectively. HCB showed higher concentrations in the austral summer, indicative of local, temperature-dependent volatilisation, while endosulfan-I appeared to show fresh, late-austral-summer input followed by temporally decreasing levels throughout the year. The current use herbicide, trifluralin, and the legacy pesticides mirex and toxaphene, were detected in Antarctic air for the first time. Trifluralin was observed at low but increasing levels over the five-year period. Its detection in the Antarctic atmosphere provides evidence of its persistence and long-range environmental transport capability. While a time frame of five years exceeds the duration of most Antarctic air monitoring efforts, it is projected that continuous monitoring at the decadal scale is required to detect an annual 10% change in atmospheric concentrations of key analytes. This finding emphasizes the importance of continuous, long-term monitoring efforts in polar regions, that serve a special role as sentinel environments of hemispheric chemical usage trends. PMID- 29120178 TI - Theoretical Design on a Series of Novel Bicyclic and Cage Nitramines as High Energy Density Compounds. AB - We designed four bicyclic nitramines and three cage nitramines by incorporating N(NO2)-CH2-N(NO2)-, -N(NO2)-, and -O- linkages based on the HMX (1,3,5,7 tetranitro-1,3,5,7-tetrazocane) framework. Then, their electronic structure, heats of formation, energetic properties, strain energy, thermal stability, and impact sensitivity were systematically studied using density functional theory (DFT). Compared to the parent compound HMX, all the title compounds have much higher density, better detonation properties, and better oxygen balance. Among them, four compounds have extraordinary high detonation properties (D > 9.70 km/s and P > 44.30 GPa). Moreover, most of the title compounds exhibit better thermal stability and lower impact sensitivity than CL-20 2,4,6,8,10,12-hexanitro 2,4,6,8,10,12-hexaazaisowurtzitane) or HNHAA (hexanitrohexaazaadamantane). Thus, all of the seven new nitramine compounds are promising candidates for high energy density compounds. In particular, five compounds exhibit a best combination of better oxygen balance, good thermal stability, excellent detonation properties superior to or comparable to CL-20 or HNHAA, and lower impact sensitivity than CL 20 or HNHAA. The results indicate that our unusual design strategy that constructing bicyclic or cage nitramines based on the HMX framework by incorporating the intramolecular linkages is very useful for developing novel energetic compounds with excellent detonation performance and low sensitivity. PMID- 29120179 TI - Dispersion Interactions in QM/EFP. AB - The dispersion energy term between quantum-mechanical (QM) and classical (represented by effective fragment potentials, EFP) subsystems is developed and implemented. A new formulation is based on long-range perturbation theory and uses dynamic polarizability tensors of the effective fragments and electric field integrals and orbital energies of the quantum-mechanical subsystem. No parametrization is involved. The accuracy of the QM-EFP dispersion energy is tested on a number of model systems; the average mean unsigned error is 0.8 kcal/mol or 13% with respect to the symmetry adapted perturbation theory on the S22 data set of noncovalent interactions. The computational cost of the dispersion energy computation is low compared to the self-consistent field calculation of the QM subsystem. The dispersion energy is sensitive to the level of theory employed for the QM part and to the electrostatic interactions in the system. The latter means that the dispersion interactions in the QM/EFP method are not purely two-body but have more complex many-body behavior. PMID- 29120180 TI - Synthesis and Application of Branched Type II Arabinogalactans. AB - The synthesis of linear and (1 -> 6)-branched beta-(1 -> 3)-d-galactans, structures found in plant arabinogalactan proteins (AGPs), is described. The synthetic strategy relies on iterative couplings of monosaccharide and disaccharide thioglycoside donors, followed by a late-stage glycosylation of heptagalactan backbone acceptors to introduce branching. A key finding from the synthetic study was the need to match protective groups in order to tune reactivity and ensure selectivity during the assembly. Carbohydrate microarrays were generated to enable the detailed epitope mapping of two monoclonal antibodies known to recognize AGPs: JIM16 and JIM133. PMID- 29120181 TI - Direct Synthesis of Dipyrrolyldipyrrins from SNAr Reaction on 1,9-Dihalodipyrrins with Pyrroles and Their NIR Fluorescence "Turn-On" Response to Zn2. AB - A set of dipyrrolyldipyrrins have been efficiently synthesized from a direct SNAr reaction on 1,9-dihalodipyrrins with pyrroles and show intense absorption in the NIR region (650-800 nm, as HCl salts). Substituents on both 1,9-dihalodipyrrins and pyrroles greatly affected the reactivity of this SNAr reaction and the absorption properties of the resultant dipyrrolyldipyrrins. These dipyrrolyldipyrrins show sensitive and selective "turn-on" fluorescence response toward Zn2+. PMID- 29120182 TI - Designing Single-Ion Magnets and Phosphorescent Materials with 1-Methylimidazole 5-carboxylate and Transition-Metal Ions. AB - Detailed structural, magnetic, and photoluminescence (PL) characterization of four new compounds based on 1-methylimidazole-5-carboxylate (mimc) ligand and transition metal ions, namely [Ni(mimc)2(H2O)4] (1), [Co(MU-mimc)2]n (2), {[Cu2(MU-mimc)4(H2O)].2H2O}n (3), and [Cd(MU-mimc)2(H2O)]n (4) is reported. The structural diversity found in the family of compounds derives from the coordination versatility of the ligand, which coordinates as a terminal ligand to give a supramolecular network of monomeric entities in 1 or acts as a bridging linker to build isoreticular 2D coordination polymers (CPs) in 2-4. Magnetic direct-current (dc) susceptibility data have been measured for compounds 1-3 to analyze the exchange interactions among paramagnetic centers, which have been indeed supported by calculations based on broken symmetry (BS) and density functional theory (DFT) methodology. The temperature dependence of susceptibility and magnetization data of 2 are indicative of easy-plane anisotropy (D = +12.9 cm 1, E = +0.5 cm-1) that involves a bistable Ms = +/-1/2 ground state. Alternating current (ac) susceptibility curves exhibit field-induced single-ion magnet (SIM) behavior that occurs below 14 K, which is characterized by two spin relaxation processes of distinct nature: fast relaxation of single ions proceeding through multiple mechanisms (Ueff = 26 K) and a slow relaxation attributed to interactions along the polymeric crystal building. Exhaustive PL analysis of compound 4 in the solid state confirms low-temperature phosphorescent green emission consisting of radiative lifetimes in the range of 0.25-0.43 s, which explains the afterglow observed during about 1 s after the removal of the UV source. Time-dependent DFT and computational calculations to estimate phosphorescent vertical transitions have been also employed to provide an accurate description of the PL performance of this long-lasting phosphor. PMID- 29120183 TI - Thermoresponsive Surface-Grafted Gels: Controlling the Bulk Volume Change Properties by Surface-Localized Polymer Grafting with Various Densities. AB - We prepared poly(N-isopropylacrylamide-r-N-3-(aminopropyl)methacrylamide) (poly(NIPAAm-r-NAPMAm)) gels with poly NIPAAm (PNIPAAm) grafted only in the surface region (so-called thermoresponsive surface-grafted gels) with various graft densities and investigated the effect of the graft density on the bulk volume change properties, shrinking and swelling, in response to temperature changes. Initiators for atom-transfer radical polymerization (ATRP) and structurally analogous compounds were introduced at certain ratios onto the surface regions of the gels, and a subsequent activator regeneration by electron transfer ATRP of NIPAAm was conducted in aqueous media. The graft densities and molecular weights of the grafted polymers were evaluated from the increment in the dry mass of the gels and the amount of introduced ATRP initiators, which was measured by elemental analyses. Three-dimensional measuring laser microscopy revealed that the prepared gels had graft-density-dependent fine wrinkle structures on their surfaces. The surface-grafted gels induced the formation of skin layers during the shrinking process in response to a temperature increase, and their permeability strongly depended on the graft density. The graft density also controlled the kinetics of the swelling behavior in response to a temperature decrease. These physical properties were discussed on the basis of Young's modulus of the surface determined by an atomic force microscopy force curve measurement and the homogeneity of the surface polymer network observed by cryo-scanning electron microscopy. This makes it possible to arbitrarily control the characteristics of gels as open or semiclosed systems, which was uniquely determined by the designs of the surface gel networks. PMID- 29120184 TI - Electronic Interplay between TTF and Extended-TCNQ Electrophores along a Ruthenium Bis(acetylide) Linker. AB - A bis(TTF-butadiynyl) ruthenium D-D'-D complex, with intramolecular electronic interplay between the three electron-donating electrophores, was easily converted through a cycloaddition-retroelectrocyclization with TCNQ into a D-A-D'-A-D pentad complex, which exhibits an intense intramolecular charge transfer together with an electronic interplay between the two acceptors along the conjugated organometallic bridge. PMID- 29120185 TI - Three-Dimensional Nanoprinting via Direct Delivery. AB - Direct writing methods are a generic and simple means to produce designed structures in three dimensions (3D). The printing is achieved by extruding printing materials through a nozzle, which provides a platform to deliver a wide range of materials. Although this method has been routinely used for 3D printing at macroscopic scales, miniaturization to micrometer and nanometer scales and building hierarchical structures at multidimensional scales represent new challenges in research and development. The current work addresses these challenges by combining the spatial precision of atomic force microscopy (AFM) and local delivery capability of microfluidics. Specialized AFM probes serve dual roles of a microscopy tip and a delivery tool, enabling the miniaturization of 3D printing via direct material delivery. Stacking grids of 20 MUm periodicity were printed layer-by-layer covering 1 mm * 1 mm regions. The spatial fidelity was measured to be several nanometers, which is among the highest in 3D printing. The results clearly demonstrate the feasibility of achieving high precision 3D nanoprinting with nanometer feature size and accuracy with practical throughput and overall size. This work paves the way for advanced applications of 3D hierarchical nanostructures. PMID- 29120186 TI - Constrained Versus Free Cholesterol in DPPC Membranes: A Comparison of Chain Ordering Ability Using Deuterium NMR. AB - We report here the first exploration of the nature of the hydrophobic region of bilayer membranes formed from sterol-modified phospholipids [Huang, Z.; Szoka, F. C., Sterol-Modified Phospholipids: Cholesterol and Phospholipid Chimeras with Improved Biomembrane Properties. J. Am. Chem. Soc. 2008, 130 (46), 15702-15712] & [Ding, J.; Starling, A. P.; East, J. M.; Lee, A. G., Binding Sites for Cholesterol on Ca(2+)-ATPase Studied by Using a Cholesterol-Containing Phospholipid. Biochemistry 1994, 33 (16), 4974-4979]. Using 2H NMR spectroscopy, we present our results for the phase behavior and acyl chain ordering of multilamellar vesicles (MLVs) of a sterol-modified phospholipid, 1 cholesterylhemisuccinoyl-2-palmitoyl(d31)-sn-glycero-3-phosphocholine (hereafter referred to as CholPPC-d31). We compared our results with the conformational order induced by cholesterol at various concentrations in 1-palmitoyl,2 palmitoyl(d31)-sn-glycero-3-phosphocholine (DPPC-d31)/cholesterol membranes. On the basis of the existing literature [Foglia, F.; Barlow, D. J.; Szoka, F. C.; Huang, Z.; Rogers, S. E.; Lawrence, M. J., Structural Studies of the Monolayers and Bilayers Formed by a Novel Cholesterol-Phospholipid Chimera. Langmuir 2011, 27 (13), 8275-8281], we expected to find that the deuterated palmitoyl chain in CholPPC-d31 membranes had an order parameter profile similar to the deuterated palmitoyl chain of sn-2 labeled DPPC-d31 in MLVs of a mixture of DPPC-d31 with 40 mol % unconstrained cholesterol. Our data indicate that the ordering ability of cholesterol in CholPPC is significantly reduced compared to free cholesterol in DPPC. This result emphasizes that cholesterol molecules must be free to move in the bilayers to reach their maximum ordering ability. In other words, when compared to unconstrained cholesterol, the constrained cholesterol moiety in CholPPC causes nonoptimal chain packing. PMID- 29120187 TI - Mechanism of Competitive Inhibition and Destabilization of Acidothermus cellulolyticus Endoglucanase 1 by Ionic Liquids. AB - The ability of ionic liquids (ILs) to solubilize cellulose has sparked interest in their use for enzymatic biomass processing. However, this potential is yet to be realized, primarily because ILs inactivate requisite cellulases by mechanisms that are yet to be identified. We used a combination of enzymology, circular dichroism (CD), nuclear magnetic resonance (NMR), and molecular dynamics (MD) methods to investigate the molecular basis for the inactivation of the endocellulase 1 (E1) from Acidothermus cellulolyticus by the imidazolium IL 1 butyl-3-methylimidazolium chloride ([BMIM][Cl]). Enzymatic studies revealed that [BMIM][Cl] inactivates E1 in a biphasic manner that involves rapid, reversible inhibition, followed by slow, irreversible deactivation. Backbone NMR signals of the 40.5 kDa E1 were assigned by triple resonance NMR methods, enabling monitoring of residue-specific perturbations. 1H-15N NMR titration experiments revealed that [BMIM][Cl] binds reversibly to the E1 active site, indicating that reversible deactivation is due to competitive inhibition of substrate binding. Prolonged incubation with [BMIM][Cl] led to substantial global changes in the 1H 15N heteronuclear single quantum coherence NMR and CD spectra of E1 indicative of protein denaturation. Notably, weak interactions between [BMIM][Cl] and residues at the termini of several helices were also observed, which, together with MD simulations, suggest that E1 denaturation is promoted by [BMIM][Cl]-induced destabilization of helix capping structures. In addition to identifying determinants of E1 inactivation, our findings establish a molecular framework for engineering cellulases with improved IL compatibility. PMID- 29120188 TI - alpha-Silyl Amides: Effective Bifunctional Lynchpins for Type I Anion Relay Chemistry. AB - Lynchpins comprising alpha-silyl amides have been validated for type I anion relay chemistry (ARC) to permit ready access to gamma-ketoamides. Importantly, the ARC protocol can be run at ambient temperature without the need of additional reagents to trigger the [1,4] Brook rearrangement. PMID- 29120189 TI - Thermodynamics of Methyl-beta-cyclodextrin-Induced Lipid Vesicle Solubilization: Effect of Lipid Headgroup and Backbone. AB - The low aqueous solubility of phospholipids makes necessary the use of lipid carriers in studies ranging from lipid traffic and metabolism to the engineering of model membranes bearing lipid transverse asymmetry. One particular lipid carrier that has proven to be particularly useful is methyl-beta-cyclodextrin (MbetaCD). To assess the interaction of MbetaCD with structurally different phospholipids, the present work reports the results of isothermal titration calorimetry in conjunction with dynamic light scattering measurements. The results showed that the interaction of MbetaCD with large unilamellar vesicles composed of a single type of lipid led to the solubilization of the lipid vesicle and, consequently, the complexation of MbetaCD with the lipids. This interaction is dependent on the nature of the lipid headgroup, with a preferable interaction with phosphatidylglycerol in comparison to phosphatidylcholine. It was also possible to show a role played by the phospholipid backbone in this interaction. In many cases, the differences in the transfer energy between one lipid and another in going from a bilayer to a cyclodextrin-bound state can be qualitatively explained by the energy required to extract the lipid from a bilayer. In all cases, the data showed that the solubilization of the vesicles is entropically driven with a large negative DeltaCp, suggesting a mechanism dependent on the hydrophobic effect. PMID- 29120190 TI - In Vitro Characterization of the Biomimetic Properties of Poly(dimethylsiloxane) To Simulate Oral Drug Absorption. AB - The potential use of poly(dimethylsiloxane) (PDMS) as an in vitro biomimetic analogue of the passive drug absorption process in the human gastrointestinal tract (GI) is assessed. PDMS is biomimetic because of similarities in small molecule transport, such as mechanism, ionization selectivity, lipophilicity. Nine molecular probes are used to evaluate the transport pathways and properties used to predict human oral absorption rates. The transport pathways through PDMS (bulk/pore) are analogous to transcellular (TCDT) and paracellular (PCDT) drug transport pathways. PDMS PCDT is assessed using positronium annihilation lifetime spectroscopy (PALS) and partition experiments; TCDT using diffusion and partition experiments. PALS determined that PDMS pores were uniform (D ~ 0.85 nm), isolated, and void volume was unaffected by drug accumulation after equilibrium partitioning. Therefore, there is no PCDT or convective flow through PDMS. A strong linear correlation exists between predicted octanol-water partition coefficients and PDMS partition coefficients (LogKPDMS = 0.736 * LogPO-W - 0.971, R2 = 0.981). The pH-partition hypothesis is confirmed in PDMS using ibuprofen over pH 2-12. Diffusivity through PDMS is a function of lipophilicity and polar surface area K * DPDMS = 4.46 * 10-8 * e2.91*LogKPDMS(R2 = 0.963) and [Formula: see text] (R2 = 0.973). Varying the mass% of curing agent changed the lipophilicity and diffusivity (p < 0.02), but not practically (K * D = 2.23 * 10 5cm2s-1 vs 2.60 * 10-5cm2s-1), and does affect elastic modulus (3.2% = 0.3 MPa to 25% = 3.2 MPa). PMID- 29120191 TI - Directed Fischer Indolization as an Approach to the Total Syntheses of (+) Aspidospermidine and (-)-Tabersonine. AB - A conceptually new synthetic approach that provides general access to the aspidosperma alkaloids (+)-aspidospermidine and (-)-tabersonine was developed. This method is based on the regioselective indolization of an ene-hydrazide, which was obtained via a base-catalyzed intramolecular aza-Michael reaction, in situ trapping of the resulting enolate, and subsequent C-N coupling with phenyl hydrazide. PMID- 29120192 TI - Weight stigma and health: The mediating role of coping responses. AB - OBJECTIVE: Considerable evidence has documented links between weight stigma and poor health, independent of weight. However, little research has assessed how individuals cope with weight stigma, and how stigma-specific coping responses contribute to health. The present study examined multiple stigma-specific coping responses as mediators of the relationship between experienced weight stigma and health. METHOD: A diverse national sample of 912 adults (53.9% female, Mage = 40.33, SD = 15.58) reporting experiences of weight stigma completed questionnaires about stigma, stigma-specific coping responses (i.e., coping with weight stigma via negative affect, maladaptive eating behavior, healthy lifestyle behavior, and exercise avoidance), and health indices including depressive symptoms, physical health, psychological wellbeing, dieting frequency, and self esteem. RESULTS: Stigma-specific coping responses mediated the relationship between experienced weight stigma and all health indices, though indirect effects of weight stigma on health varied by coping strategy. Weight stigma was indirectly associated with greater frequency of depressive symptoms, lower scores on psychological wellbeing, self-esteem and physical health through coping via negative affect. Weight stigma indirectly contributed to greater frequency of depressive symptoms and dieting, as well as lower self-esteem and poorer physical health through coping via maladaptive eating. Weight stigma was associated with less frequent depressive symptoms, more frequent dieting, better psychological wellbeing, better self-esteem, and better physical health through coping with healthy lifestyle behaviors. CONCLUSIONS: These findings suggest that it may be useful to address weight stigma and coping in the context of weight management and obesity treatment programs, to help protect individuals from negative health effects of experiencing weight stigma. (PsycINFO Database Record PMID- 29120194 TI - Effect of maternal borderline personality disorder on adolescents' experience of maltreatment and adolescent borderline features. AB - Borderline personality disorder (BPD) is a severe and chronic mental illness. Self-reported borderline features correlate highly with a diagnosis (affective instability, negative relationships, unstable sense of self, self-harm). Etiological factors of BPD include childhood maltreatment. The current study compared the experience of maltreatment in adolescent offspring of mothers with BPD, who are themselves at risk of developing the disorder, with that of offspring of mothers with no current diagnosis. Participants were 56 adolescents aged 14 to 18 years. In all, 93% of the adolescents whose mothers had BPD experienced maltreatment compared with 60% of comparisons. Specifically, adolescent offspring of mothers with BPD experienced more physical abuse, emotional abuse, and neglect, but not more sexual abuse, than did comparisons. Dimensions of maltreatment (severity, multiple subtypes, chronicity) were associated with adolescents' own total borderline features. We discuss implications for the intergenerational transmission of BPD and for clinical interventions. (PsycINFO Database Record PMID- 29120193 TI - Feel the way with a vibrotactile compass: Does a navigational aid aid navigation? AB - Knowing where north is provides a navigator with invaluable information for learning and recalling a space, particularly in places with limited navigational cues, like complex indoor environments. Although north is effectively used by orienteers, pilots, and military personnel, very little is known about whether nonexpert populations can or will use north to create an accurate representation of an indoor space. In the current study, we taught people 2 nonoverlapping routes through a complex indoor environment, with which they were not familiar-a university hospital with few windows and several turns. Along 1 route, they wore a vibrotactile compass on their arm, which vibrated continuously indicating the direction of north. Along the other route, they were only told where north was at the start of the route. At the beginning, the end, and back at the beginning of each route, participants pointed to well-known landmarks in the surrounding city and campus (external landmarks), and newly learned landmarks in the hospital (internal landmarks). We found improved performance with the compass only for external landmarks, driven by people's use of the availability of north to orient these judgments. No such improved orientation occurred for the internal landmarks. These findings reveal the utility of vibrotactile compasses for learning new indoor spaces. We speculate that such cues help users map new spaces onto familiar spaces or to familiar reference frames. (PsycINFO Database Record PMID- 29120195 TI - Personality disorder traits: Perceptions of likability, impairment, and ability to change as correlates and moderators of desired level. AB - Historical conceptualizations have framed personality disorders (PDs) as unchanging and ego-syntonic. However, recent evidence suggests that individuals with PD traits may have some insight into their personality and consider those traits to be somewhat ego-dystonic. To replicate and extend previous findings, participants (N = 328) self-reported their PD trait levels, likability of those traits, impairment, capability for change, and desired trait levels. The results demonstrated that individuals with PD traits tolerate but still dislike those traits, believe that they cause them problems, and are interested in reducing them. Level of PD trait did not relate to perception of capability for change. Likability and impairment moderated most of the relations between actual PD trait and desired level. That is, there was a stronger correlation between actual and desired levels among individuals who liked the trait more; there was also greater agreement between actual and desired levels among individuals who found the traits less impairing. For 2 of the traits-Negative Affectivity and Detachment individuals who felt more capable of changing these traits demonstrated greater agreement between their actual and desired levels. These data suggest that individuals with PD traits do not generally see them as particularly likable and see them as impairing; such impressions may have important implications for where individuals ultimately prefer to reside on these PD trait domains. (PsycINFO Database Record PMID- 29120196 TI - Psychopathy and heroism in first responders: Traits cut from the same cloth? AB - Some scholars have posited that certain traits associated with psychopathy namely, fearlessness, boldness, and willingness to take risks-are associated with greater engagement in heroic and altruistic acts; nevertheless, this conjecture has received little empirical attention. We examined the relations among psychopathic traits, heroism, altruism, workplace deviance, and leadership in first-responder (n = 138) and civilian (n = 104) samples recruited by means of an online platform. Across samples, fearless dominance, boldness, sensation seeking, and several other psychopathy-related variables were positively and significantly associated with everyday heroism and altruism. First responders scored significantly higher than did civilians on measures of psychopathy, fearlessness, boldness, heroism, and altruism, and reported significantly greater workplace deviance and participation in leadership activities. Our results support previous suggestions of ties between psychopathic traits, especially fearlessness and heroism, although they leave unresolved the question of why certain antisocial and prosocial behaviors appear to covary. (PsycINFO Database Record PMID- 29120197 TI - A three-component model of future time perspective across adulthood. AB - Although extensive findings underscore the relevance of future time perspective (FTP) in the process of aging, the assumption of FTP as a unifactorial construct has been challenged. The present study explores the factorial structure of the FTP scale (Carstensen & Lang, 1996) as one of the most widely used measures (Ntotal = 2,170). Results support that FTP reflects a higher-order construct that consists of 3 interrelated components-Opportunity, Extension, and Constraint. It is suggested that the flexible usage of the FTP scale as an all compassing 10 item measure or with focus on specific components depends on the concrete research question. (PsycINFO Database Record PMID- 29120198 TI - College counseling services: Meeting today's demands. AB - This article is an introduction to the special issue of Psychological Services highlighting college counseling services as integral agents in public service delivery. The editors hope that readers across varied environments will enjoy learning of samples of the creative work being implemented across counseling centers to the benefit of all those who are served in public service settings. (PsycINFO Database Record PMID- 29120199 TI - Are we in crisis? National mental health and treatment trends in college counseling centers. AB - The current state of college student mental health is frequently labeled a "crisis," as the demand for services and severity of symptomatology have appeared to increase in recent decades. Nationally representative findings are presented from the Center for Collegiate Mental Health, a practice research network based in the United States, composed of more than 340 university and college counseling centers, in an effort to illuminate trends in symptom severity and patterns in treatment utilization for the campus treatment seeking population. Clinical data collected over 5 academic years (2010-2015) showed small but significantly increasing trends for self-reported distress in generalized anxiety, depression, social anxiety, family distress, and academic distress, with the largest effect sizes observed for generalized anxiety, depression, and social anxiety. On the other hand, a significantly decreasing trend was observed for substance use. No significant changes were observed for eating concerns and hostility. Utilization data over 6 years indicated a gradual yet steady increase in the number of students seeking services (beyond the rate expected with increasing institutional enrollment), as well as increases in the number of appointments scheduled and attended, with great variation between centers. Within the context of changing national trends, we conclude that it is advisable to consider the specific needs of local centers to best accommodate distinct student bodies. (PsycINFO Database Record PMID- 29120200 TI - Presenting concerns in counseling centers: The view from clinicians on the ground. AB - Despite growing evidence that a greater number of students are seeking counseling in college and university counseling centers throughout the United States, there is a dearth of empirical information about (a) the presenting concerns for which students seek treatment and (b) how these concerns differ according to client demographic factors. The purpose of this descriptive and exploratory study was to explore how counseling center clinicians categorize client presenting concerns, and how these concerns vary according to client demographics. Given the importance of client suicide within the field of college counseling, the frequency of suicidality as an identified presenting concern was also explored. A sample of 1,308 clinicians from 84 counseling centers rated the presenting concerns of 53,194 clients using the Clinician Index of Client Concerns (CLICC) after an initial consultation. Results of descriptive and nonparametric analyses indicated that the most prevalent concerns were anxiety, depression, stress, family, and academic performance, and that clients who belong to different demographic groups frequently present to counseling with broadly similar types of concerns. Furthermore, suicidality represented an area of concern for 8.4% of all clients, and it ranked 20 of 44 as a clinician-rated concern. Comparable rates emerged across the range of client demographic groups examined, although rates were notably higher for a handful of groups. The findings offer one of the largest and most generalizable descriptions of why college students seek counseling services, as determined by clinicians' evaluations of presenting concerns. Implications for research and clinical applications of the findings are discussed. (PsycINFO Database Record PMID- 29120201 TI - Meeting the mental health needs of today's college student: Reinventing services through Stepped Care 2.0. AB - A new stepped care model developed in North America reimagines the original United Kingdom model for the modern university campus environment. It integrates a range of established and emerging online mental health programs systematically along dimensions of treatment intensity and associated student autonomy. Program intensity can be either stepped up or down depending on level of client need. Because monitoring is configured to give both provider and client feedback on progress, the model empowers clients to participate actively in care options, decisions, and delivery. Not only is stepped care designed to be more efficient than traditional counseling services, early observations suggest it improves outcomes and access, including the elimination of service waitlists. This paper describes the new model in detail and outlines implementation experiences at 3 North American universities. While the experiences implementing the model have been positive, there is a need for development of technology that would facilitate more thorough evaluation. (PsycINFO Database Record PMID- 29120202 TI - Collaboration, confidentiality, and care. AB - There is an increasing call to attend to the needs of students in distress (Reynolds, 2013). Furthermore, research has begun to highlight links between distress, risky, or dangerous behaviors as well as issues in mental health in the higher education population (Deasy, Coughlan, Pironom, Jourdan, & Mannix McNamara, 2014). The National Alliance on Mental Health and the Jed Foundation (National Alliance on Mental Illness & the Jed Foundation, 2016) estimate that about 20% of enrolled college students will face some type of mental illness. As such, the work of mental health professionals, which has been increasing with time, will continue to play a pivotal role on today's campus (Kitzrow, 2009). Yet mental health in higher education is too pervasive and significant of a topic for counseling and psychological centers to handle by themselves (Joint Task Force in Student Learning, 1998; Mitchell et al., 2012). Therefore, a collaborative approach is warranted as higher education professionals strive to meet the increasing mental health demands of the student population. Case studies amalgamated from housing and residence life professionals are used to gain a greater understanding of how interdepartmental work is carried out without compromising or breaching ethical or legal regulations as set by the Family Educational Rights and Privacy Act, the Health Insurance Portability and Accountability Act, and/or organizational standards like that of the International Association of Counseling Services Inc. (International Association for Counseling Services Inc., 2014) Specifically, the cases demonstrate ways inter- and intradepartmental staffers can work as a team, safeguard private and confidential information, and concurrently create an environment in which care is nurtured. (PsycINFO Database Record PMID- 29120203 TI - Outreach as intervention: The evolution of outreach and preventive programming on college campuses. AB - It is widely acknowledged that demand for clinical services at university and college counseling centers (CCs) has increased over the last several years. CCs have had to adapt service delivery methods to meet the demand for services. One of the more recent developments in CCs lies in providing primary (preventive) interventions to the campus at-large through outreach and preventive programming. These interventions are aimed toward reducing demand as opposed to promoting services and gathering potential clients. This article describes changes in outreach delivery in 3 ways. First, descriptions of some of the more prevalent and proactive outreach activities are given. Brief explanations concerning the increased emphasis on social justice, large-scale events, campus partnerships, liaison programs, satellite offices-embedded models, uses of electronic and technological advances, postvention and community response, and topic-specific programming are given. Second, the changing administrative functions of those in charge of outreach at individual CCs is described. Last, a description of the establishment and ongoing need for a national organization for outreach administrators and professionals is outlined. Recent survey data completed by outreach professionals are also discussed, as are future directions and implications for how CCs quantify training and direct service activities. (PsycINFO Database Record PMID- 29120204 TI - The relationship between students' counseling center contact and long-term educational outcomes. AB - Numerous studies have demonstrated that counseling centers deliver a positive impact on the emotional and social development of college students who receive services. These healthy outcomes, in turn, can lead to increased academic success, such as improved performance, retention, and persistence. While these short-term academic outcomes have been widely investigated, very few studies have explored the relationship between counseling center services and longer-term educational outcomes, such as final grade point average (GPA), time spent at the university, and degree completion. In the current study, counseling center usage, including appointments that were attended, cancelled, and no showed, as well as distal educational variables were examined within 2 cohorts of first-time full time students over a 6-year period. Findings revealed that both users and nonusers of counseling center services spent a similar amount of time to degree completion and achieved comparable final semester GPAs as well. However, students who utilized counseling services graduated at a significantly lower rate (79.8%) than those who did not use services (86.2%) across the 6-year time span. Post hoc analyses indicated that among students who used counseling services, those who did not graduate scheduled significantly more services than those who graduated, suggesting that students who use the counseling center, and have more chronic and severe mental health problems, may be graduating at a lower rate. Implications are discussed. (PsycINFO Database Record PMID- 29120205 TI - University counseling service for improving students' mental health. AB - The main aims of this study were to provide an initial sociodemographic and clinical characterization of university students' academic and psychological functioning and to investigate and compare the feasibility and clinical utility of psychotherapies (cognitive behavior vs. psychodynamic) delivered at a large University in Northern Italy for improving university students' mental health, using self and observer-report measures. One hundred forty-9 students (102 women; MAge = 24.55, SD = 3.35) were consecutively interviewed and extensively assessed by independent clinicians of the Service before and after the intervention, using the Clinical Outcomes in Routine Evaluation and the Global Assessment Scale. Patients were enrolled in an individual psychotherapy and allocated to cognitive behavior or psychodynamic approach according to specific criteria. Psychotherapists who were not involved in the assessment phase administered the treatment. The majority of students was female and the most severe conditions emerged among students enrolled in philosophy, arts, and communication and medical schools. At posttreatment, all students improved both in terms of well being and distress, regardless of the type of psychotherapy received. This improvement emerged both by students' self-report and clinicians' evaluations. These findings point to the feasibility and clinical utility of psychotherapy in promoting well-being and reducing young adults' distress. The importance of university counseling services for promoting students' mental health, and a positive transition to adulthood is discussed. (PsycINFO Database Record PMID- 29120206 TI - Using online interventions to deliver college student mental health resources: Evidence from randomized clinical trials. AB - This study evaluated the efficacy of Internet-based stress management programs for college students. This approach is particularly fitting for students owing to a lack of mental health resources on campus and to high levels of Internet use among students. Because a history of interpersonal trauma (IPT) is associated with more distress and poorer academic performance, IPT history was assessed as a moderator of intervention efficacy. Students (N = 365) were randomly assigned to a mindfulness plus present control intervention, a mindfulness only intervention, or a stress management information condition that served as an active comparison. Prior research has supported the efficacy of the mindfulness plus present control intervention (Nguyen-Feng et al., 2015). Outcome measures were self-report measures of stress, anxiety, depression, and perceived stress completed online at preintervention, postintervention, and 2 follow-ups (2-3 weeks and 4-5 weeks postintervention). Linear mixed modeling was used to assess change over time. Participants in all 3 groups reported significant decreases on all primary outcomes. All time-by-intervention group interaction effects were nonsignificant, suggesting that the 3 conditions were equally effective. When examining IPT history as a moderator, the mindfulness plus present control and stress management conditions were both more effective for IPT survivors than the mindfulness only intervention. Results suggested that Internet-based interventions are effective for lowering distress among college students and that specific approaches may be differentially effective for certain subgroups of students. They also suggested that providing students with stress management information without providing training in 1 specific skill may also be helpful. (PsycINFO Database Record PMID- 29120207 TI - Stigma, mental health, and counseling service use: A person-centered approach to mental health stigma profiles. AB - The current study examined reports of stigma toward mental health services, depressive symptoms, flourishing, and mental health service use among a sample of 8,285 college students across the United States who completed the Healthy Minds Study. The study aimed to: (a) identify profiles of public and personal stigma against mental health service utilization, and (b) examine the demographic predictors of stigma group membership and mental health service utilization. Latent profile analyses revealed 3 distinct groups based on public and self stigma (i.e., "High Self, High Public Stigma," "Average Self, High Public Stigma," and "Low Self, Low Public Stigma"). Subsequent analyses examined demographic characteristics and mental health across the 3 groups. Results indicated significant differences in age, gender, race/ethnicity, mental health, and mental health service use across the 3 groups. Results further showed that students with high perceived need for mental health services, identifying as male or Asian, and belonging to the "High Self, High Public Stigma" group had lower likelihood of seeking mental health services in the past year. Implications for future research and clinical practice are discussed. (PsycINFO Database Record PMID- 29120208 TI - University students' perceived need for mental health services: A study of variables related to not seeking help. AB - This study analyzed data from the 2012 Student Experience in the Research University (SERU) survey, collected from undergraduate students at 9 universities. Researchers explored how demographic and behavioral variables related to avoidance of psychological help when needed. A total of 7,992 SERU participants responded to target items included in the present study. We examined whether student characteristics and behaviors differed between 3 self-report groups: (1) students who indicated they did not need counseling services; (2) students who reported needing counseling services, but not using them; and (3) students who reported using counseling services at least once during the 2012 academic year. Students who reported needing, but not using, counseling services were significantly different from the other 2 groups in that they were more likely to be female, Hispanic, endorse financial difficulties, and work longer hours while attending school. The 3 groups did not differ in understanding others with observable disabilities. Implications for college counselors and student affairs personnel are discussed. (PsycINFO Database Record PMID- 29120209 TI - The role of personality traits and barriers to mental health treatment seeking among college students. AB - Many college students experience a mental health problem yet do not seek treatment from a mental health professional. In the present study, we examined how perceived barriers (stigma perceptions, negative attitudes about treatment, and perceptions of practical barriers), as well as the Big Five personality traits, relate to treatment seeking among college students reporting a current mental health problem. The sample consisted of 261 college students, 115 of which reported experiencing a current problem. Results of a series of logistic regressions revealed that perceived stigma from others (OR = .32), self-stigma (OR = .29), negative attitudes about treatment (OR = .27), and practical barriers (OR = .34) were all associated with a lower likelihood of having sought treatment among students experiencing a problem. Of the five-factor model personality traits, only Neuroticism was associated with a higher likelihood of having sought treatment when experiencing a mental health problem (OR = 2.71). When we considered all significant predictors in a final stepwise conditional model, only self-stigma, practical barriers, and Neuroticism remained significant unique predictors. Implications for addressing barriers to treatment and encouraging treatment seeking among college students are discussed. (PsycINFO Database Record PMID- 29120210 TI - The role of therapy fears, ethnic identity, and spirituality on access to mental health treatment among Latino college students. AB - This study examined the impact of therapy fears, ethnicity identity, and spirituality on the use of mental health service among Latino college students. Participants were 83 Latino college students (78% female) recruited from a university in Central Texas. Analyses of the results indicated that previous mental health services use was negatively correlated with spirituality. Previous use of mental health services was positively correlated with participants' views that their ethnic community and religious affiliation did not influence their decisions to seek services. Additionally, ethnic identity was positively correlated with spirituality. Furthermore, participants' views that their ethnic community did not influence their decisions to seek services were correlated with religious affiliation. Therapy fears were positively correlated with participants' views that their ethnic community and religious affiliation did not influence their decisions to seek services. MANOVA analyses indicated that only spirituality (not therapy fears or ethnic identity) significantly impacted Latino college students' decisions to seek counseling services. Finally, regression analyses indicated that spiritual meaning and religious affiliation predicts service use. Implications for research and practice in college counseling centers are discussed. (PsycINFO Database Record PMID- 29120211 TI - Mental health treatment-related stigma and professional help seeking among student veterans. AB - Record numbers of military veterans are enrolling at colleges/universities across the United States. Although a substantive subset might suffer from mental health problems, the majority of these students might not be amenable to utilizing services. The purpose of this study was to examine the role of treatment-related stigma in intentions to seek professional help among undergraduate student veterans at a university on the U.S. Gulf Coast. Focusing on 251 veterans and a gender-matched comparison group of 251 nonveterans, student veterans endorsed higher probabilities of seeking care from physicians (d = .77) and psychologists or other professionals (d = .67). In addition, nonveteran students had greater self-stigma about seeking help (d = -.27) but veterans had more negative beliefs about treatment efficacy (d = 1.07). When compared with veterans who did not exceed clinical thresholds, those with a probable need for treatment had more stigma (ds = .63). Multivariate analyses also revealed an inverse main effect of self-stigma on intentions to seek help from both professional categories. However, military experience differentially moderated associations between treatment-related beliefs and intentions to seek mental health services. Finally, exploratory analyses identified that student veterans were most likely to engage in therapy/counseling at a Veterans Affairs Medical Center or Clinic, Vet Center, or other noninstitutionally sponsored settings in the community (e.g., private practices, faith-based organizations). Looking ahead, these findings will inform research and the provision of services for addressing the mental health needs of this substantive subpopulation of college students in the United States. (PsycINFO Database Record PMID- 29120212 TI - Evidence-based practice as a potential solution to burnout in university counseling center clinicians. AB - The purpose of this study was to evaluate the impact of changes in perceptions about patient volume and severity of clinical presentations in university counseling centers (UCCS) on burnout. It was hypothesized that perceptions of increased workload and severity of conditions treated would be positively correlated with burnout. It was also hypothesized that self-reported use of evidence-based practice (EBP) would be negatively correlated with burnout. Counseling center clinicians (n = 80) completed the Copenhagen Burnout Inventory (CBI), the Evidence-Based Practice Attitudes Scale (EPBAS), and reported on factors that have been shown to impact burnout. In this sample, the following percent of respondents were at or above a level indicating potential burnout on each scale: Personal 19%, Work 15.2%, and Client 2.5%. Years of work was correlated with Client Burnout (r = .25, p < .05). Perceived increases in severity were correlated with each CBI Scale: Personal (r = .33, p < .001), Work (r = .32, p < .001), and (Client r = .33, p < .001). Self-reported use of evidence-based practice was negatively correlated with Client burnout (r = -.30, p < .001). The EBPAS Divergence Scale, which measures perception that one's usual practice is different than research based practices, was also correlated with burnout (r = .27, p < .05) and Divergence was negatively correlated with self reported use of EBP (r = -.25, p < .05). Respondents were also asked if they treat PTSD and obsessive-compulsive disorder and which therapies they use for these diagnoses. Findings suggest that dissemination and implementation of EBPS may be beneficial for UCCS. (PsycINFO Database Record PMID- 29120213 TI - Feature predictiveness and selective attention in pigeons' categorization learning. AB - Prior categorization studies have shown that pigeons reliably track features that are perfect predictors of category membership (Castro & Wasserman, 2014, 2016a). One might further ask whether pigeons would also track features that are relevant, but imperfect predictors of category membership. In our present project, pigeons had to categorize multiple exemplars from 2 different artificial categories, in which the exemplars were composed of 4 different features that were associated with 1 of 2 different report responses. Each exemplar contained 1 feature that perfectly predicted category membership; 1 feature that imperfectly predicted category membership; and, 2 irrelevant features that did not predict category membership. We monitored pigeons' choice accuracy as well as the location of their pecks to each of the 4 exemplar features to determine to which attributes the birds attended. As categorization accuracy rose, pecks to the perfect predictor of each category rose as well. Pigeons also showed evidence of attending more to the imperfect predictor than to the irrelevant features, but to a lesser degree. Overall, our results provide evidence of selective attention in pigeons' categorization behavior. (PsycINFO Database Record PMID- 29120215 TI - About bouts: A heterogeneous tandem schedule of reinforcement reveals dissociable components of operant behavior in Fischer rats. AB - According to the biexponential refractory model (BERM) of variable-interval (VI) performance, operant behavior is organized in bouts, described by 3 dissociable components: between-bout interresponse times (IRTs), within-bout IRTs, and bout lengths. Research has shown that between-bout IRTs are sensitive to changes in rate of reinforcement and reinforcer efficacy, the length of some bouts is selectively sensitive to changes in response-reinforcer contingencies, and within bout IRTs are relatively insensitive to both manipulations. BERM assumes that within- and between-bout IRTs are exponentially distributed, and bout lengths are described by a mixture of negative binomial and geometric distributions. To assess BERM assumptions and the interpretation of associated findings, Fischer 344/DuCrl rats were trained on a heterogeneous tandem VI fixed-ratio (FR) schedule of reinforcement intended to dissociate the components of operant behavior. Initial (VI) and terminal (FR) links were programmed on separate levers; no stimulus signaled the completion of the initial link. FR requirement, VI requirement, and deprivation level were varied. Typical performance consisted of single responses on the VI lever separated by response runs on the FR lever. It was hypothesized that (a) the interval between the end of each FR run and the first subsequent VI response (FR-VI IRTs) would constitute between-bout IRTs, and would be sensitive to changes in VI requirement and deprivation level, (b) FR runs would constitute response bouts, so the length of a fraction of them would be selectively sensitive to changes in FR requirement, and (c) intervals between consecutive FR responses (FR-FR IRTs) would constitute within-bout IRTs, and would be relatively robust to all manipulations. Findings were consistent with these expectations. The underlying distributions of FR-FR IRTs, FR-VI IRTs, and FR run lengths, however, were inconsistent with BERM assumptions. These data support the distinct components of operant performance, but challenge the simple processes assumed to underlie their generation. (PsycINFO Database Record PMID- 29120214 TI - Reinforcement learning models of risky choice and the promotion of risk-taking by losses disguised as wins in rats. AB - Risky decisions are inherently characterized by the potential to receive gains or incur losses, and these outcomes have distinct effects on subsequent decision making. One important factor is that individuals engage in loss-chasing, in which the reception of a loss is followed by relatively increased risk-taking. Unfortunately, the mechanisms of loss-chasing are poorly understood, despite the potential importance for understanding pathological choice behavior. The goal of the present experiment was to illuminate the mechanisms governing individual differences in loss-chasing and risky-choice behaviors. Rats chose between a low uncertainty outcome that always delivered a variable amount of reward and a high uncertainty outcome that probabilistically delivered reward. Loss-processing and loss-chasing were assessed in the context of losses disguised as wins (LDWs), which are loss outcomes that are presented along with gain-related stimuli. LDWs have been suggested to interfere with adaptive decision-making in humans and thus potentially increase loss-making. Here, the rats presented with LDWs were riskier, in that they made more choices for the high-uncertainty outcome. A series of nonlinear models were fit to individual rats' data to elucidate the possible psychological mechanisms that best account for individual differences in high-uncertainty choices and loss-chasing behaviors. The models suggested that the rats presented with LDWs were more prone to showing a stay bias following high-uncertainty outcomes compared to rats not presented with LDWs. These results collectively suggest that LDWs acquire conditioned reinforcement properties that encourage continued risk-taking and increase loss-chasing following previous high risk decisions. (PsycINFO Database Record PMID- 29120216 TI - Bridging the gap: Learning of acoustic nonadjacent dependencies by a songbird. AB - Many animal species can detect dependencies between adjacent visual or auditory items in a string. Compared with adjacent dependencies, detecting nonadjacent dependencies, as present in linguistic constructions, is more challenging as this requires detecting a relation between items irrespective of the number and nature of the intervening items. There is limited evidence that nonhuman animals can detect such dependencies. An animal group in which such abilities might be expected is songbirds, which have learned songs consisting of a series of vocal elements given in specific sequences. So far no songbird (or other bird species) has been tested for its ability to detect nonadjacent dependencies. We examined whether zebra finches can detect the dependencies between items at the edges of artificially arranged strings of song elements. Zebra finches were trained to discriminate 2 sets of dependent song elements that always appeared in the same order (A and B; C and D), from other element combinations (AD, AC, BD, CB, CA, DB). The element combinations were separated by intervening (I) elements. Subsequent tests revealed that the finches could generalize the learned dependencies over different numbers and types of intervening items. Our findings show that the ability for detecting nonadjacent dependencies is not limited to humans or primates, and lend support to theories that suggest that nonadjacent dependencies can be learned by a nonlinguistic associative learning process. (PsycINFO Database Record PMID- 29120217 TI - PDTRT special section: Treatment of personality. AB - The purpose of this Special Section of Personality Disorders: Theory, Research, and Treatment is to highlight two efforts to development treatment programs for two of the five domains of the five-factor model of personality disorder: neuroticism and conscientiousness. (PsycINFO Database Record PMID- 29120218 TI - Addressing neuroticism in psychological treatment. AB - Neuroticism has long been associated with psychopathology and there is increasing evidence that this trait represents a shared vulnerability responsible for the development and maintenance of a range of common mental disorders. Given that neuroticism may be more malleable than previously thought, targeting this trait in treatment, rather than its specific manifestations (e.g., anxiety, mood, and personality disorders), may represent a more efficient and cost-effective approach to psychological treatment. The goals of the current manuscript are to (a) review the role of neuroticism in the development of common mental disorders, (b) describe the evidence of its malleability, and (c) review interventions that have been explicitly developed to target this trait in treatment. Implications for shifting the focus of psychological treatment to underlying vulnerabilities, such as neuroticism, rather than on the manifest symptoms of mental health conditions, are also discussed. (PsycINFO Database Record PMID- 29120219 TI - How to change conscientiousness: The sociogenomic trait intervention model. AB - Conscientiousness, the propensity to be organized, responsible, self-controlled, industrious, and rule-following, is related to numerous important outcomes including many forms of psychopathology. Given the increasing awareness of the importance of conscientiousness, it is becoming common to want to understand how to foster it. In this paper we first describe and update a recent model that was put forward as a theoretically informed intervention to change conscientiousness. We then consider recent life span theories focused on conscientiousness that might inform how best to use existing interventions as well as identify potential moderators of the effectiveness of intervention. Finally, we integrate these perspectives into a framework for how to foster conscientiousness that we label the Sociogenomic Trait Intervention Model (STIM). (PsycINFO Database Record PMID- 29120220 TI - Enantioselective supercritical fluid chromatography-tandem mass spectrometry method for simultaneous estimation of risperidone and its 9-hydroxyl metabolites in rat plasma. AB - AIM: Objective of the current work was to develop a 'green chemistry' compliant selective and sensitive supercritical fluid chromatography-tandem mass spectrometry method for simultaneous estimation of risperidone (RIS) and its chiral metabolites in rat plasma. Methodology & results: Agilent 1260 Infinity analytical supercritical fluid chromatography system resolved RIS and its chiral metabolites within runtime of 6 min using a gradient chromatography method. Using a simple protein precipitation sample preparation followed by mass spectrometric detection achieved a sensitivity of 0.92 nM (lower limit of quantification). With linearity over four log units (0.91-7500 nM), the method was found to be selective, accurate, precise and robust. CONCLUSION: The method was validated and was successfully applied for simultaneous estimation of RIS and 9 hydroxyrisperidone metabolites (R & S individually) after intravenous and per oral administration to rats. PMID- 29120221 TI - [Articles of the Hungarian Medical Journal from July, 1984]. PMID- 29120222 TI - Current practices and future outlook on the integration of biomarkers in the drug development process. AB - Over the last decade, there has been broad incorporation of translational biomarkers into the early drug development process to predict safety concerns, measure target engagement and monitor disease progression. One goal of translational biomarkers is to create a cycle whereby preclinical readouts influence candidate selection and subsequent clinical data are fed back into research to facilitate better decision making. Successes have been limited and not as broad in scope as desired. Collaborations between industry and regulators have increased the number of qualified biomarkers; but the process is lengthy and expensive. A high level overview of translational biomarkers as well as a discussion of some of the successes and failures encountered in development is discussed here. PMID- 29120223 TI - [Articles of the Hungarian Medical Journal from December, 1993]. PMID- 29120224 TI - Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II-The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer. AB - CONTEXT: - The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti-programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability-high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability-high CRC. OBJECTIVES: - To review the immune response to cancer and the role of immune checkpoints, focusing on the technical and interpretation challenges of PD-1/programmed death ligand-1 (PD-L1) testing by pathologists and the clinical implications of the test and the therapeutic potential of treating CRC with checkpoint inhibitors. DATA SOURCES: - A PubMed review was performed of articles pertaining to CRC, microsatellite instability and mismatch repair systems, molecular classification, immune response, PD-1/PD L1, and immunotherapy. CONCLUSIONS: - Exciting success with anti-PD-1/PD-L1 and anticytotoxic T-lymphocyte-associated protein 4 (CTLA4) checkpoint inhibitors has already been reported in melanoma and in lung and renal carcinomas. Recently, microsatellite instability-high CRCs, expressing PD-L1 by immunohistochemistry, regardless of the level of that PD-L1 expression, appeared to respond to checkpoint blockades with anti-PD-1 or anti-PD-L1 agents, whereas microsatellite stable tumors were much less responsive. With microsatellite instability routinely tested by most centers, studies that include larger cohorts are required to study the predictive role of PD-1/PD-L1 expression in microsatellite instability-high CRC, to assess which immunohistochemistry antibodies to use, to refine the scoring criteria, and to critically analyze the interpretation pitfalls. PMID- 29120227 TI - [Articles of the Hungarian Medical Journal from July, 1969]. PMID- 29120226 TI - Qualitative interviews to identify burden of illness, impacts and costs associated with surgical site infections. AB - AIM: To gather qualitative data from patients on the burden, impacts and costs of surgical site infections (SSI) requiring second surgeries. PATIENTS & METHODS: 15 adults with SSIs from spinal (n = 4), knee replacement (n = 3) or hip replacement (n = 8) surgery participated in a focus group or individual interview. Patients completed the PROMIS Physical Functioning (PF) Short Form 10A (PROMIS-PF). RESULTS: Patients reported impacts within four primary domains: PF/activity related; social/emotional; financial/employment; and energy/sleep. The mean PROMIS-PF score was 39.3 (standard deviation = 12.1), over one standard deviation below 50, the US norm. CONCLUSION: SSIs impart a broad and significant impact on patients and their families. These burdens will be important to capture when selecting patient-reported outcome measures for this patient population. PMID- 29120225 TI - Descriptive Values for Dancers on Baseline Concussion Tools. AB - CONTEXT: Capturing baseline data before a concussion can be a valuable tool in individualized care. However, not all athletes, including dancers, have access to baseline testing. When baseline examinations were not performed, clinicians consult normative values. Dancers are unique athletes; therefore, describing values specific to dancers may assist those working with these athletes in making more informed decisions. OBJECTIVE: To describe values for key concussion measures of dancers. Our secondary aim was to examine whether differences existed between sexes and professional status. Finally, we explored factors that may affect dancers' scores. DESIGN: Cross-sectional study. SETTING: Professional dance companies and a collegiate dance conservatory. PATIENTS OR OTHER PARTICIPANTS: A total of 238 dancers (university = 153, professional = 85; women = 171; men = 67; age = 21.1 +/- 4.8 years). MAIN OUTCOME MEASURE(S): We calculated the total symptom severity from the Sport Concussion Assessment Tool 3rd edition; the Standardized Assessment of Concussion score; the modified Balance Error Scoring System score; and the King-Devick score for each participant. Group differences were analyzed with Mann-Whitney or t tests, depending on the data distribution. We used bivariate correlations to explore the effects of other potential influencing factors. RESULTS: Participants demonstrated the following baseline outcomes: symptom severity = 16.6 +/- 12.8; Standardized Assessment of Concussion = 27.5 +/- 1.8; modified Balance Error Scoring System = 3.2 +/- 3.1 errors; and King-Devick = 41.5 +/- 8.2 seconds. A Mann-Whitney test revealed differences in King-Devick scores between female (40.8 +/- 8.0 seconds) and male (43.4 +/- 8.4 seconds) dancers ( P = .04). An independent-samples t test also demonstrated a difference in modified Balance Error Scoring System scores between female (2.95 +/- 3.1 errors) and male (3.8 +/ 3.1 errors) dancers ( P = .02). Age, hours of sleep, height, and history of concussion, depression, or injury did not display moderate or strong associations with any of the outcome measures. CONCLUSIONS: Dancers' symptom severity scores appeared to be higher than the values reported for other athletes. Additional studies are needed to establish normative values and develop a model for predicting baseline scores. PMID- 29120228 TI - The 8th Japan Bioanalysis Forum symposium. AB - The 8th Japan Bioanalysis Forum symposium, the Tower Hall Funabori, Tokyo, Japan, 8-9 February 2017 The 8th Japan Bioanalysis Forum (JBF) symposium was successfully held between 8 and 9 February 2017 at the Tower Hall Funabori, Tokyo, Japan. In total, 24 speakers from Japan, USA and Europe gave presentations regarding the immunogenicity of biopharmaceuticals, ICH S3A Q&A microsampling, ICH M10 bioanalytical method validation, large molecule analysis through LC-MS, auditing activities for bioanalysis and biomarker bioanalysis. Achievements regarding eight diverse themes were also shared by Japan Bioanalysis Forum discussion groups. Over 300 scientists from regulatory agencies, industry and academia actively took part in discussions during the symposium. This article provides the highlights of all the topics discussed in this symposium. PMID- 29120229 TI - [Articles of the Hungarian Medical Journal from January, 1989]. PMID- 29120230 TI - [Articles of the Hungarian Medical Journal from November, 1987]. PMID- 29120232 TI - [Articles of the Hungarian Medical Journal from December, 1967]. PMID- 29120231 TI - Impact of Clear Corneal Incision Morphology on Incision-Site Descemet Membrane Detachment in Conventional and Femtosecond Laser-Assisted Phacoemulsification. AB - PURPOSE: To assess intraoperative morphology of clear corneal incisions (CCI) and its impact on incision-site descemet membrane detachment (DMD) in conventional phacoemulsification and femtosecond laser-assisted cataract surgery (FLACS). METHODS: Prospective comparative study of 129 eyes that underwent either conventional phacoemulsification (Group I, n = 77) or FLACS (Group II, n = 52) was undertaken at an apex tertiary care ophthalmic setup. In group I, a 2.2-mm metal keratome was used to create a biplanar CCI. In group II, femtosecond laser assisted biplanar CCI was created with 2.2 mm diameter. Incision architecture and incision-site DMD were assessed using microscope-integrated intraoperative OCT (iOCT) and anterior segment OCT on postoperative day (POD) 1 and 30. Visual acuity was assessed on POD 1 and 30. RESULTS: Smooth slit (SS) or ragged slit (RS) morphology of the proximal opening of CCI was observed immediately after creation [Group I: 68.8% SS, 31.2% RS; Group II: 86.5% SS, 13.5% RS]. DMD was observed in 87.1% cases with RS and 16.3% cases with SS morphology (p < 0.001). DMD was more frequent in group I (Group I = 38/77, Group II = 5/52; p < 0.001) and most commonly observed during the step of stromal hydration (83.7%). DMD was self-resolving and did not persist in any group at 1 month. Visual acuity was comparable in both groups on POD 1 and 30. CONCLUSION: Ragged morphology of proximal opening of CCI is the most important predictive factor for incision-site DMD. Femtosecond-laser CCIs have less incision-site DMD as compared to keratome assisted CCIs. iOCT provides real-time assessment of CCI morphology and DMD. PMID- 29120233 TI - Development of a high-performance, enterprise-level, multimode LC-MS/MS autosampler for drug discovery. PMID- 29120234 TI - Immunogenicity and biomarkers: bioanalytical challenges and considerations. PMID- 29120235 TI - [Articles of the Hungarian Medical Journal from April, 2004]. PMID- 29120236 TI - [Articles of the Hungarian Medical Journal from June, 1989]. PMID- 29120238 TI - Incurred sample reanalysis: adjusted procedure for sample size calculation. AB - AIM: The incurred sample reanalysis (ISR) helps to assure bioanalysis reliability. The regulatory guidelines recommend the reanalysis of up to 10% of the study samples for this test, but not all reanalyses are necessary to evaluate the test result. MATERIALS & METHODS: We have optimized ISR sample size calculation to eliminate negligible reanalyses. RESULTS: Adjusted procedure eliminates negligible reanalyses - up to 66% of currently analyzed ISRs - without affecting the test outcome. CONCLUSION: The procedure is universal as it may be applied in the studies compliant with EMA and US FDA requirements, for both small and large molecules. It may assist the evolution of bioanalytical method validation as the current ISR sample size recommendations seem to be ill-matched with the acceptance criteria. PMID- 29120237 TI - Does service timing matter for psychological outcomes in cardiac rehabilitation? Insights from the National Audit of Cardiac Rehabilitation. AB - Background The presence of mental health conditions in cardiac rehabilitation (CR) patients such as anxiety and depression can lead to reduced programme adherence, increased mortality and increased re-occurrence of cardiovascular events undermining the aims and benefit of CR. Earlier research has identified a relationship between delayed commencement of CR and poorer physical activity outcomes. This study wished to explore whether a similar relationship between CR wait time and mental health outcomes can be found and to what degree participation in CR varies by mental health status. Methods Data from the UK National Audit of Cardiac Rehabilitation, a dataset that captures information on routine CR practice and patient outcomes, was extracted between 2012 and 2016. Logistic and multinomial regression models were used to explore the relationship between timing of CR and mental health outcomes measured on the hospital anxiety and depression scale. Results The results of this study showed participation in CR varied by mental health status, particularly in relation to completion of CR, with a higher proportion of non-completers with symptoms of anxiety (5% higher) and symptoms of depression (8% higher). Regression analyses also revealed that delays to CR commencement significantly impact mental health outcomes post-CR. Conclusion In these analyses CR wait time has been shown to predict the outcome of anxiety and depression status to the extent that delays in starting CR are detrimental. Programmes falling outside the 4-week window for commencement of CR following referral must strive to reduce wait times to avoid negative impacts to patient outcome. PMID- 29120239 TI - New holosystolic murmur after acute myocardial infarction. AB - In the era of primary percutaneous coronary intervention, mechanical complications after acute myocardial infarction are extremely rare, with an incidence of less than 0.5%. Rupture of the ventricular septum is the least frequent occurrence. Nevertheless, current mortality remains high and a prompt diagnosis and treatment are imperative to increase survival. Despite early surgical repair, mortality still remains high. PMID- 29120240 TI - Routes to drug design via bioisosterism of carboxyl and sulfonamide groups. AB - AIM: The similarity in the biological function of the bioisosteric pair, carboxyl and sulfonamide functional groups, is studied using the quantitative tool, average electron density of the bioisosteric moiety in drug molecules and the qualitative tool, electrostatic potential. Results/methodology: Five different capping groups (methyl, phenyl, chlorine, hydrogen and amine) were considered to investigate the effect of the environment on the properties of the bioisosteres. The molecules were considered in their neutral and anionic forms to account for the change in pH depending on the medium of the drug-receptor interactions. CONCLUSION: The new developed approach, average electron density, is not only advantageous as a qualitative descriptor, it is also more consistent compared with the conventionally accepted method, electrostatic potential, especially for the anions. PMID- 29120241 TI - Communication and the Appraisal of Uncertainty: Exploring Parents' Communication with Credible Authorities in the Context of Chronic Childhood Illness. AB - Individuals with chronic illnesses must manage long-term uncertainty as they cope with the ways the illness influences their lives. In the context of pediatric illnesses, parents must manage uncertainty during the diagnosis and treatment of their child's illness. It is common for children with complex chronic illnesses to see multiple specialists for the treatment of their condition. While previous research has explored parents' uncertainty during a child's diagnosis and during end-of-life care, less is known about these experiences when the child is referred to a team of specialists for treatment. The aim of the current study was to explore how specialists, as credible authorities, influence parents' uncertainty during parents' first visit to a multidisciplinary clinic for the care of their child's complex chronic illness. Data were collected through semi structured interviews with 29 parents after their child's first visit to a vascular anomaly clinic at a large Midwestern children's hospital. The results suggest parents' communication with credible authorities facilitates effective uncertainty management primarily through the mechanism of uncertainty reappraisal. The results also suggest that specialists, as credible authorities, are a key mechanism in the appraisal of uncertainty for conditions that are often misdiagnosed and mismanaged. PMID- 29120242 TI - EHASO: Lessons for the Future. PMID- 29120243 TI - Letters From Our Readers. PMID- 29120244 TI - Letters From Our Readers. PMID- 29120247 TI - Clinician Perceptions Related to the Use of the CBT-I Coach Mobile App. AB - OBJECTIVE: Clinicians' perceptions of CBT-I Coach, a patient-facing mobile app for cognitive-behavioral therapy for insomnia (CBT-I), are critical to its adoption and integration into practice. Diffusion of innovations theory emphasizes the influence of perceptions, including the relative advantage to current practice, the compatibility to clinicians' needs, the complexity, the innovation's trialability, and observability. This study intended to evaluate the use and perceptions of CBT-I Coach among Veterans Affairs (VA)-trained CBT-I clinicians. PARTICIPANTS AND METHODS: Clinicians (N = 108) were surveyed about their use, feedback, and perceptions of CBT-I Coach a year after the app became available. RESULTS: Overall perceptions of CBT-I Coach were favorable. Fifty percent of clinicians reported using CBT-I Coach, with 98% intending to continue use. The app was perceived to increase sleep diary completion and homework compliance. Clinicians viewed the app as providing accessibility to helpful tools and improving patient engagement. Of those not using the app, 83% endorsed intention to use it. Reasons for nonuse were lack of patient access to smart phones, not being aware of the app, not having time to learn it, and inability to directly access app data. Those who reported using CBT-I Coach had more favorable perceptions across all constructs (p < .01 - p < .001), except relative advantage, compared to nonusers. Users perceived it as less complex and more compatible with their practice than nonusers. CONCLUSIONS: Continued efforts are needed to increase adoption and enhance use of CBT-I Coach, as well as study if reported benefits can be evidenced more directly. PMID- 29120248 TI - The Evaluation of Anatomic and Functional Changes in Unilateral Moderate Amblyopic Eyes Using Optical Coherence Tomography and Pupil Cycle Time. AB - PURPOSE: To investigate whether macular anatomic structure and afferent visual system function differ among amblyopic eyes, non-amblyopic fellow eyes, and controls, using spectral-domain optical coherence tomography (SD-OCT), and pupil cycle time (PCT). METHODS: This observational, cross-sectional study included 30 patients with unilateral amblyopia and 30 healthy subjects. Optical coherence tomography (OCT) and pupil cycle time (PCT) were used to evaluate patients with unilateral amblyopia and were compared with their non-amblyopic fellow eyes and age- and gender-matched healthy eyes (30 participants). The amblyopic eyes were separated into two groups: anisometropic amblyopia (n = 16) and strabismic amblyopia (n = 14). OCT maps were used to calculate central macular thickness (CMT), retinal nerve fiber layer thickness (RNFLT), and ganglion cell-inner plexiform layer (GC-IPL) thickness. RESULTS: The average RNFLT, GC-IPL thickness, and CMT did not show any significant differences among the amblyopic eyes, non amblyopic fellow eyes and controls (p > 0.05, Kruskal-Wallis test). Mean PCT was 773.57 +/- 64 msn in strabismic eyes, 771.25 +/- 58 msn in anisometropic eyes, 778.00 +/- 72 msn in non-amblyopic fellow eyes, and 774.75 +/- 69 msn in control eyes. The differences among the amblyopic eyes, its fellow and control eyes were not statistically significant (p > 0.05, Kruskal-Wallis test). CONCLUSIONS: In this study, we investigated morphological and functional differences among amblyopic eyes, non-amblyopic fellow eyes and controls by using SD-OCT and PCT. We did not find anatomical or functional changes in amblyopic eyes. PMID- 29120249 TI - Alcohol addiction - the safety of available approved treatment options. AB - INTRODUCTION: Alcohol Use Disorders (AUD) is a leading cause of mortality and morbidity worldwide. At present disulfiram, naltrexone and acamprosate are approved for the treatment of AUD in U.S. and Europe. Nalmefene is approved in Europe and sodium oxybate is approved in Italy and Austria only. Baclofen received a 'temporary recommendation for use' in France. Areas covered: The safety of the above mentioned medications on liver, digestive system, kidney function, nervous system, pregnancy and lactation and their possible side effects are described and discussed. Expert opinion: Mechanism of action and metabolism of these drugs as well as patients' clinical characteristics can affect the safety of treatment. All approved medications are valid tools for the treatment of AUD in patients without advanced liver disease. For some drugs, attention should be paid to patients with renal failure and medications may be used with caution, adjusting the dosage according to kidney function. In patients with AUD and advanced liver disease, at present only baclofen has been formally tested in randomized controlled trials showing its safety in this population. PMID- 29120250 TI - Retinal Vascular Caliber Changes After Topical Nepafenac Treatment for Diabetic Macular Edema. AB - PURPOSE: To assess changes in retinal vascular caliber in response to short-term use of nepafenac eye drops in patients with mild diabetic macular edema. MATERIALS AND METHODS: Thirty-four patients with previously untreated bilateral mild diabetic macular edema were included in this prospective study. For each participant, one eye was randomly assigned to nepafenac treatment (0.1%, three times/day) and the other eye was left untreated throughout the study. Using digital fundus photographs, retinal vascular calibers were calculated and compared in treated and untreated eyes at the baseline, week 1, and week 6. RESULTS: Baseline vessel diameters did not differ in treated and fellow eyes (p > 0.05). Over the 6 weeks of the study, significant vasoconstriction of the retinal arteriolar caliber was observed at weeks 1 (p < 0.05) and 6 (p < 0.05), while an unchanged retinal venular caliber was noted between the treated and untreated eyes (p > 0.44). Significant macular thickness difference was only observed at week 6 (p = 0.002). CONCLUSIONS: Topical nepafenac has a significant narrowing effect on the retinal arteriolar diameter and a significant reductive effect on central macular thickness in eyes with mild diabetic retinopathy. PMID- 29120251 TI - Validity of the Flemish working alliance inventory in a Dutch physiotherapy setting in patients with shoulder pain. AB - BACKGROUND: Working alliance is the interaction between the patient and therapist. It is a crucial part of the physiotherapeutic process. One instrument to measure working alliance is available in Dutch/Flemish language and validated in psychotherapy setting. OBJECTIVE: This study aims to validate the Working Alliance Inventory Short-Form in a Dutch physiotherapy setting. DESIGN: A prospective cohort study in primary-care physiotherapy. METHOD: To validate the Dutch/Flemish version of the working alliance inventory short-form (WAV-12) a RASCH analysis was used. RESULTS: Sixty-six physiotherapists enrolled in total 389 patients with an average age of 50 years and a mean duration of shoulder pain of 33 weeks. A total of 274 patients filled in one or more items of the WAV-12. The WAV-12 showes good discriminative abilities and all items contributed to a one-dimensional construct. Due to the selective nature of the missing items, we believed rewording was necessary to make it more suitable to the physiotherapy setting. We performed a Delphi study and revised the WAV-12 into the PAS (Physio Alliance Scale). The validity of the revised version is unknown and is therefore not sufficiently strong to be implemented as a measurement tool. LIMITATIONS: The response rate for three items especially was low and we found ceiling effects in ten items. CONCLUSION: Although the measurement instrument shows good internal consistency and reliability, we made adjustments to the WAV-12 for Dutch physiotherapy setting. PMID- 29120252 TI - Interprofessional ethics education seminar for undergraduate health science students: A pilot study. AB - To prepare for the modern collaborative healthcare system, health science academia is charged with educating future professionals to be competent members of the interprofessional team. The purpose of this pilot study was to assess self efficacy for interprofessional education (IPE) in medical laboratory technology, dental hygiene, and nursing students before and after an IPE session. The specific topic of ethics was the focus of the session. The interprofessional seminar was designed to compare the codes of ethics from each programme through discussion and a case-based approach. The Self-Efficacy for Interprofessional Experiential Learning scale was used to collect quantitative data. A total of 75 participants rated self-efficacy for IPE before and after the educational offering. A paired sample t-test was used to analyse data. Significant results were found in students' pre- and post-test scores that indicated increased levels of self-efficacy related to working as a collaborative team for the benefit of the patient. Overall, there was an increase in participants' self-efficacy after collaborating with students from different health professions programmes. Healthcare students that learn together are more confident in their abilities to implement a team-structured approach, and understand that doing so will foster optimal patient wellbeing. PMID- 29120253 TI - Brain-Derived Neurotrophic Factor in Patients with Primary Open-Angle Glaucoma and Age-related Cataract. AB - PURPOSE: To study brain-derived neurotrophic factor (BDNF) content in aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with age related cataract and primary open-angle glaucoma (POAG). METHODS: BDNF was studied in 57 patients with age-related cataract, 55 patients with POAG combined with cataract, and 29 healthy controls (one eye in each person). AH was sampled during cataract surgery. RESULTS: The levels of BDNF in LF and BS did not differ in cataract patients and controls. The concentration of BDNF (pg/mL) in patients with POAG and cataract was lower than in cataract patients in AH (35.2 +/- 14.2 vs. 54.6 +/- 29.6, P < 0.001), LF (78.0 +/- 25.1 vs. 116.2 +/- 43.1, P < 0.001), and BS (19230 +/- 5960 vs. 22440 +/- 7580, P < 0.02), while the AH/LF ratio was similar (0.46 +/- 0.18 vs. 0.48 +/- 0.19). The AH level of BDNF declined in early POAG and relatively increased in the next stages of the disease, inversely correlating with visual field index (Pearson's correlation coefficient r = 0.404, P = 0.002) and average retinal nerve fiber layer thickness (r = -0.322, P = 0.018). BDNF contents in LF and BS were also the lowest in early POAG. BDNF in AH strongly correlated with its content in LF (r = 0.66, P < 0.000). A formula was suggested to calculate the AH concentration of BDNF basing on its content in LF. CONCLUSIONS: BDNF contents are decreased in AH, LF, and BS of patients with POAG demonstrating a significant decrease in the early POAG and relative increase in the next stages of the disease. A strong correlation exists between BDNF contents in AH and LF. PMID- 29120254 TI - Novel compound heterozygous mutations causing Kufs disease type B. AB - BACKGROUND: Kufs disease type B (also termed CLN13), an adult-onset form of neuronal ceroid lipofuscinosis (NCL), is genetically heterogeneous and challenging to diagnose. Recently, mutations in cathepsin-F have been identified as the causative gene for autosomal recessive Kufs disease type B. RESULTS: Here, we report a sporadic case of Kufs disease type B with novel compound heterozygous mutations, a novel missense mutation c.977G>T (p.C326F) and a novel nonsense mutation c.416C>A (p.S139X), in the cathepsin-F gene. The magnetic resonance imaging findings were consistent with those demonstrated in adult neuronal ceroid lipofuscinosis: diffuse cortical atrophy, mild hyperintensity and reduction of the deep white matter on T2-weighted images. A skin biopsy was negative for abnormalities. CONCLUSIONS: Altogether, our findings broaden the mutation database in relation to the neuronal ceroid lipofuscinosis, and the clinical diagnosis of Kufs disease type B was confirmed. PMID- 29120255 TI - Comparison of the Efficacy of Dexamethasone, Nepafenac, and Bromfenac for Preventing Pseudophakic Cystoid Macular Edema: an Open-label, Prospective, Randomized Controlled Trial. AB - PURPOSE: To evaluate the incidence of pseudophakic cystoid macular edema (PCMO) in patients treated with corticosteroids alone or in combination with bromfenac or nepafenac eyedrops after uneventful cataract surgery. MATERIALS AND METHODS: Prospective, randomized, open-label, placebo-controlled clinical trial. Patients who underwent routine cataract surgery with intraocular lens (IOL) implant were randomly divided into three groups receiving either bromfenac or nepafenac in association with dexamethasone or dexamethasone alone (control group) postoperatively. Best-corrected visual acuity (BCVA) measurement, slit lamp and fundus examination and optical coherence tomography (OCT) were performed preoperatively, 1 and 5 weeks after surgery. Primary outcome was defined as patients (%) in whom macular edema developed within 5 weeks after cataract surgery; secondary end points were patients (%) with BCVA improvement from pre-op through 5 weeks after surgery and corneal toxicity. RESULTS: A total of 144 patients completed the study, 48 for each group. In all groups, mean central subfield thickness at OCT increased significantly 5 weeks after surgery (p < 0.01). However, at this time point, four patients (8.3%) of the control group and none in nepafenac and bromfenac groups developed PCMO (p = 0.016). Compared with baseline, mean BCVA significantly improved both at 1 and 5 weeks in all groups (p < 0.01). At 1 week, the nepafenac group showed a mean BCVA significantly lower compared with both the control (p = 0.038) and bromfenac group (p = 0.002). CONCLUSIONS: Co-administration of nepafenac or bromfenac and steroids in patients who underwent routine cataract surgery is associated with a lower incidence of PCMO compared with steroid monotherapy. PMID- 29120256 TI - Silent but deadly: IS200 promotes pathogenicity in Salmonella Typhimurium. AB - Bacterial transposons were long thought of as selfish mobile genetic elements that propagate at the expense of 'host' bacterium fitness. However, limited transposition can benefit the host organism by promoting DNA rearrangements and facilitating horizontal gene transfer. Here we discuss and provide context for our recently published work which reported the surprising finding that an otherwise dormant transposon, IS200, encodes a regulatory RNA in Salmonella Typhimurium. This previous work identified a trans-acting sRNA that is encoded in the 5'UTR of IS200 transposase mRNA (tnpA). This sRNA represses expression of genes encoded within Salmonella Pathogenicity Island 1 (SPI-1), and accordingly limits invasion into non-phagocytic cells in vitro. We present new data here that shows IS200 elements are important for colonization of the mouse gastrointestinal tract. We discuss our previous and current findings in the context of transposon biology and suggest that otherwise 'silent' transposons may in fact play an important role in controlling host gene expression. PMID- 29120257 TI - Maternal effects of microRNAs in early embryogenesis. AB - The window of embryonic development after fertilization but prior to the beginning of transcription from the zygotic genome is a period that relies heavily on post-transcriptional regulation of gene expression. MicroRNAs constitute one of the predominant mechanisms of post-transcriptional gene regulation, yet their biological function and molecular mechanism of action during this developmental window is poorly understood. Our recent findings demonstrate that the maternal contribution of mir-35 family members contributes to zygotic developmental decisions (sex determination) in C. elegans embryogenesis. Here, I discuss these finding in the context of data from C. elegans and other model organisms regarding the regulation of maternal microRNA activity in early animal embryogenesis. PMID- 29120259 TI - Signal Alteration in the Optic Nerve Head on 3D T2-weighted MRI: a Potential Neuroimaging Sign of Glaucomatous Optic Neuropathy. AB - PURPOSE: To investigate whether a signal alteration (SA) in the optic nerve head (ONH) on 3D T2-weighted magnetic resonance imaging (MRI) is associated with glaucomatous optic neuropathy Materials and Methods: A total of 35 patients with bilateral open-angle glaucoma and 31 age-matched controls underwent 3D high resolution (0.98 * 0.98 * 1 mm3) T2-weighted MRI and detailed ophthalmologic examinations including spectral-domain optical coherence tomography (OCT). Two independent reviewers blinded to subject data determined mild or prominent SA on 3D T2-weighted MRI for the incomplete or complete loss of ocular hypointense continuity in the ONH, respectively. The prevalence of SAs was compared between the two groups with the chi-square test. The OCT measurements were compared among the eyes with a mild or prominent SA and those without an SA using the Kruskal Wallis test. RESULTS: Of the 35 eyes with glaucoma, 26 eyes (74.3%) exhibited an SA in the ONH, whereas it was observed in 5 (16.1%) of the 31 controls (P < 0.001). The eyes with a prominent SA had a significantly different average retinal nerve fiber layer thickness (P = 0.002) and the ONH parameters except for the disk area (all P < 0.001) than those without an SA. The eyes with a mild SA had a significantly narrower neural rim area, larger cup volume, and larger average and vertical cup-to-disk ratios compared with those without an SA (P = 0.011, 0.003, 0.004, and 0.004, respectively) Conclusions: The SA in the ONH on 3D T2-weighted MRI was significantly more frequent in eyes with open-angle glaucoma than in the controls. PMID- 29120258 TI - Evaluation of the alternative classification criteria of systemic lupus erythematosus established by Systemic Lupus International Collaborating Clinics (SLICC). AB - OBJECTIVE: To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan. METHODS: This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses. RESULTS: Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p < .01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses. CONCLUSION: Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population. PMID- 29120260 TI - Physiotherapists' encounters with "obese" patients: Exploring how embodied approaches gain significance. AB - BACKGROUND: Obesity is regarded as a modern lifestyle problem, causing illness, stigma, discrimination, and psychological problems. To help patients avoid these problems, physiotherapists increasingly engage in lifestyle programs specialized in weight loss. OBJECTIVE: To explore how physiotherapists' encounters with patients diagnosed as "obese" acquire significance for their development as clinicians. METHOD: The material draws on semi-structured interviews with eight physiotherapists. We conducted a thematic analysis inspired by van Manen's hermeneutic-phenomenological approach combined with Kvale and Brinkman's critical approach. FINDINGS: The analysis identified the following four themes: 1) Striving to find one's own style of communication; 2) Relating to bodily discrepancies; 3) Developing clinical competence through bodily encounters; and 4) Gaining insight into the dilemmas of group-based lifestyle programs. Taken together, our findings highlight bodily encounters between patients and physiotherapists as an invaluable source of insight. Such insight can shape physiotherapists' development as clinicians inspiring them to develop their unique ways of communicating so that patients diagnosed as obese can feel empowerment rather than failure and shame. At the same time, our findings point to the need of critically reflecting on ones' own approach entering a double role of both controller and supporter. As such, our findings complicate and extend previous work on stigma and shame. CONCLUSION: Our research leads us to conclude that more emphasis on critical thinking in physiotherapy is necessary. We suggest that this should be given more priority in research, education, as well as in clinical practice. PMID- 29120261 TI - Effects of vision and cognitive load on static postural control in subjects with and without patellofemoral pain syndrome. AB - OBJECTIVE: To compare the effects of vision and cognitive load on static postural control in subjects with and without patellofemoral pain syndrome (PFPS). METHODS: Twenty-eight PFPS patients and 28 controls participated in the study. Postural control was assessed in isolation as well as with visual manipulation and cognitive loading on symptomatic limb. The outcome measures of postural control were quantified in terms of area, anterior-posterior (AP), medial-lateral (ML), and mean velocity (MV) of the displacements of center of pressure (COP). In addition, cognitive performance (auditory Stroop task) was measured in the forms of average reaction time and error ratio in baseline (sitting) and different postural conditions. RESULTS: PFPS subjects showed greater increases in area (p = 0.01), AP (p = 0.01), and ML (p = 0.05) displacements of COP in the blindfolded tasks as compared to control group. However, cognitive load did not differently affect postural control in the two groups. Although PFPS and control group had similar reaction times in the sitting position (p = 0.29), PFPS subjects had longer reaction times than healthy subjects in dual task conditions (p = 0.04). CONCLUSION: Visual inputs seem to be essential for discriminating postural control between PFPS and healthy individuals. PFPS patients biased toward decreasing cognitive performance more than healthy subjects when they perform the single leg stance and cognitive task concurrently. PMID- 29120262 TI - Evaluation of Efficacy and Safety of Brimonidine Tartrate Ophthalmic Solution, 0.025% for Treatment of Ocular Redness. AB - : Purpose/Aims: This study assessed the efficacy and safety of brimonidine tartrate ophthalmic solution, 0.025% for treating ocular redness in adult subjects. MATERIALS AND METHODS: This was a single-center, double-masked, randomized, vehicle-controlled, parallel-group study in subjects >=40 years, with ocular redness. Subjects were randomized 2:1 to brimonidine or vehicle, instilled QID for four weeks. Subjects completed four visits, the last occurring one week after treatment discontinuation. The investigator assessed ocular redness on a scale of 0-4 pre-instillation and 5-240 minutes post-instillation on Day 0, pre instillation and 5 minutes post-instillation on Days 14 and 28, and on Day35; subjects assessed redness in diaries throughout the 28-day treatment period and following treatment discontinuation. Safety assessments included adverse events (AEs), rebound redness on treatment discontinuation, comprehensive ophthalmic exams, and vital signs. Drop comfort was assessed upon instillation, and 30 seconds and 1 minute post-instillation at Day 0. RESULTS: Fifty-seven subjects (brimonidine, n = 38; vehicle, n = 19) were randomized. Investigator-assessed ocular redness was significantly reduced with brimonidine across the entire post instillation time period (overall treatment difference: -1.37; P < 0.0001) and at all individual time points (P < 0.0001). Subject-assessed ocular redness was also significantly lower with brimonidine (P <= 0.0005). No tachyphylaxis was evident. There were few ocular AEs, all mild to moderate in severity, and no redness rebound was observed upon brimonidine discontinuation. There were no effects on any safety measures, and both brimonidine and its vehicle were reported to be very comfortable. CONCLUSIONS: Brimonidine 0.025% appeared safe, well tolerated, and reduced ocular redness for at least 4 hours. No tachyphylaxis or rebound redness upon treatment discontinuation was observed. PMID- 29120263 TI - tRNA-derived small RNAs: New players in genome protection against retrotransposons. AB - Previously believed to be mere random degradation products, tRNA-derived small RNAs have been lately connected to a series of functions that include, surprisingly, genome protection against retrotransposons. tRNAs have been known for a long time to be involved in the replication cycle of retroviruses, pararetroviruses and retrotransposons as primers of their reverse transcription. tRNA-derived small RNAs, as functional small RNAs or as mere tRNA degradation products, have emerged as important players in the regulation of genic transcription. Nevertheless, the involvement of functional sRNAs derived from tRNA transcripts in transposon posttranscriptional control is a regulatory layer that remained elusive until now. Here I review the recent discoveries in the field that connect tRNA-derived small RNAs and retrotransposon control. PMID- 29120264 TI - Treatment options for chorea. AB - INTRODUCTION: Chorea is defined as jerk-like movements that move randomly from one body part to another. It is due to a variety of disorders and although current symptomatic therapy is quite effective there are few etiology- or pathogenesis-targeted therapies. The aim of this review is to summarize our own experience and published evidence in the treatment of chorea. Areas covered: After evaluating current guidelines and clinical practices for chorea of all etiologies, PubMed was searched for the most recent clinical trials and reviews using the term 'chorea' cross referenced with specific drug names. Expert commentary: Inhibitors of presynaptic vesicular monoamine transporter type 2 (VMAT2) that cause striatal dopamine depletion, such as tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice in patients with chorea. Some clinicians also use dopamine receptor blockers (e.g. antipsychotics) and other drugs, including anti-epileptics and anti glutamatargics. 'Dopamine stabilizers' such as pridopidine and other experimental drugs are currently being investigated in the treatment of chorea. Deep brain stimulation is usually reserved for patients with disabling chorea despite optimal medical therapy. PMID- 29120265 TI - Do Journal Clubs Work? The Effectiveness of Journal Clubs in a Clinical Pastoral Education Residency Program. AB - Journal clubs are an established means of ongoing learning in medicine. Beginning with physicians in the nineteenth century, journal clubs have gradually become established in nursing and other allied health professions. However, their use in Clinical Pastoral Education (CPE) is relatively new. We describe the creation of a journal club for CPE residents and discuss the lessons learned from this effort. Over two years, a journal club was conducted with two different cohorts of residents. Residents were surveyed regarding the perceived strengths and weaknesses of the journal club and their recommendations for improvement. A small group of six to eight residents appears to be most effective. Focusing on a specific topic is preferable to broad-based readings. Residents preferred greater discussion about the applicability of the research findings to their clinical activity. Finally, the pros and cons of residents selecting articles and use of the Rush Research Summary Worksheet are discussed. PMID- 29120267 TI - Correction to Cross (2017). PMID- 29120268 TI - Treatment Mechanisms With Homeless Veterans. AB - OBJECTIVE: Emotion regulation and social processes that longitudinally predict depressive symptom change have not yet been investigated as mechanisms of change within a residential treatment context for homeless veterans with substance use issues. METHODS: A longitudinal data analysis of 186 homeless veterans enrolled in a six-month residential rehabilitation and addiction treatment program was conducted to investigate the role of six different emotion regulation variables as well the impact of two relationship quality constructs when measured at three time points across treatment. RESULTS: A large effect size reduction in depressive symptoms occurred during treatment (eta2 = .233), and further analyses revealed that early treatment changes in a single subtype of emotion regulation, one's ability to tolerate distress while engaging in goal-directed behavior, was the only mechanism that preceded continued reductions in depressive symptoms later in treatment (beta = .13, p < .001). Social mechanisms of change were not strong predictors of depressive symptom reduction. CONCLUSIONS: Distress tolerance skills, psychoeducation on the habituation process, and focusing on goal achievement may be particularly beneficial when treating substance use issues in homeless veterans who are also experiencing depressive symptoms during residential treatment. PMID- 29120266 TI - Increased Depression and Anxiety Symptoms are Associated with More Breakdowns in Cognitive Control to Cocaine Cues in Veterans with Cocaine Use Disorder. AB - OBJECTIVE: Cue-elicited craving is a clinically important aspect of cocaine addiction directly linked to cognitive control breakdowns and relapse to cocaine taking behavior. However, whether craving drives breakdowns in cognitive control toward cocaine cues in veterans, who experience significantly more co-occurring mood disorders, is unknown. The present study tests whether veterans have breakdowns in cognitive control because of cue-elicited craving or current anxiety or depression symptoms. METHODS: Twenty-four veterans with cocaine use disorder were cue-exposed, then tested on an antisaccade task in which participants were asked to control their eye movements toward cocaine or neutral cues by looking away from the cue. The relationship among cognitive control breakdowns (as measured by eye errors), cue-induced craving (changes in self reported craving following cocaine cue exposure), and mood measures (depression and anxiety) was investigated. RESULTS: Veterans made significantly more errors toward cocaine cues than neutral cues. Depression and anxiety scores, but not cue elicited craving, were significantly associated with increased subsequent errors toward cocaine cues for veterans. CONCLUSIONS: Increased depression and anxiety are specifically related to more cognitive control breakdowns toward cocaine cues in veterans. Depression and anxiety must be considered further in the etiology and treatment of cocaine use disorder in veterans. Furthermore, treating depression and anxiety as well, rather than solely alleviating craving levels, may prove a more effective combined treatment option in veterans with cocaine use disorder. PMID- 29120269 TI - The Association Between Racial Discrimination and Suicidality among African American Adolescents and Young Adults. AB - This study assessed the association between racial discrimination and suicidality (ideation, plan, or attempt) in African-American adolescents and young adults (n = 806, mean age = 17.9 years). Structured psychiatric phone interviews were conducted in offspring and their mothers in a high-risk alcoholism family study. Logistic regression analyses using offspring's own racial discrimination as a predictor revealed elevated odds of suicidality, even after adjusting for correlated psychiatric conditions (OR = 1.76) but was reduced to non-significance after adjusting for maternal experiences of racial discrimination (OR = 3.19 in males), depression, and problem drinking. Findings support a link between racial discrimination and suicidality in African-American youth that, for males, is partially explained by maternal racial discrimination. PMID- 29120270 TI - Explaining body size beliefs in anorexia. AB - INTRODUCTION: Cognitive neuropsychiatry has had much success in providing theoretical models for the causal origins of many delusional beliefs. Recently, it has been suggested that some anorexia nervosa patients' beliefs about their own body size should be considered delusions. As such, it seems high time the methods of cognitive neuropsychiatry were turned to modelling the false body size beliefs of anorexics. METHODS: In this paper, I adopt an empiricist approach to modelling the causal origins of false body size beliefs in anorexia. Within the background of cognitive neuropsychiatry, empiricist models claim that abnormal beliefs are grounded by abnormal experiences bearing similar content. RESULTS: I discuss the kinds of abnormal experiences of body size anorexics suffer from which could ground their false beliefs about body size. These oversized experiences come in three varieties: false self-other body comparisons, spontaneous mental imagery of a fat body and distorted perception of affordances. CONCLUSIONS: Further theoretical and empirical research into the oversized experiences which anorexics suffer from presents a promising avenue for understanding and treating the disorder. PMID- 29120271 TI - Apple Polyphenol Suppresses Indomethacin-Induced Gastric Damage in Experimental Animals by Lowering Oxidative Stress Status and Modulating the MAPK Signaling Pathway. AB - Indomethacin is a nonsteroid anti-inflammatory drug (NSAID) that is used to alleviate pain and inflammation in clinical medicine. Previous studies indicated that NSAIDs can cause gastrointestinal mucosal complications, and it is associated with mucosal lipid peroxidation and oxidative damage. Based on the evidences, decreasing oxidative stress may be an ideal therapeutic strategy for preventing gastrointestinal ulcer. Apple (Rosaceae Malus sp.) is one of the most commonly consumed fruits worldwide. The abundant polyphenolic constituents have received increasing attention for decades. In both in vivo and in vitro studies, the reports showed that apple polyphenol (AP) seems to provide an indirect antioxidant protection by activating cellular antioxidant enzymes to defend against oxidative stress. To address this issue and develop AP into a healthy improvement supplement, we studied the effect and potential mechanisms of AP in indomethacin-treated animal. The results showed AP can decelerate the gastric lesion, significantly suppress lipid peroxidation, increase the level of glutathione and the activity of catalase, and regulate the MAPK signaling proteins. These findings imply that AP protects the gastric mucosa from indomethacin-caused lesions and the protection is at least partially attributable to its antioxidative properties. This alternative medical function of AP may be a safe and effective intervention for preventing indomethacin-induced gastric complications. PMID- 29120272 TI - Factors associated with adherence to nutritional recommendations before and during pregnancy. AB - Several epidemiologic studies and clinical trials have demonstrated the value of balanced nutrition during pregnancy. This study aimed to examine the degree of adherence to nutritional recommendations among 1,175 pregnant Spanish women and the factors associated with such adherence to pre-pregnancy and during the first half of pregnancy. Data were collected during June 2004-March 2007 and included socio-demographic and lifestyle factors. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression models to identify factors associated with adherence to dietary recommendations. Before pregnancy, slightly less than one quarter of the pregnant women (21 percent) did not meet the recommended intake of both vegetables and cereals, and 50 percent did not meet the recommended intake of fruits. Yet most of the participants exceeded the recommended values for proteins. During pregnancy, the adherence for all food types decreased. Factors associated with adherence to the nutritional recommendations were similar before and during pregnancy. Adherence to the Spanish Society of Community Nutrition dietary recommendations was lower among pregnant women who were younger, from a low social class, smokers, and had a low level of physical activity. These findings suggest that nutritional education should become an essential part of antenatal care. PMID- 29120273 TI - Triple Therapy in COPD: What We Know and What We Don't. AB - Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA) and a long acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit. PMID- 29120276 TI - Personality Disorder Features and Paraphilic Interests Among Undergraduates: Differential Relations and Potential Antecedents. AB - We examined the relations between: (1) narcissism, psychopathy, DSM-5 personality disorder symptom counts; and (2) paraphilic interests among undergraduates (N = 608). Base rates of paraphilic interests were appreciable. The disinhibition and meanness features of psychopathy and the entitlement and exploitativeness features of narcissism were robustly associated with paraphilic interests, particularly sexual sadism, whereas the boldness features of narcissism and psychopathy were essentially unrelated to these interests. Narcissism and psychopathy features typically manifested the most pronounced relations with paraphilic interests, although antisocial personality disorder features were also strong predictors. By and large, these relations were comparable across gender. Lastly, there was no evidence that erotophilia mediated the relations between the narcissism and psychopathy features and paraphilic interests, most likely because erotophilia was generally unrelated to paraphilic interests. Relative to other dimensions of personality disorders, facets of meanness and disinhibition from psychopathy and entitlement/exploitativeness facets from narcissism were most associated with paraphilic interests. PMID- 29120275 TI - Ethnic differences in psychosocial factors in methadone maintenance: Hmong versus non-Hmong. AB - Little is known about the characteristics of U.S.-based Asian populations undergoing methadone maintenance treatment for opioid use disorders. We evaluated psychosocial factors in 76 Hmong and 130 non-Hmong on methadone maintenance for at least two months in a single urban methadone maintenance clinic. Assessments included the Addiction Severity Index 5th Edition, the Symptom Checklist-90, and the Structured Clinical Interview for DSM-IV Axis I Disorders. The Hmong were older, predominately male, and on lower doses of methadone than the non-Hmong. Hmong had significantly lower ASI composite scores across all dimensions except employment and legal. While the SCL-90 Global Severity Index (GSI) score did not differ between groups, the Hmong had lower scores in the interpersonal sensitivity, depression, anxiety, hostility, and paranoid ideation dimensions. Sixty-seven percent of Hmong and 29% of non-Hmong were without Axis I diagnoses (p < .001). There was no difference between the groups in DSM-IV substance use diagnoses. The extent to which these psychosocial differences impact methadone dose requirements and treatment outcomes in Hmong and non-Hmong remains unknown. PMID- 29120277 TI - Real-World Effectiveness of Clozapine for Borderline Personality Disorder: Results From a 2-Year Mirror-Image Study. AB - While some second-generation antipsychotics have shown efficacy on patients with borderline personality disorder (BPD), limited data exist regarding the effect of clozapine. Thus, we aimed to investigate the effects of clozapine on naturalistic outcomes in BPD patients with a 2-year mirror-image model. Among 25,916 patients with BPD, 1,107 redeemed >= 1 clozapine prescription. Of these, 18,188 were "specific" BPD patients, and 102 redeemed >= 1 clozapine prescription. During a mean observation period of 598.51 days, in all BPD patients, clozapine was associated with a significant reduction in psychiatric admissions from 2.52 (95% CI [2.31, 2.78]) to 2.00 (95% CI [1.77, 2.23]) admissions (p < .001) and a significant reduction in psychiatric bed-days from 190.08 (95% CI [176.84, 203.33]) to 65.95 (95% CI [58.27, 73.66]) bed-days (p < .001). Similar findings were found for "specific" BPD patients. The number of patients with intentional self-harm or overdose decreased significantly from 189 to 114 individuals (p < .001) after clozapine initiation. Randomized trials evaluating the risk-benefit ratio of clozapine in patients with severe BPD are warranted. PMID- 29120278 TI - Assessment of Pathological Traits in DSM-5 Personality Disorders by the DAPP-BQ: How Do These Traits Relate to the Six Personality Disorder Types of the Alternative Model? AB - The six personality disorder (PD) types in DSM-5 section III are intended to resemble their DSM-IV/DSM-5 section II PD counterparts, but are now described by the level of personality functioning (criterion A) and an assigned trait profile (criterion B). However, concerns have been raised about the validity of these PD types. The present study examined the continuity between the DSM-IV/DSM-5 section II PDs and the corresponding trait profiles of the six DSM-5 section III PDs in a sample of 350 Dutch psychiatric patients. Facets of the Dimensional Assessment of Personality Pathology-Basic Questionnaire (DAPP-BQ) were presumed as representations (proxies) of the DSM-5 section III traits. Correlational patterns between the DAPP-BQ and the six PDs were consistent with previous research between DAPP-BQ and DSM-IV PDs. Moreover, DAPP-BQ proxies were able to predict the six selected PDs. However, the assigned trait profile for each PD didn't fully match the corresponding PD. PMID- 29120279 TI - Substance Use in Youth With Borderline Personality Disorder. AB - Co-occurring substance misuse and borderline personality disorder (BPD) in adults is associated with more severe dysfunction and poorer prognosis than BPD alone. However, it is unknown to what extent substance use in youth with BPD is normative for this age group or pathological. This study compared substance use in 117 help-seeking youth (aged 15-25 years) with their first presentation for treatment of BPD, with an epidemiological general population sample and with healthy age- and gender-matched controls. Established instruments were used to diagnose BPD and assess substance use. Alcohol dependence, daily tobacco use, and use of illicit substances in the past month were between four and nine times more prevalent in the BPD group than in the general population. Similarly, the prevalence of substance use was disproportionately higher in youth with BPD than in matched controls. The findings indicate a non-normative, alarmingly high rate of substance use among youth with BPD. PMID- 29120280 TI - Self-Compassion Mediates the Relationship Between Mindfulness and Borderline Personality Disorder Symptoms. AB - Individuals suffering from borderline personality disorder (BPD) experience difficulties with mindfulness. How mindfulness influences BPD symptoms, however, is still unknown. We hypothesized that the relationship between mindfulness and BPD symptoms would be mediated by self-compassion. In study 1, we recruited 29 individuals with BPD and 30 group-matched healthy controls. In study 2, we complemented our results with findings from a larger, nonclinical sample of 89 participants that were recruited during an open-house event at the local university. All participants completed questionnaires assessing self-compassion, mindfulness, BPD symptom severity, and emotion dysregulation. In both studies, self-compassion mediated the relationship between mindfulness and BPD symptom severity as well as between mindfulness and emotion dysregulation. Self compassion seems to be one psychological process that could explain the relationship between mindfulness and BPD symptoms. One promising approach in therapy could be to target self-compassion more directly during mindfulness trainings and interventions. PMID- 29120281 TI - Psychological Distress is Correlated with Erectile Dysfunction Among Patients Receiving Methadone Maintenance in Taiwan. AB - OBJECTIVE: Although erectile dysfunction (ED) is prevalent in patients receiving long-term methadone maintenance, studies in Chinese culture exploring the relationship between psychological distress and ED are scarce. METHODS: One hundred eighty-seven male patients in methadone maintenance treatment were assessed in this cross-sectional study. Instruments included the Opiate Treatment Index (OTI) to evaluate the health-related consequences of methadone treatment and the Chinese Health Questionnaire-12 (CHQ-12) for the assessment of psychological distress, respectively. ED was defined by the International Index of Erectile Function 15. Quality of life was measured using the European Quality of Life-5 Dimensions. We constructed a multiple linear regression model to examine the associations between the determinants and ED. RESULTS: The CHQ-12 score had a significant relationship with the severity of ED after controlling for all important variables. The social functioning domain of the OTI and methadone dose was also significantly correlated with ED. CONCLUSIONS: The strong relationship between psychological distress and ED emphasized the importance of both diagnosis and management of ED among methadone patients receiving long-term maintenance treatment. The etiological relationship between methadone dose and ED require further investigation. PMID- 29120282 TI - Surgical Infection Society: We Endorse Antimicrobial Stewardship We Stand by Our International Colleagues and Societies in the Fight for Proper Antimicrobial Therapy. PMID- 29120283 TI - Expressions of Prayer in Residential Care Homes. AB - Although the value of spiritual care in the care of older adults is supported by research, few studies have focused specifically on prayer in residential care settings. This ethnographic study with fifteen chaplains and administrators in eleven residential care homes involved analyses of walking interviews and research diaries. Findings revealed the spaces in which prayer happens and the forms it takes. The identities of chaplains-their own spiritual practices, religious beliefs, and positioning within the facility-shaped their dis/comfort with prayer and how they located prayer within public and private spaces. Where organizational leadership endorsed the legitimacy of chaplaincy services, prayer was more likely to be offered. Even in these circumstances, however, religious diversity and questions about secularism left chaplains ambivalent about the appropriateness of prayer. The results demonstrate the relevance of religion and spirituality to residential care, and illustrate how prayer functions as an opportunity for connection and understanding. PMID- 29120284 TI - Becoming Friends of Time: Disability, Timefullness, and Gentle Discipleship. John Swinton. 2016. PMID- 29120285 TI - Women's satisfaction and perception of control in childbirth in three Arab countries. AB - Women's satisfaction and perceived control in childbirth are important attributes of the childbirth experience and quality of care indicators. This article presents findings from the pre-intervention phase of a multi-centre implementation study in Egypt, Lebanon and Syria, to introduce a labour companionship model in these countries. A sample of 2620 women giving birth in three public teaching hospitals from November 2014 to July 2015 in Beirut and Mansoura, and from November 2014 to April 2015 in Damascus were interviewed by trained field workers. Additional information was abstracted from medical charts. An adapted version of the Mackey Childbirth Satisfaction Rating Scale was used to measure women's satisfaction and the shortened version of the Labor Agentry Scale was used to assess perception of control. The total satisfaction score was high in all sites with the lowest being in Egypt. Perceived control was directly related to satisfaction. Women with low education levels had higher levels of childbirth satisfaction. Women who had fewer children from Egypt and Lebanon, and those who received care by a team including both male and female physicians in the Syrian hospital were more likely to be dissatisfied than their counterparts. Variations in the management and provision of care between the three countries may explain the differences in satisfaction levels observed. Further qualitative research is needed to deepen our understanding of the concepts of control and satisfaction in the Arab culture as well as to establish the factors associated with women's positive childbirth experiences to inform the provision of quality maternity care. PMID- 29120286 TI - When he is "tied": power, vulnerability, and embodied masculinity in Egypt. AB - This paper looks at the notion of rabt [tying], the inability of the groom to engage in penetrative intercourse on the wedding night, to explore the relationship between masculinity, embodiment, and sexual performance. Drawing on ethnographic fieldwork in Egypt between 1993 and 2015, this paper explores the notion of groom rabt, how it is socially defined and managed. After presenting my conceptual framework for the study of sexuality and embodiment, the paper moves to discuss the meaning of the wedding night; the social clues people draw on when they identify rabt; how these clues relate different events to the (in)abilities of the groom; and how women, particularly mothers, work to protect and heal their male relatives from this affliction. To understand moments when individuals are unable, or "fail," to produce desirable physical and social effects, it is important that we do not exclusively consider the individual sexed body - the body that is clearly defined, bounded, and invested with unique desires and feelings. We must also consider the broader configurations that connect different bodies, endow them with certain meanings, and produce their materiality. My discussion shows that our understanding of sexuality and reproductive health will continue to be limited if we consider only men or women as separate individuals or as autonomous couples. Exploring moments of biological-social vulnerability, such as rabt, and how they relate to broader projects of gendering helps us understand issues linked to reproductive health and sexual rights in a deeper sense. PMID- 29120287 TI - Coping with cancer diagnosis and treatment: a comparative study on women with breast cancer in Turkey and occupied Palestinian territory. AB - In this article, we explore the illness narratives of women with breast cancer in Turkey and the occupied Palestinian territory (oPt), underlining the similarities and differences in the ways in which they make sense of their diagnosis and cope with cancer treatment. The article is based on 30 and 35 semi-structured qualitative interviews conducted in Turkey and the oPt, respectively. We do find some parallels in the two settings. We find that a diagnosis of breast cancer is a dramatic event with very strong reactions among many women, with women in both settings pointing to sharp increases in cancer incidence. Interestingly, the perceived increase in the prevalence of breast cancer among women appears to make cancer more manageable. There are clear variations in the degree of medicalisation and prevalence of medical discourse in the two settings, with medical discourse around cancer more common in the Turkish context. Furthermore, socio-economic variations were more discernible in the Turkish setting, and perceived to impact care. The findings affirm that women's breast cancer experiences and the ways in which they make sense of their diagnosis are largely shaped by the cultural contexts they live in, within and across country and cultural settings. PMID- 29120288 TI - Reproductive health and rights in East Jerusalem: the effects of militarisation and biopolitics on the experiences of pregnancy and birth of Palestinians living in the Kufr 'Aqab neighbourhood. AB - Research with marginalised communities points to the need to understand political determinants of reproductive health. For residents of Kufr 'Aqab neighbourhood, Israeli biopolitics in East Jerusalem can be barriers to access to maternal health. This is manifested in women having to cross military checkpoints to give birth in hospitals located in Jerusalem to make their children eligible for "permanent residency", a document required for Palestinians to live in Jerusalem. A basic qualitative design is utilised, and semi-structured in-depth interviews with 27 women and 20 men were conducted and thematic analysis was used to extract themes and subthemes. Women reported exposure to risky conditions during pregnancy and worries of giving birth at checkpoints. Social support was restricted for some women due to inability of the husband/family to reach the hospital at the time of birth. Men reported distress related to inability to attend birth. Giving birth in a Jerusalem hospital, as part of passing residency to children, was perceived as reaffirming Palestinian presence in the City and transforming sites of suffering to sites of resistance. Israeli residency policies and segregation of Jerusalem affect Kufr 'Aqab residents' pregnancy and birth on physical, social and psychological levels. Results indicate the importance of incorporating political determinants of access to maternal care and safe pregnancy in the conceptualisation of reproductive rights. PMID- 29120289 TI - The gendered workplaces of women garment workers in Istanbul. AB - Drawing on 20 semi-structured interviews with women garment workers in a low income neighbourhood of Istanbul, and observations in the ateliers where they worked, this article examines their work experiences in the gendered and sexualised work atmosphere of garment workshops. There are three interrelated levels upon which the gender-related issues emerge in women garment workers' stories. The first set of discourses portrays young female garment workers in highly sexualised terms, and the second concerns the use of kinship vocabulary and avoidance of impersonal work relationships. That is, women workers' experiences in capitalist production sites were trivialised and regulated through the sexualisation of their bodies and the deployment of kinship idioms while addressing their role at the workplace. The third level analyses women's submissive, subversive or contradictory responses to these gendered disciplinary techniques and representations, i.e. the construction of their subjectivities. These three levels point to two things: first, cultural presumptions about marriage, women's sexuality and reproductive cycles are materialised at the workplace. Second, gendered instantiations of these presumptions in a specific work environment are both informed by their familial roles (such as daughter, wife, mother, widowed) and inform their future reproductive preferences (whether they marry, have a child, get a divorce, etc.). This article shows how the ways in which women's difference is construed and acted upon in the garment industry are inseparable from women's reproductive decisions. PMID- 29120290 TI - The business of desire: "Russian" bars in Amman, Jordan. AB - This paper discusses the type of work migrant women from the former Eastern European countries perform in nightclubs in Amman, Jordan. The fieldwork for this qualitative study was conducted in 2010 and is based on in-depth interviews with 13 women. The topic is approached from the perspective of describing women's choices and journeys to this work. It juxtaposes the sexualised nature of their work with their yearning for a "normal" family life, which they imagine, yet know, is impossible to achieve with the men they meet in their workplaces. Layered on top of these private desires among both women and their clients is the business strategy of the clubs, which operate in the lucrative but marginal space of selling exotic but respectable seduction. I draw on the literature about female migration to the Middle East in order to argue that hostesses in these bars perform affective labour akin to care work, within the neoliberal global economy that individualises risk. PMID- 29120291 TI - How they see it: young women's views on early marriage in a post-conflict setting. AB - Current understandings of early marriage in conflict and post-conflict settings are incomplete and under-researched, and do not sufficiently take into consideration the views and experiences of adolescent girls. While much of the literature, development reports and mainstream media emphasise the poverty, health risks and lack of agency of young women married early, they seldom provide these teenagers an open platform from which to speak. In 2007, a Palestinian refugee camp in North Lebanon was destroyed and its residents forced to flee. Returning families experienced extreme hardships and a military cordon. Through ethnographic research undertaken in the camp a year later with adolescent girls in or en route to an early marriage, their mothers and NGO community workers, I explored decision-making processes leading to an early marriage and adolescent brides' assessments of married life. The decision to enter an early marriage, neither unilateral nor imposed, was instead described as an assessment of numerous factors, including economic hardships, insecurity and loneliness, many arising as a result of the conflict. Findings of this study challenge common understandings of early marriage - both the decision and its consequences - and call for greater nuance in designing interventions. These findings are particularly pertinent amid sensationalised media reports of early marriage in Syrian refugee communities; presenting girls in early marriages as victims garners international attention, but is not necessarily an accurate reflection of these girls' own understandings of their situation. PMID- 29120292 TI - Survival and negotiation: narratives of severe (near-miss) neonatal complications of Syrian women in Lebanon. AB - The World Health Organization has elaborated a maternal and neonatal near-miss reporting, audit and feedback system designed to improve the quality of care during and after childbirth. As part of a four-hospital comparative study in the Middle East, this article discusses the experiences of mothers whose newborns suffered from severe complications at birth in the Rafik Hariri University Hospital, the only public hospital in Beirut. Based on in-depth home interviews several weeks after childbirth, it aims to explore the experience of neonatal near-miss events through the mothers' birth narratives. The central concerns of these vulnerable and marginalised women regarded access to neonatal care, and how to negotiate hospital bureaucracy and debt. It argues that financial and bureaucratic aspects of the near-miss event should be part of the audit system and policy-making, alongside medical issues, in the quest for equitable access to and management of quality perinatal care. PMID- 29120294 TI - Health research in a turbulent region: the Reproductive Health Working Group. AB - The Reproductive Health Working Group (RHWG) was established in 1988 in Cairo to advance research in the Arab countries and Turkey on the health of women, broadly defined. The paper considers the ways in which the group contributed to global health conversations through three examples of interdisciplinary research that, in privileging local contexts, modified or even challenged prevailing approaches to health and often raised entirely new issues for consideration. The three examples cited in the paper are: (i) the network's early research on reproductive morbidity; (ii) a broad set of ongoing studies on childbirth/maternal health; and (iii) emerging research on health and conflict. The paper discusses how the RHWG has strengthened research capability in the region, and explores the reasons for the longevity of this research network. PMID- 29120295 TI - Perspectives of displaced Syrian women and service providers on fertility behaviour and available services in West Bekaa, Lebanon. AB - Prior to the conflict, Syria had relatively high fertility rates. In 2010, it had the sixth highest total fertility rate in the Arab World, but it witnessed a fertility decline before the conflict in 2011. Displacement during conflict influences fertility behaviour, and meeting the contraceptive needs of displaced populations is complex. This study explored the perspectives of women and service providers about fertility behaviour of and service provision to Syrian refugee women in Bekaa, Lebanon. We used qualitative methodology to conduct 12 focus group discussions with Syrian refugee women grouped in different age categories and 13 in-depth interviews with care providers from the same region. Our findings indicate that the displacement of Syrians to Lebanon had implications on the fertility behaviour of the participants. Women brought their beliefs about preferred family size and norms about decision-making into an environment where they were exposed to both aid and hardship. The unaffordability of contraceptives in the Lebanese privatised health system compared to their free provision in Syria limited access to family planning services. Efforts are needed to maintain health resources and monitor health needs of the refugee population in order to improve access and use of services. PMID- 29120296 TI - Gendered bodies and reproduction in the Arab countries and Turkey. PMID- 29120297 TI - Recent US bluetongue virus serotype 3 isolates found outside of Florida indicate evidence of reassortment with co-circulating endemic serotypes. AB - Since 1999, 11 serotypes of bluetongue virus (BTV) similar to Central American or Caribbean strains have been isolated in the southeastern United States, predominantly in Florida. The majority of the incursive serotypes have remained restricted to the southeastern US. In recent years, BTV serotype 3 (BTV-3) has been isolated in areas increasingly distant from Florida. The current study uses whole genome sequencing of recent and historical BTV-3 isolates from the US, Central America and the Caribbean with additional sequences from GenBank to conduct phylogenetic analyses. The individual segments of the BTV genome were analysed to determine if recent BTV-3 isolates are reassortants containing genomic segments from endemic US serotypes or if they retain a majority of Central American/Caribbean genotypes. The analyses indicate that BTV-3 isolates Mississippi 2006, Arkansas 2008 and Mississippi 2009 are closely related reassortants that contain five to six genomic segments that are of US origin and two to three segments of Central American/Caribbean origin. In contrast, the BTV 3 South Dakota 2012 isolate contains seven genomic segments that are more similar to isolates from Central American and the Caribbean. These different evolutionary histories of the BTV-3 isolates suggest that there are at least two different lineages of BTV-3 that are currently circulating in the US. PMID- 29120298 TI - ICTV Virus Taxonomy Profile: Nyamiviridae. AB - The Nyamiviridae is a family of viruses with unsegmented, negative-sense RNA genomes of 11.3-12.2 kb that produce enveloped, spherical virions. Viruses of the genus Nyavirus are tick-borne and some also infect birds. Other nyamiviruses infecting parasitoid wasps and plant parasitic nematodes have been classified into the genera Peropuvirus and Socyvirus, respectively. This is a summary of the current International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Nyamiviridae, which is available at www.ictv.global/report/nyamiviridae. PMID- 29120299 TI - Bovine leukaemia virus genotypes 5 and 6 are circulating in cattle from the state of Sao Paulo, Brazil. AB - PURPOSE: Enzootic bovine leucosis (EBL) is a silent disease caused by a retrovirus [bovine leukaemia virus (BLV)]. BLV is classified into almost 10 genotypes that are distributed in several countries. The present research aimed to describe two BLV gp51 env sequences of strains detected in the state of Sao Paulo, Brazil and perform a phylogenetic analysis to compare them to other BLV gp51 env sequences of strains around the world. METHODOLOGY: Two bovines from different herds were admitted to the Bovine and Small Ruminant Hospital, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Brazil. In both, lymphosarcoma was detected and the presence of BLV was confirmed by nested PCR. The neighbour-joining algorithm distance method was used to genotype the BLV sequences by phylogenetic reconstruction, and the maximum likelihood method was used for the phylogenetic reconstruction. The phylogeny estimates were calculated by performing 1000 bootstrap replicates. RESULTS: Analysis of the partial envelope glycoprotein (env) gene sequences from two isolates (25 and 31) revealed two different genotypes of BLV. Isolate 25 clustered with ten genotype 6 isolates from Brazil, Argentina, Thailand and Paraguay. On the other hand, isolate 31 clustered with two genotype 5 isolates (one was also from Sao Paulo and one was from Costa Rica). The detected genotypes corroborate the results of previous studies conducted in the state of Sao Paulo, Brazil. The prediction of amino acids showed substitutions, particularly between positions 136 and 150 in 11 out of 13 sequences analysed, including sequences from GenBank. CONCLUSION: BLV is still important in Brazil and this research should be continued. PMID- 29120300 TI - Enterovirus 71 antagonizes the antiviral activity of host STAT3 and IL-6R with partial dependence on virus-induced miR-124. AB - Enterovirus 71 (EV71) has caused major outbreaks of hand, foot and mouth disease. EV71 infections increase the production of many host cytokines and pro inflammatory factors, including interleukin (IL)-6, IL-10 and COX-2. Some of these molecules could stimulate the signal transducer and activator of transcription 3 (STAT3), which plays a key role in regulating host immune responses and several viral diseases. However, the role of STAT3 in EV71 infection remains unknown. This study found that the phosphorylation levels of STAT3 (pY705-STAT3) are closely related to EV71 infection. Further experiments revealed that STAT3 exerts an anti-EV71 activity. However, the antiviral activity of STAT3 is partially antagonized by EV71-induced miR-124, which directly targets STAT3 mRNA. Similarly, IL-6R, the alpha-subunit of the IL-6 receptor complex, exhibits anti-EV71 activity and is directly targeted by the virus-induced miR 124. These results indicate that EV71 can evade host IL-6R- and STAT3-mediated antiviral activities by EV71-induced miR-124. This suggests that controlling miR 124 and the downstream targets, IL-6R and STAT3, might benefit the antiviral treatment of EV71 infection. PMID- 29120301 TI - Antimicrobial susceptibility, virulence potential and sequence types associated with Arcobacter strains recovered from human faeces. AB - PURPOSE: The genus Arcobacter includes bacteria that are considered emergent pathogens because they can produce infections in humans and animals. The most common symptoms are bloody and non-bloody persistent diarrhea but cases with abdominal cramps without diarrhea or asymptomatic cases have also been described as well as cases with bacteremia. The objective was to characterize Arcobacter clinical strains isolated from the faeces of patients from three Spanish hospitals. METHODOLOGY: We have characterized 28 clinical strains (27 of A. butzleri and one of A. cryaerophilus) isolated from faeces, analysing their epidemiological relationship using the multilocus sequence typing (MLST) approach and screening them for their antibiotic susceptibility and for the presence of virulence genes.Results/Key findings. Typing results showed that only one of the 28 identified sequence types (i.e. ST 2) was already present in the MLST database. The other 27 STs constituted new records because they included new alleles for five of the seven genes or new combinations of known alleles of the seven genes. All strains were positive for the ciaB virulence gene and sensitive to tetracycline. However, 7.4 % of the A. butzleri and A. cryaerophilus strains showed resistance to ciprofloxacin. CONCLUSION: The fact that epidemiological unrelated strains show the same ST indicates that other techniques with higher resolution should be developed to effectively recognize the infection source. Resistance to ciprofloxacin, one of the antibiotics recommended for the treatment of Arcobacter intestinal infections, demonstrated in 10.7 % of the strains, indicates the importance of selecting the most appropriate effective treatment. PMID- 29120302 TI - Foods and beverages available to children in settings outside of the home: Research, policy, and monitoring considerations. PMID- 29120303 TI - Lunch is ready... but not healthy: An analysis of lunches served in childcare centres in two Canadian provinces. AB - OBJECTIVES: Childcare centres (CCs) typically offer one meal and snacks daily. This study compared what is served in CCs with what the nutritional recommendations are; described and compared the nutritional composition of lunches served in CCs in New Brunswick and Saskatchewan; and examined differences between French and English, and urban and rural centres. METHODS: The study involved 61 randomly selected CCs in New Brunswick and Saskatchewan, Canada. Lunch content was measured on two consecutive days by weighing each food item served to children and by visually documenting the food items using digital photography. Food items were categorized into food groups according to Health Canada's Eating Well with Canada's Food Guide, and nutrients were analyzed using a nutritional analysis software. One-sample t tests compared lunch content with nutritional recommendations. Independent t tests compared the nutrient and food group content of lunches in New Brunswick and Saskatchewan, French and English, and urban and rural CCs. RESULTS: On average, CCs did not meet provincial recommendations. Lunches in both provinces were low in calories (<517 kcal) and fibre (<7 g). Overall, Saskatchewan centres served greater amounts of food than New Brunswick centres (p < 0.05). French-speaking centres provided less fat (p = 0.047), less saturated fat (p = 0.01), and fewer servings of meat and alternatives (p = 0.02), and more trans fat (p = 0.03) than English-speaking centres. There were no differences between rural and urban centres. CONCLUSIONS: Few CC lunches met nutritional recommendations. Interventions are required to improve the quality of foods offered in CCs. Reviewing or developing comprehensive nutrition guidelines is warranted. PMID- 29120304 TI - An examination of school- and student-level characteristics associated with the likelihood of students' meeting the Canadian physical activity guidelines in the COMPASS study. AB - OBJECTIVES: To examine school- and student-level correlates of physical activity. METHODS: Cross-sectional Year 2 data collected from 45 298 grade 9-12 students attending 89 secondary schools in the COMPASS study were examined using multi level modelling to predict the likelihood of students a) achieving 60 minutes of moderate to vigorous physical activity (MVPA) daily; and b) achieving the Canadian Society for Exercise Physiology (CSEP) activity guideline for youth (60 minutes/MVPA daily, vigorous physical activity at least three days in a week, and resistance training at least three days in a week). RESULTS: The prevalence of students achieving 60 minutes of MVPA daily and meeting the CSEP guideline was 49.3% and 31.0% respectively. Modest between-school variability was identified (1.1% for 60 minutes MVPA and 0.8% for CSEP guideline). School-level characteristics significantly associated with the outcome measures included location, school size, quality of facilities, and accessibility of facilities. Significant student-level correlates included sex, grade, weekly income, binge drinking, fruit and vegetable consumption, and body mass index. CONCLUSIONS: Most youth in this large study reported inadequate physical activity levels. Students were more likely to achieve 60 minutes of MVPA if they attended a larger school or a school in an urban location, whereas students were less likely to meet the CSEP guideline if they attended a school in a small urban location. However, student-level factors, such as binge drinking and inadequate fruit and vegetable consumption, were more strongly associated with the outcomes examined. PMID- 29120305 TI - Correlates of accelerometer-assessed physical activity and sedentary time among adults with type 2 diabetes. AB - OBJECTIVES: The aims of this study were to describe the volume and patterns of objectively assessed sedentary behaviour, light intensity physical activity (LPA) and moderate-vigorous physical activity (MVPA), and to examine socio-demographic correlates, among adults living with type 2 diabetes. METHODS: Participants (n = 166) wore an accelerometer (Actigraph(r) GT3X+) for seven consecutive days during waking hours and completed a questionnaire. Physical activity (PA) and sedentary time were described, and multivariable linear regression was used to estimate associations between socio-demographic characteristics and sedentary time and PA. RESULTS: Participants, 46% of whom were female, had a mean age of 65.4 years (standard deviation (SD) = 9.5), body mass index (BMI) of 31.5 (6.6) kg/m2 and had been living with diabetes for an average of 13.1 (7.6) years. Participants were sedentary for 543.6 minutes/day, spent 273.4 minutes/day and 22.4 minutes/day in LPA and MVPA respectively. BMI was associated with increased sedentary time and reduced LPA (-2.5 minutes/day, 95% CI: -4.33 to -0.70) and MVPA (-0.62 minutes/day, 95% CI: -1.05 to -0.18) time. Compared with males, females had more LPA (34.4 minutes/day, 95% CI: 10.21-58.49) and less MVPA (-6.2 minutes/day, 95% CI: -12.04 to -0.41) time. Unemployed participants had 30.05 minutes more MVPA (95% CI: 3.35-56.75) than those who were employed or homemakers, and those not reporting income had 13 minutes/day more MVPA time than participants in the lowest income category (95% CI: 3.46-22.40). CONCLUSION: Adults living with type 2 diabetes were not sufficiently active and were highly sedentary. Our results emphasize the need for more research exploring the diabetes-related health outcomes of sedentary behaviour and physical inactivity among people living with type 2 diabetes. PMID- 29120306 TI - Migration and social determinants of mental health: Results from the Canadian Health Measures Survey. AB - OBJECTIVES: Studies worldwide point to increased risk of mental health problems among immigrants. However, the data on Canadian immigrants' mental health are ambiguous. To address this, we examined the relationship of both self-perceived mental health and reported diagnosis of mood disorders with age, gender, migration status, time since migration, and social determinants of health factors. METHODS: We analyzed three cycles of the Canadian Health Measures Survey. Our outcome variables were self-perceived mental health and reported diagnosis of mood disorders. We used weighted logistic regression to model time since migration conditional on age, gender, income, community belonging, education, and employment status for 12 160 participants aged 15-79 years. RESULTS: Recent (within 5 years) migrants reported better self-perceived mental health (odds ratio 3.98, 95% confidence interval [CI]: 2.06-7.70) but this effect disappeared with longer time since immigration. Other predictors were older age, higher income, better sense of community belonging, and being employed. Similarly, diagnosis of mood disorders was less likely to be reported in recent migrants (odds ratio 0.23, 95% CI: 0.10-0.53) with some weak evidence that this was also seen among longer-term migrant residents (>10 years). Diagnosis was also associated with older age, being a woman, lower income, weak sense of community belonging, and being unemployed. DISCUSSION: Our findings indicate that migrants to Canada do not have worse mental health in general, though health and social policies need to attend to the socio-economic determinants, such as low income, unemployment, and a poor sense of community belonging, which contribute to population health outcomes. PMID- 29120307 TI - Preliminary investigation of the STBBI Stigma Scale: Description and pilot results. AB - OBJECTIVES: Sexually transmitted and blood-borne infections (STBBIs) are associated with stigmatizing attitudes and beliefs, which can affect the quality of and access to health care, as well as mental health and quality of life. The current study describes the adaptation from an HIV-related stigma scale and pilot testing of a new STBBI Stigma Scale, assessing the stigmatizing attitudes and beliefs of health and social service providers in Canada. METHODS: 144 health and social service providers from across Canada completed the newly adapted scale assessing stigma associated with HIV, hepatitis C, other viral STBBIs and bacterial STBBIs, as well as demographic information, a scale of social desirability and measures of convergent and divergent validity. Participants were recruited through listservs and completed the scale online. RESULTS: The new scale, consisting of 21 items for each category, demonstrated excellent internal consistency, reliability, and convergent and divergent validity. The factor structure of the scale supports a tripartite model of stigma consisting of stereotyping, prejudice and discrimination. Stereotyping had the highest relative scores on the subscales, and attitudes regarding other viral STBBIs differed significantly from the other STBBI categories. CONCLUSION: The new scale provides a contextually relevant and applicable psychometrically valid tool to assess STBBI-related stigma among health and social service providers in Canada. The tool can be used to assess attitudes and beliefs, as well as guide self assessment and possible trainings for providers. PMID- 29120308 TI - Incidence of lower limb amputation in Canada. AB - OBJECTIVES: To determine the Canadian age-adjusted incidence rates of lower limb amputation (LLA) by province, sex, level, and cause of amputation. METHODS: Data on all hospital discharges associated with LLA from April 1, 2006, to March 31, 2012, were obtained from the Canadian Institute for Health Information's Discharge Abstract Database. National and provincial age-adjusted rates were calculated per 100 000 individuals by sex, level, and cause of LLA using the direct method of standardization. The relative risk of LLA in people with diabetes was calculated. RESULTS: There were a total of 44 430 LLAs performed in Canada over the study years. The number of LLAs increased from 7331 in 2006 to 7708 in 2011. Mean (SD) age was 65.7 (16.6) years, and 68.8% were males. Sixty five percent of the LLA cases were due to diabetes. The average age-adjusted rate of LLA in Canada was 22.9 per 100 000 individuals. The age-adjusted rates declined over the study years. The relative risk of diabetes-related LLAs was 28.9. CONCLUSION: This study provided the first Canadian national and provincial age-adjusted incidence rates of LLA and a baseline for monitoring and evaluation in the future. Understanding the incidence of LLA is essential to managing preventive and rehabilitation services for this population. Although the age adjusted LLA incidence rates have decreased, the number of new LLAs has increased. The increase in the number of LLAs has important implications for social and health care costs. PMID- 29120309 TI - Comparing "insider" and "outsider" news coverage of the 2014 Ebola outbreak. AB - OBJECTIVES: Information provided by news media during an infectious disease outbreak can affect the actions taken to safeguard public health. There has been little evaluation of how the content of news published during an outbreak varies by location of the news outlet. This study analyzes coverage of the 2014 Ebola outbreak by one news outlet operating within a country affected by the outbreak and one country not directly affected. METHODS: A qualitative content analysis was conducted of articles published in two national news outlets, The Globe and Mail (Canada) and the Vanguard (Nigeria), between January 1 and December 31, 2014. Articles available through LexisNexis Academic were sorted by date and sampled using a stratified sampling method (The Globe and Mail n = 100; Vanguard n = 105). A coding scheme was developed and modified to incorporate emerging themes until saturation was achieved. RESULTS: There were substantial differences in outbreak coverage in terms of the topic and content of the articles, as well as the sources consulted. The Globe and Mail framed the outbreak in terms of national security and national interests, as well as presenting it as an international humanitarian crisis. In contrast, the Vanguard framed the outbreak almost exclusively in terms of public health. CONCLUSION: Our findings highlight how different geographic contexts can shape reporting on the same event. Further research is required to investigate how the political, social or economic situations of a country shape its news media, potentially influencing actions taken to control disease outbreaks. PMID- 29120310 TI - Preconception health interventions delivered in public health and community settings: A systematic review. AB - OBJECTIVES: The objective of this systematic review was to assess the effects of preconception health interventions, delivered to individuals of reproductive age in public health and community settings, on reproductive, maternal, and child health outcomes. METHODS: A search of Ovid MEDLINE, CINAHL, EMBASE, PsychINFO, Scopus, Gender Studies Database, and SocINDEX from July 1999 through July 2016 was performed. We included studies that reported original data, used an interventional study design, included reproductive-aged women or men, were written in English, and were published in peer-reviewed journals. Two reviewers independently used standardized instruments for data extraction and quality assessment. A narrative synthesis was performed. SYNTHESIS: Twelve studies met the inclusion criteria. These studies included randomized controlled trials and quasi-experimental, pre-post, and time-series designs. Most studies were conducted in the United States; all but one study included only women. Interventions were mainly educational initiatives focused on nutrition, immunization, and lifestyle behaviours and were delivered in a single contact. The studies reported positive effects on health knowledge (n = 9), behaviour change (n = 4), and health outcomes (n = 1). Study quality was weak (n = 11) or moderate (n = 1), with limitations related to selection bias, blinding, data collection methods, and participant attrition. CONCLUSION: To develop a comprehensive, standardized approach to preconception health promotion and care in Canada, there is a clear need for high-quality research evaluating the effectiveness of preconception health interventions. Studies should use a health equity lens that includes all individuals of reproductive age and addresses the broad determinants of preconception health. PMID- 29120311 TI - Alberta's provincial take-home naloxone program: A multi-sectoral and multi jurisdictional response to overdose. AB - SETTING: Alberta is a prairie province located in western Canada, with a population of approximately 4.3 million. In 2016, 363 Albertans died from apparent drug overdoses related to fentanyl, an opioid 50-100 times more toxic than morphine. This surpassed the number of deaths from motor vehicle collisions and homicides combined. INTERVENTION: Naloxone is a safe, effective, opioid antagonist that may quickly reverse an opioid overdose. In July 2015, a committee of community-based harm reduction programs in Alberta implemented a geographically restricted take-home naloxone (THN) program. The successes and limitations of this program demonstrated the need for an expanded, multi sectoral, multi-jurisdictional response. The provincial health authority, Alberta Health Services (AHS), used previously established incident command system processes to coordinate implementation of a provincial THN program. OUTCOMES: Alberta's provincial THN program was implemented on December 23, 2015. This collaborative program resulted in a coordinated response across jurisdictional levels with wide geographical reach. Between December 2015 and December 2016, 953 locations, including many community pharmacies, registered to dispense THN kits, 9572 kits were distributed, and 472 reversals were reported. The provincial supply of THN kits more than tripled from 3000 to 10 000. IMPLICATIONS: Alberta was uniquely poised to deliver a large, province-wide, multi-sectoral and multi jurisdictional THN program as part of a comprehensive response to increasing opioid-related morbidity and mortality. The speed at which AHS was able to roll out the program was made possible by work done previously and the willingness of multiple jurisdictions to work together to build on and expand the program. PMID- 29120312 TI - A strategic approach to workforce development for local public health. AB - SETTING: In 2009, Peel Public Health set a vision to transform the work of public health from efficient delivery of public health services as defined by provincial mandate to the robust analysis of the health status of the local population and selection and implementation of programming to achieve best health outcomes. A strategic approach to the workforce was a key enabler. PPH is a public health unit in Ontario that serves 1.4 million people. INTERVENTION: An organization wide strategic workforce development program was instituted. It is theory-based, evidence-informed and data-driven. A first step was a conceptual framework, followed by interventions in workforce planning, human resources management, and capacity development. The program was built on evidence reviews, theory, and public health core competencies. Interventions spread across the employee work life span. OUTCOMES: Capacity development based on the public health core competencies is a main focus, particularly analytical capacity to support decision-making. Employees gain skill and knowledge in comprehensive population health. Leadership evolves as work shifts to the analysis of health status and development of interventions. Effective human resource processes ensure appropriate job design, recruitment and orientation. Analysis of the workforce leads to vigorous employee development to ensure a strong pool of potential leadership successors. IMPLICATIONS: Theory, research evidence, and data provide a robust foundation for workforce development. Competencies are important inputs to job descriptions, recruitment, training, and human resource processes. A comprehensive workforce development strategy enables the development of a skilled workforce capable of responding to the needs of the population it serves. PMID- 29120313 TI - Policy recommendations for front-of-package, shelf, and menu labelling in Canada: Moving towards consensus. AB - Greater availability of low nutritional quality foods and decreased consumption of nutrient-dense foods have negatively impacted the nutrient profile of the Canadian diet. Poor diet is now the leading risk factor for chronic disease and premature death in Canada. To help consumers choose healthful foods, nutrition labelling is one policy tool for communicating relevant nutrition information. However, there are notable shortcomings with current nutrition labelling systems, which make it difficult for Canadians to navigate the complex food environment. Government action on nutrition labelling systems, including front-of-package (FOP), shelf, and menu labelling, is required. In May 2016, we hosted a consensus conference with experts from research, policy and practice to review available evidence, share experiences and come to consensus regarding the next best steps for action on nutrition labelling in Canada. In this paper, we examine the evidence, opportunities and challenges surrounding FOP, shelf, and menu labelling. We outline recommendations, emphasizing FOP, shelf, and menu labelling as part of a standardized, coordinated and multi-pronged strategy supported by a robust, evidence-based nutrition profiling system. Recommendations for monitoring adherence to regulations and participation of stakeholders to avoid conflict of interest in policy development, implementation and evaluation are included. Within a comprehensive strategy, these recommendations can help to improve the nutrition information environment for Canadians. PMID- 29120314 TI - Ethical challenges in FASD prevention: Scientific uncertainty, stigma, and respect for women's autonomy. AB - Fetal alcohol spectrum disorder (FASD) is a leading form of neurodevelopmental delay in Canada, affecting an estimated 3000 babies per year. FASD involves a range of disabilities that entail significant costs to affected individuals, families, and society. Exposure to alcohol in utero is a necessary factor for FASD development, and this has led to FASD being described as "completely preventable". However, there are significant ethical challenges associated with FASD prevention. These challenges revolve around 1) what should be communicated about the risks of alcohol consumption during pregnancy, given some ongoing scientific uncertainty about the effects of prenatal alcohol exposure, and 2) how to communicate these risks, given the potential for stigma against women who give birth to children with FASD as well as against children and adults with FASD. In this paper, we share initial thoughts on how primary care physicians can tackle this complex challenge. First, we recommend honest disclosure of scientific evidence to women and the tailoring of information offered to pregnant women. Second, we propose a contextualized, patient-centred, compassionate approach to ensure that appropriate advice is given to patients in a supportive, non stigmatizing way. PMID- 29120315 TI - Canadian pharmacists as immunizers: Addressing questions related to this new scope of practice. AB - Currently, pharmacists in nine Canadian provinces can apply for authorization to administer drugs and vaccines by injection following the successful completion of a required training program and with evidence of certification in first aid and cardiopulmonary resuscitation. As more provinces and pharmacists embrace this new scope, questions are being raised about their readiness and ability to provide this public health service. This commentary addresses a number of questions commonly raised about pharmacists as immunizers, taking the position that pharmacists are able and willing to play a larger role in vaccination programs. PMID- 29120316 TI - Weighing in on Canadian school-based vision screening: A call for action. AB - Vision-screening programs are designed to detect common causes of visual impairment and increase the likelihood of early diagnosis and treatment. In the health authority Eastern Health - Newfoundland and Labrador, public health leaders raised a concern about the efficiency and effectiveness of the current non-routine, opportunistic vision screening protocol for school-aged children. An environmental scan of screening practices and programs across Canada was conducted, yielding a wide range of inconsistencies with respect to program type, target population, and screening tools. A significant gap in evidence-based research into universal vision-screening programs for the school-aged population (6+) was also noted. In light of these findings (both in practice and research), we recommend that researchers and public health practitioners across the country evaluate their current practice with respect to school-based vision screening and disseminate their findings through publication. We conclude that evaluation and research into current school-based screening programs (both opportunistic and universal) will provide the evidence needed to guide practice. PMID- 29120317 TI - Enhancing the capacity and effectiveness of community health volunteers to improve maternal, newborn and child health: Experience from Kenya. AB - OBJECTIVE: To determine whether a simple monitoring and tracking tool, Mwanzo Mwema Monitoring and Tracking Tool (MMATT), would enable community health volunteers (CHVs) in Kenya to 1) plan their workloads and activities, 2) identify the women, newborns and children most in need of accessing critical maternal, newborn and child health (MNCH) interventions and 3) improve key MNCH indicators. METHODS: A mixed methods approach was used. Household surveys at baseline (n = 912) and endline (n = 1143) collected data on key MNCH indicators in the four subcounties of Taita Taveta County, Kenya. Eight focus group discussions were held with 40 CHVs to ascertain their perspectives on using the tool. RESULTS: Qualitative findings revealed that the CHVs found the MMATT to be useful in planning their activities and prioritizing beneficiaries requiring more support to access MNCH services. They also identified potential barriers to care at both the community and health system levels. At endline, previously pregnant women were more likely to have received four or more antenatal care visits, facility delivery, postnatal care within two weeks of delivery and a complete package of care than baseline respondents. Among women with children under 24 months, those at endline were more likely to report early breastfeeding and exclusive breastfeeding for the first six months. These results remained after adjustment for age, subcounty, gravida, mother's education and asset index. CONCLUSION: Our results demonstrate that simple tools enable CHVs to identify disparities in service delivery and health outcomes, and to identify barriers to MNCH care. Tools that enhance CHVs' ability to plan and prioritize the women and children most in need increase CHVs' potential impact. PMID- 29120318 TI - Impacts of the Interim Federal Health Program reforms: A stakeholder analysis of barriers to health care access and provision for refugees. AB - BACKGROUND: Changes to the Interim Federal Health Program (IFHP) in 2012 reduced health care access for refugees and refugee claimants, generating concerns among key stakeholders. In 2014, a new IFHP temporarily reinstated access to some health services; however, little is known about these changes, and more information is needed to map the IFHP's impact. OBJECTIVE: This study explores barriers occurring during the time period of the IFHP reforms to health care access and provision for refugees. METHODS: A stakeholder analysis, using 23 semi structured interviews, was conducted to obtain insight into stakeholder perceptions of the 2014 reforms, as well as stakeholders' position and their influence to assess the acceptability of the IFHP changes. RESULTS: The majority of stakeholders expressed concerns about the 2014 IFHP changes as a result of the continuing barriers posed by the 2012 retrenchments and the emergence of new barriers to health care access and provision for refugees. Key barriers identified included lack of communication and awareness, lack of continuity and comprehensive care, negative political discourse and increased costs. A few stakeholders supported the reforms as they represented some, but limited, access to health care. CONCLUSION: Overall, the reforms to the IFHP in 2014 generated barriers to health care access and provision that contributed to confusion among stakeholders, the transfer of refugee health responsibility to provincial authorities and the likelihood of increased health outcome disparities, as refugees and refugee claimants chose to delay seeking health care. The study recommends that policy-makers engage with refugee health stakeholders to formulate a policy that improves health care provision and access for refugee populations. PMID- 29120319 TI - "It makes us really look inferior to outsiders": Coping with psychosocial experiences associated with the lack of access to safe water and sanitation. AB - OBJECTIVE: This paper explores daily experiences and coping resources related to the lack of access to safe water and adequate sanitation in Usoma, a lakeshore community in Western Kenya. METHODS: A qualitative approach that involved 10 focus group discussions and 9 key informant interviews with community leaders, volunteers and professionals was used to explore the research objectives. Data were collected from June to August 2013. RESULTS: Daily practices and experiences around water and sanitation, such as water collection, open defecation and shared toilets, were a major concern to residents. In the absence of safe water, residents used social networks and support, financial resources and the nearby Lake Victoria as coping resources. CONCLUSION AND IMPLICATION FOR PRACTICE: Findings from this study are important for mobilizing resources in vulnerable settings as a first step towards designing community-based interventions. For public health practice, practitioners must work with - and collaborate across - sectors to enhance and strengthen social networks and cohesion, and protect the natural environment while working toward addressing water-related challenges in deprived settings. PMID- 29120320 TI - Adapting maternal health practice to co-morbidities and social inequality: A systematic approach. AB - The process of adapting universal guidelines to local institutional and cultural settings is recognized as important to their implementation and uptake. However, clarity on what, why and how to adapt in an evidence-based manner is still somewhat elusive. Health providers in low and middle income country contexts often have to deal with widely present co-morbidities and social inequalities among pregnant women. Since neither of these problems finds adequate discussion within the usual guidelines, and given the continual pressures posed by resource scarcity, health providers respond through ad hoc adaptations inimical to maternal safety and equity. We argue for, and describe, a grounded process of systematic adaptation of available guidelines through the example of a handbook on maternal risks for primary care doctors and staff nurses. The systematic adaptation in this practical, action-oriented handbook builds on research for a long-standing community-based project on maternal safety and rights. It takes a case-based problem-solving approach. Reiterating guidelines and best practices in diagnostic decision-making and risk management, it indicates how these can respond to co-morbidities and social inequality via complex clinical cases and new social science information. PMID- 29120321 TI - ? AB - L'etude des consequences de la mondialisation sur la sante des populations est au coeur de la sante mondiale. Ce faisant, la mondialisation conditionne egalement la mise en oeuvre des projets de recherche et des interventions en sante mondiale, et les rapports sociaux inegalitaires qui s'y perpetuent. Le present commentaire propose des reflexions sur des defis epistemologiques et politiques auxquels se confronte la sante mondiale. Celles-ci sont issues d'observations et de discussions pendant et apres la Conference canadienne sur la sante mondiale, tenue en novembre 2015. Durant cet evenement, une volonte affirmee par la communaute internationale de promouvoir l'equite en sante pour tous et un meilleur partage des savoirs et des ressources au sein des partenariats s'est clairement exprimee. Ainsi, nous envisageons un avenir different, plus intersectionnel et porteur d'espoir, en proposant une deconstruction de la biopolitique hegemonique des institutions du Nord, tout en mettant au coeur de nos actions les communautes et des partenariats francs, solides et susceptibles de perdurer. Pour ce faire, des pistes sont proposees. Celles-ci nous semblent essentielles a considerer, si l'on prone l'equite et la justice sociale et ce, en commencant par nos propres actions. Notre propos s'ancre dans les pratiques et les reflexions d'un groupe de candidates au PhD en sante publique, dans l'option en sante mondiale. PMID- 29120322 TI - Diarrhea ain't dope: Canada needs to consider the food safety implications of edible cannabis. PMID- 29120323 TI - Tinkering in the dark: Critical knowledge gaps about how to fund public health in Canada. PMID- 29120324 TI - Missing the trends in the fentanyl overdose crisis: The need for immediate intervention in small and rural communities. PMID- 29120325 TI - Structural insight into TPX2-stimulated microtubule assembly. AB - During mitosis and meiosis, microtubule (MT) assembly is locally upregulated by the chromatin-dependent Ran-GTP pathway. One of its key targets is the MT associated spindle assembly factor TPX2. The molecular mechanism of how TPX2 stimulates MT assembly remains unknown because structural information about the interaction of TPX2 with MTs is lacking. Here, we determine the cryo-electron microscopy structure of a central region of TPX2 bound to the MT surface. TPX2 uses two flexibly linked elements ('ridge' and 'wedge') in a novel interaction mode to simultaneously bind across longitudinal and lateral tubulin interfaces. These MT-interacting elements overlap with the binding site of importins on TPX2. Fluorescence microscopy-based in vitro reconstitution assays reveal that this interaction mode is critical for MT binding and facilitates MT nucleation. Together, our results suggest a molecular mechanism of how the Ran-GTP gradient can regulate TPX2-dependent MT formation. PMID- 29120326 TI - The liquid structure of elastin. AB - The protein elastin imparts extensibility, elastic recoil, and resilience to tissues including arterial walls, skin, lung alveoli, and the uterus. Elastin and elastin-like peptides are hydrophobic, disordered, and undergo liquid-liquid phase separation upon self-assembly. Despite extensive study, the structure of elastin remains controversial. We use molecular dynamics simulations on a massive scale to elucidate the structural ensemble of aggregated elastin-like peptides. Consistent with the entropic nature of elastic recoil, the aggregated state is stabilized by the hydrophobic effect. However, self-assembly does not entail formation of a hydrophobic core. The polypeptide backbone forms transient, sparse hydrogen-bonded turns and remains significantly hydrated even as self-assembly triples the extent of non-polar side chain contacts. Individual chains in the assembly approach a maximally-disordered, melt-like state which may be called the liquid state of proteins. These findings resolve long-standing controversies regarding elastin structure and function and afford insight into the phase separation of disordered proteins. PMID- 29120327 TI - Capillary pericytes mediate coronary no-reflow after myocardial ischaemia. AB - After cardiac ischaemia, a prolonged decrease of coronary microvascular perfusion often occurs even after flow is restored in an upstream artery. This 'no-reflow' phenomenon worsens patient prognosis. In the brain, after stroke, a similar post ischaemic 'no-reflow' has been attributed to capillary constriction by contractile pericytes. We now show that occlusion of a rat coronary artery, followed by reperfusion, blocks 40% of cardiac capillaries and halves perfused blood volume within the affected region. Capillary blockages colocalised strongly with pericytes, where capillary diameter was reduced by 37%. The pericyte relaxant adenosine increased capillary diameter by 21% at pericyte somata, decreased capillary block by 25% and increased perfusion volume by 57%. Thus, cardiac pericytes constrict coronary capillaries and reduce microvascular blood flow after ischaemia, despite re-opening of the culprit artery. Cardiac pericytes are therefore a novel therapeutic target in ischaemic heart disease. PMID- 29120330 TI - IPAN - The Game Changer. PMID- 29120331 TI - Management of Children with Severe Acute Malnutrition in India: We Know Enough to Act, and We Should Act Now. PMID- 29120332 TI - Levamisole: Standard or Intensive Therapy? PMID- 29120333 TI - Evaluation and Validation of a Model for Identifying Serious Bacterial Infections among Children Presenting to the Emergency: Evidence-based Medicine Viewpoint. PMID- 29120334 TI - Evaluation and Validation of a Model for Identifying Serious Bacterial Infections among Children Presenting to the Emergency: Pediatric Emergency Medicine Physician's Viewpoint. PMID- 29120335 TI - Revised Kuppuswamy's Socioeconomic Status Scale: Explained and Updated. AB - Some of the facets of the Kuppuswamy's socioeconomic status scale sometimes create confusion and require explanation on how to classify, and need some minor updates to bring the scale up-to-date. This article provides a revised scale that allows for the real-time update of the scale. PMID- 29120328 TI - Neuropathological and transcriptomic characteristics of the aged brain. AB - As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer's disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia. PMID- 29120336 TI - E-Learning in Medical Education in India. AB - E-learning, or learning and teaching facilitated and supported through the application of technology, is presently being used widely in all fields of education, and also being utilized extensively in medical education. This narrative review aims to introduce the concept of e-learning, and discuss its need and scope in medical education in India. Experience shows that students and faculty are mostly in favor of adopting e-learning side-by-side with traditional learning, and the advantages far outweigh the likely discomfort associated with adoption of this new method. PMID- 29120337 TI - Psychogenic Sneezing. PMID- 29120338 TI - Double Segment Chromosomal Imbalance due to Inherited Chromosomal Translocation: Detection by Cytogenetic Microarray. AB - BACKGROUND: Balanced translocations are common with the incidence of 1 in 500. CASE CHARACTERISTICS: Two cousins with intellectual disability with family history of holoprosencephaly. RESULTS: Microarray showed gain on chromosome 7 and loss on chromosome 11 and vice versa in the other cousin. CONCLUSION: We highlight the importance of detailed family history, pedigree analysis, and utility of microarray. PMID- 29120339 TI - Hepatic Visceral Larva Migrans Causing Hepatic Venous Thrombosis and Prolonged Fever. AB - BACKGROUND: Visceral larva migrans may present with systemic symptoms such as fever, hepatomegaly, pneumonitis or ocular symptoms. CASE CHARACTERISTICS: A 7 year-old girl with fever, pain abdomen and persistent eosinophilia. Imaging and histopathology were suggestive of visceral larva migrans. MESSAGE: The diagnosis of visceral larva migrans is often delayed since similar symptoms of fever, hepatomegaly and peripheral eosinophilia occur in more common and identifiable tropical parasitic and non-parasitic diseases. PMID- 29120340 TI - Mycophenolate Sodium for Children with Frequently Relapsing or Steroid Dependent Nephrotic Syndrome. AB - In this retrospective study, patients with idiopathic frequently-relapsing nephrotic syndrome (FRNS) (n=27) and steroid dependent nephrotic syndrome (SDNS) (n=13) who received enteric coated mycophenolate sodium (ECMS) for at least 6 months, were included for analysis. Primary outcome was response to ECMS, which was defined as complete if there were no relapses, partial response if there was 1 relapse and no response if there were 2 or more relapses within 6 months of initiation. The mean (SD) dose of ECMS was 985.24 (190.82) mg/m2/day. Thirty patients(75%) had complete response, eight (20%) had partial and two (5%) patients did not respond at 6 months. ECMS seems to be a safe and effective as steroid sparing agent in children with FRNS/SDNS. PMID- 29120341 TI - Guillaine-Barre Syndrome with Retained Deep Tendon Reflexes. PMID- 29120342 TI - Relaxation processes and physical aging in metallic glasses. AB - Since their discovery in the 1960s, metallic glasses have continuously attracted much interest across the physics and materials science communities. In the forefront are their unique properties, which hold the alluring promise of broad application in fields as diverse as medicine, environmental science and engineering. However, a major obstacle to their wide-spread commercial use is their inherent temporal instability arising from underlying relaxation processes that can dramatically alter their physical properties. The result is a physical aging process which can bring about degradation of mechanical properties, namely through embrittlement and catastrophic mechanical failure. Understanding and controlling the effects of aging will play a decisive role in our on-going endeavor to advance the use of metallic glasses as structural materials, as well as in the more general comprehension of out-of-equilibrium dynamics in complex systems. This review presents an overview of the current state of the art in the experimental advances probing physical aging and relaxation processes in metallic glasses. Similarities and differences between other hard and soft matter glasses are highlighted. The topic is discussed in a multiscale approach, first presenting the key features obtained in macroscopic studies, then connecting them to recent novel microscopic investigations. Particular emphasis is put on the occurrence of distinct relaxation processes beyond the main structural process in viscous metallic melts and their fate upon entering the glassy state, trying to disentangle results and formalisms employed by the different groups of the glass science community. A microscopic viewpoint is presented, in which physical aging manifests itself in irreversible atomic-scale processes such as avalanches and intermittent dynamics, ascribed to the existence of a plethora of metastable glassy states across a complex energy landscape. Future experimental challenges and the comparison with recent theoretical and numerical simulations are discussed as well. PMID- 29120343 TI - Lanthanide stannate pyrochlores (Ln2Sn2O7; Ln = Nd, Gd, Er) at high pressure. AB - Lanthanide stannate pyrochlores (Ln2Sn2O7; Ln=Nd, Gd, and Er) were investigated in situ to 50 GPa in order to determine their structural response to compression and compare it to that of lanthanide titanate, zirconate, and hafnate pyrochlores. The cation radius ratio of A3+/B4+ in pyrochlore oxides (A2B2O7) is thought to be the dominant property that influences their compression response. The ionic radius of Sn4+ is intermediate to that of Ti4+, Zr4+, and Hf4+, but the bond in stannate pyrochlore is more covalent than the bonds in titanates, zirconate, and hafnates. In stannates, the pyrochlore cation and anion sublattices begin to disorder at 0.3 GPa. The extent of sublattice disorder vs. pressure is greater in stannates with a smaller Ln3+ cation. Stannate pyrochlores (Fd-3m) begin a sluggish transformation to a cotunnite-like structure (Pnma) at ~28 GPa; similar transitions have been observed in titanate, zirconate, and hafnate pyrochlore at varying pressures with cation radius ratio. The extent of the phase transition vs. pressure varies directly with the size of the Ln3+ cation. Post-decompression from ~50 GPa, Er2Sn2O7 and Gd2Sn2O7 adopt a pyrochlore structure, rather than the multiscale defect-fluorite + weberite structure adopted by Nd2Sn2O7 that is characteristic of titanate, zirconate, and hafnate pyrochlore treated to similar conditions. Like pyrochlore titanates, zirconates, and hafnates, the bulk modulus, B0, of stannates varies linearly and inversely with cation radius ratio. The trends of bulk moduli in stannates in this study are in excellent agreement with previous experimental studies on stannates, and suggest that the size of the Ln3+ cation is a primary determining factor of B0. Additionally, when normalized to rA/rB, the bulk moduli of stannates are comparable to those of zirconates and hafnates, which vary from titanates. Our results suggest that the cation radius ratio strongly influences the bulk moduli of stannates as well as their overall compression response. PMID- 29120344 TI - Temperature dependent structural evolution in liquid Ag50Ga50 alloy. AB - The temperature dependence of atomic structural evolution in the liquid Ag50Ga50 alloy has been studied by using in situ high energy X-ray diffraction (XRD) experiment combined with the first-principles molecular dynamics (FPMD) simulations. The experimental data show a reversible structural crossover at the temperature about 1050 K. Changes in both electrical resistivity and absolute thermoelectric power at about 1100 K strongly support the XRD results. Additionally, FPMD simulations reveal an abnormal temperature dependent behavior of partial coordination number and atomic diffusivity at about 1200 K, elucidating that the partition experimentally observed changes in structure and properties could be linked with the repartition between Ag and Ga atoms in the liquid at around 1050-1200 K. This finding will trigger more studies on the structural evolution of noble-polyvalent metals in particular and metallic liquids in general. PMID- 29120345 TI - Anharmonic, dimensionality and size effects in phonon transport. AB - We have developed and employed a numerically efficient semi- ab initio theory, based on density-functional and relaxation-time schemes, to examine anharmonic, dimensionality and size effects in phonon transport in three- and two-dimensional solids of different crystal symmetries. Our method uses third- and fourth-order terms in crystal Hamiltonian expressed in terms of a temperature-dependent Gruneisen's constant. All input to numerical calculations are generated from phonon calculations based on the density-functional perturbation theory. It is found that four-phonon processes make important and measurable contribution to lattice thermal resistivity above the Debye temperature. From our numerical results for bulk Si, bulk Ge, bulk MoS2 and monolayer MoS2 we find that the sample length dependence of phonon conductivity is significantly stronger in low dimensional solids. PMID- 29120346 TI - Inverse statistical physics of protein sequences: a key issues review. AB - In the course of evolution, proteins undergo important changes in their amino acid sequences, while their three-dimensional folded structure and their biological function remain remarkably conserved. Thanks to modern sequencing techniques, sequence data accumulate at unprecedented pace. This provides large sets of so-called homologous, i.e. evolutionarily related protein sequences, to which methods of inverse statistical physics can be applied. Using sequence data as the basis for the inference of Boltzmann distributions from samples of microscopic configurations or observables, it is possible to extract information about evolutionary constraints and thus protein function and structure. Here we give an overview over some biologically important questions, and how statistical mechanics inspired modeling approaches can help to answer them. Finally, we discuss some open questions, which we expect to be addressed over the next years. PMID- 29120347 TI - Cuff-less blood pressure measurement from dual-channel photoplethysmographic signals via peripheral pulse transit time with singular spectrum analysis. AB - OBJECTIVE: This paper proposes an unobtrusive blood pressure (BP) measurement system design with a motion artifact (MA) compensation strategy as a potential surrogate to the traditional cuff-based sphygmomanometer for self-monitoring in a less restricted environment. APPROACH: A dual-channel photoplethysmographic signal acquisition system is designed and implemented for cuff-less BP measurement based on the peripheral pulse transit time (PPTT) acquired from the forearm and wrist. Comprising a motion decision, singular spectrum analysis, PPTT calculation and BP measurement, a novel approach is proposed to realize BP measurements and suppress MA interference. MAIN RESULTS: Compared with the reference BP recorded by a cuff-based sphygmomanometer, our preliminary examinations on 30 subjects found that the correlation coefficients for systolic BP estimation and diastolic BP estimation were 0.75 and 0.78, and the mean absolute differences were 7.61 mmHg and 6.82 mmHg, respectively. Meanwhile, the proposed approach was compared with the other most widely used pulse transit time (PTT) measuring methods and BP-PTT models. All the results indicate that our work was highly effective in realizing the BP measurement. SIGNIFICANCE: The proposed system and approach have resulted in remarkable progress in cuff-less BP measurements with MA removal, and have great potential value in wearable applications without environmental restrictions. PMID- 29120348 TI - Surface electromyography for analysis of heart rate variability in preterm infants. AB - OBJECTIVE: Characterizing heart rate variability (HRV) in neonates has gained increased attention and is helpful in quantifying maturation and risk of sepsis in preterm infants. Raw data used to derive HRV in a clinical setting commonly contain noise from motion artifacts. Thoracic surface electromyography (sEMG) potentially allows for pre-emptive removal of motion artifacts and subsequent detection of interbeat interval (IBI) of heart rate to calculate HRV. We tested the feasibility of sEMG in preterm infants to exclude noisy raw data and to derive IBI for HRV analysis. We hypothesized that a stepwise quality control algorithm can identify motion artifacts which influence IBI values, their distribution in the time domain, and outcomes of nonlinear time series analysis. APPROACH: This is a prospective observational study in preterm infants <6 days of age. We used 100 sEMG measurements from 24 infants to develop a semi-automatic quality control algorithm including synchronized video recording, threshold-based sEMG envelope curve, optimized QRS-complex detection, and final targeted visual inspection of raw data. MAIN RESULTS: Analysis of HRV from sEMG data in preterm infants is feasible. A stepwise algorithm to exclude motion artifacts and improve QRS detection significantly influenced data quality (34% of raw data excluded), distribution of IBI values in the time domain, and nonlinear time series analysis. The majority of unsuitable data (94%) were excluded by automated steps of the algorithm. SIGNIFICANCE: Thoracic sEMG is a promising method to assess motion artifacts and calculate HRV in preterm neonates. PMID- 29120349 TI - Magnetic Beads-Based Sensor with Tailored Sensitivity for Rapid and Single-Step Amperometric Determination of miRNAs. AB - This work describes a sensitive amperometric magneto-biosensor for single-step and rapid determination of microRNAs (miRNAs). The developed strategy involves the use of direct hybridization of the target miRNA (miRNA-21) with a specific biotinylated DNA probe immobilized on streptavidin-modified magnetic beads (MBs), and labeling of the resulting heteroduplexes with a specific DNA-RNA antibody and the bacterial protein A (ProtA) conjugated with an horseradish peroxidase (HRP) homopolymer (Poly-HRP40) as an enzymatic label for signal amplification. Amperometric detection is performed upon magnetic capture of the modified MBs onto the working electrode surface of disposable screen-printed carbon electrodes (SPCEs) using the H2O2/hydroquinone (HQ) system. The magnitude of the cathodic signal obtained at -0.20 V (vs. the Ag pseudo-reference electrode) demonstrated linear dependence with the concentration of the synthetic target miRNA over the 1.0 to 100 pM range. The method provided a detection limit (LOD) of 10 attomoles (in a 25 MUL sample) without any target miRNA amplification in just 30 min (once the DNA capture probe-MBs were prepared). This approach shows improved sensitivity compared with that of biosensors constructed with the same anti-DNA RNA Ab as capture instead of a detector antibody and further labeling with a Strep-HRP conjugate instead of the Poly-HRP40 homopolymer. The developed strategy involves a single step working protocol, as well as the possibility to tailor the sensitivity by enlarging the length of the DNA/miRNA heteroduplexes using additional probes and/or performing the labelling with ProtA conjugated with homopolymers prepared with different numbers of HRP molecules. The practical usefulness was demonstrated by determination of the endogenous levels of the mature target miRNA in 250 ng raw total RNA (RNAt) extracted from human mammary epithelial normal (MCF-10A) and cancer (MCF-7) cells and tumor tissues. PMID- 29120350 TI - A Comprehensive Study on Pyrolysis Mechanism of Substituted beta-O-4 Type Lignin Dimers. AB - In order to understand the pyrolysis mechanism of beta-O-4 type lignin dimers, a pyrolysis model is proposed which considers the effects of functional groups (hydroxyl, hydroxymethyl and methoxyl) on the alkyl side chain and aromatic ring. Furthermore, five specific beta-O-4 type lignin dimer model compounds are selected to investigate their integrated pyrolysis mechanism by density functional theory (DFT) methods, to further understand and verify the proposed pyrolysis model. The results indicate that a total of 11 pyrolysis mechanisms, including both concerted mechanisms and homolytic mechanisms, might occur for the initial pyrolysis of the beta-O-4 type lignin dimers. Concerted mechanisms are predominant as compared with homolytic mechanisms throughout unimolecular decomposition pathways. The competitiveness of the eleven pyrolysis mechanisms are revealed via different model compounds, and the proposed pyrolysis model is ranked in full consideration of functional groups effects. The proposed pyrolysis model can provide a theoretical basis to predict the reaction pathways and products during the pyrolysis process of beta-O-4 type lignin dimers. PMID- 29120351 TI - Are PCI Service Volumes Associated with 30-Day Mortality? A Population-Based Study from Taiwan. AB - The volume-outcome relationship has been discussed for over 30 years; however, the findings are inconsistent. This might be due to the heterogeneity of service volume definitions and categorization methods. This study takes percutaneous coronary intervention (PCI) as an example to examine whether the service volume was associated with PCI 30-day mortality, given different service volume definitions and categorization methods. A population-based, cross-sectional multilevel study was conducted. Two definitions of physician and hospital volume were used: (1) the cumulative PCI volume in a previous year before each PCI; (2) the cumulative PCI volume within the study period. The volume was further treated in three ways: (1) a categorical variable based on the American Heart Association's recommendation; (2) a semi-data-driven categorical variable based on k-means clustering algorithm; and (3) a data-driven categorical variable based on the Generalized Additive Model. The results showed that, after adjusting the patient-, physician-, and hospital-level covariates, physician volume was associated inversely with PCI 30-day mortality, but hospital volume was not, no matter which definitions and categorization methods of service volume were applied. Physician volume is negatively associated with PCI 30-day mortality, but the results might vary because of definition and categorization method. PMID- 29120353 TI - Fatty Acid Profiles of In Vitro Digested Processed Milk. AB - Digestion of milkfat releases some long-chain (18-carbon) fatty acids (FAs) that can provide health benefits to the consumer, yet because they are found in small amounts and can be difficult to identify, there is limited information on the effects that common fluid milk processing may have on the digestibility of these FAs. This study provides FA profiles for raw and combinations of homogenized and/or heat-treated (high and ultra-high temperature pasteurization) milk, before and after in vitro digestion, in order to determine the effects of processing on the digestibility of these healthy fatty acids. Use of a highly sensitive separation column resulted in improved FA profiles that showed that, when milk was subjected to both pasteurization and homogenization, the release of the 18 carbon FAs, oleic acid, linoleic acid (an omega-6 FA), rumenic acid (a conjugated linoleic acid, CLA), and linolenic acid (an omega-3 FA) tended to be higher than with either pasteurization or homogenization, or with no treatment. Milk is noted for containing the omega-3 FAs and CLAs, which are associated with positive health benefits. Determining how processing factors may impact the components in milk will aid in understanding the release of healthy FAs when milk and dairy foods are consumed. PMID- 29120352 TI - Coffee Decreases the Risk of Endometrial Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies. AB - AIM: The aim of this study was to perform a comprehensive meta-analysis of the association between coffee consumption and risk of endometrial cancer. METHODS: Eligible studies were identified by searching the PubMed and EMBASE databases. The dose-response relationship as well as the risk of endometrial cancer for the highest versus the lowest categories of coffee consumption were assessed. Subgroup analyses considering the menopausal and receptor statuses, the smoking status, and the BMI (Body Mass Index) were performed in order to identify potential confounders. RESULTS: We identified a total of 12 studies eligible for meta-analysis. A dose-response meta-analysis showed a decreased risk of endometrial cancer. Moreover, a subgroup analysis indicated that coffee consumption is significantly associated with a decreased risk of postmenopausal cancer. Increasing coffee consumption by four cups per day was associated with a 20% reduction in endometrial cancer risk (relative risk (RR) 0.80; 95% confidence interval (CI) 0.72 to 0.89) and with a 24% reduction in postmenopausal cancer risk (RR 0.76; 95% CI 0.69 to 0.83). CONCLUSIONS: Our findings suggest that increased coffee consumption is associated with decreased risk of endometrial cancer, and this association is observed also for postmenopausal cancer. PMID- 29120354 TI - Trans-Plasma Membrane Electron Transport and Ascorbate Efflux by Skeletal Muscle. AB - Trans-plasma membrane electron transport (tPMET) and the antioxidant roles of ascorbate reportedly play a role in protection of cells from damage by reactive oxygen species, which have been implicated in causing metabolic dysfunction such as insulin resistance. Skeletal muscle comprises the largest whole-body organ fraction suggesting a potential role of tPMET and ascorbate export as a major source of extracellular antioxidant. We hypothesized that skeletal muscle is capable of tPMET and ascorbate efflux. To measure these processes, we assayed the ability of cultured muscle cells, satellite cells, and isolated extensor digitorum longus (EDL) and soleus (SOL) to reduce two extracellular electron acceptors, water soluble tetrazolium salt 1 (WST-1), and dichlorophenolindophenol (DPIP). Ascorbate oxidase (AO) was utilized to determine which portion of WST-1 reduction was dependent on ascorbate efflux. We found that muscle cells can reduce extracellular electron acceptors. In C2C12 myotubes and satellite cells, a substantial portion of this reduction was dependent on ascorbate. In myotubes, glucose transporter 1 (GLUT1) inhibitors along with a pan-GLUT inhibitor suppressed tPMET and ascorbate efflux, while a GLUT4 inhibitor had no effect. The adenosine 5'-monophosphate (AMP)-activated protein kinase activator 5 Aminoimidazole-4-carboxamide ribonucleotide (AICAR) suppressed both tPMET and ascorbate efflux by myotubes, while insulin had no effect. Taken together, our data suggest that muscle cells are capable of tPMET and ascorbate efflux supported by GLUT1, thus illustrating a model in which resting muscle exports electrons and antioxidant to the extracellular environment. PMID- 29120355 TI - "To Work Just Like Anyone Else"-A Narrative from a Man Aging with Spinal Cord Injury. AB - People aging with spinal cord injury (SCI) develop medical problems commonly associated with the aging process at a younger age than the general population. However, research about how the life story changes and how meaning will be experienced in occupations is lacking. The aim was to describe and offer an explanation of how a man experienced meaning in everyday occupations while aging with an SCI. Four narrative interviews were performed over a four-year period, with a man in his fifties, who lived with SCI for 39 years. The narrative analysis generated an overall plot, named "To Work Just Like Anyone Else," and gives a picture of his experiences, thoughts, and reflections about meaning in occupations, from when he became injured to the present, and in relation to his future. His life story is characterized by secondary health complications, and his experiences of negotiating with the aging body and making choices to continue working. Further, how occupational risk factors, e.g., imbalance, alienation, and deprivation, occur as a result of lack of rehabilitation and support from social systems is addressed. Future research should explore how rehabilitation and social systems can support people aging with SCI to experience meaning in everyday occupations and to have balance in everyday life. PMID- 29120356 TI - Calves Use an Automated Brush and a Hanging Rope When Pair-Housed. AB - Calf housing often only meets the basic needs of calves, but there is a growing interest in providing enrichments. This study described the behaviour of calves when they were given the opportunity to interact with two commonly available enrichment items. Female and male calves (approximately 11 days old) were pair housed in 8 identical pens fitted with an automated brush and a hanging rope. Frequency and duration of behaviours were recorded on 3 separate days (from 12:00 until 08:00 the following day. Calves spent equal time using the brush and rope (27.1 min/day), but there was less variation in the use of the brush as opposed to the rope (coefficient of variation, CV: 23 vs. 78%, respectively). Calves had more frequent (94 bouts, CV: 24%) and shorter (17.8 s/bout, CV: 24%) brush use bouts compared to fewer (38 bouts, CV: 43%) and longer (38.3 s/bout, CV: 53%) rope use bouts. There was a diurnal pattern of use for both items. Frequency of play was similar to rope use, but total time playing was 8% of rope and brush use. Variability among calves suggested that individual preference existed; however, the social dynamics of the pair-housed environment were not measured and therefore could have influenced brush and rope use. Multiple enrichment items should be considered when designing improvements to calf housing. PMID- 29120357 TI - A Decentralized Compositional Framework for Dependable Decision Process in Self Managed Cyber Physical Systems. AB - Cyber Physical Systems (CPSs) need to interact with the changeable environment under various interferences. To provide continuous and high quality services, a self-managed CPS should automatically reconstruct itself to adapt to these changes and recover from failures. Such dynamic adaptation behavior introduces systemic challenges for CPS design, advice evaluation and decision process arrangement. In this paper, a formal compositional framework is proposed to systematically improve the dependability of the decision process. To guarantee the consistent observation of event orders for causal reasoning, this work first proposes a relative time-based method to improve the composability and compositionality of the timing property of events. Based on the relative time solution, a formal reference framework is introduced for self-managed CPSs, which includes a compositional FSM-based actor model (subsystems of CPS), actor-based advice and runtime decomposable decisions. To simplify self-management, a self similar recursive actor interface is proposed for decision (actor) composition. We provide constraints and seven patterns for the composition of reliability and process time requirements. Further, two decentralized decision process strategies are proposed based on our framework, and we compare the reliability with the static strategy and the centralized processing strategy. The simulation results show that the one-order feedback strategy has high reliability, scalability and stability against the complexity of decision and random failure. This paper also shows a way to simplify the evaluation for dynamic system by improving the composability and compositionality of the subsystem. PMID- 29120358 TI - Label-Free Biomedical Imaging Using High-Speed Lock-In Pixel Sensor for Stimulated Raman Scattering. AB - Raman imaging eliminates the need for staining procedures, providing label-free imaging to study biological samples. Recent developments in stimulated Raman scattering (SRS) have achieved fast acquisition speed and hyperspectral imaging. However, there has been a problem of lack of detectors suitable for MHz modulation rate parallel detection, detecting multiple small SRS signals while eliminating extremely strong offset due to direct laser light. In this paper, we present a complementary metal-oxide semiconductor (CMOS) image sensor using high speed lock-in pixels for stimulated Raman scattering that is capable of obtaining the difference of Stokes-on and Stokes-off signal at modulation frequency of 20 MHz in the pixel before reading out. The generated small SRS signal is extracted and amplified in a pixel using a high-speed and large area lateral electric field charge modulator (LEFM) employing two-step ion implantation and an in-pixel pair of low-pass filter, a sample and hold circuit and a switched capacitor integrator using a fully differential amplifier. A prototype chip is fabricated using 0.11 MUm CMOS image sensor technology process. SRS spectra and images of stearic acid and 3T3-L1 samples are successfully obtained. The outcomes suggest that hyperspectral and multi-focus SRS imaging at video rate is viable after slight modifications to the pixel architecture and the acquisition system. PMID- 29120359 TI - Simultaneous Determination of Seven Components in Rat Plasma by the UPLC-MS/MS Method and Application of Pharmacokinetic Studies to SimiaoYong'an Decoction. AB - SimiaoYong'an Decoction (SYD) is a classical traditional Chinese prescription that is used for the treatment of gangrene, heat-clearing, detoxification and pain alleviation. We developed a sensitive ultra-performance liquid chromatography-tandem mass spectrum (UPLC-MS/MS) method for the simultaneous determination of seven major active ingredients of SYD extract (i.e., harpagide, chlorogenic acid, sweroside, loganin, liquiritin, angoroside C and harpagoside) in rat plasma. The preliminary steps in the plasma analysis were the addition of an internal standard such as linarin, followed by protein precipitation with methanol. Separation of the active ingredients was performed on an ACQUITY UPLC(r) BEH C18 column (100 mm * 2.1 mm, 1.7 MUm) at a flow rate of 0.2 mL/min with methanol/water 0.1% formic acid aqueous (V/V) as the mobile phase. Detection was performed on a triple quadrupole tandem MS (QqQ-MS) via negative ion electrospray ionization in multiple reactions monitoring (MRM) mode. All calibration curves showed good linearity (r > 0.99) over the concentration range with a low limit of quantification between 0.029 and 5.813 ng/mL. Precision was evaluated by intra-day and inter-day assays, and the percentages of the RSD were all within 8.1%. The extraction efficiency and matrix effect were 80.6-113.6% and 82.9-99.5%, respectively. The validated method was successfully applied to a pharmacokinetic study in rats after oral administration of SYD extract and the corresponding single and combined traditional Chinese medicines (TCMs). The pharmacokinetic properties of the seven ingredients showed dynamic changes due to counteraction among the different coexisting components. The established approach has proven useful in the study of the active constituents in a traditional Chinese prescription. PMID- 29120361 TI - Variation in Point-of-Care Testing of HbA1c in Diabetes Care in General Practice. AB - Background: Point-of-care testing (POCT) of HbA1c may result in improved diabetic control, better patient outcomes, and enhanced clinical efficiency with fewer patient visits and subsequent reductions in costs. In 2008, the Danish regulators created a framework agreement regarding a new fee-for-service fee for the remuneration of POCT of HbA1c in general practice. According to secondary research, only the Capital Region of Denmark has allowed GPs to use this new incentive for POCT. The aim of this study is to use patient data to characterize patients with diabetes who have received POCT of HbA1c and analyze the variation in the use of POCT of HbA1c among patients with diabetes in Danish general practice. Methods: We use register data from the Danish Drug Register, the Danish Health Service Register and the National Patient Register from the year 2011 to define a population of 44,981 patients with diabetes (type 1 and type 2 but not patients with gestational diabetes) from the Capital Region. The POCT fee is used to measure the amount of POCT of HbA1c among patients with diabetes. Next, we apply descriptive statistics and multilevel logistic regression to analyze variation in the prevalence of POCT at the patient and clinic level. We include patient characteristics such as gender, age, socioeconomic markers, health care utilization, case mix markers, and municipality classifications. Results: The proportion of patients who received POCT was 14.1% and the proportion of clinics which were "POCT clinics" was 26.9%. There were variations in the use of POCT across clinics and patients. A part of the described variation can be explained by patient characteristics. Male gender, age differences (older age), short education, and other ethnicity imply significantly higher odds for POCT. High patient costs in general practice and other parts of primary care also imply higher odds for POCT. In contrast, high patient costs for drugs and/or morbidity in terms of the Charlson Comorbidity index mean lower odds for POCT. The frequency of patients with diabetes per 1000 patients was larger in POCT clinics than Non-POCT clinics. A total of 22.5% of the unexplained variability was related to GP clinics. Conclusions: This study demonstrates variation in the use of POCT which can be explained by patient characteristics such as demographic, socioeconomic, and case mix markers. However, it appears relevant to reassess the system for POCT. Further studies are warranted in order to assess the impacts of POCT of HbA1c on health care outcomes. PMID- 29120360 TI - Elemental Ingredients in the Macrophage Cocktail: Role of ZIP8 in Host Response to Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a global epidemic caused by the infection of human macrophages with the world's most deadly single bacterial pathogen, Mycobacterium tuberculosis (M.tb). M.tb resides in a phagosomal niche within macrophages, where trace element concentrations impact the immune response, bacterial metal metabolism, and bacterial survival. The manipulation of micronutrients is a critical mechanism of host defense against infection. In particular, the human zinc transporter Zrt-/Irt-like protein 8 (ZIP8), one of 14 ZIP family members, is important in the flux of divalent cations, including zinc, into the cytoplasm of macrophages. It also has been observed to exist on the membrane of cellular organelles, where it can serve as an efflux pump that transports zinc into the cytosol. ZIP8 is highly inducible in response to M.tb infection of macrophages, and we have observed its localization to the M.tb phagosome. The expression, localization, and function of ZIP8 and other divalent cation transporters within macrophages have important implications for TB prevention and dissemination and warrant further study. In particular, given the importance of zinc as an essential nutrient required for humans and M.tb, it is not yet clear whether ZIP guided zinc transport serves as a host protective factor or, rather, is targeted by M.tb to enable its phagosomal survival. PMID- 29120363 TI - Multifunctional Woven Structure Operating as Triboelectric Energy Harvester, Capacitive Tactile Sensor Array, and Piezoresistive Strain Sensor Array. AB - This paper presents a power-generating sensor array in a flexible and stretchable form. The proposed device is composed of resistive strain sensors, capacitive tactile sensors, and a triboelectric energy harvester in a single platform. The device is implemented in a woven textile structure by using proposed functional threads. A single functional thread is composed of a flexible hollow tube coated with silver nanowires on the outer surface and a conductive silver thread inside the tube. The total size of the device is 60 * 60 mm2 having a 5 * 5 array of sensor cell. The touch force in the vertical direction can be sensed by measuring the capacitance between the warp and weft functional threads. In addition, because silver nanowire layers provide piezoresistivity, the strain applied in the lateral direction can be detected by measuring the resistance of each thread. Last, with regard to the energy harvester, the maximum power and power density were measured as 201 MUW and 0.48 W/m2, respectively, when the device was pushed in the vertical direction. PMID- 29120362 TI - Detection of Lard in Cocoa Butter-Its Fatty Acid Composition, Triacylglycerol Profiles, and Thermal Characteristics. AB - The present study investigates the detection of lard in cocoa butter through changes in fatty acids composition, triacylglycerols profile, and thermal characteristics. Cocoa butter was mixed with 1% to 30% (v/v) of lard and analyzed using a gas chromatography flame ionization detector, high performance liquid chromatography, and differential scanning calorimetry. The results revealed that the mixing of lard in cocoa butter showed an increased amount of oleic acid in the cocoa butter while there was a decrease in the amount of palmitic acid and stearic acids. The amount of POS, SOS, and POP also decreased with the addition of lard. A heating thermogram from the DSC analysis showed that as the concentration of lard increased from 3% to 30%, two minor peaks at -26 degrees C and 34.5 degrees C started to appear and a minor peak at 34.5 degrees C gradually overlapped with the neighbouring major peak. A cooling thermogram of the above adulterated cocoa butter showed a minor peak shift to a lower temperature of -36 degrees C to -41.5 degrees C. Values from this study could be used as a basis for the identification of lard from other fats in the food authentication process. PMID- 29120364 TI - Crystal Structure of the Full-Length Feline Immunodeficiency Virus Capsid Protein Shows an N-Terminal beta-Hairpin in the Absence of N-Terminal Proline. AB - Feline immunodeficiency virus (FIV) is a member of the Retroviridae family. It is the causative agent of an acquired immunodeficiency syndrome (AIDS) in cats and wild felines. Its capsid protein (CA) drives the assembly of the viral particle, which is a critical step in the viral replication cycle. Here, the first atomic structure of full-length FIV CA to 1.67 A resolution is determined. The crystallized protein exhibits an original tetrameric assembly, composed of dimers which are stabilized by an intermolecular disulfide bridge induced by the crystallogenesis conditions. The FIV CA displays a standard alpha-helical CA topology with two domains, separated by a linker shorter than other retroviral CAs. The beta-hairpin motif at its amino terminal end, which interacts with nucleotides in HIV-1, is unusually long in FIV CA. Interestingly, this functional beta-motif is formed in this construct in the absence of the conserved N-terminal proline. The FIV CA exhibits a cis Arg-Pro bond in the CypA-binding loop, which is absent in known structures of lentiviral CAs. This structure represents the first tri-dimensional structure of a functional, full-length FIV CA. PMID- 29120365 TI - Macrophage Migration Inhibitory Factor Predicts Outcome in Complex Aortic Surgery. AB - The perioperative inflammatory response is associated with outcome after complex aortic repair. Macrophage migration inhibitory factor (MIF) shows protective effects in ischemia-reperfusion (IR), but also adverse pro-inflammatory effects in acute inflammation, potentially leading to adverse outcome, which should be investigated in this trial. This prospective study enrolled 52 patients, of whom 29 (55.7%) underwent open repair (OR) and 23 (44.3%) underwent endovascular repair (ER) between 2014 and 2015. MIF serum levels were measured until 72 h post operatively. We used linear mixed models and ROC analysis to analyze the MIF time course and its diagnostic ability. Compared to ER, OR induced higher MIF release perioperatively; at 12 h after ICU admission, MIF levels were similar between groups. MIF course was significantly influenced by baseline MIF level (P = 0.0016) and acute physiology and chronic health evaluation (APACHE) II score (P = 0.0005). MIF level at 24 h after ICU admission showed good diagnostic value regarding patient survival [sensitivity, 80.0% (28.4-99.5%); specificity, 51.2% (35.1-67.1%); AUC, 0.688 (0.534-0.816)] and discharge modality [sensitivity, 87.5% (47.3-99.7%); specificity, 73.7% (56.9-86.6%), AUC, 0.789 (0.644-0.896)]. Increased perioperative MIF-levels are related to an increased risk of adverse outcome in complex aortic surgery and may represent a biomarker for risk stratification in complex aortic surgery. PMID- 29120366 TI - A Low Geriatric Nutrition Risk Index Is Associated with Progression to Dialysis in Patients with Chronic Kidney Disease. AB - Evaluating nutritional status is crucial to detecting malnutrition in patients with chronic kidney disease (CKD). The Geriatric Nutritional Risk Index (GNRI) has been associated with overall and cardiovascular mortality in the dialysis population. The aim of this study was to evaluate whether the GNRI is associated with progression to dialysis in patients with moderate to advanced CKD. We enrolled 496 patients with stage 3-5 CKD who had received echocardiographic examinations, and categorized them according to baseline GNRI values calculated using the serum albumin level and body weight. The renal end-point was defined as the commencement of dialysis. During follow-up (mean, 25.2 +/- 12.5 months; range, 3.3-50.1 months), 106 (21.4%) of the patients progressed to dialysis. The GNRI was positively correlated with the left ventricular ejection fraction (LVEF) (r = 0.111, p = 0.014), and negatively correlated with the left ventricular mass index (r = -0.116, p = 0.001), left ventricular hypertrophy (r = -0.095, p = 0.035), and LVEF < 50% (r = -0.138, p = 0.002). In multivariable Cox analysis, a low GNRI, female sex, high systolic blood pressure, high fasting glucose, and low estimated glomerular filtration rate were independently associated with progression to dialysis. A low GNRI was independently associated with progression to dialysis in our study cohort. The GNRI may be useful in predicting the risk of adverse renal outcomes in patients with CKD stages 3-5. Additional studies are needed to explore whether an improvement in GNRI delays CKD progression. PMID- 29120367 TI - Risk and Resilience Factors Related to Parental Bereavement Following the Death of a Child with a Life-Limiting Condition. AB - This paper reviews the theoretical and empirical literature on risk and resilience factors impacting on parental bereavement outcomes following the death of a child with a life-limiting condition. Over the past few decades, bereavement research has focussed primarily on a risk-based approach. In light of advances in the literature on resilience, the authors propose a Risk and Resilience Model of Parental Bereavement, thus endeavouring to give more holistic consideration to a range of potential influences on parental bereavement outcomes. The literature will be reviewed with regard to the role of: (i) loss-oriented stressors (e.g., circumstances surrounding the death and multiple losses); (ii) inter-personal factors (e.g., marital factors, social support, and religious practices); (iii) intra-personal factors (e.g., neuroticism, trait optimism, psychological flexibility, attachment style, and gender); and (iv) coping and appraisal, on parental bereavement outcomes. Challenges facing this area of research are discussed, and research and clinical implications considered. PMID- 29120368 TI - Lactobacillus bulgaricus, Lactobacillus rhamnosus and Lactobacillus paracasei Attenuate Salmonella Enteritidis, Salmonella Heidelberg and Salmonella Typhimurium Colonization and Virulence Gene Expression In Vitro. AB - Salmonella Enteritidis (SE), Salmonella Typhimurium (ST), and Salmonella Heidelberg (SH) have been responsible for numerous outbreaks associated with the consumption of poultry meat and eggs. Salmonella colonization in chicken is characterized by initial attachment to the cecal epithelial cells (CEC) followed by dissemination to the liver, spleen, and oviduct. Since cecal colonization is critical to Salmonella transmission along the food chain continuum, reducing this intestinal association could potentially decrease poultry meat and egg contamination. Hence, this study investigated the efficacy of Lactobacillus delbreuckii sub species bulgaricus (NRRL B548; LD), Lactobacillus paracasei (DUP 13076; LP), and Lactobacillus rhamnosus (NRRL B442; LR) in reducing SE, ST, and SH colonization in CEC and survival in chicken macrophages. Additionally, their effect on expression of Salmonella virulence genes essential for cecal colonization and survival in macrophages was evaluated. All three probiotics significantly reduced Salmonella adhesion and invasion in CEC and survival in chicken macrophages (p < 0.05). Further, the probiotic treatment led to a significant reduction in Salmonella virulence gene expression (p < 0.05). Results of the study indicate that LD, LP, and LR could potentially be used to control SE, ST, and SH colonization in chicken. However, these observations warrant further in vivo validation. PMID- 29120370 TI - Amorphous Solid Dispersion of Epigallocatechin Gallate for Enhanced Physical Stability and Controlled Release. AB - Epigallocatechin gallate (EGCG) has been recognized as the most prominent green tea extract due to its healthy influences. The high instability and low bioavailability, however, strongly limit its utilization in food and drug industries. This work, for the first time, develops amorphous solid dispersion of EGCG to enhance its bioavailability and physical stability. Four commonly used polymeric excipients are found to be compatible with EGCG in water-dioxane mixtures via a stepwise mixing method aided by vigorous mechanical interference. The dispersions are successfully generated by lyophilization. The physical stability of the dispersions is significantly improved compared to pure amorphous EGCG in stress condition (elevated temperature and relative humidity) and simulated gastrointestinal tract environment. From the drug release tests, one of the dispersions, EGCG-Soluplus(r) 50:50 (w/w) shows a dissolution profile that only 50% EGCG is released in the first 20 min, and the remains are slowly released in 24 h. This sustained release profile may open up new possibilities to increase EGCG bioavailability via extending its elimination time in plasma. PMID- 29120369 TI - Begomoviral Movement Protein Effects in Human and Plant Cells: Towards New Potential Interaction Partners. AB - Geminiviral single-stranded circular DNA genomes replicate in nuclei so that the progeny DNA has to cross both the nuclear envelope and the plasmodesmata for systemic spread within plant tissues. For intra- and intercellular transport, two proteins are required: a nuclear shuttle protein (NSP) and a movement protein (MP). New characteristics of ectopically produced Abutilon mosaic virus (AbMV) MP (MPAbMV), either authentically expressed or fused to a yellow fluorescent protein or epitope tags, respectively, were determined by localization studies in mammalian cell lines in comparison to plant cells. Wild-type MPAbMV and the distinct MPAbMV: reporter protein fusions appeared as curled threads throughout mammalian cells. Co-staining with cytoskeleton markers for actin, intermediate filaments, or microtubules identified these threads as re-organized microtubules. These were, however, not stabilized by the viral MP, as demonstrated by nocodazole treatment. The MP of a related bipartite New World begomovirus, Cleome leaf crumple virus (ClLCrV), resulted in the same intensified microtubule bundling, whereas that of a nanovirus did not. The C-terminal section of MPAbMV, i.e., the protein's oligomerization domain, was dispensable for the effect. However, MP expression in plant cells did not affect the microtubules network. Since plant epidermal cells are quiescent whilst mammalian cells are proliferating, the replication-associated protein RepAbMV protein was then co expressed with MPAbMV to induce cell progression into S-phase, thereby inducing distinct microtubule bundling without MP recruitment to the newly formed threads. Co-immunoprecipitation of MPAbMV in the presence of RepAbMV, followed by mass spectrometry identified potential novel MPAbMV-host interaction partners: the peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (Pin4) and stomatal cytokinesis defective 2 (SCD2) proteins. Possible roles of these putative interaction partners in the begomoviral life cycle and cytoskeletal association modes are discussed. PMID- 29120371 TI - New SmAPF Mesogens Designed for Analog Electrooptics Applications. AB - We have previously reported the first realization of an orthogonal ferroelectric bent-core SmAPF phase by directed design in mesogens with a single tricarbosilane terminated alkoxy tail. Given the potentially useful electrooptic properties of this phase, including analog phase-only electrooptic index modulation with optical latching, we have been exploring its "structure space", searching for novel SmAPF mesogens. Here, we report two classes of these-the first designed to optimize the dynamic range of the index modulation in parallel-aligned cells by lowering the bend angle of the rigid core, and the second expanding the structure space of the phase by replacing the tricarbosilane-terminated alkyl tail with a polyfluorinated polyethylene glycol oligomer. PMID- 29120373 TI - Recent Progress and Required Developments in Atmospheric Corrosion of Galvanised Steel and Zinc. AB - This paper reviews the progress in atmospheric corrosion of zinc since 2009. It firstly summarises the state of the art in 2009, then outlines progress since 2009, and then looks at the significance of this progress and the areas the need more research. Within this framework, it looks at climate effects, oxide formation, oxide properties, pitting, laboratory duplication of atmospheric corrosion, and modelling. The major findings are that there have been major advances in the fields understanding of the structure of corrosion patina, in particular their layered structure and the presence of compact layers, local corrosion attacks have been found to be a significant process in atmospheric corrosion and experiments under droplets are leading to new understanding of the criticality of drop size in regulating atmospheric corrosion processes. Further research is indicating that zinc oxide within corrosion products may promote the oxygen reduction reaction (ORR) and that, in porous oxides, the ORR would control pore chemistry and may promote oxide densification. There is a strong need for more research to understand more deeply the formation and properties of these layered oxides as well as additional research to refine and quantify our emerging understanding of corrosion under droplets. PMID- 29120372 TI - Genome and Epigenome Surveillance Processes Underlying UV Exposure in Plants. AB - Land plants and other photosynthetic organisms (algae, bacteria) use the beneficial effect of sunlight as a source of energy for the photosynthesis and as a major source of information from the environment. However, the ultraviolet component of sunlight also produces several types of damage, which can affect cellular and integrity, interfering with growth and development. In order to reduce the deleterious effects of UV, photosynthetic organisms combine physiological adaptation and several types of DNA repair pathways to avoid dramatic changes in the structure. Therefore, plants may have obtained an evolutionary benefit from combining genome and surveillance processes, to efficiently deal with the deleterious effects of UV radiation. This review will present the different mechanisms activated upon UV exposure that contribute to maintain genome and integrity. PMID- 29120374 TI - Tensile Fracture Behavior and Failure Mechanism of Additively-Manufactured AISI 4140 Low Alloy Steel by Laser Engineered Net Shaping. AB - AISI 4140 powder was directly deposited on AISI 4140 wrought substrate using laser engineered net shaping (LENS) to investigate the compatibility of a LENS deposited part with the substrate. Tensile testing at room temperature was performed to evaluate the interface bond performance and fracture behavior of the test specimens. All the samples failed within the as-deposited zone, indicating that the interfacial bond is stronger than the interlayer bond inside the deposit. The fracture surfaces were analyzed using scanning electron microscopy (SEM) and energy disperse X-ray spectrometry (EDS). Results show that the tensile fracture failure of the as-deposited part is primarily affected by lack-of-fusion defects, carbide precipitation, and oxide particles inclusions, which causes premature failure of the deposit by deteriorating the mechanical properties and structural integrity. PMID- 29120375 TI - Disaccharides: Influence on Volatiles and Phenolics of Sour Cherry Juice. AB - The food industry is continuously developing ingredients, processing methods and packaging materials to improve the quality of fruit products. The aim of this work was to study the effect of sugars, a common ingredient in the food industry, on phenolics and volatiles of sour cherry juice. Sucrose, trehalose and maltose chemical isomers were chosen for this investigation. All sugars influenced the evaluated parameters. Samples with maltose addition had lower, while samples with sucrose and trehalose addition had higher anthocyanin content than the control sample. Generally, trehalose had a higher positive effect on volatiles with the desired flavor note. PMID- 29120376 TI - Real-Time Alpine Measurement System Using Wireless Sensor Networks. AB - Monitoring the snow pack is crucial for many stakeholders, whether for hydro power optimization, water management or flood control. Traditional forecasting relies on regression methods, which often results in snow melt runoff predictions of low accuracy in non-average years. Existing ground-based real-time measurement systems do not cover enough physiographic variability and are mostly installed at low elevations. We present the hardware and software design of a state-of-the-art distributed Wireless Sensor Network (WSN)-based autonomous measurement system with real-time remote data transmission that gathers data of snow depth, air temperature, air relative humidity, soil moisture, soil temperature, and solar radiation in physiographically representative locations. Elevation, aspect, slope and vegetation are used to select network locations, and distribute sensors throughout a given network location, since they govern snow pack variability at various scales. Three WSNs were installed in the Sierra Nevada of Northern California throughout the North Fork of the Feather River, upstream of the Oroville dam and multiple powerhouses along the river. The WSNs gathered hydrologic variables and network health statistics throughout the 2017 water year, one of northern Sierra's wettest years on record. These networks leverage an ultra-low-power wireless technology to interconnect their components and offer recovery features, resilience to data loss due to weather and wildlife disturbances and real-time topological visualizations of the network health. Data show considerable spatial variability of snow depth, even within a 1 km 2 network location. Combined with existing systems, these WSNs can better detect precipitation timing and phase in, monitor sub-daily dynamics of infiltration and surface runoff during precipitation or snow melt, and inform hydro power managers about actual ablation and end-of-season date across the landscape. PMID- 29120377 TI - Concentrations of Carotenoids and Tocopherols in Breast Milk from Urban Chinese Mothers and Their Associations with Maternal Characteristics: A Cross-Sectional Study. AB - Milk composition remains the best estimate of infant requirements. The aims of this study were to quantify carotenoids and tocopherols in human milk from healthy Chinese mothers, and to explore their associations with lactation stage, region, socio-economic and obstetric characteristics, and dietary intake. Human milk was obtained from 509 healthy mothers, and concentrations of carotenoids and tocopherols were analyzed by Ultra High Performance Liquid Chromatography. The mothers' socio-economic and obstetric characteristics and dietary intake through a single 24-h dietary recall were evaluated. The median concentrations (MUg/100 mL) of each component of 0-4 days, 5-11 days, 12-30 days, 31-60 days, 61-120 days, and 121-240 days postpartum were respectively as follows: beta-carotene 8.0, 2.8, 2.1, 1.7, 1.9, 1.8; beta-cryptoxanthin 6.2, 3.4, 2.4, 1.7, 1.8, 2.1; lutein 5.7, 7.0, 2.2, 2.9, 2.8, 3.7; lycopene 6.3, 2.5, 1.8, 1.4, 1.4, 1.5; zeaxanthin 1.0, 1.4, 0.8, 0.8, 1.0, 1.1; alpha-tocopherol 645, 382, 239, 206, 212, 211; gamma-tocopherol 68, 63, 70, 73, 68, 88. The levels of those components varied significantly among different lactation stages and presented regional differences. Associations of carotenoid contents with maternal education, delivery mode, and present body mass index were found in multivariate analyses. These results suggested that lactation stage, region, and socio-economic and obstetric factors were associated with human milk concentrations of carotenoids and tocopherols in healthy Chinese mothers. PMID- 29120378 TI - Clinic Design as Placebo-Using Design to Promote Healing and Support Treatments. AB - Analogously to the medical placebo effect, people seem to anticipate the quality of treatments based on external stimuli. In order to gain insights on the effect the built environment can have on a person's judgments and behavior with a particular focus on health related issues, a quantitative survey (N = 851) with four groups before and after the renovation of a rehabilitation clinic has been conducted. In line with an overall modernization of the clinic, the entrance, the lobby, and some patient rooms have been changed. In the lobby, a service counter and coffee bar have been added as well as light colors and new flooring material to achieve a more modern and clean atmosphere in the sense of aesthetical appearance of the space. The outcome revealed that patients rate the intention to change their health behavior as well as the quality of food or significantly higher in a modernized clinic. These differences cannot be directly attributed solely to the changes in the building. Analogously to the medical placebo, an effect referred to as design placebo effect is, therefore, proposed to explain improved ratings of aspects that have not directly been changed due to the intervention. Other significant effects are attributable to winter and summer climate. During summer time, ratings for waiting area, atmosphere, patient rooms, as well as for staff were significantly higher. It is, therefore, assumed that aesthetic attributes, such as architectural design, or friendliness of the weather, exert their effects as perceptual placebos that directly influence judgment outcomes and behavioral intentions. Further research is needed to match certain design and general environmental features to their effects on patients and investigate their effect strength. PMID- 29120380 TI - In Vitro Phase I Metabolism of CRV431, a Novel Oral Drug Candidate for Chronic Hepatitis B. AB - The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0-80 min with CRV431, and the metabolite profile was assessed by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS). CRV431 was extensively metabolized through oxidation to produce various hydroxylated and demethylated species. Species identified included monohydroxylated CRV431 (two distinct products), dihydroxylated CRV431, demethylated CRV431 (two distinct products), demethylated and hydroxylated CRV431 (two distinct products), didemethylated and hydroxylated CRV431, and didemethylated and dihydroxylated CRV431. The magnitude of metabolism was greatest in monkey, followed by human, followed by rat. Importantly, all of the species identified in human microsomes were correspondingly identified in monkey and/or rat microsomes. Human liver microsome studies using selective chemical inhibition, as well as studies using recombinant human cytochrome P450 enzymes, revealed that the major enzymes involved are cytochromes P450 3A4 and 3A5. Enzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 are not involved in the in vitro metabolism of CRV431. This information will be useful for the further development of CRV431 both preclinically and clinically. PMID- 29120379 TI - Trait Rumination Predicts Elevated Evening Cortisol in Sexual and Gender Minority Young Adults. AB - Stress may contribute to illness through the impaired recovery or sustained activity of stress-responsive biological systems. Rumination, or mental rehearsal of past stressors, may alter the body's stress-responsive systems by amplifying and prolonging exposure to physiological mediators, such as cortisol. The primary aim of the current investigation was to test the extent to which the tendency to ruminate on stress predicts diminished diurnal cortisol recovery (i.e., elevated evening cortisol) in a sample of sexual and gender minority young adults. Participants included 58 lesbian, gay, bisexual, and transgender young adults (Mage = 25.0, SD = 4.1) who completed an initial online survey that assessed trait rumination and current depressed mood. Participants completed daily evening questionnaires and provided salivary cortisol samples at wake, 45 min post-wake, 12 h post-wake, and at bedtime over seven consecutive days. Trait rumination predicted significantly higher cortisol concentrations at bedtime, but was unrelated to other cortisol indices (e.g., morning cortisol, diurnal slope, total output). The association with trait rumination was not accounted for by daily negative affect, and was largely independent of depressed mood. These results have implications for identifying and treating those who may be at risk for impaired diurnal cortisol recovery and associated negative health outcomes. PMID- 29120381 TI - Mach-Zehnder Interferometer Refractive Index Sensor Based on a Plasmonic Channel Waveguide. AB - A Mach-Zehnder interferometer based on a plasmonic channel waveguide is proposed for refractive index sensing. The structure, with a small physical footprint of 20 * 120 MUm2, achieved a high figure of merit of 294. The cut-off frequency behaviour in the plasmonic channel waveguide resulted in a flat dispersion curve, which induces a 1.8 times larger change of the propagation constant for the given refractive index change compared with previously reported results. PMID- 29120383 TI - FieldSAFE: Dataset for Obstacle Detection in Agriculture. AB - In this paper, we present a multi-modal dataset for obstacle detection in agriculture. The dataset comprises approximately 2 h of raw sensor data from a tractor-mounted sensor system in a grass mowing scenario in Denmark, October 2016. Sensing modalities include stereo camera, thermal camera, web camera, 360 ? camera, LiDAR and radar, while precise localization is available from fused IMU and GNSS. Both static and moving obstacles are present, including humans, mannequin dolls, rocks, barrels, buildings, vehicles and vegetation. All obstacles have ground truth object labels and geographic coordinates. PMID- 29120382 TI - Factors Associated with Activities of Daily Life Disability among Centenarians in Rural Chongqing, China: A Cross-Sectional Study. AB - OBJECTIVE: This study aims to ascertain the health and lifestyle factors associated with the activities of daily living (ADL) disability of centenarians in rural Chongqing, China. METHOD: 564 centenarians living in rural Chongqing were selected for this cross-sectional study. Demographic characteristics and self-reported lifestyle factors were obtained from face-to-face interviews. ADL disability was measured using the Katz Activities of Daily Living Scale. RESULT: Among the respondents, 65.7% were considered ADL disability centenarians. Multivariable logistic regression analysis showed that preference for salt, drinking habits, social activities, physical activity, and failure to follow good diet habits were significantly associated with the ADL disability of centenarians. CONCLUSION: ADL disability of centenarians was associated with certain lifestyle habits. This outcome suggested that target intervention may help maintain ADL independence even among the oldest of the elderly population. PMID- 29120384 TI - ZnO Nanowire Application in Chemoresistive Sensing: A Review. AB - This article provides an overview of the recent development of ZnO nanowires (NWs) for chemoresistive sensing. Working mechanisms of chemoresistive sensors are unified for gas, ultraviolet (UV) and bio sensor types: single nanowire and nanowire junction sensors are described, giving the overview for a simple sensor manufacture by multiple nanowire junctions. ZnO NW surface functionalization is discussed, and how this effects the sensing is explained. Further, novel approaches for sensing, using ZnO NW functionalization with other materials such as metal nanoparticles or heterojunctions, are explained, and limiting factors and possible improvements are discussed. The review concludes with the insights and recommendations for the future improvement of the ZnO NW chemoresistive sensing. PMID- 29120385 TI - Hospital Audit as a Useful Tool in the Process of Introducing Falsified Medicines Directive (FMD) into Hospital Pharmacy Settings-A Pilot Study. AB - BACKGROUND: Recently, the European Union has introduced the Falsified Medicines Directive (FMD). Additionally, in early 2016, a Delegated Act (DA) related to the FMD was published. The main objective of this study was to evaluate the usefulness of external audits in the context of implementing new regulations provided by the FMD in the secondary care environment. METHODS: The external, in person workflow audits were performed by an authentication company in three Polish hospital pharmacies. Each audit consisted of a combination of supervision (non-participant observation), secondary data analysis, and expert interviews with the use of an independently designed authorial Diagnostic Questionnaire. The questionnaire included information about hospital drug distribution procedures, data concerning drug usage, IT systems, medication order systems, the processes of medication dispensing, and the preparation and administration of hazardous drugs. Data analysis included a thorough examination of hospital documentation in regard to drug management. All data were subjected to qualitative analysis, with the aim of generating meaningful information through inductive inference. RESULTS: Only one dispensing location in the Polish hospitals studied has the potential to be a primary authentication area. In the audited hospitals, an Automated Drug Dispensing System and unit dose were not identified during the study. Hospital wards contained an enclosed place within the department dedicated to drug storage under the direct supervision of senior nursing staff. An electronic order system was not available. In the largest center, unused medications are re-dispensed to different hospital departments, or may be sold to various institutions. Additionally, in one hospital pharmacy, pharmacists prepared parenteral nutrition and chemotherapeutic drugs for patients admitted to the hospital. CONCLUSIONS: External audits might prove beneficial in the course of introducing new regulations into everyday settings. However, such action should be provided before the final implementation of authentication services. To sum up, FMD can impact several hospital departments. PMID- 29120386 TI - High Quality Unigenes and Microsatellite Markers from Tissue Specific Transcriptome and Development of a Database in Clusterbean (Cyamopsis tetragonoloba, L. Taub). AB - Clusterbean (Cyamopsis tetragonoloba L. Taub), is an important industrial, vegetable and forage crop. This crop owes its commercial importance to the presence of guar gum (galactomannans) in its endosperm which is used as a lubricant in a range of industries. Despite its relevance to agriculture and industry, genomic resources available in this crop are limited. Therefore, the present study was undertaken to generate RNA-Seq based transcriptome from leaf, shoot, and flower tissues. A total of 145 million high quality Illumina reads were assembled using Trinity into 127,706 transcripts and 48,007 non-redundant high quality (HQ) unigenes. We annotated 79% unigenes against Plant Genes from the National Center for Biotechnology Information (NCBI), Swiss-Prot, Pfam, gene ontology (GO) and KEGG databases. Among the annotated unigenes, 30,020 were assigned with 116,964 GO terms, 9984 with EC and 6111 with 137 KEGG pathways. At different fragments per kilobase of transcript per millions fragments sequenced (FPKM) levels, genes were found expressed higher in flower tissue followed by shoot and leaf. Additionally, we identified 8687 potential simple sequence repeats (SSRs) with an average frequency of one SSR per 8.75 kb. A total of 28 amplified SSRs in 21 clusterbean genotypes resulted in polymorphism in 13 markers with average polymorphic information content (PIC) of 0.21. We also constructed a database named 'ClustergeneDB' for easy retrieval of unigenes and the microsatellite markers. The tissue specific genes identified and the molecular marker resources developed in this study is expected to aid in genetic improvement of clusterbean for its end use. PMID- 29120387 TI - Alteration of Vascular Responsiveness to Uridine Adenosine Tetraphosphate in Aortas Isolated from Male Diabetic Otsuka Long-Evans Tokushima Fatty Rats: The Involvement of Prostanoids. AB - We investigated whether responsiveness to dinucleotide uridine adenosine tetraphosphate (Up4A) was altered in aortas from type 2 diabetic Otsuka Long Evans Tokushima Fatty (OLETF) rats compared with those from age-matched control Long-Evans Tokushima Otsuka (LETO) rats at the chronic stage of disease. In OLETF aortas, we observed the following: (1) Up4A-induced contractions were lower than those in the LETO aortas under basal conditions, (2) slight relaxation occurred due to Up4A, but this was not observed in phenylephrine-precontracted LETO aortas, (3) acetylcholine-induced relaxation was reduced (vs. LETO), and (4) prostanoid release (prostaglandin (PG)F2alpha, thromboxane (Tx)A2 metabolite, and PGE2) due to Up4A was decreased (vs. LETO). Endothelial denudation suppressed Up4A-induced contractions in the LETO group, but increased the contractions in the OLETF group. Under nitric oxide synthase (NOS) inhibition, Up4A induced contractions in phenylephrine-precontracted aortas; this effect was greater in the LETO group (vs. the OLETF group). The relaxation response induced by Up4A was unmasked by cyclooxygenase inhibitors, especially in the LETO group, but this effect was abolished by NOS inhibition. These results suggest that the relaxant component of the Up4A-mediated response was masked by prostanoids in the LETO aortas and that the LETO and OLETF rats presented different contributions of the endothelium to the response. PMID- 29120388 TI - Synthesis and Molecular Modeling Studies of N'-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors. AB - Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N' hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme. Molecular docking studies revealed that 8a binds to IDO1 with the same binding mode as the analog, epacadostat (INCB24360). Here, we report the synthesis and biological evaluation of these hydroxyindazolecarboximidamides and present the molecular docking study of 8a with IDO1. PMID- 29120389 TI - Textile Pressure Mapping Sensor for Emotional Touch Detection in Human-Robot Interaction. AB - In this paper, we developed a fully textile sensing fabric for tactile touch sensing as the robot skin to detect human-robot interactions. The sensor covers a 20-by-20 cm 2 area with 400 sensitive points and samples at 50 Hz per point. We defined seven gestures which are inspired by the social and emotional interactions of typical people to people or pet scenarios. We conducted two groups of mutually blinded experiments, involving 29 participants in total. The data processing algorithm first reduces the spatial complexity to frame descriptors, and temporal features are calculated through basic statistical representations and wavelet analysis. Various classifiers are evaluated and the feature calculation algorithms are analyzed in details to determine each stage and segments' contribution. The best performing feature-classifier combination can recognize the gestures with a 93 . 3 % accuracy from a known group of participants, and 89 . 1 % from strangers. PMID- 29120390 TI - Functional Characterization of Waterlogging and Heat Stresses Tolerance Gene Pyruvate decarboxylase 2 from Actinidia deliciosa. AB - A previous report showed that both Pyruvatedecarboxylase (PDC) genes were significantly upregulated in kiwifruit after waterlogging treatment using Illumina sequencing technology, and that the kiwifruit AdPDC1 gene was required during waterlogging, but might not be required during other environmental stresses. Here, the function of another PDC gene, named AdPDC2, was analyzed. The expression of the AdPDC2 gene was determined using qRT-PCR, and the results showed that the expression levels of AdPDC2 in the reproductive organs were much higher than those in the nutritive organs. Waterlogging, NaCl, and heat could induce the expression of AdPDC2. Overexpression of kiwifruit AdPDC2 in transgenic Arabidopsis enhanced resistance to waterlogging and heat stresses in five-week old seedlings, but could not enhance resistance to NaCl and mannitol stresses at the seed germination stage and in early seedlings. These results suggested that the kiwifruit AdPDC2 gene may play an important role in waterlogging resistance and heat stresses in kiwifruit. PMID- 29120391 TI - Cytotoxicity of Labruscol, a New Resveratrol Dimer Produced by Grapevine Cell Suspensions, on Human Skin Melanoma Cancer Cell Line HT-144. AB - A new resveratrol dimer (1) called labruscol, has been purified by centrifugal partition chromatography of a crude ethyl acetate stilbene extract obtained from elicited grapevine cell suspensions of Vitis labrusca L. cultured in a 14-liter stirred bioreactor. One dimensional (1D) and two dimensional (2D) nuclear magnetic resonance (NMR) analyses including 1H, 13C, heteronuclear single-quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), and correlation spectroscopy (COSY) as well as high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) were used to characterize this compound and to unambiguously identify it as a new stilbene dimer, though its relative stereochemistry remained unsolved. Labruscol was recovered as a pure compound (>93%) in sufficient amounts (41 mg) to allow assessment of its biological activity (cell viability, cell invasion and apoptotic activity) on two different cell lines, including one human skin melanoma cancer cell line HT-144 and a healthy human dermal fibroblast (HDF) line. This compound induced almost 100% of cell viability inhibition in the cancer line at a dose of 100 MUM within 72 h of treatment. However, at all tested concentrations and treatment times, resveratrol displayed an inhibition of the cancer line viability higher than that of labruscol in the presence of fetal bovine serum. Both compounds also showed differential activities on healthy and cancer cell lines. Finally, labruscol at a concentration of 1.2 MUM was shown to reduce cell invasion by 40%, although no similar activity was observed with resveratrol. The cytotoxic activity of this newly-identified dimer is discussed. PMID- 29120392 TI - Impact of Lateral Transfers on the Genomes of Lepidoptera. AB - Transfer of DNA sequences between species regardless of their evolutionary distance is very common in bacteria, but evidence that horizontal gene transfer (HGT) also occurs in multicellular organisms has been accumulating in the past few years. The actual extent of this phenomenon is underestimated due to frequent sequence filtering of "alien" DNA before genome assembly. However, recent studies based on genome sequencing have revealed, and experimentally verified, the presence of foreign DNA sequences in the genetic material of several species of Lepidoptera. Large DNA viruses, such as baculoviruses and the symbiotic viruses of parasitic wasps (bracoviruses), have the potential to mediate these transfers in Lepidoptera. In particular, using ultra-deep sequencing, newly integrated transposons have been identified within baculovirus genomes. Bacterial genes have also been acquired by genomes of Lepidoptera, as in other insects and nematodes. In addition, insertions of bracovirus sequences were present in the genomes of certain moth and butterfly lineages, that were likely corresponding to rearrangements of ancient integrations. The viral genes present in these sequences, sometimes of hymenopteran origin, have been co-opted by lepidopteran species to confer some protection against pathogens. PMID- 29120393 TI - Engineering the Surface/Interface Structures of Titanium Dioxide Micro and Nano Architectures towards Environmental and Electrochemical Applications. AB - Titanium dioxide (TiO2) materials have been intensively studied in the past years because of many varied applications. This mini review article focuses on TiO2 micro and nano architectures with the prevalent crystal structures (anatase, rutile, brookite, and TiO2(B)), and summarizes the major advances in the surface and interface engineering and applications in environmental and electrochemical applications. We analyze the advantages of surface/interface engineered TiO2 micro and nano structures, and present the principles and growth mechanisms of TiO2 nanostructures via different strategies, with an emphasis on rational control of the surface and interface structures. We further discuss the applications of TiO2 micro and nano architectures in photocatalysis, lithium/sodium ion batteries, and Li-S batteries. Throughout the discussion, the relationship between the device performance and the surface/interface structures of TiO2 micro and nano structures will be highlighted. Then, we discuss the phase transitions of TiO2 nanostructures and possible strategies of improving the phase stability. The review concludes with a perspective on the current challenges and future research directions. PMID- 29120394 TI - Amaranth Protein Hydrolysates Efficiently Reduce Systolic Blood Pressure in Spontaneously Hypertensive Rats. AB - Alcalase is the enzyme of choice to release antihypertensive peptides from amaranth proteins, but the hydrolysis conditions have not been optimized yet. Furthermore, in vivo assays are needed to confirm such a hypotensive effect. Our aim was to optimize the hydrolysis of amaranth protein with alcalase and to test in vivo the hypotensive effect of the hydrolysates. A response surface analysis was carried out to optimize the hydrolysis reaction. The response variable was the Angiotensin Converting Enzyme (ACE-I) inhibition. The hydrolysis degree was determined (free alpha-amino groups measurement). The optimized hydrolysate bioavailability was assessed in the sera of mice and the hypotensive effect was assessed in spontaneously hypertensive rats. Control groups were administered captopril or water. The optimized hydrolysis conditions were: pH = 7.01, temperature = 52 degrees C, enzyme concentration 0.04 mU/mg, and time = 6.16 h. The optimized hydrolysate showed a 93.5% of ACE-I inhibition and a hydrolysis degree of 74.77%. After supplementation, the hydrolysate was bioavailable in mice from 5 to 60 min, and the hypotensive effect started at 4 h in spontaneously hypertensive rats (p < 0.05 vs. water group). This effect was similar to the captopril hypotensive effect for the next 3 h (p > 0.05). The use of amaranth optimized hydrolysates as hypotensive supplements or ingredient for functional foods seems feasible. PMID- 29120395 TI - Unexpected Synthesis of a Bulky Bis-Pocket A3B-Type Meso-Cyano Porphyrin. AB - A one-pot synthesis of bulky bis-pocket A3B-type meso-cyano porphyrin, 5-cyano 10,15,20-tris(2,4,6-triphenylphenyl)porphyrin, has been accomplished via trifluoroacetic acid (TFA) catalyzed condensation of pyrrole and 2,4,6 triphenylbenzaldehyde in an acceptable yield of about 4%. DDQ served as oxidant and the cyanating agent. PMID- 29120396 TI - Materials for Wind Turbine Blades: An Overview. AB - A short overview of composite materials for wind turbine applications is presented here. Requirements toward the wind turbine materials, loads, as well as available materials are reviewed. Apart from the traditional composites for wind turbine blades (glass fibers/epoxy matrix composites), natural composites, hybrid and nanoengineered composites are discussed. Manufacturing technologies for wind turbine composites, as well their testing and modelling approaches are reviewed. PMID- 29120397 TI - Highly Selective Polypyrrole MIP-Based Gravimetric and Electrochemical Sensors for Picomolar Detection of Glyphosate. AB - There is a global debate and concern about the use of glyphosate (Gly) as an herbicide. New toxicological studies will determine its use in the future under new strict conditions or its replacement by alternative synthetic or natural herbicides. In this context, we designed biomimetic polymer sensing layers for the selective molecular recognition of Gly. Towards this end, complementary surface acoustic wave (SAW) and electrochemical sensors were functionalized with polypyrrole (PPy)-imprinted polymer for the selective detection of Gly. Their corresponding limits of detection were on the order of 1 pM, which are among the lowest values ever reported in literature. The relevant dissociation constants between PPy and Gly were estimated at [Kd1 = (0.7 +/- 0.3) pM and Kd2 = (1.6 +/- 1.4) uM] and [Kd1 = (2.4 +/- 0.9) pM and Kd2 = (0.3 +/- 0.1) uM] for electrochemical and gravimetric measurements, respectively. Quantum chemical calculations permitted to estimate the interaction energy between Gly and PPy film: DeltaE = -145 kJ/mol. Selectivity and competitivity tests were investigated with the most common pesticides. This work conclusively shows that gravimetric and electrochemical results indicate that both MIP-based sensors are perfectly able to detect and distinguish glyphosate without any ambiguity. PMID- 29120398 TI - Bamboo-Polylactic Acid (PLA) Composite Material for Structural Applications. AB - Developing an eco-friendly industry based on green materials, sustainable technologies, and optimum processes with low environmental impact is a general societal goal, but this remains a considerable challenge to achieve. Despite the large number of research on green structural composites, limited investigation into the most appropriate manufacturing methodology to develop a structural material at industrial level has taken place. Laboratory panels have been manufactured with different natural fibers but the methodologies and values obtained could not be extrapolated at industrial level. Bamboo industry panels have increased in the secondary structural sector such as building application, flooring and sport device, because it is one of the cheapest raw materials. At industrial level, the panels are manufactured with only the inner and intermediate region of the bamboo culm. However, it has been found that the mechanical properties of the external shells of bamboo culm are much better than the average cross-sectional properties. Thin strips of bamboo (1.5 mm thick and 1500 mm long) were machined and arranged with the desired lay-up and shape to obtain laminates with specific properties better than those of conventional E Glass/Epoxy laminates in terms of both strength and stiffness. The strips of bamboo were bonded together by a natural thermoplastic polylactic acid (PLA) matrix to meet biodegradability requirements. The innovative mechanical extraction process developed in this study can extract natural strip reinforcements with high performance, low cost, and high rate, with no negative environmental impact, as no chemical treatments are used. The process can be performed at the industrial level. Furthermore, in order to validate the structural applications of the composite, the mechanical properties were analyzed under ageing conditions. This material could satisfy the requirements for adequate mechanical properties and life cycle costs at industrial sectors such as energy or automotive. PMID- 29120399 TI - A Microbiomic Analysis in African Americans with Colonic Lesions Reveals Streptococcus sp.VT162 as a Marker of Neoplastic Transformation. AB - Increasing evidence suggests a role of the gut microbiota in colorectal carcinogenesis (CRC). To detect bacterial markers of colorectal cancer in African Americans a metabolomic analysis was performed on fecal water extracts. DNA from stool samples of adenoma and healthy subjects and from colon cancer and matched normal tissues was analyzed to determine the microbiota composition (using 16S rDNA) and genomic content (metagenomics). Metagenomic functions with discriminative power between healthy and neoplastic specimens were established. Quantitative Polymerase Chain Reaction (q-PCR) using primers and probes specific to Streptococcus sp. VT_162 were used to validate this bacterium association with neoplastic transformation in stool samples from two independent cohorts of African Americans and Chinese patients with colorectal lesions. The metabolomic analysis of adenomas revealed low amino acids content. The microbiota in both cancer vs. normal tissues and adenoma vs. normal stool samples were different at the 16S rRNA gene level. Cross-mapping of metagenomic data led to 9 markers with significant discriminative power between normal and diseased specimens. These markers identified with Streptococcus sp. VT_162. Q-PCR data showed a statistically significant presence of this bacterium in advanced adenoma and cancer samples in an independent cohort of CRC patients. We defined metagenomic functions from Streptococcus sp. VT_162 with discriminative power among cancers vs. matched normal and adenomas vs. healthy subjects' stools. Streptococcus sp. VT_162 specific 16S rDNA was validated in an independent cohort. These findings might facilitate non-invasive screening for colorectal cancer. PMID- 29120400 TI - Fibrin-Enhanced Canonical Wnt Signaling Directs Plasminogen Expression in Cementoblasts. AB - Cementum is a mineralized layer on the tooth's root surface and facilitates the biomechanical anchoring of fibrous connective tissues as a part of tooth supportive complexes. Previously, we observed that OCCM30 cementoblasts cultured on fibrin matrices underwent apoptosis due to fibrin degradation through the expression of proteases. Here, we demonstrated that OCCM30 on fibrin matrices (OCCM30-fibrin) enhanced canonical Wnt signaling, which directed to plasminogen expression. The OCCM30-fibrin showed higher levels of Wnt3a expression, nuclear translocation of beta-catenin, and T-cell factor (TCF) optimal motif (TOP) reporter activity than the cells on tissue culture dishes (OCCM30-TCD), indicating that the OCCM30-fibrin enhanced canonical Wnt/beta-catenin signaling. Also, OCCM30-fibrin expressed biomineralization-associated markers at higher levels than OCCM30-TCD, of which levels were further increased with LiCl, a Wnt signaling activator. The OCCM30 cementoblasts simultaneously showed that high levels of plasminogen, a critical component of fibrinolysis, were expressed in the OCCM30-fibrin. Activation of canonical Wnt signaling with LiCl treatment or with forced lymphoid enhancer factor 1 (LEF1)-expression increased the expression of plasminogen. On the contrary, the inhibition of canonical Wnt signaling with siRNAs against Wnt3a or beta-catenin abrogated fibrin-enhanced plasminogen expression. Furthermore, there are three conserved putative response elements for the LEF1/beta-catenin complex in the plasminogen proximal promoter regions (-900 to +54). Site-directed mutations and chromatin immunoprecipitation indicated that canonical Wnt signaling directed plasminogen expression. Taken together, this study suggests that fibrin-based materials can modulate functional periodontal formations in controlling cementoblast differentiation and fibrin degradation. PMID- 29120402 TI - Effective Thermal Expansion Property of Consolidated Granular Materials. AB - Thermally-assisted compaction of granular materials is of keen interest in many engineering applications. A proper estimation of the material behavior of compacted granular materials is contingent upon the knowledge of microstructure formation, which is highly dependent on the bulk material properties and processing conditions, during the deformation stage. Originating from the pair interactions between particles, the macroscopic properties are obtained using various homogenization techniques and postulating continuum constitutive laws. While pioneers in this field have laid fundamental groundwork regarding effective medium descriptions, there exists a discrepancy between discrete and continuum level solutions. In our previous work, we elaborated a Particle Mechanics Approach (PMA) that integrates thermal contact and Hertzian deformation models to understand the thermo-mechanically-coupled consolidation problem. We also considered the analogous problem from the perspective of the conventional Continuum Mechanics Approach (CMA). In this study, following the multi-scale modeling framework, we propose an effective thermal expansion coefficient for the thermally-assisted compaction of granular materials. PMID- 29120401 TI - Does Locoregional Chemotherapy Still Matter in the Treatment of Advanced Pelvic Melanoma? AB - Pelvic Melanoma relapse occurs in 15% of patients with loco regional metastases, and 25% of cases do not respond to new target-therapy and/or immunotherapy. Melphalan hypoxic pelvic perfusion may, therefore, be an option for these non responsive patients. Overall median survival time (MST), stratified for variables, including BRAF V600E mutation and eligibility for treatments with new immunotherapy drugs, was retrospectively assessed in 41 patients with pelvic melanoma loco regional metastases. They had received a total of 175 treatments with Melphalan hypoxic perfusion and cytoreductive excision. Among the 41 patients, 22 (53.7%) patients exhibited a wild-type BRAF genotype, 11 of which were not eligible for immunotherapy. The first treatment resulted in a 97.5% response-rate in the full cohort and a 100% response-rate in the 22 wild-type BRAF patients. MST was 18 months in the full sample, 20 months for the 22 wild type BRAF patients and 21 months for the 11 wild-type BRAF patients not eligible for immunotherapy. Melphalan hypoxic perfusion is a potentially effective treatment for patients with pelvic melanoma loco regional metastases that requires confirmation in a larger multicenter study. PMID- 29120403 TI - The Electrospun Ceramic Hollow Nanofibers. AB - Hollow nanofibers are largely gaining interest from the scientific community for diverse applications in the fields of sensing, energy, health, and environment. The main reasons are: their extensive surface area that increases the possibilities of engineering, their larger accessible active area, their porosity, and their sensitivity. In particular, semiconductor ceramic hollow nanofibers show greater space charge modulation depth, higher electronic transport properties, and shorter ion or electron diffusion length (e.g., for an enhanced charging-discharging rate). In this review, we discuss and introduce the latest developments of ceramic hollow nanofiber materials in terms of synthesis approaches. Particularly, electrospinning derivatives will be highlighted. The electrospun ceramic hollow nanofibers will be reviewed with respect to their most widely studied components, i.e., metal oxides. These nanostructures have been mainly suggested for energy and environmental remediation. Despite the various advantages of such one dimensional (1D) nanostructures, their fabrication strategies need to be improved to increase their practical use. The domain of nanofabrication is still advancing, and its predictable shortcomings and bottlenecks must be identified and addressed. Inconsistency of the hollow nanostructure with regard to their composition and dimensions could be one of such challenges. Moreover, their poor scalability hinders their wide applicability for commercialization and industrial use. PMID- 29120404 TI - A Tree Based Broadcast Scheme for (m, k)-firm Real-Time Stream in Wireless Sensor Networks. AB - Recently, various unicast routing protocols have been proposed to deliver measured data from the sensor node to the sink node within the predetermined deadline in wireless sensor networks. In parallel with their approaches, some applications demand the specific service, which is based on broadcast to all nodes within the deadline, the feasible real-time traffic model and improvements in energy efficiency. However, current protocols based on either flooding or one to-one unicast cannot meet the above requirements entirely. Moreover, as far as the authors know, there is no study for the real-time broadcast protocol to support the application-specific traffic model in WSN yet. Based on the above analysis, in this paper, we propose a new (m, k)-firm-based Real-time Broadcast Protocol (FRBP) by constructing a broadcast tree to satisfy the (m, k)-firm, which is applicable to the real-time model in resource-constrained WSNs. The broadcast tree in FRBP is constructed by the distance-based priority scheme, whereas energy efficiency is improved by selecting as few as nodes on a tree possible. To overcome the unstable network environment, the recovery scheme invokes rapid partial tree reconstruction in order to designate another node as the parent on a tree according to the measured (m, k)-firm real-time condition and local states monitoring. Finally, simulation results are given to demonstrate the superiority of FRBP compared to the existing schemes in terms of average deadline missing ratio, average throughput and energy consumption. PMID- 29120405 TI - Site-Specific Antibody Conjugation for ADC and Beyond. AB - Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. These methods couple cytotoxins or chemotherapeutic drugs to specifically defined sites in antibody molecules including cysteine, glutamine, unnatural amino acids, short peptide tags, and glycans. The ADCs produced showed high homogeneity, increased therapeutic index, and strong antitumor activities in vitro and in vivo. Moreover, there are recent trends in using these next generation technologies beyond the cytotoxin-conjugated ADC. These site-specific conjugations have been applied for the generation of many different immunoconjugates including bispecific Fab or small molecule-antibody conjugates, immunosuppressive antibodies, and antibody-antibiotic conjugates. Thus, it is likely that additional technologies and related site-specific conjugates will emerge in the near future, with various chemicals or small molecular weight proteins in addition to cytotoxin for better treatment of many challenging diseases. PMID- 29120407 TI - Substrate-Influenced Thermo-Mechanical Fatigue of Copper Metallizations: Limits of Stoney's Equation. AB - Rapid progress in the reduction of substrate thickness for silicon-based microelectronics leads to a significant reduction of the device bending stiffness and the need to address its implication for the thermo-mechanical fatigue behavior of metallization layers. Results on 5 um thick Cu films reveal a strong substrate thickness-dependent microstructural evolution. Substrates with hs = 323 and 220 um showed that the Cu microstructure exhibits accelerated grain growth and surface roughening. Moreover, curvature-strain data indicates that Stoney's simplified curvature-stress relation is not valid for thin substrates with regard to the expected strains, but can be addressed using more sophisticated plate bending theories. PMID- 29120406 TI - Regulation and Sensing of Inflammasomes and Their Impact on Intestinal Health. AB - Pattern recognition receptors such as nucleotide-binding oligomerization domain (NOD)-containing protein receptors (NLRs) and the pyrin and hematopoitic interferon-inducible nuclear protein (HIN) domain (PYHIN) receptors initiate the inflammatory response following cell stress or pathogenic challenge. When activated, some of these receptors oligomerize to form the structural backbone of a signalling platform known as an inflammasome. Inflammasomes promote the activation of caspase-1 and the maturation of the proinflammatory cytokines, interleukin (IL)-1beta and IL-18. The gut dysregulation of the inflammasome complex is thought to be a contributing factor in the development of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). The importance of inflammasomes to intestinal health has been emphasized by various inflammasome-deficient mice in dextran sulphate sodium (DSS) models of intestinal inflammation and by the identification of novel potential candidate genes in population-based human studies. In this review, we summarise the most recent findings with regard to the formation, sensing, and regulation of the inflammasome complex and highlight their importance in maintaining intestinal health. PMID- 29120408 TI - Exolysin Shapes the Virulence of Pseudomonas aeruginosa Clonal Outliers. AB - Bacterial toxins are important weapons of toxicogenic pathogens. Depending on their origin, structure and targets, they show diverse mechanisms of action and effects on eukaryotic cells. Exolysin is a secreted 170 kDa pore-forming toxin employed by clonal outliers of Pseudomonas aeruginosa providing to some strains a hyper-virulent behaviour. This group of strains lacks the major virulence factor used by classical strains, the Type III secretion system. Here, we review the structural features of the toxin, the mechanism of its secretion and the effects of the pore formation on eukaryotic cells. PMID- 29120409 TI - H2S Sensing by Hybrids Based on Nanocrystalline SnO2 Functionalized with Cu(II) Organometallic Complexes: The Role of the Ligand Platform. AB - This paper deals with the functionalization of nanocrystalline SnO2 with Cu(II) complexes with organic ligands, aimed at the improvement of sensor selectivity towards gas molecules. For the synthesis of metalorganic/SnO2 hybrid material complexes of Cu(II) with phthalocyanine, porphyrinines, bipyridine and azadithiacrown etherwere used. The analysis of gas sensor properties showed the possibility of increasing the sensitivity and selectivity of hybrid materials in H2S detection due to the electron transfer from SnO2 to an adsorbed organic molecule, which changes during the interaction between H2S and Cu(II) ions. PMID- 29120410 TI - Molecular analysis of axonal-intrinsic and glial-associated co-regulation of axon degeneration. AB - Wallerian degeneration is an active program tightly associated with axonal degeneration, required for axonal regeneration and functional recovery after nerve damage. Here we provide a functional molecular foundation for our undertstanding of the complex non-cell autonomous role of glial cells in the regulation of axonal degeneration. To shed light on the complexity of the molecular machinery governing axonal degeneration we employ a multi-model, unbiased, in vivo approach combining morphological assesment and quantitative proteomics with in silico-based higher order functional clustering to genetically uncouple the intrinsic and extrinsic processes governing Wallerian degeneration. Highlighting a pivotal role for glial cells in the early stages fragmenting the axon by a cytokinesis-like process and a cell autonomous stage of axonal disintegration associated to mitochondrial dysfunction. PMID- 29120411 TI - Alternative polyadenylation of ZEB1 promotes its translation during genotoxic stress in pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. The standard chemotherapeutic drug, gemcitabine, does not offer significant improvements for PDAC management due to the rapid acquisition of drug resistance by patients. Recent evidence indicates that epithelial-to-mesenchymal transition (EMT) of PDAC cells is strictly associated to early metastasization and resistance to chemotherapy. However, it is not exactly clear how EMT is related to drug resistance or how chemotherapy influences EMT. Herein, we found that ZEB1 is the only EMT-related transcription factor that clearly segregates mesenchymal and epithelial PDAC cell lines. Gemcitabine treatment caused upregulation of ZEB1 protein through post-transcriptional mechanisms in mesenchymal PDAC cells within a context of global inhibition of protein synthesis. The increase in ZEB1 protein correlates with alternative polyadenylation of the transcript, leading to shortening of the 3' untranslated region (UTR) and deletion of binding sites for repressive microRNAs. Polysome profiling indicated that shorter ZEB1 transcripts are specifically retained on the polysomes of PDAC cells during genotoxic stress, while most mRNAs, including longer ZEB1 transcripts, are depleted. Thus, our findings uncover a novel layer of ZEB1 regulation through 3'-end shortening of its transcript and selective association with polysomes under genotoxic stress, strongly suggesting that PDAC cells rely on upregulation of ZEB1 protein expression to withstand hostile environments. PMID- 29120413 TI - Brain technology: Neurons recorded en masse. PMID- 29120412 TI - Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia. AB - MicroRNAs (miRNAs) have been suggested to repress transcription via binding the 3'-untranslated regions of mRNAs. However, the involvement and details of miRNA mediated epigenetic regulation, particularly in targeting genomic DNA and mediating epigenetic regulation, remain largely uninvestigated. In the present study, transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, a clinical and highly selective drug for leukemia treatment, and contributed to bortezomib-induced cell death. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 could target CpG islands in the 5'-flanking region of the CEBPD gene. We previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for CCAAT/enhancer binding protein delta (CEBPD) gene inactivation; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. The miRNA/Ago2/YY1/PcG group protein/DNMT complex linked the inactivation of CEBPD and genes adjacent to its 5'-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Moreover, we revealed that miRNA binding is necessary for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. The present study successfully characterized the interactions of the miRNA/Ago2/YY1/PcG group protein/DNMT complex and provided new insights for miRNA mediated epigenetic regulation in bortezomib-induced leukemic cell arrest and cell death. PMID- 29120415 TI - Neurobiology: A genetic cause of age-related decline. PMID- 29120414 TI - Genetic variation in glia-neuron signalling modulates ageing rate. AB - The rate of behavioural decline in the ageing population is remarkably variable among individuals. Despite the considerable interest in studying natural variation in ageing rate to identify factors that control healthy ageing, no such factor has yet been found. Here we report a genetic basis for variation in ageing rates in Caenorhabditis elegans. We find that C. elegans isolates show diverse lifespan and age-related declines in virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory gene-for-behavioural-ageing-1 (rgba-1), and the neuropeptide receptor gene npr-28 influence the rate of age-related decline of worm mating behaviour; these two genes might have been subjected to recent selective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which acts in serotonergic and dopaminergic neurons to accelerate behavioural deterioration. This signalling involves the SIR-2.1 dependent activation of the mitochondrial unfolded protein response, a pathway that modulates ageing. Thus, natural variation in neuropeptide-mediated glia neuron signalling modulates the rate of ageing in C. elegans. PMID- 29120416 TI - Abyssal ocean overturning shaped by seafloor distribution. AB - The abyssal ocean is broadly characterized by northward flow of the densest waters and southward flow of less-dense waters above them. Understanding what controls the strength and structure of these interhemispheric flows-referred to as the abyssal overturning circulation-is key to quantifying the ocean's ability to store carbon and heat on timescales exceeding a century. Here we show that, north of 32 degrees S, the depth distribution of the seafloor compels dense southern-origin waters to flow northward below a depth of about 4 kilometres and to return southward predominantly at depths greater than 2.5 kilometres. Unless ventilated from the north, the overlying mid-depths (1 to 2.5 kilometres deep) host comparatively weak mean meridional flow. Backed by analysis of historical radiocarbon measurements, the findings imply that the geometry of the Pacific, Indian and Atlantic basins places a major external constraint on the overturning structure. PMID- 29120420 TI - Physical chemistry: Ice niceties. PMID- 29120417 TI - Energetic eruptions leading to a peculiar hydrogen-rich explosion of a massive star. AB - Every supernova so far observed has been considered to be the terminal explosion of a star. Moreover, all supernovae with absorption lines in their spectra show those lines decreasing in velocity over time, as the ejecta expand and thin, revealing slower-moving material that was previously hidden. In addition, every supernova that exhibits the absorption lines of hydrogen has one main light-curve peak, or a plateau in luminosity, lasting approximately 100 days before declining. Here we report observations of iPTF14hls, an event that has spectra identical to a hydrogen-rich core-collapse supernova, but characteristics that differ extensively from those of known supernovae. The light curve has at least five peaks and remains bright for more than 600 days; the absorption lines show little to no decrease in velocity; and the radius of the line-forming region is more than an order of magnitude bigger than the radius of the photosphere derived from the continuum emission. These characteristics are consistent with a shell of several tens of solar masses ejected by the progenitor star at supernova-level energies a few hundred days before a terminal explosion. Another possible eruption was recorded at the same position in 1954. Multiple energetic pre supernova eruptions are expected to occur in stars of 95 to 130 solar masses, which experience the pulsational pair instability. That model, however, does not account for the continued presence of hydrogen, or the energetics observed here. Another mechanism for the violent ejection of mass in massive stars may be required. PMID- 29120418 TI - Ultra-selective looming detection from radial motion opponency. AB - Nervous systems combine lower-level sensory signals to detect higher-order stimulus features critical to survival, such as the visual looming motion created by an imminent collision or approaching predator. Looming-sensitive neurons have been identified in diverse animal species. Different large-scale visual features such as looming often share local cues, which means loom-detecting neurons face the challenge of rejecting confounding stimuli. Here we report the discovery of an ultra-selective looming detecting neuron, lobula plate/lobula columnar, type II (LPLC2) in Drosophila, and show how its selectivity is established by radial motion opponency. In the fly visual system, directionally selective small-field neurons called T4 and T5 form a spatial map in the lobula plate, where they each terminate in one of four retinotopic layers, such that each layer responds to motion in a different cardinal direction. Single-cell anatomical analysis reveals that each arm of the LPLC2 cross-shaped primary dendrites ramifies in one of these layers and extends along that layer's preferred motion direction. In vivo calcium imaging demonstrates that, as their shape predicts, individual LPLC2 neurons respond strongly to outward motion emanating from the centre of the neuron's receptive field. Each dendritic arm also receives local inhibitory inputs directionally selective for inward motion opposing the excitation. This radial motion opponency generates a balance of excitation and inhibition that makes LPLC2 non-responsive to related patterns of motion such as contraction, wide-field rotation or luminance change. As a population, LPLC2 neurons densely cover visual space and terminate onto the giant fibre descending neurons, which drive the jump muscle motor neuron to trigger an escape take off. Our findings provide a mechanistic description of the selective feature detection that flies use to discern and escape looming threats. PMID- 29120423 TI - Astronomy: The star that would not die. PMID- 29120424 TI - Role of stacking disorder in ice nucleation. AB - The freezing of water affects the processes that determine Earth's climate. Therefore, accurate weather and climate forecasts hinge on good predictions of ice nucleation rates. Such rate predictions are based on extrapolations using classical nucleation theory, which assumes that the structure of nanometre-sized ice crystallites corresponds to that of hexagonal ice, the thermodynamically stable form of bulk ice. However, simulations with various water models find that ice nucleated and grown under atmospheric temperatures is at all sizes stacking disordered, consisting of random sequences of cubic and hexagonal ice layers. This implies that stacking-disordered ice crystallites either are more stable than hexagonal ice crystallites or form because of non-equilibrium dynamical effects. Both scenarios challenge central tenets of classical nucleation theory. Here we use rare-event sampling and free energy calculations with the mW water model to show that the entropy of mixing cubic and hexagonal layers makes stacking-disordered ice the stable phase for crystallites up to a size of at least 100,000 molecules. We find that stacking-disordered critical crystallites at 230 kelvin are about 14 kilojoules per mole of crystallite more stable than hexagonal crystallites, making their ice nucleation rates more than three orders of magnitude higher than predicted by classical nucleation theory. This effect on nucleation rates is temperature dependent, being the most pronounced at the warmest conditions, and should affect the modelling of cloud formation and ice particle numbers, which are very sensitive to the temperature dependence of ice nucleation rates. We conclude that classical nucleation theory needs to be corrected to include the dependence of the crystallization driving force on the size of the ice crystallite when interpreting and extrapolating ice nucleation rates from experimental laboratory conditions to the temperatures that occur in clouds. PMID- 29120425 TI - Oceanography: Mixed up at the sea floor. PMID- 29120428 TI - Energy researcher sues the US National Academy of Sciences for millions of dollars. PMID- 29120426 TI - Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. AB - Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology. PMID- 29120429 TI - Vladimir Voevodsky (1966-2017). PMID- 29120427 TI - Fully integrated silicon probes for high-density recording of neural activity. AB - Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal-oxide-semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 * 20-MUm cross-section shank. The 6 * 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour. PMID- 29120431 TI - Dark-matter hunt fails to find the elusive particles. PMID- 29120430 TI - Build the Ebola database in Africa. PMID- 29120432 TI - Too many academics study the same people. PMID- 29120433 TI - Grant winners: Track social impact of grant types in Africa. PMID- 29120435 TI - The bitter battle over the world's most popular insecticides. PMID- 29120437 TI - Grant recipients can still give objective advice. PMID- 29120436 TI - Public participation: Time for a definition of citizen science. PMID- 29120439 TI - Skin regeneration with insights. PMID- 29120438 TI - Four ethical priorities for neurotechnologies and AI. PMID- 29120440 TI - Bibliometrics: Seven LIGO authors not accounted for. PMID- 29120441 TI - US environment agency bars scientists it funds from serving on its advisory boards. PMID- 29120442 TI - Ultrasound for the brain. PMID- 29120443 TI - Reproducibility: Developing standard measures for biology. PMID- 29120444 TI - The catalogue that made metrics, and changed science. PMID- 29120445 TI - Genetically modified apple reaches US stores, but will consumers bite? PMID- 29120446 TI - Pay for US postdocs varies wildly by institution. PMID- 29120447 TI - Science popularization: Research videos in indigenous languages. PMID- 29120448 TI - Rohingya refugees, Bulgarian protests and a prize for negative results. PMID- 29120449 TI - Newly discovered orangutan species is also the most endangered. PMID- 29120450 TI - Apnea, bradycardia and desaturation spells in premature infants: impact of a protocol for the duration of 'spell-free' observation on interprovider variability and readmission rates. AB - OBJECTIVE: To study the impact of implementing a protocol to standardize the duration of observation in preterm infants with apnea/bradycardia/desaturation spells before hospital discharge on length of stay (LOS) and readmission rates. STUDY DESIGN: A protocol to standardize the duration of in-hospital observation for preterm infants with apnea, bradycardia and desaturation spells who were otherwise ready for discharge was implemented in December 2013. We evaluated the impact of this protocol on the LOS and readmission rates of very low birth weight infants (VLBW). Data on readmission for apnea and an apparent life-threatening event (ALTE) within 30 days of discharge were collected. The pre-implementation epoch (2011 to 2013) was compared to the post-implementation period (2014 to 2016). RESULTS: There were 426 and 368 VLBW discharges before and after initiation of the protocol during 2011 to 2013 and 2014 to 2016, respectively. The LOS did not change with protocol implementation (66+/-42 vs 64+/-42 days before and after implementation of the protocol, respectively). Interprovider variability on the duration of observation for apneic spells (F-8.8, P=0.04) and bradycardia spells (F-17.4, P<0.001) decreased after implementation of the protocol. The readmission rate for apnea/ALTE after the protocol decreased from 12.1 to 3.4% (P=0.01). CONCLUSION: Implementing an institutional protocol for VLBW infants to determine the duration of apnea/bradycardia/ desaturation spell free observation period as recommended by the American Academy of Pediatrics clinical report did not prolong the LOS but effectively reduced interprovider variability and readmission rates. PMID- 29120451 TI - Effect of maternal smoking on stress physiology in healthy neonates. AB - OBJECTIVE: To assess the impact of maternal smoking during pregnancy (MSDP) on the neonatal hypothalamic-pituitary-adrenal axis. STUDY DESIGN: In a prospective observational study, salivary cortisol and cortisone levels were measured at the fourth day of life during resting conditions and in response to a pain-induced stress event in healthy neonates whose mothers smoked cigarettes during each stage of pregnancy and compared with controls. RESULTS: Neonates in the control group (n=70) exhibited a physiologic stress response with a significant increase in cortisol (1.3 to 2.1 ng ml-1; P<0.05) and cortisone (11.8 to 17.8 ng ml-1; P<0.05) from baseline levels, whereas in neonates from mothers who smoked (n=33), cortisol (0.9 to 0.8 ng ml-1; P=0.77) and cortisone (11.5 to 13.0; P=0.19) stress response was not significantly different from baseline levels. A two-way analysis of variance confirmed these findings in both groups. CONCLUSIONS: Healthy neonates whose mothers smoked during pregnancy show a blunted stress response on the fourth day of life. Thus, MSDP leads to a dysregulation of the HPA axis with continued effects in neonatal life. This might explain long-term consequences of MSDP such as overweight, diabetes mellitus and modification of blood pressure control mechanisms in adult life. PMID- 29120452 TI - Vascular aging and cardiac maladaptation in growth-restricted preterm infants. AB - OBJECTIVE: To assess arterial morphology and mechanics in preterm infants with fetal growth restriction (FGR) compared with those appropriate for gestational age (AGA) in the early neonatal period. STUDY DESIGN: This observational study involved 20 preterm FGR infants (28 to 32 weeks) of gestational age (GA) and birth weight (BW) <10th centile and 20 preterm AGA infants. Vascular ultrasound was performed to measure aortic properties. RESULTS: GA and BW of FGR and AGA infants were 29.8+/-1.3 vs 30+/-0.9 weeks (P=0.78) and 923.4+/-168 vs 1403+/-237 g (P<0.001), respectively. At 10.5+/-1.3 (s.d.) days after birth, blood pressure (systolic 51+/-3 vs 46+/-4 mm Hg, P<0.001) and maximum aorta intima-media thickness (621+/-76 vs 479+/-54 MUm; P<0.001) were significantly higher in FGR infants. Arterial wall stiffness and peripheral resistance were also increased in the FGR infants (2.36+/-0.24 vs 2.14+/-0.24, P=0.008 and 22.2+/-5 vs 13.7+/-2.3 mm Hg min ml-1, P<0.001), respectively. Significant correlations between vascular mechanics and cardiac function were observed (resistance vs E/E', r=0.7 and Tei index, r=0.79). CONCLUSION: Maladaptive arterial-ventricular coupling was noted. Early detection may aid in early therapeutic strategies such as afterload reduction. PMID- 29120453 TI - Out-of-hospital births in California 1991-2011. AB - OBJECTIVE: We investigated the frequencies and characteristics of out-of-hospital births in a 20-year period in California, where 1 of every 7 births in the United States occurs. STUDY DESIGN: Birth certificate records of deliveries in California between 1991 and 2011 were analyzed. Out-of-hospital births were assessed by year, parity, gestational age and maternal race/ethnicity. RESULTS: In the 20-year period there were 10 593,904 deliveries, of which 46 243 occurred out of hospital (0.44%). Out-of-hospital births decreased from 0.54 to 0.38% per year between 1991 and 2004, and increased from 0.41% in 2005 to 0.61% in 2011. In contrast, preterm out-of-hospital births declined from 7.2% in 2006 to 5.0% in 2011. The frequency of vaginal birth after cesarean in the out-of-hospital birth cohort increased from 1.2% (n=19) in 1996 to 4.2% (n=82) in 2011. CONCLUSION: California birth records from a 20-year period show an increase in out-of hospital births from years 2005 to 2011, following a period of decline from 1991 to 2004. PMID- 29120454 TI - Hospital volume and cesarean delivery among low-risk women in a nationwide sample. AB - OBJECTIVE: We sought to determine if hospital delivery volume was associated with a patient's risk for cesarean delivery in low-risk women. STUDY DESIGN: This study retrospectively examines a cohort of 1 657 495 deliveries identified in the 2013 Nationwide Readmissions Database. Hospitals were stratified by delivery volume quartiles. Low-risk patients were identified using the Society for Maternal-Fetal Medicine definition (n=845 056). A multivariable logistic regression accounting for hospital-level clustering was constructed to assess the factors affecting a patient's odds for cesarean delivery. RESULTS: The range of cesarean delivery rates was 2.4-51.2% among low-risk patients, and the median was 16.5% (IQR 12.8-20.5%). The cesarean delivery rate was higher in the top two volume-quartile hospitals (17.4 and 18.2%) compared to the bottom quartiles (16.4 and 16.3%) (P<0.001). Hospital volume was not associated with a patient's odds for cesarean delivery after adjusting for patient and other hospital characteristics (P=0.188). CONCLUSION: Hospital delivery volume is not an independent predictor of cesarean delivery in this population. PMID- 29120455 TI - Manipulating the microbiome: evolution of a strategy to prevent S. aureus disease in children. AB - Hospitalized infants have the highest rates of invasive Staphylococcus aureus disease of any population and infection control strategies such as decolonization have been insufficient. For decades, researchers began studying the microbiome in search of new prevention strategies. The resident microbiota was found to be closely associated with susceptibility and at times, resistance to S. aureus colonization. The evolution of nucleic acid based techniques has enhanced our understanding of the complex relationship between the nasal microbiota and S. aureus colonization. We review what is known about bacterial communities in the nasal cavity of infants and discuss how future microbiome studies may help identify novel interventions to protect high-risk infants from S. aureus disease. PMID- 29120456 TI - Indicators of skin barrier integrity among newborns massaged with mustard oil in rural Nepal. AB - OBJECTIVE: The objective of this study was to determine the skin barrier changes during postnatal month 1 among infants receiving routine mustard oil massage in the humid conditions of rural Nepal. STUDY DESIGN: This was an observational study among 500 live-born neonates receiving mustard oil massage. Skin integrity such as erythema, rash, dryness, skin pH, stratum corneum protein concentration and transepidermal water loss was measured on days 1, 3, 7, 14 and 28. RESULTS: Erythema and rash increased (worsened) during weeks 1 and 2, then decreased over weeks 3 and 4. Skin pH (6.1+/-0.5 to 5.0+/-0.6) and stratum corneum protein (16.6+/-7.9 to 13.5+/-5.9 MUg cm-2) decreased. Transepidermal water loss increased from 33.2+/-23.5 to 43.0+/-24.5 g m-2 h-1 at day 28. Skin pH and stratum corneum protein were higher for early versus late premature infants. CONCLUSION: Premature and full-term skin condition was generally poor especially during the first 2 weeks, improving thereafter. Maturational changes were evident. PMID- 29120457 TI - Management of neonatal spontaneous intestinal perforation by peritoneal needle aspiration. AB - OBJECTIVE: To describe conservative management of spontaneous intestinal perforation (SIP) in preterm infants using peritoneal needle aspiration (PNA). STUDY DESIGN: Monocentric retrospective review of SIP cases treated primarily by PNA between 1999 and 2015 (n=31). RESULTS: Mean gestational age was 29.2+/-2.4 weeks and birthweight 1149+/-428 g. SIP occurred at 3.7+/-2.2 days of life. PNA achieved definitive treatment in 18 patients (60%) with a mean of 1.8 (+/-0.8) procedures. All patients requiring more than three PNAs had secondary laparotomy. Two patients died and five presented severe cerebral lesions. Full enteral feeding was achieved 42+/-18 days after SIP. Intestinal morbidity included cholestasis (n=6), intestinal stricture (n=1) and growth restriction (n=22). On follow-up (n=25, median=4 years), no severe impairment was noted. Seventeen children (68%) had a normal development. CONCLUSION: PNA as primary therapy for SIP is a viable option, resulting in definitive treatment in 60% of cases, with limited mortality and morbidity. PMID- 29120458 TI - Precision newborn screening for lysosomal disorders. AB - PURPOSE: The implementation of newborn screening for lysosomal disorders has uncovered overall poor specificity, psychosocial harm experienced by caregivers, and costly follow-up testing of false-positive cases. We report an informatics solution proven to minimize these issues. METHODS: The Kentucky Department for Public Health outsourced testing for mucopolysaccharidosis type I (MPS I) and Pompe disease, conditions recently added to the recommended uniform screening panel, plus Krabbe disease, which was added by legislative mandate. A total of 55,161 specimens were collected from infants born over 1 year starting from February 2016. Testing by tandem mass spectrometry was integrated with multivariate pattern recognition software (Collaborative Laboratory Integrated Reports), which is freely available to newborn screening programs for selection of cases for which a biochemical second-tier test is needed. RESULTS: Of five presumptive positive cases, one was affected with infantile Krabbe disease, two with Pompe disease, and one with MPS I. The remaining case was a heterozygote for the latter condition. The false-positive rate was 0.0018% and the positive predictive value was 80%. CONCLUSION: Postanalytical interpretive tools can drastically reduce false-positive outcomes, with preliminary evidence of no greater risk of false-negative events, still to be verified by long-term surveillance. PMID- 29120459 TI - Informative priors on fetal fraction increase power of the noninvasive prenatal screen. AB - PURPOSE: Noninvasive prenatal screening (NIPS) sequences a mixture of the maternal and fetal cell-free DNA. Fetal trisomy can be detected by examining chromosomal dosages estimated from sequencing reads. The traditional method uses the Z-test, which compares a subject against a set of euploid controls, where the information of fetal fraction is not fully utilized. Here we present a Bayesian method that leverages informative priors on the fetal fraction. METHOD: Our Bayesian method combines the Z-test likelihood and informative priors of the fetal fraction, which are learned from the sex chromosomes, to compute Bayes factors. Bayesian framework can account for nongenetic risk factors through the prior odds, and our method can report individual positive/negative predictive values. RESULTS: Our Bayesian method has more power than the Z-test method. We analyzed 3,405 NIPS samples and spotted at least 9 (of 51) possible Z-test false positives. CONCLUSION: Bayesian NIPS is more powerful than the Z-test method, is able to account for nongenetic risk factors through prior odds, and can report individual positive/negative predictive values. PMID- 29120460 TI - Prenatal reflex DNA screening for trisomies 21, 18, and 13. AB - PURPOSE: The purpose of the study was to determine the screening performance of prenatal reflex DNA screening for trisomies 21 (T21), 18 (T18), and 13 (T13) as part of a routine service at five hospitals. METHODS: Women who accepted screening had a first-trimester combined test (pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, nuchal translucency interpreted with maternal age). Those with a risk of having an affected pregnancy >=1 in 800 were reflexed to a DNA sequencing test using stored plasma from the original blood sample, thereby avoiding the need to recall them. RESULTS: Of 22,812 women screened (including 106 with affected pregnancies), 2,480 (10.9%) were reflexed to DNA testing; 101/106 were detected (69/73 T21, 24/25 T18, and 8/8 T13), a 95% detection rate (95% confidence interval 89-98%) with four false positives (0.02%, 95% confidence interval 0.00-0.05%). The odds of being affected given a positive result were 25:1. Of the 105 screen-positive pregnancies, 91 (87%) had an invasive diagnostic test. Reflex DNA screening avoided up to 530 invasive diagnostic tests compared with using the combined test. CONCLUSION: Reflex DNA screening was successfully implemented in routine care, achieving a high detection rate, low false-positive rate, and, consequently, greater safety with fewer invasive diagnostic tests than other methods of screening. PMID- 29120461 TI - Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1. AB - BACKGROUND: Germ-line mutations in the exonuclease domains of the POLE and POLD1 genes are associated with an increased, but yet unquantified, risk of colorectal cancer (CRC). METHODS: We identified families with POLE or POLD1 variants by searching PubMed for relevant studies prior to October 2016 and by genotyping 669 population-based CRC cases diagnosed in patients under 60 years of age, from the Australasian Colorectal Cancer Family Registry. We estimated the age-specific cumulative risks (penetrance) using a modified segregation analysis. RESULTS: We observed 67 CRCs (mean age at diagnosis = 50.2 (SD = 13.8) years) among 364 first and second-degree relatives from 41 POLE families, and 6 CRCs (mean age at diagnosis = 39.7 (SD = 6.83) years) among 69 relatives from 9 POLD1 families. We estimated risks of CRC up to the age of 70 years (95% confidence interval) for males and females, respectively, to be 28% (95% CI, 10-42%) and 21% (95% CI, 7 33%) for POLE mutation carriers and 90% (95% CI, 33-99%) and 82% (95% CI, 26-99%) for POLD1 mutation carriers. CONCLUSION: CRC risks for POLE mutation carriers are sufficiently high to warrant consideration of colonoscopy screening and implementation of management guidelines recommended for MSH6 mutation carriers in cases of Lynch syndrome. Refinement of estimates of CRC risk for POLD1 carriers is needed; however, clinical management recommendations could follow those made for POLE carriers. PMID- 29120464 TI - Insight on the silver catalyst distribution during silicon nanowire array formation: an X-ray reflectivity study. AB - Although metal-catalysts are commonly used to create nanoscale materials at surfaces, little is quantitatively known or understood about the depth distribution profile of the catalyst during the growth process. Using X-ray reflectivity, we report the first quantitative investigation, with nanoscale resolution, of the Ag metal-catalyst depth distribution profile during metal assisted chemical etch (MACE) growth of Si nanowire (SiNW) arrays on Si(100). Given the very low optical reflectivity of these nanowire arrays, specular reflection from these materials in the X-ray region is extremely challenging to measure because it probes interfaces on the nanoscale. Nevertheless, we demonstrate that with suitable investigation, X-ray specular reflection can be measured and utilized to obtain unique structural information about the composition profile of both Ag and Si. The measurements, which also include X-ray diffraction and complementary electron microscopy, reveal that the Ag nanoparticles distribute along the length of the nanowires upon etching with a Ag density that increases towards the etch front. The Ag nanoparticles coarsen with etch time, indicating a high mobility of Ag ions even though we also find that the Ag does not migrate from the SiNW region into the etch bath during etching. The Ag density gradient and the Ag mobility suggest the existence of a strong chemical force that attracts Ag towards the etch front. These results provide unique and important new insight into the growth process for creating SiNWs from wet chemical etching using metal-catalysts. PMID- 29120462 TI - Chromatin-state discovery and genome annotation with ChromHMM. AB - Noncoding DNA regions have central roles in human biology, evolution, and disease. ChromHMM helps to annotate the noncoding genome using epigenomic information across one or multiple cell types. It combines multiple genome-wide epigenomic maps, and uses combinatorial and spatial mark patterns to infer a complete annotation for each cell type. ChromHMM learns chromatin-state signatures using a multivariate hidden Markov model (HMM) that explicitly models the combinatorial presence or absence of each mark. ChromHMM uses these signatures to generate a genome-wide annotation for each cell type by calculating the most probable state for each genomic segment. ChromHMM provides an automated enrichment analysis of the resulting annotations to facilitate the functional interpretations of each chromatin state. ChromHMM is distinguished by its modeling emphasis on combinations of marks, its tight integration with downstream functional enrichment analyses, its speed, and its ease of use. Chromatin states are learned, annotations are produced, and enrichments are computed within 1 d. PMID- 29120465 TI - Resonance Raman detection of antioxidants using an iron oxide nanoparticle catalysed decolourisation assay. AB - Nanozymes are metal nanoparticles with catalytic properties that can be used to oxidise peroxidase substrates giving a colorimetric response which can be detected using UV-vis, and recently, Raman spectroscopy. Due to their ease of synthesis and increased stability, nanozymes are being increasing investigated to replace conventional enzymes for the detection of biomolecules. Here we exploit the catalytic activity of iron oxide (Fe2O3) nanoparticles combined with the substrate 2,2-azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) in a decolourisation assay for the detection of antioxidants. Fe2O3 nanoparticles were used to catalyse the oxidation of ABTS to its green radical cation which, upon the addition of an antioxidant, resulted in a decolourisation due to the reduction of the radical cation caused by the hydrogen donating antioxidant. The assay was applied for the detection of multiple antioxidants (glutathione, chlorogenic acid and ascorbic acid), and was followed by monitoring the resonance Raman scattering from the ABTS solution using a portable Raman system with 785 nm laser excitation. This novel assay has the potential to be optimised to detect antioxidant activity in body fluid with low limits of detection with point of use monitoring. PMID- 29120463 TI - Compartmentalized partnered replication for the directed evolution of genetic parts and circuits. AB - Compartmentalized partnered replication (CPR) is an emulsion-based directed evolution method based on a robust and modular phenotype-genotype linkage. In contrast to other in vivo directed evolution approaches, CPR largely mitigates host fitness effects due to a relatively short expression time of the gene of interest. CPR is based on gene circuits in which the selection of a 'partner' function from a library leads to the production of a thermostable polymerase. After library preparation, bacteria produce partner proteins that can potentially lead to enhancement of transcription, translation, gene regulation, and other aspects of cellular metabolism that reinforce thermostable polymerase production. Individual cells are then trapped in water-in-oil emulsion droplets in the presence of primers and dNTPs, followed by the recovery of the partner genes via emulsion PCR. In this step, droplets with cells expressing partner proteins that promote polymerase production will produce higher copy numbers of the improved partner gene. The resulting partner genes can subsequently be recloned for the next round of selection. Here, we present a step-by-step guideline for the procedure by providing examples of (i) selection of T7 RNA polymerases that recognize orthogonal promoters and (ii) selection of tRNA for enhanced amber codon suppression. A single round of CPR should take ~3-5 d, whereas a whole directed evolution can be performed in 3-10 rounds, depending on selection efficiency. PMID- 29120466 TI - The generalized maximum hardness principle revisited and applied to solids (Part 2). AB - Building on Part 1 devoted to atoms and molecules (PCCP, in press 2017), we now focus on the crystal structure and electronic properties of solids as viewed from the Maximum Hardness Principle (MHP), first formulated by Pearson in 1987. The focus is on cases where nuclear potential acting on electrons does not remain constant and where substantial modifications of the nuclear geometry take place (Generalized MHP, GMHP). We present an overview of important manifestations of the (G)MHP for solids such as (i) a tendency of metals and doped-semiconductors to undergo superconducting transition at low temperatures, (ii) propensity of many types of alloys to develop a band gap or a pseudo-gap, (iii) preference for preserving the noble gas (octet, doublet) configuration of main block element ions in the solid state, (iv) preference of Jahn-Teller systems for band-gap opening vibronic-coupling-related lattice distortions, (v) pressure phenomena leading to localization of the electronic density, (vi) tendency to annihilate the null band gap via phase separation (while preserving the nominal chemical composition), (vii) absence of a large number of families of high-TC superconductors, (viii) resistance of most stable systems to chemical doping, etc. GMHP turns out to be an important qualitative guide in studies of solid state polymorphism and electronic phenomena. Exceptions from (G)MHP are discussed, and a more restrictive formulation of the principle is proposed. PMID- 29120468 TI - A novel 2-D Mn selenidostannate(iv) incorporating high-nuclear Mn clusters with spin canting behavior. AB - A solvothermal reaction of SnCl4.5H2O, Mn and Se in ethanolamine (Hea) yielded a novel 2-D Mn selenidostannate(iv) [Mn7(ea)6(SnSe4)2]n (1), which not only provides the first example of the incorporation of a hepta-nuclear Mn cluster [Mn7(ea)6]8+ into a selenidostannate(iv) framework, but also shows unusual spin canting behavior. PMID- 29120467 TI - Electrophoretic cytometry of adherent cells. AB - Cell-matrix and cell-cell interactions influence intracellular signalling and play an important role in physiologic and pathologic processes. Detachment of cells from the surrounding microenvironment alters intracellular signalling. Here, we demonstrate and characterise an integrated microfluidic device to culture single and clustered cells in tuneable microenvironments and then directly analyse the lysate of each cell in situ, thereby eliminating the need to detach cells prior to analysis. First, we utilise microcontact printing to pattern cells in confined geometries. We then utilise a microscale isoelectric focusing (IEF) module to separate, detect, and analyse lamin A/C from substrate adhered cells seeded and cultured at varying (500, 2000, and 9000 cells per cm2) densities. We report separation performance (minimum resolvable pI difference of 0.11) that is on par with capillary IEF and independent of cell density. Moreover, we map lamin A/C and beta-tubulin protein expression to morphometric information (cell area, circumference, eccentricity, form factor, and cell area factor) of single cells and observe poor correlation with each of these parameters. By eliminating the need for cell detachment from substrates, we enhance detection of cell receptor proteins (CD44 and beta-integrin) and dynamic phosphorylation events (pMLCS19) that are rendered undetectable or disrupted by enzymatic treatments. Finally, we optimise protein solubilisation and separation performance by tuning lysis and electrofocusing (EF) durations. We observe enhanced separation performance (decreased peak width) with longer EF durations by 25.1% and improved protein solubilisation with longer lysis durations. Overall, the combination of morphometric analyses of substrate-adhered cells, with minimised handling, will yield important insights into our understanding of adhesion-mediated signalling processes. PMID- 29120469 TI - Characterization of ammonia binding to the second coordination shell of the oxygen-evolving complex of photosystem II. AB - The second-shell ammonia binding sites near the OEC (oxygen-evolving complex) of PSII are characterized by combined Continuum Electrostatic/Monte Carlo (MCCE), QM/MM and DFT calculations and compared with new and earlier experimental measurements. MCCE shows ammonia has significant affinity at 6 positions but only two significantly influence the OEC. Although the pKa of ammonium ion is 9.25, it is calculated to only bind as NH3, in agreement with its low affinity at low pH. The calculations also help explain the experimentally observed competitive binding of ammonia with chloride. Ammonia and Cl- compete for one site. Electrostatic interactions cause Cl- to effect ammonia at two other sites. Cl- stabilizes the multiline g = 2.0 form of the S2 state (OEC Mn oxidation state 3444) while ammonia only binds in the g = 4.1 form of the S2 state (oxidation state 4443) due to the movement of the positive charge between Mn1 and Mn4. One ammonia binds near Mn4 and shares a proton with D2-K317, making the ion pair NH4+K3170D61-, making ammonia binding sensitive to the K317A mutation. The affinity of ammonia is also dependent on the protonation state of water 2, a primary ligand to Mn4. PMID- 29120470 TI - Modulation of cellular polarization and migration by ephrin/Eph signal-mediated boundary formation. AB - Compartment boundaries are essential for ensuring proper cell organization during embryo development and in adult tissues, yet the mechanisms underlying boundary establishment are not completely understood. A number of mechanisms, including (i) differential adhesion, (ii) differential tension, and (iii) cell signaling mediated cell repulsion, are known to contribute and likely a context-dependent balance of each of these dictates boundary implementation. The ephrin/Eph signaling pathway is known to impact boundary formation in higher animals. In different contexts, ephrin/Eph signaling is known to modulate adhesive properties and migratory behavior of cells. Furthermore it has been proposed that ephrin/Eph signaling may modulate cellular tensile properties, leading to boundary implementation. It remains unclear however, whether, in different contexts, ephrin/Eph act through distinct dominant action modes (e.g. differential adhesion vs. cell repulsion), or whether ephrin/Eph signaling elicits multiple cellular changes simultaneously. Here, using micropatterning of cells over-expressing either EphB3 or ephrinB1, we assess the contribution of each these factors in one model. We show that in this system ephrinB1/EphB3-mediated boundaries are accompanied by modulation of tissue-level architecture and polarization of cell migration. These changes are associated with changes in cell shape and cytoskeletal organization also suggestive of altered cellular tension. PMID- 29120471 TI - Rational design of a molecularly imprinted polymer for dinotefuran: theoretical and experimental studies aimed at the development of an efficient adsorbent for microextraction by packed sorbent. AB - In this work, we studied theoretically the formation process of a molecularly imprinted polymer (MIP) for dinotefuran (DNF), testing distinct functional monomers (FM) in various solvents through density functional theory calculations. The results revealed that the best conditions for MIP synthesis were established with methacrylic acid (MAA) as FM in a 1 : 4 stoichiometry and with chloroform as the solvent. This protocol showed the most favourable stabilization energies for the pre-polymerization complexes. Furthermore, the formation of the FM/template complex is enthalpy driven and the occurrence of hydrogen bonds between the DNF and MAA plays a major role in the complex stability. To confirm the theoretical results, MIP was experimentally synthesized considering the best conditions found at the molecular level and characterized by scanning electron microscopy and thermogravimetric analysis. After that, the synthesized material was efficiently employed in microextraction by packed sorbent combined with high-performance liquid chromatography in a preliminary study of the recovery of DNF from water and artificial saliva samples. PMID- 29120472 TI - Tuning of the photocatalytic performance of g-C3N4 by polyoxometalates under visible light. AB - Carbon nitride (g-C3N4), as a rising star of metal-free photocatalysts, has received considerable attention. However, for practical application, the photocatalytic efficiency of g-C3N4 remains to be further improved. Herein, a series of Keggin-type polyoxoanion (polyoxoanions = SiW12O404-, PW12O403-, PMo12O403-) modified g-C3N4 (POM/C3N4) composites have been successfully prepared. The results of XRD, TEM, XPS and EDAX reveal that a small amount of polyoxoanions was modified on the surface of g-C3N4 with electrostatic and hydrogen bonding interactions. Photocatalytic experiments indicate that these composites exhibit enhanced methyl orange (MO) degradation photocatalytic activity and water splitting H2 production under visible light irradiation. The loading amount and the type of polyoxoanion can tune the photocatalytic performance of the composites. Among these catalysts, 5% SiW12O404- (SiW12) modified g-C3N4 has the best photocatalytic performance, which is 4.4 times higher than that of pure g-C3N4 for the degradation of MO. The photocatalytic mechanism reveals that polyoxoanions can act as electron traps, which can efficiently promote the separation of photogenerated electrons and holes of C3N4, thus resulting in the enhanced photocatalytic performance of the composites. PMID- 29120473 TI - Chalcogen-atom transfer and exchange reactions of NHC-stabilized heavier silaacylium ions. AB - Heavier analogues of silaacylium ions 2-4 ([m-TerSiE(NHC)2]Cl; m-Ter = 2,6 Mes2C6H3; Mes = 2,4,6-Me3C6H2; 2 (E = S), 3 (E = Se), 4 (E = Te)) were synthesized by the reaction of the NHC-stabilized silyliumylidene cation 1 with elemental chalcogens. Fascinating regeneration of 1 from the reaction of 2-4 with AuI was achieved, as successful recovery of a parent Si(ii) species from a silachalcogen Si(iv) compound. Furthermore, unique chalcogen exchange reactions from 4 -> 3 -> 2 were observed in line with the calculated silicon-chalcogen bond energies. PMID- 29120474 TI - Highlights from the Faraday Discussion meeting "Atmospheric chemistry in the Anthropocene", York, 2017. PMID- 29120475 TI - Lithium borate Li3B5O8(OH)2 with large second harmonic generation and a high damage threshold in the deep-ultraviolet spectral range. AB - The electronic structure and linear and nonlinear optical susceptibility dispersions of lithium borate Li3B5O8(OH)2 are comprehensively investigated. The investigation is achieved on Li3B5O8(OH)2 in the form of single crystals, taking into account the influence of the packing of the structural units on the linear and nonlinear optical susceptibility dispersion. The calculations highlight that the BO3 structural unit packing is the main source of the large birefringence in Li3B5O8(OH)2 due to the high anisotropic electron distribution, and, hence, it affects the macroscopic second harmonic generation (SHG) coefficients. This work provides a new path for the design of UV-NLO materials with high SHG efficiencies and short cutoff edges by introducing an alkali metal into borates. The large SHG is due to hyperpolarizability formed by co-parallel BO3 triangle groups. The absorption edge of Li3B5O8(OH)2 occurs at lambda = 190 nm and the optical band gap is estimated to be 6.52 eV, which is in good agreement with the experimental data (6.526 eV). The energy gap value confirms that Li3B5O8(OH)2 exhibits an exceptional laser damage threshold and is expected to produce coherent radiation in the deep-ultraviolet (DUV) region. The obtained value of SHG at lambda = 1064 nm is about 1.5 times that of the well-known NLO crystal KH2PO4 (KDP) at lambda = 1064 nm and 3.5 times that of KDP at lambda = 190 nm, which is transparent down to the DUV region. Thus, one can conclude that the combination of an alkali metal with borates leads to the generation of promising DUV-NLO crystals. This work is aimed at qualitative and quantitative investigation to report a reliable SHG value and provide details of the NLO tensor for bulk Li3B5O8(OH)2 single crystals. PMID- 29120476 TI - Linking iron-deficiency with allergy: role of molecular allergens and the microbiome. AB - Atopic individuals tend to develop a Th2 dominant immune response, resulting in hyperresponsiveness to harmless antigens, termed allergens. In the last decade, epidemiological studies have emerged that connected allergy with a deficient iron status. Immune activation under iron-deficient conditions results in the expansion of Th2-, but not Th1 cells, can induce class-switching in B-cells and hampers the proper activation of M2, but not M1 macrophages. Moreover, many allergens, in particular with the lipocalin and lipocalin-like folds, seem to be capable of binding iron indirectly via siderophores harboring catechol moieties. The resulting locally restricted iron-deficiency may then lead during immune activation to the generation of Th2-cells and thus prepare for allergic sensitization. Moreover, iron-chelators seem to also influence clinical reactivity: mast cells accumulate iron before degranulation and seem to respond differently depending on the type of the encountered siderophore. Whereas deferoxamine triggers degranulation of connective tissue-type mast cells, catechol-based siderophores reduce activation and degranulation and improve clinical symptoms. Considering the complex interplay of iron, siderophores and immune molecules, it remains to be determined whether iron-deficiencies are the cause or the result of allergy. PMID- 29120477 TI - Droplet array for screening acute behaviour response to chemicals in Caenorhabditis elegans. AB - Caenorhabditis elegans is an excellent model organism for studying chemosensation as a significant part of its nervous system and genome are devoted to the detection of chemical cues. Studies of decision-making, learning, mating behaviour, and intraspecies communication require measuring the acute behavioural response to chemical stimulation. Such assays require precise and repeatable chemical delivery and are often arduous when performed manually. Microfluidic platforms have been developed for chemosensation studies in C. elegans. However, these platforms lack temporal resolution in chemical delivery necessary for screening acute behaviour and cannot selectively recover animals, a necessary feature for genetic screens. Here we present a droplet array for screening acute behavioural responses of C. elegans to chemical stimulation. Using droplets enables isolating the worms and controlling the chemical environment. The chamber design of the static array allows continuous monitoring of animal behaviour. By combining a gradient of confinement and flow restriction features, we demonstrate selective and sequential trapping of multiple droplets as well as their release on demand. These functions enable repeated capture of animals, monitoring of their behaviour upon chemical stimulation and subsequent release. To demonstrate the ability to screen multiple conditions, we measured worm thrashing activity in response to different concentrations of tetramisole. To illustrate the ability to capture acute behavioural responses, we monitored the behavioural response of male to pheromone stimulation. Due to the versatility of the chamber operation and its ultra-low volume uses of reagents, we envision this platform to be highly suited to combinatorial screening and drug discovery. PMID- 29120478 TI - Time course of neck-shoulder pain among workers: A longitudinal latent class growth analysis. AB - Objectives The aims of this study were to (i) identify trajectories of neck shoulder pain (NSP) over one year in an occupational population and (ii) determine whether these trajectories are predicted by NSP characteristics as well as personal and occupational factors at baseline. Methods This longitudinal study was conducted among Danish workers (N=748) from 2012-2014. Text messages were used to collect frequent data on NSP over one year (14 waves in total). Peak NSP intensity in the past month was rated on a 0-10 numeric scale. A baseline questionnaire covered NSP characteristics (pain intensity, duration, comorbidity, pain medication, and pain interference) as well as personal (age, gender, body mass index) and occupational (seniority, work type, physical strain at work) factors. Latent class growth analysis was used to distinguish trajectories of NSP. Multivariate regression models with odds ratios (OR) were constructed to predict trajectories of NSP. Results Six distinct trajectories of NSP were identified (asymptomatic 11%, very low NSP 10%, low recovering NSP 18%, moderate recovering NSP 28%, strong fluctuating NSP 24% and severe persistent NSP 9% of the workers). Female gender, age, physical strain at work, NSP intensity and duration, pain medication, and pain interference in daily work at baseline were positively associated with severe persistent NSP and strong fluctuating NSP (all P<0.05). Altogether, personal and occupational factors accounted for 14% of the variance, while NSP characteristics accounted for 54%. Conclusions In an occupational sample, six distinct trajectories of NSP were identified. Physical strain at work appears to be a pertinent occupational factor predicting strong fluctuating and severe persistent NSP. PMID- 29120479 TI - FATHER-CHILD PLAY DURING THE PRESCHOOL YEARS AND CHILD INTERNALIZING BEHAVIORS: BETWEEN ROBUSTNESS AND VULNERABILITY. AB - Play observations with a total of 400 toddlers and preschoolers were videotaped and rated for Intensity and Quality of play with their parents. Parents were asked about perceived stress and personality characteristics (Big 5). Child's motor, cognitive skills, temperament, and internalizing behaviors were assessed. Study 1 investigated the robustness of play across child age and gender, and examined differences between fathers and mothers. Study 2 explored the vulnerability of play with fathers of children born preterm (PT-fathers) and fathers who had experienced adverse childhoods (AC-fathers). Study 3 investigated child internalizing behaviors. Intensity of play was maintained almost independently of child age and gender. It was similar for AC- and PT-fathers, and similar to maternal Intensity. In contrast, paternal Quality of play was higher with boys and independent of fathers' personality and perceived parenting stress whereas maternal Quality of play was higher with girls and linked to mothers' perceived parenting competence, acceptability of the child, and neuroticism. AC fathers scored significantly low on Quality, as did PT-fathers, but the Quality of their play became better with growing child age, birth weight, and cognitive (but not motor and temperament) scores. Finally, child internalizing behaviors were negatively related to paternal Quality of play. PMID- 29120480 TI - Coupled Surface and Groundwater Hydrological Modeling in a Changing Climate. AB - Many current watershed modeling efforts now incorporate surface water and groundwater for managing water resources since the exchanges between groundwater and surface water need a special focus considering the changing climate. The influence of groundwater dynamics on water and energy balance components is investigated in the Snake River Basin (SRB) by coupling the Variable Infiltration Capacity (VIC) and MODFLOW models (VIC-MF) for the period of 1986 through 2042. A 4.4% increase in base flows and a 10.3% decrease in peak flows are estimated by VIC-MF compared to the VIC model in SRB. The VIC-MF model shows significant improvement in the streamflow simulation (Nash-Sutcliffe efficiency [NSE] of 0.84) at King Hill, where the VIC model could not capture the effect of spring discharge in the streamflow simulation (NSE of -0.30); however, the streamflow estimates show an overall decreasing trend. Two climate scenarios representing median and high radiative-forcings such as representative concentration pathways 4.5 and 8.5 show an average increase in the water table elevations between 2.1 and 2.6 m (6.9 and 8.5 feet) through the year 2042. The spatial patterns of these exchanges show a higher groundwater elevation of 15 m (50 feet) in the downstream area and a lower elevation of up to 3 m (10 feet) in the upstream area. Broadly, this study supports results of previous work demonstrating that integrated assessment of groundwater-surface water enables stakeholders to balance pumping, recharge and base flow needs and to manage the watersheds that are subjected to human pressures more sustainably. PMID- 29120481 TI - Medication Exposure and Risk of Recurrent Clostridium difficile Infection in Community-Dwelling Older People and Nursing Home Residents. AB - BACKGROUND/OBJECTIVES: It is unclear how medication exposures differ in their association with recurrent Clostridium difficile infection (rCDI) in elderly nursing home (NH) residents and community-dwelling individuals. This study examined these exposures to determine whether the risk of rCDI differs according to living environment. DESIGN: Retrospective. SETTING: Academic and community healthcare settings. PARTICIPANTS: Individuals aged 65 and older with CDI (N = 616). MEASUREMENTS: Information on participant characteristics and medications was extracted from the electronic medical record (EMR). We used separate extended Cox models according to living environment to identify the association between medication use and risk of rCDI. RESULTS: Of the 616 elderly adults treated for CDI, 24.1% of those living in the community and 28.1% of NH residents experienced recurrence within 1 year. For community-dwelling participants, the risk of rCDI was 1.6 times as high with antibiotic exposure and 2.5 times as high with acid reducing medication exposure, but corticosteroid exposure was associated with a 39% lower risk of recurrence. For NH residents, the risk of rCDI was 2.9 times as high with acid-reducing medication exposure and 5.9 times as high with corticosteroid medication exposure. Antibiotic exposure was associated with an increased risk of recurrence only in community-dwelling participants (adjusted hazard ratio = 1.63, 95% confidence interval = 1.00-2.67). CONCLUSION: Risk of rCDI is greater with acid-reducing medication use than antibiotic use after initial CDI treatment, although the risk varied depending on living environment. Corticosteroid use is associated with greater risk of recurrence in NH residents but lower risk in community-dwelling elderly adults. PMID- 29120482 TI - Leptospira: Molecular Detection of Pathogenic Species in Natural Sources. AB - This protocol describes a method for the rapid detection of leptospiral DNA in environmental water. In summary, the DNA is extracted from water samples and tested in a TaqMan-based real-time quantitative polymerase chain reaction (qPCR) for the presence of lipl32, a gene that is present only in pathogenic Leptospira spp. The gene target used in this assay is important in that it only detects pathogenic leptospires and not the saprophytic leptospires that may be present in environmental samples. (c) 2017 by John Wiley & Sons, Inc. PMID- 29120483 TI - Azospirillum brasilense: Laboratory Maintenance and Genetic Manipulation. AB - Bacteria of the genus Azospirillum, including the most comprehensively studied Azospirillum brasilense, are non-pathogenic soil bacteria that promote the growth of diverse plants, making them an attractive model to understand non-symbiotic, beneficial plant-bacteria associations. Research into the physiology and genetics of these organisms spans decades and a range of molecular tools and protocols have been developed for allelic exchange mutagenesis, in trans expression of genes, and fusions to reporter genes. (c) 2017 by John Wiley & Sons, Inc. PMID- 29120484 TI - ELISA for Molluscum Contagiosum Virus. AB - Molluscum contagiosum virus (MCV) is a common skin pathogen of children and young adults. Infection with MCV causes benign skin tumors in children and young adults and is mostly self-limiting. In contrast to orthopoxviruses, MCV infections tend to take a subacute clinical course but may persist for up to 12 months. Current numbers for MCV seroprevalence in different geographical areas are based on a variety of historical serological methods from complement fixation assays to MCV ELISAs based on purified MCV virions and MC133 antigen expressed in a Semliki Forest Virus expression system. A standardized ELISA for the assessment of MCV seroprevalence would be useful to determine global MCV seroprevalence. The methods described show that polypeptides derived from MCV open reading frames MC084 (residues V123 to R230 and V33 to G117), mc133 (residues M1 to N370), and glutathione S-transferase (GST)-H3L (residues I142 to W251) expressed in E. coli RIL+ as GST fusion proteins can be used to assess antibody binding in a GST capture ELISA. We show how the ELISA can be used to screen a panel of patient sera previously characterized with the mc084 V123-R230 ELISA. (c) 2017 by John Wiley & Sons, Inc. PMID- 29120485 TI - Measuring pH of the Coxiella burnetii Parasitophorous Vacuole. AB - Coxiella burnetii is the causative agent of human Q fever, a zoonotic disease that can cause a debilitating, flu-like illness in acute cases, or a life threatening endocarditis in chronic patients. An obligate intracellular bacterial pathogen, Coxiella survives and multiplies in a large lysosome-like vacuole known as the Coxiella parasitophorous vacuole (CPV). A unique characteristic of the CPV is the acidic environment (pH ~5.0), which is required to activate Coxiella metabolism and the Coxiella type 4 secretion system (T4SS), a major virulence factor required for intracellular survival. Further, inhibiting or depleting vacuolar ATPase, a host cell protein that regulates lysosomal pH, inhibits intracellular Coxiella growth. Together, these data suggest that CPV pH is an important limiting factor for Coxiella growth and virulence. This unit describes a method to determine CPV pH using live cell microscopy of a pH-sensitive fluorophore conjugated to dextran. This technique is useful to measure changes in CPV pH during infection or in response to drug treatment. (c) 2017 by John Wiley & Sons, Inc. PMID- 29120486 TI - Computational Methods for Human Microbiome Analysis. AB - As the field of microbiomics advances, the burden of computational work that scientists need to perform in order to extract biological insight has grown accordingly. Likewise, while human microbiome analyses are increasingly shifting toward a greater integration of various high-throughput data types, a core number of methods form the basis of nearly every study. In this unit, we present step-by step protocols for five core stages of human microbiome research. The protocols presented in this unit provide a base case for human microbiome analysis, complete with sufficient detail for researchers to tailor certain aspects of the protocols to the specificities of their data. (c) 2017 by John Wiley & Sons, Inc. PMID- 29120487 TI - Azospirillum brasilense, a Beneficial Soil Bacterium: Isolation and Cultivation. AB - Bacteria of the genus Azospirillum comprise 15 species to date, with A. brasilense the best studied species in the genus. Azospirillum are soil bacteria able to promote the growth of plants from 113 species spanning 35 botanical families. These non-pathogenic and beneficial bacteria are ubiquitous in soils and inhabit the roots of diverse plants. These bacteria are microaerophilic, able to fix nitrogen under free-living conditions, motile, and able to navigate in gradients of various chemicals, including oxygen. These physiological traits are used to isolate these soil bacteria from soil and plant root samples, providing isolates that can be used for studying microbial physiology and plant growth promotion. (c) 2017 by John Wiley & Sons, Inc. PMID- 29120488 TI - Normal white matter microstructure in women long-term recovered from anorexia nervosa: A diffusion tensor imaging study. AB - OBJECTIVES: Studies point to white matter (WM) microstructure alterations in both adolescent and adult patients with anorexia nervosa (AN). These include reduced fractional anisotropy in several WM fiber tracts, suggesting reduced WM integrity. The extent to which these alterations are reversible with recovery from AN is unclear. There is a paucity of research investigating the presence of WM microstructure alterations in recovered AN patients, and results are inconsistent. This study aimed to investigate the presence of WM microstructure alterations in women long-term recovered from AN. METHOD: Twenty-one adult women who were recovered from AN for at least 1 year were compared to 21 adult comparison women. Participants were recruited via user-organizations for eating disorders, local advertisements, and online forums. Diffusion tensor imaging was used to compare WM microstructure between groups. Correlations between WM microstructure and clinical characteristics were also explored. RESULTS: There were no statistically significant between-group differences in WM microstructure. These null findings remained when employing liberal alpha level thresholds. Furthermore, there were no statistically significant correlations between WM microstructure and clinical characteristics. DISCUSSION: Our findings showed normal WM microstructure in long-term recovered patients, indicating the alterations observed during the acute phase are reversible. Given the paucity of research and inconsistent findings, future studies are warranted to determine the presence of WM microstructure alterations following recovery from AN. PMID- 29120489 TI - In vitro chemosensitivity of feline injection site-associated sarcoma cell lines to carboplatin. AB - OBJECTIVE: To determine the in vitro chemosensitivity of feline injection site associated sarcoma (FISAS) cells to carboplatin concentrations generated by elution of carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads. STUDY DESIGN: In vitro study. SAMPLE: Five immortalized cell lines from histologically confirmed, primary FISASs. METHODS: For each cell line, one 96 well microplate was used for each time point (24, 48, 72 hours). In each microplate, 3 wells were seeded with ~7.5 * 103 cells per well for every carboplatin treatment added, ranging from 5 to 450 uM. Microculture plates were incubated for 24, 48, or 72 hours. Drug efficacy was assessed via a bioreductive fluorometric assay. For apoptosis analysis, 3 wells were seeded with ~5 * 104 cells per well for every carboplatin treatment added, ranging from 5 to 450 uM. Flow cytometry was performed and the relative percentages of viable, apoptotic, and late apoptotic/necrotic cells were reported. All experiments were run in triplicates. RESULTS: Carboplatin exerted dose-dependent and time-dependent effects on FISAS cell viability. The IC50 values were within the range of carboplatin concentrations eluted from CI-CSH beads. CONCLUSION: Elution of carboplatin from CI-CSH beads generate concentrations sufficient to result in 50% growth inhibition of FISAS cells in vitro. Local tumor control might be achieved by implantation of CI-CSH beads immediately following radical or marginal excision of the primary tumor or by implantation without tumor resection. PMID- 29120490 TI - Determination of MoCA Cutoff Score in Patients with Alcohol Use Disorders. AB - BACKGROUND: The Montreal Cognitive Assessment (MoCA) score is a convenient and promising tool for estimating alcoholic patients' global cognitive functioning, a major challenge for all specialized alcohol treatment centers. However, whether or not the score should be corrected for education level and whether the proposed cutoff is relevant in patients with alcohol use disorders (AUD) should be determined. METHODS: We compared the MoCA scores in patients hospitalized for AUD with and without cognitive impairment assessed by a battery of neuropsychological (NP) tests. Sensitivity, specificity, and cutoff of the MoCA score were analyzed using receiver operating characteristic curve analysis. RESULTS: Thirty-one patients with and 25 without cognitive impairment were included in the study. There were 40 men and 16 women, with a mean age of 49.5 years. The mean uncorrected MoCA score was 23.1 +/- 3.3 in those with and 27.0 +/- 1.9 in those without cognitive impairment. NP tests were significantly correlated with the MoCA score. Uncorrected MoCA scores identified more than 80% of the patients with a cutoff score equal to 26, to obtain similar accuracy with the corrected score required using a cutoff score equal to 27. CONCLUSIONS: Our results confirm that the MoCA test is a convenient and reliable screening tool to measure cognition defects in alcoholic patients. As using the 1-point education adjustment increases the cutoff score by 1 point, it is suggested to use the noncorrected score and the usual cutoff, that is, 26. Being easy to administer and only moderately time-consuming, the MoCA score should be used extensively in addiction treatment centers. PMID- 29120491 TI - Clinical studies in CRS and HIPEC: Trials, tribulations, and future directions-A systematic review. AB - BACKGROUND: The field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has suffered from a lack of clinical trials to validate its expanding use. OBJECTIVE: To evaluate published and ongoing clinical trials seeking to better define role of CRS/HIPEC in the treatment of peritoneal surface malignancies. METHODS: Systematic review by PubMed search was performed using terms "Clinical trial," "intraperitoneal chemotherapy," and "HIPEC." ClinicalTrials.gov and EudraCT registries were searched for active clinical trials. Eligibility included CRS/HIPEC trials investigating adult patient populations from published clinical reports and/or trials currently accruing or at completion. RESULTS: Thirteen published trials and 57 active clinical trials were included for review. CONCLUSIONS: Published and ongoing U.S. and international clinical trials for CRS and HIPEC are defining important parameters that include improving patient selection, strategic sequences of treatment, cytoreductive strategies, chemotherapeutics, optimal hyperthermic temperature and timing, and toxicity profiles. Main barriers or limitations to trial development remain patient enrollment, trial design, and oncologic community collaboration. Overall progress is positive with increasing number of clinical trials throughout the world. Collaboration between surgeons and the wider oncologic community will be crucial to validate this important treatment strategy. PMID- 29120492 TI - Testing for gene-environment interaction under exposure misspecification. AB - Complex interplay between genetic and environmental factors characterizes the etiology of many diseases. Modeling gene-environment (GxE) interactions is often challenged by the unknown functional form of the environment term in the true data-generating mechanism. We study the impact of misspecification of the environmental exposure effect on inference for the GxE interaction term in linear and logistic regression models. We first examine the asymptotic bias of the GxE interaction regression coefficient, allowing for confounders as well as arbitrary misspecification of the exposure and confounder effects. For linear regression, we show that under gene-environment independence and some confounder-dependent conditions, when the environment effect is misspecified, the regression coefficient of the GxE interaction can be unbiased. However, inference on the GxE interaction is still often incorrect. In logistic regression, we show that the regression coefficient is generally biased if the genetic factor is associated with the outcome directly or indirectly. Further, we show that the standard robust sandwich variance estimator for the GxE interaction does not perform well in practical GxE studies, and we provide an alternative testing procedure that has better finite sample properties. PMID- 29120493 TI - Carcinogenic Etheno DNA Adducts in Alcoholic Liver Disease: Correlation with Cytochrome P-4502E1 and Fibrosis. AB - BACKGROUND: One mechanism by which alcoholic liver disease (ALD) progresses is oxidative stress and the generation of reactive oxygen species, among others due to the induction of cytochrome P-4502E1 (CYP2E1). Experimental data underline the key role of CYP2E1 because ALD could be partially prevented in rats by the administration of the specific CYP2E1 inhibitor chlormethiazole. As CYP2E1 is linked to the formation of carcinogenic etheno DNA adducts in ALD patients, a causal role of alcohol-induced CYP2E1 in hepatocarcinogenesis is implicated. The purpose of this study was to investigate CYP2E1 induction in ALD, and its correlation with oxidative DNA lesions and with hepatic histology. METHODS: Hepatic biopsies from 97 patients diagnosed with ALD were histologically scored for steatosis, inflammation, and fibrosis. CYP2E1 and the exocyclic etheno DNA adduct 1,N6 -etheno-2'deoxyadenosine (epsilondA) were determined immunohistochemically. In addition, in 42 patients, 8-hydroxydeoxyguanosine (8 OHdG) was also evaluated using immunohistochemistry. RESULTS: A significant positive correlation was found between CYP2E1 and epsilondA (p < 0.0001) as well as between CYP2E1 and 8-OHdG (p = 0.039). Both CYP2E1 (p = 0.0094) and EdA (p < 0.0001) also correlated significantly with the stage of hepatic fibrosis. Furthermore, a significant correlation between the fibrosis stage and the grade of lobular inflammation (p < 0.0001) was observed. However, the amount of alcohol consumed did not correlate with any of the parameters determined. CONCLUSIONS: These data suggest an important role of CYP2E1 in the generation of epsilondA, in the fibrotic progression of ALD, and thus in alcohol-mediated hepatocarcinogenesis. CYP2E1 may be a target in the treatment of ALD and a potential prognostic marker for disease progression. PMID- 29120494 TI - Shallow Unconfined Flow on a Sloping Base Redux. AB - When is the impact of a sloping base large enough to justify more complex models for an unconfined aquifer? The intuitive answer that "it depends on the magnitude of the slope" is not wholly correct. Using recent mathematical results (the Lambert W function), we explicitly solve the simple sloping base problem. This explicit solution offers insights beyond those possible using Dupuit's, Polubarinov-Kochina's, Harr's, Child's, and others' implicit solutions. Specifically, it shows that the impact of the sloping base is best characterized by the saturated thickness divided by the change in base elevation, not by the slope. PMID- 29120495 TI - FATHER PLAY: IS IT SPECIAL? AB - Both mothers and fathers play with their children, but research on parent-child play interactions is conducted with mothers three times more often than it is with fathers. The articles in this special issue address this gap by focusing on the nature and quality of father-child play, across cultural contexts, and considering whether father play offers something unique and special for early human development, in infancy or early childhood. The studies show that fathers can be just as developmentally supportive as are mothers in terms of being playful and engaged with their children in ways that are related to greater child socioemotional competence, emotion regulation, and vocabulary, and to less aggression, anxiety, and negativity. We encourage future research to examine the cultural influences, family system dynamics, and specificity of timing and types of father-child play in relation to children's developmental competence. PMID- 29120496 TI - Edme Mariotte and the Beginning of Quantitative Hydrogeology. PMID- 29120498 TI - Integrated powered density: Screening ultrahigh dimensional covariates with survival outcomes. AB - Modern biomedical studies have yielded abundant survival data with high throughput predictors. Variable screening is a crucial first step in analyzing such data, for the purpose of identifying predictive biomarkers, understanding biological mechanisms, and making accurate predictions. To nonparametrically quantify the relevance of each candidate variable to the survival outcome, we propose integrated powered density (IPOD), which compares the differences in the covariate-stratified distribution functions. The proposed new class of statistics, with a flexible weighting scheme, is general and includes the Kolmogorov statistic as a special case. Moreover, the method does not rely on rigid regression model assumptions and can be easily implemented. We show that our method possesses sure screening properties, and confirm the utility of the proposal with extensive simulation studies. We apply the method to analyze a multiple myeloma study on detecting gene signatures for cancer patients' survival. PMID- 29120499 TI - Evolution of the Subsurface K-Rich Brines in the Triassic Carbonates in the Sichuan Basin of China. AB - Subsurface K-rich brines are important mineral resources for fertilizer production while the evolution of such brines is poorly documented. In the Sichuan Basin in southwest China, they are found mainly in the Middle and Lower Triassic marine carbonate aquifers. Total dissolved solids of the brines range from 176 to 378 g/L and K concentrations, from 1.9 to 53.3 g/L. We found that the brines are mainly of Cl-Na type, while Ba is absent in the brines. Comparison of the brine samples with both the trajectories of ions and the newly proposed trajectories of ion ratios of evaporated seawater suggests that the brines are enriched in Ca, Sr, Li, and I, depleted in SO4 and Mg, and neither enriched nor depleted in Cl and Na. These brines underwent four evolutionary periods: (1) deposition of marine rocks, (2) deposition of continental clastics, (3) tectonic deformation, and (4) rock erosion. Precipitation of salt minerals, dolomitization, sulfate reduction, and recrystallization during the first two periods are responsible for the enrichment and depletion of the chemical constituents of the brines. Extremely high K concentrations in two wells, both tapping the Middle Triassic Leikoupo carbonate aquifers, are attributed to the subsurface dissolution of potash salts during the migration of the brines to the anticlines formed during the third period in the Paleogene age. Saline and salty springs emanate from the outcropping carbonates in the river valleys in some anticlines in the eastern basin due to incongruent dissolution of the salt bearing carbonates during the fourth period. PMID- 29120500 TI - Oral healthcare in Fraser syndrome. AB - Fraser syndrome is a rare autosomal recessive disorder characterized by renal agenesis, cryptophthalmos, syndactyly, and laryngeal stenosis. Oral manifestations are sparsely described in the literature, and patients with this syndrome might require special dental management considerations because of the associated cardiac, renal, and cognitive defects. In this report, we describe the oral/dental findings in a 22-year-old girl with Fraser syndrome, and discuss the dental management. PMID- 29120501 TI - Analysis of the plasma proteome using iTRAQ and TMT-based Isobaric labeling. AB - Over the past decade, chemical labeling with isobaric tandem mass tags, such as isobaric tags for relative and absolute quantification reagents (iTRAQ) and tandem mass tag (TMT) reagents, has been employed in a wide range of different clinically orientated serum and plasma proteomics studies. In this review the scope of these works is presented with attention to the areas of research, methods employed and performance limitations. These applications have covered a wide range of diseases, disorders and infections, and have implemented a variety of different preparative and mass spectrometric approaches. In contrast to earlier works, which struggled to quantify more than a few hundred proteins, increasingly these studies have provided deeper insight into the plasma proteome extending the numbers of quantified proteins to over a thousand. PMID- 29120502 TI - Necrotizing Microascus tracheobronchitis in a bilateral lung transplant recipient. AB - Invasive fungal infections are a major cause of mortality among solid organ transplant recipients. Scopulariopsis species and their teleomorph Microascus are molds found in soil and decaying organic matter. We report here the case of a woman who underwent bilateral lung transplantation for severe emphysema. On day 25 after transplantation, endobronchial green-black lesions were detected during routine endoscopy. Endobronchial swabs, biopsies, and bronchoalveolar lavage samples were positive for Microascus cirrosus. This fungal infection developed despite voriconazole given for previous persistent invasive aspergillosis. Treatment consisted of a combination of antifungal medication (voriconazole, terbinafine, amphotericin B, and caspofungin) and endoscopic resection of necrosed bronchial mucosa. A favorable clinical outcome was achieved after 7 weeks of treatment. Seven cases of Scopulariopsis/Microascus infection have been previously described in solid organ transplant recipients. Only two survived after treatment with an antifungal combination therapy including echinocandins, posaconazole, and terbinafine. In immunocompromised patients, infection by Microascus species is a rare but life-threatening event because of innate resistance to most common antifungal drugs. Our patient was successfully cured by combined therapy including intravenous voriconazole and caspofungin, oral terbinafine, and inhaled voriconazole and amphotericin B administered for 7 weeks in association with iterative endoscopic debridement to reduce fungal inoculum. PMID- 29120503 TI - Route to improving Type 1 diabetes mellitus glycaemic outcomes: real-world evidence taken from the National Diabetes Audit. AB - AIM: To use general practice-level data for England, available through the National Diabetes Audit, and primary care prescribing data to identify prescription treatment factors associated with variations in achieved glucose control (HbA1c ). METHODS: General practice-level National Diabetes Audit data on Type 1 diabetes, including details of population characteristics, services, proportion of people achieving target glycaemic control [HbA1c <=58 mmol/mol (7.5%)] and proportion of people at high glycaemic risk [HbA1c >86 mmol/ml (10%)], were linked to 2013-2016 primary care diabetes prescribing data on insulin types and blood glucose monitoring for all people with diabetes. RESULTS: A wide variation was found between the 10th percentile and the 90th percentile of general practices in both target glycaemic control (15.6% to 44.8%, respectively) and high glycaemic risk (4.8% to 28.6%, respectively). Our analysis suggests that, given the extrapolated total of 280 000 people with Type 1 diabetes in the UK, there may be the potential to increase the number of those within target glycaemic control from 80 000 to 101 000; 53% of this increase (11 000 people) would result from service improvements and 47% (10 000 people) from medication and technology changes. The same improvements would also provide the opportunity to reduce the number of people at high glycaemic risk from 42 000 to 26 500. A key factor associated with practice-level target HbA1c achievement would be greater use of insulin pumps for up to an additional 56 000 people. CONCLUSION: If the HbA1c achievement rates in service provision, medication and use of technology currently seen in practices in the 90th percentile were to be matched with regard to HbA1c achievement rates in all general practices, glycaemic control might be improved for 36 500 people, with all the attendant health benefits. PMID- 29120504 TI - Well-Defined Chiral Copper NHC Complex in the Asymmetric Conjugated beta Borylation and One-Pot Metathesis-Asymmetric beta-Borylation Reactions. AB - Highly stereoselective conjugate beta-borylation, using a new chiral NHC-based copper catalyst, has been achieved. The chiral NHC copper complex was prepared in gram scale and showed high enantioselectivity and activity (up to 10 000 turnovers at 100 ppm of catalyst loading). This method was employed in the synthesis of a chiral beta-borylated ester from simple unconjugated alkenes though an unprecedented one-pot cross metathesis-asymmetric borylation sequence. PMID- 29120507 TI - Long-acting risperidone injections in a pregnant patient with bipolar disorder. PMID- 29120506 TI - History of mood or anxiety disorders and risk of gestational diabetes mellitus in a population-based cohort. AB - AIM: To examine the association between mood and anxiety disorders and the development of gestational diabetes mellitus in a retrospective population-based cohort study. METHODS: Clinical data from a provincial perinatal health registry were linked to physician claims, hospitalization records and emergency visits to identify any diagnoses of mood or anxiety disorders in the 2 years prior to pregnancy and a subsequent diagnosis of gestational diabetes during pregnancy. The study population included all singleton pregnancies in the Canadian province of Alberta from 1 April 2000 to 31 March 2010. Generalized estimating equations were used to determine the adjusted odds ratio of gestational diabetes, comparing women with and without a history of mood or anxiety disorders. RESULTS: Among 373 674 pregnancies from 253 911 women, 25.7% had a history of mood or anxiety disorders, and 3.8% developed gestational diabetes. The multivariate-adjusted odds of developing gestational diabetes were higher among women with a history of mood or anxiety disorders (odds ratio 1.10, 95% CI 1.06-1.14). CONCLUSIONS: Women with a history of mood or anxiety disorders had a moderately increased risk of developing gestational diabetes. PMID- 29120505 TI - A tutorial in small molecule identification via electrospray ionization-mass spectrometry: The practical art of structural elucidation. AB - The identification of unknown molecules has been one of the cornerstone applications of mass spectrometry for decades. This tutorial reviews the basics of the interpretation of electrospray ionization-based MS and MS/MS spectra in order to identify small-molecule analytes (typically below 2000 Da). Most of what is discussed in this tutorial also applies to other atmospheric pressure ionization methods like atmospheric pressure chemical/photoionization. We focus primarily on the fundamental steps of MS-based structural elucidation of individual unknown compounds, rather than describing strategies for large-scale identification in complex samples. We critically discuss topics like the detection of protonated and deprotonated ions ([M + H]+ and [M - H]- ) as well as other adduct ions, the determination of the molecular formula, and provide some basic rules on the interpretation of product ion spectra. Our tutorial focuses primarily on the fundamental steps of MS-based structural elucidation of individual unknown compounds (eg, contaminants in chemical production, pharmacological alteration of drugs), rather than describing strategies for large scale identification in complex samples. This tutorial also discusses strategies to obtain useful orthogonal information (UV/Vis, H/D exchange, chemical derivatization, etc) and offers an overview of the different informatics tools and approaches that can be used for structural elucidation of small molecules. It is primarily intended for beginning mass spectrometrists and researchers from other mass spectrometry sub-disciplines that want to get acquainted with structural elucidation are interested in some practical tips and tricks. PMID- 29120508 TI - Synthesis and Immunological Evaluation of a Multicomponent Cancer Vaccine Candidate Containing a Long MUC1 Glycopeptide. AB - A fully synthetic MUC1-based cancer vaccine was designed and chemically synthesized containing an endogenous helper T-epitope (MHC class II epitope). The vaccine elicited robust IgG titers that could neutralize cancer cells by antibody dependent cell-mediated cytotoxicity (ADCC). It also activated cytotoxic T lymphocytes. Collectively, the immunological data demonstrate engagement of helper T-cells in immune activation. A synthetic methodology was developed for a penta-glycosylated MUC1 glycopeptide, and antisera of mice immunized by the new vaccine recognized such a structure. Previously reported fully synthetic MUC1 based cancer vaccines that elicited potent immune responses employed exogenous helper T-epitopes derived from microbes. It is the expectation that the use of the newly identified endogenous helper T-epitope will be more attractive, because it will activate cognate CD4+ T-cells that will provide critical tumor-specific help intratumorally during the effector stage of tumor rejection and will aid in the generation of sustained immunological memory. PMID- 29120509 TI - Simulation training for medical emergencies in the dental setting using an inexpensive software application. AB - INTRODUCTION: Every dental provider needs to be educated about medical emergencies to provide safe dental care. Simulation training is available with simulators such as advanced life support manikins and robot patients. However, the purchase and development costs of these simulators are high. We have developed a simulation training course on medical emergencies using an inexpensive software application. The purpose of this study was to evaluate the educational effectiveness of this course. MATERIALS AND METHODS: Fifty-one dental providers participated in this study from December 2014 to March 2015. Medical simulation software was used to simulate a patient's vital signs. We evaluated participants' ability to diagnose and treat vasovagal syncope or anaphylaxis with an evaluation sheet and conducted a questionnaire before and after the scenario based simulation training. RESULTS: The median evaluation sheet score for vasovagal syncope increased significantly from 7/9 before to 9/9 after simulation training. The median score for anaphylaxis also increased significantly from 8/12 to 12/12 (P < .01). For the item "I can treat vasovagal syncope/anaphylaxis adequately," the percentage responding "Strongly agree" or "Agree" increased from 14% to 56% for vasovagal syncope and from 6% to 42% for anaphylaxis with simulation training. CONCLUSIONS: This simulation course improved participants' ability to diagnose and treat medical emergencies and improved their confidence. This course can be offered inexpensively using a software application. PMID- 29120511 TI - The design of behavioural interventions labelled as patient-mediated: A scoping review. AB - OBJECTIVE: Patient-mediated interventions (PMIs) directed at patients and/or physicians improve patient or provider behaviour and patient outcomes. However, what constitutes a PMI is not clear. This study described interventions explicitly labelled as "patient-mediated" in primary research. METHODS: MEDLINE, EMBASE, Allied and Complementary Medicine, PsychINFO, HealthSTAR, Social Work Abstracts, CINAHL and Cochrane Library were searched from inception on 1 January 2017 for English language studies that developed or evaluated behavioural interventions referred to as "patient-mediated" or "patient mediated" in the full text. Screening and data extraction were independently duplicated. Data were extracted and summarized on study and intervention characteristics. Interventions were categorized as 1 of 4 PMI pathways. RESULTS: Eight studies (4 randomized controlled trials, 1 observational study and 3 qualitative studies) were included. No studies explicitly defined PMI, and few PMIs were described in terms of content and format. Although 3 studies employed physician interventions, only patient interventions were considered PMIs. One study achieved positive improvement in patient behaviour. CONCLUSIONS: Research is needed to generate consensus on the PMI concept, employ theory when designing or evaluating PMIs, establish the effectiveness of different types of PMIs, and understand when and how to employ PMIs alone or combined with other interventions. PMID- 29120510 TI - In vitro characterization of gamma oscillations in the hippocampal formation of the domestic chick. AB - Avian and mammalian brains have evolved independently from each other for about 300 million years. During that time, the hippocampal formation (HF) has diverged in morphology and cytoarchitecture, but seems to have conserved much of its function. It is therefore an open question how seemingly different neural organizations can generate the same function. A prominent feature of the mammalian hippocampus is that it generates different neural oscillations, including the gamma rhythm, which plays an important role in memory processing. In this study, we investigate whether the avian hippocampus also generates gamma oscillations, and whether similar pharmacological mechanisms are involved in this function. We investigated the existence of gamma oscillations in avian HF using in vitro electrophysiology in P0-P12 domestic chick (Gallus gallus domesticus) HF brain slices. Persistent gamma frequency oscillations were induced by the bath application of the cholinergic agonist carbachol, but not by kainate, a glutamate receptor agonist. Similar to other species, carbachol-evoked gamma oscillations were sensitive to GABAA , AMPA/kainate and muscarinic (M1) receptor antagonism. Therefore, similar to mammalian species, muscarinic receptor-activated avian HF gamma oscillations may arise via a pyramidal-interneuron gamma (PING)-based mechanism. Gamma oscillations are most prominent in the ventromedial area of the hippocampal slices, and gamma power is reduced more laterally and dorsally in the HF. We conclude that similar micro-circuitry may exist in the avian and mammalian hippocampal formation, and this is likely to relate to the shared function of the two structures. PMID- 29120512 TI - Endoscopic endonasal surgery for pituitary adenomas extending to the oculomotor cistern. AB - BACKGROUND: Extension of a pituitary adenoma to the oculomotor cistern harbors the risk of oculomotor nerve impairment and further extension into the interpeduncular cistern. The role of endoscopic endonasal surgery for those lesions was investigated. METHODS: The medical records were retrospectively analyzed. Attention was paid to the oculomotor nerve function and removal rate of the tumor within the oculomotor and interpeduncular cisterns. RESULTS: Six patients were eligible for the study, including 2 with oculomotor nerve palsy. The tumor from the oculomotor and interpeduncular cistern was removed in all except on one side of the case with bilateral tumor extension. The oculomotor nerve palsy demonstrated partial recovery in both cases during the 3-month follow up. CONCLUSION: The pituitary adenoma extending to the oculomotor cistern can be removed under the endoscope. Improvement of oculomotor nerve palsy can be achieved, and further tumor extension into the interpeduncular cistern can be prevented. PMID- 29120513 TI - In modelling effects of global warming, invalid assumptions lead to unrealistic projections. AB - In their recent Opinion, Pauly and Cheung () provide new projections of future maximum fish weight (Winfinity ). Based on criticism by Lefevre et al. (2017) they changed the scaling exponent for anabolism, dG . Here we find that changing both dG and the scaling exponent for catabolism, b, leads to the projection that fish may even become 98% smaller with a 1 degrees C increase in temperature. This unrealistic outcome indicates that the current Winfinity is unlikely to be explained by the Gill-Oxygen Limitation Theory (GOLT) and, therefore, GOLT cannot be used as a mechanistic basis for model projections about fish size in a warmer world. PMID- 29120515 TI - The effects of crew resource management on teamwork and safety climate at Veterans Health Administration facilities. AB - Communication failure is a significant source of adverse events in health care and a leading root cause of sentinel events reported to the Joint Commission. The Veterans Health Administration National Center for Patient Safety established Clinical Team Training (CTT) as a comprehensive program to enhance patient safety and to improve communication and teamwork among health care professionals. CTT is based on techniques used in aviation's Crew Resource Management (CRM) training. The aviation industry has reached a significant safety record in large part related to the culture change generated by CRM and sustained by its recurrent implementation. This article focuses on the improvement of communication, teamwork, and patient safety by utilizing a standardized, CRM-based, interprofessional, immersive training in diverse clinical areas. The Teamwork and Safety Climate Questionnaire was used to evaluate safety climate before and after CTT. The scores for all of the 27 questions on the questionnaire showed an increase from baseline to 12 months, and 11 of those increases were statistically significant. A recurrent training is recommended to maintain the positive outcomes. CTT enhances patient safety and reduces risk of patient harm by improving teamwork and facilitating clear, concise, specific and timely communication among health care professionals. PMID- 29120514 TI - Assessment of venous hemodynamics and volume homeostasis during pregnancy: recommendations of the International Working Group on Maternal Hemodynamics. AB - Venous hemodynamics and volume homeostasis are important aspects of cardiovascular physiology. However, today their relevance is still very much underappreciated. Their most important role is maintenance and control of venous return and, as such, cardiac output. A high-flow/low-resistance circulation, remaining constant under physiological circumstances, is mandatory for an uncomplicated course of pregnancy. In this article, characteristics of normal and abnormal venous and volume regulating functions are discussed with respect to normal and pathologic outcomes of pregnancy, and current (non-invasive) methods to assess these functions are summarized. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29120516 TI - Carbon cycle confidence and uncertainty: Exploring variation among soil biogeochemical models. AB - Emerging insights into factors responsible for soil organic matter stabilization and decomposition are being applied in a variety of contexts, but new tools are needed to facilitate the understanding, evaluation, and improvement of soil biogeochemical theory and models at regional to global scales. To isolate the effects of model structural uncertainty on the global distribution of soil carbon stocks and turnover times we developed a soil biogeochemical testbed that forces three different soil models with consistent climate and plant productivity inputs. The models tested here include a first-order, microbial implicit approach (CASA-CNP), and two recently developed microbially explicit models that can be run at global scales (MIMICS and CORPSE). When forced with common environmental drivers, the soil models generated similar estimates of initial soil carbon stocks (roughly 1,400 Pg C globally, 0-100 cm), but each model shows a different functional relationship between mean annual temperature and inferred turnover times. Subsequently, the models made divergent projections about the fate of these soil carbon stocks over the 20th century, with models either gaining or losing over 20 Pg C globally between 1901 and 2010. Single-forcing experiments with changed inputs, temperature, and moisture suggest that uncertainty associated with freeze-thaw processes as well as soil textural effects on soil carbon stabilization were larger than direct temperature uncertainties among models. Finally, the models generated distinct projections about the timing and magnitude of seasonal heterotrophic respiration rates, again reflecting structural uncertainties that were related to environmental sensitivities and assumptions about physicochemical stabilization of soil organic matter. By providing a computationally tractable and numerically consistent framework to evaluate models we aim to better understand uncertainties among models and generate insights about factors regulating the turnover of soil organic matter. PMID- 29120517 TI - Outpatient versus inpatient thyroidectomy: A systematic review and meta-analysis. AB - BACKGROUND: Outpatient thyroidectomy has gained popularity due to improved resource utilization. METHODS: We conducted a systematic review and meta-analysis using MEDLINE, EMBASE, CINAHL, Web of Science, and the Cochrane library. We included all studies examining the outcomes of outpatient thyroidectomy as compared with those of inpatient thyroidectomy. Risk of bias was assessed using the Newcastle-Ottawa scale. Postoperative complications (hematoma, hypocalcemia, and recurrent laryngeal nerve injury) and readmission/reintervention rates were compared. RESULTS: After screening 1665 records, 10 nonrandomized observational studies were included. There were fewer complication rates in the outpatient group than the inpatient group (relative risk [RR] 0.56; 95% confidence interval [CI] 0.37-0.83). There was no difference in readmission/reintervention rates (RR 0.60; 95% CI 0.33-1.09). CONCLUSION: The results suggest outpatient thyroidectomy may be as safe as inpatient thyroidectomy in appropriately selected patients. The results are limited by high risk of bias. Well-designed prospective studies are necessary to further assess the safety of outpatient thyroidectomy. PMID- 29120518 TI - Small bowel obstruction after transoral robotic surgery. AB - BACKGROUND: Head and neck surgery is not often considered a risk factor for intestinal ileus and small bowel obstruction. However, many of these patients may have had prior abdominal surgery, a known risk factor for small bowel obstruction, and may be at risk for bowel obstruction after a surgical procedure of the head and neck. METHODS: We present a case describing a patient who, after undergoing transoral robotic surgery, experienced delayed postoperative ileus and eventual small bowel obstruction requiring exploratory laparotomy and bowel resection. RESULTS: Although the patient required total parenteral nutrition for several days, he eventually was able to resume tube feeds, and after several months was able to tolerate an oral diet. CONCLUSION: Although uncommon complications of head and neck surgery, intestinal ileus and small bowel obstruction can develop as the result of stress/inflammation, postoperative narcotic pain medication, and prior abdominal surgery. PMID- 29120519 TI - Palovarotene Inhibits Osteochondroma Formation in a Mouse Model of Multiple Hereditary Exostoses. AB - Multiple hereditary exostoses (MHE), also known as multiple osteochondromas (MO), is an autosomal dominant disorder characterized by the development of multiple cartilage-capped bone tumors (osteochondromas). The large majority of patients with MHE carry loss-of-function mutations in the EXT1 or EXT2 gene, which encodes a glycosyltransferase essential for heparan sulfate (HS) biosynthesis. Increasing evidence suggests that enhanced bone morphogenetic protein (BMP) signaling resulting from loss of HS expression plays a role in osteochondroma formation in MHE. Palovarotene (PVO) is a retinoic acid receptor gamma selective agonist, which is being investigated as a potential drug for fibrodysplasia ossificans progressiva (FOP), another genetic bone disorder with features that overlap with those of MHE. Here we show that PVO inhibits osteochondroma formation in the Fsp1Cre ;Ext1flox/flox model of MHE. Four-week daily treatment with PVO starting at postnatal day (P) 14 reduced the number of osteochondromas that develop in these mice by up to 91% in a dose-dependent manner. An inhibition of long bone growth observed in animals treated from P14 was almost entirely abrogated by delaying the initiation of treatment to P21. We also found that PVO attenuates BMP signaling in Fsp1Cre ;Ext1flox/flox mice and that aberrant chondrogenic fate determination of Ext1-deficient perichondrial progenitor cells in these mice is restored by PVO. Together, the present data support further preclinical and clinical investigations of PVO as a potential therapeutic agent for MHE. (c) 2017 American Society for Bone and Mineral Research. PMID- 29120520 TI - Large Changes in Fluorescent Color and Intensity of Symmetrically Substituted Arylmaleimides Caused by Subtle Structure Modifications. AB - Herein we report on four diarylmaleimides based on 3- or 2-substituted benzothiophene (M3S or M2S) and benzofuran (M3O or M2O), which show very different emission properties: aggregation-caused quenching (ACQ), aggregation induced emission (AIE), and dual-state strong emission (DSE) in both solution and solid states. Their emission color in the solid state can be adjusted from green yellow into red. M2O displays strong red solid-state emission at 630 nm with a quantum yield of 46.3 %. Single-crystal X-ray diffraction analysis confirms that their large distinction in solid-state emission originates from their different packing structures: hydrogen-bonded organic frameworks (HOFs) for M3S, a staggered structure for M3O, J-aggregation for M2S, and weak H-aggregation for M2O. HOF of M3S and weak H-aggregation of M2O make them produce inverse-type piezochromic fluorescence: blueshifted "turn-on" and redshifted "turn-off" emission, respectively. These results provide new insight in fluorescence manipulated by subtle structure modification. PMID- 29120521 TI - Management of chyle leakage after thyroidectomy, cervical lymph node dissection, in patients with thyroid cancer. AB - BACKGROUND: The purpose of this study was to evaluate the incidence and pattern of chyle leakage after thyroidectomy and/or cervical lymph node dissection and to establish management protocols for chyle leakage. METHODS: Patients who underwent surgical management for thyroid cancer were analyzed retrospectively. RESULTS: For this study, 131 patients with chyle leakage were identified; the overall incidence was 0.9%. Of them, 43.7% of patients underwent central neck dissection without lateral neck dissection, and chyle leakage was easily controlled with conservative management. Patients whose chyle drainage was reduced by >50% after dietary modification had a significantly shorter hospital stay (P < .001); NPO was the most effective dietary modification. CONCLUSION: The occurrence of chyle leakage after central compartment dissection even without lateral neck dissection was not rare, but was easily controlled with conservative management. Surgical management should be considered if the drainage amount does not decrease by >50% of the original amount of the day of detection after 2 days of NPO. PMID- 29120523 TI - A Magic Ratio Rule for Beginners: A Chemist's Guide to Quantum Interference in Molecules. AB - This Concept article will give a glimpse into chemical design principles for exploiting quantum interference (QI) effects in molecular-scale devices. Direct observation of room temperature QI in single-molecule junctions has stimulated growing interest in fabrication of tailor-made molecular electronic devices. Herein, we outline a new conceptual advance in the scientific understanding and technological know-how necessary to control QI effects in single molecules by chemical modification. We start by discussing QI from a chemical viewpoint and then describe a new magic ratio rule (MRR), which captures a minimal description of connectivity-driven charge transport and provides a useful starting point for chemists to design appropriate molecules for molecular electronics with desired functions. The MRR predicts conductance ratios, which are solely determined by QI within the core of polycyclic aromatic hydrocarbons (PAHs). The manifestations of QI and related quantum circuit rules for materials discovery are direct consequences of the key concepts of weak coupling, locality, connectivity, mid gap transport and phase coherence in single-molecule junctions. PMID- 29120522 TI - Association between baseline serum hepcidin levels and infection in kidney transplant recipients: Potential role for iron overload. AB - BACKGROUND: The liver-synthesized peptide hepcidin is a key regulator of iron metabolism and correlates with total iron stores. We analyzed the association between pre-transplant hepcidin-25 levels and infection after kidney transplantation (KT). METHODS: Serum hepcidin-25 levels were measured at baseline by high-sensitivity ELISA in 91 patients undergoing KT at our institution between December 2011 and March 2013. The impact of this biomarker on the incidence of post-transplant infection (excluding lower urinary tract infection) during the first year was assessed by Cox regression. RESULTS: Mean hepcidin-25 level was 82.3 +/- 67.4 ng/mL and strongly correlated with serum ferritin (Spearman's rho = 0.703; P < .001). There were no significant differences in hepcidin-25 levels between patients with or without overall infection (96.4 +/- 67.5 vs 72.6 +/- 66.7 ng/mL; P = .101). Such difference was evident for opportunistic (128.9 +/- 75.0 vs 73.0 +/- 62.3 ng/mL; P = .003) and, to a lesser extent, surgical-site infection (107.5 +/- 73.3 vs 76.5 +/- 65.2 ng/mL; P = .087). Patients with hepcidin-25 levels >=72.5 ng/mL had higher 12-month cumulative incidence of overall infection (51.2% vs 29.2%; P = .032). After multivariate adjustment, hepcidin-25 >=72.5 ng/mL acted as an independent risk factor for overall (adjusted hazard ratio [aHR] 3.86; 95% confidence interval [CI] 1.49-9.96; P = .005) and opportunistic infection (aHR 4.32; 95% CI 1.18-15.75; P = .027). CONCLUSION: Elevated baseline serum hepcidin-25 levels were associated with increased risk of infection after KT, suggesting a role for iron overload in the individual susceptibility to post-transplant infection. PMID- 29120524 TI - Efficient endo Cycloisomerization of Terminal Alkynols Catalyzed by a New Ruthenium Complex with 8-(Diphenylphosphino)quinoline Ligand and Mechanistic Investigation. AB - Several new ruthenium complexes supported by the P,N-donor ligand 8 (diphenylphosphino)quinoline (DPPQ) were synthesized, including [RuCl2 (DPPQ)2 ] (1), [Ru(MU-Cl)(DPPQ)2 ]2 (BPh4 )2 (2), and [RuCl(DPPQ)2 Py](BF4 ) (3). Complex 2, with only 1 mol % loading, was found to be catalytically active for the endo cycloisomerization of various terminal alkynols to endo-cyclic enol ethers in moderate to excellent yields. In particular, the 7- and 8-endo heterocyclization can be achieved efficiently to give the seven-membered 3-benzoxepine and eight membered 3-benzo[d]oxocine derivatives. The stoichiometric reactions of 2 with various alkynol substrates have been carried out to investigate the mechanism, which led to a series of seven-, six-, and five-membered oxacyclocarbene ruthenium complexes including [RuCl(DPPQ)2 {=CCH2 C6 H4 CH2 CH2 O}](BPh4 ) (12) and [RuCl(DPPQ)2 {=CCH2 (CH2 )n CH2 O}](BPh4 ) (n=3, 12'; n=2, 13; n=1, 14). The quantitative transformation of oxacyclocarbene 12 into catalyst 2 and 3 benzoxepine 5 a as well as the efficient catalytic activity of 12 for the endo cyclization of 2-(2-ethynylphenyl)ethanol (4 a) demonstrated that 12 is a key intermediate involved in the catalytic cycle. Moreover, comparative studies on the modeling reactions and catalytic activity of the series of oxacyclocarbene complexes indicated that the different catalytic activity of 2 for the endo cycloisomerization of different types of alkynols can be related to the reactivity of the respective ruthenium oxacyclocarbene intermediates. PMID- 29120525 TI - Heparanase level and procoagulant activity are reduced in severe sepsis. AB - BACKGROUND: During severe sepsis, levels and activity of all coagulation proteins are reduced. Heparanase is implicated in angiogenesis and tumor progression. We previously demonstrated that heparanase also affected the hemostatic system. It forms a complex and increases the activity of the blood coagulation initiator tissue factor. AIM: To evaluate heparanase levels and procoagulant activity as predictors of sepsis severity. MATERIALS AND METHODS: Twenty-one patients with non-trauma, non-surgical sepsis admitted to the intensive care unit and 35 controls were recruited. Plasma samples were drawn from the study participants on days 1 and 7 following admission. RESULTS: Heparanase levels and procoagulant activity on day 1 were significantly reduced in patients compared to controls (P < .0001, P < .0001, respectively). Day 1 heparanase procoagulant activity >=350 ng/mL yielded a negative predictive value for severe sepsis of 89%. Additionally, heparanase procoagulant activity on day 7 correlated with the change in the APACHE score between days 1 and 7 (r = .66, P = .007). CONCLUSIONS: Heparanase procoagulant activity decreases during sepsis and returns to normal levels as soon as the patient recovers. Hence, it can be potentially used to predict the risk of severe sepsis. These findings need to be further explored in large-scale studies. PMID- 29120526 TI - A Three-Component Enantioselective Cyclization Reaction Catalyzed by an Unnatural Amino Acid Derivative. AB - A new diastereo- and enantioselective three-component cyclization reaction is described. The reaction takes place between a ketone, a carboxylic acid, and a nitroalkene to yield a bicyclic octahydro-2H-indol-2-one scaffold possessing three chiral centers. This reaction involves a rearrangement of the nitro group under simple thermal conditions. A plausible mechanism is proposed for this new reaction based on DFT calculations and isotope-labeling experiments. A new concise enantioselective synthesis of the alkaloid (+)-pancracine is presented as an example of the potential of this novel organocatalytic cyclization reaction in the synthesis of natural products. PMID- 29120527 TI - CASTLE tumor of the parotid: First documented case, literature review, and genetic analysis of the cancer. AB - BACKGROUND: Carcinoma showing thymus-like elements (CASTLE) is a rare tumor that normally affects the thyroid gland and was thought to arise from either the remnants of the branchial pouch or the ectopic cervical thymic tissue. These tumors show strong immunopositivity for CD5, P63, and CD117. Most CASTLE of the thyroid gland is treated with surgery with or without adjuvant radiotherapy or chemotherapy. METHOD: A 55-year-old woman presented with a slow-growing right parotid mass. A right total parotidectomy and ipsilateral selective neck dissection were performed and the diagnosis of CASTLE was made after confirmation with an immunohistochemistry test. She received radiotherapy postoperatively. RESULTS: Genetic sequencing showed alterations in the PPARG, BRCA2, and NOTCH1 genes. She remained disease free for >1 year after treatment. CONCLUSION: We believe that this is the first reported case of CASTLE in the parotid gland. Clinicians should be aware of this rare entity and consider this differential diagnosis after ruling out other common parotid lesions. PMID- 29120528 TI - Student performance in a flipped classroom dental anatomy course. AB - PURPOSE: The purpose of this study was to assess dental student learning in a dental anatomy module between traditional lecture and flipped classroom cohorts. METHODS: Two cohorts of predoctoral dental students (N = 70 within each cohort) participated in a dental anatomy module within an Introduction to the Dental Patient (IDP) course ([traditional/lecture cohort: academic year (AY) 2012, 2013] and [flipped classroom cohort: AY 2014, 2015]). For the dental anatomy module, both cohorts were evaluated on pre-clinical tooth waxing exercises immediately after each of five lectures and tooth identification after all lectures were given. Additionally, the cohorts' performance on the overall IDP course examination was compared. RESULTS: The flipped classroom cohort had statistically significant higher waxing scores (dental anatomy module) than students in the traditional classroom. There was no statistically significant difference for tooth identification scores and the overall IDP course examination between the traditional vs flipped approach cohorts. This is due to the latter two assessments conducted at the end of the course gave all students enough time to review the lecture content prior to the assessment resulting in similar scores for both cohorts. CONCLUSION: The flipped classroom cohort promoted students' individual learning and resulted in improved students' performance on immediate evaluation but not on the end of the course evaluation. Redesign of courses to include a new pedagogical approach should be carefully implemented and evaluated for student's educational success. PMID- 29120529 TI - User experience and care for older people transitioning from hospital to home: Patients' and carers' perspectives. AB - BACKGROUND: Transitioning from hospital to home is challenging for many older people living with chronic health conditions. Transitional care facilitates safe and timely transfer of patients between levels of care and across care settings and includes communication between practitioners, assessment and planning, preparation, medication reconciliation, follow-up care and self-management education. To date, there is limited understanding of how to actively involve care recipient service users in transitional care. OBJECTIVE: This study was part of a larger research project. The objective of this article was to report the first study phase, in which we aimed to describe user experience pertaining to patients and carers. DESIGN, SETTING AND PARTICIPANTS: The study design was qualitative descriptive using interviews. Patients (n = 19) and carers (n = 7) participated in semi-structured interviews about their experience of transition from hospital to home in an urban Australian health-care setting. Interview data were analysed using thematic analysis. FINDINGS: All participants reported that they needed to become independent in transition. Participants perceived a range of social processes supported their independence at home: supportive relationships with carers, caring relationships with health-care practitioners, seeking information, discussing and negotiating the transitional care plan and learning to self-care. DISCUSSION: Findings contribute to our understanding that quality transitional care should focus on patients' need to regain independence. Social processes supporting the capacities of patients and carers should be emphasized in future initiatives. CONCLUSION: Future transitional care interventions should emphasize strategies to enable negotiation for suitable supports and assist care recipients to overcome barriers identified in this study. PMID- 29120531 TI - Building Innovation and Sustainability in Programs of Research. AB - PURPOSE: Innovation and sustainability are two important concepts of impactful programs of research. While at first glance these concepts and approaches may seem at odds, they are synergistic. APPROACH: We examine the social, political, and policy context as it relates to innovation and sustainability. We present an exemplar of a program of research and discuss factors to consider in developing innovative and sustainable programs of research. CONCLUSIONS: Innovation is an important component of sustainable programs of research. Understanding the social and political context and addressing relevant policy issues are factors to be considered in both innovation and sustainability. CLINICAL RELEVANCE: Innovation and sustainability, important components of research, are also central to clinical practice. Open communication between researchers and clinicians can support the acceleration of innovations and the integration of evidence-based findings in practice. PMID- 29120530 TI - Improvement in the Thermostability of a beta-Amino Acid Converting omega Transaminase by Using FoldX. AB - omega-Transaminases (omega-TAs) are important biocatalysts for the synthesis of active, chiral pharmaceutical ingredients containing amino groups, such as beta amino acids, which are important in peptidomimetics and as building blocks for drugs. However, the application of omega-TAs is limited by the availability and stability of enzymes with high conversion rates. One strategy for the synthesis and optical resolution of beta-phenylalanine and other important aromatic beta amino acids is biotransformation by utilizing an omega-transaminase from Variovorax paradoxus. We designed variants of this omega-TA to gain higher process stability on the basis of predictions calculated by using the FoldX software. We herein report the first thermostabilization of a nonthermostable S selective omega-TA by FoldX-guided site-directed mutagenesis. The melting point (Tm ) of our best-performing mutant was increased to 59.3 degrees C, an increase of 4.0 degrees C relative to the Tm value of the wild-type enzyme, whereas the mutant fully retained its specific activity. PMID- 29120532 TI - Sexual Orientation Concordance And (Un)Happiness About Births. AB - CONTEXT: A woman's happiness about a pregnancy and birth has implications for her child's health and her own well-being. Sexual orientation and, particularly, the extent of concordance across its dimensions (sexual identity, behavior and attraction) may be related to happiness about these events, but research on this relationship has been lacking. METHODS: Data on 5,744 pregnancies ending in births among women aged 15-44 in three waves of the National Survey of Family Growth (2006-2015) were examined. Weighted linear regression models examined the relationship between sexual orientation concordance and women's happiness about a birth. Analyses also explored whether birth intention and male partnership characteristics mediated the relationship, and whether it varied by intention status. RESULTS: Women who identified as heterosexual but reported same-sex attraction or behavior (categorized as "heterosexual-identified discordant") were less happy about their births than were women who were exclusively heterosexual (or "heterosexual-identified concordant"). The difference was more than half a point on a scale of 0-10 (coefficient, -0.7). This association was partially explained by the fact that births were less likely to be intended, and that relationships with male partners were less favorable for births, among discordant than among concordant women. Moreover, the happiness gap between concordant and discordant women was larger when births were unwanted (predicted score, 4.9 vs. 4.1) than when they were intended (9.3 vs. 9.1). CONCLUSIONS: To help ensure optimal reproductive health care for all women, research should explore whether providers take into account all dimensions of individuals' sexual orientation. PMID- 29120533 TI - Structural Insights from 59 Co Solid-State NMR Experiments on Organocobalt(I) Catalysts. AB - A series of fumarate-based organocobalt(I) [CoCp(CO)(fumarate)] catalysts is synthesized and characterized by X-ray crystallography, multinuclear (13 C and 59 Co) solid-state NMR spectroscopy, and 59 Co NQR spectroscopy. Given the dearth of 59 Co solid-state NMR studies on CoI compounds, the present work constitutes the first systematic characterization of the 59 Co electric field gradient and chemical shift tensors for a series of cobalt complexes in this oxidation state. Using X-ray crystallography, the molecular geometry about the CoI centre is found to be nearly identical in all compounds studied herein. Owing to the 59 Co nucleus' large chemical shift range, solid-state NMR experiments are found to be able to detect small structural differences between the individual organocobalt(I) compounds. With the aid of density functional theory calculations on these complexes, it is shown that the 59 Co chemical shift anisotropy and the 59 Co quadrupolar coupling constant are both extremely sensitive gauges of the Fu Co-Cp bond angle, providing a link between these 59 Co NMR observables and the catalysts' structures. PMID- 29120534 TI - Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder. AB - : Independent studies report that periconceptional folic acid (FA) may decrease the risk of autism spectrum disorder (ASD) while exposure to air pollution may increase ASD risk. We examined the joint effects of gestational FA and air pollution exposures in association with ASD. We studied 346 ASD cases and 260 typically developing controls from the CHARGE case-control study. Self-reported FA intake for each month of pregnancy was quantified. Estimates of exposure to near roadway air pollution (NRP) and criteria air pollutant measures were assigned based on maternal residential history. Among mothers with high FA intake (>800 MUg) in the first pregnancy month, exposure to increasing levels of all air pollutants, except ozone, during the first trimester was associated with decreased ASD risk, while increased ASD risk was observed for the same pollutant among mothers with low FA intake (<=800 MUg). This difference was statistically significant for NO2 (e.g., NO2 and low FA intake: OR = 1.53 (0.91, 2.56) vs NO2 and high FA intake: OR = 0.74 (0.46, 1.19), P-interaction = 0.04). Mothers exposed to higher levels (>= median) of any air pollutant during the first trimester of pregnancy and who reported low FA intake were at a higher ASD risk compared to mothers exposed to lower levels of that air pollutant and who reported high first month FA intake. Joint effects showed significant (alpha < 0.10) departures from expected interaction for NRP and NO2 . Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure. Further study is needed to replicate these findings in larger sample sizes and to understand mechanisms of this potential relationship.. Autism Res 2018, 11: 69-80. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined interactions between periconceptional folic acid (FA) and air pollution exposure on risk of ASD. Mothers exposed to higher levels of air pollution during the first trimester of pregnancy and who reported low supplemental FA intake during the first pregnancy month were at a higher ASD risk compared to mothers exposed to lower levels of air pollution and who reported high first month FA intake. Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure. PMID- 29120536 TI - Discovery of a novel class of pyridine derivatives that selectively inhibits mutant isocitrate dehydrogenase 2. AB - This paper presents synthesis and structure-activity relationship of pyridine derivatives as inhibitors of mutant isocitrate dehydrogenase 2 (IDH2). A series of 2,4,6-trisubstituted pyridine derivatives have been prepared and evaluated in vitro. Among these compounds, 14n exhibited excellent inhibition activity with the IC50 of 54.6 nm, which is approximately onefold improvement compared to drug candidate AG-221 (Enasidenib) that is in Phase III trial. Exquisite selectivity of 14n for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the wild-type IDH1 and IDH2. PMID- 29120537 TI - ? PMID- 29120535 TI - miRNA profiling identifies deregulated miRNAs associated with osteosarcoma development and time to metastasis in two large cohorts. AB - Osteosarcoma (OS) is an aggressive bone tumor primarily affecting children and adolescents. The etiology of OS is not fully understood. Thus, there is a great need to obtain a better understanding of OS development and progression. Alterations in miRNA expression contribute to the required molecular alterations for neoplastic initiation and progression. This study is the first to investigate miRNA expression in OS in a large discovery and validation cohort comprising a total of 101 OS samples. We established the signature of altered miRNA expression in OS by profiling the expression level of 752 miRNAs in 23 OS samples using sensitive LNA-enhanced qPCR assays. The identified miRNA expression changes were correlated with gene expression in the same samples. Furthermore, miRNA expression changes were validated in a second independent cohort consisting of 78 OS samples. Analysis of 752 miRNAs in the discovery cohort led to the identification of 33 deregulated miRNAs in OS. Twenty-nine miRNAs were validated with statistical significance in the second cohort comprising 78 OS samples. miRNA/mRNA targets were determined, and 361 genes with an inverse expression of the target miRNA were identified. Both the miRNAs and the identified target genes were associated with multiple pathways related to cancer as well as bone cell biology, thereby correlating the deregulated miRNAs with OS tumorigenesis. An analysis of the prognostic value of the 29 miRNAs identified miR-221/miR-222 to be significantly associated with time to metastasis in both cohorts. This study contributes to a more profound understanding of OS tumorigenesis, by substantiating the importance of miRNA deregulation. We have identified and validated 29 deregulated miRNAs in the - to our knowledge - largest discovery and validation cohorts used so far for miRNA analyses in OS. Two of the miRNAs showed a promising potential as prognostic biomarkers for the aggressiveness of OS. PMID- 29120538 TI - [Frontotemporal dementia : an update]. AB - Frontotemporal dementia is a health issue that encompasses different specialties. This type of dementia is underdiagnosed and usually confused initially with psychiatric pathologies. Its clinical aspect as well as its evolution is a challenge for the physician on a daily basis due to the heterogeneity of the various forms. The diagnosis is usually uncertain and the current treatment can only treat the symptoms. The care of the patient and his entourage must be done in a multidisciplinary way. The advancement of research in its later years has brought to light genetic mutations that have led to a better understanding of pathology and pathophysiology. In the near future, these discoveries could lead to new targeted therapies. PMID- 29120539 TI - [Hypertension, diabetes, hyperlipidemia : what are the treatment goals for the elderly ?] AB - Will my patient actually benefit from the medication that I've prescribed? Faced with an elderly, frail patient, the family doctor is often confronted by this dilemma. This article reviews the evidence that can assist clinicians in determining the best approach to treating diabetes, hypertension and hyperlipidemia in elderly patients, by defining treatment goals specific to each patients' functional and cognitive capacities. Avoiding hypoglycemia and hypotension, with all of their consequences, must remain the highest priority driving objectives for optimal management of diabetes and hypertension in the geriatric population. PMID- 29120540 TI - [Detecting and assessing the impactof anticholinergic medications]. AB - Limitation of inappropriate prescribing must be a medical concern in daily practice especially in older patients. In particular, anti-cholinergic drugs (anti-ACh), which are not all explicitly classified as anti-ACh, are commonly prescribed for a wide range of indications (pulmonary obstructive diseases, anxiety, insomnia, urinary incontinence, Parkinson's disease, congestive heart failure). Their prescription is however associated with a reduced quality of life and increased morbidity and mortality. Tools detecting inappropriate prescriptions and clinical scales that quantify the anti-ACh burden contribute, despite some limitations, to secure and optimize these drugs' prescription in this vulnerable population. PMID- 29120541 TI - [Infection of chronic wounds in elderly patients]. AB - Chronic wounds infection in the elderly patients presents the risk of functional decompensation, or irreversible worsening of a wound. The diversity of clinical situations, the absence of data from clinical trials in the literature and a certain fatalism in view of the poor prognosis of these conditions should not be allowed to delay the early preparation of a patient-centred care plan (aiming at complete scarring, remission or symptomatic relief). Diagnostic and therapeutic strategies must be flexible, to take account not only of functional issues, constraints and special features relating to the patient but also of the resources and technical means available. Antibiotic therapy is widely used and must be reduced. It needs, however, to be considered for inclusion in a care plan that must be comprehensive and multidisciplinary. PMID- 29120542 TI - [Nocturia in aged patient: in practice]. AB - Nocturia is defined as the complaint that the individual has to wake at night to urinate. In older persons, this urinary functional disorder is most often of multifactorial origin and/or the symptom (sometimes the unique one) of a chronic disease. Nocturia is very annoying and its impact on health and quality of life is related to the disturbance of sleep cycles. In aged patients, who are often polymorbide and polymedicated, the interaction between nocturia and geriatric syndromes as well as comorbidities has to be more particularly underlined. The impact on informal caregiver's health and the decision for institutional admission are also to be considered. An adapted management of nocturia improves quality of life and reduces morbidity in aged patients. PMID- 29120543 TI - [Right heart failure : important forold and young patientsA challenge from the acute to the chronic]. AB - The prevalence of the right heart failure (RHF) is poorly known. However, RHF is often a consequence of left heart failure due to an interdependance between both ventricles. RHF should be indentified because of prognostic relevance. RHF is defined by the inability to maintain adequate cardiac output through the lung circulation. It can result from volume overload, pressure overload, or a disorder of systolic function. Adaptive mechanisms such as dilation or hyper-trophy will maintain adequate hemodynamics. Once these mechanisms become insufficient, congestive signs and hemodynamic consequences will appear. Diagnosis is based on echocardiography. The treatment of RHF is similar to left heart failure. In case of acute RHF, treatment depends of the etiology of RHF. Optimization of the volemia is a central objective of therapeutics. PMID- 29120544 TI - ? PMID- 29120545 TI - [Intestinal microbiota: towards therapeutic applications]. AB - Due to technological advances in DNA sequencing, the number of microbiota studies has increased exponentially in recent years. The intestinal microbiota, characterized by high diversity and bacterial richness, received particular interest. The studies showed that the modifications of the intestinal microbiota derive from and lead to different mechanisms and explain various pathologies, including those outside the digestive system.The aim of this short article is to comment on some recent findings on the human microbiota in a clinical context. We attempt to identify the strengths of current research as well as the trends that emerge from an abundant literature of a rather heterogeneous quality. PMID- 29120546 TI - ? PMID- 29120547 TI - ? PMID- 29120548 TI - ? PMID- 29120549 TI - ? PMID- 29120550 TI - ? PMID- 29120552 TI - DirecTalk: Musings From the 10th Floor: One Health. PMID- 29120551 TI - Current Medical Strategies in the Prevention of Ovarian Hyperstimulation Syndrome AB - The purpose of this review is to analyze current medical strategies in the preventionof ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation for in vitro fertilization.Owing to contemporary preventive measures of OHSS, the incidence of moderate and severeforms of the syndrome varies between 0.18% and 1.40%. Although none of medical strategies iscompletely effective, there is high quality evidence that replacing human chorionic gonadotropin(hCG) by gonadotropin releasing hormone (GnRH) agonists after GnRH antagonists and moderate-quality evidence that GnRH antagonist protocols, dopamine agonists and mild protocols reducethe occurrence of OHSS. Among various GnRH agonists, buserelin 0.5 mg, triptorelin 0.2 mg andleuprolide acetate (0.5-4 mg) have been mostly utilized. Although GnRH trigger is currently regardedas the best tool for OHSS prevention, intensive luteal support with exogenous administrationof estradiol and progesterone or low-dose hCG on the day of oocyte retrieval or on the day of GnRHagonist trigger are required to achieve optimal conception rates due to early luteolysis. Among currentlyavailable dopamine agonists, cabergoline, quinagolide and bromocriptine are the most commondrugs that should be used for prevention of both early and late OHSS. Mild stimulation protocolsoffer attractive option in OHSS prevention with satisfactory pregnancy rates. PMID- 29120553 TI - Rituximab Maintenance Strategy in Advanced Follicular Lymphoma: Facts and Controversies AB - Rituximab is a chimeric monoclonal CD20 antibody used in the treatment ofCD20 positive non-Hodgkin lymphomas and has revolutionized treatment approach to these hematologicmalignancies in the last decade. The main aim of this review is to present data on the use ofrituximab in the treatment of follicular lymphoma (FL). We will focus on rituximab maintenancestrategies in the first and second line treatment. This approach has improved the outcome in FL patientswith better progression-free survival in all patients and better overall survival in relapsed setting.Regardless of good results, this strategy has generated controversies in medical community in therange from the lack of overall survival benefit in first line setting, adverse effects of possible overtreatmentand toxicities to its unknown role in the era of novel agents. The existing data suggest thatrituximab maintenance should be a rational therapeutic option for all patients with FL responding tofi rst line therapy and transplant-ineligible patients responding to reinduction. PMID- 29120554 TI - Accommodation to Diagnosis of Trigeminal Neuralgia AB - Trigeminal neuralgia is one of the most common causes of facial pain. It impliesshort lasting episodes of unilateral electric shock-like pain with abrupt onset and termination, in thedistribution of one or more divisions of the trigeminal nerve that are triggered by innocuous stimuli.Most cases of trigeminal neuralgia are caused by compression of the trigeminal nerve root. Dependingon the etiology, trigeminal neuralgia can be classified as classic trigeminal neuralgia or painful trigeminalneuropathy. It may be precipitated by some actions at trigger zones. The diagnosis of trigeminalneuralgia is based on diagnostic criteria for classic trigeminal neuralgia, neuroimaging andelectrophysiologic trigeminal reflex testing. Treatment of classic trigeminal neuralgia for most patientsis pharmacological therapy, while surgical approach is reserved for patients that are refractory to medicaltherapy and in cases of painful trigeminal neuropathy. PMID- 29120557 TI - Abdominal Wall Endometriosis Eleven Years After Cesarean Section: Case Report AB - Endometriosis is a common chronic disease characterized by growth of the endometrialgland and stroma outside the uterus. Symptoms affect physical, mental and social well-being.Extrapelvic location of endometriosis is very rare. Abdominal wall endometriosis occurs in 0.03%-2%of women with a previous cesarean section or other abdominopelvic operation. The leading symptomsare abdominal nodular mass, pain and cyclic symptomatology. The number of cesarean sections isincreasing and so is the incidence of abdominal wall endometriosis as a potential complication of theprocedure. There are cases of malignant transformation of abdominal wall endometriosis. Therefore, itis important to recognize this condition and treat it surgically. We report a case of a 37-year oldwoman with abdominal wall endometriosis 11 years after cesarean section. She had low abdominalpain related to menstrual cycle, which intensified at the end of menstrual bleeding. A nodule painfulto palpation was found in the medial part of previous Pfannenstiel incision. Ultrasound guided biopsywas performed and the diagnosis of endometriosis confirmed. Surgery is the treatment of choice forabdominal wall endometriosis. Excision with histologically proven free surgical margins of 1 cm ismandatory to prevent recurrence. A wide spectrum of mimicking conditions is the main reason for latediagnosis and treatment of abdominal wall endometriosis. In our case, the symptoms lasted for eightyears and had intensified in the last six months prior to surgery. PMID- 29120558 TI - Job strain may precipitate clinical depression. PMID- 29120559 TI - Interpersonal Skills in the Practice of Food Safety Inspections: A Study of Compliance Assistance. AB - Conducting food safety inspections requires interpersonal skills and technical expertise. This requirement is particularly important for agencies that adopt a compliance assistance approach by encouraging inspectors to assist industry in finding solutions to violations. This article describes a study of inspections that were conducted by inspectors from the Michigan Department of Agriculture and Rural Development Food and Dairy Division at small-scale processing facilities. Interactions between inspectors and small processors were explored through a qualitative, ethnographic approach using interviews and field observations. Inspectors emphasized the importance of interpersonal skills such as communication, patience, empathy, respect, and consideration in conducting inspections. This article examines how these skills were applied, how inspectors felt they improved compliance, the experiences through which inspectors attained these skills, and the training for which they expressed a need. These results provide new insights into the core competencies required in conducting inspections, and they provide the groundwork for further research. PMID- 29120560 TI - Klebsiella Pneumoniaeoxa-48 in a Urology Patient: Case Report AB - We present an isolate of Klebsiella pneumoniae OXA-48 isolated in a 68-year oldman who underwent radical prostatectomy due to prostate cancer. The antibiotic susceptibility testingto a wide range of antibiotics was performed by disk diffusion method and determination of minimalinhibitory concentrations. The isolate was classified as multidrug-resistant. It showed intermediatesusceptibility to imipenem and meropenem, resistance to ertapenem, and sensitivity only to colistin,amikacin, and trimethoprim-sulfamethoxazole. The isolate was positive for ESBLs, negative forAmpC. Polymerase chain reaction and sequencing revealed bla(OXA-48)', bla(CTX-M-15) and bla(SHV-11). The plasmidencoding OXA-48 beta-lactamase did not belong to any known PCR-based replicon typing. Accordingto genotyping, the isolate belonged to ST37. PMID- 29120561 TI - A Community-Based Participatory Research Approach to Identifying Environmental Concerns. AB - A community-based participatory research process was used to develop an environmental initiative in Wichita, Kansas, called the Wichita Initiative to Renew the Environment (WIRE). The two-year project, led by University of Kansas School of Medicine-Wichita faculty and a community-based organization, was funded by the U.S. Environmental Protection Agency. The project aimed to identify, prioritize, and address Wichitans' environmental concerns by engaging the community to assist in developing the project design, establish a community-based environmental leadership council to guide the project, and identify and prioritize the community's environmental concerns based on impact and perceived urgency for action. The collaboration identified community priorities as: trash disposal, pollution in the Arkansas River and groundwater, and mobile source air pollution. Through WIRE, community members actively engaged and participated in identifying and prioritizing 19 environmental concerns most pertinent to the community, establishing an organization of 25 community members, and setting the stage for future projects to address those problems. PMID- 29120563 TI - Diagnosing and managing mild cognitive impairment. AB - There has been a rapid rise in the number of people diagnosed with dementia in England from 232,000 in 2008 to 850,000 in 2014. Currently, it is estimated that the prevalence of mild cognitive impairment in adults aged 65 and over is 10-20%. It is likely that this figure will increase in line with trends in dementia diagnosis. In some cases, mild cognitive impairment may be a prodrome for dementia, and my be caused by any of the dementia pathology subtypes. The relationship between depression in the elderly and mild cognitive impairment is difficult to tease out as they are frequently comorbid conditions and both have been found to be independent risk factors for subsequent dementia: about 10% convert to dementia each year, compared with 1-2% of the general elderly population. It is important to obtain a history of cognitive changes over time, as well as information about the onset and nature of cognitive symptoms, confirmed by a reliable informant, if available. To confirm the diagnosis objective evidence of cognitive impairment is required. However, there are no specific neuropsychological tests for patients with mild cognitive impairment. On neuropsychological tests, individuals with mild cognitive impairment typically score 1-15 SD below the mean for their age and education, although these ranges are guidelines and not cut-off scores. GPs should consider referring people who signs of mild cognitive impairment for assessment by specialist memory assessment services to aid early identification of dementia, because more than 50% of people with mild cognitive impairment later develop dementia. PMID- 29120562 TI - Be vigilant for dementia in Parkinson's disease. AB - It is estimated that up to 80% of patients with Parkinson's disease will eventually develop cognitive impairment over the course of their illness. Even at the time of diagnosis, cognitive impairment has been reported in 20-25% of patients. Commonly affected cognitive domains are executive function, visuospatial ability and attention control. In addition, patients with Parkinson's disease dementia may present with deficits in language function and verbal memory. Psychosis may occur in approximately 40% of patients with Parkinson's disease, and is associated with an increased risk of developing cognitive impairment. Studies have shown that patients with Parkinson's disease with a history of visual hallucinations had an increased risk of developing dementia, four to eight years following diagnosis of the disease. Other clinical risk factors associated with cognitive decline in patients with Parkinson's disease include older age of onset, severe motor symptom burden and in particular akinetic-rigid subtype and olfactory dysfunction. Patients with Parkinson's disease who present with symptoms of cognitive decline, behavioural changes or psychotic symptoms should be referred for further investigation. PMID- 29120564 TI - Developmental Venous Anomaly Serving as a Draining Vein of Brain Arteriovenous Malformation AB - Developmental venous anomalies are cerebral vascular malformations that presentnormal venous drainage of cerebral tissue. With increased and accessible usage of modern diagnostictools, they are now one of the most commonly diagnosed cerebral vascular malformations. Althoughdevelopmental venous anomalies are considered to be benign lesions, association with arteriovenousmalformation renders malignant potential to this combined pathology. In the case presented, thesemalformations were clinically silent and diagnosed accidentally, so they were not treated either withsurgery, endovascular surgery or radiosurgery, considering the possible complications such as venousinfarction of the brain, and because there was no obvious neurologic deficit related to this pathology.The patient presents for regular neurosurgical follow up examinations and has been free from symptomsthat were present on admission. PMID- 29120565 TI - Dynamic Inefficiencies in Insurance Markets: Evidence from Long-Term Care Insurance. PMID- 29120567 TI - Use of the VectorTest for Advanced Warning of Human West Nile Virus Cases in Mississippi. AB - West Nile virus (WNV) continues to persist in Mississippi; 2012 was the worse year for human infections, with a total of 247 reported human cases and five deaths. Public health officials are keenly interested in ways to detect WNV in advance in their jurisdictions, so they can implement appropriate and timely mosquito control in affected areas. A total of 40,312 female Culex quinquefasciatus mosquitoes were collected by gravid traps in Mississippi in 2013 and 2014 and tested by VectorTest, a rapid immunochromatographic assay ("dip stick" test) that is a highly specific and effective rapid threat assessment tool. This study evaluated if and to what extent VectorTest could provide advanced warning of impending human WNV cases in a specific area. These data were examined with regard to date of onset of human WNV cases to determine the predictive value of VectorTest for WNV activity. Both years, positive mosquito pools appeared before the vast majority (87.2%) of reported human cases. Overall, in 27 out of 37 human WNV cases (73.0 %) occurring in our study sites, there was an average advanced warning of 26 days (range 11-53 days) as indicated by positive mosquito collections near the patient's home. This operational health department study, although somewhat limited, reveals that mosquito sampling and testing can inform public health and mosquito control personnel of WNV activity in an area and of impending human cases. PMID- 29120568 TI - Common Bile Duct Stricture After Laparoscopic Cholecystectomy: Case Report AB - Despite progress in laparoscopic surgery and increasing surgical experience, theincidence of bile duct injury during laparoscopic cholecystectomy fails to fall below 0.3%-0.6% and itis still higher than those recorded in the era of open cholecystectomy. Bile duct injuries belong to themost serious complications of abdominal surgery in general and often end up with liver transplantationas the only hope for cure. We present a case of a 78-year-old jaundiced male patient who sustainedcommon hepatic duct injury during laparoscopic cholecystectomy eight months earlier.Exploratory laparotomy, ERCP and MRCP revealed a metal clip placed just below hepatic duct confluenceand causing stricture of bile duct with dilatation of bile ducts proximal to the level of stenosis(Strasberg classification type E3 injury). Repair of the injury was performed by creating termino-lateralhepaticojejunostomy between the right and left hepatic ducts and retrocolic Roux en-Y jejunallimb. By presenting this case, we wish to emphasize the importance of timely conversion and executionof intraoperative cholangiography in all cases when identification of the structures of Calot'striangle is not clear enough. Successful treatment of bile duct injury is only possible with joint approachof radiologist, gastroenterologist and experienced hepatobiliary surgeon. PMID- 29120569 TI - Abdominal Ultrasound - The Leading Method in Duodenal Gist Diagnostics AB - Gastrointestinal stromal tumors (GIST) are the most common mesenchymaltumors of the digestive tract and are generally asymptomatic. A 39-year-old female patient was hospitalizedin 2012 at Clinical Department of Internal Medicine, Sestre milosrdnice University HospitalCenter, for a focal hypodense irregular circular lesion located in segment III of the left hepatic lobe,accidentally found by ultrasonography and verified by computed tomography. The findings were alsoverified with nuclear magnetic resonance and esophagogastroduodenoscopy. A biopsy sample of thelesion was analyzed by histologic and immunohistochemical methods and identified as GIST. Thepatient underwent surgical operation (tumor excision with terminoterminal anastomosis createdbetween the second segment of duodenum and jejunum and resection of liver segment III). Thehistopathologic findings matched GIST with a high probability of relapse according to the localization,size, mitotic activity and Ki-67 values. Therefore, therapy with imatinib at a dose of 400 mg/day wasadministered. Three years after the operation, the patient is still in remission. PMID- 29120570 TI - Early referral improves long-term outcomes in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a common, chronic systemic inflammatory disease of unclear aetiology leading to synovial hypertrophy and joint inflammation. It typically presents with symmetrical polyarthritis of small joints of the hands or feet, but can also involve larger joints, and have associated extra-articular manifestations. Diagnosis is based on duration of symptoms, joint distribution, level of inflammatory markers and autoantibodies i.e. rheumatoid factor(RhF) and anty-cyclic citrullinated peptide (CCP) antibodies. The presence of synovitis or effusion, either clinical or subclinical, seen on ultrasound or MRI, is essential for diagnosis. RA can sometimes present with a large joint monoarthritis or oligoarthritis. Although this is an atypical presentation, a diagnosis can be made in the presence of suggestive serology and/or histology. In cases presenting with monoarthritis, careful assessment for differential diagnoses is needed, particularly in the elderly population where other conditions such as gout, calcium pyrophosphate deposition disease and osteoarthritis are common. Early referral of patients with suspected synovitis via the rapid access early inflammatory arthritis clinic results in significant improvements in long-term outcomes. Hence it is important to consider early referral for individuals with synovitis, particularly if this is affecting small joints. PMID- 29120571 TI - A healthy HLA-matched baby born by using a combination of aCGH and Karyomapping: the first latin american case. AB - PGD for HLA typing is a procedure that can be performed when an affected child requires a transplant to treat a non-hereditary disorder related to the hematopoietic and/or immune system. Hematopoietic stem cell transplantation from an HLA-identical donor provides the best treatment option. Three conventional ovarian stimulation procedures for IVF were performed in a couple with a 10-year old child diagnosed with T-cell acute lymphoblastic leukemia of high risk. Trophectoderm biopsy and aCGH examination were performed on 15 blastocysts, three on the first IVF procedure, four on the second cycle, and eight on the third. Three euploid blastocysts HLA-compatible with the genome of the affected child were identified. One euploid blastocyst HLA-compatible with the affected child was warmed and transferred, resulting in an HLA-matched live birth. In conclusion, combined aCGH for aneuploidy screening and Karyomapping may be performed in a single biopsy procedure. PMID- 29120572 TI - Gene polymorphisms of Interleukin 1? and Metalloproteinase 3 in Hepatitis C Infected Patients and Hepatocellular Carcinoma Patients. AB - Cytokines as IL 1? and matrix metalloproteinases (MMPs) are involved in tumor growth, invasion, and remote metastasis in various cancers. IL-1? ?31T/C polymorphism in the promoter region has been linked to an elevated risk of Hepatocellular carcinoma (HCC). MMP3 polymorphism at 1171 has also been linked to an elevated risk and a highly invasive type of HCC. Studying the association between IL-1? 31C/T gene polymorphism and MMP3 11715A/6A gene polymorphism in cases of Hepatitis C virus (HCV) and HCC. The study was done on 20 HCV infected patients, 20 HCC patients and 15 healthy controls. IL-1? 31 C/T and MMP3 1171 5A/6A gene polymorphisms was investigated using restriction fragment length polymorphism discrimination assay. Data revealed that the frequency of IL-1? C/T and MMP3 5A/6A polymorphisms was higher in patient groups (HCC and HCV) compared with healthy controls. A significant association was found between IL-1? C/T, MMP3 5A/6A polymorphism and HCC susceptibility. In conclusion, IL-1? C/T and MMP3 5A/6A polymorphisms are associated with an increased risk of developing HCC in Egyptian patients. PMID- 29120573 TI - IL-17 Induced The Recruitment and Functional Activity of Granulocytes Isolated from Patients Coinfected with Schistosoma mansoni and Hepatitis C Virus. AB - The aim of this study was to investigate the role of Th17 cytokines on granulocytes recruitment and functional activity in Schistosoma mansoni/hepatitis C virus (HCV) co-infected patients. Granulocytes were isolated from the co infected blood and stimulated overnight with Schistosoma soluble egg antigen (SEA) in the presence of IL-17, IL-22, or both cytokines. In parallel, granuloma was induced in vitro using the isolated granulocytes and SEA-coated polyacrylamide beads in the presence of IL-17 and/or IL-22 then the sizes of granulomas were measured after one week. Overnight culture and granuloma supernatants levels of tumor necrosis factor-alpha (TNF-?, hydrogen peroxide (H2O2) and nitric oxide (NO) were measured using ELISA. Results revealed that Schistosoma/HCV derived granulocytes produced significant (P < 0.0001) higher levels of TNF-? and H2O2 after overnight activation with SEA in the presence of IL-17 as compared to that produced by Schistosoma alone infected granulocytes. Presence of IL-17 increased significantly (P=0.0017) the granuloma index of coinfected patients' granulocytes as compared to that of Schistosoma alone infected granulocytes after one week of granuloma induction. Additionally, TNF-? and H2O2 levels in the granuloma supernatant were increased significantly (P = 0.0009 and P=0.0074 respectively) as compared to that of Schistosoma alone infected granulocytes. However, IL-22 alone or when combined with IL-17 decreased significantly the TNF-? levels (P=0.0112 and P=0.0007 respectively), and H2O2 levels (P=0.002 and P=0.053 respectively) but increased NO levels (P < 0.0001 and P=0.002 respectively) in the granuloma supernatant. In conclusion, IL-17 induces recruitment and functional activity of granulocytes in coinfected with schistosomiasis and hepatitis C virus which may contribute to the progress of fibrosis. Neutralization of this cytokine is suggested as a therapeutic strategy against fibrosis for such category of patients. PMID- 29120574 TI - Pentraxin 3 Genetic Variants and The Risk of Active Pulmonary Tuberculosis. AB - Tuberculosis is a major health problem worldwide. Genetic factors are considered important determinants of the host susceptibility to Mycobacterium tuberculosis. The aim of the current study was to evaluate the association between pentraxin 3 genetic variants and the susceptibility and severity of active pulmonary tuberculosis. The study included 100 patients with newly diagnosed pulmonary TB and 50 healthy controls. PTX3 plasma level was assayed using ELISA and PTX3 genotypes (rs2305619, rs3816527, rs1840680) were detected by real time PCR in all participants. PTX3 rs1840680 genotype (AA) and allele (A) were significantly higher in the study group while the genotype (GG) was higher in the control group. The plasma level of PTX3 was higher in the patients than controls (P < 0.0001). There is a strong association between PTX3 plasma level and the activity and severity of pulmonary TB. PTX3 rs1840680 genotype AA is associated with increased risk of active pulmonary TB. PMID- 29120575 TI - Neutrophil CD11b, CD64 and Lipocalin-2: Early Diagnostic Markers of Neonatal Sepsis. AB - Neonatal sepsis remains a global health problem particularly in the developing countries. Its diagnosis remains one of the most difficult issues in clinical medicine. Many immunologic markers including neutrophils CD11b and CD 64 and Lipocalin-2 have been tested as biomarkers of neonatal sepsis. The aim of the present study was to assess the value of these markers for early diagnosis of neonatal sepsis. The study included 60 neonates with suspected neonatal sepsis and 20 apparently healthy controls. Lipocalin-2 serum level was assessed by ELISA while neutrophils CD11b and CD64 expressions were evaluated by flow cytometry. Neutrophils CD64 and CD11b expression levels elevated significantly in cases (67.8+/-7.57) and (57.01+/-2.46) respectively than in controls (11.78+/-7.20) and (8.26+/-4.79). Lipocalin-2 serum level was significantly higher in the patients (145.3 +/- 55.3) than in controls (22.4 +/- 12.9). In conclusion, neutrophils CD64, CD11b and Lipocalin-2 are early, specific and sensitive diagnostic markers of neonatal sepsis. PMID- 29120576 TI - Serological and Molecular Diagnosis of Occult Hepatitis B Virus Infection in Hepatitis C Chronic Liver Diseases. AB - Occult Hepatitis B infection (OBI), defined as the presence of serum HBV DNA without detectable HBsAg, can be classified into seropositive OBI [anti-HBc and/or anti-hepatitis B surface (anti- HBs) positive] and seronegative OBI (anti HBc and anti- HBs negative). We examined the role of anti-HBc as a screening test for OBI in HCV patients with chronic liver diseases and evaluated the possible impact of OBI on liver disease progression. 90 patients with hepatitis C related chronic liver diseases (CLD) and negative for HBsAg were divided into three equal groups; chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). Patients were tested for anti-HBc by ELISA and by PCR for S-gene. Total anti-HBc was found in 26 patients (28.9%). 8 patients (8.9%) had positive serum HBV DNA. Of these, 2 were positive for anti-HBc and 6 negative for anti-HBc. No correlation between OBI and severity of HCV related CLD was observed. In conclusion, as OBI was not associated with total anti-HBc, it is invaluable surrogate marker for OBI detection. PMID- 29120577 TI - Epstein-Barr Virus Infection in Multiple Sclerosis Patients. AB - Multiple sclerosis (MS) is the most common inflammatory autoimmune CNS disease, with unknown etiology. We aimed to determine the coexistence of MS with antibodies to Epstein-Barr virus and its gene sequences (EBNA1 and BHRF1). The study included 60 MS patients and 60 control subjects. Serum samples were processed by ELISA for detection of EBV antibodies, and latent EBV genes were determined by Real Time PCR in blood samples. While 18 (30%) MS cases had anti- EBV IgM antibodies, all controls were free. For IgG, no difference was noted (cases 96.6% and controls 93.3%). BHFR1 gene was more detected in MS cases (66.6%) compared to controls (26.66%), P= 0.0019. However, no difference was noted regarding EBNA1 detection. In conclusion, a high prevalence of EBV past infection among Egyptian population was documented. Furthermore, IgM and BHRF1 were more detected in MS cases compared to controls. PMID- 29120578 TI - Role of Cannabinoid CB2 Receptor Gene (CNR2) Polymorphism in Children with Immune Thrombocytopenic Purpura in Beni-Suef Governorate in Egypt. AB - The cannabinoid system is involved in the immune regulation by modulation of Th cells type 1 and 2. It is composed of the CB2 receptor which is expressed at 10 to 100 folds greater levels on immune cells than the CB1 receptors. The CB2 is encoded by the cannabinoid CB receptor gene (CNR2) gene. This study aims to investigate the polymorphism in CNR2 gene variation rs 35761398 (Q63R) in Egyptian children with immune thrombocytopenic purpura and to investigate the relation between this gene polymorphism and either the susceptibility to or the chronicity of the disease. Forty children diagnosed as ITP were included in this study and 20 healthy children as normal control. CNR2 gene was investigated in those children by PCR RFLP technique (restriction fragment length polymorphism). CNR2 genotyping revealed that 45% of ITP patients had the QR heterotype, 50% had the RR homotype and 5% had QQ, the wild type with significantly higher frequency of homomutant genotype in comparison to controls. The relative odds ratio suggested a double risk for developing ITP in RR homotype (OR 2.152). A significant overpresentation of the RR genotype and of R allele was observed in the chronic patients (P=0.002 and 0.003, respectively). The associated risk to develop chronic ITP increased more than two folds for the RR homotype (OR=2.854). In conclusion, this study confirms the role of CNR2 Q63R polymorphism in the susceptibility to ITP in children and chronicity of the disease. PMID- 29120579 TI - Expression of CD64 on Surface of Circulating Monocytes in Systemic Lupus Erythematosus Patients: Relation to Disease Activity and Lupus Nephritis. AB - CD64 is a type of integral membrane glycoprotein known as FC receptor that binds monomeric IgG-type antibodies with high affinity. It is more commonly known as FC gamma receptor 1 (FC?R1) and it is expressed on monocytes surface. The goal of this study was to investigate the association of CD64 expression on the surface of peripheral blood monocytes of systemic lupus erythematosus patients with disease activity, and lupus nephritis. 30 SLE patients were enrolled into this study. They were subdivided into: 15 SLE patients with lupus nephritis and 15 SLE patients without lupus nephritis. In addition,Together with 25 age and sex matched healthy volunteers were enrolled as controls group. Disease activity was defined by SLE Disease Activity Index (SLEDAI) score and the renal Systemic Lupus Erythematosus Disease Activity Index (rSLEDAI) score. Surface expression of CD64 on peripheral blood monocytes was evaluated by Flowcytometry. Renal biopsies of Lupus nephritis patients was obtained and evaluated using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification scheme. There was a statistically significant difference in surface expression of CD64 on circulating monocytes (P > 0.001) in SLE patients with nephritis especially those with class II/III as compared to SLE without nephritis and healthy controls. The mean fluorescent intensity of CD64 staining correlated positively with markers of systemic inflammation, lupus nephritis, SLEDAI and rSLEDAI scores. In conclusions, surface expression of CD64 on circulating monocytes reflects systemic inflammation, renal injury and could be used as a rapid approach and good biomarker for disease activity and lupus nephritis in SLE patients. PMID- 29120580 TI - Serum Level of IL17a among Cirrhotic Hepatitis C Virus Infected Patients with Incidence of Diabetes Mellitus. AB - IL17a is the key inflammatory cytokine of TH17 and contributes to the pathogenesis of diabetes mellitus which is a common endocrine disorder associated with HCV infection. Herein, 183 cirrhotic HCV infected patients were screened for ANA by ELISA and positive cases (n=40) were screened for ICA by Immunofluorescence and IL17a serum levels were measured by ELISA and compared to a control group (n=24). Out of 40 cirrhotic HCV, ANA (+) infected patients, 16 patients (40 %) were type 2 diabetic and 13 (32.5%) were non-diabetic. On the other hand, 17 positive ICA (42.5%) and 23 negative ICA (57.5%) patients were reported. IL17a serum level was significantly elevated in cirrhotic HCV infected patients who were positive for ICA than negative ICA (P < 0.0001) and was significantly higher in type 2 diabetic than both non-diabetic patients (P=0.04) and controls (P=0.0005). In conclusion, IL17 serum levels were elevated in diabetic HCV infected patients. PMID- 29120581 TI - Serum Mannose - Binding Lectin in Egyptian Patients with Chronic Hepatitis C. AB - Approximately 60 - 85% of HCV infections cannot eradicate the virus and progress to chronic hepatitis, this may be explained by failure in host immune responses or by the ability of HCV to defeat host defense mechanisms. Mannose-binding lectin (MBL) may play an immunomodulatory role. This work intended to evaluate the relationship of MBL concentration to chronic HCV infection. Two groups, a patient group (n=50) with chronic hepatitis C, and a control group, (n=35) apparently healthy non-infected subjects were studied. MBL was measured by ELISA in both patients and controls. MBL was higher in chronic HCV patients (1159.86 +/ 710.29) than in controls (329.7 +/- 68.0) (p < 0.001). There was a negative correlation with the level of vireamia, and a positive correlation with the alpha fetoprotein level. We conclude that MBL may play a role in modulating host immunity, persistence of HCV infection and the disease progression. PMID- 29120582 TI - Role of PTPN22 1858 C/T Polymorphisms in Juvenile Idiopathic Arthritis in Egyptian Patients. AB - Juvenile idiopathic arthritis (JIA) the most common chronic arthropathy of childhood is a diverse group of chronic arthritis diseases. The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T and B cells. This study aimed to study PTPN gene polymorphism in JIA. The study included 60 children with JIA and 40 age and sex matched healthy children as controls. Patients and control groups were subjected to PTPN gene polymorphism analysis. Our findings indicated a significant difference in PTPN22 polymorphism between JIA patients and the control group (P = 0.021). Different PTPN genotypes were studied in relation to patient's age, sex and relevant laboratory data. It was concluded that PTPN22 polymorphism is different in JIA patients than healthy controls. T allele is associated only in cases with JIA and it may be considered as risk allele for certain JIA subtypes. PMID- 29120583 TI - Role of Lymphocyte Subpopulations in The Immunopathogenesis of Psoriasis and The Effect of Narrow Band UVB Phototherapy on The Immunological Profile of Psoriasis Patients. AB - Psoriasis is one of the most common chronic, inflammatory, T-cell-mediated autoimmune diseases. Narrow-band UVB (NB-UVB) therapy is widely used in the treatment of psoriasis; however, its mechanism of action is still not well understood. The objective of this study was to investigate the circulating T lymphocyte subpopulations in psoriasis patients before and after NB-UVB, to get insights into the mechanism of NB-UVB in the treatment of psoriasis. The severity of psoriasis was assessed by means of the Psoriasis Area and Severity Index (PASI score). The percentage of CD4+ T helper, CD8+ T cells, CD4+ CD25+T reg cells and CD4+ CD161+ T h17 cells were determined in the peripheral blood mononuclear cells in 40 untreated psoriasis patients with moderate-to-severe disease (PASI-score ?12) and in 30 age and sex matched healthy controls using flow cytometry. Psoriasis patients were treated with NB-UVB therapy three times / week for 8 weeks. Disease severity (PASI-score) and T cells frequencies in the blood were evaluated on enrolment (W0) and at 8 (W8) weeks. Compared with healthy controls, psoriasis patients with active disease had significantly higher proportion of peripheral CD4+Th, CD8+ T cells, and CD4+CD161+Th17 with lower proportion of CD4+CD25+Treg cells. Patients demonstrating marked improvement after NB-UVB phototherapy with significantly reduced circulating Th1and Th17 and CD8+ cytotoxic T cell levels while increasing Treg cell levels with a highly statistically significant difference after therapy (P < 0.001). In conclusion, our data indicated that the overexpression of CD4+Th, CD8+ T cells and CD4+CD161+Th17 cells together with the decreased frequency of Treg cells may play an important role in the pathogenesis of psoriasis. NB-UVB phototherapy is an effective and safe treatment for psoriasis acts through the inhibition of CD4+Th and CD4+CD161+Th17 cell immune response as well as the promotion of Treg cell immune response. PMID- 29120584 TI - Autoimmune Thyroiditis: A Case Control Study on a Sample of Egyptian Type I Diabetic Patients. AB - Type 1 diabetic patients are vulnerable for autoimmune thyroid disease. The incidence of type I Diabetes in Egypt is 8/100000. Undiagnosed thyroid dysfunction impairs metabolic status and increase cardiovascular risks in diabetic patients. Objectives of the study were to underscore autoimmune thyroiditis and thyroid dysfunction on a sample of Egyptian type I diabetes mellitus. One hundred type 1 diabetic subjects without previously known thyroid diseases and 50 controls were included. Physical examination, HbA1c, thyroid profile (TSH, free T3 and free T4), thyroid ultrasound anti-peroxidase and anti thyroglobulin antibodies were assessed. Autoimmune thyroiditis was detected in 27 % of the patients, and significantly associated with parental consanguinity, familial autoimmune disease and goiter. It is concluded that autoimmune thyroiditis is evident on laboratory assessment of type 1 diabetic patients who were apparently euthyroid. Screening of type I diabetics for thyroid diseases should be done even in absence of clinical evidence for better glycemic control and to improve long term outcome. PMID- 29120585 TI - Prevalence of Occult HBV Infection Among Chronic Hepatitis C Patients in Upper Egypt. AB - Occult hepatitis B virusinfection (OBI) is defined as the presence of HBV DNA in liver or serum of individuals who test negative for hepatitis B surface antigen (HBsAg).We aimed at determining the prevalence of OBI in patients chronically infected with HCV in Upper Egypt and to evaluate the possible impact of OBI on the progression of the liver disease. This study included 200 chronic HCV infected patients. HBV DNA was detected in the serum of 21 patients (10.5%) by nested PCR. 13 of them were positive for anti-HBc. HBV viral load ranged from 4.2 60.1 IU/ml. The percentage of cirrhotics was higher among OBI/HCV dual infection (52.4%) versus HCV mono infection (34.1%). Our study concluded that the prevalence of OBI among chronic HCV patients in Upper Egypt was 10.5%. OBI correlated with the severity of liver disease. Total anti-HBc cannot be used as a surrogate marker for detection of OBI. PMID- 29120586 TI - Association of Interleukin-8 Gene Polymorphisms and Expression with Hepatocellular Carcinoma in Egyptian Patients with Liver Cirrhosis. AB - Hepatocellular Carcinoma?(HCC) is one of the most common cancer in Egypt. Interleukin-8 Single Nucleotide Polymorphisms (-251 and +781 SNPs) are proposed genes for cancer susceptibility. Our aim was to evaluate the association of these two IL-8 SNPs polymorphisms and IL-8 gene expression with HCC in Egyptian patients with liver cirrhosis. IL-8 -251 and + 781 SNPs were assayed by TaqMan technique and IL-8 gene Expression study was done by Syber green method in 50 patients with liver cirrhosis (without HCC n=25and with HCC n=25)and 50 healthy controls. The expression of IL8 was significantly high in all patients compared to controls (P = 0.001), and higher in cirrhosis patients with HCC than cirrhosis without HCC (P = 0.003). IL-8(-251) A/A genotype and A allele were significantly higher in HCC patients (P = 0.005 and 0.009 respectively), while IL-8(+781) homozygote T/T was significantly low in HCC patients (P= 0.04). Finally, haplotype A-251/C+781 were associated with HCC. PMID- 29120587 TI - Matrix Metalloproteinase 2 and Osteoprotegrin as New Markers of Increased Atherosclerotic Risk in Egyptian Patients with Chronic Kidney Disease. AB - The prevalence of chronic kidney disease (CKD) is rising continuously. Cardiovascular disease (CVD) is among the leading causes of death and premature mortality of patients with CKD. It has been suggested that the assessment of CKD associated CVD risk factors together with conventional risk factors should be performed in order to improve the prediction of coronary heart disease risk. The reduction of these factors seems to be effective in lowering cardiovascular (CV) morbidity and mortality in patients with CKD. Measuring subclinical atherosclerosis in CKD may significantly improve CVD risk prediction. Additionally, novel early atherosclerosis biomarkers, as well as possible therapeutic targets, are greatly needed in CKD patients. Matrix Metalloproteinase 2 (MMP2) and osteoprotegerin (OPG) may fall into this category of both useful markers and targets in CKD disease. The aim of this study was to investigate MMP2 and OPG as markers of increased risk of atherosclerosis in CKD. The present study included 40 patients with CKD divided into two groups: 20 patients with stage 1-4 (group I) and 20 patients with end stage renal disease (ESRD) (group II). They were compared with 20 sex and age matched healthy individuals as a control group (group III). Levels of MMP2, OPG were measured by ELISA. Cardiac echocardiography was performed to assess structural integrity and function. There was highly significant increase in MMP2 and OPG levels in group II when compared with group I and group III (P=0.000 and P=0.000 respectively) and in group I when compared with group III (P=0.000). A highly significant difference was also found between the three groups as regard mitral and aortic calcification (P=0.000) and mitral, aortic and tricuspid regurge (P=0.000, 0.002 and 0.001 respectively). There was a positive correlation between OPG and MMP2 and significant relation between OPG and mitral and aortic calcification. In conclusion, MMP-2 and OPG may be involved in the pathogenesis of atherosclerosis in patients with CKD and could potentially be of use as biomarkers of subclinical atherosclerosis in these patients. The increase in mitral and aortic calcifications may suggest the reasons for increased CV risk in these patients. PMID- 29120588 TI - Association between SERPINB2 Gene Expression by Real Time PCR in Respiratory Epithelial Cells and Atopic Bronchial Asthma Severity. AB - Atopic bronchial asthma is chronic respiratory diseases of high frequency and high morbidity and mortality especially in patients refractory to the ordinary medical management. This study aimed to investigate the association between Serpin family B Member 2 (SERPINB2) gene expression and bronchial asthma severity. A total of 127 adult patients with asthma were enrolled in this study. Allergic respiratory symptoms were assessed and patients were classified according to Global Initiative for Asthma (GINA) criteria. The patients were subjected to skin prick test (SPT) by commonly encountered aeroallergens and pulmonary function tests. Sputum samples were subjected to RNA extraction and real time PCR amplification (q PCR) of SERPINB2 mRNA. The relative gene expression was determined by fold change (2-??Ct) after calculation of delta delta Ct (Cycle threshold of patients- Cycle threshold of healthy control). Assessment of the q PCR results was done by Receiver operating characteristic curve (ROC). Patients with severe bronchial asthma constituted 44% of asthma patients and mild asthma 22% of asthmatics. SPT revealed that 23 % of the patients were mono-sensitized and 77 % were poly-sensitized. The mites and pollens were the most frequently sensitizing allergens detected by SPT (53%, and 47%, respectively. SERPINB2 gene expression in asthma group that discriminated them from healthy control was > 0.01. The highest increase of expression was found ( > 1.92 fold) severe asthma compared to the mild group. A negative correlation was found between SERPINB2 expression and pulmonary function tests FEV1/FVC % and FEV1% (r?=?-0.921 and -0.805, P < 0.001), respectively. While significant positive correlation was found between SERPINB2 expression and total IgE levels (r?=?0.932 and P-value < 0.001), and SPT results (r?=?0.923 and P value < 0.001). In conclusion, the expression level of SERPINB2 gene significantly correlated with the severity of bronchial asthma. PMID- 29120589 TI - Using New Technologies to Communicate Environmental Health. PMID- 29120590 TI - Health and Wealth among the Poor: India and South Africa Compared. PMID- 29120591 TI - Socioeconomic Differences in the Adoption of New Medical Technologies. PMID- 29120592 TI - Innovative Vector and Pest E-Learning for Environmental Health Professionals. PMID- 29120594 TI - The Future of Environmental Public Health Tracking: 2020 and Beyond. PMID- 29120593 TI - What Explains Differences in Smoking, Drinking, and Other Health-Related Behaviors? PMID- 29120595 TI - Access to Care, Provider Choice, and the Infant Health Gradient. PMID- 29120597 TI - JEH Quiz #3: A Community-Based Participatory Research Approach to Identifying Environmental Concerns. PMID- 29120598 TI - DirecTalk: Musings From the 10th Floor: Tied to the Mast. PMID- 29120599 TI - Facile C-F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent. AB - Late-stage fluorination reactions aim to reduce the synthetic limitations of conventional organofluorine chemistry with respect to substrate scope and functional group tolerance. C-F bond formation is commonly thermodynamically favorable but almost universally associated with high kinetic barriers. Apart from PhenoFluor chemistry, most modern aromatic fluorination methods reported to date rely on the use of transition metal catalysts, with C-F bonds often formed through reductive elimination. Reductive elimination chemistry to make C-X bonds becomes increasingly challenging when moving to higher atomic numbers in the periodic table from C-C to C-F, in part because of higher metal-X bond dissociation energies. The formation of C-C, C-N, and C-O bonds via reductive elimination has become routine in the 20th century, but it took until the 21st century to develop complexes that could afford general C-F bond formation. The availability of such complexes enabled the substrate scope of modern fluorination chemistry to exceed that of conventional fluorination. PhenoFluor chemistry departs from conventional reaction mechanisms for aromatic fluorination chemistry. Instead, we have revealed a concerted nucleophilic aromatic substitution reaction (CSNAr) for PhenoFluor that proceeds through a single neutral four-membered transition state. Conceptually, PhenoFluor chemistry is therefore distinct from conventional SNAr chemistry, which typically proceeds through a two-barrier process with Meisenheimer complexes as reaction intermediates. As a consequence, PhenoFluor chemistry has a larger substrate scope than conventional SNAr chemistry and can be performed on arenes as electron rich as anilines. Moreover, PhenoFluor chemistry is tolerant of protic functional groups, which sets it apart from modern metal-mediated processes. Primary and secondary amines, alcohols, thiols, and phenols are often not tolerated under metal-catalyzed late-stage fluorination reactions because C-N and C-O reductive elimination can have lower activation barriers than C-F reductive elimination. The mechanism by which PhenoFluor chemistry forms C-F bonds not only rationalizes the substrate scope and functional group tolerance but also informs the side product profile. Fluorinated isomers are not observed because the four-membered transition state necessitates ipso substitution. In addition, no reduced product, e.g., H instead of F incorporation, as is often observed with metal-mediated methods, has ever been observed with PhenoFluor. PhenoFluor chemistry can be used to deoxyfluorinate both phenols and alcohols. PhenoFluor is an expensive reagent that must be used stoichiometrically and therefore cannot replace cost-efficient methods to make simple fluorinated molecules on a large scale. However, PhenoFluor is often successful when other fluorination methods fail. The synthesis of 18F-labeled molecules for positron emission tomography (PET) is one application of modern fluorination chemistry for which material throughput is not an issue because of the small quantities of PET tracers used in imaging (typically nanomoles). The high emphasis on functional group tolerance, side product profiles, and reliability combined with less stringent cost requirements render PhenoFluor-based deoxyfluorination with 18F promising for human PET imaging. PMID- 29120600 TI - Recoil Effect and Photoemission Splitting of Trions in Monolayer MoS2. AB - The 2D geometry nature and low dielectric constant in transition-metal dichalcogenides lead to easily formed strongly bound excitons and trions. Here, we studied the photoluminescence of van der Waals heterostructures of monolayer MoS2 and graphene at room temperature and observed two photoluminescence peaks that are associated with trion emission. Further study of different heterostructure configurations confirms that these two peaks are intrinsic to MoS2 and originate from a bound state and Fermi level, respectively, of which both accept recoiled electrons from trion recombination. We demonstrate that the recoil effect allows us to electrically control the photon energy of trion emission by adjusting the gate voltage. In addition, significant thermal smearing at room temperature results in capture of recoil electrons by bound states, creating photoemission peak at low doping level whose photon energy is less sensitive to gate voltage tuning. This discovery reveals an unexpected role of bound states for photoemission, where binding of recoil electrons becomes important. PMID- 29120601 TI - Light Responsive Silk Nanofibers: An Optochemical Platform for Environmental Applications. AB - Photochromic spiropyran-doped silk fibroin poly(ethylene oxide) nanofibers which combine the attractive properties and biocompatibility of silk with the photocontrollable and reversible optical, mechanical, and chemical response of the spiropyran dopants are herein presented. As proved, the reversible variation of the absorption and emission signals of the mats and of their Young's modulus upon alternate UV and visible light irradiation is ascribed to the reversible photoconversion of the spiropyran form to its polar merocyanine counterpart. Most importantly, the interactions of the merocyanine molecules with acidic vapors as well as with heavy metal ions dispersed in solution produce analyte-specific spectral changes in the emission profile of the composite, accompanied by a characteristic chromic variation. Because of the high surface-to-volume ratio of the nanofibrous network, such interactions are fast, thus enabling both an optical and a visual detection in a 30-60 s time scale. The sensing platform can be easily regenerated for more than 20 and 3 cycles upon acid or ion depletion, respectively. Overall, the photocontrolled properties of the silk composites combined with a straightforward preparation method render them suitable as porous materials and scaffolds with tunable compliance and reusable nanoprobes for real time optical detection in biomedical, environmental, and industrial applications. PMID- 29120603 TI - A High-Sensitivity, Integrated Absorbance and Fluorescence Detection Scheme for Probing Picoliter-Volume Droplets in Segmented Flows. AB - Droplet-based microfluidic systems that incorporate flowing streams of pL-volume droplets surrounded by a continuous and immiscible carrier phase have attracted significant recent attention due to their utility in complex chemical and biological experimentation. Analysis of pL droplets, generated at kHz frequencies and moving at high linear velocities, is almost exclusively achieved using fluorescence-based detection schemes. To extend the applicability of such optical detection schemes, we herein report the development of a simple and cost effective optofluidic platform, integrating liquid-core PDMS waveguides, that allows the accurate measurement of absorbance within individual pL-volume droplets moving within segmented flows. Using such an approach, differential measurements of "sample "and "reference" droplets can be acquired at 1 kHz and yield detection limits of 400 nM for fluorescein in water. Significantly, the presented technique enables simultaneous fluorescence and absorbance interrogation of rapidly moving droplets in a fully automated manner. Proof of principle is demonstrated through the titration and monitoring of pH gradients in real time. PMID- 29120604 TI - Molecular Determinants for Substrate Interactions with the Glycine Transporter GlyT2. AB - Transporters in the SLC6 family play key roles in regulating neurotransmission and are the targets for a wide range of therapeutics. Important insights into the transport mechanisms and the specificity of drug interactions of SLC6 transporters have been obtained from the crystal structures of a bacterial homologue of the family, LeuTAa, and more recently the Drosophila dopamine transporter and the human serotonin transporter. However, there is disputed evidence that the bacterial leucine transporter, LeuTAa, contains two substrate binding sites that work cooperatively in the mechanism of transport, with the binding of a second substrate being required for the release of the substrate from the primary site. An alternate proposal is that there may be low affinity binding sites that serve to direct the flow of substrates to the primary site. We have used a combination of molecular dynamics simulations of substrate interactions with a homology model of GlyT2, together with radiolabeled amino acid uptake assays and electrophysiological analysis of wild-type and mutant transporters, to provide evidence that substrate selectivity of GlyT2 is determined entirely by the primary substrate binding site and, furthermore, if a secondary site exists then it is a low affinity nonselective amino acid binding site. PMID- 29120602 TI - Porphyrin-Assisted Docking of a Thermophage Portal Protein into Lipid Bilayers: Nanopore Engineering and Characterization. AB - Nanopore-based sensors for nucleic acid sequencing and single-molecule detection typically employ pore-forming membrane proteins with hydrophobic external surfaces, suitable for insertion into a lipid bilayer. In contrast, hydrophilic pore-containing molecules, such as DNA origami, have been shown to require chemical modification to favor insertion into a lipid environment. In this work, we describe a strategy for inserting polar proteins with an inner pore into lipid membranes, focusing here on a circular 12-subunit assembly of the thermophage G20c portal protein. X-ray crystallography, electron microscopy, molecular dynamics, and thermal/chaotrope denaturation experiments all find the G20c portal protein to have a highly stable structure, favorable for nanopore sensing applications. Porphyrin conjugation to a cysteine mutant in the protein facilitates the protein's insertion into lipid bilayers, allowing us to probe ion transport through the pore. Finally, we probed the portal interior size and shape using a series of cyclodextrins of varying sizes, revealing asymmetric transport that possibly originates from the portal's DNA-ratchet function. PMID- 29120605 TI - Targeting Heat Shock Protein 70 to Ameliorate c-Jun Expression and Improve Demyelinating Neuropathy. AB - Increased expression of the c-jun transcription factor occurs in a variety of human neuropathies and is critical in promoting Schwann cell (SC) dedifferentiation and loss of the myelinated phenotype. Using cell culture models, we previously identified KU-32 as a novobiocin-based C-terminal heat shock protein 90 (Hsp90) inhibitor that decreased c-jun expression and the extent of demyelination. Additional chemical optimization has yielded KU-596 as a neuroprotective novologue whose mechanistic efficacy to improve a metabolic neuropathy requires the expression of Hsp70. The current study examined whether KU-596 therapy could decrease c-jun expression and improve motor function in an inducible transgenic model of a SC-specific demyelinating neuropathy (MPZ-Raf mice). Treating MPZ-Raf mice with tamoxifen activates the MAPK kinase pathway, increases c-jun expression and produces a profound demyelinating neuropathy characterized by a loss of motor function and paraparesis. KU-596 therapy did not interfere with MAPK activation but reduced c-jun expression, significantly improved motor performance, and ameliorated the extent of peripheral nerve demyelination in both prevention and intervention studies. Hsp70 was necessary for the drug's neuroprotective efficacy since MPZ-Raf * Hsp70 knockout mice did not respond to KU-596 therapy. Collectively, our data indicate that modulating Hsp70 may provide a novel therapeutic approach to attenuate SC c-jun expression and ameliorate the onset of certain demyelinating neuropathies in humans. PMID- 29120606 TI - Management of Respiratory Infections with Use of Procalcitonin: Moving toward More Personalized Antibiotic Treatment Decisions. AB - Due to overlap of clinical findings and low sensitivity of bacterial diagnostic tests, differentiation between bacterial and viral respiratory tract infections remains challenging, ultimately leading to antibiotic overuse in this population of patients. Addition of procalcitonin, a blood biomarker expressed by epithelial cells in response to bacterial infections, to the clinical assessment leads to a reduction in inappropriate antibiotic initiation. Procalcitonin also provides prognostic information about the resolution of illness, and significant decreases over time are a strong signal for the discontinuation of antibiotics. Current evidence from randomized trials indicates that procalcitonin-guided antibiotic stewardship results in a reduction in antibiotic use and antibiotic side effects, which importantly translates into improved survival of patients with respiratory infections. Inclusion of procalcitonin into antibiotic stewardship algorithms thus improves the diagnostic and therapeutic management of patients presenting with respiratory illnesses and holds great promise to mitigate the global bacterial resistance crisis. PMID- 29120607 TI - The Emergence of Manganese-Based Carbonyl Hydrosilylation Catalysts. AB - In recent years, interest in homogeneous manganese catalyst development has intensified because of the earth-abundant and nontoxic nature of this metal. Although compounds of Mn have largely been utilized for epoxidation reactions, recent efforts have revealed that Mn catalysts can mediate a broad range of reductive transformations. Low-valent Mn compounds have proven to be particularly effective for the hydrosilylation of carbonyl- and carboxylate-containing substrates, and this Account aims to highlight my research group's contributions to this field. In our initial 2014 communication, we reported that the bis(imino)pyridine-supported compound (Ph2PPrPDI)Mn mediates ketone hydrosilylation with exceptional activity under solvent-free conditions. Silanes including Ph2SiH2, (EtO)3SiH, (EtO)2MeSiH, and (EtO)Me2SiH were found to partially reduce cyclohexanone in the presence of (Ph2PPrPDI)Mn, while turnover frequencies of up to 1280 min-1 were observed using PhSiH3. This led us to evaluate the hydrosilylation of 11 additional ketones and allowed for the atom efficient preparation of tertiary and quaternary silanes. At that time, it was also discovered that (Ph2PPrPDI)Mn catalyzes the dihydrosilylation of esters (by way of acyl C-O bond hydrosilylation) to yield a mixture of silyl ethers with modest activity. Earlier this year, the scope of these transformations was extended to aldehydes and formates, and the observed hydrosilylation activities are among the highest obtained for any transition-metal catalyst. The effectiveness of three related catalysts has also been evaluated: (Ph2PPrPDI)MnH, (PyEtPDEA)Mn, and [(Ph2PEtPDI)Mn]2. To our surprise, (Ph2PPrPDI)MnH was found to exhibit higher carboxylate dihydrosilylation activity than (Ph2PPrPDI)Mn, while (PyEtPDEA)Mn demonstrated remarkable carbonyl hydrosilylation activity considering that it lacks a redox-active supporting ligand. The evaluation of [(Ph2PEtPDI)Mn]2 revealed competitive aldehyde hydrosilylation and formate dihydrosilylation turnover frequencies; however, this catalyst is significantly inhibited by pyridine and alkene donor groups. In our efforts to fully understand how (Ph2PPrPDI)Mn operates, a thorough electronic structure evaluation was conducted, and the ground-state doublet calculated for this compound was found to exhibit nonclassical features consistent with a low-spin Mn(II) center supported by a singlet PDI dianion and an intermediate-spin Mn(II) configuration featuring antiferromagnetic coupling to PDI diradical dianion. A comprehensive mechanistic investigation of (Ph2PPrPDI)Mn- and (Ph2PPrPDI)MnH-mediated hydrosilylation has revealed two operable pathways, a modified Ojima pathway that is more active for carbonyl hydrosilylation and an insertion pathway that is more effective for carboxylate reduction. Although these efforts represent a small fraction of the recent advances made in Mn catalysis, this work has proven to be influential for the development of Mn-based reduction catalysts and is likely to inform future efforts to develop Mn catalysts that can be used to prepare silicones. PMID- 29120608 TI - Biochemical Gas Sensors (Biosniffers) Using Forward and Reverse Reactions of Secondary Alcohol Dehydrogenase for Breath Isopropanol and Acetone as Potential Volatile Biomarkers of Diabetes Mellitus. AB - This study describes two biosniffers to determine breath acetone and isopropanol (IPA) levels and applies them for breath measurement in healthy subjects and diabetic patients. Secondary alcohol dehydrogenase (S-ADH) can reduce acetone and oxidize nicotinamide adenine dinucleotide (NADH to NAD+) in a weak acid environment. NADH can be excited by 340 nm excitation lights and subsequently emit 490 nm fluorescence. Therefore, acetone can be measured by the decrease in NADH fluorescence intensity. S-ADH can also oxidize IPA and reduce NAD+ to NADH when it is in an alkaline environment. Thus, IPA can be detected by the increase of fluorescence. The developed biosniffers show rapid response, high sensitivity and high selectivity. The breath acetone and IPA analysis in healthy subjects shows that the mean values were 750.0 +/- 434.4 ppb and 15.4 +/- 11.3 ppb. Both acetone and IPA did not show a statistical difference among different genders and ages. The breath acetone analysis for diabetic patients shows a mean value of 1207.7 +/- 689.5 ppb, which was higher than that of healthy subjects (p < 1 * 10 6). In particularly, type-1 diabetic (T1D) patients exhaled a much higher concentration of acetone than type-2 diabetic (T2D) patients (p < 0.01). The breath IPA also had a higher concentration in diabetic patients (23.1 +/- 20.1 ppb, p < 0.01), but only T2D patients presented a statistical difference (23.9 +/ 21.3 ppb, p < 0.01). These findings are worthwhile in the study of breath biomarkers for diabetes mellitus diagnosis. Additionally, the developed biosniffers provide a new technique for volatolomics research. PMID- 29120609 TI - In Situ Carbon Isotope Analysis by Laser Ablation MC-ICP-MS. AB - Carbon isotopes have been widely used in tracing a wide variety of geological and environmental processes. The carbon isotope composition of bulk rocks and minerals was conventionally analyzed by isotope ratio mass spectrometry (IRMS), and, more recently, secondary ionization mass spectrometry (SIMS) has been widely used to determine carbon isotope composition of carbon-bearing solid materials with good spatial resolution. Here, we present a new method that couples a RESOlution S155 193 nm laser ablation system with a Nu Plasma II MC-ICP-MS, with the aim of measuring carbon isotopes in situ in carbonate minerals (i.e., calcite and aragonite). Under routine operating conditions for delta13C analysis, instrumental bias generally drifts by 0.80/00-2.00/00 in a typical analytical session of 2-3 h. Using a magmatic calcite as the standard, the carbon isotopic composition was determined for a suite of calcite samples with delta13C values in the range of -6.940/00 to 1.480/00. The obtained delta13C data are comparable to IRMS values. The combined standard uncertainty for magmatic calcite is <0.30/00 (1s). No significant matrix effects have been identified in calcite with the amplitude of chemical composition variation (i.e., MnO, SrO, MgO, or FeO) up to 2.5 wt %. Two modern corals were investigated using magmatic calcite as the calibration standard, and the average delta13C values for both corals are similar to the bulk IRMS values. Moreover, coral exhibits significant heterogeneity in carbon isotope compositions, with differences up to 4.850/00 within an individual coral. This study indicates that LA-MC-ICP-MS can serve as an appropriate method to analyze carbon isotopes of carbonate minerals in situ. PMID- 29120610 TI - Strategic Materials in the Automobile: A Comprehensive Assessment of Strategic and Minor Metals Use in Passenger Cars and Light Trucks. AB - A comprehensive component-level assessment of several strategic and minor metals (SaMMs), including copper, manganese, magnesium, nickel, tin, niobium, light rare earth elements (LREEs; lanthanum, cerium, praseodymium, neodymium, promethium, and samarium), cobalt, silver, tungsten, heavy rare earth elements (yttrium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium), and gold, use in the 2013 model year Ford Fiesta, Focus, Fusion, and F-150 is presented. Representative material contents in cars and light-duty trucks are estimated using comprehensive, component-level data reported by suppliers. Statistical methods are used to accommodate possible errors within the database and provide estimate bounds. Results indicate that there is a high degree of variability in SaMM use and that SaMMs are concentrated in electrical, drivetrain, and suspension subsystems. Results suggest that trucks contain greater amounts of aluminum, nickel, niobium, and silver and significantly greater amounts of magnesium, manganese, gold, and LREEs. We find tin and tungsten use in automobiles to be 3-5 times higher than reported by previous studies which have focused on automotive electronics. Automotive use of strategic and minor metals is substantial, with 2013 vehicle production in the United States, Canada, EU15, and Japan alone accounting for approximately 20% of global production of Mg and Ta and approximately 5% of Al, Cu, and Sn. The data and analysis provide researchers, recyclers, and decision-makers additional insight into the vehicle content of strategic and minor metals of current interest. PMID- 29120611 TI - Bulk Kosterlitz-Thouless Type Molecular Superconductor beta"-(BEDT TTF)2[(H2O)(NH4)2Cr(C2O4)3].18-crown-6. AB - A new molecular superconductor, beta"-(BEDT-TTF)2[(H2O)(NH4)2Cr(C2O4)3].18-crown 6, has been synthesized from the organic donor molecule BEDT-TTF with the anion Cr(C2O4)33-. The crystal structure consists of conducting organic layers of BEDT TTF molecules which adopt the beta" packing motif (layer A), layers of NH4+ and Lambda-Cr(C2O4)33- (layer B), layers of (H2O)(NH4)18-crown-6 (layer C), and layers of NH4+ and Delta-Cr(C2O4)33- (layer D) which produce a superstructure with a repeating pattern of ABCDABCDA. As a result of this packing arrangement, this is the 2D superconductor with the widest gap between conducting layers where only a single donor packing motif is present (beta"). Superconducting critical temperatures at ambient pressure observed by electrical transport and magnetic measurements are 4.0-4.9 and 2.5 K, respectively. The strong 2D nature of this system, the broad transition to Tzero at 1.8K, and the transition of alpha of V ? Ialpha from 1 to 3 on I-V curves strongly suggest that the superconducting transition is very close to a Kosterlitz-Thouless transition. The magnetic field dependence of the superconducting critical temperature parallel to the conducting plane gives an upper critical field MU0Hc2? > 8 T, which is over the calculated Pauli-Clogston limit for this material. PMID- 29120612 TI - Cell-Free and In Vivo Characterization of Lux, Las, and Rpa Quorum Activation Systems in E. coli. AB - Synthetic biologists have turned toward quorum systems as a path for building sophisticated microbial consortia that exhibit group decision making. Currently, however, even the most complex consortium circuits rely on only one or two quorum sensing systems, greatly restricting the available design space. High-throughput characterization of available quorum sensing systems is useful for finding compatible sets of systems that are suitable for a defined circuit architecture. Recently, cell-free systems have gained popularity as a test-bed for rapid prototyping of genetic circuitry. We take advantage of the transcription translation cell-free system to characterize three commonly used Lux-type quorum activators, Lux, Las, and Rpa. We then compare the cell-free characterization to results obtained in vivo. We find significant genetic crosstalk in both the Las and Rpa systems and substantial signal crosstalk in Lux activation. We show that cell-free characterization predicts crosstalk observed in vivo. PMID- 29120613 TI - Formularity: Software for Automated Formula Assignment of Natural and Other Organic Matter from Ultrahigh-Resolution Mass Spectra. AB - Ultrahigh resolution mass spectrometry, such as Fourier transform ion cyclotron resonance mass spectrometry (FT ICR MS), can resolve thousands of molecular ions in complex organic matrices. A Compound Identification Algorithm (CIA) was previously developed for automated elemental formula assignment for natural organic matter (NOM). In this work, we describe software Formularity with a user friendly interface for CIA function and newly developed search function Isotopic Pattern Algorithm (IPA). While CIA assigns elemental formulas for compounds containing C, H, O, N, S, and P, IPA is capable of assigning formulas for compounds containing other elements. We used halogenated organic compounds (HOC), a chemical class that is ubiquitous in nature as well as anthropogenic systems, as an example to demonstrate the capability of Formularity with IPA. A HOC standard mix was used to evaluate the identification confidence of IPA. Tap water and HOC spike in Suwannee River NOM were used to assess HOC identification in complex environmental samples. Strategies for reconciliation of CIA and IPA assignments were discussed. Software and sample databases with documentation are freely available. PMID- 29120614 TI - Connecting the Elementary Reaction Pathways of Criegee Intermediates to the Chemical Erosion of Squalene Interfaces during Ozonolysis. AB - Criegee intermediates (CI), formed in alkene ozonolysis, are central for controlling the multiphase chemistry of organic molecules in both indoor and outdoor environments. Here, we examine the heterogeneous ozonolysis of squalene, a key species in indoor air chemistry. Aerosol mass spectrometry is used to investigate how the ozone (O3) concentration, relative humidity (RH), and particle size control reaction rates and mechanisms. Although the reaction rate is found to be independent of RH, the reaction products and particle size depend upon H2O. Under dry conditions (RH = 3%) the reaction produces high-molecular weight secondary ozonides (SOZ), which are known skin irritants, and a modest change in particle size. Increasing the RH reduces the aerosol size by 30%, while producing mainly volatile aldehyde products, increases potential respiratory exposure. Chemical kinetics simulations link the elementary reactions steps of CI to the observed kinetics, product distributions, and changes in particle size. The simulations reveal that ozonolysis occurs near the surface and is O3 transport limited. The observed secondary ozonides are consistent with the formation of mainly secondary CI, in contrast to gas-phase ozonolysis mechanisms. PMID- 29120615 TI - Acentric La3(IO3)8(OH) and La(IO3)2(NO3): Partial Substitution of Iodate Anions in La(IO3)3 by Hydroxide or Nitrate Anion. AB - Partial substitution of iodate anions in La(IO3)3 by OH- or NO3- anion led to acentric La3(IO3)8(OH) and chiral La(IO3)2(NO3). The structure of La3(IO3)8(OH) can be seen as a complex three-dimensional (3D) network composed of two dimensional [La3(IO3)2(OH)]6+ cationic layers that are further bridged by remaining iodate anions, or alternatively as a 3D network composed of one dimensional [La3(IO3)6(OH)]2+ cationic columns being further interconnected by additional iodate anions, while the structure of La(IO3)2(NO3) can be seen as a novel 3D structure with planar NO3 groups serving as linkage between the [La3(IO3)6]3+ triple layers. Compared to La(IO3)3, both compounds show considerably wide band gaps and enhanced thermal stability. La(IO3)2(NO3) shows a moderate second harmonic generation (SHG) response of ~0.6 times that of KDP (KH2PO4), a wide band gap of 4.23 eV, and a high LDT value (22 * AgGaS2). Optical property measurements, thermal analysis, as well as theoretical calculations on SHG origin, were performed. It can be deduced that partial substitution of iodate anions can be a facile route to design new noncentrosymmetric metal iodates with novel structure and potential application. PMID- 29120616 TI - Redox Noninnocent Azo-Aromatic Pincers and Their Iron Complexes. Isolation, Characterization, and Catalytic Alcohol Oxidation. AB - The new redox-noninnocent azoaromatic pincers 2-(arylazo)-1,10-phenanthroline (L1) and 2,9-bis(phenyldiazo)-1,10-phenanthroline (L2) are reported. The ligand L1 is a tridentate pincer having NNN donor atoms, whereas L2 is tetradentate having two azo-N donors and two N-donor atoms from the 1,10-phenanthroline moiety. Reaction of FeCl2 with L1 or L2 produced the pentacoordinated mixed ligand Fe(II) complexes FeL1Cl2 (1) and FeL2Cl2 (2), respectively. Homoleptic octahedral Fe(II) complexes, mer-[Fe(L1)2](ClO4)2 [3](ClO4)2 and mer [Fe(L2)2](ClO4)2 [4](ClO4)2, have been synthesized from the reaction of hydrated Fe(ClO4)2 and L1 or L2. The ligand L2, although having four donor sites available for coordination, binds the iron center in a tridentate fashion with one uncoordinated pendant azo function. Molecular and electronic structures of the isolated complexes have been scrutinized thoroughly by various spectroscopic techniques, single-crystal X-ray crystallography, and density functional theory. Beyond mere characterization, complexes 1 and 2 were successfully used as catalysts for the aerobic oxidation of primary and secondary benzylic alcohols. A wide variety of substituted benzyl alcohols were found to be converted to the corresponding carbonyl compounds in high yields, catalyzed by complex 1. Several control reactions were carried out to understand the mechanism of this alcohol oxidation reactions. PMID- 29120617 TI - Live Visualization of HIV-1 Proviral DNA Using a Dual-Color-Labeled CRISPR System. AB - HIV latency is one of the major problems in HIV/AIDS cure. Imaging single-copy integrated proviral HIV DNA in host cell has both virology and clinical significance but remains technical challenge. Here, we developed a dual-color labeled CRISPR system to image the HIV-1 integrated proviral DNA in latently infected cells. The pair of CRISPRs was fluorescently labeled with two different color QDs using two alternative bioorthogonal ligation reactions. Integrated HIV sequences are successfully mapped based on the colocalized signals of QDs in living cells. Compared to the existing zinc finger proteins and TALENs, the CRISPR system is much easier to operate and more efficient in imaging of internal genomic loci. Therefore, the proposed method could be not only a powerful tool for imaging proviral HIV-1, but also a versatile platform to image single genomic loci in living cells. PMID- 29120618 TI - Comment on "Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches". PMID- 29120620 TI - Limits in Size of Taylor Dispersion Analysis: Representation of the Different Hydrodynamic Regimes and Application to the Size-Characterization of Cubosomes. AB - Taylor dispersion analysis (TDA) is an absolute method (no calibration needed) for the determination of the molecular diffusion coefficient (D) based on the band broadening of a solute in a laminar flow. TDA is virtually applicable to any solute with size ranging from angstrom to sub-micrometer. The higher sizing limit is restricted by the occurrence of possibly two regimes: convective and hydrodynamic chromatography (HDC) regimes, which have different physical origins that should not be confused. This work aims at clearly defining the experimental conditions for which these two regimes can play a role, alone or concomitantly. It also calculates the relative error on D due to the HDC regime according to the solute to capillary size ratio. It is demonstrated in this work that HDC does not significantly affect the TDA measurement as long as the hydrodynamic radius of the solute is lower than 0.0051 times the capillary radius. Experimental illustrations of the occurrence of the two regimes are given taking polystyrene nanoparticles as model solutes. Finally, application of TDA to the sizing of large real-life solutes is proposed, taking cubosomes as new drug nanocarriers of potential interest for drug delivery purposes. PMID- 29120621 TI - Chemical Substitution-Induced and Competitive Formation of 6H and 3C Perovskite Structures in Ba3-xSrxZnSb2O9: The Coexistence of Two Perovskites in 0.3 <= x <= 1.0. AB - 6H and 3C perovskites are important prototype structures in materials science. We systemically studied the structural evolution induced by the Sr2+-to-Ba2+ substitution to the parent 6H perovskite Ba3ZnSb2O9. The 6H perovskite is only stable in the narrow range of x <= 0.2, which attributes to the impressibility of [Sb2O9]. The preference of 90 degrees Sb-O-Sb connection and the strong Sb5+ Sb5+ electrostatic repulsion in [Sb2O9] are competitive factors to stabilize or destabilize the 6H structure when chemical pressure was introduced by Sr2+ incorporation. Therefore, in the following, a wide two-phase region containing 1:2 ordered 6H-Ba2.8Sr0.2ZnSb2O9 and rock-salt ordered 3C-Ba2SrZnSb2O9 was observed (0.3 <= x <= 1.0). In the final, the successive symmetry descending was established from cubic (Fm3m, 1.3 <= x <= 1.8) to tetragonal (I4/m, 2.0 <= x <= 2.4), and finally to monoclinic (I2/m, 2.6 <= x <= 3.0). Here we proved that the electronic configurations of B-site cations, with either empty, partially, or fully filled d-shell, would also affect the structure stabilization, through the orientation preference of the B-O covalent bonding. Our investigation gives a deeper understanding of the factors to the competitive formation of perovskite structures, facilitating the fine manipulation on their physical properties. PMID- 29120619 TI - A Rapid Throughput Method To Extract DNA from Formalin-Fixed Paraffin-Embedded Tissues for Biomonitoring Carcinogenic DNA Adducts. AB - Formalin-fixed paraffin-embedded (FFPE) tissues are rarely used for screening DNA adducts of carcinogens because the harsh conditions required to reverse the formaldehyde-mediated DNA cross-links can destroy DNA adducts. We recently adapted a commercial silica-based column kit used in genomics to manually isolate DNA under mild conditions from FFPE tissues of rodents and humans and successfully measured DNA adducts of several carcinogens including aristolochic acid I (AA-I), 4-aminobiphenyl (4-ABP), and 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP) (Yun et al. (2013) Anal. Chem. 85, 4251-8, and Guo et al. (2016) Anal. Chem. 88, 4780-7). The DNA retrieval methodology is robust; however, the procedure is time-consuming and labor intensive, and not amenable to rapid throughput processing. In this study, we have employed the Promega Maxwell 16 MDx system, which is commonly used in large scale genomics studies, for the rapid throughput extraction of DNA. This system streamlines the DNA isolation procedure and increases the sample processing rate by about 8-fold over the manual method (32 samples versus 4 samples processed per hour). High purity DNA is obtained in satisfactory yield for the measurements of DNA adducts by ultra performance liquid chromatography-electrospray-ionization-ion trap-multistage scan mass spectrometry. The measurements show that the levels of DNA adducts of AA-I, 4 ABP, and PhIP in FFPE rodent and human tissues are comparable to those levels measured in DNA from matching tissues isolated by the commercial silica-based column kits and in DNA from fresh frozen tissues isolated by the conventional phenol-chloroform extraction method. The isolation of DNA from tissues is one major bottleneck in the analysis of DNA adducts. This rapid throughput methodology greatly decreases the time required to process DNA and can be employed in large-scale epidemiology studies designed to assess the role of chemical exposures and DNA adducts in cancer risk. PMID- 29120622 TI - Response to "Comment on 'Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches'". PMID- 29120623 TI - Aptamer-Based ELISA Assay for Highly Specific and Sensitive Detection of Zika NS1 Protein. AB - We report here a few Zika NS1-binding ssDNA aptamers selected using the conventional SELEX protocol, and their application in an ELISA assay for sensitive diagnosis of Zika NS1 protein. Among the aptamers identified, aptamers 2 and 10 could recognize different binding epitopes of Zika NS1 protein. This complementary in binding site, when coupled with an extraordinarily high binding affinity by 2 (41-nt, KD = 45 pM) and high specificity by 10, was used successfully to construct an ELISA-based assay where 2 and 10 serve as the capture and detection agents, respectively, giving rise to a highly specific detection of Zika NS1 with a detection limit of 100 ng/mL in buffer. Further testing of a few in-house anti-Zika NS1 antibodies show that 2 could also pair with an anti-Zika NS1 antibody. Such aptamer-antibody pairing not only lowers the detection sensitivity by 3 orders of magnitude to 0.1 ng/mL in buffer but also enable highly sensitive detection of as low as 1 and 10 ng/mL of Zika NS1 to be carried out in 10% and 100% human serum, respectively. These results suggest that the selected aptamers would be useful for medical diagnosis of Zika virus infection in various aptamer-based diagnostic devices including ELISA assay. PMID- 29120624 TI - Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases. AB - The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4 dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO 4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing). PMID- 29120625 TI - Accurate and Reliable Prediction of the Binding Affinities of Macrocycles to Their Protein Targets. AB - Macrocycles have been emerging as a very important drug class in the past few decades largely due to their expanded chemical diversity benefiting from advances in synthetic methods. Macrocyclization has been recognized as an effective way to restrict the conformational space of acyclic small molecule inhibitors with the hope of improving potency, selectivity, and metabolic stability. Because of their relatively larger size as compared to typical small molecule drugs and the complexity of the structures, efficient sampling of the accessible macrocycle conformational space and accurate prediction of their binding affinities to their target protein receptors poses a great challenge of central importance in computational macrocycle drug design. In this article, we present a novel method for relative binding free energy calculations between macrocycles with different ring sizes and between the macrocycles and their corresponding acyclic counterparts. We have applied the method to seven pharmaceutically interesting data sets taken from recent drug discovery projects including 33 macrocyclic ligands covering a diverse chemical space. The predicted binding free energies are in good agreement with experimental data with an overall root-mean-square error (RMSE) of 0.94 kcal/mol. This is to our knowledge the first time where the free energy of the macrocyclization of linear molecules has been directly calculated with rigorous physics-based free energy calculation methods, and we anticipate the outstanding accuracy demonstrated here across a broad range of target classes may have significant implications for macrocycle drug discovery. PMID- 29120626 TI - Specific Inhibition of Bacterial beta-Glucuronidase by Pyrazolo[4,3-c]quinoline Derivatives via a pH-Dependent Manner To Suppress Chemotherapy-Induced Intestinal Toxicity. AB - The direct inhibition of bacterial beta-glucuronidase (betaG) activity is expected to reduce the reactivation of glucuronide-conjugated drugs in the intestine, thereby reducing drug toxicity. In this study, we report on the effects of pyrazolo[4,3-c]quinolines acting as a new class of bacterial betaG specific inhibitors in a pH-dependent manner. Refinement of this chemotype for establishing structure-activity relationship resulted in the identification of potential leads. Notably, the oral administration of 3-amino-4-(4 fluorophenylamino)-1H-pyrazolo[4,3-c]quinoline (42) combined with chemotherapeutic CPT-11 treatment prevented CPT-11-induced serious diarrhea while maintaining the antitumor efficacy in tumor-bearing mice. Importantly, the inhibitory effects of 42 to E. coli betaG was reduced as the pH decreased due to the various surface charges of the active pocket of the enzyme, which may make their combination more favorable at neutral pH. These results demonstrate novel insights into the potent bacterial betaG-specific inhibitor that would allow this inhibitor to be used for the purpose of reducing drug toxicity. PMID- 29120627 TI - Thermal Iodine Loss Cascade of W5I16. AB - Tungsten iodide compounds feature a surprising diversity of binary compounds. Their formation conditions and phase equilibria depend very much on the surrounding iodine partial pressure and temperature. Herein we focus on square pyramidal tungsten iodide cluster compounds with their iodine loss, structural rearrangements, cross-linking behavior, and final transformation into the octahedral cluster compound beta-W6I12 at elevated temperatures. Reactions depart from W5I16 at different iodine pressures and temperatures. The thermal decomposition of W5I16 at low iodine pressure passes through a number of cluster compounds (W5I15, W5I13.xI2, beta-W5I12, and W5I11) under release of iodine. At higher iodine pressures, only one intermediate compound (alpha-W5I12) was found. Thermal decomposition of W5I16 was examined by differential thermal/thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction (XRD) measurements. New compounds (W5I15, W5I13.xI2, and W5I11) were structurally characterized by means of XRD techniques. The crystal structure of W5I11 reveals a nice relationship to its transformation product W6I12. PMID- 29120628 TI - Cation-Pi Interaction: A Key Force for Sorption of Fluoroquinolone Antibiotics on Pyrogenic Carbonaceous Materials. AB - Cation-pi attraction is a major force that determines macromolecular structures and drug-receptor interactions. However, the role of the cation-pi interaction in sorption of fluoroquinolone antibiotics by pyrogenic carbonaceous materials (PCMs) has not been addressed. We studied sorption of ciprofloxacin (CIP) on graphite to quantify the contribution of the cation-pi interaction. Through competition experiments, the decreased amount of sorbed CIP by sequential treatment with hexadecane, phenanthrene and benzylamine represents the contribution of hydrophobic, pi-pi and cation-pi interactions, respectively. Benzylamine competed more strongly with CIP than n-hexadecane and phenanthrene, indicating that cation-pi is a major force. Cation-pi interactions accounted for up to 72.6% of the total sorption at an initial CIP concentration of 0.000015 mmol/L. Importantly, species transformation (CIP(0) captures H+ from water to form CIP(+1)) induced by cation-pi interactions was verified both experimentally and theoretically and can be used to explain the environmental behavior of other fluoroquinolone antibiotics and biochemical processes of amino acids that interact with aromatic moieties. Because of the significant role of cation-pi interactions, CIP desorption increased up to 2.32 times when Na+ increased from 0.01 mM to 0.45 mM, which is an environmentally relevant scenario at river estuaries. Hence, behaviors of fluoroquinolone antibiotics that are affected by ionic strength changes need to be carefully evaluated, especially in river estuaries. PMID- 29120630 TI - How Well Can Implicit Solvent Simulations Explore Folding Pathways? A Quantitative Analysis of alpha-Helix Bundle Proteins. AB - Protein folding has been posing challenges for molecular simulation for decades. Implicit solvent models are sought as routes to increase the capability of simulation, with trade-offs between computational speed and accuracy. Here, we systematically investigate the folding of a variety of alpha-helix bundle proteins ranging in size from 46 to 102 amino acids using a state-of-the-art force field and an implicit solvent model. The accurate all-atom simulated folding is enabled for six proteins, including for the first time a successful folding of protein with >100 amino acids in implicit solvent. The detailed free energy landscape analysis sheds light on a set of general principles underlying the folding of alpha-helix bundle proteins, suggesting a hybrid framework/nucleation-condensation mechanism favorably adopted in implicit solvent condition. The similarities and discrepancies of the folding pathways measured among the present implicit solvent simulations and previously reported experiments and explicit solvent simulations are deeply analyzed, providing quantitative assessment for the availability and limitation of implicit solvent simulation in exploring the folding transition of large-size proteins. PMID- 29120629 TI - Catalytic Enantioselective Hetero-dimerization of Acrylates and 1,3-Dienes. AB - 1,3-Dienes are ubiquitous and easily synthesized starting materials for organic synthesis, and alkyl acrylates are among the most abundant and cheapest feedstock carbon sources. A practical, highly enantioselective union of these two readily available precursors giving valuable, enantio-pure skipped 1,4-diene esters (with two configurationally defined double bonds) is reported. The process uses commercially available cobalt salts and chiral ligands. As illustrated by the use of 20 different substrates, including 17 prochiral 1,3-dienes and 3 acrylates, this hetero-dimerization reaction is tolerant of a number of common organic functional groups (e.g., aromatic substituents, halides, isolated mono- and di substituted double bonds, esters, silyl ethers, and silyl enol ethers). The novel results including ligand, counterion, and solvent effects uncovered during the course of these investigations show a unique role of a possible cationic Co(I) intermediate in these reactions. The rational evolution of a mechanism-based strategy that led to the eventual successful outcome and the attendant support studies may have further implications for the expanding use of low-valent group 9 metal complexes in organic synthesis. PMID- 29120631 TI - Experimental and Computational Thermochemical Study of Maleic Anhydride and Vinylene Carbonate. AB - The standard molar enthalpies of formation of maleic anhydride and vinylene carbonate in gaseous phase, at T = 298.15 K, were derived from the standard molar enthalpies of formation of the compounds in condensed phase combined with the phase transition enthalpies. The standard molar enthalpies of formation in condensed phase were obtained from the enthalpies of combustion measured using static bomb combustion calorimetry and mini-bomb combustion calorimetry for vinylene carbonate and maleic anhydride, respectively. Phase transition enthalpies were obtained by Calvet microcalorimetry. High level quantum calculations were performed at the composite G3 level of theory in order to estimate the standard molar enthalpies of formation of both compounds in gaseous phase. Good agreement was obtained between experimental and computational results. In addition, analysis of the factors affecting the relative stability of both systems has been carried out in the framework of the ab initio valence bond (VB) theory in order to clarify the aromaticity/antiaromaticity issues involving these molecular systems. PMID- 29120632 TI - Implicit Solvation Using the Superposition Approximation (IS-SPA): An Implicit Treatment of the Nonpolar Component to Solvation for Simulating Molecular Aggregation. AB - Nonpolar solute-solvent interactions are the driving force for aggregation in important chemical and biological phenomena including protein folding, peptide self-assembly, and oil-water emulsion formation. Currently, the most accurate and computationally efficient description of these processes requires an explicit treatment of all solvent and solute atoms. Previous computationally feasible implicit solvent models, such as solute surface area approaches, are unsuccessful at capturing aggregation features including both structural and energetic trends while more theoretically rigorous approaches, such as Reference Interaction Site Model (RISM), are accurate but extremely computationally demanding. Our approach, denoted Implicit Solvation using the Superposition Approximation (IS-SPA), builds on previous theory utilizing the Kirkwood superposition approximation to approximate the mean force of the solvent from solute parameters. We introduce and verify a parabolic first solvation shell truncation of atomic solvation, fitting water distributions around a molecule, and a Monte Carlo integration of the mean solvent force. These extensions allow this method to be implemented as an efficient nonpolar implicit solvent model for molecular simulation. The approximations in IS-SPA are first explored and justified for the homodimerization of an array of different sized Lennard-Jones spheres. The accuracy and transferability of the approach are demonstrated by its ability to capture the position and relative energies of the desolvation barrier and free energy minimum of alkane homodimers. The model is then shown to reproduce the phase separation and solubility of cyclohexane and water. These promising results, coupled with 2 orders of magnitude speed-up for dilute systems as compared to explicit solvent simulations, demonstrate that IS-SPA is an appealing approach to boost the time- and length-scale of molecular aggregation simulations. PMID- 29120633 TI - Neural Network Based Prediction of Conformational Free Energies - A New Route toward Coarse-Grained Simulation Models. AB - Coarse-grained (CG) simulation models have become very popular tools to study complex molecular systems with great computational efficiency on length and time scales that are inaccessible to simulations at atomistic resolution. In so-called bottom-up coarse-graining strategies, the interactions in the CG model are devised such that an accurate representation of an atomistic sampling of configurational phase space is achieved. This means the coarse-graining methods use the underlying multibody potential of mean force (i.e., free-energy surface) derived from the atomistic simulation as parametrization target. Here, we present a new method where a neural network (NN) is used to extract high-dimensional free energy surfaces (FES) from molecular dynamics (MD) simulation trajectories. These FES are used for simulations on a CG level of resolution. The method is applied to simulating homo-oligo-peptides (oligo-glutamic-acid (oligo-glu) and oligo aspartic-acid (oligo-asp)) of different lengths. We show that the NN not only is able to correctly describe the free-energy surface for oligomer lengths that it was trained on but also is able to predict the conformational sampling of longer chains. PMID- 29120634 TI - Double-Layered Composite Methods Extrapolating to Complete Basis-Set Limit for the Systems Involving More than Ten Heavy Atoms: Application to the Reaction of Heptafluoroisobutyronitrile with Hydroxyl Radical. AB - Two versions of the double-layered composite methods, including the restricted open-shell model chemistry based on the complete basis set quadratic mode (DL ROCBS-Q) and the extrapolated CBS limit of electronic energy on the basis of the coupled cluster with single, double, and noniterative triple excitations with the hierarchical sequence of the correlation-consistent basis sets (DL-RCCSD(T)/CBS), were developed to calculate the energetic reaction routes for the systems involving 13/14 heavy atoms with good balance between efficiency and accuracy. Both models have been employed to investigate the oxidation reactions of heptafluoroisobutyronitrile ((CF3)2CFCN) with hydroxyl radical. The (CF3)2CFCN + OH reaction is dominated by the C-O addition/elimination routes as bifurcated into trans- and cis-conformations. Although the formation of isocyanic acid or hydrogen fluoride is highly exothermic, the major nascent product was predicted to be the less exoergic cyanic acid. Preference of the product channels could be tuned by the single water molecule in the presence of the H2O-HO complex. The production of amide compound was found to be the most significant route accompanied by the OH regeneration. Moreover, the OH radical could be an efficient catalyst for the hydrolysis of (CF3)2CFCN. Implication of the current theoretical results in the chemistry of (CF3)2CFCN for both atmospheric sink and potential dielectric replacement gas was discussed. PMID- 29120635 TI - Total Synthesis of (-)-Himalensine A. AB - The first enantioselective synthesis of (-)-himalensine A has been achieved in 22 steps. The synthesis was enabled by a novel catalytic, enantioselective prototropic shift/furan Diels-Alder (IMDAF) cascade to construct the ACD tricyclic core. A reductive radical cyclization cascade was utilized to build the B ring, and end-game manipulations featuring a molecular oxygen mediated gamma-CH oxidation, a Stetter cyclization to access the pendant cyclopentenone, and a highly chemoselective lactam reduction delivered the natural product target. PMID- 29120636 TI - The Vibrations of V2O4: Matrix Isolation and Quantum Chemical Calculations. AB - V2O4 was generated in solid Ne and characterized by infrared spectroscopy and additionally by multireference configuration interaction and density functional calculations. Four vibrational transitions at 1003, 731.7, 640.9, and 309.1 cm-1 (16O2) were observed and, based on the calculations, assigned to bu, au, bu, and bu modes, respectively, of the C2h symmetric structure. The calculated bond distances are in good agreement with the results of previous calculations. PMID- 29120637 TI - Protection from Below: Stabilizing Hydrogenated Graphene Using Graphene Underlayers. AB - We show that dehydrogenation of hydrogenated graphene proceeds much more slowly for bilayer systems than for single layer systems. We observe that an underlayer of either pristine or hydrogenated graphene will protect an overlayer of hydrogenated graphene against a number of chemical oxidants, thermal dehydrogenation, and degradation in an ambient environment over extended periods of time. Chemical protection depends on the ease of oxidant intercalation, with good intercalants such as Br2 demonstrating much higher reactivity than poor intercalants such as 1,2-dichloro-4,5-dicyanonbenzoquinone (DDQ). Additionally, the rate of dehydrogenation of hydrogenated graphene at 300 degrees C in H2/Ar was reduced by a factor of roughly 10 in the presence of a protective underlayer of graphene or hydrogenated graphene. Finally, the slow dehydrogenation of hydrogenated graphene in air at room temperature, which is normally apparent after a week, could be completely eliminated in samples with protective underlayers over the course of 39 days. Such protection will be critical for ensuring the long-term stability of devices made from functionalized graphene. PMID- 29120639 TI - Molecular Interpretation of Preferential Interactions in Protein Solvation: A Solvent-Shell Perspective by Means of Minimum-Distance Distribution Functions. AB - Preferential solvation is a fundamental parameter for the interpretation of solubility and solute structural stability. The molecular basis for solute solvent interactions can be obtained through distribution functions, and the thermodynamic connection to experimental data depends on the computation of distribution integrals, specifically Kirkwood-Buff integrals for the determination of preferential interactions. Standard radial distribution functions, however, are not convenient for the study of the solvation of complex, nonspherical solutes, as proteins. Here we show that minimum-distance distribution functions can be used to compute KB integrals while at the same time providing an insightful view of solute-solvent interactions at the molecular level. We compute preferential solvation parameters for Ribonuclease T1 in aqueous solutions of urea and trimethylamine N-oxide (TMAO) and show that, while macroscopic solvation shows that urea is preferentially bound to the protein surface and TMAO is preferentially excluded, both display specific density augmentations at the protein surface in dilute solutions. Therefore, direct protein-osmolyte interactions can play a role in the stability and activity of the protein even for preferentially hydrated systems. The generality of the distribution function and its natural connection to thermodynamic data suggest that it will be useful in general for the study of solvation in mixtures of structurally complex solutes and solvents. PMID- 29120638 TI - Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH). AB - We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target. PMID- 29120640 TI - Structures of the Largest Amphidinol Homologues from the Dinoflagellate Amphidinium carterae and Structure-Activity Relationships. AB - Amphidinols are polyketide metabolites produced by marine dinoflagellates and are chiefly composed of a long linear chain with polyol groups and polyolefins. Two new homologues, amphidinols 20 (AM20, 1) and 21 (AM21, 2), were isolated from Amphidinium carterae collected in Korea. Their structures were elucidated by detailed NMR analyses as amphidinol 6-type compounds with remarkably long polyol chains. Amphidinol 21 (2) has the longest linear structure among the amphidinol homologues reported so far. The congeners, particularly amphidinol 21 (2), showed weaker activity in hemolysis and antifungal assays compared to known amphidinols. PMID- 29120641 TI - Understanding Translational-Rotational Coupling in Liquid Water through Changes in Mass Distribution. AB - A molecular dynamics study of liquid water and models of water has been carried out to understand the effect of changes in the mass distribution on molecular translation and rotation. Calculations on the motion of mH2O and H2nO, where m and n vary over a range of values by varying the mass at the hydrogen and oxygen positions, show that these form two distinct series. The two series exhibit different translational and rotational properties. Although a decrease in diffusivity when compared to H2O is observed in both the series, in the case of mH2O series, an enhancement in the ratio of diffusivities {D[H2O]/D[mH2O]} is found as compared to the square root of the inverse mass ratios, whereas the effect of mass distribution for H2nO is seen to lead to a reduction in the ratio of diffusivities {D[H2O]/D[H2nO]} with respect to the square root of the inverse mass ratios. However, the ratios of diffusivities in both the series deviate from the corresponding mass ratios, which can be attributed to the translation rotation coupling in liquid water. PMID- 29120643 TI - Identification of Single Adsorbed Cations on Mica-Liquid Interfaces by 3D Force Microscopy. AB - Force microscope provides atomically resolved images of surfaces immersed in a liquid. The presence of different chemical species in the interface (cations, anions, water, neutral atoms) complicates the adscription of the observed features to a given species. We develop a 3D atomic force microscopy method to identify the cations adsorbed on a mica surface from a potassium chloride solution. The method is based on measuring the peak value of the attractive force within the Stern layer. The maximum of the attractive force shows site-specific variations. The positions with the highest attractive force values are associated with the presence of adsorbed potassium ions, while the other positions are associated with a local depletion of the hydration layer. This criterion provides a surface coverage of K cations that is consistent with the one reported by other techniques. PMID- 29120642 TI - Targeted Isolation of Monoterpene Indole Alkaloids from Palicourea sessilis. AB - Phytochemical investigation of the alkaloid extract of Palicourea sessilis by LC HRMS/MS using molecular networking and an in silico MS/MS fragmentation approach suggested the presence of several new monoterpene indole alkaloids. These compounds were isolated by semipreparative HPLC, and their structures confirmed by means of HRMS, NMR, and ECD measurements as 4-N-methyllyaloside (3), 4-N methyl-3,4-dehydrostrictosidine (4), 4beta-hydroxyisodolichantoside (6), and 4alpha-hydroxyisodolichantoside (7), as well as the known alkaloids alline (1), N methyltryptamine (2), isodolichantoside (5), and 5-oxodolichantoside (8). In addition, the acetylcholinesterase inhibitory activity of the compounds was evaluated up to 50 MUM. PMID- 29120644 TI - Acid-Induced Intracellular Dissociation of beta-Cyclodextrin-Threaded Polyrotaxanes Directed toward Attenuating Phototoxicity of Bisretinoids through Promoting Excretion. AB - In the retinal pigment epithelium of patients with age-related macular degeneration (AMD), excess N-retinylidene-N-retinylethanolamine (A2E), a dimer of all-trans-retinal, accumulats to induce inflammatory cytokine secretion and phototoxic effects. Therefore, the reduction of intracellular A2E is a promising approach for the prevention and treatment of AMD. In this study, acid-labile beta cyclodextrin (beta-CD)-threaded polyrotaxanes (PRXs) were synthesized and investigated their effects on the removal of A2E accumulated in retinal pigment epithelium cells (ARPE-19) in comparison to nonlabile PRXs and 2-hydroxypropyl beta-CD (HP-beta-CD) were examined. GC-MS and HPLC studies strongly suggest that the acid-labile PRXs dissociated into their constituent molecules in cells by lysosomal acidification and threaded beta-CDs were considered to be released from the PRXs. The released beta-CDs formed an inclusion complex with A2E, which promoted the excretion of A2E. Indeed, the acid-labile PRXs effectively reduced intracellular A2E level at approximately a 10-fold lower concentration than HP beta-CD. Accompanied with A2E removal, the toxicity and phototoxicity of A2E were attenuated by treatment with acid-labile PRXs. Because the nonlabile PRX failed to reduce intracellular A2E level and attenuate phototoxicity, intracellular release of threaded beta-CDs from the acid-labile PRX might contribute to reducing intracellular A2E. We conclude that acid-labile PRXs are promising candidates for the treatment of macular diseases through the removal of toxic metabolites. PMID- 29120645 TI - Coherent Two-Quantum Two-Dimensional Electronic Spectroscopy Using Incoherent Light. AB - Two-quantum two-dimensional electronic spectroscopy (2Q 2D ES) may provide a measure of electron-correlation energies in molecules. Attempts to obtain this profound but elusive signal have relied on experimental implementations using femtosecond laser pulses, which induce an overwhelming background signal of nonresonant response. Here we explore theoretically the signatures of electron correlation in coherent 2Q 2D ES measurements that use spectrally incoherent light, I(4) 2Q 2D ES. One can use such fields to suppress nonresonant response, and therefore this method may better isolate the desired signature of electron correlation. Using an appropriate treatment of the multilevel Bloch electronic system, we find that I(4) 2Q 2D ES presents an opportunity to measure electron correlation energies in molecules. PMID- 29120646 TI - Critical Study of the Recognition between C-Reactive Protein and Surface Immobilized Phosphorylcholine by Quartz Crystal Microbalance with Dissipation. AB - C-reactive protein (CRP), a biomarker for cardiovascular disease, has been reported to have a strong affinity to zwitterionic phosphorylcholine (PC) groups in the presence of calcium ions. In addition, PC-immobilized surfaces have been used as a nonfouling coating to prevent nonspecific protein binding. By appropriately using the features of PC-immobilized surfaces, including specific recognition to CRP and nonfouling surface, it is reasonable to create an antibody free biosensor for the specific capture of CRP. In this study, PC-functionalized 3,4-ethylenedioxythiophene (EDOT) monomers were used to prepare PC-immobilized surfaces. The density of PC groups on the surface can be fine-tuned by changing the composition of the monomer solutions for the electropolymerization. The density of PC group was confirmed by X-ray photoelectron spectroscopy (XPS). The specific interaction of CRP with PC groups was monitored by using a quartz crystal microbalance with dissipation (QCM-D). The amount of protein binding could be estimated by the reduction in frequency readout. Through the QCM-D measurement, we revealed the nonfouling property and the specific CRP capture from our PC-immobilized surfaces. Notably, the dissipation energy also dropped during the binding process between CRP and PC, indicating the release of water molecules from the PC groups during CRP adsorption. We anticipate that surface bound water molecules are mainly released from areas near the immobilized PC groups. Based on Hofmeister series, we further examined the influence of ions by introducing four different anions including both kosmotrope (order maker) and chaotrope (disorder maker) into the buffer for the CRP binding test. The results showed that the concentration and the type of anions play an important role in CRP binding. The present fundamental study reveals deep insights into the recognition between CRP and surface-immobilized PC groups, which can facilitate the development of CRP sensing platforms. PMID- 29120647 TI - Underwater Oil Droplet Splitting on a Patterned Template. AB - Underwater oil droplets stretched and pinned by dual-dot oleophilic patterns on a superoleophobic substrate have been split into two nearly equal-volume daughter droplets using an underwater superoleophobic blade at substantially lower cutting speeds than reported in previous studies. A "liquid exchange model" based on Laplace pressure-driven liquid transport has been proposed to explain the mechanism of the underwater droplet split process. The dependence of droplet geometrical shape (curvature) and liquid properties (surface tension, viscosity) on the critical cutting speed that allows equal-volume split was investigated. Results demonstrate that critical cutting speed increases with increased curvature and surface tension of the split droplet, and decreases with increased droplet viscosity, which agrees with the proposed model. The ability to reproducibly split a single bulk oil droplet into daughter droplets with nearly equal volume facilitates the development of new functions for underwater microreactors. PMID- 29120648 TI - The Role of Nanoparticle Design in Determining Analytical Performance of Lateral Flow Immunoassays. AB - Rapid, simple, and cost-effective diagnostics are needed to improve healthcare at the point of care (POC). However, the most widely used POC diagnostic, the lateral flow immunoassay (LFA), is ~1000-times less sensitive and has a smaller analytical range than laboratory tests, requiring a confirmatory test to establish truly negative results. Here, a rational and systematic strategy is used to design the LFA contrast label (i.e., gold nanoparticles) to improve the analytical sensitivity, analytical detection range, and antigen quantification of LFAs. Specifically, we discovered that the size (30, 60, or 100 nm) of the gold nanoparticles is a main contributor to the LFA analytical performance through both the degree of receptor interaction and the ultimate visual or thermal contrast signals. Using the optimal LFA design, we demonstrated the ability to improve the analytical sensitivity by 256-fold and expand the analytical detection range from 3 log10 to 6 log10 for diagnosing patients with inflammatory conditions by measuring C-reactive protein. This work demonstrates that, with appropriate design of the contrast label, a simple and commonly used diagnostic technology can compete with more expensive state-of-the-art laboratory tests. PMID- 29120649 TI - [Thyroid disease in the Czech Republic: the EUthyroid project and the evaluation of the General Health Insurance Company epidemiological data for the period of 2012-2015]. AB - Institute of Endocrinology participates in the grant of European Commission EUthyroid (Towards the elimination of iodine deficiency and preventable thyroid related diseases in Europe), together with other 28 European countries. The role of Institute of Endocrinology in EUthyroid is among other things to ensure access to national registers relating to thyroid diseases. The results presented here correspond to the years 2012-2015 and are based on data from the General Health Insurance Company Czech Republic (VZP CR), which has 6 million insured persons (ratio male : female = 1 : 1). The set is sufficiently representative to be related to the whole of the Czech Republic. According to VZP data, the prevalence of thyreopathies is constantly increasing, for example according to the code of diagnoses E00-E07 and the unique birth number, the prevalence of thyreopathies increased from 6.8 % in 2012 to 7.5 % in 2015. The increase of the prevalence is mainly concentrated to clinical manifestation of hypothyroidism (code E03, an increase from 2.8 % in 2012 to 3.2 % in 2015); the second is nontoxic struma (code E04), which had a constant prevalence of 2.5 % in the given period. On the other hand, thyroiditis (code E06), the third in the order of occurrence, increased from 1.8 % in 2012 to 2 % in 2015. The decrease in prevalence only occurred in hyperthyroidism (E05) from 0.7 % in 2012 to 0.6 % in 2015. Other thyreopathies had a prevalence of less than 1 %, and was constant between 2012 and 2015 (other thyroid disorders E07 0.8 %, thyroid disorders associated with iodine deficiency E01 0.2 %, E02 0.07 %, E00 0.01 %, thyroid carcinoma C73 0.13 %).Key words: EUthyroid - General Health Insurance Company- occurrence of thyreopathies - thyroid disease in the Czech Republic. PMID- 29120650 TI - [Thyroid screening in pregnancy - guideline in practice]. AB - Thyroid diseases may adversely affect the conception, maintain pregnancy. They increase the risk of complications in pregnancy and may have a negative effect on the fetus. Therefore it is necessary to capture thyroid diseases in the population of pregnant women, in the early stage of pregnancy. In Slovakia, since 2009, the Expert Guideline of the Ministry of Health of the Slovak Republic for the diagnosis and treatment of autoimmune thyroid diseases in women during pregnancy has been in force. In our patient cohort, we monitored 666 pregnant patients, the timeliness of screening, thyroid parameters, the number of pregnancies and their complications, the need for levothyroxine treatment. We found that screening was shifted to an earlier period of pregnancy (11.4 gestational week 2015/2016 vs 8.2 gestational week 2016/2017), the most sent patients were in the first trimester of pregnancy (72 %), 81 % of patients had positive thyreoperoxidase antibodies, 10 % had overt hypothyroidism, 90 % had subclinical hypothyroidism, pathology in the pregnancy had 13 % patients. The treatment was needed in 70 % of patients. Obviously, the number of screened patients in the 1st trimester has increased (83 % 2016/2017) from the time since the introduction of screening. We can also see the high number of patients with positive autoantibodies. These are patients who need to be monitored and also treated if TSH increase more than upper limit for an actual trimester to minimize the risk of pregnancy complications.Key words: hypothyroidism - pregnancy - screening - thyroxin. PMID- 29120651 TI - [Valvular heart disease in relation to the treatment of hyperprolactinemia with dopamine agonists]. AB - Adverse effect of dopamine agonists on the heart valves aroused much attention some time ago. Gradually, as data accumulated, the approach to the problem was rationalised and further examinations were only recommended in indicated cases. The paper reviews the current knowledge about the treatment of hyperprolactinemia with dopamine agonists and the risk of valvular disease.Key words: dopamine agonists - ergolines/adverse effects - heart valve diseases - hyperprolactinemia pituitary neoplasms - prolactinoma. PMID- 29120652 TI - [Hypothyroidism in patients with heart disease]. AB - Hypothyroidism is frequently found in patients with heart disease. It is a risk factor for atherosclerosis and ischemic heart disease and has a direct negative effect on both the left and right ventricular functions (hypothyroidism-induced cardiomyopathy). The confirmed manifest hypothyroidism is always a reason for replacement therapy with levothyroxine; regarding patients with heart disease, we always begin treatment with a small dose and increase it gradually. The treatment of subclinical hypothyroidism in patients with heart disease is disputable and its benefits probably depend on age. At a higher age, the therapy-related risks often outweigh its benefits, so we make do with the target levels of the thyroid stimulating hormone being within the upper band of the normal range, or even slightly above it, rather than overdosing the patient. To summarize in a simplified way, the treatment of subclinical hypothyroidism in patients with heart disease is the most effective in younger individuals, mainly those aged below 65, while at a higher age > 80 years the risk usually outweighs the benefit.Key words: cardiovascular risk - hypothyroidism - ischemic heart disease left ventricular dysfunction - right ventricular dysfunction - subclinical hypothyroidism - thyroid peroxidase antibodies. PMID- 29120653 TI - [Thyroid carcinomas: the present view on diagnostics and therapy]. AB - Thyroid carcinoma (TC) represents 1-2 % of all human tumors, and is the seventh most common tumor. Women are in large majority among new patients. For women, this is the fifth most common tumor. In the Czech Republic, 1 143 new cases of TC were diagnosed in 2015. It is the tumor with the highest increase in incidence. Among newly diagnosed tumors, most of those are differentiated thyroid gland carcinomas (DTCs) originating from follicular thyroid cells. These tumors are follicular and papillary carcinomas and Hurthle carcinoma, accounting for 95 % of new cases. Due to the great progress in treatment, the prognosis is most commonly good for these tumors. Treatment is more difficult for other types of tumors. Anaplastic thyroid cancer (representing less than 1 % of thyroid tumors) is a rare form of thyroid cancer that is very malignant. Also found in the thyroid gland is Euro-C-cell tumor, which originates in C cells. This is the so-called medullary thyroid carcinoma, which is less common (5 % of all thyroid carcinomas). It emerges from the parapolyclic neuroendocrine cells of the thyroid gland. This tumor often metastasizes to the cervical lymph nodes, and frequently occurs in distant bone, liver and lung metastases. In 2015, in this publication we published an article: Thyroid gland carcinomas, current therapeutic procedures. This article was devoted to the diagnosis of thyroid carcinoma and individual treatment procedures. In this article, we look at differentiated thyroid carcinomas (DTCs), especially current opinions on the treatment of low risk carcinomas.Key words: differentiated thyroid cancer - radioidine - targeted therapy. PMID- 29120654 TI - [Diagnosis and management of metastatic pheochromocytoma and paraganglioma]. AB - Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare catecholamine-producing neuroendocrine tumors arising from adrenal medulla or extra-adrenal sympathetic and parasympathetic ganglia. Most of the PHEOs/PGLs are benign tumors, but metastatic disease is common, especially in patients with particular genetic background. Although PHEOs/PGLs were described more than a century ago, diagnosis and therapy of metastatic disease are still challenging. Advances in understanding molecular and metabolic changes associated with tumorigenesis lead us to identification of the background of these tumors. Novel information allowed for development of more precise diagnostic methods and molecular therapeutic targets identification, which will improve care of patients with metastatic PHEO/PGL.Key words: diagnostics - management - paraganglioma - pheochromocytoma - therapy. PMID- 29120655 TI - [Bone quality in patients with acromegaly]. AB - The impact of acromegaly on bone and the risk of fractures has not been sufficiently investigated. GH hypersecretion stimulates bone turnover, leading to an increase in bone turnover markers. Normal or even increased bone mineral density (BMD) in comparison to healthy controls have been reported, but there are some works where decreased BMD was observed among acromegaly patients with hypogonadism, particularly at lumbar spine. Less pronounced effect of GH overproduction was observed at the femoral neck, as explained by the positive effect of hypersecretion on the cortical bone (due to periosseal ossification). Several studies have documented morphometric vertebral fractures (VF) in 1/3 of acromegaly patients. The major risk factors leading to the development of VF include hypogonadism, diabetes mellitus and previous VF. Because the risk of fractures does not correlate with BMD most of the studies are currently focused on bone quality, bone strength and microstructure.Key words: bone microstructure growth hormone - IGF1 - vertebral fractures. PMID- 29120656 TI - [Syndrome of inappropriate antidiuresis and the current management of hyponatremia]. AB - Hyponatremia defined as serum sodium lower than 135 mmol/L is the most common electrolyte abnormality in outpatients and also in hospitalized patients. It has been documented that hyponatremia is associated with significantly higher morbidity, mortality and longer hospitalization stay. Hyponatremia is manifested by variety of symptoms, from mild up to life threatening conditions. Syndrome of inappropriate antidiuresis (SIAD) is the most common type of hyponatremia. This article presents new aspects in the etiology, diagnosis, differential diagnosis ant treatment of the SIAD according to European guidelines.Key words: arginin vasopressin-syndrome of inappropriate antidiuresis - diagnosis - hyponatremia - treatment. PMID- 29120657 TI - [Anabolic steroid induced hypogonadism in men: overview and case report]. AB - An important potential consequence of the anabolic steroid misuse is hypogonadotropic hypogonadism due to the inhibition of pituitary secretion of gonadotropins. By the symptoms as testicular atrophy, spermatogenic and fertility disturbances or dysfunction in sexual life, the anabolic steroids induced hypogonadism (ASIH) could be differentiated from organic hypogonadotropic hypogonadism only with difficulty unless the misuse is reported by the user. When diagnosed, the crucial step in the therapy is the stop of anabolic use. Convalescence lasts usually several months or even more than one year. First could be seen the retreat of testicular atrophy followed by the rearrangement of spermatogenesis. The users mainly well informed from internet use for amelioration of the symptoms injections of human choriogonadotropin (hCG), selective estrogen receptor modulators (SERM) or aromatase inhibitors.Key words: anabolic steroids - doping - hypogonadotropic hypogonadism - side effects. PMID- 29120658 TI - [Primary hyperparathyroidism - new clinical forms of the disease]. AB - Primary hyperparathyroidism (PHPT) has been increasingly diagnosed incidentally in its asymptomatic form owing to calcium screening tests. This form of PHPT represents 80% in developed countries. Although PHPT patients are asym-ptomatic, target organ (bone and kidney) involvement is frequently observed. Mild PHPT is associated with a reduction of bone mineral densityand, moreover, with increased risk of vertebral fractures. The extent of a patient evaluation and indications for parathyroidectomy are based on expert guidelines from 2014. Normocalcemic variant of PHPT has been recently recognized, possibly with higher prevalence in general population than the hypercalcemic form of PHPT. Normal but with respect to hypercalcemia inadequately high parathormon levels characterize normohormonal PHPT. If a hereditary form of PHPT is suspected, genetic testing is recommended. Although there are new clinical forms of PHPT, parathyroidectomy still represents the only curative approach to PHPT followed by substantial osteoprotective effect.Key words: asymptomatic form - normocalcemic form - normohormonal form - parathyroidectomy - primary hyperparathyroidism - recent guidelines for the management PHPT. PMID- 29120659 TI - [Antidiabetic drugs and their effect on bone]. AB - It is well established that osteoporosis and diabetes are prevalent diseases with significant associated morbidity and mortality. Patients with diabetes mellitus are at an increased risk of bone fractures. Today we have several groups of effective and save antidiabetic drugs, which are very given often in combination. Although diabetes-related complications are important in the etiology, the effects of medications on bone metabolism and fracture risk should not be neglected, because the diabetes medication may affect also bone health and fracture risk. Increased risk of fracture has been identified with use of thiazolidinediones, most definitively in women. Also treatment with sulfonylureas can have negative adverse effect on bone. One consequence of these findings has been greater attention to fracture outcomes in trails of new diabetes medication (incretins and SGLT2 inhibitors). The aim of the review is to summarize effects of antidiabetic treatment on bone - bone mineral density, fractures and bone turnover markers. The authors also try to recommend a strategy how to treat a diabetic patient regarding the risk of osteoporotic fractures.Key words: antidiabetic drugs - diabetes mellitus - fracture risk - osteoporosis. PMID- 29120660 TI - [Adenosine - a mediator with multisystemic effects (or a hormone?)]. AB - Adenosine is a nucleoside regulating many physiological and pathological processes in human organism. It is produced by almost all cells and is metabolised by adenosinedeaminase enzyme. Effect of adenosine is mediated by three types of adenosine receptors. Adenosinergic system significantly influences function of cardiovascular system, furthemore it plays a key role in sleep homeostasis, in regulation of bone metabolism and activation of immune system. Adenosine mediates effect of various hormones, but also adenosine itself has its own autocrine, paracrine and systemic effects. Changes in endogenous adenosine levels, or changes of adenosine receptor sensitivity, may play a role in ethiopathogenesis of many diseases. Thus adenosinergic system can become a target for new therapeutical possibilities in many fields of medicine.Key words: adenosine - adenosinedeaminase - cardiovascular system - diabetes mellitus - hormone. PMID- 29120661 TI - Rectal cancer confined to the bowel wall: the role of 3 Tesla phased-array MR imaging in T categorization. AB - OBJECTIVE: To determine the diagnostic value of 3 Tesla MR imaging in detection of mucosal (Tis), submucosal (T1) and muscularis propria (T2) invasion in patients with early rectal cancer. METHODS: A total of 50 consecutive patients who underwent 3 Tesla MR imaging and curative-intent intervention for MRI-staged Tis/T1/T2 rectal cancer from March 2012 to December 2016 were included. The radiological T category of each rectal tumour was compared retrospectively with histopathological results assessed according to the tumor, node, metastasis (TNM) classification. The sensitivities, specificities, and overall accuracy rates of 3 Tesla MR imaging for Tis, T1, and T2 cases were calculated using MedCalc statistical software v. 16. RESULTS: The sensitivity, specificity, PPV, NPV of 3 Tesla MR imaging in T categorization for T2 were: 93.7% [95% CI (0.79-0.99)], 77.7% [95% CI (0.52-0.93)], 88.2% [95% CI (0.75-0.94)] and 87.5% [95% CI (0.64 0.96)]; for T1 were 92% [95% CI (0.63-0.99)], 91.8% [95% CI (0.78-0.98)], 80% [95% CI (0.57-0.92)] and 97.1% [95% CI (0.83-0.99)]; for Tis were: 20% [95% CI (0.51-0.71)], 100% [95% CI (0.92-1)], 100%, 91.8% [95% CI (0.87-0.94)], respectively. MR categorization accuracy rates for T2, T1 and Tis were calculated as 88, 92 and 92%, respectively. CONCLUSION: 3 Tesla MR imaging seems to be useful for accurate categorization of T-stage in early rectal cancer, especially for T1 cancers. The method is not a reliable tool to detect Tis cases. The potential for overstaging and understaging of the technique should be realized and taken into consideration when tailoring the treatment protocol for each patient. Advances in knowledge: High-resolution MR with phased-array coil is being increasingly used in the pre-operative assessment of rectal cancer. 3 Tesla high-resolution MR imaging allows improved definition of bowel wall and tumour infiltration. PMID- 29120662 TI - Comparison of MRI visualization between linearly placed iron-containing and non iron-containing fiducial markers for prostate radiotherapy. AB - OBJECTIVE: Visualizing the gold marker (GM) in CT and MRI is critical, especially for registration in high-precision radiotherapy. GM sizes vary. Large markers are easily visualized in MRI. Small GMs show fewer artefacts in CT but are harder to detect in MRI because the signal is influenced by metal in MRI. Therefore, we compared MRI visualization between linearly placed new iron-containing marker and non-iron containing marker. METHODS: 27 patients underwent CT/MRI fusion-based intensity-modulated radiotherapy. The gold markers were placed by urologists. An iron-containing Gold AnchorTM (GA) marker (diameter, 0.28 mm; length, 10 mm) was placed by using a 22 G needle on one side of the prostate linearly. A non-iron containing VISICOILTM (VIS) marker (diameter, 0.35 mm; length, 10 mm) was placed by using a 19 G needle on the opposite side linearly. T2* weighted MRI was mostly performed. Two Radiation Oncologists and one Radiation Technologist evaluated and assigned visual quality scores (GA shape, CT artefacts, MRI signal voids). RESULTS: The mean visualization scores of artefacts were similar between GA and VIS in planning CT. GM visualization in MRI of the prostate was better for GA than for VIS. The visibility of the linear shape of the GA was 3.4-4.1 points when the VIS was 5 points (1 is worst and 5 is best). CONCLUSION: Visualization quality was similar between GA (iron-containing marker) and VIS (non-iron containing marker) in planning CT, but was better for GA than for VIS in MRI. To achieve high-precision radiotherapy, an iron-containing gold marker was useful for CT and MRI registration. Advances in knowledge: An iron-containing fiducial marker was useful for CT and MRI registration, especially in high-precision radiotherapy, such as stereotactic body radiotherapy and intensity-modulated radiotherapy. PMID- 29120663 TI - IFN-stimulated Genes and Non-Type 2 Inflammation. New Pathway or Red Herring? PMID- 29120664 TI - Sequestering Damage-associated Molecular Patterns in Critical Illness. A Novel Homeostatic Role for the Erythrocyte. PMID- 29120665 TI - Screening for lung cancer using sub-millisievert chest CT with iterative reconstruction algorithm: image quality and nodule detectability. AB - OBJECTIVE:: To investigate the image quality and nodules detectability using ultra-low dose (ULD) protocol with iterative model reconstruction (IMR) algorithm when compared to routine low dose (LD) chest CT in lung cancer screening. METHODS:: Chest CT scans were acquired using a 256-slice scanner for 300 subjects. The scan protocol for the ULD group was 120 kVp/17 mAs while for the LD group was 120 kVp/30 mAs. All images were reconstructed with filtered back projection (FBP), hybrid iterative reconstruction (HIR) and IMR algorithms. Effective dose was recorded. Image quality assessments were performed by two radiologists. SD of CT attenuation was measured as objective image noise. The number of non-calcified nodules detected in both groups with different reconstruction algorithms were calculated and compared. RESULTS:: The effective dose of ULD group (0.67 +/- 0.08 mSv) was about 44% reduced compared with LD group (1.20 +/- 0.08 mSv) (p < 0.01). IMR improved image quality and reduced image noise significantly than HIR and FBP in both groups (all, p < 0.01). IMR enabled a higher number of nodule detected compared to FBP and HIR in both LD and ULD groups, especially for solid nodules less than 4 mm. CONCLUSION:: IMR may improve the diagnostic accuracy of ULD CT lung screening with potential nodule detectability improvement. ADVANCES IN KNOWLEDGE:: IMR enables significant reduction of the image noise and improvement of image quality in sub-mSv (66% reduction) chest scans. PMID- 29120666 TI - Like grandparents, like parents: Empirical evidence and psychoanalytic thinking on the transmission of parenting styles. AB - The authors discuss the issue of intergenerational transmission of parenting from an empirical and psychoanalytic perspective. After presenting a framework to explain their conception of parenting, they describe intergenerational transmission of parenting as a key to interpreting and eventually changing parenting behaviors. Then they present (1) the empirical approach aimed at determining if there is actually a stability across generations that contributes to harsh parenting and eventually maltreatment and (2) the psyphoanalytic thinking that seeks to explain the continuity in terms of representations and clinical phenomena. The authors also discuss the relationship between the attachment and the caregiving systems and hypothesize a common base for the two systems in childhood experience. Finally, they propose the psychoanalytic perspective as a fruitful theoretical framework to integrate the evidence for the neurophysiological mediators and moderators of intergenerational transmission. Psychoanalytically informed research can provide clinically relevant insights and hypotheses to be tested. PMID- 29120667 TI - Sexual functioning and disordered eating: A new perspective. AB - Fears about sexual maturity and intimacy were among early explanations for the etiology of eating disorders and related concerns, and research with clinical samples revealed a relationship between eating disorders and atypical sexual experiences. In contrast, feminist scholars offer explanations for both eating disorders and sexual dysfunction that emphasize societal pressures. As an alternative approach to understanding these difficulties, the authors empirically explored the relationship between the cognitive and affective aspects of sexuality and disordered eating among a nonclinical sample of 167 university women. Participants completed the Eating Attitudes Test-Revised and the Garos Sexual Behavior Index-Research Version. Women who experienced greater psychic conflict about their sexual behavior, obsessiveness about sex, and discomfort with sexual stimulation also reported increased levels of disordered eating behavior. These results suggest a need to consider the potential disturbances in certain cognitive and affective aspects of sexual functioning when treating women with disordered eating. PMID- 29120668 TI - Listening to a patient: An exploratory experimental investigation into the effects of vocalization and therapist gender on interpreting clinical material. AB - Carefully listening to the patient is of paramount importance for psychoanalysis and psychoanalytic psychotherapy. The present study explored whether patient vocalization as well as the gender of the analyst play significant roles in clinical listening. Fifty-one psychoanalysts and psychoanalytic therapists were randomly assigned to listen to one of two dramatized psychoanalytic sessions. The content of the sessions was the same for both versions, but the sessions were dramatized differently. Some differences emerged between the versions, especially on ratings of reality testing, impulse control, pressured speech, patient was confusing, and awareness of imagery. Furthermore, differences emerged between male and female analysts in terms of ratings of intervention strategies and countertransference reactions to the patient material. Session version and gender affect different ratings. Implications of the findings are discussed as is the utility of using more ecologically valid material in conducting empirical research into clinical judgment. PMID- 29120669 TI - Schizophrenia as a psychosomatic illness: An interdisciplinary approach between Lacanian psychoanalysis and the neurosciences. AB - According to Lacan's theory of schizophrenia (as well as other delirious forms of psychosis), under certain conditions the signifying function breaks down, thus turning the schizophrenic individual's world into one in which a number of events become enigmatic and signal him or her. The schizophrenic individual tries to deal with these signs that besiege him or her either by means of an interpretative attitude (a stable delusional mood) or by apathy. These two types of responses correspond with the stereotypical (and mood) processes by which the schizophrenic individual attempts to avoid the distress provoked by the enigmatic desire of the Other, while simultaneously corresponding with psychosomatic processes of the brain organ. PMID- 29120670 TI - Correlation Between Steroid-Induced Osteonecrosis of The Femoral Head and Hepatic CYP3A Activity: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Steroid-induced osteonecrosis of the femoral head (ONFH) in young adults is a challenging disorder that can impairs the quality of life of a patient. The disease also leads to frequent occurrences of collapse of the femoral head and resultant dysfunction of the hip joint. In recent years, some scholars have studied steroid-induced lipid metabolism disorder and achieved the effect of steroid-induced ONFH treatment. This study aims to review the investigations on the hepatic CYP3A (cytochrome P4503A enzyme) genetic polymorphisms in steroid-induced ONFH patients. We then further explore its activity correlation with the development of steroid-induced ONFH in a rabbit model. METHODS: A systematic literature search of articles was conducted in PubMed, Web of Science, Google Scholar, Springerlink, and the Chinese National Knowledge Infrastructure database up to February 2017. Twelve relevant articles were retrieved. The odds ratios, standard mean difference, and 95% confidence intervals were calculated to assess the effect of hepatic CYP3A activity on the rabbit model with steroid-induced ONFH. Fixed-effects and random-effects models were used to analyze the heterogeneity. Begg's funnel plot was used to assess publication bias. RESULTS: High hepatic CYP3A activity significantly decreased the risk for steroid-induced ONFH in the rabbit model (p <. 05). The CYP3A gene may be potentially associated with increased risk of steroid-induced ONFH in the human allele model. CONCLUSION: The study suggests that high hepatic CYP3A activity decreases the risk of steroid-induced ONFH. PMID- 29120671 TI - Erythropoietin reduces collagen deposition after myocardial infarction but does not improve cardiac function. AB - Myocardial remodeling includes inappropriate collagen deposition in the interstitium. Erythropoietin (EPO) may have cardioprotective effects. We aimed to assess the role of EPO on myocardial remodeling during the chronic phase. We studied 60 Wistar rats divided into the following groups: control (CT), control + EPO (CT + EPO), myocardial infarction + EPO (MI + EPO), and myocardial infarction (MI). The interstitial collagen volume fraction (ICVF) was quantified and echocardiography was performed. We quantified asymmetric dimethylarginine and glutathione by ELISA, and used real-time PCR to assess apoptosis and inflammation. Western blotting was used to evaluate inflammatory proteins and tissue inhibitors of metalloproteinases (TIMPs), and TUNEL staining was used to detect apoptosis. For matrix metalloproteinases (MMPs), we performed zymography. Parametric and nonparametric analyses were performed according to normality testing. ICVF was greater in MI groups (p < 0.001) and was attenuated by EPO (p = 0.05). The MMP-2 did not show any difference between groups. The TIMP-1 and TIMP 2 did not have difference between groups. The MI groups had worse fraction shortening (p < 0.001), without EPO protection (p = 0.666). The MI groups had increased left ventricle diastolic dimension (p < 0.001) without EPO attenuation (p = 0.79). EPO did not act on oxidative stress. Apoptosis and inflammation were not modulated by EPO. We concluded that EPO attenuated interstitial collagen accumulation, but did not protect from heart dilation or dysfunction. PMID- 29120672 TI - An electrostatic and probabilistic simulation model to describe neurosecretion at the synaptic scale. AB - A hybrid simulation model (macro-molecular dynamics and Monte Carlo method) is proposed to reproduce neurosecretion and exocytosis. A theory has been developed for vesicular dynamics based on quasi-static electric interactions and a simple transition-state model for the vesicular fusion. Under the non-equilibrium electric conditions in an electrolytic fluid, it is considered that the motion of each synaptic vesicle is influenced by electrostatic forces exerted by the membranes of the synaptic bouton, other vesicles, the intracellular and intravesicular fluids, and external elements to the neuron. In addition, friction between each vesicle and its surrounding intracellular fluid is included in the theory, resulting in a drift type movement. To validate the vesicle equations of motion, a molecular dynamics method has been implemented, where the synaptic pool was replaced by a straight angle parallelepiped, the vesicles were represented by spheres and the fusion between each vesicle and the presynaptic membrane was simulated by a Monte Carlo type probabilistic change of state. Density profiles showing clusters of preferential activity as well as fusion distributions similar to the Poisson distributions associated with miniature end-plate potentials were obtained in the simulations. PMID- 29120673 TI - Standard Curves Are Necessary to Determine Pharmacological Properties for Ligands in Functional Assays Using Competition Binding Technologies. AB - Homogeneous functional assays that utilize competition binding technology are widely used for determining pharmacological properties such as intrinsic activity and potency. One example is time-resolved fluorescence resonance energy transfer (TR-FRET) 3',5'-cyclic adenosine monophosphate (cAMP) assays, where labeled cAMP (tracer) and a labeled anti-cAMP antibody bind together to produce a TR-FRET signal when the two constituents are proximal to each other. This signal is disrupted when unlabeled and cellularly generated cAMP competes with the tracer cAMP for binding to the labeled antibody. It is important that the resulting assay signal, usually expressed as a TR-FRET ratio, be transformed to cAMP concentration using a cAMP standard curve. However, examples are still generated in the literature wherein investigators have used the ratiometric signal (not transformed using a standard curve) to determine values for intrinsic activity and potency of ligands. Untransformed raw data often produce reasonable looking sigmoidal concentration response curves, perhaps tempting investigators to use the raw data instead of the transformed data for applying pharmacological models. In this article, we describe the correct procedure for determining the potency and intrinsic activity of ligands that result in changes in cAMP levels using a lysate dilution assay of GLP-1 (7-36)-mediated TR-FRET cAMP accumulation and simulated data. We also highlight how the inappropriate use of raw signal data can dramatically affect interpretation of intrinsic activity and potency of ligands, and how this can adversely affect drug discovery programs. These findings apply not only to cAMP functional assays but also to other functional cellular signaling assays that utilize competition binding technologies. PMID- 29120674 TI - Overproduction of Erythromycin by Ultraviolet Mutagenesis and Expression of ermE Gene in Saccharopolyspora erythraea. AB - Erythromycin is a macrolide antibiotic with broad-spectrum activity against gram positive bacteria that stops protein synthesis by binding to 50s ribosomal subunit. Classical and recombinant strain improvement, such as application of ultraviolet (UV) mutagenesis and selection of overproduction mutant, is the most important and convenient method in enhancement of antibiotic production. In the present study, Saccharopolyspora erythraea was mutagenized using UV lights and selection by tylosin resistance mutant to improve yield of erythromycin. In other sides, to improve the erythromycin yield in mutant, effects of various parameters such as carbon concentration and ermE gene expression were analyzed. In primary selection, high erythromycin producing strains and high erythromycin producer mutant were isolated by plaque agar, and an increase of 87% was observed in tylosin resistance mutant compared to wild-type strain. In secondary selection, a mutant strain (RHU233) with a production of 1.39 mg erythromycin per mL was isolated in fermentation process, which was 20 times more productive than the wild type. In contrast, it was found that glycerol can be used as an alternate carbon source in enhancement of erythromycin production. Comparison of ermE gene expression in mutants RHU233 high producer mutant RHU233 and wild type in Escherichia coli detected in accumulation of soluble hexahistidine-ermE was up to 45% of total cell protein after 18 h in mutants RHU233. Metal-chelation chromatography yielded 126 mg of hexahistidine-ermE per liter of culture with a purity slightly >95% in mutants RHU233. Finally, these optimized conditions could be used for the commercial production of this unique antibiotic. PMID- 29120675 TI - Utility of Adenosine Monophosphate Detection System for Monitoring the Activities of Diverse Enzyme Reactions. AB - Adenosine monophosphate (AMP) is a key cellular metabolite regulating energy homeostasis and signal transduction. AMP is also a product of various enzymatic reactions, many of which are dysregulated during disease conditions. Thus, monitoring the activities of these enzymes is a primary goal for developing modulators for these enzymes. In this study, we demonstrate the versatility of an enzyme-coupled assay that quantifies the amount of AMP produced by any enzymatic reaction regardless of its substrates. We successfully implemented it to enzyme reactions that use adenosine triphosphate (ATP) as a substrate (aminoacyl tRNA synthetase and DNA ligase) by an elaborate strategy of removing residual ATP and converting AMP produced into ATP; so it can be detected using luciferase/luciferin and generating light. We also tested this assay to measure the activities of AMP-generating enzymes that do not require ATP as substrate, including phosphodiesterases (cyclic adenosine monophosphate) and Escherichia coli DNA ligases (nicotinamide adenine dinucleotide [NAD+]). In a further elaboration of the AMP-Glo platform, we coupled it to E. coli DNA ligase, enabling measurement of NAD+ and enzymes that use NAD+ like monoadenosine and polyadenosine diphosphate-ribosyltransferases. Sulfotransferases use 3' phosphoadenosine-5'-phosphosulfate as the universal sulfo-group donor and phosphoadenosine-5'-phosphate (PAP) is the universal product. PAP can be quantified by converting PAP to AMP by a Golgi-resident PAP-specific phosphatase, IMPAD1. By coupling IMPAD1 to the AMP-Glo system, we can measure the activities of sulfotransferases. Thus, by utilizing the combinations of biochemical enzymatic conversion of various cellular metabolites to AMP, we were able to demonstrate the versatility of the AMP-Glo assay. PMID- 29120676 TI - Glutamine protection in an experimental model of acetaminophen nephrotoxicity. AB - Acetaminophen (APAP) is a widely prescribed analgesic and antipyretic drug. In the present work, we studied the effects of glutamine (Gln) in an in vivo model of APAP-induced nephrotoxicity in male Wistar rats. Renal function, histological characteristics, and Na+,K+-ATPase cortical abundance and distribution were analyzed. The appearance of HSP70 and actin in urine was also evaluated. Myeloperoxidase (MPO) activity in cortical tissue was measured as an index of the inflammatory response. Gln administration 30 min before APAP protected from the renal functional and histological damage promoted by APAP. Rats that received the dual treatment Gln and APAP (Gln/APAP) showed the same level of Na+,K+-ATPase cortical induction as APAP-treated animals, but the enzyme maintained its normal basolateral localization. HSP70 abundance was increased up to the same level in the Gln, APAP, and Gln/APAP groups. Urinary HSP70 and actin were detected only in the APAP-treated animals, reinforcing the protection of renal tubular integrity afforded by the Gln pretreatment. Gln pretreatment also protected from the increment in MPO activity promoted by APAP. Our results support the idea that Gln pretreatment could be a therapeutic option to prevent APAP-induced renal injury. PMID- 29120677 TI - Relationships between 25(OH)D concentration, sarcopenia and HOMA-IR in postmenopausal Korean women. AB - OBJECTIVE: Sarcopenia and insulin resistance are common co-morbidities in the elderly and are known to be associated with vitamin D deficiency. However, no previous studies have investigated interactions between all three of these factors. We aimed to investigate the relationship between 25-hydroxyvitamin D concentration, sarcopenia, and insulin resistance in postmenopausal Korean women. METHODS: This study used data from the Korea National Health and Nutrition Examination Survey 2008-2011. Participants were 3744 postmenopausal Korean women. Sarcopenia was defined as appendicular skeletal muscle mass divided by body weight >1 standard deviation below the mean for women aged 20-40 years. The serum 25-hydroxyvitamin D and fasting insulin levels were measured, and insulin resistance was calculated using the formula: fasting plasma glucose (mg/dl) * fasting insulin (mIU/l)/405. RESULTS: We found a strong inverse association between 25-hydroxyvitamin D concentration and sarcopenia in postmenopausal Korean women (p = 0.0009). There was also a significant association between sarcopenia and insulin resistance, independent of vitamin D and obesity status (p < 0.0001). However, there was no significant association between 25-hydroxyvitamin D concentration and insulin resistance. In the subgroup analysis, insulin resistance was found to be determined by sarcopenic rather than vitamin D status. CONCLUSIONS: Sarcopenia was associated with both insulin resistance and 25 hydroxyvitamin D concentration in postmenopausal Korean women, regardless of obesity status. However, 25-hydroxyvitamin D concentration was not associated with insulin resistance. Sarcopenia is therefore of greater clinical importance due to its close relationship with insulin resistance. PMID- 29120678 TI - Patterns of Uveitis at Two University-Based Referral Centres in Cape Town, South Africa. AB - PURPOSE: To analyze the pattern of uveitis at two tertiary hospitals in South Africa which has a high prevalence of HIV, TB and syphilis. METHODS: Data of 198 patients were obtained retrospectively between August 2014 and August 2016, including patient demographics, clinical examination, special investigations and final diagnosis. RESULTS: Infectious uveitis was the most common aetiological category (47%), followed by idiopathic (34.8%) and non-infectious (18.2%). Syphilis was the most common identifiable cause (16.2%). Other important causes were toxoplasmosis, herpes viruses, tuberculosis and HLA-B27. HIV positive patients, who constituted 40% of the study population, were more likely to present with a posterior or panuveitis (relative risk 1.50, 95% CI 1.19-1.89) and more likely to have an infectious cause compared to HIV negative patients (relative risk 2.47, 95% CI 1.82-3.35). CONCLUSIONS: This study emphasizes the importance of HIV testing and investigations for infectious causes of uveitis, especially syphilis, in this population. PMID- 29120680 TI - A clinical evaluation of a transparent, absorbent, adhesive wound dressing. AB - The performance of a transparent absorbent adhesive wound dressing (TAAWD) was observed over 7 days in five plastic surgery clinics across Germany. The study included 47 diverse postoperative linear wounds and donor sites with dry or minimal exudate levels. Data on ease of application and removal, adhesive strength, skin compatibility, conformability to the body, visual wound inspection and parameters of wound assessment were collected and analysed. At the end of the observation period, 100% of wounds were recorded as healing with no reported complications. Clinicians considered that the new dressing had predominantly met clinical needs in 89% of cases. The dressing was shown to be skin friendly, easy to apply, adhere and conform to the skin while protecting the wound and allowing the patient to shower. Due to its transparency, the dressing enabled direct wound surveillance without potential disruption to the wound and healing process. PMID- 29120681 TI - Introducing a new superabsorbent dressing to manage wound exudate. AB - The production of wound exudate is a natural and normal consequence of healing. However, when the constituents, volume and consistency of the exudate alter, problems can occur. This article discusses the different types of exudate and its impact on both the patient and the clinician and outlines appropriate exudate assessment and effective management and dressing selection. If these are performed appropriately, this can improve quality of life for the patient and save time and money for healthcare providers. PMID- 29120682 TI - Wound Expo 2017: zones in the spotlight. PMID- 29120683 TI - Unavoidable pressure ulcers at the end of life and nurse understanding. AB - OBJECTIVES: prevention of pressure ulcers (PUs) in end-of-life care is often problematic because both PUs and interventions to prevent them can cause suffering. The primary aim of this study was to identify and describe the different ways in which nurses understood unavoidable PUs in late palliative care. A second aim was to explore the expediency of the different levels of understanding. METHODS: a qualitative interview study with a phenomenographic approach was carried out. The study participants were nurses and healthcare assistants who worked in nursing homes or in specialist palliative inpatient care units run by private providers, non-profit foundations, municipalities and county councils. A phenomenographic analysis of the interview data was undertaken. RESULTS: all participants shared a fundamental understanding that the prevention of PUs is highly worthwhile in end-of-life care. Within this common view, practitioners' understanding of whether PUs could be prevented differed in four main ways, and were divided into categories: A: unavoidable PUs do not exist. All can be prevented if all interventions are applied, and all patients are at the same risk for developing PUs in end-of-life care; B: unavoidable PUs do not exist, but some patients do not participate in prevention interventions, which makes prevention difficult. The risk of developing pressure ulcers in end-of-life care varies between patients; C: some PUs are unavoidable because some patients do not participate in prevention interventions; the risk of developing pressure ulcers in end-of-life care differs between patients. D: some PUs are unavoidable, depending on the pathophysiological processes in the dying body. The risk of developing pressure ulcers in end-of-life care differs between patients. CONCLUSION: it is paramount to communicate to nurses that not all PUs can be prevented in dying patients, to lessen the burden of ethical stress for the nurses. PMID- 29120684 TI - Managing exudate and maceration in venous leg ulceration within the acute health setting. AB - Exudate has beneficial effects in normal wound healing but detrimental consequences for chronic wounds. Practitioners need to identify and treat its cause, and manage the exudate and prevent if from damaging periwound skin. Management involves dressings of the most appropriate absorbency and other products, and avoiding maceration of periwound skin; compression therapy is the gold standard treatment for treating oedema and venous leg ulceration. Nurses in acute settings may not have the skills to implement or maintain compression therapy; this article is intended for nurses who may have to manage these patients temporarily while they are admitted to secondary care and may not have the skills. PMID- 29120685 TI - Negative pressure wound therapy. PMID- 29120686 TI - Why is the heel particularly vulnerable to pressure ulcers? AB - In this article, the vulnerability of the soft tissues of the heel to pressure ulcers (injuries) is explained from a biomechanical engineering perspective, and emerging technologies for protecting the heel, particularly low-friction garments, are reviewed. Sustained deformations in the soft tissue of the weight bearing posterior heel cause progressive cell and tissue damage due to loss of homeostasis in the cells, as the cytoskeleton and plasma membranes of the affected cells lose integrity and functionality. This deformation damage onsets and evolves rapidly when there is no relief of the tissue distortion (e.g. in supine motionless lying). Hence, prevention should be timely and be applied across all patient populations that are at risk. In particular there is a need to protect tissues from the action of frictional forces that are shearing not only the skin but also the deep tissue structures of the heel. The internal anatomy and physiology of the posterior heel, the common hospital conditions (lying supine, head of the bed elevated) and medical conditions involving neuropathy and perfusion impairments may impose specific risk for heel (pressure) ulcers. There is growing evidence that low-friction-fabric garments may provide added benefits in preventing heel ulcers when used in addition to standard clinical and technology-supported pressure ulcer prevention strategies, as the low-friction fabric structures absorb frictional forces before these are able to considerably distort the susceptible heel tissues. PMID- 29120688 TI - Encouraging self-care through charity. PMID- 29120687 TI - A 100 patient clinical evaluation of an alternating pressure replacement mattress in a home-based setting. AB - BACKGROUND: alternating pressure air mattresses (APAMs) support the prevention and management of pressure ulcers. A health and care NHS trust was seeking an APAM that would improve clinical outcomes in relation to pressure ulcers while considering financial cost. An APAM existed that could meet the trust's needs but there was a lack of evidence over its use in a community/home setting. This study examined the effect of using the Dual Professional (IQ Medical) APAM for patients at a high risk of pressure ulceration. It also determined patient and family satisfaction, and the views of clinicians in relation to clinical outcomes. Additionally, infection prevention and control, servicing, maintenance and electrical biomechanical engineer input were considered. METHOD: a prospective observational study was undertaken of 100 patients in their own homes following a pilot study of 10 patients. The period of the evaluation was from one day up to 295 days, with a mean average of 83 days, and a total of 5809 bed days. RESULTS: with a regimen of regular repositioning of patients and a good diet, the APAM was effective in preventing pressure ulceration in the 100 patients who were at a high or very high risk of skin breakdown and pressure ulceration. CONCLUSION: selection of pressure redistributing surfaces should be based on holistic patient assessment, including risk assessment, mobility levels, grade of pressure damage and clinical judgment. PMID- 29120689 TI - Getting it right first time. PMID- 29120690 TI - Highlights from the advanced wound healing stream at the LINK Congress. AB - Sarah Kahn, Editor of the British Journal of Nursing, discusses some highlights of the recent Hartmann LINK for Wound Healing Congress, which was organised in collaboration with the Journal of Wound Care. PMID- 29120691 TI - Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL): Overview and introduction to the proceedings of the 2016 TACL investigator meeting. AB - Despite great success in the development of curative therapies for pediatric hematologic malignancies, new approaches are needed to overcome resistance to treatment and to reduce associated side effects. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium is an early phase clinical trial group dedicated to developing innovative therapies for currently incurable pediatric leukemias and lymphomas ( https://tacl.chla.usc.edu/tacl/ ). In November of 2016, a TACL Investigator Meeting was held, the proceedings of which appear in this edition of Pediatric Hematology Oncology. This introductory article provides an overview of TACL and introduces the five-part proceedings. PMID- 29120693 TI - Mesoscale behavior study of collector aggregations in a wet dust scrubber. AB - : In order to address the bottleneck problem of low fine-particle removal efficiency of self-excited dust scrubbers, this paper is focused on the influence of the intermittent gas-liquid two-phase flow on the mesoscale behavior of collector aggregations. The latter is investigated by the application of high speed dynamic image technology to the self-excited dust scrubber experimental setup. The real-time-scale monitoring of the dust removal process is provided to clarify its operating mechanism at the mesoscale level. The results obtained show that particulate capturing in self-excited dust scrubber is provided by liquid droplets, liquid films/curtains, bubbles, and their aggregations. Complex spatial and temporal structures are intrinsic to each kind of collector morphology, and these are considered as the major factors controlling the dust removal mechanism of self-excited dust scrubbers. For the specific parameters of gas-liquid two phase flow under study, the evolution patterns of particular collectors reflect the intrinsic, intermittent, and complex characteristics of the temporal structure. The intermittent initiation of the collector and the air hole formation-collapse cyclic processes provide time and space for the fine dust to escape from being trapped by the collectors. The above mesoscale experimental data provide more insight into the factors reducing the dust removal efficiency of self-excited dust scrubbers. IMPLICATIONS: This paper focuses on the reconsideration of the capturer aggregations of self-excited dust scrubbers from the mesoscale. Complex structures in time and space scales exist in each kind of capturer morphology. With changes of operating parameters, the morphology and spatial distributions of capturers diversely change. The change of the capturer over time presents remarkable, intermittent, and complex characteristics of the temporal structure. PMID- 29120694 TI - Analysis of Pig Vomeronasal Receptor Type 1 (V1R) Promoter Region Reveals a Common Promoter Motif but Poor CpG Islands. AB - Promoters are, generally, located immediately upstream of a transcription start site (TSS) and have a variety of regulatory motifs, such as transcription factors (TFs) and CpG islands (CGIs), that participate in the regulation of gene expression. Here analysis of the promoter region for pig vomeronasal receptor type 1 (V1R) was described. In the analysis, TSSs for pig V1R genes was first identified and five motifs (MV1, MV2, MV3, MV4, and MV5) were found that are shared by at least 50% of the pig V1R promoter input sequences from both strands. Among the five motifs, MV2 was identified as a common promoter motif shared by all (100%) pig V1R promoters. For further analysis, to better characterize and get deeper biological insight associated with MV2, TOMTOM web application was used. MV2 was compared to the known motif databases (such as JASPAR) to see if they are similar to a known regulatory motif (transcription factor). Hence, it was revealed that MV2 serves as the binding site mainly for the BetaBetaAlpha zinc finger (BTB-ZF) transcription factor gene family to regulate expression of pig V1R genes. Moreover, it was shown that pig V1R promoters are CpG poor, suggesting that their gene expression regulation pattern is in tissue specific manner. PMID- 29120692 TI - Epithelial Na+ Channel Regulation by Extracellular and Intracellular Factors. AB - Epithelial Na+ channels (ENaCs) are members of the ENaC/degenerin family of ion channels that evolved to respond to extracellular factors. In addition to being expressed in the distal aspects of the nephron, where ENaCs couple the absorption of filtered Na+ to K+ secretion, these channels are found in other epithelia as well as nonepithelial tissues. This review addresses mechanisms by which ENaC activity is regulated by extracellular factors, including proteases, Na+, and shear stress. It also addresses other factors, including acidic phospholipids and modification of ENaC cytoplasmic cysteine residues by palmitoylation, which enhance channel activity by altering interactions of the channel with the plasma membrane. PMID- 29120695 TI - Hypoxia and Sprint Swimming Performance of Juvenile Striped Bass, Morone saxatilis. AB - Annual hypoxia in the Chesapeake Bay has expanded to the point where Darwinian fitness of juvenile striped bass (Morone saxatilis) may depend on their ability to perform in low-oxygen environments. The locomotion they use in predator/prey dynamics relies primarily on white (type II) muscle that is powered by anaerobic metabolic pathways and has generally been thought to be immune to aquatic hypoxia. We tested the sprint performance of 15 juvenile striped bass twice under acute hypoxia (20% air saturation [AS]) 5 wk apart and once under normoxia (>85% AS) in between. Average sprint performance was lower under the first hypoxia exposure than in normoxia and increased in the second hypoxia test relative to the first. The rank order of individual sprint performance was significantly repeatable when comparing the two hypoxia tests but not when compared with sprint performance measured under normoxic conditions. The maximum sprint performance of each individual was also significantly repeatable within a given day. Thus, sprint performance of striped bass is reduced under hypoxia, is phenotypically plastic, and improves with repetitive hypoxia exposures but is unrelated to relative sprint performance under normoxia. Since energy to fuel a sprint comes from existing ATP and creatine phosphate stores, the decline in sprint performance probably reflects reduced function of a part of the reflex chain leading from detection of aversive stimuli to activation of the muscle used to power the escape response. PMID- 29120696 TI - Assessment of long term ecotoxicity of urban stormwaters using a multigenerational bioassay on Ceriodaphnia dubia: A preliminary study. AB - Standardized ecotoxicity bioassays show some limits to assess properly long-term residual toxicity of complex mixture of pollutants often present at low concentration, such as stormwaters. Among invertebrate organisms used for ecotoxicity testing, the microcrustacean Ceriodaphnia dubia (C. dubia) is considered as one of the most sensitive, especially regarding reproduction impairment as a toxicity endpoint. Consequently, this work explores the interest to perform a multigenerational assay based on the study of the reproduction of C. dubia to assess long-term ecotoxicity of complex mixture, using stormwater samples. With this in mind, a battery of standardized bioassays (Daphnia magna mobility, Pseudokirchneriella subcapitata population growth, Heterocypris incongruens growth and one generation C. dubia reproduction inhibition assays) was performed in parallel to a three generation C. dubia reproduction inhibition assay on 2 stormwater samples. Results highlighted that while all standardized bioassays failed to reveal residual toxicity in the stormwater samples, the C. dubia multigenerational assay exhibited an higher sensitivity than the previous ones. No adverse effect was observed for the first exposed generation, but an increase in mortality and a reproduction disturbance was obtained in the second and third exposed generation depending of the sample. Further experiments are now needed to optimize the exposure protocol of this multigenerational assay. PMID- 29120697 TI - Enhancing antibody patent protection using epitope mapping information. AB - As the $100B therapeutic monoclonal antibody (mAb) market continues to grow, developers of therapeutic mAbs increasingly face the need to strengthen patent protection of their products and enforce their patents in courts. In view of changes in the patent law landscape, patent applications are strategically using information on the precise binding sites of their mAbs, i.e., the epitopes, to support patent novelty, non-obviousness, subject matter, and a tightened written description requirement for broad genus antibody claims. Epitope data can also allow freedom-to-operate for second-generation mAbs by differentiation from patented first-generation mAbs. Numerous high profile court cases, including Amgen v. Sanofi over rival mAbs that block PCSK9 activity, have been centered on epitope mapping claims, highlighting the importance of epitopes in determining broad mAb patent rights. Based on these cases, epitope mapping claims must describe a sufficiently large number of mAbs that share an epitope, and each epitope must be described at amino acid resolution. Here, we review current best practices for the use of epitope information to overcome the increasing challenges of patenting mAbs, and how the quality, conformation, and resolution of epitope residue data can influence the breadth and strength of mAb patents. PMID- 29120698 TI - Platelet microaggregation in sepsis examined by quartz crystal microbalance with dissipation technology. AB - Antiplatelet therapies remain an area of potential interest for the treatment of sepsis; however, studies of platelet aggregation in sepsis have yielded conflicting results. We examined platelet aggregation patterns in patients with septic shock using quartz crystal microbalance with dissipation technology, a microfluidic device capable of measuring platelet microaggregate formation under flow conditions. Platelet aggregation was increased in the washed platelet samples of septic patients. Conversely, these same platelets aggregated less than healthy controls when examined in their plasma. PMID- 29120699 TI - Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. AB - Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 * 25 mg/m2/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 * 10 mg/m2; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m2 ch14.18/CHO (d8-17) as LTI combined with 6 * 106 IU/m2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade >=3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients. PMID- 29120700 TI - Basket Studies: Redefining Clinical Trials in the Era of Genome-Driven Oncology. AB - Understanding a tumor's detailed molecular profile has become increasingly necessary to deliver the standard of care for patients with advanced cancer. Innovations in both tumor genomic sequencing technology and the development of drugs that target molecular alterations have fueled recent gains in genome-driven oncology care. "Basket studies," or histology-agnostic clinical trials in genomically selected patients, represent one important research tool to continue making progress in this field. We review key aspects of genome-driven oncology care, including the purpose and utility of basket studies, biostatistical considerations in trial design, genomic knowledgebase development, and patient matching and enrollment models, which are critical for translating our genomic knowledge into clinically meaningful outcomes. PMID- 29120701 TI - Neighborhood Resources to Support Healthy Diets and Physical Activity Among US Military Veterans. AB - INTRODUCTION: Among the nearly 21 million military veterans living in the United States, 64.0% of women and 76.1% of men are overweight or obese, higher rates than in the civilian population (56.9% of women and 69.9% of men). Attributes of the residential environment are linked to obesity. The objective of this study was to characterize the residential environments of the US veteran population with respect to availability of food and recreational venues. METHODS: We used American Community Survey data to determine the concentration of veterans (the percentage of veterans among the adult population) in all continental US census tracts in 2013, and we used proprietary data to construct measures of availability of food and recreational venues per census tract. Using descriptive statistics and ordinary least-squares regression, we examined associations between the concentration of veterans per census tract and those residential environmental features. RESULTS: In census tracts with high concentrations of veterans, residents had, on average, 0.5 (interquartile range, 0-0.8) supermarkets within a 1-mile radius, while residents in census tracts with low concentrations of veterans had 3.2 (interquartile range, 0.6-3.7) supermarkets. Patterns were similar for grocery and convenience stores, fast food restaurants, parks, and commercial fitness facilities. In adjusted analyses controlling for census-tract-level covariates, veteran concentration remained strongly negatively associated with availability of those food and recreational venues. In nonmetropolitan tracts, adjusted associations were greatly attenuated and even positive. CONCLUSION: Where veterans live is strongly associated with availability of food outlets providing healthy (and unhealthy) foods and with recreational venues, raising questions about the contributions of veterans' residential environments to their high obesity rates. Additional research is needed to address those questions. PMID- 29120702 TI - Food Insecurity and Cardiometabolic Risk Factors in Adolescents. AB - INTRODUCTION: Food insecurity is associated with poor cardiometabolic health in adults. The extent to which this relationship exists in adolescents has yet to be defined. The objective of this study was to examine the relationship between food insecurity and cardiometabolic risk factors in adolescents. METHODS: We evaluated the association between food insecurity and several cardiometabolic risk factors by using data collected from the Youth Risk Behavior Survey at the state and city levels. Logistic regression models adjusted for sex, race/ethnicity, grade, and neighborhood safety were used to determine the association between food insecurity and cardiometabolic risk factors among a weighted sample of 495,509 adolescents. RESULTS: Of the sample studied, 12.8% reported being food insecure. Food-insecure adolescents had more than a twofold increased odds of not eating breakfast on all 7 days (adjusted odds ratio [AOR] = 2.27; 95% confidence interval [CI], 1.61-3.21; P < .001), a 60% increased odds of reporting less than 8 hours per day of sleep (AOR = 1.60; 95% CI, 1.15-2.23; P = .006), a 65% increased odds of reporting current cigarette smoking (AOR = 1.65; 95% CI, 1.16 2.36; P = .006), and a 65 % increased odds of current alcohol consumption (AOR = 1.36; CI, 1.01-1.84; P = .04), compared with food-secure adolescents. CONCLUSION: Among adolescents, in adjusted models, food insecurity was significantly associated with not consuming breakfast daily, getting less than 8 hours of sleep per day, currently smoking, and currently drinking alcohol. Food insecurity in adolescents may serve as an important precursor to poor cardiometabolic health. PMID- 29120704 TI - XVI Convegno Triennale sui Problemi Clinici e Sociali dell'Emofilia e delle Malattie Emorragiche Congenite, Napoli, 9-12 Novembre 2017. PMID- 29120703 TI - Maternal Obesity, Gestational Weight Gain, and Asthma in Offspring. AB - INTRODUCTION: Obesity is common among women of childbearing age; intrauterine exposure to maternal obesity or gestational weight gain may influence the development of asthma in early childhood. We examined the relationships of maternal obesity and gestational weight gain with asthma in offspring. METHODS: We used data from the Early Childhood Longitudinal Study-Birth Cohort, which has a nationally representative sample of children followed from birth in 2001 through age 4 (n = 6,450). Asthma was based on parental report of a medical professional's diagnosis. We used generalized estimating equation binomial models to compute adjusted odds ratios (ORs) of childhood asthma with maternal obesity and 4 measures of gestational weight gain. RESULTS: Compared with children of normal-weight mothers, children of obese mothers had increased risk of asthma (adjusted OR, 1.63; 95% confidence interval [CI], 1.26-2.12) by age 4, and children born to overweight mothers had similar risk (adjusted OR, 1.25; 95% CI, 0.99-1.59). Extreme-low weight gain (<5 kg) and extreme-high weight gain (>=25 kg) were associated with increased risk of asthma; however, the following measures were not significant predictors of asthma: meeting gestational weight gain recommendations of the Institute of Medicine, total gestational weight gain, and weekly rate of weight gain in the second and third trimesters. CONCLUSION: Extreme-low or extreme-high gestational weight gain and maternal obesity are risk factors for early childhood asthma, further evidence of the long-term impact of intrauterine exposure on children and the need to target preconception care to improve child health indicators. PMID- 29120705 TI - Effects of waterborne cadmium on metabolic rate, oxidative stress, and ion regulation in the freshwater fish, inanga (Galaxias maculatus). AB - The freshwater fish Galaxias maculatus (inanga) is a widespread Southern hemisphere species, but despite its habitation of lowland near-coastal waters with a high potential for cadmium contamination, nothing is known regarding its sensitivity to this toxic trace metal. Acute (96h) exposures were therefore performed to determine sublethal responses of inanga to waterborne cadmium at a regulatory trigger value (nominally 0.2MUgL-1; measured 1MUgL-1), an environmental level (measured at 2.5MUgL-1), and an effect level (measured at 10MUgL-1). Whole body (tissue remaining following excision of kidney and liver) cadmium burden remained constant up until an exposure concentration of 10MUgL-1, at which point cadmium concentration increased significantly. A transient effect of cadmium on metabolic rate was observed, with an impaired oxygen consumption noted at 2.5, but not 1 or 10, MUg L-1. Cadmium did not impair influx rates of either sodium or calcium, and no effects of cadmium on oxidative stress parameters (catalase activity, lipid peroxidation) were noted in the kidney. However, at cadmium concentrations of 2.5 and 10MUgL-1, lipid peroxidation in the liver increased, concomitant with a decline in hepatic catalase activity. These data indicate that there are significant differences in the mechanisms of cadmium toxicity in inanga, relative to better-studied Northern hemisphere species, especially with respect to ionoregulatory impacts. However, effects were induced at cadmium concentrations unlikely to be encountered in any but the most highly contaminated waterways, and thus our data suggest that current trigger values for cadmium concentrations in Australian and New Zealand waters are likely to be protective of inanga. PMID- 29120706 TI - Administration of cloprostenol and oxytocin before electroejaculation in goat bucks reduces the needed amount of electrical stimulation without affecting seminal quality. AB - Electroejaculation (EE) is a widely used semen collection technique; but, it is stressful and painful for the animals. Considering these concerns, it may be important to develop practices to decrease the negative implications of EE on animals. Oxytocin and prostaglandin-F2alpha (PGF2alpha) stimulate the contractions of the muscles of the male genital tract. Therefore, the aim of this study was to analyze the effectiveness of the administration of oxytocin and/or a PGF2alpha analogue (cloprostenol) to bucks in relation to their stress response and sperm parameters before semen collection by EE was performed. Semen was collected with EE from 12 Gabon bucks in a 2 * 2 factorial arrangement (factors: with or without oxytocin, with or without cloprostenol). Each treatment was applied to different animals every 3 to 6 days, allowing all the animals to receive all the four treatments. The treatments applied to bucks before EE were as follows: 1) control (ConT), bucks received no hormonal treatment; 2) oxytocin (OxyT), bucks received 10 IU of oxytocin intramuscularly (IM) 30 s before beginning the EE; 3) PGF2alpha (PgT), bucks received 250 MUg of cloprostenol IM 5 min before beginning the EE; and 4) oxytocin plus PGF2alpha (OxPgT), animals received treatment with both OxT and PgT. The number of electrical pulses, time length needed to achieve ejaculation, number of vocalizations, creatine kinase (CK) concentration and sperm parameters in goat bucks were recorded. The administration of cloprostenol and oxytocin before EE shortened the procedure and decreased the number of pulses and the pulse/voltage applied (P = 0.02 for all). This treatment also tended to decrease the number of vocalizations (P = 0.067). There were no treatment effects in the initial values; neither were there increases in heart rate and rectal temperature, or CK concentration. Seminal variables were not affected by the treatments. In conclusion, it would be important to consider the combined application of cloprostenol and oxytocin before EE, as it can shorten the process, reducing the electrical stimulus with positive effects on animal welfare and without affecting seminal quality in goat bucks. PMID- 29120707 TI - Using specific recombinant gonadotropins to induce spermatogenesis and spermiation in the European eel (Anguilla anguilla). AB - New specific European eel (Anguilla anguilla) recombinant gonadotropins (aarGths) produced in the ovarian cells of Chinese hamsters (CHO) were used to induce maturation in captive male eels. In the first experiment, five different hormonal treatments were assayed: one group was given a constant dose of recombinant European eel follicle-stimulating hormone (aarFsh; 4 MUg/fish) for 9 weeks, and the second group received a constant dose of recombinant European eel luteinizing hormone (aarLh; 2 MUg/fish) also for 9 weeks. The other three groups were injected with different combinations of both aarGths (some doses constant, some variable). All five treatments stimulated androgen synthesis, but the increase was more pronounced in the fish treated with a combination of both aarGths. Unlike aarLh, aarFsh alone was able to induce spermiation, the best results were achieved in the fish that were treated with a constant dose of aarFSH and an increasing dose of aarLH, with spermiation being induced (20% motile cells) despite the fact that these fish were immature at the start of the experiment. In order to improve sperm quality, a second experiment was performed. Immature males received three constant doses of aarFsh (2.8, 1.4 or 0.7 MUg/fish) and increasing doses of aarLh (every 3 weeks; 1, 2, 6 MUg/fish). All the treatments induced spermiation, however the best sperm quality (with >=50% motile cells) was observed in the males treated with the highest dose of aarFsh. In conclusion, these specific recombinant gonadotropins have demonstrated their capacity to induce spermatogenesis and spermiation in vivo in a teleost fish, the European eel. PMID- 29120708 TI - How to write a good peer review. PMID- 29120709 TI - Microscope-integrated intraoperative optical coherence tomography-guided small incision lenticule extraction: New surgical technique. AB - We describe the surgical technique of microscope-integrated intraoperative optical coherence tomography (OCT)-guided small-incision lenticule extraction. The technique enables manual tracking of surgical instruments and identification of the desired dissection plane. It also helps discern the relation between the dissector and the intrastromal lenticule. The dissection plane becomes hyperreflective on dissection, ensuring complete separation of the intrastromal lenticule from the overlying and underlying stroma. Inadvertent posterior plane entry, cap-lenticule adhesion, incomplete separation of the lenticule, creation of a false plane, and lenticule remnants may be recognized intraoperatively so corrective steps can be taken immediately. In cases with a hazy overlying cap, microscope-integrated intraoperative OCT enables localization and extraction of the lenticule. The technique is helpful for inexperienced surgeons, especially in cases with low amplitudes of refractive errors, ie, thin lenticules. PMID- 29120710 TI - Femtosecond laser implantation of a 340-degree intrastromal corneal ring segment in keratoconus: Short-term outcomes. AB - PURPOSE: To evaluate the short-term outcomes of femtosecond laser-assisted implantation of a 340-degree intracorneal ring (ICR) (Keraring) in patients with keratoconus. SETTING: Four centers in Iran. DESIGN: Prospective case series. METHODS: All cases had implantation of the 340-degree ICR after tunnel creation with a femtosecond laser. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, sphere, cylinder, manifest refraction spherical equivalent (MRSE), mean keratometry (K), steep K, and flat K were evaluated preoperatively and 1, 3, and 6 months postoperatively. RESULTS: Eighteen eyes of 17 patients were included. The mean follow-up was 4.33 months (range 1 to 6 months). The mean UDVA improved from 0.95 logarithm of the minimum angle of resolution (logMAR) +/- 0.33 (SD) to 0.53 +/- 0.35 logMAR (P = .001) and the mean CDVA from 0.39 +/- 0.22 logMAR to 0.26 +/- 0.21 logMAR (P = .09). The mean sphere decreased from -5.08 +/ 3.74 diopters (D) to -1.67 +/- 2.59 D, the mean cylinder from -5.83 +/- 2.02 D to -2.72 +/- 1.81 D, and the mean MRSE from -8.03 +/- 3.88 D to -3.01 +/- 2.82 D (P < .001). The mean K decreased from 51.43 +/- 3.59 D to 47.42 +/- 3.59 D (P < .001). All patients with a preoperative mean K greater than 55.0 D had worse CDVA. CONCLUSIONS: Implantation of a 340-degree ICR using femtosecond laser improved the visual, refractive, and topographic parameters in keratoconic patients. The findings indicate that patients with severe keratoconus (mean K >55.0 D) are not good candidates for this type of ICR. PMID- 29120711 TI - Combined transepithelial phototherapeutic keratectomy and conventional photorefractive keratectomy followed simultaneously by corneal crosslinking for keratoconus: Cretan protocol plus. AB - PURPOSE: To evaluate the visual, refractive, and topographic outcomes after combined transepithelial phototherapeutic keratectomy (PTK) and conventional photorefractive keratectomy (PRK) followed simultaneously by corneal crosslinking (CXL) for keratoconus. SETTING: Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece. DESIGN: Prospective case series. METHODS: Patients with progressive keratoconus had simultaneous conventional PRK followed by CXL; the corneal epithelium was removed using transepithelial PTK (Cretan protocol plus). The visual, refractive, and topographic outcomes and the endothelial cell density (ECD) were evaluated preoperatively and 1, 3, 6, and 12 months postoperatively. RESULTS: Forty-three patients (55 eyes) were enrolled. The mean uncorrected and corrected distance visual acuities improved significantly from 0.98 +/- 0.63 (SD) logarithm of minimum angle of resolution (logMAR) and 0.20 +/- 0.23 logMAR preoperatively to 0.39 +/- 0.35 logMAR (P < .001) and 0.08 +/- 0.16 logMAR (P < .001) 12 months postoperatively, respectively. The mean spherical equivalent improved significantly from -4.67 +/- 4.00 diopters (D) preoperatively to -2.24 +/- 2.81 D (P < .001) at 12 months. The mean steep keratometry (K) and flat keratometry readings decreased significantly from 50.30 +/- 5.00 D and 45.62 +/- 3.10 D preoperatively to 46.27 +/- 3.90 D (P < .001) and 43.46 +/- 3.00 D (P < .001) 12 months postoperatively, respectively. No ECD alterations were observed throughout the follow-up (P > .05). CONCLUSION: Combined transepithelial PTK and conventional PRK followed simultaneously by CXL was effective in corneal stabilization and vision improvement in keratoconic patients. PMID- 29120712 TI - Demarcation line depth after contact lens-assisted corneal crosslinking for progressive keratoconus: Comparison of dextran-based and hydroxypropyl methylcellulose-based riboflavin solutions. AB - PURPOSE: To compare the demarcation line depth after contact lens-assisted corneal crosslinking (CXL) for progressive keratoconus using dextran-based and hydroxypropyl methylcellulose (HPMC)-based riboflavin solutions. SETTING: Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. DESIGN: Retrospective case series. METHODS: Patients with preoperative epithelium-on (epi-on) minimum corneal thickness between 350 MUm and 450 MUm having contact lens-assisted CXL for progressive keratoconus were crosslinked with isoosmolar 0.1% riboflavin in 20% dextran 500 or HPMC 1.1%. The primary outcome measure was the mean demarcation line depth measured 1 month postoperatively on anterior-segment optical coherence tomography. The secondary outcome measure was change in endothelial cell density (ECD) 6 months from baseline. RESULTS: The study comprised 21 patients (21 eyes, 9 in the HPMC group and 12 in the dextran group). The mean demarcation line depth was deeper in the HPMC group (308.22 MUm +/- 84.19 [SD]) than in the dextran group (235.33 +/- 64.87 MUm) (P < .04). This difference remained significant (P = .02) even after controlling for the preoperative lesser epi-on minimum corneal thickness in the HPMC group (385.56 +/-13.81 MUm) versus the dextran group (413.08 +/- 29.58 MUm) (P < .02). The ECD 6 months after contact lens-assisted CXL was comparable to the baseline levels in both groups (P = .19 and P = .09, respectively). CONCLUSION: During contact lens-assisted CXL, HPMC-based riboflavin seemed to be associated with a deeper demarcation line than dextran-based riboflavin, although both solutions were safe for the endothelium at 6 months. PMID- 29120713 TI - Waveform analysis of deformation amplitude and deflection amplitude in normal, suspect, and keratoconic eyes. AB - PURPOSE: To evaluate the performance of waveform-derived variables in distinguishing normal, suspect, and keratoconic eyes. SETTING: Narayana Nethralaya Eye Hospital, Bangalore, India. DESIGN: Retrospective case series. METHODS: Scheimpflug tomography (Pentacam) and dynamic Scheimpflug analysis (Corvis ST) of 253 normal (253 patients) eyes and 205 keratoconic eyes (205 patients) were evaluated. Among the 205 patients, 62 had keratoconus in 1 eye, while the unaffected eye was suspect. From deformation amplitude, deflection amplitude and whole-eye movement were extracted. A biomechanical model was used to derive a linear (kc [constant]) and nonlinear measure (kc [mean]) of corneal stiffness. Multivariate logistic regression was performed to determine sensitivity and specificity. The analysis was validated in another dataset of 59 normal, 45 suspect, and 160 keratoconic eyes. RESULTS: Deformation amplitude maximum, applanation 1 time and deformation amplitude, applanation 2 time, kc (constant), kc (mean), and deflection amplitude maximum were significantly different between normal and keratoconic eyes (P < .001). The deformation characteristics of the suspect eyes were similar to those of the keratoconic eyes, particularly grade 1 (P > .05). The kc (constant) and kc (mean) had the highest area under curve (>0.98), sensitivity, and specificity greater than 90% and 91%, respectively. Logistic regression using kc (constant) and kc (mean) improved the area to 1.0, with a sensitivity and specificity equal to 99.6% and 100%, respectively. In the validation dataset, the same cutoff yielded a sensitivity, specificity, and accuracy of 99.5%, 100%, and 99.6%, respectively. CONCLUSION: Corneal stiffness and waveform analyses could be reliable differentiators of suspect and keratoconic eyes from normal eyes. PMID- 29120714 TI - Functional magnetic resonance imaging to assess neuroadaptation to multifocal intraocular lenses. AB - PURPOSE: To evaluate the use of functional magnetic resonance imaging (MRI) to assess neuroadaptation to multifocal intraocular lenses (IOLs). SETTING: Faculty of Medicine, University of Coimbra, Coimbra, Portugal. DESIGN: Prospective case study. METHODS: Patients with bilateral diffractive IOL implantation after cataract surgery had functional MRI at postoperative intervals of 3 weeks and 6 months. A nonintervention control group was included as proof of concept. Functional stimuli consisted of sinusoidal gratings with threshold contrast and a light source to induce disability glare. Subjective quality of vision and reading performance were assessed and wavefront analyses were performed. RESULTS: The study comprised 30 patients in the study group and 15 in the control group. Glare decreased the functional MRI signal measured for sinusoidal gratings initially (3 weeks) but not at 6 months (P = .04), which was confirmed by contrast detection under glare improvement (P = .002). Patients showed increased activity of cortical areas involved in visual attention, procedural learning, effortful cognitive control, and goal-oriented behavior in the early postoperative period, which normalized at 6 months. There were no differences in aberrations, Strehl ratio, or modulation transfer function despite significant decreases in questionnaire symptom scores and visual acuity and reading performance improvements. The control group remained unchanged. CONCLUSIONS: Neuroadaptation to multifocal IOLs took place initially through recruitment of visual attentional and procedural learning networks. Thereafter, a form of long-term adaptation/functional plasticity occurred, leading to brain activity regularization toward a non-effort pattern. These findings, which reinforce the crucial role of higher-level brain regions in the perceptual construction of vision, were consistent with functional and questionnaire outcomes and were unrelated to optical properties. PMID- 29120715 TI - New pinhole sulcus implant for the correction of irregular corneal astigmatism. AB - PURPOSE: To evaluate the effect on visual acuity of the implantation of a new intraocular pinhole device (Xtrafocus) in cases of irregular corneal astigmatism with significant visual impairment. SETTING: University of Sao Paulo, Sao Paulo, Brazil. DESIGN: Prospective case series. METHODS: Pseudophakic eyes of patients with irregular corneal astigmatism were treated with the pinhole device. The causes of irregular corneal astigmatism were keratoconus, post radial keratotomy (RK), post-penetrating keratoplasty (PKP), and traumatic corneal laceration. The device was implanted in the ciliary sulcus in a piggyback configuration to minimize the effect of corneal aberrations. Preoperative and postoperative visual parameters were compared. The main outcome variables were manifest refraction, uncorrected and corrected distance and near visual acuities, subjective patient satisfaction, and intraoperative and postoperative adverse events and complications. RESULTS: Twenty-one patients (ages 35 to 85 years) were included. There was statistically significant improvement in uncorrected and corrected (CDVA) distance visual acuities. The median CDVA improved from 20/200 (range 20/800 to 20/60) preoperatively to 20/50 (range 20/200 to 20/20) in the first month postoperatively and remained stable over the following months. Manifest refraction remained unchanged, while a subjective visual performance questionnaire revealed perception of improvement in all the tested working distances. No major complication was observed. One case presented with decentration of the device, which required an additional surgical intervention. CONCLUSIONS: The intraocular pinhole device performed well in patients with irregular astigmatism caused by keratoconus, RK, PKP, and traumatic corneal laceration. There was marked improvement in visual function, with high patient satisfaction. PMID- 29120716 TI - Cost comparison of commonly used postoperative topical ophthalmic antibiotics. AB - PURPOSE: To provide information on the actual fill level and cost of currently available antibiotic drops used perioperatively. DESIGN: Prospective laboratory investigation. SETTING: Robert Cizik Eye Clinic, Houston, Texas USA. METHODS: The following 9 medications were tested: moxifloxacin, gatifloxacin (branded and generic), besifloxacin, levofloxacin, ciprofloxacin, ofloxacin, trimethoprim/polymyxin B, tobramycin, and gentamicin. Actual bottle-fill volume and number of drops per bottle were measured using 10 bottles of each formulation. The percentage of the bottle used and the perioperative cost (using average wholesale price) were calculated for 3 times a day and 4 times a day dosing for 7-day, 10-day, and 14-day courses. Formulations were compared using 1 way analysis of variance with Tukey multiple comparisons. RESULTS: For medications with sticker volumes of at least 5 mL, all but 2 medications (ofloxacin, 4 times a day for 14 days; gentamicin, 4 times a day for 14 days) covered 2 perioperative courses. Besifloxacin had a fill volume less than the sticker volume. The most cost-effective perioperative antibiotic prophylaxis was trimethoprim-polymyxin B (4 times a day: $12.87 for 7-day, 10-day, and 14-day courses, and $46.88 for 4-day course; 3 times a day: $12.87 for 7-day, 10-day, and 14-day courses). CONCLUSIONS: Most antibiotics had an actual fill volume greater than sticker volume, which is a sufficient drug regimen for 2 perioperative courses. The costs of common postoperative topical antibiotic regimens vary widely depending on the drug and dosing regimen. Cost considerations for perioperative antibiotics will be increasingly important because the number of cataract surgeries is expected to increase with the growing and aging population. PMID- 29120717 TI - Cataract surgery after proton-beam irradiation for uveal tumors. AB - PURPOSE: To study the risks associated with cataract surgery in patients with previous proton-beam irradiation (PBI), focusing on preoperative risk factors, intraoperative findings, and postoperative complications. SETTING: Massachusetts Eye & Ear Infirmary, Boston, Massachusetts, USA. DESIGN: Retrospective case series. METHODS: Electronic medical records of patients who had PBI and cataract surgery between January 1, 2006, and October 1, 2016, were reviewed. RESULTS: The study comprised 29 eyes of 29 patients. Preoperative evaluation found dry eye (72.4%), posterior synechiae (24.1%), peripheral anterior synechiae (13.8%), anterior capsule fibrosis (10.3%), and iris atrophy (10.3%). Intraoperative findings included poor red reflex requiring trypan blue capsule staining (37.9%), synechiae requiring synechialysis (24.1%), evidence of previous inflammation prompting sub-Tenon triamcinolone injection (17.2%), and miosis (10.3%). Postoperative complications included posterior capsule opacification (PCO) by 1 year (48.3%), intraocular pressure spike of 23 mm Hg or greater at 1 day (24.1%), anterior chamber inflammation at 1 month (24.1%), and cystoid macular edema (CME) (17.2%). Proximity of the initial tumor to the posterior pole was associated with poor visual outcomes after cataract surgery. Compared with reference data, this cohort had higher rates of anterior chamber inflammation at 1 month, CME, fibrinous inflammation, PCO by 1 year, intraoperative requirement for trypan blue, and synechialysis. CONCLUSIONS: Complications after cataract surgery performed after PBI were similar to those seen in patients with uveitis (prolonged inflammation, CME, fibrinous inflammation, early PCO). Steroid depot administration might be useful to prevent these complications, although further research is needed to determine an optimum regimen. PMID- 29120718 TI - Wound healing in rabbit corneas after flapless refractive lenticule extraction with a 345 nm ultraviolet femtosecond laser. AB - PURPOSE: To characterize corneal wound healing in a rabbit model after flapless refractive lenticule extraction with a 345 nm ultraviolet femtosecond laser. SETTING: Departments of Ophthalmology and Anatomy II, University of Erlangen Nurnberg and Wavelight GmbH, Erlangen, Germany. DESIGN: Experimental study. METHODS: Flapless refractive lenticule extraction was performed in 1 eye each of 20 New Zealand white rabbits (-5.0 diopters). Groups of 4 animals were euthanized after 48 hours, 1 week, 2 weeks, 4 weeks, and 3 months, respectively. Corneal samples were prepared for histology and fluorescence microscopy. To assess corneal cell death, proliferation, and myofibroblastic transdifferentiation, terminal uridine deoxynucleotidyl nick end-labeling (TUNEL) assay as well as immunostaining for Ki67 and alpha-smooth muscle actin (alphaSMA) were performed on sagittal cryosections. RESULTS: Histology revealed a zone of keratocyte depletion with a thickness of approximately 50 MUm around the extraction site. At 48 hours, pronounced TUNEL staining of keratocytes was detected around the interface (159.9 cells/mm +/- 18.4 [SD]), which steadily decreased to 74.9 +/- 19.8 cells/mm at 1 week and 5.7 +/- 4.8 cells/mm at 2 weeks. Ki67 staining of keratocytes was evident at 48 hours (10.0 +/- 3.8 cells/mm), which then decreased at 1 week (5.2 +/- 1.7 cells/mm) and 2 weeks (0.4 +/- 0.5 cells/mm). From 4 weeks onward, no TUNEL or Ki67 staining was detected. The corneal stroma was alphaSMA negative at all timepoints. CONCLUSION: Application of the 345 nm laser showed no signs of problematic repair processes in the cornea, which supports the initiation of the clinical phase. PMID- 29120719 TI - Supercritical impregnation and optical characterization of loaded foldable intraocular lenses using supercritical fluids. AB - PURPOSE: To prepare drug-loaded intraocular lenses (IOLs) used to combine cataract surgery with postoperative complication treatment through supercritical impregnation while preserving their optical properties. SETTING: Aix-Marseille Universite, CNRS, Centrale Marseille, Laboratoire de Mecanique, Modelisation & Procedes Propres, Marseille, France, and He University Eye Hospital, Liaoning Province, China. DESIGN: Experimental study. METHODS: Supercritical impregnations of commercial foldable IOLs used in cataract surgery with ciprofloxacin (an antibiotic) and dexamethasone 21-phosphate disodium salt (an antiinflammatory drug) were performed in a noncontinuous mode. Impregnation amounts were determined through drug-release kinetic studies. The optical characterizations of IOLs were determined by evaluating the dioptric power and the imaging quality by determining the modulating transfer function (MTF) at a specified spatial frequency according to the International Organization for Standardization (ISO 11979-2:2014). RESULTS: Transparent IOLs presenting an effective impregnation were obtained with a prolonged drug delivery during approximately 10 days. Optical characterizations (dioptric powers and MTF values) show preserved optical properties after supercritical treatment/impregnation. CONCLUSION: Supercritical treatments/impregnations do not damage the optical properties of IOLs and are therefore adequate for the preparation of delivery devices used for cataract surgery. PMID- 29120720 TI - Advanced cataract learning experience in United States ophthalmology residency programs. AB - This study examined resident exposure to and competency in new techniques for cataract removal and intraocular lens (IOL) implantation. A questionnaire was sent to 116 United States ophthalmology program directors and completed by 71. In response to the questionnaire, program directors reported that 95.3% of their graduating seniors were competent to select and implant toric IOLs and 52.3% were competent to implant capsular tension rings (CTRs). Divide and conquer (56.6%) and stop and chop (25.4%) dominated phacoemulsification teaching. Femtosecond laser-assisted cataract surgery was performed by residents in 44.1% of programs. In 25.4%, residents observed but did not perform the procedure; in 35.6%, they received didactic-only training; and in 22.0%, they received no exposure. Most programs (73.2%) had virtual-reality simulators for cataract surgery, but wet-lab practice (91.1%), didactic training (82.1%), and watching videos (82.1%) were the primary curricular tools used to teach advanced technologies. PMID- 29120722 TI - Recurrent endothelial rejection after DSAEK and DMEK causing corneal perforation in a patient with history of Fuchs endothelial dystrophy: October consultation #1. PMID- 29120721 TI - October consultation #2. PMID- 29120723 TI - October consultation #3. PMID- 29120724 TI - October consultation #4. PMID- 29120725 TI - October consultation #5. PMID- 29120726 TI - October consultation #6. PMID- 29120727 TI - October consultation #7. PMID- 29120728 TI - Editor's Comment. PMID- 29120729 TI - October consultation #8. PMID- 29120730 TI - Reply. PMID- 29120731 TI - Reply. PMID- 29120732 TI - Risk factors for cystoid macular edema after cataract surgery in diabetic patients. PMID- 29120734 TI - Laboratory evolution of protein conformational dynamics. AB - This review focuses on recent work that has begun to establish specific functional roles for protein conformational dynamics, specifically how the conformational landscapes that proteins can sample can evolve under laboratory based evolutionary selection. We discuss recent technical advances in computational and biophysical chemistry, which have provided us with new ways to dissect evolutionary processes. Finally, we offer some perspectives on the emerging view of conformational dynamics and evolution, and the challenges that we face in rationally engineering conformational dynamics. PMID- 29120733 TI - Heart-focused anxiety and health care seeking in patients with non-cardiac chest pain: A prospective study. AB - OBJECTIVES: This study aimed to estimate the incidence of medical consultations six months after an emergency department (ED) consultation for non-cardiac chest pain (NCCP). It also investigated the role of heart-focused anxiety (HFA) and other factors in predicting an increased healthcare utilization in these patients. METHOD: This was a prospective study of 428 patients who came to an ED with NCCP. Patients completed an interview and questionnaires assessing HFA, psychological distress, the characteristics of NCCP, and comorbidities. Their medical consultations were assessed by telephone interview six months later. The contribution of each factor was assessed using a binomial negative regression. RESULTS: Eighty-three percent of patients reported at least one medical consultation (mean=3.1, standard deviation=3.9). HFA (incident rate ratio 1.01; 95% CI, 1.00-1.02), the presence of a medical condition (2.14; 1.51-3.03), NCCP frequency (1.49; 1.16-1.91) and NCCP-related interference (1.08; 1.04-1.13) were predictive of further medical consultations. CONCLUSIONS: A significant proportion of patients with NCCP are at risk of multiple medical consultations following discharge from the ED. HFA appears as a determinant of medical consultations after controlling for multiple confounding factors. PMID- 29120735 TI - The rewiring of transcription circuits in evolution. AB - The binding of transcription regulators to cis-regulatory sequences is a key step through which all cells regulate expression of their genes. Due to gains and losses of cis-regulatory sequences and changes in the transcription regulators themselves, the binding connections between regulators and their target genes rapidly change over evolutionary time and constitute a major source of biological novelty. This review covers recent work, carried out in a wide range of species, that addresses the overall extent of these evolutionary changes, their consequences, and some of the molecular mechanisms that lie behind them. PMID- 29120736 TI - Mind Your Cs and Gs. AB - How can an innate immune sensor shape viral evolution? In recent work, Takata et al. (2017) determined that the antiviral protein ZAP recognizes CG dinucleotide composition to differentiate self from non-self. This pressure may have driven CG dinucleotide suppression in HIV-1 and other RNA viruses to evade host antiviral defenses. PMID- 29120737 TI - A Swiss Army Knife to Cut Malaria Transmission. AB - The mosquito microbiota is known to naturally limit malaria transmission, acting directly on parasites and via effects on mosquito immunity and fitness. Using genetically modified bacteria and mosquitoes, two studies uncover new potential of this multipotent prospective tool to reduce disease transmission. PMID- 29120738 TI - Staphylococcus aureus: Master Manipulator of the Skin. AB - Skin colonization by Staphylococcus aureus is associated with severity of atopic dermatitis (AD). Two papers in this issue of Cell Host & Microbe by Nakagawa et al. (2017) and Liu et al. (2017) define a pathway by which epicutaneous Staphylococcus aureus promotes skin inflammation and may contribute to AD. PMID- 29120739 TI - Lipoyl-E2-PDH Gets a Second Job. AB - Pyruvate dehydrogenase (PDH) plays a well-known metabolic role inside cells. In this issue of Cell Host & Microbe, Grayczyk et al. (2017) show that the bacterial pathogen Staphylococcus aureus unexpectedly secretes and repurposes the lipoylated E2 subunit of PDH to suppress TLR-mediated activation of host macrophages by bacterial lipoproteins. PMID- 29120740 TI - Breaking the Barrier: Host Cell Invasion by Lujo Virus. AB - Lujo virus (LUJV) is an arenavirus that emerged in 2008 associated with a cluster of human cases of severe hemorrhagic fever. In this issue of Cell Host & Microbe, Raaben et al. (2017) identify neuropilin (NRP)-2 as cell surface receptor and the tetraspannin protein CD63 as intracellular entry factor for LUJV. PMID- 29120741 TI - Getting Your Head around Cerebral Malaria. AB - Cerebral malaria is one of the most severe complications of human infection by the Plasmodium falciparum parasite. In this issue of Cell Host & Microbe, Kessler et al. (2017) provide valuable insights into the diagnosis and pathogenesis of this poorly understood manifestation of malaria. PMID- 29120742 TI - The Human Microbiome and Obesity: Moving beyond Associations. AB - Mounting evidence indicates that the gut microbiome responds to diet, antibiotics, and other external stimuli with speed and high precision and in ways that impact a variety of metabolic conditions including obesity and non-alcoholic fatty liver disease. Despite a decade of research establishing a strong association between the gut microbiota and obesity in humans, a causal relationship and the underlying mechanism remain outstanding. Several technological and methodological limitations in obesity and microbiome research have made it difficult to establish causality in this complex relationship. Additionally, limited collaborative interaction between microbiome and obesity researchers has delayed progress. Here, we discuss the current status of microbiome research as it relates to understanding obesity from the perspective of both communities, outline the underlying research challenges, and suggest directions to advance the obesity-microbiome field as a whole, with particular emphasis on the development of microbiome-targeted therapies for obesity prevention and treatment. PMID- 29120744 TI - Staphylococcus aureus Virulent PSMalpha Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation. AB - Staphylococcus aureus commonly colonizes the epidermis, but the mechanisms by which the host senses virulent, but not commensal, S. aureus to trigger inflammation remain unclear. Using a murine epicutaneous infection model, we found that S. aureus-expressed phenol-soluble modulin (PSM)alpha, a group of secreted virulence peptides, is required to trigger cutaneous inflammation. PSMalpha induces the release of keratinocyte IL-1alpha and IL-36alpha, and signaling via IL-1R and IL-36R was required for induction of the pro-inflammatory cytokine IL-17. The levels of released IL-1alpha and IL-36alpha, as well as IL-17 production by gammadelta T cells and ILC3 and neutrophil infiltration to the site of infection, were greatly reduced in mice with total or keratinocyte-specific deletion of the IL-1R and IL-36R signaling adaptor Myd88. Further, Il17a-/-f-/- mice showed blunted S. aureus-induced inflammation. Thus, keratinocyte Myd88 signaling in response to S. aureus PSMalpha drives an IL-17-mediated skin inflammatory response to epicutaneous S. aureus infection. PMID- 29120743 TI - Staphylococcus aureus Epicutaneous Exposure Drives Skin Inflammation via IL-36 Mediated T Cell Responses. AB - Staphylococcus aureus colonization contributes to skin inflammation in diseases such as atopic dermatitis, but the signaling pathways involved are unclear. Herein, epicutaneous S. aureus exposure to mouse skin promoted MyD88-dependent skin inflammation initiated by IL-36, but not IL-1alpha/beta, IL-18, or IL-33. By contrast, an intradermal S. aureus challenge promoted MyD88-dependent host defense initiated by IL-1beta rather than IL-36, suggesting that different IL-1 cytokines trigger MyD88 signaling depending on the anatomical depth of S. aureus cutaneous exposure. The bacterial virulence factor PSMalpha, but not alpha-toxin or delta-toxin, contributed to the skin inflammation, which was driven by IL-17 producing gammadelta and CD4+ T cells via direct IL-36R signaling in the T cells. Finally, adoptive transfer of IL-36R-expressing T cells to IL-36R-deficient mice was sufficient for mediating S. aureus-induced skin inflammation. Together, this study defines a previously unknown pathway by which S. aureus epicutaneous exposure promotes skin inflammation involving IL-36R/MyD88-dependent IL-17 T cell responses. PMID- 29120745 TI - NRP2 and CD63 Are Host Factors for Lujo Virus Cell Entry. AB - Arenaviruses cause fatal hemorrhagic disease in humans. Old World arenavirus glycoproteins (GPs) mainly engage alpha-dystroglycan as a cell-surface receptor, while New World arenaviruses hijack transferrin receptor. However, the Lujo virus (LUJV) GP does not cluster with New or Old World arenaviruses. Using a recombinant vesicular stomatitis virus containing LUJV GP as its sole attachment and fusion protein (VSV-LUJV), we demonstrate that infection is independent of known arenavirus receptor genes. A genome-wide haploid genetic screen identified the transmembrane protein neuropilin 2 (NRP2) and tetraspanin CD63 as factors for LUJV GP-mediated infection. LUJV GP binds the N-terminal domain of NRP2, while CD63 stimulates pH-activated LUJV GP-mediated membrane fusion. Overexpression of NRP2 or its N-terminal domain enhances VSV-LUJV infection, and cells lacking NRP2 are deficient in wild-type LUJV infection. These findings uncover this distinct set of host cell entry factors in LUJV infection and are attractive focus points for therapeutic intervention. PMID- 29120747 TI - Pla2g1b Places Worms in Peril. PMID- 29120746 TI - Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs. AB - Lung complications are a major cause of rheumatoid arthritis-related mortality. Involvement of gut microbiota in lung diseases by the gut-lung axis has been widely observed, but the underlying mechanism remains mostly unknown. Using an autoimmune arthritis model, we show that a constituent of the gut microbiota, segmented filamentous bacteria (SFB), distantly provoke lung pathology. SFB induce autoantibodies in lung during the pre-arthritic phase, and SFB-dependent lung pathology requires the T helper 17 (Th17) responses. SFB-induced gut Th17 cells are preferentially recruited to lung over spleen due to robust expression in the lung of the Th17 chemoattractant, CCL20. Additionally, we found that in peripheral tissues, SFB selectively expand dual T cell receptor (TCR)-expressing Th17 cells recognizing both an SFB epitope and self-antigen, thus augmenting autoimmunity. This study reveals mechanisms for commensal-mediated gut-lung crosstalk and dual TCR-based autoimmunity. PMID- 29120748 TI - Doubling Down on BRCA-Mutated Cancer. AB - Immunotherapy is changing the landscape of cancer treatment. Nonetheless, not all malignancies respond, possibly due to low mutational load. Recent work in a TP53 /-BRCA1-mutant murine breast cancer model indicates that double blockade with two immune checkpoint inhibitors increases the number of tumor-infiltrating lymphocytes and overall survival after DNA damaging chemotherapy, whereas single blockade does not. These findings suggest an approach to enhance the impact of immune checkpoint blockade in BRCA-mutated tumors. PMID- 29120749 TI - Basal S-Nitrosylation Is the Guardian of Tissue Homeostasis. AB - Recent studies have uncovered that nitric oxide (NO) signaling is largely conducted by S-nitrosylation, involving >3000 proteins. The nitrosyl group could then travel further by transnitrosylation or be secreted, enabling regulation of the whole tissue. A subset of proteins are constitutively S-nitrosylated, playing roles in the regulation of tissue homeostasis. PMID- 29120750 TI - Lysophosphatidate Signaling: The Tumor Microenvironment's New Nemesis. AB - Lysophosphatidate (LPA) is emerging as a potent mediator of cancer progression in the tumor microenvironment. Strategies for targeting LPA signaling have recently entered clinical trials for fibrosis. These therapies have potential to improve the efficacies of existing chemotherapies and radiotherapy by attenuating chronic inflammation, irrespective of diverse mutations within cancer cells. PMID- 29120751 TI - Breast Cancer: Multiple Subtypes within a Tumor? AB - Breast cancer is a heterogeneous disease, and stratification of tumors is paramount to achieve better clinical outcomes. While it is common to stratify and treat breast tumors as a single entity, insights from studies on intratumoral heterogeneity and cancer stem cells raise the possibility that multiple breast cancer subtypes may coexist within a tumor. A role for plasticity in driving dynamic conversions between breast cancer subtypes is proposed, and the clinical implications include a need for combinatorial therapeutic strategies that account for the discrete disease entities and their plasticity. Accordingly, the advent of single-cell technologies will be crucial in enabling the diagnosis and stratification of distinct disease subtypes down to the cellular level. PMID- 29120752 TI - The Glycogen Shunt Maintains Glycolytic Homeostasis and the Warburg Effect in Cancer. AB - Despite many decades of study there is a lack of a quantitative explanation for the Warburg effect in cancer. We propose that the glycogen shunt, a pathway recently shown to be critical for cancer cell survival, may explain the excess lactate generation under aerobic conditions characteristic of the Warburg effect. The proposal is based on research on yeast and mammalian muscle and brain that demonstrates that the glycogen shunt functions to maintain homeostasis of glycolytic intermediates and ATP during large shifts in glucose supply or demand. Loss of the glycogen shunt leads to cell death under substrate stress. Similarities between the glycogen shunt in yeast and cancer cells lead us here to propose a parallel explanation of the lactate produced by cancer cells in the Warburg effect. The model also explains the need for the active tetramer and inactive dimer forms of pyruvate kinase (PKM2) in cancer cells, similar to the two forms of Pyk2p in yeast, as critical for regulating the glycogen shunt flux. The novel role proposed for the glycogen shunt implicates the high activities of glycogen synthase and fructose bisphosphatase in tumors as potential targets for therapy. PMID- 29120753 TI - Mitochondrial OXPHOS Induced by RB1 Deficiency in Breast Cancer: Implications for Anabolic Metabolism, Stemness, and Metastasis. AB - A switch from catabolic to anabolic metabolism, a major hallmark of cancer, enables rapid cell duplication, and is driven by multiple oncogenic alterations, including PIK3CA mutation, MYC amplification, and TP53 loss. However, tumor growth requires active mitochondrial function and oxidative phosphorylation (OXPHOS). Recently, loss of the retinoblastoma (RB1) tumor suppressor in breast cancer was shown to induce mitochondrial protein translation (MPT) and OXPHOS. Here, we discuss how increased OXPHOS can enhance anabolic metabolism and cell proliferation, as well as cancer stemness and metastasis. Mitochondrial STAT3, FER/FER-T, and CHCHD2 are also implicated in OXPHOS. We propose that RB1 loss represents a prototypic oncogenic alteration that promotes OXPHOS, that aggressive tumors acquire lethal combinations of oncogenes and tumor suppressors that stimulate anabolism versus OXPHOS, and that targeting both metabolic pathways would be therapeutic. PMID- 29120755 TI - Migrating into the Tumor: a Roadmap for T Cells. AB - Tumors can be divided into 'hot' (T cell inflamed) or 'cold' (T cell noninflamed) according to the presence of immune cells. In this review, we discuss variables that influence T cell migration into the tumor microenvironment. Chemokines can attract T cells to the tumor site and tumor intrinsic pathways can influence the composition of local chemokines. Tumor-induced vasculature can hamper T cell migration. Other immune cells and tumor-derived molecules can block T cell proliferation and survival. It is important to better understand these mechanisms in order to target them therapeutically. Enhancing T cell infiltration may increase response rates to immunotherapy and increase survival. PMID- 29120756 TI - Centrifugeless dispersive liquid-liquid microextraction based on salting-out phenomenon followed by high performance liquid chromatography for determination of Sudan dyes in different species. AB - In this work, a novel method, namely centrifugeless dispersive liquid-liquid microextraction, is introduced for the efficient extraction of banned Sudan dyes from foodstuff and water samples. In this method, which is based upon the salting out phenomenon, in order to accelerate the extraction process, the extraction solvent (1-undecanol, 75 MUL) is dispersed into the sample solution. Then the mixture is passed through a small column filled with 5 g sodium chloride, used as a separating reagent. In this condition, fine droplets of the extraction solvent are floated on the mixture, and the phase separation is simply achieved. This method is environmentally friendly, simple, and very fast, so that the overall extraction time is only 7 min. Under the optimal experimental conditions, the preconcentration factors in the range of 90-121 were obtained for the analytes. Also good linearities were obtained in the range of 2.5-1200 ng mL-1 (r2 >= 0.993). PMID- 29120757 TI - Phenolic profiles and antioxidant activity of Turkish Tombul hazelnut samples (natural, roasted, and roasted hazelnut skin). AB - The phenolic profiles and antioxidant status of hazelnut samples [natural (raw) hazelnut, roasted hazelnut, and roasted hazelnut skin] were compared. Free and bound (ester-linked and glycoside-linked) phenolic acids were examined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Comprehensive identification of phenolics was carried out using Q-exactive hybrid quadrupole orbitrap mass spectrometer (Q-OT-MS). Samples were also assessed for their total phenolics and antioxidant activities using three different assays. Ten free and bound phenolic acids were quantified in hazelnut samples. Roasted hazelnut skin contained the highest content of total phenolic acids, followed by natural and roasted hazelnuts. The majority of phenolic acids were present in the bound form. Using a Q-OT-MS, 22 compounds were tentatively identified, 16 of which were identified for the first time in hazelnut samples. The newly identified compounds consisted of flavonoids, phenolic acids and related compounds, hydrolysable tannins and related compounds, and other phenolics. Three antioxidant assays demonstrated similar trends that roasted hazelnut skin rendered the highest activity. The present work suggests that roasted hazelnut skin is a rich source of phenolics and can be considered as a value-added co-product for use as functional food ingredient and antioxidant. PMID- 29120754 TI - New Opportunities and Challenges to Defeat Cancer Stem Cells. AB - Cancer stem cells (CSCs) are a subpopulation of cancer cells that are capable of self-renewal, proliferation, differentiation, plastic adaptation, and immune regulation, thereby mediating tumorigenesis, metastasis, and therapy resistance. CSCs are associated with cancer progression and clinical outcome in cancer patients. Successful targeting of CSCs will therefore be necessary to eradicate and cure cancer. Functional regulators of stem cell (stemness) signaling pathways in human cancers have brought new opportunities to target CSCs and reframe cancer targeting strategies in clinical settings. However, challenges remain due to a lack of complete understanding of CSC plasticity/heterogeneity and the limited efficacy of individual stemness inhibitors in cancer treatment. In this article we review CSC signaling pathways and the current state of CSC-targeting therapeutics in combinatory treatments in clinical trials. PMID- 29120758 TI - Antioxidant capacity and major polyphenol composition of teas as affected by geographical location, plantation elevation and leaf grade. AB - Tea polyphenols have been a topic of discussion due to their health benefits. Nevertheless, detailed studies on the antioxidant capacity and polyphenol contents of teas in relation to factors including geographical locations, plantation elevations and leaf grades have been limited. In this study, 53 tea samples were analysed to determine the individual and total catechin and theaflavin contents by HPLC and the total antioxidant capacity by Oxygen Radical Absorbance Capacity (ORAC) methods. Results show that the polyphenol (catechins and theaflavins) contents were significantly influenced by plantation location. Black tea from low plantation elevation contained 22-28% more polyphenols than those from high elevation. Small tea leaves had up to 15% more polyphenols than larger leaves from similar elevation. The results were further confirmed by Principal Composition Analysis (PCA), which grouped the black and green tea samples into 3 different clusters, respectively. PMID- 29120759 TI - Untargeted metabolomics reveals specific withanolides and fatty acyl glycoside as tentative metabolites to differentiate organic and conventional Physalis peruviana fruits. AB - The agronomic production systems may affect the levels of food metabolites. Metabolomics approaches have been applied as useful tool for the characterization of fruit metabolome. In this study, metabolomics techniques were used to assess the differences in phytochemical composition between goldenberry samples produced by organic and conventional systems. To verify that the organic samples were free of pesticides, individual pesticides were analyzed. Principal component analysis showed a clear separation of goldenberry samples from two different farming systems. Via targeted metabolomics assays, whereby carotenoids and ascorbic acid were analyzed, not statistical differences between both crops were found. Conversely, untargeted metabolomics allowed us to identify two withanolides and one fatty acyl glycoside as tentative metabolites to differentiate goldenberry fruits, recording organic fruits higher amounts of these compounds than conventional samples. Hence, untargeted metabolomics technology could be suitable to research differences on phytochemicals under different agricultural management practices and to authenticate organic products. PMID- 29120760 TI - Rapid and automated on-line solid phase extraction HPLC-MS/MS with peak focusing for the determination of ochratoxin A in wine samples. AB - This study reports a fast and automated analytical procedure based on an on-line SPE-HPLC-MS/MS method for the automatic pre-concentration, clean up and sensitive determination of OTA in wine. The amount of OTA contained in 100MUL of sample (pH?5.5) was retained and concentrated on an Oasis MAX SPE cartridge. After a washing step to remove matrix interferents, the analyte was eluted in back-flush mode and the eluent from the SPE column was diluted through a mixing Tee, using an aqueous solution before the chromatographic separation achieved on a monolithic column. The developed method has been validated according to EU regulation N. 519/2014 and applied for the analysis of 41 red and 17 white wines. The developed method features minimal sample handling, low solvent consumption, high sample throughput, low analysis cost and provides an accurate and highly selective results. PMID- 29120761 TI - Complex formation between starch and stearic acid: Effect of enzymatic debranching for starch. AB - Effect of debranching for a high-amylose starch (~70% amylose) on its V-complex formation with stearic acid was examined. Gel-permeation chromatograms showed that amylopectin was degraded to smaller molecules as the debranching time increased from 6 to 24 h. Increased formation of debranched starch/stearic acid complexes (recovery yield of stearic acid from 45.17 to 89.31% and starch from 39.92 to 55.43%) was observed with increased debranching time (from 6 to 24 h) and complexation time (from 6 to 24 h). The X-ray diffraction patterns of the debranched starch/stearic acid complexes displayed a mixture of B-type and V-type patterns, with 2theta peaks at 7.6 degrees , 13.1 degrees , 17.2 degrees , 20 degrees , 21.6 degrees , and 23.4 degrees . The melting temperature and enthalpy changes of the debranched starch/stearic acid complexes were gradually enhanced with increasing debranching time. These results suggest that starch can be modified by debranching to produce a significant amount of debranched starch/stearic acid complexes. PMID- 29120762 TI - Intramuscular variations of proteome and muscle fiber type distribution in semimembranosus and semitendinosus muscles associated with pork quality. AB - Proteome analysis was performed to understand intramuscular variations in muscle fiber distribution in semimembranosus (SM) and semitendinosus (ST) muscles associated with pork quality. Fifteen SM and ST muscles were separated into dark and light portions. The relative area of oxidative fiber was higher (P < .0001) in dark portion than that in light portion, while glycolytic fiber types were distributed primarily (P < .01) in light portions regardless of muscle types. Myosin-1, myosin-4, troponin complex (fast), myosin light chains, and metabolic enzymes responsible for fast-twitch glycolytic types were overexpressed in light portions (P < .05). However, myosin-2, myosin-7, myoglobin, and mitochondrial oxidative metabolic enzymes were closely related to slow-twitch oxidative fibers. These resulted in high pH, redness, and tenderness but low lightness and drip loss of pork quality. In conclusion, differentially expressed muscle proteins are associated with fiber type (oxidative vs. glycolytic) distribution, resulting in intramuscular variations of pork quality. PMID- 29120763 TI - High-throughput authentication of edible oils with benchtop Ultrafast 2D NMR. AB - We report the use of an Ultrafast 2D NMR approach applied on a benchtop NMR system (43 MHz) for the authentication of edible oils. Our results demonstrate that a profiling strategy based on fast 2D NMR spectra recorded in 2.4 min is more efficient than the standard 1D experiments to classify oils from different botanical origins, since 1D spectra on the same samples suffer from strong peak overlaps. Six edible oils with different botanical origins (olive, hazelnut, sesame, rapeseed, corn and sunflower) have been clearly discriminated by PCA analysis. Furthermore, we show how this approach combined with a PLS model can detect adulteration processes such as the addition of hazelnut oil into olive oil, a common fraud in food industry. PMID- 29120764 TI - Effects of a combination of elicitation and precursor feeding on grape amino acid composition through foliar applications to Garnacha vineyard. AB - Vine foliar applications of phenylalanine (Phe) or methyl jasmonate (MeJ) could improve the synthesis of secondary metabolites. However, there are no reports focusing on the effects of elicitation supported by precursor feeding on must amino acid composition in grapevines. The aim of this research was to study the effect of the elicitation of methyl jasmonate (MeJ) supported by phenylalanine (Phe) as a precursor feeding (MeJ+Phe) and its application individually on must amino acid composition. Results showed that foliar Phe and MeJ treatments decreased the concentration of most of the studied amino acids with respect to the control (p<=0.05). MeJ+Phe treatment did not affect must nitrogen content. Musts obtained from MeJ+Phe showed higher concentration of several amino acids than samples from Phe and MeJ applications. Therefore, other sources of precursor feeding could support elicitation, to improve amino acid composition and be considered as a tool for viticulture. PMID- 29120765 TI - Rapid and sensitive detection of pyrimethanil residues on pome fruits by Surface Enhanced Raman Scattering. AB - Surface Enhanced Raman Scattering (SERS) supported by gold nanoparticles (AuNPs) was applied to detect and quantify residues of pyrimethanil on pome fruits, a widely used fungicide in horticultural species. Spheroidal AuNPs with different size were fabricated and compared in this study. The analytical procedure was set up on a silicon dioxide flat substrate to standardize SERS methodology. A Raman mapping strategy was exploited to increase signal reproducibility and to minimize bias due to different local surface morphologies. Univariate and multivariate regressions were compared for calibration. Multivariate PLS approach demonstrated acceptable repeatability and method stability (RMSECV = 4.79 ppm; RMSEP = 4.31 ppm) in the range 0-40 mg kg-1, providing higher accuracy and intra-day repeatability with a mean percentage error of 18.7% and 32.8% for PLS and univariate calibration, respectively. The method here proposed can be reliably applied for PMT detection on pome fruits within the European law limits. PMID- 29120766 TI - The enrichment and characterization of ginger-derived glycoprotein using magnetic particles. AB - Ginger-derived glycoproteins are a widely distributed group of biological macromolecules with multiple functions. To date, the structure of ginger-derived glycoproteins has not been clarified with regard to their complexity, their sequence diversity and their uneven micro-distribution. In this study, a lectin microarray was used to evaluate 37 types of lectins and determine the optimal lectins that can conjugate with glycoproteins based on the fluorescence intensity. Subsequently, the lectins were immobilized on magnetic beads, coupled with glycoproteins to enrich ginger-derived glycoproteins, and evaluated using SDS-PAGE. Our results showed that five lectins (e.g. VVA, ConA, STL, LEL, and LCA) were selected by the lectin microarray and that VVA showed the highest fluorescence intensity. In addition, it is indicated that the structure of the carbohydrate chains might contain GlaNAc, mannose, GlcNAc, and LacNAc. PMID- 29120767 TI - Observations using Phosphorus-31 nuclear magnetic resonance (31P-NMR) of structural changes in freeze-thawed hen egg yolk. AB - Hen egg yolk (EY) has a complicated structure consisting of lipids and proteins, and its structure is deeply related with its functional properties. 31P-NMR is an efficient technique to non-destructively detect the dynamic behaviour of phospholipids, the main component of bio-membranes. We determined conditions for measuring the 31P NMR spectra of EY and identified the components. 31P-NMR was used to detect phosvitin, inorganic phosphate, and lipoprotein as well as structural changes such as granule collapse and freeze-thaw denaturation as signal changes. Freeze-thaw denaturation generated a new denaturation peak. We separated aggregates of LDL from freeze-thawed plasma using centrifugation. TEM and 31P-NMR observations revealed that the denaturation peak corresponded to LDL aggregates. The 31P-NMR spectra suggested the formation of multiple forms of LDL aggregates in which the head groups of phospholipid molecules adopt a face-to face orientation, similar to that observed following the flocculation of lipoproteins or in the lamellar-like structures of phospholipids. PMID- 29120768 TI - Preparation of activated flavor precursor DFG, N-(1-deoxy-1-fructosylglycine) by combination of vacuum evaporation and closed system heating steps. AB - Amadori rearrangement products are potent "activated flavor precursors". This study describes a stepwise optimization of DFG (1-deoxy-1-fructosylglycine) formation from glycine and glucose, varying temperature, water activity aw, concentration, and ratio/state of precursor mix. In the solid state reaction at 50 degrees C for 16 h, yield of DFG increased with decreasing water activity with a peak at aw = 0.22-0.33. In water the conversion was slower and negatively correlated with water activity in the range aw = 0.8-1. An industrially applicable 2-step vacuum drying and heating process was explored, which first concentrates precursor solution to aw = 0.5-0.6 and then continues the heating in a closed vessel for an additional 2-4 h. Over 40 mol% conversion from glucose to DFG was obtained on a multi-gram scale. Fine tuning of conditions will be needed for other amino acid/carbohydrate combinations and may offer new perspectives for tailored product flavor generation under moderate heating. PMID- 29120769 TI - Rapid classification of intact chicken breast fillets by predicting principal component score of quality traits with visible/near-Infrared spectroscopy. AB - In this study visible/near-infrared spectroscopy (Vis/NIRS) was evaluated to rapidly classify intact chicken breast fillets. Five principal components (PC) were extracted from reference quality traits (L*, pH, drip loss, expressible fluid, and salt-induced water gain). A quality grades classification method by PC1 score was proposed. With this method, 150 chicken fillets were properly classified into three quality grades, i.e., DFD (dark, firm and dry), normal, and PSE (pale, soft and exudative). Furthermore, PC1 score could be predicted using partial least squares regression (PLSR) model based on Vis/NIRS (R2p = 0.78, RPD = 1.9), without the measurement of any quality traits. Thresholds of PC1 classification method were applied to classify the predicted PC1 score values of each fillet into three quality grades. The classification accuracy of calibration and prediction set were 85% and 80%, respectively. Results revealed that PC1 score classification method is feasible, and with Vis/NIRS, this method could be rapidly implemented. PMID- 29120770 TI - A green ionic liquid-based vortex-forced MSPD method for the simultaneous determination of 5-HMF and iridoid glycosides from Fructus Corni by ultra-high performance liquid chromatography. AB - A simple and green ionic liquid-based vortex-forced matrix solid phase dispersion (IL-VFMSPD) method was presented to simultaneously extract 5-hydroxymethyl furfurol (5-HMF) and iridoid glycosides in Fructus Corni by ultra-high performance liquid chromatography. Ionic liquid was used as a green elution reagent in vortex-forced MSPD process. A few parameters such as the type of ionic liquid, the type of sorbent, ratio of sample to sorbent, the concentration and volume of ionic liquid, grinding time and vortex time, were investigated in detail and an orthogonal design experiment was introduced to confirm the best conditions in this procedure. With the final optimized method, the recoveries of the target compounds in Fructus Corni were in the range of 95.2-103% (RSD<5.0%) and the method displayed a good linearity within the range of 0.8-200 MUg mL-1 for morroniside, sweroside, loganin, cornuside and 1.2-300 MUg mL-1 for 5-HMF. The limits of detection ranged from 0.02 to 0.08 MUg mL-1 for all compounds. The results showed that the newly established method was efficiently applied to extract and determine iridoid glycosides and 5-HMF for quality control of Fructus Corni. PMID- 29120771 TI - Extraction, structure, and emulsifying properties of pectin from potato pulp. AB - Effects of HCl, H2SO4, HNO3, citric acid, and acetic acid on the yield, structure, and emulsifying properties of potato pectins were investigated. Results showed that the highest yield (14.34%) was obtained using citric acid, followed by HNO3 (9.83%), HCl (9.72%), H2SO4 (8.38%), and acetic acid (4.08%). The degrees of methylation (37.45%) and acetylation (15.38%), protein content (6.97%), and molecular weight (3.207 * 105 g/mol) were the highest for pectin extracted using acetic acid, and (galactose + arabinose)/rhamnose was 33.34, indicating that it had a highly branched rhamnogalacturonan I domain. Fourier transform infrared spectroscopy showed a specific absorbance peak at 1064 cm-1, which corresponds to the acetyl groups in potato pectins. SEM showed that all potato pectins are morphologically different. The emulsifying activity (EA, 44.97%-47.71%) and emulsion stability (ES, 36.54%-46.00%) of the pectins were influenced by acid types, and were higher than those of commercial citrus and apple pectin. PMID- 29120772 TI - Evaluation of extractable polyphenols released to wine from cooperage byproduct by near infrared hyperspectral imaging. AB - Extractable total phenolic content of American non-toasted oak (Quercus alba L.) shavings has been determined using near infrared hyperspectral imaging. A like wine model solution was used for the simulated maceration procedure. Calibrations were performed by partial least squares regression (MPLS) using a number of spectral pre-treatments. The coefficient of determination of wood for extractable total phenolic content was 0.89, and the standard error of prediction was 6.3 mg g-1. Thus, near infrared hyperspectral imaging arises as an attractive strategy for predicting extractable total phenolic content in the range of 0-65 mg g-1, of great relevance from the point of view of quality assurance regarding wood used in the wine sector. Near infrared hyperspectral imaging arises as an attractive strategy for the feasibility of enhancing the value of cooperage byproduct through the fast determination of extractable bioactive molecules, such as polyphenols. PMID- 29120773 TI - Prediction models for assessing anthocyanins in grape berries by fluorescence sensors: Dependence on cultivar, site and growing season. AB - Fluorescence sensors are useful tools for the non-destructive assessment of grape berry anthocyanins. The Multiplex (Mx) sensor here studied provides two anthocyanin indices: ANTHR = log(1/Chl-fluorescence_R) and ANTHRG = log(Chl fluorescence_R/Chl-fluorescence_G), based on the chlorophyll (Chl) fluorescence excited with red (R) and green (G) light. These indices were calibrated against wet chemistry. The dependence of anthocyanin prediction models on cultivar, season and site was studied on four cultivars in two Italian regions during three consecutive years. The 2010 global model (all cultivars at both growing sites) gave relative prediction errors on anthocyanin content less than 14.1% (ANTHR) and 19.0% (ANTHRG). The ANTHRG was independent of season, maintaining a relative error of about 20% in both 2011 and 2012. In field applications of the calibrated Mx, it showed its ability to detect inter-plot and inter-season differences on both growing sites. PMID- 29120774 TI - A group-specific, quantitative real-time PCR assay for detection of crab, a crustacean shellfish allergen, in complex food matrices. AB - A real-time PCR assay was developed for detection of crab, a crustacean allergen, in food products. Group-specific primers and probes were developed to detect numerous species of crab. Method validation included tests of detection in complex food matrices, evaluation of commercial food products, and cross reactivity testing on a wide variety of crustaceans. The method was able to detect several species of crab spiked into complex food matrices at levels ranging from 0.1 to 105 parts per million (weight/weight), worked equally well on different platforms, exhibited high specificity for crab over other types of crustaceans, and yielded much higher signals from commercial food products listing crab as an ingredient than from those containing other crustaceans. PMID- 29120775 TI - Preparation and prebiotic potential of pectin oligosaccharides obtained from citrus peel pectin. AB - Pectin oligosaccharide (POS) fractions were obtained by controlled chemical degradation of citrus peel pectin. By adjusting trifluoroacetic acid (TFA) concentration, three oligosaccharides were obtained, of molecular weight (Mw) range 3000-4000 Da, 2000-3000 Da and lower than 2000 Da. Varying hydrogen peroxide (H2O2) concentration and reaction time produced oligosaccharides of 3000 4000 Da and 2000-3000 Da. The relative proportions of acidic monosaccharide increased from 68.58% to 89.93% (TFA) and from 63.74% to 83.26% (H2O2) as the reaction conditions intensified. Prebiotic activity scores were used to quantify POS ability to promote selective growth of specific probiotics. Sample POSH1 from H2O2 degradation showed the highest prebiotic potential with prebiotic activity score 0.41 for Lactobacillus paracasei LPC-37 and 0.92 for Bifidobacterium bifidum ATCC 29521. PMID- 29120776 TI - Comparative proteomic profiling of myofibrillar proteins in dry-cured ham with different proteolysis indices and adhesiveness. AB - Excessive proteolysis during dry-cured ham processing may lead to high adhesiveness and consumer dissatisfaction. The aim of this research is to identify biomarkers for proteolysis and adhesiveness. Two hundred biceps femoris porcine muscle samples from Spanish dry-cured ham were firstly evaluated for various physicochemical parameters, including their proteolysis indices and instrumental adhesiveness. Proteins of samples with extreme proteolysis indices were separated by two-dimensional electrophoresis and identified by tandem mass spectrometry (MALDI-TOF/TOF). We found that hams of higher proteolysis index had statistically significant increased adhesiveness. Proteomic analysis revealed statistically significant qualitative and quantitative differences between sample groups. Thus, protein fragments increased remarkably in samples with higher proteolysis index scores. In addition, higher proteolysis index hams showed increased degradation for a total of five non-redundant myofibrillar and sarcoplasmic proteins. However, myosin-1, alpha-actin and myosin-4 proteins were the biomarkers that underwent the most intense response to proteolysis and adhesiveness. PMID- 29120777 TI - Synthesis and characterization of alkylated caseinate, and its structure-curcumin loading property relationship in water. AB - Alkylated caseinates (Cn-caseinates) containing selected C8-C16 alkyl groups were successfully synthesized through a two-step reaction between the protein and fatty acids. The substitution degree (SD) of the alkyl groups was 5.2-72.9%, which depended on the feed molar ratio of reagents and fatty acid chain length. The SD value was positively associated with the surface hydrophobicity index (S0) of the Cn-caseinate. Among the tested Cn-caseinates (n = 0, 8, 12, 14 and 16), C16-caseinate showed the best self-assembly and curcumin-loading properties in water. With increased palmitoyl group SD, the critical micelle concentration (CMC) of C16-caseinate was decreased from 5.15 to 3.77 mg/L and the encapsulation efficiency of curcumin-loaded C16-caseinate self-assemblies was increased from 31.16% to 69.87%. Transmission electron microscopy analysis demonstrated a desirable sphere assembly. In addition, the C16-caseinate self-assemblies had good re-dispersibility and storage stability at 4 degrees C for 6 weeks. PMID- 29120778 TI - Kinetic investigation of the trapping of Nepsilon-(carboxymethyl)lysine by 4 methylbenzoquinone: A new mechanism to control Nepsilon-(carboxymethyl)lysine levels in foods. AB - o-Benzoquinones, formed during oxidation of polyphenols, react with amines through a Michael addition. In the present study, the ability of 4 methylbenzoquinone (4MBQ) to trap Nepsilon-(carboxymethyl)lysine (CML) through a Michael addition with the amine groups on CML was investigated at different pH values. Apparent second order rate constants (k2) for the reaction of 4MBQ with CML were determined by stopped-flow spectrophotometry at 25 degrees C to be ~0.0 M-1 s-1 at pH 5, 9.5 M-1 s-1 at pH 7, and 164.5 M-1 s-1 at pH 8 based on the loss of 4MBQ at 401 nm. The reaction between 4MBQ and CML generated coloured CML quinone compounds via colourless CML-phenol species as identified by LC-ESI MS/MS. These data provide evidence that CML formed during food production can be trapped by o-benzoquinones, which is a new mechanism by which polyphenols may be used to control CML levels in foods. PMID- 29120779 TI - 9,10-Anthraquinone deposit in tea plantation might be one of the reasons for contamination in tea. AB - 9,10-Anthraquinone (AQ) was a new contaminant, with unknown sources, occurred globally in tea. European Union (EU) fixed the maximum residue limit (MRL) of 0.02mg/kg. The pollution source of AQ in tea was traced from the view of AQ deposit on tea crop by simulation. The possible contamination pathway and main factors to decrease AQ were explored in tea cultivation- tea manufacture- tea infusion, on the basis of AQ analytical methods by using solvent extraction and gas chromatography-tandem mass spectrometry (GC-MS/MS) quantification. 58.8-84.6% of AQ degraded in tea processing, and drying played a key role to reduce the AQ contamination. Certain concentration of AQ deposited on tea shoots could resulted in AQ beyond the MRL of 0.02mg/kg in tea. AQ leaching into tea brew (about 10%) could lead to the possible health risk. AQ deposit on tea crop during the tea cultivation might cause the AQ contamination in tea. PMID- 29120780 TI - Green and efficient removal of cadmium from rice flour using natural deep eutectic solvents. AB - Natural deep eutectic solvents (NADESs) constitute a novel class of biodegradable and inexpensive solvents. In this study, twenty choline chloride- and glycerol based NADESs were prepared and investigated as washing agents in the removal of cadmium (Cd) from rice flour for the first time. Choline chloride-based NADESs demonstrated good Cd removal (51%-96%). A natural, biodegradable surfactant, saponin, was mixed with the NADESs to enhance their efficiency. No increase in Cd removal was observed when glycerol-based NADESs were combined with 1% saponin; however, synergistic effects between saponin and choline chloride-based NADESs were observed during the washing process and >99% Cd was removed using NADES saponin mixtures. Moreover, NADESs washing process did not affect the main chemical components or structure of rice flour. The mechanism of Cd removal by NADESs and regeneration of Cd-contaminated NADESs were also explored. The study presents a green and efficient way of removing Cd from contaminated rice. PMID- 29120781 TI - Balsamic type varietal vinegar from cv. Xinomavro (Northen Greece). Optimization and scale-up of the alcoholic fermentation step using indigenous multistarters. AB - Taguchi design was used to examine the effect of parameters that should be optimized in order to control the alcoholic fermentation of the concentrated grape must (CGM) from cv. Xinomavro using the best-performing indigenous Hanseniaspora uvarum and Saccharomyces cerevisiae strains as multistarters. The "optimum" combination of conditions (cell ratio of H. uvarum/S. cerevisiae; inoculum size and inoculation time of S. cerevisiae; fermentation time and temperature) resulted in an alcoholic product that meets ethanol (79 g/kg) and residual sugar (164 g/kg) content requirements for further use in the production of balsamic type vinegar. Multistarter fermentation affected positively the varietal organoleptic traits of the fermented CGM. 5-(Hydroxymethyl)-furfural content emerged as a critical factor for the standardization of this process. Scaling up experiments in 12 L barrels verified findings from small scale in 100 mL flasks. The results of this work can be used as a prototype in further similar efforts. PMID- 29120782 TI - Targeted secondary metabolic and physico-chemical traits analysis to assess genetic variability within a germplasm collection of "long storage" tomatoes. AB - "Long storage" tomato is a crop traditionally cultivated in the Mediterranean area under no water supply, that recently has attracted the interest of breeders for its high tolerance to drought and as potential genetic source in breeding programs for water stress resistance. A collection of 28 genotypes of "long storage" tomato (Solanum lycopersicum L.) was studied for carotenoid and polyphenol profile and content, vitamin C, and other physico-chemical traits of fruits. Tomato carotenoids and polyphenols were identified and quantified using high-performance liquid chromatography coupled with diode array detection and electrospray-mass spectrometry (HPLC/DAD/ESI-MS); nineteen different phenolic compounds and six different carotenoids, for a total of 25 markers, have been detected, quantified and used to discriminate among the different landraces to find out which could be the best candidate for a medium-to-large scale cultivation. Different statistical approaches (ANOVA, Principal Components Analysis, Cluster Analysis) have been used for data analysis. PMID- 29120783 TI - Micro-emulsification/encapsulation of krill oil by complex coacervation with krill protein isolated using isoelectric solubilization/precipitation. AB - This study determined feasibility of krill protein isolated with isoelectric solubilization/precipitation (ISP) as wall material to microencapsulate krill oil by freeze-drying. Effects of krill oil/krill protein ratio on properties of microcapsules were investigated. With increased ratio, crude protein of microcapsules decreased, while total lipid increased. Although microcapsule oil loading capacity increased, loading and encapsulation efficiencies decreased. Thin layer chromatography (TLC) confirmed abundance of phospholipids, which are amphiphilic; and thus, resulted in stable emulsion (emulsion stability index). Microcapsules contained omega-3 polyunsaturated fatty acids (PUFAs) at 43-60, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at 28-41 and 9-11 g/100g of total FAs, respectively. SDS-PAGE electrophoresis revealed proteolysis of ISP krill protein, probably causing reduced loading and encapsulation efficiencies. SEM showed that krill oil/krill protein ratio affected surface microstructure. ISP krill protein showed potential as a wall material to microencapsulate krill oil; and thus, expand application of krill oil/protein for human consumption. PMID- 29120784 TI - Antioxidant potency of gallic acid, methyl gallate and their combinations in sunflower oil triacylglycerols at high temperature. AB - Lipid peroxidation and polar compounds formation in sunflower oil triacylglycerols at 120 degrees C were investigated in the presence of gallic acid (GA), methyl gallate (MG), MG/GA combinations (75:25, 50:50, and 25:75), and tert-butylhydroquinone (TBHQ). Hydroperoxide-based kinetic parameters (IP, induction period, min; ki, rate constant during IP, meq/kgmin) of control sample (38.0; 2.0346) were considerably improved by TBHQ (201.1; 0.0267), followed by GA (163.8; 0.0837), MG (151.2; 0.0983), and the combinations (~184.4; ~0.0861) with an average synergy of 18.6%. Regarding the polar compounds inhibition, the best antioxidant performance (the ratio of IP to oxidized triacylglycerol monomers at IP, min/%; time reaching 10% of triacylglycerol dimers and polymers, min) in general belonged to MG/GA 75:25 (42.4; 263.0), GA (43.2; 249.9), MG (38.0; 237.5), and TBHQ (17.7; 214.4), respectively. The kinetic parameters based on the formation of polar compounds than hydroperoxides provided more reliable results to evaluate antioxidant potency at high temperature. PMID- 29120785 TI - Identification and characterization of pesticide metabolites in Brassica species by liquid chromatography travelling wave ion mobility quadrupole time-of-flight mass spectrometry (UPLC-TWIMS-QTOF-MS). AB - A new mass spectrometric method for evaluating metabolite formation of the pesticides thiacloprid, azoxystrobin, and difenoconazole was developed for the Brassica species pak choi and broccoli. Both, distribution and transformation kinetics of the active compounds and their metabolites were analyzed by UPLC TWIMS-QTOF-MS. Additionally, HR-MS analysis and structure elucidation tools such as diagnostic ions, isotopic matches, and collision cross sections were applied for metabolites identification. Following the application of two plant protection products (containing the above-mentioned active compounds) in a greenhouse study plant material was cryo-milled and extracted with water/methanol. The residual levels of active compounds were identified at certain timepoints during pre harvest intervals and in the final products. Different phase I and phase II metabolites of the pesticides were identified in different plant organs such as leaves, stems, (broccoli) heads, and roots. Three individual degradation pathways and distribution profiles are suggested including eight thiacloprid, eleven azoxystrobin and three difenoconazole metabolites. PMID- 29120786 TI - Comparison of the dietary fibre composition of old and modern durum wheat (Triticum turgidum spp. durum) genotypes. AB - It has been suggested that intensive breeding has led to decreased contents of health-promoting components in modern wheats. We therefore compared the contents and compositions of the major dietary fibre components, arabinoxylan and beta glucan, in semolina and wholemeal flour of old and modern Italian durum wheats. No differences in total arabinoxylan content were observed but the modern varieties had higher proportions of soluble arabinoxylan in wholemeals and of beta-glucan in semolina. The study therefore provides no evidence that intensive breeding has had negative effects on the contents of dietary fibre components in durum wheat. However, comparison of material grown over two years indicated that the content and composition of arabinoxylan and beta-glucan were more stable in the older than in the modern genotypes. The identification of modern cultivars with high viscosity associated with a high content of beta-glucan suggests that they are good sources of fibre for human health. PMID- 29120787 TI - Speciation analysis of six arsenic species in marketed shellfish: Extraction optimization and health risk assessment. AB - A comparative study between microwave assisted and sonication methods was carried out to extract arsenic (As) species in shellfish samples using different extractants. Six As species including arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), arsenobetaine (AsB) and arsenocholine (AsC) were simultaneously separated and determined by the HPLC-ICP MS method. The microwave assisted method exhibited higher efficiency than sonication, especially using diluted HNO3 as extractant. By compromising extraction efficiency, pretreatment time and stability of As species, the microwave assisted method using 1% HNO3 at 100 degrees C for 1.5h was selected to extract As from real samples. The proposed method has been applied to extract and determine As species in shellfish samples. The result of correlation analysis indicated that the proportion of AsB in the shellfish samples was decreased with total As concentration increasing due to the biotransformation threshold from inorganic As to AsB. PMID- 29120788 TI - Milk authenticity by ion-trap proteomics following multi-enzyme digestion. AB - The practice of adding adulterating substances in milk in order to raise profits is unfortunately worldwide. In addition, higher priced milk, coming from minor dairy species, is often illegally integrated with the lower priced cow milk. The presence of species-specific proteins, different from those declared in label, may be a serious problem for people with allergies. The development of proper analytical methods is therefore essential to protect consumer benefits and product authenticity. In this study, a proteomic approach for the detection of adulteration processes of specific milks in mixtures is proposed. Few microliters of milk samples have been digested with trypsin and chymotrypsin and analyzed by nanoLC-ESI-IT-MS/MS. A post-database processing was performed to obtain confident peptide sequence assignments, allowing the detection of milk adulteration at a level lower than 1%. Species-specific peptides from bovine beta-lactoglobulin and alphaS1 casein were identified as suitable peptide markers of milk authenticity. PMID- 29120789 TI - Laser-induced breakdown spectroscopy (LIBS) for rapid analysis of ash, potassium and magnesium in gluten free flours. AB - Gluten free (GF) diets are prone to mineral deficiency, thus effective monitoring of the elemental composition of GF products is important to ensure a balanced micronutrient diet. The objective of this study was to test the potential of laser-induced breakdown spectroscopy (LIBS) analysis combined with chemometrics for at-line monitoring of ash, potassium and magnesium content of GF flours: tapioca, potato, maize, buckwheat, brown rice and a GF flour mixture. Concentrations of ash, potassium and magnesium were determined with reference methods and LIBS. PCA analysis was performed and presented the potential for discrimination of the six GF flours. For the quantification analysis PLSR models were developed; R2cal were 0.99 for magnesium and potassium and 0.97 for ash. The study revealed that LIBS combined with chemometrics is a convenient method to quantify concentrations of ash, potassium and magnesium and present the potential to classify different types of flours. PMID- 29120790 TI - Digestion under saliva, simulated gastric and small intestinal conditions and fermentation in vitro by human intestinal microbiota of polysaccharides from Fuzhuan brick tea. AB - The aim of present study was to examine whether the digestivesystem (saliva, simulated gastric and small intestinal conditions) could break down and large intestinal microbiota could utilize the polysaccharides from Fuzhuan brick tea (FBTPS). The results showed that there was no change in molecular weight, monosaccharide content and content of reducing sugars before and after saliva, simulated gastric and small intestinal digestion, indicating that FBTPS could pass through the digestive system without being broken down and reach the large intestine safely. The content of carbohydrate was significantly decreased by fermentation in vitro of gut microbiota, suggesting that FBTPS could be broken down and utilized by gut microbiota. FBTPS could significantly modulate the composition and abundance of gut microbiota. Furthermore, the contents of short chain fatty acids were significantly increased. Therefore, FBTPS is expected to be a functional food to improve human health and prevent disease through promoting the gut health. PMID- 29120791 TI - Identification of novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides in camel milk protein hydrolysates. AB - Nine novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides (FLQY, FQLGASPY, ILDKEGIDY, ILELA, LLQLEAIR, LPVP, LQALHQGQIV, MPVQA and SPVVPF) were identified in camel milk proteins hydrolysed with trypsin. This was achieved using a sequential approach combining liquid chromatography tandem mass spectrometry (LC MS/MS), qualitative/quantitative structure activity relationship (QSAR) and confirmatory studies with synthetic peptides. The most potent camel milk protein derived DPP-IV inhibitory peptides, LPVP and MPVQA, had DPP-IV half maximal inhibitory concentrations (IC50) of 87.0 +/- 3.2 and 93.3 +/- 8.0 uM, respectively. DPP-IV inhibitory peptide sequences identified within camel and bovine milk protein hydrolysates generated under the same hydrolysis conditions differ. This was linked to differences in enzyme selectivity for peptide bond cleavage of camel and bovine milk proteins as well as dissimilarities in their amino acid sequences. Camel milk proteins contain novel DPP-IV inhibitory peptides which may play a role in the regulation of glycaemia in humans. PMID- 29120792 TI - Influence of different cultivation systems on bioactivity of asparagus. AB - Evaluation of functional and bioactive compounds of Asparagus officinalis L. growing in conventional and organic greenhouse and conventional open - field farming was the aim of this research. Polyphenols in cladodes grown conventionally were higher than organic. Flavonoids and carotenoids were the highest in cladodes in open field. Organic spears were richer in total phenolics (+6.9% and +19.1%) and flavonoids (+4.7% and 16.8%) and showed higher in vitro averages of antioxidant activities by three radical scavenging assays (+12.5% and+ 22.2%) than conventional. Partial differentiation of organically and conventionally grown samples was proved by multivariate statistics. The binding properties of polyphenols to HSA were relatively high in comparison with other plants. A strong positive correlation of binding properties and bioactivity of asparagus was estimated. All new found aspects for the first time lead to recommendation of inclusion of all investigated asparagus plants into the human diet in a wider scale. PMID- 29120793 TI - Modification of the cellular antioxidant activity (CAA) assay to study phenolic antioxidants in a Caco-2 cell line. AB - In vitro assays are widely used to analyze the antioxidant potential of compounds, but they cannot accurately predict antioxidant behavior in living systems. Cell-based assays, like the cellular antioxidant activity (CAA) assay, are gaining importance as they provide a biological perspective. When the CAA assay was employed to study phenolic antioxidants using hepatocarcinoma (HepG2) cells, quercetin showed antioxidant activity in HepG2 cells; 25 and 250MUM quercetin reduced fluorescence by 17.1+/-0.9% and 58.6+/-2.4%, respectively. (+) Catechin, a phenolic antioxidant present in many foods, bestowed virtually no CAA in HepG2 cells. When Caco-2 cells were employed, more robust antioxidant activity was observed; 50MUM (+)-catechin and quercetin reduced fluorescence by 54.1+/ 1.4% and 63.6+/-0.9%, respectively. Based on these results, likely due to differences in active membrane transport between the cell types, the Caco-2-based CAA assay appears to be a more appropriate method for the study of certain dietary phenolics. PMID- 29120794 TI - The inhibitory roles of native whey protein on the rennet gelation of bovine milk. AB - Rennet gelation is used to produce many types of cheese. The effect of native whey protein on rennet gelation kinetics was investigated. Milks with a wide range of whey protein:casein (WP:CN) ratios (with standardised casein concentrations) were made from powders produced by microfiltration. Measurements of casein macro peptide release showed that native whey protein inhibited the enzymatic action of chymosin, which delayed the onset and reduced the subsequent rate of gelation. Experiments in which increased chymosin concentrations compensated for the inhibition, demonstrated that other factors also contributed to the reduced gelation rate. Neither an increase in viscosity nor a reduction in soluble calcium was responsible, leading to the conclusion that in addition to inhibiting chymosin, native whey proteins present a physical barrier to para casein aggregation. This study demonstrates and explains how casein-enriched retentates from microfiltration gel faster than regular cheese milk that contains higher amounts of native whey protein. PMID- 29120795 TI - Correlation of lithium bioaccessibility from tea (Camellia sinensis L.) with tea type and consumption habits. AB - In this study, the total contents, leachability into tea infusions, and bioaccessibility of lithium from black, Earl Grey, and green teas were evaluated by inductively coupled plasma mass spectrometry. Leachabilities were evaluated after infusion for 2, 5, or 10min. Bioaccessibility was determined in vitro under simulated stomach and intestinal digestion conditions. Addition of lemon juice, sugar, or milk for consumption, and calcium, tannic acid, and citric acid as additives were evaluated to determine if they affected bioaccessibility of lithium from black tea. The bioaccessible lithium contributed to 0.01%, 0.02%, and 0.03% of the recommended dietary allowances of lithium for black, Earl Grey, and green tea samples, respectively. These contributions may increase up to 4.4 times or decrease up to seven times with certain additives. PMID- 29120796 TI - A rapid and simple HPLC-FLD screening method with QuEChERS as the sample treatment for the simultaneous monitoring of nine bisphenols in milk. AB - A specific, precise and accurate high performance liquid chromatographic (HPLC) analytical method with a fluorescence detector (FLD) was established for the simultaneous determination of nine bisphenols (BPs) in milk samples. Samples were extracted ultrasonically with acetonitrile and cleaned using the QuEChERS technique. Under the optimized conditions, good linearity was obtained for the nine BPs and the correlation coefficients (R2) ranged from 0.9942 to 0.9997. Recovery values for the nine bisphenols in spiked samples were 75.82-93.86% with intra-day and inter-day relative standard deviations (RSDs) from 2.6 to 11.1%. The limits of detection (LODs) and quantification (LOQs) were 1.0-3.1 MUg/kg and 3.5-9.8 MUg/kg, respectively. The results demonstrated clearly that the approach developed provides reliable, simple, rapid and environmentally-friendly quantification and identification of nine bisphenols in a fatty matrix and could be used for monitoring bisphenols in milk. PMID- 29120797 TI - Interaction of chromium(III) or chromium(VI) with catalase and its effect on the structure and function of catalase: An in vitro study. AB - Heavy metal chromium (Cr) poses a severe health risk to humans via food chain contamination. In this study, the interactions of either trivalent chromium (Cr(III)) or hexavalent chromium (Cr(VI)) with catalase (CAT) were investigated via multi-spectroscopic studies and computational simulations. The fluorescence analysis showed that Cr(III) and Cr(VI) quenched the fluorescence of CAT through a dynamic and a static quenching mechanism, respectively. The binding constant of Cr(VI) with CAT was 3.44*104lmol-1 at 298K. Other detailed binding characterizations of the Cr(VI)-CAT complex were also obtained using spectra analysis and molecular docking. Synchronous fluorescence, UV-vis and circular dichroism (CD) spectral studies showed that either Cr(III) or Cr(VI) induced conformational changes of CAT, but the degree of influence was different. The response of CAT activity to Cr(III) or Cr(VI) was found to be variable depending on their valence states and concentrations. PMID- 29120798 TI - A comparison of the kinetics of in vitro starch digestion in smooth and wrinkled peas by porcine pancreatic alpha-amylase. AB - This study describes the impact of crop genetics and processing in two pea lines (Pisum sativum L.) on starch digestion kinetics. Mutation at the rugosus (r) locus leads to wrinkled pea seeds, a reduction in starch content and a lower extent of in vitro starch digestibility. The Logarithm of Slope (LOS) kinetic model was used to analyse digestion curves obtained using porcine pancreatic alpha-amylase for a range of particle size fractions. Changes in starch structure induced by the r mutation led to clear differences in starch digestion kinetics for purified starches and pea flours. Larger particle size fractions showed slower starch digestion relative to the purified starch, but significant differences still existed between r and wild type pea lines. It is expected that this work will help inform the design of future studies where both starch structure and food structure are important determinants of digestion behaviour. PMID- 29120799 TI - Study on the effect of reactive oxygen species-mediated oxidative stress on the activation of mitochondrial apoptosis and the tenderness of yak meat. AB - This study investigated the effect of reactive oxygen species-mediated oxidative stress on activation of mitochondrial apoptosis and tenderness of yak meat during postmortem ageing. Oxidative stress degree, Ca2+ levels, membrane permeability transition pore opening, mitochondrial membrane potential, apoptotic factors and the shear force were examined. Results showed that the ROS generated by H2O2 significantly increased mitochondrial oxidative stress by decreasing the activities of superoxide dismutase, catalase and glutathione peroxidase, and increasing lipid peroxidation. Furthermore, oxidative stress enhanced Ca2+ production and cytochrome c release, changed the levels of Bcl-2 family proteins and activated caspase-9 and -3 activities. Ultimately, oxidative stress increased the apoptosis rate and tenderness of yak meat. These observations confirmed that ROS-mediated oxidative stress participates in the activation of the apoptotic cascade reaction involving Ca2+ and Bcl-2 family proteins. The results further suggested that ROS-mediated oxidative stress plays a significant role in meat tenderization through the mitochondrial apoptotic pathway. PMID- 29120800 TI - Abscisic acid stimulates anthocyanin accumulation in 'Jersey' highbush blueberry fruits during ripening. AB - Non-climacteric blueberry (Vaccinium spp.) fruits accumulate high levels of anthocyanins during ripening, which are a good source of dietary antioxidants. This study examined the effects of exogenous abscisic acid (ABA) application on fruit characteristics and anthocyanin accumulation in a northern highbush blueberry (V. corymbosum 'Jersey') during development. Fruits on shrubs were treated with 1gL-1 ABA before the initiation of fruit colouration. Application of ABA temporarily increased the level of ABA in the fruits during development. Exogenous ABA had no obvious effect on fruit growth, but stimulated fruit colouration by accelerating the accumulation of individual anthocyanins, mainly malvidin, delphinidin and petunidin glycosides. This is the first report to show that ABA promotes the accumulation of anthocyanins in blueberry fruits. However, exogenous ABA also promoted fruit softening, which is undesirable during harvest and shelf life. PMID- 29120801 TI - Sardine (Sardina pilchardus) lipid composition: Does it change after one year in captivity? AB - Atlantic sardines (Sardina pilchardus) captured in the Portuguese mainland coast and maintained in captivity for one year feeding on artificial diet showed significant differences in muscle total lipids (TL) content in relation to wild fish (25% after one year compared to 14% in wild). Captive sardines had higher percentage of non-polar lipids (NPL) in their muscle, presented higher levels of 18:1n-9 and lower of 20:5n-3 and 22:6n-3 in NPL than those observed in wild fish. TL in the liver were not significantly different between captive and wild fish, but the NPL fraction of captive sardines presented higher levels of 22:6n-3 and 20:5n-3 than those registered in the wild. Polar lipids (PL) were less influenced by captivity since the fatty acids profile was more stable. The excess of energy in the diet of captive sardines was reflected in lipid accumulation in subcutaneous layer and visceral fat and not in the liver. PMID- 29120802 TI - Corrigendum to "Formulation and processing factors affecting trichothecene mycotoxins within industrial biscuit-making" [Food Chem. (2017) 597-603]. PMID- 29120803 TI - Biosynthesis of acetate esters by dominate strains, isolated from Chinese traditional fermented fish (Suan yu). AB - Biosynthesis of acetate esters by Lactobacillus plantarum 120, Staphylococcus xylosus 135 and Saccharomyces cerevisiae 31, isolated from Chinese traditional fermented fish (Suan yu) were studied. A buffer system containing acyl donors (acetic acid/glyceryl triacetate/acetyl-CoA) and aliphatic alcohols (C2-C6) was established, inoculated with intracellular and extracellular extracts of the three strains. The results showed that the biosynthesis pathway of L. plantarum 120 was esterification and alcoholysis, while the biosynthesis pathway of S. xylosus 135 and S. cerevisiae 31 was hydrolysis and esterification, rather than alcoholysis. The ester-synthesizing activity of L. plantarum 120 via alcoholysis was higher than that via esterification at high pH value, while an opposite result for each strain was observed at low pH value. Moreover, the ester synthesis activity of L. plantarum 120 was higher than that of S. xylosus 135 and S. cerevisiae 31. In addition, microbial ester-synthesis activity increased with the increase of aliphatic alcohol carbon number. PMID- 29120804 TI - Comparison of consecutive harvests versus blending treatments to produce lower alcohol wines from Cabernet Sauvignon grapes: Impact on polysaccharide and tannin content and composition. AB - A changing climate has led to winegrapes being harvested with increased sugar levels and at greater risk of berry shrivel. A suggested easy-to-adopt strategy to manage the associated rising wine alcohol levels is the pre-fermentative substitution of juice with either "green harvest wine" or water. Our study investigates the effects of this approach on Vitis vinifera L. cv. Cabernet Sauvignon wine quality attributes. Wines were also made from fruit collected at consecutive earlier harvest time points to produce wines comparable in alcohol to the substituted wines. Tannin concentrations and colour did not change significantly in the wines with modified alcohol content even at higher juice substitution rates. Differences in polysaccharide and tannin composition indicated variability in extraction dynamics according to substitution rate and type of blending component. In scenarios where berry shrivel is inevitable, the incorporation of water in particular offers much promise as part of a strategy to manage wine alcohol content. PMID- 29120805 TI - Characterization of narrow-leaf lupin (Lupinus angustifolius L.) recombinant major allergen IgE-binding proteins and the natural beta-conglutin counterparts in sweet lupin seed species. AB - beta-conglutin has been identified as a major allergen for Lupinus angustifolius seeds. The aim of this study was to evaluate the binding of IgE to five recombinant beta-conglutin isoforms (rbeta) that we overexpressed and purified and to their natural counterparts in different lupin species and cultivars. Western blotting suggested beta-conglutins were the main proteins responsible for the IgE reactivity of the lupin species and cultivars. Newly identified polypeptides from "sweet lupin" may constitute a potential new source of primary or cross-reactive sensitization to lupin, particularly to L. albus and L. angustifolius seed proteins. Several of them exhibited qualitative and quantitative differences in IgE-binding among these species and cultivars, mainly in sera from atopic patients that react to lupin rather than peanut. IgE-binding was more consistent to recombinant beta2 than to any of the other isoforms, making this protein a potential candidate for diagnosis and immunotherapy. PMID- 29120806 TI - Extraction, identification, and quantification of antioxidant phenolics from hazelnut (Corylus avellana L.) shells. AB - Hazelnut shells are the major byproduct of the hazelnut industry. The objectives of this study were to optimize the conditions for extracting phenolics and to identify and quantify the phenolics in hazelnut shells. Preliminary optimization showed that a high recovery of phenolics could be achieved with shell particle size less than 0.5mm when extracted with acetone at 50 degrees C. Response surface experiments showed that a 10g/l liquid to solid ratio, 58% acetone, and 12h extraction time yielded the highest amount of phenolics. Twenty-seven phenolic compounds were identified in hazelnut shells by mass spectrometry. Coumaroylquinic acid, epicatechin gallate, quercetin, and six other phenolics were identified in hazelnut shells for the first time. The most abundant phenolics in hazelnut shells were catechin, epicatechin gallate, and gallic acid, as quantified by high performance liquid chromatography (HPLC). These results can be useful for the development of industrial extraction processes of natural antioxidants from hazelnut shells. PMID- 29120807 TI - Residual behavior and risk assessment of tridemorph in banana conditions. AB - An efficient method has been developed for determining tridemorph in banana using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The dissipation and terminal residue of tridemorph in banana fields were carried out at good agricultural practice (GAP) conditions. The average recoveries ranged from 84.4% to 90.0% with relative standard deviations (RSDs) of 3.0%-7.0% at three different spiking levels. The results indicated that the tridemorph dissipated quickly in banana with half-lives of 7.0-7.7days. The results of residual distribution ranged from 0.01 to 0.26mg/kg, 0.01-0.62mg/kg and <0.01mg/kg in whole banana, peel and pulp, respectively. The relationship between application factor and residue was discussed. The results of risk assessment showed that the risk quotient (RQ) value was all below RQ=1. Given that China has not set an maximum residue limit (MRL) value for tridemorph in banana, this study could provide guidance for the reasonable use of tridemorph. PMID- 29120808 TI - Alternative oil extraction methods from Echium plantagineum L. seeds using advanced techniques and green solvents. AB - The edible oil processing industry involves large losses of organic solvent into the atmosphere and long extraction times. In this work, fast and environmentally friendly alternatives for the production of echium oil using green solvents are proposed. Advanced extraction techniques such as Pressurized Liquid Extraction (PLE), Microwave Assisted Extraction (MAE) and Ultrasound Assisted Extraction (UAE) were evaluated to efficiently extract omega-3 rich oil from Echium plantagineum seeds. Extractions were performed with ethyl acetate, ethanol, water and ethanol:water to develop a hexane-free processing method. Optimal PLE conditions with ethanol at 150 degrees C during 10 min produced a very similar oil yield (31.2%) to Soxhlet using hexane for 8 h (31.3%). UAE optimized method with ethanol at mild conditions (55 degrees C) produced a high oil yield (29.1%). Consequently, advanced extraction techniques showed good lipid yields and furthermore, the produced echium oil had the same omega-3 fatty acid composition than traditionally extracted oil. PMID- 29120809 TI - Formulation and characterization of novel nanostructured lipid carriers made from beeswax, propolis wax and pomegranate seed oil. AB - The objective of this study was to develop functional nanostructured lipid carriers (NLCs) using beeswax (BW), propolis wax (PW) and pomegranate seed oil (PSO). NLCs were prepared by a melt emulsification-ultra sonication technique. The influences of solid lipid composition, surfactant blend concentration (2, 4, and 6% of formulation) and PSO content (10, 30 and 50% of total lipid phase) were investigated. Statistical evaluations revealed that the formulation variables had significant effects on physical properties of NLC. The developed nanocarriers presented particle sizes ranging from 71 to 366 nm, leading to excellent physical stability. The optimum formulations with minimum particle size and high zeta potential value were PW and BW + glycerol behenate samples, containing 10% oil and 6% surfactant. DSC and XRD studies indicated that the addition of oil to the lipid phase could disturb the crystalline order and form lattice defects. TEM observations exhibited spherical morphology of the NLCs. PMID- 29120811 TI - Magnetic resonance (MR) features in triple negative breast cancer (TNBC) vs receptor positive cancer (nTNBC). AB - Few reports in literature describe triple negative breast cancer (TNBC) imaging findings. Aim of the study is to determine MR-features of TNBC compared to receptor positive cancer (nTNBC). From May 2014 to May 2015, we retrospectively enrolled 31 consecutive patients with histological diagnosis of TNBC and a control group of 31 consecutive nTNBC observed in the same period, out of 602 cancer, diagnosed in our department in the same year. Histopathological analysis and MR-features of TNBC (31 patients) were compared to nTNBC (31 patients). MR features included dimension, fibroglandular tissue (FGT), background parenchimal enhancement (BPE), mass shape, margins, presence of rim, intratumoral signal intensity in T2w, uni-multifocality, kinetic curves. All patients were examined with MR 1,5T (Magnetom Simphony Tim, Siemens Healthcare) performing T2w fat-sat and contrast enhanced high temporal and spatial resolution T1w before and after injection of Gadolinium. 62 staging MR were reviewed. Median age was 50 (30-78ys) with a standard deviation of 10,9. TNBC showed 3 MR features in concordance with current literature: rim enhancement, hyperintensity in T2 sequence and unifocality. Rim enhancement was shown in 67.7% of TNBC (21/31) and 29% of nTNBC (9/31). Higher T2w values were shown in 83.9% of TNBC (26/31) and 58.1% of nTNBC (18/31). Cancer was multifocal in 7/31 (22.6%) of TNBC and 19/31 (61.3%) nTNBC. No correlation was found for dimension (p=0.12), FGT (p=0.959), BPE (p=0.596), homogeneity of enhancement (p=0.43), margins (p=0.671) and kinetic (p=0.37). Multivariate analysis demonstrated that rim enhancement and unifocality correlated independently with TNBC group. Area under ROC curve of our model is 0.835. Furthermore, we evaluated the clinical outcome of all 31 TNBC patients in a follow-up time ranging from 24months to 36months separating them in a free survival group (23 women) and a recurrence group (8 women with local recurrence or distant metastasis): only kinetic curves resulted to be significantly higher in recurrence group (p=0.042). PMID- 29120810 TI - Lasiodiplodia theobromae (Pat.) Griff. & Maubl.-induced disease development and pericarp browning of harvested longan fruit in association with membrane lipids metabolism. AB - Effects of Lasiodiplodia theobromae inoculation on disease development, pericarp browning and membrane lipids metabolism of harvested "Fuyan" longan fruit were studied. Compared with control fruit, L. theobromae-inoculated longans showed higher fruit disease index, pericarp browning index and cell membrane permeability, as well as higher activities of phospholipase D, lipase and lipoxygenase. Additionally, there were lower contents of membrane phospholipids but higher content of phosphatidic acid, and lower level of unsaturated fatty acids but higher level of saturated ones with lower ratio of unsaturated fatty acid to saturated fatty acid and lower index of unsaturated fatty acids in pericarp of L. theobromae-inoculated longans. These results suggested that L. theobromae-induced disease development and pericarp browning of harvested longans might be attributed to the damaged cellular membrane structural integrity, induced by the activated membrane lipids-degrading enzymes increasing the degradation of membrane phospholipids and unsaturated fatty acids in pericarp of harvested longan fruit. PMID- 29120812 TI - Imaging findings in systemic childhood diseases presenting with dermatologic manifestations. AB - PURPOSE: Many childhood diseases often present with skin abnormalities with which radiologists are largely unfamiliar. Knowledge of associated dermatologic manifestations may aid the radiologist in confirming the diagnosis and recommending targeted imaging of affected organs. METHODS: We review the imaging findings in childhood diseases associated with dermatologic manifestations. FINDINGS: Diseases include dermatologic findings which herald underlying malignancy (Neuroblastoma, leukemia/lymphoma, Langerhans cell histiocytosis),are associated with risk of malignancy (Epidermolysis Bullosa, basal cell nevus syndrome, Cowden's syndrome, Tuberous Sclerosis),or indicate a systemic inflammatory/immune disorder (Kawasaki's disease, Henoch Schonlein Purpura, systemic lupus erythematosus, scleroderma, sarcoidosis, dermatomyositis and immune thrombocytopenic purpura). CONCLUSION: Familiarity with pertinent findings in childhood diseases presenting with dermatologic manifestations in childhood diseases aids the radiologist in confirming the diagnosis and guiding imaging workup. PMID- 29120813 TI - Visibility of mammographically occult breast cancer on diffusion-weighted MRI versus ultrasound. AB - PURPOSE: To investigate the visibility of mammographically occult breast cancers on diffusion-weighted MRI (DWI) versus ultrasound. MATERIALS AND METHODS: Mammographically occult breast cancers (n=60) initially detected on contrast enhanced MRI that underwent pre-biopsy targeted ultrasound were retrospectively evaluated for visibility on DWI and ultrasound. RESULTS: More cancers were visible on DWI than ultrasound (78% vs. 63%; p=0.049), with 32 (53%) visible on both and 7 (12%) not visible on either. Visibility differences were more significant in larger lesions (92% vs. 68%, p=0.006). CONCLUSION: DWI may detect more mammographically occult cancers than ultrasound, warranting further investigation as an alternative supplemental screening technique. PMID- 29120815 TI - 3D neural tissue models: From spheroids to bioprinting. AB - Three-dimensional (3D) in vitro neural tissue models provide a better recapitulation of in vivo cell-cell and cell-extracellular matrix interactions than conventional two-dimensional (2D) cultures. Therefore, the former is believed to have great potential for both mechanistic and translational studies. In this paper, we review the recent developments in 3D in vitro neural tissue models, with a particular focus on the emerging bioprinted tissue structures. We draw on specific examples to describe the merits and limitations of each model, in terms of different applications. Bioprinting offers a revolutionary approach for constructing repeatable and controllable 3D in vitro neural tissues with diverse cell types, complex microscale features and tissue level responses. Further advances in bioprinting research would likely consolidate existing models and generate complex neural tissue structures bearing higher fidelity, which is ultimately useful for probing disease-specific mechanisms, facilitating development of novel therapeutics and promoting neural regeneration. PMID- 29120814 TI - Percutaneous CT-guided facet joint synovial cyst rupture: Success with refractory cases and technical considerations. AB - Percutaneous image-guided rupture of lumbar facet synovial cysts can improve clinical outcomes and obviate the need for open surgery. This series describes eleven patients who had successful CT-guided lumbar facet synovial cyst ruptures, 82% of which experienced excellent pain relief at a minimum of one-year follow up. Of the five patients who failed prior fluoroscopic-guided synovial cyst rupture, 80% had a successful CT-guided rupture and one-year sustained pain relief. These findings reinforce minimally invasive CT-guided treatment as an excellent option to improve patient symptoms and potentially avoid open surgery. PMID- 29120816 TI - Tumor targeted, stealthy and degradable bismuth nanoparticles for enhanced X-ray radiation therapy of breast cancer. AB - Nanoparticles of heavy elements can be used as radiosensitizers to enhance X-ray radiation therapy, but a major roadblock in translating nanoparticle radiosensitizers into clinical practice of cancer treatment is related to the non degradable nature of the nanoparticles, which can cause accumulation inside body and long-term toxicity. This paper reports the use of a folate-inserted, red blood cell membrane-modified bismuth (i.e., F-RBC bismuth) nanoparticles in X-ray radiation therapy for breast cancer, where cell membrane coating provides long blood circulation time, folate acts as tumor targeting agent, X-ray and bismuth nanoparticles interaction generates more free radicals for cancer cells damage, and physiological condition helps dissolve bismuth nanoparticles after treatment. Significant tumor inhibition and improved survival ratio in mice was confirmed when F-RBC bismuth nanoparticles were used to sensitize X-ray radiation. In vivo bio-distribution and histological analysis indicated F-RBC bismuth nanoparticles were excreted from animal body after 15 days and no evident damage or inflammatory was observed in major organs. Cell membrane modification and dissolution of bismuth nanoparticles in body allow the fine tune of the circulation, radiation enhancement and body clearance in such a way that treatment effect can be maximized and long term toxicity can be minimized. PMID- 29120817 TI - Guiding morphogenesis in cell-instructive microgels for therapeutic angiogenesis. AB - Efficient cell delivery strategies are urgently needed to improve the outcome of cell-based pro-angiogenic therapies. This study describes the design of an injectable cell delivery platform, based on biomaterial-guided morphogenesis principles. Soft high-mannuronic acid alginate microgels, oxidized and functionalized with integrin-binding peptides, provided adequate biochemical/biomechanical cues for the co-assembly of mesenchymal stem cells and outgrowth endothelial cells (OEC) into pre-vascularized microtissues. In vitro priming conditions regulated OEC tubulogenesis, which only occurred under normoxia (+O2) in the presence of angiogenic factors (+GF) and, importantly, did not revert in an ischemic-like environment. Primed (+O2+GF) microgel-entrapped cells secreted a large variety of angiogenesis-related proteins and produced endogenous extracellular-matrix, rich in fibronectin and collagen type I, fostering cell-cell/cell-matrix interactions and establishing a stable angiogenic niche. Extending the pre-culture time resulted in higher cell outward migration and in vivo angiogenic potential. Microgels partially disintegrated upon implantation in chick embryos, promoting interaction between pre-vascularized microtissues and the host. Preserved human vascular structures were still detected in vivo, and human cells showed the ability to migrate and integrate with the chick vasculature. Our results suggest that an integrated approach combining pro-angiogenic cells, cell-instructive microgels and adequate in vitro priming may provide the basis for successful therapeutic angiogenesis. PMID- 29120818 TI - Near infrared dye-conjugated oxidative stress amplifying polymer micelles for dual imaging and synergistic anticancer phototherapy. AB - The recent advances in nanotechnology have led to the development of smart nanomaterials that combine diagnostic and therapeutic functions and provide synergistic anticancer effects through the combination of different treatment modalities. Here, we report a promising theranostic nanoconstruct that can translate into multiple functionalities: fluorescence/photoacoustic imaging, acid triggered generation of ROS (reactive oxygen species), heat and singlet oxygen production under near infrared (NIR) laser irradiation, and coupling oxidative anticancer therapy to dual imaging-guided photothermal/photodynamic therapy. An NIR dye-conjugated hydroxyl radical generating biodegradable polymer (HRGP-IR) is employed as a theranostic nanoplatform. HRGP-IR could self-assemble to form micelles and elevate oxidative stress by generating hydrogen peroxide and hydroxyl radical. Under the NIR (808 nm) laser irradiation, HRGP-IR micelles also generate heat and singlet oxygen to induce cancer cell death. In mouse xenograft models, HRGP-IR micelles accumulated in tumors preferentially and the tumor could be detected by dual imaging. Effective tumor ablation was achieved by HRGP-IR micelles (5 mg/kg) combined with NIR laser irradiation, demonstrating the synergistic anticancer effects of oxidative stress with photothermal heating. Given their dual imaging capability, anticancer phototherapy and highly potent synergistic anticancer activity with NIR laser irradiation, HRGP-IR micelles hold great potential as a nanotheranostic agent for cancer treatment. PMID- 29120820 TI - Development of PEGylated aspartic acid-modified liposome as a bone-targeting carrier for the delivery of paclitaxel and treatment of bone metastasis. AB - To prevent bone metastasis, we developed polyethylene glycol (PEG)-conjugated aspartic acid (Asp)-modified liposomes (PEG-Asp-Lipo) as a bone-targeting carrier of paclitaxel (PTX) by using Asp-modified 1,2-dipalmitoyl-sn-glycero-3 phosphoethanolamine (DPPE-Asp). The affinity of Asp-modified liposomes to hydroxyapatite increased as the concentration of DPPE-Asp increased. The bone accumulation of [3H]-labeled PEG(2)-Asp(33)-Lipo was approximately 24.6% 360 min after intravenous injection in mice, in contrast to 5.4% and 6.7% of [3H]-labeled normal Lipo and PEG(2)-Lipo, respectively. Similarly, [14C]-labeled PTX encapsulated into PEG(2)-Asp(33)-Lipo predominantly accumulated in the bone. Furthermore, using an in situ imaging experiment, we observed that near-infrared fluorescence-labeled PEG(2)-Asp(33)-Lipo selectively accumulated in the bone near the joint after intravenous injection in mice. We also found that FITC-labeled PEG(2)-Asp(33)-Lipo predominantly accumulated on eroded and quiescent bone surfaces. In a bone metastatic tumor mouse model, in which B16-BL6/Luc cells were injected into the left ventricle of female C57BL/6 mice, metastatic bone tumor growth was significantly inhibited by an intravenous injection of PEG(2)-Asp(33) liposomal PTX. In contrast, PEGylated liposomal PTX hardly affected the growth of metastatic bone tumors. These findings indicate that PEG(2)-Asp(33)-Lipo is a promising bone-targeting carrier for the delivery of PTX and treatment of bone metastasis. PMID- 29120819 TI - Towards a defined ECM and small molecule based monolayer culture system for the expansion of mouse and human intestinal stem cells. AB - Current ISC culture systems face significant challenges such as animal-derived or undefined matrix compositions, batch-to-batch variability (e.g. Matrigel-based organoid culture), and complexity of assaying cell aggregates such as organoids which renders the research and clinical translation of ISCs challenging. Here, through screening for suitable ECM components, we report a defined, collagen based monolayer culture system that supports the growth of mouse and human intestinal epithelial cells (IECs) enriched for an Lgr5+ population comparable or higher to the levels found in a standard Matrigel-based organoid culture. The system, referred to as the Bolstering Lgr5 Transformational (BLT) Sandwich culture, comprises a collagen IV-coated porous substrate and a collagen I gel overlay which sandwich an IEC monolayer in between. The distinct collagen cues synergistically regulate IEC attachment, proliferation, and Lgr5 expression through maximizing the engagement of distinct cell surface adhesion receptors (i.e. integrin alpha2beta1, integrin beta4) and cell polarity. Further, we apply our BLT Sandwich system to identify that the addition of a bone morphogenetic protein (BMP) receptor inhibitor (LDN-193189) improves the expansion of Lgr5-GFP+ cells from mouse small intestinal crypts by nearly 2.5-fold. Notably, the BLT Sandwich culture is capable of expanding human-derived IECs with higher LGR5 mRNA levels than conventional Matrigel culture, providing superior expansion of human LGR5+ ISCs. Considering the key roles Lgr5+ ISCs play in intestinal epithelial homeostasis and regeneration, we envision that our BLT Sandwich culture system holds great potential for understanding and manipulating ISC biology in vitro (e.g. for modeling ISC-mediated gut diseases) or for expanding a large number of ISCs for clinical utility (e.g. for stem cell therapy). PMID- 29120822 TI - Cancer in small states - No small matter. PMID- 29120821 TI - An injectable, electrostatically interacting drug depot for the treatment of rheumatoid arthritis. AB - To the best of our knowledge, no studies have yet examined the electrostatic interaction of polyelectrolytes with electrolyte drugs for the treatment of rheumatoid arthritis (RA). Here, an injectable, electrostatically interacting drug depot is described. We prepared methoxy polyethylene glycol-b-poly(epsilon caprolactone)-ran-poly(l-lactic acid) (MC) diblock copolymers with a carboxylic acid group (MC-C) at the pendant position. MC-C was polyelectrolytes that exhibited negative zeta potentials. Sulfasalazine [Sul(-)] and minocycline [Min(+)], electrolyte RA drugs, exhibited negative and positive zeta potentials, respectively. The electrolyte RA drugs were loaded into the polyelectrolyte MC-C solution to prepare injectable, electrostatically interacting depot formulations. The formulation with an attractive electrostatic interaction [Min(+)-MC-C] exhibited gradual release of Min(+) from the MC-C depot over an extended period and suppressed the growth of inflammatory RAW 264.7 cells without affecting synovial cells. Mature chondrocytes were observed after H&E and safranin O staining of the cartilage of Min(+)-MC-C intra-articularly injected RA-induced rats. In comparison with other formulations, Min(+)-MC-C induced the suppression of the expression of pro-inflammatory proteins TNF-alpha and IL-1beta in the articular knee joint, which resulted in the amelioration of RA. In conclusion, an injectable, electrostatically interacting depot formulation administered through intra-articular injection successfully provided almost complete amelioration of RA. PMID- 29120823 TI - Cancer in the Solomon Islands. AB - INTRODUCTION: The Solomon Islands, with a population of 550,000, has significant challenges in addressing non-communicable diseases, including cancer, in the face of significant economic, cultural, general awareness and health system challenges. OBJECTIVES: To summarise the existing knowledge regarding cancer in the Solomon Islands, to gather new data and make recommendations. METHODS: A literature review was undertaken and cancer data from the National Referral Hospital, Honiara were analysed and are presented. Key stakeholders were interviewed for their perspectives including areas to target for ongoing, incremental improvements. Last, a health services audit for cancer using the WHO SARA tool was undertaken. RESULTS: Breast and cervical cancer remain the first and second most commonly identified cancers in the Solomon Islands. The Solomons cancer registry is hospital based and suffers from incomplete data collection due to its passive nature, lack of resources for data entry and processing resulting in weak data which is rarely used for decision-making. The health system audit revealed system and individual reasons for delayed diagnosis or lack of cancer treatment or palliation in the Solomon Islands. Reasons included lack of patient knowledge regarding symptoms, late referrals to the National Referral Hospital and inability of health care workers to detect cancers either due to lack of skills to do so, or lack of diagnostic capabilities, and an overall lack of access to any health care, due to geographical barriers and overall national economic fragility. CONCLUSION: The Solomon Islands is challenged in preventing, diagnosing, treating and palliating cancer. Stakeholders recommend establishing specialty expertise (in the form of a cancer unit), improved registry processes and increased collaboration between the sole tertiary hospital nationwide and other Solomon health services as important targets for incremental improvement. PMID- 29120824 TI - Cancer epidemiology in the small nations of Pacific Islands. AB - BACKGROUND: Pacific island countries and territories (PICTs) comprise 20,000 30,000 islands in the Pacific Ocean. PICTs face challenges in relation to small population sizes, geographic dispersion, increasing adoption of unhealthy life styles and the burden of both communicable and non-communicable diseases, including cancer. This study reviews data on cancer incidence and mortality in the PICTs, with special focus on indigenous populations. METHODS: PICTs with populations of <1.5 million ('small nations') were included in this study. Information on cancer incidence and mortality was extracted from the GLOBOCAN 2012 database. Scientific and grey literature was narratively reviewed for publications published after 2000. RESULTS: Of the 21 PICTs, seven countries were included in the GLOBOCAN 2012 (Fiji, French Polynesia, Guam, New Caledonia, Samoa, Solomon Islands, Vanuatu). The highest cancer incidence and mortality rates were reported in New Caledonia (age-standardized incidence and mortality rates 297.9 and 127.3 per 100.000) and French Polynesia (age-standardized incidence and mortality rates 255.0 and 134.4 per 100.000), with relatively low rates in other countries. Literature indicated that cancer was among the leading causes of deaths in most PICTs; thus they now experience a double burden of cancers linked to infections and life-style and reproductive factors. Further, ethnic differences in cancer incidence and mortality have been reported in some PICTs, including Fiji, Guam, New Caledonia and Northern Mariana Islands. CONCLUSION: Cancer incidence in the PICTs was recorded to be relatively low, with New Caledonia and French Polynesia being exceptions. Low recorded incidence is likely to be explained by incomplete cancer registration as cancer had an important contribution to mortality. Further endeavors are needed to develop and strengthen cancer registration infrastructure and practices and to improve data quality and registration coverage in the PICTs. PMID- 29120825 TI - Cancer control in the Pacific: A South Pacific collaborative approach. PMID- 29120827 TI - Detection and estimation of the increasing trend of cancer incidence in relatively small populations. AB - BACKGROUND: Detection and estimation of trends in cancer incidence rates are commonly achieved by fitting standardized rates to a joinpoint log-linear regression. The efficiency of this approach is inadequate when applied to a relatively low levels of incidence. We compared that approach with the Cuscore test with respect to detecting a log-linear increasing trend of chronic myelomonocytic leukemia (CMML) in datasets simulated to match a province of about 700,000 inhabitants. METHODS: For better efficiency, we replaced the standardized rate as the dependent variable with a continuous statistic that reflects the inverse of the standardized incidence ratio (SIR). Both procedures were applied to datasets simulated to match published results in the Girona Province of Spain. We also present the use of the q-interval in displaying the temporal pattern of the events. This approach is demonstrated by analyses of CMML diagnoses in Girona County (1994-2008). RESULTS: The Cuscore was clearly more efficient than regression in detecting the simulated trend. The relative efficiency of the Cuscore is likely to be maintained in even higher levels of incidence. The use of graphical displays in providing clues regarding interpretation of the results is demonstrated. CONCLUSIONS: The Cuscore test coupled with visual inspection of the temporal pattern of the events seems to be more efficient than regression analysis in detecting and interpreting data suspected to be at elevated risk. A confirmatory analysis is expected to weed out 75% of the superfluous significant results. PMID- 29120826 TI - Cancer in Guam and Hawaii: A comparison of two U.S. Island populations. AB - BACKGROUND: Cancer disparities within and across populations provide insight into the influence of lifestyle, environment, and genetic factors on cancer risk. METHODS: Guam cancer incidence and mortality were compared to that of Hawaii using data from their respective population-based, central cancer registries. RESULTS: In 2009-2013, overall cancer incidence was substantially lower in Guam than in Hawaii for both sexes while overall cancer mortality was higher for Guam males. Cervical cancer incidence and prostate cancer mortality were higher in Guam. Both incidence and mortality were higher among Guam men for cancers of the lung & bronchus, liver & intrahepatic bile duct, and nasopharynx; Chamorro men were disproportionately affected by these cancers. Filipinos and Whites in Guam had lower overall cancer incidence compared to Filipinos and Whites in Hawaii. Although breast cancer incidence was significantly lower in Guam compared to Hawaii, women in Guam presented at younger ages and with rarer disease histologies such as inflammatory carcinoma were more prevalent. Guam patients were also diagnosed at younger ages for cancers of bladder, pancreas, colon & rectum, liver & intrahepatic bile duct, lung & bronchus, stomach, non-Hodgkin lymphoma, and leukemia. CONCLUSION: Smoking, infectious agents, and betel nut chewing appear to be important contributors to the burden of cancer in Guam. Earlier onset of cancer in Guam suggests earlier age of exposure to key risk factors and/or a more aggressive pathogenesis. Contrasting cancer patterns within Guam and between Guam and Hawaii underscore the potential influence of genes, lifestyle, and environmental factors on cancer development and progression. PMID- 29120828 TI - The efficacy of respondent-driven sampling for the health assessment of minority populations. AB - BACKGROUND: Respondent driven sampling (RDS) is a relatively new network sampling technique typically employed for hard-to-reach populations. Like snowball sampling, initial respondents or "seeds" recruit additional respondents from their network of friends. Under certain assumptions, the method promises to produce a sample independent from the biases that may have been introduced by the non-random choice of "seeds." We conducted a survey on health communication in Guam's general population using the RDS method, the first survey that has utilized this methodology in Guam. It was conducted in hopes of identifying a cost-efficient non-probability sampling strategy that could generate reasonable population estimates for both minority and general populations. METHODS: RDS data was collected in Guam in 2013 (n=511) and population estimates were compared with 2012 BRFSS data (n=2031) and the 2010 census data. The estimates were calculated using the unweighted RDS sample and the weighted sample using RDS inference methods and compared with known population characteristics. RESULTS: The sample size was reached in 23days, providing evidence that the RDS method is a viable, cost-effective data collection method, which can provide reasonable population estimates. However, the results also suggest that the RDS inference methods used to reduce bias, based on self-reported estimates of network sizes, may not always work. Caution is needed when interpreting RDS study findings. CONCLUSIONS: For a more diverse sample, data collection should not be conducted in just one location. Fewer questions about network estimates should be asked, and more careful consideration should be given to the kind of incentives offered to participants. PMID- 29120830 TI - Areca (betel) nut chewing practices of adults and health behaviors of their children in the Freely Associated States, Micronesia: Findings from the Children's Healthy Living (CHL) Program. AB - BACKGROUND: Chewing areca (betel) nut has been deemed carcinogenic. The practice has become a public health concern in Micronesia. The Children's Healthy Living (CHL) Program included an areca (betel) nut questionnaire in a survey of household characteristics in the Freely Associated States (FAS). This paper describes areca (betel) nut chewing practices of adults and the health behaviors of their children. METHODS: A cross-section of 1200 children (2-8 year-olds) and their caregivers in Chuuk, Kosrae, Pohnpei, Republic of Palau, Republic of the Marshall Islands (RMI), and Yap were recruited. Socio-demographics, adult areca (betel) nut chewing practices, and other health behaviors of children and adults were assessed. Child anthropometric measurements were collected to estimate weight status. RESULTS: The FAS areca (betel) nut chewing prevalence was 42%, ranging from 3% (RMI) to 94% (Yap). Among chewers, 84% added tobacco, 97% added slaked lime, 85% added betel leaf, and 24% mixed the components with alcohol. Among FAS children, 95% practiced daily teeth-brushing and 53% visited the dentist annually. Compared to non-chewing households, areca (betel) nut chewing households were more likely to have very young children enrolled, more highly educated adults, and members that used tobacco and alcohol. CONCLUSION: The FAS areca (betel) nut chewing prevalence (42%) is above the world prevalence of 10 20%, with wide variability across the islands. The oral health findings in this study may inform future oral cancer prevention programs or policies. Regular monitoring of areca (betel) nut use is needed to measure the impact of such programs or policies. PMID- 29120829 TI - Risk factors for breast cancer in the breast cancer risk model study of Guam and Saipan. AB - BACKGROUND: Chamorro Pacific Islanders in the Mariana Islands have breast cancer incidence rates similar to, but mortality rates higher than, those of U.S. women. As breast cancer risk factors of women of the Mariana Islands may be unique because of ethnic and cultural differences, we studied established and suspected risk factors for breast cancer in this unstudied population. METHODS: From 2010 2013, we conducted retrospective case-control study of female breast cancer (104 cases and 185 controls) among women in the Mariana Islands. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each of various lifestyle related factors from logistic regression of breast cancer, in all women and in pre- and postmenopausal women separately. Tests for interaction of risk factors with ethnicity were based on the Wald statistics for cross-product terms. RESULTS: Of the medical and reproductive factors considered - age at menarche, breastfeeding, number of live births, age at first live birth, hormone use, and menopause - only age at first live birth was confirmed. Age at first live birth, among parous women, was higher among cases (mean 24.9 years) than controls (mean 23.2 years); with increased breast cancer risk (OR=2.53; 95% CI, 1.04-6.19 for age>=30y compared to <20y, P for trend=0.01). Of the lifestyle factors -body mass index, waist circumference, physical activity, alcohol and betel-nut intake, and education - only waist circumference (OR=1.65; 95% CI 0.87-3.14 for the highest tertile group compared to the lowest, P for trend=0.04) was significantly associated with breast cancer risk and only in Filipino women. The association with many other established risk factors, such as BMI, hormone use and physical activity, were in the expected direction but were not significant. Associations for family history of breast cancer and alcohol intake were not evident CONCLUSIONS: The results provide a basis for cancer prevention guidance for women in the Mariana Islands. PMID- 29120831 TI - Epidemiology of areca (betel) nut use in the mariana islands: Findings from the University of Guam/University of Hawai'i cancer center partnership program. AB - BACKGROUND: Areca (betel) nut is considered a Group 1 human carcinogen shown to be associated with other chronic diseases in addition to cancer. This paper describes the areca (betel) nut chewing trend in Guam, and health behaviors of chewers in Guam and Saipan. METHODS: The areca (betel) nut module in the Guam Behavioral Risk Factor Surveillance Survey was used to calculate the 5-year (2011 2015) chewing trend. To assess the association between areca (betel) nut chewing and health risks in the Mariana Islands, a cross-section of 300 chewers, >=18years old, were recruited from households in Guam and Saipan. Self-reported socio-demographics, oral health behaviors, chronic disease status, diet, and physical activity were collected. Anthropometry was measured. Only areca (betel) nut-specific and demographic information were collected from youth chewers in the household. RESULTS: The 5-year areca (betel) nut chewing prevalence in Guam was 11% and increased among Non-Chamorros, primarily other Micronesians, from 2011 (7%) to 2015 (13%). In the household survey, most adult chewers (46%) preferred areca nut with betel leaf, slaked lime, and tobacco. Most youth chewers (48%) preferred areca nut only. Common adult chronic conditions included diabetes (14%), hypertension (26%), and obesity (58%). CONCLUSION: The 5-year areca (betel) nut chewing prevalence in Guam is comparable to the world estimate (10 20%), though rising among Non-Chamorros. Adult and youth chewers may be at an increased risk for oral cancer. Adult chewers have an increased risk of other chronic health conditions. Cancer prevention and intervention strategies should incorporate all aspects of health. PMID- 29120832 TI - Cost-benefit analysis of establishing and operating radiation oncology services in Fiji. AB - BACKGROUND: Rising demand for services of cancer patients has been recognised by the Government of Fiji as a national health priority. Increasing attention has been paid to the lack of service of radiation therapy or radiotherapy in Fiji. OBJECTIVE: This study aims to estimate and compare the costs and benefits of introducing radiation oncology services in Fiji from the societal perspective. METHODS: Time horizon for cost-benefit analysis (CBA) was 15 years from 2021 to 2035. The benefits and costs were converted to the present values of 2016. Estimates for the CBA model were taken from previous studies and expert opinions and data obtained from field visits to Fiji in January 2016. Sensitivity analyses with changing assumptions were undertaken. RESULTS: The estimated net benefit, applying the national minimum wage (NMW) to measure monetary value for life-year gained, was -31,624,421 FJD with 0.69 of benefit-cost (B/C) ratio. If gross national income (GNI) per capita was used for the value of life years, net benefit was 3,975,684 FJD (B/C ratio: 1.04). With a pessimistic scenario, establishing the center appeared to be not cost-beneficial, and the net benefit was -53,634,682 FJD (B/C ratio: 0.46); net benefit with an optimistic scenario was estimated 23,178,189 FJD (B/C ratio: 1.20). CONCLUSIONS: Based on the CBA results from using GNI per capita instead of the NMW, this project would be cost beneficial. Introducing a radiation oncology center in Fiji would have potential impacts on financial sustainability, financial protection, and accessibility and equity of the health system. PMID- 29120833 TI - Radiotherapy in small countries. AB - AIM: To examine the availability of radiotherapy in small countries. METHODS: A small country was defined as a country with a population less than one million persons. The economic status of each country was defined using the World Bank Classification. The number of cancers in each country was obtained from GLOBOCAN 2012. The number of cancer cases with an indication or radiotherapy was calculated using the CCORE model. RESULTS: There were 41 countries with a population of under 1 million; 15 were classified as High Income, 15 Upper Middle Income, 10 Lower Middle Income and one Low Income. 28 countries were islands. Populations ranged from 799 (Holy See) to 886450 (Fiji) and the total number of cancer cases occurring in small countries was 21,043 (range by country from 4 to 2476). Overall the total number of radiotherapy cases in small countries was 10982 (range by country from 2 to 1239). Radiotherapy was available in all HIC islands with 80 or more new cases of cancer in 2012 but was not available in any LMIC island. Fiji was the only LMIC island with a large radiotherapy caseload. Similar caseloads in non-island LMIC all had radiotherapy services. Most non island HIC did not have radiotherapy services presumably because of the easy access to radiotherapy in neighbouring countries. CONCLUSION: There are no radiotherapy services in any LMIC islands. PMID- 29120834 TI - Cervical cancer screening in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) in four US-Affiliated Pacific Islands between 2007 and 2015. AB - BACKGROUND: Cervical cancer incidence in the US-Affiliated Pacific Islands (USAPIs) is double that of the US mainland. American Samoa, Commonwealth of Northern Mariana Islands (CNMI), Guam and the Republic of Palau receive funding from the Centers for Disease Control (CDC) National Breast and Cervical Cancer Early Detection Program (NBCCEDP) to implement cervical cancer screening to low income, uninsured or under insured women. The USAPI grantees report data on screening and follow-up activities to the CDC. MATERIALS AND METHODS: We examined cervical cancer screening and follow-up data from the NBCCEDP programs in the four USAPIs from 2007 to 2015. We summarized screening done by Papanicolaou (Pap) and oncogenic human papillomavirus (HPV) tests, follow-up and diagnostic tests provided, and histology results observed. RESULTS: A total of 22,249 Pap tests were conducted in 14,206 women in the four USAPIs programs from 2007-2015. The overall percentages of abnormal Pap results (low-grade squamous intraepithelial lesions or worse) was 2.4% for first program screens and 1.8% for subsequent program screens. Histology results showed a high proportion of cervical intraepithelial neoplasia grade 2 or worse (57%) among women with precancers and cancers. Roughly one-third (32%) of Pap test results warranting follow-up had no data recorded on diagnostic tests or follow-up done. CONCLUSION: This is the first report of cervical cancer screening and outcomes of women served in the USAPI through the NBCCEDP with similar results for abnormal Pap tests, but higher proportion of precancers and cancers, when compared to national NBCCEDP data. The USAPI face significant challenges in implementing cervical cancer screening, particularly in providing and recording data on diagnostic tests and follow-up. The screening programs in the USAPI should further examine specific barriers to follow-up of women with abnormal Pap results and possible solutions to address them. PMID- 29120835 TI - Characteristics of invasive breast cancer and overall survival of patients eligible for mass breast cancer screening in Guadeloupe compared to those of the preceding age group. AB - BACKGROUND: Mass breast cancer screening is offered to French women between the ages of 50 and 74. In the French overseas department of Guadeloupe, where the population is of mostly African ancestry, a low age at diagnosis of breast cancer has been reported, as for African-Americans. This raises the question of whether breast cancer is more aggressive in the age group preceding that eligible for mass screening (40-49) in Guadeloupe. METHODS: We compared the tumor-related prognostic factors, first line therapy and overall survival rates of breast cancer cases diagnosed between the 40-49 and 50-74 age groups, based on reports of the cancer registry of Guadeloupe for the period 2008-2013. RESULTS: The characteristics studied, risk of death after breast cancer (HR 0.84 [95% CI: 0.58 1.22] and overall survival, did not differ significantly between the two groups, except for higher tumor size (28.8 vs 24.0; p=0.004) in the younger group. CONCLUSION: These results do not show a pattern of more aggressive breast cancer in the age group preceding that eligible for mass screening in Guadeloupe. PMID- 29120836 TI - Implementing an organised cervical screening programme in the Republic of Moldova Stakeholder identification and engagement. AB - INTRODUCTION: Successfully implementing cervical screening programmes requires them to be adapted to the local context and have broad stakeholder support. This can be achieved by actively engaging local stakeholders in planning as well as implementing the programmes. The Moldovan government started implementing an organised cervical screening programme in 2010 with the first step being stakeholder identification and engagement. MATERIALS AND METHODS: This process started by contacting easily identified stakeholders with each asked to recommend others and the process continued until no new ones were identified. Stakeholders were then involved in a series of individual and group meetings over a 2-year period to build confidence and encourage progressively greater engagement. RESULTS: In total, 87 individuals from 46 organisations were identified. Over the 2-year process, the individual and group meetings facilitated a change in stakeholder attitudes from disinterest, to acceptance and finally to active cooperation in designing the screening programme and preparing an implementation plan that were both well adapted to the Moldovan context. DISCUSSION: Developing the broad support needed to implement cervical screening programmes required ongoing interaction with stakeholders over an extended period. This interaction allowed stakeholder concerns to be identified and addressed, progress to be demonstrated, and stakeholders to be educated about organised screening programmes so they had the knowledge to progressively take greater responsibility and ownership. PMID- 29120837 TI - Cancer risk reduction in the US Affiliated Pacific Islands: Utilizing a novel policy, systems, and environmental (PSE) approach. AB - BACKGROUND: The Health Directors of the US Affiliated Pacific Islands (USAPI) declared a State of Emergency due to epidemic proportions of lifestyle diseases: cancer, obesity and other non-communicable diseases (NCDs) in 2010. This paper describes the development, implementation, and evaluation of a USAPI policy, system and environment (PSE) approach to address lifestyle behaviors associated with cancer and other NCDs. METHODS: Each of USAPI jurisdictions applied the PSE approach to tobacco and nutrition interventions in a local institution, faith based, or community setting. A participatory community engagement process was utilized to: identify relevant deleterious health behaviors in the population, develop PSE interventions to modify the context in which the behavior occurs in a particular setting, implement the PSE intervention through five specified activities, and evaluate the activities and behavior change associated with the intervention. RESULTS: PSE interventions have been implemented in all USAPI jurisdictions. Current human and financial resources have been adequate to support the interventions. Process and behavior change evaluations have not been completed and is ongoing. Personnel turnover and maintaining the intervention strategy in response due to shifting community demands has been the biggest challenge in one site. CONCLUSION: From 2014 through 2016 the PSE approach has been used to implement PSE interventions in all USAPI jurisdictions. The intervention evaluations have not been completed. The PSE intervention is novel and has the potential to be a scalable methodology to prevent cancer and modify NCD risk in the USAPI and small states. PMID- 29120838 TI - Acceptability and feasibility of a community based participatory research project comparing cytology and urine HPV DNA testing for cervical cancer screening in Yap, Federated States of Micronesia. AB - Non-invasive, self-collected sampling methods for HPV DNA detection in women, which are reliable, efficient, and acceptable have the potential to address barriers to cervical cancer screening in underserved communities, including low middle income countries (LMIC) such as the island nation of the Federated States of Micronesia (FSM). Urine-based HPV testing has not been rigorously evaluated in clinical trials. A pilot community-based participatory randomized control research project evaluated use of urine HPV testing as a more culturally- and human resource appropriate method of cervical cancer screening in Yap State, FSM. Women participated in a cervical screening intervention using pap vs. urine test (N=217). This manuscript described attitudes about screening feasibility and preferences. Stakeholders and women participants were interviewed (N=23), and a survey also evaluated women's screening preferences (N=217). Qualitative content thematic analysis with multiple coders identified themes from interviews on acceptability and feasibility of screening tests. Women research participants were comfortable with the urine test (95%), despite limitations in some to provide samples. While 82.0% indicated that they felt comfortable with Pap smear, they also preferred a clinician (42%) to do the Pap smear, explaining that they preferred having a trained worker instead of themselves to do tests. Women want to be screened but accessibility remains a challenge. Education and training of professionals and community members alike will improve clinical skills, research capacity, knowledge of screening tests and behaviors including prioritizing HPV screening and testing. PMID- 29120839 TI - Mental health follow-up after deliberate self-harm and risk for repeat self-harm and death. AB - Morbidity and mortality after deliberate self-harm (DSH) are high, so mental health care shortly after DSH is recommended. Using population-level health data we determined the association between a mental health visit and risk for repeat DSH with or without intensive care unit (ICU) admission or all-cause death. Over two years, 23,140 individuals had emergency department treatment for DSH. Within 30 days, 10.7% had a family physician mental health visit, 17.1% visited a psychiatrist, 3.6% visited both and 68.6% neither. Individuals who received mental health follow-up had more chronic and severe mental illness and higher acuity DSH. Over five years, repeat DSH occurred in 4792 (20.7%). Repeat DSH was more common in those who had a mental health visit within 30 days. Adjusting for baseline characteristics attenuated these differences. Similar results were found for DSH with ICU admission (5.0%) and death (7.6%). More frequent follow-up was not associated with better outcome. Timely access to mental health care after DSH was poor at 31%. Follow-up care had virtually no association with subsequent risk, so treatment as usual is insufficient. Post-DSH care augmented with evidence-based interventions is required. PMID- 29120840 TI - Responsibility beliefs and persecutory delusions. AB - Recent research implicates cognitive processes traditionally linked to anxiety disorders in the maintenance of paranoia. Responsibility beliefs have traditionally been associated with OCD, and recent research suggests they may be transdiagnostic. The present study reports the first data on responsibility beliefs in individuals with persecutory delusions. 30 people with persecutory delusions completed measures of psychotic symptoms and responsibility beliefs. Participants were also asked to identify who they held responsible for their persecution. Quantitative data on responsibility beliefs were compared with 29 matched non-clinical control participants, and with published data from patients with OCD and anxiety disorders. People with persecutory delusions identified a number of different entities responsible for harm. The persecutory delusions group had higher responsibility beliefs than those with OCD, anxiety disorders and nonclinical controls. The results suggest that responsibility beliefs are a facet of the phenomenology of persecutory beliefs. Cognitive-behavioural therapy for psychosis might usefully draw from OCD interventions and focus on responsibility beliefs, perhaps especially in Bad Me paranoia. PMID- 29120841 TI - Mindfulness, posttraumatic stress symptoms, depression, and social functioning impairment in Chinese adolescents following a tornado: Mediation of posttraumatic cognitive change. AB - Previous studies have shown that mindfulness is associated with less negative traumatic outcomes in people who experienced traumatic events. The present study investigated how mindfulness is related to posttraumatic stress disorders (PTSD) symptoms, depression and social functioning impairment in Chinese traumatized adolescents by considering the role of posttraumatic cognitive change (PCC). A total of 247 Chinese adolescents, who had experienced a severe tornado six months prior to this study, were recruited to complete a series of questionnaires. Results showed that the proposed model fitted the data very well (chi2 = 16.200, df = 8, chi2/df = 2.025, GFI = 0.983, CFI = 0.991, TLI = 0.976, RMSEA = 0.063). Further analyses revealed that PCC mediated the relation between dispositional mindfulness and all negative posttraumatic outcomes (including PTSD symptoms, depression and social functioning impairment). Limitations, clinical implications, and directions for future research were discussed. PMID- 29120842 TI - Do cognitive deficits predict negative emotionality and aggression in schizophrenia? AB - Schizophrenia is associated with an elevated risk of aggression. Cognitive deficits have been associated with inpatient aggression and future violence. The relationship between cognitive deficits and violent behavior has however been inconsistent across studies. In addition, studies have failed to inform how cognitive deficits may contribute to aggression in schizophrenia. The current study examined the association of cognitive deficits with schizophrenia-related aggression and violent offending. It also explored the putative mediating role of negative emotionality on the impact of cognitive deficits on aggression. People with schizophrenia and schizoaffective disorder (N = 78) were recruited from a state hospital. Participants were classified based on their history of violent offending. Participants completed measures of cognition, symptoms, and aggression. Deficits in working memory, reasoning/problem-solving, and verbal learning were the most prioritized for the prediction of violent offender status. Violent offenders demonstrated greater impairments in most cognitive domains especially working memory and verbal learning. Offenders also demonstrated greater negative emotionality, excitement/agitation, and incidents of verbal and physical aggression. Negative emotionality and excitement/agitation fully transmitted the effect of cognitive deficits on impulsive aggression in meditational models. Cognitive deficits increase the risk of impulsive aggression in schizophrenia via inefficient regulation of negative affective states. PMID- 29120843 TI - The relationship between PTSD, depression and negative life events: Ya'an earthquake three years later. AB - PTSD (Posttraumatic Stress Disorder) is a common post-disaster psychological condition which research has shown to have comorbidity with depression. To explore the relationship between PTSD and depression further, a cross-sectional study design was adopted. Three years after the Ya'an earthquake, 4137 adolescents (mean age 15.12) who had personally experienced the earthquake were assessed. The study results showed that PTSD significantly predicted future depression, with the effect being partially mediated by the negative life events after the earthquake. Gender was not found to be a significant moderator between PTSD and depression. PMID- 29120844 TI - Prevalence and clinical-demographic correlates of hyperhomocysteinemia in inpatients with bipolar disorder in a Han Chinese population. AB - Recent studies have reported that hyperhomocystinemia (HHcy) is highly prevalent in patients with bipolar disorder (BD), placing them at greater risk of cardiovascular disease and possibly serving as a disease biomarker. However, the correlation of HHcy with demographic or clinical parameters is not well known. In this study, we examined the prevalence of HHcy and its association with these parameters in a sample of Chinese BD patients. Fasting plasma homocysteine (Hcy) levels were determined in 198 BD inpatients and 84 healthy controls. HHcy was defined when Hcy concentration exceeded 15.0umol/L. Affective symptomatology was assessed by the Young Mania Rating Scale, Hamilton Depression Rating Scale and the Clinical Global Impressions severity scale. Compared to healthy controls, BD patients had a significantly higher prevalence (34.85% vs. 19.05%) of HHcy and a higher absolute level of homocysteine. Logistic regression analysis demonstrated that BD patients with HHcy were more likely to be male, have elevated BMI, more frequent treatment on lithium but less on valproate. These results suggest that Chinese inpatients with bipolar disorder have a higher rate of HHcy than the general population, and those at greatest risk are male, have an elevated BMI, and take more lithium but less valproate therapy. PMID- 29120845 TI - Markers of DNA/RNA damage from oxidation as predictors of a registry-based diagnosis of psychiatric illness in type 2 diabetic patients. AB - Oxidative stress is a potential biological mediator of the higher rates of psychiatric illness (PI) observed after the onset of type 2 diabetes (T2DM). We investigated validated urinary markers of systemic DNA/RNA damage from oxidation (8-oxodG/8-oxoGuo respectively) as predictors of incident PI in a cohort of 1381 newly diagnosed T2DM patients, who were followed prospectively for a total of 19 years after diagnosis. Psychiatric diagnoses were from Danish national registries. Patients were examined at the time of diagnosis and at a 6-year follow-up. At baseline, 8-oxodG was slightly lower in PI vs. non-PI patients, while at 6-year follow-up, 8-oxoGuo was significantly higher in PI patients. Using Cox proportional hazard models, we found that higher levels of 8-oxodG at 6 year follow-up significantly predicted lower incidence of PI after the adjustment for confounders. In a subgroup analysis, this association was most predominant in minor PIs (unipolar depression and anxiety) compared to major PIs such as schizophrenia and bipolar disorder. These observations indicate that higher levels of systemic oxidative stress are not associated with a higher risk of PI after T2DM onset. Only PI patients treated in hospital care were included in the registries, and the conclusion thus only applies to these individuals. PMID- 29120846 TI - Firesetting and general criminal recidivism among a consecutive sample of Finnish pretrial male firesetters: A register-based follow-up study. AB - The rate of criminal reoffending among firesetters varies greatly. Our aim was to investigate firesetting and general criminal recidivism in a consecutive sample of Finnish males who were sent for a forensic psychiatric examination (FPE)1 after committing firesetting offenses. We also wanted to evaluate the relationships between psychopathy and criminal recidivism, and between schizophrenia-spectrum disorders and criminal recidivism. The sample comprised 113 firesetters with a mean age of 32.8 years, and the average follow-up time was 16.9 years. The FPE statements of the firesetters were reviewed and psychiatric diagnoses were collected. The psychopathy assessments were based on the 20-item Hare Psychopathy Checklist-Revised (PCL-R). Information on reoffending was gathered from the Finnish National Police Register. During the follow-up 20 (18%) persons were registered for a new firesetting and 84 (74%) for any new offense. Firesetters with high traits (PCL-R >= 25) of psychopathy were more likely than those with low traits (PCL-R < 25) to reoffend with any crime during the follow up. The risk of general criminal recidivism was lower among firesetters with a schizophrenia-spectrum disorder than among those with non-psychotic disorders. Conclusively, both firesetting and general criminal-recidivism rates were high in this sample of offenders. PMID- 29120847 TI - Quality assessment of clinical practice guidelines on tic disorders with AGREE II instrument. AB - To assess the methodological quality of existing clinical practice guidelines (CPGs) on the treatment of tic disorders (TDs) using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument and summarize the guideline recommendations. Five CPGs met our inclusion criteria. The mean percentages for the AGREE II domain scores were: scope and purpose 83.33% (95% confidence interval [CI], 77.78-94.44%), stakeholder involvement 62.22% (95% CI, 38.89 94.44%), rigor of development 47.08% (95% CI, 6.25-83.33%), clarity of presentation 87.78% (95% CI, 72.22-94.44%), applicability 56.67% (95% CI, 33.33 87.50%), and editorial independence 46.67% (95% CI, 8.33-91.67%). There were large differences among the five CPGs concerning the categorization of evidence and recommendations. The recommendations for drug therapy were similar in all five CPGs, although there was controversy in certain areas. The methodological quality of CPGs for TDs was acceptable in terms of scope and purpose, stakeholder involvement, and clarity of presentation. However, CPG developers need to pay more attention to rigorous development processes, applicability, and editorial independence. Developers of future CPGs should improve adherence to the AGREE II guidelines. In addition, high quality studies on the treatment of TDs are needed to provide more evidence for developing guidelines. PMID- 29120848 TI - Is the first cut really the deepest? Frequency and recency of nonsuicidal self injury in relation to psychopathology and dysregulation. AB - Research on nonsuicidal self-injury (NSSI) has moved beyond examination of factors that associate with the mere presence or absence of the behavior, and into more nuanced examination of which discrete features of NSSI behavior relate to pathology. This study examined two features of NSSI, frequency of occurrence and recency, as cross-sectional predictors of psychopathology in a large community sample of adults with a history of NSSI (N = 315). Results of 2 * 2 factorial ANOVAs testing the interactive effects of NSSI frequency (clinical, subclinical) and recency (current, past) revealed that current NSSI was consistently associated with poorer emotional and behavioral health (e.g., greater symptoms of depression, panic, and anxiety, worse emotion regulation, greater alcohol misuse). Results for NSSI frequency were more variable, though preliminary evidence suggested significant interactions of current NSSI and clinical frequency on emotion dysregulation, general anxiety, and panic. Possible clinical and empirical implications of the NSSI disorder frequency criteria proposed in DSM-5 are discussed. PMID- 29120850 TI - Aggression as an independent entity even in psychosis - The role of cortisol. AB - Aggression is a common entity in psychiatric disorders, particularly psychotic disorders. Glucocorticoid hypofunction has been linked to abnormal forms of aggressive behavior in various studies in a 'possibly causal' role. We hypothesise that aggression, even among those having psychosis is associated with glucocorticoid alterations similar to those who are aggressive but not psychotic. To our knowledge, this is the first study attempting to look at the cortisol functioning in relation to both aggression and psychosis. The present study included 80 participants divided into four groups depending upon presence or absence of aggression and psychosis. Morning cortisol, afternoon cortisol and their variability were measured using ELISA. The groups were compared on measures of aggression, psychosis, morning cortisol, afternoon cortisol and their variability using standard statistical instruments. The present study found lower levels of morning cortisol, afternoon cortisol and cortisol variability among the aggressive group (vs. non aggressive group) and among the diseased group (vs. non diseased group). The differences were most marked for cortisol variability which was related to both aggression and psychosis independently. There were statistically significant correlation between cortisol variability and aggression, which was retained even after controlling for psychosis. There was no significant correlation of cortisol variability with psychosis severity (after controlling for aggression score) or with age, gender or duration of psychosis. We conclude that aggression, even among patients with psychosis, is an independent entity characterized by lower levels of morning cortisol and cortisol variability. The etio-pathology may lie in some altered neuro-immune parameters executed by cortisol and psychosis as trigger. PMID- 29120849 TI - Genetic analysis of impulsive personality traits: Examination of a priori candidates and genome-wide variation. AB - Impulsive personality traits are heritable risk factors and putative endophenotypes for addiction and other psychiatric disorders involving disinhibition. This study examined the genetic basis of impulsive personality traits, defined as scores on the Barratt Impulsiveness Scale (BIS-11) and the UPPS-P Impulsive Behavior Scale (UPPS-P). In 983 healthy young adults of European ancestry, the study examined genetic variation in relation to a combined phenotype of seven subscales based on high phenotypic intercorrelations. The study first tested 14 a priori loci that have previously been associated impulsive personality traits or closely related constructs. Second, the study included an exploratory genome-wide scan (i.e., GWAS), acknowledging that only relatively large effects would be detectable in a sample size of ~ 1000. A priori SNP analyses revealed a significant association between the combined impulsivity phenotype and two SNPs within the 5-HT2a receptor gene (HTR2A; rs6313 and rs6311). Follow-up analyses suggested that the effects were specific to the Motor and Non-planning subscales on the BIS-11, and also that the two loci were in linkage disequilibrium. The GWAS yielded no statistically significant findings. This study further implicates loci within HTR2A with certain forms of self reported impulsivity and identifies candidates for future investigation from the genome-wide analyses. PMID- 29120851 TI - The generalizability of the structure of substance abuse and antisocial behavioral syndromes: A systematic review. AB - BACKGROUND: Although several authors have suggested that a single externalizing spectrum encompassing both antisocial behavioral syndromes and substance use disorder is to be preferred, this assumption has not been evaluated systematically throughout studies. PURPOSE: The objective was to establish the generalizability of transdiagnostic models of externalizing disorders across different types of disorders and populations, in regard to the strength of the evidence. METHOD: We conducted a systematic literature review using combinations of two sets of keywords: 1) "antisocial", "externalizing", "conduct disorder", "disruptive behavior disorder", "substance abuse", "substance-related disorder", "cannabis", "cocaine", "hallucinogen", "alcoholism", "opioid"; 2) "latent structure", "factor analysis", "multivariate analysis". RESULTS: Models supporting a superordinate factor appeared dominant in a limited set of different populations, on which the majority of the research sample was focused. CONCLUSIONS: Although the externalizing spectrum model is a promising angle for future research and treatment, extending research on this model in a higher diversity of populations is recommended to enhance the understanding and applicability of the externalizing spectrum model. PMID- 29120852 TI - Effect of gestational age on migration ability of the human umbilical cord vein mesenchymal stem cells. AB - PURPOSE: Migration ability of mesenchymal stem cells (MSCs) towards chemotactic mediators is a determinant factor in cell therapy. MSCs derived from different sources show different properties. Here we compared the migration ability of the term and the pre-term human umbilical cord vein MSCs (hUCV-MSCs). MATERIALS/METHODS: MSCs were isolated from term and pre-term umbilical cord vein, and cultured to passage 3-4. Migration rate of both groups was assessed in the presence of 10% FBS using chemotaxis assay. Surface expression of CXCR4 was measured by flow cytometery. The relative gene expression of CXCR4, IGF1-R, PDGFRalpha, MMP-2, MMP-9, MT1-MMP and TIMP-2 were evaluated using real time PCR. RESULTS: The isolation rate of the pre-term hUCV-MSCs was higher than the term hUCV-MSCs. Phenotype characteristics and differentiation ability of the term and pre-term hUCV-MSCs were not different. The migration rate of the pre-term hUCV MSCs was more than the term hUCV-MSCs. Gene and surface expressions of the CXCR4 were both significantly higher in the pre-term hUCV-MSCs (P<=0.05). The mRNA levels of PDGFRalpha, MMP-2, MMP-9, MT1-MMP and TIMP-2 showed no significant difference between the two groups. CONCLUSION: Our results showed that the gestational age can affect the migration ability of the hUCV-MSCs. PMID- 29120853 TI - Ultrastructural characteristics of the respective forms of hepatic stellate cells in chronic hepatitis B as an example of high fibroblastic cell plasticity. The first assessment in children. AB - PURPOSE: Activation of hepatic stellate cells (HSCs), mainly responsible for extracellular matrix synthesis, is assumed to be central event in the process of liver fibrogenesis. The major objective of the research was to analyze the ultrastructural profile of activated HSCs in children with chronic hepatitis B (chB), with respect to fibrosis intensity. MATERIALS/METHODS: Ultrastructural investigations of HSCs were conducted on liver bioptates from 70 children with clinicopathologically diagnosed chB before antiviral treatment. Biopsy material, fixed in paraformaldehyde and glutaraldehyde solution, was routinely processed for electron-microscopic analysis. RESULTS: In children with intensive liver fibrosis (S-2 and S-3), the ultrastructural picture showed almost total replacement of quiescent HSCs (Q-HSCs) by activated, i.e. transitional HSCs (T HSCs). Among T-HSCs, two types of cells were distinguished: cells exhibiting initiation of HSC activation (Ti-HSCs), never before described in chB, that were frequently accompanied by activated Kupffer cells, and cells with features of perpetuation of activation (Tp-HSCs). Tp-HSCs were elongated and characterized by substantial loss of cytoplasmic lipid material; they contained an increased number of cytoskeletal components, extremely dilated channels of granular endoplasmic reticulum and activated Golgi apparatus, which indicated their marked involvement in intensive synthesis of extracellular matrix proteins. Many collagen fibers were found to adhere directly to Tp-HSCs. CONCLUSIONS: The current study showed T-HSCs to be an important link between Q-HSCs and myofibroblastic HSCs (Mf-HSCs). Transformation of HSCs into new morphological variations (Ti-HSCs; Tp-HSCs and Mf-HSCs), observed along with growing fibrosis, indicates their high plasticity and a key role in fibrogenesis in pediatric chB. PMID- 29120854 TI - The protective effects of Bacillus licheniformis preparation on gastrointestinal disorders and inflammation induced by radiotherapy in pediatric patients with central nervous system tumor. AB - PURPOSE: we studied the effect of Bacillus licheniformis preparation (ZCS) on CNST (central nervous system tumor) patients undergoing the gastrointestinal symptoms and inflammation induced by radiotherapy. MATERIALS AND METHODS: 160 CNST patients with craniospinal irradiation (CSI) treatment were divided into experiment and control group. The experiment group patients took one capsule per time of ZCS and three times a day until the end of radiotherapy, starting one day before radiotherapy. While the patients in control group were administrated placebo without any probiotics. Serum from one day before radiotherapy and the first day after radiotherapy were collected to measure the ET, CRP, TNF-alpha, IL 1beta and IL-6. RESULTS: More than 70% CNST pediatric patients suffered from different degrees of gastrointestinal symptoms after radiotherapy, including mouth ulcer, nausea, vomiting, abdominal pain and diarrhea. And there was an obviously increased of serum ET, TNF-alpha, IL-1beta, IL-6 and CRP after RT. Importantly, a markedly decreased of ET, CRP and inflammatory cytokines were detected in the experiment group comparing to the control group after radiotherapy, as well as the relief of the gastrointestinal symptoms. However, improvement of probiotics (or ZCS) of the survival rate of CNST children and the recurrence of tumor are not observed in this study. CONCLUSIONS: Prophylactically administrated ZCS during radiotherapy for CNST patients can relieve RT-related gastrointestinal symptoms and inflammatory reaction. PMID- 29120855 TI - The application of L-PRP in AIDS patients with crural chronic ulcers: A pilot study. AB - PURPOSE: Nonhealing wounds or skin ulcerations are the result of insufficient repair and destruction of a local healing potential. Opportunistic infections which cause a lot of ulcer complications influence the worsening general condition of patients with AIDS, ultimately leading to death. The chronicity of the condition and poor results of conventional therapy have prompted the search for new methods of treatment. MATERIALS AND METHODS: We have examined venous or arteriovenous insufficiency-related extensive crural ulcers in AIDS patients. Crural ulcer healing processes were evaluated with clinical observations and histopathological, immunohistochemical and molecular examinations of tissue samples harvested from the wound edges before and on day 10 after L-PRP cover dressing. RESULTS: Clinical observations showed positive effects of L-PRP in all patients. However, complete wound closure was noted in 60% of cases. Statistical analysis of histological examination showed increased epidermal processes between samples, but the difference was nonsignificant. However, immunohistochemical investigations showed an increased healing process with strong statistical significance. The mean VEGF level before L-PRP usage was 114.3 vessels/mm2 and on day 10 118.9 (p=0.001523). The mean FLK level was 103.2 and 109.9 respectively (p=0.008241). The biggest differences were observed for CD34, with values of 68.2 on day 0 and 100.8 on day 10 (p=0.006982). Molecular analysis generally showed decreased gene expression and confirmed vascular formation and reepithelialization processes. CONCLUSIONS: In our opinion, L-PRP may be used to eradicate microorganisms from wounds, to induce neovascularization, and in unhealed cases prepare the base and edge of the ulcer for skin grafting and tissue expansion procedures. PMID- 29120856 TI - PPARgamma Pro12Ala and C161T polymorphisms in patients with acne vulgaris: Contribution to lipid and lipoprotein profile. AB - PURPOSE: The aim of present study was to clarify the role of peroxisome proliferator-activated receptor gamma (PPARgamma) Pro12Ala and C161T variants in the pathogenesis of acne vulgaris (AV) and their influence on lipid and lipoprotein profile. METHODS: The present case-control study consisted of 393 individuals including 198 patients with AV (mild-, moderate-, and severe-AV) and 195 unrelated age-matched healthy individuals from Western Iran. The PPARgamma Pro12Ala and C161T polymorphisms were identified using polymerase chain reaction restriction length polymorphism method. Also, serum lipid and lipoprotein profile and fasting blood sugar (FBS) were detected in studied individuals. RESULTS: In women patients with AV significantly higher serum levels of FBS, total cholesterol, low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol compared to healthy women were detected. Neither PPARgamma Pro12Ala nor C161T polymorphism was associated with the risk of AV but the Pro allele was a risk factor for AV among all men and women patients >=20years. The variant genotype of PPARgamma CG (Pro/Ala) was associated with significantly higher levels of total cholesterol and triglycerides compared to CC (Pro/Pro) genotype. We detected a significantly lower level of FBS in the presence of CT+TT genotype of PPARgamma C161T compared to CC genotype. Also, carriers of PPARgamma TT genotype had significantly lower serum level of total cholesterol and LDL-C compared to CC genotype. CONCLUSIONS: Our results demonstrated the association of PPARgamma Pro allele with susceptibility to AV in patients >=20years and the influence of PPARgamma Pro12Ala and C161T polymorphisms on the lipid and lipoprotein profile. PMID- 29120857 TI - The safety and efficacy of light emitting diodes-based ultraviolet A1 phototherapy in bleomycin-induced scleroderma in mice. AB - PURPOSE: To define the efficacy and safety of narrowband ultraviolet A1 (UVA1) for the treatment of dermal fibrosis in bleomycin-induced mouse model of scleroderma. MATERIALS AND METHODS: 42 DBA/2 strain mice were included in the study: healthy mice and mice with established scleroderma, treated with high or medium dose of UVA1. Non-treated groups served as control. The equipment emitting 365+/-5nm UVA1 radiation was used in the study. The average cumulative doses were 1200J/cm2 for high and 600J/cm2 for medium dose course. Histological analysis was performed for the evaluation of the dermal thickness and mast cells density. The expressions of p53 and Ki-67 proteins were assessed by immunohistochemical analyses. RESULTS: Skin thickness of mice with scleroderma, treated with high and medium dose of UVA1, were lower (272.9+/-113.2MUm and 394+/-125.9MUm, respectively) in comparison to the dermal thickness of non-treated animals (599+/ 55.7MUm). The dermal mast cells count in mice with scleroderma was reduced after high and medium dose treatment to 11+/-1.7 and 13+/-2.2, respectively, as compared to that in non-treated mice (23+/-3.0). No significant upregulation of p53 nor Ki-67 proteins was observed in the skin of healthy mice and mice with scleroderma after high- and medium-dose of UVA1. CONCLUSIONS: The results of this study indicate that 365nm UVA1 with the cumulative doses of 1200J/cm2 and 600J/cm2 is safe and effective for the dermal fibrosis treatment. PMID- 29120858 TI - Prognostic value of fibrosis-related markers in dilated cardiomyopathy: A link between osteopontin and cardiovascular events. AB - INTRODUCTION: Serum markers of fibrosis provide an insight into extracellular matrix (ECM) fibrosis in heart failure (HF) and dilated cardiomyopathy (DCM). However, their role as predictors of cardiovascular (CV) events in DCM is poorly understood. METHODS: This is an observational, prospective cohort study. 70 DCM patients (48+/-12.1years, ejection fraction - EF 24.4+/-7.4) were recruited. Markers of collagen type I and III synthesis - procollagen type I and III carboxy and amino-terminal peptides (PICP, PIIICP, PINP, PIIINP), fibrosis controlling factors - ostepontin (OPN), transforming growth factor (TGF1-beta) and connective tissue growth factor (CTGF), and matrix metalloproteinases (MMP-2, MMP-9) and tissue inhibitor (TIMP-1), were measured in serum. All patients underwent endomyocardial biopsy. The end-point was combined with CV death and urgent HF hospitalization. Patients were divided into two groups: those who did (group 1, n=45) and did not reach (group 2, n=25) an end-point. RESULTS: Over a 12-month period of observation, 6 CV deaths and 19 HF hospitalizations occurred. Qualitative and quantitative measures of ECM fibrosis were similar in both groups. The levels of all of the markers of collagen synthesis, TGF1-beta, MMP-9 and TIMP-1 were similar, however, OPN, CTGF and MMP-2 were significantly lower in group 1. CONCLUSIONS: Invasively-determined fibrosis levels were not related with CV outcomes in DCM. Out of the 11 markers of fibrosis under study, only OPN was found to be related to CV outcomes. OPN is not only the pivotal protein controlling fibrosis, but may also serve as a biomarker associated with prognosis. PMID- 29120859 TI - Tick-borne infections and co-infections in patients with non-specific symptoms in Poland. AB - AIM: The aim of the study was the evaluation of the frequency of infections and co-infections among patients hospitalized because of non-specific symptoms after a tick bite. MATERIALS AND METHODS: Whole blood, serum and cerebrospinal fluid samples from 118 patients hospitalised for non-specific symptoms up to 8 weeks after tick bite from 2010 to 2013 were examined for tick-borne infections. ELISA, Western blot and/or molecular biology (PCR; fla gene; 16S rRNA; sequencing) and thin blood smears (MDD) were used. Control group included 50 healthy blood donors. All controls were tested with PCR and serology according to the same procedure as in patients. RESULTS: Out of 118 patients 85 (72%) experienced headaches, 15 (13%) vertigo, 32 (27%) nausea, 17 (14%) vomiting, 37 (31%) muscle pain, 73 (62%) fever and 26 (22%) meningeal signs. 47.5% were infected with at least one tick-borne pathogen. Borrelia burgdorferi sensu lato infection was confirmed with ELISA, Western blot in serum and/or (PCR (fla gene) in whole blood in 29.7% cases. In blood of 11.9% patients Anaplasma phagocytophilum DNA (16S rRNA gene) was detected; in 0.9% patients 1/118 Babesia spp. DNA (18S rRNA gene) was also detected. Co-infections were observed in 5.1% of patients with non specific symptoms. B. burgdorferi s.l. - A. phagocytophilum co-infection (5/118; 4.2%) was most common. In 1/118 (0.8%) A. phagocytophilum - Babesia spp. co infection was detected. All controls were negative for examined pathogens. CONCLUSIONS: Non-specific symptoms after tick bite may be caused by uncommon pathogens or co-infection, therefore it should be considered in differential diagnosis after tick bite. PMID- 29120860 TI - Marijuana use among adults: Initiation, return to use, and continued use versus quitting over a one-year follow-up period. AB - BACKGROUND: This study examined factors associated with marijuana use initiation among never users, prior-to-past year user who return to use, and users who continue use over a 12-month follow-up period. METHODS: Two waves (W1 and W2) of the Population Assessment of Tobacco and Health (PATH) Study provided data (N=26,204 aged 18+). Multivariable logistic regression models were used to examine associations of W1 sociodemographic, health/mental health, and other substance use characteristics with W2 use status. As applicable, marijuana initiation age, use frequency, and use problems were also examined. RESULTS: At W2, 2.36% and 10.42% of W1 never users and prior-to-past year users, respectively, reported having used marijuana, and 72.54% of W1 past-year users reported continued use. Those in the 18-24 age group were most likely to initiate, resume, or continue use. Among never and prior-to-past year users, those who reported more mental health problems at W1 also had greater odds of use at W2. Marijuana initiation and return to use were significantly associated with movement from nonuse to use of other substances. Continued marijuana use, as opposed to quitting, was also associated with other substance use, initiation of marijuana use prior to age 18, weekly or more frequent use (AOR=2.34, 95% CI=1.87 2.93), and use problems (AOR=1.40, 95% CI=1.05-1.85) reported at W1. CONCLUSIONS: Movement between marijuana nonuse and use was substantial during the 12-month follow-up period. Early intervention to prevent initiation of, return to, and continued marijuana and other substance use, especially among young adults, is needed. PMID- 29120862 TI - MicroRNAs participate in the regulation of oligodendrocytes development in white matter injury. AB - White matter injury (WMI) often results in cognitive impairment, behavioral disorders, and cerebral palsy and thus imposes a tremendous burden on society. The cells in brain white matter mainly comprise oligodendrocytes (OLs), astrocytes, and microglia. The dysregulation of OLs development is the pathological hallmark of WMI. Recent studies have demonstrated that microRNAs (miRNAs or miRs) participate in the regulation of OLs development, and the dysregulation of this process represents the pathogenesis of WMI. This review summarizes the progress made in this field that will help clinicians and researchers understand the molecular etiology of WMI and develop miRNAs as new agents for the prevention and treatment of WMI. PMID- 29120863 TI - Atomic-scale distortions and temperature-dependent large pseudogap in thin films of the parent iron-chalcogenide superconductor Fe1+y Te. AB - We investigate with scanning tunneling microscopy/spectroscopy (STM/STS) and density functional theory (DFT) calculations the surface structures and the electronic properties of Fe1+y Te thin films grown by pulsed laser deposition. Contrary to the regular arrangement of antiferromagnetic nanostripes previously reported on cleaved single-crystal samples, the surface of Fe1+y Te thin films displays a peculiar distribution of spatially inhomogeneous nanostripes. Both STM and DFT calculations show the bias-dependent nature of such features and support the interpretation of spin-polarized tunneling between the FeTe surface and an unintentionally magnetized tip. In addition, the spatial inhomogeneity is interpreted as a purely electronic effect related to changes in hybridization and Fe-Fe bond length driven by local variations in the concentration of excess interstitial Fe cations. Unexpectedly, the surface density of states measured by STS strongly evolves with temperature in close proximity to the antiferromagnetic paramagnetic first-order transition, and reveals a large pseudogap of 180-250 meV at about 50-65 K. We believe that in this temperature range a phase transition takes place, and the system orders and locks into particular combinations of orbitals and spins because of the interplay between excess interstitial magnetic Fe and strongly correlated d-electrons. PMID- 29120861 TI - Preventing relapse to smoking with transcranial magnetic stimulation: Feasibility and potential efficacy. AB - Many smokers attempt to quit every year, but 90% relapse within 12 months. Converging evidence suggests relapse is associated with insufficient activation of the prefrontal cortex. Delay discounting rate reflects relative activity in brain regions associated with relapse. High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (LDLPFC) increases cortical excitability and reduces delay discounting rates, but little is known about feasibility, tolerability, and potential efficacy for smoking cessation. We hypothesized that 8 sessions of 20Hz rTMS of the LDLPFC combined with an evidence-based self-help intervention will demonstrate feasibility, tolerability, and potential efficacy in a limited double-blind randomized control trial. Smokers (n=29), abstinent for 24h, motivated to quit, and not using cessation medications, were randomized to active 20Hz rTMS at 110% of Motor Threshold or sham stimulation that replicated the look and sound of active stimulation. Stimulation site was located using the 6cm rule and neuro navigation. Multiple clinical, feasibility, tolerability, and efficacy measures were examined. Active rTMS decreased delay discounting of $100 (F (1, 25.3694)=4.14, p=.05) and $1000 (F (1, 25.169)=8.42, p<.01), reduced the relative risk of relapse 3-fold (RR 0.29, CI 0.10-0.76, Likelihood ratio chi2 with 1 df=6.40, p=.01), increased abstinence rates (active 50% vs. sham 15.4%, Chi2 (df=1)=3.80, p=.05), and increased uptake of the self-help intervention. Clinical, feasibility, and tolerability assessments were favorable. Combining 20Hz rTMS of the LDLPFC with an evidence-based self-help intervention is feasible, well-tolerated, and demonstrates potential efficacy. PMID- 29120864 TI - Dark energy two decades after: observables, probes, consistency tests. AB - The discovery of the accelerating universe in the late 1990s was a watershed moment in modern cosmology, as it indicated the presence of a fundamentally new, dominant contribution to the energy budget of the universe. Evidence for dark energy, the new component that causes the acceleration, has since become extremely strong, owing to an impressive variety of increasingly precise measurements of the expansion history and the growth of structure in the universe. Still, one of the central challenges of modern cosmology is to shed light on the physical mechanism behind the accelerating universe. In this review, we briefly summarize the developments that led to the discovery of dark energy. Next, we discuss the parametric descriptions of dark energy and the cosmological tests that allow us to better understand its nature. We then review the cosmological probes of dark energy. For each probe, we briefly discuss the physics behind it and its prospects for measuring dark energy properties. We end with a summary of the current status of dark energy research. PMID- 29120865 TI - Doping effect on the physical properties of Ca10Pt3As8(Fe2As2)5 single crystals. AB - Ca10Pt3As8(Fe2As2)5 is a unique parent compound for superconductivity, which consists of both semiconducting Pt3As8 and metallic FeAs layers. We report the observation of superconductivity induced via chemical doping in either Ca site using rare-earth (RE) elements (RE = La, Gd) or Fe site using Pt. The interlayer distance and the normal-state physical properties of the doped system change correspondingly. The coupled changes include (1) superconducting transition temperature T c increases with increasing both doping concentration and interlayer distance, (2) our T c value is higher than previously reported maximum value for Pt doping in the Fe site, (3) both the normal-state in-plane resistivity and out-of-plane resistivity change from non-metallic to metallic behavior with increasing doping concentration and T c, and (4) the transverse in plane magnetoresistance (MRab) changes from linear-field dependence to quadratic behavior upon increasing T c. For La-doped compound with the highest T c (~35 K), upper critical fields ([Formula: see text], [Formula: see text]), coherence lengths (xi ab, xi c), and in-plane penetration depth (lambda ab) are estimated. We discuss the relationship between chemical doping, interlayer distance, and physical properties in this system. PMID- 29120866 TI - Surface effects on exciton diffusion in non polar ZnO/ZnMgO heterostructures. AB - The diffusion of excitons injected in ZnO/Zn0.92Mg0.08O quantum well heterostructures grown by metal-organic-vapor-phase-epitaxy on non-polar ZnO substrates is investigated at room temperature. Cathodoluminescence linescans in a field-emission-gun scanning-electron-microscope are performed across cleaved cross-sections. A 55 nm diffusion length is assessed for excitons in bulk ZnMgO. When prepared as small angle bevels using focused ion beam (FIB), the effective diffusion length of excitons is shown to decrease down to 8 nm in the thinner part of the slab. This effect is attributed to non-radiative surface recombinations, with a 7 * 104 cm s-1 recombination velocity estimated at the FIB-machined ZnMgO surface. The strong reduction of the diffusion extent in such thin lamellae usually used for transmission electron microscopy could be use improve the spatial resolution of cathodoluminescence images, often limited by diffusion processes. PMID- 29120867 TI - Quantifying the ultrastructure of carotid arteries using high-resolution micro diffusion tensor imaging-comparison of intact versus open cut tissue. AB - Diffusion magnetic resonance imaging (dMRI) can provide insights into the microstructure of intact arterial tissue. The current study employed high magnetic field MRI to obtain ultra-high resolution dMRI at an isotropic voxel resolution of 117 um3 in less than 2 h of scan time. A parameter selective single shell (128 directions) diffusion-encoding scheme based on Stejskel-Tanner sequence with echo-planar imaging (EPI) readout was used. EPI segmentation was used to reduce the echo time (TE) and to minimise the susceptibility-induced artefacts. The study utilised the dMRI analysis with diffusion tensor imaging (DTI) framework to investigate structural heterogeneity in intact arterial tissue and to quantify variations in tissue composition when the tissue is cut open and flattened. For intact arterial samples, the region of interest base comparison showed significant differences in fractional anisotropy and mean diffusivity across the media layer (p < 0.05). For open cut flat samples, DTI based directionally invariant indices did not show significant differences across the media layer. For intact samples, fibre tractography based indices such as calculated helical angle and fibre dispersion showed near circumferential alignment and a high degree of fibre dispersion, respectively. This study demonstrates the feasibility of fast dMRI acquisition with ultra-high spatial and angular resolution at 7 T. Using the optimised sequence parameters, this study shows that DTI based markers are sensitive to local structural changes in intact arterial tissue samples and these markers may have clinical relevance in the diagnosis of atherosclerosis and aneurysm. PMID- 29120868 TI - Crystal, magnetic, calorimetric and electronic structure investigation of GdScGe1 x Sb x compounds. AB - Experimental investigations of crystal structure, magnetism and heat capacity of compounds in the pseudoternary GdScGe-GdScSb system combined with density functional theory projections have been employed to clarify the interplay between the crystal structure and magnetism in this series of RTX materials (R = rare earth, [Formula: see text] = transition metal and X = p-block element). We demonstrate that the CeScSi-type structure adopted by GdScGe and CeFeSi-type structure adopted by GdScSb coexist over a limited range of compositions [Formula: see text]. Antimony for Ge substitutions in GdScGe result in an anisotropic expansion of the unit cell of the parent that is most pronounced along the c axis. We believe that such expansion acts as the driving force for the instability of the double layer CeScSi-type structure of the parent germanide. Extensive, yet limited Sb substitutions [Formula: see text] lead to a strong reduction of the Curie temperature compared to the GdScGe parent, but without affecting the saturation magnetization. With a further increase in Sb content, the first compositions showing the presence of the CeFeSi-type structure of the antimonide, [Formula: see text], coincide with the appearance of an antiferromagnetic phase. The application of a finite magnetic field reveals a jump in magnetization toward a fully saturated ferromagnetic state. This antiferro-ferromagnetic transformation is not associated with a sizeable latent heat, as confirmed by heat capacity measurements. The electronic structure calculations for [Formula: see text] indicate that the key factor in the conversion from the ferromagnetic CeScSi-type to the antiferromagnetic CeFeSi type structure is the disappearance of the induced magnetic moments on Sc. For the parent antimonide, heat capacity measurements indicate an additional transition below the main antiferromagnetic transition. PMID- 29120869 TI - On atomic mechanisms governing the oxidation of Bi2Te3. AB - Oxidation of Bi2Te3 (space group R [Formula: see text] m) has been investigated using experimental and theoretical means. Based on calorimetry, x-ray photoelectron spectroscopy and thermodynamic modelling, Bi2Te3 is at equilibrium with Bi2O3 and TeO2, whereby the most stable compound is Bi2Te3, followed by Bi2O3. The reactivity of Bi towards oxygen is expected to be higher than that of Te. This notion is supported by density functional theory. The strongest bond is formed between Bi and Te, followed by Bi-O. This gives rise to unanticipated atomic processes. Dissociatively adsorbed oxygen diffuses through Bi and Te basal planes of Bi2Te3(0 0 0 1) and preferably interacts with Bi. The Te termination considerably retards this process. These findings may clarify conflicting literature data. Any basal plane off-cut or Bi terminations trigger oxidation, but a perfect basal cleavage, where only Te terminations are exposed to air, may be stable for a longer period of time. These results are of relevance for applications in which surfaces are of key importance, such as nanostructured Bi2Te3 thermoelectric devices. PMID- 29120870 TI - Density functional study of carbon vacancies in titanium carbide. AB - It is well established that TiC contains carbon vacancies not only in carbon deficient environments but also in carbon-rich environments. We have performed density functional calculations of the vacancy formation energy in TiC for C- as well as Ti-rich conditions using several different approximations to the exchange correlation functional, and also carefully considering the nature and thermodynamics of the carbon reference state, as well as the effect of varying growth conditions. We find that the formation of carbon vacancies is clearly favorable under Ti-rich conditions, whereas it is slightly energetically unfavorable under C-rich conditions. Furthermore, we find that the relaxations of the atoms close to the vacancy site are rather long-ranged, and that these relaxations contribute significantly to the stabilization of the vacancy. Since carbon vacancies in TiC are also experimentally observed in carbon-rich environments, we conclude that kinetics may play an important role. This conclusion is consistent with the experimentally observed high activation energies and sluggish diffusion of vacancies in TiC, effectively causing a freezing in of the vacancies. PMID- 29120871 TI - A SRSF1 self-binding mechanism restrains Mir505-3p from inhibiting proliferation of neural tumor cell lines. AB - Srsf1 has currently been demonstrated to be an oncogene that is precisely autoregulated for normal physiology. Although Mir505-3p has been reported as one of the regulatory miRNAs of Srsf1 in mouse embryonic fibroblast (MEF), the inhibitory effect of Mir505-3p on Srsf1 is poorly described in neural tumors. Whether SRSF1 autoregulation interferes with miRNA targeting on the Srsf1 transcript is unclear. In this work, we screened out one target site, out of three potential target sites on 3' UTR of Srsf1 transcript, that was required for Mir505-3p targeting. We showed that Mir505-3p was capable of inhibiting tumor proliferation driven by SRSF1 in two neural tumor cell lines, Neuro-2a (N2a) and U251, exclusively in serum-reduced condition. We observed that the protein level of SRSF1 was gradually promoted by increasing concentration of serum. We also found that overexpressed exogenous SRSF1 protein abolished this RNA interfering related targeting, suggesting that serum-rich condition restrains Mir505-3p from inhibiting Srsf1 transcript after inducing SRSF1 protein overexpression. Moreover, by applying bioinformatic analysis, the SRSF1 self-binding motif was found proximal to the Mir505-3p target site, which was required for a SRSF1 competitive self-binding interaction. The interaction of overexpressed exogenous SRSF1 protein and the SRSF1 self-binding motif was sufficient to restrain Mir505 3p from targeting the Srsf1 transcript. These results provide a better understanding of how tumorous microenvironment influences anticancer therapy in the neural system, suggesting potential strategic design for anticancer drugs. PMID- 29120872 TI - A Rare Case of Hemopericardium From a Ruptured Dissecting Pulmonary Artery Aneurysm: Postmortem Computed Tomography Scan and Autopsy Findings. AB - Nontraumatic hemopericardium is a potentially fatal pathology that is most commonly caused by myocardial wall rupture, ruptured aortic dissection, aortic aneurysm rupture, or a neoplastic process. A rare potential cause of hemopericardium is pulmonary artery dissection, with less than 100 reported cases in the literature. Pulmonary artery dissection is associated with pulmonary artery aneurysm, pulmonary artery hypertension, and congenital heart disease. We report a fatal case of nontraumatic hemopericardium caused by a ruptured dissecting pulmonary artery aneurysm in a 16-year-old girl with patent ductus arteriosus. The unenhanced postmortem computed tomography performed before autopsy was able to identify a large hemopericardium with a pulmonary artery aneurysm and lifting of mural calcification suggestive of a dissecting aneurysm. This enabled the pathologist to locate the exact rupture site that caused the hemopericardium. PMID- 29120873 TI - A Rare Case of Isolated Atrial Myocarditis Causing Death With no Post Mortem Computed Tomography Scan Correlation. AB - Acute myocarditis is a potentially fatal cardiac pathology that is thought to cause sudden death through arrhythmia and cardiac failure. Of the different subtypes, lymphocytic myocarditis is the most common form. The pathophysiology of myocarditis can be generally diffuse or focally involve the ventricles, but less frequently affects the atria. Although the clinical literature reports isolated atrial myocarditis as a cause of atrial fibrillation and enlargement, there is scant postmortem literature on the findings of this pathology. We report a fatal case of isolated lymphocytic atrial myocarditis affecting only the left atrium in a 56-year-old man, where microscopy of the left atrium confirmed a florid lymphocytic myocarditis. Retrospective postmortem computed tomography scan review did not show any abnormalities on the left atrial wall. PMID- 29120874 TI - Unusual Suicide by a Speargun Shot Through the Mouth: A Case Report. AB - We report an unusual case of suicide committed with a speargun shot through the mouth, causing a penetrating brain injury. The special features of the present case are not only related to the method chosen for the purpose but also to the difficulties encountered in confirming the diagnosis. Although this type of suicide has been previously reported, this case is particularly interesting in terms of the shooting mechanism and manner of death. Because of the length of the weapon, which was apparently used and found at the scene, a suicidal manner of death first seemed unlikely and the possibility of a simulated suicide was raised. It seemed impossible for the decedent to have shot himself without a mechanism to launch the shaft through the mouth. However, a complete forensic approach eventually allowed for a plausible mechanism of self-infliction, confirming the suicide diagnosis. PMID- 29120876 TI - Back to the bedside: Using point-of-care ultrasound. PMID- 29120877 TI - Antiphospholipid antibody syndrome: The difficulties of diagnosis. AB - Antiphospholipid antibody syndrome (APS) is an autoantibody-mediated thrombophilic disorder that causes a hypercoagulable state and can lead to venous thromboembolism, stroke, multiple miscarriages, and other pregnancy complications with the presence of antiphospholipid antibodies. This article reviews screening, diagnosis, and management of APS with a focus on the prevention of long-term complications. PMID- 29120878 TI - Investigating the effects of under-triage by existing major incident triage tools. AB - OBJECTIVES: Triage is a key principle in the effective management of a major incident. Its effectiveness is a balance between identifying those in need of life-saving intervention, and those triaged incorrectly as either needing/not needing life-saving intervention. The primary aim of this study was to report mortality in those under-triaged by existing major incident triage tools. Secondary aims were to report the ability of triage tools at identifying serious injury by body region (defined as the Abbreviated Injury Scale>=3). PATIENTS AND METHODS: Retrospective database analysis of the UK Trauma Audit Research Network for all adult patients (>=18 years) between 2006 and 2014. Patients were defined as priority one using a previously published list. Using the first recorded hospital physiology, patients were categorized by the Modified Physiological Triage Tool (MPTT), National Ambulance Resilience Unit (NARU) Sieve and existing Major Incident Medical Management and Support Triage Sieve. Categorical and continuous data were analyzed using a chi-test and Mann-Whitney U-test respectively. RESULTS: During the study period, 218 985 adult patients met the Trauma Audit Research Network inclusion criteria, with 24 791 (19.5%) priority one patients, of which 70% were male with a median age of 51 (33-71) years and injury severity score of 16 (9-25). The MPTT showed the lowest rate of under triage (42.4%, P<0.001). Compared with existing methods, the MPTT under-triage population had significantly lower mortality (5.7%, P<0.001) with significantly fewer serious thorax and head injuries under-triaged than both NARU Sieve and Triage Sieve (P<0.001). CONCLUSION: This study has defined the implications of under-triage in the context of a major trauma population. The MPTT misses fewer severely injured patients, with a significant reduction in mortality. We suggest the MPTT to be considered as an alternative to existing primary major incident triage tools. PMID- 29120879 TI - Coronary perforation to left ventricular cavity following stenting within a myocardial bridge. PMID- 29120880 TI - Culprit versus multivessel coronary intervention in ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. AB - BACKGROUND: The 2015 American College of Cardiology/American Heart Association update on primary percutaneous coronary intervention (PCI) in patients with ST segment elevation myocardial infarction (STEMI) recommended PCI of the non infarct-related artery at the time of primary PCI (class IIb recommendation). Despite evidence supporting complete revascularization in STEMI, its benefit on mortality rates is uncertain. METHODS: We searched all available databases for randomized controlled trials comparing complete multivessel percutaneous coronary intervention (CMV PCI) with infarct-artery-only revascularization in patients with STEMI. Summary risk ratios and 95% confidence intervals (CIs) were calculated for both the efficacy and safety outcomes. RESULTS: Nine randomized controlled trials fulfilled the inclusion criteria, yielding 2991 patients. Follow-up periods ranged from 6 to 36 months. Compared with infarct-related artery-only PCI, CMV PCI was associated with significantly lower rates of major adverse cardiac events [relative risk (RR)=0.54, 95% CI=0.41-0.71; P<0.00001], cardiovascular mortality (RR=0.48, 95% CI=0.28-0.80; P=0.005), and repeat revascularization (RR=0.38, 95% CI=0.30-0.47; P<0.00001). Although, contrast induced nephropathy and major bleed rates were comparable between both groups, CMV PCI failed to show any reduction in all-cause mortality (RR=0.75, 95% CI=0.53 1.07; P=0.11) and nonfatal myocardial infarction (RR=0.69, 95% CI=0.43-1.10; P=0.12). CONCLUSION: Our results suggest that in patients with STEMI and multivessel disease, complete revascularization is safe, and is associated with reduced risks of major adverse cardiac events and cardiac death along with a reduced need for repeat revascularization. However, it showed no beneficial effect on all-cause mortality and nonfatal myocardial infarction. PMID- 29120881 TI - ATP and T-cell-mediated rejection. AB - PURPOSE OF REVIEW: Purine nucleosides and nucleotides are released in the extracellular space following cell injury and act as paracrine mediators through a number of dedicated membrane receptors. In particular, extracellular ATP (eATP) significantly influences T-lymphocyte activation and phenotype. The purpose of this review is to discuss the role of ATP signaling in the T-cell-mediated alloimmune response. RECENT FINDINGS: In various animal models of solid transplantation, the purinergic axis has been targeted to prevent acute rejection and to promote long-term graft tolerance. The inhibition of ATP-gated P2X receptors has been shown to halt lymphocyte activation, to downregulate both Th1 and Th17 responses and to promote T-regulatory (Treg) cell differentiation. Similarly, the inhibition of ATP signaling attenuated graft-versus-host disease in mice undergoing hematopoietic cell transplantation. Significantly, different drugs targeting the purinergic system have been recently approved for human use and may be a viable therapeutic option for transplant patients. SUMMARY: The inhibition of eATP signaling downregulates the alloimmune response, expands Treg cells and promotes graft survival. This robust preclinical evidence and the recent advances in pharmacological research may lead to intriguing clinical applications. PMID- 29120882 TI - Donation after circulatory death and its expansion in Spain. AB - PURPOSE OF REVIEW: Donation after circulatory death (DCD) is still performed in a limited number of countries. This article summarizes the development of DCD in Spain and presents recent Spanish contributions to gain knowledge on the potential benefits and the practical use of normothermic regional perfusion (nRP). RECENT FINDINGS: DCD now contributes to 24% of deceased donors in Spain. The development of DCD has been based on an assessment of practices in the treatment of cardiac arrest and end-of-life care to accommodate the option of DCD; the creation of an adequate regulatory framework; and institutional support, professional training and public education. Appropriate posttransplant outcomes have been obtained with organs from both uncontrolled and controlled DCD donors. nRP is increasingly used, with preliminary data supporting improved results compared with other in-situ preservation/recovery approaches. Mobile teams with portable extracorporeal membrane oxygenation devices are making nRP possible in hospitals without these resources. To avoid the possibility of reestablishing brain circulation after the determination of death, a specific methodology has been validated. SUMMARY: DCD has been successfully developed in Spain following a streamlined process. nRP may become a standard in DCD, although further evidence on the benefits of this technology is eagerly awaited. PMID- 29120883 TI - Equipping the islet graft for self defence: targeting nuclear factor kappaB and implications for tolerance. AB - PURPOSE OF REVIEW: Clinical islet transplantation does not enjoy the success seen for solid organ transplants, indicating a need for new therapeutic approaches to improve patient outcomes. This has prompted investigation into islet autonomous factors and pathways that may represent druggable targets. These have the potential to synergize with approaches aimed at generating graft-specific tolerance. RECENT FINDINGS: There are emerging data that nuclear factor kappaB (NF-kappaB) activation can prevent and or overcome tolerance, whereas dampening NF-kappaB activation in immune cells is associated with prolonged allograft survival. In islet cells, NF-kappaB plays a central role in triggering the inflammatory transcriptional response that is often associated with reduced islet function and contributes to poor transplant outcomes. SUMMARY: Targeting intraislet NF-kappaB represents a promising target in islet transplantation. Here we will discuss the current state of the knowledge on the role of NF-kappaB activation in the context of islet transplantation and the implications of targeting NF-kappaB for tolerance induction. PMID- 29120885 TI - Habitual Snoring at Age 3 Years: Links with Parent-Rated Remembering in Daily Life and Academic Achievement at Age 7 Years. AB - OBJECTIVE: Habitual snoring in school-aged children is well known to link with poorer cognitive functioning and academic performance, but few studies have explored later developmental outcomes related to snoring initiated in early childhood. The aims of this study were to examine whether habitual snoring at age 3 years predicted perceived memory and academic functioning at age 7 years. METHODS: Parents (n = 460) of children aged 7 years 2 +/- 5 months completed a community follow-up survey about their perceptions of their child's sleep and health, memory in daily activities, and academic performance relevant to numeracy and literacy skills. The first survey was completed by 839 parents 4 years prior when children were aged 3 years (54.8% response rate at age 7 years). Parents rated their child's academic performance twice. First, they rated performance based on teachers' feedback relative to national standard ratings for numeracy and literacy, and second, based on their own observations. RESULTS: Children reported to snore habitually at age 3 years received lower memory and academic composite score ratings at age 7 years. Age 3 years habitual snoring history predicted small but significant unique variation in age 7 years memory (p = 0.005), literacy (p < 0.001), and overall achievement ratings (p = 0.016) in regressions controlling for covariates, with evidence suggesting that memory may mediate links between snoring history and academic performance. CONCLUSION: The findings suggest that habitual snoring in early childhood may adversely affect success in beginning schooling. More research is still needed to determine the best time for treatment so that longer-term consequences of sleep-disordered breathing may be prevented. PMID- 29120886 TI - Comparison of Alcohol-Related Neurodevelopmental Disorders and Neurodevelopmental Disorders Associated with Prenatal Alcohol Exposure Diagnostic Criteria. AB - OBJECTIVE: Recently, increased attention has been focused on the diagnosis of the most prevalent category of fetal alcohol spectrum disorders, alcohol-related neurodevelopmental disorders (ARNDs). In 2013, proposed criteria for neurodevelopmental disorders associated with prenatal alcohol exposure (ND-PAE) were included in the appendix of the latest revision of the Diagnostic and Statistical Manual of Mental Disorders. The concordance of the 2 sets of criteria is unknown. This study examines the overlap in diagnostic criteria for ND-PAE and the ARND Behavioral Checklist in children. METHODS: Clinical charts from June 2013 to July 2016 were reviewed to identify patients with an evaluation for ARNDs and where the criteria for ND-PAE were also available. RESULTS: The review found 86 charts with a diagnosis of ARNDs, which included the ARND Checklist and the ND PAE criteria. We then calculated the sensitivity and specificity comparing the ND PAE with the ARND Checklist as the comparison standard. The sensitivity was 95.0%, specificity was 75.0%, and the ND-PAE diagnosis correctly classified 89.5% of cases identified as meeting criteria for ARNDs by the checklist. The receiver operating characteristics resulted in a large shared area under the curve of 90.1%. CONCLUSION: The 2 diagnostic constructs of ARNDs and ND-PAE seem to be very similar. Both the ARND and the ND-PAE variables are written in familiar formats and could be widely used by a variety of health care providers. PMID- 29120887 TI - Study of the disparity of noninvasive and invasive blood pressure measured by the Philips Intellivue MP50 monitor in surgeries inducing gall cardiac reflex under general anesthesia. AB - OBJECTIVE: The aim of the present study was to comprehensively compare noninvasive and invasive blood pressure (BP) measured by the Philips Intellivue MP50 monitor in surgeries that may induce gall cardiac reflex under general anesthesia. PARTICIPANTS AND METHODS: Seventy-eight patients undergoing cholecyst or bile duct operations under general anesthesia were enrolled in our study. Both invasive (intraradial, femoral, or dorsalis pedis artery) and noninvasive (oscillometric) BP were monitored by the Philips Intellivue MP50 monitor simultaneously. Data were analyzed using Bland-Altman plots. RESULTS: In a supine position during operations, between intraradial and oscillometric measurements, the bias and precision (mmHg) were 9.34+/-12.98 and 12.47+/-10.00 for systolic blood pressure (SBP) and 3.26+/-8.22 and 6.53+/-5.97 for diastolic blood pressure (DBP), between intrafemoral and oscillometric measurements, the bias and precision (mmHg) were 14.40+/-14.38 and 16.93+/-11.28 for SBP and 4.35+/-9.72 and 7.52+/-7.54 for DBP, between intradorsalis pedis and oscillometric measurements, the bias and precision (mmHg) were 15.69+/-14.37 and 16.91+/-12.91 for SBP and 0.99+/-7.69 and 5.67+/-5.27 for DBP. CONCLUSION: The oscillometric BP showed poor agreement with intra-arterial BP in cholecyst or bile duct surgeries that may induce gall cardiac reflex under general anesthesia. Therefore, according to the present data, application of oscillometric BP measured by the Philips Intellivue MP50 monitor in these surgery patients under general anesthesia cannot be recommended generally. PMID- 29120888 TI - Removal of Oral Biofilm on an Implant Fixture by a Cavitating Jet. AB - PURPOSE: To demonstrate the effectiveness of the cavitating jet in removing biofilms from the rough surface of 3-dimensional structures. MATERIALS AND METHODS: The optimal nozzle dimensions and injection conditions were identified by cavitation impact measurements. Biofilm was grown intraorally for 72 hours by 4 volunteers. The stained fixtures were assigned to different experimental groups. One comparison was performed between the cavitating jet and the water jet at 60 seconds. Additional comparisons were conducted among the time course experiments at 30, 60, and 180 seconds. After injection, the residual plaque biofilm (RPB) area was measured using a digital microscope. RESULTS: The total RPB of the cavitating jet was significantly lower than that of the water jet. Although there were no significant differences between the total RPB at 30 and 60 seconds, a significant difference was detected between 60 and 180 seconds. The RPB on the root sector was significantly lower than that on the crest sector at 60 and 180 seconds. CONCLUSION: The cavitating jet can effectively clean the biofilm formed on the rough surface of the implant screw, especially on the root sector. PMID- 29120889 TI - Bone Resorption During Submerged Healing After Guided Bone Regeneration: A Prospective Case Series. AB - OBJECTIVE: The aim of this study was to evaluate bone resorption quantitatively during the healing period subsequent to ridge augmentation. MATERIALS AND METHODS: Sixteen patients requiring vertical ridge augmentation before implant placement were recruited in the study. The study used an allograft and nonresorbable membrane. A custom acrylic stent was used to measure changes in bone volume. Augmented bone was compared with remaining bone 6 months after guided bone regeneration (alpha = 0.05 by means of the paired t test). RESULTS: All sites following the six months post-surgery were analyzed. Overall changes in alveolar bone were observed with a mean resorption rate of 19.8% (p<0.001). The vertical bone measurement indicated a mean resorption rate of 22.8% (range = 18.5% - 26.5%). The horizontal measurement indicated a mean resorption rate of 18.7% (range = 12.6% - 26.0%). Among the sixteen sites, four sites with post operative complications including membrane exposure showed an average of 42.1% resorption rates. CONCLUSION: Loss in graft quantity was observed after ridge augmentation using an allograft and nonresorbable membrane during submerged healing before implant placement. Further studies with larger sample sizes are recommended to confirm its findings. PMID- 29120890 TI - Validity of Collagen Plugs for Ridge Preservation in a Canine Model. AB - PURPOSE: The purpose of the present study was to evaluate healing outcomes after collagen plug insertion in extraction-related defects. MATERIALS AND METHODS: The third and fourth mandibular premolars in canines were extracted, and the septal bone was removed. The following treatments were performed for the defects: porcine atelo-collagen plug, bovine atelo-collagen plug, and no intervention (control). The experimental animals were killed after 6, 12, or 24 weeks (n = 4, respectively). Histologic and histomorphometric analyses were performed. RESULTS: Clinical healing was uneventful, and no difference was detected among the 3 groups. Histologically, similar healing patterns were observed in all groups. Gingival healing was complete at 6 weeks, but discontinuity in the buccal crestal bone was observed. At 12 weeks, various degrees of buccal bone depression and increase in bone marrow were observed. At 24 weeks, no further healing was observed. Histomorphometrically, the ridge width at 1, 3 and 5 mm levels below the crest and the ridge dimensions 1, 3, and 5 mm above the level were not statistically different among groups or healing periods. CONCLUSION: The healing following the use of collagen plug in the extraction socket may correspond to the natural healing after extraction. PMID- 29120891 TI - Clinicians' ability, motivation, and opportunity to acquire and transfer knowledge: An age-driven perspective. AB - BACKGROUND: Many countries are seeing a dramatic increase in the average age of their clinicians. The literature often highlights the challenges of high replacement costs and the need for strategies to retain older personnel. Less discussed are the potential pitfalls of knowledge acquisition and transfer that accompany this aging issue. PURPOSE: We propose a conceptual framework for understanding how clinicians' age interact with ability, motivation, and opportunity to predict clinical knowledge transfer and acquisition in health care organizations. APPROACH: This study integrates life-span development perspectives with the ability-motivation-opportunity framework to develop a number of testable propositions on the interaction between age and clinicians' ability, motivation, and opportunity to acquire and transfer clinical knowledge. RESULTS: We posit that the interaction between ability (the knowledge and skills to acquire knowledge), motivation (the willingness to acquire and transfer knowledge), and opportunity (resources required for acquiring and transferring knowledge) is a determinant of successful knowledge management. We also suggest that clinicians' age-and more specifically, the cognitive and motivational changes that accompany aging-moderates these relationships. CONCLUSION: This study contributes to existing research by offering a set of testable propositions for future research. These propositions will hopefully encourage empirical research into this important topic and lead to guidelines for reducing the risks of organizational knowledge loss due to aging. PRACTICE IMPLICATIONS: We suggest several ways that health care organizations can tailor managerial practices in order to help capitalize on the knowledge-based resources held by their younger and older clinicians. Such initiatives may affect employees' ability (e.g., by providing specific training programs), motivation (e.g., by expanding subjective perceptions of future time at work), and opportunities (e.g., by providing mentoring, reverse mentoring, and coaching programs) to acquire and transfer knowledge. PMID- 29120892 TI - CE: Original Research: Does Certification in Vascular Access Matter? An Analysis of the PICC1 Survey. AB - : : Background: Although certification by an accredited agency is often a practice prerequisite in health care, it is not required of vascular access specialists who insert peripherally inserted central catheters (PICCs). Whether certification is associated with differences in practice among inserters is unknown. PURPOSE: The purpose of this study was to gather information regarding whether certified and noncertified PICC inserters differ with respect to their practices and views about PICC use. METHODS: We conducted a national survey of vascular access specialists, identifying certified PICC inserters as those who had received board certification from the Association for Vascular Access, the Infusion Nurses Society, or both. The 76-item survey asked about PICC policies and procedures at respondents' facilities, use of insertion technologies, device management, management of complications, perceptions about PICC use, and relationships with other health care providers. Additional data about respondents, including years in practice and primary practice settings, were also gathered. Bivariable comparisons were made using chi tests; two-sided alpha with P <= 0.05 was considered statistically significant. RESULTS: Of the 1,450 respondents in the final sample, 1,007 (69%) said they were certified inserters and 443 (31%) said they were not. Significantly higher percentages of certified than noncertified inserters reported having practiced for five or more years (78% versus 54%) and having placed 1,000 or more PICCs (58% versus 32%). Significantly more certified than noncertified inserters also reported being the vascular access lead for their facility (56% versus 44%). Reported practice patterns for insertion, care, and management of PICCs varied based on certification status. Some evidence-based practices (such as the use of ultrasound to measure catheter to-vein ratios) were more often reported by certified inserters, while others (such as the use of maximal sterile barriers during PICC insertion) were not. Asked about their perceptions of PICC use at their institution, certified inserters reported higher percentages of inappropriate insertion and removal than noncertified inserters. CONCLUSION: Certified PICC inserters appear to be a distinct group of vascular access specialists. A better understanding of how and why practices differ between certified and noncertified inserters is necessary to ensuring safer, high-quality patient care. PMID- 29120893 TI - CE: Pressure Injuries Caused by Medical Devices and Other Objects: A Clinical Update. AB - : At the April 2016 National Pressure Ulcer Advisory Panel (NPUAP) consensus conference, terminology and staging definitions were updated and two definitions were revised to describe pressure injuries (PIs) caused by medical devices or other items on the skin or mucosa. Here, the authors discuss the etiology and prevention of PIs resulting from medical and other devices, the frequency of such injuries, and the bodily sites at which they most often occur. They provide an overview of the current NPUAP guideline, highlight important risk factors, and explain why mucosal PIs cannot be staged. PMID- 29120894 TI - Advances in pharmacotherapies for movement disorders in children: current limitations and future progress. AB - PURPOSE OF REVIEW: In childhood, movement disorders are generated by a very large number of disorders of the nervous system, and the very different developmental ages at which these occur make studies of pharmacotherapy efficacy extremely difficult. In most clinical practices, medication used in management is by trial and error, and limited by lack of efficacy and/or adverse drug reactions leading to drug intolerance. Nevertheless, symptom reduction using polypharmacy must be balanced against any accompanying comorbidities such as poor attention and concentration, constipation, ileus, urinary retention, blurred vision sedation and respiratory depression. RECENT FINDINGS: A 'personalised medicine' approach may lead to specific management breakthroughs that are beneficial to a wider number of children. At present, neuromodulation with implantable devices offers greater proven efficacy for dystonia, myoclonus and dystonic-choreoathetosis, but enteral, intravenous and, more recently, transdermal medication strategies with clonidine patches and enteral gabapentin may provide important relief for both home management and critical care settings. SUMMARY: The current review brings the clinician up-to-date with the latest, albeit limited, thinking on the pharmacological management of movement disorders in children by focussing on goal directed outcome measures to improve clinical decision-making in an evidence light clinical setting. PMID- 29120895 TI - Leaving the nest: anticipatory guidance for the college-bound youth. AB - PURPOSE OF REVIEW: The number of students enrolling in college is on the rise; however, the number of students dropping out is increasing as well. Given that the transition to attending college poses challenges with independent academic functioning, social adjustment, health behaviors, and lifestyle choices, the purpose of this review is to describe some of the issues that these students will encounter so that pediatricians can help teens who are going to college successfully transition to their new academic, social, and living environment. RECENT FINDINGS: Students who have the opportunity to go to college must successfully balance their scholastic commitments and their personal development outside the classroom. Their newfound independence poses several other challenges - obtaining adequate sleep, proper nutrition, and regular exercise as well as risks related to alcohol use, drug use, and sexual activity. SUMMARY: Pediatricians can play an important role by counseling college-bound teens about these common issues, perils and pitfalls. With anticipatory counseling focused on these concerns, pediatricians can help foster the personal growth and social/intellectual development of teenagers to better prepare them for success in college and then later in life. PMID- 29120896 TI - Artificial Anterior Chamber Model Using Human Donor Corneas for DMEK Surgical Training. PMID- 29120897 TI - Corneal Endothelial and Myotonic Dystrophy. PMID- 29120898 TI - Reply. PMID- 29120900 TI - Reducing medical comorbidities associated with long-term HIV infection: beyond optimizing antiretroviral therapy regimens. PMID- 29120901 TI - Limiting cardiovascular events associated with HIV and antiretroviral therapy. PMID- 29120899 TI - Association of a 3' untranslated region polymorphism in proprotein convertase subtilisin/kexin type 9 with HIV viral load and CD4+ levels in HIV/hepatitis C virus coinfected women. AB - OBJECTIVE: To assess variation in genes that regulate cholesterol metabolism in relation to the natural history of HIV infection. DESIGN: Cross-sectional and longitudinal analysis of the Women's Interagency HIV Study. METHODS: We examined 2050 single nucleotide polymorphisms (SNPs) in 19 genes known to regulate cholesterol metabolism in relation to HIV viral load and CD4 T-cell levels in a multiracial cohort of 1066 antiretroviral therapy-naive women. RESULTS: Six SNPs were associated with both HIV viral load and CD4 T-cell levels at a false discovery rate of 0.01. Bioinformatics tools did not predict functional activity for five SNPs, located in introns of nuclear receptor corepressor 2, retinoid X receptor alpha (RXRA), and tetratricopeptide repeat domain 39B. Rs17111557 located in the 3' untranslated region of proprotein convertase subtilisin/kexin type 9 (PCSK9) putatively affects binding of hsa-miR-548t-5p and hsa-miR-4796-3p, which could regulate PCSK9 expression levels. Interrogation of rs17111557 revealed stronger associations in the subset of women with HIV/hepatitis C virus (HCV) coinfection (n = 408, 38% of women). Rs17111557 was also associated with low-density lipoprotein cholesterol levels in HIV/HCV coinfected (beta: -10.4; 95% confidence interval: -17.9, -2.9; P = 0.007), but not in HIV monoinfected (beta:1.2; 95% confidence interval: -6.3, 8.6; P = 0.76) women in adjusted analysis. CONCLUSION: PCSK9 polymorphism may affect HIV pathogenesis, particularly in HIV/HCV coinfected women. A likely mechanism for this effect is PCSK9-mediated regulation of cholesterol metabolism. Replication in independent cohorts is needed to clarify the generalizability of the observed associations. PMID- 29120902 TI - Neutralizing antiinterferon-gamma autoantibodies causing disseminated Mycobacterium avium complex infection in an HIV-infected patient on successful combination antiretroviral therapy. PMID- 29120903 TI - Should we report the proportion of late HIV diagnoses? PMID- 29120904 TI - Efavirenz precipitating hallucinations in a patient with an undetected psychotic prodrome: a call for better screening at the point of care. PMID- 29120905 TI - Fluorine-18-fluorodeoxyglucose uptake of bone marrow on PET/CT can predict prognosis in patients with colorectal cancer after curative surgical resection. AB - OBJECTIVE: This study investigated the relationship of fluorine-18 fluorodeoxyglucose (F-FDG) uptake of bone marrow (BM) on PET/computed tomography (PET/CT) with clinicopathologic factors and survival in patients with colorectal cancer. PATIENTS AND METHODS: The study retrospectively included 226 patients with colorectal cancer who underwent F-FDG PET/CT for staging workup and treated with curative surgical resection. The maximum F-FDG uptake of primary cancer (Tmax) and mean F-FDG uptake of BM [BM standardized uptake value (SUV)] were derived from PET/CT images. The relationships between BM SUV and clinicopathologic factors and prognostic value of BM SUV for predicting recurrence-free survival (RFS) were assessed. RESULTS: Patients with T3-T4 stage and hepatic metastases had significantly higher values of BM SUV than those with T1-T2 stage and no distant metastases (P<0.05). BM SUV showed significant positive correlation with Tmax, tumor size, serum C-reactive protein level, white blood cell count, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (P<0.05). Univariate survival analysis revealed that N stage, M stage, tumor involvement of resection margin, lymphatic invasion, and BM SUV were significant predictors for RFS (P<0.05), whereas Tmax failed to show significance. In multivariate analysis, N stage (P=0.012 for N1 stage and P=0.020 for N2 stage), tumor involvement of resection margin (P=0.009), and BM SUV (P=0.005) were significantly associated with RFS. CONCLUSION: Increased BM SUV was observed in patients with advanced stage and increased serum inflammatory markers. BM SUV was an independent predictor for RFS in colorectal cancer. PMID- 29120906 TI - Efficacy of ledipasvir/sofosbuvir plus ribavirin for 12 weeks in patients with chronic hepatitis C genotype 3 and compensated liver disease. AB - INTRODUCTION: In the era of direct-acting antivirals, hepatitis C virus (HCV) genotype (GT) 3 remains as the most difficult-to-treat HCV-GT. Currently, data on the efficacy of ledipasvir/sofosbuvir plus ribavirin (SOF/LDV+RBV) in GT3 infected patients are limited. We investigated the efficacy of this regimen in a real-life cohort from Austria. PATIENTS AND METHODS: A total of 55 patients with HCV-GT3 and compensated liver disease (20% treatment-experienced, 33% with cirrhosis, 7% with HIV coinfection) from four Austrian hepatitis centers received treatment with SOF/LDV+RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after end of therapy (SVR12). RESULTS: In the modified intention-to-treat analysis - excluding patients lost to follow-up - the overall SVR12 rate was 94% (95% confidence interval: 84-99%). In treatment-naive and treatment-experienced patients, SVR12 rates were 95 and 89%, respectively. SVR12 rate was 91% in patients without cirrhosis and 100% in patients with cirrhosis. There were no serious adverse events. Viral sequencing did not show the presence of any resistance-associated substitutions in any of the three relapsed patients. CONCLUSION: Despite a very weak antiviral activity of ledipasvir against HCV-GT3 in vitro, a 12-week course of SOF/LDV+RBV was highly effective, with a 94% SVR12 rate in our cohort of compensated HCV-GT3-infected patients. Thus, if pangenotypic NS5A inhibitors are not available or not reimbursed by insurances, SOF/LDV+RBV seems to be an effective alternative in patients with HCV-GT3 infection. PMID- 29120907 TI - Helicobacter pylori infection is positively associated with an increased BMI, irrespective of socioeconomic status and other confounders: a cohort study. AB - BACKGROUND: Data on the association of Helicobacter pylori infection and BMI are conflicting. The fact that both H. pylori infection and BMI are associated with low socioeconomic status (SES) makes this relationship difficult to characterize. MATERIALS AND METHODS: We aimed to evaluate the association between BMI and H. pylori infection after adjusting for multiple covariates. We analyzed a cohort of 235 107 individuals aged 18 years or older, who performed a C urease breath test (C-UBT), from 2007 to 2014. Data on BMI, age, sex, SES, ethnicity, and medications were extracted from a nationwide population-based database. BMIs were classified according to the WHO recommendations: underweight (<18.5 kg/m), normal weight (18.5-24.9 kg/m), overweight (25-29.9 kg/m), obese class I (30-34.9 kg/m), and obese class II or more (>35 kg/m). STUDY RESULTS: The positivity rate for H. pylori among underweight, normal weight, overweight, and obese class I and class II or more was 55.6, 58.5, 63.0, 64.5, and 65.5%, respectively (P<0.001, Plinear trend 0.007). The association between BMI and H. pylori infection was significant across all SES, sex, ethnicity, and age categories. After adjusting for age, sex, ethnicity, and SES, being overweight and obese class I and class II or more were associated significantly with H. pylori positivity: odds ratio 1.13 [95% confidence interval (CI): 1.11-1.15], 1.14 (95% CI: 1.11-1.17), and 1.15 (95% CI: 1.11-1.19), respectively, P value less than 0.001 for all. CONCLUSION: Among individuals who were referred to a C-UBT by primary care physician, after adjusting for multiple covariates including SES, we found a positive association between H. pylori infection and an increased BMI. PMID- 29120909 TI - Rivaroxaban-induced hepatotoxicity: review of the literature and report of new cases. AB - AIM/OBJECTIVE/BACKGROUND: Direct-acting oral anticoagulant drugs are marketed worldwide for the primary and secondary prevention and treatment of thromboembolic disorders. Rivaroxaban, an oral, direct factor Xa inhibitor, is one of the most used. Rivaroxaban-induced hepatotoxicity is unusual, although a number of adverse reports have recently been reported. Here, we report two new cases of rivaroxaban-induced hepatitis. METHODS: A systematic search of case reports on the MEDLINE database encompassing the years 2008-2016 was carried out.Additional references were obtained following a manual search of the retrieved papers. We report two new cases of adverse events occurred in patients treated with rivaroxaban (20 mg/die) to prevent systemic embolism, who presented with hepatocellular liver injury with onset at 8 weeks after initiation of the drug intake. RESULTS: Twenty-six cases were retrieved from MEDLINE (57.7% female, 42.3% male). Using the Roussel Uclaf Causality Assessment Method (RUCAM) scale, liver injury was classified as hepatocellular (42.3%), cholestatic (26.9%), or mixed (15.4%). Older age (>=65 years) was present as a risk factor in 57.7%. The time lapse between initiation of treatment and onset of hepatic injury ranged from 2 to 180 days (median: 15 days). Our two new patients were diagnosed with drug-induced liver injury (hepatocellular pattern) using the 'consensus criteria', for drug-induced liver injury. Their RUCAM scores were calculated and assessed as highly probable and probable, respectively. A clinical recovery after rivaroxaban withdrawal was observed. CONCLUSION: Direct-acting oral anticoagulants have been commonly prescribed, even if safety issues regarding the use of these drugs are still an ongoing concern, especially in patients experiencing chronic liver disease. Dedicated postauthorization safety studies should be undertaken to better define rivaroxaban-induced drug-induced liver injury. PMID- 29120908 TI - Patients' beliefs about medicine are associated with early thiopurine discontinuation in patients with inflammatory bowel diseases. AB - BACKGROUND: Patients' beliefs about medicine may either reflect the necessity for treatment or concerns regarding the treatment. We explored the extent to which these beliefs have an effect on thiopurine metabolite levels and premature discontinuation in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Patients enrolled in the 'Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory Bowel Disease Clinics' (TOPIC) trial were asked to complete the Beliefs about Medicine Questionnaire (BMQ) 4 weeks after thiopurine initiation. The BMQ measures perceptions about treatment necessity and concerns. On the basis of the necessity and concern scores, patients can be categorized as accepting, ambivalent, indifferent, or skeptical. The thiopurine discontinuation rates for these belief subgroups were compared by Kaplan-Meier curves. Furthermore, clinical response and metabolite levels were compared between the belief subgroups. RESULTS: A total of 767 patients with IBD started thiopurine treatment, of whom 576 (75%) completed the BMQ. Patients could be classified as accepting (34%), indifferent (17%), ambivalent (34%), or skeptical (15%). Compared with patients in the accepting group (discontinuation rate 22%), patients with an indifferent (35%; P=0.02), ambivalent (37%; P<0.01), or skeptical belief (54%; P<0.01) had higher thiopurine discontinuation rates. No differences were observed in the steady-state thiopurine metabolite levels between the different belief subgroups. CONCLUSION: Patients with a low perceived treatment necessity or high concerns toward IBD treatment were more likely to discontinue thiopurine treatment prematurely. Extra attention toward these patients might prevent premature discontinuation. PMID- 29120910 TI - Biomarkers for immunotherapy in urological cancers. AB - PURPOSE OF REVIEW: Immunotherapies for urological malignancies have made tremendous progress by targeting immune checkpoints and have been implemented in clinical practice nowadays. Though siginifcant number of patients does not respond to immunotherapy. Biomarkers could help to predict response to treatment, but are still under investigation. We reviewed the literature to identify relevant biomarkers in patient treated with immunotherapy. RECENT FINDINGS: A comprehensive search of PubMed through has been performed to identify important relevant publications from 2016 to 2017 on biomarkers for immunotherapies in urological cancers including reported clinical trials. In addition, abstracts of relevant oncological scientific meetings from 2017 have been implemented. SUMMARY: Checkpoint inhibitors have shown substantial improvement in the treatment of metastatic RCC and metastatic and locally advanced urothelial cancer. There is an unmet need for the development of predictive biomarkers in order to identify patients who are more likely to respond to therapy. PMID- 29120911 TI - Immunotherapy for kidney cancer: status quo and the future. AB - PURPOSE OF REVIEW: The treatment landscape in advanced and metastatic renal cell carcinoma (RCC) is moving from the inhibition of tyrosine kinases (TKI) and the mammalian target of rapamycin (mTOR) inhibitors to specific immunooncology agents like immune checkpoint inhibitors (ICI). The review focus on the recent immunooncology developments and available trial results within the last 12 months. RECENT FINDINGS: ICI as monotherapy (nivolumab) or immunooncology and immunooncology combinations (nivolumab and ipilimumab) demonstrated positive results on prolonged overall survival in phase III trials. The combination of ICI (atezolizumab) and bevacizumab provided positive signals in prolonged PFS in the PD-L1 positive subgroup. Combinations of ICI and TKI are promising in early phase I and phase II trials. Results are currently expanded in larger phase III studies. The combination of vaccine and TKI in mRCC has not provided beneficial results so far. SUMMARY: The current treatment landscape in mRCC is shifting towards immunooncology agents, which already gained ground in the clinic as ICI monotherapy (nivolumab) or is likely to do in the near future as ICI combination (nivolumab and ipilimumab). The future will hold promise of new combinations with TKIs and ICI or other immunooncology agents like vaccines and metabolic immune checkpoint inhibitors. PMID- 29120912 TI - Effects of a System Thinking-Based Simulation Program for Congestive Heart Failure. AB - This study evaluated a system thinking-based simulation program for the care of patients with congestive heart failure. Participants were 67 undergraduate nursing students from a nursing college in Seoul, South Korea. The experimental group was given a 4-hour system-thinking program and a 2-hour simulation program, whereas the control group had a 4-hour case study and a 2-hour simulation program. There were significant improvements in critical thinking in both groups, but no significant group differences between educational methods (F = 3.26, P = .076). Problem-solving ability in the experimental group was significantly higher than in the control group (F = 5.04, P = .028). Clinical competency skills in the experimental group were higher than in the control group (t = 2.12, P = .038). A system thinking-based simulation program is a more effective learning method in terms of problem-solving ability and clinical competency skills compared to the existing simulation program. Further research using a longitudinal study is needed to test the long-term effect of the intervention and apply it to the nursing curriculum. PMID- 29120913 TI - Effectiveness of Specimen Collection Technology in the Reduction of Collection Turnaround Time and Mislabeled Specimens in Emergency, Medical-Surgical, Critical Care, and Maternal Child Health Departments. AB - The objective of this study was to evaluate the impact of specimen collection technology implementation featuring computerized provider order entry, positive patient identification, bedside specimen label printing, and barcode scanning on the reduction of mislabeled specimens and collection turnaround times in the emergency, medical-surgical, critical care, and maternal child health departments at a community teaching hospital. A quantitative analysis of a nonrandomized, pre post intervention study design evaluated the statistical significance of reduction of mislabeled specimen percentages and collection turnaround times affected by the implementation of specimen collection technology. Mislabeled specimen percentages in all areas decreased from an average of 0.020% preimplementation to an average of 0.003% postimplementation, with a P < .001. Collection turnaround times longer than 60 minutes decreased after the implementation of specimen collection technology by an average of 27%, with a P < .001. Specimen collection and identification errors are a significant problem in healthcare, contributing to incorrect diagnoses, delayed care, lack of essential treatments, and patient injury or death. Collection errors can also contribute to an increased length of stay, increased healthcare costs, and decreased patient satisfaction. Specimen collection technology has structures in place to prevent collection errors and improve the overall efficiency of the specimen collection process. PMID- 29120914 TI - Patients with anxious depression: overview of prevalence, pathophysiology and impact on course and treatment outcome. AB - PURPOSE OF REVIEW: Major depressive disorder with a comorbid anxiety disorder or with significant anxiety symptoms (here called anxious depression) is common and has been associated with poor clinical course trajectories. However, various dichotomous as well as dimensional definitions have been used to label anxious depression and it remains unclear to which extent these result in inconsistent findings. This review provides an overview of recent literature on the impact of anxiety in depressed patients on clinical course trajectories, treatment outcomes, and underlying neurobiological dysregulations. RECENT FINDINGS: Anxious depression seems associated with poorer clinical course trajectories and treatment nonresponse as compared with 'pure' depression, regardless of which definition is used. Recent studies have attempted to determine specific efficacy of novel pharmacological treatments for anxious depressed patients, but have not been conclusive because of the insufficient number of studies and differences in definitions and assessment of anxious depression. Neurobiology studies suggest that anxious depression is associated with increased immune dysregulation, more cortical thinning, and corticolimbic dysfunctions as compared with 'pure' depression. SUMMARY: Anxious depression appears to be a common and clinically relevant subtype of depression as it predicts poorer course trajectories. As populations with anxious depression may benefit from specific treatment regimens, further research is necessary to better delineate its definition and neurobiology. The relatively new Diagnostic and Statistical Manual of Mental Disorders-5 anxious distress specifier is a welcome development and should be further investigated and compared against other anxiety constructs. PMID- 29120915 TI - Schema therapy for emotional dysregulation in personality disorders: a review. AB - PURPOSE OF REVIEW: To give an update on the most recent studies regarding the role of schema therapy in the treatment of emotion dysregulation related to personality disorders. RECENT FINDINGS: In personality disorders, a lack of emotion regulation can be found. Schema therapy treats emotion dysregulation with a series of techniques, such as imagery rescripting, limited reparenting, chairwork, and cognitive restructuring to remove dysregulatory mechanism. SUMMARY: Schema therapy is one of the most efficient therapies for personality disorders. However, there is a lack of recent studies on how it treats emotion dysregulation. Although the treatment of emotional dysregulation is not the core of schema therapy, it is certainly important inside this theoretical framework. The mode model helps clinicians address their work toward the reduction of dysfunctional modes, whereas fostering functional modes. PMID- 29120916 TI - Impulsivity in personality disorders: current views and future directions. AB - PURPOSE OF REVIEW: Impulsivity is considered a trans-diagnostic feature of many mental disorders, yet our understanding of the concept and approaches to measurement have evolved significantly with advances in neuroimaging. This review will provide an overview of impulsivity as it is currently understood, its association with personality disorder and implications for treatment. RECENT FINDINGS: Impulsivity is now considered to involve failure of inhibitory control, either motor or cognitive, and deficits of the reward valuation system. Inhibitory control, and discounting of rewards are both independently associated with personality disorder. The tendency to choose immediate rewards over those with an associated delay is a feature of borderline personality disorder (BPD) regardless of conditions of stress. Deficits in response inhibition were also associated with BPD and were worsened under conditions of stress. These findings indicate that state impulsivity has an important role in the expression of impulsive behaviour. Exploratory studies measuring changes in these networks following psychotherapy have confirmed such methods could be used to measuring treatment response. SUMMARY: Understanding the discrete mechanisms of impulsive decision-making and behavior, and their implications in personality disorder, offers new targets for diagnosis and intervention. Future research should aim to understand changes of impulsivity with development. Identifying the role of psychological and pharmacological intervention in modulating the development of impulsivity may prevent progression to personality disorder, and associated adverse outcomes. PMID- 29120917 TI - Personality disorders: three classifications with a fly in the ointment. PMID- 29120918 TI - Tissue is more important than time: insights into acute ischemic stroke from modern brain imaging. AB - PURPOSE OF REVIEW: The clinical practice of acute ischemic stroke treatment has undergone a major change over the last 5 years, as multimodal imaging becomes more accessible, and evidence mounts that individualized treatment is possible. Multimodal imaging performed before treatment provides invaluable information to treating clinicians, which includes confirmation of the diagnosis, and provides guidance on the appropriateness and the likely outcome of intravenous or endovascular treatment for individual patients (and their families). However, often health systems struggle to keep pace with science; thus, a one-size fits all protocol-driven basic imaging approach is still the norm in many stroke centers. RECENT FINDINGS: Comprehensive multimodal computed tomography (CT) (incorporating noncontrast CT, CT angiography, and perfusion CT) provides rapid, reliable information about stroke pathophysiology that cannot be provided by more limited imaging prior to treatment. Multimodal CT identifies treatment responders for both intravenous thrombolysis and endovascular therapy. Now we are in the era of thrombectomy, the use of multimodal imaging routinely to guide treatment can no longer be avoided. SUMMARY: In light of the ground breaking thrombectomy trial results and previous studies validating the use of multimodal imaging, there is now a strong rationale for performing comprehensive multimodal CT assessments before treatment as a standard of care for all stroke patients. PMID- 29120919 TI - Nystagmus. AB - PURPOSE OF REVIEW: The clinical and laboratory assessment of nystagmus in patients with neurologic disorders can provide crucial elements for a state-of the-art differential diagnosis. An increasing number of publications in the fields of neuro-otology and neuro-ophthalmology have nystagmus in the center of interest, which makes frequent updates on the diagnostic and therapeutic relevance of these contributions indispensable. This review covers important clinical studies and studies in basic research relevant for the neurologist published from January 2016 to August 2017. RECENT FINDINGS: Current themes include vestibular nystagmus, positional nystagmus, optokinetic nystagmus and after-nystagmus, vibration-induced nystagmus, head-shaking nystagmus, postrotatory nystagmus, caloric nystagmus, nystagmus in cerebellar disorders, differential diagnosis of nystagmus and treatment approaches (whereas infantile nystagmus syndrome is not addressed in this review). These studies address mechanisms/pathomechanisms, differential diagnoses and treatment of different forms of nystagmus. SUMMARY: In clinical practice, a structured description of nystagmus including its three-dimensional beating direction, trigger factors and duration is of major importance. The differential diagnosis of downbeat nystagmus is broad and includes acute intoxications, neurodegenerative disorders and cerebrovascular causes amongst others. In patients with positional nystagmus, the distinction between frequent benign peripheral and rare but dangerous central causes is imperative. PMID- 29120920 TI - The growing clinical spectrum of cerebral amyloid angiopathy. AB - PURPOSE OF REVIEW: Cerebral amyloid angiopathy (CAA) is diagnosed primarily as a cause of lobar intracerebral hemorrhages (ICH) in elderly patients. With improving MRI techniques, however, the role of CAA in causing other symptoms has become clear. Recognizing the full clinical spectrum of CAA is important for diagnosis and treatment. In this review we summarize recent insights in clinical CAA features, MRI biomarkers, and management. RECENT FINDINGS: The rate of ICH recurrence in CAA is among the highest of all stroke subtypes. Cortical superficial siderosis (cSS) and cortical subarachnoid hemorrhage (cSAH) are important imaging predictors for recurrent ICH. CAA also causes cognitive problems in multiple domains. In patients with nondemented CAA, the risk of developing dementia is high especially after ICH. CAA pathology probably starts years before the first clinical manifestations. The first signs in hereditary CAA are white matter lesions, cortical microinfarcts, and impaired occipital cerebral vasoreactivity. Visible centrum semiovale perivascular spaces, lobar located lacunes, and cortical atrophy are new nonhemorrhagic MRI markers. SUMMARY: CAA should be in the differential diagnosis of elderly patients with lobar ICH but also in those with cognitive decline and episodic transient neurological symptoms. Physicians should be aware of the cognitive effects of CAA. In patients with a previous ICH, cSS, or cSAH, anticoagulation should be considered risky. The increasing number of MRI markers may help to discriminate CAA from other small vessel diseases and dementia subtypes. PMID- 29120921 TI - Pregnancy and ischemic stroke: a practical guide to management. AB - PURPOSE OF REVIEW: Ischemic stroke during pregnancy or the puerperium is a devastating disease during a crucial period in life and warrants a specific approach. To date, current practice is mainly based on expert opinion because of a lack of randomized controlled trials and high-quality observational studies. The present review is intended as a practical guide to (acute) management of ischemic stroke during pregnancy and puerperium. RECENT FINDINGS: Recent findings showed that the incidence of stroke during pregnancy is rising. In 2014, the first guideline for the prevention of stroke in women was released, however on many (pregnancy) related topics the evidence was too scarce to make clear evidence-based recommendations. SUMMARY: The risk of ischemic stroke is elevated especially from the third trimester until 6 weeks postpartum. MRI is the most accurate and well tolerated diagnostic option but low-dose CT-head is a valid alternative. Reperfusion therapies should not be withheld from a pregnant woman with moderate-to-severe stroke when benefits outweigh the risk. Aspirin up to 150 mg daily is considered well tolerated during pregnancy and lactation period. Multidisciplinary care is essential when counseling these women in the acute and later stages. PMID- 29120922 TI - Gender dysphoria in youth: a review of recent literature. AB - PURPOSE OF REVIEW: Transgender individuals including pubertal young people require hormonal therapy, in conjunction with mental health support. These youths are a unique population, with specific and individual desires and needs as they move through the physical and mental transition to the gender with which they identify. RECENT FINDINGS: The number of transgender youth presenting for treatment is increasing rapidly. They continue to have a high prevalence of mental health disorders, though not when supported in their sex identities by family in younger age. Older children are more susceptible to peer support or lack thereof. Treatment with gonadotropin-releasing hormone agonists remains a mainstay of early therapy, but is associated with high costs and decrease in bone mineral density; androgenic progestogens could be used as a lower cost alternative. Fertility preservation is discussed with the majority of transgender youth, but use of such services is low. SUMMARY: Transgender youth are an increasingly identified population in need of medical and mental health treatment, as well as social support throughout life. PMID- 29120924 TI - Potential mechanisms underlying the effect of bariatric surgery on eating behaviour. AB - PURPOSE OF REVIEW: Reduced energy intake, resulting from favourable changes in eating behaviour, is the predominant driver of weight loss following bariatric surgery. Here we review the most recent studies examining the impact of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, the two most common bariatric procedures, upon eating behaviour and the suggested underlying biological mechanisms. RECENT FINDINGS: Following RYGB or sleeve gastrectomy, most people report subjective changes in appetite, taste and food preference, with decreased high-fat preference most commonly reported. Objective postsurgery changes in taste and olfactory acuity occur. A new phenomenon, 'meal-size aversion', may contribute to reduced postoperative energy intake. Recent studies provide evidence for peptide YY3-36, glucagon-like peptide-1, ghrelin, neurotensin and oleoylethanolamide as mediators of postoperative eating behaviour changes. Factors modulating these changes include sex, type 2 diabetes status, genetics and bariatric procedure. New studies implicate central dopaminergic and opioid receptor signalling as key neural mediators driving altered eating behaviour. Brain neuroimaging studies show that obesity-associated changes in food-cue responses, brain connectivity and structural abnormalities are normalized following bariatric surgery. SUMMARY: Understanding the biological mechanisms mediating the eating behaviour changes engendered by bariatric surgery may lead to the development of novel therapeutic strategies for people with obesity. PMID- 29120925 TI - Noonan syndrome: an update on growth and development. AB - PURPOSE OF REVIEW: To provide an update on recent developments on Noonan syndrome with a special focus on endocrinology, bone, and metabolism aspects. The key issues still to be resolved and the future therapeutic perspectives will be discussed. RECENT FINDINGS: The discovery of the molecular genetic causes of Noonan syndrome and Noonan-syndrome-related disorders has permitted us to better understand the mechanisms underlying the different symptoms of these diseases and to establish genotype-phenotype correlations (in growth patterns for example). In addition to the classical clinical hallmarks of Noonan syndrome, new important aspects include decreased fertility in men, lean phenotype with increased energy expenditure and possible impact on carbohydrate metabolism/insulin sensitivity, and impaired bone health. Further clinical studies are needed to investigate the long-term impact of these findings and their possible interconnections. Finally, the understanding of the crucial role of RAS/mitogen-activated protein kinases dysregulation in the pathophysiology of Noonan syndrome allows us to devise new therapeutic approaches. Some agents are currently undergoing clinical trials in Noonan syndrome patients. SUMMARY: On the last 10 years, our knowledge of the molecular basis and the pathophysiology of Noonan syndrome has greatly advanced allowing us to gain insight in all the aspects of this disease and to devise new specific therapeutic strategies. PMID- 29120926 TI - Recent insights into biological functions of mammalian bombesin-like peptides and their receptors. AB - PURPOSE OF REVIEW: The current review highlights recent advances in physiological and pharmacological researches in biology of mammalian bombesin-like peptides (BLPs). RECENT FINDINGS: BLPs and their receptors were found to have regulatory roles in many biological processes in central nervous system. Two BLPs, neuromedin B and gastrin-releasing peptide (GRP), and their receptors are required for regulation of basal and induced sighing activity in rodents. This is the first study demonstrating central pathways involved in regulation of sighing activity. GRP receptor (GRPR) expressing neurons are excitatory glutamatergic interneurons located in the dorsal lamina without projections outside the spinal cord and mediate itch signals via vesicular glutamate transporter 2. Those neurons receive itch signals and make synapses with the parabrachial nucleus projecting spinal neurons to transmit itch signals to parabrachial nucleus. GRP expressing interneurons function in a proposed 'leaky gate model' to interpret the mechanism of both pain and itch transmission. In addition to recent advances of biology in nervous system, BLPs and their receptors were found to play potential regulatory roles in innate and adaptive immune responses and tissue development. SUMMARY: Several important biological roles of BLPs and their receptors in nervous system were identified. Together with researches regarding central roles of BLPs, studies revealing the regulatory roles of BLPs and their receptors in immunology and tissue development provide us with novel insights into understanding of the biology of BLPs and their receptors. PMID- 29120923 TI - Carcinoid-syndrome: recent advances, current status and controversies. AB - PURPOSE OF REVIEW: To review recent advances and controversies in all aspects of carcinoid-syndrome. RECENT FINDINGS: Over the last few years there have been a number of advances in all aspects of carcinoid syndrome as well as new therapies. These include new studies on its epidemiology which demonstrate it is increasing in frequency; increasing insights into the pathogenesis of its various clinical manifestations and into its natural history: definition of prognostic factors; new methods to verify its presence; the development of new drugs to treat its various manifestations, both initially and in somatostatin-refractory cases; and an increased understanding of the pathogenesis, natural history and management of carcinoid heart disease. These advances have generated several controversies and these are also reviewed. SUMMARY: There have been numerous advances in all aspects of the carcinoid-syndrome, which is the most common functional syndrome neuroendocrine tumors produce. These advances are leading to new approaches to the management of these patients and in some cases to new controversies. PMID- 29120928 TI - Oncologic considerations in the elderly. AB - PURPOSE OF REVIEW: Elderly patients presenting with thoracic malignancies tend to be largely undertreated because of a presumption that this group will incur a high treatment-associated morbidity and mortality. The current review highlights the current practice and recent updates in the surgical management of thoracic malignancies, mainly lung cancer, in the elderly population. RECENT FINDINGS: Lung resections appears to be relatively safe in the elderly patients presenting with lung cancer. Whenever possible, a lobectomy should be offered to patients with a good performance status who present with early stage disease. However, a limited resection may offer a valuable comparable alternative in patients with advanced comorbidities and borderline pulmonary functions. The use of minimally invasive approaches, namely video-assisted thoracoscopic surgery and robotic surgery are associated with lower morbidity and improved perioperative outcomes compared with the traditional thoracotomy approach and are ideal for the aged. In elderly patients presenting with advanced staged lung cancer, major lung resections following induction therapy, although feasible, should be discussed in a multispecialty tumor board committee. SUMMARY: There is growing evidence from the literature that surgical resection is relatively safe in the elderly population. Age by itself should not preclude patients from having curative resection. Resections can be tailored to performance status of the patient. PMID- 29120927 TI - Improve postoperative sleep: what can we do? AB - PURPOSE OF REVIEW: We reviewed evidences regarding occurrence, risk factors, harmful effects, prevention, and management of sleep disturbances in patients after surgery. RECENT FINDINGS: Normal sleep is important to maintain physical and mental health. Sleep disturbances frequently occur in patients after surgery. Factors associated with the development of postoperative sleep disturbances include old age, preoperative comorbidity, type of anesthesia, severity of surgical trauma, postoperative pain, environment stress, as well as other factors leading to discomfort of patients. Development of sleep disturbances produces harmful effects on postoperative patients, that is, leading to higher risk of delirium, increased sensitivity to pain, more cardiovascular events, and poorer recovery. Both nonpharmacological and pharmacological measures (such as zolpidem, melatonin, and dexmedetomidine) can be used to improve postoperative sleep. Recent evidences show that sleep promotion may improve patients' outcome, but requires further evidences. SUMMARY: Sleep disturbances are common in patients after surgery and produce harmful effects on postoperative recovery. Sleep promotion therapy may be helpful to improve postoperative recovery, but long-term effects deserve further study. PMID- 29120929 TI - Risk factors for opioid-induced respiratory depression and failure to rescue: a review. AB - PURPOSE OF REVIEW: The primary objective of this review is to identify the risk factors for opioid-induced respiratory depression (OIRD) in the postoperative period. RECENT FINDINGS: In the postoperative period, OIRD has often been reported resulting in morbidity and mortality. The risk factors which predispose surgical patients to increased risk of OIRD are not clearly defined. A literature search was performed for adult surgical patients who were prescribed opioids during their hospital stay and any available reports on postoperative respiratory depression/respiratory events. SUMMARY: Elderly, female sex, presence of obstructive sleep apnea, chronic obstructive pulmonary disease, cardiac disease, diabetes mellitus, hypertension, neurologic disease, renal disease, obesity, two or more comorbidities, opioid dependence, use of patient controlled analgesia, different routes of administration of opioids and concomitant administration of sedatives are significant risk factors for postoperative OIRD. The majority of patients with OIRD are deeply sedated and inadequately monitored. In patients with underlying risk factors, the dose of opioids should be carefully titrated. Enhanced monitoring of sedation level, respiratory rate, pulse oximetry and capnography is needed in the first 24 h after surgery. PMID- 29120930 TI - Enhanced recovery for thoracic surgery in the elderly. AB - PURPOSE OF REVIEW: Both surgical workload and the age of those patients being considered for radial pulmonary resection are increasing. Enhanced recovery programmes are now well established in most surgical disciplines and are increasingly reported in thoracic procedures. This review will discuss the relevant principles of these programmes as applied to an increasing elderly population. RECENT FINDINGS: Elderly patients undergoing less radial surgical resections without lymphadenectomy have comparable outcomes to those undergoing classical curative treatment. Patients require careful assessment and self reported quality of life metrics or function may be a better marker of outcome than static measures such as lung function. Hypotension, low values for bispectral index and low anaesthetic gas mean alveolar concentration values are common and independent predictors of mortality in the elderly. Paravertebral blockade is preferred to epidural anaesthesia because of a more favourable side effect profile and comparable efficacy. As yet no robust work has examined the efficacy of an integrated enhanced recovery programme in thoracic surgery. SUMMARY: Elderly patients are suitable for enhanced recovery programmes but these must be tailored to individual circumstance. Further work is required to comprehensively assess their value in a modern healthcare setting. PMID- 29120931 TI - Perioperative neurocognition in elderly patients. AB - PURPOSE OF REVIEW: The extrinsic risk factors for postoperative cognitive disturbance have been a source of concern during the perioperative period, and these risk factors remain the subject of controversy. This review of recent studies focuses on the effect of these factors on postoperative cognitive disturbance during the perioperative period. RECENT FINDINGS: Impairment of cerebral autoregulation may predispose patients to intraoperative cerebral malperfusion, which may subsequently induce postoperative cognitive disturbance. The neurotoxicity of several volatile anesthetics may contribute to cognitive functional decline, and the impact of intravenous anesthesia on cognitive function requires further exploration. Multimodal analgesia may not outperform traditional postoperative analgesia in preventing postoperative delirium. Furthermore, acute pain and chronic pain may exacerbate the cognitive functional decline of patients with preexisting cognitive impairment. The nuclear factor kappa beta pathway is an important node in the neuroinflammatory network. SUMMARY: Several intraoperative factors are associated with postoperative cognitive disturbance. However, if these factors are optimized in perioperative management, postoperative cognitive disturbance will improve. PMID- 29120932 TI - An update on preoperative assessment and preparation of surgical patients with obstructive sleep apnea. AB - PURPOSE OF REVIEW: There is a high prevalence of obstructive sleep apnea (OSA) in the surgical population, however, a significant proportion of patients are undiagnosed. The Society of Anesthesia and Sleep Medicine (SASM) has issued recent guidelines for preoperative assessment and preparation of patients with known or suspected OSA. The purpose of this review is to highlight key points in the new guidelines and explore the possibilities of different strategies in optimizing patients with OSA preoperatively. RECENT FINDINGS: Recent knowledge on phenotypes and endotypes has provided a better understanding of the disease and its underlying pathogenesis. Phenotypes refer to the predominant morphological characteristics of an individual whereas endotypes refer to the predominant underlying mechanism of the disease. Phenotypes and endotypes in OSA are heterogenous. Heterogeneity in the pathogenic mechanisms implies that opportunities other than the use of continuous positive airway pressure (CPAP) may exist to optimize or manage OSA patients preoperatively. SUMMARY: The prevalence of OSA in surgical patients is high. SASM has made recommendations in their published guidelines for the optimum preoperative preparation of patients with OSA. In the future, research may shift towards finding the underlying mechanism of OSA for targeted therapy. PMID- 29120933 TI - An overview of perioperative considerations in elderly patients for thoracic surgery: demographics, risk/benefit, and resource planning. AB - PURPOSE OF REVIEW: Increasing numbers of geriatric patients will present for thoracic surgery as the population ages. The changes in physiologic reserve as well as the increase in comorbid conditions among this population must be considered in order to optimize patient care in the perioperative period. RECENT FINDINGS: For elderly patients with cancer, the risk-benefit relationship for thoracic surgery remains favorable. Consideration of comorbidities, especially chronic obstructive pulmonary disease and congestive heart failure, is important in the setting of surgical treatment, as they have implications for perioperative care as well as postoperative morbidity and mortality. Overall survival, quality of life, and health status must be considered in decisions regarding cancer treatment. SUMMARY: Elderly patients with early-stage lung cancer derive benefit from surgical treatment, despite their increased prevalence of comorbidities, because survival associated with untreated lung cancer is so dismal. Some studies suggest that even late-stage lung cancer patients may benefit from surgery as part of a multimodal approach. Further studies could help target implementation of resources to optimize overall patient health and physiologic condition in order to decrease morbidity and mortality and to optimize quality of life. PMID- 29120934 TI - Predictors of Program Completion and NCLEX-RN Success in an Associate Degree Nursing Program. AB - Unsuccessful nursing students have a great impact on nursing programs. The purpose of this study was to determine the relationships among preadmission HESI A2 (Health Education Systems, Incorporated Admission Assessment) score, science and math course grades, program completion, and NCLEX-RN success in an associate degree nursing program using a retrospective, correlational research design. A statistically significant relationship was found between preadmission examination scores and successful NCLEX-RN passage on first attempt. Program completion had a positive correlation with preadmission science grades and HESI A2 scores. PMID- 29120935 TI - Neuropathic Pain Experiences of Spinal Cord Injury Patients. AB - BACKGROUND: Neuropathic pain (NP) is a common, severe problem that affects spinal cord injury (SCI) patients. Only SCI patients truly understand the impact and extent of this type of pain. PURPOSE: The aim of this study was to understand the NP experienced by SCI patients and the influence of this type of pain on their daily life. METHOD: A qualitative design was used. An interview guide including a semistructured questionnaire and in-depth interviews was conducted with SCI patients with NP in a neurorehabilitation department at a medical center in northern Taiwan. The data were collected using a purposive sampling method. Content analysis was performed on the interview data, which were obtained from 13 SCI patients with NP. RESULTS: Three themes and eight subthemes were identified that described the NP experience of the participants and the influence of NP on their daily life. The three themes included elusive pain (changing and individual pain sensations, erratically haunting threat, and phantom limb sensations), complicated feelings about pain (converting depression into an active attitude toward life, having feelings of anticipation and anxiety about future pain relief, and facing and experiencing pain), and renewed hope (bravely fighting pain and seeking pain relief methods). CONCLUSIONS: This study revealed three important themes of NP experienced by SCI patients, including elusive pain, complicated feelings about pain, and renewed hope. Nurses should understand the nature of NP, provide a thorough pain assessment, and design a proper pain management plan to care effectively for patients with NP. PMID- 29120936 TI - Factor Structure of the Quality of Life Scale for Mental Disorders in Patients With Schizophrenia. AB - BACKGROUND: The Quality of Life for Mental Disorders (QOLMD) scale was designed to measure health-related quality of life (HRQOL) in patients with mental illness, especially schizophrenia. The QOLMD contains 45 items, which are divided into eight domains. However, the factor structure of the QOLMD has not been evaluated, which restricts the interpretations of the results of this scale. PURPOSE: The purpose of this study was to evaluate the factor structures (i.e., unidimensionality, eight-factor structure, and second-order model) of the QOLMD in patients with schizophrenia. METHODS: Two hundred thirty-eight outpatients with schizophrenia participated. We first conducted confirmatory factor analysis to evaluate the unidimensionality of each domain. After the unidimensionality of the eight individual domains was supported, we examined the eight-factor structure and second-order model. RESULTS: The results of unidimensionality showed sufficient model fit in all of the domains with the exception of the autonomy domain. A good model fit was confirmed for the autonomy domain after deleting two of the original items. The eight-factor structure for the 43-item QOLMD showed an acceptable model fit, although the second-order model showed poor model fit. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Our results supported the unidimensionality and eight-factor structure of the 43-item QOLMD. The sum score for each of the domains may be used to reflect its domain-specific function. We recommend using the 43-item QOLMD to capture the multiple domains of HRQOL. However, the second-order model showed an unsatisfactory model fit. Furthermore, caution is advised when interpreting overall HRQOL using the total score for the eight domains. PMID- 29120937 TI - Lifestyle in Visually Impaired or Blind Massage Therapists: A Preliminary Study. AB - BACKGROUND: Lifestyle is among the most important factors affecting individual health status. Limited access to health information may limit the ability of people with visual impairment or blindness to practice healthy lifestyles. However, no studies have investigated how lifestyle practices affect health specifically in visually impaired and blind populations. PURPOSE: The aim of this study was to investigate the lifestyle behaviors of visually impaired and blind massage therapists (VIBMTs) in Taiwan. METHODS: This exploratory study used a purposive sampling technique to recruit 50 VIBMTs who were employed at massage stations in southern Taiwan. All of the participants completed the Health Promoting Lifestyle Profile II (HPLP-II) and a survey of demographic characteristics. Descriptive and inferential statistical tests, including the Mann-Whitney U test and the Kruskal-Wallis H test, were used. Statistical significance was defined as p < .05 in two-tailed tests. RESULTS: Fifty participants completed both the HPLP-II and the demographic survey. The mean subscale score for the HPLP-II was 2.52 +/- 0.37. The lowest scores were on the physical activity (2.09 +/- 0.67) and nutrition (2.35 +/- 0.39) subscales, and the highest scores were on the spiritual growth (2.89 +/- 0.56) and interpersonal relations (2.79 +/- 0.46) subscales. Scores on the stress management and physical activity subscales were significantly higher in men than in women (p < .05). In addition, mean HPLP-II scores were significantly higher in VIBMTs who exercised regularly compared with those who did not (p < .05). Compared with nonsmokers, current smokers had significantly higher scores on the stress management subscale (p < .05). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The low physical activity scores in this population may be improved by developing physical activity programs for the home and workplace and by establishing community recreational and exercise facilities for visually impaired populations. The low scores for nutrition may be improved by establishing nutrition education programs that are designed specifically for VIBMTs to increase their consumption of fresh produce and other healthy foods and by requiring food manufacturers to use labels that may be easily read or understood by visually impaired populations. PMID- 29120938 TI - Fibrinogen on Admission in Trauma score: Early prediction of low plasma fibrinogen concentrations in trauma patients. AB - BACKGROUND: Early recognition of low fibrinogen concentrations in trauma patients is crucial for timely haemostatic treatment and laboratory testing is too slow to inform decision-making. OBJECTIVE: To develop a simple clinical tool to predict low fibrinogen concentrations in trauma patients on arrival. DESIGN: Retrospective cohort study. SETTING: Three designated level 1 trauma centres in the Paris Region, from January 2011 to December 2013. PATIENTS: Patients admitted in accordance with national triage guidelines for major trauma and plasma fibrinogen concentration testing on admission. INTERVENTION: Construction of a clinical score [Fibrinogen on Admission in Trauma (FibAT) score] in a derivation cohort to predict fibrinogen plasma concentration 1.5 g l or less after multiple regressions. One point was given for each predictive factor. The score was the sum of all. Validation was performed in a separate validation cohort. MAIN OUTCOME MEASURE: Predictive accuracy of FibAT score. RESULTS: In total, 2936 patients were included, 2124 in the derivation cohort and 812 in the validation cohort. In the derivation cohort, a multivariate logistic model identified the following predictive factors for plasma fibrinogen concentrations 1.5 g l or less: age less than 33 years, prehospital heart rate more than 100 beats per minute, prehospital SBP less than 100 mmHg, blood lactate concentration on admission more than 2.5 mmol l, free intraabdominal fluid on sonography, decrease in haemoglobin concentration from prehospital to admission of more than 2 g dl, capillary haemoglobin concentration on admission less than 12 g dl and temperature on admission less than 36 degrees C. The FibAT score had an area under the receiver operating characteristic curve of 0.87 [95% confidence interval (0.86 to 0.91)] in the derivation cohort and of 0.82 (95% confidence interval (0.86 to 0.91)] in the validation cohort to predict a low plasma fibrinogen. CONCLUSION: The FibAT score accurately predicts plasma fibrinogen levels 1.5 g l or less on admission in trauma patients. This easy-to-use score could allow early, goal-directed therapy to trauma patients. PMID- 29120939 TI - Clinical signs and electroencephalographic patterns of emergence from sevoflurane anaesthesia in children: An observational study. AB - BACKGROUND: Few studies have systematically described relationships between clinical-behavioural signs, electroencephalographic (EEG) patterns and age during emergence from anaesthesia in young children. OBJECTIVE: To identify the relationships between end-tidal sevoflurane (ETsevoflurane) concentration, age and frontal EEG spectral properties in predicting recovery of clinical behavioural signs during emergence from sevoflurane in children 0 to 3 years of age, with and without exposure to nitrous oxide. The hypothesis was that clinical signs occur sequentially during emergence, and that for infants aged more than 3 months, changes in alpha EEG power are correlated with clinical-behavioural signs. DESIGN: An observational study. SETTING: A tertiary paediatric teaching hospital from December 2012 to August 2016. PATIENTS: Ninety-five children aged 0 to 3 years who required surgery below the neck. OUTCOME MEASURES: Time-course of, and ETsevoflurane concentrations at first gross body movement, first cough, first grimace, dysconjugate eye gaze, frontal (F7/F8) alpha EEG power (8 to 12 Hz), frontal beta EEG power (13 to 30 Hz), surgery-end. RESULTS: Clinical signs of emergence followed an orderly sequence of events across all ages. Clinical signs occurred over a narrow ETsevoflurane, independent of age [movement: 0.4% (95% confidence interval (CI), 0.3 to 0.4), cough 0.3% (95% CI, 0.3 to 0.4), grimace 0.2% (95% CI, 0 to 0.3); P > 0.5 for age vs. ETsevoflurane]. Dysconjugate eye gaze was observed between ETsevoflurane 1 to 0%. In children more than 3 months old, frontal alpha EEG oscillations were present at ETsevoflurane 2.0% and disappeared at 0.5%. Movement occurred within 5 min of alpha oscillation disappearance in 99% of patients. Nitrous oxide had no effect on the time course or ETsevoflurane at which children showed body movement, grimace or cough. CONCLUSION: Several clinical signs occur sequentially during emergence, and are independent of exposure to nitrous oxide. Eye position is poorly correlated with other clinical signs or ETsevoflurane. EEG spectral characteristics may aid prediction of clinical-behavioural signs in children more than 3 months. PMID- 29120940 TI - Bilateral hemispheric changes and language outcomes in chronic left hemisphere stroke. AB - The role of the right hemisphere in recovery of language function after left hemisphere stroke remains unclear. This prospective study aimed to determine the relationship between bilateral hemispheric changes and severity of aphasia in patients with chronic left hemisphere stroke. Twenty-three patients with left hemisphere stroke with aphasia and 10 healthy control patients underwent high resolution T1-weighted and diffusion tensor imaging. Patients with aphasia were assessed using the Korean version of the Western Aphasia Battery, and severity of aphasia was quantified in terms of aphasia quotient; patients were classified into two groups - the mild-to-moderate and severe groups - on the basis of severity of aphasia. Brain volume and fractional anisotropy in language associated areas of the brain were determined by voxel-based morphometry analysis. Volume of white matter in the left hemisphere and fractional anisotropy of the bilateral pars opercularis, pars triangularis, angular gyrus, supramarginal gyrus, and superior longitudinal fasciculus were significantly lower in the severe aphasia group than in the control group. The findings of this study demonstrate the importance of right hemispheric integrity for recovery of language function in patients with chronic poststroke aphasia. PMID- 29120941 TI - Effects of gynosaponin TN-2 on L-DOPA-induced cytotoxicity in PC12 cells. AB - Gynosaponins have pharmacological effects on 3,4-L-dihydroxyphenylalanine (L DOPA)-related or dopamine-related neurological diseases; however, the neuroprotective functions of single compound of gynosaponins remain undefined. This study investigated the cytotoxic effects of gynosaponin TN-2 on L-DOPA in pheochromocytoma 12 cells. Gynosaponin TN-2, at 0.5-3 MUM, did not exhibit cytotoxicity and protected against L-DOPA (100 and 200 MUM)-induced cell death. Gynosaponin TN-2 (0.5 and 1.0 MUM) inhibited the L-DOPA (100 and 200 MUM)-induced sustained extracellular signal-regulated protein kinases 1 and 2 phosphorylation. Gynosaponin TN-2 at 0.5 and 1.0 MUM also reduced L-DOPA (100 and 200 MUM)-induced JNK1/2 phosphorylation and cleaved caspase-3 expression. These results suggested that gynosaponin TN-2 exerts protective effects on L-DOPA (100 and 200 MUM) induced apoptotic cell death by modulating extracellular signal-regulated protein kinases 1 and 2 activation in pheochromocytoma 12 cells. PMID- 29120942 TI - Quetiapine prevents Abeta25-35-induced cell death in cultured neuron by enhancing brain-derived neurotrophic factor release from astrocyte. AB - beta-Amyloid (Abeta)-induced neuronal toxicity is an early event in the pathogenesis of Alzheimer's disease. Quetiapine (QTP) is an atypical antipsychotic drug that has neuroprotectant properties, but little is known about its direct protective effects on neurons against the Abeta-induced cell toxicity. In the present study, we investigated the neuroprotective effects of QTP on Abeta25-35-induced cell death and the possible underlying mechanisms in primary cultures of neurons. Exposure of cortical neurons to 10 MUM or more Abeta25-35 caused significant viability loss in a MTT assay, and the toxic effects were not significantly prevented by the simultaneous coadministration of QTP. However, pretreated astrocyte conditioned medium (ACM) with QTP (ACMQTP) for 24 h markedly protected the neurons against the amyloid-induced cell loss. Furthermore, we revealed that QTP increased both the release of brain-derived neurotrophic factor from cultured astrocytes and the phosphorylation of extracellular signal regulated kinase after 24 h of treatment, which might be responsible for its protective effects on neurons. Consistent with the aforementioned findings, the protective effects of ACM on neurons could potentially be abolished by the extracellular signal-regulated kinase inhibitor and tropomyosin receptor kinase B receptor blocker. In conclusion, our data demonstrated that QTP exerted its neuroprotective effects against amyloid toxicity by enhancing the brain-derived neurotrophic factor release from astrocytes. PMID- 29120943 TI - Native prion protein homodimers are destabilized by oligomeric amyloid beta 1-42 species as shown by single-molecule imaging. AB - Prion proteins (PrPc) are receptors for amyloid beta 1-42 (Abeta1-42) oligomers, but we do not know the impact of Abeta1-42 binding to PrPc on the interaction of membrane-bound PrPc with molecules that regulate downstream biological pathways. Stability of the PrPc dimeric complex and subsequent intermolecular interactions with membranous or cytoplasmic molecules are important for physiological functions of PrPc including neuroprotection. The principal aim of this study was to determine whether homodimer lifetime of PrPc is affected by the presence of Abeta1-42 oligomers. Single-molecule imaging analysis was carried out by total internal reflection fluorescence microscopy in PrPc-transfected CHO-K1 cells in the absence or presence of characterized Abeta1-42 oligomers. The contribution of different Abeta1-42 oligomer conformations to Alzheimer's disease pathophysiology and to the associated neurotoxicity is unknown. To be precise, with the oligomeric species used in our study, we biochemically analyzed the molecular weight of oligomers formed from Abeta1-42 monomers under our experimental conditions. The lifetime of PrPc homodimers was 210 ms, and in the presence of Abeta1-42 oligomers, the lifetime was significantly reduced (to 92 ms). The reduction of PrPc homodimer lifetime by Abeta1-42 oligomers may impair PrPc mediated downstream neuroprotective signaling. PMID- 29120944 TI - Targeted Genotyping Identifies Susceptibility Locus in Brain-derived Neurotrophic Factor Gene for Chronic Postsurgical Pain. AB - BACKGROUND: The purpose of this study was to evaluate the association between single-nucleotide polymorphisms and chronic postsurgical pain. METHODS: Using GoldenGate genotyping assays, we genotyped 638 polymorphisms within 54 pain related genes in 1,152 surgical patients who were enrolled in our Persistent Pain after Surgery Study. Patients were contacted by phone to determine whether they had chronic postsurgical pain at 12 months. Polymorphisms identified were validated in a matched cohort of 103 patients with chronic postsurgical pain and 103 patients who were pain free. The functions of targeted polymorphisms were tested in an experimental plantar incisional nociception model using knock-in mice. RESULTS: At 12 months after surgery, 246 (21.4%) patients reported chronic postsurgical pain. Forty-two polymorphisms were found to be associated with chronic postsurgical pain, 19 decreased the risk of pain, and 23 increased the risk of pain. Patients carrying allele A of rs6265 polymorphism in brain-derived neurotrophic factor (BDNF) had a lower risk of chronic postsurgical pain in the discovery and validation cohorts, with an adjusted odds ratio (95% CI) of 0.62 (0.43 to 0.90) and 0.57 (0.39 to 0.85), respectively. Age less than 65 yr, male sex, and prior history of pain syndrome were associated with an increased risk of pain. Genetic polymorphisms had higher population attributable risk (7.36 to 11.7%) compared with clinical risk factors (2.90 to 5.93%). Importantly, rs6265 is a substitution of valine by methionine at amino acid residue 66 (Val66Met) and was associated with less mechanical allodynia in BDNF mice compared with BDNF group after plantar incision. CONCLUSIONS: This study demonstrated that genetic variation of BDNF is associated with an increased risk of chronic postsurgical pain. PMID- 29120946 TI - Early-onset Neonatal Pneumococcal Sepsis: A Fatal Case Report and Brief Literature Review. AB - Sepsis caused by Streptococcus pneumoniae is rare in neonates although associated with high morbidity and mortality. We report a fatal case of invasive pneumococcal disease in a term neonate whose mother was healthy and did not receive any pneumococcal vaccine. Investigation of the infection source yielded negative results. Acquisition of infection through the birth canal was considered unlikely. PMID- 29120945 TI - A Comparison of Red Cell Rejuvenation versus Mechanical Washing for the Prevention of Transfusion-associated Organ Injury in Swine. AB - BACKGROUND: We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. METHODS: White-landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device. Functional, biochemical, and histologic markers of organ injury were assessed for up to 24 h posttransfusion. RESULTS: Transfusion of 14 day red cells resulted in lung injury (lung injury score vs. sham, mean difference -0.3 (95% CI, -0.6 to -0.1; P = 0.02), pulmonary endothelial dysfunction, and tissue leukocyte sequestration. Mechanical washing reduced red cell-derived microvesicles but increased cell-free hemoglobin in 14-day red cell units. Transfusion of washed red cells reduced leukocyte sequestration but did not reduce the lung injury score (mean difference -0.2; 95% CI, -0.5 to 0.1; P = 0.19) relative to 14-day cells. Transfusion of washed red cells also increased endothelial activation and kidney injury. Rejuvenation restored adenosine triphosphate to that of fresh red cells and reduced microvesicle concentrations without increasing cell-free hemoglobin release. Transfusion of rejuvenated red cells reduced plasma cell-free hemoglobin, leukocyte sequestration, and endothelial dysfunction in recipients and reduced lung and kidney injury relative to 14-day or washed 14-day cells. CONCLUSIONS: Reversal of the red cell storage lesion by rejuvenation reduces transfusion-associated organ injury in swine. PMID- 29120947 TI - Novel techniques for the study of drugs and behaviour. PMID- 29120949 TI - Cardiac vagal tone as a reliable index of pain chronicity and severity. PMID- 29120950 TI - Reply. PMID- 29120951 TI - Reporting randomized controlled trial quality and search date in systematic reviews and meta-analyses. PMID- 29120952 TI - Reply. PMID- 29120948 TI - Parvalbumin-containing GABA cells and schizophrenia: experimental model based on targeted gene delivery through adeno-associated viruses. AB - Understanding the contribution of transmitter systems in behavioural pharmacology has a long tradition. Multiple techniques such as transmitter-specific lesions, and also localized administration of pharmacological toxins including agonists and antagonists of selected receptors have been applied. More recently, modern genetic tools have permitted cell-type selective interferences, for example by expression of light-sensitive channels followed by optogenetic stimulation in behaviourally meaningful settings or by engineered channels termed DREADDS that respond to peripherally administered drugs. We here took a similar approach and employed a Cre recombinase-dependent viral delivery system (adeno-associated virus) to express tetanus toxin light chain (TeLc) and thus, block neural transmission specifically in parvalbumin-positive (PV+) neurons of the limbic and infralimbic prefrontal circuitry. PV-TeLc cohorts presented with normal circadian activity as recorded in PhenoTyper home cages, but a reproducible increase in anxiety was extracted in both the open field and light-dark box. Interestingly, working memory assessed in a spontaneous alternation Y-maze task was impaired in PV-TeLc mice. We also recorded local field potentials from a separate cohort and found no global changes in brain activity, but found a behaviourally relevant lack of modulation in the gamma spectral band. These anomalies are reminiscent of endophenotypes of schizophrenia and appear to be critically dependent on GABAergic signalling through PV neurones. At the same time, these observations validate the use of viral vector delivery and its expression in Cre-lines as a useful tool for understanding the role of selective components of the brain in behaviour and the underpinning physiology. PMID- 29120953 TI - Improving Quality on the Telemetry Unit: Back to Basics. PMID- 29120954 TI - Using a Theory-Driven Approach to Manage the Relocation of an Intensive Care Unit: An Exemplar. AB - Proactive planning and managing moving from old to newly built hospitals, and the relocation process of patients for complex specialized units such as intensive care units, are necessary for both patient safety and staff well-being. This article provides an exemplar for how theory can be used to facilitate a positive relocation experience. Using change management theory, a systematic approach to cocreate implementation strategy among researchers and clinicians was critical to the success of this project. PMID- 29120955 TI - Improving Oral Hygiene for Veterans With Dementia in Residential Long-term Care. AB - Oral hygiene care is neglected in long-term care (LTC) due to patient-, staff-, and systems-level barriers. A dementia-specific oral hygiene program, implemented and evaluated in a Department of Veterans Affairs LTC unit, addressed barriers to oral care at multiple levels. Improved staff competency, access to oral care supplies, and standardized documentation systems were accompanied by reduced oral plaque and gingivitis, demonstrating the feasibility and benefits of direct care staff providing improved oral hygiene in LTC. PMID- 29120956 TI - Protein kinase Calpha deletion causes hypotension and decreased vascular contractility. AB - AIM: Protein kinase Calpha (PKCalpha) is a critical regulator of multiple cell signaling pathways including gene transcription, posttranslation modifications and activation/inhibition of many signaling kinases. In regards to the control of blood pressure, PKCalpha causes increased vascular smooth muscle contractility, while reducing cardiac contractility. In addition, PKCalpha has been shown to modulate nephron ion transport. However, the role of PKCalpha in modulating mean arterial pressure (MAP) has not been investigated. In this study, we used a whole animal PKCalpha knock out (PKC KO) to test the hypothesis that global PKCalpha deficiency would reduce MAP, by a reduction in vascular contractility. METHODS: Radiotelemetry measurements of ambulatory blood pressure (day/night) were obtained for 18 h/day during both normal chow and high-salt (4%) diet feedings. PKCalpha mice had a reduced MAP, as compared with control, which was not normalized with high-salt diet (14 days). Metabolic cage studies were performed to determine urinary sodium excretion. RESULTS: PKC KO mice had a significantly lower diastolic, systolic and MAP as compared with control. No significant differences in urinary sodium excretion were observed between the PKC KO and control mice, whether fed normal chow or high-salt diet. Western blot analysis showed a compensatory increase in renal sodium chloride cotransporter expression. Both aorta and mesenteric vessels were removed for vascular reactivity studies. Aorta and mesenteric arteries from PKC KO mice had a reduced receptor-independent relaxation response, as compared with vessels from control. Vessels from PKC KO mice exhibited a decrease in maximal contraction, compared with controls. CONCLUSION: Together, these data suggest that global deletion of PKCalpha results in reduced MAP due to decreased vascular contractility. PMID- 29120957 TI - Deletion of protein kinase B2 preserves cardiac function by blocking interleukin 6-mediated injury and restores blood pressure during angiotensin II/high-salt diet-induced hypertension. AB - OBJECTIVE: Protein kinase B2 (AKT2) is implicated in cardiomyocyte survival during various stress conditions. However, the role of AKT2 in heart function, cardiac hypertrophy and blood pressure (BP) control during hypertension is not fully understood. Therefore, we sought to determine whether the deletion of AKT2 protects cardiac function during angiotensin II/high-salt-diet (AngII/HSD) treatment and find out the signaling pathway. METHODS: Male C57BL/6J (wild type), AKT2 knockout and interleukin (IL)-6 knockout mice were fed a 4% NaCl diet for 5 weeks. In the last week, mice were split in two groups and infused subcutaneously with either vehicle or AngII (1.5 MUg/h per mouse) for 1 week. Then, BP and cardiac function were assessed. Immunohistology of IL-6 and monocyte chemoattractant protein 1 was performed to detect inflammation in the heart. Masson's trichrome staining was performed to evaluate cardiac fibrosis. Heart tissue homogenates and neonatal mice cardiomyocytes were collected to analyze oxidative stress. RESULTS: Compared with wild-type mice, AKT2 knockout mice maintained BP and showed better left ventricle ejection fraction, lower level of fibrosis, reduced oxidative stress, reduced IL-6 expression and less macrophage infiltration, when treated with AngII/HSD. IL-6 knockout mice treated with AngII/HSD also showed alleviated left ventricular function, fibrosis, oxidative stress and macrophage infiltration compared with wild type. CONCLUSION: AKT2 deficiency prevents the development of AngII/HSD-induced hypertension, cardiac dysfunction and myocardial injury including oxidative stress, fibrosis and inflammation by suppressing IL-6 expression. These data reveal an important role of the AKT2-IL-6 pathway in mediating AngII/HSD-induced hypertension and cardiomyopathy. PMID- 29120958 TI - Best antihypertensive strategies to improve blood pressure control in Latin America: position of the Latin American Society of Hypertension. AB - : Evidence from randomized trials has shown that effective treatment with blood pressure (BP)-lowering medications reduces the risk of cardiovascular morbidity and mortality in patients with hypertension. Therefore, hypertension control and prevention of subsequent morbidity and mortality should be achievable for all patients worldwide. However, many people in Latin America remain undiagnosed, untreated or have inadequately controlled BP, even where this is access to health systems. Barriers to hypertension control in low-income countries include difficulties in transportation to health services; inappropriate opening hours; difficulties in making clinic appointments; inaccessible healthcare facilities, lack of insurance and high treatment costs. After a review of the best recent available evidence on the efficacy and tolerability of antihypertensive drugs and strategies, the Latin American Society of Hypertension experts conclude that all major classes of BP-lowering drugs be available to hypertensive patients, because all have been shown to reduce major cardiovascular outcomes compared with placebo, and have shown to be associated with a comparable risk of major cardiovascular events and mortality when compared between classes. Within each class, no evidence whatsoever is available to show that one compound is more effective than another in outcome prevention. Therefore, the selection of individual drugs may be based mainly on the capacity of Latin American governments to obtain the lowest prices of the different molecules manufactured by companies with high production quality standards. PMID- 29120959 TI - Effect of total, domain-specific, and intensity-specific physical activity on all cause and cardiovascular mortality among hypertensive adults in China. AB - OBJECTIVES: We aimed to prospectively examine the associations of total, domain specific, and intensity-specific physical activity with all-cause and cardiovascular mortality among Chinese hypertensive adults. METHODS: We performed a prospective cohort study in 150 391 hypertensive participants aged 30-79 years from the China Kadoorie Biobank study of 512 891 participants recruited from 10 diverse areas across China during 2004-2008. Participants with heart disease, stroke, chronic obstructive pulmonary disease, and cancer at baseline were excluded. RESULTS: During 1069 863 person-years of follow-up (median 7.1 years), a total of 5332 men and 4384 women died. Compared with hypertensive participants in the lowest level of total physical activity, the hazard ratios for all-cause mortality were 0.80 (0.76-0.84), 0.69 (0.65-0.73), and 0.67 (0.62-0.72) for those in quartiles 2-4 (Ptrend < 0.001), respectively. Inverse associations were also observed for cardiovascular mortality. Being active in occupational, domestic, and leisure time were associated with lower risk of all-cause and cardiovascular mortality. However, the adjusted ratio for active commuting was 1.08 (1.02-1.15) for all-cause mortality. High levels of low-intensity, moderate-intensity, and vigorous-intensity physical activity were consistently associated with lower risks of all-cause and cardiovascular mortality. CONCLUSION: Among Chinese hypertensive adults, a higher level of physical activity reduces all-cause and cardiovascular mortality, independent of intensities of physical activity. Not only leisure-time but also occupational and domestic physical activities were benefited. PMID- 29120960 TI - External validation and comparison of formulae estimating 24-h sodium intake from a fasting morning urine sample. AB - OBJECTIVE: The relationship between sodium intake and cardiovascular events is controversial, but most large epidemiological studies estimated sodium intake using formulae based on single urine samples, the validity of which is debated. We evaluated sodium intake estimating formulae in a large cohort of adult patients. DESIGN AND METHODS: Patients were asked to collect 24-h urine the day before admission. Validity of the 24-h urine collection was assessed by comparing creatinine clearance from this collection to the mean creatinine clearance from six fractionated urine samples. Only collections with creatinine clearance within +/-15% of fractionated clearance were considered valid. The Kawasaki, INTERSALT and Tanaka formulae, using a morning fasting urine sample obtained upon admission, were compared with 24-h urine sodium excretion. The relationship between sodium intake, either measured or estimated, and blood pressure was assessed. RESULTS: Amongst 2278 patients referred to our physiology department between September 2006 and August 2016, 1018 had complete 24-h urine collections and were included in this analysis. Mean age was 51 +/- 14 years and mean sodium excretion was 3624 +/- 1614 mg/day. The intraclass correlation coefficient was higher for the Kawasaki (0.54; 95% confidence interval, 0.48-0.60), than for the INTERSALT (0.38; 0.33-0.42, P < 0.001), and Tanaka (0.42; 0.37-0.46, P < 0.001) formulae. The Kawasaki formula displayed the lowest mean bias (248; 157-339 mg/day). There was a significant positive association between measured sodium intake and blood pressure, and the Kawasaki formula yielded a similar association. CONCLUSION: All formulae have poor precision and accuracy and are not suitable for estimating individual sodium intake. This does not dismiss their potential value for assessment of sodium intake in population studies. PMID- 29120961 TI - Carotid stiffness is significantly correlated with wall-to-lumen ratio of retinal arterioles. AB - BACKGROUD AND PURPOSE: Wall-to-lumen ratio of retinal arterioles (W/L ratio) might serve as an in-vivo parameter of microvascular damage. No study has investigated the relationship between carotid stiffness and W/L ratio of retinal arteries. Therefore, the aim of the current study was to assess the correlation between local carotid stiffness, as assessed by echotracking technique, and W/L ratio of retinal arterioles, as assessed by noninvasive flowmetry in normotensive patients and in patients with primary hypertension. METHODS: Two hundred and twenty-seven patients underwent renal arteries W/L ratio and local carotid-pulse wave velocity (carotid PWV) measurement. One hundred and fifteen patients had a diagnosis of primary hypertension, whereas 112 were normotensive patients. RESULTS: W/L ratio and carotid PWV were both related with clinic SBP (r = 0.17, P < 0.05; r = 0.50, P < 0.001), clinic pulse pressure (r = 0.22, P < 0.001; r = 0.55, P < 0.001), carotid SBP (r = 0.18, P < 0.05; r = 0.51, P < 0.001) and carotid pulse pressure (r = 0.24, P < 0.001; r = 0.56, P < 0.001). W/L ratio was correlated with carotid PWV (r = 0.18, P < 0.005). At multivariate analysis, carotid PWV remained independently associated with W/L ratio. CONCLUSION: In hypertensive and normotensive patients, carotid stiffness is significantly correlated with W/L ratio of retinal arteries, independently of possible confounders. PMID- 29120962 TI - Endothelial factors in the pathogenesis and treatment of chronic kidney disease Part I: General mechanisms: a joint consensus statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors and The Japanese Society of Hypertension. AB - : Kidney damage is a common consequence of arterial hypertension, but is also a cause of atherogenesis. Dysfunction and/or harm of the endothelium in glomeruli and tubular interstitium damage the function of these structures and translates into dynamic changes of filtration fraction, with progressive reduction in glomerular filtration rate, expansion of extracellular fluid volume, abnormal ion balance, and hypoxia, ultimately leading to chronic kidney disease. Considering the key role played by endothelial dysfunction in chronic kidney disease, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension have critically reviewed available knowledge on the mechanisms underlying endothelial cell injury. This resulted into two articles: in the first, we herein examine the mechanisms by which endothelial factors induce vascular remodeling and the role of different players, including endothelin-1, the renin-angiotensin-aldosterone system and their interactions, and of oxidative stress; in the second, we discuss the role of endothelial dysfunction in the major disease conditions that affect the kidney. PMID- 29120963 TI - High-dose Versus Low-dose Tranexamic Acid to Reduce Transfusion Requirements in Pediatric Scoliosis Surgery. AB - BACKGROUND: Our objective was to quantify blood loss and transfusion requirements for high-dose and low-dose tranexamic acid (TXA) dosing regimens in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis. Previous investigators have established the efficacy of TXA in pediatric scoliosis surgery; however, the dosing regimens vary widely and the optimal dose has not been established. METHODS: We retrospectively analyzed electronic medical records for 116 patients who underwent spinal fusion surgery for idiopathic scoliosis by a single surgeon and were treated with TXA. In total, 72 patients received a 10 mg/kg loading dose with a 1 mg/kg/h maintenance dose (low-dose) and 44 patients received 50 mg/kg loading dose with a 5 mg/kg/h maintenance dose (high-dose). Estimated blood loss and transfusion requirements were compared between dosing groups. RESULTS: Patient characteristics were nearly identical between the 2 groups. Compared with the low-dose TXA group, the high-dose TXA group had decreased estimated blood loss (695 vs. 968 mL, P=0.01), and a decrease in both intraoperative (0.3 vs. 0.9 units, P=0.01) and whole hospitalization (0.4 vs. 1.0 units, P=0.04) red blood cell transfusion requirements. The higher-dose TXA was associated with decreased intraoperative (P=0.01), and whole hospital transfusion (P=0.01) requirements, even after risk-adjustment for potential confounding variables. CONCLUSIONS: High-dose TXA is more effective than low-dose TXA in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery. LEVEL OF EVIDENCE: Level-III, retrospective cohort study. PMID- 29120964 TI - Analysis of survival of patients treated with vemurafenib, ipilimumab and dabrafenib for advanced skin melanoma in daily clinical practice (Real-World Data): retrospective analysis of patients treated under drug/reimbursement programmes in Poland in 2013-2016. AB - Vemurafenib, ipilimumab and dabrafenib were registered for the treatment of advanced skin melanoma pursuant to the results of randomized phase III clinical trials. Real-world data on survival time for patients treated with those drugs in daily clinical practice are so far limited. Patients with advanced skin melanoma treated under reimbursement programmes (drug programmes), for which they were qualified pursuant to uniform inclusion criteria in force in all oncology centres in Poland. Data were obtained from the electronic databases of the national payer (NFZ) responsible for the implementation and monitoring of reimbursement (drug) programmes. The analysis included all patients included for treatment with vemurafenib (since March of 2013), ipilimumab (since March of 2014) and dabrafenib (since July of 2015) until December 2016. The end date of the observation was set to 31 December 2016. The total survival analysis was performed using the Kaplan-Meier estimator. Until 31 December 2016, 759 patients were treated with vemurafenib, 370 with ipilimumab and 181 with dabrafenib. The overall survival (OS) median was 9.8 months for patients treated with vemurafenib (95% confidence interval: 8.8-10.6) and 6.9 months for patients treated with ipilimumab (95% confidence interval: 5.7-9.2). For patients treated with dabrafenib, the OS median was not reached because of an overly short observation period. The probability of surviving 12 months in the group of patients treated with vemurafenib was 40.5%, ipilimumab was 35.1% and dabrafenib was 60.7%. The probability of surviving 24 and 36 months in the group of patients treated with vemurafenib or ipilimumab amounted to, respectively, 20.1, 15.4 and 21, 18.8%. OS of patients with advanced melanoma treated in daily clinical practice may be comparable to the ones achieved in registration trials. The use of appropriate treatment inclusion criteria may affect the obtained OS. PMID- 29120965 TI - Exploring the Views of Individuals With Chronic Obstructive Pulmonary Disease on the Use of Rollators: A QUALITATIVE STUDY. AB - PURPOSE: Although it has been well documented that the progressive exercise limitation associated with chronic obstructive pulmonary disease can be helped with an assistive device, such as a rollator, many individuals use it infrequently. This study seeks to explore the views of individuals with chronic obstructive pulmonary disease regarding the use of rollators. METHODS: A qualitative study design was used. Twelve individuals with moderate to very severe chronic obstructive pulmonary disease were recruited from an outpatient pulmonary rehabilitation program to participate in semistructured interviews. Inductive thematic analysis was applied. RESULTS: Analysis revealed 5 themes: (1) "acquiring a rollator" reflecting the process of obtaining a device either via a health care professional or self-referral; (2) "acceptance versus resistance" describing opposing views regarding rollator usage; (3) "rollator roadblocks" describing practical barriers to use; (4) "participation" reflecting how rollators can promote reintegration into society; and (5) "revising perceptions" whereby participants embodied an eventual acceptance of rollators. CONCLUSION: Rollator acquisition appeared to be a unilateral, prescriptive process. Individuals described initial resistance to use, although in the long-term, negative perceptions were outweighed by the functional and social benefits of rollator use. Encouraging users to participate in deciding whether to use a rollator and providing adequate education on its indications, benefits, barriers, and facilitators are likely to promote optimal use of a rollator. PMID- 29120966 TI - Validity and Reliability of Accelerometers in Patients With COPD: A SYSTEMATIC REVIEW. AB - PURPOSE: Reduced physical activity is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Accelerometers have greatly improved quantification of physical activity by providing information on step counts, body positions, energy expenditure, and magnitude of force. The purpose of this systematic review was to compare the validity and reliability of accelerometers used in patients with COPD. METHODS: An electronic database search of MEDLINE and CINAHL was performed. Study quality was assessed with the Strengthening the Reporting of Observational Studies in Epidemiology checklist while methodological quality was assessed using the modified Quality Appraisal Tool for Reliability Studies. RESULTS: The search yielded 5392 studies; 25 met inclusion criteria. The SenseWear Pro armband reported high criterion validity under controlled conditions (r = 0.75-0.93) and high reliability (ICC = 0.84-0.86) for step counts. The DynaPort MiniMod demonstrated highest concurrent validity for step count using both video and manual methods. DISCUSSION: Validity of the SenseWear Pro armband varied between studies especially in free-living conditions, slower walking speeds, and with addition of weights during gait. A high degree of variability was found in the outcomes used and statistical analyses performed between studies, indicating a need for further studies to measure reliability and validity of accelerometers in COPD. CONCLUSION: The SenseWear Pro armband is the most commonly used accelerometer in COPD, but measurement properties are limited by gait speed variability and assistive device use. DynaPort MiniMod and Stepwatch accelerometers demonstrated high validity in patients with COPD but lack reliability data. PMID- 29120967 TI - Life Values as an Intrinsic Guide for Cardiopulmonary Rehabilitation Program Engagement: A QUALITATIVE ANALYSIS. AB - PURPOSE: Participation in cardiovascular and pulmonary rehabilitation (CVPR) programs can lead to improved functional abilities and improved quality of life, but attendance and adherence to these programs remain suboptimal. Behavioral therapies have emphasized the importance of life value identification as a guide for goal setting and behavior change for both psychological and physical health conditions. Individuals who choose to engage in behaviors that align with their life values are thought to be intrinsically reinforced. The purpose of the following qualitative study was to interview patients enrolled in CVPR about their own life values and motivating factors related to healthy behavior changes. METHODS: Thirty cardiac or pulmonary patients were recruited from a CVPR program and participated in a semistructured interview about their life values and motivating factors related to program engagement. The data were transcribed and analyzed thematically. RESULTS: Participants identified a wide range of values related to program engagement, and only half of the participants endorsed health as a value. The most frequently endorsed life values included being active, family, and independence. The interviews indicated that, although patients make lifestyle changes in the program to improve their physical health, there are often other values that primarily guide their choice to engage in and maintain lifestyle behaviors. CONCLUSIONS: Life values can serve as a powerful guide for individual behavior change. The present study suggests that the piloting of brief values interventions early in CVPR treatment is warranted and has the potential to improve patient outcomes. PMID- 29120968 TI - Effect of Pulmonary Rehabilitation on Inspiratory Capacity During 6-min Walk Test in Patients With COPD: A PROSPECTIVE CONTROLLED STUDY. AB - PURPOSE: Purpose of this study was to analyze the impact of a pulmonary rehabilitation (PR) program on the measured inspiratory capacity (IC) in patients with chronic obstructive pulmonary disease (COPD) while performing a 6-min walk test (6MWT). METHODS: Before and after PR, IC was measured by spirometry both at the beginning and at the end of the 6MWT for 15 patients with COPD in the PR group (PRG) and compared with a similar calisthenics training group (CTG; n = 15). In addition, the COPD Assessment Test (CAT), St George's Respiratory Questionnaire (SGRQ), and other lung function tests were recorded and compared. RESULTS: Both groups were not significantly different at baseline. Compared with the CTG, the PRG achieved a significant increase in the delta of IC measured during the 6MWT (0.5 +/- 0.2 L [PRG] vs -0.2 + 0.2 L [CTG], P = .001). Significant differences were found for the 6MWT walking distance (PRG: 99 +/- 36 m vs CTG: 5 +/- 25 m, P = .001). No significant increase in dyspnea while performing the 6MWT was found in either group. The differences in the CAT score and the SGRQ Global score were significant only for the PRG in intragroup comparisons, whereas the intergroup comparison showed no significant differences. Except for residual volume, no significant changes in all parameters of the static lung function tests were observed in either group. CONCLUSION: Participation in a PR may lead to a significant and clinically relevant increase in IC and the walking distance. Additional research is necessary to define the effects of this increase in IC on exercise capacity. PMID- 29120969 TI - Clinical and Physiological Effects of Rollators in Individuals With Chronic Obstructive Pulmonary Disease: A SYSTEMATIC REVIEW. AB - PURPOSE: To determine the effects of using a rollator in people with chronic obstructive pulmonary disease (COPD). METHODS: Studies were systematically identified from literature searches of MEDLINE, CINAHL, PEDro, PubMed, EMBASE, and the Cochrane Library databases and the reference lists of included studies. Two reviewers independently selected randomized controlled or crossover studies examining the effects of rollator usage compared with no aid in individuals with COPD. Methodologic quality was assessed by 2 reviewers independently using the Cochrane Risk of Bias tool. Two reviewers also used a customized form to extract characteristics of and outcomes for subjects related to exercise capacity, symptoms, health-related quality of life (HRQOL), physiological, and gait parameters. Weighted mean differences (WMD) with 95% CI were calculated using a fixed-effects model. RESULTS: A total of 7 studies (126 participants) were included. Use of a rollator during a 6-Minute Walk Test (6MWT) improved distance walked (WMD = 13 m; 95% CI, 5-22) and lowered end-6MWT dyspnea rating (WMD = 0.97; 95% CI, 0.63-1.32). Longer-term use did not appear to impact exercise capacity or HRQOL, although this may be related to the frequency of use. CONCLUSIONS: When used in the short-term, rollators resulted in a small increase in 6MWT and a reduction in dyspnea. Details on patient adherence are required to accurately evaluate the longer-term effects of rollator usage. PMID- 29120970 TI - Effect of Smoking Status on Exercise Perception and Intentions for Cardiac Rehabilitation Enrollment Among Patients Hospitalized With an Acute Cardiac Condition. AB - PURPOSE: Cardiac rehabilitation (CR) attendance has been associated with higher smoking cessation (SC) rates. However, for unclear reasons, smokers are consistently less likely to enroll in CR than nonsmokers, and it is uncertain what might encourage them to attend. METHODS: We surveyed patients eligible for CR who were cigarette smokers at the time of hospital admission. We assessed patient intention to quit smoking, start exercising, and enroll in CR. We also measured anxiety and depression levels. RESULTS: Of the 105 patients approached, 81 (77%) completed the survey (69% males, aged 57 +/- 10 y, 72% white). Most patients reported interest in SC (80%) and attending CR (78%). Many felt that SC medications (41%), stress management programs (35%), and an exercise program with SC counseling (30%) would increase their likelihood to attend CR; however, 30% stated that they would be less likely to enroll in CR if they continued smoking following discharge. Many patients indicated high levels of anxiety (51%) and depression (27%); many desired to reduce stress following discharge (73%), with 35% stating that stress management programs would increase their likelihood to attend CR. CONCLUSIONS: Hospitalized smokers eligible for CR report significant interest in SC, attending CR, and beginning an exercise program. These patients show high levels of anxiety and depression and indicate a strong interest in stress management programs. These results suggest that messages emphasizing the role of CR in the treatment of depression, anxiety, and stress are likely to resonate with smokers, increase their enrollment in CR, and support long-term SC. PMID- 29120971 TI - Systematic Review of Salivary Versus Blood Concentrations of Antituberculosis Drugs and Their Potential for Salivary Therapeutic Drug Monitoring. AB - BACKGROUND: Therapeutic drug monitoring is useful in the treatment of tuberculosis to assure adequate exposure, minimize antibiotic resistance, and reduce toxicity. Salivary therapeutic drug monitoring could reduce the risks, burden, and costs of blood-based therapeutic drug monitoring. This systematic review compared human pharmacokinetics of antituberculosis drugs in saliva and blood to determine if salivary therapeutic drug monitoring could be a promising alternative. METHODS: On December 2, 2016, PubMed and the Institute for Scientific Information Web of Knowledge were searched for pharmacokinetic studies reporting human salivary and blood concentrations of antituberculosis drugs. Data on study population, study design, analytical method, salivary Cmax, salivary area under the time-concentration curve, plasma/serum Cmax, plasma/serum area under the time-concentration curve, and saliva-plasma or saliva-serum ratio were extracted. All included articles were assessed for risk of bias. RESULTS: In total, 42 studies were included in this systematic review. For the majority of antituberculosis drugs, including the first-line drugs ethambutol and pyrazinamide, no pharmacokinetic studies in saliva were found. For amikacin, pharmacokinetic studies without saliva-plasma or saliva-serum ratios were found. CONCLUSIONS: For gatifloxacin and linezolid, salivary therapeutic drug monitoring is likely possible due to a narrow range of saliva-plasma and saliva-serum ratios. For isoniazid, rifampicin, moxifloxacin, ofloxacin, and clarithromycin, salivary therapeutic drug monitoring might be possible; however, a large variability in saliva-plasma and saliva-serum ratios was observed. Unfortunately, salivary therapeutic drug monitoring is probably not possible for doripenem and amoxicillin/clavulanate, as a result of very low salivary drug concentrations. PMID- 29120972 TI - Comparison of Antifactor Xa and Activated Partial Thromboplastin Time Monitoring for Heparin Dosing in Vascular Surgery Patients: A Single-Center Retrospective Study. AB - BACKGROUND: Vascular surgery patients often require anticoagulation with intravenous unfractionated heparin monitored through antifactor Xa (anti-Xa) levels or the activated partial thromboplastin time (aPTT). This study compares the 2 monitoring strategies in terms of major bleeding events in the vascular surgery population. METHODS: This was a single-center, retrospective study that included patients treated with a pharmacy-managed heparin protocol monitored by either anti-Xa or aPTT after vascular surgery. The primary outcome was the percentage of patients experiencing major bleeding events after procedure. Secondary outcomes evaluated minor bleeding episodes, postprocedure packed red blood cell transfusions, and the incidence of thrombotic events. In a secondary analysis, simultaneously measured anti-Xa and aPTT values were identified and analyzed for discordance. RESULTS: Major bleeding occurred in 12/72 patients (17%) on the anti-Xa-monitored protocol versus 5/62 patients (8%) on the aPTT monitored protocol (P = 0.19). Minor bleeding episodes were documented in 10% of the patients in the anti-Xa group versus 6% in the aPTT group (P = 0.54). There were no significant differences between the 2 groups in packed red blood cell transfusions and thrombotic events. Of 109 pairs of simultaneously measured anti Xa and aPTT values, 39 pairs (36%) showed relatively high aPTT values compared with corresponding anti-Xa levels. Nine patients who had these discordant test results experienced bleeding while their heparin drip was titrated based on lower anti-Xa values. CONCLUSIONS: The use of anti-Xa levels for heparin titration showed higher rates of major bleeding complications in vascular surgery patients compared with aPTT monitoring, but no significant difference was identified in this study. Vascular surgery patients with relatively high aPTT to anti-Xa values may have an increased risk of bleeding complications when heparin is titrated based on anti-Xa levels. PMID- 29120973 TI - Acute Intoxications and Fatalities From Illicit Fentanyl and Analogues: An Update. AB - Illicit fentanyl and its analogues are very dangerous synthetic opioids, with high abuse potential and severe adverse effects including coma and death. They are used as adulterants in street heroin, cocaine, and methamphetamine, or as heroin substitutes sold to unaware users with a high risk of overdoses. Fentanyl and its analogues have also been identified in counterfeit medicinal products, such as oxycodone, hydrocodone, and alprazolam tablets, or as components of speedball mixtures together with cocaine or other stimulants. In recent years, a number of epidemics involving acute intoxications and deaths related to illicit fentanyl or its analogues have occurred in the United States, Europe, Canada, Australia, and Japan. In several cases, fatalities involved polysubstance use. A review of the most recent case reports or case series of acute intoxications and fatalities involving illicit fentanyl and its newest analogues is herein provided, together with the available information on intoxication symptoms, eventual death cause, and metabolites detected in different biological fluids and reported concentrations. PMID- 29120974 TI - Plasma 7-Hydroxymethotrexate Levels Versus Methotrexate to Predict Delayed Elimination in Children Receiving High-Dose Methotrexate. AB - BACKGROUND: The aim of this study was to investigate the correlation between 7 hydroxymethotrexate (7-OHMTX) and creatinine and to evaluate the predictive value of 7-OHMTX levels on delayed elimination at 24 and 48 hours. In addition, differences in methotrexate (MTX), 7-OHMTX levels, and MTX metabolism using the ratio MTX/7-OHMTX were determined according to age. METHODS: The authors included a total of 106 cycles, corresponding to 33 patients (mean age: 9.8 years, range: 2-18 years) suffering from acute lymphoblastic leukemia, non-Hodgkin lymphoma and osteosarcoma and receiving high-dose MTX (HD-MTX). Plasma MTX, 7-OHMTX, and creatinine at T24 and T48 hours were measured. RESULTS: Children older than 14 years had significantly higher MTX levels at T48 hours (1.25 versus 0.5 MUmol/L, P < 0.05) and a higher MTX/7-OHMTX ratio (0.63 versus 0.20, P < 0.05) than children younger than 6 years. Plasma 7-OHMTX at T24 and T48 hours was positively correlated with serum creatinine and creatinine ratio at T24 and T48 hours. MTX levels provided a better specificity and sensitivity at both 24 and 48 hours than 7-OHMTX to predict delayed MTX elimination. A MTX threshold close to 0.83 MUmol/L at T48 hours improved specificity from 58% to 82% and keeps sensitivity at 100%. The authors identified a cut-off at 65 MUmol/L for MTX at T24 hours with a good sensitivity (75%) and specificity above 50%. CONCLUSIONS: These results confirm the concentration-dependent nephrotoxicity of 7-OHMTX. Children older than 14 years old had a higher MTX levels at 48 hours and a higher MTX/7-OHMTX ratio, suggesting a faster metabolism in younger children. This study identified a higher and more specific MTX threshold at T48 hours compared to those currently used, and a new threshold at T24 hours. PMID- 29120975 TI - Refractive Error in a Sample of Black High School Children in South Africa. AB - SIGNIFICANCE: This study focused on a cohort that has not been studied and who currently have limited access to eye care services. The findings, while improving the understanding of the distribution of refractive errors, also enabled identification of children requiring intervention and provided a guide for future resource allocation. PURPOSE: The aim of conducting the study was to determine the prevalence and distribution of refractive error and its association with gender, age, and school grade level. METHODS: Using a multistage random cluster sampling, 1586 children, 632 males (40%) and 954 females (60%), were selected. Their ages ranged between 13 and 18 years with a mean of 15.81 +/- 1.56 years. The visual functions evaluated included visual acuity using the logarithm of minimum angle of resolution chart and refractive error measured using the autorefractor and then refined subjectively. Axis astigmatism was presented in the vector method where positive values of J0 indicated with-the-rule astigmatism, negative values indicated against-the-rule astigmatism, whereas J45 represented oblique astigmatism. RESULTS: Overall, patients were myopic with a mean spherical power for right eye of -0.02 +/- 0.47; mean astigmatic cylinder power was -0.09 +/- 0.27 with mainly with-the-rule astigmatism (J0 = 0.01 +/- 0.11). The prevalence estimates were as follows: myopia (at least -0.50) 7% (95% confidence interval [CI], 6 to 9%), hyperopia (at least 0.5) 5% (95% CI, 4 to 6%), astigmatism (at least -0.75 cylinder) 3% (95% CI, 2 to 4%), and anisometropia 3% (95% CI, 2 to 4%). There was no significant association between refractive error and any of the categories (gender, age, and grade levels). CONCLUSIONS: The prevalence of refractive error in the sample of high school children was relatively low. Myopia was the most prevalent, and findings on its association with age suggest that the prevalence of myopia may be stabilizing at late teenage years. PMID- 29120976 TI - Case Report: Masquerading Large-vessel Giant Cell Arteritis. AB - SIGNIFICANCE: Large-vessel giant cell arteritis (GCA) can be a diagnostic dilemma for the eye care provider because it may not involve the typical cranial arteries. When any of its potential ocular complications are diagnosed, it is important to consider this unusual form of GCA. PURPOSE: To report an unusual ophthalmic presentation of large-vessel GCA with sequential bilateral anterior ischemic optic neuropathy and branch retinal artery occlusion. METHODS: A 65-year old previously healthy woman experienced sequential bilateral anterior ischemic optic neuropathy with branch retinal artery occlusion in the absence of other signs and symptoms suggestive of cranial GCA. RESULTS: Extensive workup, including temporal artery biopsy, failed to demonstrate vascular inflammation suggestive of GCA or vascular abnormalities, such as atheromatous plaques, but coincidentally revealed a breast tumor, which was excised. Positron emission tomography scan was performed revealing distinct hypermetabolism of the thoracic and abdominal aorta consistent with large-vessel GCA, and corticosteroid therapy was initiated. CONCLUSIONS: Large-vessel GCA is an underdiagnosed and undertreated type of GCA that does not typically affect the cranial arteries but rather larger proximal aortic branches. When associated with ocular complications, it can be a puzzling diagnostic dilemma for the eye care provider. PMID- 29120977 TI - Use of A-scan Ultrasound and Optical Coherence Tomography to Differentiate Papilledema From Pseudopapilledema. AB - SIGNIFICANCE: Differentiating papilledema from pseudopapilledema reflecting tilted/crowded optic discs or disc drusen is critical but can be challenging. Our study suggests that spectral-domain optical coherence tomography (OCT) peripapillary retinal nerve fiber layer thickness and retrobulbar optic nerve sheath diameter (ONSD) measured by A-scan ultrasound provide useful information when differentiating the two conditions. PURPOSE: To evaluate the use of A-scan ultrasound and spectral-domain OCT retinal nerve fiber layer thickness (RNFLT) in differentiating papilledema associated with idiopathic intracranial hypertension from pseudopapilledema. METHODS: Retrospective cross-sectional analysis included 23 papilledema and 28 pseudopapilledema patients. Ultrasound-measured ONSD at primary gaze, percent change in ONSD at lateral gaze (30 degrees test), and peripapillary RNFLT were analyzed. Receiver operating characteristic curves were constructed using one eye from each subject. RESULTS: Compared with pseudopapilledema, papilledema eyes showed larger mean ONSD (5.4 +/- 0.6 vs. 4.0 +/- 0.3 mm, P < .0001), greater change of ONSD at lateral gaze (22.4 +/- 8.4% vs. 2.8 +/- 4.8%, P < .0001), and thicker retinal nerve fiber layer (219.1 +/- 104.6 vs. 102.4 +/- 20.1 MUm, P < .0001). Optic nerve sheath diameter and 30 degrees test had the greatest area under the receiver operating characteristic curve, 0.98 and 0.97, respectively; followed by inferior quadrant (0.90) and average RNFLT (0.87). All papilledema eyes with Frisen scale greater than grade II were accurately diagnosed by ONSD, 30 degrees test, or OCT. In mild papilledema (Frisen scale grades I and II, n = 15), area under the receiver operating characteristic curve remained high for ONSD (0.95) and 30 degrees test (0.93) but decreased to 0.61 to 0.71 for RNFLT. At 95% specificity, sensitivities for ONSD, 30 degrees test, and RNFLT were 91.3%, 91.3%, and 56.5%, respectively, for the entire papilledema group and 80.0%, 86.7%, and 13.3% for the mild papilledema subgroup. CONCLUSIONS: Retinal nerve fiber layer thickness can potentially be used to detect moderate to severe papilledema. A-scan may further assist differentiation of mild papilledema from pseudopapilledema. PMID- 29120979 TI - Asymmetries In Isometric Force-Time Charcteristics Are Not Detrimental To Change Of Direction Speed. AB - The purpose of this study was to determine the impact of between limb asymmetries in IMTP force-time characteristics on change of direction speed (CODS). Twenty multisport collegiate athletes (mean +/- SD: age: 21.0 +/- 1.9 years; mass: 78.7 +/- 8.9 kg; height: 1.77 +/- 0.04 m) performed three unilateral stance IMTP trials per limb and three modified 505 CODS trials each side to establish imbalances between left and right, and dominant (D) and non-dominant (ND) limbs. Limb dominance was defined as the limb that produced the highest isometric force time value or faster CODS performance. Paired sample t-tests and Hedges' g effect sizes revealed no significant differences in IMTP force-time characteristics and CODS performance between left and right limbs (p > 0.05, g <= 0.37). However, significant differences were observed between D and ND limbs for all IMTP force time characteristics and CODS performance (p < 0.001, g = 0.39-0.73). No significant correlations were observed between IMTP asymmetries and CODS asymmetry (p >= 0.380, r <= -0.35), and no significant differences were observed in CODS performance between athletes of lesser and greater IMTP asymmetries (p >= 0.10, g <= 0.76). Poor percentage agreements (40-60%) between like for like classifications of asymmetry (i.e. either both asymmetrical or both balanced) for CODS and IMTP force-time characteristics were demonstrated. Asymmetries in IMTP force-time characteristics and CODS performance were present; however, greater IMTP asymmetries had no detrimental impact on CODS performance and did not equate to greater asymmetries in CODS performance. Therefore, collegiate athletes with asymmetries within the range reported within this study (<=13%) should not experience detriments to CODS or faster performance from that limb during 180 degrees turns. PMID- 29120978 TI - Effect of Load Carriage on Tactical Performance in Special Weapons and Tactics Operators. AB - Thomas, JM, Pohl, MB, Shapiro, R, Keeler, J, and Abel, MG. Effect of load carriage on tactical performance in special weapons and tactics operators. J Strength Cond Res 32(2): 554-564, 2018-Special weapons and tactics (SWAT) operators are specially trained personnel that are required to carry equipment to perform high-risk tasks. Given the need to carry this equipment, it is important to understand the potentially deleterious effect that the additional load may have on tactical performance. Furthermore, it is important to identify physical fitness characteristics that are associated with the potential decrement in performance. Therefore, the purpose of this study was to evaluate the effect of load carriage on tactical physical ability and marksmanship and to identify fitness characteristics associated with any decrement in performance. Twelve male SWAT operators were timed while performing a simulated tactical test (STT) on a live firing range with (loaded condition) and without equipment (unloaded condition). A battery of physical fitness assessments were used to assess anaerobic and aerobic power, muscular endurance, strength, agility, and flexibility. Paired-samples t-tests were used to identify differences between STT conditions, and bivariate correlations were used to determine relationships between STT and fitness outcomes. Time to complete the STT in the loaded condition increased by 7.8% compared with the unloaded condition (p < 0.001). Nine of the 13 STT tasks were performed significantly slower in the loaded condition. Fatigue index (r = 0.64) and V[Combining Dot Above]O2peak (r = -0.62) were associated with the decrement in the overall STT time. Marksmanship was not different between load carriage conditions (p = 0.816). These findings indicate that resistance to anaerobic fatigue and aerobic power are related to the decrement in tactical performance produced by load carriage. PMID- 29120980 TI - Effect of Cold-Water Immersion on Elbow Flexors Muscle Thickness After Resistance Training. AB - Matos, F, Neves, EB, Rosa, C, Reis, VM, Saavedra, F, Silva, S, Tavares, F, and Vilaca-Alves, J. Effect of cold-water immersion on elbow flexors muscle thickness after resistance training. J Strength Cond Res 32(3): 756-763, 2018-Cold-water immersion (CWI) is commonly applied to speed up the recovery process after exercise. Muscle damage may induce a performance reduction and consequence of the intramuscular pressure induced by the muscular swelling. The aim of the study was to verify the CWI effects on muscle thickness (MT) behavior of the elbow flexors after a strength training (ST) protocol. Eleven men were submitted to an ST, performed in 2 different weeks. In one of the weeks, subjects experienced a passive recovery. In the other, subjects were submitted to a CWI (20 minutes at 5 10 degrees C). Ultrasound (US) images were taken before, after, as well as 24, 48, and 72 hours after exercise, to evaluate the MT. Muscle thickness in both exercise arm (EA) and control arm (CA) was significantly higher 48 and 72 hours after exercise when subjects were submitted to a passive recovery compared with the CWI (p = 0.029, p = 0.028, p = 0.009, and p = 0.001, 48 hours, 72 hours, EA, and CA, respectively). When each arm was analyzed with or without using CWI individually, significantly higher MT was observed in the EA with CWI: before exercise in relation to 72 hours after exercise (p = 0.042) and after exercise in relation to the other measurements (p = 0.003, p = 0.003, p = 0.038, and p < 0.0001, before exercise and 24, 48, 72 hours after exercise, respectively). The evaluation of MT by US provides evidence that CWI after ST (and 24 hours after exercise) may reduce muscle swelling in the postexercise days when compared with a passive recovery. Seems to be a paradox between the uses of CWI for an acute reduction of muscle swelling. PMID- 29120981 TI - Biomechanical Methods to Quantify Muscle Effort During Resistance Exercise. AB - Chiu, LZF. Biomechanical methods to quantify muscle effort during resistance exercise. J Strength Cond Res 32(2): 502-513, 2018-Muscle hypertrophy and strength adaptations elicited by resistance training are dependent on the force exerted by active muscles. As an exercise may use many muscles, determining force for individual muscles or muscle groupings is important to understand the relation between an exercise and these adaptations. Muscle effort-the amount of force or a surrogate measure related to the amount of force exerted during a task can be quantified using biomechanical methods. The purpose of this review was to summarize the biomechanical methods used to estimate muscle effort in movements, particularly resistance training exercises. These approaches include the following: (a) inverse dynamics with rigid body models, (b) forward dynamics and EMG-driven models, (c) normalized EMG, and (d) inverse dynamics with point-mass models. Rigid body models quantify muscle effort as net joint moments. Forward dynamics and EMG-driven models estimate muscle force as well as determine the effect of a muscle's action throughout the body. Nonlinear relations between EMG and muscle force and normalization reference action selection affect the usefulness of EMG as a measure of muscle effort. Point-mass models include kinetics calculated from barbell (or other implement) kinematics recorded using electromechanical transducers or measured using force platforms. Point-mass models only allow the net force exerted on the barbell or lifter-barbell system to be determined, so they cannot be used to estimate muscle effort. Data from studies using rigid body models, normalized EMG, and musculoskeletal modeling should be combined to develop hypotheses regarding muscle effort; these hypotheses should be verified by training interventions. PMID- 29120982 TI - Total and Segmental Body Composition Examination in Collegiate Football Players Using Multifrequency Bioelectrical Impedance Analysis and Dual X-ray Absorptiometry. AB - Raymond, CJ, Dengel, DR, and Bosch, TA. Total and segmental body composition examination in collegiate football players using multifrequency bioelectrical impedance analysis and dual X-ray absorptiometry. J Strength Cond Res 32(3): 772 782, 2018-The current study examined the influence of player position on the agreement between multifrequency bioelectrical impedance analysis (MfBIA) and dual X-ray absorptiometry (DXA) when assessing total and segmental percent body fat (BF%), fat mass (FM), and fat-free mass (FFM) in National Collegiate Athletic Association Division I collegiate football athletes. Forty-four male collegiate athletes (age = 19 +/- 1 year; height = 1.9 +/- 1.0 m; and body mass = 106.4 +/- 18.8 kg) participated. Player positions included: offensive linemen (OL; n = 7), tight ends (TE; n = 4), wide receivers (WR; n = 9), defensive linemen (DL; n = 6), defensive backs (DB; n = 8), linebackers (LB; n = 6), and running backs (RB; n = 4). Total and segmental body composition measured using MfBIA were compared with values obtained using DXA. Compared with DXA, MfBIA underestimated BF% (3.0 +/- 3.8%), total FM (2.5 +/- 4.3 kg), arm FM (0.4 +/- 0.8 kg), arm FFM (1.4 +/- 0.9 kg), leg FM (2.8 +/- 2.0 kg), and leg FFM (5.4 +/- 2.4 kg) (all p < 0.001; arm FM p = 0.002) and overestimated total FFM (-2.4 +/- 4.5 kg) (p < 0.001). Limits of agreement (LOAs) were: +/-7.39% (BF%), +/-8.50 kg (total FM), +/-1.50 kg (arm FM), +/-1.83 kg (arm FFM), +/-3.83 kg (leg FM), +/-4.62 kg (leg FFM), and +/-8.83 kg (total FFM). No significant differences were observed between devices for trunk FM (-0.3 +/- 3.0 kg; p = 0.565) and trunk FFM (0.4 +/- 2.4 kg; p = 0.278), with LOAs of +/-5.92 and +/-4.69 kg, respectively. Player position significantly affected all between-device mean body composition measurement differences (adjusted p <= 0.05), with OL demonstrating the greatest effect on each variable. Therefore, MfBIA does not seem accurate in examining between player body composition in college football players. PMID- 29120983 TI - Assessing Differences in Anthropometric and Fitness Characteristics Between Police Academy Cadets and Incumbent Officers. AB - Orr, RM, Dawes, JJ, Pope, R, and Terry, J. Assessing differences in anthropometric and fitness characteristics between police academy cadets and incumbent officers. J Strength Cond Res 32(9): 2641-2650, 2018-The physical fitness of police officers must be developed in new cadets and sustained in incumbent officers. The aims of this study were to profile and compare the anthropometric and fitness characteristics of police academy cadets and incumbent officers of varying ages from a single police force. Retrospective data for 84 police academy cadets (? = 66, mean age = 27.96 +/- 5.73 years; ? = 18, mean age = 30.50 +/- 5.76 years) and 80 incumbent police officers (? = 73, mean age = 39.43 +/- 8.28 years; ? = 7, mean age = 37.86 +/- 3.67 years) were compiled. Data included participant age, anthropometric (body mass, lean mass, and fat mass), and fitness measurements (1-minute push-up, 1-minute sit-up, 1 repetition maximum bench press, vertical jump, 300-m, and 1.5-mile run). Male cadets exhibited significantly lower fat mass than male officers (12.4 vs. 15.1 kg, p = 0.003). These differences were fully explained by the age differences between these groups (p = 0.046). Male cadets were more aerobically fit with greater muscular endurance than male officers (p < 0.001 for all measures). This difference was not explained by age differences (p > 0.80 for all measures). Male cadets also exhibited higher anaerobic fitness than male officers (p < 0.001). Age differences only partially explained this difference (p = 0.01). Female cadets exhibited greater upper-body strength and muscular endurance than female officers (p < 0.004 for all measures), independent of age. Being a police officer, rather than age progression, may largely account for observed lower levels of fitness in incumbent officers when compared with cadets. Formalized physical training programs for incumbent police officers are needed if their fitness is to be maintained and risk of cardiovascular disease minimized. PMID- 29120984 TI - Effects of Different Resistance Training Systems on Muscular Strength and Hypertrophy in Resistance-Trained Older Women. AB - Ribeiro, AS, Aguiar, AF, Schoenfeld, BJ, Nunes, JP, Cavalcanti, EF, Cadore, EL, and Cyrino, ES. Effects of different resistance training systems on muscular strength and hypertrophy in resistance-trained older women. J Strength Cond Res 32(2): 545-553, 2018-The purpose of this study was to investigate the effect of resistance training (RT) performed in a pyramid (PR) vs. constant (CT) load system on muscular strength and hypertrophy in resistance-trained older women. Thirty-three older women (69.7 +/- 5.9 years, 69.1 +/- 15.0 kg, 156.6 +/- 6.2 cm, and 28.1 +/- 5.4 kg.m) were randomized into 2 groups: one that performed RT with a CT load (n = 16) and another group that performed RT in an ascending PR fashion (n = 17). Outcomes included 1 repetition maximum (RM) tests and assessment of skeletal muscle mass estimated by dual-energy X-ray absorptiometry. The study lasted 32 weeks, with 24 weeks dedicated to preconditioning and 8 weeks for the actual experiment. The RT program was conducted 3 d.wk; the CT consisted of 3 sets of 8-12RM with same load across sets, whereas the PR consisted of 3 sets of 12/10/8RM with incremental loads for each set. A significant (p <= 0.05) change from pretraining to posttraining was observed for chest press total strength (CT: pre = 122.8 +/- 21.0 kg, post = 128.9 +/- 21.4 kg, effect size [ES] = 0.28; PR: pre = 120.5 +/- 22.8 kg, post = 125.8 +/- 22.9 kg, ES = 0.24) and muscle mass (CT: pre = 21.4 +/- 3.6 kg, post = 21.7 +/- 3.5 kg, ES = 0.09; PR: pre = 20.9 +/- 3.4 kg, post = 21.1 +/- 3.4 kg, ES = 0.06) without differences between groups. Results suggest that both systems are effective to improve strength and muscle growth, but PR is not superior to CT for inducing improvements in previously trained older women. PMID- 29120985 TI - Influence of Team Rating on Running Performance in Elite Gaelic Football. AB - Mangan, S, Malone, S, Ryan, M, Mc Gahan, J, Warne, J, Martin, D, O'Neill, C, Burns, C, and Collins, K. Influence of team rating on running performance in elite Gaelic football. J Strength Cond Res 32(9): 2584-2591, 2017-It is currently unknown how team rating influences running performance in Gaelic football. Global positioning system technologies were used to quantify match-running performance within 5 elite Gaelic football teams over a period of 5 years (2012-2016). In total 780 player data sets were collected over 95 matches. Running performance variables included total distance, high-speed distance (>=17 km.h), and the percentage of high-speed distance. Team ratings were determined objectively using the Elo rating system for Gaelic football. Reference team rating had trivial effects on total distance (p = 0.011, partial eta = 0.008) and high-speed distance (p = 0.011, partial eta = 0.008). Opposition team rating had small effects on total distance (p = 0.005, partial eta = 0.016) and high-speed distance (p = 0.001, partial eta = 0.020). Top-tier teams cover greater total distances and high-speed distance than lower tier teams. Players cover considerably less total distance and high-speed distance against tier-3 and tier 4 teams. Tier-1 players ran a significantly higher percentage of distance at high speed than players who played for tier-2 teams (p = 0.020). The competitive advantage of top-tier Gaelic football teams is closely linked with their ability to demonstrate a higher physical intensity than lower tier teams. PMID- 29120986 TI - Acute Capsaicin Supplementation Improves 1,500-m Running Time-Trial Performance and Rate of Perceived Exertion in Physically Active Adults. AB - de Freitas, MC, Cholewa, JM, Gobbo, LA, de Oliveira, JVNS, Lira, FS, and Rossi, FE. Acute capsaicin supplementation improves 1,500-m running time-trial performance and rate of perceived exertion in physically active adults. J Strength Cond Res 32(2): 572-577, 2018-The purpose of this study was to investigate the acute effect of capsaicin supplementation on performance, rate of perceived exertion (RPE), and blood lactate concentrations during short-duration running in physically active adults. Ten physically active men (age = 23.5 +/- 1.9 years, mass = 78.3 +/- 12.4 kg, and height = 177.9 +/- 5.9 cm) completed 2 randomized, double-blind trials: Capsaicin condition (12 mg) or a placebo condition. Forty-five minutes after supplement consumption, the participants performed a 1,500-m running time trial. Time (in seconds) was recorded. Blood lactate concentration was analyzed at rest, immediately after exercise, after 5, 10, and 30 minutes during recovery and the RPE was collected after exercise. The time was significantly (t = 3.316, p = 0.009) lower in the capsaicin (371.6 +/- 40.8 seconds) compared with placebo (376.7 +/- 39 seconds). Rate of perceived exertion was significantly (t = 2.753, p = 0.022) less in the capsaicin (18.0 +/- 1.9) compared with the placebo (18.8 +/- 1.3). Lactate increased across time for both conditions without significant differences between (p > 0.05). In summary, acute capsaicin supplementation improves middle distance running (1,500 m) performance and reduced RPE in physically active adults. PMID- 29120987 TI - Continuous and Accumulated Bouts of Cycling Matched by Intensity and Energy Expenditure Elicit Similar Acute Blood Pressure Reductions in Prehypertensive Men. AB - Fonseca, GF, Farinatti, PTV, Midgley, AW, Ferreira, A, de Paula, T, Monteiro, WD, and Cunha, FA. Continuous and accumulated bouts of cycling matched by intensity and energy expenditure elicit similar acute blood pressure reductions in prehypertensive men. J Strength Cond Res 32(3): 857-866, 2018-This study investigated differences in postexercise hypotension (PEH) after continuous vs. accumulated isocaloric bouts of cycling. Ten prehypertensive men, aged 23-34 years, performed 2 bouts of cycling at 75% oxygen uptake reserve, with total energy expenditures of 400 kcal per bout. One exercise bout was performed continuously (CONTIN) and the other as 2 smaller bouts each expending 200 kcal (INTER1 and INTER2). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and cardiac autonomic control were monitored in a supine position for 10 minutes before and 60 minutes after each exercise bout, and during a control session. Compared with control, blood pressure was significantly reduced after CONTIN (SBP: [INCREMENT] - 3.4 mm Hg, p < 0.001; MAP: [INCREMENT] - 2.5 mm Hg, p = 0.001), INTER1 (SBP: [INCREMENT] - 2.2 mm Hg, p = 0.045), and INTER2 (SBP: [INCREMENT] - 4.4 mm Hg, p < 0.001; DBP: [INCREMENT] - 2.7 mm Hg, p = 0.045; MAP: [INCREMENT] - 3.3 mm Hg, p = 0.001). The PEH was similar in CONTIN and INTER2, whereas INTER2 elicited greater PEH than INTER1 (SBP and MAP: [INCREMENT] - 2.0 and [INCREMENT] - 1.8 mm Hg, respectively, p <= 0.05). Increases in sympathovagal balance from baseline were inversely related to changes in SBP and DBP after CONTIN and INTER2 (r = -0.64 to -0.71; p = 0.021 0.047). These findings indicate that similar amounts of PEH are observed when exercise is performed as a single 400-kcal exercise bout or 2 * 200-kcal bouts and that the exercise recovery pattern of cardiac autonomic activity may be important in eliciting PEH. PMID- 29120988 TI - Measuring Vertical Stiffness in Sport With Accelerometers: Exercise Caution! AB - Eggers, TM, Massard, TI, Clothier, PJ, and Lovell, R. Measuring vertical stiffness in sport with accelerometers: Exercise caution! J Strength Cond Res 32(7): 1919-1922, 2018-This study aimed to determine the measurement accuracy of triaxial accelerometers, to determine vertical stiffness (Kvert) during overground running, and to examine the influence of device location. Seventeen healthy adults wore 2 triaxial accelerometers (positioned between scapulae and at lumbar spine) during a 2-minute continuous 20-m shuttle run (12 km.h), which was repeated 7 days later. Accelerometer-derived Kvert data were compared with that calculated from corresponding force-plate ground contacts (criterion measure). Moderate correlations (r = 0.65-0.66) between the accelerometer and criterion measure were identified, irrespective of unit location. However, accelerometer determined Kvert had questionable reliability in both positions (intraclass correlation coefficient = 0.70-0.71). These results suggest caution be taken when using accelerometer-derived Kvert during overground running. PMID- 29120989 TI - Validity and Reliability of a New Test of Planned Agility in Elite Taekwondo Athletes. AB - Chaabene, H, Negra, Y, Capranica, L, Bouguezzi, R, Hachana, Y, Rouahi, MA, and Mkaouer, B. Validity and reliability of a new test of planned agility in elite taekwondo athletes. J Strength Cond Res 32(9): 2542-2547, 2018-This study aimed to examine the validity, reliability, and sensitivity of a new test of planned agility in elite taekwondo athletes and to establish its relationship with sprint time, jumping ability, and dynamic balance. Twenty-seven (20 males and 7 females) taekwondo athletes participated in this study. They performed taekwondo-specific agility test (TSAT) in 2 occasions (i.e., test-retest). In addition, they performed jumping ability (i.e., squat jump, countermovement jump, standing long jump, and 3-hop jump), sprint-time (5- and 20-m dash), and dynamic balance (i.e., Y-test) tests along with a planned agility test (i.e., T-test). To establish TSAT's construct validity, 2 subgroups were identified based on their international and national taekwondo results: top elite (9 males and 2 females) and elite (11 males and 2 females). Taekwondo-specific agility test showed high relative and absolute reliability as well as a good ability to detect small and meaningful performance change. Top-elite athletes showed greater (p < 0.001) TSAT performances (4.5 +/- 0.4 seconds) compared with their elite (5.3 +/- 0.4 seconds) counterparts. Receiving operating characteristic (ROC) analysis showed that TSAT was able to discriminate athletes of different competitive level as revealed by an area under the ROC curve of 0.94 (95% confidence interval: 0.76 0.99). Taekwondo-specific agility test demonstrated significant association with the T-test (r = 0.71; shared variance = 50%), which is considered as a gold standard planned agility test. In addition, results showed moderate-to-large associations between TSAT and jumping ability, sprint-time, and dynamic balance tests. The TSAT might be considered as a valid and reliable test to evaluate specific agility of taekwondo athletes. PMID- 29120990 TI - Re: "Correction of Lower Eyelid Retraction Using Acellular Human Dermis During Orbital Decompression". PMID- 29120991 TI - Reply re: "Correction of Lower Eyelid Retraction Using Acellular Human Dermis During Orbital Decompression". PMID- 29120992 TI - Lower Eyelid Retraction Associated With Topical Retinol Use. PMID- 29120993 TI - Restless legs syndrome and nocturnal leg cramps: a review and guide to diagnosis and treatment. AB - Restless legs syndrome (RLS) and nocturnal leg cramps (NLCs) are common disorders affecting 7.0% and 24.1% of the population in some European countries, respectively. Patients suffering from RLS experience uncomfortable nocturnal sensations in the legs with the urge to move that dissipates while moving. NLC is characterized by abrupt muscle contraction, most often in the gastrocnemius or foot muscles, which occurs at night and may result in significant sleep disturbances. The diagnosis of these disorders has presented a challenge to health care providers because of symptom overlap with other sensory and motor disturbances with nocturnal predominance. Treatment options and approaches are lacking, partially because of our currently incomplete understanding of the pathophysiological mechanisms underlying these conditions. We reviewed the medical literature to provide a comprehensive assessment of RLS and NLC with a focus on improved diagnostic accuracy and treatment approaches. PMID- 29120994 TI - Inhaled Corticosteroids in Asthma: Promoting or Protecting Against Atherosclerosis? AB - BACKGROUND Bronchial asthma is an inflammatory disease of the respiratory system. However, it may also induce systemic effects. Although reports suggest patients with asthma are at increased risk of cardiovascular events, the association between asthma and atherosclerosis is unclear. The aim of the present study was to compare the progression of atherosclerosis between patients with asthma treated with inhaled corticosteroids and healthy controls. MATERIAL AND METHODS In 102 adult patients with asthma, markers of arterial stiffness (pulse wave velocity and augmentation index) were evaluated by applanation tonometry. Structural atherosclerotic changes (intima-media complex thickness and presence of atherosclerotic plaque) were assessed sonographically. Lipid profile and fasting glucose level were measured. Clinical data concerning the course of asthma, its severity, and management strategy were obtained. A group of 102 healthy, age-matched controls were examined according to the same protocol. RESULTS The majority of patients presented well-controlled asthma of moderate severity. When adjusted for weight, age, and systolic blood pressure, no significant differences were observed in pulse wave velocity, in augmentation index, or in intima-media complex thickness between groups. In controls, atherosclerotic plaque occurred significantly more often than in patients with asthma (p=0.0226). Moreover, in patients with asthma, the intima-media complex thickness of the right common carotid artery was significantly correlated with forced expiratory volume in 1 second (R2=-0.2951, p=0.0083). There was no significant difference in any of the atherosclerosis markers between different types and doses of administered inhaled corticosteroids. CONCLUSIONS Patients with bronchial asthma presented a decreased risk of atherosclerosis in comparison to healthy controls. PMID- 29120996 TI - Announcement: National Chronic Obstructive Pulmonary Disease Awareness Month - November 2017. PMID- 29120995 TI - Surveillance for Lyme Disease - United States, 2008-2015. AB - PROBLEM/CONDITION: Lyme disease is the most commonly reported vectorborne disease in the United States but is geographically focal. The majority of Lyme disease cases occur in the Northeast, mid-Atlantic, and upper Midwest regions. Lyme disease can cause varied clinical manifestations, including erythema migrans, arthritis, facial palsy, and carditis. Lyme disease occurs most commonly among children and older adults, with a slight predominance among males. REPORTING PERIOD: 2008-2015. DESCRIPTION OF SYSTEM: Lyme disease has been a nationally notifiable condition in the United States since 1991. Possible Lyme disease cases are reported to local and state health departments by clinicians and laboratories. Health department staff conduct case investigations to classify cases according to the national surveillance case definition. Those that qualify as confirmed or probable cases of Lyme disease are reported to CDC through the National Notifiable Diseases Surveillance System. States with an average annual incidence during this reporting period of >=10 confirmed Lyme disease cases per 100,000 population were classified as high incidence. States that share a border with those states or that are located between areas of high incidence were classified as neighboring states. All other states were classified as low incidence. RESULTS: During 2008-2015, a total of 275,589 cases of Lyme disease were reported to CDC (208,834 confirmed and 66,755 probable). Although most cases continue to be reported from states with high incidence in the Northeast, mid Atlantic, and upper Midwest regions, case counts in most of these states have remained stable or decreased during the reporting period. In contrast, case counts have increased in states that neighbor those with high incidence. Overall, demographic characteristics associated with confirmed cases were similar to those described previously, with a slight predominance among males and a bimodal age distribution with peaks among young children and older adults. Yet, among the subset of cases reported from states with low incidence, infection occurred more commonly among females and older adults. In addition, probable cases occurred more commonly among females and with a higher modal age than confirmed cases. INTERPRETATION: Lyme disease continues to be the most commonly reported vectorborne disease in the United States. Although concentrated in historically high-incidence areas, the geographic distribution is expanding into neighboring states. The trend of stable to decreasing case counts in many states with high incidence could be a result of multiple factors, including actual stabilization of disease incidence or artifact due to modifications in reporting practices employed by some states to curtail the resource burden associated with Lyme disease surveillance. PUBLIC HEALTH ACTION: This report highlights the continuing public health challenge of Lyme disease in states with high incidence and demonstrates its emergence in neighboring states that previously experienced few cases. Educational efforts should be directed accordingly to facilitate prevention, early diagnosis, and appropriate treatment. As Lyme disease emerges in neighboring states, clinical suspicion of Lyme disease in a patient should be based on local experience rather than incidence cutoffs used for surveillance purposes. A diagnosis of Lyme disease should be considered in patients with compatible clinical signs and a history of potential exposure to infected ticks, not only in states with high incidence but also in areas where Lyme disease is known to be emerging. These findings underscore the ongoing need to implement personal prevention practices routinely (e.g., application of insect repellent and inspection for and removal of ticks) and to develop other effective interventions. PMID- 29120997 TI - Waterborne Disease Outbreaks Associated With Environmental and Undetermined Exposures to Water - United States, 2013-2014. AB - Waterborne disease outbreaks in the United States are associated with a wide variety of water exposures and are reported annually to CDC on a voluntary basis by state and territorial health departments through the National Outbreak Reporting System (NORS). A majority of outbreaks arise from exposure to drinking water (1) or recreational water (2), whereas others are caused by an environmental exposure to water or an undetermined exposure to water. During 2013 2014, 15 outbreaks associated with an environmental exposure to water and 12 outbreaks with an undetermined exposure to water were reported, resulting in at least 289 cases of illness, 108 hospitalizations, and 17 deaths. Legionella was responsible for 63% of the outbreaks, 94% of hospitalizations, and all deaths. Outbreaks were also caused by Cryptosporidium, Pseudomonas, and Giardia, including six outbreaks of giardiasis caused by ingestion of water from a river, stream, or spring. Water management programs can effectively prevent outbreaks caused by environmental exposure to water from human-made water systems, while proper point-of-use treatment of water can prevent outbreaks caused by ingestion of water from natural water systems. PMID- 29120999 TI - Erratum: Vol. 66, No. 34. PMID- 29120998 TI - QuickStats: Percentage* of Children and Teens Aged 6-17 Years Who Missed >10 Days of School in the Past 12 Months Because of Illness or Injury,? by Serious Emotional or Behavioral Difficulties StatusS and Age Group - National Health Interview Survey, 2014-2016 . AB - During 2014-2016, children aged 6-17 years whose parent or guardian indicated the child had serious emotional or behavioral difficulties (EBDs) were almost four times as likely to miss >10 days of school because of illness or injury compared with children without serious EBDs (13.4% compared with 3.5%). Among children with serious EBDs, those aged 6-10 years were less likely (8.0%) to miss >10 days of school compared with children aged 11-14 years (15.6%) and children aged 15-17 years (19.5%). Among children without serious EBDs those aged 15-17 years (4.7%) were more likely to miss >10 school days compared with children aged 6-10 years (3.0%) and children aged 11-14 years (3.3%). PMID- 29121000 TI - Meeting Summary: State and Local Implementation Strategies for Increasing Access to Contraception During Zika Preparedness and Response - United States, September 2016. AB - Zika virus infection during pregnancy is a cause of microcephaly and other serious brain abnormalities (1). To support state and territory response to the threat of Zika, CDC's Interim Zika Response Plan outlined activities for vector control; clinical management of exposed pregnant women and infants; targeted communication about Zika virus transmission among women and men of reproductive age; and primary prevention of Zika-related adverse pregnancy and birth outcomes by prevention of unintended pregnancies through increased access to contraception.* The most highly effective,? reversible contraception includes intrauterine devices and implants, known as long-acting reversible contraception (LARC). On September 28, 2016, the Association of Maternal and Child Health Programs (AMCHP) and CDC facilitated a meeting in Atlanta, Georgia, of representatives from 15 states to identify state-led efforts to implement seven CDC-published strategies aimed at increasing access to contraception in the context of Zika virus (2). Qualitative data were collected from participating jurisdictions. The number of states reporting implementation of each strategy ranged from four to 11. Participants identified numerous challenges, particularly for strategies implemented less frequently. Examples of barriers were discussed and presented with corresponding approaches to address each barrier. Addressing these barriers could facilitate increased access to contraception, which might decrease the number of unintended pregnancies affected by Zika virus. PMID- 29121001 TI - Tobacco Product Use Among Adults - United States, 2015. AB - Tobacco use remains the leading cause of preventable disease and death in the United States (1). Despite declining cigarette smoking prevalence among U.S. adults, shifts in the tobacco product landscape have occurred in recent years (2,3). Previous estimates of tobacco product use among U.S. adults were obtained from the National Adult Tobacco Survey, which ended after the 2013-2014 cycle. This year, CDC and the Food and Drug Administration (FDA) assessed the most recent national estimates of tobacco product use among adults aged >=18 years using, for the first time, data from the 2015 National Health Interview Survey (NHIS), an annual, nationally representative, in-person survey of the noninstitutionalized U.S. civilian population. The 2015 NHIS adult core questionnaire included 33,672 adults aged >=18 years, reflecting a 55.2% response rate. Data were weighted to adjust for differences in selection probability and nonresponse, and to provide nationally representative estimates. In 2015, 20.1 % of U.S. adults currently (every day or some days) used any tobacco product, 17.6% used any combustible tobacco product, and 3.9% used >=2 tobacco products. By product, 15.1% of adults used cigarettes; 3.5% used electronic cigarettes (e cigarettes); 3.4% used cigars, cigarillos, or filtered little cigars; 2.3% used smokeless tobacco; and 1.2% used regular pipes, water pipes, or hookahs.* Current use of any tobacco product was higher among males; persons aged <65 years; non Hispanic American Indian/Alaska natives (AI/AN), whites, blacks, and persons of multiple races; persons living in the Midwest; persons with a General Educational Development (GED) certificate; persons with annual household income of <$35,000; persons who were single, never married, or not living with a partner or divorced, separated, or widowed; persons who were insured through Medicaid or uninsured; persons with a disability; and persons who identified as lesbian, gay, or bisexual (LGB). Current use of any tobacco product was 47.2% among adults with serious psychological distress compared with 19.2% among those without serious psychological distress. Proven population-level interventions that focus on the diversity of tobacco product use are important to reducing tobacco-related disease and death in the United States (1). PMID- 29121002 TI - Announcement: U.S. Antibiotic Awareness Week - November 13-19, 2017. PMID- 29121003 TI - Surveillance for Waterborne Disease Outbreaks Associated with Drinking Water - United States, 2013-2014. AB - Provision of safe water in the United States is vital to protecting public health (1). Public health agencies in the U.S. states and territories* report information on waterborne disease outbreaks to CDC through the National Outbreak Reporting System (NORS) (https://www.cdc.gov/healthywater/surveillance/index.html). During 2013-2014, 42 drinking water-associated? outbreaks were reported, accounting for at least 1,006 cases of illness, 124 hospitalizations, and 13 deaths. Legionella was associated with 57% of these outbreaks and all of the deaths. Sixty-nine percent of the reported illnesses occurred in four outbreaks in which the etiology was determined to be either a chemical or toxin or the parasite Cryptosporidium. Drinking water contamination events can cause disruptions in water service, large impacts on public health, and persistent community concern about drinking water quality. Effective water treatment and regulations can protect public drinking water supplies in the United States, and rapid detection, identification of the cause, and response to illness reports can reduce the transmission of infectious pathogens and harmful chemicals and toxins. PMID- 29121004 TI - Country Immunization Information System Assessments - Kenya, 2015 and Ghana, 2016. AB - The collection, analysis, and use of data to measure and improve immunization program performance are priorities for the World Health Organization (WHO), global partners, and national immunization programs (NIPs). High quality data are essential for evidence-based decision-making to support successful NIPs. Consistent recording and reporting practices, optimal access to and use of health information systems, and rigorous interpretation and use of data for decision making are characteristics of high-quality immunization information systems. In 2015 and 2016, immunization information system assessments (IISAs) were conducted in Kenya and Ghana using a new WHO and CDC assessment methodology designed to identify root causes of immunization data quality problems and facilitate development of plans for improvement. Data quality challenges common to both countries included low confidence in facility-level target population data (Kenya = 50%, Ghana = 53%) and poor data concordance between child registers and facility tally sheets (Kenya = 0%, Ghana = 3%). In Kenya, systemic challenges included limited supportive supervision and lack of resources to access electronic reporting systems; in Ghana, challenges included a poorly defined subdistrict administrative level. Data quality improvement plans (DQIPs) based on assessment findings are being implemented in both countries. IISAs can help countries identify and address root causes of poor immunization data to provide a stronger evidence base for future investments in immunization programs. PMID- 29121005 TI - De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy. AB - PurposeAs part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.MethodsWe compiled and analyzed exome sequence data from 54 genetically undiagnosed trios using a validated analysis pipeline. We evaluated the significance of the genetic findings by reanalyzing sequence data generated at Ambry Genetics, and from a number of additional case and control cohorts.ResultsIn 54 previously undiagnosed trios, we identified two de novo missense variants in SCN8A in the highly expressed alternative exon 5 A-an exon only recently added to the Consensus Coding Sequence database. One additional undiagnosed epilepsy patient harboring a de novo variant in exon 5 A was found in the Ambry Genetics cohort. Missense variants in SCN8A exon 5 A are extremely rare in the population, further supporting the pathogenicity of the de novo alterations identified.ConclusionThese results expand the range of SCN8A variants in epileptic encephalopathy patients and illustrate the necessity of ongoing reanalysis of negative exome sequences, as advances in the knowledge of disease genes and their annotations will permit new diagnoses to be made. PMID- 29121007 TI - Third-quarter biotech job picture. PMID- 29121009 TI - Around the world in a month. PMID- 29121006 TI - Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS: results of the TRIDENT study. AB - PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (59 years a er admission to the hospital ward. Data from medical history about diseases, taken medicines, falls, length of hospital stay and mortality were compared in patients with ISAR score of 0-1 and over 1 and in subjects with and without history of falls. Regression analysis was used to detect predictors of the length of hospital stay or death. RESULTS: The sample consisted of 102 subjects aged 80.9 +/- 7.9 years, 45.5% of men, 34.6% had history of falls. The number of diseases was 11.3 +/- 3.9 and number of medicines - 8.9 +/- 3.7. The score of ISAR >=2 was found in 90.2% of patients, length of hospital stay was 10.3 +/- 8.4 days, mortality rate was 9.9%. Patients with ISAR score <2 were younger, showed a smaller number of diseases, used less drugs and had less frequency of falls than those with score >=2. Patients with history of falls had higher mean ISAR score, higher number of diseases and medicines than the others. The increased number of diseases and higher ISAR score significantly influenced the length of hospital stay. None of the analyzed factors had any impact on mortality. CONCLUSION: The score of ISAR scale together with number of diseases have a positive impact on the length of hospital stay. PMID- 29121034 TI - The impact of advanced opioid drugs and analgesic adjuvants on murine macrophage oxygen burst. AB - Macrophages (Mf) are a versatile group of phagocytic cells responsible for fulfilling a variety of immune functions, most notably for mounting the initial anti-microbial response and for the clearance of cellular debris and apoptotic bodies. The key processes for fulfilling these functions include the production of reactive oxygen intermediates (ROIs) and nitric oxide (NO). Mf also express a variety of receptors, including opioid, serotonin, and norepinephrine receptors, and thus can react to various substances. Our study aimed to examine the effects of oxycodone and buprenorphine on the production ROIs and NO by Mf from intraperitoneally-treated mice, as compared to the previously studied morphine, fentanyl, and methadone, as well as the effects of the analgesic adjuvants gabapentin, amitriptyline, and venlafaxine. ROIs was estimated via luminol and lucigenin dependent chemiluminescence assay, and NO secretion was estimated via a colorimetric method utilizing a modified Griess reaction. We observed an overall decrease in both ROIs and NO production by Mf from adjuvant-treated mice, especially with amitriptyline. Opioids, however, resulted in enhanced ROIs production and mixed NO secretion, with oxycodone and buprenorphine have the least immunomodulatory effects. As ROIs and NO are potent mediators of Mf activity during the innate immune response, our current results express great translational potential. Our results suggest that OPs administration may boost Mf anti-microbial response. On the other hand, during sterile in ammation, enhanced generation of ROIs by Mf influenced by opioids may increase the risk of tissue damage, but co-administration of adjuvants could abolish this adverse effect. PMID- 29121035 TI - Ischemic conditioning of human heart muscle depends on opioid-receptor system. AB - BACKGROUND: Despite progress in the invasive treatment of ischemic heart disease, the ability to limit ischemia-reperfusion (I/R) injury remains largely unrealized. Ischemic pre-conditioning (IPC) and post-conditioning (POC) induce the protective mechanisms of resistance against I/R injury. Stimulation of opioid receptors mimic the protective effect of IPC or POC in an animal models. We tested the hypothesis, that IPC and POC provide cardioprotection in opioid dependent mechanism in human myocardium. METHODS: Human atrial trabeculae were subjected to I/R injury. To achieve IPC, single hypoxia period preceded the applied lethal hypoxia, to achieve POC triple hypoxia periods followed lethal hypoxia. Naloxone was used at the onset of lethal hypoxia in IPC protocol, and at the time of re-oxygenation in POC protocol. Contractive function of the myocardium was assessed as maximal force of contraction (Amax), rate of rise of force of contraction (+dV/dT) and diastolic parameter - rate of decay of force of contraction (-dV/dT). RESULTS: Co-application of naloxone with IPC or POC resulted in decrease of Amax, +dV/dT and -dV/dT during re-oxygenation period as compared to IPC or POC only. CONCLUSIONS: Naloxone abrogates beneficial effect of IPC and POC. IPC and POC in humans provide cardioprotection in opioid receptor system dependent mechanism. PMID- 29121036 TI - Correlation based analysis of sEMG signals during complex muscle activity. Feasibility study of new methodology. AB - Assessment of complex motor task (CMT) competency is still very prone to bias. Objective assessment is based either on outcomes leaving the process out of the equitation or on checklists with all their limitations. We tested the hypothesis that muscular recruitment patterns assessed with surface Electromyography (sEMG) will be different between novices and skilled trainees. sEMG signals of the muscles that potentially are characterized by the highest level of engagement at complex motor task were submitted to comprehensive correlation analysis. Standard methods of estimating the correlation coefficients were compared with more advanced analysis including cross-wavelet coherence and calculation of mutual information. We conclude that with appropriate analytical tools it is possible to compare sEMG signals during complex motor tasks and that at least on our very small sample it differs between individuals. PMID- 29121037 TI - Transient testicular torsion: from early diagnosis to appropriate therapeutic intervention (a prospective clinical study). AB - Transient testicular torsion (TTT) occurs when the torsion of the spermatic cord is reversed automatically within few minutes, with subsequent restoration of the blood ow to the suffering testis. e main clinical manifestation is acute scrotal pain, which resolves within a short period of time, usually few minutes. In 25% of patients su er from nausea and vomiting, besides the scrotal discomfort. Episodes of torsion can be repeated 1-30 times, leading progressively to development of ischemic trauma of the testis, while in 30-61% of all cases they constitute a precursor of testicular torsion. From January, 2016 to December, 2016, 11 patients in total were admitted to the Emergency Department due to acute scrotal pain that lasted a few minutes (1-5 minutes in most), which had already elapsed at the time of their admission, accompanied with nausea in all patients and vomiting in 5 of them. No swelling or rubor of the scrotum was revealed during physical examination, while in 9 patients it was observed that the suffering testis had transverse orientation. Ultrasonography was negative for pseudotumor or Whirlpool sign, while transverse orientation of the testis was confirmed in 9 patients. All the patients underwent surgical investigation of the suffering hemiscrotum, while Bell Clapper Deformity was found in 9 patients. Fixation of the suffering testis to the mesoscrotal diaphragm with 3 separate sutures by using non-absorbable suture followed. By the same surgical approach, the contralateral hemiscrotum was also investigated. Bilateral high adhesion of the tunica vaginalis was found in 8 out of 9 patients, in whom preventive unilateral orchidopexy was performed. All the patients are followed-up on a 6 month basis, without report of a similar, transient episode of acute scrotal pain. TTT should always be included in differential diagnosis in cases of acute scrotal pain in the past, with transverse orientation of the suffering testis. Prompt diagnosis and early treatment of the subject anatomic deformity (Bell Clapper Deformity) prevents the ischemic consequences on testicular parenchyma due to either recurrent episode of TTT or as a consequence of intravaginal testicular torsion. PMID- 29121038 TI - Is mean platelet volume a good predictor of sustained response to one year infliximab therapy in pediatric patients with Crohn's disease? AB - Over the past years, there is a growing number of newly diagnosed pediatric patients with Crohn's disease (CD). Severe course of CD often requires biological treatment with Infliximab (IFX). Loss of response to biological treatment is a major problem. Mean platelet volume (MPV) was reported as a good marker of sustained response to IFX therapy in adults. This study is to determine whether MPV measured prior to IFX therapy and a er its third dose can be used as a predictive marker of sustained response to biological therapy in children with severe course of CD. 43 pediatric patients with CD who underwent IFX therapy were enrolled into this study. The clinical response was evaluated after the third dose and after one year of IFX treatment (sustained response). The MPV values at baseline and week 14 were compared to the patients with good response to IFX to those with loss of the response. During 52-week IFX therapy, 2 out of 43 patients enrolled in the study did not achieve primary response a er the third dose, another 18 children lost their response to the above therapy a er one year. There was no significant association between baseline and 14th week values of MPV between patients with the sustained response to those with loss of response. In opposite to adult patients, MPV cannot be regarded as predictive factor of sustained response to IFX treatment in pediatric patients. PMID- 29121039 TI - The prevalence and determinants of multimorbidity in hospitalized patients with heart failure. AB - OBJECTIVE: The aim of this study was to assess the prevalence of multimorbidity and co-existed diseases in hospitalized patients with heart failure (HF) in relation to age and gender. METHODS: The nationwide cross-sectional survey had been conducted in Poland (April-November 2013), in 260 randomly selected hospital wards. A trained nurse contacted with one physician, drawn from the list of all doctors working in the selected hospital's wards, who completed the study questionnaires regarding to clinical characteristics of the last five HF patients, who were discharged from an internal or cardiology ward. RESULTS: Mean age +/- SD of the patients was 72.1 +/- 10.1 years, 50% were female but the women were significantly older than men. Criterion of multimorbidity met almost 100% of the HF patients. There were no significant differences in the number of co existed cardiovascular (CV) and non-CV diseases according to gender, but different clinical profile of HF men and women was observed. Women more frequently had thyroid disease, peripheral artery disease and cognitive impairment, whereas men was characterized by higher prevalence of cardiac, pulmonary and hepatic diseases. The co-morbidity significantly increased with age, notably due to increasing prevalence of non-CV diseases. Diabetes, chronic kidney disease, hypercholesterolemia and anemia were the most common non-CV diseases. Among HF patients, 83% suffered from three or more co-morbidities. CONCLUSIONS: The study confirms, that multimorbidity is a considerable problem in patients with HF. Besides age, multimorbidity pattern is strongly dependent on gender. The multidisciplinary approach is warranted in particular in elderly subjects who su er from HF. PMID- 29121040 TI - Ossification of the petrosphenoid ligament - a case study. AB - The current study presents a case in which a human skull revealed a partially ossified petrosphenoid ligament. The ossified ligament appears as a hooked bony trabecula emerging below the right posterior clinoid process. Another bony trabecula arises from the petrous apex and runs towards the clivus. Both trabecula face each other but do not fuse, having a small gap between their tips. Their positions clearly indicate that they must have formed an overhang above the abducens nerve. Therefore, they should be considered a part of the walls of Dorello's canal, which is a conduit for the abducens nerve and associated vascular structures. PMID- 29121041 TI - The incidence rate of surgical interventions in patients with Crohn's disease treated with anti-tumour necrosis factor biologics. AB - BACKGROUND: Anti-tumour necrosis factor alpha drugs (anti-TNF-alpha) effectively reduce the risk of surgery in Crohn's disease (CD). Unsatisfactory response to anti-TNF-alpha agents leads to the development of disease complications in a great percentage of patients. Simultaneously, possible predictive factors for ares during biological treatment remain uncertain. AIMS: To investigate the incidence rate of intestinal resection during biological treatment and search for predicting factors for ares demanding a surgical intervention. METHODS: A retrospective study of 68 patients qualified for anti-TNF-alpha therapy. The data consisting of demographic details, disease duration and laboratory results before the first drug administration and at the post induction period were collected. The association between these parameters and loss of response (LOR) demanding a surgical intervention was evaluated. RESULTS: LOR to the anti-TNF-alpha therapy was observed in 10/68 patients (14.7%). Mean disease duration at initiation of therapy was statistically longer in operated patients (8.8 +/- 2.04 y vs. 4.93 +/ 4.29 y; p < 0.02). That group revealed higher CRP values in post induction period compared to group with sustained response (48.24 +/- 61.99 mg/l vs. 7.29 +/- 13.43 mg/l; p < 0.05), contrary to hematocrit levels, which were lower in this group at each point of the study (30.58 +/- 6.19% vs. 36.69 +/- 16.0%; p = 0.04) (18.62 +/- 18.19% vs. 40.27 +/- 4.72%; p < 0.05) (4.01 +/- 0.9 x106/MUl; p = 0.009) (40.27 +/- 4.72 g/dl vs. 18.62 +/- 18.19 g/dl; p < 0.05). CDAI was significantly higher at post induction evaluation in the group with LOR (260.75 +/- 98.1 vs. 118.12 +/- 4.59; p < 0.05). CONCLUSION: CRP and CDAI, expressing in ammation severity, RBC, Hgb, Hct and the disease duration may serve as predictive factors for LOR to biological therapy. PMID- 29121042 TI - Polish translation of the Anatomical Quality Assurance (AQUA) Checklist: new guidelines for reporting in original anatomical studies. AB - Recently, an improvement of the quality of reporting and methodology in original research has been observed. Major fields in research have introduced checklists aimed at promoting clear and univocal reporting of methods and results. The basis of evidence-based medicine (EBM) lies in transparent reporting of primary studies. Although clinical research progressed rapidly into evidence-based guidelines, the basic sciences, including anatomy, just recently started to use the rules of EBM. No anatomy-specific standardized research checklist has been introduced so far. Evidence-based anatomy (EBA) emerged as a new approach to research in anatomy that incorporates methods, such as meta-analysis and systematic review. High quality methodology and clear reporting of results of original studies are the basis of EBA. The Anatomical Quality Assurance (AQUA) Checklist is a new tool aimed to introduce univocal reporting of original anatomical studies. The checklist consists of 29 reporting items, which are essential in obtaining unambiguous and high-quality reporting of methods and results and ensuing straightforward interpretation and reproducibility. The AQUA Checklists been endorsed by anatomical associations, including the International Federation of Associations of Anatomists. Therefore, the authors of this study believe that introduction of the Polish version of AQUA Checklist into practice will improve the quality of original anatomical studies in Poland and will promote the EBA standards for years to come. PMID- 29121043 TI - The poverty-related neglected diseases: Why basic research matters. AB - Together, malaria and the neglected tropical diseases (NTDs) kill more than 800,000 people annually, while creating long-term disability in millions more. International support for mass drug administration, bed nets, and other preventive measures has resulted in huge public health gains, while support for translational research is leading to the development of some new neglected disease drugs, diagnostics, and vaccines. However, funding for basic science research has not kept up, such that we are missing opportunities to create a more innovative pipeline of control tools for parasitic and related diseases. There is an urgent need to expand basic science approaches for neglected diseases, especially in the areas of systems biology and immunology; ecology, evolution, and mathematical biology; functional and comparative OMICs; gene editing; expanded use of model organisms; and a new single-cell combinatorial indexing RNA sequencing approach. The world's poor deserve access to innovation for neglected diseases. It should be considered a fundamental human right. PMID- 29121044 TI - Information-theoretic analysis of the directional influence between cellular processes. AB - Inferring the directionality of interactions between cellular processes is a major challenge in systems biology. Time-lagged correlations allow to discriminate between alternative models, but they still rely on assumed underlying interactions. Here, we use the transfer entropy (TE), an information theoretic quantity that quantifies the directional influence between fluctuating variables in a model-free way. We present a theoretical approach to compute the transfer entropy, even when the noise has an extrinsic component or in the presence of feedback. We re-analyze the experimental data from Kiviet et al. (2014) where fluctuations in gene expression of metabolic enzymes and growth rate have been measured in single cells of E. coli. We confirm the formerly detected modes between growth and gene expression, while prescribing more stringent conditions on the structure of noise sources. We furthermore point out practical requirements in terms of length of time series and sampling time which must be satisfied in order to infer optimally transfer entropy from times series of fluctuations. PMID- 29121045 TI - High myopia in Greater Beijing School Children in 2016. AB - PURPOSE: To assess prevalence and associated factors of myopia and high myopia in schoolchildren in Greater Beijing. METHODS: The school-based, cross-sectional Greater Beijing School Children Myopia study was carried out in the year 2016 in 54 schools randomly selected from 15 districts in Beijing. Non-cycloplegic auto refractometry of the right eyes was performed. RESULTS: The study included 35,745 (99.4%) out of 35,968 eligible pupils with a mean age of 12.6+/-3.4 years (range 6-18 years). Prevalence of myopia defined as myopic refractive error of >=-0.50 diopters (D),>=-1D,>=-6D,>=-8D and >=-10D was 70.9%(95% confidence intervals (CI):70.5,71.4), 60.9% (95%CI:60.4,61.4), 8.6%(95%CI:8.4,8.9), 2.2%(95%CI:2.0,2.4), and 0.3% (95%CI:0.3,0.4), respectively. The frequency of high myopia (>=-6D, >=-8D, >=-10D) increased from 1.5% (95%CI:1.0,2.0), 0.4% (95%CI:0.1,0.6) and 0.1% (95%CI:0.00,0.02), respectively in 10-year-olds to 19.4% (95%CI:17.3,21.6), 5.2% (95%CI:4.0,6.4) and 0.9% (95%CI:0.4,1.5), respectively, in 18-year-olds. Mean refractive error in the 18-year-olds was -3.74+/-2.56D (median:-3.63D;range:-19.6D to + 6.25D). Higher prevalence of high myopia (>=-6D and >=-8D) was correlated (all P<0.001) with older age (OR:1.18, and 1.15, respectively), female gender (OR: 1.44 and 1.40, respectively), higher body mass index (OR: 1.02 and 1.03, respectively), taller body height (OR: 1.03 and 1.02, respectively), urban region of habitation (OR: 1.26 and 1.33, respectively) and higher school type (OR:1.57 and 2.22, respectively). Prevalence of severe high myopia (>=-10D) was associated only with older age (P<0.001; OR: 1.44; 95%CI: 1.31, 1.59) but not with any education-related parameter such as higher school type (P = 0.48), urban region of habitation (P = 0.07) or female gender (P = 0.37). CONCLUSION: In this most recent survey, prevalence of high myopia (>= 6D:19.4%;>=-8D:5.2%;>=-10D:0.9%) in 18-year-old school children was higher than in previous surveys from mainland China. In contrast to minor high myopia and moderate high myopia (defined as myopic refractive error of <-10D), severe high myopia (myopic refractive error >=-10D) was not strongly correlated with educational parameters. PMID- 29121047 TI - Dosimetric comparison of CT-guided iodine-125 seed stereotactic brachytherapy and stereotactic body radiation therapy in the treatment of NSCLC. AB - This study aimed to assess the dosimetric differences between iodine-125 seed stereotactic brachytherapy (SBT) and stereotactic body radiation therapy (SBRT) in the treatment of non-small cell lung cancer (NSCLC). An SBT plan and an SBRT plan were generated for eleven patients with T1-2 NSCLC. Prescription of the dose and fractionation (fr) for SBRT was 48Gy/4fr. The planning aim for SBT was D90 (dose delivered to 90% of the target volume)>=120Gy. Student's paired t test was used to compare the dosimetric parameters. The SBT and SBRT plans had comparable PTV D90 (104.73+/-2.10Gyvs.107.64+/-2.29Gy), and similar mean volume receiving 100% of the prescription dose (V100%) (91.65% vs.92.44%, p = 0.410). The mean volume receiving 150% of the prescribed dose (V150%) for SBT was 64.71%, whereas it was 0% for SBRT. Mean heterogeneity index (HI) deviation for SBT vs. SBRT was 0.73 vs. 0.19 (p<0.0001), and the mean conformity index (CI) for SBT vs. SBRT was 0.77 vs. 0.81 (p = 0.031). The mean lung doses (MLD) in SBT were significantly lower than those in SBRT (1.952+/-0.713 vs. 5.618+/-2.009, p<0.0001). In conclusion, compared with SBRT, SBT can generate a comparable dose within PTV, while the organs at risk (OARs) only receive a very low dose. But the HI and CI in SBT were lower than in SBRT. PMID- 29121046 TI - Holistic word processing in dyslexia. AB - People with dyslexia have difficulty learning to read and many lack fluent word recognition as adults. In a novel task that borrows elements of the 'word superiority' and 'word inversion' paradigms, we investigate whether holistic word recognition is impaired in dyslexia. In Experiment 1 students with dyslexia and controls judged the similarity of pairs of 6- and 7-letter words or pairs of words whose letters had been partially jumbled. The stimuli were presented in both upright and inverted form with orthographic regularity and orientation randomized from trial to trial. While both groups showed sensitivity to orthographic regularity, both word inversion and letter jumbling were more detrimental to skilled than dyslexic readers supporting the idea that the latter may read in a more analytic fashion. Experiment 2 employed the same task but using shorter, 4- and 5-letter words and a design where orthographic regularity and stimuli orientation was held constant within experimental blocks to encourage the use of either holistic or analytic processing. While there was no difference in reaction time between the dyslexic and control groups for inverted stimuli, the students with dyslexia were significantly slower than controls for upright stimuli. These findings suggest that holistic word recognition, which is largely based on the detection of orthographic regularity, is impaired in dyslexia. PMID- 29121048 TI - Anatomical variations of the deep head of Cruveilhier of the flexor pollicis brevis and its significance for the evolution of the precision grip. AB - Cruveilhier described in 1834 the human flexor pollicis brevis (FPB), a muscle of the thenar compartment, as having a superficial and a deep head, respectively, inserted onto the radial and ulnar sesamoids of the thumb. Since then, Cruveilhier's deep head has been controversially discussed. Often this deep head is confused with Henle's "interosseous palmaris volaris" or said to be a slip of the oblique adductor pollicis. In the 1960s, Day and Napier described anatomical variations of the insertions of Cruveilhier's deep head, including its absence, and hypothesized, that the shift of the deep head's insertion from ulnar to radial facilitated "true opposability" in anthropoids. Their general thesis for muscular arrangements underlying the power and precision grip is sound, but they did not delineate their deep head from Henle's muscle or the adductor pollicis, and their description of the attachments of Cruveilhier's deep head were too vague and not supported by a significant portion of the anatomical literature. Here, we reinvestigated Cruveilhier's deep head to resolve the controversy about it and because many newer anatomy textbooks do not describe this muscle, while it is often an obvious functionally (writing, texting, precision grip) and clinically significant thenar muscle. For the first time, we empirically delineated Cruveilhier's deep head from neighboring muscles with which it was previously confused. We observed 100% occurrence of the uncontested deep head in 80 human hands, displaying a similar variability of insertions as Day and Napier, but in significantly different numbers. Furthermore, we found variability in the origin and included as important landmarks the trapezoid and the ligamentum carpi radiatum. We tested the assertion regarding the evolutionary morphology and its role in the improvements in thumb movements during various precision grips. Our overall conclusions differ with respect to the developmental and evolutionary origin of the FPB heads. PMID- 29121050 TI - A robust anonymous biometric-based authenticated key agreement scheme for multi server environments. AB - In order to improve the security in remote authentication systems, numerous biometric-based authentication schemes using smart cards have been proposed. Recently, Moon et al. presented an authentication scheme to remedy the flaws of Lu et al.'s scheme, and claimed that their improved protocol supports the required security properties. Unfortunately, we found that Moon et al.'s scheme still has weaknesses. In this paper, we show that Moon et al.'s scheme is vulnerable to insider attack, server spoofing attack, user impersonation attack and guessing attack. Furthermore, we propose a robust anonymous multi-server authentication scheme using public key encryption to remove the aforementioned problems. From the subsequent formal and informal security analysis, we demonstrate that our proposed scheme provides strong mutual authentication and satisfies the desirable security requirements. The functional and performance analysis shows that the improved scheme has the best secure functionality and is computational efficient. PMID- 29121051 TI - Process evaluation of knowledge transfer across industries: Leveraging Coca Cola's supply chain expertise for medicine availability in Tanzania. AB - Persistent gaps in the availability of essential medicines have slowed the achievement of global health targets. Despite the supply chain knowledge and expertise that ministries of health might glean from other industries, limited empirical research has examined the process of knowledge transfer from other industries into global public health. We examined a partnership designed to improve the availability of medical supplies in Tanzania by transferring knowledge from The Coca-Cola system to Tanzania's Medical Stores Department (MSD). We conducted a process evaluation including in-depth interviews with 70 participants between July 2011 and May 2014, corresponding to each phase of the partnership, with focus on challenges and strategies to address them, as well as benefits perceived by partners. Partners faced challenges in (1) identifying relevant knowledge to transfer, (2) translating operational solutions from Coca Cola to MSD, and (3) maintaining momentum between project phases. Strategies to respond to these challenges emerged through real-time problem solving and included (1) leveraging the receptivity of MSD leadership, (2) engaging a boundary spanner to identify knowledge to transfer, (3) promoting local recognition of commonalities across industries, (4) engaging external technical experts to manage translation activities, (5) developing tools with visible benefits for MSD, (6) investing in local relationships, and (7) providing time and space for the partnership model to evolve. Benefits of the partnership perceived by MSD staff included enhanced collaboration and communication, more proactive orientations in managing operations, and greater attention to performance management. Benefits perceived by Coca-Cola staff included strengthened knowledge transfer capability and enhanced job satisfaction. Linking theoretical constructs with practical experiences from the field, we highlight the challenges, emergent strategies, and perceived benefits of a partnership across industry boundaries that may be useful to others seeking to promote the transfer of knowledge to improve global health. PMID- 29121049 TI - Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia. AB - BACKGROUND: 8-oxoG, a common DNA lesion resulting from reactive oxygen species (ROS), has been shown to be associated with cancer initiation. hOGG1 DNA glycosylase is the primary enzyme responsible for excision of 8-oxoG through base excision repair (BER). Integrins are members of a family of cell surface receptors that mediate the cell-cell and extracellular matrix (ECM) interactions. Integrins are involved in almost every aspect of carcinogenesis, from cell differentiation, cell proliferation, metastasis to angiogenesis. Loss of ITGA2 expression was associated with enhanced tumor intravasation and metastasis of breast and colon cancer. XPD gene encodes DNA helicase enzyme that is involved in nucleotide excision repair (NER). It is shown in previous research that XPD homozygous wildtype Lys/Lys genotype was associated with higher odds of NPC. METHODS: We conducted a 1 to N case-control study involving 300 nasopharyngeal carcinoma (NPC) cases and 533 controls matched by age, gender and ethnicity to investigate the effect of hOGG1 Ser326Cys, ITGA2 C807T and XPD Lys751Gln polymorphisms on NPC risk. Linkage disequilibrium and haplotype analysis were conducted to explore the association of allele combinations with NPC risk. Restriction fragment length polymorphism (RFLP-PCR) was used for DNA genotyping. RESULTS: No significant association was observed between hOGG1 Ser326Cys and ITGA2 C807T polymorphisms with NPC risk after adjustment for age, gender, ethnicity, cigarette smoking, alcohol and salted fish consumption. Lys/Lys genotype of XPD Lys751Gln polymorphism was associated with increased NPC risk (OR = 1.60, 95% CI = 1.06-2.43). Subjects with history of smoking (OR = 1.81, 95% CI = 1.26-2.60), and salted fish consumption before age of 10 (OR = 1.77, 95% CI = 1.30-2.42) were observed to have increased odds of NPC. The odds of developing NPC of CGC haplotype was significantly higher compared to reference AGC haplotype (OR = 2.20, 95% CI = 1.06-4.58). CONCLUSION: The allele combination of CGC from hOGG1, ITGA2 and XPD polymorphisms was significantly associated with increased odds of NPC. PMID- 29121052 TI - A causal mediation model of ischemia reperfusion injury in the retina. AB - The goal of this study is to develop a model that explains the relationship between microRNAs, transcription factors, and their co-target genes. This relationship was previously reported in gene regulatory loops associated with 24 hour (24h) and 7 day (7d) time periods following ischemia-reperfusion injury in a rat's retina. Using a model system of retinal ischemia-reperfusion injury, we propose that microRNAs first influence transcription factors, which in turn act as mediators to influence transcription of genes via triadic regulatory loops. Analysis of the relative contributions of direct and indirect regulatory influences on genes revealed that a substantial fraction of the regulatory loops (69% for 24 hours and 77% for 7 days) could be explained by causal mediation. Over 40% of the mediated loops in both time points were regulated by transcription factors only, while about 20% of the loops were regulated entirely by microRNAs. The remaining fractions of the mediated regulatory loops were cooperatively mediated by both microRNAs and transcription factors. The results from these analyses were supported by the patterns of expression of the genes, transcription factors, and microRNAs involved in the mediated loops in both post ischemic time points. Additionally, network motif detection for the mediated loops showed a handful of time specific motifs related to ischemia-reperfusion injury in a rat's retina. In summary, the effects of microRNAs on genes are mediated, in large part, via transcription factors. PMID- 29121053 TI - ADEPt, a semantically-enriched pipeline for extracting adverse drug events from free-text electronic health records. AB - Adverse drug events (ADEs) are unintended responses to medical treatment. They can greatly affect a patient's quality of life and present a substantial burden on healthcare. Although Electronic health records (EHRs) document a wealth of information relating to ADEs, they are frequently stored in the unstructured or semi-structured free-text narrative requiring Natural Language Processing (NLP) techniques to mine the relevant information. Here we present a rule-based ADE detection and classification pipeline built and tested on a large Psychiatric corpus comprising 264k patients using the de-identified EHRs of four UK-based psychiatric hospitals. The pipeline uses characteristics specific to Psychiatric EHRs to guide the annotation process, and distinguishes: a) the temporal value associated with the ADE mention (whether it is historical or present), b) the categorical value of the ADE (whether it is assertive, hypothetical, retrospective or a general discussion) and c) the implicit contextual value where the status of the ADE is deduced from surrounding indicators, rather than explicitly stated. We manually created the rulebase in collaboration with clinicians and pharmacists by studying ADE mentions in various types of clinical notes. We evaluated the open-source Adverse Drug Event annotation Pipeline (ADEPt) using 19 ADEs specific to antipsychotics and antidepressants medication. The ADEs chosen vary in severity, regularity and persistence. The average F measure and accuracy achieved by our tool across all tested ADEs were 0.83 and 0.83 respectively. In addition to annotation power, the ADEPT pipeline presents an improvement to the state of the art context-discerning algorithm, ConText. PMID- 29121054 TI - Differing long term trends for two common amphibian species (Bufo bufo and Rana temporaria) in alpine landscapes of Salzburg, Austria. AB - This study focuses on the population trends of two widespread European anuran species: the common toad (Bufo bufo) and the common frog (Rana temporaria). The basis of this study is data gathered over two decades of amphibian fencing alongside roads in the Austrian state of Salzburg. Different statistical approaches were used to analyse the data. Overall average increase or decrease of each species was estimated by calculating a simple average locality index. In addition the statistical software TRIM was used to verify these trends as well as to categorize the data based on the geographic location of each migration site. The results show differing overall trends for the two species: the common toad being stable and the common frog showing a substantial decline over the last two decades. Further analyses based on geographic categorization reveal the strongest decrease in the alpine range of the species. Drainage and agricultural intensification are still ongoing problems within alpine areas, not only in Salzburg. Particularly in respect to micro-climate and the availability of spawning places these changes appear to have a greater impact on the habitats of the common frog than the common toad. Therefore we consider habitat destruction to be the main potential reason behind this dramatic decline. We also conclude that the substantial loss of biomass of a widespread species such as the common frog must have a severe, and often overlooked, ecological impact. PMID- 29121055 TI - Video summarization using line segments, angles and conic parts. AB - Video summarization is a process to extract objects and their activities from a video and represent them in a condensed form. Existing methods for video summarization fail to detect moving (dynamic) objects in the low color contrast area of a video frame due to the pixel intensities of objects and non-objects are almost similar. However, edges of objects are prominent in the low contrast regions. Moreover, to represent objects, geometric primitives (such as lines, arcs) are distinguishable and high level shape descriptors than edges. In this paper, a novel method is proposed for video summarization using geometric primitives such as conic parts, line segments and angles. Using these features, objects are extracted from each video frame. A cost function is applied to measure the dissimilarity of locations of geometric primitives to detect the movement of objects between consecutive frames. The total distance of object movement is calculated and each video frame is assigned a probability score. Finally, a set of key frames is selected based on the probability scores as per user provided skimming ratio or system default skimming ratio. The proposed approach is evaluated using three benchmark datasets-BL-7F, Office, and Lobby. The experimental results show that our approach outperforms the state-of-the-art method in terms of accuracy. PMID- 29121056 TI - Epidemic spreading in multiplex networks influenced by opinion exchanges on vaccination. AB - Through years, the use of vaccines has always been a controversial issue. People in a society may have different opinions about how beneficial the vaccines are and as a consequence some of those individuals decide to vaccinate or not themselves and their relatives. This attitude in face of vaccines has clear consequences in the spread of diseases and their transformation in epidemics. Motivated by this scenario, we study, in a simultaneous way, the changes of opinions about vaccination together with the evolution of a disease. In our model we consider a multiplex network consisting of two layers. One of the layers corresponds to a social network where people share their opinions and influence others opinions. The social model that rules the dynamic is the M-model, which takes into account two different processes that occurs in a society: persuasion and compromise. This two processes are related through a parameter r, r < 1 describes a moderate and committed society, for r > 1 the society tends to have extremist opinions, while r = 1 represents a neutral society. This social network may be of real or virtual contacts. On the other hand, the second layer corresponds to a network of physical contacts where the disease spreading is described by the SIR-Model. In this model the individuals may be in one of the following four states: Susceptible (S), Infected(I), Recovered (R) or Vaccinated (V). A Susceptible individual can: i) get vaccinated, if his opinion in the other layer is totally in favor of the vaccine, ii) get infected, with probability beta if he is in contact with an infected neighbor. Those I individuals recover after a certain period tr = 6. Vaccinated individuals have an extremist positive opinion that does not change. We consider that the vaccine has a certain effectiveness omega and as a consequence vaccinated nodes can be infected with probability beta(1 - omega) if they are in contact with an infected neighbor. In this case, if the infection process is successful, the new infected individual changes his opinion from extremist positive to totally against the vaccine. We find that depending on the trend in the opinion of the society, which depends on r, different behaviors in the spread of the epidemic occurs. An epidemic threshold was found, in which below beta* and above omega* the diseases never becomes an epidemic, and it varies with the opinion parameter r. PMID- 29121058 TI - Estimating future temperature maxima in lakes across the United States using a surrogate modeling approach. AB - A warming climate increases thermal inputs to lakes with potential implications for water quality and aquatic ecosystems. In a previous study, we used a dynamic water column temperature and mixing simulation model to simulate chronic (7-day average) maximum temperatures under a range of potential future climate projections at selected sites representative of different U.S. regions. Here, to extend results to lakes where dynamic models have not been developed, we apply a novel machine learning approach that uses Gaussian Process regression to describe the model response surface as a function of simplified lake characteristics (depth, surface area, water clarity) and climate forcing (winter and summer air temperatures and potential evapotranspiration). We use this approach to extrapolate predictions from the simulation model to the statistical sample of U.S. lakes in the National Lakes Assessment (NLA) database. Results provide a national-scale scoping assessment of the potential thermal risk to lake water quality and ecosystems across the U.S. We suggest a small fraction of lakes will experience less risk of summer thermal stress events due to changes in stratification and mixing dynamics, but most will experience increases. The percentage of lakes in the NLA with simulated 7-day average maximum water temperatures in excess of 30 degrees C is projected to increase from less than 2% to approximately 22% by the end of the 21st century, which could significantly reduce the number of lakes that can support cold water fisheries. Site-specific analysis of the full range of factors that influence thermal profiles in individual lakes is needed to develop appropriate adaptation strategies. PMID- 29121057 TI - Trafficking and processing of bacterial proteins by mammalian cells: Insights from chondroitinase ABC. AB - BACKGROUND: There is very little reported in the literature about the relationship between modifications of bacterial proteins and their secretion by mammalian cells that synthesize them. We previously reported that the secretion of the bacterial enzyme Chondroitinase ABC by mammalian cells requires the strategic removal of at least three N-glycosylation sites. The aim of this study was to determine if it is possible to enhance the efficacy of the enzyme as a treatment for spinal cord injury by increasing the quantity of enzyme secreted or by altering its cellular location. METHODOLOGY/PRINCIPAL FINDINGS: To determine if the efficiency of enzyme secretion could be further increased, cells were transfected with constructs encoding the gene for chondroitinase ABC modified for expression by mammalian cells; these contained additional modifications of strategic N-glycosylation sites or alternative signal sequences to direct secretion of the enzyme from the cells. We show that while removal of certain specific N-glycosylation sites enhances enzyme secretion, N-glycosylation of at least two other sites, N-856 and N-773, is essential for both production and secretion of active enzyme. Furthermore, we find that the signal sequence directing secretion also influences the quantity of enzyme secreted, and that this varies widely amongst the cell types tested. Last, we find that replacing the 3'UTR on the cDNA encoding Chondroitinase ABC with that of beta-actin is sufficient to target the enzyme to the neuronal growth cone when transfected into neurons. This also enhances neurite outgrowth on an inhibitory substrate. CONCLUSION/SIGNIFICANCE: Some intracellular trafficking pathways are adversely affected by cryptic signals present in the bacterial gene sequence, whilst unexpectedly others are required for efficient secretion of the enzyme. Furthermore, targeting chondroitinase to the neuronal growth cone promotes its ability to increase neurite outgrowth on an inhibitory substrate. These findings are timely in view of the renewed prospects for gene therapy, and of direct relevance to strategies aimed at expressing foreign proteins in mammalian cells, in particular bacterial proteins. PMID- 29121059 TI - Effects of decades of physical driving on body movement and motion sickness during virtual driving. AB - We investigated relations between experience driving physical automobiles and motion sickness during the driving of virtual automobiles. Middle-aged individuals drove a virtual automobile in a driving video game. Drivers were individuals who had possessed a driver's license for approximately 30 years, and who drove regularly, while non-drivers were individuals who had never held a driver's license, or who had not driven for more than 15 years. During virtual driving, we monitored movement of the head and torso. During virtual driving, drivers became motion sick more rapidly than non-drivers, but the incidence and severity of motion sickness did not differ as a function of driving experience. Patterns of movement during virtual driving differed as a function of driving experience. Separately, movement differed between participants who later became motion sick and those who did not. Most importantly, physical driving experience influenced patterns of postural activity that preceded motion sickness during virtual driving. The results are consistent with the postural instability theory of motion sickness, and help to illuminate relations between the control of physical and virtual vehicles. PMID- 29121060 TI - The effects of demographic, social, and environmental characteristics on pathogen prevalence in wild felids across a gradient of urbanization. AB - Transmission of pathogens among animals is influenced by demographic, social, and environmental factors. Anthropogenic alteration of landscapes can impact patterns of disease dynamics in wildlife populations, increasing the potential for spillover and spread of emerging infectious diseases in wildlife, human, and domestic animal populations. We evaluated the effects of multiple ecological mechanisms on patterns of pathogen exposure in animal populations. Specifically, we evaluated how ecological factors affected the prevalence of Toxoplasma gondii (Toxoplasma), Bartonella spp. (Bartonella), feline immunodeficiency virus (FIV), and feline calicivirus (FCV) in bobcat and puma populations across wildland-urban interface (WUI), low-density exurban development, and wildland habitat on the Western Slope (WS) and Front Range (FR) of Colorado during 2009-2011. Samples were collected from 37 bobcats and 29 pumas on the WS and FR. As predicted, age appeared to be positively related to the exposure to pathogens that are both environmentally transmitted (Toxoplasma) and directly transmitted between animals (FIV). In addition, WS bobcats appeared more likely to be exposed to Toxoplasma with increasing intraspecific space-use overlap. However, counter to our predictions, exposure to directly-transmitted pathogens (FCV and FIV) was more likely with decreasing space-use overlap (FCV: WS bobcats) and potential intraspecific contacts (FIV: FR pumas). Environmental factors, including urbanization and landscape covariates, were generally unsupported in our models. This study is an approximation of how pathogens can be evaluated in relation to demographic, social, and environmental factors to understand pathogen exposure in wild animal populations. PMID- 29121061 TI - A randomized, double-blind, active-control trial to evaluate the efficacy and safety of a three day course of tafenoquine monotherapy for the treatment of Plasmodium vivax malaria. AB - BACKGROUND: Tafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen. METHODS: This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120. RESULTS: Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83-98%) with tafenoquine, and 100% (22/22) (90%CI 87-100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92-100%), and 95% (19/20) (90%CI 78-100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4-25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5-5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient. DISCUSSION: Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing. TRIAL REGISTRATION: Clinicaltrials.gov NCT01290601. PMID- 29121062 TI - Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion. AB - Immune evasion is a well-recognized hallmark of cancer and recent studies with immunotherapy agents have suggested that tumors with increased numbers of neoantigens elicit greater immune responses. We hypothesized that the immune system presents a common selective pressure on high mutation burden tumors and therefore immune evasion mutations would be enriched in high mutation burden tumors. The JAK family of kinases is required for the signaling of a host of immune modulators in tumor, stromal, and immune cells. Therefore, we analyzed alterations in this family for the hypothesized signature of an immune evasion mutation. Here, we searched a database of 61,704 unique solid tumors for alterations in the JAK family kinases (JAK1/2/3, TYK2). We used The Cancer Genome Atlas and Cancer Cell Line Encyclopedia data to confirm and extend our findings by analyzing gene expression patterns. Recurrent frameshift mutations in JAK1 were associated with high mutation burden and microsatellite instability. These mutations occurred in multiple tumor types including endometrial, colorectal, stomach, and prostate carcinomas. Analyzing gene expression signatures in endometrial and stomach adenocarcinomas revealed that tumors with a JAK1 frameshift exhibited reduced expression of interferon response signatures and multiple anti-tumor immune signatures. Importantly, endometrial cancer cell lines exhibited similar gene expression changes that were expected to be tumor cell intrinsic (e.g. interferon response) but not those expected to be tumor cell extrinsic (e.g. NK cells). From these data, we derive two primary conclusions: 1) JAK1 frameshifts are loss of function alterations that represent a potential pan cancer adaptation to immune responses against tumors with microsatellite instability; 2) The mechanism by which JAK1 loss of function contributes to tumor immune evasion is likely associated with loss of the JAK1-mediated interferon response. PMID- 29121064 TI - Correction: Ten simple rules for structuring papers. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005619.]. PMID- 29121063 TI - Malignancy risk estimation of pulmonary nodules in screening CTs: Comparison between a computer model and human observers. AB - PURPOSE: To compare human observers to a mathematically derived computer model for differentiation between malignant and benign pulmonary nodules detected on baseline screening computed tomography (CT) scans. METHODS: A case-cohort study design was chosen. The study group consisted of 300 chest CT scans from the Danish Lung Cancer Screening Trial (DLCST). It included all scans with proven malignancies (n = 62) and two subsets of randomly selected baseline scans with benign nodules of all sizes (n = 120) and matched in size to the cancers, respectively (n = 118). Eleven observers and the computer model (PanCan) assigned a malignancy probability score to each nodule. Performances were expressed by area under the ROC curve (AUC). Performance differences were tested using the Dorfman, Berbaum and Metz method. Seven observers assessed morphological nodule characteristics using a predefined list. Differences in morphological features between malignant and size-matched benign nodules were analyzed using chi-square analysis with Bonferroni correction. A significant difference was defined at p < 0.004. RESULTS: Performances of the model and observers were equivalent (AUC 0.932 versus 0.910, p = 0.184) for risk-assessment of malignant and benign nodules of all sizes. However, human readers performed superior to the computer model for differentiating malignant nodules from size-matched benign nodules (AUC 0.819 versus 0.706, p < 0.001). Large variations between observers were seen for ROC areas and ranges of risk scores. Morphological findings indicative of malignancy referred to border characteristics (spiculation, p < 0.001) and perinodular architectural deformation (distortion of surrounding lung parenchyma architecture, p < 0.001; pleural retraction, p = 0.002). CONCLUSIONS: Computer model and human observers perform equivalent for differentiating malignant from randomly selected benign nodules, confirming the high potential of computer models for nodule risk estimation in population based screening studies. However, computer models highly rely on size as discriminator. Incorporation of other morphological criteria used by human observers to superiorly discriminate size matched malignant from benign nodules, will further improve computer performance. PMID- 29121065 TI - Proteomic analysis reveals novel ligands and substrates for LNX1 E3 ubiquitin ligase. AB - Ligand of Numb protein X1 (LNX1) is an E3 ubiquitin ligase that contains a catalytic RING (Really Interesting New Gene) domain and four PDZ (PSD-95, DlgA, ZO-1) domains. LNX1 can ubiquitinate Numb, as well as a number of other ligands. However, the physiological relevance of these interactions in vivo remain unclear. To gain functional insights into the LNX family, we have characterised the LNX1 interactome using affinity purification and mass spectrometry. This approach identified a large number of novel LNX1-interacting proteins, as well as confirming known interactions with NUMB and ERC2. Many of the novel interactions mapped to the LNX PDZ domains, particularly PDZ2, and many showed specificity for LNX1 over the closely related LNX2. We show that PPFIA1 (liprin-alpha1), KLHL11, KIF7 and ERC2 are substrates for ubiquitination by LNX1. LNX1 ubiquitination of liprin-alpha1 is dependent on a PDZ binding motif containing a carboxyl terminal cysteine that binds LNX1 PDZ2. Surprisingly, the neuronally-expressed LNX1p70 isoform, that lacks the RING domain, was found to promote ubiquitination of PPFIA1 and KLHL11, albeit to a lesser extent than the longer RING-containing LNX1p80 isoform. Of several E3-ligases identified in the LNX1 interactome we confirm interactions of LNX1 with MID2/TRIM1 and TRIM27. On this basis we propose a model whereby LNX1p70, despite lacking a catalytic RING domain, may function as a scaffold to promote ubiquitination of its ligands through recruitment of other E3-ligases. These findings provide functional insights into the LNX protein family, particularly the neuronal LNX1p70 isoform. PMID- 29121066 TI - Probability of lek collapse is lower inside sage-grouse Core Areas: Effectiveness of conservation policy for a landscape species. AB - Greater sage-grouse (Centrocercus urophasianus) occupy sagebrush (Artemisia spp.) habitats in 11 western states and 2 Canadian provinces. In September 2015, the U.S. Fish and Wildlife Service announced the listing status for sage-grouse had changed from warranted but precluded to not warranted. The primary reason cited for this change of status was that the enactment of new regulatory mechanisms was sufficient to protect sage-grouse populations. One such plan is the 2008, Wyoming Sage Grouse Executive Order (SGEO), enacted by Governor Freudenthal. The SGEO identifies "Core Areas" that are to be protected by keeping them relatively free from further energy development and limiting other forms of anthropogenic disturbances near active sage-grouse leks. Using the Wyoming Game and Fish Department's sage-grouse lek count database and the Wyoming Oil and Gas Conservation Commission database of oil and gas well locations, we investigated the effectiveness of Wyoming's Core Areas, specifically: 1) how well Core Areas encompass the distribution of sage-grouse in Wyoming, 2) whether Core Area leks have a reduced probability of lek collapse, and 3) what, if any, edge effects intensification of oil and gas development adjacent to Core Areas may be having on Core Area populations. Core Areas contained 77% of male sage-grouse attending leks and 64% of active leks. Using Bayesian binomial probability analysis, we found an average 10.9% probability of lek collapse in Core Areas and an average 20.4% probability of lek collapse outside Core Areas. Using linear regression, we found development density outside Core Areas was related to the probability of lek collapse inside Core Areas. Specifically, probability of collapse among leks >4.83 km from inside Core Area boundaries was significantly related to well density within 1.61 km (1-mi) and 4.83 km (3-mi) outside of Core Area boundaries. Collectively, these data suggest that the Wyoming Core Area Strategy has benefited sage-grouse and sage-grouse habitat conservation; however, additional guidelines limiting development densities adjacent to Core Areas may be necessary to effectively protect Core Area populations. PMID- 29121067 TI - High yields of hydrogen production from methanol steam reforming with a cross-U type reactor. AB - This paper presents a numerical and experimental study on the performance of a methanol steam reformer integrated with a hydrogen/air combustion reactor for hydrogen production. A CFD-based 3D model with mass and momentum transport and temperature characteristics is established. The simulation results show that better performance is achieved in the cross-U type reactor compared to either a tubular reactor or a parallel-U type reactor because of more effective heat transfer characteristics. Furthermore, Cu-based micro reformers of both cross-U and parallel-U type reactors are designed, fabricated and tested for experimental validation. Under the same condition for reforming and combustion, the results demonstrate that higher methanol conversion is achievable in cross-U type reactor. However, it is also found in cross-U type reactor that methanol reforming selectivity is the lowest due to the decreased water gas shift reaction under high temperature, thereby carbon monoxide concentration is increased. Furthermore, the reformed gas generated from the reactors is fed into a high temperature proton exchange membrane fuel cell (PEMFC). In the test of discharging for 4 h, the fuel cell fed by cross-U type reactor exhibits the most stable performance. PMID- 29121068 TI - Metabolic regulation of GLP-1 and PC1/3 in pancreatic alpha-cell line. AB - BACKGROUND AND AIMS: An intra-islet incretin system has been recently suggested to operate through modulation of the expression and activity of proconvertase 1/3 and 2 (PC1/3, PC2) in pancreatic alpha-cell accounting for local release of GLP 1. Little is known, whether this alpha-cell activity can be affected by the metabolic alterations occurring in type 2 diabetes, such as hyperglycemia, hyperlipidemia or hyperglucagonemia. MATERIALS AND METHODS: AlphaTC1/6 cells from a mice pancreatic cell line were incubated in the presence of two glucose (G) concentration (5.5 and 16.7 mM) for 16 h with or without free fatty acid, IL6 or glucagon. GLP-1 secretion was measured by ELISA and expression of PC1/3 and PC2 by RT-PCR and western blot; cell viability was determined by MTT method, Reactive Oxygen Species generation (ROS) by H2DCFDA fluorescence and apoptosis by Annexin staining and Propidium Iodine (PI) fluorescence. RESULTS: Upon 16.7G incubation, GLP-1 secretion (total and active) was significantly increased in parallel with a significant increment in PC1/3 expression, a slight increase in cell viability and ROS generation and by a decrement in PC2 expression with no change in cell apoptosis. When cells were incubated at 5.5mM glucose with FFA, also an increment in GLP-1 secretion and PC1/3 expression was observed together an increment in ROS generation, a decrement in cell viability, and a modest increment in apoptosis. When incubated with 16.7mM glucose with FFA, the increment in GLP-1 secretion was reduced to basal, accompanied by an increment in apoptosis and ROS generation. This was also observed with IL-6, but in this case, no modification in ROS generation or apoptosis was observed when compared to 16.7mM glucose. The presence of glucagon did not modify any of the parameters studied. CONCLUSION: These data suggest that under hyperglycemic, hyperlipidemia or inflammatory conditions, alpha cells can increase expression PC1/3 and activate GLP-1 secretion, which may contribute protecting both alpha and beta-cells from glucose and lipotoxicity, while this effect seems to be lost in the presence of both pathophysiological conditions. PMID- 29121069 TI - Developing selective media for quantification of multispecies biofilms following antibiotic treatment. AB - The lungs of cystic fibrosis (CF) patients are chronically colonized by a polymicrobial biofilm community, leading to difficult-to-treat infections. To combat these infections, CF patients are commonly treated with a variety of antibiotics. Understanding the dynamics of polymicrobial community composition in response to antibiotic therapy is essential in the search for novel therapies. Culture-dependent quantification of individual bacteria from defined multispecies biofilms is frequently carried out by plating on selective media. However, the influence of the selective agents in these media on quantitative recovery before or after antibiotic treatment is often unknown. In the present study we developed selective media for six bacterial species that are frequently co-isolated from the CF lung, i.e. Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus anginosus, Achromobacter xylosoxidans, Rothia mucilaginosa, and Gemella haemolysans. We show that certain supplementations to selective media strongly influence quantitative recovery of (un)treated biofilms. Hence, the developed media were optimized for selectivity and quantitative recovery before or after treatment with antibiotics of four major classes, i.e. ceftazidime, ciprofloxacin, colistin, or tobramycin. Finally, in a proof of concept experiment the novel selective media were applied to determine the community composition of multispecies biofilms before and after treatment with tobramycin. PMID- 29121070 TI - Identification and characterization of intestine microRNAs and targets in red swamp crayfish, Procambarus clarkii infected with white spot syndrome virus. AB - MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules that play important roles in the innate immunity system of invertebrates, especially in the aspect of antivirus. In the present study, high-throughput small RNA Illumina sequencing systems were used to identify differentially expressed miRNAs (DEMs) from the intestines of Procambarus clarkii that were infected with white spot syndrome virus (WSSV). As a result, 39 known and 12 novel miRNAs were identified in both NG and WG small RNA libraries. Seven DEMs were determined to be involved in the antiviral innate immunity in the intestines of P. clarkii. The results of the target gene predictions of the DEMs showed that the putative target genes of these 7 DEMs are related to tight junctions, vascular smooth muscle contraction regulation of the actin cytoskeleton, focal adhesion, RNA transport, mRNA surveillance, viral carcinogenesis, and Salmonella infection. These results provide theoretical insights for future studies on the antiviral immunity of crustaceans. PMID- 29121071 TI - From nerves to brain to gastrointestinal tract: A time-based study of parrot bornavirus 2 (PaBV-2) pathogenesis in cockatiels (Nymphicus hollandicus). AB - Parrot bornaviruses (PaBVs) are the causative agents of proventricular dilatation disease, however key aspects of its pathogenesis, such as route of infection, viral spread and distribution, and target cells remain unclear. Our study aimed to track the viral spread and lesion development at 5, 10, 20, 25, 35, 40, 60, 80, 95 and 114 dpi using histopathology, immunohistochemistry, and RT-PCR. After intramuscular inoculation of parrot bornavirus 2 (PaBV-2) in the pectoral muscle of cockatiels, this virus was first detected in macrophages and lymphocytes in the inoculation site and adjacent nerves, then reached the brachial plexus, centripetally spread to the thoracic segment of the spinal cord, and subsequently invaded the other spinal segments and brain. After reaching the central nervous system (CNS), PaBV-2 centrifugally spread out the CNS to the ganglia in the gastrointestinal (GI) system, adrenal gland, heart, and kidneys. At late points of infection, PaBV-2 was not only detected in nerves and ganglia but widespread in the smooth muscle and/or scattered epithelial cells of tissues such as crop, intestines, proventriculus, kidneys, skin, and vessels. Despite the hallmark lesion of PaBVs infection being the dilation of the proventriculus, our results demonstrate PaBV-2 first targets the CNS, before migrating to peripheral tissues such as the GI system. PMID- 29121072 TI - Accuracy of echocardiographic indices for serial monitoring of right ventricular systolic function in patients with precapillary pulmonary hypertension. AB - BACKGROUND: Serial assessment of right ventricular ejection fraction (RVEF) predicts the clinical outcome of patients with pulmonary hypertension (PH). Cardiac magnetic resonance imaging (CMRI) enables RVEF monitoring, but its applicability is limited in clinical practice. This study aimed to examine the correlation between changes in CMRI-derived RVEF with those in echocardiographic indices in patients with precapillary PH. METHODS: CMRI and echocardiographic indices of RV systolic function were evaluated at baseline and follow-up in 54 consecutive patients with precapillary PH (pulmonary arterial hypertension (PAH), n = 23; non-PAH, n = 31). During follow-up, medical treatment was optimized according to the guidelines for PH. Using CMRI-derived RVEF as the gold standard, we examined the accuracy of five echocardiographic indices by correlation analysis and receiver operating characteristic (ROC) analysis and by calculating sensitivity, specificity, and positive and negative predictive values. RESULTS: After an average period of 9.5 months, CMRI-derived RVEF improved from 30.2% +/- 10.6% at baseline to 41.4% +/- 11.3% at follow-up. These changes significantly correlated with those in the five echocardiographic indices, i.e., %RV fractional shortening (r = 0.27), %RV area change (r = 0.46), tricuspid annular plane systolic excursion (TAPSE) (r = 0.84), RV myocardial performance index (RVMPI) (r = -0.72), and systolic lateral tricuspid annular motion velocity (TVlat) (r = 0.66). Of these indices, %RV area change, TAPSE, and TVlat significantly correlated with those of CMRI-derived RVEF in both PAH and non-PAH subgroups. ROC analysis showed that improvement in echocardiographic indices predicted a pre specified improvement in CMRI-derived RVEF (>2.9%), with TAPSE and TVlat showing better accuracy over the other three indices. CONCLUSIONS: Echocardiographic indices modestly correlate with the changes in CMRI-derived RVEF in precapillary PH patients. Comparison among the five echocardiographic indices revealed that TAPSE and TVlat provide better accuracy than %RV fractional shortening, %RV area change, and RVMPI. PMID- 29121073 TI - DiffSLC: A graph centrality method to detect essential proteins of a protein protein interaction network. AB - Identification of central genes and proteins in biomolecular networks provides credible candidates for pathway analysis, functional analysis, and essentiality prediction. The DiffSLC centrality measure predicts central and essential genes and proteins using a protein-protein interaction network. Network centrality measures prioritize nodes and edges based on their importance to the network topology. These measures helped identify critical genes and proteins in biomolecular networks. The proposed centrality measure, DiffSLC, combines the number of interactions of a protein and the gene coexpression values of genes from which those proteins were translated, as a weighting factor to bias the identification of essential proteins in a protein interaction network. Potentially essential proteins with low node degree are promoted through eigenvector centrality. Thus, the gene coexpression values are used in conjunction with the eigenvector of the network's adjacency matrix and edge clustering coefficient to improve essentiality prediction. The outcome of this prediction is shown using three variations: (1) inclusion or exclusion of gene co expression data, (2) impact of different coexpression measures, and (3) impact of different gene expression data sets. For a total of seven networks, DiffSLC is compared to other centrality measures using Saccharomyces cerevisiae protein interaction networks and gene expression data. Comparisons are also performed for the top ranked proteins against the known essential genes from the Saccharomyces Gene Deletion Project, which show that DiffSLC detects more essential proteins and has a higher area under the ROC curve than other compared methods. This makes DiffSLC a stronger alternative to other centrality methods for detecting essential genes using a protein-protein interaction network that obeys centrality lethality principle. DiffSLC is implemented using the igraph package in R, and networkx package in Python. The python package can be obtained from git.io/diffslcpy. The R implementation and code to reproduce the analysis is available via git.io/diffslc. PMID- 29121074 TI - Proteome profiling in the aorta and kidney of type 1 diabetic rats. AB - Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes. PMID- 29121076 TI - Male group size, female distribution and changes in sexual segregation by Roosevelt elk. AB - Sexual segregation, or the differential use of space by males and females, is hypothesized to be a function of body size dimorphism. Sexual segregation can also manifest at small (social segregation) and large (habitat segregation) spatial scales for a variety of reasons. Furthermore, the connection between small- and large-scale sexual segregation has rarely been addressed. We studied a population of Roosevelt elk (Cervus elaphus roosevelti) across 21 years in north coastal California, USA, to assess small- and large-scale sexual segregation in winter. We hypothesized that male group size would associate with small-scale segregation and that a change in female distribution would associate with large scale segregation. Variation in forage biomass might also be coupled to small and large-scale sexual segregation. Our findings were consistent with male group size associating with small-scale segregation and a change in female distribution associating with large-scale segregation. Females appeared to avoid large groups comprised of socially dominant males. Males appeared to occupy a habitat vacated by females because of a wider forage niche, greater tolerance to lethal risks, and, perhaps, to reduce encounters with other elk. Sexual segregation at both spatial scales was a poor predictor of forage biomass. Size dimorphism was coupled to change in sexual segregation at small and large spatial scales. Small scale segregation can seemingly manifest when all forage habitat is occupied by females and large scale segregation might happen when some forage habitat is not occupied by females. PMID- 29121075 TI - Functional evaluation of therapeutic response of HCC827 lung cancer to bevacizumab and erlotinib targeted therapy using dynamic contrast-enhanced and diffusion-weighted MRI. AB - This study aimed to investigate the therapeutic responses of lung cancer mice models with adenocarcinoma HCC827 (gefitinib sensitive) and HCC827R (gefitinib resistant) to the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib alone and in combination with the anti-angiogenesis agent bevacizumab using dynamic contrast enhanced (DCE) and diffusion-weighted MRI. In the HCC827 model, temporal changes in DCE-MRI derived parameters (Ktrans, kep, and iAUC90) and apparent diffusion coefficient (ADC) were significantly correlated with tumor size. Ktrans and iAUC90 significantly decreased at week 2 in the groups receiving erlotinib alone and in combination with bevacizumab, whereas kep decreased at week 1 and 2 in both treatment groups. In addition, there was a significant difference in iAUC90 between the treatment groups at week 1. Compared to the control group of HCC827, there was a significant reduction in microvessel density and increased tumor apoptosis in the two treatment group. ADC value increased in the erlotinib alone group at week 1 and week 2, and in the erlotinib combined with bevacizumab group at week 2. Enlarged areas of central tumor necrosis were associated with a higher ADC value. However, progressive enlargement of the tumors but no significant differences in DCE parameters or ADC were noted in the HCC827R model. These results showed that both erlotinib alone and in combination with bevacizumab could effectively inhibit tumor growth in the gefitinib sensitive lung cancer mice model, and that this was associated with decreased vascular perfusion, increased ADC percentage, decreased microvessel density, and increased tumor apoptosis with a two-week treatment cycle. PMID- 29121077 TI - A functional pipeline framework for landmark identification on 3D surface extracted from volumetric data. AB - Landmarks, also known as feature points, are one of the important geometry primitives that describe the predominant characteristics of a surface. In this study we proposed a self-contained framework to generate landmarks on surfaces extracted from volumetric data. The framework is designed to be a three-fold pipeline structure. The pipeline comprises three phases which are surface construction, crest line extraction and landmark identification. With input as a volumetric data and output as landmarks, the pipeline takes in 3D raw data and produces a 0D geometry feature. In each phase we investigate existing methods, extend and tailor the methods to fit the pipeline design. The pipeline is designed to be functional as it is modularised to have a dedicated function in each phase. We extended the implicit surface polygonizer for surface construction in first phase, developed an alternative way to compute the gradient of maximal curvature for crest line extraction in second phase and finally we combine curvature information and K-means clustering method to identify the landmarks in the third phase. The implementations are firstly carried on a controlled environment, i.e. synthetic data, for proof of concept. Then the method is tested on a small scale data set and subsequently on huge data set. Issues and justifications are addressed accordingly for each phase. PMID- 29121078 TI - Indocyanine green fluorescence in second near-infrared (NIR-II) window. AB - Indocyanine green (ICG), a FDA approved near infrared (NIR) fluorescent agent, is used in the clinic for a variety of applications including lymphangiography, intra-operative lymph node identification, tumor imaging, superficial vascular imaging, and marking ischemic tissues. These applications operate in the so called "NIR-I" window (700-900 nm). Recently, imaging in the "NIR-II" window (1000-1700 nm) has attracted attention since, at longer wavelengths, photon absorption, and scattering effects by tissue components are reduced, making it possible to image deeper into the underlying tissue. Agents for NIR-II imaging are, however, still in pre-clinical development. In this study, we investigated ICG as a NIR-II dye. The absorbance and NIR-II fluorescence emission of ICG were measured in different media (PBS, plasma and ethanol) for a range of ICG concentrations. In vitro and in vivo testing were performed using a custom-built spectral NIR assembly to facilitate simultaneous imaging in NIR-I and NIR-II window. In vitro studies using ICG were performed using capillary tubes (as a simulation of blood vessels) embedded in Intralipid solution and tissue phantoms to evaluate depth of tissue penetration in NIR-I and NIR-II window. In vivo imaging using ICG was performed in nude mice to evaluate vascular visualization in the hind limb in the NIR-I and II windows. Contrast-to-noise ratios (CNR) were calculated for comparison of image quality in NIR-I and NIR-II window. ICG exhibited significant fluorescence emission in the NIR-II window and this emission (similar to the absorption profile) is substantially affected by the environment of the ICG molecules. In vivo imaging further confirmed the utility of ICG as a fluorescent dye in the NIR-II domain, with the CNR values being ~2 times those in the NIR-I window. The availability of an FDA approved imaging agent could accelerate the clinical translation of NIR-II imaging technology. PMID- 29121079 TI - Challenges and opportunities for Moringa growers in southern Ethiopia and Kenya. AB - Moringa oleifera (MO) and M. stenopetala (MS) are two commonly cultivated species of the Moringaceae family. Some households in southern Ethiopia (S. ETH) and Kenya (KEN) plant MS and MO, respectively. The edible parts of these species are rich in amino acids, vitamins and minerals, especially selenium. Despite their nutritional value, Moringa is sometimes considered as a "famine food". The aim of this study was to determine the extent of dietary utilization of these plants by Moringa Growing Households (MGHs). Moringa growing households were surveyed in 2015. Twenty-four and 56 heads of MGHs from S. ETH and KEN, respectively, were interviewed using semi-structured questionnaires. Subsistence agriculture was the main source of livelihood for all MGHs in S. ETH and 71% of those in KEN. All MGHs in S. ETH cultivated MS while those in KEN cultivated MO. Of the MGH heads in S. ETH, 71% had grown MS as long as they remember; the median cultivation period of MO in KEN was 15 years. All MGHs in S. ETH and 79% in KEN used Moringa leaves as a source of food. Forms of consumption of leaves were boiled fresh leaves, and leaf powder used in tea or mixed with other dishes. Other uses of Moringa include as medicine, fodder, shade, agroforestry, and as a source of income. Although MO and MS have multiple uses, MGHs face several challenges, including a lack of reliable information on nutritional and medicinal values, inadequate access to markets for their products, and pest and disease stresses to their plants. Research and development to address these challenges and to promote the use of these species in the fight against hidden hunger are necessary. PMID- 29121080 TI - Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys. AB - Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in young children and older adults throughout the world. Prevention of severe RSV disease through active immunization is optimal but no RSV vaccine has been licensed so far. Immune mechanisms of protection against RSV infection in humans have not been fully established, thus a comprehensive characterization of virus-specific immune responses in a relevant animal model will be beneficial in defining correlates of protection. In this study, we infected juvenile naive AGMs with RSV A2 strain and longitudinally assessed virus-specific humoral and cellular immune responses in both peripheral blood and the respiratory tract. RSV viral loads at nasopharyngeal surfaces and in the lung peaked at around day 5 following infection, and then largely resolved by day 10. Low levels of neutralizing antibody titers were detected in serum, with similar kinetics as RSV fusion (F) protein-binding IgG antibodies. RSV infection induced CD8+, but very little CD4+, T lymphocyte responses in peripheral blood. Virus-specific CD8+ T cell frequencies were ~10 fold higher in bronchoaveolar lavage (BAL) compared to peripheral blood and exhibited effector memory (CD95+CD28-) / tissue resident memory (CD69+CD103+) T (TRM) cell phenotypes. The kinetics of virus-specific CD8+ T cells emerging in peripheral blood and BAL correlated with declining viral titers, suggesting that virus-specific cellular responses contribute to the clearance of RSV infection. RSV-experienced AGMs were protected from subsequent exposure to RSV infection. Additional studies are underway to understand protective correlates in these seropositive monkeys. PMID- 29121081 TI - Intraoperative ventilatory leak predicts prolonged air leak after lung resection: A retrospective observational study. AB - Prolonged air leak (PAL), defined as air leak more than 5 days after lung resection, has been associated with various adverse outcomes. However, studies on intraoperative risk factors for PAL are not sufficient. We investigated whether the intraoperative ventilatory leak (VL) can predict PAL. A retrospective study of 1060 patients with chest tubes after lung resection was conducted. Tidal volume data were retrieved from the electronic anesthesia records. Ventilatory leak (%) was calculated as [(inspiratory tidal volume-expiratory tidal volume)/ inspiratory tidal volume * 100] and was measured after restart of two-lung ventilation. Cox proportional hazards regression analysis was performed using VL as a predictor, and PAL as the dependent outcome. The odds ratio of the VL was then adjusted by adding possible risk factors including patient characteristics, pulmonary function and surgical factors. The incidence of PAL was 18.7%. VL >9.5% was a significant predictor of PAL in univariable analysis. VL remained significant as a predictor of PAL (1.59, 95% CI, 1.37-1.85, P <0.001) after adjusting for 7 additional risk factors including male gender, age >60 years, body mass index <21.5 kg/m2, forced expiratory volume in 1 sec <80%, thoracotomy, major lung resection, and one-lung ventilation time >2.1 hours. C-statistic of the prediction model was 0.80 (95% CI, 0.77-0.82). In conclusion, VL was a quantitative measure of intraoperative air leakage and an independent predictor of postoperative PAL. Monitoring VL during lung resection may be uselful in recommending additional surgical repair or use of adjuncts and thus, help reduce postoperative PAL. PMID- 29121082 TI - The Mouse Model of Pancreatic Cancer Atlas (MMPCA) for classification of pancreatic cancer lesions: A large histological investigation of the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the leading forms of cancer related deaths in the United States. With limited treatment options and unreliable diagnostic methods, long-term survival rates following a diagnosis of pancreatic cancer remain poor. Pancreatic intraepithelial neoplasia (PanIN) are precancerous lesions that precede progression towards PDAC. PanIN occur in increasing complexity as the disease progresses and the description of PanIN plays a critical role in describing, staging and diagnosing PDAC. Inconsistencies in PanIN classifications exist even amongst leading pathologists. This has led to debate and confusion among researchers and pathologists involved in pancreatic cancer research, diagnosis and treatment. We have sought to initiate a discussion with leading pathologists with a goal of increasing consensus in the interpretation of PanIN and associated structures within the precancerous pancreas. Toward achieving this goal, we are in the process of conducting an extensive study of over 1000 male and female pancreata in varying stages of PanIN progression isolated from the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer. Using this extensive database, we have established the Mouse Model of Pancreatic Cancer Atlas (MMPCA) to serve as a platform for meaningful and interactive discussion among researchers and pathologists who study pancreatic disease. We hope that the MMPCA will be an effective tool for promoting a more consistent and accurate consensus of PanIN classifications in the future. PMID- 29121083 TI - Structural and biochemical analysis of atypically low dephosphorylating activity of human dual-specificity phosphatase 28. AB - Dual-specificity phosphatases (DUSPs) constitute a subfamily of protein tyrosine phosphatases, and are intimately involved in the regulation of diverse parameters of cellular signaling and essential biological processes. DUSP28 is one of the DUSP subfamily members that is known to be implicated in the progression of hepatocellular and pancreatic cancers, and its biological functions and enzymatic characteristics are mostly unknown. Herein, we present the crystal structure of human DUSP28 determined to 2.1 A resolution. DUSP28 adopts a typical DUSP fold, which is composed of a central beta-sheet covered by alpha-helices on both sides and contains a well-ordered activation loop, as do other enzymatically active DUSP proteins. The catalytic pocket of DUSP28, however, appears hardly accessible to a substrate because of the presence of nonconserved bulky residues in the protein tyrosine phosphatase signature motif. Accordingly, DUSP28 showed an atypically low phosphatase activity in the biochemical assay, which was remarkably improved by mutations of two nonconserved residues in the activation loop. Overall, this work reports the structural and biochemical basis for understanding a putative oncological therapeutic target, DUSP28, and also provides a unique mechanism for the regulation of enzymatic activity in the DUSP subfamily proteins. PMID- 29121084 TI - Fission yeast strains with circular chromosomes require the 9-1-1 checkpoint complex for the viability in response to the anti-cancer drug 5 fluorodeoxyuridine. AB - Thymidine kinase converts 5-fluorodeoxyuridine to 5-fluorodeoxyuridine monophosphate, which causes disruption of deoxynucleotide triphosphate ratios. The fission yeast Schizosaccharomyces pombe does not express endogenous thymidine kinase but 5-fluorodeoxyuridine inhibits growth when exogenous thymidine kinase is expressed. Unexpectedly, we found that 5-fluorodeoxyuridine causes S phase arrest even without thymidine kinase expression. DNA damage checkpoint proteins such as the 9-1-1 complex were required for viability in the presence of 5 fluorodeoxyuridine. We also found that strains with circular chromosomes, due to loss of pot1+, which have higher levels of replication stress, were more sensitive to loss of the 9-1-1 complex in the presence of 5-fluorodeoxyuridine. Thus, our results suggest that strains carrying circular chromosomes exhibit a greater dependence on DNA damage checkpoints to ensure viability in the presence of 5-fluorodeoxyuridine compared to stains that have linear chromosomes. PMID- 29121085 TI - Biomechanical simulation of vocal fold dynamics in adults based on laryngeal high speed videoendoscopy. AB - MOTIVATION: Human voice is generated in the larynx by the two oscillating vocal folds. Owing to the limited space and accessibility of the larynx, endoscopic investigation of the actual phonatory process in detail is challenging. Hence the biomechanics of the human phonatory process are still not yet fully understood. Therefore, we adapt a mathematical model of the vocal folds towards vocal fold oscillations to quantify gender and age related differences expressed by computed biomechanical model parameters. METHODS: The vocal fold dynamics are visualized by laryngeal high-speed videoendoscopy (4000 fps). A total of 33 healthy young subjects (16 females, 17 males) and 11 elderly subjects (5 females, 6 males) were recorded. A numerical two-mass model is adapted to the recorded vocal fold oscillations by varying model masses, stiffness and subglottal pressure. For adapting the model towards the recorded vocal fold dynamics, three different optimization algorithms (Nelder-Mead, Particle Swarm Optimization and Simulated Bee Colony) in combination with three cost functions were considered for applicability. Gender differences and age-related kinematic differences reflected by the model parameters were analyzed. RESULTS AND CONCLUSION: The biomechanical model in combination with numerical optimization techniques allowed phonatory behavior to be simulated and laryngeal parameters involved to be quantified. All three optimization algorithms showed promising results. However, only one cost function seems to be suitable for this optimization task. The gained model parameters reflect the phonatory biomechanics for men and women well and show quantitative age- and gender-specific differences. The model parameters for younger females and males showed lower subglottal pressures, lower stiffness and higher masses than the corresponding elderly groups. Females exhibited higher subglottal pressures, smaller oscillation masses and larger stiffness than the corresponding similar aged male groups. Optimizing numerical models towards vocal fold oscillations is useful to identify underlying laryngeal components controlling the phonatory process. PMID- 29121086 TI - Improved segmented modified Look-Locker inversion recovery T1 mapping sequence in mice. AB - OBJECT: To develop and evaluate a 2D modified Look-Locker (MOLLI) for high resolution T1 mapping in mice using a 3T MRI scanner. MATERIALS AND METHODS: To allow high-resolution T1 mapping in mice at high heart rates a multi-shot ECG triggered 2D MOLLI sequence was developed. In the proposed T1 mapping sequence the optimal number of sampling points and pause cardiac cycles following an initial adiabatic inversion pulse was investigated in a phantom. Seven native control and eight mice, 3 days post myocardial infarction (MI) after administration of gadolinium were scanned. Two experienced readers graded the visual T1 map quality. RESULTS: In T1 phantoms, there were no significant differences (<0.4% error) between 12, 15 and 20 pause cardiac cycles (p = 0.1, 0.2 and 0.6 respectively) for 8 acquisition cardiac cycles for 600bpm in comparison to the conventional inversion recovery spin echo T1 mapping sequence for short T1's (<600 ms). Subsequently, all in-vivo scans were performed with 8 data acquisitions and 12 pause cardiac cycles to minimize scan time. The mean native T1 value of myocardium in control animal was 820.5+/-52 ms. The post contrast T1 measured 3 days after MI in scar was 264+/-59 ms and in healthy myocardium was 512+/-62 ms. The Bland-Altman analysis revealed mean difference of only -1.06% of infarct size percentage between T1 maps and LGE. CONCLUSIONS: A multi-shot 2D MOLLI sequence has been presented that allows reliable measurement of high spatial resolution T1 maps in mice for heart rates up to 600bpm. PMID- 29121087 TI - The gram-negative sensing receptor PGRP-LC contributes to grooming induction in Drosophila. AB - Behavioral resistance protects insects from microbial infection. However, signals inducing insect hygiene behavior are still relatively unexplored. Our previous study demonstrated that olfactory signals from microbes enhance insect hygiene behavior, and gustatory signals even induce the behavior. In this paper, we postulated a cross-talk between behavioral resistance and innate immunity. To examine this hypothesis, we employed a previously validated behavioral test to examine the function of taste signals in inducing a grooming reflex in decapitated flies. Microbes, which activate different pattern recognition systems upstream of immune pathways, were applied to see if there was any correlation between microbial perception and grooming reflex. To narrow down candidate elicitors, the grooming induction tests were conducted with highly purified bacterial components. Lastly, the role of DAP-type peptidoglycan in grooming induction was confirmed. Our results demonstrate that cleaning behavior can be triggered through recognition of DAP-type PGN by its receptor PGRP-LC. PMID- 29121088 TI - Vaccination and nutritional status of children in Karawari, East Sepik Province, Papua New Guinea. AB - Delivery of health care services to rural and remote populations in Papua New Guinea (PNG) is problematic. This is mainly due to difficulties with transportation and communication. Hence, the children in this region of PNG are likely to be at risk of malnutrition compounded by inadequate vaccination that may predispose them to preventable diseases. This study was conducted to determine the vaccination and nutritional status of children less than 5 years old in the remote and rural Karawari area of PNG. 105 children were included in the study, of whom 55% were male and 45% female. The mean age of children included in the study was 32.6 months. Their age, height, and weight by gender was not significantly different. Overall, 85% of children had incomplete vaccination. However, children above the median age of 32 months (34%) were more likely to be fully vaccinated for their age, chi2 (1) = 23.294, p < 0.005. In addition, 25% of children were below the -1 SD (Z-scores) for weight-for-height, 33% below the -1 SD for weight-for-age, and 25.5% below the -1 SD for height-for age compared to WHO standards. A large proportion of children had poor nutrition status and lack protection from vaccine preventable diseases. This study recommends that the government should introduce a surveillance system for detecting issues of importance to the rural majority. We also recommend that the PNG government reopen the nearby health centre, and/ or establish new facilities within the region, with adequately trained and compensated staff. PMID- 29121089 TI - Habitat suitability and movement corridors of grey wolf (Canis lupus) in Northern Pakistan. AB - Habitat suitability models are useful to understand species distribution and to guide management and conservation strategies. The grey wolf (Canis lupus) has been extirpated from most of its historic range in Pakistan primarily due to its impact on livestock and livelihoods. We used non-invasive survey data from camera traps and genetic sampling to develop a habitat suitability model for C. lupus in northern Pakistan and to explore the extent of connectivity among populations. We detected suitable habitat of grey wolf using a maximum entropy approach (Maxent ver. 3.4.0) and identified suitable movement corridors using the Circuitscape 4.0 tool. Our model showed high levels of predictive performances, as seen from the values of area under curve (0.971+/-0.002) and true skill statistics (0.886+/ 0.021). The main predictors for habitat suitability for C. lupus were distances to road, mean temperature of the wettest quarter and distance to river. The model predicted ca. 23,129 km2 of suitable areas for wolf in Pakistan, with much of suitable habitat in remote and inaccessible areas that appeared to be well connected through vulnerable movement corridors. These movement corridors suggest that potentially the wolf range can expand in Pakistan's Northern Areas. However, managing protected areas with stringent restrictions is challenging in northern Pakistan, in part due to heavy dependence of people on natural resources. The habitat suitability map provided by this study can inform future management strategies by helping authorities to identify key conservation areas. PMID- 29121090 TI - Differences between racing and non-racing drivers: A simulator study using eye tracking. AB - Motorsport has developed into a professional international competition. However, limited research is available on the perceptual and cognitive skills of racing drivers. By means of a racing simulator, we compared the driving performance of seven racing drivers with ten non-racing drivers. Participants were tasked to drive the fastest possible lap time. Additionally, both groups completed a choice reaction time task and a tracking task. Results from the simulator showed faster lap times, higher steering activity, and a more optimal racing line for the racing drivers than for the non-racing drivers. The non-racing drivers' gaze behavior corresponded to the tangent point model, whereas racing drivers showed a more variable gaze behavior combined with larger head rotations while cornering. Results from the choice reaction time task and tracking task showed no statistically significant difference between the two groups. Our results are consistent with the current consensus in sports sciences in that task-specific differences exist between experts and novices while there are no major differences in general cognitive and motor abilities. PMID- 29121091 TI - Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension. AB - OBJECTIVE: In order to search for metabolic biomarkers of antihypertensive drug responsiveness, we measured >600 biochemicals in plasma samples of subjects participating in the GENRES Study. Hypertensive men received in a double-blind rotational fashion amlodipine, bisoprolol, hydrochlorothiazide and losartan, each as a monotherapy for one month, with intervening one-month placebo cycles. METHODS: Metabolomic analysis was carried out using ultra high performance liquid chromatography-tandem mass spectrometry. Full metabolomic signatures (the drug cycles and the mean of the 3 placebo cycles) became available in 38 to 42 patients for each drug. Blood pressure was monitored by 24-h recordings. RESULTS: Amlodipine (P values down to 0.002), bisoprolol (P values down to 2 x 10-5) and losartan (P values down to 2 x 10-4) consistently decreased the circulating levels of long-chain acylcarnitines. Bisoprolol tended to decrease (P values down to 0.002) the levels of several medium- and long-chain fatty acids. Hydrochlorothiazide administration was associated with an increase of plasma uric acid level (P = 5 x 10-4) and urea cycle metabolites. Decreases of both systolic (P = 0.06) and diastolic (P = 0.04) blood pressure after amlodipine administration tended to associate with a decrease of plasma hexadecanedioate, a dicarboxylic fatty acid recently linked to blood pressure regulation. CONCLUSIONS: Although this systematic metabolomics study failed to identify circulating metabolites convincingly predicting favorable antihypertensive response to four different drug classes, it provided accumulating evidence linking fatty acid metabolism to human hypertension. PMID- 29121092 TI - Relationship between fine particulate matter, weather condition and daily non accidental mortality in Shanghai, China: A Bayesian approach. AB - There are concerns that the reported association of ambient fine particulate matter (PM2.5) with mortality might be a mixture of PM2.5 and weather conditions. We evaluated the effects of extreme weather conditions and weather types on mortality as well as their interactions with PM2.5 concentrations in a time series study. Daily non-accidental deaths, individual demographic information, daily average PM2.5 concentrations and meteorological data between 2012 and 2014 were obtained from Shanghai, China. Days with extreme weather conditions were identified. Six synoptic weather types (SWTs) were generated. The generalized additive model was set up to link the mortality with PM2.5 and weather conditions. Parameter estimation was based on Bayesian methods using both the Jeffreys' prior and an informative normal prior in a sensitivity analysis. We estimate the percent increase in non-accidental mortality per 10 MUg/m3 increase in PM2.5 concentration and constructed corresponding 95% credible interval (CrI). In total, 336,379 non-accidental deaths occurred during the study period. Average daily deaths were 307. The results indicated that per 10 MUg/m3 increase in daily average PM2.5 concentration alone corresponded to 0.26-0.35% increase in daily non-accidental mortality in Shanghai. Statistically significant positive associations between PM2.5 and mortality were found for favorable SWTs when considering the interaction between PM2.5 and SWTs. The greatest effect was found in hot dry SWT (percent increase = 1.28, 95% CrI: 0.72, 1.83), followed by warm humid SWT (percent increase = 0.64, 95% CrI: 0.15, 1.13). The effect of PM2.5 on non-accidental mortality differed under specific extreme weather conditions and SWTs. Environmental policies and actions should take into account the interrelationship between the two hazardous exposures. PMID- 29121093 TI - Fish oil omega-3 polyunsaturated fatty acids attenuate oxidative stress-induced DNA damage in vascular endothelial cells. AB - OBJECTIVE: Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), likely prevent cardiovascular disease, however their mechanisms remain unclear. Recently, the role of DNA damage in atherogenesis has been receiving considerable attention. Here, we investigated the effects of EPA and DHA on DNA damage in vascular endothelial cells to clarify their antiatherogenic mechanisms. METHODS AND RESULTS: We determined the effect of EPA and DHA on H2O2-induced DNA damage response in human aortic endothelial cells. Immunofluorescence staining showed that gamma-H2AX foci formation, a prominent marker of DNA damage, was significantly reduced in the cells treated with EPA and DHA (by 47% and 48%, respectively). H2O2-induced activation of ATM, a major kinase orchestrating DNA damage response, was significantly reduced with EPA and DHA treatment (by 31% and 33%, respectively). These results indicated EPA and DHA attenuated DNA damage independently of the DNA damage response. Thus the effects of EPA and DHA on a source of DNA damage were examined. EPA and DHA significantly reduced intracellular reactive oxygen species under both basal condition and H2O2 stimulation. In addition, the mRNA levels of antioxidant molecules, such as heme oxygenase-1, thioredoxin reductase 1, ferritin light chain, ferritin heavy chain and manganese superoxide dismutase, were significantly increased with EPA and DHA. Silencing nuclear factor erythroid 2-related factor 2 (NRF2) remarkably abrogated the increases in mRNA levels of antioxidant molecules and the decrease in intracellular reactive oxygen species. Furthermore, EPA and DHA significantly reduced H2O2-induced senescence-associated beta-galactosidase activity in the cells (by 31% and 22%, respectively), which was revoked by NRF2 silencing. CONCLUSIONS: Our results suggested that EPA and DHA attenuate oxidative stress induced DNA damage in vascular endothelial cells through upregulation of NRF2 mediated antioxidant response. Therefore omega-3 fatty acids likely help prevent cardiovascular disease, at least in part, by their genome protective properties. PMID- 29121094 TI - Pleckstrin homology-like domain family A, member 3 (PHLDA3) deficiency improves islets engraftment through the suppression of hypoxic damage. AB - Islet transplantation is a useful cell replacement therapy that can restore the glycometabolic function of severe diabetic patients. It is known that many transplanted islets failed to engraft, and thus, new approaches for overcoming graft loss that may improve the outcome of future clinical islet transplantations are necessary. Pleckstrin homology-like domain family A, member 3 (PHLDA3) is a known suppressor of neuroendocrine tumorigenicity, yet deficiency of this gene increases islet proliferation, prevents islet apoptosis, and improves their insulin-releasing function without causing tumors. In this study, we examined the potential use of PHLDA3-deficient islets in transplantation. We observed that: 1) transplanting PHLDA3-deficient islets into diabetic mice significantly improved their glycometabolic condition, 2) the improved engraftment of PHLDA3-deficient islets resulted from increased cell survival during early transplantation, and 3) Akt activity was elevated in PHLDA3-deficient islets, especially under hypoxic conditions. Thus, we determined that PHLDA3-deficient islets are more resistant against stresses induced by islet isolation and transplantation. We conclude that use of islets with suppressed PHLDA3 expression could be a novel and promising treatment for improving engraftment and consequent glycemic control in islet transplantation. PMID- 29121095 TI - The pedunculopontine tegmentum controls renal sympathetic nerve activity and cardiorespiratory activities in nembutal-anesthetized rats. AB - Elevated renal sympathetic nerve activity (RSNA) accompanies a variety of complex disorders, including obstructive sleep apnea, heart failure, and chronic kidney disease. Understanding pathophysiologic renal mechanisms is important for determining why hypertension is both a common sequelae and a predisposing factor of these disorders. The role of the brainstem in regulating RSNA remains incompletely understood. The pedunculopontine tegmentum (PPT) is known for regulating behaviors including alertness, locomotion, and rapid eye movement sleep. Activation of PPT neurons in anesthetized rats was previously found to increase splanchnic sympathetic nerve activity and blood pressure, in addition to altering breathing. The present study is the first investigation of the PPT and its potential role in regulating RSNA. Microinjections of DL-homocysteic acid (DLH) were used to probe the PPT in 100-MUm increments in Nembutal-anesthetized rats to identify effective sites, defined as locations where changes in RSNA could be evoked. A total of 239 DLH microinjections were made in 18 rats, which identified 20 effective sites (each confirmed by the ability to evoke a repeatable sympathoexcitatory response). Peak increases in RSNA occurred within 10-20 seconds of PPT activation, with RSNA increasing by 104.5 +/- 68.4% (mean +/ standard deviation) from baseline. Mean arterial pressure remained significantly elevated for 30 seconds, increasing from 101.6 +/- 18.6 mmHg to 135.9 +/- 36.4 mmHg. DLH microinjections also increased respiratory rate and minute ventilation. The effective sites were found throughout the rostal-caudal extent of the PPT with most located in the dorsal regions of the nucleus. The majority of PPT locations tested with DLH microinjections did not alter RSNA (179 sites), suggesting that the neurons that confer renal sympathoexcitatory functions comprise a small component of the PPT. The study also underscores the importance of further investigation to determine whether sympathoexcitatory PPT neurons contribute to adverse renal and cardiovascular consequences of diseases such as obstructive sleep apnea and heart failure. PMID- 29121096 TI - Personal exposure to fine particulate air pollution while commuting: An examination of six transport modes on an urban arterial roadway. AB - Traffic-related air pollution in urban areas contributes significantly to commuters' daily PM2.5 exposures, but varies widely depending on mode of commuting. To date, studies show conflicting results for PM2.5 exposures based on mode of commuting, and few studies compare multiple modes of transportation simultaneously along a common route, making inter-modal comparisons difficult. In this study, we examined breathing zone PM2.5 exposures for six different modes of commuting (bicycle, walking, driving with windows open and closed, bus, and light rail train) simultaneously on a single 2.7 km (1.68 mile) arterial urban route in Salt Lake City, Utah (USA) during peak "rush hour" times. Using previously published minute ventilation rates, we estimated the inhaled dose and exposure rate for each mode of commuting. Mean PM2.5 concentrations ranged from 5.20 MUg/m3 for driving with windows closed to 15.21 MUg/m3 for driving with windows open. The estimated inhaled doses over the 2.7 km route were 6.83 MUg for walking, 2.78 MUg for cycling, 1.28 MUg for light-rail train, 1.24 MUg for driving with windows open, 1.23 MUg for bus, and 0.32 MUg for driving with windows closed. Similarly, the exposure rates were highest for cycling (18.0 MUg/hr) and walking (16.8 MUg/hr), and lowest for driving with windows closed (3.7 MUg/hr). Our findings support previous studies showing that active commuters receive a greater PM2.5 dose and have higher rates of exposure than commuters using automobiles or public transportation. Our findings also support previous studies showing that driving with windows closed is protective against traffic related PM2.5 exposure. PMID- 29121098 TI - Correction: Skeleton of an unusual, cat-sized marsupial relative (Metatheria: Marsupialiformes) from the middle Eocene (Lutetian: 44-43 million years ago) of Turkey. AB - [This corrects the article DOI: 10.1371/journal.pone.0181712.]. PMID- 29121097 TI - Sex-based differences in veterans with pulmonary hypertension: Results from the veterans affairs-clinical assessment reporting and tracking database. AB - Women have an increased risk of pulmonary hypertension (PH) but better survival compared to men. Few studies have explored sex-based differences in population based cohorts with PH. We sought to determine whether sex was associated with hemodynamics and survival in US veterans with PH (mean pulmonary artery pressure [mPAP] >= 25 mm Hg) from the Veterans Affairs Clinical Assessment, Reporting, and Tracking database. The relationship between sex and hemodynamics was assessed with multivariable linear mixed modeling. Cox proportional hazards models were used to compare survival by sex for those with PH and precapillary PH (mPAP >= 25 mm Hg, pulmonary artery wedge pressure [PAWP] <= 15 mm Hg and pulmonary vascular resistance [PVR] > 3 Wood units) respectively. The study population included 15,464 veterans with PH, 516 (3%) of whom were women; 1,942 patients (13%) had precapillary PH, of whom 120 (6%) were women. Among those with PH, women had higher PVR and pulmonary artery pulse pressure, and lower right atrial pressure and PAWP (all p <0.001) compared with men. There were no significant differences in hemodynamics according to sex in veterans with precapillary PH. Women with PH had 18% greater survival compared to men with PH (adjusted HR 0.82, 95% CI 0.69 0.97, p = 0.020). Similarly, women with precapillary PH were 29% more likely to survive as compared to men with PH (adjusted HR 0.71, 95% CI 0.52-0.98, p = 0.040). In conclusion, female veterans with PH have better survival than males despite higher pulmonary afterload. PMID- 29121099 TI - Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components. AB - Dengue virus (DENV) is the most prevalent, medically important mosquito-borne virus. Disease ranges from uncomplicated dengue to life-threatening disease, characterized by endothelial dysfunction and vascular leakage. Previously, we demonstrated that DENV nonstructural protein 1 (NS1) induces endothelial hyperpermeability in a systemic mouse model and human pulmonary endothelial cells, where NS1 disrupts the endothelial glycocalyx-like layer. NS1 also triggers release of inflammatory cytokines from PBMCs via TLR4. Here, we examined the relative contributions of inflammatory mediators and endothelial cell intrinsic pathways. In vivo, we demonstrated that DENV NS1 but not the closely related West Nile virus NS1 triggers localized vascular leak in the dorsal dermis of wild-type C57BL/6 mice. In vitro, we showed that human dermal endothelial cells exposed to DENV NS1 do not produce inflammatory cytokines (TNF-alpha, IL-6, IL-8) and that blocking these cytokines does not affect DENV NS1-induced endothelial hyperpermeability. Further, we demonstrated that DENV NS1 induces vascular leak in TLR4- or TNF-alpha receptor-deficient mice at similar levels to wild-type animals. Finally, we blocked DENV NS1-induced vascular leak in vivo using inhibitors targeting molecules involved in glycocalyx disruption. Taken together, these data indicate that DENV NS1-induced endothelial cell-intrinsic vascular leak is independent of inflammatory cytokines but dependent on endothelial glycocalyx components. PMID- 29121100 TI - A community detection algorithm using network topologies and rule-based hierarchical arc-merging strategies. AB - The authors use four criteria to examine a novel community detection algorithm: (a) effectiveness in terms of producing high values of normalized mutual information (NMI) and modularity, using well-known social networks for testing; (b) examination, meaning the ability to examine mitigating resolution limit problems using NMI values and synthetic networks; (c) correctness, meaning the ability to identify useful community structure results in terms of NMI values and Lancichinetti-Fortunato-Radicchi (LFR) benchmark networks; and (d) scalability, or the ability to produce comparable modularity values with fast execution times when working with large-scale real-world networks. In addition to describing a simple hierarchical arc-merging (HAM) algorithm that uses network topology information, we introduce rule-based arc-merging strategies for identifying community structures. Five well-studied social network datasets and eight sets of LFR benchmark networks were employed to validate the correctness of a ground truth community, eight large-scale real-world complex networks were used to measure its efficiency, and two synthetic networks were used to determine its susceptibility to two resolution limit problems. Our experimental results indicate that the proposed HAM algorithm exhibited satisfactory performance efficiency, and that HAM-identified and ground-truth communities were comparable in terms of social and LFR benchmark networks, while mitigating resolution limit problems. PMID- 29121101 TI - Validation of a light-scattering PM2.5 sensor monitor based on the long-term gravimetric measurements in field tests. AB - BACKGROUND: Portable direct-reading instruments by light-scattering method are increasingly used in airborne fine particulate matter (PM2.5) monitoring. However, there are limited calibration studies on such instruments by applying the gravimetric method as reference method in field tests. METHODS: An 8-month sampling was performed and 96 pairs of PM2.5 data by both the gravimetric method and the simultaneous light-scattering real-time monitoring (QT-50) were obtained from July, 2015 to February, 2016 in Shanghai. Temperature and relative humidity (RH) were recorded. Mann-Whitney U nonparametric test and Spearman correlation were used to investigate the differences between the two measurements. Multiple linear regression (MLR) model was applied to set up the calibration model for the light-scattering device. RESULTS: The average PM2.5 concentration (median) was 48.1MUg/m3 (min-max 10.4-95.8MUg/m3) by the gravimetric method and 58.1MUg/m3 (19.2-315.9MUg/m3) by the light-scattering method, respectively. By time trend analyses, they were significantly correlated with each other (Spearman correlation coefficient 0.889, P<0.01). By MLR, the calibration model for the light-scattering instrument was Y(calibrated) = 57.45 + 0.47 * X(the QT - 50 measurements) - 0.53 * RH - 0.41 * Temp with both RH and temperature adjusted. The 10-fold cross-validation R2 and the root mean squared error of the calibration model were 0.79 and 11.43 MUg/m3, respectively. CONCLUSION: Light scattering measurements of PM2.5 by QT-50 instrument overestimated the concentration levels and were affected by temperature and RH. The calibration model for QT-50 instrument was firstly set up against the gravimetric method with temperature and RH adjusted. PMID- 29121103 TI - Central conduction time in auditory brainstem response and ear advantage in dichotic listening across menstrual cycle. AB - The ovarian hormones fluctuate during the menstrual cycle in women. Such fluctuation of sex hormones, in particular estrogen, is believed to affect the central conduction time in auditory function as well as the language lateralization in cognitive function. However, findings are inconsistent. The underlying mechanisms are also unclear. This paper examined if there was any relation between the central conduction time and the language lateralization at different times during the menstrual cycle. Twenty young women with normal menstrual cycle were tested four times (5 to 7 days apart) across the menstrual cycle. The test battery included the electrophysiological measurement of auditory evoked response in brainstem and the speech performance in dichotic listening with monosyllables as stimulus pairs. The dichotic listening task was conducted under the non-forced, forced-right and forced-left attention. The central conduction time was defined by the time elapsed between two auditory elicited responses along the auditory pathway. The language lateralization in dichotic listening was expressed in ear advantage, which was the right-ear score minus the left-ear score. The results showed that the effects of test time were significant on both the central conduction time and the ear advantage under the forced-left attention. Overall, the interaural difference in the central conduction time correlates with the ear advantage (non-forced attention) at the beginning of the menstrual cycle. The change in central conduction time between two test times correlates significantly with the change in ear advantage under the non-forced and forced-left attention. Conclusively, the central conduction time depends on the time during the menstrual cycle, which in turn may affect the performance in dichotic listening. PMID- 29121102 TI - Histopathologic and immunohistochemical features of capsular tissue around failed Ahmed glaucoma valves. AB - Impervious encapsulation around Ahmed glaucoma valve (AGV) results in surgical failure raising intraocular pressure (IOP). Dysregulation of extracellular matrix (ECM) molecules and cellular factors might contribute to increased hydraulic resistance to aqueous drainage. Therefore, we examined these molecules in failed AGV capsular tissue. Immunostaining for ECM molecules (collagen I, collagen III, decorin, lumican, chondroitin sulfate, aggrecan and keratan sulfate) and cellular factors (alphaSMA and TGFbeta) was performed on excised capsules from failed AGVs and control tenon's tissue. Staining intensity of ECM molecules was assessed using Image J. Cellular factors were assessed based on positive cell counts. Histopathologically two distinct layers were visible in capsules. The inner layer (proximal to the AGV) showed significant decrease in most ECM molecules compared to outer layer. Furthermore, collagen III (p = 0.004), decorin (p = 0.02), lumican (p = 0.01) and chondroitin sulfate (p = 0.02) was significantly less in inner layer compared to tenon's tissue. Outer layer labelling however was similar to control tenon's for most ECM molecules. Significantly increased cellular expression of alphaSMA (p = 0.02) and TGFbeta (p = 0.008) was detected within capsular tissue compared to controls. Our results suggest profibrotic activity indicated by increased alphaSMA and TGFbeta expression and decreased expression of proteoglycan (decorin and lumican) and glycosaminoglycans (chondroitin sulfate). Additionally, we observed decreased collagen III which might reflect increased myofibroblast contractility when coupled with increased TGFbeta and alphaSMA expression. Together these events lead to tissue dysfunction potentially resulting in hydraulic resistance that may affect aqueous flow through the capsular wall. PMID- 29121104 TI - Evaluation of the major changes in eighth edition of the American Joint Committee on Cancer pathological staging for prostate cancer treated with prostatectomy. AB - This study aimed to evaluate the major changes of the eighth edition of the American Joint Committee on Cancer (AJCC) pathologic staging for prostate cancer treated with radical prostatectomy. A total of 138,176 patients diagnosed with prostate adenocarcinoma undergoing radical prostatectomy were selected from the Surveillance, Epidemiology and End Results (SEER) database during 2004-2014 period. Excluded were cases with incomplete or unavailable staging, PSA and Gleason score information. Two subgroups were established: group a, T2 stage with PSA>=20ng/ml; group b, T2 stage with Gleason score grade group 5 and PSA<20ng/ml. The median follow-up time was 58 months. The median age at diagnosis for the overall group was 61 years, and the median PSA was 5.7ng/ml. Cancer-specific survival (CSS) at tenth years was 99.3% for T2a/T2b, 99.2% for T2c, respectively. The survival differences between T2a/T2b and T2c did not have statistical significance (P = .323). It was necessary for the current eighth edition to define a single pathologic T2 category, eliminating the subcategories, for all organ-confined disease.CSS at the tenth years was 98.4% for group a, 92.6% for group b, respectively. The prognosis of group a was worse than AJCC II (P = .002). The prognosis of group b was not only worse than AJCC II (P < .001), but also worse than AJCC IIIB. There was necessity to separate the disease with PSA>=20ng/ml or Gleason score grade group 5 from other organ-confined disease. The present study supported the scientificity of the eighth edition of AJCC pathologic staging for prostate cancer. PMID- 29121105 TI - Economic evaluation of the one-hour rule-out and rule-in algorithm for acute myocardial infarction using the high-sensitivity cardiac troponin T assay in the emergency department. AB - BACKGROUND: The 1-hour (h) algorithm triages patients presenting with suspected acute myocardial infarction (AMI) to the emergency department (ED) towards "rule out," "rule-in," or "observation," depending on baseline and 1-h levels of high sensitivity cardiac troponin (hs-cTn). The economic consequences of applying the accelerated 1-h algorithm are unknown. METHODS AND FINDINGS: We performed a post hoc economic analysis in a large, diagnostic, multicenter study of hs-cTnT using central adjudication of the final diagnosis by two independent cardiologists. Length of stay (LoS), resource utilization (RU), and predicted diagnostic accuracy of the 1-h algorithm compared to standard of care (SoC) in the ED were estimated. The ED LoS, RU, and accuracy of the 1-h algorithm was compared to that achieved by the SoC at ED discharge. Expert opinion was sought to characterize clinical implementation of the 1-h algorithm, which required blood draws at ED presentation and 1h, after which "rule-in" patients were transferred for coronary angiography, "rule-out" patients underwent outpatient stress testing, and "observation" patients received SoC. Unit costs were for the United Kingdom, Switzerland, and Germany. The sensitivity and specificity for the 1-h algorithm were 87% and 96%, respectively, compared to 69% and 98% for SoC. The mean ED LoS for the 1-h algorithm was 4.3h-it was 6.5h for SoC, which is a reduction of 33%. The 1-h algorithm was associated with reductions in RU, driven largely by the shorter LoS in the ED for patients with a diagnosis other than AMI. The estimated total costs per patient were L2,480 for the 1-h algorithm compared to L4,561 for SoC, a reduction of up to 46%. CONCLUSIONS: The analysis shows that the use of 1 h algorithm is associated with reduction in overall AMI diagnostic costs, provided it is carefully implemented in clinical practice. These results need to be prospectively validated in the future. PMID- 29121106 TI - Proteomics of Staphylococcus aureus biofilm matrix in a rat model of orthopedic implant-associated infection. AB - The matrix proteins of Staphylococcus aureus biofilm have not been well defined. Previous efforts to identify these proteins were performed using in vitro systems. Here we use a proteomic approach to identify biofilm matrix proteins directly from infected bone implants using a rat model of orthopedic implant associated S. aureus infection. Despite heavy presence of host proteins, a total of 28 and 105 S. aureus proteins were identified during acute infection and chronic infection, respectively. Our results show that biofilm matrix contains mostly intracellular cytoplasmic proteins and, to a much less extent, extracellular and cell surface-associated proteins. Significantly, leukocidins were identified in the biofilm matrix during chronic infection, suggesting S. aureus is actively attacking the host immune system even though they are protected within the biofilm. The presence of two surface-associated proteins, Ebh and SasF, in the infected bone tissue during acute infection was confirmed by immunohistochemistry. In addition, a large number of host proteins were found differentially expressed in response to S. aureus biofilm formed on bone implants. PMID- 29121107 TI - Durability of immunity by hepatitis B vaccine in Japanese health care workers depends on primary response titers and durations. AB - BACKGROUND: Health care workers (HCWs) are frequently exposed to hepatitis B virus (HBV) infection. The efficacy and safety of immunization with the hepatitis B (HB) vaccine are well recognized, but the durability of immunity and need for booster doses in those with secondary vaccine response failure remains controversial. METHODS: This was a retrospective cohort study performed at Osaka University Hospital, Japan. We examined antibodies against HB surface antigen (anti-HBs) titers annually after immunization for previously non-immunized HCWs. Primary responders were categorized by their sero-positive durations as short responders (those whose anti-HBs titers declined to negative range within 3 years), and long responders (those who retained positive anti-HBs levels for 3 years and more). We re-immunized short responders with either single or 3-dose boosters, the long responders with a single booster when their titers dropped below protective levels, and examined their sero-protection rates over time thereafter. RESULTS: From 2001 to 2012, data of 264 HCWs with a median age of 25.3 were collected. The rate of anti-HBs positivity after primary vaccination were 93.0% after three doses (n = 229), 54.5% after two doses (n = 11), and 4.2% after a single dose (n = 24). Of 213 primary responders, the anti-HBs levels of 95 participants (44.6%) fell below the protective levels, including 46 short responders and 49 long responders. HCWs with higher initial anti-HBs titers after primary vaccination had significantly longer durations of sero-positivity. For short responders, 3-dose booster vaccination induced a longer duration of anti HBs positivity compared to a single-dose booster, whereas for long responders, a single-dose booster alone could induce prolonged anti-HBs positivity. CONCLUSION: Our preliminary data suggested that it may be useful to differentiate HB vaccine responders based on their primary response durations to maintain protective levels of anti-HBs efficiently. A randomized, prospective, large-scale study is warranted to support our findings. PMID- 29121108 TI - Spatio-temporal dynamics of multimodal EEG-fNIRS signals in the loss and recovery of consciousness under sedation using midazolam and propofol. AB - On sedation motivated by the clinical needs for safety and reliability, recent studies have attempted to identify brain-specific signatures for tracking patient transition into and out of consciousness, but the differences in neurophysiological effects between 1) the sedative types and 2) the presence/absence of surgical stimulations still remain unclear. Here we used multimodal electroencephalography-functional near-infrared spectroscopy (EEG fNIRS) measurements to observe electrical and hemodynamic responses during sedation simultaneously. Forty healthy volunteers were instructed to push the button to administer sedatives in response to auditory stimuli every 9-11 s. To generally illustrate brain activity at repetitive transition points at the loss of consciousness (LOC) and the recovery of consciousness (ROC), patient controlled sedation was performed using two different sedatives (midazolam (MDZ) and propofol (PPF)) under two surgical conditions. Once consciousness was lost via sedatives, we observed gradually increasing EEG power at lower frequencies (<15 Hz) and decreasing power at higher frequencies (>15 Hz), as well as spatially increased EEG powers in the delta and lower alpha bands, and particularly also in the upper alpha rhythm, at the frontal and parieto-occipital areas over time. During ROC from unconsciousness, these spatio-temporal changes were reversed. Interestingly, the level of consciousness was switched on/off at significantly higher effect-site concentrations of sedatives in the brain according to the use of surgical stimuli, but the spatio-temporal EEG patterns were similar, regardless of the sedative used. We also observed sudden phase shifts in fronto-parietal connectivity at the LOC and the ROC as critical points. fNIRS measurement also revealed mild hemodynamic fluctuations. Compared with general anesthesia, our results provide insights into critical hallmarks of sedative-induced (un)consciousness, which have similar spatio-temporal EEG-fNIRS patterns regardless of the stage and the sedative used. PMID- 29121109 TI - iTRAQ-based quantitative proteomic analysis in vernalization-treated faba bean (Vicia faba L.). AB - Vernalization is classically defined as the induction of flowering process by exposure of the plants to a prolonged cold condition. Normally, it is considered as a precondition of flowering. Vicia faba, commonly known as faba bean, belongs to family Fabaceae. It is one of the plant species that has been cultivated in the earliest human settlements. In this study, an iTRAQ-LC-MS/MS-based quantitative proteomic analysis has been conducted to compare the vernalized faba bean seedlings and its corresponding control. In total, 91 proteins from various functional categories were observed to be differentially accumulated in vernalized faba bean seedlings. Subsequent gene ontology analysis indicated that several biological processes or metabolic pathways including photosynthesis and phytic acid metabolism were differentially respond to vernalization in comparison to the control sample. Further investigation revealed that a family of proteins nominated as glycine-rich RNA-binding factor was accumulated in vernalized seedlings, indicating an extra layer of regulation by alternative splicing on transcript abundance in response to vernalization. These findings raise a possibility that these candidate proteins could be important to represent the responsive network under vernalization process. Therefore, we propose that the regulation of vernalization in faba bean not only occurs at the transcriptional level as previously reported, but also at the post-transcriptional level. PMID- 29121110 TI - Symmetry recognition by pigeons: Generalized or not? AB - This note looks into the reasons why earlier reports may have arrived at differing conclusions about pigeons' capacity to categorize bilaterally symmetric and asymmetric visual patterns. Attention is drawn to pigeons' comparatively superior visual flicker resolution and superior visual linear acuity by reporting results of two ad-hoc experiments. This circumstance turns out to constrain conclusions drawn by earlier symmetry-asymmetry studies that used computer generated patterns displayed on cathode ray tube monitors as these suffered from pictorial distortions. Additionally one of the studies involved patterns of inconsistent symmetry at global and local levels. A smaller-scale experiment using slide-projected unequivocal symmetric and asymmetric patterns yielded results compatible with the supposition that pigeons are capable of a symmetry asymmetry categorization. The possibility that an artfactual cue may have inadvertently accentuated this capability in an earlier own experiment is considered. PMID- 29121111 TI - Genetic and physical mapping of anther extrusion in elite European winter wheat. AB - The production and cultivation of hybrid wheat is a possible strategy to close the yield gap in wheat. Efficient hybrid wheat seed production largely depends on high rates of cross-pollination which can be ensured through high anther extrusion (AE) by male parental lines. Here, we report the AE capacity and elucidate its genetics in 514 elite European winter wheat varieties via genome wide association studies (GWAS). We observed a wide range of variation among genotypes and a high heritability (0.80) for AE. The whole panel was genotyped with the 35k Affymetrix and 90k iSELECT single nucleotide polymorphism (SNP) arrays plus Ppd-D1, Rht-B1 and Rht-D1 candidate markers. GWAS revealed 51 marker trait associations (MTAs) on chromosomes 1A, 1B, 2A, 4D and 5B, with Rht-D1 (4D) being the most significant marker. Division of whole panel according to the Rht D1 genotype resulted in 212 and 294 varieties harboring Rht-D1a and Rht-D1b allele, respectively. The presence of Rht-D1a compared to Rht-D1b (mutant) allele had a large phenotypic influence on AE resulting in its ~17% increase. GWAS performed on the sub-panels detected novel MTAs on chromosomes 2D, 3B and 6A with increased phenotypic variance imparted by individual markers. Our study shows that AE is a highly quantitative trait and wild type Rht-D1a allele greatly improves AE. Moreover, demarcating the quantitative trait loci regions based on intra-chromosomal linkage disequilibrium revealed AE's candidate genes/genomic regions. Understanding the genetics of AE in elite European wheat and utilizing the linked markers in breeding programs can help to enhance cross-pollination for better exploitation of heterosis. PMID- 29121112 TI - Fetal overgrowth in women with type 1 and type 2 diabetes mellitus. AB - OBJECTIVES: Despite improved glycemic control, the rate of large-for-gestational age (LGA) infants remains high in pregnancies complicated by diabetes mellitus type 1 (T1DM) and type 2 (T2DM). Poor glycemic control, obesity, and excessive gestational weight gain are the main risk factors. The aim of this study was to determine the relative contribution of these risk factors for LGA in women with T1DM and T2DM, after controlling for important confounders such as age, smoking, and parity. METHODS: In this retrospective chart review study, we analyzed the medical files of pregnant women with T1DM and T2DM who attended the antenatal care program at Skane University Hospital during the years 2006 to 2016. HbA1c was used as a measure of glycemic control. Maternal weight in early pregnancy and at term was registered. LGA was defined as birth weight > 2 standard deviations of the mean. Univariable and multivariable logistic regression analysis was used to calculate odds ratios (OR's) and 95% confidence intervals (CIs) for LGA. RESULTS: Over the 11-year period, we identified 308 singleton pregnancies in 221 women with T1DM and in 87 women with T2DM. The rate of LGA was 50% in women with T1DM and 23% in women with T2DM. The multivariable regression model identified gestational weight gain and second-trimester HbA1c as risk factors for LGA in T1DM pregnancies (OR = 1.107, 95% CI: 1.044-1.17, and OR = 1.047, 95% CI: 1.015 1.080, respectively) and gestational weight gain as a risk factor in T2DM pregnancies (OR = 1.175, 95% CI: 1.048-1.318), independent of body mass index. CONCLUSIONS: Gestational weight gain was associated with LGA in women with T1DM and T2DM, independent of maternal body mass index. The findings suggest that monitoring and regulation of gestational weight gain is important in the clinical care of these women, to minimize the risk of fetal overgrowth. PMID- 29121113 TI - Facial width-to-height ratio differs by social rank across organizations, countries, and value systems. AB - Facial Width-to-Height Ratio (fWHR) has been linked with dominant and aggressive behavior in human males. We show here that on portrait photographs published online, chief executive officers (CEOs) of companies listed in the Dow Jones stock market index and the Deutscher Aktienindex have a higher-than-normal fWHR, which also correlates positively with their company's donations to charitable causes and environmental awareness. Furthermore, we show that leaders of the world's most influential non-governmental organizations and even the leaders of the Roman Catholic Church, the popes, have higher fWHR compared to controls on public portraits, suggesting that the relationship between displayed fWHR and leadership is not limited to profit-seeking organizations. The data speak against the simplistic view that wider-faced men achieve higher social status through antisocial tendencies and overt aggression, or the mere signaling of such dispositions. Instead they suggest that high fWHR is linked with high social rank in a more subtle fashion in both competitive as well as prosocially oriented settings. PMID- 29121114 TI - CD4+ levels control the odds of induction of humoral immune responses to tracer doses of therapeutic antibodies. AB - Rapidly increasing number of therapeutic antibodies are being repurposed to imaging probes for noninvasive diagnosis, as well as monitoring during treatment or disease recurrence. Though antibody-based imaging involves tracer doses (~3 log lower than therapeutic doses), and immune responses are severely reduced in patients with impaired immunity, formation of anti-tracer antibodies (ATA) has been observed hampering further diagnostic monitoring. Here, we explored the potential to develop humoral responses to intravenously administered tracer dose of a monoclonal antibody F(ab?)2 fragment, and associated with host related immune measures in 49 rhesus macaques categorized into healthy (uninfected controls), SIV-progressors, SIV non-progressors, or total body irradiated (TBI). Antibody fragment administered in tracer amount (~100MUg) induced immune responses with significantly lower odds in SIV-progressors or TBI macaques (P<0.005) as compared to healthy animals. Peripheral blood (PB) CD4+ cell counts, but not CD20+ cell levels, were associated with significantly higher risk of developing a humoral response (P<0.001). Doubling the PB CD4+ counts is associated with an odds ratio of developing an immune response of 1.73. Among SIV infected animals, CD4+ cell count was a stronger predictor of immune response than plasma SIV-RNA levels. Both SIV-progressors and TBI macaques showed higher odds of responses with increasing CD4+ counts, however when compared to healthy or SIV non-progressors with similar CD4+ count, they were still functionally incompetent in generating a response (P<0.01). Moreover, presence of ATA in systemic circulation altered the in vivo biodistribution by increasing hepatic uptake and decreasing plasma radiotracer clearance, with minimal to no binding detected in targeted tissues. PMID- 29121116 TI - Got herpes? (Yep, you probably do!). PMID- 29121117 TI - Correction: Genome-Wide Investigation Using sRNA-Seq, Degradome-Seq and Transcriptome-Seq Reveals Regulatory Networks of microRNAs and Their Target Genes in Soybean during Soybean mosaic virus Infection. AB - [This corrects the article DOI: 10.1371/journal.pone.0150582.]. PMID- 29121115 TI - The response of gene expression associated with lipid metabolism, fat deposition and fatty acid profile in the longissimus dorsi muscle of Gannan yaks to different energy levels of diets. AB - The energy available from the diet, which affects fat deposition in vivo, is a major factor in the expression of genes regulating fat deposition in the longissimus dorsi muscle. Providing high-energy diets to yaks might increase intramuscular fat deposition and fatty acid concentrations under a traditional grazing system in cold seasons. A total of fifteen adult castrated male yaks with an initial body weight 274.3 +/- 3.14 kg were analyzed for intramuscular adipose deposition and fatty acid composition. The animals were divided into three groups and fed low-energy (LE: 5.5 MJ/kg), medium-energy (ME: 6.2 MJ/kg) and high-energy (HE: 6.9 MJ/kg) diets, respectively. All animals were fed ad libitum twice daily at 08:00-09:00 am and 17:00-18:00 pm and with free access to water for 74 days, including a 14-d period to adapt to the diets and the environment. Intramuscular fat (IMF) content, fatty acid profile and mRNA levels of genes involved in fatty acid synthesis were determined. The energy levels of the diets significantly (P<0.05) affected the content of IMF, total SFA, total MUFA and total PUFA. C16:0, C18:0 and C18:1n9c account for a large proportion of total fatty acids. Relative expression of acetyl-CoA carboxylase (ACACA), fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD), sterol regulatory element-binding protein 1c (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARgamma) and fatty acid-binding protein 4 (FABP4) was greater in HE than in LE yaks (P<0.05). Moreover, ME yaks had higher (P<0.05) mRNA expression levels of PPARgamma, ACACA, FASN, SCD and FABP4 than did the LE yaks. The results demonstrate that the higher energy level of the diets increased IMF deposition and fatty acid content as well as increased intramuscular lipogenic gene expression during the experimental period. PMID- 29121118 TI - Diversity and characterization of bacteria associated with the deep-sea hydrothermal vent crab Austinograea sp. comparing with those of two shallow-water crabs by 16S ribosomal DNA analysis. AB - For deep-sea hydrothermal vent crabs, recent investigations have revealed some epibiotic bacteria, but no study has described the bacterial community associated with the gill and intestine. In this study, the microbiota attached to the gill and intestine of the hydrothermal vent crab Austinograea sp. and two shallow water crab species (Eriocheir sinensis and Portunus trituberculatus) were compared by high-throughput sequencing of 16S rDNA genes. The highest and lowest diversity in bacterial communities were observed in the gill and intestine of Austinograea sp., respectively. Non-metric multidimensional scaling (NMDS) analysis indicated that Austinograea sp. harbored a distinct microbial community. Operational taxonomic units (OTUs) for phylum Fusobacteria, class Epsilonproteobacteria, and genera Leucothrix, Polaribacter, Fusibacter, etc. were dominant in Austinograea sp. Of these, Leucothrix, Sulfurospirillum, and Arcobacter may be involved in oxidizing reduced sulfur compounds and sulfur metabolism; Marinomonas, Polaribacter adapted to the low temperature, and Fusibacter and Psychrilyobacter may survive well under hypoxic conditions. Bacteria commonly present in seawater were dominant in the gill, whereas anaerobic bacteria showed strikingly high abundance in the intestine. Interestingly, Firmicutes and Epsilonproteobacteria may complement each other in Austinograea sp., forming an internal environment. The diversified microbial community of Austinograea sp. reveals adaptation to the hydrothermal vent environment. PMID- 29121119 TI - How alkalinization drives fungal pathogenicity. PMID- 29121120 TI - Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity. AB - Cancer is considered one of the primary diseases that cause morbidity and mortality in millions of people worldwide and due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. However, the traditional process of drug discovery and development is lengthy and expensive, so the application of in silico techniques and optimization algorithms in drug discovery projects can provide a solution, saving time and costs. A set of 617 approved anticancer drugs, constituting the active domain, and a set of 2,892 natural products, constituting the inactive domain, were employed to build predictive models and to index natural products for their anticancer bioactivity. Using the iterative stochastic elimination optimization technique, we obtained a highly discriminative and robust model, with an area under the curve of 0.95. Twelve natural products that scored highly as potential anticancer drug candidates are disclosed. Searching the scientific literature revealed that few of those molecules (Neoechinulin, Colchicine, and Piperolactam) have already been experimentally screened for their anticancer activity and found active. The other phytochemicals await evaluation for their anticancerous activity in wet lab. PMID- 29121122 TI - Photosensitive atopic dermatitis exacerbated by UVB exposure. AB - Photosensitive atopic dermatitis (AD) is a rare disease entity that many physicians are not familiar with, thus it often is misdiagnosed. It can be life altering, as patients often strictly avoid the sun and may only leave the house at night. Effective treatments are available, and therefore diagnosis is key to improve quality of life for these patients. We describe a case of photosensitive AD exacerbated by UVB exposure. The diagnosis was made with phototesting, and the patient was able to begin treatment with narrowband UVB (NB-UVB) hardening while on immunosuppression. The literature on photosensitive AD is limited, and this entity typically is not found in the main dermatology textbooks. Our case emphasizes the diagnostic problems and complexity of photosensitive AD. Histopathologic findings are nonspecific. A thorough history and physical examination can provide the necessary clues for further workup. Phototesting should be performed to confirm the diagnosis and evaluate the degree of sensitivity to UV light and the specific wavelength eliciting the cutaneous response. Photoprovocation and photopatch testing also can be useful to confirm the diagnosis. PMID- 29121121 TI - Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein. AB - Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression. PMID- 29121123 TI - Clinical pearl: mastering the flexible scalpel blade with the banana practice model. AB - This article describes the various applications of the flexible scalpel blade (FSB), the utility of the banana as a convenient and exceptional training instrument, and the intricacies of mastering the technique for students of different training levels. PMID- 29121124 TI - Atopic dermatitis prevention and treatment. AB - Atopic dermatitis (AD) is the cause of substantial morbidity including severe pruritus and impaired personal and familial quality of life. Furthermore, the rising incidence and familial association of AD have highlighted the need for disease prevention. It is largely genetic in nature and cannot be avoided in all cases. However, low-risk prevention strategies have been attempted to reduce triggering of first onset of AD in predisposed individuals. Therapeutics for active disease include trigger avoidance, barrier repair, topical medicaments including topical corticosteroids (TCs) and nonsteroidal agents, phototherapy, and antibacterial interventions. PMID- 29121125 TI - Presumed serum sickness following thymoglobulin treatment of acute cellular rejection of a cardiac allograft. AB - Serum sickness is a hypersensitivity reaction to proteins in antiserum derived from nonhuman animal sources and can be seen in patients being treated with antiserum to prevent transplant rejection. Serum sickness may display variable clinical presentations. Because cutaneous findings may be the initial symptom in some cases, it is important for dermatologists to be able to recognize this condition given its potentially life-threatening symptoms. We present a case of a 35-year-old man with presumed serum sickness after receiving thymoglobulin for the treatment of acute cellular rejection of a heart transplant. The clinical presentation, laboratory findings, and treatment options are reviewed. PMID- 29121126 TI - The atopic dermatitis biologic era has begun. PMID- 29121127 TI - Tender edematous nodules on the hand. PMID- 29121128 TI - Acronymic despair: MACRA, MIPS, and me. PMID- 29121129 TI - Orange nodules on the scalp. PMID- 29121130 TI - Optical coherence tomography in dermatology. AB - Optical coherence tomography (OCT), an emerging noninvasive imaging modality, recently received category III Current Procedural Terminology (CPT) codes from the American Medical Association, enabling tracking of its use in the medical community. In this article, we review OCT imaging and its variant systems, discussing its applications and limitations for clinical use. Future directions of OCT technology and goals for obtaining category I CPT codes and reimbursement also are discussed. PMID- 29121131 TI - Noxious nocebos in dermatology. PMID- 29121132 TI - Recalcitrant ulcer on the lower leg. PMID- 29121133 TI - Hyperpigmented patch on the leg. PMID- 29121134 TI - Laugier-Hunziker syndrome. PMID- 29121135 TI - Sporotrichoid pattern of Mycobacterium chelonae-abscessus infection. PMID- 29121136 TI - Pityriasis rubra pilaris and severe hypereosinophilia. PMID- 29121137 TI - Sweet syndrome induced by oral acetaminophen-codeine following repair of a facial fracture. AB - Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an uncommon condition that is clinically characterized by painful, well-demarcated, indurated, erythematous plaques or nodules that typically favor the head, neck, and arms, and are accompanied by fever. The disease is divided into several categories based on the underlying etiology, with the drug-induced variant comprising a rising number of the total cases and being reported in association with an increasing number of medications. We report a rare case of SS induced by an oral acetaminophen-codeine suspension and tablets. The importance of this case lies in the ability to educate both physicians and pharmacists alike regarding a newly recognized cutaneous adverse effect of acetaminophen-codeine so that the medication may be discontinued or substituted upon recognition of this adverse reaction to decrease patient morbidity. PMID- 29121138 TI - Imipramine-induced hyperpigmentation. AB - Imipramine is a tricyclic medication that has been used for the treatment of depression and other mood disorders. Although rare, a slate gray discoloration of sun-exposed skin may occur in patients taking this medication. We present the case of a 63-year-old woman who had been taking imipramine for depression for more than 20 years when she developed a bluish gray discoloration on the face and neck that was diagnosed as imipramine-induced hyperpigmentation based on histopathology and clinical history. A number of other drugs that may cause hyperpigmentation also are reviewed as well as their histopathologic staining characteristics. PMID- 29121139 TI - Atypical fibroxanthoma arising within erosive pustular dermatosis of the scalp. AB - We describe a painful atypical fibroxanthoma (AFX) arising in a setting of erosive pustular dermatosis of the scalp. Complete excision was curative and also was associated with resolution of pain and clearance of the erosive pustular dermatosis of the scalp. We review the diagnosis and management of AFX and discuss the role of actinic damage in this process. PMID- 29121141 TI - Status of Testing for High-Level Microsatellite Instability/Deficient Mismatch Repair in Colorectal Carcinoma. PMID- 29121140 TI - Complications of cosmetic eye whitening. AB - Introduced in 2008 and subsequently popularized in South Korea, cosmetic eye whitening has been offered as a treatment of chronic conjunctival hyperemia. Patients undergo conjunctivectomy with topical mitomycin C (MMC) 0.02% application to achieve a whitened appearance from bleaching of avascular sclera. Much speculation has arisen from this procedure given the limited available evidence on its efficacy and safety. A literature search was performed to review common complications of cosmetic eye whitening, including chronic conjunctival epithelial defects, scleral thinning, avascular zones in the sclera, dry eye syndrome, and diplopia requiring strabismus surgery. Informing the general public of the risks of this procedure is of great importance for dermatologists and other cosmetic surgeons. PMID- 29121142 TI - Close Call. PMID- 29121143 TI - Mismatch Repair Deficiency Testing in Patients With Colorectal Cancer and Nonadherence to Testing Guidelines in Young Adults. AB - Importance: Mismatch repair (MMR) deficiency of DNA has been observed in up to 15% of sporadic colorectal cancers (CRCs) and is a characteristic feature of Lynch syndrome, which has a higher incidence in young adults (age, <50 years) with CRC. Mismatch repair deficiency can be due to germline mutations or epigenetic inactivation, affects prognosis and response to systemic therapy, and results in unrepaired repetitive DNA sequences, which increases the risk of multiple malignant tumors. Objective: To evaluate the utilization of MMR deficiency testing in adults with CRC and analyze nonadherence to long-standing testing guidelines in younger adults using a contemporary national data set to help identify potential risk factors for nonadherence to newly implemented universal testing guidelines. Design, Setting, and Participants: Adult (age, <30 to >=70 years) and, of these, younger adult (<30 to 49 years) patients with invasive colorectal adenocarcinoma diagnosed between 2010 and 2012 and known MMR deficiency testing status were identified using the National Cancer Database. The study was conducted from March 16, 2016, to March 1, 2017. Exposures: Patient sociodemographic, facility, tumor, and treatment characteristics. Main Outcomes and Measures: The primary outcome of interest was receipt of MMR deficiency testing. Multivariable logistic regression was used to identify independent predictors of testing in adult and/or young adult patients. Results: A total of 152 993 adults with CRC were included in the study (78 579 [51.4%] men; mean [SD] age, 66.9 [13.9] years). Of these patients, only 43 143 (28.2%) underwent MMR deficiency testing; the proportion of patients tested increased between 2010 and 2012 (22.3% vs 33.1%; P<.001). Among 17 218 younger adult patients with CRC, only 7422 (43.1%) underwent MMR deficiency testing; the proportion tested increased between 2010 and 2012 (36.1% vs 48.0%; P < .001). Irrespective of age, higher educational level (OR, 1.38; 95% CI, 1.15-1.66), later diagnosis year (OR, 1.81; 95% CI, 1.65-1.98), early stage disease (OR, 1.24; 95% CI, 1.18-1.30), and number of regional lymph nodes examined (>=12) (OR, 1.44; 95% CI, 1.34-1.55) were independently associated with MMR deficiency testing, whereas older age (OR, 0.31; 95% CI, 0.26-0.37); Medicare (OR, 0.89; 95% CI, 0.84-0.95), Medicaid (OR, 0.83; 95% CI, 0.73-0.93), or uninsured (OR, 0.78; 95% CI, 0.66-0.92) status; nonacademic vs academic/research facility type (OR, 0.44; 95% CI, 0.34-0.56); rectosigmoid or rectal tumor location (OR, 0.76; 95% CI, 0.68-0.86); unknown grade (OR, 0.61; 95% CI, 0.53-0.69); and nonreceipt of definitive surgery (OR, 0.33; 95% CI, 0.30-0.37) were associated with underuse of MMR deficiency testing. Conclusions and Relevance: Despite recent endorsement of universal use of MMR deficiency testing in patients with CRC and well-established guidelines aimed at high-risk populations, overall utilization of testing is poor and significant underuse of testing among young adults persists. Interventions tailored to groups at risk for nonadherence to guidelines may be warranted in the current era of universal testing. PMID- 29121145 TI - A Young Man With Disseminated Intra-abdominal Masses. PMID- 29121144 TI - Positron Emission Tomography/Computed Tomography-Based Assessments of Androgen Receptor Expression and Glycolytic Activity as a Prognostic Biomarker for Metastatic Castration-Resistant Prostate Cancer. AB - Importance: Androgen receptor-signaling inhibitor (ARSi) drugs prolong life in metastatic castration-resistant prostate cancer (mCRPC), but such tumors eventually become resistant and progress. Comprehensive positron emission tomography/computed tomography (PET/CT) imaging using fluoro-2-D-deoxyglucose F 18 ([18F]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([18F] FDHT) for androgen receptor (AR) expression determine heterogeneity of imaging phenotypes, which may be useful in distinguishing patients who will benefit from ARSi drugs from those who need alternative treatments. Objective: To test the hypothesis that PET/CT-based assessments of AR expression and glycolytic activity would reveal heterogeneity affecting prognosis. Design, Setting, and Participants: Between April 6, 2007, and October 4, 2012, patients with mCRPC underwent imaging with both [18F]-FDG and [18F]-FDHT at Memorial Sloan Kettering Cancer Center. The patients were naive to ARSi treatment with enzalutamide or abiraterone acetate and were referred during documented disease progression. Image-directed biopsy determined the presence or absence of prostate cancer at positive imaging sites. Interventions: PET/CT imaging was performed with [18F] FDHT and [18F]-FDG; select individual lesions were biopsied to correlate imaging phenotype with histologic findings. Main Outcomes and Measures: All metabolically active lesions were interpreted as [18F]-FDHT-positive (AR1) or [18F]-FDHT negative (AR0) and as [18F]-FDG-positive (Glyc1) or [18F]-FDG-negative (Glyc0). Correlation was performed with overall survival for both individual lesion imaging phenotype as well as patient-specific imaging phenotype. Results: The mean (SD) age of the 133 patients was 68 (8.6) years. Imaging phenotypes of 2405 PET/CT-positive lesions (median, 12.0 per patient) included 1713 (71.2%) AR1Glyc1, 386 (16.0%) AR1Glyc0, and 306 (12.7%) AR0Glyc1. On multivariate analysis, each phenotype had an independent negative impact effect on survival, most pronounced for AR0Glyc1 lesions (hazard ratio [HR], 1.11; 95% CI, 1.05-1.16; P < .001), followed by AR1Glyc1 lesions (HR, 1.05; 95% CI, 1.03-1.06; P < .001) and AR1Glyc0 lesions (HR, 1.03; 95% CI, 1.00-1.05; P = .048). When sorted by lesion type, 4 patient-specific groups emerged: (1) concordant, with all AR1Glyc1 (34 patients [25.6%]); (2) AR predominant, with AR1Glyc1 and varying numbers of AR1Glyc0 (33 [24.8%]); (3) Glyc predominant, with AR1Glyc1 and varying numbers of AR0Glyc1 (40 [30.1%]); and (4) mixed, with AR1Glyc1 plus a mixture of varying numbers of AR1Glyc0 and AR0Glyc1 (26 [19.5%]). Conclusions and Relevance: Heterogeneity of PET/CT imaging phenotype has clinical relevance on a lesion and individual patient level. With regard to mCRPC lesions, most express ARs, consistent with initial benefit of ARSi drugs. On a patient basis, 49% (groups 3 and 4) had at least 1 AR0Glyc1 lesion-the imaging phenotype with the most negative effect on survival, possibly due to ARSi resistance. PMID- 29121148 TI - Issues of Awareness Related to Human Papillomavirus Infection Positivity Among US Adult Men. PMID- 29121147 TI - A Systematic Process for Weaning Children With Aspiration From Thickened Fluids. AB - Importance: Thickening of fluids is a common strategy for feeding patients with oropharyngeal dysphagia but has known risks and should be stopped once it is safe to do so. Weaning children from thickened fluids safely can be challenging, and novel methods are required. Objective: To describe the use of a systematic weaning process (SWP) for children who received thickened liquids owing to oropharyngeal dysphagia and identified risk of aspiration. Design, Setting, and Participants: Retrospective case series (2010 to 2015) at a tertiary care center of 50 children with documented aspiration by clinical swallowing assessment, airway evaluation, and videofluoroscopic swallow study with at least 4 months of follow-up. All patients were initially receiving thickened fluids. A 10% reduction in thickness was made every 2 weeks based on clinical symptoms. Caregivers progressed to the next incremental level if there were no signs or symptoms of aspiration. Main Outcomes and Measures: Number of patients weaned to a thin-fluid diet. Results: Of 50 children (32 [64%] male; median [interquartile range] age, 0.7 [1.0] y at presentation and 1.8 [1.3] y at start of wean) using the SWP, 44 (88%) were able to reduce the amount of thickener used. A successful wean from thickened fluids to thin fluids was completed in 39 (78%). The mean (SD) duration of a successful wean was 0.9 (0.6) years. Five patients tolerated a reduction in thickener but not a full wean to thin fluids. For 6 patients, weaning failed and they continued to receive thickened fluids. Of those whose weaning failed, 2 patients developed pneumonia. Of the 39 successfully weaned patients, 14 (36%) experienced a temporary stall but eventually tolerated thin fluids. Only 2 (5%) developed pneumonia while all other successfully weaned patients (n = 37 [95%]) did not experience any substantial respiratory issues. Overall, 46 (92%) of children required 2 or fewer videofluoroscopic swallow study evaluations. Conclusions and Relevance: Patients with oropharyngeal dysphagia and aspiration should be gradually weaned off of thickened fluids. The SWP uses small incremental steps to gradually reduce the amount of thickener. Using this method, most children tolerated a reduction in thickeners and a thin-fluid diet. The SWP presents a safe and effective way of gradually returning children to a more normal diet. PMID- 29121146 TI - Association Between Head and Neck Squamous Cell Carcinoma Survival, Smoking at Diagnosis, and Marital Status. AB - Importance: While the adverse association between smoking and head and neck squamous cell carcinoma (HNSCC) survival has been well described, there are also inconclusive studies and those that report no significant changes in HNSCC survival and overall mortality due to smoking. There is also a lack of studies investigating the association of marital status on smoking status at diagnosis for patients with HNSCC. Objective: To examine the association between patient smoking status at HNSCC diagnosis and survival and the association between marital status and smoking in these patients. Design, Setting, and Participants: This retrospective cohort study was conducted by querying the Saint Louis University Hospital Tumor Registry for adults with a diagnosis of HNSCC and treated at the university academic medical center between 1997 and 2012; 463 confirmed cases were analyzed. Main Outcomes and Measures: Cox proportional hazards regression analysis was used to evaluate association of survival with smoking status at diagnosis and covariates. A multivariate logistic regression model was used to assess whether marital status was associated with smoking at diagnosis adjusting for covariates. Results: Of the 463 total patients (338 men, 125 women), 92 (19.9%) were aged 18 to 49 years; 233 (50.3%) were aged 50 to 65 years; and 138 (29.8%) were older than 65 years. Overall, 56.2% of patients were smokers at diagnosis (n = 260); 49.6% were married (n = 228); and the mortality rate was 54.9% (254 died). A majority of patients were white (81.0%; n = 375). Smokers at diagnosis were more likely to be younger (ie, <65 years), unmarried, and to drink alcohol. We found a statistically significant difference in median survival time between smokers (89 months; 95% CI, 65-123 months) and nonsmokers at diagnosis (208 months; 95% CI, 129-235 months). In the adjusted Cox proportional hazards model, patients who were smokers at diagnosis were almost twice as likely to die during the study period as nonsmokers (hazard ratio, 1.98; 95% CI, 1.42-2.77). In the multivariate logistic regression analysis, unmarried patients were 76% more likely to use tobacco than married patients (adjusted odds ratio, 1.76; 95% CI, 1.08-2.84). Conclusions and Relevance: Smokers were almost twice as likely as nonsmokers to die during the study period. We also found that those who were married were less likely to be smokers at diagnosis. Our study suggests that individualized cancer care should incorporate social support and management of cancer risk behaviors. PMID- 29121149 TI - Sarcoid, Bayes, and the Challenges of Laboratory Testing for Uveitis. PMID- 29121150 TI - Issues of Awareness Related to Human Papillomavirus Infection Positivity Among US Adult Men-Reply. PMID- 29121151 TI - Association Between Cognitive Function and Quality of Life in Patients With Head and Neck Cancer. PMID- 29121152 TI - Diagnostic Accuracy of Traditional Measures of Phonological Ability for Bilingual Preschoolers and Kindergarteners. AB - Purpose: Bilingual children whose phonological skills are evaluated using measures designed for monolingual English speakers are at risk for misdiagnosis of speech sound disorders (De Lamo White & Jin, 2011). Method: Forty-four children participated in this study: 15 typically developing monolingual English speakers, 7 monolingual English speakers with phonological disorders, 14 typically developing bilingual Spanish-English speakers, and 8 bilingual children with phonological disorders. Children's single-word speech productions were examined on Percentage Consonants Correct-Revised (Shriberg, Austin, Lewis, McSweeny, & Wilson, 1997a) and accuracy of early-, middle-, and late-developing sounds (Shriberg, 1993) in English. Consonant accuracy in English was compared between monolinguals and bilinguals with and without speech sound disorders. Logistic regression and receiver operating characteristic curves were used to observe diagnostic accuracy of the measures examined. Results: Percentage Consonants Correct-Revised was found to be a good indicator of phonological ability in both monolingual and bilingual English-speaking children at the age of 5;0. No significant differences were found between language groups on any of the measures examined. Conclusions: Our results suggest that traditional measures of phonological ability for monolinguals could provide good diagnostic accuracy for bilingual children at the age of 5;0 years. These findings are preliminary, and children younger than 5;0 years should be examined for risk of misdiagnosis. PMID- 29121153 TI - Evolution of Practice Patterns for the Treatment of Fungal Keratitis. PMID- 29121154 TI - Diagnostic Value of Serum-Soluble Interleukin 2 Receptor Levels vs Angiotensin Converting Enzyme in Patients With Sarcoidosis-Associated Uveitis. AB - Importance: New and improved diagnostic tests for sarcoidosis-associated uveitis are needed because the currently available laboratory diagnostic biomarkers (eg, lysozyme and angiotensin-converting enzyme [ACE]) are lacking in high sensitivity and specificity. Objective: To compare the value of soluble interleukin 2 receptor (sIL-2R) with ACE as diagnostic biomarkers of sarcoidosis in patients with uveitis. Design, Setting, and Participants: A cross-sectional retrospective study was conducted using data collected from 249 consecutive patients with uveitis at the Erasmus University Medical Center uveitis outpatient clinic, Rotterdam, the Netherlands, from April 3, 2013, through November 25, 2015. Measurements of sIL-2R and ACE in serum samples and data extraction from patient files were conducted from December 2016 through February 2017, and analysis from April to May 2017. Main Outcomes and Measures: Serum levels of sIL-2R and ACE and chest radiographic findings were assessed. Receiver operating characteristics analysis was used to determine the probability that individual tests correctly identified patients with sarcoidosis. The Youden Index was used to determine the optimal cutoff points for serum sIL-2R and ACE levels to define sarcoidosis in patients with uveitis. Results: Data were analyzed from 249 patients with uveitis who had their serum sIL-2R and ACE levels determined and underwent chest radiography. Mean (SD) age at the time of sampling was 51 (16) years, 161 patients (64.7%) were women, and 191 (76.7%) were white. Although patients with sarcoidosis-associated uveitis had the highest mean (SD) serum sIL-2R (6047 [2533] pg/mL) and ACE (61 [38] U/L) levels, elevated serum sIL-2R levels were also found in patients with HLA-B27-associated (4460 [2465] pg/mL) and varicella zoster virus-associated (5386 [1778] pg/mL) uveitis. Serum sIL-2R and ACE levels were significantly correlated (Pearson correlation coefficient, 0.205; P = .001, 2-sided), but no association was found between uveitis activity and sIL-2R (Spearman rank correlation coefficient [rho], 0.070, P = .27) nor uveitis activity and ACE (rho, -0.071; P = .27). The highest Youden index for sIL-2R alone was 0.45, corresponding to an optimal cutoff of 4000 pg/mL and providing 81% (95% CI, 74%-89%) sensitivity and 64% (95% CI, 56%-72%) specificity alone but combined with chest radiography yielded 92% sensitivity and 58% specificity. Chest radiography combined with sIL-2R at a cutoff of 6000 pg/mL resulted in 77% sensitivity and 73% specificity. Combined chest radiography and serum ACE levels at the standard cutoff of 68 U/L resulted in 70% sensitivity and 79% specificity. Conclusions and Relevance: This cross-sectional study demonstrates that sIL-2R is a useful marker for diagnosing sarcoidosis in patients with uveitis and has slightly better diagnostic value than ACE. PMID- 29121155 TI - Presence of Trainees and Appointment Times. PMID- 29121157 TI - Omitted Disclosures of Potential Conflicts of Interest. PMID- 29121156 TI - Labeling the lines: A test of a six-mechanism model of chromatic detection. AB - Six linear chromatic mechanisms are sufficient to account for the pattern of threshold elevations produced by chromatic noise masking in the (L,M) plane of cone space (Shepard, Swanson, McCarthy, & Eskew, 2016). Here, we report results of asymmetric color matching of the threshold-level tests from that detection study and use those matches to test the detection model. We assume the mechanisms are univariant labeled lines (Rushton, 1972; Watson & Robson, 1981), implying that the chromaticities of physically different stimuli that are detected by a single mechanism should all be the same-they are postreceptoral metamers-but the chromaticities of two stimuli detected by different mechanisms should be different. The results show that color matches fall into six clusters in CIE (u',v') space (across all the noise conditions) and that these clusters correspond closely to the six mechanisms in the model. Most importantly, where the detection model determines that a given test angle is detected by different mechanisms under different noise conditions, the hue of that test angle changes in a consistent way. These color matches allow us to apply a color label to each of the mechanisms, confirm the six-mechanism model, and quantify the hue signaled by each mechanism. PMID- 29121158 TI - Opioid Use by Patients After Rhinoplasty. AB - Importance: Given the increase in opioid addiction and overdose in the United States, reasoned opioid use after outpatient surgery may affect prescription medication abuse. Objectives: To examine patient use of opioids after rhinoplasty and establish an optimal postrhinoplasty pain management regimen. Design, Setting, and Participants: In this case series, opioid use was evaluated in 62 patients who underwent rhinoplasty performed by 3 fellowship-trained facial plastic surgeons, 2 in private practice in Texas and 1 in an academic setting in Michigan, from February 2016 to September 2016. Main Outcomes and Measures: Opioid use, pain control, and adverse effects were examined and opioid use was compared across patient demographic and surgical procedure characteristics, including rhinoplasty and septoplasty, open vs closed techniques, revision vs primary operations, reduction of turbinates, and use of osteotomies. Opioid use was self-reported as the number of prescribed tablets containing a combination of hydrocodone bitartrate (5 mg) and acetaminophen (325 mg) that were consumed. Results: The mean (SEM) age of the patients was 38.7 (16.4) years and included 50 female patients (81%). Of the initially prescribed 20 to 30 hydrocodone acetaminophen combination tablets, the 62 patients included in this study used a mean (SEM) of 8.7 (0.9) tablets, only 40% of those prescribed after rhinoplasty. In addition, 46 patients (74%) consumed 15 or fewer tablets, whereas only 3 patients (5%) required refills of pain medication. Sex, age, concurrent septoplasty or turbinate reduction, use of osteotomy, and history of a rhinoplasty were not associated with the number of tablets used. The most common adverse effects included drowsiness in 22 patients (35%), nausea in 7 (11%), light-headedness in 3 (5%), and constipation in 3 (5%). Conclusions and Relevance: To mitigate the misuse or diversion of physician-prescribed opioid medications, surgeons must be steadfast in prescribing an appropriate amount of pain medication after surgery. A multifaceted pain control program is proposed to manage postoperative pain and ascertain the balance between controlling pain and avoiding overprescribing narcotics. Level of Evidence: NA. PMID- 29121159 TI - Structure and function analysis of Polygonatum cyrtonema lectin by site-directed mutagenesis. AB - The crystal structure of mature Polygonatum cyrtonema lectin (PCL) showed three similar carbohydrate-binding sites (CBS I, CBS II, and CBS III). The Gln58 and Asp60 residues of CBS II are substituted with His58 and Asn60. To establish the relationship between the key amino acid residues and structure or activity of PCL, we constructed four recombinant mutants in CBS I, CBS II, and CBS III. The experimental results indicate that CBS I, CBS III and the disulfide bond play vital roles in the binding with mannose. Furthermore, molecular dynamics simulations and binding free energy calculation illustrate that CBS I has a direct and strong relationship with the activity of PCL. CBS II does not play a critical role in the model for mannose binding by PCL. Although CBS III does not enhance the activity, it helps to maintain the activity and 3D structure. These results suggest that the carbohydrate-binding site of PCL may be in a hydrophilic environment, and Asn and Tyr are the key amino acids involved in its binding with sugar, but Gln and Asp are not necessary to maintain its activity. PMID- 29121160 TI - Reproducibility of Dual-Microphone Voice Range Profile Equipment. AB - Purpose: The aim of this study was to add further knowledge about the usefulness of the Voice Range Profile (VRP) assessment in clinical settings and research by analyzing VRP dual-microphone equipment precision, reliability, and room effect. Method: Test-retest studies were conducted in an anechoic chamber and an office: (a) comparing sound pressure levels (SPLs) from a dual-microphone VRP device, the Voice Profiler, when given the same input repeatedly (test-retest reliability); (b) comparing SPLs from 3 devices when given the same input repeatedly (intervariation); and (c) assessing the room effect. Results: (a) The mean standard deviation across 17 measurement points was 0.7 dB for 1 device. (b) One device was less precise than the other 2 devices. All devices presented high SPLs at low frequencies compared with the reference. (c) Mean SPLs were almost equal in the anechoic chamber and the office. Conclusions: The high test-retest reliability of the dual-microphone VRP equipment, especially in general office surroundings, is a positive finding. Attention must be paid to specific factors such as using the same device when comparing the same voice before and after treatment, caution in headset placement, and manual recalibrations when automatic recalibration occurs. We suggest recalibrations verified with a reference source at regular intervals. PMID- 29121161 TI - Transforming the Military Health System. PMID- 29121162 TI - The Effect of Adaptive Nonlinear Frequency Compression on Phoneme Perception. AB - Purpose: This study implemented a fitting method, developed for use with frequency lowering hearing aids, across multiple testing sites, participants, and hearing aid conditions to evaluate speech perception with a novel type of frequency lowering. Method: A total of 8 participants, including children and young adults, participated in real-world hearing aid trials. A blinded crossover design, including posttrial withdrawal testing, was used to assess aided phoneme perception. The hearing aid conditions included adaptive nonlinear frequency compression (NFC), static NFC, and conventional processing. Results: Enabling either adaptive NFC or static NFC improved group-level detection and recognition results for some high-frequency phonemes, when compared with conventional processing. Mean results for the distinction component of the Phoneme Perception Test (Schmitt, Winkler, Boretzki, & Holube, 2016) were similar to those obtained with conventional processing. Conclusions: Findings suggest that both types of NFC tested in this study provided a similar amount of speech perception benefit, when compared with group-level performance with conventional hearing aid technology. Individual-level results are presented with discussion around patterns of results that differ from the group average. PMID- 29121163 TI - Gene expression profiling reveals heterogeneity of perivascular adipose tissues surrounding coronary and internal thoracic arteries. AB - The internal thoracic artery (ITA) that differs from coronary artery (CA), rarely develops atherosclerosis. Understanding the mechanism underlying such a difference will help to pave a new way to the prevention and treatment of the disease. We hypothesize herein that the difference in susceptibility to atherosclerosis between CA and ITA is attributable to the heterogeneity of perivascular adipose tissues (PVATs) surrounding these two kinds of arteries, i.e. PVAT-CA and PVAT-ITA. We isolated PVAT from eight patients of coronary heart disease (CHD) and four non-CHD patients. Gene expression patterns were analyzed by using Agilent whole gene expression profile chips. By comparison between PVAT CA and PVAT-ITA, we identified 2053 differentially expressed genes, of which 1042 were up-regulated and 1011 were down-regulated, respectively, in CHD group. KEGG pathway and gene ontology (GO) analysis revealed that those differentially expressed genes related to inflammation, lipid metabolism and myocardial processes were particularly noted in the CHD group, but not in non-CHD. Several selected genes, including interleukin-1beta (IL-1beta), interleukin-6 (IL-6), Toll-like receptor 2 (TLR2), Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), serum amyloid A2 (SAA2), and Leptin were validated by real-time PCR analysis. The results showed that the expression levels of IL 1beta, IL-6, and Leptin were significantly higher in PVAT-CA than in PVAT-ITA (P = 0.016, 0.021, and 0.018) in CHD patients. Levels of TLR2, TIRAP, and SAA2 expression were also higher in PVAT-CA, however no significant difference was observed (P = 0.054, 0.092, and 0.058). In conclusion, our findings demonstrate differential gene expression patterns between PVAT-CA and PVAT-ITA, revealing a high heterogeneity in PVAT. Particularly, those genes related to inflammation, lipid metabolism and myocardial processes are differentially expressed in PVAT-CA and PVAT-ITA in CHD patients, suggesting an important role of PVAT in the development of coronary atherosclerosis. PMID- 29121164 TI - Granulomatosis With Polyangiitis-A Moral Impetus for Change. PMID- 29121165 TI - PERF: an exhaustive algorithm for ultra-fast and efficient identification of microsatellites from large DNA sequences. AB - Motivation: Microsatellites or Simple Sequence Repeats (SSRs) are short tandem repeats of DNA motifs present in all genomes. They have long been used for a variety of purposes in the areas of population genetics, genotyping, marker assisted selection and forensics. Numerous studies have highlighted their functional roles in genome organization and gene regulation. Though several tools are currently available to identify SSRs from genomic sequences, they have significant limitations. Results: We present a novel algorithm called PERF for extremely fast and comprehensive identification of microsatellites from DNA sequences of any size. PERF is several fold faster than existing algorithms and uses up to 5-fold lesser memory. It provides a clean and flexible command-line interface to change the default settings, and produces output in an easily parseable tab-separated format. In addition, PERF generates an interactive and stand-alone HTML report with charts and tables for easy downstream analysis. Availability and implementation: PERF is implemented in the Python programming language. It is freely available on PyPI under the package name perf_ssr, and can be installed directly using pip or easy_install. The documentation of PERF is available at https://github.com/rkmlab/perf. The source code of PERF is deposited in GitHub at https://github.com/rkmlab/perf under an MIT license. Contact: tej@ccmb.res.in. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29121166 TI - Characteristics, Diagnosis, and Management of Ehlers-Danlos Syndromes: A Review. AB - Importance: Ehlers-Danlos syndromes (EDSs) are a group of heritable connective tissue disorders. Patients with EDSs can develop excessive facial rhytids, nasal deformities, and facial scarring, for which they may seek consultation with a facial plastic surgeon. Ehlers-Danlos syndromes can be associated with serious surgical complications and should be identified preoperatively to facilitate optimal treatment. To our knowledge, no management guidelines for patients with EDSs exist in the facial plastic surgery literature. We present a review of the literature and management recommendations for the facial plastic surgeon. Observations: We performed a PubMed/MEDLINE search for all publications in the English language related to surgical experience in patients with EDSs. A total of 37 publications (including reviews and case series) were included. Ehlers-Danlos syndromes are more common than appreciated, with an overall point prevalence between 1 in 2500 and 1 in 5000 according to existing literature. There are 6 main subtypes of EDSs that have significant phenotypic heterogeneity. Patients with classic type and hypermobile EDS (the 2 most common subtypes) can typically undergo elective facial plastic surgery without major complications. However, specific preoperative, intraoperative, and postoperative issues, as outlined in this review, must be taken into consideration. Vascular EDS should serve as a contraindication to elective surgery given its potential for life-threatening complications. Conclusions and Relevance: Because of their skin laxity, patients with EDSs may present more frequently to facial plastic surgeons' offices. Simple screening questions can help the surgeon identify potential patients with EDSs. Treatment should be individualized and performed with extreme care to ensure optimal outcomes. PMID- 29121167 TI - Basal Cells Show Increased Expression of Aromatase and Estrogen Receptor alpha in Prostate Epithelial Lesions of Male Aging Rats. AB - Besides androgens, estrogen signaling plays a key role in normal development and pathologies of the prostate. Irreversible synthesis of estrogens from androgens is catalyzed by aromatase. Interestingly, animals lacking aromatase do not develop cancer or prostatitis, whereas those with overexpression of aromatase and, consequently, high estrogen levels develop prostatitis and squamous metaplasia via estrogen receptor 1 (ERalpha). Even with this evidence, the aromatase expression in the prostate is controversial. Moreover, little is known about the occurrence of age-dependent variation of aromatase and its association with histopathological changes commonly found in advanced age, a knowledge gap that is addressed herein. For this purpose, the immunoexpression of aromatase was evaluated in the prostatic complex of young adult to senile Wistar rats. ERalpha was also investigated, to extend our understanding of estrogen responsiveness in the prostate. Moderate cytoplasmic immunoreactivity for aromatase was detected in the glandular epithelium. Eventually, some basal cells showed intense staining for aromatase. The expression pattern for aromatase appeared similar in the normal epithelium when young and senile rats were compared; this result was corroborated by Western blotting. Conversely, in senile rats, there was an increase in the frequency of basal cells intensely stained for aromatase, which appeared concentrated in areas of intraepithelial proliferation and prostatitis. These punctual areas also presented increased ERalpha positivity. Together, these findings suggest a plausible source for hormonal imbalance favoring estrogen production, which, by acting through ERalpha, may favor the development of prostatic lesions commonly found in advanced age. PMID- 29121169 TI - MOAT: efficient detection of highly mutated regions with the Mutations Overburdening Annotations Tool. AB - Summary: Identifying genomic regions with higher than expected mutation count is useful for cancer driver detection. Previous parametric approaches require numerous cell-type-matched covariates for accurate background mutation rate (BMR) estimation, which is not practical for many situations. Non-parametric, permutation-based approaches avoid this issue but usually suffer from considerable compute-time cost. Hence, we introduce Mutations Overburdening Annotations Tool (MOAT), a non-parametric scheme that makes no assumptions about mutation process except requiring that the BMR changes smoothly with genomic features. MOAT randomly permutes single-nucleotide variants, or target regions, on a relatively large scale to provide robust burden analysis. Furthermore, we show how we can do permutations in an efficient manner using graphics processing unit acceleration, speeding up the calculation by a factor of ~250. Availability and implementation: MOAT is available at moat.gersteinlab.org. Contact: mark@gersteinlab.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29121170 TI - Pediatric Patient With T-Cell Lymphoblastic Lymphoma and Acute Vision Loss. PMID- 29121171 TI - Recognition and Comprehension of "Narrow Focus" by Young Adults With Prelingual Hearing Loss Using Hearing Aids or Cochlear Implants. AB - Purpose: The stressed word in a sentence (narrow focus [NF]) conveys information about the intent of the speaker and is therefore important for processing spoken language and in social interactions. The ability of participants with severe-to profound prelingual hearing loss to comprehend NF has rarely been investigated. The purpose of this study was to assess the recognition and comprehension of NF by young adults with prelingual hearing loss compared with those of participants with normal hearing (NH). Method: The participants included young adults with hearing aids (HA; n = 10), cochlear implants (CI; n = 12), and NH (n = 18). The test material included the Hebrew Narrow Focus Test (Segal, Kaplan, Patael, & Kishon-Rabin, in press), with 3 subtests, which was used to assess the recognition and comprehension of NF in different contexts. Results: The following results were obtained: (a) CI and HA users successfully recognized the stressed word, with the worst performance for CI; (b) HA and CI comprehended NF less well than NH; and (c) the comprehension of NF was associated with verbal working memory and expressive vocabulary in CI users. Conclusions: Most CI and HA users were able to recognize the stressed word in a sentence but had considerable difficulty understanding it. Different factors may contribute to this difficulty, including the memory load during the task itself and linguistic and pragmatic abilities. Supplemental Material: https://doi.org/10.23641/asha.5572792. PMID- 29121168 TI - delta-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice. AB - The PTEN/PI3K/AKT axis plays a critical role in regulating cell growth, differentiation and survival. Activation of this signaling pathway is frequently found in human cancers. Our previous studies demonstrated that delta-tocopherol (delta-T) attenuates the activation of AKT by growth factor in prostate cancer cell lines, leading to inhibition of proliferation and induction of apoptosis. Herein, we investigated whether delta-T inhibits the development of prostate adenocarcinoma in prostate-specific Pten-/- (Ptenp-/-) mice in which the activation of AKT is the major driving force for tumorigenesis. By feeding Ptenp /- mice with AIN93M or 0.2% delta-T supplemented diet starting at the age of 6 or 12 weeks, we found that delta-T treatment reduced prostate adenocarcinoma multiplicity at the age of 40 weeks by 53.3 and 42.7%, respectively. Immunohistochemical (IHC) analysis demonstrated that the phosphorylation of AKT (T308) was reduced in the prostate of the mice administered the delta-T diet. Consistently, proliferation was reduced and apoptosis was increased in prostate lesions of mice on the delta-T diet. Oxidative stress, as determined by IHC staining of 8-OH-dG, was not altered during prostate tumorigenesis, nor was it affected by administration of delta-T. In contrast, alpha-tocopherol (alpha-T) at 0.2% in the diet did not affect prostate adenocarcinoma multiplicity in the Ptenp /- mice. This finding is consistent with data from our previous study that delta T, but not alpha-T, inhibits the activation of AKT and the growth of prostate cancer cells. Together, these results demonstrate that delta-T inhibits the development of prostate adenocarcinoma in Ptenp-/- mice, mainly through inhibition of AKT activation. PMID- 29121173 TI - Managing the Left Atrial Appendage. PMID- 29121172 TI - Freezing-induced uptake of disaccharides for preservation of chromatin in freeze dried stallion sperm during accelerated aging. AB - Nonviable freeze-dried sperm have intact chromatin and can be used for fertilization via intracytoplasmic sperm injection. Freeze-dried sperm preferably should be stored at 4 degrees C or lower, because DNA damage accumulates during storage at room temperature. Disaccharides are known to protect biomolecules both during freezing and drying, by forming a glassy state. Their use is challenging because cellular membranes are normally impermeable for disaccharides. In the current study, we demonstrate that membrane impermeable compounds, including lucifer yellow and trehalose, are taken up by stallion sperm when exposed to freezing. Trehalose uptake likely occurs during freezing-induced membrane phase transitions. Stallion sperm was freeze-dried in various formulations consisting of reducing or nonreducing sugars combined with albumin as bulking agent. Chromatin stability was studied during storage at 37 degrees C, using the flow cytometric sperm chromatin structure assay and microscopic assessment of chromatin dispersion and DNA fragmentation after electrophoresis. Freeze-drying did not affect sperm chromatin, irrespective of the formulation that was used. DNA fragmentation index (DFI) values ranged from 5 to 8%. If sperm was freeze dried without protectants or in a combination of glucose and proteins, DNA damage rapidly accumulated during storage at 37 degrees C, reaching DFI values of respectively 95 +/- 4 and 64 +/- 42% after 1 month. DFI values of sperm freeze dried with sucrose or trehalose ranged between 9-11% and 33-52% after 1 and 3 months storage, respectively. In conclusion, freeze-drying sperm with disaccharides results in uptake during freezing, which greatly reduces chromatin degradation during dried storage. PMID- 29121174 TI - The European Association of Cardiovascular Imaging Research and Innovations Committee: a platform for research in cardiovascular imaging. PMID- 29121175 TI - Association of the Presence of Trainees With Outpatient Appointment Times in an Ophthalmology Clinic. AB - Importance: Physicians face pressure to improve clinical efficiency, particularly with electronic health record (EHR) adoption and gradual shifts toward value based reimbursement models. These pressures are especially pronounced in academic medical centers, where delivery of care must be balanced with medical education. However, the association of the presence of trainees with clinical efficiency in outpatient ophthalmology clinics is not known. Objective: To quantify the association of the presence of trainees (residents and fellows) and efficiency in an outpatient ophthalmology clinic. Design, Setting, and Participants: This single-center cohort study was conducted from January 1 through December 31, 2014, at an academic department of ophthalmology. Participants included 49 448 patient appointments with 33 attending physicians and 40 trainees. Exposures: Presence vs absence of trainees in an appointment or clinic session, as determined by review of the EHR audit log. Main Outcomes and Measures: Patient appointment time, as determined by time stamps in the EHR clinical data warehouse. Linear mixed models were developed to analyze variability among clinicians and patients. Results: Among the 33 study physicians (13 women [39%] and 20 men [61%]; median age, 44 years [interquartile range, 39-53 years]), appointments with trainees were significantly longer than appointments in clinic sessions without trainees (mean [SD], 105.0 [55.7] vs 80.3 [45.4] minutes; P < .001). The presence of a trainee in a clinic session was associated with longer mean appointment time, even in appointments for which the trainee was not present (mean [SD], 87.2 [49.2] vs 80.3 [45.4] minutes; P < .001). Among 33 study physicians, 3 (9%) had shorter mean appointment times when a trainee was present, 1 (3%) had no change, and 29 (88%) had longer mean appointment times when a trainee was present. Linear mixed models showed the presence of a resident was associated with a lengthening of appointment time of 17.0 minutes (95% CI, 15.6 18.5 minutes; P < .001), and the presence of a fellow was associated with a lengthening of appointment time of 13.5 minutes (95% CI, 12.3-14.8 minutes; P < .001). Conclusions and Relevance: Presence of trainees was associated with longer appointment times, even for patients not seen by a trainee. Although numerous limitations to this study design might affect the interpretation of the findings, these results highlight a potential challenge of maintaining clinical efficiency in academic medical centers and raise questions about physician reimbursement models. PMID- 29121176 TI - Breaking the Ceiling of Human Maximal Life span. AB - While average human life expectancy has increased dramatically in the last century, the maximum life span has only modestly increased. These observations prompted the notion that human life span might have reached its maximal natural limit of ~115 years. To evaluate this hypothesis, we conducted a systematic analysis of all-cause human mortality throughout the 20th century. Our analyses revealed that, once cause of death is accounted for, there is a proportional increase in both median age of death and maximum life span. To examine whether pathway targeted aging interventions affected both median and maximum life span, we analyzed hundreds of interventions performed in multiple organisms (yeast, worms, flies, and rodents). Three criteria: median, maximum, and last survivor life spans were all significantly extended, and to a similar extent. Altogether, these findings suggest that targeting the biological/genetic causes of aging can allow breaking the currently observed ceiling of human maximal life span. PMID- 29121177 TI - Out-of-Pocket and Health Care Spending Changes for Patients Using Orally Administered Anticancer Therapy After Adoption of State Parity Laws. AB - Importance: Oral anticancer medications are increasingly important but costly treatment options for patients with cancer. By early 2017, 43 states and Washington, DC, had passed laws to ensure patients with private insurance enrolled in fully insured health plans pay no more for anticancer medications administered by mouth than anticancer medications administered by infusion. Federal legislation regarding this issue is currently pending. Despite their rapid acceptance, the changes associated with state adoption of oral chemotherapy parity laws have not been described. Objective: To estimate changes in oral anticancer medication use, out-of-pocket spending, and health plan spending associated with oral chemotherapy parity law adoption. Design, Setting, and Participants: Analysis of administrative health plan claims data from 2008-2012 for 3 large nationwide insurers aggregated by the Health Care Cost Institute. Data analysis was first completed in 2015 and updated in 2017. The study population included 63 780 adults living in 1 of 16 states that passed parity laws during the study period and who received anticancer drug treatment for which orally administered treatment options were available. Study analysis used a difference-in-differences approach. Exposures: Time period before and after adoption of state parity laws, controlling for whether the patient was enrolled in a plan subject to parity (fully insured) or not (self-funded, exempt via the Employee Retirement Income Security Act). Main Outcomes and Measures: Oral anticancer medication use, out-of-pocket spending, and total health care spending. Results: Of the 63 780 adults aged 18 through 64 years, 51.4% participated in fully insured plans and 48.6% in self-funded plans (57.2% were women; 76.8% were aged 45 to 64 years). The use of oral anticancer medication treatment as a proportion of all anticancer treatment increased from 18% to 22% (adjusted difference-in-differences risk ratio [aDDRR], 1.04; 95% CI, 0.96-1.13; P = .34) comparing months before vs after parity. In plans subject to parity laws, the proportion of prescription fills for orally administered therapy without copayment increased from 15.0% to 53.0%, more than double the increase (12.3%-18.0%) in plans not subject to parity (P < .001). The proportion of patients with out-of-pocket spending of more than $100 per month increased from 8.4% to 11.1% compared with a slight decline from 12.0% to 11.7% in plans not subject to parity (P = .004). In plans subject to parity laws, estimated monthly out-of-pocket spending decreased by $19.44 at the 25th percentile, by $32.13 at the 50th percentile, and by $10.83 at the 75th percentile but increased at the 90th ($37.19) and 95th ($143.25) percentiles after parity (all P < .001, controlling for changes in plans not subject to parity). Parity laws did not increase 6-month total spending for users of any anticancer therapy or for users of oral anticancer therapy alone. Conclusions and Relevance: While oral chemotherapy parity laws modestly improved financial protection for many patients without increasing total health care spending, these laws alone may be insufficient to ensure that patients are protected from high out-of-pocket medication costs. PMID- 29121178 TI - Exploration of Predictive Biomarkers of Early Infliximab Response in Acute Severe Colitis: A Prospective Pilot Study. AB - Background: The outcomes of acute severe ulcerative colitis [ASUC] appear to be dependent on early intervention with the first and/or further infliximab [IFX] doses, although parameters to guide decision-making remain uncertain. Aim: To assess whether serum/faecal IFX levels and inflammatory biomarkers early after IFX dose can predict ASUC outcomes. Methods: This prospective pilot study consecutively recruited inpatients with steroid-refractory ASUC, who then received 1-3 IFX rescue doses [5 mg/kg per dose] at the discretion of the treating clinician. Serum IFX, C-reactive protein [CRP], albumin and faecal calprotectin [FC] concentrations were measured daily as an inpatient, and then 7, 14, 28 and 42 days post-first IFX. Faecal IFX was measured 1 day post-IFX. The primary end point was clinical remission (partial Mayo [PM] = 0) and CRP <=3 mg/l at 6 weeks. Secondary end points were 12-week clinical remission or colectomy during follow-up. Results: Of 24 ASUC patients with a median follow-up of 28 months [range 13-44], 10 [42%] achieved remission at 6 weeks, 12 [50%] achieved 12-week remission, six [25%] had colectomy. In total, 97% received either two or three IFX doses. Post-first dose, receiver-operator curve-derived cutoffs of the area-under-curve [AUC, Days 4-7] concentrations for serum IFX, FC and PM scores each predicted the primary end point with 100% sensitivity, and predicted future colectomy with 89-94% sensitivity. In multivariate analyses, faecal IFX >1 ug/g (odds ratio [OR] 0.04 [0.2, 0.9]), PM AUCd1-3 < 20 (OR 20.2 [1.01, 404], each P < 0.05), FC AUCd1-3 < 10000 ug/ml [OR 13.6 [0.6, 294], trend only, p = 0.09) were each associated with clinical and CRP remission [6 weeks]. Conclusions: In ASUC, post-first dose IFX, early assessment of serum/faecal IFX, calprotectin and PM scores can accurately predict future remission and colectomy, and thus potentially aid in decision-making, i.e. accelerated IFX dosing or surgical planning if/when needed. PMID- 29121179 TI - Organotypic myocardial slices as model system to study heterocellular interactions. PMID- 29121180 TI - Categorical Perception of Mandarin Chinese Tones 1-2 and Tones 1-4: Effects of Aging and Signal Duration. AB - Purpose: The purpose of this study was to investigate the aging effect on the categorical perception of Mandarin Chinese tones with varied fundamental frequency (F0) contours and signal duration. Method: Both younger and older native Chinese listeners with normal hearing were recruited in 2 experiments: tone identification and tone discrimination on a series of stimuli with the F0 contour systematically varying from the flat tone to the rising-falling tones. Apart from F0 contour, tone duration was manipulated at 3 levels: 100, 200, and 400 ms. Results: Results suggested that, compared with younger listeners, older listeners performed with shallower slope in the identification function and smaller peakedness in the discrimination function, particularly for Tones 1 and 2, whereas for Tones 1 and 4, comparable categorical perception was found between younger and older listeners. Conclusions: The current study suggested that longer duration facilitated categorical perception in the flat-rising tones for the older listeners. Such an aging effect was not found with the flat-falling tones, suggesting that the aging-related deficit in categorical perception might relate to different tone types. Aging resulted in less categoricality of Mandarin tone perception for the flat-rising tones with short duration like 100 ms, possibly due to the aging-related decline in temporal processing. PMID- 29121183 TI - Primary vs Secondary Endoscopic Dacryocystorhinostomy for Acute Dacryocystitis With Lacrimal Sac Abscess Formation: A Randomized Clinical Trial. AB - Importance: Endoscopic dacryocystorhinostomy (EN-DCR) is emerging as the preferred procedure in the management of nasolacrimal duct obstructions. However, its safety and long-term efficacy in the setting of acute dacryocystitis with lacrimal sac abscess have not been well studied. Objective: To compare outcomes of EN-DCR as primary treatment with EN-DCR as a secondary treatment after percutaneous drainage of lacrimal sac abscess in acute dacryocystitis. Design, Setting, and Participants: This randomized clinical trial was conducted from October 1, 2012, to October 31, 2015, at a tertiary ophthalmic center. The assessors of success at postoperative year 1 were masked to the procedures received by the participants. All surgical procedures were performed by 2 oculoplastic surgeons with different levels of EN-DCR experience. Eligible participants had acute dacryocystitis and lacrimal sac abscess presenting within 2 weeks of onset, who were 18 to 90 years of age. Analysis was of the intention to-treat population. Interventions: Patients were allocated by block randomization to receive either percutaneous drainage of lacrimal sac abscess followed by EN-DCR after the acute episode subsided (control group) or primary EN DCR within 2 weeks of presentation (intervention group). Both groups received a course of empirical systemic antibiotics (amoxicillin and clavulanic acid, 375 mg, to be taken 3 times a day for 1 week). Main Outcomes and Measures: Primary outcomes were time from presentation to documentation of symptom resolution and recurrence within 3 months. Results: Thirty-two patients were randomized equally into 2 treatment arms (control and intervention). The mean (SD) age of patients was 61 (13) years, and there was a predominance of women (27 [84%]). The mean (SD) time to symptom resolution was 13.8 (5.8) days in the intervention group compared with 31.7 (27.1) days in the control group (mean difference, 17.9; 95% CI, 3.71-32.01; P = .02). The mean (SD) time to surgery in the intervention group was shorter at 11.9 (6.3) days compared with 45.6 (30.1) days in the control group (mean difference, 33.6; 95% CI, 17.92-49.33; P < .001). Recurrences occurred once in the control group and did not occur in the intervention group. No differences in operation time and complications between the 2 groups were identified. The anatomical and functional success was 87.5% (14 of 16 cases) in both groups at postoperative year 1. Conclusions and Relevance: Primary EN-DCR in acute dacryocystitis with lacrimal sac abscess results in faster resolution compared with secondary treatment. No differences in recurrence, safety, or outcomes at postoperative year 1 were noted between the 2 treatment groups. PMID- 29121184 TI - Barrel Cortical Neuron Integrates Triple Associated Signals for Their Memory Through Receiving Epigenetic-Mediated New Synapse Innervations. AB - Associative learning is common way for information acquisition. Associative memory is essential to logical reasoning and associative thinking. The storages of multiple associated signals in individual neurons facilitate their integration, expand memory volume, and strengthen cognition ability. Associative memory cells that encode multiple signals have been reported, however, the mechanisms underlying their recruitment and working principle remain to be addressed. We have examined the recruitment of associative memory cells that integrate and store triple sensory signals as well as the potential mechanism of their recruitment. Paired mouse whisker, olfaction, and tail stimulations lead to odorant-induced motion and tail-induced whisker motion. In mice of expressing this cross-modal response, their barrel cortical neurons become to encode odor and tail signals alongside whisker signal. These barrel cortical neurons receive new synapse innervations from piriform and S1-tail cortical neurons. The emergence of cross-modal responses as well as the recruitments of new synapse innervations and associative memory cells in the barrel cortex need miRNA-324 and miRNA-133a, which downregulate Ttbk1 and Tet3. The co-activations of sensory cortices recruit their mutual synapse innervations and associative memory cells that integrate and store multiple associated signals through epigenetic-mediated process. PMID- 29121187 TI - Error in Figure. PMID- 29121185 TI - Molecular Characteristics of Conjunctival Melanoma Using Whole-Exome Sequencing. AB - Importance: Conjunctival melanoma (CM) is a highly aggressive ocular cancer for which treatment options are limited; the molecular pathogenesis is poorly understood. Objective: To identify the molecular characteristics of CM using next generation whole-exome sequencing (WES). Design, Setting, and Participants: Whole exome sequencing was performed on tumor DNA extracted from the archived specimens of 5 patients with CM who had been treated with surgical excision between 2006 and 2011. These samples were analyzed at a tertiary academic ocular oncology referral center using a customized bioinformatic pipeline. Main Outcomes and Measures: Sample analyses were designed to detect driver mutations, chromosome copy number aberrations, and mutation signatures. Results: The study's 5 patients ranged in age from 51 to 77 years. Four of the 5 were female, and all were white. Mutations were detected in known oncogenes, including BRAF, NRAS, NF1, EGFR, ALK, TERT, and APC. None of the mutations associated with uveal melanoma were found. All samples demonstrated a C->T mutation signature typical of UV-induced DNA damage. The most common CNA was a gain in chromosome 6p. Conclusions and Relevance: In these 5 patients, WES allowed identification of mutations that can be targeted with therapy and supported the role of UV light in CM pathogenesis. These findings indicate a need for larger studies to evaluate the diagnostic, prognostic, and therapeutic value of WES for CM. PMID- 29121186 TI - Are Moral and Socio-conventional Knowledge Impaired in Severe Traumatic Brain Injury? AB - Objective: The aim of this study was to investigate explicit moral and socio conventional knowledge in Traumatic Brain Injury (TBI) patients. Method: A group of 28 TBI patients was tested on a new set of moral and socio-conventional items. Responses of TBI patients were compared with those of 28 matched controls. Participants had to report how hard would be to perform specific moral or socio conventional transgressions, using a 10-point Likert scale. We analyzed our data through mixed-effects models, to jointly assess by-participants and by-items variance. The factors considered were Type of Item (Moral vs. Socio-conventional) and Group (TBI vs. Controls). Results: Results revealed a significant interaction between Type of Item and Group (chi2[1] = 25.5, p < .001). Simple-effects analyses showed that TBI, as Controls, were able to differentiate moral and socio conventional transgressions (chi2[1] = 72.3, p < .001), as they deemed the former as more difficult to enact. TBI patients, however, evaluated moral transgressions as easier to fulfill (chi2[1] = 12.2, p = .001). Conclusions: TBI patients can clearly differentiate moral and socio-conventional transgressions, suggesting that the explicit knowledge of these two dimensions is spared. TBI patients, however, considered moral transgressions as easier to fulfill with respect to Controls. This finding may suggest a tendency in TBI patients to underestimate the weight of moral transgressions. PMID- 29121188 TI - Complete Vision Loss From Granulomatosis With Polyangiitis. PMID- 29121189 TI - Macular Horseshoe-Shaped Tear Following Cricket Injury. PMID- 29121190 TI - Bleb-Associated Exogenous Nocardia Endophthalmitis. PMID- 29121191 TI - En Face Optical Coherence Tomography of Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis. PMID- 29121194 TI - Cost-effectiveness of colchicine treatment on post-operative atrial fibrillation events in patients of major cardiac surgery. AB - Aims: Post-operative atrial fibrillation (POAF) occurs in 20-50% of patients amid post-operative stay after Cardiac Surgery. We intend to determine whether colchicine therapy in patients undergoing cardiac surgery is a cost-effective strategy for prevention of POAF. To undertake cost utility analysis and calculate incremental cost utility ratio (ICUR) for colchicine therapy in these subgroup of patients. Methods and results Design: Decision tree model to calculate the ICUR comparing two treatment strategies in patients undergoing cardiac surgery. One wherein patients received colchicine along with usual care and second where they received placebo or just usual care. Cost utility analysis was undertaken using relevant data from the systematic review and meta-analysis of the available randomized controlled trials till June 2016 and mean cost calculations from validated available sources across various jurisdictions. Results: Colchicine treatment based on mean costs for life expectancy calculated at 10 years' post surgery using recommended discounting rates of 3.5% was ? 17544.80 cheaper per quality-adjusted life-year (QALY) gained. The incremental cost is negative and the incremental effect (QALY) is positive (South East quadrant), Hence the intervention of colchicine treatment is unequivocally cost-effective, meaning it is dominant and achieves better outcomes at a lower cost. Conclusion: Our findings provide a benchmark for current and future analyses relating to effectiveness of colchicine on POAF events after cardiac surgery. Currently, there are few reports that provide cutting edge estimates of the higher expenses associated with POAF. Future analyses should likewise explore the impact of added costs from using pharmacologic efforts to prevent and treat POAF after cardiac surgery. PMID- 29121195 TI - A National Survey of Simulation Use in University Programs in Communication Sciences and Disorders. AB - Purpose: This study provides a framework for understanding the range and diversity of simulation use, along with the benefits and challenges to the growth of simulation in university programs in communication sciences and disorders (CSD) across the United States. Method: A web-based questionnaire was developed and deployed to educators in undergraduate and graduate speech-language pathology and audiology programs in the American Speech-Language-Hearing Association EdFind database (N = 309). Responses from 44% (n = 136) of the American Speech-Language Hearing Association-accredited CSD programs were analyzed. Results: Overall, 51% (n = 69) of respondents reported using simulations in clinical education. Of the 5 categories of health care simulation, programs most often employed standardized patients and/or computer-based simulations. Barriers to using simulations included a lack of knowledge, limited financial resources, undertrained faculty, and little guidance from accrediting bodies. A significant number of respondents (n = 66) agreed with the statement that simulated experiences could account for up to 25% of required direct clinical hours in speech-language pathology and audiology. Conclusions: Results of this study suggest an emerging acceptance of simulations as a method of augmenting clinical education within CSD programs. Expanding educational efforts and increasing opportunities for faculty training are essential in realizing the full potential of future professionals using simulations in CSD. Supplemental Material: https://doi.org/10.23641/asha.5576296. PMID- 29121196 TI - The Role of Phonological Working Memory and Environmental Factors in Lexical Development in Italian-Speaking Late Talkers: A One-Year Follow-Up Study. AB - Purpose: This follow-up study assessed (a) the influence of phonological working memory (pWM), home literacy environment, and a family history of linguistic impairments in late talkers (LTs); (b) the diagnostic accuracy of a task of nonword repetition (NWR) in identifying LTs; and (c) the persistence of lexical weaknesses after 10 months. Method: Two hundred ninety-three children were assessed at approximately 32 (t1) and 41 (t2) months. At t1, they were administered the Italian adaptation of the Language Development Survey, an NWR task (used to assess pWM), and questionnaires assessing home literacy environment and family history of language impairments. Thirty-three LTs were identified. The linguistic skills of the participants were evaluated at t2 by administering tasks assessing Articulation, Naming, Semantic Fluency, and Lexical Comprehension. Results: At t2, LTs performed more poorly as compared with age-matched typically developing peers in articulatory and naming skills, had reduced lexical comprehension abilities, and had limited lexical knowledge. Their performance on the NWR task at t1 correlated with the extension of their vocabularies at t2 (as estimated with a Semantic Fluency task). Conclusions: The Language Development Survey recently adapted to Italian is sensitive to LTs. Former LTs still have a mild lexical delay at approximately 40 months. As an indirect measure of pWM, the task of NWR is an early indicator of future lexical deficits. PMID- 29121199 TI - The Next 19 Years of the American Head and Neck Society. PMID- 29121197 TI - Higher accuracy of complex medication reconciliation through improved design of electronic tools. AB - Objective: Investigate the accuracy of 2 different medication reconciliation tools integrated into electronic health record systems (EHRs) using a cognitively demanding scenario and complex medication history. Materials and Methods: Seventeen physicians reconciled medication lists for a polypharmacy patient using 2 EHRs in a simulation study. The lists contained 3 types of discrepancy and were transmitted between the systems via a Continuity of Care Document. Participants updated each EHR and their interactions were recorded and analyzed for the number and type of errors. Results: Participants made 748 drug comparisons that resulted in 53 errors (93% accuracy): 12 using EHR2 (3% rate, 0-3 range) and 41 using EHR1 (11% rate, 0-9 range; P < .0001). Twelve clinicians made completely accurate reconciliations with EHR2 (71%) and 6 with EHR1 (35%). Most errors (28, 53%) occurred in medication entries containing discrepancies: 4 in EHR2 and 24 in EHR1 (P = .008). The order in which participants used the EHRs to complete the task did not affect the results. Discussion: Significantly fewer errors were made with EHR2, which presented lists in a side-by-side view, automatically grouped medications by therapeutic class and more effectively identified duplicates. Participants favored this design and indicated that they routinely used several workarounds in EHR1. Conclusion: Accurate assessment of the safety and effectiveness of electronic reconciliation tools requires rigorous testing and should prioritize complex rather than simpler tasks that are currently used for EHR certification and product demonstration. Higher accuracy of reconciliation is likely when tools are designed to better support cognitively demanding tasks. PMID- 29121200 TI - Exploring Summarization Differences for Two Types of Expository Discourse in Adolescents With Traumatic Brain Injury. AB - Purpose: Annually, nearly 700,000 U.S. children and adolescents experience a traumatic brain injury (TBI). Many of them struggle academically, despite failing to qualify for special education services because their cognitive communication impairments are subtle. Method: In this exploratory study, five adolescents with TBI provided verbal summaries of two expository lectures (compare-contrast, cause effect) and participated in cognitive and expressive syntax testing. Their performance on these tasks was compared descriptively to that of 50 adolescents with typical development. Results: For adolescents with TBI, mean summary quality scores for both exposition types were at least 1 SD lower than those of adolescents with typical development and notably 2 SDs below for the cause-effect passage. The adolescents with TBI who had below-average cognitive scores showed better performance on compare-contrast summaries compared to cause-effect, whereas the majority of adolescents with typical development showed the opposite tendency. Conclusions: These results provide preliminary evidence that students with TBI, particularly those with cognitive deficits, may struggle with expository discourse despite acceptable performance on a measure of expressive syntax. This study also indicates that researchers should explore how students with TBI perform on academically relevant discourse tasks in order to inform future assessment and intervention efforts. Supplemental Materials: https://doi.org/10.23641/asha.5572786. PMID- 29121202 TI - Adaptive Designs for Clinical Trials: Application to Healthcare Epidemiology Research. AB - Clinical trials with adaptive designs use data that accumulate during the course of the study to modify study elements in a prespecified manner. The goal is to provide flexibility such that a trial can serve as a definitive test of its primary hypothesis, preferably in a shorter time period, involving fewer human subjects, and at lower cost. Elements that may be modified include the sample size, end points, eligible population, randomization ratio, and interventions. Accumulating data used to drive these modifications include the outcomes, subject enrollment (including factors associated with the outcomes), and information about the application of the interventions. This review discusses the types of adaptive designs for clinical trials, emphasizing their advantages and limitations in comparison with conventional designs, and opportunities for applying these designs to healthcare epidemiology research, including studies of interventions to prevent healthcare-associated infections, combat antimicrobial resistance, and improve antimicrobial stewardship. PMID- 29121203 TI - Functional characterization of tektin-1 in motile cilia and evidence for TEKT1 as a new candidate gene for motile ciliopathies. AB - A child presenting with Mainzer-Saldino syndrome (MZSDS), characterized by renal, retinal and skeletal involvements, was also diagnosed with lung infections and airway ciliary dyskinesia. These manifestations suggested dysfunction of both primary and motile cilia, respectively. Targeted exome sequencing identified biallelic mutations in WDR19, encoding an IFT-A subunit previously associated with MZSDS-related chondrodysplasia, Jeune asphyxiating thoracic dysplasia and cranioectodermal dysplasia, linked to primary cilia dysfunction, and in TEKT1 which encodes tektin-1 an uncharacterized member of the tektin family, mutations of which may cause ciliary dyskinesia. Tektin-1 localizes at the centrosome in cycling cells, at basal bodies of both primary and motile cilia and to the axoneme of motile cilia in airway cells. The identified mutations impaired these localizations. In addition, airway cells from the affected individual showed severe motility defects without major ultrastructural changes. Knockdown of tekt1 in zebrafish resulted in phenotypes consistent with a function for tektin-1 in ciliary motility, which was confirmed by live imaging. Finally, experiments in the zebrafish also revealed a synergistic effect of tekt1 and wdr19. Altogether, our data show genetic interactions between WDR19 and TEKT1 likely contributing to the overall clinical phenotype observed in the affected individual and provide strong evidence for TEKT1 as a new candidate gene for primary ciliary dyskinesia. PMID- 29121201 TI - High Prevalence of Radiological Vertebral Fractures in Women on Thyroid Stimulating Hormone-Suppressive Therapy for Thyroid Carcinoma. AB - Context: Bone loss and nonvertebral fractures have been reported in patients with differentiated thyroid carcinoma (DTC) undergoing thyroid-stimulating hormone (TSH) suppressive therapy. Radiological vertebral fractures (VFs) are an early and clinically crucial marker of bone fragility. Objective and Design: A cross sectional study to evaluate the prevalence and determinants of radiological VFs in women receiving l-thyroxine (L-T4) therapy for DTC. Patients and Interventions: A total of 179 consecutive women (median age, 59 years; n = 178 postmenopausal) who had undergone thyroidectomy for DTC and were currently receiving L-T4 were evaluated for radiological VFs and bone mineral density (BMD). There were three TSH target levels [<0.5 mU/L, group 1 (n = 83); 0.5 to 1.0 mU/L, group 2 (n = 50); >1.0 mU/L, group 3 (n = 46)]. Results: VFs were found in 51 patients (28.5%), with significantly (P < 0.001) higher prevalence in group 1 (44.6%) as compared with group 2 (24.0%) and group 3 (4.3%). VF prevalence was not significantly different among patients in group 1 with normal BMD, osteopenia, or osteoporosis, whereas in groups 2 and 3, VFs were more frequent in patients with osteoporosis than in those with either osteopenia or normal BMD. In the whole population, VFs were significantly and independently associated with TSH level <1.0 mU/L; densitometric diagnosis of osteoporosis at lumbar spine, femoral neck, or total hip; age of patients; and duration of L-T4 therapy. Conclusion: The prevalence of VFs was high in women with DTC who were undergoing long-term, suppressive L-T4 therapy. PMID- 29121204 TI - Mantle-Cell Lymphoma-Taming the Tiger. PMID- 29121206 TI - Effects of Temperatures on Immature Development and Survival of the Invasive Stink Bug (Hemiptera: Pentatomidae). AB - Bagrada hilaris (Burmeister) (Hemiptera: Pentatomidae) is a non-native stink bug that feeds primarily on cole crops and wild mustards. Its invasion into desert agriculture in California and Arizona presents a conundrum between rapid pest development at warm temperatures and severe damage to cool season crops. In this study, the development and survival of B. hilaris were determined at nine constant temperatures (ranging from 20-42 degrees C) when reared on organically grown broccoli florets. Egg hatching was greatly delayed at 20 degrees C, and first instar nymphs did not survive at this temperature. No eggs hatched at 42 degrees C. The highest survival rates (70.0-86.7%) of B. hilaris were observed at temperatures ranging from 24 to 35 degrees C. The total developmental rate of B. hilaris from egg to adult increased from 0.027 to 0.066/d from 24 to 35 degrees C, and then slightly dropped to 0.064/d at 39 degrees C. Based on the linear model, B. hilaris requires 285.4 degree-days to complete its development. The Briere 1 model predicted the lower and upper temperature thresholds as 16.7 and 42.7 degrees C, respectively. The optimal temperature for development (TOpt) was estimated as 36 degrees C. According to the results, B. hilaris is well adapted to warm conditions, and temperatures of 33-39 degrees C are well suited for B. hilaris development. Information from this study helps explain the rapid range expansion of B. hilaris across the southern United States and will be instrumental in predicting future expansion across the rest of the country and in other parts of the world. The relationship between thermal thresholds and invasion dynamics of this pest are discussed. PMID- 29121205 TI - Pregnancy and Lifetime Exposure to Fine Particulate Matter and Infant Mortality in Massachusetts, 2001-2007. AB - Many studies have found associations between particulate matter having an aerodynamic diameter of <=2.5 MUm (PM2.5) and adult mortality. Comparatively few studies evaluated particles and infant mortality, although infants and children are particularly vulnerable to pollution. Moreover, existing studies mostly focused on short-term exposure to larger particles. We investigated PM2.5 exposure during pregnancy and lifetime and postneonatal infant mortality. The study included 465,682 births with 385 deaths in Massachusetts (2001-2007). Exposures were estimated from PM2.5-prediction models based on satellite imagery. We applied extended Cox proportional hazards modeling with time-dependent covariates to total, respiratory, and sudden infant death syndrome mortality. Exposure was calculated from birth to death (or end of eligibility for outcome, at age 1 year) and pregnancy (gestation and each trimester). Models adjusted for sex, birth weight, gestational length, season of birth, temperature, relative humidity, and maternal characteristics. Hazard ratios for total, respiratory, and sudden infant death syndrome mortality per-interquartile-range increase (1.3 MUg/m3) in lifetime PM2.5 exposure were 2.66 (95% confidence interval (CI): 2.11, 3.36), 3.14 (95% CI: 2.39, 4.13), and 2.50 (95% CI: 1.56, 4.00), respectively. We did not observe a statistically significant relationship between gestational exposure and mortality. Our findings provide supportive evidence that lifetime exposure to PM2.5 increases risk of infant mortality. PMID- 29121207 TI - Interfering With Inner Speech Selectively Disrupts Problem Solving and Is Linked With Real-World Executive Functioning. AB - Purpose: According to Vygotskian theory, verbal thinking serves to guide our behavior and underpins critical self-regulatory functions. Indeed, numerous studies now link inner speech usage with performance on tests of executive function (EF). However, the selectivity of inner speech contributions to multifactorial executive planning performance and links with real-world functioning are limited. Therefore, the present study seeks to fill this gap in our knowledge. Method: Fifty-one adults completed the Tower of London under 2 conditions, (a) articulatory suppression and (b) foot tapping, and provided self ratings of real-world executive functioning (utilizing the Behavior Rating Inventory of Executive Function-Adult Version; Roth, Isquith, & Gioia, 2006). Results: Interfering with inner speech selectively disrupted Tower of London performance over and above a simultaneous motor task (i.e., foot tapping). Furthermore, this selectivity in performance was linked with real-world self monitoring. Conclusion: These results provide further evidence for specific links between verbal thinking and EF (particularly using multifactorial tasks of planning) and suggest that inner speech might serve as a key intervention target in clinical disorders where EF deficits are prominent. PMID- 29121208 TI - Dynamics of Bacterial Colonization With Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis During Symptomatic and Asymptomatic Viral Upper Respiratory Tract Infection. AB - Background: Virus is detected in about 80% of upper respiratory tract infections (URTIs) in children and is also detectable in the nasopharynx of 30% of asymptomatic children. The effect of asymptomatic viral infection on the dynamics of bacterial density and colonization of the nasopharynx has not been reported. The current study was performed to assess the presence and density of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the nasopharynx of 4-7-year-old children during URTI and when well. Methods: Nasal samples were obtained during 4 surveillance periods when children were asymptomatic and whenever they had symptoms of URTI. Respiratory viruses and bacterial pathogens were identified and quantified using polymerase chain reaction. Results: The proportion of children colonized with all 3 bacteria was higher during visits for acute URTI than during asymptomatic surveillance visits. Mean bacterial densities were significantly higher at all visits for all 3 pathogens when a virus was detected. The differences between the means were 1.0, 0.4, and 0.7 log10 colony-forming unit equivalents per milliliter for S. pneumoniae, H. influenzae, and M. catarrhalis, respectively, compared with visits in which virus was not detected. The percentage of children colonized and density were also higher at asymptomatic visits in which virus was detected than at visits in which virus was not detected. Conclusion: The density and frequency of colonization with S. pneumoniae, H. influenzae, and M. catarrhalis in nasal wash samples increase during periods of both symptomatic and asymptomatic viral infection. Increases in bacterial colonization observed during asymptomatic viral infection were nearly the same magnitude as when children were symptomatic. PMID- 29121210 TI - Impact of baseline plasma HIV-1 RNA and time to virological suppression on virological rebound according to first-line antiretroviral regimen. PMID- 29121209 TI - Genomic Environment Impacts Color Vision Evolution in a Family with Visually Based Sexual Selection. AB - Many models of evolution by sexual selection predict a coevolution of sensory systems and mate preferences, but the genomic architecture (number and arrangement of contributing loci) underlying these characters could constrain this coevolution. Here, we examine how the genomic organization and evolution of the opsin genes (responsible for tuning color vision) can influence the evolutionary trajectory of sexually selected traits across 15 species in the family Poeciliidae, which includes classic systems for studies of color-mediated sexual selection such as guppies, swordtails, and mollies. Although male coloration patterns and the importance of this coloration in female mate choice vary widely within and among genera, sequencing revealed low variability at amino acid sites that tune Long Wavelength-Sensitive (LWS) opsins in this speciose family. Although most opsin genes in these species appear to have evolved along traditional mutation-selection dynamics, we identified high rates of gene conversion between two of the LWS loci (LWS-1 and LWS-3), likely due to the inverted tandem repeat nature of these genes. Yet members of the subgenus Lebistes appear to resist LWS gene conversion. The LWS opsins are responsible for detecting and discriminating red and orange coloration-a key sexually selected trait in members of the subgenus Lebistes. Taken together these results suggest selection is acting against the homogenizing effects of gene conversion to maintain LWS-1/LWS-3 differences within this subgenus. PMID- 29121211 TI - External Validation and Update of the RICP-A Multivariate Model to Predict Chronic Postoperative Pain. AB - Objective: The development of chronic postsurgical pain (CPSP) is influenced by several factors. The risk index for chronic pain (RICP) was developed to identify patients at high risk for CPSP. The aim of this study was the external validation and update of the RICP. Design: Prospective cohort study. Setting: Two German hospitals. Subjects: Participants who underwent orthopedic surgery, general surgery, visceral surgery, and neurosurgery. Methods: The predicted outcome was CPSP at six months. We validated the original RICP externally and performed a model update. Analysis was performed using logistic regression. We analyzed the discrimination and calibration of the model. Furthermore, the updated model was internally validated. Results: We included 205 patients. The mean age of participants was 51 years. CPSP was reported by 53.9% of participants. In our population, the original RICP (preoperative pain in the operating field, other preoperative pain, postoperative acute pain, capacity overload, and comorbid stress symptoms) showed a sensitivity of 0.708 and a specificity of 0.727 (area under the curve [AUC] = 0.766, 95% confidence interval [CI] = 0.688-0.843). The updated RICP (preoperative pain in the operating field, other preoperative pain, postoperative acute pain, sex, marital status) yielded a sensitivity of 0.746 and a specificity of 0.726 (AUC = 0.813, 95% CI = 0.740-0.886). The results were confirmed by cross-validation. Pre- and postoperative pain measures showed the highest predictive ability. Discussion: The study indicates external validity of the original RICP. The updated RICP also showed good predictive ability. The results are limited by the small sample size and the amount of missing outcome data. PMID- 29121212 TI - Effectiveness and safety of rivaroxaban vs. warfarin in patients 80+ years of age with non-valvular atrial fibrillation. PMID- 29121213 TI - Towards Cardio-Precision medicine. PMID- 29121214 TI - Missing data and technical variability in single-cell RNA-sequencing experiments. AB - Until recently, high-throughput gene expression technology, such as RNA Sequencing (RNA-seq) required hundreds of thousands of cells to produce reliable measurements. Recent technical advances permit genome-wide gene expression measurement at the single-cell level. Single-cell RNA-Seq (scRNA-seq) is the most widely used and numerous publications are based on data produced with this technology. However, RNA-seq and scRNA-seq data are markedly different. In particular, unlike RNA-seq, the majority of reported expression levels in scRNA seq are zeros, which could be either biologically-driven, genes not expressing RNA at the time of measurement, or technically-driven, genes expressing RNA, but not at a sufficient level to be detected by sequencing technology. Another difference is that the proportion of genes reporting the expression level to be zero varies substantially across single cells compared to RNA-seq samples. However, it remains unclear to what extent this cell-to-cell variation is being driven by technical rather than biological variation. Furthermore, while systematic errors, including batch effects, have been widely reported as a major challenge in high-throughput technologies, these issues have received minimal attention in published studies based on scRNA-seq technology. Here, we use an assessment experiment to examine data from published studies and demonstrate that systematic errors can explain a substantial percentage of observed cell-to-cell expression variability. Specifically, we present evidence that some of these reported zeros are driven by technical variation by demonstrating that scRNA-seq produces more zeros than expected and that this bias is greater for lower expressed genes. In addition, this missing data problem is exacerbated by the fact that this technical variation varies cell-to-cell. Then, we show how this technical cell-to-cell variability can be confused with novel biological results. Finally, we demonstrate and discuss how batch-effects and confounded experiments can intensify the problem. PMID- 29121216 TI - Fast Inhibitory Decay Facilitates Adult-like Temporal Processing in Layer 5 of Developing Primary Auditory Cortex. AB - The protracted maturational process of temporal processing in layer 4 (L4) of primary auditory cortex (A1) has been extensively studied. Accumulating evidences show that layer 5 (L5) receives direct thalamic inputs as well. How the temporal responses in L5 may developmentally emerge remains unclear. Using in vivo loose patch recordings in rat A1, we found that putative pyramidal (Pyr) neurons in developing L5 exhibited adult-like stimulus-following ability but less bursting shortly after hearing onset. L5 Pyr neurons in adult A1 exhibited phase-locking similar to L4 neurons, while L5 fast-spiking (FS) neurons showed greater phase locking at 7 and 12.5 pps. In developing L5, whole-cell recordings revealed inhibition with decay constant comparable to that in adult L5, thereby avoiding the summation of inhibition that contributed to the strong adaptation in L4. Given the targets of L5 outputs, the relatively precocious temporal processing in L5 might contribute to temporal response maturation in connected cortical and subcortical areas. Our findings were in agreement with the idea that L5 may be a "hub" for processing cortical inputs and outputs that can operate independently of L4. PMID- 29121215 TI - Trabecular Bone Morphology Correlates With Skeletal Maturity and Body Composition in Healthy Adolescent Girls. AB - Context: Growth in healthy children is associated with changes in bone density and microarchitecture. Trabecular morphology is an additional important determinant of bone strength, but little is currently known about trabecular morphology in healthy young people. Objective: To investigate associations of trabecular morphology with increasing maturity and with body composition in healthy girls. Design: Cross-sectional study. Setting: Academic research center. Participants: Eighty-six healthy girls aged 9 to 18 years. Main Outcome Measures: High-resolution peripheral quantitative computed tomography and individual trabecula segmentation were used to assess volumetric bone density, microarchitecture, and trabecular morphology (plate-like vs rod-like) at the distal radius and tibia. Results: Plate-like bone volume divided by total volume (pBV/TV) increased statistically significantly at the tibia (R = 0.41, P < 0.001), whereas rod-like BV/TV (rBV/TV) decreased statistically significantly at both the radius and tibia (R = -0.34, P = 0.003 and R = -0.28, P = 0.008, respectively) with increasing bone age. In multivariable models, lean mass positively correlated with pBV/TV and plate number at the radius and with plate thickness at both sites. In contrast, fat mass negatively correlated with plate thickness at the tibia and plate surface at both sites. In addition, fat mass positively correlated with rBV/TV and number at the tibia. pBV/TV at both the distal radius and tibia was positively correlated with spine bone mineral density. Conclusions: Increasing maturity across late childhood and adolescence is associated with changes in trabecular morphology anticipated to contribute to bone strength. Body composition correlates with trabecular morphology, suggesting that muscle mass and adiposity in youth may contribute to long-term skeletal health. PMID- 29121218 TI - The Syrian Vulnerable Person Resettlement Programme: evaluation of Edinburgh's reception arrangements. AB - Background: During 2015 and 2016 a group of Syrian refugees were resettled in Edinburgh, Scotland under the United Kingdom Government Syrian Vulnerable Person Resettlement Programme. We evaluate the strengths and weaknesses of the settling in arrangements for these refugees. Methods: Semi-structured interviews were conducted with five Arabic interpreters who had worked extensively with these refugees. Interviews sought their impressions about what went well or was not successful. Interviews were transcribed and key themes extracted and analysed. Results: Six themes emerged: 'first impressions', language skills, different healthcare systems, health of the refugees, relationships between the interpreters and refugees and support for the interpreters. Conclusions: The welcoming arrangements went well and exceeded refugees' and interpreters' expectations. There was perhaps too much information given immediately and reinforcing details about various public services and facilities after a first few months would be worthwhile. The Syrians were unfamiliar with NHS structures and found lack of direct specialist access surprising. Problems were amplified by low English levels. A need for Arabic literacy classes was also identified. Interpreters were often used informally out-of-hours and a better system with first contact in Arabic should be established. Interpreters find this work particularly stressful and the provision of psychological support for them should be prioritized. PMID- 29121217 TI - Effect of ulipristal acetate and mifepristone at emergency contraception dose on the embryo-endometrial attachment using an in vitro human trophoblastic spheroid and endometrial cell co-culture model. AB - STUDY QUESTION: Do both ulipristal acetate (UPA) and mifepristone inhibit embryo endometrial attachment at concentrations corresponding to the emergency contraception (EC) dose? SUMMARY ANSWER: Both UPA and mifepristone at concentrations corresponding to the EC dose do not have an inhibitory effect on embryo implantation, although mifepristone at a higher concentration appeared to have such an effect. WHAT IS KNOWN ALREADY: Levonorgestrel is commonly used for EC, but it only acts through inhibition of ovulation. UPA and mifepristone have higher efficacy as EC compared to levonorgestrel; while there is some suggestion that mifepristone may interfere with implantation, whether UPA has post-ovulatory action in inhibiting implantation is yet to be confirmed. STUDY DESIGN, SIZE, DURATION: An in vitro experimental study using trophoblastic spheroids made from JAr cell line as the embryo surrogate, and the Ishikawa cell line and primary human endometrial cells cultured to monolayer as the endometrial surrogate. The primary endometrial cells were collected from nine volunteer women in the mid luteal phase with consent. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university gynaecology unit. The JAr and Ishikawa cell lines (or primary endometrial cells) were treated with graded concentrations of UPA (0, 0.04, 0.4 and 4 MUM) or mifepristone (0, 0.1, 1 and 10 MUM) for 24 h. Embryo endometrial attachment was studied using an in vitro JAr spheroid-endometrial co culture model. Expressions of progesterone receptor, beta-catenin and glycogen synthase kinase 3 beta (GSK-3beta) were studied with real-time RT-PCR and Western blotting, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In the Ishikawa experiments, there was no significant difference in the JAr spheroid attachment rate after treatment with UPA at 0 (93.0%), 0.04 (93.6%), 0.4 (93.4%) and 4 (91.4%) MUM concentrations (P > 0.05); the attachment rate was reduced after treatment with mifepristone only at 10 MUM (79.8%, P < 0.0001) but not at 0.1 (92.1%) or 1.0 (95.2%) MUM concentrations. In the primary endometrial cell experiments, again no significant difference was observed in the JAr spheroid attachment rate after treatment with UPA 4 MUM (42.6%) compared to control (46.5%, P > 0.05). Both UPA and mifepristone could significantly up-regulate progesterone receptor expression. There was no significant alteration in expression of beta-catenin and GSK-3beta after treatment with UPA 4 MUM or mifepristone 10 MUM (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: The co-culture model is only a surrogate which may not fully represent the complicated process of embryo implantation in vivo, although there is no existing perfect model for studying implantation in vitro which fully resembles the latter. WIDER IMPLICATIONS OF THE FINDINGS: The lack of inhibitory effect on embryo implantation by UPA and possibly mifepristone at concentrations corresponding to the EC dose is an important information for contraceptive counseling. STUDY FUNDING/COMPETING INTEREST(S): We had free supply of the UPA compound used in this study from Laboratoire HRA Pharma. This work was supported by a Seed Fund from the Centre of Reproduction, Development and Growth, Faculty of Medicine, The University of Hong Kong, Hong Kong. PMID- 29121219 TI - Clinicopathological Features of Ocular Adnexal Mantle-Cell Lymphoma in an International Multicenter Cohort. AB - Importance: To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort. Objective: To characterize the clinical features of OA-MCL. Design, Setting, and Participants: This retrospective multicenter study included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months. Main Outcomes and Measures: Overall survival, disease-specific survival, and progression-free survival were the primary end points. Results: Fifty-five patients were included; ocular adnexal MCL was found to be most common in older individuals (mean age, 70 years) and men (n = 42 of 55; 76%). Patients with OA-MCL frequently presented with disseminated lymphoma (n = 34 of 55; 62%), and were likely to experience stage IVE disease (n = 35 of 55; 64%), with bilateral involvement (n = 27 of 55; 47%), tumor masses (n = 27 of 36; 75%), and involvement of the orbit (n = 32 of 55; 58%). Chemotherapy with or without external beam radiation therapy was the most frequently used treatment. Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease specific survival adjusted by eye cancer center was better in patients who had received rituximab in addition to the chemotherapy regimen (hazard ratio, 3.3; 95% CI, 1.0-14.7; P = .06). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) in patients who experienced recurrence after primary treatment, and 4.1 years (95% CI, 3.9-4.3 years) in patients who presented with a relapse of systemic lymphoma in the ocular adnexal region. Conclusions and Relevance: These results suggest that the distinctive features of OA-MCL are its appearance in older male individuals, advanced stage and bilateral manifestation at the time of diagnosis, and aggressive course. The prognosis of patients with OA-MCL might be improved by addition of rituximab to chemotherapy treatment. PMID- 29121220 TI - Pathway-Specific Control of Striatal Neuron Vulnerability by Corticostriatal Cannabinoid CB1 Receptors. AB - The vast majority of neurons within the striatum are GABAergic medium spiny neurons (MSNs), which receive glutamatergic input from the cortex and thalamus, and form two major efferent pathways: the direct pathway, expressing dopamine D1 receptor (D1R-MSNs), and the indirect pathway, expressing dopamine D2 receptor (D2R-MSNs). While molecular mechanisms of MSN degeneration have been identified in animal models of striatal damage, the molecular factors that dictate a selective vulnerability of D1R-MSNs or D2R-MSNs remain unknown. Here, we combined genetic, chemogenetic, and pharmacological strategies with behavioral and neurochemical analyses, and show that the pool of cannabinoid CB1 receptor (CB1R) located on corticostriatal terminals efficiently safeguards D1R-MSNs, but not D2R MSNs, from different insults. This cell-specific response relies on the regulation of glutamatergic signaling, and is independent from the CB1R-dependent control of astroglial activity in the striatum. These findings define cortical CB1R as a pivotal synaptic player in dictating a differential vulnerability of D1R-MSNs versus D2R-MSNs, and increase our understanding of the role of coordinated cannabinergic-glutamatergic signaling in establishing corticostriatal circuits and its dysregulation in neurodegenerative diseases. PMID- 29121221 TI - Short atrioventricular delay pacing therapy in young and old patients with hypertrophic obstructive cardiomyopathy: good long-term results and a low need for reinterventions. AB - Aims: Examination of long-term results following different treatments in hypertrophic obstructive cardiomyopathy (HOCM) in a complete geographical cohort. Methods and results: HOCM patients attending during 2002-13 in all 10 hospitals in the West Gotaland Region, Sweden, were identified (n = 251), follow-up 14.4 (+/-8.9) years (mean +/- SD), 121 managed medically, 42 treated with myectomy and 88 with short atrioventricular (AV) delay pacing as first interventional procedure. Post-intervention follow-up was 12.9 +/- 8.7 years and 12.2 +/- 5.0 years, respectively. Both intervention treatments improved New York Heart Association (NYHA) class and outflow gradients significantly. Patients treated with pacing were older (median age 64 vs. 43 years, P < 0.001). Freedom from disease-related death post-procedure at 5, 10, and 20 years were 93%, 80%, 56% vs. 93%, 93%, 57% in pacing and myectomy groups, respectively (log-rank P = 0.43). Survival after diagnosis was not different in patients just treated conservatively (P = 0.51 pacing/conservative; P = 0.39 myectomy/conservative). Reintervention for outflow gradients in patients >=18 years at procedure occurred in 3.5% in pacing group and 15.6% in myectomy group (P = 0.007). Pacing therapy was equally effective in patients aged 13-64 years (n = 44), as in patients >=65 years (n = 44): resting gradient pre-procedure and at last follow-up were median (IQR) 65 (71) and 12 (20) mmHg for <65 year-olds (P < 0.001), and 75 (64) and 14 (38) mmHg, respectively, for >=65 year-olds (P < 0.001). New York Heart Association class improved significantly in both age ranges to 1.6 +/- 0.6 and 1.8 +/- 0.7, respectively (P < 0.001; P < 0.001). Conclusion: Short AV delay pacing provided lasting satisfactory relief of symptoms and outflow obstruction in the majority of patients, with low risk of requiring reintervention. Our findings support the view that pacing therapy should be considered a valid option to treat patients with HOCM. PMID- 29121222 TI - Neurological effects of proprotein convertase subtilisin/kexin type 9 inhibitors: direct comparisons. AB - Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably alter the lipid profile. We sought to examine the rates of ischaemic stroke and neurocognitive deficits in patients treated with and without PCSK9 inhibitors. Methods and results: Randomized controlled trials (RCTs) reporting rates of ischaemic stroke and neurocognitive deficits in patients using PCSK9 inhibitors were identified. Standard meta-analysis techniques were used to compare these outcomes among patients treated with and without PCSK9 inhibitors and the two US Food and Drug Administration-approved PCSK9 inhibitors, evolocumab and alirocumab. The results were presented in terms of risk ratio (RR) with 95% confidence intervals (CIs). Sixteen RCTs with 39 104 patients were included. Evolocumab was used in six RCTs with 33 450 patients, whereas alirocumab was used in 10 RCTs with 5654 patients. We observed a significantly lower risk of ischaemic stroke among those treated with PCSK9 inhibitors (RR 0.77, 95% CI 0.64 0.93) when compared with those without. We did not observe any difference in the risk of neurocognitive deficits between the aforementioned groups (RR 1.11, 95% CI 0.93-1.32). The lower stroke risk in the PCSK9 inhibitors group was driven by evolocumab studies. We observed no difference in the risk of neurocognitive deficits among evolocumab and alirocumab when compared with no PCSK9 inhibitors group. Conclusion: Treatment with PCSK9 inhibitors significantly lowers the risk of ischaemic stroke, without any increased risk of neurocognitive deficits. PCSK9 inhibitors are neuroprotective due to the decrease in ischaemic-mediated neurovascular events and should be considered cognitively innocuous medications. PMID- 29121223 TI - Health system strengthening: prospects and threats for its sustainability on the global health policy agenda. AB - In 2013, Hafner and Shiffman applied Kingdon's public policy process model to explain the emergence of global attention to health system strengthening (HSS). They questioned, however, HSS's sustainability on the global health policy agenda, citing various concerns. Guided by the Grindle and Thomas interactive model of policy implementation, we advance and elaborate a proposition: a confluence of developments will contribute to maintaining HSS's prominent place on the agenda until at least 2030. Those developments include (1) technical, managerial, financial, and political responses to unpredictable public health crises that imperil the routine functioning of health systems, such as the 2014 2015 Ebola virus disease (Ebola) epidemic in West Africa; (2) similar responses to non-crisis situations requiring fully engaged, robust health systems, such as the pursuit of the new Sustainable Development Goal for health (SDG3); and (3) increased availability of new knowledge about system change at macro, meso, and micro levels and its effects on people's health and well-being. To gauge the accuracy of our proposition, we carried out a speculative assessment of credible threats to our premise by discussing all of the Hafner-Shiffman concerns. We conclude that (1) the components of our proposition and other forces that have the potential to promote continuing attention to HSS are of sufficient strength to counteract these concerns, and (2) prospective monitoring of HSS agenda status and further research on agenda sustainability can increase confidence in our threat assessment. PMID- 29121224 TI - Hill's Heuristics and Explanatory Coherentism in Epidemiology. AB - In this essay, I argue that Ted Poston's theory of explanatory coherentism is well-suited as a tool for causal explanation in the health sciences, particularly in epidemiology. Coherence has not only played a role in epidemiology for more than half a century as one of Hill's viewpoints, it can also provide background theory for the development of explanatory systems by integrating epidemiologic evidence with a diversity of other error-independent data. I propose that computational formalization of Hill's viewpoints in an explanatory coherentist framework would provide an excellent starting point for a formal epistemological (knowledge-theoretical) project designed to improve causal explanation in the health sciences. As an example, I briefly introduce Paul Thagard's ECHO system and offer my responses to possible objections to my proposal. PMID- 29121225 TI - Time-dependent glucocorticoid administration differently affects peripheral circadian rhythm in rats. AB - There is a growing recognition that glucocorticoid (GC) acts as an internal timing signal for peripheral circadian oscillators. However, the transcription process of GC-related clock gene in the peripheral tissues is not fully understood. The present study was designed to explore the potential role of clock genes in the GC-induced peripheral circadian gene expression in vivo. Real-time RT-PCR analysis indicated that the transcript levels of Per1 and Dec1 were rapidly up-regulated within 0.5 and 1 h in the heart and kidney respectively after stimulation with dexamethasone (Dex). These results suggest that Per1 and Dec1 serve as the primary and secondary responsers respectively in initiating the GC-induced peripheral circadian gene expression. By comparing the effects of the different GC administration schedules on the circadian rhythm of clock genes in peripheral tissues in rats, we found that the circadian phases of Bmal1 and Per1 were shifted more in the ZT0 (endogenous valley time) Dex stimulation group than in the ZT12 (endogenous peak time) Dex stimulation group in heart and kidney under the normal LD cycle. Under the jet lag condition, the circadian phases of Bmal1 and Per1 were also shifted more in the ZT0 Dex stimulation group than in the ZT12 Dex stimulation group. Therefore, the GC stimulation in the endogenous valley time caused circadian disorder in the normal LD cycle, but it might benefit the circadian resetting of peripheral clocks under the LD reversal condition. PMID- 29121227 TI - Patient engagement. PMID- 29121228 TI - Antonio Colombo MD. PMID- 29121229 TI - A Swiss National Strategy for 2017-2024. PMID- 29121226 TI - Optical frequency domain imaging vs. intravascular ultrasound in percutaneous coronary intervention (OPINION trial): one-year angiographic and clinical results. AB - Aims: Optical frequency domain imaging (OFDI) is a recently developed, light based, high-resolution intravascular imaging technique. Intravascular ultrasound (IVUS) is a widely used, conventional imaging technique for guiding percutaneous coronary intervention (PCI). We aimed to demonstrate the non-inferiority of OFDI guided PCI compared with IVUS-guided PCI in terms of clinical outcomes. Methods and results: We did a prospective, multicentre, randomized (ratio 1:1), active controlled, non-inferiority study to compare head-to-head OFDI vs. IVUS in patients undergoing PCI with a second generation drug-eluting stent. The primary endpoint was target vessel failure defined as a composite of cardiac death, target-vessel related myocardial infarction, and ischaemia-driven target vessel revascularization until 12 months after the PCI. The major secondary endpoint was angiographic binary restenosis at 8 months. We randomly allocated 829 patients to receive OFDI-guided PCI (n = 414) or IVUS-guided PCI (n = 415). Target vessel failure occurred in 21 (5.2%) of 401 patients undergoing OFDI-guided PCI, and 19 (4.9%) of 390 patients undergoing IVUS-guided PCI, demonstrating non-inferiority of OFDI-guided PCI to IVUS-guided PCI (hazard ratio 1.07, upper limit of one sided 95% confidence interval 1.80; Pnon-inferiority = 0.042). With 89.8% angiographic follow-up, the rate of binary restenosis was comparable between OFDI guided PCI and IVUS-guided PCI (in-stent: 1.6% vs. 1.6%, P = 1.00; and in segment: 6.2% vs. 6.0%, P = 1.00). Conclusion: The 12-month clinical outcome in patients undergoing OFDI-guided PCI was non-inferior to that of patients undergoing IVUS-guided PCI. Both OFDI-guided and IVUS-guided PCI yielded excellent angiographic and clinical results, with very low rates of 8-month angiographic binary restenosis and 12-month target vessel failure. Clinical registration: ClinicalTrials.gov, number NCT01873027. PMID- 29121231 TI - Advances in Cardiac Ultrasound, Davos 2018. PMID- 29121230 TI - The Seven Countries Study. PMID- 29121232 TI - Francesco Paneni MD PhD FESC. PMID- 29121233 TI - The London Cardiology Update. PMID- 29121234 TI - Optimizing percutaneous coronary interventions: Heart Team, SYNTAX II Score, physiology and imaging guidance, modern stents, and guideline-based medication. PMID- 29121235 TI - Management of an Outbreak of Exophiala dermatitidis Bloodstream Infections at an Outpatient Oncology Clinic. AB - We report the presentation and management of 17 cases of Exophiala dermatitidis and Rhodotorula mucilaginosa bloodstream infections caused by a compounded parenteral medication at an oncology clinic. Twelve patients were asymptomatic. All central venous catheters were removed and antifungal therapy, primarily voriconazole, was administered to patients. Three patients died. PMID- 29121236 TI - Directors of public health as 'a protected species': qualitative study of the changing role of public health professionals in England following the 2013 reforms. AB - Background: The Health and Social Care Act 2012 gave councils in England responsibility for improving the health of their populations. Public health teams were transferred from the National Health Service (NHS), accompanied by a ring fenced public health grant. This study examines the changing role of these teams within local government. Methods: In-depth case study research was conducted within 10 heterogeneous councils. Initial interviews (n = 90) were carried out between October 2015 and March 2016, with follow-up interviews (n = 21) 12 months later. Interviewees included elected members, directors of public health (DsPH) and other local authority officers, plus representatives from NHS commissioners, the voluntary sector and Healthwatch. Results: Councils welcomed the contribution of public health professionals, but this was balanced against competing demands for financial resources and democratic leverage. DsPH-seen by some as a 'protected species'-were relying increasingly on negotiating and networking skills to fulfil their role. Both the development of the existing specialist public health workforce and recruitment to, and development of, the future workforce were uncertain. This poses both threats and opportunities. Conclusions: Currently the need for staff to retain specialist skills and maintain UKPH registration is respected. However, action is needed to address how future public health professionals operating within local government will be recruited and developed. PMID- 29121237 TI - Human Ageing Genomic Resources: new and updated databases. AB - In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR's main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts and regularly updated to ensure a high quality data. Cross-links across our databases and to external resources help researchers locate and integrate relevant information. HAGR is freely available online (http://genomics.senescence.info/). PMID- 29121238 TI - Structural social relations and cognitive ageing trajectories: evidence from the Whitehall II cohort study. AB - Background: Social relations are important for health, particularly at older ages. We examined the salience of frequency of social contacts and marital status for cognitive ageing trajectories over 21 years, from midlife to early old age. Methods: Data are from the Whitehall II cohort study, including 4290 men and 1776 women aged 35-55 years at baseline (1985-88). Frequency of social contacts and marital status were measured in 1985-88 and 1989-90. Assessment of cognitive function on five occasions (1991-94, 1997-99, 2003-04, 2007-09 and 2012-13) included the following tests: short-term memory, inductive reasoning, verbal fluency (phonemic and semantic) and a combined global score. Cognitive trajectories over the study period were analysed using longitudinal latent growth class analyses, and the associations of these latent classes (trajectory memberships) with social relations were analysed using multinominal logistic regression. Results: More frequent social contacts [relative risk (RRR) 0.96, 95% confidence interval (CI) 0.94 - 0.98] and being married (RRR 0.70, 95% CI 0.58 - 0.84) were associated with lower probability of being on a low rather than high cognitive performance trajectory over the subsequent 21 years. These associations persisted after adjustment for covariates. Of the sub-tests, social relations variables had the strongest association with phonemic fluency (RRR 0.95, 95% CI 0.94 - 0.97 for frequent contact; RRR 0.59, 95% CI 0.48 - 0.71 for being married). Conclusions: More frequent social contacts and having a spouse were associated with more favourable cognitive ageing trajectories. Further studies are needed to examine whether interventions designed to improve social connections affect cognitive ageing. PMID- 29121240 TI - Privacy-preserving techniques of genomic data-a survey. AB - Genomic data hold salient information about the characteristics of a living organism. Throughout the past decade, pinnacle developments have given us more accurate and inexpensive methods to retrieve genome sequences of humans. However, with the advancement of genomic research, there is a growing privacy concern regarding the collection, storage and analysis of such sensitive human data. Recent results show that given some background information, it is possible for an adversary to reidentify an individual from a specific genomic data set. This can reveal the current association or future susceptibility of some diseases for that individual (and sometimes the kinship between individuals) resulting in a privacy violation. Regardless of these risks, our genomic data hold much importance in analyzing the well-being of us and the future generation. Thus, in this article, we discuss the different privacy and security-related problems revolving around human genomic data. In addition, we will explore some of the cardinal cryptographic concepts, which can bring efficacy in secure and private genomic data computation. This article will relate the gaps between these two research areas-Cryptography and Genomics. PMID- 29121239 TI - Overproduction of Sinorhizobium meliloti ArgC (N-acetyl-gamma-glutamyl phosphate reductase) promotes growth delay and inefficient nodules. AB - argC encodes N-acetyl-gamma-glutamyl phosphate reductase, the enzyme that catalyzes the high-energy-consuming third step in the arginine synthesis pathway. A comparative analysis revealed two translation start sites in argC from Sinorhizobium meliloti. To determine whether both protein versions are synthesized in the organism and their functional role, we obtained genetic constructs with one (1S) or two (2S) start sites, with promoters of low (pspeB) or high (plac) transcriptional rate. The constructs were transferred to the S. meliloti 1021 derivative argC mutant strain. Both protein versions were found in the free-living proteomes, but only ArgC 1S showed post-translational modification. Expression levels from argC 1S were five times higher than those of 2S, when transcribed by plac, and in concordance, its protein activity was 3-fold greater. The overexpression of both versions under plac delayed cellular growth. Inoculation of Medicago sativa plants with the S. meliloti strain harboring the argC 1S under plac induced nodulation but not nitrogen fixation. However, the strain with the argC 2S under the same promoter had a positive phenotype. Overproduction of ArgC protein for the synthesis of arginine induced physiological and symbiotic effects. PMID- 29121241 TI - Suppressing Type 2C Protein Phosphatases Alters Fruit Ripening and the Stress Response in Tomato. AB - Although ABA signaling has been widely studied in Arabidopsis, the roles of core ABA signaling components in fruit remain poorly understood. Herein, we characterize SlPP2C1, a group A type 2C protein phosphatase that negatively regulates ABA signaling and fruit ripening in tomato. The SlPP2C1 protein was localized in the cytoplasm close to AtAHG3/AtPP2CA. The SlPP2C1 gene was expressed in all tomato tissues throughout development, particularly in flowers and fruits, and it was up-regulated by dehydration and ABA treatment. SlPP2C1 expression in fruits was increased at 30 d after full bloom and peaked at the B + 1 stage. Suppression of SlPP2C1 expression significantly accelerated fruit ripening which was associated with higher levels of ABA signaling genes that are reported to alter the expression of fruit ripening genes involved in ethylene release and cell wall catabolism. SlPP2C1-RNAi (RNA interference) led to increased endogenous ABA accumulation and advanced release of ethylene in transgenic fruits compared with wild-type (WT) fruits. SlPP2C1-RNAi also resulted in abnormal flowers and obstructed the normal abscission of pedicels. SlPP2C1 RNAi plants were hypersensitized to ABA, and displayed delayed seed germination and primary root growth, and increased resistance to drought stress compared with WT plants. These results demonstrated that SlPP2C1 is a functional component in the ABA signaling pathway which participates in fruit ripening, ABA responses and drought tolerance. PMID- 29121242 TI - A sinusoidal function and the Nelder-Mead simplex algorithm applied to growth data from broiler chickens. AB - There has been much recent interest in mathematical developments for the analysis of growth in poultry. In this paper, we present a sinusoidal function to describe the evolution of growth as a function of time based on real life experiments. The function was evaluated with regard to its ability to describe the relationship between body weight and age in broilers and was compared to 4 standard growth functions: Gompertz, logistic, Lopez, and Richards. In order to estimate the model parameters, we adopted a global optimization method based on a direct search method instead of using gradient-based techniques. The results of this study show that both the sinusoidal function and the direct search method precisely describe the growth dynamics of broiler chickens. Fitting the growth functions to different data profiles nearly always led to the same or less maximized log-likelihood values for the sinusoidal equation, which is an indication of its superiority in describing growth data from broiler chickens. PMID- 29121243 TI - A structured training program for minimally invasive esophagectomy for esophageal cancer- a Delphi consensus study in Europe. AB - Evidence suggests that structured training programs for laparoscopic procedures can ensure a safe standard of skill acquisition prior to independent practice. Although minimally invasive esophagectomy (MIO) is technically demanding, no consensus on requirements for training for the MIO procedure exists. The aim of this study is to determine essential steps required for a structured training program in MIO using the Delphi consensus methodology. Eighteen MIO experts from 13 European hospitals were asked to participate in this study. The consensus process consisted of two structured meetings with the expert panel, and two Delphi questionnaire rounds. A list of items required for training MIO were constructed for three key domains of MIO, including (1) requisite criteria for units wishing to be trained and (2) to proctor MIO, and (3) a framework of a MIO training program. Items were rated by the experts on a scale 1-5, where 1 signified 'not important' and 5 represented 'very important.' Consensus for each domain was defined as achieving Cronbach alpha >=0.70. Items were considered as fundamental when >=75% of experts rated it important (4) or very important (5). Both Delphi rounds were completed by 16 (89%) of the 18 invited experts, with a median experience of 18 years with minimally invasive surgery. Consensus was achieved for all three key domains. Following two rounds of a 107-item questionnaire, 50 items were rated as essential for training MIO. A consensus among European MIO experts on essential items required for training MIO is presented. The identified items can serve as directive principles and core standards for creating a comprehensive training program for MIO. PMID- 29121244 TI - Host Plant-Herbivore-Predator Interactions in Chrysoperla carnea (Neuroptera: Chrysopidae) and Myzus persicae (Homoptera: Aphididae) on Four Plant Species Under Laboratory Conditions. AB - The common green lacewing, Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae), is a well-known biocontrol agent. The current study examined host plant-herbivore-predator interactions with C. carnea and Myzus persicae on four host plants (peach, almond, pepper, and potato). The experiments were carried out at 25 +/- 1 degrees C and 65 +/- 5% RH at a photoperiod of 16:8 (L:D) h). Duration of the preadult growth period, adult longevity, fecundity, and population growth parameters were analyzed based on the age-stage, two-sex life table theory. The shortest and longest preadult developmental times of the predator were observed on the peach and potato, respectively. The highest and lowest predation rate, oviposition period, and male and female longevity of predator were also observed on the peach and potato, respectively. The lowest intrinsic rate of increase (r) and finite rate of increase (lambda) were observed on the potato (0.1087 and 1.11 d-1, respectively) and the highest on the peach (0.1460 and 1.15 d-1, respectively). The maximum and minimum mean generation times (T) were 41.84 and 35.59 d in the potato and peach, respectively. Overall, peach was found to be a more appropriate host than the other host plants for development and predation fitness of C. carnea. These findings reveal that information on tritrophic interactions and subsequent life table evaluation of natural enemies improves integrated pest management programs. PMID- 29121245 TI - Education setting-based health promotion in New Zealand: evaluating the wellbeing and vitality in education (WAVE) programme. AB - Wellbeing and vitality in education (WAVE) is an education setting based health promotion initiative in South Canterbury, New Zealand. A mixed method approach was used for assessing change over time. Over ninety percent of education settings (94%) were participating in WAVE (n = 95). A total of 73 education settings completed the questionnaire at both baseline and follow-up. Evaluation of the WAVE programme shows that a robust partnership between health and education sectors can provide the basis for high levels of participation and significant changes in practice across all levels of education and a whole province. Evaluation results included that professional development for staff in some health related topics had improved. There was evidence of increasing partnerships between schools and community. Teachers had become role models for health messages and students had taken on leadership roles. Although the approach was based on health promoting schools literature, early engagement with education settings allowed the development of a local programme and branding. The overall outcome of WAVE has been a culture change in South Canterbury, where promoting the health of students, staff and families is becoming part of normal business for education settings. The results provide reason for optimism regarding the careful use of a health promoting schools framework, working in partnership with a range of stakeholders towards improving the health and subsequent life chances of young people. PMID- 29121246 TI - The Reference Intervals of Thyroid Hormones for Pregnant Women in Zhejiang Province. AB - Gestation-specific reference intervals for thyroid hormones are used to estimate thyroid function in pregnant women. This study was to establish the reference intervals for pregnant women in Zhejiang province, China. A total of 9038 cases were recruited. The values of thyroid-stimulating hormone (TSH), free thyroxine, free triiodothyronine, total thyroxine, and total triiodothyronine were determined by Beckman Coulter DxI-800 analyzers. Our results indicated that the level of TSH declined in the first trimester and then rose as pregnancy progressed. Conversely, the level of free triiodothyronine rose in the first trimester and then declined. The ranges of free thyroxine kept the decreasing trend crossing the gestation period. For total triiodothyronine, the ranges increased as pregnancy progressed and declined in the third trimester. The variation trends of total triiodothyronine and total thyroxine were similar. Our data confirmed the importance of the reference intervals of thyroid hormones for pregnant women. PMID- 29121247 TI - Prediction of individual outcomes for asthma sufferers. AB - We consider the problem of individual-specific medication level recommendation (initiation, removal, increase, or decrease) for asthma sufferers. Asthma is one of the most common chronic diseases in both adults and children, affecting 8% of the US population and costing $37-63 billion/year in the United States of America. Asthma is a complex disease, whose symptoms may wax and wane, making it difficult for clinicians to predict outcomes and prognosis. Improved ability to predict prognosis can inform decision making and may promote conversations between clinician and provider around optimizing medication therapy. Data from the US Medical Expenditure Panel Survey (MEPS) years 2000-2010 were used to fit a longitudinal model for a multivariate response of adverse events (Emergency Department or in-patient visits, excessive rescue inhaler use, and oral steroid use). To reduce bias in the estimation of medication effects, medication level was treated as a latent process which was restricted to be consistent with prescription refill data. This approach is demonstrated to be effective in the MEPS cohort via predictions on a validation hold out set and a synthetic data simulation study. This framework can be easily generalized to medication decisions for other conditions as well. PMID- 29121248 TI - Fusion of positron emission tomography/computed tomography with magnetic resonance imaging reveals hamstring peritendonitis in polymyalgia rheumatica. AB - Objectives: To characterize 18F-fluorodeoxyglucose (18F-FDG) uptake on whole-body PET/CT in PMR, and identify its precise anatomic correlate using MRI. Methods: Patients with newly diagnosed PMR according to the 2012 EULAR/ACR classification criteria were prospectively recruited. Participants with GCA were excluded. A whole-body 18F-FDG PET/CT scan was performed in all untreated patients. Qualitative and semiquantitative [standardized uptake value maximum (SUVmax)] scoring of abnormal 18F-FDG uptake was undertaken. MRI of the pelvis, knee and wrist and hand was performed in three representative patients with anatomical correlation of FDG-avid sites carried out using Medview fusion software. Results: Twenty-two patients with PMR were recruited. Their mean age was 68.3 years (s.d. 6.3) and 13/22 were male. On whole-body PET/CT, 18F-FDG uptake adjacent to the ischial tuberosities was observed in 21 participants (95.4%) and recorded the highest mean SUVmax value [3.6 (s.d. 1.7)]. A high frequency of posteromedial knee (61.9%) and wrist and/or hand involvement (66.7%) was also appreciated. MRI of the pelvis revealed high T2 signal surrounding the proximal hamstring tendon origins of both semimembranosus and the conjoint tendon of the semitendinosus and biceps femoris. At the knee, peritendonitis at the distal insertion of the semimembranosus was observed. PET/MRI fusion at the pelvis and knee confirmed semimembranosus peritendonitis as the anatomical correlate of 18F-FDG uptake adjacent to the ischial tuberosities and of posteromedial knee structures. Conclusion: Hamstring peritendonitis is a common and distinctive manifestation of PMR on whole-body PET/CT. Trial registration: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, ACTRN1261400696695. PMID- 29121249 TI - Surgical Management of Anterolateral and Posteromedial Incisural Tentorial Meningioma. AB - BACKGROUND: Tentorial meningiomas are a broad and consistent category of tumors but their definition is still unclear and their classification uncertain. OBJECTIVE: To report the clinical and surgical characteristics of tentorial hiatus meningiomas based on a revised classification of tentorial meningiomas. METHODS: We reviewed the records of 14 patients who had undergone microsurgical removal of incisural tentorial meningioma. Two tumor subgroups, anterolateral (AL) and posteromedial (PM), were distinguished according to their site of attachment: the middle third and the posterior third of the tentorial free margin, respectively. Clinical presentation, radiological findings, surgical approaches, extent of resection, and outcome were compared. RESULTS: The 2 subgroups differed by tumor size (larger in PM), incidence of the direction of growth (infratentorial in PM), and hydrocephalus (only in PM), as well as by some clinical aspects. Surgical approach depended on tumor location: lateral (pterional, subtemporal, and retromastoid) for AL lesions; medial (occipital or supracerebellar infratentorial) for PM lesions. Total removal (Simpson grade I II) was performed in 64% of cases and complications occurred in 14%. Stereotactic radiosurgery was performed in cases of incomplete resection. At a mean follow-up of 104.5 mo, clinical improvement with low recurrence (9%) was achieved. CONCLUSION: Reallocation of tentorial edge meningiomas is the premise to compare treatment and further improve the approach case-by-case. In spite of their deep site, good outcomes can be achieved in both AL and PM tentorial meningiomas. Also of note is the indolent behavior of residual tumor. PMID- 29121250 TI - Mosquitoes (Diptera: Culicidae) Collected From Residential Yards and Dog Kennels in Florida Using Two Aspirators, a Sweep Net, or a CDC Trap. AB - Mosquito surveillance typically uses Centers for Disease Control and Prevention (CDC) mosquito light traps baited with CO2. From January 2013 to March 2015, we sampled seven field sites using three active mosquito-trapping techniques (two different aspirators and a sweep net) and the stationary CO2-baited CDC mosquito light trap to determine mosquito capture efficacy for each technique. Sampling occurred in four suburban backyards and three dog kennel facilities near Gainesville, FL, USA; species collection and relative abundance were measured. A total of 32 species and 70,090 individual mosquitoes were collected, including a new record for Alachua County, Florida, Aedes hendersoni (Cockerell). The dominant (>5% of total capture) mosquito species collected during the study included Aedes atlanticus (Dyar and Knab), Aedes infirmatus (Dyar and Knab), Anopheles crucians Wiedemann, Culiseta melanura (Coquillett), Culex erraticus (Dyar and Knab), Culex nigripalpus Theobald, and Uranotaenia sapphirina (Osten Sacken). The CDC trap captured the most species (29), followed by large aspirator (28), small aspirator (26), and the sweep net (23). All dominant species were captured with each sampling technique. Excluding Wyeomyia mitchellii (Theobald), all subdominant species (1-5% of total capture) were collected with each sampling technique. Future sampling should consider the utility (e.g., large numbers are readily collected) and limitations (e.g., personnel requirements) of aspirator collections when designing field-based mosquito sampling projects, especially those in residential areas or those focused upon species captured. PMID- 29121252 TI - Tuberous sclerosis complex. PMID- 29121251 TI - Protective effect of FGF-2 and low-molecular-weight heparin/protamine nanoparticles on radiation-induced healing-impaired wound repair in rats. AB - We examined the effectiveness of localized administration of fibroblast growth factor-2 containing low-molecular-weight heparin/protamine nanoparticles (FGF 2&LMWH/P NPs) on apoptosis in vivo and on healing of radiation-induced skin injury in a rat model. FGF-2 binds onto LMWH/P NPs, which can significantly enhance and stabilize FGF-2 as a local carrier. X-irradiation at a dose of 25 Gy was administered to the lower part of the back (using a lead sheet with two holes) 1 h before the administration of FGF-2&LMWH/P NPs. Cutaneous full thickness defect wounds were then formed in X-irradiated areas to examine the time-course of wound healing, and the wound tissues were microscopically and histologically compared and examined. Wound healing was significantly delayed by X-irradiation, but FGF-2&LMWH/P NPs administration prior to irradiation led to a significantly shorter delay compared with FGF-2 alone, LMWH/P NPs alone, and controls. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining showed that the proportions of apoptotic dermal fibroblasts in X-irradiated skin were significantly lower in rats administered FGF-2&LMWH/P NPs than in controls. However, 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining showed no differences. Thus, localized administration of FGF-2&LMWH/P NPs prior to irradiation may alleviate X-irradiation-induced healing-impaired wound repair in normal tissue. PMID- 29121254 TI - Impact of donor and recipient human cytomegalovirus status on kidney transplantation. AB - Human cytomegalovirus (HCMV) is considered to be a major pathogen that affects the outcome of solid organ transplantation (TX). Both recipient and donor may be HCMV positive, therefore HCMV re-infection is possible after TX. However, little is known how cytomegalovirus (CMV) transmitted from an infected donor to an infected recipient modulates the recipient's already suppressed immunity, and what the clinical consequences are. To investigate these issues, 52 kidney recipients were followed up for 2 years after TX. T, B and natural killer (NK) lymphocytes, naive and memory T subsets, CD28 expression, relative telomere length, CMV-specific lymphocytes and serum cytokines were measured several times post-TX. Patients were monitored for signs of CMV viremia and other infections. The most important observation was that CMV-specific lymphocytes expand vastly in HCMV-infected recipients who received kidneys from infected donors, in comparison with uninfected donors. Despite this, a higher rate of HCMV viremia was found. Immune deterioration was confirmed by an increased number of CD28-negative T lymphocytes, inverted CD4/CD8 index and shortened telomeres. This was superior in HCMV-infected recipients transplanted from infected donors, when compared with uninfected. In conclusion, CMV alters the immune system in kidney transplant recipients and promotes immune exhaustion. PMID- 29121255 TI - Adipocyte Expression of SLC19A1 Links DNA Hypermethylation to Adipose Tissue Inflammation and Insulin Resistance. AB - Context: Insulin resistance (IR) is promoted by a chronic low-grade inflammation in white adipose tissue (WAT). The latter might be regulated through epigenetic mechanisms such as DNA methylation. The one carbon cycle (1CC) is a central metabolic process governing DNA methylation. Objective: To identify adipocyte expressed 1CC genes linked to WAT inflammation, IR, and their causal role. Design: Cohort study. Setting: Outpatient academic clinic. Participants: Obese and nonobese subjects. Methods: Gene expression and DNA methylation arrays were performed in subcutaneous WAT and isolated adipocytes. In in vitro differentiated human adipocytes, gene knockdown was achieved by small interfering RNA, and analyses included microarray, quantitative polymerase chain reaction, DNA methylation by enzyme-linked immunosorbent assay and pyrosequencing, protein secretion by enzyme-linked immunosorbent assay, targeted metabolomics, and luciferase reporter and thermal shift assays. Main Outcome Measures: Effects on adipocyte inflammation. Results: In adipocytes from obese individuals, global DNA hypermethylation was associated positively with gene expression of proinflammatory pathways. Among the 1CC genes, IR in vivo and proinflammatory gene expression in WAT were most strongly and inversely associated with SLC19A1, a gene encoding a membrane folate carrier. SLC19A1 knockdown in human adipocytes perturbed intracellular 1CC metabolism, induced global DNA hypermethylation, and increased expression of proinflammatory genes. Several CpG loci linked SLC19A1 to inflammation; validation studies were focused on the chemokine C-C motif chemokine ligand 2 (CCL2) in which methylation in the promoter (cg12698626) regulated CCL2 expression and CCL2 secretion through altered transcriptional activity. Conclusions: Reduced SLC19A1 expression in human adipocytes induces DNA hypermethylation, resulting in increased expression of specific proinflammatory genes, including CCL2. This constitutes an epigenetic mechanism that might link dysfunctional adipocytes to WAT inflammation and IR. PMID- 29121253 TI - The Role of NRG1 in the Predisposition to Papillary Thyroid Carcinoma. AB - Context: Previous genome-wide association studies have shown that single nucleotide polymorphism (SNP) rs2439302 in chromosome 8p12 is significantly associated with papillary thyroid carcinoma (PTC) risk and dysregulated NRG1 expression. The underlying mechanisms remain to be discovered. Objective: To evaluate the expression of NRG1 isoforms, candidate functional variants, and potential genes downstream of NRG1 in thyroid tissue. Methods: Quantitative reverse transcription polymerase chain reaction was applied for gene expression analysis. SNaPshot assay, haplotype, and computer analyses were performed to evaluate candidate functional variants. Other functional assays [chromatin immunoprecipitation (ChIP) assay, luciferase assay, small interfering RNA knockdown, and RNA sequencing] were performed. Results: Three NRG1 isoforms (NM_004495, NM_013958, and NM_001160008) tested were highly expressed in thyroid tissue. The expression levels of the three isoforms were significantly correlated with the genotypes of rs2439302. A DNA block of ~32 kb containing the risk G allele of rs2439302 was revealed, harboring multiple candidate functional variants. ChIP assay for active chromatin markers indicated at least nine regions in the DNA block showing strong H3Kme1 and H3K27Ac signals in thyroid tissue. Luciferase reporter assays revealed differential allelic activities associated with seven SNPs. Knocking down NRG1 in primary thyroid cells revealed downstream or interacting genes related to NRG1. Conclusions: Our data suggest a role for transcriptional regulation of NRG1 in the predisposition to PTC. PMID- 29121257 TI - Next generation heart valve substitutes. PMID- 29121258 TI - Challenges in translating tissue engineered heart valves into clinical practice. PMID- 29121256 TI - Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling. AB - STUDY QUESTION: What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? SUMMARY ANSWER: No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). WHAT IS KNOWN ALREADY: Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. STUDY DESIGN, SIZE, DURATION: This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. PARTICIPANTS/MATERIALS, SETTING, METHODS: Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. MAIN RESULTS AND ROLE OF CHANCE: The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT associated SNPs. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A limited number of cases were included. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests. PMID- 29121259 TI - Exercise ameliorates neurocognitive impairments in a translational model of pediatric radiotherapy. AB - Background: While cranial radiation therapy (CRT) is an effective treatment, healthy areas surrounding irradiation sites are negatively affected. Frontal lobe functions involving attention, processing speed, and inhibition control are impaired. These deficits appear months to years after CRT and impair quality of life. Exercise has been shown to rejuvenate the brain and aid in recovery post injury through its effects on neurogenesis and cognition. Methods: We developed a juvenile rodent CRT model that reproduces neurocognitive deficits. Next, we utilized the model to test whether exercise ameliorates these deficits. Fischer rats (31 days old) were irradiated with a fractionated dose of 4 Gy * 5 days, trained and tested at 6, 9, and 12 months post-CRT using 5-choice serial reaction time task. After testing, fixed rat brains were imaged using diffusion tensor imaging and immunohistochemistry. Results: CRT caused early and lasting impairments in task acquisition, accuracy, and latency to correct response, as well as causing stunting of growth and changes in brain volume and diffusion. Exercising after irradiation improved acquisition, behavioral control, and processing speed, mitigated the stunting of brain size, and increased brain fiber numbers compared with sedentary CRT values. Further, exercise partially restored global connectome organization, including assortativity and characteristic path length, and while it did not improve the specific regional connections that were lowered by CRT, it appeared to remodel these connections by increasing connectivity between alternate regional pairs. Conclusions: Our data strongly suggest that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT. PMID- 29121261 TI - RE: Hypofractionated Radiotherapy for Patients with Early-Stage Glottic Cancer: Patterns of Care and Survival. PMID- 29121260 TI - An Arf-GAP promotes endocytosis and hyphal growth of Ashbya gossypii. AB - The ADP-ribosylation factor (ARF) family of GTPases are highly conserved from yeast to human and regulate vesicle budding. Sec7 domain containing proteins stimulate the guanine nucleotide exchange on Arf proteins, while ARF-GTPase activating proteins stimulate the hydrolysis of GTP. Since vesicle trafficking is important for hyphal growth, we studied the Ashbya gossypii homolog of Saccharomyces cerevisiae ARF3 along with its putative GEF and GTPase-activating protein (GAP) encoded by YEL1 and GTS1, respectively. Deletion of YEL1 had no discernible phenotype and deletion of ARF3 had only a minor defect in vacuolar fusion. In contrast, deletion of GTS1 severely impaired hyphal growth, and mutants showed defects in the maintenance of polarity and the localization of cortical actin patches. The uptake of the lipophilic dye FM4-64 was delayed in gts1 hyphae, indicating a defect in endocytosis. Gts1 has several protein domains, of which the Arf-GAP domain is required for complementation of the gts1 mutant phenotype. GFP-tagged GTS1 under control of its endogenous promoter localized to the plasma membrane but was enriched at hyphal tips and septal sites corresponding to a role in polarized vesicle trafficking. Our results indicate that this ARF-GTPase module plays an important role for filamentous hyphal growth. PMID- 29121262 TI - Cambial injury in lodgepole pine (Pinus contorta): mountain pine beetle vs fire. AB - Both mountain pine beetle (MPB) Dendroctonus ponderosae Hopkins and fire leave scars with similar appearance on lodgepole pine Pinus contorta Dougl. ex Loud. var. latifolia Engelm. that have never been compared microscopically, despite the pressing need to determine the respective effects of MPB and fire injury on tree physiology. We analysed changes in wood formation in naturally caused scars on lodgepole pine, and tested the hypotheses that (i) MPB and fire injury elicit distinct anomalies in lodgepole pine wood and (ii) anomalies differ in magnitude and/or duration between MPB and fire. Mountain pine beetle and fire injury reduced radial growth in the first year post-injury. Otherwise, radial growth and wood density increased over more than 10 years in both MPB and fire scars. We found that the general increase in radial growth was of greater magnitude (up to 27%) and of longer duration (up to 5 years) in fire scars compared with MPB scars, as shown in earlywood width. We also observed that the increase in latewood density was of greater magnitude (by 12%) in MPB scars, but of longer duration (by 4 years) in fire scars. Crystallinity decreased following MPB and fire injury, while microfibril angle increased. These changes in fibre traits were of longer duration (up to 4 years) in MPB scars compared with fire scars, as shown in microfibril angle. We found no significant changes in carbon and nitrogen concentrations. In conclusion, we stress that reduced competition and resistance to cavitation play an important role alongside cambial injury in influencing the type and severity of changes. In addition, more research is needed to validate the thresholds introduced in this study. Our findings serve as a foundation for new protocols to distinguish between bark beetle and fire disturbance, which is essential for improving our knowledge of historical bark beetle and fire regimes, and their interactions. PMID- 29121263 TI - High prevalence of diabetes in patients with rheumatoid arthritis: results from a questionnaire survey linked to claims data. AB - Objectives: To investigate the prevalence of diabetes in patients with RA and the impact of diabetes on self-reported outcomes and health care. Methods: RA patients between the ages of 18 and 79 years were randomly selected from a nationwide statutory health insurance fund and were surveyed about rheumatological care and disease burden. Comorbid diabetes (E10-14) was analysed regarding age, sex, BMI and socioeconomic status. Disease burden, comorbidity and prescriptions were compared in RA patients with and without diabetes. Predictors of rheumatological care were identified by multivariate regression. Results: Of the 2535 RA patients, 498 (20%) had diabetes. Diabetes was more frequent in males, in older patients, in patients with a higher BMI and in those with a lower socioeconomic status. All disease outcomes were poorer in RA-diabetes patients and were mainly attributable to a higher BMI. RA-diabetes patients received less DMARDs (40% vs 48%) and had more hospital stays (41% vs 30%) than patients without diabetes (all P < 0.05). Rates of cardiovascular disease (35% vs 15%), depression (39% vs 26%) and renal failure (23% vs 8%) were higher in RA-diabetes patients (all P < 0.0001). They were less frequently treated by rheumatology specialists: 57% vs 67%; odds ratio = 0.64 (95% CI: 0.45, 0.92), after controlling for confounders. Conclusion: The prevalence of diabetes in patients with RA is high and is associated with known sociodemographic factors. More than 40% of patients with RA and diabetes were not under rheumatological care even though they reported a high disease burden, were frequently hospitalized and often presented with further comorbidities. PMID- 29121264 TI - Persistent CNS toxicity in a patient receiving posaconazole tablets after discontinuation of voriconazole due to supratherapeutic serum levels. PMID- 29121265 TI - Decisions at The end of Life: 'The Inimitable Hallmark of the Lawyer'? AB - THIS case commentary analyses the application of the best interests standard in section 4 of the Mental Capacity Act 2005 by the Court in the decision in Abertawe Bro Morgannwg University Local Health Board v RY (by his litigation friend the official solicitor) and CP [2017] EWCOP 2. It evaluates the way in which the law impacted on how clinical decisions in respect of RY were made and identifies systemic concerns arising from the case. PMID- 29121266 TI - Stress-Inducible Galactinol Synthase of Chickpea (CaGolS) is Implicated in Heat and Oxidative Stress Tolerance Through Reducing Stress-Induced Excessive Reactive Oxygen Species Accumulation. AB - Raffinose family oligosaccharides (RFOs) participate in various aspects of plant physiology, and galactinol synthase (GolS; EC 2.4.1.123) catalyzes the key step of RFO biosynthesis. Stress-induced accumulation of RFOs, in particular galactinol and raffinose, has been reported in a few plants; however, their precise role and mechanistic insight in stress adaptation remain elusive. In the present study, we have shown that the GolS activity as well as galactinol and raffinose content are significantly increased in response to various abiotic stresses in chickpea. Transcriptional analysis indicated that the CaGolS1 and CaGolS2 genes are induced in response to different abiotic stresses. Interestingly, heat and oxidative stress preferentially induce CaGolS1 over CaGolS2. In silco analysis revealed several common yet distinct cis-acting regulatory elements in their 5'-upstream regulatory sequences. Further, in vitro biochemical analysis revealed that the CaGolS1 enzyme functions better in stressful conditions than the CaGolS2 enzyme. Finally, Arabidopsis transgenic plants constitutively overexpressing CaGolS1 or CaGolS2 exhibit not only significantly increased galactinol but also raffinose content, and display better growth responses than wild-type or vector control plants when exposed to heat and oxidative stress. Further, improved tolerance of transgenic lines is associated with reduced accumulation of reactive oxygen species (ROS) and consequent lipid peroxidation as compared with control plants. Collectively, our data imply that GolS enzyme activity and consequent galactinol and raffinose content are significantly increased in response to stresses to mitigate stress-induced growth inhibition by restricting excessive ROS accumulation and consequent lipid peroxidation in plants. PMID- 29121267 TI - Loss of CHCHD10-CHCHD2 complexes required for respiration underlies the pathogenicity of a CHCHD10 mutation in ALS. AB - Coiled-helix coiled-helix domain containing protein 10 (CHCHD10) and its paralogue CHCHD2 belong to a family of twin CX9C motif proteins, most of which localize to the intermembrane space of mitochondria. Dominant mutations in CHCHD10 cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia, and mutations in CHCHD2 have been associated with Parkinson's disease, but the function of these proteins remains unknown. Here we show that the p.R15L CHCHD10 variant in ALS patient fibroblasts destabilizes the protein, leading to a defect in the assembly of Complex I, impaired cellular respiration, mitochondrial hyperfusion, an increase in the steady-state level of CHCHD2, and a severe proliferation defect on galactose, a substrate that forces cells to synthesize virtually all of their ATP aerobically. CHCHD10 and CHCHD2 appeared together in distinct foci by immunofluorescence analysis and could be quantitatively immunoprecipitated with antibodies against either protein. Blue native polyacrylamide gel electrophoresis analyses showed that both proteins migrated in a high molecular weight complex (220 kDa) in control cells, which was, however, absent in patient cells. CHCHD10 and CHCHD2 levels increased markedly in control cells in galactose medium, a response that was dampened in patient cells, and a new complex (40 kDa) appeared in both control and patient cells cultured in galactose. Re-entry of patient cells into the cell cycle, which occurred after prolonged culture in galactose, was associated with a marked increase in Complex I, and restoration of the oxygen consumption defect. Our results indicate that CHCHD10-CHCHD2 complexes are necessary for efficient mitochondrial respiration, and support a role for mitochondrial dysfunction in some patients with ALS. PMID- 29121269 TI - Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder. AB - STUDY QUESTION: Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety? SUMMARY ANSWER: Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed. WHAT IS KNOWN ALREADY: Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response. STUDY DESIGN SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost effectiveness were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28 0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (?4.622 versus ?4.714, delta costs/woman ?92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings. WIDER IMPLICATIONS OF THE FINDINGS: In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657. TRIAL REGISTRATION DATE: 20 December 2010. DATE OF FIRST PATIENT'S ENROLMENT: 12 May 2011. PMID- 29121270 TI - The effect of ATP marination on the depolymerization of actin filament in goose muscles during postmortem conditioning. AB - In order to study the tenderization mechanism of ATP treatments by depolymerizing actin filaments, breast muscles of Eastern Zhejiang White Geese were randomly divided into 3 groups: control, 10 and 20 mM groups. Shear force (SF), sarcomere length (SL) and myofibrillar fraction index (MFI), the content of F-actin and G actin, the expression of actin associated proteins (cofilins and tropomodulins) were investigated during conditioning. In 20 mM group, cofilins content increased from 48 to 168 h, while tropomodulins decreased; the content of F-actin decreased from 24 to 168 h, while the increased G-actin was observed upto 48 h. In the control, the degraded tropomodulins were observed at 168 h, and the increased cofilins and G-actin were detected at the same time; the increase of MFI and decrease of F-actin content were shown at 96 and 168 h. Compared to control group, 20 mM group accelerated the transformation of F-actin into G-actin; it showed higher SL and MFI, and lower SF at 48, 96 and 168 h, respectively. We concluded that depolymerization of actin filaments, which was regulated by cofilins and tropomodulins, contributed to myofibrillar fraction and low SF during conditioning. PMID- 29121271 TI - Genome-Wide Identification of Arabidopsis LBD29 Target Genes Reveals the Molecular Events behind Auxin-Induced Cell Reprogramming during Callus Formation. AB - Auxin-induced callus formation represents an important cell reprogramming process during in vitro regeneration of plants, in which the pericycle or pericycle-like cells within plant organs are reprogrammed into the pluripotent cell mass termed callus that is generally required for subsequent regeneration of root or shoot. However, the molecular events behind cell reprogramming during auxin-induced callus formation are largely elusive. We previously identified that auxin-induced LATERAL ORGAN BOUNDARIES DOMAIN (LBD) transcription factors act as the master regulators to trigger auxin-induced callus formation. Here, by ChIP-seq (chromatin immunoprecipitation-based sequencing) and RNA sequencing approaches, we identified the potential LBD29 target genes at the genome-wide level and outlined the molecular events of LBD-triggered cell reprogramming during callus formation. We showed that LBD29 preferentially bound to the G-box (CACGTG) and TGGGC[C/T] motifs and potentially targeted >350 genes, among which the genes related to methylation, reactive oxygen species (ROS) metabolism, cell wall hydrolysis and lipid metabolism were rapidly activated, while most of the light responsive genes were suppressed by LBD29. Further examination of a few representative genes validated that they were targeted by LBD29 and participated in the regulation of cell reprogramming during callus formation. Our data not only outline a framework of the early molecular events behind auxin-induced cell reprogramming of callus formation, but also provide a valuable resource for identification of genes that regulate cell fate switch during in vitro regeneration of plants. PMID- 29121272 TI - Chronic Cigarette Smoking Associates Directly and Indirectly with Self-Reported Olfactory Alterations: Analysis of the 2011-2014 National Health and Nutrition Examination Survey (NHANES). AB - Introduction: Population-based studies show inconsistent effects of cigarette smoking on olfactory function. We aimed to identify direct and indirect associations between measures of smoking exposure/nicotine dependence and altered olfaction in a nationally-representative sample of adults. Methods: NHANES 2011 2014 (n=7,418) participants (mean age=57.8+/-12.2 years) self-reported olfaction and related health and demographic risks. Affirmative answers to three questions defined altered olfaction (olfactory problems in past year; worse ability since age 25; phantom smells). Smoking (never, former, current) was self-reported by chronicity (pack years, PY) and dependency (time to first cigarette upon waking), and verified by serum cotinine. Associations were tested with logistic regression, reporting odds ratios (OR) and 95% confidence intervals (CI), and mediation models. Results: Estimated prevalence of altered olfaction was 22.3%, with age-related increases. Nearly half of the sample were former/current smokers (47.4%). Controlling for olfactory-related risks, >=10 PY smokers had significantly greater odds of altered olfaction versus never smokers [OR 1.36, CI: 1.06-1.74]. The odds of altered olfaction were heightened among current smokers (>=10 PY) who also had high nicotine dependence (smoked <=30 minutes of waking) [OR 1.41, CI: 1.01-1.99]. Light smokers (<=10 PY smokers) did not show increased odds versus never smokers. Current smokers who also were heavy drinkers (>=4 drinks/day) had the highest odds for altered olfaction (OR 1.96, CI: 1.20 3.19). Olfactory-related pathologies (sinonasal problems, serious head injury, tonsillectomy, xerostomia) partially-mediated the association between smoking and altered olfaction. Conclusions: Chronic cigarette smoking was associated with increased odds of self-reported olfactory alterations, directly and indirectly via olfactory-related pathologies. IMPLICATIONS: Analysis of U.S. nationally representative data revealed significant positive associations between chronic smoking and alterations in the sense of smell. Rates of smell alteration (self reported problems in the past year, losses with aging, phantom smells) increased from 23% among adults to 33% for chronic smokers and 38% for chronic smokers who also reported heavy drinking. Chronic smoking showed associations with smell alteration that were direct and indirect through exposure to olfactory-related pathologies (naso-sinus problems, dry mouth, head/facial injury). Smell alteration can impact smokers' quality of life by challenging the ability to sense warning odors, food flavor, and olfactory-stimulated emotions and memories. PMID- 29121268 TI - Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study. AB - Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. Design, Setting, and Participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. Main Outcomes and Measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 * 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. Conclusions and Relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium. PMID- 29121273 TI - Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999-2014). AB - Objective: Patients with SLE have increased morbidity and premature mortality. Whether this mortality gap has improved in recent years, as in RA, is unknown. Methods: We conducted a population-based cohort study using a medical records database representative of the general population of the UK. We identified incident SLE cases and matched non-SLE controls between 1999 and 2014, divided into two subgroups based on year of SLE diagnosis, forming the early cohort (1999 2006) and late cohort (2007-14). We compared the mortality rates and hazard ratios, adjusting for potential confounders. Results: We identified 1470 and 1666 incident SLE cases in the early and late cohorts, respectively. In both cohorts, SLE patients had similar levels of excess mortality compared with their matched comparators [15.9 vs 7.9 deaths/1000 person-years (PY) in the early cohort and 13.8 vs 7.0 deaths/1000 PY in the late cohort]. The corresponding mortality hazard ratios were 2.15 (95% CI 1.63, 2.83) and 2.12 (95% CI 1.61, 2.80) in the early and late cohorts, respectively (P-value for interaction = 0.95). The absolute mortality differences were 8.0 (95% CI 4.3, 11.8) and 6.8 (95% CI 3.5, 10.0) deaths/1000 PY, respectively (P-value for interaction = 0.61). Conclusion: This general population-based cohort study suggests that excess mortality has not improved among SLE patients in recent years, remaining greater than double that of comparators, unlike RA during the same period. This highlights a critical unmet need for the development of new therapeutic agents and improved management strategies for SLE and its comorbidities. PMID- 29121275 TI - Black swans: challenging the relationship of anaesthetic-induced unconsciousness and electroencephalographic oscillations in the frontal cortex. PMID- 29121274 TI - Quality of life in the GLARIUS trial randomizing bevacizumab/irinotecan versus temozolomide in newly diagnosed, MGMT-nonmethylated glioblastoma. AB - Background: The GLARIUS trial, which investigated the efficacy of bevacizumab (BEV)/irinotecan (IRI) compared with standard temozolomide in the first-line therapy of O6-methylguanine-DNA methyltransferase (MGMT)-nonmethylated glioblastoma, showed that progression-free survival was significantly prolonged by BEV/IRI, while overall survival was similar in both arms. The present report focuses on quality of life (QoL) and Karnofsky performance score (KPS) during the whole course of the disease. Methods: Patients (n = 170) received standard radiotherapy and were randomized (2:1) for BEV/IRI or standard temozolomide. At least every 3 months KPS was determined and QoL was measured using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life and 20-item Brain Neoplasm questionnaires. A generalized estimating equation (GEE) model evaluated differences in the course of QoL and KPS over time. Also, the time to first deterioration and the time to postprogression deterioration were analyzed separately. Results: In all dimensions of QoL and KPS, GEE analyses and time to first deterioration analyses did not detect significant differences between the treatment arms. At progression, 82% of patients receiving second-line therapy in the standard arm received BEV second-line therapy. For the dimensions of motor dysfunction and headaches, time to postprogression deterioration was prolonged in the standard arm receiving crossover second-line BEV in the vast majority of patients at the time of evaluation. Conclusions: GLARIUS did not find indications for a BEV-induced detrimental effect on QoL in first-line therapy of MGMT-nonmethylated GBM patients. Moreover, GLARIUS provided some indirect corroborative data supporting the notion that BEV may have beneficial effects upon QoL in relapsed GBM. PMID- 29121276 TI - Fading whispers down the lane: signal propagation in anaesthetized cortical networks. PMID- 29121277 TI - Ultrasound-guided percutaneous cryoneurolysis for treatment of acute pain: could cryoanalgesia replace continuous peripheral nerve blocks? PMID- 29121278 TI - Frontal alpha-delta EEG does not preclude volitional response during anaesthesia: prospective cohort study of the isolated forearm technique. AB - Background: The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept. Methods: Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling. Results: Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power-frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders. Conclusions: Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia. Clinical trial registration: NCT02248623. PMID- 29121279 TI - Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review. AB - This review provides an update on the current clinical and preclinical understanding of chemotherapy induced peripheral neuropathy (CIPN). The overview of the clinical syndrome includes a review of its assessment, diagnosis and treatment. CIPN is caused by several widely-used chemotherapeutics including paclitaxel, oxaliplatin, bortezomib. Severe CIPN may require dose reduction, or cessation, of chemotherapy, impacting on patient survival. While CIPN often resolves after chemotherapy, around 30% of patients will have persistent problems, impacting on function and quality of life. Early assessment and diagnosis is important, and we discuss tools developed for this purpose. There are no effective strategies to prevent CIPN, with limited evidence of effective drugs for treating established CIPN. Duloxetine has moderate evidence, with extrapolation from other neuropathic pain states generally being used to direct treatment options for CIPN. The preclinical perspective includes a discussion on the development of clinically-relevant rodent models of CIPN and some of the potentially modifiable mechanisms that have been identified using these models. We focus on the role of mitochondrial dysfunction, oxidative stress, immune cells and changes in ion channels from summary of the latest literature in these areas. Many causal mechanisms of CIPN occur simultaneously and/or can reinforce each other. Thus, combination therapies may well be required for most effective management. More effective treatment of CIPN will require closer links between oncology and pain management clinical teams to ensure CIPN patients are effectively monitored. Furthermore, continued close collaboration between clinical and preclinical research will facilitate the development of novel treatments for CIPN. PMID- 29121280 TI - Continuing chronic beta-blockade in the acute phase of severe sepsis and septic shock is associated with decreased mortality rates up to 90 days. AB - Background: There is growing evidence that beta-blockade may reduce mortality in selected patients with sepsis. However, it is unclear if a pre-existing, chronic oral beta-blocker therapy should be continued or discontinued during the acute phase of severe sepsis and septic shock. Methods: The present secondary analysis of a prospective observational single centre trial compared patient and treatment characteristics, length of stay and mortality rates between adult patients with severe sepsis or septic shock, in whom chronic beta-blocker therapy was continued or discontinued, respectively. The acute phase was defined as the period ranging from two days before to three days after disease onset. Multivariable Cox regression analysis was performed to compare survival outcomes in patients with pre-existing chronic beta-blockade. Results: A total of 296 patients with severe sepsis or septic shock and pre-existing, chronic oral beta-blocker therapy were included. Chronic beta-blocker medication was discontinued during the acute phase of sepsis in 129 patients and continued in 167 patients. Continuation of beta blocker therapy was significantly associated with decreased hospital (P=0.03), 28 day (P=0.04) and 90-day mortality rates (40.7% vs 52.7%; P=0.046) in contrast to beta-blocker cessation. The differences in survival functions were validated by a Log-rank test (P=0.01). Multivariable analysis identified the continuation of chronic beta-blocker therapy as an independent predictor of improved survival rates (HR = 0.67, 95%-CI (0.48, 0.95), P=0.03). Conclusions: Continuing pre existing chronic beta-blockade might be associated with decreased mortality rates up to 90 days in septic patients. PMID- 29121281 TI - Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database. AB - Background: New sepsis and septic shock definitions could change the epidemiology of sepsis because of differences in criteria. We therefore compared the sepsis populations identified by the old and new definitions. Methods: We used a high quality, national, intensive care unit (ICU) database of 654 918 consecutive admissions to 189 adult ICUs in England, from January 2011 to December 2015. Primary outcome was acute hospital mortality. We compared old (Sepsis-2) and new (Sepsis-3) incidence, outcomes, trends in outcomes, and predictive validity of sepsis and septic shock populations. Results: From among 197 724 Sepsis-2 severe sepsis and 197 142 Sepsis-3 sepsis cases, we identified 153 257 Sepsis-2 septic shock and 39 262 Sepsis-3 septic shock cases. The extrapolated population incidence of Sepsis-3 sepsis and Sepsis-3 septic shock was 101.8 and 19.3 per 100 000 person-years, respectively, in 2015. Sepsis-2 severe sepsis and Sepsis-3 sepsis had similar incidence, similar mortality and showed significant risk adjusted improvements in mortality over time. Sepsis-3 septic shock had a much higher Acute Physiology And Chronic Health Evaluation II (APACHE II) score, greater mortality and no risk-adjusted trends in mortality improvement compared with Sepsis-2 septic shock. ICU admissions identified either as Sepsis-3 sepsis or septic shock and as Sepsis-2 severe sepsis or septic shock had significantly greater risk-adjusted odds of death compared with non-sepsis admissions (P<0.001). The predictive validity was greatest for Sepsis-3 septic shock. Conclusions: In an ICU database, compared with Sepsis-2, Sepsis-3 identifies a similar sepsis population with 92% overlap and much smaller septic shock population with improved predictive validity. PMID- 29121282 TI - Effects of intraoperative and early postoperative normal saline or Plasma-Lyte 148(r) on hyperkalaemia in deceased donor renal transplantation: a double-blind randomized trial. AB - Background: Administration of saline in renal transplantation is associated with hyperchloraemic metabolic acidosis, but the effect of normal saline (NS) on the risk of hyperkalaemia or postoperative graft function is uncertain. Methods: We compared NS with Plasma-Lyte 148(r) (PL) given during surgery and for 48 h after surgery in patients undergoing deceased donor renal transplantation. The primary outcome was hyperkalaemia within 48 h after surgery. Secondary outcomes were need for hyperkalaemia treatment, change in acid-base status, and graft function. Results: Twenty-five subjects were randomized to NS and 24 to PL. The incidence of hyperkalaemia in the first 48 h after surgery was higher in the NS group; 20 patients (80%) vs 12 patients (50%) in the PL group (risk difference: 0.3; 95% confidence interval: 0.05, 0.55; P=0.037). The mean (sd) peak serum potassium was NS 6.1 (0.8) compared with PL 5.4 (0.9) mmol litre-1 (P=0.009). Sixteen participants (64%) in the NS group required treatment for hyperkalaemia compared with five (21%) in the PL group (P=0.004). Participants receiving NS were more acidaemic [pH 7.32 (0.06) vs 7.39 (0.05), P=0.001] and had higher serum chloride concentrations (107 vs 101 mmol litre-1, P<0.001) at the end of surgery. No differences in the rate of delayed graft function were observed. Subjects receiving PL who did not require dialysis had a greater reduction in creatinine on day 2 (P=0.04). Conclusions: Compared with PL, participants receiving NS had a greater incidence of hyperkalaemia and hyperchloraemia and were more acidaemic. These biochemical differences were not associated with adverse clinical outcomes. Clinical trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12612000023853. PMID- 29121283 TI - Postoperative pulmonary complications, pulmonary and systemic inflammatory responses after lung resection surgery with prolonged one-lung ventilation. Randomized controlled trial comparing intravenous and inhalational anaesthesia. AB - Background: Recent studies report the immunomodulatory lung-protective role of halogenated anaesthetics during lung resection surgery (LRS) but have not investigated differences in clinical postoperative pulmonary complications (PPCs). The main goal of the present study was to compare the effect of sevoflurane and propofol on the incidence of PPCs in patients undergoing LRS. The second aim was to compare pulmonary and systemic inflammatory responses to LRS. Methods: Of 180 patients undergoing LRS recruited, data from 174 patients were analysed. Patients were randomized to two groups (propofol or sevoflurane) and were managed otherwise using the same anaesthetic protocol. Bronchoalveolar lavage (BAL) was performed in both lungs before and after one-lung ventilation for analysis of cytokines. Arterial blood was drawn for measurement of the cytokines analysed in the BAL fluid at five time points. Intraoperative haemodynamic and respiratory parameters, PPCs (defined following the ARISCAT study), and mortality during the first month and yr were recorded. Results: More PPCs were detected in the propofol group (28.4% vs 14%, OR 2.44 [95% CI, 1.14 5.26]). First-yr mortality was significantly higher in the propofol group (12.5% vs 2.3%, OR 5.37 [95% CI, 1.23-23.54]). Expression of lung and systemic pro inflammatory cytokines was greater in the propofol group than in the sevoflurane group. Pulmonary and systemic IL-10 release was less in the propofol group. Conclusions: Our results suggest that administration of sevoflurane during LRS reduces the frequency of the PPCs recorded in our study and attenuates the pulmonary and systemic inflammatory response. Clinical trial registration: NCT 02168751; EudraCT 2011-002294-29. PMID- 29121284 TI - Neuropathic pain in cancer: systematic review, performance of screening tools and analysis of symptom profiles. AB - Background: The objectives of this study were to evaluate the methodological quality of rigorous neuropathic pain assessment tools in applicable clinical studies, and determine the performance of screening tools for identifying neuropathic pain in patients with cancer. Methods: Systematic literature search identified studies reporting use of Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Douleur Neuropathique en 4 (DN4) or painDETECT (PDQ) in cancer patients with a clinical diagnosis of neuropathic or not neuropathic pain. Individual patient data were requested to examine descriptor item profiles. Results: Six studies recruited a total of 2301 cancer patients of which 1564 (68%) reported pain. Overall accuracy of screening tools ranged from 73 to 94%. There was variation in description and rigour of clinical assessment, particularly related to the rigour of clinical judgement of pain as the reference standard. Individual data from 1351 patients showed large variation in the selection of neuropathic pain descriptor items by cancer patients with neuropathic pain. LANSS and DN4 items characterized a significantly different neuropathic pain symptom profile from non-neuropathic pain in both tumour- and treatment-related cancer pain aetiologies. Conclusions: We identified concordance between the clinician diagnosis and screening tool outcomes for LANSS, DN4 and PDQ in patients with cancer pain. Shortcomings in relation to standardized clinician assessment are likely to account for variation in screening tool sensitivity, which should include the use of the neuropathic pain grading system. Further research is needed to standardize and improve clinical assessment in patients with cancer pain. Until the standardization of clinical diagnosis for neuropathic cancer pain has been validated, screening tools offer a practical approach to identify potential cases of neuropathic cancer pain. PMID- 29121285 TI - Non-steroidal anti-inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature. AB - Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesic drugs. Recent studies have indicated a potential beneficial effect on long-term survival outcomes after cancer surgery but a negative impact on anastomotic leaks. The objective of this study was to objectively assess the implications of the perioperative NSAIDs use on anastomotic leaks and cancer recurrence. Methods: We searched PubMed, MEDLINE, Embase and Cochrane Library for publications up to mid-January 2017. Randomized controlled trials (RCTs) and observational studies in adults undergoing cancer surgery were included for quality assessment. We excluded animal studies, in vitro experiments and case reports. The selected sudies were graded using the Jadad score or Newcastle Ottawa scale for RCTs and observational retrospective studies, respectively. Results: The systematic review identified 25 trials that explored the impact of NSAIDs on anastomotic leaks and 16 trials that assessed the association between perioperative NSAIDs and cancer recurrence. Meta-analyses were not performed because of high heterogeneity and low quality of the included studies. Conclusions: The literature is not conclusive on whether the use of NSAIDs is associated with anastomotic leaks after gastrointestinal cancer surgery. Also, the current evidence is equivocal regarding the effects of short-term NSAIDs on cancer recurrence after major cancer surgery. Three RCTs are being conducted to assess the impact of NSAIDs on cancer recurrence. There are no registered RCTs that are testing the hypothesis of whether the perioperative use of NSAIDs increases the rate of anastomotic leaks. PMID- 29121286 TI - Prediction of persistent post-surgery pain by preoperative cold pain sensitivity: biomarker development with machine-learning-derived analysis. AB - Background: To prevent persistent post-surgery pain, early identification of patients at high risk is a clinical need. Supervised machine-learning techniques were used to test how accurately the patients' performance in a preoperatively performed tonic cold pain test could predict persistent post-surgery pain. Methods: We analysed 763 patients from a cohort of 900 women who were treated for breast cancer, of whom 61 patients had developed signs of persistent pain during three yr of follow-up. Preoperatively, all patients underwent a cold pain test (immersion of the hand into a water bath at 2-4 degrees C). The patients rated the pain intensity using a numerical ratings scale (NRS) from 0 to 10. Supervised machine-learning techniques were used to construct a classifier that could predict patients at risk of persistent pain. Results: Whether or not a patient rated the pain intensity at NRS=10 within less than 45 s during the cold water immersion test provided a negative predictive value of 94.4% to assign a patient to the "persistent pain" group. If NRS=10 was never reached during the cold test, the predictive value for not developing persistent pain was almost 97%. However, a low negative predictive value of 10% implied a high false positive rate. Conclusions: Results provide a robust exclusion of persistent pain in women with an accuracy of 94.4%. Moreover, results provide further support for the hypothesis that the endogenous pain inhibitory system may play an important role in the process of pain becoming persistent. PMID- 29121287 TI - Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study. AB - Background: Behavioural pain tools are used in Intensive Care Unit (ICU) patients unable to self-report their pain-intensity but need sustained efforts to educate and train the ICU team because of the subjective nature of these clinical tools. This study measured the validity and performance of an electrophysiological monitoring tool based on the spectral analysis of heart rate variability, the Analgesia Nociception Index (ANI) which varies from 0 (minimal parasympathetic tone, maximal stress-response and pain) to 100 (maximal parasympathetic tone, minimal stress-response and pain). Methods: Mean-ANI (ANIm) and Instant-ANI (ANIi) were continuously recorded then compared with the Behavioral Pain Scale (BPS) before, during and after routine care procedures in critically-ill non comatose patients. Results: 969 assessments were performed in 110 patients. ANIi was the most discriminative pain tool. It was significantly correlated with BPS (r=-0.30; 95%CI -0.37 to -0.25; P<0.001). For an ANIi threshold of 42.5, the sensitivity, specificity, positive and negative predictive values were respectively 61.4%, 77.4%, 37.0%, and 90.4%. Compared with the BPS, ANIi had no significantly different ability to change during turning and tracheal-suctioning but changed significantly more during dressing change. ANIi increased independently with age, obesity and severity of illness, and controlled mechanical-ventilation, vasopressors use and analgesia. ANIi decreased independently when vigilance status and respiratory rate increased. ANIm demonstrated poor psychometric properties to detect pain. Conclusions: Despite low sensitivity/specificity, ANIi>=43 had a Negative-Predictive-Value of 90%. Hence ANIi may be of highest benefit for excluding significant pain. A randomized controlled trial should compare sedation-analgesia protocols based on ANIi to presently recommended behavioural-pain-tools. PMID- 29121288 TI - Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses. AB - Pregabalin has demonstrated anti-hyperalgesic properties and was introduced into acute pain treatment in 2001. Our aim was to evaluate the beneficial and harmful effects of pregabalin in postoperative pain management. We included randomized clinical trials investigating perioperative pregabalin treatment in adult surgical patients. The review followed Cochrane methodology, including Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and used trial sequential analyses (TSAs). The primary outcomes were 24 h morphine i.v. consumption and the incidence of serious adverse events (SAEs) defined by International Conference of Harmonisation Good Clinical Practice guidelines. Conclusions were based primarily on trials with low risk of bias. Ninety-seven randomized clinical trials with 7201 patients were included. The 24 h morphine i.v. consumption was reported in 11 trials with overall low risk of bias, finding a reduction of 5.8 mg (3.2, 8.5; TSA adjusted confidence interval: 3.2, 8.5). Incidence of SAEs was reported in 21 trials, with 55 SAEs reported in 12 of these trials, and 22 SAEs reported in 10 trials with overall low risk of bias. In trials with overall low risk of bias, Peto's odds ratio was 2.9 (1.2, 6.8; TSA adjusted confidence interval: 0.1, 97.1). Based on trials with low risk of bias, pregabalin may have a minimal opioid-sparing effect, but the risk of SAEs seems increased. However, the GRADE-rated evaluations showed only moderate to very low quality of evidence. Consequently, a routine use of pregabalin for postoperative pain treatment cannot be recommended. PMID- 29121289 TI - Association between intraoperative non-depolarising neuromuscular blocking agent dose and 30-day readmission after abdominal surgery. AB - Background: We hypothesised that intraoperative non-depolarising neuromuscular blocking agent (NMBA) dose is associated with 30-day hospital readmission. Methods: Data from 13,122 adult patients who underwent abdominal surgery under general anaesthesia at a tertiary care hospital were analysed by multivariable regression, to examine the effects of intraoperatively administered NMBA dose on 30-day readmission (primary endpoint), hospital length of stay, and hospital costs. Results: Clinicians used cisatracurium (mean dose [SD] 0.19 mg kg-1 [0.12]), rocuronium (0.83 mg kg-1 [0.53]) and vecuronium (0.14 mg kg-1 [0.07]). Intraoperative administration of NMBAs was dose-dependently associated with higher risk of 30-day hospital readmission (adjusted odds ratio 1.89 [95% Confidence Interval (CI) 1.26-2.84] for 5th quintile vs 1st quintile; P for trend: P<0.001), prolonged hospital length of stay (adjusted incidence rate ratio [aIRR] 1.20 [95% CI 1.11-1.29]; P for trend: P<0.001) and increased hospital costs (aIRR 1.18 [95% CI 1.13-1.24]; P for trend: P<0.001). Admission type (same day vs inpatient surgery) significantly modified the risk (interaction term: aOR 1.31 [95% CI 1.05-1.63], P=0.02), and the adjusted odds of readmission in patients undergoing ambulatory surgical procedures who received high-dose NMBAs vs low-dose NMBAs amounted to 2.61 [95% CI 1.11-6.17], P for trend: P<0.001. Total intraoperative neostigmine dose increased the risk of 30-day readmission (aOR 1.04 [1.0-1.08], P=0.048). Conclusions: In a retrospective analysis, high doses of NMBAs given during abdominal surgery was associated with an increased risk of 30-day readmission, particularly in patients undergoing ambulatory surgery. PMID- 29121290 TI - Pain in cancer survivors; filling in the gaps. AB - Cancer survivorship represents a growing clinical challenge for pain clinicians. The population of cancer survivors is rapidly expanding and many of these patients experience pain as a sequelae of their disease and its treatment. The features, pathophysiology and natural history of some painful conditions observed in cancer survivors, such as direct tumour effects, cancer induced bone pain (CIBP) or chronic post-surgical pain have received extensive exposure elsewhere in the literature. In this narrative review, we attempt to 'fill in the gaps' in the knowledge, by providing a succinct outline of a range of less well known pain states encountered in the cancer survivor population. These include neuropathies as a result of graft versus host disease (GVHD), novel chemotherapeutic agents and monoclonal antibodies (mAb), and radiation induced pain states. The increasing prevalence of visceral post-surgical pain and aromatase inhibitor induced arthralgia (AIA) is also detailed. Additionally an overview of suggested approaches to the assessment of pain in cancer survivors is provided and potential treatment strategies, with a focus on novel approaches are discussed. PMID- 29121291 TI - Pectoral nerve block1 versus modified pectoral nerve block2 for postoperative pain relief in patients undergoing modified radical mastectomy: a randomized clinical trial. AB - Background: Pectoral nerve block1 (PEC1) given between pectoralis major and minor, and modified pectoral nerve block2 (mPEC2) performed between pectoralis minor and serratus anterior, can provide continuous analgesia after modified radical mastectomy (MRM) when catheters are placed before skin closure. This study was designed to compare PEC1 and mPEC2 block for providing postoperative pain relief after MRM. Methods: Sixty-two physically fit patients undergoing MRM were assigned into two groups (Group PEC1, n=31 and Group mPEC2, n=31). Before wound closure, epidural catheter was placed in the group designated muscle plane and 30ml of 0.25% bupivacaine was injected through the catheter after wound closure. Bupivacaine 15ml of 0.25% top up was given on patient's demand or whenever visual analogue scale (VAS) score was>4. Time for first analgesia (TFA), number of top ups and VAS was recorded at 0.5, 6, 12, 18, 24 h after surgery. Sensory blockade was assessed 30 min after extubation. Results: Analgesia was significantly prolonged in group mPEC2 [mean(SD)] 313.45(43.05) vs 258.87(34.71) min in group PEC1, P<0.001. Total pain experienced over 24 h was significantly less in group mPEC2 [mean(SD)] 9.77(6.93) than in group PEC1 24.19(10.81), P<0.0001. Consequently, top up requirements were significantly reduced in group mPEC2 than in group PEC1 [median(range)] 3(2-4) vs 4(3-5) respectively, P<0.001. Lateral pectoral (77.42% and 35.48%) and thoracodorsal nerves (93.55% and 48.39%) had higher incidence of sensory block in group mPEC2 than group PEC1, P<0.001. Conclusions: mPEC2 provides better postoperative analgesia than PEC1 when catheters are placed under direct vision after MRM. Clinical trial registration: CTRI/2017/02/007811 (REF/2015/11/010185). PMID- 29121292 TI - Preadmission statin use improves the outcome of less severe sepsis patients - a population-based propensity score matched cohort study. AB - Background: Randomized controlled trials on the post-admission use of statins in sepsis patients have not shown a survival benefit. Whether preadmission use of statins would confer any beneficial effects in sepsis patients has not been well studied. Methods: We conducted a population-based cohort study on a national health insurance claims database between 1999 and 2011. Sepsis patients were identified by ICD-9 codes compatible with the third International consensus definitions for sepsis. Use of statin was defined as the cumulative use of any statin for more than 30 days before the indexed sepsis admission. We determined the association between statin use and sepsis outcome by multivariate-adjusted Cox proportional hazard models and propensity score matched analysis. To minimize baseline imbalance between statin users and non-statin users, we matched/adjusted for social economic status, comorbidities, proxies for healthy lifestyle, health care facility utilization, and use of medications. Results: We identified 52 737 sepsis patients, of which 3599 received statin treatment. Statins use was associated with a reduced 30-day mortality after multivariable adjustment (HR 0.86, 95% CI, 0.78-0.94) and propensity score matching (HR, 0.88; 95% CI, 0.78 0.99). On subgroup analysis, the beneficial effects of statins were not significant in patients receiving ventilator support or requiring ICU admission. Conclusions: In this national cohort study, preadmission statin therapy before sepsis development was associated with a 12% reduction in mortality when compared with patients who never received a statin. There were no consistent beneficial effects of statins in all patient subgroups. PMID- 29121293 TI - Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep. AB - Background: We used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep. Methods: Connectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets. Results: In all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol. Conclusions: Thalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation. Trial registry number: Committee number: 'Comite d'Ethique Hospitalo Facultaire Universitaire de Liege' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website. PMID- 29121294 TI - Low-dose buprenorphine infusion to prevent postoperative hyperalgesia in patients undergoing major lung surgery and remifentanil infusion: a double-blind, randomized, active-controlled trial. AB - Background: Postoperative secondary hyperalgesia arises from central sensitization due to pain pathways facilitation and/or acute opioid exposure. The latter is also known as opioid-induced hyperalgesia (OIH). Remifentanil, a potent MU-opioid agonist, reportedly induces postoperative hyperalgesia and increases postoperative pain scores and opioid consumption. The pathophysiology underlying secondary hyperalgesia involves N-methyl-D-aspartate (NMDA)-mediated pain pathways. In this study, we investigated whether perioperatively infusing low dose buprenorphine, an opioid with anti-NMDA activity, in patients receiving remifentanil infusion prevents postoperative secondary hyperalgesia. Methods: Sixty-four patients, undergoing remifentanil infusion during general anaesthesia and major lung surgery, were randomly assigned to receive either buprenorphine i.v. infusion (25 MUg h-1 for 24 h) or morphine (equianalgesic dose) perioperatively. The presence and extent of punctuate hyperalgesia were assessed one day postoperatively. Secondary outcome variables included postoperative pain scores, opioid consumption and postoperative neuropathic pain assessed one and three months postoperatively. Results: A distinct area of hyperalgesia or allodynia around the surgical incision was found in more patients in the control group than in the treated group. Mean time from extubation to first morphine rescue dose was twice as long in the buprenorphine-treated group than in the morphine-treated group: 18 vs 9 min (P=0.002). At 30 min postoperatively, patients receiving morphine had a higher hazard ratio for the first analgesic rescue dose than those treated with buprenorphine (P=0.009). At three months, no differences between groups were noted. Conclusions: Low-dose buprenorphine infusion prevents the development of secondary hyperalgesia around the surgical incision but shows no long-term efficacy at three months follow-up. PMID- 29121296 TI - Are perioperative therapeutic doses of statins associated with postoperative pain and opioid consumption after hip surgery under spinal anaesthesia? AB - Background: The anti-inflammatory effects of statins have been suggested to relieve postoperative pain. This retrospective study tested the association between the perioperative routine use of statins in therapeutic doses, and opioid requirements and pain scores, after hip replacement surgery. Methods: With IRB approval, data was obtained for adult patients who had elective hip replacement surgery under spinal anaesthesia at Cleveland Clinic between 2005 and 2015. Patients were compared using a joint hypothesis framework. We used the inverse probability of treatment weighting method to control for observed confounding factors (a total of 26). Results: We included 611 statin users and 780 non-statin users. Pain score during the initial 72 h after surgery was 0.07 higher (95% CI: 0.02, 0.17) in statin users (noninferiority test in both directions P<0.001). The estimated ratio of geometric means in the cumulative i.v. morphine equivalent opioid consumption was 1.01 (95% CI: 0.93, 1.10) for statin vs non-statin users (noninferiority test P=0.001 in the hypothesized direction and<0.001 in the other direction) during the initial 72 h after surgery. The statin and non-statin patients were deemed equivalent on postoperative opioid consumption and pain score. Conclusions: This is the first large retrospective clinical study that investigates the effects of statin use on postoperative pain and opioid consumption. We observed no difference between statin users and non-users during the initial 72 h after hip surgery. Our findings do not support the routine use of statins as part of an analgesic regimen. PMID- 29121295 TI - Disruption of cortical network activity by the general anaesthetic isoflurane. AB - Background: Actions of general anaesthetics on activity in the cortico-thalamic network likely contribute to loss of consciousness and disconnection from the environment. Previously, we showed that the general anaesthetic isoflurane preferentially suppresses cortically evoked synaptic responses compared with thalamically evoked synaptic responses, but how this differential sensitivity translates into changes in network activity is unclear. Methods: We investigated isoflurane disruption of spontaneous and stimulus-induced cortical network activity using multichannel recordings in murine auditory thalamo-cortical brain slices. Results: Under control conditions, afferent stimulation elicited short latency, presumably monosynaptically driven, spiking responses, as well as long latency network bursts that propagated horizontally through the cortex. Isoflurane (0.05-0.6 mM) suppressed spiking activity overall, but had a far greater effect on network bursts than on early spiking responses. At isoflurane concentrations >0.3 mM, network bursts were almost entirely blocked, even with increased stimulation intensity and in response to paired (thalamo-cortical + cortical layer 1) stimulation, while early spiking responses were <50% blocked. Isoflurane increased the threshold for eliciting bursts, decreased their propagation speed and prevented layer 1 afferents from facilitating burst induction by thalamo-cortical afferents. Conclusions: Disruption of horizontal activity spread and of layer 1 facilitation of thalamo-cortical responses likely contribute to the mechanism by which suppression of cortical feedback connections disrupts sensory awareness under anaesthesia. PMID- 29121297 TI - Age and other perioperative risk factors for postoperative systemic inflammatory response syndrome after cardiac surgery. AB - Background: The inflammatory response to surgery varies considerably between individual patients. Age might be a substantial factor in this variability. Our objective was to examine the association of patient age and other potential risk factors with the occurrence of a postoperative systemic inflammatory response syndrome, during the first 24 h after cardiac surgery. Methods: This was a retrospective cohort study, using linked data from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) Database and the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database. Data from patients who underwent coronary artery bypass grafting and/or valve surgery were used. The association between age and postoperative SIRS was analysed using Poisson regression, and corrected for other risk factors. Restricted cubic splines were used to determine relevant age categories. Results are expressed as risk ratios (RR) with 95% confidence intervals (CI). Results: Data from 28 513 patients were used. In both univariable and multivariable models, increased patient age was strongly associated with reduced postoperative SIRS prevalence. Using 73-83 yr as the reference category, the RRs (95% CI) for the age categories were 1.38 (1.28-1.49) for <=43 yr, 1.15 (1.09-1.20) for 44-63 yr, 1.05 (1.00 1.09) for 64-72 yr, and 1.03 (0.94-1.12) for >83 yr, respectively. The predictive value for postoperative SIRS of the final model, however, was moderate (c statistic: 0.61). Conclusions: We have demonstrated that advanced patient age is associated with a decreased risk of postoperative SIRS among cardiac surgery patients, where patients aged over 72 yr had the lowest risk. PMID- 29121299 TI - Gender, power and leadership: the effect of a superior's gender on respiratory therapists' ability to challenge leadership during a life-threatening emergency. AB - Background: Effective communication within teams is crucial, especially in crisis situations. Hierarchy gradients between team members can contribute to communication failures and are influenced by many factors. The effect of gender on team performance has not been well studied. The objective of this study was to examine the effect of the physician's gender on respiratory therapists' ability to effectively challenge clearly incorrect clinical decisions during a life threatening crisis. Methods: Respiratory therapists were recruited to take part in a high-fidelity simulation of can't-intubate can't-oxygenate scenarios. They were randomized into two groups, either assisting a male or a female anaesthetist in managing an airway crisis during which the anaesthetist made incorrect clinical decisions. Two independent raters scored the performances using the modified Advocacy-Inquiry Score (min 1, max 6). Results: Twenty-nine subjects completed the study. The median best challenge score when the staff anaesthetist was female was 4 (3-5 IQR [2-6 range]) compared with 3 (3-3[0-3]) for challenges to a male anaesthetist (P=0.017). The median of the total challenges against a female staff member 11 (7.3-14.8 [2-18]) was significantly higher compared with 4 (3.5-7 [2-11.5]) for a male staff (P=0.006). Conclusions: The study showed a significant effect of superiors' gender on a respiratory therapist's ability to challenge leadership. A female staff anaesthetist was challenged more often and with greater assertiveness and effectiveness. This has implications for an educational intervention targeting the ability to challenge a wrong decision by a supervisor and emphasizing the effect of gender on the willingness to speak up. PMID- 29121300 TI - Perioperative statins surgery and postoperative pain. PMID- 29121298 TI - Human neural correlates of sevoflurane-induced unconsciousness. AB - Sevoflurane, a volatile anaesthetic agent well-tolerated for inhalation induction, provides a useful opportunity to elucidate the processes whereby halogenated ethers disrupt consciousness and cognition. Multiple molecular targets of sevoflurane have been identified, complementing imaging and electrophysiologic markers for the mechanistically obscure progression from wakefulness to unconsciousness. Recent investigations have more precisely detailed scalp EEG activity during this transition, with practical clinical implications. The relative timing of scalp potentials in frontal and parietal EEG signals suggests that sevoflurane might perturb the propagation of neural information between underlying cortical regions. Spatially distributed brain activity during general anaesthesia has been further investigated with positron emission tomography (PET) and resting-state functional magnetic resonance imaging (fMRI). Combined EEG and PET investigations have identified changes in cerebral blood flow and metabolic activity in frontal, parietal, and thalamic regions during sevoflurane-induced loss of consciousness. More recent fMRI investigations have revealed that sevoflurane weakens the signal correlations among brain regions that share functionality and specialization during wakefulness. In particular, two such resting-state networks have shown progressive breakdown in intracortical and thalamocortical connectivity with increasing anaesthetic concentrations: the Default Mode Network (introspection and episodic memory) and the Ventral Attention Network (orienting of attention to salient feature of the external world). These data support the hypotheses that perturbations in temporally correlated activity across brain regions contribute to the transition between states of sevoflurane sedation and general anaesthesia. PMID- 29121301 TI - Tissue Doppler assessment of diastolic function and relationship with mortality in critically ill septic patients: a systematic review and meta-analysis. AB - Background: Myocardial dysfunction may contribute to circulatory failure in sepsis. There is growing evidence of an association between left ventricular diastolic dysfunction (LVDD) and mortality in septic patients. Utilizing echocardiography, we know that tissue Doppler imaging (TDI) variables e' and E/e' are reliable predictors of LVDD and are useful measurements to estimate left ventricular (LV) filling pressures. Methods: We conducted a systematic review and meta-analysis to investigate the association of e' and E/e' with mortality of patients with severe sepsis or septic shock. In the primary analysis, we included studies providing transthoracic TDI data for e' and E/e' and their association with mortality. Subgroup analyses were conducted according to myocardial regional focus of TDI assessment (septal, lateral or averaged). Three secondary analyses were performed: one included data from a transoesophageal study, another excluded studies reporting data at a very early (<6 h) or late (>48 h) stage following diagnosis, and the third pooled data only from studies excluding patients with heart valve disease. Results: The primary analysis included 16 studies with 1507 patients with severe sepsis and/or septic shock. A significant association was found between mortality and both lower e' [standard mean difference (SMD) 0.33; 95% confidence interval (CI): 0.05, 0.62; P=0.02] and higher E/e' (SMD -0.33; 95% CI: -0.57, -0.10; P=0.006). In the subgroup analyses, only the lateral TDI values showed significant association with mortality (lower e' SMD 0.45; 95% CI: 0.11, 0.78; P=0.009; higher E/e' SMD -0.49; 95% CI: -0.76, -0.22; P=0.0003). The findings of the primary analysis were confirmed by all secondary analyses. Conclusions: There is a strong association between both lower e' and higher E/e' and mortality in septic patients. PMID- 29121302 TI - Is the bougie redundant in direct laryngoscopic grade 3 intubations? PMID- 29121303 TI - Treatment of chronic venous ulcers with topical sevoflurane: a retrospective clinical study. PMID- 29121304 TI - Age and inflammation after cardiac surgery. PMID- 29121305 TI - NeuPSIG: investing in solutions to the growing global challenge of neuropathic pain. PMID- 29121306 TI - Monitoring nociception-getting 'there yet' might be easier with a road map. PMID- 29121307 TI - Humour therapy intervention to reduce stress and anxiety in paediatric anaesthetic induction, a pilot study. PMID- 29121308 TI - Speaking up: does anaesthetist gender influence teamwork and collaboration? PMID- 29121309 TI - Hierarchy in disruption of large-scale networks across altered arousal states. PMID- 29121310 TI - The dilemma of interventional pain trials: thinking beyond the box. PMID- 29121311 TI - Guidelines for perioperative pain management: need for re-evaluation. PMID- 29121312 TI - Readmission after surgery: are neuromuscular blocking drugs a cause? PMID- 29121313 TI - Does surrounding temperature influence the rate of hypothermia during Caesarean section? PMID- 29121314 TI - Ambient operating room temperature: mother, baby or surgeon? PMID- 29121316 TI - Routine videolaryngoscopy is likely to improve skills needed to use a videolaryngoscope when laryngoscopy is difficult. PMID- 29121315 TI - The paradox in the current use of videolaryngoscopes in the UK. PMID- 29121317 TI - An algorithm for suboptimally placed supraglottic airway devices: the choice of videolaryngoscope. PMID- 29121318 TI - Reply to Tobin and colleagues. PMID- 29121319 TI - Should we use hypotonic or isotonic maintenance intravenous fluids in sick patients? Why a study in healthy volunteers will not provide the answer: Response to: Effect of isotonic versus hypotonic maintenance fluid therapy on urine output, fluid balance, and electrolyte homeostasis: a crossover study in fasting adult volunteers. PMID- 29121320 TI - Cardiopulmonary exercise testing in preoperative risk assessment and patient management. PMID- 29121321 TI - Response to: Emergency front-of-neck access: scalpel or cannula-and the parable of Buridan's ass. PMID- 29121322 TI - Special section on pain: progress in pain assessment and management. PMID- 29121323 TI - Diastolic dysfunction and sepsis: the devil is in the detail. PMID- 29121324 TI - In the October BJA .... PMID- 29121325 TI - Basic fibroblast growth factor protects against influenza A virus-induced acute lung injury by recruiting neutrophils. AB - Influenza virus (IAV) infection is a major cause of severe respiratory illness that affects almost every country in the world. IAV infections result in respiratory illness and even acute lung injury and death, but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated. In this study, the basic fibroblast growth factor 2 (FGF2) level was markedly increased in H1N1 virus-infected humans and mice. FGF2, which is predominately derived from epithelial cells, recruits and activates neutrophils via the FGFR2 PI3K-AKT-NFkappaB signaling pathway. FGF2 depletion or knockout exacerbated influenza-associated disease by impairing neutrophil recruitment and activation. More importantly, administration of the recombinant FGF2 protein significantly alleviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice. Based on the results from experiments in which neutrophils were depleted and adoptively transferred, FGF2 protected mice against IAV infection by recruiting neutrophils. Thus, FGF2 plays a critical role in preventing IAV-induced lung injury, and FGF2 is a promising potential therapeutic target during IAV infection. PMID- 29121327 TI - Short-Acting Opioids Are Associated with Comparable Analgesia to Long-Acting Opioids in Patients with Chronic Osteoarthritis with a Reduced Opioid Equivalence Dosing. AB - Setting: There are no studies that exist within the primary care setting that address optimal opioid therapy in osteoarthritis patients. In light of the recently released US Centers for Disease Control and Prevention guidelines on opioid use in chronic noncancer pain, there is a pressing need to better characterize the effectiveness of long- and short-acting opioids. Objective: To examine the effectiveness of short-acting opioids (SAO) vs long-acting opioids (LAO) and combination therapies (SAO and LAO) for treating chronic osteoarthritis pain in a retrospective trial. Methods: Average and lowest pain scores approximately one to two weeks prior to patient appointments were collected and averaged for both SAO and LAO patients who were actively enrolled in a pain clinic at an academic medical center. Results: There was no statistical difference between reported average and low pain scores for the SAO vs LAO groups (P = 0.201 and P = 0.296, respectively), although the SAO group on average had a significantly lower morphine equivalence (P < 0.001). Various covariates for both groups were tested in an adjusted model to look at trends in the use of nonopioid medications (i.e., acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, and adjunct analgesic agents). No significant differences in pain scores existed when comparing covariates for the SAO vs LAO groups. Conclusions: The study suggests that in addition to being effective, short-acting opioid medications may also provide a safer and cheaper alternative to long acting opioid therapies in the treatment of chronic osteoarthritis. Perspective: This article investigates the effectiveness of short-acting vs long-acting opioids for the treatment of chronic noncancer pain, specifically osteoarthritis. This information could potentially aid practitioners in primary care environments to design equally efficacious and less costly opioid regimens, while simultaneously enhancing patient safety. PMID- 29121326 TI - Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder. AB - STUDY QUESTION: Does an increased FSH dose result in higher cumulative live birth rates in women with a predicted poor ovarian response, apparent from a low antral follicle count (AFC), scheduled for IVF or ICSI? SUMMARY ANSWER: In women with a predicted poor ovarian response (AFC < 11) undergoing IVF/ICSI, an increased FSH dose (225/450 IU/day) does not improve cumulative live birth rates as compared to a standard dose (150 IU/day). WHAT IS KNOWN ALREADY: In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can predict ovarian response to stimulation. The FSH starting dose is often adjusted based on the ORT from the belief that it will improve live birth rates. However, the existing RCTs on this topic, most of which show no benefit, are underpowered. STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label multicentre RCT in women with an AFC < 11 (Dutch Trial Register NTR2657). The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. We needed 300 women to assess whether an increased dose strategy would increase the cumulative live birth rate from 25 to 40% (two-sided alpha error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC <= 7 were randomized to an FSH dose of 450 IU/day or 150 IU/day, and women with an AFC 8-10 were randomized to 225 IU or 150 IU/day. In the standard group, dose adjustment was allowed in subsequent cycles based on pre-specified criteria. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 511 women were randomized, 234 with an AFC <= 7 and 277 with an AFC 8-10. The cumulative live birth rate for increased versus standard dosing was 42.4% (106/250) versus 44.8% (117/261), respectively [relative risk (RR): 0.95 (95%CI, 0.78-1.15), P = 0.58]. As an increased dose strategy was more expensive [delta costs/woman: ?1099 (95%CI, 562-1591)], standard FSH dosing was the dominant strategy in our economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. As this open study permitted small dose adjustments between cycles, potential selective cancelling of cycles in women treated with 150 IU could have influenced the cumulative results. However, since first cycle live birth rates point in the same direction we consider it unlikely that the open design masked a potential benefit for the individualized strategy. WIDER IMPLICATIONS OF THE FINDINGS: Since an increased dose in women scheduled for IVF/ICSI with a predicted poor response (AFC < 11) does not improve live birth rates and is more expensive, we recommend using a standard dose of 150 IU/day in these women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). T.C.T., H.L.T. and S.C.O. received an unrestricted personal grant from Merck BV. H.R.V. receives monetary compensation as a member on an external advisory board for Ferring pharmaceutical BV. B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number NTR2657. TRIAL REGISTRATION DATE: 20 December 2010. DATE OF FIRST PATIENT'S ENROLMENT: 12 May 2011. PMID- 29121328 TI - Active heavy cigarette smoking is associated with poor survival in Japanese patients with advanced renal cell carcinoma: sub-analysis of the multi institutional national database of the Japanese Urological Association. AB - Objective: The association between cigarette smoking and survival in patients with renal cell carcinoma is not well studied. We examined the impact of cigarette smoking on survival of patients with advanced renal cell carcinoma using the multi-institutional national database of the Japanese Urological Association. Methods: From 340 Japanese institutions, 963 patients with renal cell carcinoma of clinical Stage 3 or higher were analyzed. Univariate analysis using the Kaplan-Meier method and multivariate Cox regression models with stepwise selection was used to evaluate overall and cause-specific survival. Results: Median duration of follow-up was 842 days, and overall and cancer death occurred in 392 (40.7%) and 351 (36.4%) patients, respectively. In multivariate analysis, smoking 20 or more cigarettes daily at diagnosis was associated with poorer overall and cancer-specific survival, especially in Stage 3. According to a Cox proportional hazards model, heavy cigarette smoking at diagnosis and the variables of underweight, fever symptoms, serum lactic dehydrogenase value, serum C-reactive protein value, serum creatinine value, Eastern Cooperative Oncology Group performance status, nephrectomy and clinical stage were significant (P < 0.05) for overall and cancer-specific survival. Conclusions: We could compare the smoking status at diagnosis and the prognosis of renal cell carcinoma at national wide scale. Heavy active smoking was an independent prognostic factor for overall and cancer-specific survival in patients with advanced renal cell carcinoma, especially in Stage 3. PMID- 29121329 TI - Response. PMID- 29121330 TI - Age-Varying Relationships Between Physical Function and Cognition in Older Adulthood. AB - Objectives: There are positive relationships between physical and cognitive function in older adulthood; however, the strength of these relationships are inconsistent across studies. Although novel statistical tools provide flexibility to explore age-related differences in relationship magnitude, such methods have not been implemented in gerontological research. This study applied such methods to examine variations in relationship magnitude between physical function and cognition in healthy older adults (N = 2,783). Method: Time-varying effects modeling (TVEM) is an extension of regression that models changes in relationships as a function of time-varying metrics like age. TVEM was used to examine if physical function (Turn 360, grip strength) predicted cognitive performance (memory, processing speed/attention, and reasoning) similarly across adults aged 65-90. Results: All associations between Turn 360 and all cognitive domains were significant and positive; however, speed of processing had significant magnitude variation across age such that the young-old and the old old demonstrated the strongest relationships. Associations between grip strength and all cognitive domains significantly strengthened with increased age. Discussion: Results suggest that depending on the sample age, there may be inconsistencies in the relationships between physical and cognitive performance. Future research should explore these relationships longitudinally to better elucidate discrepant findings. PMID- 29121331 TI - Estimating Prey Consumption in Natural Populations of Harmonia axyridis (Coleoptera: Coccinellidae) Using Production of Feces. AB - Production of feces (PF) is a useful proxy indicating quantity of ingested food. Although influenced by many uncontrolled factors PF provides insight into food consumption under natural conditions. In Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae) variation in PF was investigated in populations of various hostplants at localities of central Bohemia (50N, 14E), throughout the season of 2016. The adults collected from these hostplants were starved for 48 h at standard conditions, and dry mass of feces produced during this period was measured. Despite enormous differences in PF among individuals, significant variation over the season occurred in average PF of both males and females. PF increased with abundance of aphids and was significantly greater in females than males. Gravidity, as manifested through oviposition within 48 h after capture, was associated with increased PF, while hostplant and color morph did not affect variation in PF among individuals. From PF as measured in this study, it can be estimated that at sites hosting abundant aphid populations H. axyridis (as an adult male or female) may consume 19 (male) to 45 (female) aphids per day (assumed body length 1mm). In the absence of aphids, adults may consume one to nine individuals of alternative prey per day (body length 1-2 mm). PMID- 29121332 TI - Frontostriatal and Dopamine Markers of Individual Differences in Reinforcement Learning: A Multi-modal Investigation. AB - Prior studies have shown that dopamine (DA) functioning in frontostriatal circuits supports reinforcement learning (RL), as phasic DA activity in ventral striatum signals unexpected reward and may drive coordinated activity of striatal and orbitofrontal regions that support updating of action plans. However, the nature of DA functioning in RL is complex, in particular regarding the role of DA clearance in RL behavior. Here, in a multi-modal neuroimaging study with healthy adults, we took an individual differences approach to the examination of RL behavior and DA clearance mechanisms in frontostriatal learning networks. We predicted that better RL would be associated with decreased striatal DA transporter (DAT) availability and increased intrinsic functional connectivity among DA-rich frontostriatal regions. In support of these predictions, individual differences in RL behavior were related to DAT binding potential in ventral striatum and resting-state functional connectivity between ventral striatum and orbitofrontal cortex. Critically, DAT binding potential had an indirect effect on reinforcement learning behavior through frontostriatal connectivity, suggesting potential causal relationships across levels of neurocognitive functioning. These data suggest that individual differences in DA clearance and frontostriatal coordination may serve as markers for RL, and suggest directions for research on psychopathologies characterized by altered RL. PMID- 29121333 TI - Is It Now Institutionally Appropriate for the Courts to Consider Whether the Assisted Dying Ban is Human Rights Compatible? Conway v Secretary of State for Justice. AB - Noel Conway has ultimately been granted permission to apply for judicial review, to seek a declaration under section 4(2) Human Rights Act 1998 that section 2(1) Suicide Act 1961 is incompatible with his right to respect for private life under Article 8(1) ECHR. Both decisions in the application process are significant. They attempt to deal with the qualitative elements in the reasoning of Lords Neuberger, Mance and Wilson, in Nicklinson v Ministry of Justice: what Parliament is required to have done to have 'satisfactorily addressed' the question of relaxing or modifying section 2(1) Suicide Act. In failing to consider the explicit use of qualitative reasoning, both courts fail to interpret Nicklinson properly-that Parliament must change the law, with a declaration of incompatibility likely if it failed to do so. The Court of Appeal was correct to overrule the High Court's unqualified approach to whether it was now institutionally appropriate for a court to consider issuing a declaration of incompatibility, for the purposes of granting permission to apply for judicial review. However, the Court of Appeal directly signals their belief that a range of primary evidence bears out a system of assisted suicide for those in Mr Conway's position could feasibly be devised. This question though, as to evidence of a feasible system in the future, is irrelevant to whether permission to apply for judicial review should be granted to argue it is institutionally appropriate to make a declaration of incompatibility regarding current legislation. This is a problem Nicklinson has made for assisted dying and incompatibility debates. PMID- 29121334 TI - Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea. AB - Study Objectives: There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study. Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully blinded parallel groups, placebo-controlled randomized trial of dronabinol in people with moderate or severe OSA. Methods: By random assignment, 73 adults with moderate or severe OSA received either placebo (N = 25), 2.5 mg dronabinol (N = 21), or 10 mg dronabinol (N = 27) daily, 1 hour before bedtime for up to 6 weeks. Results: At baseline, overall apnea-hypopnea index (AHI) was 25.9 +/- 11.3, Epworth Sleepiness Scale (ESS) score was 11.45 +/- 3.8, maintenance of wakefulness test (MWT) mean latency was 19.2 +/- 11.8 minutes, body mass index was 33.4 +/- 5.4 kg/m2, and age was 53.6 +/- 9.0 years. The number and severity of adverse events, and treatment adherence (0.3 +/- 0.6 missed doses/week) were equivalent among all treatment groups. Participants receiving 10 mg/day of dronabinol expressed the highest overall satisfaction with treatment (p = .04). In comparison to placebo, dronabinol dose-dependently reduced AHI by 10.7 +/- 4.4 (p = .02) and 12.9 +/- 4.3 (p = .003) events/hour at doses of 2.5 and 10 mg/day, respectively. Dronabinol at 10 mg/day reduced ESS score by -3.8 +/- 0.8 points from baseline (p < .0001) and by -2.3 +/- 1.2 points in comparison to placebo (p = .05). MWT sleep latencies, gross sleep architecture, and overnight oxygenation parameters were unchanged from baseline in any treatment group. Conclusions: These findings support the therapeutic potential of cannabinoids in people with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved self-reported sleepiness, and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA. PMID- 29121335 TI - Community characteristics and regional variations in sepsis. AB - Background: Sepsis may contribute to more than 200 000 annual deaths in the USA. Little is known about the regional patterns of sepsis mortality and the community characteristics that explain this relationship. We aimed to determine the influence of community characteristics upon regional variations in sepsis incidence and case fatality. Methods: We performed a retrospective analysis of data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Using US sepsis mortality data, we used two strategies for defining geographic regions: (i) Sepsis 'Belt' vs Non-Belt and (ii) Sepsis 'Cluster' vs Non-Cluster. We determined sepsis incidence and case fatality among REGARDS participants in each region, adjusting for participant characteristics. We examined the mediating effect of community characteristics upon regional variations in sepsis incidence and case fatality. Results: Among 29 680 participants, 16 493 (55.6%) resided in the Sepsis Belt and 2958 (10.0%) resided in a Sepsis Cluster. Sepsis incidence was higher for Sepsis Belt than Non-Belt participants [adjusted hazard ratio (HR) = 1.14; 95% confidence interval (CI) = 1.02-1.24] and higher for Sepsis Cluster than Non-Cluster participants (adjusted HR = 1.18; 95% CI = 1.01-1.39). Sepsis case fatality was similar between Sepsis Belt and Non-Belt participants, as well as between Cluster and Non-Cluster participants. Community poverty mediated the regional differences in sepsis incidence. Conclusions: Regional variations in sepsis incidence may be partly explained by community poverty. Other community characteristics do not explain regional variations in sepsis incidence or case fatality. PMID- 29121336 TI - Changes in Brain Structure and Activation May Augment Abnormal Movement Patterns: An Emerging Challenge in Musculoskeletal Rehabilitation. PMID- 29121337 TI - PARP1 changes from three-dimensional DNA damage searching to one-dimensional diffusion after auto-PARylation or in the presence of APE1. AB - PARP1-dependent poly-ADP-ribosylation (PARylation) participates in the repair of many forms of DNA damage. Here, we used atomic force microscopy (AFM) and single molecule fluorescence microscopy to examine the interactions of PARP1 with common DNA repair intermediates. AFM volume analysis indicates that PARP1 binds to DNA at nicks, abasic (AP) sites, and ends as a monomer. Single molecule DNA tightrope assays were used to follow the real-time dynamic behavior of PARP1 in the absence and presence of AP endonuclease (APE1) on AP DNA damage arrays. These experiments revealed that PARP1 conducted damage search mostly through 3D diffusion. Co localization of APE1 with PARP1 on DNA was found capable of inducing 1D diffusion of otherwise nonmotile PARP1, while excess APE1 also facilitated the dissociation of DNA-bound PARP1. Moreover, auto-PARylation of PARP1 allowed the protein to switch its damage search strategy by causing a 3-fold increase in linear diffusion. Finally, we demonstrated that PARP inhibitor olaparib did not significantly alter the rate of PARP1 dissociation from DNA, but instead resulted in more motility of DNA-bound PARP1 molecules. PMID- 29121338 TI - Efficacy of beta-mannanase on broiler growth performance and energy utilization in the presence of increasing dietary galactomannan. AB - An experiment was conducted to investigate the impact of beta-mannanase inclusion on growth performance, viscosity, and energy utilization in broilers fed diets varying in galactomannan (GM) concentrations. Treatments were arranged as a 3 (GM concentration) * 3 (beta-mannanase inclusion) factorial randomized complete block design with 12 replicates of 29 male broilers per replicate for a 42-d experiment. Efforts were made to reduce the amount of soybean meal, and thus GM, in the basal diet with guar gum included at 0, 0.21, or 0.42% to achieve a GM supplementation of 1,500 and 3,000 ppm, respectively. Beta-mannanase was included at 0, 200, or 400 g/ton. Broilers were fed a starter (d 0 to 14), grower (d 15 to 28), and finisher diets (d 29 to 42). Growth performance was monitored and ileal contents collected on d 14, 28, and 42 to determine ileal digestible energy (IDE) and intestinal viscosity. Increasing levels of GM negatively (P < 0.05) influenced body weight (BW) following the starter and grower periods and increased (P < 0.01) mortality corrected feed conversion ratio (FCR) throughout the study. Reduced growth performance was associated with increased (P < 0.05) intestinal viscosity and decreased (P < 0.05) IDE when GM inclusion was increased. Inclusion of beta-mannanase in diets containing supplemental GM on d 28, increased average BW to levels similar to diets without supplemental GM. Improvements in FCR were also observed with beta-mannanase inclusion in diets containing supplemental GM. Ileal digestible energy was increased (P < 0.05) with the addition of beta-mannanase on d 28 of age. Multiple interactions in growth performance, intestinal viscosity, and IDE were associated with beta-mannanase administration. In conclusion, beta-mannanase improved IDE, reduced intestinal viscosity, and improved growth performance; however, the observed benefit was dependent upon dietary GM concentration. PMID- 29121341 TI - Advancing Physical Therapist Interventions by Investigating Causal Mechanisms. PMID- 29121340 TI - HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo. AB - Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of hace1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. Hace1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, hace1 overexpression mitigates mutant huntingtin (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response. Here, we show that the genetic ablation of hace1 in the YAC128 mouse model of HD accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes in vivo. We find that both the expression of mHTT and the ablation of hace1 alone are sufficient to cause deficits in astrocytic mitochondrial respiration. We confirm the crucial role of hace1 in astrocytes in vivo, since its ablation is sufficient to cause dramatic astrogliosis in wild-type FVB/N mice. Astrogliosis is not observed in the presence of mHTT but a strong dysregulation in the expression of astrocytic markers in HACE1-/- x YAC128 striatum suggests an additive effect of mHTT expression and hace1 loss on this cell type. HACE1-/- x YAC128 mice and primary cells derived from these animals therefore provide model systems that will allow for the further dissection of Nrf2 pathways and astrocyte dysfunction in the context of HD. PMID- 29121342 TI - Yellow mealworm larvae (Tenebrio molitor) inclusion in diets for male broiler chickens: effects on growth performance, gut morphology, and histological findings. AB - This study evaluated the effects of Tenebrio molitor (TM) larvae meal inclusion in diets for broilers. A total of 160 male broiler chicks (Ross 708) at one-day of age were randomly allotted to four dietary treatments: a control (C) group and three TM groups, in which TM meal was included at 50 (TM5), 100 (TM10), and 150 (TM15) g/kg, respectively. The experimental diets were isonitrogenous and isoenergetic. Each group consisted of five pens as replicates (8 chicks/pen). After the evaluation of growth performance and haematochemical parameters, the animals were slaughtered at 53 days and carcass traits were recorded. Morphometric investigations were performed on duodenum, jejunum, and ileum and histopathological alterations were assessed for liver, spleen, thymus, bursa of Fabricius, kidney, and heart. The live weight (LW) showed a linear (12 and 25 days, P < 0.001 and P < 0.05, maximum with TM15 and TM10) and quadratic (53 days, P < 0.05, maximum with TM5) response to dietary TM meal inclusion. A linear (1 to 12 and 12 to 25 days, P < 0.001, maximum with TM15) and quadratic (12 to 25 days, P = 0.001, maximum with TM15) effect was also observed for the daily feed intake (DFI). The feed conversion ratio (FCR) showed a linear response (25 to 53 and 1 to 53 days, P = 0.001 and P < 0.05, maximum with TM15). Haematological and serum biochemical traits, carcass traits and histopathological findings were not affected by dietary TM meal inclusion (P > 0.05). TM15 birds showed lower villus height (P < 0.05), higher crypt depth (P < 0.05), and lower villus height to crypt depth ratio (P = 0.001) compared with C and TM5. In conclusion, increasing levels of dietary TM meal inclusion in male broiler chickens may improve body weight and feed intake, but negatively affect feed efficiency and intestinal morphology, thus suggesting that low levels may be more suitable. However, no effect on haematochemical parameters, carcass traits, and histological findings were observed in relation to TM meal utilization. PMID- 29121343 TI - Larval Development of Culicoides sonorensis (Diptera: Ceratopogonidae) in Mud Supplemented With Manure of Various Farm Animals. AB - Understanding factors that affect Culicoides larval development is critical in suppressing adult midge populations that transmit economically important pathogens to ruminants such as bluetongue virus and epizootic hemorrhagic disease virus. In this study, development of Culicoides sonorensis Wirth and Jones (Diptera: Ceratopogonidae) was investigated in sterilized mud mixed with varying concentrations (3.2, 6.4, 12.6, 25.0, 50.0, and 100.0%) of dairy cattle and white tailed deer manures. In addition, C. sonorensis development was also evaluated in manure (25.0% concentration) of six other farm animals (beef cattle, sheep, goat, pig, horse, and chicken). First instar larvae (~100/treatment) were added to each substrate, and adult emergence and development times were monitored for 90 d. In substrates with dairy cattle manure, significantly more adults emerged (>=76.7%) and development time was shorter (<=25.5 d) from 25.0% manure substrate than from lower or higher manure concentrations (<=41.3% emerged; >=31.2 d). Comparatively, white-tailed deer and chicken manures supported C. sonorensis development poorly with low emergence rates (deer <= 13.0%; chicken = 0%) and longer development time (deer >= 29.0 d). Mud enriched with manure of beef cattle, sheep, goat, pig, and horse generally supported C. sonorensis development, although adult emergence and development times varied widely between species. These results suggest that manure of several farm animals, except for white-tailed deer and chicken, can contribute substantially to C. sonorensis development in the field. Therefore, the potential of animals other than cattle in sustaining local populations of C. sonorensis cannot be overlooked when designing management strategies. PMID- 29121339 TI - Conserved non-coding elements: developmental gene regulation meets genome organization. AB - Comparative genomics has revealed a class of non-protein-coding genomic sequences that display an extraordinary degree of conservation between two or more organisms, regularly exceeding that found within protein-coding exons. These elements, collectively referred to as conserved non-coding elements (CNEs), are non-randomly distributed across chromosomes and tend to cluster in the vicinity of genes with regulatory roles in multicellular development and differentiation. CNEs are organized into functional ensembles called genomic regulatory blocks dense clusters of elements that collectively coordinate the expression of shared target genes, and whose span in many cases coincides with topologically associated domains. CNEs display sequence properties that set them apart from other sequences under constraint, and have recently been proposed as useful markers for the reconstruction of the evolutionary history of organisms. Disruption of several of these elements is known to contribute to diseases linked with development, and cancer. The emergence, evolutionary dynamics and functions of CNEs still remain poorly understood, and new approaches are required to enable comprehensive CNE identification and characterization. Here, we review current knowledge and identify challenges that need to be tackled to resolve the impasse in understanding extreme non-coding conservation. PMID- 29121344 TI - Rational design of Pleurotus eryngii versatile ligninolytic peroxidase for enhanced pH and thermal stability through structure-based protein engineering. AB - Versatile peroxidase (VP) from Pleurotus eryngii is a high redox potential peroxidase. It has aroused great biotechnological interest due to its ability to oxidize a wide range of substrates, but its application is still limited due to low pH and thermal stability. Since CiP (Coprinopsis cinerea peroxidase) and PNP (peanut peroxidase) exhibited higher pH and thermal stability than VP, several motifs, which might contribute to their pH and thermal stability, were identified through structure and sequence alignment. Six VP variants incorporating the beneficial motifs were designed and constructed. Most variants were nearly completely inactivated except V1 (Variant 1) and V4. V1 showed comparable activity to WT VP against ABTS, while V4 exhibited reduced activity. V1 displayed improved pH stability than WT VP, at pH 3.0 in particular, whereas the pH stability of V4 did not change a lot. The thermal stabilities of V1 and V4 were enhanced with T50 raised by 3 degrees C. The results demonstrated that variants containing the beneficial motifs of CiP and PNP conferred VP with improved pH and thermal stability. PMID- 29121345 TI - Early Postnatal Exposure to Airborne Fine Particulate Matter Induces Autism-like Phenotypes in Male Rats. AB - Epidemiological studies have revealed that ambient fine particulate matter (PM2.5) exposure is closely associated with autism spectrum disorder (ASD). However, there is a relative paucity of laboratory data to support this epidemic finding. In order to assess the relationship between PM2.5 exposure and ASD, neonatal male Sprague-Dawley rats were chosen and exposed to PM2.5 (2 or 20 mg/kg body weight, once a day) by intranasal instillation from postnatal day 8 to 22. It was found that when exposed to PM2.5 in the early neonatal period for two weeks, both groups of the exposure rats manifested typical behavioral features of autism, including communication deficits, poor social interaction, and novelty avoidance. And, we further found, among five ASD candidate genes we chose, both the mRNA level and protein expression of SH3 and multiple ankyrin repeat domains 3 (Shank3) decreased significantly in the rat hippocampus after high dose of PM2.5 exposure. Moreover, results showed that PM2.5-exposure significantly increased the levels of proinflammatory cytokines, interleukin 1beta, interleukin 6, and tumor necrosis factor alpha in the hippocampus and prefrontal cortex. The expression of glial fibrillary acidic protein and ionized calcium-binding adapter molecule, markers of astrocytes and microglial cell activation, respectively, also increased in the exposed animals. Our work provides new data on the link between postnatal exposure to ambient PM2.5 and the onset of ASD-like symptoms in human beings, and the increased inflammatory response and abnormalities in Shank3 expression in the brain may contribute to the mechanisms of PM2.5 exposure induced ASD. PMID- 29121346 TI - Commentary: 3 Senators, 3 Votes-Glioblastoma's Uncanny Historical Parallels. PMID- 29121347 TI - Race/Ethnic Variations in Quitline Use Among US Adult Tobacco Users in 45 States, 2011-2013. AB - Introduction: State quitlines provide free telephone-based cessation services and are available in all states. However, quitlines presently reach 1% of US cigarette smokers. We assessed variations in quitline reach by race/ethnicity across 45 US states included in the National Quitline Data Warehouse, a repository on non-identifiable data reported by state quitlines. Methods: During 2011 to 2013, we analyzed 1 220 171 records from the National Quitline Data Warehouse. Annual quitline reach was defined as the proportion of cigarette smokers and smokeless tobacco users who utilized quitline services during each year, and was calculated by dividing the number of state-specific quitline registrants in each year by the number of adult cigarette smokers and smokeless tobacco users in the state. Results: Average annual reach ranged from: 0.08% (Tennessee) to 3.42% (Hawaii) among non-Hispanic whites; 0.17% (Tennessee) to 3.85% (Delaware) among non-Hispanic blacks; 0.27% (Nevada) to 9.98% (Delaware) among non-Hispanic American Indians/Alaska Native; 0.03% (Alabama) to 2.43% (Hawaii) among non-Hispanic Asian/Pacific Islanders; and from 0.08% (Tennessee) to 3.18% (Maine) among Hispanics. Average annual reach was highest among non Hispanic American Indians/Alaska Native in 27 states, non-Hispanic blacks in 14 states, and non-Hispanic whites in four states. Conclusions: Quitlines appear to be reaching minority populations; however, overall reach remains low and variations in quitline reach exist by race/ethnicity. Opportunities exist to increase the utilization of quitlines and other effective cessation treatments among racial/ethnic minority populations. Implications: Some studies have assessed quitline reach across demographic groups in individual states; however, no studies have provided multistate data about quitline reach across race/ethnic groups. Ongoing monitoring of the use of state quitlines can help guide targeted outreach to particular race/ethnic groups with the goal of increasing the overall proportion and number of tobacco users that use quitlines. These efforts should be complemented by comprehensive tobacco control initiatives that increase cessation including mass media campaigns, smoke-free policies, increased tobacco prices, expansion of health insurance coverage, and health systems change. PMID- 29121348 TI - Changes in genomic 5-methylcytosine level mirror the response of orthodox (Acer platanoides L.) and recalcitrant (Acer pseudoplatanus L.) seeds to severe desiccation. AB - Poor storability of recalcitrant seeds is due to their inability to tolerate low moisture content. Understanding the processes underlying their recalcitrance is a prerequisite to developing a maintenance strategy and prolonging their lifespan. Multiple studies have investigated the differences between orthodox (desiccation tolerant) and recalcitrant (desiccation-sensitive) seeds. Information on epigenetic regulation, however, is lacking and thus limits our understanding of the processes defining the physiology of seeds. In the present comparative study, changes in the global levels of 5-methylcytosine (m5C) in orthodox and recalcitrant seeds of Acer platanoides L. and Acer pseudoplatanus L. were characterized during progressive stages of severe drying. Concomitant with their differential sensitivity to desiccation stress, we demonstrate variation in the response of embryonic axes and cotyledons to water deficit at the level of DNA methylation. Results indicate that desiccation-induced changes in m5C are both tissue- and seed category-specific and are highly correlated with recalcitrant seed viability. Moreover, we demonstrate that m5C global changes in response to desiccation are not retained in DNA isolated from seedlings, except in seedlings that are derived from strongly desiccated orthodox seeds (moisture content of 3.5%). Finally, the potential utilization of m5C status as a universal seed viability marker is discussed. PMID- 29121349 TI - Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells. AB - STUDY QUESTION: Does the flavonoid naringenin inhibit proliferation of human endometriosis cells? SUMMARY ANSWER: Naringenin suppresses proliferation and increases apoptosis via depolarization of mitochondrial membrane potential and generation of reactive oxygen species (ROS) in human endometriosis cells. WHAT IS KNOWN ALREADY: For management of endometriosis, hormonal therapy is commonly used to decrease production of estrogens by the ovaries, but that has limitations including undesirable side effects with long-term therapies. To overcome these limitations, it is important to discover novel compounds which have no adverse effects, but inhibit expression of target molecules involved in the pathogenesis of endometriosis. STUDY DESIGN SIZE, DURATION: Well-established endometriosis cell lines (VK2/E6E7 and End1/E6E7) were purchased from the American Type Culture Collection. Effects of naringenin on VK2/E6E7 and End1/E6E7 cells were assessed in diverse assays in a dose- and time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Effects of naringenin on viability, apoptosis (Annexin V expression, propidium iodide staining, TUNEL and invasion assays), mitochondria mediated apoptosis, production of ROS and endoplasmic reticulum (ER) stress proteins of VK2/E6E7 and End1/E6E7 cells were determined. Signal transduction pathways in VK2/E6E7 and End1/E6E7 cells in response to naringenin were determined by western blot analyses. MAIN RESULTS AND THE ROLE OF CHANCE: In the present study, we demonstrated that naringenin suppressed proliferation and increased apoptosis through depolarization of mitochondrial membrane potential and inducing pro-apoptotic proteins, Bax and Bak, in both endometriosis cell lines. In addition, naringenin increased ROS, ER stress, through activation of eIF2alpha and IRE1alpha, GADD153 and GRP78 proteins in a dose-dependent manner. Furthermore, the induction of apoptosis by naringenin involved activation of MAPK and inactivation of PI3K pathways in VK2/E6E7 and End1/E6E7 cells. LIMITATIONS REASONS FOR CAUTION: Lack of in vivo animal studies is a major limitation of this research. Effectiveness of naringenin to induce apoptosis of human endometriosis cells requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that naringenin is a promising therapeutic compound for treatment of endometriosis in women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810 awarded to G.S. and HI17C0929 awarded to W.L.). The authors declare that there are no conflicts of interest. PMID- 29121350 TI - Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis. AB - STUDY QUESTION: Is there a difference in live birth rate and/or cost effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment? SUMMARY ANSWER: In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose. WHAT IS KNOWN ALREADY: In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists. STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping. PARTICIPANTS/MATERIALS, SETTING, METHODS: In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti Mullerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, 0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = ?275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were ?35). The analysis based on AMH as a tool for dose individualization suggested comparable results. LIMITATIONS, REASONS FOR CAUTION: Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response. WIDER IMPLICATIONS OF THE FINDINGS: Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657. PMID- 29121352 TI - Arsenic Induces Members of the mmu-miR-466-669 Cluster Which Reduces NeuroD1 Expression. AB - Chronic arsenic exposure can result in adverse development effects including decreased intellectual function, reduced birth weight, and altered locomotor activity. Previous in vitro studies have shown that arsenic inhibits stem cell differentiation. MicroRNAs (miRNAs) are small noncoding RNAs that regulate multiple cellular processes including embryonic development and cell differentiation. The purpose of this study was to examine whether altered miRNA expression was a mechanism by which arsenic inhibited cellular differentiation. The pluripotent P19 mouse embryonal carcinoma cells were exposed to 0 or 0.5 MUM sodium arsenite for 9 days during cell differentiation, and changes in miRNA expression was analyzed using microarrays. We found that the expression of several miRNAs important in cellular differentiation, such as miR-9 and miR-199 were decreased by 1.9- and 1.6-fold, respectively, following arsenic exposure, while miR-92a, miR-291a, and miR-709 were increased by 3-, 3.7-, and 1.6-fold, respectively. The members of the miR-466-669 cluster and its host gene, Scm-like with 4 Mbt domains 2 (Sfmbt2), were significantly induced by arsenic from 1.5- to 4-fold in a time-dependent manner. Multiple miRNA target prediction programs revealed that several neurogenic transcription factors appear to be targets of the cluster. When consensus anti-miRNAs targeting the miR-466-669 cluster were transfected into P19 cells, arsenic-exposed cells were able to more effectively differentiate. The consensus anti-miRNAs appeared to rescue the inhibitory effects of arsenic on cell differentiation due to an increased expression of NeuroD1. Taken together, we conclude that arsenic induces the miR-466-669 cluster, and that this induction acts to inhibit cellular differentiation in part due to a repression of NeuroD1. PMID- 29121351 TI - Construction of multiple linear regression models using blood biomarkers for selecting against abdominal fat traits in broilers. AB - Plasma very low-density lipoprotein (VLDL) can be used to select for low body fat or abdominal fat (AF) in broilers, but its correlation with AF is limited. We investigated whether any other biochemical indicator can be used in combination with VLDL for a better selective effect. Nineteen plasma biochemical indicators were measured in male chickens from the Northeast Agricultural University broiler lines divergently selected for AF content (NEAUHLF) in the fed state at 46 and 48 d of age. The average concentration of every parameter for the 2 d was used for statistical analysis. Levels of these 19 plasma biochemical parameters were compared between the lean and fat lines. The phenotypic correlations between these plasma biochemical indicators and AF traits were analyzed. Then, multiple linear regression models were constructed to select the best model used for selecting against AF content. and the heritabilities of plasma indicators contained in the best models were estimated. The results showed that 11 plasma biochemical indicators (triglycerides, total bile acid, total protein, globulin, albumin/globulin, aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, uric acid, creatinine, and VLDL) differed significantly between the lean and fat lines (P < 0.01), and correlated significantly with AF traits (P < 0.05). The best multiple linear regression models based on albumin/globulin, VLDL, triglycerides, globulin, total bile acid, and uric acid, had higher R2 (0.73) than the model based only on VLDL (0.21). The plasma parameters included in the best models had moderate heritability estimates (0.21 <= h2 <= 0.43). These results indicate that these multiple linear regression models can be used to select for lean broiler chickens. PMID- 29121354 TI - Exogenous glutathione enhances cadmium accumulation and alleviates its toxicity in Populus * canescens. AB - Glutathione (GSH) plays an important role in cadmium (Cd) tolerance in woody plants, but the underlying mechanisms remain largely unknown. To elucidate the physiological and transcriptional regulation mechanisms of GSH-mediated Cd tolerance in woody plants, we exposed Populus * canescens (Ait.) Smith saplings to either 0 or 75 MUM Cd together with one of three external GSH levels. Glutathione treatments include buthionine sulfoximine (BSO, an inhibitor of GSH biosynthesis), no external GSH and exogenous GSH. External GSH resulted in higher Cd2+ uptake rate in the roots, greater Cd amount in poplars, lower Cd-induced H2O2 levels in the roots, and higher contents of endogenous GSH in Cd-treated roots and leaves. Furthermore, external GSH led to upregulated transcript levels of several genes including zinc/iron regulated transporter related protein 6.2 (ZIP6.2) and natural resistance-associated macrophage protein 1.3 (NRAMP1.3), which probably take part in Cd uptake, glutathione synthetase 2 (GS2) implicated in Cd detoxification, metal tolerance protein 1 (MTP1) and ATP-binding cassette transporter C3 (ABCC3) involved in Cd vacuolar accumulation in the roots, gamma glutamylcysteine synthetase (ECS) and phytochelatin synthetase family protein 1 (PCS1) involved in Cd detoxification, and oligopeptide transporter 7 (OPT7) probably implicated in Cd detoxification in the leaves of Cd-exposed P. * canescens. In contrast, BSO often displayed the opposite effects on Cd-triggered physiological and transcriptional regulation responses in poplars. These results suggest that exogenous GSH can enhance Cd accumulation and alleviate its toxicity in poplars. This is probably attributed to external-GSH-induced higher net Cd2+ influx in the roots, greater Cd accumulation in aerial parts, stronger scavenging of reactive oxygen species, and transcriptional overexpression of several genes involved in Cd uptake, detoxification and accumulation. PMID- 29121353 TI - Secondary structure forming sequences drive SD-MMEJ repair of DNA double-strand breaks. AB - Alternative end-joining (alt-EJ) repair of DNA double-strand breaks is associated with deletions, chromosome translocations, and genome instability. Alt-EJ frequently uses annealing of microhomologous sequences to tether broken ends. When accessible pre-existing microhomologies do not exist, we have postulated that new microhomologies can be created via limited DNA synthesis at secondary structure forming sequences. This model, called synthesis-dependent microhomology mediated end joining (SD-MMEJ), predicts that differences between DNA sequences near double-strand breaks should alter repair outcomes in predictable ways. To test this hypothesis, we injected plasmids with sequence variations flanking an I SceI endonuclease recognition site into I-SceI expressing Drosophila embryos and used Illumina amplicon sequencing to compare repair junctions. As predicted by the model, we found that small changes in sequences near the I-SceI site had major impacts on the spectrum of repair junctions. Bioinformatic analyses suggest that these repair differences arise from transiently forming loops and hairpins within 30 nucleotides of the break. We also obtained evidence for 'trans SD MMEJ,' involving at least two consecutive rounds of microhomology annealing and synthesis across the break site. These results highlight the importance of sequence context for alt-EJ repair and have important implications for genome editing and genome evolution. PMID- 29121355 TI - Navigating the Options for the Treatment of Intraocular Lens Malposition. PMID- 29121356 TI - Pain Associated With a Subconjunctival Cefazolin-Lidocaine Mixture in Retinal Surgery:A Randomized Control Trial. AB - BACKGROUND AND OBJECTIVE: The purpose of this randomized, single-masked clinical trial is to explore whether cefazolin mixed with 2% lidocaine can reduce pain. PATIENTS AND METHODS: Patients naive to ophthalmic surgery were randomized to subconjunctival injection of either a 0.5 mL cefazolin-balanced salt solution (0.3 mL cefazolin and 0.2 mL balanced salt solution) or 0.5 mL cefazolin lidocaine solution (0.3 mL cefazolin and 0.2 mL 2% lidocaine) during retinal surgery with a retrobulbar block. Pain scores were obtained at the start of surgery, middle of surgery, before and after cefazolin administration, and postoperatively. RESULTS: A total of 54 patients were recruited; 44.6% were male, and the mean age was 60.1 years +/- 13.5 years. There were no statistically significant differences between the groups' operative characteristics or pain scores at each study time point. CONCLUSION: In pars plana vitrectomy with or without phacoemulsification and intraocular lens insertion, subconjunctival cefazolin mixed with lidocaine conferred no added analgesic benefit. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:881-886.]. PMID- 29121357 TI - Comparison of Pneumatic Retinopexy and Scleral Buckle for Primary Rhegmatogenous Retinal Detachment Repair. AB - BACKGROUND AND OBJECTIVE: To compare pneumatic retinopexy (PR) and scleral buckle for the repair of primary rhegmatogenous retinal detachment. PATIENTS AND METHODS: Retrospective analysis of 90 patients undergoing surgery for primary rhegmatogenous retinal detachment, with 46 patients undergoing PR compared with 44 patients undergoing scleral buckle procedure (SBP). RESULTS: Both groups had similar baseline characteristics. Single surgery reattachment rate was 95.5% with SBP and 67% with PR (P = .00057). Final reattachment rate was 100% with SBP and 97.8% with PR. A final visual acuity (VA) of 20/40 or better occurred in 89% of patients with SBP and 72% of patients with PR (P = .04). PR and SBP had a similar mean VA if the primary procedures were successful, whereas those patients with unsuccessful PR had lower mean final acuities. CONCLUSIONS: This study demonstrates that SBP has a significantly higher rate of single surgery reattachment than PR, along with improved final VA. Initial success of PR may be an important predictor of final visual outcome. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:887-893.]. PMID- 29121358 TI - Optical Coherence Tomography Findings in Endogenous Fungal Chorioretinitis, Retinitis, and Endophthalmitis. AB - BACKGROUND AND OBJECTIVE: To describe spectral-domain optical coherence tomography (SD-OCT) findings in eyes with endogenous fungal chorioretinitis and endophthalmitis. PATIENTS AND METHODS: Retrospective, observational case series of subjects at Wills Eye Hospital and William Beaumont Hospital were identified by screening OCT billing data and cross-referencing with patient charts. Clinical and imaging data were collected for each patient and reviewed. RESULTS: Twelve eyes of seven consecutive patients were identified, demonstrating two patterns of posterior ocular involvement: chorioretinal infiltration and superficial retinal/retinal vascular infiltration without choroidal involvement. Six of 12 eyes had follow-up imaging performed after antifungal treatment, which demonstrated decreased size of choroidal and/or retinal infiltrates. CONCLUSIONS: All patients with follow-up imaging had anatomic improvement by OCT of the lesions with treatment. In the future, OCT imaging may provide a method to assess therapeutic response and prognosis for visual recovery in patients with endogenous fungal ocular disease. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:894-901.]. PMID- 29121359 TI - Single-Spot Yellow Laser Versus Conventional Green Laser on Panretinal Photocoagulation: Patient Pain Scores and Preferences. AB - BACKGROUND AND OBJECTIVE: Panretinal photocoagulation (PRP) is the mainstay therapy for proliferative diabetic retinopathy. Pain during and after its application is a complication that affects patients' therapeutic adherence. This study aimed to compare pain perception and patient preference for the 577-nm yellow laser (YL-577) (LIGHTL as 577; LIGHTMED, San Clemente, CA) and the conventional 532-nm green laser (GL-532) (Purepoint Laser; Alcon, Fort Worth, TX) with PRP. PATIENTS AND METHODS: A total of 92 patient eyes with proliferative diabetic retinopathy treated with PRP were randomly assigned to receive both GL 532 and YL-577 (184 eyes) - one on each eye, with the order of application randomized, as well. Afterward, verbal rapid answer and visual analogue scale (VAS) scores for pain perception and patient preference were evaluated. RESULTS: VAS score was 7 +/- 2 for the GL-532 group compared to 5 +/- 3 in the YL-577 group (P = .001). Overall, 75% of the patients preferred YL-577 therapy if they were to receive a second PRP session. CONCLUSION: The use of YL-577 as an alternative approach for PRP reduces pain perception and is preferred by patients. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:902-905.]. PMID- 29121360 TI - Quantitative Choriocapillaris Perfusion Before and After Vitrectomy in Idiopathic Epiretinal Membrane by Optical Coherence Tomography Angiography. AB - BACKGROUND AND OBJECTIVES: To compare choriocapillaris perfusion of the fovea between patients with idiopathic epiretinal membrane (iERM) and normal controls and determine whether surgery affects it. PATIENTS AND METHODS: Both eyes of 45 patients with iERM and 28 healthy subjects were scanned by optical coherence tomography angiography (OCTA) preoperatively, and 25 of the patients were scanned postoperatively. Central parameters measured included flow area and parafovea vessel density of the foveal choriocapillaris. RESULTS: Both parameters were significantly lower in eyes with iERM (both P < .001) compared with both the unaffected fellow eyes and the normal control eyes (both P < .001) preoperatively, and they increased as the result of surgery, although it did not reach statistical significance. However, the differences between both eyes of patients became insignificant after surgery (both P > .05). CONCLUSIONS: OCTA may provide quantitative information regarding choriocapillaris perfusion. iERM influences the foveal choriocapillaris perfusion, which is reversible by surgery. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:906-915.]. PMID- 29121361 TI - Valved 25-Gauge Cannula for Vitreous Tap and Injection. AB - BACKGROUND AND OBJECTIVES: To describe a technique that reduces patient discomfort by using a valved 25-gauge trocar for vitreous tap and intravitreal injection of medications in previously vitrectomized eyes with suspected infectious endophthalmitis. PATIENTS AND METHODS: A commercially available 25 gauge valved entry system is used to enter the vitreous cavity. A 25-gauge needle attached to a syringe is used to obtain a vitreous specimen for microbiological access and administer intravitreal injections of antibiotics and steroids. No vitreous volume is lost during these procedures because of the cannula's valve. At the completion of the tap and injections, the cannula is removed with forceps and the single wound tamponaded with a cotton-tipped applicator. RESULTS: With this method, a vitreous tap and injection of pharmacologic agents only requires one piercing through the sclera, instead of the usual four piercings. CONCLUSION: With this new technique, it is possible to enhance patient comfort, decreased pain, and reduce trauma to the conjunctiva. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:916-917.]. PMID- 29121362 TI - DualTrack Technology Improves Optical Coherence Tomography Angiography Image Quality. AB - BACKGROUND AND OBJECTIVE: To evaluate the effects of DualTrack Motion Correction Technology on the performance of AngioVue optical coherence tomography angiography (Optovue, Freemont, CA). PATIENTS AND METHODS: Fifty subjects underwent two consecutive examinations with AngioVue. The operator inactivated the eye-tracking (ET) technology before the second examination. Two operators measured execution time, excluded low-quality images, and counted the number of motion artifacts per image. RESULTS: The mean execution time was lower without ET in all the groups (P < .05), regardless of retinal diseases. Percentages of available images and low-quality images were 75.0% and 25.0%, respectively, with ET and 63.0% and 37.0%, respectively, without ET. Mean number of motion artifacts was significantly lower in images obtained using ET compared to images obtained without ET in all the groups (P < .0001), regardless of retinal diseases. CONCLUSION: Although ET technology increases the mean execution time, the reduction of motion artifacts and the increase of high-quality images may represent a great advantage in clinical practice. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:918-926.]. PMID- 29121363 TI - Treatment of Ipilimumab-Induced Vogt-Koyanagi-Harada Syndrome With Oral Dexamethasone. AB - The author presents a retrospective case report of a 54-year-old male with ipilimumab (Yervoy; Bristol-Myers Squibb, New York City, NY)-induced Vogt Koyanagi-Harada Disease (VKH), which consisted of uveitis, optic neuritis, and choroiditis that was successfully treated with oral dexamethasone. The patient demonstrated resolution of uveitis, optic neuritis, and choroiditis 1 month following initiation of oral dexamethasone. Ipilimumab is a recently approved therapy for malignant melanoma. Reports have identified that VKH disease is a potential side effect of the medication. Oral dexamethasone is a safe and effective treatment for this side effect of the medication. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:928-931.]. PMID- 29121364 TI - Swept-Source Optical Coherence Tomography Angiography Findings in Torpedo Maculopathy. AB - Torpedo maculopathy is a rare congenital anomaly of the retinal pigment epithelium (RPE). Various imaging modalities have been used to assess cases of torpedo maculopathy, including optical coherence tomography (OCT) and fundus autofluorescence (FAF). OCT angiography (OCTA) offers combined structural and flow characteristics of imaged lesions. The authors present OCTA findings in two cases of torpedo maculopathy. Common features include loss of RPE and choriocapillaris allowing greater visualization of larger vessels in the outer choroid. This confirms the potential of OCTA to provide greater detail of retinal and choroidal architecture and elucidate the histopathology of retino-choridal lesions. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:932-935.]. PMID- 29121365 TI - Irvine-Gass Macular Edema Responding to the Combination of Oral Mineralocorticoid Receptor Antagonist With Dexamethasone Drops. AB - Long-lasting postoperative macular edema is a therapeutic challenge. The authors report an efficient combination therapy of oral mineralocorticoid receptor antagonists (eplerenone [Inspra; Pfizer, New York City, NY] or spironolactone, 25 mg/day to 50 mg/day) and topical dexamethasone (four times/day and progressive dose tapering) in three refractory cases following complex cataract or retinal detachment surgery. In Case 1, central macular thickness (CMT) decreased from 523 MUm to 214 MUm and visual acuity (VA) improved from 20/200 to 20/50 during a 6 month period. In Cases 2 and 3, CMT improved from 505 MUm to 333 MUm and from 438 MUm to 316 MUm during 5- and 3-month periods, respectively; however, VA remained unchanged (20/100 and 20/200) due to photoreceptor damage. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:936-942.]. PMID- 29121366 TI - Nonconforming Deep Focal Choroidal Excavation in a Patient With Choroidal Osteoma: A Diagnostic Dilemma. AB - Evolution of an osteoma may result in neurosensory detachment, deossification, and choroidal neovascularization (CNV). The authors report a rare case of choroidal osteoma with CNV associated with a deep non-conforming focal choroidal excavation. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:944-947.]. PMID- 29121367 TI - Idiopathic Retinal Vasculitis, Aneurysms, and Neuroretinitis Syndrome Presenting With Branch Retinal Artery Occlusion. AB - Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) is a rare syndrome affecting the retinal and optic disc vasculature. Diffuse retinal ischemia, macular edema, and neovascularization may lead to bilateral vision loss. The authors report a case of a 36-year-old woman presenting with branch retinal artery occlusion (BRAO) in her right eye who was subsequently diagnosed with IRVAN syndrome. She was treated with panretinal photocoagulation for peripheral retinal ischemia and pars plana vitrectomy for vitreous hemorrhage. She later developed a BRAO in her left eye. This case demonstrates that BRAO may be a presenting feature of IRVAN syndrome. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:948-951.]. PMID- 29121368 TI - Good teaching is not a race to cover content: Less can be more. PMID- 29121369 TI - Endoscopic view of a drainage pathway of a concha bullosa. PMID- 29121370 TI - Laryngeal hemangioma presenting as a laryngocele. PMID- 29121371 TI - Nasal septum granuloma gravidarum. PMID- 29121372 TI - Acrokeratosis paraneoplastica (Bazex syndrome). PMID- 29121373 TI - Pediatric sinonasal desmoid tumor. PMID- 29121374 TI - Boomerang-shaped vs. shield-shaped chondroperichondrial cartilage grafts for type 1 tympanoplasty in children: A study of 121 patients. AB - Many techniques and graft materials have been used for the reconstruction of the tympanic membrane. We conducted a retrospective study to compare anatomic and functional outcomes of type 1 tympanoplasty that we performed with boomerang shaped chondroperichondrial cartilage grafts (BSGs) and shield-shaped chondroperichondrial cartilage grafts (SSGs) in pediatric patients. Our study population was made up 121 patients-61 boys and 60 girls, aged 7 to 16 years (mean: 12.4)-who had undergone a type 1 tympanoplasty. Patients were divided into two groups according to the grafting technique used; there were 59 patients in the BSG group and 62 patients in the SSG group. Ear examinations were performed at postoperative months 3, 6, 12, and 24, and pure-tone average (PTA) for air conduction threshold values and air-bone gaps (ABGs) were evaluated at 0.5, 1.0, 2.0, and 4.0 kHz at the same visits. We also investigated the impact of the graft material on functional graft success and intergroup differences (if any) in surgical success. Mean postoperative follow-up periods were 30.5 and 30.2 months in the BSG and SSG groups, respectively. We found that the success rates for tympanic membrane reconstruction were not significantly different in the two groups (91.5 and 88.7%). Postoperatively, the mean PTA and ABG values in both groups at 3, 6, 12, and 24 months were significantly lower than the preoperative values (p < 0.05). There were no significant differences in mean PTA values between the two groups at 3, 6, 12, and 24 months. However, the extent of the decrease in PTA values in the BSG group at 3 months was significantly greater than that of the SSG group (p < 0.05). There were no significant differences in mean ABG values between the two groups at 3, 6, and 12 months, but at 24 months, the value was significantly higher in the BSG group (p < 0.05). Finally, the extent of the decrease in ABG in the BSG group at both 3 and 6 months was significantly greater than that of the SSG group (p < 0.05). We conclude that the BSG procedure is a reliable and safe method of performing pediatric tympanoplasty. PMID- 29121375 TI - Management of benign middle ear tumors: A series of 7 cases. AB - Benign middle ear tumors represent a rare group of neoplasms that vary widely in their pathology, anatomy, and clinical findings. These factors have made it difficult to establish guidelines for the resection of such tumors. Here we present 7 unique cases of these rare and diverse tumors and draw from our experience to recommend optimal surgical management. Based on our experience, a postauricular incision is necessary in nearly all cases. Mastoidectomy is required for tumors that extend into the mastoid cavity. Whenever exposure or hemostasis is believed to be inadequate with simple mastoidectomy, canal-wall down mastoidectomy should be performed. Finally, disarticulation of the ossicular chain greatly facilitates tumor excision and should be performed early in the procedure. PMID- 29121376 TI - Effects of septoplasty on olfactory function evaluated by the Brief Smell Identification Test: A study of 116 patients. AB - We conducted a prospective study of 116 patients-61 men and 55 women, aged 17 to 64 years (mean: 26.4)-to investigate the effects of septoplasty on olfactory function in patients with septal deviation (SD). The Mladina classification system was used to define SD types, and olfactory function was assessed with the Brief Smell Identification test (BSIT). The BSIT, which includes 12 odorants, was administered preoperatively and at postoperative months 1 and 3. The most common SD types were types 2 (20.7% of patients) and 1 (19.0%), followed by types 3 and 5 (both 16.4%). At postoperative month 1, the mean BSIT score was significantly higher in men than in the women. For patients with types 1 and 2 SD, BSIT scores at 1 month were significantly lower than the scores preoperatively and 3 months postoperatively. For types 3 and 4, BSIT values were significantly higher at 3 months than preoperatively or at 1 month. For type 3 SD, the preoperative mean score was significantly lower than those for types 1, 4, 5, 6, and 7; for type 2 SD, the BSIT score was significantly lower than those of types 5 and 6 only. At 1 month, the scores for types 2 and 3 were significantly lower than those for types 4, 5, 6, and 7. At 3 months, the BSIT score for type 2 was significantly lower than those of types 1, 3, 4, 5, and 6; the type 3 SD score at 3 months was significantly higher than those for types 1, 2, 5, 6, and 7. We conclude that septoplasty surgery for patients with a type 3 SD may improve olfactory function. In contrast, we found that olfactory function in patients with a type 2 SD did not improve to a satisfactory degree, even when good nasal patency was achieved with a corrected septum and an enlarged intranasal volume. Our findings should be investigated further in future studies. PMID- 29121377 TI - Managing head and neck malignancy arising in a field of Crohn disease inflammation: Report of a case. AB - Some of the clinical characteristics of Crohn disease of the head and neck overlap those of squamous cell carcinoma of the head and neck. We describe the diagnostic and therapeutic complexities we encountered in an unusual case of piriform sinus cancer that had arisen in a field of pharyngeal Crohn disease. Based on our initial failure to recognize the predominant inflammatory component of the lesion, we discuss the special considerations that must be made for the detection, staging, and management of head and neck cancer in Crohn disease patients. We further describe the multiple potential interactions among smoking, inflammation, and immunosuppression therapy in the colocalized pathogenesis of the two disease states. PMID- 29121378 TI - Myopericytoma of the neck originating in the middle scalene muscle: A case report. AB - We report a case of myopericytoma of the neck. A 23-year-old woman noticed a small, nontender mass in her left supraclavicular fossa. The mass had grown over a period of 5 months, prompting her to seek evaluation. On examination, no motor or sensory deficits were present. Imaging suggested that a mass had originated in the middle scalene muscle. Computed-tomography-guided core needle biopsy demonstrated a spindle-cell neoplasm with smooth-muscle differentiation. Complete surgical excision was performed. Histopathologic and immunohistochemical evaluations of the tissue sample suggested a myopericytoma. Myopericytoma is an extremely rare tumor of the head and neck. To the best of our knowledge, this is the first reported case of a myopericytoma originating in a scalene muscle. PMID- 29121379 TI - Olfactory dysfunction in beta-thalassemia major patients treated with iron chelating agents. AB - Ocular and ophthalmologic adverse effects may occur in patients with beta thalassemia major (BTM) treated regularly with blood transfusions and iron chelating agents. We hypothesized that olfactory dysfunction may be present in this patient population. We aimed to investigate olfactory dysfunction in patients with BTM and to determine etiologic factors. A total of 43 patients with BTM were included in the study. Forty-three subjects without nasal complaints, history of facial trauma, or nasal surgery were included as the controls. All participants had nasal endoscopy. The use of iron-chelating agents by patients with BTM and their duration of use were recorded, as well as hemoglobin and ferritin levels. The Sniffin' Sticks test (SST) was used to assess olfactory function, comparing results between the BTM and control groups. The correlations of SST scores with the other study parameters were analyzed. Eight (18.6%) of 43 patients in the BTM group and none of the subjects in the control group had hyposmia (p < 0.001). Older age, low hemoglobin level, and longer use of deferoxamine were found to be correlated with olfactory dysfunction. Olfactory dysfunction can occur in patients with BTM treated with iron-chelating agents. The results suggest that screening for olfactory function should be part of the routine follow-up of patients with BTM. PMID- 29121380 TI - Clinical application of nasometry in patients with nasal obstruction. AB - The purpose of this case-control study is to report on the clinical application of nasometry as a diagnostic tool in patients with the symptom of nasal obstruction compared with subjects with no history of nasal obstruction. Thirty eight adult patients (mean age: 28.1 years) complaining of nasal obstruction were enrolled in the study, and another group of 38 adults (mean age: 25.9 years) with no history of nasal obstruction served as controls. Demographic data, including age and sex, were collected. Patients were asked to read three passages; the Zoo passage, the Rainbow passage, and nasal sentences. Nasalance scores were reported on all subjects using a Nasometer II instrument. The control and patient groups each included 22 men and 16 women. No statistically significant difference in nasalance score was found between the study group and the control group in any of the Zoo passage, Rainbow passage and nasal sentences. We conclude that nasometry has limited value in the objective assessment of nasal obstruction as a symptom, which we attribute to nasal obstruction's not always reflecting the volume and pressure in the nasal cavity. PMID- 29121381 TI - Nasal smear eosinophils and allergic rhinitis. AB - Our aim was to find out the association between nasal smear eosinophil count and allergic rhinitis (AR) and to determine a cutoff value that is significant for a diagnosis of AR. We also wanted to determine whether this count is related to the predominant symptoms, duration, or type and severity of AR, or to the presence of coexisting asthma. We selected 100 patients with a clinical diagnosis of allergic rhinitis across all age groups and an equal number of age- and sex-matched controls for the study. Their nasal smear eosinophil counts were recorded in terms of the number of eosinophils per high-power field (HPF). All patients were then clinically assessed for asthma and underwent spirometry. The data were recorded and appropriate statistical analysis done. The difference in the mean eosinophil counts of patients with AR and controls was found to be statistically significant (p = 0.000). A nasal smear eosinophil count of >0.3 per HPF had a 100% specificity and a 100% positive predictive value for AR. Asthma was associated with allergic rhinitis in 40% of patients; an association was not found between nasal smear eosinophil count and the symptoms, duration, type, and severity of allergic rhinitis or coexistent asthma. We conclude that an eosinophil count of >0.3 per HPF in nasal smears is a highly specific criterion for the diagnosis of AR. However, nasal smear eosinophil counts are poor indicators of the degree, duration, or type of upper or associated lower airway inflammation due to allergy. PMID- 29121382 TI - Guidelines for radiographic imaging of cranial neuropathies. AB - Disruption of the complex pathways of the 12 cranial nerves can occur at any site along their course, and many, varied pathologic processes may initially manifest as dysfunction and neuropathy. Radiographic imaging (computed topography or magnetic resonance imaging) is frequently used to evaluate cranial neuropathies; however, indications for imaging and imaging method of choice vary considerably between the cranial nerves. The purpose of this review is to provide an analysis of the diagnostic yield and the most clinically appropriate means to evaluate cranial neuropathies using radiographic imaging. Using the PubMed MEDLINE NCBI database, a total of 49,079 articles' results were retrieved on September 20, 2014. Scholarly articles that discuss the etiology, incidence, and use of imaging in the context of evaluation and diagnostic yield of the 12 cranial nerves were evaluated for the purposes of this review. We combined primary research, guidelines, and best practice recommendations to create a practical framework for the radiographic evaluation of cranial neuropathies. PMID- 29121383 TI - A novel etiology for pneumolabyrinth after temporal bone fracture without otic capsule involvement. AB - Pneumolabyrinth has been considered an indicator of otic capsule involvement in temporal bone fractures. We present a novel theory for the etiology of pneumolabyrinth in a trauma patient without an otic capsule fracture: passage of intrathecal air into the labyrinth. Our patient experienced transient bilateral pneumolabyrinth after head trauma due to a motor vehicle collision. The patient was noted to have extensive pneumocephalus and a unilateral temporal bone fracture that spared the otic capsule. Initial computed tomography (CT) scans demonstrated air in the cochlea and both internal auditory canals. A high resolution CT scan 6 hours later showed resolution of this air. Pneumolabyrinth may not be a sensitive indicator of otic capsule involvement in temporal bone fractures. In addition to middle ear sources, air in the labyrinth can also plausibly originate intrathecally, especially in the setting of pneumocephalus. PMID- 29121385 TI - A controlled comparison of auditory steady-state responses and pure-tone audiometry in patients with hearing loss. AB - We performed a prospective interventional study to evaluate correlations between hearing thresholds determined by pure-tone audiometry (PTA) and auditory steady state response (ASSR) testing in two types of patients with hearing loss and a control group of persons with normal hearing. The study was conducted on 240 ears 80 ears with conductive hearing loss, 80 ears with sensorineural hearing loss, and 80 normal-hearing ears. We found that mean threshold differences between PTA results and ASSR testing at different frequencies did not exceed 15 dB in any group. Using Pearson correlation coefficient calculations, we determined that the two responses correlated better in patients with sensorineural hearing loss than in those with conductive hearing loss. We conclude that measuring ASSRs can be an excellent complement to other diagnostic methods in determining hearing thresholds. PMID- 29121384 TI - Correlation between sensorineural hearing loss and chronic otorrhea. AB - Many studies have attempted to correlate chronic otorrhea in children and in adults with the sensorineural hearing loss in the affected ear, with contradictory results. This loss might be the result of the likely toxicity of the bacteria involved, effects of inflammatory cytokines, or constant use of ototoxic antibiotics. All studies evaluated to date compared the affected ear with the normal contralateral ear. From the digitized archive of otologic surgery files of the Department of Otorhinolaryngology at Santa Casa de Sao Paulo School of Medical Sciences, the ears of patients with chronic otorrhea were evaluated visually and compared with the normal contralateral ears. Ears with otorrhea were also compared with ears of other patients with dry tympanic perforation. Ears with suppuration were evaluated for cholesteatoma. The duration of otorrhea was considered. The sensorineural hearing threshold was evaluated for the frequencies of 500, 1,000, 2,000, and 4,000 Hz. A total of 98 patients with chronic otorrhea and 60 with dry tympanic membrane perforation were evaluated. A correlation between sensorineural hearing loss and chronic otorrhea was observed when compared with both contralateral normal ears and dry perforated ears of other patients. No relationship between hearing loss and the duration of suppuration or cholesteatoma was found. Sensorineural hearing loss occurs in ears with chronic otorrhea. The duration of otorrhea and the etiology of suppuration did not influence the hearing loss. PMID- 29121386 TI - "Live" tinnitus. PMID- 29121387 TI - Measles: A missed cause of acute tonsillitis. PMID- 29121388 TI - Metal detection tests: Preventive tools for "Fiddler's Neck" [Letter]. PMID- 29121389 TI - Analyzing community-weighted trait means across environmental gradients: should phylogeny stay or should it go? AB - Functional traits mediate ecological responses of organisms to the environment, determining community structure. Community-weighted trait means (CWM) are often used to characterize communities by combining information on species traits and distribution. Relating CWM variation to environmental gradients allows for evaluating species sorting across the metacommunity, either based on correlation tests or ordinary least squares (OLS) models. Yet, it is not clear if phylogenetic signal in both traits and species distribution affect those analyses. On one hand, phylogenetic signal might indicate niche conservatism along clade evolution, reinforcing the environmental signal in trait assembly patterns. On the other hand, it might introduce phylogenetic autocorrelation to mean trait variation among communities. Under this latter scenario, phylogenetic signal might inflate type I error in analysis relating CWM variation to environmental gradients. We explore multiple ways phylogenetic history may influence analysis relating CWM to environmental gradients. We propose the concept of neutral trait diffusion, which predicts that for a functional trait x, CWM variation among local communities does not deviate from the expectation that x evolved according to a neutral evolutionary process. Based on this framework we introduce a graphical tool called neutral trait diffusion representation (NTDR) that allows for the evaluation of whether it is necessary to carry out phylogenetic correction in the trait prior to analyzing the association between CWM and environmental gradients. We illustrate the NTDR approach using simulated traits, phylogenies and metacommunities. We show that even under moderate phylogenetic signal in both the trait used to define CWM and species distribution across communities, OLS models relating CWM variation to environmental gradients lead to inflated type I error when testing the null hypothesis of no association between CWM and environmental gradient. To overcome this issue, we propose a phylogenetic correction for OLS models and evaluate its statistical performance (type I error and power). Phylogeny-corrected OLS models successfully control for type I error in analysis relating CWM variation to environmental gradients but may show decreased power. Combining the exploratory tool of NTDR and phylogenetic correction in traits, when necessary, guarantees more precise inferences about the environmental forces driving trait-mediated species sorting across metacommunities. PMID- 29121390 TI - Dynamic preferential allocation to arbuscular mycorrhizal fungi explains fungal succession and coexistence. AB - Evidence accumulates about the role of arbuscular mycorrhizal (AM) fungi in shaping plant communities, but little is known about the factors determining the biomass and coexistence of several types of AM fungi in a plant community. Here, using a consumer-resource framework that treats the relationship between plants and fungi as simultaneous, reciprocal exploitation, we investigated what patterns of dynamic preferential plant carbon allocation to empirically-defined fungal types (on-going partner choice) would be optimal for plants, and how these patterns depend on successional dynamics. We found that ruderal AM fungi can dominate under low steady-state nutrient availability, and competitor AM fungi can dominate at higher steady-state nutrient availability; these are conditions characteristic of early and late succession, respectively. We also found that dynamic preferential allocation alone can maintain a diversity of mutualists, suggesting that on-going partner choice is a new coexistence mechanism for mutualists. Our model can therefore explain both mutualist coexistence and successional strategy, providing a powerful tool to derive testable predictions. PMID- 29121391 TI - Groundwater Microbial Communities Along a Generalized Flowpath in Nomhon Area, Qaidam Basin, China. AB - Spatial distribution (horizonal and vertical) of groundwater microbial communities and the hydrogeochemistry in confined aquifers were studied approximately along the groundwater flow path from coteau to plain in the Nomhon area, Qinghai-Tibet plateau, China. The confined groundwater samples at different depths and locations were collected in three boreholes through a hydrogeological section in this arid and semi-arid area. The phylogenetic analysis of 16S rRNA genes and multivariate statistical analysis were used to elucidate similarities and differences between groundwater microbial communities and hydrogeochemical properties. The integrated isotopic geochemical measurements were applied to estimate the source and recharge characteristics of groundwater. The results showed that groundwater varied from fresh to saline water, and modern water to ancient water following the flowpath. The recharge characteristics of the saline water was distinct with that of fresh water. Cell abundance did not vary greatly along the hydrogeochemical zonality; however, dissimilarities in habitat-based microbial community structures were evident, changing from Betaproteobacteria in the apex of alluvial fan to Gammaproteobacteria and then to Epsilonproteobacteria in the core of the basin (alluvial-lacustrine plain). Rhodoferax, Hydrogenophaga, Pseudomonas, and bacterium isolated from similar habitats unevenly thrived in the spatially distinct fresh water environments, while Sulfurimonas dominanted in the saline water environment. The microbial communities presented likely reflected to the hydrogeochemical similarities and zonalities along groundwater flowpath. PMID- 29121392 TI - Ethanol and the Cardiovascular System: Friend or Enemy? PMID- 29121393 TI - Short-term storage stability of NaOCl solutions when combined with Dual Rinse HEDP. AB - AIM: To assess the stability of NaOCl solutions when combined with a novel product for clinical use, Dual Rinse HEDP, which contains etidronate (1 hydroxyethane 1,1-diphosphonate). METHODOLOGY: Mixtures of NaOCl solutions with Dual Rinse HEDP were prepared so that they initially contained 5.0%, 2.5% or 1.0% NaOCl and always 9.0% of dissolved Dual Rinse HEDP powder per total weight. NaOCl solutions alone were used as controls. The stability of these solutions over 8 h was assessed in transparent borosilicate glass bottles at ambient temperature (23 degrees C). Subsequently, the effects of heating (60 degrees C) or storing the solutions at 5 degrees C were studied in polypropylene syringes. NaOCl concentrations were measured by iodometric titration, that is free available chlorine contents. Experiments were performed in triplicate. RESULTS: In the glass bottles at 23 degrees C, the 5.0% NaOCl/9.0% Dual Rinse HEDP solution lost 20% of the available chlorine after 1 h, whilst the corresponding 2.5% NaOCl and 1.0% NaOCl solutions retained this relative amount of available chlorine for 2 and 4 h, respectively. Results obtained in the glass bottles were similar to those achieved in the syringes. Heating of the NaOCl/Dual Rinse HEDP mixtures had a detrimental effect on available chlorine, with a complete loss after 1 h. In contrast, storing the NaOCl/Dual Rinse HEDP mixtures in a refrigerator at 5 degrees C kept the available chlorine high for 7 h, with the expected loss after a further hour of storage at 23 degrees C. CONCLUSIONS: Initial NaOCl concentration and temperature both affected short-term storage stability of combined solutions containing Dual Rinse HEDP. PMID- 29121395 TI - Multiple-Dose Oritavancin Evaluation in a Retrospective Cohort of Patients with Complicated Infections. AB - OBJECTIVE: Oritavancin is a lipoglycopeptide antibiotic approved for use in acute bacterial skin and skin structure infections as a single 1200-mg parenteral dose. Because of oritavancin's long half-life and broad gram-positive activity, interest in its use for other infections is high. METHODS: This study is a retrospective cohort evaluation of patients receiving oritavancin at a single academic medical center. All patients receiving more than one dose of oritavancin were included. Patients were excluded if therapy was interrupted by more than 14 days. Efficacy, defined a priori as clinical success, improvement, or failure, and adverse drug effect outcomes were collected. RESULTS: Seventeen patients received multiple oritavancin doses (range 2-18 doses) for the treatment of complicated infections including osteomyelitis, surgical site infection, intravascular infections, and pneumonia. All patients achieved clinical success or improvement with oritavancin. Four patients (24%) had an adverse event requiring oritavancin discontinuation that reversed rapidly. CONCLUSIONS: Off label oritavancin use may be a safe and effective alternative to daily antibiotic infusions to treat complicated infectious disease processes. This study is limited by small sample size and retrospective design, but it provides information on using oritavancin in these complex gram-positive infections. PMID- 29121396 TI - Role of Gut-Derived Endotoxin on Type I Collagen Production in the Rat Pancreas After Chronic Alcohol Exposure. AB - BACKGROUND: Pancreatic fibrosis is a key pathological feature of alcoholic chronic pancreatitis (ACP). Bacterial endotoxin lipopolysaccharide (LPS) is considered as an important cofactor in the fibrogenesis of ACP. However, there are limitations in the use of exogenous LPS for evaluating the role of endotoxin in ACP pathogenesis. In this study, we determined the relationship between the concentration of LPS in the portal vein and pancreatic type I collagen (Col1) content in chronic alcohol-fed rats. METHODS: Male Sprague Dawley rats were divided into 2 groups and fed with Lieber-DeCarli isocaloric control (CON) liquid diet or ethanol (EtOH) (15 g/kg/d) liquid diet. Eleven CON or EtOH rats were euthanized at the end of week 8, 9, or 10. The plasma LPS from portal vein was determined. Pancreatic inflammatory injury and fibrosis were assessed. Pancreatic stellate cells (PSCs) and macrophages were identified; pancreatic type I collagen alpha 1 (Col1A1) and Toll-like receptor (TLR4) mRNA and protein were examined; pancreatic chemokines and transforming growth factor-beta1 (TGF-beta1) were determined. RESULTS: Pancreatic inflammatory scores were increased in 10-week EtOH rats compared with CON rats, but there was no significant difference in collagen deposition between 2 groups. The levels of portal vein LPS and pancreatic TLR4 and Col1A1 mRNA and protein were increased in a time-dependent fashion in EtOH rats, with the highest levels occurring at 10 weeks. Additionally, by 8 weeks, pancreatic TLR4 and Col1A1 mRNA in EtOH rats were statistically increased as compared to CON rats, whereas portal vein LPS remained unchanged. The number of PSCs and macrophages and expression of chemokines (MCP 1, MIP-1alpha, and RANTES), TGF-beta1, or Col1A1 were significantly increased, each of which was positively correlated with the level of portal vein LPS in 10 week EtOH rats. CONCLUSIONS: These results suggest that LPS is associated with alcohol-induced fibrosis in pancreatitis and targeting of bacterial endotoxin may be a promising therapeutic strategy for ACP. PMID- 29121394 TI - Larval Echinococcus multilocularis infection reduces dextran sulphate sodium induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions. AB - The tumour-like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune-mediated processes. Parasite-mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine dextran sodium sulphate (DSS) -induced colitis. At 3 months after E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with haematoxylin & eosin for assessing inflammatory reactions. Cytokine levels were measured by flow cytometry and quantitative RT-PCR. Colitis severity was assessed (by board-certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semi-quantitative score of morphological changes. The histopathological analysis of the colon showed a significant reduction of DSS-induced gut inflammation by concomitant E. multilocularis infection, which correlated with down-regulation of T helper type 1 (Th1)/Th17 T-cell responses in the colon tissue. Echinococcus multilocularis infection markedly reduced the severity of DSS-induced gut inflammation upon down-regulation of Th1/Th17 cytokine expression and attenuation of CD11b+ cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS-induced colitis in mice by attenuating Th1/Th17-mediated immune reactions. PMID- 29121397 TI - Virtual phantom magnetic resonance imaging (ViP MRI) on a clinical MRI platform. AB - PURPOSE: The purpose of this study was to implement Virtual Phantom Magnetic Resonance Imaging (ViP MRI), a technique that allows for generating reference signals in MR images using radiofrequency (RF) signals, on a clinical MR system and to test newly designed virtual phantoms. METHODS: MRI experiments were conducted on a 1.5 T MRI scanner. Electromagnetic modelling of the ViP system was done using the principle of reciprocity. The ViP RF signals were generated using a compact waveform generator (dimensions of 26 cm * 18 cm * 16 cm), connected to a homebuilt 25 mm-diameter RF coil. The ViP RF signals were transmitted to the MRI scanner bore, simultaneously with the acquisition of the signal from the object of interest. Different types of MRI data acquisition (2D and 3D gradient echo) as well as different phantoms, including the Shepp-Logan phantom, were tested. Furthermore, a uniquely designed virtual phantom - in the shape of a grid - was generated; this newly proposed phantom allows for the investigations of the vendor distortion correction field. RESULTS: High quality MR images of virtual phantoms were obtained. An excellent agreement was found between the experimental data and the inverse cube law, which was the expected functional dependence obtained from the electromagnetic modelling of the ViP system. Short-term time stability measurements yielded a coefficient of variation in the signal intensity over time equal to 0.23% and 0.13% for virtual and physical phantom, respectively. MR images of the virtual grid-shaped phantom were reconstructed with the vendor distortion correction; this allowed for a direct visualization of the vendor distortion correction field. Furthermore, as expected from the electromagnetic modelling of the ViP system, a very compact coil (diameter ~ cm) and very small currents (intensity ~ mA) were sufficient to generate a signal comparable to that of physical phantoms in MRI experiments. CONCLUSIONS: The ViP MRI technique was successfully implemented on a clinical MR system. One of the major advantages of ViP MRI over previous approaches is that the generation and transmission of RF signals can be achieved with a self-contained apparatus. As such, the ViP MRI technique is transposable to different platforms (preclinical and clinical) of different vendors. It is also shown here that ViP MRI could be used to generate signals whose characteristics cannot be reproduced by physical objects. This could be exploited to assess MRI system properties, such as the vendor distortion correction field. PMID- 29121398 TI - Protein phosphatase 2A and tau: an orchestrated 'Pas de Deux'. AB - The neuronal microtubule-associated protein tau serves a critical role in regulating axonal microtubule dynamics to support neuronal and synaptic functions. Furthermore, it contributes to glutamatergic regulation and synaptic plasticity. Emerging evidence also suggests that tau serves as a signaling scaffold. Tau function and subcellular localization are tightly regulated, in part, by the orchestrated interplay between phosphorylation and dephosphorylation events. Significantly, protein phosphatase type 2A (PP2A), encompassing the regulatory PPP2R2A (or Balpha) subunit, is a major brain heterotrimeric enzyme and the primary tau Ser/Thr phosphatase in vivo. Herein, we closely examine how the intimate and compartmentalized interactions between PP2A and tau regulate tau phosphorylation and function, and play an essential role in neuronal homeostasis. We also review evidence supporting a strong link between deregulation of tau-PP2A functional interactions and the molecular underpinnings of various neurodegenerative diseases collectively called tauopathies. Lastly, we discuss the opportunities and associated challenges in more specifically targeting PP2A tau interactions for drug development for tauopathies. PMID- 29121399 TI - Alcohol Drinking and Blood Alcohol Concentration Revisited. AB - BACKGROUND: It is widely assumed that the amount of alcohol in the blood reflects the amount of alcohol consumed. However, several factors in addition to amount of alcohol consumed can influence blood alcohol concentration (BAC). This study examines the effect of alcohol dose, concentration, and volume on BAC in rats with a high-alcohol-drinking (HAD) phenotype. METHODS: Study 1 examined the relationship between the amount of alcohol consumed and BAC. Alcohol-naive, male, HAD rats (N = 7) were given access to alcohol for 2 h/d for 9 consecutive days with food and water ad libitum. Alcohol intake and BAC were measured at 30, 60, and 90 minutes after onset of access. Study 2 examined the effects of altering alcohol dose, concentration, and volume on BAC (as measured by area under the curve). Alcohol-naive, male, HAD rats (N = 39) were infused, via an intragastric cannulus, with 1.16, 2.44, or 3.38 g alcohol/kg body weight (BW), produced by varying alcohol volume while holding concentration constant or by holding volume constant while varying concentration. Other rats were infused with 10, 15, or 20% v/v alcohol solutions while holding dose constant. RESULTS: BAC was more strongly correlated with the ratio of alcohol intake (g/kg BW) to total fluid intake (mls) (R = 0.85 to 0.97, p < 0.05 to p < 0.001) than it was with the amount of alcohol consumed (g/kg BW) (R = 0.70 to 0.81, p < 0.05). No effect of alcohol dose was seen during the first hour following the onset of an alcohol infusion regardless of whether dose was achieved by altering alcohol volume or concentration. After 1 hour, higher alcohol doses were predictive of greater BACs. CONCLUSIONS: The fact that a 3-fold difference in alcohol dose did not result in significant differences in BACs during the first 30 minutes after ingestion of alcohol has potentially important implications for interpretation of studies that measure alcohol-sensitive end points during this time. PMID- 29121400 TI - Dexamethasone as an adjuvant to peripheral nerve block. AB - BACKGROUND: Peripheral nerve block (infiltration of local anaesthetic around a nerve) is used for anaesthesia or analgesia. A limitation to its use for postoperative analgesia is that the analgesic effect lasts only a few hours, after which moderate to severe pain at the surgical site may result in the need for alternative analgesic therapy. Several adjuvants have been used to prolong the analgesic duration of peripheral nerve block, including perineural or intravenous dexamethasone. OBJECTIVES: To evaluate the comparative efficacy and safety of perineural dexamethasone versus placebo, intravenous dexamethasone versus placebo, and perineural dexamethasone versus intravenous dexamethasone when added to peripheral nerve block for postoperative pain control in people undergoing surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, DARE, Web of Science and Scopus from inception to 25 April 2017. We also searched trial registry databases, Google Scholar and meeting abstracts from the American Society of Anesthesiologists, the Canadian Anesthesiologists' Society, the American Society of Regional Anesthesia, and the European Society of Regional Anaesthesia. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) comparing perineural dexamethasone with placebo, intravenous dexamethasone with placebo, or perineural dexamethasone with intravenous dexamethasone in participants receiving peripheral nerve block for upper or lower limb surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 35 trials of 2702 participants aged 15 to 78 years; 33 studies enrolled participants undergoing upper limb surgery and two undergoing lower limb surgery. Risk of bias was low in 13 studies and high/unclear in 22. Perineural dexamethasone versus placeboDuration of sensory block was significantly longer in the perineural dexamethasone group compared with placebo (mean difference (MD) 6.70 hours, 95% confidence interval (CI) 5.54 to 7.85; participants1625; studies 27). Postoperative pain intensity at 12 and 24 hours was significantly lower in the perineural dexamethasone group compared with control (MD -2.08, 95% CI -2.63 to 1.53; participants 257; studies 5) and (MD -1.63, 95% CI -2.34 to -0.93; participants 469; studies 9), respectively. There was no significant difference at 48 hours (MD -0.61, 95% CI -1.24 to 0.03; participants 296; studies 4). The quality of evidence is very low for postoperative pain intensity at 12 hours and low for the remaining outcomes. Cumulative 24-hour postoperative opioid consumption was significantly lower in the perineural dexamethasone group compared with placebo (MD 19.25 mg, 95% CI 5.99 to 32.51; participants 380; studies 6). Intravenous dexamethasone versus placeboDuration of sensory block was significantly longer in the intravenous dexamethasone group compared with placebo (MD 6.21, 95% CI 3.53 to 8.88; participants 499; studies 8). Postoperative pain intensity at 12 and 24 hours was significantly lower in the intravenous dexamethasone group compared with placebo (MD -1.24, 95% CI -2.44 to -0.04; participants 162; studies 3) and (MD -1.26, 95% CI -2.23 to -0.29; participants 257; studies 5), respectively. There was no significant difference at 48 hours (MD -0.21, 95% CI -0.83 to 0.41; participants 172; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. Cumulative 24-hour postoperative opioid consumption was significantly lower in the intravenous dexamethasone group compared with placebo (MD -6.58 mg, 95% CI -10.56 to -2.60; participants 287; studies 5). Perinerual versus intravenous dexamethasoneDuration of sensory block was significantly longer in the perineural dexamethasone group compared with intravenous by three hours (MD 3.14 hours, 95% CI 1.68 to 4.59; participants 720; studies 9). We found that postoperative pain intensity at 12 hours and 24 hours was significantly lower in the perineural dexamethasone group compared with intravenous, however, the MD did not surpass our pre-determined minimally important difference of 1.2 on the Visual Analgue Scale/Numerical Rating Scale, therefore the results are not clinically significant (MD -1.01, 95% CI -1.51 to -0.50; participants 217; studies 3) and (MD -0.77, 95% CI -1.47 to 0.08; participants 309; studies 5), respectively. There was no significant difference in severity of postoperative pain at 48 hours (MD 0.13, 95% CI -0.35 to 0.61; participants 227; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. There was no difference in cumulative postoperative 24-hour opioid consumption (MD -3.87 mg, 95% CI -9.93 to 2.19; participants 242; studies 4). Incidence of severe adverse eventsFive serious adverse events were reported. One block-related event (pneumothorax) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however group allocation was not reported. Four non-block-related events occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the placebo group required hospitalization within one week of surgery; one for a fall and one for a bowel infection. One participant in the placebo group developed Complex Regional Pain Syndrome Type I and one in the intravenous dexamethasone group developed pneumonia. The quality of evidence is very low due to the sparse number of events. AUTHORS' CONCLUSIONS: Low- to moderate-quality evidence suggests that when used as an adjuvant to peripheral nerve block in upper limb surgery, both perineural and intravenous dexamethasone may prolong duration of sensory block and are effective in reducing postoperative pain intensity and opioid consumption. There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not apply to participants at risk of dexamethasone-related adverse events for whom clinical trials would probably be unsafe.There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not be apply to participants who at risk of dexamethasone related adverse events for whom clinical trials would probably be unsafe. The nine ongoing trials registered at ClinicalTrials.gov may change the results of this review. PMID- 29121401 TI - MP29-02 reduces nasal hyperreactivity and nasal mediators in patients with house dust mite-allergic rhinitis. AB - BACKGROUND: Nasal hyperreactivity (NHR) is an important clinical feature of allergic rhinitis (AR). The efficacy of MP29-02 (azelastine hydrochloride (AZE) and fluticasone propionate [FP]) nasal spray on local inflammatory mediators and NHR in AR is unknown. We tested if MP29-02 decreases inflammatory mediators and NHR in AR and if this effect is due to restoration of nasal epithelial barrier function. METHODS: A 4-week double-blinded placebo-controlled trial with MP29-02 treatment was conducted in 28 patients with house dust mite (HDM) AR. The presence of NHR was evaluated by measuring reduction in nasal flow upon cold dry air exposure. The effects of AZE +/- FP on barrier integrity and airway inflammation were studied in a murine model of HDM-induced NHR and on reduced activation of murine sensory neurons and human mast cells. RESULTS: MP29-02 but not placebo reduced NHR (P < .0001 vs P = .21), levels of substance P (P = .026 vs P = .941), and beta-hexosaminidase (P = .036 vs P = .632) in human nasal secretions. In wild-type C57BL6 mice, the reduction in beta-hexosaminidase levels (P < .0001) by AZE + FP treatment upon HDM challenge was found in parallel with a decreased transmucosal passage (P = .0012) and completely reversed eosinophilic inflammation (P = .0013). In vitro, repeated applications of AZE + FP desensitized sensory neurons expressing the transient receptor potential channels TRPA1 and TRPV1. AZE + FP reduced MC degranulation to the same extent as AZE alone. CONCLUSION: MP29-02 treatment reduces inflammatory mediators and NHR in AR. The effects of AZE + FP on MC degranulation, nasal epithelial barrier integrity, and TRP channels provide novel insights into the pathophysiology of allergic rhinitis. PMID- 29121402 TI - Incorporating Functional Genomic Information to Enhance Polygenic Signal and Identify Variants Involved in Gene-by-Environment Interaction for Young Adult Alcohol Problems. AB - BACKGROUND: Characterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene-by-environment (G * E) interaction effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit G * E effects. METHODS: We examined these questions in the young adult FinnTwin12 sample (n = 1,170). We used genomewide association estimates from an independent sample to derive 2 types of polygenic scores for alcohol problems in FinnTwin12. Genomewide polygenic scores included all SNPs surpassing a designated p-value threshold. DNase polygenic scores were a subset of the genomewide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a nonpsychiatric model phenotype to evaluate the consistency of effects. For the G * E analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant G * E effects in an interaction between romantic relationship status and intoxication frequency. RESULTS: Contrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per-SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In G * E models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. CONCLUSIONS: These findings highlight the potential utility of integrating functional genomic annotation information to increase the signal-to-noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification. PMID- 29121404 TI - The Association of British Neurologists' myasthenia gravis guidelines. AB - Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction for which many therapies were developed before the era of evidence-based medicine. Despite the basic principles of treatment being well known, patients continue to receive suboptimal treatment. A myasthenia gravis guidelines group was therefore established under the aegis of the Association of British Neurologists. These guidelines attempt to steer a path between evidence-based practice where available and established best practice where evidence is unavailable. It is not possible to consider all the potential decisions in managing MG without resorting to opinion rather than evidence. Where there is insufficient evidence or a choice of options, the guidelines invite the clinician to seek the opinion of a myasthenia expert. The guidelines support clinicians in using the right treatments in the right order and in optimizing the use of well-known therapeutic agents. Clinical practice can be audited against these guidelines. PMID- 29121405 TI - The impact of visceral adipose tissue amount on the adequacy of lymph node retrieval in colorectal cancer surgery. AB - BACKGROUND: Obesity is increasing worldwide, potentially influencing surgical outcomes in colorectal cancer (CRC) patients. We analyzed the effects of obesity indexes on lymph node (LN) retrieval in CRC patients. METHOD: We applied obesity indexes of body mass index (BMI) and visceral (VAT) and subcutaneous (SAT) adipose tissue volumes to stage I-III CRC patients. The primary outcome was the effect of these indexes on the number of retrieved LNs (12 > LNs >= 12). RESULTS: Among 519 patients, 35.6% had a BMI >= 25 kg/m2 . After adjusting for gender, age, tumor location, resected colon length, and local invasion and LN statuses, patients in the highest VAT quartile showed a 5.848 decrease in the number of retrieved LNs, with an odds ratio of 0.483 (95% confidence interval [CI] 0.260 0.8979) for adequate LN retrieval (>=12), compared with those in the lowest quartile (P < 0.001 for both). Analysis of the model predicting LN retrieval revealed VAT as the only obesity index (area under the curve [AUC] = 0.721) providing significant additional predictive power (P = 0.037) to the model including age, gender, staging, tumor location, and resected colon length (AUC = 0.707). CONCLUSION: Increased VAT may cause inadequate LN retrieval in CRC patients. In viscerally obese patients, VAT volumes should be considered when clinically interpreting LN status. PMID- 29121406 TI - Multiple mechanisms of early plant community assembly with stochasticity driving the process. AB - Initial plant establishment is one of the most critical phases in ecosystem development, where an early suite of physical (environmental filtering), biological (seed limitation, species interactions) and stochastic factors may affect successional trajectories and rates. While functional traits are commonly used to study processes that influence plant community assembly in late successional communities, few studies have applied them to primary succession. The objective here was to determine the importance of these factors in shaping early plant community assembly on a glacial outwash plain, Skeidararsandur, in SE Iceland using a trait based approach. We used data on vascular plant assemblages at two different spatial scales (community and neighborhood) sampled in 2005 and 2012, and compiled a dataset on seven functional traits linked to species dispersal abilities, establishment, and persistence for all species within these assemblages. Trait-based null model analyses were used to determine the processes that influenced plant community assembly from the regional species pool into local communities, and to determine if the importance of these processes in community assembly was dependent on local environment or changed with time. On the community scale, for most traits, random processes dominated the assembly from the regional species pool. However, in some communities, there was evidence of non-random assembly in relation to traits linked to species dispersal abilities, persistence, and establishment. On the neighborhood scale, assembly was mostly random. The relative importance of different processes varied spatially and temporally and the variation was linked to local soil conditions. While stochasticity dominated assembly patterns of our early successional communities, there was evidence of both seed limitation and environmental filtering. Our results indicated that as soil conditions improved, environmental constraints on assembly became weaker and the assembly became more dependent on species availability. PMID- 29121403 TI - Mechanisms of radial glia progenitor cell lineage progression. AB - The mammalian cerebral cortex is responsible for higher cognitive functions such as perception, consciousness, and acquiring and processing information. The neocortex is organized into six distinct laminae, each composed of a rich diversity of cell types which assemble into highly complex cortical circuits. Radial glia progenitors (RGPs) are responsible for producing all neocortical neurons and certain glia lineages. Here, we discuss recent discoveries emerging from clonal lineage analysis at the single RGP cell level that provide us with an inaugural quantitative framework of RGP lineage progression. We further discuss the importance of the relative contribution of intrinsic gene functions and non cell-autonomous or community effects in regulating RGP proliferation behavior and lineage progression. PMID- 29121407 TI - Strong and frequent T-cell responses to the minor allergen Phl p 12 in Spanish patients IgE-sensitized to Profilins. AB - BACKGROUND: Profilins are dominant pan-allergens known to cause cross sensitization, leading to clinical symptoms such as pollen-food syndrome. This study aimed to determine the T-cell response to Phl p 12 in profilin-sensitized patients, by measuring the prevalence, strength and cross-reactivity to clinically relevant profilins. METHODS: The release of Phl p allergens from pollen was determined by mass spectrometry and immunochemistry. T-cell responses, epitope mapping and cross-reactivity to profilins (Phl p 12, Ole e 2, Bet v 2 and Mal d 4) were measured in vitro using PBMCs from 26 Spanish grass-allergic donors IgE-sensitized to profilin. Cross-reactivity was addressed in vivo using 2 different mouse strains (BALB/c and C3H). RESULTS: Phl p 12 and Phl p 1 are released from pollen simultaneously and in similar amounts. Both T-cell response frequency (17/26 donors) and strength were comparable between Phl p 12 and Phl p 1. T-cell cross-reactivity to other profilins correlated with overall sequence homology, and 2 immunodominant epitope regions of Phl p 12 were identified. Data from mice immunized with Phl p 12 showed that cross-reactivity to Bet v 2 was mediated by conserved epitopes and further influenced by additional genetic factors, likely to be MHC II. CONCLUSION: The strength, prevalence and cross reactivity of T-cell responses towards Phl p 12 are comparable to the major allergen Phl p 1, which supports the hypothesis that T cells to Phl p 12 can play an important role in development of allergic symptoms, such as those associated with pollen-food syndrome. PMID- 29121408 TI - Community Health Workers Supporting Clinical Pharmacists in Diabetes Management: A Randomized Controlled Trial. AB - OBJECTIVES: To evaluate the effectiveness of clinical pharmacists and community health workers (CHWs) in improving glycemic control within a low-income ethnic minority population. METHODS: In a two-arm 2-year crossover trial, 179 African American and 65 Hispanic adult patients with uncontrolled diabetes mellitus (hemoglobin A1c [HbA1C] of 8% or higher) were randomized to CHW support either during the first or second year of the study. All participants received clinical pharmacist support for both years of the study. The primary outcome was change in HbA1C over 1 and 2 years. RESULTS: Similar HbA1C declines were noted after receiving the 1 year of CHW support: -0.45% (95% confidence interval [CI] -0.96 to 0.05) with CHW versus -0.42% (95% CI -0.93 to 0.08) without CHW support. In addition, no differences were noted in change on secondary outcome measures including body mass index, systolic blood pressure, high-density lipoprotein and low-density lipoprotein cholesterol, quality of life, and perceived social support. A difference in diastolic blood pressure change was noted: 0.80 mm Hg (95% CI -1.92 to 3.53) with CHW versus -1.85 mm Hg (95% CI -4.74 to 1.03) without CHW support (p=0.0078). Patients receiving CHW support had more lipid-lowering medication intensifications (0.39 [95% CI 0.27-0.52]) compared with those without CHW support (0.26 [95% CI 0.14-0.38], p<0.0001). However, no significant differences in intensification of antihyperglycemic and antihypertensive medications were observed between patients receiving CHW support and those without CHW support. Patients with low health literacy completed significantly more encounters with the pharmacist and CHW than those with high health literacy, although outcomes were comparable. CONCLUSIONS: No significant differences were noted between a clinical pharmacist-CHW team and clinical pharmacist alone in improving glycemic control within a low-income ethnic minority population. PMID- 29121409 TI - Image quality and dose for a multisource cone-beam CT extremity scanner. AB - PURPOSE: This work investigates the dose characteristics and image quality of a multisource cone-beam CT scanner dedicated for extremity imaging. METHODS: The scanner has an x-ray source with three separate anode-cathode units evenly distributed along the longitudinal direction. A nominal scan protocol fires the three sources sequentially, and a total of 600 projections (200 for each source) are acquired over a source-detector orbit of 210o . Dose was measured using a Farmer chamber in three CTDI phantoms stacked end-to-end. Measurements were performed at the central and four peripheral locations of a CTDI phantom on the axial plane and repeated along the longitudinal direction. The extent of 3D sampling of the three-source configuration was assessed in the Fourier domain through noise power spectrum measurements from air scans and compared with that from a single-source scan. A modified Defrise phantom and anthropomorphic knee and hand phantoms were used for visual assessment of cone-beam artifacts in the reconstructed images. RESULTS: The dose distribution for the three-source configuration exhibits radial asymmetry on the axial plane consistent with a short-scan geometry. Along the longitudinal direction, the highest dose was measured at the central axial plane where the field of view (FOV) from all three sources overlaps and falls off more slowly toward the end compared to a single source configuration. The extent of 3D sampling is improved throughout the FOV as each source compensates for missing frequencies from the adjacent source. As a result, the reduction in streak and shading artifacts is apparent in the reconstructed images of all three phantoms. The improvement in image quality from the three-source configuration is most pronounced in joint spaces farther from the central axial plane. CONCLUSIONS: Initial assessment of the multisource scanner demonstrated the advantages over single-source designs in a compact scanner with large longitudinal FOV. The reduction in cone-beam artifact is particularly valuable for extremity imaging where high-contrast articular surfaces are present away from the central axial plane and/or throughout the FOV. PMID- 29121410 TI - Medication Management of Patients Undergoing Transcatheter Aortic Valve Replacement. AB - Aortic stenosis (AS) is the most common form of valvular heart disease. A detailed diagnostic workup is necessary to promptly stage and classify disease severity to determine optimal management. Medical therapy and valvuloplasty are options that fail to delay or reverse disease progression. Surgical aortic valve replacement (SAVR) is curative but has significant limitations for some patient populations. A newer option, transcatheter aortic valve replacement (TAVR), has become more widely available to patients with intermediate- or high-operative risk. Periprocedural medication management is imperative for successful valve implantation and to minimize adverse events. Stroke remains one of the most common complications of TAVR and is associated with increased mortality. Thus, intra- and postprocedural antithrombotic therapy is required, although the regimen that best minimizes thromboembolic events and bleeding complications has yet to be defined. Patients undergoing TAVR with comorbid conditions requiring oral anticoagulation or individuals who develop subvalvular thromboses pose unique challenges. Antiplatelet and anticoagulant therapy should be carefully balanced. This article summarizes key literature supporting the pharmacologic management of patients receiving TAVR. PMID- 29121411 TI - Probiotic Lactobacillus rhamnosus GG prevents alveolar bone loss in a mouse model of experimental periodontitis. AB - AIM: This study investigated the role of Lactobacillus rhamnosus GG (LGG) on bone loss and local and systemic inflammation in an in vivo mouse model of experimental periodontitis (PD). MATERIALS AND METHODS: Experimental PD was induced in mice by oral inoculation with Porphyromonas gingivalis and Fusobacterium nucleatum over a period of 44 days. The probiotic LGG was administered via oral inoculation or oral gavage prior to, and during disease induction. The antimicrobial activity of LGG on the inoculum was also tested. Alveolar bone levels and gingival tissue changes were assessed using in vivo microcomputed tomography and histological analysis. Serum levels of mouse homologues for IL-8 were measured using multiplex assays. RESULTS: Pre-treatment with probiotics either via oral gavage or via oral inoculation significantly reduced bone loss (p < .0001) and gingival inflammation (p < .0001) when compared with PD group. Oral gavage treatment group had significantly less tartrate resistant acid phosphatase positive cells (p < .02) then PD group. LGG showed no antimicrobial activity against P. gingivalis and F. nucleatum. CONCLUSIONS: Lactobacillus rhamnosus GG effectively suppresses bone loss in a mouse model of induced PD irrespective of the mode of administration. PMID- 29121412 TI - Galectin-3, A Potential Therapeutic Target For Rheumatoid Arthritis? PMID- 29121413 TI - Person-centredness in elder care: A secondary analysis of data from a study among home-dwelling men and women in the Faroe Islands. AB - AIMS AND OBJECTIVES: As individuals in Western societies age, there is increasing demand for home-based care to help older people stay in their homes for as long as possible and provide services that ensure a person's quality of life in old age. Numerous attempts are made to develop a framework to secure quality of care. However, research has shown insufficient quality in care for older people. In this study, the purpose is to study how older people's experiences with home care reflect a person-centred approach to care. Data derived from an earlier study on ageing among home-dwelling men and women who are aged 67-91 and living in the Faroe Islands. BACKGROUND: Person-centredness as a concept is an often quoted, but ill-defined concept. Most studies concerning person-centred care are conducted within hospital wards or long-term care institutions. Empirical studies concerning home-dwelling older people receiving home care are scarce. METHODS: The study is a secondary analysis of data from an earlier qualitative study. Latent thematic analysis was used which meant coding issues of potential interest and collecting these codes into themes. RESULTS: Three themes appeared to combine the initial codes: sense of involvement, sense of meaningfulness and contextual conditions. Overall, the analysis showed that the users were seldom involved in planning or scheduling the care they received. What they were offered did not always make sense to them or correspond to their needs or preferences. CONCLUSIONS: The number of interviews included was limited. However, findings from this study point at some possible barriers to successful implementation of person-centredness within elder care. Especially, contextual conditions seem to limit the facilitation of person-centred practices. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers must take the user's preferences, resources and networks into consideration when coordinating and planning home care and, importantly, be open for negotiating needs. It is important to draw attention to the contrast between political intentions regarding elder care and the limited options for putting the intentions into practice. PMID- 29121414 TI - Stress-induced suppression of neuropeptide Y-induced hunger in anorexic chicks involves corticotrophin-releasing factor signalling and the paraventricular nucleus of the hypothalamus. AB - The Virginia lines of chickens have been selected for low (LWS) or high (HWS) juvenile body weight and have different severities of anorexia and obesity, respectively. The LWS that are exposed to stressors at hatch are refractory to neuropeptide Y (NPY)-induced food intake and the objective of the present study was to determine the underlying mechanisms. Chicks were exposed to a stressor ( 20 degrees C for 6 minutes and 22 degrees C and delayed access to food for 24 hours) after hatching and the hypothalamic nuclei, including the lateral hypothalamus (LH), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and arcuate nucleus (ARC), were collected 5 days later. In LWS but not HWS, stress exposure up-regulated corticotrophin-releasing factor (CRF), CRF receptor subtypes 1 and 2 (CRFR1 and CRFR2, respectively), melanocortin receptor 4 and urocortin 3 in the PVN, as well as CRFR2 mRNA in the VMH and ARC. In LWS, stress exposure was also associated with greater NPY and NPY receptor subtype 5 mRNA in the ARC and PVN, respectively, as well as decreased agouti-related peptide mRNA in the ARC. In HWS, stress exposure was associated with increased CRFR1 and decreased cocaine- and amphetamine-regulated transcript in the ARC and PVN, respectively. Refractoriness of the food intake response to NPY in LWS may thus result from the over-riding anorexigenic tone in the PVN associated with CRF signalling. Indeed, the orexigenic effect of NPY was restored when LWS were injected with a CRF receptor antagonist, astressin, before stress exposure. The results of the present study provide insights into the molecular basis of eating disorders and suggest that CRF signalling in the PVN may exacerbate the anorexic phenotype in the presence of environmental stressors. PMID- 29121416 TI - Pregnant outcomes of atypical polypoid adenomyoma treated with progestin therapy. AB - AIM: We aimed to investigate the long-term clinical and pregnancy outcome in patients with atypical polypoid adenomyoma (APA) after hysteroscopic excision. METHODS: We analyzed the clinicopathological features, including pregnancy outcomes, in 10 APA patients who had been treated with hysteroscopic excision of the lesion and progesterone therapy. RESULTS: The patients were all nulliparous, and nine had been clinically diagnosed as infertile. There were five patients with complex endometrial hyperplasia at the time of initial diagnosis, two of them had had recurrence of complex hyperplasia, and there was another one who had had complex hyperplasia 18 months after initial diagnosis. The patients had been treated with polypectomy under hysteroscopy and a long-term progestin therapy. They had achieved complete regression, but four had a recurrent or persistent disease. Two patients had eventually undergone hysterectomy due to endometrial carcinoma at 102 months (patient 2) or persisting complex atypical hyperplasia at 131 months (patient 5) after initial diagnosis. All patients were alive with no evidence of disease during a follow-up period of 19-145 months. Seven patients had succeeded in pregnancy with nine live births. Three pregnancies had been achieved by in vitro fertilization and embryo transfer. CONCLUSION: Fertility sparing surgery under hysteroscopy with progesterone therapy and appropriate assistant reproduction technology is an alternative option for young APA patients. However, close follow-up is required for these patients. PMID- 29121415 TI - Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine. AB - Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non competitive inhibitor of MEK1/MEK2. In this phase IIa open-label, single-arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12-week non-PD rate. Secondary assessments included safety, progression-free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non-PD rate at week 12 was 10% (95% confidence interval, 1.2 31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6-12.1) and 1-year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end-point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864. PMID- 29121418 TI - The panorama of cerebral palsy in Sweden part XII shows that patterns changed in the birth years 2007-2010. AB - AIM: This was the 12th population-based study to explore the epidemiology of cerebral palsy (CP) in western Sweden. METHODS: From 2007 to 2010, there were 104 713 live births in the area. We analysed the birth characteristics, aetiology and neuroimaging findings, calculated the prevalence and compared the results with previous study cohorts. RESULTS: Cerebral palsy was found in 205 children, corresponding to a crude prevalence of 1.96 per 1000 live births. The gestational age-specific prevalence for <28 gestational weeks was 59.0 per 1000 live births, 45.7 for 28-31 weeks, 6.0 for 32-36 weeks and 1.2 for >36 weeks. Hemiplegia accounted for 44%, diplegia for 34%, tetraplegia for 5%, dyskinetic CP for 12% and ataxia for 3%. Neuroimaging showed maldevelopment in 12%, white matter lesions in 49%, cortical/subcortical lesions in 15% and basal ganglia lesions in 11%. The aetiology was considered prenatal in 38%, peri/neonatal in 38% and remained unclassified in 24%. CP due to term or near-term asphyxia had decreased. CONCLUSION: A nonsignificant decrease in CP prevalence was seen in term-born children. Hemiplegia was still the most prevalent CP type, while the prevalence of dyskinetic CP had decreased. One in two children had white matter lesions, indicating late second- or early third-trimester timing. PMID- 29121417 TI - Transabdominal cerclage (TAC) for patients with ultra-short uterine cervix after uterine cervix surgery and its impact on pregnancy. AB - AIM: Patients with an ultra-short uterine cervix as a result of large conization, repeated conization or radical trachelectomy (RT), are at high risk of preterm premature rupture of the membrane, which leads to preterm birth. We have commenced performing transabdominal cerclage (TAC) of the uterine cervix for these patients. In this study, we examined the safety of TAC and its impact on pregnancy. METHODS: We have performed TAC in 11 patients before pregnancy: in six after large cervical operations, such as repeated conization; and in five for difficulties with cervical cerclage after RT. After laparotomy, a Teflon thread was placed in the avascular space between the uterine vessels and the uterine muscle, and tied. The clinical course of the patients after TAC and their pregnancy course were retrospectively reviewed. RESULTS: TAC was performed safely without any complications. The mean operative duration was 53 +/- 10 min, and the mean blood loss during the operation was 49 +/- 64 mL. Seven women conceived within 2 years after TAC. Their pregnancy courses were favorable. Five of the women underwent scheduled cesarean sections, while two pregnancies are ongoing. CONCLUSIONS: Although there are risks of various complications as a result of the use of non-absorbable thread and the need for two extra laparotomies, TAC can be a safe and useful option for patients who show cervical incompetence after large uterine cervical operations, such as RT or large conization. PMID- 29121419 TI - Nitrogen limitation of decomposition and decay: How can it occur? AB - The availability of nitrogen (N) is a critical control on the cycling and storage of soil carbon (C). Yet, there are conflicting conceptual models to explain how N availability influences the decomposition of organic matter by soil microbial communities. Several lines of evidence suggest that N availability limits decomposition; the earliest stages of leaf litter decay are associated with a net import of N from the soil environment, and both observations and models show that high N organic matter decomposes more rapidly. In direct contrast to these findings, experimental additions of inorganic N to soils broadly show a suppression of microbial activity, which is inconsistent with N limitation of decomposition. Resolving this apparent contradiction is critical to representing nutrient dynamics in predictive ecosystem models under a multitude of global change factors that alter soil N availability. Here, we propose a new conceptual framework, the Carbon, Acidity, and Mineral Protection hypothesis, to understand the effects of N availability on soil C cycling and storage and explore the predictions of this framework with a mathematical model. Our model simulations demonstrate that N addition can have opposing effects on separate soil C pools (particulate and mineral-protected carbon) because they are differentially affected by microbial biomass growth. Moreover, changes in N availability are frequently linked to shifts in soil pH or osmotic stress, which can independently affect microbial biomass dynamics and mask N stimulation of microbial activity. Thus, the net effect of N addition on soil C is dependent upon interactions among microbial physiology, soil mineralogy, and soil acidity. We believe that our synthesis provides a broadly applicable conceptual framework to understand and predict the effect of changes in soil N availability on ecosystem C cycling under global change. PMID- 29121420 TI - Obesity during pregnancy in the mouse alters the Netrin-1 responsiveness of foetal arcuate nucleus neuropeptide Y neurones. AB - When individuals undergo gestation in an obese dam, they are at increased risk for impairments in the ability of the brain to regulate body weight. In rodents, gestation in an obese dam leads to a number of changes to the development of the hypothalamic neurones that regulate body weight, including reduced neuronal connectivity at birth. In the present study, we aimed to clarify how this neural circuitry develops normally, as well as to explore the mechanism underpinning the deficiency in connectivity seen in foetuses developing in obese dams. First, we developed an in vitro model for observing and manipulating the axonal growth of foetal arcuate nucleus (ARN) neuropeptide (NPY) neurones. We then used this model to test 2 hypotheses: (i) ARN NPY neurones respond to Netrin-1, one of a small number of axon growth and guidance factors that regulate neural circuit formation throughout the developing brain; and (ii) Netrin-1 responsiveness would be lost upon exposure to the inflammatory cytokine interleukin (IL)-6, which is elevated in foetuses developing in obese dams. We observed that ARN NPY neurones responded to Netrin-1 with a significant expansion of their growth cones, comprising the terminal apparatus that neurones use to navigate. Unexpectedly, we found further that NPY neurones from obese pregnancies had a reduced responsiveness to Netrin 1, raising the possibility that ARN NPY neurones from foetuses developing in obese dams were phenotypically different from normal NPY neurones. Finally, we observed that IL-6 treatment of normal NPY neurones in vitro led to a reduced growth cone responsiveness to Netrin-1, essentially causing them to behave similarly to NPY neurones from obese pregnancies. These results support the hypothesis that IL-6 can disrupt the normal process of axon growth from NPY neurones, and suggest one possible mechanism for how the body weight regulating circuitry fails to develop properly in the offspring of obese dams. PMID- 29121421 TI - Assessment of biologically aggressive, recurrent glandular odontogenic cysts for mastermind-like 2 (MAML2) rearrangements: histopathologic and fluorescent in situ hybridization (FISH) findings in 11 cases. AB - BACKGROUND: Glandular odontogenic cyst (GOC) demonstrates a significant predilection toward localized biologic aggressiveness and recurrence. GOC shares certain histopathologic features with intraosseous mucoepidermoid carcinoma (IMEC). The current investigation evaluates a group of recurrent, biologically aggressive GOCs to determine whether any cases demonstrated unique histologic features or mastermind-like2 (MAML2) rearrangements common to IMEC. METHODS: Microscopic slides from 11 previously diagnosed GOCs were stained with hematoxylin and eosin and assessed by 2 study participants for 10 classic histopathologic features required to establish a diagnosis of GOC. Cases were evaluated utilizing break-apart fluorescent in situ hybridization (FISH) analysis for the presence of MAML2 gene rearrangements. Clinical and demographic data on all patients were recorded. RESULTS: The mean age for patients included in the study was 55.27 years with a range of 36 to 72 years. The most common presenting symptom was a jaw expansion, and all cysts presented initially as a unilocular or multilocular radiolucency. Cysts displayed a minimum of 6 of 10 histologic parameters necessary for a diagnosis of GOC. One case demonstrated MAML2 rearrangements by FISH. That case also showed marked ciliation of cyst-lining epithelial cells and extensive mucous-secreting goblet cell proliferation. CONCLUSION: Findings in the current study are in concert with previous investigations, and although this study finds only limited molecular evidence to support the premise that recurrent biologically aggressive GOCs are a precursor to IMEC, detection of MAML2 rearrangements in 1 case suggests that such a theoretic transition, while rare, is possible. PMID- 29121423 TI - On open access, special issues and strategies for increasing the readership of your neuroscience research. PMID- 29121422 TI - Investigating the hepatitis B virus life cycle using engineered reporter hepatitis B viruses. AB - Chronic infection with hepatitis B virus (HBV) increases the risk of developing fibrosis, cirrhosis or hepatocellular carcinoma. Current therapies are limited to type-I interferons and/or nucleos(t)ide analogues; however, these are only partially effective. The development of novel anti-HBV agents for new treatment strategies has been hampered by the lack of a suitable system that allows the in vitro replication of HBV. Studies of virus infection/replication at the molecular level using wild-type HBV are labor-intensive and time-consuming. To overcome these problems, we previously constructed a recombinant reporter HBV bearing the NanoLuc gene and showed its usefulness in identifying factors that affect HBV proliferation. Because this system mimics the early stage of the HBV life cycle faithfully, we conducted a quantitative analysis of HBV infectivity to several human hepatocyte cell lines as well as the effect of dimethyl sulfoxide and HBV protein X on the early stage of HBV proliferation using this system. Furthermore, we developed a system to produce a reporter HBV expressing a pol gene. These reporter HBV may provide an opportunity to enhance our understanding of the HBV life cycle and aid strategies for the development of new anti-HBV agents. PMID- 29121424 TI - Numerical time-domain modelling of hoof-ground interaction during the stance phase. AB - BACKGROUND: Hoof-ground interaction impacts on the health and performance characteristics of horses. Due to complex interactions between hoof and ground during the stance phase, previous experimentally dominated studies concentrated on subproblems of the phenomena observed. A multidisciplinary methodology with mathematical modelling, material testing and in vivo experimental measurements seems promising. OBJECTIVES: With the help of a mathematical approach, this contribution aims to explain from a biomechanical point of view the phenomena observed during experimental investigations (hoof acceleration, interacting forces) and aims to contribute to an overall experimental-mathematical multidisciplinary approach. STUDY DESIGN: In silico modelling of hoof-ground interaction (limb, hoof and horizontally unbounded ground). METHODS: Hoof-ground interaction is represented by a time-domain finite element model including the limb, the hoof and the unbounded representation of the ground via the scaled boundary finite element method to capture radiation damping during the stance phase. Motoric forces (driving forces) of the horse during locomotion are included. RESULTS: Numerical model results for acceleration-time relations (hoof) at different trotting velocities are compared with previously published acceleration-time relations and show qualitative agreement. From the model approach, power loss due to different ground properties and ground damping is computed in combination with the maximum limb force during the stance phase. MAIN LIMITATIONS: Intentionally, a simplified model approach for the material and structural representation of the limb, the hoof and the ground in terms of material features and spatial resolution has been used for this study, which might be the basis for a model refinement in terms of contact properties as well as the integration of bone and joint structures. CONCLUSIONS: The comparison to experimentally obtained results demonstrates the applicability of the model, which, in turn, enables an insight into the processes taking place during hoof ground interaction. PMID- 29121425 TI - Phosphorescence Tuning through Heavy Atom Placement in Unsymmetrical Difluoroboron beta-Diketonate Materials. AB - Difluoroboron beta-diketonates (BF2 bdks) show both fluorescence (F) and room temperature phosphorescence (RTP) when confined to a rigid matrix, such as poly(lactic acid). These materials have been utilized as optical oxygen sensors (e.g., in tumors, wounds, and cells). Spectral features include charge transfer (CT) from the major aromatic donor to the dioxaborine acceptor. A series of naphthyl-phenyl dyes (BF2 nbm) (1-6) were prepared to test heavy-atom placement effects. The BF2 nbm dye (1) was substituted with Br on naphthyl (2), phenyl (3), or both rings (4) to tailor the fluorescence/phosphorescence ratio and RTP lifetime-important features for designing O2 sensing dyes by means of the heavy atom effect. Computational studies identify the naphthyl ring as the major donor. Thus, Br substitution on the naphthyl ring produced greater effects on the optical properties, such as increased RTP intensity and decreased RTP lifetime compared to phenyl substitution. However, for electron-donating piperidyl-phenyl dyes (5), the phenyl aromatic is the major donor. As a result, Br substitution on the naphthyl ring (6) did not alter the optical properties significantly. Experimental data and computational modeling show the importance of Br position. The S1 and T1 states are described by two singly occupied MOs (SOMOs). When both of these SOMOs have substantial amplitude on the heavy atom, passage from S1 to T1 and emission from T1 to S0 are both favored. This shortens the excited-state lifetimes and enhances phosphorescence. PMID- 29121426 TI - Xanthohumol inhibits angiogenesis by suppressing nuclear factor-kappaB activation in pancreatic cancer. AB - Xantohumol, a prenylated chalcone from hops (Humulus lupulus L.), has been shown to inhibit proliferation in some cancers. However, little is known regarding the effects of xanthohumol in pancreatic cancer. We have previously reported that activation of the transcription factor nuclear factor-kappaB (NF-kappaB) plays a key role in angiogenesis in pancreatic cancer. In this study, we investigated whether xanthohumol inhibited angiogenesis by blocking NF-kappaB activation in pancreatic cancer in vitro and in vivo. We initially confirmed that xanthohumol significantly inhibited proliferation and NF-kappaB activation in pancreatic cancer cell lines. Next, we demonstrated that xanthohumol significantly suppressed the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) at both the mRNA and protein levels in pancreatic cancer cell lines. We also found that coculture with BxPC-3 cells significantly enhanced tube formation in human umbilical vein endothelial cells, and treatment with xanthohumol significantly blocked this effect. In vivo, the volume of BxPC-3 subcutaneous xenograft tumors was significantly reduced in mice treated with weekly intraperitoneal injections of xanthohumol. Immunohistochemistry revealed that xanthohumol inhibited Ki-67 expression, CD31-positive microvessel density, NF-kappaB p65 expression, and VEGF and IL-8 levels. Taken together, these results showed, for the first time, that xanthohumol inhibited angiogenesis by suppressing NF-kappaB activity in pancreatic cancer. Accordingly, xanthohumol may represent a novel therapeutic agent for the management of pancreatic cancer. PMID- 29121428 TI - Efficacy of medroxyprogesterone acetate treatment and retreatment for atypical endometrial hyperplasia and endometrial cancer. AB - AIM: Medroxyprogesterone acetate (MPA) is used to preserve fertility in patients with Grade 1 endometrial cancer without myometrial invasion (G1EA) and those with atypical endometrial hyperplasia (AEH). However, the efficacy of retreatment with MPA has not been sufficiently established for patients who experience recurrence but wish to retain their fertility. This study aimed to show the effectiveness of MPA treatment and retreatment for AEH and G1EA. METHODS: A total of 39 patients received MPA treatment between 2005 and 2015, including nine with G1EA and 30 with AEH. The patients received high-dose (600 mg/day) MPA for 26 weeks. If a complete response was not achieved, MPA treatment was continued. After complete remission, if there was a recurrence, the patient was offered a choice of a hysterectomy or retreatment with MPA. The gynecologic and obstetric outcomes were retrospectively analyzed. RESULTS: The median age was 34 years, and the median body mass index was 23.3 kg/m2 . The median follow-up period was 52 months. Complete response rates for the initial treatment were 89% for G1EA and 93% for AEH. Recurrence occurred in 88% of patients with G1EA (7/8) and 50% of those with AEH (14/28). Seven patients with G1EA and 11 with AEH received MPA retreatment, and 100% and 92% of these achieved a complete response. During the study period, a total of 14 pregnancies were recorded with 10 live births. CONCLUSION: MPA can be effective for G1EA and AEH treatment even when they recur. PMID- 29121427 TI - Long-term survival with bevacizumab in heavily pretreated and platinum-resistant mucinous ovarian cancer: A case report. AB - The prognosis of patients with recurrent and platinum-resistant ovarian cancer is quite poor. Randomized trials have shown that bevacizumab (BEV) can be effective, even in platinum-resistant ovarian cancer, but only a few such cases of long-term survival with BEV have been reported. Furthermore, there is no consensus on how many cycles of BEV should be administered. Herein, we report a case of refractory mucinous ovarian cancer showing long-term survival after six cycles of weekly paclitaxel with BEV followed by 26 cycles of BEV maintenance. Although six prior chemotherapy regimens resulted in progressive disease, the BEV treatment controlled the patient's ascites and improved her performance status. For a further 30 months and 32 cycles of BEV, neither progression of the disease nor severe adverse events have been observed. Our case demonstrates that BEV administration could result in a favorable outcome in heavily pretreated and platinum-resistant ovarian cancer patients. PMID- 29121429 TI - Reproductive health decision-making among US-dwelling Somali Bantu refugee women: A qualitative study. AB - AIMS AND OBJECTIVES: To explore Somali Bantu refugee women's reproductive health decision-making, as influenced by their resettlement in the USA. BACKGROUND: Available literature on reproductive health of refugee women is mostly from the healthcare provider perspective, neglecting the lived experience of the population. DESIGN: Qualitative descriptive. METHODS: A purposive sample of 30 women was recruited for five focus groups. Data were collected via demographic survey and semi-structured focus group discussion. Content analysis was used to analyse the data. RESULTS: Our study revealed that Somali Bantu women considered children as wealth. Reproductive health decision-making was influenced by three main factors: family influence, cultural/religious ideas and experience with various hormonal birth control methods. CONCLUSIONS: Nurses and other healthcare providers would better serve refugee women if equipped with a more nuanced understanding of factors in their reproductive healthcare decision-making. This study can inform tailored and cultural relevant interventions to improve reproductive health among those at greatest need. RELEVANCE TO CLINICAL PRACTICE: Our findings can serve to guide nurses and other healthcare providers' clinical approach to a subset of the population whose cultural beliefs and practices regarding reproductive health may be unfamiliar. Incorporating the perspective of the Somali Bantu women will facilitate the provision of person-centred care and ensure women receive appropriate, efficient and quality care that meets their needs, which may potentially reduce financial costs to the healthcare system. PMID- 29121430 TI - The journey of adult psoriasis patients towards biologics: past and present - Results from the BioCAPTURE registry. AB - BACKGROUND: A considerable disease period often precedes initiation of a biologic in patients with psoriasis. Little is known about this important period in patients' lives. Evaluation of this 'journey' can reveal important insights and opportunities for physicians and healthcare decision makers. OBJECTIVES: (i) To describe patient and treatment characteristics until the start of biologic treatment in patients with severe psoriasis, (ii) to assess shifts in early (2005 2009) versus established (2010-2015) biologics prescription periods, (iii) to assess changes in hospital/day care admissions before vs. after starting biologics. METHODS: Explorative, retrospective study on the treatment characteristics of the disease period until first biologic, presented with descriptive statistics of patients included in the BioCAPTURE registry. Journeys of 2005-2009 and 2010-2015 were compared with statistical tests to identify important shifts. RESULTS: Median TUS (time until conventional systemic) was 11.0 years and median TUB (time until biologic) was 18.9 years for all patients treated from 2005 to 2015. Most patients received three different conventional antipsoriatic systemic therapies. We noticed a small trend towards a shorter journey (TUB) with only two conventional systemic agents instead of three before initiating a biologic in later years (2010-2015, vs. 2005-2009). We also noticed a significant decrease in (day care) admissions comparing the two years before, versus the first two years after the start of a biologic treatment (17.7 vs. 8.6 admissions/100 follow-up years, P < 0.001). Cyclosporine, intensive topical treatment (dithranol), retinoids and PUVA therapy lost popularity in recent years. CONCLUSION: The 'journey' of patients with psoriasis towards a biologic is still long and characterized by many different treatments. Shifts towards fewer conventional drugs before biologic initiation and a clear decrease in hospital and day care admissions before vs. after a biologic are seen. Improvement of this journey, especially in young or recently diagnosed patients, can decrease negative influences on patients' lives and reduce societal impact. PMID- 29121431 TI - Outcomes of oral lichen planus and oral lichenoid lesions treated with topical corticosteroid. AB - OBJECTIVE: To determine corticosteroid treatment effectiveness in patients with oral lichen planus/oral lichenoid lesions (OLP/OLL). MATERIAL AND METHODS: Twenty one patients with OLP and eighty-one patients with OLL received 0.05% clobetasol propionate (CP) or 0.05% triamcinolone acetonide (TA) in aqueous solution (AS) or orabase (OB), evaluating responses to treatment and follow-up compliance. RESULTS: Lesions were atrophic (72 of 102; 70.6%), extensive (58 of 100; 58%), producing eating difficulties (62 of 102; 60.8%), and spontaneous pain (30 of 102; 29.4%); 50 patients (49%) received CP-AS. The mean +/- SD percentage of follow-ups attended was 43 +/- 32%. Symptom remission was achieved in 46% of patients receiving CP-AS, 36.36% of those receiving TA-AS, 20% of those receiving CP-OB, and 25% of those receiving TA-OB. Follow-up compliance was poor in 66.7% of patients. Among 51 patients with continuous symptoms, 64.7% evidenced total remission at treatment completion; among 33 with intermittent symptoms, 73.1% had outbreaks 2-3 times/year and 51.5% controlled outbreaks with <6 corticosteroid applications. Adverse effects were observed in seven patients (6.8%) (moon face, hirsutism, capillary fragility) in induction stage, subsiding with dose; among 15 patients under maintenance treatment for >6 months, one showed hypothalamic pituitary-adrenal (HPA) axis inhibition but not adrenal insufficiency. CONCLUSIONS: Our treatment proved highly effective and safe. Recall programs are desirable to enhance follow-up compliance. PMID- 29121432 TI - Effectiveness of alpine climate treatment for children with difficult to treat atopic dermatitis: Results of a pragmatic randomized controlled trial (DAVOS trial). AB - BACKGROUND: Alpine climate treatment has historically been used in Europe to treat atopic dermatitis (AD), but no randomized trials have been conducted to provide evidence for its effectiveness. OBJECTIVE: To investigate the long-term effectiveness of alpine climate treatment for children with difficult to treat AD. MATERIALS & METHODS: A pragmatic, open, randomized controlled trial was conducted. Children diagnosed with AD that was considered difficult to treat, aged between 8 and 18 years and willing to be treated in Switzerland were randomized to a six-week personalized integrative multidisciplinary treatment period in a clinical setting in the alpine climate (Switzerland) or an outpatient setting in moderate maritime climate (Netherlands). Study assessments were conducted at the Wilhelmina Children's Hospital; an electronic portal was used for the collection of questionnaire data. Primary outcomes were disease activity (SAEASI), quality of life (CDLQI) and catastrophizing thoughts (JUCKKI/JU) 6 months after intervention. Other assessments were immediately and 6 weeks after intervention. Subgroup analyses concerned asthma-related outcomes. Children were randomly assigned to either the intervention or control group using a covariate adaptive randomization method, taking age and asthma diagnosis into account. Children, parents and healthcare professionals involved in treatment were not blinded to group assignment. Data were analysed according to intention-to-treat with linear mixed-effects models for continuous outcomes. The trial is registered at Current Controlled Trials ISCRTN88136485. RESULTS: Between 14 September 2010 and 30 September 2014, 88 children were enrolled in the trial, 84 children were randomized (41 assigned to intervention, 43 to control) of whom 77 completed the intervention (38 of 41 (93%) intervention, 39 of 43 (91%) control) and 74 completed follow-up (38 of 41 (93%) intervention, 36 of 43 (84%) control). Six months after intervention there were no significant differences between the groups on disease activity (SAEASI mean difference -3.4 (95%CI -8.5 to 1.7)), quality of life (CDLQI mean difference -0.3 (95%CI -2.0 to 1.4)) and catastrophizing thoughts (JUCCKI/JU subscale mean difference -0.7 (95%CI -1.4 to 0.0)). Immediately and 6 weeks after intervention, disease activity and quality of life were significantly different in favour of alpine climate treatment. Mean differences on SAEASI were -10.1 (95%CI -14.5 to -5.8) and -8.4 (95%CI -12.2 to 4.6) and on CDLQI -1.9 (95%CI -3.3 to -0.5) and -1.5 (95%CI -2.8 to -0.3) immediately and 6 weeks after the intervention, respectively. There were no long term differences on asthma-related outcomes. Five serious adverse events occurred during the study period, which were not thought to be related to the treatment. CONCLUSIONS & CLINICAL RELEVANCE: For children with difficult to treat AD, there was no additional long-term benefit of alpine climate treatment, in contrast to the short-term, compared to an outpatient treatment programme in moderate maritime climate, using a personalized integrative multidisciplinary treatment approach. PMID- 29121433 TI - Structural arrangement of vesicouterine fistula revisited: An immunohistochemical study documenting the presence of the endometrium. AB - Previous research has described a woman of reproductive age who presented with a vesicouterine fistula (VUF) of 20 months' duration. The VUF was lined with a metaplastic glandular epithelium containing both estrogen receptors (ER) and progesterone receptors (PR) in abundance. The aim of the present investigation was to evaluate the histology of the VUF canal when exposure to urine of the cellular elements within the fistula was of much shorter duration. A 41-year-old woman who developed a VUF during her third cesarean section was treated with transvesical fistula excision, electrocoagulation, and subsequent attempted hormonal treatment. Later, the patient underwent open surgery fistula repair. Postoperative specimens were subjected to anatomopathological examination together with immunohistochemical staining for ER and PR using monoclonal anti human antibodies. Herein, we present for the first time detailed microscopic evidence that, at two separate timepoints, the fistulous tract was lined with the endometrium, which covered approximately 80% of the length of the VUF canal. In its intermediate segment, the urothelium formed an additional layer on the surface of the endometrium. At both timepoints, in the columnar epithelial and stromal endometrial cells lining the fistula, both ER and PR were present in abundance. In conclusion, VUF in subjects of reproductive age fulfill criteria for endometriosis. This study provides a rationale for the conservative treatment of VUF consistent with the hormonal treatment of endometriosis. PMID- 29121434 TI - Spontaneous post-partum rupture of bilateral ovarian arteries treated with transarterial embolization. AB - Rupture of an ovarian artery aneurysm in the peripartum period occurs in both traumatic and atraumatic settings. To our knowledge, this is the first reported case of spontaneous atraumatic rupture of the bilateral ovarian arteries. This report describes a multiparous recently post-partum patient with abdominal pain and signs of hemodynamic compromise, the sequela of hemoperitoneum from ruptured bilateral ovarian arteries. With a multidisciplinary approach, this patient was successfully treated with transarterial embolization. PMID- 29121435 TI - Altered intracellular signaling by imatinib increases the anti-cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells. AB - Tyrosine kinase inhibitors (TKI), including imatinib (IM), improve the outcome of CML therapy. However, TKI treatment is long-term and can induce resistance to TKI, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome-positive CML cell line, and its subsequent sensitivity to anti-cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKI. Cancer energy metabolism, characterized by abnormal glycolysis, is linked to cancer cell survival. Interestingly, glycolytic activity was suppressed by continuous exposure to IM, and autophagy increased to maintain cell viability by compensating for glycolytic suppression. Notably, increased sensitivity to TKI was not caused by glycolytic inhibition but by altered intracellular signaling, causing glycolytic suppression and increased autophagy, as evidenced by suppression of p70 S6 kinase 1 (S6K1) and activation of AMP-activated protein kinase (AMPK). Using another human CML cell line (KCL22 cells) and BCR/ABL+ Ba/F3 cells (mimicking Philadelphia chromosome-positive CML cells) confirmed that suppressing S6K1 and activating AMPK increased sensitivity to TKI. Furthermore, suppressing S6K1 and activating AMPK had a synergistic anti-cancer effect by inhibiting autophagy in the presence of TKI. The present study provides new insight into the importance of signaling pathways that affect cellular energy metabolism, and suggests that co-treatment with agents that disrupt energy metabolic signaling (using S6K1 suppressors and AMPK activators) plus blockade of autophagy may be strategies for TKI-based CML therapy. PMID- 29121436 TI - Association of dental and maxillary sinus pathologies with ear, nose, and throat symptoms. AB - OBJECTIVES: To investigate the correlation between cone-beam computerized tomography (CBCT) findings in the maxillary sinus, ear-nose-throat (ENT) symptoms and dental pathologies in asymptomatic patients. MATERIALS AND METHODS: A total 81 patients were referred for CBCT and filled a standard ENT visual analog scale (VAS) questionnaire. CBCT images were analyzed for sinus ostium obstruction, Schneiderian membrane thickening, sinus floor turbidity, and the presence of polyps. Dental pathologies were evaluated with the aid of CBCT images, periapical X-rays, and clinical examination. A possible correlation between the CBCT findings and the ENT/dental parameters was examined by applying Student's t test and the chi-squared test. RESULTS: Despite being asymptomatic, most of the 81 patients reported ENT symptoms in the questionnaire, thereby indicating that these symptoms were mainly subclinical. A significant correlation was found between the presence of polyps in the sinus and a decrease in smell/taste. Obstruction of the sinus meatus was associated with coughing; turbidity was associated with ear congestion. Thickening of the Schneiderian membrane showed an association with both coughing and ear congestion. The mean number of missing posterior teeth correlated with postnasal drip and nasal congestion. Periapical pathology was associated with nasal discharge/runny nose. CONCLUSION: The results emphasize the need to evaluate ENT symptoms when radiographic findings are identified in CBCT. PMID- 29121437 TI - A novel PITX2 mutation in non-syndromic orodental anomalies. AB - OBJECTIVE: To identify orodental characteristics and genetic aetiology of a family affected with non-syndromic orodental anomalies. SUBJECTS AND METHODS: Physical and oral features were characterised. DNA was collected from an affected Thai family. Whole-exome sequencing was employed to identify the pathogenic variants associated with inherited orodental anomalies. The presence of the identified mutation was confirmed by Sanger sequencing. RESULTS: We observed unique orodental manifestations including oligodontia, retained primary teeth, taurodont molars, peg-shaped maxillary central incisors, high attached frenum with nodule and midline diastema in the proband and her mother. Mutation analyses revealed a novel heterozygous frameshift deletion, c.573_574delCA, p.L193QfsX5, in exon 5 of PITX2A in affected family members. The amino acid alterations, localised in the transcriptional activation domain 2 in the C-terminus of PITX2, were evolutionarily conserved. Mutations in PITX2 have been associated with autosomal-dominant Axenfeld-Rieger syndrome and non-syndromic eye abnormalities, but never been found to cause isolated oral anomalies. CONCLUSIONS: This study for the first time demonstrates that the PITX2 mutation could lead to non syndromic orodental anomalies in humans. We propose that the specific location in the C-terminal domain of PITX2 is exclusively necessary for tooth development. PMID- 29121438 TI - Platelet rescue by macrophage depletion in obese ADAMTS-13-deficient mice at risk of thrombotic thrombocytopenic purpura. AB - : Essentials Obesity is a potential risk factor for development of thrombotic thrombocytopenic purpura (TTP). Obese ADAMTS-13-deficient mice were triggered with von Willebrand factor (VWF). Depletion of hepatic and splenic macrophages protects against thrombocytopenia in this model. VWF enhances phagocytosis of platelets by macrophages, dose-dependently. SUMMARY: Background Thrombotic thrombocytopenic purpura (TTP) is caused by the absence of ADAMTS-13 activity. Thrombocytopenia is presumably related to the formation of microthrombi rich in von Willebrand factor (VWF) and platelets. Obesity may be a risk factor for TTP; it is associated with abundance of macrophages that may phagocytose platelets. Objectives To evaluate the role of obesity and ADAMTS-13 deficiency in TTP, and to establish whether macrophages contribute to thrombocytopenia. Methods Lean or obese ADAMTS-13-deficient (Adamts-13-/- ) and wild-type (WT) mice were injected with 250 U kg-1 of recombinant human VWF (rVWF), and TTP characteristics were evaluated 24 h later. In separate experiments, macrophages were depleted in the liver and spleen of lean and obese WT or Adamts-13-/- mice by injection of clodronate-liposomes, 48 h before injection of rVWF. Results Obese Adamts-13-/- mice had a lower platelet count than their lean counterparts, suggesting that they might be more susceptible to TTP development. Lean Adamts-13-/- mice triggered with a threshold dose of rVWF did not develop TTP, whereas typical TTP symptoms developed in obese Adamts-13-/- mice, including severe thrombocytopenia and higher lactate dehydrogenase (LDH) levels. Removal of hepatic and splenic macrophages by clodronate injection in obese Adamts-13-/- mice before treatment with rVWF preserved the platelet counts measured 24 h after the trigger. In vitro experiments with cultured macrophages confirmed a VWF dose-dependent increase of platelet phagocytosis. Conclusions Obese Adamts-13-/- mice are more susceptible to the induction of TTP-related thrombocytopenia than lean mice. Phagocytosis of platelets by macrophages contributes to thrombocytopenia after rVWF injection in this model. PMID- 29121439 TI - Beyond Solar Fuels: Renewable Energy-Driven Chemistry. AB - The future feasibility of decarbonized industrial chemical production based on the substitution of fossil feedstocks (FFs) with renewable energy (RE) sources is discussed. Indeed, the use of FFs as an energy source has the greatest impact on the greenhouse gas emissions of chemical production. This future scenario is indicated as "solar-driven" or "RE-driven" chemistry. Its possible implementation requires to go beyond the concept of solar fuels, in particular to address two key aspects: i) the use of RE-driven processes for the production of base raw materials, such as olefins, methanol, and ammonia, and ii) the development of novel RE-driven routes that simultaneously realize process and energy intensification, particularly in the direction of a significant reduction of the number of the process steps. PMID- 29121440 TI - D-tyrosine negatively regulates melanin synthesis by competitively inhibiting tyrosinase activity. AB - Although L-tyrosine is well known for its melanogenic effect, the contribution of D-tyrosine to melanin synthesis was previously unexplored. Here, we reveal that, unlike L-tyrosine, D-tyrosine dose-dependently reduced the melanin contents of human MNT-1 melanoma cells and primary human melanocytes. In addition, 500 MUM of D-tyrosine completely inhibited 10 MUM L-tyrosine-induced melanogenesis, and both in vitro assays and L-DOPA staining MNT-1 cells showed that tyrosinase activity is reduced by D-tyrosine treatment. Thus, D-tyrosine appears to inhibit L tyrosine-mediated melanogenesis by competitively inhibiting tyrosinase activity. Furthermore, we found that D-tyrosine inhibited melanogenesis induced by alpha MSH treatment or UV irradiation, which are the most common environmental factors responsible for melanin synthesis. Finally, we confirmed that D-tyrosine reduced melanin synthesis in the epidermal basal layer of a 3D human skin model. Taken together, these data suggest that D-tyrosine negatively regulates melanin synthesis by inhibiting tyrosinase activity in melanocyte-derived cells. PMID- 29121441 TI - Influence on jitter measurement of components from distant fibres in potential recorded by single-fibre electrode. PMID- 29121442 TI - Enteric Infections in Young Children are Associated with Environmental Enteropathy and Impaired Growth. AB - OBJECTIVE: To investigate the relationship between faecal contamination in child play spaces, enteric infections, environmental enteropathy (EE) and impaired growth among young children. METHODS: A prospective cohort study was conducted of 203 children 6-30 months of age in rural Bangladesh. Stool samples were analysed by quantitative PCR for Shigella, Enterotoxigenic Escherichia coli (ETEC), Campylobacter jejuni, Giardia intestinalis and Cryptosporidium spp. Four faecal markers of intestinal inflammation were also measured: alpha-1-antitrypsin, myeloperoxidase, neopterin and calprotectin. Child growth was measured at baseline and 9 months after enrolment. E. coli was measured in soil in child play spaces. RESULTS: Forty-seven percent of study children had three or more enteric pathogens in their stool. Thirty five percent (71/203) of children had Shigella, 30% (61/203) had ETEC, 73% (148/203) had C. jejuni, 79% (160/203) had Giardia intestinalis and none had Cryptosporidium. Children with ETEC had significantly higher calprotectin concentrations (Coefficient: 1.35, 95% Confidence Interval [CI]: 1.005, 1.82). Children with Shigella had a significantly higher odds of being stunted at our 9-month follow-up (OR: 2.01, 95% CI: 1.02, 3.93). Children with Giardia intestinalis had significantly higher E.coli counts in the soil collected from their play spaces (OR: 1.23, 95% CI: 1.02, 1.48). CONCLUSION: Enteric infections were significantly associated with EE and impaired growth in rural Bangladesh. These findings provide further evidence to support the hypothesis that contaminated soil in child play spaces can lead to enteric infections, many of which are likely subclinical, resulting in EE and impaired growth in young children. PMID- 29121443 TI - Can Escherichia coli fly? The role of flies as transmitters of E. coli to food in an urban slum in Bangladesh. AB - OBJECTIVE: To investigate the transmission of faecal bacteria by flies to food under natural settings. METHODS: Over a period of 2 months, paired (exposed and non-exposed) containers with cooked rice were placed on the ground in kitchen areas in an urban slum area in Dhaka, Bangladesh, and the numbers of flies landing on the exposed rice were counted. Following exposure, the surface of the rice was microbiologically and molecularly analysed for the presence of Escherichia coli and genes of diarrhoeagenic E. coli and Shigella strains. RESULTS: Rice was at greater risk (P < 0.001) of being contaminated with E. coli if flies landed on the rice than if no flies landed on the rice (odds ratio 5.4 (P < 0.001, 95% CI: 2.5-11.7). Mean contamination in exposed rice samples (n = 60) was 3.1 * 103 CFU/g (95% CI: 2.2 * 103-4.0 * 103). Furthermore, for approximately half of the observed fly landings, the average CFU per fly landing was >0.6 * 103 CFU. Genes of diarrhoeagenic E. coli and Shigella species were detected in 39 of 60 (65%) of exposed rice samples. Two fly species were identified: the common housefly (Musca domestica) and the oriental latrine fly (Chrysomya megacephala). CONCLUSION: Flies may transmit large quantities of E. coli to food under field settings. The findings highlight the importance of implementing control measures to minimise exposure of food to flies to ensure food safety. Fly control measures should be considered for the prevention of diarrhoeal diseases caused by E. coli. PMID- 29121444 TI - Neurocognitive functioning, clinical course and functional outcome in first treatment bipolar I disorder patients with and without clinical relapse: A 1-year follow-up study. AB - OBJECTIVES: Due to limited research on the association between recurrence of mood episodes and the longitudinal course of neurocognitive functioning in early phase bipolar I disorder (BD I), the impact of recurrence on neurocognition remains unclear. Further, a strong correlation between neurocognitive impairment and functional impairment has been demonstrated. The longitudinal relationship between neurocognitive impairment and functional outcome in relation to recurrence is, however, not established. METHODS: The current study investigated the longitudinal relationship between neurocognition, recurrence of mood episodes and functional outcome in a sample of first-treatment (FT) BD I patients (N = 42), with and without relapse, during a 1-year follow-up period. The longitudinal course of neurocognitive functioning in the patients was also compared to that of a group of healthy controls (N = 143). RESULTS: Compared to both patients with relapse and healthy controls, no-relapse patients showed neurocognitive improvements. The polarity of the relapse episodes was mostly depressive, and for the no-relapse patients, reduction of symptoms was associated with neurocognitive improvement. No-relapse patients showed better global and occupational functioning. CONCLUSIONS: The current study found different neurocognitive and functional trajectories in FT BD I patients with and without relapse, with differences at follow-up to some degree being mediated by current symptoms. The current findings highlight the importance of treatment focusing on neurocognition and symptom states with the aim of improving functional recovery. PMID- 29121445 TI - Viraemia before, during and after pregnancy in HIV-infected women on antiretroviral therapy in rural KwaZulu-Natal, South Africa, 2010-2015. AB - OBJECTIVES: Pregnancy and post-partum viral load suppression is critical to prevent mother-to-child HIV transmission and ensure maternal health. We measured viraemia risk before, during and after pregnancy in HIV-infected women. METHODS: Between 2010 and 2015, 1425 HIV-infected pregnant women on lifelong antiretroviral therapy (ART) for at least six months pre-pregnancy were enrolled in a cohort study in rural KwaZulu-Natal, South Africa. Odds ratios were estimated in multilevel logistic regression, with pregnancy period time-varying. RESULTS: Over half of 1425 women received tenofovir-based regimens (n = 791). Median pre-pregnancy ART duration was 2.1 years. Of 988 women (69.3%) with pre pregnancy viral loads, 82.0%, 6.8% and 11.2% had VL <50, 50-999 and >=1000 copies/ml, respectively. During pregnancy and at six, 12 and 24 months, viral load was >=1000 copies/ml in 15.2%, 15.7%, 17.8% and 16.6% respectively; viral load <50 was 76.9%, 77%, 75.5% and 75.8%, respectively. Adjusting for age, clinical and pregnancy factors, viraemia risk (viral load >=50 copies/ml) was not significantly associated with pregnancy [adjusted OR (aOR) 1.31; 95% CI 0.90 1.92], six months (aOR 1.30; 95% CI 0.83-2.04), 12 months (aOR 0.96; 95% CI 0.58 1.58) and 24 months (aOR 1.40; 95% CI 0.89-2.22) post-partum. Adjusting for ART duration-pregnancy period interaction, viraemia risk was 1.8 during pregnancy and twofold higher post-partum. CONCLUSIONS: While undetectable viral load before pregnancy through post-partum was common, the UNAIDS goal to suppress viraemia in 90% of women was not met. Women on preconception ART remain vulnerable to viraemia; additional support is required to prevent mother-to-child HIV transmission and maintain maternal health. PMID- 29121446 TI - VBP1 represses cancer metastasis by enhancing HIF-1alpha degradation induced by pVHL. AB - von Hippel-Lindau-binding protein 1 (VBP1) physically interacts with pVHL, an E3 ubiquitin ligase, which degrades HIF-1alpha in an oxygen-dependent manner. HIF-1 is a key regulator of adaptive responses to a lack of oxygen that controls glucose metabolism, angiogenesis, proliferation, invasion, and metastasis. However, the role of VBP1 in pVHL-mediated degradation of HIF-1alpha is not yet known. In this study, we show that VBP1 enhances the stability of pVHL and facilitates pVHL-mediated ubiquitination of HIF-1alpha. Furthermore, VBP1 suppresses HIF-1alpha-induced epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. These findings suggest that VBP1 is a bona fide tumor suppressor protein associated with HIF-1alpha regulation. PMID- 29121447 TI - In Vitro, In Silico Elucidation of Antiurease Activity, Kinetic Mechanism and COX 2 Inhibitory Efficacy of Coagulansin A of Withania coagulans. AB - Urease enzyme plays a crucial role in the survival of Helicobacter pylori that contributes to different diseases, including peptic ulcer (gastric and duodenal ulcers). Coagulansin A is the steroidal lactone (withanolide) found in plants of solanaceae family such Withania coagulans. The current study was carried out to examine the in vitro urease, COX-2 inhibitory activity and effect on type II collagen expression of coagulansin A. Moreover, we investigated cytotoxic effects on rabbit articular chondrocytes through MTT assay. COX-2 and type II collagen expressions were determined through a Western blot method. Molecular docking and simulation studies of urease (PDBID 4H9M) and COX-2 (PDBID 5F1A) proteins were also performed as an in silico approach. Results showed that COX-2 expression was decreased dose dependably, significantly higher expression of type II collagen was observed at higher doses. In the current study, coagulansin A was found as non-toxic, and showed notable urease inhibitory activity in non-competitive manner with IC50 23.14 MUm in comparison to reference drug thiourea 17.81 MUm. Significant decrease in COX-2 expression (40%) and increase in type II collagen (20%) were observed as compared to control. In silico results unveiled the strong binding affinities of coagulansin A with both of these urease and COX-2 proteins. Therefore, herein we proposed the significant antiurease potential of this compound that could be used in treating different diseases such as ulcers. Moreover, detailed in vivo studies and molecular mechanism based studies are suggested. PMID- 29121448 TI - Malaria exacerbates inflammation-associated elevation in ferritin and soluble transferrin receptor with only modest effects on iron deficiency and iron deficiency anaemia among rural Zambian children. AB - OBJECTIVE: In 4- to 8-year-old Zambian children (n = 744), we evaluated the effects of adjusting for inflammation (alpha1-acid glycoprotein >1 g/l), with or without additional adjustment for malaria, on prevalence estimates of iron deficiency (ID) and iron deficiency anaemia (IDA) during low malaria (LowM) and high malaria (HighM) transmission seasons. METHODS: To estimate adjustment factors, children were classified as: (i) reference (malaria negative without inflammation), (ii) inflammation without malaria (I), (iii) malaria without inflammation (M) and (iv) inflammation with malaria (IM). We estimated the unadjusted ID or IDA prevalence, and then adjusted for inflammation alone (IDI or IDAI ) or inflammation and malaria (IDIM or IDAIM ). RESULTS: Mean ferritin was 38 (reference), 45 (I), 43 (M) and 54 MUg/l (IM) in LowM, increasing to 44, 56, 96 and 167 MUg/l, respectively, in HighM. Corresponding mean sTfR was 6.4, 6.9, 7.9 and 8.4 mg/l in LowM, increasing to 8.2, 9.2. 8.7 and 9.7 mg/l in HighM. Ferritin-based ID, IDI and IDIM were 7.8%, 8.7% or 9.1%, respectively, in LowM and 4.6%, 10.0% or 11.7%, respectively, in HighM. Corresponding soluble transferrin receptor (sTfR)-based estimates were 27.0%, 24.1% and 19.1%, respectively, in LowM, increasing to 53.6%, 46.5% and 45.3%, respectively, in HighM. Additional adjustment for malaria resulted in a ~1- to 2-percentage point change in IDA, depending on biomarker and season. CONCLUSIONS: In this population, malaria substantially increased ferritin and sTfR concentrations, with modest effects on ID and IDA prevalence estimates. PMID- 29121449 TI - Effect of Solvents on the Behavior of Lithium and Superoxide Ions in Lithium Oxygen Battery Electrolytes. AB - The molecular life of intermediates, namely, O2- and Li+ , produced during the discharge of aprotic Li-O2 batteries was investigated by molecular dynamics simulation. This work is of potential interest in the development of new electrolytes for Li-air batteries. We present the results on the structure and stability of the Li+ and O2- solvation shells and the thermodynamics and kinetics of the ion-association reaction in solvents such as dimethyl sulfoxide (DMSO), dimethoxyethane (DME), and acetonitrile (ACN). The residence time of solvent molecules in the Li+ solvation shell increases with the solvent donor number and is 100 times larger in DMSO than in ACN. In DMSO and DME, the Li+ ion diffuses with its solvation shell as a whole. On the contrary, in ACN it diffuses as a "bare" ion because of weak solvation. The rate constant for the association of the lithium ion with the superoxide anion in DMSO is two orders of magnitude slower than that in ACN due to fact that the free-energy barrier is 2.5 times larger in DMSO than in ACN. In addition, we show that despite the strong dependence of the Li+ shell stability on donor number, the rate of association does not necessarily correlate with this solvent property. PMID- 29121450 TI - Urethral afferent signalling: role of 5-HT paraneurons. PMID- 29121451 TI - Metal Phosphides as Co-Catalysts for Photocatalytic and Photoelectrocatalytic Water Splitting. AB - Solar-to-hydrogen conversion based on photocatalytic and photoelectrocatalytic water splitting is considered as a promising technology for sustainable hydrogen production. Developing earth-abundant H2 -production materials with robust activity and stability has become the mainstream in this field. Due to the unique properties and characteristics, transition metal phosphides (TMPs) have been proven to be high performance co-catalysts to replace some of the classic precious metal materials in photocatalytic water splitting. In this Minireview, we summarize the recent significant progress of TMPs as cocatalysts for water splitting reaction with high activity and stability. Firstly, the characteristic of TMPs is briefly introduced. Then, we mainly discuss the recent research efforts toward their application as photocatalytic co-catalysts in photocatalytic H2 -production, O2 -evolution and photoelectrochemical water splitting. Finally, the catalytic mechanism, current existing challenges and future working directions for improving the performance of TMPs are proposed. PMID- 29121453 TI - Preventing Obstructions of Nanosized Drug Delivery Systems by the Extracellular Matrix. AB - Although nanosized drug delivery systems are promising tools for the treatment of severe diseases, the extracellular matrix (ECM) constitutes a major obstacle that endangers therapeutic success. Mobility of diffusing species is restricted not only by small pore size (down to as low as 3 nm) but also by electrostatic interactions with the network. This article evaluates commonly used in vitro models of ECM, analytical methods, and particle types with respect to their similarity to native conditions in the target tissue. In this cross-study evaluation, results from a wide variety of mobility studies are analyzed to discern general principles of particle-ECM interactions. For instance, cross linked networks and a negative network charge are essential to reliably recapitulate key features of the native ECM. Commonly used ECM mimics comprised of one or two components can lead to mobility calculations which have low fidelity to in vivo results. In addition, analytical methods must be tailored to the properties of both the matrix and the diffusing species to deliver accurate results. Finally, nanoparticles must be sufficiently small to penetrate the matrix pores (ideally Rd/p < 0.5; d = particle diameter, p = pore size) and carry a neutral surface charge to avoid obstructions. Larger (Rd/p >> 1) or positively charged particles are trapped. PMID- 29121454 TI - Editorial: The Innate and Adaptive Immune Response Are Both Involved in Drug Induced Autoimmunity. PMID- 29121452 TI - 3D Maskless Micropatterning for Regeneration of Highly Organized Tubular Tissues. AB - Micropatterning is a widely used powerful tool to create highly ordered microstructures on material surfaces. However, due to technical limitations, the integration of micropatterned microstructures into bioinspired 3D scaffolds to successfully regenerate well-organized functional tissues is not achieved. In this work, a unique maskless micropatterning technology is reported to create 3D nanofibrous matrices with highly organized tubular architecture for tissue regeneration. This micropatterning method is a laser-guided, noncontact, high precision, flexible computer programming of machining process that can create highly ordered tubules with the density ranged from 1000 to 60 000 mm-2 and the size varied from 300 nm to 30 um in the bioinspired 3D matrix. The tubular architecture presents pivotal biophysical cues to control dental pulp stem cell alignment, migration, polarization, and differentiation. More importantly, when using this 3D tubular hierarchical matrix as a scaffold, this study successfully regenerates functional tubular dentin that has the same well-organized microstructure as its natural counterpart. This 3D maskless micropattern approach represents a powerful avenue not only for the exploration of cell-material interactions in 3D, but also for the regeneration of functional tissues with well organized microstructures. PMID- 29121455 TI - Editorial: Bench to Bedside-and Back Again: Finding the Goldilocks Zone Within the Scleroderma Universe. PMID- 29121456 TI - Ruthenium Ion-Complexed Graphitic Carbon Nitride Nanosheets Supported on Reduced Graphene Oxide as High-Performance Catalysts for Electrochemical Hydrogen Evolution. AB - Carbon-based materials are promising, low-cost electrocatalysts toward hydrogen evolution reaction (HER), although the catalytic performance needs to be further improved before commercialization. In this study, ruthenium ions are incorporated into graphitic carbon nitride/reduced graphene oxide (rGO) hybrids to form Ru-C3 N4 /rGO composites through Ru-N coordination bonds. The incorporation of Ru ions, at a loading of 1.93 at. %, leads to electron redistribution within the materials and dramatically enhances the HER performance over those of C3 N4 , C3 N4 /rGO, and Ru-C3 N4 , with an overpotential of only -80 mV to reach a current density of 10 mA cm-2 , a Tafel slope of 55 mV dec-1 , and an exchange current density of 0.462 mA cm-2 . This performance is comparable to that of Pt/C, and ascribed to the positive shift of the conduction band of the composite, where the charge carrier density increases by a factor of about 250 over that of C3 N4 , leading to a lower energy barrier for hydrogen evolution. The results suggest a new strategy in the design and engineering of functional nanocomposites for effective HER electrocatalysis by embedding select metal ions into carbon-based molecular skeletons. PMID- 29121457 TI - Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation. AB - OBJECTIVE: Aberrant neutrophil extracellular trap (NET) formation has been implicated as a mechanism to induce autoreactivity in individuals at risk of autoimmune diseases. The objective of this study was to assess whether medications implicated in cases of drug-induced autoimmunity (hydralazine and procainamide) and medications less commonly associated with drug-induced autoimmunity (minocycline and clozapine) induce NET formation and/or prevent NET degradation. METHODS: Human neutrophils were incubated with the drugs of interest and resultant NET formation was quantified by fluorescent microscopy. The ability of these drugs to interfere with NET degradation by serum nuclei was assessed. Pathways of drug-induced NET formation were studied with pharmacologic inhibitors of reactive oxygen species (ROS), peptidylarginine deiminases (PADs), and muscarinic receptors, and by assessment of intracellular calcium levels by flow cytometry. To determine if NET protein cargo varies by drug stimulus and/or neutrophil source, proteomic analysis of NET lysates induced by specific medications was compared using neutrophils from healthy donors and from patients with autoimmune diseases. RESULTS: Hydralazine and procainamide significantly induced NET formation while minocycline and clozapine did not. None of the medications significantly impaired NET degradation. NETosis induced by these drugs required NADPH oxidase and PAD4 activation. Procainamide triggered NETs via muscarinic receptor engagement on neutrophils, while hydralazine modulated calcium release from intracellular stores. Differences in protein cargo, particularly histone content, were observed in NETs induced by hydralazine and procainamide. CONCLUSION: Medications commonly implicated in drug-induced autoimmunity trigger NET formation displaying distinct protein cargo, via common and specific pathways. NETosis may play a role in the pathogenesis of drug induced autoimmunity. PMID- 29121458 TI - Placental Drug Transport-on-a-Chip: A Microengineered In Vitro Model of Transporter-Mediated Drug Efflux in the Human Placental Barrier. AB - The current lack of knowledge about the effect of maternally administered drugs on the developing fetus is a major public health concern worldwide. The first critical step toward predicting the safety of medications in pregnancy is to screen drug compounds for their ability to cross the placenta. However, this type of preclinical study has been hampered by the limited capacity of existing in vitro and ex vivo models to mimic physiological drug transport across the maternal-fetal interface in the human placenta. Here the proof-of-principle for utilizing a microengineered model of the human placental barrier to simulate and investigate drug transfer from the maternal to the fetal circulation is demonstrated. Using the gestational diabetes drug glyburide as a model compound, it is shown that the microphysiological system is capable of reconstituting efflux transporter-mediated active transport function of the human placental barrier to limit fetal exposure to maternally administered drugs. The data provide evidence that the placenta-on-a-chip may serve as a new screening platform to enable more accurate prediction of drug transport in the human placenta. PMID- 29121459 TI - Extramural Perineural Invasion in pT3 and pT4 Gastric Carcinomas. AB - BACKGROUND: Perineural invasion (PNI) is widely studied in malignant tumors, and its prognostic significance is well demonstrated. Most studies have focused on evaluating the mural PNI (mPNI); however, extramural PNI (ePNI) may influence the prognosis in gastric cancer. We evaluated the prognostic value of ePNI compared with mPNI in gastric cancer in this observational comparative cross-sectional study. METHODS: Seventy-three pT3 and pT4 gastric carcinomas with PNI were evaluated. Forty-eight (65.7%) were in the mPNI group and the remaining in the ePNI group. RESULTS: Clinicopathologic characteristics between the two groups were similar, except for the outcomes. The 5-year disease-specific survival (DSS) rate was 64% for the mPNI group and 50% for the ePNI group (p=.039), a difference that did not remain significant in multivariate analysis. The only independent adverse prognostic factor in multivariate analysis was the presence of lymph node metastasis (hazard ratio, 1.757; 95% confidence interval, 1.082 to 2.854; p=.023). CONCLUSIONS: We demonstrated the prognostic effect of ePNI for DSS in surgically resected pT3-pT4 gastric cancer patients. ePNI could be considered in the staging and prognostic systems of gastric cancer to stratify patients with a high risk of recurrence. PMID- 29121460 TI - Diverse Class 2 CRISPR-Cas Effector Proteins for Genome Engineering Applications. AB - CRISPR-Cas genome editing technologies have revolutionized modern molecular biology by making targeted DNA edits simple and scalable. These technologies are developed by domesticating naturally occurring microbial adaptive immune systems that display wide diversity of functionality for targeted nucleic acid cleavage. Several CRISPR-Cas single effector enzymes have been characterized and engineered for use in mammalian cells. The unique properties of the single effector enzymes can make a critical difference in experimental use or targeting specificity. This review describes known single effector enzymes and discusses their use in genome engineering applications. PMID- 29121461 TI - Nanomagnetic System for Rapid Diagnosis of Acute Infection. AB - Pathogen-activated antibody-secreting cells (ASCs) produce and secrete antigen specific antibodies. ASCs are detectable in the peripheral blood as early as 3 days after antigen exposure, which makes ASCs a potential biomarker for early disease detection. Here, we present a magnetic capture and detection (MCD) assay for sensitive, on-site detection of ASCs. In this approach, ASCs are enriched through magnetic capture, and secreted antibodies are magnetically detected by a miniaturized nuclear magnetic resonance (MUNMR) system. This approach is based entirely on magnetics, which supports high contrast against biological background and simplifies assay procedures. We advanced the MCD system by (i) synthesizing magnetic nanoparticles with high magnetic moments for both cell capture and antibody detection, (ii) developing a miniaturized magnetic device for high-yield cell capture, and (iii) optimizing the MUNMR assay for antibody detection. Antibody responses targeting hemolysin E (HlyE) can accurately identify individuals with acute enteric fever. As a proof-of-concept, we applied MCD to detect antibodies produced by HlyE-specific hybridoma cells. The MCD achieved high sensitivity in detecting antibodies secreted from as few as 5 hybridoma cells (50 cells/mL). Importantly, the assay could be performed with whole blood with minimal sample processing. PMID- 29121462 TI - Design of Lubricant Infused Surfaces. AB - Lubricant infused surfaces (LIS) are a recently developed and promising approach to fluid repellency for applications in biology, microfluidics, thermal management, lab-on-a-chip, and beyond. The design of LIS has been explored in past work in terms of surface energies, which need to be determined empirically for each interface in a given system. Here, we developed an approach that predicts a priori whether an arbitrary combination of solid and lubricant will repel a given impinging fluid. This model was validated with experiments performed in our work as well as in literature and was subsequently used to develop a new framework for LIS with distinct design guidelines. Furthermore, insights gained from the model led to the experimental demonstration of LIS using uncoated high-surface-energy solids, thereby eliminating the need for unreliable low-surface-energy coatings and resulting in LIS repelling the lowest surface tension impinging fluid (butane, gamma ~ 13 mN/m) reported to date. PMID- 29121463 TI - Determining the Cytotoxicity of Rare Earth Element Nanoparticles in Macrophages and the Involvement of Membrane Damage. AB - Rare earthelement nanomaterials (REE NPs) hold considerable promise, with high availability and potential applications as superconductors, imaging agents, glass additives, fertilizers additives and feed additives. These results in potential REE NP exposure to humans and the environment through different routes and adverse effects induced by biological application of these materials are becoming an increasing concern. This study investigates the cytotoxicity of REE NPs: nLa2O3, nEu2O3, nDy2O3 and nYb2O3 from 2.5 to 80 MUg/mL, in macrophages. A significant difference was observed in the extent of cytotoxicity induced in macrophages by differential REE NPs. The high-atomic number materials (i.e., nYb2O3) tending to be no toxic whereas low-atomic number materials (nLa2O3 and nEu2O3 and nDy2O3) induced 75.1%, 53.6% and 20.7% dead cells. With nLa2O3 as the representative material, we demonstrated that nLa2O3 induced cellular membrane permeabilization, through the sequestration of phosphates from membrane. The further mechanistic investigation established that membrane damage induced intracellular calcium increased to 3.0- to 7.3-fold compared to control cells. This caused the sustained overload of mitochondrial calcium by approximately 2.4 fold, which regulated cell necrosis. In addition, the injury of cellular membrane led to the release of cathepsins into cytosol which also contributed to cell death. This detailed investigation of signaling pathways driving REE NP-induced toxicity to macrophages is essential for better understanding of their potential health risks to humans and the environment. PMID- 29121464 TI - The Experimental Measurement of Local and Bulk Oxygen Transport Resistances in the Catalyst Layer of Proton Exchange Membrane Fuel Cells. AB - Remarkable progress has been made in reducing the cathodic Pt loading of PEMFCs; however, a huge performance loss appears at high current densities, indicating the existence of a large oxygen transport resistance associated with the ultralow Pt loading catalyst layer. To reduce the Pt loading without sacrificing cell performance, it is essential to illuminate the oxygen transport mechanism in the catalyst layer. Toward this goal, an experimental approach to measure the oxygen transport resistance in catalyst layers is proposed and realized for the first time in this study. The measuring approach involves a dual-layer catalyst layer design, which consists of a dummy catalyst layer and a practical catalyst layer, followed by changing the thickness of dummy layer to respectively quantify the local and bulk resistances via limiting current measurements combined with linear extrapolation. The experimental results clearly reveal that the local resistance dominates the total resistance in the catalyst layer. PMID- 29121466 TI - Reaching a Vapor Sensitivity of 0.01 Parts Per Quadrillion in the Screening of Large Volume Freight. AB - The feasibility of detecting explosives in the atmosphere at concentrations as low as 0.01 ppq hinges on the poorly known question of what interfering species exist at these or higher concentrations. To clarify the issue, hundreds of samples of ambient air, either clean or loaded with explosives (from lightly contaminated environments) have been collected in fiberglass/stainless steel filters coated with Tenax-GR, thermally desorbed at variable temperature, and ionized with Cl- via secondary electrospray (SESI). They are analyzed with a narrow-band mobility filter (SEADM's P5 DMA) and a triple quadrupole mass spectrometer (Sciex's 5500), configured in series to transmit precursor and fragment ions of the explosives Nitroglycerin, PETN, RDX, and TNT. Blanks were sampled outdoors at a rural site (Boecillo, Valladolid, Spain), and loads were sampled at diverse locations. For RDX and TNT, atmospheric background inhibits detection below 1 part/trillion (ppt) without mobility filtering. This interference was drastically reduced by the DMA, allowing detection up to 1 part/quadrillion (ppq). Further sensitivity increase was achieved by scanning over a mobility region several percent around that of the target explosive, to separate various isobaric compounds by Gaussian deconvolution. (i) All four MS/MS channels analyzed exhibit several background peaks within the narrow mobility intervals investigated. At least one of these interferents is much stronger than the instrument background at the explosive's mobility, making DMA separation most helpful. (ii) For Nitroglycerin and PETN the combined filtering techniques have not lowered ambient chemical noise down to 0.01 ppq. (iii) Interferents are greatly reduced for TNT and RDX, resulting in minimal chemical noise: 322 blank tests for RDX yielded mean signal of 0.0012 ppq and standard deviation sigma = 0.0035 ppq (mean + 3sigma detection limit of 0.01 ppq). PMID- 29121467 TI - Nanodisc-Based Bioelectronic Nose Using Olfactory Receptor Produced in Escherichia coli for the Assessment of the Death-Associated Odor Cadaverine. AB - Cadaverine (CV), a death-associated odor, is an important target molecule for various sensor applications, including the evaluation of food spoilage. In this study, we developed an oriented nanodisc (ND)-functionalized bioelectronic nose (ONBN), based on carbon nanotube transistors and nanodiscs embedded with an olfactory receptor produced in Escherichia coli (E. coli) for detection of CV. To fabricate ONBN devices, a trace-amine-associated receptor 13c (TAAR13c) binding to CV was produced in E. coli, purified, reconstituted into NDs, and assembled, in the desired orientation, onto a carbon- nanotube-based field-effect transistor with floating electrodes. The ONBN showed high performance in terms of sensitivity and selectivity. Moreover, the ONBN was used to measure CV in diverse real-food samples for the determination of food freshness. These results indicate ONBN devices can be utilized to evaluate the quality of food samples quantitatively, which should enable versatile practical applications such as food safety and preservative development. Moreover, the ONBN could provide a useful tool for detection of corpses, which could be practically used in disaster responses. PMID- 29121468 TI - Effect of Extended Benzannelation Orientation on Bergman and Related Cyclizations of Isomeric Quinoxalenediynes. AB - A combined computational and experimental study was conducted to examine the effect of extended benzannelation orientation on C1-C5 and C1-C6 cyclization of acyclic quinoxalenediynes. Calculations (mPW1PW91/cc-pVTZ//mPW1PW91/6-31G(d,p)) on terminal and phenylethynyl-substituted 5,6-diethynylquinoxaline and 6,7 diethynylquinoxaline showed C1-C6 Bergman cyclization as the favored thermodynamic reaction pathway, with larger C1-C6 preference for the angular quinoxalenediynes due to gain of a new aromatic sextet. Kinetic studies, as a function of 1,4-cyclohexadiene concentration, revealed retro-Bergman ring opening predominates over hydrogen atom abstraction (k-1 > k2) for 6,7 diethynylquinoxaline while 5,6-diethynylquinoxaline undergoes irreversible Bergman cyclization indicative of a large retro-Bergman ring opening barrier (k2 > k-1). The effect of extended linear versus angular benzannelation on reaction pathway shows in the contrasting photocyclizations of phenylethynyl derivatives. While angular 5,6-diethynylquinoxalines gave exclusive C1-C6 photocyclization, linear 6,7-diethynylquinoxaline afforded C1-C5 fulvene products. Computed singlet triplet gaps and biradical stabilization energies indicated weak interaction between the nitrogen lone pair and proximal radical center in angular 5,6 diethynylquinoxalines. The overall data indicates extended angular benzannelation effectively renders Bergman cyclization irreversible due to favorable aromatic stabilization energy, while extended linear benzannelation results in increased retro-Bergman ring opening, allowing C1-C5 cyclization to become a competitive reaction channel. PMID- 29121465 TI - Coculture of Marine Invertebrate-Associated Bacteria and Interdisciplinary Technologies Enable Biosynthesis and Discovery of a New Antibiotic, Keyicin. AB - Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such "cryptic" or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions. We report here that coculturing of a Rhodococcus sp. and a Micromonospora sp. affords keyicin, a new and otherwise unattainable bis nitroglycosylated anthracycline whose mechanism of action (MOA) appears to deviate from those of other anthracyclines. The structure of keyicin was elucidated using high resolution MS and NMR technologies, as well as detailed molecular modeling studies. Sequencing of the keyicin BGC (within the Micromonospora genome) enabled both structural and genomic comparisons to other anthracycline-producing systems informing efforts to characterize keyicin. The new NP was found to be selectively active against Gram-positive bacteria including both Rhodococcus sp. and Mycobacterium sp. E. coli-based chemical genomics studies revealed that keyicin's MOA, in contrast to many other anthracyclines, does not invoke nucleic acid damage. PMID- 29121469 TI - Removal of Soluble Phosphorus from Surface Water Using Iron (Fe-Fe) and Aluminum (Al-Al) Electrodes. AB - The removal of soluble phosphorus using iron and aluminum electrodes was studied in water samples from the Red River, a hyper-eutrophic stream in Winnipeg, Canada. Four trials were conducted: (I) mixed batch with 150-900 mA applied for 1 min to 1 L, (II) stagnant batch with 600-900 mA applied for 1 min to 1 L, and (III and IV) continuously stirred-tank reactor with 6.25-10 min hydraulic retention times and constant 900 mA. Maximum soluble phosphorus removals of 70 80% were observed in mixed batch, and there was no significant difference between aluminum and iron electrodes (P value of 0.0526-0.9487). Aluminum electrodes performed significantly worse than iron electrodes under higher hydraulic loads, with iron removing >70% soluble phosphorus and aluminum <40% (P values of 0.0035 0.0143). The estimated cost of consumables, reported per million liters of water treated, to remove 70% soluble phosphorus from eutrophic waters with 0.35 g m-3 soluble phosphorus would include 5-17.5 USD electricity costs and material costs of 5.3-12.2 USD for iron and 39.2 USD for aluminum. PMID- 29121470 TI - Conformational Clusters of Phosphorylated Tyrosine. AB - Tyrosine phosphorylation plays an important role in many cellular and intercellular processes including signal transduction, subcellular localization, and regulation of enzymatic activity. In 1999, Blom et al., using the limited number of protein data bank (PDB) structures available at that time, reported that the side chain structures of phosphorylated tyrosine (pY) are partitioned into two conserved conformational clusters ( Blom, N.; Gammeltoft, S.; Brunak, S. J. Mol. Biol. 1999 , 294 , 1351 - 1362 ). We have used the spectral clustering algorithm to cluster the increasingly growing number of protein structures with pY sites, and have found that the pY residues cluster into three distinct side chain conformations. Two of these pY conformational clusters associate strongly with a narrow range of tyrosine backbone conformation. The novel cluster also highly correlates with the identity of the n + 1 residue, and is strongly associated with a sequential pYpY conformation which places two adjacent pY side chains in a specific relative orientation. Further analysis shows that the three pY clusters are associated with distinct distributions of cognate protein kinases. PMID- 29121471 TI - Visible-Light-Mediated Annulation of Electron-Rich Alkenes and Nitrogen-Centered Radicals from N-Sulfonylallylamines: Construction of Chloromethylated Pyrrolidine Derivatives. AB - A visible-light-mediated annulation of N-sulfonylallylamines and olefins is reported. Rapid access to highly functionalized chloromethylated pyrrolidines can be achieved using mild conditions for the generation of nitrogen-centered radicals. Both a transition-metal-based catalyst and an organic dye can be used as photosensitizers with 0.5 mol % loading. The reaction was found to be applicable to a large variety of electron-rich and electron-neutral olefins. PMID- 29121472 TI - Comparing the UV/Monochloramine and UV/Free Chlorine Advanced Oxidation Processes (AOPs) to the UV/Hydrogen Peroxide AOP Under Scenarios Relevant to Potable Reuse. AB - Utilities incorporating the potable reuse of municipal wastewater are interested in converting from the UV/H2O2 to the UV/free chlorine advanced oxidation process (AOP). The AOP treatment of reverse osmosis (RO) permeate often includes the de facto UV/chloramine AOP because chloramines applied upstream permeate RO membranes. Models are needed that accurately predict oxidant photolysis and subsequent radical reactions. By combining radical scavengers and kinetic modeling, we have derived quantum yields for radical generation by the UV photolysis of HOCl, OCl-, and NH2Cl of 0.62, 0.55, and 0.20, respectively, far below previous estimates that incorporated subsequent free chlorine or chloramine scavenging by the *Cl and *OH daughter radicals. The observed quantum yield for free chlorine loss actually decreased with increasing free chlorine concentration, suggesting scavenging of radicals participating in free chlorine chain decomposition and even free chlorine reformation. Consideration of reactions of *ClO and its daughter products (e.g., ClO2-), not included in previous models, were critical for modeling free chlorine loss. Radical reactions (indirect photolysis) accounted for ~50% of chloramine decay and ~80% of free chlorine loss or reformation. The performance of the UV/chloramine AOP was comparable to the UV/H2O2 AOP for degradation of 1,4-dioxane, benzoate and carbamazepine across pH 5.5-8.3. The UV/free chlorine AOP was more efficient at pH 5.5, but only by 30% for 1,4-dioxane. At pH 7.0-8.3, the UV/free chlorine AOP was less efficient. *Cl converts to *OH. The modeled *Cl:*OH ratio was ~20% for the UV/free chlorine AOP and ~35% for the UV/chloramine AOP such that *OH was generally more important for contaminant degradation. PMID- 29121473 TI - Polyvinylidene Fluoride Micropore Membranes as Solid-Phase Extraction Disk for Preconcentration of Nanoparticulate Silver in Environmental Waters. AB - Efficient separation and preconcentration of trace nanoparticulate silver (NAg) from large-volume environmental waters is a prerequisite for reliable analysis and therefore understanding the environmental processes of silver nanoparticles (AgNPs). Herein, we report the novel use of polyvinylidene fluoride (PVDF) filter membrane for disk-based solid phase extraction (SPE) of NAg in 1 L of water samples with the disk-based SPE system, which consists of a syringe pump and a syringe filter holder to embed the filter membrane. While the PVDF membrane can selectively adsorb NAg in the presence of Ag+, aqueous solution of 2% (m/v) FL-70 is found to efficiently elute NAg. Analysis of NAg is performed following optimization of filter membrane and elution conditions with an enrichment factor of 1000. Additionally, transmission electron microscopy (TEM), UV-vis spectroscopy, and size-exclusion chromatography coupled with ICP-MS (SEC-ICP-MS) analysis showed that the extraction gives rise to no change in NAg size or shape, making this method attractive for practical applications. Furthermore, feasibility of the protocol is verified by applying it to extract NAg in four real waters with recoveries of 62.2-80.2% at 0.056-0.58 MUg/L spiked levels. This work will facilitate robust studies of trace NAg transformation and their hazard assessments in the environment. PMID- 29121474 TI - Outcomes after Video-assisted Thoracoscopic Lobectomy versus Open Lobectomy for Early-Stage Lung Cancer in Older Adults. AB - RATIONALE: Video-assisted thoracoscopic surgery (VATS) and open lobectomy are both standard of care for the treatment of early-stage non-small cell lung cancer (NSCLC) because of equivalent long-term survival. OBJECTIVES: To evaluate whether the improved perioperative outcomes associated with VATS lobectomy are explained by surgeon characteristics, including case volume and specialty training. METHODS: We analyzed the Surveillance, Epidemiology, and End Results-Medicare linked registry to identify stage I-II NSCLC in patients above 65 years of age. We used a propensity score model to adjust for differences in patient characteristics undergoing VATS versus open lobectomy. Perioperative complications, extended length of stay, and perioperative mortality among patients were compared after adjustment for surgeon's volume and specialty using linear mixed models. We compared survival using a Cox model with robust standard errors. RESULTS: We identified 9,508 patients in the registry who underwent lobectomy for early-stage NSCLC. VATS lobectomies were more commonly performed by high-volume surgeons (P < 0.001) and thoracic surgeons (P = 0.01). VATS lobectomy was associated with decreased adjusted odds of cardiovascular complications (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.47-0.90), thromboembolic complications (OR = 0.47; 95% CI = 0.38-0.58), extrapulmonary infections (OR = 0.75; 95% CI = 0.61-0.94), extended length of stay (OR = 0.47; 95% CI = 0.40 0.56), and perioperative mortality (OR = 0.33; 95% CI = 0.23-0.48) even after controlling for differences in surgeon volume and specialty. Long-term survival was equivalent for VATS and open lobectomy (hazard ratio = 0.95; 95% CI = 0.85 1.08) after controlling for patient and tumor characteristics, surgeon volume, and specialization. CONCLUSIONS: VATS lobectomy for NSCLC is associated with better postoperative outcomes, but similar long-term survival, compared with open lobectomy among older adults, even after controlling for surgeon experience. PMID- 29121475 TI - Longitudinal Relationships Between Parents' and Children's Behavior Need Not Implicate the Influence of Parental Behavior and May Reflect Genetics: Comment on Waldinger and Schulz (2016). PMID- 29121476 TI - Hepatic transporter drug-drug interactions: an evaluation of approaches and methodologies. AB - INTRODUCTION: Drug-drug interactions (DDIs) continue to account for 5% of hospital admissions and therefore remain a major regulatory concern. Effective, quantitative prediction of DDIs will reduce unexpected clinical findings and encourage projects to frontload DDI investigations rather than concentrating on risk management ('manage the baggage') later in drug development. A key challenge in DDI prediction is the discrepancies between reported models. Areas covered: The current synopsis focuses on four recent influential publications on hepatic drug transporter DDIs using static models that tackle interactions with individual transporters and in combination with other drug transporters and metabolising enzymes. These models vary in their assumptions (including input parameters), transparency, reproducibility and complexity. In this review, these facets are compared and contrasted with recommendations made as to their application. Expert opinion: Over the past decade, static models have evolved from simple [I]/ki models to incorporate victim and perpetrator disposition mechanisms including the absorption rate constant, the fraction of the drug metabolised/eliminated and/or clearance concepts. Nonetheless, models that comprise additional parameters and complexity do not necessarily out-perform simpler models with fewer inputs. Further, consideration of the property space to exploit some drug target classes has also highlighted the fine balance required between frontloading and back-loading studies to design out or 'manage the baggage'. PMID- 29121478 TI - Statement of Removal. PMID- 29121477 TI - The Blind Psychological Scientists and the Elephant: Reply to Sherlock and Zietsch. PMID- 29121479 TI - Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses. AB - RATIONALE: Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations. OBJECTIVES: To determine whether rs6967330 influences RV-C infections and illnesses in early childhood. METHODS: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses. MEASUREMENTS AND MAIN RESULTS: The CDHR3 asthma risk allele (rs6967330 A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05-1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC2010 (IRR = 1.89 [1.14-3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02-1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13-2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92-1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages. CONCLUSIONS: The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3. PMID- 29121481 TI - Production of sludge-incorporated paver blocks for efficient waste management. AB - : Waste management plays a vital role in the reuse of industry wastes in to useful conversions. The treatment of effluents from the combined textile effluent treatment plant and hypo sludge from the paper industry results in sludge generation, which poses a huge challenge for its disposal. Therefore, an eco friendly attempt is made to utilize them in the production of paver blocks. Paver blocks are construction units that have vast applications in street roads, walking paths, fuel stations, and so on. In this study, an innovative attempt has been made to manufacture paver blocks incorporating textile effluent treatment plant sludge and hypo sludge, to utilize them in suitable proportions. The effect of adding silica fume and polypropylene fibre in paver blocks has also been studied. Paver blocks containing sludge with different proportions were cast based on the recommendations in Indian Standards (IS) 15658, and the test results were compared with the nominal M20 grade and M30 grade paver blocks. The outcomes of the paver block combinations were studied and found to be an effective utilization of sludge with substantial cement replacement of up to 35%, resulting in effective waste management for specific industries. IMPLICATIONS: Presently, paver blocks are construction units that have vast application in street roads and other constructions like walking paths, fuel stations, and so on. Also, paver blocks possess easy maintenance during breakages. Based on this application, an innovative attempt has been made to manufacture paver blocks incorporating textile effluent treatment plant sludge and hypo sludge to utilize them in suitable proportions. PMID- 29121480 TI - Palliative Care Planner: A Pilot Study to Evaluate Acceptability and Usability of an Electronic Health Records System-integrated, Needs-targeted App Platform. AB - RATIONALE: The quality and patient-centeredness of intensive care unit (ICU) based palliative care delivery is highly variable. OBJECTIVE: To develop and pilot an app platform for clinicians and ICU patients and their family members that enhances the delivery of needs-targeted palliative care. METHODS: In the development phase of the study, we developed an electronic health record (EHR) system-integrated mobile web app system prototype, PCplanner (Palliative Care Planner). PCplanner screens the EHR for ICU patients meeting any of five prompts (triggers) for palliative care consultation, allows families to report their unmet palliative care needs, and alerts clinicians to these needs. The evaluation phase included a prospective before/after study conducted at a large academic medical center. Two control populations were enrolled in the before period to serve as context for the intervention. First, 25 ICU patients who received palliative care consults served as patient-level controls. Second, 49 family members of ICU patients who received mechanical ventilation for at least 48 hours served as family-level controls. Afterward, 14 patients, 18 family members, and 10 clinicians participated in the intervention evaluation period. Family member outcomes measured at baseline and 4 days later included acceptability (Client Satisfaction Questionnaire [CSQ]), usability (Systems Usability Scale [SUS]), and palliative care needs, assessed with the adapted needs of social nature, existential concerns, symptoms, and therapeutic interaction (NEST) scale; the Patient-Centeredness of Care Scale (PCCS); and the Perceived Stress Scale (PSS). Patient outcomes included frequency of goal concordant treatment, hospital length of stay, and discharge disposition. RESULTS: Family members reported high PCplanner acceptability (mean CSQ, 14.1 [SD, 1.4]) and usability (mean SUS, 21.1 [SD, 1.7]). PCplanner family member recipients experienced a 12.7-unit reduction in NEST score compared with a 3.4-unit increase among controls (P = 0.002), as well as improved mean scores on the PCCS (6.6 [SD, 5.8]) and the PSS (-0.8 [SD, 1.9]). The frequency of goal-concordant treatment increased over the course of the intervention (n = 14 [SD, 79%] vs. n = 18 [SD, 100%]). Compared with palliative care controls, intervention patients received palliative care consultation sooner (3.9 [SD, 2.7] vs. 6.9 [SD, 7.1] mean days), had a shorter mean hospital length of stay (20.5 [SD, 9.1] vs. 22.3 [SD, 16.0] patient number), and received hospice care more frequently (5 [36%] vs. 5 [20%]), although these differences were not statistically significant. CONCLUSIONS: PCplanner represents an acceptable, usable, and clinically promising systems-based approach to delivering EHR-triggered, needs-targeted ICU-based palliative care within a standard clinical workflow. A clinical trial in a larger population is needed to evaluate its efficacy. PMID- 29121482 TI - Feasibility of coupling a thermal/optical carbon analyzer to a quadrupole mass spectrometer for enhanced PM2.5 speciation. AB - : A thermal/optical carbon analyzer (TOA), normally used for quantification of organic carbon (OC) and elemental carbon (EC) in PM2.5 (fine particulate matter) speciation networks, was adapted to direct thermally evolved gases to an electron impact quadrupole mass spectrometer (QMS), creating a TOA-QMS. This approach produces spectra similar to those obtained by the Aerodyne aerosol mass spectrometer (AMS), but the ratios of the mass to charge (m/z) signals differ and must be remeasured using laboratory-generated standards. Linear relationships are found between TOA-QMS signals and ammonium (NH4+), nitrate (NO3-), and sulfate (SO42-) standards. For ambient samples, however, positive deviations are found for SO42-, compensated by negative deviations for NO3-, at higher concentrations. This indicates the utility of mixed-compound standards for calibration or separate calibration curves for low and high ion concentrations. The sum of the QMS signals across all m/z after removal of the NH4+, NO3-, and SO42- signals was highly correlated with the carbon content of oxalic acid (C2H2O4) standards. For ambient samples, the OC derived from the TOA-QMS method was the same as the OC derived from the standard IMPROVE_A TOA method. This method has the potential to reduce complexity and costs for speciation networks, especially for highly polluted urban areas such as those in Asia and Africa. IMPLICATIONS: Ammonium, nitrate, and sulfate can be quantified by the same thermal evolution analysis applied to organic and elemental carbon. This holds the potential to replace multiple parallel filter samples and separate laboratory analyses with a single filter and a single analysis to account for a large portion of the PM2.5 mass concentration. PMID- 29121483 TI - Effects of N-carbamylglutamate and l-arginine on gonadotrophin-releasing hormone (GnRH) gene expression and secretion in GT1-7 cells. AB - Recent studies have shown that N-carbamylglutamate (NCG) and arginine (ARG) supplementation improves reproductive performance in livestock. The objectives of the present study were to evaluate the effects of NCG and ARG on GT1-7 cell gonadotrophin-releasing hormone (GnRH) secretion, gene expression and cell proliferation. GT1-7 cells were treated in vitro with different concentrations of NCG (0-1.0mM) or ARG (0-4.0mM) in serum-free medium for 12 or 24h. For GnRH secretion and cell proliferation, GT1-7 cells were more sensitive to NCG than ARG. NCG treatment after 12h increased cell numbers and inhibited GnRH secretion in a dose-dependent manner (P<0.05), although there was no significant effect of NCG on these parameters after 24h culture. ARG treatment decreased GnRH secretion after 24h (P<0.05), whereas it had no effect after 12h. GT1-7 cells express GnRH, Kiss-1 metastasis-suppressor (Kiss1), G-protein coupled receptor 54 (GPR54), neuronal nitric oxide synthase (nNOS) and estrogen receptor alpha (ERalpha) genes. High concentrations of NCG (1.0mM) and ARG (4.0mM) inhibited (P<0.05) GnRH and nNOS mRNA abundance in GT1-7 cells. ARG treatment decreased Kiss1 and increased ERalpha mRNA abundance. Thus, high concentrations of NCG (1.0mM) and ARG (4.0mM) may act both directly and indirectly to regulate GnRH neuron function by downregulating genes related to GnRH synthesis and secretion to slow GnRH production while stimulating GT1-7 cell proliferation. PMID- 29121484 TI - ERP evidence of distinct processes underlying semantic facilitation and interference in word production. AB - In everyday conversations, we take advantage of lexical-semantic contexts to facilitate speech production, but at the same time, we also have to reduce interference and inhibit semantic competitors. The blocked cyclic naming paradigm (BCNP) has been used to investigate such context effects. Typical results on production latencies showed semantic facilitation (or no effect) during the first presentation cycle, and interference emerging in subsequent cycles. Even if semantic contexts might be just as facilitative as interfering, previous BCNP studies focused on interference, which was interpreted as reflecting lemma selection and self-monitoring processes. Facilitation in the first cycle was rarely considered/analysed, although it potentially informs on word production to the same extent as interference. Here we contrasted the event-related potential (ERP) signatures of both semantic facilitation and interference in a BCNP. ERPs differed between homogeneous and heterogeneous blocks from about 365 msec post picture onset in the first cycle (facilitation) and in an earlier time-window (270 msec post picture onset) in the third cycle (interference). Three different analyses of the ERPs converge towards distinct processes underlying semantic facilitation and interference (post-lexical vs lexical respectively). The loci of semantic facilitation and interference are interpreted in the context of different theoretical frameworks of language production: the post-lexical locus of semantic facilitation involves interactive phonological-semantic processes and/or self-monitoring, whereas the lexical locus of semantic interference is in line with selection through increased lexical competition. PMID- 29121485 TI - Distinct modulation of interhemispheric inhibitory mechanisms during movement preparation reveals the influence of cognition on action control. AB - When selecting actions based on visual warning stimuli (WS), corticospinal excitability (CSE) is initially suppressed, consistent with a neural mechanism to prevent premature release of the competing responses. Despite being implicated in between-hand movement selection and preparation, the role that interhemispheric inhibition (IHI) may play in this 'impulse control' mechanism is not known. Participants performed a warned, between-hand, choice reaction time (RT) task in which the informativeness of the WS (with regards to which hand would be required to respond) was manipulated. Transcranial magnetic stimulation (TMS) assessed CSE of the right primary motor cortex (M1) and IHI from left to right M1 with 10 (IHI10) and 40 (IHI40) msec interstimulus intervals during movement selection and preparation. Consistent with impulse control, CSE was initially suppressed prior to both left and right hand actions, irrespective of WS informativeness. Subsequent CSE increases occurred in the responding hand which were larger, and occurred earlier, following an informative WS. Importantly, these increases strongly predicted response times. In contrast to the generic CSE suppression, an informative WS permitted a hand-specific release of IHI10 in the responding hand, whereas IHI40 was released in both hands. As releases of IHI cannot explain a simultaneous suppression of CSE, this suggests several distinct movement preparation mechanisms are at play with IHI modulation occurring independently from impulse control. Notably, the findings support the notion that IHI10 and IHI40 between contralateral motor regions are mediated by discrete transcallosal pathways, and are differently modulated by specific motor and cognitive attributes of a rapid choice task. PMID- 29121486 TI - Is it time for Brazil to prioritize TB preventive therapy for all people living with HIV? PMID- 29121488 TI - Analysis of Facial Symmetry After Zygomatic Bone Fracture Management. AB - PURPOSE: The location of the zygomatic bone plays an important role in facial symmetry and esthetics. The aim of this study was to determine and compare the frequency of facial asymmetry in a sample of patients who had undergone treatment of unilateral zygomaticomaxillary complex (ZMC) fractures (study group) and a sample of patients without ZMC fracture (control group). MATERIALS AND METHODS: This was a retrospective controlled cross-sectional study. The primary predictor variable was the type of ZMC fracture (linear or comminuted). The primary outcome variable was facial asymmetry characterized by the bilateral difference in the position of the malar eminence (ME) in 3 dimensions based on computed tomographic images. The other variables for this study were classified as demographic (age and gender) and anatomic (side of ZMC fracture). Descriptive and bivariate statistics were computed. Statistical significance was set at a P value less than .05 with 95% reliability. RESULTS: The entire sample consisted of 134 patients (n = 67 per group). The mean bilateral difference of the ME position in the study group was markedly greater than in the control group. More than half the study patients had facial symmetry and almost 10% of them had marked asymmetry, whereas none of the control patients had marked asymmetry. All patients with marked asymmetry and approximately 70% of them with greater than maximum normal asymmetry had a comminuted fracture. CONCLUSIONS: The results of this study show that although the frequency of facial asymmetry in patients with ZMC fracture was higher than in the control patients, it was found in all patients to a certain extent. Patients' awareness of this fact can decrease their dissatisfaction. PMID- 29121487 TI - Risk of cardiac events in Long QT syndrome patients when taking antiseizure medications. AB - Many antiseizure medications (ASMs) affect ion channel function. We investigated whether ASMs alter the risk of cardiac events in patients with corrected QT (QTc) prolongation. The study included people from the Rochester-based Long QT syndrome (LQTS) Registry with baseline QTc prolongation and history of ASM therapy (n = 296). Using multivariate Anderson-Gill models, we assessed the risk of recurrent cardiac events associated with ASM therapy. We stratified by LQTS genotype and predominant mechanism of ASM action (Na+ channel blocker and gamma-aminobutyric acid modifier.) There was an increased risk of cardiac events when participants with QTc prolongation were taking vs off ASMs (HR 1.65, 95% confidence interval [CI] 1.36-2.00, P < 0.001). There was an increased risk of cardiac events when LQTS2 (HR 1.49, 95% CI 1.03-2.15, P = 0.036) but not LQTS1 participants were taking ASMs (interaction, P = 0.016). Na+ channel blocker ASMs were associated with an increased risk of cardiac events in participants with QTc prolongation, specifically LQTS2, but decreased risk in LQTS1. The increased risk when taking all ASMs and Na+ channel blocker ASMs was attenuated by concurrent beta adrenergic blocker therapy (interaction, P < 0.001). Gamma-aminobutyric acid modifier ASMs were associated with an increased risk of events in patients not concurrently treated with beta-adrenergic blockers. Female participants were at an increased risk of cardiac events while taking all ASMs and each class of ASMs. Despite no change in overall QTc duration, pharmacogenomic analyses set the stage for future prospective clinical and mechanistic studies to validate that ASMs with predominantly Na+ channel blocking actions are deleterious in LQTS2, but protective in LQTS1. PMID- 29121489 TI - Health impacts quantification of ambient air pollutants using AirQ model approach in Hamadan, Iran. AB - Iranian western cities, including Hamadan, have been experiencing Middle East Dust Storms (MEDS) phenomenon problems in recent years, so the air quality is getting worse every year in these cities. The aim of this study was to evaluate the human health impacts of criteria air pollutants including PM10, PM2.5, NO2, SO2, CO and O3 on the citizens of Hamadan using AirQ model software 2.2.3. Considering the determined baseline incidence (BI) and relative risk (RR) rate, the attributable proportion (AP) of deaths due to cardiovascular and respiratory mortality attributed to PM2.5, PM10, O3, NO2, and CO pollutants was estimated to be 4.42%, 3.37%, 1.75%, 1.74% and 0.92% (95% CI) of the total mortality and the excess death cases were respectively estimated to be 131.9, 100.4, 52.1, 51.9 and 27.3 persons. In addition, cardiovascular mortality brings more contribution than respiratory mortality in total death number. The results of our study also showed that PM2.5 poses the greatest health effects on the citizens. Analyzing the average seasonal concentrations of studied pollutants (PM10, PM2.5, and NO2) and the mean seasonal temperature values revealed a positive linear correlation. Significant negative correlations were observed between the studied pollutants (PM10, PM2.5 and NO2) and relative humidity, and between PM and wind speed. This study, therefore, provides additional data in decision-makings for the development of strategies for reduction of ambient air pollution which will result in improvements of air quality. PMID- 29121490 TI - Inter-joint coordination changes during and after muscle fatigue. AB - People produce multi-joint movements by organizing many degrees of freedom into a few major covarying relationships, indicating a high level of inter-joint coordination. These relationships can be identified using data decomposition analyses (e.g. principal components analysis, non-negative matrix factorization). The purpose of this study was to determine how movement coordination changes during muscle fatigue by analyzing the covariance structure of multi-joint movements. Sixteen (16) healthy adults completed a continuous, timed ratcheting task with the right arm for three 1-min intervals before, during, and after an intermittent shoulder fatigue protocol. Joint angles from the right arm and trunk were tracked for subsequent principal components analysis. Principal component waveforms were constructed from the original joint angles, and changes in the waveforms during fatigue were assessed using cross-correlations. The variance explained by the first four principal components reached a maximum of 90.5% in the second minute of the pre-test and decreased to a minimum of 86.0% in the last minute of fatigue (p = .033). In the last minute of the post-test, explained variance (87.1%) did not differ from any other pre, fatigue, or post-test time point (p > .23). These results suggest that inter-joint coordination decreased during fatigue. Changes in the movement patterns and principal component waveforms suggest that subjects adopted a more rigid movement strategy when fatigued. However, the rigid movement strategy was not observed during the post test. The results suggest that people adopted a new pattern of inter-joint coordination while using novel kinematics. PMID- 29121491 TI - Examination of reactive motor responses to Achilles tendon vibrations during an inhibitory stepping reaction time task. AB - Inhibition is known to influence balance, step initiation and gait control. A specific subcomponent of inhibition, the perceptual inhibition process, has been suggested to be specifically involved in the integration of proprioceptive information that is necessary for efficient postural responses. This study aimed to investigate the inhibition requirements of planning and executing a choice step initiation task in young adults following experimental perturbation of proprioceptive information using Achilles tendon vibrations. We developed an inhibitory stepping reaction time task in which participants had to step in response to visual arrows that manipulated specific perceptual or motor inhibition according to two proprioceptive configurations: without or with application of vibrations. Performance of twenty-eight participants (mean age 21 years) showed that Achilles tendon vibrations induced an increase in attentional demands (higher reaction time and longer motor responses). Further, this increase in attentional demands did not affect specifically the different inhibitory processes tested in this reactive stepping task. It suggests that attentional demands associated with the vibratory perturbation to postural control do not lead to a shift from automatic to more attentional inhibition processes, at least in young adults. PMID- 29121492 TI - The association of parental obesity with physical activity and sedentary behaviors of their children: the CASPIAN-V study. AB - OBJECTIVE: Low physical activity and sedentary behaviors, two important determinants of childhood obesity, may be influenced by parental lifestyle and weight status. This study aims to determine the association of parental weight status with children's physical activity and screen time. METHODS: This study was conducted on 14,440 Iranian schools students, aged 7-18 years, and one of their parents, who participated in the large national school-based surveillance program. The children's screen-based and physical activities were evaluated based on the World Health Organization's Global School Student Health Survey. Children and parental height, weight, and waist circumference were measured using standardized methods. RESULTS: Overall, 14,274 students and one of their parents completed the survey (participation rate: 99%). Mean (standard deviation) age of students was 12.3 (3.2) years, and the prevalence of low physical activity and high screen time was 58.2% and 17.7%, respectively. In multivariate model, the parental general obesity and abdominal obesity increased the odds of children having low physical activity, by 21% and 13%, respectively. Parental overweight, general obesity, and abdominal obesity increased the odds of the combination of low physical activity/high screen time in children by 33%, 26%, and 20%, respectively. CONCLUSIONS: This study showed that parental obesity was associated with increased screen-based activities and low physical activity in children. Focus on parental weight status, as an important factor influenced by their lifestyle, can be helpful for preventing sedentary behaviors in their children. PMID- 29121493 TI - Prevalence of consumption and nutritional content of breakfast meal among adolescents from the Brazilian National Dietary Survey. AB - OBJECTIVE: To estimate the prevalence of breakfast consumption and describe the foods and nutrients consumed at this meal and throughout the day by Brazilian adolescents. METHOD: A total of 7276 adolescents aged 10-19 years were evaluated in the Brazilian National Dietary Survey 2008-9, a population-based cross sectional study. Individuals' information was collected at home. Dietary data were obtained by two food records. Breakfast was defined as the first eating occasion of the day that occurred between 6 and 9:59am. Differences between breakfast consumers, occasional consumers, and skippers were tested through Pearson's chi-squared test or F-test of regression analysis. RESULTS: Breakfast was consumed by 93% of adolescents and it was associated with age, income, geographic region and household area. The most frequently consumed foods at breakfast were white bread, coffee, butter/margarine, refined cookies and crackers, and whole milk. The mean daily intakes of total energy, sugar, and calcium were higher among occasional consumers and skippers. Breakfast consumers had higher intake of vitamins B12, C, and D. Breakfast contributed more to total intake of calcium, phosphorus, thiamin, riboflavin, and vitamins A, B6, and D (17 32%), trans fat and sodium (about 30%) and less to folate, vitamin C, iron, zinc, and fiber (8-12%) and energy intake (16%). CONCLUSIONS: Although the prevalence of breakfast consumption among Brazilian adolescents was high, the overall nutritional quality of this meal is suboptimal, highlighting the need to support adolescents and their families to make more nutrient-dense food choices. PMID- 29121494 TI - Being a mother of preterm multiples in the context of socioeconomic disadvantage: perceived stress and psychological symptoms. AB - OBJECTIVE: This study aimed to examine the differences between mothers of preterm multiples and mothers of preterm singletons regarding perceived stress and maternal psychological symptoms, and to explore the putative adverse amplified effect of socioeconomic disadvantage. METHOD: Ninety-five mothers of 1-year-olds born preterm participated in this cross-sectional study. Data collection was carried out in two public hospitals from Northern Portugal. To assess maternal perceived daily stress and psychological symptoms, mothers completed two questionnaires. Mothers reported on socioeconomic factors, including family poverty, parent unemployment, and low education, and two groups of family socioeconomic disadvantage were created. A child medical risk index was calculated. RESULTS: Results indicated that mothers of preterm multiples reported higher levels of stress than mothers of preterm singletons. Moreover, and specifically regarding psychological functioning, mothers of preterm multiples reported more symptoms than mothers of preterm singletons, but only when living in a context of socioeconomic adversity. CONCLUSIONS: The results of the present study have important implications for practice. Mothers of preterm multiples are at higher risk to present mental health difficulties, in comparison to mothers of singletons, especially when exposed to socioeconomic adversities. The development of psychosocial intervention programs and public policies are of decisive importance in helping mothers of multiples adjust to parenthood. PMID- 29121495 TI - Energy expenditure, growth, and nutritional therapy in appropriate and small for gestational age preterm infants. AB - OBJECTIVE: To evaluate the resting energy expenditure, growth, and quantity of energy and macronutrients intake in a group of preterm newborns. METHODS: The cohort study was performed with appropriate and small for gestational age preterm infants (birth weight lower than 1500g or gestational age<32 weeks). Resting energy expenditure was measured using indirect calorimetry on the 7th, 14th, 21st, and 28th days of life, and at discharge. Length, head circumference and body weight were assessed weekly. Nutritional therapy was calculated during the hospital stay and the information for each type of food was recorded in software that calculates the total amount of energy and macronutrients. RESULTS: 61 preterm infants were followed; 43 appropriate and 18 small for gestational age infants. There was no statistical difference for resting energy expenditure between the groups, and it increased from the first to the fourth week of life (appropriate: 26.3% and small: 21.8%). Energy intake in the first two weeks of life was well below the energy requirement. CONCLUSION: Considering that the results demonstrate high energy expenditure during the first weeks of life, there is an evident need to provide the best quality of nutrition for each child in the first weeks of life so that preterm infants with or without intrauterine growth restriction can achieve their maximum potential for growth and development. PMID- 29121496 TI - Properties of two fungal endo-beta-1,3-galactanases and their synergistic action with an exo-beta-1,3-galactanase in degrading arabinogalactan-proteins. AB - Arabinogalactan-proteins (AGPs) are plant proteoglycans, which are widely encountered in the plant kingdom, usually localized on the cell surface. The carbohydrate moieties of AGPs consist of beta-1,3-galactan main chains and beta 1,6-galactan side chains, to which other auxiliary sugars are attached. To date, FvEn3GAL isolated from Flammulina velutipes is the sole beta-1,3-galactanase acting on beta-1,3-galactan in an endo-manner. Here we cloned two homologous genes, designated Af3G and NcEn3GAL, possibly encoding endo-beta-1,3-galactanase from Aspergillus flavus and Neurospora crassa, respectively. The recombinant Af3G (rAf3G) and rNcEn3GAL expressed in Pichia pastoris specifically hydrolyzed beta 1,3-galactan in an endo-manner, as did the rFvEn3GAL. Among galactooligosaccharides, beta-1,3-galactotriose was identified as the smallest substrate for these enzymes. These results suggest that enzymatic characteristics are conserved in many endo-beta-1,3-galactanases belonging to the glycoside hydrolase 16 family. On the other hand, rAf3G and rNcEn3GAL generated more beta 1,3-galactobiose from beta-1,3-galactotetraose than did rFvEn3GAL, suggesting that rAf3G and rNcEn3GAL prefer hydrolyzing the central beta-1,3-glycosidic linkage of three in beta-1,3-galactotetraose. Although rAf3G and rNcEn3GAL alone hardly hydrolyze native AGP, they acted synergistically with a fungal exo-beta 1,3-galactanase on the AGP. These endo-beta-1,3-galactanases presumably aid hydrolysis by internally breaking up AGPs, which creates more sites of attack for exo-beta-1,3-galactanase. PMID- 29121497 TI - Mannosylcalix[n]arenes as multivalent ligands for DC-SIGN. AB - DC-SIGN is a receptor protruded from the membrane of immature dendritic cells (DCs) that participates in the activation of the immune response through the recognition of pathogen-associated molecular patterns (PAMPs). On the other hand, HIV exploits the interaction between high-mannose structures of its envelope glycoprotein gp120 and DC-SIGN to be transported towards and infect T-cells. DC SIGN is involved in the recognition process in the form of a tetramer and the multiple exposition of carbohydrate recognition sites (CRSs) is amplified by the formation on the DCs membrane of patches of tetramers. DC-SIGN is then considered an interesting target to fight the virus and multivalent systems exposing multiple copies of ligating units for its CRSs are becoming valuable tools to reach this goal. We herein prepared four mannosylated calix[n]arenes (1a-d) and tested them by Surface Plasmon Resonance (SPR) competition assays as inhibitors of the binding between DC-SIGN and a mannosylated BSA used as model of HIV gp120. IC50s in the MUM range were found evidencing in particular for compound 1a that, although rather moderate, a multivalent effect is taking place in the inhibition activity of this cluster. A relative potency (rp/n) around 4, respect to the monovalent methyl alpha-mannoside and normalized for the number of monosaccharide on the scaffold, was observed. This result, compared with previously reported data relative to dendrimers with the same valency, indicates the calixarene as a promising scaffold to build efficient inhibitors for DC-SIGN and, in perspective, for HIV. PMID- 29121498 TI - Cardiac involvement in myotonic dystrophy: The role of troponins and N-terminal pro B-type natriuretic peptide. AB - BACKGROUND AND AIMS: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are dominant inherited muscular dystrophies with multiple systemic involvement, often producing cardiac injury. This study sought to determine the clinical significance of elevated high sensitivity cardiac troponin T and I (hs-cTnT and hs-cTnI), and N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in this population. METHODS: Sixty DM patients (35 men and 25 women; mean age: 45.1 years, range: 12-73 years) underwent clinical cardiac investigations and measurements of serum hs-cTnT, hs-cTnI, creatine kinase (CK), and NT-proBNP. Left ventricular (LV) ejection fraction (EF) was assessed by echocardiography. RESULTS: Genetic analysis revealed that 46 of the 60 patients were DM1, and 14 DM2. Blood measurements showed persistent elevation of hs-cTnT and CK in 55/60 DM patients (91.73%). In contrast, hs-cTnI values were persistently normal throughout the study. Only 2 patients showed an EF <50%, being the overall range of this population between 40% and 79%. We found ECG abnormalities in 19 patients. Of these patients, 13 showed first or second-degree atrio ventricular (AV) blocks (PR interval >= 200 ms), 4 showed a left bundle branch block (LBBB) prolonged (QRS duration >=120 ms), and 2 had an incomplete bundle branch block (QRS duration between 110 and 119 ms). After excluding patients with EF <50%, NT pro-BNP measurement > 125 pg/mL was an independent predictor of ECG abnormalities. CONCLUSIONS: NT-pro-BNP levels may be considered to be used clinically to identify DM patients at increased risk of developing myocardial conduction abnormalities. PMID- 29121499 TI - Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis. AB - BACKGROUND AND AIMS: Activation of brown adipose tissue (BAT) reduces both hyperlipidemia and atherosclerosis by increasing the uptake of triglyceride derived fatty acids by BAT, accompanied by formation and clearance of lipoprotein remnants. We tested the hypothesis that the hepatic uptake of lipoprotein remnants generated by BAT activation would be accelerated by concomitant statin treatment, thereby further reducing hypercholesterolemia and atherosclerosis. METHODS: APOE*3-Leiden.CETP mice were fed a Western-type diet and treated without or with the selective beta3-adrenergic receptor (AR) agonist CL316,243 that activates BAT, atorvastatin (statin) or both. RESULTS: beta3-AR agonism increased energy expenditure as a result of an increased fat oxidation by activated BAT, which was not further enhanced by statin addition. Accordingly, statin treatment neither influenced the increased uptake of triglyceride-derived fatty acids from triglyceride-rich lipoprotein-like particles by BAT nor further lowered plasma triglyceride levels induced by beta3-AR agonism. Statin treatment increased the hepatic uptake of the formed cholesterol-enriched remnants generated by beta3-AR agonism. Consequently, statin treatment further lowered plasma cholesterol levels. Importantly, statin, in addition to beta3-AR agonism, also further reduced the atherosclerotic lesion size as compared to beta3-AR agonism alone, without altering lesion severity and composition. CONCLUSIONS: Statin treatment accelerates the hepatic uptake of remnants generated by BAT activation, thereby increasing the lipid-lowering and anti-atherogenic effects of BAT activation in an additive fashion. We postulate that, in clinical practice, combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular disease. PMID- 29121500 TI - Validation of a Salmonella loop-mediated isothermal amplification assay in animal food. AB - Loop-mediated isothermal amplification (LAMP) has emerged as a promising alternative to PCR for pathogen detection in food testing and clinical diagnostics. This study aimed to validate a Salmonella LAMP method run on both turbidimetry (LAMP I) and fluorescence (LAMP II) platforms in representative animal food commodities. The U.S. Food and Drug Administration (FDA)'s culture based Bacteriological Analytical Manual (BAM) method was used as the reference method and a real-time quantitative PCR (qPCR) assay was also performed. The method comparison study followed the FDA's microbiological methods validation guidelines, which align well with those from the AOAC International and ISO. Both LAMP assays were 100% specific among 300 strains (247 Salmonella of 185 serovars and 53 non-Salmonella) tested. The detection limits ranged from 1.3 to 28 cells for six Salmonella strains of various serovars. Six commodities consisting of four animal feed items (cattle feed, chicken feed, horse feed, and swine feed) and two pet food items (dry cat food and dry dog food) all yielded satisfactory results. Compared to the BAM method, the relative levels of detection (RLODs) for LAMP I ranged from 0.317 to 1 with a combined value of 0.610, while those for LAMP II ranged from 0.394 to 1.152 with a combined value of 0.783, which all fell within the acceptability limit (2.5) for an unpaired study. This also suggests that LAMP was more sensitive than the BAM method at detecting low-level Salmonella contamination in animal food and results were available 3days sooner. The performance of LAMP on both platforms was comparable to that of qPCR but notably faster, particularly LAMP II. Given the importance of Salmonella in animal food safety, the LAMP assays validated in this study holds great promise as a rapid, reliable, and robust method for routine screening of Salmonella in these commodities. PMID- 29121501 TI - Does c-Met remain a rational target for therapy in patients with EGFR TKI resistant non-small cell lung cancer? AB - Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5-20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c-Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC. Selective c-Met TKIs exhibit more favorable properties, targeting both hepatocyte growth factor (HGF)-dependent and independent c-Met activity, with a reduced risk of toxicity compared to non selective c-Met TKIs. Phase Ib/II trials of the selective c-Met TKIs capmatinib and tepotinib have shown encouraging signs of efficacy. Factors affecting the success of ongoing and future trials of c-Met inhibitors in patients with EGFR TKI-resistant, c-Met-positive NSCLC are considered. PMID- 29121502 TI - The prognostic role of epigenetic dysregulation in bladder cancer: A systematic review. AB - BACKGROUND: Despite adequate treatment and follow-up, around one fifth of patients with localized bladder cancer will present with disease progression. Adequate prognostic biomarkers are lacking to define patients who are at risk. Mutations in chromatin remodeling genes are more frequently found in bladder cancer than in any other solid tumor. However, the prognostic relevance of epigenetic dysregulation has not been established and may offer an opportunity for biomarker discovery. METHODS: Looking for prognostic epigenetic factors, we performed a comprehensive PubMed search using keywords such as "bladder cancer", "chromatin remodeling", "gene methylation" and "epigenetics". We only included studies reporting on the association of epigenetic markers with prognostic outcomes such as recurrence, progression or survival. RESULTS: Of 1113 results, 87 studies met the inclusion criteria, which represented a total of 85 epigenetic markers with potential prognostic relevance. No prospective studies were identified. Seventy-three percent (64/87) of the studies involved mixed cohorts of muscle invasive and non-muscle invasive bladder cancer. Promoter methylation of genes with putative prognostic value affected cellular processes such as cell cycle, apoptosis, cell-adhesion or migration, as well as critical pathways such as MAP-kinase or Wnt. Alteration of chromatin regulatory elements suggest a prognostic relevance alterations leading to a predominantly silenced chromatin state. CONCLUSIONS: The prognostic impact of epigenetic alterations in bladder cancer is still unclear. Prospective evaluation of methylation marks and chromatin remodeling gene alterations using consistent methods and criteria is warranted. PMID- 29121503 TI - Biohydrogen production at pH below 3.0: Is it possible? AB - Biological hydrogen production was investigated in continuous acidogenic reactors fed with sucrose at 30 degrees C without pH control. In the first experimental phase, three reactors were compared: a structured fixed-bed (FB), a granular UASB (UG) and a flocculent UASB (UF-1). They were run at 3.3 h HRT and 33 gCOD L-1d-1 OLR. Hydrogen production occurred throughout the experimental period with an average effluent pH of only 2.8. The FB, UG and UF-1 reactors presented volumetric hydrogen production rates (VHPR) of 95 +/- 69, 45 +/- 37 and 54 +/- 32 mLH2 L-1h-1, respectively; and H2 yields (HY) of 1.5 +/- 0.8, 0.8 +/- 0.6 and 1.2 +/- 0.7 molH2 mol-1 sucroseconsumed, respectively. The UF-1 reactor showed intermediate VHPR and HY, but no declining trend, contrary to what was observed in the FB reactor. Thus, aiming at continuous and long-term H2 production, a flocculent UASB was applied in the second experimental phase. In this phase, the HRT of the acidogenic reactor, which was named UF-2, was raised to 4.6 h, resulting in an OLR of 25 gCOD L-1d-1. The VHPR and the HY increased considerably to 175 +/- 44 mLH2 L-1h-1 and 3.4 +/- 0.7 molH2 mol-1 sucroseconsumed, respectively. These improvements were accompanied by greater sucrose removal, higher suspended biomass concentration, less production of lactate and more of acetate, and high ethanol concentration. Contradicting the current published literature data that reports strong inhibition of H2 production by dark fermentation at pH less than 4.0, the UF-2 reactor presented stable, long-term H2 production with satisfactory yields at pH 2.7 on average. 16 S rDNA sequencing revealed that two sequences assigned as Ethanoligenens and Clostridium accounted for over 70% of the microbiota in all the reactors. The non-necessity of adding alkalizing agents and the successful H2 production under very acid conditions, demonstrated in this study, open a new field of investigation in biological hydrogen production by dark fermentation towards a more sustainable and feasible technology. PMID- 29121504 TI - Too little, too much, or just right? Does the amount of distraction make a difference during contamination-related exposure? AB - BACKGROUND AND OBJECTIVES: The extant literature has shown mixed results regarding the impact of distraction use on exposure outcome; however, a wide variety of distraction tasks have been utilized across studies. In order to better understand these discrepant findings, we aimed to evaluate the impact of differing levels of distraction on exposure outcome. Additionally, treatment acceptability and changes in self-efficacy were assessed to evaluate how these may differ as a function of distraction use. METHODS: In Experiment 1 (N = 176 participants tested), distraction tasks were experimentally validated through assessing changes in reaction time when completing concurrent tasks. Based on Experiment 1, distraction tasks were selected for use in Experiment 2, in which contamination-fearful participants were randomly assigned to one of four conditions: no, low, moderate, or high distraction during an exposure session. Participants (N = 124) completed a behavioural approach test and self-efficacy measure pre- and post-exposure and at one-week follow-up. Treatment acceptability was assessed immediately following the exposure session. RESULTS: There were no significant differences between conditions for changes in behavioural approach pre-to post-exposure or at one-week follow-up. However, increases in self efficacy pre-to post-exposure were greatest for moderate distraction, and treatment acceptability was highest with moderate and high distraction. LIMITATIONS: Participants were not assessed for clinical severity, were not treatment-seeking, and only one specific type of fear was investigated. CONCLUSIONS: Distraction (at any level) did not appear to negatively impact exposure outcome (all conditions improved pre-to post-exposure and at follow-up), but utilizing moderate to high amounts of distraction increased treatment acceptability. PMID- 29121505 TI - Reduced reciprocal giving in social anxiety - Evidence from the Trust Game. AB - BACKGROUND AND OBJECTIVES: Social anxiety is known to impair interpersonal relationships. These impairments are thought to partly arise from difficulties to engage in affiliative interactions with others, such as sharing favors or reciprocating prosocial acts. Here, we examined whether individuals high compared to low in social anxiety differ in giving towards strangers in an economic game paradigm. METHODS: One hundred and twenty seven non-clinical participants who had been pre-screened to be either particularly high or low in social anxiety played an incentivized Trust Game to assess trustful and reciprocal giving towards strangers in addition to providing information on real life interpersonal functioning (perceived social support and attachment style). RESULTS: We found that reciprocal, but not trustful giving, was significantly decreased among highly socially anxious individuals. Both social anxiety and reciprocal giving furthermore showed significant associations with self-reported real life interpersonal functioning. LIMITATIONS: Participants played the Trust Game with the strategy method; results need replication with a clinical sample. CONCLUSIONS: Individuals high in social anxiety showed reduced reciprocal, but intact trustful giving, pointing to a constraint in responsiveness. The research may contribute to the development of new treatment and prevention programs to reduce the interpersonal impairments in socially anxious individuals. PMID- 29121506 TI - What factors determine the preferred gait transition speed in humans? A review of the triggering mechanisms. AB - Human locomotion is a fundamental skill that is required for daily living, yet it is not completely known how human gait is regulated in a manner that seems so effortless. Gait transitions have been analyzed to gain insight into the control mechanisms of human locomotion since there is a known change that occurs as the speed of locomotion changes. Specifically, as gait speed changes, there is a spontaneous transition between walking and running that occurs at a particular speed. Despite the growing body of research on the determinants of this preferred transition speed and thus the triggering mechanisms of human gait transitions, a clear consensus regarding the control mechanisms of gait is still lacking. Therefore, this article reviews the determinants of the preferred transition speed using concepts of the dynamic systems theory and how these determinants contribute to four proposed triggers (i.e. metabolic efficiency, mechanical efficiency, mechanical load and cognitive and perceptual) of human gait transitions. While individual anthropometric and strength characteristics influence the preferred transition speed, they do not act to trigger a gait transition. The research has more strongly supported the mechanical efficiency and mechanical load determinants as triggering mechanisms of human gait transitions. These mechanical determinants, combined with cognitive and perceptual processes may thus be used to regulate human gait patterns through proprioceptive and perceptual feedback as the speed of locomotion changes. PMID- 29121507 TI - The effects of trunk extensor and abdominal muscle fatigue on postural control and trunk proprioception in young, healthy individuals. AB - The purpose of this study was to induce both trunk extensor and abdominal muscle fatigue, on separate occasions, and compare their effects on standing postural control and trunk proprioception, as well as look at the effects of a recovery period on these outcome measures. A total of 20 individuals participated, with 10 (5 males and 5 females) completing either a standing postural control or lumbar axial repositioning protocol. Participants completed their randomly assigned protocol on two occasions, separated by at least 4 days, with either their trunk extensor or abdominal muscles being fatigued on either day. Postural control centre of pressure variables and trunk proprioception errors were compared pre- and post-fatigue. Results showed that both trunk extensor and abdominal muscle fatigue significantly degraded standing postural control immediately post fatigue, with recovery occurring within 2 min post-fatigue. In general, these degradative effects on postural control appeared to be greater when the trunk extensor muscles were fatigued compared to the abdominal muscles. No statistically significant changes in trunk proprioception were found after either fatigue protocol. The present findings demonstrate our body's ability to quickly adapt and reweight somatosensory information to maintain postural control and trunk proprioception, as well as illustrate the importance of considering the abdominal muscles, along with the trunk extensor muscles, when considering the impact of fatigue on trunk movement and postural control. PMID- 29121508 TI - Host and virus ecology as determinants of influenza A virus transmission in wild birds. AB - Low pathogenic influenza A virus (LPIAV) prevalence and subtype distribution differs between and across bird taxa. A crucial factor in the epidemiology of these viruses and virus subtypes is the ability to transmit between and within different host taxa and individuals. Successful viral transmission depends on availability of susceptible hosts and exposure of host to virus. Exposure to viruses and susceptibility to virus infection and/or disease are shaped by both host and virus traits. In this review we have identified key host and virus traits that can affect LPIAV transmission, both in terms of exposure and susceptibility. Furthermore we highlight current challenges in assessment of these traits and identify methodological considerations for future studies. PMID- 29121509 TI - Modifications in lower leg muscle activation when walking barefoot or in minimalist shoes across different age-groups. AB - Ageing is associated with a decline in muscle strength and impaired sensory mechanisms which contribute to an increased risk of falls. Walking barefooted has been suggested to promote increased muscle strength and improved proprioceptive sensibility through better activation of foot and ankle musculature. Minimalist footwear has been marketed as a method of reaping the suggested benefits of barefoot walking whilst still providing a protective surface. The aim of this study was to investigate if walking barefoot or in minimalist footwear provokes increased muscle activation compared to walking in conventional footwear. Seventy healthy adults (age range 20-87) volunteered for this study. All participants walked along a 7m walking lane five times in four different footwear conditions (barefoot (BF), minimalist shoes (MSH), their own shoes (SH) and control shoes (CON)). Muscle activity of their tibialis anterior (TA), gastrocnemius medialis (GCM) and peroneus longus (PL) were recorded simultaneously and normalised to the BF condition. MSH are intermediate in terms of ankle kinematics and muscle activation patterns. Walking BF or in MSH results in a decrease in TA activity at initial stance due to a flatter foot at contact in comparison to conventional footwear. Walking BF reduces PL activity at initial stance in the young and middle age but not the old. Walking in supportive footwear appears to reduce the balance modulation role of the GCM in the young and middle age but not the old, possibly as a result of slower walking speed when BF. PMID- 29121510 TI - EMG normalization method based on grade 3 of manual muscle testing: Within- and between-day reliability of normalization tasks and application to gait analysis. AB - Electromyography (EMG) is an important parameter in Clinical Gait Analysis (CGA), and is generally interpreted with timing of activation. EMG amplitude comparisons between individuals, muscles or days need normalization. There is no consensus on existing methods. The gold standard, maximum voluntary isometric contraction (MVIC), is not adapted to pathological populations because patients are often unable to perform an MVIC. The normalization method inspired by the isometric grade 3 of manual muscle testing (isoMMT3), which is the ability of a muscle to maintain a position against gravity, could be an interesting alternative. The aim of this study was to evaluate the within- and between-day reliability of the isoMMT3 EMG normalizing method during gait compared with the conventional MVIC method. Lower limb muscles EMG (gluteus medius, rectus femoris, tibialis anterior, semitendinosus) were recorded bilaterally in nine healthy participants (five males, aged 29.7+/-6.2years, BMI 22.7+/-3.3kgm-2) giving a total of 18 independent legs. Three repeated measurements of the isoMMT3 and MVIC exercises were performed with an EMG recording. EMG amplitude of the muscles during gait was normalized by these two methods. This protocol was repeated one week later. Within- and between-day reliability of normalization tasks were similar for isoMMT3 and MVIC methods. Within- and between-day reliability of gait EMG normalized by isoMMT3 was higher than with MVIC normalization. These results indicate that EMG normalization using isoMMT3 is a reliable method with no special equipment needed and will support CGA interpretation. The next step will be to evaluate this method in pathological populations. PMID- 29121511 TI - Medical egg freezing and cancer patients' hopes: Fertility preservation at the intersection of life and death. AB - Egg freezing (i.e., oocyte cryopreservation) is a new reproductive technology that allows women's eggs to be frozen and stored for future use. Over the past five years, so-called "medical egg freezing" (MEF) has begun to play a major role as a form of fertility preservation for young women with cancer and other fertility-threatening medical conditions. Indeed, women who are candidates for MEF are often facing the "double jeopardy" of fertility loss and potential death. In this article, we examine the experiences of the first generation of women to use MEF in the United States and Israel, two countries where experimental use of MEF began early, and where MEF is now offered clinically in many in vitro fertilization (IVF) clinics. Through an ethnographic, interview-based study carried out between June 2014 and August 2016 with 45 women (33 American, 12 Israeli) who had completed at least one cycle of MEF, we highlight women's reflections on their egg freezing experiences, and their considerable hopes for future recovery and motherhood. However, MEF is a Janus-faced new "hope technology." On the one hand, it holds out the promise of life in terms of recovery and future childbearing. As such, women's reflections on MEF reveal hope and gratitude for the technology's existence. However, as with IVF itself, future motherhood can never be guaranteed. This is especially true for women facing death from advanced or aggressive forms of cancers. Three ethnographic case studies of cancer patients, two from the US and one from Israel, highlight how MEF offers hope for life among women confronted with a deadly disease. PMID- 29121512 TI - Composite-pulse and partially dipolar dephased multiCP for improved quantitative solid-state 13C NMR. AB - Improved multiple cross polarization (multiCP) pulse sequences for quickly acquiring quantitative 13C NMR spectra of organic solids are presented. Loss of 13C magnetization due to imperfect read-out and storage pulses in multiCP has been identified as a significant mechanism limiting polarization enhancement for 13C sites with weak couplings to 1H. This problem can be greatly reduced by composite 90 degrees pulses with non-orthogonal phases that flip the magnetization onto the spin-lock field and back to the longitudinal direction for the 1H repolarization period; the observed loss is <3% for over +/-10 kHz resonance offset and up to 20% flip-angle error. This composite-pulse multiCP (ComPmultiCP) sequence consistently provides performance superior to that of conventional multiCP, without any trade-off. The longer total CP time enabled by the composite pulses allows for a wider amplitude ramp during CP, which decreases the sensitivity to Hartmann-Hahn mismatch by a factor of two, with a <7% root mean-square deviation within a 1-dB range for Boc-alanine. In samples with very short T1rho, under-polarization of non-protonated carbons can be compensated by slight dipolar dephasing of CHn signals resulting from relatively weak decoupling during the Hahn spin echo period before detection. Quantitative spectra have been obtained by ComPmultiCP for low-crystallinity branched polyethylene at 4.5 kHz MAS, and in combination with partial dipolar dephasing for soil organic matter at 14 kHz MAS. PMID- 29121513 TI - Psychiatric morbidity develops after onset of pediatric multiple sclerosis: A Danish nationwide population-based study. AB - BACKGROUND: Pediatric-onset multiple sclerosis (MS) affects life at a stage vital for social and educational achievements and psychiatric co-morbidity is common after MS onset. Few studies have examined psychiatric morbidity before MS onset. METHODS: In this nationwide study, detailed case ascertainment was performed in all children with pediatric MS, including chart review. For each MS patient, we selected five controls using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data as a nested case-control study with psychiatric morbidity as exposure and MS as outcome, and a matched cohort study with MS as exposure and psychiatric co morbidity as outcome. Hazard ratios (HR) including 95% confidence intervals (CI) were estimated using Cox regression. RESULTS: We identified 212 children with MS and 1060 controls. No association between psychiatric morbidity and the rate of MS was found before MS onset. After MS onset, children with MS had two times higher hazard for psychiatric co-morbidity compared with children without MS (HR=2.0; 95% CI=1.3-3.1; p<0.001). CONCLUSION: Psychiatric morbidity seems to commence after MS onset, making screening for neuropsychiatric conditions pertinent in newly-diagnosed children with MS. PMID- 29121514 TI - Nonsense-mediated mRNA Decay and Cancer. AB - Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance pathway that cells use to ensure the quality of transcripts and to fine-tune transcript abundance. The role of NMD in cancer development is complex. In some cases, tumors have exploited NMD to downregulate gene expression by apparently selecting for mutations causing destruction of key tumor-suppressor mRNAs. In other cases, tumors adjust NMD activity to adapt to their microenvironment. Understanding how particular tumors exploit NMD for their benefit may augment the development of new therapeutic interventions. PMID- 29121515 TI - The genetic basis underlying variation in production of the flavour compound diacetyl by Lactobacillus rhamnosus strains in milk. AB - Diacetyl and the closely related compound acetoin impart desirable buttery flavour and odour to many foods including cheese and are generated through the metabolism of citrate by lactic acid bacteria (LAB). To increase the levels of these compounds, adjunct cultures capable of producing them can be added to cheese fermentations. In this study, we compared the diacetyl and acetoin producing abilities of 13 Lactobacillus rhamnosus strains from cheese sources. Diacetyl and acetoin production was found to be a common feature of Lb. rhamnosus grown in milk, with 12 strains producing these compounds. Whole genome sequencing of four strains revealed that genes encoding the citrate metabolising pathway present in other LAB are conserved in Lb. rhamnosus. One strain was, however, totally defective in diacetyl and acetoin production. This was likely due to an inability to produce the diacetyl/acetoin precursor compound acetolactate resulting from a frameshift mutation in the acetolactate synthase (als) gene. Complementation of this defective strain with a complete als gene from a diacetyl producing strain restored production of diacetyl and acetoin to levels equivalent to naturally high producing strains. Introduction of the same als-containing plasmid into the probiotic Lb. rhamnosus strain GG also increased diacetyl and acetoin levels. In model cheesemaking experiments, the als-complemented strain produced very high levels of diacetyl and acetoin over 35days of ripening. These findings identify the genetic basis for natural variation in production of a key cheese flavour compound in Lb. rhamnosus strains. PMID- 29121517 TI - Suicide risk reduction in youths with attention-deficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) youths have increased suicide risk. Nevertheless, the beneficial effects of methylphenidate (MPH) on suicide attempt have received relatively little attention. AIMS: To investigate the MPH usage and the risk of suicide attempt among ADHD youths. METHODS: We identified 84,898 youths less than 18 years old with ADHD diagnosis between 1997 and 2013 from National Health Insurance, and examined whether MPH use affected suicide attempt risk using Cox proportional-hazards models. OUTCOME AND RESULTS: Among ADHD youths, reduction of suicide risk was found in patients prescribed 90 180days of MPH after adjusting for confounding factors (hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.19-0.90) and a greater reduction in those prescribed more than 180days of MPH (HR: 0.28, 95% CI: 0.17-0.48). CONCLUSIONS AND IMPLICATIONS: We observed a 59% suicide attempt risk reduction among ADHD youths prescribed between 90 and 180days and a 72% risk reduction in those prescribed more than 180days of MPH. The protective benefit observed by the group prescribed MPH for longer duration underscores the importance of psychoeducation and compliance enhancement as part of ADHD management. Indication bias is identified as a limitation of this study, and future self-case control study to investigate the association between suicide attempt and ADHD medication is suggested. WHAT THIS PAPER ADDS: This nationwide population-based cohort study showed that among ADHD youths, reduction of suicide risk was observed in patients prescribed MPH for duration 90days and longer, underscoring the importance of appropriate ADHD pharmacotherapy and enhancing drug compliance. PMID- 29121518 TI - Genome-wide identification, phylogenetic analysis, and expression profiles of ATP binding cassette transporter genes in the oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). AB - The ATP-binding cassette (ABC) is the largest transporter gene family and the genes play key roles in xenobiotic resistance, metabolism, and development of all phyla. However, the specific functions of ABC gene families in insects is unclear. We report a genome-wide identification, phylogenetic, and transcriptional analysis of the ABC genes in the oriental fruit fly, Bactrocera dorsalis (Hendel). We identified a total of 47 ABC genes (BdABCs) from the transcriptomic and genomic databases of B. dorsalis and classified these genes into eight subfamilies (A-H), including 7 ABCAs, 7 ABCBs, 9 ABCCs, 2 ABCDs, 1 ABCE, 3 ABCFs, 15 ABCGs, and 3 ABCHs. Comparative phylogenetic analysis of the ABCs suggests an orthologous relationship between B. dorsalis and other insect species in which these genes have been related to pesticide resistance and essential biological processes. Comparison of transcriptome and relative expression patterns of BdABCs indicated diverse multifunctions within different B. dorsalis tissues. The expression of 4, 10, and 14 BdABCs from 18 BdABCs was significantly upregulated after exposure to LD50s of malathion, avermectin, and beta-cypermethrin, respectively. The maximum expression level of most BdABCs (including BdABCFs, BdABCGs, and BdABCHs) occurred at 48h post exposures, whereas BdABCEs peaked at 24h after treatment. Furthermore, RNA interference-mediated suppression of BdABCB7 resulted in increased toxicity of malathion against B. dorsalis. These data suggest that ABC transporter genes might play key roles in xenobiotic metabolism and biosynthesis in B. dorsalis. PMID- 29121519 TI - Iguratimod ameliorates inflammatory responses by modulating the Th17/Treg paradigm in dextran sulphate sodium-induced murine colitis. AB - Inflammatory bowel disease (IBD) is an autoimmune disease with an abnormal and persistent immune response. Iguratimod, a novel anti-rheumatic drug, exhibits anti-inflammatory effects and regulates immune response. The role of iguratimod in intestinal mucosal inflammation and immunity has not been examined. The aim of this study was to investigate whether iguratimod ameliorates dextran sulphate sodium (DSS)-induced murine colitis and its potential regulatory mechanism. Murine colitis was induced by administering 2.5% DSS for 5days. Some mice were administered iguratimod (5, 30mg/kg) by oral gavage once daily for 7days, beginning on the day 3 after colitis induction. Our study showed that iguratimod alleviates the symptoms of colitis and suppresses intestinal tissue damage, including macroscopic and histopathological manifestations. Moreover, iguratimod reduced interleukin (IL)-6, IL-17, and tumour necrosis factor-alpha levels, and increased the expression levels of IL-10 and TGF-beta. In addition, iguratimod downregulated the proportion of Th17 cells, the level of transcription factor retinoic acid-related orphan receptor gammat (RORgammat), and the phosphorylation of signal transducer and activator of transcription-3 (STAT3), and upregulated the proportion of Treg cells, the level of transcription factor forkhead box p3 (Foxp3), and the phosphorylation of STAT5 in the colonic tissues. In conclusion, iguratimod plays a protective role in mice with DSS-induced colitis via anti inflammatory effects and regulation of Th17/Treg cells. Therefore, use of iguratimod may serve as a novel therapeutic strategy for the treatment of IBD. PMID- 29121516 TI - Comparing motor performance, praxis, coordination, and interpersonal synchrony between children with and without Autism Spectrum Disorder (ASD). AB - Children with Autism Spectrum Disorder (ASD) have basic motor impairments in balance, gait, and coordination as well as autism-specific impairments in praxis/motor planning and interpersonal synchrony. Majority of the current literature focuses on isolated motor behaviors or domains. Additionally, the relationship between cognition, symptom severity, and motor performance in ASD is unclear. We used a comprehensive set of measures to compare gross and fine motor, praxis/imitation, motor coordination, and interpersonal synchrony skills across three groups of children between 5 and 12 years of age: children with ASD with high IQ (HASD), children with ASD with low IQ (LASD), and typically developing (TD) children. We used the Bruininks-Oseretsky Test of Motor Proficiency and the Bilateral Motor Coordination subtest of the Sensory Integration and Praxis Tests to assess motor performance and praxis skills respectively. Children were also examined while performing simple and complex rhythmic upper and lower limb actions on their own (solo context) and with a social partner (social context). Both ASD groups had lower gross and fine motor scores, greater praxis errors in total and within various error types, lower movement rates, greater movement variability, and weaker interpersonal synchrony compared to the TD group. In addition, the LASD group had lower gross motor scores and greater mirroring errors compared to the HASD group. Overall, a variety of motor impairments are present across the entire spectrum of children with ASD, regardless of their IQ scores. Both, fine and gross motor performance significantly correlated with IQ but not with autism severity; however, praxis errors (mainly, total, overflow, and rhythmicity) strongly correlated with autism severity and not IQ. Our study findings highlight the need for clinicians and therapists to include motor evaluations and interventions in the standard-of-care of children with ASD and for the broader autism community to recognize dyspraxia as an integral part of the definition of ASD. PMID- 29121520 TI - Effects of growth hormone-releasing hormone gene targeted ablation on ghrelin induced feeding. AB - Impairment of growth hormone (GH) signaling has been associated with increased feeding and adiposity. The gastric hormone ghrelin, in addition to its GH secretagogue effects, stimulates food intake after both central and peripheral administration. In the present study we further investigated the feeding regulatory role of the ghrelin-GH axis in a mouse model of isolated GH deficiency due to targeted ablation of the GH-releasing hormone (GHRH) gene [GHRH knockout (GHRHKO)]. We evaluated the effects of intracerebroventricular ghrelin administration on feeding behavior, related hypothalamic neuropeptides and neurotransmitters, and serum ghrelin levels in mice homozygous for GHRHKO allele (-/-) and heterozygous (+/-) control animals. Vehicle-treated GHRHKO mice showed increased food intake compared to heterozygotes, associated with increased circulating ghrelin levels. Moreover, -/- mice showed elevated hypothalamic levels of neuropeptide Y (NPY), agouti-related peptide (AgRP) mRNAs and norepinephrine (NE) and decreased corticotropin-releasing hormone (CRH) mRNA levels. Ghrelin treatment significantly augmented food intake in both genotypes, but the relative increase compared to vehicle-treated animals was higher in -/- than +/- mice. In the hypothalamus, ghrelin increased AgRP and decreased CRH gene expression only in heterozygous mice, while it induced a significant reduction in proopiomelanocortin (POMC) mRNA levels in -/- mice. Ghrelin treatment also decreased hypothalamic serotonin (5-hydroxytriptamine, 5-HT) and dopamine (DA) levels in both genotypes. Additionally, we observed increased DA metabolism induced by ghrelin in both genotypes. In conclusion, dysregulation of the ghrelin GHRH-GH axis in GHRHKO mice could lead to increased feeding secondary to elevated circulating levels of ghrelin, and the obesogenic phenotype is likely mediated by elevated NPY and AgRP, and decreased CRH gene expression in the hypothalamus. PMID- 29121521 TI - Induced pluripotent stem cells derived from an autosomal dominant polycystic kidney disease patient carrying a PKD1 Q533X mutation. AB - Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent monogenic kidney disorder leading to kidney failure. We generated induced pluripotent stem cells (iPSCs) from a 37-year-old man carrying a PKD1 Q533X mutation who suffered from kidney failure and a myocardial infarction. The iPSCs were reprogrammed from the patient's peripheral blood mononuclear cells using the Sendai virus system, and were confirmed to possess the specific PKD1 Q533X mutation and normal karyotype. Pluripotency was confirmed using in vitro and in vivo assays. This iPSC line will be useful for studying the mechanisms driving the complicated pathophysiology of ADPKD. PMID- 29121522 TI - Effects of vitamin K antagonist on aortic valve degeneration in non-valvular atrial fibrillation patients: Prospective 4-year observational study. AB - BACKGROUND: The prevalence of atrial fibrillation (AF) is high in elder subjects. Our previous observational study suggested that vitamin K antagonist (VKA) promotes aortic valve degeneration, a principal cause of aortic stenosis in the elderly, and that angiotensin receptor blocker (ARB) attenuates its progression. This study aimed to prospectively investigate these observations in non-valvular AF patients. METHODS: Of enrolled 430 patients with calcification on no or one aortic valve leaflet, all of the planned 4-year follow-up data were obtained in 122 non-valvular AF patients treated with warfarin (warfarin group) and 101 patients with cardiovascular diseases and without AF and prescription of warfarin (non-warfarin group). RESULTS: Despite higher atherosclerotic risks in the non warfarin group, 2 or 3 newly calcified leaflets emerged during 4years in 18.0% of patients in the warfarin group and in 6.9% in the non-warfarin group (p=0.014). Aortic valve area (AVA) did not significantly change in the non-warfarin group during the follow-up, but tended to decrease in the warfarin group (p=0.057). Non vitamin K antagonist oral anticoagulant got available in Japan after this study started, and warfarin was discontinued in 15 patients of the warfarin group. The reduction of AVA was significant in the remaining 107 patients on the continuous warfarin treatment (p=0.002). The effects of ARB on AVA were obscure. CONCLUSION: Major bleeding associated with VKA is well recognized. This study suggests that the development of aortic valve degeneration is another risk of long-term use of VKA in non-valvular AF patients with no or mild aortic valve degeneration. PMID- 29121523 TI - Spectroscopic studies of the silicone oil impact on the ophthalmic hydrogel based materials conducted in time dependent mode. AB - Silicone oil is the one of the artificial materials used in vitreoretinal surgery for retinal detachment treatment. Since the silicone oil is sometimes applied along with intraocular lens (IOL) implantation the direct influence of silicone oil on the artificial implant should be taken into account. Presented study was performed in order to determine the time-dependent impact of silicone oil on hydrogel based ophthalmic materials. Two kinds of IOLs based on hydroxyethyl 2 methacrylate (HEMA) hydrogel material were immersed in silicone oil based on linear poly(dimethylsiloxane) (PDMS). Incubation in oil medium was performed in 37 degrees C for 1, 3 and 6months. After appropriate period of the incubation samples were examined by means of FTIR-ATR method as the technique of surface study as well as Positron Annihilation Lifetime Spectroscopy (PALS) as the method of internal structure investigation. Results obtained during the study revealed that silicone oil is not capable to penetrate the internal structure of investigated materials and its impact has come down to interaction with the samples surfaces only. PMID- 29121524 TI - Eating quality traits of shoulder roast and stir fry cuts outperformed loin and silverside cuts sourced from entire and immunocastrated male pigs. AB - This study investigated the effects of ageing period (2 or 7days), endpoint temperature (70 or 75 degrees C), cut type (loin (M. longissimus thoracis et lumborum), silverside (M. biceps femoris), blade (M. triceps brachii) and chuck tender (M. supraspinatus)), cooking method (roast and stir fry (all cuts) and steak (loin only)) on eating quality attributes of pork from entire and immunocastrated male pigs. Higher intramuscular fat levels were found in all cuts from immunocastrated males compared with entire males. Of the seven cut type*cooking method combinations evaluated, shoulder cuts had the lowest fail rate (P<0.001) and loin steak and silverside cuts scored lowest (P<0.001) for tenderness, juiciness, overall liking, quality grade and re-purchase intention. Although no differences in sensory scores due to gender were observed, boar taint was identified in 10% of entire males. Minimising adverse risks in eating quality due to boar taint in males remains a key industry issue to ensure consistent delivery of high quality pork. PMID- 29121525 TI - Psychometric properties of the Affordances in the Home Environment for Motor Development inventory for use with Iranian children aged 18-42 months. AB - OBJECTIVE: The aim of this study was to translate the original English language version of the Affordances in the Home Environment for Motor Development (AHEMD) inventory and test its psychometric properties for use with Iranian children aged 18-42 months. METHODS: For this purpose, the tool was translated into Farsi (a Persian language) using the forward-backward translation method and some of its psychometric properties were examined. Multistage stratified-cluster sampling was used to study 1019 families having children aged 18-42 months from among the regional divisions of Tehran urban community health centers. The questionnaire evaluated five factors: outside space, inside space, variety of stimulation, fine motor toys and gross motor toys. Expert opinion was used for content-related validity evaluation and confirmatory factor analysis was used to determine construct validity. For test-retest reliability, parents completed identical questionnaires two weeks apart. Internal consistency was evaluated using inter examiner reliability, Cronbach's alpha and construct reliability. Linear regression analysis was used to explain and predict the effects of toys on AHEMD total score. RESULTS: Results showed that content-related validity was 0.92. Data confirmatory factor analysis showed an acceptable fit to the original five factors. Reliability over time was 0.91 and internal consistency was 0.93. It was also found that fine- and gross-motor toys showed a significant 55% predictability of affordance provision in the home. CONCLUSION: The Farsi translation of the AHEMD is acceptable for use with Iranian children aged 18-42 month. PMID- 29121526 TI - Waiting for a treat. Studying behaviors related to self-regulation in 18- and 24 month-olds. AB - The ability to delay gratification - conceived as an early expression of self regulation - develops in the second half of the second year of life. We used inductive methodology to identify different behaviors and set of behaviors performed by children while waiting for a treat. We asked which sets are more effective when it comes to successfully delaying gratification and how all observed sets change during toddler age. 130 children were tested twice - at 18 and at 24 months - using a Snack Delay Task. We observed 20 different behaviors and distinguished 4 sets of behaviors. The most important and effective set for delaying gratification in 18 and in 24 month olds was the set called Attention and Movements. We concluded that growth in the ability to delay gratification resulted from increased ability to overcome temptation by using an active strategy mainly based on attention. PMID- 29121527 TI - The role of distress tolerance in the relationship between cognitive schemas and alcohol problems among college students. AB - INTRODUCTION: The current study tested the role of distress tolerance in the relationship between three early maladaptive cognitive schemas (Abandonment, Defectiveness/Shame, and Insufficient Self-Control) and alcohol problems among college students (N=364). Previous research suggests that maladaptive cognitive schemas may be a risk factor for alcohol-related problems. However, the mechanism underlying this association is unclear. One's tolerance for emotional distress may play an important role in understanding the nature of this association. METHODS: We tested a structural equation model where distress tolerance was expected to explain or moderate associations between early maladaptive schemas and alcohol outcomes. RESULTS: Results indicated distress tolerance partially mediated the relationships between schemas of Abandonment and Insufficient Self Control and alcohol problems. Distress tolerance also significantly moderated the relationship between the Defectiveness/Shame schema and alcohol-related problems, reducing the strength of the association. CONCLUSIONS: Distress tolerance is a modifiable risk factor and the results of this study support the inclusion of emotional regulation strategies in the prevention and treatment of alcohol problems among young adults. PMID- 29121528 TI - A detailed examination of the longitudinal associations between individual and team sports and alcohol use. AB - This study examined the longitudinal associations between participation in individual and team sports and indicators of alcohol use during the high school years and beyond. A total of 310 youths were surveyed over six waves of data collection (ages 12, 14 to 17, and 19). Participation in individual and team sports was measured through phone interviews, whereas frequency of alcohol use, frequency of intoxication, and problematic alcohol use were self-reported. Control variables included participation in other types of organized activities, sex, family income and structure, parental education and knowledge, problem behaviors, deviant peers, and peer status. The results of autoregressive latent trajectory models revealed reciprocal associations between time spent in individual sports and frequency of alcohol use and intoxication. The results also revealed that time spent in team sports predicted an increase in frequency of alcohol use in middle adolescence. Lastly, the only significant finding at age 19 suggested that the initial number of hours spent in individual sports predicted lower scores on alcohol intoxication. These findings suggest that team sports act as a risk factor for less severe forms of alcohol use in middle adolescence, whereas individual sports act as a protective factor against more severe forms of alcohol use during adolescence and beyond. PMID- 29121529 TI - An examination of heavy drinking, depressed mood, drinking related constructs, and consequences among high-risk college students using a person-centered approach. AB - INTRODUCTION: Research has identified college students who experience depressed mood and consume alcohol are at an increased risk for experiencing alcohol problems. The present study identified profiles of differential alcohol use, depression, key psychosocial indicators of drinking (e.g., normative perceptions) and examined the relationship between these profiles and alcohol-related consequences. METHOD: Students with a history of risky drinking and elevated depressed mood (n=311; 62.4% female) completed a web-based survey assessing typical and peak drinking, depressive symptoms, descriptive norms, drinking to cope motives, protective behavioral strategies, and alcohol-related consequences. RESULTS: Latent profile analysis was used to classify participants into distinct profiles focusing on alcohol use patterns and level of depressed mood and drinking related constructs. Profiles were then compared based on their association with reported rates of alcohol-related consequences. Four profiles emerged: 1) Mild Depression, Heavy Drinkers; 2) Mild Depression, Severe Drinkers; 3) Moderate Depression, Heavy Drinkers; and 4) Moderate Depression, Severe Drinkers. Findings revealed significant differences between the four profiles on both risky drinking and alcohol-related consequences. CONCLUSION: These findings suggest the importance of assessing and addressing depressive symptoms among college students in order to reduce rates of risky drinking and alcohol-related consequences. PMID- 29121530 TI - An ecological momentary intervention for smoking cessation: The associations of just-in-time, tailored messages with lapse risk factors. AB - BACKGROUND: Smartphone apps can provide real-time, tailored interventions for smoking cessation. The current study examines the effectiveness of a smartphone based smoking cessation application that assessed risk for imminent smoking lapse multiple times per day and provided messages tailored to current smoking lapse risk and specific lapse triggers. METHODS: Participants (N=59) recruited from a safety-net hospital smoking cessation clinic completed phone-based ecological momentary assessments (EMAs) 5 times/day for 3 consecutive weeks (1week pre-quit, 2weeks post-quit). Risk for smoking lapse was estimated in real-time using a novel weighted lapse risk estimator. With each EMA, participants received messages tailored to current level of risk for imminent smoking lapse and self reported presence of smoking urge, stress, cigarette availability, and motivation to quit. Generalized linear mixed model analyses determined whether messages tailored to specific lapse risk factors were associated with greater reductions in these triggers than messages not tailored to specific triggers. RESULTS: Overall, messages tailored to smoking urge, cigarette availability, or stress corresponded with greater reductions in those triggers than messages that were not tailored to specific triggers (p's=0.02 to <0.001). Although messages tailored to stress were associated with greater reductions in stress than messages not tailored to stress, the association was non-significant (p=0.892) when only moments of high stress were included in the analysis. CONCLUSIONS: Mobile technology can be used to conduct real-time smoking lapse risk assessment and provide tailored treatment content. Findings provide initial evidence that tailored content may impact users' urge to smoke, stress, and cigarette availability. PMID- 29121531 TI - Decreased pain tolerance before surgery and increased postoperative narcotic requirements in abstinent tobacco smokers. AB - INTRODUCTION: The clinical influence of smoking cessation on pain tolerance before surgery and postoperative pain perception is not fully understood. This clinical study investigated the effect of smoking cessation on pain threshold during the perioperative period in patients undergoing hepatic resection. METHODS: We enrolled 148 male patients (68 non-smokers and 80 abstinent smokers) who underwent hepatic resection and received postoperative patient-controlled intravenous analgesia. Patients were tested for preoperative pain thresholds in response to electrical stimuli. We recorded the cumulative amount of extra morphine equivalent required during the first 48h after surgery. Pain intensity was evaluated at 1h, 6h, 24h and 48h after surgery using the visual analogue scale (VAS). Additionally, button-pressing consumption was recorded by a patient controlled analgesia (PCA) pump. RESULTS: The groups did not differ with respect to baseline clinical characteristics. Compared with non-smokers, abstinent smokers exhibited lower pain thresholds before surgery and demanded a larger quantity of extra morphine equivalent during the first 48h after surgery. Abstinent smokers also exhibited more severe postoperative pain than non-smokers. Postoperative complications, such as nausea, vomiting, dizziness, sedation, and respiratory depression, did not significantly differ between the two groups. CONCLUSIONS: In this study, smokers deprived of cigarettes exhibited decreased pain tolerance before surgery and required a larger quantity of postoperative extra morphine equivalent than non-smokers. Health care providers must be aware of the potential for increased narcotic requirements in smokers. PMID- 29121532 TI - Paeoniflorin inhibits VSMCs proliferation and migration by arresting cell cycle and activating HO-1 through MAPKs and NF-kappaB pathway. AB - The proliferation, migration and inflammation of vascular smooth muscle cells (VSMCs) contributes to the pathogenesis and progression of atherosclerosis. Paeoniflorin (PF) as active compound in the Rhizoma Atractylodes macrocephala has been used for various diseases like cancer, splenic asthenia, anaphylaxis and anorexia. This study aimed to explore whether and how PF regulated the inflammation, proliferation and migration of VSMCs under ox-LDL stimulation. Here, we found that PF dose-dependently inhibited ox-LDL-induced VSMCs proliferation and migration, and decreased inflammatory cytokines and chemokine overexpression. Mechanistically, PF prevented p38, ERK1/2 and NF-kappaB phosphorylation, and arrested cell cycle in S phase. Meanwhile, PF regulated the HO-1 and PCNA expression. Furthermore, PF blocked the foam cell formation in macrophages induced by ox-LDL. These results indicate that PF antagonizes the ox LDL-induced VSMCs proliferation, migration and inflammation through activation of HO-1, cell cycle arrest and then suppression of p38, ERK1/2/MAPK and NF-kappaB signaling pathways. PMID- 29121533 TI - Novel treatments for chronic hepatitis C: closing the remaining gaps. AB - Direct acting antivirals (DAAs) have revolutionized the treatment of chronic hepatitis C virus (HCV) infection with cure rates >90% for the majority of patients and excellent safety profile. However, there remain certain unmet needs in treating HCV including treatment for patients that failed a prior DAA regimen and for those with advanced chronic kidney disease. In addition, shortening the duration of DAA regimens has the potential to increase compliance and decrease the cost of care. New regimens that were approved by the FDA in 2017 address these unmet needs and will be discussed in this concise review. PMID- 29121534 TI - Public health regulation and mortality: Evidence from early 20th century milk laws. AB - In this paper, I estimate the impact of city-level public health regulations in the market for cow's milk on the mortality of infants and young children between 1900 and 1920. I find that the introduction of city-level dairy farm inspections reduced mortality from Diarrhea & Enteritis for one-year-old children by 1.3 annual deaths per thousand, a 14 percent effect relative to the baseline rate for this cause and a 3 percent effect relative to the baseline rate for all causes for this age group. Back-of-the-envelope calculations reveal that the benefits from these regulations exceeded costs by at least a factor of two. PMID- 29121535 TI - In vitro effects of benzimidazole/thioether-copper complexes with antitumor activity on human erythrocytes. AB - Two cytotoxic copper(II) complexes with N-H and N-methylated benzimidazole derived ligands (Cu-L1 and Cu-L1Me; L1=bis(2-methylbenzimidazolyl)(2 methylthioethyl)amine, L1Me=bis(1-methyl-2-methylbenzimidazolyl)(2 methylthioethyl)amine) were synthesized and exposed to human erythrocytes and molecular models of its membrane. The latter were bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), classes of lipids present in the external and internal moieties of the human red cell membrane, respectively. Scanning electron microscopy (SEM) of erythrocytes incubated with solutions of both Cu(II) complexes showed that they induced morphological changes to the normal cells to echinocytes, and hemolysis at higher concentrations. Real-time observation of the dose-dependent effects of the complexes on live erythrocytes by defocusing microscopy (DM) confirmed SEM results. The formation of echinocytes implied that complex molecules inserted into the outer moiety of the red cell membrane. X-ray diffraction studies on DMPC and DMPE showed that none of these complexes interacted with DMPE and only Cu-L1 interacted with DMPC. This difference was explained by the fact that Cu-L1Me complex is more voluminous than Cu-L1 because it has two additional methyl groups; on the other hand, DMPC molecule has three methyl groups in its bulky terminal amino end. Thus, by steric hindrance Cu-L1Me molecules cannot intercalate into DMPC bilayer, which besides is present in the gel phase. These results, together with the increased antiproliferative capacity of the N methylated complex Cu-L1Me over that of Cu-L1 are rationalized mainly based on its higher lipophilicity. PMID- 29121536 TI - A far greater sense of community: The impact of volunteer behaviour on the wellness of rural older Australians. AB - This paper builds on place-based research investigating the transformative potential of volunteering for service-deprived, ageing rural communities. Here, we critically explore the relationship between communities of place, voluntarism and wellness for rural older Australians. We draw on data from a large qualitative multi-site study, and utilise Ryan et al.'s (2005) systemic model of community attachment. Findings support the dual perspective of strong community sentiments through social embeddedness in rural communities; and personal interests, associated with rational choice theory, through healthy ageing practices. Both aspects have demonstrated positive impact on wellness, but also risks to wellness associated with over-expectations of volunteers. PMID- 29121537 TI - Permethrin drastically affects the developmental cycle of the non-target slime mould Dictyostelium discoideum. AB - The use of pyrethroids has increased throughout the world over the past few decades, as organophosphate, carbamate and organochlorine insecticides are being phased out. Permethrin is widely used in the USA for crops treatment, at concentrations around 750 * 103 MUg/L. In our study 3.6 MUg/L permethrin decreases the fission-rate and the fruiting bodies formation of slime mould Dictyostelium discoideum. Whereas 3.6 * 104 MUg/L kills the 100% of amoebae, showing a 24 h-LC50 = 96.6 MUg/L. This concentration induces an increase in the pseudocholinesterase activity as well as in both butyrylcholinesterase and heat shock-protein 70 presence. Our results highlight the high sensitivity of Dictyostelium to permethrin, at concentration of about 105 lesser than what used for agricultural pest control. If we match our results on 6 days of exposure, with the permethrin relatively slow permanence (30 days) in the aerobic soil, as well as the higher effect of permethrin than organophosphate, carbamate and organochlorine pesticides on D. discoideum, the damage on the dictyostelids community, by use of permethrin, is clear. Our data suggest that, if the sustainable agriculture implementation is a topic of the modern "industrial" farming, the permethrin cannot represent a reliable alternative to organochlorine, organophosphate or carbamate pesticides, in implementing Integrated Pest Management programmes. PMID- 29121538 TI - Therapeutic options for leukemic transformation in patients with myeloproliferative neoplasms. AB - Approximately 5-10% of patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPN) comprising of essential thrombocythemia, polycythemia vera and primary myelofibrosis) experience transformation to acute myeloid leukemia (AML, >=20% blasts). Treatment options for post-MPN AML patients are limited, as conventional approaches like standard chemotherapy, fail to offer long-term benefit. Median survival for secondary AML is ~2.4 months. Post-MPN AML therefore represents an area of urgent clinical need. At present, allogeneic stem cell transplant (ASCT) following induction therapy is the best therapeutic option. Patients ineligible for ASCT are treated with hypomethylating agents. New agents under investigation include histone deacetylase inhibitors, JAKinhibitors and agents targeting the BRD4 protein. Combined treatment strategies involving these novel agents are being tested. In this review we present the current evidence regarding treatment options for post-MPN AML patients. PMID- 29121540 TI - Computer aided diagnosis of diabetic foot using infrared thermography: A review. AB - Diabetes mellitus (DM) is a chronic metabolic disorder that requires regular medical care to prevent severe complications. The elevated blood glucose level affects the eyes, blood vessels, nerves, heart, and kidneys after the onset. The affected blood vessels (usually due to atherosclerosis) may lead to insufficient blood circulation particularly in the lower extremities and nerve damage (neuropathy), which can result in serious foot complications. Hence, an early detection and treatment can prevent foot complications such as ulcerations and amputations. Clinicians often assess the diabetic foot for sensory deficits with clinical tools, and the resulting foot severity is often manually evaluated. The infrared thermography is a fast, nonintrusive and non-contact method which allows the visualization of foot plantar temperature distribution. Several studies have proposed infrared thermography-based computer aided diagnosis (CAD) methods for diabetic foot. Among them, the asymmetric temperature analysis method is more superior, as it is easy to implement, and yielded satisfactory results in most of the studies. In this paper, the diabetic foot, its pathophysiology, conventional assessments methods, infrared thermography and the different infrared thermography-based CAD analysis methods are reviewed. PMID- 29121539 TI - Clinical and biological significance of isolated Y chromosome loss in myelodysplastic syndromes and chronic myelomonocytic leukemia. A report from the Spanish MDS Group. AB - Isolate loss of chromosome Y (-Y) in myelodysplastic syndromes (MDS) is associated to a better outcome but it is also well described as an age-related phenomenon. In this study we aimed to analyze the prognostic impact of -Y in the context of the IPSS-R cytogenetic classification, evaluate the clinical significance of the percentage of metaphases with isolated -Y, and test whether finding -Y may predispose to over-diagnose MDS in patients with borderline morphological features. We evaluated 3581 male patients from the Spanish MDS Registry with a diagnosis of MDS or chronic myelomonocytic leukemia (CMML). -Y was identified in 177 patients (4.9%). Compared with the 2246 male patients with normal karyotype, -Y group showed a reduced risk of leukemic transformation that did not translate into a survival advantage. The overall survival and the risk of leukemic transformation were not influenced by the percentage of metaphases with Y. The -Y group was not enriched in patients with minor morphologic traits of dysplasia, suggesting that the better outcome in the -Y group cannot be explained by enrichment in cases misdiagnosed as MDS. In conclusion, our results support the current recommendation of classifying patients with -Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated -Y would be of interest as it may provide a biological basis of protection against progression to acute leukemia. PMID- 29121541 TI - Development of a Reinforcement Learning-based Evolutionary Fuzzy Rule-Based System for diabetes diagnosis. AB - The early diagnosis of disease is critical to preventing the occurrence of severe complications. Diabetes is a serious health problem. A variety of methods have been developed for diagnosing diabetes. The majority of these methods have been developed in a black-box manner, which cannot be used to explain the inference and diagnosis procedure. Therefore, it is essential to develop methods with high accuracy and interpretability. In this study, a Reinforcement Learning-based Evolutionary Fuzzy Rule-Based System (RLEFRBS) is developed for diabetes diagnosis. The proposed model involves the building of a Rule Base (RB) and rule optimization. The initial RB is constructed using numerical data without initial rules; after learning the rules, redundant rules are eliminated based on the confidence measure. Next, redundant conditions in the antecedent parts are pruned to yield simpler rules with higher interpretability. Finally, an appropriate subset of the rules is selected using a Genetic Algorithm (GA), and the RB is constructed. Evolutionary tuning of the membership functions and weight adjusting using Reinforcement Learning (RL) are used to improve the performance of RLEFRBS. Moreover, to deal with uncovered instances, it makes use of an efficient rule stretching method. The performance of RLEFRBS was examined using two common datasets: Pima Indian Diabetes (PID) and BioSat Diabetes Dataset (BDD). The experimental results show that the proposed model provides a more compact, interpretable and accurate RB that can be considered to be a promising alternative for diagnosis of diabetes. PMID- 29121542 TI - Risk factors for three-month mortality after discharge in a cohort of non oncologic hospitalized elderly patients: Results from the REPOSI study. AB - BACKGROUND: Short-term prognosis, e.g. mortality at three months, has many important implications in planning the overall management of patients, particularly non-oncologic patients in order to avoid futile practices. The aims of this study were: i) to investigate the risk of three-month mortality after discharge from internal medicine and geriatric wards of non-oncologic patients with at least one of the following conditions: permanent bedridden status during the hospital stay; severely reduced kidney function; hypoalbuminemia; hospital admissions in the previous six months; severe dementia; ii) to establish the absolute risk difference of three-month mortality of bedridden compared to non bedridden patients. METHODS: This prospective cohort study was run in 102 Italian internal medicine and geriatric hospital wards. The sample included all patients with three-months follow-up data. Bedridden condition was defined as the inability to walk or stand upright during the whole hospital stay. The following parameters were also recorded: estimated GFR<=29mL/min/1.73m2; severe dementia; albuminemia ?2.5g/dL; hospital admissions in the six months before the index admission. RESULTS: Of 3915 patients eligible for the analysis, three-month follow-up were available for 2058, who were included in the study. Bedridden patients were 112 and the absolute risk difference of mortality at three months was 0.13 (CI 95% 0.08-0.19, p?0.0001). Logistic regression analysis also adjusted for age, sex, number of drugs and comorbidity index found that bedridden condition (OR 2.10, CI 95% 1.12-3.94), severely reduced kidney function (OR 2.27, CI 95% 1.22-4.21), hospital admission in the previous six months (OR 1.96, CI 95% 1.22-3.14), severe dementia (with total or severe physical dependence) (OR 4.16, CI 95% 2.39-7.25) and hypoalbuminemia (OR 2.47, CI 95% 1.12-5.44) were significantly associated with higher risk of three-month mortality. CONCLUSIONS: Bedridden status, severely reduced kidney function, recent hospital admissions, severe dementia and hypoalbuminemia were associated with higher risk of three month mortality in non-oncologic patients after discharge from internal medicine and geriatric hospital wards. PMID- 29121543 TI - Up-stream mechanisms for up-regulation of miR-125b from triclosan exposure to zebrafish (Danio rerio). AB - Triclosan (TCS) exposure has widely adverse biological effects such as influencing biological reproduction and endocrine disorders. While some studies have addressed TCS-induced expression changes of miRNAs and their related down stream target genes, no data are available concerning how TCS impairs miRNA expression leading us to study up-stream regulating mechanisms. Four miRNAs (miR 125b, miR-205, miR-142a and miR-203a) showed differential expression between TCS exposure treatments and the control group; their functions mainly involved fatty acid synthesis and metabolism. TCS exposure led to the up-regulation of mature miR-125b that was concomitant with consistent changes in pri-mir-125b-1 and pri mir-125b-3 among its 3 pri-mir-125bs. Up-regulation of miR-125b originated from direct shear processes involving the two up-regulated precursors, but not pri-mir 125b2. Increased expression of pri-mir-125b-1 and pri-mir-125b-3 resulted from nfe2l2- and c/ebpalpha-integration with positive control elements of promoters for the two precursors. The overexpression of transcriptional factors, nfe2l2 and c/ebpalpha, initiated the promoter activity for the miR-125b precursor. CpG islands and Nfe2l2 were involved in constitutive expression of mir-125b-1 and mir 125b-3. The activities of two promoter regions, -487 to -1bp for pri-mir-125b1 and -1327 to +14bp for pri-mir-125b-3 having binding sites for NFE2 and Nfe2l2/MAF:NFE2, were higher than other regions, further demonstrating that the transcriptional factor Nfe2l2 was involved in the regulation of pri-mir-125b1 and pri-mir-125b-3. TCS's estrogen activity resulted from its effects on GPER, a novel membrane receptor, rather than the classical ERalpha and ERbeta. These results explain, to some extent, the up-stream mechanism for miR-125b up regulation, and also provide a guidance to future mechanistic study on TCS exposure. PMID- 29121544 TI - Brain volumetric analysis and cortical thickness in adults with saccadic intrusions (ocular flutter or opsoclonus-myoclonus syndrome). AB - OBJECTIVES: Ocular flutter (OF) and opsoclonus are considered a continuum with a similar pathogenesis. Due to the rarity of this disease in the adult population, little is known about the brain morphological changes in the chronic phase of the disease. PATIENTS AND METHODS: Six magnetic resonance imaging from adults with previous history of OF/Opsoclonus and 12 healthy patients (paired by age and sex) were analyzed in order to identify the long term cortical thickness pattern in this rare disease by using Freesurfer. RESULTS: Patients with OF/Opsoclonus showed reduced cerebellum cortical volume with a subsequent diminution in total cerebellar volume. White mater cerebellum volume was not modified. In addition, we have also identified a significant supratentorial gray matter volume decrease in OF/Opsoclonus patients, involving both the cortical and the subcortical gray matter. CONCLUSIONS: OF/Opsoclonus in adults may be associated with cortical and subcortical gray matter atrophy, as well as decreased cerebellar cortical volume. Further larger prospective studies are necessary to confirm these results. PMID- 29121546 TI - Pectoral nerves 1 block is effective for silent manipulation of frozen shoulder. PMID- 29121545 TI - Higher-order cognitive training effects on processing speed-related neural activity: a randomized trial. AB - Higher-order cognitive training has shown to enhance performance in older adults, but the neural mechanisms underlying performance enhancement have yet to be fully disambiguated. This randomized trial examined changes in processing speed and processing speed-related neural activity in older participants (57-71 years of age) who underwent cognitive training (CT, N = 12) compared with wait-listed (WLC, N = 15) or exercise-training active (AC, N = 14) controls. The cognitive training taught cognitive control functions of strategic attention, integrative reasoning, and innovation over 12 weeks. All 3 groups worked through a functional magnetic resonance imaging processing speed task during 3 sessions (baseline, mid training, and post-training). Although all groups showed faster reaction times (RTs) across sessions, the CT group showed a significant increase, and the WLC and AC groups showed significant decreases across sessions in the association between RT and BOLD signal change within the left prefrontal cortex (PFC). Thus, cognitive training led to a change in processing speed-related neural activity where faster processing speed was associated with reduced PFC activation, fitting previously identified neural efficiency profiles. PMID- 29121547 TI - Magnesium suprascapular nerve block for the management of painful shoulder disorders. PMID- 29121548 TI - Point-of-care viscoelastic testing improves the outcome of pregnancies complicated by severe postpartum hemorrhage. AB - Study Objective. To compare the clinical outcomes of patients with severe postpartum hemorrhage (PPH) managed with and without the use of Point-of-Care Viscoelastic Testing (PCVT) to direct blood product replacement. Design. A retrospective cohort study of consecutive cases of severe PPH managed at a single tertiary care center between January 1, 2011 and July 31, 2015. Cases included patients managed using PCVT. Controls were patients managed using a standardized massive hemorrhage transfusion protocol, either because PCVT was not yet available or because no PCVT credentialed providers were on site. Setting. Delivery room, postoperative recovery area, intensive care unit. Patients. There were 6,708 cesarean deliveries and 13,641 vaginal births during the study period. Eighty six patients (0.4% of all deliveries) developed severe PPH. Severe PPH occurred in 1% (68/6,708) of cesarean and 0.1% (18/13,641) of vaginal deliveries. Twenty-eight of these 86 patients (32.6%) were managed with PCVT and 58 (67.4%) without PCVT. Interventions. Patients with severe PPH were managed according to a standardized massive transfusion protocol or a PCVT-based protocol to direct blood product replacement. Measurements. PCVT testing was performed using a ROTEM delta device. Results. Patients in the PCVT cohort received significantly fewer transfusions of packed red blood cells, fresh frozen plasma, and platelet concentrates. They also had a significantly lower estimated blood loss, and a significantly lower incidence of cesarean hysterectomy and postoperative ICU admission as compared with patients not managed using PCVT. The length of postpartum hospitalization was also significantly shorter in the PCVT cohort. Among patients who gave birth within 24 hours of admission, the direct cost of hospitalization was 40% lower for patients in the PCVT cohort. Conclusions. PCVT based goal-directed blood product replacement management was associated with substantial benefits over a standardized massive transfusion protocol both in terms of patient outcomes and cost of care. PMID- 29121549 TI - Failed neonatal intubation rescued with a tongue stitch and Glidescope-assisted fiberoptic technique. PMID- 29121550 TI - Attitudes, beliefs and comfort levels of midwifery students regarding sexual counselling in Turkey. AB - OBJECTIVE: this aim of this study was to determine midwifery students' attitudes and beliefs regarding sexual counselling, the factors preventing effective sexual counselling and comfort levels towards sexual counselling. PARTICIPANTS: the study was conducted with 650 students studying in the midwifery departments of eight universities in Turkey (response rate 59.1%). DESIGN: the data were obtained through a self-administered questionnaire in early 2016, which collected sociodemographic characteristics and comfort levels, and used the Sexuality Attitudes and Beliefs Survey. FINDINGS: just over half (52.4%) of the students had been confronted in clinical practice with caring for a woman who reported having sexual problems and 74.9% reported that the women they were caring for requested sexual counselling from them. Just under a half (48.8%), stated that midwives talk about these issues during care and a similar proportion (48.3%) reported that issues about sexual counselling were part of their midwifery education. Just over half (53.5%) of the midwifery students stated that sexuality is a very special subject to discuss with women but that insufficient time created a barrier to being able to discuss sexual problems. The students did not feel comfortable counselling all women, including homosexual women or sex workers who may be potentially carrying HIV. CONCLUSIONS: even though the attitudes of midwifery students toward sexual counselling were good, students were not always comfortable to provide counselling, especially to particular groups of women. IMPLICATIONS FOR PRACTICE: attitudes, beliefs and comfort levels of midwifery students about sexuality and sexual counselling can be improved. Students are an important group to target as they are specialised in women's health, Different groups should be supported through training concerning sexual counselling. PMID- 29121551 TI - Trans-generational transmission of altered phenotype resulting from flubendiamide induced changes in apoptosis in larval imaginal discs of Drosophila melanogaster. AB - The eye and wing morphology of Drosophila melanogaster maintain unique, stable pattern of genesis from larval eye and wing imaginal discs. Increased apoptosis in cells of eye and wing discs was found to be associated with flubendiamide (fluoride containing insecticide) exposure (at the range 0.25-10MUg/mL) in D. melanogaster larvae. The chemical fed larvae on attaining adulthood revealed alterations in morphology and symmetry of their compound eyes and wings through scanning electron microscopy. Nearly 40% and 30% of flies (P generation) demonstrated alterations in eyes and wings respectively. Transmission electron microscopic study (at the range 1-20MUg/mL) also established variation in the rhabdomere and pigment cell orientation as well as in the shape of the ommatidium. Subsequent SEM study with F1 and F2 generation flies also revealed structural variation in eye and wing. Decrease in percentage of altered eye and wing phenotype was noted in subsequent generations (P> F1>F2). Thus, the diamide insecticide, flubendiamide, expected to be environmentally safe at sub-lethal concentrations was found to increase apoptosis in larvae and thereby cause morphological alteration in the adult D. melanogaster. This study further demonstrated trans-generational transmission of altered phenotype in three subsequent generations of a non-target insect model, D. melanogaster. PMID- 29121552 TI - Developing digital educational materials for nursing and sustainability: The results of an observational study. AB - BACKGROUND: There is limited European literature on nursing and sustainability; nursing students are poorly prepared on the connections between resources, climate change, sustainability, and health, so they must acquire knowledge and develop skills and competencies in this field. The use of digital technologies and teaching via E-learning has grown, and has been widely adopted as a learning method for nursing. OBJECTIVES: The aim of the current study was to test and evaluate digital educational materials on environmental sustainability and health, in the context of university nursing education in different European countries. DESIGN: An observational cross-sectional design. SETTINGS: University of Plymouth, University of Jaen, and University of Esslingen for Nursing Degree Studies. PARTICIPANTS: 299 nursing students: 161 students from University of Jaen; 106 from Plymouth; and 32 from Esslingen. 22 professional evaluators with different profiles were recruited: Teachers, Clinical professionals, Delphi Experts, and Technical Experts. METHODS: We conducted a piloting and validation process. The materials were designed and adapted to the NurSusTOOLKIT Sustainability Literacy and Competency framework. Evaluation was developed by professionals and students. We used the Spanish Standard for the assessment of Digital Educational Material Quality at University level questionnaire. All students provided informed consent prior to taking part in the learning and evaluation. RESULTS: The overall evaluations of materials by students and professionals were 7.98+/-1.28 and 8.50+/-1.17, respectively. The Ability to generate learning was scored higher among students (mean difference: 0.84; 0.22 1.47; p=0.008). In the overall assessment by students, statistically significant differences were found between the three universities (Welch: 11.69, p<0.001). CONCLUSIONS: Students, professionals, and technical experts considered the materials to be very good quality, especially regarding the quality of contents, format, and design. For students, these materials can generate reflection and learning regarding environmental and health issues during nursing training. PMID- 29121553 TI - Stewards of children education: Increasing undergraduate nursing student knowledge of child sexual abuse. AB - BACKGROUND: Child sexual abuse and exploitation are an increasing public health problem. In spite of the fact that nurses are in a unique position to identify and intervene in the lives of children suffering from abuse due to their role in providing health care in a variety of settings, nursing curricula does not routinely include this focus. OBJECTIVES: The goal was to document the effectiveness of the Stewards of Children child sexual abuse training as an effective educational intervention to increase the knowledge level of undergraduate nursing students on how to prevent, recognize, and react responsibly to child sexual abuse and trafficking. DESIGN: Undergraduate nursing students were required to take the Stewards of Children training in their last semester prior to graduation. DATA SOURCES: Students in the study were given a pre-test prior to the class and a post-test following the class. REVIEW METHODS: Pre- and post-tests were graded and the results were compared along with an item indicating the participants' perception of the educational intervention in improving their confidence and competence in this area. RESULTS: Data analysis revealed that post-test scores following training were significantly improved: pre-test mean=45.5%; post-test mean score=91.9%. The statistical significance of the improvement was marked, p<0.01, N=119. The mean response for the perceived values scale was 1.65 from a potential score of 2. CONCLUSIONS: This study found a statistically significant increase in the knowledge level of undergraduate nursing students on how to prevent, recognize, and react responsibly to child sexual abuse and trafficking following the Stewards of Children training. Students also reported a high level of confidence in how to prevent abuse and react skillfully when child sexual abuse had occurred. The authors concluded that Stewards of Children is an effective option to educate nursing students on this topic. PMID- 29121554 TI - Age of onset of non-suicidal self-injury in Dutch-speaking adolescents and emerging adults: An event history analysis of pooled data. AB - OBJECTIVE: Non-Suicidal Self-Injury (NSSI) has emerged as an important mental health concern. However, epidemiological features like age of onset of NSSI have remained understudied. Therefore, the current study investigated the distribution of age of onset of NSSI in pooled sample of Dutch-speaking adolescents and emerging adults using event history analysis. METHOD: Eleven datasets measuring age at first NSSI in community and clinical participants collected by researchers in the Dutch-speaking part of Belgium were pooled together. The final dataset consisted of 1973 community males, 1901 community females, and 505 clinical females. Discrete-time event history analysis was used to model the effect of gender and psychiatric disorders on the age of onset of NSSI. RESULTS: Twenty-one percent of adolescents from the community samples engaged in at least one episode of NSSI by the age of 25years. Irrespective of the type of sample (community or psychiatric disorder), the probability of age of onset peaked around the age of 14-15years. A second peak was observed around the age of 20 and 24years in the community and psychiatric samples respectively. CONCLUSIONS: Psychosocial interventions for prevention of NSSI should not only target adolescence through school mental health programs but also target emerging adults at the university level. PMID- 29121555 TI - The relationship between ADHD traits and sensory sensitivity in the general population. AB - Preliminary studies in children and adults with Attention Deficit Hyperactivity Disorder (ADHD) report both hypo-responsiveness and hyper-responsiveness to sensory stimuli, as well as problems modulating sensory input. As it has been suggested that those with ADHD exist at the extreme end of a continuum of ADHD traits, which are also evident in the general population, we investigated the link between ADHD and sensory sensitivity in the general population. Two online questionnaires measuring ADHD traits and sensory responsivity across various sensory domains were administered to 234 participants. Results showed a highly significant positive correlation between the number of ADHD traits and the frequency of reported sensory processing problems. An increased number of sensory difficulties across all modalities were associated with the level of ADHD. Furthermore, ADHD traits predicted sensory difficulties and exploratory factor analysis revealed a factor that combined ADHD trait and sensory processing items. This is the first study to identify a positive relationship between sensory processing and ADHD traits in the general population. Our results suggest that sensory difficulties could be part of the ADHD phenotype. PMID- 29121556 TI - The efficacy of interventions for low back pain in nurses: A systematic review. AB - OBJECTIVES: To investigate the efficacy of interventions for the prevention and treatment of low back pain in nurses. DESIGN: Systematic review. DATA SOURCES: The review was registered on the PROSPERO database (CRD42015026941) and followed the PRISMA statement guidelines. A two phase approach was used. In phase one, all randomised controlled trials included in the systematic review of Dawson et al. (2007) which reviewed interventions for low back pain in nurses until 2004 were selected. In phase two, relevant randomised controlled trials and cluster randomised controlled trials published from 2004 until December 2015 were identified by an electronic search of nine databases (Embase, CINAHL, SPORTDiscus, PsycARTICLES, Cochrane Library, Web of Science, PEDro, Scopus and MEDLINE). To be eligible, trials had to examine the efficacy of interventions either for the prevention or treatment of low back pain in nurses. Primary outcomes of interest were any measure of pain and/or disability. REVIEW METHODS: Three reviewers independently assessed eligibility and two reviewers independently conducted a risk of bias assessment (Cochrane Back and Neck Group). RESULTS: Four studies were retrieved from phase one. In phase two, 15,628 titles and abstracts were scanned. From these, 150 full-text studies were retrieved and ten were eligible. Fourteen studies (four from phase one, ten from phase two) were eligible for risk of bias assessment. The included trials were highly heterogeneous, differing in pain and disability outcome measures, types of intervention, types of control group and follow-up durations. Only four of the included studies (n=644 subjects) had a low risk of bias (>=6/12). Manual handling training and stress management in isolation were not effective in nurses with and without low back pain (risk of bias, 7/12, n=210); the addition of a stretching exercise intervention was better than only performing usual activities (risk of bias, 6/12, n=127); combining manual handling training and back school was better than passive physiotherapy (risk of bias, 7/12, n=124); and a multidimensional intervention (risk of bias, 7/12, n=183) was not superior to a general exercise program in reducing low back pain in nurses. CONCLUSIONS: Only four relevant low risk of bias randomised controlled trials were found. At present there is no strong evidence of efficacy for any intervention in preventing or treating low back pain in nurses. Additional high quality randomised controlled trials are required. It may be worth exploring the efficacy of more individualised multidimensional interventions for low back pain in the nursing population. PMID- 29121557 TI - A ratiometric electrochemical biosensor for the exosomal microRNAs detection based on bipedal DNA walkers propelled by locked nucleic acid modified toehold mediate strand displacement reaction. AB - Sensitive and selective detection of microRNAs (miRNAs) in cancer cells derived exosomes have attracted rapidly growing interest owing to their potential in diagnostic and prognostic applications. Here, we design a ratiometric electrochemical biosensor based on bipedal DNA walkers for the attomolar detection of exosomal miR-21. In the presence of miR-21, DNA walkers are activated to walk continuously along DNA tracks, resulting in conformational changes as well as considerable increases of the signal ratio produced by target respond and target-independent reporters. With the signal cascade amplification of DNA walkers, the biosensor exhibits ultrahigh sensitivity with the limit of detection (LOD) down to 67 aM. Furthermore, owing to the background-correcting function of target-independent reporters termed as reference reporters, the biosensor is robust and stable enough to be applied in the detection of exosomal miR-21 extracted from breast cancer cell lines and serums. In addition, because locked nucleic acid (LNA) modified toehold mediate strand displacement reaction (TMSDR) has extraordinary discriminative ability, the biosensor displays excellent selectivity even against the single-base-mismatched target. It is worth mentioning that our sensor is regenerative and stable for at least 5 cycles without diminution in sensitivity. In brief, the high sensitivity, selectivity and reproducibility, together with cheap, make the proposed biosensor a promising approach for exosomal miRNAs detection, in conjunction with early point-of-care testing (POCT) of cancer. PMID- 29121558 TI - High-performance and versatile electrochemical aptasensor based on self-supported nanoporous gold microelectrode and enzyme-induced signal amplification. AB - Herein, novel and versatile electrochemical aptasensors were constructed on a self-supported nanoporous gold (np-Au) microelectrode, integrating with an exonuclease III (Exo III) induced signal amplification strategy. Self-supported np-Au microelectrode with 3D bicontinuous nanoporous structures possesses tremendously large specific area, clean surface, high stability and biocompatibility, bringing about significant advantages in both molecular recognition and signal response. As paradigms, two analytes of bisphenol A (BPA) and ochratoxin A (OTA) were selected to demonstrate the superiority and versatility of designed aptasensors. Trace amounts of mDNA (associated with BPA or OTA concentration) hybridized with cDNA strands assembled on np-Au microelectrode, activating the cleavage reaction with Exo III. Thus, cDNA was digested and mDNA was released to undergo a new hybridization and cleavage cycle. Finally, residual cDNA strands were recognized by methylene blue labelled rDNA/AuNPs with the assistance of hDNA to generate the electrochemical signals, which were used to quantitatively monitor targets. Under the optimized conditions, prepared aptasensors exhibited wide linear ranges (25pg/mL to 2ng/mL for BPA, 10pg/mL to 5ng/mL for OTA) with ultralow detection limits (10pg/mL for BPA, 5pg/mL for OTA), excellent selectivity and stability, and reliable detection in real samples. This work opens a new horizon for constructing promising electrochemical aptasensors for environmental monitoring, medical diagnostics and food safety. PMID- 29121559 TI - A screen-printed paper microbial fuel cell biosensor for detection of toxic compounds in water. AB - Access to safe drinking water is a human right, crucial to combat inequalities, reduce poverty and allow sustainable development. In many areas of the world, however, this right is not guaranteed, in part because of the lack of easily deployable diagnostic tools. Low-cost and simple methods to test water supplies onsite can protect vulnerable communities from the impact of contaminants in drinking water. Ideally such devices would also be easy to dispose of so as to leave no trace, or have a detrimental effect on the environment. To this aim, we here report the first paper microbial fuel cell (pMFC) fabricated by screen printing biodegradable carbon-based electrodes onto a single sheet of paper, and demonstrate its use as a shock sensor for bioactive compounds (e.g. formaldehyde) in water. We also show a simple route to enhance the sensor performance by folding back-to-back two pMFCs electrically connected in parallel. This promising proof of concept work can lead to a revolutionizing way of testing water at point of use, which is not only green, easy-to-operate and rapid, but is also affordable to all. PMID- 29121560 TI - Evaluation of attempted older adults suicides admitted to a University Hospital Emergency Department: Izmir study. AB - INTRODUCTION: Advanced age is one of the risk factors for attempting suicide. Suicide attempts are one of the reasons for elderly patients to admit emergency services. The aim of this study was to investigate the relationship between suicidal behavior and sociodemographic factors and concurrent somatic diseases. METHODS: The medical records of patients aged 60 years and over who presented to the emergency department of our university hospital for attempted suicide between the dates of January 1, 2007 and December 31, 2015 were screened retrospectively. Individuals recorded as cases of suicide on the forensic case report form were identified, the data recorded at our hospital were obtained, and telephone interviews were conducted to acquire any missing data. RESULTS: A total of 63 patients with a mean age of 65.88 years were included in the study. A large proportion of the suicide attempts occurred in the years 2014 and 2015. Overall, 23.8% of the patients had a previous history of suicide attempt. Overdose was the method in 74.6% of the suicide attempts, and 70.2% were impulsive; 63.5% of the patients had a history of psychiatric disease. The most common psychopathology was major depressive disorder. CONCLUSION: We found that suicide attempts were more common among older adults with a history of depression, that approximately one in four had previously attempted suicide, and that the majority of individuals attempting suicide chose to use their own medication. PMID- 29121561 TI - FLIP: An assisting software in structure based drug design using fingerprint of protein-ligand interaction profiles. AB - With the growing number of labor-intensive data in the pharmaceutical industries and public domain for protein-ligand complexes, a significant challenge is still remaining in managing and leveraging this vast information. Here, a standalone application is presented for analysis, organization, and illustration of structural data and molecular interactions for exploiting 3D-structures into simple 1D fingerprints. The utility of the approach was shown in unraveling a feasible solution for post-processing of docking results in parallel with providing fruitful analysis for users in order to investigate molecular interactions. Remarkably, all interaction possibilities including (hydrogen bond, water-bridged, electrostatic, and hydrophobic as well as pi- pi and cation-pi interactions) are supported both in the form of fingerprints and compelling reports. These investigations are mainly considered based on right orientation, location, and geometry of the interacting pairs rather than the acquisition of the energy terms. The reasonable efficiency of our application in different models was comparable to recent methods It is clearly presented that FLIP provides a faster way to generate usable fingerprints for ligand and protein binding modes. FLIP is free for academic use and is available at: http://zistrayan.com/development/download/flip/package.zip. PMID- 29121563 TI - Benthic invertebrate exposure and chronic toxicity risk analysis for cyclic volatile methylsiloxanes: Comparison of hazard quotient and probabilistic risk assessment approaches. AB - This study utilized probabilistic risk assessment techniques to compare field sediment concentrations of the cyclic volatile methylsiloxane (cVMS) materials octamethylcyclotetrasiloxane (D4, CAS # 556-67-2), decamethylcyclopentasiloxane (D5, CAS # 541-02-6), and dodecamethylcyclohexasiloxane (D6, CAS # 540-97-6) to effect levels for these compounds determined in laboratory chronic toxicity tests with benthic organisms. The concentration data for D4/D5/D6 in sediment were individually sorted and the 95th centile concentrations determined in sediment on an organic carbon (OC) fugacity basis. These concentrations were then compared to interpolated 5th centile benthic sediment no-observed effect concentration (NOEC) fugacity levels, calculated from a distribution of chronic D4/D5/D6 toxicologic assays per OECD guidelines using a variety of standard benthic species. The benthic invertebrate fugacity biota NOEC values were then compared to field measured invertebrate biota fugacity levels to see if risk assessment evaluations were similar on a field sediment and field biota basis. No overlap was noted for D4 and D5 95th centile sediment and biota fugacity levels and their respective 5th centile benthic organism NOEC values. For D6, there was a small level of overlap at the exposure 95th centile sediment fugacity and the 5th centile benthic organism NOEC fugacity value; the sediment fugacities indicate that a negligible risk (1%) exists for benthic species exposed to D6. In contrast, there was no indication of risk when the field invertebrate exposure 95th centile biota fugacity and the 5th centile benthic organism NOEC fugacity values were compared. PMID- 29121562 TI - P-glycoproteins play a role in ivermectin resistance in cyathostomins. AB - Anthelmintic resistance is a global problem that threatens sustainable control of the equine gastrointestinal cyathostomins (Phylum Nematoda; Superfamily Strongyloidea). Of the three novel anthelmintic classes that have reached the veterinary market in the last decade, none are currently licenced in horses, hence current control regimens focus on prolonging the useful lifespan of licenced anthelmintics. This approach would be facilitated by knowledge of the resistance mechanisms to the most widely used anthelmintics, the macrocyclic lactones (ML). There are no data regarding resistance mechanisms to MLs in cyathostomins, although in other parasitic nematodes, the ABC transporters, P glycoproteins (P-gps), have been implicated in playing an important role. Here, we tested the hypothesis that P-gps are, at least in part, responsible for reduced sensitivity to the ML ivermectin (IVM) in cyathostomins; first, by measuring transcript levels of pgp-9 in IVM resistant versus IVM sensitive third stage larvae (L3) pre-and post-IVM exposure in vitro. We then tested the effect of a range of P-gp inhibitors on the effect of IVM against the same populations of L3 using the in vitro larval development test (LDT) and larval migration inhibition test (LMIT). We demonstrated that, not only was pgp-9 transcription significantly increased in IVM resistant compared to IVM sensitive L3 after anthelmintic exposure (p < 0.001), but inhibition of P-gp activity significantly increased sensitivity of the larvae to IVM in vitro, an effect only observed in the IVM resistant larvae in the LMIT. These data strongly implicate a role for P gps in IVM resistance in cyathostomins. Importantly, this raises the possibility that P-gp inhibitor-IVM combination treatments might be used in vivo to increase the effectiveness of IVM against cyathostomins in Equidae. PMID- 29121564 TI - Effect of 1-methyl-3-hexylimidazolium bromide on zebrafish (Danio rerio). AB - Room-temperature ionic liquids, generally referred to ionic liquids (ILs), are "green solvents". Antioxidant responses and DNA damage in zebrafish livers exposed to 1-methyl-3-hexylimidazolium bromide ([C6mim]Br) were evaluated at various doses (5-40 mg/L) for a 28-day IL-exposure. A significant decrease of superoxide dismutase (SOD) activity was exhibited, and catalase (CAT) was inhibited at the highest dose (40 mg/L). Reactive oxygen species (ROS) levels were significantly promoted at most exposure interval times except for the dose of 5 mg/L on day 21 in male and days 21 and 28 in female. Malonaldehyde (MDA) contents remarkable increased exposed to [C6mim]Br. Besides, a notable increase was exhibited, which indicated an inducement of DNA damage with respect to control groups. Thus, we believed that [C6mim]Br causes oxidative stress and DNA damage in zebrafish. Gender differences were insignificant in almost all the tested biomarkers, thus, male and female zebrafish could be mixed at a ratio of 1:1 in the future evaluation. The present study may also provide basic toxicology information for IL evaluation to aquatic organisms. PMID- 29121565 TI - Dynamics of metals in backfill of a phosphate mine of guiyang, China using a three-step sequential extraction technique. AB - Phosphate rock in Guiyang (Southwest of China) is used for the phosphate production, and hence generating a by-product phosphogypsum (PG). From 2007, part of the PG was used as main raw material for cemented backfill. The main objective of this paper is to investigate the geochemical evolution of metals before and after the PG inclusion into the backfill matrix. A sequential extraction procedure was selected to determine the chemical speciation of metals in phosphate rock, PG, binder and field backfill samples. Dynamics of metals going from phosphate rock and PG to backfill have been evaluated. The results showed that almost all the metals in the PG and binder had been effectively transferred to the backfill. Furthermore, compared to metals taken out along with phosphate rock exploitation, PG-based cemented backfill might bring some metals back but with only little metals in mobile fraction. Additionally, in order to determine the long-term behavior of metals in PG-based cemented backfill, the field samples which were backfilled from 2007 to 2016 were collected and analyzed. The results showed that total amounts of metals in backfill were all within similar range, indicating that the cemented PG backfill could be an effective method to solidify/stabilize metals in PG. Nevertheless, Due to the high water-soluble fractions detected, the concentrations of As, Mn and Zn should be continuously monitored. PMID- 29121566 TI - Novel two-tiered approach of ecological risk assessment for pesticide mixtures based on joint effects. AB - Ecological risk assessments for mixtures have attracted considerable attention. In this study, 38 pesticides in the real environment were taken as objects and their toxicities to different organisms from three trophic levels were employed to assess the ecological risk of the mixture. The first tier assessment was based on the CA effect and the obtained sum of risk quotients (SRQspecies-CA) were 3.06 9.22. The second tier assessment was based on non-CA effects and the calculated SRQspecies-TU are 5.37-9.29 using joint effects (TUsum) as modified coefficients, which is higher than SRQspecies-CA and indicates that ignoring joint effects might run the risk of underestimating the actual impact of pesticide mixtures. Due to the influences of synergistic and antagonistic effects, risk contribution of components to mixture risks based on non-CA effects are different from those based on the CA effect. Moreover, it was found that the top 8 dominating components explained 95.5%-99.8% of mixture risks in this study. The dominating components are similar in the two tiers for a given species. Accordingly, a novel two-tiered approach was proposed to assess the ecological risks of mixtures based on joint effects. This study provides new insights for ecological risk assessments with the consideration of joint effects of components in the pesticide mixtures. PMID- 29121567 TI - Carbonate-activated hydrogen peroxide oxidation process for azo dye decolorization: Process, kinetics, and mechanisms. AB - Advanced oxidation processes offer effective solutions in treating wastewater from various industries. This study is the first time to investigate the potential of carbonate-activated hydrogen peroxide (CAP) oxidation process for the removal of organic pollutant from highly alkaline wastewaters. Azo dye acid orange 7 (AO7) was selected as a model pollutant. The influences of various parameters on AO7 decolorization by the CAP oxidation were evaluated. Furthermore, the active species involved in AO7 degradation were explored using scavenger experiments and electron spin resonance analysis. Additionally, AO7 degradation products by the CAP oxidation were identified to elucidate possible transformation pathways. Results showed that the CAP oxidation had better AO7 decolorization performance compared to bicarbonate-activated hydrogen peroxide method. The AO7 decolorization efficiency augmented from 3.70 +/- 0.76% to 54.27 +/- 2.65% when carbonate concentration was increased from 0 to 50 mM at pH 13.0, and then changed slightly with further increasing carbonate concentration to 70 mM. It increased almost linearly from 5.95 +/- 0.32% to 94.03 +/- 0.39% as H2O2 concentration was increased from 5 to 50 mM. Moreover, trace amount of Co(II) could facilitate AO7 decolorization by the CAP reaction. Superoxide and carbonate radicals might be the main reactive oxygen species involved in the CAP process. Finally, a possible degradation pathway of AO7 by the CAP oxidation was proposed based on the identified products. PMID- 29121568 TI - A metabolic exposure-oriented network regulation strategy for the identification of effective combination in the extract of Ginkgo biloba L. AB - Nowadays, network pharmacology-based methods were increasing proposed to screen synergistic or combinatorial compounds from herbal medicines (HMs), while these researches mainly focused on structural prediction or experiment-based interaction between single compound and target protein. The proportion of each chemical in the nature and their metabolic process was ignored, which might decide an optimized composition for their synergistic effect. To exact the effective combination of HMs, a metabolic distribution-oriented network regulation strategy was developed for the identification of effective combination. Firstly, comprehensive chemical profiling and metabolic exposure of HMs in a pathological state were conducted. Then the effective combination for HMs was screened by combining network regulation and the metabolic exposure level of HMs. Finally, with the extract of Ginkgo biloba (EGB) as a case, a combination of 12 active compounds was found for treating ischemia stroke, showing bioactivity equivalence with original herb. The results also indicated that beside the well-known ginkgolides and flavonoids, trace compounds might also play an important role of the holistic effect of EGB. This method can be used as an alternative for effective combination screening. PMID- 29121569 TI - Comparison of the analytical methods (solid state NMR, FT-IR, PXRD) in the analysis of the solid drug forms with low concentration of an active ingredient - 17-beta-estradiol case. AB - The application of various techniques (FT-IR, PXRD, ssNMR) in the analysis of solid dosage forms with low concentration of an API (17-beta-estradiol hemihydrate, EBHH) was tested. PXRD analysis of Estrofem Mite tablets (EMT) confirmed the presence of the main crystalline excipient, alpha-lactose monohydrate. In the PXRD pattern of EMT the strong background from polycrystalline excipients, i.e. hydroxypropylmethylcellulose and corn starch was observed. FT-IR spectra were characterized by the broad peaks in the 3000-3600cm 1 region of the OH stretching modes coming from multiple hydrogen bonds that are present in the structures of the excipients (alpha-lactose monohydrate, corn starch) and API. The only technique which unambiguously confirmed the presence of an API in the EMT was solid state NMR. Despite the tabletting process each of the EMT component retained its characteristic features like relaxation time and T1rhoI. Due to the possibility of the manipulation in the experimental registration parameters like recycle delay (RD), evolution time (tau) and contact time (CT) it was possible to perform multiple experiments on the same sample of EMT. The most valuable were the inversion recovery CP experiments in which, by setting the proper values of tau, it was possible to selectively observe the signals of the chosen component of the drug formulation. In this study the great potential of solid state NMR in the analysis of solid dosage forms, as the unique technique that combines the possibility of selective observation of the chosen signals with the non destructive character that enables further analysis of the same sample, was confirmed. PMID- 29121570 TI - A facile and selective approach for enrichment of l-cysteine in human plasma sample based on zinc organic polymer: Optimization by response surface methodology. AB - In this research, a facile and selective method was described to extract l cysteine (l-Cys), an essential alpha-amino acid for anti-ageing playing an important role in human health, from human blood plasma sample. The importance of this research was the mild and time-consuming synthesis of zinc organic polymer (Zn-MOP) as an adsorbent and evaluation of its ability for efficient enrichment of l-Cys by ultrasound-assisted dispersive micro solid-phase extraction (UA DMSPE) method. The structure of Zn-MOP was investigated by FT-IR, XRD and SEM. Analysis of variance (ANOVA) was applied for the experimental data to reach the best optimum conditions. The quantification of l-Cys was carried out by high performance liquid chromatography with UV detection set at lambda=230nm. The calibration graph showed reasonable linear responses towards l-Cys concentrations in the range of 4.0-1000MUg/L (r2=0.999) with low limit of detection (0.76MUg/L, S/N=3) and RSD<=2.18 (n=3). The results revealed the applicability and high performance of this novel strategy in detecting trace l-Cys by Zn-MOP in complicated matrices. PMID- 29121571 TI - High throughput MU-SPE based elution coupled with UPLC-MS/MS for determination of eluxadoline in plasma sample: Application in pharmacokinetic characterization of PLGA nanoparticle formulations in rats. AB - Eluxadoline is a novel MU- and kappa-opioid receptor (OR) agonist and delta-OR antagonist, recently approved as a first line therapy for the treatment of irritable bowel syndrome. Due to abuse potential, poor bioavailability and high intersubject variability, a sensitive and reliable assay is prerequisite for its determination in biological samples. This work first time report the development and validation of UPLC-MS/MS assay for determination of eluxadoline in rat plasma sample using risperidone as an internal standard (IS). A high-throughput 96-well plate format MU-SPE technique was used for plasma sample extraction. The extracted samples were separated on Acquity BEHTM C18 column (100*2.1mm, 1.7MUm) using mobile phase elution of acetonitrile: 20mM ammonium acetate (80:20, v/v) at a flow rate of 0.3mLmin-1. The precursor to product ion transition of m/z 570.16 >118.12 (qualifier), 570.16->171.08 (quantifier) for eluxadoline, and m/z 411.18 >191.07 for IS were used for MRM monitoring. The calibration curves were linear in concentration range of 0.15-50ngmL-1 with LOD and LOQ of 0.07 and 0.15ngmL-1, respectively. The validation results satisfied the criteria of USFDA and SWGTOX guidelines and were within the acceptable limit. Finally, the method was successfully applied in bioavailability enhancement study of the newly developed PLGA nanoparticles and Eudragit coated PLGA nanoparticles of eluxadoline in rats. PMID- 29121572 TI - Simultaneous determination of rutin and ascorbic acid in a sequential injection lab-at-valve system. AB - A green, simple, accurate and highly sensitive sequential injection lab-at-valve procedure has been developed for the simultaneous determination of ascorbic acid (Asc) and rutin using 18-molybdo-2-phosphate Wells-Dawson heteropoly anion (18 MPA). The method is based on the dependence of the reaction rate between 18-MPA and reducing agents on the solution pH. Only Asc is capable of interacting with 18-MPA at pH 4.7, while at pH 7.4 the reaction with both Asc and rutin proceeds simultaneously. In order to improve the precision and sensitivity of the analysis, to minimize reagent consumption and to remove the Schlieren effect, the manifold for the sequential injection analysis was supplemented with external reaction chamber, and the reaction mixture was segmented. By the reduction of 18 MPA with reducing agents one- and two-electron heteropoly blues are formed. The fraction of one-electron heteropoly blue increases at low concentrations of the reducer. Measurement of the absorbance at a wavelength corresponding to the isobestic point allows strictly linear calibration graphs to be obtained. The calibration curves were linear in the concentration ranges of 0.3-24mgL-1 and 0.2 14mgL-1 with detection limits of 0.13mgL-1 and 0.09mgL-1 for rutin and Asc, respectively. The determination of rutin was possible in the presence of up to a 20-fold molar excess of Asc. The method was applied to the determination of Asc and rutin in ascorutin tablets with acceptable accuracy and precision (1-2%). PMID- 29121573 TI - Rufinamide: Crystal structure elucidation and solid state characterization. AB - Rufinamide (R) is a triazole derivative approved for the management of partial seizures and seizures associated with Lennox-Gastaut Syndrome, in November 2007. Crystal structure, solid state characterization, drug-excipient compatibility and solubility play a pivotal role in formulation development. This work deals with the crystal structure elucidation of R by single crystal X-ray diffraction and solid state characterization by thermal, spectroscopic and crystallographic techniques. Drug- excipient compatibility was assessed by differential scanning calorimetry (DSC). New RP-HPLC method for quantification of R was developed with improved retention time. Solubility and dissolution of drug in different media was determined. Additionally, the flow behavior of the drug was evaluated by measuring Carr's index and Hausner's ratio, while the compressibility behavior was studied using Well's protocol. R crystallized from dimethylformamide (R-DMF) was utilized for single crystal analysis. The drug crystallized in triclinic crystal system with P-1 space group. Asymmetric unit cell consists of two molecules of R held by intermolecular hydrogen bond (connected by NH?O, which forms the catemeric chain). Analytical outcomes from DSC, thermogravimetric analysis (TGA) and powder X-ray diffraction (PXRD) revealed that the drug was present in pure crystalline form and was devoid of any polymorphic or pseudopolymorphic impurities. Influence of pH on the solubility and dissolution of R-DMF was found to be insignificant. The drug exhibited poor aqueous solubility, which was improved nearly 4.6 fold with the addition of 2% sodium lauryl sulphate (SLS). The drug exhibits poor flow and elastic compression nature. Excipients such as poly ethylene glycol (PEG) 8000, SLS, lactose monohydrate, starch and Hydroxypropyl methylcellulose (HPMC) E15 were incompatible with R-DMF as identified by thermal analysis. It is envisaged that these information regarding solid state properties of R-DMF would aid in identifying a logical path for formulation development. PMID- 29121574 TI - In vitro interaction of cefotaxime with calf thymus DNA: Insights from spectroscopic, calorimetric and molecular modelling studies. AB - Cefotaxime is third generation antibiotic with known therapeutic efficacy against bacterial infections including cerebral abscesses and bacterial meningitis. The beta-lactam group of drugs are considered safest antibiotics. Many antibiotics directly interact with DNA and alter their expression profile. Thus, it is necessary to understand the binding mode and its relevance to drug activity and toxicity. There is considerably a remarkable focus on deciphering the binding mechanism of these therapeutic agents as DNA is one of the major target for wide range of drugs. Cefotaxime has been extensively studied for its pharmacological properties while its binding mode to DNA has not been explicated so far. In this study, we have unveiled the binding mechanism of cefotaxime to DNA by using various biophysical, thermodynamic and in silico techniques. UV-vis spectroscopy confirmed the formation cefotaxime-DNA complex along with a brief idea about the extent of interaction. Fluorescence spectroscopy yielded the values of various binding constants and explained mode of fluorescence quenching to be static. CD spectroscopy, thermal denaturation, KI quenching and viscosity measurement explained that cefotaxime is groove binder. Measuring the effect of ions on cefotaxime-DNA complex ensured that it does not bind to DNA electrostatically. Dye displacement experiments finally confirmed that cefotaxime binds to the minor groove of DNA. ITC gave the thermodynamic profile of this binding in which negative value of Gibb's free energy change revealed that the process is spontaneous. Molecular modelling finally strengthened our experimental results that cefotaxime was located in curved contour of minor groove of DNA. The findings support on safety of drug and may have a little interference on normal biological functions. PMID- 29121575 TI - Niche modelling of marsh plants based on occurrence and abundance data. AB - The information of species' response (optimum or critical limits along environmental gradients) is a key to understanding ecological questions and to design management plans. A large number of plots (762) from 70 transects of 13 wetland sites in Northeast China were sampled along flooding gradient from marsh to wet meadow. Species response (abundance and occurrence) to flooding were modelled with Generalized Additive Models for 21 dominant plant species. We found that 20 of 21 species showed a significant response to flooding for the occurrence and abundance models, and four types of response were found: monotonically increasing, monotonically decreasing, skewed unimodal and symmetric unimodal. The species with monotonically increasing response have the deepest flooding optimum and widest niche width, followed by those with unimodal curve, and the monotonically decreasing ones have the smallest values. The optima and niche width (whether based on occurrence or abundance models) both significantly correlated with the frequency, but not with mean abundance. Abundance models outperformed occurrence models based on goodness of fit. The abundance models predicted a rather sharp shift from dominance of helophytes (Carex pseudo-curaica and C. lasiocarpa) to wet meadow species (Calamagrostis angustifolia and Carex appendiculata) if water levels drop from about 10cm above soil surface to below the surface. The defined optima and niche width based on the abundance models can be applied to better instruct restoration management. Given the time required to collect abundance data, an efficient strategy could be to monitor occurrence in many plots and abundance in a subset of these. PMID- 29121576 TI - Soil geochemical factors regulate Cd accumulation by metal hyperaccumulating Noccaea caerulescens (J. Presl & C. Presl) F.K. Mey in field-contaminated soils. AB - Cadmium contamination in soil is a substantial global problem, and of significant concern due to high food-chain transfer. Cadmium hyperaccumulators are of particular interest because of their ability to tolerate and take up significant amounts of heavy metal pollution from soils. One particular plant, Noccaea caerulescens (formerly, Thlaspi caerulescens), has been extensively studied in terms of its capacity to accumulate heavy metals (specifically Zn and Cd), though these studies have primarily utilized hydroponic and metal-spiked model soil systems. We studied Cd and nutrient uptake by two N. caerulescens ecotypes, Prayon (Zn-only hyperaccumulator) and Ganges (Zn- and Cd-hyperaccumulator) in four long-term field-contaminated soils. Our data suggest that individual soil properties such as total soil Cd, Zn:Cd molar ratio, or soil pH do not accurately predict Cd uptake by hyperaccumulating plants. Additionally, total Cd uptake by the hyperaccumulating Ganges ecotype was substantially less than its physiological capacity, which is likely due to Cd-containing solid phases (primarily iron oxides) and pH that play an important role in regulating and limiting Cd solubility. Increased P accumulation in the Ganges leaves, and greater plant Fe accumulation from Cd-containing soils suggests that rhizosphere alterations via proton, and potentially organic acid, secretion may also play a role in nutrient and Cd acquisition by the plant roots. The current study highlights the role that soil geochemical factors play in influencing Cd uptake by hyperaccumulating plants. While these plants may have high physiological potential to accumulate metals from contaminated soils, individual soil geochemical factors and the plant-soil interactions in that soil will dictate the actual amount of phytoextractable metal. This underlines the need for site specific understanding of metal-containing solid phases and geochemical properties of soils before undertaking phytoextraction efforts. PMID- 29121577 TI - Halogenated and parent polycyclic aromatic hydrocarbons in vegetables: Levels, dietary intakes, and health risk assessments. AB - Halogenated polycyclic aromatic hydrocarbons (HPAHs) are attracting increasing concern because of their greater toxicity than their corresponding parent PAHs. However, human exposure to HPAHs via food consumption is not fully understood. In this study, daily intake via vegetable ingestion of 11 HPAHs and 16 PAHs and subsequent cancer risk were assessed for population in Beijing. A total of 80 vegetable samples were purchased from markets, including five leafy vegetables and three root vegetables. The concentrations of total HPAHs (?HPAHs) were 0.357 0.874ng/g in all vegetables, lower than that of total PAHs (?PAHs, 10.6 47.4ng/g). ?HPAHs and ?PAHs concentrations in leafy vegetables were higher than those in root vegetables, suggesting that the atmospheric deposition might be the dominant source of PAHs and HPAHs in leafy vegetables. Among the HPAH congeners, 2-BrFle and 9-ClFle were the predominant compounds and frequently detected in the vegetable samples. HPAHs and PAHs were also found in certificated vegetables at the concentrations of 0.466-0.751ng/g and 10.6-38.9ng/g, respectively, which were lower than those in non-certificated vegetables except for spinach. For leafy vegetables from local farms, the ?PAHs and ?HPAHs levels in the rape and Chinese cabbage samples significantly decreased with increasing the distance away from the incineration plant. The incremental lifetime cancer risks of HPAHs were below the acceptable risk level (10-6), suggesting that there might be little or no risk to consumers from these compounds in vegetables. For all population groups, children were the most sensitive population to PAHs and HPAHs, and their health issues should be paid more attention. PMID- 29121578 TI - Carbon and nitrogen burial in a plateau lake during eutrophication and phytoplankton blooms. AB - Organic carbon (OC) buried in lake sediment is an important component of the global carbon cycle. The impact of eutrophication on OC burial in lakes should be addressed due to worldwide lake eutrophication. Fourteen 210Pb- and 137Cs-dated sediment cores taken in Dianchi Lake (China) in August 2006 (seven cores) and July 2014 (seven cores) were analyzed to evaluate the response of the organic carbon accumulation rate (OCAR) to eutrophication and algal blooms over the past hundred years. The mean value of OCAR before eutrophication occurred in 1979, 16.62+/-7.53 (mean value+/-standard deviation), increased to 54.33+/-27.29gm-2yr 1 after eutrophication. It further increased to 61.98+/-28.94gm-2yr-1 after algal blooms occurred (1989). The accumulation rate of organic nitrogen (ONAR) is coupled with OCAR. The high loss rate of OC and organic nitrogen (ON) leads to a long-term burial efficiency of only 10% and 5% of OC and ON. However, this efficiency can still lead to an increase in OCAR by a factor of 4.55 during algal blooms in Dianchi Lake. Dianchi Lake stored 1.26+/-0.32 Tg carbon and 0.071+/ 0.018 Tg nitrogen, including 0.94+/-0.23 Tg OC and 0.32+/-0.14 Tg inorganic carbon, 0.066+/-0.018 Tg ON, 0.002+/-0.001 Tg nitrate nitrogen (NO3-N) and 0.003+/-0.001 Tg ammonium nitrogen (NH4-N) between 1900 and 2012. PMID- 29121579 TI - A process-oriented hydro-biogeochemical model enabling simulation of gaseous carbon and nitrogen emissions and hydrologic nitrogen losses from a subtropical catchment. AB - Quantification of nitrogen losses and net greenhouse gas (GHG) emissions from catchments is essential for evaluating the sustainability of ecosystems. However, the hydrologic processes without lateral flows hinder the application of biogeochemical models to this challenging task. To solve this issue, we developed a coupled hydrological and biogeochemical model, Catchment Nutrients Management Model - DeNitrification-DeComposition Model (CNMM-DNDC), to include both vertical and lateral mass flows. By incorporating the core biogeochemical processes (including decomposition, nitrification, denitrification and fermentation) of the DNDC into the spatially distributed hydrologic framework of the CNMM, the simulation of lateral water flows and their influences on nitrogen transportation can be realized. The CNMM-DNDC was then calibrated and validated in a small subtropical catchment belonged to Yanting station with comprehensive field observations. Except for the calibration of water flows (surface runoff and leaching water) in 2005, stream discharges of water and nitrate in 2007, the model validations of soil temperature, soil moisture, crop yield, water flows in 2006 and associated nitrate loss, fluxes of methane, ammonia, nitric oxide and nitrous oxide, and stream discharges of water and nitrate in 2008 were statistically in good agreement with the observations. Meanwhile, our initial simulation of the catchment showed scientific predictions. For instance, it revealed the following: (i) dominant ammonia volatilization among the losses of nitrogenous gases (accounting for 11-21% of the applied annual fertilizer nitrogen in croplands); (ii) hotspots of nitrate leaching near the main stream; and (iii) a net GHG sink function of the catchment. These results implicate the model's promising capability of predicting ecosystem productivity, hydrologic nitrogen loads, losses of gaseous nitrogen and emissions of GHGs, which could be used to provide strategies for establishing sustainable catchments. In addition, the model's capability would be further proved by applying in other catchments with different backgrounds. PMID- 29121580 TI - Gas-fired power in the UK: Bridging supply gaps and implications of domestic shale gas exploitation for UK climate change targets. AB - There is a projected shortcoming in the fourth carbon budget of 7.5%. This shortfall may be increased if the UK pursues a domestic shale gas industry to offset projected decreases in traditional gas supply. Here we estimate that, if the project domestic gas supply gap for power generation were to be met by UK shale gas with low fugitive emissions (0.08%), an additional 20.4MtCO2e1 would need to be accommodated during carbon budget periods 3-6. We find that a modest fugitive emissions rate (1%) for UK shale gas would increase global emissions compared to importing an equal quantity of Qatari liquefied natural gas. Additionally, we estimate that natural gas electricity generation would emit 420 466MtCO2e (460 central estimate) during the same time period within the traded EU emissions cap. We conclude that domestic shale gas production with even a modest 1% fugitive emissions rate would risk exceedance of UK carbon budgets. We also highlight that, under the current production-based greenhouse gas accounting system, the UK is incentivized to import natural gas rather than produce it domestically. PMID- 29121581 TI - Clinicopathology and treatment of a giant malignant phyllodes tumor of the breast: A case report and literature review. AB - INTRODUCTION: Phyllodes tumors (PTs) of the breast are extremely rare accounting for less than 1% of all breast tumors globally. Case records at the Trinidad and Tobago Cancer Registry show that only 0.003% of the reported breast cancer cases between 1995 and 2009 were PTs. PRESENTATION OF THE CASE: We report a 45-year-old woman who presented with swelling of the left breast. Ultrasound, mammogram and computed tomography imaging confirmed the presence of a mass in the right upper inner quadrant of the left breast. A biopsy revealed features supportive of a benign phyllodes tumor. A wide local excision was performed with the removal of a 19*11*10cm mass. Histopathological analysis revealed features consistent with malignant phyllodes tumor. A complete mastectomy of the left breast was subsequently performed. Follow up over a 5-year period did not reveal any evidence of local recurrence or residual disease. To the best of our knowledge, this is the first case report of a malignant PT from the Caribbean and Latin America. DISCUSSION: Phyllodes tumors are classified as benign, borderline, or malignant based on histologic features including presence of a clear margin, cellularity, stromal overgrowth, tumor necrosis and mitotic index. The clinical challenge is to assess the risk of local tumor and metastatic recurrence in the context of fluid classifications. CONCLUSION: Our case management approach shows that for patients with malignant PT, a thorough preoperative workup regimen followed by appropriate surgical intervention can result in a desirable prognosis. PMID- 29121582 TI - Intermammary pilonidal sinus: The first case series. AB - INTRODUCTION: Pilonidal sinus (PNS) is an inflammatory condition caused by hair penetration into the epidermis. It occurs usually in sacro-coccygeal area. Intermammary pilonidal sinus is a very rare variant with a few case reports in literature. The aim of this study is to highlight the presentation and management of intermammary pilonidal sinus. METHOD: A retrospective multicenter case series. Including all cases of intermammary PNS admitted to either of 5 major tertiary hospitals in Kurdistan region of Iraq. Inclusion criteria were any case of intermammary PNS diagnosed by histopathological examination. The data were taken from the medical records and direct interview with the patients. RESULTS: The case series included 12 patients, all case were female. The age range was from 13 to 29. All of cases were obese with body mass index (BMI) ranged between 30.1 32.2kg/m2. All of them presented with discharge for a long time ranging between four weeks to two years. Nine cases (75) were diagnosed preoperatively as cases of infected sebaceous cysts. Resection and direct closure without flap were done for nine (75%) of them and in other three cases (25%), the PNS were resected and left for secondary healing. Three of the patients (25%) developed recurrence. CONCLUSION: Intermammary PNS occurs in young, obese ladies with large breasts which are kept in tight brassieres. Resection and primary closure is the main method of management. PMID- 29121583 TI - A case report of gastric lymphocytic phlebitis, a rare mimic for malignancy. AB - INTRODUCTION: Lymphocytic phlebitis is a benign condition characterised by inflammation of the veins and rarely affects the gastrointestinal tract. Reported cases present as acute abdomen and involve the colon or small intestine. We report the fourth case of gastric lymphocytic phlebitis in the literature. PRESENTATION OF CASE: A 74-year-old female presented with eight weeks of abdominal pain. Findings at endoscopy were suggestive of a malignant ulcer on the greater curvature of antrum, while biopsies showed chronic gastritis without malignancy. Appearance at diagnostic laparoscopy was consistent with a malignant gastric ulcer with serosal changes. Due to persistent pain and the macroscopic appearance, she proceeded to have an open subtotal gastrectomy and D2 lymph node clearance. Despite macroscopic appearance, the microscopic examination demonstrated no malignancy, and was consistent with lymphocytic phlebitis with overlying ulceration. DISCUSSION: This case was a mimic for gastric malignancy, with the benign diagnosis only being made after surgical resection. Gastric lymphocytic phlebitis is a rare differential diagnosis for gastric ulcers when biopsies are negative, although preoperative diagnosis is difficult given the lesions do not involve the mucosa. CONCLUSION: If clinical history and endoscopic findings are suspicious for malignancy, despite normal biopsies, an aggressive surgical resection remains reasonable given the rarity gastric lymphocytic phlebitis. PMID- 29121584 TI - A case report of primary pancreatic leiomyosarcoma requiring six additional resections for recurrences. AB - INTRODUCTION: Primary pancreatic leiomyosarcoma is extremely rare. We report a case in which six additional resections were required to treat recurrent tumors in a 5-year period following the primary operation. PRESENTATION OF CASE: A 69 year-old man presented with a pancreatic tumor. Abdominal computed tomography scan showed a large heterogeneous mass with a necrotic area arising from the pancreatic body. We performed distal pancreatectomy, splenectomy, and wide resection of the transverse mesocolon. Histopathological examination confirmed the diagnosis of a pancreatic leiomyosarcoma. We repeatedly performed surgery on recurrent tumors. DISCUSSION: Primary pancreatic leiomyosarcoma is considered to be a highly aggressive malignancy. The most effective treatment is complete surgical resection with tumor-free margins. Even when tumors recur, it is possible to improve the prognosis by further resection. CONCLUSION: Long-term survival is achievable by repeated resection of recurrent tumors. PMID- 29121586 TI - Pre-sepsis: A necessary concept to complete the SEPSIS-3 picture? PMID- 29121585 TI - Schwann cells participate in synapse elimination at the developing neuromuscular junction. AB - During the initial stages of innervation of developing skeletal muscles, the terminal branches of axons from multiple motor neurons form neuromuscular junctions (NMJs) on a small region of each muscle fiber, the motor endplate. Subsequently, the number of axonal inputs at the endplate region is reduced so that, at maturity, each muscle fiber is innervated by the terminals of a single motor neuron. The Schwann cells associated with the axon terminals are involved in the removal of these synapses but do not select the axon that is ultimately retained on each fiber. Schwann cells perform this function by disconnecting terminal branches from the myofiber surface and by attacking them phagocytically. Here we discuss how this behavior is regulated and argue that such regulation is not unique to development of neuromuscular innervation but is also expressed in the response of the mature NMJ to various manipulations and pathologies. PMID- 29121587 TI - Social attention directs working memory maintenance. AB - Visual working memory (vWM) performance is enhanced when a memorized object is cued after encoding. This so-called retro-cue effect is typically observed with a predictive (80% valid), retrospective cue. The current study examined whether a nonpredictive (50% valid) retro-cue can similarly enhance internal memory representations in cases where the cue conveys social signals. To this end, gaze cues were presented during the retention interval of a change-detection task, which are capable to engender a mutual attentional focus of two individuals towards one location. In line with our prediction, Experiment 1 demonstrated that a polygon presented at the gazed-at location was remembered better than that at both non-gazed and gazed-away locations. Experiments 2 and 3 showed that low level motion cues did not elicit attentional orienting in a comparable manner as the gaze cue, and these differences in cuing were found to be reliable and independent of memory load. Furthermore, the gaze retro-cue effect disappeared when the face was inverted (Experiment 4). In sum, these results clearly show that sharing the focus of another individual establishes a point of reference from which visual information is restored with priority, suggesting that a gaze retro-cue leads to social attention, thus, modulating vWM maintenance in a reflexive, automatic manner. PMID- 29121588 TI - Infants' sensitivity to vowel harmony and its role in segmenting speech. AB - A critical part of infants' ability to acquire any language involves segmenting continuous speech input into discrete word forms. Certain properties of words could provide infants with reliable cues to word boundaries. Here we investigate the potential utility of vowel harmony (VH), a phonological property whereby vowels within a word systematically exhibit similarity ("harmony") for some aspect of the way they are pronounced. We present evidence that infants with no experience of VH in their native language nevertheless actively use these patterns to generate hypotheses about where words begin and end in the speech stream. In two sets of experiments, we exposed infants learning English, a language without VH, to a continuous speech stream in which the only systematic patterns available to be used as cues to word boundaries came from syllable sequences that showed VH or those that showed vowel disharmony (dissimilarity). After hearing less than one minute of the streams, infants showed evidence of sensitivity to VH cues. These results suggest that infants have an experience independent sensitivity to VH, and are predisposed to segment speech according to harmony patterns. We also found that when the VH patterns were more subtle (Experiment 2), infants required more exposure to the speech stream before they segmented based on VH, consistent with previous work on infants' preferences relating to processing load. Our findings evidence a previously unknown mechanism by which infants could discover the words of their language, and they shed light on the perceptual mechanisms that might be responsible for the emergence of vowel harmony as an organizing principle for the sound structure of words in many languages. PMID- 29121589 TI - Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. AB - Tauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have investigated whether dimethyl fumarate (DMF), an inducer of the transcription factor NRF2, could mitigate tauopathy in a mouse model. The signaling pathways modulated by DMF were also studied in mouse embryonic fibroblast (MEFs) from wild type or KEAP1-deficient mice. The effect of DMF on neurodegeneration, astrocyte and microglial activation was examined in Nrf2+/+ and Nrf2-/- mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with DMF (100mg/kg, i.g) during three weeks. DMF induces the NRF2 transcriptional through a mechanism that involves KEAP1 but also PI3K/AKT/GSK-3-dependent pathways. DMF modulates GSK-3beta activity in mouse hippocampi. Furthermore, DMF modulates TAU phosphorylation, neuronal impairment measured by calbindin-D28K and BDNF expression, and inflammatory processes involved in astrogliosis, microgliosis and pro-inflammatory cytokines production. This study reveals neuroprotective effects of DMF beyond disruption of the KEAP1/NRF2 axis by inhibiting GSK3 in a mouse model of tauopathy. Our results support repurposing of this drug for treatment of these diseases. PMID- 29121590 TI - Influence of soil temperature and moisture on biochemical biomarkers in earthworm and microbial activity after exposure to propiconazole and chlorantraniliprole. AB - Predicted climate change could impact the effects that various chemicals have on organisms. Increased temperature or change in precipitation regime could either enhance or lower toxicity of pesticides. The aim of this study is to assess how change in temperature and soil moisture affect biochemical biomarkers in Eisenia fetida earthworm and microbial activity in their excrements after exposure to a fungicide - propiconazole (PCZ) and an insecticide - chlorantraniliprole (CAP). For seven days, earthworms were exposed to the pesticides under four environmental conditions comprising combinations of two different temperatures (20 degrees C and 25 degrees C) and two different soil water holding capacities (30% and 50%). After exposure, in the collected earthworm casts the microbial activity was measured through dehydrogenase activity (DHA) and biofilm forming ability (BFA), and in the postmitochondrial fraction of earthworms the activities of acetylcholinesterase (AChE), catalase (CAT) and glutathione-S-transferase (GST) respectively. The temperature and the soil moisture affected enzyme activities and organism's response to pesticides. It was determined that a three way interaction (pesticide concentration, temperature and moisture) is statistically significant for the CAT and GST after the CAP exposure, and for the AChE and CAT after the PCZ exposure. Interestingly, the AChE activity was induced by both pesticides at a higher temperature tested. The most important two-way interaction that was determined occurred between the concentration and temperature applied. DHA and BFA, as markers of microbial activity, were unevenly affected by PCZ, CAP and environmental conditions. The results of this experiment demonstrate that experiments with at least two different environmental conditions can give a very good insight into some possible effects that the climate change could have on the toxicity of pesticides. The interaction of environmental factors should play a more important role in the risk assessments for pesticides. PMID- 29121591 TI - Proteomic and enzymatic response under Cr(VI) overload in yeast isolated from textile-dye industry effluent. AB - Cyberlindnera jadinii M9 and Wickerhamomyces anomalus M10 isolated from textile dye liquid effluents has shown capacity for chromium detoxification via Cr(VI) biological reduction. The aim of the study was to evaluate the effect of hexavalent chromium on synthesis of novel and/or specific proteins involved in chromium tolerance and reduction in response to chromium overload in two indigenous yeasts. A study was carried out following a proteomic approach with W. anomalus M10 and Cy. jadinii M9 strains. For this, proteins extracts belonging to total cell extracts, membranes and mitochondria were analyzed. When Cr(VI) was added to culture medium there was an over-synthesis of 39 proteins involved in different metabolic pathways. In both strains, chromium supplementation changed protein biosynthesis by upregulating proteins involved in stress response, methionine metabolism, energy production, protein degradation and novel oxide reductase enzymes. Moreover, we observed that Cy. jadinii M9 and W. anomalus M10 displayed ability to activate superoxide dismutase, catalase and chromate reductase activity. Two enzymes from the total cell extracts, type II nitroreductase (Frm2) and flavoprotein wrbA (Ycp4), were identified as possibly responsible for inducing crude chromate-reductase activity in cytoplasm of W. anomalus M10 under chromium overload. In Cy.jadinii M9, mitochondrial Ferredoxine NADP reductase (Yah1) and membrane FAD flavoprotein (Lpd1) were identified as probably involved in Cr(VI) reduction. To our knowledge, this is the first study proposing chromate reductase activity of these four enzymes in yeast and reporting a relationship between protein synthesis, enzymatic response and chromium biospeciation in Cy. jadinii and W. anomalus. PMID- 29121592 TI - Electrocatalytic degradation and minimization of specific energy consumption of synthetic azo dye from wastewater by anodic oxidation process with an emphasis on enhancing economic efficiency and reaction mechanism. AB - This work focused on the knowledge-based methodology for the development of an electrochemical system, enabling simultaneous optimization of various operating parameters such as current density (j), initial dye concentration (Co), NaCl concentration (CN) for the mineralization of Reactive Violet 2 (RV-2) and Acid Brown 14 (AB-14) dye on the efficiency of removal, energy consumption (EC), Chemical Oxygen Demands (COD), apparent rate constants (kapp) and Electrical Energy per Order (EEO) all of which have been examined. The relationship between kapp and EEO is also discussed. The degradation efficiency and kapp always rising at higher j and lower Co and CN while EC, EEO, and operating cost increased at higher j, Co and CN. On the other hand, The COD increased with decrease j, Co and higher CN. Due to the strong formation of hydroxyl radicals from water discharge, the graphite electrode possesses a strong power of electro-generation rate and competitive wasting reactions of organic compounds. The results demonstrated that the relatively high dye removal, COD and low specific energy consumption are obtained simultaneously only if the various parameters are regulated to a plausible value j of 79Am-2, Co of 100mg/L and CN of 1g/L within 60min of electrolysis. The color removal efficiency is much faster for RV-2 compared to AB 14 due to the contribution of azo bond in the dye molecule. Also, the EC and kapp are higher for RV-2 than AB-14 while is lower in terms of EEO and COD. A comprehensive reaction sequence of RV-2 and AB-14 mineralization involving all oxidation products was proposed. Formation and evolution of aromatic and aliphatic (short-chain carboxylic acids) intermediates during the treatment and a mineralization pathway is proposed. The estimated cost of operation for degradation at optimum conditions is calculated as 1.54 and 1.29 USD m-3/g dye for complete degradation RV-2 and AB-14, respectively. PMID- 29121593 TI - Stimulation of liver IGF-1 expression promotes peak bone mass achievement in growing rats: a study with pomegranate seed oil. AB - Peak bone mass (PBM) achieved at adulthood is a strong determinant of future onset of osteoporosis, and maximizing it is one of the strategies to combat the disease. Recently, pomegranate seed oil (PSO) has been shown to have bone-sparing effect in ovariectomized mice. However, its effect on growing skeleton and its molecular mechanism remain unclear. In the present study, we evaluated the effect of PSO on PBM in growing rats and associated mechanism of action. PSO was given at various doses to 21-day-old growing rats for 90 days by oral gavage. The changes in bone parameters were assessed by micro-computed tomography and histology. Enzyme-linked immunosorbent assay was performed to analyze the levels of serum insulin-like growth factor type 1 (IGF-1). Western blotting from bone and liver tissues was done. Chromatin immunoprecipitation assay was performed to study the histone acetylation levels at IGF-1 gene. The results of the study show that PSO treatment significantly increases bone length, bone formation rate, biomechanical parameters, bone mineral density and bone microarchitecture along with enhancing muscle and brown fat mass. This effect was due to the increased serum levels of IGF-1 and stimulation of its signaling in the bones. Studies focusing on acetylation of histones in the liver, the major site of IGF-1 synthesis, showed enrichment of acetylated H3K9 and H3K14 at IGF-1 gene promoter and body. Further, the increased acetylation at H3K9 and H3K14 was associated with a reduced HDAC1 protein level. Together, our data suggest that PSO promotes the PBM achievement via increased IGF-1 expression in liver and IGF-1 signaling in bone. PMID- 29121594 TI - Recovery of balance function among individuals with total knee arthroplasty: Comparison of responsiveness among four balance tests. AB - BACKGROUND AND AIM: Balance deficits are common after total knee arthroplasty (TKA); however the responsiveness of commonly used balance measurement tools has not been well defined. The objective of this prospective study was to compare the internal and external responsiveness of four measurement tools in assessing recovery of balance function following TKA. METHODS: A total of 134 individuals with TKA (95 women; age: 66.3+/-6.6years) completed the Balance Evaluation Systems Test (BESTest), Mini-BESTest, Brief-BESTest, and Berg Balance Scale (BBS) at 2, 4, 8, 12, and 24 weeks post-TKA. The Functional Gait Assessment (FGA) served as the anchor measure, and was also measured across these time points. Internal responsiveness was indicated by the standardized response mean (SRM), while external responsiveness was reflected by the degree of association of the changes of balance scores with those of FGA. RESULTS: The SRM ranged from 0.60 1.14 for the BESTest, 0.40-0.94 for the Mini-BESTest, 0.27-0.91 for the Brief BESTest, and 0.19-0.70 for the BBS, over time. The change in BESTest and Mini BESTest scores predicted the change in the FGA scores across all time periods, except for the Mini-BESTest between weeks 12-24, accounting for 13-27%, and 12 24% of the variance, respectively. The Brief-BESTest scores only predicted FGA scores between the weeks 2-4 (R2=20%). The changes in BBS scores were not associated with the FGA. CONCLUSION: The BESTest is the most responsive in measuring recovery of balance among individuals with TKA. The Mini-BESTest is a reasonable option during time constraints. PMID- 29121595 TI - From the psychosis prodrome to the first-episode of psychosis: No evidence of a cognitive decline. AB - Cognitive deficits have an important role in the neurodevelopment of schizophrenia and other psychotic disorders. However, there is a continuing debate as to whether cognitive impairments in the psychosis prodrome are stable predictors of eventual psychosis or undergo a decline due to the onset of psychosis. In the present study, to determine how cognition changes as illness emerges, we examined baseline neurocognitive performance in a large sample of helping-seeking youth ranging in clinical state from low-risk for psychosis through individuals at clinical high-risk (CHR) for illness to early first episode patients (EFEP). At baseline, the MATRICS Cognitive Consensus battery was administered to 322 individuals (205 CHRs, 28 EFEPs, and 89 help-seeking controls, HSC) that were part of the larger Early Detection, Intervention and Prevention of Psychosis Program study. CHR individuals were further divided into those who did (CHR-T; n = 12, 6.8%) and did not (CHR-NT, n = 163) convert to psychosis over follow-up (Mean = 99.20 weeks, SD = 21.54). ANCOVAs revealed that there were significant overall group differences (CHR, EFEP, HSC) in processing speed, verbal learning, and overall neurocognition, relative to healthy controls (CNTL). In addition, the CHR-NTs performed similarly to the HSC group, with mild to moderate cognitive deficits relative to the CTRL group. The CHR-Ts mirrored the EFEP group, with large deficits in processing speed, working memory, attention/vigilance, and verbal learning (>1 SD below CNTLs). Interestingly, only verbal learning impairments predicted transition to psychosis, when adjusting for age, education, symptoms, antipsychotic medication, and neurocognitive performance in the other domains. Our findings suggest that large neurocognitive deficits are present prior to illness onset and represent vulnerability markers for psychosis. The results of this study further reinforce that verbal learning should be specifically targeted for preventive intervention for psychosis. PMID- 29121597 TI - Rapid synthesis of 125I integrated gold nanoparticles for use in combined neoplasm imaging and targeted radionuclide therapy. AB - The selective delivery of radionuclides to tissues of interest remains a problematic task during treatment. The lack of tissue specificity for many therapeutics limit their efficacy by putting healthy organs and tissues at risk (e.g., side effects). Therefore, high specificity therapeutic strategies are needed to overcome these risks. The objective of this study was to use a modified citrate reduction technique to synthesize gold nanoparticles (AuNPs) containing 125I in order to combine their unique therapeutic and diagnostic properties. This task was accomplished by varying the insertion time of 125I, which will cause complete aggregation if added too early in the AuNP synthesis process. Even though 125I was utilized in this experiment, studies are underway to see if this approach can be extrapolated to shorter-lived isotopes (e.g., 211At). Characterization of the 125I-AuNPs was carried out using UV-Vis spectrometry and Transmission Electron Microscopy (TEM). The appropriate addition time of 125I was determined to be approximately 50s after the addition of sodium citrate. TEM measured the nanoparticles' diameters to be in the 10-20nm range. The AuNPs were found to be extremely stable, with no observable leaching of radioactivity into the solution. 125I-AuNPs could be beneficial as a contrast agent in CT imaging and therapy since AuNPs enhance the bio-delivery of 125I to neoplasms. PMID- 29121596 TI - The impact of long-term moderate and heavy alcohol consumption on incident atherosclerosis among persons living with HIV. AB - BACKGROUND: Level of alcohol consumption is associated with differential risk of atherosclerosis, but little research has investigated this association among HIV+ persons. We evaluated the association between long-term alcohol use and incident atherosclerosis among HIV+ persons. METHODS: We utilized data from HIV+ participants of the Women's Interagency HIV Study (n=483) and the Multicenter AIDS Cohort Study (n=305) without history of cardiovascular disease. Atherosclerosis was assessed two times by B-mode carotid artery ultrasound imaging from 2004 to 2013. Presence of plaque was defined as focal carotid intima media thickness over 1.5mm. Those with no plaque at baseline and plaque at follow up were considered incident cases of atherosclerosis. Group-based trajectory models were used to categorize participants into 10-year drinking patterns representing heavy, moderate, or abstinent-low. Multivariable logistic regressions were conducted to assess the association of long-term moderate and heavy use on atherosclerosis, compared to abstinent-low. RESULTS: Heavy alcohol consumption was not statistically significantly associated with risk for incident atherosclerosis in women (AOR 1.10, CI 0.40-3.02) or men (AOR 1.31, CI 0.43 4.00), compared to abstinence-low. Moderate consumption was associated with 54% lower odds for incident disease in men (AOR 0.46, CI 0.21-1.00), but not in women (AOR 1.08, CI 0.58-2.00). In cohort-combined analyses, alcohol consumption was not statistically significantly association with incident atherosclerosis (moderate AOR 0.78, CI 0.48-1.27; heavy AOR 1.33, CI 0.66-2.69). CONCLUSION: Moderate alcohol consumption was associated with a significant protective effect on incident atherosclerosis in men only. No other levels of alcohol consumption significantly predicted atherosclerosis in men and women compared to abstinent low. PMID- 29121599 TI - Polyaniline (PANI): an innovative support for sampling and removal of VOCs in air matrices. AB - Polyaniline (PANI)-based materials for both removal and sampling of volatile organic compounds (VOCs) from air by rapid adsorption/desorption processes have been developed. The polymer was synthesized in form of emeraldine as both salt and base using different synthetic approaches, a traditional one and a "green" one. VOCs adsorption/desorption efficiency was evaluated for all the materials analyzing the desorbed VOCs fractions by GC/MS technique and obtaining results similar to the presently adopted method employing commercial activated carbon. Most important, in this work it has been demonstrated for the first time that the use of PANI-based sorbents allowed the substitution of the toxic CS2, recommended in official methods, with the less hazardous CH3OH as the VOCs extraction solvent. Moreover, a complete regeneration of the polymers could be realized by a few rapid washing steps. Finally, the best PANI-based material was subjected to recycling tests thereby showing a high adsorption/desorption efficiency retention up to four runs. PMID- 29121598 TI - Novel C-Terminal Heat Shock Protein 90 Inhibitors (KU711 and Ku757) Are Effective in Targeting Head and Neck Squamous Cell Carcinoma Cancer Stem cells. AB - Advanced head and neck squamous cell carcinoma (HNSCC) remains a therapeutic challenge due to the development of therapy resistance. Several studies have implicated the development of cancer stem cells as a possible mechanism for therapy resistance in HNSCC. Heat shock protein 90's (Hsp90's) molecular chaperone function is implicated in pathways of resistance in HNSCC. Therefore, in the present study, we investigated the efficacy of novel C-terminal Hsp90 inhibitors (KU711 and KU757) in targeting HNSCC cancer stem cells (CSCs). Treatment of HNSCC human cell lines MDA1986, UMSCC 22B, and UMSCC 22B cisplatin resistant cells with the KU compounds indicated complete blockage of self-renewal for the resistant and parent cell lines starting from 20 MUM KU711 and 1 MUM KU757. Dose-dependent decrease in the cancer stem cell markers CD44, ALDH, and CD44/ALDH double-positive cells was observed for all cell lines after treatment with KU711 and KU757. When cells were treated with either drug, migration and invasion were downregulated greater than 90% even at the lowest concentrations of 20 MUM KU711 and 1 MUM KU757. Western blot showed >90% reduction in client protein "stemness" marker BMI-1 and mesenchymal marker vimentin, as well as increase in epithelial marker E-cadherin for both cell lines, indicating epithelial to mesenchymal transition quiescence. Several CSC-mediated miRNAs that play a critical role in HNSCC therapy resistance were also downregulated with KU treatment. In vivo, KU compounds were effective in decreasing tumor growth with no observed toxicity. Taken together, these results indicate that KU compounds are effective therapeutics for targeting HNSCC CSCs. PMID- 29121600 TI - Use of surrogate indicators for the evaluation of potential health risks due to poor urban water quality: A Bayesian Network approach. AB - Urban water pollution poses risks of waterborne infectious diseases. Therefore, in order to improve urban liveability, effective pollution mitigation strategies are required underpinned by predictions generated using water quality models. However, the lack of reliability in current modelling practices detrimentally impacts planning and management decision making. This research study adopted a novel approach in the form of Bayesian Networks to model urban water quality to better investigate the factors that influence risks to human health. The application of Bayesian Networks was found to enhance the integration of quantitative and qualitative spatially distributed data for analysing the influence of environmental and anthropogenic factors using three surrogate indicators of human health risk, namely, turbidity, total nitrogen and fats/oils. Expert knowledge was found to be of critical importance in assessing the interdependent relationships between health risk indicators and influential factors. The spatial variability maps of health risk indicators developed enabled the initial identification of high risk areas in which flooding was found to be the most significant influential factor in relation to human health risk. Surprisingly, population density was found to be less significant in influencing health risk indicators. These high risk areas in turn can be subjected to more in depth investigations instead of the entire region, saving time and resources. It was evident that decision making in relation to the design of pollution mitigation strategies needs to account for the impact of landscape characteristics on water quality, which can be related to risk to human health. PMID- 29121601 TI - NOx promotion of SO2 conversion to sulfate: An important mechanism for the occurrence of heavy haze during winter in Beijing. AB - In this study, concentrations of NOx, SO2, O3 and fine particles (PM2.5) were measured at three monitoring stations in Beijing during 2015. For extreme haze episodes during 25 Nov. - 3 Dec. 2015, observation data confirmed that high concentrations of NOx promoted the conversion of SO2 to sulfate. Annual data confirmed that this is an important mechanism for the occurrence of heavy haze during winter in Beijing. Furthermore, in situ perturbation experiments in a potential aerosol mass (PAM) reactor were carried out at Shengtaizhongxin (STZX) station during both clean and polluted days. The concentrations of SO42-, NH4+, NO3- and organic aerosol were positively related to the concentration of added NO2. These results provide definitive evidence that NO2 can promote the conversion of SO2 to sulfate. At the same time, we found that NO2 can promote the formation of NH4+ and organic compounds in the aerosols. Our results illustrate that strengthened controls of nitrogen oxides is a key step in reducing the fine particles level in China. PMID- 29121602 TI - Environmental exposure to metals and the risk of hypertension: A cross-sectional study in China. AB - Metal pollution is a severe environmental issue in China, which has been recently linked with the risk of hypertension. However, relevant epidemiological studies are limited. The present exploratory study was conducted to assess the associations of environmental exposure to metals with the odds of hypertension as well as blood pressure (BP) levels using urine samples in a Chinese general population. From May 2016 to April 2017, a total of 823 eligible participants were consecutively enrolled in our study in Wuhan, China. Hypertension was defined as systolic BP (SBP) of >=140 mmHg or diastolic BP (DBP) of >=90 mmHg, a self-reported physician diagnosis, or current use of antihypertensive medication. We used urine samples as biomarkers to reflect the levels of environmental exposure to 20 metals. Multivariable regression models were applied to assess the potential association. Multi-metal models were conducted to investigate the impacts of co-exposure to various metals. Based on the results from various models, positive trends for increased odds of hypertension with increasing quartiles of vanadium (V), iron (Fe), zinc (Zn) and selenium (Se) were suggested. Compared with those in the lowest quartiles, participants in the highest quartiles of V, Fe, Zn and Se had a 4.4-fold, 4.9-fold, 4.2-fold and 2.5-fold increased odds of having hypertension, respectively. High urinary Hg level was found to increase the levels of DBP. Individuals in the highest group of Hg were found to have a 4.3 mmHg higher level of DBP. Our findings suggest that environmental exposure to V, Fe, Zn, Se and Hg might increase the risk of hypertension or elevate the levels of BP. These findings warrant further prospective studies in a larger population. PMID- 29121604 TI - Occupational exposure to indoor air pollution among bakery workers in Ethiopia; A comparison of electric and biomass cookstoves. AB - The indoor air pollution (IAP) produced by the domestic combustion of solid fuels is responsible for up to 4 million deaths annually, especially among low and middle income countries. Occupational exposure within the food preparation industries of these nations remains underexplored. We investigated occupational exposure to the IAP produced during the commercial production of injera, a staple of the Ethiopian diet, from bakeries in Addis Ababa, Ethiopia. Measurements of PM2.5, black carbon (via the proxy measure PM2.5 absorbance) and CO were collected from 30 bakeries and their employees for an average of 4-h per working day. Measurements were compared between bakeries using biomass and electric cookstoves. Further, the respiratory health data of 35 bakery employees were collected by interview-based questionnaire. Personal exposure to PM2.5 from biomass cookstoves was double that of electric cookstoves (430 MUg/m3 vs. 216 MUg/m3), black carbon exposure was four times higher among biomass users (67 * 10 5m-1 vs. 15 * 10-5m-1), and CO exposure was twenty times higher among biomass users (22 ppm vs. 1 ppm). Mixed effect models indicated that the number of stoves in use and additional solid fuel usage (e.g. coffee brewing) also contributed to exposure levels. These findings indicate that the use of biomass powered cookstoves during commercial injera production significantly contributes to IAP and self-reported respiratory symptoms. As injera is the staple foodstuff of Ethiopia, a widespread conversion to electric cookstoves is likely to have a significant impact. However, as high levels of IAP were also observed within the electric bakeries, further identification of pollution sources is required. PMID- 29121603 TI - Assessment of light extinction at a European polluted urban area during wintertime: Impact of PM1 composition and sources. AB - In this paper, results from receptor modelling performed on a well-characterised PM1 dataset were combined to chemical light extinction data (bext) with the aim of assessing the impact of different PM1 components and sources on light extinction and visibility at a European polluted urban area. It is noteworthy that, at the state of the art, there are still very few papers estimating the impact of different emission sources on light extinction as we present here, although being among the major environmental challenges at many polluted areas. Following the concept of the well-known IMPROVE algorithm, here a tailored site specific approach (recently developed by our group) was applied to assess chemical light extinction due to PM1 components and major sources. PM1 samples collected separately during daytime and nighttime at the urban area of Milan (Italy) were chemically characterised for elements, major ions, elemental and organic carbon, and levoglucosan. Chemical light extinction was estimated and results showed that at the investigated urban site it is heavily impacted by ammonium nitrate and organic matter. Receptor modelling (i.e. Positive Matrix Factorization, EPA-PMF 5.0) was effective to obtain source apportionment; the most reliable solution was found with 7 factors which were tentatively assigned to nitrates, sulphates, wood burning, traffic, industry, fine dust, and a Pb-rich source. The apportionment of aerosol light extinction (bext,aer) according to resolved sources showed that considering all samples together nitrate contributed at most (on average 41.6%), followed by sulphate, traffic, and wood burning accounting for 18.3%, 17.8% and 12.4%, respectively. PMID- 29121605 TI - Nano-rod Ca-decorated sludge derived carbon for removal of phosphorus. AB - Recovering phosphorus (P) from waste streams takes the unique advantage in simultaneously addressing the crisis of eutrophication and the shortage of P resource. A novel calcium decorated sludge carbon (Ca-SC) was developed from dyeing industry wastewater treatment sludge by decorating calcium (Ca) to effectively adsorb phosphorus from solution. The X-ray diffraction (XRD) and Fourier transform infrared (FTIR) techniques were used to characterize the Ca SCs, followed by isotherm and kinetic sorption experiments. A preferred design with CaCO3 to sludge mass ratio of 1:2 was found to have a sorption capacity of 116.82 mg/g for phosphorus. This work reveals the crucial role of well-dispersed nano-rod calcium on the Ca-SC surface for the sorption of phosphorus. Moreover, the decoration of nano-rod calcium was found to further promote the uptake of phosphorus through the formation of hydroxylapatite (Ca5(PO4)3(OH)). Thus, the development of decorated Ca-SC for sorption of phosphorus is very important in solving the P pollution and resource loss. PMID- 29121606 TI - Pattern of hematological malignancies in adolescents and young adults in Bangladesh. AB - INTRODUCTION: The adolescent and young adult (AYA) age group (15-39 years) bears distinct characteristics in terms of cancer biology, long-term health and treatment-related complications and psychosocial aspects. The overall scenario of cancer including hematological malignancies (HMs) is largely unknown in Bangladesh, where a significant proportion of people (44% of total population) belong to AYA age group. This study aims to describe the patterns of HM among AYA in the context of Bangladesh METHODS: Two previously published datasets (on hematological malignancies and childhood and adolescent cancer) were merged to construct a comprehensive dataset focusing exclusively on HMs in AYA age group. Univariate descriptive statistics were calculated and bivariate association were tested using Pearson's Chi-square test. RESULTS: A total of 2144 diagnosed HM related cases over a period of 2007-2014 were analyzed. Acute myeloid leukemia (AML) was the most frequent HM (35.1%) in AYAs, which was followed by acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) constituting 22.7% and 20.8%, respectively. Among lymphomas, Non-Hodgkin lymphoma (NHL) constituted 13.9% of all HMs while 4.6% was for Hodgkin's lymphoma (HL). CONCLUSION: This is the first attempt to provide a glimpse on the pattern and distribution of HMs among AYA in Bangladesh. Future studies are essential to get a better insight on the epidemiology, biology, potential risk factors and treatment outcomes for the AYA age group. PMID- 29121607 TI - Preparation of fluorescently labeled silica nanoparticles using an amino acid catalyzed seeds regrowth technique: Application to latent fingerprints detection and hemocompatibility studies. AB - The efficiency of an amino acid catalyzed seed regrowth technique (ACSRT) in synthesizing twelve fluorescently labeled core-shell silica nanoparticles (FLSNPs) with tunable sizes, tailored hydrophobicity, low polydispersity as well as high labeling efficiency and minimized dye leakage using different combinations of organosilicate monomers and fluorophores have been systematically investigated in this report. The utilization of some of these FLSNPs in some applications that are facilitated by hydrophobicity such as developing and visualizing latent fingerprints (LFPs) on different surfaces was also investigated. The non-specific binding affinity of the developed nanoparticles to human serum albumin (HSA) and immunoglobulin G (IgG) has also been studied. Fluorescein, fluorescein isothiocyanate and its more hydrophilic butenamine derivative (WA6) have been used in this study. Also, the alkoxysilane precursor, tetraethoxyorthosilicate (TEOS) and its binary mixture with phenyltriethoxysilane (PTEOS) or 3-aminopropyl triethoxysilane (APTES) have been used in preparing the FLSNPs with tailored compositions for the core and shell of the nanoparticles. The mean diameters of the PTEOS-coated FLSNPs were between 33.4+/-5.9 and 42.2+/ 10.8 nm as shown by the SEM measurements. The obtained results highlight the advantages of having a hydrophobic surface along with proper selection of the monomers forming the core to match the properties of the fluorescent reporters for clear detection of LFPs even using dyes of low hydrophobicity such as fluorescein and WA6. Furthermore, some of the developed FLSNPs were compared with bare silica nanoparticles in terms of nonspecific protein adsorption and hemolysis. The obtained results proved that the selected FLSNPs had a superior hemocompatibility in comparison with bare silica nanoparticles. These FLSNPs could also be used in some bio-related and diagnostic applications such as immunoassays and cell imaging purposes. PMID- 29121608 TI - Synthesis of tetrahexahedral Au-Pd core-shell nanocrystals and reduction of graphene oxide for the electrochemical detection of epinephrine. AB - An innovative epinephrine sensor was fabricated by integrating tetrahexahedral (THH) Au-Pd core-shell nanocrystals on reduced graphene oxide (rGO) nanosheets. Furthermore, the nanocomposites combined the large specific areas of rGO with the high-index facets and excellent electrocatalytic activity of the THH Au-Pd nanocrystals, and the nanocomposites were an essential adapter for detecting epinephrine. In the present work, transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) were used to identify and characterize these unique nanocomposites, and the results revealed that a unique THH Au-Pd/rGO core-shell nanostructure was synthesized successfully. To further explore the electrochemical behaviors of these nanomaterials at a GC electrode, we applied cyclic voltammetry (CV), differential pulse voltammetry (DPV) and amperometry to study the conductivity and electrocatalytic activity of the proposed sensor, and the results suggested that the sensor based on Au-Pd/rGO presented a lower limit of detection (0.0012 MUM at a signal to noise ratio of 3), wide linear detection range (0.001 uM to 1000 uM), and extraordinary selectivity and reproducibility. Moreover, the data showed that the sensor possessed good stability and acceptable accuracy to detect epinephrine in human serum samples. In summary, this work is not only a potential way to manufacture various nonenzymatic sensors but also a significant contribution to further studies in catalysis, cell fuel cells and other relevant applications. PMID- 29121609 TI - Ionic liquid-based slab optical waveguide sensor for the detection of ammonia in human breath. AB - HYPOTHESIS: A novel slab optical waveguide sensor exploiting an ionic liquid (trihexyl(tetradecyl)phosphonium chloride)-based film can be used to detect gaseous ammonia. Bromothymol blue (BTB) incorporated into the ethyl cellulose supported ionic liquid film can absorb the evanescent wave generated in the sensor and act as an indicator. The diffusion of gaseous ammonia across the sensing film is thus expected to change the absorbance of bromothymol blue, providing the basis for sensitive ammonia detection. EXPERIMENTS: The above sensor was exposed to different concentrations of ammonia gas, showing fast and reproducible responses and being superior to previously reported waveguiding based sensors. Moreover, the fabricated system was used to detect ammonia in the breath of human volunteers. FINDINGS: Under optimal conditions, gaseous ammonia was accurately detected in the range of 100-1800 ppb, with a detection limit of 69 ppb (3sigma/s). The developed sensor was re-usable due to exhibiting reversible gas sorption/desorption dynamics and was successfully applied to the determination of ammonia content in human breath. PMID- 29121610 TI - Hydrogen bond-assisted synthesis of MoS2/reduced graphene oxide composite with excellent electrochemical performances for lithium and sodium storage. AB - MoS2/reduced graphene oxide composites (MoS2/rGO) were successfully prepared by a designed tris(hydroxymethyl)methyl aminomethane (named THAM)-assisted hydrothermal method, which involves the modification of THAM on the surfaces of graphene oxide via hydrogen bonds and then the adsorption of MoO42- on the decorated surfaces due to the electrostatic attraction. The three-dimensional framework of interconnected rGO nanosheets provides good electronic conductivity and facile strain release during the electrochemical reaction, thus enhancing the overall performance of the MoS2-based electrode. Herein, the composite delivers high specific capacity, excellent cycling stability and rate performance for lithium- and sodium- ions batteries (LIBs and SIBs). The MoS2/rGO anode exhibits capacities of 880 mAh g-1 at 1 A g-1 after 200 cycles and 396 mAh g-1 even at 2 A g-1 after 2000 cycles for LIBs. As to SIBs, the reversible capacities of 485 mAh g-1 and 339 mAh g-1 can be retained at 0.1 A g-1 after 60 cycles and 0.5 A g-1 after 300 cycles, respectively. Our results demonstrate that the MoS2/rGO anode is one of the attractive anodes for LIBs and SIBs. Furthermore, the facile method can be extended to biosensing, catalytic, and biomedical applications. PMID- 29121611 TI - Colloidal design of plasmonic sensors based on surface enhanced Raman scattering. AB - This feature article focuses on the use of colloid chemistry to engineer metallic nanostructures toward application in surface enhanced Raman scattering (SERS) sensing, in particular for 'real-life' applications, where the analyte may be present in complex mixtures. We present a broad summary of the field, including recent advances that have been developed during the past 10 years. Real-life applications require a rational design and we aimed at identifying the key elements involved in it. The discussion is centered around colloidal plasmonic nanoparticles and therefore we start from the library of morphologies that have been reported in the literature. To complete the picture, colloidal self assembly, surface chemistry and the combination with materials science techniques are highlighted. Considering the progress in the field, SERS may ultimately realize its full potential as an ultrasensitive tool for routine analytical applications. PMID- 29121612 TI - Coordination of growth in root and shoot apices by AIL/PLT transcription factors. AB - Growth at the root tip and organ generation at the shoot tip depend on the proper functioning of apical meristems and the transitioning of meristematic cell descendants from a proliferating state to cell elongation and differentiation. Members of the AINTEGUMENTA-LIKE/PLETHORA (AIL/PLT) transcription factor family, a clade of two-AP2 domain proteins, specify both stem cell fate and control cellular progression of stem cell daughter cells toward differentiation. Here we highlight the importance of an AIL/PLT protein gradient in controlling distinct cellular behaviors in the root through the regulation of distinct targets in different parts of the root tip. Within the shoot, AIL/PLT proteins also promote organ growth and inhibit differentiation pointing to conserved roles in meristem function. However, they exhibit unequal genetic redundancy in these functions and do not always act in a purely additive manner. Differences in AIL/PLT regulation and perhaps transcriptional targets in roots and shoots suggest that these growth regulators have adapted to mediate growth control in distinct ways in these organ systems. PMID- 29121613 TI - Mussel-inspired polydopamine-polyethylenimine conjugated nanoparticles as efficient gene delivery vectors for mammalian cells. AB - Efficient delivery of DNA to cells is the primary concern to address the objective of gene therapy. Many attempts have been made to develop polymeric carriers for gene delivery. To have an efficient carrier, it is vital to understand the properties of the vector for better stability, transfection efficiency and minimal toxicity. Branched polyethylenimine (bPEI) has been considered as the 'gold standard' for gene delivery but suffers a major drawback of exhibiting high cytotoxicity. Here, we have attempted to develop a mussel derived polymer, polydopamine (PDA), conjugated polyethylenimine nanoparticles in such a way that the toxic nature of bPEI is suppressed by the conversion of free primary amine groups to secondary and tertiary amines. Keeping the amount of PDA fixed, varying amounts of bPEIs of different molecular weights (25, 10 and 1.8kDa) were conjugated via Michael addition and/or Schiff base. A trend in hydrodynamic size of the conjugated nanoparticles was observed in the range from 160 to 300nm and zeta potential from +12-30mV in the projected three series, viz., (i) PDA1-25bPEI0.5, PDA1-25bPEI1, PDA1-25bPEI2; (ii) PDA1-10bPEI0.5, PDA1 10bPEI1, PDA1-10bPEI2; and (iii) PDA1-1.8bPEI0.5, PDA1-1.8bPEI1, PDA1-1.8bPEI2. A visible trend in the DNA condensation ability and buffering capacity was also noticed. Further, cell cytotoxicity assays revealed that pDNA complexes of PDA bPEI nanoparticles were non-toxic to mammalian cells and these complexes exhibited several folds higher transfection efficiency than the complexes of native bPEIs as demonstrated by fluorescence measurements and flow cytometry. Altogether, the results advocate the promising potential of these conjugated nanoparticles for future in vivo applications. PMID- 29121614 TI - Interaction of semiochemicals with model lipid membranes: A biophysical approach. AB - Unravelling the chemical language of insects has been the subject of intense research in the field of chemical ecology for the past five decades. Insect communication is mainly based on chemosensation due to the small body size of insects, which limits their ability to produce or perceive auditory and visual signals, especially over large distances. Chemicals involved in insect communication are called semiochemicals. These volatiles and semivolatiles compounds allow to Insects to find a mate, besides the oviposition site in reproduction and food sources. Actually, insect olfaction mechanism is subject to study, but systematic analyses of the role of neural membranes are scarce. In the present work we evaluated the interactions of alpha-pinene, benzaldehyde, eugenol, and grandlure, among others, with a lipid membrane model using surface pressure experiments and Monte Carlo computational analysis. This allowed us to propose a plausible membranotropic mechanism of interaction between semiochemicals and insect neural membrane. PMID- 29121615 TI - Restructuration kinetics of amphiphilic intraocular lenses during aging. AB - Photooxidation and hydrolysis are the two primary aging factors of intraocular lenses. Opacifications, dislocations, glistening and yellowing of the implanted acrylic lenses, which are due to chain scissions and depolymerization, are the consequences of aging from the clinical perspective. The purpose of this study was to examine the consequence of the aging of intraocular lenses on chemical and surface properties. Acrylic lenses made of poly acrylic-co-polystyrene polymer were artificially aged by photooxidation and hydrolysis from 2 to 20 years. Degradation products were observed by Reverse-phase High-Performance Liquid Chromatography RP-HPLC and thermogravimetric analysis (TGA). The surface, which was analyzed by atomic force microscopy (AFM) and fibronectin adhesion kinetics, was chosen as an indicator of intraocular biocompatibility. Low-molecular-weight degradation products (LMWP) result from chain scission under both hydrolysis and photooxidation. The osmotic effects of water enable degradation products to migrate through the polymer. A portion of the degradation products exudate in the surrounding center, whereas a portion link with lateral chains of the polymer. At the same time, the surface roughness evolves to externalize the most hydrophilic chains. As a result, the fibronectin adhesion level decrease with time, which indicates the existence of a biocompatible kinetic for implanted intraocular lenses. PMID- 29121616 TI - Loading Cu-doped magnesium oxide onto surface of magnetic nanoparticles to prepare magnetic disinfectant with enhanced antibacterial activity. AB - In this article, Cu-doped magnesium oxide was loaded onto the surface of Fe3O4 magnetic nanoparticles via a hydrophilic carbon intermediate layer to synthesize Fe3O4@C@MgO-Cu magnetic composite. The potential application as disinfectant in water purification was investigated by examining the antibacterial activity of the Fe3O4@C@MgO-Cu composite toward Gram negative Escherichia coli and Gram positive Staphylococcus aureus. The practical bactericidal efficiency in inactivation experiment was also studied and the copper doping amount was optimized. The results show that the as-obtained magnetic composite, with good dispersion and typical multilayer structure, exhibited high antibacterial activity to both strains and the Cu-doping improved the antibacterial performance significantly. Moreover, an increasing bactericidal ability of the nanocomposite was observed with the increasing Cu-doping amount and 312.5mgL-1 of Fe3O4@C@MgO Cu disinfectant with a 1.5% Cu-doping amount (wt% of MgO) could inactivate 99% of the tested bacteria in normal saline solution within 60minutes. The Fe3O4@C@MgO Cu composite, with a high magnetic saturation value of 29.07emug-1, can be readily recovered from matrix solution for reuse with an external magnet, which simplified the disinfection operation greatly and avoided the waste of disinfectant. PMID- 29121617 TI - pH-Sensitive mesoporous silica nanoparticles for chemo-photodynamic combination therapy. AB - In order to optimize the chemotherapeutic efficacy of doxorubicin (DOX) and improve the photodynamic therapeutic effectiveness of rose bengal (RB), a mesoporous silica nanoparticle system was designed as the carrier of RB and DOX for chemo-photodynamic combination therapy. A pH-sensitive strategy has been exploited to enhance the delivery efficiency. Our results suggested that the production of singlet oxygen was independent of the release of RB while strongly influenced by the external DOX layer. This method showed several benefits, including accelerating cellular uptake of the payloads and enabling chemo photodynamic combination therapy for synergistic cancer treatment. Our study provides a new way for co-delivery of chemotherapy agents and photosensitizers. PMID- 29121618 TI - Estimating normal lung weight measurement using postmortem CT in forensic cases. AB - PURPOSE: The aim of this study is to estimate the lung weight using postmortem CT in well aerated lung autopsy cases. The correlation coefficients to the lung weight were also evaluated for the cadavers' height, weight, whole body surface area (WBSA), body mass index, and estimated lung volume. MATERIALS AND METHODS: From October 2015 to July 2016, 31 cadavers (male 12, female 19, age 20-98 (mean 66.9) y.o., postmortem interval 0.3-75.0 (5.7) days) were compared as regards body weight, height, whole body surface area (WBSA), body mass index (BMI), lung volume on CT, and total lung volume classified into several CT number categories, with their lung weight in autopsy. RESULTS: The lung weight (mean +/- SE) was 284.9 +/- 14.8 g in right lung and 249.3 +/- 12.9 g in left lung. The %ALV was 79.9 +/- 0.9 HU (mean +/- standard error (SE)) in both lungs, 80.3 +/- 1.3 HU in right lung, and 77.6 +/- 2.0 HU in left lung. Using a simple linear regression test, there was no statistically significant correlation between the lung weight and the categories (R2: body height 0.234, weight 0.224, WBSA 0.309, BMI 0.046, lung volume 0.059). The volume for each individual CT density category showed no significant correlation, but the stepwise regression test yielded an excellent correlation coefficient (R2 = 0.840). CONCLUSION: The well aerated lung weight was 284.9 +/- 14.8 g in right lung and 249.3 +/- 12.9 g in left lung, and the postmortem CT could estimate the lung weight with high correlation coefficient. PMID- 29121619 TI - Metformin: a golden oldie. PMID- 29121620 TI - Dispensing patterns for antidiabetic agents in New Zealand: are the guidelines being followed? AB - AIMS: Type 2 diabetes mellitus (T2DM) is a significant public health issue in New Zealand. Effective management and glycaemic control is critical for reducing diabetes-related complications. Treatment guidelines are well established in New Zealand. Using dispensing data as a proxy for prescribing data, this paper aims to describe the pattern of first- and second-line antidiabetic agent (AA) dispensing for T2DM in New Zealand and assess adherence with treatment guidelines. METHODS: Analysis of national dispensing data for AA medications using the Pharmaceutical Collection database from 2007/08 to 2015/16. RESULTS: Metformin monotherapy remains the most commonly prescribed first-line T2DM medication prescribed, accounting for 85% of initial agents prescribed. Sulfonylureas are the most common second-line agents used, accounting for 70% of all second-line agents. CONCLUSION: There is a high degree of adherence with the T2DM treatment guidelines in New Zealand. PMID- 29121621 TI - A review of squamous cell vulvar cancers in Waikato region, New Zealand. AB - BACKGROUND: Squamous cell vulvar cancers (SCVC) are rare. Although management guidelines have recently been published, New Zealand studies presenting "real world" outcomes are limited. METHODS: Retrospective single-centre review of SCVC diagnosed between 1 January 2000 and 31 August 2015. Clinical characteristics and outcomes were reviewed. RESULTS: Among 47 cases reviewed, 38 were ethnically European and 9 Maori. Cases identified as Stage 1 (16), Stage 2 (5), Stage 3 (17), Stage 4 (9). For Stages 1, 2, 3 and 4, (16, 4, 17 and 6) were managed by local excision; (9, 1, 14 and 2) by node dissection and (2, 1, 3 and 5) by chemoradiotherapy respectively. Wound cellulitis (10) and lymphedema (8) were the commonest acute and late complication, respectively. Seven patients were treated with 5-Fluorouracil and Mitomycin, and four received weekly Cisplatin. Grade 3 toxicities seen in five cases treated with 5-Fluorouracil and Mitomycin versus none in the Cisplatin group. No local recurrences observed in patients treated with chemoradiation. Patients with Age Adjusted Charlson Comorbid Index Score (ACCIS) <5 had better overall survival (OS) compared to scores >=5 (60% versus 41%) with 33 months median follow-up. Five-year OS and disease-free specific survival was 73% and 94% (Stage 1), 40% and 60% (Stage 2), 44% and 59% (Stage 3) and 29% (Stage 4) respectively. CONCLUSIONS: We present "real world" outcomes of vulvar cancers in this older and comorbid population. Larger, prospective multi centre studies are proposed. PMID- 29121622 TI - Child morbidity as described by hospital admissions for primary school aged children in Tonga 2009-2013. AB - AIMS: To describe inpatient utilisation patterns for primary school aged children in Tonga. METHODS: We described admissions for children aged 5-11 years to the main hospital in Tonga from January 2009 to December 2013. Rates with 95% confidence intervals (CI) were compared using rate ratios (RR). RESULTS: There were 1,816 admissions. The average annual admission rate was 20.2/1,000 (95% CI 19.3-21.1). Hospital admission rates were higher in younger than older children (5-7 versus 8-11 years, RR=1.28, 95% CI 1.18-1.41) and in boys than girls (RR=1.52, 95% CI 1.38-1.68). Injury and poisoning (28%), non-respiratory infectious diseases (19%), respiratory conditions (16%), abdominal/surgical conditions (13%) and dental (9%) were the most frequent admission reasons. A larger proportion of younger versus older children were hospitalised for dental (16% vs 1%, P<0.001) or respiratory conditions (18% vs 14%, P=0.02). A larger proportion of older children were hospitalised for abdominal/surgical conditions (15% vs 11%, P=0.008), other infectious diseases (21% vs 17%, P=0.04), other conditions (10% vs 6%, P<0.001) and cardiac conditions (2% vs 1%, P<0.001). CONCLUSIONS: In children 5-11 years in Tonga, 85% of admissions were for five groups of conditions. These data inform priority areas for healthcare spending and enable comparisons over time and between different Pacific countries. PMID- 29121624 TI - Remembering the 1918 influenza pandemic: national survey of memorials and scope for enhancing educational value around pandemic preparedness. AB - AIM: To systematically identify physical memorials to the 1918 influenza pandemic in an entire country. METHODS: Internet searches, contact with local historians and field expeditions were conducted. RESULTS: Despite the high impact of the 1918 influenza pandemic in New Zealand (~8,600 deaths), only seven publicly accessible local memorials which referred this pandemic were identified. Another 11 memorials were identified, but these were in private settings or did not refer to the pandemic. There is no national memorial and a marked contrast exists with the number of war memorials (260 times more per 1,000 deaths for one war), and for 20 smaller mass fatality events (one of which has eight memorials alone). The current educational value of these pandemic memorials is likely to be minimal since only three are in cities, there is a lack of supporting signage and there are no links to online resources. CONCLUSIONS: Despite the major impact of the 1918 influenza pandemic in New Zealand, publicly accessible memorials were found to be rare. This was in marked contrast to other disaster-related memorials and particularly to war memorials. There appears to be major scope for enhancing public education around the persisting threat of future pandemics via improved use of physical memorials and linkages to online resources. PMID- 29121623 TI - Metabolic monitoring in New Zealand district health board mental health services. AB - AIM: To audit New Zealand district health boards' (DHBs) metabolic monitoring policies in relation to consumers prescribed second-generation antipsychotic medications using a best practice guideline. METHODS: Metabolic monitoring policies from DHBs and one private clinic were analysed in relation to a best practice standard developed from the current literature and published guidelines relevant to metabolic syndrome. RESULTS: Fourteen of New Zealand's 20 DHBs currently have metabolic monitoring policies for consumers prescribed antipsychotic medication. Two of those policies are consistent with the literature-based guideline. Eight policies include actions to be taken when consumers meet criteria for metabolic syndrome. Four DHBs have systems for measuring their rates of metabolic monitoring. There is no consensus on who is clinically responsible for metabolic monitoring. CONCLUSIONS: Metabolic monitoring by mental health services in New Zealand reflects international experience that current levels of monitoring are low and policies are not always in place. Collaboration across the mental health and primary care sectors together with the adoption of a consensus guideline is needed to improve rates of monitoring and reduce current rates of physical health morbidities. PMID- 29121625 TI - Face-to-face versus telephone delivery of the Green Prescription for Maori and New Zealand Europeans with type-2 diabetes mellitus: influence on participation and health outcomes. AB - AIM: In Aotearoa/New Zealand, the proportion of Maori who participate in the national Green Prescription lifestyle programme is lower than for New Zealand Europeans. We compared the uptake and effectiveness of two modes of Green Prescription delivery: face-to-face and telephone among both Maori and New Zealand Europeans. METHOD: Sixty-eight Maori and 70 New Zealand Europeans with type-2 diabetes participated in this six-month randomised trial of the two modes of delivery. Recruitment integrated an explicitly Maori culturally sensitive approach. All participants received lifestyle intervention. Anthropometry, blood lipids and glycated haemoglobin were measured before and after the intervention. RESULTS: The face-to-face approach (first meeting) yielded 100% uptake into the programme among both Maori and New Zealand Europeans. At six months there were overall reductions in weight (1.8; [95 CI%, 0.6, 2.9kg]), waist circumference (3.7 [2.6, 4.8cm]), and total cholesterol (0.6 [0.3, 0.9mmol/l]) and glycated haemoglobin (3.1 [-0.2, 6.7mmol/mol]). There were no significant differences by mode of delivery, ethnicity or gender. CONCLUSION: The Green Prescription programme resulted in small but clinically favourable improvements in health outcomes for type-2 diabetes patients, regardless of the mode of delivery for both Maori and New Zealand Europeans. PMID- 29121626 TI - Whanau perceptions and experiences of acute rheumatic fever diagnosis for Maori in Northland, New Zealand. AB - AIM: In New Zealand, acute rheumatic fever (ARF) remains a significant health problem with persistent ethnic inequities. Maori children 5-15 years of age in Northland have some of the highest ARF rates nationally. This study explored Maori whanau experiences of ARF, including pathways to primary healthcare and barriers and facilitators for diagnosis of ARF. METHODS: The study applied a qualitative kaupapa Maori approach including eight whanau, two individual interviews and participant observations with 36 participants. RESULTS: Barriers to accessing primary healthcare included: geographic distance, unavailability of appointments, cost, poor trust and rapport between health providers and whanau. Good rapport, communication and trust with health professionals facilitated utilisation of services. Barriers to diagnosis were lack of throat swabbing and inappropriate prescription of antibiotics. Access to primary care, having health professionals follow sore throat guidelines and trust in health professionals facilitated diagnosis. CONCLUSION: Health services could better support ARF diagnosis through the development of an effective quality improvement strategy for sore throat management, promoting free rapid response throat swabbing for high-risk populations, and exploring options of self-swabbing. Training and evaluation targeted at rapport building should also be established for health professionals to facilitate primary healthcare utilisation. PMID- 29121627 TI - Audit on first seizure presentation to Taranaki Base Hospital: a secondary centre experience. AB - BACKGROUND: Management of first seizure should be based on treating the underlying cause and tailoring investigations to identify those patients at high risk of recurrence. AIM: To establish the incidence of first seizure presentation to Taranaki Base Hospital and investigate the management of these patients. METHOD: A retrospective audit was performed identifying patients presenting to Taranaki Base Hospital from 1 January 2015 to 31 December 2015 with a first seizure. RESULTS: Thirty-seven patients presented with their first seizure with 50% found to have an easily reversible precipitant. Forty-three percent had a history of previous brain insult and 52% had an abnormality identified on neuroimaging. Only 14% received formal neurology follow-up and only 8% had electroencephalography. Forty-three percent received chronic antiepileptic drug therapy and 27% had a recurrent seizure within 12 months. Only 43% had documented driving advice. CONCLUSIONS: The incidence of first seizure presentation to Taranaki Base Hospital is similar to worldwide data. In general, patients receive basic investigations in keeping with international guidelines. This audit has helped to identify a number of areas to address with the current service provision, including ways to improve access to important investigations and ways to develop a guideline to standardise care. PMID- 29121628 TI - Achieving health equity in Aotearoa: strengthening responsiveness to Maori in health research. AB - Excellent health research is essential for good health outcomes, services and systems. Health research should also build towards equity and in doing so ensure that no one is left behind. As recipients of government funding, researchers are increasingly required to demonstrate an understanding of their delegated responsibilities to undertake research that has the potential to address Maori health needs and priorities. These requirements form the basis of responsiveness to Maori in health research, and several research institutions have implemented systems to support their organisational approach to this endeavour. However, many health researchers have a narrow view of responsiveness to Maori and how it might be relevant to their work. In this viewpoint paper we provide an overview of existing frameworks that can be used to develop thinking and positioning in relation to the Treaty of Waitangi and responsiveness to Maori. We also describe an equity-based approach to responsiveness to Maori and highlight four key areas that require careful consideration, namely: (1) relevance to Maori; (2) Maori as participants; (3) promoting the Maori voice, and; (4) human tissue. Finally, we argue for greater engagement with responsiveness to Maori activities as part of our commitment to achieving equitable health outcomes. PMID- 29121629 TI - Overwhelming support for smokefree cars that are carrying children-is the Government listening? PMID- 29121630 TI - The battle for better nutrition: the role of the escalating fruit and vegetable prices. PMID- 29121631 TI - New Zealand's legal action against IQOS postponed, consultation with Big Tobacco follows. PMID- 29121632 TI - Antifungal susceptibility results of vaginal yeast isolates from New Zealand women, 2001-2015. PMID- 29121633 TI - Response to Dr Caleb Armstrong: proposed Waikato medical school. PMID- 29121634 TI - Errata. PMID- 29121635 TI - Oviposition activity of Drosophila suzukii as mediated by ambient and fruit temperature. AB - The invasive pest Drosophila suzukii was introduced to southern Europe in 2008 and spread throughout Central Europe in the following years. Precise reliable data on the temperature-dependent behavior of D. suzukii are scarce but will help forecasting and cultivation techniques. Depending on physico-chemical properties, surface temperature of objects may differ from ambient temperatures, determining physical activity, and affect oviposition on or into substrate, determining preimaginal development later. Therefore, the preferred ambient temperatures of D. suzukii and fruit temperature for oviposition were examined on a linear temperature gradient device. Thirty adults (15 ?; 15 ?) were adapted to different temperatures (10, 20, 30 degrees C) for six days and then exposed to different temperature gradients (10-25, 20-35, 25-40 degrees C). D. suzukii adapted to 10 degrees C remained in cooler regions and suffered from a significantly higher mortality at the 25-40 degrees C gradient. Animals adapted to warmer temperatures had a wider temperature preference on the gradient device. Acclimation to lower temperatures and the resulting lower temperature preferences may allow the flies to disperse better in spring to search for oviposition sites. The oviposition activity decreased continuously at a fruit temperature above 28 degrees C and below 15 degrees C, with highest oviposition activity in fruits with temperatures between 19.7 degrees C and 24.8 degrees C. The preferred fruit temperature is in accordance with the temperature optimum of reproduction biology and preimaginal development of D. suzukii reported in the literature. PMID- 29121636 TI - Improving diagnostic sensitivity of combined dermoscopy and reflectance confocal microscopy imaging through double reader concordance evaluation in telemedicine settings: A retrospective study of 1000 equivocal cases. AB - BACKGROUND: Reflectance confocal microscopy (RCM) is an imaging device that permits non-invasive visualization of cellular morphology and has been shown to improve diagnostic accuracy of dermoscopically equivocal cutaneous lesions. The application of double reader concordance evaluation of dermoscopy-RCM image sets in retrospective settings and its potential application to telemedicine evaluation has not been tested in a large study population. OBJECTIVE: To improve diagnostic sensitivity of RCM image diagnosis using a double reader concordance evaluation approach; to reduce mismanagement of equivocal cutaneous lesions in retrospective consultation and telemedicine settings. METHODS: 1000 combined dermoscopy-RCM image sets were evaluated in blind by 10 readers with advanced training and internship in dermoscopy and RCM evaluation. We compared sensitivity and specificity of single reader evaluation versus double reader concordance evaluation as well as the effect of diagnostic confidence on lesion management in a retrospective setting. RESULTS: Single reader evaluation resulted in an overall sensitivity of 95.2% and specificity of 76.3%, with misdiagnosis of 8 melanomas, 4 basal cell carcinomas and 2 squamous cell carcinomas. Combined double reader evaluation resulted in an overall sensitivity of 98.3% and specificity of 65.5%, with misdiagnosis of 1 in-situ melanoma and 2 basal cell carcinomas. CONCLUSION: Evaluation of dermoscopy-RCM image sets of cutaneous lesions by single reader evaluation in retrospective settings is limited by sensitivity levels that may result in potential mismanagement of malignant lesions. Double reader blind concordance evaluation may improve the sensitivity of diagnosis and management safety. The use of a second check can be implemented in telemedicine settings where expert consultation and second opinions may be required. PMID- 29121638 TI - Impact of inability to turn in bed assessed by a wearable three-axis accelerometer on patients with Parkinson's disease. AB - BACKGROUND: Difficulty turning over in bed is a common night-time symptom in Parkinson's disease (PD). We aimed to quantitatively evaluate overnight turnover movements using a three-axis accelerometer and to investigate whether inability to turn in bed is related to daytime sleepiness, sleep quality, and depressive mood in PD patients. METHODS: We examined 64 patients with PD (mean age, 73.3+/ 8.21 years; modified Hoehn-Yahr [mH-Y] stage, 3.0+/-1.0; disease duration, 7.2+/ 6.3 years; unified Parkinson's disease rating scale [UPDRS], 36.9+/-18.3). Overnight monitoring of turnover movements using a wearable three-axis accelerometer was performed in all patients. Nocturnal kinetic parameters including total time recumbent, total time supine, number of turnover movements, and mean interval between turnover movements were obtained. Daytime immobility was assessed using the Barthel index (B-I), UPDRS, and mH-Y stage. Patients were also assessed with the Epworth Sleepiness Scale (ESS), Parkinson's Disease Sleep Scale-2 (PDSS-2), and Beck Depression Inventory (BDI). RESULTS: Number of turnover movements in bed correlated negatively with disease duration (r = 0.305; p<0.05), L-dopa-equivalent dose (r = -0.281; p<0.05), mH-Y staging (r = 0.336; p<0.01), total score of UPDRS (r = -0.386; p<0.01) and positively with B-I score (r = 0.365; p<0.01). Number of turnover movements in bed was generally inconsistent with awareness of turnover movement impairment as evaluated by PDSS 2 Item 9 scores, but patients who were never aware of impaired turnover movements showed >=5 turnover movements overnight. Multivariate logistic regression analyses revealed no correlations between number of nocturnal turnover movements in bed and BDI, ESS, or PDSS-2. Use of anti-psychotic drugs was associated with ESS (p = 0.045). UPDRS was associated with PDSS-2 (p = 0.016). CONCLUSION: Decreased number of turnover movements may not be a direct determinant of daytime sleepiness, sleep disorders, or depressive mood in PD patients. Use of anti psychotic drugs and higher UPDRS score are factors significantly associated with daytime sleepiness and uncomfortable sleep, respectively. PMID- 29121637 TI - The combinatorial control of alternative splicing in C. elegans. AB - Normal development requires the right splice variants to be made in the right tissues at the right time. The core splicing machinery is engaged in all splicing events, but which precise splice variant is made requires the choice between alternative splice sites-for this to occur, a set of splicing factors (SFs) must recognize and bind to short RNA motifs in the pre-mRNA. In C. elegans, there is known to be extensive variation in splicing patterns across development, but little is known about the targets of each SF or how multiple SFs combine to regulate splicing. Here we combine RNA-seq with in vitro binding assays to study how 4 different C. elegans SFs, ASD-1, FOX-1, MEC-8, and EXC-7, regulate splicing. The 4 SFs chosen all have well-characterised biology and well-studied loss-of-function genetic alleles, and all contain RRM domains. Intriguingly, while the SFs we examined have varied roles in C. elegans development, they show an unexpectedly high overlap in their targets. We also find that binding sites for these SFs occur on the same pre-mRNAs more frequently than expected suggesting extensive combinatorial control of splicing. We confirm that regulation of splicing by multiple SFs is often combinatorial and show that this is functionally significant. We also find that SFs appear to combine to affect splicing in two modes-they either bind in close proximity within the same intron or they appear to bind to separate regions of the intron in a conserved order. Finally, we find that the genes whose splicing are regulated by multiple SFs are highly enriched for genes involved in the cytoskeleton and in ion channels that are key for neurotransmission. Together, this shows that specific classes of genes have complex combinatorial regulation of splicing and that this combinatorial regulation is critical for normal development to occur. PMID- 29121639 TI - A subset of sweet-sensing neurons identified by IR56d are necessary and sufficient for fatty acid taste. AB - Fat represents a calorically potent food source that yields approximately twice the amount of energy as carbohydrates or proteins per unit of mass. The highly palatable taste of free fatty acids (FAs), one of the building blocks of fat, promotes food consumption, activates reward circuitry, and is thought to contribute to hedonic feeding underlying many metabolism-related disorders. Despite a role in the etiology of metabolic diseases, little is known about how dietary fats are detected by the gustatory system to promote feeding. Previously, we showed that a broad population of sugar-sensing taste neurons expressing Gustatory Receptor 64f (Gr64f) is required for reflexive feeding responses to both FAs and sugars. Here, we report a genetic silencing screen to identify specific populations of taste neurons that mediate fatty acid (FA) taste. We find neurons identified by expression of Ionotropic Receptor 56d (IR56d) are necessary and sufficient for reflexive feeding response to FAs. Functional imaging reveals that IR56d-expressing neurons are responsive to short- and medium-chain FAs. Silencing IR56d neurons selectively abolishes FA taste, and their activation is sufficient to drive feeding responses. Analysis of co-expression with Gr64f identifies two subpopulations of IR56d-expressing neurons. While physiological imaging reveals that both populations are responsive to FAs, IR56d/Gr64f neurons are activated by medium-chain FAs and are sufficient for reflexive feeding response to FAs. Moreover, flies can discriminate between sugar and FAs in an aversive taste memory assay, indicating that FA taste is a unique modality in Drosophila. Taken together, these findings localize FA taste within the Drosophila gustatory center and provide an opportunity to investigate discrimination between different categories of appetitive tastants. PMID- 29121641 TI - Identification of a t(3;4)(p1.3;q1.5) translocation breakpoint in pigs using somatic cell hybrid mapping and high-resolution mate-pair sequencing. AB - Reciprocal translocations are the most frequently occurring constitutional structural rearrangements in mammalian genomes. In phenotypically normal pigs, an incidence of 1/200 is estimated for such rearrangements. Even if constitutional translocations do not necessarily induce defects and diseases, they are responsible for significant economic losses in domestic animals due to reproduction failures. Over the last 30 years, advances in molecular and cytogenetic technologies have led to major improvements in the resolution of the characterization of translocation events. Characterization of translocation breakpoints helps to decipher the mechanisms that lead to such rearrangements and the functions of the genes that are involved in the translocation. Here, we describe the fine characterization of a reciprocal translocation t(3;4) (p1.3;q1.5) detected in a pig line. The breakpoint was identified at the base pair level using a positional cloning and chromosome walking strategy in somatic cell hybrids that were generated from an animal that carries this translocation. We show that this translocation occurs within the ADAMTSL4 gene and results in a loss of expression in homozygous carriers. In addition, by taking this translocation as a model, we used a whole-genome next-generation mate-pair sequencing approach on pooled individuals to evaluate this strategy for high throughput screening of structural rearrangements. PMID- 29121640 TI - The influence of physical activity, sedentary behavior on health-related quality of life among the general population of children and adolescents: A systematic review. AB - BACKGROUND: The association between physical activity, sedentary behavior and health-related quality of life in children and adolescents has been mostly investigated in those young people with chronic disease conditions. No systematic review to date has synthesized the relationship between physical activity, sedentary behavior and health-related quality of life in the general healthy population of children and adolescents. The purpose of this study was to review systematically the existing literature that evaluated the relations between physical activity, sedentary behavior and health-related quality of life in the general population of children and adolescents. METHODS: We conducted a computer search for English language literature from databases of MEDLINE, EMBASE, PSYCINFO and PubMed-related articles as well as the reference lists of existing literature between 1946 and the second week of January 2017 to retrieve eligible studies. We included the studies that assessed associations between physical activity and/or sedentary behavior and health-related quality of life among the general population of children and adolescents aged between 3-18 years. The study design included cross-sectional, longitudinal and health intervention studies. We excluded the studies that examined associations between physical activity, sedentary behavior and health-related quality of life among children and adolescents with specific chronic diseases, and other studies and reports including reviews, meta-analyses, study protocols, comments, letters, case reports and guidelines. We followed up the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement in the reporting of this review. The risk of bias of the primary studies was assessed by the Newcastle Ottawa Scale. We synthesized the difference in health-related quality of life scores between different levels of physical activity and sedentary time. RESULTS: In total, 31 studies met the inclusion criteria and were synthesized in the review. Most of the included studies used a cross-sectional design (n = 21). There were six longitudinal studies and three school-based physical activity intervention studies. One study used both cross-sectional and longitudinal designs. We found that higher levels of physical activity were associated with better health-related quality of life and increased time of sedentary behavior was linked to lower health-related quality of life among children and adolescents. A dose-response relation between physical activity, sedentary behavior and health-related quality of life was observed in several studies suggesting that the higher frequency of physical activity or the less time being sedentary, the better the health-related quality of life. CONCLUSIONS: The findings in this study suggest that school health programs promoting active lifestyles among children and adolescents may contribute to the improvement of health-related quality of life. Future research is needed to extend studies on longitudinal relationships between physical activity, sedentary behavior and health-related quality of life, and on effects of physical activity interventions on health-related quality of life among children and youth. PMID- 29121642 TI - Limbic system damage in MS: MRI assessment and correlations with clinical testing. AB - Volume loss in some limbic region structures has been observed in multiple sclerosis (MS) patients. However, in vivo evaluation of existing tissue cellular microstructure integrity has received less attention. The goal of studies reported here was to quantitatively assess loss of limbic system volumes and tissue integrity, and to evaluate associations of these measures with cognitive and physical dysfunction in MS patients. Thirty-one healthy controls (HC) and 80 MS patients, including 32 relapsing remitting (RRMS), 32 secondary progressive (SPMS) and 16 primary progressive (PPMS), participated in this study. Tissue cellular integrity was evaluated by means of recently introduced tissue-specific parameter R2t* that was calculated from multi-gradient-echo MRI signals using a recently developed method that separates R2t* from BOLD (blood oxygen level dependent) contributions to GRE signal decay rate constant (R2*), and accounting for physiological fluctuations and artifacts from background gradients. Volumes in limbic system regions, normalized to skull size (NV), were measured from standard MPRAGE images. MS patients had lower R2t* and smaller normalized volumes in the hippocampus, amygdala, and several other limbic system regions, compared to HC. Alterations in R2t* of several limbic system regions correlated with clinical and neurocognitive test scores in MS patients. In contrast, smaller normalized volumes in MS were only correlated with neurocognitive test scores in the hippocampus and amygdala. This study reports the novel finding that R2t*, a measure that estimates tissue integrity, is more sensitive to tissue damage in limbic system structures than is atrophy. R2t* measurements can serve as a biomarker that is distinct from and complementary to volume measurements. PMID- 29121643 TI - PFI1785w: A highly conserved protein associated with pregnancy associated malaria. AB - Pregnancy-associated malaria (PAM) is one of the severe forms of Plasmodium falciparum infection. The main antigen VAR2CSA is the target of vaccine development. However, the large size of VAR2CSA protein and its high degree of variability limit to the efficiency of the vaccination. Using quantitative mass spectrometry method, we detected and quantified proteotypic peptides from 5 predicted PAM associated proteins. Our results confirmed that PFI1785w is over expressed in PAM samples. Then, we investigated PFI1785w variability among a set of parasite samples from various endemic areas. PFI1785w appear to be more conserved than VAR2CSA. PFB0115w, another PAM associated protein, seems also associated with the pathology. Further vaccination strategies could integrate other proteins in addition to the major VAR2CSA antigen to improve immune response to vaccination. PMID- 29121644 TI - Imaging extracellular ATP with a genetically-encoded, ratiometric fluorescent sensor. AB - Extracellular adenosine triphosphate (ATP) is a key purinergic signal that mediates cell-to-cell communication both within and between organ systems. We address the need for a robust and minimally invasive approach to measuring extracellular ATP by re-engineering the ATeam ATP sensor to be expressed on the cell surface. Using this approach, we image real-time changes in extracellular ATP levels with a sensor that is fully genetically-encoded and does not require an exogenous substrate. In addition, the sensor is ratiometric to allow for reliable quantitation of extracellular ATP fluxes. Using live-cell microscopy, we characterize sensor performance when expressed on cultured Neuro2A cells, and we measure both stimulated release of ATP and its clearance by ectonucleotidases. Thus, this proof-of-principle demonstrates a first-generation sensor to report extracellular ATP dynamics that may be useful for studying purinergic signaling in living specimens. PMID- 29121645 TI - Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease. AB - BACKGROUND: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD). METHODS: Primary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169. RESULTS: Dasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313). CONCLUSIONS: In patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT00764309. PMID- 29121646 TI - The phosphomimetic mutation of syndecan-4 binds and inhibits Tiam1 modulating Rac1 activity in PDZ interaction-dependent manner. AB - The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs). Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu) mutant of syndecan-4 (SDC4). SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan. In this study we show that the Ser179Glu mutant binds strongly Tiam1, a Rac1-GEF reducing Rac1-GTP by 3-fold in MCF-7 breast adenocarcinoma cells. Mutational analysis unravels the PDZ interaction between SDC4 and Tiam1 is indispensable for the suppression of the Rac1 activity. Neither of the SDC4 interactions is effective alone to block the Rac1 activity, on the contrary, lack of either of interactions can increase the activity of Rac1, therefore the Rac1 activity is the resultant of the inhibitory and stimulatory effects. In addition, SDC4 can bind and tether RhoGDI1 (GDP-dissociation inhibitor 1) to the membrane. Expression of the phosphomimetic SDC4 results in the accumulation of the Rac1-RhoGDI1 complex. Co-immunoprecipitation assays (co IP-s) reveal that SDC4 can form complexes with RhoGDI1. Together, the regulation of the basal activity of Rac1 is fine tuned and SDC4 is implicated in multiple ways. PMID- 29121647 TI - Update of the Dutch manual for costing studies in health care. AB - OBJECTIVES: Dutch health economic guidelines include a costing manual, which describes preferred research methodology for costing studies and reference prices to ensure high quality studies and comparability between study outcomes. This paper describes the most important revisions of the costing manual compared to the previous version. METHODS: An online survey was sent out to potential users of the costing manual to identify topics for improvement. The costing manual was aligned with contemporary health economic guidelines. All methodology sections and parameter values needed for costing studies, particularly reference prices, were updated. An expert panel of health economists was consulted several times during the review process. The revised manual was reviewed by two members of the expert panel and by reviewers of the Dutch Health Care Institute. RESULTS: The majority of survey respondents was satisfied with content and usability of the existing costing manual. Respondents recommended updating reference prices and adding some particular commonly needed reference prices. Costs categories were adjusted to the international standard: 1) costs within the health care sector; 2) patient and family costs; and 3) costs in other sectors. Reference prices were updated to reflect 2014 values. The methodology chapter was rewritten to match the requirements of the costing manual and preferences of the users. Reference prices for nursing days of specific wards, for diagnostic procedures and nurse practitioners were added. CONCLUSIONS: The usability of the costing manual was increased and parameter values were updated. The costing manual became integrated in the new health economic guidelines. PMID- 29121648 TI - Correction: Dignity and Distress towards the End of Life across Four Non-Cancer Populations. AB - [This corrects the article DOI: 10.1371/journal.pone.0147607.]. PMID- 29121649 TI - Spatiotemporal dynamics of HSV genome nuclear entry and compaction state transitions using bioorthogonal chemistry and super-resolution microscopy. AB - We investigated the spatiotemporal dynamics of HSV genome transport during the initiation of infection using viruses containing bioorthogonal traceable precursors incorporated into their genomes (HSVEdC). In vitro assays revealed a structural alteration in the capsid induced upon HSVEdC binding to solid supports that allowed coupling to external capture agents and demonstrated that the vast majority of individual virions contained bioorthogonally-tagged genomes. Using HSVEdC in vivo we reveal novel aspects of the kinetics, localisation, mechanistic entry requirements and morphological transitions of infecting genomes. Uncoating and nuclear import was observed within 30 min, with genomes in a defined compaction state (ca. 3-fold volume increase from capsids). Free cytosolic uncoated genomes were infrequent (7-10% of the total uncoated genomes), likely a consequence of subpopulations of cells receiving high particle numbers. Uncoated nuclear genomes underwent temporal transitions in condensation state and while ICP4 efficiently associated with condensed foci of initial infecting genomes, this relationship switched away from residual longer lived condensed foci to increasingly decondensed genomes as infection progressed. Inhibition of transcription had no effect on nuclear entry but in the absence of transcription, genomes persisted as tightly condensed foci. Ongoing transcription, in the absence of protein synthesis, revealed a distinct spatial clustering of genomes, which we have termed genome congregation, not seen with non-transcribing genomes. Genomes expanded to more decondensed forms in the absence of DNA replication indicating additional transitional steps. During full progression of infection, genomes decondensed further, with a diffuse low intensity signal dissipated within replication compartments, but frequently with tight foci remaining peripherally, representing unreplicated genomes or condensed parental strands of replicated DNA. Uncoating and nuclear entry was independent of proteasome function and resistant to inhibitors of nuclear export. Together with additional data our results reveal new insight into the spatiotemporal dynamics of HSV genome uncoating, transport and organisation. PMID- 29121650 TI - Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway. AB - Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane. However, the underlying mechanisms for the formation of these metabolites remain poorly understood. In the present study, we performed in vitro and in vivo investigations to elucidate the involvement of flavin-containing monooxygenase-3 (FMO3) and cytochrome P450 enzymes (CYPs) in Bu metabolic pathway. Rapid clearance of THT was observed when incubated with human liver microsomes. Furthermore, among different recombinant microsomal enzymes, the highest intrinsic clearance for THT was obtained via FMO3 followed by several CYPs including 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4. In Bu- or THT-treated mice, inhibition of FMO3 by phenylthiourea significantly suppressed the clearance of both Bu and THT. Moreover, the simultaneous administration of a high dose of THT (200MUmol/kg) to Bu-treated mice reduced the clearance of Bu. Consistently, in patients undergoing HSCT, repeated administration of Bu resulted in a significant up-regulation of FMO3 and glutathione-S-transfrase -1 (GSTA1) genes. Finally, in a Bu-treated patient, additional treatment with voriconazole (an antimycotic drug known as an FMO3-substrate) significantly altered the Bu clearance. In conclusion, we demonstrate for the first time that FMO3 along with CYPs contribute a major part in busulphan metabolic pathway and certainly can affect its kinetics. The present results have high clinical impact. Furthermore, these findings might be important for reducing the treatment-related toxicity of Bu, through avoiding interaction with other concomitant used drugs during conditioning and hence improving the clinical outcomes of HSCT. PMID- 29121651 TI - A modeling study of budding yeast colony formation and its relationship to budding pattern and aging. AB - Budding yeast, which undergoes polarized growth during budding and mating, has been a useful model system to study cell polarization. Bud sites are selected differently in haploid and diploid yeast cells: haploid cells bud in an axial manner, while diploid cells bud in a bipolar manner. While previous studies have been focused on the molecular details of the bud site selection and polarity establishment, not much is known about how different budding patterns give rise to different functions at the population level. In this paper, we develop a two dimensional agent-based model to study budding yeast colonies with cell-type specific biological processes, such as budding, mating, mating type switch, consumption of nutrients, and cell death. The model demonstrates that the axial budding pattern enhances mating probability at an early stage and the bipolar budding pattern improves colony development under nutrient limitation. Our results suggest that the frequency of mating type switch might control the trade off between diploidization and inbreeding. The effect of cellular aging is also studied through our model. Based on the simulations, colonies initiated by an aged haploid cell show declined mating probability at an early stage and recover as the rejuvenated offsprings become the majority. Colonies initiated with aged diploid cells do not show disadvantage in colony expansion possibly due to the fact that young cells contribute the most to colony expansion. PMID- 29121652 TI - Risk of predation makes foragers less choosy about their food. AB - Animals foraging in the wild have to balance speed of decision making and accuracy of assessment of a food item's quality. If resource quality is important for maximizing fitness, then the duration of decision making may be in conflict with other crucial and time consuming tasks, such as anti-predator behaviours or competition monitoring. Individuals facing the risk of predation and/or competition should adjust the duration of decision making and, as a consequence, their level of choosiness for resources. When exposed to predation, the forager could either maintain its level of choosiness for food items but accept a reduction in the amount of food items consumed or it could reduce its level of choosiness and accept all prey items encountered. Under competition risk, individuals are expected to reduce their level of choosiness as slow decision making exposes individuals to a higher risk of opportunity costs. To test these predictions, the level of choosiness of a seed-eating carabid beetle, Harpalus affinis, was examined under 4 different experimental conditions of risk: i) predation risk; ii) intraspecific competition; iii) interspecific competition; and, iv) control. All the risks were simulated using chemical cues from individual conspecifics or beetles of different species that are predatory or granivorous. Our results show that when foraging under the risk of predation, H. affinis individuals significantly reduce their level of choosiness for seeds. Reductions in level of choosiness for food items might serve as a sensible strategy to reduce both the total duration of a foraging task and the cognitive load of the food quality assessment. No significant differences were observed when individuals were exposed to competition cues. Competition, (i.e opportunity cost) may not be perceived as risk high enough to induce changes in the level of choosiness. Our results suggest that considering the amount of items consumed, alone, would be a misleading metric when assessing individual response to a risk of predation. Foraging studies should therefore also take in account the decision making process. PMID- 29121653 TI - Comparison of the new Exponential Injury Severity Score with the Injury Severity Score and the New Injury Severity Score in trauma patients: A cross-sectional study. AB - OBJECTIVE: To compare Exponential Injury Severity Score (EISS) with Injury Severity Score (ISS) and New Injury Severity Score (NISS) in terms of their predictive capability of the outcomes and medical expenses of hospitalized adult trauma patients. SETTING: This study was based at a level I trauma center in Taiwan. METHODS: Data for 17,855 adult patients hospitalized from January 1, 2009 to December 31, 2015 were retrieved from the Trauma Registry System. The primary outcome was in-hospital mortality. Secondary outcomes were the hospital length of stay (LOS), intensive care unit (ICU) admission rate, ICU LOS, and medical expenses. Chi-square tests were used for categorical variables to determine the significance of the associations between the predictor and outcome variables. Student t-tests were applied to analyze normally distributed data for continuous variables, while Mann-Whitney U tests were used to compare non-normally distributed data. RESULTS: According to the survival rate-to-severity score relationship curve, we grouped all adult trauma patients based on EISS scores of >= 27, 9-26, and < 9. Significantly higher mortality rates were noted in patients with EISS >= 27 and those with EISS of 9-26 when compared to patients with EISS < 9; this finding concurred to the findings for groups classified by the ISS and NISS with the cut-off points set between 25 and 16. The hospital LOS, ICU admission rates, and medical expenses for patients with EISS >= 27 and patients with EISS of 9-26 were also significantly longer and higher than that of patients with EISS < 9. When comparing the demographics and detailed medical expenses of very severely injured adult trauma patients classified according to ISS, NISS, and EISS, patients with ISS >= 25 and NISS >= 25 both had significantly lower mortality rates, lower ICU admission rates, and shorter ICU LOS compared to patients with EISS >= 27. CONCLUSIONS: EISS 9 and 27 can serve as two cut-off points regarding injury severity, and patients with EISS >= 27 have the greatest injury severity. Additionally, these patients have the highest mortality rate, the highest ICU admission rate, and the longest ICU LOS compared to those with ISS >= 25 and NISS >= 25, suggesting that patients with EISS >= 27 have the worst outcome. PMID- 29121654 TI - Burden of tuberculosis in Xinjiang between 2011 and 2015: A surveillance data based study. AB - BACKGROUND: Despite the reduction in reported incidence of tuberculosis globally, the burden of pulmonary tuberculosis (PTB) remains high in low- and middle- income countries, including China. The current study aims to evaluate the distribution and trend of PTB incidence in Xinjiang, the region with the highest PTB burden in China. METHODS: We identified all confirmed PTB case records reported to the Chinese TB Information Management System (TBIMS) between 2011 and 2015. We analyzed these records to measure the annual incidence of reported smear positive PTB cases in Xinjiang and its trend over time. We also analyzed incidence by gender, residential area, and region. Spatial analysis was used to describe the inter-regional disparity of the disease burden during the study period. RESULTS: We identified 212,216 smear-positive PTB cases between 2011 and 2015. The reported incidence increased from 180.8 cases in 2011 to 195.8 cases in 2015 per 100,000 population. The southern region of Xinjiang had the highest disease burden (257.8/100,000 in 2011 and 312.7/100,000 in 2015). More than 60% cases occurred in persons >45 years, and 76% of cases lived in rural areas. CONCLUSION: To reach the goal of elimination and control of TB, more comprehensive STOP TB strategies should be implemented in Xinjiang. Residents in the southern region and rural areas of Xinjiang require particular attention. PMID- 29121656 TI - The association between social capital and HIV treatment outcomes in South Africa. AB - BACKGROUND: HIV treatment has reduced morbidity and mortality. By 2012, it was estimated that 60.4% of eligible South Africans accessed antiretroviral treatment; however, treatment adherence and retention remain the greatest challenges. There is a growing belief that social capital, seen as "the features of social organization that facilitate cooperation for mutual benefit", is important in promoting HIV treatment retention. The aim of this study was to establish whether social capital is associated with HIV treatment outcomes. METHODS AND FINDINGS: This was a cross-sectional analysis of data from a cohort study that investigated how patient outcomes were linked to clinical characteristics, and included exploratory factor and logistic regression analysis. Data from 943 patients were analyzed. Outcomes for the analysis were visit non-adherence, unsuppressed viral load, and treatment failure. Sixteen percent of patients (n = 118) had unsuppressed viral loads; 19% (n = 179) were non-adherent; and 32% (n = 302) experienced treatment failure. Social capital had two dimensions that were described by two factors. There was no association between either factor and visit non-adherence. Social capital factor 1 was marginally associated with lower risks of unsuppressed viral load and treatment failure at 12 months (OR = 0.78; 95% CI = 0.58-1.03 and OR = 0.76; 95% CI = 0.62 0.93, respectively); but not with visit non-adherence (OR = 0.93; 95% CI = 0.71 1.22). After controlling for confounders, the odds of both unsuppressed viral load and treatment failure decreased with an increase in social capital factor 1. CONCLUSION: This study suggests that social capital, in terms of the number of groups to which an HIV-infected person belongs, the diversity of the groups, availability of child support, and time available for community projects, is protective against poor HIV treatment outcomes. Implementers and policy makers in the areas of HIV treatment and prevention need to consider the inclusion of social capital in the design of HIV/AIDS treatment program. PMID- 29121655 TI - Experimental blunt chest trauma-induced myocardial inflammation and alteration of gap-junction protein connexin 43. AB - OBJECTIVE: Severe blunt chest trauma in humans is associated with high mortality rates. Whereas lung tissue damage and lung inflammation after blunt chest trauma have extensively been investigated, the traumatic and posttraumatic effects on the heart remain poorly understood. Therefore, the purpose of this study was to define cardiac injury patterns in an experimental blunt chest trauma model in rats. METHODS: Experimental blunt chest trauma was induced by a blast wave in rats, with subsequent analysis of its effects on the heart. The animals were subjected either to a sham or trauma procedure. Systemic markers for cardiac injury were determined after 24 h and 5 days. Postmortem analysis of heart tissue addressed structural injury and inflammation 24 h and 5 days after trauma. RESULTS: Plasma levels of extracellular histones were elevated 24 h and 5 days after blunt chest trauma compared to sham-treated animals. In the heart, up regulation of interleukin-1beta 24 h after trauma and increased myeloperoxidase activity 24 h and 5 days after trauma were accompanied by reduced complement C5a receptor-1 expression 24 h after trauma. Histological analysis revealed extravasation of erythrocytes and immunohistochemical analysis alteration of the pattern of the gap-junction protein connexin 43. Furthermore, a slight reduction of alpha-actinin and desmin expression in cardiac tissue was found after trauma together with a minor increase in sarcoplasmatic/endoplasmatic reticlulum calcium ATPase (SERCA) expression. CONCLUSIONS: The clinically highly relevant rat model of blast wave-induced blunt chest trauma is associated with cardiac inflammation and structural alterations in cardiac tissue. PMID- 29121657 TI - Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. AB - Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac beta-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations. PMID- 29121658 TI - Risk factors for postoperative deep infection in bone tumors. AB - BACKGROUND: Postoperative deep infection after bone tumor surgery remains a serious complication. Although there are numerous reports about risk factors for postoperative deep infection in general surgery, there is only a small number of reports about those for bone tumor surgery. This retrospective study aimed to identify risk factors for postoperative deep infection after bone tumor resection. METHODS: We reviewed data of 681 patients (844 bone tumors) who underwent surgery. Associations between variables, including age, recurrent tumor, pathological fracture, surgical site (pelvis/other), chemotherapy, biological reconstruction, augmentation of artificial bone or bone cement, the use of an implant, intraoperative blood loss, operative time, additional surgery for complications, and postoperative deep infection were evaluated. RESULTS: The rate of postoperative deep infection was 3.2% (27/844 tumors). A pelvic tumor (odds ratio [OR]: 3.4, 95% confidence interval [CI]: 1.0-11.3) and use of an implant (OR: 9.3, 95% CI: 1.9-45.5) were associated with an increased risk of deep infection. CONCLUSIONS: This retrospective study showed that pelvic tumor and use of an implant were independent risk factors for deep infection. This information will help surgeons prepare an adequate surgical plan for patients with bone tumors. PMID- 29121659 TI - Polyclonal antibodies for the detection of Trypanosoma cruzi circulating antigens. AB - BACKGROUND: Detection of Trypanosoma cruzi antigens in clinical samples is considered an important diagnostic tool for Chagas disease. The production and use of polyclonal antibodies may contribute to an increase in the sensitivity of immunodiagnosis of Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: Polyclonal antibodies were raised in alpacas, rabbits, and hens immunized with trypomastigote excreted-secreted antigen, membrane proteins, trypomastigote lysate antigen and recombinant 1F8 to produce polyclonal antibodies. Western blot analysis was performed to determine specificity of the developed antibodies. An antigen capture ELISA of circulating antigens in serum, plasma and urine samples was developed using IgY polyclonal antibodies against T. cruzi membrane antigens (capture antibody) and IgG from alpaca raised against TESA. A total of 33 serum, 23 plasma and 9 urine samples were analyzed using the developed test. Among serum samples, compared to serology, the antigen capture ELISA tested positive in 55% of samples. All plasma samples from serology positive subjects were positive in the antigen capture ELISA. All urine positive samples had corresponding plasma samples that were also positive when tested by the antigen capture ELISA. CONCLUSIONS: Polyclonal antibodies are useful for detection of circulating antigens in both the plasma and urine of infected individuals. Detection of antigens is direct evidence of the presence of the parasite, and could be a better surrogate of current infection status. PMID- 29121660 TI - Associations between fatty liver index and asymptomatic intracranial vertebrobasilar stenosis in Chinese population. AB - Metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic syndromes (MetS) have been recognized as the important risk factors for asymptomatic intracranial vertebrobasilar stenosis (IVBS). Although fatty liver index (FLI) is significantly related with these diseases, the association between FLI and IVBS remains unclear. In the present study, 2368 participants (30-75 years) were recruited from a Chinese prospective cohort study of PMMJS. Amongst them, 2281 individuals who did not have IVBS at baseline were enrolled in the 6 year following-up study. In cross-sectional analysis based on the baseline characteristics, the results showed that FLI was positively related with IVBS prevalence. Compared to the participants with FLI < 30, the adjusted OR (95% CI) of IVBS was 2.07 (1.18, 3.62) and 2.85 (1.39, 5.18) in the groups of 30 <= FLI < 60 and FLI >= 60, respectively. In longitudinal analysis, the results showed that the participants with FLI >= 60 had an increased risk of asymptomatic IVBS compared to those with FLI < 30 [adjusted HR (95%CI): 1.65 (1.05, 2.60)]. Moreover, exclusion of persons with hypertension, T2DM and MetS did not alter the associations between FLI and asymptomatic IVBS. Therefore, our results suggest that elevated FLI is an independent risk factor for asymptomatic IVBS in Chinese adults. PMID- 29121661 TI - High prevalence of non-communicable diseases and associated risk factors amongst adults living with HIV in Cambodia. AB - BACKGROUND: With rapid expansion of antiretroviral therapy for HIV, there are rising life expectancies among people living with HIV. As a result, co-morbidity from non-communicable diseases in those living and aging with HIV is increasingly being reported. Published data on this issue have been limited in Cambodia. The aim of this study was to determine the prevalence of diabetes mellitus, hypertension and hypercholesterolemia and associated risk factors in adults living with HIV in Cambodia. METHODS: This cross-sectional study was conducted in five provinces of Cambodia from May-June 2015. Information was obtained on socio demographic and clinical characteristics through face-to-face interviews using a structured questionnaire, and anthropometric and biochemical measurements were performed. Diabetes mellitus was diagnosed with fasting blood glucose >=126 mg/dl, hypertension with systolic blood pressure >=140 mmHg and/or diastolic blood pressure >= 90 mmHg and hypercholesterolemia with fasting blood cholesterol >=190 mg/dl. Multivariable logistic regression analyses were used to explore risk factors. RESULTS: The study sample included 510 adults living with HIV; 67% were female, with a mean age of 45 (standard deviation = 8) years. Of these, 8.8% had diabetes mellitus, 15.1% had hypertension and 34.7% had hypercholesterolemia. Of the total participants with non-communicable diseases (n = 244), 47.8% had one or more diseases, and 75% were not aware of their diseases prior to the study: new disease was diagnosed in 90% of diabetes mellitus, 44% of hypertension and 90% of hypercholesterolemia. Single disease occurred in 81%, dual disease in 17% and triple disease in 2%. In adjusted analyses, those consuming 1 serving of fruit compare to 2 servings as significantly with diabetes mellitus, those eating 1 serving of fruit compare to 2 servings and using lard for cooking were significantly associated with hypertension, and those being unemployed, having monthly income less than 100 USD and being underweighted were significantly associated with hypercholesterolemia. CONCLUSIONS: The prevalence of diabetes mellitus, hypertension and hypercholesterolemia in adults living with HIV in this study was considerably high, with most of these diseases newly identified through active screening in the survey. These findings strongly suggest that screening of non-communicable diseases should be integrated into routine HIV care in Cambodia. PMID- 29121662 TI - Qualitative and quantitative assessment of Illumina's forensic STR and SNP kits on MiSeq FGxTM. AB - Massively parallel sequencing (MPS) is a powerful tool transforming DNA analysis in multiple fields ranging from medicine, to environmental science, to evolutionary biology. In forensic applications, MPS offers the ability to significantly increase the discriminatory power of human identification as well as aid in mixture deconvolution. However, before the benefits of any new technology can be employed, a thorough evaluation of its quality, consistency, sensitivity, and specificity must be rigorously evaluated in order to gain a detailed understanding of the technique including sources of error, error rates, and other restrictions/limitations. This extensive study assessed the performance of Illumina's MiSeq FGx MPS system and ForenSeqTM kit in nine experimental runs including 314 reaction samples. In-depth data analysis evaluated the consequences of different assay conditions on test results. Variables included: sample numbers per run, targets per run, DNA input per sample, and replications. Results are presented as heat maps revealing patterns for each locus. Data analysis focused on read numbers (allele coverage), drop-outs, drop-ins, and sequence analysis. The study revealed that loci with high read numbers performed better and resulted in fewer drop-outs and well balanced heterozygous alleles. Several loci were prone to drop-outs which led to falsely typed homozygotes and therefore to genotype errors. Sequence analysis of allele drop-in typically revealed a single nucleotide change (deletion, insertion, or substitution). Analyses of sequences, no template controls, and spurious alleles suggest no contamination during library preparation, pooling, and sequencing, but indicate that sequencing or PCR errors may have occurred due to DNA polymerase infidelities. Finally, we found utilizing Illumina's FGx System at recommended conditions does not guarantee 100% outcomes for all samples tested, including the positive control, and required manual editing due to low read numbers and/or allele drop-in. These findings are important for progressing towards implementation of MPS in forensic DNA testing. PMID- 29121664 TI - Does preoperative mechanical prophylaxis have additional effectiveness in preventing postoperative venous thromboembolism in elderly patients with hip fracture?-Retrospective case-control study. AB - BACKGROUND: Elderly patients undergoing hip fracture surgery (HFS) are at increased risk of postoperative venous thromboembolism (VTE). To reduce this risk, combined postoperative mechanical and chemical thromboprophylaxis has been routinely performed after HFS in these patients. This retrospective case-control study was conducted to evaluate the additional effectiveness of preoperative mechanical thromboprophylaxis for the prevention of VTE following HFS in elderly patients. METHODS: Of 539 consecutive patients aged 70 years or older undergoing HFS, 404 (control group) did not receive preoperative mechanical thromboprophylaxis, while 135 (study group) received mechanical thromboprophylaxis using an intermittent pneumatic compression device and graduated compression stockings from the time of admission until surgery. All patients received combined postoperative mechanical and chemical thromboprophylaxis following HFS in accordance with the same protocol. The incidence of symptomatic VTE confirmed based on clinical symptoms and 3 dimensional CT angiography within one month of surgery was investigated in both groups. RESULTS: The American Society of Anesthesiologists grade was higher (p = 0.016) in the study group and more patients in this group had concomitant cardiovascular and neurologic diseases (p = 0.005 and p = 0.009, respectively). In addition, more patients in the study group had received anticoagulant medication preinjury owing to comorbidities (39% vs 28%, p = 0.025). The overall incidences of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) were 7.4% and 3.7%, and 2.2% and 1.5% in the control and study groups, respectively. According to multiple logistic regression, symptomatic DVT significantly reduced in the study group (OR 0.28, p = 0.042), while there was no significant difference in the incidence of symptomatic PE between the two groups (p = 0.223). CONCLUSIONS: Preoperative mechanical thromboprophylaxis may confer an additional benefit by preventing postoperative VTE without adding more risk of perioperative bleeding in elderly patients with hip fracture. PMID- 29121663 TI - Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice. AB - BACKGROUND: Cardiac rupture is an important cause of death in the acute phase after myocardial infarction (MI). Macrophages play a pivotal role in cardiac remodeling after MI. Apoptosis inhibitor of macrophage (AIM) is secreted specifically by macrophages and contributes to macrophage accumulation in inflamed tissue by maintaining survival and recruiting macrophages. In this study, we evaluated the role of AIM in macrophage accumulation in the infarcted myocardium and cardiac rupture after MI. METHODS AND RESULTS: Wild-type (WT) and AIM-/- mice underwent permanent left coronary artery ligation and were followed up for 7 days. Macrophage accumulation and phenotypes (M1 pro-inflammatory macrophage or M2 anti-inflammatory macrophage) were evaluated by immunohistological analysis and RT-PCR. Matrix metalloproteinase (MMP) activity levels were measured by gelatin zymography. The survival rate was significantly higher (81.1% vs. 48.2%, P<0.05), and the cardiac rupture rate was significantly lower in AIM-/- mice than in WT mice (10.8% vs. 31.5%, P<0.05). The number of M1 macrophages and the expression levels of M1 markers (iNOS and IL-6) in the infarcted myocardium were significantly lower in AIM-/- mice than in WT mice. In contrast, there was no difference in the number of M2 macrophages and the expression of M2 markers (Arg-1, CD206 and TGF-beta1) between the two groups. The ratio of apoptotic macrophages in the total macrophages was significantly higher in AIM-/- mice than in WT mice, although MCP-1 expression did not differ between the two groups. MMP-2 and 9 activity levels in the infarcted myocardium were significantly lower in AIM-/- mice than in WT mice. CONCLUSIONS: These findings suggest that AIM depletion decreases the levels of M1 macrophages, which are a potent source of MMP-2 and 9, in the infarcted myocardium in the acute phase after MI by promoting macrophage apoptosis, and leads to a decrease in the incidence of cardiac rupture and improvements in survival rates. PMID- 29121665 TI - Self-reported adherence and pharmacy refill adherence are both predictive for an undetectable viral load among HIV-infected migrants receiving cART. AB - HIV-infected migrants were shown to have poorer treatment outcomes than Dutch HIV infected patients, often due to worse treatment adherence. Self-reported adherence would be an easy way to monitor adherence, but its validity relative to pharmacy refill adherence has not been extensively evaluated in migrants. All HIV infected migrants older than 18 years and in care at the two Rotterdam HIV treatment centers were eligible. Refill data with leftover medication (PRL) (residual pill count) were obtained from their pharmacies up to 15 months prior to inclusion. Self-reported adherence to combination Antiretroviral Therapy was assessed by four questions about adherence at inclusion. Additionally, risk factors for pharmacy refill non-adherence were examined. In total, 299 HIV infected migrants were included. Viral load (VL) was detectable in 11% of the patients. Specificity of PRL was 53% for patients with an adherence of 100% and decreased with lower cut-off values. Sensitivity and negative predictive value (NPV) were 68% and 15% and increased with lower cut-off values. Positive predictive value (PPV) was around 93% for all cut-off values. Using the self reported questions, 139 patients (47%) reported to be adherent. Sensitivity was 49% and specificity was 72%. PPV and NPV were 95% and 13%. No risk factors for pharmacy refill non-adherence were found in multivariable analyses. Both PRL and self-reported adherence, can predict undetectable VL in HIV-infected migrants. PPV and NPV are similar for both methods. This study shows that using four self reported items is sufficient to predict adherence which is crucial for optimal clinical outcome in HIV-infected migrants. PMID- 29121667 TI - Quantifying unpredictability: A multiple-model approach based on satellite imagery data from Mediterranean ponds. AB - Fluctuations in environmental parameters are increasingly being recognized as essential features of any habitat. The quantification of whether environmental fluctuations are prevalently predictable or unpredictable is remarkably relevant to understanding the evolutionary responses of organisms. However, when characterizing the relevant features of natural habitats, ecologists typically face two problems: (1) gathering long-term data and (2) handling the hard-won data. This paper takes advantage of the free access to long-term recordings of remote sensing data (27 years, Landsat TM/ETM+) to assess a set of environmental models for estimating environmental predictability. The case study included 20 Mediterranean saline ponds and lakes, and the focal variable was the water surface area. This study first aimed to produce a method for accurately estimating the water-surface area from satellite images. Saline ponds can develop salt-crusted areas that make it difficult to distinguish between soil and water. This challenge was addressed using a novel pipeline that combines band ratio water indices and the short near-infrared band as a salt filter. The study then extracted the predictable and unpredictable components of variation in the water surface area. Two different approaches, each showing variations in the parameters, were used to obtain the stochastic variation around a regular pattern with the objective of dissecting the effect of assumptions on predictability estimations. The first approach, which is based on Colwell's predictability metrics, transforms the focal variable into a nominal one. The resulting discrete categories define the relevant variations in the water-surface area. In the second approach, we introduced General Additive Model (GAM) fitting as a new metric for quantifying predictability. Both approaches produced a wide range of predictability for the studied ponds. Some model assumptions-which are considered very different a priori-had minor effects, whereas others produced predictability estimations that showed some degree of divergence. We hypothesize that these diverging estimations of predictability reflect the effect of fluctuations on different types of organisms. The fluctuation analysis described in this manuscript is applicable to a wide variety of systems, including both aquatic and non-aquatic systems, and will be valuable for quantifying and characterizing predictability, which is essential within the expected global increase in the unpredictability of environmental fluctuations. We advocate that a priori information for organisms of interest should be used to select the most suitable metrics for estimating predictability, and we provide some guidelines for this approach. PMID- 29121666 TI - SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types. AB - SOX9 has been previously shown to be involved in hepatocellular carcinoma (HCC) and other types of cancer. However, prognostic studies so far involved rather small cohorts or lack external validation and experimental data. In this study, we firstly determined the histological expression pattern of SOX9 in human HCC by immunohistochemistry (n = 84) and evaluated its prognostic value. External cohorts of publicly available datasets were used to validate its prognostic relevance in HCC (n = 359) and other types of cancer including breast (n = 3951), ovarian (n = 1306), lung (n = 1926) and gastric cancer (n = 876). Functional SOX9 knock-down studies using siRNA and cancer stem cell models were generated in a panel of liver and breast cancer cell lines. High level of SOX9 was associated with poor survival even after adjustment for other prognostic factors in multivariate analysis (HR = 2.103, 95%CI = 1.064 to 4.156, p = 0.021). SOX9 prevailed a poor prognostic factor in all cancer validation cohorts (p<0.05). Reduced SOX9 expression by siRNA decreased the growth of liver cancer cells (p<0.05). SOX9 expression was associated with stem cell features in all tested cell lines (p<0.05). In conclusion, this study demonstrated in a large number of patients from multiple cohorts that high levels of SOX9 are a consistent negative prognostic factor. PMID- 29121668 TI - Seasonal recurrence of cowpox virus outbreaks in captive cheetahs (Acinonyx jubatus). AB - Cowpox virus infections in captive cheetahs (Acinonyx jubatus) with high morbidity and mortality have already been reported in the UK and Russia in the 1970s. However, most of the reported cases have been singular events. Here, we report a total of five cowpox virus outbreaks in cheetahs in the same safari park in Denmark between 2010 and 2014. Nine cheetahs showed varying severity of clinical disease; two of them died (22%). All episodes occurred between August and October of the respective year. No other carnivores kept at the same institution nor the keepers taking care of the animals were clinically affected. The clinical picture of cowpox was confirmed by extensive laboratory investigations including histopathological and molecular analyses as well as cell culture isolation of a cowpox virus. High anti-orthopoxvirus antibody titers were detected in all 9 diseased cheetahs compared to seven contact cheetahs without clinical signs and 13 cheetahs not in direct contact. Additionally, whole genome sequencing from one sample of each cluster with subsequent phylogenetic analysis showed that the viruses from different outbreaks have individual sequences but clearly form a clade distinct from other cowpox viruses. However, the intra-clade distances are still larger than those usually observed within clades of one event. These findings indicate multiple and separate introductions of cowpox virus, probably from wild rodent populations, where the virus keeps circulating naturally and is only sporadically introduced into the cheetahs. Sero-positivity of voles (Arvicola amphibious) caught in zoo grounds strengthens this hypothesis. As a consequence, recommendations are given for medical and physical management of diseased cheetahs, for hygienic measures as well as for pre-shipment isolation before cheetah export from zoo grounds. PMID- 29121669 TI - Application and interpretation of functional data analysis techniques to differential scanning calorimetry data from lupus patients. AB - BACKGROUND: DSC is used to determine thermally-induced conformational changes of biomolecules within a blood plasma sample. Recent research has indicated that DSC curves (or thermograms) may have different characteristics based on disease status and, thus, may be useful as a monitoring and diagnostic tool for some diseases. Since thermograms are curves measured over a range of temperature values, they are considered functional data. In this paper we apply functional data analysis techniques to analyze differential scanning calorimetry (DSC) data from individuals from the Lupus Family Registry and Repository (LFRR). The aim was to assess the effect of lupus disease status as well as additional covariates on the thermogram profiles, and use FD analysis methods to create models for classifying lupus vs. control patients on the basis of the thermogram curves. METHODS: Thermograms were collected for 300 lupus patients and 300 controls without lupus who were matched with diseased individuals based on sex, race, and age. First, functional regression with a functional response (DSC) and categorical predictor (disease status) was used to determine how thermogram curve structure varied according to disease status and other covariates including sex, race, and year of birth. Next, functional logistic regression with disease status as the response and functional principal component analysis (FPCA) scores as the predictors was used to model the effect of thermogram structure on disease status prediction. The prediction accuracy for patients with Osteoarthritis and Rheumatoid Arthritis but without Lupus was also calculated to determine the ability of the classifier to differentiate between Lupus and other diseases. Data were divided 1000 times into separate 2/3 training and 1/3 test data for evaluation of predictions. Finally, derivatives of thermogram curves were included in the models to determine whether they aided in prediction of disease status. RESULTS: Functional regression with thermogram as a functional response and disease status as predictor showed a clear separation in thermogram curve structure between cases and controls. The logistic regression model with FPCA scores as the predictors gave the most accurate results with a mean 79.22% correct classification rate with a mean sensitivity = 79.70%, and specificity = 81.48%. The model correctly classified OA and RA patients without Lupus as controls at a rate of 75.92% on average with a mean sensitivity = 79.70% and specificity = 77.6%. Regression models including FPCA scores for derivative curves did not perform as well, nor did regression models including covariates. CONCLUSION: Changes in thermograms observed in the disease state likely reflect covalent modifications of plasma proteins or changes in large protein-protein interacting networks resulting in the stabilization of plasma proteins towards thermal denaturation. By relating functional principal components from thermograms to disease status, our Functional Principal Component Analysis model provides results that are more easily interpretable compared to prior studies. Further, the model could also potentially be coupled with other biomarkers to improve diagnostic classification for lupus. PMID- 29121671 TI - Separating conditional and unconditional cooperation in a sequential Prisoner's Dilemma game. AB - Most theories of social exchange distinguish between two different types of cooperation, depending on whether or not cooperation occurs conditional upon the partner's previous behaviors. Here, we used a multinomial processing tree model to distinguish between positive and negative reciprocity and cooperation bias in a sequential Prisoner's Dilemma game. In Experiments 1 and 2, the facial expressions of the partners were varied to manipulate cooperation bias. In Experiment 3, an extinction instruction was used to manipulate reciprocity. The results confirm that people show a stronger cooperation bias when interacting with smiling compared to angry-looking partners, supporting the notion that a smiling facial expression in comparison to an angry facial expression helps to construe a situation as cooperative rather than competitive. Reciprocity was enhanced for appearance-incongruent behaviors, but only when participants were encouraged to form expectations about the partners' future behaviors. Negative reciprocity was not stronger than positive reciprocity, regardless of whether expectations were manipulated or not. Experiment 3 suggests that people are able to ignore previous episodes of cheating as well as previous episodes of cooperation if these turn out to be irrelevant for predicting a partner's future behavior. The results provide important insights into the mechanisms of social cooperation. PMID- 29121670 TI - Quantitative membrane proteomics reveals a role for tetraspanin enriched microdomains during entry of human cytomegalovirus. AB - Human cytomegalovirus (HCMV) depends on and modulates multiple host cell membrane proteins during each stage of the viral life cycle. To gain a global view of the impact of HCMV-infection on membrane proteins, we analyzed HCMV-induced changes in the abundance of membrane proteins in fibroblasts using stable isotope labeling with amino acids (SILAC), membrane fractionation and protein identification by two-dimensional liquid chromatography and tandem mass spectrometry. This systematic approach revealed that CD81, CD44, CD98, caveolin-1 and catenin delta-1 were down-regulated during infection whereas GRP-78 was up regulated. Since CD81 downregulation was also observed during infection with UV inactivated virus we hypothesized that this tetraspanin is part of the viral entry process. Interestingly, additional members of the tetraspanin family, CD9 and CD151, were also downregulated during HCMV-entry. Since tetraspanin-enriched microdomains (TEM) cluster host cell membrane proteins including known CMV receptors such as integrins, we studied whether TEMs are required for viral entry. When TEMs were disrupted with the cholesterol chelator methyl-beta cylcodextrin, viral entry was inhibited and this inhibition correlated with reduced surface levels of CD81, CD9 and CD151, whereas integrin levels remained unchanged. Furthermore, simultaneous siRNA-mediated knockdown of multiple tetraspanins inhibited viral entry whereas individual knockdown had little effect suggesting essential, but redundant roles for individual tetraspanins during entry. Taken together, our data suggest that TEM act as platforms for receptors utilized by HCMV for entry into cells. PMID- 29121672 TI - Beyond genome-wide scan: Association of a cis-regulatory NCR3 variant with mild malaria in a population living in the Republic of Congo. AB - Linkage studies have revealed a linkage of mild malaria to chromosome 6p21 that contains the NCR3 gene encoding a natural killer cell receptor, whereas NCR3 412G>C (rs2736191) located in its promoter region was found to be associated with malaria in Burkina Faso. Here we confirmed the association of rs2736191 with mild malaria in a Congolese cohort and investigated its potential cis-regulatory effect. Luciferase assay results indicated that rs2736191-G allele had a significantly increased promoter activity compared to rs2736191-C allele. Furthermore, EMSAs demonstrated an altered binding of two nuclear protein complexes to the rs2736191-C allele in comparison to rs2736191-G allele. Finally, after in silico identification of transcription factor candidates, pull-down western blot experiments confirmed that both STAT4 and RUNX3 bind the region encompassing rs2736191 with a higher affinity for the G allele. To our knowledge, this is the first report that explored the functional role of rs2736191. These results support the hypothesis that genetic variation within natural killer cell receptors alters malaria resistance in humans. PMID- 29121673 TI - Influence of vitamin D on key bacterial taxa in infant microbiota in the KOALA Birth Cohort Study. AB - Vitamin D has immunomodulatory properties giving it the potential to affect microbial colonization of the intestinal tract. We investigated whether maternal vitamin D supplemention, maternal plasma 25-hydroxyvitamin D concentration, or direct supplementation of the infant influences key bacterial taxa within microbiota of one month old infants. Infant and maternal vitamin D supplement use was ascertained via questionnaires. Maternal plasma 25-hydroxyvitamin D was determined at approximately the 36th week of pregnancy. In 913 one month old infants in the prospective KOALA Birth Cohort Study, fecal Bifidobacterium spp., Escherichia coli, Clostridium difficile, Bacteroides fragilis group, Lactobacillus spp. and total bacteria were quantified with real-time polymerase chain reaction assays targeting 16S rRNA gene sequences. The association between vitamin D exposure and prevalence or abundance of a specific bacterial group or species was analyzed using logistic or linear regression, respectively. There was a statistically significant negative linear trend between counts of Bifidobacterium spp. and levels of maternal vitamin D supplementation and maternal 25-hydroxyvitamin D quintiles, respectively. In addition, a positive linear trend between quintile groups and B. fragilis group counts was observed. Lower counts of C. difficile were associated with vitamin D supplementation of breast fed infants whose mothers were more likely to adhere to an alternative lifestyle in terms of, e.g., dietary habits. These data suggest that vitamin D influences the abundance of several key bacterial taxa within the infant microbiota. Given that intestinal microbiotic homeostasis may be an important factor in the prevention of immune mediated diseases and that vitamin D status is a modifiable factor, further investigation of the impact of postnatal vitamin D supplementation should be conducted in older infants. PMID- 29121674 TI - The helicase DinG responds to stress due to DNA double strand breaks. AB - Neisseria meningitidis (Nm) is a Gram-negative nasopharyngeal commensal that can cause septicaemia and meningitis. The neisserial DNA damage-inducible protein DinG is a helicase related to the mammalian helicases XPD and FANCJ. These helicases belong to superfamily 2, are ATP dependent and exert 5' -> 3' directionality. To better understand the role of DinG in neisserial genome maintenance, the Nm DinG (DinGNm) enzymatic activities were assessed in vitro and phenotypical characterization of a dinG null mutant (NmDeltadinG) was performed. Like its homologues, DinGNm possesses 5' -> 3' directionality and prefers DNA substrates containing a 5'-overhang. ATPase activity of DinGNm is strictly DNA dependent and DNA unwinding activity requires nucleoside triphosphate and divalent metal cations. DinGNm directly binds SSBNm with a Kd of 313 nM. Genotoxic stress analysis demonstrated that NmDeltadinG was more sensitive to double-strand DNA breaks (DSB) induced by mitomycin C (MMC) than the Nm wildtype, defining the role of neisserial DinG in DSB repair. Notably, when NmDeltadinG cells grown under MMC stress assessed by quantitative mass spectrometry, 134 proteins were shown to be differentially abundant (DA) compared to unstressed NmDeltadinG cells. Among the DNA replication, repair and recombination proteins affected, polymerase III subunits and recombinational repair proteins RuvA, RuvB, RecB and RecD were significantly down regulated while TopA and SSB were upregulated under stress condition. Most of the other DA proteins detected are involved in metabolic functions. The present study shows that the helicase DinG is probably involved in regulating metabolic pathways as well as in genome maintenance. PMID- 29121676 TI - Naringin prevents HIV-1 protease inhibitors-induced metabolic complications in vivo. AB - BACKGROUND: Insulin resistance, glucose intolerance and overt diabetes are known metabolic complications associated with chronic use of HIV-Protease Inhibitors. Naringin is a grapefruit-derived flavonoid with anti-diabetic, anti-dyslipidemia, anti-inflammatory and anti-oxidant activities. OBJECTIVES: The study investigated the protective effects of naringin on glucose intolerance and impaired insulin secretion and signaling in vivo. METHODS: Male Wistar rats were divided into six groups (n = 6) and were daily orally treated with distilled water {3.0 ml/kg body weight (BW)}, atazanavir (133 mg/kg BW), saquinavir (333 mg/kg BW) with or without naringin (50 mg/kg BW), respectively for 56 days. Body weights and water consumption were recorded daily. Glucose tolerance tests were carried out on day 55 of the treatment and thereafter, the rats were sacrificed by halothane overdose. RESULTS: Atazanavir (ATV)- or saquinavir (SQV)-treated rats exhibited significant weight loss, polydipsia, elevated Fasting blood glucose (FBG), reduced Fasting Plasma Insulin (FPI) and expression of phosphorylated, Insulin Receptor Substrate-1 (IRS-1) and Akt proteins, hepatic and pancreatic glucokinase levels, and also increasing pancreatic caspase-3 and -9 as well as UCP2 protein expressions compared to controls, respectively. These effects were completely reversed by naringin treatment. CONCLUSION: Naringin prevents PI-induced glucose intolerance and impairment of insulin signaling and as nutritional supplement it could therefore alleviate metabolic complications associated with antiretroviral therapy. PMID- 29121675 TI - Astaxanthin prevents ischemia-reperfusion injury of the steatotic liver in mice. AB - Steatosis has a low tolerance against ischemia-reperfusion injury (IRI). To prevent IRI in the steatotic liver, we attempted to elucidate the protective effect of astaxanthin (ASTX) in the steatotic liver model by giving mice a methionine and choline-deficient high fat (MCDHF) diet. Levels of lipid peroxidation and apoptosis, the expression of inflammatory cytokines and heme oxygenase (HO)-1, in the liver were assessed. Reactive oxygen species (ROS), inflammatory cytokines, apoptosis-related proteins and members of the signaling pathway were also examined in isolated Kupffer cells and/or hepatocytes from the steatotic liver. ASTX decreased serum ALT and AST levels, the amount of TUNEL, F4/80, or 4HNE-positive cells and the mRNA levels of inflammatory cytokines in MCDHF mice by IRI. Moreover, HO-1 and HIF-1alpha, phosphorylation of Akt and mTOR expressions were increased by ASTX. The inflammatory cytokines produced by Kupffer, which were subjected to hypoxia and reoxygenation (HR), were inhibited by ASTX. Expressions of Bcl-2, HO-1 and Nrf2 in hepatocytes by HR were increased, whereas Caspases activation, Bax and phosphorylation of ERK, MAPK, and JNK were suppressed by ASTX. Pretreatment with ASTX has a protective effect and is a safe therapeutic treatment for IRI, including for liver transplantation of the steatotic liver. PMID- 29121677 TI - Socioeconomic inequalities in frailty and frailty components among community dwelling older citizens. AB - BACKGROUND: So far, it has not yet been studied whether socioeconomic status is associated with distinct frailty components and for which frailty component this association is the strongest. We aimed to examine the association between socioeconomic status and frailty and frailty components. In addition we assessed the mediating effect of the number of morbidities on the association between socioeconomic status and other frailty components. METHODS: This is a cross sectional study of pooled data of The Older Persons and Informal Caregivers Survey Minimum DataSet in the Netherlands among community-dwelling persons aged 55 years and older (n = 26,014). Frailty was measured with a validated Frailty Index that consisted of 45 items. The Frailty Index contained six components: morbidities, limitations in activities of daily living (ADL), limitations in instrumental ADL (IADL), health-related quality of life, psychosocial health and self-rated health. Socioeconomic indicators used were education level and neighbourhood socioeconomic status. RESULTS: Persons with primary or secondary education had higher overall frailty and frailty component scores compared to persons with tertiary education (P < .001). Lower education levels were most consistently associated with higher overall frailty, more morbidities and worse self-rated health (P < .05 in all age groups). The strongest association was found between primary education and low psychosocial health for persons aged 55 69 years and more IADL limitations for persons aged 80+ years. Associations between neighborhood socioeconomic status and frailty (components) also showed inequalities, although less strong. The number of morbidities moderately to strongly mediated the association between socioeconomic indicators and other frailty components. CONCLUSION: There are socioeconomic inequalities in frailty and frailty components. Inequalities in frailty, number of morbidities and self rated health are most consistent across age groups. The number of morbidities a person has play an important role in explaining socioeconomic inequalities in frailty and should be taken into account in the management of frailty. PMID- 29121679 TI - Quality Control of Valerianae Radix by Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) Spectroscopy. AB - (Acetoxy-)valerenic acid and total essential oil content are important quality attributes of pharmacy grade valerian root (Valerianae radix). Traditional analysis of these quantities is time-consuming and necessitates (harmful) solvents. Here we investigated an application of attenuated total reflection Fourier transform infrared spectroscopy for extractionless analysis of these quality attributes on a representative sample comprising 260 wild-crafted individuals covering the Central European taxonomic diversity of the Valeriana officinalis L. s. l. species aggregate with its three major ploidy cytotypes (i.e., di-, tetra- and octoploid). Calibration models were built by orthogonal partial least squares regression for quantitative analysis of (acetoxy-)valerenic acid and total essential oil content. For the latter, we propose a simplistic protocol involving apolar extraction followed by gas chromatography as a reference method for multivariate calibration in order to handle the analysis of samples taken from individual plants. We found good predictive ability of chemometric models for quantification of valerenic acid, acetoxyvalerenic acid, total sesquiterpenoid acid, and essential oil content with a root mean squared error of cross-validation of 0.064, 0.043, and 0.09 and root mean squared error of prediction of 0.066, 0.057, and 0.09 (% content), respectively. Orthogonal partial least squares discriminant analysis revealed good discriminability between the most productive phenotype (i.e., the octoploid cytotype) in terms of sesquiterpenoid acids, and the less productive ones (i.e., di- and tetraploid). All in all, our results demonstrate the application of attenuated total reflection Fourier transform infrared spectroscopy for rapid, extractionless estimation of the most important quality attributes of valerian root and minimally invasive identification of the most productive phenotype in terms of sesquiterpenoid acids. PMID- 29121680 TI - Effects of Drop-height and Surface Instability on Jump Performance and Knee Kinematics. AB - The purpose of this study was to examine the combined effects of drop-height and surface condition on drop jump (DJ) performance and knee joint kinematics. DJ performance, sagittal and frontal plane knee joint kinematics were measured in jump experienced young male and female adults during DJs on stable, unstable and highly unstable surfaces using different drop-heights (20, 40, 60 cm). Findings revealed impaired DJ performance (Delta5-16%; p<0.05; 1.43<=d<=2.82), reduced knee valgus motion (Delta33-52%; p<0.001; 2.70<=d<=3.59), and larger maximum knee flexion angles (Delta13-19%; p<0.01; 1.74<=d<=1.75) when using higher (60 cm) compared to lower drop-heights (<=40 cm). Further, lower knee flexion angles and velocity were found (Delta8-16%; p<0.01; 1.49<=d<=2.38) with increasing surface instability. When performing DJs from high (60 cm) compared to moderate drop heights (40 cm) on highly unstable surfaces, higher knee flexion velocity and maximum knee valgus angles were found (Delta15-19%; p<0.01; 1.50<=d<=1.53). No significant main and/or interaction effects were observed for the factor sex. In conclusion, knee motion strategies were modified by the factors 'drop-height' and/or 'surface instability'. The combination of high drop-heights (>40 cm) together with highly unstable surfaces should be used cautiously during plyometrics because this may increase the risk of injury due to higher knee valgus stress. PMID- 29121682 TI - [Not Available]. PMID- 29121681 TI - Concurrent Training with Blood Flow Restriction does not Decrease Inflammatory Markers. AB - The aging process is associated with several changes in the elderly such as the decrease in cardiorespiratory fitness, strength and muscle mass, in addition to chronic low-grade inflammation. Concurrent training with blood flow restriction can be an interesting alternative to improve functional capacity with low mechanical stress in the elderly. The purpose of this study was to compare the inflammatory effects in older individuals submitted to two different protocols of concurrent training. Twenty-two healthy older adults (63.7+/-3.8 years; 69.8+/ 8.9 kg; 1.6+/-0.1 m) performed 12 weeks of concurrent training (CT) or concurrent training with blood flow restriction (CTBFR) and the effects on inflammatory markers were analyzed. We found inflammatory behavior for the CTBFR group with a significant difference in serum concentration of C-reactive protein between pre- and post-moment (0.96+/-0.37 to 1.71+/-1.45, p=0.049), with no difference between groups, and a time effect in interleukin-6 (pre=0.86+/-0.43; post=1.02+/-0.46, p=0.016). We conclude that the CTBFR showed a pro-inflammatory profile after the period of intervention whereas the CT showed the opposite. PMID- 29121683 TI - [Validity of the ICD-10 Symptom Rating (ISR) in a Non-Clinical Sample]. AB - Introduction The ICD-10 symptom rating (ISR) is a self-rating instrument that is based on ICD-10 syndromes. Can previous findings concerning its validity be replicated in a non-clinical sample? Material & Methods N=428 study participants mainly students - completed the ISR and the SCL-90-R in an online survey. Results The assumed factorial structure was replicated with a good model fit. The correlations between the content-related scales of the two instruments ranged from rmin=0.60 to rmax=0.85. Study participants indicated that they did not find completing the ISR stressful. Discussion and Conclusions These results indicate good validity and applicability of the ISR. PMID- 29121684 TI - [Does Personality Organization Influence Day Clinic Treatment Success? Results of a Longitudinal Study]. AB - We conducted an exploratory questionnaire-based study (n=63) to assess the importance of personality organization for therapy success in a day treatment setting. Patients completed self-report measures at the beginning and end of treatment spanning 4-6 week capturing impairments in personality organization (IPO-16), acute symptom severity (SCL-90-R, BDI-2), personality disorders (ADP IV), and traumatic experiences in childhood and adolescence (CTQ). We observed strong associations between impairments in personality organization, personality pathology, traumatic experiences, and acute symptom severity. Impairments in personality organization did not change during treatment. In contrast to other studies, an influence of personality organization on treatment success could not be demonstrated. The importance of personality organization for therapy planning should be studied further. PMID- 29121685 TI - Godina's Principles in the Twenty-First Century and the Evolution of Lower Extremity Trauma Reconstruction. AB - BACKGROUND: February of 2016 marked 30 years since the passing of Marko Godina, a pioneer and prodigy in the field of reconstructive microsurgery. Most noteworthy among his many contributions was his method of radical debridement of contaminated compound fractures followed by early free tissue transfer for wound closure. In the last three decades, the landscape of reconstructive surgery has undergone significant transformation owing to advances in reconstructive techniques and wound care technology, as well as new data. METHODS: Dr. Godina's work and legacy are reviewed, compared and contrasted with new and evolving data regarding lower extremity trauma reconstruction. RESULTS: Advancements in technique and technology have greatly molded lower extremtiy reconstruction over the past thirty years. Nonetheless, Dr. Godina's principles of timely care and early vascularized soft tissue coverage have withstood the test of time. CONCLUSION: Marko Godina's contribution to reconstructive microsurgery cannot be overstated and his groundbreaking work continues to serve as the foundation of lower extremity trauma reconstruction. Three decades after his seminal work, we honor Dr. Godina's legacy and explore how his principles have endured, evolved, or been replaced. PMID- 29121686 TI - A Review of the Incidence, Manifestation, Predisposing Factors, and Management of Recurrent Pediatric Inguinal Hernia. PMID- 29121687 TI - Screening for Type 1 Diabetes Risk in Newborns: The Freder1k Pilot Study in Saxony. AB - An increased risk for type 1 diabetes can be identified using genetic and immune markers. The Freder1k study introduces genetic testing for type 1 diabetes risk within the context of the newborn screening in order to identify newborns with a high risk to develop type 1 diabetes for follow-up testing of early stage type 1 diabetes and for primary prevention trials. Consent for research-based genetic testing of type 1 diabetes risk is obtained with newborn screening. Increased risk is assessed using three single nucleotide polymorphisms for HLA DRB1*03 (DR3), HLA DRB1*04 (DR4), HLA DQB1*0302 (DQ8) alleles, and defined as 1. an HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype or 2. an HLA DR4-DQ8 haplotype and a first-degree family history of type 1 diabetes. Families of infants with increased risk are asked to participate in follow-up visits at infant age 6 months, 2 years, and 4 years for autoantibody testing and early diagnosis of type 1 diabetes. After 8 months, the screening rate has reached 181 per week, with 63% coverage of newborns within Freder1k-clinics and 24% of all registered births in Saxony. Of 4178 screened, 2.6% were identified to have an increased risk, and around 80% of eligible infants were recruited to follow-up. Psychological assessment of eligible families is ongoing with none of 31 families demonstrating signs of excessive burden associated with knowledge of type 1 diabetes risk. This pilot study has shown that it is feasible to perform genetic risk testing for childhood disease within the context of newborn screening programs. PMID- 29121688 TI - Long-Term Follow-Up in Patients with Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) Without a Suspicion of Persistent Disease in Postoperative Assessment. AB - The objective was to determine whether negative assessment after surgery is a predictor of no relevant change of the results in subsequent evaluations in patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Six months after surgery, "absence of persistent disease" was defined when concentration of thyroglobulin (Tg) is <=2 ng/ml in patients undergoing total thyroidectomy and <=10 ng/ml in those undergoing lobectomy, in the absence of antithyroglobulin antibodies (TgAb), and neck ultrasonography (US) without abnormalities. One hundred thirteen patients met the definition of "absence of persistent disease". The patients were followed up for 18-150 months. None of the patients developed structural disease. In the 56 patients undergoing total thyroidectomy, 380 Tg measurements were obtained and an increase in concentrations was not observed in any of them. During the same period, 332 US scans were performed and a suspicious lymph node was detected on only one occasion, but was not metastatic on fine needle aspiration (FNA). In the 57 patients undergoing lobectomy, 382 Tg measurements were obtained and increases or persistent concentrations>10 ng/ml were not observed in any patient. During the same period, 376 US scans were performed and nodules with an indication for FNA were detected in 4 patients, but malignancy was not confirmed in any of them. Finally, TgAb were not elevated in any of the 762 measurements obtained from the 113 patients. After complete resection of NIFTP, negative postoperative assessment can be used to exclude the need for long-term repetition of these tests. PMID- 29121689 TI - [Public Health Practice - Results of the Working Group 12 of the Forum Future Public Health, Berlin 2016]. AB - This report focuses on the topic of Public Health in practice. The article summarizes the discussion of the Working Group 12. A first diagram shows how broad the definition of "Public Health practice" can be. Challenges as well as visions were articulated. In order to ensure individual and diverse health promotion for all, public health must be integrated as a central vision for the future in the daily routine and in the various living environments of the people as part of social life. To achieve this goal, public health actors in general and the public health service in particular must work closely with policy makers, cost-bearers, science and teaching and complement each other's work, while respecting their spheres of action. A precondition is adequate financial and human resources. Public health therefore deals with the design of living environments as well as with political structures and strategies. PMID- 29121690 TI - [Education and Research in Public Health - where do we stand today? - Plenary Lecture of the Forum Future Public Health, Berlin 2016]. PMID- 29121691 TI - [Eosinophilic Esophagitis Update: New Guidelines of the European Study Group EUREOS]. AB - Eosinophilic esophagitis is now considered to be a frequent chronic esophageal disease and is one of the most common causes for dysphagia and bolus obstruction in children and adults. The increasing significance and new scientific insights in this disorder required an update of currently existing guidelines. Therefore, the European Study Group of Eosinophilic Esophagitis (EUREOS) has elaborated new guidelines for the management of eosinophilic esophagitis, based on a systematic literature search and, for the first time, using the GRADE methodology (Grading of Recommendations Assessment, Development, and Evaluation). The aim of the present article is to summarize and comment on new developments and clinical recommendations of this guideline to further increase the awareness for this relevant esophageal disease. PMID- 29121692 TI - Reproducibility and Reliability of Repeated Quantitative Fluorescence Angiography. AB - INTRODUCTION: When using fluorescence angiography (FA) in perioperative perfusion assessment, repeated measures with re-injections of fluorescent dye (ICG) may be required. However, repeated injections may cause saturation of dye in the tissue, exceeding the limit of fluorescence intensity that the camera can detect. As the emission of fluorescence is dependent of the excitatory light intensity, reduction of this may solve the problem. The aim of the present study was to investigate the reproducibility and reliability of repeated quantitative FA during a reduction of excitatory light. PMID- 29121693 TI - Short-Term Results of Eluvia? Paclitaxel-Eluting Stent in External Iliac and Femoropopliteal Lesions. AB - INTRODUCTION: The aim of this study was to independently evaluate the real-world performances of Eluvia? paclitaxel drug-eluting stents (DES) (Boston Scientific, Marlborough, Massachusetts) for the treatment of external iliac and femoropopliteal artery lesions. MATERIALS AND METHODS: We prospectively collected, and retrospectively reviewed, data for all patients who underwent an endovascular treatment with an Eluvia? DES for the treatment of an external iliac or femoropopliteal lesion. Patient demographics, concomitant procedures, arterial lesions characteristics, procedural details, and follow-up were reviewed. RESULTS: Between April and October 2016, 15 Eluvia? DES were placed in 15 consecutive adult patients with a technical success of 100%. The treated lesions had a mean length of 93.9 +/-58 mm. Sixty percent of the lesions were total occlusions and 13% were restenosis of previous stents. An additional inflow treatment was performed in 40% of the cases. At six months, two patients were lost at follow-up and one had an occluded stent. We had a primary patency rate and freedom from TLR of 92%. All remaining patients had an improved Rutherford class, improved quality of life and wound healing, and an increase in walking distance. Survival and limb salvage rates were 100%. CONCLUSIONS: This study confirms the good result of DES, in general, and of the Eluvia? stent, in particular, in the treatment of external iliac and femoropopliteal arterial lesions, with a primary patency rate and a freedom from TLR of 92% at six months. A larger number of patients and longer follow-up will be required to determine the true real-world efficacy of the Eluvia? DES, but short-term experience is encouraging. PMID- 29121694 TI - Right-Sided versus Left-Sided Colectomies for Cancer: Surgical Outcomes and Novel Considerations. AB - INTRODUCTION: The aim of this study is to compare short-term outcomes of right versus left colectomies performed as a form of cancer treatment. MATERIALS AND METHODS: This study includes 305 consecutive patients with adenocarcinoma treated by laparoscopic or open colectomy. Right colectomy has been compared with left colectomy. The study endpoints were the first flatus day, the first evacuation day, the first day of postoperative solid oral diet intake, and the postoperative hospital stay length. RESULTS: There were 140 (45.9%) right colectomies and 165 (54.1%) left colectomies performed. The cut-off values for the considered (median) endpoints were three, five, four, and eight days, respectively. The first day of postoperative solid oral diet intake and the length of postoperative hospital stay are significantly associated with the type of resection. CONCLUSIONS: The colon cancer patients treated by right-sided colectomy assumed a solid oral diet and presented a longer postoperative hospital stay compared with the patients treated by left-sided colectomy. PMID- 29121695 TI - The Effect of Preoperative Physical Status on Pain Management in Total Knee Arthroplasty Patients Receiving Adductor Canal Blockade. AB - INTRODUCTION: Managing postoperative pain can be challenging for arthroplasty surgeons. While pain control modalities, such as adductor canal blockade (ACB), have been proven effective, the multifactorial nature of pain perception may serve as an obstacle for optimizing pain control. This study assesses the effect of patient pre-operative physical status on patient perception of pain. Specifically, we compared 1) lengths of hospital stay (LOS), 2) pain levels, and 3) opioid consumption in patients receiving total knee arthroplasty (TKA) who presented with an American Society of Anesthesiologists physical status score (ASA) of 2 and 3. MATERIALS AND METHODS: A single hospital, single surgeon database was reviewed for patients who had TKA between January 2015 and April 2016. Only patients with an ASA class of 2 or 3 who received ACB were analyzed. This yielded 106 patients with a mean age of 63 years, comprised of 36 men and 70 women. Patients were stratified into those with an ASA class of 2 (n= 58) and those with an ASA class of 3 (n= 48). Electronic medical records were reviewed to obtain demographic and endpoint data. Pain was quantified using Visual Analog Scale (VAS). Continuous variables were compared using the student' s t-test and analysis of variance, while categorical variables were compared using chi-square analysis. RESULTS: There was no significant difference found between the two groups in LOS (2.25 days vs. 2.19 days; p=0.805), VAS scores (4.95 vs. 5.75; p=0.306), and opioid consumption on day 0 (17.77 morphine eq vs. 23.49 morphine eq; p=0.233) and day 3 (9.11 morphine eq vs. 19.87 morphine eq; p=0.100). However, patients with an ASA score of 2 had a significantly lower opioid consumption on day 1 (32.20 morphine eq vs. 52.70 morphine eq; p=0.049), day 2 (19.21 morphine eq vs. 40.71 morphine eq; p=0.018), and overall (78.30 morphine eq vs. 135.77 morphine eq; p=0.024). CONCLUSION: Despite the effectiveness of ACB in controlling pain, patient pre-operative status may affect perception of pain. This study demonstrates that patients with a higher ASA physical status classification consumed more opioid medication postoperatively, despite having similar pain scores and lengths of stay to those with a lower classification. Future studies should assess all ASA classifications and stratify for preoperative opioid consumption and tolerance as a possible confounder. PMID- 29121696 TI - Quadriceps and Hamstring Muscle Strength Improves After Unicompartmental Knee Arthroplasty. AB - INTRODUCTION: The ability to reach functional capacity following knee arthroplasty depends on the strength of the quadriceps and hamstring muscles. Following total knee arthroplasty, weakness of these muscles can persist for up to one year postoperatively; however, this phenomenon is not well-studied in unicompartmental knee arthroplasty (UKA) patients. Therefore, we assessed: 1) quadriceps muscle strength; 2) hamstring muscle strength; and 3) correlation to functional outcomes. MATERIALS AND METHODS: A review of all patients with medial compartment osteoarthritis treated with UKA at a minimum of one-year follow-up was performed. This yielded 26 patients (32 knees), comprising of eight females and 18 males who had a mean age of 67 years (range, 47 to 83 years). Muscle strength was assessed pre-and postoperatively via dynamometer. Functional outcomes were assessed using Knee Society Scores (KSS). Comparisons of groups were performed by paired t-tests. RESULTS: At a minimum one-year postoperatively, quadriceps muscle strength was 27 Nm (range, 13 to 71Nm) and hamstring muscle strength was 19.5Nm (range, 7 to 81Nm). Quadriceps muscle strength increased by 40% (p=0.002) and hamstring muscle strength by 26% (p=0.057). The mean KSS pain was 97 points (range, 85 to 100 points) and mean KSS function was 90 points (range, 45 to 100 points) at the final follow-up. Range of motion was 125 degrees (range, 110 degrees to 135 degrees ) at the final follow-up. The Pearson Correlation Coefficient for postoperative extension strength and postoperative flexion strength to postoperative KSS functional scores were 0.268 and 0.220 respectively. CONCLUSION: Within one-year following UKA, patients can expect restoration of quadriceps and hamstring muscle strength with a corresponding functional improvement. Although long-term follow-up is warranted to determine sustainability, the short-term results demonstrate excellent restoration of function. PMID- 29121697 TI - A Simplified Novel Approach for Total Laparoendoscopic Single-Site (LESS) Hysterectomy. AB - Total laparoendoscopic single-site (LESS) hysterectomy is a technically challenging minimally-invasive gynecologic procedure. Multiple technological innovations assist surgeons to overcome the challenges that are usually encountered during this advanced approach. Simplifying the steps of this advanced surgery is an invaluable addition in overcoming associated challenges with this procedure. We present our novel technique for a total laparoscopic hysterectomy that will optimize a single-site approach (LESS) for surgeons. PMID- 29121698 TI - Respiration of thermogenic inflorescences of skunk cabbage Symplocarpus renifolius in heliox. AB - The respiration rate of the thermogenic inflorescences of Japanese skunk cabbage Symplocarpus renifolius can reach 300 nmol s-1 g-1 , which is sufficient to raise spadix temperature (Ts ) up to 15 degrees C above ambient air temperature (Ta ). Respiration rate is inversely related to Ta , such that the Ts achieves a degree of independence from Ta , an effect known as temperature regulation. Here, we measure oxygen consumption rate (Mo2 ) in air (21% O2 in mainly N2 ) and in heliox (21% O2 in He) to investigate the diffusive conductance of the network of gas-filled spaces and the thermoregulatory response. When Ts was clamped at 15 degrees C, the temperature that produces maximal Mo2 in this species, exposure to high diffusivity heliox increased mean Mo2 significantly from 137 +/- 17 to 202 +/- 43 nmol s-1 g-1 FW, indicating that respiration in air is normally limited by diffusion in the gas phase and some mitochondria are unsaturated. When Ta was clamped at 15 degrees C and Ts was allowed to vary, exposure to heliox reduced Ts 1 degrees C and increased Mo2 significantly from 116 +/- 10 to 137 +/- 19 nmol s-1 g-1 , indicating that enhanced heat loss by conduction and convection can elicit the thermoregulatory response. PMID- 29121700 TI - Difference in the Gut Microbiome between Ovariectomy-Induced Obesity and Diet Induced Obesity. AB - During menopausal transition, the imbalance of estrogen causes body weight gain. Although gut microbiome dysbiosis has been reported in postmenopausal obesity, it is not clear whether there is any difference in the microbiome profile between dietary-induced obesity and postmenopausal obesity. Therefore, in this study, we analyzed intestinal samples from ovariectomized mice and compared them with those of mice with high-fat diet-induced obesity. To further evaluate the presence of menopause-specific bacteria-gene interactions, we also analyzed the liver transcriptome. Investigation of the 16S rRNA V3-V4 region amplicon sequence profile revealed that menopausal obesity and dietary obesity resulted in similar gut microbiome structures. However, Bifidobacterium animalis was exclusively observed in the ovariectomized mice, which indicated that menopausal obesity resulted in a different intestinal microbiome than dietary obesity. Additionally, several bacterial taxa (Dorea species, Akkermansia muciniphila, and Desulfovibrio species) were found when the ovariectomized mice were treated with a high-fat diet. A significant correlation between the above-mentioned menopause-specific bacteria and the genes for female hormone metabolism was also observed, suggesting the possibility of bacteria-gene interactions in menopausal obesity. Our findings revealed the characteristics of the intestinal microbiome in menopausal obesity in the mouse model, which is very similar to the dietary obesity microbiome but having its own diagnostic bacteria. PMID- 29121701 TI - Impact of the Isolation Source on the Biofilm Formation Characteristics of Bacillus cereus. AB - The human pathogen and food spoiler Bacillus cereus can form biofilms that act as a persistent source of contamination, which is of public health concern. This study aimed to understand how the source of isolation might affect the behavior of biofilm formation. Biofilm formation abilities of 56 strains of B. cereus isolated from different environments, including human food poisoning, farm, and food, were determined. Crystal violet assay results revealed significant (p < 0.05) differences in biofilm formation abilities among the strains isolated from different sources only at an early stage of incubation. However, strain origin showed no impact on later stage of biofilm formation. Next, correlation of the group of isolates on the basis of their biofilm-forming abilities with the number of sessile cells, sporulation, and extracellular polymeric substance (EPS) formation was determined. The number of sessile cells and spores in biofilms was greatly influenced by the groups of isolates that formed dense, moderate, and weak biofilms. The contribution of extracellular DNA and/or proteins to EPS formation was also positively correlated with biofilm formation abilities. Our results that the source of isolation had significant impact on biofilm formation might provide important information to develop strategies to control B. cereus biofilm formation. PMID- 29121702 TI - Preventive Effects of a Probiotic Mixture in an Ovalbumin-Induced Food Allergy Model. AB - Although there has been a steady increase in the prevalence of food allergies worldwide in recent decades, no effective therapeutic strategies have been developed. Modulation of the gut microbiota composition and/or function through probiotics has been highlighted as a promising target for protection against food allergies. In this study, we aimed to investigate the allergy-reducing effects of a probiotic mixture (P5: Lactococcus lactis KF140, Pediococcus pentosaceus KF159, Lactobacillus pentosus KF340, Lactobacillus paracasei 698, and Bacillus amyloliquefaciens 26N) in mice with ovalbumin (OVA)-induced food allergy. Administration of P5 significantly suppressed the oral OVA challenge-induced anaphylactic response and rectal temperature decline, and reduced diarrhea symptoms. Moreover, P5 also significantly inhibited the secretion of IgE, Th2 cytokines (interleukin (IL)-4, IL-5, IL-10, and IL-13), and Th17 cytokines (IL 17), which were increased in mice with OVA-induced food allergy, and induced generation of CD4+Foxp3+ regulatory T cells. These results revealed that P5 may have applications as a preventive agent against food allergy. PMID- 29121703 TI - Effect of Gene actA on the Invasion Efficiency of Listeria monocytogenes, as Observed in Healthy and Senescent Intestinal Epithelial Cells. AB - Listeria monocytogenes can asymptomatically inhabit the human intestine as a commensal bacterium. However, the mechanism by which L. monocytogenes is able to inhabit the intestine without pathogenic symptoms remains unclear. We compared the invasion efficiency of L. monocytogenes strains with the 268- and 385-bp-long actA gene. Clinical strains SMFM-CI-3 and SMFM-CI-6 with 268-bp actA isolated from patients with listeriosis, and strains SMFM-SI-1 and SMFM-SI-2 with the 385 bp gene isolated from carcasses, were used for inoculum preparation. The invasion efficiency of these strains was evaluated using Caco-2 cells (intestinal epithelial cell line), prepared as normal and healthy cells with tightened tight junctions and senescent cells with loose tight junctions that were loosened by adriamycin treatment. The invasion efficiency of L. monocytogenes strains with the 268-bp-long actA gene was 1.1-2.6-times lower than that of the strains with the 385-bp-long gene in normal and healthy cells. However, the invasion efficiency of both types of strains did not differ in senescent cells. Thus, L. monocytogenes strains with the 268-bp-long actA gene can inhabit the intestine asymptomatically as a commensal bacterium, but they may invade the intestinal epithelial cells and cause listeriosis in senescent cells. PMID- 29121704 TI - Development and Metabolite Profiling of Elephant Garlic Vinegar. AB - Elephant garlic (Allium ampeloprasum var. ampeloprasum), which belongs to the Alliaceae family along with onion and garlic, has a flavor and shape similar to those of normal garlic but is not true garlic. Additionally, its properties are largely unknown, and its processing and product development have not been reported. In this study, we focused on using elephant garlic to produce a new type of vinegar, for which the market is rapidly growing because of its health benefits. First, we evaluated the effects of elephant garlic addition on acetic acid fermentation of rice wine by Acetobacter pasteurianus. In contrast to normal garlic, for which 2% (w/v) addition completely halted fermentation, addition of elephant garlic enabled slow but successful fermentation of ethanol to acetic acid. Metabolite analysis suggested that sulfur-containing volatile compounds were less abundant in elephant garlic than in normal garlic; these volatile compounds may be responsible for inhibiting acetic acid fermentation. After acetic acid fermentation, vinegar with elephant garlic did not have any sulfur containing volatile compounds, which could positively contribute to the vinegar flavor. Moreover, the amino acid profile of the vinegar suggested that nutritional and sensory properties were more enhanced following addition of elephant garlic. Thus, elephant garlic may have applications in the development of a new vinegar product with improved flavor and quality and potential health benefits. PMID- 29121705 TI - Reactive Oxygen Species Depletion by Silibinin Stimulates Apoptosis-Like Death in Escherichia coli. AB - Silibinin is the major active component of silymarin, extracted from the medicinal plant Silybum marianum. Silibinin has potent antibacterial activity; however, the exact mechanism underlying its activity has not been elucidated. Here, we investigated the novel mechanism of silibinin against Escherichia coli. Time-kill kinetic assay showed that silibinin possess a bactericidal effect at minimal inhibitory concentration (MIC) and higher concentrations (2- and 4-fold MIC). At the membrane, depolarization and increased intracellular Ca2+ levels were observed, considered as characteristics of bacterial apoptosis. Additionally, cells treated with MIC and higher concentrations showed apoptotic features like DNA fragmentation, phosphatidylserine exposure, and caspase-like protein expression. Generally, apoptotic death is closely related with ROS generation; however, silibinin did not induce ROS generation but acted as a scavenger of intracellular ROS. These results indicate that silibinin dosedependently induces bacterial apoptosis-like death, which was affected by ROS depletion, suggesting that silibinin is a potential candidate for controlling bacteria. PMID- 29121706 TI - Protective Effect of Fucoidan Extract from Ecklonia cava on Hydrogen Peroxide Induced Neurotoxicity. AB - We evaluated the antioxidant activity and neuronal cell-protective effect of fucoidan extract from Ecklonia cava (FEC) on hydrogen peroxide (H2O2)-induced cytotoxicity in PC-12 and MC-IXC cells to assess its protective effect against oxidative stress. Antioxidant activities were examined using the ABTS radical scavenging activity and malondialdehyde-inhibitory effect, and the results showed that FEC had significant antioxidant activity. Intracellular ROS contents and neuronal cell viability were investigated using the DCF-DA assay and MTT reduction assay. FEC also showed remarkable neuronal cell-protective effect compared with vitamin C as a positive control for both H2O2-treated PC-12 and MC IXC cells. Based on the neuronal cell-protective effects, mitochondrial function was analyzed in PC-12 cells, and FEC significantly restored mitochondrial damage by increasing the mitochondrial membrane potential (Deltapsim) and ATP levels and regulating mitochondrial-mediated proteins (p-AMPK and BAX). Finally, the inhibitory effects against acetylcholinesterase (AChE), which is a critical hydrolyzing enzyme of the neurotransmitter acetylcholine in the cholinergic system, were investigated (IC50 value = 1.3 mg/ml) and showed a mixed (competitive and noncompetitive) pattern of inhibition. Our findings suggest that FEC may be used as a potential material for alleviating oxidative stress-induced neuronal damage by regulating mitochondrial function and AChE inhibition. PMID- 29121707 TI - Reconstruction of Medial Orbital Wall Fractures without Subperiosteal Dissection: The "Push-Out" Technique. AB - BACKGROUND: Various surgical methods for repairing medial orbital wall fractures have been introduced. The conventional technique requires total separation of the displaced orbital bones from the orbital soft tissues. However, subperiosteal dissection around the fracture can cause additional damage. The aim of the present study is to introduce a method of reconstructing medial orbital wall fractures without subperiosteal dissection named the "push-out" technique. METHODS: Six patients with post-traumatic enophthalmos resulting from an old medial orbital wall fracture and 10 patients with an acute medial orbital wall fracture were included. All were treated with the push-out technique. Postoperative computed tomography (CT) was performed to assess the correct positioning of the implants. The Hertel scale and a comparison between preoperative and postoperative orbital volume were used to assess the surgical results. RESULTS: Restoration of the normal orbital cavity shape was confirmed by examining the postoperative CT scans. In the old fracture group, the median orbital volume of the fractured side was 29.22 cm3 preoperatively, and significantly improved postoperatively to a value of 25.13 cm3. In the acute fracture group, the median orbital volume of the fractured side was 28.73 cm3 preoperatively, and significantly improved postoperatively to a value of 24.90 cm3. Differences on the Hertel scale also improved, from 2.13 mm preoperatively to 0.25 mm postoperatively in the old fracture group and from 1.67 mm preoperatively to 0.33 mm postoperatively in the acute fracture group. CONCLUSIONS: The push-out technique can be considered a good alternative choice for old medial orbital wall fractures with posttraumatic enophthalmos, acute medial orbital wall fractures including large fractured bone segments, and single hinged greenstick fractures. PMID- 29121708 TI - Factors Associated with a Prolonged Length of Hospital Stay in Patients with Diabetic Foot: A Single-Center Retrospective Study. AB - BACKGROUND: We conducted this study to identify factors that may prolong the length of the hospital stay (LHS) in patients with diabetic foot (DF) in a single institution setting. METHODS: In this single-center retrospective study, we evaluated a total of 164 patients with DF, and conducted an intergroup comparison of their baseline demographic and clinical characteristics, including sex, age, duration of diabetes, smoking status, body mass index, underlying comorbidities (e.g., hypertension or diabetic nephropathy), wound characteristics,type of surgery, the total medical cost, white blood cell (WBC) count, C-reactive protein (CRP) levels, erythrocyte sedimentation rate, and albumin, protein, glycated hemoglobin, and 7-day mean blood glucose (BG) levels. RESULTS: Pearson correlation analysis showed that an LHS of >5 weeks had a significant positive correlation with the severity of the wound (r=0.647), WBC count (r=0.571), CRP levels (r=0.390), DN (r=0.020), and 7-day mean BG levels (r=0.120) (P<0.05). In multiple regression analysis, an LHS of >5 weeks had a significant positive correlation with the severity of the wound (odds ratio [OR]=3.297; 95% confidence interval [CI], 1.324-10.483; P=0.020), WBC count (OR=1.423; 95% CI, 0.046-0.356; P=0.000), CRP levels (OR=1.079; 95% CI, 1.015-1.147; P=0.014), albumin levels (OR=0.263; 95% CI, 0.113-3.673; P=0.007), and 7-day mean BG levels (OR=1.018; 95% CI, 1.001-1.035; P=0.020). CONCLUSIONS: Surgeons should consider the factors associated with a prolonged LHS in the early management of patients with DF. Moreover, this should also be accompanied by a multidisciplinary approach to reducing the LHS. PMID- 29121709 TI - Applied mediation analyses: a review and tutorial. AB - In recent years, mediation analysis has emerged as a powerful tool to disentangle causal pathways from an exposure/treatment to clinically relevant outcomes. Mediation analysis has been applied in scientific fields as diverse as labour market relations and randomized clinical trials of heart disease treatments. In parallel to these applications, the underlying mathematical theory and computer tools have been refined. This combined review and tutorial will introduce the reader to modern mediation analysis including: the mathematical framework; required assumptions; and software implementation in the R package medflex. All results are illustrated using a recent study on the causal pathways stemming from the early invasive treatment of acute coronary syndrome, for which the rich Danish population registers allow us to follow patients' medication use and more after being discharged from hospital. PMID- 29121710 TI - Effects of living alone versus with others and of housemate type on smoking, drinking, dietary habits, and physical activity among elderly people. AB - OBJECTIVES: This study examined differences in health behaviors between elderly people living alone and with others; it also investigated whether the effect of living with others differs according to housemate type, namely a spouse and/or younger generations. METHODS: Gender-stratified data from the 2013 Korea Community Health Survey for individuals aged 60 to 74 living in Seoul were analyzed. Logistic regression modeling was conducted to obtain odds ratios (ORs) and 95% confidence intervals (CIs) of the outcome variables (smoking, drinking, eating salty foods, inactive lifestyle) for the variables of interest (living alone/with others, housemate type). Models were adjusted for confounding variables including history of medical conditions, employment type, and adjusted household income. RESULTS: Analysis involved 1,814 men and 2,199 women. Risk of smoking was 1.80 times (95% CI, 1.21 to 2.67) higher for men living alone than living with others. Risk of eating salty foods was 0.78 times lower (95% CI, 0.62 to 0.98) for men living with a spouse than a spouse and younger generations. Risk of inactive lifestyle was 1.47 times higher (95% CI, 1.13 to 1.92) for women living alone. Risk of smoking was higher for women living alone (OR, 1.41; 95% CI, 1.03 to 1.92) or with younger generations (OR, 9.12; 95% CI, 2.04 to 40.80) than with a spouse and younger generations. CONCLUSIONS: Living alone was associated with smoking in men and physical activity in women; housemate type was associated with dietary habits in men and smoking in women. These gender-specific findings can help identify groups of individuals vulnerable to risky health behaviors and to develop policies. PMID- 29121711 TI - Differences in agricultural activities related to incidence of scrub typhus between Korea and Japan. AB - OBJECTIVES: The purpose of this study was to establish a basis for improving or strengthening the preventive strategy against scrub typhus in Korea by comparing and analyzing the difference of prevention behaviors contributing to the occurrence of scrub typhus in Japan and Korea. METHODS: The survey was carried out in Jeollabuk-do, which is a high risk and high incidence area, and Fukuoka Prefecture, which is a high risk and low incidence area. The study included 406 Korean farmers and 216 Japanese farmers. Data were collected through face-to-face surveys by interviewers who had completed standardized education. RESULTS: Korean farmers have a higher percentage of agricultural working posture that involved contact with weeds than Japanese farmers (p<0.05). The frequency and proportion of weeding were lower in Korean farmers than in Japanese farmers (p<0.05). The level of knowledge about scrub typhus was significantly higher among Korean farmers than among Japanese farmers (p<0.05). Mostly, the behavior of agriculture work was more appropriate for Japanese farmers than for Korean farmers (p<0.05). The total average level of agricultural work was lower in Korea than in Japan, lower in men than women, and lower in part-time farmers than full-time farmers (p<0.05). CONCLUSIONS: This study suggests that it is reasonable to develop and provide a program that can improve the level of preventive behavior taking into consideration the characteristics of the subject in order to reduce the incidence of diseases in high-risk areas for scrub typhus. PMID- 29121712 TI - Clinical and laboratory findings of rhabdomyolysis in opioid overdose patients in the intensive care unit of a poisoning center in 2014 in Iran. AB - OBJECTIVES: The aim of this study was to investigate the clinical and demographic characteristics and some laboratory findings of hospitalized patients with acute opioid toxicity and rhabdomyolysis. METHODS: This cross-sectional study investigated 354 patients hospitalized at Baharloo Hospital in Tehran in 2014 with acute illicit drug toxicity. Data were collected using an investigator-made checklist. The collected data (such as mortality rate, demographic data, and renal function tests, as well as serum biochemical findings) were analyzed by descriptive statistics and the chi-square test. RESULTS: A total of 354 patients were admitted to the hospital in 2014 with acute illicit drug toxicity, including 291 males and 63 females. The total number of patients with rhabdomyolysis was 76 (21.5% of the total), of whom 69 (90.8%) were male and 7 (9.2%) were female. Most cases of rhabdomyolysis were associated with methadone abuse, followed by opium abuse. Rhabdomyolysis was most common in those 20-29 and 30-39 years old, with methadone and opium the most commonly abused illicit drugs. The mean blood urea level was 3.8+/-1.0 mg/dL, and the mean serum potassium and sodium levels were 3.8+/-0.3 mg/dL and 140.4+/-4.0 mg/dL, respectively. Five patients, all of whom were male, passed away due to severe renal failure (6.5%). CONCLUSIONS: Toxicity caused by opioids is associated with clinical complications and laboratory disorders, such as electrolyte disorders, which can lead to lethal or life threatening results in some cases. Abnormal laboratory test findings should be identified in patients with opioid toxicity in order to initiate efficient treatment. PMID- 29121713 TI - Health-Related Quality of Life in Non-Hodgkin Lymphoma Survivors: A Prospective Cohort Study. AB - PURPOSE: We evaluated health-related quality of life (HRQOL) in long-term survivors of indolent and aggressive non-Hodgkin lymphoma (NHL). Materials and Methods: TheHRQOLwas assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) at diagnosis in NHL patients between 2008 and 2011, and follow-up evaluation was conducted from June 2014 to February 2015 using EORTC QLQ-C30 and the quality of life in cancer survivors (QOL-CS) questionnaire. We used linear mixed models to compare changes in HRQOL between indolent and aggressive NHL over time. RESULTS: The HRQOL of long-term survivors with aggressive NHL improved to the similar level of indolent NHL during the follow-up survey. However, survivors of NHL were found to fear the probability of relapse and second malignancy, and the degree of fear was not different between survivors with aggressive stage I/II or III/IV NHL (p > 0.05). Furthermore, a half of survivors reported impaired sense of psychosocial well-being regardless of aggressiveness and stage during follow-up survey. More than 65% of survivors thought they did not receive sufficient support from others, and patients who had financial difficulties at diagnosis were more frequently associated with suffering from insufficient support. Impaired physical and cognitive functioning at diagnosis was significantly associated with lack of life purpose in long-term survivors. CONCLUSION: The HRQOL of aggressive NHL survivors improved to a similar level to that of indolent NHL. However, the majority of survivors still had fear of relapse, and psychosocial well-being remained unmet needs. PMID- 29121714 TI - Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy. AB - Purpose: Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. Materials and Methods: We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs. Results: HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. Conclusion: The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation. PMID- 29121715 TI - Evaluation of a course to prepare international students for the United States Medical Licensing Examination step 2 clinical skills exam. AB - PURPOSE: United States (US) and Canadian citizens attending medical school abroad often desire to return to the US for residency, and therefore must pass US licensing exams. We describe a 2-day United States Medical Licensing Examination (USMLE) step 2 clinical skills (CS) preparation course for students in the Technion American Medical School program (Haifa, Israel) between 2012 and 2016. METHODS: Students completed pre- and post-course questionnaires. The paired t test was used to measure students' perceptions of knowledge, preparation, confidence, and competence in CS pre- and post-course. To test for differences by gender or country of birth, analysis of variance was used. We compared USMLE step 2 CS pass rates between the 5 years prior to the course and the 5 years during which the course was offered. RESULTS: Ninety students took the course between 2012 and 2016. Course evaluations began in 2013. Seventy-three students agreed to participate in the evaluation, and 64 completed the pre- and post-course surveys. Of the 64 students, 58% were US-born and 53% were male. Students reported statistically significant improvements in confidence and competence in all areas. No differences were found by gender or country of origin. The average pass rate for the 5 years prior to the course was 82%, and the average pass rate for the 5 years of the course was 89%. CONCLUSION: A CS course delivered at an international medical school may help to close the gap between the pass rates of US and international medical graduates on a high-stakes licensing exam. More experience is needed to determine if this model is replicable. PMID- 29121716 TI - Risk prediction in post-infarction patients with moderately reduced left ventricular ejection fraction by combined assessment of the sympathetic and vagal cardiac autonomic nervous system. AB - AIM: Most deaths after myocardial infarction (MI) occur in patients with normal or moderately reduced left ventricular ejection fraction (LVEF >35%). Periodic repolarization dynamics (PRD) and deceleration capacity (DC) are novel ECG-based markers related to sympathetic and vagal cardiac autonomic nervous system activity. Here, we test the combination of PRD and DC to predict risk in post infarction patients with LVEF >35%. METHODS AND RESULTS: We included 823 survivors of acute MI with LVEF >35%, aged <=80years and in sinus rhythm. PRD and DC were obtained from 30-min ECG-recordings within the second week after index infarction and dichotomized at established cut-off values of >=5.75deg2 and <=2.5ms, respectively. Patients were classified as having normal (CAF 0), partly abnormal (DC or PRD abnormal; CAF 1) or abnormal cardiac autonomic function (DC and PRD abnormal; CAF 2). Primary endpoint was 5-year all-cause mortality. Within the first 5years of follow-up, 51 patients died (6.2%). PRD and DC effectively stratified patients into low-risk (CAF 0; n=562), intermediate-risk (CAF 1; n=193) and high-risk patients (CAF 2; n=68) with cumulative 5-year mortality rates of 2.9%, 9.4% and 25.2%, respectively (p<0.001). On multivariable analyses, CAF was independent from established risk factors (GRACE-score, diabetes mellitus, mean heart rate, heart rate variability). Addition of CAF significantly improved the model (increase of C-statistics from 0.732 (0.651-0.812) to 0.777 (0.703-0.850), p=0.047; continuous NRI (0.400, 95% CI 0.230-0.560, p<0.001); IDI (0.056, 95% CI 0.022-0.122, p<0.001)). CONCLUSION: CAF identifies new high-risk post-MI patients with LVEF >35% which might benefit from prophylactic strategies. PMID- 29121717 TI - Age and comorbidities should not preclude a liberal use of PCI in myocardial infarction. PMID- 29121718 TI - Non-invasive assessment of liver changes in Eisenmenger patients. AB - BACKGROUND: Eisenmenger syndrome as a severe form of cyanotic congenital heart disease results in a complex multisystemic disorder. Due to increased systemic venous pressure and the inability to ensure systemic perfusion and metabolic requirements, the liver may develop congestion, fibrosis or cirrhosis. This study aimed to assess hepatic abnormalities in Eisenmenger patients non-invasively. METHODS AND RESULTS: 10 adults with Eisenmenger syndrome (six female; median age 44.2years; range 23-62years) were enrolled and hepatic involvement was assessed - using clinical assessment, laboratory analysis, hepatic fibrotic markers, abdominal sonography and liver stiffness measurements (transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)). Using imaging and laboratory analysis, 60% (6/10) of the Eisenmenger patients had signs of liver fibrosis (5/10) or cirrhosis (1/10). While TE, however, showed no relevant liver abnormalities in any Eisenmenger patient, ARFI detected liver fibrosis in 5/10 and cirrhosis and 1/10 patients. CONCLUSIONS: Adult Eisenmenger patients are at increased risk of hepatic impairment. Non-invasive screening could be helpful in detecting liver alterations. In our small series, however, TE could not detect fibrosis or cirrhosis in any affected patient, while ARFI was very reliable. Patients should be transferred to centres, where a multidisciplinary expert knowledge is available and a close collaboration between cardiologists and hepatologists exists. PMID- 29121719 TI - Implantable cardioverter defibrillator therapy in repaired tetralogy of Fallot after pulmonary valve replacement: Implications for the mechanism of ventricular arrhythmia. AB - BACKGROUND: Ventricular tachycardia (VT), which is related to haemodynamic and electrophysiological alterations, is an important complication in repaired tetralogy of Fallot (rTOF) patients. We defined the role of implantable cardioverter defibrillator (ICD) therapy after pulmonary valve replacement (PVR) and the implications of coexisting long QT gene mutations/polymorphisms. METHODS: From 2003 to 2016, rTOF patients with VT who received ICD implantation were enrolled. rTOF patients without VT served as a control group. We performed long QT gene mutation analysis through the direct sequencing method. RESULTS: In total, 12 (male/female, 8/4) patients with VT received ICD implantation. The mean age at TOF repair and ICD implantation was 4.4+/-4.5years and 27.1+/-11.5years, respectively. All but one patient received PVR for severe pulmonary regurgitation or repair for a residual ventricular septal defect. After 5.4+/-4.0years of follow-up, six patients (50%) had at least one episode of appropriate shock: two had received PVR with intraoperative arrhythmia ablation and two had received PVR only. Compared with 121 patients without VT, the ICD patients had a higher frequency of long QT gene mutation/polymorphisms (10/12 vs. 54/121, p=0.014), especially in the hERG and SCN5A genes. The mechanism of VT in rTOF was discussed thoroughly. CONCLUSION: In rTOF patients who received ICD as secondary prevention, the appropriate shock rate remained high despite PVR and intraoperative arrhythmia ablation. Coexisting long QT gene mutations/polymorphisms may be associated with ventricular arrhythmia. PMID- 29121720 TI - Incidence, predictors and outcomes of infective endocarditis in a contemporary adult congenital heart disease population. AB - BACKGROUND: The prevalence of congenital heart disease (CHD) in the adult population is steadily increasing. A substrate of prosthetic material and residual lesions, constantly evolving as surgical techniques change over time, predispose these patients to the potentially devastating complication of infective endocarditis (IE). METHODS: We retrospectively reviewed 2935 patients in our adult CHD database for all cases of endocarditis between 1991 and 2016. Incidence, clinical course and predictors of outcomes were analysed. RESULTS: We document 74 episodes in 62 patients, with an incidence of 0.9 cases/1000 patient years (py). IE was more common in complex CHD (1.4 cases/1000py) and ventricular septal defects (VSDs) (1.9 cases/1000py). Prosthetic material was involved in 47% and left-sided infection predominated (66%). The incidence in bicuspid aortic valves post aortic valve replacement (AVR) was significantly higher than in unoperated valves, being 1.8 and 1.1 cases/1000 patient years respectively. Streptococcus was the most frequently implicated causative organism (37%). Emboli occurred in 34% of cases with a cerebral predilection. 46% of patients required surgery during the admission for IE, most frequently to replace a severely regurgitant bicuspid aortic valve. Early endocarditis-related mortality was 15%, associated with cerebral emboli and acute renal failure. CONCLUSIONS: In a contemporary adult CHD cohort, those with complex underlying lesions, VSDs or an AVR were at higher risk for IE. Mortality remains substantial and is more likely in patients with cerebral emboli and/or acute renal failure. PMID- 29121721 TI - Liver dysfunction and congenital heart disease: Are we ready for the epidemic? PMID- 29121722 TI - Infective endocarditis in patients with congenital heart disease: When, where and how. PMID- 29121723 TI - Atrial fibrillation and use of antithrombotic medications in older people: A population-based study. AB - BACKGROUND: Trends in the use of antithrombotic drugs in elderly patients with atrial fibrillation (AF) are largely unknown. We estimated the prevalence of AF in an older population, and examined whether use of anticoagulant and antiplatelet drugs in older AF patients has changed over time. METHODS: Data from the population-based Swedish National study on Aging and Care in Kungsholmen (n=3363, age>=60years, 64.9% women) were used (2001-2004 and 2007-2010). AF cases were identified through 12-lead electrocardiogram, physician examinations, and patient register records (ICD-10 code I48). We used the CHADS2 and CHA2DS2-VASc scores to estimate stroke risk, and an incomplete HAS-BLED score to estimate bleeding risk. RESULTS: At baseline (2001-2004), 328 persons (9.8%) were ascertained to have AF. The prevalence of AF increased significantly with age from 2.8% in people aged 60-66years to 21.2% in those >=90years, and was more common in men than in women (11.2% vs. 9.0%). Among AF patients with CHADS2 score >=2 at baseline, 25% were taking anticoagulant drugs and 54% were taking antiplatelet drugs. High bleeding risk was significantly associated with not using anticoagulant drugs in AF patients (multi-adjusted OR=2.50, p=0.015). Between 2001-2004 and 2007-2010, use of anticoagulant drugs increased significantly, especially in AF patients with CHA2DS2-VASc score >=2 (23% vs. 33%, p=0.008) and in those with HAS-BLED score <3 (32% vs. 53%, p=0.004). CONCLUSION: AF is common among old people. The use of anticoagulant drugs increased over time in AF patients, yet still two-thirds of those with high stroke risk remained untreated. PMID- 29121724 TI - NOACs and atrial fibrillation: Incidence and predictors of left atrial thrombus in the real world. AB - AIMS: Despite optimal oral anticoagulation with vitamin K antagonist, left atrial (LA) thrombus could be detected in the left appendage (LAA) in >2% of patients with atrial fibrillation (AF) and CHA2DS2-VASc score>=1 but few data are available for patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). We evaluated the occurrence and predictors of LA thrombi by means of transesophageal echocardiography (TOE) in consecutive patients with non-valvular AF who received for at least 3weeks Apixaban, Dabigatran, or Rivaroxaban. METHODS: This study included 414 consecutive patients (male 252, 60.6%, mean age 67.3years) referred to our Centers for catheter ablation of AF (n=220, 53.1%) or scheduled electrical cardioversion (n=194, 46.9%). Patients were on Dabigatran (n=160), Rivaroxaban (n=150) or Apixaban (n=104). TOE was performed in all cases within 12h prior to ablation or cardioversion. RESULTS: Preprocedural TOE revealed LA thrombus in 15/414 patients (3.6%), all located in the LAA (Apixaban 3/104 2.9%, Dabigatran 5/160 3.1%, and Rivaroxaban 7/150 4.7%, p=0.69). Of these, 14 patients had persistent AF. Patients with LAA thrombus had a mean CHA2DS2-VASc score of 3 (3-4). Higher CHA2DS2-VASc score (p=0.02), but not the type of NOAC, significantly predicted the presence of LA thrombus. CONCLUSION: The incidence of LAA thrombus in a cohort of patients anticoagulated with NOACs is low but not negligible, in any case similar among the 3 drugs. Preprocedural TOE should be considered in patients with a CHA2DS2-VASc score>3. PMID- 29121725 TI - Real-world study of low-density lipoprotein cholesterol levels and cardiovascular outcomes in Chinese: A retrospective cohort study in post-percutaneous coronary intervention acute coronary syndrome patients. AB - BACKGROUND: This study aimed to assess the effect of low-density lipoprotein cholesterol (LDL-C) goal attainments (of <2.6mmol/L and <1.8mmol/L) on first major adverse cardiovascular events (MACEs) for acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI). METHODS: A retrospective cohort study was conducted using case reviews of post-PCI ACS patients at an acute public hospital in Hong Kong between January 2009 and August 2015. Patients were followed from the date of PCI procedure until the first documented MACE (including all-cause death, myocardial infarction, heart failure, documented unstable angina, revascularization, and stroke) or to the end of the first year. Kaplan-Meier estimates were used to evaluate the impact of LDL-C goal attainments prior to the event on event-free time. RESULTS: A total of 1684 patients were identified (79.0% males). At one-year endpoint, 658 (39.1%) attained the LDL-C goal of <1.8mmol/L, 727 (43.2%) had the LDL-C level between 1.8mmol/L and 2.6mmol/L, and 299 (17.8%) had the LDL-C level>=2.6mmol/L. About 10% experienced a MACE within one year. After adjustment for other available risk factors, attainment of LDL-C goal <2.6mmol/L was significantly associated with lower rates of MACEs during the one-year follow-up; and those who achieved the LDL-C level of 1.8mmol/L did not seem to carry any incremental clinical benefits. CONCLUSIONS: Among post-PCI ACS patients, we merely observed a high correlation between the lipid goal attainment of <2.6mmol/L and MACEs through one-year follow up, but not for the goal of <1.8mmol/L. PMID- 29121726 TI - Why is there still undertreatment with oral anticoagulants in elderly high risk patients with AF? PMID- 29121727 TI - The emerging role of hybrid ablation for atrial fibrillation. PMID- 29121728 TI - Response to: "The emerging role of hybrid ablation for ablation" by Spartialis M. et al. PMID- 29121729 TI - Atrial fibrillation, hip fracture, and oral anticoagulant therapy. PMID- 29121730 TI - Atrial fibrillation, hip fracture, and oral anticoagulation therapy. PMID- 29121731 TI - Normal findings on noninvasive cardiac assessment and the prediction of heart failure: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: It is unknown if normal findings on noninvasive cardiac assessment are able to identify individuals who are low risk for developing heart failure (HF). METHODS: We examined if normal findings on the routine electrocardiogram (ECG) and cardiac magnetic resonance imaging (MRI) were able to identify individuals who are low risk for developing HF in 4986 (mean age=62+/-10years; 52% women; 39% White; 13% Chinese-American; 26% Black; 22% Hispanic) participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent HF at baseline. A normal ECG was defined as the absence of major abnormalities by Minnesota Code Classification, and a normal MRI was defined as absence of structural abnormalities and systolic dysfunction. RESULTS: There were 3988 (80%) participants with normal findings at baseline on both ECG and MRI, 894 (18%) who had either a normal ECG or normal MRI, and 104 (2%) who had abnormal findings on ECG and MRI. Over a median follow-up of 12.2years, 177 (3.6%) HF events occurred. Normal ECG (HR=0.41, 95%CI=0.29, 0.56) and MRI (HR=0.32, 95%CI=0.23, 0.45) were each associated with lower risk of HF compared with abnormal, and their combination was associated with a lower HF risk (HR=0.13, 95%CI=0.08, 0.21) than either in isolation. CONCLUSION: Normal findings on noninvasive cardiac assessment identify individuals in whom the risk of HF is low. Further studies are needed to explore the utility of this low-risk profile in HF prevention strategies. PMID- 29121732 TI - Quality of life improvement in older patients with heart failure initiated on ivabradine: Results from the UK multi-centre LIVE:LIFE prospective cohort study. AB - AIMS: LIVE:LIFE is a multi-centre, open-label, prospective observational cohort study assessing health-related quality of life (HRQoL) in older patients with chronic heart failure (CHF) following initiation of ivabradine. The primary endpoint is change in Minnesota Living with Heart Failure Questionnaire (MLWHFQ) total score after 6months. METHODS AND RESULTS: Consenting patients aged >=70years with CHF, in whom ivabradine was initiated within its licensed indication, were enrolled. Demographic, clinical and HRQoL (MLWHFQ, SF-12) data were collected at baseline (V1), 2 (V2) and 6months (V3). Over 14months, 240 patients were recruited from 44 UK centres. Ninety-nine (41%) were female and 28% aged >=80years. Aetiology was ischaemic in 152 (63%) and 59% had been diagnosed with CHF for <=2yrs. 52% of patients were New York Heart Association (NYHA) Class III and 57% had left ventricular ejection fraction <35%. 57% received beta blockers. Patients had multiple comorbidities (144 (60%) hypertension, 105 (44%) asthma/COPD, 80 (33%) diabetes) and were prescribed a mean of 9+/-3 daily medications. Resting heart rate was 83bpm at baseline and fell 13bpm by V3. In patients completing both visits (n=187), comparing V3 to baseline: MLWHFQ total score improved by 9 points (p<0.0001, 95% CI: 7-12); 30% of patients improved >=1 NYHA class and global assessment improved from patient (59%) and physician (60%) perspectives. 88% of patients completing V3 were still taking ivabradine. CONCLUSIONS: These contemporary prospective UK data demonstrate improvements in HRQoL and functional status with ivabradine therapy in typical older CHF patients. Despite comorbidities and polypharmacy, ivabradine was well tolerated. PMID- 29121733 TI - Pheochromocytoma as a reversible cause of cardiomyopathy: Analysis and review of the literature. AB - CONTEXT: Pheochromocytoma and paraganglioma are rare neuroendocrine tumors which overproduce catecholamines and arise from the adrenal gland or extra-adrenal chromaffin cells of the sympathetic and parasympathetic ganglia (1). Excessive catecholamine-induced stimulation of cardiac myocytes leads to damage which manifests in several forms ranging from Takotsubo to dilated cardiomyopathy. Diagnosis of pheochromocytoma-related cardiomyopathies is often delayed due to the atypical presentation associated with many cases. OBJECTIVE: Limited data exists on the presentation and outcomes of the various forms of pheochromocytoma induced cardiomyopathies. We performed a literature review to assess the association of pheochromocytoma and cardiomyopathy to aide in further understanding this clinical entity. DESIGN: 163 cases from 150 articles published between 1991 and November 2016 were included from a PubMed search. RESULTS: There were 163 occurrences of pheochromocytoma and cardiomyopathy (63 dilated cardiomyopathy, 38 Takotsubo cardiomyopathy, 30 inverted Takotsubo cardiomyopathy, 10 HOCM, 8 myocarditis, and 14 unspecified cardiomyopathy). Many patients lacked classic signs or symptoms of pheochromocytoma with hypertension as a presenting symptom in 65% and the triad of headache, palpitations, and diaphoresis only in 4%. Resection of the pheochromocytoma led to improvement of the cardiomyopathy in 96% while lack of resection was associated with death or cardiac transplantation in 44%. CONCLUSION: Pheochromocytoma should be considered in the evaluation of non-ischemic, non-valvular cardiomyopathy even in the absence of symptoms of catecholamine excess. Our study highlights the importance of early suspicion and diagnosis of pheochromocytoma in cases of idiopathic heart failure as early resection may prevent progression to irreversible myocardial remodeling and death. PMID- 29121734 TI - Desmoplakin: Highlights on a left ventricular arrhythmogenic disorder. PMID- 29121735 TI - Excluding the pheochromocytoma. PMID- 29121736 TI - Negative risk markers for improving prediction of heart failure: Risk stratification implementation or simply the other side of existing risk scores? PMID- 29121737 TI - Ivabradine - well tolerated in elderly patients with systolic heart failure. PMID- 29121738 TI - Rate of intramyocardial NCAM re-expression in dilated cardiomyopathy: More pronounced in the left than in the right ventricle? PMID- 29121739 TI - Regulation of cardiomyocyte expression of neural cell adhesion molecule in adult cardiomyopathies - Further investigations are pertinent. PMID- 29121740 TI - Renal denervation: Should we ignore the proximal segment of renal artery? PMID- 29121741 TI - Comparison of branch and distally focused main renal artery denervation using two different radio-frequency systems in a porcine model. PMID- 29121742 TI - Retinopathy and left ventricular hypertrophy in patients with chronic kidney disease: Interrelationship and impact on clinical outcomes. AB - BACKGROUND: Retinopathy and left ventricular hypertrophy (LVH) are representative markers of microvascular and cardiac dysfunction in patients with chronic kidney disease (CKD). However, their relationship and their combined effects on clinical outcomes are unknown. METHODS: We included 401 patients with nondialysis dependent CKD stage 3-5 who had been examined with fundus photography for diabetic or hypertensive retinopathy. The presence of LVH was identified by echocardiography. The clinical significance of retinopathy and LVH was evaluated in terms of the rate of renal function decline and for any cardiovascular event (CVE)/death. RESULTS: CKD patients with retinopathy had a higher prevalence of LVH than those without retinopathy (38.9% vs. 27.6%, P=0.017). The presence of retinopathy was independently associated with LVH (odds ratio 1.69, 95% confidence interval [CI] 1.02, 2.80). Compared with subjects without either retinopathy or LVH, the coexistence of retinopathy and LVH was independently associated with rapid renal function decline (beta=-3.28; 95% CI -6.52, -0.04), whereas retinopathy or LVH alone were not. Patients with both retinopathy and LVH had a higher risk of CVE/death (adjusted hazard ratio 2.75; 95% CI 1.44, 5.26) than patients with either factor alone. A significant synergistic interaction was observed between retinopathy and LVH to predict CVE/death (P for interaction=0.049). CONCLUSIONS: Retinopathy was independently associated with LVH. The coexistence of retinopathy and LVH was associated with higher risks of CKD progression and CVE/death than was either factor alone, and their combined effects synergized to predict the risk of CVE/death. PMID- 29121744 TI - Excessive daytime sleepiness, sympathetic nervous system activation and arterial stiffening in patients with mild-to-moderate obstructive sleep apnoea. PMID- 29121743 TI - Profiling of cardiovascular and cerebrovascular disease associated microRNA expression in umbilical cord blood in gestational hypertension, preeclampsia and fetal growth restriction. AB - BACKGROUND AND METHODS: Gene expression of 29 cardiovascular and cerebrovascular disease associated microRNAs was assessed in whole umbilical cord blood, compared between groups [47 gestational hypertension (GH), 56 preeclampsia (PE), 37 fetal growth restriction (FGR) and 44 normal pregnancies] and correlated with the severity of the disease with respect to clinical signs (mild PE vs. severe PE), delivery date (before and after 34weeks of gestation), and Doppler ultrasound parameters [pulsatility index (PI) in the umbilical artery, PI in the middle cerebral artery and the cerebroplacental ratio]. RESULTS: GH showed a down regulation of miR-195-5p (p=0.025). The down-regulation of miR-26a-5p (p=0.031, p=0.05), miR-145-5p (p=0.042, p=0.015), and miR-574-3p (p=0.002, p=0.022) was observed in severe PE pregnancies requiring termination before 34weeks of gestation. Severe PE occurring regardless of the delivery date was associated with downregulation of miR-195-5p (p=0.01), miR-199a-5p (p=0.048), and miR-221-3p (p=0.028). On the other hand, mild PE showed upregulation of miR-92a-3p (p=0.044). The centralization of fetal circulation tended to higher levels of miR 1-3p (rho=-0.302, p=0.045) and miR-133a-3p (rho=-0.348, p=0.020) in PE pregnancies. FGR pregnancies with abnormal values of flow rate in the umbilical artery (miR-221-3p: rho=-0.390, p=0.017) and the middle cerebral artery (miR-143 3p: rho=0.350, p=0.036) demonstrated down-regulation of relevant microRNAs. CONCLUSION: Epigenetic changes induced by pregnancy-related complications in umbilical cord blood may appear as a result of dysfunctional placenta and impaired maternal cardiovascular function (hidden cardiovascular and cerebrovascular diseases) and may cause later onset of cardiovascular and cerebrovascular diseases in offspring. PMID- 29121745 TI - Excessive daytime sleepiness, sympathetic nervous system activation and arterial stiffening in patients with mild-to-moderate obstructive sleep apnoea. Reply. PMID- 29121746 TI - Clinical characteristics and survival of pulmonary arterial hypertension associated with three major connective tissue diseases: Methodological issues. PMID- 29121747 TI - Response to letter "Clinical characteristics and survival of pulmonary arterial hypertension associated with three major connective tissue diseases: Methodological issues". PMID- 29121748 TI - High-temperature requirement protein A2 (HtrA2): A promising biomarker to predict the ischemia-reperfusion injuries in STEMI patients. PMID- 29121749 TI - Circulating HtrA2 after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: A potential novel biomarker for mitochondrial induced cardiomyocyte apoptosis and ischemia-reperfusion injury. PMID- 29121750 TI - Novel ECG parameters are strongly associated with inflammatory 18F-FDG PET findings in patients with suspected cardiac sarcoidosis. AB - BACKGROUND: 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a feasible method to investigate the inflammatory activity of the myocardium in cardiac sarcoidosis. However, PET is costly and not as widely available as standard electrocardiogram (ECG). Current ECG findings related to cardiac sarcoidosis are highly non-specific. In this study, our aim was to determine whether novel ECG parameters are associated with pathological PET findings in patients with suspected cardiac sarcoidosis. METHODS: A total of 133 patients underwent cardiac FDG PET examination in Tampere University Hospital between August 2012 and September 2015. The left ventricular FDG uptake was categorized as either normal or pathological. Additionally, in-depth analyses of resting ECG were performed. Among other parameters, the presence of septal and inferolateral remodelling was assessed. These are novel ECG parameters related to local structural changes in the myocardium. RESULTS: In the ECG, septal and inferolateral remodelling, as well as widespread QRS fragmentation were significantly associated with pathological left ventricular FDG uptake even if adjusted for age, sex, body mass index, underlying cardiovascular disease and cardiac medication (p<0.05 for all). When all these ECG parameters were combined in a logistic regression model, only septal remodelling remained independently associated with abnormal left ventricular uptake (p<0.05). CONCLUSIONS: Our findings show that novel ECG parameters septal and inferolateral remodelling, as well as diffuse QRS fragmentation, are strongly associated with pathological cardiac findings in FDG PET. Thus, the presence of these ECG findings may warrant the clinician to consider the possibility of cardiac sarcoidosis. PMID- 29121751 TI - Prognostic implications of global myocardial mechanics in hypertrophic cardiomyopathy by cardiovascular magnetic resonance feature tracking. Relations to left ventricular hypertrophy and fibrosis. AB - BACKGROUND: Interstitial fibrosis, myocardial fiber disarray and non-uniform shortening are common histological features of hypertrophic cardiomyopathy (HCM). The degree of LV hypertrophy and fibrosis are postulated to contribute to the impairment of myocardial shortening. Cardiovascular magnetic resonance myocardial (CMR) feature tracking (CMR-FT) has emerged as a robust method that provides quantitative measurements of myocardial deformation. Our aim was first to evaluate LV strain parameters in HCM by CMR-FT and their dependence on both functional parameters and late gadolinium enhancement (LGE); and secondly we sought to determine their association with major cardiovascular outcomes. METHODS AND RESULTS: 74 patients with HCM and 75 controls subjects underwent a CMR study including LGE imaging. Global peak longitudinal, circumferential and radial systolic strain values (GLS, GCS, GRS) were measured by CMR-FT. A primary endpoint of all-cause mortality and secondary combined endpoint of hospital admission related to heart failure, lethal ventricular arrhythmias or cardiovascular death were defined. Patients with HCM showed attenuation of all LV strain values (p<0.001). Multivariate analysis showed that both LV hypertrophy and %of LGE were independent predictors of attenuated LV strains. All systolic LV strain parameters were impaired in patients with primary and secondary endpoints (follow up time: 25.6+/-9.9months, p<0.05 and p<0.01 respectively). Abnormal GLS, GCS and GRS were significantly associated with primary and secondary endpoints. CONCLUSION: Both LV hypertrophy and fibrosis contribute to the impairment of LV myocardial mechanics in HCM. In this population, reduced LV strain is associated with poor cardiac outcomes, particularly cardiovascular mortality and HF. PMID- 29121753 TI - The evolving purpose of imaging for low risk patients with suspected acute coronary syndromes. PMID- 29121752 TI - Identification of coronary artery calcification can optimize risk stratification in patients with acute chest pain. AB - BACKGROUND: The number of patients presenting to the emergency department (ED) with suspected acute coronary syndrome (ACS) is substantial. We tested whether identification of coronary artery calcium (CAC) can improve the negative predictive value (NPV) of clinical risk assessment for ACS in patients with acute chest pain. METHODS AND RESULTS: We included 826 consecutive patients (mean age: 53+/-11years; 42% female) without known coronary artery disease (CAD) or initially elevated serum biomarkers, whom underwent non-contrast CT, to assess the CAC score, and CT angiography (CTA), to detect coronary stenosis. We analyzed the diagnostic performance of CAC and the Thrombolysis In Myocardial Infarction (TIMI) risk score for our primary outcomes (ACS and obstructive CAD). No CAC was found in 54% (n=444) of all patients, 63% (n=524) had a TIMI score of 0 and 40% (n=328) had both. The prevalence of obstructive CAD was 16% for >=50% stenosis and 8.7% for >=70% stenosis. The incidence of ACS was 7.9%, (MI=11, UAP=54). The NPV of CAC=0 was 99.5% for ACS. The NPV of a combination of TIMI score=0 and no CAC was 89% for any CAD (any plaque or stenosis) and 99.7% for >=50% stenosis. A 100% NPV was found for >=70% stenosis and ACS, correctly identifying 328 (40%) patients. CONCLUSIONS: The exclusion of CAC, in combination with clinical risk assessment, has high clinical value in patients with acute chest pain, as it identifies patients at low risk for ACS and obstructive CAD more accurately as compared to clinical risk assessment alone. PMID- 29121754 TI - The role of feature tracking in cardiovascular magnetic resonance imaging in hypertrophic cardiomyopathy. PMID- 29121755 TI - Plaque vulnerability, post-PCI tissue prolapse and neoatherosclerosis. PMID- 29121756 TI - Reply to letter to the editor: "Plaque vulnerability, post-PCI tissue prolapse and neoatherosclerosis". PMID- 29121757 TI - Association between QRS duration on prehospital ECG and mortality in patients with suspected STEMI. AB - BACKGROUND: QRS duration has previously shown association with mortality in patients with acute myocardial infarction treated with thrombolytics, less is known in patients with suspected ST segment elevation myocardial infarction (STEMI) when assessing QRS duration on prehospital ECG. Thus, the objective was to investigate the prognostic effect of QRS duration on prehospital ECG and presence of classic left and right bundle branch block (LBBB/RBBB) for all-cause mortality in patients with suspected STEMI. METHOD: In total 2105 consecutive patients (mean age 64+/-13years, 72% men) with suspected STEMI were prospectively included. QRS duration was registered from automated QRS measurement on prehospital ECG and patients were divided according to quartiles of QRS duration (<89ms, 89-98ms, 99-111ms and >111ms). Primary endpoint was all-cause 30-day mortality. Predictors of all-cause mortality were assessed using Cox proportional hazards analysis. RESULTS: Among all patients median QRS duration was 98ms (IQR 88-112ms). RBBB-morphology was seen in 126 patients (6.0%) and LBBB in 88 patients (4.2%), 80% were treated with percutaneous coronary intervention and the final diagnosis was STEMI in 1777 patients (84%). Thirty-day mortality was 7.6% in patients with suspected STEMI. In multivariable analysis, QRS duration>111ms (hazard ratio (HR) 3.08; 95% confidence interval (CI): 1.71-5.57, p=0.0002), LBBB - morphology (HR 3.0; 95% CI: 1.38-6.53, p=0.006) and RBBB (HR 3.68; 95% CI: 1.95 6.95, p<0.0001) were associated with 30 day all-cause mortality. CONCLUSION: In patients with suspected STEMI, QRS prolongation, LBBB, and RBBB on prehospital ECG are associated with increased risk of death. PMID- 29121758 TI - Tpeak-Tend dispersion as a predictor for malignant arrhythmia events in patients with vasospastic angina. AB - BACKGROUND: Tpeak-Tend interval (Tp-e interval) in electrocardiogram (ECG) has been reported to predict malignant arrhythmia events (MAE) in ST-segment elevation myocardial infarction and ion channelopathy. Tp-e interval and other ECG parameters as predictors for MAE was evaluated in patients with vasospastic angina (VA). METHODS AND RESULTS: Sixty-two patients with VA (Non-MAE group) and 20 patients with VA complicated by MAE (MAE group) were enrolled in our Division of Cardiology between January 2010 and December 2015. Continuous variables were analyzed by t-test and categorical variables by Chi-square analysis. Patients with MAE showed greater QTc (corrected QT interval) dispersion (P=0.005), Tp-ec (corrected Tp-e) interval (P=0.001), Tp-ec dispersion (P<0.001) and Tp-e/QT ratio (P<0.001) than those in non-MAE groups when ST-segment elevated. After elevated ST-segment returned, there were no significant differences in these ECG parameters between two groups (All P>0.05). At univariate binary logistic regression analysis QTc dispersion (odds ratio(OR)=1.133; P=0.013), Tp-ec (OR=1.058; P=0.003), Tp-e/QT (OR=1.403; P=0.001), and Tp-ec dispersion (OR=1.497; P=0.004) were significantly associated with MAE. At multivariable logistic regression analysis, Tp-ec dispersion remained a predictor of MAE. Receiver operating characteristic (ROC) curve analysis showed that only AUC (Area under curve) of Tp-ec dispersion had significant difference with those in QTc dispersion (P<0.001), Tp-ec (P=0.003), and Tp-e/QT ratio (P=0.012), respectively. CONCLUSIONS: QTc dispersion, Tp-ec, Tp-e/QT and Tp-ec dispersion were significantly increased in VA patients with MAE than those without MAE when coronary spasm was onset. Prolonged Tp-ec dispersion was the best discriminators and a strong independent predictor of MAE in VA patients. PMID- 29121759 TI - Comparison of prasugrel and ticagrelor in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A meta-analysis of randomized and non-randomized studies. AB - BACKGROUND: The newer oral P2Y12 receptor antagonists (i.e. prasugrel and ticagrelor) are recommended over clopidogrel for patients with acute coronary syndrome (ACS) going for percutaneous coronary intervention (PCI). As the superiority of one agent over the other remains unclear, we designed a systematic review and meta-analysis of these agents in patients with ACS undergoing PCI. METHODS: PUBMED, EMBASE, Cochrane CENTRAL, CINAHL and manual search were performed through 11/02/2016. Mortality, myocardial infarction (MI), stroke, repeat revascularization, stent thrombosis (ST) and BARC bleeding >=2 were the major outcomes. RESULTS: A total of 9 studies with 21,360 total patients were included in the meta-analysis. Compared to ticagrelor, prasugrel was associated with lower rate of MI [0.8% vs. 1.9%; 0.54 (0.29-0.99); P=0.05] but no difference was noted in mortality [2.1% vs. 2.4%; 0.84 (0.64-1.09); P=0.19], repeat revascularization [1.6% vs. 2.1%; 0.82 (0.61-1.10); P=0.19] and stroke [0.2% vs. 0.3%; 0.68 (0.25-1.83); P=0.44] between two agents. In addition, prasugrel was associated with lower risk of BARC >=2 bleeding [2.5% vs. 3.8%; 0.75 (0.59-0.95); P=0.02] and showed a trend toward a lower risk of ST [0.3% vs. 0.6%; 0.55 (0.28 1.07); P=0.08] in comparison with ticagrelor. CONCLUSIONS: Based on this meta analysis of observational and randomized studies, prasugrel appears to be equivalent or superior to ticagrelor in patients with ACS undergoing PCI on the 30-day follow up. Larger randomized trials with longer follow-ups are needed to establish superiority of one agent over the other. PMID- 29121760 TI - Measurement of cardiovascular autonomic function: Where to go from here? PMID- 29121761 TI - Tpeak-Tend as a predictor of ventricular arrhythmogenesis. PMID- 29121762 TI - Ticagrelor versus prasugrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention: An unresolved issue. PMID- 29121763 TI - Vasospastic angina behaves differently in men and women. PMID- 29121764 TI - Comment on "The influence of training characteristics on the effect of exercise training in patients with coronary artery disease: Systematic review and meta regression analysis". PMID- 29121765 TI - Comment on: "The influence of training characteristics on the effect of exercise training in patients with coronary artery disease: Systematic review and meta regression analysis". PMID- 29121766 TI - Percutaneous coronary intervention reduces mortality in myocardial infarction patients with comorbidities: Implications for elderly patients with diabetes or kidney disease. AB - BACKGROUND: Percutaneous coronary intervention (PCI) reduces mortality in most myocardial infarction (MI) patients but the effect on elderly patients with comorbidities is unclear. Our aim was to analyse the effect of PCI on in-hospital mortality of MI patients, by age, sex, ST elevation on presentation, diabetes mellitus (DM) and chronic kidney disease (CKD). METHODS: Cohort study of 79,791 MI patients admitted at European hospitals during 2000-2014. The effect of PCI on in-hospital mortality was analysed by age group (18-74, >=75years), sex, presence of ST elevation, DM and CKD, using propensity score matching. The number needed to treat (NNT) to prevent a fatal event was calculated. Sensitivity analyses were conducted. RESULTS: PCI was associated with lower in-hospital mortality in ST and non-ST elevation MI (STEMI and NSTEMI) patients. The effect was stronger in men [Odds ratio (95% confidence interval) 0.30 (0.25-0.35)] than in women [0.46 (0.39 0.54)] aged >=75years, and in NSTEMI [0.22 (0.17-0.28)] than in STEMI patients [0.40 (0.31-0.5)] aged <75years. PCI reduced in-hospital mortality risk in patients with and without DM or CKD (54-72% and 52-73% reduction in DM and CKD patients, respectively). NNT was lower in patients with than without CKD [>=75years: STEMI=6(5-8) vs 9(8-10); NSTEMI=10(8-13) vs 16(14-20)]. Sensitivity analyses such as exclusion of hospital stays <2days yielded similar results. CONCLUSIONS: PCI decreased in-hospital mortality in MI patients regardless of age, sex, and presence of ST elevation, DM and CKD. This supports the recommendation for PCI in elderly patients with DM or CKD. PMID- 29121767 TI - From Pulmonary Surfactant, Synthetic KL4 Peptide as Effective siRNA Delivery Vector for Pulmonary Delivery. AB - Pulmonary delivery of small interfering RNA (siRNA) has huge potential for the treatment of a wide range of respiratory diseases. The ability of naked siRNA to transfect cells in the lungs without a delivery vector has prompted the investigation of whether an endogenous component is at least partially responsible for the cellular uptake of siRNA, and whether a safe and efficient delivery system could be developed from this component to further improve the transfection efficiency. Surfactant protein B (SP-B), a positively charged protein molecule found in lung surfactant, is one of the possible candidates. While the role of SP-B in siRNA transfection remains to be determined, the SP-B mimic, synthetic KL4 peptide, was investigated in this study as a potential siRNA carrier. KL4 is a 21-residue cationic peptide that was able to bind to siRNA to form nanosized complexes. It mediated siRNA transfection effectively in vitro on human lung epithelial cells, A549 cells, and BEAS-2B cells, which was comparable to Lipofectamine 2000. When commercial pulmonary surfactant (Infasurf) was added in the transfection medium, the gene silencing effect of siRNA in cells transfected with Lipofectamine 2000 was completely abolished, whereas those transfected with KL4 remained unaffected. At 4 degrees C, KL4 failed to deliver siRNA into the cells, indicating that an energy-dependent process was involved in the uptake of the complexes. Chlorpromazine (inhibitor of chathrin-mediated endocytosis), but not nystatin (inhibitor of caveolae-mediated endocytosis), inhibited the uptake of KL4/siRNA complexes, suggesting that they entered cells through clathrin-mediated endocytosis. There was no sign of cytotoxicity or immune response caused by KL4 and KL4/siRNA complexes. Overall, this study demonstrated that synthetic KL4 peptide is a promising candidate for siRNA carrier for pulmonary delivery and could be a potential platform for delivering other types of nucleic acid therapeutics. PMID- 29121768 TI - Comparative Analysis of Tocopherol Biosynthesis Genes and Its Transcriptional Regulation in Soybean Seeds. AB - Tocopherols composed of four isoforms (alpha, beta, gamma, and delta) and its biosynthesis comprises of three pathways: methylerythritol 4-phosphate (MEP), shikimate (SK) and tocopherol-core pathways regulated by 25 enzymes. To understand pathway regulatory mechanism at transcriptional level, gene expression profile of tocopherol-biosynthesis genes in two soybean genotypes was carried out, the results showed significantly differential expression of 5 genes: 1-deoxy d-xylulose-5-P-reductoisomerase (DXR), geranyl geranyl reductase (GGDR) from MEP, arogenate dehydrogenase (TyrA), tyrosine aminotransferase (TAT) from SK and gamma tocopherol methyl transferase 3 (gamma-TMT3) from tocopherol-core pathways. Expression data were further analyzed for total tocopherol (T-toc) and alpha tocopherol (alpha-toc) content by coregulation network and gene clustering approaches, the results showed least and strong association of gamma TMT3/tocopherol cyclase (TC) and DXR/DXS, respectively, with gene clusters of tocopherol biosynthesis suggested the specific role of gamma-TMT3/TC in determining tocopherol accumulation and intricacy of DXR/DXS genes in coordinating precursor pathways toward tocopherol biosynthesis in soybean seeds. Thus, the present study provides insight into the major role of these genes regulating the tocopherol synthesis in soybean seeds. PMID- 29121769 TI - Potential-Resolved Multicolor Electrochemiluminescence of N-(4-Aminobutyl)-N ethylisoluminol/tetra(4-carboxyphenyl)porphyrin/TiO2 Nanoluminophores. AB - Most electrochemiluminescence (ECL) studies involve single luminophore with a unique emission process, which severely limits its applications. Recently, multicolor ECL has attracted considerable interests. Herein, we report a novel nanoluminophore prepared by coating 5,10,15,20-tetrakis(4-carboxyphenyl) porphyrin (TCPP) and N-(4-aminobutyl)-N-ethylisoluminol (ABEI) on the surface of TiO2 nanoparticles (TiO2-TCPP-ABEI), which exhibited unique potential-resolved multicolor ECL emissions using H2O2 and K2S2O8 as coreactants in an aqueous solution. Three ECL peaks, ECL-1 at 458 nm, ECL-2 at 686 nm, and ECL-3 at 529 nm, were obtained with peak potentials of 1.05, -1.65, and -1.85 V, which were attributed to the ECL emission of ABEI, TCPP, and TiO2 moiety of the nanoluminophores, respectively. Potential-resolved multicolor ECL from a nanoluminophore was observed for the first time in an aqueous solution. It opens a new research area of multicolor ECL of nanoluminophores, which is of great importance in ECL field from fundamental studies to practical applications. PMID- 29121770 TI - Assessment of Quantification Precision of Histone Post-Translational Modifications by Using an Ion Trap and down To 50 000 Cells as Starting Material. AB - Histone post-translational modifications (PTMs) are fundamental players of chromatin regulation, as they contribute to editing histone chemical properties and recruiting proteins for gene transcription and DNA repair. Mass spectrometry (MS)-based proteomics is currently the most widely adopted strategy for high throughput quantification of hundreds of histone PTMs. Samples such as primary tissues, complex model systems, and biofluids are hard to retrieve in large quantities. Because of this, it is critical to know whether the amount of sample available would lead to an exhaustive analysis if subjected to MS. In this work, we assessed the reproducibility in quantification of histone PTMs using a wide range of starting material, that is, from 5 000 000 to 50 000 cells. We performed the experiment using four different cell lines, that is, HeLa, 293T, human embryonic stem cells (hESCs), and myoblasts, and we quantified a list of 205 histone peptides using ion trap MS and our in-house software. Results highlighted that the relative abundance of some histone PTMs deviated as little as just 4% when comparing high starting material with histone samples extracted from 50 000 cells, for example, H3K9me2 (40% average abundance). Low abundance PTMs such as H3K4me2 (<3% average abundance) showed higher variability, but still ~34%. This indicates that most PTMs, and especially abundant ones, are quantified with high precision starting from low cell counts. This study will help scientists to decide whether specific experiments are feasible and to plan how much sample should be reserved for histone analysis using MS. PMID- 29121771 TI - Switching Peroxidase-Mimic Activity of Protein Stabilized Platinum Nanozymes by Sulfide Ions: Substrate Dependence, Mechanism, and Detection. AB - In the present work, we use beta-casein as a model protein to prepare a smart beta-casein stabilized Pt nanoparticle (CM-PtNP) with peroxidase mimicking activity and systematically investigate sulfide-mediated switching effect and mechanism of CM-PtNP nanozyme's activity. Sulfide-mediated activity switching effect depends heavily on the physicochemical properties of nanozymes and the identity of substrate. On one hand, the binding of sulfide to a Pt nanozyme surface leads to the transform from Pt2+ to Pt0, resulting in more active sites and the activity "switching on"; on the other hand, the binding of sulfide ions via Pt-S interaction blocks the active sites, resulting in the activity "switching off". For substrates 3,3',5,5'-tetramethylbenzidine and 2,2' azinobis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt, the two factors play different decisive roles since the interaction of substrate molecules with nanozyme allows their different distributions on nanozyme surfaces. By virtue of this specific response, excellent sulfide colorimetric sensors with different limits of detection were developed based on CM-PtNP with different substrates. This is the first report about a fundamental understanding of how substrates influence the anion-mediated activity switching effect by illuminating the nature of anion-nanozyme interaction and nanozyme-substrate interaction. This may be useful to rationally predict the environment factors on the activities of the nanozyme and to design an effective signal amplification based on target-induced nanozyme deactivation/activation. PMID- 29121772 TI - Scalable Syntheses of 4-Substituted Pyridine-Diimines. AB - A concise benchtop and scalable synthesis of pyridine-diimine (PDI) ligand frameworks is presented using inexpensive commercial starting materials as opposed to previous syntheses of these ligands, which have confronted long and tedious routes that employ toxic and often difficult to scale pyrophoric reagents. The streamlined synthesis is derived from the facile delivery of 4 functionalized diacetylpyridines from a Minisci reaction using pyruvic acid, silver nitrate, and persulfate. As the PDI ligand scaffold has been adopted for a range of catalytic applications, the ability to modulate the electronic properties of the ligand with facility may be useful for optimizing a variety of catalytic transformations. PMID- 29121775 TI - Developments in optical imaging for gastrointestinal surgery. AB - To improve outcomes for patients with cancer, in terms of both survival and a reduction in the morbidity and mortality that results from surgical resection and treatment, there are two main areas that require improvement. Accurate early diagnosis of the cancer, at a stage where curative and, ideally, minimally invasive treatment is achievable, is desired as well as identification of tumor margins, lymphatic and distant disease, enabling complete, but not unnecessarily extensive, resection. Optical imaging is making progress in achieving these aims. This review discusses the principles of optical imaging, focusing on fluorescence and spectroscopy, and the current research that is underway in GI tract carcinomas. PMID- 29121773 TI - Systems Biology Approaches to Redox Metabolism in Stress and Disease States. AB - SIGNIFICANCE: All cellular metabolic processes are tied to the cellular redox environment. Therefore, maintaining redox homeostasis is critically important for normal cell function. Indeed, redox stress contributes to the pathobiology of many human diseases. The cellular redox response system is composed of numerous interconnected components, including free radicals, redox couples, protein thiols, enzymes, metabolites, and transcription factors. Moreover, interactions between and among these factors are regulated in time and space. Owing to their complexity, systems biology approaches to the characterization of the cellular redox response system may provide insights into novel homeostatic mechanisms and methods of therapeutic reprogramming. Recent Advances: The emergence and development of systems biology has brought forth a set of innovative technologies that provide new avenues for studying redox metabolism. This article will review these systems biology approaches and their potential application to the study of redox metabolism in stress and disease states. CRITICAL ISSUES: Clarifying the scope of biological intermediaries affected by dysregulated redox metabolism requires methods that are suitable for analyzing big datasets as classical methods that do not account for multiple interactions are unlikely to portray the totality of perturbed metabolic systems. FUTURE DIRECTIONS: Given the diverse redox microenvironments within cells, it will be important to improve the spatial resolution of omic approaches. Futures studies on the integration of multiple systems-based methods and heterogeneous omics data for redox metabolism are required to accelerate the development of the field of redox systems biology. Antioxid. Redox Signal. 29, 953-972. PMID- 29121774 TI - Sphingolipids and Redox Signaling in Renal Regulation and Chronic Kidney Diseases. AB - SIGNIFICANCE: Sphingolipids play critical roles in the membrane biology and intracellular signaling events that influence cellular behavior and function. Our review focuses on the cellular mechanisms and functional relevance of the cross talk between sphingolipids and redox signaling, which may be critically implicated in the pathogenesis of different renal diseases. Recent Advances: Reactive oxygen species (ROS) and sphingolipids can regulate cellular redox homeostasis through the regulation of NADPH oxidase, mitochondrial integrity, nitric oxide synthase (NOS), and antioxidant enzymes. Over the last two decades, there have been significant advancements in the field of sphingolipid research, and it was in 2010 for the first time that sphingolipid receptor modulator was exploited as a therapeutic in humans. The cross talk of sphingolipids with redox signaling pathways becomes an important mechanism in the development of many different diseases such as renal diseases. CRITICAL ISSUES: The critical issues to be addressed in this review are how sphingolipids interact with the redox signaling pathway to regulate renal function and even result in chronic kidney diseases. Ceramide, sphingosine, and sphingosine-1-phosphate (S1P) as main signaling sphingolipids are discussed in more detail. FUTURE DIRECTIONS: Although sphingolipids and ROS may mediate or modulate cellular responses to physiological and pathological stimuli, more translational studies and mechanistic pursuit in a tissue- or cell-specific way are needed to enhance our understanding of this important topic and to develop effective therapeutic strategies to treat diseases associated with redox signaling and sphingolipid cross talk. Antioxid. Redox Signal. 00, 000-000. PMID- 29121777 TI - Treatment and prognostic factors of patients with thymic epithelial tumors at first recurrence or progression. AB - AIM: The treatment of patients with recurrent or progressive thymic epithelial tumors remains uncertain due to limited data in this rare disease. MATERIALS & METHODS: A retrospective 10-year monoinstitutional analysis was conducted on 25 patients with first recurrence or disease progression following primary treatment. RESULTS: Twenty patients had thymoma, five thymic carcinomas. Ten patients (40%) received surgery, four (40%) following chemotherapy; 17 (68%) had chemotherapy, with a combination regimen in 16 of them (94%). Surgery had a significant effect both on overall survival and progression-free survival-2 by univariate analysis (p = 0.04), combination chemotherapy only on progression-free survival-2 (p = 0.03). CONCLUSION: Combination chemotherapy and surgery at first recurrence/progression of thymic epithelial tumors were associated with improved survival. DISCUSSION: Although several limitations may have affected this retrospective study on a relatively small number of patients with this rare entity of recurrent thymic malignancies, we suggest the use of combination chemotherapy and surgery at their first recurrence may have contributed to the high overall and progression-free survival observed with adequate follow-up and deserve further investigations in broader retrospective and comparative studies. PMID- 29121776 TI - Psychosocial Benefits of Cooking Interventions: A Systematic Review. AB - OBJECTIVES: Cooking interventions are used in therapeutic and rehabilitative settings; however, little is known about the influence of these interventions on psychosocial outcomes. This systematic review examines the research evidence regarding the influence of cooking interventions on psychosocial outcomes. METHODS: A systematic review of the literature examined peer-reviewed research using Embase, PubMed, CINALH Plus, and PsychInfo with the following search terms: cooking, culinary, baking, food preparation, cookery, occupational therapy, mental health, mood, psychosocial, affect, confidence, self-confidence, self esteem, socialization, and rehabilitation. Inclusion criteria were the following: adults, English, influence of cooking interventions on psychosocial outcomes. PRISMA guidelines were used. RESULTS: The search yielded 377 articles; and 11 ultimately met inclusion criteria and were reviewed. Generally, the quality of the research was weak due to nonrandomization, unvalidated research tools, and small sample sizes. However, inpatient and community-based cooking interventions yielded positive influences on socialization, self-esteem, quality of life, and affect. CONCLUSIONS: Finding benefits to cooking that extend beyond nutritional may be helpful in increasing motivation and frequency of cooking. This review suggests that cooking interventions may positively influence psychosocial outcomes, although this evidence is preliminary and limited. Further qualitative and rigorous quantitative research are needed to identify mechanisms by which cooking interventions may improve psychosocial outcomes. PMID- 29121778 TI - Intraoperative image-guided surgery in neuro-oncology with specific focus on high grade gliomas. AB - Surgery is paramount in glioma management and extent of resection is an independent significant prognostic factor. However, these tumors are often invisible intraoperatively. Hence imaging plays an important role in surgical guidance. A critical literature review, using MEDLINE/PubMed service was carried out. It demonstrated a gross total resection (GTR) with neuronavigation (NNS) of 31-36%, adding 5-aminolevulinic acid or fluorescein fluorescence, or intraoperative ultrasound or MRI improved GTR to 69.1, 84.4, 73.4 and 70% respectively. The differences between the four intraoperative technologies were not statistically significant. Therefore, NNS provided a platform for planning surgical approaches and localization of lesions, however significant brain shift rendered NNS useless without the addition of intraoperative imaging, of which 5 aminolevulinic acid, fluorescein, intraoperative ultrasound and intraoperative MRI significantly improved GTR and outcome of glioma surgery. PMID- 29121779 TI - Image-guided surgery in gynecologic oncology. AB - Image-guided surgery is a relevant way to reduce surgical morbidity and maximize cytoreductive surgery approach especially in ovarian cancer. Sentinel lymph node detection is a promising approach to avoid radical lymph node dissection and is slightly becoming standard in daily practice in endometrial and cervical cancer surgery even if it needs to be evaluated more precisely. Regarding carcinomatosis of ovarian origin, detection and treatment of microscopic disease could be appropriate to avoid local recurrences. Photodiagnosis and photodynamic therapy are innovative techniques that allow to precise limits of excision (fluorescence guided surgery) and to treat microscopic disease. Further developments of those strategies are necessary to become standard diagnosis tools and treatment options. PMID- 29121780 TI - Long noncoding RNA identification in lymphoma. AB - It has been found that long noncoding RNA (lncRNA) are abnormally expressed in lymphoma and play an important role in its pathogenesis. Through the detection and analysis of lncRNA, it was found that lncRNA could be used as an excellent biomarker for the diagnosis and prognosis of cancer. In lymphoma, abnormal lncRNA expression is associated with the patient's clinical characteristics, it can be used to determine the prognosis of the patient and serve as a therapeutic target in the disease. PMID- 29121781 TI - Image-guided radiation therapy: looking beyond what we currently see. PMID- 29121782 TI - Imaging in cutaneous surgery. AB - Skin cancer is the most commonly diagnosed cancer in the USA. Mohs micrographic surgery is a microscopically controlled surgical technique that excises lateral and deep surgical margins while also sparing function and achieving a good cosmetic outcome. Given the increasing incidence in skin cancer worldwide and its associated treatment costs, techniques are being developed to improve the time and cost efficacy of this procedure. The use of noninvasive imaging, both in vivo and ex vivo, has the potential to increase efficiency of diagnosis and surgical management of skin cancers. These devices are useful in delineating lateral and deep tumor margins prior to surgery in vivo as well as to detect residual tumor ex vivo virtually in real time. PMID- 29121783 TI - Trends in Upper Extremity Injuries Presenting to US Emergency Departments. AB - BACKGROUND: The purpose of this study was to identify the incidence of upper extremity injuries presenting to emergency departments (EDs) nationally. METHODS: The Nationwide Emergency Department Sample (NEDS) database was queried using International Classification of Diseases, Ninth Revision (ICD-9) codes specific for hand/wrist injuries to identify national estimates of ED visits. The incidence, mean age, gender, payer mix, hospital type, location (metropolitan vs nonmetropolitan), and geographic region were recorded. RESULTS: In total, 2 791 257 patients with upper extremity injuries and infections were treated at an ED in 2010. In total, 7.4% resulted in hospital admission; 57% of patients were male. Most common age group affected was 18 to 44 years (44%), followed by those less than 17 years (24%) and 45 to 64 years (21%). The 3 most common injury classifications were soft tissue contusions (37%), fractures (27%), and infections (17%). Thirty-seven percent of patients had private insurance, 21% had Medicaid, 19% were uninsured, 13% Medicare, and 10% other. In total, 63% of visits were seen in nonteaching EDs, 80% were seen in metropolitan cities, and 65% of visits were seen at non-trauma-designated hospitals. Geographically, 37% of visits were in the South, 25% Midwest, 20% Northeast, and 18% in the West. CONCLUSIONS: Soft tissue contusion was the most frequent diagnosis. More than half of the patients were male, while the majority of patients were under the age of 44. Ninety-three percent of patients did not require hospital admission. Half had private insurance and the two-thirds of these patients were seen at nonteaching facilities. PMID- 29121784 TI - Electronic patient-reported outcomes: a revolutionary strategy in cancer care. PMID- 29121785 TI - Psychometric Investigation of the Raven's Colored Progressive Matrices Test in a Sample of Preschool Children. AB - The present study investigated the psychometric properties of the Raven's Colored Progressive Matrices (CPM) test in a sample of preschoolers from Brazil ( n = 582; age: mean = 57 months, SD = 7 months; 46% female). We investigated the plausibility of unidimensionality of the items (confirmatory factor analysis) and differential item functioning (DIF) for sex and age (multiple indicators multiple causes method). We tested four unidimensional models and the one with the best fit index was a reduced form of the Raven's CPM. The DIF analysis was carried out with the reduced form of the test. A few items presented DIF (two for sex and one for age), confirming that the Raven's CPM items are mostly measurement invariant. There was no effect of sex on the general factor, but increasing age was associated with higher values of the g factor. Future research should indicate if the reduced form is suitable for evaluating the general ability of preschoolers. PMID- 29121786 TI - Perioperative Morbidity of Open Versus Minimally Invasive Partial Nephrectomy: A Contemporary Analysis of the National Surgical Quality Improvement Program. AB - INTRODUCTION AND OBJECTIVES: In recent years, there has been a shift to minimally invasive partial nephrectomy (MIPN) with the dissemination of robot-assisted technology. However, contemporary data on the comparative morbidity of open partial nephrectomy (OPN) and MIPN are lacking. We, therefore, evaluated the perioperative morbidity of OPN and MIPN using a contemporary national cohort. METHODS: We identified 13,658 patients aged 18 to 89 who underwent PN from 2010 to 2015 in the National Surgical Quality Improvement Program (NSQIP) database, of whom 9018 (66.0%) underwent MIPN. The associations of MIPN with 30-day morbidity were evaluated using logistic regression, adjusted for patient features. RESULTS: Median age at surgery was 60 (interquartile range [IQR] 51, 68) years. Overall, 30-day complications occurred in 6.7% of patients. Compared with OPN, MIPN was associated with lower rates of 30-day complications (4.9% vs 10.1%, p < 0.0001), perioperative blood transfusion (3.8% vs 12.5%, p < 0.0001), prolonged hospitalization (5.6% vs 23.4%, p < 0.0001), readmission (4.4% vs 7.8%, p < 0.0001), reoperation (1.8% vs 3.2%, p < 0.0001), and 30-day mortality (0.3% vs 0.6%, p = 0.001). On multivariable analysis, MIPN was independently associated with a reduced risk of 30-day complications (odds ratio [OR] 0.46, p < 0.0001), perioperative blood transfusion (OR 0.27, p < 0.0001), prolonged hospitalization (OR 0.19, p < 0.0001), readmission (OR 0.59, p < 0.0001), and reoperation (OR 0.57, p < 0.0001). Postoperative complications occurred predominantly early after surgery, whereas hospital readmissions and reoperation occurred at a consistent rate. CONCLUSIONS: In this contemporary national cohort, MIPN was independently associated with reduced rates of 30-day complications, perioperative blood transfusion, prolonged hospitalization, hospital readmission, and reoperation, compared with OPN. PMID- 29121787 TI - Factors associated with reporting results for pulmonary clinical trials in ClinicalTrials.gov. AB - Background/aims The Food and Drug Administration Amendments Act mandates that applicable clinical trials report basic summary results to the ClinicalTrials.gov database within 1 year of trial completion or termination. We aimed to determine the proportion of pulmonary trials reporting basic summary results to ClinicalTrials.gov and assess factors associated with reporting. Methods We identified pulmonary clinical trials subject to the Food and Drug Administration Amendments Act (called highly likely applicable clinical trials) that were completed or terminated between 2008 and 2012 and reported results by September 2013. We estimated the cumulative percentage of applicable clinical trials reporting results by pulmonary disease category. Multivariable Cox regression modeling identified characteristics independently associated with results reporting. Results Of 1450 pulmonary highly likely applicable clinical trials, 380 (26%) examined respiratory neoplasms, 238 (16%) asthma, 175 (12%) chronic obstructive pulmonary disease, and 657 (45%) other respiratory diseases. Most (75%) were pharmaceutical highly likely applicable clinical trials and 71% were industry-funded. Approximately 15% of highly likely applicable clinical trials reported results within 1 year of trial completion, while 55% reported results over the 5-year study period. Earlier phase highly likely applicable clinical trials were less likely to report results compared to phase 4 highly likely applicable clinical trials (phases 1/2 and 2 (adjusted hazard ratio 0.41 (95% confidence interval: 0.31-0.54)), phases 2/3 and 3 (adjusted hazard ratio 0.55 (95% confidence interval: 0.42-0.72)) and phase not applicable (adjusted hazard ratio 0.43 (95% confidence interval: 0.29-0.63)). Pulmonary highly likely applicable clinical trials without Food and Drug Administration oversight were less likely to report results compared with those with oversight (adjusted hazard ratio 0.65 (95% confidence interval: 0.51-0.83)). Conclusion A total of 15% of pulmonary clinical highly likely applicable clinical trials report basic summary results to ClinicalTrials.gov within 1 year of trial completion. Strategies to improve reporting are needed within the pulmonary community. PMID- 29121788 TI - Fluorescence image-guided neurosurgery. AB - Surgery plays an important role in the management of high-grade gliomas (HGG) and imparts significant tumor-free and overall survival advantages. However HGG margins are often invisible, making their gross total resection (GTR) a difficult task. Hence intraoperative technology such as intraoperative fluorescence was a revolutionary discovery. A critical literature review revealed fluorescence improved the GTR of HGG from 36% using standard surgery to 74.5 and 84.4% using aminolevulinic acid (ALA) or fluorescein (FLCN), respectively. The differences between ALA-fluorescence image-guided neurosurgery (FIGS) and FLCN-FIGS in HGG were not statistically significant. However, the cost per quality added life years was US$16,218 and US$3181 for ALA-FIGS and FLCN-FIGS, respectively. Therefore, FIGS provided a reliable intraoperative tumor marker. Both ALA- and FLCN-FIGS significantly improved GTR and were cost-effective. PMID- 29121789 TI - A Descriptive Analysis of End-of-Life Conversations With Long-Term Glioblastoma Survivors. AB - BACKGROUND: Early, high-quality serious illness (SI) conversations are critical for patients with glioblastoma (GBM) but are often mistimed or mishandled. OBJECTIVE: To describe the prevalence, timing, and quality of documented SI conversations and evaluate their focus on patient goals/priorities. DESIGN/PARTICIPANTS: Thirty-three patients with GBM enrolled in the control group of a randomized controlled trial of a communication intervention and were followed for 2 years or until death. At baseline, all patients answered a validated question about preferences for life-extending versus comfort-focused care and completed a Life Priorities Survey about their goals/priorities. In this secondary analysis, retrospective chart review was performed for 18 patients with GBM who died. Documented SI conversations were systematically identified and evaluated using a codebook reflecting 4 domains: prognosis, goals/priorities, end of-life planning, and life-sustaining treatments. Patient goals/priorities were compared to documentation. MEASUREMENTS/RESULTS: At baseline, 16 of 24 patients preferred life-extending care. In the Life Priorities Survey, goals/priorities most frequently ranked among the top 3 were "Live as long as possible," "Be mentally aware," "Provide support for family," "Be independent," and "Be at peace." Fifteen of 18 patients had at least 1 documented SI conversation (range: 1-4). Median timing of the first documented SI conversation was 84 days before death (range: 29-231; interquartile range: 46-119). Fifteen patients had documentation about end-of-life planning, with "hospice" and "palliative care" most frequently documented. Five of 18 patients had documentation about their goals. CONCLUSION: Patients with GBM had multiple goals/priorities with potential treatment implications, but documentation showed SI conversations occurred relatively late and infrequently reflected patient goals/priorities. PMID- 29121790 TI - Knowledge, Skills, and Attitudes Regarding the Use of Medical Cannabis in the Hospice Population: An Educational Intervention. AB - BACKGROUND: Currently, 28 states and the District of Columbia have legalized cannabis for medical use despite its remaining Schedule I federally. Benefits of medical cannabis (MC) have been demonstrated in nausea/vomiting associated with chemotherapy, cachexia associated with HIV/AIDS, and certain types of neuropathic pain. However, it is unclear how comfortable hospice providers are with the concept of MC. OBJECTIVE: The aim of this study is to determine changes in knowledge, self-perceived skills, and attitudes (KSA) of hospice providers regarding MC after an online educational intervention. METHODS: The educational intervention consisted of 3 learning modules covering information from 6 learning domains. Participants took a pre- and postcourse survey to assess changes in KSA. Participant demographics were analyzed using descriptive statistics. To detect any differences between pre- and postsurvey answers, a paired t test was used to reduce intersubject variability. RESULTS: Attitudes about the importance of cannabis knowledge were overall positive and did not change significantly after the intervention (N = 94). Both self-perceived skills and knowledge increased significantly, with providers reporting more positive skills, and >75% of respondents answering questions correctly after the intervention. There was a significant difference in attitudes in all domains in the postsurvey between participants who have practiced in hospice <3 years or >=4 years, but no difference in perceived skills or knowledge. CONCLUSION: Providers' attitudes regarding the importance of MC knowledge were strong and the same before and after. Both the self-perception of skills and direct knowledge were significantly increased after the educational intervention. PMID- 29121791 TI - Unexpected Survivors: Children With Life-Limiting Conditions of Uncertain Prognosis. AB - OBJECTIVE: Prognostication of survival is difficult in children with life limiting illnesses because of the rarity of these conditions and technological advances improving survival. The objective of this article is to describe the characteristics of children with life-limiting illnesses who survived longer than the expectations of health-care providers. STUDY DESIGN: This is a retrospective cohort study conducted in a tertiary-care children's hospital in North Carolina. "Unexpected survivors," defined as children who survived despite a prognosis of imminent death or significantly longer than prognosticated by health-care providers, were identified from among 349 children enrolled in a pediatric palliative care program between March 2008 and October 2012. Children's clinical courses were followed until September 2015 or their death. RESULTS: Eighteen (5%) children were identified as unexpected survivors; 17 (10 girls and 7 boys) were included. Congenital anomalies were the most common diagnoses. Neonatal intensive care unit was the most frequent setting of prognostication. Thirteen children used some form of medical technology at the time of prognostication. Eleven children received hospice services. Eight died during the observation period but survived significantly longer than expected (median survival time 1.5 years), and 9 survived beyond the observation period (median survival time 5.9 years). CONCLUSIONS: Unexpected survivors are a small group of children with life limiting conditions. Clinicians should be aware of the possibility of prognostic inaccuracy, able to communicate prognostic uncertainty to parents, and engage supportive services when prognosticating poor survival. Prospective studies are needed to understand outcomes of children with life-limiting illnesses of uncertain prognosis. PMID- 29121792 TI - Are You Covered? Associations Between Patient Protection and Affordable Care Act Knowledge and Preventive Reproductive Service Use. AB - PURPOSE: Sexual and reproductive health conditions (eg, infections, cancers) represent public health concerns for American women. The present study examined how knowledge of the Patient Protection and Affordable Care Act (PPACA) relates to receipt of preventive reproductive health services among women. DESIGN: Cross sectional online survey. SETTING: Online questionnaires were completed via Amazon Mechanical Turk, a crowdsourcing website where individuals complete web-based tasks for compensation. PARTICIPANTS: Cisgendered women aged 18 to 44 years (N = 1083) from across the United States. MEASURES: Participants completed online questionnaires assessing demographics, insurance status, preventive service use, and knowledge of PPACA provisions. ANALYSIS: Chi-squares showed that receipt of well-woman, pelvic, and breast examinations, as well as pap smears, was related to insurance coverage, with those not having coverage at all during the previous year having significantly lower rates of use. Hierarchical logistic regressions determined the independent relationship between PPACA knowledge and use of health services after controlling for demographic factors and insurance status. RESULTS: Knowledge of PPACA provisions was associated with receiving well-woman, pelvic, and breast examinations, human papillomavirus vaccination, and sexually transmitted infections testing, after controlling for these factors. Results indicate that expanding knowledge about health-care legislation may be beneficial in increasing preventive reproductive health service use among women. CONCLUSION: Current findings provide support for increasing resources for outreach and education of the general population about the provisions and benefits of health care legislation, as well as personal health coverage plans. PMID- 29121793 TI - Total Sugar-Sweetened Beverage Intake Among US Adults Was Lower When Measured Using a 1-Question Versus 4-Question Screener. AB - PURPOSE: To compare the performance of a 1-question survey screener measuring total sugar-sweetened beverage (SSB) intake to a screener measuring SSB types separately using 4 questions. DESIGN: Cross-sectional. SETTING: Web-based 2014 SummerStyles survey. PARTICIPANTS: A total of 4167 US adults (>=18 years). MEASURES: Frequency of SSB intake measured using a 1-question screener was compared to frequency using a 4-question screener (regular soda, fruit drinks, sports/energy drinks, sweetened coffee/tea). SSB intake (number of time/day) was categorized as 0, >0 to <1, and >=1 time/day; difference in mean intake was calculated between 4 questions versus 1. ANALYSIS: Paired t tests were used, and agreement was evaluated using weighted kappa and Lin's concordance correlation coefficient (CCC). RESULTS: Mean SSB intake was 1.7 (95% confidence interval [CI]: 1.65-1.79) times/day using 4 questions and 0.6 (95% CI: 0.56-0.62) times/day using 1 question ( P < .001). Intake frequency based on 4 questions versus 1 was 16.0% versus 38.5% for 0 time/day, 15.6% versus 42.5% for >0 to <1 time/day, and 68.4% versus 18.9% for >=1 time/day. There was fair agreement for the 3 SSB intake categories (kappa: .27) and poor absolute agreement between the 2 continuous measures (Lin's CCC: 0.31). CONCLUSION: Daily SSB intake was significantly lower using a 1-question screener versus a 4-question screener. Researchers should assess SSB types separately or consider that daily SSB intake is likely underestimated with 1 question. PMID- 29121794 TI - What Factors Explain Bicycling and Walking for Commuting by ELSA-Brasil Participants? AB - PURPOSE: To analyze the factors associated with commuting by bicycling and walking in adult participants from ELSA-Brasil (Longitudinal Study of Adult Health). DESIGN: Cross-sectional. SETTING: Six teaching/research institutions throughout Brazil. PARTICIPANTS: A total of 15 105 civil servants. MEASURES: Commuting by bicycling and walking was analyzed using the long-form International Physical Activity Questionnaire. ANALYSIS: A hierarchical model containing possible factors associated with commuting by bicycling and walking was constructed. Crude and adjusted odds ratios were calculated using multinomial logistic regression. RESULTS: Considering the 2 forms of commuting, 66% of the participants were being considered inactive or insufficiently active. In women, being "heavier," feeling unsafe practicing physical activity, and being a former smoker were factors negatively associated with commuting by bicycling and walking. In men, active commuting was less common among those who were overweight or had abdominal obesity, those with a negative perception of safety, and those reporting that there was nowhere suitable in the neighborhood to practice physical activity. CONCLUSION: Obesity and negative perceptions in the neighborhood are associated with inactive or insufficiently active commuting. The relevance of this finding for public health is reinforce developing policies aimed at promoting health in Brazil and in other countries with similar characteristics. PMID- 29121795 TI - Berberine Ameliorates Diabetic Neuropathy: TRPV1 Modulation by PKC Pathway. AB - In recent years, berberine has increasingly become a topic of research as a treatment for diabetes due to its repair function, which recovers damaged pancreatic beta cells. However, it is the complications of diabetes that seriously affect patients' life quality and longevity, among which diabetic neuropathy and the consequent acute pain are the most common. In this study, we established STZ-induced diabetic models to observe whether berberine, a main constitute of Coptis chinensis Franch which has shown good hypoglycemic effects, could relieve diabetes-induced pain and explored its possible mechanism in rats and mice. Behavior assays showed increasing mechanical allodynia and thermal hyperalgesia thresholds by the Von Frey test and tail flick test during the treatment of berberine. It was found that the administration of berberine (20, 60 mg/kg; 30, 90 mg/kg) suppressed the expression of PKCepsilon and TRPV1 which could be activated by hyperglycemia-induced inflammatory reaction. Our results also presented its capability to reduce the over expression of TNF-[Formula: see text] in diabetic rats and mice. TNF-[Formula: see text] is an inflammatory cytokine, which is closely related to diabetic peripheral neuropathy (DPN). Consequently, we supposed that berberine exerts its therapeutic effects in part by suppressing the inflammatory process and blocking the PKC pathway to inhibit TRPV1 activation, which damages neurons and causes diabetic pain. PMID- 29121796 TI - Absorption Properties of Luteolin and Apigenin in Genkwa Flos Using In Situ Single-Pass Intestinal Perfusion System in the Rat. AB - The flower bud of Daphne genkwa (Genkwa Flos) is a commonly used herbal medicine in Asian countries. Luteolin and apigenin are two recognized active flavonoids in Genkwa Flos. The aim of this study was to investigate the intestinal absorption mechanisms of Genkwa Flos flavonoids using in situ single-pass intestinal perfusion rat model. Using HPLC, we determined its major effective flavonoids luteolin, apigenin, as well as, hydroxygenkwanin and genkwanin in biological samples. The intestinal absorption mechanisms of the total flavonoids in Genkwa Flos (TFG) were investigated using in situ single-pass intestinal perfusion rat model. Comparing the TFG absorption rate in different intestinal segments, data showed that the small intestine absorption was significantly higher than that of the colon ([Formula: see text]). Compared with duodenum and ileum, the jejunum was the best small intestinal site for TFG absorption. The high TFG concentration (61.48[Formula: see text][Formula: see text]g/ml) yielded the highest permeability ([Formula: see text]). Subsequently, three membrane protein inhibitors (verapamil, pantoprazole and probenecid) were used to explore the TFG absorption pathways. Data showed probenecid, a multidrug resistance protein (or MRP) inhibitor, effectively enhanced the TFG absorption ([Formula: see text]). Furthermore, by comparing commonly used natural absorption enhancers on TFG, it was observed that camphor was the most effective. In Situ single-pass intestinal perfusion experiment shows that TFG absorption is much higher in the small intestine than in the colon, and the TFG is absorbed mainly via an active transport pathway with MRP-mediated efflux mechanism. Camphor obviously enhanced the TFG absorption, and this could be an effective TFG formulation preparation method to increase clinical effectiveness after Genkwa Flos administration. Our study elucidated the TFG absorption mechanisms, and provided new information for its formulation preparation. PMID- 29121797 TI - Effectiveness of Acupuncture and Electroacupuncture for Chronic Neck Pain: A Systematic Review and Meta-Analysis. AB - The aim of this systematic review was to assess evidence from randomized controlled trials (RCTs) on the effectiveness and safety of acupuncture and electroacupuncture in patients with chronic neck pain. We searched nine databases including Chinese, Japanese and Korean databases through 30 July 2016. The participants were adults with chronic neck pain and were treated with acupuncture or electroacupuncture. Eligible trials were those with intervention groups receiving acupuncture and electroacupuncture with or without active control, and control groups receiving other conventional treatments such as physical therapy or medication. Outcomes included pain intensity, disability, quality of life (QoL) and adverse effects. For statistical pooling, the standardized mean difference (SMD) and its 95% confidence interval (CI) were calculated using a fixed-effects model. Sixteen RCTs were selected. The comparison of the sole acupuncture group and the active control group did not come out with a significant difference in pain (SMD 0.24, 95% CI [Formula: see text]0.27-0.75), disability (SMD 0.51, 95% CI [Formula: see text]0.01-1.02), or QoL (SMD [Formula: see text]0.37, 95% CI [Formula: see text]1.09-0.35), showing a similar effectiveness of acupuncture with active control. When acupuncture was added into the control group, the acupuncture add-on group showed significantly higher relief of pain in studies with unclear allocation concealment (SMD [Formula: see text]1.78, 95% CI [Formula: see text]2.08-[Formula: see text]1.48), but did not show significant relief of pain in studies with good allocation concealment (SMD [Formula: see text]0.07, 95% CI [Formula: see text]0.26-0.12). Significant relief of pain was observed when the sole electroacupuncture group was compared to the control group or electroacupuncture was added onto the active control group, but a lot of the results were evaluated to have low level of evidence, making it difficult to draw clear conclusions. In the result reporting adverse effects, no serious outcome of adverse event was confirmed. Acupuncture and conventional medicine for chronic neck pain have similar effectiveness on pain and disability when compared solely between the two of them. When acupuncture was added onto conventional treatment it relieved pain better, and electroacupuncture relieved pain even more. It is difficult to draw conclusion because the included studies have a high risk of bias and imprecision. Therefore better designed large-scale studies are needed in the future. PMID- 29121798 TI - Angelica sinensis Exerts Angiogenic and Anti-apoptotic Effects Against Cerebral Ischemia-Reperfusion Injury by Activating p38MAPK/HIF-1[Formula: see text]/VEGF-A Signaling in Rats. AB - This study evaluated the effects of Angelica sinensis extract [Dang Gui (DG)] administered before 60[Formula: see text]min of middle cerebral artery occlusion followed by 3[Formula: see text]d of reperfusion and investigated the involvement of mitogen-activated protein kinase (MAPK)/hypoxia-inducible factor (HIF) 1[Formula: see text] signaling in the cortical ischemic penumbra. DG was intraperitoneally administered at a dose of 0.25[Formula: see text]g/kg (DG 0.25g), 0.5[Formula: see text]g/kg (DG-0.5g), or 1[Formula: see text]g/kg (DG-1g) 30[Formula: see text]min before the onset of cerebral ischemia. Our study results revealed that DG-0.5g and DG-1g pretreatment effectively attenuated cerebral infarct and improved neurological deficits. DG-0.5g and DG-1g pretreatment significantly downregulated glial fibrillary acidic protein (GFAP), cytochrome c, and cleaved caspase-3 expression and upregulated phospho-p38 MAPK (p-p38 MAPK)/p38 MAPK, phospho-cAMP response element-binding protein (p-CREB)/CREB, cytosolic and mitochondrial phospho-Bad (p-Bad)/Bad ratios, and HIF-1[Formula: see text], vascular endothelial growth factor-A (VEGF-A), phospho-90 kDa ribosomal S6 kinase (p-p90RSK), and von Willebrand factor (vWF) expression in the cortical ischemic penumbra. Pretreatment with SB203580, a p38 MAPK inhibitor, dramatically abrogated the upregulating effects of DG-1g on p-p38 MAPK/p38 MAPK, p-CREB/CREB, and p-Bad/Bad ratios and HIF-1[Formula: see text], VEGF-A, and vWF expression and the downregulating effects of DG-1g on GFAP, cytochrome c, cleaved caspase-3, and cerebral infarction. DG-0.5g and DG-1g pretreatment provided neuroprotective effects against astrocyte-mediated cerebral infarction by activating angiogenic and anti-apoptotic signaling. Moreover, the angiogenic and anti-apoptotic effects of DG pretreatment can be attributed to the activation of p38 MAPK/HIF-1[Formula: see text]/VEGF-A/vWF signaling and p38 MAPK/HIF 1[Formula: see text]/VEGF-A/p-Bad-related regulation of cytochrome c/caspase-3 signaling, respectively, in the cortical ischemic penumbra 3[Formula: see text]d after reperfusion. PMID- 29121799 TI - Pueraria lobate Inhibits RANKL-Mediated Osteoclastogenesis Via Downregulation of CREB/PGC1beta/c-Fos/NFATc1 Signaling. AB - Puerariae radix, the dried root of Pueraria lobate Ohwi, is known to prevent bone loss in ovariectomized mice; however, the precise molecular mechanisms are not understood. In this study, we investigated the effects and underlying mechanisms of action of Puerariae radix extract (PRE) on receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis. PRE dose-dependently inhibited osteoclast differentiation and formation, decreased the bone-resorbing activity of osteoclasts, and downregulated the expression of osteoclast differentiation marker genes. The expression of osteoclastogenic factors produced by PRE-treated osteoblasts such as RANKL, macrophage colony-stimulating factor (M-CSF), and osteoprotegerin (OPG) was comparable to that of untreated (control) cells. However, the formation of osteoclasts via bone marrow cell and calvaria-derived osteoblast co-cultures was suppressed by PRE treatment. Therefore, the inhibitory effects of PRE on osteoclastogenesis clearly targeted osteoclasts, but not osteoblasts. PRE treatment considerably reduced RANKL-induced mitogen-activated protein kinases (MAPKs) activity, especially c-Jun N-terminal kinase, in osteoclast precursor cells. In addition, PRE markedly suppressed cAMP response element-binding protein (CREB) activation and the induction of peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC1beta), which stimulate osteoclastogenesis - an effect that was not observed for puerarin and 17-beta estradiol. Finally, PRE treatment significantly repressed the expression of c-Fos and the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is a master transcription factor for osteoclastogenesis in vitro and in vivo. Overall, these results strongly suggest that PRE is an effective inhibitor of RANKL-induced osteoclastogenesis and may be a potent therapeutic agent for bone-related diseases such as osteoporosis, rheumatoid arthritis, and periodontitis. PMID- 29121800 TI - Protective Effects of Ginsenosides on 17[Formula: see text]-Ethynyelstradiol Induced Intrahepatic Cholestasis via Anti-Oxidative and Anti-Inflammatory Mechanisms in Rats. AB - The present study was designed to assess the effects and potential mechanisms of ginsenosides on 17[Formula: see text]-ethynyelstradiol (EE)-induced intrahepatic cholestasis (IC). Ginsenoside at doses of 30, 100, 300[Formula: see text]mg/kg body weight was intragastrically (i.g.) given to rats for 5 days to examine the effect on EE-induced IC. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bile acid (TBA) were measured. Hepatic malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were determined. Protein expression of proinflammatory cytokines TNF-[Formula: see text], IL-6 and IL-1[Formula: see text] was analyzed by immunohistochemistry and Western blot. Results indicated that ginsenosides remarkably prevented EE-induced increase in the serum levels of AST, ALT, ALP and TBA. Moreover, the elevation of hepatic MDA content induced by EE was significantly reduced, while hepatic SOD activities were significantly increased when treated with ginsenosides. Histopathology of the liver tissue showed that pathological injuries were relieved after treatment with ginsenosides. In addition, treatment with ginsenosides could significantly downregulate the protein expression of TNF-[Formula: see text], IL-6 and IL-1[Formula: see text] compared with EE group. These findings indicate that ginsenosides exert the hepatoprotective effect on EE-induced intrahepatic cholestasis in rats, and this protection might be attributed to the attenuation of oxidative stress and inflammation. PMID- 29121801 TI - Usefulness of Chinese Herbal Medicines as Host-Directed Therapeutics against Mycobacterial Infections: A Review. AB - The high incidence of tuberculosis (TB) in developing countries, the resurgence of TB in industrialized countries, and the worldwide increase in the prevalence of Mycobacterium avium complex infections have prompted the quest for new antimycobacterial drugs. However, the development of such chemotherapeutics is currently making very slow progress. It therefore appears that devising improved administration protocols for clinical treatment against intractable mycobacteriosis using existing chemotherapeutics is more practical than awaiting the development of novel antimycobacterial drugs. The modulation of host immune responses using immunoadjunctive agents may increase the efficacy of antimicrobial treatment against mycobacteriosis. Particularly, the mild and long term up-regulation of host immune reactions against mycobacterial pathogens using Chinese herbal medicines (CHMs) may be beneficial for immunoadjunctive therapy. This review focuses on the current status and future prospects regarding the development of CHMs that can be useful for the clinical control of intractable mycobacterial infections. PMID- 29121802 TI - Hispolon Suppresses LPS- or LTA-Induced iNOS/NO Production and Apoptosis in BV-2 Microglial Cells. AB - Hispolon (HIS) is an active polyphenol compound derived from Phellinus linteus (Berkeley & Curtis), and our previous study showed that HIS effectively inhibited inflammatory responses in macrophages [Yang, L.Y., S.C. Shen, K.T. Cheng, G.V. Subbaraju, C.C. Chien and Y.C. Chen. Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages. J. Ethnopharmacol. 156: 61-72, 2014]; however, its effect on neuronal inflammation is still undefined. In this study, HIS concentration- and time-dependently inhibited lipopolysaccharide (LPS)- and lipoteichoic acid (LTA) induced inducible nitric oxide (NO) synthase (iNOS)/NO production with increased heme oxygenase (HO)-1 proteins in BV-2 microglial cells. Accordingly, HIS protected BV-2 cells from LPS- or LTA-induced apoptosis, characterized by decreased DNA ladder formation, and caspase-3 and poly(ADP ribose) polymerase (PARP) protein cleavage in BV-2 cells. Similarly, the NOS inhibitor, N-nitro-L arginine methyl ester (NAME), inhibited LPS- or LTA-induced apoptosis of BV-2 cells, but neither NAME nor HIS showed any inhibition of NO production or cell death induced by the NO donor, sodium nitroprusside (SNP), indicating the involvement of NO in the inflammatory apoptosis of microglial cells. Activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-[Formula: see text]B contributed to LPS- or LTA-induced iNOS/NO production and apoptosis of BV-2 cells, and that was suppressed by HIS. Additionally, HIS possesses activity to induce HO-1 protein expression via activation of extracellular signal-regulated kinase (ERK) in BV-2 cells, and application of the HO inhibitor, tin protoporphyrin (SnPP), or knockdown of HO-1 protein by HO-1 small interfering (si)RNA significantly reversed HIS inhibition of NO production and cell death in BV-2 cells stimulated by LPS. Results of an analysis of the effects of HIS and two structurally related chemicals, i.e. dehydroxy-HIS (D-HIS) and HIS-methyl ester (HIS-ME), showed that HIS expressed the most potent inhibitory effects on iNOS/NO production, JNK activation, and apoptosis in BV-2 microglial cells activated by LPS with increased HO-1 protein expression. Overall these results suggested that HIS possesses inhibitory activity against LPS- or LTA-induced inflammatory responses including iNOS/NO production and apoptosis in BV-2 microglial cells and that the mechanisms involve upregulation of the HO-1 protein and downregulation of JNK/NF-[Formula: see text]B activation. A critical role of hydroxyl at position C3 in the anti-inflammatory actions of HIS against activated BV-2 microglial cells was suggested. PMID- 29121803 TI - Carnosol-Induced ROS Inhibits Cell Viability of Human Osteosarcoma by Apoptosis and Autophagy. AB - Carnosol is an anti-oxidant and anti-inflammatory compound from rosemary. In this paper, we investigated antitumor activity of carnosol against human osteosarcoma cells. We found the viability of human osteosarcoma MG-63 cells was significantly decreased in the presence of carnosol (cell viabilities: 17.2% for 20[Formula: see text]MUg/ml of CS vs. 100% for control, [Formula: see text]). Carnosol induced apoptosis and cell cycle arrest in a dose-dependent manner in MG-63 cells. Furthermore, carnosol exposure increased the levels of reactive oxygen species (ROS). The pre-treatment of NAC, the ROS scavenger, blocked the inhibition of cell viability in the carnosol treatment, indicating that ROS is important in the antiproliferation effect. Moreover, we demonstrated that carnosol significantly induced autophagy and co-administration of autophagy inhibitor reduced the antiproliferating effect of carnosol. This result exhibited the cytotoxic effect of autophagy induced by carnosol in MG-63 cells. Interestingly, the treatment of NAC decreased carnosol-induced autophagy. Collectively, these data indicate that carnosol suppresses the viability of human osteosarcoma MG-63 cells by upregulation of apoptosis and autophagy, which are both mediated by ROS. Thus, carnosol might serve as a potential therapeutic agent against osteosarcoma. PMID- 29121804 TI - Melaleuca alternifolia Induces Heme Oxygenase-1 Expression in Murine RAW264.7 Cells through Activation of the Nrf2-ARE Pathway. AB - Melaleuca alternifolia concentrate (MAC) is the refined essential oil of the Australian native plant Melaleuca alternifolia. MAC has been reported to suppress the production of pro-inflammatory cytokines in both murine RAW264.7 macrophages and human monocytes stimulated with lipopolysaccharide (LPS). However, the mechanisms involved in this effect remain unclear. This study aims to delineate the molecular mechanisms that drive the anti-inflammatory activity of MAC and its active component, terpinen-4-ol, in macrophages. The effects of MAC on RAW264.7 cells were studied using western blotting, real-time PCR, an electrophoretic mobility shift assay (EMSA), and NF-[Formula: see text]B luciferase reporter assays. Our results showed that MAC significantly increased both the mRNA and protein levels of heme oxygenase-1 (HO-1) via p38 and JNK MAPK activation. In addition, we showed that MAC significantly increased the activation and nuclear translocation of NF-E2-related factor 2 (Nrf2), a key transcription factor regulating HO-1 induction. MAC was also associated with significant inhibition of iNOS expression, NO production, and NF-[Formula: see text]B activation. HO-1 was required for these anti-inflammatory effects as tin protoporphyrin IX (SnPPIX), an HO-1 inhibitor, abolished the effects of MAC on LPS-induced iNOS, NO, and NF [Formula: see text]B activation. Our results indicate that MAC induces HO-1 expression in murine macrophages via the p38 MAPK and JNK pathways and that this induction is required for its anti-inflammatory activity. PMID- 29121805 TI - Prostate Cancer Xenograft Inhibitory Activity and Pharmacokinetics of Decursinol, a Metabolite of Angelica gigas Pyranocoumarins, in Mouse Models. AB - We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice. Since we and others have shown in rodents and humans that D and DA rapidly and extensively convert to decursinol, here we tested whether decursinol might be an in vivo active compound for suppressing xenograft growth of human prostate cancer cells expressing AR. In SCID-NSG mice carrying subcutaneously inoculated human LNCaP/AR-Luc cells overexpressing the wild type AR, we compared the efficacy of 4.5[Formula: see text]mg decursinol per mouse with equi-molar dose of 6[Formula: see text]mg D/DA per mouse. The result showed that decursinol decreased xenograft tumor growth by 75% and the lung metastasis, whereas D/DA exerted a much less effect. Measurement of plasma decursinol concentration, at 3[Formula: see text]h after the last dose of respective dosing regimen, showed higher circulating level in the decursinol-treated NSG mice than in the D/DA-treated mice. In a subsequent single-dose pharmacokinetic experiment, decursinol dosing led to 3.7-fold area under curve (AUC) of plasma decursinol over that achieved by equi-molar D/DA dosing. PK advantage notwithstanding, decursinol represents an active compound to exert in vivo prostate cancer growth and metastasis inhibitory activity in the preclinical model. PMID- 29121807 TI - Could gonadotropin-releasing hormone analogs be helpful in the treatment of triple-negative breast cancer? AB - AIM: Treatment of triple-negative breast cancer (TNBC) imposes great challenges, due to a lack of molecular targets. While use of gonadotropin-releasing hormone (GnRH) analogs has been validated in ER-positive breast cancer, this option has not been investigated in TNBC, even though a significant portion of these tumors upregulate GnRH receptors. We performed a meta-analysis of the literature to evaluate the effect of GnRH analogs in TNBC. METHODS: Four studies were included in this study. RESULTS: We detected a non-significant improvement in overall survival with GnRH analogs, while progression-free survival was unchanged. DISCUSSION: The majority of the trials evaluated in this analysis were designed to test efficacy of GnRH analogs in preventing premature ovarian failure. This may represent a limitation of our study as these trials were not specifically designed to detect differences in survival outcome measures. CONCLUSION: Our results suggest that GnRH analogs may be useful as a targeted therapy in TNBC. Randomized prospective clinical trials are needed to investigate this hypothesis in the clinic. PMID- 29121808 TI - The Prognostic Value of Lipoprotein-Associated Phospholipase A2 in the Long-Term Care of Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention. AB - Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor for cardiovascular disease. Accordingly, studies from many countries around the world have shown an association between Lp-PLA2 and cardiovascular events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), but this association has not been documented among the Chinese. The aim of this study was to assess the use of Lp-PLA2 as a useful marker for predicting the long-term prognosis of Chinese patients with ACS undergoing PCI. A total of 651 consecutive patients undergoing PCI between September 2013 and January 2015 were divided into 2 groups: the high Lp-PLA2 group (n = 262, Lp-PLA2 > 138 nmol/L) and the low Lp-PLA2 group (n = 389, Lp-PLA2 <= 138 nmol/L). The end point was all-cause mortality and rehospitalization. The median follow-up was 24 months. Multivariate analysis showed that high Lp-PLA2 was an independent predictor of all-cause mortality and rehospitalization (hazard ratio: 1.429, 95% confidence interval [CI]: 1.411-1.448; P < .05). The Lp-PLA2 had good accuracy for predicting all-cause mortality and rehospitalization among patients with ACS undergoing PCI (area under the receiver-operating characteristic curve: 0.858, 95% CI: 0.819-0.898; P < .05), and a good correlation with the Global Registry of Acute Coronary Event score ( r = 0.525, P < .05). This study provided evidence that Lp-PLA2 could predict all-cause mortality and rehospitalization risk among patients with ACS undergoing PCI. PMID- 29121806 TI - Les soins medicaux de jeunes hommes et de jeunes femmes qui decedent par suicide. AB - OBJECTIVE: Prior year medical care was compared among youth dying by suicide to their peers. Effect modification of these associations by age or place of residency (rural versus larger community sizes) was examined in a large, medically insured population. METHOD: This population-based case control study used data from the Office of the Chief Coroner in Ontario, Canada, linked to health care administrative data to examine associations between medical care for mental health or other reasons (versus no medical care) and suicide. Decedents ( n = 1203 males and n = 454 females) were youth (aged 10 to 25 years) who died by suicide in Ontario between April 2003 and March 2014, inclusive. Peers of the same ages were frequency matched to decedents on sex and place of residency. Logistic regression was used to calculate odds ratios and 95% confidence intervals and to test effect modification. RESULTS: Associations with mental health care were stronger in decedents than peers with a gradation of care (i.e., outpatient only, emergency department [ED], inpatient care) in both sexes. However, these associations were weaker among youth living in rural communities. Furthermore, older males (aged 18 to 25 years) were less likely than younger males (aged 10 to 17 years) to access the ED (ambulatory care only). This decrease was observed in rural and larger communities alongside no increase in medical care for other reasons. CONCLUSIONS: Geographical and age-related barriers to mental health care exist for youth who die by suicide. Preventive efforts can address these barriers, intervening early and integrating services, including the ED. PMID- 29121809 TI - Further Investigations of the Effects of Anti-beta2GP1 Antibodies on Collagen Induced Platelet Aggregation. AB - Anti-beta-2-glycoprotein 1 (anti-beta2GP1) antibodies are associated with increased thrombotic risk in patients with autoimmune disease. There is conflicting evidence on the effects of anti-beta2GP1 antibodies on platelets, with both enhanced and inhibited aggregation previously reported. However, previous studies did not include isotype antibodies to ensure the observed effects were due to anti-beta2GP1 antibodies. The aims of this study were to (1) investigate the effects of anti-beta2GP1 antibodies on collagen-induced platelet aggregation in parallel with negative control (buffer normal saline) and isotype control antibodies and (2) determine the lupus anticoagulant (LA) activity of anti-beta2GP1 antibodies used. Three animal-derived anti-human-beta2GP1 antibodies (1.25, 2.5, and 5 MUg/mL) incubated with healthy platelet-rich plasma were activated by collagen (2.5 MUg/mL). Each anti-beta2GP1 antibody demonstrated the inhibition of aggregation compared to negative control, but not to isotype control. No anti-beta2GP1 antibody demonstrated LA activity, suggesting they were probably nonpathological. This study highlights both negative and isotype control markers are important to validate the effects of anti-beta2GP1 antibodies. Assays to measure anti-domain I-beta2GP1 antibodies are recommended to be used in conjunction with functional measures to further investigate the effects of anti beta2GP1 antibodies. PMID- 29121810 TI - The Relationship Between Grandiosity, Psychopathy, and Narcissism in an Offender Sample. AB - Clinical accounts suggest grandiosity is an important characteristic of both psychopathy and narcissism. This study examined the relationships between grandiosity and each of these personality disorder syndromes, using a novel index, namely the Grandiosity Index. Seventy-five incarcerated males completed clinical interviews of psychopathy and narcissism and a self-report inventory of narcissism and were rated on interpersonal measures of psychopathy and narcissism. Trained research assistants rated participants on the Grandiosity Index. Analyses provided preliminary evidence of construct validity for the index. Scores on the Grandiosity Index were significantly correlated with scores on both clinical and interpersonal measures of psychopathy and narcissism and with self-reported narcissism. Regressions demonstrated that the Grandiosity Index explained substantial unique variance in psychopathy after controlling for scores on narcissism. This study demonstrates that grandiose features are associated uniquely with clinical ratings of psychopathy, though not significantly more with psychopathy than with narcissism. PMID- 29121811 TI - Evidence for Two Levels of Intimate Partner Violence and Aggression Among Incarcerated Young Male Violent Offenders. AB - Furthering knowledge of the subset of incarcerated partner violent offenders distinguished by aggression, anger, and hostility is relevant, as these offenders are guilty of the more severe kinds of intimate partner violence (IPV). Our aim was to identify groups with different patterns of IPV among convicted young Swedish male offenders, using data from the Development of Aggressive Antisocial Behavior Study, including 171 young men (18-25 years) convicted of a violent crime. Cluster analysis was used to identify different clusters based on amount and severity of IPV in combination with measures of anger, hostility, aggression, and psychopathic personality traits. The results point to an association between antisocial development, criminal history, the severity of current crime, and measures of aggression, hostility, and partner abuse. The cluster defined by higher levels of partner abuse and aggression was significantly associated with early onset conduct disorder. PMID- 29121812 TI - Risk Assessment Interviews: Exploring the Perspectives of Psychologists and Indeterminate Sentenced Prisoners in the United Kingdom. AB - This study explores the forensic risk assessment interview from the perspectives of qualified prison-based psychologists and indeterminate sentenced prisoners in the United Kingdom. It focuses on the psychologist-prisoner relationship in the interview context. Twenty-one in-depth individual interviews were conducted with psychologists and prisoners and analysed using Grounded Theory methods. The analysis identified the following categories reflecting participants' descriptions of risk assessment interviews: "Emphasising Clarity and Transparency," "Collaborative Engagement," "Making a Respectful, Boundaried yet Human Connection," "Respecting Individuality," and "Having a Purposeful Conversation." Analysis demonstrated that these categories of meaning reflected the broader notion of risk assessment interviewing as "A Difficult Balancing Act." The views of prisoners and psychologists about the risk assessment interview were remarkably similar and provide some direction and guidance for practitioners navigating this challenging but essential aspect of forensic psychological work. PMID- 29121813 TI - Long-term outcomes after arthroscopic single-bundle reconstruction of the posterior cruciate ligament: A 7-year follow-up study. AB - Objective Arthroscopy is the most popular technique in posterior cruciate ligament (PCL) reconstruction surgery. However, no consensus on long-term outcomes after arthroscopic PCL reconstruction has been reached. This study was performed to evaluate the long-term outcomes after arthroscopic autologous hamstring or allogeneic tendon single-bundle reconstruction of the PCL. Methods Fifty-eight patients who underwent arthroscopic PCL reconstruction in Anhui, China from 2007 to 2009 were included. The follow-up period ranged from 56 to 83 months. During the follow-up, the Lysholm knee score and Tegner activity score were used to assess knee function. The KT-2000 arthrometer (MEDmetric Corp., San Diego, CA, USA) was used to assess the stability of the reconstructed PCL. Results The mean Lysholm score, mean Tegner score, and mean forward and backward displacements were not significantly different between the final follow-up and 1 year after the surgery. Additionally, no significant differences were observed in any of the above-mentioned parameters between autologous and allogeneic reconstruction at the final follow-up. Conclusion Both autologous and allogeneic reconstruction had few complications and satisfactory long-term outcomes. PMID- 29121814 TI - Sex Difference in Homicide: Comparing Male and Female Violent Crimes in Korea. AB - The comparison of the South Korean male and female homicide offenders' characteristics and crime scene behaviours is presented in this study. A total of 537 cases of homicide offenders prosecuted in Korea between 2006 and 2010 were analyzed in terms of offenders' characteristics, victim-offender interaction, places of crime, and crime scene actions. Significant differences between male and female offenders were revealed in prior criminal history, offenders' personal characteristics, choice of victim, crime scene behaviours during and after the homicide, and choice of weapon. The parallel with the gender differences in homicides found in Western countries is discussed as well as the possible explanations for the gender-related characteristics found in this study. PMID- 29121816 TI - Long-Term Prognosis and Causes of Death After Pleural Infections. AB - BACKGROUND AND AIMS: The development of pleural infection may imply a worse state of health and prognosis. The objective of this study was to ascertain the long term survival and causes of death after pleural infections and to compare them to those of matched controls. MATERIAL AND METHODS: Altogether 191 patients treated for pleural infections at a single University Hospital between January 2000 and December 2008 and 1910 age- and gender-matched controls were included. Survival data and the causes of death for non-survivors were obtained from national databases and compared between the groups. RESULTS: The etiology of pleural infection was pulmonary infection in 70%, procedural complication in 9%, trauma in 5%, malignancy in 4%, other in 7%, and unknown in 5% of patients. The course of treatment was surgical in 82%, drainage only in 12%, and conservative in 5% of included patients. The median follow-up time was 11 years. Mortality rates were 8.4% versus 0.8% during the first 90 days, p < 0.001, and 46.6% versus 24.5% overall, p < 0.001, in patients and controls, respectively. Mortality was significantly higher in patients with pulmonary infection, procedural complication, or malignancy as the etiology of pleural infection. In multivariable analysis, advanced age, previous malignancies, institutional care, alcoholism, and malignant etiology for the infection were associated with inferior survival. Deaths caused by malignancies, respiratory diseases, and digestive diseases were significantly more common in patients than in controls. CONCLUSION: Long-term survival in patients with pleural infections is significantly inferior to that of age and gender-matched controls. PMID- 29121815 TI - Preclinical Animal Models for Temporomandibular Joint Tissue Engineering. AB - There is a paucity of in vivo studies that investigate the safety and efficacy of temporomandibular joint (TMJ) tissue regeneration approaches, in part due to the lack of established animal models. Review of disease models for study of TMJ is presented herein with an attempt to identify relevant preclinical animal models for TMJ tissue engineering, with emphasis on the disc and condyle. Although degenerative joint disease models have been mainly performed on mice, rats, and rabbits, preclinical regeneration approaches must employ larger animal species. There remains controversy regarding the preferred choice of larger animal models between the farm pig, minipig, goat, sheep, and dog. The advantages of the pig and minipig include their well characterized anatomy, physiology, and tissue properties. The advantages of the sheep and goat are their easier surgical access, low cost per animal, and its high tissue availability. The advantage of the dog is that the joint space is confined, so migration of interpositional devices should be less likely. However, each species has limitations as well. For example, the farm pig has continuous growth until about 18 months of age, and difficult surgical access due to the zygomatic arch covering the lateral aspect of joint. The minipig is not widely available and somewhat costly. The sheep and the goat are herbivores, and their TMJs mainly function in translation. The dog is a carnivore, and the TMJ is a hinge joint that can only rotate. Although no species provides the gold standard for all preclinical TMJ tissue engineering approaches, the goat and sheep have emerged as the leading options, with the minipig as the choice when cost is less of a limitation; and with the dog and farm pig serving as acceptable alternatives. Finally, naturally occurring TMJ disorders in domestic species may be harnessed on a preclinical trial basis as a clinically relevant platform for translation. PMID- 29121818 TI - Reporting of ethical considerations in clinical trials in Chinese nursing journals. AB - BACKGROUND: It is acknowledged that publishers now require all primary research papers to demonstrate that they have obtained ethical approval for their research. OBJECTIVES: To assess the rate of reporting of ethical approval in clinical trials in core nursing journals in mainland China. RESEARCH DESIGN: A retrospective observational study. PARTICIPANTS: All clinical trials published in all of the 12 core nursing periodicals from 2016 edition China Science and Technology Journal Citation Report (core version) between 2013 and 2016 were retrieved by hand to explicate rate of reporting ethical approval and informed consent. Ethical considerations: The study did not require approval from the research ethics committee as it did not involve human subjects or records. RESULTS: In total, 40,278 papers were published in 12 nursing periodicals between 2013 and 2016. Out of these, 9488 (23.6%) focused on clinical trials. Informed consent obtained from patients or the legally authorized representative was reported in 51.8% of clinical trials. Notably, only 27.4% of clinical trials reported that they had obtained written consent. Furthermore, 25.9% of clinical trials described ethical approval; however, the rate of reporting informed consent and ethical approval in these 12 nursing journals in China during 4 years from 2013 to 2016 improved markedly, with 38.1%, 44.0%, 59.0% and 66.6%, respectively ( p < 0.001), and 17.6%, 21.9%, 28.6% and 35.8%, respectively ( p < 0.001). In addition, both reporting informed consent and reporting written informed consent had a positive significant correlation with the reporting ethical approval ( p < 0.05 or < 0.01). CONCLUSION: Chinese scientific nursing journals have improved the rate of reporting informed consent and ethical approval in clinical trials during the last 4 years. However, it should be noted that nearly half of clinical trials still did not report either ethical approval or whether informed consent was obtained. Efforts from editors, researchers, sponsors and authors are needed to ensure the transparency of ethical scrutiny and adherence to ethical guidelines in publishing clinical trials in Chinese nursing journals. PMID- 29121817 TI - Stromal Cell-Derived Factor-1alpha Promotes Endothelial Colony-Forming Cell Migration Through the Ca2+-Dependent Activation of the Extracellular Signal Regulated Kinase 1/2 and Phosphoinositide 3-Kinase/AKT Pathways. AB - Stromal cell-derived factor-1alpha (SDF-1alpha) drives endothelial colony-forming cell (ECFC) homing and incorporation within neovessels, thereby restoring tissue perfusion in ischemic tissues and favoring tumor vascularization and metastasis. SDF-1alpha stimulates ECFC migration by activating the Gi-protein-coupled receptor, CXCR4, and then engaging the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Sporadic evidence showed that SDF-1alpha may also act through an increase in intracellular Ca2+ concentration ([Ca2+]i) in bone marrow-derived hematopoietic progenitor cells and fully differentiated endothelial cells. Of note, recent evidence demonstrated that intracellular Ca2+ signals play a key role in controlling the proangiogenic activity of ECFCs. The present investigation was, therefore, undertaken to assess whether and how SDF-1alpha induces ECFC motility by triggering intracellular Ca2+ signals. We found that SDF 1alpha caused a dose-dependent increase in [Ca2+]i that was inhibited by ADM3100, a selective CXCR4 antagonist. Pharmacological manipulation revealed that the Ca2+ response to [Ca2+]i was shaped by an initial intracellular Ca2+ release through inositol-1,4,5-trisphosphate receptors (InsP3Rs), followed by a sustained phase of extracellular Ca2+ entry through store-operated Ca2+ channels. InsP3-dependent Ca2+ release and store-operated Ca2+ entry (SOCE) were both necessary for SDF 1alpha-induced extracellular signal-regulated kinases 1/2 (ERK 1/2) and AKT phosphorylation. Finally, SDF-1alpha employed intracellular Ca2+ signals, ERK 1/2, and PI3K/AKT to promote ECFC migration in vitro and neovessel formation in vivo. These data, therefore, provide the first evidence that SDF-1alpha induces ECFC migration through the Ca2+-dependent activation of the ERK 1/2 and PI3K/AKT pathways. PMID- 29121819 TI - Ethical decision-making based on field assessment: The experiences of prehospital personnel. AB - INTRODUCTION: Due to the stressful nature of prehospital emergency providers' duties, as well as difficulties such as distance to information resources and insufficient time to analyze situations, ethical decision-making in prehospital services is a daily challenge. OBJECTIVES: This study aimed to describe the experiences of Iranian prehospital emergency personnel in the field of ethical decision-making. METHODS: The data were collected by semi-structured interviews (n = 15) in Iran and analyzed using the content analysis approach. Ethical considerations: This study was conducted in accordance with the principles of research ethics and national rules and regulations relating to informed consent and confidentiality. RESULTS: The results obtained were categorized into three main categories that included "assessment of the scene atmosphere, assessment of patients' condition and their family, and predicting outcomes of decision making." The central category was "field assessment," which demonstrated the strategy of ethical decision-making by prehospital providers when facing ethical conflicts. CONCLUSION: Although findings showed that the majority of prehospital providers make ethical decisions based on the patients' benefit, they also consider consequences of their decisions in dealing with personal and professional threats. This article identifies and describes a number of ethical values of prehospital providers and discusses how the values may be considered by paramedics when facing ethical conflicts. PMID- 29121820 TI - Which computer-use behaviours are most indicative of cognitive decline? Insights from an expert reference group. AB - Computer use is becoming ubiquitous among older adults. As computer use depends on complex cognitive functions, measuring individuals' computer-use behaviours over time may provide a way to detect changes in their cognitive functioning. However, it is uncertain which computer-use behaviour changes are most likely to be associated with declines of particular cognitive functions. To address this, we convened six experts from clinical and cognitive neurosciences to take part in two workshops and a follow-up survey to gain consensus on which computer-use behaviours would likely be the strongest indicators of cognitive decline. This resulted in a list of 21 computer-use behaviours that the majority of experts agreed would offer a 'strong indication' of decline in a specific cognitive function, across Memory, Executive function, Language and Perception and Action domains. This list enables a hypothesis-driven approach to analysing computer-use behaviours predicted to be markers of cognitive decline. PMID- 29121821 TI - Morphometric study of the orientation of lumbar zygapophyseal joints in a South Indian population. AB - PURPOSE: To determine the orientation of lumbar zygapophyseal joints and prevalence of facet tropism (FT) identified by computerized tomographic (CT) scans. METHODS: In a cross-sectional study, 124 CT scans of patients with spinal injuries, seen between 2011and 2015, were retrospectively studied. A total of 566 uninjured motion segments were analysed. The right and left zygapophyseal joint angles (ZJAs) from L1-L2 to L5-S1 were measured on axial sections at uninjured levels. The absolute difference between the right and left ZJA was calculated to determine the prevalence and severity of FT at each level. RESULTS: The mean ZJA (mean +/- SD) at L1-L2, L2-L3, L3-L4, L4-L5 and L5-S1 was 23.55 +/- 7.21, 27.97 +/- 6.95, 39.47 +/- 6.07, 48.32 +/- 6.38 and 53.45 +/- 6.67, respectively. Prevalence of FT at L1-L2, L2-L3, L3-L4, L4-L5 and L5-S1 was 22.42%, 25%, 27.19%, 47.82% and 38.5%, respectively. One-way repeated analysis of variance test showed a statistically significant difference in mean ZJA ( p < 0.05) and prevalence of FT ( p < 0.05) at different levels of the lumbar spine. CONCLUSIONS: This study confirms that ZJA is not the same at different levels of the lumbar spine. The mean ZJA progressively increases from L1-L2 to L5-S1. This could explain the greater range of movements in the lumbar spine at the lower levels. The higher prevalence of FT at L4-L5 and L5-S1 seen in this study could explain the greater incidence of disc prolapse and other degenerative disorders at these levels. PMID- 29121822 TI - Investigation of efficacy of treatment in spinal cord injury: Erythropoietin versus methylprednisolone. AB - BACKGROUND: Investigation of the expression of platelet-derived growth factor (PDGF)-beta and glial fibrillary acidic protein (GFAP) in rats with spinal cord injury as a marker of neurologic recovery between groups treated with erythropoietin (EPO) and methylprednisolone (MP). METHODS: Thirty adult female rats were randomly divided into three even groups. A laminectomy was applied to thoracic ninth vertebra and contusion injury was induced by extradural application of an aneurysm clip. Group 1 rats received one-time intrathecal administration of normal saline, group 2 rats received MP, and group 3 rats received EPO. Motor neurological function was evaluated by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. Thirty days after the surgery, T8-10 segments of the spinal cords were extracted and the immunohistochemical assay revealed the number of PDGF-beta- and GFAP-positive cells. RESULTS: Evaluation of the last control animal showed that BBB score in the EPO group showed an increase from 1 to 12 ( p < 0.05). The immunohistochemical assay revealed that the number of PDGF-beta- and GFAP-positive cells was significantly higher in EPO group ( p = 0.000) when compared to MP and control groups. After studying the effect of PDGF beta expression on the locomotor function, we determined that PDGF-beta expression and locomotor function after a spinal injury has a strong relationship ( p < 0.05). CONCLUSION: EPO seems to better increase the expression of PDGF beta, thus produce better results in locomotor functions when compared to MP. PMID- 29121823 TI - Effect of Tumor Necrosis Factor Alpha Dose and Exposure Time on Tumor Necrosis Factor-Induced Gene-6 Activation by Neonatal and Adult Mesenchymal Stromal Cells. AB - Tumor necrosis factor alpha (TNF-alpha) induced protein 6 is a major anti inflammatory mediator released by activated mesenchymal stromal cells (MSCs). Neonatal MSCs are considered more metabolically active than cells derived from adult tissues, and potentially less heterogeneous. We hypothesized that a TNF alpha-activated neonatal MSC population [human umbilical cord perivascular cells (HUCPVCs)] would show an enhanced level of TSG-6 activation compared with adult bone marrow MSCs (BMMSCs). Thus, we stimulated HUCPVCs, and both human BMMSCs (hBMMSCs) and mouse BMMSCs (mBMMSCs) with 1, 10, 50, and 100 ng/mL of recombinant TNF-alpha over various exposure times. Supernatant, and total RNA, of the cells were collected for measurement of both TSG-6 RNA expression, and secreted TSG-6 protein. To compare gene levels, quantification was done by normalizing the expression levels of TSG-6 to the geometric mean of the three most stable reference genes, out of a cohort of 30 tested genes, using the Pfaffl method. We found that HUCPVCs exhibited both an enhanced and more rapid response to low dose (1 ng/mL) TNF-alpha exposure resulting in ~11.5-fold increase in TSG-6 expression within the first 30 min. In contrast, hBMMSCs showed 2-fold increase by 1 h that increased to 9.5-fold with a higher (50 ng/mL) TNF-alpha exposure for the same time. mBMMSCs showed a two-fold increase after 24 h that was independent of TNF alpha concentration. Thus, although TSG-6 expression level varied among donors, both hMSC populations exhibited enhanced TSG-6 upregulation, upon TNF-alpha stimulation, compared with mBMMSCs. In conclusion, HUCPVCs showed higher sensitivity, and a prompter response to TNF-alpha stimulation compared with hBMMSCs. Thus, neonatal MSCs may be a stronger candidate population than those derived from adult bone marrow to treat inflammatory diseases. PMID- 29121824 TI - Interpersonal Processes of Couples' Daily Support for Goal Pursuit: The Example of Physical Activity. AB - Little is known about how couples' social support facilitates the pursuit of important goals in daily life. Using an interpersonal perspective, we examined the effects of support provision and receipt on same-day physical activity, and studied the role of partners' joint engagement in activities. One hundred nineteen heterosexual couples reported on target persons' received and partners' provided support across 28 diary days, yielding 2,854 valid days. A dyadic report on couples' joint engagement was obtained from a subset of 88 couples. Target persons' daily activity was objectively assessed via accelerometers. On days with high versus low levels of provided support, target persons' activity was 25 min higher. Support receipt mediated 20% of this effect. Joint engagement accounted for around half of the effects of provided and received support. Support provision is uniquely linked to goal implementation in everyday life. Joint engagement in activities may be one explanation for how support is facilitated. PMID- 29121825 TI - The impact of staff training on special educational needs professionals' attitudes toward and understanding of applied behavior analysis. AB - BACKGROUND: Research-based evidence points to the efficacy and value of applied behavior analysis (ABA) in meeting the needs of individuals with learning disabilities and autism. Nonetheless, public, government, and professional perception of ABA can be negative. The current study was designed to measure the impact of a short intervention on professionals' attitudes toward, and knowledge of, ABA. METHOD: Teachers and classroom assistants from two separate schools for children with severe learning difficulties completed a self-report survey on knowledge of and attitudes toward ABA. They were then presented with a 90-min training module designed to increase their knowledge of the history of ABA and their functional assessment skills. Following training, the self-report was readministered. RESULTS: The mean scores for each group increased only after the training had been delivered. DISCUSSION AND CONCLUSIONS: Further research is needed to address the impact of training on classroom practice. PMID- 29121826 TI - Treatment of Traumatic Brain Injury with Vepoloxamer (Purified Poloxamer 188). AB - Vepoloxamer is an amphipathic polymer that has shown potent hemorrheologic, cytoprotective, and anti-inflammatory effects in both pre-clinical and clinical studies. This study was designed to investigate the therapeutic effects of vepoloxamer on sensorimotor and cognitive functional recovery in rats after traumatic brain injury (TBI) induced by controlled cortical impact. Young adult male Wistar rats were randomly divided into the following groups: 1) sham; 2) saline; or 3) vepoloxamer. Vepoloxamer (300 mg/kg) or saline was administered over 60 min via intravenous infusion into tail veins starting at 2 h post-injury. Sensorimotor function and spatial learning were assessed using a modified neurological severity score and foot fault test, and Morris water maze test, respectively. The animals were sacrificed 35 days after injury and their brains were processed for measurement of lesion volume and neuroinflammation. Compared with the saline treatment, vepoloxamer initiated 2 h post-injury significantly improved sensorimotor functional recovery (Days 1-35; p < 0.0001) and spatial learning (Days 32-35; p < 0.0001), reduced cortical lesion volume by 20%, and reduced activation of microglia/macrophages and astrogliosis in many brain regions including injured cortex, corpus callosum, and hippocampus, as well as normalized the bleeding time and reduced brain hemorrhage and microthrombosis formation. In summary, vepoloxamer treatment initiated 2 h post-injury provides neuroprotection and anti-inflammation in rats after TBI and improves functional outcome, indicating that vepoloxamer treatment may have potential value for treatment of TBI. Further investigation of the optimal dose and therapeutic window of vepoloxamer treatment for TBI and the mechanisms underlying beneficial effects are warranted. PMID- 29121827 TI - Gaze-Cueing With Crossed Eyes: Asymmetry Between Nasal and Temporal Shifts. AB - A person's direction of gaze (and visual attention) can be inferred from the direction of the parallel shift of the eyes. However, the direction of gaze is ambiguous when there is a misalignment between the eyes. The use of schematic drawings of faces in a previous study demonstrated that gaze-cueing was equally effective, even when one eye looked straight and the other eye was averted. In the current study, we used more realistic computer-generated face models to re examine if the diverging direction of the eyes affected gaze-cueing. The condition where one eye was averted nasally while the other looked straight produced a significantly smaller gaze-cueing effect in comparison with when both eyes were averted in parallel or one eye was averted temporally. The difference in the gaze-cueing effect disappeared when the position of one eye was occluded with a rectangular surface or an eye-patch. These results highlight the possibility that the gaze-cueing effect might be weakened when a direct gaze exists between the cueing eye (i.e., nasally oriented eye) and the target and the effect magnitude might depend on which type of face stimulus are used as a cue. PMID- 29121828 TI - Preference option randomized design (PORD) for comparative effectiveness research: Statistical power for testing comparative effect, preference effect, selection effect, intent-to-treat effect, and overall effect. AB - Comparative effectiveness research trials in real-world settings may require participants to choose between preferred intervention options. A randomized clinical trial with parallel experimental and control arms is straightforward and regarded as a gold standard design, but by design it forces and anticipates the participants to comply with a randomly assigned intervention regardless of their preference. Therefore, the randomized clinical trial may impose impractical limitations when planning comparative effectiveness research trials. To accommodate participants' preference if they are expressed, and to maintain randomization, we propose an alternative design that allows participants' preference after randomization, which we call a "preference option randomized design (PORD)". In contrast to other preference designs, which ask whether or not participants consent to the assigned intervention after randomization, the crucial feature of preference option randomized design is its unique informed consent process before randomization. Specifically, the preference option randomized design consent process informs participants that they can opt out and switch to the other intervention only if after randomization they actively express the desire to do so. Participants who do not independently express explicit alternate preference or assent to the randomly assigned intervention are considered to not have an alternate preference. In sum, preference option randomized design intends to maximize retention, minimize possibility of forced assignment for any participants, and to maintain randomization by allowing participants with no or equal preference to represent random assignments. This design scheme enables to define five effects that are interconnected with each other through common design parameters-comparative, preference, selection, intent to-treat, and overall/as-treated-to collectively guide decision making between interventions. Statistical power functions for testing all these effects are derived, and simulations verified the validity of the power functions under normal and binomial distributions. PMID- 29121829 TI - Variable selection for accelerated lifetime models with synthesized estimation techniques. AB - We develop variable selection approaches for accelerated failure time models, consisting of a group of algorithms based on a synthesis of two widely used techniques in the area of variable selection for survival analysis-the Buckley James method and the Dantzig selector. Two algorithms are based on proposed modified Buckley-James estimating methods that are designed for high-dimensional censored data. Another two algorithms are based on a two-stage weighted Dantzig selector method where weights are obtained from the two proposed synthesis-based algorithms. The methods are easy to understand and they perform estimation and variable selection simultaneously. Furthermore, they can deal with collinearity among the covariates. We conducted several simulation studies and one empirical analysis with a microarray dataset; these studies demonstrated satisfactory variable selection performance. In addition, the microarray data analysis shows the methods performing similarly to three other correlation-based greedy variable selection techniques in the literature-sure independence screening, tilted correlation screening (TCS), and partial correlation (PC) simple. This empirical study also found that the sure independence screening technique considerably improves the performance of most of the proposed methods. PMID- 29121830 TI - Acute reversible toxic encephalopathy during capecitabine and oxaliplatin treatment. AB - Introduction Capecitabine is a fluoropyrimidine commonly used in the treatment of colorectal cancer which may cause central nervous system toxicity, namely cerebellar dysfunction. Case report We describe a 77-year-old man undergoing adjuvant treatment of colon cancer with capecitabine and oxaliplatin who presented with acute cerebellar ataxia and encephalopathy that progressed to coma. Diagnosis of toxic encephalopathy was made after the exclusion of alternative causes of neurological dysfunction and complete resolution of clinical findings with permanent discontinuation of chemotherapy. Discussion When patients with cancer develop symptoms and signs of central nervous dysfunction, metabolic and infectious causes plus tumor involvement of central nervous system must be sought. However, chemotherapy may also cause toxicity to the central nervous system. Capecitabine is no exception, although cerebellar dysfunction is rarely reported. Conclusion Although rare, capecitabine-induced encephalopathy may be severe and physicians should be aware of this possible side effect. PMID- 29121831 TI - Functions of mHealth applications: A user's perspective. AB - The usage of mobile health (mHealth) applications is rapidly increasing. This research has been aimed mostly at reviewing existing mHealth apps and their functionality. However, studies from users' perspectives are rather scarce. This exploratory study addresses that gap and, using cross-sectional survey data, seeks to reveal the socio-demographic and individual characteristics of users who utilize specific functions of mHealth apps. The data were collected via an online survey through websites oriented toward eating habits, exercising, dieting, and weight loss. From the original sample (1002 users; M = 24.8, standard deviation = 6.9; 81.6% females), the final sub-sample of 406 participants aged from 13 to 39 years (M = 23.8, standard deviation = 5.3, 86.9% females) who reported usage of mHealth apps was examined. The analyses revealed demographic and individual differences in predicting usage of various functions of mHealth apps. The drive for thinness was associated with functions for weight monitoring and planning functions. Excessive exercise was associated with weight monitoring, socializing functions, and functions for planning and monitoring goals. These findings imply that mHealth apps should be individually tailored to incorporate components such as risk-specific warnings or the provision of information related to seeking professional help for at-risk audiences. PMID- 29121832 TI - How a Simple Ankle Sprain Turned Into Neuropathic Pain: Complex Reflex Sympathetic Dystrophy Versus Erythromelalgia. AB - A 36-year-old woman sustained a Grade 2 ankle sprain at work. Two days after the injury, the ankle and foot became red and she complained of "intense burning pain." First diagnosed with complex reflex sympathetic dystrophy, the employee was prescribed medications that provided some pain relief; a subsequent temporary nerve block provided additional relief. However, the symptoms returned and she was treated unsuccessfully with surgical sympathectomy. The employee was referred to a neurologist and diagnosed with primary erythromelalgia, a rare pain disorder that can be mistaken as complex reflex sympathetic dystrophy. PMID- 29121833 TI - Fitbit Activity Trackers Interrupt Workplace Sedentary Behavior: A New Application. AB - This study investigated whether Fitbit devices can reduce sedentary behavior among employees in the workplace. Participants were asked to wear Fitbits during 8-hour work shifts, 5 days per week, for 8 weeks. They were instructed to stand at least once every 30 minutes throughout the workday. The goal of the study was to determine whether standing once every 30 minutes was a feasible strategy for reducing sedentary workplace behavior. On average, participants completed 36 of 40 workdays using Fitbits. The number of times participants stood during an 8 hour workday averaged 12 stands per day (maximum 16 stands per day). These results indicate that Fitbit technology is effective for recording and tracking interruptions in sitting time; however, to reduce sitting behavior, alternate approaches are required to motivate larger numbers of workers to participate. PMID- 29121835 TI - Helen P. Cleary, MPH, ScD, CHES (1920-2016). PMID- 29121834 TI - Head Injuries in Urban Environment Skiing and Snowboarding: A Retrospective Study on Injury Severity and Injury Mechanisms. AB - BACKGROUND AND AIM: During the last decade urban skiing and snowboarding has gained a lot of popularity. In urban skiing/snowboarding riders try to balance on handrails and jump off buildings. Previous studies in skiing and snowboarding accidents have mostly been conducted at hospitals located close to alpine terrain with big ski resort areas. The aim of this study is to evaluate the types and severity of traumatic brain injuries occurring in small, suburban hills and in urban environment, and to characterize injury patterns to find out the specific mechanisms of injuries behind. MATERIALS AND METHODS: This study included all patients admitted to the Helsinki University Hospital Trauma Unit from 2006 to 2015 with a head injury (ICD 10 S06-S07) from skiing or snowboarding accidents in Helsinki capital area. Head injuries that did not require a CT-scan, and injuries older than 24 hours were excluded from this study. RESULTS: There were a total of 72 patients that met the inclusion criteria Mean length of stay in hospital was 2.95 days. According to the AIS classification, 30% had moderate, 14% had severe, and 10% had critical head injuries. Patients who got injured in terrain parks or on streets where more likely to be admitted to ICU than those injured on slopes. Based on GOS score at discharge, 78% were classified as having a good recovery from the injury, 13% had a moderate disability, 5% had a severe disability and 3% of the injuries were fatal. There were no statistically significant differences in decreased GOS between the accident sites. CONCLUSION: Head injuries occurring in small suburban hills and in urban environments can be serious and potentially fatal. The profile and severity of skiing injuries in urban environments and small, suburban hills is comparable to those on alpine terrain. PMID- 29121836 TI - Retroesophageal Infracardiac Total Anomalous Pulmonary Venous Drainage. AB - This case report describes the management of a term baby, born cyanotic, who was preoperatively diagnosed to have an obstructed total anomalous pulmonary venous drainage (TAPVD) in association with a functionally univentricular heart. An urgent repair of the anomalous pulmonary venous drainage was done, and a modified Blalock-Taussig shunt was constructed. Intraoperative difficulties were encountered when the pulmonary venous confluence was not seen in the usual location in the posterior mediastinal space, anterior to the esophagus. This report describes the rare finding of infracardiac TAPVD that is located in the retroesophageal space. PMID- 29121837 TI - Triple Outlet Right Ventricle, With Duplication of the Aortic Root and Intrapericardial Ascending Aorta. AB - We present a case of a highly unusual congenital cardiac malformation, namely, triple outlet right ventricle with duplication of the aortic root and the intrapericardial component of the ascending aorta. A girl, aged five, presented with complaints of cyanosis and effort intolerance and was diagnosed with double outlet right ventricle and subpulmonary infundibular stenosis. Intraoperatively, we noted that the aortic root was guarded by two separate aortic valves, oriented anteroposteriorly relative to each other, and separated within the right ventricle by a muscle bar. Postoperative interrogation by both echocardiography and computed tomography confirmed the surgical findings. To the best of our knowledge, our case is the first example of duplication of the aortic root to produce triple outlet right ventricle. PMID- 29121838 TI - Possible Trimethoprim-Sulfamethoxazole-Induced Hemolytic Anemia: A Case Report. AB - OBJECTIVE: To report a case of hemolytic anemia in a patient who received trimethoprim/sulfamethoxazole (TMP-SMX) for a urinary tract infection (UTI). SUMMARY: A 47-year-old woman recently diagnosed with uncomplicated UTI received 3 doses of TMP-SMX. She developed yellowing of the skin and eyes, lethargy, mild abdominal pain, and dry mucous membranes. Laboratory testing demonstrated significant anemia with red blood cells (RBCs) of 1.99, hemoglobin (Hgb) of 6.3 g/dL, and hematocrit (Hct) of 18.1%. TMP-SMX was immediately discontinued. The patient was given methylprednisolone 60 mg intravenously (IV) followed by oral steroids and infused with 3 units of packed RBCs over the course of a 10-day inpatient admission. On discharge, the patient continued oral steroids. Outpatient follow-up indicated Hgb of 11.0 g/dL and Hct of 32.7%, 41 days after hospital discharge. Utilizing the Naranjo adverse drug reaction probability scale, there is a probable association between the patient's hemolytic anemia and TMP-SMX. CONCLUSION: We report a case of hemolytic anemia resulting from the use of TMP-SMX. Although this is a rare adverse effect, clinicians should be aware of the signs and symptoms of hemolytic anemia, and so appropriate treatment can be administered should it occur. PMID- 29121839 TI - Simplifying Piperacillin/Tazobactam Dosing: Pharmacodynamics of Utilizing Only 4.5 or 3.375 g Doses for Patients With Normal and Impaired Renal Function. AB - OBJECTIVES: To evaluate the pharmacodynamic exposure of piperacillin/tazobactam across the renal function range using 4.5 or 3.375 g dosing regimens. METHODS: A 5000-patient Monte Carlo simulation was conducted to determine the probability of achieving 50% free time above the minimum inhibitory concentration ( fT > MIC) for piperacillin. Proposed regimens, using solely 4.5 or 3.375 g strengths, were compared with regimens listed in piperacillin/tazobactam prescribing information over creatinine clearance (CrCl) ranges of 120 mL/min to hemodialysis. The probability of target attainment (PTA) at MICs <= 16 MUg/mL was compared between proposed and standard regimens. RESULTS: At CrCl 41 to 120 mL/min, prolonged infusions of 4.5 g (3 hours) and 3.375 g (4 hours) every 6 hours resulted in >=95% PTA versus >=76% for standard regimens (0.5 hour). At CrCl 20 to 40 mL/min, 4.5 and 3.375 g every 8 hours as prolonged infusions achieved slightly higher PTA (>=98%) versus standard regimens (>=93%). Similarly, PTA achieved with prolonged infusions of 4.5 and 3.375 g every 12 hours (>=93%) was comparable with those of standard regimens (>=91%) at CrCl 1 to 19 mL/min. In hemodialysis, 100% PTA was achieved with prolonged infusion regimens. CONCLUSION: Piperacillin/tazobactam regimens designed around the 4.5 or 3.375 g dose and prolonged infusions provided similar or better PTA at MICs <= 16 MUg/mL compared with standard regimens. These observations may support the stocking and use of a single piperacillin/tazobactam strength to simplify dosing. PMID- 29121840 TI - Role of Irrational Beliefs and Anger Rumination on Nurses' Anger Expression Styles. AB - The aim of this study was to identify whether certain cognitive factors, such as irrational beliefs and anger rumination, affect nurses' anger expression styles. A total of 335 nurses employed at four tertiary hospitals in Korea completed surveys between July 29 and September 25, 2015. The surveys included Shortened General Attitude and Belief Scale, the Korean Version of the Anger Rumination Scale, and the State-Trait Anger Expression Inventory-Korean version. Results revealed that higher levels of irrational beliefs and anger rumination were associated with more anger-in and anger-out, and less anger-control expressions. Findings indicate that the presence of specific cognitive characteristics could lead to maladaptive anger expressions. Active consideration of these cognitive risk factors is essential when developing anger-management programs for nurses. PMID- 29121841 TI - Prophylactic Inferior Vena Cava Filter Utilization and Risk Factors for Nonretrieval. AB - PURPOSE: Inferior vena cava filters (IVCFs) are often placed for prophylactic indications. We sought to better define the range of practice indications for placement of prophylactic IVCFs, as well as the specific retrieval rate and risk factors for nonretrieval. METHODS: A retrospective, single-institution review of patients undergoing IVCF placement over a 2-year period was performed. Patients undergoing prophylactic IVCF placement were selected from a prospectively collected database. Risk factors for nonretrieval were identified using a multivariate logistic regression model. RESULTS: Of 615 IVCFs placed, 256 were retrievable filters placed for prophylactic indications and comprised the study cohort. The most common indications were a history of venous thromboembolic disease (43.7%), malignancy (35.1%), bleeding risk precluding anticoagulation (33.9%), and trauma (22.6%). One hundred sixty-three (63.6%) were placed preoperatively. Placement was performed in 70.3% by interventional radiology, 21.4% by vascular surgery, and 8.2% by cardiology. The most common requesting services were orthopedics (67%), general surgery (11%), neurosurgery (9%), and bariatric surgery (7%). Of all, 67.6% were placed in the inpatient setting and 32.4% in outpatients. Seventy-one (27.7%) of the 256 prophylactic filters were retrieved, with a mean indwelling time of 92 +/- 74 days. Inpatients were significantly less likely to have their IVCF removed (32.4% vs 57.8%; P < .001), as were preoperative patients. CONCLUSIONS: This study helps define current practice trends for the placement of prophylactic IVCFs. Importantly, the specific retrieval rate for prophylactic filters is low. This suggests that prophylactic IVCF usage is suboptimal and efforts should be taken to increase retrieval, especially among inpatients and perioperative patients. PMID- 29121842 TI - Superior Mesenteric Vein Injury During Oncologic Right Colectomy: Current Vascular Repair Modalities. AB - PURPOSE: To review the different vascular repair options of superior mesenteric vein (SMV) damage during oncologic right colectomy. METHODS: This is a retrospective chart review of 5 cases in which severe damage to the SMV occurred during oncological right colectomy in an academic medical center. RESULTS: During a 10-year study period, we encountered 5 cases in which severe damage to the SMV and its tributaries occurred. Two of the patients underwent primary venous repair for partial lacerations. The other 3 underwent interposition graft repair using a great saphenous vein (GSV) graft. Two of the grafts remained patent, while the third required replacement with a bovine pericardial patch. CONCLUSIONS: The SMV injury during oncologic right colectomy is a technically challenging injury. Based on our own experience and review of the literature, we formulated the following set of recommendations: (1) Venous ligation should be avoided, and revascularization should be attempted whenever feasible. (2) Primary venorrhaphy in cases of partial lacerations is the preferred treatment option. (3) End-to-end anastomosis is an efficient but seldom available repair option in the setting of complete SMV transection without segmental loss. (4) Autologous vein graft using the GSV is the preferred mode of repair during SMV injury with tissue loss. (5) Use of polytetrafluoroethylene (PTFE) graft should be avoided if possible due to greater risk of graft contamination. (6) A low threshold for reexploration depending on laboratory and imaging findings is advisable. PMID- 29121843 TI - Bifurcated Stent Technique: A Viable Option for Treatment of Patients With Unusual Anatomy Presenting With Combined Chronic Mesenteric Ischemia and Diffuse Ischemic Gastric Ulcers. AB - Treatment of chronic mesenteric ischemia has evolved over the last two decades. Endovascular therapy is now the treatment of choice for patients with lesions amenable to such an approach. Open revascularization remains the standard of care but is frequently being reserved for lesions containing intraluminal thrombus or severe calcification. In most cases, celiac axis (CA) stenting is not needed since revascularization of the superior mesenteric artery (SMA) alone results in symptomatic resolution. This report describes a case of a patient with chronic mesenteric ischemia and diffuse gastric ulcers found to have a common origin of the SMA and CA that was treated endovascularly using a bifurcated stent technique. PMID- 29121844 TI - Patient and Aneurysm Characteristics Predicting Prolonged Length of Stay After Elective Open AAA Repair in the Endovascular Era. AB - INTRODUCTION: Open aortic aneurysm repair (AAA) repair can be resource intensive and associated with a prolonged length of stay (LOS). We sought to examine patient and aneurysm predictors of prolonged LOS to better identify those at risk in the preoperative setting. METHODS: Patient data were obtained from the targeted AAA American College of Surgery National Surgical Quality Improvement Program database from 2012 to 2014 of patients undergoing open AAA repair. Multivariable logistic regression was used to determine predictors of prolonged postoperative LOS defined as greater than 10 days (75th percentile). RESULTS: There were 1172 open AAA repairs identified. The majority (54%) of patients were older than 70 years and male (74%). Surgical approach was transperitoneal (70.9%) and retroperitoneal (29.1%). Aneurysms were 51.4% infrarenal, 33% juxtarenal, 5.7% pararenal, 7.4% suprarenal, and 2.5% type IV thoracoabdominal. Mean and median LOS were 9.1 +/- 7.4 and 7 (0-72) days, respectively. Independently associated with extended LOS factors were visceral revascularization (odds ratio [OR]: 5.32, 95% confidence interval [CI]: 2.77-10.22, P < .001), type IV thoracoabdominal extent (OR: 3.09, 95% CI: 1.01-9.46, P = .048), suprarenal extent (OR: 1.89, 95% CI: 1.07-3.34, P = .029) and juxtarenal (OR: 1.43, 95% CI: 1.01-2.02, P = .004), non-Caucasian race (OR: 2.80, 95% CI: 1.77-4.41, P < .001), chronic obstructive pulmonary disease (OR: 1.76, 95% CI: 1.20-2.59, P = .004), not-from-home admission (OR: 1.91, 95% CI: 1.13-3.24), and age greater than 70 (OR: 1.49, 95% CI: 1.08-2.05, P = .014). CONCLUSION: We identified patient and aneurysm characteristics independently associated with protracted LOS following open AAA repair. Prospective identification of high-risk patients may allow physicians and hospitals to engage in multidisciplinary collaborations preoperatively to try to improve LOS in this resource-intensive population. PMID- 29121845 TI - Improving Outcomes for Lower Extremity Amputations Using Intraoperative Fluorescent Angiography to Predict Flap Viability. AB - OBJECTIVES: Nearly 25% of vascular surgery patients operated on for peripheral vascular disease are readmitted within 30 days. Development of adjuncts to minimize wound complications remains an area of great interest. Here, we present our experience with intraoperative fluorescent angiography (IFA) as a tool to predict skin flap viability following lower extremity amputations (LEAs). METHODS: Experience with IFA using indocyanine green (ICG) dye was reviewed retrospectively at a single institution. Records of patients undergoing LEA with use of IFA by 2 vascular surgeons from 2013 to 2014 were reviewed. Absolute and relative tissue perfusion values were evaluated for sensitivity and specificity in regard to skin flap viability. RESULTS: Thirteen patients with a mean age of 70.5 years (standard deviation [SD] = 12.0, range: 49-93 years) underwent 17 amputations. Indications included rest pain, tissue gangrene, and vascular disease unsuitable for revascularization. Amputation levels included toe (23%), transmetatarsal (18%), below knee (41%), and above knee (18%). Six (35%) amputations required revision with a mean time-to-revision of 26.1 days (SD = 19.9, range: 9-61 days). Of these revisions, 14 (83%) patients proceeded to a proximal-level amputation. Mean follow-up was 235 days (SD = 148, range: 5-448 days), and IFA was used in all cases. Absolute perfusion values (APVs) between 5 and 9 displayed sensitivity and specificity of 50% and 64%, respectively. Additionally, a relative perfusion value (RPV) of <=31% displayed 100% sensitivity and specificity. Sensitivity and specificity fell to 83% at a relative perfusion of <=27% and <=35%, respectively. CONCLUSION: IFA during LEA is safe and easily performed by the vascular surgeon. The RPVs as a predictor of skin flap viability correlate well with those reported in breast reconstructive surgery. Unfortunately, APVs fail to support any predication for flap failure or success. Patient comorbidities and intraoperative variables such as vasopressor use may contribute to this finding. PMID- 29121846 TI - Retrograde Ascending Dissection After Thoracic Endovascular Aortic Repair Combined With the Chimney Technique and Successful Open Repair Using the Frozen Elephant Trunk Technique. AB - The chimney technique can be combined with thoracic endovascular aortic repair (TEVAR) to both obtain an appropriate landing zone and maintain blood flow of the arch vessels. However, surgical repair becomes more complicated if retrograde type A aortic dissection occurs after TEVAR with the chimney technique. We herein report a case involving a 73-year-old woman who developed a retrograde ascending dissection 3 months after TEVAR for acute type B aortic dissection. To ensure an adequate proximal sealing distance, the proximal edge of the stent graft was located at the zone 2 level and an additional bare stent was placed at the left subclavian artery (the chimney technique) at the time of TEVAR. Enhanced computed tomography revealed an aortic dissection involving the ascending aorta and aortic arch. Surgical aortic repair using the frozen elephant trunk technique was urgently performed. The patient survived without stroke, paraplegia, renal failure, or other major complications. Retrograde ascending dissection can occur after TEVAR combined with the chimney technique. The frozen elephant trunk technique is useful for surgical repair in such complicated cases. PMID- 29121847 TI - In this issue: tools and processes that translate knowledge into practice. AB - The theme of In This Issue is how informatics provides tools and processes that help translate knowledge into practice. PMID- 29121848 TI - Effectively reducing amylase testing using computer order entry in the emergency department: quality improvement without eliminating physician choice. AB - BACKGROUND: Amylase and lipase, pancreatic biomarkers, are measured in acute pancreatitis diagnosis. Since amylase testing does not add diagnostic value, lipase testing alone is recommended. Despite new recommendations, many physicians and staff continue to test both amylase and lipase. OBJECTIVE: To reduce unnecessary diagnostic testing in acute pancreatitis. METHODS: The pre-checked amylase test within the Emergency Department's Computerized Provider Order Entry (CPOE) abdominal pain order set was changed to an un-checked state, but kept as an option to order with a single click. Amylase testing, lipase testing and cost were measured for one year pre and post intervention. RESULTS: Simple de selection intervention reduced redundant amylase testing from 71% to 9%, resulting in a percent of decrease of 87% and an annualized saving of approximately $719,000 in charges. CONCLUSION: CPOE de-selection is an effective tool to reduce non-value added activity and reduce cost while maintaining quality patient care and physician choice. PMID- 29121849 TI - Attitudes and concerns of doctors and nurses about using a translation application for in-hospital brief interactions with Korean patients. AB - BACKGROUND: New Zealand is becoming more ethnically diverse, with rising numbers of people with limited English language proficiency. Consequently, hospital interactions are increasing where patients have insufficient English to communicate adequately with doctors or nurses for appropriate, effective, and safe care. Translation technology is rapidly evolving, but evidence is limited regarding its usefulness to clinicians. OBJECTIVE: To examine the acceptability to doctors and nurses of a translation application (app) used on a tablet, in brief interactions with Korean patients. METHOD: An app was developed to facilitate brief conversations between patients and clinicians as part of clinical care. We used the Technology Acceptance Model 2 to develop semi structured interview questions for 15 junior and senior doctors and nurses in an urban hospital. Participants used the app to interact with the interviewer as part of a scenario. The interviews were analysed thematically. RESULTS: The app was easy to use, learn to use, and to memorise for future use. It was considered useful for everyday brief interactions, urgent situations where there is no time to call an interpreter, and after hours, to augment the work of interpreters. Subject to perceived usefulness, there appears to be little need for social normalisation of a translation app, other than management support for the costs, maintenance, and implementation of the app for everyday use. CONCLUSION: Guidelines are required for the use of a translation app by doctors and nurses to augment the interpreter role. A larger study and future research on the patient's perspective are required. PMID- 29121850 TI - The challenge of involving elderly patients in primary care by using an electronic communication tool with their professionals: a mixed methods study. AB - BACKGROUND: Elderly patients in primary care often have multiple health problems,with different healthcare professionals involved. For consistency in care, it is required that communication amongst professionals and patient-systems (patient and informal-carers) be well tuned. Electronic-communication can make it easier for patient-system to be active in care. OBJECTIVE: To examine whether an e-communication tool (Congredi) designed for professionals, including a care plan and secure e-mail, is usable for patient-systems and what their experiences are. METHODS: In a multi-method study, home-dwelling elderly patients with two or more professionals were invited to use Congredi; data were gathered from the system after 42 weeks. Also semi-structured interviews were undertaken with patient systems with topics retrieved from literature. Analysis took place by two researchers independently; the themes were extracted together by consensus. RESULTS: Data about actual use of the tool were gathered from 22 patients. Four profiles of Congredi-users were distinguished, varying in intensity of use. Data from interviews with members of patient-systems (n = 7) showed that they were motivated and able to use Congredi. Barriers in daily use were limited participation of professionals, unanswered e-mail and not being alerted about actions. Despite limitations, patient-systems retained their motivation. CONCLUSION: Congredi was usable for patient-systems. The barriers found seem not to be tool-related but primarily user-related. An important barrier for daily use was limited active participation of involved professionals in a complete feedback loop. Potential for future implementation was found, as patient-systems were intrinsically motivated for better feedback with the professionals, even though in this study it only partly met their expectations. PMID- 29121852 TI - An Informatics Approach to Interprofessional Management of Low Back Pain: A Feasibility Study using the Omaha System. AB - BACKGROUND: Low back pain (LBP) is a complex health care issue that often involves multiple providers across various care settings. Health information technology (HIT) holds promise to improve care delivery by providing infrastructure for communication, clinical documentation, and management of patient data. Standardized terminology is essential for interoperability and enables evaluation of clinical data generated by documentation in an electronic health record (EHR). OBJECTIVE: The purpose of this study was to demonstrate the feasibility of mapping evidence-based practice for conservative management of low back pain to the Omaha System and foster inter-professional communication and collaboration among diverse practitioners and patients. METHODS: Evidence-based practice (EBP) guidelines for non-invasive treatment of low back pain were mapped to the Omaha System using a clinical expert approach with attention to content feasibility, linguistic validity, and granularity of terms. RESULTS: A clinical guideline for low back pain management was developed consisting of 13 interventions for Pain and Neuro-musculo-skeletal problems. The most common intervention categories were Case management followed by Treatments and procedures, Teaching, guidance, and counseling and Surveillance. Scope of practice overlap was identified between primary care, chiropractic, and physical therapy practice. CONCLUSION: Use of the guideline may facilitate clinical documentation using the Omaha System for low back pain management, and has potential to generate meaningful data to evaluate clinical effectiveness and promote quality research. The use of encoded EBP evidence within an EHR can increase use of available evidence, enable interprofessional communication, improve quality of care, and enhance usability of data across care settings. PMID- 29121851 TI - Outputs and Growth of Primary Care Databases in the United Kingdom: Bibliometric Analysis. AB - BACKGROUND: Electronic health database (EHD) data is increasingly used by researchers. The major United Kingdom EHDs are the 'Clinical Practice Research Datalink' (CPRD), 'The Health Improvement Network' (THIN) and 'QResearch'. Over time, outputs from these databases have increased, but have not been evaluated. OBJECTIVE: This study compares research outputs from CPRD, THIN and QResearch assessing growth and publication outputs over a 10-year period (2004-2013). CPRD was also reviewed separately over 20 years as a case study. METHODS: Publications from CPRD and QResearch were extracted using the Science Citation Index (SCI) of the Thomson Scientific Institute for Scientific Information (Web of Science). THIN data was obtained from University College London and validated in Web of Science. All databases were analysed for growth in publications, the speciality areas and the journals in which their data have been published. RESULTS: These databases collectively produced 1,296 publications over a ten-year period, with CPRD representing 63.6% (n=825 papers), THIN 30.4% (n=394) and QResearch 5.9% (n=77). Pharmacoepidemiology and General Medicine were the most common specialities featured. Over the 9-year period (2004-2013), publications for THIN and QResearch have slowly increased over time, whereas CPRD publications have increased substantially in last 4 years with almost 75% of CPRD publications published in the past 9 years. CONCLUSION: These databases are enhancing scientific research and are growing yearly, however display variability in their growth. They could become more powerful research tools if the National Health Service and general practitioners can provide accurate and comprehensive data for inclusion in these databases. PMID- 29121853 TI - Addendum to Informatics for Health 2017: Advancing both science and practice. AB - This article presents presentation and poster abstracts that were mistakenly omitted from the original publication. PMID- 29121854 TI - Monitoring Interactions Inside Cells by Advanced Spectroscopies: Overview of Copper Transporters and Cisplatin. AB - BACKGROUND: Resistance, either at the onset of the treatment or developed after an initial positive response, is a major limitation of antitumor therapy. In the case of platinum- based drugs, copper transporters have been found to interfere with drug trafficking by facilitating the import or favoring the platinum export and inactivation. METHODS: The use of powerful spectroscopic, spectrometric and computational methods has allowed a deep structural insight into the mode of interaction of platinum drugs with the metal-binding domains of the transporter proteins. RESULTS: This review article focuses on the mode in which platinum drugs can compete with copper ion for binding to transport proteins and consequent structural and biological effects. Three types of transporters are discussed in detail: copper transporter 1 (Ctr1), the major responsible for Cu+ uptake; antioxidant-1 copper chaperone (Atox1), responsible for copper transfer within the cytoplasm; and copper ATPases (ATP7A/B), responsible for copper export into specific subcellular compartments and outside the cell. CONCLUSION: The body of knowledge summarized in this review can help in shaping current chemotherapy to optimize the efficacy of platinum drugs (particularly in relation to resistance) and to mitigate adverse effects on copper metabolism. PMID- 29121855 TI - Saccade adaptation deficits in developmental dyslexia suggest disruption of cerebellar-dependent learning. AB - BACKGROUND: Estimates of the prevalence of developmental dyslexia in the general population range from 5% to as many as 10%. Symptoms include reading, writing, and language deficits, but the severity and mix of symptoms can vary widely across individuals. In at least some people with dyslexia, the structure and function of the cerebellum may be disordered. Saccadic adaptation requires proper function of the cerebellum and brainstem circuitry and might provide a simple, noninvasive assay for early identification and sub-phenotyping in populations of children who may have dyslexia. METHODS: Children between the ages of 7 and 15 served as participants in this experiment. Fifteen had been diagnosed with developmental dyslexia and an additional 15 were typically developing children. Five of the participants diagnosed with dyslexia were also diagnosed with an attention deficit hyperactivity disroder and were excluded from further analyses. Participants performed in a saccadic adaptation task in which visual errors were introduced at the end of saccadic eye movements. The amplitudes of primary saccades were measured and plotted as a function of the order in which they occurred. Lines of best fit were calculated. Significant changes in the amplitude of primary saccades were identified. RESULTS: 12/15 typically developing children had significant adaptation of saccade amplitude in this experiment. 1/10 participants with dyslexia appropriately altered saccade amplitudes to reduce the visual error introduced in the saccade adaptation paradigm. CONCLUSIONS: Proper cerebellar function is required for saccadic adaptation, but in at least some children with dyslexia, cerebellar structure and function may be disordered. Consistent with this hypothesis, the data presented in this report clearly illustrate a difference in the ability of children with dyslexia to adapt saccade amplitudes in response to imposed visual errors. Saccadic adaptation might provide a noninvasive assay for early identification of dyslexia. Future work will determine whether reduced saccadic adaptation is pervasive in dyslexia or whether this identifies a sub-phenotype within the larger population of people identified with reading and language deficits. PMID- 29121856 TI - Genome-wide identification and analysis of MAPK and MAPKK gene family in Chinese jujube (Ziziphus jujuba Mill.). AB - BACKGROUND: Chinese jujube (Ziziphus jujuba Mill.) is one of the most important members in the Rhamnaceae family. The whole genome sequence and more than 30,000 proteins of Chinese jujube have been obtained in 2014. Mitogen-activated protein kinase cascades are universal signal transduction modules in plants, which is rapidly activated under various biotic and abiotic stresses. To date, there has been no comprehensive analysis of the MAPK and MAPKK gene family in Chinese jujube at the whole genome level. RESULTS: By performing a series of bioinformatics analysis, ten MAPK and five MAPKK genes were identified from the genome database of Chinese jujube, and then compared with the homologous genes from Arabidopsis. Phylogenetic analysis showed that ZjMAPKs was classified into four known groups, including A, B, C and D. ZjMAPKs contains five members of the TEY phosphorylation site and five members with the TDY motif. The ZjMAPKK family was subsequently divided into three groups, A, B and D. The gene structure, conserved motifs, functional annotation and chromosome distribution of ZjMAPKs and ZjMAPKKs were also predicted. ZjMAPKs and ZjMAPKKs were distributed on nine pseudo-chromosomes of Chinese jujube. Subsequently, expression analysis of ZjMAPK and ZjMAPKK genes using reverse transcription PCR and quantitative real-time PCR was carried out. The majority of ZjMAPK and ZjMAPKK genes were expressed in all tested organs/tissues with considerable differences in transcript levels indicating that they might be constitutively expressed. Moreover, ZjMKK5 was specific expressed in early development stage of jujube flower bud, indicating it plays some roles in reproductive organs development. The transcript expression of most ZjMAPK and ZjMAPKK genes was down-regulated in response to plant growth regulators, darkness treatment and phytoplasma infection. CONCLUSIONS: We identified ten ZjMAPK and five ZjMAPKK genes from the genome database of Chinese jujube, the research results shown that ZjMPKs and ZjMKKs have the different expression patterns, indicating that they might play different roles in response to various treatments. The results provide valuable information for the further elucidation of physiological functions and biological roles of jujube MAPKs and MAPKKs. PMID- 29121857 TI - Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution. AB - BACKGROUND: Genotyping and whole-genome sequencing data have been generated for hundreds of thousands of cattle. International consortia used these data to compile imputation reference panels that facilitate the imputation of sequence variant genotypes for animals that have been genotyped using dense microarrays. Association studies with imputed sequence variant genotypes allow for the characterization of quantitative trait loci (QTL) at nucleotide resolution particularly when individuals from several breeds are included in the mapping populations. RESULTS: We imputed genotypes for 28 million sequence variants in 17,229 cattle of the Braunvieh, Fleckvieh and Holstein breeds in order to compile large mapping populations that provide high power to identify QTL for milk production traits. Association tests between imputed sequence variant genotypes and fat and protein percentages in milk uncovered between six and thirteen QTL (P < 1e-8) per breed. Eight of the detected QTL were significant in more than one breed. We combined the results across breeds using meta-analysis and identified a total of 25 QTL including six that were not significant in the within-breed association studies. Two missense mutations in the ABCG2 (p.Y581S, rs43702337, P = 4.3e-34) and GHR (p.F279Y, rs385640152, P = 1.6e-74) genes were the top variants at QTL on chromosomes 6 and 20. Another known causal missense mutation in the DGAT1 gene (p.A232K, rs109326954, P = 8.4e-1436) was the second top variant at a QTL on chromosome 14 but its allelic substitution effects were inconsistent across breeds. It turned out that the conflicting allelic substitution effects resulted from flaws in the imputed genotypes due to the use of a multi-breed reference population for genotype imputation. CONCLUSIONS: Many QTL for milk production traits segregate across breeds and across-breed meta analysis has greater power to detect such QTL than within-breed association testing. Association testing between imputed sequence variant genotypes and phenotypes of interest facilitates identifying causal mutations provided the accuracy of imputation is high. However, true causal mutations may remain undetected when the imputed sequence variant genotypes contain flaws. It is highly recommended to validate the effect of known causal variants in order to assess the ability to detect true causal mutations in association studies with imputed sequence variants. PMID- 29121858 TI - Detection of circulating miRNAs: comparative analysis of extracellular vesicle incorporated miRNAs and cell-free miRNAs in whole plasma of prostate cancer patients. AB - BACKGROUND: Circulating cell-free miRNAs have emerged as promising minimally invasive biomarkers for early detection, prognosis and monitoring of cancer. They can exist in the bloodstream incorporated into extracellular vesicles (EVs) and ribonucleoprotein complexes. However, it is still debated if EVs contain biologically meaningful amounts of miRNAs and may provide a better source of miRNA biomarkers than whole plasma. The aim of this study was to systematically compare the diagnostic potential of prostate cancer-associated miRNAs in whole plasma and in plasma EVs. METHODS: RNA was isolated from whole plasma and plasma EV samples from a well characterised cohort of 50 patient with prostate cancer (PC) and 22 patients with benign prostatic hyperplasia (BPH). Nine miRNAs known to have a diagnostic potential for PC in cell-free blood were quantified by RT qPCR and the relative quantities were compared between patients with PC and BPH and between PC patients with Gleason score >= 8 and <=6. RESULTS: Only a small fraction of the total cell-free miRNA was recovered from the plasma EVs, however the EV-incorporated and whole plasma cell-free miRNA profiles were clearly different. Four of the miRNAs analysed showed a diagnostic potential in our patient cohort. MiR-375 could differentiate between PC and BPH patients when analysed in the whole plasma, while miR-200c-3p and miR-21-5p performed better when analysed in plasma EVs. EV-incorporated but not whole plasma Let-7a-5p level could distinguish PC patients with Gleason score >= 8 vs <=6. CONCLUSIONS: This study demonstrates that for some miRNA biomarkers EVs provide a more consistent source of RNA than whole plasma, while other miRNAs show better diagnostic performance when tested in the whole plasma. PMID- 29121859 TI - Alterations in PGC1alpha expression levels are involved in colorectal cancer risk: a qualitative systematic review. AB - BACKGROUND: Colorectal cancer (CRC) is a major global public health problem and the second leading cause of cancer-related death. Mitochondrial dysfunction has long been suspected to be involved in this type of tumorigenesis, as supported by an accumulating body of research evidence. However, little is known about how mitochondrial alterations contribute to tumorigenesis. Mitochondrial biogenesis is a fundamental cellular process required to maintain functional mitochondria and as an adaptive mechanism in response to changing energy requirements. Mitochondrial biogenesis is regulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A or PGC1alpha). In this paper, we report a systematic review to summarize current evidence on the role of PGC1alpha in the initiation and progression of CRC. The aim is to provide a basis for more comprehensive research. METHODS: The literature search, data extraction and quality assessment were performed according to the document Guidance on the Conduct of Narrative Synthesis in Systematic Reviews and the PRISMA declaration. RESULTS: The studies included in this review aimed to evaluate whether increased or decreased PGC1alpha expression affects the development of CRC. Each article proposes a possible molecular mechanism of action and we create two concept maps. CONCLUSION: Our systematic review indicates that altered expression of PGC1alpha modifies CRC risk. Most studies showed that overexpression of this gene increases CRC risk, while some studies indicated that lower than normal expression levels could increase CRC risk. Thus, various authors propose PGC1alpha as a good candidate molecular target for cancer therapy. Reducing expression of this gene could help to reduce risk or progression of CRC. PMID- 29121860 TI - Pneumatosis cystoides intestinalis associated with sunitinib and a literature review. AB - BACKGROUND: Pneumatosis cystoides intestinalis (PCI) is a rare self-limiting condition characterized by air-filled cysts within intestinal walls. Diagnosis should be prudent because it can mimic pneumoperitoneum leading to unnecessary treatment such as surgical exploration. Although various drugs including anti neoplastic agents have been suggested as etiologies, cases related to sunitinib are sparse. Because of the rarity of this unusual side effect by sunitinib, we report the case report. CASE PRESENTATION: A 68-year-old female with pancreatic neuroendocrine tumor who was treated with sunitinb for 4 months visited to our hospital complaining of severe diarrhea and mild abdominal discomfort. The abdominal X-ray showed subdiaphragmatic air mimicking intestinal perforation. After the meticulous evaluation including abdomino-pelvic computed tomography, the patient was diagnosed of PCI induced by sunitinib and fully recovered with conservative management. CONCLUSIONS: It is important to note that PCI can develop after treatment with sunitinib because PCI has not been widely known as an adverse event caused by the agent. Furthemore, emergent surgery while sunitinib was administrated without adequate washout period can result in substantial surgical complications which could be avoided with the precise diagnosis. PMID- 29121861 TI - Transcriptomics, metabolomics and histology indicate that high-carbohydrate diet negatively affects the liver health of blunt snout bream (Megalobrama amblycephala). AB - BACKGROUND: Global trend of the introduction of high levels of relatively cheap carbohydrates to reduce the amount of costly protein in the aquatic animal feed production has affected the aquaculture of an economically important cyprinid fish, blunt snout bream (Megalobrama amblycephala). This dietary shift has resulted in increased prevalence of metabolic disorders, often causing economic losses. High dietary intake of carbohydrates, associated with obesity, is one of the major causes of non-alcoholic fatty liver disease (NAFLD) in humans. RESULTS: We have conducted an eight-week feeding trial to better understand how a high carbohydrate diet (HCBD) affects the liver health in this fish. Hepatosomatic index and lipid content were significantly (P < 0.05) higher in the HCBD group. Histology results also suggested pathological changes in the livers of HCBD group, with excessive lipid accumulation and indication of liver damage. Metabolomics and serum biochemistry analyses showed that a number of metabolites indicative of liver damage were increased in the HCBD group. This group also exhibited low levels of betaine, which is a metabolite crucial for maintaining the healthy liver functions. Transcriptomic and qPCR analyses indicated that HCBD had a strong impact on the expression of a large number of genes associated with the NAFLD and insulin signalling pathways, which may lead to the development of insulin resistance in hepatocytes, pathological liver changes, and eventually the NAFLD. CONCLUSIONS: Transcriptomics, metabolomics and histology results all indicate early symptoms of liver damage. However whether these would actually lead to the development of NAFLD after a longer period of time, remains inconclusive. Additionally, a very high number of upregulated genes in the HCBD group associated with several neurodegenerative diseases is a strong indication of neurodegenerative changes caused by the high-carbohydrate diet in blunt snout bream. This suggests that fish might present a good model to study neurodegenerative changes associated with high-carbohydrate diet in humans. PMID- 29121863 TI - Multiplex real-time PCR assay for detection of Escherichia coli O157:H7 and screening for non-O157 Shiga toxin-producing E. coli. AB - BACKGROUND: Shiga toxin-producing Escherichia coli (STEC), including E. coli O157:H7, are responsible for numerous foodborne outbreaks annually worldwide. E. coli O157:H7, as well as pathogenic non-O157:H7 STECs, can cause life-threating complications, such as bloody diarrhea (hemolytic colitis) and hemolytic-uremic syndrome (HUS). Previously, we developed a real-time PCR assay to detect E. coli O157:H7 in foods by targeting a unique putative fimbriae protein Z3276. To extend the detection spectrum of the assay, we report a multiplex real-time PCR assay to specifically detect E. coli O157:H7 and screen for non-O157 STEC by targeting Z3276 and Shiga toxin genes (stx1 and stx2). Also, an internal amplification control (IAC) was incorporated into the assay to monitor the amplification efficiency. METHODS: The multiplex real-time PCR assay was developed using the Life Technology ABI 7500 System platform and the standard chemistry. The optimal amplification mixture of the assay contains 12.5 MUl of 2 * Universal Master Mix (Life Technology), 200 nM forward and reverse primers, appropriate concentrations of four probes [(Z3276 (80 nM), stx1 (80 nM), stx2 (20 nM), and IAC (40 nM)], 2 MUl of template DNA, and water (to make up to 25 MUl in total volume). The amplification conditions of the assay were set as follows: activation of TaqMan at 95 degrees C for 10 min, then 40 cycles of denaturation at 95 degrees C for 10 s and annealing/extension at 60 degrees C for 60 s. RESULTS: The multiplex assay was optimized for amplification conditions. The limit of detection (LOD) for the multiplex assay was determined to be 200 fg of bacterial DNA, which is equivalent to 40 CFU per reaction which is similar to the LOD generated in single targeted PCRs. Inclusivity and exclusivity determinants were performed with 196 bacterial strains. All E. coli O157:H7 (n = 135) were detected as positive and all STEC strains (n = 33) were positive for stx1, or stx2, or stx1 and stx2 (Table 1). No cross reactivity was detected with Salmonella enterica, Shigella strains, or any other pathogenic strains tested. CONCLUSIONS: A multiplex real time PCR assay that can rapidly and simultaneously detect E. coli O157:H7 and screen for non-O157 STEC strains has been developed and assessed for efficacy. The inclusivity and exclusivity tests demonstrated high sensitivity and specificity of the multiplex real-time PCR assay. In addition, this multiplex assay was shown to be effective for the detection of E. coli O157:H7 from two common food matrices, beef and spinach, and may be applied for detection of E. coli O157:H7 and screening for non-O157 STEC strains from other food matrices as well. PMID- 29121862 TI - Human papillomavirus in semen and the risk for male infertility: a systematic review and meta-analysis. AB - BACKGROUND: Human papillomavirus (HPV) is one of the most prevalent sexually transmitted viruses. Despite the increasing evidence of HPV prevalence in semen, the worldwide distribution of HPV types in semen and risk for male infertility remain inconclusive. METHODS: Four electronic databases were searched for English language studies conducted between January 1990 and December 2016 that reported HPV DNA prevalence in semen. Based on the PRISMA guidelines, HPV prevalence was estimated among general population and fertility clinic attendees, respectively, and heterogeneity testing was performed using Cochran's Q and I 2 statistics. The association between HPV positivity and male infertility was evaluated by a meta analysis of case-control studies. RESULTS: A total of 31 eligible studies comprising 5194 males were included. The overall prevalence of HPV DNA in semen was 11.4% (95% CI = 7.8-15.0%) in general population (n = 2122) and 20.4% (95% CI = 16.2-24.6%) in fertility clinic attendees (n = 3072). High-risk type prevalence was 10.0% (95% CI = 5.9-14.0%) and 15.5% (95% CI = 11.4-19.7%), respectively. HPV16 was the most common type, with a prevalence of 4.8% (95% CI = 1.7-7.8%) in general population and 6.0% (95% CI = 3.8-8.2%) in fertility clinic attendees. A significantly increased risk of infertility was found for males with HPV positivity in semen (OR = 2.93, 95% CI = 2.03-4.24). CONCLUSIONS: Seminal HPV infection is common worldwide, which may contribute to the risk of male infertility. PMID- 29121864 TI - Comparative Transcriptome and DNA methylation analyses of the molecular mechanisms underlying skin color variations in Crucian carp (Carassius carassius L.). AB - BACKGROUND: Crucian carp is a popular ornamental strain in Asia with variants in body color. To further explore the genetic mechanisms underlying gray and red body color formation in crucian carp, the skin transcriptomes and partial DNA methylation sites were obtained from red crucian carp (RCC) and white crucian carp (WCC). Here, we show significant differences in mRNA expression and DNA methylation sites between skin tissues of RCC and WCC. RESULTS: Totals of 3434 and 3683 unigenes had significantly lower and higher expression in WCC, respectively, compared with unigenes expressed in RCC. Some potential genes for body color development were further identified by quantitative polymerase chain reaction, such as mitfa, tyr, tyrp1, and dct, which were down-regulated, and foxd3, hpda, ptps, and gch1, which were up-regulated. A KEGG pathway analysis indicated that the differentially expressed genes were mainly related to mitogen activated protein kinase (MAPK), Wnt, cell cycle, and endocytosis signaling pathways, as well as variations in melanogenesis in crucian carp. In addition, some differentially expressed DNA methylation site genes were related to pigmentation, including mitfa, tyr, dct, foxd3, and hpda. The differentially expressed DNA methylation sites were mainly involved in signaling pathways, including MAPK, cAMP, endocytosis, melanogenesis, and Hippo. CONCLUSIONS: Our study provides the results of comparative transcriptome and DNA methylation analyses between RCC and WCC skin tissues and reveals that the molecular mechanism of body color variation in crucian carp is strongly related to disruptions in gene expression and DNA methylation during pigmentation. PMID- 29121865 TI - Temporally distinct transcriptional regulation of myocyte dedifferentiation and Myofiber growth during muscle regeneration. AB - BACKGROUND: Tissue regeneration requires a series of steps, beginning with generation of the necessary cell mass, followed by cell migration into damaged area, and ending with differentiation and integration with surrounding tissues. Temporal regulation of these steps lies at the heart of the regenerative process, yet its basis is not well understood. The ability of zebrafish to dedifferentiate mature "post-mitotic" myocytes into proliferating myoblasts that in turn regenerate lost muscle tissue provides an opportunity to probe the molecular mechanisms of regeneration. RESULTS: Following subtotal excision of adult zebrafish lateral rectus muscle, dedifferentiating residual myocytes were collected at two time points prior to cell cycle reentry and compared to uninjured muscles using RNA-seq. Functional annotation (GAGE or K-means clustering followed by GO enrichment) revealed a coordinated response encompassing epigenetic regulation of transcription, RNA processing, and DNA replication and repair, along with protein degradation and translation that would rewire the cellular proteome and metabolome. Selected candidate genes were phenotypically validated in vivo by morpholino knockdown. Rapidly induced gene products, such as the Polycomb group factors Ezh2 and Suz12a, were necessary for both efficient dedifferentiation (i.e. cell reprogramming leading to cell cycle reentry) and complete anatomic regeneration. In contrast, the late activated gene fibronectin was important for efficient anatomic muscle regeneration but not for the early step of myocyte cell cycle reentry. CONCLUSIONS: Reprogramming of a "post-mitotic" myocyte into a dedifferentiated myoblast requires a complex coordinated effort that reshapes the cellular proteome and rewires metabolic pathways mediated by heritable yet nuanced epigenetic alterations and molecular switches, including transcription factors and non-coding RNAs. Our studies show that temporal regulation of gene expression is programmatically linked to distinct steps in the regeneration process, with immediate early expression driving dedifferentiation and reprogramming, and later expression facilitating anatomical regeneration. PMID- 29121866 TI - The roles of call wall invertase inhibitor in regulating chilling tolerance in tomato. AB - BACKGROUND: Hexoses are important metabolic signals that respond to abiotic and biotic stresses. Cold stress adversely affects plant growth and development, limiting productivity. The mechanism by which sugars regulate plant cold tolerance remains elusive. RESULTS: We examined the function of INVINH1, a cell wall invertase inhibitor, in tomato chilling tolerance. Cold stress suppressed the transcription of INVINH1 and increased that of cell wall invertase genes, Lin6 and Lin8 in tomato seedlings. Silencing INVINH1 expression in tomato increased cell wall invertase activity and enhanced chilling tolerance. Conversely, transgenic tomatoes over-expressing INVINH1 showed reduced cell wall invertase activity and were more sensitive to cold stress. Chilling stress increased glucose and fructose levels, and the hexoses content increased or decreased by silencing or overexpression INVINH1. Glucose applied in vitro masked the differences in chilling tolerance of tomato caused by the different expressions of INVINH1. The repression of INVINH1 or glucose applied in vitro regulated the expression of C-repeat binding factors (CBFs) genes. Transcript levels of NCED1, which encodes 9-cisepoxycarotenoid dioxygenase (NCED), a key enzyme in the biosynthesis of abscisic acid, were suppressed by INVINH1 after exposure to chilling stress. Meanwhile, application of ABA protected plant from chilling damage caused by the different expression of INVINH1. CONCLUSIONS: In tomato, INVINH1 plays an important role in chilling tolerance by adjusting the content of glucose and expression of CBFs. PMID- 29121867 TI - Successful pregnancy without disease progression of radioiodine refractory papillary thyroid carcinoma: a case report. AB - BACKGROUND: Pregnancy is an unquantifiable risk to accelerate tumor growth of papillary thyroid carcinoma (PTC), and whether pregnancy induces an unfavorable prognosis of radioiodine refractory papillary thyroid carcinoma (RR-PTC) remains unknown. CASE PRESENTATION: We investigated the impact of pregnancy on the prognosis of pulmonary metastases in an RR-PTC woman via a long-term clinical follow-up and consecutive computed tomography examinations and serum tests. After a successful pregnancy, the metastatic lesions shrank with serum thyroglobulin slightly fluctuated under sustained thyroid stimulating hormone (TSH) suppression, demonstrating a favorable outcome. CONCLUSIONS: This case study indicates that metastatic RR-PTC may not be aggravated by pregnancy under TSH suppression, and pregnancy should not be contraindicated in RR-PTC patients with stable disease. PMID- 29121868 TI - Sequence-based information-theoretic features for gene essentiality prediction. AB - BACKGROUND: Identification of essential genes is not only useful for our understanding of the minimal gene set required for cellular life but also aids the identification of novel drug targets in pathogens. In this work, we present a simple and effective gene essentiality prediction method using information theoretic features that are derived exclusively from the gene sequences. RESULTS: We developed a Random Forest classifier and performed an extensive model performance evaluation among and within 15 selected bacteria. In intra-organism predictions, where training and testing sets are taken from the same organism, AUC (Area Under the Curve) scores ranging from 0.73 to 0.90, 0.84 on average, were obtained. Cross-organism predictions using 5-fold cross-validation, pairwise, leave-one-species-out, leave-one-taxon-out, and cross-taxon yielded average AUC scores of 0.88, 0.75, 0.80, 0.82, and 0.78, respectively. To further show the applicability of our method in other domains of life, we predicted the essential genes of the yeast Schizosaccharomyces pombe and obtained a similar accuracy (AUC 0.84). CONCLUSIONS: The proposed method enables a simple and reliable identification of essential genes without searching in databases for orthologs and demanding further experimental data such as network topology and gene-expression. PMID- 29121869 TI - Ablation of epidermal RXRalpha in cooperation with activated CDK4 and oncogenic NRAS generates spontaneous and acute neonatal UVB induced malignant metastatic melanomas. AB - BACKGROUND: Understanding the underlying molecular mechanisms involved in the formation of cutaneous malignant melanoma is critical for improved diagnosis and treatment. Keratinocytic nuclear receptor Retinoid X Receptor alpha (RXRalpha) has a protective role against melanomagenesis and is involved in the regulation of keratinocyte and melanocyte homeostasis subsequent acute ultraviolet (UV) irradiation. METHODS: We generated a trigenic mouse model system (RXRalpha ep-/- | Tyr-NRAS Q61K | CDK4 R24C/R24C ) harboring an epidermal knockout of Retinoid X Receptor alpha (RXRalpha ep-/- ), combined with oncogenic NRAS Q61K (constitutively active RAS) and activated CDK4 R24C/R24C (constitutively active CDK4). Those mice were subjected to a single neonatal dose of UVB treatment and the role of RXR alpha was evaluated by characterizing the molecular and cellular changes that took place in the untreated and UVB treated trigenic RXRalpha ep-/- mice compared to the control mice with functional RXRalpha. RESULTS: Here we report that the trigenic mice develops spontaneous melanoma and exposure to a single neonatal UVB treatment reduces the tumor latency in those mice compared to control mice with functional RXRalpha. Melanomas from the trigenic RXRalpha ep-/- mice are substantial in size, show increased proliferation, exhibit increased expression of malignant melanoma markers and exhibit enhanced vascularization. Altered expression of several biomarkers including increased expression of activated AKT, p21 and cyclin D1 and reduced expression of pro-apoptotic marker BAX was observed in the tumor adjacent normal (TAN) skin of acute ultraviolet B treated trigenic RXRalpha ep-/- mice. Interestingly, we observed a significant increase in p21 and Cyclin D1 in the TAN skin of un-irradiated trigenic RXRalpha ep-/- mice, suggesting that those changes might be consequences of loss of functional RXRalpha in the melanoma microenvironment. Loss of RXRalpha in the epidermal keratinocytes in combination with oncogenic NRAS Q61K and CDK4 R24C/R24C mutations in trigenic mice led to significant melanoma invasion into the draining lymph nodes as compared to controls with functional RXRalpha. CONCLUSIONS: Our study demonstrates the protective role of keratinocytic RxRalpha in (1) suppressing spontaneous and acute UVB-induced melanoma, and (2) preventing progression of the melanoma to malignancy in the presence of driver mutations like activated CDK4 R24C/R24C and oncogenic NRAS Q61K . PMID- 29121870 TI - Trends in newborn umbilical cord care practices in Sokoto and Bauchi States of Nigeria: the where, who, how, what and the ubiquitous role of traditional birth attendants: a lot quality assurance sampling survey. AB - BACKGROUND: Neonatal infections caused by unsafe umbilical cord practices account for the majority of neonatal deaths in Nigeria. We examined the trends in umbilical cord care practices between 2012 and 2015 that coincided with the introduction of chlorhexidine digluconate 7.1% gel in Bauchi and Sokoto States. METHODS: We obtained data from three rounds of lot quality assurance samples (LQAS) surveys conducted in 2012, 2013 and 2015. Households were randomly sampled in each round that totaled 1140 and 1311 households in Bauchi and Sokoto States respectively. Mothers responded to questions on cord care practices in the last delivery. Coverage estimates of practice indicators were obtained for each survey period. Local Government Area (LGA) estimates for each indicator were obtained with alpha <= 5%, and beta <=20% statistical errors and aggregated to State-level estimates with finite sample correction relative to the LGA population. RESULTS: Over 75 and 80% of deliveries in Bauchi and Sokoto States respectively took place at home. The proportion of deliveries in public facilities reported by mothers ranged from 19% in 2012 to 22.4% in 2015 in Bauchi State and from 12.9 to 13.2% in 2015 in Sokoto State. Approximately 50% of deliveries in Bauchi and more than 80% in Sokoto States were assisted by traditional birth attendants (TBAs) or relatives and friends, with little change in the survey periods. In Bauchi and in Sokoto States, over 75% and over 80% of newborn cords were cut with razor blades underscoring the pervasive role of the TBAs in the immediate postpartum period. Use of chlorhexidine digluconate 7.1% gel for cord dressing significantly increased to the highest level in 2015 in both States. Health workers who attended deliveries in health facilities switched from methylated spirit to chlorhexidine. There were no observable changes in cord care practices among the TBAs. CONCLUSION: Unsafe umbilical cord care practices remained prevalent in Bauchi and Sokoto States of Nigeria, although a recent introduction of chlorhexidine digluconate 7.1% gel positively changed the cord care practices toward safer practices among public health providers. TBAs, friends and relatives played the strongest immediate postpartum roles and mostly retained the unsafe cord care practices such as use of ash, cow dung and hot compress. We recommend that existing TBAs are retrained and refocused to forge stronger links between communities and the primary health centers to increase mothers' access to skilled birth attendants. PMID- 29121871 TI - Predictive abilities of cardiovascular biomarkers to rapid decline of renal function in Chinese community-dwelling population: a 5-year prospective analysis. AB - BACKGROUND: Predictive abilities of cardiovascular biomarkers to renal function decline are more significant in Chinese community-dwelling population without glomerular filtration rate (GFR) below 60 ml/min/1.73m2, and long-term prospective study is an optimal choice to explore this problem. Aim of this analysis was to observe this problem during the follow-up of 5 years. METHODS: In a large medical check-up program in Beijing, there were 948 participants with renal function evaluated at baseline and follow-up of 5 years. Physical examinations were performed by well-trained physicians. Blood samples were analyzed by qualified technicians in central laboratory. RESULTS: Median rate of renal function decline was 1.46 (0.42-2.91) mL/min/1.73m2/year. Rapid decline of renal function had a prevalence of 23.5% (223 participants). Multivariate linear and Logistic regression analyses confirmed that age, sex, baseline GFR, homocysteine and N-terminal pro B-type natriuretic peptide (NT-proBNP) had independently predictive abilities to renal function decline rate and rapid decline of renal function (p < 0.05 for all). High-sensitivity cardiac troponin T (hs-cTnT), carotid femoral pulse wave velocity and central augmentation index had no statistically independent association with renal function decline rate and rapid decline of renal function (p > 0.05 for all). CONCLUSIONS: Homocysteine and NT-proBNP rather than hs-cTnT had independently predictive abilities to rapid decline of renal function in Chinese community-dwelling population without GFR below 60 ml/min/1.73m2. Baseline GFR was an independent factor predicting the rapid decline of renal function. Arterial stiffness and compliance had no independent effect on rapid decline of renal function. This analysis has a significant implication for public health, and changing the homocysteine and NT proBNP levels might slow the rapid decline of renal function. PMID- 29121872 TI - Diagnostic and prognostic value of CEA, CA19-9, AFP and CA125 for early gastric cancer. AB - BACKGROUND: The diagnostic and prognostic significance of carcinoembryonic antigen (CEA), carbohydrate associated antigen 19-9 (CA19-9), alpha-fetoprotein (AFP) and cancer antigen 125 (CA125) in early gastric cancer have not been investigated yet. Thus, the present study aimed to explore the diagnostic and prognostic significance of the four tumor markers for early gastric cancer. METHODS: From September 2008 to March 2015, 587 early gastric cancer patients were given radical gastrectomy in our center. The clinicopathological characteristics were recorded. The association between levels of CEA and CA19-9 and clinicopathological characteristics and prognosis of patients were analyzed. RESULTS: There were 444 men (75.6%) and 143 women (24.4%). The median age was 57 years (ranged 21-85). The 1-, 3- and 5-year overall survival rate was 99.1%, 96.8% and 93.1%, respectively. The positive rate of CEA, CA19-9, AFP and CA125 was 4.3%, 4.8%, 1.5% and 1.9%, respectively. The positive rate of all markers combined was 10.4%. The associations between the clinicopathological features and levels of CEA and CA19-9 were analyzed. No significant association was found between CEA level and clinicopathological features. However, elevated CA19-9 level was correlated with female gender and presence of lymph node metastasis. Age > 60 years old, presence of lymph node metastasis and elevation of CEA level were independent risk factors for poor prognosis of early gastric cancer. CONCLUSIONS: The positive rates of CEA, CA19-9, APF and CA125 were relatively low for early gastric cancer. Elevation of CA19-9 level was associated with female gender and presence of lymph node metastasis. Elevation of CEA level was an independent risk factor for the poor prognosis of early gastric cancer. PMID- 29121873 TI - Barriers to HPV self-sampling and cytology among low-income indigenous women in rural areas of a middle-income setting: a qualitative study. AB - BACKGROUND: Data is needed about barriers to self-collection of Human Papillomavirus (HPV) samples and cytology among low-income, disadvantaged women living in rural areas of lower-income countries as these women are at increased risk of cervical cancer mortality. METHODS: Individual interviews (n = 29), focus groups (n = 7, 5-11 participants) and discussion groups (n = 2, 18-25 participants) were organized with women from three indigenous ethnic groups residing in rural areas in Mexico, after they were provided with free, self sampled HPV tests. These groups are low-income, underserved by healthcare and have historically been on the receiving end of racism and social exclusion. Descriptive, qualitative content analysis was done, including two cycles of coding. RESULTS: Interview and focus/discussion group data indicate women had limited understanding of HPV's role in cervical cancer etiology. They identified HPV's existence, that cytology detects cervical cancer, the need for regular testing and that cervical cancer is sexually transmitted. Organizational barriers to clinic-based cytology included irregular supplies of disposable speculums, distance to clinics and lack of clear communication by healthcare personnel. Women considered self-collected HPV-testing easy, less embarrassing and less painful than cytology, an opportunity for self-care and most felt they understood how to take a self-sample after a 20-min explanation. Some women feared hurting themselves when taking the self-sample or that they would take the sample incorrectly, which they worried would make the test useless. Attending HPV testing in groups facilitated use by allowing women to discuss their doubts and fears before doing self-collection of the sample or to ask other women who were the first to do the self-sampling what the experience had been like (whether it hurt and how easy it was). Lack of indoor bathrooms was a barrier to doing HPV self-sampling at home, when those homes were resource-poor (one-room dwellings). CONCLUSIONS: Low-income, indigenous Mexican women residing in rural, underserved areas identified their need for cervical cancer screening but encountered multiple barriers to cytology-based screening. They found a number of advantages of HPV self-sampled tests. Employing self-collected HPV-testing instead of cytology could resolve some but not all gender-related, organizational or technical quality-of-care issues within cervical cancer detection and control programs. PMID- 29121874 TI - Evaluating the effectiveness of IV iron dosing for anemia management in common clinical practice: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). AB - BACKGROUND: Anemia management protocols in hemodialysis (HD) units differ conspicuously regarding optimal intravenous (IV) iron dosing; consequently, patients receive markedly different cumulative exposures to IV iron and erythropoiesis-stimulating agents (ESAs). Complementary to IV iron safety studies, our goal was to gain insight into optimal IV iron dosing by estimating the effects of IV iron doses on Hgb, TSAT, ferritin, and ESA dose in common clinical practice. METHODS: 9,471 HD patients (11 countries, 2009-2011) in the DOPPS, a prospective cohort study, were analyzed. Associations of IV iron dose (3 month average, categorized as 0, <300, >=300 mg/month) with 3-month change in Hgb, TSAT, ferritin, and ESA dose were evaluated using adjusted GEE models. RESULTS: Relative change: Monotonically positive associations between IV iron dose and Hgb, TSAT, and ferritin change, and inverse associations with ESA dose change, were observed across multiple strata of prior Hgb, TSAT, and ferritin levels. Absolute change: TSAT, ferritin, and ESA dose changes were nearest zero with IV iron <300 mg/month, rather than 0 mg/month or >=300 mg/month by maintenance or replacement dosing. Findings were robust to numerous sensitivity analyses. CONCLUSIONS: Though residual confounding cannot be ruled out in this observational study, findings suggest that IV iron dosing <300 mg/month, as commonly seen with maintenance dosing of 100-200 mg/month, may be a more effective approach to support Hgb than the higher IV iron doses (300-400 mg/month) often given in many European and North American hemodialysis clinics. Alongside studies supporting the safety of IV iron in 100-200 mg/month dose range, these findings help guide the rational dosing of IV iron in anemia management protocols for everyday hemodialysis practice. PMID- 29121875 TI - Effect of short term diet restriction on gene expression in the bovine hypothalamus using next generation RNA sequencing technology. AB - BACKGROUND: Negative energy balance (NEB) is an imbalance between energy intake and energy requirements for lactation and body maintenance affecting high yielding dairy cows and is of considerable economic importance due to its negative impact on fertility and health in dairy herds. It is anticipated that the cow hypothalamus experiences extensive biochemical changes during the early post partum period in an effort to re-establish metabolic homeostasis. However, there is variation in the tolerance to NEB between individual cows. In order to understand the genomic regulation of ovulation in hypothalamic tissue during NEB, mRNA transcriptional patterns between tolerant and sensitive animals were examined. A short term dietary restriction heifer model was developed which induced abrupt onset of anoestrus in some animals (Restricted Anovulatory; RA) while others maintained oestrous cyclicity (Restricted Ovulatory; RO). A third control group (C) received a higher level of normal feeding. RESULTS: A total of 15,295 genes were expressed in hypothalamic tissue. Between RA and C groups 137 genes were differentially expressed, whereas between RO and C, 32 genes were differentially expressed. Differentially expressed genes were involved in the immune response and cellular motility in RA and RO groups, respectively, compared to C group. The largest difference between groups was observed in the comparison between RA and RO heifers, with 1094 genes shown to be significantly differentially expressed (SDE). Pathway analysis showed that these SDE genes were associated with 6 canonical pathways (P < 0.01), of which neuroactive ligand receptor interaction was the most significant. Within the comparisons the main over-represented pathway functions were immune response including neuroprotection (CXCL10, Q1KLR3, IFIH1, IL1 and IL8; RA v C and RA v RO); energy homeostasis (AgRP and NPY; RA v RO); cell motility (CADH1, DSP and TSP4; RO v C) and prevention of GnRH release (NTSR1 IL1alpha, IL1beta, NPY and PACA; RA v RO). CONCLUSIONS: This information will assist in understanding the genomic factors regulating the influence of diet restriction on fertility and may assist in optimising nutritional and management systems for the improvement in reproductive performance. PMID- 29121876 TI - Perceived stigmatization and its impact on quality of life - results from a large register-based study including breast, colon, prostate and lung cancer patients. AB - BACKGROUND: To date, research on stigmatization among cancer patients and related psychosocial consequences has been scarce and mostly based on small and highly selected samples. We investigated stigmatization and its impact on quality of life among a large sample including four major tumor entities. METHODS: We assessed 858 patients with breast, colon, lung or prostate cancer from two cancer registries. Stigmatization and quality of life (QoL) was assessed with the Social Impact Scale (SIS-D) and the EORTC Quality of Life Questionnaire (European Organization for Research and Treatment of Cancer), respectively. Group effects were analyzed via analyses of variance, relationships were investigated via Pearson's r and stepwise regression analyses. RESULTS: The mean age was 60.7 years, 54% were male. Across cancer sites, the dimensions of stigmatization (isolation, social rejection, financial insecurity and internalized shame) were in the lower and middle range, with the highest values found for isolation. Stigmatization was lowest among prostate cancer patients. Stigmatization predicted all five areas of QoL among breast cancer patients (p < .05), but only affected emotional functioning (p < .01) among lung cancer patients. CONCLUSIONS: We found an inverse relationship between perceived cancer-related stigmatization and various dimensions of QoL, with variation between cancer sites. Breast cancer patients should be focused in individual therapies regarding the negative consequences accompanied by perceived stigmatization. PMID- 29121877 TI - A systematic survey to identify lethal recessive variation in highly managed pig populations. AB - BACKGROUND: Lethal recessive variation can cause prenatal death of homozygous offspring. Although usually present at low-frequency in populations, the impact on individual fitness can be substantial. Until recently, the presence of recessive embryonic lethal variation could only be measured indirectly through reduced fertility. In this study, we estimate the presence of genetic loci associated with both early and late termination of development during gestation in pigs from the wealth of genome data routinely generated by a commercial breeding company. RESULTS: We examined three commercial pig (Sus scrofa) populations for potentially deleterious genetic variation based on 80 K SNP-chip genotypes, and estimate the effects on reproductive traits. 24,000 pigs from three populations were analyzed for missing or depletion of homozygous haplotypes. We identified 145 haplotypes (ranging from 0.5-4 Mb in size) in the genome with complete absence or depletion of homozygous animals. Thirty-five haplotypes show a negative effect on at least one of the analysed reproductive traits (total number born, number of stillborn, and number of mummified piglets). One variant in particular appeared to result in relative late termination of development of fetuses, responsible for a significant fraction of observed stillborn piglets ('mummies'), as they die mid-gestation. Moreover, we identified the BMPER gene as a likely candidate underlying this phenomenon. CONCLUSIONS: Our study shows that although lethal recessive variation is present, the frequency of these alleles is invariably low in these highly managed populations. Nevertheless, due to cumulative effects of deleterious variants, large numbers of affected offspring are produced. Furthermore, our study demonstrates the use of a large-scale commercial genetic experiment to systematically screen for 'natural knockouts' that can increase understanding of gene function. PMID- 29121878 TI - Comparison of femtosecond laser-assisted corneal intrastromal xenotransplantation and the allotransplantation in rhesus monkeys. AB - BACKGROUND: In our previous study, we showed that both allogeneic and autogeneic small-incision femtosecond laser-assisted corneal intrastromal transplantation are safe and effective surgeries. However, the results of small-incision femtosecond laser-assisted intrastromal xenotransplantation have not yet been explored. Additionally, we suggest that glycerol-dehydrated corneal lamellae might provide a possible alternative for this xenogenic implantation approach. METHODS: Corneal inlay lamellae were produced from rabbits and humans using femtosecond laser-assisted surgeries and were dehydrated in glycerol for 1 week at 4 degrees C. These xenogeneic glycerol-dehydrated grafts and fresh allogeneic monkey lamellae were then implanted into rhesus monkeys using small-incision femtosecond laser assistance. Postoperatively, clinical examinations, AS-OCT measurements and tear inflammatory mediator assays were performed. RESULTS: There were no significant changes in the transparency of the corneal lamellae after glycerol dehydration. Following implantation, no evidence of tissue rejection or severe inflammatory responses was observed in the monkeys, and the host corneas remained transparent throughout a 6-month observation period. The grafts were clearly visible via AS-OCT. Corneal thickness increased 1 week postoperatively but subsequently declined and remained unchanged 1 month after surgery. Significant changes were observed in all tear inflammatory mediators in the 'Rabbit to Monkey' group. The trends in changes of tear inflammatory mediators in the 'Human to Monkey' group were similar to those in the 'Rabbit to Monkey' group. At 1 month post-surgery, the levels of most tear inflammatory mediators had decreased, with the exception of IL-1beta, TGF-beta1 and IFN-gamma in the allotransplantation group. CONCLUSION: Small-incision femtosecond laser-assisted intrastromal transplantation minimized invasiveness and improved surgical efficiency. In addition, the host cornea maintained a high level of biocompatibility. Glycerol-dehydrated corneal lamellae might be potentially useful as an alternative inlay xenogeneic material. In this study, we also describe a new treatment that can be used in keratoconus, corneal ectasia, presbyopia, hyperpresbyopia and other diseases. PMID- 29121879 TI - Hypnotic susceptibility and affective states in bipolar I and II disorders. AB - BACKGROUND: Highly hypnotizable individuals have impaired executive function, elevated motor impulsivity and increased emotional sensitivity, which are sometimes found in bipolar disorder patients. It is then reasonable to assume that certain aspects of hypnotic susceptibility differ with the types of bipolar disorder. METHODS: The Stanford Hypnotic Susceptibility Scale: Form C (SHSS:C) test, the Mood Disorder Questionnaire (MDQ), the Hypomanic Checklist-32 (HCL-32) and the Plutchick-van Praag Depression Inventory (PVP) were applied to 62 patients with bipolar I disorder, 33 bipolar II disorder, and 120 healthy volunteers. RESULTS: The passing rate of the SHSS:C 'Moving hands apart' item was higher in bipolar I patients than in controls, whereas for 'Mosquito hallucination' the rate was lower. Bipolar I and II patients scored significantly higher on MDQ, HCL-32 and PVP scales than controls. The passing rates of 'Mosquito hallucination' in controls, 'Arm rigidity' in bipolar I, and 'Age regression' in bipolar II predicted the respective MDQ scores. CONCLUSION: In contrast to cognitive suggestions, bipolar I patients followed motor suggestions more often under hypnosis. Furthermore, both bipolar disorder patients and healthy volunteers demonstrated associations between mania levels and certain hypnotic susceptibility features. Our study aids in better understanding the altered conscious states in bipolar disorders, and encourages the use of related psychotherapy for these patients. PMID- 29121880 TI - Comparison of different therapeutic strategies for complete hydatidiform mole in women at least 40 years old: a retrospective cohort study. AB - BACKGROUND: There are three main therapeutic strategies, namely expectant management (dilation and curettage only), prophylactic chemotherapy and prophylactic total hysterectomy for treating older women with complete hydatidiform mole (CHM). However, the scientific community has so far, not unanimously accepted the above-mentioned methods. The objective of this study was to evaluate the effectiveness of these therapeutic strategies in preventing post molar gestational trophoblastic neoplasia (GTN) pertaining to patients with CHM who were at least 40 years old. METHODS: Hundred and seventy-one patients from our hospital who had histologically been diagnosed of CHM and underwent treatment from January 2004 to December 2013 were included. All patients were followed continuously for a minimum of 2 years after which relevant clinical data were extracted and analysed. RESULTS: All patients were divided to three groups. Group 1 consisted of 124 patients, treated by expectant management, and the incidence of post-molar GTN was 37.1%. Group 2 included 12 patients who received prophylactic chemotherapy, with an incidence of 41.7%. The remaining 35 patients, Group 3, underwent prophylactic total hysterectomy, with the lowest incidence of 11.4%. A significantly lower incidence was noted in group 3 as compared to group 1 (P = 0.004). GTN patients who received prophylactic chemotherapy required, on average, longer time to be diagnosed of GTN and had higher probability of chemotherapy resistance (P = 0.031 and P = 0.024). CONCLUSIONS: This retrospective analysis showed that prophylactic total hysterectomy was the most effective therapeutic strategy for treating CHM in women at least 40 years old of age. PMID- 29121881 TI - Optimal interval of endoscopic screening based on stage distributions of detected gastric cancers. AB - BACKGROUND: Although Korea and Japan have a national gastric cancer screening program, their screening intervals are different. The optimal screening interval of endoscopic screening in Japan was investigated based on the stage distributions of screen-detected gastric cancers. METHODS: Patients with gastric cancer detected by endoscopic and radiographic screenings were selected from the Niigata City Medical Association database. The stage distributions of the detected gastric cancers were compared among patients with different screening histories in both groups. Gastric cancer specific survival rates were analyzed using the Kaplan-Meier method with the log-rank test. RESULTS: There were 1585 and 462 subjects in the endoscopic and radiographic screening groups, respectively. In the endoscopic screening group, the stage IV proportion was lower in patients with screening history 1 and 2 years before diagnosis than in patients without screening history. Stage IV development was significantly related to the absence of screening history (p < 0.001); however, there were no differences between patients who had endoscopic screening history 2 and 3 years before diagnosis. The survival rates were not significantly different between patients with endoscopic screening 1 and 2 years previously (p = 0.7763). The survival rates were significantly higher in patients with endoscopic screening history 1 and 2 years before diagnosis than in patients without screening history (p < 0.001), and in patients with endoscopic screaming 3 years before diagnosis (P < 0.0069). CONCLUSION: The endoscopic screening interval for gastric cancer can be expanded to at least 2 years based on the stage distributions of detected cancers and the patient survival rates. PMID- 29121882 TI - Effectiveness of Balancing Everyday Life (BEL) versus standard occupational therapy for activity engagement and functioning among people with mental illness a cluster RCT study. AB - BACKGROUND: Many with a mental illness have an impoverished everyday life with few meaningful activities and a sedentary lifestyle. The study aim was to evaluate the effectiveness of the 16-week Balancing Everyday Life (BEL) program, compared to care as usual (CAU), for people with mental illness in specialized and community-based psychiatric services. The main outcomes concerned different aspects of subjectively evaluated everyday activities, in terms of the engagement and satisfaction they bring, balance among activities, and activity level. Secondary outcomes pertained to various facets of well-being and functioning. It was hypothesized that those who received the BEL intervention would improve more than the comparison group regarding activity, well-being and functioning outcomes. METHODS: BEL is a group and activity-based lifestyle intervention. CAU entailed active support, mainly standard occupational therapy. The BEL group included 133 participants and the CAU group 93. They completed self-report questionnaires targeting activity and well-being on three occasions - at baseline, after completed intervention (at 16 weeks) and at a six-month follow up. A research assistant rated the participants' level of functioning and symptom severity on the same occasions. Non-parametric statistics were used since these instruments produced ordinal data. RESULTS: The BEL group improved more than the CAU group from baseline to 16 weeks on primary outcomes in terms of activity engagement (p < 0.001), activity level (p = 0.036) and activity balance (p < 0.042). The BEL group also improved more on the secondary outcomes of symptom severity (p < 0.018) and level of functioning (p < 0.046) from baseline to 16 weeks, but not on well-being. High intra-class correlations (0.12-0.22) indicated clustering effects for symptom severity and level of functioning. The group differences on activity engagement (p = 0.001) and activity level (p = 0.007) remained at the follow-up. The BEL group also improved their well-being (quality of life) more than the CAU group from baseline to the follow-up (p = 0.049). No differences were found at that time for activity balance, level of functioning and symptom severity. CONCLUSION: The BEL program was effective compared to CAU in terms of activity engagement. Their improvements were not, however, greater concerning other subjective perceptions, such as satisfaction with daily activities and self-rated health, and clustering effects lowered the dependability regarding findings of improvements on symptoms and functioning. Although the CAU group had "caught up" at the follow-up, the BEL group had improved more on general quality of life. BEL appeared to be important in shortening the time required for participants to develop their engagement in activity and in attaining improved quality of life in a follow-up perspective. TRIAL REGISTRATION: The study was registered with ClinicalTrial.gov. Reg. No. NCT02619318 . PMID- 29121883 TI - The association of duration of boarding in the emergency room and the outcome of patients admitted to the intensive care unit. AB - BACKGROUND: The demand for critical care beds is increasing out of proportion to bed availability. As a result, some critically ill patients are kept in the Emergency Department (ED boarding) awaiting bed availability. The aim of our study is to examine the impact of boarding in the ED on the outcome of patients admitted to the Intensive Care Unit(ICU). METHODS: This was a retrospective analysis of ICU data collected prospectively at King Abdulaziz Medical City, Riyadh from ED between January 2010 and December 2012 and all patients admitted during this time were evaluated for their duration of boarding. Patients were stratified into three groups according to the duration of boarding from ED. Those admitted less than 6 h were classified as Group I, between 6 and 24 h, Group II and more than 24 h as Group III. We carried out multivariate analysis to examine the independent association of boarding time with the outcome adjusting for variables like age, sex, APACHE, Mechanical ventilation, Creatinine, Platelets, INR. RESULTS: During the study period, 940 patients were admitted from the ED to ICU, amongst whom 227 (25%) were admitted to ICU within 6 h, 358 (39%) within 6 24 h and 355 (38%) after 24 h. Patients admitted to ICU within 6 h were younger [48.7 +/- 22.2(group I) years, 50.6 +/- 22.6 (group II), 58.2 +/- 20.9 (group III) (P = 0.04)]with less mechanical ventilation duration[5.9 +/- 8.9 days (Group I), 6.5 +/- 8.1 (Group II) and 10.6 +/- 10.5 (Group III), P = 0.04]. There was a significant increase in hospital mortality [51(22.5), 104(29.1), 132(37.2), P = 0.0006) and the ICU length of stay(LOS) [9.55 days (Group I), 9.8 (Group II) and 10.6 (Group III), (P = 0.002)] with increase in boarding duration. In addition, the delay in admission was an independent risk factor for ICU mortality(OR for group III vs group I is 1.90, P = 0.04) and hospital mortality(OR for group III vs Group I is 2.09, P = 0.007). CONCLUSION: Boarding in the ED is associated with higher mortality. This data highlights the importance of this phenomenon and suggests the need for urgent measures to reduce boarding and to improve patient flow. PMID- 29121884 TI - Evaluation of a physical activity intervention for new parents: protocol paper for a randomized trial. AB - BACKGROUND: Identifying critical life transitions in people's physical activity behaviors may illuminate the most opportune intervention apertures for chronic disease prevention. A substantive evidence base now indicates that parenthood is one of these critical transition points for physical activity decline. This study will examine whether a brief theory-based intervention can prevent a decline in physical activity among new parents over 6 months following intervention. This study protocol represents the first dyad-based physical activity initiative in the parenthood literature involving both mothers and fathers; prior research has focused on only mothers or only fathers (albeit limited), and has shown only short-term changes in physical activity. This study will be investigating whether a theory-based physical activity intervention can maintain or improve moderate to vigorous intensity physical activity measured via accelerometry of new parents over a 6 month period following intervention compared to a control group. METHODS: This study is a 6-month longitudinal randomized controlled trial. Parents are measured at baseline (2 months postpartum) with two assessment points at 6 weeks (3.5 months postpartum) and 3 months (5 months postpartum) and a final follow-up assessment at 6 months (8 months postpartum). The content of the theory based intervention was derived from the results of our prior longitudinal trial of new parents using an adapted theory of planned behavior framework to predict changes in physical activity. RESULTS: A total of 152 couples have been recruited to date. Sixteen couples dropped out after baseline and a total of 88 couples have completed their 6-month measures. DISCUSSION: If the intervention proves successful, couple-based physical activity promotion efforts among parents could be a promising avenue to pursue to help mitigate the declines of physical activity levels during parenthood. These findings could inform public health materials and practitioners. TRIAL REGISTRATION: This trial has been registered with the Clinical Trials Registry maintained by the National Library of Medicine at the National Institutes of Health on April 19, 2014. The registration ID is NCT02290808 . PMID- 29121885 TI - Robotic versus laparoscopic distal pancreatectomy: an up-to-date meta-analysis. AB - BACKGROUND: Laparoscopic distal pancreatectomy (LDP) reduces postoperative morbidity, hospital stay and recovery as compared with open distal pancreatectomy. Many authors believe that robotic surgery can overcome the difficulties and technical limits of LDP thanks to improved surgical manipulation and better visualization. Few studies in the literature have compared the two methods in terms of surgical and oncological outcome. The aim of this study was to compare the results of robotic (RDP) and laparoscopic distal pancreatectomy. METHODS: A systematic review and meta-analysis was conducted of control studies published up to December 2016 comparing LDP and RDP. Two Reviewers independently assessed the eligibility and quality of the studies. The meta-analysis was conducted using either the fixed-effect or the random-effect model. RESULTS: Ten studies describing 813 patients met the inclusion criteria. This meta-analysis shows that the RDP group had a significantly higher rate of spleen preservation [OR 2.89 (95% confidence interval 1.78-4.71, p < 0.0001], a lower rate of conversion to open OR 0.33 (95% CI 0.12-0.92), p = 0.003] and a shorter hospital stay [MD -0.74; (95% CI -1.34 -0.15), p = 0.01] but a higher cost than the LDP group, while other surgical outcomes did not differ between the two groups. CONCLUSION: This meta-analysis suggests that the RDP procedure is safe and comparable in terms of surgical results to LDP. However, even if the RDP has a higher cost compared to LDP, it increases the rate of spleen preservation, reduces the risk of conversion to open surgery and is associated to shorter length of hospital stay. PMID- 29121886 TI - The strange case of Mr. H. Starting dialysis at 90 years of age: clinical choices impact on ethical decisions. AB - BACKGROUND: Starting dialysis at an advanced age is a clinical challenge and an ethical dilemma. The advantages of starting dialysis at "extreme" ages are questionable as high dialysis-related morbidity induces a reflection on the cost- benefit ratio of this demanding and expensive treatment in a person that has a short life expectancy. Where clinical advantages are doubtful, ethical analysis can help us reach decisions and find adapted solutions. CASE PRESENTATION: Mr. H is a ninety-year-old patient with end-stage kidney disease that is no longer manageable with conservative care, in spite of optimal nutritional management, good blood pressure control and strict clinical and metabolic evaluations; dialysis is the next step, but its morbidity is challenging. The case is analysed according to principlism (beneficence, non-maleficence, justice and respect for autonomy). In the setting of care, dialysis is available without restriction; therefore the principle of justice only partially applied, in the absence of restraints on health-care expenditure. The final decision on whether or not to start dialysis rested with Mr. H (respect for autonomy). However, his choice depended on the balance between beneficence and non-maleficence. The advantages of dialysis in restoring metabolic equilibrium were clear, and the expected negative effects of dialysis were therefore decisive. Mr. H has a contraindication to peritoneal dialysis (severe arthritis impairing self performance) and felt performing it with nursing help would be intrusive. Post dialysis fatigue, poor tolerance, hypotension and intrusiveness in daily life of haemodialysis patients are closely linked to the classic thrice-weekly, four-hour schedule. A personalized incremental dialysis approach, starting with one session per week, adapting the timing to the patient's daily life, can limit side effects and "dialysis shock". CONCLUSIONS: An individualized approach to complex decisions such as dialysis start can alter the delicate benefit/side-effect balance, ultimately affecting the patient's choice, and points to a narrative, tailor-made approach as an alternative to therapeutic nihilism, in very old and fragile patients. PMID- 29121887 TI - Biological activities and chemical compositions of slime tracks and crude exopolysaccharides isolated from plasmodia of Physarum polycephalum and Physarella oblonga. AB - BACKGROUND: The myxomycetes derive their common name (slime molds) from the multinucleate trophic stage (plasmodium) in the life cycle, which typically produces a noticeable amount of slimy materials, some of which is normally left behind as a "slime track" as the plasmodium migrates over the surface of a particular substrate. The study reported herein apparently represents the first attempt to investigate the chemical composition and biological activities of slime tracks and the exopolysaccharides (EPS) which cover the surface of the plasmodia of Physarum polycephalum and Physarella oblonga. RESULTS: Chemical analyses indicated that the slime tracks and samples of the EPS consist largely of carbohydrates, proteins and various sulphate groups. Galactose, glucose and rhamnose are the monomers of the cabohydrates present. The slime tracks of both species and the EPS of Phy. oblonga contained rhamnose, but the EPS of Ph. polycephalum had glucose as the major monomer. In term of biological activities, the slime tracks displayed no antimicrobial activity, low anticancer activity and only moderate antioxidant activity. However, EPSs from both species showed remarkable antimicrobial activities, especially toward Candida albicans (zone of inhibition >=20 mm). Minimum inhibitory concentrations of this fungus were found to be 2560 MUg/mL and 1280 MUg/mL for EPS from Phy. oblonga and Ph. polycephalum, respectively. These EPS samples also showed moderate antioxidant activities. However, they both displayed cytotoxicity towards MCF-7 and HepG2 cancer cells. Notably, EPS isolated from the plasmodium of Phy. oblonga inhibited the cell growth of MCF-7 and HepG2 at the half inhibitory concentration (IC50) of 1.22 and 1.11 mg/mL, respectively. CONCLUSIONS: EPS from Ph. polycephalum plasmodium could be a potential source of antifungal compounds, and EPS from Phy. oblonga could be a potential source of anticancer compounds. PMID- 29121888 TI - Comparison of formula and number-right scoring in undergraduate medical training: a Rasch model analysis. AB - BACKGROUND: Progress testing is an assessment tool used to periodically assess all students at the end-of-curriculum level. Because students cannot know everything, it is important that they recognize their lack of knowledge. For that reason, the formula-scoring method has usually been used. However, where partial knowledge needs to be taken into account, the number-right scoring method is used. Research comparing both methods has yielded conflicting results. As far as we know, in all these studies, Classical Test Theory or Generalizability Theory was used to analyze the data. In contrast to these studies, we will explore the use of the Rasch model to compare both methods. METHODS: A 2 * 2 crossover design was used in a study where 298 students from four medical schools participated. A sample of 200 previously used questions from the progress tests was selected. The data were analyzed using the Rasch model, which provides fit parameters, reliability coefficients, and response option analysis. RESULTS: The fit parameters were in the optimal interval ranging from 0.50 to 1.50, and the means were around 1.00. The person and item reliability coefficients were higher in the number-right condition than in the formula-scoring condition. The response option analysis showed that the majority of dysfunctional items emerged in the formula scoring condition. CONCLUSIONS: The findings of this study support the use of number-right scoring over formula scoring. Rasch model analyses showed that tests with number-right scoring have better psychometric properties than formula scoring. However, choosing the appropriate scoring method should depend not only on psychometric properties but also on self-directed test-taking strategies and metacognitive skills. PMID- 29121889 TI - Prevalence and associated factors of medication non-adherence in hematological oncological patients in their home situation. AB - BACKGROUND: Medication non-adherence is associated with poor health outcomes and increased health care costs. Depending on definitions, reported non-adherence rates in cancer patients ranges between 16 and 100%, which illustrates a serious problem. In malignancy, non-adherence reduces chances of achievement of treatment response and may thereby lead to progression or even relapse. Except for Chronic Myeloid Leukemia (CML), the extent of non-adherence has not been investigated in hematological-oncological patients in an outpatient setting. In order to explore ways to optimize cancer treatment results, this study aimed to assess the prevalence of self-administered medication non-adherence and to identify potential associated factors in hematological-oncological patients in their home situation. METHODS: This is an exploratory cross-sectional study, carried out at the outpatient clinic of the Department of Hematology at the VU University medical center, Amsterdam, the Netherlands between February and April 2014. Hematological-oncological outpatients were sent questionnaires retrieving information on patient characteristics, medication adherence, beliefs about medication, anxiety, depression, coping, and quality of life. We performed uni- and multivariable analysis to identify predictors for medication non-adherence. RESULTS: In total, 472 participants were approached of which 259 (55%) completed the questionnaire and met eligibility criteria. Prevalence of adherence in this group (140 male; 54,1%; median age 60 (18-91)) was 50%. In univariate analysis, (lower) age, (higher) education level, living alone, working, perception of receiving insufficient social support, use of bisphosphonates, depression, helplessness (ICQ), global health, role function, emotional function, cognitive function, social functioning, fatigue, dyspnea, diarrhea were found to be significantly related (p = <0.20) to medication non-adherence. In multivariable analysis, younger age, (higher) education level and fatigue remained significantly related (p = <0.10) to medication non-adherence. CONCLUSIONS: This cross-sectional study shows that 50% of the participants were non-adherent. Lower age, living alone and perception of insufficient social support were associated factors of non-adherence in hematological-oncological adult patients in their home-situation. PMID- 29121890 TI - RAM score is an effective predictor for early mortality and recurrence after hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: Liver resection had been regarded as a standard treatment for primary hepatocellular carcinoma (HCC). However, early mortality and recurrence after surgery were still of major concern. RAM (Risk Assessment for early Mortality) scoring system is a newly developed tool for assessing early mortality after hepatectomy for HCC. In this study, we compared RAM scoring system with ALBI and MELD scores for their capability of predicting short-term outcome. METHODS: We retrospectively reviewed patients with hepatocellular carcinoma who were treated with hepatectomy at Chang Gung Memorial Hospital between 1986 and 2015. Their clinical characteristics and perioperative variables were collected. We applied RAM, albumin-bilirubin (ALBI), and model for end-stage liver disease (MELD) scoring systems to predict early mortality and early recurrence in HCC patients after surgery. We investigated the discriminative power of each scoring system by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). RESULTS: A total of 1935 patients (78% male) who underwent liver resection for HCC were included in this study. The median follow-up period was 41.9 months. One hundred and forty-nine patients (7.7%) died within 6 months after hepatectomy (early mortality). All the three scoring systems were effective predictor for early mortality, with higher score indicating higher risk of early mortality (AUC of RAM = 0.723, p < 0.001; AUC of ALBI = 0.682, p < 0.001; AUC of MELD = 0.590, p = 0.002). Cox regression multivariate analysis demonstrated that the RAM class was the most significant independent predictor of early mortality after surgery, while MELD grade failed to discriminatively predict early mortality. In addition to early mortality, the RAM score was also predictive of early recurrence in HCC after surgery. CONCLUSIONS: This study demonstrated that RAM score is an effective and user-friendly bedside scoring system to predict early mortality and early recurrence after hepatectomy for HCC. In addition, the predictive capability of RAM score is superior to ALBI and MELD scores. Further study is warranted to validate our findings. PMID- 29121891 TI - Conference presentation to publication: a retrospective study evaluating quality of abstracts and journal articles in medical education research. AB - BACKGROUND: There is little evidence regarding the comparative quality of abstracts and articles in medical education research. The Medical Education Research Study Quality Instrument (MERSQI), which was developed to evaluate the quality of reporting in medical education, has strong validity evidence for content, internal structure, and relationships to other variables. We used the MERSQI to compare the quality of reporting for conference abstracts, journal abstracts, and published articles. METHODS: This is a retrospective study of all 46 medical education research abstracts submitted to the Society of General Internal Medicine 2009 Annual Meeting that were subsequently published in a peer reviewed journal. We compared MERSQI scores of the abstracts with scores for their corresponding published journal abstracts and articles. Comparisons were performed using the signed rank test. RESULTS: Overall MERSQI scores increased significantly for published articles compared with conference abstracts (11.33 vs 9.67; P < .001) and journal abstracts (11.33 vs 9.96; P < .001). Regarding MERSQI subscales, published articles had higher MERSQI scores than conference abstracts in the domains of sampling (1.59 vs 1.34; P = .006), data analysis (3.00 vs 2.43; P < .001), and validity of evaluation instrument (1.04 vs 0.28; P < .001). Published articles also had higher MERSQI scores than journal abstracts in the domains of data analysis (3.00 vs 2.70; P = .004) and validity of evaluation instrument (1.04 vs 0.26; P < .001). CONCLUSIONS: To our knowledge, this is the first study to compare the quality of medical education abstracts and journal articles using the MERSQI. Overall, the quality of articles was greater than that of abstracts. However, there were no significant differences between abstracts and articles for the domains of study design and outcomes, which indicates that these MERSQI elements may be applicable to abstracts. Findings also suggest that abstract quality is generally preserved from original presentation to publication. PMID- 29121892 TI - Correlates of depressive symptoms in late middle-aged Taiwanese women: findings from the 2009 Taiwan National Health Interview Survey. AB - BACKGROUND: Previous studies have shown that depressive symptoms in middle-aged women were associated with a number of factors such as climacteric symptoms. Nevertheless, studies based on population-based data with a wide range of potential correlates are still scarce. Therefore, the aim of this study was to investigate the correlates of depressive symptoms in late middle-aged Taiwanese women using data from a nationally-representative, population-based survey. METHODS: Women aged 50.0-65.0 years were identified from the dataset of the 2009 Taiwan National Health Interview Survey. The outcome measure was depressive symptoms in the past week, evaluated using the Center for Epidemiologic Studies Short Depression Scale (CES-D 10) with a cut-off score of 10 or greater. Univariate and multiple logistic regression analyses were used to evaluate the correlates of depressive symptoms. RESULTS: The mean age of the 533 respondents was 56.7 years. Depressive symptoms were present in 53 respondents (9.9%). Multiple logistic regression analysis revealed that an education level of elementary school or below (adjusted odds ratio [AOR] = 3.19, P = 0.003), nulliparity (AOR = 8.10, P = 0.001), living alone (AOR = 5.47, P = 0.003), never having worked (AOR = 4.14, P = 0.008), lack of regular exercise (AOR = 3.01, P = 0.003), a perceived health status of fair or bad (AOR = 4.34, P < 0.001), and somatic climacteric symptoms (AOR = 2.32, P = 0.012) were independent and significant factors of depressive symptoms in late middle-aged Taiwanese women. CONCLUSIONS: Findings from this secondary analysis of a population-based survey suggested independent associations of somatic climacteric symptoms, and a number of socio-demographic and health-related factors with depressive symptoms in late middle-aged Taiwanese women. PMID- 29121894 TI - Frequency of acute cervical and lumbar pathology in common types of motor vehicle collisions: a retrospective record review. AB - BACKGROUND: There are more than 5 million motor vehicle collisions annually in the United States, resulting in more than 2 million injured occupants. The most common types of collisions are head-on impacts, rear-ends, side-swipes, and t bones, whilst the most common injury sites are the cervical and lumbar spine. The purpose of this retrospective record review was to examine the differences in frequency of cervical and lumbar pathology across and between these common collision types. METHODS: Nine-hundred and three patients were included in this analysis, 88 of whom described being in a head-on collision, 546 in a rear-end, 123 in a side-swipe, and 146 in a t-bone. Four diagnoses were examined, two each for the cervical and lumbar regions: disc derangement and radiculitis. Pearson's Chi-squared contingency tables were used to test whether there were differences in clinical diagnosis frequencies across collision type, while Marascuilo's post hoc multiple proportion comparisons were conducted to determine inter-group differences. RESULTS: There were significant differences across collision type for cervical disc derangement (p < 0.0001), cervical radiculitis (p < 0.00001), lumbar disc derangement (p = 0.0002) and lumbar radiculitis (p < 0.00001). There were also significant differences in pathology frequency between collision types. CONCLUSIONS: Symptomatic cervical disc derangements were more common among patients who were involved in aside-swipe, whereas symptomatic lumbar disc derangements were more common among those in head-on or side-swipe collisions. Expanded controlled prospective studies are encouraged to better understand the mechanisms of injury and determine radiculitis tolerance limits. PMID- 29121893 TI - Association of pelvic fracture patterns, pelvic binder use and arterial angio embolization with transfusion requirements and mortality rates; a 7-year retrospective cohort study. AB - BACKGROUND: Pelvic fractures are severe injuries with frequently associated multi system trauma and a high mortality rate. The value of the pelvic fracture pattern for predicting transfusion requirements and mortality is not entirely clear. To address hemorrhage from pelvic injuries, the early application of pelvic binders is now recommended and arterial angio-embolization is widely used for controlling arterial bleeding. Our aim was to assess the association of the pelvic fracture pattern according to the Tile classification system with transfusion requirements and mortality rates, and to evaluate the correlation between the use of pelvic binders and arterial angio-embolization and the mortality of patients with pelvic fractures. METHODS: Single-center retrospective cohort study including all consecutive patients with a pelvic fracture from January 2008 to June 2015. All radiological fracture patterns were independently reviewed and grouped according to the Tile classification system. Data on patient demographics, use of pelvic binders and arterial angio-embolization, transfusion requirements and mortality were extracted from the institutional trauma registry and analyzed. RESULTS: The present study included 228 patients. Median patient age was 43.5 years and 68.9% were male. The two independent observers identified 105 Tile C (46.1%), 71 Tile B (31.1%) and 52 Tile A (22.8%) fractures, with substantial to almost perfect interobserver agreement (Kappa 0.70-0.83). Tile C fractures were associated with a higher mortality rate (p = 0.001) and higher transfusion requirements (p < 0.0001) than Tile A or B fractures. Arterial angio-embolization for pelvic bleeding (p = 0.05) and prehospital pelvic binder placement (p = 0.5) were not associated with differences in mortality rates. CONCLUSIONS: Tile C pelvic fractures are associated with higher transfusion requirements and a higher mortality rate than Tile A or B fractures. No association between the use of pelvic binders or arterial angio-embolization and survival was observed in this cohort of patients with pelvic fractures. PMID- 29121895 TI - The relationship between resident burnout and safety-related and acceptability related quality of healthcare: a systematic literature review. AB - BACKGROUND: There has been increasing interest in examining the relationship between physician wellbeing and quality of patient care. However, few reviews have specifically focused on resident burnout and quality of patient care. The purpose of this systematic literature review of the current scientific literature is to address the question, "How does resident burnout affect the quality of healthcare related to the dimensions of acceptability and safety?" METHODS: This systematic literature review uses a multi-step screening process of publicly available peer-reviewed studies from five electronic databases: (1) Medline Current, (2) Medline In-process, (3) PsycINFO, (4) Embase, and (5) Web of Science. RESULTS: The electronic literature search resulted in the identification of 4638 unique citations. Of these, 10 articles were included in the review. Studies were assessed for risk of bias. Of the 10 studies that met the inclusion criteria, eight were conducted in the US, one in The Netherlands, and one in Mexico. Eight of the 10 studies focused on patient safety. The results of these included studies suggest there is moderate evidence that burnout is associated with patient safety (i.e., resident self-perceived medical errors and sub-optimal care). There is less evidence that specific dimensions of burnout are related to acceptability (i.e., quality of care, communication with patients). CONCLUSIONS: The results of this systematic literature review suggest a relationship between patient safety and burnout. These results potentially have important implications for the medical training milieu because residents are still in training and at the same time are asked to teach students. The results also indicate a need for more evidence-based interventions that support continued research examining quality of care measures, especially as they relate to acceptability. PMID- 29121896 TI - Pre-pregnancy body mass index and gestational weight gain and their effects on pregnancy and birth outcomes: a cohort study in West Sumatra, Indonesia. AB - BACKGROUND: Indonesia has a considerably high incidence of maternal and infant mortality. The country has however been experiencing a social and economic transition, influencing its general population demographics and nutritional status including the state of health and nutrition of pregnant women. This study aimed to explore body mass index (BMI) and gestational weight gain (GWG), and their relationship with pregnancy outcomes in a sample of Indonesian pregnant women. METHODS: This observational cohort study included a total of 607 pregnant women who were recruited in 2010 from maternity clinics in Western Sumatra, Indonesia. Multiple logistic and regression analyses were undertaken to compare pregnancy and birth outcomes for different BMI and GWG, using normal weight women and women with a recommended weight gain as the referent groups. RESULTS: The prevalence of underweight (BMI < 18.5 kg/m2) in pregnancy was high at 20.1%; while 21.7% of women were overweight (BMI: 23.0-27.4 kg/m2) and 5.3% obese (BMI >= 27.5 kg/m2) using the Asian BMI classifications. The incidence of overweight (BMI: 25.0-29.9 kg/m2) and obese (BMI >= 30.0 kg/m2) according to the international BMI classifications were 13.5% and 1.1% respectively. The majority of women gained inadequate weight in pregnancy compared to the Institute of Medicine (IOM) recommendations, especially those who had a normal BMI. Birthweight adjusted mean difference aMD (95% confidence interval) 205 (46,365) and the odds of macrosomia adjusted odds ratio aOR 13.46 (2.32-77.99) significantly increased in obese women compared to those with a normal BMI. Birthweight aMD -139 (-215, -64) significantly decreased in women with inadequate GWG compared to those with recommended GWG, while SGA aOR 5.44 (1.36, 21.77) and prematurity aOR 3.55 (1.23, 10.21) increased. CONCLUSIONS: Low nutritional status and inadequate GWG remain a cause for concern in these women. The higher odds of macrosomia with increasing maternal BMI and higher odds of prematurity and small for gestational age infants with inadequate weight gain also require attention. Research and practice recommendations: Urgent attention is required by researchers, policy makers and decision-makers to facilitate development of culturally sensitive interventions to enhance nutritional status and health of mothers and babies, in an area known for its high incidence of maternal and neonatal mortality. PMID- 29121897 TI - Differences between medical student and faculty perceptions of the competencies needed for the first year of residency. AB - BACKGROUND: Different guidelines and frameworks like the CanMEDs model or entrustable professional activities (EPAs) describe competencies required for successful and professional work of residents. Not all competencies are of equal importance for graduates when they start their residency. The aim of this study was to evaluate the relevance of different competencies for a first year resident from the perspective of physicians and medical students. METHODS: In an online study, 178 of 475 surgeons and internists including residents and attendings and 102 of 728 first and last year undergraduate medical students from the University Medical Center Hamburg-Eppendorf ranked 25 competencies according to their relevance for entrustment decisions in first year residents. The rankings of the competencies by residents and attendings and by first year and last year medical student were compared. Additionally, the rankings were also compared to the literature. RESULTS: Physicians and medical students rated 'Responsibility' as the most important competency for first year residents. Physicians ranked 'Teamwork and collegiality' and 'Structure, work planning and priorities' within the top 10 competencies significantly higher than medical students. The competency ranks between attendings and residents only showed one significant difference between attendings and residents, where 'Coping with mistakes', was ranked significantly higher by residents. Medical students ranked 'Active listening to patients', 'Advising patients' and 'Handling emotions of patients and their relatives' significantly higher than physicians. Final year students ranked 'Structure, work planning and priorities', 'Coping with mistakes', and 'Verbal communication with colleagues and supervisors' significantly higher than first year students. CONCLUSIONS: Even though physicians and medical students agree that 'Responsibility' is the most important competency for entrustment decisions in the first year of residency, medical students rate competencies regarding patient communication very highly while physicians rate competencies required for patient managements significantly higher for entrustment decision. Undergraduate medical curricula seem to prepare students well with respect to patient-centeredness but need to be developed more specifically to prepare students equally well for patient management competencies which are required in the first year of residency for entrustment decisions from the attendings perspective. PMID- 29121899 TI - p21-/- mice exhibit enhanced bone regeneration after injury. AB - BACKGROUND: p21(WAF1/CIP1/SDI1), a cyclin dependent kinase inhibitor has been shown to influence cell proliferation, differentiation and apoptosis; but more recently, p21 has been implicated in tissue repair. Studies on p21(-/-) knockout mice have demonstrated results that vary from complete regeneration and healing of tissue to attenuated healing. There have however been no studies that have evaluated the role of p21 inhibition in bone healing and remodeling. METHODS: The current study employs a burr-hole fracture model to investigate bone regeneration subsequent to an injury in a p21-/- mouse model. p21-/- and C57BL/6 mice were subjected to a burr-hole fracture on their proximal tibia, and their bony parameters were measured over 4 weeks via in vivo MUCT scanning. RESULTS: p21-/- mice present with enhanced healing from week 1 through week 4. Differences in bone formation and resorption potential between the two mouse models are assessed via quantitative and functional assays. While the MUCT analysis indicates that p21-/- mice have enhanced bone healing capabilities, it appears that the differences observed may not be due to the function of osteoblasts or osteoclasts. Furthermore, no differences were observed in the differentiation of progenitor cells (mesenchymal or monocytic) into osteoblasts or osteoclasts respectively. CONCLUSIONS: Therefore, it remains unknown how p21 is regulating enhanced fracture repair and further studies are required to determine which cell type(s) are responsible for this regenerative phenotype. PMID- 29121898 TI - Clinicopathologic and prognostic features of breast cancer in young women: a series from North of Morocco. AB - BACKGROUND: Literature data reported a higher frequency of breast cancer in young women (BCYW) in developing countries. BCYW is associated with delayed diagnosis, aggressive biology and poor prognosis. However, our knowledge of biological profile, treatment received and outcome of young patients is still limited in Morocco. We propose to analyze clinicopathologic, therapeutic and prognostic features of BCYW among a series of patients native and/or inhabitant of North of Morocco. METHODS: We carried out a retro-prospective study of 331 infiltrating breast cancer cases registered between January 2010 and December 2015. Details of tumor pathology, treatment and outcome were collected. Disease-Free Survival (DFS) and Overall Survival (OS) were assessed by Kaplan-Meier analysis. RESULTS: A total of 82 patients were diagnosed with breast cancer at the age of 40 or younger (24.8%). Median age was 36 years. More than one quarter (26%) of patients had family history of breast or ovarian cancer. Advanced stages accounted for 34.2% of cases. Median tumor diameter was 2.8 cm. Intermediate and high-grade tumors represented 47.6% and 40.2%, respectively. Nodal involvement was present in 58.5% and lymphovascular invasion was found in 47.7% of the patients. About two thirds (66.2%) of tumors were hormone receptor positive, 29.2% over-expressed HER2 receptor and 23% were triple negative. Patients underwent breast conserving surgery in 38.2% of cases, 61.7% were offered adjuvant chemotherapy and 84.6% received hormone therapy. Five-year DFS and OS were respectively 88.9% and 75.6%. Locoregional recurrence occurred in 2.8% of cases and 8.3% of patients developed distant metastases. CONCLUSION: Our findings are in accordance with previous studies that have shown a higher frequency of breast cancer among Moroccan young women. In line with literature data, clinicopathologic profile seems to be aggressive and prognosis is pejorative in our series. PMID- 29121900 TI - Synergistic gastroprotective activity of methanolic extract of a mixture of Melastoma malabathricum and Muntingia calabura leaves in rats. AB - BACKGROUND: Melastoma malabathricum L. (family Melastomaceae; MM) and Muntingia calabura L. (family Elaeocarpaceae; MC) have been separately reported to possess gastroprotective activity. In an attempt to develop a pharmaceutical product with antiulcer potential, the synergistic gastroprotective activity of methanolic extract of a mixture of MM and MC (MMMC) at various ratios was evaluated in rat models. METHODS: Rats were pre-treated orally with 2% Tween 80 (vehicle), 100 mg/kg ranitidine (reference drug) or MMMC (ratios of 1:1, 1:3 and 3:1 (v/v); doses of 15, 150 or 300 mg/kg) and then subjected to the ethanol-induced gastric ulcer or pyloric ligation assays. Stomach of rats from the former assay was collected and subjected to the macroscopic and microscopic observations, and enzymatic and non-enzymatic antioxidant studies while the gastric juice content and tissue from the latter assay were subjected to the antisecretory activity study. The UHPLC analysis of MMMC was also performed. RESULT: MMMC, in the ratio 1:1, demonstrated the most effective (P < 0.001) gastroprotective activity indicated by the highest reduction in ethanol-induced ulcer area formation. These macroscopic findings were supported by the microscopic observations. Except for pH and total acidity, MMMC also significantly (P < 0.001) reduced the volume of gastric content but increased the gastric wall mucus content in the pyloric ligation test. MMMC also demonstrated remarkable antioxidant activity indicated by the highest total phenolic content (TPC) value and oxygen radical absorbance capacity (ORAC) activity with the recorded IC50 value of approximately 53 MUg/mL for the 2,2- diphenyl-1-picrylhydrazyl (DPPH) scavenging activity. MMMC also improved the catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), prostaglandin E2 (PGE2) and malondialdehyde (MDA) activities of the gastric tissue intoxicated by ethanol. UHPLC analysis of MMMC confirmed the presence several flavonoid-based bioactive compounds. CONCLUSION: MMMC, at the ratio of 1:1 (v/v), exerts gastroprotective activity partly by activating its antisecretory and antioxidant activities, and via modulation of the gastric tissue endogenous antioxidant system. PMID- 29121901 TI - Couple's concordance and discordance in household decision-making and married women's use of modern contraceptives in Bangladesh. AB - BACKGROUND: Although a large body of studies documents that women's autonomy in the household is associated with better reproductive health outcomes, these studies typically examined autonomy only from women's point of view. The current study employs husband's and wife's perspectives together to examine the relationship between the decision-making arrangements in the household and the women's use of modern contraceptives in Bangladesh. METHODS: The study used the couple dataset of 2007 Bangladesh Demographic and Health Survey. The sample was comprised of 3336 married couples. Binary logistic regression models were used to examine the associations between the selected items on household decision-making and the use of modern contraceptives. RESULTS: Our results indicate that the couples disagree considerably as to who in the household exercises the decision making power. The pattern of decision-making regarding visiting family and relatives emerged as an important predictor of use of modern contraceptives in the multivariate regression analysis. The results suggest that compared to the couple's concordant joint decision-making, the husband-only decision-making is associated with lower odds of contraceptives use (OR 0.49; 95% CI 0.28-0.85). Only a small part of this association is explained by spousal communication about family planning issues while the socio-demographic correlates hardly affected the association. On the contrary, the wife-only decision-making did not result in increased contraceptives use (OR 0.71; 95% CI 0.45-1.13). CONCLUSIONS: The study findings imply that women's greater autonomy may not necessarily result in improved reproductive health behavior, and therefore, a balance of power in the spousal relationship is warranted. PMID- 29121902 TI - Online or face-to-face instruction? A qualitative study on the electrocardiogram course at the University of Ulm to examine why students choose a particular format. AB - BACKGROUND: Since the introduction of the e-learning electrocardiogram (ECG) course 'ECG Online' into the curriculum at the University of Ulm, a small but relatively constant number of students have decided not to participate in the online course but to attend the face-to-face course, although the content of both courses is identical. The present study examined why students prefer one format or the other. METHODS: In a qualitative research approach, ten medical students were questioned in a guided interview. At the time of the survey the interviewees were enrolled in the 7th to 10th semesters. Among the respondents, 2 had participated only in the face-to-face ECG course, 4 only in the online version and 4 in both the face-to-face and the online course. RESULTS: Interestingly, the very factors associated with e-learning - and always praised as advantages of it are viewed critically by the students. Thus, although the 24-h access to learning content was consistently evaluated positively, the unlimited availability (lack of expiry date) was not seen as conducive to learning. The lack of fixed time constraints and the attendant lack of pressure were important reasons why some of the students had discontinued the online course prematurely. A similar distinction was seen in the flexibility of location for e-learning, because the very obligation to be physically present on a particular day at a fixed time led to a higher degree of commitment to courses and a willingness to actually attend the course until the end. In addition, if the content has a high degree of perceived professional relevance face-to-face courses are preferred because they offer the possibility of direct interaction. CONCLUSIONS: Even though the small sample size limits the generalisability of the results, our findings indicate that when developing online courses students' needs could be better met if measures were included to strengthen extrinsic and intrinsic motivation and formats were favoured that enable students to have a minimum level of personal interaction with the lecturer. PMID- 29121903 TI - Diagnostic errors by medical students: results of a prospective qualitative study. AB - BACKGROUND: Diagnostic errors occur frequently in daily clinical practice and put patients' safety at risk. There is an urgent need to improve education on clinical reasoning to reduce diagnostic errors. However, little is known about diagnostic errors of medical students. In this study, the nature of the causes of diagnostic errors made by medical students was analyzed. METHODS: In June 2016, 88 medical students worked on eight cases with the chief complaint dyspnea in a laboratory setting using an electronic learning platform, in summary 704 processed cases. The diagnostic steps of the students were tracked and analyzed. Furthermore, after each case the participants stated their presumed diagnosis and explained why they came to their diagnostic conclusion. The content of these explanations was analyzed qualitatively. RESULTS: Based on the diagnostic data gathering process and the students' explanations, eight different causes could be identified of which the lack of diagnostic skills (24%) and inadequate knowledge base (16%) were the most common. Other causes that often contributed to a diagnostic error were faulty context generation (15%) and premature closure (10%). The causes of misdiagnosis varied per case. CONCLUSIONS: Inadequate skills/knowledge and faulty context generation are the major problems in students' clinical reasoning process. These findings are valuable for improving medical education and thus reducing the frequency of diagnostic errors in students' later everyday clinical practice. PMID- 29121904 TI - Generation of murine macrophage-derived cell lines expressing porcine CD163 that support porcine reproductive and respiratory syndrome virus infection. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) exhibits a highly restricted tropism for cells of the monocyte-macrophage lineage, utilizing porcine CD163 (pCD163) as an indispensable cellular receptor for infection. Transfection the gene of pCD163 into several non-permissive cell lines followed by protein expression confers susceptibility to PRRSV. A lack of specialized porcine antibody tools for use with existing porcine-derived primary cells and cell lines has hampered studies of both PRRSV pathogenesis and virus triggering of immune response cascades. Therefore, we constructed PRRSV susceptible murine alveolar macrophage-derived MH-S and peritoneal macrophage like RAW264.7 cell lines by achieving pCD163 cell surface expression in these cells. We then evaluated PRRSV susceptibility and cytokine expression patterns induced upon PRRSV infection of these pCD163-expressing cell lines. RESULTS: Growth of MH-SCD163 and RAW264.7CD163 cells was indistinguishable from growth of un-transfected parental cell lines. Meanwhile, various stages of the PRRSV replication cycle, including viral particle attachment, internalization, disassembly and infection were confirmed in both pCD163-transfected cell lines. Analysis of PRRSV replication using immunofluorescence staining of virus and viral titration of cell lysates demonstrated that both MH-SCD163 and RAW264.7CD163 cells supported replication of various genotype 2 PRRSV isolates. Moreover, PRRSV replication in MH-SCD163 cells was similar to that observed in porcine alveolar macrophages (PAMs) and was more efficient than in RAW264.7CD163 cells. However, peak virus titers in MH-SCD163 cells were attained at 60 h post infection (pi) versus 48 hpi in PAMs. Analysis of cytokine expression showed that post-PRRSV infection, mRNA expression patterns of anti-inflammatory cytokines (IL 4 and IL-10) and pro-inflammatory cytokines (TNF-alpha and IFN-gamma) in MH SCD163 cells were more similar to those observed in PAMs versus levels in RAW264.7CD163 cells. CONCLUSIONS: MH-S and RAW264.7 cells were not susceptible to PRRSV infection until transfection and subsequent expression of pCD163 were achieved in these cell lines. The PRRSV-susceptible MH-SCD163 cell line efficiently supported viral replication of various genotype 2 PRRSV isolates and exhibited similar cytokine expression patterns as observed in PAMs. In conclusion, this work describes the development of new tools to further understand PRRSV pathogenesis and immune response mechanisms to PRRSV infection. PMID- 29121905 TI - The trafficking of women and girls in Taiwan: characteristics of victims, perpetrators, and forms of exploitation. AB - BACKGROUND: Prior to the passing of 2009 Human Trafficking Prevention Act (HTPA), human trafficking was underestimated in Taiwan. In the past, domestic trafficking in women and girls often targeted vulnerable groups such as young girls from poor families or minority groups. Since the 1990s, an increasing flow of immigrant women, mainly from Vietnam and Indonesia and some from China, into Taiwan has created a new group of Human Trafficking victims. The current study intends to identify, describe, and categorize reported and prosecuted human trafficking cases involving women and girls according to the HTPA in Taiwan. METHODS: Using the court proceedings of prosecuted trafficking in women and girls cases under Taiwan's HTPA from all 21 districts in Taiwan from 2009 to 2012 under the title keyword of 'Human Trafficking', this current study aims to categorize different patterns of existing trafficking in women and girls in Taiwan. The analysis is based on 37 court cases, involving 195 victimized women and girls and 118 perpetrators. RESULTS: This study identifies six forms of Human Trafficking victims according to their country of origin, vulnerability status, and means of transport. This study found that women and girls suffer from both labor and sexual exploitation, from mainly domestic male perpetrators. While sexual exploitation is more evenly distributed among citizens and immigrants and affects both adults and minors, labor exploitation seems to be an exclusive phenomenon among women immigrant workers in the data. CONCLUSIONS: Human Trafficking cases in Taiwan share many of the similarities of Human Trafficking in other regions, which are highly associated with gender inequality and gender-based vulnerability. PMID- 29121906 TI - Impaired contractile function of the supraspinatus in the acute period following a rotator cuff tear. AB - BACKGROUND: Rotator cuff (RTC) tears are a common clinical problem resulting in adverse changes to the muscle, but there is limited information comparing histopathology to contractile function. This study assessed supraspinatus force and susceptibility to injury in the rat model of RTC tear, and compared these functional changes to histopathology of the muscle. METHODS: Unilateral RTC tears were induced in male rats via tenotomy of the supraspinatus and infraspinatus. Maximal tetanic force and susceptibility to injury of the supraspinatus muscle were measured in vivo at day 2 and day 15 after tenotomy. Supraspinatus muscles were weighed and harvested for histologic analysis of the neuromuscular junction (NMJ), intramuscular lipid, and collagen. RESULTS: Tenotomy resulted in eventual atrophy and weakness. Despite no loss in muscle mass at day 2 there was a 30% reduction in contractile force, and a decrease in NMJ continuity and size. Reduced force persisted at day 15, a time point when muscle atrophy was evident but NMJ morphology was restored. At day 15, torn muscles had decreased collagen packing density and were also more susceptible to contraction-induced injury. CONCLUSION: Muscle size and histopathology are not direct indicators of overall RTC contractile health. Changes in NMJ morphology and collagen organization were associated with changes in contractile function and thus may play a role in response to injury. Although our findings are limited to the acute phase after a RTC tear, the most salient finding is that RTC tenotomy results in increased susceptibility to injury of the supraspinatus. PMID- 29121907 TI - "Helping my neighbour is like giving a loan..." -the role of social relations in chronic illness in rural Uganda. AB - BACKGROUND: Understanding individuals' experience of accessing care and tending to various other needs during chronic illness in a rural context is important for health systems aiming to increase access to healthcare and protect poor populations from unreasonable financial hardship. This study explored the impact on households of access to free healthcare and how they managed to meet needs during chronic illness. METHODS: Rich data from the life stories of individuals from 22 households in rural south-western Uganda collected in 2009 were analysed. RESULTS: The data revealed that individuals and households depend heavily on their social relations in order to meet their needs during illness, including accessing the free healthcare and maintaining vital livelihood activities. The life stories illustrated ways in which households draw upon social relations to achieve the broader social protection necessary to prevent expenses becoming catastrophic, but also demonstrated the uncertainty in relying solely on informal relations. CONCLUSION: Improving access to healthcare in a rural context greatly depends on broader social protection. Thus, the informal social protection that already exists in the form of strong reciprocal social relations must be acknowledged, supported and included in health policy planning. PMID- 29121908 TI - A model for the use of blended learning in large group teaching sessions. AB - BACKGROUND: Although blended learning has the potential to enhance the student experience, both in terms of engagement and flexibility, it can be difficult to effectively restructure existing courses. To achieve these goals for an introductory Pathology course, offered to more than 250 undergraduate students at UNSW Sydney, we devised a novel approach. METHODS: For each topic presented over 2-3 weeks, a single face-to-face overview lecture was retained. The remaining content that had previously been delivered as conventional lectures was converted into short (12-18 min) online modules. These were based on lecture slides with added animations/highlights, plus narration using edited excerpts of previous lecture recordings. The modules also incorporated interactive questions and review quizzes with feedback which used various question types. Modules were developed in PowerPoint and iSpring and uploaded to Moodle as SCORM packages. Each topic concluded with an interactive large-group session focussing on integration of the content, with in-class questions to which students could respond via the Echo360 Active Learning Platform (ALP). Overall, more than 50% of face-to-face lecture time was replaced by online modules and interactive large group sessions. Quantitative evaluation data included usage statistics from 264 students and feedback via online survey responses from 41 students. Qualitative evaluation data consisted of reflective commentaries from 160 student ePortfolios, which were analysed to identify factors affecting learning benefits and user acceptability. RESULTS: All of the modules were completed by 74% of students and on average, 83.1% of students eventually passed the optional review quizzes. Notably, 88.4% of students responded to in-class questions during the integration and feedback sessions via the ALP. Student reflections emphasised that the modules promoted understanding, which was reinforced through active learning. The modules were described as enjoyable, motivating and were appreciated for their flexibility, which enabled students to work at their own pace. CONCLUSIONS: In transforming this introductory Pathology course, we have demonstrated a model for the use of blended learning in large group teaching sessions, which achieved high levels of completion, satisfaction and value for learning. PMID- 29121909 TI - Successful production of the potato antimicrobial peptide Snakin-1 in baculovirus infected insect cells and development of specific antibodies. AB - BACKGROUND: Snakin-1 (StSN1) is a broad-spectrum antimicrobial cysteine-rich peptide isolated from Solanum tuberosum. Its biotechnological potential has been already recognized since it exhibits in vivo antifungal and antibacterial activity. Most attempts to produce StSN1, or homologous peptides, in a soluble native state using bacterial, yeast or synthetic expression systems have presented production bottlenecks such as insolubility, misfolding or low yields. RESULTS: In this work, we successfully expressed a recombinant StSN1 (rSN1) in Spodoptera frugiperda (Sf9) insect cells by optimizing several of the parameters for its expression in the baculovirus expression system. The recombinant peptide lacking its putative signal peptide was soluble and was present in the nuclear fraction of infected Sf9 cells. An optimized purification procedure allowed the production of rSN1 that was used for immunization of mice, which gave rise to polyclonal antibodies that detect the native protein in tissue extracts of both agroinfiltrated plants and stable transgenic lines. Our results demonstrated that this system circumvents all the difficulties associated with recombinant antimicrobial peptides expression in other heterologous systems. CONCLUSIONS: The present study is the first report of a successful protocol to produce a soluble Snakin/GASA peptide in baculovirus-infected insect cells. Our work demonstrates that the nuclear localization of rSN1 in insect cells can be exploited for its large-scale production and subsequent generation of specific anti-rSN1 antibodies. We suggest the use of the baculovirus system for high-level expression of Snakin/GASA peptides, for biological assays, structural and functional analysis and antibody production, as an important step to both elucidate their accurate physiological role and to deepen the study of their biotechnological uses. PMID- 29121910 TI - Thai plants with high antioxidant levels, free radical scavenging activity, anti tyrosinase and anti-collagenase activity. AB - BACKGROUND: Ultraviolet radiation from sunlight induces overproduction of reactive oxygen species (ROS) resulting in skin photoaging and hyperpigmentation disorders. Novel whitening and anti-wrinkle compounds from natural products have recently become of increasing interest. The purpose of this study was to find products that reduce ROS in 14 Thai plant extracts. METHODS: To determine total phenolic and flavonoid content, antioxidant activity, anti-tyrosinase activity and anti-collagenase activity, we compared extracts of 14 Thai plants prepared using different solvents (petroleum ether, dichloromethane and ethanol). Antioxidant activities were determined by DPPH and ABTS assays. RESULTS: Total phenolic content of the 14 Thai plants extracts was found at the highest levels in ethanol followed by dichloromethane and petroleum ether extracts, respectively, while flavonoid content was normally found in the dichloromethane fraction. Scavenging activity ranged from 7 to 99% scavenging as assessed by DPPH and ABTS assays. The ethanol leaf extract of Ardisia elliptica Thunb. had the highest phenolic content, antioxidant activity and collagenase inhibition, while Cassia alata (L.) Roxb. extract had the richest flavonoid content. Interestingly, three plants extracts, which were the ethanolic fractions of Annona squamosa L., Ardisia elliptica Thunb. and Senna alata (L.) Roxb., had high antioxidant content and activity, and significantly inhibited both tyrosinase and collagenase. CONCLUSION: Our finding show that the ethanol fractions of Annona squamosa L., Ardisia elliptica Thunb. and Senna alata (L.) Roxb. show promise as potential ingredients for cosmetic products such as anti-wrinkle agents and skin whitening products. PMID- 29121912 TI - The exploration of medical resources utilization among inguinal hernia repair in Taiwan diagnosis-related groups. AB - BACKGROUND: This study centered on differences in medical costs, using the Taiwan diagnosis-related groups (Tw-DRGs) on medical resource utilization in inguinal hernia repair (IHR) in hospitals with different ownership to provide suitable reference information for hospital administrators. METHODS: The 2010-2011 data for three hospitals under different ownership were extracted from the Taiwan National Health Insurance claims database. A retrospective method was applied to analyze the age, sex, length of stay, diagnosis and surgical procedure code, and the change in financial risk of medical costs in IHR cases after introduction of Tw-DRGs. The study calculated the cost using Tw-DRG payment principles, and compared it with estimated inpatient medical costs calculated using the fee-for service policy. RESULTS: There were 723 IHR cases satisfying the Tw-DRGs criteria. Cost control in the medical care corporation hospital (US$764.2/case) was more efficient than that in the public hospital (US$902.7/case) or nonprofit proprietary hospital (US$817.1/case) surveyed in this study. For IHR, anesthesiologists in the public hospital preferred to use general anesthesia (86%), while those in the two other hospitals tended to administer spinal anesthesia. We also discovered the difference in anesthesia cost was high, at US$80.2/case on average. CONCLUSIONS: Because the Tw-DRG-based reimbursement system produces varying hospital costs, hospital administrators should establish a financial risk assessment system as early as possible to improve healthcare quality and financial management efficiency. This would then benefit the hospital, patient, and Bureau of National Health Insurance. PMID- 29121911 TI - Immunohistochemical staining of leptin is associated with grade, stage, lymph node involvement, recurrence, and hormone receptor phenotypes in breast cancer. AB - BACKGROUND: Obesity is part of the established risk factors for breast cancer (BC) in postmenopausal females. Circulating leptin increases in parallel with the increase of body weight and fat reservoir. METHODS: This research investigated the link between leptin phenotype and the clinicopathological factors in BC. A large set of breast cancer cases (449), and 27 non-cancerous tissue samples of breast were employed for leptin expression recognition using immunohistochemistry staining. RESULTS: Cytoplasmic immunohistochemical staining of leptin was recognized in 376 (83.7%) and 25 (92.6%) of BC and control cases respectively. Leptin immunostaining were significantly associated with age, histotypes, grade, stage, lymph node involvement, tumor recurrence, hormone receptor phenotypes, ER and HER2 expressions, and p-values were (P = 0.0233), (P = 0.0001), (P = 0.050), (P = 0.0291), (P = 0.0300), (P = 0.0023), (P = 0.0021), (P = 0.0279) respectively. Reasonable proportion of cases with low staining score was more prevalent in all subgroups of clinicopathological parameters except ER- PR+ HER2- hormone receptor phenotype and mucinous carcinoma which showed high level of leptin immunoreactivity. Tumor recurrence is less prevailing in high score leptin immunostaining cases. Furthermore, Log Rank (Mantel-Cox) test findings revealed considerably different survival distributions were observed for the different categories of leptin immunostaining scores (P = 0.032). Negative leptin immunostaining is related to poor survival. CONCLUSIONS: Our preliminary findings support leptin clinical value in confirming BC diagnosis as well as prognosis. These results suggest that leptin molecule is an important biomarker that could identify type, grade, stage, lymph node involvement, relapse and prognosis in breast cancer. PMID- 29121913 TI - Predicting health-related quality of life in cancer patients receiving chemotherapy: a structural equation approach using the self-control model. AB - BACKGROUND: According to the self-control model, self-control works as a protective factor and a psychological resource. Although an understanding of the effect(s) of peripheral neuropathy on quality of life is important to healthcare professionals, previous studies do not facilitate broad comprehension in this regard. The purpose of this cross-sectional study was to test the multidimensional assumptions of quality of life of patients with cancer, with focus on their self-control. METHODS: A structural equation model was tested on patients with cancer at the oncology clinic of a university hospital where patients received chemotherapy. A model was tested using structural equation modeling, which allows the researcher to find the empirical evidence by testing a measurement model and a structural model. The model comprised three variables, self-control, health related quality of life, and chemotherapy-induced peripheral neuropathy. Among the variables, self-control was the endogenous and mediating variable. RESULTS: The proposed models showed good fit indices. Self-control partially mediated chemotherapy-induced peripheral neuropathy and quality of life. It was found that the physical symptoms of peripheral neuropathy influenced health-related quality of life both indirectly and directly. CONCLUSIONS: Self control plays a significant role in the protection and promotion of physical and mental health in various stressful situations, and thus, as a psychological resource, it plays a significant role in quality of life. Our results can be used to develop a quality of life model for patients receiving chemotherapy and as a theoretical foundation for the development of appropriate nursing interventions. PMID- 29121914 TI - Splice variants of the extracellular region of RON receptor tyrosine kinase in lung cancer cell lines identified by PCR and sequencing. AB - BACKGROUND: Altered expression of receptor tyrosine kinases (RTKs) is a major driver of growth and metastasis of cancers. Recepteur d'origine nantais (RON) receptor is a single-pass transmembrane RTK aberrantly expressed in a number of cancers. Efforts to block deregulated RON signaling in tumors using small molecule kinase inhibitors or antibodies are complicated by the presence of unknown number/types of isoforms of RON, which, despite having similar sequences, are localized differently and mediate varied functions. The objective of this study was to identify splice variants of RON transcripts between exons 1 and 10 that code for the extracellular region. METHODS: Direct cDNA sequencing was performed for the transcript between exons 1-10 of RON by Sanger sequencing in various lung cancer cell lines. RESULTS: PCR amplification and bi-directional sequencing of cDNA for section between exons 1 and 10 from lung cancer cell lines revealed the presence of several splice variants of RON transcripts; the variants were formed by skipping of exons 2, 2-3, 5-6, 6 and 8-9. Each of these transcript variants were found in one or more cell lines. While the variants formed by skipping of exons 2, 2-3 and 5-6 resulted in loss of 63, 106 and 109 amino acids, respectively, and didn't cause reading-frameshift, the transcripts formed by skipping of exons 6 and 8-9 caused reading-frameshift. Splice variant lacking exons 8-9 was found in 13 out of 23 cell lines tested. CONCLUSION: Lung cancer cell lines contain several splice variants of RON which involve skipping of exons coding for extracellular region. Some of the splicing changes result in reading frameshift and the N-terminally truncated isoforms are expected to be secreted out. The ubiquitous nature of alternative splicing events in RON suggests the need for isoform specific approaches to functional analysis and therapeutic targeting of RON. PMID- 29121915 TI - Clinical monitoring of cardiac output assessed by transoesophageal echocardiography in anaesthetised dogs: a comparison with the thermodilution technique. AB - BACKGROUND: Cardiac output (CO) is an important haemodynamic parameter to monitor in patients during surgery. However, the majority of the techniques for measuring CO have a limited application in veterinary practice due to their invasive approach and associated complexity and risks. Transoesophageal echocardiography (TEE) is a technique used to monitor cardiac function in human patients during surgical procedures and allows CO to be measured non-invasively. This prospective clinical study aimed to compare the transoesophageal echocardiography using a transgastric view of the left ventricular outflow tract (LVOT) and the thermodilution (TD) technique for the assessment of CO during mean arterial pressure of 65-80 mmHg (normotension) and <65 mmHg (hypotension) in dogs undergoing elective surgery. Eight dogs were pre-medicated with acepromazine (0.05 mg/kg, IM), tramadol (4 mg/kg, IM) and atropine (0.03 mg/kg, IM), followed by anaesthetic induction with propofol (3-5 mg/kg IV) and maintenance with isoflurane associated with a continuous infusion rate of fentanyl (bolus of 3 MUg/kg followed by 0.3 MUg/kg/min). The CO was measured by TEE (COTEE) and TD (COTD) at the end of expiration during normotension and hypotension (induced by isoflurane). RESULTS: There was a strong positive correlation between COTEE and COTD (r = 0.925; P < 0.0001). The bias between COTD and COTEE was 0.14 +/- 0.29 L/min (limits of agreement, -0.44 to 0.72 L/min). The percentage error of CO measured by the two methods was 12.32%. In addition, a strong positive correlation was found between COTEE and COTD during normotension (r = 0.995; P < 0.0001) and hypotension (r = 0.78; P = 0.0223). CONCLUSIONS: The results of this study indicated that the transgastric view of the LVOT by TEE was a minimally invasive alternative to clinically monitoring CO in dogs during anaesthesia. However, during hypotension, the CO obtained by TEE was less reliable, although still acceptable. PMID- 29121916 TI - A longitudinal study looking at and beyond care recipient health as a predictor of long term care home admission. AB - BACKGROUND: The unpaid care provided by informal caregivers allows care recipients to live longer in their homes, which often results in fewer unnecessary long term care home (LTCH) admissions. Although the relationship between care recipient's health characteristics and institutionalization is well known, the influence of caregiver distress and caregiving coresidence and relationship on this outcome is less clear. This study examines the association of care recipient care needs, caregiver distress and caregiving coresidence and relationship with care recipient long term care home admission. METHODS: A total of 94,957 resident assessment instruments-home care (RAI-HC), completed between April 01st 2013 and April 01st, 2014 as part of a clinical practice by 14 Local Health Integration Networks (LHINs) in Ontario, Canada, were linked to LTCH admissions within 1 year after completion of the first RAI-HC assessment. Cox models were used to examine whether care recipient health care needs, caregiver distress and caregiving characteristics such as coresidence and relationship were associated with LTCH admission. Age, marital status and gender of the care recipient were included as covariates in the model. RESULTS: Care recipient health care needs and age were the strongest predictors of LTCH admission followed by caregiver distress and caregiving coresidence and relationship. Care recipient marital status was not significant in the survival model. Interestingly, care recipients who were cared for by a coresiding adult child caregiver were less likely to be admitted to a LTCH than care recipients cared for by a spouse caregiver coresiding or not with care recipient. Hazard rates (HR) of admission for care recipients cared for by caregivers coresiding and with other type of relationship with care recipient were not significantly different than HR of care recipients cared for by coresiding child caregivers. CONCLUSIONS: These results emphasize the influence of caregiver distress in LTCH admission and highlight the impact of caregiving relationship and coresidence on this outcome. Policy and decision makers should consider these findings when developing and evaluating interventions aiming to avoid LTCH admissions. Moreover, caregiving coresidence and relationship should be explored in future studies with similar aims, as this information has been neglected in past research. PMID- 29121918 TI - "No generics, Doctor!" The perspective of general practitioners in two French regions. AB - BACKGROUND: Generic medicines are essential to controlling health expenditures. Their market share is still small in France. The discourse and practices of prescribers may play a major role in their use. The purpose of this study was to explore the knowledge, attitudes and practices of general practitioners (GPs) toward generic medicines in two French regions with the lowest penetration rate of these products. METHODS: An observational study was carried out from October 2015 to February 2016 in Guadeloupe and Martinique. The first qualitative phase involved a diversified sample of 14 GPs who underwent semi-structured interviews. The second phase involved a random sample of 316 GPs (response rate = 74%) who were administered a structured questionnaire developed from the results of the first phase. RESULTS: Seventy-eight percent of the participants defined a generic drug as a drug containing an active substance identical to a brand-name drug, but only 11% considered generic drugs to be equivalent to brand-name drugs, and the same proportion believed that the generic drugs were of doubtful quality. The primary recognized advantage of generic medicines was their lower cost (82%). The main drawbacks cited were the variability of their presentation (44%), the confusion that they caused for some patients (47%), frequent allegations of adverse side effects (37%) and a lack of efficacy (24%), and frequent refusal by patients (26%). Seventy-four percent of the participants stated that they adapted their prescribing practices to the situation, and of this group, 47% prescribed the originator product simply on demand. CONCLUSION: Most surveyed GPs were not hostile towards generic medicines. They were caught between the requirements of health insurance regimes and the opposition of numerous users and suggested that the patient information provided by health authorities should be improved and that drug composition and packaging should be made uniform. PMID- 29121917 TI - A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration. AB - BACKGROUND: Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. RESULTS: The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. CONCLUSIONS: Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM. PMID- 29121919 TI - Effects of hypoglycemia on myocardial susceptibility to ischemia-reperfusion injury and preconditioning in hearts from rats with and without type 2 diabetes. AB - BACKGROUND: Hypoglycemia is associated with increased mortality rate in patients with diabetes. The underlying mechanisms may involve reduced myocardial tolerance to ischemia and reperfusion (IR) or reduced capacity for ischemic preconditioning (IPC). As IPC is associated with increased myocardial glucose uptake (MGU) during reperfusion, cardioprotection is linked to glucose metabolism possibly by O linked beta-N-acetylglucosamine (O-GlcNAc). We aimed to investigate the impact of hypoglycemia in hearts from animals with diabetes on myocardial IR tolerance, on the efficacy of IPC and whether modulations of MGU and O-GlcNAc levels are involved in the underlying mechanisms. METHODS: In a Langendorff model using diabetic ZDF (fa/fa) and non-diabetic (fa/+) rats (n = 6-7 in each group) infarct size (IS) was evaluated after 40 min of global ischemia and 120 min reperfusion during hypoglycemia [(glucose) = 3 mmol/l] and normoglycemia [(glucose) = 11 mmol/l]. Myocardial glucose uptake and O-GlcNAc levels were evaluated during reperfusion. IPC was induced by 2 * 5 min of global ischemia prior to index ischemia. RESULTS: IS increased in hearts from animals with (p < 0.01) and without (p < 0.01) diabetes during hypoglycemia compared to normoglycemia. IPC reduced IS during normoglycemia in both animals with (p < 0.01) and without (p < 0.01) diabetes. During hypoglycemia, however, IPC only reduced IS in hearts from animals with diabetes (p < 0.05). IPC increased MGU during reperfusion and O GlcNAc levels in animals with diabetes during hypo- (MGU: p < 0.05, O-GlcNAc: p < 0.05) and normoglycemia (MGU: p < 0.01, O-GlcNAc: p < 0.05) and in animals without diabetes only during normoglycemia (MGU: p < 0.05, O-GlcNAc: p < 0.01). CONCLUSIONS: Hypoglycemia increases myocardial susceptibility to IR injury in hearts from animals with and without diabetes. In contrast to hearts from animals without diabetes, the hearts from animals with diabetes are amenable to cardioprotection during hypoglycemia. In parallel with IPC induced cardioprotection, MGU and O-GlcNAc levels increase suggesting that increased MGU and O-GlcNAc levels are involved in the mechanisms of IPC. PMID- 29121920 TI - Telephone triage utilization among patients with limited English proficiency. AB - BACKGROUND: Communication between patients with limited English proficiency (LEP) and telephone triage services has not been previously explored. The purpose of this study was to determine the utilization characteristics of a primary care triage call center by patients with LEP. METHODS: This was a retrospective cohort study of the utilization of a computer-aided, nurse-led telephone triage system by English proficiency status of patients empaneled to a large primary care practice network in the Midwest United States. Interpreter Services (IS) need was used as a proxy for LEP. RESULTS: Call volumes between the 587 adult patients with LEP and an age-frequency matched cohort of English-Proficient (EP) patients were similar. Calls from patients with LEP were longer and more often made by a surrogate. Patients with LEP received recommendations for higher acuity care more frequently (49.4% versus 39.0%; P < 0.0004), and disagreed with recommendations more frequently (30.1% versus 20.9%; P = 0.0004). These associations remained after adjustment for comorbidities. Patients with LEP were also less likely to follow recommendations (60.9% versus 69.4%; P = 0.0029), even after adjusting for confounders (adjusted odds ratio [AOR] = 0.65; 95% confidence interval [CI], 0.49, 0.85; P < 0.001). CONCLUSION: Patients with LEP who utilized a computer aided, nurse-led telephone triage system were more likely to receive recommendations for higher acuity care compared to EP patients. They were also less likely to agree with, or follow, recommendations given. Additional research is needed to better understand how telephone triage can better serve patients with LEP. PMID- 29121921 TI - Transcatheter aortic valve implantation and surgical aortic valve replacement among hospitalized patients with and without type 2 diabetes mellitus in Spain (2014-2015). AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is strongly related to the in hospital and short-term prognosis in patients with cardiovascular diseases needing surgical or invasive interventions. How T2DM might influence the treatment of aortic stenosis (AS) has not been completely elucidated for surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI). The aims of this study were: (1) to describe the use of aortic valve replacement procedures (TAVI and SAVR) among hospitalized patients with and without T2DM; and (2) to identify factors associated with in hospital mortality (IHM) among patients undergoing these procedures. METHODS: We analyzed data from the Spanish National Hospital Discharge Database between January 1, 2014 and December 31, 2015 for patients aged >= 40 years. We selected patients whose medical procedures included TAVI (ICD-9-CM codes 35.05, 35.06) and SAVR (ICD-9-CM codes 35.21, 35.22). We stratified each cohort by diabetes status: T2DM (ICD-9-CM codes 250.x0, 250.x2) and no diabetes. We retrieved data about specific comorbidities, risk factors, procedures, and specific in-hospital postoperative complications. Hospital outcome variables included IHM, and length of hospital stay (LOHS). RESULTS: We identified a total of 2141 and 16,013 patients who underwent TAVI (n = 715; 33.39% with T2DM) and SAVR (n = 4057; 25.33% with T2DM). In patients who underwent TAVI we found no differences in IHM (3.64% in T2DM vs. 5.12% in non-T2DM, p = 0.603). In the cohort of SAVR, mean LOHS was significantly lower in patients with T2DM than in non-diabetic patients (13.77 vs. 17.27 days). IHM was lower in patients with T2DM (4.36% vs. 6.31%, p < 0.01). After multivariable adjustment for both procedures, patients with T2DM had significantly lower IHM than patients without diabetes (adjusted OR 0.60; IC 95% 0.37-0.99 for TAVI and adjusted OR 0.80; IC 95% 0.66-0-96 for SAVR). CONCLUSIONS: T2DM diabetic patients with AS undergoing a valvular replacement procedure through SAVR or TAVI did not have a worse prognosis compared to non-diabetic patients during hospitalization, showing lower IHM after multivariable adjustment. However, given the limitations of administrative data more prospective studies and clinical trials aimed at evaluating the influence of these procedures in diabetic patients with AS are needed. PMID- 29121922 TI - Assisting differential clinical diagnosis of cattle diseases using smartphone based technology in low resource settings: a pilot study. AB - BACKGROUND: The recent rise in mobile phone use and increased signal coverage has created opportunities for growth of the mobile Health sector in many low resource settings. This pilot study explores the use of a smartphone-based application, VetAfrica-Ethiopia, in assisting diagnosis of cattle diseases. We used a modified Delphi protocol to select important diseases and Bayesian algorithms to estimate the related disease probabilities based on various clinical signs being present in Ethiopian cattle. RESULTS: A total of 928 cases were diagnosed during the study period across three regions of Ethiopia, around 70% of which were covered by diseases included in VetAfrica-Ethiopia. Parasitic Gastroenteritis (26%), Blackleg (8.5%), Fasciolosis (8.4%), Pasteurellosis (7.4%), Colibacillosis (6.4%), Lumpy skin disease (5.5%) and CBPP (5.0%) were the most commonly occurring diseases. The highest (84%) and lowest (30%) levels of matching between diagnoses made by student practitioners and VetAfrica-Ethiopia were for Babesiosis and Pasteurellosis, respectively. Multiple-variable logistic regression analysis indicated that the putative disease indicated, the practitioner involved, and the level of confidence associated with the prediction made by VetAfrica-Ethiopia were major determinants of the likelihood that a diagnostic match would be obtained. CONCLUSIONS: This pilot study demonstrated that the use of such applications can be a valuable means of assisting less experienced animal health professionals in carrying out disease diagnosis which may lead to increased animal productivity through appropriate treatment. PMID- 29121923 TI - Decentralised training for medical students: a scoping review. AB - BACKGROUND: Increasingly, medical students are trained at sites away from the tertiary academic health centre. A growing body of literature identifies the benefits of decentralised clinical training for students, the health services and the community. A scoping review was done to identify approaches to decentralised training, how these have been implemented and what the outcomes of these approaches have been in an effort to provide a knowledge base towards developing a model for decentralised training for undergraduate medical students in lower and middle-income countries (LMICs). METHODS: Using a comprehensive search strategy, the following databases were searched, namely EBSCO Host, ERIC, HRH Global Resources, Index Medicus, MEDLINE and WHO Repository, generating 3383 references. The review team identified 288 key additional records from other sources. Using prespecified eligibility criteria, the publications were screened through several rounds. Variables for the data-charting process were developed, and the data were entered into a custom-made online Smartsheet database. The data were analysed qualitatively and quantitatively. RESULTS: One hundred and five articles were included. Terminology most commonly used to describe decentralised training included 'rural', 'community based' and 'longitudinal rural'. The publications largely originated from Australia, the United States of America (USA), Canada and South Africa. Fifty-five percent described decentralised training rotations for periods of more than six months. Thematic analysis of the literature on practice in decentralised medical training identified four themes, each with a number of subthemes. These themes were student learning, the training environment, the role of the community, and leadership and governance. CONCLUSIONS: Evident from our findings are the multiplicity and interconnectedness of factors that characterise approaches to decentralised training. The student experience is nested within a particular context that is framed by the leadership and governance that direct it, and the site and the community in which the training is happening. Each decentralised site is seen to have its own dynamic that may foreground certain elements, responding differently to enabling student learning and influencing the student experience. The insights that have been established through this review have relevance in informing the further expansion of decentralised clinical training, including in LMIC contexts. PMID- 29121924 TI - Impact of overweight on left ventricular function in type 2 diabetes mellitus. AB - BACKGROUND: Coexistence of left ventricular (LV) longitudinal myocardial systolic dysfunction with LV diastolic dysfunction could lead to heart failure with preserved ejection fraction (HFpEF). Diabetes mellitus (DM) is known as a significant factor associated with HFpEF. Although the mechanisms of DM-related LV myocardial injury are complex, it has been postulated that overweight contributes to the development of LV myocardial injury in type 2 diabetes mellitus (T2DM) patients. However, the precise impact of overweight on LV longitudinal myocardial systolic function in T2DM patients remains unclear. METHODS: We studied 145 asymptomatic T2DM patients with preserved LV ejection fraction (LVEF) without coronary artery disease. LV longitudinal myocardial systolic function was assessed by global longitudinal strain (GLS), which was defined as the average peak strain of 18-segments obtained from standard apical views. Overweight was defined as body mass index (BMI) >= 25 kg/m2. Ninety age-, gender- and LVEF-matched healthy volunteers served as controls. RESULTS: GLS of overweight T2DM patients was significantly lower than that of non-overweight patients (17.9 +/- 2.4% vs. 18.9 +/- 2.6%, p < 0.05), whereas GLS of both overweight and non-overweight controls was similar (19.8 +/- 1.3% vs. 20.4 +/- 2.1%, p = 0.38). Furthermore, multiple regression analysis revealed that for T2DM patients, BMI was the independent determinant parameters for GLS as well as LV mass index. CONCLUSIONS: Overweight has a greater effect on LV longitudinal myocardial systolic function in T2DM patients than on that in non-DM healthy subjects. Our finding further suggests that the strict control of overweight in T2DM patients may be associated with prevention of the development of HFpEF. PMID- 29121925 TI - Advances and challenges in cirrhosis and portal hypertension. AB - BACKGROUND: Liver cirrhosis is the fourth cause of death in adults in Western countries, with complications of portal hypertension being responsible for most casualties. In order to reduce mortality, development of accurate diagnostic methods for early diagnosis, effective etiologic treatment, improved pharmacological therapy for portal hypertension, and effective therapies for end stage liver failure are required. DISCUSSION: Early detection of cirrhosis and portal hypertension is now possible using simple non-invasive methods, leading to the advancement of individualized risk stratification in clinical practice. Despite previous assumptions, cirrhosis can regress if its etiologic cause is effectively removed. Nevertheless, while this is now possible for cirrhosis caused by chronic hepatitis C, the incidence of cirrhosis due to non-alcoholic steatohepatitis has increased dramatically and effective therapies are not yet available. New drugs acting on the dynamic component of hepatic vascular resistance are being studied and will likely improve the future management of portal hypertension. CONCLUSION: Cirrhosis is now seen as a dynamic disease able to progress and regress between the compensated and decompensated stages. This opinion article aims to provide the author's personal view of the current major advances and challenges in this field. PMID- 29121926 TI - Quantitative and qualitative aspects of standing-up behavior and the prevalence of osteochondrosis in Warmblood foals on different farms: could there be a link? AB - BACKGROUND: Osteochondrosis (OC) is a common, clinically important joint disorder in which endochondral ossification is focally disturbed. Reduced blood supply to growing cartilage is considered an important cause of the condition, which has both genetic and environmental origins. Housing conditions can influence cartilage injury through peak-pressure changes during limb sliding. Additionally, circulatory perturbation can cause the avascular necrosis of cartilage. In this study, we evaluated the type and frequency of limb sliding during standing up and the occurrence of OC in foals aged up to 12 months on different farms. METHODS: Standing-up behavior was observed in 50 weaned, group-housed, Dutch Warmblood foals aged 6-9 months at five farms using black-and-white surveillance cameras, and their standing-up behavior was scored using a predetermined ethogram. OC was scored using a categorical scale between 6 and 12 months of age in 50 foals in the weanling period, and in 48 from the weanling to yearling periods because two foals died in this time. RESULTS: At both 6 and 12 months of age, the total prevalence of OC differed between the farms: the lowest prevalence was observed on a farm with no sliding, and the highest prevalence was evident on a farm with a higher sliding frequency. The mean ratio of sliding versus normal standing-up behavior was 29% (range: 0-50%); i.e., foals experienced limb sliding during around 29% of standing-up maneuvres. The frequency of sliding instead of normal standing-up behavior differed significantly between the farms (range: 0-50%; P < 0.05), but significantly decreased when foals could better prepare themselves to stand, e.g., when there was an obvious provocation such as the announced approach of another foal (P < 0.05). CONCLUSIONS: Small but significant differences exist between farms in the sliding frequency and total OC incidence in Warmblood foals, but whether environmental factors are causally related to these differences requires further elucidation. PMID- 29121927 TI - Divide and conquer? Size adjustment with allometry and intermediate outcomes. AB - Many trait measurements are size-dependent, and while we often divide these traits by size before fitting statistical models to control for the effect of size, this approach does not account for allometry and the intermediate outcome problem. We describe these problems and outline potential solutions. PMID- 29121928 TI - A yeast two-hybrid system for the screening and characterization of small molecule inhibitors of protein-protein interactions identifies a novel putative Mdm2-binding site in p53. AB - BACKGROUND: Protein-protein interactions (PPIs) are fundamental to the growth and survival of cells and serve as excellent targets to develop inhibitors of biological processes such as host-pathogen interactions and cancer cell proliferation. However, isolation of PPI inhibitors is extremely challenging. While several in vitro assays to screen for PPI inhibitors are available, they are often expensive, cumbersome, and require large amounts of purified protein. In contrast, limited in vivo assays are available to screen for small-molecule inhibitors of PPI. METHODS: We have engineered a yeast strain that is suitable for screening of small-molecule inhibitors of protein-protein interaction using the Yeast 2-hybrid Assay. We have optimised and validated the assay using inhibitors of the p53-Mdm2 interaction and identified a hitherto unreported putative Mdm2-binding domain in p53. RESULTS: We report a significantly improved and thoroughly validated yeast two-hybrid (Y2H) assay that can be used in a high throughput manner to screen for small-molecule PPI inhibitors. Using the p53-Mdm2 interaction to optimize the assay, we show that the p53-Mdm2 inhibitor nutlin-3 is a substrate for the yeast ATP-binding cassette (ABC) transporter Pdr5. By deleting nine ABC transporter-related genes, we generated a ABC9Delta yeast strain that is highly permeable to small molecules. In the ABC9Delta strain, p53 Mdm2 interaction inhibitors, like AMG232 and MI-773, completely inhibited the p53 Mdm2 interaction at nanomolar concentrations in the Y2H assay. In addition, we identified a conserved segment in the core DNA-binding domain of p53 that facilitates stable interaction with Mdm2 in yeast cells and in vitro. CONCLUSION: The Y2H assay can be utilized for high-throughput screening of small-molecule inhibitors of PPIs and to identify domains that stabilize PPIs. PMID- 29121929 TI - Variation in the immune responses against Plasmodium falciparum merozoite surface protein-1 and apical membrane antigen-1 in children residing in the different epidemiological strata of malaria in Cameroon. AB - BACKGROUND: Studies to assess the immune responses against malaria in Cameroonian children are limited. The purpose of this study was to assess the immune responses against Plasmodium falciparum merozoite surface protein-1 (MSP-119) and apical membrane antigen-1 (AMA-1) in children residing in the different epidemiological strata of malaria in Cameroon. METHODS: In a cross-sectional survey performed between April and July 2015, 602 children between 2 and 15 years (mean +/- SD = 5.7 +/- 3.7), comprising 319 (53%) males were enrolled from five epidemiological strata of malaria in Cameroon including: the sudano-sahelian (SS) strata, the high inland plateau (HIP) strata, the south Cameroonian equatorial forest (SCEF) strata, the high western plateau (HWP) strata, and the coastal (C) strata. The children were screened for clinical malaria (defined by malaria parasitaemia >= 5000 parasites/ul plus axillary temperature >= 37.5 degrees C). Their antibody responses were measured against P. falciparum MSP-119 and AMA-1 vaccine candidate antigens using standard ELISA technique. RESULTS: A majority of the participants were IgG responders 72.1% (95% CI 68.3-75.6). The proportion of responders was higher in females (p = 0.002) and in children aged 10 years and above (p = 0.005). The proportion of responders was highest in Limbe (C strata) and lowest in Ngaoundere (HIP strata) (p < 0.0001). Similarly, the mean IgG antibody levels were higher in children aged 10 years and above (p < 0.0001) and in Limbe (p = 0.001). The IgG antibody levels against AMA-1 were higher in females (p = 0.028), meanwhile no gender disparity was observed with MSP-1. Furthermore the risk of clinical malaria (p < 0.0001) and the mean parasite density (p = 0.035) were higher in IgG non-responders. CONCLUSION: A high proportion of IgG responders was observed in this study, suggesting a high degree exposure of the target population to malaria parasites. The immune responses varied considerably across the different strata: the highest levels observed in the C strata and the lowest in the HIP strata. Furthermore, malaria transmission in Cameroon could be categorized into two major groups based on the serological reaction of the children: the southern (comprising C and SCEF strata) and northern (comprising HWP, HIP and SS strata) groups. These findings may have significant implications in the design of future trials for evaluating malaria vaccine candidates in Cameroon. PMID- 29121930 TI - Buckyballs conjugated with nucleic acid sequences identifies microorganisms in live cell assays. AB - BACKGROUND: Rapid identification of bacteria can play an important role at the point of care, evaluating the health of the ecosystem, and discovering spatiotemporal distributions of a bacterial community. We introduce a method for rapid identification of bacteria in live cell assays based on cargo delivery of a nucleic acid sequence and demonstrate how a mixed culture can be differentiated using a simple microfluidic system. METHODS: C60 Buckyballs are functionalized with nucleic acid sequences and a fluorescent reporter to show that a diversity of microorganisms can be detected and identified in live cell assays. The nucleic acid complexes include an RNA detector, targeting a species-specific sequence in the 16S rRNA, and a complementary DNA with an attached fluorescent reporter. As a result, each bacterium can be detected and visualized at a specific emission frequency through fluorescence microscopy. RESULTS: The C60 probe complexes can detect and identify a diversity of microorganisms that include gram-position and negative bacteria, yeast, and fungi. More specifically, nucleic-acid probes are designed to identify mixed cultures of Bacillus subtilis and Streptococcus sanguinis, or Bacillus subtilis and Pseudomonas aeruginosa. The efficiency, cross talk, and accuracy for the C60 probe complexes are reported. Finally, to demonstrate that mixed cultures can be separated, a microfluidic system is designed that connects a single source-well to multiple sinks wells, where chemo attractants are placed in the sink wells. The microfluidic system allows for differentiating a mixed culture. CONCLUSIONS: The technology allows profiling of bacteria composition, at a very low cost, for field studies and point of care. PMID- 29121931 TI - Individual and household characteristics of persons with Plasmodium falciparum malaria in sites with varying endemicities in Kinshasa Province, Democratic Republic of the Congo. AB - BACKGROUND: The Democratic Republic of the Congo (DRC) bears a large share of global malaria burden despite efforts to control and eliminate the disease. More detailed understanding of individual and household level characteristics associated with malaria are needed, as is an understanding of how these characteristics vary spatiotemporally and across different community-level malaria endemicities. An ongoing study in Kinshasa Province is designed to address gaps in prior malaria surveillance in the DRC by monitoring malaria across seasons, age groups and in high and low malaria sites. Across seven sites, 242 households and 1591 individuals are participating in the study. Results of the enrollment questionnaire, rapid diagnostic tests and PCR testing of dried blood spots are presented. RESULTS: Overall malaria prevalence in the study cohort is high, 27% by rapid diagnostic test and 31% by polymerase chain reaction, and malaria prevalence is highly varied across very small geographic distances. Malaria prevalence is highest in children aged 6-15. While the majority of households own bed nets, bed net usage is less than 50%. CONCLUSIONS: The study cohort will provide an understanding of how malaria persists in populations that have varying environmental exposures, varying community-level malaria, and varying access to malaria control efforts. PMID- 29121932 TI - Hemodynamics analysis of the serial stenotic coronary arteries. AB - Coronary arterial stenoses, particularly serial stenoses in a single branch, are responsible for complex hemodynamic properties of the coronary arterial trees, and the uncertain prognosis of invasive intervention. Critical information of the blood flow redistribution in the stenotic arterial segments is required for the adequate treatment planning. Therefore, in this study, an image based non invasive functional assessment is performed to investigate the hemodynamic significances of serial stenoses. Twenty patient-specific coronary arterial trees with different combinations of stenoses were reconstructed from the computer tomography angiography for the evaluation of the hemodynamics. Our results showed that the computed FFR based on CTA images (FFRCT) pullback curves with wall shear stress (WSS) distribution could provide more effectively examine the physiological significance of the locations of the segmental narrowing and the curvature of the coronary arterial segments. The paper thus provides the diagnostic efficacy of FFRCT pullback curve for noninvasive quantification of the hemodynamics of stenotic coronary arteries with serial lesions, compared to the gold standard invasive FFR, to provide a reliable physiological assessment of significant amount of coronary artery stenosis. Further, we were also able to demonstrate the potential of carrying out virtual revascularization, to enable more precise PCI procedures and improve their outcomes. PMID- 29121933 TI - Biochemical analysis and the preliminary crystallographic characterization of D tagatose 3-epimerase from Rhodobacter sphaeroides. AB - BACKGROUND: D-Tagatose 3-epimerase epimerizes D-fructose to yield D-psicose, which is a rare sugar that exists in small quantities in nature and is difficult to synthesize chemically. We aim to explore potential industrial biocatalysts for commercial-scale manufacture of this rare sugar. A D-tagatose 3-epimerase from Rhodobacter sphaeroides (RsDTE) has recently been identified as a D-tagatose 3 epimerase that can epimerize D-fructose to yield D-psicose with a high conversion rate. RESULTS: The purified RsDTE by Ni-affinity chromatography, ionic exchange chromatography and gel filtration forms a tetramer in solution. The maximal activity was in Tris-HCl buffer pH 8.5, and the optimal temperature was at 35 degrees C. The product, D-psicose, was confirmed using HPLC and NMR. Crystals of RsDTE were obtained using crystal kits and further refined under crystallization conditions such as 10% PEG 8000,0.1 M HEPES pH 7.5, and 8% ethylene glycol at 20 degrees C using the sitting-drop vapor diffusion method. The RsDTE homology model showed that it possessed the characteristic TIM-barrel fold. Four residues, Glu156, Asp189, Gln215 and Glu250, forms a hydrogen bond network with the active Mn(II) for the hydride transfer reaction. These residues may constitute the catalytic tetrad of RsDTE. The residues around O1, O2 and O3 of the substrates were conserved. However, the binding-site residues are different at O4, O5 and O6. Arg118 formed the unique hydrogen bond with O4 of D-fructose which indicates RsDTE's preference of D-fructose more than any other family enzymes. CONCLUSIONS: RsDTE possesses a different metal-binding site. Arg118, forming unique hydrogen bond with O4 of D-fructose, regulates the substrate recognition. The research on D-tagatose 3-epimerase or D-psicose 3-epimerase enzymes attracts enormous commercial interest and would be widely used for rare sugar production in the future. PMID- 29121934 TI - Effect of rosuvastatin on fasting and postprandial endothelial biomarker levels and microvascular reactivity in patients with type 2 diabetes and dyslipidemia: a preliminary report. AB - BACKGROUND: The cardiovascular benefits of statins have been proven, but their effect on circulation in small vessels has not been examined fully. We investigated the effect of 20 mg rosuvastatin on biomarkers, including paraoxonase-1 (PON-1) and asymmetric dimethylarginine (ADMA), and on microvascular reactivity. METHOD: We enrolled 20 dyslipidemic patients with type 2 diabetes and 20 age- and body mass index (BMI)-matched healthy controls. Rosuvastatin (20 mg/day) was given to the patient group for 12 weeks. Biochemical parameters, including PON-1 and ADMA, were compared between the patient and control groups, and before and after rosuvastatin treatment in the patient group. Fasting and 2 h postprandial levels of PON-1 and ADMA after mixed-meal challenge were also compared. Microvascular reactivity in a peripheral artery was examined using laser Doppler flowmetry. RESULTS: The respective mean +/- standard deviation of age and BMI were 50.1 +/- 3.8 year and 25.8 +/- 3.7 kg/m2 in the patients and 50.2 +/- 3.2 year and 25.4 +/- 3.4 kg/m2 in the controls. The patient group had worse profiles of cardiometabolic biomarkers, including PON-1 and ADMA, than the controls. In the patients treated with 20 mg rosuvastatin, low density lipoprotein (LDL)-cholesterol decreased from 147.2 +/- 26.5 to 68.3 +/- 24.5 mg/dL and high-density lipoprotein (HDL)-cholesterol increased from 42.4 +/- 5.2 to 44.7 +/- 6.2 mg/dL (both P < 0.05). Both fasting and 2 h postprandial levels of PON-1 increased and those of ADMA decreased after treatment with rosuvastatin for 12 weeks. The changes in postprandial levels of both biomarkers were greater than those after fasting. Microcirculation assessed as reactive hyperemia in the patients after an ischemic challenge increased significantly from 335.3 +/- 123.4 to 402.7 +/- 133.4% after rosuvastatin treatment. The postprandial changes in the biomarkers were significantly associated with improvement of microvascular reactivity. CONCLUSIONS: Rosuvastatin treatment for 12 weeks improved microvascular reactivity with concomitant beneficial changes in the postprandial levels of PON-1 and ADMA. These results suggest that rosuvastatin improves the postprandial cardiometabolic milieu in type 2 diabetes. Trial registration ClinicalTrials.gov: NCT02185963 (July 7, 2014). PMID- 29121935 TI - Bioconversion of distillers' grains hydrolysates to advanced biofuels by an Escherichia coli co-culture. AB - BACKGROUND: First generation bioethanol production utilizes the starch fraction of maize, which accounts for approximately 60% of the ash-free dry weight of the grain. Scale-up of this technology for fuels applications has resulted in a massive supply of distillers' grains with solubles (DGS) coproduct, which is rich in cellulosic polysaccharides and protein. It was surmised that DGS would be rapidly adopted for animal feed applications, however, this has not been observed based on inconsistency of the product stream and other logistics-related risks, especially toxigenic contaminants. Therefore, efficient valorization of DGS for production of petroleum displacing products will significantly improve the techno economic feasibility and net energy return of the established starch bioethanol process. In this study, we demonstrate 'one-pot' bioconversion of the protein and carbohydrate fractions of a DGS hydrolysate into C4 and C5 fusel alcohols through development of a microbial consortium incorporating two engineered Escherichia coli biocatalyst strains. RESULTS: The carbohydrate conversion strain E. coli BLF2 was constructed from the wild type E. coli strain B and showed improved capability to produce fusel alcohols from hexose and pentose sugars. Up to 12 g/L fusel alcohols was produced from glucose or xylose synthetic medium by E. coli BLF2. The second strain, E. coli AY3, was dedicated for utilization of proteins in the hydrolysates to produce mixed C4 and C5 alcohols. To maximize conversion yield by the co-culture, the inoculation ratio between the two strains was optimized. The co-culture with an inoculation ratio of 1:1.5 of E. coli BLF2 and AY3 achieved the highest total fusel alcohol titer of up to 10.3 g/L from DGS hydrolysates. The engineered E. coli co-culture system was shown to be similarly applicable for biofuel production from other biomass sources, including algae hydrolysates. Furthermore, the co-culture population dynamics revealed by quantitative PCR analysis indicated that despite the growth rate difference between the two strains, co-culturing didn't compromise the growth of each strain. The q-PCR analysis also demonstrated that fermentation with an appropriate initial inoculation ratio of the two strains was important to achieve a balanced co-culture population which resulted in higher total fuel titer. CONCLUSIONS: The efficient conversion of DGS hydrolysates into fusel alcohols will significantly improve the feasibility of the first generation bioethanol process. The integrated carbohydrate and protein conversion platform developed here is applicable for the bioconversion of a variety of biomass feedstocks rich in sugars and proteins. PMID- 29121936 TI - Molecular characterization of a novel Muscovy duck parvovirus isolate: evidence of recombination between classical MDPV and goose parvovirus strains. AB - BACKGROUND: Muscovy duck parvovirus (MDPV) and Goose parvovirus (GPV) are important etiological agents for Muscovy duck parvoviral disease and Derzsy's disease, respectively; both of which can cause substantial economic losses in waterfowl industry. In contrast to GPV, the complete genomic sequence data of MDPV isolates are still limited and their phylogenetic relationships largely remain unknown. In this study, the entire genome of a pathogenic MDPV strain ZW, which was isolated from a deceased Muscovy duckling in 2006 in China, was cloned, sequenced, and compared with that of other classical MDPV and GPV strains. RESULTS: The genome of strain ZW comprises of 5071 nucleotides; this genome was shorter than that of the pathogenic MDPV strain YY (5075 nt). All the four deleted nucleotides produced in strain ZW are located at the base-pairing positions in the palindromic stem of inverted terminal repeats (ITR) without influencing the formation of a hairpin structure. Recombination analysis revealed that strain ZW originated from genetic recombination between the classical MDPV and GPV strain. The YY strain of MDPV acts as the major parent, whereas the virulent strains YZ99-6 and B and the vaccine strain SYG61v of GPV act as the minor parents in varying degrees. Two recombination sites were detected in strain ZW, with the small recombination site surrounding the P9 promoter, and the large recombination site situated in the middle of the VP3 gene. The SYG61V strain is a vaccine strain used for preventing goose parvoviral disease. This strain was found to be solely involved in the recombination event detected in the P9 promoter region. Phylogenetic analyses between strain ZW and other classical strains of MDPV and GPV were performed. The results supported the in silico recombination analysis conclusion. CONCLUSIONS: MDPV Strain ZW is a novel recombinant parvovirus, and the bulk of its genome originates from the classical MDPV strain. Two virulent strains and a vaccine strain of GPV were involved in the recombination process in varying degrees. PMID- 29121937 TI - Functional analysis of the global repressor Tup1 for maltose metabolism in Saccharomyces cerevisiae: different roles of the functional domains. AB - BACKGROUND: Tup1 is a general transcriptional repressor of diverse gene families coordinately controlled by glucose repression, mating type, and other mechanisms in Saccharomyces cerevisiae. Several functional domains of Tup1 have been identified, each of which has differing effects on transcriptional repression. In this study, we aim to investigate the role of Tup1 and its domains in maltose metabolism of industrial baker's yeast. To this end, a battery of in-frame truncations in the TUP1 gene coding region were performed in the industrial baker's yeasts with different genetic background, and the maltose metabolism, leavening ability, MAL gene expression levels, and growth characteristics were investigated. RESULTS: The results suggest that the TUP1 gene is essential to maltose metabolism in industrial baker's yeast. Importantly, different domains of Tup1 play different roles in glucose repression and maltose metabolism of industrial baker's yeast cells. The Ssn6 interaction, N-terminal repression and C terminal repression domains might play roles in the regulation of MAL transcription by Tup1 for maltose metabolism of baker's yeast. The WD region lacking the first repeat could influence the regulation of maltose metabolism directly, rather than indirectly through glucose repression. CONCLUSIONS: These findings lay a foundation for the optimization of industrial baker's yeast strains for accelerated maltose metabolism and facilitate future research on glucose repression in other sugar metabolism. PMID- 29121938 TI - Effects of soybean meal fermented by L. plantarum, B. subtilis and S. cerevisieae on growth, immune function and intestinal morphology in weaned piglets. AB - BACKGROUND: The present study compared the effects of soybean meal fermented by three different probiotics organisms with non-fermented soybean meal on growth performance, serum parameters, immune chemistry and intestinal morphology in weaned piglets. METHODS: One hundred and forty-four 35-day old crossbred (Duroc * Landrace * Yorkshire) piglets were randomly allocated into four different dietary treatments (n = 36 per group) containing 0, 5, 10 and 15% fermented soybean meal. RESULTS: The piglets fed fermented soybean meal showed an increase (p < 0.05) in average daily weight gain and a reduction in feed consumption (p < 0.05).The piglets fed 10 and 15% fermented soybean meal showed the greatest growth improvement with higher levels of serum alkaline phosphatase and total serum proteins. Serum urea nitrogen in the experimental group was significantly lower than control whereas serum IgG, IgM and IgA levels were all significantly higher. Moreover, villus height in the duodenum, jejunum, and ileum was significantly higher (p < 0.05) and the crypt depth was significantly lower (p < 0.05). The levels of the autophagy factor LC3B in piglets showed a downward trend in the jejunum and ileum compared to control. CONCLUSIONS: Fermented soybean meal could significantly improve the growth, immune function and intestinal health in weaned piglets, and the best effective benefits showed in 10% FSBM group. PMID- 29121939 TI - Case definition terminology for paratuberculosis (Johne's disease). AB - Paratuberculosis (Johne's disease) is an economically significant condition caused by Mycobacterium avium subsp. paratuberculosis. However, difficulties in diagnosis and classification of individual animals with the condition have hampered research and impeded efforts to halt its progressive spread in the global livestock industry. Descriptive terms applied to individual animals and herds such as exposed, infected, diseased, clinical, sub-clinical, infectious and resistant need to be defined so that they can be incorporated consistently into well-understood and reproducible case definitions. These allow for consistent classification of individuals in a population for the purposes of analysis based on accurate counts. The outputs might include the incidence of cases, frequency distributions of the number of cases by age class or more sophisticated analyses involving statistical comparisons of immune responses in vaccine development studies, or gene frequencies or expression data from cases and controls in genomic investigations. It is necessary to have agreed definitions in order to be able to make valid comparisons and meta-analyses of experiments conducted over time by a given researcher, in different laboratories, by different researchers, and in different countries. In this paper, terms are applied systematically in an hierarchical flow chart to enable classification of individual animals. We propose descriptive terms for different stages in the pathogenesis of paratuberculosis to enable their use in different types of studies and to enable an independent assessment of the extent to which accepted definitions for stages of disease have been applied consistently in any given study. This will assist in the general interpretation of data between studies, and will facilitate future meta-analyses. PMID- 29121940 TI - Plasma irisin is elevated in type 2 diabetes and is associated with increased E selectin levels. AB - BACKGROUND: Irisin is a hormone released mainly from skeletal muscle after exercise which increases adipose tissue energy expenditure. Adipocytes can also release irisin after exercise, acting as a local adipokine to induce white adipose tissue to take on a brown adipose tissue-like phenotype, suggesting that irisin and its receptor may represent a novel molecular target for the treatment of obesity and obesity-related diabetes. Previous reports provide conflicting evidence regarding circulating irisin levels in patients with type 2 diabetes (T2DM). METHODS: This study investigated plasma irisin concentrations in 79 T2DM individuals, assessing potential associations with measures of segmental body composition, markers of endothelial dysfunction and peripheral blood mononuclear cell telomere length (TL). RESULTS: Resting, overnight-fasted plasma irisin levels were significantly higher in this group of T2DM patients compared with levels we previously reported in healthy volunteers (p < 0.001). Moreover, plasma irisin displayed a positive correlation with body mass index (p = 0.04), body fat percentage (p = 0.03), HbA1c (p = 0.03) and soluble E-selectin (p < 0.001). A significant negative association was observed between plasma irisin and visceral adiposity (p = 0.006) in T2DM patients. Multiple regression analysis revealed that circulating soluble E-selectin levels could be predicted by plasma irisin (p = 0.004). Additionally, cultured human umbilical vein endothelial cells (HUVEC) exposed to 200 ng/ml irisin for 4 h showed a significant fourfold increase in E selectin and 2.5-fold increase in ICAM-1 gene expression (p = 0.001 and p = 0.015 respectively), and there was a 1.8-fold increase in soluble E-selectin in conditioned media (p < 0.05). CONCLUSION: These data suggest that elevated plasma irisin in T2DM is associated with indices of adiposity, and that irisin may be involved in pro-atherogenic endothelial disturbances that accompany obesity and T2DM. Accordingly, irisin may constitute a potentially novel therapeutic opportunity in the field of obesity and cardiovascular diabetology. PMID- 29121941 TI - The nutritional status affects the complete blood count of goats experimentally infected with Haemonchus contortus. AB - BACKGROUND: Gastrointestinal nematode (GIN) remains the most important pathogenic constraint of small ruminant production worldwide. The improvement of the host immune response against GIN though breeding for improved animal resistance, vaccination and nutritional supplementation appear as very promising methods. The objective of this study was to investigate the effect of four nutritional status differing in protein and energy levels (Hay: 5.1 MJ/Kg of dry matter (DM) and 7.6% of crude protein (CP), Ban: 8.3 MJ/Kg of DM and 7.5% of CP, Soy: 7.6 MJ/Kg of DM and 17.3% of CP, BS: 12.7 MJ/Kg of DM and 7.4% of CP) on the haematological disturbances due to Haemonchus contortus infection in Creole kid goats. RESULTS: No significant effect of the nutritional status was observed for faecal egg count (FEC) but the experimental infection induced haematological disturbances whose intensity and lengthening were dependent on the nutritional status. A transient marked regenerative macrocytic hypochromic anaemia as revealed by a decrease of packed cell volume (PCV), red blood cells (RBC) and hemoglobin and an increase of reticulocytes was observed in all infected groups except Hay. In this latter, the anaemia settled until the end of the experiment. Furthermore, H. contortus induced a thrombocytopenia significantly more pronounced in the group under the lowest nutritional status in term of protein (Hay and Ban). A principal component analysis revealed that the variables that discriminated the nutritional status were the average daily gain (ADG) and the PCV, considered as measures of the level of resilience to H. contortus infection. Moreover, the variables that discriminated infected and non-infected animals were mostly related to the biology of RBC (i.e. size and hemoglobin content) and they were correlated with FEC. CONCLUSIONS: The severity and the lengthening of the regenerative anaemia and the thrombocytopenia induced by H. contortus have been affected by the nutritional status. The protein enriched diets induced resilience to the infection rather than resistance. This suggests that resilience is associated with an improved regenerative capacity of the bone marrow. However, this needs to be further investigated to understand the relationships between resistance, resilience and dietary supplementation. PMID- 29121942 TI - Ethical aspects of brain computer interfaces: a scoping review. AB - BACKGROUND: Brain-Computer Interface (BCI) is a set of technologies that are of increasing interest to researchers. BCI has been proposed as assistive technology for individuals who are non-communicative or paralyzed, such as those with amyotrophic lateral sclerosis or spinal cord injury. The technology has also been suggested for enhancement and entertainment uses, and there are companies currently marketing BCI devices for those purposes (e.g., gaming) as well as health-related purposes (e.g., communication). The unprecedented direct connection created by BCI between human brains and computer hardware raises various ethical, social, and legal challenges that merit further examination and discussion. METHODS: To identify and characterize the key issues associated with BCI use, we performed a scoping review of biomedical ethics literature, analyzing the ethics concerns cited across multiple disciplines, including philosophy and medicine. RESULTS: Based on this investigation, we report that BCI research and its potential translation to therapeutic intervention generate significant ethical, legal, and social concerns, notably with regards to personhood, stigma, autonomy, privacy, research ethics, safety, responsibility, and justice. Our review of the literature determined, furthermore, that while these issues have been enumerated extensively, few concrete recommendations have been expressed. CONCLUSIONS: We conclude that future research should focus on remedying a lack of practical solutions to the ethical challenges of BCI, alongside the collection of empirical data on the perspectives of the public, BCI users, and BCI researchers. PMID- 29121943 TI - Managing intra-EU mobility-do WHO principles of ethical recruitment have relevance? AB - BACKGROUND: The WHO Global Code of Practice on the International Recruitment of Health Personnel provides for guidance in health workforce management and cooperation in the international context. This article aims to examine whether the principles of the voluntary WHO Global Code of Practice can be applied to trigger health policy decisions within the EU zone of free movement of persons. METHODS: In the framework of the Joint Action on European Health Workforce Planning and Forecasting project (Grant Agreement: JA EUHWF 20122201 (see healthworkforce.eu)), focus group discussions were organised with over 30 experts representing ministries, universities and professional and international organisations. Ideas were collected about the applicability of the principles and with the aim to find EU law compatible, relevant solutions using a qualitative approach based on a standardised, semi-structured interview guide and pre-defined statements. RESULTS: Based on implementation practices summarised, focus group experts concluded that positive effects of adhering to the Code can be identified and useful ideas-compatible with EU law-exist to manage intra-EU mobility. The most relevant areas for intervention include bilateral cooperations, better use of EU financial resources, improved retention and integration policies and better data flow and monitoring. Improving retention is of key importance; however, ethical considerations should also apply within the EU. Compensation of source countries can be a solution to further elaborate on when developing EU financial mechanisms. Intra-EU circular mobility might be feasible and made more transparent if directed by tailor-made, institutional-level bilateral cooperations adjusted to different groups and profiles of health professionals. Integration policies should be improved as discrimination still exists when offering jobs despite the legal environment facilitating the recognition of professional qualifications. A system of feedback on registration/licencing data should be promoted providing for more evidence on intra-EU mobility and support its management. CONCLUSIONS: Workforce planning in EU Member States can be supported, and more equitable distribution of the workforce can be provided by building policy decisions on the principles of the WHO Code. Political commitment has to be strengthened in EU countries to adopt implementation solutions for intra-EU problems. Long-term benefits of respecting global principles of the Code should be better demonstrated in order to incentivise all parties to follow such long-term objectives. PMID- 29121944 TI - First experience of robotic spleen-preserving distal pancreatectomy in a child with insulinoma. AB - BACKGROUND: An insulinoma is a functional neuroendocrine pancreatic tumor, and surgical resection is indicated. Robot-assisted laparoscopic surgeries have been shown to be generally safe and feasible for treatment of pediatric cases of urologic and digestive disease. CASE PRESENTATION: In July 2016, a 9-year-old girl (24 kg, 120 cm) was admitted with a pancreatic tail insulinoma and underwent robot-assisted spleen-preserving laparoscopic distal pancreatectomy. The total procedure time was 155 min, and the blood loss was about 10 ml. The patient recovered without complications. CONCLUSIONS: This case supports that robot assisted spleen-preserving laparoscopic distal pancreatectomy may be safe and feasible in pediatric insulinoma patients. PMID- 29121945 TI - Potential dosimetric benefits of adaptive tumor tracking over the internal target volume concept for stereotactic body radiation therapy of pancreatic cancer. AB - BACKGROUND: Radiotherapy for pancreatic cancer has two major challenges: (I) the tumor is adjacent to several critical organs and, (II) the mobility of both, the tumor and its surrounding organs at risk (OARs). A treatment planning study simulating stereotactic body radiation therapy (SBRT) for pancreatic tumors with both the internal target volume (ITV) concept and the tumor tracking approach was performed. The two respiratory motion-management techniques were compared in terms of doses to the target volume and organs at risk. METHODS AND MATERIALS: Two volumetric-modulated arc therapy (VMAT) treatment plans (5 * 5 Gy) were created for each of the 12 previously treated pancreatic cancer patients, one using the ITV concept and one the tumor tracking approach. To better evaluate the overall dose delivered to the moving tumor volume, 4D dose calculations were performed on four-dimensional computed tomography (4DCT) scans. The resulting planning target volume (PTV) size for each technique was analyzed. Target and OAR dose parameters were reported and analyzed for both 3D and 4D dose calculation. RESULTS: Tumor motion ranged from 1.3 to 11.2 mm. Tracking led to a reduction of PTV size (max. 39.2%) accompanied with significant better tumor coverage (p<0.05, paired Wilcoxon signed rank test) both in 3D and 4D dose calculations and improved organ at risk sparing. Especially for duodenum, stomach and liver, the mean dose was significantly reduced (p<0.05) with tracking for 3D and 4D dose calculations. CONCLUSIONS: By using an adaptive tumor tracking approach for respiratory-induced pancreatic motion management, a significant reduction in PTV size can be achieved, which subsequently facilitates treatment planning, and improves organ dose sparing. The dosimetric benefit of tumor tracking is organ and patient-specific. PMID- 29121946 TI - Improving precision of glomerular filtration rate estimating model by ensemble learning. AB - BACKGROUND: Accurate assessment of kidney function is clinically important, but estimates of glomerular filtration rate (GFR) by regression are imprecise. METHODS: We hypothesized that ensemble learning could improve precision. A total of 1419 participants were enrolled, with 1002 in the development dataset and 417 in the external validation dataset. GFR was independently estimated from age, sex and serum creatinine using an artificial neural network (ANN), support vector machine (SVM), regression, and ensemble learning. GFR was measured by 99mTc-DTPA renal dynamic imaging calibrated with dual plasma sample 99mTc-DTPA GFR. RESULTS: Mean measured GFRs were 70.0 ml/min/1.73 m2 in the developmental and 53.4 ml/min/1.73 m2 in the external validation cohorts. In the external validation cohort, precision was better in the ensemble model of the ANN, SVM and regression equation (IQR = 13.5 ml/min/1.73 m2) than in the new regression model (IQR = 14.0 ml/min/1.73 m2, P < 0.001). The precision of ensemble learning was the best of the three models, but the models had similar bias and accuracy. The median difference ranged from 2.3 to 3.7 ml/min/1.73 m2, 30% accuracy ranged from 73.1 to 76.0%, and P was > 0.05 for all comparisons of the new regression equation and the other new models. CONCLUSIONS: An ensemble learning model including three variables, the average ANN, SVM, and regression equation values, was more precise than the new regression model. A more complex ensemble learning strategy may further improve GFR estimates. PMID- 29121947 TI - Interleukin-1beta signaling in fenestrated capillaries is sufficient to trigger sickness responses in mice. AB - BACKGROUND: The physiological and behavioral symptoms of sickness, including fever, anorexia, behavioral depression, and weight loss can be both beneficial and detrimental. These sickness responses are triggered by pro-inflammatory cytokines acting on cells within the brain. Previous research demonstrates that the febrile response to peripheral insults depends upon prostaglandin production by vascular endothelial cells, but the mechanisms and specific cell type(s) responsible for other sickness responses remain unknown. The purpose of the present study was to identify which cells within the brain are required for sickness responses triggered by central nervous system inflammation. METHODS: Intracerebroventricular (ICV) administration of 10 ng of the potent pro inflammatory cytokine interleukin-1beta (IL-1beta) was used as an experimental model of central nervous system cytokine production. We examined which cells respond to IL-1beta in vivo via fluorescent immunohistochemistry. Using multiple transgenic mouse lines expressing Cre recombinase under the control of cell specific promoters, we eliminated IL-1beta signaling from different populations of cells. Food consumption, body weight, movement, and temperature were recorded in adult male mice and analyzed by two-factor ANOVA to determine where IL-1beta signaling is essential for sickness responses. RESULTS: Endothelial cells, microglia, ependymal cells, and astrocytes exhibit nuclear translocation of NF kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) in response to IL-1beta. Interfering with IL-1beta signaling in microglia, endothelial cells within the parenchyma of the brain, or both did not affect sickness responses. Only mice that lacked IL-1beta signaling in all endothelium including fenestrated capillaries lacked sickness responses. CONCLUSIONS: These experiments show that IL-1beta-induced sickness responses depend on intact IL 1beta signaling in blood vessels and suggest that fenestrated capillaries act as a critical signaling relay between the immune and nervous systems. TRIAL REGISTRATION: Not applicable. PMID- 29121948 TI - Assessing the health workforce implications of health policy and programming: how a review of grey literature informed the development of a new impact assessment tool. AB - BACKGROUND: In their adoption of WHA resolution 69.19, World Health Organization Member States requested all bilateral and multilateral initiatives to conduct impact assessments of their funding to human resources for health. The High-Level Commission for Health Employment and Economic Growth similarly proposed that official development assistance for health, education, employment and gender are best aligned to creating decent jobs in the health and social workforce. No standard tools exist for assessing the impact of global health initiatives on the health workforce, but tools exist from other fields. The objectives of this paper are to describe how a review of grey literature informed the development of a draft health workforce impact assessment tool and to introduce the tool. METHOD: A search of grey literature yielded 72 examples of impact assessment tools and guidance from a wide variety of fields including gender, health and human rights. These examples were reviewed, and information relevant to the development of a health workforce impact assessment was extracted from them using an inductive process. RESULTS: A number of good practice principles were identified from the review. These informed the development of a draft health workforce impact assessment tool, based on an established health labour market framework. The tool is designed to be applied before implementation. It consists of a relatively short and focused screening module to be applied to all relevant initiatives, followed by a more in-depth assessment to be applied only to initiatives for which the screening module indicates that significant implications for HRH are anticipated. It thus aims to strike a balance between maximising rigour and minimising administrative burden. CONCLUSION: The application of the new tool will help to ensure that health workforce implications are incorporated into global health decision-making processes from the outset and to enhance positive HRH impacts and avoid, minimise or offset negative impacts. PMID- 29121949 TI - Quantifying engineered nanomaterial toxicity: comparison of common cytotoxicity and gene expression measurements. AB - BACKGROUND: When evaluating the toxicity of engineered nanomaterials (ENMS) it is important to use multiple bioassays based on different mechanisms of action. In this regard we evaluated the use of gene expression and common cytotoxicity measurements using as test materials, two selected nanoparticles with known differences in toxicity, 5 nm mercaptoundecanoic acid (MUA)-capped InP and CdSe quantum dots (QDs). We tested the effects of these QDs at concentrations ranging from 0.5 to 160 ug/mL on cultured normal human bronchial epithelial (NHBE) cells using four common cytotoxicity assays: the dichlorofluorescein assay for reactive oxygen species (ROS), the lactate dehydrogenase assay for membrane viability (LDH), the mitochondrial dehydrogenase assay for mitochondrial function, and the Comet assay for DNA strand breaks. RESULTS: The cytotoxicity assays showed similar trends when exposed to nanoparticles for 24 h at 80 ug/mL with a threefold increase in ROS with exposure to CdSe QDs compared to an insignificant change in ROS levels after exposure to InP QDs, a twofold increase in the LDH necrosis assay in NHBE cells with exposure to CdSe QDs compared to a 50% decrease for InP QDs, a 60% decrease in the mitochondrial function assay upon exposure to CdSe QDs compared to a minimal increase in the case of InP and significant DNA strand breaks after exposure to CdSe QDs compared to no significant DNA strand breaks with InP. High-throughput quantitative real-time polymerase chain reaction (qRT-PCR) data for cells exposed for 6 h at a concentration of 80 ug/mL were consistent with the cytotoxicity assays showing major differences in DNA damage, DNA repair and mitochondrial function gene regulatory responses to the CdSe and InP QDs. The BRCA2, CYP1A1, CYP1B1, CDK1, SFN and VEGFA genes were observed to be upregulated specifically from increased CdSe exposure and suggests their possible utility as biomarkers for toxicity. CONCLUSIONS: This study can serve as a model for comparing traditional cytotoxicity assays and gene expression measurements and to determine candidate biomarkers for assessing the biocompatibility of ENMs. PMID- 29121950 TI - The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity. AB - BACKGROUND: HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells. RESULTS: Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non treated virus. Autologous CD4+ T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable. CONCLUSIONS: Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune response against HIV-1 in animal models. PMID- 29121952 TI - Association between oxidative stress and cord serum lipids in relation to delayed cord clamping in term neonates. AB - BACKGROUND: Although delayed cord clamping (DCC) is a recent WHO recommendation, early cord clamping (ECC) is still a routine practice in many countries. Limited researches studied the effect of delayed cord clamping on oxidative stress in term neonates; In this study we aim to assess the influence of cord clamping either early or late on oxidative stress in term neonates and to evaluate the association of oxidative stress and cord blood lipids. METHODS: One-hundred mothers and their term neonates were included in the present study. Umbilical cord blood samples were collected from the umbilical vein and umbilical artery immediately following labor. RESULTS: Total cholesterol, total triglycerides and phospholipids levels were significantly higher in the ECC group than the DCC group (p < 0.001 in all). Plasma total antioxidant status was higher in the DCC group than the ECC group (p < 0.001). While, plasma hydroperoxides were lower in the DCC group than the ECC group (p < 0.001). Levels of erythrocytes catalase cytosol, superoxide dismutase and glutathione peroxidase were significantly higher in the DCC group than the ECC group (p < 0.001). CONCLUSION: DCC was associated with a decrease in cord blood lipids and an augmented antioxidant activity. This suggests the protective effect of DCC on the future health of the term neonates and supports the application of DCC in active management of 3rd stage of labor in term neonates. PMID- 29121951 TI - Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication. AB - BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) structural protein Gag is necessary and sufficient to form viral particles. In addition to encoding the amino acid sequence for Gag, the underlying RNA sequence could encode cis acting elements or nucleotide biases that are necessary for viral replication. Furthermore, RNA sequences that inhibit viral replication could be suppressed in gag. However, the functional relevance of RNA elements and nucleotide biases that promote or repress HIV-1 replication remain poorly understood. RESULTS: To characterize if the RNA sequence in gag controls HIV-1 replication, the matrix (MA) region was codon modified, allowing the RNA sequence to be altered without affecting the protein sequence. Codon modification of nucleotides (nt) 22-261 or 22-378 in gag inhibited viral replication by decreasing genomic RNA (gRNA) abundance, gRNA stability, Gag expression, virion production and infectivity. Comparing the effect of these point mutations to deletions of the same region revealed that the mutations inhibited infectious virus production while the deletions did not. This demonstrated that codon modification introduced inhibitory sequences. There is a much lower than expected frequency of CpG dinucleotides in HIV-1 and codon modification introduced a substantial increase in CpG abundance. To determine if they are necessary for inhibition of HIV-1 replication, codons introducing CpG dinucleotides were mutated back to the wild type codon, which restored efficient Gag expression and infectious virion production. To determine if they are sufficient to inhibit viral replication, CpG dinucleotides were inserted into gag in the absence of other changes. The increased CpG dinucleotide content decreased HIV-1 infectivity and viral replication. CONCLUSIONS: The HIV-1 RNA sequence contains low abundance of CpG dinucleotides. Increasing the abundance of CpG dinucleotides inhibits multiple steps of the viral life cycle, providing a functional explanation for why CpG dinucleotides are suppressed in HIV-1. PMID- 29121953 TI - Risk of tuberculosis among Alabama children and adolescents treated with tumor necrosis factor inhibitors: a retrospective study. AB - BACKGROUND: Tumor Necrosis Factor inhibitors (TNFi) have dramatically improved the outlook for patients with inflammatory arthritides and bowel disease (IBD), but are associated with increased infection risks, including tuberculosis (TB). Pediatric inflammatory diseases are uncommon, and the risk of TB in children taking TNFi remains unclear. The objective of this study was to report the incidence of TB disease among TNFi recipients at a single pediatric medical center serving most of Alabama compared to that of the general population of Alabama children. METHODS: Instances of TNFi usage among patients under age 20 years from July 1, 2007 through April 17, 2015 were captured from electronic health records at Children's of Alabama (CoA), which has the only pediatric rheumatology clinic in Alabama, and where a substantial number of children in Alabama with inflammatory bowel disease receive care., and reports of TB cases were obtained from the Alabama Department of Public Health (ADPH). Incidence was expressed as TB cases/10,000 person-years, using population estimates from the Alabama Center for Health Statistics. RESULTS: 1033 Alabama patients at CoA who were residents of Alabama were identified who received TNFi for a total of 1564 person-years. One adolescent on TNFi developed severe extrapulmonary TB (incidence density = 6.4 per 10,000; 95% CI 0.9-45.4 per 10,000). Sixty-three cases occurred in persons not on TNFi (incidence density = 0.064 per 10,000; 95% CI 0.050-0.082 per 10,000). CONCLUSIONS: One case of TB disease among TNFi exposed children was identified for 1564 person-years in Alabama residents. Although rare, this is higher than expected relative to the general rate of TB in Alabama. Thus, continued diagnostic vigilance for TB in children taking TNFi is required. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 29121954 TI - Temporal variation in confirmed diagnosis of fever-related malarial cases among children under-5 years by community health workers and in health facilities between years 2013 and 2015 in Siaya County, Kenya. AB - BACKGROUND: Malaria case management continues to experience dynamic changes. Building community capacity is instrumental in both prevention and treatment of malaria. The World Health Organization (WHO) recommends utilization of well trained and supervised community health workers (CHWs) to reduce the burden of malaria deaths among children under-5 years of age in Africa. Longitudinally tracked information on utilization of CHWs by communities in terms of trends in diagnosis of malaria in children under-5 years of age is essential in influencing national and local malaria control policies and strategies. METHODS: A desktop review was carried out of a database consisting of confirmed uncomplicated malaria cases in 10 villages using CHWs and out-patient departments of 10 health facilities in children under-five for the period of 3 years between January 2013 and December 2015. Analyses of association between the diagnosed cases and satellite-based rainfall, village and time (months and years) were carried out using a Poisson regression model. RESULTS: Analysis of malaria diagnoses made by CHWs showed the following trends: (i) the incidence of reported documented malaria-positive fever cases increased with time (2013-2015) and the difference over the years was statistically significant (P < 0.001), (ii) specific village was significantly associated (P < 0.001) with reporting malaria-positive fever cases, (iii) the long-term monthly sequence starting from highest to lowest incidence of reported malaria-positive fever cases was July, May and June, March, August, April, September, November, and February, October and, finally, January, and the difference in reported malaria-positives between the months was statistically significant (P = 0.001) and (iv) none of the tested rainfall regimes (current, lagged or cumulative) was associated with reported malaria positive fever cases during the 3-year period (P > 0.1). Looking at the number of diagnoses made at the health facilities, (i) The number of reported malaria positive fever cases decreased with time (2013-2015) and the difference among the years was not statistically significant (P = 0.399), (ii) The long-term monthly sequence starting from highest to lowest number of reported malaria-positive fever cases was July, June, May, April, January, August, March, February, September, November, October and December, and the difference between the months was statistically significant (P < 0.001). CONCLUSIONS: CHWs have the potential to play a major role in diagnosing and treating malaria, thereby decreasing under five children mortality. Temporally, the risk of diagnosing malaria seems predictable and this may present opportunities for policy-targeted malaria preparedness and control. The findings are expected to support policy actions that may scale-up community health services in remote rural settings. PMID- 29121955 TI - CD146, a novel target of CD44-signaling, suppresses breast tumor cell invasion. AB - BACKGROUND: We have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-beta2, and further characterized the players underlying their separate signaling pathways. In the present study, we identified CD146 as a potential novel target, negatively regulated by CD44. While the exact function of CD146 in breast cancer (BC) is not completely understood, substantial evidence from our work and others support the hypothesis that CD146 is a suppressor of breast tumor progression. METHODS: Therefore, using molecular and pharmacological approaches both in vitro and in breast tissues of human samples, the present study validated CD146 as a novel target of CD44-signaling suppressed during BC progression. RESULTS: Our results revealed that CD44 activation could cause a substantial decrease of CD146 expression with an equally notable converse effect upon CD44-siRNA inhibition. More interestingly, activation of CD44 decreased cellular CD146 and increased soluble CD146 through CD44-dependent activation of MMP. CONCLUSION: Here, we provide a possible mechanism by which CD146 suppresses BC progression as a target of CD44-downstream signaling, regulating neovascularization and cancer cell motility. PMID- 29121956 TI - Regional differences in prognostic value of cardiac valve plane displacement in systemic light-chain amyloidosis. AB - BACKGROUND: To compare the prognostic value of cardiac valve plane displacement (CVPD) on various locations in cardiac light chain (AL) amyloidosis. METHODS: Consecutive patients with biopsy-proven cardiac involvement in AL amyloidosis who had undergone cardiovascular magnetic resonance (CMR) between 2005 and 2014 in our institution, were retrospectively identified and data analyzed. The primary combined endpoint was all-cause mortality or heart transplantation. Systolic CVPD were obtained from standard cine bSSFP in 2-, 3- and 4-chamber views at anterior aortic plane systolic excursion (AAPSE); anterior, anterolateral, inferolateral, inferior, inferoseptal mitral (MAPSE); and lateral tricuspid (TAPSE) annular segments. RESULTS: We identified 68 patients (58 +/- 10 years; 59% male). Median follow-up period was 1.2 years (IQR, 0.3-4.1). Significant differences in CVPD between patients who reached a primary endpoint (n = 44) and transplant-free survivors were found only for AAPSE (6.1 mm (IQR, 4.6-9.4) vs. 8.8 mm (IQR, 6.9 10.4); p = 0.02) and MAPSEanterolateral (7.3 mm (IQR, 5.4-11.7) vs. 10.5 mm (IQR, 8.1-13.4); p = 0.03). AAPSE (chi2 = 15.6; p = 0.0002) provided the best predictive value for transplant-free survival compared to all other valvular plane locations. A high-risk cutoff (AAPSE <= 7.6 mm) was calculated by ROC analysis to predict all-cause death or heart transplantation within 6 months from index examination (AUC = 0.80; CI: 0.68 to 0.89; p < 0.0001). AAPSE added incremental prognostic power to an imaging prediction model of late gadolinium enhancement and global longitudinal strain (GLS) (?chi2 = 5.8, p = 0.02) as well as to a clinical model including Karnofsky index and NT-proBNP (?chi2 = 6.2, p = 0.01). CONCLUSION: In patients with cardiac involvement in AL amyloidosis, systolic CVPD obtained from standard long axis cine views appear to indicate outcome better, when obtained in the anterior aortic plane (AAPSE) and provide incremental prognostic value to LGE and strain measurements. PMID- 29121957 TI - Pathways through which higher neighborhood crime is longitudinally associated with greater body mass index. AB - BACKGROUND: Although crime and perceived safety are associated with obesity and body mass index (BMI), the pathways are less clear. Two likely pathways by which crime and perceived safety may impact obesity are through distress and physical activity. METHODS: We examined data from 2013 to 2014 for 644 predominantly African-American adults (mean age 57 years; 77% female) living in low-income Pittsburgh, PA neighborhoods, including self-reported perceptions of safety and emotional distress, interviewer-measured height/weight, and physical activity measured via accelerometry. We used secondary data on neighborhood crime from 2011 to 2013. We built a structural equation model to examine the longitudinal direct and indirect pathways from crime to BMI through perceived safety, distress and physical activity. RESULTS: Long-term exposure to crime was positively associated with lack of perceived safety (beta = 0.11, p = 0.005) and lack of perceived safety was positively associated with BMI (beta = 0.08, p = 0.03). The beneficial association between physical activity and BMI (beta = -0.15, p < 0.001) was attenuated by a negative association between crime and physical activity (beta = -0.09, p = 0.01). Although crime was associated with distress we found no evidence of a path from crime to BMI via distress. CONCLUSIONS: Our findings suggest decrements in perceived safety and physical activity are important processes that might explain why neighborhood crime is associated with greater BMI. PMID- 29121958 TI - Institutional capacity to generate and use evidence in LMICs: current state and opportunities for HPSR. AB - BACKGROUND: Evidence-informed decision-making for health is far from the norm, particularly in many low- and middle-income countries (LMICs). Health policy and systems research (HPSR) has an important role in providing the context-sensitive and -relevant evidence that is needed. However, there remain significant challenges both on the supply side, in terms of capacity for generation of policy relevant knowledge such as HPSR, and on the demand side in terms of the demand for and use of evidence for policy decisions. This paper brings together elements from both sides to analyse institutional capacity for the generation of HPSR and the use of evidence (including HPSR) more broadly in LMICs. METHODS: The paper uses literature review methods and two survey instruments (directed at research institutions and Ministries of Health, respectively) to explore the types of institutional support required to enhance the generation and use of evidence. RESULTS: Findings from the survey of research institutions identified the absence of core funding, the lack of definitional clarity and academic incentive structures for HPSR as significant constraints. On the other hand, the survey of Ministries of Health identified a lack of locally relevant evidence, poor presentation of research findings and low institutional prioritisation of evidence use as significant constraints to evidence uptake. In contrast, improved communication between researchers and decision-makers and increased availability of relevant evidence were identified as facilitators of evidence uptake. CONCLUSION: The findings make a case for institutional arrangements in research that provide support for career development, collaboration and cross-learning for researchers, as well as the setting up of institutional arrangements and processes to incentivise the use of evidence among Ministries of Health and other decision-making institutions. The paper ends with a series of recommendations to build institutional capacity in HPSR through engaging multiple stakeholders in identifying and maintaining incentive structures, improving research (including HPSR) training, and developing stronger tools for synthesising non-traditional forms of local, policy-relevant evidence such as grey literature. Addressing challenges on both the supply and demand side can build institutional capacity in the research and policy worlds and support the enhanced uptake of high quality evidence in policy decisions. PMID- 29121959 TI - Why European and United States drug regulators are not speaking with one voice on anti-influenza drugs: regulatory review methodologies and the importance of 'deep' product reviews. AB - BACKGROUND: Relenza represents the first neuraminidase inhibitor (NI), a class of drugs that also includes the drug Tamiflu. Although heralded as breakthrough treatments in influenza, NI efficacy has remained highly controversial. A key unsettled question is why the United States Food and Drug Administration (FDA) has approved more cautious efficacy statements in labelling than European regulators for both drugs. METHODS: We conducted a qualitative analysis of United States and European Union regulatory appraisals for Relenza to investigate the reasons for divergent regulatory interpretations, pertaining to Relenza's capacity to alleviate symptoms and reduce frequency of complications of influenza. RESULTS: In Europe, Relenza was evaluated via the so-called national procedure with Sweden as the reference country. We show that FDA reviewers, unlike their European (i.e. Swedish) counterpart, (1) rejected the manufacturer's insistence on pooling efficacy data, (2) remained wary of subgroup analyses, and (3) insisted on stringent statistical analyses. These differences meant that the FDA was less likely to depart from prevailing regulatory and scientific standards in interpreting trial results. We argue that the differences are explained largely by divergent institutionalised review methodologies, i.e. the European regulator's reliance on manufacturer-compiled summaries compared to the FDA's examination of original data and documentation from trials. CONCLUSIONS: The FDA's more probing and meticulous evaluative methodology allowed its reviewers to develop 'deep' knowledge concerning the clinical and statistical facets of trials, and more informed opinions regarding suitable methods for analysing trial results. These findings challenge the current emphasis on evaluating regulatory performance mainly in terms of speed of review. We propose that persistent uncertainty and knowledge deficits regarding NIs could have been ameliorated had regulators engaged in the public debates over the drugs' efficacy and explained their contrasting methodologies and judgments. Regulators use major resources to evaluate drugs, but if regulators' assessments are not effectively disseminated and used, resources are used inefficiently. PMID- 29121960 TI - Non-invasive quantification of age-related changes in the vertebral endplate in rats using in vivo DCE-MRI. AB - BACKGROUND: Small animal models that can mimic degenerative disc disease (DDD) are commonly used to examine DDD progression. However, assessments such as histological studies and macroscopic measurements do not allow for longitudinal studies because they can only be completed after the animal is sacrificed. Dynamic contrast-enhanced MRI (DCE-MRI) may provide a reliable, non-invasive in vivo method for detecting the progression. METHODS: The present study investigated the progression of changes in lumbar discs and the effect of endplate conditions on diffusion into the lumbar discs of aging sand rats after intravenous administration of gadolinium-containing contrast medium through the tail vein. Contrast enhancement was measured in the lumbar intervertebral discs on each image. The results were compared with those from conventional histological characterizations. RESULTS: T2-weighted images revealed that with aging, the shape of L3-L4, L4-L5, L5-L6, and L6-S1 nucleus pulposus (NP) became irregular, while the mean areas, signal intensities, and T2 values of the NP were significantly decreased. Each of the observed disc changes demonstrated a progressive increase in phase during 2-min scout scans. Post-contrast MRI showed impaired endplate nutritional diffusion to the disc with aging, enhancement was significantly greater in young animals than in old animals. Endplate calcification or sclerosis was histologically confirmed; histologic score was correlated with the age. We found the histological score of the endplate negatively corresponded to the DCE-MRI results. CONCLUSIONS: DCE-MRI studies offer a non-invasive in vivo method for investigating the progress of diffusion into the discs and the functional conditions of the endplate. We conclude that quantitative DCE-MRI can identify the severity of disc degeneration and efficiently reflect the progression of vertebral endplate changes in the aging sand rat lumbar spine via the NP contrast enhancement patterns. PMID- 29121961 TI - A multicomponent intervention for the management of chronic pain in older adults: study protocol for a randomized controlled trial. AB - BACKGROUND: Studies have shown that physical interventions and psychological methods based on the cognitive behavioral approach are efficacious in alleviating pain and that combining both tends to yield more benefits than either intervention alone. In view of the aging population with chronic pain and the lack of evidence-based pain management programs locally, we developed a multicomponent intervention incorporating physical exercise and cognitive behavioral techniques and examined its long-term effects against treatment as usual (i.e., pain education) in older adults with chronic musculoskeletal pain in Hong Kong. METHODS/DESIGN: We are conducting a double-blind, cluster-randomized controlled trial. A sample of 160 participants aged >= 60 years will be recruited from social centers or outpatient clinics and will be randomized on the basis of center/clinic to either the multicomponent intervention or the pain education program. Both interventions consist of ten weekly sessions of 90 minutes each. The primary outcome is pain intensity, and the secondary outcomes include pain interference, pain persistence, pain self-efficacy, pain coping, pain catastrophizing cognitions, health-related quality of life, depressive symptoms, and hip and knee muscle strength. All outcome measures will be collected at baseline, postintervention, and at 3 and 6 months follow-up. Intention-to-treat analysis will be performed using mixed-effects regression to see whether the multicomponent intervention alleviates pain intensity and associated outcomes over and above the effects of pain education (i.e., a treatment * time intervention effect). DISCUSSION: Because the activities included in the multicomponent intervention were carefully selected for ready implementation by allied health professionals in general, the results of this study, if positive, will make available an efficacious, nonpharmacological pain management program that can be widely adopted in clinical and social service settings and will hence improve older people's access to pain management services. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IIR-16008387. Registered on 28 April 2016. PMID- 29121962 TI - Direct interaction with 14-3-3gamma promotes surface expression of Best1 channel in astrocyte. AB - BACKGROUND: Bestrophin-1 (Best1) is a calcium-activated anion channel (CAAC) that is expressed broadly in mammalian tissues including the brain. We have previously reported that Best1 is expressed in hippocampal astrocytes at the distal peri synaptic regions, called microdomains, right next to synaptic junctions, and that it disappears from the microdomains in Alzheimer's disease mouse model. Although Best1 appears to be dynamically regulated, the mechanism of its regulation and modulation is poorly understood. It has been reported that a regulatory protein, 14-3-3 affects the surface expression of numerous membrane proteins in mammalian cells. METHODS: The protein-protein interaction between Best1 and 14-3-3gamma was confirmed by yeast-two hybrid assay and BiFC method. The effect of 14-3-3gamma on Best1-mediated current was measured by whole-cell patch clamp technique. RESULTS: We identified 14-3-3gamma as novel binding partner of Best1 in astrocytes: among 7 isoforms of 14-3-3 protein, only 14-3-3gamma was found to bind specifically. We determined a binding domain on the C-terminus of Best1 which is critical for an interaction with 14-3-3gamma. We also revealed that interaction between Best1 and 14-3-3gamma was mediated by phosphorylation of S358 in the C-terminus of Best1. We confirmed that surface expression of Best1 and Best1-mediated whole-cell current were significantly decreased after a gene-silencingof 14-3-3gamma without a significant change in total Best1 expression in cultured astrocytes. Furthermore, we discovered that 14-3-3gamma-shRNA reduced Best1-mediated glutamate release from hippocampal astrocyte by recording a PAR1 receptor-induced NMDA receptor-mediated current from CA1 pyramidal neurons in hippocampal slices injected with adenovirus carrying 14-3-3gamma-shRNA. Finally, through a structural modeling, we found critical amino acid residues containing S358 of Best1 exhibiting binding affinities to 14-3-3gamma. CONCLUSIONS: 14-3-3gamma promotes surface expression of Best1 channel in astrocytes through direct interaction. PMID- 29121963 TI - Reassessment of asymptomatic carriers of Plasmodium spp. in an endemic area with a very low incidence of malaria in extra-Amazonian Brazil. AB - BACKGROUND: Regions with residual transmission are potential obstacles to the elimination of malaria. It is, therefore, essential to understand the factors associated with the maintenance of endemic malaria in these areas. The objective was to investigate whether the status of asymptomatic carriers of Plasmodium spp. DNA is maintained in the long term in an extra-Amazonian region of Brazil with low incidence, residual malaria transmission. METHODS: Asymptomatic carriers of Plasmodium DNA detected in a survey carried out between 2001 and 2004 were reassessed between 2010 and 2011 using questionnaires, PCR and thick and thin blood smear tests three times at 3-month intervals. RESULTS: Of the 48 carriers detected between 2001 and 2004, 37 were located. Of these, only two had positive PCR results and, as in the first survey, Plasmodium malariae DNA was detected. CONCLUSION: The findings suggest that untreated dwellers from this extra Amazonian region, who initially harbour malaria parasites, may become negative without ever developing apparent symptoms of the disease. Although the possibility of re-infection cannot be ruled out, the finding of two individuals harbouring P. malariae, both in the first and in the second survey, may be compatible with a long-term carrier state for this parasite. Since most clinical cases of malaria in the region are a consequence of infection by Plasmodium vivax, the epidemiological impact of such long-term carriage would be limited. PMID- 29121964 TI - Muscle force distribution of the lower limbs during walking in diabetic individuals with and without polyneuropathy. AB - BACKGROUND: Muscle force estimation could advance the comprehension of the neuromuscular strategies that diabetic patients adopt to preserve walking ability, which guarantees their independence as they deal with their neural and muscular impairments due to diabetes and neuropathy. In this study, the lower limb's muscle force distribution during gait was estimated and compared in diabetic patients with and without polyneuropathy. METHODS: Thirty individuals were evaluated in a cross-sectional study, equally divided among controls (CG) and diabetic patients with (DNG) and without (DG) polyneuropathy. The acquired ground reaction forces and kinematic data were used as input variables for a scaled musculoskeletal model in the OpenSim software. The maximum isometric force of the ankle extensors and flexors was reduced in the model of DNG by 30% and 20%, respectively. The muscle force was calculated using static optimization, and peak forces were compared among groups (flexors and extensors of hip, knee, and ankle; ankle evertors; and hip abductors) using MANOVAs, followed by univariate ANOVAs and Newman-Keuls post-hoc tests (p < 0.05). RESULTS: From the middle to late stance phase, DG showed a lower soleus muscle peak force compared to the CG (p=0.024) and the DNG showed lower forces in the gastrocnemius medialis compared to the DG (p=0.037). At the terminal swing phase, the semitendinosus and semimembranosus peak forces showed lower values in the DG compared to the CG and DNG. At the late stance, the DNG showed a higher peak force in the biceps short head, semimembranosus, and semitendinosus compared to the CG and DG. CONCLUSION: Peak forces of ankle (flexors, extensors, and evertors), knee (flexors and extensors), and hip abductors distinguished DNG from DG, and both of those from CG. Both diabetic groups showed alterations in the force production of the ankle extensors with reductions in the forces of soleus (DG) and gastrocnemius medialis (DNG) seen in both diabetic groups, but only DNG showed an increase in the hamstrings (knee flexor) at push-off. A therapeutic approach focused on preserving the functionality of the knee muscles is a promising strategy, even if the ankle dorsiflexors and plantarflexors are included in the resistance training. PMID- 29121965 TI - Chronic cerebral hypoperfusion induces post-stroke dementia following acute ischemic stroke in rats. AB - BACKGROUND: Post-stroke dementia (PSD) is one of the major consequences after stroke. Chronic cerebral hypoperfusion (CCH) can induce vascular cognitive impairment and potentiate amyloid pathology. We investigated how CCH contributes to the development of PSD after stroke in the context of neuroinflammation and amyloid pathology. METHODS: We designed a unique animal model for PSD. We performed middle cerebral artery occlusion (MCAO) surgery in rats mimicking acute territorial infarct, which was followed by bilateral common carotid artery occlusion (BCCAo) surgery mimicking CCH. We performed behavioral tests including neurologic function test and water maze task and histological investigations including neuroinflammation, neuronal cell death, amyloid pathology, and aquaporin 4 (AQP4) distribution. RESULTS: Spatial memory was synergistically impaired when BCCAo was superimposed on MCAO. Neuroinflammation with astroglial or microglial activation and amyloid pathology were enhanced in the ipsilateral cortex, thalamus, and hippocampus when BCCAo was superimposed on MCAO. Glymphatic pathway-related AQP4 distribution changed from perivascular to parenchymal pattern. CONCLUSIONS: Our experimental results suggest that CCH may contribute to the development of PSD by interfering with amyloid clearance through the glymphatic pathway and concomitant neuroinflammation. Therapeutic strategy to clear brain metabolic waste through the glymphatic pathway may be a promising approach to prevent PSD after stroke. PMID- 29121967 TI - IHMC's experience competing in the Cybathlon compared to the DARPA robotics challenge. AB - BACKGROUND: As a research scientist, my work tends to focus on scientific investigations. Our group occasionally makes discoveries or has a successful demonstration, and sometimes we can even repeatedly demonstrate something working on the hardware. This mode of operation works for research, but not for competitions. In the past few years, I have participated in two international robotics competitions, the DARPA Robotics Challenge (DRC) and the Cybathlon; the research and development process for these competitions is significantly different from our typical research work. This commentary discusses our experience preparing for the Cybathlon, and contrasts it with our experience with the DRC. MAIN BODY: The human in the loop for the Cybathlon was the biggest differentiator between the DRC and the Cybathlon. Having the human at the center of the competition not only changed the way we developed, but changed how we viewed the impact of our work. For the DRC, a physics based dynamic simulation was a powerful, and invaluable, tool for not only the algorithm developers, but the robot operator as well. For the Cybathlon, simulation was of little use because the all of closed-loop control was performed by the pilot. In the software development cycle for the Cybathlon, the push was to just come up with something that works and "lock it down" and do not change it, so that the pilot could train with a given set of motions that would not change and make up for any deficiencies with his own abilities. The Cybathlon was more of an athletic challenge for the human who was assisted by technology. The DRC was the opposite, it was a robotics challenge assisted by a human. This commentary focuses on describing the Florida Institute for Human and Machine Cognition's (IHMC) experience leading up to and at the Cybathlon, with some comparisons to the DRC experience. CONCLUSION: The Cybathlon was a very worthwhile experience me, my team, and of course our pilot. Knowing that our development could improve the quality of life and health for a group of people was very motivating and rewarding. Engineering competitions accelerate development, engage the public, and in the case of the Cybathlon, increase public awareness of issues for people with disabilities. The Cybathlon also revealed that the powered exoskeleton technology is still nascent in its ability to be a viable alternative to the wheelchair. But with continued developments toward the 2020 Cybathlon, we hope the capabilities of these devices can offer will be significantly improved. PMID- 29121966 TI - Radioprotective agents to prevent cellular damage due to ionizing radiation. AB - Medical imaging has become a central component of patient care to ensure early and accurate diagnosis. Unfortunately, many imaging modalities use ionizing radiation to generate images. Ionizing radiation even in low doses can cause direct DNA damage and generate reactive oxygen species and free radicals, leading to DNA, protein, and lipid membrane damage. This cell damage can lead to apoptosis, necrosis, teratogenesis, or carcinogenesis. As many as 2% of cancers (and an associated 15,000 deaths annually) can be linked to computed tomography exposure alone. Radioprotective agents have been investigated using various models including cells, animals, and recently humans. The data suggest that radioprotective agents working through a variety of mechanisms have the potential to decrease free radical damage produced by ionizing radiation. Radioprotective agents may be useful as an adjunct to medical imaging to reduced patient morbidity and mortality due to ionizing radiation exposure. Some radioprotective agents can be found in high quantities in antioxidant rich foods, suggesting that a specific diet recommendation could be beneficial in radioprotection. PMID- 29121968 TI - Association of IFITM3 rs12252 polymorphisms, BMI, diabetes, and hypercholesterolemia with mild flu in an Iranian population. AB - BACKGROUND: IFITM3 has been suggested to be associated with infection in some ethnic groups. Diabetes and hypercholesterolemia are also important clinical conditions that can predispose individuals to infection. The aim of this study was to investigate the association of rs12252 C polymorphism, BMI, diabetes, and hypercholesterolemia with mild flu in an Iranian population. METHODS: We conducted a case-control study, including 79 mild flu and 125 flu-negative individuals attending primary care centers of three provinces of Iran (i.e, Markazi, Semnan, and Zanjan). Pharyngeal swab specimens were collected from all participants, and were subjected to RNA and DNA extractions for Real-time PCR and PCR tests. All PCR products were then sequenced to find T/C polymorphisms in the rs12252 region. Data on demographic, anthropometric, and clinical variables were collected from participants' medical records available in the primary care centers. The data was analyzed using DNASIS (v. 2.5) and Stata (v.11) software. RESULTS: All participants were of Fars ethnic background. The allele frequency for rs12252-C was found to be 9.49% among cases and 2.40% among controls. Carriers of the rs12252 C allele (CT + CC genotypes) showed 5.92 folds increase in the risk of mild flu comparing to the T allele homozygotes (P value: 0.007). We also found a significant positive association between rs12252 C allele heterozygote and mild flu (OR: 7.62, P value: 0.008), but not in C allele homozygote group (OR: 2.71, P value: 0.406). Similarly, we did not find a significant association between mild flu and BMI (OR: 1.06, P value: 0.087), diabetes (OR: 0.61, P value: 0.392), and hypercholesterolemia (OR: 0.50, P value: 0.393) in multivariable logistic regression. CONCLUSIONS: This is the first study evaluating the association between rs12252 polymorphisms, diabetes, hypercholesterolemia, and BMI and susceptibility to mild flu in an Iranian population. Our results suggest a significant positive association between mild flu and rs12252 C allele heterozygous and carriage. Future replication of the strong association observed here between rs12252 C allele carriage and mild flu might candidate this polymorphism as a genetic marker for early screening of susceptibility to mild flu. Lack of significant association between C allele homozygous and mild flu, observed in this study, might be the result of small sample size in this group. TRIAL REGISTRATION: IR.PII.REC.1395.3. PMID- 29121969 TI - Microglial dynamics after axotomy-induced retinal ganglion cell death. AB - BACKGROUND: Microglial cells (MCs) are the sentries of the central nervous system. In health, they are known as surveying MCs because they examine the tissue to maintain the homeostasis. In disease, they activate and, among other functions, become phagocytic to clean the cellular debris. In this work, we have studied the behavior of rat retinal MCs in two models of unilateral complete intraorbital optic nerve axotomy which elicit a different time course of retinal ganglion cell (RGC) loss. METHODS: Albino Sprague-Dawley rats were divided into these groups: (a) intact (no surgery), (b) fluorogold (FG) tracing from the superior colliculi, and (c) FG tracing + crush or transection of the left optic nerve. The retinas were dissected from 2 days to 2 months after the lesions (n = 4-12 group/lesion and time point) and then were subjected to Brn3a and Iba1 double immunodetection. In each intact retina, the total number of Brn3a+RGCs and Iba+MCs was quantified. In each traced retina (b and c groups), FG-traced RGCs and phagocytic microglial cells (PMCs, FG+Iba+) were also quantified. Topographical distribution was assessed by neighbor maps. RESULTS: In intact retinas, surveying MCs are homogenously distributed in the ganglion cell layer and the inner plexiform layer. Independently of the axotomy model, RGC death occurs in two phases, one quick and one protracted, and there is a lineal and topographical correlation between the appearance of PMCs and the loss of traced RGCs. Furthermore, the clearance of FG+RGCs by PMCs occurs 3 days after the actual loss of Brn3a expression that marks RGC death. In addition, almost 50% of MCs from the inner plexiform layer migrate to the ganglion cell layer during the quick phase of RGC loss, returning to the inner plexiform layer during the slow degeneration phase. Finally, in contrast to what happens in mice, in rats, there is no microglial phagocytosis in the contralateral uninjured retina. CONCLUSIONS: Axotomy-induced RGC death occurs earlier than RGC clearance and there is an inverse correlation between RGC loss and PMC appearance, both numerically and topographically, suggesting that phagocytosis occurs as a direct response to RGC death rather than to axonal damage. PMID- 29121970 TI - Endothelial alpha6beta4 integrin protects during experimental autoimmune encephalomyelitis-induced neuroinflammation by maintaining vascular integrity and tight junction protein expression. AB - BACKGROUND: Extracellular matrix (ECM) proteins play critical functions regulating vascular formation and function. Laminin is a major component of the vascular basal lamina, and transgenic mice deficient in astrocyte or pericyte laminin show defective blood-brain barrier (BBB) integrity, indicating an important instructive role for laminin in cerebral blood vessels. As previous work shows that in the normal brain, vascular expression of the laminin receptor alpha6beta4 integrin is predominantly restricted to arterioles, but induced on all vessels during neuroinflammation, it is important to define the role of this integrin in the maintenance of BBB integrity. METHODS: alpha6beta4 integrin expression was analyzed using dual immunofluorescence (dual-IF) of brain sections taken from the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To investigate the role of endothelial alpha6beta4 integrin, transgenic mice lacking beta4 integrin in endothelial cells (beta4-EC KO) and wild-type (WT) littermates were subject to EAE, and clinical score and various neuropathological parameters were examined by immunofluorescence. In addition, beta4 integrin null brain endothelial cells (BECs) were examined in culture for expression of tight junction proteins using immunocytochemistry and flow cytometry. RESULTS: Cerebrovascular expression of beta4 integrin was markedly upregulated during EAE progression, such that by the acute stage of EAE (day 21), the vast majority of blood vessels expressed beta4 integrin. In the EAE model, while the beta4-EC-KO mice showed the same time of disease onset as the WT littermates, they developed significantly worse clinical disease over time, resulting in increased clinical score at the peak of disease and maintained elevated thereafter. Consistent with this, the beta4-EC-KO mice showed enhanced levels of leukocyte infiltration and BBB breakdown and also displayed increased loss of the endothelial tight junction proteins claudin-5 and ZO-1. Under pro inflammatory conditions, primary cultures of beta4KO BECs also showed increased loss of claudin-5 and ZO-1 expression. CONCLUSIONS: Taken together, our data suggest that alpha6beta4 integrin upregulation is an inducible protective mechanism that stabilizes the BBB during neuroinflammatory conditions. PMID- 29121971 TI - CMR-based blood oximetry via multi-parametric estimation using multiple T2 measurements. AB - BACKGROUND: Measurement of blood oxygen saturation (O2 saturation) is of great importance for evaluation of patients with many cardiovascular diseases, but currently there are no established non-invasive methods to measure blood O2 saturation in the heart. While T2-based CMR oximetry methods have been previously described, these approaches rely on technique-specific calibration factors that may not generalize across patient populations and are impractical to obtain in individual patients. We present a solution that utilizes multiple T2 measurements made using different inter-echo pulse spacings. These data are jointly processed to estimate all unknown parameters, including O2 saturation, in the Luz-Meiboom (L-M) model. We evaluated the accuracy of the proposed method against invasive catheterization in a porcine hypoxemia model. METHODS: Sufficient data diversity to estimate the various unknown parameters of the L-M model, including O2 saturation, was achieved by acquiring four T2 maps, each at a different tau 180 (12, 15, 20, and 25 ms). Venous and arterial blood T2 values from these maps, together with hematocrit and arterial O2 saturation, were jointly processed to derive estimates for venous O2 saturation and other nuisance parameters in the L M model. The technique was validated by a progressive graded hypoxemia experiment in seven pigs. CMR estimates of O2 saturation in the right ventricle were compared against a reference O2 saturation obtained by invasive catheterization from the right atrium in each pig, at each hypoxemia stage. O2 saturation derived from the proposed technique was also compared against the previously described method of applying a global calibration factor (K) to the simplified L-M model. RESULTS: Venous O2 saturation results obtained using the proposed CMR oximetry method exhibited better agreement (y = 0.84* + 12.29, R2 = 0.89) with invasive blood gas analysis when compared to O2 saturation estimated by a global calibration method (y = 0.69* + 27.52, R2 = 0.73). CONCLUSIONS: We have demonstrated a novel, non-invasive method to estimate O2 saturation using quantitative T2 mapping. This technique may provide a valuable addition to the diagnostic utility of CMR in patients with congenital heart disease, heart failure, and pulmonary hypertension. PMID- 29121972 TI - Long noncoding RNA NORAD, a novel competing endogenous RNA, enhances the hypoxia induced epithelial-mesenchymal transition to promote metastasis in pancreatic cancer. AB - BACKGROUND: Pancreatic cancer, one of the top two most fatal cancers, is characterized by a desmoplastic reaction that creates a dense microenvironment, promoting hypoxia and inducing the epithelial-to-mesenchymal transition (EMT) to facilitate invasion and metastasis. Recent evidence indicates that the long noncoding RNA NORAD may be a potential oncogenic gene and that this lncRNA is significantly upregulated during hypoxia. However, the overall biological role and clinical significance of NORAD remains largely unknown. METHODS: NORAD expression was measured in 33 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of NORAD on pancreatic cancer cells were studied by overexpression and knockdown in vitro. Insights into the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatics analyses and luciferase assays. In vivo, metastatic potential was identified using an orthotopic model of PDAC and quantified using bioluminescent signals. Alterations in RhoA expression and EMT levels were identified and verified by immunohistochemistry and Western blotting. RESULTS: NORAD is highly expressed in pancreatic cancer tissues and upregulated in hypoxic conditions. NORAD upregulation is correlated with shorter overall survival in pancreatic cancer patients. Furthermore, NORAD overexpression promoted the migration and invasion of pancreatic carcinoma cells, while NORAD depletion inhibited EMT and metastasis in vitro and in vivo. In particular, NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p, thereby promoting EMT. CONCLUSIONS: Elevated expression of NORAD in pancreatic cancer tissues is linked to poor prognosis and may confer a malignant phenotype upon tumor cells. NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p. This finding may contribute to a better understanding of the role played by lncRNAs in hypoxia-induced EMT and provide a potential novel diagnostic and therapeutic target for pancreatic cancer. PMID- 29121973 TI - In vitro investigations on extracellular proteins secreted by Aphanomyces invadans, the causative agent of epizootic ulcerative syndrome. AB - BACKGROUND: Proteases produced by many microorganisms, including oomycetes, are crucial for their growth and development. They may also play a critical role in disease manifestation. Epizootic ulcerative syndrome is one of the most destructive fish diseases known. It is caused by the oomycete Aphanomyces invadans and leads to mass mortalities of cultured and wild fish in many countries. The areas of concern are Australia, China, Japan, South and Southeast Asian countries and the USA. Extracellular proteases produced by this oomycete are believed to trigger EUS pathogenesis in fish. To address this activity, we collected the extracellular products (ECP) of A. invadans and identified the secreted proteins using SDS-PAGE and mass spectrometery. A. invadans was cultivated in liquid Glucose-Peptone-Yeats media. The culture media was ultra filtered through 10 kDa filters and analysed using SDS-PAGE. Three prominent protein bands from the SDS gel were excised and identified by mass spectrometery. Furthermore, we assessed their proteolytic effect on casein and immunoglobulin M (IgM) of rainbow trout (Oncorhynchus mykiss) and giant gourami (Osphronemus goramy). Antiprotease activity of the fish serum was also investigated. RESULTS: BLASTp analysis revealed that the prominent secreted proteins were proteases, mainly of the serine and cysteine types. Proteins containing fascin-like domain and bromodomain were also identified. We could demonstrate that the secreted proteases showed proteolytic activity against the casein and the IgM of both fish species. The anti-protease activity experiment showed that the percent inhibition of the common carp serum was 94.2% while that of rainbow trout and giant gourami serum was 7.7 and 12.9%, respectively. CONCLUSIONS: The identified proteases, especially serine proteases, could be the potential virulence factors in A. invadans and, hence, are candidates for further functional and host-pathogen interaction studies. The role of identified structural proteins in A. invadans also needs to be investigated further. PMID- 29121974 TI - A randomised, double-blind, placebo-controlled trial of minocycline and/or omega 3 fatty acids added to treatment as usual for at-risk mental states (NAYAB): study protocol. AB - BACKGROUND: The at-risk mental state (ARMS) describes individuals at high risk of developing schizophrenia or psychosis. The use of antipsychotics in this population is not supported, because most individuals with ARMS are unlikely to develop psychosis. Anti-inflammatory treatments and polyunsaturated fatty acids (PUFAs) may have some beneficial effects in the treatment of ARMS. There have been no controlled clinical trials in which researchers have investigated the use of minocycline for ARMS and no trials involving PUFAs in combination with other proposed treatments. There is a need to find effective, tolerable and inexpensive interventions for individuals with ARMS that are available in high-, low- and middle-income countries. METHODS/DESIGN: A 6-month intervention study of minocycline and/or omega-3 fatty acids added to treatment as usual (TAU) in patients with ARMS will be conducted in Pakistan using a randomised, placebo controlled, double-blind factorial design. A total of 320 consenting patients with capacity will be recruited from the community, general practitioner clinics and psychiatric units. Allowing for a 25% dropout rate, we will recruit 59 completing participants into each study arm, and in total 236 will complete the study. We will determine whether the addition of minocycline and/or omega-3 fatty acids to TAU attenuates the rate of transition from ARMS to first-episode psychosis and improves symptoms and/or level of functioning in ARMS. We will also investigate whether any candidate risk factors, such as negative symptoms, influence treatment response in the ARMS group. The primary efficacy endpoint is conversion to psychotic disorder at 12 months after study entry. Analysis will be done according to the intention to treat principle using analysis of variance, chi-square tests and adjusted ORs to assess between-group differences. Cox regression analysis will be used to evaluate potential between-group differences in time to onset of psychosis. DISCUSSION: The outcomes of this trial will provide evidence of the potential benefits of minocycline and PUFAs in the treatment of ARMS. Both minocycline and PUFAs are inexpensive, are readily available in low-/middle-income countries such as Pakistan, and if proven, may be safe and effective for treating individuals with ARMS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02569307 . Registered on 3 October 2015. PMID- 29121975 TI - The Pocket-4-Life project, bioavailability and beneficial properties of the bioactive compounds of espresso coffee and cocoa-based confectionery containing coffee: study protocol for a randomized cross-over trial. AB - BACKGROUND: Coffee is an important source of bioactive compounds, including caffeine, phenolic compounds (mainly chlorogenic acids), trigonelline, and diterpenes. Several studies have highlighted the preventive effects of coffee consumption on major cardiometabolic diseases, but the impact of coffee dosage on markers of cardiometabolic risk is not well understood. Moreover, the pool of coffee-derived circulating metabolites and the contribution of each metabolite to disease prevention still need to be evaluated in real-life settings. The aim of this study will be to define the bioavailability and beneficial properties of coffee bioactive compounds on the basis of different levels of consumption, by using an innovative experimental design. The contribution of cocoa-based products containing coffee to the pool of circulating metabolites and their putative bioactivity will also be investigated. METHODS: A three-arm, crossover, randomized trial will be conducted. Twenty-one volunteers will be randomly assigned to consume three treatments in a random order for 1 month: 1 cup of espresso coffee/day, 3 cups of espresso coffee/day, and 1 cup of espresso coffee plus 2 cocoa-based products containing coffee twice per day. The last day of each treatment, blood and urine samples will be collected at specific time points, up to 24 hours following the consumption of the first product. At the end of each treatment the same protocol will be repeated, switching the allocation group. Besides the bioavailability of the coffee/cocoa bioactive compounds, the effect of the coffee/cocoa consumption on several cardiometabolic risk factors (anthropometric measures, blood pressure, inflammatory markers, trimethylamine N oxide, nitric oxide, blood lipids, fasting indices of glucose/insulin metabolism, DNA damage, eicosanoids, and nutri-metabolomics) will be investigated. DISCUSSION: Results will provide information on the bioavailability of the main groups of phytochemicals in coffee and on their modulation by the level of consumption. Findings will also show the circulating metabolites and their bioactivity when coffee consumption is substituted with the intake of cocoa-based products containing coffee. Finally, the effect of different levels of 1-month coffee consumption on cardiometabolic risk factors will be elucidated, likely providing additional insights on the role of coffee in the protection against chronic diseases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03166540 . Registered on May 21, 2017. PMID- 29121977 TI - Intrahepatic biliary cystadenoma mimicking hydatid cyst of liver: a clinicopathologic study of six cases. AB - BACKGROUND: Intrahepatic biliary cystadenomas are rare hepatic neoplasms, which are usually cystic. These tumors are often misdiagnosed as simple liver cysts and hydatid cysts clinically and radiologically owing to nonspecific clinical and radiologic features. These tumors require complete resection, as recurrence and malignant transformation can occur following incomplete excision. It is essential that these tumors be diagnosed accurately so that they can be adequately excised. METHODS: Clinical and radiological features of six cases of biliary cystadenoma are described. RESULTS: All of these cases were resected with the clinical and/or radiological impression of simple liver cysts and/or hydatid cysts. Out of the six patients, five were female and one was male. Ages of the patients ranged from 28 to 60 years (mean 45 years). The patients presented with nonspecific symptoms. Internal septations were seen on preoperative imaging (when available). On gross examination, all tumors were cystic; their sizes varied from 5.5 to 14 cm, mean size was 9.0 cm. On histopathologic examination, cystic spaces were lined by cuboidal to columnar mucin-secreting epithelium with underlying ovarian-type stroma. In one case, ovarian-type stroma was not seen. Recurrence was seen in three cases at 1 to 5 years of follow up. CONCLUSIONS: Owing to their malignant potential and high recurrence rate following incomplete resection, an aggressive surgical approach is recommended. Prognosis is excellent after complete resection. PMID- 29121976 TI - Prevalence of tick-borne pathogens in questing Ixodes ricinus ticks in urban and suburban areas of Switzerland. AB - BACKGROUND: Throughout Europe, Ixodes ricinus transmits numerous pathogens. Its widespread distribution is not limited to rural but also includes urbanized areas. To date, comprehensive data on pathogen carrier rates of I. ricinus ticks in urban areas of Switzerland is lacking. RESULTS: Ixodes ricinus ticks sampled at 18 (sub-) urban collection sites throughout Switzerland showed carrier rates of 0% for tick-borne encephalitis virus, 18.0% for Borrelia burgdorferi (sensu lato), 2.5% for Borrelia miyamotoi, 13.5% for Rickettsia spp., 1.4% for Anaplasma phagocytophilum, 6.2% for "Candidatus Neoehrlichia mikurensis", and 0.8% for Babesia venatorum (Babesia sp., EU1). Site-specific prevalence at collection sites with n > 45 ticks (n = 9) significantly differed for B. burgdorferi (s.l.), Rickettsia spp., and "Ca. N. mikurensis", but were not related to the habitat type. Three hundred fifty eight out of 1078 I. ricinus ticks (33.2%) tested positive for at least one pathogen. Thereof, about 20% (71/358) were carrying two or three different potentially disease-causing agents. Using next generation sequencing, we could detect true pathogens, tick symbionts and organisms of environmental or human origin in ten selected samples. CONCLUSIONS: Our data document the presence of pathogens in the (sub-) urban I. ricinus tick population in Switzerland, with carrier rates as high as those in rural regions. Carriage of multiple pathogens was repeatedly observed, demonstrating the risk of acquiring multiple infections as a consequence of a tick bite. PMID- 29121978 TI - Coinfection of intestinal schistosomiasis and malaria and association with haemoglobin levels and nutritional status in school children in Mara region, Northwestern Tanzania: a cross-sectional exploratory study. AB - BACKGROUND: Schistosomiasis represents a major public health problem in Tanzania despite ongoing national control efforts. This study examined whether intestinal schistosomiasis is associated with malaria and assessed the contribution of intestinal schistosomiasis and malaria on anaemia and undernutrition in school children in Mara region, North-western Tanzania. METHODS: Stool samples were collected from each of 928 school children randomly selected from 5 schools and examined for intestinal schistosomiasis using the Kato Katz method. Finger prick blood samples were collected and examined for malaria parasites and haemoglobin concentrations using the Giemsa stain and Haemocue methods, respectively. Nutritional status was assessed by taking anthropometric measurements. RESULTS: The overall prevalence and infection intensity of S. mansoni was 85.6% (794/928) and 192 (100-278), respectively. The prevalence of malaria was 27.4% (254/928) with significant differences among villages (chi 2 = 96.11, p < 0.001). The prevalence of anaemia was 42.3% (392/928) with significant differences among villages (chi 2 = 39.61, p < 0.001). The prevalence of stunting, thinness and underweight was 21, 6.8 and 1.3%, respectively. Stunting varied significantly by sex (chi 2 = 267.8, p < 0.001), age group (chi 2 = 96.4, p < 0.001) and by village (chi 2 = 20.5, p < 0.001). Out of the 825 infected children, 217 (26.4%) had multiple parasite infections (two to three parasites). The prevalence of co infections occurred more frequently in boys than in girls (chi 2 = 21.65, p = 0.010). Mean haemoglobin concentrations for co-infected children was significantly lower than that of children not co-infected (115.2 vs 119.6; t = 0.01, p = 0.002). Co-infected children were more likely to be stunted than children who were not co-infected (chi 2 = 11.6, p = 0.003). On multivariate analysis, age group, village of residence and severe anaemia were significant predictors of stunting after adjusting for sex and infection status. CONCLUSIONS: Intestinal schistosomiasis and malaria are prevalent in Mara region. Coinfections of these parasites as well as chronic undernutrition were also common. We recommend Mara region to be included in national schistosomiasis control programmes. PMID- 29121980 TI - A complicated prosthetic valve endocarditis due to methicillin resistant Staphylococci treated with linezolid and ciprofloxacin: a case report. AB - BACKGROUND: Prosthetic valve endocarditis (PVE) due to methicillin resistant Staphylococcus aureus (MRSA) is a rare disease with significant mortality and morbidity. With the emerging resistance and adverse effect profile of vancomycin which is the standard treatment, there is a compelling necessity of an effective alternative for vancomycin. Linezolid is proved as such an agent for infections caused by MRSA in other sites. However to-date the evidence for successful use of linezolid for MRSA prosthetic valve endocarditis is limited only for few case studies. We here present the third case reported as effective treatment of PVE by MRSA with linezolid and probably the first case reported with successful treatment with linezolid in a patient with multiple complications who is a candidate for surgery in standard guidelines. CASE PRESENTATION: A 45 years old male from Kandy Sri Lanka, who had undergone prosthetic valve replacement 10 years back, presented with prosthetic mitral valve endocarditis caused by MRSA. He failed to respond to vancomycin and cotrimoxazole while sustaining cerebral haemorrhages, as well as life threatening ventricular arrhythmias. Treatment with intravenous linezolid and ciprofloxacin resulted in a complete response with disappearance of the vegetations and sterilization of blood cultures. CONCLUSIONS: Linezolid can be considered as a good option for treating PVE by MRSA infections who are not responding to vancomycin and may negate the need for a surgery in patients awaiting an early surgery. Further studies including randomized controlled trials are needed to assess the efficacy of linezolid in PVE due to MRSA. PMID- 29121979 TI - Platelet inhibition during ticagrelor monotherapy versus ticagrelor plus aspirin in patients with coronary artery disease (TEMPLATE study): study protocol for a randomised controlled trial. AB - BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin (ASP) and a P2Y12 blocker is currently standard care after percutaneous coronary intervention (PCI) with stent insertion, and aims to inhibit platelet function in order to prevent stent thrombosis. The P2Y12 blocker ticagrelor (TIC) has greater antiplatelet effect than the previously used members of this class, such as clopidogrel. In healthy volunteers, TIC is sufficient to cause strong platelet inhibition, with little additional effect from ASP. Omission of ASP may improve the safety of antiplatelet regimes by reducing bleeding. However, the effect of single antiplatelet treatment with TIC, compared to DAPT with TIC + ASP, has not been studied in detail in patients with coronary artery disease. METHODS: To compare TIC with TIC + ASP, we have initiated a single centre, open-label randomised controlled trial (TEMPLATE study) in adults receiving DAPT following PCI with a sample size of 110 patients. Patients are invited to join the study when, as part of standard care, they are due to switch from DAPT (ASP + any P2Y12 blocker) to single antiplatelet treatment with ASP alone after 6-12 months. Patients are randomised to receive either TIC or TIC + ASP for 4 weeks. All patients then revert to standard care with ASP alone. Blood samples and clinical data are collected at three study visits: at baseline during treatment with ASP + any P2Y12 blocker (visit 1); approximately 4 weeks after visit 1 during treatment with either TIC or TIC + ASP (visit 2); and approximately 8 weeks after visit 1 when treatment has reverted to ASP alone (visit 3). The primary outcome is the extent of platelet inhibition, measured by light transmission aggregation, flow cytometry, flow chamber and plasma biomarker tests. The primary analysis will compare the extent of platelet inhibition between the TIC and TIC + ASP groups at visit 2, adjusted for baseline platelet reactivity. Secondary analyses will compare the extent of platelet inhibition at visit 2 with that at visit 3. DISCUSSION: This is the first study to compare in detail the extent of platelet inhibition in patients who are receiving TIC compared with TIC + ASP. The study findings will complement larger-scale trials of the clinical efficacy and safety of TIC compared to TIC + ASP. TRIAL REGISTRATION: ISRCTN registry, identifier ISRCTN84335288 . Registered on 23 June 2014. PMID- 29121981 TI - Intrinsic DNA curvature in trypanosomes. AB - BACKGROUND: Trypanosoma cruzi and Trypanosoma brucei are protozoan parasites causing Chagas disease and African sleeping sickness, displaying unique features of cellular and molecular biology. Remarkably, no canonical signals for RNA polymerase II promoters, which drive protein coding genes transcription, have been identified so far. The secondary structure of DNA has long been recognized as a signal in biological processes and more recently, its involvement in transcription initiation in Leishmania was proposed. In order to study whether this feature is conserved in trypanosomatids, we undertook a genome wide search for intrinsic DNA curvature in T. cruzi and T. brucei. RESULTS: Using a region integrated intrinsic curvature (RIIC) scoring that we previously developed, a non random distribution of sequence-dependent curvature was observed. High RIIC scores were found to be significantly correlated with transcription start sites in T. cruzi, which have been mapped in divergent switch regions, whereas in T. brucei, the high RIIC scores correlated with sites that have been involved not only in RNA polymerase II initiation but also in termination. In addition, we observed regions with high RIIC score presenting in-phase tracts of Adenines, in the subtelomeric regions of the T. brucei chromosomes that harbor the variable surface glycoproteins genes. CONCLUSIONS: In both T. cruzi and T. brucei genomes, a link between DNA conformational signals and gene expression was found. High sequence dependent curvature is associated with transcriptional regulation regions. High intrinsic curvature also occurs at the T. brucei chromosome subtelomeric regions where the recombination processes involved in the evasion of the immune host system take place. These findings underscore the relevance of indirect DNA readout in these ancient eukaryotes. PMID- 29121982 TI - Application of ultrasound imaging biomarkers (HistoScanningTM) improves staging reliability of prostate biopsies. AB - OBJECTIVE: Imaging biomarkers like HistoScanningTM augment the informative value of ultrasound. Analogue image-guidance might improve the diagnostic accuracy of prostate biopsies and reduce misclassifications in preoperative staging and grading. RESULTS: Comparison of 77 image-guided versus 88 systematic prostate biopsies revealed that incorrect staging and Gleason misclassification occurs less frequently in image-guided than in systematic prostate biopsies. Systematic prostate biopsies (4-36 cores, median 12 cores) tended to detect predominantly unilateral tumors (39% sensitivity, 90.9% specificity, 17.5% negative and 50% positive predictive values). Bilateral tumors were diagnosed more frequently by image-guided prostate biopsies (87.9% sensitivity, 72.7% specificity, 50% negative and 96.8% positive predictive values). Regarding the detection of lesions with high Gleason scores >= 3 + 4, systematic prostate and image-guided biopsies yielded sensitivity and specificity rates of 66.7% vs 93.5%, 86% vs 64.5%, as well as negative and positive predictive values of 71.2% vs 87%, and 83.3% vs 79.6%, respectively. Potential reason for systematic prostate biopsies missing the correct laterality and the correct Gleason score was a mismatch between the biopsy template and the respective pathological cancer localization. This supports the need for improved detection techniques such as ultrasound imaging biomarkers and image-adapted biopsies. PMID- 29121983 TI - Early psychological screening of intensive care unit survivors: a prospective cohort study. AB - BACKGROUND: A majority of patients survive their episode of critical illness but up to 30% of patients suffer from psychological problems such as post-traumatic stress, anxiety and depression in the year after intensive care unit (ICU) stay. A method to identify discharged patients at risk for adverse psychological outcome would be helpful in the triage for ICU follow-up and could enable early intervention. The aim of this study was to evaluate whether early screening with validated questionnaires after ICU discharge can identify patients at risk for symptoms of post-traumatic stress, anxiety and depression 3 months after ICU stay. METHODS: We performed a prospective observational cohort study in the general ICU at the Karolinska University Hospital Solna, Stockholm, Sweden. All adult patients surviving >= 24 hours in the ICU in a 9-month period were eligible for inclusion. Patients with mental disability, serious auditory and visual disorder, aphasia or who were unable to understand Swedish were excluded. One hundred and thirty-two patients were included and visited by a follow-up nurse within 1 week after ICU discharge. The Hospital Anxiety and Depression Scale (HADS) and the Post-Traumatic Stress Symptoms Checklist-10 (PTSS-10) were administered. Three months after ICU discharge the patients received the same questionnaires by postal mail. We assessed the predictive values of the questionnaires using the area under the receiver operating characteristic curve (AUROC). For correlation calculations, we used Spearman's rank correlation coefficient. Negative and positive predictive values for each questionnaire were calculated. RESULTS: Eighty-two patients returned the follow-up questionnaires. We found correlation between early and late scores and reasonable predictive precision regarding 3-month outcomes, with an AUROC of 0.90 for PTSS-10 part B, 0.80 for the HADS anxiety subscale and 0.75 for the HADS depression subscale. CONCLUSIONS: Symptoms of post-traumatic stress, anxiety and depression assessed 1 week after ICU stay correlate with 3-month psychological outcome. The HADS and PTSS-10 may be useful aids to identify ICU survivors at high risk for clinically significant symptoms of post-traumatic stress, anxiety and depression 3 months post ICU stay. PMID- 29121984 TI - Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas. AB - BACKGROUND: To summarize the research activities of the "clinical research group heavy ion therapy", funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics (grading, hypoxia) on local tumor control after carbon (12C-) ion- and photon irradiations. METHODS: Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either 12C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days. The relative biological effectiveness (RBE) of 12C-ions was calculated from TCD50 values (dose at 50% tumor control probability) of photons and 12C-ions and correlated with intrinsic tumor parameters. For the HI-subline, larger tumors (diameter 18 mm) were irradiated with either carbon ions, oxygen ions or photons under ambient as well as hypoxic conditions to determine the variability of the RBE under different oxygenation levels. In addition, imaging, histology and molecular analyses were performed to decipher the underlying mechanisms. RESULTS: Experimental results revealed (i) a smaller variation of the TCD50-values between the three tumor sublines for 12C-ions (23.6 - 32.9 Gy) than for photons (38.2 - 75.7 Gy), (ii) steeper dose-response curves for 12C-ions, and (iii) an RBE that increased with tumor grading (1.62 +/- 0.11 (H) vs 2.08 +/- 0.13 (HI) vs 2.30 +/- 0.08 (AT1)). Large HI-tumors resulted in a marked increase of TCD50, which was increased further by 15% under hypoxic relative to oxic conditions. Noninvasive imaging, histology and molecular analyses identified hypoxia as an important radioresistance factor in photon therapy. CONCLUSIONS: The dose-response studies revealed a higher efficacy of 12C-ions relative to photon therapy in the investigated syngeneic tumor model. Hypoxia turned out to be at least one important radioresistance factor, which can be partly overridden by high-LET ion beams. This might be used to increase treatment effectiveness also in patients. The results of this project served as a starting point for several ongoing research projects. PMID- 29121985 TI - Incidence of dengue and chikungunya viruses in mosquitoes and human patients in border provinces of Vietnam. AB - BACKGROUND: Dengue virus remains a major threat in Vietnam, while chikungunya virus is expected to become one. Surveillance was conducted from 2012 to 2014 in Vietnam to assess the presence of dengue and chikungunya viruses in patients hospitalized with acute fever in five Vietnam provinces neighboring Lao PDR and Cambodia. Surveillance was extended to mosquitoes present in the vicinity of the patients' households. RESULTS: A total 558 human serum samples were collected along with 1104 adult mosquitoes and 12,041 larvae from 2250 households. Dengue virus was found in 17 (3%) human serum samples and in 9 (0.8%) adult mosquitoes. Chikungunya virus was detected in 2 adult mosquitoes (0.18%) while no chikungunya virus was detected in humans. Differing densities of mosquito populations were found, with the highest in the Long An Province border with Cambodia. Long An Province also displayed the lowest rate of infection, despite a very high Breteau Index, high human population density and presence of the main cross border road system. The highest incidence was found in Dac Nong Province, where the Breteau and Container indices were the second lowest. Dengue virus was detected in five Aedes albopictus, three Aedes aegypti and one Culex vishnui. Chikungunya virus was detected in two Ae. aegypti. All infected mosquitoes belonged to haplotypes described in other parts of the world and a number of novel haplotypes were found among uninfected mosquitoes. CONCLUSIONS: Dengue is considered to be regularly introduced to Vietnam from Cambodia, mostly through human movement. The data reported here provides a complementary picture. Due to intensive international trade, long-distance transportation of mosquito populations may play a role in the regular importation of dengue in Vietnam through Ho Chi Minh City. It is important to decipher the movement of mosquitoes in Vietnam, not only at the Lao PDR and Cambodia borders but also through international trade routes. Mosquito surveillance programs should address and follow mosquito populations instead of mosquito species. PMID- 29121986 TI - Farm-level risk factors for Fasciola hepatica infection in Danish dairy cattle as evaluated by two diagnostic methods. AB - BACKGROUND: The prevalence of bovine fasciolosis in Denmark is increasing but appropriate guidelines for control are currently lacking. In order to help develop a control strategy for liver fluke, a risk factor study of farm management factors was conducted and the utility of bulk tank milk (BTM ELISA) as a tool for diagnosis in Danish dairy cattle farms was assessed. METHODS: This case-control study aimed to identify farm-level risk factors for fasciolosis in Danish dairy farms (> 50 animals slaughtered in 2013) using two diagnostic methods: recordings of liver condemnation at slaughter, and farm-level Fasciola hepatica antibody levels in BTM. A case farm was defined as having a minimum of 3 incidents of liver condemnation due to liver fluke at slaughter (in any age group) during 2013, and control farms were located within 10 km of at least one case farm and had no history of liver condemnation due to liver fluke during 2011 2013. The selected farmers were interviewed over telephone about grazing and control practices, and BTM from these farms was collected and analysed by ELISA in 2014. The final complete dataset consisting of 131 case and 63 control farms was analysed using logistic regression. RESULTS: Heifers grazing on wet pastures, dry cows grazing on wet pastures, herd size, breed and concurrent beef cattle production were identified as risk factors associated with being classified as a case farm. With the categorised BTM ELISA result as the response variable, heifers grazing on wet pastures, dry cows grazing on wet pastures, and purchase of cows were identified as risk factors. Within the case and control groups, 74.8 and 12.7% of farms were positive for fasciolosis on BTM ELISA, respectively. The differences are likely to be related to the detection limit of the farm-level prevalence by the BTM ELISA test, time span between slaughter data and BTM, and the relatively low sensitivity of liver inspection at slaughter. CONCLUSIONS: Control of bovine fasciolosis in Denmark should target heifers and dry cows through grazing management and appropriate anthelmintic treatment, and BTM ELISA can be a useful diagnostic tool for fasciolosis in Danish dairy farms. PMID- 29121987 TI - Sequence analysis and characterization of pyruvate kinase from Clonorchis sinensis, a 53.1-kDa homopentamer, implicated immune protective efficacy against clonorchiasis. AB - BACKGROUND: Clonorchis sinensis, the causative agent of clonorchiasis, is classified as one of the most neglected tropical diseases and affects more than 15 million people globally. This hepatobiliary disease is highly associated with cholangiocarcinoma. As key molecules in the infectivity and subsistence of trematodes, glycolytic enzymes have been targets for drug and vaccine development. Clonorchis sinensis pyruvate kinase (CsPK), a crucial glycolytic enzyme, was characterized in this research. RESULTS: Differences were observed in the sequences and spatial structures of CsPK and PKs from humans, rats, mice and rabbits. CsPK possessed a characteristic active site signature (IKLIAKIENHEGV) and some unique sites but lacked the N-terminal domain. The predicted subunit molecular mass (Mr) of CsPK was 53.1 kDa. Recombinant CsPK (rCsPK) was a homopentamer with a Mr. of approximately 290 kDa by both native PAGE and gel filtration chromatography. Significant differences in the protein and mRNA levels of CsPK were observed among four life stages of C. sinensis (egg, adult worm, excysted metacercaria and metacercaria), suggesting that these developmental stages may be associated with diverse energy demands. CsPK was widely distributed in adult worms. Moreover, an intense Th1-biased immune response was persistently elicited in rats immunized with rCsPK. Also, rat anti-rCsPK sera suppressed C. sinensis adult subsistence both in vivo and in vitro. CONCLUSIONS: The sequences and spatial structures, molecular mass, and expression profile of CsPK have been characterized. rCsPK was indicated to be a homopentamer. Rat anti-rCsPK sera suppressed C. sinensis adult subsistence both in vivo and in vitro. CsPK is worthy of further study as a promising target for drug and vaccine development. PMID- 29121988 TI - Efficacy of Banha-sasim-tang on functional dyspepsia classified as excess pattern: study protocol for a randomized controlled trial. AB - BACKGROUND: Functional dyspepsia (FD) refers to the presence of one or more gastrointestinal symptoms including postprandial fullness, epigastric pain, burning, and early satiety without an organic explanation for chronic symptoms. FD causes considerable discomfort in patients and affects their everyday activity and productivity. Because most conventional treatments have limited efficacy, numerous patients seek alternatives such as herbal medicines. In this proposed study, we will conduct a clinical trial of an herbal drug, Banha-sasim-tang (BST). Furthermore, participants will be limited to those classified as having an excess pattern by using an instrument of pattern identification for FD to determine the efficacy of BST in a specific subset of patients. METHODS: This randomized, blinded, parallel-group clinical trial of BST versus placebo will consist of 4 weeks of oral administration of BST or placebo and a 4-week follow up period. The Korean version of the symptom-based questionnaire of the Nepean Dyspepsia Index (NDI-K) will be used as the primary outcome measure. Secondary outcome measures will include the quality-of-life (QoL) evaluation from the NDI K, the FD-related QoL (FD-QoL) scale, assessment of gastric myoelectrical dysrhythmias (GMA), and a Visual Analog Scale (VAS) analysis. DISCUSSION: The results of this trial are expected to provide relevant evidence demonstrating that BST can be used as an effective treatment in a specific subset of FD subjects. TRIAL REGISTRATION: KCT 0002013 . Registered at Clinical Research Information Service in the Republic of Korea on 18 August 2016. PMID- 29121990 TI - Identification of functional single nucleotide polymorphisms in the branchpoint site. AB - BACKGROUND: The human genome contains millions of single nucleotide polymorphisms (SNPs); many of these SNPs are intronic and have unknown functional significance. SNPs occurring within intron branchpoint sites, especially at the adenine (A), would presumably affect splicing; however, this has not been systematically studied. We employed a splicing prediction tool to identify human intron branchpoint sites and screened dbSNP for identifying SNPs located in the predicted sites to generate a genome-wide branchpoint site SNP database. RESULTS: We identified 600 SNPs located within branchpoint sites; among which, 216 showed a change in A. After scoring the SNPs by counting the As in the +/- 10 nucleotide region, only four SNPs were identified without additional As (rs13296170, rs12769205, rs75434223, and rs67785924). Using minigene constructs, we examined the effects of these SNPs on splicing. The three SNPs (rs13296170, rs12769205, and rs75434223) with nucleotide substitution at the A position resulted in abnormal splicing (exon skipping and/or intron inclusion). However, rs67785924, a 5-bp deletion that abolished the branchpoint A nucleotide, exhibited normal RNA splicing pattern, presumably using two of the downstream As as alternative branchpoints. The influence of additional As on splicing was further confirmed by studying rs2733532, which contains three additional As in the +/- 10 nucleotide region. CONCLUSIONS: We generated a high-confidence genome-wide branchpoint site SNP database, experimentally verified the importance of A in the branchpoint, and suggested that other nearby As can protect branchpoint A substitution from abnormal splicing. PMID- 29121989 TI - Determining the impact of a new physiotherapist-led primary care model for back pain: protocol for a pilot cluster randomized controlled trial. AB - BACKGROUND: Back pain is a leading contributor to disability, healthcare costs, and lost work. Family physicians are the most common first point of contact in the healthcare system for people with back pain, but physiotherapists (PTs) may be able to support the primary care team through evidence-based primary care. A cluster randomized trial is needed to determine the clinical, health system, and societal impact of a primary care model that integrates physiotherapists at the first visit for people with back pain. Prior to conducting a future fully powered cluster randomized trial, we need to demonstrate feasibility of the methods. Therefore, the purpose of this pilot study will be to: 1) Determine feasibility of patient recruitment, assessment procedures, and retention. 2) Determine the feasibility of training and implementation of a new PT-led primary care model for low back pain (LBP) 3) Explore the perspectives of patients and healthcare providers (HCPs) related to their experiences and attitudes towards the new service delivery model, barriers/facilitators to implementation, perceived satisfaction, perceived value, and impact on clinic processes and patient outcomes. METHODS: This pilot cluster randomized controlled trial will enroll four sites and randomize them to implement a new PT-led primary care model for back pain or a usual physician-led primary care model. All adults booking a primary care visit for back pain will be invited to participate. Feasibility outcomes will include: recruitment and retention rates, completeness of assessment data, PT training participation and confidence after training, and PT treatment fidelity. Secondary outcomes will include the clinical, health system, cost, and process outcomes planned for the future fully powered cluster trial. Results will be analyzed and reported descriptively and qualitatively. To explore perspectives of both HCPs and patients, we will conduct semi-structured qualitative interviews with patients and focus groups with HCPs from participants in the PT-led primary care sites. DISCUSSION: If this pilot demonstrates feasibility, a fully powered trial will provide evidence that has the potential to transform primary care for back pain. The full trial will inform future service design, whether these models should be more widely implemented, and training agendas. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03320148 . Submitted for registration on 17 September 2017. PMID- 29121991 TI - Medical students as health coaches: Implementation of a student-initiated Lifestyle Medicine curriculum. AB - BACKGROUND: By 2020, the World Health Organization predicts that two-thirds of all diseases worldwide will be the result of lifestyle choices. Physicians often do not counsel patients about healthy behaviors, and lack of training has been identified as one of the barriers. Between 2010 and 2014, Hebrew University developed and implemented a 58-h Lifestyle Medicine curriculum spanning five of the 6 years of medical school. Content includes nutrition, exercise, smoking cessation, and behavior change, as well as health coaching practice with friends/relatives (preclinical years) and patients (clinical years). This report describes this development and diffusion process, and it also presents findings related to the level of acceptance of this student-initiated Lifestyle Medicine (LM) curriculum. METHODS: Students completed an online semi-structured questionnaire after the first coaching session (coaching questionnaire) and the last coaching session (follow-up questionnaire). RESULTS: Nine hundred and twenty three students completed the coaching questionnaire (296 practices were with patients, 627 with friends /relatives); and 784 students completed the follow-up questionnaire (208 practices were with patients, 576 with friends /relatives). They reported overall that health coaching domains included smoking cessation (263 students), nutrition (79), and exercise (117); 464 students reported on combined topics. Students consistently described a high acceptance of the curriculum and their active role in coaching. Further, most students reported that they were eager to address their own health behaviors. CONCLUSIONS: We described the development and acceptance of a student-initiated comprehensive LM curriculum. Students perceived LM as an important component of physicians' professional role and were ready to explore it both as coaches and in their personal lives. Thus, medical school deans might consider developing similar initiatives in order to position medical schools as key players within a preventive strategy in healthcare policy. PMID- 29121992 TI - A mouse anti-myostatin antibody increases muscle mass and improves muscle strength and contractility in the mdx mouse model of Duchenne muscular dystrophy and its humanized equivalent, domagrozumab (PF-06252616), increases muscle volume in cynomolgus monkeys. AB - BACKGROUND: The treatments currently approved for Duchenne muscular dystrophy (DMD), a progressive skeletal muscle wasting disease, address the needs of only a small proportion of patients resulting in an urgent need for therapies that benefit all patients regardless of the underlying mutation. Myostatin is a member of the transforming growth factor-beta (TGF-beta) family of ligands and is a negative regulator of skeletal muscle mass. Loss of myostatin has been shown to increase muscle mass and improve muscle function in both normal and dystrophic mice. Therefore, myostatin blockade via a specific antibody could ameliorate the muscle weakness in DMD patients by increasing skeletal muscle mass and function, thereby reducing patients' functional decline. METHODS: A murine anti-myostatin antibody, mRK35, and its humanized analog, domagrozumab, were developed and their ability to inhibit several TGB-beta ligands was measured using a cell-based Smad activity reporter system. Normal and mdx mice were treated with mRK35 to examine the antibody's effect on body weight, lean mass, muscle weights, grip strength, ex vivo force production, and fiber size. The humanized analog (domagrozumab) was tested in non-human primates (NHPs) for changes in skeletal muscle mass and volume as well as target engagement via modulation of circulating myostatin. RESULTS: Both the murine and human antibodies are specific and potent inhibitors of myostatin and GDF11. mRK35 is able to increase body weight, lean mass, and muscle weights in normal mice. In mdx mice, mRK35 significantly increased body weight, muscle weights, grip strength, and ex vivo force production in the extensor digitorum longus (EDL) muscle. Further, tibialis anterior (TA) fiber size was significantly increased. NHPs treated with domagrozumab demonstrated a dose-dependent increase in lean mass and muscle volume and exhibited increased circulating levels of myostatin demonstrating target engagement. CONCLUSIONS: We demonstrated that the potent anti-myostatin antibody mRK35 and its clinical analog, domagrozumab, were able to induce muscle anabolic activity in both rodents, including the mdx mouse model of DMD, and non-human primates. A Phase 2, potentially registrational, clinical study with domagrozumab in DMD patients is currently underway. PMID- 29121993 TI - Transcriptomic analyses reveal the underlying pro-malignant functions of PTHR1 for osteosarcoma via activation of Wnt and angiogenesis pathways. AB - BACKGROUND: Increasing evidence has indicated parathyroid hormone type 1 receptor (PTHR1) plays important roles for the development and progression of osteosarcoma (OS). However, its function mechanisms remain unclear. The goal of this study was to further illuminate the roles of PTHR1 in OS using microarray data. METHODS: Microarray data were available from the Gene Expression Omnibus database under the accession number GSE46861, including six tumors from mice with PTHR1 knockdown (PTHR1.358) and six tumors from mice with control knockdown (Ren.1309). Differentially expressed genes (DEGs) between PTHR1.358 and Ren.1309 were identified using the LIMMA method, and then, protein-protein interaction (PPI) network was constructed using data from STRING database to screen crucial genes associated with PTHR1. KEGG pathway enrichment analysis was performed to investigate the underlying functions of DEGs using DAVID tool. RESULTS: A total of 1163 genes were identified as DEGs, including 617 downregulated (Lef1, lymphoid enhancer-binding factor 1) and 546 upregulated genes (Dkk1, Dickkopf related protein 1). KEGG enrichment analysis indicated upregulated DEGs were involved in Renin-angiotensin system (e.g., Agt, angiotensinogen) and Wnt signaling pathway (e.g., Dkk1), while downregulated DEGs participated in Basal cell carcinoma (e.g., Lef1). A PPI network (534 nodes and 2830 edges) was constructed, in which Agt gene was demonstrated to be the hub gene and its interactive genes (e.g., CCR3, CC chemokine receptor 3; and CCL9, chemokine CC chemokine ligand 9) were inflammation related. CONCLUSIONS: Our present study preliminarily reveals the pro-malignant effects of PTHR1 in OS cells may be mediated by activating Wnt, angiogenesis, and inflammation pathways via changing the expressions of the crucial enriched genes (Dkk1, Lef1, Agt-CCR3, and Agt CCL9). PMID- 29121994 TI - Dyslipidaemia in a Black African diabetic population: burden, pattern and predictors. AB - OBJECTIVES: This study sought to assess the burden, pattern and predictors of dyslipidaemia in 425 adult diabetic patients in Uganda. RESULTS: The median (IQR) age of the study participants was 53 (43.5-62) years with a female majority (283, 66.9%). Dyslipidaemia defined as presence of >= 1 lipid abnormalities was observed in 374 (88%) study participants. Collectively, the predictors of dyslipidaemia were: female gender, study site (private hospitals), type of diabetes (type 2 diabetes mellitus), statin therapy, increased body mass index and diastolic blood pressure. Proactive screening of dyslipidaemia and its optimal management using lipid lowering therapy should be emphasised among adult diabetic patients in Uganda. PMID- 29121995 TI - Round cell sarcoma of the colon with CIC rearrangement. AB - BACKGROUND: The CIC-rearranged sarcoma is a very rare highly aggressive malignant soft tissue group of tumors. It has recently been described as highly aggressive soft tissue tumors of children and young adults sharing similar morphological features with the Ewing sarcoma. The digestive localization is exceptional. CASE PRESENTATION: A 14-year-old male presented with a history of abdominal pain for 1 year, which increased in intensity over the last 2 months. Imaging findings showed a large heterogeneous mesenteric mass on the left flank of the abdomen. Exploratory laparotomy was performed and revealed a large cystic hypervascularized mass depending on the transverse colon and mesocolon. A wide excision of the lesion was performed with segmental colectomy. No postoperative complications were noted. The microscopic examination revealed a vaguely nodular growth of undifferentiated small round cells, arranged in solid sheets separated by thin fibrous septa with a scarce stroma. After an uncomplicated post-operative course, the patient was referred for chemotherapy. The patient died 2 months later with a peritoneal and pleural progression. CONCLUSIONS: The CIC-rearranged sarcoma is an aggressive tumor. There is no standard therapy for this rare disease. Their treatment includes surgery and chemotherapy. Resistance to chemotherapy is common. Further publications and studies will help to determine a standard therapy for this rare disease. PMID- 29121996 TI - Production and characterization of monoclonal antibodies against Encephalitozoon intestinalis and Encephalitozoon sp. spores and their developmental stages. AB - BACKGROUND: Microsporidia are intracellular obligate parasites traditionally associated with immunosuppressed patients; their detection in immunocompetent patients has increased, highlighting their possible importance as emerging pathogens. Detection of spores in stools, urine, body fluids and tissues is difficult and immunological techniques such as immunofluorescence have proved to be a useful and reliable tool in the diagnosis of human microsporidiosis. For this reason, we have produced and characterized monoclonal antibodies (MAbs) specific for Encephalitozoon intestinalis (the second most frequent microsporidian infecting humans), and other Encephalitozoon species, that can be used in different diagnostic techniques. RESULTS: Seven MAbs were selected in accordance with their optical density (OD). Four (4C4, 2C2, 2E5 and 2H2) were isotype IgG2a; two (3A5 and 3C9) isotype IgG3, and one Mab, 1D7, IgM isotype. The selected monoclonal antibody-secreting hybridomas were characterized by indirect immunofluorescence antibody test (IFAT), enzyme-linked immunosorbent assay (ELISA), Western blot, immunoelectron microscopy (Immunogold) and in vitro cultures. The study by IFAT showed different behavior depending on the MAbs studied. The MAbs 4C4, 2C2, 2E5 and 2H2 showed reactivity against epitopes in the wall of the spore (exospore and endospore) epitopes located in Encephalitozoon sp. spores, whereas the MAbs 3A5, 1D7 and 3C9 showed reactivity against internal epitopes (cytoplasmic contents or sporoplasm) of E. intestinalis spores. All MAbs recognized the developing parasites in the in vitro cultures of E. intestinalis. Additionally, 59 formalin-fixed stool samples that had been previously analyzed were screened, with 26 (44%) presenting microsporidian spores (18 samples with E. intestinalis and 8 samples with Enterocytozoon bieneusi). Detection of microsporidian spores by microscopy was performed using Calcofluor stain, Modified Trichrome, Quick-Hot Gram Chromotrope, as well as IFAT using MAbs 4C4, 2C2, 2E5 and 2H2. The 4 MAbs tested clearly recognized the larger spores corresponding to E. intestinalis, but showed no reactivity with Enterocytozoon bieneusi spores. The mass spectrometry and proteomic study revealed that the Mabs 4C4, 2C2, 2E5 and 2H2 recognized the Spore Wall Protein 1 (SWP1) as the antigenic target. CONCLUSIONS: The IFAT-positive MAbs exhibited excellent reactivity against spores and developmental stages, permitting their use in human and animal diagnosis. The epitopes recognized (exospore, endospore and cytoplasmic contents) by the different MAbs developed need further study, and may reveal potential targets for vaccine development, immunotherapy and chemotherapy. PMID- 29121997 TI - Family planning need of people living with HIV/AIDS in antiretroviral therapy clinics of Horro Guduru Wollega zone, Ethiopia. AB - OBJECTIVE: The purpose of this study was to identify factors associated with family planning needs among people living with human immunodeficiency virus (HIV) in Ethiopia. RESULTS: Three hundred twenty-one participants provided information on family planning methods and associated factors. Forty-six-point four percent of respondents reported using at least one form of family planning method; injectables (50.3%) and condoms (70.2%) were the most commonly used type of family planning method before and after HIV diagnosis, respectively. Age, the desire to have children, and the desire to have more than two children were significantly associated with the use of family planning methods. PMID- 29121999 TI - Improving adherence in mental health service users with severe mental illness in South Africa: a pilot randomized controlled trial of a treatment partner and text message intervention vs. treatment as usual. AB - OBJECTIVES: Medication non-adherence is a significant problem in treatment of severe mental disorders and is associated with poor clinical outcomes and increased demand on services. Task-shifting interventions incorporating mobile health may improve adherence in mental health service users in low- and middle income countries. Seventy-seven participants were recruited from a psychiatric hospital in Cape Town, with 42 randomized to receive the intervention and 35 to treatment as usual. Intervention pairs underwent treatment-partner contracting and psychoeducation, and received monthly text message reminders of clinic appointments. Primary outcomes were intervention acceptability and feasibility. Secondary outcome for efficacy were adherence to clinic visit; relapse; quality of life; symptomatic relief and medication adherence. RESULTS: Treatment partner and psychoeducation components were acceptable and feasible. The text message component was acceptable but not feasible in its current form. Efficacy outcomes favoured the intervention but did not reach statistical significance. A treatment partner intervention is acceptable and feasible in a low- and middle-income setting. Work is needed to ensure that additional components of such interventions are tailored to the local context. Appropriately powered efficacy studies are needed. Trial Registration PACTR PACTR201610001830190, Registered 21 October 2016 (Retrospectively registered). PMID- 29122000 TI - A foot-care program to facilitate self-care by the elderly: a non-randomized intervention study. AB - OBJECTIVE: We aimed to evaluate a foot-care awareness program designed to improve foot morphology, physical functioning, and fall prevention among the community dwelling elderly. Eleven independent community-dwelling elderly women (aged 61-83 years) were provided with foot-care advice and shown effective foot-care techniques to perform regularly for 6 months, and compared with a control group of 10 elderly women who did not receive any intervention. Measurements of foot form, functional capacity, subjective foot movement, and physical function were taken at baseline and 6-month follow-up. RESULTS: At follow-up, improvements were seen in the intervention group in foot morphology, subjective foot movement, foot pressure, and balance. In the intervention group, 90% of women had maintained or improved foot form and none of them had fallen during the post-intervention period, compared to the control group where 30% improved foot form (p = 0.0075) and four (40%) of them had fallen. Therefore, a foot-care program may have the potential to prevent falls and improve mobility among the elderly. Trial Registration UMIN-CTR No. UMIN000029632. Date of Registration: October 19, 2017. PMID- 29121998 TI - Circulating brain-enriched microRNAs as novel biomarkers for detection and differentiation of neurodegenerative diseases. AB - BACKGROUND: Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS: In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer's Disease Center, the Parkinson's Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic. Each group was randomly divided into training and confirmation sets of equal size. To evaluate the potential of circulating microRNAs enriched in specific brain regions affected by NDs and present in synapses as biomarkers of NDs, the levels of 37 brain-enriched and inflammation-associated microRNAs in the plasma of all participants were measured using individual qRT-PCR. A "microRNA pair" approach was used for data normalization. RESULTS: MicroRNA pairs and their combinations (classifiers) capable of differentiating NDs from control and from each other were defined using independently and jointly analyzed training and confirmation datasets. AD, PD, FTD, and ALS are differentiated from control with accuracy of 0.89, 0.90, 0.88, and 0.83 (AUCs, 0.96, 0.96, 0.94, and 0.93), respectively; NDs are differentiated from each other with accuracy ranging from 0.77 (AUC, 0.87) for AD vs. FTD to 0.93 (AUC, 0.98) for AD vs. ALS. The data further indicate sex dependence of some microRNA markers. The average increase in accuracy in distinguishing ND from control for all and male/female groups is 0.06; the largest increase is for ALS, from 0.83 for all participants to 0.92/0.98 for male/female participants. CONCLUSIONS: The work presented here suggests the possibility of developing microRNA-based diagnostics for detection and differentiation of NDs. Larger multicenter clinical studies are needed to further evaluate circulating brain-enriched microRNAs as biomarkers for NDs and to investigate their association with other ND biomarkers in clinical trial settings. PMID- 29122001 TI - Development of a peer-supported, self-management intervention for people following mental health crisis. AB - BACKGROUND: A documented gap in support exists for service users following discharge from acute mental health services, and structured interventions to reduce relapse are rarely provided. Peer-facilitated self-management interventions have potential to meet this need, but evidence for their effectiveness is limited. This paper describes the development of a peer-provided self-management intervention for mental health service users following discharge from crisis resolution teams (CRTs). METHODS: A five-stage iterative mixed methods approach of sequential data collection and intervention development was adopted, following the development and piloting stages of the MRC framework for developing and evaluating complex interventions. Evidence review (stage 1) included systematic reviews of both peer support and self-management literature. Interviews with CRT service users (n = 41) regarding needs and priorities for support following CRT discharge were conducted (stage 2). Focus group consultations (n = 12) were held with CRT service-users, staff and carers to assess the acceptability and feasibility of a proposed intervention, and to refine intervention organisation and content (stage 3). Qualitative evaluation of a refined, peer-provided, self-management intervention involved qualitative interviews with CRT service user participants (n = 9; n = 18) in feasibility testing (stage 4) and a pilot trial (stage 5), and a focus group at each stage with the peer worker providers (n = 4). RESULTS: Existing evidence suggests self management interventions can reduce relapse and improve recovery. Initial interviews and focus groups indicated support for the overall purpose and planned content of a recovery-focused self-management intervention for people leaving CRT care adapted from an existing resource: The personal recovery plan (developed by Repper and Perkins), and for peer support workers (PSWs) as providers. Participant feedback after feasibility testing was positive regarding facilitation of the intervention by PSWs; however, the structured self-management booklet was underutilised. Modifications to the self-management intervention manual and PSWs' training were made before piloting, which confirmed the acceptability and feasibility of the intervention for testing in a future, definitive trial. CONCLUSIONS: A manualised intervention and operating procedures, focusing on the needs and priorities of the target client group, have been developed through iterative stages of intervention development and feedback for testing in a trial context. Trial Registration ISRCTN01027104 date of registration: 11/10/2012. PMID- 29122002 TI - A European network for food-borne parasites (Euro-FBP): meeting report on 'Analytical methods for food-borne parasites in human and veterinary diagnostics and in food matrices'. AB - Food-borne parasites (FBPs) are a neglected topic in food safety, partly due to a lack of awareness of their importance for public health, especially as symptoms tend not to develop immediately after exposure. In addition, methodological difficulties with both diagnosis in infected patients and detection in food matrices result in under-detection and therefore the potential for underestimation of their burden on our societies. This, in consequence, leads to lower prioritization for basic research, e.g. for development new and more advanced detection methods for different food matrices and diagnostic samples, and thus a vicious circle of neglect and lack of progress is propagated. The COST Action FA1408, A European Network for Foodborne Parasites (Euro-FBP) aims to combat the impact of FBP on public health by facilitating the multidisciplinary cooperation and partnership between groups of researchers and between researchers and stakeholders. The COST Action TD1302, the European Network for cysticercosis/taeniosis, CYSTINET, has a specific focus on Taenia solium and T. saginata, two neglected FBPs, and aims to advance knowledge and understanding of these zoonotic disease complexes via collaborations in a multidisciplinary scientific network. This report summarizes the results of a meeting within the Euro-FBP consortium entitled 'Analytical methods for food-borne parasites in human and veterinary diagnostics and in food matrices' and of the joined Euro-FBP and CYSTINET meeting. PMID- 29122003 TI - Docosahexaenoic acid mechanisms of action on the bovine oocyte-cumulus complex. AB - BACKGROUND: Supplementation of bovine oocyte-cumulus complexes during in vitro maturation (IVM) with 1 MUM of docosahexaenoic acid (DHA), C22:6 n-3 polyunsaturated fatty acid, was reported to improve in vitro embryo development. The objective of this paper was to decipher the mechanisms of DHA action. RESULTS: Transcriptomic analysis of 1 MUM DHA-treated and control cumulus cells after 4 h IVM showed no significant difference in gene expression. MALDI-TOF mass spectrometry analysis of lipid profiles in DHA-treated and control oocytes and cumulus cells after IVM showed variations of only 3 out of 700 molecular species in oocytes and 7 out of 698 species in cumulus cells (p < 0.01). We showed expression of free fatty acid receptor FFAR4 in both oocytes and cumulus cells, this receptor is known to be activated by binding to DHA. FFAR4 protein was localized close to the cellular membrane by immunofluorescence. Functional studies demonstrated that supplementation with FFAR4 agonist TUG-891 (1 MUM or 5 MUM) during IVM led to an increased blastocyst rate (39.5% +/- 4.1%, 41.3% +/- 4.1%), similar to DHA 1 MUM treatment (39.2% +/- 4.1%) as compared to control (25.2% +/- 3.6%). FFAR4 activation via TUG-891 led to beneficial effect on oocyte developmental competence and might explain in part similar effects of DHA. CONCLUSIONS: In conclusion, we suggested that low dose of DHA (1 MUM) during IVM might activate regulatory mechanisms without evident effect on gene expression and lipid content in oocyte-cumulus complexes, likely through signaling pathways which need to be elucidated in further studies. PMID- 29122004 TI - Identification and characterization of serovar-independent immunogens in Actinobacillus pleuropneumoniae. AB - Despite numerous actions to prevent disease, Actinobacillus pleuropneumoniae (A. pleuropneumoniae) remains a major cause of porcine pleuropneumonia, resulting in economic losses to the swine industry worldwide. In this paper, we describe the utilization of a reverse vaccinology approach for the selection and in vitro testing of serovar-independent A. pleuropneumoniae immunogens. Potential immunogens were identified in the complete genomes of three A. pleuropneumoniae strains belonging to different serovars using the following parameters: predicted outer-membrane subcellular localization; <= 1 trans-membrane helices; presence of a signal peptide in the protein sequence; presence in all known A. pleuropneumoniae genomes; homology with other well characterized factors with relevant data regarding immunogenicity/protective potential. Using this approach, we selected the proteins ApfA and VacJ to be expressed and further characterized, both in silico and in vitro. Additionally, we analysed outer membrane vesicles (OMVs) of A. pleuropneumoniae MIDG2331 as potential immunogens, and compared deletions in degS and nlpI for increasing yields of OMVs compared to the parental strain. Our results indicated that ApfA and VacJ are highly conserved proteins, naturally expressed during infection by all A. pleuropneumoniae serovars tested. Furthermore, OMVs, ApfA and VacJ were shown to possess a high immunogenic potential in vitro. These findings favour the immunogen selection protocol used, and suggest that OMVs, along with ApfA and VacJ, could represent effective immunogens for the prevention of A. pleuropneumoniae infections in a serovar independent manner. This hypothesis is nonetheless predictive in nature, and in vivo testing in a relevant animal model will be necessary to verify its validity. PMID- 29122005 TI - Memories of paternal relations are associated with coping and defense mechanisms in breast cancer patients: an observational study. AB - BACKGROUND: Breast cancer diagnosis and treatment represent stressful events that demand emotional adjustment, thus recruiting coping strategies and defense mechanisms. As parental relations were shown to influence emotion regulation patterns and adaptive processes in adulthood, the present study investigated whether they are specifically associated to coping and defense mechanisms in patients with breast cancer. METHODS: One hundred and ten women hospitalized for breast cancer surgery were administered questionnaires assessing coping with cancer, defense mechanisms, and memories of parental bonding in childhood. RESULTS: High levels of paternal overprotection were associated with less mature defenses, withdrawal and fantasy and less adaptive coping mechanisms, such as hopelessness/helplessness. Low levels of paternal care were associated with a greater use of repression. No association was found between maternal care, overprotection, coping and defense mechanisms. Immature defenses correlated positively with less adaptive coping styles, while mature defenses were positively associated to a fighting spirit and to fatalism, and inversely related to less adaptive coping styles. CONCLUSIONS: These data suggest that paternal relations in childhood are associated with emotional, cognitive, and behavioral regulation in adjusting to cancer immediately after surgery. Early experiences of bonding may constitute a relevant index for adaptation to cancer, indicating which patients are at risk and should be considered for psychological interventions. PMID- 29122006 TI - Single nucleotide polymorphisms in the angiogenic and lymphangiogenic pathways are associated with lymphedema caused by Wuchereria bancrofti. AB - BACKGROUND: Lymphedema (LE) is a chronic clinical manifestation of filarial nematode infections characterized by lymphatic dysfunction and subsequent accumulation of protein-rich fluid in the interstitial space-lymphatic filariasis. A number of studies have identified single nucleotide polymorphisms (SNPs) associated with primary and secondary LE. To assess SNPs associated with LE caused by lymphatic filariasis, a cross-sectional study of unrelated Ghanaian volunteers was designed to genotype SNPs in 285 LE patients as cases and 682 infected patients without pathology as controls. One hundred thirty-one SNPs in 64 genes were genotyped. The genes were selected based on their roles in inflammatory processes, angiogenesis/lymphangiogenesis, and cell differentiation during tumorigenesis. RESULTS: Genetic associations with nominal significance were identified for five SNPs in three genes: vascular endothelial growth factor receptor-3 (VEGFR-3) rs75614493, two SNPs in matrix metalloprotease-2 (MMP-2) rs1030868 and rs2241145, and two SNPs in carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) rs8110904 and rs8111171. Pathway analysis revealed an interplay of genes in the angiogenic/lymphangiogenic pathways. Plasma levels of both MMP-2 and CEACAM-1 were significantly higher in LE cases compared to controls. Functional characterization of the associated SNPs identified genotype GG of CEACAM-1 as the variant influencing the expression of plasma concentration, a novel finding observed in this study. CONCLUSION: The SNP associations found in the MMP-2, CEACAM-1, and VEGFR-3 genes indicate that angiogenic/lymphangiogenic pathways are important in LE clinical development. PMID- 29122008 TI - Deposition of mutant ubiquitin in parkinsonism-dementia complex of Guam. PMID- 29122007 TI - Pancreatic cyst fluid harbors a unique microbiome. AB - BACKGROUND: It is clear that specific intestinal bacteria are involved in the development of different premalignant conditions along the gastrointestinal tract. An analysis of the microbial constituents in the context of pancreatic cystic lesions has, however, as yet not been performed. This consideration prompted us to explore whether endoscopically obtained pancreatic cyst fluids (PCF) contain bacterial DNA and to determine the genera of bacteria present in such material. METHODS: Total DNA was isolated from 69 PCF samples. Bacterial 16S rRNA gene-specific PCR was performed followed by Sanger sequencing and de novo deep sequencing for the V3-V4 variable region of 16S rRNA gene. RESULTS: We observed that 98.2% of the samples were positive in conventional PCR, and that 100% of selected PCF samples (n = 33) were positive for bacterial microbiota as determined by next generation sequencing (NGS). Comprehensive NGS data analysis of PCF showed the presence of 408 genera of bacteria, of which 17 bacterial genera were uniquely abundant to PCF, when compared to the Human Microbiome Project (HMP) database and 15 bacterial microbiota were uniquely abundant in HMP only. Bacteroides spp., Escherichia/Shigella spp., and Acidaminococcus spp. which were predominant in PCF, while also a substantial Staphylococcus spp. and Fusobacterium spp. component was detected. CONCLUSION: These results reveal and characterize an apparently specific bacterial ecosystem in pancreatic cyst fluid samples and may reflect the local microbiota in the pancreas. Some taxa with potential deleterious functions are present in the bacterial abundance profiles, suggesting that the unique microbiome in this specific niche may contribute to neoplastic processes in the pancreas. Further studies are needed to explore the intricate relationship between pathophysiological status in the host pancreas and its microbiota. PMID- 29122009 TI - Nasopharyngeal carcinoma incidence and mortality in China, 2013. AB - BACKGROUND: We estimated the incidence and mortality of nasopharyngeal carcinoma (NPC) in China in 2010 according to the data of 145 domestic population-based cancer registries in 2014, and no such reports since then. Hence, to further and better understand its epidemiology in China and to provide more precise scientific information for its control and prevention in China, we analyzed the NPC incidence and mortality of 255 domestic population-based cancer registries, and estimated the national rates in 2013 again. METHODS: NPC incidence and mortality data of 255 domestic cancer registries in 2013, accepted by the 2016 National Cancer Registry Annual Report, were collected and collated, and the indices of NPC such as the numbers of new cases and deaths, crude rates, age standardized rates, and truncated rates of incidence and mortality were calculated and analyzed. The incidence and mortality in China and its constituent areas were estimated according to the national population in 2013. RESULTS: An estimated 42,100 new cases and 21,320 deaths were attributed to NPC in China in 2013, accounting for 1.14% of all new cancer cases and 0.96% of all cancer related deaths that year in China. Crude incidence and mortality of NPC were 3.09/100,000 and 1.57/100,000, respectively. World age-standardized incidence and mortality were 2.17/100,000 and 1.08/100,000, respectively. The incidence and mortality of males were obviously higher than those of females and slightly higher in urban areas than in rural areas. Among seven Chinese administrative regions, NPC incidence and mortality were obviously higher in South China than in other regions and lowest in North China. Top 3 incidence and mortality provinces and registering areas all located in South China. The age-specific incidence and mortality rose quickly from age 25-29 and 35 to 39 years, respectively, peaked at different ages and varied by location. CONCLUSIONS: These results demonstrated that NPC incidence and mortality in China in 2013 were also at high levels worldwide, which suggested that its control and prevention should be enhanced. PMID- 29122010 TI - Expression of voltage-gated sodium channel Nav1.5 in non-metastatic colon cancer and its associations with estrogen receptor (ER)-beta expression and clinical outcomes. AB - BACKGROUND: Voltage-gated sodium channel 1.5 (Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-beta (ER-beta) expression in non-metastatic colon cancer patients receiving radical resection. METHODS: A total of 269 consecutive patients with pathologically confirmed stages I-III colon cancer who underwent radical resection were selected. Nav1.5 and ER-beta expression was detected by using immunohistochemistry (IHC) on tissue microarray constructed from paraffin embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coefficient, Chi square test or Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards models. RESULTS: We found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues (5.1 +/- 3.5 vs. 3.5 +/- 2.7, P < 0.001). The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio (OR) = 2.980; 95% confidential interval (CI) 1.163-7.632; P = 0.023] and high ER-beta expression (OR = 2.808; 95% CI 1.243-6.343; P = 0.013). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival (DFS) rate in colon cancer patients (77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-beta expression tumor (76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression [hazard ratio (HR) = 2.738; 95% CI 1.100-6.819; P = 0.030] and lymph node metastasis (HR = 2.633; 95% CI 1.632-4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients. CONCLUSIONS: High expression of Nav1.5 was associated with high expression of ER-beta and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer. PMID- 29122011 TI - Entity recognition in the biomedical domain using a hybrid approach. AB - BACKGROUND: This article describes a high-recall, high-precision approach for the extraction of biomedical entities from scientific articles. METHOD: The approach uses a two-stage pipeline, combining a dictionary-based entity recognizer with a machine-learning classifier. First, the OGER entity recognizer, which has a bias towards high recall, annotates the terms that appear in selected domain ontologies. Subsequently, the Distiller framework uses this information as a feature for a machine learning algorithm to select the relevant entities only. For this step, we compare two different supervised machine-learning algorithms: Conditional Random Fields and Neural Networks. RESULTS: In an in-domain evaluation using the CRAFT corpus, we test the performance of the combined systems when recognizing chemicals, cell types, cellular components, biological processes, molecular functions, organisms, proteins, and biological sequences. Our best system combines dictionary-based candidate generation with Neural Network-based filtering. It achieves an overall precision of 86% at a recall of 60% on the named entity recognition task, and a precision of 51% at a recall of 49% on the concept recognition task. CONCLUSION: These results are to our knowledge the best reported so far in this particular task. PMID- 29122014 TI - Attitude-Scenario-Emotion (ASE) sentiments are superficial. AB - Gervais & Fessler's (G&F's) Attitude-Scenario-Emotion (ASE) model reduces sentiments to superficial patterns of emotional responding that emerge when an underlying evaluative attitude interacts with appraisals of a range of specific scenarios. Thus construed, sentiments are epiphenomenal. We argue that G&F would do better to identify each sentiment (love, say) with the attitude that underlies and explains the patterns of emotional responding (in the case of love, this might be the attitude of valuing the good of a specific other). PMID- 29122012 TI - Drug target ontology to classify and integrate drug discovery data. AB - BACKGROUND: One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome. RESULTS: As part of that effort, we have developed a framework to integrate, navigate, and analyze drug discovery data based on formalized and standardized classifications and annotations of druggable protein targets, the Drug Target Ontology (DTO). DTO was constructed by extensive curation and consolidation of various resources. DTO classifies the four major drug target protein families, GPCRs, kinases, ion channels and nuclear receptors, based on phylogenecity, function, target development level, disease association, tissue expression, chemical ligand and substrate characteristics, and target-family specific characteristics. The formal ontology was built using a new software tool to auto-generate most axioms from a database while supporting manual knowledge acquisition. A modular, hierarchical implementation facilitate ontology development and maintenance and makes use of various external ontologies, thus integrating the DTO into the ecosystem of biomedical ontologies. As a formal OWL DL ontology, DTO contains asserted and inferred axioms. Modeling data from the Library of Integrated Network-based Cellular Signatures (LINCS) program illustrates the potential of DTO for contextual data integration and nuanced definition of important drug target characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. CONCLUSIONS: DTO was built based on the need for a formal semantic model for druggable targets including various related information such as protein, gene, protein domain, protein structure, binding site, small molecule drug, mechanism of action, protein tissue localization, disease association, and many other types of information. DTO will further facilitate the otherwise challenging integration and formal linking to biological assays, phenotypes, disease models, drug poly-pharmacology, binding kinetics and many other processes, functions and qualities that are at the core of drug discovery. The first version of DTO is publically available via the website http://drugtargetontology.org/ , Github ( http://github.com/DrugTargetOntology/DTO ), and the NCBO Bioportal ( http://bioportal.bioontology.org/ontologies/DTO ). The long-term goal of DTO is to provide such an integrative framework and to populate the ontology with this information as a community resource. PMID- 29122015 TI - Two kinds of respect for two kinds of contempt: Why contempt can be both a sentiment and an emotion. AB - Gervais & Fessler argue that because contempt is a sentiment, it cannot be an emotion. However, like many affective labels, it could be that "contempt" refers both to a sentiment and to a distinct emotion. This possibility is made salient by the fact that contempt can be defined by contrast with respect, but that there are different kinds of respect. PMID- 29122013 TI - Suppression of methylmercury-induced MIP-2 expression by N-acetyl-L-cysteine in murine RAW264.7 macrophage cell line. AB - BACKGROUND: The aim of this study is to examine the inflammatory-cytokine expressions in the presence of non-cytotoxic dose of methylmercury (MeHg) in murine macrophages, which is suspected to play an important role in brain damage caused by MeHg exposure. We focused on murine macrophage inflammatory protein-2 (MIP-2), keratinocyte chemoattractant (KC), and monocyte chemoattractant protein 5 (MCP-5). MIP-2 and KC are murine functional homologues of human IL-8 and MCP-5 for human MCP-1. Furthermore, we examined the suppressive effect of N-acetyl-L cysteine (NAC) on the MeHg-induced inflammatory cytokines. METHODS: In a murine RAW264.7 macrophage cell line, MeHg-induced cytokine expressions were measured using real-time PCR. The suppressive effect of NAC was examined by putting it into the culture medium together with MeHg (co-treatment). In addition, pre- and post-treatment experiments were conducted, in which the cells were treated with NAC before and after MeHg exposure, respectively. RESULTS: Exposure to a non cytotoxic dose of MeHg up-regulated the mRNA expression of MIP-2 and MCP-5. On the other hand, KC expression was not induced in the presence of MeHg. Effect of MeHg on MIP-2 expressions was suppressed by pre-, co-, and post-treatment with NAC. However, the suppressive effect of pre-treatment was less than the post treatment, which was as effective as co-treatment. CONCLUSION: In functional homologues of human IL-8, only MIP-2 expression, not KC, was activated in the presence of non-cytotoxic dose of MeHg in murine RAW264.7 macrophage cell line. The more evident inhibitory effect of NAC observed in post-treatment experiments suggests a possible involvement of intracellular activities such as antioxidant effects. PMID- 29122016 TI - Building a house of sentiment on sand: Epistemological issues with contempt. AB - Contempt shares its features with other emotions, indicating that there is no justification for creating "sentiment" as a new category of feelings. Scientific categories must be created or updated on the basis of evidence. Building a new category on the currently limited contempt literature would be akin to building a house on sand - likely to fall at any moment. PMID- 29122017 TI - We need more precise, quantitative models of sentiments. AB - The constructs of attitudes, emotions, and sentiments are often only verbally defined and therefore somewhat vague. The sentiment construct might be fruitfully modeled as a result of sampling processes, complementing the Attitude-Scenario Emotion model in explaining similarities and differences in sentiments across different cultures. PMID- 29122018 TI - Dominance as a competence domain, and the evolutionary origins of respect and contempt. AB - The hypothesis of a phylogenetic connection between protorespect in primate dominance hierarchies and respect in human prestige hierarchies lies in the principle that dominance is a domain of competence like others and, hence, that high-ranking primates have protoprestige. The idea that dominant primates manifest protocontempt to subordinates suggests that "looking down on" followers is intrinsic to leadership in humans, but that the expression of contempt varies critically in relation to the socioecological context. PMID- 29122019 TI - Contempt, like any other social affect, can be an emotion as well as a sentiment. AB - Gervais & Fessler assert that contempt is (a) not an emotion (or an attitude) but (b) a sentiment. Here, we challenge the validity and empirical basis of these two assertions, arguing that contempt, like many other emotions, can be both an emotion and a sentiment. PMID- 29122020 TI - From disgust to contempt-speech: The nature of contempt on the map of prejudicial emotions. AB - Analyzing the contempt as an intergroup emotion, we suggest that contempt and anger are not built upon each other, whereas disgust seems to be the most elementary and specific basic-emotional antecedent of contempt. Concurring with Gervais & Fessler, we suggest that many instances of "hate speech" are in fact instances of "contempt speech" - being based on disgust-driven contempt rather than hate. PMID- 29122021 TI - Warmth and competence as distinct dimensions of value in social emotions. AB - Gervais & Fessler's analysis collapses across two orthogonal dimensions of social value to explain contempt: relational value, predicted by cooperation, and agentic value, predicted by status. These dimensions interact to potentiate specific social emotions and behaviors in intergroup contexts. By neglecting the unique roles of these dimensions - and their associated attributes: warmth and competence - the sentiment framework cedes predictive precision. PMID- 29122022 TI - Prognostic value of lymph node ratio in metastatic papillary thyroid carcinoma. AB - OBJECTIVE: Cervical metastases in papillary thyroid carcinoma are associated with increased recurrence. However, their effect on survival remains controversial. This study evaluated literature on the prognostic value of lymph node ratio for loco-regional recurrence and survival in metastatic papillary thyroid carcinoma. METHODS: The PubMed database was systematically searched using the terms 'papillary thyroid carcinoma' and 'lymph node ratio'. Articles addressing the association between lymph node ratio and loco-regional recurrence or survival were identified. RESULTS: Nine retrospective studies were included, comprising 12 400 post-thyroidectomy and neck dissection papillary thyroid carcinoma patients (median age, 48.6 years; 76 per cent females). Lymph node ratio was associated with worse recurrence-free survival in 60 and 75 per cent of studies investigating the effect of central compartment metastases and both central and lateral compartment metastases on recurrence-free survival, respectively. One large population-based study showed an association between lymph node ratio and disease-specific mortality in N1 nodal disease, but failed to maintain the same association when N1b patients were excluded. CONCLUSION: Regional lymph node ratio is an independent predictor for loco-regional recurrence in pathologically staged N1 patients with papillary thyroid carcinoma. Patients with a high lymph node ratio should be closely followed up. PMID- 29122023 TI - Further implications in analyzing contempt in modern society. AB - The target article by Gervais & Fessler represents a comprehensive analysis of contempt but is not fully adequate in addressing how contempt produces hatred, how contempt is used manipulatively by aspiring leaders, and how contempt can be cured or at least mitigated. This commentary addresses these concerns. PMID- 29122024 TI - Prejudice is a general evaluation, not a specific emotion. AB - Prejudice, like contempt, is a general evaluation rather than a specific emotion. I explore the idea that emotions and attitudes are conceptually distinct by applying Gervais & Fessler's model to the intergroup context. I argue that prejudice is an affective representation of a social group's relational value (friend or foe) and dispute the idea that there are many distinct prejudices. PMID- 29122025 TI - Affect in social media: The role of audience and the presence of contempt in cyberbullying. AB - Gervais & Fessler's Attitude-Scenario-Emotion (ASE) model is a useful tool for the detection of affect in social media. In this commentary, an addition to the model is proposed - the audience - and its role in the manifestation of affect is discussed using a cyberbullying scenario. The presence of contempt in cyberbullying is also discussed. PMID- 29122026 TI - Are sentiments subject to selection pressures? The case of oxytocin. AB - We argue that natural selection operates on emotional and cognitive capacities supporting the subjective experience of sentiments, rather than on discrete sentiments themselves. We support this argument by examining the case of oxytocin in relation to the sentiment of love. We also explore future directions for health psychology research that includes "cold" aspects of contempt in conjunction with "hot" aspects. PMID- 29122027 TI - Warmth, competence, and closeness may provide more empirically grounded starts for a theory of sentiments. AB - Gervais & Fessler dissect the folk concept of "contempt" to argue for a functionally integrated model of attitudes and emotions in the context of social relationships. Existing studies of how evaluations of warmth, competence, and closeness shape people's reactions and behaviors towards others may help in operationalizing and testing the proposed model. PMID- 29122028 TI - Sentiments and the motivational psychology of parental care. AB - Beyond its implications for contempt, it remains to be determined whether the sentiment concept might be applied usefully to other domains of social affect. This commentary considers its applicability to the domain of parental caregiving. Characteristic features of sentiments are considered in conjunction with empirical research on the motivational psychology of parental care. PMID- 29122029 TI - Above and below the surface: Genetic and cultural factors in the development of values. AB - In the Attitude-Scenario-Emotion (ASE) model, social relationships are subpersonnally realized by sentiments: a network of emotions/attitudes representing relational values. We discuss how relational values differ from moral values and raise the issue of their ontogeny from genetic and cultural factors. Because relational values develop early in life, they cannot rely solely on cognition as suggested by the notion of attitude. PMID- 29122030 TI - Oxytocin shapes the priorities and neural representations of attitudes and values. AB - The phylogenetically ancient neuropeptide oxytocin has been linked to a plethora of social behaviors. Here, we argue that the action of oxytocin is not restricted to the downstream level of emotional responses, but substantially alters higher representations of attitudes and values by exerting a distant modulatory influence on cortical areas and their reciprocal interplay with subcortical regions and hormonal systems. PMID- 29122031 TI - Contempt - Where the modularity of the mind meets the modularity of the brain? AB - "Contempt" is proposed to be a unique aspect of human nature, yet a non-natural kind. Its psychological construct is framed as a sentiment emerging from a stratification of diverse basic emotions and dispositional attitudes. Accordingly, "contempt" might transcend traditional conceptual levels in social psychology, including experience and recognition of emotion, dyadic and group dynamics, context-conditioned attitudes, time-enduring personality structure, and morality. This strikes us as a modern psychological account of a high-level, social-affective cognitive facet that joins forces with recent developments in the social neuroscience by drawing psychological conclusions from brain biology. PMID- 29122032 TI - A sentimental education: The place of sentiments in personality and social psychology. AB - "Sentiment" is a potentially appealing concept for social and personality psychologists. It can render some complex affective phenomena theoretically tractable, help refine accounts of social perception, and illuminate some personality dispositions. The success of a future sentimental psychology depends on whether "sentiment" can be delimited as a distinct domain, and whether a credible classification of sentiments can be developed. PMID- 29122033 TI - How dare you not recognize the role of my contempt? Insight from experimental psychopathology. AB - Gervais & Fessler argue that contempt is an attitude state defined as a lack of respect that potentiates the activation and deactivation of two different clusters of emotions. However, clinical and experimental findings do not support this view. We provide evidence that contempt is not an emotion, nor an attitude, but a reactive defensive mechanism evolved to help individuals avoid shame. PMID- 29122034 TI - Constructing contempt. AB - Gervais & Fessler argue that contempt is a natural kind and that its experience cannot be explained by a constructionist account of emotion. We dispute these claims and offer a positive constructionist model of contempt that accounts for the existing evidence and unifies conflicting findings in the literature on contempt. PMID- 29122035 TI - Deep mechanisms of social affect - Plastic parental brain mechanisms for sensitivity versus contempt. AB - Insensitive parental thoughts and affect, similar to contempt, may be mapped onto a network of basic emotions moderated by attitudinal representations of social relational value. Brain mechanisms that reflect emotional valence of baby signals among parents vary according to individual differences and show plasticity over time. Furthermore, mental health problems and treatments for parents may affect these brain systems toward or away from contempt, respectively. PMID- 29122036 TI - Seeing the elephant: Parsimony, functionalism, and the emergent design of contempt and other sentiments. AB - The target article argues that contempt is a sentiment, and that sentiments are the deep structure of social affect. The 26 commentaries meet these claims with a range of exciting extensions and applications, as well as critiques. Most significantly, we reply that construction and emergence are necessary for, not incompatible with, evolved design, while parsimony requires explanatory adequacy and predictive accuracy, not mere simplicity. PMID- 29122037 TI - Grey matter volume and thickness abnormalities in young people with a history of childhood abuse. AB - BACKGROUND: Childhood abuse is associated with abnormalities in brain structure and function. Few studies have investigated abuse-related brain abnormalities in medication-naive, drug-free youth that also controlled for psychiatric comorbidities by inclusion of a psychiatric control group, which is crucial to disentangle the effects of abuse from those associated with the psychiatric conditions. METHODS: Cortical volume (CV), cortical thickness (CT) and surface area (SA) were measured in 22 age- and gender-matched medication-naive youth (aged 13-20) exposed to childhood abuse, 19 psychiatric controls matched for psychiatric diagnoses and 27 healthy controls. Both region-of-interest (ROI) and whole-brain analyses were conducted. RESULTS: For the ROI analysis, the childhood abuse group compared with healthy controls only, had significantly reduced CV in bilateral cerebellum and reduced CT in left insula and right lateral orbitofrontal cortex (OFC). At the whole-brain level, relative to healthy controls, the childhood abuse group showed significantly reduced CV in left lingual, pericalcarine, precuneus and superior parietal gyri, and reduced CT in left pre-/postcentral and paracentral regions, which furthermore correlated with greater abuse severity. They also had increased CV in left inferior and middle temporal gyri relative to healthy controls. Abnormalities in the precuneus, temporal and precentral regions were abuse-specific relative to psychiatric controls, albeit at a more lenient level. Groups did not differ in SA. CONCLUSIONS: Childhood abuse is associated with widespread structural abnormalities in OFC-insular, cerebellar, occipital, parietal and temporal regions, which likely underlie the abnormal affective, motivational and cognitive functions typically observed in this population. PMID- 29122039 TI - Is humility a sentiment? AB - Gervais & Fessler reintroduce the concept of a sentiment as a framework for conceptualizing contempt, a construct with both attitudinal and emotional components. We propose that humility might also fit this mold. We review recent findings regarding the antecedents, phenomenology, and functional consequences of humility, and discuss why conceptualizing it as a sentiment may advance our understanding of this construct. PMID- 29122038 TI - Underweight among rural Indian adults: burden, and predictors of incidence and recovery. AB - OBJECTIVE: To study the magnitude and predictors of underweight, incident underweight and recovery from underweight among rural Indian adults. DESIGN: Prospective cohort study. Each participant's BMI was measured in 2008 and 2012 and categorized as underweight (BMI<18.5 kg/m2), normal (BMI=18.5-22.9 kg/m2) or overweight/obese (BMI >=23.0 kg/m2). Incident underweight was defined as a transition from normal weight or overweight/obese in 2008 to underweight in 2012, and recovery from underweight as a transition from underweight in 2008 to normal weight in 2012. Bivariate and multivariable logistic regression analyses were employed. SETTING: The Birbhum Health and Demographic Surveillance System, West Bengal, India. SUBJECTS: Predominantly rural individuals (n 6732) aged >=18 years enrolled in 2008 were followed up in 2012. RESULTS: In 2008, the prevalence of underweight was 46.5 %. From 2008 to 2012, 25.8 % of underweight persons transitioned to normal BMI, 12.9 % of normal-weight persons became underweight and 0.1 % of overweight/obese persons became underweight. Multivariable models reveal that people aged 25-49 years, educated and wealthier people, and non smokers had lower odds of underweight in 2008 and lower odds of incident underweight. Odds of recovery from underweight were lower among people aged >=36 years and higher among educated (Grade 6 or higher) individuals. CONCLUSIONS: The current study highlights a high incidence of underweight and important risk factors and modifiable predictors of underweight in rural India, which may inform the design of local nutrition interventions. PMID- 29122040 TI - Video modeling for the development of personal hygiene skills in youth with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder mainly characterised by deficits in social communication as well as by narrow patterns of behaviour and interests (American Psychiatric Association, 2013), often accompanied by language, intellectual and sensory impairments. The severity of these impairments may lead to deficits in the development of daily living activities such as simple meal preparation and feeding, community skills (e.g. buying groceries), personal care (e.g. dressing) and personal hygiene skills (bathing, toileting, hand washing, teeth brushing) needed for independence. Among others, the lack of independence in personal hygiene skills increases the burden of the caregiver and makes children with ASD more dependent (Flynn & Healy, 2012). Therefore, it is important to develop tools for helping individuals with ASD in increasing their ability to perform these basic life activities which will lead to savings that can be invested in other critical areas of needs. PMID- 29122041 TI - Socioecological factors are linked to changes in prevalence of contempt over time. AB - Gervais & Fessler argue that the perceived legitimacy of contempt has declined over time in the United States, citing evidence of a decrease in the frequency of its use in the American English corpus. We argue that this decline in contempt, as reflected in cultural products, is linked to shifts in key socioecological features previously associated with other forms of cultural change. PMID- 29122042 TI - Peroxisome proliferator-activated receptor gamma (PPARgamma) agonist fails to overcome trans-10, cis-12 conjugated linoleic acid (CLA) inhibition of milk fat in dairy sheep. AB - The trans-10, cis-12 conjugated linoleic acid (CLA) causes milk fat depression by downregulating expression of genes and transcription factors involved in lipogenesis and it has been proposed that peroxisome proliferator-activated receptor gamma (PPARgamma) can be inhibited by trans-10, cis-12 CLA. The PPARgamma is a nuclear receptor activated by natural or synthetic ligands and promotes expression of lipogenic genes and its effect on mammary lipogenesis and the interaction with trans-10, cis-12 CLA in lactating ewes was evaluated using thiazolidinedione (TZD), a chemical PPARgamma agonist. A total of 24 lactating ewes were randomly assigned to one of the following treatments for 7 days: (1) Control (5 ml/day of saline solution); (2) TZD (4 mg/kg of BW/day in 5 ml of saline solution); (3) CLA (27 g/day with 29.9% of trans-10, cis-12); (4) TZD+CLA. Compared with Control, milk fat content was not changed by TZD, but was decreased 22.3% and 20.5% by CLA and TZD+CLA treatments. In the mammary gland, TZD increased PPARgamma gene expression by 174.8% and 207.8% compared with Control and TZD+CLA treatments, respectively. Conjugated linoleic acid reduced sterol regulatory element-binding transcription protein 1 (SREBP1) gene expression 89.2% and 75.3% compared with Control and TZD+CLA, respectively, demonstrating that TZD fails to overcome CLA inhibition of SREBP1 signaling. In adipose tissue, the expression of SREBP1 and stearoyl CoA desaturase 1 (SCD1) genes were increased by the TZD+CLA treatment, compared with the other treatments. Conjugated linoleic acid decreased milk fat concentration and expression of lipogenic genes, while TZD had no effect on milk fat concentration, expression of lipogenic enzymes or regulators in the mammary gland and failed to overcome the inhibition of these by CLA. Therefore, CLA inhibition of milk fat synthesis was independent of the PPARgamma pathway in lactating dairy ewes. PMID- 29122043 TI - Physical activity promotion by health practitioners: a distance-learning training component to improve knowledge and counseling. AB - : Aim To report an evaluation of health professionals' participation in a distance-learning physical activity training course developed in a low socio economic region of Sao Paulo city, Brazil. BACKGROUND: In countries with public universal health systems, physical activity promotion in primary health care settings can reap results, particularly given that such interventions have the potential to reach a large percentage of the population. However, few studies proposed physical activity training for health professionals in low- and middle income countries. Brazil is a continental country and has the Unified Health System which incorporates family health teams in over 85% of Brazilian cities. METHODS: The physical activity training was part of the fifth module of an educational intervention throughout a distance-learning course focusing on health professionals at M'Boi Mirim district in Sao Paulo city. The training totaled 3 h and had five themes of physical activity: (1) concepts, definitions benefits; (2) evaluation; (3) recommendation; (4) interventions; (5) physical activity counseling. The opinion of health professionals was evaluated after training by two open questions. Findings Out of 106 professionals who took part of the course, only 22.6% (n=24) had accessed the fifth module. These professionals were predominantly female (79.2%), nurses (66.7%) and aged 30 years or older. Responses highlighted the course approach focused on physical activity for improving patient's quality of life and well-being, disease prevention and health improvements. Regarding the themes for improvement, the health professionals identified that there was a need to experience physical activity classes first hand, and the need to link physical activity counseling to the local venues that provide structured physical activity programs. We recommend that further training courses can be conducted based on this model for health professionals to promote physical activity to the community in Brazil. PMID- 29122044 TI - Psychological and psychosocial interventions for refugee children resettled in high-income countries. AB - Large numbers of refugee children are arriving in high-income countries. The evidence to date suggests that they have mental health needs that are higher than for the general population and that these are exacerbated by the numbers of traumatic events they have experienced and the post-migration stressors they continue to be exposed to. The importance of a thorough and thoughtful assessment is discussed. Treatments of note are described for post-traumatic stress disorder, family functioning, general mental health problems and school environments. Future opportunities to operationalise outcome measures, develop multimodal interventions and utilise implementation science methodology are considered. PMID- 29122045 TI - Field-Dependent Measurement of GaAs Composition by Atom Probe Tomography. AB - The composition of GaAs measured by laser-assisted atom probe tomography may be inaccurate depending on the experimental conditions. In this work, we assess the role of the DC field and the impinging laser energy on such compositional bias. The DC field is found to have a major influence, while the laser energy has a weaker one within the range of parameters explored. The atomic fraction of Ga may vary from 0.55 at low-field conditions to 0.35 at high field. These results have been interpreted in terms of preferential evaporation of Ga at high field. The deficit of As is most likely explained by the formation of neutral As complexes either by direct ejection from the tip surface or upon the dissociation of large clusters. The study of multiple detection events supports this interpretation. PMID- 29122046 TI - MODEL-BASED COST-EFFECTIVENESS OF CONVENTIONAL AND INNOVATIVE CHEMO-RADIATION IN LUNG CANCER. AB - INTRODUCTION: Optimizing radiotherapy with or without chemotherapy through advanced imaging and accelerated radiation schemes shows promising results in locally advanced non-small-cell lung cancer (NSCLC). This study compared the cost effectiveness of positron emission tomography-computed tomography based isotoxic accelerated sequential chemo-radiation (SRT2) and concurrent chemo-radiation with daily low-dose cisplatin (CRT2) with standard sequential (SRT1) and concurrent chemo-radiation (CRT1). METHODS: We used an externally validated mathematical model to simulate the four treatment strategies. The model was built using data from 200 NSCLC patients treated with curative sequential chemo-radiation. For concurrent strategies, data from a meta-analysis and a single study were included in the model. Costs, utilities, and resource use estimates were obtained from literature. Primary outcomes were the incremental cost-effectiveness and cost utility ratio (ICUR) of each strategy. Scenario analyses were carried out to investigate the impact of uncertainty. RESULTS: Total undiscounted costs and quality-adjusted life-years (QALYs) for SRT1, CRT1, SRT2, and CRT2 were EUR 17,288, EUR 18,756, EUR 19,072, EUR 17,360 and QALYs 1.10, 1.15, 1.40, and 1.40, respectively. Compared with SRT1, the ICURs were EUR 38,024/QALY for CRT1, EUR 6,249/QALY for SRT2, and EUR 346/QALY for CRT2. CRT2 was highly cost-effective compared with SRT1. Moreover, CRT2 was more effective and less costly than CRT1 and SRT2. Therefore, these strategies were dominated by CRT2. CONCLUSION: Optimized sequential and concurrent chemo-radiation strategies are more effective and cost-effective than the current conventional sequential and concurrent strategies. Concurrent chemo-radiation with a daily low dose cisplatin regimen is the most cost-effective treatment option for locally advanced inoperable NSCLC patients. PMID- 29122047 TI - Antipsychotic polypharmacy in older Australians. AB - : ABSTRACTBackground:Antipsychotics are commonly used, and the rate of use is highest, among those aged 65 years or over, where the risk of adverse events is also high. Up to 20% of younger adults use more than one antipsychotic concurrently; however there are few studies on the prevalence of antipsychotic polypharmacy in older people. We aimed to analyze antipsychotic use in elderly Australians, focusing on the prevalence of antipsychotic polypharmacy and the use of medicines to manage adverse events associated with antipsychotics. METHODS: A cross-sectional study was conducted using Australian Department of Veterans' Affairs (DVA) administrative claims data for the period 1 March 2014 to 30 June 2014. Veterans dispensed at least one antipsychotic medicine during the study period was included. We determined the number of participants dispensed antipsychotic polypharmacy and the number of participants dispensed medicines to manage antipsychotic side effects. RESULTS: There were 7,412 participants with a median age of 86 years. Fifty-one percent (n=3,784) were women and 48% (n=3,569) lived in residential aged-care. Fifty one participants (0.7%) were dispensed anticholinergic medicines indicated for the management of antipsychotic associated extrapyramidal movement disorders and eight (0.1%) were dispensed medicines for the management of hyperprolactinemia. Five percent of participants (n=365) received dual antipsychotics. Dual antipsychotic users were more likely to be under the care of a psychiatrist or to have had a mental health hospitalization than those using a single antipsychotic. CONCLUSIONS: Antipsychotic polypharmacy occurred in one in 20 elderly persons, indicating that there is room for improvement in antipsychotic use in elderly patients. PMID- 29122048 TI - EVALUATION OF PATIENT AND PUBLIC INVOLVEMENT INITIATIVES IN HEALTH TECHNOLOGY ASSESSMENT: A SURVEY OF INTERNATIONAL AGENCIES. AB - OBJECTIVES: Although there is increased awareness of patient and public involvement (PPI) among health technology assessment (HTA) organizations, evaluations of PPI initiatives are relatively scarce. Our objective as members of Health Technology Assessment International's (HTAi's) Patient and Citizen Involvement Group (PCIG) was to advance understanding of the range of evaluation strategies adopted by HTA organizations and their potential usefulness. METHODS: In March 2016, a survey was sent to fifty-four HTA organizations through the International Network of Agencies for Health Technology Assessment (INAHTA) and contacts of members of HTAi's PCIG. Respondents were asked about their organizational structure; how patients and members of the public are involved; whether and how PPI initiatives have been evaluated, and, if so, which facilitators and challenges to evaluation were found and how results were used and disseminated. RESULTS: Fifteen (n = 15) programs from twelve countries responded (response rate 27.8 percent) that involved patients (14/15) and members of the public (10/15) in HTA activities. Seven programs evaluated their PPI activities, including participant satisfaction (5/7), process (5/7) and impact evaluations (4/7). Evaluation results were used to improve PPI activities, identify education and training needs, and direct strategic priorities. Facilitators and challenges revolved around the need for stakeholder buy-in, sufficient resources, senior leadership, and including patients in evaluations. CONCLUSIONS: A small but diverse set of HTA organizations evaluate their PPI activities using a range of strategies that reflect the range of rationales and approaches to PPI in HTA. It will be important for HTA organizations to draw on evaluation theories and methods. PMID- 29122049 TI - Predictive factors associated with psychological distress of caregivers of people with dementia in Japan: a cross-sectional study. AB - : ABSTRACTBackground:Caregivers of people with dementia are likely to have psychological distress that sometimes results in mental health problems, such as depression. The objective of this study was to examine some predictive factors that are thought to be associated with psychological distress of caregivers of people with dementia in Japan. METHODS: Design: A cross-sectional study. SAMPLE: As part of a study to estimate the cost of dementia in Japan, 1,437 people with dementia-caregiver dyads were enrolled in the current informal care time study. The measurements in the study included were the basic characteristics of the caregivers and the people with dementia, and the informal care time during a week. ANALYSIS: Factors that predict caregivers' psychological distress, which was measured by Kessler's Psychological Distress scale (K6) score, were evaluated using univariate and multivariate regression analyses. RESULTS: Approximately 69% of the caregivers recorded a K6 score higher than 4, while 18% scored higher than 12. According to the results of the logistic regression analysis (cut-off 4/5), the K6 score was associated with mental and comorbid diseases of people with dementia, informal care time, its lower number of caregivers, and the level of nursing care. According to the results of logistic regression analysis (cut-off 12/13), the K6 score was associated with mental symptoms and comorbid disease of people with dementia, sex of caregivers, informal care time, and its lower number of caregivers. CONCLUSION: Our findings indicated that the psychological distress of the caregivers is quite high and that informal care time and behavioral and psychological symptoms of dementia are associated with it. These results corroborate with previous findings. PMID- 29122050 TI - Contempt as the absence of appraisal, not recognition, respect. AB - Gervais & Fessler's defense of a sentiment construct for contempt captures features distinguishing the phenomenon from basic emotions and highlights the fact that it comprises a coordinated syndrome of responses. However, their conceptualization of contempt as the absence of respect equivocates. Consequently, a "dignity" culture that prescribes respect does not thereby limit legitimate contempt in the manner the authors claim. PMID- 29122051 TI - Including pride and its group-based, relational, and contextual features in theories of contempt. AB - Sentiment includes emotional and enduring attitudinal features of contempt, but explaining contempt as a mixture of basic emotion system affects does not adequately address the family resemblance structure of the concept. Adding forms of individual, group-based, and widely shared arrogance and contempt is necessary to capture the complex mixed feelings of proud superiority when "looking down upon" and acting harshly towards others. PMID- 29122052 TI - Ultra-processing. An odd 'appraisal'. AB - It is now generally agreed that the impact of the current nature, purpose and extent of food processing on human well-being, health and disease needs to be better understood and explained, in order to improve public health. The special issue of Public Health Nutrition devoted to the concept of ultra-processing of food, and the NOVA classification of which ultra-processed foods are one category, is a great step forward in this work. Coincidentally, a polemical 'critical appraisal' of ultra-processing was recently published in another journal. Debate and discussion are an essential part of the scientific endeavour. In this commentary, we correct inaccurate statements made about NOVA in the 'appraisal,' rebut points raised, and discuss the larger issue of scientific responsibility for publishing opposing views on controversial topics. PMID- 29122053 TI - Associations of rumen parameters with feed efficiency and sampling routine in beef cattle. AB - Characterizing ruminal parameters in the context of sampling routine and feed efficiency is fundamental to understand the efficiency of feed utilization in the bovine. Therefore, we evaluated microbial and volatile fatty acid (VFA) profiles, rumen papillae epithelial and stratum corneum thickness and rumen pH (RpH) and temperature (RT) in feedlot cattle. In all, 48 cattle (32 steers plus 16 bulls), fed a high moisture corn and haylage-based ration, underwent a productive performance test to determine residual feed intake (RFI) using feed intake, growth, BW and composition traits. Rumen fluid was collected, then RpH and RT logger were inserted 5.5+/-1 days before slaughter. At slaughter, the logger was recovered and rumen fluid and rumen tissue were sampled. The relative daily time spent in specific RpH and RT ranges were determined. Polynomial regression analysis was used to characterize RpH and RT circadian patterns. Animals were divided into efficient and inefficient groups based on RFI to compare productive performance and ruminal parameters. Efficient animals consumed 1.8 kg/day less dry matter than inefficient cattle (P?0.05) while achieving the same productive performance (P?0.10). Ruminal bacteria population was higher (P?0.05) (7.6*1011 v. 4.3*1011 copy number of 16S rRNA gene/ml rumen fluid) and methanogen population was lower (P?0.05) (2.3*109 v. 4.9*109 copy number of 16S rRNA gene/ml rumen fluid) in efficient compared with inefficient cattle at slaughter with no differences (P?0.10) between samples collected on-farm. No differences (P?0.10) in rumen fluid VFA were also observed between feed efficiency groups either on farm or at slaughter. However, increased (P?0.05) acetate, and decreased (P?0.05) propionate, butyrate, valerate and caproate concentrations were observed at slaughter compared with on-farm. Efficient had increased (P?0.05) rumen epithelium thickness (136 v. 126 um) compared with inefficient cattle. Efficient animals also spent 318% and 93.2% more time (P?0.05) in acidotic (4.14% v. 1.30%) (pH?5.6) and optimal (5.60.05) Conclusion: BiodentineTM and mineral trioxide aggregate did not differ significantly in combined clinical and radiographic success after 24 months. PMID- 29122068 TI - Prescription of Panoramic Radiographs in Children: A Health Services Assessment of Current Guidelines. AB - PURPOSE: To (1) determine adherence to guidelines when prescribing panoramic radiographs (PR) for patients 18 y.o. and younger; and 2) compare PR prescriptions between general dentists (GPs) and pediatric dentists (PDs). METHODS: A retrospective analysis of insurance claims included codes for PRs and associated codes for two cities between 2008 and 2015. Chi-square tests ascertained the likelihood of a PR being associated within three days of routine exams. RESULTS: A total of 81,699 pediatric patients were seen by 2,077 GPs and 103 PDs. There were 11,993 PRs, 119,068 routine exams (7,343 associated with a PR), 13,819 orthodontic procedures (378 associated with a PR), 798 third molar procedures (172 associated with a PR), and 16,636 procedures for acute problems (1,670 associated with a PR). Patients aged eight years old and younger had the largest discrepancy between GPs and PDs. GPs prescribed proportionally more films in patients five years old and younger, but PDs prescribed more in seven and eight year olds. Nine- to 18 year olds. had more similar patterns between GPs and PDs, except for 14- to 15 year olds, when GPs prescribed more. CONCLUSIONS: GPs prescribed PR in patients younger than five years old more often and were somewhat less likely to follow guidelines. PMID- 29122069 TI - Potential Risk for Localized Aggressive Periodontitis in African American Preadolescent Children. AB - PURPOSE: This study aimed to evaluate the potential risk for localized aggressive periodontitis (LAgP) in African American children by detection of the potential periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) using polymerase chain reaction (PCR) and microbiome analysis. METHODS: Twenty-one pre-adolescents (age range equals 10.7 to 13.1 years old) were recruited, for this IRB-approved study. Oral examination included limited periodontal examination determining bleeding index (BOP) and periodontal probing (PD). An oral mucosa sample was used for analysis. RESULTS: Nine of 21 children were Aa+ by PCR. The Aa+ group had a significantly higher proportion of teeth with BOP and PD greater than four mm than the Aa- group (P=0.014 and 0.006 for percent BOP and percent PD equal to or greater than four mm, respectively; Mann Whitney Test). No significant differences in microbe abundance or composition were found from comparison of Aa+ versus Aa- samples. CONCLUSIONS: Detection of Aa from preadolescent African American children was associated with signs of periodontal inflammation. Although none of these children were diagnosed with LAgP, PCR targeting Aa could be a risk factor. Further study is indicated; however, the usefulness of PCR in dental practice setting to assess risk may be cost-effective for early diagnosis and prevention of LAgP. PMID- 29122070 TI - Caretakers' Self-Selected Oral Health Goals: Self-Efficacy, Perceived Compliance, and Effect on Recall Attendance. AB - PURPOSE: The purpose of this study was to describe caretakers' self-selected pediatric oral health goals, self-reported compliance, perceived self-efficacy, and perceived barriers to goal accomplishment. The effect of self-management plans on recall attendance was also evaluated. METHODS: Fifty caretaker-patient pairs who presented for examinations at a university pediatric dental clinic were assigned to an intervention group. Fifty age-matched subjects were assigned to the comparison group. At baseline both groups completed a demographic survey. The intervention group developed a self-management plan and selected oral health goals. Follow-up surveys were administered to the intervention group two weeks and six months later. RESULTS: The most frequently selected oral-health goals were brush twice daily (21 percent) and toothbrush before bed (17 percent). At the two-week follow-up, 39 percent of contacted caretakers recalled their chosen goals correctly, compared to 26 percent at six months. Approximately half of the participants in both groups attended the six-month follow-up visit. The difference in recall attendance between intervention and comparison group was not significant (P=0.80). CONCLUSIONS: Caretakers most frequently selected goals that were associated with toothbrushing. They initially reported high confidence levels; however, recall and compliance with self-selected oral-health goals decreased significantly over the course of six months. PMID- 29122071 TI - Costs and Resource Use Among Child Patients Receiving Silver Nitrate/Fluoride Varnish Caries Arrest. AB - PURPOSE: The purpose of this study was to assess the impact of silver nitrate/fluoride varnish (SN/FV) on care costs. METHODS: A retrospective matched cohort study, using Oregon Medicaid claims (January 1, 2012 to December 31, 2014) for patients younger than 21 years old, compared patients treated with SN/FV to matched patients not treated with SN/FV. The number of services and costs were compared using student's t test and generalized estimating equation (GEE) regression models. RESULTS: Patients treated with SN/FV (n equals 4,612) and matched patients treated conventionally (n equals 13,498) averaged 28+/-7 (SD) months of continuous eligibility based on initial treatment date. The number of first-year services and total services over an average of 28 months were higher for patients treated with SN/FV (10.6 versus 6.7 in year one; 19.3 versus 8.8 overall; P<0.0001). Excluding diagnostic/preventive services, costs were higher in patients treated conventionally than patients treated with SN/FV in the first year. Overall costs were similar ($698 versus $707; P=.52). The average number of services was 58 percent higher (95 percent confidence interval [CI] 1.54 to 1.63) for patients treated with SN/FV, but costs remained similar. CONCLUSION: Patients treated with silver nitrate/fluoride varnish accrued a greater number of services and higher total costs over approximately 28 months but lower treatment costs than patients treated conventionally. PMID- 29122072 TI - Inhibition of Residual Cariogenic Bacteria in Atraumatic Restorative Treatment by Chlorhexidine: Disinfection or Incorporation. AB - PURPOSE: The purpose of this study was to compare the efficacy of chlorhexidine (CHX) cavity disinfection and of CHX containing glass ionomer cement (GIC) in inhibiting residual cariogenic bacteria. METHODS: Ninety, five- to nine-year-olds were randomly allocated to three groups: Group 1-CHX containing GIC; Group 2-CHX cavity disinfection; and Group 3-conventional GIC. Total viable count (TVC), Streptococcus mutans (SM), and Lactobacillus (LB) were analyzed pre-, post-, and three months after atraumatic restorative treatment (ART). The results were statistically analyzed by one-way analysis of variance. RESULTS: At three months microbial evaluation, Group 1 showed 65 percent reduction of both TVC and LB and 67 percent of SM. Group two showed 64 percent, 58 percent, and 56 percent reduction of TVC, LB, and SM respectively. Group 3 exhibited 41 percent, 42 percent, and 46 percent reduction in mean TVC, LB, and SM counts respectively. Residual microbial counts for Group 3 were 0.41, 0.61, and 0.53 (105 colony forming units) for TVC, LB, and SM, respectively, which was significantly higher (P<0.01) compared to the respective microbial counts in Groups 1 and 2. CONCLUSION: Both chlorhexidine disinfection and incorporation showed superior efficacy in inhibiting residual microbes compared to conventional ART. PMID- 29122073 TI - Survival and Associated Risk Factors of Resin-based Composite Restorations in Primary Teeth: A Clinical, Retrospective, University-based Study. AB - PURPOSE: This clinical retrospective study evaluated the survival and risk factors associated with failures of resin-based composite restorations in primary teeth. METHODS: A total of 212 restorations in primary teeth from records of 76 high caries-risk children were included. The restorations' longevity for up to six years of follow-up was assessed using the Kaplan-Meier survival test. Multivariate Cox regression analysis with shared frailty was used to evaluate the factors associated with failures (P<0.05). RESULTS: Mean survival time was 4.3 years (95 percent confidence interval (CI) equals 4.0 to 4.6). The survival of the restorations reached 35.3 percent, up to the sixth year, with an annual failure rate of 18.8 percent. Restorations placed in teeth with pulp treatment had a lower survival rate than those in vital teeth (hazard ratio [HR] equals 2.16, 95 percent CI equals 1.02 to 4.58). Patients who did not use standard fluoride toothpaste had more risk of failure in their restorations (HR equals 6.12, 95 percent CI equals 1.47 to 25.49). CONCLUSIONS: Composite restorations placed in high caries-risk children presented limited survival after six years of follow-up. Standard fluoride toothpaste use was a protection factor, while pulp treatment was a risk factor for restoration failure. PMID- 29122074 TI - Cone Beam Computed Tomography Evaluation of Hand Nickel-Titanium K-Files and Rotary System in Primary Teeth. AB - PURPOSE: The purpose of this study was to compare canal transportation, centering ability, and removed dentin thickness (RDT) using hand nickel-titanium (NiTi) K flex files and rotary systems in primary molars and using cone beam computed tomography (CBCT). METHODS: This study was conducted on 20 primary maxillary and 20 primary mandibular molars, which were randomly divided into two groups to be instrumented with hand NiTi K-flex files and a rotary system. Pre- and post instrumentation slices were taken at three predetermined levels using CBCT to evaluate all the parameters by using Digital Imaging Communications in Medicine (DICOM) software. The results were statistically evaluated. RESULTS: Rotary instruments caused significantly less canal transportation and showed more centering ability than hand NiTi instruments at all levels and in all directions, except at the cervical level in the mesiodistal direction, where the hand group showed significantly superior results. The hand NiTi K-flex files removed significantly more dentin than rotary instrumentation at all levels and in all directions, except at the apical level in the buccodistal direction, where no significant difference between the two groups was observed. CONCLUSION: Rotary files showed less canal transportation, more conservation of tooth structure, and superior centering ability compared to hand nickel-titanium K-flex files. PMID- 29122075 TI - The scientific dating of standing buildings. AB - The techniques of dendrochronology (tree-ring dating) and radiocarbon (14C) dating are described, as they are applied to historic buildings. Both rely on determining the felling dates of the trees used in their construction. For dendrochronology, the construction of master chronologies and the matching of individual ring-width sequences to them is described and, for radiocarbon dating, the use of tree-ring results in calibration. Results of dating are discussed, ranging from the cathedrals of Peterborough and Beauvais and the development of crown-post roof structures, to the dating and identification of standing medieval peasant houses, particularly those built using cruck construction. PMID- 29122076 TI - A systematic review of secondary cerebrospinal fluid leaks. AB - BACKGROUND: Secondary cerebrospinal leaks (CSF) are leaks that recur after an initial endoscopic repair of CSF leaks. Identification of characteristics that could predict secondary leaks may allow surgeons to plan repairs with the knowledge that these defects are more likely to fail. OBJECTIVE: To identify characteristics that could predict secondary CSF leaks. METHODS: A search of all studies that reported outcomes after endoscopic repair of CSF leaks was conducted by using medical literature data bases. Studies with the following criteria were included: written in the English language, secondary CSF leaks after primary repair, and assessment of success of fistula repair. Data extracted included the etiology of the leak, site of the leak, reconstructive materials used, and success of the repair. RESULTS: Ninety-four studies, from 1988 to 2015, with a total of 3149 primary CSF leaks were included. Sixty-three studies (67%) had a success rate of >=80%; 77 studies (82%) had secondary leak rates of <40%. For 88 of the 94 studies (94%), the success rate after secondary repair improved to 81.0 100%. Of 48 studies that included leaks of more than one site, the sphenoid was the most common site of leak in 26 studies (55%), the ethmoid was the most common site in 16 studies (34%), and the cribriform was the most common site in 11 studies (23%). CONCLUSION: The rate of secondary CSF leaks was low due to advances in endoscopic repair techniques. Spontaneous and iatrogenic CSF leaks were more likely to recur, especially without adequate control of underlying factors, such as increased intracranial pressure and obesity. Further studies with consistent reporting are required for more definitive conclusions about secondary CSF leaks. PMID- 29122078 TI - The role of regulatory T cells in the regulation of upper airway inflammation. AB - Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) are inflammatory diseases of the upper airway, with a similar immunologic profile, characterized by aberrant and persistent type 2 inflammation. One cell population that has been identified as altered in both disease types is regulatory T cell (Treg). Tregs have the capacity to modulate T-effector function and suppress inflammatory cytokine production in a broad range of cell types. Given the ability of Tregs to control inflammation, the role of Tregs in respiratory diseases has attracted much attention. As discussed in this article, alterations in the Treg numbers and function, or both, have been identified in AR and CRSwNP, although much of the data is conflicting. Here, we explored what is known and, in many cases, unknown about the mechanisms by which Tregs differentiate and function, and how these functions can be controlled in the mucosal microenvironment. By gaining a greater understanding of these processes, it may be possible to harness the natural immunosuppressive activity of Tregs to ameliorate the chronic inflammation associated with AR and CRSwNP. PMID- 29122079 TI - Sinonasal T-cell expression of cytotoxic mediators granzyme B and perforin is reduced in patients with chronic rhinosinusitis. AB - BACKGROUND: CD8+ T cells and natural killer (NK) cells are cytotoxic cells that use granzyme B (GrB) and perforin. Defective cytotoxic function is known to play a role in dysregulated immune response as seen in chronic sinusitis, also referred to as chronic rhinosinusitis (CRS). However, to our knowledge, in the United States, neither GrB or perforin expression has been reported in patients with CRS. OBJECTIVE: The aim of this study was to investigate sinonasal cytotoxic cells, their mediators, and cell-specific distribution of these mediators in patients with CRS with nasal polyp (CRSwNP) and in patients with CRS without nasal polyp (CRSsNP). METHODS: Blood and sinus tissue samples were taken from patients with CRSsNP (n = 8) and CRSwNP (n = 8) at the time of surgery. Control subjects (n = 8) underwent surgery for cerebrospinal fluid leak repair or to remove non-hormone-secreting pituitary tumors. The cells were analyzed via flow cytometry by using CD8 expression to identify cytotoxic T cells and CD56 expression to identify NK cells. Intracellular GrB and perforin expression were analyzed with flow cytometry. RESULTS: We observed no significant differences in plasma or peripheral blood immune cell numbers or specific levels of GrB or perforin among the groups. In the sinonasal mucosa of the patients with CRSsNP and the patients with CRSwNP, there was a significant decrease in GrB and perforin levels (p < 0.05) despite similar or increased numbers of cytotoxic cells when compared with the controls. The overall decrease in GrB and perforin in the sinonasal mucosa of the patients with CRSsNP and the patients with CRSwNP was due to decreased T cell production. There was no difference in total NK cell count or expression of perforin or GrB among all the groups. CONCLUSION: Total levels of sinonasal GrB and perforin were decreased in the sinonasal mucosa of both the patients with CRSwNP and the patients with CRSsNP compared with the controls, whereas sinonasal CD8+ T cells, (but not NK cells,), intracellular stores of GrB and perforin were reduced in the patients with CRSwNP compared with the controls. PMID- 29122080 TI - Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts. AB - PURPOSE: Activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin, as a master regulator of metabolism, is involved in airway tissue remodeling. Here, we investigated the physical role of AMPK on cell migration, matrix contraction, and the production of matrix metalloproteinases (MMP) in nasal polyp-derived fibroblasts (NPDF). METHODS: Primary NPDFs from six patients with chronic rhinosinusitis and nasal polyps were isolated and cultured. To assess the effect of AMPK on fibroblast migration, we conducted scratch and migration assays in NPDF treated with metformin and/or compound C. A collagen gel contraction assay measured activity of contractile. MMP expression was measured with reverse transcription-polymerase chain reaction, Western blot, and zymography. To evaluate for specific AMPK action, we examined by AMPK small interfering RNA. RESULTS: Metformin, an activator of AMPK, significantly inhibited cell migration in NPDFs in a dose-dependent manner. Compound C, an inhibitor of AMPK, partially reversed the inhibitory effect of metformin. Metformin also significantly decreased contractile activity, with a concomitant reduction in the production of MMP-1 and MMP-2 but not of MMP-9. Specific silencing that targeted AMPK resulted in the enhancement of mobility and contractility and in the production of MMP-1 and MMP-2. CONCLUSION: AMPK played an important role in regulating cell migration, matrix contraction, and MMP production in NPDFs, which provided data that AMPK activator might be a therapeutic target for the prevention of tissue remodeling in nasal polyps. PMID- 29122081 TI - Gender-specific differences in serum immunoglobulin E levels and prevalence of fungus in sinonasal tissue noted in patients with chronic rhinosinusitis who underwent endoscopic sinus surgery. AB - BACKGROUND: We previously presented that women with chronic rhinosinusitis (CRS) who elected endoscopic sinus surgery (ESS) have a higher symptom burden than men. Causes of these gender-based differences warranted further study. OBJECTIVES: To study gender differences in another cohort of adult patients with CRS who underwent ESS and to compare key histopathologic and serologic features Methods: Patients with CRS who underwent ESS (from 2011 to 2014) with structured histopathology reports on surgical samples were studied. The 13-item structured histopathology report detailed key metrics of inflammation and the presence of fungal elements. Clinical, 22-item Sino-Nasal Outcome Test (SNOT-22) score, Lund Mackay computed tomography (CT) score, serologic (immunoglobulin E [IgE] level, absolute eosinophil count) and histopathologic data were compared between male and female patients by using statistical software. RESULTS: We studied 130 eligible subjects (mean age, 54.7 years; 49.2% women). Compared with the men, the women had significantly higher preoperative SNOT-22 scores (women, 48.7; men 38.0 [p = 0.004]) but similar CT scores. Serum IgE levels were significantly higher among women versus men (peak, 433.3 versus 190.8 kU/L [p = 0.03]; closest to surgery, 435.0 versus 190.8 kU/L [p = 0.03]). Tissue fungal elements were significantly more prevalent in women versus men (19.0 versus 5.2%; p = 0.02). Up to this point, the analysis was agnostic of clinical details of the subjects. Further analysis was conducted regarding clinical features. Allergic fungal sinusitis (AFS) was found significantly more commonly in the female versus male patients (21.9 versus 9.1%; p = 0.04). Women versus men had a higher prevalence of migraine (19.4 versus 4.6%; p = 0.01) or any primary headache disorders (23.0 versus 6.2%; p = 0.007). CONCLUSION: Women who underwent ESS for CRS had higher SNOT-22 symptom burden. Worsened symptomatology may be secondary to a higher prevalence of primary headache disorders in women. However, surgeons should also be aware that female patients with CRS who seek ESS may have a higher prevalence of severe disease endotypes (more tissue fungal elements, elevated serum IgE levels) and phenotypes. PMID- 29122082 TI - The relationship between social determinants of health and utilization of tertiary rhinology care. AB - BACKGROUND: Chronic rhinosinusitis (CRS) has a high prevalence and significant cost and quality of life implications. Many types of practitioners care for patients with rhinosinusitis; however, patients with chronic or complicated conditions are often referred for tertiary rhinology services. It is unclear how social determinants of health affect access and utilization of these services. A better understanding of social barriers to tertiary rhinology care is needed to reduce health care disparities and improve health outcomes. The aim of the present study was to measure whether income, insurance status, race, and education affect utilization of tertiary rhinology care. METHODS: All adult patients diagnosed with CRS by rhinologists at a single tertiary care hospital were identified (2010-2014). Patient characteristics (age, gender, race, insurance status) were compared with population-level data from the hospital and from Davidson County, Tennessee, which includes Nashville. Rhinology utilization rates were calculated for each ZIP code within the county. The association between determinants of health (race, insurance status, education, median income) and tertiary rhinology utilization were measured by using multivariable regression analyses. RESULTS: A total of 1341 unique patients with CRS (median age, 50 years; 55% women, 80% white, 82% with private insurance) from Davidson County used tertiary rhinology services. These patients were significantly older and more likely to be female, white, and privately insured than patients seen hospital-wide or among the population of Davidson County (p < 0.001). Utilization rates were higher in ZIP codes with a lower proportion of minorities, a higher median income, and higher rates of private insurance and college education. However, in adjusted analysis, only attainment of a college education was independently associated with utilization of tertiary rhinology services. Utilization was 4% higher for every 1% increase in college-educated population (coefficient 0.04 [95% CI, 0.01-0.07]; p = 0.01). CONCLUSION: Results of this study indicated that some social determinants of health (race, income, educational level, insurance status) do affect utilization of tertiary rhinology services. Higher utilization among those with higher income and educational attainment are contradictory to the data, which indicated that lower socioeconomic status was associated with a higher CRS rate. Further study is required to understand the disparities in rhinology utilization rates. PMID- 29122083 TI - Biocompatibility and pharmacokinetics of fluticasone-eluting sinus implant in a rabbit model. AB - BACKGROUND: A novel, bioabsorbable, fibrinogen-based implant has been developed as a mucosal dressing after endoscopic sinus surgery (ESS). This implant can be formulated with fluticasone propionate (FP) for local elution of corticosteroid to reduce postoperative inflammation and promote mucosal healing. OBJECTIVE: This study investigated the biocompatibility and pharmacokinetics of the implant in a rabbit model. METHODS: Implants with and without FP were placed on both intact and demucosalized maxillary sinuses of 33 New Zealand White rabbits. Sinuses with either intact or denuded bone without implants acted as controls. Histopathologic assessments were carried out at 5, 15, and 28 days. Concentrations of FP in the maxillary sinus mucosa, nasal cavity mucosa, and plasma were measured for up to 44 days. RESULTS: Implants placed on intact mucosa or denuded bone were grossly integrated within 15 days. Minimal foreign body reaction was seen with negligible differences for inflammation, fibrosis, or bone remodeling among controls, sinuses with the implant, or sinuses with the implant plus FP, at all time points. All samples also showed complete or near-complete percentage reepithelialization at 28 days, although the denuded bone controls demonstrated greater percentage reepithelialization at 5 days compared with denuded bone with the implant or implant plus FP (p < 0.0001). The maxillary sinus mucosa demonstrated levels of FP of >140 ng/g up to 44 days. Plasma concentrations of FP were generally very low and were undetectable after day 7. CONCLUSIONS: The implant and the implant plus FP seemed to be biocompatible in rabbits. The implant plus FP effectively eluted steroid locally over at least 44 days, with negligible plasma concentrations. Further studies are warranted regarding potential therapeutic applications in patients undergoing ESS for chronic rhinosinusitis. PMID- 29122084 TI - Vitamin D3 deficiency and its association with nasal polyposis in patients with cystic fibrosis and patients with chronic rhinosinusitis. AB - BACKGROUND: Currently vitamin D3 (VD3) or cholecalciferol is considered an immunomodulator that may be implicated in nasal polyposis (NP) pathophysiology. OBJECTIVES: This study aimed to investigate if deficiency of VD3 is associated with the presence of NP in patients with cystic fibrosis (CF) and patients with chronic rhinosinusitis (CRS). METHODS: In total, 152 adult participants were included in five phenotypic groups: CF with NP (CFwNP) (n = 27), CF without NP (CFsNP) (n = 31), CRS with NP (CRSwNP) (n = 32), CRS without NP (CRSsNP) (n = 30), and controls (n = 32). The serum levels of 25(OH)-VD3 < 20 ng/mL are considered as a deficiency, 21-29 ng/mL as insufficiency, and >30 ng/mL as sufficiency. Endoscopic and imaging staging of the mucosal disease performed with the Lund-Kennedy (LK) and Lund-Mackay (LM) scoring systems, respectively. The genotype of the patients with CF and the nasal microbial colonization of the patients with CF and patients with CRS were also recorded. RESULTS: The patients with CFwNP had the lowest percentage of sufficiency in VD3 and the highest percentage in insufficiency among all the groups. The LM imaging scores were inversely correlated with the VD3 levels in both arms of the study (CF and CRS). Moreover, the LK endoscopic scores had a similar correlation in the CF groups; however, this was not the case with the CRS groups. The genotype of the patients with CF was not correlated with the VD3 serum levels. The patients with positive microbial colonization (mainly Pseudomonas and Staphylococcus aureus) had significantly lower VD3 serum levels in both the CF and CRS process. CONCLUSION: VD3 deficiency seemed to be associated with the presence of nasal polyps in the patients with CRS and in the patients with CF in a similar manner. The lower the level of serum VD3, the more severe the mucosal disease was found in the imaging studies and the more frequent microbial colonization of the patients with CF and the patients with CRS. PMID- 29122085 TI - Influence of chitosan-based dressing on prevention of synechia and wound healing after endoscopic sinus surgery: A meta-analysis. AB - INTRODUCTION: Endoscopic sinus surgery (ESS) has had many complications, e.g., synechia formation. This meta-analysis investigated the effect of a novel chitosan-based dressing on prevention of synechia and wound healing after ESS. METHODS: We systematically searched various medical literature data bases and included the randomized controlled trials (RCT) regarding the effect of novel chitosan-based dressing on ESS. The study outcomes included synechia, granulations, hemostasis, crusting scores, and infection. RESULTS: Six RCTs, which involved 337 patients, were included in the meta-analysis. Compared with control intervention after ESS, chitosan-based gel dressing substantially inhibited synechia (risk ratio [RR] 0.28 [95% confidence interval {CI}, 0.15 0.54]; p = 0.0001), improved granulations (RR 1.47 [95% CI, 1.07-2.03]; p = 0.02), and hemostasis (RR 1.47 [95% CI, 1.07-2.03]; p = 0.02) but demonstrated no effect on crusting scores (standard mean difference -0.41 [95% CI, -1.06 to 0.23]; p = 0.21) and infection (RR 0.88 [95% CI, 0.51-1.52]; p = 0.64). CONCLUSION: Compared with control intervention, chitosan-based dressing was associated with significantly reduced synechia and with increased granulations and hemostasis but showed no influence on crusting and infection after ESS. PMID- 29122086 TI - Endonasal endoscopic management of frontal sinus cerebrospinal fluid leak. AB - BACKGROUND: A frontal sinus leak is uncommon and is seen in ~15% of cases of patients with cerebrospinal fluid (CSF) rhinorrhea. Now, endonasal endoscopic techniques have been reported to reconstruct skull base defects in the frontal sinus with a favorable outcome. OBJECTIVE: To review our experience in the repair of frontal sinus CSF leaks through an endonasal endoscopic approach. METHODS: Twenty-four patients with a frontal sinus leak who underwent endonasal endoscopic repair entered the study. Clinical presentation, location, frontal sinusotomy, graft material, follow-up, and frontal sinus status were evaluated. RESULTS: Among >100 cases of surgically repaired CSF rhinorrhea, the frontal sinus was the site of the leak in 24 patients (mean age, 28.9 years; mean follow-up, 22 months). The etiology consisted of spontaneous leak and traumatic leak; whereas patients with skull base reconstruction after removal of tumor were excluded. Surgical approaches included Draf IIb, Draf III, Draf IIa in 20, 3, and 1 patients, respectively. Free autografts as two-layer inlay fat-muscle and onlay fascia lata were used in the majority of patients. A success rate was achieved in 95.83% of the patients. CONCLUSION: Endonasal endoscopic repair of a frontal sinus leak was a successful procedure, with a low failure rate and minimal morbidity. PMID- 29122087 TI - Comparison of two concentrations of triamcinolone injection in the prevention of supratip edema after external rhinoplasty: A randomized trial. AB - BACKGROUND: A comparison of the two methods of corticosteroid (triamcinolone) use in reducing supratip edema (pollybeak deformity) after rhinoplasty. METHODS: Ninety patients who were candidates for rhinoplasty were randomly divided into three groups. Group A received no treatment, group B received 8 mg/mL of triamcinolone, and group C received 16 mg/mL of triamcinolone. Their effects on dorsal edema were evaluated by using the patients' and surgeons' visual analog scale scores. Also, dorsal edema was measured by using photo editing software. RESULTS: There was no significant difference in the patients' characteristics in the study groups. The surgeons' visual analog scale scores were significantly better in those patients who received triamcinolone injection than in the control group (p = 0.02). However, none of the other assessment methods showed significant differences among the study groups. There was no significant difference between the two evaluated concentrations. CONCLUSION: Triamcinolone injection had positive temporary effects on reducing supratip edema without any important complications. PMID- 29122088 TI - Factors that contribute to disagreement in satisfaction between surgeons and patients after corrective septorhinoplasty. AB - BACKGROUND: Corrective septorhinoplasty is one of the most common facial plastic surgeries. However, surgeons and patients sometimes disagree about postoperative outcome satisfaction after corrective septorhinoplasty. OBJECTIVE: We investigated the factors that influenced the disagreement in satisfaction between surgeons and patients after corrective septorhinoplasty. METHODS: Surgeon satisfaction was assessed by other plastic surgeons by comparing patient photographs taken at the preoperative and 12-month postoperative periods. Patient satisfaction was assessed by the Rhinoplasty Outcome Evaluation Questionnaire (ROEQ) before surgery and 12 months after surgery. The dissatisfied group was defined as showing a negative change or no change in the ROEQ quartile between baseline and 12 months after surgery. RESULTS: A total of 70 patients were included. No significant differences were observed between the satisfied and dissatisfied groups in sex, marital status, depression history, and major anesthetic problems. However, the dissatisfied group was significantly younger, more likely to be employed, and better educated than the satisfied group. In addition, a multivariate logistic regression analysis indicated that being highly educated was a predictor of disagreement in satisfaction between surgeons and patients. CONCLUSION: Our findings indicated that highly educated patients who underwent corrective septorhinoplasty required more detailed preoperative guidance, including more complete information on the limitations of the surgery. PMID- 29122089 TI - Acute radiology rarely confirms sinus disease in suspected recurrent acute rhinosinusitis. PMID- 29122090 TI - Prevalence and Years of Life Lost due to Disability from Dental Caries among Children and Adolescents in Western China, 1990-2015. AB - OBJECTIVE: To analyze the prevalence and years lived with disability (YLD) from dental caries among children and adolescents and the time trends over the past two decades in Sichuan province, the largest province in west China. METHODS: Based on the Global Burden of Disease Study 2015 (GBD2015), which systematically assessed the epidemiological characteristics of major diseases and their transitions by country and region from 1990 to 2015, we extracted the estimated results for China. We then used the Bayesian meta-regression method to estimate the sex- and age-specific prevalences and YLDs from dental caries among children and adolescents under 15 years old in Sichuan province and compared them with global and national indicators for the same period. RESULTS: In 2015, there were almost 6 million cases of dental caries in children and adolescents (aged < 15 years) in Sichuan province, accounting for 6% of the total cases in China. For children under 5 years, the prevalence of deciduous caries was 55.9%, and the YLDs value was 10.8 per 100,000, while it was 24.3% and 5.1 per 100,000 respectively among 5- to 14-year-olds; for those aged 5 to 14 years, the prevalence of permanent caries was 21.5%, and the YLDs value was 11.5 per 100,000. From 1990 to 2015, the prevalence of dental caries for children under 5 years increased substantially, by 16.2%, and the YLDs increased by 8.7%. Among those aged 5 to 14 years, the prevalence increased and the YLDs decreased. CONCLUSION: Dental caries remains a huge health burden in Western China. In contrast to the global and national data, the trend has increased rapidly over the past 25 years in this region. This work provides suggestions for the prevention and control for oral health in China with the policy of two-child. PMID- 29122091 TI - Temporal Trend in Lung Cancer Burden Attributed to Ambient Fine Particulate Matter in Guangzhou, China. AB - OBJECTIVE: To estimate the lung cancer burden that may be attributable to ambient fine particulate matter (PM2.5) pollution in Guangzhou city in China from 2005 to 2013. METHODS: The data regarding PM2.5 exposure were obtained from the 'Ambient air pollution exposure estimation for the Global Burden of Disease 2013' dataset at 0.1 degrees *0.1 degrees spatial resolution. Disability-adjusted life years (DALYs) were estimated based on the information of mortality and incidence of lung cancer. Comparative risk analysis and integrated exposure-response function were used to estimate attributed disease burden. RESULTS: The population-weighted average concentration of PM2.5 was increased by 34.6% between 1990 and 2013, from 38.37 MUg/m3 to 51.31 MUg/m3. The lung cancer DALYs in both men and women were increased by 36.2% from 2005 to 2013. The PM2.5 attributed lung cancer DALYs increased from 12105.0 (8181.0 for males and 3924.0 for females) in 2005 to 16489.3 (11291.7 for males and 5197.6 for females) in 2013. An average of 23.1% lung cancer burden was attributable to PM2.5 pollution in 2013. CONCLUSION: PM2.5 has caused serious but under-appreciated public health burden in Guangzhou and the trend deteriorates. Effective strategies are needed to tackle this major public health problem. PMID- 29122092 TI - Rapid and Accurate Sequencing of Enterovirus Genomes Using MinION Nanopore Sequencer. AB - OBJECTIVE: Knowledge of an enterovirus genome sequence is very important in epidemiological investigation to identify transmission patterns and ascertain the extent of an outbreak. The MinION sequencer is increasingly used to sequence various viral pathogens in many clinical situations because of its long reads, portability, real-time accessibility of sequenced data, and very low initial costs. However, information is lacking on MinION sequencing of enterovirus genomes. METHODS: In this proof-of-concept study using Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) strains as examples, we established an amplicon-based whole genome sequencing method using MinION. We explored the accuracy, minimum sequencing time, discrimination and high-throughput sequencing ability of MinION, and compared its performance with Sanger sequencing. RESULTS: Within the first minute (min) of sequencing, the accuracy of MinION was 98.5% for the single EV71 strain and 94.12%-97.33% for 10 genetically-related CA16 strains. In as little as 14 min, 99% identity was reached for the single EV71 strain, and in 17 min (on average), 99% identity was achieved for 10 CA16 strains in a single run. CONCLUSION: MinION is suitable for whole genome sequencing of enteroviruses with sufficient accuracy and fine discrimination and has the potential as a fast, reliable and convenient method for routine use. PMID- 29122093 TI - Association between Phthalate Exposure and the Use of Plastic Containers in Shanghai Adults. AB - OBJECTIVE: Consuming phthalates may be due to the presence of food contact materials, such as plastic containers. In this study, we investigated the association between plastic container use and phthalate exposure in 2,140 Shanghai adults. METHODS: Participants completed a questionnaire on the frequency of using plastic containers in different scenarios in the previous year (e.g., daily, weekly) and on the consumption of plastic-packaged foods in the previous three days (yes or no). Urinary phthalate metabolites were used to assess the association between phthalate exposure and the use of plastic containers. RESULTS: The metabolites of di-(2-ethylhexyl) phthalate (DEHP) were the most frequently detected in urine. The results revealed that phthalate exposure was associated with consumption of plastic-packaged breakfast or processed food items in the previous three days. The consumption of these two food items had strong synergistic effects on increasing urinary concentrations of most phthalate metabolites. CONCLUSION: Our results of plastic-packaged breakfast and processed food may be explained by the use of flexible plastic containers, indicating the importance of risk assessment for the application of flexible plastic containers. PMID- 29122094 TI - Periconceptional Folic Acid Supplementation in Chinese Women: A Cross-sectional Study. AB - OBJECTIVE: To investigate the status of folic acid (FA) supplementation and determinants of its use in pregnant Chinese women. METHODS: In this cross sectional study, questionnaires were used to collect information of participants and FA supplementation. Women were recruited between 6 and 12 weeks postpartum in Tianjin, China, between July 2015 and July 2016. RESULTS: A total of 1,921 women were recruited in the study. Approximately 93.1% of the study participants used FA, while 14.4% of the women taking FA from three months prior to preconception to three months post-conception. Women who took FA for three months prior to preconception through at least three months into their pregnancy were more likely to be between 30 and 34 years old (OR = 2.91, 95% CI: 1.15, 7.33), employed (OR = 2.07, 95% CI: 1.17, 3.67), primigravida (OR = 5.20, 95% CI: 3.02, 8.96), married to spouses with an intermediate education level (OR = 2.92, 95% CI: 1.45, 5.89), and earn a high family income (OR = 3.19, 95% CI: 1.57, 6.49). CONCLUSION: The prevalence of periconceptional FA intake was far below the requirements of the National Health and Family Planning Commission of China; therefore, knowledge of FA supplementation should be strengthened among women who are or planning to become pregnant. PMID- 29122095 TI - Night Sleep Duration and Risk of Cognitive Impairment in a Chinese Population: A Cross-sectional Study. AB - OBJECTIVE: Although sleep is one of the most important health-related behavioral factors, the association between night sleep duration and cognitive impairment has not been fully understood. A cross-sectional study was conducted with a random sample of 2,514 participants (? 40 years of age; 46.6% women) in China to examine the association between night sleep duration and cognitive impairment. METHODS: Night sleep duration was categorized as ? 5, 6, 7, 8, or ? 9 h per night. Cognitive function was measured using the Mini-Mental State Examination. A multivariate regression analysis was used to analyze the association of night sleep duration with cognitive impairment. A total of 122 participants were diagnosed with cognitive impairment. RESULTS: A U-shaped association between night sleep duration and cognitive impairment was found. The odds ratios (95% confidence intervals) of cognitive impairment (with 7 h of daily sleep being considered as the reference) for individuals reporting ? 5, 6, 8, and ? 9 h were 2.14 (1.20-3.83), 1.13 (0.67-1.89), 1.51 (0.82-2.79), and 5.37 (1.62-17.80), respectively (P ? 0.01). CONCLUSION: Short or long night sleep duration was an important sleep-related factor independently associated with cognitive impairment and may be a useful marker for increased risk of cognitive impairment.. PMID- 29122096 TI - Association between BMI and Dental Caries among School Children and Adolescents in Jiangsu Province, China. AB - Obesity and dental caries are increasing epidemics, especially among children and adolescents. This epidemiological observational cross-sectional study was conducted to assess the possible association between body mass index (BMI) and dental caries among 111,792 school children and adolescents in Jiangsu Province. We found that 13.14% participants of the study sample were overweight, and 7.37% were obese. The prevalence of dental caries was 12.95% in overweight and 7.89% in obese students. There were significant differences in caries prevalence by sex, region, age group, and BMI. Overweight and obesity statuses were associated with dental caries among the study population. BMI and dental caries present a continuous health problem. Thus, we recommend that oral health promotion be used for caries prevention and control. PMID- 29122097 TI - Potential Effects of Desalinated Seawater on Arteriosclerosis in Rats. AB - To evaluate the potential risk of arteriosclerosis caused by desalinated seawater, Wistar rats were provided desalinated seawater over a 1-year period, and blood samples were collected at 0, 90, 180, and 360 days. Blood calcium, magnesium, and arteriosclerosis-related indicators were investigated. Female rats treated with desalinated seawater for 180 days showed lower magnesium levels than the control rats (P < 0.05). The calcium and magnesium levels in female rats and the magnesium level in male rats were lower than the levels in the controls, following treatment with desalinated seawater for 360 days (P < 0.05). Blood levels of arteriosclerosis-related lipid peroxidation indicators and C-reactive protein (CRP) in the treatment group did not differ from those in the controls. The levels of lipid peroxidation indicators and CRP in rats were not significantly affected by drinking desalinated seawater, and no increase in risk of arteriosclerosis was observed. PMID- 29122098 TI - Contribution of 3CD Region to the Virulence of Enterovirus 71. AB - Enterovirus 71 is a neuroinvasive virus that is associated with severe neurological complications. We had earlier suggested that the replication capacity of a severe strain was higher than that of a mild strain. The recombinant 3CRV and 3CDRV virus strains were successfully rescued in our previous study. In the present study, we found no difference in virulence between 3CRV and severe strains. However, the capacity of replication and to cause cell injury of 3CDRV strain decreased in vitro, especially at 39.5 degrees C. Replacement of 3CD region in the severe strain led to milder symptoms, less body weight loss, and lower viral load in ICR mice. Histopathological findings indicated less severe injury in mice infected with 3CDRV strain. This study suggests that the 3CD region contributes to the attenuation of the severe strain, including its replication capacity and temperature sensitivity. PMID- 29122099 TI - A Genetic Susceptibility Study of Lung Cancer Risk Potentially Associated with Polycyclic Aromatic Hydrocarbon Inhalation Exposure. AB - To establish a genetic susceptibility assessment model of lung cancer risk potentially associated with polycyclic aromatic hydrocarbon (PAH) inhalation exposure among non-smokers in China, a total of 143 patients with lung adenocarcinoma and 143 cancer-free individuals were recruited. Sixty-eight genetic polymorphisms in 10 pathways related to PAH metabolism and tumorigenesis were selected and examined. It was observed that 3 genetic polymorphisms, along with 10 additional genetic polymorphisms via gene-gene interactions, significantly influenced lung cancer risk potentially associated with PAH inhalation exposure. Most polymorphisms were associated with PAH metabolism. According to the established genetic susceptibility score (GSS), lung cancer risk increased with a rise in the GSS level, thereby indicating a positive dose response relationship. PMID- 29122100 TI - Occupational Carbon Monoxide Poisoning Associated with Diesel Motor Operation in an Air-raid Shelter in June 2015, Jinan City, China-An Epidemiological Investigation. AB - Occupational carbon monoxide (CO) poisoning related to diesel motor fumes in an air-raid shelter (ARS) was first identified in Jinan City, China, in June 2015. A total of 17 cases were identified, including 14 possible cases of firemen and 3 confirmed cases of water channel clean-up workers. The overall attack rate (AR) of firemen was 42% (14/33). The firemen had a significantly higher AR with a longer exposure and more protracted time of rescue in the ARS (P < 0.05). All the cases stated that they did not realize the potentially high level of exposure to CO in the ARS. CO poisoning posed a risk to both patients and service providers. Occupational safety and health education should be promoted and enforced in all workplaces where CO sources exist. PMID- 29122101 TI - The Revival of the Doctor-Patient Relationship. PMID- 29122102 TI - Work-Time Distribution of Physicians at a German University Hospital. AB - BACKGROUND: The effective utilization of staff resources is of decisive importance for the adequate, appropriate, and economical delivery of hospital services. The goal of this study was to determine the distribution of working time among doctors in a German university hospital-in particular, in terms of type of activities and time of day. METHODS: The distribution of working time was determined from 14-day samples taken in seven clinical departments of the Medical Center-University of Freiburg. In each 14-day sample, the activities being carried out at multiple, randomly chosen times were recorded. RESULTS: A total of 250 doctors (participation rate: 83%) took part in the study. A total of 20 715 hours of working time was analyzed, representing twelve years of full-time employment. Overall, 46% of working time in the inpatient sector was spent in direct contact with patients, with relevant differences among the participating clinical departments: for instance, the percentage of time taken up by patient contact was 35% in pediatrics and 60% in oral and maxillofacial surgery. Patient contact was highest (over 50% overall) in the period 8 a.m. to 12 noon. CONCLUSION: The amount of working time taken up by activities other than direct patient contact was found to be lower than in previous studies. It remains unclear what distribution of working time is best for patient care and whether it would be possible or desirable to increase the time that doctors spend in direct contact with patients. PMID- 29122103 TI - Skeletal Hyperostosis as a Cause of Aspiration. PMID- 29122105 TI - Significant Data Available. PMID- 29122106 TI - In Reply. PMID- 29122104 TI - The Diagnosis of Chronic Coronary Heart Disease. AB - BACKGROUND: Chronic coronary heart disease (CHD) and acute myocardial infarction are endemic conditions. In Germany, an estimated 900 000 cardiac catheterizations were performed in the year 2014, and a percutaneous intervention was carried out in 40% of these procedures. It would be desirable to lessen the number of invasive diagnostic procedures while preserving the reliability of diagnosis. In this article, we present the updated recommendations of the German National Care Guideline for Chronic CHD with regard to diagnostic evaluation. METHODS: Updated recommendations for the diagnostic evaluation of chronic CHD were developed on the basis of existing guidelines and a systematic literature review and approved by a formal consensus process. RESULTS: 8-11% of patients with chest pain who present to a general practitioner and 20-25% of those who present to a cardiologist have chronic CHD. General practitioners should estimate the probability of CHD with the Marburg Heart Score. Specialists can use detailed tables for determining the pre-test probability of CHD; if this lies in the range of 15% to 85%, then non-invasive tests should be primarily used for evaluation and treatment planning. If the pretest probability is less than 15%, other potential causes should be ruled out first. If it is over 85%, the presence of CHD should be presumed and treatment planning should be initiated. Coronary angiography is needed only if therapeutic implications are expected (revascularization). Psychosocial risk factors for the development and course of CHD and the patient's quality of life should be regularly assessed as well. CONCLUSION: Non-invasive testing and invasive coronary angiography should be used only if their findings are expected to have therapeutic implications. Psychosocial risk factors, the quality of life, and adherence to treatment are important components of these patients' diagnostic evaluation and long-term care. PMID- 29122107 TI - Editorial. PMID- 29122109 TI - IDF Congress 2017: Scientific programme. PMID- 29122108 TI - Predictors of insulin uptake among adults with type 2 diabetes in the Stepping Up Study. AB - AIMS: We aimed to investigate predictors of insulin uptake, and change in insulin appraisals, among adults with type 2 diabetes mellitus (T2DM) who participated in the Stepping Up trial. METHODS: The Stepping Up model of care, supporting timely insulin initiation in primary care, was evaluated in a two-armed cluster randomised controlled trial. Participants were 266 adults (mean+/-SD age 62+/ 10years; 39% women) with T2DM (median (IQR) duration 8.5 (5, 13)years) from 74 primary care practices (Stepping Up intervention: 57%, control 43%). At 12months, 47% (n=126) had commenced insulin. Controlling for randomisation, logistic regression was used to explore baseline predictors of insulin uptake, including: demographic and clinical characteristics, emotional wellbeing (depressive symptoms and diabetes-related distress), insulin treatment appraisals, and, 'willingness' to initiate insulin. Two-way analysis of variance examined effects of, and interaction between, randomisation and insulin uptake on 12-month change in insulin appraisals. RESULTS: Participants using insulin at 12months were more likely (all p<0.05) than those with non-insulin-treated T2DM to report: lower socioeconomic status, higher baseline HbA1c (median difference: 0.3%; 3mmol/mol), greater willingness to commence insulin (very willing: 27% vs 12%), and less negative and more positive insulin appraisals. All contributed significantly to the final model (chi2(8)=92.1, p<0.001) except insulin appraisals. Regardless of trial allocation, those initiating insulin reported significantly greater reductions in negative insulin appraisals. CONCLUSIONS: Controlling for randomisation, 12-month insulin use was predicted by higher baseline HbA1c and 'willingness' to use insulin if recommended. Negative insulin appraisals reduced following insulin initiation. PMID- 29122110 TI - Survival from Prolonged Cardiac Arrest in the Wilderness. PMID- 29122111 TI - Temperature-sensitive Medications in Interfacility Transport: The Ice Pack Myth. AB - INTRODUCTION: Critical Care Transport teams use various strategies to maintain temperature sensitive drugs and equipment at optimal temperature. The purpose of this study was to examine the effectiveness of current passive refrigeration of temperature sensitive transport medications/equipment. METHODS: Initially, we performed a retrospective review of transport durations. Subsequently, an experimental paradigm was created using a temperature probe inside of the transport cooler packs utilizing various configurations and initial starting temperatures with high and low "in range" temperature margins of 8 degrees C (max) and 2 degrees C (min). RESULTS: The mean round-trip transport time was 2.5 hours and over 15% of transports last longer than 4 hours. At a starting temperature of -3.9 degrees C, the cooler and ice pack maintained "in range" temperatures for 3 hours. When the ice pack starting temperature was -12.9 degrees C, high temperatures excursions weren't experienced until 6 hours 55 minutes, but initially low excursions fell below for up to 3 hours. iSTAT(r) cartridges remained within range between 1-4 hours at cooler and ice pack starting temperature of -3.9 degrees C. CONCLUSION: The current system of passive refrigeration does not appear to be sufficient for safely storing medications or point-of-care testing equipment for our transport services. This might reveal a flaw in the existing practices around medication refrigeration in transport. PMID- 29122112 TI - Prehospital Transfusion for Gastrointestinal Bleeding. AB - OBJECTIVE: Gastrointestinal (GI) bleeding is a common medical emergency with significant morbidity and mortality. Many patients are coagulopathic, which may perpetuate bleeding. Remote damage control resuscitation, including early correction of coagulopathy and anemia, may benefit exsanguinating patients with GI bleeding. METHODS: We conducted a retrospective review of patients with acute GI bleeding who received packed red blood cells (pRBC) and/or plasma during transportation to our institution between 2010 and 2014. A comparison group of patients who were not transfused en route was selected, and demographics, outcomes, and response to resuscitation were compared. RESULTS: A total of 112 patients with GI bleeding received pRBC (82%, n = 92 pRBC, mean 1.7 +/- 0.9 units), plasma (62%, n = 69, mean 1.7 +/- 0.8 units) or both (44%, n = 49) en route. The comparison group comprised 49 patients transported by helicopter who were not transfused en-route. Demographics, crystalloid resuscitation, transfusion prior to transfer, rate of intervention, ICU days, length of stay, and mortality were similar between groups. Patients transfused en route had a significant increase in hemoglobin from 8.3 +/- 2.2 to 8.9 +/- 2.1 (P = .03) and decrease in INR from 2.0 +/- 1.0 to 1.6 +/- 1.4 (P = .01), whereas those not transfused en route experienced stable hemoglobin (8.7 +/- 2.8 to 9.4 +/- 2.5; P = .21) and INR values (1.9 +/- 1.0 to 1.6 +/- 1.4; P = .32). Both groups had a significant improvement in hemodynamic parameters with resuscitation. CONCLUSION: Prehospital damage control resuscitation with pRBC and/or plasma resulted in the improvement of hemodynamic instability, coagulopathy and anemia in patients with acute GI bleeding. Almost all patients required additional inpatient interventions and/or transfusions, suggesting that pre-hospital transfusion is being utilized for appropriately selected patients. PMID- 29122113 TI - Recognition and Treatment of Eclampsia on a Rural Scene Call: A Case Study of Coordinated Ground and Air Emergency Medical Services. PMID- 29122114 TI - Frequency and perforin expression of different lymphocyte subpopulations in patients with lower limb fracture and thoracic injury. AB - INTRODUCTION: Trauma with multiple injuries is associated with a high risk of complications, which may be related to excessive stimulation of inflammatory and anti-inflammatory responses. Although the effects of polytrauma on the immune response have been well established at the cellular and molecular levels, there is little information about the changes in the cytolytic potential of immunocompetent cells, including expression of cytotoxic molecules such as perforin. Therefore, the objective of the present study was to analyse and compare differences in the frequency and perforin expression of leukocyte subpopulations in the peripheral blood of patients with lower limb fracture, thoracic injury, and simultaneous lower limb fracture and thoracic injury. PATIENTS AND METHODS: Forty-five patients with trauma injury (15 patients with lower limb injury, 15 patients with thoracic injury, and 15 patients with simultaneous lower limb and thoracic injury) were included in the study. Peripheral blood of 15 sex- and age-matched healthy volunteers served as the control group. Peripheral blood samples were taken from all subjects included in the study and peripheral blood mononuclear cells were isolated by gradient centrifugation. The frequency of T lymphocytes, natural killer (NK) and NK T cells, and their subsets, as well as their perforin expression levels were simultaneously detected and analysed by flow cytometry. RESULTS: There was a statistically significant decrease in the frequency of T lymphocytes, NK and NK T cells as well as perforin expression in the patients with simultaneous lower limb and thoracic injury compared with the other two groups, with a predominantly marked decrease in NK and NK T cells. CONCLUSION: The decrease in the frequency and cytotoxic potential of peripheral blood lymphocytes is related to the severity of trauma injury, which can explain the underlying mechanism contributing to complication occurrence. PMID- 29122115 TI - Humeral shaft cerclage wiring: a safe technique to prevent radial nerve injury. AB - Humeral periprosthetic fractures are a challenging problem and their occurrence has increased, particularly over the last decade. The role of cerclage wires or cables in these fractures includes revisions with longer stems, and augmentation of a plate osteosynthesis in which the stem does not allow additional screw placement or structural bone grafts as supplementary fixation. These procedures are demanding because of the proximity of the radial nerve within the operating field. Placing a cerclage wire or cable around the fractured fragments offers a simple and safe procedure to avoid radial nerve injury or palsy in the treatment of complex humeral shaft fractures. This new technique is a simple and safe procedure to place a cerclage wire or cable around the humeral shaft. PMID- 29122116 TI - MIPO of proximal humerus fractures through an anterolateral acromial approach. Is the axillary nerve at risk? AB - PURPOSE: It is known that shoulder surgery may cause iatrogenic injury to the axillary nerve as a serious complication, but there is little evidence to indicate whether the axillary nerve is at risk of injury during an anterolateral acromial approach for minimally-invasive plate osteosynthesis (MIPO) of proximal humerus fractures. We hypothesised that this surgical method is safe for the axillary nerve and would preserve it from iatrogenic injury. MATERIALS AND METHODS: We conducted a prospective follow-up cohort study on 49 consecutive patients with proximal humerus fractures who were managed with MIPO through an anterolateral approach. All patients underwent standardised electroneurographic testing, with assessment of amplitudes of evoked compound muscle action potentials (CMAP) and distal motor latencies (DML) of the axillary nerves, pre- and post-operatively. Six weeks after injury, all patients underwent needle electromyographic (EMG) testing of anterior, middle, posterior deltoid, teres minor and paraspinal muscles for detecting abnormal muscle activity as a sign of acute denervation. After six months of physical rehabilitation, patients with axillary nerve injury underwent control electroneurographic testing to check the recovery of neurographic features (CMAP, DML). All nerve measurements were compared to reference values, and between right and left side. RESULTS: Five patients had a mild-to-moderate traumatic axillary nerve injury before surgery. There were no significant differences between amplitudes of CMAP (p = 0.575) and DML (p = 0.857) pre- and post-surgical procedure. CONCLUSIONS: These results confirmed safety of this surgical method in the preservation of axillary nerve from iatrogenic injury, but the course of the axillary nerve must be kept in mind. PMID- 29122117 TI - Plate versus intramedullary fixation of two-part and multifragmentary displaced midshaft clavicle fractures - a long-term analysis. AB - INTRODUCTION: Surgical fixation of displaced midshaft clavicle fractures is predominantly achieved with intramedullary (IM) or plate fixation. Both techniques have potential pitfalls: plate fixation involves greater periosteal stripping and protuberance of the implant, whereas IM fixation may be associated with implant-related complications, such as migration or skin irritation, which may lead to further surgery for implant removal. The aim of this study was to compare these two methods in simple (Robinson 2b.1) and multifragmentary (Robinson 2b.2) displaced midshaft clavicle fractures. METHODS: A total of 133 consecutive patients who underwent surgical fixation for a displaced midshaft clavicle fracture with either IM fixation using a 2.5-mm Kirschner wire or plate fixation using an 8-hole Dynamic Compression Plate (DCP) were retrospectively reviewed. Follow-up was a minimum of 1 year. The patients were allocated into two injury groups: displaced simple 2-part fractures (64 IM vs. 16 DCP) and displaced multifragmentary fractures (27 IM vs. 26 DCP). The major observed outcome measures were: infection rate, non-union rate, reoperation rate and postoperative range of motion (ROM). RESULTS: Rates of non-union for displaced 2-part fractures were 2/64 (3.13%) with IM fixation and 0/16 (0.00%) with plate fixation (p = 0.477). For displaced multifragmentary fractures, rates of non-union were 2/27 (7.41%) with IM fixation and 0/26 (0.00%) with plate fixation (p = 0.161). No significant difference was observed between the two fixation modalities in patient-reported time to regain ROM on the injured side for displaced 2-part fractures (p = 0.129) and displaced multifragmentary fractures (p = 0.070). Deep infection rate was zero (p = 1.000) overall in the study, and reoperation rate for IM and plate fixation, respectively, was 3.13% and 6.25% in the Robinson 2b.1 group (p = 0.559) and 7.41% and 7.69% in the Robinson 2b.2 group (p = 0.969). CONCLUSION: IM fixation of displaced midshaft clavicle fractures (Robinson 2b.1) has an equivalent non-union rate to plate fixation and similarly low complication and reoperation rates. For displaced midshaft multifragmentary clavicle fractures (Robinson 2b.2), the higher non-union rates observed with IM fixation leads us to recommend consideration of plate fixation for Robinson 2b.2 fractures. PMID- 29122118 TI - Safe intramedullary fixation of displaced midshaft clavicle fractures with 2.5mm Kirschner wires - technique description and a two-part versus multifragmentary fracture fixation outcome comparison. AB - INTRODUCTION: The aim of this study was to present a modified Murray and Schwarz 2.5-mm Kirschner wire (K-wire) intramedullary (IM) technique for fixation of displaced midshaft clavicle fractures (DMCF), and to compare the differences in treatment outcome of two-part (Robinson 2B.1) and multifragmentary (Robinson 2B.2) DMCF. METHODS: A retrospective analysis of 91 patients who underwent IM fixation with a 2.5-mm K-wire for DMCF and had a 1-year post-operative follow-up between 2000 and 2012 was performed. The patients were allocated into two groups: Robinson 2B.1 (n = 64) and Robinson 2B.2 (n = 27). Assessed outcomes were non union, reoperation rate, wire migration and infection. RESULTS: There was no statistically significant difference in the rate of non-union (2B.1,2B.2; 3.13%, 7.41%; p = 0.365), reoperation (2B.1, 2B.2; 3.13%, 7.41%; p = 0.365), K-wire migration (2B.1, 2B.2; 0.00%, 0.00%; p = 1.00) and clavicle shortening at 12 months (2B.1, 2B.2; 3.13%, 7.41%; p = 0.365). CONCLUSION: Intramedullary clavicle fixation with a 2.5-mm K-wire is a safe surgical technique. 2B.1 injuries treated with 2.5-mm IM K-wire fixation have relatively improved outcome compared with displaced 2B.2 fractures for both non-union and reoperation rates. There were no occurrences of implant migration with either 2B.1 or 2B.2 injuries, and a non significant difference in implant irritation was documented with IM K-fixation. The non-union rate with K-wire IM fixation of 2B.1 injuries concords with the published results of other IM devices and thus this technique should be added to the surgeon's armamentarium when considering surgical treatment of such injuries. PMID- 29122119 TI - Avoiding radial nerve palsy in proximal radius shaft plating - a cadaver study. AB - BACKGROUND: Opinions vary concerning the position of forearm rotation during detachment of the supinator in radial nerve palsy Henry's and Thompson's approaches. PURPOSE: To define the optimal forearm position for a safe detachment of the supinator during these approaches and to clarify their close relationship to the posterior interosseous nerve (PIN). METHODS: The study sample comprised 90 upper extremities of 45 human adult cadavers, embalmed using Thiel's method. After detection of the radial nerve in the interval between the brachialis and brachioradialis, its pathway was traced to the Arcade of Frohse (AF). Measurements involved the distance between the AFand the radial border of the distal biceps tendon (DBT) in pronation and supination, the interval between the AF and the radiocapitellar joint space (RCJS) in supination and the radial length (RL). RESULTS: Distances between the DBT and the AF were significantly shorter during pronation (right side: 14.1 +/- 3.4mm; left side: 13.5 +/- 3.2mm) compared with supination (right side: 20.5 +/- 3.6mm; left side: 19.8 +/- 3.5mm) for both right and left extremities. The mean interval between the AF and the centre of the RCJS was 25.2 +/- 5.9mm for the right side and 24.7 +/- 5.6mm for the left side, which correlated positively with the RL. CONCLUSION: These results indicate a safe detachment of the supinator from the radius with the forearm placed in supination during both Henry's and Thompson's approaches. PMID- 29122120 TI - Comparison of volar and dorsal plate osteosynthesis for radial shaft fractures: an anatomical pilot study. AB - BACKGROUND: No publication has yet described the interface between the radius and the plate in various positions. Neither clinical examination nor assessment of fracture radiographs provides information about the anatomy of the radius before injury. PURPOSE: We investigated radius anatomy to analyse dorsal and volar plate to-bone fit for radial shaft fracture management. METHODS: We examined 20 specimens from human adult cadavers. An 8-hole 3.5-mm titanium locking plate was used at three different positions on the dorsal and the volar side of the bone. The space between the well-positioned plate and the radial shaft was attained for each hole of the plate. RESULTS: The average space between the midshaft radial cortex and the plate holes for all positions was 0.69mm (range: 0.0mmto 2.38mm). The greatest mean distance between the plate and the radial cortex was measured at the volar mid-diaphyseal position of the plate with an average of 1.31mm. CONCLUSION: This incongruence between the radial cortex at the volar diaphysis and the plate should be considered when applying plates to this position of the radius. The results of this cadaver study indicate that radius plate osteosynthesis should preferably be done from the dorsal side. PMID- 29122121 TI - A biomechanical comparison of four fixed-angle dorsal plates in a finite element model of dorsally-unstable radius fracture. AB - PURPOSE: To compare the finite element models of two different composite radius fracture patterns, reduced and stabilised with four different fixed-angle dorsal plates during axial, dorsal and volar loading conditions. METHODS: Eight different plastic models representing four AO/ASIF type 23-A3 distal radius fractures and four AO/ASIF 23-C2 distal radius fractures were obtained and fixed each with 1 of 4 methods: a standard dorsal non-anatomical fixed angle T-plate (3.5mm Dorsal T-plate, Synthes), anatomical fixed-angle double plates (2.4mm LCP Dorsal Distal Radius, Synthes), anatomical fixed angle T-plate (2.4mm Acu-Loc Dorsal Plate, Acumed) or anatomical variable-angle dorsal T-plate (3.5mm, Dorsal Plate, Zrinski). Composite radius with plate and screws were scanned with a 3D optical scanner and later processed in Abaqus Software to generate the finite element model. All models were axially loaded at 3 points (centrally, volarly and dorsally) with 50 N forces to avoid the appearance of plastic deformations of the models. Total displacements at the end of the bone and the stresses in the bones and plates were determined and compared. RESULTS: Maximal von Mises stress in bone for 3-part fracture models was very similar to that in 2-part fracture models. The biggest difference between models and the largest displacements were seen during volar loading. The stresses in all models were the highest above the fracture gap. The best performance in all parameters tested was with the Zrinski plate and the most modest results were with the Synthes T-plate. CONCLUSION: There was no significant difference between 2-part (AO/ASIF type 23-A3) and 3 part (AO/ASIF 23-C2) fracture models. Maximal stresses in the plates appeared above the fracture gap; therefore, it is worth considering the development of plates without screw holes above the gap. PMID- 29122122 TI - Scaphoid screw placement under minimal radiation exposure. AB - BACKGROUND: Percutaneous scaphoid fixation through either a volar or dorsal approach has the advantage of minor soft tissue damage compared with ORIF, and faster fracture union compared with conservative treatment. However, this technique demands highly intraoperative reliance on X-ray control, including increased radiation exposure and all associated side effects. PURPOSE: To test the possibility and efficacy of volar percutaneous scaphoid screw placement under minimalradiation exposure. METHODS: The sample included 20 hands (seven left, 13 right) from human adult cadavers. For this study, the utilised wrists were assumed to have non-displaced scaphoid fractures. Using a percutaneous approach, a 2-mm Kirschner wire (K-wire) was advanced to the distal pole of the scaphoid and placed in a 45 degrees horizontal and vertical angle under monitoring with the C-arm. The K-wire was inserted blindly alongside the estimated length of the scaphoid. Following K-wire insertion, four X-rays were taken to depict K-wire positioning and to assess positioning alongside the axis of the scaphoid and K wire protrusion. The rating scale comprised 1 (good), 2 (moderate) or 3 (poor). RESULTS: All tested radiographic views were evaluated with a median of 2 points (moderate position) regardingplacement alongside the scaphoid axis. CONCLUSION: Our results indicate that percutaneous scaphoid fixation with the guide wire placed in a 45 degrees horizontal and vertical angle enables primary moderate positioning, which may lead to quicker adjustment to the ideal position and a decrease of radiation exposure. PMID- 29122123 TI - General versus spinal anaesthesia in proximal femoral fracture surgery - treatment outcomes. AB - BACKGROUND: Proximal femoral fractures are a major public health problem because of the increasing proportion of elderly individuals in the general population. The mode of choice for anaesthesia in surgical treatment of these fractures is still debated in terms of better postoperative outcome. The aim of our study was to compare the effect of general over spinal anaesthesia on mortality in proximal femoral fracture surgery. PATIENTS AND METHODS: This study was a retrospective analysis of 115 patients aged at least 70 years who underwent surgery for proximal femoral fracture. The survey was conducted from 1 January to 31 December 2015 at the General Hospital Karlovac, Croatia. Patients were divided into two groups: group 1 - general anaesthesia and group 2 - spinal anaesthesia. The primary outcome measure was the effect of mode of anaesthesia, general versus spinal, on mortality within 30 days, six months and one year after surgery. RESULTS: General anaesthesia (EndoTracheal Anaesthesia) was administered in 77 patients (67%; group I - ETA) and spinal anaesthesia in 38 patients (33%; group 2 - SPIN). Both groups had more female than male patients: 69 patients (89.6%) in the ETA group and 32 patients (84.2%) in the SPIN group were female. The mean age in the ETA group was 82.91 years and in the SPIN group was 80.18 years. ASA II status was more common in patients in the SPIN group (25 patients [65.8%]). The average time from hospitalisation to surgery was 53.44 hours in the ETA group and 53.33 hours in the SPIN group. There was no significant difference between groups in the number of comorbidities, or intraoperative and postoperative complications. There was no statistically significant difference in mortality between the groups. Mortality after surgery in the ETA and SPIN groups, respectively, was as follows: 10.4% and 10.5% at 30 days, 23.4% and 15.8% at six months, and 32.5% and 31.6% at one year. CONCLUSION: The results indicate that the mode of anaesthesia (general vs spinal) has no effect on postoperative mortality, and that the mode of anaesthesia should be applied on an individual basis in correlation with associated comorbidities. PMID- 29122124 TI - Anatomical and radiological evaluation of less invasive stabilisation system (LISS) in correlation with knee lateral collateral ligament insertion. AB - INTRODUCTION: The Less Invasive Stabilisation System (LISS) is an angle-stable plate that enables treatment of distal femoral comminuted and periprosthetic fracture. As it is placed through a minimally-invasive lateral approach, lateral knee pain is a commonly described symptom after its application. This study investigates knee lateral collateral ligament (LCL) iatrogenic injury during LISS plate fixation. A cadaver study was performed and a retrospective radiological investigation with the analysis of its clinical application was conducted to evaluate possible knee LCL damage. METHODS: The cadaver study included 13 human lower extremities, treated with LISS. After application, lateral knee side was dissected, implants were removed and distances between the drill holes and LCL origin were measured. In the retrospective radiological evaluation, postoperative X-rays for patients treated with distal femoral LISS plate in the University Hospital Regensburg, Germany from January 2010 to December 2015 were examined. Following a protocol described by Pietrini et al., the LCL origin on postoperative X-rays was calculated, both in lateral and anterior-posterior (AP) view, and distances between the plate and its closest locking screw to the LCL origin were measured. RESULTS: In the cadaver study, the mean distance between the closest drilling hole and the ligament origin was 14.0mm (range 9-21mm; SD 3.8mm). Twenty-two patients matched the inclusion criteria for the retrospective radiological study. In lateral view, the mean distance between the origin and the closest locking screw was 6.3mm (range 0-16.4mm; SD 4.7mm); the mean distance between the origin and the plate was 3.1mm (range 0-13.9mm; SD 4.1mm). In AP view, the mean distance between LCL origin and the nearest screw was 2.4mm (range 0-7.6mm; SD 2.4mm). The mean distance between the origin and the most distal locking screw was 9.2mm (range 0-17.5mm; SD 4.0mm). DISCUSSION: The LISS is a safe option to treat distal femoral fractures in respect to the LCL. Due to close proximity, the LCL might be harmed; therefore, lateral knee pain or lateral instability after implantation should be assessed in further treatment. PMID- 29122125 TI - Tibial plateau fracture management: arthroscopically-assisted versus ORIF procedure - clinical and radiological comparison. AB - INTRODUCTION: Tibial plateau fractures are articular injuries that may influence final functional outcome of the knee. Although these fractures comprise only 1% of all fractures, the fracture pattern is usually complex and requires anatomical reduction and absolutely stable fixation to achieve satisfactory results. The development of knee osteoarthritis is a common late complication and it can be strongly influenced by additional, underestimated cartilage defects, and meniscal and ligament tears. MATERIALS AND METHODS: Between January 2012 and February 2015, a total of 78 patients with tibial plateau fractures (Schatzker type I-III) were enrolled in the study. Patients were divided into two groups: one group was treated with arthroscopically-assisted reduction and internal fixation (ARIF) and the other with open reduction and internal fixation (ORIF). The final number of patients was 75; 40 in the ARIF group and 35 in the ORIF group. Radiography and computed tomography were used to assess fracture pattern. An immediate postoperative radiograph was performed, and then repeated at 6 weeks, and 3,6 and 12 months after surgery. Demographic data (age and sex), additional intraarticular injuries, hospital stay and complications were noted, and clinical and radiological Rasmunssen score at 3, 6 and 12 months after surgery were evaluated. RESULTS: Additional intraarticular lesions were found in 27 patients; 20 in the ARIF group and 7 in the ORIF group (p = 0.06). There was a statistically significant difference in average duration of hospital stay: 3.10 +/- 0.63 days for the ARIF group and 5.51 +/- 1.66 days for the ORIF group (p = 0.0001). All fractures healed within 3 months following surgery. The overall complication rate was 12%. There was no statistically significant difference in complication rate between the two groups (p = 0.63). Clinical and radiological scores were excellent in most patients in both groups. There was no statistically significant difference in average clinical and radiological Rasmunssen scores between the two groups. CONCLUSIONS: Both ARIF and ORIF can provide equally good results; however, ARIF seems to offer a more precise evaluation and treatment of associated intraarticular lesions and to reduce the duration of hospital stay. PMID- 29122126 TI - Posterior fragment in ankle fractures: anteroposterior vs posteroanterior fixation. AB - INTRODUCTION: The aim of this study was to compare reduction quality and functional outcome of posterior malleolus fractures treated with indirect reduction and anteroposterior (AP) fixation or with direct reduction via a posterolateral approach and posteroanterior (PA) fixation. METHODS: Forty-eight patients with trimalleolar fracture were enrolled in the study. Patients were randomised in two groups: indirect reduction and AP fixation (AP group) and direct reduction and PA fixation (PA group). Inclusion criteria were: posterior fragment involving more than 25% of the articular surface, displacement over 2mm and ankle instability. The quality of reduction was evaluated using postoperative plain radiographs. Residual displacement of the posterior fragment, articular step-off and/or articular surface gap were analysed. The reduction was considered excellent (<1mm), good (1-2mm) or poor (>2mm). Range of motion (ROM) was measured bilaterally, and the difference in dorsiflexion between the injured and uninjured side was considered as dorsiflexion restriction. Demographic data (age, sex), type of fracture (AO/ASIF classification) and complications were noted. RESULTS: Forty-six patients completed all follow-up examinations. There was no statistically significant difference in age (p = 0.41), sex (p = 0.29) or specific type of fracture (p = 0.83) distribution between the AP and PA groups. All fractures completely healed within 3 months. The overall complication rate was 8.7%. There was no statistically significant difference in complication rate between the two groups (p = 0.71). Radiological evaluation of the ankle showed there was significantly better quality of reduction with direct reduction via a posterolateral approach in the PA group. Excellent reduction was achieved in 79.2% and 45.5% of the PA and AP groups, respectively. The quality of reduction was significantly higher in the PA group compared with the AP group (p = 0.04). The mean restriction of dorsiflexion was lower in the PA group (5.96 +/- 0.65 degrees ) compared with the AP group (6.45 +/- 1.06 degrees ), but this difference did not reach statistical significance (p = 0.07). CONCLUSIONS: The direct reduction technique via a posterolateral approach and PA fixation enables higher quality of reduction and better functional outcome in the management of the posterior fragment compared with indirect reduction and percutaneous AP fixation. PMID- 29122127 TI - Fluoroscopic iliosacral screw placement made safe. AB - AIM: Unstable posterior pelvic ring injuries should be stabilised successfully by percutaneous iliosacral screwing. The intervention takes place under intraoperative fluoroscopic guidance. The inlet and outlet views are crucial and are performed by tilting the image intensifier. Safely interpreting fluoroscopic views can be challenging in certain clinical scenarios. We demonstrated on a series of patients howpreoperative CT scans can be used to anticipate the appropriate intraoperative inlet and outlet fluoroscopic views and positioning of the patient on the operating table, thereby avoiding possible operating table obstacles. MATERIALS AND METHODS: We analysed at random 30 pelvic CT scans from patients of different ages and both sexes, utilising the sagittal reconstructions. Inlet and outlet angle measurements were calculated on the scans to determine the appropriate intraoperative inlet and outlet views. RESULTS: The analysed CT scans showed an average inlet view of 22.3 degrees (range 10.4 degrees -39.8 degrees ) and an average outlet view of 42.3 degrees (range 31.5 degrees -53.1 degrees ). Sex and age had no influence on results. The calculated required free space under the operating table for unobstructed tilting of the C arm was a minimum of 145cm. CONCLUSION: The significant anatomic variations of the posterior pelvic ring have been well documented in the literature. The angles required to obtain appropriate intraoperative inlet and outlet views are not perpendicular and differ greatly from traditional settings, which directed the beam 45 degrees caudally and 45 degrees cranially. The fluoroscopic beam would need to be angled differently in each patient to obtain ideal cardinal views that ultimately assist in safe iliosacral screw placement. To avoid collision of the C arm with the operating table, it is essential to provide secure free space under the operating table of at least 145cm. PMID- 29122128 TI - Carbon-Fibre-Reinforced PEEK radiolucent intramedullary nail for humeral shaft fracture fixation: technical features and a pilot clinical study. AB - PURPOSE: This prospective pilot study investigated the safety and efficacy of a novel radiolucent intramedullary nail (IMN) made of Carbon-Fibre-Reinforced Polyaryl-Ether-Ether-Ketone (CFR-PEEK) for humeral shaft fracture fixation. STUDY DESIGN: A prospective, single-arm, four-centre study. PATIENTS AND METHODS: A total of 46 patients with 46 humeral fractures classified as 12 A-B were treated with a novel CFR-PEEK IMN and followed for 12 months. RESULTS: Most of the patients (65%) were female; the mean age was 65 +/- 17 years. The average operating time was 66.75 +/- 19.84 minutes and X-ray exposure was 104.11 +/- 98.01 seconds. All patients postoperatively reported selflimiting shoulder pain and three patients developed iatrogenic transient radial palsy. Two patients required repositioning of the implant. No implant-related complications were observed. Radiological consolidation was achieved in all 43 patients who completed the 12-month follow-up. CONCLUSIONS: The CFR-PEEK IMN is user-friendly and safe. Its bone-matching elastic modulus seems to contribute to its clinical efficacy. This, together with compatibility with modern imaging techniques, can be considered a further evolution of IMN designed to stabilise humeral shaft fractures. PMID- 29122129 TI - A New Algorithm for Crossing Chronic Total Occlusions From the Asia Pacific Chronic Total Occlusion Club. AB - Although the hybrid chronic total occlusion (CTO) algorithm had many excellent recommendations, there has been infrequent adoption in the Asia Pacific region. The Asia Pacific CTO club propose an algorithm for case selection based on the Japan-CTO score and a new CTO algorithm, which is applicable globally. This algorithm allows for differing skill sets and equipment availability and contains practical teaching for CTO percutaneous coronary intervention. Similar to the hybrid algorithm there are 3 main questions that determine whether the primary approach is antegrade or retrograde: 1) is there proximal cap ambiguity; 2) is the distal vessel of poor quality; and 3) are there interventional collaterals present. In contrast to the hybrid algorithm occlusion length alone does not determine the choice of either a wire escalation strategy or a dissection re entry strategy. Rather a combination of factors including ambiguity of the vessel course, severe calcification, tortuosity, length, and previous failure are used to determine this. The role of intravascular ultrasound-guided entry to overcome proximal cap ambiguity and the CrossBoss catheter in occlusive in-stent restenosis are highlighted in the algorithm. Both the parallel wire technique and dissection re-entry with the Stingray system have been included as options when the initial antegrade wire passage fails. Intravascular ultrasound-guided wiring along with limited subintimal tracking and re-entry are included as final options in the algorithm. Finally, the algorithm incorporates guidance on when to stop the procedure. It is hoped that this algorithm will serve as the basis for future CTO percutaneous coronary intervention proctoring and training. PMID- 29122131 TI - CTO PCI in Patients With Diabetes Mellitus: Sweet Perspectives. PMID- 29122130 TI - Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention in Patients With Diabetes: Insights From the OPEN CTO Registry. AB - OBJECTIVES: Few studies have evaluated the relationship of diabetes with technical success and periprocedural complications, and no studies have compared patient-reported health status after chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in patients with and without diabetes. BACKGROUND: CTOs are more common in patients with diabetes, yet CTO PCI is less often attempted in patients with diabetes than in patients without. The association between diabetes and health status after CTO PCI is unknown. METHODS: In the 12 center OPEN-CTO PCI registry (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Registry), patients with and without diabetes were assessed for technical success, periprocedural complications, and health status over 1 year following CTO PCI using the Seattle Angina Questionnaire and the Rose Dyspnea Scale. Hierarchical modified Poisson regression was used to examine the independent association between diabetes and technical success, and hierarchical multivariable linear regression was used to assess the association between diabetes and follow-up health status. RESULTS: Diabetes was common (41.2%) and associated with a lower crude rate of technical success (83.5% vs. 88.1%; p = 0.04). After adjustment, there was no significant difference between diabetic and nondiabetic patients (relative risk: 0.96, 95% confidence interval: 0.91 to 1.01). There were no significant differences in complication rates between patients with and without diabetes. Angina burden, quality of life, and overall health status scores were similar between diabetic and nondiabetic patients over 1 year. CONCLUSIONS: Although technical success was lower in patients with diabetes, this reflected lower success among patients with prior bypass surgery, without any significant difference in success rate after adjusting for prior bypass and disease complexity. CTO PCI complication rates are similar in diabetic and nondiabetic patients, and symptom improvement following CTO PCI is robust and of a similar magnitude regardless of diabetes status. PMID- 29122132 TI - Clinical Endpoints and Key Data Elements in Percutaneous Coronary Intervention of Coronary Chronic Total Occlusion Studies: A Call to the Academic Research Consortium for Standardized Definitions. PMID- 29122134 TI - Left Atrial Appendage Closure: Continuous Progress With Remaining Challenges. PMID- 29122133 TI - Percutaneous Left Atrial Appendage Closure With the LAmbre Device for Stroke Prevention in Atrial Fibrillation: A Prospective, Multicenter Clinical Study. AB - OBJECTIVES: The authors sought to assess the clinical outcomes of left atrial appendage (LAA) closure with the LAmbre closure system in patients with nonvalvular atrial fibrillation (NVAF). BACKGROUND: Over 90% of thrombi are located in the LAA in NVAF patients. METHODS: A prospective, multicenter study was conducted in 153 NVAF patients with CHADS2 score >=1. RESULTS: The LAA was successfully occluded in 152 patients. Serious complications occurred in 5 patients. During the 12-month follow-up, ischemic stroke occurred in 2 patients, 1 patient had incomplete LAA sealing, and there was no device embolization. CONCLUSIONS: LAA closure with the LAmbre device shows encouraging results for stroke prevention. PMID- 29122135 TI - Transseptal Puncture Through Amplatzer Atrial Septal Occluder for Left Atrial Appendage Closure. PMID- 29122136 TI - Transcatheter Closure of Perimembranous Ventricular Septal Defects With Amplatzer Duct Occluders. PMID- 29122137 TI - Transcatheter Patent Foramen Ovale Closure After Cryptogenic Stroke: An Updated Meta-Analysis of Randomized Trials. PMID- 29122138 TI - CTO-Chronic Total Occlusions and Continuous Training Opportunity. PMID- 29122139 TI - Role of Exercise Testing in Hypertrophic Cardiomyopathy. AB - Over the last 25 years, patients with hypertrophic cardiomyopathy (HCM) have been studied with a variety of methods employing physiological exercise that have made major contributions to disease management and are performed without increased risk. Previously under-utilized in HCM, exercise (stress) echocardiography has become incorporated into the standard clinical assessment and diagnostic armamentarium of HCM using upright or supine symptom-limited treadmill or bicycle modalities. In patients without outflow gradients at rest, exercise echocardiography is the most appropriate method for provoking obstruction, with the capability of predicting future development of progressive heart failure symptoms, and differentiating patients with provocable obstruction from those without obstruction, with major implications for dictating treatment options, that is, surgical myectomy (alternatively, alcohol septal ablation) versus heart transplant. Reduced myocardial oxygen consumption with metabolic (cardiopulmonary) exercise testing provides an independent and quantitative assessment of functional limitation for individual patients when the personal history is ambiguous, and also guides eligibility for heart transplant. Hypotensive blood pressure response to exercise can be an arbitrator in risk stratification decisions. Exercise testing with a variety of methods has become an integral and powerful component of the noninvasive evaluation of HCM, and in some patients can determine treatment strategy. PMID- 29122140 TI - Cardiac Tissue Characterization and Imaging in Autoimmune Rheumatic Diseases. AB - Inflammation, microvascular and macrovascular ischemia, valvular disease, and fibrosis are the main causes of cardiovascular disease (CVD) in autoimmune rheumatic diseases (ARDs). The silent presentation and the high mortality and/or morbidity of CVD in ARDs necessitate a reliable tool for early diagnosis. Noninvasive cardiovascular imaging, including echocardiography, nuclear imaging, cardiovascular computed tomography (CT), cardiac magnetic resonance (CMR), and hybrid imaging modalities, constitutes the main tool for monitoring of CVD in ARDs. Echocardiography is the cornerstone for CVD evaluation, but it is operator dependent and cannot perform tissue characterization. Nuclear imaging and CT, although promising, have the disadvantage of ionizing radiation. CMR can assess inflammation, ischemia, and fibrosis without ionizing radiation, thus making it a necessary adjunct, which is especially relevant for ARDs with new-onset heart failure, conflicting data from other imaging modalities, and recent onset of chest pain and/or arrhythmias. Recently, hybrid imaging with positron emission tomography (PET)/CT and PET/CMR has shown promise in ARDs, although these modalities currently have prohibitive costs. PMID- 29122142 TI - Correction. PMID- 29122141 TI - ECV for Patients With Aortic Stenosis: Which Patient Will Benefit? PMID- 29122143 TI - Correction. PMID- 29122144 TI - Exercise as antidepressant treatment: Time for the transition from trials to clinic? AB - The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 29122145 TI - Exercise effects on depression: Possible neural mechanisms. AB - Depression is a syndrome of stress- and emotion-dysregulation, involving compromised structural integrity of frontal-limbic networks. Meta-analytic evidence indicates that volumetric reductions in the hippocampus, anterior cingulate cortex, prefrontal cortex, striatum, and amygdala, as well as compromised white matter integrity are frequently observed in depressed adults. Exercise has shown promise as an effective treatment for depression, but few studies have attempted to characterize or identify the neural mechanisms of these effects. In this review, we examined the overlap between structural brain abnormalities in depression and the effects of exercise on brain structure in adults, to highlight possible neural mechanisms that may mediate the positive effects of exercise on depressive symptoms. The prefrontal cortex, anterior cingulate cortex, hippocampus, and corpus callosum emerged as structural neural markers that may serve as targets for exercise-based treatments for depression. These findings highlight the need for randomized exercise interventions to test these proposed neurobiological mechanisms of exercise on depression. PMID- 29122146 TI - Physical activity correlates in people with anxiety: Data from 46 low- and middle income countries. AB - OBJECTIVE: There is a lack of nationally-representative data on the correlates of physical activity (PA) among people with anxiety symptoms. Thus, we investigated PA correlates among community-dwelling adults with anxiety symptoms in 46 low- and middle-income countries (LMICs) using predominantly nationally-representative data. METHOD: Cross-sectional data from the World Health Survey were analysed. PA was assessed by the International Physical Activity Questionnaire (IPAQ) and participants were dichotomised into those that do (>=150min moderate-vigorous PA) and do not (<150min) meet recommended PA weekly targets. Multivariable logistic regression was used to assess the correlates. RESULTS: The analysis included 24,850 people with anxiety symptoms (43.3+/-16.6years; 39.7% males). The prevalence of low PA was 33.1% (95%CI=31.6%-34.6%). Older age [e.g., OR=4.57 for age>=65 vs. 18-24years], not married/cohabiting (vs. married/cohabiting OR=1.36), being in the richest quintile (vs. poorest OR=1.41), unemployed (vs. employed OR=2.18), inadequate vegetable consumption (vs. adequate OR=1.66), and poor sleep/energy, worse cognition, pain/discomfort and mobility difficulties were all significant correlates of low PA. CONCLUSIONS: PA is associated with a range of factors among people with anxiety symptoms. Future interventions might target the identified correlates in order to facilitate people with anxiety to be more physically active. PMID- 29122147 TI - Physical activity and psychosocial function following cardiac rehabilitation: One year follow-up of the ENHANCED study. AB - OBJECTIVE: To examine the long-term association between physical activity (PA) and psychosocial functioning following completion of cardiac rehabilitation (CR) among participants in the ENHANCED study. METHOD: ENHANCED was a 3-month clinical trial examining standard CR with and without stress management training (SMT). Participants completed the Leisure-Time Exercise Questionnaire (LTEQ), Beck Depression Inventory-II (BDI-II), and the Spielberger State-Trait Anxiety Inventory (STAI) at baseline, 3- and 12-months after randomization. Prospective associations between physical activity and psychosocial function, as well as treatment group differences, were examined using repeated measures mixed modeling. RESULTS: One hundred nineteen participants were available at 12month follow-up. During the 12-month follow-up, PA remained higher compared to baseline (P<0.001), with the majority of participants reporting that they engaged in PA on a regular basis. Depressive and anxious symptoms continued to remain lower than baseline (Ps<0.001) Higher levels of PA at 12-month follow-up were associated with lower depressive (P=0.032) and anxious (P=0.003) symptoms. CONCLUSIONS: Higher physical activity levels following CR are associated with lower depressive and anxious symptoms. Encouraging patients to sustain higher levels of PA may promote both cardiovascular and mental health. PMID- 29122149 TI - Direct and indirect effects of exercise on posttraumatic stress disorder symptoms: A longitudinal study. AB - OBJECTIVE: Emerging evidence suggests that exercise may have beneficial effects on posttraumatic stress disorder (PTSD), and that this relationship may be indirectly affected by sleep, pain, and alcohol/substance use. The present study examined the longitudinal direct and indirect effects of exercise on PTSD symptoms. METHOD: A national sample of 182 individuals, screening positive for PTSD, completed online assessments of PTSD symptoms, exercise behavior, psychological distress, sleep quality, and alcohol/substance use at baseline and three-month follow-up. RESULTS: There were direct effects of strenuous intensity exercise on avoidance/numbing (b=-2.18, SE=1.12, p=0.05) and hyperarousal symptoms (b=-1.87, SE=0.82, p=0.03); and direct effects of total exercise on avoidance/numbing symptoms (b=-1.76, SE=0.94, p=0.05). Strenuous intensity exercise was indirectly associated with total PTSD symptoms (ab=-2.53, 95% CI: 5.72 to -0.38), avoidance/numbing (ab=-0.99, 95% CI: -2.43 to -0.05), and hyperarousal symptoms (ab=-0.78, 95% CI: -1.88 to -0.07) through sleep, while total exercise was indirectly associated with total PTSD symptoms through alcohol use (ab=0.32, 95% CI: 0.18-1.42). CONCLUSION: Findings suggest that exercise has a complex, longitudinal, and beneficial association with PTSD symptoms. Future studies should continue to examine this relationship and any direct and indirect effects exercise may have on PTSD and its related conditions. PMID- 29122148 TI - A pilot randomized controlled trial of aerobic exercise as an adjunct to OCD treatment. AB - OBJECTIVE: The purpose of the current study was to conduct a randomized controlled trial testing the efficacy of aerobic exercise for decreasing OCD symptom severity, other mental health outcomes, and increasing exercise behaviors and cardiorespiratory fitness among individuals with OCD. METHOD: Fifty-six patients (64% female; mean age=38.8years) with OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of 16 or greater despite engaging in OCD treatment were randomized to 12-weeks of supervised plus home-based moderate intensity aerobic exercise (AE; n=28) or to 12-weeks of health education sessions (HE; n=28). RESULTS: Random intercepts mixed models examined differences between conditions at post-treatment. Though no difference between conditions on outcomes was observed, both AE and HE showed significant reduction in OCD symptom severity, depression and anxiety at post-treatment. Relative to HE, significant increases were noted in amount of exercise and cardiorespiratory fitness for those in the AE condition. At post-treatment, 30.4% of the AE condition (7 of 23) were treatment-responders (using the commonly accepted measure of 35% symptom reduction from baseline). In the HE condition, 7.7% of the sample (2 of 26) met this criterion at post-treatment. CONCLUSION: The results of this preliminary study suggest that exercise and health-focused interventions may be beneficial adjuncts to existing OCD treatment. Future studies with larger samples are needed to more definitively answer questions the efficacy of AE for reducing OCD symptoms and improving related clinical outcomes. PMID- 29122150 TI - Moving Towards Wellness: Physical activity practices, perspectives, and preferences of users of outpatient mental health service. AB - OBJECTIVE: This study assessed the beliefs, barriers and preferences for physical activity (PA) among users of outpatient mental health (MH) services. Outpatient discussions with MH providers were also evaluated. METHOD: Between September December 2014, patient advisors approached adult and family members in an academic MH clinic's waiting room on high volume patient visit days during peak clinic hours; 83% participated in the survey. Analyses were restricted to MH services users (n=295). RESULTS: Fully 84% of respondents reported a link between PA and their mood or anxiety level and 85% wanted to be more active. Less than half currently met US PA guidelines (>=150min/week). Most (52%) reported their mood limited their involvement in PA. Only 37% reported their MH providers regularly discussed PA with them. Beliefs about the benefits of physical activity (p<0.0001), mood limiting their ability to be physically active (p=0.03), and wanting to be more physically active (p=0.02) were significant predictors of PA (min/week) in the multivariate linear regression model. CONCLUSIONS: Most MH outpatients may need and want assistance in increasing PA. Patient-centered research could inform the development of PA programs in MH settings. PMID- 29122151 TI - Biologic Therapy for Atopic Dermatitis: Moving Beyond the Practice Parameter and Guidelines. AB - Atopic dermatitis (AD), a common chronic pruritic inflammatory skin disease, impacts the quality of life of patients and caregivers and has become a global health problem. It is increasingly recognized as a disease not only of children but also of adults who may have a persistent or relapsing course from childhood or who develop new-onset adult disease. Besides well-established atopic comorbidities, associations with a number of nonatopic comorbidities have been reported. AD is characterized by both immune dysregulation and epidermal barrier dysfunction. The findings that nonlesional skin in AD has both terminal keratinocyte differentiation defects and immune abnormalities as well as multiple markers of immune and inflammatory activation in the circulation point to the systemic nature of the disease and have important translational implications. Although AD is predominantly associated with type 2 immune responses, activation of other cytokine pathways including TH1, TH22, and TH17/IL-23 has been reported, suggesting potential therapeutic targets and provide a rationale for treatment with novel biologics. Dupilumab, a fully human mAb targeting the IL-4 Ralpha subunit, blocks signaling of both IL-4 and IL-13 and is the first biologic to be approved for the treatment of moderate-to-severe AD in adult patients. Other biologics in current trials for AD are targeting the IL-31 receptor, IL-13, and the common p40 subunit of IL-12/IL-23. PMID- 29122153 TI - Are Biotherapeutics Revolutionizing Treatment of "Allergic" Diseases? PMID- 29122154 TI - Feeling Burned Out? Half of Us Are: The Urgent Need to Address Provider Health and Wellness in Allergy and Immunology. PMID- 29122152 TI - Biologic Agents for the Treatment of Hypereosinophilic Syndromes. AB - Hypereosinophilic syndromes (HES) are a heterogeneous group of rare disorders defined by the presence of marked peripheral or tissue eosinophilia resulting in end-organ damage. Although conventional therapies, including glucocorticoids, hydroxyurea, and IFN-alpha, are initially effective in reducing eosinophilia and symptoms in a majority of patients with platelet-derived growth factor mutation negative HES, the development of resistance and treatment-related toxicity are common. In contrast, targeted therapy with the tyrosine kinase inhibitor, imatinib, is well tolerated but effective only in the subset of patients with HES with a primary myeloid disorder. Eosinophil-targeted biotherapeutics offer the potential of improved efficacy with few, if any, adverse effects. The aims of this review are to provide an overview of current approaches to the use of conventional HES therapies and a discussion of existing biotherapeutics that target eosinophils and their potential use in the treatment of HES. With the continuing expansion of eosinophil-targeted biotherapeutics, the future for patients with eosinophilic disorders is promising. PMID- 29122155 TI - Rituximab Hypersensitivity: Evaluation, Desensitization, and Potential Mechanisms. AB - BACKGROUND: Rituximab (Rituxan) hypersensitivity (RITS) can be severe and limits the ability to further administer the treatment. Understanding its pattern and desensitization may permit administration in difficult cases. OBJECTIVE: Analyze RITS patient characteristics, hypersensitivity pattern, and desensitization outcomes to optimize management. METHODS: Twenty-five patients with RITS were referred to the Allergy/Immunology Unit at Massachusetts General Hospital over 5 1/2 years. Their clinical reaction patterns were analyzed. Drug desensitizations were performed using 3 related continuous intravenous protocols that were chosen on the basis of clinical history, skin test reactivity, and the patient's previous desensitization outcomes. RESULTS: Of the 25 referred patients, 23 had lymphoma of various types. The 25 patients underwent 170 continuous intravenous desensitizations based on 3 related protocols, with most based on the intermediate protocol. All but 2 desensitizations were completed successfully. Overall 24% of the desensitizations were complicated by hypersensitivity reactions. Two patients with serum sickness and a patient with mast cell disorder were also successfully managed. The average hypersensitivity reaction grade was 3.0 (2-4) before desensitization and 0.41 with desensitization. Skin tests were performed in 18 patients, with 5 patients positive initially and 2 more converted from negative to positive. Skin test status was not helpful for risk stratification for hypersensitivity reactions. Tryptase level was elevated during 21% of desensitizations with reactions but rare among asymptomatic desensitizations. CONCLUSIONS: Nearly all patients with severe sensitivity to rituximab can be successfully desensitized. IgE-mediated mechanism and mast cell degranulation, in addition to cytokine release syndrome and tumor lysis syndrome, may contribute to a significant portion of hypersensitivity reactions among patients with RITS. PMID- 29122157 TI - Nasal Polyps and Biomarkers. PMID- 29122156 TI - Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma. AB - BACKGROUND: In placebo-controlled trials, reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. OBJECTIVE: This open label extension study evaluated safety and efficacy of reslizumab for up to 24 months. METHODS: After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. RESULTS: In the open-label extension, 1,051 patients received >=1 reslizumab dose (480 reslizumab-naive, 571 reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in reslizumab-naive and reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo controlled studies, was >=12 months for 740 patients and >=24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; reslizumab-naive patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after reslizumab discontinuation. CONCLUSIONS: In patients with moderate-to-severe eosinophilic asthma, intravenous reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies. PMID- 29122158 TI - Diagnosis of Allergic Bronchopulmonary Aspergillosis Exacerbations. PMID- 29122159 TI - Opioid Analgesic Drugs: Misuse, Toxicity, and Hypersensitivity. PMID- 29122160 TI - Contact Dermatitis. PMID- 29122161 TI - Reply. PMID- 29122162 TI - Revisiting recurrent acute rhinosinusitis prevention by azithromycin in children. PMID- 29122163 TI - Icatibant for ACE-inhibitor angioedema, an opportunity to treat the patients? PMID- 29122165 TI - Throat-derived eosinophil peroxidase is not a reliable biomarker of pediatric eosinophilic esophagitis. PMID- 29122164 TI - Reply. PMID- 29122166 TI - Reply. PMID- 29122167 TI - Reply. PMID- 29122168 TI - An alternative explanation for immediate hypersensitivity reactions to opioids. PMID- 29122169 TI - Eosinophilic asthma with nasal polyposis march: Is aspirin-exacerbated respiratory disease the last station? PMID- 29122170 TI - Reply. PMID- 29122171 TI - Correction. PMID- 29122172 TI - The C2H2 transcription factor VdMsn2 controls hyphal growth, microsclerotia formation, and virulence of Verticillium dahliae. AB - Verticillium dahliae is a notorious pathogen that causes vascular wilt disease in numerous plant species worldwide. The fungus produces melanized microsclerotia, which helps it survive adverse environmental conditions that it may encounter within its hosts and in the soil. Previously, we determined that the high osmolarity glycerol (HOG) pathway is involved in the environmental stress response of V. dahliae. In this study, we investigated the function of VdMsn2, a homologue of the yeast C2H2 transcription factor Msn2, which is predicted to function as a downstream player in the HOG pathway. Disruption of VdMsn2 has a discernible effect on hyphal growth and septation, but not on diverse stresses including hyperosmotic stresses and cell wall inhibitory agents. Furthermore, we show that VdMsn2 deletion mutants produce significantly more microsclerotia than the wild-type and exhibit attenuated virulence to smoke trees because of poor penetration. Taken together, our findings suggest that VdMsn2 controls hyphal growth, microsclerotia formation, and virulence but does not significantly contribute to stress responses in V. dahliae. PMID- 29122173 TI - The homothallic mating-type locus of the conifer needle endophyte Phialocephala scopiformis DAOMC 229536 (order Helotiales). AB - We describe the complete mating-type (MAT) locus for Phialocephala scopiformis Canadian Collection of Fungal Cultures (DAOMC) 229536 - a basal lineage within Vibrisseaceae. This strain is of interest due to its ability to produce the important antiinsectan rugulosin. We also provide some of the first insights into the genome structure and gene inventory of nonclavicipitalean endophytes. Sequence was obtained through shotgun sequencing of the entire P. scopiformis genome, and the MAT locus was then determined by comparing this genomic sequence to known MAT loci within the Phialocephala fortinii s.l.-Acephala applanata species complex. We also tested the relative levels of sequence conservation for MAT genes within Vibrisseaceae (n = 10), as well as within the Helotiales (n = 27). Our results: (1) show a homothallic gene arrangement for P. scopiformis [MAT1-1-1, MAT1-2-1, and MAT1-1-3 genes are present], (2) increase the genomic survey of homothallism within Vibrisseaceae, (3) confirm that P. scopiformis contains a unique S-adenosyl-l-methionine-dependent methyltransferase (SAM-Mtase) gene proximal to its MAT locus, while also lacking a cytoskeleton assembly control protein (sla2) gene, and (4) indicate that MAT1-1-1 is the more useful molecular marker amongst the MAT genes for phylogenetic reconstructions aimed at tracking evolutionary shifts in reproductive strategy and/or MAT loci gene composition within the Helotiales. PMID- 29122174 TI - Differential gene expression profiling analysis in Pleurotus ostreatus during interspecific antagonistic interactions with Dichomitus squalens and Trametes versicolor. AB - This study provided analysis of differentially expressed genes (DEGs) in Pleurotus ostreatus under the interaction with Dichomitus squalens and Trametes versicolor, which is valuable for exploration on the fungal defence system against stressful condition caused by interspecific antagonistic interaction. Our result showed significant upregulation of abundant defence-related genes encoding laccase, manganese peroxidase, aldo-keto reductase, and glutathione S transferase, which all play important roles in oxidative stress-resistant response. Importantly, Lacc2 and Lacc10 were found to be dominantly induced laccase genes in P. ostreatus under interspecific interaction. Meanwhile, a large number of carbohydrate metabolism-related and energy production-related genes involved in nutrient and territory competition were also enhanced. These genes were annotated as glycoside hydrolase, citrate synthase, malate dehydrogenase, succinate dehydrogenase, succinyl-CoA synthetase, NADH dehydrogenase, cytochrome c reductase/oxidase, and ATP synthase. Also, 12 DEGs were selected for validation by quantitative real-time PCR (qRT-PCR), all these genes showed consistent expression between the result of qRT-PCR and RNA-seq. PMID- 29122175 TI - Enhancing taxol production in a novel endophytic fungus, Aspergillus aculeatinus Tax-6, isolated from Taxus chinensis var. mairei. AB - Taxol is a curatively effective but rare anti-tumor agent extracted from Taxus (yew) barks; however, the high cost and low production of the extraction method have limited its widespread use. In this study, fungi isolated from Taxus chinensis var. mairei were tested for their ability to produce taxol. High performance liquid chromatography combined with mass spectrometry confirmed that Aspergillus aculeatinus Tax-6, one of the endophytic fungi, could produce taxol in potato dextrose agar liquid medium. NaOAc, Cu2+, and salicylic acid were introduced into the medium to enhance taxol production of strain Tax-6 because NaOAc is an important precursor of taxol, Cu2+ may enhance the activity of oxidase and catalyze the formation of taxol, and salicylic acid could be an elicitor signal. Application of response surface methodology to optimize the culture led to the addition of CuSO4, salicylic acid and sodium acetate at 0.1 mg L-1, 10 mg L-1 and 8 g L-1 to improve taxol yield from 334.92 to 1337.56 MUg L-1. Overall, the results of this study confirmed that fungal taxol has the potential to be broadly applied by optimizing the culture conditions. PMID- 29122176 TI - Evaluating the response to Fusarium ananatum inoculation and antifungal activity of phenolic acids in pineapple. AB - Fusarium ananatum causes fruitlet core rot (FCR) in pineapple (Ananas comosus var. comosus) when the fruit reaches maturity. Hidden symptoms make it difficult to assess the disease, regardless of its stage, and basic questions concerning the involvement of the phenolic compounds in response to infection remain unknown. A direct inoculation method of F. ananatum in pineapple fruitlets was developed to monitor the growth of black spots and the changes in phenolic acids and ascorbic acid concentration under controlled conditions. After inoculation, infection began with a flesh discolouration at the inoculation point and then spread in a darker shade to form a black spot. Coumaroyl-isocitric and caffeoyl isocitric acids levels respectively showed a 150- and 200-fold increase in infected fruitlet when compared to healthy fruitlet. These hydroxycinnamic acids increased minimally in the adjacent fruitlet and remained stable in the other parts of the fruit. By contrast, sinapic acid and hydroxybenzoic acid isomers (HBA) decreased after F. ananatum inoculation in the infected fruitlet, whereas they remained stable in the adjacent and healthy fruitlets. Ascorbic acid decreased to zero in the infected fruitlet. The antifungal activity of phenolic compounds and ascorbic acid was evaluated against the mycelial growth of F. ananatum. p-Coumaric acid exhibited a total inhibition of the mycelial growth at 1000 MUg g-1. Ferulic acid inhibited 64 % of mycelial growth at a concentration of 1000 MUg g-1. Caffeoylquinic acid, sinapic acid, and ascorbic acid also showed significant antifungal activity, but to a lesser extent. Finally, coinoculation of the hydroxycinnamic acids with the pathogen restrains its development in the fruit. This is the first study to highlight the involvement of phenolic compounds in the pineapple FCR disease. PMID- 29122177 TI - Ascospore release in apple scab underlies infrared sensation. AB - The agent of apple scab disease (Venturia inaequalis) is the most common pathogen in apple cultivation. Its ascospores are released in spring, mainly during daylight hours and triggered by rain events. To investigate the causes of diurnal rhythm of ascospore dissemination of the apple scab fungus ascospore releases were examined continuously with spore traps in the orchard and with laboratory assays. One of the spore traps was illuminated at night with different light sources in each year during 2011-2015. The laboratory assays were performed with different light sources with varying wavelengths and intensities. In field and laboratory conditions only light including infrared radiation stimulated ascospore release, but not with light in the visible spectrum only. Artificial illumination during night was correlated with an increase of up to 46 % of ascospores released overnight in the field. We proved that infrared radiation induces V. inaequalis to release its spores. This is the first report in which spore discharge could be stimulated during night under field conditions. PMID- 29122178 TI - PdSlt2 Penicillium digitatum mitogen-activated-protein kinase controls sporulation and virulence during citrus fruit infection. AB - The Slt2 mitogen-activated protein (MAP) kinase homologue of Penicillium digitatum, the most relevant pathogen-producing citrus green mould decay during postharvest, was identified and explored. The P. digitatum Slt2-MAPK coding gene (PdSlt2) was functionally characterized by homologous gene elimination and transcriptomic evaluation. The absence of PdSlt2 gene resulted in significantly reduced virulence during citrus infection. The DeltaPdSlt2 mutants were also defective in asexual reproduction, showing impairment of sporulation during citrus infection. Gene expression analysis revealed that PdSlt2 was highly induced during citrus fruit infection at early stages (1 dpi). Moreover, PdSlt2 deletion altered gene expression profiles. The relative gene expression (RGE) of fungicide resistance- and fungal virulence-related genes showed that PdSlt2 acts as negative regulator of several transporter encoding genes (ABC and MFS transporters) and a positive regulator of two sterol demethylases. This study indicates that PdSlt2 MAPK is functionally preserved in P. digitatum and highlights the relevant role of the PdSlt2 MAP kinase-mediated signalling pathway in regulating diverse genes crucial for infection and asexual reproduction. PMID- 29122179 TI - Pathogenic potential of environmental resident fungi from ornithogenic soils of Antarctica. AB - We assessed the diversity of cultivable fungi in the ornithogenic soil nests of bird species like Phalacrocorax atriceps, Macronectes giganteus, Pygoscelis antarcticus, and Pygoscelis papua in the Antarctic islands. From 481 fungi isolated at 15 degrees C, only 50 displayed growth at 37 degrees C, and were identified as 14 species of 15 genera. Aspergillus fumigatus, Penicillium chrysogenum, and Rhodotorula mucilaginosa were the most abundant species obtained. Fifty taxa grew at 40 degrees C; displayed haemolytic and phospholipase activities; produced tiny spores, capsule, and melanin; showed growth at different pH; and showed resistance to amphotericin B. Interestingly, the minimum inhibitory concentration of amphotericin B increased by 5-10 fold for some A. fumigatus isolates after phagocytosis by amoeba. Our results show relations among fungal community compositions present in Antarctic ornithogenic soil and their pathogenic risk to humans in vitro. As the Antarctica Peninsula is a major region of the planet affected by global climate changes, our results, though preliminary, raise concerns about the dispersal of potential pathogenic microbes present in Antarctic substrates by wild birds, which can fly great distances and spread potential pathogens mainly to South America and Oceania. PMID- 29122180 TI - Associations between heat exposure, vigilance, and balance performance in summer tree fruit harvesters. AB - BACKGROUND: We sought to evaluate potential mediators of the relationship between heat exposure and traumatic injuries in outdoor agricultural workers. METHODS: Linear mixed models were used to estimate associations between maximum work-shift Wet Bulb Globe Temperature (WBGTmax) and post-shift vigilance (reaction time) and postural sway (total path length) in a cross-sectional sample of 46 Washington State tree fruit harvesters in August-September 2015. RESULTS: The mean (SD) WBGTmax was 27.4 (3.2) degrees C in August and 21.2 (2.0) degrees C in September. The mean pre-work-shift participant urine specific gravity indicated minimal dehydration. Twenty-four percent of participants exhibited possible excessive sleepiness. There was no association between WBGTmax and post-shift reaction time or total path length. CONCLUSIONS: Heat exposure was not associated with impaired vigilance or balance in this study, in which the overall mean (SD) WBGTmax was 25.9 (4.2) degrees C. However, the study identified opportunities to ensure adequate pre-work-shift hydration and to optimize sleep and work-shift timing in order to reduce occupational injury and heat-related illness risk. PMID- 29122181 TI - Safer healthcare at home: Detecting, correcting and learning from incidents involving infusion devices. AB - OBJECTIVE: Complex medical devices such as infusion pumps are increasingly being used in patients' homes with little known about the impact on patient safety. Our aim was to better understand the risks to patient safety in this situation and how these risks might be minimised, by reference to incident reports. DESIGN: We identified 606 records of incidents associated with infusion devices that had occurred in a private home and were reported to the UK National Reporting and Learning Service (2005-2015 inclusive). We used thematic analysis to identify key themes. RESULTS: In this paper we focus on two emergent themes: detecting and diagnosing incidents; and locating the patient, lay caregivers and their family in incident reports. The majority of incidents were attributed to device malfunction, and resulted in the patient being under-dosed. Delays in recognising and responding to problems were identified, alongside challenges in identifying the cause. We propose a process model for fault diagnosis and correction. Patients and caregivers did not feature strongly in reports; we highlight how the device is in the home but of the care system, and propose an agent model to describe this; we also identify ways of mitigating this disjoint. CONCLUSION: Devices need to be appropriately tailored to the setting in which they are employed, and within a system of care that ensures they are used optimally and safely. Suggested features to improve patient safety include devices that can provide better feedback to identify problems and support resolution, alongside greater monitoring and technical support by care providers for both patients and frontline professionals. The proposed process and agent models provide a structure for reviewing safety and learning from incidents in home health care. PMID- 29122182 TI - Work-related physical, psychosocial and individual factors associated with musculoskeletal symptoms among surgeons: Implications for ergonomic interventions. AB - This study evaluated the effect of physical, psychosocial and individual factors on the presence of musculoskeletal symptoms (MSS) among surgeons (n = 312) in Iran. Data were collected using questionnaires and analysed by multivariate logistic regression. The prevalence of MSS, particularly in the knees (48.7%), neck (45.8%), low back (42.3%) and shoulders (40.1%) was relatively high. Work related factors including time spent on surgeries each week (>25 h/week), number of hours working in standing position per day (>4 h/day), moderate to high levels of work-family conflict, duration of each surgery (>3 h), number of years worked as a surgeon (>10 years) and surgical specialty (particularly cardiothoracic and obstetric/gynecologic surgeries) were independently associated with the presence of MSS in different body regions. Individual factors including gender (being female) and little or no involvement in sport and physical activity were also independently associated with the occurrence of complaints. Implications of the findings for further research and development work for improving the working conditions and consequently reducing MSS among this working group are discussed. PMID- 29122183 TI - Mind the gap: Drivers underestimate the impact of the behaviour of other traffic on their workload. AB - This study examines the effect of traffic demand on driver workload by varying a range of characteristics of traffic behaviour, in particular focusing on the influence of a lane change performed by a neighbouring vehicle. To examine drivers' ability to manage their own workload in these traffic situations, a self initiated, surrogate mobile phone task was presented to them, to coincide with changes in traffic demand. Results showed that whilst participants delayed the initiation of the task when the lane change was performed in close proximity to them, the delay was insufficient to mitigate the effects of the increased workload, leading to task errors. This was attributed to driver's willingness to engage in secondary tasks, even though their (self-reported) workload had not returned to baseline levels. The minimum workload recovery period was calculated as being 12 s after the onset of the adjacent vehicle's manoeuvre, and this has implications for the design of workload managers. PMID- 29122184 TI - Ergonomic evaluation of pilot oxygen mask designs. AB - A revised pilot oxygen mask design was developed for better fit to the Korean Air Force pilots' faces. The present study compared an existing pilot oxygen mask and a prototype of the revised mask design with 88 Korean Air Force pilots in terms of subjective discomfort, facial contact pressure, and slip distance on the face in high gravity. The average discomfort levels, facial contact pressures, and slip distance of the revised mask were reduced by 33%-56%, 11%-33%, and 24%, respectively, compared to those of the existing oxygen mask. The mask evaluation method employed in the study can be applied to ergonomic evaluation of full- or half-face mask designs. PMID- 29122185 TI - Smartphone form factors: Effects of width and bottom bezel on touch performance, workload, and physical demand. AB - This study aimed at investigating the effect of two smartphone form factors (width and bottom bezel) on touch behaviors with one-handed interaction. User experiments on tapping tasks were conducted for four widths (67, 70, 72, and 74 mm) and five bottom bezel levels (2.5, 5, 7.5, 10, and 12.5 mm). Task performance, electromyography, and subjective workload data were collected to examine the touch behavior. The success rate and task completion time were collected as task performance measures. The NASA-TLX method was used to observe the subjective workload. The electromyogram signals of two thumb muscles, namely the first dorsal interosseous and abductor pollicis brevis, were observed. The task performances deteriorated with increasing width level. The subjective workload and electromyography data showed similar patterns with the task performances. The task performances of the bottom bezel devices were analyzed by using three different evaluation criteria. The results from these criteria indicated that tasks became increasingly difficult as the bottom bezel level decreased. The results of this study provide insights into the optimal range of smartphone form factors for one-handed interaction, which could contribute to the design of new smartphones. PMID- 29122186 TI - Accuracy of angular displacements and velocities from inertial-based inclinometers. AB - The objective of this study was to evaluate the accuracy of various sensor fusion algorithms for measuring upper arm elevation relative to gravity (i.e., angular displacement and velocity summary measures) across different motion speeds. Thirteen participants completed a cyclic, short duration, arm-intensive work task that involved transfering wooden dowels at three work rates (slow, medium, fast). Angular displacement and velocity measurements of upper arm elevation were simultaneously measured using an inertial measurement unit (IMU) and an optical motion capture (OMC) system. Results indicated that IMU-based inclinometer solutions can reduce root-mean-square errors in comparison to accelerometer-based inclination estimates by as much as 87%, depending on the work rate and sensor fusion approach applied. The findings suggest that IMU-based inclinometers can substantially improve inclinometer accuracy in comparison to traditional accelerometer-based inclinometers. Ergonomists may use the non-proprietary sensor fusion algorithms provided here to more accurately estimate upper arm elevation. PMID- 29122187 TI - Dynamic and static shoulder strength relationship and predictive model. AB - Static strength is typically used to standardize occupational tasks in an effort to limit over-exertion injuries; however, workplace tasks are commonly dynamic in nature. The purpose of this investigation was to assess factors influencing isokinetic shoulder strength and to develop predictive equations for isokinetic shoulder flexion and extension strength using isometric strength. Fifteen women performed a set of concentric isokinetic and isometric shoulder flexion and extension maximal exertions across a series of movement planes, angular velocities, and grip types. Data were used to generate two stepwise multiple regression models for predicting isokinetic shoulder flexion and exertion strength across the various exertion parameters. The final regression models explained a high degree of variance in predicting isokinetic shoulder flexion (R2 = 0.59) and extension (R2 = 0.67) with a subset of four and five inputs, respectively. The predictive equations can help establish acceptable force limits for workplace tasks requiring dynamic actions using more easily attainable static forces. PMID- 29122188 TI - Identifying a practice-based implementation framework for sustainable interventions for improving the evolving working environment: Hitting the Moving Target Framework. AB - Our aim was to identify implementation components for sustainable working environment interventions in the nursing assistant sector to generate a framework to optimize the implementation of workplace improvement initiatives. The implementation framework was informed by: 1) an industry advisory group, 2) interviews with key stakeholder, 3) concept mapping workshops, and 4) an e-mail survey. Thirty five stakeholders were interviewed and contributed in the concept mapping workshops. Eleven implementation components were derived across four domains: 1) A supportive organizational platform, 2) An engaged workplace with mutual goals, 3) The intervention is sustainably fitted to the workplace, and 4) the intervention is an attractive choice. The highest rated component was "Engaged and Active Management" (mean 4.1) and the lowest rated was "Delivered in an Attractive Form" (mean 2.8). The framework provides new insights into implementation in an evolving working environment and is aiming to assist with addressing gaps in effectiveness of workplace interventions and implementation success. PMID- 29122189 TI - Identifying knowledge gaps between practice and research for implementation components of sustainable interventions to improve the working environment - A rapid review. AB - In a recent study, we involved all relevant stakeholders to identify practice based implementation components for successful implementation and sustainability in work environment interventions. To understand possible knowledge gaps between evidence and practice, the aim of this paper is to investigate if effectiveness studies of the 11 practice-based implementation components can be identified in existing scientific literature. PubMed/MEDLINE, PsycINFO, and Web of Science were searched for relevant studies. After screening, 38 articles met the inclusion criteria. Since some of the studies describe more than one practice-based implementation concept a total of 125 quality criteria assessments were made. The overall result is that 10 of the 11 practice-based implementation components can be found in the scientific literature, but the evaluation of them is poor. From this review it is clear that there are knowledge gaps between evidence and practice with respect to the effectiveness of implementation concepts. PMID- 29122190 TI - The effect of metacognitive monitoring feedback on performance in a computer based training simulation. AB - This laboratory experiment was designed to study the effect of metacognitive monitoring feedback on performance in a computer-based training simulation. According to prior research on metacognition, the accurate checking of learning is a critical part of improving the quality of human performance. However, only rarely have researchers studied the learning effects of the accurate checking of retrospective confidence judgments (RCJs) during a computer-based military training simulation. In this study, we provided participants feedback screens after they had completed a warning task and identification task in a radar monitoring simulation. There were two groups in this experiment. One group (group A) viewed the feedback screens with the flight path of all target aircraft and the triangular graphs of both RCJ scores and human performance together. The other group (group B) only watched the feedback screens with the flight path of all target aircraft. There was no significant difference in performance improvement between groups A and B for the warning task (Day 1: group A - 0.347, group B - 0.305; Day 2: group A - 0.488, group B - 0.413). However, the identification task yielded a significant difference in performance improvement between these groups (Day 1: group A - 0.174, group B - 0.1555; Day 2: group A - 0.324, group B - 0.199). The results show that debiasing self-judgment of the identification task produces a positive training effect on learners. The findings of this study will be beneficial for designing an advanced instructional strategy in a simulation-based training environment. PMID- 29122191 TI - Identifying interactive effects of task demands in lifting on estimates of in vivo low back joint loads. AB - This investigation examined interactions between the magnitude of external load, movement speed and (a)symmetry of load placement on estimates of in vivo joint loading in the lumbar spine during simulated occupational lifting. Thirty-two participants with manual materials handling experience were included in the study. Three-dimensional motion data, ground reaction forces, and activation of six bilateral trunk muscle groups were captured while participants performed lifts with two loads at two movement speeds and using two load locations. L4-L5 joint compression and shear force-time histories were estimated using an EMG assisted musculoskeletal model of the lumbar spine. Results from this investigation provide strong evidence that known mechanical low back injury risk factors should not be viewed in isolation. Rather, injury prevention efforts need to consider the complex interactions that exist between external task demands and their combined influence on internal joint loading. PMID- 29122192 TI - Physiological consequences of using an upper limb exoskeleton during manual handling tasks. AB - This study aimed to assess the physiological consequences of using an upper limb exoskeleton during manual handling task, as muscle activity, upper limb kinematics, postural balance and cardiac cost. Participants performed three tasks (load lifting (LIFT), carrying (WALK) and stacking-unstacking (STACK)) with (EXOS) and without (FREE) an exoskeleton. During LIFT and STACK, the activity of the deltoid anterior muscle was significantly lower for EXOS than for FREE. During LIFT, the activity of the triceps brachii (TB) and tibialis anterior muscles significantly increased for EXO. The TB muscle activity significantly decreased for EXOS during WALK. The cardiac cost tended to increase with the use of the exoskeleton during LIFT, compared to FREE. The upper limb kinematics significantly differed between the EXOS and FREE conditions for all tasks. The benefits of the upper limb exoskeleton to reduce shoulder flexor muscle activity has been demonstrated, while broader physiological consequences have also been evidenced as increased antagonist muscle activity, postural strains, cardiovascular demand, and modified kinematics. PMID- 29122193 TI - Use of a footrest to reduce low back discomfort development due to prolonged standing. AB - Prolonged standing is common in many occupations and has been associated with low back discomfort (LBD). No recent studies have investigated a footrest as an intervention to reduce LBD associated with prolonged standing. This study investigated the effect of a footrest on LBD and sought to determine if LBD changes were accompanied by changes in muscle fatigue and low back end-range posture and movement. Twenty participants stood for two 2-h trials, one with and one without a footrest. LBD, lumbar erector spinae electromyography, upper lumbar (UL) and lower lumbar (LL) angles were measured. A significant increase in LBD occurred in both conditions but the footrest did not significantly decrease LBD. The only significant finding between conditions was that UL lordosis became more similar to usual standing over time with footrest use. These findings suggest that footrest use may not reduce LBD development and that development of LBD with prolonged standing is unlikely to be due to muscle fatigue or end-range posture mechanisms. PMID- 29122194 TI - Multi-directional one-handed strength assessments using AnyBody Modeling Systems. AB - Digital human modeling tools support proactive ergonomics in optimizing work tasks and workplace layouts. Empirical-statistical model based tools are often used to estimate the force exertion capability of the operators. This work is intended to serve as an initial probing into the usability of a musculoskeletal model based software, AnyBody Modeling Systems (AMS), in evaluating the force exertion capability at different points in the workspace and for various exertion directions. As a first step, it focuses on the modeling approach and the accuracy of one-handed isometric strength estimates of AMS. An existing literature database was used to compare the predicted strength at 8 hand locations and in 26 exertion directions, while simulating the empirical postures. The results show a correlation coefficient of 0.7 between the simulated and the experimental strength. AMS emphasizes the biomechanical advantages in strength due to the alignment of force exertion direction with the shoulder. Additionally, some discrepancies have been identified and discussed. PMID- 29122195 TI - How we can measure the non-driving-task engagement in automated driving: Comparing flow experience and workload. AB - In automated driving, a driver can completely concentrate on non-driving-related tasks (NDRTs). This study investigated the flow experience of a driver who concentrated on NDRTs and tasks that induce mental workload under conditional automation. Participants performed NDRTs under different demand levels: a balanced demand-skill level (fit condition) to induce flow, low-demand level to induce boredom, and high-demand level to induce anxiety. In addition, they performed the additional N-Back task, which artificially induces mental workload. The results showed participants had the longest reaction time when they indicated the highest flow score, and had the longest gaze-on time, road-fixation time, hands-on time, and take-over time under the fit condition. Significant differences were not observed in the driver reaction times in the fit condition and the additional N-Back task, indicating that performing NDRTs that induce a high flow experience could influence driver reaction time similar to performing tasks with a high mental workload. PMID- 29122196 TI - The effect of short duration low back vibration on pain developed during prolonged standing. AB - The purpose of this study was to determine if vibration, a potential method of pain management, applied to the low back could alleviate pain developed during prolonged standing. Eighteen healthy individuals participated in a 2.5-h standing task during which vibration (3-min duration) was applied at the 2-h and 2.25-h marks. During the full 2.5 h, participants recorded their perceived pain scores every 15 min using a 10 cm visual analogue scale (VAS). Following each vibration bout, those who developed low back pain (LPB) reported statistically lower VAS scores compared to prior to the vibration; however, when the vibration ceased, LBP returned to pre-vibration levels. It appears that vibration may be an effective method of alleviating LBP caused by prolonged standing; however, the effects seem to be temporary. Further research is needed to investigate the optimal vibration frequency and time period to maximize pain management effectiveness. PMID- 29122197 TI - Effect of examination stress on intraocular pressure in university students. AB - Intraocular pressure (IOP) has been investigated as a possible objective index of mental stressors. Here, we assessed the effect of examination stress on IOP in 33 university students. A repeated-measures design was used with two experimental conditions (examination and control) and two points of measurements (pre- and post-sessions). Also, the cardiovascular response, subjective perceived stress, as well as calculated ocular perfusion pressure and blood-pulse pressure were determined. A Bayesian statistical analysis showed higher IOP values in the examination in comparison to the control condition (BF01 < 0.001). A similar pattern was found for the cardiovascular indices (diastolic and systolic blood pressure, and heart rate), and these findings were corroborated by subjective reports (BF01 < 0.001 in all cases). Our data incorporates evidence in relation to the utility of IOP as an objective marker of examination stress, and it may help in the assessment and management of stress in applied scenarios. PMID- 29122198 TI - Effect of police mobile computer terminal interface design on officer driving distraction. AB - Several crash reports have identified in-vehicle distraction to be a primary cause of emergency vehicle crashes especially in law enforcement. Furthermore, studies have found that mobile computer terminals (MCTs) are the most frequently used in-vehicle technology for police officers. Twenty police officers participated in a driving simulator-based assessment of visual behavior, performance, workload and situation awareness with current and enhanced MCT interface designs. In general, results revealed MCT use while driving to decrease officer visual attention to the roadway, but usability improvements can reduce the level of visual distraction and secondary-task completion time. Results also suggest that use of MCTs while driving significantly reduces perceived level of driving environment awareness for police officers and increases cognitive workload. These findings may be useful for MCT manufacturers in improving interface designs to increase police officer and civilian safety. PMID- 29122199 TI - Tracking and discrete dual task performance for different visual spatial stimulus response mappings with focal and ambient vision. AB - The effect of spatial compatibility for various display-control configurations on human performance was studied with a dual-task paradigm using a tracking task and a discrete response task. Degradation of performance on both tasks within the visual modality was observed and was considered to be most likely due to resource competition resulting from simultaneous task operation. It was found that the more complicated the mapping for the discrete spatial compatibility response task, the more severe the interference with the tracking task. Although performance on both the tracking and spatial response tasks was impaired, the magnitude of impairment was not as great as expected, implying that focal and ambient vision required for the tracking task and spatial task, respectively, might be deployed, at least partly, from separate resources. Participants here seemed to successfully use focal vision for tracking and ambient vision for identifying signal lights concurrently, reducing the expected keen competition for visual resources. PMID- 29122200 TI - Applying social network analysis to the examination of interruptions in healthcare. AB - Examinations of interruptions in healthcare often focus on a single clinical discipline, and solutions are targeted accordingly. This approach does not take into account the inter-disciplinary dependencies and other sociotechnical aspects that make up the healthcare work system, and suggested solutions may not meet the needs of all stakeholders. In this article a sociotechnical systems perspective is used to uncover the interdependencies between 16 unique work roles that result in interruptions in an intensive care unit (ICU). By applying social network analysis techniques to data collected using the Dual Perspectives Method, we identified targeted systems-based interventions that may reduce unnecessary interruptions while avoiding unintended consequences that impose additional burden on ICU staff. The rich insights gained into the interruptive communication patterns in the ICU work system stand in contrast to findings that would have otherwise been obtained by focusing only on a single clinical discipline or a single perspective. PMID- 29122201 TI - Factors determining workers' pace while conducting continuous sequential lifting, carrying, and lowering tasks. AB - To plan a new manual material handling work process, it is necessary to predict the times required to complete each task. Current time prediction models lack validity when the handled object's mass exceeds 2 kg. In this study, we investigated the effect of workplace design parameters on continuous sequential lifting, carrying, and lowering of boxes weighing from 2 kg to 14 kg. Both laboratory and field experiments were conducted. Results revealed that the box's weight and the lifting and lowering heights influenced the tasks' times. Further, the time to perform a task was influenced by the performance of other tasks in the same work process. New time prediction models were developed using the laboratory experiment data. Our models were found to be more accurate on average than the Maynard Operation Sequence Technique (MOST) and Methods Time Measurement (MTM-1) by 42% and 20%, respectively, for predicting the times of real workers at an actual workplace. PMID- 29122202 TI - Human responses to wave slamming vibration on a polar supply and research vessel. AB - A polar supply and research vessel is pre-disposed to wave slamming which has caused complaints among crew and researchers regarding interference with sleep, equipment use and research activities. The present work undertook to survey passenger claims of sleep interference, disturbed motor tasks and equipment damage as a result of wave slamming during normal operations of this vessel. The hypothesis was investigated that whole-body vibration metrics from ISO 2631-1 are potentially suitable for the prediction of human slamming complaints. Full-scale acceleration measurements were performed and wave slamming events were subsequently identified from the human weighted acceleration time histories. A daily diary survey was also conducted to gather the human response. The vibration caused by wave slamming was found to be strongly correlated with sleep disturbances and activity interference. Sleep and equipment use were found to be the most affected parameters by slamming. Daily vibration dose values were determined by accumulating the vibration as a result of slamming over 24 h periods. This metric accounted for increased magnitudes and frequency of slamming incidents and proved to be the best metric to represent human responses to slamming vibration. The greatest percentage of activities affected by slamming related to sleep regardless of daily cumulative VDV magnitude. More than 50% of the recorded responses related to sleep when the daily cumulative VDV ranged between 8.0 m/s1.75-10.0 m/s1.75. The peak vertical vibration levels recorded on the vessel reach magnitudes which are associated with sleep disturbance in environments where acoustic noise is present. PMID- 29122204 TI - Insights on the apparel needs and limitations for athletes with disabilities: The design of wheelchair rugby sports-wear. AB - Wheelchair rugby is a sport that has been gaining popularity with athletes with disabilities. However, as it is relatively new and not played by the masses, market specific sports-wear is not available for this sport, which impacts directly on performance and clothing satisfaction of the athletes. Therefore, the main objective of this research was to identify the problems that wheelchair rugby players face with the sports-wear they use for playing the game. The data was collected using a focus group and a questionnaire with 61 wheelchair rugby players in the United Kingdom. Based on their suggestions, on the team expertise, and on the literature, a set of design recommendations was proposed for the upper body garments (tops), lower body garments (bottoms), and gloves. The results demonstrated that the gloves currently available negatively impact on players' ability to participate with satisfactory levels of protection and comfort. Moreover, tops and bottoms also present issues, mainly in the fit and ability to regulate the core body temperature. Hence, the recommendations proposed can provide designers with key information on the specific sports-wear requirements and allow them to design and develop products that can satisfy real needs of specific end-users. This paper intends to raise awareness of the needs of sports wear for those playing wheelchair rugby and promote the inclusivity of athletes with disabilities. PMID- 29122203 TI - Accident ahead? Difficulties of drivers with and without reading impairment recognising words and pictograms in variable message signs. AB - A timely and accurate acquisition of the information provided by variable message signs (VMS) can be crucial while driving. In the current study, we assess the difficulties of adults with dyslexia acquiring the information shown in VMS and provide evidence to discuss the controversial use of pictograms as potential countermeasures. Twenty-two adults with dyslexia and 22 matched controls completed a simulated driving session. The legibility of 12 VMS was assessed, including six text messages (e.g. "ACCIDENT") and six single pictograms (e.g. the icon for "accident ahead"). On average, participants with dyslexia started reading text messages when they were closer to the VMS. In addition, while approaching text VMS, they dedicated more gazes and manifested worse control of speed. Regarding pictogram VMS, we observed no differences in response distance, accuracy, response duration, or number of gazes. To sum up, the evidence provided reveals that adults with dyslexia, despite potential compensation effects, may still find difficulties reading text messages in VMS (shorter legibility distances, longer reading times, and increased cognitive effort), whereas we found no such differences in the recognition of pictograms (only some difficulties keeping a steady speed). Research on inclusive measures to improve reading in low-skilled or dyslexic drivers must be encouraged. PMID- 29122205 TI - Enhancing the effectiveness of human-robot teaming with a closed-loop system. AB - With technological developments in robotics and their increasing deployment, human-robot teams are set to be a mainstay in the future. To develop robots that possess teaming capabilities, such as being able to communicate implicitly, the present study implemented a closed-loop system. This system enabled the robot to provide adaptive aid without the need for explicit commands from the human teammate, through the use of multiple physiological workload measures. Such measures of workload vary in sensitivity and there is large inter-individual variability in physiological responses to imposed taskload. Workload models enacted via closed-loop system should accommodate such individual variability. The present research investigated the effects of the adaptive robot aid vs. imposed aid on performance and workload. Results showed that adaptive robot aid driven by an individualized workload model for physiological response resulted in greater improvements in performance compared to aid that was simply imposed by the system. PMID- 29122206 TI - The evolution of accelerated long-term forgetting: Evidence from the TIME study. AB - OBJECTIVE: Accelerated long-term forgetting (ALF) occurs when newly learned information decays faster than normal over extended delays. It has been recognised most frequently in temporal lobe epilepsy, including Transient Epileptic Amnesia (TEA), but can also be drug-induced. Little is known about the evolution of ALF over time and its impacts upon other memory functions, such as autobiographical memory (ABM). Here we investigate the long-term outcome of ALF and ABM in a group of patients with TEA and a single case of baclofen-induced ALF. METHODS: Study 1 involved a longitudinal follow-up of 14 patients with TEA over a 10-year period. Patients repeated a neuropsychological battery, three ALF measures (with free recall probed at 30-min and 1-week), and a modified Autobiographical Memory Interview (MAMI). Performance was compared with a group of healthy age-matched controls. In Study 2, patient CS, who previously experienced baclofen-induced ALF, was followed over 4 years, and re-tested now, 18 months after ceasing baclofen. CS repeated a neuropsychological battery, three ALF experimental tasks (each probed after 30 min and 1 week), and a modified autobiographical interview (AI). Her performance was compared with healthy age matched controls. RESULTS: On ALF measures, the TEA group performed significantly below controls, but when analysed individually, 4 of the 7 patients who originally showed ALF no longer did so. In two, this was accompanied by improvements in ABM for recent but not remote memory. Patient CS no longer demonstrated ALF on standard lab-based tests and now appeared to retain new episodic autobiographical events with a similar degree of episodic richness as controls. CONCLUSION: Long-term follow up suggests that ALF can resolve, with improvements translating to recent ABM in some cases. PMID- 29122207 TI - [Massive pulmonary embolism. When medical treatment is not enough]. AB - Emergency bedside veno-arterious ECMO implantation can be the only saving gesture in the suspicion of acute massive pulmonary embolism leading to haemodynamic failure, even before CT-scan imaging. Once the massive pulmonary embolism is confirmed it is possible to undergo surgical or percutaneous pulmonary thrombectomy, when thrombolytic therapy is contraindicated. PMID- 29122208 TI - Diabetes in the elderly: primum non nocere. PMID- 29122209 TI - Choice of fluids in the perioperative period of kidney transplantation. AB - Normal saline has traditionally been the resuscitation fluid of choice in the perioperative period of kidney transplantation over balanced potassium solutions. However, the problems arising from hyperchloraemia triggered by the infusion of normal saline have led to studies being conducted that compare this solution with balanced solutions. From this narrative review it can be concluded that the use of balanced crystalloids containing potassium in the perioperative period of kidney transplantation can be considered safe. These solutions do not affect serum potassium levels any more than normal saline, whilst maintaining a better acid-base balance in these patients. PMID- 29122210 TI - Strategies to increase patient safety in Hemodialysis: Application of the modal analysis system of errors and effects (FEMA system). AB - BACKGROUND: Haemodialysis (HD) patients are a high-risk population group. For these patients, an error could have catastrophic consequences. Therefore, systems that ensure the safety of these patients in an environment with high technology and great interaction of the human factor is a requirement. OBJECTIVES: To show a systematic working approach, reproducible in any HD unit, which consists of recording the complications and errors that occurred during the HD session; defining which of those complications could be considered adverse event (AE), and therefore preventable; and carrying out a systematic analysis of them, as well as of underlying real or potential errors, evaluating their severity, frequency and detection; as well as establishing priorities for action (Failure Mode and Effects Analysis system [FMEA systems]). METHODS: Retrospective analysis of the graphs of all HD sessions performed during one month (October 2015) on 97 patients, analysing all recorded complications. The consideration of these complications as AEs was based on a consensus among 13 health professionals and 2 patients. The severity, frequency and detection of each AE was evaluated by the FMEA system. RESULTS: We analysed 1303 HD treatments in 97 patients. A total of 383 complications (1 every 3.4 HD treatments) were recorded. Approximately 87.9% of them was deemed AEs and 23.7% complications related with patients' underlying pathology. There was one AE every 3.8 HD treatments. Hypertension and hypotension were the most frequent AEs (42.7 and 27.5% of all AEs recorded, respectively). Vascular-access related AEs were one every 68.5 HD treatments. A total of 21 errors (1 every 62 HD treatments), mainly related to the HD technique and to the administration of prescribed medication, were registered. The highest risk priority number, according to the FMEA, corresponded to errors related to patient body weight; dysfunction/rupture of the catheter; and needle extravasation. CONCLUSIONS: HD complications are frequent. Consideration of some of them as AEs could improve safety by facilitating the implementation of preventive measures. The application of the FMEA system allows stratifying real and potential errors in dialysis units and acting with the appropriate degree of urgency, developing and implementing the necessary preventive and improvement measures. PMID- 29122211 TI - Citrate dialysate does not induce oxidative stress or inflammation in vitro as compared to acetate dialysate. AB - : Increased acetataemia during haemodialysis sessions has been associated with a number of abnormalities, including increased oxidative stress, pro-inflammatory cytokines and nitric oxide synthesis. However, citric acid may play an alternative role to acetate as a dialysate stabiliser given that the effect of citrate on complement and leukocyte activation is different to that of acetate. The purpose of this study was to compare the inflammatory effect in immunocompetent blood cells of acetate dialysate and citrate dialysate. MATERIAL AND METHODS: The effect of acetate and/or citrate was investigated in the whole blood of uraemic patients and in healthy in vitro samples. Four types of dialysate were tested: dialysate 1, acetate-free with 1mmol/L of citrate; dialysate 2, with 0.8mmol/L of citrate and 0.3mmol/L of acetate; dialysate 3, citrate-free with 3mmol/L of acetate; and dialysate 4, citrate-free with 4mmol/L of acetate. The cell types used were: human monocyte culture (THP-1); and peripheral blood mononuclear cells (PBMCs) from healthy subjects and uraemic patients on haemodialysis. ICAM-1 was determined and levels of reactive oxygen species and total microvesicles were quantified. RESULTS: Unlike the citrate dialysates, the dialysates with acetate (dialysate 3 and dialysate 4) induced increased ICAM-1 expression density in THP-1 cells; an increase in ICAM-1 expression was observed in the immunocompetent cells of healthy subjects with acetate dialysate (dialysate 3 and dialysate 4) but not with citrate dialysate (dialysate 1 and dialysate 2). No significant ICAM-1 differences were found between the different dialysates in the cells of haemodialysed patients. Reactive oxygen species expression and the number of microvesicles increased significantly with acetate dialysate but not with citrate dialysate in the cells of both healthy subjects and haemodialysed patients. CONCLUSIONS: At the concentrations in which it is generally used in clinical practice, acetate-based dialysate increases oxidative stress and the total number of microvesicles and may induce other pro-inflammatory stimuli typical of uraemic patients on haemodialysis. Citrate dialysates do not induce this activation, which could make them a suitable alternative in clinical practice. PMID- 29122212 TI - Calcimimetics have had no impact on the indications for surgery of tertiary hyperparathyroidism. PMID- 29122213 TI - Renal damage associated to intravitreal administration of ranibizumab. PMID- 29122214 TI - Immediate re-transplantation: An audacious approach to early vascular renal transplant failure. PMID- 29122215 TI - Acute renal failure in a tertiary referal hospital, a relevant cause of chronic renal failure and mortality. PMID- 29122216 TI - Peritoneal dialysis as a perpetuating cause of hyponatremia. PMID- 29122217 TI - Kidney failure caused by tubular intersticial intersticial nephropathy with Fanconi syndrome after treatment with zoledronic acid. PMID- 29122218 TI - Study and treatment of the couple in post-coital urinary tract infection in women. PMID- 29122220 TI - Barriers for the development of home hemodialysis in Spain. Spanish nephrologists survey. PMID- 29122219 TI - TSC2/PKD1 contiguous gene sindrome. PMID- 29122221 TI - Qualitative and quantitative contrast-enhanced ultrasonography for the characterisation of non-palpable testicular tumours. AB - AIM: To assess the diagnostic performance of conventional ultrasound (US) and contrast-enhanced ultrasonography (CEUS) in the differential diagnosis of non palpable intratesticular tumours. MATERIALS AND METHODS: The local ethics review board approved the protocol, and all of the patients provided written informed consent. Between December 2011 and February 2014, men with non-palpable testicular tumours and normal tumour markers who were referred for surgery were included. The tumours were analysed by conventional US, including B-mode and colour Doppler US (CDUS) as well as by CEUS. Morphological aspects and qualitative and quantitative CEUS criteria, based on visual enhancement and time intensity curves, were assessed for each lesion. RESULTS: Forty patients were ultimately included. Based on histopathological results, the tumours were classified into three groups: benign tumours (n=16), malignant tumours (n=15), and burned-out tumours (n=9). In B-mode, the morphological aspects were significantly different between benign and malignant tumours (p-values from 0.0002 to 0.008). Qualitative and quantitative analyses of the CEUS images revealed that burned-out tumours exhibited significantly less enhancement than malignant and benign tumours: in burned-out tumours, time-intensity curves were flat, whereas in both benign and malignant tumours the curves had a bell-shaped pattern. All intensity parameters were lower for burned-out tumours compared to benign and malignant tumours (p-value from 0.0001 to 0.026). Both benign and malignant tumours enhanced strongly, however, and no significant difference between the two was noted (p-value from 0.0721 to 0.0953). CONCLUSION: Unlike conventional US, which enable benign lesions to be differentiated from malignant or burned-out tumours, CEUS failed to enabled differentiation between benign lesions and malignant vascularised testicular tumours. CEUS appears to have the potential, however, to differentiate burned-out tumours from vascularised testicular tumours. PMID- 29122222 TI - Imaging features of combined hepatocellular-cholangiocarcinoma on contrast enhanced ultrasound: correlation with clinicopathological findings. AB - AIM: To evaluate the relationship between the imaging features of combined hepatocellular-cholangiocarcinoma (CHC) on contrast-enhanced ultrasound (CEUS) and clinicopathological findings. MATERIALS AND METHODS: From August 2004 to August 2016, 40 patients (29 males, 11 females; mean age 52.8+/-11.2 years) with histopathologically proven CHC were investigated. The CEUS imaging features and clinicopathological findings of CHC were analysed and compared retrospectively. RESULTS: On CEUS, peripheral irregular rim-like enhancement, diffuse heterogeneous enhancement, and diffuse homogeneous enhancement was illustrated in 13 (32.5%), 21 (52.5%), and six (15%) lesions, respectively. Histopathological findings showed hepatocellular carcinoma (HCC) predominance and cholangiocarcinoma (CC) predominance throughout the tumour were illustrated in 21 (52.5%) and 19 (47.5%) cases, respectively. HCC-predominant CHCs displayed diffuse heterogeneous enhancement more frequently than peripheral irregular rim like enhancement (p=0.005), whereas CC-predominant CHCs displayed peripheral irregular rim-like enhancement more frequently than diffuse heterogeneous enhancement and homogeneous enhancement (p=0.005 and p=0.01, respectively). CHCs >5 cm displayed diffuse heterogeneous enhancement more frequently than diffuse homogeneous enhancement, whereas CHCs <=5 cm displayed diffuse homogeneous enhancement more frequently than diffuse heterogeneous enhancement (p=0.004). CONCLUSION: The enhancement pattern of CHC on CEUS depended on the relative proportions of the HCC and CC components and showed size-dependent characteristics. PMID- 29122223 TI - The utility of ultrasound superb microvascular imaging for evaluation of breast tumour vascularity: comparison with colour and power Doppler imaging regarding diagnostic performance. AB - AIM: To investigate the utility of superb microvascular imaging (SMI) for evaluating the vascularity of breast masses in comparison with colour or power Doppler ultrasound (US) and the effect on diagnostic performance. MATERIALS AND METHODS: A total of 191 biopsy-proven masses (99 benign and 92 malignant) in 166 women with greyscale, colour Doppler, power Doppler, and SMI images were enrolled in this retrospective study. Three radiologists analysed the vascular images using a three-factor scoring system to evaluate the number, morphology, and distribution of tumour vessels. They assessed the Breast Imaging-Reporting and Data System categories for greyscale US alone and combinations of greyscale US and each type of vascular US. The Kruskal-Wallis test was performed and the area under the receiver-operating characteristic curve (AUC) measured. On SMI, vascular scores were compared between benign and malignant masses and the optimal cut-off value for the overall score was determined. RESULTS: SMI showed higher vascular scores than colour or power Doppler US and malignant masses had higher scores than benign masses (p<0.001). The diagnostic performance of the combination of greyscale US and SMI was higher than those of greyscale US alone and greyscale and colour or power Doppler US (AUC, 0.815 versus 0.774, 0.789, 0.791; p<0.001). The optimal cut-off value of the overall vascular score was 5 with a sensitivity of 82.3% and a specificity of 65.3% (AUC, 0.808). CONCLUSION: SMI is superior to colour or power Doppler US for characterising the vascularity in breast masses and improving diagnostic performance. PMID- 29122224 TI - [Mental health in the healthcare system]. PMID- 29122225 TI - [Web Visit Patterns for the Clinical Practice Guidelines for Management of Depressive Disorder and Alcohol Abuse-Dependence]. AB - INTRODUCTION: Clinical practice guidelines (CPG) are a set of recommendations for professionals, patients, and families, in order to make decisions about health care. The CPG respond to the need for concise, accurate, practical, and up to date information. In the field of mental health, Colombia has developed three GPC; alcohol (GPC-OH), depression (GPC-TDA), and schizophrenia. OBJECTIVES: To describe the Web Portal traffic related to psychiatry guidelines, with emphasis on the number of visits, distribution throughout Colombian cities, and estimating user behaviour patterns. METHODS: An evaluation was made of the traffic at the Clinical Practice Guidelines Web Portal of the Ministry of Health and Social Protection between 2013 and 2015 (two years of observation since the inauguration of the Portal). RESULTS: Out of the 45 GPC published on the website, the CPG-OH represented 1.21% of all page views of the Portal. CPG-TDA reached 1.52% (accumulated percentage of 2.73%), being the eighth most consulted guideline, with CPG-OH being number 16. The highest mean monthly number of visits for this group of guideliness was for the CPG-OH for health professionals (353 visits/month), and the lowest was for the CPG-AD for patients and relatives (24 single visits/month). Bogota D.C. was the city where health carers accessed the guidelines more often. The guidelines for patients and relatives were consulted more in Villavicencio, Cucuta, Manizales, Pereira, and Pasto. CONCLUSIONS: The web portal partially fulfills the purpose of circulating the CPG in Colombia. The visits to the CPG of mental health is quite low, and requires better dissemination strategies that allow the use of information and communication technology. PMID- 29122226 TI - [Relationship between personality organization and the prevalence of symptoms of depression, anxiety and stress among university students in health careers in the Region of Coquimbo, Chile]. AB - OBJECTIVE: The literature reports a set of variables associated with depression, anxiety and stress in health career students. The only one of these that could have a constant input is the structure of personality organisation. The present study aims to determine the relationship between the dimensions of personality organization and depression, anxiety, and stress symptoms reported by first-year university health career students. METHODS: Under a non-experimental ex-post facto design, the personality organisation was evaluated in 235 1st year university, medical, nursing, and kinesiology from three universities of La Serena and Coquimbo (Chile). Inventory of personality organization and scale of depression, anxiety and stress to sift participants was used. The relationship of personality with depressive, anxiety and stress symptoms was determined by multiple regression analysis. RESULTS: It was found that the primary and overall personality dimensions explained 28% of the variance of depression (P<.01), 20% of anxiety, and stress 22%, with the use of primitive defenses and identity diffusion dimensions that largely contribute to the explanatory model. CONCLUSIONS: The dimensions of personality organization could have a significant relationship with the emergence of depression, anxiety and stress, as the explanatory burden dimension provides the primitive defenses and identity diffusion. These results may be useful for early recognition of aspects of personality of applicants, and to perform actions that strengthen them in order to improve efficiency. PMID- 29122227 TI - Association Between Religion and Suicidal Behaviors in Cancer Patients. AB - BACKGROUND: Whereas most studies have focused on how the religious beliefs positively interfere with the presence or execution of suicidal behaviors, few have identified differences among religious beliefs and how these can not only be consider as a protective factor for suicide, but also as a variable that influences the expression of the suicidal related behaviors. OBJECTIVE: To provide evidence about the effect of religious practices and beliefs on suicidal behavior in cancer patients in Colombia. METHODS: This is a hospital-based cross sectional study with a sample of 132 patients with cancer. Socio-demographic data were measured, in which the religious affiliation was included. The instruments used include the Scale of Suicidal Ideation (SSI), the item 9 of Beck Depression Scale (BDI-IA) and the Beck Hopelessness Inventory (BHS). RESULTS: In our study, 93% of the patients had advanced stages of cancer, where 51.52% of them were in stage IV. Cancer patients who reported non-Catholic Christians were 3 and 4 times more likely to have some manifestation of suicidal behavior. CONCLUSIONS: It is recognized in non-Catholic Christians patients a greater chance to express suicidal ideation, which could be related to their level of suicide acceptability. It is considered that religion and their perception of death affects the expression and acceptance of suicidal ideation, reason why it is necessary more research on the effect of different religions on suicidal behavior, in order to include these aspects in the patient intervention. PMID- 29122228 TI - [Depressive Symptoms and Psychosocial Risk Factors in High Complexity Obstetric Patients Admitted to a Critical Care Obstetric Unit in Cali, Colombia]. AB - Depression is the main cause of years lossed due to disability in the world, and it affects 50% more women 50% than men. Perinatal depression has been linked with more anxiety, a chronic course, and disability than depression in other life stages. In spite of its high prevalence and serious health effects on both mother and foetus, it is frequently under-diagnosed. This study was performed on all high risk obstetric patients admitted to a critical care obstetric unit in Cali, Colombia, from January to June, 2014. Depressive symptoms and psychosocial risk factors were screened by means of a survey and the Edinburgh Prenatal Depression Scale (EPDS). A total of 695 women were included, of whom 30.2% had depressive symptoms on the EPDS, and 3.6% reported having self-injury thoughts in the last 7 days. Our findings are consistent with previous reports on a history of child abuse and family depression as risk factors. It was also suggested that lower socio-economic status is associated with more vulnerability. Early screening is needed to ensure timely detection and treatment. PMID- 29122230 TI - Cognitive Stimulation of Elderly Residents in Social Protection Centers in Cartagena, 2014. AB - OBJECTIVE: To determine the effectiveness of a program of cognitive stimulation of the elderly residents in Social Protection Centers in Cartagena, 2014. METHODS: Quasi-experimental study with pre and post tests in control and experimental groups. A sample of 37 elderly residents in Social Protection Centers participated: 23 in the experimental group and 14 in the control group. A survey and a mental evaluation test (Pfeiffer) were applied. The experimental group participated in 10 sessions of cognitive stimulation. RESULTS: The paired t test showed statistically significant differences in the Pfeiffer test, pre and post intervention, compared to the experimental group (P=.0005). The unpaired t test showed statistically significant differences in Pfeiffer test results to the experimental and control groups (P=.0450). The analysis of the main components showed that more interrelated variables were: age, diseases, number of errors and test results; which were grouped around the disease variable, with a negative association. CONCLUSIONS: The intervention demonstrated a statistically significant improvement in cognitive functionality of the elderly. Nursing can lead this type of intervention. It should be studied further to strengthen and clarify these results. PMID- 29122229 TI - [Study of genetic variants in the BDNF, COMT, DAT1 and SERT genes in Colombian children with attention deficit disorder]. AB - BACKGROUND: Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. OBJECTIVES: To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. METHODS: We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. RESULTS: The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. CONCLUSIONS: Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population. PMID- 29122231 TI - Suicide in the Indigenous Population of Latin America: A Systematic Review. AB - OBJECTIVE: Due to the high rates of suicide reported among many ethnic minorities, a systematic review is presented on suicide in indigenous populations of Latin America. METHODS: Systematic review in PubMed, Scopus, PsycNET, Scielo and Scholar Google. RESULTS: From an initial total of 1862 articles, 41 were included for data extraction. They include 21 from Brazil, 13 from Colombia, 2 from Chile, 1 from Peru, and 4 articles grouped from different countries. Suicide is a public health issue in many communities. Lifestyle changes, industrialisation, environmental degradation, and alcohol have led the indigenous population experiencing what has been described as "cultural death." PMID- 29122232 TI - [Obstructive sleep apnea syndrome in patients attending a psychiatry outpatient service: a case series]. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a condition associated with multiple negative outcomes. People with mental illness might be at increased risk of having it, given that medication given has adverse effects on weight and there are alterations in sleep associated with them; however, there are few studies in this population. OBJECTIVE: Describe the patients and the results of polysomnography ordered based on clinical symptoms in a psychiatric outpatient clinic between 2012 and 2014. METHODS: A case series in which medical records were evaluated. RESULTS: 58 patients who underwent polysomnography, 89% of them had OSAS, 16% were obese and 19% were been treated with benzodiazepines. CONCLUSIONS: This is a condition that must be considered during the clinical evaluation of patients with mental illness, since its presence should make clinicians think about drug treatment and follow up. PMID- 29122233 TI - [Cyberbullying and Suicidal Behavior: What is the Connection? About a Case]. AB - INTRODUCTION: Social networks have increased in recent decades, and with them the bullying, causing difficulties in young people's mental health expressed through depressive symptoms, suicidal ideation and suicide attempts. Up next, we present a case that exemplifies this situation. OBJECTIVE: To describe a case report that exemplifies this new outlook in young people and how it affects their mental health. METHODOLOGY: Case report and non-systematic literature review. RESULTS: One case report, treated at a hospital in Medellin due to two suicide attempts related to social networks is presented. DISCUSSION: Currently, there are multiple social media resources, the advent of internet and smartphones is not only a strategy for improving social interactions, but it also contributes to impair mental health of some vulnerable young people. CONCLUSION: This case sensitize us, about the relationship between the growing social networking and cyberbullying as well as suicidal thoughts / attempts; thanks to this case and the available literature, we can't establish causality but we could deduce that the internet utter a increased risk for young people who are exposed and more vulnerable. PMID- 29122234 TI - [Suspicion Index: Psychiatric Manifestations of NMDAR Encephalitis in Paediatric Patients]. AB - Immune encephalitis is a diverse group of disorders that share some unique diagnostic approaches and specific treatments. Some of the initial manifestations are non-specific and difficult to distinguish from encephalitis of other aetiologies, and even with modern diagnostic tools there are still a number of cases for which definitive causes cannot be clarified. Among these, N-methyl-D aspartate receptor (NMDAR) encephalitis is a particular form of immune encephalitis that has some distinctive clinical manifestations, which allows the clinical evaluator to suggest a more accurate diagnosis and start treatments even in the absence of specific laboratory tests. Three paediatric patients, who were treated for NMDAR encephalitis are described in this article, as well as comparing their clinical presentation. This specific disorder and some of the more relevant features of its physiopathology are reviewed in order to explain the initial psychiatric manifestations, for which early recognition is critical for an appropriate diagnosis and treatment. PMID- 29122235 TI - [Acute Stress and Broken Heart Syndrome. A Case Report]. AB - INTRODUCTION: Stress has been associated with an acute heart failure syndrome of important morbidity and mortality. METHODS: Case report and non-systematic review of the relevant literature. CASE PRESENTATION: A 65-year-old woman with a history of an untreated generalized anxiety disorder, whom after the violent death of her son presented with oppressive chest pain irradiated to neck and left superior extremity, lasting for more than 30minutes, initial clinical suspect suggests acute coronary syndrome. LITERATURE REVIEW: Tako-tsubo cardiomyopathy is characterized by a reversible left ventricular dysfunction and wall movement abnormalities, without any compromise of the coronary arteries, associated to high plasma levels of catecholamines which in most cases correlates with an acute stress of emotional or physical type. CONCLUSIONS: Tako-tsubo cardiomyopathy has to be considered by physicians among the differential diagnosis when facing a patient with suspected acute coronary syndrome, especially in post-menopausal women with a history of psychiatric comorbidities such as a generalized anxiety disorder. PMID- 29122236 TI - Commentary on the article "A prospective study of a vein sparing technique for the management of varicose vein disease" by M Zmudzinski et al. PMID- 29122237 TI - Osseointegration of zirconia dental implants in animal investigations: A systematic review and meta-analysis. AB - OBJECTIVE: To determine the osseointegration rate of zirconium dioxide (ZrO2) dental implants in preclinical investigations. DATA: Data on the osseointegration rate was extracted considering the bone to implant contact (BIC), removal torque analysis (RTQ) and push-in tests. Meta analyses were conducted using multilevel multivariable mixed-effects linear regression models. The Sidak method was used in case of multiple testing. SOURCES: An electronic screening of the literature (MEDLINE/Pubmed, Cochrane Library and Embase) and a supplementary manual search were performed. Animal investigations with a minimum sample size of 3 units evaluating implants made of zirconia (ZrO2) or its composites (ZrO2>50vol.%) were included. STUDY SELECTION: The search provided 4577 articles, and finally 54 investigations were included and analyzed. Fifty-two studies included implants made from zirconia, 4 zirconia composite implants and 37 titanium implants. In total, 3435 implants were installed in 954 animals. CONCLUSIONS: No significant influence of the evaluated bulk materials on the outcomes of interest could be detected. When comparing different animal models, significant differences for the evaluated variables could be found. These results might be of interest for the design of further animal investigations. PMID- 29122238 TI - Environmental control of harmful dinoflagellates and diatoms in a fjordic system. AB - Fjordic coastlines provide an ideal protected environment for both finfish and shellfish aquaculture operations. This study reports the results of a cruise to the Scottish Clyde Sea, and associated fjordic sea lochs, that coincided with blooms of the diarrhetic shellfish toxin producing dinoflagellate Dinophysis acuta and the diatom genus Chaetoceros, that can generate finfish mortalities. Unusually, D. acuta reached one order of magnitude higher cell abundance in the water column (2840cellsL-1) than the more common Dinophysis acuminata (200cellsL 1) and was linked with elevated shellfish toxicity (maximum 601+/-237MUg OA eq/kg shellfish flesh) which caused shellfish harvesting closures in the region. Significant correlations between D. acuta abundance and that of Mesodinium rubrum were also observed across the cruise transect potentially supporting bloom formation of the mixotrophic D. acuta. Significant spatial variability in phytoplankton that was related to physical characteristics of the water column was observed, with a temperature-driven frontal region at the mouth of Loch Fyne being important in the development of the D. acuta, but not the Chaetoceros bloom. The front also provided important protection to the aquaculture located within the loch, with neither of the blooms encroaching within it. Analysis based on a particle-tracking model confirms the importance of the front to cell transport and shows significant inter-annual differences in advection within the region, that are important to the harmful algal bloom risk therein. PMID- 29122239 TI - Early warning of limit-exceeding concentrations of cyanobacteria and cyanotoxins in drinking water reservoirs by inferential modelling. AB - An early warning scheme is proposed that runs ensembles of inferential models for predicting the cyanobacterial population dynamics and cyanotoxin concentrations in drinking water reservoirs on a diel basis driven by in situ sonde water quality data. When the 10- to 30-day-ahead predicted concentrations of cyanobacteria cells or cyanotoxins exceed pre-defined limit values, an early warning automatically activates an action plan considering in-lake control, e.g. intermittent mixing and ad hoc water treatment in water works, respectively. Case studies of the sub-tropical Lake Wivenhoe (Australia) and the Mediterranean Vaal Reservoir (South Africa) demonstrate that ensembles of inferential models developed by the hybrid evolutionary algorithm HEA are capable of up to 30days forecasts of cyanobacteria and cyanotoxins using data collected in situ. The resulting models for Dolicospermum circinale displayed validity for up to 10days ahead, whilst concentrations of Cylindrospermopsis raciborskii and microcystins were successfully predicted up to 30days ahead. Implementing the proposed scheme for drinking water reservoirs enhances current water quality monitoring practices by solely utilising in situ monitoring data, in addition to cyanobacteria and cyanotoxin measurements. Access to routinely measured cyanotoxin data allows for development of models that predict explicitly cyanotoxin concentrations that avoid to inadvertently model and predict non-toxic cyanobacterial strains. PMID- 29122240 TI - Geosmin production and polyphasic characterization of Oscillatoria limosa Agardh ex Gomont isolated from the open canal of a large drinking water system in Tianjin City, China. AB - Taste and odor (T & O) episodes always cause strong effects on drinking water supply system. Luanhe River diversion into Tianjin City in China is an important drinking water resource. Massive growth of a benthic filamentous cyanobacterium with geosmin production in the open canal caused a strong earthy odor episode in Tianjin. On the basis of the morphological and molecular identification of this cyanobacterium as Oscillatoria limosa Agardh ex Gomont, the genetic basis for geosmin biosynthesis and factors influencing growth and geosmin production of O. limosa CHAB 7000 were studied in this work. A 2268-bp open reading frame, encoding 755 amino acids, was amplified and characterized as the geosmin synthase gene (geo), followed by a cyclic nucleotide-binding protein gene (cnb). Phylogenetic analysis implied that the evolution of the geosmin genes in O. limosa CHAB 7000 might involve a horizontal gene transfer event. Examination on the growth and geosmin production of O. limosa CHAB 7000 at different light intensities showed that the maximum geosmin production was observed at 10MUmol photons m-2s-1, while the optimum growth was at 60MUmol photons m-2s-1. Under three temperature conditions (15 degrees C, 25 degrees C, and 35 degrees C), the maximum growth and geosmin production were observed at 25 degrees C. Most amounts of geosmin were retained in cells during the growth phase, but high temperature and low light intensity increased the release of geosmin into the medium, implying that O. limosa CHAB 7000 had a high potential harm for the release of geosmin from its cells at these adverse conditions. PMID- 29122241 TI - Variation within and between cyanobacterial species and strains affects competition: Implications for phytoplankton modelling. AB - Cyanobacteria Microcystis aeruginosa and Cylindrospermopsis raciborskii are two harmful species which co-occur and successively dominate in freshwaters globally. Within-species strain variability affects cyanobacterial population responses to environmental conditions, and it is unclear which species/strain would dominate under different environmental conditions. This study applied a Monte Carlo approach to a phytoplankton dynamic growth model to identify how growth variability of multiple strains of these two species affects their competition. Pairwise competition between four M. aeruginosa and eight C. raciborskii strains was simulated using a deterministic model, parameterized with laboratory measurements of growth and light attenuation for all strains, and run at two temperatures and light intensities. 17 000 runs were simulated for each pair using a statistical distribution with Monte Carlo approach. The model results showed that cyanobacterial competition was highly variable, depending on strains present, light and temperature conditions. There was no absolute 'winner' under all conditions as there were always strains predicted to coexist with the dominant strains, which were M. aeruginosa strains at 20 degrees C and C. raciborskii strains at 28 degrees C. The uncertainty in prediction of species competition outcomes was due to the substantial variability of growth responses within and between strains. Overall, this study demonstrates that within-species strain variability has a potentially large effect on cyanobacterial population dynamics, and therefore this variability may substantially reduce confidence in predicting outcomes of phytoplankton competition in deterministic models, that are based on only one set of parameters for each species or strain. PMID- 29122242 TI - Mitigation of harmful algal blooms using modified clays: Theory, mechanisms, and applications. AB - Clay dispersal is one of only a few mitigation methods for harmful algal blooms (HABs) ever applied in the field; however, low flocculation efficiency has always been the most significant drawback associated with natural unmodified clays. This review discusses key factors affecting the flocculation efficiency, based on results obtained in studies of the mechanisms underlying interactions between clay particles and HAB organisms. It further elaborates clay surface modification theory and methods for improving removal efficiency of HAB cells, followed by descriptions of various modified clays successfully prepared with removal efficiencies of HAB cells that are up to hundreds of times greater than natural clays and have lower dosing requirements of 4-10t/km2. Presently, modified clays are the most widely used method for the mitigation of HAB in the field in China. This review also evaluates potential ecological effects of modified clay disposal on water quality, typical aquatic organisms, benthic environments, and ecosystems. Both laboratory and field results have demonstrated that modified clays markedly can actually improve water quality after treatment and pose no negative effects on aquatic ecosystems. PMID- 29122243 TI - The influence of salinity in the domoic acid effect on estuarine phytoplankton communities. AB - Toxic species of the diatom genus Pseudo-nitzschia, observed worldwide from coastal waters to the open ocean, produce the neurotoxin domoic acid (DA). DA is an important environmental and economic hazard due to shellfish contamination with subsequent effects on higher trophic levels. Previous research has demonstrated that, among other environmental factors, salinity influences the abundance and toxicity of Pseudo-nitzschia. In this study, the environmental factors driving the growth of Pseudo-nitzschia and the production of dissolved DA (dDA) in North Inlet estuary were examined. The effect of salinity on the growth inhibition of phytoplankton induced by the initial presence as well as by an addition of dDA was also assessed. Initially, the diatom abundance was negatively correlated with the abundance of Pseudo-nitzschia and with the concentration of dDA. With the addition of a concentrated solution of dDA, the percent inhibition of cryptophytes and diatoms was significantly correlated with salinity and suggested a higher sensitivity to dDA at extreme salinities. These results emphasize the importance of salinity in assessing the properties of DA and potentially of other phycotoxins on phytoplankton. PMID- 29122244 TI - Bloom dynamics and chemical defenses of benthic cyanobacteria in the Indian River Lagoon, Florida. AB - Cyanobacterial blooms are predicted to become more prominent in the future as a result of increasing seawater temperatures and the continued addition of nutrients to coastal waters. Many benthic marine cyanobacteria have potent chemical defenses that protect them from top down pressures and contribute to the persistence of blooms. Blooms of benthic cyanobacteria have been observed along the coast of Florida and within the Indian River Lagoon (IRL), a biodiverse estuary system that spans 250km along Florida's east coast. In this study, the cyanobacterial bloom progression at three sites within the central IRL was monitored over the course of two summers. The blooms consisted of four unique cyanobacterial species, including the recently described Okeania erythroflocculosa. The cyanobacteria produced a range of known bioactive compounds including malyngolide, lyngbyoic acid, microcolins A-B, and desacetylmicrocolin B. Ecologically-relevant assays showed that malyngolide inhibited the growth of marine fungi (Dendryphiella salina and Lindra thalassiae); microcolins A-B and desacetylmicrocolin B inhibited feeding by a generalist herbivore, the sea urchin Lytechinus variegatus; and lyngbyoic acid inhibited fungal growth and herbivore feeding. These chemical defenses likely contribute to the persistence of cyanobacterial blooms in the IRL during the summer growing period. PMID- 29122245 TI - Methods for segmentation of rheumatoid arthritis bone erosions in high-resolution peripheral quantitative computed tomography (HR-pQCT). AB - OBJECTIVE: The comparison between different techniques to quantify the 3 dimensional size of inflammatory bone erosions in rheumatoid arthritis(RA) patients. METHODS: Anti-cyclic citrullinated peptide antibody(ACPA) positive RA patients received high-resolution peripheral quantitative computed tomography (HR pQCT) scans of the metacarpophalangeal joints (MCP). Erosions were measured by three different segmentation techniques: (1) manual method with calculation by half-ellipsoid formula, (2) semi-automated modified Evaluation Script for Erosions (mESE), and (3) semi-automated Medical Image Analysis Framework (MIAF) software. Bland & Altman plots were used to describe agreement between methods. Furthermore, shape of erosions was classified as regular or irregular and then compared to the sphericity obtained by MIAF. RESULTS: A total of 76 erosions from 65 RA patients (46 females/19 males), median age 57 years, median disease duration 6.1 years and median disease activity score 28 of 2.8 units were analyzed. While mESE and MIAF showed good agreement in the measurement of erosion size, the manual method with calculation by half-ellipsoid formula underestimated erosions size, particularly with larger erosions. Accurate segmentation is particularly important in larger erosions, which are irregularly shaped. In all three segmentation techniques irregular erosions were larger in size than regular erosions (MIAF: 19.7 vs. 3.4mm3; mESE: 15.5 vs. 2.3mm3; manual = 7.2 vs. 1.52mm3; all p < 0.001). In accordance, sphericity of erosions measured by MIAF significantly decreased with their size (p < 0.001). CONCLUSION: MIAF and mESE allow segmentation of inflammatory bone erosions in RA patients with excellent inter reader reliability. They allow calculating erosion volume independent of erosion shape and therefore provide an attractive tool to quantify structural damage in individual joints of RA patients. PMID- 29122246 TI - Nurses' knowledge, clinical practice and attitude towards unconventional medicine: Implications for intercultural healthcare. AB - OBJECTIVE: The aim of this hospital-based, cross-sectional study was to examine nurses' knowledge, personal and professional practices and attitude towards complementary and alternative medical therapies in urban Ghana. METHOD: Using convenience sampling technique, cross-sectional data were collected from 210 registered and practicing nurses with self-administered questionnaire based on the Complementary and Alternative Medicine (CAM) Health Belief Questionnaire (CHBQ). Descriptive statistics and the associations between variables were calculated using Pearson's Chi-square test and/or Fisher's exact test with p < 0.05. RESULTS: The mean score of nurses' knowledge on CAM therapies was low (mean +/- SD, 38.39 +/- 10.11; possible range, 18-72) which was built on nurses' personal experiences. Nurses, therefore, lacked the confidence to recommend CAM therapies to patients. Despite the isolated cases of non-herbal supplements, relaxation techniques, massage and prayer healing, the study found an overall low personal use of CAM (mean +/- SD, 32.97 +/- 10.78; possible range, 18-72) among nurses over the last 12 months. Yet, nurses exhibited a positive attitude towards CAM (mean +/- SD, 72.7 +/- 12.5, possible range, 67-110). We observed significant associations among nurses' CAM knowledge and education [chi2 (2) = 6.69, p = 0.035] and religion [chi2 (2) = 7.96, p = 0.019]; nurses' personal use of CAM and income [chi2 (2) = 16.07, p < 0.001] and religion [chi2 (2) = 18.65, p < 0.001]; and nurses' clinical CAM use and income [chi2 (2) = 7.01, p = 0.030]. CONCLUSION: Despite the overall positive attitude towards CAM therapies, Ghanaian nurses do not perceive themselves to have sufficient knowledge of CAM. Integrating CAM education into the nurses' training curriculum can improve CAM knowledge and professional practice among nurses, and in turn, enhance evidence-based patient care within the framework of intercultural healthcare system in Ghana. PMID- 29122247 TI - A qualitative investigation of Australian psychologists' perceptions about complementary and alternative medicine for use in clinical practice. AB - This study explored psychologists' knowledge of, attitude toward, and experience with complementary and alternative medicine (CAM) use for clinical purposes. Using a qualitative design, 18 Australian psychologists participated in a semi structured interview. Psychologists had some understanding about CAM; yet, there was a mismatch between their perceived and actual knowledge. While psychologists were, in general, open toward using CAM with clients they were also sceptical. Attitudes did not overly influence psychologists' views about using CAM in practice, rather adhering to the scientist-practitioner model and embracing a client-centred approach affected their beliefs. Different views emerged as guiding psychologists' use of CAM; however, the codes of conduct played a major role in informing psychologists' use in clinical practice. Psychologists appear open to the idea to use some forms of CAM to enhance client care; yet, they experience unique difficulties such as ethical constraints that may prevent their actual use of CAM for clinical purposes. PMID- 29122248 TI - Effects of Qigong on symptom management in cancer patients: A systematic review. AB - PURPOSE: Qigong as a complementary and alternative therapy is often used by cancer patients for symptom management. The aim of this systematic review is to critically evaluate the effectiveness of Qigong on symptom management among cancer patients. METHODS: A systematic search was conducted in the following databases from their inception through May 2016: Cochrane Library, PubMed/MEDLINE, CINAHL, PsycINFO, PEDRO. All controlled clinical trials of Qigong among cancer patients were included. The strength of the evidence was evaluated for all included studies using the Oxford Centre for Evidence-based Medicine Levels of Evidence. The risk of bias was assessed using the Cochrane Collaboration's Tool for Assessing Risk of Bias. RESULTS: Twenty-two studies including fifteen randomized controlled trials and eight controlled clinical trials examined the efficacy of Qigong in symptom management among patients with various cancers. Results of these studies indicated that symptoms in the Qigong group were significantly improved or there was an observed positive trend from pre-to post-interventions scores for physical symptoms and psychological symptoms. CONCLUSION: The effectiveness of Qigong as a health practice adopted by cancer patients to manage their symptoms during their cancer journey is not proven, but there are promising results that need further verification in future research. PMID- 29122249 TI - The effect of reflexology on the quality of life with breast cancer patients. AB - BACKGROUND: This study aims to identify the effect of reflexology on the quality of life in patients with breast cancer. METHODS: The population of the study conducted comprised of 60 patients; 30 forming the control and 30 the experimental groups (30 experimental, 30 control). Patient identification forms and EORTC QLQC30 Quality of Life Scale were used to collect the data. STATISTICAL ANALYSIS USED: The data obtained as a result of the study were assessed via computer using 'Statistical Package for Social Science 21.0' software. RESULTS: The results of the experiment demonstrated that the within-group symptom total score average of the patients in the experiment/treatment group decreased after the reflexology treatment; while the general health and functional total score averages in the treatment group increased; and the difference between pretest and posttest measurements was statistically significant (p = 0.000). Once symptom, functional, and general health total score averages from the posttest measurement are compared across treatment and control groups, symptom total score average of the patients in the treatment group turned out to be significantly lower than that of the patients in the control group (p = 0.001). In terms of functional and general health score averages, patients in the treatment group scored significantly higher than those in the control group (p = 0.000). CONCLUSION: Reflexology was found to reduce the symptoms experienced by breast cancer patients, while at the same time increasing the functional and general health status. PMID- 29122250 TI - Trunk and hip muscle activation during yoga poses: Implications for physical therapy practice. AB - OBJECTIVE: To determine and compare activation of core muscles during yoga to traditional back exercises. METHODS: Surface electromyography was used to quantify activation of the rectus abdominis (RA), abdominal obliques (AO), lumbar extensors (LE), and gluteus maximus (GMX) during four yoga poses. Data were expressed as 100% of a maximum voluntary isometric contraction. Separate analyses of variance with repeated measures were used to compare muscle activity across each exercise. RESULTS: Subjects generated greater RA (P < 0.0001) and AO (P < 0.0001) activity during the Plank. They generated greater AO activity (P < 0.0001) during the Upward-Facing Dog than the Chair and Dominant-Side Warrior 1. LE activity was greatest (P < 0.0001) during the Chair. GMX activity was similar (P = 0.09) during all exercises. CONCLUSION: Yoga poses may help improve core endurance and strength. Clinicians may use these data when developing and implementing an evidence-based core exercise program for individuals who prefer a yoga treatment strategy. PMID- 29122251 TI - The effect of acupressure on pain, anxiety, and the physiological indexes of patients with cancer undergoing bone marrow biopsy. AB - OBJECTIVES: This study aimed to determine the effect of acupressure on pain intensity, anxiety, and physiological indexes of patients with cancer undergoing bone marrow biopsy and aspiration. METHODS: The study was designed as a randomized, double-blinded, controlled trial. Ninety samples was selected using the convenience sampling method, then for allocation groups random block sampling was used (30 for each group). The three groups were similar by age and gender. LI4 and HT7 (Shen Men) acupressure points were examined for the intervention. Sham pressure was used in the placebo group while no intervention was applied in the control group. RESULTS: The results showed that the lowest average anxiety score (1.5 +/- 0.5; P = 0.01) and the lowest average pain score (4.9 +/- 0.8) after the intervention were related to the acupressure method (P = 0.001). CONCLUSION: Cost effectiveness and short-term simple education make acupressure method useful in clinical settings for different illnesses. PMID- 29122252 TI - The quality of life of chiropractors using PROMIS: Results from a practice-based research network. PMID- 29122253 TI - The effect of nature sounds on physiological indicators among patients in the cardiac care unit. AB - BACKGROUND AND OBJECTIVES: Environmental noises may create physiological and psychological disorders in patients hospitalized in the CCU. Therefore, this study was conducted to investigate the effects of nature sounds on physiological indicators among patients in the CCU. MATERIALS & METHODS: This randomized clinical trial was conducted on 93 patients hospitalized in the cardiac care units of three teaching hospitals in 2016. The patients were selected using the convenient method with three randomized blocks. The patients were assigned into three groups as nature sounds, silence that received a set of headphones without playing sounds, and control groups. In addition to routine care, the patients in the intervention group listened to nature sounds for 30 min using a set of headphones for two days. The patients in the control group only received routine care. In addition to routine care, the patients in the silence group used a set of headphones for 30 min to block noises and no sound was played for them. Physiological indicators such as heartbeat rate, systolic and diastolic blood pressures, respiration rate, and arterial O2 saturation were assessed using monitoring devices. Descriptive and inferential statistics were used for data analysis via the SPSS software. FINDINGS: Nature sounds and silence had no statistically significant effects on physiological indicators. However, a statistically significant difference was reported in the heart rate in the nature sound group before and after the intervention in the first day of the intervention (P = 0.046). In the second day of the intervention, there were statistically significant differences in the diastolic blood pressure in the nature sounds group (P = 0.028), heart rate (P = 0.001) and diastolic blood pressure (P = 0.013) in the silence group, and heart rate (P = 0.014) in the control group before and after the intervention. CONCLUSION: Listening to nature sounds or the use of headphones blocked environmental noises and could influence mean arterial pressure. Future studies can examine the effects of this intervention implemented for a longer term using nature sounds by patients. PMID- 29122254 TI - YOGA and self-regulation in management of essential arterial hypertension and associated emotional symptomatology: A randomized controlled trial. PMID- 29122255 TI - The medium-term effects of diadynamic currents in chronic low back pain; TENS versus diadynamic currents: A randomised, follow-up study. AB - OBJECTIVE: The aims of the study were to evaluate the medium-term effects of diadynamic (DD) currents on relieving symptoms/improving physical functionality in patients with chronic low back pain (LBP) and to compare the efficacy of DD versus TENS. METHODS: The patients were divided into two groups as the TENS group (n = 26) and the DD group (n = 29). Additional treatment of hot pack + therapeutic ultrasound was applied to all patients. The therapy programs were administered as a total of 10 sessions over a period of 2 weeks. Roland Morris Disability Questionnaire (RDQ), Oswestry Disability Index and Visual Analog Scale (VAS) values were recorded. RESULTS: Both groups showed significant improvements in VAS and RDQ scores after one month of the therapies (all p < 0.05). CONCLUSION: Using TENS and DD currents in chronic LBP can lead to reduced pain, and improved physical functions. Hence, DD currents can be used as an adjuvant therapy for rehabilitation of chronic LBP. PMID- 29122256 TI - Cupping therapy: An analysis of the effects of suction on skin and the possible influence on human health. AB - BACKGROUND: Cupping therapy is a traditional therapy that has been employed worldwide for thousands of years. Despite a lack of quality clinical studies evaluating the efficacy of cupping therapy, its long history and widespread use throughout the world suggests the commonly claimed health benefits should not be completely discounted as without merit. PURPOSE: The goal of this paper is to present the research detailing what is known concerning the effects of suction on skin and underlying tissue, and the reaction of the body to that stimulus. Understanding the literature on the physiological effects of this mechanical force may help elaborate an explanation for the advertised local and systemic effects of cupping therapy. FINDINGS: Negative pressure causes stretching of the skin and underlying tissue and dilation of the capillaries. This stimulates an increase in tissue blood flow, eventually leading to capillary rupture and ecchymosis. Macrophages phagocytize the erythrocytes in the extravascular space which stimulates the production of Heme Oxygenase-1 (HO-1) to metabolize the heme. Heme catalysis results in the production of carbon monoxide (CO), biliverdin(BV)/bilirubin(BR) and iron. HO-1, BV, BR, and CO has been shown to have antioxidant, anti-inflammatory, antiproliferative, and neuromodulatory effects in animal and human systems. These substances also stimulate a shift of macrophages to the anti-inflammatory M2 phenotype. There is evidence that the effects are both local and systemic. CONCLUSION: Besides the mechanical effect of cupping increasing the local blood flow and stretching underlying tissue, activation of the HO-1 system could account for many of cupping therapy's claimed local and systemic health benefits. PMID- 29122257 TI - Auricular therapy for lactation: A systematic review. AB - BACKGROUND: Support for breastfeeding has been a matter of considerable interest in healthcare. In the field of traditional and complementary medicine, the effectiveness of auricular therapy on lactation has been investigated by several clinical studies. AIM AND OBJECTIVES: This review was mainly performed to assess the current evidence of auricular therapy on lactation. The objectives were to assess the current evidence of AT for lactation, examine the intervention protocols and outcome measures adopted by the studies included, and inform clinical application and future research in this area. STUDY DESIGN: Systematic review. METHOD: Narrative synthesis methodology was used to incorporate diverse forms of evidence within this systematic review. RESULTS: Twenty-three randomized controlled trials and three non-randomized controlled trials were identified, of which 25 studies applied auricular acupressure with vaccaria seeds as the sole form of auricular therapy. Relative risks calculated on the onset of lactation and milk production are all less than 1. These results indicate that women in the auricular therapy group lactated earlier than their counterparts in the control group and the risk of low milk production was reduced while on auricular therapy. Absolute risk differences showed magnitude of effect ranging from small to medium. Standardized mean differences calculated on serum prolactin data generally favor auricular therapy over routine care. Overall, mothers treated by auricular therapy exhibited better lactation outcomes. CONCLUSION: The available data show evidence of benefits for postpartum lactation from auricular therapy. However, research using a more stringent design, standardized protocol, and valid outcome measures are warranted before it can be considered to be evidence-based practice. Issues from the current studies are highlighted and may serve to inform future trials. PMID- 29122258 TI - The role of massage in reducing the risk of burnout in employees of large corporations. PMID- 29122259 TI - Diet and lifestyle intervention on chronic moderate to severe depression and anxiety and other chronic conditions. AB - This group study explored how an intervention of diet, lifestyle and behavior modification, including a plant-based diet, daily exercise and mindfulness techniques, would affect 500 adult men and women participants diagnosed with chronic moderate to severe depression and anxiety and other conditions during a 12 week period. An analysis of the health outcomes detailed in self-reported diary entries was carried out at the conclusion of the 12 week period. These reports noted improvements in depression, anxiety and all other conditions addressed by the study, with the majority of participants reporting substantial benefits. A six month follow up indicated that these benefits persisted in most of the participants. These results demonstrate that an intervention of diet, exercise, lifestyle and behavior modification may provide considerable benefits for moderate to severe depression and anxiety as well as other conditions. PMID- 29122260 TI - Effects of pleasant olfactory mental imagery on the arterial oxygenation in patients with open heart surgery: A randomized controlled trial. AB - BACKGROUND AND PURPOSE: Arterial hypoxemia is one of the most common respiratory complications following cardiac surgery. This study was intended to examine the effects of pleasant olfactory mental imagery on postoperative hypoxemia in patients undergoing open heart surgery. MATERIALS AND METHODS: This is a randomized controlled clinical trial. The sample consisted of 80 patients who were randomly assigned to either practice olfactory mental imagery (experimental group) or receive routine care (control group). A card with the image of roses was given to patients and they were asked to look at the image, visualize the scent of roses in the mind, and then sniff as much as possible, hold their breath for 2 s and eventually exhale slowly through the nose. This procedure was consecutively repeated five times. After a fifteen-minute break, patients proceeded to practice olfactory mental imagery with other fruit images. The experimental group executed the olfactory mental imagery for two hours in the morning and two hours in the afternoon on postoperative days 1 and 2. RESULTS: No statistically significant differences were observed between the experimental and control groups regarding sociodemographic characteristics, medical and surgical information. This study also demonstrated that the mean Spao2 was significantly higher in the experimental group (97.400 +/- 1.70) than the control group (96.465 +/- 1.70) (p = 0.015). CONCLUSION: The results of this study suggest that olfactory mental imagery can improve arterial oxygenation in patients with cardiac surgery. PMID- 29122262 TI - Effects of geranium aroma on anxiety among patients with acute myocardial infarction: A triple-blind randomized clinical trial. AB - OBJECTIVE: The is study examined the effects of geranium aroma on anxiety among patients with AMI. METHODS: This randomized, triple-blind, placebo-controlled clinical trial recruited 80 patients with AMI through convenience sampling. The patients were allocated to geranium and placebo groups (n = 40 each) using stratified block randomization. On the second day of admission three drops of geranium essential oil and placebo were poured on absorbing patches attached inside the oxygen masks of the geranium and placebo groups, respectively. The patients were asked to inhale the aroma for 20 min a day on two consecutive days. RESULTS: all stages of the intervention, the two groups had a significant difference in anxiety scores, i.e. geranium aroma caused significantly greater reductions in the anxiety scores (P < 0.001). CONCLUSION: Inhalation aromatherapy with geranium essential oil is recommended as an easy-to-use, intervention to reduce anxiety among patients with AMI. PMID- 29122261 TI - Evaluation of New Zealand osteopathy patients experiences of their treatment. AB - OBJECTIVES: To investigate the experiences of patients seeking osteopathy treatment in New Zealand; and to describe their perceptions of osteopathic treatment. DESIGN: Survey-based research design. SETTING: Private osteopathy practices. MAIN OUTCOME MEASURES: Demographic survey and the Patient Perception Measure-Osteopathy (PPM-O). RESULTS: Twelve osteopaths were recruited as practitioners. Responses from 107 patients were analysed. Approximately 75% of patients reported receiving a 'mostly cranial' treatment approach. The majority of patients (96.2%) indicated that osteopathic treatment helped their condition. The most frequently experienced sensation was 'relaxed'. A positive relationship was observed between the PPM-O and demographic variables. CONCLUSIONS: This is the first study to report on New Zealand osteopathy patient's experience of their treatment. The sensations and emotions experienced are largely consistent with previous Australian research. Predominantly positive perceptions of osteopathic treatment were reported. The current study provides some evidence of the construct validity of the PPM-O in a New Zealand patient population. PMID- 29122263 TI - Knowledge, attitude, and beliefs toward traditional herbal medicine use among diabetics in Jeddah Saudi Arabia. AB - Herbs have long been used in the treatment of diabetes. Therefore, a cross sectional study of a random sample of diabetic patients was conducted to assess their knowledge, attitude, and beliefs about the use of herbs to control diabetes. Approximately 64% of the patients had previously used herbs for controlling diabetes; 27%, 20.3%, 15.2%, and 10.8% used myrrh, black seeds, fenugreek, and aloe, respectively. Approximately 55.1% patients preferred using herbs to prescription drugs, while 75.2% used herbs with the prescribed medications. Only 38.3% patients informed their doctors about using herbs. Moreover, 54.2% of respondents experienced no side effects using herbs, and 64.5% noticed an improvement in blood sugar level while using herbs. No significant relationship between demographic characteristics and herbal medicine use was found. In conclusion, most diabetic patients exhibited low knowledge, attitude, and beliefs regarding herbal use. Therefore, the development of an awareness program is needed to improve these factors. PMID- 29122264 TI - The effects of breathing techniques training on the duration of labor and anxiety levels of pregnant women. AB - OBJECTIVE: To assess the effects of breathing techniques training on anxiety levels of pregnant women and the duration of labor. MATERIALS AND METHODS: The study utilizes a randomized controlled trial design. The pregnant women were divided into control (n = 35) or experimental group (n = 35) randomly. The experimental group received breathing techniques training in the latent phase and these techniques were applied in the following phases accordingly. The anxiety levels of pregnant women were evaluated three times in total. The duration of labor was considered as the duration of the first stage of labor and the duration of the second stage of labor. RESULTS: There were significant differences between the two groups regarding the mean State Anxiety Inventory (SAI) and the mean duration of labor. CONCLUSIONS: This study concludes that breathing techniques are an effective method in the reduction of anxiety and influence the duration of delivery during labor. PMID- 29122266 TI - Tone as a health concept: An analysis. AB - STUDY DESIGN: Concept analysis. INTRODUCTION: This paper is a report on the analysis of the concept of tone in chiropractic. PURPOSE: The purpose of this paper is to clarify the concept of tone as originally understood by Daniel David Palmer from 1895 to 1914 and to monitor its evolution over time. METHODS: Data was sourced from Palmer's original work, published between 1895 and 1914. A literature search from 1980 to 2016 was also performed on the online databases CINHAL, PubMed and Scopus with key terms including 'tone', 'chiropractic', 'Palmer', 'vitalism', 'health', 'homeostasis', 'holism' and 'wellness'. Finally hand-searches were conducted through chiropractic books and professional literature from 1906 to 1980 for any references to 'tone'. Rodgers' evolutionary method of analysis was used to categorise the data in relation to the surrogates, attributes, references, antecedents and consequences of tone. RESULTS: A total of 49 references were found: five from publications by Palmer; three from the database searches, and; the remaining 41 from professional books, trade journals and websites. MAJOR CONCLUSIONS: There is no clear interpretation of tone in the contemporary chiropractic literature. Tone is closely aligned with functional neurology and can be understood as an interface between the metaphysical and the biomedical. Using the concept of tone as a foundation for practice could strengthen the identity of the chiropractic profession. PMID- 29122265 TI - A mixed methods evaluation of a Mindfulness-Based Stress Reduction course for people with Parkinson's disease. AB - OBJECTIVE: The aim of this study was to evaluate the effects of an 8-week Mindfulness-Based Stress Reduction course (MBSR) on people with Parkinson's disease who experienced depression, anxiety, stress or difficulty coping with Parkinson's. METHODS: Thirteen participants were recruited and six completed the full MBSR course. Data were analysed using repeated measures analysis of variance and thematic analysis. RESULTS: There were significant improvements in levels of depression, anxiety and stress at weeks eight and sixteen, as measured by the Depression Anxiety and Stress Scale, short version (DASS-21). Themes of 'mindfulness as challenging' and 'mindfulness as life-enhancing' were identified from follow-up questionnaire responses. All participants reported they would recommend MBSR to other people with Parkinson's. CONCLUSION: This study supports previous preliminary findings that mindfulness-based interventions could benefit people with Parkinson's experiencing non-motor symptoms. Further research using larger sample sizes, a control group, and a longer follow-up period is required. PMID- 29122267 TI - Effects of traditional Chinese exercises on the rehabilitation of limb function among stroke patients: A systematic review and meta-analysis. AB - OBJECTIVE: To systematically review literature about the rehabilitative effects of traditional Chinese exercises (TCEs) on limb function among patients with stroke. METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs). Twelve electronic databases were searched from their inceptions to February 2017, including PudMed, The Cochrane Library, Web of Science, EMBase, Science Direct, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine, Chinese Scientific Journal Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and WanFang Data. RCTs were located to examine the rehabilitative effects of TCEs on limb function among stroke patients. Two authors independently screened the literature, extracted data and assessed the risk bias of the included studies. Methodological quality evaluation and meta-analysis of included studies was performed by using Cochrane Collaboration's tool (RevMan 5.3). RESULTS: A total of 31 RCTs with 2349 participants were included. Results of meta analysis showed that TCEs produced positive effects on limb motor function (random effects model, standardized mean difference [SMD] = 1.21, 95% confidence interval [CI] = 0.66 to 1.77, P < 0.01), balance function{Berg balance scale: (random effects model, SMD = 2.07, 95%CI = 1.52 to 2.62, P < 0.01), timed-up-and go test: (fixed effects model, mean difference [MD] = -1.77, 95%CI = -2.87 to 0.67, P < 0.01)}, activities of daily living (ADL) ability {Barthel Index scale: (random effects model, MD = 15.60, 95%CI = 7.57 to 23.63, P < 0.01), Modified Barthel Index scale: (random effects model, MD = 12.30, 95%CI = 7.48 to 17.12, P < 0.01)}, and neurological impairment (fixed effects model, MD = -2.57, 95%CI = 3.14 to -2.00, P < 0.01). After subgroup analysis and sensitivity analysis, the positive effects did not be affected by different types of TCEs and different lengths of intervention time. However, TCEs were no benefit to physical function on Short Physical Performance Battery and 2-min Step Test among stroke patients. CONCLUSION: Current evidence showed that TCEs produced positive effects on limb motor function, balance function, ADL ability and neurological impairment among stroke patients. More large-scale, high-quality, multiple center RCTs are required to further verify above conclusions in the future. PMID- 29122268 TI - Comparison of pediatric self reports and parent proxy reports utilizing PROMIS: Results from a chiropractic practice-based research network. AB - OBJECTIVE: To measure the cross-informant variant of pediatric quality of life (QoL) based on self-reports and parent proxy measures. METHODS: A secondary analysis of baseline data obtained from two independent studies measuring the QoL based on the pediatric PROMIS-25 self-report and the PROMIS parent-proxy items banks. A scoring manual associated raw scores to a T score metric (mean = 50; SD = 10). Reliability of QoL ratings utilized the ICC while comparison of mean T Scores utilized the unpaired t-test. RESULTS: A total of 289 parent-child dyads comprised our study responders. Average age for parents and children was 41.27 years and 12.52 years, respectively. The mean T score (child self-report: parent proxy) for each QoL domains were: mobility (50.82:52.58), anxiety (46.73:44.21), depression (45.18:43.60), fatigue (45.59:43.92), peer-relationships (52.15:52.88) and pain interference (47.47:44.80). CONCLUSION: Parents tend to over-estimate their child's QoL based on measures of anxiety, depression, fatigue, peer relationships and pain interference. PMID- 29122269 TI - The effect of self-selected soothing music on fistula puncture-related pain in hemodialysis patients. AB - OBJECTIVE: This study was intended to examine the effect of selective soothing music on fistula puncture-related pain in hemodialysis patients. MATERIALS AND METHODS: This is a randomized clinical trial in which 114 participants were selected from two hemodialysis units by means of a non-random, convenience sampling method. The participants were then allocated in three groups of music (N = 38), headphone (N = 38), and control (N = 38). The fistula puncture-related pain was measured 1 min after venipuncture procedure in all three groups. The music group listened to their self-selected and preferred music 6 min before needle insertion into a fistula until the end of procedure. The headphone group wore a headphone alone without listening to music 6 min before needle insertion into a fistula until the end of procedure. The control group did not receive any intervention from the research team during needle insertion into a fistula. The pain intensity was measured immediately after the intervention in all three groups. RESULTS: This study showed a significant difference between the music and control groups, and the music and headphone groups in terms of the mean pain score after the intervention. However, the analysis did not indicate any significant difference between the headphone and control groups with regard to the mean pain score after the intervention. CONCLUSION: It is concluded that music can be used effectively for pain related to needle insertion into a fistula in hemodialysis patients. Future research should investigate the comparative effects of pharmacological and non-pharmacological interventions on fistula puncture-related pain. PMID- 29122270 TI - Sound as a supportive design intervention for improving health care experience in the clinical ecosystem: A qualitative study. AB - PURPOSE: Most prior hospital noise research usually deals with sound in its noise facet and is based merely on sound level abatement, rather than as an informative or orientational element. This paper stimulates scientific research into the effect of sound interventions on physical and mental health care in the clinical environment. METHODS: Data sources comprised relevant World Health Organization guidelines and the results of a literature search of ISI Web of Science, ProQuest Central, MEDLINE, PubMed, Scopus, JSTOR and Google Scholar. RESULTS: Noise induces stress and impedes the recovery process. Pleasant natural sound intervention which includes singing birds, gentle wind and ocean waves, revealed benefits that contribute to perceived restoration of attention and stress recovery in patients and staff. CONCLUSIONS: Clinicians should consider pleasant natural sounds perception as a low-risk non-pharmacological and unobtrusive intervention that should be implemented in their routine care for speedier recovery of patients undergoing medical procedures. PMID- 29122271 TI - Utilization and perceived benefits of homeopathy and herbal therapies in U.S. adults: Implications of patient-centered care. AB - We evaluated reasons for and perceived benefits of using homeopathic and herbal therapies in U.S. adults. Data were collected from the 2012 National Health Interview Survey, which represents non-institutionalized U.S. adults (n = 33,167 unweighted). In the past 12 months, 18.6% (41.95 million) of U.S. adults reported using either homeopathy and/or herbal therapies. Among these users, 34.8% and 5.1% used them for wellness only and treatment only, respectively. 60.1% reported using homeopathic and herbal therapies for a combination of both treatment and wellness. In four out of seven self-reported perceived benefit measures, users for wellness only and for a combination of both treatment and wellness had higher likelihood of reporting benefits, compared to those who used CAM for treatment only (p < 0.001). Overall, homeopathic and herbal therapies maybe a promising lifestyle approach to enhance health-related quality of life in U.S. adults, but future research is needed to establish safety and efficacy issues. PMID- 29122273 TI - SPN Position Statement: The Role of Pediatric Nurses in the Promotion and Protection of Human Milk and Breastfeeding. PMID- 29122272 TI - Enhancing yoga participation: A qualitative investigation of barriers and facilitators to yoga among predominantly racial/ethnic minority, low-income adults. AB - Yoga is underutilized among racial/ethnic minorities and low-income populations. To enhance participation among these demographic groups and to inform a future clinical trial, we conducted a qualitative formative investigation, informed by the Social Contextual Model of health behavior change, to identify barriers and facilitators to yoga that could impact study participation. We recruited twenty four racially/ethnically diverse adults, with and without prior yoga experience, from a low-income, urban housing community to participate in either an individual interview or focus group. A thematic data analysis approach was employed. Barriers to yoga engagement included the perception that yoga lacks physicality and weight loss benefits, fear of injury, lack of ability/self-efficacy to perform the practices, preference for other physical activities, and scheduling difficulties. Facilitators of yoga engagement included a quality yoga instructor who provides individualized instruction, beginner level classes, and promotional messaging that highlights the potential benefits of yoga, such as stress reduction. PMID- 29122274 TI - Frequency and Significance of Intravascular Hemolysis Before and After Transcatheter Aortic Valve Implantation in Patients With Severe Aortic Stenosis. AB - Intravascular hemolysis (IVH) has been identified in patients with surgical prosthetic valves, but few have been reported after transcatheter aortic valve implantation (TAVI). We conducted a prospective analysis of 64 TAVI patients. The hemolysis profiles were collected at baseline and 6 months after TAVI. The echocardiography was performed at baseline and 6 months after TAVI. There are 14 patients (21.9%) with IVH before and 24(37.5%) after TAVI. The serum haptoglobin values before and 6 months after TAVI are 126.7 +/- 75.1 vs 86.3 +/- 57.1 mg/dl (p < 0.001). More >=moderate paravalvular leakage (PVL) (50% vs 7.5%, p < 0.001), bicuspid aortic valve (BAV) (33.3% vs 5.0%, p = 0.004), use of 23 mm prosthesis (29.2% vs 7.5%, p = 0.03), higher residual valvular pressure gradient (17.9 +/- 6.8 mm Hg vs 14.7 +/- 5.7 mm Hg, p = 0.05), and lower effective orifice area index (1.05 +/- 0.21 vs 1.21 +/- 0.29, p = 0.03) were observed in patients with post-TAVI IVH. On multivariate regression analysis, BAV and >=moderate PVL are independently related to post-TAVI IVH. With log-rank test, 1-year rates of readmission due to cardiovascular cause were significantly higher in patients with post-TAVI IVH (odds ratio 4.5; 95% confidence interval 1.3 to 15.6; p = 0.02), after adjusting age and gender. In conclusion, >=moderate PVL and BAV are predictors of post-TAVI IVH, which is associated with increased cardiovascular readmission in 1-year follow-up. PMID- 29122275 TI - Bleeding Complications After Percutaneous Mitral Valve Repair With the MitraClip. AB - Bleeding after cardiac surgery or cardiovascular interventions is associated with worse patient outcome. Only very limited data are available on the subject of bleeding after percutaneous edge-to-edge mitral valve repair (PMVR). We performed a single center analysis including 347 consecutive patients who underwent PMVR. Bleeding was defined according to the Mitral Valve Academic Research Consortium (MVARC) end point definition. The incidence of MVARC bleeding was 21.6% (n = 75), whereas major MVARC bleeding (hemoglobin decrease >=3 g/dl) occurred in 7.4% (n = 26). Only 33.3% of all bleeding cases were access site-related. In multivariate regression analyses, independent predictors of MVARC bleeding were the presence of coronary artery disease (2.809, 95% CI 1.123 to 7.022, p = 0.027) and intervention duration (1.010, 95% CI 1.002 to 1.018, p = 0.010). Patients experiencing MVARC bleeding had longer hospital stays (p = 0.026); however, neither major nor extensive MVARC bleeding was associated with increased 30-day or 1-year mortality. A decrease in hemoglobin levels >=3 g/dl without clinically visible bleeding sign-not considered in the MVARC bleeding definition-occurred in 9.5% of patients. A hemoglobin decrease of >=4 g/dl had a strong association with worse survival in those patients with obscure bleeding. In conclusion, these data show a relevant incidence of bleeding after PMVR. In contrast to other cardiovascular interventions, the majority of bleedings were not access site related. Particularly, patients with obscure bleeding, which are not included in the MVARC end point definitions, had worse outcomes and should therefore be considered for a more intensive workup. PMID- 29122276 TI - Comparison of Delay Times Between Symptom Onset of an Acute ST-elevation Myocardial Infarction and Hospital Arrival in Men and Women <65 Years Versus >=65 Years of Age.: Findings From the Multicenter Munich Examination of Delay in Patients Experiencing Acute Myocardial Infarction (MEDEA) Study. AB - Early administration of reperfusion therapy in acute ST-elevation myocardial infarctions (STEMI) is crucial to reduce mortality. Although female sex and old age are key factors contributing to an inadequate long prehospital delay time, little is known whether women >=65 years are a particular risk population. Hence, we studied the interaction of sex and age (<65 years or >=65 years) and the contribution of chest pain to delay time during STEMI. Bedside interview data were collected in 619 STEMI patients from the Munich Examination of Delay in Patients Experiencing Acute Myocardial Infarction (MEDEA) study. Sex and age group stratification disclosed an excess delay risk for women >=65 years, accounting for a 2.39 (95% confidence interval (CI) 1.39 to 4.10)-fold higher odds to delay longer than 2 hours compared with all other patient groups including younger women (p <=0.002). Median delay time was 266 minutes in women >=65 years and 148 minutes in younger women (p <0.001). Chest pain during STEMI had the lowest frequency both in women (81%) and men >=65 years (83%) and the highest frequency (95%) in younger women. Experiencing non-chest pain was 2.32 fold (95% CI, 1.20 to 4.46, p <0.05) higher in women >=65 years than in all other patients. Mediation analysis disclosed that the effect accounted for only 9% of the variance. Age specific educational strategies targeting women >=65 years at risk are urgently needed. To tailor adequate strategies, more research is required to understand age- and sex driven barriers to timely identification of ischemic symptoms. PMID- 29122277 TI - Influence of Body Mass Index on Long-Term Survival After Cardiac Catheterization. AB - We examined 18,654 patients who underwent cardiac catheterization in a single center to clarify the association between catheterization indication, body mass index (BMI), and long-term survival over a mean follow-up of 81 months. Patients were grouped by indication for catheterization: (a) acute coronary syndromes (ACS), 7,426 patients; (b) coronary artery disease (CAD) evaluation in stable clinical presentation, 6,911 patients; and (c) primarily non-CAD cardiac evaluations, 4,317 patients. Compared with normal weight, overweight and obesity (but not morbid obesity) was associated with lower risk of long-term mortality. Underweight patients had the greatest risk of mortality. After multivariate adjustment, survival benefit of the overweight and obese was retained in the ACS group [hazard ratio 0.86, 95% confidence interval (0.77-0.96), p = 0.006 and 0.79, (0.68-0.91), p = 0.001, respectively] and in overweight patients in the stable presentation CAD group [0.83, (0.72-0.94), p = 0.005], whereas there was no survival benefit in any of the BMI categories in those catheterized primarily for non-CAD indications. Further analysis of matched cohorts showed similar patterns of survival benefit of the overweight/obese. In conclusion, among patients who underwent cardiac catheterization, an inverse association between BMI and long-term mortality was observed, with the lowest risk noted in the overweight and obese population; the obesity paradox was principally demonstrated in patients with ACS, and was eliminated after covariate adjustment in those catheterized primarily for non-CAD indications. PMID- 29122279 TI - Stem cell-based bone regeneration in diseased microenvironments: Challenges and solutions. AB - Restoration of extensive bone loss and defects remain as an unfulfilled challenge in modern medicine. Given the critical contributions to bone homeostasis and diseases, mesenchymal stem cells (MSCs) have shown great promise to jumpstart and facilitate bone healing, with immense regenerative potential in both pharmacology based endogenous MSC rescue/mobilization in skeletal diseases and emerging application of MSC transplantation in bone tissue engineering and cytotherapy. However, efficacy of MSC-based bone regeneration was not always achieved; particularly, fulfillment of MSC-mediated bone healing in diseased microenvironments of host comorbidities remains as a major challenge. Indeed, impacts of diseased microenvironments on MSC function rely not only on the dynamic regulation of resident MSCs by surrounding niche to convoy pathological signals of bone, but also on the profound interplay between transplanted MSCs and recipient components that mediates and modulates therapeutic effects on skeletal conditions. Accordingly, novel solutions have recently been developed, including improving resistance of MSCs to diseased microenvironments, recreating beneficial microenvironments to guarantee MSC-based regeneration, and usage of subcellular vesicles of MSCs in cell-free therapies. In this review, we summarize state-of the-art knowledge regarding applications and challenges of MSC-mediated bone healing, further offering principles and effective strategies to optimize MSC based bone regeneration in aging and diseases. PMID- 29122278 TI - Meta-Analysis of Aspirin Versus Dual Antiplatelet Therapy Following Coronary Artery Bypass Grafting. AB - Although aspirin monotherapy is considered the standard of care after coronary artery bypass grafting (CABG), more recent evidence has suggested a benefit with dual antiplatelet therapy (DAPT) after CABG. We performed a meta-analysis of observational studies and randomized controlled trials comparing outcomes of aspirin monotherapy with DAPT in patients after CABG. Subgroup analyses were conducted according to surgical technique (i.e., on vs off pump) and clinical presentation (acute coronary syndrome vs no acute coronary syndrome). Random effects overall risk ratios (RR) were calculated using the DerSimonian and Laird model. Eight randomized control trials and 9 observational studies with a total of 11,135 patients were included. At a mean follow-up of 23 months, major adverse cardiac events (10.3% vs 12.1%, RR 0.84, confidence interval [CI] 0.71 to 0.99), all-cause mortality (5.7% vs 7.0%, RR 0.67, CI 0.48 to 0.94), and graft occlusion (11.3% vs 14.2%, RR 0.79, CI 0.63 to 0.98) were less with DAPT than with aspirin monotherapy. There was no difference in myocardial infarction, stroke, or major bleeding between the 2 groups. In conclusion, DAPT appears to be associated with a reduction in graft occlusion, major adverse cardiac events, and all-cause mortality, without significantly increasing major bleeding compared with aspirin monotherapy in patients undergoing CABG. PMID- 29122280 TI - The psychological impact of external fixation using the Ilizarov or Orthofix LRS method to treat tibial osteomyelitis with a bone defect. AB - OBJECTIVE: To examine the psychological impact of external fixation for a tibial bone defect due to osteomyelitis, and to compare the Orthofix limb reconstruction system (LRS) with the Ilizarov external fixator. MATERIALS AND METHODS: The SCL 90-R questionnaire was administered at four different time points (before surgery, while patients wore the external fixation device, when the device was removed, and two to three months after). The scores at the four time points were compared, as were the two different methods of external fixation (Orthofix LRS vs. Ilizarov). RESULTS: The patients experienced a significant adverse impact on their mental health, with the worst outcomes at Time 2 (while wearing the external fixator), but with some negative effects still present even several months after removal of the fixation device. Although the Orthofix LRS and Ilizarov groups showed similar mental health scores at Time 1 (preoperatively) and Time 3 (upon removal of the fixation device), the Orthofix LRS was associated with better scores, specifically in the Hostility (Time 2), Phobic Anxiety (Time 2), Psychoticism (Times 2 and 4), and Other (Time 2) sub-scores, as well as the total score (Times 2 and 4). CONCLUSIONS: Although both Ilizarov and Orthofix LRS fixation resolved the bone defects, external fixation had a negative impact on the patients' mental health, which persisted even after removal of the devices. Although both methods led to negative effects on the patients' mental, the impact of the Orthofix LRS was less severe. PMID- 29122281 TI - Good functional outcome in patients suffering fragility fractures of the pelvis treated with percutaneous screw stabilisation: Assessment of complications and factors influencing failure. AB - BACKGROUND: Low energy pelvic ring fractures in the elderly have traditionally been treated conservatively, a treatment with potential long-term complications and loss of self-independence. Percutaneous screw stabilisation of the posterior pelvic ring is a new treatment modality that enables immediate mobilisation. The aim of this study was to assess the functional outcome after sacroiliac stabilisation in the elderly. METHODS: All elderly patients with a surgically stabilised low energy pelvic fracture between 2010 and 2015 were included. In 2016 a radiographic follow up and functional test was performed at least one year postoperative. RESULTS: The 50 operated patients had a mean age of 79 years and a one-year mortality of 10% (5/50). Only six patients lost independency after the pelvic fracture and moved to nursing home. The mean Timed Up and Go test was 16s at follow-up. The operation of the posterior pelvic ring averaged 63min with a radiation equal to a diagnostic pelvic CT. One intra-foraminally placed screw was immediately removed and 9 patients were later re-operated on due to symptomatic loosening of one or more screws. No loosening of screws was seen in 11 patients where both S1 and S2 were stabilised and out of 23 trans-sacral screws (crossing both sacroiliac joints) only two loosened. DISCUSSION: CT guided stabilisation of the posterior pelvis is safe and most patients resumed good function and independent living. The risk of a revision operation was 20%, but trans-sacral screw stabilisation in both S1 and S2 could reduce the risk of implant loosening. PMID- 29122282 TI - Masquelet technique with external locking plate for recalcitrant distal tibial nonunion. AB - OBJECTIVE: In the present retrospective study, we aimed to analyze the results of treatment for recalcitrant distal tibial nonunion using Masquelet technique with locking plate as a definitive external fixator. MATERIALS: We included 15 consecutive cases of distal tibial nonunion treated at our hospital between January 2012 and December 2015. The reconstructive procedure comprised debridement of the nonunion site, deformity correction, stabilization with an external locked plate, defect filling with cement spacer for inducing membrane formation, and bone reconstruction using a cancellous bone autograft (Masquelet technique). All patients were followed-up for at least one year. RESULTS: Fracture union occurred in all cases after a median of 6.5 months (range, 5-12 months). Mean ankle motion ranged from 12.3 (range, 5-20) degrees of dorsiflexion to 35 (range, 5-55) degrees of plantar flexion. At the final follow-up, the median Iowa ankle score was 83 (range, 68-91). Eight patients had excellent scores, six had good scores, and one had fail score. CONCLUSION: Although the current study involved only a small number of patients and the intervention comprised two stages, we consider that the used protocol is a simple and valuable alternative for the treatment of recalcitrant distal tibial nonunion. PMID- 29122283 TI - Fast and highly selective determination of hemagglutinin content in quadrivalent influenza vaccine by reversed-phase high-performance liquid chromatography method. AB - Seasonal inactivated quadrivalent influenza vaccines are currently formulated to include antigens from two strains of influenza A and a strain from each of the two circulating influenza B virus lineages. However, the applicability of the potency assay currently required for the release of vaccines has been hindered due to cross-reactivity between the two B strains. In this study, a reversed phase high-performance liquid chromatography method previously developed for the separation and quantitative determination of the hemagglutinin content in trivalent influenza vaccine preparations was further extended and found to be adaptable for the assessment of all four hemagglutinin antigens present in quadrivalent influenza vaccines. Vaccines prepared from monovalent bulks and commercial quadrivalent products from the past three vaccination seasons in the Northern Hemisphere were tested with the new method. The results showed excellent resolution of all four hemagglutinins from frequently interfering formulation agents such as surfactants. This method provides a simple approach for fast evaluation of quality and hemagglutinin strain identification in influenza vaccines. It is also the only physicochemical method capable of distinguishing the B strains in quadrivalent influenza vaccines. PMID- 29122284 TI - Broad screening of illicit ingredients in cosmetics using ultra-high-performance liquid chromatography-hybrid quadrupole-Orbitrap mass spectrometry with customized accurate-mass database and mass spectral library. AB - Comprehensive identification and quantitation of 100 multi-class regulated ingredients in cosmetics was achieved using ultra-high-performance liquid chromatography (UHPLC) coupled with hybrid quadrupole-Orbitrap high-resolution mass spectrometry (Q-Orbitrap HRMS). A simple, efficient, and inexpensive sample pretreatment protocol was developed using ultrasound-assisted extraction (UAE), followed by dispersive solid-phase extraction (dSPE). The cosmetic samples were analyzed by UHPLC-Q-Orbitrap HRMS under synchronous full-scan MS and data dependent MS/MS (full-scan MS1/dd-MS2) acquisition mode. The mass resolution was set to 70,000 FWHM (full width at half maximum) for full-scan MS1 and 17,500 FWHM for dd-MS2 stage with the experimentally measured mass deviations of less than 2ppm (parts per million) for quasi-molecular ions and 5ppm for characteristic fragment ions for each individual analyte. An accurate-mass database and a mass spectral library were built in house for searching the 100 target compounds. Broad screening was conducted by comparing the experimentally measured exact mass of precursor and fragment ions, retention time, isotopic pattern, and ionic ratio with the accurate-mass database and by matching the acquired MS/MS spectra against the mass spectral library. The developed methodology was evaluated and validated in terms of limits of detection (LODs), limits of quantitation (LOQs), linearity, stability, accuracy, and matrix effect. The UHPLC-Q-Orbitrap HRMS approach was applied for the analysis of 100 target illicit ingredients in 123 genuine cosmetic samples, and exhibited great potential for high-throughput, sensitive, and reliable screening of multi-class illicit compounds in cosmetics. PMID- 29122285 TI - Determination of gamma-hydroxybutyrate in human urine samples by ion exclusion and ion exchange two-dimensional chromatography system. AB - A two-dimensional ion chromatography system was developed for the determination of gamma-hydroxybutyrate (GHB) in human urine samples. Ion exclusion chromatography was used in the first dimensional separation for elimination of urine matrices and detection of GHB above 10mgL-1, ion exchange chromatography was used in the second dimensional separation via column-switching technique for detection of GHB above 0.08mgL-1. Under the optimized chromatographic conditions, the ion exclusion and ion exchange chromatography separation system exhibited satisfactory repeatability (RSD<3.1%, n=6) and good linearity in the range of 50 1000mgL-1 and 0.5-100mgL-1, respectively. By this method, concentrations of GHB in the selected human urine samples were detected in the range of 0-1.57mgL-1. The urine sample containing 0.89mgL-1 GHB was selected to evaluate the accuracy; the spiked recoveries of GHB were 95.9-102.8%. The results showed that the two dimensional ion chromatography system was convenient and practical for the determination of GHB in human urine samples. PMID- 29122286 TI - Integrated microreactor for enzymatic reaction automation: An easy step toward the quality control of monoclonal antibodies. AB - The main purpose of the present work is to provide a fully integrated miniaturized electrophoretic methodology in order to facilitate the quality control of monoclonal antibodies (mAbs). This methodology called D-PES, which stands for Diffusion-mediated Proteolysis combined with an Electrophoretic Separation, permits to perform subsequently mAb tryptic digestion and electrophoresis separation of proteolysis products in an automated manner. Tryptic digestion conditions were optimized regarding the influence of enzyme concentration and incubation time in order to achieve similar enzymatic digestion efficiency to that obtained with the classical methodology (off-line). Then, the optimization of electrophoretic separation conditions concerning the nature of background electrolyte (BGE), ionic strength and pH was realized. Successful and repeatable electrophoretic profiles of three mAbs digests (Trastuzumab, Infliximab and Tocilizumab), comparable to the off-line digestion profiles, were obtained demonstrating the feasibility and robustness of the proposed methodology. In summary, the use of the proposed and optimized in-line approach opens a new, fast and easy way for the quality control of mAbs. PMID- 29122287 TI - Radiologic and Histopathologic Correlation of Different Growth Patterns of Metastatic Uveal Melanoma to the Liver. AB - PURPOSE: The purpose of this study was to correlate magnetic resonance imaging (MRI) radiographic results with histopathologic growth patterns of metastatic uveal melanoma (UM) to the liver. DESIGN: Clinicopathologic correlation. PARTICIPANTS: Patients with metastatic UM to the liver. METHODS: A retrospective review of MRI images of patients with metastatic UM to the liver at a single institution between 2004 and 2016 was performed. The MRI growth patterns were classified as nodular or diffuse. The histopathologic findings of core liver biopsies of liver metastases identified by needle localization in a subset of these patients were reviewed. The core samples were evaluated by routine light microscopy, including immunohistochemical/immunofluorescent staining for CD31, CD105, and HMB45, and classified as exhibiting an infiltrative or nodular growth pattern. MAIN OUTCOME MEASURES: Magnetic resonance images and core biopsy findings. RESULTS: A total of 32 patients were identified with metastatic UM to the liver that was imaged by MRI, and 127 lesions were identified. A total of 46 lesions were classified by MRI as infiltrative and 81 as nodular. There were 9 needle-localized core biopsies that corresponded to MRI of metastatic lesions. Of these 9 lesions, 3 that were classified as infiltrative on MRI exhibited stage I infiltrative histologic growth patterns; of the remaining 6 that were classified as nodular by MRI, 5 histologically demonstrated stage II or stage III infiltrative growth patterns and 1 histologically demonstrated a nodular growth pattern. CONCLUSIONS: Magnetic resonance imaging of hepatic infiltrative growth patterns of metastatic UM corresponded to stage I histologic infiltrative growth in the sinusoidal spaces, whereas MRI nodular growth patterns corresponded to stage II/III histologic infiltrative growth that replaced the hepatic lobule or histologic nodular growth in the portal triad that effaced adjacent hepatic parenchyma. PMID- 29122288 TI - Bioprocessing Strategies for Pluripotent Stem Cells Based on Waddington's Epigenetic Landscape. AB - As increasing numbers of cell-based therapies advance through clinical trials towards approval for use in humans, the need for robust and well-characterized cell culturing strategies is becoming increasingly apparent. We discuss here novel stem cell bioprocessing strategies based on the concept of using Waddington's epigenetic landscape to represent the process of cellular decision making during development. Specifically, we focus on the manner in which cell behavior triggers cell signaling pathways related to the initial cell fate decision. We also consider how various biochemical engineering strategies can be used to develop these bioprocesses to further enhance their utility in research and therapy. PMID- 29122289 TI - Single-Molecule Analysis of G Protein-Coupled Receptor Stoichiometry: Approaches and Limitations. AB - How G protein-coupled receptors (GPCRs) are organized at the cell surface remains highly contentious. Single-molecule (SM) imaging is starting to inform this debate as receptor behavior can now be visualized directly, without the need for interpreting ensemble data. The limited number of SM studies of GPCRs undertaken to date have strongly suggested that dimerization is at most transient, and that most receptors are monomeric at any given time. However, even SM data has its caveats and needs to be interpreted carefully. Here, we discuss the types of SM imaging strategies used to examine GPCR stoichiometry and consider some of these caveats. We also emphasize that attempts to resolve the debate ought to rely on orthogonal approaches to measuring receptor stoichiometry. PMID- 29122291 TI - Respiratory support therapy after extubation: Who and how? PMID- 29122290 TI - Bacterial community dynamic associated with autochthonous bioaugmentation for enhanced Cu phytoremediation of salt-marsh sediments. AB - Autochthonous bioaugmentation for metal phytoremediation is still little explored, particularly its application to estuarine salt marshes, but results obtained so far are promising. Nevertheless, understanding the behaviour of the microbial communities in the process of bioaugmentation and their role in improving metal phytoremediation is very important to fully validate the application of this biological technology. This study aimed to characterize the bacterial community dynamic associated with the application of autochthonous bioaugmentation in an experimentation which showed that Phragmites australis rhizosphere microorganisms could increase this salt marsh plant potential to phytoremediate Cu contaminated sediments. Bacterial communities present in the autochthonous microbial consortium resistant to Cu added to the medium and in the sediment at the beginning and at the end of the experiment were characterized by ARISA. Complementarily, the consortium and the sediment used for its production were characterized by next generation sequencing using the pyrosequencing platform 454. The microbial consortium resistant to Cu obtained from non vegetated sediment was dominated by the genus Lactococcus (46%), Raoultella (25%), Bacillus (12%) and Acinetobacter (11%), whereas the one obtained form rhizosediment was dominated by the genus Gluconacetobacter (77%), Bacillus (17%) and Dyella (3%). Results clearly showed that, after two months of experiment, Cu caused a shift in the bacterial community structure of sediments, an effect that was observed either with or without addition of the metal resistant microbial consortium. Therefore, bioaugmentation application improved the process of phytoremediation (metal translocation by the plant was increased) without inducing long term changes in the bacterial community structure of the sediments. So, phytoremediation combined with autochthonous bioaugmentation can be a suitable technology for the recovery of estuarine areas, contributing for an efficient risk management strategy of these coastal zones. PMID- 29122292 TI - Right versus left congenital diaphragmatic hernia - What's the difference? AB - BACKGROUND: Right-sided congenital diaphragmatic hernias (CDH) and bigger defect sizes have been associated with poorer outcomes. AIM: The aim of this study was to evaluate right- and left-sided CDH in terms of size, survival, associated anomalies, and morbidity. MATERIAL AND METHODS: We used information from a multicenter, multinational database including patients with CDH born between 2007 and 2015. All infants with data on defect side were included for this analysis. We compared differences in outcomes between right- and left-sided CDH. Further analysis on the association between side, size of the defect, and outcome was performed. RESULTS: A total of 3754 cases of CDH were entered in the registry between January 2007 and September 2015, with an overall survival of 71%. Of those, 598 (16%) were right-sided and 3156 left-sided, with a survival rate of 67% and 72%, respectively. Right-sided CDH had a larger proportion of C and D defects (p<0.001 and 0.04, respectively). Survival rates for the same size defect were similar, independent of the side of the defect. Multivariable logistic regression analysis with survival as dependent variable identified a significant correlation with defect size, but not side. CONCLUSIONS: The higher proportion of large defects (C & D) in right-sided CDH, not the side itself, accounts for the reported poorer survival in right-sided CDH. LEVEL OF EVIDENCE: Level I for a prognosis study - This is a high-quality, prospective cohort study with 99% of patients followed to the study end point (death or discharge). PMID- 29122293 TI - Placental mesenchymal stromal cells seeded on clinical grade extracellular matrix improve ambulation in ovine myelomeningocele. AB - PURPOSE: The purpose of this study was to investigate the effects of placental mesenchymal stromal cells (PMSCs) seeded on a clinical grade porcine small intestinal submucosa (SIS)-derived extracellular matrix (ECM) on hindlimb motor function in an ovine fetal repair model of myelomeningocele (MMC). METHODS: MMC defects were surgically created in 21 fetuses at median gestational age 78 (range 76-83) days. Fetuses were randomly assigned to repair 25days later with ECM only or PMSC-ECM. Surviving fetuses were delivered at term. Motor function was evaluated using the Sheep Locomotor Rating (SLR) scale (0-15). Histologic analysis of the spinal cord (SC) was completed. RESULTS: Fetal viability was 71%. 5 of 8 (63%) lambs repaired with PMSC-ECM ambulated independently versus only 1 of 6 (17%) repaired with ECM only (p=0.04, chi2 test). SLR scores and large neuron densities were higher in the PMSC-ECM group. The cross-sectional areas of the SC and the gray matter were equally preserved. CONCLUSIONS: Fetal repair of MMC with PMSCs seeded on SIS-ECM improves hindlimb motor function in lambs. Using ECM helps to preserve the architecture of the SC, but adding PMSCs improves the lamb's ability to walk and increases large neuron density. Clinical studies are needed to show benefits in humans. LEVELS OF EVIDENCE/TYPE OF STUDY: Basic Science. PMID- 29122294 TI - ZIKA vasculitis: A new cause of stroke in children? AB - Viral infectious vasculitis is a cause of stroke in children. Zika virus infection is often asymptomatic. Neurological complications have however been reported: Guillain-Barre, ADEM, meningoencephalitis, myelitis, microcephaly in the fetus of infected mothers. We discuss the case of a child presenting acute infection with ZIKV that was associated with a stroke. A 10-months-old boy without medical history presented after 2days of fever and cutaneous rash, conjunctivitis on day 5, a right hemiparesis on day 6. Brain MRI found an ischemic stroke in the left superficial MCA territory with distal occlusion of left M1 portion of the MCA. Specific real-time reverse PCR detected Zika virus in serum. There are no known cases of cerebral infarction associated with Zika infection. However, cases of cerebral infarcts associated with dengue vasculitis have rarely been described. It has been recently showed that there is a tropism of the Zika virus for endothelial cells. This could be responsible for stroke, possibly particularly in young children. PMID- 29122295 TI - A case of neuromyelitis optica spectrum disorder presenting with undiagnosed Sjogren's syndrome and a single, atypical tumefactive lesion: A clinical conundrum. PMID- 29122296 TI - A case of neuromyelitis optica spectrum disorder presenting with undiagnosed Sjogren's syndrome and a single, atypical tumefactive lesion: A diagnostic challenge. PMID- 29122297 TI - Cytochemical identification of turbot myeloperoxidase-positive granulocytes by potassium iodide and oxidized pyronine Y staining. AB - Cytomorphological and cytochemical staining are important methods for the identification of cell types, in particular in fish which often lack biological tools such as specific antibodies. Myeloperoxidase (MPO) is usually used as an intracellular marker of neutrophil accumulation in tissues and a marker of neutrophil activity in plasma. In this study, we reported a potassium iodide and oxidized pyronine Y (KI-PyY) staining method for rapid and highly sensitive detection of MPO-positive cells in turbot blood, peritoneum, and tissues. MPO positive cells, which mostly represented neutrophils, were stained brown and clearly distinguished from other cells, such as lymphocytes, monocytes, and macrophages, which were stained pink. Following bacterial stimulation, the proportions of neutrophils were 27.49% and 38.05% in peripheral blood leukocytes and peritoneum, respectively, judging by the stained MPO. Kidney granulocytes contained abundant MPO-positive cells which were probably immature neutrophils with low expression of MPO. It is noteworthy that MPO-positive cells were detected in the tissue sections of kidney, spleen, and gut, with distribution profiles specific to each tissue. However, the cell morphology was not distinct in the stained tissue sections. These results indicate that the KI-PyY staining method is highly sensitive, applicable to different types of samples, and will be useful for the study of neutrophils in different compartments of fish. PMID- 29122298 TI - Evoked potential and EEG study of the neurotoxicity of hydramethylnon in rats. AB - The objective of the study was to assess the neurotoxicity, using electrodiagnostic tests, of hydramethylnon (Amdro, AC 217,300), an insecticide marketed for the treatment of red imported fire ants, cockroaches, and other insects. Animals were male Fisher 344 albino rats and Long-Evans hooded rats. Brainstem auditory, visual, and somatosensory evoked potentials (BAER, VEP, SEP) and electroencephalograms (EEG) were recorded from implanted screw electrodes before and at multiple time points through day 10 after a single oral dose of hydramethylnon (at 50% or 75% of the LD50) plus vehicle, or vehicle alone. No evidence of nervous system toxicity was detected with either BAER, VEP, or SEP recordings. Spectral analysis of EEGs recorded over 7days demonstrated a time limited increase in power at low frequencies and decrease at high frequencies, reflecting a sedative effect. A dose-dependent weight loss was observed. Single exposure poisonings with AC 217,300 can be expected to produce anorexia and CNS depression, but not lethality. PMID- 29122299 TI - Heterozygous FGA p.Asp473Ter (fibrinogen Nieuwegein) presenting as antepartum cerebral thrombosis. AB - INTRODUCTION: The propositus - a two-week-old boy - was transferred to our university hospital for investigation of increased head circumference and full fontanel. On ultrasound, thrombosis of the right internal cerebral vein and intraventricular haemorrhage was diagnosed, confirmed by MRI. Family history revealed a bleeding history in the mother. A haemostatic work-up in both mother and child was performed in order to rule out congenital coagulopathy. AIM: We document a clinical case of congenital dysfibrinogenemia, caused by heterozygosity for the mutation FGA p.Asp473Ter, previously reported as fibrinogen Nieuwegein in homozygosity in an asymptomatic patient. METHODS: Fibrinogen activity in plasma was determined by functional Clauss assay, and immunological fibrinogen concentration by nephelometry. In vitro fibrin clot investigations and genetic analysis of the fibrinogen gene were performed. Complete haemostatic work-up was done by conventional methods. RESULTS AND DISCUSSION: After full laboratory work-up, dysfibrinogenemia was diagnosed, based on fibrinogen activity:antigen ratio, thrombin time, and reptilase time. Molecular analysis showed a frameshift mutation in exon 5 of FGA: c.1415_1416 insC, leading to a termination codon immediately after the insertion (CCT GAT>CCC TGA) and resulting in a truncated alphaC-domain. This mutation has been reported earlier as fibrinogen Nieuwegein. Further in vitro investigations revealed an abnormally tight clot structure, prolonged clot lysis time and affected polymerization, suggesting a thrombotic phenotype. Cerebral imaging revealed thrombosis, most likely developed in the antenatal period, leading to extensive intraventricular haemorrhage and posthaemorrhagic ventricular dilatation. CONCLUSION: We highlight the combined thrombotic and haemorrhagic phenotype linked to heterozygous fibrinogen Nieuwegein, in contrast to the previously reported asymptomatic homozygous case. PMID- 29122300 TI - Using prognostic models in CLL to personalize approach to clinical care: Are we there yet? AB - Four decades ago, two staging systems were developed to help stratify CLL into different prognostic categories. These systems, the Rai and the Binet staging, depended entirely on abnormal exam findings and evidence of anemia and thrombocytopenia. Better understanding of biologic, genetic, and molecular characteristics of CLL have contributed to better appreciating its clinical heterogeneity. New prognostic models, the GCLLSG prognostic index and the CLL IPI, emerged. They incorporate biologic and genetic information related to CLL and are capable of predicting survival outcomes and cases anticipated to need therapy earlier in the disease course. Accordingly, these newer models are helping develop better informed surveillance strategies and ultimately tailor treatment intensity according to presence (or lack thereof) of certain prognostic markers. This represents a step towards personalizing care of CLL patients. We anticipate that as more prognostic factors continue to be identified, the GCLLSG prognostic index and CLL-IPI models will undergo further revisions. PMID- 29122301 TI - The use of PRNs medications with hospitalized older adults. AB - The use of pro re nata (PRN) medications are a routine part of the treatment provided to most hospitalized older adults. The purpose of this article is to review the risks and benefits of using PRN medications in the acutely medically ill hospitalized older adult. After the discussion of a case study, recommendations are provided nurses and prescribers to reduce the risk of short and long term adverse consequences for the senior in the acute care hospital setting. PMID- 29122302 TI - Multiple subpial transections and magnetic resonance imaging. AB - INTRODUCTION: Multiple subpial transection (MST) has been applied to the treatment of refractory epilepsy when epileptogenic zone involves eloquent areas since 1989. However, there is a lack of data evaluating the effect of this surgical technique on the cortex as measured by Magnetic Resonance Imaging (MRI). PATIENTS AND METHODS: Ten consecutive patients (3F/7M, average age: 18.5 years) were operated on using radiating MST (average: 39; min: 19, max: 61) alone (n=3) or associated with another technique (n=7). Seven patients underwent a post operative 3.0T MRI while 3 had a 1.5T MRI. Three patients had an early post operative MRI and 7 a late MRI, among which 3 previously had an intraoperative MRI. RESULTS: The MR sequences that allowed the best assessment of MST-induced changes were T2 and T2*. The traces of MST are more visible on late MRI. These discrete non-complicated stigmas of MST were observed in all 10 studied patients: on the intraoperative MRI they are seen as micro-hemorrhagic spots (hypo-T2), on the early postoperative MRI as a discreet and limited cortical edema whether associated or not with micro-hemorrhagic spots and on the late MRI as liquid micro-cavities (hyper-T2) surrounded with a fine border of hemosiderin. CONCLUSIONS: MST-induced cerebral lesions are best visualized in T2-sequences, mainly on the late postoperatively MRIs. On all the MRI examinations in this study, the MST are only associated with limited modifications of the treated cortical regions. PMID- 29122303 TI - Is it really possible to predict the consistency of a pituitary adenoma preoperatively? AB - OBJECTIVES: To determine if the consistency of pituitary adenomas can be predicted based on a preoperative MRI study and to assess the surgical outcome of firm pituitary adenomas. MATERIALS AND METHODS: One hundred consecutive patients with pituitary adenomas and suprasellar extension were operated by a transsphenoidal approach from July 2003 to December 2006. In addition to the neurological examination, the patients were evaluated by ophthalmological, endocrinological and radiological workups. The signal intensity of the lesion on T2WI and other dimensions of the tumors were included in the MRI study. RESULTS: There were 52 male and 48 female patients with a mean age of 42.47 years. The mean diameter of the tumor was 32.97mm and the mean SSE was 14.95mm. Six out of 100 patients had firm adenomas peroperatively. Only one of the six patients had isointense SI on T2 WI. Of these 6 patients, total excision was performed in 1 patient, subtotal in 3 patients and partial excision in 2 patients. Among the six patients with firm adenomas, 4 had preoperative hypopituitarism (P<0.001). There was a statistically significant correlation between consistency and the postoperative permanent hypopituitarism (P<0.001). The average follow up was 43.5 months. The literature is reviewed and various aspects of pituitary adenoma consistency are discussed. CONCLUSIONS: With the present study, the consistency of pituitary adenomas cannot be reliably predicted based on a preoperative MRI study. Patients with firm adenomas likely to have more incidence of preoperative hypopituitarism and postoperative permanent hypopituitarism. PMID- 29122304 TI - [The efficacy of multimodal treatment for symptomatic vertebral hemangiomas: A report of 27 cases and a review of the literature]. AB - INTRODUCTION: Vertebral hemangiomas (VH) represent the most common primary bone tumor of the spine and are rarely symptomatic. Currently, there is no consensus for treatment and many therapeutic options are available, alone or in combination including cementoplasty, sclerotherapy, surgery, embolization and/or radiotherapy. OBJECTIVE: To evaluate the clinical and radiological outcome of a multimodal management for symptomatic VH. METHODS: A consecutive prospective and retrospective multicenter study was conducted to review cases of symptomatic VHs between 2005 and 2015. Clinical and radiological aspects, treatment modalities and complications were evaluated preoperatively; postoperatively and at last follow-up. We also reviewed the literature of studies concerning case series of VH, published after 1990 and involving more than 10 patients. RESULTS: Twenty seven VHs were included in our series (mean age at diagnosis: 47.9 years), out of which 26 were symptomatic. Ten presented with neurologic deficit (37%). An epidural extension was noted in 13 patients (48%). Eleven patients (41%) underwent multimodal treatments. In the multimodal group, eradication was observed in 6 patients (54%), stable residue in 5 cases (46%) with no recurrence versus 3 eradication (23%), 9 stable residue (69%) and no recurrence in the monomodal group, (P>0.05). The literature comprised 14 studies including 458 patients. Only 4 studies were focused on multimodal treatments. CONCLUSION: Based on this study, the multimodal management of symptomatic VHs appeared safe and effective. Finally, we propose an algorithm for symptomatic VHS management based on the severity of epidural extension and fracture risk. PMID- 29122305 TI - Reconstruction of cranioplasty using medpor porouspolyethylene implant. AB - INTRODUCTION: We describe our experience of cranioplasty after a calvarial defect, following an external decompressive craniectomy, with the Medpor(r) (Stryker(r)) porous polyethylene implant for cosmetic cranioplasty and reconstruction. METHODS: A retrospective chart review was performed on 23 consecutive patients who underwent cranioplasty at a single institution between January 2013 and January 2016: 9 patients after head injury and 14 patients after vascular event (ruptured aneurysm, intraprenchymal haematoma, malignant cerebrovascular accident). All patients with cranioplasties after oncological resection or infection were excluded. These cranioplasties were performed using porous polyethylene sheet (Medpor(r)) and contoured with a burr or scissors in the sterile field, and fixed to the calvarial bone with screws. RESULTS: Porous polyethylene sheet (Medpor(r)) is a proven material used for cranial reconstruction in neurosurgery and maxillofacial surgery with a biocompatibility advantage. The implant can be directly used in an emergency context. The average operating time was 72minutes. An average delay of 527 days (1 year and 5months) with a median of 985 days (43; 4206) occurred between craniectomy and the cranioplasty. There was only one set back implant due to scalp necrosis with infection for a recovery-unit patient. CONCLUSION: Porous polyethylene is an excellent restorative material for the reconstruction of large sized cranial defects and can be also used safely in reconstruction of the cranium. The cosmetic results are good, easy to perform, with a low complication rate. PMID- 29122306 TI - Carmustine wafer implantation for high-grade gliomas: Evidence-based safety efficacy and practical recommendations from the Neuro-oncology Club of the French Society of Neurosurgery. AB - There is a growing body of evidence that carmustine wafer implantation during surgery is an effective therapeutic adjunct to the standard combined radio chemotherapy regimen using temozolomide in newly diagnosed and recurrent high grade glioma patient management with a statistically significant survival benefit demonstrated across several randomized clinical trials, as well as prospective and retrospective studies (grade A recommendation). Compelling clinical data also support the safety of carmustine wafer implantation (grade A recommendation) in these patients and suggest that observed adverse events can be avoided in experienced neurosurgeon hands. Furthermore, carmustine wafer implantation does not seem to impact negatively on the quality of life and the completion of adjuvant oncological treatments (grade C recommendation). Moreover, emerging findings support the potential of high-grade gliomas molecular status, especially the O(6)-Methylguanine-DNA Methyltransferase promoter methylation status, in predicting the efficacy of such a surgical strategy, especially at recurrence (grade B recommendation). Finally, carmustine wafer implantation appears to be cost-effective in high-grade glioma patients when performed by an experienced team and when total or subtotal resection can be achieved. Altogether, these data underline the current need for a new randomized clinical trial to assess the impact of a maximal safe resection with carmustine wafer implantation followed by the standard combined chemoradiation protocol stratified by molecular status in high-grade glioma patients. PMID- 29122307 TI - Role of serial ultrasonic optic nerve sheath diameter monitoring in head injury. AB - OBJECTIVES: To compare optic nerve sheath diameter (ONSD) measurements in head injury patients with a group of normal subjects and investigate the significance of serial ONSD monitoring in head injury patients. METHODS: All patients with a head injury admitted to our hospital with a program of conservative management at the time of admission were included in this prospective study. On admission, the patient was assessed using the Glasgow Coma Scale (GCS), orbital ultrasound for optic nerve sheath diameter (ONSD), and CT brain scan. CT scan findings were tabulated with Marshall and Rotterdam scores. The patient was serially assessed with ONSD every 24 to 48hours. If the patient deteriorated, repeat CT and ONSD measurements were performed. A control group consisting of normal subjects was used for comparison. RESULTS: The case group consisted of 40 patients and the control group included 16 volunteers. The mean age of the case group was 38.9 years and the control group 36.3 years. The mean ONSD was 4.8mm in the case group as compared to 3.4mm in control group (P<0.0001). In the case group, we found a significant correlation between GCS and ONSD, GCS and radiological scores and ONSD and radiological scores. The change in serial recordings of ONSD measurements were termed ascending, descending or static. All the patients with descending trend in serial ONSD values had good outcome and required no surgical intervention. CONCLUSIONS: Ultrasound ONSD measurement is a useful investigation tool in a setting where invasive ICP monitoring is not available. Serial recording of ONSD is valuable and provides valuable information regarding decision making. PMID- 29122308 TI - Diagnosis and suggested treatment against an isolated unilateral rupture of the alar ligament - Concerning one case. AB - BACKGROUND: An isolated rupture of the alar ligament is a rare occurrence with only a few cases reported in the literature. CASE REPORT: The objective was to report the case of a young man with a unilateral rupture of the alar ligament that we closely monitored, clinically and radiologically, in order to describe the evolution of the alar ligament lesions. CONCLUSION: Radiological diagnosis using cervical MRI and duration of the conservative treatment remain debated and we proposed a close radiological follow-up in order to best understand the nature of these ligament lesions and their evolution following specific treatment. PMID- 29122309 TI - The keys to successful TIPS in patients with portal vein thrombosis and cavernous transformation. AB - Portal vein thrombosis is a common complication in patients with cirrhosis. Anticoagulation involves a high risk of bleeding secondary to portal hypertension, so placing transjugular intrahepatic portosystemic shunts (TIPS) has become an alternative treatment for portal vein thrombosis. Three strategies for TIPS placement have been reported: 1) portal recanalization and conventional implantation of the TIPS through the jugular vein; 2) portal recanalization through percutaneous transhepatic/transsplenic) access; and (3) insertion of the TIPS between the suprahepatic vein and a periportal collateral vessel without portal recanalization. We describe different materials that can be used as fluoroscopic targets for the TIPS needle and for portal recanalization. This article aims to show the success of TIPS implantation using different combinations of the techniques listed above, which is a good treatment alternative in these patients whose clinical condition makes them difficult to manage, and to show that portal vein thrombosis/cavernous transformation should not be considered a contraindication for TIPS. PMID- 29122310 TI - Idiopathic infratentorial superficial siderosis of the central nervous system: case report and review of literature. AB - The superficial siderosis (SS) of the central nervous system (CNS) is a rare condition characterized by a wide range of neurological manifestations directly linked to an acquired iron-mediated neurodegeneration. First described more than 100 years ago, only recently SS has been divided into two distinct entities, according to the distribution of iron deposition in the CNS: cortical superficial siderosis (cSS) and infratentorial superficial siderosis (iSS). Here we describe an adult case of iSS, with detailed clinical and radiological features. Moreover, we extensively review the literature of SS, particularly focusing on the pathogenesis, clinical-radiological classification, diagnostic algorithm and treatment options of this rare condition. PMID- 29122311 TI - [Uveitis: Diagnostic work-up. Recommendations from an expert committee]. AB - INTRODUCTION: Diagnostic work-up of uveitis involves many uncertainties. Search for an etiology should take into account the epidemiology of uveitis and focus on the most severe diseases or those, which can be treated. This work was undertaken to establish recommendations for the diagnosis work-up of uveitis. METHODS: Recommendations were developed by a multidisciplinary panel of 15 experts, including internists, ophthalmologists and a rheumatologist and are based on a review of the literature with regard to effectiveness of investigations and the results of the ULISSE study, which is the first prospective study assessing the efficiency of a standardized strategy for the etiological diagnosis of uveitis. Children, immunocompromised patients, severe retinal vasculitis and specific ophthalmological entities are excluded from these recommendations. RESULTS: Investigations should be first guided by the history and physical examination. Serological screening for syphilis is the only test appropriate in all forms of uveitis. If no diagnosis is made after this stage, we propose investigations guided by the anatomic characteristics of uveitis. It includes HLA B27 testing (in unilateral acute anterior non-granulomatous uveitis), serum angiotensin converting enzyme, interferon-gamma release assay and chest CT (chronic uveitis), cerebral MRI and anterior chamber tap with IL10 analysis (intermediate or posterior uveitis in patients over 40 years). Investigations ordered in the absence of orientation are almost always unhelpful. CONCLUSIONS: We propose a strategy for the etiologic diagnosis of uveitis. The recommendations should be updated regularly. The efficiency of more invasive investigations has yet to be evaluated. PMID- 29122312 TI - Gestational exposure to volatile organic compounds (VOCs) in Northeastern British Columbia, Canada: A pilot study. AB - BACKGROUND: Northeastern British Columbia (Canada) is an area of intense hydraulic fracturing for unconventional natural gas exploitation. There have been multiple reports of air and water contamination by volatile organic compounds in the vicinity of gas wells. Although these chemicals are known developmental toxicants, no biomonitoring effort has been carried out in the region. OBJECTIVE: To evaluate gestational exposure to benzene and toluene in the Peace River Valley, Northeastern British Columbia (Canada). METHODS: Urine samples were collected over five consecutive days from 29 pregnant women. Metabolites of benzene (s-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t,t-MA)) and toluene (s-benzylmercapturic acid (S-BMA)) were measured in pooled urine samples from each participant. Levels of benzene metabolites were compared to those from the general Canadian population and from a biomonitoring study of residents from an area of active gas exploitation in Pavillion, Wyoming (USA). Levels measured in participants from the two recruitment sites, and self identifying as Indigenous or non-Indigenous, were also compared. RESULTS: Whereas the median S-PMA level (0.18MUg/g creatinine) in our study was similar to that in the general Canadian population, the median t,t-MA level (180MUg/g creatinine) was approximately 3.5 times higher. Five women had t,t-MA levels above the biological exposure index(r) proposed by the American Conference of Governmental Industrial Hygienists. The median urinary S-BMA level in our pilot study was 7.00MUg/g creatinine. Urinary metabolite levels were slightly higher in self identifying Indigenous women, but this difference was only statistically significant for S-PMA. DISCUSSION: Urinary t,t-MA levels, but not S-PMA levels, measured in our study are suggestive of a higher benzene exposure in participating pregnant women from the Peace River Valley than in the general Canadian population. Given the small sample size and limitations of t,t-MA measurements (e.g., non-specificity), more extensive monitoring is warranted. PMID- 29122313 TI - Has the question of e-waste opened a Pandora's box? An overview of unpredictable issues and challenges. AB - Despite regulatory efforts and position papers, electrical and electronic waste (e-waste) remains ill-managed as evidenced by the extremely low rates of proper e waste recycling (e-recycling) worldwide, ongoing illegal shipments to developing countries and constantly reported human health issues and environmental pollution. The objectives of this review are, first, to expose the complexity of e-waste problems, and then to suggest possible upstream and downstream solutions. Exploring e-waste issues is akin to opening a Pandora's box. Thus, a review of prevailing e-waste management practices reveals complex and often intertwined gaps, issues and challenges. These include the absence of any consistent definition of e-waste to date, a prevalent toxic potential still involving already banned or restricted hazardous components such as heavy metals and persistent and bioaccumulative organic compounds, a relentless growth in e-waste volume fueled by planned obsolescence and unsustainable consumption, problematic e-recycling processes, a fragile formal e-recycling sector, sustained and more harmful informal e-recycling practices, and more convoluted and unpredictable patterns of illegal e-waste trade. A close examination of the e-waste legacy contamination reveals critical human health concerns, including significant occupational exposure during both formal and informal e-recycling, and persistent environmental contamination, particularly in some developing countries. However, newly detected e-waste contaminants as well as unexpected sources and environmental fates of contaminants are among the emerging issues that raise concerns. Moreover, scientific knowledge gaps remain regarding the complexity and magnitude of the e-waste legacy contamination, specifically, a comprehensive characterization of e-waste contaminants, information on the scale of legacy contamination in developing countries and on the potential environmental damage in developed countries, and a stronger body of evidence of adverse health effects specifically ascribed to e-waste contaminants. However, the knowledge accumulated to date is sufficient to raise awareness and concern among all stakeholders. Potential solutions to curb e-waste issues should be addressed comprehensively, by focusing on two fronts: upstream and downstream. Potential upstream solutions should focus on more rational and eco-oriented consumer habits in order to decrease e-waste quantities while fostering ethical and sustained commitments from manufacturers, which include a limited usage of hazardous compounds and an optimal increase in e-waste recyclability. At the downstream level, solutions should include suitable and pragmatic actions to progressively reduce the illegal e-waste trade particularly through international cooperation and coordination, better enforcement of domestic laws, and monitoring in both exporting and receiving countries, along with the supervised integration of the informal sector into the recycling system of developing countries and global expansion of formal e-waste collection and recycling activities. Downstream solutions should also introduce stronger reverse logistics, together with upgraded, more affordable, and eco-friendly and worker-friendly e-recycling technologies to ensure that benefits are derived fully and safely from the great economic potential of e waste. PMID- 29122314 TI - Blood transcriptional and microRNA responses to short-term exposure to disinfection by-products in a swimming pool. AB - BACKGROUND: Swimming in a chlorinated pool results in high exposure levels to disinfection by-products (DBPs), which have been associated with an increased risk of bladder cancer. OBJECTIVES: By studying molecular responses at the blood transcriptome level we examined the biological processes associated with exposure to these compounds. METHODS: Whole-genome gene expression and microRNA analysis was performed on blood samples collected from 43 volunteers before and 2h after 40min swimming in an indoor chlorinated pool (PISCINAII study). Exposure to THMs was measured in exhaled breath. Heart rate and kcal expenditure were measured as proxies for physical activity. Associations between exposure levels and gene expression were assessed using multivariate normal models (MVN), correcting for age, body mass index and sex. A Bonferroni threshold at 5% was applied. RESULTS: MVN-models for the individual exposures identified 1778 genes and 23 microRNAs that were significantly associated with exposure to at least one DBP. Due to co linearity it was not possible to statistically disentangle responses to DBP exposure from those related to physical activity. However, after eliminating previously reported transcripts associated with physical activity a large number of hits remained associated with DBP exposure. Among those, 9 were linked with bladder and 31 with colon cancer. Concordant microRNA/mRNA expressions were identified in association with DBP exposure for hsa-mir-22-3p and hsa-miR-146a-5p and their targets RCOR1 and TLR4, both related to colon cancer in association with DBP exposure. CONCLUSIONS: Short-term exposure to low levels of DBPs shows genomics responses that may be indicative of increased cancer risk. PMID- 29122315 TI - Can in Vivo Medial Gastrocnemius Muscle-Tendon Unit Lengths be Reliably Estimated by Two Ultrasonography Methods? A Within-Session Analysis. AB - A clinically feasible method to reliably estimate muscle-tendon unit (MTU) lengths could provide essential diagnostic and treatment planning information. A 3-D freehand ultrasound (3-DfUS) method was previously validated for extracting in vivo medial gastrocnemius (MG) lengths, although the processing time can be considered substantial for the clinical environment. This investigation analyzed a quicker and simpler method using the US transducer as a spatial pointer (US PaP), where the within-session reliability of extracting the muscle-tendon unit (MTU) and tendon lengths are estimated. MG MTU lengths were extracted in a group of 14 healthy adults using both 3-DfUS and US-PaP. Two consecutive acquisitions were performed per participant, and the data processed by two researchers independently. The intra-class correlation coefficients were above 0.97, and the standard error of measurements below 3.6 mm (1.5%). This investigation proposes that the simplified US-PaP method is a viable alternative for estimating MG MTU lengths. PMID- 29122316 TI - Diagnostic Accuracy of 2-D Shear Wave Elastography for the Non-Invasive Staging of Liver Fibrosis in Patients with Elevated Alanine Aminotransferase Levels. AB - This study assessed the diagnostic accuracy of 2-D shear wave elastography (2-D SWE) for the non-invasive staging of liver fibrosis and compared the findings with those for biochemical markers (the aspartate aminotransferase-to-platelet index and fibrosis-4 index) of liver fibrosis in patients with elevated alanine aminotransferase (ALT) levels (>5 * the upper limit of normal). Patients with chronic liver diseases and elevated ALT levels who underwent liver biopsy were consecutively included. Receiver operating characteristic (ROC) curves were constructed to assess overall accuracy and to identify optimal cutoff values. After exclusions, data from 105 patients were analyzed. The areas under the ROC curves (AUROCs) for significant fibrosis, severe fibrosis and cirrhosis were 0.83, 0.86 and 0.91, respectively. The optimal cutoff values for predicting significant fibrosis, severe fibrosis and cirrhosis were 10.6, 13.2 and 17.6 kPa, respectively. The AUROCs of 2-D-SWE were significantly higher than those of biochemical markers for predicting significant fibrosis, severe fibrosis and cirrhosis (all p values < 0.05). Therefore, the diagnostic performance of 2-D-SWE in assessing liver fibrosis stages in patients with elevated ALT levels was promising. The optimal cutoff values were increased but appropriate for this cohort because the baseline levels of liver stiffness measurements were increased in these patients, even in the absence of fibrosis. PMID- 29122317 TI - Sonographic and Anatomic Description of the Subtalar Joint. AB - Our study provides a detailed anatomic and sonographic description of the subtalar joint, a single joint that, anatomically, is divided into the anterior subtalar joint (ASTJ) and the posterior subtalar joint (PSTJ). Cadaver specimens of the ankle and foot were examined in detail by ultrasound (US), and the subtalar joints of all the specimens were injected with colored latex of a contrasting color under US guidance. Compatible with other studies, examination of the sections revealed lack of communication between the ASTJ and the PSTJ and communication between the PSTJ and the posterior recess of the tibiotalar joint. A recommended list of standardized ultrasound scans was developed using a Delphi consensus process, which allows sonographers to evaluate both the ASTJ and PSTJ from the medial, lateral and posterior aspects. The recommended ultrasound scans were found to be applicable based on a test of agreement between images acquired in cadaver specimens and images acquired in four centers using healthy patients. PMID- 29122318 TI - Corrigendum to "Quantitative models of feline lumbosacral dorsal root ganglia neuronal cell density" [J. Neurosci. Methods 290 (2017) 116-124]. PMID- 29122319 TI - Author Reply. PMID- 29122320 TI - Editorial Comment. PMID- 29122321 TI - Each procedure matters: threshold for surgeon volume to minimize complications and decrease cost associated with adrenalectomy. AB - BACKGROUND: An association has been suggested between increasing surgeon volume and improved patient outcomes, but a threshold has not been defined for what constitutes a "high-volume" adrenal surgeon. METHODS: Adult patients who underwent adrenalectomy by an identifiable surgeon between 1998-2009 were selected from the Healthcare Cost and Utilization Project National Inpatient Sample. Logistic regression modeling with restricted cubic splines was utilized to estimate the association between annual surgeon volume and complication rates in order to identify a volume threshold. RESULTS: A total of 3,496 surgeons performed adrenalectomies on 6,712 patients; median annual surgeon volume was 1 case. After adjustment, the likelihood of experiencing a complication decreased with increasing annual surgeon volume up to 5.6 cases (95% confidence interval, 3.27-5.96). After adjustment, patients undergoing resection by low-volume surgeons (<6 cases/year) were more likely to experience complications (odds ratio 1.71, 95% confidence interval, 1.27-2.31, P = .005), have a greater hospital stay (relative risk 1.46, 95% confidence interval, 1.25-1.70, P = .003), and at increased cost (+26.2%, 95% confidence interval, 12.6-39.9, P = .02). CONCLUSION: This study suggests that an annual threshold of surgeon volume (>=6 cases/year) that is associated with improved patient outcomes and decreased hospital cost. This volume threshold has implications for quality improvement, surgical referral and reimbursement, and surgical training. PMID- 29122322 TI - Discussion. PMID- 29122323 TI - Discussion. PMID- 29122324 TI - Hemodynamic instability during surgery for pheochromocytoma: comparing the transperitoneal and retroperitoneal approach in a multicenter analysis of 341 patients. AB - BACKGROUND: Intraoperative hemodynamic instability is a major challenge during adrenalectomy for pheochromocytoma. Typically, pheochromocytoma is performed laparoscopically either through the retroperitoneal or transperitoneal approach. We aimed to determine if the operative approach affects intraoperative hemodynamic instability during surgery for pheochromocytoma in a large multicenter multicenter cohort. METHODS: Retrospective, multicenter analysis of consecutive patients with pheochromocytoma who underwent total unilateral laparoscopic adrenalectomy without conversion were included. Statistical analysis was performed using established intraoperative criteria for intraoperative hemodynamic instability: 1) systolic blood pressure >160 mm Hg; 2) systolic blood pressure > 200 mm Hg; 3) mean arterial pressure <60 mm Hg; 4) systolic blood pressure >160 mm Hg + mean arterial pressure <60 mm Hg; and 5) systolic blood pressure >200 mm Hg + mean arterial pressure <60 mm Hg; and 6) intravenous vasopressor + vasodilator. RESULTS: In total, 341 patients met the inclusion criteria, 101 (29.6%) underwent retroperitoneal adrenalectomy and 240 (70.4%) transperitoneal adrenalectomy. Multivariate analysis showed that retroperitoneal adrenalectomy carries greater risk for mean arterial pressure <60 mm Hg (odds ratio 6.255, confidence interval 1.134-34.235, P = .035) compared with transperitoneal adrenalectomy. Overall and cardiovascular morbidity rates were comparable between the 2 approaches. The medical center was a significant independent influencing factor for all 6 intraoperative hemodynamic instability definitions. CONCLUSION: Variability in institutional management of pheochromocytoma intraoperatively has significant impact on all 6 intraoperative hemodynamic instability definitions. Standardization of anesthesia should be considered to reduce this variability. PMID- 29122325 TI - Impact of autofluorescence-based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study. AB - BACKGROUND: The clinical impact of intraoperative autofluorescence-based identification of parathyroids using a near-infrared camera remains unknown. METHODS: In a before and after controlled study, we compared all patients who underwent total thyroidectomy by the same surgeon during Period 1 (January 2015 to January 2016) without near-infrared (near-infrared- group) and those operated on during Period 2 (February 2016 to September 2016) using a near-infrared camera (near-infrared+ group). In parallel, we also compared all patients who underwent surgery without near-infrared during those same periods by another surgeon in the same unit (control groups). Main outcomes included postoperative hypocalcemia, parathyroid identification, autotransplantation, and inadvertent resection. RESULTS: The near-infrared+ group displayed significantly lower postoperative hypocalcemia rates (5.2%) than the near-infrared- group (20.9%; P < .001). Compared with the near-infrared- patients, the near-infrared+ group exhibited an increased mean number of identified parathyroids and reduced parathyroid autotransplantation rates, although no difference was observed in inadvertent resection rates. Parathyroids were identified via near-infrared before they were visualized by the surgeon in 68% patients. In the control groups, parathyroid identification improved significantly from Period 1 to Period 2, although autotransplantation, inadvertent resection and postoperative hypocalcemia rates did not differ. CONCLUSION: Near-infrared use during total thyroidectomy significantly reduced postoperative hypocalcemia, improved parathyroid identification and reduced their autotransplantation rate. PMID- 29122326 TI - Editorial: Risk of disease progression during active surveillance of papillary thyroid cancer. AB - With the rapid rise in incidence of micropapillary carcinoma, there is considerable interest in active surveillance or deferred intervention in patients with incidental micropapillary carcinoma. The risk of disease progression is different based on the age of the patient. It is high in third and fourth decade, while very low in sixth and seventh decade. Appropriate selection and close surveillance is very critical, with active involvement of the multidisciplinary team. PMID- 29122327 TI - Discussion. PMID- 29122328 TI - Lobectomy for treatment of differentiated thyroid cancer: can patients avoid postoperative thyroid hormone supplementation and be compliant with the American Thyroid Association guidelines? AB - BACKGROUND: The American Thyroid Association recommended thyroid lobectomy as an alternative for low-risk differentiated thyroid cancer. One hypothetical benefit includes avoiding lifelong thyroid hormone supplementation; however, guidelines recommend maintaining the thyroid-stimulating hormone <2 mIU/L postoperatively in low-risk patients. Our hypothesis is that most patients will require hormone supplementation to maintain thyroid-stimulating hormone <2 mIU/L, minimizing this advantage of lobectomy. The goal of this study is to determine how often patients have thyroid-stimulating hormone <2 mIU/L after lobectomy without thyroid hormone supplementation. METHODS: A retrospective review of 555 consecutive patients who underwent thyroid lobectomy was performed. Thyroid hormone supplementation was documented, along with thyroid-stimulating hormone levels preoperatively, 7 to 10 days, and 2 to 12 months postoperatively. RESULTS: In the study, 478/555 (86%) patients did not take thyroid hormone before thyroidectomy; 394/478 (82%) had thyroid-stimulating hormone levels available at 7 to 10 days postoperatively, and of these, 218 (55%) had thyroid-stimulating hormone >2 mIU/L. From 2 to 12 months postoperatively, of the 225 patients who continued to remain off thyroid hormone supplementation, 132 (59%) experienced a thyroid-stimulating hormone increase to >2 mIU/L; therefore, 350/478 (73%) patients after thyroid lobectomy had thyroid stimulating hormone levels >2 mIU/L within a year. CONCLUSION: It is important to counsel patients that to be compliant with the American Thyroid Association guidelines for differentiated thyroid cancer, the majority of patients undergoing thyroid lobectomy may require thyroid hormone supplementation to maintain a thyroid-stimulating hormone level <2 m IU/L. PMID- 29122329 TI - Discussion. PMID- 29122331 TI - Discussion. PMID- 29122332 TI - Epidural catheter breakage. PMID- 29122330 TI - Genotype-phenotype pancreatic neuroendocrine tumor relationship in multiple endocrine neoplasia type 1 patients: A 23-year experience at a single institution. AB - BACKGROUND: The aim of this study was to investigate the genotype-phenotype relationship of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 treated at our institution. METHODS: We conducted a retrospective chart review of all patients with multiple endocrine neoplasia type 1 treated at our center from January 1993 to December 2015. Presence of a pancreatic neuroendocrine tumor was determined based on imaging performed at any time from presentation to conclusion of follow-up. RESULTS: We reviewed 188 patients. The most common site of multiple endocrine neoplasia type 1 mutation was in exon 2 (34/188; 18%). Of 188 patients, 125 had a pancreatic neuroendocrine tumor (61%). Among all patients, 30 of 34 (88%) with an exon 2 mutation had a pancreatic neuroendocrine tumor compared with 95 of 154 (62%) with a mutation in exons 3-10 (P = .002). In the age group of 20 to 40 years, 8 of 9 patients with an exon 2 mutation had a pancreatic neuroendocrine tumor, compared with 24 of 52 patients (46%) with a mutation in exons 3-10 (P = .028). Patients with an exon 2 mutation had a greater frequency of pancreatic neuroendocrine tumor distant metastasis (53% vs 23%, P = .049). CONCLUSION: Young patients with multiple endocrine neoplasia type 1 and an exon 2 mutation appear to have a 2-fold greater risk for developing a pancreatic neuroendocrine tumor, and patients with an exon 2 mutation may be at greater risk for developing distant metastasis. Consideration should be given to more intensive screening and more liberal application of primary operative intervention in this potentially high-risk group. PMID- 29122334 TI - Alpha-1 Antitrypsin Deficiency Associated with the PI*Q0ourem Allele in a 2-Year old Girl and Family Study. An Unusual Case. PMID- 29122333 TI - Translation and Validation of the Multidimensional Dyspnea-12 Questionnaire. AB - INTRODUCTION: Dyspnea is a multidimensional symptom, but this multidimensionality is not considered in most dyspnea questionnaires. The Dyspnea-12 takes a multidimensional approach to the assessment of dyspnea, specifically the sensory and the affective response. The objective of this study was to translate into Spanish and validate the Dyspnea-12 questionnaire. METHODS: The original English version of the Dyspnea-12 questionnaire was translated into Spanish and backtranslated to analyze its equivalence. Comprehension of the text was verified by analyzing the responses of 10 patients. Reliability and validation of the questionnaire were studied in an independent group of COPD patients attending the pulmonology clinics of Hospital Universitario Marques de Valdecilla, diagnosed and categorized according to GOLD guidelines. RESULTS: The mean age of the group (n=51) was 65 years and mean FEV1 was 50%. All patients understood all questions of the translated version of Dyspnea-12. Internal consistency of the questionnaire was alpha=0.937 and intraclass correlation coefficient was=.969; P<.001. Statistically significant correlations were found with HADS (anxiety r=.608 and depression r=.615), mMRC dyspnea (r=.592), 6MWT (r=-0.445), FEV1 (r= 0.312), all dimensions of CRQ-SAS (dyspnea r=-0.626; fatigue r=-0.718; emotional function r=-0.663; mastery r=-0.740), CAT (r=0.669), and baseline dyspnea index (r=-0.615). Dyspnea-12 scores were 10.32 points higher in symptomatic GOLD groups (B and D) (P<.001). CONCLUSION: The Spanish version of Dyspnea-12 is a valid and reliable instrument to study the multidimensional nature of dyspnea. PMID- 29122335 TI - Tracheobronchopathia Osteochondroplastica. A Chance Finding. PMID- 29122336 TI - Can Environmental Pollution Cause Asthma? PMID- 29122337 TI - Study of anatomical variations of the zygomaticofacial foramen and calculation of reliable reference points for operation. AB - Dissection on to the facial aspect of the zygoma is common in procedures of the midface for trauma, craniofacial deformity, and cosmesis. These procedures carry the risk of injury to the neurovascular structures that exit from the zygomaticofacial foramen (ZFF). The purpose of this study was to map the ZFF, and to establish reliable reference points from which to identify it before and during operation. We also aimed to compare the anatomy of the ZFF between sexes and among geographical populations. A total of 429 adult skulls from nine geographical sites were used. A cross-line laser was superimposed on to each zygoma to generate consistent landmarks (lines 1 and 2) from which to measure the ZFF, and the number of ZFF on each zygoma was recorded. The site and incidence of ZFF differed significantly among geographical populations, but not between sexes. Of all 858 sides, no foramina were found in 16.3%, one foramen in 49.8%, two foramina in 29%, three in 3.4% and four in 1.4%. A total of 93% of foramina were within a 25mm diameter zone (ZFF zone) centred 5mm anterior to the intersection of lines 1 and 2 on the right zygoma, and 94% were within equivalent measurements on the left. Using these landmarks, we propose a new method of identifying a ZFF zone that is irrespective of sex or geographical population. This technique may be useful in the prevention of iatrogenic damage to the ZFF neurovascular bundle during procedures on the midface and in local nerve blocks. PMID- 29122338 TI - Multiple myeloma of the mandibular condyle: a rare presentation. PMID- 29122339 TI - Salivary Aerobics. PMID- 29122340 TI - Robot-assisted excision of the submandibular gland by a postauricular facelift approach: comparison with the conventional transcervical approach. AB - Various approaches have been described for excision of a submandibular gland including endoscopic and robot-assisted techniques. We present the outcome of excision by a robot-assisted postauricular facelift approach and compare it with the conventional transcervical approach. We studied 30 cases of excision of the gland for benign disease (16 transcervical and 14 robot-assisted), and collected clinical and personal data, and details of patients' satisfaction with the result. The most common conditions were sialadenitis (n=15) and pleomorphic adenoma (n=12). The robot-assisted operations took significantly longer (p=0.045), had more drainage (p<0.001), and a significantly better cosmetic outcome (p=0.002). Robot-assisted excision of the submandibular gland may prove to be a viable option in the treatment of benign conditions for those patients seeking a better cosmetic outcome. PMID- 29122341 TI - Effects of prescribed fire for pasture management on soil organic matter and biological properties: A 1-year study case in the Central Pyrenees. AB - Prescribed burning has been readopted in the last decade in the Central Pyrenees to stop the regression of subalpine grasslands in favour of shrublands, dominated among others by Echinospartum horridum (Vahl) Rothm. Nevertheless, the effect of this practice on soil properties is uncertain. The aim of this work was to analyse the effects of these burnings on topsoil organic matter and biological properties. Soil sampling was carried out in an autumnal prescribed fire in Buisan (NE-Spain, November 2015). Topsoil was sampled at 0-1cm, 1-2cm and 2-3cm depth in triplicate just before (U), ~1h (B0), 6months (B6) and 12months (B12) after burning. We analysed soil total organic C (TOC), total nitrogen (TN), microbial biomass C (Cmic), soil respiration (SR) and beta-D-glucosidase activity. A maximum temperature of 438 degrees C was recorded at soil surface while at 1cm depth only 31 degrees C were reached. Burning significantly decreased TOC (-52%), TN (-44%), Cmic (-57%), SR (-72%) and beta-D-glucosidase ( 66%) at 0-1cm depth while SR was also reduced (-45%) at 1-2cm depth. In B6 and B12, no significant changes in these properties were observed as compared to B0. It can be concluded that the impact of prescribed burning has been significant and sustained over time, although limited to the first two topsoil centimetres. PMID- 29122342 TI - Development of a new methodology for the creation of water temperature scenarios using frequency analysis tool. AB - Thermal quality in river ecosystems is a fundamental property for the development of biological processes and many of the human activities linked to the aquatic environment. In the future, this property is going to be threatened due to global change impacts, and basin managers will need useful tools to evaluate these impacts. Currently, future projections in temperature modelling are based on the historical data for air and water temperatures, and the relationship with past temperature scenarios; however, this represents a problem when evaluating future scenarios with new thermal impacts. Here, we analysed the thermal impacts produced by several human activities, and linked them with the decoupling degree of the thermal transfer mechanism from natural systems measured with frequency analysis tools (wavelet coherence). Once this relationship has been established we develop a new methodology for simulating different thermal impacts scenarios in order to project them into future. Finally, we validate this methodology using a site that changed its thermal quality during the studied period due to human impacts. Results showed a high correlation (r2=0.84) between the decoupling degree of the thermal transfer mechanisms and the quantified human impacts, obtaining 3 thermal impact scenarios. Furthermore, the graphic representation of these thermal scenarios with its wavelet coherence spectrums showed the impacts of an extreme drought period and the agricultural management. The inter conversion between the scenarios gave high morphological similarities in the obtained wavelet coherence spectrums, and the validation process clearly showed high efficiency of the developed model against old methodologies when comparing with Nash-Stucliffe criterion. Although there is need for further investigation with different climatic and anthropic management conditions, the developed frequency models could be useful in decision-making processes by managers when faced with future global change impacts. PMID- 29122343 TI - Seasonal variations of nitrous oxide fluxes and soil denitrification rates in subtropical freshwater and brackish tidal marshes of the Min River estuary. AB - Estuarine tidal marshes provide favorable conditions for nitrous oxide (N2O) production. Saltwater intrusion caused by sea-level rise would exert complex effects on the production and emission of N2O in estuarine tidal marshes; however, few studies have been conducted on its effects on N2O emissions. Salinity gradients are a common occurrence in estuarine tidal marshes. Studies on production and emission of N2O in tidal marshes with different salinities may elucidate the impact of saltwater intrusion on the emission of greenhouse gases. This study explores the seasonal variations of N2O fluxes and soil denitrification rates in freshwater (Daoqingzhou wetland) and brackish (Shanyutan wetland) tidal marshes dominated by Cyperus malaccensis var. brevifolius (shichito matgrass) in the Min River estuary, southeastern China. N2O fluxes in both marshes showed strong temporal variability. The highest N2O fluxes were observed in the hot and wet summer months, whereas the lowest fluxes were observed in the cold winter and autumn months. N2O fluxes from the freshwater marsh (48.81+/-9.01MUgm-2h-1) were significantly higher (p<0.05) than those from the brackish-water marsh (27.69+/-4.01MUgm-2h-1). Soil denitrification rates showed a similar temporal pattern, with the highest rates observed in summer and the lowest in winter. Similarly, soil denitrification rates were significantly higher (p<0.05) in the freshwater marsh (32.72+/-19.15MUmolNm-2h-1) than in the brackish-water marsh (4.97+/-2.64MUmolNm-2h-1). Temperature and the salinity, sulfate (SO42-), and ammonia nitrogen (NH4+-N) concentrations of the overlying water were key factors affecting soil denitrification rates. N2O fluxes and soil denitrification rates demonstrated negative correlations with salinity and SO42- concentrations in both marshes. The results indicate that increased seawater intrusion would reduce N2O emissions from estuarine tidal wetlands and exert a negative feedback on the climate system. PMID- 29122344 TI - Obesity mediated the association of exposure to polycyclic aromatic hydrocarbon with risk of cardiovascular events. AB - Exposure to polycyclic aromatic hydrocarbons (PAHs) could cause high blood pressure (BP) and increased risk for atherosclerotic cardiovascular disease (ASCVD). However, the mechanisms underlying the relationship between them were unclear. We investigated potential mediation effect of obesity on the association of exposure to PAHs with high BP and increased risk for ASCVD. In the repeated measures study, 106 community-dwelling residents in Wuhan, China finished the physical examination in the winter and summer seasons, eight urinary PAHs metabolites were measured. Associations of urinary PAHs with high BP and increased risk for ASCVD were assessed using either linear mixed effect models or generalized estimating equations models. Mediation analysis was performed to evaluate the mediating effect of obesity on the association of urinary PAHs metabolites with high BP or increased risk of ASCVD. We observed the positive association between urinary PAHs metabolites and BP or the odds ratios for high BP (all P<0.05). Additionally, each one-unit increase in ln-transformed urinary levels of 4-hydroxyphenanthrene or the total of PAH metabolites was associated with a 12.63% or 11.91% increase in the estimated 10-year ASCVD risk (both P<0.05). The waist-to-height ratio mediated 29.0% of the association of urinary 4 hydroxyphenanthrene with increased risk of ASCVD (P<0.05). The findings suggest that PAHs exposure may be associated with elevated BP and an increased risk of ASCVD. Obesity may partially mediate the association between PAHs exposure and higher BP or increased risk of ASCVD. PMID- 29122345 TI - Increased spruce tree growth in Central Europe since 1960s. AB - Tree growth response to recent environmental changes is of key interest for forest ecology. This study addressed the following questions with respect to Norway spruce (Picea abies, L. Karst.) in Central Europe: Has tree growth accelerated during the last five decades? What are the main environmental drivers of the observed tree radial stem growth and how much variability can be explained by them? Using a nationwide dendrochronological sampling of Norway spruce in the Czech Republic (1246 trees, 266 plots), novel regional tree-ring width chronologies for 40(+/-10)- and 60(+/-10)-year old trees were assembled, averaged across three elevation zones (break points at 500 and 700m). Correspondingly averaged drivers, including temperature, precipitation, nitrogen (N) deposition and ambient CO2 concentration, were used in a general linear model (GLM) to analyze the contribution of these in explaining tree ring width variability for the period from 1961 to 2013. Spruce tree radial stem growth responded strongly to the changing environment in Central Europe during the period, with a mean tree ring width increase of 24 and 32% for the 40- and 60-year old trees, respectively. The indicative General Linear Model analysis identified CO2, precipitation during the vegetation season, spring air temperature (March-May) and N-deposition as the significant covariates of growth, with the latter including interactions with elevation zones. The regression models explained 57% and 55% of the variability in the two tree ring width chronologies, respectively. Growth response to N-deposition showed the highest variability along the elevation gradient with growth stimulation/limitation at sites below/above 700m. A strong sensitivity of stem growth to CO2 was also indicated, suggesting that the effect of rising ambient CO2 concentration (direct or indirect by increased water use efficiency) should be considered in analyses of long-term growth together with climatic factors and N-deposition. PMID- 29122346 TI - Vulnerability of forest vegetation to anthropogenic climate change in China. AB - China has large areas of forest vegetation that are critical to biodiversity and carbon storage. It is important to assess vulnerability of forest vegetation to anthropogenic climate change in China because it may change the distributions and species compositions of forest vegetation. Based on the equilibrium assumption of forest communities across different spatial and temporal scales, we used species distribution modelling coupled with endemics-area relationship to assess the vulnerability of 204 forest communities across 16 vegetation types under different climate change scenarios in China. By mapping the vulnerability of forest vegetation to climate change, we determined that 78.9% and 61.8% of forest vegetation should be relatively stable in the low and high concentration scenarios, respectively. There were large vulnerable areas of forest vegetation under anthropogenic climate change in northeastern and southwestern China. The vegetation of subtropical mixed broadleaf evergreen and deciduous forest, cold temperate and temperate mountains needleleaf forest, and temperate mixed needleleaf and broadleaf deciduous forest types were the most vulnerable under climate change. Furthermore, the vulnerability of forest vegetation may increase due to high greenhouse gas concentrations. Given our estimates of forest vegetation vulnerability to anthropogenic climate change, it is critical that we ensure long-term monitoring of forest vegetation responses to future climate change to assess our projections against observations. We need to better integrate projected changes of temperature and precipitation into climate adaptive conservation strategies for forest vegetation in China. PMID- 29122347 TI - Stable and radioactive cesium: A review about distribution in the environment, uptake and translocation in plants, plant reactions and plants' potential for bioremediation. AB - Radiocesium in water, soil, and air represents a severe threat to human health and the environment. It either acts directly on living organisms from external sources, or it becomes incorporated through the food chain, or both. Plants are at the base of the food chain; it is therefore essential to understand the mechanisms of plants for cesium retention and uptake. In this review we summarize investigations about sources of stable and radioactive cesium in the environment and harmful effects caused by internal and external exposure of plants to radiocesium. Uptake of cesium into cells occurs through molecular mechanisms such as potassium and calcium transporters in the plasma membrane. In soil, bioavailability of cesium depends on the chemical composition of the soil and physical factors such as pH, temperature and tilling as well as on environmental factors such as soil microorganisms. Uptake of cesium occurs also from air through interception and absorption on leaves and from water through the whole submerged surface. We reviewed information about reducing cesium in the vegetation by loss processes, and we extracted transfer factors from the available literature and give an overview over the uptake capacities of 72 plants for cesium from the substratum to the biomass. Plants with high uptake potential could be used to remediate soil and water from radiocesium by accumulation and rhizofiltration. Inside plants, cesium distributes fast between the different plant organs and cells, but cesium in soil is extremely stable and remains for decades in the rhizosphere. Monitoring of contaminated soil therefore has to continue for many decades, and edible plants grown on such soil must continuously be monitored. PMID- 29122348 TI - Associations of urinary phthalate metabolites with residential characteristics, lifestyles, and dietary habits among young children in Shanghai, China. AB - Exposure to household phthalates has been reported to have adverse effects on children's health. In this paper, we used phthalate metabolites in the first morning urine as indicators of household phthalate exposures and examined their associations with residential characteristics, lifestyles and dietary habits among young children. During 2013-2014, we collected morning urines from children aged 5-10years in Shanghai, China and obtained the related information about analyzed factors in this study by questionnaires. Urinary phthalate metabolites were analyzed by isotope dilution-high performance liquid chromatography (HPLC) heated electrospray ionization source (HESI) coupled with a triple quadrupole mass spectrometry. ANOVA, the Mann-Whitney or Kruskai-Wallis rank tests, and multivariate linear regression analyses were used to examine the target associations. Ten metabolites of seven phthalates in 434 urine samples were analyzed. The detection rates of eight metabolites (MiBP, MnBP, MEHP, MECPP, MEHHP, MEOHP, MEP, and MMP) were >90%, except for MBzP (51.2%), and MCHP with <10.0% of detection rate was not included in analyses. By multivariate linear regression analyses, factors significantly associated with higher concentrations of metabolites included non-usage household air cleaners (MEP and MEHP), changing the child's pillowcase less than one time a week (DEHP metabolites), dusting furniture in the child's bedroom less than three times a week (MMP and MnBP), using more plastic toys (DEHP metabolites and MEP), often having soft drinks (DEHP metabolites) and candies (MiBP). Our results indicated that phthalate exposures were common among Shanghai children and residential characteristics had less significant associations with urinary phthalate metabolites compared with lifestyles and dietary habits. Using less plastic toys, having less candies and soft drinks, using household air cleaner, as well as frequently changing the child's pillowcase and dusting furniture in the child's bedroom could reduce phthalate exposures among children. PMID- 29122349 TI - Impact of brominated amines on monochloramine stability during in-line and pre formed chloramination assessed by kinetic modelling. AB - In this study, a comprehensive kinetic model was developed and validated to predict the stability of monochloramine (NH2Cl) in presence of iodide and bromide for both pre-formed and in-line chloramination application in absence of organic matter. pH had the greatest influence on the stability of NH2Cl in waters containing bromide. For in-line chloramination, the NH2Cl decay over 3days was only 10% for pH9 and 58% for pH7 (400MUgBr-/L and 3 mgCl2/L). Bromide also greatly affected the stability of NH2Cl by influencing the formation and speciation of the halamines produced during chloramination. In-line chloramination is commonly used since the pre-chlorination oxidises iodide to the non-toxic iodate. During pre-chlorination, brominated organics are formed from reaction between bromine and dissolved organic matter (DOM). In the case of the Colorado River DOM, 26% of the bromine was sequestered in only 4min, and therefore not available to form brominated amines during chloramination. Following ammonia addition, an immediate loss of oxidant was observed in water containing bromide at pH7 and 8. This is due to the reaction between NHBrCl and NHBr2, and the auto-decomposition of NHBr2 formed from NH2Br. Once NHBr2 was consumed, NHBrCl accumulated and then slowly decayed. Thereafter, the total oxidant concentration decayed slowly due to the auto-decomposition of NHCl2 and the reaction between NHBrCl and NHBr2. In the presence of DOM, the CHBr3 concentration increased, while the CHCl3 concentration (formed during pre chlorination) was constant during chloramination, indicating that brominated amines may continue to form disinfection by-products (DBPs). PMID- 29122350 TI - Evaluating residents' preferences for remediation technologies: A choice experiment approach. AB - The choice of technologies used to remediate contaminated environments is increasingly made through engagement with a multitude of stakeholders including affected residents. Despite this, little is known about how residents perceive remediation technology applications. In this study a choice experiment is designed to explore ways of understanding and measuring residents' preferences for different remediation technologies approaches using a sample of 944 residents in New South Wales, Australia. Analysis reveals that the residents' acceptability of remediation technologies can be explained by both the efficacy of the technology in improving the environmental quality of the community, and the reputational value of the technology. In particular it is found that residents prefer Monitor Natural Attenuation and Bioremediation to other remediation technologies. In particular they are willing to pay an increase in yearly taxes of $44.60 and $41.15 respectively for implementing such technologies instead of alternative remediation technologies like Chemical remediation. PMID- 29122351 TI - Macroaggregation and soil organic carbon restoration in a highly weathered Brazilian Oxisol after two decades under no-till. AB - Conclusions based on studies of the impacts of soil organic carbon (SOC) fractions and soil texture on macroaggregation and SOC stabilization in long-term (>20years) no-till (NT) fields remain debatable. This study was based on the hypothesis that the amount and frequency of biomass-C input associated with NT can be a pathway to formation of macroaggregates and to SOC buildup. The objectives were to: 1) assess the macroaggregate distribution (proportional mass, class mass) and the SOC and particulate organic carbon (POC) stocks of extra large (8-19mm), large (2-8mm) and small (0.25-2mm) macroaggregate size classes managed for two decades by NT, and 2) assess the recovery of SOC stocks in extra large macroaggregates compared to adjacent native vegetation (Andropogon sp., Aristida sp., Paspalum sp., and Panicum sp.). The crop rotation systems were: soybean (Glycine max L.), maize (Zea mays L.) and beans (Phaseolus vulgaris L.) in summer; and black oat (Avena strigosa Schreb), white oat (Avena sativa), vetch (Vicia sativa L.), black oat.+vetch (Avena strigosa Schreb+vetch) and wheat (Triticum aestivum L.) in winter. The experimental was laid out as 2*2 randomized block factorial with 12 replicates of a NT experiment established in 1997 on two highly weathered Oxisols. The factors comprised of: (a) two soil textural types: clay loam and sandy clay, and (b) two sampling depths: 0-5 and 5-20cm. The three classes of macroaggregates were obtained by wet sieving, and the SOC content was determined by the dry combustion method. The extra-large macroaggregate classes in 0-20cm depth for sandy clay (SdC) and clay loam (CL) Oxisol represented 75.2 and 72.4% of proportional mass, respectively. The SOC and POC stocks among macroaggregate classes in 0-5 and 5-20cm depths decreased in the order: 8-19mm>2 8mm ~ 0.25-2mm. The SdC plots under soybean/maize at 3:1 ratio recovered 58.3%, while those at 1:1 ratio (high maize frequency) in CL recovered 73.1% of SOC stock in the extra-large macroaggregates compared with the same under native vegetation for 0-20cm depth. Thus, partial restoration of the SOC stock in original extra-large macroaggregate confirms the hypothesis that NT through higher maize cultivation frequency can be a pathway to fomation of macroaggregates and SOC buildup. PMID- 29122352 TI - Microbial community response to silver nanoparticles and Ag+ in nitrifying activated sludge revealed by ion semiconductor sequencing. AB - Silver nanoparticles (AgNPs), which are known to act as biocides, are incorporated into medical and consumer products including athletic clothing, stuffed animals, liquid dietary supplements, and more. The increasing use of AgNPs in these products is likely to lead to their entry into both natural and engineered systems, which has the potential to disrupt bacterial processes including those involved in nutrient cycling in wastewater treatment. In the present study, sequencing batch reactors (SBR) mimicking secondary wastewater treatment were operated to determine the effects of AgNPs on the microbial communities contained within activated sludge of wastewater treatment plants (WWTP). SBRs were treated with 0.2 and 2ppm of either gum Arabic (GA)-coated AgNPs, citrate (Ca)-coated AgNPs, or Ag+ as AgNO3. Cell samples were collected and DNA isolated periodically throughout SBR operation. DNA was used for Ion Torrent Next Gen Sequencing of the V3 region of the 16S rDNA gene. Subsequent analyses revealed that the microbial community both shifted and recovered quickly in response to Ag+. Both AgNP treatments resulted in slower initial community shifts than that observed with the Ag+ treatment. GA-AgNPs elicited the longest lasting effect. Additional examination of nitrogen removal bacteria suggested the possibility of an increase in sludge bulking species with increased concentrations of AgNPs in WWTPs. This study supports the hypothesis that Ag+ release from AgNPs is largely coating-dependent and thus a key driver in dictating AgNP toxicity. PMID- 29122353 TI - Enteric methane emissions and their response to agro-ecological and livestock production systems dynamics in Zimbabwe. AB - Without disregarding its role as one of the key sources of sustainable livelihoods in Zimbabwe and other developing countries, livestock production contributes significantly to greenhouse gas (GHG) emissions through enteric fermentation. For the livestock sector to complement global efforts to mitigate climate change, accurate estimations of GHG emissions are required. Methane emissions from enteric fermentation in Zimbabwe were quantified over 35years under four production systems and five agro-ecological regions. The Intergovernmental Panel on Climate Change emission factor methodology was used to derive CH4 emissions from seven livestock categories at national level. Emission intensities based on human population, domestic export of livestock meat and climate variables were used to assess emission drivers and predict future emission trends. Over the past 35years, enteric fermentation CH4 emissions from all livestock categories ranged between 158.3 and 204.3Ggyear-1. Communal lands, typified by indigenous livestock breeds, had the highest contribution of between 58% and 75% of the total annual emissions followed by livestock from large scale commercial (LSC) farms. The decreasing livestock population on LSC farms and consequent decline in production could explain the lack of a positive response of CH4 emissions to human population growth, and decreasing emissions per capita over time at -0.3kg CH4capita-1year-1. The emissions trend showed that even if Zimbabwe's national livestock population doubles in 2030 relative to the 2014 estimates, the country would still remain with similar magnitude of CH4 emission intensity as that of 1980. No significant correlations (P>0.05) were found between emissions and domestic export of beef and pork. Further research on enhanced characterisation of livestock species, population and production systems, as well as direct measurements and modelling of emissions from indigenous and exotic livestock breeds were recommended. PMID- 29122354 TI - Potentials and limitations of remote fire monitoring in protected areas. AB - Protected areas (PAs) play an important role in maintaining the biodiversity and ecological processes of the site. One of the greatest challenges for the PA management in several biomes in the world is wildfires. The objective of this work was to evaluate the potentialities and limitations of the use of data obtained by orbital remote sensing in the monitoring fire occurrence in PAs. Fire Occurrence Records (FORs) were analyzed in Serra do Brigadeiro State Park, Minas Gerais, Brazil, from 2007 to 2015, using photo interpreted data from TM, ETM+ and OLI sensors of the Landsat series and the Hot Spot Database (HSD) from the Brazilian Institute of Space Research - INPE. It was also observed the time of permanence of the scar left by fire on the landscape, through the multitemporal analysis of the behavior of NDVI (Normalized Difference Vegetation Index) and NBR (Normalized Burn Ratio) indexes, before and after the occurrence. The greatest limitation found for the orbital remote monitoring was the presence of clouds in the passage of the sensor in dates close to the occurrence of the fires. The burned area identified by photo interpretation was 54.9% less than the area contained in the FOR. Although the HSD reported fire occurrences in the buffer zone (up to 10km from the Park), no FORs were found at a distance greater than 1100m from the boundaries of the PA. As the main potential of remote sensing, the possibility of identifying burned areas throughout the park and surroundings is highlighted, with low costs and greater accuracy. PMID- 29122355 TI - Current status of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) exposure among mothers and their babies of Korea-CHECK cohort study. AB - Despite the global ban, organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) have been a persistent and significant environmental health issue worldwide. Prenatal exposure to these persistent organic pollutants (POPs) has been identified as a major route of exposure among developing fetuses and newborn infants. Among Children's Health and Environmental Health of Korea (CHECK) cohort population, pregnant females (n=148) and their matching newborn infants (n=117) recruited from four cities of Korea in 2011 were investigated. The blood serum and cord blood serum were sampled at delivery, and measured for 19 OCPs and 19 PCBs. In addition, a questionnaire regarding demographic characteristics, and dietary habits were conducted. The most frequently detected POPs in both maternal blood and cord blood were p,p'-dichlorodiphenyl dichloroethylene (DDE) (99% detection in maternal, and 98% in cord blood serum) and PCB153 (95% in maternal, 74% in cord blood serum). The levels of dichlorodiphenyl trichloroethanes (DDTs) in both maternal (average 82.5ng/g lw) and cord blood serum (average 77.5ng/g lw) were comparable to or greater than those reported in Japan about a decade ago. Approximately two thirds of the pregnant women and newborn infants showed the p,p'-DDE concentrations exceeding the biological equivalent (BE) corresponding to 10-6 excess cancer risk. In addition, less chlorinated PCBs were detected higher in both maternal and cord serum. Less chlorinated PCBs also showed greater transplacental ratio. Dairy consumption among the subjects was positively associated, and tea consumption was negatively associated with serum levels of several POPs. Our results show that the exposure to legacy POPs, especially DDTs, among pregnant women and newborn infants is still prevailing, thus warrants measures for exposure mitigation among these vulnerable populations. PMID- 29122356 TI - Wearable Technology and Physical Activity in Chronic Disease: Opportunities and Challenges. PMID- 29122357 TI - Kidney Injury Molecule-1 Level is Associated with the Severity of Renal Interstitial Injury and Prognosis in Adult Henoch-Schonlein Purpura Nephritis. AB - BACKGROUND AND AIMS: Kidney injury molecule-1 (KIM-1) was identified the most highly upregulated protein in chronic kidney diseases and prolonged KIM-1 expression may be maladaptive. The present study was aimed to investigate urinary, renal and plasma KIM-1 levels and to analyze association between KIM-1 levels with clinical and pathological indexes in adult Henoch-Schonlein purpura (HSP) patients. METHODS: Twenty healthy individuals, 20 HSP patients without nephritis and 35 HSP patients with nephritis were recruited. Urinary and plasma KIM-1 levels were determined by ELISA and Luminex, respectively. Renal KIM-1 expression was evaluated by immunohistochemistry. RESULTS: HSP patients with nephritis were characterized as elevated levels of urinary, renal and plasma KIM 1. Those with more severe tubular injury of renal biopsy tissues presented significantly higher urinary and renal KIM-1 levels compared to control and patients without nephritis. Urinary and renal levels of KIM-1 were positively correlated with blood urea nitrogen and proteinuria, while they were negatively correlated with eGFR at both baseline and after two years follow-up. Moreover, plasma KIM-1 levels were associated with blood urea nitrogen and proteinuria as well. Further univariate correlation analysis indicated urinary and renal KIM-1 levels were positively correlated with interstitial inflammation index and tubulointerstitial chronicity index. Only urinary KIM-1 levels were associated with interstitial inflammation index, tubulointerstitial chronicity index and extracapillary glomerular activity index, after logistic regression analysis. The area under the curve (AUC) for urinary KIM-1/Cr predicting progression of renal damage was significantly greater than the AUC for proteinuria. CONCLUSIONS: This finding suggests that measurement of urinary and renal KIM-1 level may be helpful to evaluate severity of renal pathological damage and prognosis in adult HSP patients with nephritis. PMID- 29122358 TI - Post-radiochemotherapy PET radiomics in head and neck cancer - The influence of radiomics implementation on the reproducibility of local control tumor models. AB - PURPOSE: This study investigated an association of post-radiochemotherapy (RCT) PET radiomics with local tumor control in head and neck squamous cell carcinoma (HNSCC) and evaluated the models against two radiomics software implementations. MATERIALS AND METHODS: 649 features, available in two radiomics implementations and based on the same definitions, were extracted from HNSCC primary tumor region in 18F-FDG PET scans 3 months post definitive RCT (training cohort n = 128, validation cohort n = 50) and compared using the intraclass correlation coefficient (ICC). Local recurrence models were trained, separately for both implementations, using principal component analysis (PCA) and the least absolute shrinkage and selection operator. The reproducibility of the concordance indexes (CI) in univariable Cox regression for features preselected in PCA and the final multivariable models was investigated using respective features from the other implementation. RESULTS: Only 80 PET radiomic features yielded ICC > 0.8 in the comparison between the implementations. The change of implementation caused high variability of CI in the univariable analysis. However, both final multivariable models performed equally well in the training and validation cohorts (CI > 0.7) independent of radiomics implementation. CONCLUSION: The two post-RCT PET radiomic models, based on two different software implementations, were prognostic for local tumor control in HNSCC. However, 88% of the features was not reproducible between the implementations. PMID- 29122359 TI - Prognostic impact of RITA expression in patients with anal squamous cell carcinoma treated with chemoradiotherapy. AB - BACKGROUND: RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signalling pathway and its deregulation is involved in the pathogenesis of several tumour entities. RITA's impact on the response of anal squamous cell carcinoma (SCC) to anticancer treatment, however, remains elusive. MATERIALS AND METHODS: In our retrospective study immunohistochemical evaluation of RITA was performed on 140 pre-treatment specimens and was correlated with clinical and histopathologic characteristics and clinical endpoints cumulative incidence of local control (LC), distant recurrence (DC), disease-free survival (DFS) and overall survival (OS). RESULTS: We observed significant inverse correlations between RITA expression and tumour grading, the levels of HPV-16 virus DNA load, CD8 (+) tumour infiltrating lymphocytes and programmed death protein (PD-1) immunostaining. In univariate analyses, elevated levels of RITA expression were predictive for decreased local control (p = 0.001), decreased distant control (p = 0.040), decreased disease free survival (p = 0.001) and overall survival (p < 0.0001), whereas in multivariate analyses RITA expression remained significant for decreased local control (p = 0.009), disease free survival (p = 0.032) and overall survival (p = 0.012). CONCLUSION: These data indicate that elevated levels of pretreatment RITA expression are correlated with unfavourable clinical outcome in anal carcinoma treated with concomitant chemoradiotherapy. PMID- 29122360 TI - Association between treatment planning and delivery factors and disease progression in prostate cancer radiotherapy: Results from the TROG 03.04 RADAR trial. AB - BACKGROUND AND PURPOSE: To evaluate the impact of treatment planning and delivery factors on treatment outcome as measured by post-treatment disease progression. MATERIALS AND METHODS: Accruing 813 external beam radiotherapy participants during 2003-2007, the RADAR trial collected a comprehensive range of clinical treatment factor data for each participant. Both the Fine and Gray competing risks modelling and the Kaplan-Meier (KM) analysis were undertaken to determine the impact of these factors on local-composite progression (LCP), with 709 participants available for analysis. RESULTS: Participants with treatments involving 7 or more beams experienced significantly higher incidence of LCP, with a sub-hazard ratio (relative to 3-beam participants) of 3.056 (CI: 1.446-6.458, p < 0.0034). Participants treated with a more rigorous dose calculation algorithm also displayed significantly higher incidence of LCP, with a sub-hazard ratio of 1.686 (CI: 1.334-2.132, p < 0.0001). The KM analysis resulted in the same groups showing a higher incidence of LCP, with log-rank test results of p = 0.0005 and p = 0.0008 respectively. CONCLUSIONS: The RADAR dataset has enabled a successful secondary analysis in which the impact of technical modifications has been assessed, challenging several established hypotheses. Increasingly precise treatments should be complemented with increasing accuracy to avoid potential geometric miss. PMID- 29122361 TI - Ventilation measured on clinical 4D-CBCT: Increased ventilation accuracy through improved image quality. AB - BACKGROUND AND PURPOSE: Ventilation measured on 4D cone-beam computed tomography (CBCT) using deformable image registration (DIR) may predict specific radiation sensitivity, but the measurement is affected by the current image quality. With 4D computed tomography (CT) measured ventilation acting as a gold standard the current study investigates if image improvements increase the accuracy of 4D-CBCT measured ventilation. MATERIAL AND METHODS: The study consists of 4D-CBCT and 4D CT scans of 20 non-small-cell lung cancer patients. Raw CBCT projections were subjected to a standard or an improved projection correction and reconstructed by the common FDK-algorithm or the more advanced SART-algorithm. Ventilation was measured as Jacobians calculated from DIR and the comparison between CBCT and CT was done by Spearman correlation. RESULTS: A significant increase in the mean correlation was observed when combining improved projection correction and SART reconstruction (0.34) compared to the clinical standard (0.21). The correlation further increased when averaging ventilation measured from three successive CBCT scans (0.38). CONCLUSION: The study showed that the combination of improved projection correction and the SART reconstruction increased the accuracy of CBCT ventilation and this result can be a stepping stone to extract dynamic changes in respiration pattern of patients during radiotherapy. PMID- 29122362 TI - With or without consolidation chemotherapy using cisplatin/5-FU after concurrent chemoradiotherapy in stage II-III squamous cell carcinoma of the esophagus: A propensity score-matched analysis. AB - BACKGROUND AND PURPOSE: The benefit of consolidation chemotherapy for locally advanced squamous cell carcinoma of the esophagus is unknown. The aim of this study was to investigate the efficacy of consolidation chemotherapy with cisplatin and 5-fluorouracil (5-FU) after concurrent chemoradiotherapy (CCRT) with the same agents in patients with stage II-III disease. MATERIAL AND METHODS: Data for patients with stage II-III squamous cell carcinoma of the esophagus treated with CCRT were retroactively reviewed. Patients who received CCRT alone (observation group) were compared with those who underwent CCRT followed by consolidation chemotherapy (consolidation group) with regard to progression-free survival, overall survival, treatment failure and toxicity. Differences in baseline characteristics were adjusted using the propensity score matching method. RESULTS: From September 2006 to September 2012, 812 patients were recruited (n = 272 for observation; n = 540 for consolidation). Among them, 290 (35.7%) had clinical stage II disease and 522 (64.3%) had stage III disease. In the overall study cohort, the median progression-free survival (22.1 months vs. 22.0 months, P = 0.917) and median overall survival (33.8 months vs. 31.3 months, P = 0.591) were comparable between the observation group and consolidation group. Comparisons of the observation and consolidation group in the matched population (262 patients in each group) showed median progression-free survival of 23.0 months and 25.4 months (hazard ratio [HR], 0.93; 95% CI [confidence interval], 0.74-1.15; P = 0.491), and median overall survival of 34.6 months and 35.0 months (HR, 0.92; 95% CI, 0.80-1.27; P = 0.919), respectively. There were no significant differences in local/regional failure and persistence disease (50.4% vs. 48.5%) and distant failure (10.7% vs. 8.8%) between the two groups. CONCLUSIONS: Compared to CCRT alone, consolidation chemotherapy did not further prolong progression-free survival and overall survival for patients with stage II-III squamous cell carcinoma of the esophagus. The role of consolidation therapy needs to be studied further. PMID- 29122363 TI - Clustering of multi-parametric functional imaging to identify high-risk subvolumes in non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: We aimed to identify tumour subregions with characteristic phenotypes based on pre-treatment multi-parametric functional imaging and correlate these subregions to treatment outcome. The subregions were created using imaging of metabolic activity (FDG-PET/CT), hypoxia (HX4-PET/CT) and tumour vasculature (DCE-CT). MATERIALS AND METHODS: 36 non-small cell lung cancer (NSCLC) patients underwent functional imaging prior to radical radiotherapy. Kinetic analysis was performed on DCE-CT scans to acquire blood flow (BF) and volume (BV) maps. HX4-PET/CT and DCE-CT scans were non-rigidly co registered to the planning FDG-PET/CT. Two clustering steps were performed on multi-parametric images: first to segment each tumour into homogeneous subregions (i.e. supervoxels) and second to group the supervoxels of all tumours into phenotypic clusters. Patients were split based on the absolute or relative volume of supervoxels in each cluster; overall survival was compared using a log-rank test. RESULTS: Unsupervised clustering of supervoxels yielded four independent clusters. One cluster (high hypoxia, high FDG, intermediate BF/BV) related to a high-risk tumour type: patients assigned to this cluster had significantly worse survival compared to patients not in this cluster (p = 0.035). CONCLUSIONS: We designed a subregional analysis for multi-parametric imaging in NSCLC, and showed the potential of subregion classification as a biomarker for prognosis. This methodology allows for a comprehensive data-driven analysis of multi-parametric functional images. PMID- 29122364 TI - Photocatalytic degradation of 4-amino-6-chlorobenzene-1,3-disulfonamide stable hydrolysis product of hydrochlorothiazide: Detection of intermediates and their toxicity. AB - In this work we have investigated in details the process of degradation of the 4 amino-6-chlorobenzene-1,3-disulfonamide (ABSA), stable hydrolysis product of frequently used pharmaceutical hydrochlorothiazide (HCTZ), as one of the most ubiquitous contaminants in the sewage water. The study encompassed investigation of degradation by hydrolysis, photolysis, and photocatalysis employing commercially available TiO2 Degussa P25 catalyst. The process of direct photolysis and photocatalytic degradation were investigated under different type of lights. Detailed insights into the reactive properties of HCTZ and ABSA have been obtained by density functional theory calculations and molecular dynamics simulations. Specifically, preference of HCTZ towards hydrolysis was confirmed experimentally and explained using computational study. Results obtained in this study indicate very limited efficiency of hydrolytic and photolytic degradation in the case of ABSA, while photocatalytic degradation demonstrated great potential. Namely, after 240 min of photocatalytic degradation, 65% of ABSA was mineralizated in water/TiO2 suspension under SSI, while the nitrogen was predominantly present as NH4+. Reaction intermediates were studied and a number of them were detected using LC-ESI-MS/MS. This study also involves toxicity assessment of HCTZ, ABSA, and their mixtures formed during the degradation processes towards mammalian cell lines (rat hepatoma, H-4-II-E, human colon adenocarcinoma, HT-29, and human fetal lung, MRC-5). Toxicity assessments showed that intermediates formed during the process of photocatalysis exerted only mild cell growth effects in selected cell lines, while direct photolysis did not affect cell growth. PMID- 29122365 TI - Chemical characterization of polycyclic aromatic hydrocarbons (PAHs) in 2013 Rayong oil spill-affected coastal areas of Thailand. AB - Among Southeast Asian countries, Thailand has gradually accustomed to extremely prompt urbanization, motorization, and industrialization. Chonburi and Rayong provinces are two provinces involved in "eastern seaboard" industrial zones, which is an emerging economic region that plays a key role in Thailand's economy. The 2013 Rayong oil spill did not only cause damages to the coastal and maritime environment, but also undermine trust in the overall safety system and negatively affect the investor confidence. In this study, 69 coastal soils collected around Koh Samed Island were chemically extracted and analyzed for 15 PAHs by using a Shimadzu GCMS-QP2010 Ultra system comprising a high-speed performance system with ASSP function. In this study, numerous diagnostic binary ratios were applied to identify potential sources of PAHs. Advanced statistical techniques such as hierarchical cluster analysis coupled with principal component analysis were also conducted for further investigations of source identifications. PMID- 29122366 TI - Associations between residential traffic noise exposure and smoking habits and alcohol consumption-A population-based study. AB - BACKGROUND: Traffic noise stresses and disturbs sleep. It has been associated with various diseases, and has recently also been associated with lifestyle. Hence, the association between traffic noise and disease could partly operate via a pathway of lifestyle habits, including smoking and alcohol intake. OBJECTIVES: We investigated associations between modelled residential traffic noise and smoking habits and alcohol consumption. METHODS: In a cohort of 57,053 participants, we performed cross-sectional analyses using data from a baseline questionnaire (1993-97), and longitudinal analyses of change between baseline and follow-up (2000-02). Smoking status (never, former, current) and intensity (tobacco, g/day) and alcohol consumption (g/day) was self-reported at baseline and follow-up. Address history from 1987-2002 for all participants were found in national registries, and road traffic and railway noise was modelled 1 and 5 years before enrolment, and from baseline to follow-up. Analyses were performed using logistic and linear regression, and adjusted for demographics, socioeconomic variables, leisure-time sports, and noise from the opposite source (road/railway). RESULTS: Road traffic noise exposure 5 years before baseline was positively associated with alcohol consumption (adjusted difference per 10 dB: 1.38 g/day, 95% confidence interval (CI): 1.10-1.65), smoking intensity (adjusted difference per 10 dB: 0.40 g/day, 95% CI: 0.19-0.61), and odds for being a current vs. never/former smoker at baseline (odds ratio (OR): 1.14; 95% CI: 1.10 1.17). In longitudinal analyses, we found no association between road traffic noise and change in smoking and alcohol habits. Railway noise was not associated with smoking habits and alcohol consumption, neither in cross-sectional nor in longitudinal analyses. CONCLUSION: The study suggests that long-term exposure to residential road traffic is associated with smoking habits and alcohol consumption, albeit only in cross-sectional, but not in longitudinal analyses. PMID- 29122367 TI - Stabilization of arsenic and lead by magnesium oxide (MgO) in different seawater concentrations. AB - Ongoing sea level rise will have a major impact on mobility and migration of contaminants by changing a number of natural phenomena that alter geochemistry and hydrology of subsurface environment. In-situ immobilization techniques may be a promising remediation strategy for mitigating contaminant mobility induced by sea level rise. This study investigated the reaction mechanisms of magnesium oxide (MgO) with aqueous Pb and As under freshwater and seawater using XAFS spectroscopy. Initial concentrations of Pb and As in freshwater strongly controlled the characteristics of the reaction product of MgO. Our study revealed that i) the removal of aqueous Pb and As by MgO was increased by the elevation of seawater concentration, and ii) the removal of As was attributed primarily to (inner-sphere) surface adsorption on MgO, independent on seawater concentrations, and iii) the retention mechanism of Pb was dependent on seawater concentrations where formations of Pb oxides and adsorption on the MgO surface were predominant in solutions with low and high salinity, respectively. The release of As fixed with MgO significantly increased in seawater compared to freshwater, although the amount of As desorbed accounted for <0.2% of total As. PMID- 29122368 TI - The parietal opercular auditory-sensorimotor network in musicians: A resting state fMRI study. AB - Auditory-sensorimotor coupling is critical for musical performance, during which auditory and somatosensory feedback signals are used to ensure desired outputs. Previous studies reported opercular activation in subjects performing or listening to music. A functional connectivity analysis suggested the parietal operculum (PO) as a connector hub that links auditory, somatosensory, and motor cortical areas. We therefore examined whether this PO network differs between musicians and non-musicians. We analyzed resting-state PO functional connectivity with Heschl's gyrus (HG), the planum temporale (PT), the precentral gyrus (preCG), and the postcentral gyrus (postCG) in 35 musicians and 35 non-musicians. In musicians, the left PO exhibited increased functional connectivity with the ipsilateral HG, PT, preCG, and postCG, whereas the right PO exhibited enhanced functional connectivity with the contralateral HG, preCG, and postCG and the ipsilateral postCG. Direct functional connectivity between an auditory area (the HG or PT) and a sensorimotor area (the preCG or postCG) did not significantly differ between the groups. The PO's functional connectivity with auditory and sensorimotor areas is enhanced in musicians relative to non-musicians. We propose that the PO network facilitates musical performance by mediating multimodal integration for modulating auditory-sensorimotor control. PMID- 29122369 TI - Preserved metacognitive ability despite unilateral or bilateral anterior prefrontal resection. AB - Brodmann area 10 (BA10) is thought to be at the summit of the prefrontal cortex's hierarchical organization. It is widely accepted that metacognitive abilities depend on the structural and functional properties of BA10. Our objective was to assess whether metacognition can be maintained after low-grade glioma surgery with BA10 resection. Three groups of participants were recruited: (i) patients having undergone resection of the right prefrontal cortex, including BA10 (n = 9); (ii) patients having undergone resection of the right prefrontal cortex but not BA10 (n = 10); and (iii) healthy controls (n = 38). Importantly, we also included a patient (referred to as "PR") with resection of BA10 in the two hemispheres. The patients with resection of right BA10 had metacognitive performances that were indistinguishable from those of brain-damaged control patients and healthy controls. Crucially, PR's metacognitive ability was not only maintained but was even in the upper quartile of normal performances. Our findings demonstrate that the brain can redistribute and remap metacognition in response to injury. We thus provide experimental evidence against the conventional hypothesis whereby cognitive functions are directly and lastingly linked to particular cortical structures. The latter hypothesis seems to be particularly false for the highest levels of human cognition and for BA10. PMID- 29122370 TI - Effectiveness of the graded motor imagery to improve hand function in patients with distal radius fracture: A randomized controlled trial. AB - STUDY DESIGN: Single-blinded randomized controlled trial. INTRODUCTION: Pain management is essential in the early stages of the rehabilitation of distal radius fractures (DRFx). Pain intensity at the acute stage is considered important for determining the individual recovery process, given that higher pain intensity and persistent pain duration negatively affect the function and cortical activity of pain response. Graded motor imagery (GMI) and its components are recent pain management strategies, established on a neuroscience basis. PURPOSE OF THE STUDY: To investigate the effectiveness of GMI in hand function in patients with DRFx. METHODS: Thirty-six participants were randomly allocated to either GMI (n = 17; 52.59 [9.8] years) or control (n = 19; 47.16 [10.5] years) groups. The GMI group received imagery treatment in addition to traditional rehabilitation, and the control group received traditional rehabilitation for 8 weeks. The assessments included pain at rest and during activity using the visual analog scale, wrist and forearm active range of motion (ROM) with universal goniometer, grip strength with the hydraulic dynamometer (Jamar; Bolingbrook, IL), and upper extremity functional status using the Disability of the Arm, Shoulder and Hand Questionnaire, and the Michigan Hand Questionnaire. Assessments were performed twice at baseline and at the end of the eighth week. RESULTS: The GMI group showed greater improvement in pain intensity (during rest, 2.24; activity, 6.18 points), wrist ROM (flexion, -40.59; extension, -45.59; radial deviation, -25.59; and ulnar deviation, -26.77 points) and forearm ROM (supination, -43.82 points), and functional status (Disability of the Arm, Shoulder and Hand Questionnaire, 38.00; Michigan Hand Questionnaire, -32.53 points) when compared with the control group (for all, P < .05). CONCLUSION: The cortical model of pathological pain suggests new strategies established on a neuroscience basis. These strategies aim to normalize the cortical proprioceptive representation and reduce pain. One of these recent strategies, GMI appears to provide beneficial effects to control pain, improve grip strength, and increase upper extremity functions in patients with DRFx. PMID- 29122371 TI - The Sound of Silence. PMID- 29122372 TI - Sufentanil sublingual tablet 30mcg for moderate-to-severe acute pain in the ED. AB - BACKGROUND: Pharmacological properties of the sufentanil sublingual tablet 30mcg (SST 30mcg) could offer potential analgesic advantages in settings requiring noninvasive, acute pain management. The feasibility of using SST 30mcg for moderate-to-severe pain management in the emergency department (ED) was evaluated. METHODS: This open-label, multicenter feasibility study included patients aged >=18years who presented to the ED with moderate-to-severe pain (>=4 on the numeric rating scale of pain intensity (NRS); opioid-tolerant patients were excluded. Patients received a single SST 30-mcg dose (single-dose cohort) or, upon request, <=3 additional doses >=60min apart (multiple-dose cohort) and were evaluated over 1 or 2h. Effectiveness was assessed by patient-reported pain scores (11-point NRS; 5-point pain relief scale). Safety and tolerability were also assessed. RESULTS: Overall, 76 patients enrolled into the single-dose (n=40) and multiple-dose (n=36) cohorts. In the first hour (combined cohorts), mean pain intensity was significantly lower 15-min post-dosing (P<0.001; clinically meaningful within 30-minutes post-dosing) and continued to decrease during the first hour (P<0.001 for each 15-minute interval). Mean pain intensity (multiple dose cohort) decreased from 7.6 at baseline to 4.5 at 1h and to 4.6 at 2h (P<0.001 for both); mean pain relief increased from baseline to 1.9 at 1h (P<0.001) and to 2.0 at 2h (P<0.001). Most (79%) patients had no adverse events (AEs), and there were no severe AEs. CONCLUSIONS: SST 30mcg was feasible for managing moderate-to-severe acute pain in an ED setting. PMID- 29122373 TI - Characteristics and resource utilization of patients presenting to the ED from mass gathering events. AB - INTRODUCTION: At many mass gathering events (MGEs), emergency medical services decrease the number of patient transfers to the hospital; however, little information is known regarding the characteristics of attendees presenting to or requiring transfer to the emergency department (ED). The purpose of this study is to describe the characteristics of patients presenting from MGEs to the ED. A secondary aim of this study is to describe ED resources utilized by these patients. METHODS: This was a single-center, retrospective review evaluating patients attending MGEs who presented to the ED. Electronic medical records of patients seen in the ED of a tertiary academic medical center between October 13, 2013 and December 31, 2015 were reviewed and a descriptive analysis performed. RESULTS: We reviewed and included 209 patients. The majority of patients presenting to the ED were from large outdoor concerts (n=186, 89%), young (median age 20years), single (n=156, 87%) and had no past medical history (n=114, 63%). Alcohol use was reported in a majority (n=140, 78%) and polysubstance use in over a quarter of patients (n=55, 31%). The most frequently administered medications were intravenous fluids (n=94, 52%) and antiemetics (n=59, 33%). The majority of patients (n=161, 89%) were discharged directly from the ED, and median length of stay in the ED was 3.3h [IQR 2.3 to 5.3]. CONCLUSION: Patients presenting to the ED from MGEs generally required minimal medical care beyond supportive management with low rates of hospital admission. Further controlled studies are needed to confirm these findings. PMID- 29122374 TI - Effect of law enforcement action on K2 abuse trends. PMID- 29122375 TI - Blunt traumatic axillary artery truncation, in the absence of associated fracture. AB - BACKGROUND: Axillary artery injuries can be associated with both proximal humeral fractures (Naouli et al., 2016; Ng et al., 2016) [1,2] as well as shoulder dislocations (Leclerc et al., 2017; Karnes et al., 2016) [3,4]. We report a rare case of an isolated axillary artery truncation following blunt trauma without any associated fracture or dislocation. CASE REPORT: A 58-year-old male presented to the emergency department for evaluation after falling on his outstretched right arm. The patient was found to have an absent right radial pulse with decreased sensation to the right arm. Point of care ultrasound showed findings suspicious for traumatic axillary artery injury, and X-rays did not demonstrate any fracture. Computed tomography with angiography confirmed axillary artery truncation with active extravasation. The patient underwent successful vascular repair with an axillary artery bypass. Although extremity injuries are common in emergency departments, emergency physicians need to recognize the risk for vascular injuries, even without associated fracture or dislocation. PMID- 29122376 TI - Explaining regional variation in home care use by demand and supply variables. AB - In the Netherlands, home care services like district nursing and personal assistance are provided by private service provider organizations and covered by private health insurance companies which bear legal responsibility for purchasing these services. To improve value for money, their procurement increasingly replaces fee-for-service payments with population based budgets. Setting appropriate population budgets requires adaptation to the legitimate needs of the population, whereas historical costs are likely to be influenced by supply factors as well, not all of which are necessarily legitimate. Our purpose is to explain home care costs in terms of demand and supply factors. This allows for adjusting historical cost patterns when setting population based budgets. Using expenses claims of 60 Dutch municipalities, we analyze eight demand variables and five supply variables with a multiple regression model to explain variance in the number of clients per inhabitant, costs per client and costs per inhabitant. Our models explain 69% of variation in the number of clients per inhabitant, 28% of costs per client and 56% of costs per inhabitant using demand factors. Moreover, we find that supply factors explain an additional 17-23% of variation. Predictors of higher utilization are home care organizations that are integrated with intramural nursing homes, higher competition levels among home care organizations and the availability of complementary services. PMID- 29122377 TI - The Role of Surgery in Metastatic Bladder Cancer: A Systematic Review. AB - CONTEXT: The role of surgery in metastatic bladder cancer (BCa) is unclear. OBJECTIVE: In this collaborative review article, we reviewed the contemporary literature on the surgical management of metastatic BCa and factors associated with outcomes to support the development of clinical guidelines as well as informed clinical decision-making. EVIDENCE ACQUISITION: A systematic search of English language literature using PubMed-Medline and Scopus from 1999 to 2016 was performed. EVIDENCE SYNTHESIS: The beneficial role of consolidation surgery in metastatic BCa is still unproven. In patients with clinically evident lymph node metastasis, data suggest a survival advantage for patients undergoing postchemotherapy radical cystectomy with lymphadenectomy, especially in those with measurable response to chemotherapy (CHT). Intraoperatively identified enlarged pelvic lymph nodes should be removed. Anecdotal reports of resection of pulmonary metastasis as part of multimodal approach suggest possible improved survival in well-selected patients. Cytoreductive radical cystectomy as local treatment has also been explored in patients with metastatic disease, although its benefits remain to be assessed. CONCLUSIONS: Consolidative extirpative surgery may be considered in patients with clinically evident pelvic or retroperitoneal lymph nodal metastases but only if they have had a response to CHT. Surgery for limited pulmonary metastases may also be considered in very selected cases. Best candidates are those with resectable disease who demonstrate measurable response to CHT with good performance status. In the absence of data from prospective randomized studies, each patient should be evaluated on an individual basis and decisions made together with the patient and multidisciplinary teams. PATIENT SUMMARY: Surgical resection of metastases is technically feasible and can be safely performed. It may help improve cancer control and eventually survival in very selected patients with limited metastatic burden. In a patient who is motivated to receive chemotherapy and to undergo extirpative surgical intervention, surgery should be discussed with the patient among other consolidation therapies in the setting of multidisciplinary teams. PMID- 29122378 TI - Customizing Daily Management of Castrate-resistant Prostate Cancer: Waiting for the Next Step. PMID- 29122379 TI - [Acute angle closure glaucoma as presenting sign of posterior segment inflammatory disease: Report of two cases]. PMID- 29122380 TI - [Macular ischemia in Waldenstrom's macroglobulinemia]. PMID- 29122381 TI - The dialyser in the year 2017: much more than a membrane. PMID- 29122382 TI - Using Biological Insight and Pragmatism When Thinking about Pseudoreplication. AB - Pseudoreplication is controversial across experimental biology. Researchers in the same field can disagree on whether a given study suffers from pseudoreplication and on to what extent any pseudoreplication undermines the value of a study. A recent survey indicated that concerns about pseudoreplication can strongly impact peer review of manuscripts submitted for publication. Here we explore controversies around pseudoreplication, identify issues requiring resolution, and in each case offer a resolution. We emphasise that having non independence in data points and pseudoreplicating are not the same thing. Researchers should be able to demonstrate that in a given experiment they have minimised and controlled the risk of non-independence weakening their study. If they do that to the satisfaction of others, they have avoided pseudoreplication. PMID- 29122383 TI - First hurdle for optimal treatment of acute myocardial infarction. PMID- 29122385 TI - Prevalence and factors associated with influenza vaccination of persons over 65 years old in Spain (2009-2014). AB - BACKGROUND: Influenza is a major public health problem. Achieving 65% coverage in people over 65 years old is a health policy priority in Spain. OBJECTIVE: To determine the coverage of influenza vaccination in Spain in 2014 for people over 65 years and to analyze the factors associated with coverage and its progression between 2009 and 2014. METHODS: A descriptive cross-sectional study was conducted that included 18,442 non-institutionalized individuals over 65 years who had participated in the National Health Survey in Spain in 2011 and in the European Health Survey in Spain in 2009 and 2014. Socio-demographic variables, health variables, and influenza vaccination data were used. A logistic regression analysis was performed to determine the variables associated with anti-influenza vaccination. RESULTS: Influenza vaccination coverage has declined from 2009 (74.5%) to 2014 (57.4%). There are significant differences in the vaccination coverage among the different Spanish autonomous communities in the different years studied. Influenza vaccination was associated with males, low social class, and low level of education. There is greater participation in other preventive measures, such as assessing blood pressure, blood glucose, and cholesterol, than in influenza vaccination. CONCLUSIONS: Fewer people over 65 years old than recommended by the WHO participated in the influenza vaccination campaign in Spain in 2014. This coverage declined progressively from 2009 to 2014. PMID- 29122384 TI - Strengthening global vaccine access for adolescents and adults. AB - Global immunization efforts to date have heavily focused on infants and children, with noted success on public health. Healthy adolescents and adults contribute to the economic growth and development of countries but efforts to ensure vaccine coverage for these groups receive inadequate global attention and resources. Emerging epidemics for a number of infectious diseases including Ebola, Zika, dengue, malaria and the continuing epidemics of tuberculosis and several sexually transmitted infections, including HIV, HPV and Hepatitis B, have high incidence and prevalence in adolescents and adults. New vaccines under development for these diseases and under-used vaccines such as for human papilloma virus will have the greatest health and economic impact in these populations. Global consensus, political will, policies, global and country infrastructure, and financing mechanisms are needed to accelerate access for the billions of adolescents and adults living under the threat of devastating infectious disease outbreaks and epidemics, especially in lower income countries. The global health community and countries cannot afford to delay planning for implementation of adolescent and adult vaccine programs that will potentially save millions of lives and strengthen global and national economies. The article examines this next challenge and suggests a research agenda and a framework for action to galvanize global and national policy decision-makers to begin preparations for future immunization challenges. PMID- 29122387 TI - Protection against Schistosoma haematobium infection in hamsters by immunization with Schistosoma mansoni gut-derived cysteine peptidases, SmCB1 and SmCL3. AB - We examined the immunogenicity and protective potential of SmCB1 and SmCL3 cysteine peptidases, alone and in combination, in hamsters challenged with S. haematobium. For each of two independent experiments, eight Syrian hamsters were immunized twice with a three week-interval with 0 (controls), 20 ug SmCB1, 20 ug SmCL3, or 10 ug SmCB1 plus 10 ug SmCL3, and then percutaneously exposed eight weeks later to 100 S. haematobium cercariae. Hamsters from each group were assessed for humoral and whole blood culture cytokine responses on day 10 post challenge infection, and examined for parasitological parameters 12 weeks post infection. At day 10 post-infection we found that SmCB1 and SmCL3 elicited low antibody titres and weak but polarized cytokine type 2 responses. Nevertheless, both cysteine peptidases, alone or in combination, evoked reproducible and highly significant reduction in challenge worm burden (>70%, P < 0.02) as well as a significant reduction in worm egg counts and viability. The data support our previous findings and show that S. mansoni cysteine peptidases SmCB1 and SmCL3 are efficacious adjuvant-free vaccines that induce protection in mice and hamsters against both S. mansoni and S. haematobium. PMID- 29122386 TI - Towards replacement of the acellular pertussis vaccine safety test: Comparison of in vitro cytotoxic activity and in vivo activity in mice. AB - Because of the exquisite sensitivity of the murine histamine sensitization test (HIST) in detecting minute amounts of active pertussis toxin (PTx), this animal based test has been used to assure the safety of acellular pertussis vaccines in the United States and other countries around the world. Prompted by humane considerations, efforts are underway to find a suitable in vitro replacement assay that has critical attributes comparable to that of the HIST. In this study, we compared the sensitivity of the in vivo HIST with an in vitro Chinese Hamster Ovary (CHO) cell-based assay. Using vaccine samples that had been spiked with PTx, we found that both assays were capable of detecting as little as 4-10 ng of active pertussis toxin per dose of vaccine; thus, the sensitivities of the two assays are comparable. Because the strength of adsorption of PTx to the vaccine adjuvant could change over time, we also used both assays to examine the bioavailability of PTx in spiked vaccine samples that had been stored at 25 degrees C for 9 weeks, mimicking long term vaccine storage conditions. We found that both assays detected similar amounts of active PTx in these samples, indicating that bioavailability of the toxin in stored samples was similar. Taken together, our results indicate that critical attributes of the HIST are met by the CHO cell assay used in this study and provide proof of concept that the CHO cell assay may be further considered as a replacement for the in vivo HIST. PMID- 29122388 TI - Pelvic Tilt Displacement Before and After Artificial Hip Joint Replacement Surgery. AB - BACKGROUND: Prediction of pelvic displacement before total hip arthroplasty (THA) is important for accurate acetabular implant placement. This study aimed to evaluate the effect of contralateral joint conditions on pelvic displacement after THA. METHODS: A total of 355 cases that underwent computed tomography before and after THA for osteoarthritis due to developmental dysplasia were assessed. The pelvic plane was based on preoperative and postoperative day 1 computed tomography images. The displacement in the anteversion direction was expressed as +. Subjects with a minimal joint space <2 mm in the contralateral hip joint were in group N; subjects with >=2 mm were in group W; subjects with THA were in group P; and subjects who underwent THA simultaneously on both sides were in group B. The Bartlett test was used when conducting the equal variance test among the groups. The F test was used for pairwise comparison. A P value <.01 was considered statistically significant. RESULTS: Groups N, W, P, and B had 49, 227, 55, and 24 cases, respectively, and their displacements were -0.2 degrees +/- 2.7 degrees , 0.8 degrees +/- 3.9 degrees , 0.5 degrees +/- 2.6 degrees , and 1.1 degrees +/- 4.0 degrees , respectively; the variance between the groups was significantly different (P = .0001). The differences between groups W and N (P = .0020), between groups W and P (P = .0003), and between groups P and B (P = .0086) were statistically significant. CONCLUSION: When the contralateral joint space is wide, the variance of the displacement is high. The contralateral joint affects pelvic displacement. PMID- 29122389 TI - The nutritional geometry of liver disease including non-alcoholic fatty liver disease. AB - Nutrition has a profound effect on chronic liver disease, especially non alcoholic fatty liver disease (NAFLD). Most observational studies and clinical trials have focussed on the effects of total energy intake, or the intake of individual macronutrients and certain micronutrients, such as vitamin D, on liver disease. Although these studies have shown the importance of nutrition on hepatic outcomes, there is not yet any unifying framework for understanding the relationship between diet and liver disease. The Geometric Framework for Nutrition (GFN) is an innovative model for designing nutritional experiments or interpreting nutritional data that can determine the effects of nutrients and their interactions on animal behaviour and phenotypes. Recently the GFN has provided insights into the relationship between dietary energy and macronutrients on obesity and ageing in mammals including humans. Mouse studies using the GFN have disentangled the effects of macronutrients on fatty liver and the gut microbiome. The GFN is likely to play a significant role in disentangling the effects of nutrients on liver disease, especially NAFLD, in humans. PMID- 29122390 TI - Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? AB - Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. NAFLD has traditionally been considered a consequence of metabolic syndrome (MetS). However, the link between NAFLD and MetS components, especially type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) is more complex than previously thought. Indeed, the adverse effects of NAFLD extend far beyond the liver, with a large body of clinical evidence now suggesting that NAFLD may precede and/or promote the development of T2DM, HTN and atherosclerosis/CVD. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD is associated with an increased risk of incident T2DM and HTN. Moreover, long-term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. In this review, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NAFLD and CVD morbidity and mortality. Finally, we discuss the most updated putative biological mechanisms through which NAFLD may contribute to the development of HTN, T2DM and CVD. PMID- 29122391 TI - Genetics and epigenetics of NAFLD and NASH: Clinical impact. AB - Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed. PMID- 29122392 TI - Differences in psychosocial determinants of hand hygiene between health care professional groups: Insights from a mixed-methods analysis. AB - BACKGROUND: Good hand hygiene (HH) prevents health care-associated infections. We compared psychosocial and organizational factors associated with HH compliance and perceived need for improvement among physicians, nurses, and allied health professionals (AHPs). METHODS: We conducted a mixed-methods study in a 1,600-bed adult tertiary-care hospital in Singapore. Seven focus group discussions were conducted and data were analyzed using thematic analysis. The subsequent cross sectional survey involved 1,064 staff members. Principal components analysis was performed to derive the latent factor structure that was applied in multivariable analyses. RESULTS: All staff members acknowledged that HH was an integral part of their work, but were noncompliant due to competing priorities. Physicians were forgetful but appreciated reminders. Nurses were intrinsically motivated for HH. After adjusting for gender, staff category, seniority, and dermatitis history, having positive knowledge-attitudes-behaviors (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.23-1.69), personal motivators-enablers (OR, 1.60; 95% CI, 1.38-1.86), and emotional motivators (OR, 1.62; 95% CI 1.40-1.88) were positively associated with good HH compliance. Women (OR, 3.91; 95% CI, 1.37 11.11), seniors (OR, 2.88; 95% CI, 1.08-7.68), nurses (OR, 4.05; 95% CI, 1.51 10.87), and staff with personal motivators-enablers for HH (OR, 1.60; 95% CI, 1.08-2.37) were more likely to perceive a need for improvement. CONCLUSIONS: Factors influencing self-reported HH differed between health care professional groups. Group-specific interventions are needed to improve compliance. PMID- 29122393 TI - How do professional relationships influence surgical antibiotic prophylaxis decision making? A qualitative study. AB - BACKGROUND: Surgical antibiotic prophylaxis (SAP) is a critical area to optimize to reduce the escalation of antimicrobial resistance. This article explores the ways by which interpersonal relationships influence SAP decision making. METHODS: Twenty surgeons and anesthetists participated in in-depth semistructured interviews on SAP prescribing. Results were analyzed using the framework approach. RESULTS: Analysis revealed 3 ways by which interpersonal relationships influence SAP: relationship dynamics between the surgeon and the anesthetist determine appropriateness of SAP, particularly operative risk ownership; perceived hierarchies within, and between, surgical and anesthetist specialties influence antibiotic prescribing decisions; and surgical distance from the antimicrobial stewardship team, which influences use of antimicrobial stewardship principles. CONCLUSIONS: Interventions to optimize SAP are more likely to be effective in enacting sustained change if they consider the interpersonal and social contexts, including issues of familiarity and cohesiveness, hierarchical patterns, and sense of place within a team. Significant relational dynamics in SAP decision making are centered around risk; that is, personal/reputational risk to different professional groups and ownership of risk for individual patient outcomes. Risk must therefore be considered for sustainable SAP optimization interventions. PMID- 29122394 TI - Scientific Notebook Software: Applications for Academic Radiology. AB - OBJECTIVES: The goal of this article is to introduce the concept of scientific notebook software, and to illustrate how it can be used to document a research project, to perform image analysis and to create interactive teaching tools. METHODS: We describe the installation of scientific notebook software known as Project Jupyter, which is free, open-source and available for the Macintosh, Windows and Linux operating systems. RESULTS: We have created 2 scientific notebooks that demonstrate applications germane to radiologists, particularly those in academic radiology. The first notebook provides a tutorial that summarizes basic features of the Project Jupyter notebook, and gives numerous examples of how the notebooks can display explicatory text, perform statistical computations, and display plots, interactive graphics, and audio files. The second notebook provides a toolbox for viewing and manipulating images in the Digital Imaging and Communications in Medicine format. CONCLUSIONS: Scientific notebook software allows its users to document their work in a form that combines text, graphics, images, data, interactive calculations and image analysis within a single document. Scientific notebooks also provide interactive teaching tools, which are can help explain complex topics in imaging physics to residents. PMID- 29122395 TI - The Clinical and Medicolegal Implications of Radiology Results Communication. AB - Multiple guidelines and legal precedents have established the radiologist's duty to inform clinicians directly of critical findings, or findings that will greatly impact patient health in a timely manner [1]. While the number one cause for radiology malpractice cases is misdiagnosis, the literature shows a growing portion of lawsuits surrounding breakdowns in communication between radiologists and ordering providers [2,3]. As such, a review of guidelines related to the communication of imaging results is warranted. We will describe and provide our perspective on results communication as well as attempt to further define ideal communication practices in healthcare scenarios that fall outside of normal cases. PMID- 29122396 TI - [Cannabis and crossed allergy with food]. AB - Cannabis use has increased over the last decade. At the same time, we see cannabis allergies appearing, ranging from simple rhinoconjunctivitis to anaphylactic-type reactions, some of which are severe since fatal cases have been described, but we also see allergic-induced food allergies cross-linked in the family of lipid transfer proteins (LTP). Indeed, cannabis contains an LTP called Can s 3. The LT are very widespread in the vegetable kingdom and are present in many vegetables and fruits. LTPs have a similar chemical structure and therefore cross-allergy is common. Thus, by becoming aware of the LTP of cannabis, it is possible to become allergic by a mechanism of cross-allergy to the other LTPs present in fruits and vegetables. This syndrome is referred to as cannabis-fruit vegetable syndrome. PMID- 29122397 TI - [Role of therapeutic education for patients with COPD participating in respiratory rehabilitation programs]. AB - National and international guidelines confirm that therapeutic education should be an integral part of respiratory rehabilitation programs. Here we outline the pathophysiological foundation of respiratory rehabilitation in order to better apprehend the underlying rationale while taking into consideration each patient's symptoms, the real justification of any therapeutic intervention. Therapeutic education points out the fact that it is the patient who is being treated, not the illness. It is also the occasion to recall that long-term efficacy implies patient-centered interventions. Therapeutic education thus plays a central role in respiratory rehabilitation. It is implicated in all phases of rehabilitation and particularly for disease-specific indications. It optimizes the chances of long-term success, a clinical, if not evidence-based, observation. PMID- 29122398 TI - [The pentoxifylline, a corticosteroid sparing in the treatment of sarcoidosis: A case report]. AB - INTRODUCTION: The pentoxifylline seems to have some effects on immune cells by inhibiting tumor necrosis factor alpha (TNFalpha). Its role as a sparing corticosteroids in the treatment of sarcoidosis remains to be defined. CLINICAL CASE: We present the case of a patient with sarcoidosis corticodependent despite the use of azathioprine. It was finally improved clinically, functionally and by a thoracic computed tomography with addition of pentoxifylline. CONCLUSION: When the tolerance of the pentoxifylline is good and there is not a bleeding risk, the benefit-risk in the long term might be interesting in some patients with sarcoidosis corticodependent. PMID- 29122399 TI - [Sleep apneas, metabolic syndrome and cardiovascular risk: Data from the Pays de la Loire sleep cohort]. AB - Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a prevalent disease characterized by recurrent episodes of partial or complete obstruction of upper airway during sleep. Untreated moderate to severe OSAHS is recognized as a cardiovascular (CV) risk factor. Data from the Pays de la Loire sleep cohort and other clinic- or population-based cohorts demonstrate a strong association between OSAHS and the different components of the metabolic syndrome including systemic hypertension, diabetes and impaired lipid metabolism. Beside sleep disordered breathing severity, these factors contribute to increase the risk of CV events in OSAHS patients. Continuous positive airway pressure (CPAP) therapy of OSAHS is associated with a modest but clinically significant blood pressure reduction. Conversely, there is no clear evidence in support of a metabolic impact of CPAP in OSAHS patients. Considering the multifactorial pathophysiology of CV risk in OSAHS patients and the beneficial impact of various lifestyle and pharmacologic interventions on blood pressure and metabolic dysfunction, combined modality therapy is a promising strategy to improve CV outcomes in individuals with OSAHS. PMID- 29122400 TI - Aberrant promoter methylation of the PAQR3 gene is associated with prostate cancer. AB - Methylation markers are promising tools for diagnosis, prognosis and targeted treatment of cancer. In prostate carcinoma, aberrant promoter hypermethylation occurs earlier in the disease course and more consistently than recurrent somatic mutations. PAQR3, a tumor suppressor gene, was recently found to be downregulated in prostate cancer cell lines. We hypothesized that promoter methylation could be responsible for PAQR3 silencing in prostate cancer tissues. We aimed to investigate PAQR3 promoter methylation in prostate cancer by comparing it to benign prostatic hyperplasia (BPH). A total of 154 human prostate tissue samples, including 92 cases with prostate cancer and 62 cases with BPH, were examined by methylation-specific PCR. Clinicopathological correlation between PAQR3 promoter methylation and prognostically relevant variables was studied by statistical analysis. Promoter methylation of PAQR3 was significantly more frequent in prostate carcinoma compared to BPH (73.9% vs. 25.8%, p<0.01). The high prevalence of PAQR3 methylation in cancer foci was also confirmed with microdissection technique in 12 samples of prostate adenocarcinoma. PAQR3 hypermethylation was associated with perineural invasion (p=0.03), an adverse clinicopathological feature of prostate cancer. We concluded that PAQR3 can be a promising methylation marker candidate for the detection and monitoring of prostate cancer. PMID- 29122401 TI - The efficacy of adrenocorticotropic hormone in a girl with anti-N-methyl-D aspartate receptor encephalitis. AB - BACKGROUND: Immunomodulatory therapy has shown some therapeutic benefits in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. In this report, we describe the use of adrenocorticotropic hormone (ACTH) immunotherapy with good outcome in a patient with anti-NMDAR encephalitis. SUBJECT AND METHODS: A 4-year-old girl developed convulsions in her right arm and leg without impaired consciousness. These convulsions occurred frequently in clusters of 10-20 events of 10-20 s duration. She was admitted to our hospital on the 6th day following her initial series of convulsions. Flaccid paralysis of the right hand and leg was also found. Interictal electroencephalography showed high amplitude slow waves. No abnormal findings were shown on MRI. 99mTc-ECD brain SPECT on the 14th day showed hyperperfusion in the left hemisphere, including the left basal ganglia. The convulsions ceased following the oral administration of valproic acid on the 10th day; however, paralysis associated with choreic dyskinesia of the right arm and leg remained. ACTH immunotherapy was then performed on the 15th day. We identified the presence of N-methyl-D-aspartate receptor antibody in CSF samples taken on the 6th day. After ACTH therapy, the patient fully recovered from the paralysis associated with choreic dyskinesia of the right arm and leg. She has not had a relapse and has not required medication for over a year. CONCLUSION: ACTH immunotherapy may be a useful treatment option for patients with anti-NMDAR encephalitis, although further evaluation is required. PMID- 29122402 TI - Altered corticostriatal pathway in first-episode paranoid schizophrenia: Resting state functional and causal connectivity analyses. AB - Neuroimaging studies suggest the abnormal structure and function of basal ganglion may contribute to the pathophysiology of schizophrenia. However, little is investigated about the both aberrant functional and causal connectivity of striatum in first-episode paranoid schizophrenia (FEPS). Resting-state functional magnetic resonance imaging was used to characterize the functional connectivity (FC) and casual connectivity within the corticostriatal circuit in 31 patients with FEPS and 33 healthy controls. Degree centrality (DC) was used to explore the regions influenced in schizophrenia at the whole-brain level. Subsequently, a seed-based Granger causality analysis was performed to analyze the causal connectivity. We identified reduced DC of the bilateral putamen in the patients, compared to the controls. In the causal connectivity analysis, we found causal dysconnectivity between the putamen and several regions of default mode network, right orbital part of inferior frontal cortex and right fusiform in the patients. Further, the abnormal causal effect was associated with cognitive impairment in FEPS. The present study highlighted the abnormal functional and causal integrity of the striatum in the patients with FEPS during resting state and suggests a potentially implicated role for the cortical-striatal circuit, especially the striatal-default mode network loop, in the pathophysiology of schizophrenia. PMID- 29122403 TI - Validation of simple and cost-effective stains to assess acrosomal status, DNA damage and mitochondrial activity in rooster spermatozoa. AB - Several methods have been developed to evaluate spermatozoa function in birds but many of these are sometimes complicated, costly and not applicable to field studies (i.e., performed within poultry breeding facilities). The objective was, therefore, to validate efficient, practical and inexpensive procedures to determine DNA fragmentation, acrosomal integrity, and mitochondrial activity in poultry spermatozoa. Initially, ejaculates were individually diluted and divided into control (4 degrees C, 4h) and UV-irradiated aliquots (room temperature, 4h), and then samples containing different percentages of DNA-damaged spermatozoa (0%, 25%, 50%, 75% and 100%) were subjected to Toluidine Blue (TB) and Sperm Chromatin Dispersion assessments (SCD). Fast Green-Rose Bengal (FG-RB) and FITC-PSA staining protocols were subsequently used to assess acrosome status in aliquots comprising assorted amounts of acrosome-reacted spermatozoa. Furthermore, to validate 3,3'-diaminobenzidine (DAB) assay, ejaculates containing different gradients of spermatozoa with great amounts of mitochondrial activity were concurrently evaluated using DAB and JC-1 stains. The proportion of spermatozoa with abnormal DNA integrity when evaluated using the TB assessment correlated significantly with the expected percentages of UV-irradiated spermatozoa and with SCD results. A significant linear regression coefficient was also observed between expected amounts of acrosome-intact spermatozoa and FG-RB readings, and there was a significant correlation of the data when FG-RB and FITC-PSA were used. Likewise, the use of the DAB assay enabled for accurately ascertaining percentages of rooster spermatozoa with greater and lesser mitochondrial function, and results were highly correlated to results with staining with JC-1. Altogether, findings of the present study indicate acrosomal status, DNA integrity and mitochondrial activity in rooster spermatozoa can be easily and reliably determined using FG-RB, TB and DAB stains. PMID- 29122404 TI - Are we ready for the global emergence of multidrug-resistant Candida auris in Taiwan? AB - Candida auris is a recently identified multi-resistant Candida species, first reported in Japan in 2009, and poses a serious global health threat. Lack of awareness of this new Candida species and difficulties with laboratory identification have impacted significantly on outbreak detection and management, and compromised patient outcome. Accordingly, there is an urgent need to raise awareness of healthcare personnel to this emerging pathogen and determine its prevalence, impact, and challenges to the Taiwan healthcare system. Enhanced laboratory testing strategies are needed to differentiate C. auris from other Candida species to provide accurate diagnosis and implement control measures early enough to prevent hospital outbreaks. In this report, we review the key epidemiological, microbiological and clinical characteristics of C. auris and provide the results of a multicenter surveillance study of C. auris in Taiwan. We also conducted a web-based survey to determine awareness of the medical community to C. auris and the capability of Taiwanese hospital laboratories to identify this microorganism. C. auris has not yet been isolated from humans in Taiwan, but the unique features of this microorganism and its ability to reach across international boundaries justify the importance of these initiatives in Taiwan. PMID- 29122405 TI - Theory of mind impairment and its clinical correlates in patients with schizophrenia, major depressive disorder and bipolar disorder. AB - BACKGROUND: Although Theory of Mind (ToM) impairment has been observed in patients with a wide range of mental disorders, the similarity and uniqueness of these deficits across diagnostic groups has not been thoroughly investigated. METHODS: We recruited 35 participants with schizophrenia (SCZ), 35 with bipolar disorder (BD), 35 with major depressive disorder (MDD), and 35 healthy controls in this study. All participants were matched in age, gender proportion and IQ estimates. The Yoni task, capturing both the cognitive and affective components of ToM at the first- and second-order level was administered. Repeated-measure ANOVA and MANOVA were conducted to compare the group differences in ToM performance. A network was then constructed with ToM performances, psychotic and depressive symptoms, and executive function as nodes exploring the clinical correlates of ToM. RESULTS: Overall, ToM impairments were observed in all patient groups compared with healthy controls, with patients with SCZ performing worse than those with BD. In second-order conditions, patients with SCZ and MDD showed deficits in both cognitive and affective conditions, while patients with BD performed significantly poorer in cognitive conditions. Network analysis showed that second-order affective ToM performance was associated with psychotic and depressive symptoms as well as executive dysfunction, while second-order affective ToM performance and negative symptoms showed relatively high centrality in the network. CONCLUSIONS: Patients with SCZ, MDD and BD exhibited different types and severity of impairments in ToM sub-components. Impairment in higher order affective ToM appears to be closely related to clinical symptoms in both psychotic and affective disorders. PMID- 29122406 TI - Sensitive skin is highly frequent in extrinsic atopic dermatitis and correlates with disease severity markers but not necessarily with skin barrier impairment. AB - BACKGROUND: Sensitive skin is a condition of cutaneous hypersensitivity to environmental factors. Lactic acid stinging test (LAST) is commonly used to assess sensitive skin and composed of four distinct sensations (pain, burning sensation, itch, and crawly feeling). A link between sensitive skin and barrier dysfunction has been proposed in atopic dermatitis (AD) patients. However, clinical and laboratory factors that are associated with sensitive skin remain unelucidated. OBJECTIVE: To investigate relationship between sensitive skin and AD-associated markers. METHODS: Forty-two Japanese AD patients and 10 healthy subjects (HS) were enrolled. AD patients were divided into extrinsic (EAD; high IgE levels) and intrinsic (IAD; normal IgE levels) types. We conducted 1% LAST by assessing the four distinct sensations and calculated the frequencies of sensitive skin in EAD, IAD, and HS. We also performed clinical AD-related tests, including transepidermal water loss (TEWL), visual analogue scale (VAS) of pruritus, and quality of life, and measured laboratory markers, including blood levels of IgE, CCL17/TARC, lactate dehydrogenase (LDH) and eosinophil counts, and concentration levels of serum Th1/Th2 cytokines. Filaggrin (FLG) mutations were examined in 21 patients. These values were subjected to correlation analyses with each of the four sensation elements. RESULTS: According to the standard criteria for LAST positivity, the frequencies of LAST-positive subjects were 54.8% and 10.0% in AD and HS, respectively (P=0.014). EAD patients showed a significantly (P=0.026) higher frequency of positive LAST (65.6%) than did IAD patients (20.0%). Among the four LAST sensation elements, the crawly feeling and pain scores positively correlated with VAS of pruritus, total serum IgE, mite-specific IgE, CCL17/TARC, and/or LDH. There was no association of the LAST scores with serum Th1/Th2 cytokine levels. Notably, neither TEWL nor FLG mutations correlated with LAST positivity or any sensation scores. CONCLUSIONS: The frequency of sensitive skin is higher in EAD than in IAD. Sensitive skin is associated with AD severity, but not necessarily with barrier condition. PMID- 29122407 TI - Three-dimensional poly lactic-co-glycolic acid scaffold containing autologous platelet-rich plasma supports keloid fibroblast growth and contributes to keloid formation in a nude mouse model. AB - BACKGROUND: There is a lack of proper animal models to study keloid formation. AIM: To create three-dimensional poly lactic-co-glycolic acid (PLGA) scaffolds containing autologous platelet-rich plasma (PRP) as an in vitro culture environment for keloid fibroblasts (KL), and to study their implantation into nude mice to mimic the process of keloid formation. METHODS: Normal fibroblasts (FB) and KL cells were isolated from surgical specimens and transduced with lentivirus loaded with green fluorescent protein (GFP) and luciferase genes. The FB and KL cells were three-dimensionally cultured for 14-18days in PLGA scaffolds containing PRP. Ten mice were implanted with KL cells in their left forelimbs(KL), and FB-scaffolds (FB+PLGA) in their right forelimbs. An additional ten mice were implanted with PLGA scaffolds without cells (PLGA) in their left forelimbs, and KL-scaffolds (KL+PLGA) in their right forelimbs. Graft volume and collagen content were analyzed 120days after the implantation. RESULTS: in vivo luminescence cell imaging showed that the FB cells proliferated in the PLGA scaffolds within 60days after implantation, and reached a plateau afterwards until 120days after implantation. The KL cells continuously proliferated in the PLGA scaffolds until 120days after implantation. The KL+PLGA group showed higher graft volumes than the FB+PLGA group 120days after the implantation (median volume, 166.95 vs. 63.34mm3); however, the difference is not statistically significant (P=0.743), due to a large variation of the graft volume within each group. Furthermore, Sirius red staining revealed increased collagen I deposition, and immunohistochemistry showed large-scale accumulation of alpha-smooth muscle actin (alpha-SMA), collagen I, and collagen III in the KL+PLGA grafts. CONCLUSION: The three-dimensional PLGA scaffold containing PRP supports keloid fibroblast growth and contributes to keloid formation in a nude mouse model. PMID- 29122408 TI - Q fever endocarditis: First reported case in Mayotte. PMID- 29122409 TI - Understanding the virulence of Streptococcus suis: A veterinary, medical, and economic challenge. AB - Streptococcus suis is a major swine pathogen worldwide and causes considerable economic losses in the swine industry. S. suis is also an emerging zoonotic agent, mainly in Asia. In pigs and humans, S. suis can cause septicemia, pneumonia, endocarditis, arthritis, and meningitis with irreversible sequelae. Identification and characterization of the virulence factors produced by S. suis are major advances in the understanding of the pathogenesis of S. suis infections and has therefore opened promising avenues for vaccine development against this pathogen. This literature review aimed to update the current knowledge of the virulence mechanisms of S. suis and of the vaccination strategies tested until now. PMID- 29122410 TI - Non-compliance with IDSA guidelines for patients presenting with methicillin susceptible Staphylococcus aureus prosthetic joint infection is a risk factor for treatment failure. AB - OBJECTIVE: The long-term impact of treatment strategies proposed by the IDSA guidelines for patients presenting with methicillin-susceptible S. aureus (MSSA) prosthetic joint infection (PJI) is not well-known. PATIENTS AND METHODS: Retrospective (2000-2010) cohort study including patients presenting with MSSA hip or knee PJI. A univariate Cox analysis was performed to determine if the non compliance with IDSA surgical guidelines was a risk factor for treatment failure. RESULTS: Eighty-nine patients with a mean follow-up of 2.8 years were included. Non-compliance with IDSA surgical guidelines was associated with treatment failure (hazard ratio 2.157; 95% CI [1.022-4.7]). The American Society of Anesthesiologists score, inadequate antimicrobial therapy, and a rifampicin-based regimen did not significantly influence patient outcome. CONCLUSION: Based on the IDSA guidelines, if a patient presenting with MSSA PJI is not eligible for implant retention, complete implant removal is needed to limit treatment failure. PMID- 29122411 TI - Comparative investigation of percutaneous plating and intramedullary nailing effects on IL-6 production in patients with tibia shaft fracture. AB - OBJECTIVE: The aim of this study was to analyze the effect of intramedullary nailing (IMN), open plating and percutaneous plating on the induction of IL-6 in patients with tibia fractures. METHODS: A total of 30 patients with tibia shaft fracture underwent either intramedullary nailing (IMN, n = 15; 14 males and 1 female; mean age: 32.1 +/- 15.6), ORIF plating (n = 8; 5 males and 3 females; mean age: 60.0 +/- 17.8), or percutaneous plating (n = 7; 6 males and 1 female; mean age: 43.1 +/- 21.4). Serum IL-6 cytokine levels were measured prior to, and 6 and 24 h after the surgery, using a special ELISA kit. RESULTS: The IL-6 concentration increased to peak levels at 6 h in both IMN and percutaneous plating groups, and at 24 h in ORIF plating group (p < 0.001). The mean IL-6 concentration of percutaneous plating group was significantly lower than that of the IMN group at 6 h following the surgery (p = 0.022). In addition, the mean IL 6 concentration of ORIF plating group was significantly higher than that of the percutaneous plating group at 24 h post operation (p = 0.009). CONCLUSION: Our results suggest that percutaneous plating compared to the IMN has lower effects on IL-6 production in patients with tibia fracture. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29122413 TI - Differences between Subjective and Objective Assessment of Speech Deficiency in Parkinson Disease. AB - OBJECTIVES: This study aims to establish the frequency at which patients with Parkinson disease subjectively assess the intensity of their speech disorders, factors that the patients believe determine the severity of their vocal impairment, and how their subjective self-assessment of vocal impairment by means of the Voice Handicap Index compares with the objective evaluation of the performance of the articulatory organs by means of Frenchay Dysarthria Assessment. MATERIALS AND METHODS: The methods used Voice Handicap Index, Frenchay Dysarthria Assessment, and the Hoehn and Yahr scale. RESULTS: Positive correlation was found between the subjective assessment of the performance of the speech organs and the impaired differentiation of lip movements and tongue sideways movements, impaired saliva control, dysfunction of the soft palate, and the pitch. Negative correlation was found between the subjective assessment of the severity of speech disorder, breathing at rest, and sentence comprehension. CONCLUSIONS: Although we observed correlation between the subjective perception of certain speech disorders of patients with Parkinson disease and the objective assessment carried out by means of the Frenchay Dysarthria Assessment scale, the subjects did not believe the disorders had a significant impact on the quality of speech. Negative results of an examination do not necessarily reflect the subjective perception of the decline in the functioning of the articulatory organs. It should be assumed that lack of correlation between the subjective perception measured using Voice Handicap Index and the objective Frenchay Dysarthria-based assessment of the performance of the articulatory organs may result from a good adaptation to the progressive changes. PMID- 29122412 TI - Determining the role of nasolaryngoscopy in the initial evaluation for upper airway injury in patients with facial burns. AB - BACKGROUND: Upper airway injuries can be fatal in burn patients if not recognized, a scenario that causes a significant amount of anxiety for physicians providing initial assessment of burn patients. Early elective intubation is often performed; sometimes unnecessarily. However, some providers employ nasolaryngoscopy for patients presenting with facial burns or signs/symptoms of upper airway injury in order to assess the need for intubation, but this practice is not considered standard of care and may also be unnecessary. Evidence is currently lacking about the utility of nasolaryngoscopy as an adjuvant assessment during evaluation of potential upper airway burn injuries. The objective of this study was to determine if nasolaryngoscopy provides additional information to the history and physical in making the decision to electively intubate patients with facial burns. METHODS: This study was a retrospective analysis of all patients who underwent fiberoptic nasolaryngoscopy after facial burn injury to evaluate for upper airway injury associated with burns over a 2 year period at a regional burn center. During this time period, all patients who presented with facial burns, soot, or carbonaceous sputum underwent nasolaryngoscopy to look for upper airway injury regardless of mechanism of injury. Patients intubated prior to arrival were excluded from the study. Patients were considered to have signs/symptoms of airway injury (symptomatic) if they presented with dyspnea, tachypnea, hypoxia, or significant burns to buccal mucosa. Procedure notes were used to determine if supraglottic/glottic injury (erythema or edema) was present on nasolaryngoscopy. Presence of pathologic changes and whether they led to intubation were evaluated in the asymptomatic and the symptomatic groups of patients. Select individual records were inspected further to help determine if the nasolaryngoscopy findings altered management plans and if intubation was ultimately necessary based upon the presence or absence of a cuff leak and the duration of intubation. RESULTS: Twenty-two patients were symptomatic upon presentation, 14 of which had positive findings on laryngoscopy and 7 (50%) were intubated. One-hundred and eighty-eight patients were asymptomatic, 58 (31%) of which had either erythema or edema or carbonaceous debris on nasolaryngoscopy, and only 2 (1%) were intubated. These patients were both extubated within two days. None of the 130 asymptomatic patients with negative nasolaryngoscopy were intubated. CONCLUSIONS: This study showed disparity between signs and symptoms of airway injury and nasolaryngoscopy findings. Asymptomatic patients showed pathologic changes in 30% of scopes, but this finding only changed management 1% of the time. Furthermore, the two patients in this group were extubated quickly, suggesting they may have been suitable for observation without intubation. These results indicate that the presence of erythema or edema is of questionable clinical significance in asymptomatic patients and nasolaryngoscopy is of limited benefit in this group. Only 50% of the symptomatic patients with airway injury evident on nasolaryngoscopy were actually intubated, also bringing into question the significance of the pathologic changes in this group. However, negative nasolaryngoscopy may have had some benefit in preventing intubation in a few, select symptomatic patients. This study suggests that a thorough history and physical is the best tool to identify patients at higher risk of upper airway injury who need intubation, but this should be further studied in prospective trials to determine the definitive role of nasolaryngoscopy. PMID- 29122414 TI - The Effect of Hydration on Voice Quality in Adults: A Systematic Review. AB - OBJECTIVES: We aimed to critically appraise scientific, peer-reviewed articles, published in the past 10 years on the effects of hydration on voice quality in adults. STUDY DESIGN: This is a systematic review. METHODS: Five databases were searched using the key words "vocal fold hydration", "voice quality", "vocal fold dehydration", and "hygienic voice therapy". The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were followed. The included studies were scored based on American Speech-Language-Hearing Association's levels of evidence and quality indicators, as well as the Cochrane Collaboration's risk of bias tool. RESULTS: Systemic dehydration as a result of fasting and not ingesting fluids significantly negatively affected the parameters of noise-to-harmonics ratio (NHR), shimmer, jitter, frequency, and the s/z ratio. Water ingestion led to significant improvements in shimmer, jitter, frequency, and maximum phonation time values. Caffeine intake does not appear to negatively affect voice production. Laryngeal desiccation challenges by oral breathing led to surface dehydration which negatively affected jitter, shimmer, NHR, phonation threshold pressure, and perceived phonatory effort. Steam inhalation significantly improved NHR, shimmer, and jitter. Only nebulization of isotonic solution decreased phonation threshold pressure and showed some indication of a potential positive effect of nebulization substances. Treatments in high humidity environments prove to be effective and adaptations of low humidity environments should be encouraged. CONCLUSIONS: Recent literature regarding vocal hydration is high quality evidence. Systemic hydration is the easiest and most cost-effective solution to improve voice quality. Recent evidence therefore supports the inclusion of hydration in a vocal hygiene program. PMID- 29122415 TI - Observer Agreement for Measurements in Videolaryngostroboscopy. AB - OBJECTIVE: This study evaluated the levels of intraobserver and interobserver agreement for measurements of visuoperceptual variables in videolaryngostroboscopic examinations and compared the observers' behavior during independent versus consensus panel rating. STUDY DESIGN: This is a retrospective study. SETTING: This study was conducted in a single-center tertiary care facility. PARTICIPANTS: Sixty-four patients with dysphonia of heterogeneous etiology were included. EXPOSURE: All subjects underwent a standardized videolaryngostroboscopic examination. MAIN OUTCOME AND MEASURES: Two experienced and trained observers scored exactly the same examinations, first independently and then on a consensus panel. Specific visuoperceptual variables and the clinical diagnosis (as recommended by the Committee on Phoniatrics and the Phonosurgery Committee of the European Laryngological Society and advised by the American Speech-Language-Hearing Association) were scored. Descriptive and kappa statistics were used. RESULTS: In general, intraobserver agreement was better than agreement between observers for measurements of several variables. The intrapanel observer agreement levels were slightly higher than the intraobserver agreement levels on the independent rating task. When rating on the consensus panel, the observers deviated considerably from the scores they had previously given on the independent rating task. CONCLUSION AND RELEVANCE: Observer agreement in videolaryngostroboscopic assessment has important implications not only for the diagnosis and treatment of dysphonic patients but also for the interpretation of the results of scientific studies using videolaryngostroboscopic outcome parameters. The identification of factors that can influence the levels of observer agreement can provide a better understanding of the rating process and its limitations. The results of this study suggest that future research could achieve better agreement levels by rating the visuoperceptual variables in a panel setting. PMID- 29122416 TI - Restructuring the Vocal Fatigue Index Using Mokken Scaling: Insights Into the Complex Nature of Vocal Fatigue. AB - Vocal fatigue is a frequent symptom and a debilitating condition affecting individuals with voice disorders. In spite of the various attempts to define and quantify vocal fatigue, this complex trait has not been well understood. Mokken scaling was performed on the Vocal Fatigue Index (VFI) to develop a hierarchical understanding of the latent trait of vocal fatigue. Two hundred nine patients with voice disorders completed the VFI and provided the item responses necessary to complete the Mokken scaling. Results revealed a moderately strong Mokken scale and that the VFI presents a hierarchical structure to the underlying trait of vocal fatigue. Mokken scaling contributes to the ongoing investigation to the underlying construct of vocal fatigue and may provide additional information about specific complaints within the population of those with voice disorders. PMID- 29122417 TI - The Effects of Amplification on Vocal Dose in Teachers with Dysphonia. AB - PURPOSE: The purpose of this study was to determine if voice amplification influenced vocal dose in female teachers with dysphonia. MATERIAL AND METHODS: This was an experimental study with comparative intrasubjects in which 15 individuals were compared in two different moments: condition 1 (C1) without voice amplification and condition 2 (C2) with voice amplification. All of them were female, kindergarten and elementary school teachers who presented organic or functional dysphonia. The search was carried out at the school where the teachers work. The professional voice use was considered the teachers' activity for a continuous period of two classes (average recording time of 96 minutes, with no difference in time between C1 and C2). To measure the dose we used the vocal dosimeter composed of a microphone, an accelerometer fixed to the neck, and a portable unit that stores the vocal data. The phonation data (intensity, fundamental frequency, phonation percentage, cycle dose, and distance dose) were analyzed by the equipment software (VoxLog). RESULTS: The use of vocal amplification in teachers promotes a reduction of the fundamental frequency (295.6-267.7 Hz), the voice intensity (96.2-93.3 dB sound pressure level), the cycle doses (489.4-345.2 thousand cycles per second), and distance doses (3,800 2,300 m). CONCLUSION: The vocal amplification allows the teacher to maintain the same phonation time (phonation percentage) but decreases the number of vocal fold oscillations (cycle dose) and the total distance traveled by the vocal fold tissue during phonation (distance dose), reducing the exposure of the vocal folds to voice trauma. PMID- 29122419 TI - Reply to: "Reliability and Validity of Speech Evaluation in Adductor Spasmodic Dysphonia; Common Mistake and Statistical Issues" by Saori Yanagida. PMID- 29122418 TI - Clinical Features of Psychogenic Voice Disorder and the Efficiency of Voice Therapy and Psychological Evaluation. AB - OBJECTIVES: The aim of this study was to define the clinical features of psychogenic voice disorder (PVD) and explore the treatment efficiency of voice therapy and psychological evaluation. METHOD: Fifty-eight patients who received treatment following the PVD diagnosis and had no organic or other functional voice disorders were assessed retrospectively based on laryngoscopic examinations and subjective and objective assessments. Epidemiological characteristics, accompanying organic and psychological disorders, preferred methods of treatment, and previous treatment outcomes were examined for each patient. A comparison was made based on voice disorders and responses to treatment between patients who received psychotherapy and patients who did not. RESULTS: Participants in this study comprised 58 patients, 10 male and 48 female. Voice therapy was applied in all patients, 54 (93.1%) of whom had improvement in their voice. Although all patients were advised to undergo psychological assessment, only 60.3% (35/58) of them underwent psychological assessment. No statistically significant difference was found between patients who did receive psychological support concerning their treatment responses and patients who did not. Relapse occurred in 14.7% (5/34) of the patients who applied for psychological assessment and in 50% (10/20) of those who did not. There was a statistically significant difference in relapse rates, which was higher among patients who did not receive psychological support (P < 0.005). CONCLUSION: Voice therapy is an efficient treatment method for PVD. However, in the long-term follow-up, relapse of the disease is observed to be higher among patients who failed to follow up on the recommendation for psychological assessment. PMID- 29122420 TI - Locked in and Growing Old: The Psychiatric, Forensic, and Cognitive Correlates of 30 Years of Psychiatric Hospitalization. AB - OBJECTIVE: As the number of older adults in the United States continues to grow, the population of older adults with severe mental illness in institutional settings (OASIS) is expected to place a significant demand on healthcare resources. This study presents an update to research regarding the clinical characteristics of OASIS inpatients with histories of extensive hospitalization through the use of a newly developed psychiatric measure: the Clinician-Rated Dimension of Psychosis Symptom Severity. METHODS: We investigated an OASIS sample (N = 55) with an average of nearly 30 continuous years of hospitalization at a forensic state psychiatric hospital. RESULTS: The average OASIS patient exhibited the most prominent psychiatric symptoms via delusions and negative symptoms, received psychotropic medications at substantially higher doses than recommended therapeutic levels, rarely committed acts of institutional violence (IV), and performed more than two standard deviations below the normative mean on cognitive testing. More severe hallucination symptoms were associated with higher psychotropic medication dosage, and more severe depressive symptoms were associated with more IV incidents. OASIS inpatients performed moderately worse than general psychiatric inpatients in the areas of overall cognition, immediate memory, and delayed memory; older age was associated with poorer language and attention. No psychiatric or cognitive factors predicted IV incidents. CONCLUSION: These results highlight the continued importance of understanding the psychiatric, forensic, and cognitive factors associated with aging in an institutional setting and how these factors among OASIS inpatients may vary from general psychiatric inpatients. PMID- 29122421 TI - Evaluating strategies for reducing scattered radiation in fixed-imaging hybrid operating suites. AB - OBJECTIVE: High-resolution fixed C-arm fluoroscopic systems allow high-quality endovascular imaging but come at a cost of greater scatter radiation generation and increased occupational exposure for surgeons. The purpose of this study was to evaluate the efficacy of two methods in reducing scattered radiation exposure. METHODS: There were 164 endovascular cases analyzed in three phases. In phase 1 (P1), baseline radiation exposure was calculated. In phase 2 (P2), staff used real-time radiation dose monitoring (dosimetry badges [RaySafe; Unfors, Hopkinton, Mass]). In phase 3 (P3), a software imaging algorithm was installed that reduced radiation (EcoDose software; Philips Healthcare, Best, The Netherlands). RESULTS: A total of 72 cases in P1, 34 cases in P2, and 58 cases in P3 were analyzed. Total mean dose-area product decreased across each phase, with statistical significance achieved for P1 vs P3 (mean +/- standard error of the mean, 186,173 +/- 16,754 mGy/cm2 vs 121,536 +/- 11,971 mGy/cm2; P = .002) and P2 vs P3 (171,921 +/- 26,276 mGy/cm2 vs 121,536 +/- 11,971 mGy/cm2; P = .04), whereas total mean fluoroscopy time did not significantly differ across any phase. The radiation exposure to the primary operator did not change significantly from P1 to P2 but fell significantly in P3 (0.08 +/- 0.02 mSv vs 0.03 +/- 0.01 mSv; P = .02). The addition of dose reduction software had the most impact on endovascular aneurysm repair, with reductions in median room dose (P = .03) and primary operator exposure (P2 vs P3; 0.19 +/- 0.04 mSv vs 0.03 +/- 0.02 mSv; P < .01). CONCLUSIONS: Dose reduction software may be an effective technique to lower radiation exposure. Implementation of system-based strategies to reduce radiation is needed to reduce lifetime occupational radiation exposure for endovascular staff and to improve patient safety. PMID- 29122422 TI - Comparison of open surgical techniques for repair of types III and IV thoracoabdominal aortic aneurysms. AB - OBJECTIVE: The objective of this study was to compare outcomes after repair of type III and type IV thoracoabdominal aortic aneurysms (TAAAs) by three different open surgical techniques at a tertiary care institution. METHODS: Consecutive patients who underwent elective repair of type III and type IV TAAAs at our institution between 1999 and 2011 were retrospectively reviewed. Patients were divided into three groups according to surgical technique: clamp and sew (CS), left-sided heart bypass (LHB), and visceral branching (VB) followed by aortic reconstruction. Primary end points were early mortality and complications; secondary end points were need for blood transfusion, duration of operation, and long-term survival. RESULTS: Between 1999 and 2011, there were 121 consecutive patients (83 men, 38 women) with 52 type III and 69 type IV TAAAs who underwent elective repair (CS, 65 patients; LHB, 31 patients; VB, 25 patients). Perioperative spinal drainage was used in 84%. Procedure duration was longest in the VB group (mean, 9.1 hours vs 7.7 hours and 5.7 hours for CS and LHB; P < .001), but transfusion requirement was largest in the LHB group (mean, 3.5 L vs 1.7 L and 2.1 L for CS and VB; P = .015). Mean duration of mesenteric ischemia was significantly shorter in the VB group vs CS and LHB (18 minutes vs 35 minutes for CS and 30 minutes for LHB; P < .0001). Mean intensive care unit and hospital stays were the same (9, 10, and 8 days [P = .82]; 18, 20, and 18 days [P = .76]). Overall 30-day mortality was 6.6%, not different between groups (6%, 10%, and 4%; P = .68). Mean follow-up was 45 +/- 42 months, and actuarial overall survival at 3 and 5 years was 70% and 64%, with no difference between groups (P = .36). CONCLUSIONS: For repair of type III and type IV TAAAs, the sequential VB technique has the longest duration, but it has the advantage of the shortest mesenteric and visceral ischemia times without improvement in early outcomes. Irrespective of the techniques used, complications, early mortality, risk of spinal cord injury, and survival were the same. PMID- 29122424 TI - Scaphoid Healing Required for Unrestricted Activity: A Biomechanical Cadaver Model. AB - PURPOSE: To determine if scaphoid fractures with bridging bone of 50% of their width treated with a centrally placed screw will restore biomechanical integrity equivalent to that of the intact scaphoid. METHODS: Twenty-four fresh cadaver scaphoids were used. Six were left intact to serve as the control group. Six were osteotomized 50% of their width and made up the osteotomy without screw group. Six were included in the 50% osteotomy plus compression screw group. The remaining 6 were to be treated with an osteotomy of 25% or 75% with a screw, based upon the results of the 50% osteotomy with screw group. Biomechanical testing was performed using an Instron testing machine, with a load applied to the scaphoid's distal pole. Load to failure and stiffness were measured. RESULTS: Intact scaphoids had an average load to failure of 610.0 N. The average load to failure of the 50% osteotomy group without a screw was 272.0 N and with a screw was 666.3 N. There was no significant difference in load to failure between the 50% osteotomy plus screw and the intact scaphoid. The 75% osteotomy plus screw was found to have a load to failure of 174.0 N, significantly lower than the intact scaphoid. The 50% osteotomy plus screw had a significantly higher stiffness than the intact scaphoid control. CONCLUSIONS: A 50% intact scaphoid with a centrally placed screw showed similar load to failure and significantly higher stiffness than the intact scaphoid when tested in cantilever bending. CLINICAL RELEVANCE: This study demonstrates that patients with scaphoid waist fractures who undergo surgery with a compression screw may be able to return to unrestricted activity with 50% partial healing. PMID- 29122423 TI - Efferent modulation of pre-neural and neural distortion products. AB - Distortion product otoacoustic emissions (DPOAEs) and distortion product frequency following responses (DPFFRs) are respectively pre-neural and neural measurements associated with cochlear nonlinearity. Because cochlear nonlinearity is putatively linked to outer hair cell electromotility, DPOAEs and DPFFRs may provide complementary measurements of the human medial olivocochlear (MOC) reflex, which directly modulates outer hair cell function. In this study, we first quantified MOC reflex-induced DPOAE inhibition at spectral fine structure peaks in 22 young human adults with normal hearing. The f1 and f2 tone pairs producing the largest DPOAE fine structure peak for each subject were then used to evoke DPFFRs with and without MOC reflex activation to provide a related neural measure of efferent inhibition. We observed significant positive relationships between DPOAE fine structure peak inhibition and inhibition of DPFFR components representing neural phase locking to f2 and 2f1-f2, but not f1. These findings may support previous observations that the MOC reflex inhibits DPOAE sources differentially. That these effects are maintained and represented in the auditory brainstem suggests that the MOC reflex may exert a potent influence on subsequent subcortical neural representation of sound. PMID- 29122425 TI - Analgesic Consumption Following Outpatient Carpal Tunnel Release. AB - PURPOSE: Few studies have examined the consumption of prescribed opioid medications after elective outpatient surgery. A better understanding of opioid consumption after elective upper-extremity surgery may lead to improved prescribing practices, decreased costs, and less leftover medication available for potential misuse. The goal of this study was to evaluate pain control and quantify the amount of leftover pain medication after outpatient carpal tunnel release. METHODS: We performed a prospective study of patients scheduled for outpatient carpal tunnel surgery. All patients had failed nonsurgical treatment and had an electromyelogram/nerve conduction study confirming the clinical diagnosis. All patients were encouraged to remove the dressing on the first postoperative day. A total of 56 patients were initially enrolled in the study; 7 did not meet the inclusion criteria, which left 49 patients who completed the study. Average age was 57 years; 66% of patients were female. Information collected included analgesic prescribed, number of tablets consumed, and number of tablets remaining. Use of postoperative orthoses, complications, use of other analgesic medications, and reasons for not taking the prescribed analgesics were recorded. RESULTS: Paracetamol with codeine and paracetamol with tramadol accounted for all prescriptions. Patients most frequently were given a prescription for 40 tablets. Average number of tablets consumed was 10 (range, 0 40 tablets). More than half of patients consumed fewer than 2 tablets. The average number of postoperative days of analgesic consumption was 2 (range, 0-7 days). Overall 1,531 tablets were leftover from the entire cohort. CONCLUSIONS: This study demonstrates that excess prescription analgesics are being prescribed after carpal tunnel surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29122426 TI - Anatomical Factors Contributing to Radial Nerve Excursion at the Brachium: A Cadaveric Study. AB - PURPOSE: The radial nerve appears to be more vulnerable to injury in the brachium than the median and ulnar nerves. The underlying mechanism for this increased vulnerability is not well explained. We hypothesize that the radial nerve has less excursion than the median and ulnar nerves because it is anatomically tethered by the lateral intermuscular septum (LIS) and that elbow positioning and LIS release will improve its excursion. METHODS: Eight paired fresh-frozen cadaveric upper extremity specimens were used. The radial, median, and ulnar nerves were transected at the level of the spiral groove. Nerve excursion was determined at a constant tension of 100 g from 0 degrees to 90 degrees of elbow flexion and repeated for the radial nerve after releasing the LIS. The cross sectional areas of nervous and connective tissue were then determined histologically. RESULTS: Radial and median nerve excursion correlated positively with increased elbow flexion, and ulnar nerve excursion correlated negatively with increased elbow flexion. Release of the LIS significantly improved radial nerve excursion at 0 degrees , 60 degrees , and 90 degrees of elbow flexion. Release of the LIS with 90 degrees of elbow flexion increased radial nerve excursion by approximately 3 times. Histological analysis demonstrated similar mean composition of nonnervous connective tissue among the 3 nerves. CONCLUSIONS: The radial nerve is anatomically tethered in the brachium by the LIS and has limited excursion compared with the median and ulnar nerves. Radial nerve excursion improves with elbow flexion and LIS release. Flexing the elbow to 90 degrees doubles radial nerve excursion. Releasing the LIS as well triples the excursion of the radial nerve. Histological composition was similar among the three nerves at the brachium. CLINICAL RELEVANCE: Releasing the LIS and flexing the elbow improve radial nerve excursion. These steps may be useful during humeral fracture fixation. PMID- 29122427 TI - Transcanal endoscopic ear surgery for perilymphatic fistula after electric acoustic stimulation. AB - Transcanal endoscopic ear surgery (TEES) will become a very useful therapeutic option. A perilymphatic fistula (PLF) is defined as sudden sensorineural hearing loss and/or vertigo caused by leakage of the perilymph through a fistula from the oval window and/or round window. We report a case of PLF after electric acoustic stimulation (EAS), a kind of cochlear implant, successfully treated by TEES. A 38 year-old man presented to our hospital with vertigo and hearing loss (HL). His vertigo was induced by Valsalva maneuvers. Eight months ago, he underwent EAS for his right ear for congenital sensorineural HL. Although he maintained his hearing level after EAS, his pure tone audiogram this time showed deterioration of hearing at low frequencies in his right ear. A diagnosis of right PLF was made. After confirming the non-effectiveness of oral prednisolone treatment, PLF repair surgery to patch the oval and round windows by TEES was performed. His vertigo did not recur after the surgery. To the best of our knowledge, this is the first report of PLF repair surgery by TEES without a microscope. The wide-field view of the middle ear by TEES was useful to prevent electrode damage in a PLF patient with a cochlear implant. PMID- 29122428 TI - Complex Problems, Care Demands, and Quality of Life Among People Living With HIV in the Antiretroviral Era in Indonesia. AB - People living with HIV (PLWH) suffer from physical and psychological distress that palliative care could alleviate. Our cross-sectional study identified HIV related problems and demands for palliative care at different disease stages, and their interactions with quality of life (QOL) in 215 PLWH from a referral hospital and an AIDS nongovernmental organization in Indonesia. A brief survey of demographic information, the Bahasa version of Problems and Needs of Palliative Care, and the World Health Organization Quality of Live in HIV-infected Persons instrument (WHOQOL-HIV BREF; Cronbach's alpha = .89) were used for data collection. Mean age was 33.5 years (SD = 4.7); 66% were male. Fatigue (67%) was the most prevalent symptom, and the symptom sleeping problems (54.9%) was the priority for palliative care. Higher spiritual and financial demands were found in PLWH with stage IV HIV. Multivariable analysis indicated negative associations between QOL and psychosocial problems, and demands for social and financial support. Interventions focused on psychosocial issues would improve the QOL for PLWH. PMID- 29122429 TI - Predictors of Abstaining From Sex and of Using Condoms for Rural Malawian Female Adolescents. PMID- 29122430 TI - Quadricuspid Aortic Valve Or a Rare Complication of Cocaine Abuse? PMID- 29122431 TI - Nonsurgical Strategies to Reduce Mortality in Patients Undergoing Cardiac Surgery: An Updated Consensus Process. AB - OBJECTIVE: A careful choice of perioperative care strategies is pivotal to improve survival in cardiac surgery. However, there is no general agreement or particular attention to which nonsurgical interventions can reduce mortality in this setting. The authors sought to address this issue with a consensus-based approach. DESIGN: A systematic review of the literature followed by a consensus based voting process. SETTING: A web-based international consensus conference. PARTICIPANTS: More than 400 physicians from 52 countries participated in this web based consensus conference. INTERVENTIONS: The authors identified all studies published in peer-reviewed journals that reported on interventions with a statistically significant effect on mortality in the setting of cardiac surgery through a systematic Medline/PubMed search and contacts with experts. These studies were discussed during a consensus meeting and those considered eligible for inclusion in this study were voted on by clinicians worldwide. MEASUREMENTS AND MAIN RESULTS: Eleven interventions finally were selected: 10 were shown to reduce mortality (aspirin, glycemic control, high-volume surgeons, prophylactic intra-aortic balloon pump, levosimendan, leuko-depleted red blood cells transfusion, noninvasive ventilation, tranexamic acid, vacuum-assisted closure, and volatile agents), whereas 1 (aprotinin) increased mortality. A significant difference in the percentages of agreement among different countries and a variable gap between agreement and clinical practice were found for most of the interventions. CONCLUSIONS: This updated consensus process identified 11 nonsurgical interventions with possible survival implications for patients undergoing cardiac surgery. This list of interventions may help cardiac anesthesiologists and intensivists worldwide in their daily clinical practice and can contribute to direct future research in the field. PMID- 29122433 TI - Anterior Cruciate Ligament Graft Removal Versus Retention in the Setting of Septic Arthritis After Reconstruction: A Systematic Review and Expected Value Decision Analysis. AB - PURPOSE: To provide further guidance on the optimal decision between anterior cruciate ligament (ACL) graft removal versus retention in the setting of septic arthritis following reconstruction using an expected value decision analysis. METHODS: A systematic review and expected value decision analysis and sensitivity analyses were performed to quantify the clinical decision. A decision tree was created with 5 outcomes of interest: nonoperative complications, revision surgery, early reoperation, late reoperation, and "well." Pooled probabilities of each outcome were generated through a systematic literature review. We included only peer-reviewed studies, published in English, with at least 6 months of follow-up. One hundred randomly selected volunteers were given descriptions of the clinical scenario, the 2 treatment options, and outcomes of interest. Patients younger than 18 and older than 50 years and those previously treated for either ACL injury or septic arthritis, or both, were excluded from the analysis to minimize bias. These hypothetical patients indicated preferences for each outcome on a visual analog scale and responses were averaged to generate overall "utility values." Fold-back analysis summed products of pooled outcomes probabilities with respective averaged utility values. The resulting overall expected values for graft removal and debridement were compared, with the highest expected value considered to be superior. We then performed 1-way sensitivity analyses to mitigate sample bias. RESULTS: Fold-back analysis revealed graft removal to be strongly favored over retention, with overall expected values of 17.2 and 8.64, respectively. The most important contributor to the difference in overall expected values was late reoperation (8.59 vs 2.50 for removal and retention, respectively). Despite adjustments made to the rates of revision and early reoperation during the 1-way sensitivity analyses, graft removal remained the optimal strategy. CONCLUSIONS: This expected value decision analysis revealed that ACL graft removal was strongly favored by patients over graft retention in the setting of postoperative septic arthritis when consideration was given to the probabilities of wellness, nonoperative complications, revision surgery, early reoperation, and late reoperation. Sensitivity analysis revealed that although variation in rates of other outcomes did not impact this preference, the rate of late reoperation had a substantial impact. Only a sizable increase in the probability of late reoperation (from 0% to 60%) after graft removal would cause potential patients to favor graft retention. LEVEL OF EVIDENCE: Level IV, systematic review and decision analysis. PMID- 29122432 TI - Widespread recent increases in county-level heart disease mortality across age groups. AB - PURPOSE: Recent national trends show decelerating declines in heart disease mortality, especially among younger adults. National trends may mask variation by geography and age. We examined recent county-level trends in heart disease mortality by age group. METHODS: Using a Bayesian statistical model and National Vital Statistics Systems data, we estimated overall rates and percent change in heart disease mortality from 2010 through 2015 for four age groups (35-44, 45-54, 55-64, and 65-74 years) in 3098 US counties. RESULTS: Nationally, heart disease mortality declined in every age group except ages 55-64 years. County-level trends by age group showed geographically widespread increases, with 52.3%, 58.5%, 69.1%, and 42.0% of counties experiencing increases with median percent changes of 0.6%, 2.2%, 4.6%, and -1.5% for ages 35-44, 45-54, 55-64, and 65-74 years, respectively. Increases were more likely in counties with initially high heart disease mortality and outside large metropolitan areas. CONCLUSIONS: Recent national trends have masked local increases in heart disease mortality. These increases, especially among adults younger than age 65 years, represent challenges to communities across the country. Reversing these trends may require intensification of primary and secondary prevention-focusing policies, strategies, and interventions on younger populations, especially those living in less urban counties. PMID- 29122434 TI - A Method of Accurate Bone Tunnel Placement for Anterior Cruciate Ligament Reconstruction Based on 3-Dimensional Printing Technology: A Cadaveric Study. AB - PURPOSE: To explore a method of bone tunnel placement for anterior cruciate ligament (ACL) reconstruction based on 3-dimensional (3D) printing technology and to assess its accuracy. METHODS: Twenty human cadaveric knees were scanned by thin-layer computed tomography (CT). To obtain data on bones used to establish a knee joint model by computer software, customized bone anchors were installed before CT. The reference point was determined at the femoral and tibial footprint areas of the ACL. The site and direction of the bone tunnels of the femur and tibia were designed and calibrated on the knee joint model according to the reference point. The resin template was designed and printed by 3D printing. Placement of the bone tunnels was accomplished by use of templates, and the cadaveric knees were scanned again to compare the concordance of the internal opening of the bone tunnels and reference points. RESULTS: The twenty 3D printing templates were designed and printed successfully. CT data analysis between the planned and actual drilled tunnel positions showed mean deviations of 0.57 mm (range, 0-1.5 mm; standard deviation, 0.42 mm) at the femur and 0.58 mm (range, 0 1.5 mm; standard deviation, 0.47 mm) at the tibia. CONCLUSIONS: The accuracy of bone tunnel placement for ACL reconstruction in cadaveric adult knees based on 3D printing technology is high. CLINICAL RELEVANCE: This method can improve the accuracy of bone tunnel placement for ACL reconstruction in clinical sports medicine. PMID- 29122435 TI - Arthroscopic Versus Open Ankle Arthrodesis: A Systematic Review. AB - PURPOSE: To perform a systematic review comparing the clinical scores, union rate, complications, reoperations, hospital stay, and operation time between open ankle arthrodesis (OAA) and arthroscopic ankle arthrodesis (AAA). METHODS: We conducted a comprehensive search in the MEDLINE, Embase, and Cochrane Library databases. Only comparative studies were included in this meta-analysis. The literature search, data extraction, and quality assessment were conducted by 2 independent reviewers. The outcomes analyzed included clinical scores, union rate, complications, reoperations, hospital stay, operation time, and intraoperative blood loss. RESULTS: A total of 7 retrospective comparative studies were included in this systematic review. Clinical scores were noted in 3 studies. The American Orthopaedic Foot & Ankle Society ankle-hindfoot score and the Ankle Osteoarthritis Scale score were better in the AAA group than in the OAA group. The union rate was similar between the OAA (70%-100%) and AAA (76.2%-100%) groups. The complication rate was higher in the OAA group (6.7%-47.1%) than in the AAA group (0%-23.8%) in 6 studies. The reoperation rate was similar between the OAA (0%-26.5%) and AAA (0%-27.6%) groups. The hospital stay was shorter in the AAA group in 6 studies. Among the 5 studies that reported operation time, 4 reported no significant difference. Two studies showed that intraoperative blood loss was significantly less in the AAA group. CONCLUSIONS: AAA was shown to offer the advantages of better clinical scores, fewer complications, a shorter hospital stay, and less blood loss compared with OAA. However, the union rate, reoperation rate, and operation time were similar overall between the 2 groups. LEVEL OF EVIDENCE: Level III, systematic review of Level III studies. PMID- 29122436 TI - Looking for new frontiers in atrial fibrillation ablation. A remaining challenge for health care. PMID- 29122437 TI - The effects of protein intake on albuminuria in different estimated glomerular filtration rate: A population-based study. AB - BACKGROUND: Chronic kidney disease (CKD) is a serious condition associated with early mortality, decreased quality of life, and increased health-care expenditures. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) collected from 1999 to 2012 were used. Subjects were divided into 4 estimated glomerular filtration rate (eGFR) categories: stage 1: eGFR>=90mL/min/1.73m2, stage 2: eGFR 60-89, stage 3: eGFR 30-59, and stage 4/5: eGFR<30, and 3 age strata (<45y, 45-64, 65+). Associations between protein intake and albuminuria were determined. RESULTS: A total of 45,259 subjects were included. Despite decreasing protein intake, there was a significant increase in the prevalence of albuminuria with decreasing levels of eGFR. Multivariable analysis showed that albuminuria was associated with daily protein intake in patients >=65years old with stage 1 disease, and that diabetes was associated with albuminuria in patients >=65years old with stage 2 and 3 diseases. Overall, albuminuria in patients with stage 1 disease was associated with hours of sitting per day and blood glucose level. CONCLUSION: Albuminuria was associated with daily protein intake in patients of 45-64years old with stage 1 CKD disease, and was associated with hours of sitting per day and blood glucose level. These data further support the importance of lifestyle changes in the management of CKD, especially in patients with early-stage disease. PMID- 29122438 TI - Life expectancy is unaffected by thyroid function parameters in euthyroid subjects: The PREVEND cohort study. PMID- 29122439 TI - Successful removal of porcine circovirus-1 from immunoglobulin G formulated in glycine solution using nanofiltration. AB - Porcine circovirus (PCV) is a potentially harmful virus that has been shown to contaminate biological products. The virus is resistant to many inactivation and/or removal procedures performed during manufacturing. Anion exchange chromatography has been shown to be useful for PCV type 1 (PCV1) removal; however, reduction of PCV1 using methods such as heat inactivation, low pH, nanofiltration, UV-C, and gamma irradiation has not been successful. Therefore, in this study, we evaluate various conditions for process solutions during nanofiltration using PCV1. The results indicated that PCV could be effectively removed from glycine solution at 0.1-0.3 M, pH 4.0 without IgG, using a nanofilter with a pore size of 19 nm (19-nm filter); log reduction values (LRVs) of >=4.5 and >= 5.0, respectively, were obtained. In contrast, PCV1 was significantly removed (LRV: 2.2) in glycine solution at 0.3 M, pH 6.0 with 1.0% IgG using the 19-nm filter, but some virus genomes were detected in the filtrates. In summary, the use of a 19-nm filter in glycine solution with/without IgG is an appropriate condition for PCV removal. PMID- 29122440 TI - Exploiting the human peptidome for novel antimicrobial and anticancer agents. AB - Infectious diseases and cancers are leading causes of death and pose major challenges to public health. The human peptidome encompasses millions of compounds that display an enormous structural and functional diversity and represents an excellent source for the discovery of endogenous agents with antimicrobial and/or anticancer activity. Here, we discuss how to exploit the human peptidome for novel antimicrobial and anticancer agents through the generation of peptide libraries from human body fluids and tissues and stepwise purification of bioactive compounds. PMID- 29122441 TI - A study of 2-component i, i + 3 peptide stapling using thioethers. AB - Peptides are promising scaffolds for use as therapeutics, targeting interactions previously considered to be "undruggable" by small molecules. While short peptides are generally unstructured in solution and rapidly degraded by proteases in the cell cytosol, peptide stapling offers an effective method to both stabilize peptides in a helical structure and increase resistance to proteolytic degradation. Most studies of peptide stapling have focused on residues with i, i + 4 and i, i + 7 spacing, while stapling of residues with i, i + 3 spacing has been understudied. Herein, we evaluated a suite of bifunctional linkers for stapling between residues with i, i + 3 spacing, comparing the ability of each compound to react with the peptide and the degree of helicity conferred. Finally, we evaluated the ability of the stapling to increase proteolytic resistance in cell lysates, comparing stapling of i, i + 3 and i, i + 4 spacing, with i, i + 3 spacing resulting in a greater increase in peptide half-life in the model system. This presents an effective stapling strategy, adding to the peptide stapling toolbox. PMID- 29122442 TI - Serum Fetuin-A levels in obese children with biopsy proven nonalcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Fetuin-A has been proposed as a marker of liver damage in adults with obesity-related NAFLD. The aim of this study was to test serum fetuin A concentrations in obese children with NAFLD diagnosed either by ultrasonography or by liver biopsy and to determine its applicability as predictive tool in pediatric NAFLD. METHODS AND RESULTS: Metabolic parameters and fetuin-A levels were investigated in 81 obese children with NAFLD diagnosed by biopsy, 79 obese children with NAFLD defined by liver ultrasonography and 23 lean subjects. Serum fetuin-A correlated significantly with age, waist circumference, systolic blood pressure, fasting insulin and 2-h postload insulin during OGTT, HOMA-IR, ISI, CRP, and apo B levels. Obese children with NAFLD detected by ultrasonography had significantly higher fetuin-A levels compared to those with normal liver. In obese children who underwent liver biopsy, no significant differences were detected in fetuin-A levels between subject with nonalcoholic steatohepatitis and those with simple steatosis. Fetuin-A was not different between obese and lean children. CONCLUSION: Fetuin-A is not related with the degree of liver damage in obese children with NAFLD and its routine measurement as marker of liver disease severity is therefore not recommended. PMID- 29122443 TI - Identification of serum metabolites associated with obesity and traditional risk factors for metabolic disease in Chinese adults. AB - BACKGROUND AND AIMS: Obesity is a major worldwide health problem and is often associated with many metabolic diseases. Levels of several serum-specific metabolites may be altered in patients with these metabolic diseases. We aimed to investigate the associations of serum metabolite levels with obesity and traditional risk factors for metabolic disease in Chinese individuals. METHODS AND RESULTS: Six-hundred Chinese individuals undergoing annual physical exams were recruited and categorized into overweight/obese and control groups (1:1 ratio). We simultaneously quantified the serum lysophosphatidylcholine (LPC), branched-chain amino acids (BCAA), aromatic amino acids (AAA), 25-hydroxyvitamin D, glutamine (Gln), glutamic acid (Glu), and Gln/Glu ratio levels using our previously established targeted serum metabolomic method. The overweight/obesity group had significantly higher levels of BCAA, AAA, and Glu, as well as lower levels of unsaturated LPC, Gln, and Gln/Glu, than the control group. Correlation analyses revealed significant and positive relationships of saturated LPC, BCAA, AAA, and Glu with blood pressure, glucose, triglycerides, apolipoprotein B, and high-sensitivity C-reactive protein, while unsaturated LPC, Gln, Gln/Glu, and 25 hydroxyvitamin D exhibited an opposite trend. In the multifactor logistic regression model, low unsaturated LPC and Gln/Glu, as well as high BCAA and AAA levels, were found to be independent risk factors for obesity; the odds ratios (95% confidence interval) of the highest quartile compared to the lowest quartile were 0.241 (0.139-0.417), 0.436 (0.252-0.755), 3.944 (2.094-7.430), and 2.357 (1.274-4.361) (P < 0.01), respectively. CONCLUSION: LPC, BCAA, AAA, and Gln/Glu are significantly related to obesity development and risk factors of some metabolic diseases. PMID- 29122444 TI - Cerebellum and dystonia: The story continues. Will the patients benefit from new discoveries? PMID- 29122445 TI - A method for the topographical identification and quantification of high frequency oscillations in intracranial electroencephalography recordings. AB - OBJECTIVE: To develop a reliable software method using a topographic analysis of time-frequency plots to distinguish ripple (80-200 Hz) oscillations that are often associated with EEG sharp waves or spikes (RonS) from sinusoid-like waveforms that appear as ripples but correspond with digital filtering of sharp transients contained in the wide bandwidth EEG. METHODS: A custom algorithm distinguished true from false ripples in one second intracranial EEG (iEEG) recordings using wavelet convolution, identifying contours of isopower, and categorizing these contours into sets of open or closed loop groups. The spectral and temporal features of candidate groups were used to classify the ripple, and determine its duration, frequency, and power. Verification of detector accuracy was performed on the basis of simulations, and visual inspection of the original and band-pass filtered signals. RESULTS: The detector could distinguish simulated true from false ripple on spikes (RonS). Among 2934 visually verified trials of iEEG recordings and spectrograms exhibiting RonS the accuracy of the detector was 88.5% with a sensitivity of 81.8% and a specificity of 95.2%. The precision was 94.5% and the negative predictive value was 84.0% (N = 12). Among, 1,370 trials of iEEG recording exhibiting RonS that were reviewed blindly without spectrograms the accuracy of the detector was 68.0%, with kappa equal to 0.01 +/- 0.03. The detector successfully distinguished ripple from high spectral frequency 'fast ripple' oscillations (200-600 Hz), and characterize ripple duration and spectral frequency and power. The detector was confounded by brief bursts of gamma (30-80 Hz) activity in 7.31 +/- 6.09% of trials, and in 30.2 +/- 14.4% of the true RonS detections ripple duration was underestimated. CONCLUSIONS: Characterizing the topographic features of a time-frequency plot generated by wavelet convolution is useful for distinguishing true oscillations from false oscillations generated by filter ringing. SIGNIFICANCE: Categorizing ripple oscillations and characterizing their properties can improve the clinical utility of the biomarker. PMID- 29122447 TI - A Tale of Two Viruses: Does Heterologous Flavivirus Immunity Enhance Zika Disease? AB - The rise of Zika virus (ZIKV) and its unusual clinical manifestations provided ground for speculative debate. The clinical severity of secondary dengue virus (DENV) infections is associated with antibody-dependent enhancement (ADE), and it was recently suggested that previous exposure to DENV may worsen ZIKV clinical outcomes. In this Opinion article we analyze the relationship among different flaviviruses and ADE. We discuss new evidence obtained in non-human primates and human cohorts demonstrating that there is no correlation to ADE when ZIKV infection occurs in the presence of pre-existing DENV immunity. We propose a redefinition of ADE in the context of complex immunological flavivirus interactions to provide a more objective perspective when translating in vitro or in vivo observations into the clinical setting. PMID- 29122446 TI - Review of the comparative effectiveness of radical prostatectomy, radiation therapy, or expectant management of localized prostate cancer in registry data. AB - : Evidence regarding the effectiveness of treatment for prostate cancer is primarily based on randomized controlled trials. Long-term outcomes are generally difficult to evaluate within experimental studies and may benefit from large pools of observational data. We conducted a systematic review of administrative and registry studies to evaluate the comparative effectiveness of treatment for clinically localized prostate cancer on overall and prostate-cancer specific mortality. MATERIALS AND METHODS: In accordance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P, 2015), we conducted a systematic search of Ovid Medline and Embase (1946-February 2017) and identified studies that evaluated the relationship between types of treatment for localized prostate cancer and mortality. Additional articles were identified through manual search. Randomized, prospective, and single institution studies were excluded. The risk of bias for each study was evaluated with the Newcastle Ottawa scale. Multivariable adjusted hazard ratios were reported to evaluate overall and cancer-specific mortality. RESULTS: We screened 4,721 studies and included for review, 19 that were published between 2001 and 2015. The pooled population included 228,444 patients. Countries of origin included the United States, Canada, China, Switzerland, the Netherlands, and Sweden, and the sources included administrative (n = 6) and cancer registry or prostate databases (n = 11). Overall and cancer-specific mortality were lowest among definitive treatment arms as compared to conservative therapy with no treatment, observation, or active surveillance. Radiotherapy was associated with worse overall and cancer specific mortality than radical prostatectomy. CONCLUSION: Although observational studies using large, population-based cohorts have the potential for bias, we found consistent evidence that high-quality observational studies may be used to evaluate the comparative effectiveness of prostate cancer treatment. Methodologic limitations of observational data should be considered. PMID- 29122448 TI - Validating the association between plasma tumour necrosis factor receptor 1 levels and the presence of renal injury and functional decline in patients with Type 2 diabetes. AB - AIMS: Elevated plasma soluble tumour necrosis factor receptor 1 (TNFR1) predicts long-term progression of chronic kidney disease. We investigated the association between elevated TNFR1 and the presence of renal disease in patients with Type 2 diabetes mellitus registering a haemoglobin A1c (HbA1c) >48mmol/mol despite medical therapy. METHODS: Using sensitivity, specificity and regression analyses we interrogated the association between plasma TNFR1 and presence of chronic kidney disease as assessed by the presence of microalbuminuria and/or an estimated glomerular filtration rate of less than 60ml/min/1.73m2 (stages 3-5 chronic kidney disease). The association of TNFR1 with C-reactive protein and leptin-adiponectin ratio as plasma markers of systemic inflammation and adipose stress respectively was also investigated. RESULTS: Upper quartile TNFR1 is independently associated with elevated urinary albumin-creatinine ratios, reductions in eGFR and strongly predicts the presence of stages 3-5 chronic kidney disease in regression modelling. Elevated TNFR1 levels are associated with increased plasma C-reactive protein and augmented leptin-adiponectin ratio. CONCLUSIONS: Our study confirms plasma TNFR1 as a surrogate of renal structural and functional impairment in patients with type 2 diabetes mellitus. Association of TNFR1 with markers of systemic inflammation and adipose stress indicates that TNFR1 may be a biomarker of these processes as components of the pathogenesis of diabetic kidney disease. PMID- 29122450 TI - Interstitial tears of the rotator cuff: difficulty in preoperative diagnosis. AB - BACKGROUND: Few studies have investigated the characteristic findings of preoperative magnetic resonance imaging (MRI) and the clinical and radiologic outcomes of interstitial tear of the rotator cuff treated with arthroscopic repair after tear completion. METHODS: Forty-one patients (14 men and 27 women; mean age, 56.5 years) with arthroscopically confirmed interstitial tears underwent single-row repair after tear completion. The minimum follow-up period was 2 years. RESULTS: Twenty-eight patients (68.3%) were properly evaluated with MRI before surgery. Seven cases (17.1%) were misdiagnosed as bursal-sided tears and 5 cases (12.2%) were misdiagnosed as articular-sided tears on the basis of presurgical MRI findings. Arthroscopy revealed fibrillation and dimpling of the tendon surface in all cases and congestion within the defect in 36 cases (87.8%). At the final follow-up, the visual analog scale score for pain during motion decreased to 0.8 from a preoperative mean of 6.1 (P <.001). Moreover, at the final follow-up, the mean University of California-Los Angeles score and Constant score improved from 15.7 and 51.8 to 32.1 and 83.8, respectively (P <.001 for all). At 9 months after surgery, MRI revealed no cases of retear. CONCLUSION: Interstitial tears are difficult to diagnose before surgery because MRI findings may lead to the misdiagnosis of interstitial tears as articular- or bursal-sided tears. If MRI-based diagnosis is indicative of articular- or bursal-sided tears but arthroscopy reveals fibrillation and dimpling of the tendon surface, interstitial tears should be suspected. The defective sites in interstitial tears are usually accompanied by congestion. PMID- 29122449 TI - Long-Term Effectiveness of the Zilver PTX Drug-Eluting Stent for Femoropopliteal Peripheral Artery Disease in Patients with No Patent Tibial Runoff Vessels Results from the Zilver PTX Japan Post-Market Surveillance Study. AB - PURPOSE: To evaluate 2-year results of the Zilver PTX (Cook Medical, Bloomington, Indiana) drug-eluting stent (DES) for femoropopliteal peripheral artery disease (PAD) in patients with no continuous patent infrapopliteal runoff arteries compared with patients with >= 1 continuous patent runoff vessels. MATERIALS AND METHODS: A retrospective analysis of patients with femoropopliteal PAD enrolled in the Zilver PTX Post-Market Surveillance Study in Japan was performed. There were no exclusion criteria. Outcomes, including freedom from target lesion revascularization (TLR), patency, and clinical benefit, for the no-runoff group (n = 54) were compared with the runoff group (n = 846). RESULTS: The 2 groups were similar in terms of demographics, lesion characteristics, and comorbidities (P > .05). There was a higher incidence of critical limb ischemia in the no runoff group compared with the runoff group (44.8% vs 19.7%; P < .01). There were 3 amputations (5.6%) in the no-runoff group versus 7 amputations (0.8%) in the runoff group (P = .02). At 2 years, freedom from TLR rates were 81.3% versus 83.8% (P = .87), patency rates were 68.4% versus 70.7% (P = .95), and clinical benefit rates were 73.7% versus 80.0% (P = .16) in the no-runoff versus runoff group, respectively. CONCLUSIONS: Results in patients with no continuous patent tibial runoff were favorable through 2 years and similar to results for patients with >= 1 continuous patent runoff vessels, indicating that the Zilver PTX DES may be a valid treatment option for patients with these difficult-to-treat lesions. PMID- 29122451 TI - In vivo tibiofemoral skeletal kinematics and cartilage contact arthrokinematics during decline walking after isolated meniscectomy. AB - We investigated the effects of isolated meniscectomy on tibiofemoral skeletal kinematics and cartilage contact arthrokinematics in vivo. We recruited nine patients who had undergone isolated medial or lateral meniscectomy, and used a dynamic stereo-radiography (DSX) system to image the patients' knee motion during decline walking. A volumetric model-based tracking process determined 3D tibiofemoral kinematics from the recorded DSX images. Cartilage contact arthrokinematics was derived from the intersection between tibial and femoral cartilage models co-registered to the bones. The kinematics and arthrokinematics were analyzed for early stance and loading response phase (30% of a gait cycle), comparing the affected and intact knees. Results showed that four patients with medial meniscectomy had significantly greater contact centroid excursions in the meniscectomized medial compartments while five patients with lateral meniscectomy had significantly greater cartilage contact area and lateral shift of contact centroid path in the meniscectomized lateral compartments, comparing to those of the same compartments in the contralateral intact knees. No consistent difference however was identified in the skeletal kinematics. The current study demonstrated that cartilage-based intra-articular arthrokinematics is more sensitive and insightful than the skeletal kinematics in assessing the meniscectomy effects. PMID- 29122452 TI - Estimated landmark calibration of biomechanical models for inverse kinematics. AB - Inverse kinematics is emerging as the optimal method in movement analysis to fit a multi-segment biomechanical model to experimental marker positions. A key part of this process is calibrating the model to the dimensions of the individual being analysed which requires scaling of the model, pose estimation and localisation of tracking markers within the relevant segment coordinate systems. The aim of this study is to propose a generic technique for this process and test a specific application to the OpenSim model Gait2392. Kinematic data from 10 healthy adult participants were captured in static position and normal walking. Results showed good average static and dynamic fitting errors between virtual and experimental markers of 0.8 cm and 0.9 cm, respectively. Highest fitting errors were found on the epicondyle (static), feet (static, dynamic) and on the thigh (dynamic). These result from inconsistencies between the model geometry and degrees of freedom and the anatomy and movement pattern of the individual participants. A particular limitation is in estimating anatomical landmarks from the bone meshes supplied with Gait2392 which do not conform with the bone morphology of the participants studied. Soft tissue artefact will also affect fitting the model to walking trials. PMID- 29122453 TI - Action research on education in Ayurveda. PMID- 29122454 TI - Ayurveda formulations: A roadmap to address the safety concerns. AB - It is a matter of serious concern that the number of case reports pointing at a possible association between the clinical toxicity and the use of Ayurveda formulations is increasing significantly over the years in scientific medical literature. Though most of these cases are connected with the presence of heavy metals such as lead, mercury and arsenic in these formulations, there are also reports suggesting toxicity due to the presence of toxic chemicals of herbal origin. In the year 2008, the Government of India took an initiative of establishing the National Pharmacovigilance Programme for Ayurveda, Siddha and Unani drugs in a structured way. However, due to lack of sustained support, this program has now become defunct. This issue is of vital importance and needs to be addressed effectively on a priority basis. In this communication, we propose the following crucial policy interventions to be introduced at different levels: a. Amendments to Drug and Cosmetic Act, b. Issuing consumer guidelines, c. Issuing prescription guidelines, d. Issuing clinical monitoring guidelines, e. Implementation of good manufacturing guidelines, f. Promoting documentation of clinical safety, g. Identifying the sources of contamination, and, h. Provision for stringent punishment. If these policy interventions are taken up and implemented, a significant positive change in the scenario can be expected in the near future. PMID- 29122455 TI - Looking at prescription quality in Ayurveda: Developing, validating and pilot testing a prescription quality index for Ayurveda. AB - BACKGROUND: Prescription quality can be a direct predictor of the net outcome of a health care delivery effort. Quality of prescription may be considered as a cumulative matrix of multiple components of a prescription on the basis of their relative importance. Prescription quality index is a recognized tool in clinical medicine for multiple purposes including the prediction of health care intervention outcome. OBJECTIVES: Considering the importance of prescription quality among every system of medicine, an attempt was made to design a prescription quality index for Ayurveda. MATERIALS AND METHODS: The Prescription Quality Index for Ayurveda was designed through item selection following a thorough literature search and was validated through multiple peer group discussions. Final draft of index containing 38 individual items carrying different scores as per their importance in the prescription was subjected to a pilot test upon 1576 indoor prescriptions generated in 2015 at State Ayurvedic College Hospital, Lucknow. RESULTS: The study revealed large information gaps in the components of the prescription where it was supposed to be noted by the prescribers. These gaps in the Ayurvedic prescriptions were most significant in the areas pertaining to Ayurvedic fundamentals of clinical examination, disease diagnosis and Ayurvedic drug intake methods. CONCLUSION: Prescription Quality Index for Ayurveda was found useful in underlining the gaps between the ideal and generated prescriptions. This can be utilized as a useful tool to evaluate the quality of Ayurvedic prescriptions by seeing their adherence to the standard prescription template. PMID- 29122457 TI - Radiotherapy for Tracheal-Bronchial Cystic Adenoid Carcinomas. AB - AIMS: Primary tracheal-bronchial adenoid cystic carcinoma (thoracic adenoid cystic carcinoma; TACC) is a rare and aggressive malignant tumour. Radiotherapy results have not been previously individualised in this setting. PATIENTS AND METHODS: Records of 31 patients with TACC (74% tracheal and 26% bronchial) who received radiotherapy between February 1984 and September 2014 were retrospectively analysed. RESULTS: Surgical removal of the primary tumour was carried out for most (71%) patients, and 13/22 (59%) had R1 or R2 (1/22) margins. The mean tumour size was 4.1 cm, 10 (32%) had associated lymph node involvement and 13 (41%) had perineural invasion (PNI). Adjuvant and definitive radiotherapy were delivered for 22 (71%) and nine patients, respectively. The mean delivered dose was 62 Gy (40-70 Gy) and eight patients had a radiotherapy boost (mean 19 Gy, range 9-30 Gy, two with endobronchial brachytherapy). At a median follow-up of 5.7 years, the 5 year overall survival and progression-free survival (PFS) rates were 88% and 61%, respectively. There were three local relapses and 10 metastatic relapses (mean delay 3.2 years), resulting in 5 year local and metastatic relapse rates of 10% and 26%, respectively. The prognostic factors in the univariate analysis for both decreased overall survival and PFS were: age >=50 years (hazard ratio 6.2 and 3.8) and the presence of PNI (hazard ratio 10.3 and 4.1); and for PFS only: a radiotherapy dose <= 60 Gy (hazard ratio 3.1). Late toxicities were: tracheotomy due to symptomatic tracheal stenosis (n = 5), G3 dyspnoea (n = 4), hypothyroidism (n = 5) and pericarditis (n = 4). CONCLUSION: Radiotherapy dose may affect local control and the presence of PNI should be considered as an adverse prognostic factor. TACC irradiation conferred good local control rates, when comparing these results with historical series. PMID- 29122456 TI - Sentinels of the Type 2 Immune Response. AB - Type 2 immune responses have evolved to sense and respond to large, non replicating infections or non-microbial noxious compounds in tissues. The development of these responses therefore depends upon highly coordinated and tightly regulated tissue-residing cellular sensors and responders. Multiple exposure to type 2 helper T cell (Th2)-inducing stimuli further enhances both the diversity and potency of the response. This review discusses advances in our understanding of the interacting cellular subsets that comprise both primary and secondary type 2 responses. Current knowledge regarding type 2 immune responses in the lung are initially presented and are then contrasted with what is known about the small intestine. The studies described portray an immune response that depends upon well-organized tissue structures, and suggest their modulation as a therapeutic strategy. PMID- 29122458 TI - Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Integrating the literature on hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). AB - Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive degenerative white matter disorder. ALSP was previously recognized as two distinct entities, hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). However, recent identification of mutations in the tyrosine kinase domain of the colony stimulating factor 1 receptor (CSF1R) gene, which regulates mononuclear cell lineages including microglia, have provided genetic and mechanistic evidence that POLD and HDLS should be regarded as a single clinicopathologic entity. We describe two illustrative cases of ALSP which presented with neuropsychiatric symptoms, progressive cognitive decline, and motor and gait disturbances. Antemortem diagnoses of autopsy-confirmed ALSP vary significantly, and include primary progressive multiple sclerosis, frontotemporal dementia, Alzheimer disease, atypical cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), corticobasal syndrome, and atypical Parkinson disease, suggesting that ALSP may be significantly underdiagnosed. This article presents a systematic review of ALSP in the context of two illustrative cases to help integrate the literature on HDLS and POLD. Consistent use of the term ALSP is suggested for clarity in the literature going forward. PMID- 29122459 TI - Resolution of Anton-Babinski syndrome after systemic thrombolysis and mechanical thrombectomy with a stentriever. AB - Anton-Babinski syndrome is a rare neuropsychiatric syndrome characterized by bilateral cortical blindness and anosognosia with visual confabulation. We present the case of a patient presenting with occlusion of both posterior cerebral arteries (PCA), with Anton-Babinski syndrome, completely solved after combined systemic thrombolysis and mechanical thrombectomy with a stent retriever. PMID- 29122460 TI - Anaerobic digestion of grape pomace: Effect of the hydraulic retention time on process performance and fibers degradability. AB - To optimize the anaerobic digestion of grape pomace under mesophilic conditions, continuous digesters were operated at different hydraulic retention times (HRT) (30, 20, 15 and 10 days) equivalent to organic loading rates (OLR) of 2.5, 3.7, 5.7 and 7.3 kg COD m-3 d-1, respectively. At HRTs of 30 and 20 days, steady state conditions were observed with methane yields of 0.984 +/- 0.013 NL d-1 and 1.362 +/- 0.018 NL d-1, respectively. The HRT of 15 days was found critical because of acids accumulation through the experiments. When the OLR of 5.7 kg COD m-3 d-1 was reached, methane production was found to be instable. Finally, at HRT of 10 days, a failure of the system was observed due to the washing of the methanogenic microorganisms. Regarding the degradability of the lignocellulosic fractions, the maximum reduction yields for hemicellulose and cellulose were noted for HRTs of 30 and 20 days, while lignin was not degraded throughout the different experiments. For an optimization of the process, HRT of 20 days can therefore be recommended for productive use in large-scale applications. PMID- 29122462 TI - Yoga may be noninferior to physical therapy for disability and pain at 12 weeks and both might improve function more than education in low resource adults with chronic nonspecific low back pain. PMID- 29122463 TI - Immunogenicity and safety of one versus two doses of tetravalent dengue vaccine in healthy children aged 2-17 years in Asia and Latin America: 18-month interim data from a phase 2, randomised, placebo-controlled study. AB - BACKGROUND: Development of vaccines that are effective against all four dengue virus serotypes (DENV-1-4) in all age groups is important. Here, we present 18 month interim data from an ongoing study undertaken to assess the immunogenicity and safety of Takeda's tetravalent dengue vaccine (TDV) candidate over 48 months in children living in dengue-endemic countries. METHODS: We undertook a phase 2, multicentre, randomised, double-blind, placebo-controlled study at three sites in the Dominican Republic, Panama, and the Philippines. We randomly assigned children aged 2-17 years to receive either two TDV doses 3 months apart (group 1), one TDV dose (group 2), one TDV dose and a booster dose 1 year later (group 3), or placebo (group 4). We did the randomisation (1:2:5:1) using an interactive web response system stratified by age. The primary endpoint of this 18-month interim analysis was DENV serotype-specific antibody geometric mean titres (GMTs) in the per-protocol immunogenicity subset on days 1, 28, 91, 180, 365, 393, and 540. Secondary safety endpoints were the proportions of participants with serious adverse events and with virologically confirmed dengue in the safety set, and solicited and unsolicited adverse events in the immunogenicity subset. This trial is registered with ClinicalTrials.gov, number NCT02302066. FINDINGS: Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to group 1 (n=201), group 2 (n=398), group 3 (n=1002), and group 4 (n=199). 1794 participants received at least one dose of TDV or placebo (safety set), of whom 562 participated in the immunogenicity subset and 509 were included in the per protocol set. Antibody titres remained elevated 18 months after vaccination in all TDV groups. At day 540, in groups 1, 2, 3, and 4, respectively, DENV-1 GMTs were 476 (95% CI 286-791), 461 (329-647), 1056 (804-1388), and 92 (49-173); DENV 2 GMTs were 1212 (842-1744), 1242 (947-1628), 1457 (1182-1796), and 177 (93-337); DENV-3 GMTs were 286 (171-478), 298 (205-433), 548 (411-730), and 78 (44-137); and DENV-4 GMTs were 98 (65-150), 102 (75-139), 172 (133-222), and 33 (21-52). Limited differences in GMTs were observed between groups 1 and 2 (in which participants received one and two doses of TDV, respectively). In baseline seronegative participants, a 1-year booster clearly increased GMTs. Vaccine related unsolicited adverse events occurred in 14 (2%) of 562 participants, but no vaccine-related serious adverse events arose. Symptomatic, virologically confirmed dengue was recorded in 21 (1.3%) of 1596 participants vaccinated with TDV compared with nine (4.5%) of 198 placebo recipients. INTERPRETATION: TDV was well tolerated and immunogenic against all four dengue serotypes, irrespective of baseline dengue serostatus. These data provide proof of concept for TDV and support the ongoing phase 3 efficacy assessment of two doses 3 months apart. FUNDING: Takeda Vaccines. PMID- 29122464 TI - Encouraging results but questions remain for dengue vaccine. PMID- 29122465 TI - Real-World Experience with Idarucizumab to Reverse Anticoagulant Effect in Dabigatran-Treated Patients: Report of 11 Cases from Taiwan. AB - BACKGROUND: This study aims to observe the effectiveness and safety of idarucizumab in dabigatran-treated patients with severe bleeding or requiring surgery in Taiwan. METHODS AND RESULTS: In Taiwan, 11 dabigatran-treated patients developed severe bleeding, fracture that needed surgery, and acute ischemic stroke requiring thrombolysis. These patients were treated with idarucizumab and obtained adequate hemostasis. Our experiences reconfirmed the efficacy and safety of idarucizumab in Asian patients. CONCLUSIONS: Idarucizumab improves safety in dabigatran-treated patients. Continued education about the availability and appropriate use of idarucizumab is necessary in Asia. PMID- 29122461 TI - Histone Marks in the 'Driver's Seat': Functional Roles in Steering the Transcription Cycle. AB - Particular chromatin modifications are associated with different states of gene transcription, yet our understanding of which modifications are causal 'drivers' in promoting transcription is incomplete. Here, we discuss new developments describing the ordered, mechanistic role of select histone marks occurring during distinct steps in the RNA polymerase II (Pol II) transcription cycle. In particular, we highlight the interplay between histone marks in specifying the 'next step' of transcription. While many studies have described correlative relationships between histone marks and their occupancy at distinct gene regions, we focus on studies that elucidate clear functional consequences of specific histone marks during different stages of transcription. These recent discoveries have refined our current mechanistic understanding of how histone marks promote Pol II transcriptional progression. PMID- 29122467 TI - Socioeconomic Disadvantage Is Associated with a Higher Incidence of Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) incidence is not well studied. Varied definitions of "subarachnoid hemorrhage" have led to a lack of clarity regarding aSAH incidence. The impact of area-level socioeconomic disadvantage and geographical location on the incidence of aSAH also remains unclear. Using a population-based statewide study, we examined the incidence of aSAH in relation to socioeconomic disadvantage and geographical location. METHODS: A retrospective cohort study of nontraumatic subarachnoid hemorrhages from 2010 to 2014 was undertaken. Researchers manually collected data from multiple overlapping sources including statewide administrative databases, individual digital medical records, and death registers. Age-standardized rates (ASRs) per 100,000 person years were calculated using the 2001 Australian population. Differences in incidence rate ratios were calculated by age, sex, area-level socioeconomic status, and geographical location using Poisson regression. RESULTS: The cohort of 237 cases (mean age, 61.0 years) with a female predominance of 166 (70.04%) included 159 confirmed aSAH, 52 community-based deaths, and 26 probable cases. The ASR for aSAH was 9.99 (95% confidence interval [CI], 8.69-11.29). A significant association between area-level socioeconomic disadvantage and incidence was observed, with the rate of aSAH in disadvantaged geographical areas being 1.40 times higher than that in advantaged areas (95% CI, 1.11-1.82; P = .012). CONCLUSION: This study uses a comprehensive search of multiple data sources to define a new baseline of aSAH within an Australian population. This study presents a higher incidence rate of aSAH with socioeconomic variations. As a key risk factor that may explain this paradox, addressing socioeconomic inequalities is important for effective prevention and management interventions. PMID- 29122466 TI - Novel Algorithm to Help Identify Stroke Mimics. AB - BACKGROUND: Stroke is a major cause of disability in the United States. A portion of patients presenting with stroke-like symptoms in the emergency room who receive tissue plasminogen activator (tPA) do not end up having a true stroke, leading to unnecessary health-care costs. The aim of our study is to identify those patients who have a high likelihood of experiencing a stroke mimic using a novel stroke mimic score and to identify a cutoff point with a high specificity of ruling in stroke mimics. METHODS: We reviewed literature on stroke mimics and the various associated risk factors. We devised a 9-point scoring system and applied it retrospectively to patients who received tPA from 2010 to 2014 to calculate a score for each patient. RESULTS: The final sample size was 105 patients, out of which 25% turned out to be patients with stroke mimics. Patients with stroke mimic were significantly younger and more likely to have history of seizure, migraine, or prior psychiatric illness. History of atrial fibrillation had the highest correlation with true stroke. We found approximately 100% specificity in ruling in a stroke mimic if a patient scored more than 5 points. CONCLUSIONS: Our stroke mimic scoring system along with a basic neurologic examination could be a useful tool in the identification of stroke mimics with a high specificity in the emergency room setting. These patients may require further studies such as rapid magnetic resonance imaging, which would decrease unnecessary tPA administration and hospital admissions. PMID- 29122468 TI - An intronic variation in SLC52A1 causes exon skipping and transient riboflavin responsive multiple acyl-CoA dehydrogenation deficiency. AB - Vitamin B2, riboflavin is essential for cellular function, as it participates in a diversity of redox reactions central to human metabolism, through its role as precursor for the cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are electron carriers. The electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH), uses FAD as cofactor. The ETF and ETFDH are forming the electron transport pathway for many mitochondrial flavoprotein dehydrogenases involved in fatty acid, amino acid and choline metabolism. A variation in either ETF or ETFDH causes multiple acyl-CoA dehydrogenation deficiency (MADD), but genetic variations in the riboflavin metabolism or transportation of riboflavin can also cause MADD. The most common variations are located in the riboflavin transporter 2 (RFVT2) and 3 (RFVT3), that are highly expressed in brain and intestinal tissues, respectively. Deficiency of riboflavin transporter 1 (RFVT1), encoded by the SLC52A1 gene, highly expressed in the placenta, has only been reported once. We here report a case of transient MADD, caused by a heterozygous intronic variation, c.1134+11G>A, in the SLC52A1 gene encoding RFVT1. This variation creates a binding site for the splice inhibitory hnRNP A1 protein and causes exon 4 skipping. Riboflavin deficiency and maternal malnutrition during pregnancy might have been the determining factor in the outcome of this case. PMID- 29122470 TI - Accuracy of Computed Tomographic Enterography for Obscure Gastrointestinal Bleeding: A Diagnostic Meta-analysis. AB - RATIONALE AND OBJECTIVES: Obscure gastrointestinal bleeding (OGIB) is the bleeding from the gastrointestinal tract without definite source that persists and recurs after a negative endoscopic evaluation. The study aimed to systematically evaluate the diagnostic accuracy of computed tomography enterography on OGIB detection by meta-analysis. MATERIALS AND METHODS: Studies were searched in relevant databases. With predefined inclusion criteria, eligible studies were included, followed by quality assessment using the Quality Assessment of Diagnostic Accuracy Studies scoring system. The Meta-DiSc software was used to implement the meta-analysis, and sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio with their 95% confidence intervals (CIs) were used as the effect size. Publication bias was determined by Egger test. RESULTS: A set of nine studies was included in this meta-analysis, having a relatively high quality. Under the random effects model, the pooled sensitivity and specificity were 0.724 (95% CI: 0.651-0.789) and 0.752 (95% CI: 0.691-0.807), respectively. Under the fixed effects model, the pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 2.949 (95% CI: 2.259-3.850), 0.393 (95% CI: 0.310-0.497), and 9.452 (95% CI: 5.693-15.692), respectively. The area under curve of the summary receiver operating characteristic curve was 0.7916 (95% CI: 0.723-0.860). No obvious publication bias was detected (t = 1.62, P = .181). CONCLUSIONS: Computed tomography enterography might be used as a complementary to video capsule endoscopy instead of an alternative for the detection of OGIB. PMID- 29122472 TI - Can Radiologists Learn From Airport Baggage Screening?: A Survey About Using Fictional Patients for Quality Assurance. AB - RATIONALE AND OBJECTIVES: For both airport baggage screeners and radiologists, low target prevalence is associated with low detection rate, a phenomenon known as "prevalence effect." In airport baggage screening, the target prevalence is artificially increased with fictional weapons that are digitally superimposed on real baggage. This strategy improves the detection rate of real weapons and also allows airport supervisors to monitor screener performance. A similar strategy using fictional patients could be applied in radiology. The purpose of this study was twofold: (1) to review the psychophysics literature regarding low target prevalence and (2) to survey radiologists' attitudes toward using fictional patients as a quality assurance tool. MATERIALS AND METHODS: We reviewed the psychophysics literature on low target prevalence and airport x-ray baggage screeners. An online survey was e-mailed to all members of the Association of University Radiologists to determine their attitudes toward using fictional patients in radiology. RESULTS: Of the 1503 Association of University Radiologists member recipients, there were 153 respondents (10% response rate). When asked whether the use of fictional patients was a good idea, the responses were as follows: disagree (44%), neutral (25%), and agree (31%). The most frequent concern was the time taken away from doing clinical work (89% of the respondents). CONCLUSIONS: The psychophysics literature supports the use of fictional targets to mitigate the prevalence effect. However, the use of fictional patients is not a popular idea among academic radiologists. PMID- 29122471 TI - 3D Registration of mpMRI for Assessment of Prostate Cancer Focal Therapy. AB - RATIONALE AND OBJECTIVES: This study aimed to assess a novel method of three dimensional (3D) co-registration of prostate magnetic resonance imaging (MRI) examinations performed before and after prostate cancer focal therapy. MATERIALS AND METHODS: We developed a software platform for automatic 3D deformable co registration of prostate MRI at different time points and applied this method to 10 patients who underwent focal ablative therapy. MRI examinations were performed preoperatively, as well as 1 week and 6 months post treatment. Rigid registration served as reference for assessing co-registration accuracy and precision. RESULTS: Segmentation of preoperative and postoperative prostate revealed a significant postoperative volume decrease of the gland that averaged 6.49 cc (P = .017). Applying deformable transformation based on mutual information from 120 pairs of MRI slices, we refined by 2.9 mm (max. 6.25 mm) the alignment of the ablation zone, segmented from contrast-enhanced images on the 1-week postoperative examination, to the 6-month postoperative T2-weighted images. This represented a 500% improvement over the rigid approach (P = .001), corrected by volume. The dissimilarity by Dice index of the mapped ablation zone using deformable transformation vs rigid control was significantly (P = .04) higher at the ablation site than in the whole gland. CONCLUSIONS: Our findings illustrate our method's ability to correct for deformation at the ablation site. The preliminary analysis suggests that deformable transformation computed from mutual information of preoperative and follow-up MRI is accurate in co-registration of MRI examinations performed before and after focal therapy. The ability to localize the previously ablated tissue in 3D space may improve targeting for image-guided follow-up biopsy within focal therapy protocols. PMID- 29122469 TI - Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. AB - Pompe disease is a metabolic myopathy with a wide spectrum of clinical presentation. The gold-standard diagnostic test is acid alpha-glucosidase assay on skin fibroblasts, muscle or blood. Identification of two GAA pathogenic variants in-trans is confirmatory. Optimal effectiveness of enzyme replacement therapy hinges on early diagnosis, which is challenging in late-onset form of the disease due to non-specific presentation. Next-generation sequencing-based panels effectively facilitate diagnosis, but the sensitivity of whole-exome sequencing (WES) in detecting pathogenic GAA variants remains unknown. We analyzed WES data from 93 patients with confirmed Pompe disease and GAA genotypes based on PCR/Sanger sequencing. After ensuring that the common intronic variant c.-32 13T>G is not filtered out, whole-exome sequencing identified both GAA pathogenic variants in 77/93 (83%) patients. However, one variant was missed in 14/93 (15%), and both variants were missed in 2/93 (2%). One complex indel leading to a severe phenotype was incorrectly called a nonsynonymous substitution c.-32-13T>C due to misalignment. These results demonstrate that WES may fail to diagnose Pompe disease. Clinicians need to be aware of limitations of WES, and consider tests specific to Pompe disease when WES does not provide a diagnosis in patients with proximal myopathy, progressive respiratory failure or other subtle symptoms. PMID- 29122473 TI - Automated Radiology-Operative Note Communication Tool; Closing the Loop in Musculoskeletal Imaging. AB - RATIONALE AND OBJECTIVES: Correlation of imaging studies and reference standard outcomes is a significant challenge in radiology. This study evaluates the effectiveness of a new communication tool by assessing the ability of this system to correctly match the imaging studies to arthroscopy reports and qualitatively assessing radiologist behavior before and after the implementation of this system. MATERIALS AND METHODS: Using a commercially available communication or educational tool and applying a novel matching rule algorithm, radiology and arthroscopy reports were matched from January 17, 2017 to March 1, 2017 based on anatomy. The interpreting radiologist was presented with email notifications containing the impression of the imaging report and the entire arthroscopy report. Total correlation rate of appropriate report pairings, modality-specific correlation rate, and the anatomy-specific correlation rate were calculated. Radiologists using the system were given a survey. RESULTS: Overall correlation rate for all musculoskeletal imaging was 83.1% (433 or 508). Low correlation was found in fluoroscopic procedures at 74.4%, and the highest correlation was found with ultrasound at 88.4%. Anatomic location varied from 51.6% for spine to 98.8% for hips and pelvis studies. Survey results revealed 87.5% of the respondents reporting being either satisfied or very satisfied with the new communication tool. The survey also revealed that some radiologists reviewed more cases than before. CONCLUSIONS: Matching of radiology and arthroscopy reports by anatomy allows for excellent report correlation (83.1%). Automated correlation improves the quality and efficiency of feedback to radiologists, providing important opportunities for learning and improved accuracy. PMID- 29122474 TI - Predicting individual risk for medial tibial stress syndrome in navy recruits. AB - OBJECTIVES: Quantifying individual risk for medial tibial stress syndrome (MTSS) is valuable due to the high prevalence, substantial financial and service costs, and lengthy recovery time of the condition. Identification of those at risk is a key first step in prevention of the condition. This study aimed to test a suite of best evidence risk factors in a cohort of Navy recruits and to develop a predictive model for individuals at risk of MTSS. DESIGN: Prospective cohort study of Navy recruits undergoing initial training METHODS: A prospective cohort design, this study screened recruits by assessing gender, MTSS history, years of running experience, orthotic use, BMI, navicular drop, ankle plantarflexion and hip external rotation at the beginning of basic training. Follow-up was conducted at completion of training (11 weeks). RESULTS: Volunteers included 123 recruits (28 females and 95 males). Thirty developed MTSS (19 males and 11 females). Stepwise logistic regression of one half of the data produced a significant model (p<0.001), comprising female gender (OR 4.4, 95% CI 1.0, 18.9, p=0.05), MTSS history (OR 18.3, 95% CI 3.6, 91.5, p<0.01) and increased hip ER (OR 1.1 per degree, 95% CI 1.0, 1.202, p=0.05). Findings validated with the other half of the cohort and receiver operating characteristic curve analysis showed the model had 82% sensitivity and 84% specificity. CONCLUSIONS: This predictive model provides military institutions, clinicians and instructors with a strong and accurate calculator for predicting an individual recruit's risk of MTSS. PMID- 29122475 TI - Head impact exposure from match participation in women's rugby league over one season of domestic competition. AB - OBJECTIVES: To quantify the magnitude, frequency, duration and distribution of head impact exposure in a women's rugby league competition. DESIGN: Prospective cohort study. METHODS: Twenty-one players had a wireless impact measuring device (X2Biosystems XPatch) behind their right ear during match participation. Head impact data were collected and downloaded for analysis. Median peak linear and rotational accelerations and impact locations between player positions were assessed using a Friedman repeated measures ANOVA on ranks with a Wilcoxon signed rank test for post hoc analysis with a Bonferroni correction. RESULTS: A total of 1659 impacts to the head >10g were recorded (range 10g-91g) over the nine competition matches. There was a mean of 184+/-18 impacts per-match resulting in a mean of 14+/-12 impacts per-player per-match. The No. 8 prop recorded a mean of 29+/-27 impacts per-match, the No. 12 second-row forward recorded the highest median peak resultant linear acceleration (16g) per-match and the No. 11 second row forward recorded the highest median peak resultant rotational acceleration (3696rad/s2). CONCLUSIONS: Our cohort of 21 female rugby league athletes were exposed to repetitive sub-concussive head impact exposure with an average of 14 impacts per-player per-match. Forwards were exposed to more impacts per-match than backs and these impacts were of higher magnitude. Most impacts occurred on the side of the head and were sustained during the second half of the game. Clinicians, coaches and players should be aware of the rates and magnitude of head impacts in female rugby league athletes. PMID- 29122476 TI - Efficacy of leptospiral commercial vaccines on the protection against an autochtonous strain recovered in Brazil. AB - In swine and bovines, leptospirosis prevention and control is carried out via vaccination of susceptible animals using bacterins. However, the efficiency of leptospirosis vaccines has been questioned. This work aimed to investigate the potency of five leptospirosis vaccines sold commercially in Brazil, challenging the animals with one autochthonous strain of Leptospira, Canicola serovar, denoted LO4, isolated from swine. The standard protocol was followed, and renal carriers of Leptospira were identified among the surviving animals by culture and PCR. Of the five vaccines tested, only two proved effective. None of the surviving animals was positive by culture; however, one animal was positive by PCR. Three of the five vaccines sold commercially in Brazil for the immunization of swine or bovines failed the test of the efficacy to protect the vaccinated animals following challenge with an autochthonous Leptospira strain, Canicola serovar. The two vaccines provided protection against the renal carrier state in the surviving animals. The criteria used to produce leptospirosis bacterins sold commercially in Brazil must be reviewed. The industry should support researches on leptospiral vaccinology to improve the quality of the present vaccines and discover new immunogenic strains, because it is known that vaccination is one of the most important tools to increase the reproduction rates in livestock. PMID- 29122477 TI - Development and characterization of an innovative synbiotic fermented beverage based on vegetable soybean. AB - Soymilk was produced from vegetable soybean and fermented by probiotics (Lactobacillus acidophilus La-5, Bifidobacterium animalis Bb-12) in co-culture with Streptococcus thermophilus. The composition of the fermented beverage and oligosaccharides content were determined. The effect of fructooligosaccharides and inulin on the fermentation time and viability of probiotic microorganisms throughout 28 days of storage at 5 degrees C were evaluated. The soymilk from vegetable soybeans was fermented in just 3.2h, when pH reached 4.8. Fermentation reduced the contents of stachyose and raffinose in soymilk. Prebiotics had no effect on acidification rate and on viability of B. animalis and S. thermophilus in the fermented beverage. The viable counts of B. animalis Bb-12 remained above 108CFUmL-1 in the fermented soymilk during 28 days of storage at 5 degrees C while L. acidophilus La-5 was decreased by 1logCFUmL-1. The fermented soymilk from vegetable soybeans showed to be a good food matrix to deliver probiotic bacteria, as well as a soy product with a lower content of non-digestible oligosaccharides. PMID- 29122478 TI - Long-term cryopreservation of basidiomycetes. AB - Basidiomycetes have several biotechnological and industrial applications such as enzyme production, bioremediation, pharmaceutical and functional food production. Due to climatic features, the preservation of several basidiomycetes is threatened, and to guarantee the preservation of this genetic resource, the development of long-term preservation techniques is necessary once there is no universal protocol for the cryopreservation of basidiomycetes. Cryopreservation is a technique in which microorganisms are submitted to ultralow temperatures. Therefore, this study aimed to collect information on the main conditions for long-term cryopreservation of basidiomycetes in the last 20 years. Scientific articles on cryopreservation of basidiomycetes published from 1997 to 2016, were researched, and only the studies on two intervals of cryopreservation were considered: from 1 to 2 years and for longer than 2 years. The analyzed conditions of basidiomycete cryopreservation were: most studied genera, cryopreservation temperature, substrate, cryoprotectant (and preservation substrate), cryopreservation period, thawing temperature and cultivation medium after thawing, physiological and genetic stability of basidiomycetes after thawing in cryopreservation. In this review, the viability of the main cryopreservation conditions of basidiomycetes studied in the last 20 years are presented and discussed. PMID- 29122479 TI - Draft genome sequence of Paraburkholderia tropica Ppe8 strain, a sugarcane endophytic diazotrophic bacterium. AB - Paraburkholderia tropica (syn Burkholderia tropica) are nitrogen-fixing bacteria commonly found in sugarcane. The Paraburkholderia tropica strain Ppe8 is part of the sugarcane inoculant consortium that has a beneficial effect on yield. Here, we report a draft genome sequence of this strain elucidating the mechanisms involved in its interaction mainly with Poaceae. A genome size of approximately 8.75Mb containing 7844 protein coding genes distributed in 526 subsystems was de novo assembled with ABySS and annotated by RAST. Genes related to the nitrogen fixation process, the secretion systems (I, II, III, IV, and VI), and related to a variety of metabolic traits, such as metabolism of carbohydrates, amino acids, vitamins, and proteins, were detected, suggesting a broad metabolic capacity and possible adaptation to plant association. PMID- 29122480 TI - Azolylthioacetamides as a potent scaffold for the development of metallo-beta lactamase inhibitors. AB - In an effort to develop new inhibitors of metallo-beta-lactamases (MbetaLs), twenty-eight azolylthioacetamides were synthesized and assayed against MbetaLs. The obtained benzimidazolyl and benzioxazolyl substituted 1-19 specifically inhibited the enzyme ImiS, and 10 was found to be the most potent inhibitor of ImiS with an IC50 value of 15 nM. The nitrobenzimidazolyl substituted 20-28 specifically inhibited NDM-1, with 27 being the most potent inhibitor with an IC50 value of 170 nM. Further studies with 10, 11, and 27 revealed a mixed inhibition mode with competitive and uncompetitive inhibition constants in a similar range as the IC50 values. These inhibitors resulted in a 2-4-fold decrease in imipenem MIC values using E. coli cells producing ImiS or NDM-1. While the source of uncompetitive (possibly allosteric) inhibition remains unclear, docking studies indicate that 10 and 11 may interact orthosterically with Zn2 in the active site of CphA, while 27 could bridge the two Zn(II) ions in the active site of NDM-1 via its nitro group. PMID- 29122481 TI - Protective effect of casuarinin against glutamate-induced apoptosis in HT22 cells through inhibition of oxidative stress-mediated MAPK phosphorylation. AB - Glutamate is the major excitatory neurotransmitter in the central nervous system and is involved in oxidative stress during neurodegeneration. In the present study, casuarinin prevented glutamate-induced HT22 murine hippocampal neuronal cell death by inhibiting intracellular reactive oxygen species (ROS) production. Moreover, casuarinin reduced chromatin condensation and annexin-V-positive cell production induced by glutamate. We also confirmed the underlying protective mechanism of casuarinin against glutamate-induced neurotoxicity. Glutamate markedly increased the phosphorylation of extracellular signal regulated kinase (ERK)-1/2 and p38, which are crucial in oxidative stress-mediated neuronal cell death. Conversely, treatment with casuarinin diminished the phosphorylation of ERK1/2 and P38. In conclusion, the results of this study suggest that casuarinin, obtained from natural products, acts as potent neuroprotective agent by suppressing glutamate-mediated apoptosis through the inhibition of ROS production and activation of the mitogen activated protein kinase (MAPK) pathway. Thus, casuarinin can be a potential therapeutic agent in the treatment of neurodegenerative diseases. PMID- 29122482 TI - Indirubin derivatives protect against endoplasmic reticulum stress-induced cytotoxicity and down-regulate CHOP levels in HT22 cells. AB - Indirubin and its derivatives have been reported to exhibit anti-cancer and anti inflammatory activities. Recently, some of its derived analogs have been shown to have neuroprotective potential. Endoplasmic reticulum (ER) stress has been demonstrated to contribute to the pathogenesis of various neurodegenerative diseases, whereas the effects of indirubin derivatives on ER stress-induced cell death have not been addressed. In the present study, a series of 44 derivatives of indirubin was prepared to search for a novel class of neuroprotective agents against ER stress-induced neuronal death. The MTT reduction assay indicated that tunicamycin (TM), an inducer of ER stress, significantly decreased the viability of hippocampal neuronal HT22 cells. Among the compounds tested, eight showed significant inhibitory activity against TM-induced cell death. Western blot analysis showed that application of these analogs to the cells simultaneously with TM reduced the TM-induced expression of CHOP, an established mediator of ER stress. Our results suggest that the preventive effect of these indirubin derivatives against ER stress-induced neuronal death may be due, at least in part, to attenuation of the CHOP-dependent signaling system. PMID- 29122483 TI - New terpenoids and thiophene derivatives from the aerial parts of Artemisia sieversiana. AB - One new highly oxygenated nortriterpene, named sieverlactone (1), one new sesquiterpene, 1beta,10beta-epoxy-8alpha-acetoxyachillin (2), one new natural product, 5-propinyl-thiophene-2-carboxylic acid (3), and one new thiophene, 3 hydroxy-5-propinyl-2-acetyl-thiophene (4), together with 10 other known compounds (5-14), were isolated from the dried aerial parts of Artemisia sieversiana. Their structures were elucidated by a combination of extensive spectroscopic analysis, including 1D, 2D NMR spectroscopic and mass spectrometric data. Meanwhile, the stereochemistry of 1 and 2 was confirmed by single-crystal X-ray diffraction technique using Cu radiation. All the isolates were evaluated for their anti neuroinflammatory effects on the lipopolysaccharide-induced nitric oxide production in BV-2 murine microglial cells. Compounds 2, 5, and 6 exhibited the significant activities with IC50 values of 6.5 +/- 0.5, 11.9 +/- 0.7, and 10.1 +/ 0.3 MUM, respectively, comparable to the positive control, quercetin, with an IC50 value of 16.3 +/- 0.4 MUM. PMID- 29122484 TI - Delphinidin inhibits BDNF-induced migration and invasion in SKOV3 ovarian cancer cells. AB - Brain-derived neurotrophic factor (BDNF), the TrkB ligand, is associated with aggressive malignant behavior, including migration and invasion, in tumor cells and a poor prognosis in patients with various types of cancer. Delphinidin is a diphenylpropane-based polyphenolic ring structure-harboring compound, which exhibits a wide range of pharmacological activities, anti-tumor, anti-oxidant, anti-inflammatory, anti-angiogenic and anti-mutagenic activity. However, the possible role of delphinidin in the cancer migration and invasion is unclear. We investigated the suppressive effect of delphinidin on the cancer migration and invasion. Thus, we found that BDNF enhanced cancer migration and invasion in SKOV3 ovarian cancer cell. To exam the inhibitory role of delphinidin in SKOV3 ovarian cancer migration and invasion, we investigated the use of delphinidin as inhibitors of BDNF-induced motility and invasiveness in SKOV3 ovarian cancer cells in vitro. Here, we found that delphinidin prominently inhibited the BDNF induced increase in cell migration and invasion of SKOV3 ovarian cancer cells. Furthermore, delphinidin remarkably inhibited BDNF-stimulated expression of MMP-2 and MMP-9. Also, delphinidin antagonized the phosphorylation of Akt and nuclear translocation of NF-kappaB permitted by the BDNF in SKOV3 ovarian cancer cells. Taken together, our findings provide new evidence that delphinidin suppressed the BDNF-induced ovarian cancer migration and invasion through decreasing of Akt activation. PMID- 29122485 TI - Treatment outcomes of locally advanced squamous cell carcinoma of the maxillary sinus treated with chemoradioselection using superselective intra-arterial cisplatin and concomitant radiation: Implications for prognostic factors. AB - BACKGROUND: This study clarified the clinical results of locally advanced squamous cell carcinoma of the maxillary sinus (SCC-MS) that was treated with chemoradioselection using superselective intra-arterial cisplatin and concomitant radiation (RADPLAT). Prognostic factors were also investigated. METHODS: We retrospectively analyzed 63 locally advanced SCC-MS patients treated with initial RADPLAT followed by sequential RADPLAT (S-RADPLAT) or surgery. RESULTS: The 5 year progression-free survival (PFS) and overall survival (OS) rates of patients with T3, T4a, or T4b disease were 72.2%, 46.6%, and 33.3% (p = 0.104) and 83.3%, 51.6%, and 33.3% (p = 0.031), respectively. The 5-year PFS and OS rates of the S RADPLAT or surgery groups with T4 disease were 39.6% and 60.6% (p = 0.199) and 44.7% and 63.3% (p = 0.276), respectively. Tumor extension into the medial and/or lateral pterygoid muscle (p < 0.001) and N classification (p = 0.012) were considered significant factors for PFS. Regarding OS, tumor extension into the medial and/or lateral pterygoid muscle (p = 0.005) was considered a statistically significant risk factor. CONCLUSIONS: It may be better for T4 non-responders to initial RADPLAT to undergo surgery. Patients with high risk factors of positive neck metastasis or pterygoid muscle extension may need adjuvant chemotherapy. PMID- 29122486 TI - Trapezius flaps for reconstruction of head and neck defects following oncological resection - A systematic review. AB - OBJECTIVE: Head and neck (H&N) reconstruction after cancer resection is challenging. Myocutaneous trapezius flaps provide an alternative reconstruction for patients not suitable for microvascular free tissue transfer. METHODS: A systematic review was performed on studies involving trapezius flaps for H&N reconstruction post oncological resection between the years 1985-2015. Data extracted included patient numbers and demographics, operative technique and complications. Complication rates, for the study cohort, were calculated and a univariate analysis was preformed evaluating patient and flap-related risk factors. RESULTS: Seventeen studies met the inclusion criteria, with a total of 157 trapezius flaps. Intraoral defects were the most frequent recipient site (74.5%). The mean skin paddle width was 6.84 cm (range 3-15 cm) and length was 11.1 cm (range 4-25 cm). Type 2 (superficial branch of transverse cervical artery) accounted for 77.1% (118/153) of all trapezius flaps performed. The complication rate was 15.9%, with 15 reported flap related and 7 donor site complications. Skin paddle size, pedicle selection, primary versus salvage reconstruction and radiotherapy were not identified risk factors for complications. CONCLUSION: Trapezius flaps are a reliable and versatile myocutaneous flap for both primary and salvage surgery reconstruction of H&N defects following oncological resection. PMID- 29122487 TI - [Prostate cancer diagnostic by saturation randomized biopsy versus rigid targeted biopsy]. AB - INTRODUCTION: Optimal diagram teaming up randomized biopsy (BR) to targeted biopsy (BC) is still missing for the diagnostic of prostate cancer (CP). This study compares diagram of 6, 12 or 18 BR with or without BC rigid. METHODS: Between January 2014 and May 2016, 120 patients had prostate biopsy BR and BC. Each patient had 18 BR and BC. Results compared sextant (6 BR), standard (12 BR) and saturation (18 BR) protocol with or without the adding of BC for the detection of CP. RESULTS: Rectal examination was normal, mean PSA at 8.99ng/mL and mean volume at 54cm3. It was first round for 48% of patients. Forty-four cancers were found by the group 18 BR+BC (control). The detection rate was respectively, for 6, 12 and 18 BR of 61%, 82% and 91%. The add of BC increased this detection of +27% for 6 BR+BC, +13% for 12 BR+BC and +9% for 18 BR+BC. BC found 70% of all CP. Nine percent of CP were missed by BR only. Significant CP (Gleason>=7) diagnostic was the same for 12 BR+BC and 18 BR+BC. CONCLUSION: The add of BC to BR increase the detection of CP by 10%. Twelve BR+BC is the optimal diagram for the diagnostic of CP finding 95% of CP and 97% of significant CP. LEVEL OF EVIDENCE: 4. PMID- 29122488 TI - [Triorchidism: A rare cause of the scrotal mass?] PMID- 29122489 TI - Reliability and reproducibility of the American Association for the Surgery of Trauma scaling for renal injury and impact on radiologic follow-up. AB - INTRODUCTION: The American Association for the Surgery of Trauma (AAST) Organ Injury Scale (OIS) is the most used classification for renal trauma. It determines the radiologic monitoring, only recommended for high-grade injuries. The aim of this study was to assess the subjectivity of AAST scaling and its impact on short-term follow-up. METHODS: We retrospectively reviewed all patients with blunt renal injuries admitted at a university hospital between 2010 and 2015. Computed Tomography (CT) scan were analyzed and injuries graded according to AAST OIS independently by a senior radiologist, a senior urologist who was blind to clinical data and a resident urologist. Grading disagreements were analyzed collegially to obtain a final rating. The agreement of AAST scaling was evaluated through the Cohen's Kappa coefficient. RESULTS: Ninety-seven patients had 101 renal injuries: low grade in 58.4% (11.9% grade I, 17.8% grade II, 28.7% grade III) and high grade in 41.6% of cases (23.6% grade IV and 17.8% grade V). The agreement was fair with Kappa coefficient at 0.36. The agreement was moderate in severity sub-division analysis (low or high grade): Kappa coefficient at 0.59. There was a disagreement in 49.5% between the senior urologist's and the senior radiologist's ratings. Those differences brought to a severity group change and radiologic follow-up modification in 34% (n=17). CONCLUSION: AAST OIS for renal trauma suffers from subjectivity but is improved by severity sub-group analysis. This subjectivity influences the radiologic follow-up but could be reduced by collegiate rating. LEVEL OF EVIDENCE: 4. PMID- 29122490 TI - Robot-assisted laparoscopy in benign gynecology: Advantageous device or controversial gimmick? AB - The growth of robot-assisted laparoscopic surgery has been exponential since its FDA approval for use in gynecologic surgery in the spring of 2005; however, controversy surrounding its use has been associated with this rise in utilization. Much of this discussion has pitted the conventional laparoscopist against the robotic surgeon particularly as it relates to issues such as operative time, costs, and the current scientific evidence. Although drawbacks exist in robotic technology, there are also clear and obvious advantages that are difficult to quantify in the scientific literature but evident to users. This chapter highlights the current state of affairs regarding the scientific literature with an evidence-based focus on the most commonly applied application benign hysterectomy. PMID- 29122491 TI - Inflammation and Autism: From Maternal Gut to Fetal Brain. AB - Maternal immune activation (MIA) during pregnancy is associated with an increased risk of behavioral disorders in the offspring of affected mothers. Two recent studies highlight how maternal inflammation disrupts inhibitory interneuron networks and suggest that the maternal gut microbiome may be a contributing risk factor for MIA-induced behavioral abnormalities. PMID- 29122493 TI - Postepileptic seizure PTSD: A very rare psychiatric condition in patients with epilepsy. AB - PURPOSE: It has been shown that relatives of patients with epilepsy could experience a seizure as a traumatic event followed by a posttraumatic stress disorder (PTSD). In one questionnaire study, 51% of the patients with epilepsy were reported to have a PTSD caused by a traumatic seizure, termed postepileptic seizure PTSD by the authors. However, it remained unclear whether these patients had further psychiatric comorbidities and if certain seizure features may foster the development of the proposed epilepsy-specific PTSD. METHODS: We conducted a structured clinical interview assessing psychiatric disorders in 120 patients with difficult-to-treat epilepsies. We also used a modified version of the Posttraumatic Stress Diagnostic Scale conducted as an interview to assess the number of patients who fulfilled the criteria for a PTSD caused by an epileptic seizure. We additionally compared certain features of traumatic versus nontraumatic seizures. RESULTS: Fifty of the 120 patients identified a seizure that fulfilled the criteria for a traumatic event, whereas 28 patients identified a worst seizure not meeting the trauma definition. Six patients fulfilled all PTSD criteria caused by a traumatic seizure. However, three of these patients also had a regular PTSD, and in two further patients, the results of the clinical interview suggested that the PTSD-like symptoms could be better explained by an adjustment disorder. We could not identify seizure characteristics differentiating traumatic from nontraumatic seizures. CONCLUSION: Our results showed that it is recommendable to conceptualize an epileptic seizure as being potentially traumatic in nature when assessing PTSD in patients with epilepsy, although we could not identify specific characteristics that could differentiate between traumatic and nontraumatic seizures. However, while using interview-based psychiatric assessment, we found a very low rate of a postepileptic seizure PTSD. It is worth conducting a comprehensive psychiatric diagnostic interview to differentiate PTSD-like symptoms from other comorbidities, such as epilepsy related adjustment disorder. PMID- 29122492 TI - d-Leucine: Evaluation in an epilepsy model. AB - BACKGROUND: Current medicines do not provide sufficient seizure control for nearly one-third of patients with epilepsy. New options are needed to address this treatment gap. We recently found that the atypical amino acid d-leucine protected against acutely-induced seizures in mice, but its effect in chronic seizures has not been explored. We hypothesized that d-leucine would protect against spontaneous recurrent seizures. We also investigated whether mice lacking a previously-described d-leucine receptor (Tas1R2/R3) would be protected against acutely-induced seizures. METHODS: Male FVB/NJ mice were subjected to kainic acid induced status epilepticus and monitored by video-electroencephalography (EEG) (surgically implanted electrodes) for 4weeks before, during, and after treatment with d-leucine. Tas1R2/R3 knockout mice and controls underwent the maximal electroshock threshold (MES-T) and 6-Hz tests. RESULTS: There was no difference in number of calendar days with seizures or seizure frequency with d-leucine treatment. In an exploratory analysis, mice treated with d-leucine had a lower number of dark cycles with seizures. Tas1R2/R3 knockout mice had elevated seizure thresholds in the MES-T test but not the 6-Hz test. CONCLUSIONS: d-Leucine treatment was ineffective against chronic seizures after kainic acid-induced status epilepticus, but there was some efficacy during the dark cycle. Because d leucine is highly concentrated in the pineal gland, these data suggest that d leucine may be useful as a tool for studying circadian patterns in epilepsy. Deletion of the Tas1R2/R3 receptor protected against seizures in the MES-T test and, therefore, may be a novel target for treating seizures. PMID- 29122494 TI - Penile Rehabilitation Therapy Following Radical Prostatectomy: A Meta-Analysis. AB - BACKGROUND: Penile rehabilitation, defined as the use of any drug or device at or after radical prostatectomy to maximize erectile function recovery, is commonly used for post-prostatectomy erectile dysfunction; however, conflicting results based on each study make it difficult to give a recommendation for clinical practice. AIM: To clarify the effect of oral phosphodiesterase type 5 inhibitors (PDE5is), vacuum erection devices, intracorporeal injection therapy, and the combination of these treatments on penile rehabilitation. METHODS: A comprehensive publication search was done through the PubMed and Embase databases up to February 8, 2017. The reference lists of the retrieved studies also were investigated. Data were analyzed using STATA 12.0. A fixed- or random-effects model was used to calculate the overall combined odds ratio (OR) or standard mean differences (SMDs). Publication bias was assessed using the Begg and Egger tests. OUTCOMES: Change in sexual function before and after treatment. RESULTS: After screening, 11 randomized controlled trials and 5 case-control studies were included. The overall meta-analysis showed that penile rehabilitation with PDE5is, vacuum erection devices, and intracorporeal injection significantly increased the number of patients with erectile function improvement (OR = 2.800, 95% CI = 1.932-4.059, P = .000) and International Index of Erectile Function (IIEF) score (SMD = 5.896, 95% CI = 4.032-7.760, P = .000). In subgroup analysis based on study design, randomized controlled trials and case-control studies showed that penile rehabilitation increased the number of patients with erectile function improvement (randomized controlled trials: OR = 2.154, 95% CI = 1.600 2.895, P = .000; case-control studies: OR = 2.800, 95% CI = 1.932-4.059, P = .000). Subgroup analysis for PDE5i treatment also only demonstrated an increased patient response rate (OR = 2.161, 95% CI = 1.675-2.788, P = .000) and IIEF scores (SMD = 0.922, 95% CI = 0.545-1.300, P = .000). However, after PDE5i washout, there was no improvement of spontaneous erectile function (OR = 1.027, 95% CI = 0.713-1.478, P = .610). CLINICAL TRANSLATION: This study provides information about the efficacy of penile rehabilitation that can help clinicians decide treatment strategies. STRENGTHS AND LIMITATIONS: This meta-analysis has higher statistical power than each study. Preoperative patient characteristics, various treatment methods, and different follow-up times might bring bias to pooled effects. CONCLUSION: Our meta-analysis confirmed that administration of PDE5is, vacuum erection devices, and intracorporeal injection after radical prostatectomy can increase erection function during treatments. However, current evidence does not support that penile rehabilitation with PDE5is can improve recovery of spontaneous erectile function. Further studies with adequate follow up and larger samples should be conducted to generate a comprehensive conclusion. Liu C, Lopez DS, Chen M, Wang R. Penile Rehabilitation Therapy Following Radical Prostatectomy: A Meta-Analysis. J Sex Med 2017;14:1496-1503. PMID- 29122495 TI - Up-regulation of serum periostin and squamous cell carcinoma antigen levels in infants with acute bronchitis due to respiratory syncytial virus. AB - BACKGROUND: Periostin and squamous cell carcinoma antigen (SCCA) are involved in the pathogenesis of asthma. Acute bronchitis due to respiratory syncytial virus (RSV) infection during infancy exhibits an asthma-like pathogenesis, suggesting that it may be associated with the subsequent development of asthma. However, the mechanism by which RSV infection leads to development of asthma has not yet been fully elucidated. METHODS: Infants younger than 36 months were enrolled and classified into three groups. Group I included patients hospitalized with RSV induced bronchitis. These patients were further stratified into two sub-groups according to whether the criteria for the modified Asthma Predictive Index (mAPI) had been met: Group I consisted of mAPI (+) and mAPI (-) patients; Group II included patients with food allergy as a positive control group; and Group III included children with no allergy as a negative control group. Serum periostin and SCCA levels were measured in the groups. This study was registered as a clinical trial (UMIN000012339). RESULTS: We enrolled 14 subjects in Group I mAPI (+), 22 in Group I mAPI (-), 18 in Group II, and 18 in Group III. In Group I, the serum periostin and SCCA levels were significantly higher during the acute phase compared with the recovery phase. However, no significant differences were found between Group I mAPI (+) and mAPI (-). CONCLUSIONS: The serum periostin and SCCA levels increased during acute RSV bronchitis. Both periostin and SCCA may play a role in the pathogenesis of acute bronchitis due to RSV. PMID- 29122496 TI - Determinants of low bone mineral density in children with epilepsy. AB - INTRODUCTION: Children with epilepsy on long-term antiepileptic drugs (AEDs) are at risk of low bone mineral density (BMD). The aims of our study were to evaluate the prevalence and determinants of low BMD among Malaysian children with epilepsy. METHOD: Cross-sectional study of ambulant children with epilepsy on long-term AEDs for >1 year seen in a tertiary hospital in Malaysia from 2014 to 2015. Detailed assessment of anthropometric measurements; environmental lifestyle risk factors; serum vitamin D, calcium and parathyroid hormone levels; genotyping of single nucleotide polymorphisms of genes in vitamin D and calcium metabolism; and lumbar spine BMD were obtained. Low BMD was defined as BMD Z-score <= -2.0 SD. RESULTS: Eighty-seven children with mean age of 11.9 years (56 males) participated in the study. The prevalence of low lumbar BMD was 21.8% (19 patients). Multivariate logistic regression analysis identified polytherapy >2 AEDs (OR: 7.86; 95% CI 1.03-59.96), small frame size with wrist breadth of <15th centile (OR 14.73; 95% CI 2.21-98.40), and body mass index Z-score < -2.0 (OR 8.73, 95% CI 1.17-65.19) as significant risk factors for low BMD. CONCLUSION: One fifth of Malaysian children with epilepsy on long-term AEDs had low BMD. Targeted BMD should be performed for those who are on >2 AEDs, underweight or with small frame size as they are at higher risk of having low BMD. PMID- 29122498 TI - A single-centre, retrospective proof-of-concept review of salvage of infected or exposed implant breast reconstructions with explantation and one-stage free flap replacement. AB - INTRODUCTION: Implant-based breast reconstruction has relatively high complication rates. Removal of infected implants and immediate autologous reconstruction is a safe single-stage procedure that preserves the native breast skin envelope. METHODS: A single-centre, retrospective proof-of-concept review of all salvage procedures performed for acute/chronic infected or exposed implant based reconstructions by a single surgeon over a 6-year period. RESULTS: We present 13 cases of a particularly difficult subgroup of acute/chronic infection/extrusion over a 6-year period. All were successfully salvaged in a single procedure by implant removal and immediate free flap reconstruction with no significant complications. All patients had a change of pocket from subpectoral to subcutaneous and partial capsulectomies. Four patients had unilateral DIEP flaps for unilateral reconstruction, 3 bi-pedicle DIEP flaps for unilateral reconstruction, 2 bilateral TUG flaps for unilateral reconstruction, 3 bilateral DIEP flaps for bilateral reconstruction and 1 unilateral DIEP and implant for unilateral reconstruction. CONCLUSIONS: These patients are often slim with limited donor sites and pose technical challenges, often requiring double free flap reconstructions. Single-stage implant removal and autologous reconstruction preserves the breast skin envelope to maximise cosmesis in a single procedure. The introduction of healthy, well-vascularised tissue may also help treat the infection. PMID- 29122499 TI - Micro-autologous fat transplantation for rejuvenation of the dorsal surface of the aging hand. AB - BACKGROUND: Rejuvenation of the dorsal surface of the hand for various conditions, such as cutaneous dyschromia, fine wrinkling, skin laxity, visible extensor tendons, and varicosities appear vital to prevent wrist and digit flexion resulting from hiding of the aged appearance of the hand. Numerous fillers have been applied to re-contour the aging dorsal surface of the hand and the results were variable. The micro-autologous fat transplantation (MAFT) technique, proposed by Lin et al. in 2006, has demonstrated its feasibility in facial rejuvenation. In this study, we applied the MAFT technique for the rejuvenation of the dorsal portion of the hand. METHODS: MAFT was performed in 68 female patients. Fat was harvested by performing liposuction, processed, and refined by centrifugation. Purified fat was micro-transplanted to the dorsal surface of the hand in parcels of small volume. RESULTS: The mean age of the patients was 56 years (range, 38-70 years). MAFT was completed in 72 min, on average. The average amount of delivered fat was 13.9 and 13.8 mL for the right and left hands, respectively. The mean follow-up period was 32 months (range, 10 64 months). The 5-point Likert scale revealed that 58.8% of patients were very satisfied and 39.7% were satisfied about their outcome. CONCLUSIONS: MAFT has changed the concept of fat grafting, from an operation with unpredictable clinical results to an easy and reliable procedure. MAFT demonstrated high patient satisfaction with long-term results and is an effective approach to rejuvenate the dorsal surface of the hand. PMID- 29122500 TI - Effects of infraorbital nerve's anatomical course on the fracture pattern of the orbital floor. AB - In this study, details of the infraorbital nerve's (ION's) anatomical course variants were compared using computed tomography (CT), and relationships between the variants and fracture patterns in the orbital floor were investigated. Fifty two normal individuals and 50 patients with unilateral isolated orbital floor fractures were enrolled in this study. Four measurements in normal individuals and five measurements in fracture patients were obtained in parasagittal sections. The anatomical variations of the ION were categorized into three types according to the classification by Ferences et al. Among the normal individuals, 42 orbits were classified as type 1 ION, 48 orbits as type 2, and 14 orbits as type 3. The distance from the inferior orbital rim to the upper border of the inferior orbital foramen and the length of descension portion of the ION in type 1 ION were significantly shorter than in type 2 and type 3 IONs. In patients with orbital floor fractures, the distance from the inferior orbital rim to the upper border of the inferior orbital foramen was positively correlated with herniation level of bone and soft tissue. The ION had three anatomical variants according to the degree of descension in the anterior portion of the orbit. When fracture of the orbital floor occurs in patients with type 1 ION, inferior displacement of the fractured orbital bone and orbital soft tissue may be less severe than in patients with other ION types. PMID- 29122497 TI - Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases. AB - Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy. PMID- 29122501 TI - Psychoneuroimmunological approach to gastrointestinal related pain. AB - BACKGROUND AND PURPOSE (AIMS): Psychoneuroimmunology is both a theoretical and practical field of medicine in which human biology and psychology are considered an interconnected unity. Through such a framework it is possible to elucidate complex syndromes in gastrointestinal related pain, particularly chronic non malignant. The aim is to provide insight into pathophysiological mechanisms and suggest treatment modalities according to a comprehensive paradigm. The article also presents novel findings that may guide clinicians to recognize new targets or scientists to find new research topics. METHODS: A literature search of 'PubMed' and 'Google Scholar' databases was performed. Search terms included: 'Visceral pain', 'Psychoneuroimmunology', 'Psychoneuroimmunology and pain', 'Pain in GI system', 'GI related pain', 'Pain and microbiota', 'Enteric nervous system', 'Enteric nervous system and inflammation', 'CNS and pain', 'Inflammation and pain in GI tract', 'Neurogastroenterology', 'Neuroendocrinology', 'Immune system in GI pain'. After searching and reading sources deemed recent and relevant, a narrative review was written with a tendency to discriminate the peripheral, intermediate, and central pathophysiological mechanisms or treatment targets. RESULTS: Recent evidence point out the importance of considering the brain-gut axis as the main connector of the central and peripheral phenomena encountered in patients suffering from chronic non-malignant gastrointestinal related pain. This axis is also a prime clinical target with multiple components to be addressed in order for therapy to be more effective. Patients suffering from inflammatory bowel disease or functional gastrointestinal disorders represent groups that could benefit most from the proposed approach. CONCLUSIONS (BASED ON OUR FINDINGS): Rather than proceeding with established allopathic single-target central or peripheral treatments, by non-invasively modulating the brain-gut axis components such as the psychological and neuroendocrinological status, microbiota, enteric nervous system, or immune cells (e.g. glial or mast cells), a favourable clinical outcome in various chronic gastrointestinal related pain syndromes may be achieved. Clinical tools are readily available in forms of psychotherapy, prebiotics, probiotics, nutritional advice, and off-label drugs. An example of the latter is low-dose naltrexone, a compound which opens the perspective of targeting glial cells to reduce neuroinflammation and ultimately pain. IMPLICATIONS (OUR OPINION ON WHAT OUR FINDINGS MEAN): Current findings from basic science provide sound mechanistic evidence and once entering clinical practice should yield more effective outcomes for patients. In addition to well established pharmacotherapy comprised notably of anti-inflammatories, antibiotics, and proton-pump inhibitors, valid treatment strategies may contain other options. These disease modulating add-ons include probiotics, prebiotics, food supplements with anti-inflammatory properties, various forms of psychotherapy, and low-dose naltrexone as a glial modulator that attenuates neuroinflammation. Clearly, a broader and still under exploited set of evidence based tools is available for clinical use. PMID- 29122502 TI - Clinical and pathologic analyses of tuberculosis in the oral cavity: report of 11 cases. AB - OBJECTIVE: The aim of this study was to analyze tuberculosis (TB) in the oral cavity according to clinical appearance, clinical differential diagnosis, treatment, and outcome. STUDY DESIGN: We enrolled 11 patients with TB in the oral cavity between November 2012 and November 2016. Glossal lymphoid TB was excluded. Clinical symptoms, auxiliary examinations, treatments, and outcomes were recorded and analyzed. RESULTS: The study population comprised 6 men and 5 women, with a mean age of 59 years. Five patients presented with ulcer, 5 with a mass, and 1 with osteomyelitis. Excisional biopsy was performed in 3 patients, mass resection in 7, and curettage of mandibular lesion in 1. After pathologic diagnosis of TB in the oral cavity in 8 patients; 6 of them underwent purified protein derivative examination, and 4 of them had positive results and received drug therapy. The mean follow-up period was 24.9 months, and there was no recurrence. CONCLUSIONS: TB in the oral cavity is rare and has no specific clinical features. Pathology, acid-fast staining, polymerase chain reaction, and DNA testing for Mycobacterium tuberculosis are useful for final diagnosis. Surgery is recommended as the treatment of choice to achieve good clinical outcomes. PMID- 29122503 TI - Social Media Scholarship and Alternative Metrics for Academic Promotion and Tenure. AB - Traditionally, scholars focused their efforts in the domains of clinical care, research, and education; however, the last decade has witnessed the rise of novel areas of development such as innovation, quality improvement, informatics, and recently, digital scholarship. Academic institutions adapted and began considering these fields for academic promotion and tenure. Social media has become a critical space for the dissemination of knowledge and outreach to community and policy makers and also for the creation of communities of practice. This new realm brings multiple challenges, such as the appraisal of the quality and appropriateness of the content, the evaluation of impact on the academe and general populations, coupled to the creation of a system to reward scholars engaged in this novel endeavor. In this article, we describe the current state of academic promotion and the definition, nature, and merit of digital scholarship. We outline new strategies and tools for the assessment of dissemination and impact of these works, such as altmetrics, and finally, we reference innovative concepts on how to organize and use this digital academia on career promotion and tenure. PMID- 29122504 TI - #TwittIR: Understanding and Establishing a Twitter Ecosystem for Interventional Radiologists and Their Practices. AB - The use of social media among interventional radiologists is increasing, with Twitter receiving the most attention. Twitter is an ideal forum for open exchange of ideas from around the world. However, it is important for Twitter users to gain a rudimentary understanding of the many potential communication pathways to connect with other users. An intentional approach to Twitter is vital to efficient and successful use. This article describes several common communication pathways that can be utilized by physicians in their interventional radiology practice. PMID- 29122505 TI - Mayo Clinic Care Network: A Collaborative Health Care Model. AB - By leveraging its experience and expertise as a consultative clinical partner, the Mayo Clinic developed an innovative, scalable care model to accomplish several strategic goals: (1) create and sustain high-value relationships that benefit patients and providers, (2) foster relationships with like-minded partners to act as a strategy against the development of narrow health care networks, and (3) increase national and international brand awareness of Mayo Clinic. The result was the Mayo Clinic Care Network. PMID- 29122506 TI - Medical Journals in the Age of Ubiquitous Social Media. AB - Medical journals increasingly use social media to engage their audiences in a variety of ways, from simply broadcasting content via blogs, microblogs, and podcasts to more interactive methods such as Twitter chats and online journal clubs. Online discussion may increase readership and help improve peer review, for example, by providing postpublication peer review. Challenges remain, including the loss of nuance and context of shared work. Furthermore, uncertainty remains regarding how to assess the impact of journal social media outreach, abundant but unclear metrics, and the magnitude of benefit (if any), particularly given the substantial work required for substantive interactive engagement. Continued involvement and innovation from medical journals through social media offers potential in engaging journal audiences and improving knowledge translation. PMID- 29122507 TI - Impact of a Physician-Led Social Media Sharing Program on a Medical Journal's Web Traffic. AB - PURPOSE: The use of social media by health professionals and medical journals is increasing. The aim of this study was to compare online views of articles in press (AIPs) released by Annals of Emergency Medicine before and after a nine person social media team started actively posting links to AIPs using their personal Twitter accounts. METHODS: An observational before-and-after study was conducted. Web traffic data for Annals were obtained from the publisher (Elsevier), detailing the number of page views to annemergmed.com by referring websites during the study period. The preintervention time period was defined as January 1, 2013, to June 30, 2014, and the postintervention period as July 1, 2014, to July 31, 2015. The primary outcome was page views from Twitter per AIP released each month to account for the number of articles published each month. Secondary outcomes included page views from Facebook (on which there was no article-sharing intervention) and total article views per month. RESULTS: The median page views from Twitter per individual AIP released each month increased from 33 in the preintervention period to 130, for an effect size of 97 (95% confidence interval, 56-111; P < .001). There was a smaller increase in median page views from Facebook per individual AIP of 21 (95% confidence interval, 10 32). There was no significant increase in these median values for total page views per AIP. CONCLUSIONS: Twitter sharing of AIPs increased the number of page views that came from Twitter but did not increase the overall number of page views. PMID- 29122508 TI - Facebook Live: A Free Real-Time Interactive Information Platform. PMID- 29122509 TI - Exploring Social Media in Health Care: Beyond Its Pervasiveness. PMID- 29122510 TI - Social Media, Health Policy, and Knowledge Translation. AB - Social media has been cited as a methodology for reducing the knowledge translation gap, creating communities of practice, and reducing traditional hierarchical divisions. Social movements have also embraced social media as a means of spreading their aims and reaching wide audiences. However, its impact on health policy is seldom considered. The author examines the complexity of clinicians' use of social media to influence policy and how policy and government groups may use social media to help their own objectives. PMID- 29122511 TI - From bench to clinical trials the EORTC experience in biology-based clinical cancer research. AB - For over 50years the European Organization for Research and Treatment of Cancer (EORTC) has delivered major advances in cancer clinical research and cancer therapeutics. The introduction of molecularly targeted agents has led to significant improvements in outcome for patients with specific tumor types; however conventional chemotherapy remains the mainstay of treatment for the majority of patients. Due to increasing knowledge about the diversity of molecular pathways driving malignant progression, strategies to integrate biology into clinical research and development are continuously evolving. The challenges and the experience of the EORTC regarding how translational research is to be an indispensable component of the clinical research environment, which aims to deliver more sophisticated treatment approaches will be discussed in this perspective article. PMID- 29122512 TI - [Salvage prostate brachytherapy: A solution for local failures after a primary radiation therapy?] AB - Salvage brachytherapy after a first prostate radiation therapy is an emerging technique, which has to be considered in the therapeutic armamentarium in the clinically challenging context of patients with isolated local failure from prostate cancer who may still be considered for cure. These occult failures are more and more frequently diagnosed at an early stage, thanks to targeted biopsies and advances in imaging modalities, such as multiparametric MRI and PET-CT. Salvage brachytherapy benefits from the implantation accuracy of brachytherapy procedures using 3D dosimetry and has resulted in more than 50% tumour control rates with long-term. Incontinence rates are always below those of other salvage treatments such as radical prostatectomy, HIFU or cryotherapy. Today, a consensus has been reached to better define good candidates for salvage brachytherapy with respect to disease characteristics at baseline and at failure. No consensus has been clearly defined yet regarding the choice of the technique (low or high dose rate), the total dose to be delivered, or the volume to be implanted (whole gland or focal). While we await robust data from recently completed phase II studies and given the heterogeneous results in the literature, this technique (although already included in the last 2016 NCCN guidelines) remains to be precisely evaluated, optimally within the frame of controlled trials. PMID- 29122513 TI - Tako-tsubo Syndrome in Men: Rare, but With Poor Prognosis. AB - INTRODUCTION AND OBJECTIVES: Tako-tsubo syndrome is a potentially serious disease during the acute phase. It mimics myocardial infarction, but with no potentially causative coronary lesions. The aim of this study was to analyze the clinical course and outcome of patients with tako-tsubo syndrome by sex. METHODS: We analyzed the characteristics of patients included in the RETAKO registry from 2003 to 2015, a multicenter registry with participation of 32 Spanish hospitals. RESULTS: Of 562 patients included, 493 (87.7%) were women. Chest pain was less frequent as an initial symptom in men than in women (43 [66.2%] vs 390 [82.8%]; P < .01). The prognosis was worse in men, with higher in-hospital mortality (3 [4.4%] vs 1 [0.2%]; P < .01), longer intensive care stay (4.2 +/- 3.7 vs 3.2 +/- 3.2 days; P = .03) and a higher frequency of severe heart failure (22 [33.3%] vs 95 [20.3%]; P = .02). However, dynamic obstruction at the left-ventricular outflow tract occurred exclusively in women (39 [7.9%] vs 0 [0.0%]; P = .02). The incidence of functional mitral regurgitation was also higher in women (52 [10.6%] vs 2 [2.9%]; P = .04). CONCLUSIONS: Tako-tsubo syndrome shows wide differences by sex in terms of its incidence, presentation, and outcomes. Prognosis is worse in men. PMID- 29122514 TI - Chlamydia trachomatis and its interaction with the cellular retromer. AB - Chlamydia trachomatis is an important human pathogen. This obligate intracellular bacterium grows inside the eukaryotic cell in a membrane-bound compartment, the inclusion. Recent global approaches describe the interactions of C. trachomatis with its host cell and indicate the inclusion is an intracellular trafficking hub embedded into the cellular vesicular trafficking pathways recruiting subunits of the retromer protein complex of the host cell. Here we review these recent developments in deciphering Chlamydia-host cell interactions with emphasis on the role of the retromer complex. PMID- 29122515 TI - Xer1-independent mechanisms of Vpma phase variation in Mycoplasma agalactiae are triggered by Vpma-specific antibodies. AB - Despite their small genomes mycoplasmas maintain large multigene families devoted to surface antigenic variation. Although implicated as important factors for mycoplasma pathogenicity and persistence, the role of these antigenic switches in host immune evasion has never been unequivocally proven in these minimalist microbes. Mycoplasma agalactiae exhibits antigenic variation due to Xer1-mediated site-specific DNA inversions of vpma genes encoding abundant multiple surface lipoproteins. To evaluate the biological significance of Vpma oscillations the xer1 recombinase gene has been disrupted in earlier studies to abolish Vpma switching and to generate stable phase-locked mutants (PLMs) steadily expressing a single Vpma product. However, in previous animal infection studies, surprisingly these PLMs switched to new different Vpma phenotypes. The aim of the current study was to demonstrate the influence of anti-Vpma antibodies on change of Vpma expression in PLMs as well as on the wildtype strain. In in vitro assays it is shown that wild type M. agalactiae escapes the negative effects of Vpma specific antibodies by high-frequency Xer1-mediated switching to alternative Vpma phenoytpes. Even for Xer1-disrupted PLMs that stably expressed the same Vpma for several in vitro generations, the presence of the corresponding Vpma-specific antibody caused repression of the target Vpma and induction of new Vpma phenotypes by novel complex vpma rearrangements like intragenic deletions and gene chimeras. These Xer1-independent vpma recombinations correlated very well with similar PLM switches observed in vivo in an earlier independent study, clearly demonstrating that Vpma phase variation is necessary to express 'Vpma immune evasion proteins' in order to escape the immune response and to survive in the immunocompetent host. The data clearly demonstrate that although the Xer1 recombinase is the sole factor responsible for Vpma switching of wild type M. agalactiae in vitro, other alternative molecular switches operate in its absence under the selective pressure of the immune response. Furthermore, this evasion from the immune attack of the host involves complex vpma rearrangements, a causal relationship that was so far never demonstrated for M. agalactiae, thereby illustrating novel features of its regulation under immune pressure. The results are anticipated to have a direct impact on understanding the in vivo role of surface antigenic variation systems and the immune evasion tactics of other pathogenic mycoplasma species. PMID- 29122516 TI - Placenta-derived PLX-PAD mesenchymal-like stromal cells are efficacious in rescuing blood flow in hind limb ischemia mouse model by a dose- and site dependent mechanism of action. AB - BACKGROUND: In peripheral artery disease (PAD), blockage of the blood supply to the limbs, most frequently the legs, leads to impaired blood flow and tissue ischemia. Pluristem's PLX-PAD cells are placenta-derived mesenchymal stromal-like cells currently in clinical trials for the treatment of peripheral artery diseases. METHODS: In this work, the hind limb ischemia (HLI) mouse model was utilized to study the efficacy and mechanism of action of PLX-PAD cells. ELISA assays were performed to characterize and quantitate PLX-PAD secretions in vitro. RESULTS: PLX-PAD cells administered intramuscularly rescued blood flow to the lower limb after HLI induction in a dose-dependent manner. While rescue of blood flow was site-dependent, numerous administration regimes enabled rescue of blood flow, indicating a systemic effect mediated by PLX-PAD secretions. Live PLX-PAD cells were more efficacious than cell lysate in rescuing blood flow, indicating the importance of prolonged cytokine secretion for maximal blood flow recovery. In vitro studies showed a multifactorial secretion profile including numerous pro angiogenic proteins; these are likely involved in the PLX-PAD mechanism of action. DISCUSSION: Live PLX-PAD cells were efficacious in rescuing blood flow after the induction of HLI in the mouse model in a dose- and site-dependent manner. The fact that various administration routes of PLX-PAD rescued blood flow indicates that the mechanism of action likely involves one of systemic secretions which promote angiogenesis. Taken together, the data support the further clinical testing of PLX-PAD cells for PAD indications. PMID- 29122517 TI - The Guinea Worm: A Zoonotic Parasite of Dogs. PMID- 29122518 TI - Lipids and Pathogen Blocking by Wolbachia. AB - Mosquito-borne viruses are major human pathogens. Introducing Wolbachia into mosquitoes could reduce disease burdens because these bacteria block virus transmission. How Wolbachia does this is unclear, but new data show that modulation of host-cell lipids is critical. PMID- 29122519 TI - Traumatic brain injury: a priority for public health policy. PMID- 29122520 TI - The CENTER-TBI core study: The making-of. PMID- 29122521 TI - Traumatic brain injury: a global challenge. PMID- 29122522 TI - Subcutaneous IgG for chronic inflammatory demyelinating polyneuropathy. PMID- 29122525 TI - Iatrogenic corticosteroids induced Takotsubo cardiomyopathy. PMID- 29122526 TI - Extracorporeal myocardial shockwave therapy; a precious blast for refractory angina patients. AB - INTRODUCTION: Refractory Angina Pectoris (RAP) dramatically affects patients' life quality and medical costs. External Shockwave Myocardial Revascularization (ESMR) improves the cardiac blood flow thanks to its pro-angiogenetic action on ischaemic tissues. We hereby describe our experience of ESMR in RAP patients. MATERIALS AND METHODS: This is a retrospective study encompassing all patients referred to OSR for RAP treatment. Efficacy of ESMR was assessed considering the difference between pre and post therapy data in SAQ score and CCS, stress test performance, 24h ECG monitoring, NT-proBNP and echocardiographic measures. RESULTS: From a total of 97 patients with RAP, 19 patients underwent ESMR, whereas 4 were considered as control group. After the end of the treatment, ESWT group showed a significant improvement in CCS class (-1.32+/-0.58; p<0.001) and in each of the five variables of the SAQ score (p<0.05). Patients also improved their exercise duration (50,74+/-29.40 seconds; p<0,001) and double product (1340,53+/-1321,77; p<0,001) and reduced the number of daily ST segment depression (-1,16+/-1,01; p<0,01). Ejection Fraction (2,05+/-1,84%; p<0,01) and Cardiac Output (0,20+/-0,28L, p<0,01) improved too. No changes were documented in the control group. CONCLUSION: ESMR is an efficient therapy for refractory angina capable to improve both symptoms and instrumental tests. PMID- 29122523 TI - Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo controlled, phase 3 trial. AB - BACKGROUND: Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. METHODS: Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1:1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials.gov, number NCT01545076. FINDINGS: In this randomised, double blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. INTERPRETATION: This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP. FUNDING: CSL Behring. PMID- 29122527 TI - Implementation of enhanced recovery programs for bariatric surgery. Results from the Francophone large-scale database. AB - BACKGROUND: The feasibility, safety, and efficacy of programs for enhanced recovery after bariatric surgery (ERABS) are now well established. However, data concerning their large-scale implementation remain insufficient. OBJECTIVES: The objective of the present study was to review the multicenter implementation of ERABS SETTING: This retrospective analysis of a prospective database was conducted in 15 Groupe francophone de Rehabilitation Amelioree apres ChirurgiE centers from data from March 2014 to January 2017. METHODS: The Francophone working Group for Enhanced Recovery After Surgery (Groupe francophone de Rehabilitation Amelioree apres ChirurgiE) edited and released protocols of ERABS for its members. Compliance with ERABS, lengths of hospital stay, and postoperative morbidity were obtained from the Groupe francophone de Rehabilitation Amelioree apres ChirurgiE-audit database. RESULTS: In this study, 1667 patients were included. Procedures were sleeve gastrectomy (n = 1011), gastric bypass (n = 300), or mini-bypass (n = 356). Mean body mass index was 41.8 +/- 8.3 kg/m2. Global morbidity was 2.57%, and surgery-related morbidity was 1.67% (mostly anastomotic leakages and hemorrhage). Mean length of hospital stay was 2.4 +/- 3.6 days. Overall compliance was 79.6%. Among the 23 elements of the ERABS program, 14 were applied in>70% of instances, 6 in between 50% and 70%, and 3 in<50%. The elements least often applied were limb intermittent pneumatic compression during surgery (23.3%), multimodal analgesia (49.5%), and optimal perioperative fluid management (43.8%). CONCLUSION: This study shows that even if the overall compliance was good, the large-scale implementation of ERABS can still be improved, as several elements remain insufficiently applied. This finding highlights the importance of thorough, continuous training in addition to the need for repeated audits by centers involved in ERABS programs. PMID- 29122528 TI - Safety of open ventral hernia repair in high-risk patients with metabolic syndrome: a multi-institutional analysis of 39,118 cases. AB - BACKGROUND: Metabolic syndrome (MetS) entails the simultaneous presence of a constellation of dangerous risk factors including obesity, diabetes, hypertension, and dyslipidemia. The prevalence of MetS in Western society continues to rise and implies an elevated risk for surgical complications and/or poor surgical outcomes within the affected population. OBJECTIVE: To assess the risks and outcomes of multi-morbid patients with MetS undergoing open ventral hernia repair. SETTING: Multi-institutional case-control study in the United States. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was sampled for patients undergoing initial open ventral hernia repair from 2012 through 2014 and then stratified into 2 cohorts based on the presence or absence of MetS. Statistical analyses were performed to evaluate preoperative co-morbidities, intraoperative details, and postoperative morbidity and mortality to identify risk factors for adverse outcomes. RESULTS: Mean age (61.0 versus 56.0 yr, P<.001), body mass index (39.2 versus 31.1, P<.001), and prevalence of co-morbidities of multiple organ systems were significantly higher (P<.001) in the MetS cohort compared to control. Patients with MetS received higher American Society of Anesthesiologists classifications (81.0% versus 43.1% class 3 or higher, P<.001), were more likely to require operation as emergency cases (11.4% versus 7.2%, P<.001), required longer operative times (103 versus 87 min, P<.001), had longer hospitalizations (3.5 versus 2.4 d, P<.001), and had more contaminated wounds (15.9% versus 12.0% class 2 or higher, P<.001). Overall, they had more medical (7.5% versus 4.2%, P<.001), and surgical complications (9.7% versus 5.4%, P<.001), experienced more readmissions (8.3% versus 5.7%, P<.001) and reoperations (3.4% versus 2.5%, P<.001), and were at higher risk for eventual death (.8% versus .5%, P=.008). CONCLUSIONS: The presence of MetS is related to a multitude of unfavorable outcomes and increased mortality after open ventral hernia repair compared with a non-MetS control group. MetS is a useful marker for high operative risk in a population that is generally prone to obesity and its associated diseases. PMID- 29122529 TI - ? AB - Mucormycosis is a rare life-threatening opportunistic infection caused by fungi of the order Mucorales. We report a case of rhinocerebral mucormycosis caused by Rhizopus arrhizus var. tonkinensis, the first formally reported case in the literature. Early diagnosis, reversal of predisposing factors, surgical debridement and prompt administration of antifungal therapy are critical for good outcome. PMID- 29122530 TI - [Study of the infectivity of Candida on peripheral vascular catheters collected from the University Hospital of Tlemcen]. AB - Yeasts can adhere to medical implants and cause infections responsible for high morbidity and mortality among hospitalized patients. The objective of this study is to investigate the infectivity on peripheral vascular catheters collected from general surgery and cardiology in University Hospital of Tlemcen. The results showed that from 29 samples altered by yeast, 35 Candida sp. strains were isolated. However, Candida albicans is the most isolated species in an infectious context. Risk factors that accompanied the infections are the duration of implantation, male gender, and bacterial presence. PMID- 29122531 TI - UPLC-PDA-ESI-qTOF-MS profiling and potent anti-HSV-II activity of Eucalyptus sideroxylon leaves. AB - Eucalyptus is one of the most important and highly exploited genus in family Myrtaceae. An UPLC/PDA/ESI-qTOF-MS method was adopted to identify Eucalyptus sideroxylon Cunn. ex Woolls leaves phytoconstituents. Cytotoxicity of E. sideroxylon leaves phloroglucinol-rich extract (PGRE) on VERO cells was determined. The antiviral effect of PGRE against hepatitis A (HAV), herpes simplex type 1 (HSV-I), herpes simplex type 2 (HSV-II), coxsackie (CoxB4), and adenoviruses was in vitro evaluated using MTT assay (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyl tetrazolium bromide). UPLC-MS analysis allowed the identification of 70 metabolites including: 26 triterpenes, 13 phloroglucinols, 8 fatty acids, 5 flavonoids, 5 oleuropeic acid glucosides, 3 gallic acid derivatives, and 10 miscellaneous. Twenty four metabolites identified in the leaves of E. sideroxylon and four in the genus Eucalyptus are reported herein for the first time. PGRE was found to be non-cytotoxic; the concentration that reduced the cell viability by 50% (CC50) was 0.808mg/mL. Maximum non-toxic concentration (MNTC) of PGRE on Vero cells was 0.312mg/mL. The best antiviral activity was observed against HSV-II. Its mechanism was through decreasing the viral replication (IC50 189.36MUg/mL, 87.65% inhibition) and attachment on Vero cells (IC50 199.34MUg/mL, 83.13% inhibition) rather than virucidal effect (IC50 293.1MUg/mL, 50.68% inhibition). This study provides a complete map for E. sideroxylon leaves composition. It also suggests the plant as a source of new antiviral agents. PMID- 29122533 TI - [Radiological outcomes of unstable thoraco-lumbar fractures without neurological deficit treated through percutaneous surgery]. AB - OBJECTIVE: To analyse the radiological outcomes in the long term of unstable thoracic and lumbar fractures treated through percutaneous surgery. MATERIAL AND METHODS: Retrospective review of a series of patients with unstable thoracic and lumbar fractures treated with percutaneous minimally invasive surgery between 2010 and 2015 in three different hospital centres. Six radiological parameters were measured annually during a 2-year period: Fracture angle, kyphotic deformity, sagittal index, percentage of compression, degree of displacement and deformation angle. RESULTS: A total of 37 patients were included with a median age of 41.3 years and a median follow-up period of 2.2 years. Fracture angle rose from 14.8 degrees to 17.1 degrees (increase of 15.54%), kyphotic deformity from 15.9 degrees to 17.7 degrees (increase of 11.32%), sagittal index from 10.1 to 12.3 (increase of 21.78%), percentage of compression from 32.7% to 36.8% (increase of 12.53%), degree of displacement from 3.0mm to 4.4mm (increase of 50%) and deformation angle from 20.7 degrees to 22.9 degrees (increase of 10.62%). CONCLUSIONS: All the radiological parameters studied lost correction throughout the 24 months of follow-up; the degree of displacement and the sagittal index were the most marked. Nevertheless, the greatest loss of correction occurred in the first postoperative year, the parameters then stabilised over the 24 months of follow up. We routinely recommend the measurement of all previous parameters for the follow up of unstable thoracic and lumbar fractures treated through percutaneous surgery. PMID- 29122524 TI - Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. PMID- 29122534 TI - Influence of antithrombotic agents on recurrence rate and clinical outcome in patients operated for chronic subdural hematoma. AB - INTRODUCTION: Chronic subdural hematoma (cSDH) is a common pathology encountered in neurosurgical practice, especially in elderly patients, who frequently require antithrombotic agents. The aim of this study was to investigate the influence of antithrombotic agents on recurrence rates and clinical outcomes in patients operated for cSDH. METHODS: A cohort of patients operated for cSDH at one center during a 5 years period was analyzed retrospectively. Presenting symptoms, coagulation testing, history of antithrombotic agents and comorbidities were obtained from the patient charts. The standard neurosurgical procedure was a single burr hole under local anesthesia with insertion of a subdural drainage. Questionnaires and telephone interviews were used to assess the clinical outcome using the modified Rankin Scale (mRS). Good outcome was defined as mRS 0 to 3 and poor outcome as mRS 4 to 6. RESULTS: 201 patients with cSDH underwent initial surgical treatment and were enrolled in the study. The median follow-up was 81 weeks. 41 patients (20.4%) were on antiplatelet drug and 43 (21.4%) were on phenprocoumon. A recurrent hematoma required surgery in 37 patients (18.4%). A poor outcome was seen in 36 patients (17.9%). Each of older age and administration of phenprocoumon at admission was an independent risk factor predictive of poor outcome, (p=0.001 and p=0.031, respectively)) Administration of antithrombotic agents had no impact on hematoma recurrence. CONCLUSION: Administration of phenprocoumon and older age might increase the risk of poor outcome in patients with cSDH. Neither the administration of phenprocoumon nor antiplatelet drug influenced the recurrence rate of subdural hematoma in our patient cohort. PMID- 29122532 TI - Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium. AB - Effect of pathological prolongation of action potential duration on the alpha adrenoceptor-mediated negative inotropy was studied in streptozotocin-induced diabetic mice myocardium. In streptozotocin-treated mouse ventricular myocardium, which had longer duration of action potential than that in control mice, the negative inotropic response induced by phenylephrine was smaller than that in control mice. 4-Aminopyridine prolonged the action potential duration and decreased the negative inotropy in control mice. Cromakalim shortened the action potential duration and increased the negative inotropy in streptozotocin-treated mice. These results suggest that the reduced alpha-adrenoceptor-mediated inotropy in the diabetic mouse myocardium is partly due to its prolonged action potential. PMID- 29122535 TI - Limited output transcranial electrical stimulation (LOTES-2017): Engineering principles, regulatory statutes, and industry standards for wellness, over-the counter, or prescription devices with low risk. AB - We present device standards for low-power non-invasive electrical brain stimulation devices classified as limited output transcranial electrical stimulation (tES). Emerging applications of limited output tES to modulate brain function span techniques to stimulate brain or nerve structures, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial pulsed current stimulation (tPCS), have engendered discussion on how access to technology should be regulated. In regards to legal regulations and manufacturing standards for comparable technologies, a comprehensive framework already exists, including quality systems (QS), risk management, and (inter)national electrotechnical standards (IEC). In Part 1, relevant statutes are described for medical and wellness application. While agencies overseeing medical devices have broad jurisdiction, enforcement typically focuses on those devices with medical claims or posing significant risk. Consumer protections regarding responsible marketing and manufacture apply regardless. In Part 2 of this paper, we classify the electrical output performance of devices cleared by the United States Food and Drug Administration (FDA) including over-the-counter (OTC) and prescription electrostimulation devices, devices available for therapeutic or cosmetic purposes, and devices indicated for stimulation of the body or head. Examples include iontophoresis devices, powered muscle stimulators (PMS), cranial electrotherapy stimulation (CES), and transcutaneous electrical nerve stimulation (TENS) devices. Spanning over 13 FDA product codes, more than 1200 electrical stimulators have been cleared for marketing since 1977. The output characteristics of conventional tDCS, tACS, and tPCS techniques are well below those of most FDA cleared devices, including devices that are available OTC and those intended for stimulation on the head. This engineering analysis demonstrates that with regard to output performance and standing regulation, the availability of tDCS, tACS, or tPCS to the public would not introduce risk, provided such devices are responsibly manufactured and legally marketed. In Part 3, we develop voluntary manufacturer guidance for limited output tES that is aligned with current regulatory standards. Based on established medical engineering and scientific principles, we outline a robust and transparent technical framework for ensuring limited output tES devices are designed to minimize risks, while also supporting access and innovation. Alongside applicable medical and government activities, this voluntary industry standard (LOTES-2017) further serves an important role in supporting informed decisions by the public. PMID- 29122536 TI - A Systematic Review of Treatments of Relapsed/Refractory Mantle Cell Lymphoma. AB - A systematic review was conducted to evaluate the clinical effectiveness and safety of treatments for patients with relapsed/refractory mantle cell lymphoma (MCL) unsuitable for intensive treatment. The criteria for inclusion of the trials were established before the review. A search of Medline, Embase, and the Cochrane library databases was conducted to identify phase II or III randomized controlled trials (RCTs), reported from January 1, 1994 to May 29, 2016. Relevant conference abstracts, citation lists from the included articles, published guidelines, and on-going clinical trial databases were also searched. Studies were included if they had evaluated any single agent or combination of treatments for adult patients with relapsed/refractory MCL who had received >= 1 previous line of therapy. Seven RCTs were identified. Only 1 treatment appeared in > 1 trial; therefore, the results from each trial could not be quantitatively pooled for meta-analysis. The lack of common comparators, differences in baseline characteristics and inclusion and exclusion criteria, and variances in the response criteria used to measure outcomes made comparison of the results difficult. Although the direction of effect for progression-free survival (PFS) and overall survival (OS) was in favor of the experimental drug in all trials, the difference in PFS was statistically significant in 5 and OS in 2. None showed statistical significance for both. A noticeable lack of RCTs evaluating treatments for patients with relapsed/refractory MCL made meaningful comparisons of effectiveness across trials rather difficult. This trend continues, because all, bar 1, of the 85 ongoing trials in this area are single-arm studies. RCTs are required to enable better evaluation of the optimal treatment regimen for this group of patients. PMID- 29122537 TI - A coil placement technique to treat intracranial aneurysm with incorporated artery. AB - BACKGROUND: Endovascular coil embolization is an accepted treatment option for intracranial aneurysms. However, the coiling of aneurysms with an incorporated artery (IA) poses a high risk of IA occlusion. Here we report our experience of endovascular coil placement using a technique that avoids IA occlusion in aneurysms with IAs. METHODS: Over a 6-year period, 185 patients harboring 206 intracranial aneurysms underwent endosaccular coiling. Forty-two of these patients with 45 aneurysms were treated by coil placement to avoid IAs occlusion. We assessed the anatomy of the aneurysms and IAs, technical feasibility of the procedure, and degree of aneurysm occlusion. Clinical and angiographic outcomes were assessed as well. RESULTS: Aneurysms were located in the supra-clinoid intracranial internal carotid artery (n = 24), anterior cerebral artery (n = 6), middle cerebral artery (n = 7), and vertebrobasilar artery (n = 8). The IA was at the aneurysm neck in 34 patients, body in 10, and dome in 1. Immediate post coiling angiogram showed preservation of blood flow through the IA in all aneurysms. Coil compaction with aneurysmal regrowth was found in 7 of 36 patients having follow-up conventional angiography. One patient had an IA territory infarction after embolization. All 42 patients were followed up (mean: 21 months) and showed no re-bleeding. CONCLUSION: This technique is effective and safe in managing intracranial aneurysms with IAs. Although aneurysmal recurrence may occur in some aneurysms because of insufficient coiling, this technique is simpler to perform and requires less skill than other techniques. It can be an alternative option for treating some selected intracranial aneurysms with IAs. PMID- 29122538 TI - Mixed simulation course increases participants' positive stress coping abilities. AB - BACKGROUND: Lack of health professional awareness of interprofessional collaborative practice (IPCP) often results in stress and conflicts between team members in the medical system. Our study aimed to compare the effectiveness of mixed simulation-interprofessional education (IPE) courses to enhance coping strategies for IPCP-associated stress. METHODS: Participants (n = 54) from the disciplines of physicians (n = 12), nurses (n = 28) and pharmacists (n = 14) were enrolled. Over the course of the study period, all participants were asked to complete pre-course (T1), post-course (T2) and end-of-study (T3) questionnaires for self-assessment of perceived stress scale (PSS), stress coping preference scale (SCPS), and IPCP proficiency. RESULTS: Basically, physicians felt less IPCP associated stress than did nurses and pharmacists. For physicians, nurses and pharmacists, the mean post-course (T2) PSS scores were significantly lower than pre-course (T1) PSS scores, which indicated decreased IPCP-associated stress after mixed simulation-IPE courses. In comparison with physicians, the greater difference (T2-T1 scores) in the PSS and positive coping SCPS subscales scores were noted among nurses and pharmacists. For nurses and pharmacists, the further improvements in stress coping abilities (PSS scale and positive SCPS subscale) were noted at the end-of-study self-assessment by comparison of post-course scores with end-of-study scores. For IPCP proficiency, all participants gave more positive responses to the specific questions in the end-of-study questionnaires. CONCLUSION: Our study supports the use of mixed simulation-IPE courses as part of continuing education to enhance positive stress coping strategies. PMID- 29122539 TI - A new polyacetylene glucoside from Vernonia scorpioides and its potential antihyperglycemic effect. AB - Natural polyacetylene compounds have been found mainly in seven botanical families and remain underexplored and understudied, despite its inherent chemical and biological reactivity, due to the presence of conjugated triple bonds. Some polyacetylene glucosides have been found to stimulate glucose uptake in C5BL/ks db/db obese diabetic mice, and since polyacetylene glucosides previously found in Vernonia scorpioides showed little to none cytotoxicity, in this study the antihyperglycemic potential of a new V. scorpioides polyacetylene glucoside has been accessed in order to shine a new light on the biological activity of this unique scaffold. For the isolation of this new compound an optimized method of Centrifugal Partition Chromatography (CPC) is for the first time described together with its X-ray data. The results demonstrate that 3,4-dihydrovernoniyne 4-O-beta-glucoside has significant effect on glycaemia at low dose 0.5 mg/kg, and pointing that the anti-hyperglycemic effect may be due in part to the inhibition of intestinal disaccharidases. PMID- 29122540 TI - Bone abnormalities in young male rats with iron intervention and possible mechanisms. AB - Studies suggest iron overload may cause bone lesion. The mechanisms are not well understood at present. Therefore, this study was designed to observe the effect of iron overload on bone metabolism in young male rats and explore its possible mechanism. Eighteen SD rats were randomly assigned to iron-loading and control groups. Fe-dextran (250 mg/kg of body weight) was injected intraperitoneally into the rats from iron-loading group, every other day for 5 weeks. The bone mineral density (BMD) of femur, length and diameter of tibia, and histological microstructure of femur and vertebra was determined. The concentrations of serum superoxide dismutase (SOD) and malondialdehyde (MDA) were assayed by ELISA. The mRNA expression of cytokines was detected by real-time PCR. The results showed an obvious bone abnormality after iron intervention, such as significantly decreased content of Ca in bone tissue, shorter length of tibia, lower BMD of femur, and obvious lesion of bone microarchitecture. At the same time, with iron intervention, the concentrations of serum SOD decreased but MDA increased; the mRNA expression of osteocalcin and osteoprotegerin (OPG) decreased, whereas that of receptor activator of nuclear factor kappa B ligand (RANKL) and IL-6 increased significantly. In summary, iron overload indeed give rise to the abnormal changes of bone metabolism independently. Increased bone resorption, and probably decreased bone formation are involved in the process of bone lesion caused by iron overload. Oxidative stress and RANKL participate in the pathological process, and IL-6 may play a supporting role. PMID- 29122541 TI - The Simultaneous measurement of serum testosterone and 5alpha-dihydrotestosterone by gas chromatography-mass spectrometry (GC-MS). AB - BACKGROUND: Simultaneous measurement of testosterone (T) and 5alpha dihydrotestosterone (DHT) is important for diagnosing androgen deficiency states and hyperandrogenism in males and females, respectively. However, immunoassays used for T and DHT determination suffer from inadequate specificity and sensitivity, while tandem mass spectrometry is expensive and demanding in use. METHODS AND RESULTS: We developed a selective gas chromatography-mass spectrometry (GC-MS) method for parallel T and DHT measurement. The assay showed a linear response up to 46.5nmol/L, intra- and interassay imprecision and inaccuracy <15% and recoveries in spiked samples >90% for both analytes. The limit of quantitation was 0.117nmol/L for T and 0.168nmol/L for DHT. Comparison with immunoassays revealed good agreement for T in males, but a bias in favour of immunoassays at low concentrations for T in females and DHT in both sexes. We established reference ranges for T and DHT and suggest interval partitioning for T according to age in men and menstrual cycle in women. Assay validation in a clinical setting suggests that measuring DHT or T/DHT ratio may help identify patients with polycystic ovary syndrome. CONCLUSION: We developed a selective, simple and inexpensive GC-MS method for parallel measurement of T and DHT with potential use in the clinical laboratory. PMID- 29122542 TI - Twin-twin transfusion syndrome - What we have learned from clinical trials. AB - Monochorionic twin pregnancies are at increased risk for adverse outcome compared to dichorionic twin pregnancies and singletons. Monochorionic-specific complications include twin-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence, single intrauterine fetal demise and its consequences on the co-twin, and selective intrauterine growth restriction. Whereas the natural history of monochorionic-specific complications carries a high risk of fetal death or severe neurologic disability, a framework now exists, based on well designed clinical trials, for optimal treatment of these entities. Fetoscopic selective laser coagulation of anastomotic vessels on the chorionic plate has been clearly demonstrated to improve survival and neurologic outcomes for Quintero stage >=2 TTTS. However, many challenges remain unsolved, the most important of which is preterm premature rupture of membranes. Further improvement in the outcomes of monochorionic pregnancies will require improvements in the rate of premature delivery, and improved diagnosis and treatment strategies for early and late onset TTTS. PMID- 29122543 TI - Dense, Mysterious, Small Balls in the Abdomen. PMID- 29122544 TI - Population Health Management for Inflammatory Bowel Disease. AB - Inflammatory bowel diseases (IBDs) are chronic and impose significant, multidimensional burdens on patients and health care systems. The increasing prevalence of IBD will only worsen this problem globally-population health management (PHM) strategies are needed to increase quality of care and population health outcomes while reducing health care costs. We discuss the key components of PHM in IBD. Effective implementation of PHM strategies requires accurate identification of at-risk patients and key areas of variability in care. Improving outcomes of the at-risk population requires implementation of a multicomponent chronic care model designed to shift delivery of ambulatory care from acute, episodic, and reactive encounters, to proactive, planned, long-term care. This is achieved through team care of an activated patient with the help of remote monitoring, clinical information systems, and integrated decision support, with accompanying changes in delivery systems. Performance measurement is integral to any PHM strategy. This involves developing and implementing meaningful metrics of different phases of quality of IBD care and measuring them efficiently using modern clinical information systems. Such an integrated framework of PHM in IBD will facilitate the delivery of high-value care to patients. PMID- 29122545 TI - Portal Hypertension and Unexplained Diarrhea in an 80-Year-Old Man. PMID- 29122546 TI - No Increase in Risk of Acute Myocardial Infarction in Privately Insured Adults Prescribed Proton Pump Inhibitors vs Histamine-2 Receptor Antagonists (2002 2014). AB - BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly used medications. Recent studies reported an increased risk of acute myocardial infarction (MI) in PPI users vs non-users. We evaluated MI risk associated with PPIs compared with histamine-2 receptor antagonists (H2RAs) in privately insured adults in the United States. METHODS: Using administrative claims from commercial and Medicare Supplemental plans (2001-2014), we compared risk of MI in patients who started a new prescription for PPIs vs H2RAs. Enrollees were followed from their first prescription until MI, medication discontinuation, plan disenrollment, or December 31, 2014. MI was defined using hospital diagnosis codes. Risk differences (RD), risk ratios, and 95% confidence intervals (CIs) were estimated using Kaplan-Meier methods at 3, 12, and 36 months after treatment initiation. Standardized morbidity ratio weights were used to control measured confounding. Analyses were stratified by plan type (commercial vs Medicare Supplemental). RESULTS: We identified more than 5 million new users of prescription PPIs and H2RAs. Median follow-up time was 60 days for patients with commercial insurance and 96 days in patients with Medicare Supplemental insurance. The 12-month weighted risk of MI was low overall (approximately 2 cases per 1000 among patients in commercial plans; 8 per 1000 among patients in Medicare Supplemental plans). In the RD analysis, we found no significant differences in MI risk between patients who started PPIs vs H2RAs for the first 12 months, either in the commercial population (weighted RD per 1000, -0.08; 95% CI, -0.51 to 0.36) or the Medicare Supplemental population (weighted RD per 1000, -0.45; 95% CI, -1.53 to 0.58). CONCLUSION: In an analysis of administrative claims from commercial and Medicare Supplemental plans, we found no evidence that prescription PPIs increase risk of MI compared with prescription H2RAs. Physicians and patients should not avoid starting a PPI because of concerns related to MI risk. PMID- 29122547 TI - Low-Dose Aspirin Use Does Not Increase Survival in 2 Independent Population-Based Cohorts of Patients With Esophageal or Gastric Cancer. AB - BACKGROUND & AIMS: Preclinical studies have shown aspirin to have anticancer properties and epidemiologic studies have associated aspirin use with longer survival times of patients with cancer. We studied 2 large cohorts to determine the association between aspirin use and cancer-specific mortality in patients with esophageal or gastric cancer. METHODS: We performed a population-based study using cohorts of patients newly diagnosed with esophageal or gastric cancer, identified from cancer registries in England from 1998 through 2012 and the Scottish Cancer Registry from 2009 through 2012. Low-dose aspirin prescriptions were identified from linkages to the United Kingdom Clinical Research Practice Datalink in England and the Prescribing Information System in Scotland. Deaths were identified from linkage to national mortality records, with follow-up until September 2015 in England and January 2015 in Scotland. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by low-dose aspirin use after adjusting for potential confounders. Meta-analysis was used to pool results across the 2 cohorts. RESULTS: The combined English and Scottish cohorts contained 4654 patients with esophageal cancer and 3833 patients with gastric cancer, including 3240 and 2392 cancer-specific deaths, respectively. The proportions surviving 1 year, based on cancer-specific mortality, were similar in aspirin users vs non-users after diagnosis with esophageal cancer (48% vs 50% in England and 49% vs 46% in Scotland, respectively) or gastric cancer (58% vs 57% in England and 59% vs 55% in Scotland, respectively). There was no association between postdiagnosis use of low-dose aspirin and cancer-specific mortality among patients with esophageal cancer (pooled adjusted HR, 0.98; 95% CI, 0.89-1.09) or gastric cancer (pooled adjusted HR, 0.96; 95% CI, 0.85-1.08). Long-term aspirin use was not associated with cancer-specific mortality after diagnosis of esophageal cancer (pooled adjusted HR, 1.03; 95% CI, 0.85-1.25) or gastric cancer (pooled adjusted HR, 1.06; 95% CI, 0.85-1.32). CONCLUSIONS: In analyses of 2 large independent cohorts in the United Kingdom, low-dose aspirin usage was not associated with increased survival of patients diagnosed with esophageal or gastric cancer. PMID- 29122548 TI - Experimental models for evaluating non-genomic estrogen signaling. AB - Non-genomic effects of estrogen receptor alpha (ERalpha) signaling have been described for decades. However, the mechanisms and physiological processes resulting solely from non-genomic signaling are poorly understood. Challenges in studying these effects arise from the strongly nucleophilic tendencies of estrogen receptor, and many approaches to excluding ERalpha from the nucleus have been explored over the years. In this review, we discuss past strategies for studying ERalpha's non-genomic action and current models, specifically H2NES ERalpha, first described by Burns et al. (2011). In vitro and preliminary in vivo data from H2NES ERalpha and H2NES mice suggest a promising avenue for pinpointing specific non-genomic ERalpha action. PMID- 29122549 TI - Chronic low-dose pro-oxidant treatment stimulates transcriptional activity of telomeric retroelements and increases telomere length in Drosophila. AB - It has been proposed that oxidative stress, elicited by high levels of reactive oxygen species, accelerates telomere shortening by erosion of telomeric DNA repeats. While most eukaryotes counteract telomere shortening by telomerase driven addition of these repeats, telomeric loss in Drosophila is compensated by retrotransposition of the telomeric retroelements HeT-A, TART and TAHRE to chromosome ends. In this study we tested the effect of chronic exposure of flies to non-/sub-lethal doses of paraquat, which is a redox cycling compound widely used to induce oxidative stress in various experimental paradigms including telomere length analyses. Indeed, chronic paraquat exposure for five generations resulted in elevated transcriptional activity of both telomeric and non-telomeric transposable elements, and extended telomeric length in the tested fly lines. We propose that low oxidative stress leads to increased telomere length within Drosophila populations. For a mechanistic understanding of the observed phenomenon we discuss two scenarios: adaption, acting through a direct stimulation of telomere extension, or positive selection favoring individuals with longer telomeres within the population. PMID- 29122550 TI - Supply and demand: How does variation in atmospheric oxygen during development affect insect tracheal and mitochondrial networks? AB - Atmospheric oxygen is one of the most important atmospheric component for all terrestrial organisms. Variation in atmospheric oxygen has wide ranging effects on animal physiology, development, and evolution. This variation in oxygen has the potential to affect both respiratory systems (the supply side) and mitochondrial networks (the demand side) in animals. Insect respiratory systems supplying oxygen to tissues in the gas phase through blind ended tracheal systems are particularly susceptible to this variation. While the large conducting tracheae have previously been shown to respond developmentally to changes in rearing oxygen, the effect of oxygen on the tracheolar network has been relatively unexplored, especially in adult insects. Similarly, mitochondrial networks that meet energy demand in insects and other animals are dynamic and their enzyme activities have been shown to vary in the presence of oxygen. These two systems together should be under selective pressure to meet the aerobic metabolic requirements of insects. To test this hypothesis, we reared Mito-YFP Drosophila under three different oxygen concentrations hypoxia (12%), normoxia (21%), and hyperoxia (31%) and imaged their tracheolar and mitochondrial networks within their flight muscle using confocal microscopy. In terms of oxygen supply, hypoxia increased mean (mid-length) tracheolar diameters, tracheolar tip diameters, the number of tracheoles per main branch and affected tracheal branching patterns, while the opposite was observed in hyperoxia. In terms of oxygen demand, hypoxia increased mitochondrial investment and mitochondrial to tracheolar volume ratios; while the opposite was observed in hyperoxia. Generally, hypoxia had a stronger effect on both systems than hyperoxia. These results show that insects are capable of developmentally changing investment in both their supply and demand networks to increase overall fitness. PMID- 29122552 TI - Nephroprotection through the Akt/eNOS pathway by centrally administered erythropoietin in a rat model of fixed-volume hemorrhage. AB - AIMS: This study was designed to investigate the protective effects of centrally administered erythropoietin (EPO) on brain oxidative stress and inflammatory markers to protect the kidneys during hemorrhagic shock (HS). MAIN METHODS: Animals were assigned into three groups (n=6). Sham rats were subjected to cannulation of femoral artery and vein as well as stereotaxic surgery. In HS group, 50% of total blood volume was withdrawn and resuscitation was started 2h later. In EPO group, stereotaxic surgery in lateral ventricle was performed one week before induction of HS for administration of EPO (2IU) just before resuscitation. Plasma samples, kidney and brain tissues were allocated after a further 3h in all animals. KEY FINDINGS: There was a significant increase in survival rate in the EPO group (69.3%) compared to the HS group (35.7%). Brain EPO administration significantly attenuated the rises in BUN, plasma Cr and NGAL, brain and renal MDA content and also increased SOD activity in the kidney and brain compared to the HS group. Brain, plasma and kidney TNF-alpha and IL-6 levels were significantly reduced by EPO compared to HS group. EPO increased the phosphorylation of Akt on Ser473 and eNOS mRNA expression in the kidney tissue compared to the HS group. SIGNIFICANCE: In conclusion, centrally administered EPO reduced pro-inflammatory and oxidative stress indices in the kidney and reduced apoptosis by activation of the Akt/eNOS signaling pathway. Hence, it can be hypothesized that EPO may play a major role in the central regulation of renal system as a neuromodulator. PMID- 29122551 TI - CRISPR-mediated deletion of the PECAM-1 cytoplasmic domain increases receptor lateral mobility and strengthens endothelial cell junctional integrity. AB - AIMS: PECAM-1 is an abundant endothelial cell surface receptor that becomes highly enriched at endothelial cell-cell junctions, where it functions to mediate leukocyte transendothelial migration, sense changes in shear and flow, and maintain the vascular permeability barrier. Homophilic interactions mediated by the PECAM-1 extracellular domain are known to be required for PECAM-1 to perform these functions; however, much less is understood about the role of its cytoplasmic domain in these processes. MAIN METHODS: CRISPR/Cas9 gene editing technology was employed to generate human endothelial cell lines that either lack PECAM-1 entirely, or express mutated PECAM-1 missing the majority of its cytoplasmic domain (?CD-PECAM-1). The endothelial barrier function was evaluated by Electric Cell-substrate Impedance Sensing, and molecular mobility was assessed by fluorescence recovery after photobleaching. KEY FINDINGS: We found that ?CD PECAM-1 concentrates normally at endothelial cell junctions, but has the unexpected property of conferring increased baseline barrier resistance, as well as a more rapid rate of recovery of vascular integrity following thrombin-induced disruption of the endothelial barrier. Fluorescence recovery after photobleaching analysis revealed that ?CD-PECAM-1 exhibits increased mobility within the plane of the plasma membrane, thus allowing it to redistribute more rapidly back to endothelial cell-cell borders to reform the vascular permeability barrier. SIGNIFICANCE: The PECAM-1 cytoplasmic domain plays a novel role in regulating the rate and extent of vascular permeability following thrombotic or inflammatory challenge. PMID- 29122553 TI - Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. AB - AIM: In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D galactose (D-gal) induced accelerated and natural aging models of rat. MAIN METHODS: Fisetin was supplemented (15mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500mg/kg b.w subcutaneously) and naturally aged rats for 6weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane bound ion transporter activities in brain tissues. KEY FINDINGS: Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1beta and TNF-alpha) and Sirt-2 genes respectively in aging brain. SIGNIFICANCE: The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain. PMID- 29122554 TI - Physiological roles of ASK family members in innate immunity and their involvement in pathogenesis of immune diseases. AB - Cells are always exposed to various types of stress, including physical, chemical, and biological stresses, and are required to sense immediately and respond appropriately to these stresses. The apoptosis signal-regulating kinase (ASK) family members are stress-responsive kinases, which are activated by not only physicochemical stresses, such as oxidative stress, osmotic pressure, calcium overload, and anti-cancer drugs, but also biological stresses, such as inflammatory cytokines and pathogen infection. Recently, we found that ASK1, a member of ASK family, is activated by bacterial components, such as lipopolysaccharide, in a reactive oxygen species (ROS)-dependent manner, demonstrating that ASK1 is required for the innate immune response and plays a critical role in the regulation of innate immune signaling. Moreover, our findings indicate that ROS are common mediators in physicochemical stress signaling, including redox signaling, and biological stress signaling, including innate immune signaling. This review especially focuses on the roles of ASK family in innate immunity and provides recent progress in our knowledge on activation mechanisms and physiological functions of ASK family kinases in innate immune responses. PMID- 29122555 TI - Diffuse recurrent cutaneous melanoma of the scalp and neck successfully treated with volumetric modulated arc therapy and concurrent ipilimumab. PMID- 29122556 TI - Effect of imaging frequency on PTV margins and geographical miss during image guided radiation therapy for prostate cancer. AB - BACKGROUND: The relationship between frequency of imaging during image guided radiation therapy (IGRT) and planning target volume (PTV) margin remains unclear. This issue is of practical significance given resource and time intensive nature of IGRT. The purpose of this study was to evaluate PTV margins with predefined and commonly used less-than-daily IGRT schedules using data obtained from patients treated with daily IGRT for prostate cancer. METHODS AND MATERIALS: Daily setup error and 3-dimensional daily alignment data for a total of 108 consecutive patients with prostate cancer treated with 2700 fractions of daily image guidance on tomotherapy were retrospectively analyzed. Five IGRT scenarios were simulated: alternate day, twice weekly, once weekly, first 3 days only, and no image guidance. The daily alignment data were modeled to simulate the 5 predefined scenarios by applying appropriate corrections to determine the PTV margin for each image guidance scenario. The data were also analyzed to predict possible geographical miss in any direction using 2 frequently used PTV margins of 7 and 5 mm for all the scenarios. RESULTS: Decreasing the frequency of image guidance increased the mean systematic error and the standard deviation of the systematic error. With decreased image guidance frequency, an increase in PTV margins was required to achieve adequate coverage of the clinical target volume. With reduction in image guidance from 50% to 12%, a gradual increase in percentage of fractions with predicted geographical miss using an isotropic PTV margin of 7 or 5 mm was seen. With every 15% decrease in imaging, a 5% increased risk of geographical miss was estimated. CONCLUSIONS: The use of less-than-daily IGRT requires larger PTV margins for patients treated with intensity modulated radiation therapy for prostate cancer. With every 15% reduction, a 5% increased risk of geographical miss was estimated. PMID- 29122557 TI - [Maternal deaths due to anesthesia complications. Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Over the period 2010-2012, maternal mortality linked to anesthesia accounted for 2% of maternal deaths, with no significant change since 2007-2009. Of the 7 maternal deaths analyzed by the expert committee, anesthetic complications were in 5 cases the main cause of death: 4 attributed to direct causes related to anesthetic procedures during childbirth and 1 to indirect cause in connection with an ENT complication during pregnancy. The anesthetic causes of maternal mortality were for the 2010-2012 period: cardiac arrest under spinal anesthesia during caesarean section, local anesthetic intoxication with unsuccessful resuscitation after cardiac arrest without intralipid administration, acute respiratory distress syndrome in the postpartum period after pulmonary aspiration during caesarean section, cardiac arrest during caesarean section under general anesthesia in a context of non-Hodgkin lymphoma with mediastinal syndrome, unsuccessful endotracheal intubation in a context of cellulitis of the oral cavity floor. In two other cases, anesthetic complications were identified as associated causes of death, the primary cause being intracerebral hemorrhage stroke and pulmonary hypertension. In most of the cases analyzed over the period 2010-2012, anesthesia and resuscitation have been involved in the occurrence of maternal deaths, mainly through strategic errors in the management of patients with severe pathology before delivery, as well as through insufficient cardiac resuscitation duration after cardiac arrest. PMID- 29122558 TI - Optimal housing temperatures for mice to mimic the thermal environment of humans: An experimental study. AB - OBJECTIVES: The laboratory mouse is presently the most common model for examining mechanisms of human physiology and disease. Housing temperatures can have a large impact on the outcome of such experiments and on their translatability to the human situation. Humans usually create for themselves a thermoneutral environment without cold stress, while laboratory mice under standard conditions (~20 degrees C) are under constant cold stress. In a well-cited, theoretical paper by Speakman and Keijer in Molecular Metabolism, it was argued that housing mice under close to standard conditions is the optimal way of modeling the human metabolic situation. This tenet was mainly based on the observation that humans usually display average metabolic rates of about 1.6 times basal metabolic rate. The extra heat thereby produced would also be expected to lead to a shift in the 'lower critical temperature' towards lower temperatures. METHODS: To examine these tenets experimentally, we performed high time-resolution indirect calorimetry at different environmental temperatures on mice acclimated to different housing temperatures. RESULTS: Based on the high time-resolution calorimetry analysis, we found that mice already under thermoneutral conditions display mean diurnal energy expenditure rates 1.8 times higher than basal metabolism, remarkably closely resembling the human situation. At any temperature below thermoneutrality, mice metabolism therefore exceeds the human equivalent: Mice under standard conditions display energy expenditure 3.1 times basal metabolism. The discrepancy to previous conclusions is probably attributable to earlier limitations in establishing true mouse basal metabolic rate, due to low time resolution. We also found that the fact that mean energy expenditure exceeds resting metabolic rate does not move the apparent thermoneutral zone (the lower critical temperature) downwards. CONCLUSIONS: We show that housing mice at thermoneutrality is an advantageous step towards aligning mouse energy metabolism to human energy metabolism. PMID- 29122560 TI - A measuring stick for other minds: Comment on 'Seeing mental states: An experimental strategy for measuring the observability of other minds' by Cristina Becchio et al. PMID- 29122559 TI - Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos(r) on parasympathetic tone and hepatic energy metabolism. AB - OBJECTIVE: Brain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos(r) on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 +/- 6 yrs, BMI 25.5 +/- 2.7 kg/m2). METHODS: Heart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-2H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from 1H/31P magnetic resonance spectroscopy at baseline and for 180 min following stimulation. RESULTS: taVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected. CONCLUSION: Non invasive vagus stimulation by Cerbomed Nemos(r) does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin mediated effects on peripheral homeostasis in humans. PMID- 29122561 TI - Measuring how typical and atypical minds read other's intentions: Comment on "Seeing mental states: An experimental strategy for measuring the observability of other minds" by Cristina Becchio et al. PMID- 29122562 TI - Lifting the Markov blankets of socio-cultural evolution: A comment on "Answering Schrodinger's question: A free-energy formulation" by Maxwell James Desormeau Ramstead et al. PMID- 29122563 TI - Towards a unification of evolutionary dynamics: Comment on "Answering Schrodinger's question: A free-energy formulation" by Maxwell James Desormeau Ramstead et al. PMID- 29122564 TI - A model to investigate intention understanding in autism?: Comment on "Seeing mental states: An experimental strategy for measuring the observability of other minds" by Cristina Becchio et al. PMID- 29122565 TI - Cultural Markov blankets? Mind the other minds gap!: Comment on "Answering Schrodinger's question: A free-energy formulation" by Maxwell James Desormeau Ramstead et al. PMID- 29122567 TI - ? PMID- 29122568 TI - Treatment decision analysis for palatally-displaced canines based on orthodontists' opinion and CBCT. AB - OBJECTIVES: The aim of this study was to assess difficulty of treatment of palatally-displaced canines (PDC) according to experts' opinion using CBCT data and to determine a cut-off point for extraction versus forced eruption. SUBJECTS AND METHODS: Seven CBCT variables of thirty PDC cases were measured with Dolphin 3D software. In addition to measurements of each case, nine 3D and 2D views were prepared on one page and uploaded on the website (canineimpaction.com). Thirty four orthodontists were asked to judge the difficulty of bringing the impacted canine into occlusal plane. Then, they scored from 1 to 5 the effect of each variable on treatment difficulty and also decided whether to force-erupt or extract the impacted tooth. RESULTS: Overlap in frontal view, angulation of the canine to the occlusal plan, vertical distance to the occlusal plane, age, dilaceration and rotation had significant relationship with the level of treatment difficulty. The treatment plan decision for PDC with treatment difficulty>7.5 was extraction rather than forced eruption. CONCLUSION: We can predict treatment difficulty of PDC by measuring CBCT variables and decide to extract or force-erupt with a reasonable level of agreement among a panel of orthodontists. PMID- 29122566 TI - Mutations of candidate tumor suppressor genes at chromosome 3p in intrahepatic cholangiocarcinoma. AB - The genetic status of candidate tumor suppressor genes (TSGs) at chromosome 3p has not yet been elucidated in intrahepatic cholangiocarcinoma (iCCA). Herein, we retrospectively investigated 32 fresh iCCA case samples from a single medical institution to clarify mutations of 11 TSGs by next-generation sequencing. Validation of the mutations was performed on the MassARRAY platform or by high resolution melting curve analysis. We then integrated the gene mutations into copy number alterations at chromosome 3p that had been generated in a previous study using the same fresh iCCA samples, and correlated the integration results with the clinicopathologic features. Nine of the 32 (28.1%) iCCA patients had gene mutations at chromosome 3p, totaling 11 mutations across five genes. Those included five (15.6%) BAP1 mutations, two each (6.3%) of CACNA2D3 and RASSF1 mutations, and one each (3.1%) of ATG7 and PLCD1 mutations. Six (18.8%) cases had concurrent loss of chromosome 3p and gene mutations. Patients with TSG mutations had shorter disease-free and survival times than those without the mutations. Our data showed that iCCA patients with TSG mutations at chromosome 3p faced an adverse prognosis. BAP1 was the common target of mutational inactivation and may be a principal driver of 3p21 losses. PMID- 29122569 TI - ? PMID- 29122570 TI - Relationships between facial divergence and DMD parameters. AB - INTRODUCTION: The aim of this study was to examine the relationship between facial divergence and the parameters of dentomaxillary discrepancy (DMD), in particular crowding, the curve of Spee and the position of the incisors in the sagittal dimension. MATERIAL AND METHODS: A total of 90 young adult patients was selected from among the Moroccan orthodontic population attending the dentofacial orthopedic department and satisfying the following inclusion criteria: complete permanent dentition and a skeletal class I pattern with no previous orthodontic treatment, no crossbite, no periodontal disease, no mandibular asymmetry and no condylodiscal disunion. On cephalometric tracings, measurements were made of angles FMA, Go-Gn/SN, Occ/SN in the vertical direction, and of the values I/NA et i/NB in the sagittal direction. The curve of Spee and dental crowding were assessed using the one-way ANOVA test and the Bonferroni post-hoc test. Correlation analysis was performed between divergence and the different variables measured, using SPSS software with a 0.05 significance threshold. RESULTS: Patients recruited for the study had a mean age of 19.8+/-0.5 and were distributed as follows: 28 normodivergent, 31 hypodivergent and 31 hyperdivergent, 42 females and 48 males. Comparison showed that hypodivergent subjects had less crowding than hypo- or normodivergent individuals (P<0.05). Hypodivergent subjects had a more pronounced curve of Spee than the other two groups. This difference was not significant (P>0.05). Hyperdivergent subjects presented more labioversion and vestibular positioning of the incisors compared with the hypodivergent (P<0.05) and normodivergent (P<0.05) groups. Correlation analysis showed that crowding and the incisor positions in millimeters and in degrees were positively correlated to a moderate extent with facial divergence (r=0.3, r=0.5, r=0.4; P<0.05), while the curve of Spee was not (P>0.05). No correlation was found between age or sex and the DMD parameters (P>0.05). PMID- 29122571 TI - 360 degrees Operative Videos: A Randomised Cross-Over Study Evaluating Attentiveness and Information Retention. AB - OBJECTIVE: Although two-dimensional (2D) and three-dimensional videos have traditionally provided foundations for reviewing operative procedures, the recent 360o format may provide new dimensions to surgical education. This study sought to describe the production of a high quality 360o video for an index-operation (augmented with educational material), while evaluating for variances in attentiveness, information retention, and appraisal compared to 2D. DESIGN: A 6 camera synchronised array (GoPro Omni, [California, United States]) was suspended inverted and recorded an elective laparoscopic cholecystectomy in 2016. A single blinded randomised cross-over study was performed to evaluate this video in 360o vs 2D formats. Group A experienced the 360o video using Samsung (Suwon, South Korea) GearVR virtual-reality headsets, followed by the 2D experience on a 75 inch television. Group B were reversed. Each video was probed at designated time points for engagement levels and task-unrelated images or thoughts. Alternating question banks were administered following each video experience. Feedback was obtained via a short survey at study completion. SETTING: The New Academic and Education Building (NAEB) in Dublin, Royal College of Surgeons in Ireland, July 2017. PARTICIPANTS: Preclinical undergraduate students from a medical university in Ireland. RESULTS: Forty students participated with a mean age of 23.2 +/- 4.5 years and equal sex involvement. The 360o video demonstrated significantly higher engagement (p < 0.01) throughout the experience and lower task-unrelated images or thoughts (p < 0.01). Significant variances in information retention between the 2 groups were absent (p = 0.143) but most (65%) reported the 360o video as their learning platform of choice. Mean appraisal levels for the 360o platform were positive with mean responses of >8/10 for the platform for learning, immersion, and entertainment. CONCLUSIONS: This study describes the successful development and evaluation of a 360o operative video. This new video format demonstrated significant engagement and attentiveness benefits compared to traditional 2D formats. This requires further evaluation in the field of technology enhanced learning. PMID- 29122572 TI - Characterization of Vessel Deformations During EVAR: A Preliminary Retrospective Analysis to Improve Fidelity of Endovascular Simulators. AB - OBJECTIVE: During endovascular aneurysm repair (EVAR), vessel deformations occur due to the insertion of tools and deployment of stent grafts in the arteries. We present a method for the characterization of vessel deformations during EVAR, and its application on patient datasets for a preliminary retrospective analysis that may be used to improve fidelity of endovascular simulators. DESIGN: The method provides the extraction of vessel profiles from intraoperative fluoroscopic images and the calculation of a tortuosity index in the 2D fluoroscopy view (tau2D) used to quantify the vessel deformations (delta%) during EVAR caused by the stiff guidewire insertion (delta%Stiff) and the stent graft deployment (delta%Graft), when compared with the undeformed vessel configuration (no device inserted). We applied the method to analyze retrospectively 7 EVAR patient datasets, including vasculature anatomies with different grades of vessel tortuosity or calcification: 2 patients (Pts) with absent tortuosity and mild calcification, 2 with mild tortuosity and mild calcification, 2 with severe tortuosity and mild calcification, and 1 with severe tortuosity and severe calcification. The analysis was focused on deformations of the left common iliac artery (LCIA), which is one of the arterial segments most affected by deformations. RESULTS: In patients with mild LCIA calcification, the vessel straightening effect due to the stiff guidewire insertion increases as the severity of LCIA tortuosity increases (delta%Stiff = 0 +/- 2%, -19 +/- 2%, -45 +/ 2% for absent, mild, and severe tortuosity, respectively). In patients with mild/severe LCIA tortuosity, the artery with the deployed graft seems to retain part of the straightening effect caused by the stiff guidewire (delta%Graft = -9 +/- 3%, -31 +/- 2%, for mild and severe tortuosity, respectively). In case of severe LCIA calcification, the stiff guidewire causes only a slight straightening effect (delta%Stiff = -12%) despite the severe vessel tortuosity. CONCLUSION: The method was effective in characterizing real vessel deformations during EVAR. Results gave evidence of a relationship between the obtained deformations and the anatomical vessel conformation. These results may be useful to drive predictive models of vessel deformations during EVAR to be implemented in endovascular patient-specific simulators for improving their fidelity. PMID- 29122573 TI - Cause-specific life-years lost in people with mental disorders: a nationwide, register-based cohort study. AB - BACKGROUND: People with mental disorders have higher mortality rates than the general population and more detailed estimates of mortality differences are needed to address this public health issue. We aimed to assess whether differences in cause-specific mortality between people with and without mental disorders have changed between 1995 and 2014 by quantifying life-years lost and assessing differences over time. METHODS: Using a cohort design, we linked nationwide population data from the Danish Civil Registration System to information about hospital contacts from the Psychiatric Central Research Register and deaths from the Danish Cause of Death register. All linked data sources contained longitudinal information covering all individuals aged 15-94 years living in Denmark between 1995 and 2014. We assessed cause-specific mortality differences using rate ratios and average life-years lost. FINDINGS: Between 1995 and 2014, 6 107 234 individuals (3 026 132 men and 3 081 102 women) aged 15-94 years were living in Denmark. The study population was observed over 89 216 177 person-years (men: 43 914 948; women 45 301 229). Cause-specific mortality rates were higher for people with mental disorders than those without (total mortality rate per 1000 person-years in men 27.1 vs 11.4, respectively, and in women 21.2 vs 11.0). When compared with individuals without mental disorders, men and women with mental disorders had 10.20 and 7.34 excess life years lost, respectively. The largest cause-specific differences between those with and without mental disorders in terms of excess life-years lost were for respiratory diseases (men: 0.9; women: 1.4) and alcohol misuse (men: 2.8; women: 1.2). Between 1995 and 2014, we noted an increase in excess life-years lost for neoplasms (men: 0.7; women: 0.4), heart diseases (men: 1.2; women: 0.3), and respiratory diseases (men: 0.3; women: 0.2), and a decrease for suicide (men: 0.7; women: -0.5) and accidents (men: -0.9; women: -0.5). INTERPRETATION: By applying a novel approach, more precise estimates of life-years lost were obtained. The increase in excess mortality due to medical diseases and disorders among people with mental disorders emphasises the need for future interventions to address these aspects as well as the continued high shares of excess mortality due to alcohol misuse, suicide, and accidents. FUNDING: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). PMID- 29122574 TI - Long way to go to close the mortality gap. PMID- 29122575 TI - Identification of Functional Patterns of Androgenetic Alopecia Using Transcriptome Profiling in Distinct Locations of Hair Follicles. PMID- 29122576 TI - Intracellular diminazene aceturate content and adenosine incorporation in diminazene aceturate-resistant Babesia gibsoni isolate in vitro. AB - The mechanism of the development of diminazene aceturate (DA) resistance in Babesia gibsoni is still unknown even though DA-resistant B. gibsoni isolate was previously developed in vitro. To clarify the mechanisms of DA-resistance in B. gibsoni, we initially examined the intracellular DA content in the DA-resistant isolate using high-performance liquid chromatography, and compared it with that in the wild-type. As a result, the intracellular DA content in the DA-resistant isolate was significantly lower than that in the wild-type, suggesting that the decreased DA content may contribute to DA-resistance. Additionally, the glucose consumption of the DA-resistant isolate was significantly higher than that of the wild-type, indicating that a large amount of glucose is utilized to maintain DA resistance. It is possible that a large amount of energy is utilized to maintain the mechanisms of DA-resistance. It was reported that as the structure of DA is similar with that of adenosine, DA may be taken up by the P2 transporter, which contributes to the uptake of adenosine, in Trypanosoma brucei brucei, and that the uptake of adenosine is decreased in DA-resistant T. brucei brucei. In the present study, the adenosine incorporation in the DA-resistant B. gibsoni isolate was higher than in the wild-type. Moreover, the adenosine incorporation in the wild-type was not inhibited by the presence of DA. These results suggest that adenosine transport in B. gibsoni is not affected by DA and may not mediate DA resistance. To clarify the mechanism of the development of DA resistance in B. gibsoni, we should investigate the cause of the decreased DA content in the DA resistant isolate in the future. PMID- 29122577 TI - Interobserver Agreement Among Uveitis Experts on Uveitic Diagnoses: The Standardization of Uveitis Nomenclature Experience. AB - PURPOSE: To evaluate the interobserver agreement among uveitis experts on the diagnosis of the specific uveitic disease. DESIGN: Interobserver agreement analysis. METHODS: Five committees, each comprised of 9 individuals and working in parallel, reviewed cases from a preliminary database of 25 uveitic diseases, collected by disease, and voted independently online whether the case was the disease in question or not. The agreement statistic, kappa, was calculated for the 36 pairwise comparisons for each disease, and a mean kappa was calculated for each disease. After the independent online voting, committee consensus conference calls, using nominal group techniques, reviewed all cases not achieving supermajority agreement (>75%) on the diagnosis in the online voting to attempt to arrive at a supermajority agreement. RESULTS: A total of 5766 cases for the 25 diseases were evaluated. The overall mean kappa for the entire project was 0.39, with disease-specific variation ranging from 0.23 to 0.79. After the formalized consensus conference calls to address cases that did not achieve supermajority agreement in the online voting, supermajority agreement overall was reached on approximately 99% of cases, with disease-specific variation ranging from 96% to 100%. CONCLUSIONS: Agreement among uveitis experts on diagnosis is moderate at best but can be improved by discussion among them. These data suggest the need for validated and widely used classification criteria in the field of uveitis. PMID- 29122579 TI - Analysis of the editorial review process of the Journal of Molecular and Cellular Cardiology. PMID- 29122580 TI - Psychometric Evaluation of the Brachial Assessment Tool Part 1: Reproducibility. AB - OBJECTIVE: To evaluate reproducibility (reliability and agreement) of the Brachial Assessment Tool (BrAT), a new patient-reported outcome measure for adults with traumatic brachial plexus injury (BPI). DESIGN: Prospective repeated measure design. SETTING: Outpatient clinics. PARTICIPANTS: Adults with confirmed traumatic BPI (N=43; age range, 19-82y). INTERVENTIONS: People with BPI completed the 31-item 4-response BrAT twice, 2 weeks apart. Results for the 3 subscales and summed score were compared at time 1 and time 2 to determine reliability, including systematic differences using paired t tests, test retest using intraclass correlation coefficient model 1,1 (ICC1,1), and internal consistency using Cronbach alpha. Agreement parameters included standard error of measurement, minimal detectable change, and limits of agreement. MAIN OUTCOME MEASURE: BrAT. RESULTS: Test-retest reliability was excellent (ICC1,1=.90-.97). Internal consistency was high (Cronbach alpha=.90-.98). Measurement error was relatively low (standard error of measurement range, 3.1-8.8). A change of >4 for subscale 1, >6 for subscale 2, >4 for subscale 3, and >10 for the summed score is indicative of change over and above measurement error. Limits of agreement ranged from +/-4.4 (subscale 3) to 11.61 (summed score). CONCLUSIONS: These findings support the use of the BrAT as a reproducible patient-reported outcome measure for adults with traumatic BPI with evidence of appropriate reliability and agreement for both individual and group comparisons. Further psychometric testing is required to establish the construct validity and responsiveness of the BrAT. PMID- 29122578 TI - A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. AB - BACKGROUND: Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs), small non-coding RNAs that post-transcriptionally regulate target genes. MiR-125b-5p is downregulated in patients with end-stage dilated and ischemic cardiomyopathy, and has been proposed as a biomarker of heart failure. We previously reported that the beta-blocker carvedilol promotes cardioprotection via beta-arrestin-biased agonism of beta1-adrenergic receptor while stimulating miR-125b-5p processing in the mouse heart. We hypothesize that beta1-adrenergic receptor/beta-arrestin1-responsive miR-125b-5p confers the improvement of cardiac function and structure after acute myocardial infarction. METHODS AND RESULTS: Using cultured cardiomyocyte (CM) and in vivo approaches, we show that miR-125b 5p is an ischemic stress-responsive protector against CM apoptosis. CMs lacking miR-125b-5p exhibit increased susceptibility to stress-induced apoptosis, while CMs overexpressing miR-125b-5p have increased phospho-AKT pro-survival signaling. Moreover, we demonstrate that loss-of-function of miR-125b-5p in the mouse heart causes abnormalities in cardiac structure and function after acute myocardial infarction. Mechanistically, the improvement of cardiac function and structure elicited by miR-125b-5p is in part attributed to repression of the pro-apoptotic genes Bak1 and Klf13 in CMs. CONCLUSIONS: In conclusion, these findings reveal a pivotal role for miR-125b-5p in regulating CM survival during acute myocardial infarction. PMID- 29122581 TI - Physical Activity-Based Interventions Using Electronic Feedback May Be Ineffective in Reducing Pain and Disability in Patients With Chronic Musculoskeletal Pain: A Systematic Review With Meta-Analysis. AB - OBJECTIVE: To investigate the effectiveness of physical activity-based interventions using electronic feedback in reducing pain and disability compared to minimal or no interventions in patients with chronic musculoskeletal pain. DATA SOURCES: The following electronic databases were searched: EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, SPORTDiscus, Web of Science, Physiotherapy Evidence Database, and main clinical trial registers. STUDY SELECTION: Randomized controlled trials investigating the effect of physical activity interventions using electronic feedback (eg, physical activity monitors) on pain and disability compared to minimal or no interventions in adults with chronic musculoskeletal pain were considered eligible. DATA EXTRACTION: Pooled effects were calculated using the standardized mean difference (SMD), and the Grading of Recommendations Assessment, Development and Evaluation system was used to assess the overall quality of the evidence. DATA SYNTHESIS: Four published randomized controlled trials and 4 registered unpublished randomized controlled trials were included. At short-term follow-up, pooled estimations showed no significant differences in pain (2 trials: n=116; SMD=-.50; 95% confidence interval, -1.91 to 0.91) and disability (2 trials: n=116; SMD=-.81; 95% confidence interval, -2.34 to 0.73) between physical activity-based interventions and minimal interventions. Similarly, nonsignificant results were found at intermediate-term follow-up. According to Grading of Recommendations Assessment, Development and Evaluation, the overall quality of the evidence was considered to be of low quality. CONCLUSIONS: Our findings suggest that physical activity-based interventions using electronic feedback may be ineffective in reducing pain and disability compared to minimal interventions in patients with chronic musculoskeletal pain. Clinicians should be cautious when implementing this intervention in patients with chronic musculoskeletal pain. PMID- 29122582 TI - Biorelevant Media Slows the Solution-Mediated Phase Transformation of Amorphous Spironolactone. AB - Solution-mediated phase transformation (SMPT) can reduce the high drug concentration expected from amorphous formulations, eliminating the improvement in drug absorption one hoped to gain from this high energy drug state. The differences in SMPT of a supersaturating system were compared in biorelevant media (fasted state simulated intestinal fluid and fed state simulated intestinal fluid) and United States Pharmacopeia compendial medium, simulated intestinal fluid without pancreatin. Amorphous spironolactone underwent SMPT to the same hydrate of spironolactone in all 3 media which was confirmed by the decrease in dissolution rates assessed in a flow-through dissolution apparatus, as well as by the appearance of crystals on the amorphous solid surface detected by polarized light microscopy. Longer duration of supersaturation which may lead to greater in vivo oral drug absorption was found in both biorelevant media, compared to compendial (average > 90 vs. 20 min), indicating that the presence of surfactants in biorelevant media delays crystal growth. Surface profiles and polarized light micrographs suggest that (1) a significant increase in surface area due to 3D crystal formation, (2) amorphous areas remaining exposed on the surface, and (3) a lower nucleation rate are potential reasons for an elevated dissolution rate even after SMPT. PMID- 29122583 TI - Is it better at home with my family? The effects of people and place on children's eating behavior. AB - The people and places children eat with can influence food consumption. This study investigates the people and places Swiss school-aged children ate with over a 7-day period and analyses the effects of eating at home with family on food consumption. Children completed a 7-day food diary documenting the foods they consumed, the people with whom they ate, and the place where they ate. Analyses were conducted for all meals and included 9911 meal occasions. Most meals (80.5%) were consumed at home with family. Generalized estimating equations were used to model the effects of the home-family dyad on the child's chance of consuming a certain food while controlling for age, gender and BMI of the child, education, nationality and BMI of the parent. Compared to eating in other dyads (e.g. school peers or restaurant-family), eating in the home-family dyad was associated with higher consumption of vegetables (+66% and +142% at weekday lunch and dinner and +180% and +67% at weekend lunch and dinner), lower consumption of sweets (-45% and -49% at weekday lunch and dinner; -43% and -49% at weekend lunch and dinner), and fewer soft drinks (-37% and -61% at weekday lunch and dinner; -66% and -78% at weekend lunch and dinner). This study shows the positive influence of eating at home with the family on food consumption in a sample of Swiss children. Interventions and policies that encourage children and parents to eat together at home could serve as effective prevention against a poor diet. PMID- 29122584 TI - How to build an allogeneic hematopoietic cell transplant unit in 2016: Proposal for a practical framework. AB - Allogeneic hematopoietic cell transplantation is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic hematopoietic cell transplantation leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of hematopoietic cell transplantation are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for the construction and layout of a unit treating patients during the acute phase of the transplantation procedure or at readmission for different complications are not well defined. In addition, the infrastructure of such a unit may be decisive for optimized care of these fragile patients. Here we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of infrastructural requirements for hospitals caring for people with severe immunosuppression. PMID- 29122585 TI - Strong sonic hedgehog signaling in the mouse ventral spinal cord is not required for oligodendrocyte precursor cell (OPC) generation but is necessary for correct timing of its generation. AB - In the mouse neural tube, sonic hedgehog (Shh) secreted from the floor plate (FP) and the notochord (NC) regulates ventral patterning of the neural tube, and later is essential for the generation of oligodendrocyte precursor cells (OPCs). During early development, the NC is adjacent to the neural tube and induces ventral domains in it, including the FP. In the later stage of development, during gliogenesis in the spinal cord, the pMN domain receives strong Shh signaling input. While this is considered to be essential for the generation of OPCs, the actual role of this strong input in OPC generation remains unclear. Here we studied OPC generation in bromi mutant mice which show abnormal ciliary structure. Shh signaling occurs within cilia and has been reported to be weak in bromi mutants. At E11.5, accumulation of Patched1 mRNA, a Shh signaling reporter, is observed in the pMN domain of wild type but not bromi mutants, whereas expression of Gli1 mRNA, another Shh reporter, disappeared. Thus, Shh signaling input to the pMN domain at E12.5 was reduced in bromi mutant mice. In these mutants, induction of the FP structure was delayed and its size was reduced compared to wild type mice. Furthermore, while the p3 and pMN domains were induced, the length of the Nkx2.2-positive region and the number of Olig2 positive cells decreased. The number of OPCs was also significantly decreased in the E12.5 and E14.5 bromi mutant spinal cord. In contrast, motor neuron (MN) production, detected by HB9 expression, significantly increased. It is likely that the transition from MN production to OPC generation in the pMN domain is impaired in bromi mutant mice. These results suggest that strong Shh input to the pMN domain is not required for OPC generation but is essential for producing a sufficient number of OPCs. PMID- 29122586 TI - The evolutionary dynamics of language. AB - The well-established framework of evolutionary dynamics can be applied to the fascinating open problems how human brains are able to acquire and adapt language and how languages change in a population. Schemas for handling grammatical constructions are the replicating unit. They emerge and multiply with variation in the brains of individuals and undergo selection based on their contribution to needed expressive power, communicative success and the reduction of cognitive effort. Adopting this perspective has two major benefits. (i) It makes a bridge to neurobiological models of the brain that have also adopted an evolutionary dynamics point of view, thus opening a new horizon for studying how human brains achieve the remarkably complex competence for language. And (ii) it suggests a new foundation for studying cultural language change as an evolutionary dynamics process. The paper sketches this novel perspective, provides references to empirical data and computational experiments, and points to open problems. PMID- 29122587 TI - The splicing code. AB - This issue dedicated to the code of life tackles very challenging and open questions in Biology. The genetic code, brilliantly uncovered over 50 years ago is an example of a univocal biological code. In fact, except for very few and marginal variations, it is the same from bacteria to man, the RNA stretch: 5' GUGUUC 3' reads as the dipeptide: Val-Phe in bacteria, in yeast, in Arabidopsis, in zebra fish, in mouse and in human. A degree of ambiguity is possible if mutations are introduced in the tRNAs in a way that the anticodon reads one amino acid but the aminoacyl-transferase attaches a different one onto the tRNA. These were the very useful suppressor genes that aided greatly the study of bacterial genetics. Other biological codes however, are more akin to social codes and are less amenable to an unambiguous deciphering. Legal and ethical codes, weather we like it or not, are flexible and depend on the structure and history of the society that has produced them, as well as a specific point in time. The codes that govern RNA splicing have similar characteristics. In fact, the splicing code depends on a myriad of different factors that in part are influenced by the background in which they are read such as different cells, tissues or developmental stages. Given the complexity of the splicing process, the construction of an algorithm that can define exons or their fate with certainty has not yet been achieved. However a substantial amount of information towards the deciphering of the splicing code has been gathered and in this manuscript we summarize the point reached. PMID- 29122588 TI - Anesthesia for patients with tracheal bronchus. AB - Tracheal bronchus is a congenital anatomical variant of patients with accessory bronchus in the right upper lobe deriving directly from the supracarinal trachea. Pre-operative consultation with the anesthesiologist is important for patient safety and can avoid adverse effects induced by endotracheal intubation. In this report, we described a case of tracheal bronchus in which general anesthesia was performed for video-assisted thoracoscopic surgery. We discussed some of the issues surrounding to complications in tracheal bronchus. PMID- 29122589 TI - Naringin prevents the inhibition of intestinal Ca2+ absorption induced by a fructose rich diet. AB - This study tries to elucidate the mechanisms by which fructose rich diets (FRD) inhibit the rat intestinal Ca2+ absorption, and determine if any or all underlying alterations are prevented by naringin (NAR). Male rats were divided into: 1) controls, 2) treated with FRD, 3) treated with FRD and NAR. The intestinal Ca2+ absorption and proteins of the transcellular and paracellular Ca2+ pathways were measured. Oxidative/nitrosative stress and inflammation parameters were evaluated. FRD rats showed inhibition of the intestinal Ca2+ absorption and decrease in the protein expression of molecules of both Ca2+ pathways, which were blocked by NAR. FRD rats showed an increase in the superoxide anion, a decrease in the glutathione and in the enzymatic activities of the antioxidant system, as well as an increase in the NO content and in the nitrotyrosine content of proteins. They also exhibited an increase in both IL-6 and nuclear NF-kappaB. All these changes were prevented by NAR. In conclusion, FRD inhibit both pathways of the intestinal Ca2+ absorption due to the oxidative/nitrosative stress and inflammation. Since NAR prevents the oxidative/nitrosative stress and inflammation, it might be a drug to avoid alteration in the intestinal Ca2+ absorption caused by FRD. PMID- 29122590 TI - Physiological serum copper concentrations found in malignancies cause unfolding induced aggregation of human serum albumin in vitro. AB - Malignancies are characterized by several drastic metabolic changes, one of which is a progressive rise in the levels of serum copper. This rise in serum copper is documented across all malignancies and across malignancies in several species. This study aims to explore in vitro the effect of increased copper levels on the structure of the blood protein human serum albumin. Exposure of human serum albumin to physiologically relevant copper concentrations for 21 days resulted in structural modifications in the protein which were evident by changes in the intrinsic florescence. A loss of the predominantly alpha helical structure of human serum albumin was recorded along with a tendency to form protein aggregates. This aggregation was characterized by Thioflavin T and Congo Red assays. Rayleigh light scattering and turbidity assays confirmed aggregation. The aggregates were visually confirmed using transmission electron microscopy. This is the first report implicating increased copper levels as a cause of aggregation of blood proteins in malignancies. The physiological and biochemical implications of this phenomenon are discussed. PMID- 29122591 TI - Spiking and Excitatory/Inhibitory Input Dynamics of Barrel Cells in Response to Whisker Deflections of Varying Velocity and Angular Direction. AB - The spiking of barrel regular-spiking (RS) cells is tuned for both whisker deflection direction and velocity. Velocity tuning arises due to thalamocortical (TC) synchrony (but not spike quantity) varying with deflection velocity, coupled with feedforward inhibition, while direction selectivity is not fully understood, though may be due partly to direction tuning of TC spiking. Data show that as deflection direction deviates from the preferred direction of an RS cell, excitatory input to the RS cell diminishes minimally, but temporally shifts to coincide with the time-lagged inhibitory input. This work constructs a realistic large-scale model of a barrel; model RS cells exhibit velocity and direction selectivity due to TC input dynamics, with the experimentally observed sharpening of direction tuning with decreasing velocity. The model puts forth the novel proposal that RS->RS synapses can naturally and simply account for the unexplained direction dependence of RS cell inputs - as deflection direction deviates from the preferred direction of an RS cell, and TC input declines, RS >RS synaptic transmission buffers the decline in total excitatory input and causes a shift in timing of the excitatory input peak from the peak in TC input to the delayed peak in RS input. The model also provides several experimentally testable predictions on the velocity dependence of RS cell inputs. This model is the first, to my knowledge, to study the interaction of direction and velocity and propose physiological mechanisms for the stimulus dependence in the timing and amplitude of RS cell inputs. PMID- 29122592 TI - New Perspectives on the Brain Lesion Approach - Implications for Theoretical Models of Human Memory. AB - Human lesion studies represent the cornerstone of modern day neuropsychology and provide an important adjunct to functional neuroimaging methods. The study of human lesion groups with damage to distinct regions of the brain permits the identification of underlying mechanisms and structures not only associated with, but essential for, complex cognitive processes. Here, we consider a recent review by McCormick et al., 2018 in which the power of the lesion model approach is elegantly presented with respect to a host of sophisticated cognitive endeavors, including autobiographical memory, future thinking, spatial navigation, and decision-making. By comparing profiles of loss and sparing in hippocampal (HC) and ventromedial prefrontal cortex (vmPFC) lesion groups, the authors provide new insights into the underlying neuroarchitecture of these diverse cognitive functions. Building on this framework, we consider how vmPFC and HC degeneration, in the context of large-scale network dysfunction in dementia, impacts discrete facets of memory and social cognition. Notably, we find remarkable concordance between the available evidence in dementia and that of the HC and vmPFC lesion literature. We further assess the role of the prefrontal cortex in modulating aspects of spatial navigation and discuss the role of schema-related processing in the service of memory more broadly. Far from being obsolete, we contend that human lesion work occupies a crucial position in cognitive neuroscience and offers an array of exciting areas for future study within this field. PMID- 29122593 TI - Editorial. PMID- 29122594 TI - Inhibition of the NLRP3 inflammasome attenuates foam cell formation of THP-1 macrophages by suppressing ox-LDL uptake and promoting cholesterol efflux. AB - The NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the development of atherosclerosis. The activated NLRP3 inflammasome has been reported to promote macrophage foam cell formation, but not all studies have obtained the same result, and how NLRP3 inflammasome is involved in the formation of foam cells remains elusive. We used selective NLRP3 inflammasome inhibitors and NLRP3-deficient THP-1 cells to assess the effect of NLRP3 inflammasome inhibition on macrophage foam cell formation, oxidized low-density lipoprotein (ox-LDL) uptake, esterification, and cholesterol efflux, as well as the expression of associated proteins. Inhibition of the NLRP3 inflammasome attenuated foam cell formation, diminished ox-LDL uptake, and promoted cholesterol efflux from THP-1 macrophages. Moreover, it downregulated CD36, acyl coenzyme A: cholesterol acyltransferase-1 and neutral cholesterol ester hydrolase expression; upregulated ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) expression; but had no effect on the expression of scavenger receptor class A and ATP-binding cassette transporter G1. Collectively, our findings show that inhibition of the NLRP3 inflammasome decreases foam cell formation of THP-1 macrophages via suppression of ox-LDL uptake and enhancement of cholesterol efflux, which may be due to downregulation of CD36 expression and upregulation of ABCA1 and SR-BI expression, respectively. PMID- 29122595 TI - An AT-hook protein DEPRESSED PALEA1 physically interacts with the TCP Family transcription factor RETARDED PALEA1 in rice. AB - The cereal crops (such as rice and maize) which belong to the grass family, are the most important grain crops for human beings, and the development of their flower and inflorescence architecture has attracted extensive attention. Although multiple genes involved in the regulation of floral and inflorescence organogenesis have been identified, the underlying molecular mechanisms are largely unknown. Previously, we identified rice depressed palea1 (dp1) mutants with defects in main structure of palea and its enhancer RETARDED PALEA1 (REP1). DP1 is an AT-hook protein while REP1 is a TCP transcription factor, both of which are important regulators of palea development. However, the relationship of these two proteins has not been elucidated yet. Here, we demonstrated that DP1 interacts physically with REP1 both in yeast and in rice protoplasts. Considering the close phylogenetic relationship between maize and rice, we further hypothesize that their orthologs in maize, BARREN STALK FASTIGIATE (BAF1) and BRANCH ANGLE DEFECTIVE 1 (BAD1), may interact physically. Subsequently, we verified their physical interaction, indicating that the interaction between AT hook proteins and TCP proteins is conserved in rice and maize. Our findings may reveal a novel molecular mechanism of floral and inflorescence development in grasses. PMID- 29122596 TI - Studies of lysine cyclodeaminase from Streptomyces pristinaespiralis: Insights into the complex transition NAD+ state. AB - Lysine cyclodeaminase (LCD) catalyzes the piperidine ring formation in macrolide pipecolate natural products metabolic pathways from a lysine substrate through a combination of cyclization and deamination. This enzyme belongs to a unique enzyme class, which uses NAD+ as the catalytic prosthetic group instead of as the co-substrate. To understand the molecular details of NAD+ functions in lysine cyclodeaminase, we have determined four ternary crystal structure complexes of LCD-NAD+ with pipecolic acid (LCD-PA), lysine (LCD-LYS), and an intermediate (LCD INT) as ligands at 2.26-, 2.00-, 2.17- and 1.80 A resolutions, respectively. By combining computational studies, a NAD+-mediated "gate keeper" function involving NAD+/NADH and Arg49 that control the binding and entry of the ligand lysine was revealed, confirming the critical roles of NAD+ in the substrate access process. Further, in the gate opening form, a substrate delivery tunnel between epsilon carboxyl moiety of Glu264 and the alpha-carboxyl moiety of Asp236 was observed through a comparison of four structure complexes. The LCD structure details including NAD+-mediated "gate keeper" and substrate tunnel may assist in the exploration the NAD+ function in this unique enzyme class, and in regulation of macrolide-pipecolate natural product synthesis. PMID- 29122597 TI - Upper GI involvement in children with familial adenomatous polyposis syndrome: single-center experience and meta-analysis of the literature. AB - BACKGROUND AND AIMS: Familial adenomatous polyposis (FAP) is a hereditary syndrome that can affect the entire GI tract. Current screening recommendations include EGD starting at age 25 to 30 years or earlier in symptomatic patients. However, few reports describe upper GI tract involvement in children with FAP that support the notion of early screening. The aim of our study is to understand the prevalence and severity of upper GI involvement in children with FAP. METHODS: We performed a retrospective review of the Mayo Clinic records, between 1992 and 2016, to identify children with the diagnosis of FAP who underwent EGD examinations. A systematic review of the literature was performed to include published studies reporting children with FAP and upper GI findings. RESULTS: The retrospective study included 69 children with a mean age of 13.5 years (range, 3 18). Thirty-six children (52%) had duodenal adenoma with low-grade dysplasia. Five children required an ampullectomy secondary to enlarged and polypoid ampullas. Combined with published studies, a total of 206 children with upper GI findings were identified, of which 87 (42%) had duodenal adenoma (1 had high grade dysplasia). Meta-analysis of 5 series demonstrated duodenal adenoma detection rate of 39% (95% confidence interval, 21%-57%; I2 = 85%). CONCLUSIONS: The available data to date show that children with FAP can have clinically relevant lesions in the upper GI tract earlier than previously foreseen, suggesting that earlier screening may be indicated. Larger multicenter prospective studies are needed to determine the best approach and optimal age for EGD screening in children with FAP. PMID- 29122598 TI - Effects of EUS-guided intratumoral injection of oligonucleotide STNM01 on tumor growth, histology, and overall survival in patients with unresectable pancreatic cancer. AB - BACKGROUND AND AIMS: Carbohydrate sulfotransferase 15 (CHST15) promotes tumor growth and invasion and is considered to be an emergent therapeutic target for pancreatic cancer. The aim of this study was to evaluate the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, the double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer. METHODS: Six patients with unresectable pancreatic cancer, treated at Tokyo Metropolitan Geriatric Hospital, were used in this open-labeled, investigator-initiated trial. A total of 16 mL STNM01 (250 nM) was injected into the tumor through EUS-FNI. The study's primary endpoint was safety, with a secondary endpoint of tumor response 4 weeks after the initial injection. Some patients received a series of infusions as extensions. The local expression of CHST15 and overall survival (OS) were also evaluated. RESULTS: There were no adverse events. The mean tumor diameter changed from 30.7 to 29.3 mm 4 weeks after injection. Four patients exhibited necrosis of tumor in biopsy specimens. CHST15 was highly expressed at baseline, with 2 patients showing large reductions of CHST15 at week 4. The mean OS of these 2 patients was 15 months, whereas it was 5.7 months for the other 4 patients. CONCLUSIONS: EUS-FNI of STNM01 in pancreatic cancer is safe and feasible. The CHST15 reduction could predict tumor progression and OS. Injections of STNM01 during the beginning of treatment may reduce CHST15 and warrants further investigation. PMID- 29122599 TI - Impact of experience on self-assessment accuracy of clinical colonoscopy competence. AB - BACKGROUND AND AIMS: Self-assessment is important for life-long learning and a recommended assessment method for endoscopy skills. Prior literature has not investigated self-assessment accuracy of colonoscopic competence in the clinical setting. This study aimed to determine the self-assessment accuracy of novice, intermediate, and experienced endoscopists. METHODS: Novice (performed <50 previous colonoscopies), intermediate (50-500), and experienced (>1000) endoscopists from 5 hospitals each performed a clinical colonoscopy. Video recordings of procedures were independently assessed by 2 blinded expert endoscopists by using the Gastrointestinal Endoscopy Competency Assessment Tool (GiECAT). Externally assessed and self-assessed GiECAT scores were defined as the mean of the 2 video-based ratings and as participants' own assigned ratings, respectively. Self-assessment accuracy between the externally assessed and self assessed scores was evaluated by using absolute difference scores, intraclass correlation coefficients, and the Bland-Altman analysis. RESULTS: Twenty novice, 10 intermediate, and 10 experienced endoscopists participated. There was moderate agreement of externally assessed and self-assessed GiECAT scores, with an intraclass correlation coefficient of 0.65 (95% confidence interval, 0.44-0.80). The absolute difference scores among the 3 groups were significantly different (P = .002), with experienced endoscopists demonstrating a more accurate self assessment ability compared with novices (P = .002). Bland-Altman plots suggest that novice and experienced endoscopists tend to overrate and underrate their clinical competence, respectively; no specific trends were associated with intermediates. CONCLUSION: Participants demonstrated moderate self-assessment accuracy of clinical competence. Endoscopist experience was positively associated with self-assessment accuracy; novices demonstrated lower self-assessment accuracy compared with experienced endoscopists. Moreover, novices tended to overestimate their performances. Novice endoscopists may benefit from targeted interventions to improve self-assessment accuracy. PMID- 29122600 TI - Width and depth of resection for small colorectal polyps: hot versus cold snare polypectomy. AB - BACKGROUND AND AIMS: Curability is associated with resection width and depth in polypectomy. We evaluated the resection width and depth achieved with hot snare polypectomy (HSP) and cold snare polypectomy (CSP) for small colorectal polyps. METHODS: In this single-center, prospective, randomized controlled study, patients with rectal or rectosigmoid polyps <=10 mm in diameter were treated with HSP or CSP. Resection width was evaluated as mucosal defect size, measured immediately postprocedure and 1 day later. Resection depth was histologically evaluated using obtained specimens. RESULTS: Fifty-two patients were enrolled. Mean lesion size was 5.6 mm with HSP (n = 27) and 5.8 mm with CSP (n = 25). Mean mucosal defect diameter immediately after HSP and CSP was 5.1 mm and 7.5 mm, respectively (P < .001). The diameter 1 day after the procedure increased by 29% (95% confidence interval [CI], 17%-41%) with HSP and decreased by 25% (95% CI, 18%-32%) with CSP (P < .001). Muscularis mucosa was obtained similarly with HSP and CSP (96% [95% CI, 82%-99%] vs 92% [95% CI, 75%-98%]; P = .603). Submucosal tissue was obtained significantly more frequently with HSP than with CSP (81% [95% CI, 63%-92%] vs 24% [95% CI, 11%-43%]; P < .001). CONCLUSIONS: The resection width immediately after CSP was larger than that after HSP but was significantly smaller at day 1 after resection. Although the resection depth after CSP was more superficial, muscularis mucosa was obtained in most specimens. Thus, CSP has sufficient resection width and depth to enable complete polyp resection and potentially has a superior safety profile than HSP. PMID- 29122602 TI - Utility of multi-detector computed tomography scans after colorectal endoscopic submucosal dissection: a prospective study. AB - BACKGROUND AND AIMS: Several reports have described major adverse events after endoscopic submucosal dissection (ESD), such as perforation or bleeding. However, few studies have discussed the occurrence of post-ESD electrocoagulation syndrome (PEECS) after colorectal ESD. In addition, the occurrence of fever without abdominal pain in patients requires postoperative management similar to that required for PEECS. Therefore, we have defined post-ESD inflammatory syndrome (PEIS) composed of both PEECS and fever without abdominal pain. This study aimed to evaluate the correlation between the findings of multi-detector computed tomography (MDCT) imaging and PEIS in patients. METHODS: Between January 2015 and October 2015, we performed colorectal ESD in 100 patients; after this, all patients underwent abdominal examinations by MDCT scans. Nine patients who experienced intraoperative perforations or penetrations were excluded; 91 patients were enrolled in our prospective study. MDCT findings in patients were classified according to the amount of extraluminal gas. The patients were divided into 2 groups based on the presence or absence of extraluminal gas and were assessed for co-occurring PEIS. RESULTS: Among the 91 patients, extraluminal gas was observed in 31 (34%); of these, PEIS occurred in 14 (15%) patients. Patients with extraluminal gas had increased incidence of PEIS compared with patients without extraluminal gas (29% vs 8%, P = .014). CONCLUSIONS: Extraluminal gas was detected by MDCT in many cases and significantly correlated with the occurrence of PEIS, even in cases without obvious intraoperative perforation or penetration. MDCT findings after ESD may be useful for predicting PEIS and appropriate perioperative management. PMID- 29122601 TI - Per-oral endoscopic myotomy in patients with or without prior Heller's myotomy: comparing long-term outcomes in a large U.S. single-center cohort (with videos). AB - BACKGROUND AND AIMS: Heller's myotomy (HM) is one of the most effective treatments for esophageal achalasia. However, failures do exist, and the success rate tends to decrease with time. The efficacy of rescue treatments for patients with failed HM is limited. A few small-scale studies have reported outcomes of per-oral endoscopic myotomy (POEM) in these patients. We conducted this study to systematically assess feasibility, safety, and efficacy of POEM on patients who have had HM. METHODS: Patients at least 3 months out from POEM were selected from our prospective database: 318 consecutive POEMs performed from October 2009 to October 2016. The efficacy and safety of POEM were compared between the 46 patients with prior HM and the remaining 272 patients. RESULTS: Patients with prior HM had longer disease history, more advanced disease, more type I and less type II achalasia, lower before-POEM Eckardt scores, and lower before-POEM lower esophageal sphincter (LES) pressure (all P < .01). Procedure parameters and follow-up results (clinical success rate, Eckardt score, LES pressure, GERD score, esophagitis, and pH testing) showed no significant difference between the 2 groups. For the 46 HM-POEM patients, no clinically significant perioperative adverse events occurred. Their overall clinical success rate (Eckardt score <=3 and no other treatment needed) was 95.7% at a median follow-up of 28 months. CONCLUSION: POEM as a rescue treatment for patients with achalasia who failed HM is feasible, safe, and highly effective. It should be the treatment of choice in managing these challenging cases at centers with a high level of experience with POEM. PMID- 29122603 TI - The role of colorectal endoscopic submucosal dissection in patients with ulcerative colitis. AB - BACKGROUND AND AIM: Patients with ulcerative colitis have an increased risk of colorectal dysplasia. Endoscopic submucosal dissection (ESD) for neoplastic lesions in ulcerative colitis remains controversial. The aim of this study was to clarify the role of ESD in the treatment strategy for ulcerative colitis. METHODS: We retrospectively investigated 25 patients with ulcerative colitis in clinical remission who underwent colorectal ESD at 2 referral centers. We analyzed short-term and long-term outcomes. Preoperative diagnoses based on biopsy or endoscopy were also compared with the histologic diagnoses of resected specimens. RESULTS: The mean size of the resected specimens was 34.9 +/- 17.1 mm. The mean procedure time for ESD was 71.3 minutes. En bloc resection and R0 resection rates were achieved in 100% (25/25) and 76% (19/25), respectively. Postoperative bleeding and perforation during the procedure occurred in 0% and 4%, respectively. Five patients with noncurative resection underwent additional surgery. During a median 21 months (range, 8-80 months) follow-up, local recurrence did not occur. Metachronous high-grade dysplasia occurred in 1 case (4%). The biopsy predicted a final histologic diagnosis of carcinoma with a sensitivity of 72.2% (95% confidence interval [CI], 46.5-90.3), accuracy of 78.2% (95% CI, 56.3-92.5). The endoscopic findings predicted a final histologic diagnosis of carcinoma with a sensitivity of 72.2% (95% CI, 46.5-90.3), accuracy of 76% (95% CI, 54.9-90.6). CONCLUSION: ESD for neoplasms in ulcerative colitis is feasible by expert endoscopists and may avoid unnecessary surgery. Because the biopsy and endoscopic findings had relatively low accuracy for the final histology, ESD could have a curative as well as a diagnostic purpose. PMID- 29122604 TI - Clinical predictors of histologic type of gastric cancer. AB - BACKGROUND AND AIMS: Gastric cancer is classified into differentiated and undifferentiated types according to the degree of glandular differentiation. Undifferentiated-type early gastric cancer (EGC) carries a higher risk of lymph node metastasis than differentiated type, and therefore the indication criteria for endoscopic resection differ. This study aimed to clarify the ability of clinical predictors to distinguish between differentiated-type and undifferentiated-type EGCs. METHODS: This was a post hoc study of a multicenter prospective trial carried out in 5 Japanese hospitals, including 343 patients with cT1 EGC of >=10 mm. According to the protocol, age, sex, and endoscopic findings of cancer (diameter, location, macroscopic type, and invasion depth) were evaluated, and the final diagnosis was confirmed from resected specimens. We evaluated the associations between these clinical factors and the histologic type of cancer and calculated the ability of the factors to diagnose differentiated type EGC. The diagnostic ability of forceps biopsy was also calculated as a reference. RESULTS: Multivariate analysis identified older age (>=72 years), male sex, larger tumor size (>30 mm), elevated type, and shallower invasion depth (cT1a) as independent significant predictors for differentiated-type EGC, with elevated type showing the highest positive likelihood ratio. The sensitivity, specificity, accuracy, and positive and negative likelihood ratios of elevated type for differentiated-type EGC were 24%, 99%, 38%, 15.7, and 0.77, respectively, compared with 96%, 86%, 95%, 7.0, and 0.04 for forceps biopsy. CONCLUSIONS: Endoscopic elevated type is a significant predictor for differentiated-type EGC and may exclude undifferentiated-type EGC without the need for forceps biopsy. PMID- 29122606 TI - Foodborne cryptosporidiosis. AB - Foodborne illness, the majority of which is caused by enteric infectious agents, costs global economies billions of dollars each year. The protozoan parasite Cryptosporidium is particularly suited to foodborne transmission and is responsible for >8 million cases of foodborne illness annually. Procedures have been developed for sensitive detection of Cryptosporidium oocysts on fresh produce and molecular diagnostic assays have been widely used in case linkages and infection source tracking, especially during outbreak investigations. The integrated use of advanced diagnostic techniques with conventional epidemiological studies is essential to improve our understanding of the occurrence, source and epidemiology of foodborne cryptosporidiosis. The implementation of food safety management tools such as Good Hygienic Practices (GHP), Hazard Analysis and Critical Control Points (HACCP), and Quantitative Microbial Risk Assessment (QMRA) in industrialised nations and Water, Sanitation, and Hygiene (WASH) in developing countries is central for prevention and control and foodborne cryptosporidiosis in the future. PMID- 29122607 TI - Morphological variation in the cosmopolitan fish parasite Neobenedenia girellae (Capsalidae: Monogenea). AB - Intra-species morphological variation presents a considerable problem for species identification and can result in taxonomic confusion. This is particularly pertinent for species of Neobenedenia which are harmful agents in captive fish populations and have historically been identified almost entirely based on morphological characters. This study aimed to understand how the morphology of Neobenedenia girellae varies with host fish species and the environment. Standard morphological features of genetically indistinct parasites from various host fish species were measured under controlled temperatures and salinities. An initial field-based investigation found that parasite morphology significantly differed between genetically indistinct parasites infecting various host fish species. The majority of the morphological variation observed (60%) was attributed to features that assist in parasite attachment to the host (i.e. the posterior and anterior attachment organs and their accessory hooks) which are important characters in monogenean taxonomy. We then experimentally examined the effects of the interaction between host fish species and environmental factors (temperature and salinity) on the morphology of isogenic parasites derived from a single, isolated hermaphroditic N. girellae infecting barramundi, Lates calcarifer. Experimental infection of L. calcarifer and cobia, Rachycentron canadum, under controlled laboratory conditions did not confer host-mediated phenotypic plasticity in N. girellae, suggesting that measured morphological differences could be adaptive and only occur over multiple parasite generations. Subsequent experimental infection of a single host species, L. calcarifer, at various temperatures (22, 30 and 32 degrees C) and salinities (35 and 400/00) showed that in the cooler environments (22 degrees C) N. girellae body proportions were significantly smaller compared with warmer temperatures (30 and 32 degrees C; P < 0.0001), whereas salinity had no effect. This is evidence that temperature can drive phenotypic plasticity in key taxonomic characters of N. girellae under certain environmental conditions. PMID- 29122609 TI - Structural connections support emotional connections: Uncinate Fasciculus microstructure is related to the ability to decode facial emotion expressions. AB - The Uncinate Fasciculus (UF) is an association fibre tract connecting regions in the frontal and anterior temporal lobes. UF disruption is seen in several disorders associated with impaired social behaviour, but its functional role is unclear. Here we set out to test the hypothesis that the UF is important for facial expression processing, an ability fundamental to adaptive social behaviour. In two separate experiments in healthy adults, we used high-angular resolution diffusion-weighted imaging (HARDI) and constrained spherical deconvolution (CSD) tractography to virtually dissect the UF, plus a control tract (the corticospinal tract (CST)), and quantify, via fractional anisotropy (FA), individual differences in tract microstructure. In Experiment 1, participants completed the Reading the Mind in the Eyes Task (RMET), a well validated assay of facial expression decoding. In Experiment 2, a different set of participants completed the RMET, plus an odd-emotion-out task of facial emotion discrimination. In both experiments, participants also completed a control odd-identity-out facial identity discrimination task. In Experiment 1, FA of the right-, but not the left-hemisphere, UF was significantly correlated with performance on the RMET task, specifically for emotional, but not neutral expressions. UF FA was not significantly correlated with facial identity discrimination performance. In Experiment 2, FA of the right-, but not left hemisphere, UF was again significantly correlated with performance on emotional items from the RMET, together with performance on the facial emotion discrimination task. Again, no significant association was found between UF FA and facial identity discrimination performance. Our findings highlight the contribution of right-hemisphere UF microstructure to inter-individual variability in the ability to decode facial emotion expressions, and may explain why disruption of this pathway affects social behaviour. PMID- 29122610 TI - Links between action perception and action production in 10-week-old infants. AB - In order to understand how experience of an action alters functional brain responses to visual information, we examined the effects of reflex walking on how 10-week-old infants processed biological motion. We gave experience of the reflex walk to half the participants, and did not give this experience to the other half of the sample. The participant's electrical brain activity in response to viewing upright and inverted walking and crawling movements indicated the detection of biological motion only for that group which experience the reflex walk, as evidenced by parietal electrode greater positivity for the upright than the inverted condition. This effect was observed only for the walking stimuli. This study suggests that parietal regions are associated with the perception of biological motion even at 9-11 weeks. Further, this result strongly suggests that experience refines the perception of biological motion and that at 10 weeks of age, the link between action perception and action production is tightly woven. PMID- 29122608 TI - Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity. AB - Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu2+/Zn2+-induced neurotoxicity. Firstly, HSA Trx was found to clearly suppress Cu2+/Zn2+-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu2+/Zn2+-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu2+ and Zn2+ after Cu2+/Zn2+ treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu2+/Zn2+ treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu2+/Zn2+-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases. PMID- 29122611 TI - Effect of ergosterol on the fungal membrane properties. All-atom and coarse grained molecular dynamics study. AB - Cell membranes are complex multicomponent systems consisting of thousands of different lipids with numerous embedded membrane proteins and many types of sterols. We used all-atom and coarse-grained molecular dynamics simulations to study the structural and dynamical properties of phospholipid bilayers containing four types of phospholipids and different amount of ergosterol, main sterol component in the fungal membranes. To characterize the influence of ergosterol on the membrane properties we analyzed the surface area per lipid, bilayer thickness, area compressibility modulus, mass density profiles, deuterium order parameters, and lateral diffusion coefficients. The presence of ergosterol induces the ordering of lipids leading to their denser packing, to reducing the lateral diffusion of lipids and lipid surface area, to increasing the thickness of bilayer and compressibility modulus. In addition, we evaluated each calculated property between the two simulation methods. PMID- 29122612 TI - MALDI imaging of enzymatic degradation of glycerides by lipase on textile surface. AB - Most modern laundry detergents contain enzymes such as proteases, amylases, and lipases for more efficient removal of stains containing proteins, carbohydrates, and lipids during wash at low temperature. The function of the lipases is to hydrolyse the hydrophobic triglycerides from fats and oils to the more hydrophilic lipids diglycerides, monoglycerides and free fatty acids. Here, we use MALDI imaging to study the effect of enzymatic degradation of triglycerides by lipases directly on the textile surface. Textile samples were created by using swatches of different textile blends, adding a lipid stain and simulating washing cycles using well-defined detergents with lipase concentrations ranging between 0 and 0.5ppm. After washing, the textile swatches as well as cryo-sections of the swatches were imaged using MALDI imaging in positive ion mode at pixel sizes of 15-75MUm. Similar samples were imaged by DESI-MSI for comparison. Despite the rough surface and non-conductive nature of textile, MALDI imaging of glycerides on textile was readily possible. The results show extensive enzymatic degradation of triglycerides into diglycerides, and images suggest that this degradation takes place in a quite heterogeneous manner as also observed in images of cross sections. DESI-imaging reveals the same kind of enzymatic degradation, but with a more homogeneous appearance. While the enzymatic degradation is exemplified in a few images, the overall degradations process was monitored by extraction of ion intensities from 298 individual ion masses of mono-, di- and triglycerides and free fatty acids. MALDI imaging of glycerides was possible directly from a textile surface, allowing visualization of the enzymatic degradation of fatty stains on textile during the laundry process. The images showed an inhomogeneous presence of diglycerides after lipase treatment both in planar images of the textile surface as well as in cross-sections suggesting a non-uniform enzyme effect or extraction of the lipase reaction products from the textile. PMID- 29122605 TI - Phenotypic characterization of P23H and S334ter rhodopsin transgenic rat models of inherited retinal degeneration. AB - We produced 8 lines of transgenic (Tg) rats expressing one of two different rhodopsin mutations in albino Sprague-Dawley (SD) rats. Three lines were generated with a proline to histidine substitution at codon 23 (P23H), the most common autosomal dominant form of retinitis pigmentosa in the United States. Five lines were generated with a termination codon at position 334 (S334ter), resulting in a C-terminal truncated opsin protein lacking the last 15 amino acid residues and containing all of the phosphorylation sites involved in rhodopsin deactivation, as well as the terminal QVAPA residues important for rhodopsin deactivation and trafficking. The rates of photoreceptor (PR) degeneration in these models vary in proportion to the ratio of mutant to wild-type rhodopsin. The models have been widely studied, but many aspects of their phenotypes have not been described. Here we present a comprehensive study of the 8 Tg lines, including the time course of PR degeneration from the onset to one year of age, retinal structure by light and electron microscopy (EM), hemispheric asymmetry and gradients of rod and cone degeneration, rhodopsin content, gene dosage effect, rapid activation and invasion of the outer retina by presumptive microglia, rod outer segment disc shedding and phagocytosis by the retinal pigmented epithelium (RPE), and retinal function by the electroretinogram (ERG). The biphasic nature of PR cell death was noted, as was the lack of an injury induced protective response in the rat models. EM analysis revealed the accumulation of submicron vesicular structures in the interphotoreceptor space during the peak period of PR outer segment degeneration in the S334ter lines. This is likely due to the elimination of the trafficking consensus domain as seen before as with other rhodopsin mutants lacking the C-terminal QVAPA. The 8 rhodopsin Tg lines have been, and will continue to be, extremely useful models for the experimental study of inherited retinal degenerations. PMID- 29122613 TI - Hemin- and myoglobin-catalyzed reaction of 1-palmitoyl-2-linoleoyl-3-sn phosphatidylcholine 13-hydroperoxide with gamma-tocopherol in micelles and liposomes. AB - The secondary process of lipid peroxidation proceeds by the free radical reaction to produce some toxic aldehydes. Since gamma-tocopherol (gamma-TH), one of the major forms of vitamin E in some vegetable oils, acts as a free radical scavenger, gamma-TH may suppress the formation of such aldehydes. This study reports the effect and reaction products of gamma-TH on the hemin- or myoglobin catalyzed decomposition of 1-palmitoyl-2-linoleoyl-3-sn-phosphatidylcholine 13 hydroperoxide (PLPC-OOH) in micelles and liposomes. gamma-TH and PLPC-OOH in micelles were reacted in the presence of hemin, and the reaction products were characterized as 1-palmitoyl-2-[(8a-dioxy-gamma-tocopherone)-12,13 epoxyoctadecenoyl]-3-sn-phosphatidylcholines (gammaT-OO-epoxyPLPC), 1-palmitoyl-2 [(gamma-tocopheroxy)-12,13-epoxyoctadecenoyl]-3-sn-phosphatidylcholines (gammaT epoxyPLPC), and the adducts of gamma-TH dimer with PLPC-OOH derived epoxyperoxyl and epoxyalkyl radicals (gammaTD-OO-epoxyPLPC and gammaTD-epoxyPLPC). The hemin- and myoglobin-catalyzed decomposition of PLPC-OOH in micelles produced hexanal and 4-hydroxy-2-nonenal as the major aldehydic products. gamma-TH suppressed the formation of these aldehydes as the same level as alpha-TH did, and gamma tocopherylquinone, tocored, gamma-TH dimers, and the addition products (gammaT-OO epoxyPLPC, gammaT-epoxyPLPC, gammaTD-OO-epoxyPLPC, and gammaTD-epoxyPLPC) were formed during the reaction. In liposomes, hexanal was detected as the major aldehyde and its suppression by gamma-TH was less effective than that by alpha TH. The results indicate that gamma-TH may suppress the formation of aldehydes by trapping the epoxyperoxyl and epoxyalkyl radicals derived from PLPC-OOH although its ability is weak in liposomal systems. PMID- 29122614 TI - A recombinant fusion protein-based, fluorescent protease assay for high throughput-compatible substrate screening. AB - In connection with the intensive investigation of proteases, several methods have been developed for analysis of the substrate specificity. Due to the great number of proteases and the expected target molecules to be analyzed, time- and cost efficient high-throughput screening (HTS) methods are preferred. Here we describe the development and application of a separation-based HTS-compatible fluorescent protease assay, which is based on the use of recombinant fusion proteins as substrates of proteases. The protein substrates used in this assay consists of N terminal (hexahistidine and maltose binding protein) fusion tags, cleavage sequences of the tobacco etch virus (TEV) and HIV-1 proteases, and a C-terminal fluorescent protein (mApple or mTurquoise2). The assay is based on the fluorimetric detection of the fluorescent proteins, which are released from the magnetic bead-attached substrates by the proteolytic cleavage. The protease assay has been applied for activity measurements of TEV and HIV-1 proteases to test the suitability of the system for enzyme kinetic measurements, inhibition studies, and determination of pH optimum. We also found that denatured fluorescent proteins can be renatured after SDS-PAGE of denaturing conditions, but showed differences in their renaturation abilities. After in-gel renaturation both substrates and cleavage products can be identified by in-gel UV detection. PMID- 29122615 TI - Ultrastructural and molecular characterization of Vairimorpha austropotamobii sp. nov. (Microsporidia: Burenellidae) and Thelohania contejeani (Microsporidia: Thelohaniidae), two parasites of the white-clawed crayfish, Austropotamobius pallipes complex (Decapoda: Astacidae). AB - The microsporidiosis of the endangered white-clawed crayfish Austropotamobius pallipes complex has generally been attributed to only one species, Thelohania contejeani, the agent of porcelain disease. Species identification was mostly assessed by macroscopic examination or microscopic evaluation of muscle samples rather than by molecular or ultrastructural analyses. A survey conducted on A. pallipes complex populations in Northern Italy highlighted the presence of two different microsporidia causing similar muscular lesions, T. contejeani and an undescribed octosporoblastic species Vairimorpha austropotamobii sp. nov. Mature spores and earlier developmental stages of V. austropotamobii sp. nov. were found within striated muscle cells of the thorax, abdomen, and appendages of the crayfish. Only octosporoblastic sporogony within sporophorous vesicles (SPVs) was observed. Diplokaryotic sporonts separated into two uninucleate daughter cells, which gave rise to a rosette-shaped plasmodium, and eight uninucleate spores were produced within the persistent SPV. Ultrastructural features of stages in the octosporoblastic sequence were similar to those described for Vairimorpha necatrix, the type species. Mature spores were pyriform in shape and an average of 3.9 * 2.2 um in size. The polar filament was coiled 11-14 times, lateral to the posterior vacuole. The small subunit ribosomal RNA gene (SSU rRNA) and the large subunit RNA polymerase II gene (RPB1) of V. austropotamobii sp. nov. were sequenced and compared with other microsporidia. The highest sequence identity of SSU rRNA (99%) and RPB1 (74%) genes was with the amphipod parasite Nosema granulosis and subsequently with V. cheracis, which infects the Australian yabby Cherax destructor. In our work we discuss about the reasons for placing this new species in the genus Vairimorpha. In addition, we provide for T. contejeani a RPB1 gene sequence, supplemental sequences of SSU rRNA gene and ultrastructural details of its sporogony in the host A. pallipes complex. PMID- 29122616 TI - Practice Patterns of Medications for Patients With Malignant Bowel Obstruction Using a Nationwide Claims Database and the Association Between Treatment Outcomes and Concomitant Use of H2-Blockers/Proton Pump Inhibitors and Corticosteroids With Octreotide. AB - CONTEXT: Malignant bowel obstruction impairs the quality of life in patients with advanced cancer. Octreotide, acid-suppressing medications such as H2-receptor antagonists (H2-blockers) and proton pump inhibitors (PPIs), and corticosteroids are often used in combination for symptom control. OBJECTIVES: We evaluated the practice patterns of medications for patients hospitalized with malignant bowel obstruction using a large claims database in Japan. In addition, we explored the association of adding H2-blockers/PPIs or corticosteroids to octreotide on treatment outcomes. METHODS: We analyzed data from a nationwide medical claims database from April 2010 to March 2015 containing 975,000 patients. We included all adult inpatients with cancer who used octreotide 300 MUg/day or more and summarized each patient's medication use. We also assessed whether concomitant use of H2-blockers/PPIs or corticosteroids was associated with the number of days of nasogastric tube (NGT) insertion; logistic regression was used to adjust the patients' baseline factors. RESULTS: We included 3090 patients; octreotide alone was used in 1649 (53%) cases. A combination of octreotide and H2-blockers or PPIs was used in 419 and 337 cases (14% and 11%), respectively; a combination of octreotide and corticosteroids was used in 374 cases (12%). Of the 1595 patients who underwent NGT insertion, those using corticosteroids with octreotide had a higher odds ratio of NGT removal within four days of insertion (adjusted odds ratio = 1.16; 95% CI = 1.08-1.23). CONCLUSION: Octreotide alone was used in the majority of patients, and the concomitant use of corticosteroids was more likely to be associated with early NGT removal. PMID- 29122617 TI - The Collusion Classification Grid: A Supervision and Research Tool. PMID- 29122618 TI - Effects of Tai Chi Exercise on Cancer-Related Fatigue in Patients With Nasopharyngeal Carcinoma Undergoing Chemoradiotherapy: A Randomized Controlled Trial. AB - CONTEXT: Tai Chi exercise has been shown to improve cancer-related fatigue (CRF) and autonomic nervous system (ANS) balance in some cancer patients or survivors; however, such effects are yet to be verified in nasopharyngeal carcinoma (NPC) patients undergoing chemoradiotherapy. OBJECTIVES: To explore the effects of Tai Chi exercise on CRF in NPC patients undergoing chemoradiotherapy and then to evaluate ANS information indicated by heart rate variability parameters and their association with CRF. METHODS: A randomized controlled trial of Tai Chi exercise was conducted from January 2014 to August 2015. Participants in the Tai Chi group practiced Tai Chi a one-hour session, five sessions/week during chemoradiotherapy. Participants in the control group received usual care. The primary end points were scores of the multidimensional fatigue symptom inventory short form (MFSI-SF). Secondary end points were heart rate variability parameters, including normalized low-frequency (nLF) power, normalized high frequency (nHF) power, and the nLF/nHF ratio, and their association with CRF. RESULTS: One hundred fourteen patients were recruited in this study, and 83 patients completed the trial. The Tai Chi group and the control group had comparable baseline characteristics. After chemoradiotherapy, the Tai Chi group exhibited lower MFSI-SF total score and three negative subscale (general, physical, and emotional fatigue) scores and higher vigor score compared with the control group (P < 0.01 for all). The nLF/nHF ratio was significantly lower in the Tai Chi group compared to the control group after chemoradiotherapy. The MFSI SF total score was markedly correlated with the nLF/nHF ratio. CONCLUSION: Tai Chi exercise is conducive to alleviate CRF in NPC patients undergoing chemoradiotherapy. The improvement in ANS balance might fit into the process of Tai Chi for CRF management in this population. PMID- 29122620 TI - Three-Year Outcomes of the Prospective, Randomized Controlled Rezum System Study: Convective Radiofrequency Thermal Therapy for Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia. AB - OBJECTIVE: To report 3-year outcomes of a prospective, multicenter, randomized, blinded control trial after treatment with convective radiofrequency (RF) water vapor thermal therapy for moderate to severe lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Fifteen centers enrolled and randomized 197 men >=50 years old with International Prostate Symptom Score (IPSS) >=13, maximum flow rate (Qmax) <=15 mL/s, and prostate volume 30 to 80 cc to thermal therapy with Rezum System or control (2:1). Rigid cystoscopy with simulated active treatment sound effects served as the control procedure. Convective RF thermal energy was delivered into obstructive prostate tissue including the median lobe as needed. After randomized comparison at 3 months, thermal therapy subjects were followed annually for 3 years. RESULTS: Convective RF thermal therapy yielded IPSS improvement of 160% compared with control subjects at 3 months (P <.0001). Maximal symptom relief of at least 50% improvement in IPSS, quality of life, Qmax, and BPH Impact Index remained durable throughout 3 years (P <.0001). Subjects with a treated median lobe had similar responses. No late-related adverse events occurred, and no de novo erectile dysfunction was reported. The surgical retreatment rate was 4.4% over 3 years. CONCLUSION: The minimally invasive convective RF thermal therapy is an office or ambulatory outpatient procedure with minimal transient perioperative side effects. It provides early effective and durable relief of BPH symptoms with preservation of sexual function in subjects followed up for 3 years and is applicable to treatment of the median lobe and hyperplastic central zone tissue. PMID- 29122621 TI - Simple Operating Room Bundle Reduces Superficial Surgical Site Infections After Major Urologic Surgery. AB - OBJECTIVE: To reduce our superficial surgical site infection rate following major urologic surgery by implementing a simple operating room bundle. METHODS: A simple operating room bundle was applied to all major urologic cases (cystectomy, nephrectomy, and prostatectomy) at a single tertiary referral center. The bundle included allowing skin prep to dry appropriately, changing gloves before skin closure, irrigating the wound before skin closure, and using a new separate sterile closing instrument set for skin closure. Alcohol-based preps were also introduced hospital-wide 3 months into the study period. The SSI rate was obtained from the National Surgical Quality Improvement Program (NSQIP) database. RESULTS: The surgical site infection (SSI) rate was assessed after a 14-month study period for a total of 510 cases. Before instituting the alcohol-based prep, but after the bundle was implemented, 138 cases were analyzed over a 3-month period with an SSI rate of 0%. For the remaining 11 months with both the alcohol based prep and the infection prevention bundle in place, the infection rate was 1.37% (7/510) as compared with 3.57% (22/615) for the 12-month period before bundle introduction, a statistically significant reduction (P = .023). CONCLUSION: The SSI rate after major urologic surgery at 1 center was reduced after the introduction of a simple, fast, low-cost, and easily reproducible bundle into the operating room. The use of this bundle reduces SSI, which is critical for the patient and the physician in this era of public reporting and reimbursement based on outcomes. PMID- 29122619 TI - Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor. AB - BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted. PMID- 29122622 TI - Epidural Abscess Following Prostate Biopsy. PMID- 29122623 TI - Intussusception of the Small Bowel Secondary to Benign Ectopic Prostate Tissue. PMID- 29122624 TI - Incidental Asymptomatic Leiomyoma of the Urinary Bladder. PMID- 29122625 TI - Comparison of Intraoperative and Early Postoperative Outcomes of Caudal vs Dorsal Penile Nerve Blocks for Outpatient Penile Surgeries. AB - OBJECTIVE: To compare intraoperative and 1-hour postoperative outcomes in caudal vs dorsal penile nerve block (DPNB) patients undergoing penile surgeries. MATERIALS AND METHODS: We performed a retrospective cohort study of boys <10 years old undergoing penile procedures (2013-2015) using the Pediatric Regional Anesthesia Network, Pediatric Health Information System databases, and our medical records. The primary outcome was a maximum Faces Limbs Activity Crying Consolability pain score of >3. Secondary outcomes were intraoperative postanesthesia care unit (PACU) narcotics, preincision anesthesia time, adjusted operating room charges, and complications. We performed bivariate and multivariable analyses controlling for demographic and procedural characteristics and clustering by surgeon. RESULTS: Of 738 patients (mean age 2.1 years), 74.1% had a caudal block. DPNB patients were more likely to have a maximum pain score of >3 (19.5% vs 8.1%, P <.0001), receive intraoperative (33.0% vs 2.9%, P <.0001) and PACU (15.7% vs 7.5%, P = .0009) narcotics, and had shorter preincision anesthesia times (19.5 vs 27.9 minutes, P <.0001) and lower adjusted operating room charges ($9,402 vs $12,760, P <.0001). In a bivariate logistic regression, DPNB patients had 2.7 times the odds of a maximum pain score of >3 (95% confidence interval 1.7-4.4, P <.0001) and 5.2 times the odds of intraoperative and PACU narcotic administration (95% confidence interval 3.3-8.1, P <.0001). In multivariable analyses, caudal patients had longer preincision anesthesia times (27.9 +/- 7.4 vs 19.5 +/- 6.6 minutes, P <.0001) and higher adjusted operating room charges ($12,760 +/- 4077 vs $9,402 +/- 3741, P = .01). CONCLUSION: Caudal blocks may offer a small advantage in the immediate postoperative period, although cost-effectiveness is unproven. PMID- 29122626 TI - A Periurethral Mass in a Female Patient With Sarcoidosis. PMID- 29122627 TI - Glial function (and dysfunction) in the normal & ischemic brain. AB - Astrocytes are the most abundant cell type in the central nervous system (CNS). Once considered to be of fairly homogeneous phenotype throughout the brain and spinal cord, they are now understood to be heterogeneous in both structure and function. They are important in brain functions as diverse as ion and fluid balance in the interstitial space, contributing to integrity of the neurovascular unit (blood-brain barrier), neurotransmitter regulation, metabolism of energy substrates and possibly even axonal regeneration. After ischemic or hemorrhagic brain/spinal cord injury, formation of an astrocytic scar adjacent to the 'lesion' is a characteristic histopathologic feature, and this astrogliosis can be demonstrated by immunohistochemistry, usually using primary antibodies to glial fibrillary acidic protein (GFAP). Astrocytes interact with microglia and oligodendroglia in novel ways that will be discussed in this review. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 29122629 TI - Long-term cilostazol administration prevents age-related decline of hippocampus dependent memory in mice. AB - Phosphodiesterases (PDEs) are enzymes that hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and/or 3', 5'-cyclic guanosine monophosphate (cGMP). The regulation of intracellular signaling pathways mediated by cyclic nucleotides is imperative to synaptic plasticity and memory in animals. Because PDEs play an important role in this regulation, PDE inhibitors are considered as candidate compounds for treating cognitive and memory disorders. In the present study, we tested whether cilostazol, a selective PDE3 inhibitor, prevents the cognitive deterioration that occurs during the course of normal aging in mice. Ten months of cilostazol administration (1.5%) in 13-month-old mice improved spatial memory when tested at 23 months of age. First, it prevented the decline in the ability of these aged mice to recognize a change in an object's location in the object recognition task. Second, spatial memory of these cilostazol treated aged mice in the Morris water maze was comparable to that of untreated middle-aged mice (13 months old). Cilostazol administration had no effect on the emotional states and physical ability of aged mice. Thus, long-term cilostazol administration prevented hippocampus-dependent memory decline in aged mice, allowing them to achieve a level of cognitive performance similar to middle-aged mice and without negative behavioral side effects. Considering its well established safety in other medical contexts, cilostazol may be a potential therapeutic candidate drug for staving off cognitive decline in the aging human population. PMID- 29122628 TI - A novel curcumin derivative for the treatment of diabetic neuropathy. AB - Neuropathy is a common complication of long-term diabetes. Proposed mechanisms of neuronal damage caused by diabetes that are downstream of hyperglycemia and/or loss of insulin signaling include ischemic hypoxia, inflammation and loss of neurotrophic support. The curcumin derivative J147 is a potent neurogenic and neuroprotective drug candidate initially developed for the treatment of neurodegenerative conditions associated with aging that impacts many pathways implicated in the pathogenesis of diabetic neuropathy. Here, we demonstrate efficacy of J147 in ameliorating multiple indices of neuropathy in the streptozotocin-induced mouse model of type 1 diabetes. Diabetes was determined by blood glucose, HbA1c, and insulin levels and efficacy of J147 by behavioral, physiologic, biochemical, proteomic, and transcriptomic assays. Biological efficacy of systemic J147 treatment was confirmed by its capacity to decrease TNFalpha pathway activation and several other markers of neuroinflammation in the CNS. Chronic oral treatment with J147 protected the sciatic nerve from progressive diabetes-induced slowing of large myelinated fiber conduction velocity while single doses of J147 rapidly and transiently reversed established touch-evoked allodynia. Conduction slowing and allodynia are clinically relevant markers of early diabetic neuropathy and neuropathic pain, respectively. RNA expression profiling suggests that one of the pathways by which J147 imparts its protection against diabetic induced neuropathy may be through activation of the AMP kinase pathway. The diverse biological and therapeutic effects of J147 suggest it as an alternative to the polypharmaceutical approaches required to treat the multiple pathogenic mechanisms that contribute to diabetic neuropathy. PMID- 29122630 TI - Four Years as Editor-in-Chief. PMID- 29122632 TI - New C16-noriridals and formyl-monocycloiridals from the rhizomes of Iris pseudoacorus. AB - Four new C16-noriridals (1-4) and two reported C16-noriridals (5-6), together with two new formyl-monocycloiridals (7-8) and three known monocycloiridals (9 11) were isolated from the rhizomes of Iris pseudoacorus. Irispseudoacorins A-D (1-4) and iridojaponals A-B (5-6) were C16-noriridals which shared a 6/5/7 tricyclic ring system (1-2, 5-6) or 6/5 tricyclic ring system (3-4). The formyl monocycloiridals (7-8) were detected in the crude extracts of I. pseudoacorus by LC-MS analysis which suggested they were originated from natural sources rather than artificial products during the isolation. Their structures were determined by UV, IR, extensive NMR spectra and X-ray diffraction analyses. The known monocycloiridals 9-10 displayed pronounced cytotoxic effects against five human tumor cell lines. The IC50 values of 9 were ranging from 12.63 to 24.69MUM. PMID- 29122631 TI - Mitral Valve Prolapse: Multimodality Imaging and Genetic Insights. AB - Mitral valve prolapse (MVP) is a common heritable valvulopathy affecting approximately 2.4% of the population. It is the most important cause of primary mitral regurgitation (MR) requiring surgery. MVP is characterized by fibromyxomatous changes and displacement of one or both mitral leaflets into the left atrium. Echocardiography represents the primary diagnostic modality for assessment of MVP. Accurate quantitation of ventricular volumes and function for surgical planning in asymptomatic severe MR can be provided with both echocardiography and cardiac magnetic resonance. In addition, assessment of myocardial fibrosis using late gadolinium enhancement and T1 mapping allows better understanding of the impact of MVP on the myocardium. Imaging in MVP is important not only for diagnostic and prognostic purposes, but is also essential for detailed phenotyping in genetic studies. Genotype-phenotype studies in MVP pedigrees have allowed the identification of milder, non-diagnostic MVP morphologies by echocardiography. Such morphologies represent early expression of MVP in gene carriers. This review focuses on multimodality imaging and the phenotypic spectrum of MVP. Moreover, the review details the recent genetic discoveries that have increased our understanding of the pathophysiology of MVP, with clues to mechanisms and therapy. PMID- 29122633 TI - Iridoids and sfingolipids from Hedyotis diffusa. AB - Seven new compounds were isolated from the aerial part of Hedyotis diffusa, including three iridoid glycosides, hedyoiridoidside A - C (1-3), two cerebrosides, hedyocerenoside F (4) and G (5), and two new ceramides, hedyoceramide A (6) and B (7). And six known iridoid glycosides (8-13) were also obtained. Their structures were established by their physico-chemical constants and spectroscopic analysis. The cytotoxicity of all compounds against tumor cell lines of human cervical cancer HeLa, human leukemia HL-60, human lung cancer A459, human hepatoma HepG2, human gastric gland carcinoma BCG-823, human nasopharyngeal cancer CNE-2, human colon cancer HCT15, and human prostate cancer PC-3 were also evaluated in vitro. As a result, new compound 1 exhibited evident cytotoxicity to all tumor cell lines, and the IC50 values are from 9.5MUM to 28.2MUM, while new compound 2 exhibited evident cytotoxicity to Hela, HL-60, A459, HepG2, BGC-823, CNE-2, and HCT15, and the IC50 values are from 15.8MUM to 26.2MUM. Known compound 11 also exhibited evident cytotoxicity to HL-60, A459, HepG2, BGC-823, CNE-2, and HCT15, and the IC50 values are from 16.5MUM to 40.4MUM. New compounds 4-7 and known compounds 12 and 13 showed moderate cytotoxicity to some tumor cell lines. PMID- 29122634 TI - Development of molecular and cellular tools to decipher the type I IFN pathway of the common vampire bat. AB - Though the common vampire bat, Desmodus rotundus, is known as the main rabies virus reservoir in Latin America, no tools are available to investigate its antiviral innate immune system. To characterize the IFN-I pathway, we established an immortalized cell line from a D. rotundus fetal lung named FLuDero. Then we molecularly characterized some of the Toll-like receptors (TLR3, 7, 8 and 9), the three RIG-I-like receptor members, as well as IFNalpha1 and IFNbeta. Challenging the FLuDero cell line with poly (I:C) resulted in an up-regulation of both IFNalpha1 and IFNbeta and the induction of expression of the different pattern recognition receptors characterized. These findings provide evidence of the intact dsRNA recognition machinery and the IFN-I signaling pathway in our cellular model. Herein, we generated a sum of insightful specific molecular and cellular tools that will serve as a useful model to study virus-host interactions of the common vampire bat. PMID- 29122635 TI - Inpatient Proton Pump Inhibitor Administration and Hospital-Acquired Clostridium difficile Infection: Evidence and Possible Mechanism. AB - The incidence of Clostridium difficile infection continues to increase globally. Particularly concerning are hospital-acquired cases that attribute significant morbidity, mortality, and expenditures to the health care system. Proton pump inhibitors, which are widely prescribed and generally considered to have minimal adverse effects, have recently come under scrutiny for positive associations with C. difficile infection development. This article will specifically review the current state of evidence demonstrating a positive association between nosocomial proton pump inhibitor administration and the incidence of hospital-acquired C. difficile infection. In addition, the article delivers state-of-the-art knowledge relative to mechanisms by which proton pump inhibitor exposure may propagate the manifestation of C. difficile infection. PMID- 29122636 TI - Clinical Outcomes and History of Fall in Patients with Atrial Fibrillation Treated with Oral Anticoagulation: Insights From the ARISTOTLE Trial. AB - PURPOSE: We assessed outcomes among anticoagulated patients with atrial fibrillation and a history of falling, and whether the benefits of apixaban vs warfarin are consistent in this population. METHODS: Of the 18,201 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, 16,491 had information about history of falling 753 with history of falling and 15,738 without history of falling. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding. RESULTS: When compared with patients without a history of falling, patients with a history of falling were older, more likely to be female and to have dementia, cerebrovascular disease, depression, diabetes, heart failure, osteoporosis, fractures, and higher CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >=75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism, Vascular disease, Age 65-74 years, Sex category female) and HAS BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile international normalized ratio, Elderly, Drugs or alcohol) scores. Patients with a history of falling had higher rates of major bleeding (adjusted hazard ratio [HR] 1.39; 95% confidence interval [CI], 1.05-1.84; P = .020), including intracranial bleeding (adjusted HR 1.87; 95% CI, 1.02-3.43; P = .044) and death (adjusted HR 1.70; 95% CI, 1.36-2.14; P < .0001), but similar rates of stroke or systemic embolism and hemorrhagic stroke. There was no evidence of a differential effect of apixaban compared with warfarin on any outcome, regardless of history of falling. Among those with a history of falling, subdural bleeding occurred in 5 of 367 patients treated with warfarin and 0 of 386 treated with apixaban. CONCLUSIONS: Patients with atrial fibrillation and a history of falling receiving anticoagulation have a higher risk of major bleeding, including intracranial, and death. The efficacy and safety of apixaban compared with warfarin were consistent, irrespective of history of falling. PMID- 29122637 TI - Side effect burden of antipsychotic drugs in real life - Impact of gender and polypharmacy. AB - BACKGROUND: Antipsychotic-associated side effects are well known and represent a significant treatment challenge. Still, few large studies have investigated the overall side effect burden of antipsychotics in real-life settings. OBJECTIVE: To describe the occurrence of side effects and perceived burden of antipsychotics in a large naturalistic sample, taking polypharmacy and patient characteristics into account. METHOD: Patients (n=1087) with psychotic disorders were assessed for side effects using the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale in addition to assessment of clinical and pharmacological data. Statistical analyses were performed controlling for possible confounding factors. RESULTS: Use of antipsychotics showed significant associations to neurologic and sexual symptoms, sedation and weight gain, and >75% of antipsychotics-users reported side effects. More side effects were observed in patients using several antipsychotics (p=0.002), with increasing total dose (p=0.021) and with antipsychotics in combinations with other psychotropic drugs. Patients and investigators evaluated the side effect burden differently, particularly related to severity, gender and antipsychotics dose. Twice as many females described side effect burden as severe (p=0.004). CONCLUSION: Patients with psychotic disorders have a high occurrence of symptoms associated with use of antipsychotics, and polypharmacy and female gender are seemingly risk factors for reporting a severe side effect burden. Due to the cross-sectional design evaluation of causality is tentative, and these findings should be further investigated in prospective studies. PMID- 29122638 TI - Neural indices of emotional reactivity and regulation predict course of PTSD symptoms in combat-exposed veterans. AB - After diagnosis, veterans with posttraumatic stress disorder (PTSD) display significant variability in the natural course of illness (Bonanno et al., 2012)). Cross-sectional work reveals that abnormal neural response during emotion reactivity-measured using the late positive potential (LPP)-correlates with PTSD symptom severity; however, whether the LPP during emotional reactivity and regulation predicts symptoms over time is unknown. The current study examined the LPP during emotion reactivity and regulation as predictors of PTSD symptoms over one year in OEF/OIF/OND combat-exposed veterans. At baseline, participants completed an Emotion Regulation Task (ERT) during electroencephalogram recording. The Clinician Administered PTSD Scale (CAPS) was completed at baseline (N=86), 6 months (N=54) and 1-year (N=49) later. During ERT, participants viewed negative pictures; partway through they were instructed to "reappraise" (i.e., reduce negative affect/regulate) or "look" (i.e., passively react). Change in LPP during emotional reactivity (DeltaLPP-E) and reappraisal (DeltaLPP-R) were calculated and used in multilevel mixed modeling to predict CAPS over time. Findings demonstrated that deficiency in reappraisal (DeltaLPP-R) predicted more overall symptoms over time, while greater neural responses to emotion (DeltaLPP-E) and greater change in neural response as a function of reappraisal (DeltaLPP-R) predicted a decline in avoidance symptoms over time. Together, results support the utility of neural markers of emotional reactivity and regulation as predictors of PTSD symptoms-and change in symptoms-across one year. PMID- 29122639 TI - The P2RX7 polymorphism rs2230912 is associated with depression: A meta-analysis. AB - Various studies have investigated whether single nucleotide polymorphisms (SNPs) in the gene purinergic receptor P2X7 (P2RX7), and rs2230912 specifically, were associated with mood disorders. While some studies found positive evidence, a large number of studies reported no significant associations. In a previously published meta-analysis, Feng et al. did not find a significant association and only moderate odds ratios (ORs) in case-control studies. They reported significant findings only for family-based studies. We revisited this finding and conducted a meta-analysis including 8,652 cases and 11,153 controls, adding unpublished results from the Munich Antidepressant Response Signature (MARS) study. We found a significant association between rs2230912 and combined mood disorders (major depressive disorder (MDD) or bipolar disorder (BD)) for the allelic, dominant and heterozygous-disadvantage model, all withstanding the threshold of correction for multiple testing. Stratifying by disorder revealed significant findings for the MDD-subgroup (OR of 1.12 for the allelic model), while the BD-subgroup presented with a lower effect size (OR of 1.05) and no significance. P2RX7 encodes a purinergic receptor which is expressed in the brain and also localized in immune cells. Animal studies and functional studies will be necessary to enlighten its involvement in the etiology of mood disorders and its applicability for pharmacological purposes. PMID- 29122640 TI - The influence of periodic increases of human activity on crepuscular and nocturnal mammals: Testing the weekend effect. AB - Human recreation can negatively affect wildlife, particularly on weekends when human activity is highest (i.e., the weekend effect). Much of what we understand about the weekend effect is based on research conducted on diurnal species, which have greater temporal overlap with humans. Because nocturnal species generally avoid times when humans are active, they are likely less affected by anthropogenic activity on weekends. Our objective was to test the weekend effect in relation to the degree of nocturnality of mammals in a recreational area. We predicted that as nocturnality increased, the effect of human activity would decrease. To address our objective, we placed 50 remote cameras along the Diamond Fork River in Utah from January to June 2015. We found that three out of the four focal species supported our predictions. Mule deer (crepuscular) reduced activity throughout our entire study area during weekends and avoided campgrounds. Beavers and mountain lions (both nocturnal) did not negatively respond to increased human activity. Raccoons (nocturnal) reduced activity during weekends, but only within campground areas. Our findings indicate that as the temporal overlap increases between wildlife and humans, so does the influence that humans have on wildlife. PMID- 29122641 TI - Regularities in zebra finch song beyond the repeated motif. AB - The proliferation of birdsong research into the neural mechanisms of vocal learning is indebted to the remarkable stereotypy of the zebra finch's song motif. Motifs are composed of several syllables, which birds learn to produce in a fixed order. But at a higher level of organization-the bout-zebra finch song is no longer stereotyped. Song bouts include several repetitions of the motif, which are often linked by a variable number of short "connector" vocalizations. In this conceptual methods paper, we show that combinatorial analysis alone yields an incomplete description of this bout-level structure. In contrast, studying birdsong as a time-varying analog signal can reveal patterns of flexibility in the rhythmic organization of song bouts. Visualizing large song-samples in sorted raster plots shows that motifs are strung together via two distinct categories of connections: tight or loose. Loose connections allow considerable timing variation across renditions. Even among co-tutored birds that acquired similar motifs, we observe strong individual variability in rhythms and temporal plasticity of song bouts. These findings suggest that vocal flexibility could potentially allow individuals to express a variety of behavioral states through their songs, even in species that sing only a single stereotyped motif. PMID- 29122642 TI - Evaluation of the Roche(r) Elecsys and the Diasorin(r) Liaison S100 kits in the management of mild head injury in the emergency room. AB - INTRODUCTION: The aim of this single-center prospective study is to compare two commercially available S100beta kits (the Roche(r) Elecsys and the Diasorin(r) Liaison S100 kits) in terms of analytical and clinical performances in a population admitted in the emergency room for mild traumatic brain injury (mTBI). MATERIAL AND METHOD: 110 patients were enrolled from September 2014 to May 2015. Blood sample draws were performed within 3h after head trauma and the study population was split into pediatric and adult subpopulations (>18years of age). RESULTS: Although both kits correlated well, we observed a significant difference in terms of S100beta levels (P value<0.05) in both subpopulations. In the pediatric subpopulation, both kits showed elevated S100beta levels for the only patient (3.5%) who displayed abnormal findings on a CT-scan. However, we observed a poor agreement between both kits (Cohen's kappa=0.345, P value=0.077). In the adult subpopulation, a total of 10 patients (12.2%) had abnormal head computed tomography scans. Using the Roche(r) (cut off=0.1MUg/L) and the Diasorin(r) (cut off=0.15MUg/L) S100beta kits, brain injuries were detected with a sensitivity of 100% (95% CI: 65-100%) and 100% (95% CI: 63-100%) and a specificity of 15.28% (95% CI: 7.9-25.7%) and 24.64% (95% CI: 15-36.5) respectively. Finally, a moderate agreement was concluded between both kits (Cohen's kappa=0.569, P value=0.001). CONCLUSION: Although a good correlation could be found between both kits, emergency physicians should be aware of discrepancies observed between both methods, making those immunoassays not interchangeable. Furthermore, more studies are still needed to validate cut off used according to technique and to age, especially in the population below the age of 2years. PMID- 29122643 TI - Parathyroid hormone related protein concentration in human serum and CSF correlates with age. AB - BACKGROUND: Parathyroid Hormone-Related Protein (PTHrP) is involved in intracellular calcium (Ca) regulation, and has been demonstrated to participate in regulation of Ca in brain cells, activation of neurons, and modulation of pain. However, there are conflicting reports regarding the presence of PTHrP in CSF. DESIGN AND METHODS: PTHrP and Ca were quantified in paired CSF and serum samples using mass spectrometry-based methods. Associations between PTHrP and Ca concentrations with age, sex and concentrations of nine CSF diagnostic markers in a set of 140 paired serum and CSF patient samples were evaluated. RESULTS: The observed median PTHrP concentration in CSF was 51 times higher than in serum; the median concentration of Ca in CSF was 1.8 times lower than in serum. We observed positive correlation between concentrations of PTHrP in CSF and serum (p=0.013). Distribution of PTHrP concentrations in serum was associated with age (p=0.0068) and the concentrations were higher in women. In samples with serum calcium concentrations within the reference intervals (n=118), central 95% distribution of concentrations for Ca-CSF, PTHrP-serum and PTHrP-CSF were 5.4 (4.5-6.1) mg/dL, 1.2 (0.5-2.5) pmol/L, 62 (22-125) pmol/L, respectively. CONCLUSIONS: Our data demonstrate that PTHrP is a normal constituent of human CSF with median concentrations 51 fold higher than in serum. Elevated serum PTHrP concentrations were positively correlated with age and significantly higher in women. Our data suggest that CSF could be a significant source of circulating PTHrP. PMID- 29122644 TI - A neo-virus lifestyle exhibited by a (+)ssRNA virus hosted in an unrelated dsRNA virus: Taxonomic and evolutionary considerations. AB - Recent studies illustrate that fungi as virus hosts provides a unique platform for hunting viruses and exploring virus/virus and virus/host interactions. Such studies have revealed a number of as-yet-unreported viruses and virus/virus interactions. Among them is a unique intimate relationship between a (+)ssRNA virus, yado-kari virus (YkV1) and an unrelated dsRNA virus, yado-nushi virus (YnV1). YkV1 dsRNA, a replicated form of YkV1, and RNA-dependent RNA polymerase, are trans-encapsidated by the capsid protein of YnV1. While YnV1 can complete its replication cycle, YkV1 relies on YnV1 for its viability. We previously proposed a model in which YkV1 diverts YnV1 capsids as the replication sites. YkV1 is neither satellite virus nor satellite RNA, because YkV1 appears to encode functional RdRp and enhances YnV1 accumulation. This represents a unique mutualistic virus/virus interplay and similar relations in other virus/host fungus systems are detectable. We propose to establish the family Yadokariviridae that accommodates YkV1 and recently discovered viruses phylogenetically related to YkV1. This article overviews what is known and unknown about the YkV1/YnV1 interactions. Also discussed are the YnV1 Phytoreo_S7 and YkV1 2A-like domains that may have been captured via horizontal transfer during the course of evolution and are conserved across extant diverse RNA viruses. Lastly, evolutionary scenarios are envisioned for YkV1 and YnV1. PMID- 29122645 TI - Interleukin-33 levels are elevated in chronic allograft dysfunction of kidney transplant recipients and promotes epithelial to mesenchymal transition of human kidney (HK-2) cells. AB - This study is aimed to investigate the potential role of interleukin (IL)-33 in transplanted kidney interstitial fibrosis and the associated mechanism. Serum IL 33 levels were detected using an enzyme-linked immunosorbent assay (ELISA) in healthy volunteers, stable kidney transplantation recipients (KTRs) (stable), KTRs with acute rejection (AR), and KTRs with chronic allograft dysfunction (CAD) (CAD). Immunohistochemical (IHC) staining, Western blotting, and quantitative real-time PCR (qRT-PCR) were used to detect the expression of IL-33 in human kidney tissues obtained from control and CAD patients. In addition, human kidney (HK)-2 cells were treated with human IL-33 at different doses or intervals, and the markers of epithelial to mesenchymal transition (EMT) were assessed by the presence of proteins and mRNA extracted from these cells using Western blotting and qRT-PCR. Cell motility and migration were evaluated with a cell motility and migration assay. The mechanism involved in EMT induced by IL-33 was investigated by Western blot. Finally, fibronectin, E-cadherin, and alpha-SMA expression, as well as the level of activity in the MAPK signaling pathway in the kidney tissues from the control and CAD group were also detected using a Western blot and an IHC staining assay. The intensity of fibrosis was substantially higher in the CAD group. IL-33 was significantly upregulated in the CAD patients compared to the control group. In vitro, IL-33 could induce EMT in a dose-dependent and time dependent manner and promoted both the cellular motility and migration capabilities of HK-2 cells. Moreover, the p38 MAPK signaling pathway might be involved in the pathogenesis of EMT induced by IL-33, which was consistent with the in vivo results of the kidney specimens from the control and CAD patients. IL 33 was upregulated in CAD patients and could promote EMT of HK-2 cells. PMID- 29122647 TI - An automatic system for the comprehensive retrospective analysis of cardiac rhythms in resuscitation episodes. AB - AIM: An automatic resuscitation rhythm annotator (ARA) would facilitate and enhance retrospective analysis of resuscitation data, contributing to a better understanding of the interplay between therapy and patient response. The objective of this study was to define, implement, and demonstrate an ARA architecture for complete resuscitation episodes, including chest compression pauses (CC-pauses) and chest compression intervals (CC-intervals). METHODS: We analyzed 126.5h of ECG and accelerometer-based chest-compression depth data from 281 out-of-hospital cardiac arrest (OHCA) patients. Data were annotated by expert reviewers into asystole (AS), pulseless electrical activity (PEA), pulse generating rhythm (PR), ventricular fibrillation (VF), and ventricular tachycardia (VT). Clinical pulse annotations were based on patient-charts and impedance measurements. An ARA was developed for CC-pauses, and was used in combination with a chest compression artefact removal filter during CC-intervals. The performance of the ARA was assessed in terms of the unweighted mean of sensitivities (UMS). RESULTS: The UMS of the ARA were 75.0% during CC-pauses and 52.5% during CC-intervals, 55-points and 32.5-points over a random guess (20% for five categories). Filtering increased the UMS during CC-intervals by 5.2-points. Sensitivities for AS, PEA, PR, VF, and VT were 66.8%, 55.8%, 86.5%, 82.1% and 83.8% during CC-pauses; and 51.1%, 34.1%, 58.7%, 86.4%, and 32.1% during CC intervals. CONCLUSIONS: A general ARA architecture was defined and demonstrated on a comprehensive OHCA dataset. Results showed that semi-automatic resuscitation rhythm annotation, which may involve further revision/correction by clinicians for quality assurance, is feasible. The performance (UMS) dropped significantly during CC-intervals and sensitivity was lowest for PEA. PMID- 29122646 TI - Drug response prediction in high-risk multiple myeloma. AB - A Drug Response Prediction (DRP) score was developed based on gene expression profiling (GEP) from cell lines and tumor samples. Twenty percent of high-risk patients by GEP70 treated in Total Therapy 2 and 3A have a progression-free survival (PFS) of more than 10years. We used available GEP data from high-risk patients by GEP70 at diagnosis from Total Therapy 2 and 3A to predict the response by the DRP score of drugs used in the treatment of myeloma patients. The DRP score stratified patients further. High-risk myeloma with a predicted sensitivity to melphalan by the DRP score had a prolonged PFS, HR=2.4 (1.2-4.9, P=0.014) and those with predicted sensitivity to bortezomib had a HR 5.7 (1.2-27, P=0.027). In case of predicted sensitivity to bortezomib, a better response to treatment was found (P=0.022). This method may provide us with a tool for identifying candidates for effective personalized medicine and spare potential non-responders from suffering toxicity. PMID- 29122648 TI - Early Deterioration Indicator: Data-driven approach to detecting deterioration in general ward. AB - INTRODUCTION: Early detection of deterioration could facilitate more timely interventions which are instrumental in reducing transfer to higher levels of care such as Intensive Care Unit (ICU) and mortality [1,2]. METHODS AND RESULTS: We developed the Early Deterioration Indicator (EDI) which uses log likelihood risk of vital signs to calculate continuous risk scores. EDI was developed using data from 11,864 general ward admissions. To validate EDI, we calculated EDI scores on an additional 2418 general ward stays and compared it to the Modified Early Warning Score (MEWS) and National Early Warning Score (NEWS). EDI was trained using the most significant variables in predicting deterioration by leveraging the knowledge from a large dataset through data mining. It was implemented electronically for continuous automatic computation. The discriminative performance of EDI, MEWS, and NEWS was calculated before deterioration using the area under the receiver operating characteristic curve (AUROC). Additionally, the performance of the 3 scores for 24h prior to deterioration were computed. EDI was a better discriminator of deterioration than MEWS or NEWS; AUROC values for the validation dataset were: EDI - 0.7655, NEWS - 0.6569, MEWS - 0.6487. EDI also identified more patients likely to deteriorate for the same specificity as NEWS or MEWS. EDI had the best performance among the 3 scores for the last 24h of the patient stay. CONCLUSION: EDI detects more deteriorations for the same specificity as the other two scores. Our results show that EDI performs better at predicting deterioration than commonly used NEWS and MEWS. PMID- 29122649 TI - The impact of global hemodynamics, oxygen and carbon dioxide on epileptiform EEG activity in comatose survivors of out-of-hospital cardiac arrest. AB - AIM: To study the association between global hemodynamics, blood gases, epileptiform EEG activity and survival after out-of-hospital CA (0HCA). METHODS: We retrospectively analyzed 195 comatose post-CA patients. At least one EEG recording per patient was evaluated to diagnose epileptiform EEG activity. Refractory epileptiform EEG activity was defined as persisting epileptic activity on EEG despite the use of 2 or more anti-epileptics. The time weighted average mean arterial pressure 48h (TWA-MAP48), the percentage of time with a MAP below 65 and above 85mmHg and the percentage of time with normoxia, hypoxia (<70mmHg), hyperoxia (>150mmHg), normocapnia, hypocapnia (<35mmHg) and hypercapnia (>45mmHg) were calculated. RESULTS: We observed epileptiform EEG activity in 57 patients (29%). A shockable rhythm was associated with a decreased likelihood of epileptic activity on the EEG (OR: 0.41, 95%CI 0.22-0.79). We did not identify an association between the TWA-MAP48, the percentage of time with MAP below 65mmHg or above 85mmHg, blood gas variables and the risk of post-CA epileptiform EEG activity. The presence of epileptiform activity decreased the likelihood of survival independently (OR: 0.10, 95% CI: 0.04-0.24). Interestingly, survival rates of patients in whom the epileptiform EEG resolved (n=20), were similar compared to patients without epileptiform activity on EEG (60% vs 67%,p=0.617). Other independent predictors of survival were presence of basic life support (BLS) (OR:5.08, 95% CI 1.98-13.98), presence of a shockable rhythm (OR: 7.03, 95% CI: 3.18-16.55), average PaO2 (OR=0.93, CI 95% 0.90-0.96) and% time MAP<65mmHg (OR: 0.96, CI 95% 0.94-0.98). CONCLUSION: Epileptiform EEG activity in post-CA patients is independently and inversely associated with survival and this effect is mainly driven by patients in whom this pattern is refractory over time despite treatment with anti-epileptic drugs. We did not identify an association between hemodynamic factors, blood gas variables and epileptiform EEG activity after CA, although both hypotension, hypoxia and epileptic EEG activity were predictors of survival. PMID- 29122650 TI - Phylogeny, new generic-level classification, and historical biogeography of the Eucera complex (Hymenoptera: Apidae). AB - The longhorn bee tribe Eucerini (Hymenoptera: Apidae) is a diverse, widely distributed group of solitary bees that includes important pollinators of both wild and agricultural plants. About half of the species in the tribe are currently assigned to the genus Eucera and to a few other related genera. In this large genus complex, comprising ca. 390 species, the boundaries between genera remain ambiguous due to morphological intergradation among taxa. Using ca. 6700 aligned nucleotide sites from six gene fragments, 120 morphological characters, and more than 100 taxa, we present the first comprehensive molecular, morphological, and combined phylogenetic analyses of the 'Eucera complex'. The revised generic classification that we propose is congruent with our phylogeny and maximizes both generic stability and ease of identification. Under this new classification most generic names are synonymized under an expanded genus Eucera. Thus, Tetralonia, Peponapis, Xenoglossa, Cemolobus, and Syntrichalonia are reduced to subgeneric rank within Eucera, and Synhalonia is retained as a subgenus of Eucera. Xenoglossodes is reestablished as a valid subgenus of Eucera while Tetraloniella is synonymized with Tetralonia and Cubitalia with Eucera. In contrast, we suggest that the venusta-group of species, currently placed in the subgenus Synhalonia, should be recognized as a new genus. Our results demonstrate the need to evaluate convergent loss or gain of important diagnostic traits to minimize the use of potentially homoplasious characters when establishing classifications. Lastly, we show that the Eucera complex originated in the Nearctic region in the late Oligocene, and dispersed twice into the Old World. The first dispersal event likely occurred 24.2-16.6 mya at a base of a clade of summer-active bees restricted to warm region of the Old World, and the second 13.9-12.3 mya at the base of a clade of spring-active bees found in cooler regions of the Holarctic. Our results further highlight the role of Beringia as a climate-regulated corridor for bees. PMID- 29122651 TI - Downregulation of lipocalin-2 and Bim expression after remote limb preconditioning in the ischemic rat brain. AB - Although it has been proved that remote limb preconditioning (RPC) can exert neurological protection effects after ischemic cerebral stroke (ICS), the underlying mechanisms of RPC still need to be elucidated for its better transformation to clinical application. Lipocalin-2 (LCN2) was upregulated after cerebral ischemia and mediated reperfusion injury in the models of ischemic stroke. So here, we investigated that whether RPC could downregulate the levels of LCN2 protein and its receptor resulting from cerebral ischemia reperfusion (I/R) injury. The results showed that RPC could decrease the expression of LCN2 protein, but having no obvious effects on its receptor except the time point of 72 h after cerebral ischemia. Furthermore, we observed the downregulation of Bim after RPC in the course of ICS. PMID- 29122652 TI - How Can We Best Reduce Pain Catastrophizing in Adults With Chronic Noncancer Pain? A Systematic Review and Meta-Analysis. AB - : Pain catastrophizing (PC), defined as an exaggerated negative cognitive affective orientation toward pain, is one of the strongest psychological predictors of pain outcomes. Although regularly included as a process variable in clinical trials, there have been no comprehensive reviews of how it can be modified. Using a registered protocol (PROSPERO 2016 CRD42016042761), we searched MEDLINE, PsychINFO, EMBASE, CINAHL, and CENTRAL up to November 2016 for all randomized controlled trials measuring PC in adults with chronic noncancer pain. Two authors independently screened studies and assessed bias risk using the Cochrane tool. Quality of evidence was rated according to Grading of Recommendations Assessment, Development and Evaluation criteria. We included 79 studies (n = 9,914), which mostly recruited participants with musculoskeletal pain and had low risk of bias. Meta-analyses (standardized mean difference) showed 9 interventions had efficacy compared with waitlist/usual care or active control, although evidence quality was often low. The best evidence (moderate high quality) was found for cognitive-behavioral therapy, multimodal treatment, and acceptance and commitment therapy. Effects were generally of medium strength and had questionable clinical significance. When only the 8 studies targeting people with high PC were included, effects were larger and more consistent. Multimodal treatment showed the strongest effects when all studies were considered, whereas cognitive-behavioral therapy had the best evidence among targeted studies. PERSPECTIVE: PC is a modifiable characteristic but most interventions produce only modest benefit unless targeted to people with high PC. More research into theory-driven interventions matched to specific patient profiles is required to improve treatment efficacy and efficiency. PMID- 29122653 TI - Validation of an automated bilateral feet cold pressor test. AB - The Cold Pressor Test (CPT) is often used in psychobiological research. However, the classical CPT version (unilateral hand immersion into ice-water) involves some disadvantages: hands may be needed for further applications, attentional drift towards the affected sensory hemi-field and/or physiological activation of the contralateral hemisphere may produce a laterality bias. Furthermore, instruction-induced motor activity may bias physiologic reactivity. To avoid these problems, a fully automated bilateral feet CPT was developed and tested for validity and feasibility. The test procedure is based on computerized control of water influx and efflux. This allows for maximal standardization and precise timing. Furthermore, water is kept in permanent flow to prohibit formation of stable temperature layers in skin proximity. Laterality bias, instructions effects and motor responses (e.g. lifting feet out of a water basin) are avoided. In a counterbalanced within-subject design, 28 healthy male students were exposed to the CPT and to a warm water control (CNT) condition twice, one week apart. Cardiovascular parameters, salivary cortisol and subjective ratings (stress, arousal and pain) were assessed before, during, and after interventions. The CPT profoundly affected physiology as well as subjective ratings. Expectation effects (immediately before testing) were small. Furthermore, post-CPT (presumably compensatory/counter-regulatory) effects on heart rate and stroke volume were found. In conclusion, the automated bilateral feet CPT is a valid and feasible stress test modification. Hemodynamic, subjective and endocrine stress responses are substantial, suggesting that this test version represents an advanced and suitable tool in human stress research. PMID- 29122654 TI - A processing schema for children in the auditory equiprobable Go/NoGo task: ERP components and behaviour. AB - A sequential processing model for adults in the auditory equiprobable Go/NoGo task has been developed in recent years. This used temporal principal components analysis (PCA) to decompose Go/NoGo event related potential (ERP) data into components that mark stages of perceptual and cognitive processing. The model has been found useful in frameworking several studies in young and older adults, and in children. Recently, it has been demonstrated that the common PCA approach of decomposing Go and NoGo ERP data together results in misallocation of variance between the conditions, distorting the timing, topography, and amplitudes of the resultant components in each condition. The present study thus reanalyses data from a child study, conducting separate PCAs on the data from each condition. Multiple regression was then used to seek links with behavioural measures from the task. In addition to confirming the previous NoGo N2b/inhibitory processing link, novel NoGo Negative Slow Wave/error evaluation and Go N1-1/RT variability links were obtained. Based on these outcomes, the recommended separate application of PCAs to Go and NoGo data was confirmed. The present data were used to develop a child-specific sequential processing schema for this paradigm, suggesting earlier separation of the Go and NoGo processing chains, and the need to include an additional inhibition and evaluation stage. The child schema should be useful in future studies involving this and other two-choice reaction tasks. PMID- 29122655 TI - Pathology-radiology correlation of common and uncommon computed tomographic patterns of organizing pneumonia. AB - Organizing pneumonia (OP) is a common pattern of lung injury that can be associated with a wide range of etiologies. Typical and not-so-typical imaging features of OP occur, as both common and rare lung pathologies can mimic the same imaging pattern as that of OP. This article will attempt to describe the difference between confusing terminologies that have been used in the past for OP and existence of primary versus secondary OP. The role of a multidisciplinary approach as an essential component to correctly diagnose and effectively manage challenging cases of OP will be highlighted. Additionally, we will discuss the limitation of transbronchial and importance of open lung biopsy to make the correct diagnosis. One example of an emerging diagnosis in the spectrum of OP and diffuse alveolar damage is acute fibrinous and organizing pneumonia. Ultimately, the reader should feel comfortable recognizing the many variable presentations of OP and be able to participate knowledgeably in a multidisciplinary team after reading this article. OP is a disease entity with variable radiographic and distinct histological characteristics that requires a multidisciplinary approach to correctly diagnose cryptogenic OP. Classic radiologic findings of OP occur in as low as 60% of cases. Secondary causes include infections, neoplasms, inflammatory disorders, and iatrogenic. Acute fibrinous and organizing pneumonia can appear similarly, but miliary nodules are a clue to diagnosis. PMID- 29122656 TI - Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. AB - The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Because efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in more than 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases, respectively, and PD-L1 but not PD-L2 expression correlated with Epstein-Barr virus in tumor cells. PD-L1 staining was detected in 80% of anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and follicular dendritic cell sarcoma; 75% of nodular lymphocyte-predominant Hodgkin lymphoma; 53% of primary mediastinal large B-cell lymphoma; 39% of extranodal NK/T cell lymphoma; 26% of peripheral T-cell lymphoma; 10% of diffuse large B cell lymphoma; and very rare examples of mantle, marginal zone, and small lymphocytic lymphomas. PD-L2 staining was present in 78% of primary mediastinal large B-cell lymphoma but in fewer cases in all other categories including 40% of follicular dendritic cell sarcoma and 7% of anaplastic large cell lymphoma. Our results confirm and extend prior studies of PD-L1 and provide new data of PD-L2 expression in lymphomas. The differential expression patterns in some tumor types and the expression of PD-L2 in the absence of PD-L1 raise the possibility of targeted therapy for additional subsets of patients with lymphoma. PMID- 29122657 TI - Diagnostic significance of intratumoral CD8+ tumor-infiltrating lymphocytes in medullary carcinoma. AB - Invasive ductal carcinomas of breast with marked stromal lymphocytic infiltration have come to be classified as lymphocyte-predominant breast cancer (LPBC) because it obtains high pathological complete response rates with neoadjuvant chemotherapy. Medullary carcinoma (MC), which is independent from LPBC, is a rare histological subtype of invasive breast carcinoma accompanied by abundant lymphoplasmacytic infiltration as LPBC. Although MC shows marked cellular and structural atypia, it usually has a favorable outcome. It is occasionally difficult to distinguish MC from LPBC because both subtypes have nonspecific morphological features according to the present diagnostic criteria. Herein, we adopted multiplexed fluorescent immunohistochemistry to perform quantitative and simultaneous analyses of tumor-infiltrating lymphocytes (TILs) considering their spatial distribution and examined focal immune reaction differences between MC and LPBC. We found that CD8+ TILs are predominant in the intratumoral region, whereas CD4+ TILs are less common in MC. In non-luminal-type cancers, the numbers of stromal and intratumoral CD8+ TILs were significantly higher in MC than in LPBC. Stratified analyses by CD4+ TIL subsets showed robust infiltration of intratumoral CD8+ TILs in non-luminal-type MC even in suppressive environments, such a low T helper 1-to-regulatory T cell ratio. Our results suggest that extensive intratumoral CD8+ TIL infiltration might well be a promising biomarker for distinguishing MC from LPBC, especially in non-luminal-type cancers. Intratumoral CD8+ TILs and nonluminal intrinsic subtypes may serve as diagnostic characteristics allowing reliable histological criteria to be established for reproducibly diagnosing MC. PMID- 29122658 TI - Endothelium-derived contraction in a model of rheumatoid arthritis is mediated via angiotensin II type 1 receptors. AB - A role for endothelium-derived constricting factors (EDCF), and the angiotensin II type 1 receptor (AT1R) pathway, in the vascular impairment found in the rat Freund's complete adjuvant (FCA)-model of rheumatoid arthritis (RA) was examined. FCA arthritis was induced in rats+/-losartan. Vehicle-treated rats served as controls. Knee-joint swelling and red blood cell (RBC) aggregation were measured as indicators of inflammation and endothelium reactivity assessed by response to acetylcholine (ACh) on aortic rings. Results show that knee-joint swelling and RBC aggregation were elevated in the FCA+vehicle group and restored to control levels in the FCA+losartan-treated animals. ACh-induced relaxation of aortic rings taken from FCA+vehicle animals was significantly impaired compared to vehicle-controls and this vasoreactivity was restored to control levels in the FCA+losartan-treated group. Further examination of aorta from the FCA+vehicle animals revealed an EDCF that was reliant on cyclooxygenase-2 (but not cyclooxygenase-1), generation of superoxide anion generation (but not hydrogen peroxide) and activation of thromboxane-prostanoid receptor. Losartan administration in vivo or ex vivo (to aortic rings) prevented the generation of the EDCF. In summary, this is the first evidence of an EDCF in a model of RA and identifies this mechanism as potentially significant in the cardiovascular disorder associated with the disease. PMID- 29122659 TI - Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease. AB - BACKGROUND: Allergic diseases caused by fungi are common. The best understood conditions are allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Our knowledge of the fungal microbiome (mycobiome) is limited to a few studies involving healthy individuals, asthmatics, and smokers. No study has yet examined the mycobiome in fungal lung disease. OBJECTIVES: The main aim of this study was to determine the mycobiome in lungs of individuals with well-characterized fungal disease. A secondary objective was to determine possible effects of treatment on the mycobiome. METHODS: After bronchoscopy, ribosomal internal transcribed spacer region 1 DNA was amplified and sequenced and fungal load determined by real-time PCR. Clinical and treatment variables were correlated with the main species identified. Bronchopulmonary aspergillosis (n = 16), severe asthma with fungal sensitization (n = 16), severe asthma not sensitized to fungi (n = 9), mild asthma patients (n = 7), and 10 healthy control subjects were studied. RESULTS: The mycobiome was highly varied with severe asthmatics carrying higher loads of fungus. Healthy individuals had low fungal loads, mostly poorly characterized Malasezziales. The most common fungus in asthmatics was Aspergillus fumigatus complex and this taxon accounted for the increased burden of fungus in the high-level samples. Corticosteroid treatment was significantly associated with increased fungal load (P < .01). CONCLUSIONS: The mycobiome is highly variable. Highest loads of fungus are observed in severe asthmatics and the most common fungus is Aspergillus fumigatus complex. Individuals receiving steroid therapy had significantly higher levels of Aspergillus and total fungus in their bronchoalveolar lavage. PMID- 29122660 TI - A potential role of galectin-1 in promoting mouse trophoblast stem cell differentiation. AB - Galectin-1 is highly expressed in blastocysts and trophoblast giant cells during implantation, and dysregulated galectin-1 is associated with many pregnancy related abnormalities. Elevated galectin-1 contributes to cancer cells invasion. Here, we found that galectin-1 is expressed in mouse oocytes, preimplantation embryos (all stages), and trophoblast stem (TS) cells. Peak levels of galectin-1 mRNA and protein were detected on day 4 and day 5 after the induction of TS cells differentiation. Overexpression of galectin-1 increased TS cells migration and invasion, whereas knockdown of galectin-1 attenuated these effects. Additionally, knockdown of galectin-1 in TS cells decreased the expression of matrix metalloproteinase (MMP) 2/9, ZEB-1, Snail, N-cadherin, TGF-beta, Nodal, and phospho-Smad2/3, whereas the expression of E-cadherin was increased. In contrast, overexpression of galectin-1 in TS cells increased the expression of MMP2/9, ZEB 1, and N-cadherin, whereas the expression of E-cadherin was decreased. These findings suggest a potential role of galectin-1 in the differentiation of mouse TS cells. PMID- 29122661 TI - Leakage kinetics of the liposomal chemotherapeutic agent Doxil: The role of dissolution, protonation, and passive transport, and implications for mechanism of action. AB - Doxil, a liposomal formulation of the chemotherapeutic drug doxorubicin, is FDA approved for multiple indications. Doxil liposomes are designed to retain doxorubicin in circulation, minimize clearance by the mononuclear phagocyte system, and limit uptake in healthy tissue. Although pharmacokinetic data and survival statistics from clinical trials provide insight into distribution and efficacy, many details of the mechanism of action remain unresolved, despite the importance in translating liposome-based drug delivery systems to other molecules and cargo. Therefore, the objective of this study is to quantitatively assess the kinetics of doxorubicin leakage from Doxil liposomes. In contrast to previous studies, we consider three processes: dissolution of solid doxorubicin, protonation/deprotonation of soluble doxorubicin, and passive transport of neutral doxorubicin across the lipid bilayer of the liposomes. Experiments were performed for Doxil, Doxil-like liposomes, and Doxil-like liposomes with reduced cholesterol and pegylation. To mimic physiological conditions, we also performed experiments in serum and under slightly acidic conditions at pH5. We show that crystalline doxorubicin dissolution can be described by a first order rate constant of 1.0*10-9cms-1 at 37 degrees C. Doxorubicin leakage can be described by first order rate constant for transport across the lipid bilayer with values in the range from 1 to 3*10-12cms-1 at 37 degrees C. Based on these results we discuss implications for the mechanism of action, taking Doxil pharmacokinetics into account. PMID- 29122662 TI - Remote-loading of liposomes with manganese-52 and in vivo evaluation of the stabilities of 52Mn-DOTA and 64Cu-DOTA using radiolabelled liposomes and PET imaging. AB - Liposomes are nanoparticles used in drug delivery that distribute over several days in humans and larger animals. Radiolabeling with long-lived positron emission tomography (PET) radionuclides, such as manganese-52 (52Mn, T1/2=5.6days), allow the imaging of this biodistribution. We report optimized protocols for radiolabeling liposomes with 52Mn, through both remote-loading and surface labeling. For comparison, liposomes were also remote-loaded and surface labeled with copper-64 (64Cu, T1/2=12.7h) through conventional means. The chelator DOTA was used in all cases. The in vivo stability of radiometal chelates is widely debated but studies that mimic a realistic in vivo setting are lacking. Therefore, we employed these four radiolabeled liposome types as platforms to demonstrate a new concept for such in vivo evaluation, here of the chelates 52Mn DOTA and 64Cu-DOTA. This was done by comparing "shielded" remote-loaded with "exposed" surface labeled variants in a CT26 tumor-bearing mouse model. Remote loading (90min at 55 degrees C) and surface labeling (55 degrees C for 2h) of 52Mn gave excellent radiolabeling efficiencies of 97-100% and 98-100% respectively, and the liposome biodistribution was imaged by PET for up to 8days. Liposomes with surface-conjugated 52Mn-DOTA exhibited a significantly shorter plasma half-life (T1/2=14.4h) when compared to the remote-loaded counterpart (T1/2=21.3h), whereas surface-conjugated 64Cu-DOTA cleared only slightly faster and non-significantly, when compared to remote-loaded (17.2+/-2.9h versus 20.3+/ 1.2h). From our data, we conclude the successful remote-loading of liposomes with 52Mn, and furthermore that 52Mn-DOTA may be unstable in vivo whereas 64Cu-DOTA appears suitable for quantitative imaging. PMID- 29122664 TI - Biophysical exploration of dynamical ordering of biomolecular systems. PMID- 29122663 TI - FTIR study of secondary structure changes in Epidermal Growth Factor by gold nanoparticle conjugation. AB - Conformation of protein is vital to its function, but may get affected when processing to manufacture products. It is therefore important to understand structural changes during each step of production. In this study, we investigate secondary structure changes in the targeting protein Epidermal Growth Factor (EGF) during synthesis of theranostic bifunctional nanoparticle, devised for Photodynamic therapy of breast cancer. We acquired FTIR spectra of EGF; unconjugated, post treatment with alpha-lipoic acid, attached to gold nanoparticle, and bound to the bifunctional nanoprobe. We observed decreasing disordered structures and turns, and increasing loops, as the synthesis process progressed. There was an overall increase in beta-sheets in final product compared to pure EGF, but this increase was not linear and fluctuated. Previous crystal structure studies on EGF-EGFR complex have shown loops and beta-sheets to be important in the binding interaction. Since our study found increase in these structures in the final product, no adverse effect on binding function of EGF was expected. This was confirmed by functional assays. Such studies may help modify synthesis procedures, and thus secondary structures of proteins, enabling increased functionality and optimum results. PMID- 29122665 TI - In vitro screening of dual flavonoid combinations for reversing P-glycoprotein mediated multidrug resistance: Focus on antiepileptic drugs. AB - The combined use of different P-glycoprotein (P-gp) inhibitors may be a relevant approach to the synergistic and safer inhibition of the P-gp-mediated drug efflux. Herein, we aimed to explore dual combinations of the flavonoids baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin to reverse the interference of P-gp on the intracellular accumulation of antiepileptic drugs (AEDs). The intracellular accumulation of rhodamine 123 (a classic P-gp substrate) and of several commonly used AEDs (carbamazepine, phenytoin, oxcarbazepine) or their metabolites (carbamazepine-10,11-epoxide and licarbazepine) was evaluated in MDCK-MDR1 cells in the presence and absence of individual flavonoids and their combinations. A selected flavonoid combination [( )-epigallocatechin gallate/silymarin] was also evaluated in transepithelial transport experiments using licarbazepine (active metabolite of oxcarbazepine) as a model compound. Most flavonoid combinations increased rhodamine 123 intracellular uptake in a greater extent than their additive individual effects at similar concentrations. Moreover, selected (-)-epigallocatechin gallate/silymarin and kaempferol/baicalein combinations also enhanced the intracellular accumulation of all AEDs and metabolites. Overall, the combination of (-)-epigallocatechin gallate/silymarin was the most promising one. Thus, dual flavonoid combinations may be useful to overcome the P-gp-mediated efflux of AEDs and their metabolites, making their association to AED therapy a potentially valuable approach to circumvent pharmacoresistance in epilepsy. PMID- 29122666 TI - Regulation of Seed Vigor by Manipulation of Raffinose Family Oligosaccharides in Maize and Arabidopsis thaliana. AB - Raffinose family oligosaccharides (RFOs) accumulate in seeds during maturation desiccation in many plant species. However, it remains unclear whether RFOs have a role in establishing seed vigor. GALACTINOL SYNTHASE (GOLS), RAFFINOSE SYNTHASE (RS), and STACHYOSE SYNTHASE (STS) are the enzymes responsible for RFO biosynthesis in plants. Interestingly, only raffinose is detected in maize seeds, and a unique maize RS gene (ZmRS) was identified. In this study, we found that two independent mutator (Mu)-interrupted zmrs lines, containing no raffinose but hyperaccumulating galactinol, have significantly reduced seed vigor, compared with null segregant controls. Unlike maize, Arabidopsis thaliana seeds contain several RFOs (raffinose, stachyose, and verbascose). Manipulation of A. thaliana RFO content by overexpressing ZmGOLS2, ZmRS, or AtSTS demonstrated that co overexpression of ZmGOLS2 and ZmRS, or overexpression of ZmGOLS2 alone, significantly increased the total content of RFOs and enhanced Arabidopsis seed vigor. Surprisingly, while overexpression of ZmRS increased seed raffinose content, its overexpression dramatically decreased seed vigor and reduced the seed amounts of galactinol, stachyose, and verbascose. In contrast, the atrs5 mutant seeds are similar to those of the wild type with regard to seed vigor and RFO content, except for stachyose, which accumulated in atrs5 seeds. Total RFOs, RFO/sucrose ratio, but not absolute individual RFO amounts, positively correlated with A. thaliana seed vigor, to which stachyose and verbascose contribute more than raffinose. Taken together, these results provide new insights into regulatory mechanisms of seed vigor and reveal distinct requirement for RFOs in modulating seed vigor in a monocot and a dicot. PMID- 29122668 TI - Estimation of physiological sources of nonlinearity in blood oxygenation level dependent contrast signals. AB - Blood oxygenation level-dependent (BOLD) contrast appears through a variation in the transverse relaxation rate of magnetic resonance signals induced by neurovascular coupling and is known to have nonlinear characteristics along echo time (TE) due to the intra-vasculature. However, the physiological causes of this nonlinearity are unclear. We attempted to estimate the physiological information related to the nonlinearity of BOLD signals by using a two-compartment model. For this purpose, we used a multi-echo gradient-echo echo-planar imaging sequence and developed a computational method to estimate the physiological information from the TE-dependent BOLD signals. The results showed that the average chemical exchange time in the intra-vasculature varied during stimulation, which might be the essential source of the nonlinearity. PMID- 29122667 TI - Is breast MRI a helpful additional diagnostic test in suspicious mammographic microcalcifications? AB - PURPOSE: Microcalcifications are a common finding in mammography and usually require invasive procedures to diagnose or exclude malignancy. As many microcalcifications are due to benign lesions, we wanted to assess whether breast MRI as an additional diagnostic tool may be used to distinguish benign from malignant in this setting. MATERIALS AND METHODS: Eligible for this retrospective, IRB-approved observational study were 858 consecutive patients (mean age 54+/-11years) undergoing stereotactically-guided biopsies of suspicious mammographic microcalcifications during three year at our institution. Finally included were 152 patients who also underwent breast MRI <8weeks prior to biopsy. In case of malignant or lesions of uncertain malignant potential, subsequent surgery was performed. Benign findings were confirmed by imaging follow-up. BI RADS category assignments from the original mammography and breast MRI reports were compared to the final diagnosis (benign vs. malignant) to determine diagnostic benchmarks. RESULTS: Histopathology revealed 81 benign (53.3%), 41 DCIS (27%) and 30 (19.7%) invasive cancers. Sensitivity, specificity, positive and negative predictive values for breast MRI were 97.2% (69/71), 39.5% (32/81), 58.5% (69/118) and 94.1% (32/34), respectively. Thus, 32/81 unnecessary biopsies in benign lesions (39.5%) may have been avoided, missing 2/71 malignant lesions (2.8%), both DCIS G2. CONCLUSION: Breast MRI as an additional diagnostic tool can be used to accurately distinguish benign from malignant mammographic microcalcifications and may thus be helpful to reduce unnecessary breast biopsies. PMID- 29122669 TI - Osteoanabolic activity of whey-derived anti-oxidative (MHIRL and YVEEL) and angiotensin-converting enzyme inhibitory (YLLF, ALPMHIR, IPA and WLAHK) bioactive peptides. AB - Exploring bone rebuilding anabolic agents has been gaining much attention due to their potential therapeutic effects in treating several bone disorders including osteoporosis. Whey protein has been reported to affect bone health osteoanabolically, in terms of proliferation and differentiation of primary osteoblast cells. This study investigates whether whey derived anti-oxidative (AO) (P1- MHIRL, P2- YVEEL) and angiotensin converting enzyme inhibitory (ACE inhibitory) (P3- YLLF, P4-ALPMHIR, P5-IPA, P6- WLAHK) bioactive peptides affect the proliferation and differentiation of primary osteoblast cells isolated from rat calvaria. The proliferation and osteogenic activity of osteoblast cells in presence of these peptides were determined by MTT assay, DNA quantification study, Alkaline phosphatase activity (ALP) and ALP staining, Alizarin red activity and staining, and secretory osteocalcin measurement. The expression of osteogenesis-related genes (COLI-alpha, ALP, OCN and RUNX2) were determined by real-time quantitative PCR (RT-PCR) analysis over a period of 21days. The peptide treated osteoblasts showed a significant increase in viable cell density and proliferation in the order of P2>P6>P3 at optimised concentration. Furthermore, the osteoblastic differentiation markers in response to these peptides were found to be significantly up regulated in the order of P2>P6>P3 when compared to the controls. These results demonstrated that bioactive whey-derived AO and ACE inhibitory peptides can play a potential therapeutic role in osteoporosis by activating osteoblasts anabolically. PMID- 29122670 TI - Infection of neuroblastoma cells by rabies virus is modulated by the virus titer. AB - Rabies is a lethal viral infection that can affect almost all mammals, including humans. To better understand the replication of Rabies lyssavirus, we investigated if the viral load in brains naturally infected with rabies influences viral internalization and viral growth kinetics in neuroblastoma cells, and if the viral load affects mortality in mice after intradermal infection. We noted that high initial viral loads in brains (group II) were unfavourable for increasing viral titers during serial passages in neuroblastoma cells when compared to low initial viral loads in brains (group I). In addition, group I strains showed higher viral growth and enhanced internalization efficiency in neuroblastoma cells than group II strains. However, we observed that the dominant virus subpopulation in group II promoted efficient viral infection in the central nervous system in the new host, providing a selective advantage to the virus. Our data indicate that rabies infection in animal models depends on not only the virus strain but also the amount of virus. This study may serve as a basis for understanding the biologic proprieties of Rabies lyssavirus strains with respect to the effects on viral replication and the impact on pathogenesis, improving virus yields for use in vaccine development. PMID- 29122672 TI - Influence of high-carbon basal fertiliser on the structure and composition of a soil microbial community under tobacco cultivation. AB - Soil microorganisms play a crucial role in cycling soil nutrients and providing organic nutrients for plant growth and development. Fertilisation balances soil fertility and quality, and affects soil microbial communities. Fertilisation is a frontier subject in agricultural and environmental sciences. Here we showed that the application of high-carbon basal fertiliser treatment could improve the tobacco yield and quality when compared to chemical fertiliser, high-carbon basal fertiliser and mixed high-carbon chemical fertiliser. The potential reason is that different fertiliser treatments influence soil fertility, such as nitrogen, phosphorus, and other contents, besides soil organic matter. Further experiments revealed that populations of bacteria, fungi and actinomycetes fluctuated during tobacco development under different fertilisation treatments. Then we performed high-throughput sequencing of the 16S rRNA gene, and the results showed that the fertilisation treatments had significant effects on the microbial community, particularly within the finer taxonomic divisions or non-dominant taxa. Moreover, proteobacteria and fungal genera had significantly different relative abundances during tobacco growth under various tobacco developmental stages and fertilisation treatments. These results indicated that mixed high-carbon chemical fertiliser could improve soil fertility by influencing the soil microorganism, and that the fertilisation treatments impacted on the structure and composition of the microbial community, and especially the diversity of non-dominant taxa. However, more studies are needed to confirm their reliability. PMID- 29122671 TI - Temporal cytokine and lymphoid responses to an inhaled TLR7 antedrug agonist in the cynomolgus monkey demonstrates potential safety and tolerability of this approach. AB - AZD8848 is a TLR7 agonist antedrug developed for administration by inhalation dosing for the treatment of allergic diseases, such as asthma. Allergic asthma is associated with increased levels of Th2 cytokines which are suppressed for extended periods by TLR7 agonists in a number of preclinical models of allergic airway inflammation. However, TLRs form a central part of innate immunity and their activation often results in proinflammatory responses. Whilst AZD8848's antedrug mechanism is designed to restrict its pharmacological action beyond the lung, the effect of chronic, supramaximal dosing to the target tissue has yet to be defined. To support clinical development of this potentially disease modifying approach the nonclinical safety and pharmacodynamics of AZD8848 were evaluated in cynomolgus monkeys in studies examining single or multiple weekly inhaled doses. Here we show that following a single dose nearly all responses returned to baseline within a week. During multiple dosing serum biomarkers were quantified over the dosing period and indicated a limited systemic response. The dose at which maximal interferon responses were seen was dependent on dose. Thorough histopathological examination revealed a dose related increase of size and cells of lymphoid tissues in the lung and nose. Local lymphoid responses were recovered after the treatment free period. These studies are the first to evaluate safety of an inhaled TLR7 agonist and demonstrate AZD8848 is safe with a no observed adverse effect level at 26MUg/kg allowing progression to man with weekly inhalation dosing. PMID- 29122673 TI - Dual mechanisms of anti-muscarinic and Ca++ antagonistic activities to validate the folkloric uses of Cyperus niveus Retz. as antispasmodic and antidiarrheal. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cyperus species are famous for their traditional uses and very commonly used for their anti-spasmodic and anti-diarrheal activities. Cyperus niveus Retz. is used in local traditional system of medicine in Pakistan to treat diarrhea and emesis. AIM OF THE STUDY: The aim of the study was to validate the traditional uses and to provide the possible mechanisms for the medicinal use of Cyperus niveus Retz. as anti-spasmodic, anti-diarrheal and anti emetic. MATERIALS AND METHODS: The in-vivo studies of anti-diarrheal, charcoal meal GI transit test and anti-emetic activities were conducted in rats, mice and chicks respectively, while isolated tissues of rabbit's jejunum and rat's ileum were used for in-vitro experiments. Phytochemical analysis was also undertaken. RESULTS: The phytochemical study of hydro-ethanolic extract of Cyperus niveus Retz. showed the presence of flavonoids, phenols, alkaloids, tannins, saponins and glycosides. Cn. Cr caused significant inhibition of castor oil-induced diarrhea in rats (300,500 & 700mg/kg) using loperamide (10mg/kg, p.o) as standard. Cn. Cr also significantly decreased the motility in charcoal meal GI transit test at 100-200mg/kg in mice, using atropine (3.0mg/kg) as positive control. In jejunum tissue, Cn. Cr relaxed carbachol(1uM) and K+(80mM)-induced contractions, similar to the effect of dicyclomine. Pre-incubation of isolated rat ileum tissues with Cn. Cr (0.1mg/mL) caused the corresponding shift of CCh concentration response curve (CRC) to right without decrease in max. response whereas at the concentration of 0.3mg/mL caused the rightward nonparallel shift with max. response suppression, similar to dicyclomine. Antimuscarinic effect was further confirmed when prior administration of Cn. Cr (0.1, 0.3 and 1mg/mL) caused concentration dependent inhibition of induced contractions of carbachol, comparable to atropine (1uM). To confirm the Ca2+ channel blocking (CCB), the rabbit jejunum was pre-incubated with Cn. Cr (0.3 & 1.0mg/mL), produced a shift in CRCs of calcium toward right with decrease in the maximum response at next concentration, similar to that of dicyclomine. The organic fraction of Cyperus niveus Retz. (Cn. Dcm) showed Ca2+ antagonist and anticholinergic activities with higher potency against K+(80mM) induced contractions, like verapamil, while aqueous fraction (Cn. Aq) relaxed only carbachol(1uM) induced contractions with no prominent effect on K+ (80mM)-contractions even at the higher concentration of 10mg/mL, similar to atropine. Cn. Cr also showed significant anti-emetic effect in Chick emesis model using chlorpromazine as standard. CONCLUSION: This study shows the presence of antidiarrheal and spasmolytic activities in Cyperus niveus Retz. extract, mediated by dual blocking mechanisms of muscarinic receptors and Ca2+ channels. The results further indicate the presence of anti-emetic activity in Cn. Cr, which may be because of its anti-muscarinic potential. This study provides the scientific bases to the traditional use of Cn. Cr in diarrhea and emesis. PMID- 29122674 TI - Antibiofilm activity of nanoemulsions of Cymbopogon flexuosus against rapidly growing mycobacteria. AB - Rapidly growing mycobacteria (RGM) are opportunistic microorganisms that can cause both local and disseminated infections. When in biofilm, these pathogens become highly resistant to antimicrobials used in clinical practice. Composed abundantly of polymeric substances, biofilms delay the diffusion of antimicrobials, preventing the drug from penetrating the deeper layers and having an effective action. Therefore, the search for new and alternative therapeutic options has become of fundamental importance. Natural products fall into these options, especially essential oils. However, these oils present problems, such as low miscibility in water (which decreases its bioavailability) and degradation by light and temperature. Thus, the objective of this work was to explore the action of free essential oil and nanoemulsions of Cymbopogon flexuosus on strains of RGM, in planktonic and sessile forms. In this work, standard strains of Mycobacterium fortuitum (ATCC 6841), Mycobacterium massiliense (ATCC 48898) and Mycobacterium abscessus (ATCC 19977) were used. The susceptibility of the microorganisms in planktonic form was obtained by conventional microdilution techniques and by cell viability curve. The analysis of the antibiofilm activity was performed by a semi-quantitative macrotechnique. The nanoemulsion exhibited significant antimicrobial activity, with minimum inhibitory concentration values lower than those presented by the free essential oil, against strains in the planktonic state. However, both were efficient in destroying the already formed biofilm, whereas only the free oil inhibited the formation of mycobacterial biofilm. This study demonstrated the therapeutic potential of C. flexuosus essential oil, especially in its nanostructured form, which can be demonstrated against infections caused by rapidly growing mycobacteria. PMID- 29122675 TI - High-throughput method for extracting and visualizing the spatial gene expressions from in situ hybridization images: A case study of the early development of the sea anemone Nematostella vectensis. AB - Studying the spatial gene expression profiles from in situ hybridization images of the embryo is one of the first steps toward the comprehensive understanding of gene interactions in an organism. In the case of N. vectensis, extracting and collecting these data is a challenging task due to the difficulty of detecting the cell layer through the transparent body plan and changing morphology during the blastula and gastrula stages. Here, first, we introduce a method to algorithmically identify and track the cell layer in N. vectensis embryo from the late blastula to the late gastrula stage. With this, we will be able to extract spatial expression profiles of genes alongside the cell layer and consequently reconstructing the 1D representation of gene expression profiles. Furthermore, we use the morphological configurations of the embryo extracted from confocal images, to model the dynamics of embryos morphology during the gastrulation process in 2D. Ultimately, we provide a visualization tool for studying and comparing the extracted spatial gene expression profiles over the simulated embryo. We anticipate that our method of extraction and visualization to be a starting point for quantifying and collecting more in situ images from various sources, which can potentially accelerate our understanding of gene interactions in the early development of N. vectensis. The method allows researchers to visualize and compare the different gene expressions from different in situ images or different experiments. As an example, we were able to show the complementary expression of NvFoxA-NvSnailA and NvBra-NvErg in the central domain and central/external rings during the development which suggests the possible repression effects between each pair; as it has been discovered by functional analysis. PMID- 29122676 TI - A six-gene expression toolbox for the glands, epithelium and chondrocytes in the mouse nasal cavity. AB - The nose is the central feature of the amniote face. In adults, the nose is a structurally and functionally complex organ that consists of bone, cartilage, glands and ducts. In an ongoing expression screen in our lab, we found several novel markers for specific tissues in the nasal region. Here, using in situ hybridization expression experiments, we report that Alx1, Ap-2beta, Crispld1, Eya4, Moxd1, and Penk have tissue specific expression during murine nasal development. At E11.5, we observed that Alx1, Ap-2beta, Crispld1, and Eya4 are expressed in the medial and lateral nasal prominences. We found that Moxd1 and Penk are expressed in the lateral nasal prominences. At E15.5, Alx1 is expressed in nasal septum. Ap-2beta and Crispld1 are expressed in nasal glands and cartilages. Eya4 is expressed in olfactory epithelium. Intriguingly at E15.5 Moxd1 is expressed in all the nasal cartilage while the expression of Penk is restricted to chondrocytes contributing to the posterior nasal septum. The expression domains reported here suggest that these genes warrant functional studies to determine their role in nasal capsule morphogenesis. PMID- 29122677 TI - Inducible knockdown of procollagen I protects mice from liver fibrosis and leads to dysregulated matrix genes and attenuated inflammation. AB - Organ fibrosis is characterized by a chronic wound-healing response, with excess deposition of extracellular matrix components. Here, collagen type I represents the most abundant scar component and a primary target for antifibrotic therapies. Liver fibrosis can progress to cirrhosis and primary liver cancer, which are the major causes of liver related morbidity and mortality. However, a (pro-)collagen type I specific therapy remains difficult and its therapeutic abrogation may incur unwanted side effects. We therefore designed tetracycline-regulated procollagen alpha1(I) short hairpin (sh)RNA expressing mice that permit a highly efficient inducible knockdown of the procollagen alpha1(I) gene in activated (myo )fibroblasts, to study the effect of induced procollagen type I deficiency. Transgenic mice were generated using recombinase-mediated integration in embryonic stem cells or zinc-finger nuclease-aided genomic targeting combined with miR30-shRNA technology. Liver fibrosis was induced in transgenic mice by carbon tetrachloride, either without or with doxycycline supplementation. Doxycycline treated mice showed an 80-90% suppression of procollagen alpha1(I) transcription and a 40-50% reduction in hepatic collagen accumulation. Procollagen alpha1(I) knockdown also downregulated procollagens type III, IV and VI and other fibrosis related parameters. Moreover, this was associated with an attenuation of chronic inflammation, suggesting that collagen type I serves not only as major scar component, but also as modulator of other collagens and promoter of chronic inflammation. PMID- 29122680 TI - Nonabsorbable versus absorbable sutures in large, hang-back medial rectus muscle recessions. PMID- 29122678 TI - Exosomes and cardioprotection - A critical analysis. AB - Exosomes are nano-sized vesicles released by numerous cell types that appear to have diverse beneficial effects on the injured heart. Studies using exosomes from stem cells or from the blood have indicated that they are able to protect the heart both in models of acute ischaemia and reperfusion, and during chronic ischaemia. In addition to decreasing initial infarct size, they are able to stimulate angiogenesis, reduce fibrosis and remodelling, alter immune cell function and improve long-term cardiac contractile function. However, since the technology and techniques used for the study of exosomes is relatively immature and continually evolving, there remain many important caveats to the interpretation of studies. This review presents a critical analysis of the field of exosomes and cardioprotection. We analyse the effects of exosomes from all types of stem cells investigated to date, summarize the major effects observed and their potential mechanism, and offer our perspective on the major outstanding issues. PMID- 29122681 TI - Reply. PMID- 29122679 TI - Extracellular vesicles: Novel mediator for cell to cell communications in liver pathogenesis. AB - Extracellular vesicles (EVs) are membrane derived nanometer-sized vesicles. EVs are released by normal, diseased, and transformed cells in vitro and in vivo, and carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. Transferring biological information via EVs to neighboring cells and inter cellular communication not only maintain physiological functions, but also involve in the pathogenesis of several diseases, including cancer. The aim of this review is to discuss the emerging role of EVs in viral hepatitis, non alcoholic or alcoholic liver disease and liver cancers. We summarize what is known about exosome biogenesis, and role in liver disease progression, and discuss the potential clinical applications of EVs as predictive biomarkers and therapeutic modalities. PMID- 29122682 TI - Reply. PMID- 29122683 TI - High CXCL10/IP-10 levels are a hallmark in the clinical evolution of the HIV infection. AB - The aim of this study was to investigate the modulation of plasma CXCL10, CCL20, CCL22, CCL2, CCL17 and CCL24 levels in HIV-positive patients grouped according to extreme phenotypes of progression to AIDS, and at different stages of HIV infection. HIV-positive individuals with extreme phenotypes of AIDS progression (n=58) at different clinical stages (chronic individuals, both pre-HAART and under-HAART) and HIV-negative controls (n=20) were evaluated. Additionally, HIV positive individuals that initiated HAART with >350CD4+T-cells/mm3 were compared with those who initiated treatment with <350CD4+T-cells/mm3. Plasma levels of six chemokines were quantified by a Luminex assay. Higher CXCL10 levels were observed in individuals immediately before their CD4+T-cell levels were indicative for HAART (pre-HAART), independently of their progressor status, i.e. slow (SPs) or rapid progressors (RPs). SPs pre-HAART showed higher CXCL10 levels compared to elite controllers and RPs under HAART (pc=0.009 and pc=0.007, respectively). CXCL10 levels were higher in SPs HAART CD4<350 (initiated HAART with <350 CD4+T cells) when compared with SPs HAART CD4>350 (initiated HAART with >350 CD4+T cells) (1096 vs. 360.33pg/mL, p=0.0101). Normalisation of CXCL10 levels seems to depend on the CD4+T-cell nadir at HAART initiation. CCL20 levels were higher in chronic SPs, SPs pre-HAART, SPs HAART and RPs HAART compared with the HIV negative controls, indicating persistent CCL20 expression. In conclusion, our results indicate that CXCL10 levels are a hallmark in the clinical evolution of HIV infection. However, our results must be verified in a study evaluating a larger number of AIDS progressors. PMID- 29122685 TI - Molecular and enzoinformatics perspectives of targeting Polo-like kinase 1 in cancer therapy. AB - Cancer is a disease that has been the focus of scientific research and discovery and continues to remain so. Polo-like kinases (PLKs) are basically serine/threonine kinase enzymes that control cell cycle from yeast to humans. PLK 1 stands for 'Polo-like kinase-1'. It is the most investigated protein among PLKs. It is crucial for intracellular processes, hence a 'hot' anticancer drug target. Accelerating innovations in Enzoinformatics and associated molecular visualization tools have made it possible to literally perform a 'molecular level walk' traversing through and observing the minutest contours of the active site of relevant enzymes. PLK-1 as a protein consists of a kinase domain at the protein N-terminal and a Polo Box Domain (PBD) at the C-terminal connected by a short inter-domain linking region. PBD has two Polo-Boxes. PBD of PLK-1 gives the impression of "a small clamp sandwiched between two clips", where the two Polo Boxes are the 'clips' and the 'phosphopeptide' is the small 'clamp'. Broadly, two major sites of PLK-1 can be potential targets: one is the adenosine-5' triphosphate (ATP)-binding site in the kinase domain and the other is PBD (more preferred due to specificity). Targeting PLK-1 RNA and the interaction of PLK-1 with a key binding partner can also be approached. However, the list of potent small molecule inhibitors targeting the PBD site of PLK-1 is still not long enough and needs due input from the scientific community. Recently, eminent scientists have proposed targeting the 'Y'-shaped pocket of PLK-1-PBD and encouraged design of ligands that should be able to concurrently bind to two or more modules of the 'Y' pocket. Hence, it is suggested that during molecular interaction analyses, particular focus should be kept on the moiety in each ligand/drug candidate which directly interacts with the amino acid residue(s) that belong(s) to one of the three binding modules which together create this Y shaped cavity. This obviously includes (but it is not limited to) the 'shallow cleft'-forming residues i.e. Trp414, H538 and K540, as significance of these binding residues has been consistently highlighted by many studies. The present article attempts to give a concise yet critically updated overview of targeting PLK-1 for cancer therapy. PMID- 29122684 TI - Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 339 adults from Managua, Nicaragua. AB - DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on anonymized samples provided by 339 healthy adult blood bank donors in Managua, Nicaragua. The purpose of the study was to characterize allele frequencies in the local population to support studies of T cell immunity against pathogens, including Dengue virus. Deviations from Hardy Weinberg proportions were detected for all class II loci (HLA-DPB1, -DQA1, -DQB1 and -DRB1), and at the class I C locus, but not at the class I A and B loci. The genotype data will be available in the Allele Frequencies Net Database. PMID- 29122686 TI - An artificially constructed dimer through deformation of a short zinc-binding loop. AB - We have analyzed the crystal structure of the dimeric form of d-glycero-d-manno heptose-1,7-bisphosphate phosphatase from Burkholderia thailandensis (BtGmhB), catalyzing the removal of the phosphate at the 7 position of d-glycero-d-manno heptose-1,7-bisphosphate. The crystal structure of BtGmhB revealed a dimeric form caused by a disruption of a short zinc-binding loop. The dimeric BtGmhB structure was induced by triggering the loss of Zn2+via the protonation of cysteine residues at pH 4.8 of the crystallization condition. Similarly, the addition of EDTA also causes the dimerization of BtGmhB. It appears there are two dimeric forms in solution with and without the disulfide bridge mediated by Cys95. The disulfide-free dimer produced by the loss of Zn2+ in the short zinc-binding loop is further converted to a stable disulfide-bonded dimer in vitro. Though the two dimeric forms are reversible, both of them are inactive due to a deformation of the active site. Single and triple mutant experiments confirmed the presence of two dimeric forms in vitro. Phosphatase assay results showed that only a zinc bound monomeric form contains catalytic activity in contrast to the inactive zinc free dimeric forms. The monomer-to-dimer transition caused by the loss of Zn2+ observed in this study is an example of reversal phenomenon caused by artificial proteins containing protein engineered zinc-finger motifs where the monomer-to dimer transitions occurred in the presence of Zn2+. Therefore, this unusual dimerization process may be applicable to designing proteins possessing a short zinc-binding loop with a novel regulatory role. PMID- 29122687 TI - Is anatomic acetabular orientation related to pelvic morphology? CT analysis of 150 healthy pelvises. AB - BACKGROUND: Links between sagittal spinal alignment and acetabular orientation attract considerable research attention with the goal of optimising prosthetic cup position. However, whether pelvic incidence (PI) is related to anatomic acetabular orientation remains unknown. We therefore conducted a radiological study with the following objectives: to look for correlations between PI and anatomic acetabular parameters; to describe the sacro-pubic angle (SPA), defined by fixed bony pelvic landmarks, and its relations with acetabular anteversion; and to determine whether anatomical parameters (PI and SPA) correlate with demographic characteristics. HYPOTHESIS: PI correlates with anatomical acetabular parameters. MATERIALS AND METHODS: We conducted a computed tomography (CT) study of the pelvises of 150 patients free of degenerative disease. Three parameters were measured: anatomic acetabular orientation in the Lewinnek reference plane, PI, and the SPA subtended by the line connecting the midpoint of the sacral endplate to the pubic symphysis and the anterior pelvic plane. Statistical tests were performed to look for correlations among these parameters. RESULTS: Intra observer and inter-observer reproducibility was considered highly satisfactory (inter-class correlation coefficient, >86% and >82%, respectively). Mean PI was 58.6 degrees +/-10.2 degrees (range, 32.8 degrees -97.6 degrees ), with no significant differences between genders or across age groups. Mean SPA was 34.7 degrees +/-5.5 degrees (range, 18.3 degrees -49.8 degrees ). Mean anatomic acetabular anteversion (AAA) was greater in females (23.4 degrees ; range, 11.5 degrees -34.5 degrees ) than in males (20 degrees ; range, 7.5 degrees -34.5 degrees ) (P<0.001). PI did not correlate with any of the acetabular parameters (PI/AAA, r=0.8 and P=0.33; PI/acetabular inclination on the horizontal, r=-0.96 and P=0.24). SPA correlated significantly with both PI (r=0.33 and P<0.001) and AAA (r=0.33 and P<0.001). DISCUSSION: This CT study of normal pelvises showed that AAA was significantly greater in females and that SPA correlated significantly with both PI and acetabular anteversion. SPA could serve to define the "theoretical" AAA of each individual patient and could thus be incorporated into surgical planning protocols or intra-operative guidance methods for hip replacement surgery. LEVEL OF EVIDENCE: IV, retrospective study with no control group. PMID- 29122688 TI - Lower-limb lengths and angles in children older than six years: Reliability and reference values by EOS(r) stereoradiography. AB - BACKGROUND: Lower-limb alignment in children is classically assessed clinically or based on conventional radiography, which is associated with projection bias. Low-dose biplanar radiography was described recently as an alternative to conventional imaging. The primary objective of this study was to assess the reliability of length and angle values inferred from 3D reconstructions in children seen in everyday practice. The secondary objective was to obtain reference values for goniometry parameters in children. HYPOTHESIS: 3D reconstructions can be used to assess the lower limbs in children. MATERIAL AND METHODS: The paediatric reliability study was done in 18 volunteers who were divided into three groups based on whether they were typically developing (TD) children, had skeletal development abnormalities, or had cerebral palsy. The reference data were obtained in 129 TD children. Each study participant underwent biplanar radiography with 3D reconstruction performed by experts and radiology technicians. Goniometry parameters were computed automatically. Reproducibility was assessed based on the intra-class coefficient (ICC) and the ISO 5725 standard (standard deviation of reproducibility, SDR). RESULTS: For length parameters, the ICCs ranged from 0.94 to 1.00 and the SDR from 2.1 to 3.5mm. For angle parameters, the ICC and SDR ranges were 0.60-0.95 and 0.9 degrees -4.6 degrees , respectively. No significant differences were found across experts or radiology technicians. Age-specific reference data are reported. DISCUSSION: These findings confirm the reliability of low-dose biplanar radiography for assessing lower-limb parameters in children seen in clinical practice. In addition, the study provides reference data for commonly measured parameters. LEVEL OF EVIDENCE: IV. PMID- 29122689 TI - Spatiotemporal analysis of brucellosis incidence in Iran from 2011 to 2014 using GIS. AB - OBJECTIVE: To investigate the distribution and trends associated with brucellosis incidence rates in Iran from 2011 to 2014. METHODS: The reported incidence rates of brucellosis for the years 2011-2014 were collected and entered into GIS 10.1. The Cochran-Armitage test for linear trends, choropleth maps, hot-spot analysis, and high-low clustering analysis were used to investigate patterns of the disease over the study period and by season, and to identify high-risk areas and any clustering of the disease. The significance level was set at p<0.05. RESULTS: A total of 68493 cases of brucellosis were reported during the study period, giving an average brucellosis incidence rate for this period of 38.67/100000. In 2011, the highest rate of brucellosis was observed in Koohrang County of Chaharmahal Bakhtiari Province, with 317/100 000. In the subsequent years, 2012-2014, Charuymaq County of East-Azerbaijan Province had incidence rates of 384, 534, and 583/100000, respectively. However, the incidence rate of the disease did not follow a linear trend (p<0.001). The maximum and minimum incidence rates of the disease occurred in mid-summer and mid-winter, respectively. The results of the hot-spot analysis showed that the distribution of the disease was highest in the mountainous areas of Iran, particularly along the Zagros mountain range and in most cities near the Zagros Mountains (p<0.01). In addition, the cluster analysis showed a clustering pattern in these high incidence areas (p<0.01). CONCLUSIONS: There were significant differences in the geographic distribution of brucellosis, with the incidence rates being highest in most of the cities in the west and north-west of the country. The incidence of this disease also increased during the summer. It is important to take these patterns into account when allocating resources to combat this disease and to ensure that health programs and other interventions focus on the areas of greatest need. PMID- 29122690 TI - Rifabutin: Is it useful in the treatment of multidrug-resistant tuberculosis? PMID- 29122692 TI - Blockade of platelet-activating factor receptor attenuates abnormal behaviors induced by phencyclidine in mice through down-regulation of NF-kappaB. AB - Accumulating evidence suggests that neuroinflammation is one of the important etiologic factors of abusive and neuropsychiatric disorders. Platelet-activating factor (PAF) is potent proinflammatory lipid mediat1or and plays a pivotal role in neuroinflammatory disorders through the specific PAF receptor (PAF-R). Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia. Here, we investigated the role of PAF-R in the abnormal behaviors induced by PCP in mice. Repeated treatment with PCP resulted in a significant increase in PAF-R gene expression in the prefrontal cortex (PFC) and in the hippocampus. This increase was more pronounced in the PFC than hippocampus. Treatment with PCP resulted in a significant increase in nuclear translocation of the nuclear factor kappa beta (NF-kappaB) p65 and DNA binding activity, indicating that the proinflammatory molecule NF-kappaB was increased through up regulation of PAF-R. Consistently, NF-kappaB activation was significantly protected by the PAF-R antagonist, ginkgolide B (Gink B), in PAF-R knockout mice and by the NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). In addition, PCP-induced abnormal behaviors (i.e., reduced sociability, depression, cognitive impairment, and behavioral sensitization) were significantly attenuated by Gink B, in PAF-R knockout mice, and by PDTC. Importantly, PDTC did not significantly alter the attenuations observed in Gink B-treated mice or PAF-R knockout mice, indicating that NF-kappaB is a critical target for neuropsychotoxic modulation of PAF-R. Therefore, the results suggest that PAF-R mediates PCP-induced neuropsychotoxicity via a NF-kappaB-dependent mechanism, and that up-regulation of PAF-R may be associated with schizophrenia-like behavior in animal models. PMID- 29122691 TI - Sexually diergic hypothalamic-pituitary-adrenal axis responses to selective and non-selective muscarinic antagonists prior to cholinergic stimulation by physostigmine in rats. AB - Central cholinergic systems regulate the hypothalamic-pituitary-adrenal (HPA) axis differentially in males and females (sexual diergism). We previously investigated the role of muscarinic receptors in this regulation by administering physostigmine (PHYSO), an acetylcholinesterase inhibitor, to male and female rats pretreated with scopolamine (SCOP), a nonselective muscarinic antagonist. SCOP pretreatment enhanced adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses in both sexes, but males had greater ACTH responses while females had greater CORT responses. In the present study, we further explored the role of muscarinic receptor subtypes in HPA axis regulation by administering PHYSO to male and female rats following SCOP or various doses of either the M1 or the M2 selective muscarinic receptor antagonists, pirenzepine (PIREN) or methoctramine (METHO). Blood was sampled before and at multiple times after PHYSO. ACTH and CORT were determined by highly specific immunoassays. M1 antagonism by PIREN prior to PHYSO resulted in sustained, dose-dependent increases in ACTH and CORT: ACTH responses were similar in both sexes, and CORT responses were greater in females. M2 antagonism by METHO prior to PHYSO resulted in overall decreases in ACTH and CORT: ACTH and CORT responses were higher in females but lower in both sexes than the hormone responses following PIREN or SCOP pretreatment. Area under the curve analyses supported these findings. These results suggest that specific muscarinic receptor subtypes differentially influence the HPA axis in a sexually diergic manner. PMID- 29122694 TI - Pharmacotherapy for NASH: Current and emerging. AB - Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant of NAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH. Given the disease burden, there is an important unmet need for pharmacologic treatment options for this patient population. The underlying pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex and reflected by the myriad of therapies, with different targets, currently under investigation. In broad strokes, drug development has focused on modulation of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis. Although much progress has been made in enhancing our understanding of NAFLD pathogenesis, development of pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complexities in clinical trial design. The compounds in phase IIa have provided promising results in terms of potential benefits on various aspects of histopathology. Agents in later stages of development have shown fairly modest results in terms of reduction of hepatic steatosis, necroinflammation and fibrosis. If longer term safety and efficacy are established among heterogeneous cohorts, these medications may help mitigate potential morbidity and mortality for this burgeoning patient population. PMID- 29122695 TI - Should we undertake surveillance for HCC in patients with NAFLD? AB - The pandemic of obesity and its related complications is rapidly changing the epidemiology of many types of cancer, including hepatocellular carcinoma (HCC). Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of HCC, with a steadily rising trend compared to viral or alcohol-induced chronic hepatitis. The much greater prevalence of the underlying liver disease in the general population and the chance of HCC occurrence in non-cirrhotic liver are the most worrisome aspects of HCC in NAFLD. Effective screening programmes are currently hampered by limited knowledge of the pathways of carcinogenesis and a lack of tools able to stratify the risk of HCC in the NAFLD population. Hence, poor surveillance has prevented the development of an adequate treatment for NAFLD related HCC. Systemic and hepatic molecular mechanisms involved in hepatocarcinogenesis, as well as potential early markers of HCC are being extensively investigated. This review describes the current clinical impact of HCC in NAFLD and discusses the most important unmet needs for its effective management. PMID- 29122693 TI - Vitamin A improves the symptoms of autism spectrum disorders and decreases 5 hydroxytryptamine (5-HT): A pilot study. AB - Autism spectrum disorders (ASD) are complicated neurodevelopmental disorders. Many studies have demonstrated that children with autism have multiple nutritional deficiencies and increased serum 5-hydroxytryptamine (5-HT) levels. In our previous study, 77.9% of autistic children were found to have vitamin A deficiency, and the concentration of vitamin A was negatively associated with the CARS score. In the present study, we sought to test whether vitamin A supplementation could improve autistic symptoms and decrease serum 5-HT levels. The DSM-V criteria and CARS score were used for symptom description and symptom assessment of the patients, respectively, before and after vitamin A supplementation (VAS). Serum retinol and 5-HT levels, mRNA levels of RAR alpha, beta, and gamma and TpH 1 expression were detected in autistic children before and after VAS and in normal children. Serum retinol levels in children with ASD were significantly lower than in control children. Serum 5-HT levels in children with ASD were higher than in control children, which were correlated with symptom severity of children with autism. After VA supplementation, the children with ASD exhibited significant improvement in autism symptoms. Serum retinol concentrations of children with ASD were significantly increased, and serum 5-HT levels were decreased. Moreover, statistically significant changes were observed in mRNA expression levels of RAR alpha, RAR gamma and TpH 1 after VAS compared to baseline. This study suggested that VA supplementation may improve symptoms and reduce 5-HT levels in children with ASD, indicating that VA supplementation is a reasonable therapy at least for a subset of children with autism. PMID- 29122696 TI - ES2 enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells in vitro and in vivo. AB - ES2 is a new type of jatrophane diterpenoid ester isolated from the fructus E. sororia, a traditional Uyghur medicine in China. Here we reported the multidrug resistance (MDR) reversal effect of ES2 in vitro and in vivo by modulating the function of ATP-binding cassette subfamily B member 1 (ABCB1). ES2 exhibited low cytotoxicity to ABCB1-overexpressing MDR cells and their parental sensitive cells, but sensitized the MDR cells and ABCB1-transfected HEK293 cells to chemotherapeutic drugs that are ABCB1 substrates. The reversal ability of ES2 was primarily due to the inhibition of the efflux function of ABCB1. Moreover, ES2 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. There was no change in the expression of ABCB1 in the presence of ES2. The molecular docking analysis indicated that ES2 bond to the drug-binding site of ABCB1 transporter. Importantly, ES2 significantly enhanced the anti-tumor effect of vinorelbine against KBv200 cell xenografts in nude mice. Overall, these findings demonstrate that ES2 inhibits the ABCB1 transporter function and consequently reverses ABCB1-mediated MDR, indicating the potential use of ES2 in combination therapy with conventional chemotherapeutic drugs for cancer treatment. PMID- 29122698 TI - Emergence of methicillin-resistant Staphylococcus aureus ST398 in pigs in China. PMID- 29122697 TI - Early administration of appropriate antimicrobial agents to improve the outcome of carbapenem-resistant Acinetobacter baumannii complex bacteraemic pneumonia. AB - Carbapenem-resistant Acinetobacter baumannii complex (CRABC) is an emerging pathogen that causes bloodstream infections and nosocomial pneumonia. This study aimed to describe severe infection associated with CRABC bacteraemic pneumonia and to investigate risk factors for 28-day mortality. All patients aged >=18 years with CRABC bacteraemic pneumonia were enrolled retrospectively at five teaching hospitals in South Korea. Empirical antimicrobial therapy was defined as appropriate if administration of at least one antimicrobial agent, to which the causative pathogen was susceptible, for >48 h, within 5 days of the onset of bacteraemia. During the study period, 146 patients with CRABC bacteraemic pneumonia were enrolled. Among them, 128 (87.7%) patients were treated in the intensive care unit; of these, 110 (75.3%) had ventilator-associated pneumonia. A total of 42 patients (28.8%) received appropriate empirical therapy. There was no difference in baseline characteristics between the appropriate and inappropriate empirical treatment groups. However, 28-day mortality was higher in the inappropriate therapy group (54.8% vs. 76.9%; P = 0.008). Multivariate Cox regression analysis revealed that Acute Physiology and Chronic Health Evaluation (APACHE) II score >=20 [hazard ratio (HR) = 1.28, 95% confidence interval (CI) 1.04-1.58; P = 0.02], septic shock (HR = 3.49, 95% CI 2.15-5.67; P <0.001) and inappropriate empirical therapy (HR = 3.24, 95% CI 1.94-5.42; P <0.001) were independently associated with an adverse outcome. In conclusion, the mortality rate of CRABC bacteraemic pneumonia was extremely high. Appropriate empirical therapy might improve the outcome of patients with CRABC bacteraemic pneumonia. PMID- 29122699 TI - Recommendations for primary studies evaluating therapeutic medical devices were identified and systematically reported through reviewing existing guidance. AB - OBJECTIVES: The aim of the study was to review existing recommendations on study design, conduct, analysis, and reporting for primary studies of therapeutic medical devices (TMDs) and the closely related field of interventional procedures. STUDY DESIGN AND SETTING: We performed a targeted literature review of publications with recommendations for study design, conduct, analysis, and reporting for primary studies of TMDs and related technologies. We combined an electronic database search with a systematic screening of tables of content of selected journals and scanning the reference lists of relevant articles. RESULTS: We identified 40 publications authored or commissioned primarily by regulators, health technology assessment agencies, and expert groups. We identified study designs of randomized clinical trials that specifically address the quick, incremental development of TMDs and provider and patient preferences. The importance of contextual factors for TMD interventions should be considered during the selection of patients, providers, and centers, as well as in data collection and analysis. We also identified guidance for the analysis and quantification of learning curves as well as for the design and analysis of large registries of high quality. CONCLUSION: The methodology to conduct primary research for TMDs should be disseminated to support improvement of the evidence base for health technology assessments. PMID- 29122700 TI - Using reference values to define disease based on the lower limit of normal biased the population attributable fraction, but not the population excess risk: the example of chronic airflow obstruction. AB - BACKGROUND: The impact of disease on population health is most commonly estimated by the population attributable fraction (PAF), or less commonly by the excess risk, an alternative measure that estimates the absolute risk of disease in the population that can be ascribed to the exposure. Using chronic airflow obstruction as an example, we examined the impact on these estimates of defining disease based on different "normal" values. METHOD: We estimated PAF and the excess risk in scenarios in which the true rate of disease was 10% in the exposed and 5% in the unexposed, and where either 50% or 20% of the population was exposed. Disease definition was based on a "lower limit of normal", using the 5th, 1st and 0.2nd centile of values in a "normal" population as thresholds to define normality. RESULTS: Where normality is defined by centiles of values in a "normal" population, PAF is strongly influenced by which centile is selected to define normality. This is not true for the population excess risk. CONCLUSION: Care should be taken when interpreting estimates of PAF when disease is defined from a centile of a normal population. PMID- 29122701 TI - Predictors of quality of life improvement after surgery for metastatic tumors of the spine: prospective cohort study. AB - BACKGROUND CONTEXT: Surgical decompression and stabilization followed by radiosurgery represents an effective method for local tumor control and neurologic preservation for patients with metastatic epidural spinal cord compression (MESCC). We have previously demonstrated improvement in health related quality of life (HrQOL) after this combined modality treatment ("hybrid therapy"). PURPOSE: The current analysis focuses on delineation of patient specific prognostic factors predictive of HrQOL change after combined surgery stereotactic radiosurgery (SRS) treatment of MESCC. STUDY DESIGN: This is a prospective, single-center, cohort study. PATIENT SAMPLE: One hundred and eleven patients with MESCC who underwent separation surgery followed by SRS were included. OUTCOME MEASURES: Prognostic factors associated with improved patient reported outcome (PRO) measures. METHODS: Patient-reported outcome tools, that is, Brief Pain Inventory (BPI) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP), both validated in the cancer population, were prospectively collected. Numeric prognostic factors were correlated with PRO measures using the Spearman rank correlation coefficient. Categorical prognostic factors were correlated with PRO measures using the Wilcoxon two-sample test (for two categories) or the Kruskal-Wallis test (for three or more categories). All statistical tests were two-sided with a level of significance <.05 for correlation of prognostic factors with PRO constructs and a level of significance <.0014 for correlation of prognostic factors with PRO items. Statistical analyses were done in SAS (version 9.4, Cary, NC, USA). RESULTS: One hundred and eleven patients were included in this analysis. Patients with lower preoperative Medical Research Council (MRC) motor scores experienced a greater decrease in symptom interference (BPI interference construct (p=.03) and individual functional measures including general activity (p=.001), walking (p=.001), and normal work (p=.006)). Lumbar location was associated with better outcomes than cervical or thoracic as noted on the BPI pain experience construct (p=.03) and MDASI-SP interference (p=.01) and core symptom (p=.002) constructs. Patients with American Spinal Injury Association (ASIA) scores of C or D benefit more than those with ASIA E on BPI interference construct (p=.04). Patients with higher Eastern Cooperative Oncology Group (ECOG) scores at presentation benefit more than those with low ECOG scores on MDASI-SP interference construct (p=.03). Women benefit more than men on BPI interference (p=.03) and pain experience (p=.04) constructs. Patients with prior spinal surgery at the current level of interest benefit less than those who are naive surgical patients in MDASI-SP interference construct (p=.04). CONCLUSIONS: Delineation of patient characteristics associated with HrQOL improvement provides crucial information for patient selection, patient education, and setting treatment expectations. For patients with MESCC treated with hybrid therapy using surgery and radiosurgery, the presence of neurologic deficits and diminished performance status, lumbar tumor level, and female gender were associated with greater PRO improvement. PMID- 29122702 TI - Estrogenic effects following larval exposure to the putative anti-estrogen, fulvestrant, in the fathead minnow (Pimephales promelas). AB - The objective of the present study was to investigate the consequences of early life exposure to fulvestrant on estrogenic gene expression in fathead minnow larvae. To address this objective, fathead minnow larvae were exposed to fulvestrant (ICI 182,780) during the window of sexual differentiation between 0 to 30 days post-hatch (dph). The four treatment groups in this study included: filtered water controls (never exposed), solvent controls (ethanol 0.01%), and nominally low (0.10MUg/L) and high (10.0MUg/L) doses of fulvestrant. Following 30 d exposure to their respective treatment, larvae were transferred to filtered water aquaria and assessed for alterations in endocrine-responsive gene expression (i.e., RT-qPCR), body size and survival. The remaining fish depurated in filtered water until reaching sexual maturity (180dph) for assessment of persistent effects on sex characteristics, reproductive performance and sex ratio. Following the 30-d early life exposure, larvae showed upregulations of the endocrine-responsive genes ar, erbeta and vtg in response to both low and high doses of fulvestrant, but showed no differences in survival or body mass. Upon reaching sexual maturity under depuration conditions, male minnows previously exposed to fulvestrant as larvae showed reductions in gonad mass along with the feminization of secondary sex characteristics with no observed effects in females. Exposure to fulvestrant had no effects on gonadal histology, reproductive performance or final sex ratio as adults. Results from this study demonstrate that aqueous exposure to fulvestrant is estrogenic in fathead minnow larvae and is capable of feminizing male fish as adults following early life exposure. PMID- 29122703 TI - Improving metabolic efficiency of the reverse beta-oxidation cycle by balancing redox cofactor requirement. AB - Previous studies have made many exciting achievements on pushing the functional reversal of beta-oxidation cycle (r-BOX) to more widespread adoption for synthesis of a wide variety of fuels and chemicals. However, the redox cofactor requirement for the efficient operation of r-BOX remains unclear. In this work, the metabolic efficiency of r-BOX for medium-chain fatty acid (C6-C10, MCFA) production was optimized by redox cofactor engineering. Stoichiometric analysis of the r-BOX pathway and further experimental examination identified NADH as a crucial determinant of r-BOX process yield. Furthermore, the introduction of formate dehydrogenase from Candida boidinii using fermentative inhibitor byproduct formate as a redox NADH sink improved MCFA titer from initial 1.2g/L to 3.1g/L. Moreover, coupling of increasing the supply of acetyl-CoA with NADH to achieve fermentative redox balance enabled product synthesis at maximum titers. To this end, the acetate re-assimilation pathway was further optimized to increase acetyl-CoA availability associated with the new supply of NADH. It was found that the acetyl-CoA synthetase activity and intracellular ATP levels constrained the activity of acetate re-assimilation pathway, and 4.7g/L of MCFA titer was finally achieved after alleviating these two limiting factors. To the best of our knowledge, this represented the highest titer reported to date. These results demonstrated that the key constraint of r-BOX was redox imbalance and redox engineering could further unleash the lipogenic potential of this cycle. The redox engineering strategies could be applied to acetyl-CoA-derived products or other bio-products requiring multiple redox cofactors for biosynthesis. PMID- 29122704 TI - Comparing the different response of PNS and CNS injured neurons to mesenchymal stem cell treatment. AB - Mesenchymal stem cells (MSCs) are adult bone marrow-derived stem cells actually proposed indifferently for the therapy of neurological diseases of both the Central (CNS) and the Peripheral Nervous System (PNS), as a panacea able to treat so many different diseases by their immunomodulatory ability and supportive action on neuronal survival. However, the identification of the exact mechanism of MSC action in the different diseases, although mandatory to define their real and concrete utility, is still lacking. Moreover, CNS and PNS neurons present many different biological properties, and it is still unclear if they respond in the same manner not only to MSC treatment, but also to injuries. For these reasons, in this study we compared the susceptibility of cortical and sensory neurons both to toxic drug exposure and to MSC action, in order to verify if these two neuronal populations can respond differently. Our results demonstrated that Cisplatin (CDDP), Glutamate, and Paclitaxel-treated sensory neurons were protected by the co-culture with MSCs, in different manners: through direct contact able to block apoptosis for CDDP- and Glutamate-treated neurons, and by the release of trophic factors for Paclitaxel-treated ones. A possible key soluble factor for MSC protection was Glutathione, spontaneously released by these cells. On the contrary, cortical neurons resulted more sensitive than sensory ones to the toxic action of the drugs, and overall MSCs failed to protect them. All these data identified for the first time a different susceptibility of cortical and sensory neurons, and demonstrated a protective action of MSCs only against drugs in peripheral neurotoxicity. PMID- 29122705 TI - Age-related changes in STriatal-Enriched protein tyrosine Phosphatase levels: Regulation by BDNF. AB - Recent results indicate that STriatal-Enriched protein tyrosine Phosphatase (STEP) levels are regulated by brain-derived neurotrophic factor (BDNF), whose expression changes during postnatal development and aging. Here, we studied STEP ontogeny in mouse brain and changes in STEP with age with emphasis on the possible regulation by BDNF. We found that STEP expression increased during the first weeks of life, reaching adult levels by 2-3weeks of age in the striatum and cortex, and by postnatal day (P) 7 in the hippocampus. STEP protein levels were unaffected in BDNF+/- mice, but were significantly reduced in the striatum and cortex, but not in the hippocampus, of BDNF-/- mice at P7 and P14. In adult wild type mice there were no changes in cortical and hippocampal STEP61 levels with age. Conversely, striatal STEP levels were reduced from 12months of age, correlating with higher ubiquitination and increased BDNF content and signaling. Lower STEP levels in older mice were paralleled by increased phosphorylation of its substrates. Since altered STEP levels are involved in cellular malfunctioning events, its reduction in the striatum with increasing age should encourage future studies of how this imbalance might participate in the aging process. PMID- 29122706 TI - Mid to long term outcomes of Laparoscopic Sleeve Gastrectomy in Indian population: 3-7 year results - A retrospective cohort study. AB - INTRODUCTION: Few studies have addressed the mid to long term impact of Laparoscopic Sleeve Gastrectomy (LSG) on weight loss and obesity associated co morbidities, particularly in Indian population. The aim of this study is to assess the efficacy of LSG in morbid obesity over 3-7 years follow up. MATERIALS AND METHODS: Data of all patients who underwent LSG between January 2008 and March 2015 and completed their at least 1 year follow up till March 2016 was retrospectively reviewed using a prospectively collected database. RESULTS: 424 patients undergoing primary LSG were included. The mean age (+/-2SD) was 39.8 +/- 22.5 years and the mean Body Mass Index (BMI) (+/-2SD) was 46.67 +/- 15.8 kg/m2. 124 patients (29.2%) were super-obese (BMI >50 kg/m2). The percentage follow-up at 1 year, 3 years, 5 years and 7 years was 78.3%, 66.7%, 42.3% and 38.4% respectively. The mean percentage Excess weight Loss (%EWL) (+/-2SD) at 1year, 3years, 5years, and 7years was 71.8 (+/-50.5%), 64.95% (+/-41.8%), 61.7% (+/ 46.2%) and 57.15% (+/-50.2%) respectively. The preoperative BMI significantly correlated with %EWL at 5 year (r2 = 0.107, p = 0.018). The overall complication rate was 5.8%. Early complications included staple line leak (1.2%), bleeding (1.2%), deep venous thrombosis (0.4%) and 30-day mortality (0.21%). Late complications included stricture formation (0.21%) and new onset Gastro esophageal Reflux Disease (GERD) (2.8%).At 5 years, 83.3% of diabetic patients showed remission while rest showed improvement in glycemic control with decrease in dosage. 69.3% patients showed improvement in hypertension, 100% patients showed improvement in Obstructive Sleep Apnea Syndrome, 75% patients showed improvement in hypothyroidism after surgery. GERD resolved in 62.8% patients while worsened in 11.4% patients. CONCLUSIONS: LSG has durable weight loss at 5 year with %EWL of 61% and significant resolution of obesity associated co morbidities. PMID- 29122707 TI - Robotic versus laparoscopic distal pancreatectomy: A comparative study of clinical outcomes and costs analysis. AB - BACKGROUND: The robotic surgery cost presents a critical issue which has not been well addressed yet. This study aims to compare the clinical outcomes and cost differences of robotic distal pancreatectomy (RDP) versus laparoscopic distal pancreatectomy (LDP). METHODS: Data were abstracted prospectively from 2011 to 2017. An independent company performed the financial analysis. RESULTS: A total of 28 RDP and 26 LDP were included. The mean operative time was significantly lower in the LDP (294 vs 241 min; p = 0.02). The main intra and post-operative data were similar, except for the conversion rate (RDP: 3.6% vs LDP: 19.2%; p = 0.04) and hospital stay (RDP: 8.9 vs LDP 13.1 days; p = 0.04). The mean total costs were similar in both groups (RDP: 9198.64 ? vs LDP: 9399.74 ?; p > 0.5). CONCLUSIONS: RDP showed lower conversion rate and shorter hospital stay than LDP at the price of longer operative time. RDP is financially comparable to LDP. PMID- 29122708 TI - Combinatory effects of phytoestrogens and exercise on body fat mass and lipid metabolism in ovariectomized female rats. AB - The purpose of this study was to investigate the combinatory effects of an isoflavone (ISO)-rich diet and exercise on fat mass and lipid metabolism in ovariectomized (OVX) rats. Therefore the female Wistar rats were sedentary, performed an intense treadmill uphill running, received ISOs, or a combination of ISOs and running after ovariectomy. The exercise reduced visceral fat mass, adipocyte size and serum leptin in Sham animals and antagonized the increases of these parameters induced by OVX. ISOs reduced OVX induced increase of serum leptin. The combination of training and ISOs was most effective in reducing serum triglyceride levels. In OVX rats the training stimulated the expression of genes associated with fatty acid synthesis (SREBP-1c and FAS) in adipose tissue, soleus muscle, liver and genes associated with fatty acid oxidation (PPARdelta and PGC 1alpha) in adipose tissue. ISOs stimulated the expression of SREBP-1c and FAS in soleus muscle and PGC-1alpha in adipose tissue, whereas suppressed hepatic SREBP 1c and FAS expression. Strong additive effects of ISOs combined with the training were observed for PPARdelta and PGC-1alpha expressions in soleus muscle. In conclusion our results demonstrate that both the training and ISOs affect fat mass and fatty acid metabolism in OVX rats. The training seems to have a higher impact than ISO exposure in regulating gene expression in adipose tissue. However, the strongest effects for several of the addressed parameters could be observed in the combination group especially in the soleus muscle. Therefore a combination of training and an ISO-rich diet may have beneficial effects on fatty acid metabolism and could be a concept for the prevention of obesity in postmenopausal females. PMID- 29122709 TI - Evaluation of effect of letrozole prior to misoprostol in comparison with misoprostol alone in success rate of induced abortion. AB - BACKGROUND: Abortion, spontaneous or induced, is a common complication of pregnancy and exploration of available and safe regimens for medical abortion in developing countries seems crucial. AIMS: The present study was aimed to assess the effect of letrozole in combination with misoprostol in women eligible for legal therapeutic abortion with gestational age <=14weeks. MATERIALS AND METHODS: This clinical randomized trial was conducted on 78 women who were candidate of medical abortion and eligible for legal abortion with gestational age <=14 weeks that were randomly divided into two groups of case and controls. Case group received daily oral dose of 10mg letrozole for three days followed by vaginal misoprostol. In control group the patients received only vaginal misoprostol. The rate of complete abortion, induction-of-abortion time, and side-effects were assessed. RESULTS: Complete abortion was observed in 30 patients (76.9%) in case group and 9 (23.1%) cases were failed. In control group there was 16 (41.03%) complete abortions and 23 (58.97%) cases were failed to abort. Patients with gestational age of between 6 and 10 weeks did not show significant difference in both groups (P=0.134). Regarding pregnancy remnants there were significant differences between two groups (P=0.034). The time form admission to discharge in case groups were significantly shorter than those in control group (P=0.001). The indication for curettage in case group was significantly less than control group (P=0.001). CONCLUSION: A 3-day course of letrozole (10mg/daily) followed by misoprostol was associated with a higher complete abortion and lower curettage rates and reduction in time from admission to discharge in women with gestational age <=14 weeks compared to misoprostol alone. PMID- 29122710 TI - Adenosine deaminase activity and gene expression patterns are altered after chronic ethanol exposure in zebrafish brain. AB - Ethanol alters the homeostasis between excitatory and inhibitory neurotransmitters and its intoxication reveals adenosine as responsible to modify several responses including signal transduction. Zebrafish has been recently investigated for knowledge the prolonged effect of ethanol on behavioral and biochemical parameters. The aim of this study was to evaluate the soluble and membrane adenosine deaminase activities and gene expression in zebrafish brain. Animals were exposed to 0.5% ethanol for 7, 14, and 28days. There were no significant changes in ADA activity from soluble fraction after all treatments. However, we verified a decrease of ADA activity in membrane fraction after 28days (44%) of ethanol exposure. ADA1 was not altered whereas mRNA transcript levels for ADAL presented an increase after 28days of ethanol exposure (34%). ADA2-1 showed a decrease (26%) followed by an increase (17%) of transcripts after 14 and 28days of ethanol exposure, respectively. However, ADA2-1 truncated alternative splice isoform (ADA2-1/T) demonstrated a reduction after 28days (20%). ADA2-2 was decreased (22%) followed by an increase (109%) of transcripts after 14 and 18days of ethanol exposure, respectively. Altogether, the purine catabolism promoted by ADA may be an important target of the chronic toxicity induced for ethanol. PMID- 29122711 TI - Developmental refinement of synaptic transmission on micropatterned single layer graphene. AB - : Interfacing neurons with graphene, a single atomic layer of sp2 hybridized C atoms, is a key paradigm in understanding how to exploit the unique properties of such a two-dimensional system for neural prosthetics and biosensors development. In order to fabricate graphene-based circuitry, a reliable large area patterning method is a requirement. Following a previously developed protocol, we monitored the in vitro neuronal development of geometrically ordered neural network growing onto patterned Single Layer Graphene (SLG) coated with poly-D-lysine. The microscale patterns were fabricated via laser micromachining and consisted of SLG stripes separated by micrometric ablated stripes. A comprehensive analysis of the biointerface was carried out combining the surface characterization of SLG transferred on the glass substrates and Immunohistochemical (IHC) staining of the developing neural network. Neuronal and glial cells proliferation, as well as cell viability, were compared on glass, SLG and SLG-patterned surfaces. Further, we present a comparative developmental study on the efficacy of synaptic transmission on control glass, on transferred SLG, and on the micropatterned SLG substrates by recording miniature post synaptic currents (mPSCs). The mPSC frequencies and amplitudes obtained on SLG-stripes, SLG only and on glass were compared. Our results indicate a very similar developmental trend in the three groups, indicating that both SLG and patterned SLG preserve synaptic efficacy and can be potentially exploited for the fabrication of large area devices for neuron sensing or stimulation. STATEMENT OF SIGNIFICANCE: This paper compares the morphological and functional development of neural networks forming on glass, on Single Layer Graphene (SLG) and on microsized patterned SLG substrates after neuron spontaneous migration. Neurons developing on SLG are viable after two weeks in vitro, and, on SLG, glial cell proliferation is enhanced. The functionality of the neural networks is demonstrated by measuring the development of neuron synapses in the first and second week in vitro. Preserving the neuron synaptic efficacy, both homogeneous and patterned interfaces based on graphene can be potentially exploited for the fabrication of large area devices for neuron sensing or stimulation, as well as for next generation of bio-electronic systems, to be used as brain-interfaces. PMID- 29122712 TI - Development of PLGA nanoparticles loaded with clofazimine for oral delivery: Assessment of formulation variables and intestinal permeability. AB - The use of polymeric nanoparticles as delivery systems is a promising tool to overcome drawbacks related to low aqueous solubility of drugs, which limit their in vivo bioavailability. The aim of this study was to decrease clofazimine (CLZ) toxicity using experimental design to formulate CLZ loaded in PLGA nanoparticles (NPs-CLZ) through a Plackett-Burman design (PBD). A screening PBD was constructed with twelve formulations involving six variables among process and formulation parameters and the selected responses were particle size, polydispersity index (PDI), association efficiency (AE) and drug loading (DL). The formulation was achieved based on the desirability tool, and the obtained NPs-CLZ formulation was characterized regarding morphology, physicochemical properties, in vitro release and cellular studies. Particle size, PDI, AE and DL were found to be 211+/-3nm, 0.211+/-0.009, 70+/-5% and 12+/-1%, respectively. Physicochemical studies confirmed the absence of chemical interactions between CLZ and other nanoparticles constituents and the amorphous state of CLZ, while morphological analysis revealed the spherical shape of the particles. In vitro release profile of CLZ from NPs-PLGA showed a slow pattern of drug release. Cell viability studies towards intestinal cells revealed that NPs-CLZ did not show CLZ toxicity on Caco-2 and HT29-MTX cells compared to free CLZ solutions. Moreover, CLZ could permeate Caco-2 monolayers substantially at the end of 8h. It can be concluded that the proposed NPs-CLZ represent a promising platform to the oral delivery of CLZ as they were able to decrease its intrinsic toxicity, with improved absorption. PMID- 29122713 TI - Fabrication and characterization of nanobiocomposite scaffold of zein/chitosan/nanohydroxyapatite prepared by freeze-drying method for bone tissue engineering. AB - In this investigation, porous composite scaffolds were prepared using a freeze drying procedure by mixing zein (ZN), chitosan (CS) and nanohydroxyapatite (nHAp) in different inorganic/organic weight ratios. The gained nanocomposite scaffolds were studied using X-ray diffractometer (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and N2-adsorption-desorption technique. Also, swelling, porosity, mechanical properties, biomineralization capability, degradation, cell attachment, and cell viability of the composite scaffolds were studied. The results showed a porous nature with acceptable pore dimensions and interconnections for cell penetration and colonization. In addition, the cytocompatibility of the ZN/CS/nHAp scaffolds was surveyed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) evaluation and cell attachment studies using human bone cancer cells. Studies indicated non- toxicity to the cells, and the cells were found to be attached to the pore walls within the scaffolds. The results related to physicochemical properties and superior cytocompatibility suggested that ZN/CS/nHAp scaffold could be potential candidate materials for the tissue engineering. PMID- 29122714 TI - Diethanolamine-modified pectin based core-shell composites as dual working gastroretentive drug-cargo. AB - The current study aimed at developing diethonolamine-modified high-methoxyl pectin (DMP)-alginate (ALG) based core-shell composites for controlled intragastric delivery of metformin HCl (MFM) by combined approach of floating and bioadhesion. DMP with degree of amidation of 48.72% was initially accomplished and characterized by FTIR, DSC and XRD analyses. MFM-loaded core matrices were then fabricated by ionotropic gelation technique employing zinc acetate as cross linker. The core matrices were further coated by fenugreek gum (FG)-ALG gel membrane via diffusion-controlled interfacial complexation method. Various formulations demonstrated excellent drug encapsulation efficiency (DEE, 51-70%) and sustained drug eluting behavior (Q8h, 72-96%), which were extremely influenced by polymer-blend (ALG:DMP) ratios, low density additives (olive oil/magnesium stearate) and FG-ALG coating inclusion. The drug release profile of the core-shell matrices (F-7) was best fitted in zero-order kinetic model with case-II transport driven mechanism. It also portrayed outstanding gastroretentive characteristics. Moreover, the composites were analyzed for surface morphology, drug-excipients compatibility, thermal behavior and drug crystallinity. Thus, the developed composites are appropriate for controlled stomach-specific delivery of MFM for type 2 diabetes management. PMID- 29122715 TI - Nematicidal activity of a water soluble lectin from seeds of Moringa oleifera. AB - Gastrointestinal nematodes are the major cause of animal diseases, and the indiscriminate use of synthetic anthelmintic contributes to the development of drug resistance. Natural bioproducts are noteworthy since they have proved to be promising for alternative antiparasitic therapies. This study evaluated the in vitro effect of WSMoL (water soluble Moringa oleifera lectin) on hatching of eggs and on the development of early-stage larvae of gastrointestinal nematodes from naturally infected goats. In addition, the interference of WSMoL on activity of proteases was determined and the affinity of the lectin for glycosylated molecules of these parasites was investigated using fluorescein isothiocyanate (FITC)-labeled WSMoL. WSMoL at 250MUgmL-1 interfered on hatching of eggs (40.4% of not hatched eggs; p=0.018), and on larval development (stages L1-L3) (IC50 of 78.22MUgmL-1). The activity of secreted proteases showed a significant increase in the presence of WSMoL (307.14U/mg-1031U/mg). FITC-labeled WSMoL recognized embryonic egg content and larval content after hatching, which suggests that WSMoL interact with intestinal glycoconjugate receptors in the embryo, as well as in cuticle of the larvae. PMID- 29122716 TI - Performances of local chitosan and its nanocomposite 5%Bentonite/Chitosan in the removal of chromium ions (Cr(VI)) from wastewater. AB - The present work focuses on the study of the application of abundant and less expensive materials such as chitosan (CS) and bentonite/chitosan nanobiocomposite (nano 5%Bt/CS) in the removal of hexavalent chromium. The adsorption behavior of the prepared materials (CS and nano 5%Bt/CS) was tested for the removal of chromium (VI) ions in a synthetic solution and wastewater from a tanning industry. Spectroscopic analysis like techniques FTIR, XRD and SEM/EDX have been used to characterise the adsorbents before and after their contact with chromium ions. The experimental data indicate that the adsorption of chromium proceeds kinetically according to a pseudo-second order model on both adsorbents and the apparent activation energy (Ea) have been measured to be 4.11kJmol-1 and 15.98kJmol-1 for chitosan and nano 5%Bt/CS, respectively. It was found that the non-linear modelling of experimental isotherms was well adapted to the Langmuir and Redlich-Peterson models. Thermodynamic parameters (i.e., change in the free energy (DeltaG degrees ), the enthalpy (DeltaH degrees ), and the entropy (DeltaS degrees )) have been also, evaluated and the results revealed that the removal of chromium ions on both solids was done via physical adsorption. The adsorption test on a real rejection of the tanning industry shows that the CS and nano 5%Bt/CS can substitute other more expensive adsorbents. PMID- 29122717 TI - Synthesis and characterization of methyl pyrazolone functionalized magnetic chitosan composite for visible light photocatalytic degradation of methylene blue. AB - TiO2/Fe3O4, TiO2/Fe3O4/chitosan and Methylpyrazolone functionalized TiO2/Fe3O4/chitosan (MPyTMChi) were successfully prepared. The chemical structure of the prepared materials was confirmed by FT-IR spectra, XRD, SEM and TEM. BET surface area increased from 2.4 to 3.1m2/g, Eg decreased from 2.58 to 2.25eV and more quenching of PL emission spectra was observed upon functionalization of TMChi by MPy. Moreover, high Ti and oxygen percentages were detected by EDX. Magnetization value (Ms) reached 21 emu.g-1 for MPyTMChi. MPyTMChi showed enhanced photocatalytic degradation rate of methylene blue (MB) dye under visibe light irradiation (99.8% after 40min) as compared with that for TiO2/Fe3O4 (96.7% after 100min) and TMChi (98.9% after 60min), respectively. It was regarded that the photocatalytic degradation of MB dye on MPyTMChi follows apparent pseudo first-order according to the Langmuir-Hinshelwood (L-H) model and kapp value was 0.089min-1. Active species trapping experiment revealed that h+ and O2- played the main role in the photodegradation of MB dye while OH quenching did not greatly affect photodegradation rate. Additionally, MPyTMChi can be efficiently reused for six repetitive cycles. MPyTMChi showed higher antimicrobial activity against gram-positive, gram- negative bacterial and fungal strains while large inhibition zone was observed for gram-positive bacteria. PMID- 29122718 TI - Near-Infrared Autofluorescence Image-Guided Parathyroid Gland Mapping in Thyroidectomy. AB - BACKGROUND: Studies to date have shown that near-infrared autofluorescence imaging (NIR) can detect the parathyroid gland during thyroidectomy. However, there are no reports that NIR imaging can identify the parathyroid gland when it's covered with fibrofatty tissue before identification by a surgeon's naked eye. In this study, we investigated the feasibility of parathyroid gland mapping to facilitate early identification of the parathyroid gland during thyroidectomy. STUDY DESIGN: Seventy parathyroid glands from 38 patients who underwent thyroidectomy for papillary thyroid cancer were included in this prospective study. Near-infrared with infrared illumination (NIR-IR) imaging using a 780-nm light-emitting diode was conducted at the predicted locations of the superior or inferior parathyroid glands. Parathyroid mapping was conducted in 3 stages. Stages P1, P2, and P3 were defined as imaging before identification of the gland by direct visualization, imaging after identification, and imaging in the removed specimen, respectively. RESULTS: Sixty-four parathyroid glands (92.8%) could be localized in stage P1 before surgical dissection and exposure of the gland. Five parathyroid glands that were not detected at stage P1 were identified in stages P2 (4 cases, 5.8%) and P3 (1 case, 1.4%). One parathyroid gland was not identified in either the NIR imaging or the pathologic examination. The sensitivity, specificity, and accuracy of parathyroid gland mapping in stages P1, P2, and P3 were all 100%. CONCLUSIONS: Parathyroid gland mapping using our NIR-IR imaging technique was feasible, with an excellent accuracy rate. This technique may be helpful for early identification of parathyroid glands during thyroidectomy. PMID- 29122719 TI - Interocular interaction of contrast and luminance signals in human primary visual cortex. AB - Interocular interaction in the visual system occurs under dichoptic conditions when contrast and luminance are imbalanced between the eyes. Human psychophysical investigations suggest that interocular interaction can be explained by a contrast normalization model. However, the neural processes that underlie such interactions are still unresolved. We set out to assess, for the first time, the proposed normalization model of interocular contrast interactions using magnetoencephalography (MEG) and to extend this model to incorporate interactions based on interocular luminance differences. We used MEG to record steady-state visual evoked responses (SSVER), and functional magnetic resonance imaging (fMRI) to obtain individual retinotopic maps that we used in combination with MEG source imaging in healthy participants. Binary noise stimuli were presented in monocular or dichoptic viewing and were frequency-tagged at 4 and 6 Hz. The contrast of the stimuli was modulated in a range between 0 and 32%. Monocularly, we reduced the luminance by placing a 1.5 ND filter over one eye in the maximal contrast condition. This ND filter reduces the mean light level by a factor of 30 without any alteration to the physical contrast. We observed in visual area V1 a monotonic increase in the magnitude of SSVERs with changes in contrast from 0 to 32%. For both eyes, dichoptic masking induced a decrease in SSVER signal power. This power decrease was well explained by the normalization model. Reducing mean luminance delayed monocular processing by approximately 38 ms in V1. The reduced luminance also decreased the masking ability of the eye under the filter. Predictions based on a temporal filtering model for the interocular luminance difference prior to the model's binocular combination stage were incorporated to update the normalization model. Our results demonstrate that the signals resulting from different contrast or luminance stimulation of the two eyes are combined in a way that can be explained by an interocular normalization model. PMID- 29122720 TI - Connectome-based predictive modeling of attention: Comparing different functional connectivity features and prediction methods across datasets. AB - Connectome-based predictive modeling (CPM; Finn et al., 2015; Shen et al., 2017) was recently developed to predict individual differences in traits and behaviors, including fluid intelligence (Finn et al., 2015) and sustained attention (Rosenberg et al., 2016a), from functional brain connectivity (FC) measured with fMRI. Here, using the CPM framework, we compared the predictive power of three different measures of FC (Pearson's correlation, accordance, and discordance) and two different prediction algorithms (linear and partial least square [PLS] regression) for attention function. Accordance and discordance are recently proposed FC measures that respectively track in-phase synchronization and out-of phase anti-correlation (Meskaldji et al., 2015). We defined connectome-based models using task-based or resting-state FC data, and tested the effects of (1) functional connectivity measure and (2) feature-selection/prediction algorithm on individualized attention predictions. Models were internally validated in a training dataset using leave-one-subject-out cross-validation, and externally validated with three independent datasets. The training dataset included fMRI data collected while participants performed a sustained attention task and rested (N = 25; Rosenberg et al., 2016a). The validation datasets included: 1) data collected during performance of a stop-signal task and at rest (N = 83, including 19 participants who were administered methylphenidate prior to scanning; Farr et al., 2014a; Rosenberg et al., 2016b), 2) data collected during Attention Network Task performance and rest (N = 41, Rosenberg et al., in press), and 3) resting state data and ADHD symptom severity from the ADHD-200 Consortium (N = 113; Rosenberg et al., 2016a). Models defined using all combinations of functional connectivity measure (Pearson's correlation, accordance, and discordance) and prediction algorithm (linear and PLS regression) predicted attentional abilities, with correlations between predicted and observed measures of attention as high as 0.9 for internal validation, and 0.6 for external validation (all p's < 0.05). Models trained on task data outperformed models trained on rest data. Pearson's correlation and accordance features generally showed a small numerical advantage over discordance features, while PLS regression models were usually better than linear regression models. Overall, in addition to correlation features combined with linear models (Rosenberg et al., 2016a), it is useful to consider accordance features and PLS regression for CPM. PMID- 29122721 TI - A common periodic representation of interaural time differences in mammalian cortex. AB - Binaural hearing, the ability to detect small differences in the timing and level of sounds at the two ears, underpins the ability to localize sound sources along the horizontal plane, and is important for decoding complex spatial listening environments into separate objects - a critical factor in 'cocktail-party listening'. For human listeners, the most important spatial cue is the interaural time difference (ITD). Despite many decades of neurophysiological investigations of ITD sensitivity in small mammals, and computational models aimed at accounting for human perception, a lack of concordance between these studies has hampered our understanding of how the human brain represents and processes ITDs. Further, neural coding of spatial cues might depend on factors such as head-size or hearing range, which differ considerably between humans and commonly used experimental animals. Here, using magnetoencephalography (MEG) in human listeners, and electro-corticography (ECoG) recordings in guinea pig-a small mammal representative of a range of animals in which ITD coding has been assessed at the level of single-neuron recordings-we tested whether processing of ITDs in human auditory cortex accords with a frequency-dependent periodic code of ITD reported in small mammals, or whether alternative or additional processing stages implemented in psychoacoustic models of human binaural hearing must be assumed. Our data were well accounted for by a model consisting of periodically tuned ITD detectors, and were highly consistent across the two species. The results suggest that the representation of ITD in human auditory cortex is similar to that found in other mammalian species, a representation in which neural responses to ITD are determined by phase differences relative to sound frequency rather than, for instance, the range of ITDs permitted by head size or the absolute magnitude or direction of ITD. PMID- 29122722 TI - Stimulus-invariant auditory cortex threat encoding during fear conditioning with simple and complex sounds. AB - Learning to predict threat depends on amygdala plasticity and does not require auditory cortex (ACX) when threat predictors (conditioned stimuli, CS) are simple sine tones. However, ACX is required in rodents to learn from some naturally occurring CS. Yet, the precise function of ACX, and whether it differs for different CS types, is unknown. Here, we address how ACX encodes threat predictions during human fear conditioning using functional magnetic resonance imaging (fMRI) with multivariate pattern analysis. As in previous rodent work, CS+ and CS- were defined either by direction of frequency modulation (complex) or by frequency of pure tones (simple). In an instructed non-reinforcement context, different sets of simple and complex sounds were always presented without reinforcement (neutral sounds, NS). Threat encoding was measured by separation of fMRI response patterns induced by CS+/CS-, or similar NS1/NS2 pairs. We found that fMRI patterns in Heschl's gyrus encoded threat prediction over and above encoding the physical stimulus features also present in NS, i.e. CS+/CS- could be separated better than NS1/NS2. This was the case both for simple and complex CS. Furthermore, cross-prediction demonstrated that threat representations were similar for simple and complex CS, and thus unlikely to emerge from stimulus specific top-down, or learning-induced, receptive field plasticity. Searchlight analysis across the entire ACX demonstrated further threat representations in a region including BA22 and BA42. However, in this region, patterns were distinct for simple and complex sounds, and could thus potentially arise from receptive field plasticity. Strikingly, across participants, individual size of Heschl's gyrus predicted strength of fear learning for complex sounds. Overall, our findings suggest that ACX represents threat predictions, and that Heschl's gyrus contains a threat representation that is invariant across physical stimulus categories. PMID- 29122723 TI - The neuronal network involved in self-attribution of an artificial hand: A lesion network-symptom-mapping study. AB - The feeling of body-ownership can be experimentally manipulated using the rubber hand illusion (RHI) paradigm. Participants experience a sense of ownership over an artificial hand when their hidden real hand and the visible artificial hand are synchronously stroked. Using lesion masks and behavioral data from a previous study on RHI failure in acute stroke patients, we here employed lesion network symptom-mapping (LNSM) based on normative functional connectome data to identify lesion-dependent network connectivity related to the experience of self attribution of an artificial hand in the RHI paradigm. We found that failure to experience the RHI was associated with higher normative lesion-dependent network connectivity to the right temporoparietal junction (rTPJ), right anterior Insula (raI) and right inferior frontal gyrus (rIFG). Since these areas were spared by the infarction in most patients with RHI failure (89% for rTPJ and 94% for raI/rIFG), the analysis suggests that remote dysfunction in rTPJ, raI, and rIFG accounted for RHI failure. These results highlight the potential role of rTPJ, raI, and rIFG in bodily self-consciousness. LNSM is a powerful tool capable of delineating the architecture of functional networks underlying complex cognitive function. PMID- 29122724 TI - Detection of new atrial fibrillation in patients with cardiac implanted electronic devices and factors associated with transition to higher device detected atrial fibrillation burden. AB - BACKGROUND: In patients with cardiac implanted electronic devices, detection of new atrial fibrillation (AF) is associated with an increased risk of stroke. OBJECTIVE: To characterize daily AF burden at first detection and the rate of temporal transition to higher device-detected AF burden. METHODS: A pooled analysis of data from 3 prospective projects was analyzed, and 6580 patients (mean age 68 +/- 12 years, 72% male) with no history of AF and no use of anticoagulants at baseline were identified. Various thresholds of daily AF burden (5 minutes and 1, 6, 12, and 23 hours) were analyzed. RESULTS: Among the study population of 6580 patients, a new AF, with an AF burden of >=5 minutes, was detected in 2244 patients (34%) during a follow-up period of 2.4 +/- 1.7 years. Among these patients, 1091 (49.8%) transitioned to a higher AF-burden threshold during follow-up. A higher duration of daily AF burden manifest at first detection and CHADS2 score >=2 were associated with faster transition to a subsequent higher burden. Approximately 24% of patients transitioned from a lower threshold to a daily AF burden of >=23 hours during follow-up. CONCLUSION: More than one-third of patients with no history of AF developed device-detected AF, with attainment of different thresholds of daily AF burden over time. Continuous long-term monitoring, especially when the initial detection corresponds to a higher daily AF burden and the CHADS2 score is >=2, could support timely clinical decisions on anticoagulation by capturing transitions to higher AF-burden thresholds. PMID- 29122725 TI - An imaging flow cytometry method to assess ricin trafficking in A549 human lung epithelial cells. AB - The endocytosis and trafficking of ricin in mammalian cells is an important area of research for those producing ricin anti-toxins and other ricin therapeutics. Ricin trafficking is usually observed by fluorescence microscopy techniques. This gives good resolution and leads to a detailed understanding of the internal movement of ricin within cells. However, microscopy techniques are often hampered by complex analysis and quantification techniques, and the inability to look at ricin trafficking in large populations of cells. In these studies we have directly labelled ricin and assessed if its trafficking can be observed using Imaging Flow Cytometry (IFC) both to the cytoplasmic region of cells and specifically to the Golgi apparatus. Using IDEAS(r) data analysis software the specific fluorescence location of the ricin within the cells was analysed. Then, using cytoplasmic masking techniques to quantify the number of cells with endocytosed cytoplasmic ricin or cells with Golgi-associated ricin, kinetic endocytosis curves were generated. Here we present, to the authors' knowledge, the first example of using imaging flow cytometry for evaluating the subcellular transport of protein cargo, using the trafficking of ricin toxin in lung cells as a model. PMID- 29122726 TI - Improvement of ubiquitylation site detection by Orbitrap mass spectrometry. AB - : Ubiquitylation is an important posttranslational protein modification that is involved in many cellular events. Immunopurification of peptides containing a K epsilon-diglycine (diGly) remnant as a mark of ubiquitylation combined with mass spectrometric detection has resulted in an explosion of the number of identified ubiquitylation sites. Here, we present several significant improvements to this workflow, including fast, offline and crude high pH reverse-phase fractionation of tryptic peptides into only three fractions with simultaneous desalting prior to immunopurification and better control of the peptide fragmentation settings in the Orbitrap HCD cell. In addition, more efficient sample cleanup using a filter plug to retain the antibody beads results in a higher specificity for diGly peptides and less non-specific binding. These relatively simple modifications of the protocol result in the routine detection of over 23,000 diGly peptides from HeLa cells upon proteasome inhibition. The efficacy of this strategy is shown for lysates of both non-labeled and SILAC labeled cell lines. Furthermore, we demonstrate that this strategy is useful for the in-depth analysis of the endogenous, unstimulated ubiquitinome of in vivo samples such as mouse brain tissue. This study presents a valuable addition to the toolbox for ubiquitylation site analysis to uncover the deep ubiquitinome. SIGNIFICANCE: A K-epsilon diglycine (diGly) mark on peptides after tryptic digestion of proteins indicates a site of ubiquitylation, a posttranslational modification involved in a wide range of cellular processes. Here, we report several improvements to methods for the isolation and detection of diGly peptides from complex biological mixtures such as cell lysates and brain tissue. This adapted method is robust, reproducible and outperforms previously published methods in terms of number of modified peptide identifications from a single sample. In-depth analysis of the ubiquitinome using mass spectrometry will lead to a better understanding of the roles of protein ubiquitylation in cellular events. PMID- 29122727 TI - Gender-related metabolomics and lipidomics: From experimental animal models to clinical evidence. AB - Lipidomics and metabolomics have emerged as important tools for the characterization of specific physiological and pathological traits. The selection of the analytical approaches and the choice of a targeted rather than an untargeted strategy in metabolomics find their reasons in the driving hypothesis of the study, sample features and instrumental availability. Moreover, in the last years, -omics approaches have found their application in the study of sex related dimorphism. In this review, lipidomic and metabolomic analyses are presented in a biomedical perspective. Here, we provide an updated overview covering recent applications of metabolomics and lipidomics in the area of sex related differences in human and preclinical models. Experimental evidence underlines that sex is one of the most relevant biological variables significantly influencing metabolomic and lipidomic profiles. This knowledge can be exploited for the identification of novel sex-specific biomarkers and innovative targets relevant for gender medicine. PMID- 29122728 TI - Comparative proteomics and codon substitution analysis reveal mechanisms of differential resistance to hypoxia in congeneric snails. AB - : Although high-throughput proteomics has been widely applied to study mechanisms of environmental adaptation, the conclusions from studies that are based on one species can be confounded by phylogeny. We compare the freshwater snail Pomacea canaliculata (a notorious invasive species) and its congener Pomacea diffusa (a non-invasive species) to understand the molecular mechanisms of their differential resistance to hypoxia. A 72-h acute exposure experiment showed that P. canaliculata is more tolerant to hypoxia than P. diffusa. The two species were then exposed to three levels of dissolved oxygen (6.7, 2.0 and 1.0mgL-1) for 8h, and their gill proteins were analyzed using iTRAQ-coupled LC-MS/MS. The two species showed striking differences in protein expression profiles, with the more hypoxia tolerant P. canaliculata having more up-regulated proteins in signal transduction and down-regulated proteins in glycolysis and the tricarboxylic acid cycle. Evolutionary analysis revealed five orthologous genes encoding differentially expressed proteins having clear signal of positive selection, indicating selection has acted on some of the hypoxia responsive genes. Our case study has highlighted the potential of integrated proteomics and comparative evolutionary analysis for understanding the genetic basis of adaptation to global environmental change in non-model species. SIGNIFICANCE: Rapid globalization in recent decades has greatly facilitated species introduction around the world. Successfully established introduced species, so-called invasive species, have threatened the invaded ecosystems. There has been substantial interest in studying how invasive species respond to extreme environmental conditions because the results can help not only predict their range of expansion and manage their impact, but also may reveal the adaptive mechanisms underlying their invasiveness. Our study has adopted a comparative approach to study the differential physiological and proteomic responses of two congeneric snails to various hypoxic conditions, as well as codon substitution analysis at transcriptomic level to detect signals of positive selection in hypoxia responsive genes. The integrated physiological, proteomic and transcriptomic approach can be applied in other non-model species to understand the molecular mechanisms of adaptation to global environmental change. PMID- 29122729 TI - Draft genome sequence of Enterobacter cloacae HBY, a ST128 clinical strain co producing KPC-2 and NDM-1 carbapenemases. AB - OBJECTIVES: Enterobacter cloacae is one of the major pathogens responsible for a variety of human infections. Here we report the draft genome sequence of multidrug-resistant E. cloacae strain HBY isolated from a female patient in China. METHODS: Whole genomic DNA of E. cloacae strain HBY was extracted and was sequenced using an Illumina HiSeqTM 2000 platform. The generated sequence reads were assembled using CLC Genomics Workbench. The draft genome was annotated using Rapid Annotations using Subsystems Technology (RAST), and the presence of antimicrobial resistance genes was identified. RESULTS: The 5799439-bp genome contains various antimicrobial resistance genes conferring resistance to aminoglycosides, beta-lactams, fosfomycin, macrolides, sulphonamides and fluoroquinolones. Notably, the strain was identified to carry two main carbapenemase genes (blaKPC-2 and blaNDM-1). CONCLUSIONS: The genome sequence reported in this study will provide valuable information to understand antibiotic resistance mechanisms in this strain. It is important to monitor the spread strains of Enterobacter sp. encoding both of these carbapenemase genes. PMID- 29122730 TI - Cerebral Venous Sinus Thrombosis Following Second Transsphenoidal Surgery: Report of a Rare Complication and Review of Literature. AB - BACKGROUND: Cushing disease, induced by a pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma, is associated with high risk of stroke. At present, transsphenoidal surgery remains the first line of therapy. Cerebral venous sinus thrombosis (CVST) is an uncommon form of stroke with variable presentations. There are no previous reports of its occurrence in patients with Cushing disease following transsphenoidal surgery. CASE DESCRIPTION: We report a patient with Cushing disease who sustained CVST several days after a second transsphenoidal surgery. With adequate care and treatment, along with timely diagnosis, the patient made a near-complete recovery with only minor sequelae. CONCLUSIONS: In view of the poor outcome of untreated CVST, symptoms such as severe headache, nausea and vomiting, and cerebrospinal fluid leakage after transsphenoidal surgery could be of valuable assistance in early diagnosis, allowing immediate medical intervention with consequent improved prognosis. PMID- 29122731 TI - Postsurgical Cavity Evolution After Brain Metastasis Resection: How Soon Should Postoperative Radiosurgery Follow? AB - BACKGROUND: Postoperative stereotactic radiosurgery (SRS) to the cavity after resection of brain metastases improves local control. We hypothesized that significant cavity constriction would occur from the immediate postoperative period to the time of SRS and aimed to elucidate optimal treatment timing. METHODS: We retrospectively reviewed 79 consecutive patients with 85 resection cavities treated with SRS after gross total resection of a brain metastasis. Preoperative lesion, immediate postoperative cavity, and cavity at the time of SRS were contoured for each patient. Factors influencing cavity size and interval cavity change were analyzed. RESULTS: Median immediate postoperative cavity volume was 7.5 cm3, and median SRS cavity volume was 8.7 cm3. Median time from surgery to SRS was 20 days. Median volumetric cavity change was an increase of 28%. Of cavities, 34 (40%) increased in size >2 cm3, whereas only 8 cavities (9%) decreased in size >2 cm3; 43 cavities (51%) had <=2 cm3 change. The largest postoperative cavities experienced the smallest percentage cavity change in the time interval to SRS (Spearman correlation -0.32, P = 0.003). CONCLUSIONS: Cavity size after brain metastasis resection increased a median of 28% from immediate postoperative scan to time of SRS. Greater than 90% of postoperative cavities either increased >2 cm3 or remained within 2 cm3 of their immediate postoperative cavity volume. Early postoperative SRS within 2-3 weeks may be appropriate to minimize cavity growth. Delaying postoperative SRS beyond 3 weeks in hopes of significant cavity contraction is not warranted. PMID- 29122732 TI - Overcoming End-to-End Vessel Mismatch During Superficial Temporal Artery-Radial Artery-M2 Interposition Grafting for Cerebral Ischemia: Tapering Technique. AB - Cerebral revascularization procedures, such as the external carotid-internal carotid bypass, have been used in the clinical management of cerebral ischemic states. Among the most commonly performed bypasses is the superficial temporal artery-middle cerebral artery (STA-MCA) bypass to restore cerebral blood flow. In cases of a foreshortened STA donor vessel, a radial artery (RA) graft is often used as an interposition graft between the STA and MCA. However, addressing the vessel size mismatch between the radial artery and donor can be problematic and challenging. We present the case of an 80-year-old male presenting with positional-onset expressive aphasia and right-sided hemiparesis. Computed tomography perfusion demonstrated a diffusion-perfusion mismatch in a left MCA distribution. Angiography showed a complete left internal cerebral artery occlusion and poor distal filling of the STA. We performed an external carotid artery-to-internal carotid artery bypass through interposing an RA graft to the STA proximally with an end-to-end anastomosis and to the MCA distally using an end-to-side anastomosis. The mismatch between 2 bypass vessel sizes was corrected by removing a small piece from the RA graft at 1 margin and suturing it to itself to reduce the size of the RA vessel diameter opening on the side used to sew to the STA. The patient did well clinically with improved right-sided strength, a patent graft, and no postoperative complications. Addressing vessel mismatch when using RA interposition grafts for bypass is challenging. Various operative approaches to address mismatch should be individualized on the basis of the particular vascular anatomy and needs of the case. Nevertheless, our method of cutting and suturing 1 side of the RA graft into a semiblind end to match donor vessel diameter may be of use to cerebrovascular surgeons in select cases. PMID- 29122733 TI - Readmissions in Patients with Anticoagulated Intracranial Hemorrhage: A Retrospective Review. AB - OBJECTIVE: To determine the effect of direct oral anticoagulants (DOACs) compared with warfarin on the 30-day readmission rates in patients with traumatic intracranial hemorrhage (ICH). METHODS: We conducted a retrospective review of patients from our hospital's trauma database admitted between June 2011 and October 2015 to our level II trauma center after sustaining a traumatic ICH while receiving anticoagulant therapy. Patients were stratified based on the anticoagulation drug (DOAC or warfarin) prescribed on admission. The readmission rates between the 2 groups were compared using chi2 analysis and multivariate logistic regression. Patients who died during their initial admission were excluded. RESULTS: Over the 4-year period, 160 patients were admitted with traumatic ICH. Seventy-nine were receiving warfarin and 57 were receiving a DOAC at admission. Data collected included age, sex, injury severity score, admission Glasgow Coma Score, Abbreviated Injury Scale (head), mechanism of injury, hospital and intensive care unit lengths of stay, discharge destination (eg, home, rehabilitation facility, nursing facility), comorbidities, operative interventions, readmissions, and reasons for the readmissions. The rate of readmission for rebleeding of ICH was significantly lower in the DOAC group compared with the warfarin group (5.3% vs. 17.7%; P = 0.04). Multivariate logistic regression suggests that warfarin use, but not DOAC use, is associated with increased readmission both for all causes and for ICH rebleeding. CONCLUSIONS: Warfarin use is associated with higher readmission rates in patients with intracranial bleeding for both all-cause readmissions and for intracranial rebleeding. PMID- 29122734 TI - Gene editing of MPS I human fibroblasts by co-delivery of a CRISPR/Cas9 plasmid and a donor oligonucleotide using nanoemulsions as nonviral carriers. AB - Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by the deficiency of alpha-L-iduronidase (IDUA). This study shows the use of nanoemulsions co-complexed with the plasmid of CRISPR/Cas9 system and a donor oligonucleotide aiming at MPS I gene editing in vitro. Nanoemulsions composed of MCT, DOPE, DOTAP, DSPE-PEG, and water were prepared by high-pressure homogenization. The DNA was complexed by adsorption (NA) or encapsulation (NE) of preformed DNA/DOTAP complexes with nanoemulsions at +4/-1 charge ratio. The incubation in pure DMEM or supplemented with serum showed that the complexation with DNA was stable after 1 h of incubation, but the complexes tended to release the adsorbed DNA after 24 h of incubation, while the encapsulated DNA remained complexed in the oil core of the nanoemulsions even 48 h after incubation with DMEM. The treatment of MPS I patient's fibroblasts homozygous for the p.Trp402* mutation led to a significant increase in IDUA activity at 2, 15, and 30 days when compared to MPS I untreated fibroblasts. Flow cytometry and confocal microscopy demonstrated that there was a reduction in the area of lysosomes to values similar to normal, an indicator of correction of the cellular phenotype. These results show that the nanoemulsions co-complexed with the CRISPR/Cas9 system and a donor oligonucleotide could effectively transfect MPS I p.Trp402* patient's fibroblasts, as well as enable the production of IDUA, and represent a potential new treatment option for MPS I. PMID- 29122736 TI - Enhanced antimalalarial activity of a prolonged release in situ gel of arteether lumefantrine in a murine model. AB - The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treatment of falciparum malaria. Arteether (ART), an artemisinin derivative, is effective against Plasmodium falciparum, but it is available only as painful oily intramuscular (i.m.) injections. We formulated lyotropic liquid crystalline preconcentrates of ART and Lumefantrine (LUM) ACT with and without biodegradable polymer for antimalarial therapy. Following i.m. injection, both formed intact gels in situ due to rapid transition into liquid crystalline phase (LCP) which was confirmed by small angle neutron scattering (SANS), X-ray diffraction (XRD), polarization optical microscopy (POM) and rheological changes. Ex vivo release studies revealed prolong release of ART-LUM over 72 h from polymeric lyotropic liquid crystalline phases (P-LLCPr). In vitro hemolysis assay and myotoxicity studies confirmed intramuscular safety. Treatment with ART-LUM P-LLCPr conferred complete protection with no mortality at 1/40th of therapeutic dose in modified Peter's four-day suppressive test as compared to marketed ART formulation resulted in 100% mortality within 20 days. In the clinical simulation model, P-LLCPr treatment resulted in complete cure with no recrudescence or mortality at 1/20th of therapeutic dose, while marketed formulation which resulted in 100% mortality. The high efficacy with significantly reduced dose and a single administration with single shot therapy suggest ART-LUM P-LLCPr as a promising new patient friendly alternative for antimalarial therapy. PMID- 29122735 TI - Intranasal immunization with dry powder vaccines. AB - Vaccination represents a cost-effective weapon for disease prevention and has proven to dramatically reduce the incidences of several diseases that once were responsible for significant mortality and morbidity worldwide. The nasal cavity constitutes the initial stage of the respiratory system and the first contact with inhaled pathogens. The intranasal (IN) route for vaccine administration is an attractive alternative to injection, due to the ease of administration as well as better patient compliance. Many published studies have demonstrated the safety and effectiveness of IN immunization with liquid vaccines. Currently, two liquid IN vaccines are available and both contain live attenuated influenza viruses. FluMist(r) was approved in 2003 in the United States, and Nasovac(r) H1N1 vaccine was approved in India in 2010. Preclinical studies showed that IN immunization with dry powder vaccines (DPVs) is feasible. Although there is not a commercially available DPV yet, DPVs have the inherent advantage of being relatively more stable than liquid vaccines. This review focuses on recent developments of DPVs as next-generation IN vaccines. PMID- 29122737 TI - The Effect of the Move More Pack on the Physical Activity of Cancer Survivors: Protocol for a Randomized Waiting List Control Trial with Process Evaluation. AB - BACKGROUND: Physical activity can improve many common side effects of cancer treatment as well as improve physical function and quality of life (QOL). In addition, physical activity can improve survival rate and reduce cancer recurrence. Despite these benefits, only 23% of cancer survivors in England are active to recommended levels. Cancer survivors are interested in lifestyle behavior change. Home-based interventions offer a promising means for changing physical activity behavior. Prediagnosis levels of physical activity and self efficacy have been reported to be predictors of physical activity behavior change. The Move More Pack, which has undergone revision, is a printed resource with supporting Internet-based tools that aims to increase the physical activity of cancer survivors in the United Kingdom. The revised Move More Pack is underpinned by the theory of planned behavior and the social cognitive theory. OBJECTIVE: The aim of this proposed study was to investigate the effect of the revised Move More Pack, supported by Internet-based tools, on physical activity, self-efficacy, and health-related QOL (HRQOL) of cancer survivors in the United Kingdom. METHODS: This study is a two-arm waiting list randomized control trial with embedded process evaluation. A sample of 99 participants per arm will be recruited by invitation through an email database of cancer survivors held by UK charity Macmillan Cancer Support and an advert placed on the Macmillan Cancer Support Facebook page. Each participant is randomized to receive brief physical activity information and the UK guidelines for physical activity, or brief physical activity information and the revised Move More Pack with supporting Internet-based tools. The intervention and control arm will be followed up at 12 weeks to identify changes in self-reported physical activity, self-efficacy, and HRQOL based on Web-based questionnaires. The control arm will receive the revised Move More Pack at 12 weeks with follow-up at 24 weeks. The intervention arm is followed up at 24 weeks to determine maintenance of reported changes. Subgroup analyses will be completed based on participants' prediagnosis level of physical activity and baseline self-efficacy as possible predictors of positive changes. Use of each component of the revised Move More Pack will be assessed using a 4 point Likert scale. Semistructured phone interviews will evaluate the use and perceived usefulness of the revised Move More Pack. RESULTS: Participant recruitment started in March 2017. Projected completion of this study is October 2018. CONCLUSIONS: This study's findings will identify if the proposed low-cost broad reach intervention improves physical activity, self-efficacy, and the HRQOL of cancer survivors. The process evaluation is designed to contextualize the use and perceived usefulness of the revised Move More Pack, help augment its efficient distribution, and identify potential improvements to its design. PMID- 29122738 TI - Performance of a Mobile Phone App-Based Participatory Syndromic Surveillance System for Acute Febrile Illness and Acute Gastroenteritis in Rural Guatemala. AB - BACKGROUND: With their increasing availability in resource-limited settings, mobile phones may provide an important tool for participatory syndromic surveillance, in which users provide symptom data directly into a centralized database. OBJECTIVE: We studied the performance of a mobile phone app-based participatory syndromic surveillance system for collecting syndromic data (acute febrile illness and acute gastroenteritis) to detect dengue virus and norovirus on a cohort of children living in a low-resource and rural area of Guatemala. METHODS: Randomized households were provided with a mobile phone and asked to submit weekly reports using a symptom diary app (Vigilant-e). Participants reporting acute febrile illness or acute gastroenteritis answered additional questions using a decision-tree algorithm and were subsequently visited at home by a study nurse who performed a second interview and collected samples for dengue virus if confirmed acute febrile illness and norovirus if acute gastroenteritis. We analyzed risk factors associated with decreased self reporting of syndromic data using the Vigilant-e app and evaluated strategies to improve self-reporting. We also assessed agreement between self-report and nurse collected data obtained during home visits. RESULTS: From April 2015 to June 2016, 469 children in 207 households provided 471 person-years of observation. Mean weekly symptom reporting rate was 78% (range 58%-89%). Households with a poor (<70%) weekly reporting rate using the Vigilant-e app during the first 25 weeks of observation (n=57) had a greater number of children (mean 2.8, SD 1.5 vs mean 2.5, SD 1.3; risk ratio [RR] 1.2, 95% CI 1.1-1.4), were less likely to have used mobile phones for text messaging at study enrollment (61%, 35/57 vs 76.7%, 115/150; RR 0.6, 95% CI 0.4-0.9), and were less likely to access care at the local public clinic (35%, 20/57 vs 67.3%, 101/150; RR 0.4, 95% CI 0.2-0.6). Parents of female enrolled participants were more likely to have low response rate (57.1%, 84/147 vs 43.8%, 141/322; RR 1.4, 95% CI 1.1-1.9). Several external factors (cellular tower collapse, contentious elections) were associated with periods of decreased reporting. Poor response rate (<70%) was associated with lower case reporting of acute gastroenteritis, norovirus-associated acute gastroenteritis, acute febrile illness, and dengue virus-associated acute febrile illness (P<.001). Parent-reported syndromic data on the Vigilant-e app demonstrated agreement with nurse-collected data for fever (kappa=.57, P<.001), vomiting (kappa=.63, P<.001), and diarrhea (kappa=.61, P<.001), with decreased agreement as the time interval between parental report and nurse home visit increased (<1 day: kappa=.65-.70; >=2 days: kappa=.08-.29). CONCLUSIONS: In a resource-limited area of rural Guatemala, a mobile phone app-based participatory syndromic surveillance system demonstrated a high reporting rate and good agreement between parental reported data and nurse-reported data during home visits. Several household-level and external factors were associated with decreased syndromic reporting. Poor reporting rate was associated with decreased syndromic and pathogen-specific case ascertainment. PMID- 29122739 TI - Public Awareness and Use of German Physician Ratings Websites: Cross-Sectional Survey of Four North German Cities. AB - BACKGROUND: Physician rating websites (PRWs) allow patients to rate, comment, and discuss physicians' quality. The ability of PRWs to influence patient decision making and health care quality is dependent, in part, on sufficient awareness and usage of PRWs. However, previous studies have found relatively low levels of awareness and usage of PRWs, which has raised concerns about the representativeness and validity of information on PRWs. OBJECTIVE: The objectives of this study were to examine (1) participants' awareness, use, and contribution of ratings on PRWs and how this compares with other rating websites; (2) factors that predict awareness, use, and contribution of ratings on PRWs; and (3) participants' attitudes toward PRWs in relation to selecting a physician. METHODS: A mailed cross-sectional survey was sent to a random sample (N=1542) from four North German cities (Nordhorn, Hildesheim, Bremen, and Hamburg) between April and July 2016. Survey questions explored respondents' awareness, use, and contribution of ratings on rating websites for service (physicians, hospitals, and hotels and restaurants) and products (media and technical) in general and the role of PRWs when searching for a new physician. RESULTS: A total of 280 completed surveys were returned (280/1542, 18.16% response rate), with the following findings: (1) Overall, 72.5% (200/276) of respondents were aware of PRWs. Of the respondents who were aware of PRWs, 43.6% (86/197) had used PRWs. Of the respondents who had used PRWs, 23% (19/83) had rated physicians at least once. Awareness, use, and contribution of ratings on PRWs were significantly lower in comparison with all other rating websites, except for hospital rating websites. (2) Except for the impact of responders' gender and marital status on the awareness of PRWs and responders' age on the use of PRWs, no other predictors had a relevant impact. (3) Whereas 31.8% (85/267) of the respondents reported that PRWs were a very important or somewhat important information source when searching for a new physician, respondents significantly more often reported that family, friends and colleagues (259/277, 93.5%), other physicians (219/274, 79.9%), and practice websites (108/266, 40.6%) were important information sources. CONCLUSIONS: Whereas awareness of German PRWs appears to have substantially increased, the use of PRWs and contribution of ratings remains relatively low. Further research is needed to examine the reasons why only a few patients are rating physicians. However, given the information inequality between provider and consumer will always be higher for consumers using the services of physicians, it is possible that people will always rely more on interpersonal recommendations than impersonal public information before selecting a physician. PMID- 29122740 TI - The Perceptions of Medical School Students and Faculty Toward Obesity Medicine Education: Survey and Needs Analysis. AB - BACKGROUND: Recent trends in obesity show that over two-thirds of US adults are considered at least overweight (body mass index, BMI>=25 kg/m2) and of those, about one-third are categorized as obese (BMI>=30 kg/m2). Physicians can address the health impacts of obesity; yet research has suggested that physicians-in training frequently fail to recognize obesity, are not properly educated regarding treatment options, and spend relatively little clinic time treating obesity. Medical school is a unique opportunity to address this area of need so that the doctors of tomorrow are prepared to treat obesity appropriately. OBJECTIVES: The objective of this study was to determine perceptions of where clinical training for medical students on the topic of obesity and its treatment should improve and expand so that we could address the needs identified in a computerized clinical simulation. METHODS: We conducted a literature review, as well as a needs analysis with medical school students (N=17) and faculty (N=12). Literature review provided an overview of the current state of the field. Students provided input on their current needs, learning preferences, and opinions. Faculty provided feedback on current training and their perceptions of future needs. RESULTS: Most students were familiar with obesity medicine from various courses where obesity medicine was a subtopic, most frequently in Biochemistry or Nutrition, Endocrinology, and Wellness courses. Student knowledge about basic skills, such as measuring waist circumference, varied widely. About half of the students did not feel knowledgeable about recommending weight loss treatments. Most students did not feel prepared to provide interventions for patients in various categories of overweight/obesity, patients with psychosocial issues, obesity-related comorbidities, or failed weight loss attempts. However, most students did feel that it was their role as health professionals to provide these interventions. Faculty rated the following topics as most important to supplement the curriculum: patient-centered treatment of weight, bringing up the topic of weight, discussing weight and well-being, discussing the relationship between weight and comorbidities, and physician role with overweight or obese patients. CONCLUSIONS: A review of the literature as well as surveyed medical students and faculty identified a need for supplementation of the current obesity medicine curriculum in medical schools. Specific needed topics and skills were identified. PMID- 29122741 TI - Family Integrated Care: changing the culture in the neonatal unit. PMID- 29122743 TI - Deviation from national guidance can have better results. PMID- 29122742 TI - Myotube migration to cover and shape the testis of Drosophila depends on Heartless, Cadherin/Catenin, and myosin II. AB - During Drosophila metamorphosis, nascent testis myotubes migrate from the prospective seminal vesicle of the genital disc onto pupal testes and then further to cover the testes with multinucleated smooth-like muscles. Here we show that DWnt2 is likely required for determination of testis-relevant myoblasts on the genital disc. Knock down of fibroblast growth factor receptor (FGFR) heartless by RNAi and a dominant-negative version revealed multiple functions of Heartless, namely regulation of the amount of myoblasts on the genital disc, connection of seminal vesicles and testes, and migration of muscles along the testes. Live imaging indicated that the downstream effector Stumps is required for migration of testis myotubes on the testis towards the apical tip. After myoblast fusion, myosin II is needed for migration of nascent testis myotubes, in which Thisbe-dependent fibroblast growth factor (FGF) signaling is activated. Cadherin-N is essential for connecting these single myofibers and for creating a firm testis muscle sheath that shapes and stabilizes the testis tubule. Based on these results, we propose a model for the migration of testis myotubes in which nascent testis myotubes migrate as a collective onto and along the testis, dependent on FGF-regulated expression of myosin II. PMID- 29122744 TI - Patients' views were sidelined as STPs were launched, says Healthwatch England. PMID- 29122745 TI - Government faces legal challenge over data agreement that may put "migrants at risk". PMID- 29122746 TI - GMC to push for erasure of paediatrician convicted of manslaughter. PMID- 29122747 TI - Government launches scheme to deliver five "breakthrough technologies" a year. PMID- 29122748 TI - Infographic: ACL injury reconstruction and recovery. PMID- 29122750 TI - Uganda's hospitals doctors strike over low pay. PMID- 29122751 TI - Tropical cyclones and public health: how climate change is driving increasingly extreme weather-an essay by Fintan Hughes, Jack Hodkinson, and Hugh Montgomery. PMID- 29122752 TI - Number of UK patients with metastatic breast cancer isn't known. PMID- 29122749 TI - Frontline defenders: goblet cell mediators dictate host-microbe interactions in the intestinal tract during health and disease. AB - Goblet cells (GCs) are the predominant secretory epithelial cells lining the luminal surface of the mammalian gastrointestinal (GI) tract. Best known for their apical release of mucin 2 (Muc2), which is critical for the formation of the intestinal mucus barrier, GCs have often been overlooked for their active contributions to intestinal protection and host defense. In part, this oversight reflects the limited tools available to study their function but also because GCs have long been viewed as relatively passive players in promoting intestinal homeostasis and host defense. In light of recent studies, this perspective has shifted, as current evidence suggests that Muc2 as well as other GC mediators are actively released into the lumen to defend the host when the GI tract is challenged by noxious stimuli. The ability of GCs to sense and respond to danger signals, such as bacterial pathogens, has recently been linked to inflammasome signaling, potentially intrinsic to the GCs themselves. Moreover, further work suggests that GCs release Muc2, as well as other mediators, to modulate the composition of the gut microbiome, leading to both the expansion as well as the depletion of specific gut microbes. This review will focus on the mechanisms by which GCs actively defend the host from noxious stimuli, as well as describe advanced technologies and new approaches by which their responses can be addressed. Taken together, we will highlight current insights into this understudied, yet critical, aspect of intestinal mucosal protection and its role in promoting gut defense and homeostasis. PMID- 29122753 TI - Flu vaccination by pharmacists leads to suboptimal medical records. PMID- 29122754 TI - Limited role of kininogen in the host response during gram-negative pneumonia derived sepsis. AB - High-molecular-weight kininogen (HK), together with factor XI, factor XII and prekallikrein, is part of the contact system that has proinflammatory, prothrombotic, and vasoactive properties. We hypothesized that HK plays a role in the host response during pneumonia-derived sepsis. To this end mice were depleted of kininogen (KNG) to plasma HK levels of 28% of normal by repeated treatment with a specific antisense oligonucleotide (KNG ASO) for 3 wk before infection with the common human sepsis pathogen Klebsiella pneumoniae via the airways. Whereas plasma HK levels increased during infection in mice treated with a scrambled control ASO (Ctrl ASO), HK level in the KNG ASO-treated group remained reduced to 25-30% of that in the corresponding Ctrl ASO group both before and after infection. KNG depletion did not influence bacterial growth in lungs or dissemination to distant body sites. KNG depletion was associated with lower lung CXC chemokine and myeloperoxidase levels but did not impact neutrophil influx, lung pathology, activation of the vascular endothelium, activation of the coagulation system, or the extent of distant organ injury. These results were corroborated by studies in mice with a genetic deficiency of KNG, which were indistinguishable from wild-type mice during Klebsiella-induced sepsis. Both KNG depletion and KNG deficiency were associated with strongly reduced plasma prekallikrein levels, indicating the carrier function of HK for this zymogen. This study suggests that KNG does not significantly contribute to the host defense during gram-negative pneumonia-derived sepsis. PMID- 29122755 TI - Renin-angiotensin system regulates pulmonary arterial smooth muscle cell migration in chronic thromboembolic pulmonary hypertension. AB - Pulmonary arterial smooth muscle cell (PASMC) migration plays a key role in vascular remodeling, which occurs during development of chronic thromboembolic pulmonary hypertension (CTEPH). Activation of the renin-angiotensin system (RAS) contributes to vascular remodeling observed in many diseases, including idiopathic pulmonary arterial hypertension. However, the role of RAS imbalance in CTEPH has not been characterized. Here, we hypothesize that RAS imbalance regulates vascular remodeling by promoting PASMC migration in CTEPH. Serum renin and angiotensin II levels in patients with CTEPH were quantified by ELISA. The pulmonary endarterectomy tissues were stained and analyzed by immunohistochemistry. PASMCs were isolated and verified by immunofluorescence staining. PASMC migration was determined by Transwell assay. Phosphorylation and protein level were detected by Western blotting. Serum levels of renin and angiotensin II were increased in patients with CTEPH {renin [median (25th percentile, 75th percentile) in pg/ml], 1,199.94 [690.85, 1,656.90] vs. 595.43 [351.48, 936.43], P < 0.001; angiotensin II [in pg/ml], 63.97 [45.97, 345.24] vs. 56.85 [11.20, 90.37], P < 0.05}. The migration of PASMCs isolated from patients with CTEPH was enhanced compared with control. Angiotensin II promoted the migration of PASMCs via activation of angiotensin II receptor 1 and phosphorylation of ERK1/2, whereas angiotensin-(1-7) counteracted this effect through activation of the Mas receptor and ERK1/2. These results demonstrate that the renin-angiotensin system regulates migration of PASMCs from patients with CTEPH via the ERK1/2 pathway. Our findings suggest that angiotensin-(1-7) or reagents targeting the renin-angiotensin system will be beneficial in the development of novel therapies for CTEPH. PMID- 29122758 TI - Should doctors support restrictions on anti-abortion protests? PMID- 29122756 TI - FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy. AB - Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease, yet prognostication relies predominantly on clinical tools. We recently demonstrated that integration of mutation status of 7 genes, including EZH2 and MEF2B, improves risk stratification. We mined gene expression data to uncover genes that are differentially expressed in EZH2- and MEF2B-mutated cases. We focused on FOXP1 and assessed its protein expression by immunohistochemistry (IHC) in 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 patients with FL treated with rituximab, cyclophosphamide, vincristine, and prednisone, and a clinical trial validation cohort comprising 395 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) +/- rituximab were used. We found FOXP1 to be significantly downregulated in both EZH2- and MEF2B-mutated cases. By IHC, 76 specimens in the training cohort (54%) had high FOXP1 expression (>10%), which was associated with reduced 5-year failure-free survival (FFS) rates (55% vs 70%). In the validation cohort, high FOXP1 expression status was observed in 248 patients (63%) and correlated with significantly shorter FFS in patients treated with R-CHOP (hazard ratio [HR], 1.95; P = .017) but not in patients treated with CHOP (HR, 1.15; P = .44). The impact of high FOXP1 expression on FFS in immunochemotherapy-treated patients was additional to the Follicular Lymphoma International Prognostic Index. High FOXP1 expression was associated with distinct molecular features such as TP53 mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal center or activated B cells. In summary, FOXP1 is a downstream phenotypic commonality of gene mutations and predicts outcome following rituximab-containing regimens. PMID- 29122759 TI - Diffusion-Weighted Imaging of the Head and Neck: Influence of Fat-Suppression Technique and Multishot 2D Navigated Interleaved Acquisitions. AB - BACKGROUND AND PURPOSE: DWI of the head and neck can reveal valuable information, but the effects of fat suppression and multishot acquisition on image quality have not been thoroughly investigated. We aimed to comprehensively compare the quality of head and neck DWI at 3T using 2 fat-suppression techniques, STIR, and spectral presaturation with inversion recovery, which were used with both single- and multishot EPI. MATERIALS AND METHODS: Sixty-five study participants underwent 3 DWI sequences of single-shot EPI-STIR, single-shot EPI-spectral presaturation with inversion recovery, and multishot EPI-spectral presaturation with inversion recovery of the head and neck. In multiple anatomic regions, 2 independent readers assessed 5-point visual scores for fat-suppression uniformity and image distortion, and 1 reader measured the contrast-to-noise ratio and ADC. RESULTS: The mean visual score for fat-suppression uniformity was higher in single-shot EPI-STIR than in other sequences (all regions except for the orbital region, P < .05). The mean visual score for image distortion was higher in multishot EPI spectral presaturation with inversion recovery than in single-shot EPI sequences (all regions, P < .001). Contrast-to-noise ratio was mostly lower in single-shot EPI-STIR than in other sequences (P < .001), and ADC was significantly higher in multishot EPI-spectral presaturation with inversion recovery than in single-shot EPI sequences (P <= .001). CONCLUSIONS: Overall, multishot EPI-spectral presaturation with inversion recovery provided the best image quality, with relatively homogeneous fat suppression, less image distortion than single-shot EPI sequences, and higher contrast-to-noise ratio than single-shot EPI-STIR. The measured ADC values can be higher in multishot EPI-spectral presaturation with inversion recovery, which necessitates cautious application of the previously reported ADC values to clinical settings. PMID- 29122757 TI - CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. AB - Adoptive transfer of T cells genetically modified to express a cancer-specific T cell receptor (TCR) has shown significant therapeutic potential for both hematological and solid tumors. However, a major issue of transducing T cells with a transgenic TCR is the preexisting expression of TCRs in the recipient cells. These endogenous TCRs compete with the transgenic TCR for surface expression and allow mixed dimer formation. Mixed dimers, formed by mispairing between the endogenous and transgenic TCRs, may harbor autoreactive specificities. To circumvent these problems, we designed a system where the endogenous TCR-beta is knocked out from the recipient cells using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) technology, simultaneously with transduction with a cancer reactive receptor of choice. This TCR replacement strategy resulted in markedly increased surface expression of transgenic alphabeta and gammadelta TCRs, which in turn translated to a stronger, and more polyfunctional, response of engineered T cells to their target cancer cell lines. Additionally, the TCR-plus-CRISPR modified T cells were up to a thousandfold more sensitive to antigen than standard TCR-transduced T cells or conventional model proxy systems used for studying TCR activity. Finally, transduction with a pan-cancer-reactive gammadelta TCR used in conjunction with CRISPR/Cas9 knockout of the endogenous alphabeta TCR resulted in more efficient redirection of CD4+ and CD8+ T cells against a panel of established blood cancers and primary, patient-derived B-cell acute lymphoblastic leukemia blasts compared with standard TCR transfer. Our results suggest that TCR transfer combined with genome editing could lead to new, improved generations of cancer immunotherapies. PMID- 29122760 TI - Spinal Cord Gray Matter Atrophy in Amyotrophic Lateral Sclerosis. AB - BACKGROUND AND PURPOSE: There is an emerging need for biomarkers to better categorize clinical phenotypes and predict progression in amyotrophic lateral sclerosis. This study aimed to quantify cervical spinal gray matter atrophy in amyotrophic lateral sclerosis and investigate its association with clinical disability at baseline and after 1 year. MATERIALS AND METHODS: Twenty-nine patients with amyotrophic lateral sclerosis and 22 healthy controls were scanned with 3T MR imaging. Standard functional scale was recorded at the time of MR imaging and after 1 year. MR imaging data were processed automatically to measure the spinal cord, gray matter, and white matter cross-sectional areas. A statistical analysis assessed the difference in cross-sectional areas between patients with amyotrophic lateral sclerosis and controls, correlations between spinal cord and gray matter atrophy to clinical disability at baseline and at 1 year, and prediction of clinical disability at 1 year. RESULTS: Gray matter atrophy was more sensitive to discriminate patients with amyotrophic lateral sclerosis from controls (P = .004) compared with spinal cord atrophy (P = .02). Gray matter and spinal cord cross-sectional areas showed good correlations with clinical scores at baseline (R = 0.56 for gray matter and R = 0.55 for spinal cord; P < .01). Prediction at 1 year with clinical scores (R2 = 0.54) was improved when including a combination of gray matter and white matter cross sectional areas (R2 = 0.74). CONCLUSIONS: Although improvements over spinal cord cross-sectional areas were modest, this study suggests the potential use of gray matter cross-sectional areas as an MR imaging structural biomarker to monitor the evolution of amyotrophic lateral sclerosis. PMID- 29122761 TI - Effect of an Arm Traction Device on Image Quality and Radiation Exposure during Neck CT: A Prospective Study. AB - BACKGROUND AND PURPOSE: The image quality of neck CT is frequently disturbed by streak artifact from the shoulder girdles. Our aim was to determine the effects of an arm traction device on image quality and radiation exposure in neck CT. MATERIALS AND METHODS: Patients with lymphoma with complete remission who were scheduled to undergo 2 consecutive follow-up neck CT scans for surveillance within a 1-year interval were enrolled in this prospective study. They underwent 2 consecutive neck CT scans (intervention protocol: patients with an arm traction device; standard protocol: no positioning optimization) on the same CT system. The primary outcome measures were image noise in the lower neck and dose-length product. Secondary outcomes were streak artifacts in the supraclavicular fossa, volume CT dose index, and the extent of the biacromial line shift. RESULTS: Seventy-three patients were enrolled and underwent 2 consecutive CT scans with a mean interval of 155 days. In the intervention protocol, a mean noise reduction in the lower neck of 25.2%-28.5% (P < .001) was achieved, and a significant decrease in dose-length product (413 versus 397, P < .001) was observed. The intervention protocol significantly decreased streak artifacts (P < .001) and volume CT dose index (13.9 versus 13.4, P < .001) and could lower the biacromial line an average of 2.1 cm. CONCLUSIONS: An arm traction device can improve image quality and reduce radiation exposure during neck CT. The device can be simply applied in cooperative patients with suspected lower neck lesions, and the approach offers distinct advantages over the conventional imaging protocol. PMID- 29122762 TI - Long-Term Effectiveness of Direct CT-Guided Aspiration and Fenestration of Symptomatic Lumbar Facet Synovial Cysts. AB - BACKGROUND AND PURPOSE: Lumbar facet synovial cysts are commonly seen in facet degenerative arthropathy and may be symptomatic when narrowing the spinal canal or compressing nerve roots. The purpose of this study was to analyze the safety, effectiveness, and long-term outcomes of direct CT-guided lumbar facet synovial cyst aspiration and fenestration for symptom relief and for obviating an operation. MATERIALS AND METHODS: We retrospectively reviewed the medical records and imaging studies of 64 consecutive patients between 2006 and 2016 who underwent 85 CT-guided lumbar facet synovial cyst fenestration procedures in our department. We recorded patient demographics, lumbar facet synovial cyst imaging characteristics, presenting symptoms, change in symptoms after the procedure, and whether they underwent a subsequent operation. We also assessed long-term outcomes from the medical records and via follow-up telephone surveys with patients. RESULTS: Direct CT-guided lumbar facet synovial cyst puncture was technically successful in 98% of procedures. At first postprocedural follow-up, 86% of patients had a complete or partial symptomatic response. During a mean follow-up of 49 months, 56% of patients had partial or complete long-term relief without the need for an operation; 44% of patients underwent an operation. Patients with calcified, thick-rimmed, or low T2 signal intensity cysts were less likely to respond to the procedure and more likely to need an operation. CONCLUSIONS: CT-guided direct lumbar facet synovial cyst aspiration and fenestration procedures are safe, effective, and minimally invasive for symptomatic treatment of lumbar synovial facet cysts. This procedure obviates an operation in a substantial number of patients, even at long-term follow-up, and should be considered before surgical intervention. PMID- 29122763 TI - Prediction of IDH1-Mutation and 1p/19q-Codeletion Status Using Preoperative MR Imaging Phenotypes in Lower Grade Gliomas. AB - BACKGROUND AND PURPOSE: WHO grade II gliomas are divided into three classes: isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant and no 1p/19q codeletion, and IDH-mutant and 1p/19q-codeleted. Different molecular subtypes have been reported to have prognostic differences and different chemosensitivity. Our aim was to evaluate the predictive value of imaging phenotypes assessed with the Visually AcceSAble Rembrandt Images lexicon for molecular classification of lower grade gliomas. MATERIALS AND METHODS: MR imaging scans of 175 patients with lower grade gliomas with known IDH1 mutation and 1p/19q-codeletion status were included (78 grade II and 97 grade III) in the discovery set. MR imaging features were reviewed by using Visually AcceSAble Rembrandt Images (VASARI); their associations with molecular markers were assessed. The predictive power of imaging features for IDH1-wild type tumors was evaluated using the Least Absolute Shrinkage and Selection Operator. We tested the model in a validation set (40 subjects). RESULTS: Various imaging features were significantly different according to IDH1 mutation. Nonlobar location, larger proportion of enhancing tumors, multifocal/multicentric distribution, and poor definition of nonenhancing margins were independent predictors of an IDH1 wild type according to the Least Absolute Shrinkage and Selection Operator. The areas under the curve for the prediction model were 0.859 and 0.778 in the discovery and validation sets, respectively. The IDH1-mutant, 1p/19q-codeleted group frequently had mixed/restricted diffusion characteristics and showed more pial invasion compared with the IDH1-mutant, no codeletion group. CONCLUSIONS: Preoperative MR imaging phenotypes are different according to the molecular markers of lower grade gliomas, and they may be helpful in predicting the IDH1-mutation status. PMID- 29122764 TI - MR Imaging of the Superior Cervical Ganglion and Inferior Ganglion of the Vagus Nerve: Structures That Can Mimic Pathologic Retropharyngeal Lymph Nodes. AB - BACKGROUND AND PURPOSE: The superior cervical ganglion and inferior ganglion of the vagus nerve can mimic pathologic retropharyngeal lymph nodes. We studied the cross-sectional anatomy of the superior cervical ganglion and inferior ganglion of the vagus nerve to evaluate how they can be differentiated from the retropharyngeal lymph nodes. MATERIALS AND METHODS: This retrospective study consists of 2 parts. Cohort 1 concerned the signal intensity of routine neck MR imaging with 2D sequences, apparent diffusion coefficient, and contrast enhancement of the superior cervical ganglion compared with lymph nodes with or without metastasis in 30 patients. Cohort 2 used 3D neurography to assess the morphology and spatial relationships of the superior cervical ganglion, inferior ganglion of the vagus nerve, and the retropharyngeal lymph nodes in 50 other patients. RESULTS: All superior cervical ganglions had homogeneously greater enhancement and lower signal on diffusion-weighted imaging than lymph nodes. Apparent diffusion coefficient values of the superior cervical ganglion (1.80 +/- 0.28 * 10-3mm2/s) were significantly higher than normal and metastatic lymph nodes (0.86 +/- 0.10 * 10-3mm2/s, P < .001, and 0.73 +/- 0.10 * 10-3mm2/s, P < .001). Ten and 13 of 60 superior cervical ganglions were hypointense on T2 weighted images and had hyperintense spots on both T1- and T2-weighted images, respectively. The latter was considered fat tissue. The largest was the superior cervical ganglion, followed in order by the retropharyngeal lymph node and the inferior ganglion of the vagus nerve (P < .001 to P = .004). The highest at vertebral level was the retropharyngeal lymph nodes, followed, in order, by the inferior ganglion of the vagus nerve and the superior cervical ganglion (P < .001 to P = .001). The retropharyngeal lymph node, superior cervical ganglion, and inferior ganglion of the vagus nerve formed a line from anteromedial to posterolateral. CONCLUSIONS: The superior cervical ganglion and the inferior ganglion of the vagus nerve can be almost always differentiated from retropharyngeal lymph nodes on MR imaging by evaluating the signal, size, and position. PMID- 29122765 TI - Semiautomated Evaluation of the Primary Motor Cortex in Patients with Amyotrophic Lateral Sclerosis at 3T. AB - BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis is a neurodegenerative disease involving the upper and lower motor neurons. In amyotrophic lateral sclerosis, pathologic changes in the primary motor cortex include Betz cell depletion and the presence of reactive iron-loaded microglia, detectable on 7T MR images as atrophy and T2*-hypointensity. Our purposes were the following: 1) to investigate the signal hypointensity-to-thickness ratio of the primary motor cortex as a radiologic marker of upper motor neuron involvement in amyotrophic lateral sclerosis with a semiautomated method at 3T, 2) to compare 3T and 7T results, and 3) to evaluate whether semiautomated measurement outperforms visual image assessment. MATERIALS AND METHODS: We investigated 27 patients and 13 healthy subjects at 3T, and 19 patients and 18 healthy subjects at 7T, performing a high-resolution 3D multiecho T2*-weighted sequence targeting the primary motor cortex. The signal hypointensity-to-thickness ratio of the primary motor cortex was calculated with a semiautomated method depicting signal intensity profiles of the cortex. Images were also visually classified as "pathologic" or "nonpathologic" based on the primary motor cortex signal intensity and thickness. RESULTS: The signal hypointensity-to-thickness ratio of the primary motor cortex was greater in patients than in controls (P < .001), and it correlated with upper motor neuron impairment in patients (rho = 0.57, P < .001). The diagnostic accuracy of the signal hypointensity-to-thickness ratio was high at 3T (area under the curve = 0.89) and even higher at 7T (area under the curve = 0.94). The sensitivity of the semiautomated method (0.81) outperformed the sensitivity of the visual assessment (0.56-0.63) at 3T. CONCLUSIONS: The signal hypointensity-to thickness ratio of the primary motor cortex calculated with a semiautomated method is suggested as a radiologic marker of upper motor neuron burden in patients with amyotrophic lateral sclerosis. This semiautomated method may be useful for improving the subjective radiologic evaluation of upper motor neuron pathology in patients suspected of having amyotrophic lateral sclerosis. PMID- 29122768 TI - Recombinant ADAMTS-13: goodbye, allergic reactions! PMID- 29122769 TI - Prognostic relevance of CCAs/Ph- in CML settled. PMID- 29122770 TI - 'Tis one thing to adhere, another to migrate. PMID- 29122771 TI - Releasing the FKBP12 brake on hepcidin. PMID- 29122767 TI - Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia. AB - Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B-/- mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia.Significance: This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Cancer Res; 78(1); 75-87. (c)2017 AACR. PMID- 29122772 TI - FcgammaR and SCD alloimmunization: a nonclass(ical) act. PMID- 29122773 TI - Notching up B-cell pathology in chronic GVHD. PMID- 29122774 TI - Aleukemic mast cell leukemia associated with chronic myelomonocytic leukemia and chronic lymphocytic leukemia. PMID- 29122775 TI - Classical Hodgkin lymphoma arising in a patient with chronic lymphocytic leukemia (Richter syndrome). PMID- 29122776 TI - Margaret McCartney: General practice can't just exclude sick people. PMID- 29122778 TI - NIH Initiative Aims to Improve Immunotherapy. AB - The NIH has launched a new collaboration with 11 biopharmaceutical companies and four academic cancer centers to identify the most effective biomarkers for immunotherapy. The public-private partnership will analyze patient samples from clinical trials and aims to develop a standard panel of biomarkers to determine which patients are likely to benefit from immunotherapy and to track their responses. PMID- 29122779 TI - A young man with palpitations and pre-syncope. PMID- 29122777 TI - Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer. AB - The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. (c)2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Pectasides et al., p. 37This article is highlighted in the In This Issue feature, p. 1. PMID- 29122780 TI - Countdown tracks progress on health effects of climate change. PMID- 29122781 TI - Simulation-based inter-professional education to improve attitudes towards collaborative practice: a prospective comparative pilot study in a Chinese medical centre. AB - OBJECTIVES: Inter-professional education (IPE) builds inter-professional collaboration (IPC) attitude/skills of health professionals. This interventional IPE programme evaluates whether benchmarking sharing can successfully cultivate seed instructors responsible for improving their team members' IPC attitudes. DESIGN: Prospective, pre-post comparative cross-sectional pilot study. SETTING/PARTICIPANTS: Thirty four physicians, 30 nurses and 24 pharmacists, who volunteered to be trained as seed instructors participated in 3.5-hour preparation and 3.5-hour simulation courses. Then, participants (n=88) drew lots to decide 44 presenters, half of each profession, who needed to prepare IPC benchmarking and formed Group 1. The remaining participants formed Group 2 (regular). Facilitators rated the Group 1 participants' degree of appropriate transfer and sustainable practice of the learnt IPC skills in the workplace according to successful IPC examples in their benchmarking sharing. RESULTS: For the three professions, improvement in IPC attitude was identified by sequential increase in the post-course (second month, T2) and end-of-study (third month, T3) Interdisciplinary Education Perception Scale (IEPS) and Attitudes Towards Healthcare Teams Scale (ATHCTS) scores, compared with pre-course (first month, T1) scores. By IEPS and ATHCTS-based assessment, the degree of sequential improvements in IPC attitude was found to be higher among nurses and pharmacists than in physicians. In benchmarking sharing, the facilitators' agreement about the degree of participants'appropriate transfer and sustainable practice learnt 'communication and teamwork' skills in the workplace were significantly higher among pharmacists and nurses than among physicians. The post-intervention random sampling survey (sixth month, Tpost) found that the IPC attitude of the three professions improved after on-site IPC skill promotion by new programme-trained seed instructors within teams. CONCLUSIONS: Addition of benchmark sharing to a diamond-based IPE simulation programme enhances participants' IPC attitudes, self reflection, workplace transfer and practice of the learnt skills. Furthermore, IPC promotion within teams by newly trained seed instructors improved the IPC attitudes across all three professions. PMID- 29122782 TI - Study protocol for the Cities Changing Diabetes programme: a global mixed-methods approach. AB - INTRODUCTION: Urban living has been shown to affect health in various ways. As the world is becoming more urbanised and almost two-thirds of people with diabetes now live in cities, research into the relationship between urban living, health and diabetes is key to improving the lives of many. The majority of people with diabetes have type 2 diabetes, a subset linked to overweight and obesity, decreased physical activity and unhealthy diets. Diabetes has significant consequences for those living with the condition as well as their families, relationships and wider society. Although care and management are improving, complications remain common, and diabetes is among the leading causes of vision loss, amputation, neuropathy and renal and cardiovascular disease worldwide. We present a research protocol for exploring the drivers of type 2 diabetes and its complications in urban settings through the Cities Changing Diabetes (CCD) partnership programme. METHODS AND ANALYSIS: A global study protocol is implemented in eight collaborating CCD partner cities. In each city, academic institutions, municipal representatives and local stakeholders collaborate to set research priorities and plan implementation of findings. Local academic teams execute the study following the global study protocol presented here. A quantitative Rule of Halves analysis obtains measures of the magnitude of the diabetes burden, the diagnosis rates in each city and the outcomes of care. A qualitative Diabetes Vulnerability Assessment explores the urban context in vulnerability to type 2 diabetes and identifies social factors and cultural determinants relevant to health, well-being and diabetes. ETHICS AND DISSEMINATION: The protocol steers the collection of primary and secondary data across the study sites. Research ethics board approval has been sought and obtained in each site. Findings from each of the local studies as well as the result from combined multisite (global) analyses will be reported in a series of core scientific journal papers. PMID- 29122783 TI - Clinical characteristics and prognosis of drug-associated acute respiratory distress syndrome compared with non-drug-associated acute respiratory distress syndrome: a single-centre retrospective study in Japan. AB - OBJECTIVES: To report the clinical features and prognosis of drug-associatedacute respiratory distress syndrome (ARDS). DESIGN: A retrospective analysis of data collected during a prospective cohort study. SETTING: Intensive care unit in a teaching hospital. PARTICIPANTS: A total of 197 Japanese patients with ARDS diagnosed by the Berlin definition who were admitted to the Division of Respiratory Medicine from October 2004 to December 2015 were enrolled in the study and were classified as two groups according to their causes: a drug associated ARDS group (n=27) and a non-drug-associated ARDS group (n=170). Primary outcome measure is 28-day mortality, and the secondaryoutcome measure is ventilator-free days. RESULTS: The Acute Physiology and Chronic Health Evaluation II scores were significantly lower in the drug-associated ARDS group than in the non-drug-associated ARDS group (median (IQR): 18.0 (16.5-21.0) vs 23.0 (18.0 26.0), p<0.001), and the arterial oxygen tension/fractional inspired oxygen ratio was higher (148.0 (114.1-177.5) vs 101.0 (71.5-134.0), p=0.003). In the drug associated ARDS group, although high-resolution CT scores indicative of the extent of fibroproliferation (301.6 (244.1-339.8) vs 208.3 (183.4-271.6), p<0.001), serum lactate dehydrogenase levels (477 (365-585) vs 322 (246-434), p=0.003) and the McCabe scores (score 1/2/3, n (%): 20 (74)/4 (15)/3 (11)vs154 (91)/7 (4)/9 (5), p=0.04) were significantly higher, ventilator weaning was earlier (p<0.001) and 28-day mortality was better (p=0.043). After adjusting for potentially confounding covariates, drug-associated ARDS group was associated with lower 28-day mortality (adjusted HR (HR) 0.275; 95% CI 0.106 to 0.711; p=0.008). CONCLUSIONS: Although more severe lung damage with fibroproliferation was observed in patients with drug-associated ARDS, ventilator weaning was earlier, and their prognosis was better than the others. Further well-designed prospective studies are needed. PMID- 29122784 TI - Impact of heterogeneity and effect size on the estimation of the optimal information size: analysis of recently published meta-analyses. AB - OBJECTIVE: To estimate the proportion of systematic reviews that meet the optimal information size (OIS) and assess the impact heterogeneity and effect size have on the OIS estimate by type of outcome (eg, mortality, semiobjective or subjective). METHODS: We carried out searches of Medline and Cochrane to retrieve meta-analyses published in systematic reviews from 2010 to 2012. We estimated the OIS using Trial Sequential Analysis software (TSA V.0.9) and based on several heterogeneity and effect size scenarios, stratifying by type of outcome (mortality/semiobjective/subjective) and by Cochrane/non-Cochrane reviews. RESULTS: We included 137 meta-analyses out of 218 (63%) potential systematic reviews (one meta-analysis from each systematic review). Of these reviews, 83 (61%) were Cochrane and 54 (39%) non-Cochrane. The Cochrane reviews included a mean of 6.5 (SD 6.1) studies and the non-Cochrane included a mean of 13.2 (SD 10.2) studies. The mean number of patients was 2619.1 (SD 6245.8 or median 586.0) for the Cochrane and 19 888.5 (SD 32 925.7 or median 6566.5) patients for the non Cochrane reviews. The percentage of systematic reviews that achieved the OIS for all-cause mortality outcome were 0% Cochrane and 25% for non-Cochrane reviews; for semiobjective outcome 17% for Cochrane and 46% for non-Cochrane reviews and for subjective outcome 45% for Cochrane and 72% for non-Cochrane reviews. CONCLUSIONS: The number of systematic reviews that meet an optimal information size is low and varies depending on the type of outcome and the type of publication. Less than half of primary outcomes synthesised in systematic reviews achieve the OIS, and therefore the conclusions are subject to substantial uncertainty. PMID- 29122785 TI - Naoxuekang, Xinnaoshutong and Xuesaitong capsules for treating stroke: a protocol for a randomised controlled trial. AB - INTRODUCTION: After stroke, hemiplegia, dysphasia and facial paralysis can manifest during the convalescent period. Currently, no Chinese patent medicine (CPM) is previously reported to cure each of these symptoms primarily, and thus, there are no relevant instructions for the use of CPM. This study presents a new approach based on comparative effectiveness research to distinguish the curative effects of three CPMs that are often used in stroke convalescence to determine the ideal medicine for the treatment of each symptom. METHODS AND ANALYSIS: In this multicentre and double-blind clinical trial, stratified randomisation is used to group the patients according to their primary symptoms (hemiplegia, dysphasia and facial paralysis). Three strata will be enrolled, with 80 eligible participants included in each stratum. Each stratum will be randomly and equally divided into four groups, and each group will receive one of the following treatments: Naoxuekang, Xinnaoshutong (XNST), Xuesaitong (XST) or placebo. This study will include two stages: the initial treatment period (30 days) and a follow-up period (180 days). Three replicates for each data point will be completed during this trial. The first visit will occur on day 0 after enrolment, the second visit on day 30+/-2 and the third visit on day 210+/-5. The Delphi technique is adopted to achieve index weighting, which ensures that the evaluation outcome is patient oriented. The weighted index value will be computed as the final measurement index of the outcome. ETHICS AND DISSEMINATION: This study has been approved by the Medical Ethics Committee of Tianjin University of Traditional Chinese Medicine (registration number TJUTCM-EC20160007). The results will be offered for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-17010397). The date of registration was 11 January 2017. PMID- 29122786 TI - A nationwide population-based cohort study of peripartum hysterectomy and arterial embolisation in Belgium: results from the Belgian Obstetric Surveillance System. AB - OBJECTIVES: To assess the prevalence of major obstetric haemorrhage managed with peripartum hysterectomy and/or interventional radiology (IR) in Belgium. To describe women characteristics, the circumstances in which the interventions took place, the management of the obstetric haemorrhage, the outcome and additional morbidity of these women. DESIGN: Nationwide population-based prospective cohort study. SETTING: Emergency obstetric care. Participation of 97% of maternities covering 98.6% of deliveries in Belgium. PARTICIPANTS: All women who underwent peripartum hysterectomy and/or IR procedures in Belgium between January 2012 and December 2013. RESULTS: We obtained data on 166 women who underwent peripartum hysterectomy (n=84) and/or IR procedures (n=102), corresponding to 1 in 3030 women undergoing a peripartum hysterectomy and another 1 in 3030 women being managed by IR, thereby preserving the uterus. Seventeen women underwent hysterectomy following IR and three women needed further IR despite hysterectomy. Abnormal placentation and/or uterine atony were the reported causes of haemorrhage in 83.7%. Abnormally invasive placenta was not detected antenatally in 34% of cases. The interventions were planned in 15 women. Three women were transferred antenatally and 17 women postnatally to a hospital with emergency IR service. Urgent peripartum hysterectomy was averted in 72% of the women who were transferred, with no significant difference in need for transfusion. IR procedures were able to stop the bleeding in 87.8% of the attempts. Disseminated intravascular coagulation secondary to major haemorrhage was reported in 32 women (19%). CONCLUSION: The prevalence in Belgium of major obstetric haemorrhage requiring peripartum hysterectomy and/or IR is estimated at 6.6 (95% CI 5.7 to 7.7) per 10 000 deliveries. Increased clinician awareness of the risk factors of abnormal placentation could further improve the management and outcome of major obstetric haemorrhage. A case-by-case in-depth analysis is necessary to reveal whether the hysterectomies and arterial embolisations performed in this study were appropriate or preventable. PMID- 29122787 TI - EFFECT of daily antiseptic body wash with octenidine on nosocomial primary bacteraemia and nosocomial multidrug-resistant organisms in intensive care units: design of a multicentre, cluster-randomised, double-blind, cross-over study. AB - INTRODUCTION: Nosocomial infections are serious complications that increase morbidity, mortality and costs and could potentially be avoidable. Antiseptic body wash is an approach to reduce dermal micro-organisms as potential pathogens on the skin. Large-scale trials with chlorhexidine as the antiseptic agent suggest a reduction of nosocomial infection rates. Octenidine is a promising alternative agent which could be more effective against Gram-negative organisms. We hypothesise that daily antiseptic body wash with octenidine reduces the risk of intensive care unit (ICU)-acquired primary bacteraemia and ICU-acquired multidrug-resistant organisms (MDRO) in a standard care setting. METHODS AND ANALYSIS: EFFECT is a controlled, cluster-randomised, double-blind study. The experimental intervention consists in using octenidine-impregnated wash mitts for the daily routine washing procedure of the patients. This will be compared with using placebo wash mitts. Replacing existing washing methods is the only interference into clinical routine.Participating ICUs are randomised in an AB/BA cross-over design. There are two 15-month periods, each consisting of a 3-month wash-out period followed by a 12-month intervention and observation period. Randomisation determines only the sequence in which octenidine-impregnated or placebo wash mitts are used. ICUs are left unaware of what mitts packages they are using.The two coprimary endpoints are ICU-acquired primary bacteraemia and ICU-acquired MDRO. Endpoints are defined based on individual ward-movement history and microbiological test results taken from the hospital information systems without need for extra documentation. Data on clinical symptoms of infection are not collected. EFFECT aims at recruiting about 45 ICUs with about 225 000 patient-days per year. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of the University of Leipzig (number 340/16-ek) in November 2016. Findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: DRKS-ID: DRKS00011282. PMID- 29122788 TI - Cohort profile: workers' compensation in a changing Australian labour market: the return to work (RTW) study. AB - PURPOSE: Workers' compensation claims for older workers and workers who have suffered psychological injury are increasing as a proportion of total claims in many jurisdictions. In the Australian state of Victoria, claims from both these groups are associated with higher than average wage replacement and healthcare expenditures. This cohort profile describes a longitudinal study which aims to investigate differences in the return to work (RTW) process for older workers compared with younger workers and claimants with musculoskeletal injuries compared with those with psychological injuries. PARTICIPANTS: This prospective cohort study involved interviewing workers' compensation claimants at three time points. The cohort was restricted to psychological and musculoskeletal claims. Only claimants aged 18 and over were recruited, with no upper age limit. A total of 869 claimants completed the baseline interview, representing 36% of the eligible claimant population. Ninety-one per cent of participants agreed at baseline to have their survey responses linked to administrative workers' compensation data. Of the 869 claimants who participated at baseline, 632 (73%) took part in the 6-month follow-up interview, and 572 (66%) participated in the 12-month follow-up interview. FINDINGS TO DATE: Information on different aspects of the RTW process and important factors that may impact the RTW process was collected at the three survey periods. At baseline, participants and non participants did not differ by injury type or age group, but were more likely to be female and from the healthcare and social assistance industry. The probability of non-participation at follow-up interviews showed younger age was a statistically significant predictor of non-participation. FUTURE PLANS: Analysis of the longitudinal cohort will identify important factors in the RTW process and explore differences across age and injury type groups. Ongoing linkage to administrative workers' compensation data will provide information on wage replacement and healthcare service use into the future. PMID- 29122789 TI - Validation of an automated delirium prediction model (DElirium MOdel (DEMO)): an observational study. AB - OBJECTIVES: Delirium is an underdiagnosed, severe and costly disorder, and 30% 40% of cases can be prevented. A fully automated model to predict delirium (DEMO) in older people has been developed, and the objective of this study is to validate the model in a hospital setting. SETTING: Secondary care, one hospital with two locations. DESIGN: Observational study. PARTICIPANTS: The study included 450 randomly selected patients over 60 years of age admitted to Zuyderland Medical Centre. Patients who presented with delirium on admission were excluded. PRIMARY OUTCOME MEASURES: Development of delirium through chart review. RESULTS: A total of 383 patients were included in this study. The analysis was performed for delirium within 1, 3 and 5 days after a DEMO score was obtained. Sensitivity was 87.1% (95% CI 0.756 to 0.939), 84.2% (95% CI 0.732 to 0.915) and 82.7% (95% CI 0.734 to 0.893) for 1, 3 and 5 days, respectively, after obtaining the DEMO score. Specificity was 77.9% (95% CI 0.729 to 0.882), 81.5% (95% CI 0.766 to 0.856) and 84.5% (95% CI 0.797 to 0.884) for 1, 3 and 5 days, respectively, after obtaining the DEMO score. CONCLUSION: DEMO is a satisfactory prediction model but needs further prospective validation with in-person delirium confirmation. In the future, DEMO will be applied in clinical practice so that physicians will be aware of when a patient is at an increased risk of developing delirium, which will facilitate earlier recognition and diagnosis, and thus will allow the implementation of prevention measures. PMID- 29122790 TI - Cohort profile: design and first results of the Dutch IBD Biobank: a prospective, nationwide biobank of patients with inflammatory bowel disease. AB - PURPOSE: The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank. PARTICIPANTS: Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected. FINDINGS TO DATE: As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies. FUTURE PLANS: The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app. PMID- 29122791 TI - Quality of reporting of pilot and feasibility cluster randomised trials: a systematic review. AB - OBJECTIVES: To systematically review the quality of reporting of pilot and feasibility of cluster randomised trials (CRTs). In particular, to assess (1) the number of pilot CRTs conducted between 1 January 2011 and 31 December 2014, (2) whether objectives and methods are appropriate and (3) reporting quality. METHODS: We searched PubMed (2011-2014) for CRTs with 'pilot' or 'feasibility' in the title or abstract; that were assessing some element of feasibility and showing evidence the study was in preparation for a main effectiveness/efficacy trial. Quality assessment criteria were based on the Consolidated Standards of Reporting Trials (CONSORT) extensions for pilot trials and CRTs. RESULTS: Eighteen pilot CRTs were identified. Forty-four per cent did not have feasibility as their primary objective, and many (50%) performed formal hypothesis testing for effectiveness/efficacy despite being underpowered. Most (83%) included 'pilot' or 'feasibility' in the title, and discussed implications for progression from the pilot to the future definitive trial (89%), but fewer reported reasons for the randomised pilot trial (39%), sample size rationale (44%) or progression criteria (17%). Most defined the cluster (100%), and number of clusters randomised (94%), but few reported how the cluster design affected sample size (17%), whether consent was sought from clusters (11%), or who enrolled clusters (17%). CONCLUSIONS: That only 18 pilot CRTs were identified necessitates increased awareness of the importance of conducting and publishing pilot CRTs and improved reporting. Pilot CRTs should primarily be assessing feasibility, avoiding formal hypothesis testing for effectiveness/efficacy and reporting reasons for the pilot, sample size rationale and progression criteria, as well as enrolment of clusters, and how the cluster design affects design aspects. We recommend adherence to the CONSORT extensions for pilot trials and CRTs. PMID- 29122792 TI - Understanding the implementation of 'sick day guidance' to prevent acute kidney injury across a primary care setting in England: a qualitative evaluation. AB - OBJECTIVES: The study sought to examine the implementation of sick day guidance cards designed to prevent acute kidney injury (AKI), in primary care settings. DESIGN: Qualitative semistructured interviews were conducted and comparative analysis informed by normalisation process theory was undertaken to understand sense-making, implementation and appraisal of the cards and associated guidance. SETTING: A single primary care health setting in the North of England. PARTICIPANTS: 29 participants took part in the qualitative evaluation: seven general practitioners, five practice nurses, five community pharmacists, four practice pharmacists, two administrators, one healthcare assistant and five patients. INTERVENTION: The sick day guidance intervention was rolled out (2015 2016) in general practices (n=48) and community pharmacies (n=60). The materials consisted of a 'medicine sick day guidance' card, provided to patients who were taking the listed drugs. The card provided advice about medicines management during episodes of acute illness. An information leaflet was provided to healthcare practitioners and administrators suggesting how to use and give the cards. RESULTS: Implementation of sick day guidance cards to prevent AKI entailed a new set of working practises across primary care. A tension existed between ensuring reach in administration of the cards to at risk populations while being confident to ensure patient understanding of their purpose and use. Communicating the concept of temporary cessation of medicines was a particular challenge and limited their administration to patient populations at higher risk of AKI, particularly those with less capacity to self-manage. CONCLUSIONS: Sick day guidance cards that focus solely on medicines management may be of limited patient benefit without adequate resourcing or if delivered as a standalone intervention. Development and evaluation of primary care interventions is urgently warranted to tackle the harm associated with AKI. PMID- 29122794 TI - Consensus validation of the POSAMINO (POtentially Serious Alcohol-Medication INteractions in Older adults) criteria. AB - OBJECTIVES: Older adults are particularly vulnerable to adverse effects from concurrent alcohol and medication use. However, there is limited evidence regarding the prevalence of these adverse outcomes among older adults, and there is a lack of consensus regarding what constitutes an alcohol-interactive medicine. The objective of this study was to develop an explicit list of potentially serious alcohol-medication interactions for use in older adults. DESIGN: Following a systematic review, review of drug compendia and clinical guidance documents, a two-round Delphi consensus method was conducted. SETTING: Ireland and the United Kingdom (UK), primary care and hospital setting. PARTICIPANTS: The Project Steering Group developed a list of potentially serious alcohol-medication interactions. The Delphi panel consisted of 19 healthcare professionals (general practitioners, geriatricians, hospital and community pharmacists, clinical pharmacologists and pharmacists, and physicians specialising in substance misuse). RESULTS: An inventory of 52 potentially serious alcohol-medication interactions was developed by the Project Steering Group. British National Formulary black dot warnings (n=8) were included in the final criteria as they represent 'potentially serious' interactions. The remaining 44 criteria underwent a two-round Delphi process. In the first round, 13 criteria were accepted into the POtentially Serious Alcohol-Medication INteractions in Older adults (POSAMINO) criteria. Consensus was not reached on the remaining 31 criteria; 9 were removed and 8 additional criteria were included following a review of panellist comments. The remaining 30 criteria went to round 2, with 17 criteria reaching consensus, providing a final list of 38 potentially serious alcohol-medication interactions: central nervous system (n=15), cardiovascular system (n=9), endocrine system (n=5), musculoskeletal system (n=3), infections (n=3), malignant disease and immunosuppression (n=2), and respiratory system (n=1). CONCLUSIONS: POSAMINO is the first set of explicit potentially serious alcohol-medication interactions for use in older adults. Following future validation studies, these criteria may allow for the risk stratification of older adults at the point of prescribing. PMID- 29122793 TI - Developing a classification system for haemoglobin management in patients with end-stage renal disease on haemodialysis: a secondary data analysis. AB - BACKGROUND: Ongoing discussion on anaemia management and target haemoglobin (Hb) levels in patients on haemodialysis with erythropoietin treatment require a systematic approach in evaluating current practice. Aim of the present study was to develop a new classification system to easily monitor Hb trajectories and categorise patients on haemodialysis. METHODS: Routine data from five dialysis centres in the USA collected between 2010 and 2016. Data were anonymised and only those from patients with fortnightly Hb values were included in the analysis. Entries on blood parameters and medication were standardised to achieve overall comparability. Data from each patient was grouped in periods of 120 days. Hb values above or below the target level of 10-12 g/dL were counted for each period. Periods were then assigned to Hb-classes according to the number of Hb values out of range per period: Hb-class I with 0-2, Hb-class II for 3-5 and Hb class III for >=6 values out of range. RESULTS: Records from 3349 patients with fortnightly Hb values, information on haemodialysis data, laboratory parameters correlated to red blood cells and data on medication with erythropoiesis stimulating agents (ESAs) were available. Patients were 64.4+/-15.9 years old; 55.0% were men. Statistical analysis revealed significant differences between Hb classes in all of the examined parameters, except erythrocytes mean corpuscular volume and C reactive protein above the threshold, with more critical values in higher Hb-classes. The usage of ESAs showed a mean difference between Hb-class III and Hb-class I of 6.4 units/day and kilogram body weight in a 120-day period. CONCLUSION: Our classification system allows an easily achievable overview of the patients' responsiveness and performance of Hb management. Integrated into a disease management programme or continuous quality improvement, the classification delivers an instant appraisal without complex statistical or mathematical processing. PMID- 29122795 TI - Association of type 2 diabetes with in-hospital complications among women undergoing breast cancer surgical procedures. A retrospective study using the Spanish National Hospital Discharge Database, 2013-2014. AB - OBJECTIVES: To compare the type of surgical procedures used, comorbidities, in hospital complications (IHC) and in-hospital outcomes between women with type 2 diabetes mellitus (T2DM) and age-matched women without diabetes who were hospitalised with breast cancer. In addition, we sought to identify factors associated with IHC in women with T2DM who had undergone surgical procedures for breast cancer. DESIGN: Retrospective study using the National Hospital Discharge Database, 2013-2014. SETTING: Spain. PARTICIPANTS: Women who were aged >=40 years with a primary diagnosis of breast cancer and who had undergone a surgical procedure. We grouped admissions by T2DM status. We selected one matched control for each T2DM case. MAIN OUTCOME MEASURES: The type of procedure (breast conserving surgery (BCS) or mastectomy), clinical characteristics, complications, length of hospital stay and in-hospital mortality. RESULTS: We identified 41 458 admissions (9.23% with T2DM). Overall, and in addition to the surgical procedure, we found that comorbidity, hypertension and obesity were more common among patients with T2DM. We also detected a higher incidence of mastectomy in women with T2DM (44.69% vs 42.42%) and a greater rate of BCS in patients without T2DM (57.58% vs 55.31%). Overall, non-infectious complications were more common among women with T2DM (6.40% vs 4.56%). Among women who had undergone BCS or a mastectomy, IHC were more frequent among diabetics (5.57% vs 3.04% and 10.60% vs 8.24%, respectively). Comorbidity was significantly associated with a higher risk of IHC in women with diabetes, independent of the specific procedure used.province CONCLUSIONS: Women with T2DM who undergo surgical breast cancer procedures have more comorbidity, risk factors and advanced cancer presentations than matched patients without T2DM. Mastectomies are more common in women with T2DM. Moreover, the procedures among women with T2DM were associated with greater IHC. Comorbidity was a strong predictor of IHC in women with T2DM. PMID- 29122796 TI - Association between organisational and workplace cultures, and patient outcomes: systematic review. AB - DESIGN AND OBJECTIVES: Every organisation has a unique culture. There is a widely held view that a positive organisational culture is related to positive patient outcomes. Following the Preferred Reporting Items for Systematic Review and Meta Analyses statement, we systematically reviewed and synthesised the evidence on the extent to which organisational and workplace cultures are associated with patient outcomes. SETTING: A variety of healthcare facilities, including hospitals, general practices, pharmacies, military hospitals, aged care facilities, mental health and other healthcare contexts. PARTICIPANTS: The articles included were heterogeneous in terms of participants. This was expected as we allowed scope for wide-ranging health contexts to be included in the review. PRIMARY AND SECONDARY OUTCOME MEASURES: Patient outcomes, inclusive of specific outcomes such as pain level, as well as broader outcomes such as patient experience. RESULTS: The search strategy identified 2049 relevant articles. A review of abstracts using the inclusion criteria yielded 204 articles eligible for full-text review. Sixty-two articles were included in the final analysis. We assessed studies for risk of bias and quality of evidence. The majority of studies (84%) were from North America or Europe, and conducted in hospital settings (89%). They were largely quantitative (94%) and cross-sectional (81%). The review identified four interventional studies, and no randomised controlled trials, but many good quality social science studies. We found that overall, positive organisational and workplace cultures were consistently associated with a wide range of patient outcomes such as reduced mortality rates, falls, hospital acquired infections and increased patient satisfaction. CONCLUSIONS: Synthesised, although there was no level 1 evidence, our review found a consistently positive association held between culture and outcomes across multiple studies, settings and countries. This supports the argument in favour of activities that promote positive cultures in order to enhance outcomes in healthcare organisations. PMID- 29122798 TI - Impact of prenatal diagnosis on survival of newborns with four congenital heart defects: a prospective, population-based cohort study in France (the EPICARD Study). AB - OBJECTIVES: (1) Assess the population-level probability of prenatal diagnosis and termination of pregnancy for fetal anomaly for four major congenital heart defects; (2) Examine, using population-based data, the relation between timing of (prenatal vs postnatal) diagnosis and risk of infant (ie, < 1 year) mortality for four major congenital heart defects (CHDs). DESIGN: Population-based cohort (the EPIdemiologie des CARDiopathies congenitales) study. SETTING: Greater Paris area (Paris and its surrounding suburbs). PATIENTS: Three hundred and fifty-four cases of four major CHDs, including functionally univentricular heart (FUH, N=132), d transposition of great arteries (d-TGA, N=85), tetralogy of Fallot (TOF, N=60) and coarctation of aorta (CoA, N=77). Statistical analysis included the Mantel Haenszel method and a test of homogeneity of risk ratios. RESULTS: Approximately 95% of FUH, more than two-thirds of d-TGA and TOF, and 40% of CoA were prenatally diagnosed. Overall, we did not find any statistically significant association between timing of (prenatal vs postnatal) diagnosis of CHD and risk of infant mortality (Mantel-Haenszel risk ratio 1.1, 95% CI 0.5 - 2.7); and the differences between the risk ratios of the association between prenatal diagnosis and infant mortality across the four CHDs was not statistically significant. CONCLUSION: These results imply that at least in the settings where specialised services are readily available, survival may no longer be the most relevant outcome, or the best criterion, for evaluating the impact of prenatal diagnosis on the outcome of CHD. The beneficial effects of prenatal diagnosis may be better sought by looking at more 'subtle' or long-term neurodevelopmental outcomes. PMID- 29122797 TI - Association between respiratory syncytial viral disease and the subsequent risk of the first episode of severe asthma in different subgroups of high-risk Australian children: a whole-of-population-based cohort study. AB - OBJECTIVE: To determine the contribution of respiratory syncytial virus (RSV) to the subsequent development of severe asthma in different subgroups of children at risk of severe RSV disease. SETTINGS: The study was conducted in New South Wales (NSW), Australia. PARTICIPANTS: The study comprised all children born in NSW between 2000 and 2010 with complete follow-up till 31 December 2011. The cohort was divided into three subgroups: (1) non-Indigenous high-risk children: non Indigenous children born preterm or born with a low birth weight; (2) Indigenous children: children of mothers whose Indigenous status was recorded as Aboriginal and/or Torres Strait Islander and (3) non-Indigenous standard risk children: all other non-Indigenous term children. PRIMARY OUTCOME MEASURE: Risk of development of severe asthma in different subgroups of children who had RSV hospitalisation in the first 2 years of life compared with those who did not. DESIGN: We performed a retrospective cohort analysis using population-based linked administrative data. Extended Cox model was used to determine HR and 95% CI around the HR for first asthma hospitalisation in different subgroups of children. RESULTS: The cohort comprised 847 516 children born between 2000 and 2010. In the adjusted Cox model, the HR of first asthma hospitalisation was higher and comparable across all subgroups of children who had RSV hospitalisation compared with those who did not. The HR (95% CI) was highest in children aged 2-3 years; 4.3 (95% CI 3.8 to 4.9) for high-risk, 4.0 (95% CI 3.3 to 4.8) for Indigenous and 3.9 (95% CI 3.7 to 4.1) for non-Indigenous standard risk children. This risk persisted beyond 7 years of age. CONCLUSION: This large study confirms a comparable increased risk of first asthma hospitalisation following RSV disease in the first 2 years of life across different subgroups children at risk. PMID- 29122799 TI - Qualitative study to understand the barriers to recruiting young people with cancer to BRIGHTLIGHT: a national cohort study in England. AB - OBJECTIVES: BRIGHTLIGHT is a national evaluation of cancer services for teenagers and young adults in England. Following challenges with recruitment, our aim was to understand more fully healthcare professionals' perspectives of the challenges of recruiting young people to a low-risk observational study, and to provide guidance for future recruitment processes. DESIGN: Qualitative. SETTING: National Health Service (NHS) hospitals in England. METHODS: Semistructured telephone interviews with a convenience sample of 23 healthcare professionals. Participants included principal investigators/other staff recruiting into the BRIGHTLIGHT study. Data were analysed using framework analysis. RESULTS: The emergent themes were linked to levels of research organisational management, described using the levels of social network analysis: micro-level (the individual; in this case the target population to be recruited-young people with cancer); meso-level (the organisation; refers to place of recruitment and people responsible for recruitment); and macro-level (the large-scale or global structure; refers to the wider research function of the NHS and associated policies). Study-related issues occurred across all three levels, which were influenced by the context of the study. At the meso-level, professionals' perceptions of young people and communication between professionals generated age/cancer type silos, resulting in recruitment of either children or adults, but not both by the same team, and only in the cancer type the recruiting professional was aligned to. At the macro-level the main barrier was discordant configuration of a research service with a clinical service. CONCLUSIONS: This study has identified significant barriers to recruitment mainly at the meso-level and macro-level, which are more challenging for research teams to influence. We suggest that interconnected whole-system changes are required to facilitate the success of interventions designed to improve recruitment. Interventions targeted at study design/management and the micro-level only may be less successful. We offer solutions to be considered by those involved at all levels of research for this population. PMID- 29122800 TI - Studying Impact of Nutrition on Growth (SING): a prospective cohort for comparing the health outcomes of young children with the dietary quality score. AB - INTRODUCTION: This study aims to explore the prospective association between the dietary quality (DQ) of preschoolers and their health status in Hong Kong, with the body mass index as the main outcome variable. METHODS AND ANALYSIS: This prospective cohort study has recruited 3539 children aged between 2 and 4 years old, with a follow-up period of 4 years. Their diet was reported by their parents by a 3-day food diary, and their body weight and height were measured yearly with standardised instruments. Questionnaires were administered to parents to acquire information of the children's prenatal development and dietary intake before their age of 2 years and of their baseline lifestyle and family backgrounds. The DQ was measured by the Healthy Eating Index as a continuous scale, while the exposure was defined as having a higher dietary quality score. Data were analysed using SPSS V.24. Linear and logistic regressions were used to examine the association of those predictive factors to the outcomes. Generalised estimating equations will be used to examine the longitudinal changes of the outcomes. A pilot study has been conducted, the preliminary results from which are presented in this cohort profile. ETHICS AND DISSEMINATION: This study has been approved by the Joint Chinese University of Hong Kong and New Territory East Cluster Clinical Research Ethics Committee (CREC Ref No: 2013-632). Written informed consent was obtained from all subjects. The results will be published in due course. PMID- 29122801 TI - How are clinical commissioning groups managing conflicts of interest under primary care co-commissioning in England? A qualitative analysis. AB - OBJECTIVES: From April 2015, NHS England (NHSE) started to devolve responsibility for commissioning primary care services to clinical commissioning groups (CCGs). The aim of this paper is to explore how CCGs are managing potential conflicts of interest associated with groups of GPs commissioning themselves or their practices to provide services. DESIGN: We carried out two telephone surveys using a sample of CCGs. We also used a qualitative case study approach and collected data using interviews and meeting observations in four sites (CCGs). SETTING/PARTICIPANTS: We conducted 57 telephone interviews and 42 face-to-face interviews with general practitioners (GPs) and CCG staff involved in primary care co-commissioning and observed 74 meetings of CCG committees responsible for primary care co-commissioning. RESULTS: Conflicts of interest were seen as an inevitable consequence of CCGs commissioning primary care. Particular problems arose with obtaining unbiased clinical input for new incentive schemes and providing support to GP provider federations. Participants in meetings concerning primary care co-commissioning declared conflicts of interest at the outset of meetings. Different approaches were pursued regarding GPs involvement in subsequent discussions and decisions with inconsistency in the exclusion of GPs from meetings. CCG senior management felt confident that the new governance structures and policies dealt adequately with conflicts of interest, but we found these arrangements face limitations. While the revised NHSE statutory guidance on managing conflicts of interest (2016) was seen as an improvement on the original (2014), there still remained some confusion over various terms and concepts contained therein. CONCLUSIONS: Devolving responsibility for primary care co commissioning to CCGs created a structural conflict of interest. The NHSE statutory guidance should be refined and clarified so that CCGs can properly manage conflicts of interest. Non-clinician members of committees involved in commissioning primary care require training in order to make decisions requiring clinical input in the absence of GPs. PMID- 29122802 TI - Emergency obstetric care provision in Southern Ethiopia: a facility-based survey. AB - OBJECTIVES: To assess the provision of basic emergency obstetric and newborn care (BEmONC), knowledge of high-risk pregnancies and referral capacity at health centres in Southern Ethiopia. DESIGN: A facility-based survey, using an abbreviated version of the Averting Maternal Death and Disability needs assessment tool for emergency obstetric and newborn care. Modules included infrastructure, staffing, number of deliveries, maternal and perinatal mortality, BEmONC signal functions, referral capacity and knowledge of risk factors in pregnancy. SETTING: Primary healthcare centres providing delivery services in the Eastern Gurage Zone, a predominantly rural area in Southern Ethiopia. PARTICIPANTS: All 20 health centres in the study area were selected for the assessment. One was excluded, as no delivery services had been provided in the 12 months prior to the study. RESULTS: Three out of 19 health centres met the government's staffing norm. In the 12 months prior to the survey, 10 004 ([Formula: see text]) deliveries were attended to at the health centres, but none had provided all seven BEmONC signal functions in the three months prior to the survey ([Formula: see text]). Eight maternal and 32 perinatal deaths occurred. Most health centres had performed administration of parenteral uterotonics (17/89.5%), manual removal of placenta (17/89.5%) and neonatal resuscitation (17/89.5%), while few had performed assisted vaginal delivery (3/15.8%) or administration of parenteral anticonvulsants (1/5.3%). Reasons mentioned for non performance were lack of patients with appropriate indications, lack of training and supply problems. Health workers mentioned on average 3.9+/-1.4 of 11 risk factors for adverse pregnancy outcomes. Five ambulances were available in the zone. CONCLUSION: BEmONC provision is not guaranteed to women giving birth in health centres in Southern Ethiopia. Since the government aims to increase facility deliveries, investments in capacity at health centres are urgently needed. PMID- 29122804 TI - The messages presented in online electronic cigarette promotions and discussions: a scoping review protocol. AB - INTRODUCTION: Electronic cigarettes have become increasingly popular over the last 10 years. These devices represent a new paradigm for tobacco control offering smokers an opportunity to inhale nicotine without inhaling tobacco smoke. To date there are no definite conclusions regarding the safety and long term health effects of electronic cigarettes; however, there is evidence that they are being marketed online as a healthier alternative to traditional cigarettes. This scoping review aims to identify and describe the breadth of messages (eg, health, smoking-cessation and price related claims) presented in online electronic cigarette promotions and discussions. METHODS AND ANALYSIS: A scoping review will be undertaken adhering to the methodology outlined in The Joanna Briggs Institute Manual for Scoping Reviews. Six key electronic databases will be searched to identify eligible studies. Studies must be published in English between 2007 and 2017, examine and/or analyse content captured from online electronic cigarette promotions or discussions and report results for electronic cigarettes separately to other forms of tobacco delivery. Studies will be screened initially by title and abstract, followed by full-text review. Results of the search strategy will be reported in a PRISMA flow diagram and presented in tabular form with accompanying narrative summary. ETHICS AND DISSEMINATION: The methodology consists of reviewing and collecting data from publicly available studies, and therefore does not require ethics approval. Results will be published in a peer reviewed journal and be presented at national/international conferences. Additionally, findings will be disseminated via social media and online platforms. Advocacy will be key to informing policy makers of regulatory and health issues that need to be addressed. REGISTRATION DETAILS: The review was registered prospectively with The Joanna Briggs Institute Systematic Reviews database. PMID- 29122803 TI - A population-based case-control study of hospitalisation due to head injuries among bicyclists and motorcyclists in Taiwan. AB - INTRODUCTION: According to official statistics in Taiwan, the main body region of injury causing bicyclist deaths is the head, and bicyclists are 2.6 times more likely to be fatally injured than motorcyclists. There is currently a national helmet law for motorcyclists but not for bicyclists. OBJECTIVES: The primary aim of this study was to determine whether bicyclist casualties have higher odds of head-related hospitalisation than motorcyclists. This study also aims to investigate the determinants of head injury-related hospitalisation among bicyclists and motorcyclists. METHODS: Using linked data from the National Traffic Accident Dataset and the National Health Insurance Research Database for the period 2003-2012, this study investigates the crash characteristics of bicyclist and motorcyclist casualties presenting to hospitals due to motor vehicle crashes. Head injury-related hospitalisation was used as the study outcome for both road users to evaluate whether various factors (eg, human attributes, road and weather conditions, vehicle characteristics) are related to hospital admission of those who sustained serious injuries. RESULTS: Among 1 239 474 bicyclist and motorcyclist casualties, the proportion of bicyclists hospitalised for head injuries was higher than that of motorcyclists (10.0% vs 6.5%). However, the multiple logistic regression model shows that, after adjustment of this result for other factors such as helmet use, bicyclists were 18% significantly less likely to be hospitalised for head injuries than motorcyclists (AOR 0.82, 95% CI 0.79 to 0.85). Other important determinants of head injury-related hospitalisation for bicyclists and motorcyclists include female riders, elderly riders, crashes occurring in rural areas, moped riders, riding unhelmeted, intoxicated bicyclists and motorcyclists, unlicensed motorcyclists, dusk and dawn conditions and single-vehicle crashes. CONCLUSIONS: Our finding underscores the importance of helmet use in reducing hospitalisation due to head injuries among bicyclists while current helmet use is relatively low. PMID- 29122805 TI - Impact of UV-irradiation on electrical impedance spectroscopy of benign nevi: study protocol for a prospective, controlled, clinical study. AB - INTRODUCTION: The clinical and histological changes of nevi after ultraviolet (UV) irradiation have been studied in detail. In contrast, the impact of UV irradiation on electrical impedance spectroscopy scores of nevi has not been investigated. However, for physicians, it is essential to know the extent to which changes in electrical impedance spectroscopy scores of nevi may be attributed to seasonal effects of UV irradiation. METHODS: This is a prospective, controlled, clinical study evaluating the impact of UV irradiation on the electrical impedance spectroscopy scores of benign nevi in 50 patients undergoing phototherapy. To this end, benign nevi of patients with a medical indication for phototherapy will be measured by electrical impedance spectroscopy before, during and after UV irradiation. At the same time, non-irradiated nevi of the same patient will be measured to account for changes over time that are independent of direct UV irradiation. ETHICS AND DISSEMINATION: Ethical approval was obtained from the ethics committee of the medical faculty of the University of Heidelberg (ethics approval number S-279/2017). The design and the final results of the study will be published and made available to the public. TRIAL REGISTRATION NUMBER: DRKS00012456; Pre-results. PMID- 29122806 TI - Diagnostic utility of appetite loss in addition to existing prediction models for community-acquired pneumonia in the elderly: a prospective diagnostic study in acute care hospitals in Japan. AB - OBJECTIVE: Diagnosis of community-acquired pneumonia (CAP) in the elderly is often delayed because of atypical presentation and non-specific symptoms, such as appetite loss, falls and disturbance in consciousness. The aim of this study was to investigate the external validity of existing prediction models and the added value of the non-specific symptoms for the diagnosis of CAP in elderly patients. DESIGN: Prospective cohort study. SETTING: General medicine departments of three teaching hospitals in Japan. PARTICIPANTS: A total of 109 elderly patients who consulted for upper respiratory symptoms between 1 October 2014 and 30 September 2016. MAIN OUTCOME MEASURES: The reference standard for CAP was chest radiograph evaluated by two certified radiologists. The existing models were externally validated for diagnostic performance by calibration plot and discrimination. To evaluate the additional value of the non-specific symptoms to the existing prediction models, we developed an extended logistic regression model. Calibration, discrimination, category-free net reclassification improvement (NRI) and decision curve analysis (DCA) were investigated in the extended model. RESULTS: Among the existing models, the model by van Vugt demonstrated the best performance, with an area under the curve of 0.75(95% CI 0.63 to 0.88); calibration plot showed good fit despite a significant Hosmer-Lemeshow test (p=0.017). Among the non-specific symptoms, appetite loss had positive likelihood ratio of 3.2 (2.0-5.3), negative likelihood ratio of 0.4 (0.2-0.7) and OR of 7.7 (3.0-19.7). Addition of appetite loss to the model by van Vugt led to improved calibration at p=0.48, NRI of 0.53 (p=0.019) and higher net benefit by DCA. CONCLUSIONS: Information on appetite loss improved the performance of an existing model for the diagnosis of CAP in the elderly. PMID- 29122807 TI - Contribution of the voluntary sector to mental health crisis care in England: protocol for a multimethod study. AB - INTRODUCTION: Timely access to the right kind of support for people experiencing a mental health crisis can be problematic. The voluntary sector (VS) plays a key role in providing support and enabling access, but there is a knowledge gap concerning its contribution and interface with public services in mental health crisis care. This study aims to address this. METHODS AND ANALYSIS: The study has three empirical elements: (1) a national survey of voluntary sector organisations (VSOs) in England and national stakeholder interviews to develop a typology of organisations and interventions provided by VSOs; (2) detailed mapping of VS services in two regions through interviews and extending the national survey; (3) four case studies, identified from the regional mapping, of VS mental health crisis services and their interface with National Health Service (NHS) and local authority services, at both a system and individual level. Data collection will involve interviews with commissioners; VSO and NHS or local authority providers; and focus groups with people who have experience of VSO crisis support, both service users and carers; and mapping the crisis trajectory of 10 service users in each study site through narrative interviews with service users and informal carers to understand the experience of VSO crisis care and its impact. ETHICS AND DISSEMINATION: The University of Birmingham Humanities and Social Sciences Ethical Review Committee granted ethical approval (reference ERN_16-1183) for the national and regional elements of the study. Ethical review by the Health Research Authority will be required for the case study research once the sites have been identified from the first two elements of the study. A range of methods including a policy seminar, publication in academic journals and a tool kit for commissioners and practitioners will be produced to maximise the impact of the findings on policy and practice. PMID- 29122809 TI - Eligibility for PCSK9 Inhibitors According to American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines After Acute Coronary Syndromes. AB - BACKGROUND: The American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) have recently published recommendations for the use of proprotein convertase subtilisin/kexin-9 (PCSK9) inhibitors in situations of very high risk. We aim to assess in the real world the suitability of PCSK9 inhibitors for acute coronary syndromes. METHODS AND RESULTS: We analyzed a prospective Swiss cohort of 2023 patients hospitalized for acute coronary syndromes between 2009 and 2014 with available data for low density lipoprotein cholesterol and lipid-lowering therapy at 1 year. Clinical familial hypercholesterolemia was defined using the Dutch Lipid Clinic Network algorithm as unlikely, possible, probable, or definite. We simulated a fixed relative reduction of 24% in low-density lipoprotein cholesterol levels at 1 year in all patients not treated with ezetimibe, irrespective of the low-density lipoprotein cholesterol levels and statin regimen. At 1 year, 94.3% of patients were treated with statin, 5.8% with ezetimibe, and 35.8% of patients had on target low-density lipoprotein cholesterol levels (<1.8 mmol/L); 25.6% met criteria for possible or probable/definite familial hypercholesterolemia. After a simulation of the lipid-lowering effect of ezetimibe, the proportion of patients who would be eligible for PCSK9 inhibitors at 1 year was 13.4% using American College of Cardiology criteria and 2.7% using European Society of Cardiology/European Atherosclerosis Society criteria. Patients with possible or probable/definite familial hypercholesterolemia were more eligible for PCSK9 inhibitors compared with their non-familial hypercholesterolemia counterparts: 27.6% versus 8.8% according to American College of Cardiology criteria and 6.6% versus 1.8% according to European Society of Cardiology/European Atherosclerosis Society criteria (P<0.001). CONCLUSIONS: Recommendations made by the American College of Cardiology guidelines would lead to 5-fold higher eligibility rates for PCSK9 inhibitors compared to the European Society of Cardiology/European Atherosclerosis Society consensus statement in acute coronary syndrome patients. PMID- 29122808 TI - Study design and protocol for a mixed methods evaluation of an intervention to reduce and break up sitting time in primary school classrooms in the UK: The CLASS PAL (Physically Active Learning) Programme. AB - INTRODUCTION: Children engage in a high volume of sitting in school, particularly in the classroom. A number of strategies, such as physically active lessons (termed movement integration (MI)), have been developed to integrate physical activity into this learning environment; however, no single approach is likely to meet the needs of all pupils and teachers. This protocol outlines an implementation study of a primary school-based MI intervention: CLASS PAL (Physically Active Learning) programme. This study aims to (A) determine the degree of implementation of CLASS PAL, (B) identify processes by which teachers and schools implement CLASS PAL and (C) investigate individual (pupil and teacher) level and school-level characteristics associated with implementation of CLASS PAL. METHODS AND ANALYSIS: The intervention will provide teachers with a professional development workshop and a bespoke teaching resources website. The study will use a single group before-and-after design, strengthened by multiple interim measurements. Six state-funded primary schools will be recruited within Leicestershire, UK.Evaluation data will be collected prior to implementation and at four discrete time points during implementation: At measurement 0 (October 2016), school, teacher and pupil characteristics will be collected. At measurements 0 and 3 (June-July 2017), accelerometry, cognitive functioning, self reported sitting and classroom engagement data will be collected. At measurements 1(December 2016-March 2017) and 3 , teacher interviews (also at measurement 4; September-October 2017) and pupil focus groups will be conducted, and at measurements 1 and 2 (April-May 2017), classroom observations. Implementation will be captured through website analytics and ongoing teacher completed logs. ETHICS AND DISSEMINATION: Ethical approval was obtained through the Loughborough University Human Participants Ethics Sub-Committee (Reference number: R16-P115). Findings will be disseminated via practitioner and/or research journals and to relevant regional and national stakeholders through print and online media and dissemination event(s). PMID- 29122810 TI - Bleeding Complications in Anticoagulated Patients With Atrial Fibrillation and Sepsis: A Propensity-Weighted Cohort Study. AB - BACKGROUND: Sepsis may adversely affect bleeding risk in anticoagulated patients with atrial fibrillation (AF), but the impact of warfarin treatment in such patients is poorly described. This registry-based nationwide cohort study examined safety of oral anticoagulant treatment (OAC) in patients with preexisting AF who were hospitalized because of incident sepsis in the period 2000-2015. METHODS AND RESULTS: We identified 3030 AF patients who were warfarin users at the time of sepsis diagnosis, and we used inverse probability of treatment weighting to compare the rates of bleeding, thromboembolic events, and death within 90 days after sepsis diagnosis with a comparable cohort of 55721 patients without warfarin treatment and known AF. Weighted 90-day bleeding rates were slightly higher among warfarin users compared with nonusers (0.14 versus 0.12 per 100 person-years), yielding a weighted hazard ratio of 1.19 (95% confidence interval, 1.00-1.41). Thromboembolic event rates during the 90-days after sepsis were marginally higher among warfarin users versus nonusers (0.04 versus 0.03; hazard ratio: 1.25, 95% confidence interval, 0.89-1.76), while the 90-day all-cause mortality was substantially lower among warfarin users (hazard ratio: 0.64, 95% confidence interval, 0.58-0.69). Various sensitivity analyses conducted to challenge the robustness these findings yielded results that were consistent with the main findings. CONCLUSIONS: AF patients who are on warfarin therapy at sepsis diagnosis experienced an increase in bleeding rates within the 3 months following sepsis. Warfarin use was associated with lower mortality, despite virtually comparable thromboembolic event rates. PMID- 29122811 TI - Comparison of Inappropriate Shocks and Other Health Outcomes Between Single- and Dual-Chamber Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death: Results From the Cardiovascular Research Network Longitudinal Study of Implantable Cardioverter-Defibrillators. AB - BACKGROUND: In US clinical practice, many patients who undergo placement of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death receive dual-chamber devices. The superiority of dual-chamber over single-chamber devices in reducing the risk of inappropriate ICD shocks in clinical practice has not been established. The objective of this study was to compare risk of adverse outcomes, including inappropriate shocks, between single- and dual-chamber ICDs for primary prevention. METHODS AND RESULTS: We identified patients receiving a single- or dual-chamber ICD for primary prevention who did not have an indication for pacing from 15 hospitals within 7 integrated health delivery systems in the Longitudinal Study of Implantable Cardioverter Defibrillators from 2006 to 2009. The primary outcome was time to first inappropriate shock. ICD shocks were adjudicated for appropriateness. Other outcomes included all-cause hospitalization, heart failure hospitalization, and death. Patient, clinician, and hospital-level factors were accounted for using propensity score weighting methods. Among 1042 patients without pacing indications, 54.0% (n=563) received a single-chamber device and 46.0% (n=479) received a dual-chamber device. In a propensity-weighted analysis, device type was not significantly associated with inappropriate shock (hazard ratio, 0.91; 95% confidence interval, 0.59-1.38 [P=0.65]), all-cause hospitalization (hazard ratio, 1.03; 95% confidence interval, 0.87-1.21 [P=0.76]), heart failure hospitalization (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21 [P=0.59]), or death (hazard ratio, 1.19; 95% confidence interval, 0.93-1.53 [P=0.17]). CONCLUSIONS: Among patients who received an ICD for primary prevention without indications for pacing, dual-chamber devices were not associated with lower risk of inappropriate shock or differences in hospitalization or death compared with single-chamber devices. This study does not justify the use of dual chamber devices to minimize inappropriate shocks. PMID- 29122813 TI - American Heart Association Principles on the Accessibility and Affordability of Drugs and Biologics: A Presidential Advisory From the American Heart Association. AB - Net US spending on pharmaceuticals reached $309.5 billion in 2015, an 8.5% increase from the year before, and is expected to reach between $370 and $400 billion by 2020. These current and projected levels have raised serious concerns by policy makers, providers, payers, and patient groups that they are unsustainable and threaten the affordability of and accessibility to much-needed therapies for patients. Two trends related to drugs/biologics and generic drugs/biosimilars underlie this overall increase in spending. First, the market entry prices of innovator pharmaceutical products, or brand drugs and biologics, are at levels that some assessments consider unaffordable to the healthcare system. Second, prices for some established generic drugs such as digoxin and captopril have seen sharp and rapid increases. As an evidence-based patient advocacy organization dedicated to improving the cardiovascular health of all Americans, the American Heart Association has a unique role in advocating for treatments, including medicines that are available, affordable, and accessible to patients. This advisory serves to lay out a set of principles that will guide association engagement in pursuit of this goal. PMID- 29122812 TI - Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure. AB - BACKGROUND: Vascular endothelial fibrinolytic function is impaired in adults with prehypertension and hypertension and plays a mechanistic role in the development of atherothrombotic events. The influence of beta-blockers on endothelial fibrinolysis is unknown. This study compared the effects of chronic nebivolol and metoprolol treatment on endothelial tissue-type plasminogen activator (t-PA) release in adults with elevated blood pressure (BP). METHODS AND RESULTS: Forty four middle-aged adults (36% women) with elevated BP completed a 3-month, double blind, randomized, placebo-controlled trial comparing nebivolol (5 mg/d), metoprolol succinate (100 mg/d), and placebo. Net endothelial t-PA release was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside before and after each intervention. In a subset, the dose response curves to bradykinin and sodium nitroprusside were repeated with a coinfusion of the antioxidant vitamin C. At baseline, resting BP and endothelial t-PA release were comparable between the 3 groups. BP decreased to a similar extent (~10 mm Hg) in the nebivolol- and metoprolol-treated groups. There was a substantial increase (~30%; P<0.05) in the capacity of the endothelium to release t-PA following chronic treatment with nebivolol but not metoprolol or placebo. Mitigating oxidant stress with vitamin C coinfusion potentiated t-PA release (90%; P<0.05) at baseline in all groups. However, after the intervention, t-PA release was unchanged by vitamin C coinfusion in the nebivolol group only. CONCLUSIONS: Nebivolol but not metoprolol improves endothelial t-PA release in adults with elevated BP. This may be an important vascular benefit of nebivolol. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01595516. PMID- 29122815 TI - Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression-Brief Report. AB - OBJECTIVE: To reanalyze data from recent randomized trials of statins to assess whether the benefits and risks of statins are mediated primarily via their LDL-C (low-density lipoprotein cholesterol) lowering effects or via other mechanisms. APPROACH AND RESULTS: We adapted Egger regression, a technique frequently used in Mendelian randomization studies to detect genetic pleiotropy, to reanalyze the available randomized control trial data of statin therapy. For cardiovascular end points, each 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 0.77 (95% confidence interval, 0.71-0.84) with an intercept that was indistinguishable from zero (intercept, -0.0032; [95% confidence interval, 0.090 to 0.084]; P=0.94), indicating no pleiotropy. For incident diabetes mellitus, a 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 1.07 (95% confidence interval, 0.99-1.16) and an intercept nondistinguishable from zero (intercept, -0.015; [95% confidence interval, -0.30 to 0.27]; P=0.91), again indicating no pleiotropy. CONCLUSIONS: Our reanalysis of the randomized control trial data using Egger regression adds to the existing evidence that the cardiovascular benefits of statins and their association with incident diabetes mellitus are mediated primarily, if not entirely, via their LDL C lowering properties rather than by any pleiotropic effects. PMID- 29122814 TI - Non-Endoplasmic Reticulum-Based Calr (Calreticulin) Can Coordinate Heterocellular Calcium Signaling and Vascular Function. AB - OBJECTIVE: In resistance arteries, endothelial cell (EC) extensions can make contact with smooth muscle cells, forming myoendothelial junction at holes in the internal elastic lamina (HIEL). At these HIEL, calcium signaling is tightly regulated. Because Calr (calreticulin) can buffer ~50% of endoplasmic reticulum calcium and is expressed throughout IEL holes in small arteries, the only place where myoendothelial junctions form, we investigated the effect of EC-specific Calr deletion on calcium signaling and vascular function. APPROACH AND RESULTS: We found Calr expressed in nearly every IEL hole in third-order mesenteric arteries, but not other ER markers. Because of this, we generated an EC-specific, tamoxifen inducible, Calr knockout mouse (EC Calr Delta/Delta). Using this mouse, we tested third-order mesenteric arteries for changes in calcium events at HIEL and vascular reactivity after application of CCh (carbachol) or PE (phenylephrine). We found that arteries from EC Calr Delta/Delta mice stimulated with CCh had unchanged activity of calcium signals and vasodilation; however, the same arteries were unable to increase calcium events at HIEL in response to PE. This resulted in significantly increased vasoconstriction to PE, presumably because of inhibited negative feedback. In line with these observations, the EC Calr Delta/Delta had increased blood pressure. Comparison of ER calcium in arteries and use of an ER-specific GCaMP indicator in vitro revealed no observable difference in ER calcium with Calr knockout. Using selective detergent permeabilization of the artery and inhibition of Calr translocation, we found that the observed Calr at HIEL may not be within the ER. CONCLUSIONS: Our data suggest that Calr specifically at HIEL may act in a non-ER dependent manner to regulate arteriolar heterocellular communication and blood pressure. PMID- 29122816 TI - Local Hemodynamic Forces After Stenting: Implications on Restenosis and Thrombosis. AB - Local hemodynamic forces are well-known to modulate atherosclerotic evolution, which remains one of the largest cause of death worldwide. Percutaneous coronary interventions with stent implantation restores blood flow to the downstream myocardium and is only limited by stent failure caused by restenosis, stent thrombosis, or neoatherosclerosis. Cumulative evidence has shown that local hemodynamic forces affect restenosis and the platelet activation process, modulating the pathophysiological mechanisms that lead to stent failure. This article first covers the pathophysiological mechanisms through which wall shear stress regulates arterial disease formation/neointima proliferation and the role of shear rate on stent thrombosis. Subsequently, the article reviews the current evidence on (1) the implications of stent design on the local hemodynamic forces, and (2) how stent/scaffold expansion can influence local flow, thereby affecting the risk of adverse events. PMID- 29122818 TI - Optical coherence tomographic angiography identifies peripapillary microvascular dilation and focal non-perfusion in giant cell arteritis. AB - AIMS: We set out to determine the optical coherence tomographic angiography (OCT A) characteristics of arteritic anterior ischaemic optic neuropathy (AAION) in the context of giant cell arteritis (GCA). METHODS: This is an observational case series of four patients with AAION secondary to GCA, three with unilateral AAION and one with bilateral AAION. We reviewed the charts, fundus photography, visual fields, fluorescein angiography (FA) and OCT-A images for all patients to identify a unifying theme in a range of AAION clinical severity. Imaging of two healthy control eyes from two patients of similar age to the patients in our series were used for comparison. RESULTS: Superficial peripapillary capillary dilation was seen in eyes with acute AAION. It was also noted in the fellow eyes of two patients. Retinal capillary perfusion defects corresponded to visual field loss. Dense optic disc oedema and cotton-wool spots imparted blockage effects. OCT-A laminar analysis did not highlight the choroidal/choriocapillaris perfusion defects seen on FA in two patients. Follow-up OCT-A was obtained in two patients and revealed progression to superficial peripapillary capillary attenuation that corresponded with visual field loss. CONCLUSIONS: There are acute and chronic vascular changes in AAION that are detectable by OCT-A that correspond with visual function. Though the microvascular changes seen in GCA and AAION are not specific, the nearly ubiquitous findings among preclinical and clinically affected eyes in this series of patients with GCA support OCT-A as a potentially useful adjunctive diagnostic test in the work-up of ambiguous cases of suspected ischaemic optic neuropathy. PMID- 29122819 TI - Treatment of conjunctival melanoma in a Dutch referral centre. AB - AIMS: To evaluate the treatment of conjunctival melanoma at a large Dutch referral centre and to make recommendations for clinical management. METHODS: A retrospective review was performed of clinical and histological data of 70 patients treated for a primary conjunctival melanoma between 2001 and 2014 at the Leiden University Medical Center, Leiden, the Netherlands. Detailed follow-up data were available for all patients. RESULTS: The mean follow-up time was 70.2 months. The overall 5-year recurrence rate was 29%, the 5-year metastasis rate 12% and the 5-year melanoma-related survival 90%. Treatment with excision alone had a significantly higher 5-year recurrence rate than (the combination of) other treatments (HR 3.73,95% CI 1.19 to 11.6, P=0.02). Initial treatment in an ocular oncology centre was associated with fewer recurrences compared with initial treatment by a local ophthalmologist of a referring centre (HR 0.32,95% CI 0.11 to 0.94, P=0.04), despite similar tumour baseline characteristics. CONCLUSION: Conjunctival melanoma is a rare disease with a high recurrence rate. A treatment strategy with local excision and adjuvant therapy gave a good clinical outcome, excision alone as a treatment should be considered obsolete. Initial treatment in a large referral centre improves clinical outcome, and patients should be referred to a specialised centre as soon as possible. PMID- 29122817 TI - Apo A-I (Apolipoprotein A-I) Vascular Gene Therapy Provides Durable Protection Against Atherosclerosis in Hyperlipidemic Rabbits. AB - OBJECTIVE: Gene therapy that expresses apo A-I (apolipoprotein A-I) from vascular wall cells has promise for preventing and reversing atherosclerosis. Previously, we reported that transduction of carotid artery endothelial cells with a helper dependent adenoviral (HDAd) vector expressing apo A-I reduced early (4 weeks) fatty streak development in fat-fed rabbits. Here, we tested whether the same HDAd could provide long-term protection against development of more complex lesions. APPROACH AND RESULTS: Fat-fed rabbits (n=25) underwent bilateral carotid artery gene transfer, with their left and right common carotids randomized to receive either a control vector (HDAdNull) or an apo A-I-expressing vector (HDAdApoAI). Twenty-four additional weeks of high-fat diet yielded complex intimal lesions containing lipid-rich macrophages as well as smooth muscle cells, often in a lesion cap. Twenty-four weeks after gene transfer, high levels of apo A-I mRNA (median >=250-fold above background) were present in all HDAdApoAI treated arteries. Compared with paired control HDAdNull-treated arteries in the same rabbit, HDAdApoAI-treated arteries had 30% less median intimal lesion volume (P=0.03), with concomitant reductions (23%-32%) in intimal lipid, macrophage, and smooth muscle cell content (P<=0.05 for all). HDAdApoAI-treated arteries also had decreased intimal inflammatory markers. VCAM-1 (vascular cell adhesion molecule 1)-stained area was reduced by 36% (P=0.03), with trends toward lower expression of ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein 1), and TNF-alpha (tumor necrosis factor-alpha; 13%-39% less; P=0.06 0.1). CONCLUSIONS: In rabbits with severe hyperlipidemia, transduction of vascular endothelial cells with an apo A-I-expressing HDAd yields at least 24 weeks of local apo A-I expression that durably reduces atherosclerotic lesion growth and intimal inflammation. PMID- 29122820 TI - Comparing a new hydroexpression technique with conventional forceps method for SMILE lenticule removal. AB - BACKGROUND: We described a modified 'hydroexpression' technique for the lenticule removal during small-incision lenticule extraction (SMILE) surgery and compared the results with conventional forceps method. METHODS: This was a retrospective, comparative study of 50 patients who underwent SMILE surgery by the same surgeon. We compared the 1-week and 3-months postoperative results after SMILE using the hydroexpression technique with the conventional forceps technique. Main outcome measures included uncorrected distance visual acuity, corrected distance visual acuity, refractive accuracy, safety index and efficacy index. RESULTS: The baseline characteristics were comparable between both groups. At postoperative 1 week, the safety index in forceps and hydroexpression group was 0.93+/-0.11 and 0.97+/-0.10, respectively (P=0.246). At 3 months, they were 1.00+/-0.06 and 0.99+/-0.09 (P=0.850). For efficacy indices, at 1 week they were 0.84+/-0.17 and 0.91+/-0.17 (P=0.158). At 3 months, they were 0.92+/-0.13 and 0.94+/-0.19 (P=0.624). All eyes aimed for a plano target. 96% in forceps group and 90% in hydroexpression group were within +/-0.50 dioptre (D) in spherical equivalent refraction (SEQ) correction at postoperative 3 months (P=0.567). The mean errors of SEQ correction were -0.10+/-0.21 D in forceps group and -0.08+/-0.30 D in hydroexpression group (P=0.705). CONCLUSION: Hydroexpression was simple and safe and had early results comparable to the conventional forceps technique. This technique was particularly useful for cases with more adhesions between lenticule and anterior cap, thin lenticule cases and for the inexperienced SMILE surgeons. PMID- 29122822 TI - Posterior keratoconus. AB - Posterior keratoconus (PKC) is a rare, typically non-inflammatory condition that is characterised by an abnormal posterior corneal curvature, which may be accompanied by overlying stromal opacification. It is usually congenital and can be associated with other ocular and systemic abnormalities. PKC remains a clinical diagnosis, although imaging techniques including ultrasound biomicroscopy and anterior segment optical coherence tomography may be useful tools for confirmation and classification. Genetic studies should be considered, although no specific genetic defects have been identified thus far. As a potential cause of amblyopia, early diagnosis and management are crucial in maximising visual potential. Occasionally, management considerations may also include surgical intervention, such as corneal transplantation. Intraocular lens power calculation at the time of cataract surgery requires special consideration. Here, we review the present literature on PKC and consider future directions in the management of this rare entity. PMID- 29122821 TI - Metagenomic deep sequencing of aqueous fluid detects intraocular lymphomas. AB - INTRODUCTION: Currently, the detection of pathogens or mutations associated with intraocular lymphomas heavily relies on prespecified, directed PCRs. With metagenomic deep sequencing (MDS), an unbiased high-throughput sequencing approach, all pathogens as well as all mutations present in the host's genome can be detected in the same small amount of ocular fluid. METHODS: In this cross sectional case series, aqueous fluid samples from two patients were submitted to MDS to identify pathogens as well as common and rare cancer mutations. RESULTS: MDS of aqueous fluid from the first patient with vitreal lymphoma revealed the presence of both Epstein-Barr virus (HHV-4/EBV) and human herpes virus 8 (HHV-8) RNA. Aqueous fluid from the second patient with intraocular B-cell lymphoma demonstrated a less common mutation in the MYD88 gene associated with B-cell lymphoma. CONCLUSION: MDS detects pathogens that, in some instances, may drive the development of intraocular lymphomas. Moreover, MDS is able to identify both common and rare mutations associated with lymphomas. PMID- 29122823 TI - Comparative evaluation of progression rate in keratoconus before and after collagen crosslinking. AB - PURPOSE: To compare the rate of disease progression in keratoconus before and after corneal collagen crosslinking (CXL). METHODS: 145 eyes were followed without CXL (no-CXL group) for a median duration of 31 months whereas 45 eyes were followed up for 41 months before (pre-CXL) and after (post-CXL) accelerated, epithelium-off crosslinking. Progression was defined based on significant slope found in linear mixed effect models against time. Swept-source optical coherence tomography was used for measurement of anterior steep keratometry, anterior flat keratometry (Ant Kf), anterior average keratometry (Ant Avg K); posterior steep keratometry, posteriorflat keratometry (Post Kf), posterior average keratometry (Post Avg K) and corneal thickness. RESULTS: The patients in pre-CXL group were significantly younger (26.3+/-5.48 years) compared with the patients in no-CXL group (32.7+/-10.24 years) (P=0.004). Significant differences were observed during baseline examination for all parameters (P<=0.035) between pre-CXL and no CXL groups except Ant Cyl and Post Cyl. During observation period, statistically significant differences were noted between pre-CXL and no-CXL groups in the progression rate of Ant Kf, Ant Avg K, Post Kf and Post Avg K (P<=0.045). After CXL, the progression rate in post-CXL group was comparable to that in no-CXL group. All corneal parameters remained stable in no-CXL group throughout the follow-up period. CONCLUSIONS: Serial tomographic examination is useful to document disease progression before and after CXL. In our study, a decrease in progression rate of corneal parameters was noted after CXL. In cases with stable corneal parameters over time, careful monitoring can be considered instead of collagen crosslinking. PMID- 29122824 TI - Ruthenium-106 brachytherapy for iris and iridociliary melanomas. AB - BACKGROUND AND PURPOSE: To evaluate ruthenium-106 (Ru106) brachytherapy as eye conserving treatment of iris melanomas (IMs) and iridociliary melanomas (ICMs). MATERIALS AND METHODS: Eighty-eight patients received Ru106 brachytherapy between 2006 and 2016. Primary outcome was local control, and secondary outcomes were metastasis, survival, eye preservation, complications and visual acuity (VA). RESULTS: Overall median follow-up was 36 months. Of 88 patients, 58 (65.9%) had IM and 30 (34.1%) had ICM. ICM were on average larger and more advanced than IM. Local failure-free survival at 3years was 98.9% (SE 1.2%). Metastasis-free survival was 98.2% (SE 1.8%) at 3years; no deaths due to melanoma occurred during follow-up. Eye preservation rate was 97.7%. Treatment-related toxicities were mostly mild and observed in 80.7% of the patients. Common toxicities were worsening of pre-existing or new cataract (51.1%), dry eyes (29.5%) and glaucoma (20.5%). VA was not affected by Ru106 brachytherapy, with only 2.3% having VA <0.33 (low vision) at follow-up. CONCLUSIONS: Ru106 for IM and ICM yielded excellent local control (98.9%) and eye preservation (97.7%). Toxicities were common, but mostly mild and transient. Moreover, Ru106 did not affect visual acuity. PMID- 29122825 TI - Controversies in PSA screening. PMID- 29122826 TI - Digging deep. PMID- 29122828 TI - Referrals to a perinatal specialist palliative care consult service in Ireland, 2012-2015. AB - OBJECTIVE: To analyse the referral patterns of perinatal patients referred to a specialist palliative care service (SPCS), their demographics, diagnoses, duration of illness, place of death and symptom profile. DESIGN: A retrospective chart review of all perinatal referrals over a 4-year period to the end of 2015. SETTING: A consultant-led paediatric SPCS at Our Lady's Children's Hospital, Crumlin, Dublin, and the Coombe Women & Infants University Hospital, Dublin. RESULTS: 83 perinatal referrals were received in a 4-year period. Chromosomal abnormalities accounted for 35% of diagnoses, congenital heart disease 25%, complex neurological abnormalities 11% and renal agenesis 4%. 22 referrals (26.5%) were made antenatally, with 61 (73.5%) postnatally. Of the postnatal referrals, 27 (44%) were asymptomatic on referral. An opioid medication was recommended (regularly or as required) in 46 cases. Symptom control was achieved without dose titration in 43 of these cases (93%). Of 47 deaths in this group referred postnatally, 22 of these (47%) died at home with support from community teams. Discharge home for best supportive care required complex interagency communication and cooperation. CONCLUSIONS: Perinatal palliative care requires effective multidisciplinary work, whether delivered in the inpatient setting or in the community. With appropriate support, end-of-life care can be delivered in the community. PMID- 29122827 TI - Fitness Costs and Variation in Transmission Distortion Associated with the Abnormal Chromosome 10 Meiotic Drive System in Maize. AB - Meiotic drive describes a process whereby selfish genetic elements are transmitted at levels greater than Mendelian expectations. Maize abnormal chromosome 10 (Ab10) encodes a meiotic drive system that exhibits strong preferential segregation through female gametes. We performed transmission assays on nine Ab10 chromosomes from landraces and teosinte lines and found a transmission advantage of 62-79% in heterozygotes. Despite this transmission advantage, Ab10 is present at low frequencies in natural populations, suggesting that it carries large negative fitness consequences. We measured pollen transmission, the percentage of live pollen, seed production, and seed size to estimate several of the possible fitness effects of Ab10. We found no evidence that Ab10 affects pollen transmission, i.e., Ab10 and N10 pollen are transmitted equally from heterozygous fathers. However, at the diploid (sporophyte) level, both heterozygous and homozygous Ab10-I-MMR individuals show decreased pollen viability, decreased seed set, and decreased seed weight. The observed fitness costs can nearly but not entirely account for the observed frequencies of Ab10. Sequence analysis shows a surprising amount of molecular variation among Ab10 haplotypes, suggesting that there may be other phenotypic variables that contribute to the low but stable equilibrium frequencies. PMID- 29122830 TI - Think about the 'C' (in custard and crackers). AB - CASE HISTORY: A 9-year-old girl with autistic spectrum disorder (ASD) was admitted for a flare-up of chronic recurrent multi-osteomyelitis (CRMO). She complained of leg pain over 3 months, was unable to weight-bear and had a petechial rash for 10 days. She had bleeding gums and a long history of only eating custard and crackers.CRMO was diagnosed at age 3. She'd had shoulder, knee, and ankle involvement, two courses of pamidronate (2011 and 2015) and was currently taking simple analgesia.On examination, she was afebrile, with a widespread petechial rash, most pronounced over her ankles/shins. Her knees and ankles were tender; her ankles had small medial effusions. INVESTIGATIONS: Mild hypochromic anaemia, normal platelets, white cell countand coagulation. CRP 16. Figures 1 and 2 show her knee radiograph and MRI, respectively.edpract;103/6/304/F1F1F1Figure 1edpract;103/6/304/F2F2F2Figure 2 QUESTION 1: Give four differential diagnoses of petechial rash, bleeding gums and leg pain in an afebrile child? QUESTION 2: Name three behaviours associated with ASD with health consequences. Answers to the questions are on page 02 ANSWERS TO THE QUESTIONS ON PAGE 02. PMID- 29122829 TI - Retrospective cohort analysis on pancreatic enzyme substitution in very low birthweight infants with postnatal growth failure. AB - OBJECTIVE: To evaluate the effects of pancreatic enzyme substitution (PES) in selected very low birthweight (VLBW) infants with poor postnatal growth despite intensified nutritional support. DESIGN: Retrospective historic cohort study with matched controls. SETTING: Single level III neonatal intensive care unit. PATIENTS: Infants with a gestational age at birth <32 weeks and birth weight <1500 g born between 1 January 2005 and 31 December 2014 (n=26) who received PES for restricted postnatal growth despite intensified enteral nutritional support in comparison with infants matched for birth weight, birth year, gestational and postnatal age (n=52). INTERVENTIONS: PES 15-93 mg/g fat with enteral feeds. MAIN OUTCOME MEASURES: The difference in SD score (SDS) differences for weight during the 7 days before and after onset of PES and weight gain in g/kg/d. Data are presented as median (P10-P90). RESULTS: Gestational age was 26.6 (24.4-29.9) weeks in enzyme substituted versus 26.4 (24.7-29.9) weeks in matched controls, and birth weight was 648(420-950)g versus 685(453-949)g. SDS differences for weight improved after onset of PES by 0.18(-0.12 to 0.53) in PES infants versus 0.04(-0.31 to 0.44) in controls. Weight gain increased in the PES group from 13.6 (4.2-22.9) g/kg/day in the week before to 19.0 (10.9-29.1) g/kg/day in the week after the onset of PES. There was no difference in weight gain in substituted subgroups receiving formula/pasteurised human milk versus unpasteurised human breast milk or who had pancreatic-specific elastase-1 concentrations in stool >200 ug/g versus<=200 ug/g. No adverse effects were noted. CONCLUSIONS: PES in selected VLBW infants with growth failure despite intensified enteral nutritional support was associated with a significant increase in weight gain in the first 7 days of PES.k. PMID- 29122831 TI - Fifteen-minute consultation: liver disease in children. AB - Liver disease in children can present in many ways from the frequently encountered prolonged neonatal jaundice to the comparatively rare acute liver failure. In this article, we will discuss 'red flags' of liver disease, the initial investigations required and when to refer to a specialist liver centre. Across all presentations, the degree of elevation of alanine aminotransferase or aspartate aminotransferase provides only little diagnostic information. Measurement of clotting is vital, and coagulopathy should be followed by a trial of intravenous vitamin K before being repeated. PMID- 29122832 TI - Fifteen-minute consultation: A child with a suspected drug allergy. AB - Adverse drug reactions are common in children, but true drug allergy is rare. It can be difficult to determine whether signs such as skin rashes are caused by the underlying illness or medications prescribed. Accurate diagnosis is important for patient safety and optimal treatment. We review the presentation of drug allergy and discuss current management options for children. PMID- 29122833 TI - Advanced therapies push regulatory boundaries: Novel therapeutic approaches require more regulatory flexibility and transparency. PMID- 29122834 TI - Liquid Biopsy in Prostate Cancer: A Case for Comprehensive Genomic Characterization of Circulating Tumor Cells. PMID- 29122835 TI - Multiple Hotspot Mutations Scanning by Single Droplet Digital PCR. AB - BACKGROUND: Progress in the liquid biopsy field, combined with the development of droplet digital PCR (ddPCR), has enabled noninvasive monitoring of mutations with high detection accuracy. However, current assays detect a restricted number of mutations per reaction. ddPCR is a recognized method for detecting alterations previously characterized in tumor tissues, but its use as a discovery tool when the mutation is unknown a priori remains limited. METHODS: We established 2 ddPCR assays detecting all genomic alterations within KRAS exon 2 and EGFR exon 19 mutation hotspots, which are of clinical importance in colorectal and lung cancer, with use of a unique pair of TaqMan(r) oligoprobes. The KRAS assay scanned for the 7 most common mutations in codons 12/13 but also all other mutations found in that region. The EGFR assay screened for all in-frame deletions of exon 19, which are frequent EGFR-activating events. RESULTS: The KRAS and EGFR assays were highly specific and both reached a limit of detection of <0.1% in mutant allele frequency. We further validated their performance on multiple plasma and formalin-fixed and paraffin-embedded tumor samples harboring a panel of different KRAS or EGFR mutations. CONCLUSIONS: This method presents the advantage of detecting a higher number of mutations with single-reaction ddPCRs while consuming a minimum of patient sample. This is particularly useful in the context of liquid biopsy because the amount of circulating tumor DNA is often low. This method should be useful as a discovery tool when the tumor tissue is unavailable or to monitor disease during therapy. PMID- 29122837 TI - Twenty-Seven Ways a Heat Wave Can Kill You: Deadly Heat in the Era of Climate Change. PMID- 29122836 TI - Multiplex Gene Expression Profiling of In Vivo Isolated Circulating Tumor Cells in High-Risk Prostate Cancer Patients. AB - BACKGROUND: Molecular characterization of circulating tumor cells (CTCs) is important for selecting patients for targeted treatments. We present, for the first time, results on gene expression profiling of CTCs isolated in vivo from high-risk prostate cancer (PCa) patients compared with CTC detected by 3 protein based assays-CellSearch(r), PSA-EPISPOT, and immunofluorescence of CellCollector(r) in vivo-captured CTCs-using the same blood draw. METHODS: EpCAM positive CTCs were isolated in vivo using the CellCollector from 108 high-risk PCa patients and 36 healthy volunteers. For 27 patients, samples were available before and after treatment. We developed highly sensitive multiplex RT-qPCR assays for 14 genes (KRT19, EpCAM, CDH1, HMBS, PSCA, ALDH1A1, PROM1, HPRT1, TWIST1, VIM, CDH2, B2M, PLS3, and PSA), including epithelial markers, stem cell markers, and epithelial-to-mesenchymal-transition (EMT) markers. RESULTS: We observed high heterogeneity in gene expression in the captured CTCs for each patient. At least 1 marker was detected in 74 of 105 patients (70.5%), 2 markers in 45 of 105 (40.9%), and 3 markers in 16 of 105 (15.2%). Epithelial markers were detected in 31 of 105 (29.5%) patients, EMT markers in 46 of 105 (43.8%), and stem cell markers in 15 of 105 (14.3%) patients. EMT-marker positivity was very low before therapy (2 of 27, 7.4%), but it increased after therapy (17 of 27, 63.0%), whereas epithelial markers tended to decrease after therapy (2 of 27, 7.4%) compared with before therapy (13 of 27, 48.1%). At least 2 markers were expressed in 40.9% of patients, whereas the positivity was 19.6% for CellSearch, 38.1% for EPISPOT, and 43.8% for CellCollector-based IF-staining. CONCLUSIONS: The combination of in vivo CTC isolation with downstream RNA analysis is highly promising as a high-throughput, specific, and ultrasensitive approach for multiplex liquid biopsy-based molecular diagnostics. PMID- 29122838 TI - Soluble CD80 Protein Delays Tumor Growth and Promotes Tumor-Infiltrating Lymphocytes. AB - Tumor cells use various immune-suppressive strategies to overcome antitumor immunity. One such method is tumor expression of programmed death ligand-1 (PD L1), which triggers apoptotic death or anergy upon binding programmed death-1 (PD 1) on T cells. Our previous in vitro cellular studies with human and mouse PD-L1+ tumor cells demonstrated that a soluble form of the costimulatory molecule CD80 prevented PD-L1-mediated immune suppression and restored T-cell activation by binding PD-L1 and blocking interaction with PD-1. We now report that in vivo treatment of established syngeneic PD-L1+ CT26 colon carcinoma and B16F10 melanoma tumors with CD80-Fc delays tumor growth and promotes tumor-infiltrating T cells. Studies with PD-1-/- and CD28-/- mice demonstrate that soluble CD80 acts in vivo by simultaneously neutralizing PD-1 suppression and activating through CD28. We also report that soluble CD80 mediates its effects by activating transcription factors EGR1-4, NF-kappaB, and MAPK, downstream signaling components of the CD28 and T-cell receptor pathways. Soluble CD80 binds to CTLA-4 on activated human peripheral blood mononuclear cells. However, increasing quantities of CTLA-4 antagonist antibodies do not increase T-cell activation. These results indicate that soluble CD80 does not suppress T-cell function through CTLA-4 and suggest that CTLA-4 acts as a decoy receptor for CD80, rather than functioning as a suppressive signaling receptor. Collectively, these studies demonstrate that soluble CD80 has therapeutic efficacy in vivo in mouse tumor systems and that its effects are due to its ability to inhibit PD-1-mediated suppression while concurrently activating T cells through CD28. Cancer Immunol Res; 6(1); 59-68. (c)2017 AACR. PMID- 29122840 TI - Juvenile hormone signaling in short germ-band hemimetabolan embryos. AB - The role of juvenile hormone (JH) in insect embryos is far from understood, especially in short germ-band hemimetabolan species. To shed light on this issue, we depleted the mRNA levels of Kruppel homolog 1, Methoprene-tolerant and JH acid O-methyltransferase, key elements of JH signaling, in embryos of the short germ band hemimetabolan species Blattella germanica This precluded the formation of the germ-band anlage in a group of embryos. Hatchability was also reduced, which might have been caused by premature upregulation of laccase 2, a promoter of cuticle tanning. In other cases, development was interrupted in mid embryogenesis, involving defects related to dorsal closure and appendage formation. These phenotypes possibly result from the low levels of Broad-complex (BR-C) produced under JH-depleted conditions. This contrasts with holometabolan species, in which JH does not promote BR-C expression, which remains low during embryo development. Possibly, the stimulatory role of JH on BR-C expression and the morphogenetic functions of BR-C in hemimetabolan embryos were lost in holometabolan species. If so, this might have been a key driver for the evolution of holometabolan metamorphosis. PMID- 29122839 TI - FGF receptors control alveolar elastogenesis. AB - Alveologenesis, the final step of lung development, is characterized by the formation of millions of alveolar septa that constitute the vast gas-exchange surface area. The genetic network driving alveologenesis is poorly understood compared with earlier steps in lung development. FGF signaling through receptors Fgfr3 and Fgfr4 is crucial for alveologenesis, but the mechanisms through which they mediate this process remain unclear. Here we show that in Fgfr3;Fgfr4 (Fgfr3;4) global mutant mice, alveolar simplification is first observed at the onset of alveologenesis at postnatal day 3. This is preceded by disorganization of elastin, indicating defects in the extracellular matrix (ECM). Although Fgfr3 and Fgfr4 are expressed in the mesenchyme and epithelium, inactivation in the mesenchyme, but not the epithelium, recapitulated the defects. Expression analysis of components of the elastogenesis machinery revealed that Mfap5 (also known as Magp2), which encodes an elastin-microfibril bridging factor, is upregulated in Fgfr3;4 mutants. Mfap5 mutation in the Fgfr3;4 mutant background partially attenuated the alveologenesis defects. These data demonstrate that, during normal lung maturation, FGF signaling restricts expression of the elastogenic machinery in the lung mesenchyme to control orderly formation of the elastin ECM, thereby driving alveolar septa formation to increase the gas exchange surface. PMID- 29122842 TI - Noninvasive Imaging Post-ST-Segment-Elevation Myocardial Infarction: Towards Targeted Therapy or Targeted End Points? PMID- 29122841 TI - Hedgehog participates in the establishment of left-right asymmetry during amphioxus development by controlling Cerberus expression. AB - Correct patterning of left-right (LR) asymmetry is essential during the embryonic development of bilaterians. Hedgehog (Hh) signaling is known to play a role in LR asymmetry development of mouse, chicken and sea urchin embryos by regulating Nodal expression. In this study, we report a novel regulatory mechanism for Hh in LR asymmetry development of amphioxus embryos. Our results revealed that Hh-/- embryos abolish Cerberus (Cer) transcription, with bilaterally symmetric expression of Nodal, Lefty and Pitx In consequence, Hh-/- mutants duplicated left side structures and lost right-side characters, displaying an abnormal bilaterally symmetric body plan. These LR defects in morphology and gene expression could be rescued by Hh mRNA injection. Our results indicate that Hh participates in amphioxus LR patterning by controlling Cer gene expression. Curiously, however, upregulation of Hh signaling failed to alter the Cer expression pattern or LR morphology in amphioxus embryos, indicating that Hh might not provide an asymmetric cue for Cer expression. In addition, Hh is required for mouth opening in amphioxus, hinting at a homologous relationship between amphioxus and vertebrate mouth development. PMID- 29122844 TI - Optimized Prognosis Assessment in ST-Segment-Elevation Myocardial Infarction Using a Cardiac Magnetic Resonance Imaging Risk Score. AB - BACKGROUND: Cardiac magnetic resonance (CMR) demonstrated great potential for the prediction of major adverse cardiac events (MACE) in ST-segment-elevation myocardial infarction. The aim of this study was to develop and validate a CMR based risk score for ST-segment-elevation myocardial infarction patients. METHODS AND RESULTS: The scoring model was developed and validated on ST-segment elevation myocardial infarction cohorts from 2 independent randomized controlled trials (n=738 and n=458 patients, respectively) and included left ventricular (LV) ejection fraction, infarct size, and microvascular obstruction. Primary end point was the 12-month MACE rate consisting of death, reinfarction, and new congestive heart failure. In the derivation cohort, LV ejection fraction <=47%, infarct size >=19%LV, and microvascular obstruction >=1.4%LV were identified as the best cutoff values for MACE prediction. According to the hazard ratios in multivariable regression analysis, the CMR risk score was created by attributing 1 point for LV ejection fraction <=47%, 1 point for infarct size >=19%LV, and 2 points for microvascular obstruction >=1.4%LV. In the validation cohort, the score showed a good prediction of MACE (area under the curve: 0.76). Stratification into a low (0/1 point) and high-risk group (>=2 points) resulted in significantly higher MACE rates in high-risk patients (9.0% versus 2.2%; P=0.001). Inclusion of the CMR score in addition to a model of clinical risk factors led to a significant increase of C statistics from 0.74 to 0.83 (P=0.037), a net reclassification improvement of 0.18 (P=0.009), and an integrated discriminative improvement of 0.04 (P=0.010). CONCLUSIONS: Our approach integrates the prognostic information of CMR imaging into a simple risk score that showed incremental prognostic value over clinical risk factors in ST segment-elevation myocardial infarction patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00712101 and NCT02158468. PMID- 29122843 TI - Multiorgan, Multimodality Imaging in Cardiometabolic Disease. AB - Cardiometabolic disease, spanning conditions such as obesity to type 2 diabetes mellitus with excess cardiovascular risk, represents a major public health burden. Advances in preclinical translational science point to potential targets across multiple organ systems for early intervention to improve cardiometabolic health. Validation in clinical trials and translation to care would benefit from in vivo diagnostic techniques that facilitate therapeutic advancements. This review provides a state-of-the-art, multimodality perspective spanning the multiple organ systems that contribute to cardiometabolic disease. PMID- 29122845 TI - Ascending Aortic Dimensions in Former National Football League Athletes. AB - BACKGROUND: Ascending aortic dimensions are slightly larger in young competitive athletes compared with sedentary controls, but rarely >40 mm. Whether this finding translates to aortic enlargement in older, former athletes is unknown. METHODS AND RESULTS: This cross-sectional study involved a sample of 206 former National Football League (NFL) athletes compared with 759 male subjects from the DHS-2 (Dallas Heart Study-2; mean age of 57.1 and 53.6 years, respectively, P<0.0001; body surface area of 2.4 and 2.1 m2, respectively, P<0.0001). Midascending aortic dimensions were obtained from computed tomographic scans performed as part of a NFL screening protocol or as part of the DHS. Compared with a population-based control group, former NFL athletes had significantly larger ascending aortic diameters (38+/-5 versus 34+/-4 mm; P<0.0001). A significantly higher proportion of former NFL athletes had an aorta of >40 mm (29.6% versus 8.6%; P<0.0001). After adjusting for age, race, body surface area, systolic blood pressure, history of hypertension, current smoking, diabetes mellitus, and lipid profile, the former NFL athletes still had significantly larger ascending aortas (P<0.0001). Former NFL athletes were twice as likely to have an aorta >40 mm after adjusting for the same parameters. CONCLUSIONS: Ascending aortic dimensions were significantly larger in a sample of former NFL athletes after adjusting for their size, age, race, and cardiac risk factors. Whether this translates to an increased risk is unknown and requires further evaluation. PMID- 29122846 TI - Is Big Truly Bad? Aortic Dilation in Former National Football League Players. PMID- 29122847 TI - Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by the deposition of excessive extracellular matrix and the destruction of lung parenchyma, resulting from an aberrant wound-healing response. Although IPF is often associated with an imbalance in protease activity, the mechanisms underlying the sustained repair mechanisms are not fully understood. Here, we addressed the role of the recently identified, membrane-anchored serine protease human airway trypsin-like protease (HAT). In the present study, we show that both HAT expression and activity were up-regulated in human IPF specimens. Next, adenoviral overexpression of HAT before bleomycin challenge attenuated lung injury as well as extracellular matrix deposition in the bleomycin-induced pulmonary fibrosis model. In vitro, HAT prevented specific fibrosis-associated responses in primary human pulmonary fibroblasts and induced the expression of mediators associated with the prostaglandin E2 pathway. Altogether, our findings suggested that HAT could have a protective role in IPF and other fibrotic lung disorders.-Menou, A., Flajolet, P., Duitmen, J., Justet, A., Moog, S., Jaillet, M., Tabeze, L., Solhonne, B., Garnier, M., Mal, H., Mordant, P., Castier, Y., Cazes, A., Sallenave, J.-M., Mailleux, A. A., Crestani, B. Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis. PMID- 29122849 TI - Modeling the Evolution of Female Meiotic Drive in Maize. AB - Autosomal drivers violate Mendel's law of segregation in that they are overrepresented in gametes of heterozygous parents. For drivers to be polymorphic within populations rather than fixing, their transmission advantage must be offset by deleterious effects on other fitness components. In this paper, we develop an analytical model for the evolution of autosomal drivers that is motivated by the neocentromere drive system found in maize. In particular, we model both the transmission advantage and deleterious fitness effects on seed viability, pollen viability, seed to adult survival mediated by maternal genotype, and seed to adult survival mediated by offspring genotype. We derive general, biologically intuitive conditions for the four most likely evolutionary outcomes and discuss the expected evolution of autosomal drivers given these conditions. Finally, we determine the expected equilibrium allele frequencies predicted by the model given recent estimates of fitness components for all relevant genotypes and show that the predicted equilibrium is within the range observed in maize land races for levels of drive at the low end of what has been observed. PMID- 29122848 TI - Reducing insulin via conditional partial gene ablation in adults reverses diet induced weight gain. AB - Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor ( Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circulating insulin that are too fine to adversely affect glucose homeostasis nonetheless exert control over adiposity.-Page, M. M., Skovso, S., Cen, H., Chiu, A. P., Dionne, D. A., Hutchinson, D. F., Lim, G. E., Szabat, M., Flibotte, S., Sinha, S., Nislow, C., Rodrigues, B., Johnson, J. D. Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain. PMID- 29122850 TI - Differential preventive activity of sulindac and atorvastatin in Apc+/Min FCCCmice with or without colorectal adenomas. AB - OBJECTIVE: The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation. DESIGN: Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both. RESULTS: The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of Hoxb13 and Rprm significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1). CONCLUSIONS: The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent. PMID- 29122852 TI - An unstable knee. PMID- 29122851 TI - Guidelines on the management of abnormal liver blood tests. AB - These updated guidelines on the management of abnormal liver blood tests have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines, which this document supersedes, were written in 2000 and have undergone extensive revision by members of the Guidelines Development Group (GDG). The GDG comprises representatives from patient/carer groups (British Liver Trust, Liver4life, PBC Foundation and PSC Support), elected members of the BSG liver section (including representatives from Scotland and Wales), British Association for the Study of the Liver (BASL), Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England (implementation and screening), Royal College of General Practice, British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and Society of Acute Medicine. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. These guidelines deal specifically with the management of abnormal liver blood tests in children and adults in both primary and secondary care under the following subheadings: (1) What constitutes an abnormal liver blood test? (2) What constitutes a standard liver blood test panel? (3) When should liver blood tests be checked? (4) Does the extent and duration of abnormal liver blood tests determine subsequent investigation? (5) Response to abnormal liver blood tests. They are not designed to deal with the management of the underlying liver disease. PMID- 29122853 TI - Genome-Wide Screen for Saccharomyces cerevisiae Genes Contributing to Opportunistic Pathogenicity in an Invertebrate Model Host. AB - Environmental opportunistic pathogens can exploit vulnerable hosts through expression of traits selected for in their natural environments. Pathogenicity is itself a complicated trait underpinned by multiple complex traits, such as thermotolerance, morphology, and stress response. The baker's yeast, Saccharomyces cerevisiae, is a species with broad environmental tolerance that has been increasingly reported as an opportunistic pathogen of humans. Here we leveraged the genetic resources available in yeast and a model insect species, the greater waxmoth Galleria mellonella, to provide a genome-wide analysis of pathogenicity factors. Using serial passaging experiments of genetically marked wild-type strains, a hybrid strain was identified as the most fit genotype across all replicates. To dissect the genetic basis for pathogenicity in the hybrid isolate, bulk segregant analysis was performed which revealed eight quantitative trait loci significantly differing between the two bulks with alleles from both parents contributing to pathogenicity. A second passaging experiment with a library of deletion mutants for most yeast genes identified a large number of mutations whose relative fitness differed in vivovs.in vitro, including mutations in genes controlling cell wall integrity, mitochondrial function, and tyrosine metabolism. Yeast is presumably subjected to a massive assault by the innate insect immune system that leads to melanization of the host and to a large bottleneck in yeast population size. Our data support that resistance to the innate immune response of the insect is key to survival in the host and identifies shared genetic mechanisms between S. cerevisiae and other opportunistic fungal pathogens. PMID- 29122855 TI - Complete Annotated Genome Sequences of Four Klebsiella pneumoniae Phages Isolated from Sewage in Poland. AB - Four lytic phages, vB_KpnP_BIS33, vB_KpnP_IL33, and vB_KpnP_PRA33 of the Podoviridae family and vB_KpnM_BIS47 of the Myoviridae family, which act against animal-pathogenic Klebsiella pneumoniae strains, were isolated from sewage plants in Poland. They possess double-stranded DNA genomes of 41,697 bp, 41,335 bp, 40,605 bp, and 147,443 bp, respectively. PMID- 29122854 TI - The Substrates of Nonsense-Mediated mRNA Decay in Caenorhabditis elegans. AB - Nonsense-mediated mRNA decay (NMD) is a conserved pathway that strongly influences eukaryotic gene expression. Inactivating or inhibiting NMD affects the abundance of a substantial fraction of the transcriptome in numerous species. Transcripts whose abundance is altered in NMD-deficient cells may represent either direct substrates of NMD or indirect effects of inhibiting NMD. We present a genome-wide investigation of the direct substrates of NMD in Caenorhabditis elegans Our goals were (i) to identify mRNA substrates of NMD and (ii) to distinguish those mRNAs from others whose abundance is indirectly influenced by the absence of NMD. We previously demonstrated that Upf1p/SMG-2, the central effector of NMD in all studied eukaryotes, preferentially associates with mRNAs that contain premature translation termination codons. We used this preferential association to distinguish direct from indirect effects by coupling immunopurification of Upf1/SMG-2 with high-throughput mRNA sequencing of NMD deficient mutants and NMD-proficient controls. We identify 680 substrates of NMD, 171 of which contain novel spliced forms that (i) include sequences of annotated introns and (ii) have not been previously documented in the C. elegans transcriptome. NMD degrades unproductively spliced mRNAs with sufficient efficiency in NMD-proficient strains that such mRNAs were not previously known. Two classes of genes are enriched among the identified NMD substrates: (i) mRNAs of expressed pseudogenes and (ii) mRNAs of gene families whose gene number has recently expanded in the C. elegans genome. Our results identify novel NMD substrates and provide a context for understanding NMD's role in normal gene expression and genome evolution. PMID- 29122856 TI - First Draft Genome Sequences of Three Strains of Francisella tularensis subsp. holarctica, Isolated from Hares and a Tick in France. AB - Here, we report the complete genome sequences of three strains of Francisella tularensis subsp. holarctica (11-789-5S, 11-935-13S, and 11-930-9S), isolated from brown hares and a tick during a tularemia outbreak in France, where tularemia is endemic. PMID- 29122857 TI - Complete Genome Sequence of Klebsiella pneumoniae Phages SopranoGao, MezzoGao, and AltoGao. AB - The Klebsiella pneumoniae phages SopranoGao, MezzoGao, and AltoGao were isolated from the Seneca Wastewater Treatment Plant in Germantown, MD. The following reports the complete genome sequence of these bacteriophages and describes their major features. PMID- 29122859 TI - Genome Sequences of 12 Cluster AN Arthrobacter Phages. AB - Twelve siphoviral phages isolated using Arthrobacter sp. strain ATCC 21022 were sequenced. The phages all have relatively small genomes, ranging from 15,319 to 15,556 bp. All 12 phages are closely related to previously described cluster AN Arthrobacter phages. PMID- 29122858 TI - Genome Sequences of Chancellor, Mitti, and Wintermute, Three Subcluster K4 Phages Isolated Using Mycobacterium smegmatis mc2155. AB - Mycobacteriophages Chancellor, Mitti, and Wintermute infect Mycobacterium smegmatis mc2155 and are closely related to phages Cheetobro and Fionnbharth in subcluster K4. Genome sizes range from 57,697 bp to 58,046 bp. Phages are predicted to be temperate and to infect the pathogen Mycobacterium tuberculosis. PMID- 29122860 TI - Genome Sequences of Three Cluster AU Arthrobacter Phages, Caterpillar, Nightmare, and Teacup. AB - Caterpillar, Nightmare, and Teacup are cluster AU siphoviral phages isolated from enriched soil on Arthrobacter sp. strain ATCC 21022. These genomes are 58 kbp long with an average G+C content of 50%. Sequence analysis predicts 86 to 92 protein-coding genes, including a large number of small proteins with predicted transmembrane domains. PMID- 29122861 TI - Genome Sequences of Subcluster K5 Mycobacteriophages AlleyCat, Edugator, and Guillsminger. AB - Bacteriophages AlleyCat, Edugator, and Guillsminger were isolated on Mycobacterium smegmatis mc2155 from enriched soil samples. All are members of mycobacteriophage subcluster K5, with genomes of 62,112 to 63,344 bp. Each genome contains 92 to 99 predicted protein-coding genes and one tRNA. Guillsminger is the first mycobacteriophage to carry an IS1380 family transposon. PMID- 29122862 TI - Genome Sequences of Mycobacteriophages Findley, Hurricane, and TBond007. AB - We report here the genome sequences of three newly isolated phages that infect Mycobacterium smegmatis mc2155. Phages Findley, Hurricane, and TBond007 were discovered in geographically distinct locations and are related to cluster K mycobacteriophages, with Findley being similar to subcluster K2 phages and Hurricane and TBond007 being similar to subcluster K3 phages. PMID- 29122863 TI - Complete Genome Sequence of Indigo-Producing Bacterium Celeribacter sp. Strain TSPH2. AB - Celeribacter sp. strain TSPH2, a novel producer of indigo, was isolated from oil contaminated sediment. We present here its genome sequence consisting of one circular chromosome (4 Mb) and one plasmid (0.15 Mb), with an overall G+C content of 60.9%. This strain contains oxygenase genes involved in indigo synthesis, such as flavin-containing monooxygenase. PMID- 29122865 TI - Draft Genome Sequence of Burkholderia contaminans 293K04B, an Endosymbiont of the Sponge-Derived Fungus Stachylidium bicolor. AB - Here, we present the draft genome of the endofungal symbiotic bacterium Burkholderia contaminans 293K04B, isolated from Stachylidium bicolor 293K04 (Ascomycota). The fungus was originally isolated from the sponge Callyspongia cf. C. flammeaS. bicolor 293K04 produces the endolides A-B, bioactive cyclic peptides possibly biosynthesized by its endobacterium B. contaminans 293K04B. PMID- 29122866 TI - Genome Sequence of a Porcine Bocavirus Detected in Feces of Domestic Minks in China. AB - We report here the genome sequence of porcine bocavirus strain PBov-JZ08, which was isolated from mink feces in China. Sequence analysis implied that PBov-JZ08 clustered with three porcine bocaviruses. PMID- 29122867 TI - Draft Genome Sequence of a Methicillin-Resistant Sequence Type 39 Staphylococcal Isolate Obtained from Seafood. AB - The draft genome sequence of a methicillin-resistant Staphylococcus aureus (MRSA) sequence type 39 (ST 39) isolate obtained from the dried ribbonfish of Gujarat, India, is reported here. Staphylococcus-specific genes were present in this MRSA isolate. The whole-genome sequence of this strain contains 2,693 protein-coding genes and 70 RNAs within the 2.82-Mb genome. PMID- 29122864 TI - Complete Genome Sequences of Mycobacteriophages Clautastrophe, Kingsolomon, Krypton555, and Nicholas. AB - We report here the complete genome sequences of four subcluster L3 mycobacteriophages newly isolated from soil samples, using Mycobacterium smegmatis mc2155 as the host. Comparative genomic analyses with four previously described subcluster L3 phages reveal strong nucleotide similarity and gene conservation, with several large insertions/deletions near their right genome ends. PMID- 29122868 TI - Genome Sequence of Fusarium graminearum ITEM 124 (ATCC 56091), a Mycotoxigenic Plant Pathogen. AB - Fusarium graminearum is among the main causal agents of Fusarium head blight (FHB), or scab, of wheat and other cereals, caused by a complex of Fusarium species, worldwide. Besides causing economic losses in terms of crop yield and quality, F. graminearum poses a severe threat to animal and human health. Here, we present the first draft whole-genome sequence of the mycotoxigenic Fusarium graminearum strain ITEM 124, also providing useful information for comparative genomics studies. PMID- 29122869 TI - Complete Genome Sequence of Streptococcus thermophilus Strain B59671, Which Naturally Produces the Broad-Spectrum Bacteriocin Thermophilin 110. AB - Streptococcus thermophilus strain B59671 is a Gram-positive lactic acid bacterium that naturally produces a broad-spectrum bacteriocin, thermophilin 110, and is capable of producing gamma-aminobutyric acid (GABA). The complete genome sequence for this strain contains 1,821,173 nucleotides, 1,936 predicted genes, and an average G+C content of 39.1%. PMID- 29122870 TI - Draft Genome Sequences of Clinical and Nonclinical Isolates of Klebsiella spp. Exhibiting Nonheritable Tolerance toward Antimicrobial Compounds. AB - A clinical isolate and a nonclinical isolate of Klebsiella pneumoniae were found to exhibit nonheritable tolerance in response to antimicrobial compounds. The draft genome sequences of both isolates are presented here. PMID- 29122871 TI - Draft Genome Sequences of Nonclinical and Clinical Enterobacter cloacae Isolates Exhibiting Multiple Antibiotic Resistance and Virulence Factors. AB - Enterobacter spp. have been implicated as opportunistic pathogens which over the years have gained resistance toward most of the available therapeutic drugs. We sequenced two multidrug-resistant Enterobacter cloacae isolates harboring multiple efflux pump genes. These isolates exhibited strain-specific modulation of efflux pump protein expression. PMID- 29122872 TI - Genome Sequence of the Alcelaphine Gammaherpesvirus 1 Attenuated Laboratory Strain WC11. AB - The complete genome sequence of the alcelaphine gammaherpesvirus 1 (AIHV-1) attenuated laboratory strain WC11 was determined from purified virion DNA. The viral light DNA (L-DNA) genome of 127,215 bp is mostly conserved compared to the pathogenic strain C500; however, 3.3 kb is deleted in two regions, affecting 4 of 10 AIHV-1-specific open reading frames. PMID- 29122873 TI - Draft Genome Sequences of Ciprofloxacin-Resistant Salmonella enterica Strains with Multiple-Antibiotic Resistance, Isolated from Imported Foods. AB - We report here the draft genome sequences of 15 ciprofloxacin-resistant Salmonella enterica strains with resistance to multiple other antibiotics, including aminoglycosides, beta-lactams, sulfonamides, tetracycline, and trimethoprim, isolated from different imported foods. Three strains (NCTR75, NCTR281, and NCTR350) showed a high level of ciprofloxacin resistance compared to that of the other isolates. The whole-genome sequencing data provide a better understanding of the antibiotic resistance mechanisms and virulence properties of these isolates. PMID- 29122874 TI - Whole-Genome Sequences of Variants of Bacillus anthracis Sterne and Their Toxin Gene Deletion Mutants. AB - Here, we report the draft genome sequences of three laboratory variants of Bacillus anthracis Sterne and their double (Deltalef Deltacya) and triple (Deltapag Deltalef Deltacya) toxin gene deletion derivatives. PMID- 29122875 TI - Complete Genome Sequences of Three Border Disease Virus Strains of the Same Subgenotype, BDSwiss, Isolated from Sheep, Cattle, and Pigs in Switzerland. AB - We report here the complete genome sequences of three border disease virus (BDV) strains of the same subgenotype isolated in Switzerland from a sheep, a cow, and a pig, respectively. This is the first report of full-length sequences of a tentatively new subgenotype isolated from three different species of cloven hoofed farm animals. PMID- 29122876 TI - Genome Sequence of Foot-and-Mouth Disease Virus of Serotype O Lineage Ind-2001d Isolated from Cattle in Mongolia in 2015. AB - We report the whole-genome sequence of the foot-and-mouth disease virus (FMDV) O/MOG/BU/2-7/2015 isolated in Mongolia in 2015. This virus is closely related to isolates identified in Southeast Asia in 2015 and is classified under the O/ME SA/Ind-2001d lineage. This is the first detection of an FMDV of this lineage in Mongolia. PMID- 29122877 TI - Draft Genome Sequences of Three Terrestrial Isoprene-Degrading Rhodococcus Strains. AB - Isoprene is produced in abundance by plants and constitutes a carbon source for microbes. The genomes of three isoprene degraders isolated from tree leaves or soil from the campus of the University of East Anglia were sequenced. These high GC-content isolates are actinobacteria belonging to the genus Rhodococcus. PMID- 29122878 TI - Complete Genome Sequence of Bacillus altitudinis Type Strain SGAir0031 Isolated from Tropical Air Collected in Singapore. AB - Bacillus altitudinis strain SGAir0031 (Firmicutes) was isolated from tropical air samples collected in Singapore. Its genome was assembled using short reads and single-molecule real-time sequencing, comprising one chromosome with 3.81 Mb and one plasmid with 32 kb. The genome consists of 3,820 protein-coding genes, 81 tRNAs, and 24 rRNAs. PMID- 29122879 TI - Complete Genome Sequence of the Fruiting Myxobacterium Melittangium boletus DSM 14713. AB - The formation of spore-filled fruiting bodies in response to starvation represents a hallmark of many members of the order Myxococcales Here, we present the complete 9.9-Mb genome of the fruiting type strain Melittangium boletus DSM 14713, the first member of this genus to have its genome sequenced. PMID- 29122880 TI - Draft Genome Sequence of Novosphingobium panipatense Strain P5:ABC, Isolated from Hydrocarbon-Contaminated Soil from Noonmati Refinery, Assam, India. AB - Novosphingobium panipatense P5:ABC is a hydrocarbon-degrading bacterium isolated from petroleum-contaminated soil. Here, we present the 5.74-Mb draft genome sequence with 5,206 genes and an average G+C content of 64.7%. The genomic information will improve our understanding of the diversity of N. panipatense and the mechanisms of microbe-based hydrocarbon degradation. PMID- 29122881 TI - Whole-Genome Sequencing of a Human Clinical Isolate of emm28 Streptococcus pyogenes Causing Necrotizing Fasciitis Acquired Contemporaneously with Hurricane Harvey. AB - We discovered an emm28 Streptococcus pyogenes isolate causing necrotizing fasciitis in a patient exposed to the floodwaters of Hurricane Harvey in the Houston, TX, metropolitan area in August 2017. The Oxford Nanopore MinION instrument provided sufficient genome sequence data within 1 h of beginning sequencing to close the genome. PMID- 29122882 TI - Complete Genome Sequence of a Novel Strain of Infectious Bronchitis Virus, Isolated from Chickens in China in 2016. AB - An avian infectious bronchitis virus (IBV) was detected from trachea swabs of chickens in Hubei province, China, in 2016. The complete genome of the IBV strain, CK/CH/HB/2016, was characterized and analyzed to better understand IBV epidemiology in China. PMID- 29122883 TI - Whole-Genome Sequencing of Lactobacillus Species from Two Commercial Probiotic Products. AB - Eight Lactobacillus strains, each intrinsically resistant to an antibiotic, were isolated from two commercial probiotic products. Whole-genome sequencing identified two efflux transporters, a multidrug and extrusion protein (MATE) efflux transporter, and LmrCD, which may contribute to their intrinsic antibiotic resistance and may therefore facilitate their survival in the intestinal microbiota following antibiotic therapy. PMID- 29122884 TI - Complete Genome Sequence of a Novel Human Papillomavirus Isolated from Oral Rinse. AB - A novel human papillomavirus (HPV TG550) isolated from the oral rinse of a Chinese male resident was fully characterized. The L1 open reading frame of HPV TG550 shares 82.5% nucleotide sequence similarity with its closest relative, HPV166, and clusters within the species group Gammapapillomavirus 19. PMID- 29122885 TI - C/EBPalpha transcription factor is regulated by the RANK cytoplasmic 535IVVY538 motif and stimulates osteoclastogenesis more strongly than c-Fos. AB - Binding of receptor activator of NF-kappaB ligand (RANKL) to its receptor RANK on osteoclast (OC) precursors up-regulates c-Fos and CCAAT/enhancer-binding protein alpha (C/EBPalpha), two critical OC transcription factors. However, the effects of c-Fos and C/EBPalpha on osteoclastogenesis have not been compared. Herein, we demonstrate that overexpression of c-Fos or C/EBPalpha in OC precursors up regulates OC genes and initiates osteoclastogenesis independently of RANKL. However, although C/EBPalpha up-regulated c-Fos, c-Fos failed to up-regulate C/EBPalpha in OC precursors. Consistently, C/EBPalpha overexpression more strongly promoted OC differentiation than did c-Fos overexpression. RANK has a cytoplasmic 535IVVY538 (IVVY) motif that is essential for osteoclastogenesis, and we found that mutation of the IVVY motif blocked OC differentiation by partly inhibiting expression of C/EBPalpha but not expression of c-Fos. We therefore hypothesized that C/EBPalpha overexpression might rescue osteoclastogenesis in cells expressing the mutated IVVY motif. However, overexpression of C/EBPalpha or c-Fos failed to stimulate osteoclastogenesis in the mutant cells. Notably, the IVVY motif mutation abrogated OC gene expression compared with a vector control, suggesting that the IVVY motif might counteract OC inhibitors during osteoclastogenesis. Consistently, the IVVY motif mutant triggered up-regulation of recombinant recognition sequence-binding protein at the Jkappa site (RBP-J) protein, a potent OC inhibitor. Mechanistically, C/EBPalpha or c-Fos overexpression in the mutant cells failed to control the up-regulated RBP-J expression, leading to suppression of OC genes. Accordingly, RBP-J silencing in the mutant cells rescued osteoclastogenesis with C/EBPalpha or c-Fos overexpression with C/EBPalpha exhibiting a stronger osteoclastogenic effect. Collectively, our findings indicate that C/EBPalpha is a stronger inducer of OC differentiation than c-Fos, partly via C/EBPalpha regulation by the RANK 535IVVY538 motif. PMID- 29122886 TI - Mechanism of polypurine tract primer generation by HIV-1 reverse transcriptase. AB - HIV-1 reverse transcriptase (RT) possesses both DNA polymerase activity and RNase H activity that act in concert to convert single-stranded RNA of the viral genome to double-stranded DNA that is then integrated into the DNA of the infected cell. Reverse transcriptase-catalyzed reverse transcription critically relies on the proper generation of a polypurine tract (PPT) primer. However, the mechanism of PPT primer generation and the features of the PPT sequence that are critical for its recognition by HIV-1 RT remain unclear. Here, we used a chemical cross linking method together with molecular dynamics simulations and single-molecule assays to study the mechanism of PPT primer generation. We found that the PPT was specifically and properly recognized within covalently tethered HIV-1 RT-nucleic acid complexes. These findings indicated that recognition of the PPT occurs within a stable catalytic complex after its formation. We found that this unique recognition is based on two complementary elements that rely on the PPT sequence: RNase H sequence preference and incompatibility of the poly(rA/dT) tract of the PPT with the nucleic acid conformation that is required for RNase H cleavage. The latter results from rigidity of the poly(rA/dT) tract and leads to base-pair slippage of this sequence upon deformation into a catalytically relevant geometry. In summary, our results reveal an unexpected mechanism of PPT primer generation based on specific dynamic properties of the poly(rA/dT) segment and help advance our understanding of the mechanisms in viral RNA reverse transcription. PMID- 29122889 TI - The Landscape of Quality Measures and Quality Improvement for the Care of Hospitalized Children in the United States: Efforts Over the Last Decade. PMID- 29122887 TI - A reference-based protein degradation assay without global translation inhibitors. AB - Although it is widely appreciated that the use of global translation inhibitors, such as cycloheximide, in protein degradation assays may result in artefacts, these inhibitors continue to be employed, owing to the absence of robust alternatives. We describe here the promoter reference technique (PRT), an assay for protein degradation with two advantageous features: a reference protein and a gene-specific inhibition of translation. In PRT assays, one measures, during a chase, the ratio of a test protein to a long-lived reference protein, a dihydrofolate reductase (DHFR). The test protein and DHFR are coexpressed, in the yeast Saccharomyces cerevisiae, on a low-copy plasmid from two identical P TDH3 promoters containing additional, previously developed DNA elements. Once transcribed, these elements form 5'-RNA aptamers that bind to the added tetracycline, which represses translation of aptamer-containing mRNAs. The selectivity of repression avoids a global inhibition of translation. This selectivity is particularly important if a component of a relevant proteolytic pathway (e.g. a specific ubiquitin ligase) is itself short-lived. We applied PRT to the Pro/N-end rule pathway, whose substrates include the short-lived Mdh2 malate dehydrogenase. Mdh2 is targeted for degradation by the Gid4 subunit of the GID ubiquitin ligase. Gid4 is also a metabolically unstable protein. Through analyses of short-lived Mdh2 as a target of short-lived Gid4, we illustrate the advantages of PRT over degradation assays that lack a reference and/or involve cycloheximide. In sum, PRT avoids the use of global translation inhibitors during a chase and also provides a "built-in" reference protein. PMID- 29122888 TI - TNF-stimulated gene 6 promotes formation of hyaluronan-inter-alpha-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness. AB - Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (AHR). TNF-stimulated gene 6 (TSG-6) is required to transfer inter-alpha-inhibitor heavy chains (HC) to hyaluronan (HA), facilitating HA receptor binding. TSG-6 is necessary for AHR in allergic asthma, because it facilitates the development of a pathological HA-HC matrix. However, the role of TSG-6 in acute airway inflammation is not well understood. Here, we hypothesized that TSG-6 is essential for the development of HA- and ozone-induced AHR. TSG-6-/ and TSG-6+/+ mice were exposed to ozone or short-fragment HA (sHA), and AHR was assayed via flexiVent. The AHR response to sHA was evaluated in the isolated tracheal ring assay in tracheal rings from TSG-6-/- or TSG-6+/+, with or without the addition of exogenous TSG-6, and with or without inhibitors of Rho associated, coiled-coil-containing protein kinase (ROCK), ERK, or PI3K. Smooth muscle cells from mouse tracheas were assayed in vitro for signaling pathways. We found that TSG-6 deficiency protects against AHR after ozone (in vivo) or sHA (in vitro and in vivo) exposure. Moreover, TSG-6-/- tracheal ring non-responsiveness to sHA was reversed by exogenous TSG-6 addition. sHA rapidly activated RhoA, ERK, and Akt in airway smooth-muscle cells, but only in the presence of TSG-6. Inhibition of ROCK, ERK, or PI3K/Akt blocked sHA/TSG-6-mediated AHR. In conclusion, TSG-6 is necessary for AHR in response to ozone or sHA, in part because it facilitates rapid formation of HA-HC complexes. The sHA/TSG-6 effect is mediated by RhoA, ERK, and PI3K/Akt signaling. PMID- 29122890 TI - microRNA-30c reduces plasma cholesterol in homozygous familial hypercholesterolemic and type 2 diabetic mouse models. AB - High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce the risk of atherosclerosis. A way to lower plasma lipids is to curtail lipoprotein production; however, this is associated with steatosis. We previously showed that microRNA (miR)-30c lowers diet-induced hypercholesterolemia and atherosclerosis in C57BL/6J and Apoe-/- mice. Here, we tested the effect of miR-30c on plasma lipids, transaminases, and hepatic lipids in different mouse models. Hepatic delivery of miR-30c to chow-fed leptin deficient (ob/ob) and leptin receptor-deficient (db/db) hypercholesterolemic and hyperglycemic mice reduced cholesterol in total plasma and VLDL/LDL by ~28% and ~25%, respectively, without affecting triglyceride and glucose levels. And these mice had lower plasma transaminases and creatine kinase activities than controls. Moreover, miR-30c significantly lowered plasma cholesterol and atherosclerosis in Western diet-fed Ldlr-/- mice with no effect on plasma triglyceride, glucose, and transaminases. In these studies, hepatic lipids were similar in control and miR 30c-injected mice. Mechanistic studies showed that miR-30c reduced hepatic microsomal triglyceride transfer protein activity and lipid synthesis. Thus miR 30c reduced plasma cholesterol in several diet-induced and diabetic hypercholesterolemic mice. We speculate that miR-30c may be beneficial in lowering plasma cholesterol in different metabolic disorders independent of the origin of hypercholesterolemia. PMID- 29122891 TI - Correction: Valacyclovir-associated neurotoxicity treated with intensification of peritoneal dialysis. PMID- 29122892 TI - Subclinical First Trimester Renal Abnormalities Are Associated With Preeclampsia in Normoalbuminuric Women With Type 1 Diabetes. AB - OBJECTIVE: This study was conducted to determine the utility of tubular (urinary/plasma neutrophil gelatinase-associated lipocalin [NGAL] and urinary kidney injury molecule 1 [KIM-1]) and glomerular (estimated glomerular filtration rate [eGFR]) biomarkers in predicting preeclampsia (PE) in pregnant women with type 1 diabetes mellitus (T1DM) who were free of microalbuminuria and hypertension at the first trimester. RESEARCH DESIGN AND METHODS: This was a prospective study of T1DM pregnancy. Maternal urinary and plasma NGAL, urinary KIM-1 (ELISA of frozen samples), and eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) were determined at three study visits (V1: 12.4 +/- 1.8; V2: 21.7 +/- 1.4; V3: 31.4 +/- 1.5 weeks' gestation [mean +/- SD]) in 23 women with T1DM with subsequent PE (DM+PE+), 24 who remained normotensive (DM+PE-), and, for reference, in 19 normotensive pregnant women without diabetes (DM-). The groups with diabetes were matched for age, diabetes duration, and parity. All subjects were normotensive and free of microalbuminuria or albuminuria at V1. All study visits preceded the onset of PE. RESULTS: Urinary creatinine-corrected NGAL (uNGALcc, ng/mg) was significantly elevated at V1 in DM+PE+ vs. DM+PE- women (P = 0.01); this remained significant after exclusion of leukocyte-positive samples (5 DM+PE+ and 2 DM+PE-) (P = 0.02). Accounting for BMI, HbA1c, and total daily insulin dose, a doubling of uNGALcc at V1 conferred a sevenfold increase in risk for PE (P = 0.026). In contrast, neither plasma NGAL nor urinary KIM-1 predicted PE. Also at V1, eGFR was elevated in DM+PE+ vs. DM+PE- (P = 0.04). CONCLUSIONS: Early tubular and glomerular dysfunction may predict PE in first trimester women with T1DM, even if free of microalbuminuria. These data suggest that subclinical renal tubular and glomerular injury, if present early in pregnancy, may predispose women with T1DM to PE. PMID- 29122893 TI - Prospective Postmarketing Surveillance of Acute Myocardial Infarction in New Users of Saxagliptin: A Population-Based Study. AB - OBJECTIVE: The cardiovascular safety of saxagliptin, a dipeptidyl-peptidase 4 inhibitor, compared with other antihyperglycemic treatments is not well understood. We prospectively examined the association between saxagliptin use and acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS: We identified patients aged >=18 years, starting from the approval date of saxagliptin in 2009 and continuing through August 2014, using data from 18 Mini-Sentinel data partners. We conducted seven sequential assessments comparing saxagliptin separately with sitagliptin, pioglitazone, second-generation sulfonylureas, and long-acting insulin, using disease risk score (DRS) stratification and propensity score (PS) matching to adjust for potential confounders. Sequential testing kept the overall chance of a false-positive signal below 0.05 (one-sided) for each pairwise comparison. RESULTS: We identified 82,264 saxagliptin users and more than 1.5 times as many users of each comparator. At the end of surveillance, the DRS-stratified hazard ratios (HRs) (95% CI) were 1.08 (0.90-1.28) in the comparison with sitagliptin, 1.11 (0.87-1.42) with pioglitazone, 0.79 (0.64-0.98) with sulfonylureas, and 0.57 (0.46-0.70) with long-acting insulin. The corresponding PS-matched HRs were similar. Only one interim analysis of 168 analyses met criteria for a safety signal: the PS-matched saxagliptin pioglitazone comparison from the fifth sequential analysis, which yielded an HR of 1.63 (1.12-2.37). This association diminished in subsequent analyses. CONCLUSIONS: We did not find a higher AMI risk in saxagliptin users compared with users of other selected antihyperglycemic agents during the first 5 years after U.S. Food and Drug Administration approval of the drug. PMID- 29122894 TI - Dyspnoea in lupus. AB - A 32-year-old woman suffering from systemic lupus erythematosus presented with a 6-week history of progressive dyspnoea and pleuritic chest pain. Examination was normal apart from reduced air entry at the lung bases.Arterial blood gases showed hypoxaemia and chest X-ray revealed raised hemidiaphragms without any pleural effusions. Lung function showed a restrictive pathology while high-resolution chest CT and CT pulmonary angiogram were negative. Echocardiography showed normal ventricular diameters and no pericardial effusion. Reduced lung volumes and a positive fluoroscopic sniff test lead to a diagnosis of shrinking lung syndrome. Symptoms improved following treatment with glucocorticoids and non-invasive ventilation, but there was no change in lung function.A year later, our patient presented again with worsening dyspnoea. This time echocardiography revealed severe mitral stenosis with pulmonary hypertension. Mitral valve replacement was performed and dyspnoea resolved. Histology showed Libman-Sachs endocarditis. PMID- 29122895 TI - Migration of ventriculoperitoneal shunt to urethral and rectal orifices. AB - Ventriculoperitoneal (VP) shunt surgery remains the most widely used neurosurgical procedure for the management of hydrocephalus. However, shunt complications are common and may require multiple surgical procedures during a patient's lifetime. We report the case of a 29-year-old patient with a background of Dandy-Walker malformation, occipital encephalocele, recurrent hydrocephalus, spina bifida and epilepsy presented with VP shunt migration into urinary and gastrointestinal tracts. In absence of sepsis or peritonism from either bowel or bladder perforation, local control of stent extrusion was successful for several years, although surgery was eventually undertaken. PMID- 29122896 TI - Persistent bacteraemia caused by Staphylococcus aureus in the gall bladder. AB - Staphylococcus aureusbacteraemia (SAB) remains a complex disease with a high associated morbidity and mortality, especially when it is able to establish an occult nidus safe from antimicrobial eradication. Without rapid identification and intervention, the nidus can cause persistent relapse of disease, morbidity and mortality. Having a high clinical suspicion for the foci of occult S. aureus is important, and awareness of potential sites of infection is critical and can be life-saving.We present a unique case of a 65-year-old man with end-stage renal disease receiving haemodialysis who developed septic shock from SAB. Despite 18 days of appropriate antibiotics, the patient had persistent high-grade bacteraemia until his gall bladder was ultimately percutaneously drained. The day after drainage, he cleared his blood cultures, although he ultimately passed away as he decided to transition his care to focus on comfort measures. PMID- 29122897 TI - Polymyalgia rheumatica development in a patient under PI3K inhibitor therapy for chronic lymphocytic leukaemia. AB - We report a patient with chronic lymphocytic leukaemia (CLL) who was treated with idelalisib, a PI3Kdelta inhibitor with rituximab. After 20 weeks of treatment, the patient developed classical signs and symptoms of polymyalgia rheumatica (PMR) in association with an elevated C reactive protein of 74 mg/L. After 2 weeks of prednisolone 15 mg daily symptoms had resolved and acute phase markers normalised. To our knowledge, this is the first report of PMR developing as a complication of PI3Kdelta inhibitor treatment of CLL. PMID- 29122898 TI - Acute renal artery infarction secondary to dysfibrinogenemia. AB - Renal infarction is a rare occurrence accounting for 0.007% of patients seen in the emergency department for renal insufficiency or hypertension. Dysfibrinogenemia is also rare, and the combination of renal artery infarct in the setting of congenital dysfibrinogenemia has not been described in the literature. Our patient, with a remote history of congenital dysfibrinogenemia with no known haemorrhagic or thrombotic complications, presented with acute flank pain and was subsequently diagnosed with an acute renal arterial infarction. He was treated with subcutaneous enoxaparin and then transitioned to lifelong anticoagulation with rivaroxaban therapy. PMID- 29122899 TI - Congenital pseudarthrosis of the clavicle treated by Masquelet technique. AB - Congenital pseudarthrosis of the clavicle (CPC) is a very rare pathology of which over 200 cases have been reported. Usually discovered during the first months of life, CPC is characterised by a definitive bone defect in the middle third of the clavicle. Generally asymptomatic, the pseudarthrosis of the clavicle can cause aesthetic issues and functional symptoms indicating a surgical repair. Different reconstruction techniques have been reported with various complications. We present a 14-year-old boy diagnosed with CPC and concerned about the cosmetic aspect of a swelling of his right clavicle. We performed a two-stage surgical repair using the induced membrane technique described by Masquelet. A complete bone union has been obtained, and patient is satisfied with the cosmetic appearance. In our opinion, the Masquelet technique is a safe and reproducible procedure to treat CPC in high-risk older patients with long gap allowing a rapid and lasting bone union. PMID- 29122900 TI - A 30-year delayed presentation of disseminated histoplasmosis in a heart transplant recipient: diagnostic challenges in a non-endemic area. AB - A 70-year-old man with history of heart transplant performed in 1986, presented with altered mental status. CT scan of brain showed ring-enhancing lesions, raising suspicion for metastatic malignancy. Work-up revealed bilateral adrenal masses, biopsy showed granulomatous changes consistent with histoplasmosis. The possibility of histoplasmosis was less likely as the patient had no prior history of symptomatic disease and had lived in the endemic area 30 years prior to presentation. Brain biopsy confirmed central nervous system involvement. Amphotericin B was initiated for disseminated disease but his hospital course was complicated by renal failure and new liver hypodensities on follow-up imaging. Acute progressive disseminated histoplasmosis can manifest after decades of initial exposure and should always be in differential diagnosis even in non endemic areas for prompt diagnosis and better clinical outcome. PMID- 29122901 TI - Spinal epidural empyema extending from a pleural empyema: case description and anatomical overview. AB - We present a case of a patient with diabetes with a pleural empyema originated from a pyomyositis process established after a central line procedure. This empyema later on extended into the spinal canal deriving into an epidural empyema, leading towards a spinal neurogenic shock and death. We discuss the anatomical substrate for this extension as well as the anatomopathological findings observed in the autopsy. PMID- 29122902 TI - A rare case of unilateral discoid lupus erythematosus mimicking lupus vulgaris. AB - Discoidlupus erythematosus (DLE) is a chronic type of cutaneous lupus erythematosus which can present in various morphologies, and the diagnosis can be rather confounding. Prompt evaluation and treatment is necessary to prevent disfigurement and systemic involvement associated with DLE. The following case presented a diagnostic dilemma as the lesion mimicked lupus vulgaris. PMID- 29122903 TI - Giant cystic pheochromocytoma. AB - A 56-year-old healthy woman presents with 2-year history of symptoms classic for pheochromocytoma. Evaluation revealed one of the largest cystic pheochromocytomas reported but without any metastatic disease. After achieving medical management of her symptoms, surgical removal was performed successfully and without any complications intraoperatively. Pathology of the mass confirmed the diagnosis. The patient had complete resolution of her symptoms thereafter. PMID- 29122904 TI - Male with watery rhinorrhoea and disturbed consciousness after trauma. PMID- 29122905 TI - Healthy donor faecal transplant for corticosteroid non-responsive severe alcoholic hepatitis. AB - Patients with severe alcoholic hepatitis (SAH) have high mortality in the presence of steroid unresponsiveness in the absence of clear treatment recommendations. Liver transplantation is the curative option in such cases but is controversial in the wake of severe infections, post-transplant recidivism and long waiting on deceased donor listing. Animal and human studies have shed light on the beneficial effects of gut microbiota modulation in alcoholic liver disease. We present the first report of faecal microbiota transplantation (FMT) in a steroid non-responder in whom, clinical, biochemical and liver disease severity scores improved post-FMT and demonstrate distinct bacterial population changes pre-FMT and post-FMT. Healthy donor FMT could be safe and efficacious in SAH not responding to corticosteroid treatment, as a bridge to liver transplantation (LT) or in candidates who are unwilling or not ideal for LT for improvement in short-term transplant free survival. Larger controlled studies are required for confirmation. PMID- 29122906 TI - Safety netting versus overtreatment in paediatrics: viral infection or incomplete Kawasaki disease? AB - Kawasaki disease (KD) is the most common systemic vasculitis of childhood. The following presentation of a 4-year-old Irish boy referred to a secondary care paediatric service from the community with prolonged fever, oral mucous membrane changes and painless blistering lesions of the hands and feet in the presence of elevated inflammatory markers serves as an opportunity to discuss the diagnostic criteria and treatment for KD and incomplete KD, an often missed diagnosis with significant paediatric morbidity outside an academic paediatric centre. PMID- 29122907 TI - Clival metastasis from a gastrointestinal adenocarcinoma causing multiple cranial neuropathies. AB - A 78-year-old man with a history of benign prostatic hyperplasia presented with double vision, facial pain, altered taste and headache for 7 weeks. Neurological exam was notable for palsies of the right V, VI, VII and XII cranial nerves. An expansive clival mass and multiple lesions in the vertebra were found on MRI. Radionuclide studies showed extensive tumour burden in his liver and peritoneum. His serologies showed normal carcinoembryonic antigen and carbohydrate antigen 19 9 levels and modestly elevated prostate-specific antigen, which was a red herring. Biopsy of his omentum was consistent with metastatic adenocarcinoma with immunostaining indicating an upper gastrointestinal primary tumour. The patient underwent several cycles of radiation therapy, but ultimately elected to pursue hospice care. This case demonstrates the presentation of multiple cranial neuropathies from a clival mass and an unusual primary source from an upper gastrointestinal tumour. PMID- 29122908 TI - Congenital non-syndromic anonychia totalis with acroosteolysis. PMID- 29122909 TI - Critical pitfall: another cause of wheezing. PMID- 29122910 TI - Large oesophageal haematoma as a result of transoesophageal echocardiogram (TEE). PMID- 29122911 TI - Prognosis of Patients with Cirrhosis and AKI Who Initiate RRT. AB - BACKGROUND AND OBJECTIVES: Literature on the prognosis of patients with cirrhosis who require RRT for AKI is sparse and is confounded by liver transplant eligibility. An update on outcomes in the nonlisted subgroup is needed. Our objective was to compare outcomes in this group between those diagnosed with hepatorenal syndrome and acute tubular necrosis, stratifying by liver transplant listing status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective cohort study of patients with cirrhosis acutely initiated on hemodialysis or continuous RRT at five hospitals, including one liver transplant center. Multivariable regression and survival analysis were performed. RESULTS: Four hundred seventy-two subjects were analyzed (341 not listed and 131 listed for liver transplant). Among nonlisted subjects, 15% (51 of 341) were alive at 6 months after initiating RRT. Median survival was 21 (interquartile range [IQR], 8, 70) days for those diagnosed with hepatorenal syndrome and 12 (IQR, 3, 43) days for those diagnosed with acute tubular necrosis (P=0.25). Among listed subjects, 48% (63 of 131) received a liver transplant. Median transplant-free survival was 15 (IQR, 5, 37) days for those diagnosed with hepatorenal syndrome and 14 (IQR, 4, 31) days for those diagnosed with acute tubular necrosis (P=0.60). When stratified by transplant listing, with adjusted Cox models we did not detect a difference in the risk of death between hepatorenal syndrome and acute tubular necrosis (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.59 to 1.11, among those not listed; HR, 0.73; 95% CI, 0.44 to 1.19, among those listed). CONCLUSIONS: Cause of AKI was not significantly associated with mortality in patients with cirrhosis who required RRT. Among those not listed for liver transplant, mortality rates were extremely high in patients both with hepatorenal syndrome and acute tubular necrosis. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2017_11_09_CJASNPodcast_18_1_A.mp3. PMID- 29122912 TI - Spatially-Resolved Top-down Proteomics Bridged to MALDI MS Imaging Reveals the Molecular Physiome of Brain Regions. AB - Tissue spatially-resolved proteomics was performed on 3 brain regions, leading to the characterization of 123 reference proteins. Moreover, 8 alternative proteins from alternative open reading frames (AltORF) were identified. Some proteins display specific post-translational modification profiles or truncation linked to the brain regions and their functions. Systems biology analysis performed on the proteome identified in each region allowed to associate sub-networks with the functional physiology of each brain region. Back correlation of the proteins identified by spatially-resolved proteomics at a given tissue localization with the MALDI MS imaging data, was then performed. As an example, mapping of the distribution of the matrix metallopeptidase 3-cleaved C-terminal fragment of alpha-synuclein (aa 95-140) identified its specific distribution along the hippocampal dentate gyrus. Taken together, we established the molecular physiome of 3 rat brain regions through reference and hidden proteome characterization. PMID- 29122913 TI - Infertility in an adult cohort with primary ciliary dyskinesia: phenotype-gene association. PMID- 29122914 TI - Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient. AB - With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ~3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45 1.17) higher in CF. However, there was no significant association between LCI z score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up. PMID- 29122915 TI - Elevated lung clearance index in infants with cystic fibrosis shortly after birth. AB - It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (+/-1.64 z-scores) in CF.We enrolled 53 infants with CF (mean age 7.8 weeks) and 57 controls (mean age 5.2 weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02-0.60; p=0.034 and 14.5 mL, 95% CI 7.7-21.3 mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group. PMID- 29122916 TI - TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications. AB - TWIK-related acid-sensitive potassium channel 1 (TASK-1 encoded by KCNK3) belongs to the family of two-pore domain potassium channels. This gene subfamily is constitutively active at physiological resting membrane potentials in excitable cells, including smooth muscle cells, and has been particularly linked to the human pulmonary circulation. TASK-1 channels are sensitive to a wide array of physiological and pharmacological mediators that affect their activity such as unsaturated fatty acids, extracellular pH, hypoxia, anaesthetics and intracellular signalling pathways. Recent studies show that modulation of TASK-1 channels, either directly or indirectly by targeting their regulatory mechanisms, has the potential to control pulmonary arterial tone in humans. Furthermore, mutations in KCNK3 have been identified as a rare cause of both familial and idiopathic pulmonary arterial hypertension. This review summarises our current state of knowledge of the functional role of TASK-1 channels in the pulmonary circulation in health and disease, with special emphasis on current advancements in the field. PMID- 29122917 TI - Final treatment outcomes of multidrug- and extensively drug-resistant tuberculosis patients in Latvia receiving delamanid-containing regimens. PMID- 29122918 TI - Recommending prolonged bedaquiline use for the treatment of highly resistant strains of tuberculosis. PMID- 29122919 TI - Action levels for indoor radon: different risks for the same lung carcinogen? PMID- 29122920 TI - Digital health to end tuberculosis in the Sustainable Development Goals era: achievements, evidence and future perspectives. PMID- 29122921 TI - Bedaquiline: how better to use it. PMID- 29122922 TI - Elucidating progression of early cystic fibrosis lung disease. PMID- 29122923 TI - "Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients." Myriam Delaunay, Jacques Cadranel, Amelie Lusque, Nicolas Meyer, Valerie Gounant, Denis Moro-Sibilot, Jean-Marie Michot, Judith Raimbourg, Nicolas Girard, Florian Guisier, David Planchard, Anne-Cecile Metivier, Pascale Tomasini, Eric Dansin, Maurice Perol, Marion Campana, Oliver Gautschi, Martin Fruh, Jean David Fumet, Clarisse Audigier-Valette, Sebastien Couraud, Stephane Dalle, Marie Therese Leccia, Marion Jaffro, Samia Collot, Gregoire Prevot, Julie Milia and Julien Mazieres. Eur Respir J 2017; 50: 1700050. PMID- 29122924 TI - Author reply: 'Response to: Pleural abnormalities in the Framingham Heart Study: prevalence and CT image features' by Araki et al. PMID- 29122926 TI - Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy. AB - BACKGROUND: Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. METHODS: In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ~490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C beta 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP2) to inositol 1,4,5 triphosphate (IP3) and diacylglycerol. RESULTS: The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. CONCLUSIONS: Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD). PMID- 29122927 TI - Antipsychotic-induced hyperprolactinaemia: case studies and review. AB - Antipsychotics are a known cause of hyperprolactinaemia and can be associated with significant health issues in short term and long term. The effects vary with gender and age of the individual and can contribute towards non-concordance and hence relapse in mental health of our patients. Clinicians need to educate the patients about this significant side effect of not only antipsychotic medications but other medications causing hyperprolactinaemia commonly prescribed in primary care. PMID- 29122925 TI - Genetic circuit characterization and debugging using RNA-seq. AB - Genetic circuits implement computational operations within a cell. Debugging them is difficult because their function is defined by multiple states (e.g., combinations of inputs) that vary in time. Here, we develop RNA-seq methods that enable the simultaneous measurement of: (i) the states of internal gates, (ii) part performance (promoters, insulators, terminators), and (iii) impact on host gene expression. This is applied to a three-input one-output circuit consisting of three sensors, five NOR/NOT gates, and 46 genetic parts. Transcription profiles are obtained for all eight combinations of inputs, from which biophysical models can extract part activities and the response functions of sensors and gates. Various unexpected failure modes are identified, including cryptic antisense promoters, terminator failure, and a sensor malfunction due to media-induced changes in host gene expression. This can guide the selection of new parts to fix these problems, which we demonstrate by using a bidirectional terminator to disrupt observed antisense transcription. This work introduces RNA seq as a powerful method for circuit characterization and debugging that overcomes the limitations of fluorescent reporters and scales to large systems composed of many parts. PMID- 29122929 TI - Improving outcomes in chronic aortic regurgitation: timely diagnosis, access to specialist assessment and earlier surgery. PMID- 29122928 TI - Surgical safety checklist training: a national study of undergraduate medical and nursing student teaching, understanding and influencing factors. AB - INTRODUCTION: Use of the WHO surgical safety checklist is consistently recognised to reduce harm caused by human error during the perioperative period. Inconsistent engagement is considered to contribute to persistence of surgical Never Events in the National Health Service. Most medical and nursing graduates will join teams responsible for the perioperative care of patients, therefore appropriate undergraduate surgical safety training is needed. AIMS: To investigate UK medical and nursing undergraduate experience of the surgical safety checklist training. METHODS: An eight-item electronic questionnaire was distributed electronically to 32 medical schools and 72 nursing schools. Analysis was conducted for the two cohorts, and responses from final year students were included. RESULTS: 87/224 (38.8%) of medical students received teaching on the surgical safety checklist, compared with 380/711 (52.0%) of nursing students. 172/224 (76.8%) of medical students and 489/711 (66.9%) of nursing students understood its purpose and 8/224 (3.6%) medical students and 54/711 (7.4%) nursing students reported never being included in the Time Out. After adjusting for confounding factors, provision of formal teaching in checklist use increased understanding significantly (OR 50.39 (14.07 to 325.79, P<0.001)), as did routine student involvement in time outs (OR 5.72 (2.36 to 14.58, P<0.001)). DISCUSSION: Knowledge of perioperative patient safety systems and the ability to participate in safety protocols are important skills that should be formally taught at the undergraduate level. Results of this study show that UK undergraduate surgical safety checklist training does not meet the minimum standards set by the WHO. PMID- 29122930 TI - Peripartum cardiomyopathy: diagnosis and management. PMID- 29122931 TI - Outcome of left atrial appendage occlusion in high-risk patients. AB - OBJECTIVE: Percutaneous left atrial appendage (LAA) occlusion can be an interventional alternative to oral anticoagulation for stroke prevention in patients with atrial fibrillation. METHODS: We delivered LAA occlusion therapy using a standardised approach to patient referral, multidisciplinary team assessment, implant criteria, imaging and follow-up. We analysed patient characteristics, efficacy and safety of the implant procedure, and 12-month outcomes. RESULTS: Of 143 referrals from October 2014 to December 2016, 83 patients (age 76+/-8years, 32.5% female, mean CHAD2S2-VASc score 4 +/-1) were offered LAA occlusion. Eighty (95.3%) had previous major bleeding (intracranial in 59%). LAA occluder implantation with an Amulet device was successful in 82 (98.8%), with periprocedural major adverse events occurring in 5 (6.0%) patients (2 device embolisations including 1 death, 2 major bleeds). Cardiac imaging in 75 (94%) patients 2months following implant showed device-related thrombus in 1 case (1.3%) and minor (<5mm) device leaks in 13 (17.1%). Over a median 12-month follow up, 3 (3.8%) ischaemic strokes, 2 (2.5%) haemorrhagic strokes and 5 (6.3%) major extracranial bleeds occurred. All-cause mortality was 10%, with most deaths (7, 87.5%) due to non-cardiovascular causes. CONCLUSIONS: LAA occlusion may be a reasonable option for stroke prevention inhigh-risk patients with atrial fibrillation ineligible for anticoagulation. However, procedural complication rates are not insignificant, and patients remain at risk of serious adverse events and death even after successful implant. PMID- 29122933 TI - Kinnier Wilson's puzzling features of amyotrophic lateral sclerosis. PMID- 29122932 TI - Diagnostic performance of an acoustic-based system for coronary artery disease risk stratification. AB - OBJECTIVE: Diagnosing coronary artery disease (CAD) continues to require substantial healthcare resources. Acoustic analysis of transcutaneous heart sounds of cardiac movement and intracoronary turbulence due to obstructive coronary disease could potentially change this. The aim of this study was thus to test the diagnostic accuracy of a new portable acoustic device for detection of CAD. METHODS: We included 1675 patients consecutively with low to intermediate likelihood of CAD who had been referred for cardiac CT angiography. If significant obstruction was suspected in any coronary segment, patients were referred to invasive angiography and fractional flow reserve (FFR) assessment. Heart sound analysis was performed in all patients. A predefined acoustic CAD score algorithm was evaluated; subsequently, we developed and validated an updated CAD-score algorithm that included both acoustic features and clinical risk factors. Low risk is indicated by a CAD-score value <=20. RESULTS: Haemodynamically significant CAD assessed from FFR was present in 145 (10.0%) patients. In the entire cohort, the predefined CAD-score had a sensitivity of 63% and a specificity of 44%. In total, 50% had an updated CAD-score value <=20. At this cut-off, sensitivity was 81% (95% CI 73% to 87%), specificity 53% (95% CI 50% to 56%), positive predictive value 16% (95% CI 13% to 18%) and negative predictive value 96% (95% CI 95% to 98%) for diagnosing haemodynamically significant CAD. CONCLUSION: Sound-based detection of CAD enables risk stratification superior to clinical risk scores. With a negative predictive value of 96%, this new acoustic rule-out system could potentially supplement clinical assessment to guide decisions on the need for further diagnostic investigation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02264717; Results. PMID- 29122934 TI - Genotyping Natural Killer Immune Checkpoints to Discover Biomarkers of Response. AB - Immune checkpoints have been a focus of immunotherapy in the recent decade. Killer cell immunoglobulin-like receptors (KIR) and their cognate human leukocyte antigen (HLA) class I ligands have evolved as checkpoints to ensure self tolerance of natural killer cells. Both KIR and HLA genetic profiles are potential biomarkers of immunotherapy outcome. Clin Cancer Res; 24(1); 3-5. (c)2017 AACRSee related article by Erbe et al., p. 189. PMID- 29122936 TI - Reply to Kalinkat et al.: Smallest terrestrial vertebrates are highly imperiled. PMID- 29122938 TI - Meet the First Authors. PMID- 29122937 TI - Exceptional body size-extinction risk relations shed new light on the freshwater biodiversity crisis. PMID- 29122939 TI - To Seek the Holy Grail of Cardiac Progenitor Cells: An Opera in Four Acts. PMID- 29122935 TI - In vivo measurements of interindividual differences in DNA glycosylases and APE1 activities. AB - The integrity of our DNA is challenged with at least 100,000 lesions per cell on a daily basis. Failure to repair DNA damage efficiently can lead to cancer, immunodeficiency, and neurodegenerative disease. Base excision repair (BER) recognizes and repairs minimally helix-distorting DNA base lesions induced by both endogenous and exogenous DNA damaging agents. Levels of BER-initiating DNA glycosylases can vary between individuals, suggesting that quantitating and understanding interindividual differences in DNA repair capacity (DRC) may enable us to predict and prevent disease in a personalized manner. However, population studies of BER capacity have been limited because most methods used to measure BER activity are cumbersome, time consuming and, for the most part, only allow for the analysis of one DNA glycosylase at a time. We have developed a fluorescence-based multiplex flow-cytometric host cell reactivation assay wherein the activity of several enzymes [four BER-initiating DNA glycosylases and the downstream processing apurinic/apyrimidinic endonuclease 1 (APE1)] can be tested simultaneously, at single-cell resolution, in vivo. Taking advantage of the transcriptional properties of several DNA lesions, we have engineered specific fluorescent reporter plasmids for quantitative measurements of 8-oxoguanine DNA glycosylase, alkyl-adenine DNA glycosylase, MutY DNA glycosylase, uracil DNA glycosylase, and APE1 activity. We have used these reporters to measure differences in BER capacity across a panel of cell lines collected from healthy individuals, and to generate mathematical models that predict cellular sensitivity to methylmethane sulfonate, H2O2, and 5-FU from DRC. Moreover, we demonstrate the suitability of these reporters to measure differences in DRC in multiple pathways using primary lymphocytes from two individuals. PMID- 29122940 TI - Cortical Bone Stem Cells Administered at Reperfusion Attenuate Remote Zone Myocyte Remodeling. PMID- 29122941 TI - Posology for Regenerative Therapy. PMID- 29122943 TI - Onur Kanisicak: From Toy Tinkerer to Scientific Innovator. PMID- 29122942 TI - A Special Report on the NHLBI Initiative to Study Cellular and Molecular Mechanisms of Arterial Stiffness and Its Association With Hypertension. PMID- 29122945 TI - Correction to: Association of Serum Retinoic Acid With Risk of Mortality in Patients With Coronary Artery Disease. PMID- 29122944 TI - Synergistic Research Between the Center of Arrhythmia Research and the Michigan Biology of Cardiovascular Aging at the University of Michigan. PMID- 29122946 TI - Correction to: Association of Plasma 7-Ketocholesterol With Cardiovascular Outcomes and Total Mortality in Patients With Coronary Artery Disease. PMID- 29122947 TI - Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene. AB - Activation-induced cytidine deaminase (AID) is a mutator enzyme that targets immunoglobulin (Ig) genes to initiate antibody somatic hypermutation (SHM) and class switch recombination (CSR). Off-target AID association also occurs, which causes oncogenic mutations and chromosome rearrangements. However, AID occupancy does not directly correlate with DNA damage, suggesting that factors beyond AID association contribute to mutation targeting. CSR and SHM are regulated by phosphorylation on AID serine38 (pS38), but the role of pS38 in off-target activity has not been evaluated. We determined that lithium, a clinically used therapeutic, induced high AID pS38 levels. Using lithium and an AID-S38 phospho mutant, we compared the role of pS38 in AID activity at the Ig switch region and off-target Myc gene. We found that deficient pS38 abated AID chromatin association and CSR but not mutation at Myc. Enhanced pS38 elevated Myc translocation and mutation frequency but not CSR or Ig switch region mutation. Thus, AID activity can be differentially targeted by phosphorylation to induce oncogenic lesions. PMID- 29122949 TI - The effects of extended crawling on the physiology and swim performance of loggerhead and green sea turtle hatchlings. AB - Following emergence from the nest, sea turtle hatchling dispersal can be disrupted by artificial lights or skyglow from urban areas. Misorientation or disorientation may increase exposure to predation, thermal stress and dehydration, and consume valuable energy, thus decreasing the likelihood of survival. In this study hatchlings were run on a treadmill for 200 or 500 m to investigate the physiological impacts of disorientation crawling in loggerhead (Caretta caretta) and green (Chelonia mydas) sea turtle hatchlings. Oxygen consumption, lactate production and blood glucose levels were determined, and swim performance was measured over 2 h following crawls. Crawl distances were also determined for hatchlings that disoriented on the Boca Raton beach in Florida, with plasma lactate and blood glucose sampled for both properly oriented and disoriented hatchlings. Green and loggerhead hatchlings rested for 8-12% and 22-25% of crawl time, respectively, both in the laboratory and when disoriented on the beach, which was significantly longer than the time spent resting in non disoriented turtles. As a result of these rest periods, the extended crawl distances had little effect on oxygen consumption, blood glucose or plasma lactate levels. Swim performance over 2 h following the crawls also changed little compared with controls. Plasma lactate concentrations were significantly higher in hatchlings sampled in the field, but did not correlate with crawl distance. The greatest immediate impact of extended crawling as a result of disorientation events is likely to be the significantly greater period of time spent on the beach and thus exposure to predation. PMID- 29122948 TI - MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation. AB - MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17~92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17~92-deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17~92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and TH2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses. PMID- 29122950 TI - Myosin phosphorylation potentiates steady-state work output without altering contractile economy of mouse fast skeletal muscles. AB - Skeletal myosin light chain kinase (skMLCK)-catalyzed phosphorylation of the myosin regulatory light chain (RLC) increases (i.e. potentiates) mechanical work output of fast skeletal muscle. The influence of this event on contractile economy (i.e. energy cost/work performed) remains controversial, however. Our purpose was to quantify contractile economy of potentiated extensor digitorum longus (EDL) muscles from mouse skeletal muscles with (wild-type, WT) and without (skMLCK ablated, skMLCK-/-) the ability to phosphorylate the RLC. Contractile economy was calculated as the ratio of total work performed to high-energy phosphate consumption (HEPC) during a period of repeated isovelocity contractions that followed a potentiating stimulus (PS). Consistent with genotype, the PS increased RLC phosphorylation measured during, before and after isovelocity contractions in WT but not in skMLCK-/- muscles (i.e. 0.65 and 0.05 mol phosphate mol-1 RLC, respectively). In addition, although the PS enhanced work during repeated isovelocity contractions in both genotypes, the increase was significantly greater in WT than in skMLCK-/- muscles (1.51+/-0.03 versus 1.10+/ 0.05, respectively; all data P<0.05, n=8). Interestingly, the HEPC determined during repeated isovelocity contractions was statistically similar between genotypes at 19.03+/-3.37 and 16.02+/-3.41 MUmol P; respectively (P<0.27). As a result, despite performing significantly more work, the contractile economy calculated for WT muscles was similar to that calculated for skMLCK-/- muscles (i.e. 5.74+/-0.67 and 4.61+/-0.71 J kg-1 MUmol-1 P, respectively (P<0.27). In conclusion, our results support the notion that myosin RLC phosphorylation enhances dynamic contractile function of mouse fast skeletal muscle but does so without decreasing contractile economy. PMID- 29122951 TI - Dive heart rate in harbour porpoises is influenced by exercise and expectations. AB - The dive response, a decrease in heart rate (fH) and peripheral vasoconstriction, is the key mechanism allowing breath-hold divers to perform long-duration dives. This pronounced cardiovascular response to diving has been investigated intensely in pinnipeds, but comparatively little is known for cetaceans, in particular in ecologically relevant settings. Here, we studied the dive fH response in one of the smallest cetaceans, the harbour porpoise (Phocoena phocoena). We used a novel multi-sensor data logger to record dive behaviour, fH, ventilations and feeding events in three trained porpoises, providing the first evaluation of cetacean fH regulation while performing a variety of natural behaviours, including prey capture. We predicted that tagged harbour porpoises would exhibit a decrease in fH in all dives, but the degree of bradycardia would be influenced by dive duration and activity, i.e. the dive fH response would be exercise modulated. In all dives, fH decreased compared with surface rates by at least 50% (mean maximum surface fH=173 beats min-1, mean minimum dive fH=50 beats min-1); however, dive fH was approximately 10 beats min-1 higher in active dives as a result of a slower decrease in fH and more variable fH during pursuit of prey. We show that porpoises exhibit the typical breath-hold diver bradycardia during aerobic dives and that the fH response is modulated by exercise and dive duration; however, other variables such as expectations and individual differences are equally important in determining diving fH. PMID- 29122952 TI - Organ-level validation of a cross-bridge cycling descriptor in a left ventricular finite element model: effects of ventricular loading on myocardial strains. AB - Although detailed cell-based descriptors of cross-bridge cycling have been applied in finite element (FE) heart models to describe ventricular mechanics, these multiscale models have never been tested rigorously to determine if these descriptors, when scaled up to the organ-level, are able to reproduce well established organ-level physiological behaviors. To address this void, we here validate a left ventricular (LV) FE model that is driven by a cell-based cross bridge cycling descriptor against key organ-level heart physiology. The LV FE model was coupled to a closed-loop lumped parameter circulatory model to simulate different ventricular loading conditions (preload and afterload) and contractilities. We show that our model is able to reproduce a linear end systolic pressure volume relationship, a curvilinear end-diastolic pressure volume relationship and a linear relationship between myocardial oxygen consumption and pressure-volume area. We also show that the validated model can predict realistic LV strain-time profiles in the longitudinal, circumferential, and radial directions. The predicted strain-time profiles display key features that are consistent with those measured in humans, such as having similar peak strains, time-to-peak-strain, and a rapid change in strain during atrial contraction at late-diastole. Our model shows that the myocardial strains are sensitive to not only LV contractility, but also to the LV loading conditions, especially to a change in afterload. This result suggests that caution must be exercised when associating changes in myocardial strain with changes in LV contractility. The methodically validated multiscale model will be used in future studies to understand human heart diseases. PMID- 29122953 TI - Dietary weight loss-induced changes in RBP4, FFA, and ACE predict weight regain in people with overweight and obesity. AB - Adipokines and other biomarkers were previously identified with roles in energy expenditure, appetite, satiety, and adiposity. Therefore, we investigated whether dietary weight loss-induced changes in adipokines and other biomarkers known to play a role in weight regulation or energy expenditure could predict weight regain in people with overweight and obesity. In this randomized controlled trial 26 males and 30 females (BMI: 28-35 kg/m2) followed either a low-calorie diet (LCD; 1250 kcal/day) for 12 weeks or a very-low-calorie diet (VLCD; 500 kcal/day) for 5 weeks followed by a weight stable period of 4 weeks (dietary intervention (DI) period) and a 9-month follow-up period. Blood samples were taken before and after each period to measure FFA, TAG, total cholesterol, insulin, glucose, angiotensin-converting enzyme (ACE) activity, IL-6, RBP4, apelin, leptin, adiponectin, vaspin, and nesfatin-1 concentrations. Weight loss was similar between groups (LCD: -8.2 +/- 0.5 kg; VLCD: -8.9 +/- 0.4 kg, P = 0.30). Only changes in ACE activity, FFA and RBP4 concentrations during DI were correlated with weight regain in the whole group (r = -0.299, P = 0.030, r = -0.274, P = 0.047, and r = 0.357, P = 0.008, respectively). Together they explained 28% (r = 0.532) of weight regain variation. Dietary weight loss-induced changes in ACE activity, FFA and RBP4 independently contribute to weight regain prediction. PMID- 29122954 TI - Pregnancy-adapted uterine artery endothelial cell Ca2+ signaling and its relationship with membrane potential. AB - Pregnancy-derived uterine artery endothelial cells (P-UAEC) express P2Y2 receptors and at high cell density show sustained and synchronous [Ca2+]i burst responses in response to ATP Bursts in turn require coupling of transient receptor potential canonical type3 channel (TRPC3) and inositol 1,4,5 triphosphate receptor type 2 (IP3R2), which is upregulated in P-UAEC in a manner dependent on connexin 43 (Cx43) gap junctions. While there is no known direct interaction of TRPC3 with Cx43, early descriptions of TRPC3 function showed it may also be influenced by altered membrane potential (Vm). Herein, we ask if enhanced TRPC3 Ca2+ bursting due to enhanced Cx43 coupling may be coupled via dynamic alterations in Vm in P-UAEC, as reported in some (HUVEC) but not all endothelial cells. Following basic electrical characterization of UAEC, we employed a high sensitivity cell imaging system to simultaneously monitor cell Vm and [Ca2+]i in real time in continuous monolayers of UAEC Our findings show that while acute and sustained phase [Ca2+]i bursting occur dose-dependently in response to ATP, Vm is not coregulated with any periodicity related to [Ca2+]i bursting. Only a small but significant progressive change in Vm is seen, and this is more closely related to overall mobilization of Ca2+. Surprisingly, this is also most apparent in NP-UAEC > P-UAEC In contrast [Ca2+]i bursting is more synchronous in P-UAEC and even achieves [Ca2+]i waves passing through the P-UAEC monolayer. The relevance of these findings to mechanisms of pregnancy adaptation and its failure in hypertensive pregnancy are discussed. PMID- 29122955 TI - DNPEP is not the only peptidase that produces SPAK fragments in kidney. AB - SPAK (STE20/SPS1-related proline/alanine-rich kinase) regulates Na+ and Cl- reabsorption in the distal convoluted tubule, and possibly in the thick ascending limb of Henle. This kinase phosphorylates and activates the apical Na-Cl cotransporter in the DCT. Western blot analysis reveals that SPAK in kidney exists as a full-length protein as well as shorter fragments that might affect NKCC2 function in the TAL. Recently, we showed that kidney lysates exerts proteolytic activity towards SPAK, resulting in the formation of multiple SPAK fragments with possible inhibitory effects on the kinase. The proteolytic activity is mediated by a Zn2+ metalloprotease inhibited by 1,10-phenanthroline, DTT, and EDTA. Size exclusion chromatography demonstrated that the protease was a high-molecular-weight protein. Protein identification by mass-spectrometry analysis after ion exchange and size exclusion chromatography identified multiple proteases as possible candidates and aspartyl aminopeptidase, DNPEP, shared all the properties of the kidney lysate activity. Furthermore, recombinant GST-DNPEP produced similar proteolytic pattern. No mouse knockout model was, however, available to be used as negative control. In this study, we used a DNPEP-mutant mouse generated by EUCOMM as well as a novel CRISPR/cas9 mouse knockout to assess the activity of their kidney lysates towards SPAK. Two mouse models had to be used because different anti-DNPEP antibodies provided conflicting data on whether the EUCOMM mouse resulted in a true knockout. We show that in the absence of DNPEP, the kidney lysates retain their ability to cleave SPAK, indicating that DNPEP might have been misidentified as the protease behind the kidney lysate activity, or that the aspartyl aminopeptidase might not be the only protease cleaving SPAK in kidney. PMID- 29122956 TI - Characterization of age-related penile microvascular hemodynamic impairment using laser speckle contrast imaging: possible role of increased fibrogenesis. AB - Current technology for penile hemodynamic evaluations in small animals is invasive and has limitations. We evaluated a novel laser speckle contrast imaging (LSCI) technique to determine age-related changes in penile microvascular perfusion (PMP) and tested the role of cavernosal muscle (CC) fibrosis mediated by Wnt-TGF beta1 signaling pathways in a mouse model. Ten young (2-3 months) and old (24-28 months) wild-type C57BL6 male mice were subjected to PMP measured using a LSCI system. Penile blood flow (PBF, peak systolic velocity, PSV) was also measured using a color Doppler ultrasound for comparison. Measurements were made before and after injection of vasoactive drugs: prostaglandin E1 (PGE1) and acetylcholine (ACh). CC was processed for immunohistochemical studies for markers of endothelium and fibrosis. Protein levels were quantified by Western blot.PMP and PBF increased significantly from baseline after injection of vasoactive drugs. Peak PMP after PGE1 and ACh was higher in young mice (225.0 +/- 12.0 and 211.3 +/- 12.1 AU) compared to old (155.9 +/- 7.1 and 162.6 +/- 5.1 AU, respectively). PSV after PGE1 was higher in young than old mice (112.7 +/- 8.5 vs. 78.2 +/- 4.6 mm/sec). PSV after ACh was also higher in young (112.7 +/- 5.6 mm/sec) than older mice (69.2 +/- 7.1 mm/sec). PMP positively correlated with PSV (r = 0.867, P = 0.001). Immunostaining and Western blot showed increased protein expression of all fibrosis markers with aging. LSCI is a viable technique for evaluating penile hemodynamics. Increased cavernosal fibrosis may cause impaired penile hemodynamics and increased incidence of erectile dysfunction in older men. PMID- 29122957 TI - Diminished dynamic cerebral autoregulatory capacity with forced oscillations in mean arterial pressure with elevated cardiorespiratory fitness. AB - The effect that cardiorespiratory fitness has on the dynamic cerebral autoregulatory capacity during changes in mean arterial pressure (MAP) remains equivocal. Using a multiple-metrics approach, challenging MAP across the spectrum of physiological extremes (i.e., spontaneous through forced MAP oscillations), we characterized dynamic cerebral autoregulatory capacity in 19 male endurance athletes and eight controls via three methods: (1) onset of regulation (i.e., time delay before an increase in middle cerebral artery (MCA) conductance [MCA blood velocity (MCAv)/MAP] and rate of regulation, after transient hypotension induced by sit-to-stand, and transfer function analysis (TFA) of MAP and MCAv responses during (2) spontaneous and (3) forced oscillations (5-min of squat stand maneuvers performed at 0.05 and 0.10 Hz). Reductions in MAP and mean MCAv (MCAVmean) during initial orthostatic stress (0-30 sec after sit-to-stand) and the prevalence of orthostatic hypotension were also determined. Onset of regulation was delayed after sit-to-stand in athletes (3.1 +/- 1.7 vs. 1.5 +/- 1.0 sec; P = 0.03), but rate of regulation was not different between groups (0.24 +/- 0.05 vs. 0.21 +/- 0.09 sec-1; P = 0.82). While both groups had comparable TFA metrics during spontaneous oscillations, athletes had higher TFA gain during 0.10 Hz squat-stand versus recreational controls (P = 0.01). Reductions in MAP (P = 0.15) and MCAVmean (P = 0.11) during orthostatic stress and the prevalence of initial orthostatic hypotension (P = 0.65) were comparable between groups. These results indicate an intact ability of the cerebral vasculature to react to spontaneous oscillations but an attenuated capability to counter rapid and large changes in MAP in individuals with elevated cardiorespiratory fitness. PMID- 29122958 TI - A comparison of postoperative morphometric and hemodynamic changes between saphenous vein and left internal mammary artery grafts. AB - There is higher long-term failure of the saphenous vein graft (SVG) compared with the left internal mammary artery (LIMA) graft, which is affected by the hemodynamic environment. A comprehensive analysis of postoperative structure function changes is important to study the atherogenesis in the SVG A comparison of morphometric and hemodynamic parameters was carried out between LIMA grafts and SVGs and between different time points postoperatively. Various parameters were obtained from the image reconstruction and flow simulation in patients, who underwent CT exams for ~1 year, 5 and 10 years after revascularization. Morphometric data showed a decrease in lumen size in the entire SVG and anastomosis of different patients in a sequence of ~1 year, 5 and 10 years postoperatively despite negligible changes of LIMA size. Computational results indicated the fourfold increased surface area ratio (SAR) of low time-averaged wall shear stress (TAWSS) in the SVG and anastomosis at postoperative 10 years than that at postoperative ~1 year. The SAR of high TAWSS gradient (TAWSSG) at the distal anastomosis between SVG and coronary arteries was significantly higher (14 +/- 9% vs. 6 +/- 8%) than that in the LIMA group at postoperative ~1 year. There were strong correlations between morphometric and hemodynamic parameters in the SVG and distal anastomosis at various time points postoperatively, which showed deterioration relevant to persistent diffuse diseases at postoperative ~10 years. PMID- 29122959 TI - Prefrontal oxygenation correlates to the responses in facial skin blood flows during exposure to pleasantly charged movie. AB - Our laboratory reported that facial skin blood flow may serve as a sensitive tool to assess an emotional status. Cerebral neural correlates during emotional interventions should be sought in relation to the changes in facial skin blood flow. To test the hypothesis that prefrontal activity has positive relation to the changes in facial skin blood flow during emotionally charged stimulation, we examined the dynamic changes in prefrontal oxygenation (with near-infrared spectroscopy) and facial skin blood flows (with two-dimensional laser speckle and Doppler flowmetry) during emotionally charged audiovisual challenges for 2 min (by viewing comedy, landscape, and horror movie) in 14 subjects. Hand skin blood flow and systemic hemodynamics were simultaneously measured. The extents of pleasantness and consciousness for each emotional stimulus were estimated by subjective rating from -5 (the most unpleasant; the most unconscious) to +5 (the most pleasant; the most conscious). Positively charged emotional stimulation (comedy) simultaneously decreased (P < 0.05) prefrontal oxygenation and facial skin blood flow, whereas negatively charged (horror) or neutral (landscape) emotional stimulation did not alter or slightly decreased them. Any of hand skin blood flow and systemic cardiovascular variables did not change significantly during positively charged emotional stimulation. The changes in prefrontal oxygenation had a highly positive correlation with the changes in facial skin blood flow without altering perfusion pressure, and they were inversely correlated with the subjective rating of pleasantness. The reduction in prefrontal oxygenation during positively charged emotional stimulation suggests a decrease in prefrontal neural activity, which may in turn elicit neurally mediated vasoconstriction of facial skin blood vessels. PMID- 29122960 TI - MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesicles. AB - MicroRNAs contribute to the maintenance of optimal cellular functions by fine tuning protein expression levels. In the pancreatic beta-cells, imbalances in the exocytotic machinery components lead to impaired insulin secretion and type 2 diabetes (T2D). We hypothesize that dysregulated miRNA expression exacerbates beta-cell dysfunction, and have earlier shown that islets from the diabetic GK rat model have increased expression of miRNAs, including miR-335-5p (miR-335). Here, we aim to determine the specific role of miR-335 during development of T2D, and the influence of this miRNA on glucose-stimulated insulin secretion and Ca2+ dependent exocytosis. We found that the expression of miR-335 negatively correlated with secretion index in human islets of individuals with prediabetes. Overexpression of miR-335 in human EndoC-betaH1 and in rat INS-1 832/13 cells (OE335) resulted in decreased glucose-stimulated insulin secretion, and OE335 cells showed concomitant reduction in three exocytotic proteins: SNAP25, Syntaxin binding protein 1 (STXBP1), and synaptotagmin 11 (SYT11). Single-cell capacitance measurements, complemented with TIRF microscopy of the granule marker NPY-mEGFP demonstrated a significant reduction in exocytosis in OE335 cells. The reduction was not associated with defective docking or decreased Ca2+ current. More likely, it is a direct consequence of impaired priming of already docked granules. Earlier reports have proposed reduced granular priming as the cause of reduced first-phase insulin secretion during prediabetes. Here, we show a specific role of miR-335 in regulating insulin secretion during this transition period. Moreover, we can conclude that miR-335 has the capacity to modulate insulin secretion and Ca2+-dependent exocytosis through effects on granular priming. PMID- 29122961 TI - Whole-body heat stress and exercise stimulate the appearance of platelet microvesicles in plasma with limited influence of vascular shear stress. AB - Intense, large muscle mass exercise increases circulating microvesicles, but our understanding of microvesicle dynamics and mechanisms inducing their release remains limited. However, increased vascular shear stress is generally thought to be involved. Here, we manipulated exercise-independent and exercise-dependent shear stress using systemic heat stress with localized single-leg cooling (low shear) followed by single-leg knee extensor exercise with the cooled or heated leg (Study 1, n = 8) and whole-body passive heat stress followed by cycling (Study 2, n = 8). We quantified femoral artery shear rates (SRs) and arterial and venous platelet microvesicles (PMV-CD41+) and endothelial microvesicles (EMV CD62E+). In Study 1, mild passive heat stress while one leg remained cooled did not affect [microvesicle] (P >= 0.05). Single-leg knee extensor exercise increased active leg SRs by ~12-fold and increased arterial and venous [PMVs] by two- to threefold, even in the nonexercising contralateral leg (P < 0.05). In Study 2, moderate whole-body passive heat stress increased arterial [PMV] compared with baseline (mean+/-SE, from 19.9 +/- 1.5 to 35.5 +/- 5.4 PMV.MUL 1.103, P < 0.05), and cycling with heat stress increased [PMV] further in the venous circulation (from 27.5 +/- 2.2 at baseline to 57.5 +/- 7.2 PMV.MUL-1.103 during cycling with heat stress, P < 0.05), with a tendency for increased appearance of PMV across exercising limbs. Taken together, these findings demonstrate that whole-body heat stress may increase arterial [PMV], and intense exercise engaging either large or small muscle mass promote PMV formation locally and systemically, with no influence upon [EMV]. Local shear stress, however, does not appear to be the major stimulus modulating PMV formation in healthy humans. PMID- 29122962 TI - Frequent drinking of small volumes improves cardiac function and survival in rats with chronic heart failure. AB - Fluid retention is the main reason for the high hospitalization rate among patients with chronic heart failure (CHF). Given the lack of knowledge about fluid intake regulation and its consequences in patients with CHF, current guidelines do not provide clear direction for fluid management. Using a rat model of CHF, we investigated altering drinking behaviors and explored fluid management strategies. CHF was induced by ligating the left anterior descending coronary arteries in 8-week-old, male, Sprague-Dawley rats. A custom-designed drop counting and feedback control system was used to record and modulate drinking behaviors. During the first month after an induced myocardial infarction (MI), we observed that the spontaneous per drinking volume (PDV) was significantly increased in animals with prolonged intervals between drinking episodes. In addition, there was a significant inverse correlation between the early PDV and the post-MI lifespan (r = -0.907; P < 0.001). Moreover, modulating the drinking behavior of rats with CHF to involve frequent drinking of small PDVs significantly enhanced hemodynamics and prevented cardiac remodeling, with a significant improvement in the 180-day survival rate, compared with animals allowed to drink freely (50% vs. 36%; P < 0.01). The results of dynamic PDV changes, after MI, suggest that an impaired thirst mechanism is associated with the sensing and regulating of fluid balance in rats with CHF These results suggest that increasing the drinking frequency, with small PDVs, may be beneficial to preventing progression of cardiac dysfunction in CHF. PMID- 29122963 TI - Not merely a protective packing organ? A review of fascia and its force transmission capacity. AB - Recent research indicates that fascia is capable of changing its biomechanical properties. Moreover, as it links the skeletal muscles, forming a body-wide network of multidirectional myofascial continuity, the classical conception of muscles as independent actuators has been challenged. Hence, the present synthesis review aims to characterize the mechanical relevance of the connective tissue for the locomotor system. Results of cadaveric and animal studies suggest a clinically relevant myofascial force transmission to neighboring structures within one limb (e.g., between synergists) and in the course of muscle-fascia chains (e.g., between leg and trunk). Initial in vivo trials appear to underpin these findings, demonstrating the existence of nonlocal exercise effects. However, the factors influencing the amount of transmitted force (e.g., age and physical activity) remain controversial, as well as the role of the central nervous system within the context of the observed remote exercise effects. PMID- 29122964 TI - Enhanced muscle blood flow with intermittent pneumatic compression of the lower leg during plantar flexion exercise and recovery. AB - This study tested the hypothesis that intermittent compression of the lower limb would increase blood flow during exercise and postexercise recovery. Data were collected from 12 healthy individuals (8 men) who performed 3 min of standing plantar flexion exercise. The following three conditions were tested: no applied compression (NoComp), compression during the exercise period only (ExComp), and compression during 2 min of standing postexercise recovery. Doppler ultrasound was used to determine superficial femoral artery (SFA) blood flow responses. Mean arterial pressure (MAP) and cardiac stroke volume (SV) were assessed using finger photoplethysmography, with vascular conductance (VC) calculated as VC = SFA flow/MAP. Compared with the NoComp condition, compression resulted in increased MAP during exercise [+3.5 +/- 4.1 mmHg (mean +/- SD)] but not during postexercise recovery (+1.6 +/- 5.9 mmHg). SV increased with compression during both exercise (+4.8 +/- 5.1 ml) and recovery (+8.0 +/- 6.6 ml) compared with NoComp. There was a greater increase in SFA flow with compression during exercise (+52.1 +/- 57.2 ml/min) and during recovery (+58.6 +/- 56.7 ml/min). VC immediately following exercise was also significantly greater in the ExComp condition compared with the NoComp condition (+0.57 +/- 0.42 ml.min-1.mmHg-1), suggesting the observed increase in blood flow during exercise was in part because of changes in VC. Results from this study support the hypothesis that intermittent compression applied during exercise and recovery from exercise results in increased limb blood flow, potentially contributing to changes in exercise performance and recovery. NEW & NOTEWORTHY Blood flow to working skeletal muscle is achieved in part through the rhythmic actions of the skeletal muscle pump. This study demonstrated that the application of intermittent pneumatic compression during the diastolic phase of the cardiac cycle, to mimic the mechanical actions of the muscle pump, accentuates muscle blood flow during exercise and elevates blood flow during the postexercise recovery period. Intermittent compression during and after exercise might have implications for exercise performance and recovery. PMID- 29122967 TI - Hepatic accumulation of S-Adenosylmethionine in hamsters with non-alcoholic-fatty liver disease associated to metabolic syndrome under selenium and vitamin E deficiency. AB - Progression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of overrepresented transcription factors revealed a central role of c myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control towards senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation. PMID- 29122966 TI - Skeletal muscle function during the progression of cancer cachexia in the male ApcMin/+ mouse. AB - While cancer-induced skeletal muscle wasting has been widely investigated, the drivers of cancer-induced muscle functional decrements are only beginning to be understood. Decreased muscle function impacts cancer patient quality of life and health status, and several potential therapeutics have failed in clinical trials due to a lack of functional improvement. Furthermore, systemic inflammation and intrinsic inflammatory signaling's role in the cachectic disruption of muscle function requires further investigation. We examined skeletal muscle functional properties during cancer cachexia and determined their relationship to systemic and intrinsic cachexia indices. Male ApcMin/+ (MIN) mice were stratified by percent body weight loss into weight stable (WS; <5% loss) or cachectic (CX; >5% loss). Age-matched C57BL/6 littermates served as controls. Tibialis anterior (TA) twitch properties, tetanic force, and fatigability were examined in situ. TA protein and mRNA expression were examined in the nonstimulated leg. CX decreased muscle mass, tetanic force (Po), and specific tetanic force (sPo). Whole body and muscle fatigability were increased in WS and CX. CX had slower contraction rates, +dP/d t and -dP/d t, which were inversely associated with muscle signal transducer and activator of transcription 3 ( STAT3) and p65 activation. STAT3 and p65 activation were also inversely associated with Po. However, STAT3 was not related to sPo or fatigue. Muscle suppressor of cytokine signaling 3 mRNA expression was negatively associated with TA weight, Po, and sPo but not fatigue. Our study demonstrates that multiple functional deficits that occur with cancer cachexia are associated with increased muscle inflammatory signaling. Notably, muscle fatigability is increased in the MIN mouse before cachexia development. NEW & NOTEWORTHY Recent studies have identified decrements in skeletal muscle function during cachexia. We have extended these studies by directly relating decrements in muscle function to established cachexia indices. Our results demonstrate that a slow-fatigable contractile phenotype is developed during the progression of cachexia that coincides with increased muscle inflammatory signaling. Furthermore, regression analysis identified predictors of cancer induced muscle dysfunction. Last, we report the novel finding that whole body and muscle fatigability were increased before cachexia development. PMID- 29122965 TI - Impact of dairy protein during limb immobilization and recovery on muscle size and protein synthesis; a randomized controlled trial. AB - Muscle disuse results in the loss of muscular strength and size, due to an imbalance between protein synthesis (MPS) and breakdown (MPB). Protein ingestion stimulates MPS, although it is not established if protein is able to attenuate muscle loss with immobilization (IM) or influence the recovery consisting of ambulatory movement followed by resistance training (RT). Thirty men (49.9 +/- 0.6 yr) underwent 14 days of unilateral leg IM, 14 days of ambulatory recovery (AR), and a further six RT sessions over 14 days. Participants were randomized to consume an additional 20 g of dairy protein or placebo with a meal during the intervention. Isometric knee extension strength was reduced following IM (-24.7 +/- 2.7%), partially recovered with AR (-8.6 +/- 2.6%), and fully recovered after RT (-0.6 +/- 3.4%), with no effect of supplementation. Thigh muscle cross sectional area decreased with IM (-4.1 +/- 0.5%), partially recovered with AR ( 2.1 +/- 0.5%), and increased above baseline with RT (+2.2 +/- 0.5%), with no treatment effect. Myofibrillar MPS, measured using deuterated water, was unaltered by IM, with no effect of protein. During AR, MPS was increased only with protein supplementation. Protein supplementation did not attenuate the loss of muscle size and function with disuse or potentiate recovery but enhanced myofibrillar MPS during AR. NEW & NOTEWORTHY Twenty grams of daily protein supplementation does not attenuate the loss of muscle size and function induced by 2 wk of muscle disuse or potentiate recovery in middle-age men. Average mitochondrial but not myofibrillar muscle protein synthesis was attenuated during immobilization with no effect of supplementation. Protein supplementation increased myofibrillar protein synthesis during a 2-wk period of ambulatory recovery following disuse but without group differences in phenotype recovery. PMID- 29122968 TI - Energy landscape differences among integrins establish the framework for understanding activation. AB - Why do integrins differ in basal activity, and how does affinity for soluble ligand correlate with cellular adhesiveness? We show that basal conformational equilibrium set points for integrin alpha4beta1 are cell type specific and differ from integrin alpha5beta1 when the two integrins are coexpressed on the same cell. Although alpha4beta1 is easier to activate, its high-affinity state binds vascular cell adhesion molecule and fibronectin 100- to 1,000-fold more weakly than alpha5beta1 binds fibronectin. Furthermore, the difference in affinity between the high- and low-affinity states is more compressed in alpha4beta1 (600- to 800-fold) than in alpha5beta1 (4,000- to 6,000-fold). alpha4beta1 basal conformational equilibria differ among three cell types, define affinity for soluble ligand and readiness for priming, and may reflect differences in interactions with intracellular adaptors but do not predict cellular adhesiveness for immobilized ligand. The measurements here provide a necessary framework for understanding integrin activation in intact cells, including activation of integrin adhesiveness by application of tensile force by the cytoskeleton, across ligand-integrin-adaptor complexes. PMID- 29122969 TI - Single Ca2+ transients vs oscillatory Ca2+ signaling for assisted oocyte activation: limitations and benefits. AB - Oocyte activation is a calcium (Ca2+)-dependent process that has been investigated in depth, in particular, regarding its impact on assisted reproduction technology (ART). Following a standard model of signal transduction, Ca2+ drives the meiotic progression upon fertilization in all species studied to date. However, Ca2+ changes during oocyte activation are species specific, and they can be classified in two modalities based on the pattern defined by the Ca2+ signature: a single Ca2+ transient (e.g. amphibians) or repetitive Ca2+ transients called Ca2+ oscillations (e.g. mammals). Interestingly, assisted oocyte activation (AOA) methods have highlighted the ability of mammalian oocytes to respond to single Ca2+ transients with normal embryonic development. In this regard, there is evidence supporting that cellular events during the process of oocyte activation are initiated by different number of Ca2+ oscillations. Moreover, it was proposed that oocyte activation and subsequent embryonic development are dependent on the total summation of the Ca2+ peaks, rather than to a specific frequency pattern of Ca2+ oscillations. The present review aims to demonstrate the complexity of mammalian oocyte activation by describing the series of Ca2+-linked physiological events involved in mediating the egg-to embryo transition. Furthermore, mechanisms of AOA and the limitations and benefits associated with the application of different activation agents are discussed. PMID- 29122970 TI - A novel form of RNA double helix based on G.U and C.A+ wobble base pairing. AB - Wobble base pairs are critical in various physiological functions and have been linked to local structural perturbations in double-helical structures of nucleic acids. We report a 1.38-A resolution crystal structure of an antiparallel octadecamer RNA double helix in overall A conformation, which includes a unique, central stretch of six consecutive wobble base pairs (W helix) with two G.U and four rare C.A+ wobble pairs. Four adenines within the W helix are N1-protonated and wobble-base-paired with the opposing cytosine through two regular hydrogen bonds. Combined with the two G.U pairs, the C.A+ base pairs facilitate formation of a half turn of W-helical RNA flanked by six regular Watson-Crick base pairs in standard A conformation on either side. RNA melting experiments monitored by differential scanning calorimetry, UV and circular dichroism spectroscopy demonstrate that the RNA octadecamer undergoes a pH-induced structural transition which is consistent with the presence of a duplex with C.A+ base pairs at acidic pH. Our crystal structure provides a first glimpse of an RNA double helix based entirely on wobble base pairs with possible applications in RNA or DNA nanotechnology and pH biosensors. PMID- 29122971 TI - Poly(A) site choice and Pol2 CTD Serine-5 status govern lncRNA control of phosphate-responsive tgp1 gene expression in fission yeast. AB - Expression of fission yeast glycerophosphate transporter Tgp1 is repressed in phosphate-rich medium and induced during phosphate starvation. Repression is enforced by transcription of the nc-tgp1 locus upstream of tgp1 to produce a long noncoding (lnc) RNA. Here we identify two essential elements of the nc-tgp1 promoter: a TATA box -30TATATATA-23 and a HomolD box -64CAGTCACA-57, mutations of which inactivate the nc-tgp1 promoter and de-repress the downstream tgp1 promoter under phosphate-replete conditions. The nc-tgp1 lncRNA poly(A) site maps to nucleotide +1636 of the transcription unit, which coincides with the binding site for Pho7 (1632TCGGACATTCAA1643), the transcription factor that drives tgp1 expression. Overlap between the lncRNA template and the tgp1 promoter points to transcriptional interference as the simplest basis for lncRNA repression. We identify a shorter RNA derived from the nc-tgp1 locus, polyadenylated at position +508, well upstream of the tgp1 promoter. Mutating the nc-tgp1-short RNA polyadenylation signal abolishes de-repression of the downstream tgp1 promoter elicited by Pol2 CTD Ser5Ala phospho-site mutation. Ser5 mutation favors utilization of the short RNA poly(A) site, thereby diminishing transcription of the lncRNA that interferes with the tgp1 promoter. Mutating the nc-tgp1-short RNA polyadenylation signal attenuates induction of the tgp1 promoter during phosphate starvation. Polyadenylation site choice governed by CTD Ser5 status adds a new level of lncRNA control of gene expression and reveals a new feature of the fission yeast CTD code. PMID- 29122972 TI - Eating Disorders, Autoimmune, and Autoinflammatory Disease. AB - OBJECTIVES: Identifying factors associated with risk for eating disorders is important for clarifying etiology and for enhancing early detection of eating disorders in primary care. We hypothesized that autoimmune and autoinflammatory diseases would be associated with eating disorders in children and adolescents and that family history of these illnesses would be associated with eating disorders in probands. METHODS: In this large, nationwide, population-based cohort study of all children and adolescents born in Denmark between 1989 and 2006 and managed until 2012, Danish medical registers captured all inpatient and outpatient diagnoses of eating disorders and autoimmune and autoinflammatory diseases. The study population included 930 977 individuals (48.7% girls). Cox proportional hazards regression models and logistic regression were applied to evaluate associations. RESULTS: We found significantly higher hazards of eating disorders for children and adolescents with autoimmune or autoinflammatory diseases: 36% higher hazard for anorexia nervosa, 73% for bulimia nervosa, and 72% for an eating disorder not otherwise specified. The association was particularly strong in boys. Parental autoimmune or autoinflammatory disease history was associated with significantly increased odds for anorexia nervosa (odds ratio [OR] = 1.13, confidence interval [CI] = 1.01-1.25), bulimia nervosa (OR = 1.29; CI = 1.08-1.55) and for an eating disorder not otherwise specified (OR = 1.27; CI = 1.13-1.44). CONCLUSIONS: Autoimmune and autoinflammatory diseases are associated with increased risk for eating disorders. Ultimately, understanding the role of immune system disturbance for the etiology and pathogenesis of eating disorders could point toward novel treatment targets. PMID- 29122973 TI - Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome in Adolescents: A Case Series. AB - Cannabinoid hyperemesis syndrome (CHS) is an underrecognized diagnosis among adolescents. In the adult literature, it is characterized as nausea, vomiting, and abdominal pain in patients with chronic marijuana use. CHS is often refractory to the standard treatment of nausea and vomiting. Unconventional antiemetics, such as haloperidol, have been successful in alleviating symptoms; however, even 1 dose of haloperidol can lead to grave adverse effects, such as dystonia, extrapyramidal reactions, and neuroleptic malignant syndrome. The use of topical capsaicin cream to treat CHS has been well described in the adult literature. This treatment is cost-effective and is associated with few serious side effects. Here, we describe 2 adolescent patients with nausea, vomiting, and abdominal pain in the setting of chronic cannabis use whose symptoms were not relieved by standard antiemetic therapies, but who responded well to topical capsaicin administration in our pediatric emergency department. We also discuss the pathophysiology behind capsaicin's efficacy. These are the first reported cases in which capsaicin was successfully used to treat CHS in pediatric patients. PMID- 29122975 TI - Efficiency and thoroughness trade-offs in high-volume organisational routines: an ethnographic study of prescribing safety in primary care. AB - BACKGROUND: Prescribing is a high-volume primary care routine where both speed and attention to detail are required. One approach to examining how organisations approach quality and safety in the face of high workloads is Hollnagel's Efficiency and Thoroughness Trade-Off (ETTO). Hollnagel argues that safety is aligned with thoroughness and that a choice is required between efficiency and thoroughness as it is not usually possible to maximise both. This study aimed to ethnographically examine the efficiency and thoroughness trade-offs made by different UK general practices in the achievement of prescribing safety. METHODS: Non-participant observation was conducted of prescribing routines across eight purposively sampled UK general practices. Sixty-two semistructured interviews were also conducted with key practice staff alongside the analysis of relevant practice documents. RESULTS: The eight practices in this study adopted different context-specific approaches to safely handling prescription requests by variably prioritising speed of processing by receptionists (efficiency) or general practitioner (GP) clinical judgement (thoroughness). While it was not possible to maximise both at the same time, practices situated themselves at various points on an efficiency-thoroughness spectrum where one approach was prioritised at particular stages of the routine. Both approaches carried strengths and risks, with thoroughness-focused approaches considered safer but more challenging to implement in practice due to GP workload issues. Most practices adopting efficiency-focused approaches did so out of necessity as a result of their high workload due to their patient population (eg, older, socioeconomically deprived). CONCLUSIONS: Hollnagel's ETTO presents a useful way for healthcare organisations to optimise their own high-volume processes through reflection on where they currently prioritise efficiency and thoroughness, the stages that are particularly risky and improved ways of balancing competing priorities. PMID- 29122974 TI - Anorexia and Autoimmunity: Challenging the Etiologic Constructs of Disordered Eating. PMID- 29122976 TI - Roadmap for improving the accuracy of respiratory rate measurements. PMID- 29122977 TI - Abeta inhibits SREBP-2 activation through Akt inhibition. AB - We previously demonstrated that oligomeric amyloid beta42 (oAbeta42) inhibits the mevalonate pathway impairing cholesterol synthesis and protein prenylation. Enzymes of the mevalonate pathway are regulated by the transcription factor SREBP 2. Here, we show that in several neuronal types challenged with oAbeta42, SREBP-2 activation is reduced. Moreover, SREBP-2 activation is also decreased in the brain cortex of the Alzheimer's disease (AD) mouse model, TgCRND8, suggesting that SREBP-2 may be affected in vivo early in the disease. We demonstrate that oAbeta42 does not affect enzymatic cleavage of SREBP-2 per se, but may impair SREBP-2 transport from the endoplasmic reticulum (ER) to the Golgi. Trafficking of SREBP-2 from the ER to the Golgi requires protein kinase B (Akt) activation. oAbeta42 significantly reduces Akt phosphorylation and this decrease is responsible for the decline in SREBP-2 activation. Overexpression of constitutively active Akt prevents the effect of oAbeta42 on SREBP-2 and the downstream inhibition of cholesterol synthesis and protein prenylation. Our work provides a novel mechanistic link between Abeta and the mevalonate pathway, which will impact the views on issues related to cholesterol, isoprenoids, and statins in AD. We also identify SREBP-2 as an indirect target of Akt in neurons, which may play a role in the cross-talk between AD and diabetes. PMID- 29122980 TI - Correction: HIV-1 Tat potently stabilises Mdm2 and enhances viral replication. PMID- 29122979 TI - Using an epidemiological framework and bovine spongiform encephalopathy investigation questionnaire to investigate suspect bovine spongiform encephalopathy cases: an example from a bovine spongiform encephalopathy case in Ireland in 2015. AB - In several EU member states, bovine spongiform encephalopathy (BSE) cases have been identified in cattle born after the reinforced ban (BARB cases), for reasons that are not entirely clear. Epidemiological investigation of these cases has proved challenging. The European Food Safety Authority recently recommended the collection of a predefined set of epidemiological data from BSE suspects and confirmed BSE cases to aid future investigations. In this study, we present an epidemiological framework and BSE investigation questionnaire to aid the investigation of suspect BSE cases, and illustrate its application during the investigation of a BSE case in Ireland in 2015. It is recommended that the framework and questionnaire are used concurrently: the framework provides structure and focus, whereas the questionnaire (with 135 questions) aids data collection. The framework focuses on confirmation and discrimination, estimating the date and location of exposure, and determining the method/source of exposure. The BSE case in Ireland in 2015 was a BARB case born in 2010. It was identified with classical BSE at an authorised knackery as part of Ireland's targeted active surveillance programme for BSE. No definitive source of infection with the BSE agent could be attributed in this case. PMID- 29122981 TI - In situ imaging of mitochondrial translation shows weak correlation with nucleoid DNA intensity and no suppression during mitosis. AB - Although mitochondrial translation produces only 13 proteins, we show here how this process can be visualised and detected in situ by fluorescence microscopy with a simple, rapid and inexpensive procedure using non-canonical amino acid labelling and click chemistry. This allows visualisation of the translational output in different mitochondria within a cell, their position within that cell and a comparison of mitochondrial translation between cells. The most highly translationally active mitochondria were closest to the nucleus but were also found at the distal end of long cellular projections. There were substantial differences in translation between adjacent mitochondria and this did not readily correlate with apparent mitochondrial genome content. Mitochondrial translation was unchanged during mitosis when cytoplasmic translation was suppressed. This method will serve both fundamental cell biology and clinically orientated studies, in which mitochondrial function is a key parameter. PMID- 29122982 TI - Real-time observation of light-controlled transcription in living cells. AB - Gene expression is tightly regulated in space and time. To dissect this process with high temporal resolution, we introduce an optogenetic tool termed blue light induced chromatin recruitment (BLInCR) that combines rapid and reversible light dependent recruitment of effector proteins with a real-time readout for transcription. We used BLInCR to control the activity of a cluster of reporter genes in the human osteosarcoma cell line U2OS by reversibly recruiting the viral transactivator VP16. RNA production was detectable ~2 min after VP16 recruitment and readily decreased when VP16 dissociated from the cluster in the absence of light. Quantitative assessment of the activation process revealed biphasic activation kinetics with a pronounced early phase in cells treated with the histone deacetylase inhibitor SAHA. Comparison with kinetic models of transcription activation suggests that the gene cluster undergoes a maturation process when activated. We anticipate that BLInCR will facilitate the study of transcription dynamics in living cells.This article has an associated First Person interview with the first author of the paper. PMID- 29122978 TI - The structural basis of ryanodine receptor ion channel function. AB - Large-conductance Ca2+ release channels known as ryanodine receptors (RyRs) mediate the release of Ca2+ from an intracellular membrane compartment, the endo/sarcoplasmic reticulum. There are three mammalian RyR isoforms: RyR1 is present in skeletal muscle; RyR2 is in heart muscle; and RyR3 is expressed at low levels in many tissues including brain, smooth muscle, and slow-twitch skeletal muscle. RyRs form large protein complexes comprising four 560-kD RyR subunits, four ~12-kD FK506-binding proteins, and various accessory proteins including calmodulin, protein kinases, and protein phosphatases. RyRs share ~70% sequence identity, with the greatest sequence similarity in the C-terminal region that forms the transmembrane, ion-conducting domain comprising ~500 amino acids. The remaining ~4,500 amino acids form the large regulatory cytoplasmic "foot" structure. Experimental evidence for Ca2+, ATP, phosphorylation, and redox sensitive sites in the cytoplasmic structure have been described. Exogenous effectors include the two Ca2+ releasing agents caffeine and ryanodine. Recent work describing the near atomic structures of mammalian skeletal and cardiac muscle RyRs provides a structural basis for the regulation of the RyRs by their multiple effectors. PMID- 29122983 TI - Restricted cell functions on micropillars are alleviated by surface-nanocoating with amino groups. AB - The topographical and chemical surface features of biomaterials are sensed by the cells, affecting their physiology at the interface. When placed on titanium, we recently discovered osteoblasts attempted caveolae-mediated phagocytosis of the sharp-edged microstructures. This active, energy-consuming process resulted in decreased osteoblastic cell functions (e.g. secretion of extracellular matrix proteins). However, chemical modification with plasma polymerized allylamine (PPAAm) was able to amplify osteoblast adhesion and spreading, resulting in better implant osseointegration in vivo In the present in vitro study, we analyzed whether this plasma polymer nanocoating is able to attenuate the microtopography-induced changes of osteoblast physiology. On PPAAm, we found cells showed a higher cell interaction with the geometrical micropillars by 30 min, and a less distinct reduction in the mRNA expression of collagen type I, osteocalcin and fibronectin after 24 h of cell growth. Interestingly, the cells were more active and sensitive on PPAAm-coated micropillars, and react with a substantial Ca2+ ion mobilization after stimulation with ATP. These results highlight that it is important for osteoblasts to establish cell surface contact for them to perform their functions. PMID- 29122984 TI - Effects of mutating alpha-tubulin lysine 40 on sensory dendrite development. AB - Microtubules are essential for neuronal structure and function. Axonal and dendritic microtubules are enriched in post-translational modifications that impact microtubule dynamics, transport and microtubule-associated proteins. Acetylation of alpha-tubulin lysine 40 (K40) is a prominent and conserved modification of neuronal microtubules. However, the cellular role of microtubule acetylation remains controversial. To resolve how microtubule acetylation might affect neuronal morphogenesis, we mutated endogenous alpha-tubulin in vivo using a new Drosophila strain that facilitates the rapid knock-in of designer alphaTub84B alleles (the predominant alpha-tubulin-encoding gene in flies). Leveraging our new strain, we found that microtubule acetylation, as well as polyglutamylation and (de)tyrosination, is not essential for survival. However, we found that dendrite branch refinement in sensory neurons relies on alpha tubulin K40. Mutagenesis of K40 reveals moderate yet significant changes in dendritic lysosome transport, microtubule polymerization and Futsch protein distribution in dendrites but not in axons. Our studies point to an unappreciated role for alpha-tubulin K40 and acetylation in dendrite morphogenesis. While our results are consistent with the idea that acetylation tunes microtubule function within neurons, they also suggest there may be an acetylation-independent requirement for alpha-tubulin K40.This article has an associated First Person interview with the first author of the paper. PMID- 29122985 TI - TsNAC1 Is a Key Transcription Factor in Abiotic Stress Resistance and Growth. AB - NAC proteins constitute one of the largest families of plant-specific transcription factors, and a number of these proteins participate in the regulation of plant development and responses to abiotic stress. T. HALOPHILA STRESS RELATED NAC1 (TsNAC1), cloned from the halophyte Thellungiella halophila, is a NAC transcription factor gene, and its overexpression can improve abiotic stress resistance, especially in salt stress tolerance, in both T. halophila and Arabidopsis (Arabidopsis thaliana) and retard the growth of these plants. In this study, the transcriptional activation activity of TsNAC1 and RD26 from Arabidopsis was compared with the target genes' promoter regions of TsNAC1 from T. halophila, and the results showed that the transcriptional activation activity of TsNAC1 was higher in tobacco (Nicotiana tabacum) and yeast. The target sequence of the promoter from the target genes also was identified, and TsNAC1 was shown to target the positive regulators of ion transportation, such as T. HALOPHILA H+-PPASE1, and the transcription factors MYB HYPOCOTYL ELONGATION RELATED and HOMEOBOX12 In addition, TsNAC1 negatively regulates the expansion of cells, inhibits LIGHT-DEPENDENT SHORT HYPOCOTYLS1 and UDP-XYLOSYLTRANSFERASE2, and directly controls the expression of MULTICOPY SUPPRESSOR OF IRA14 Based on these results, we propose that TsNAC1 functions as an important upstream regulator of plant abiotic stress responses and vegetative growth. PMID- 29122986 TI - Coexpression Analysis Identifies Two Oxidoreductases Involved in the Biosynthesis of the Monoterpene Acid Moiety of Natural Pyrethrin Insecticides in Tanacetum cinerariifolium. AB - Flowers of Tanacetum cinerariifolium produce a set of compounds known collectively as pyrethrins, which are commercially important pesticides that are strongly toxic to flying insects but not to most vertebrates. A pyrethrin molecule is an ester consisting of either trans-chrysanthemic acid or its modified form, pyrethric acid, and one of three alcohols, jasmolone, pyrethrolone, and cinerolone, that appear to be derived from jasmonic acid. Chrysanthemyl diphosphate synthase (CDS), the first enzyme involved in the synthesis of trans-chrysanthemic acid, was characterized previously and its gene isolated. TcCDS produces free trans-chrysanthemol in addition to trans chrysanthemyl diphosphate, but the enzymes responsible for the conversion of trans-chrysanthemol to the corresponding aldehyde and then to the acid have not been reported. We used an RNA sequencing-based approach and coexpression correlation analysis to identify several candidate genes encoding putative trans chrysanthemol and trans-chrysanthemal dehydrogenases. We functionally characterized the proteins encoded by these genes using a combination of in vitro biochemical assays and heterologous expression in planta to demonstrate that TcADH2 encodes an enzyme that oxidizes trans-chrysanthemol to trans chrysanthemal, while TcALDH1 encodes an enzyme that oxidizes trans-chrysanthemal into trans-chrysanthemic acid. Transient coexpression of TcADH2 and TcALDH1 together with TcCDS in Nicotiana benthamiana leaves results in the production of trans-chrysanthemic acid as well as several other side products. The majority (58%) of trans-chrysanthemic acid was glycosylated or otherwise modified. Overall, these data identify key steps in the biosynthesis of pyrethrins and demonstrate the feasibility of metabolic engineering to produce components of these defense compounds in a heterologous host. PMID- 29122987 TI - Glutathione Transferase U13 Functions in Pathogen-Triggered Glucosinolate Metabolism. AB - Glutathione (GSH) and indole glucosinolates (IGs) exert key functions in the immune system of the model plant Arabidopsis (Arabidopsis thaliana). Appropriate GSH levels are important for execution of both pre- and postinvasive disease resistance mechanisms to invasive pathogens, whereas an intact PENETRATION2 (PEN2)-pathway for IG metabolism is essential for preinvasive resistance in this species. Earlier indirect evidence suggested that the latter pathway involves conjugation of GSH with unstable products of IG metabolism and further processing of the resulting adducts to biologically active molecules. Here we describe the identification of Glutathione-S-Transferase class-tau member 13 (GSTU13) as an indispensable component of the PEN2 immune pathway for IG metabolism. gstu13 mutant plants are defective in the pathogen-triggered biosynthesis of end products of the PEN2 pathway, including 4-O-beta-d-glucosyl-indol-3-yl formamide, indole-3-ylmethyl amine, and raphanusamic acid. In line with this metabolic defect, lack of functional GSTU13 results in enhanced disease susceptibility toward several fungal pathogens including Erysiphe pisi, Colletotrichum gloeosporioides, and Plectosphaerella cucumerina Seedlings of gstu13 plants fail also to deposit the (1,3)-beta-glucan cell wall polymer, callose, after recognition of the bacterial flg22 epitope. We show that GSTU13 mediates specifically the role of GSH in IG metabolism without noticeable impact on other immune functions of this tripeptide. We postulate that GSTU13 connects GSH with the pathogen-triggered PEN2 pathway for IG metabolism to deliver metabolites that may have numerous functions in the innate immune system of Arabidopsis. PMID- 29122988 TI - KinG Is a Plant-Specific Kinesin That Regulates Both Intra- and Intercellular Movement of SHORT-ROOT. AB - Both endogenous plant proteins and viral movement proteins associate with microtubules to promote their movement through plasmodesmata. The association of viral movement proteins with microtubules facilitates the formation of virus associated replication complexes, which are required for the amplification and subsequent spread of the virus. However, the role of microtubules in the intercellular movement of plant proteins is less clear. Here we show that the SHORT-ROOT (SHR) protein, which moves between cells in the root to regulate root radial patterning, interacts with a type-14 kinesin, KINESIN G (KinG). KinG is a calponin homology domain kinesin that directly interacts with the SHR-binding protein SIEL (SHR-INTERACING EMBRYONIC LETHAL) and localizes to both microtubules and actin. Since SIEL and SHR associate with endosomes, we suggest that KinG serves as a linker between SIEL, SHR, and the plant cytoskeleton. Loss of KinG function results in a decrease in the intercellular movement of SHR and an increase in the sensitivity of SHR movement to treatment with oryzalin. Examination of SHR and KinG localization and dynamics in live cells suggests that KinG is a nonmotile kinesin that promotes the pausing of SHR-associated endosomes. We suggest a model in which interaction of KinG with SHR allows for the formation of stable movement complexes that facilitate the cell-to-cell transport of SHR. PMID- 29122989 TI - Recent Discoveries on the Role of TOR (Target of Rapamycin) Signaling in Translation in Plants. PMID- 29122990 TI - Expression of COBLL1 encoding novel ROR1 binding partner is robust predictor of survival in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia is a disease with up-regulated expression of the transmembrane tyrosine-protein kinase ROR1, a member of the Wnt/planar cell polarity pathway. In this study, we identified COBLL1 as a novel interaction partner of ROR1. COBLL1 shows clear bimodal expression with high levels in chronic lymphocytic leukemia patients with mutated IGHV and approximately 30% of chronic lymphocytic leukemia patients with unmutated IGHV. In the remaining 70% of chronic lymphocytic leukemia patients with unmutated IGHV, COBLL1 expression is low. Importantly, chronic lymphocytic leukemia patients with unmutated IGHV and high COBLL1 have an unfavorable disease course with short overall survival and time to second treatment. COBLL1 serves as an independent molecular marker for overall survival in chronic lymphocytic leukemia patients with unmutated IGHV. In addition, chronic lymphocytic leukemia patients with unmutated IGHV and high COBLL1 show impaired motility and chemotaxis towards CCL19 and CXCL12 as well as enhanced B-cell receptor signaling pathway activation demonstrated by increased PLCgamma2 and SYK phosphorylation after IgM stimulation. COBLL1 expression also changes during B-cell maturation in non-malignant secondary lymphoid tissue with a higher expression in germinal center B cells than naive and memory B cells. Our data thus suggest COBLL1 involvement not only in chronic lymphocytic leukemia but also in B-cell development. In summary, we show that expression of COBLL1, encoding novel ROR1-binding partner, defines chronic lymphocytic leukemia subgroups with a distinct response to microenvironmental stimuli, and independently predicts survival of chronic lymphocytic leukemia with unmutated IGHV. PMID- 29122991 TI - Maternal embryonic leucine zipper kinase is a novel target for proliferation associated high-risk myeloma. AB - Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene expression profiling-defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified in order to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analyzed the activity of the MELK inhibitor OTSSP167 both in vitro and in vivoMELK was found to be significantly overexpressed in the proliferative subgroup of myeloma. This finding translated into poor overall survival in patients with high vs low MELK expression. Enrichment analysis of upregulated genes in myeloma cells of MELKhigh patients confirmed the strong implications in myeloma cell proliferation. Targeting MELK with OTSSP167 impaired the growth and survival of myeloma cells, thereby affecting central survival factors such as MCL 1 and IRF4 This activity was also observed in the 5TGM.1 murine model of myeloma. OTSSP167 reduced bone marrow infiltration and serum paraprotein levels in a dose dependent manner. In addition, we revealed a strong link between MELK and other proliferation-associated high-risk genes (PLK-1, EZH2, FOXM1, DEPDC1) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature and that pharmacological inhibition of MELK represents an attractive novel approach to overcome the poor prognosis of high-risk patients with a proliferative expression pattern. PMID- 29122992 TI - Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes. AB - Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non transferrin bound iron levels were visible early in follow-up of all transfusion dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860. PMID- 29122993 TI - Microenvironmental stromal cells abrogate NF-kappaB inhibitor-induced apoptosis in chronic lymphocytic leukemia. AB - Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) is known to play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). Several NF-kappaB inhibitors were shown to successfully induce apoptosis of CLL cells in vitro Since the microenvironment is known to be crucial for the survival of CLL cells, herein, we tested whether NF-kappaB inhibition may still induce apoptosis in these leukemic cells in the presence of protective stromal interaction. We used the specific NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). Microenvironmental support was mimicked by co-culturing CLL cells with bone marrow-derived stromal cell lines (HS-5 and M2-10B4). NF-kappaB inhibition by DHMEQ in CLL cells could be confirmed in both the monoculture and co-culture setting. In line with previous reports, NF-kappaB inhibition induced apoptosis in the monoculture setting by activating the intrinsic apoptotic pathway resulting in poly (ADP-ribose) polymerase (PARP) cleavage; however, it was unable to induce apoptosis in leukemic cells co cultured with stromal cells. Similarly, small interfering ribonucleic acid (siRNA)-mediated RELA downregulation induced apoptosis of CLL cells cultured alone, but not in the presence of supportive stromal cells. B-cell activating factor (BAFF) was identified as a microenvironmental messenger potentially protecting the leukemic cells from NF-kappaB inhibition-induced apoptosis. Finally, we show improved sensitivity of stroma-supported CLL cells to NF-kappaB inhibition when combining the NF-kappaB inhibitor with the SYK inhibitor R406 or the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, agents known to inhibit the stroma-leukemia crosstalk. We conclude that NF-kappaB inhibitors are not promising as monotherapies in CLL, but may represent attractive therapeutic partners for ibrutinib and R406. PMID- 29122994 TI - Childhood psychosocial adversity and female reproductive timing: a cohort study of the ALSPAC mothers. AB - BACKGROUND: Previous studies of childhood psychosocial adversity and age at menarche mostly evaluated single or a few measures of adversity, and therefore could not quantify total psychosocial adversity. Limited knowledge is currently available regarding childhood psychosocial adversity in relation to age at menopause and reproductive lifespan. METHODS: We examined the associations of total and specific components of childhood psychosocial adversity with age at menarche (n=8984), age at menopause (n=945), and length of reproductive lifespan (n=841), in mothers participating in the Avon Longitudinal Study of Parents and Children. We used confirmatory factor analysis to characterise lack of care, maladaptive family functioning, non-sexual abuse, overprotective parenting, parental mental illness and sexual abuse. These specific components of childhood psychosocial adversity were combined into a total psychosocial adversity score using a second-order factor analysis. We used structural equation models to simultaneously conduct the factor analysis and estimate the association with the continuous outcomes of interest. RESULTS: Total childhood psychosocial adversity was not associated with age at menarche, age at menopause or length of reproductive lifespan. When we examined the separate psychosocial adversity constructs, sexual abuse was inversely associated with age at menarche, with a mean difference of -0.17 (95% CI -0.23 to -0.12) years per SD higher factor score, and with age at menopause, with a mean difference of -0.17 (95% CI -0.52 to 0.18) per SD higher factor score. CONCLUSION: Childhood sexual abuse was associated with lower age at menarche and menopause, but the latter needs to be confirmed in larger samples. PMID- 29122995 TI - Families First Home Visiting programme reduces population-level child health and social inequities. AB - BACKGROUND: Home visiting has been shown to reduce child maltreatment and improve child health outcomes. In this observational study, we explored whether Families First, a home visiting programme in Manitoba, Canada, decreased population-level inequities in children being taken into care of child welfare and receiving complete childhood immunisations. METHODS: De-identified administrative health and social services data for children born 2003-2009 in Manitoba were linked to home visiting programme data. Programme eligibility was determined by screening for family risk factors. We compared probabilities of being taken into care and receiving immunisations among programme children (n=4575), eligible children who did not receive the programme (n=5186) and the general child population (n=87 897) and tested inequities using differences of risk differences (DRDs) and ratios of risk ratios (RRRs). RESULTS: Programme children were less likely to be taken into care (probability (95% CI) at age 1, programme 7.5 (7.0 to 8.0) vs non programme 10.0 (10.0 to 10.1)) and more likely to receive complete immunisations (probability at age 1, programme 77.3 (76.5 to 78.0) vs non-programme 73.2 (72.1 to 74.3)). Inequities between programme children and the general population were reduced for both outcomes (being taken into care at age 1, DRD -2.5 (-3.7 to 1.2) and RRR 0.8 (0.7 to 0.9); complete immunisation at age 1, DRD 4.1 (2.2 to 6.0) and RRR 1.1 (1.0 to 1.1)); these inequities were also significantly reduced at age 2. CONCLUSION: Home visiting programmes should be recognised as effective strategies for improving child outcomes and reducing population-level health and social inequities. PMID- 29122996 TI - Early life cognitive function and health behaviours in late childhood: testing the neuroselection hypothesis. AB - BACKGROUND: Higher cognitive function in childhood is associated with healthier behaviours and a reduced risk of chronic disease in adulthood, but it is unclear whether this selection of healthier behaviours occurs in childhood or later in life. The present study investigated how cognitive function at age 3-7 years was associated with health behaviours at age 11. METHODS: Verbal, non-verbal and spatial abilities were assessed using the British Ability Scales at ages 3-7. At age 11, children reported how often they engaged in sport/physical activity, sedentary behaviours (eg, reading and games console usage), cigarette smoking and alcohol consumption. Logistic regression was used to estimate odds of engaging in health behaviours at age 11 according to early life cognition. RESULTS: A 1 SD increase in early childhood verbal ability was associated with reduced odds of attempting smoking in boys and girls (OR 0.69 (95% CI 0.57 to 0.84)) and reduced odds of computer gaming in girls (OR 0.79 (95% CI 0.72 to 0.86)) by age 11. Early childhood verbal ability was also associated with reduced odds of regular participation in sport/active games (boys: OR 0.91 (95% CI 0.84 to 0.99); girls: OR 0.81 (95% CI 0.74 to 0.88)) and increased odds of reading for enjoyment (boys: OR 1.47 (95% CI 1.35 to 1.60); girls: OR 1.48 (95% CI 1.36 to 1.62)) at age 11. Early childhood non-verbal ability was associated with reduced odds of alcohol consumption in boys and girls (OR 0.92 (95% CI 0.85 to 0.99)) and reduced odds of online messaging in boys (OR 0.89 (95% CI 0.81 to 0.98)) at age 11. Early childhood spatial ability was associated with reduced odds of participating in sport/active games in boys at age 11 (OR 0.88 (95% CI 0.82 to 0.95). CONCLUSION: Neuroselection may occur during early childhood resulting in some, but not all, healthier behaviours by age 11. PMID- 29122997 TI - Level of moderate-intensity leisure-time physical activity and reduced mortality in middle-aged and elderly Chinese. AB - BACKGROUND: Few studies have prospectively evaluated the association of leisure time physical activity (LTPA) with mortality in Asians, who are more susceptible to insulin resistance than their Caucasian counterparts. METHODS: Data from two large prospective cohort studies conducted in Shanghai were evaluated. After excluding participants who had a history of cancer, coronary heart disease or stroke at baseline, or who died within the first 3 years after study enrolment, 53 839 men and 66 888 women, followed for an average of 9.2 and 14.7 years, respectively, remained for the study. RESULTS: Compared with those who reported no exercise, a reduction in mortality with an HR of 0.86 (95% CI 0.80 to 0.93) was observed in those who regularly engage in moderate-intensity LTPA, even those who reported an LTPA level lower than the minimum amount recommended by the current physical activity guidelines (150 min or 7.5 metabolic equivalent hours per week). The association between moderate-intensity exercise and mortality followed a dose-response pattern until the amount of LTPA reached 3-5 times the recommended minimum level. A similar pattern of association was observed for cause-specific mortality due to cardiovascular disease (CVD), cancer or other causes. CONCLUSION: Regular participation in moderate-intensity LTPA was associated with reduced mortality, particularly CVD mortality, even when the LTPA was below the minimum level recommended by current guidelines. Increasing the amount of moderate-intensity LTPA was associated with further risk reduction up to a potential threshold of 3-5 times the recommended minimum. PMID- 29122998 TI - Overcoming Low Health Literacy to Strengthen Modality Choices Requires Individualized Responses. PMID- 29123000 TI - Do We Need Tailored Physical Interventions to Improve Physical Function and Physical Activity Levels in Patients with Chronic Kidney Disease Treated with Peritoneal Dialysis? PMID- 29122999 TI - Can Home Hemodialysis and Peritoneal Dialysis Programs Coexist and Grow Together? PMID- 29123001 TI - Effective Remedy for Encapsulating Peritoneal Sclerosis with Ureteroileal Fistula. AB - Encapsulating peritoneal sclerosis (EPS), treated with surgical enterolysis as a final option, may become refractory to surgical intervention due to intraperitoneal complications. We report the case of a 59-year-old man presenting with EPS who underwent enterolysis at the age of 50, following 15 years of peritoneal dialysis (PD) and peritonitis. During the patient's first surgery, complete surgical enterolysis could not be performed due to severe intestinal adhesions with a deteriorated/calcified small bowel. Six months after the surgery, the obstructive bowel symptoms occurred several times a year. Nine years later, the patient suffered cystitis-like symptoms and fecal discharge from the urinary meatus. The patient was subsequently diagnosed with EPS recurrence with ureteroileal fistula between the right ureter and ileum. During the second surgical intervention, we conducted a divided jejunostomy, as surgical enterolysis and fistulectomy were unachievable due to severe ileal adhesion with calcified capsule and inflammation. Thereafter, symptoms reduced dramatically and oral intake became possible. Three years following surgery, the patient's condition is improved, with no evidence of EPS recurrence or cystitis-like symptoms. Although EPS with ureteroileal fistula is extremely rare, we propose that jejunostomy may be an effective treatment option for patients with EPS refractory to surgical enterolysis or intestinal bypass due to intraperitoneal complications. PMID- 29123002 TI - Peritoneal Dialysis Catheter Removal Post-Transplant - A Rare Case of Delayed Bowel Perforation. AB - Peritoneal dialysis (PD) is a well-established form of renal replacement therapy and the practice of leaving catheters in situ post-transplantation widely accepted. We present a rare complication: a child presenting with anal protrusion of the PD catheter.The patient is an 11-year-old boy with a background of renal dysplasia and congenital cutis laxa. Twenty-three weeks after dialysis was commenced, the patient underwent a renal transplant. Thirteen weeks post transplant, the patient felt an unusual sensation after defecation. The curled end of the catheter was seen protruding from the anus. He was admitted, and investigations showed stable graft function, with abdominal X ray showing no free air.Intraoperative findings showed a small perforation of the sigmoid colon sealed off by adherence of several small intestinal loops. This was repaired laparoscopically after removal of the distal part of the catheter per rectum. No peritoneal contamination was seen. He was treated with 5 days of intravenous antibiotics and gradual introduction of enteral feeds. His graft function remained stable throughout.Timing of catheter removal varies, from the time of transplantation to over 3 months post-transplantation. Bowel perforation due to PD catheter insertion is rare and tends to occur at the time of insertion. Anal protrusion of a PD catheter in childhood is extremely rare and unrecorded in a pediatric patient with a connective tissue disorder. Our case highlights that serious complications can occur in the period between transplantation and elective PD catheter removal and that, in the immunocompromised patient, signs can be subtle. PMID- 29123003 TI - Outcomes of Peritoneal Dialysis Catheter Left In Place after Kidney Transplantation. AB - No clear consensus has been reached regarding the optimal time to remove the peritoneal dialysis catheter (PDC) after kidney transplantation (KT). This retrospective observational study, conducted in a single peritoneal dialysis (PD) unit including all PD patients who received a KT between 1995 - 2015, was undertaken to evaluate the clinical outcomes and potential complications associated with a PDC left in place after KT. Of the 132 PD patients who received a KT, 20 were excluded from the study. Of the remaining, 112 (85%) patients with functioning KT were discharged with their PDC left in place and had it removed in a mean interval of 5 +/- 3 months after KT, after achieving optimal graft function. During this follow-up period, 7 patients (6%) developed exit-site infection and there were 2 cases (2%) of peritonitis; all of them were successfully treated. Delayed PDC removal after KT is associated with low complication rates, although regular examination is needed so that mild infections can be detected early and therapy promptly instituted. PMID- 29123004 TI - Klebsiella pneumoniae Renal Abscess and Peritonitis in a Peritoneal Dialysis Patient: A Novel Route of Infection. AB - We present a peritoneal dialysis (PD) patient who had a renal biopsy performed during an episode of urosepsis and subsequently presented with a renal abscess at the biopsy site along with concurrent peritonitis. Microbiology from the PD effluent and from the renal abscess were both positive for Klebsiella pneumoniae We propose that the PD peritonitis was the result of seeding of the peritoneal cavity with bacteria from the renal abscess. Successful treatment was achieved through drainage of the abscess and intraperitoneal antibiotics. PMID- 29123005 TI - Percutaneous Ablation for Hepatocellular Carcinoma and Peritoneal Dialysis. AB - Hepatocellular carcinoma (HCC) is the second leading cause of death by cancer worldwide. Resection and liver transplantation are the gold standards, but only a minority of people are eligible. Percutaneous ablation therapies, such as microwave ablation (MWA), have consequently been developed. There is a lack of guidelines regarding the treatment of HCCs in end-stage renal disease (ESRD) patients. Here, we report the case of a 67-year-old patient who was undergoing peritoneal dialysis (PD) for chronic congestive heart failure and who presented with an HCC while undergoing PD. The tumor size was 48 mm. Due to the patient's comorbidities, MWA was chosen as a first-line treatment. Peritoneal dialysis was stopped 1 day before the MWA, which was performed by an interventional radiology department. There were no complications from the procedure. The treated area completely covered the tumoral lesion. Peritoneal dialysis was resumed 3 weeks after the MWA without any complications. The computed tomography (CT) scan performed 3 months later showed that the tumor mass had completely regressed; a year and a half after the MWA, no recurrence has been observed. This report shows that an MWA of an HCC in PD patients is a feasible and safe procedure. PMID- 29123006 TI - Outcomes of Simultaneous Peritoneal Dialysis and Arteriovenous Fistula Placement in End-Stage Renal Disease Patients. AB - Peritoneal dialysis (PD) interruption requiring hemodialysis (HD) is not uncommon and its frequently abrupt nature prevents timely creation of permanent HD access and avoidance of central venous catheters (CVC). We retrospectively studied a cohort of 24 end-stage renal disease (ESRD) patients (mean age 50.7 years, 83.3% African-Americans, 58.3% females, time on dialysis interquartile range [IQR] 0 - 65 days) who had simultaneous PD catheter insertion and backup arteriovenous fistula (AVF) creation between January 1, 2012, and December 31, 2013. The primary outcome of interest was the percent of patients receiving HD through the backup AVF at the time of PD interruption. A median (IQR) for PD catheter use after its insertion was 10.5 (2 - 20) days. After the mean follow-up of 19.6 months, 12 patients remained on PD, 2 patients received a kidney transplant, and 1 patient died. The overall AVF patency was 66.7%. A total of 9 (37.5%) patients had PD interruption requiring permanent (8 patients) or temporary (1 patient) HD after the mean (standard deviation [SD]) follow-up of 12.3 (8.2) months. Arteriovenous fistula was used as the initial access in 4 patients, and in 3 patients the original AVF was used after additional surgical revision. Forty-four percent of patients with a backup AVF fistula avoided CVC at the time of PD interruption requiring HD. The simultaneous AVF creation at the time of PD catheter insertion reduced but did not fully eliminate CVC at the time of PD interruption. Larger studies are needed to evaluate the utility of a backup AVF in PD patients. PMID- 29123007 TI - Strongyloides stercoralis Infection in the Peritoneal Cavity of a Patient Receiving PD. PMID- 29123008 TI - Reproducibility of MR-Based Attenuation Maps in PET/MRI and the Impact on PET Quantification in Lung Cancer. AB - Quantitative PET/MRI is dependent on reliable and reproducible MR-based attenuation correction (MR-AC). In this study, we evaluated the quality of current vendor-provided thoracic MR-AC maps and further investigated the reproducibility of their impact on 18F-FDG PET quantification in patients with non-small cell lung cancer. Methods: Eleven patients with inoperable non-small cell lung cancer underwent 2-5 thoracic PET/MRI scan-rescan examinations within 22 d. 18F-FDG PET data were acquired along with 2 Dixon MR-AC maps for each examination. Two PET images (PETA and PETB) were reconstructed using identical PET emission data but with MR-AC from these intrasubject repeated attenuation maps. In total, 90 MR-AC maps were evaluated visually for quality and the occurrence of categorized artifacts by 2 PET/MRI-experienced physicians. Each tumor was outlined by a volume of interest (40% isocontour of maximum) on PETA, which was then projected onto the corresponding PETB SUVmean and SUVmax were assessed from the PET images. Within-examination coefficients of variation and Bland-Altman analyses were conducted for the assessment of SUV variations between PETA and PETBResults: Image artifacts were observed in 86% of the MR-AC maps, and 30% of the MR-AC maps were subjectively expected to affect the tumor SUV. SUVmean and SUVmax resulted in coefficients of variation of 5.6% and 6.6%, respectively, and scan-rescan SUV variations were within +/-20% in 95% of the cases. Substantial SUV variations were seen mainly for scan-rescan examinations affected by respiratory motion. Conclusion: Artifacts occur frequently in standard thoracic MR-AC maps, affecting the reproducibility of PET/MRI. These, in combination with other well-known sources of error associated with PET/MRI examinations, lead to inconsistent SUV measurements in serial studies, which may affect the reliability of therapy response assessment. A thorough visual inspection of the thoracic MR-AC map and Dixon images from which it is derived remains crucial for the detection of MR-AC artifacts that may influence the reliability of SUV. PMID- 29123009 TI - New Challenges in Nuclear Endocrinology. PMID- 29123010 TI - Reply: PSMA Ligands for Imaging Prostate Cancer: Alternative Labeling by Complex Formation with Al18F2. PMID- 29123011 TI - Imaging Synaptic Density: A Different Look at Neurologic Diseases. PMID- 29123012 TI - Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT. AB - Prostate-specific membrane antigen (PSMA)-ligand PET imaging provides unprecedented accuracy for whole-body staging of prostate cancer. As PSMA-ligand PET/CT is increasingly adopted in clinical trials and routine practice worldwide, a unified language for image reporting is urgently needed. We propose a molecular imaging TNM system (miTNM, version 1.0) as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI. miTNM is designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions. Additionally, flowcharts integrating findings of PSMA-ligand PET and morphologic imaging have been designed to guide image interpretation. Specific applications, such as assessment of prognosis or impact on management, should be evaluated in future trials. miTNM is a living framework that evolves with clinical experience and scientific data. PMID- 29123015 TI - The Irony of PET Tau Probe Specificity. PMID- 29123013 TI - 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. AB - Target volume delineations for prostate cancer (PCa) salvage radiotherapy (SRT) after radical prostatectomy are usually drawn in the absence of visibly recurrent disease. 68Ga-labeled prostate-specific membrane antigen (PSMA-11) PET/CT detects recurrent PCa with sensitivity superior to standard-of-care imaging at serum prostate-specific antigen (PSA) values low enough to affect target volume delineations for routine SRT. Our objective was to map the recurrence pattern of PCa early biochemical recurrence (BCR) after radical prostatectomy with 68Ga-PSMA 11 PET/CT in patients with serum PSA levels of less than 1 ng/mL, determine how often consensus clinical target volumes (CTVs) based on the Radiation Therapy Oncology Group (RTOG) guidelines cover 68Ga-PSMA-11 PET/CT-defined disease, and assess the potential impact of 68Ga-PSMA-11 PET/CT on SRT. Methods: This was a post hoc analysis of an intention-to-treat population of 270 patients who underwent 68Ga-PSMA-11 PET/CT at 4 institutions for BCR after prostatectomy without prior radiotherapy at a PSA level of less than 1 ng/mL. RTOG consensus CTVs that included both the prostate bed and the pelvic lymph nodes were contoured on the CT dataset of the PET/CT image by a radiation oncologist masked to the PET component. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11-positive lesions not covered by planning volumes based on the consensus CTVs were considered to have a potential major impact on treatment planning. Results: The median PSA level at the time of 68Ga-PSMA-11 PET/CT was 0.48 ng/mL (range, 0.03-1 ng/mL). One hundred thirty-two of 270 patients (49%) had a positive 68Ga-PSMA-11 PET/CT result. Fifty-two of 270 (19%) had at least one PSMA-11-positive lesion not covered by the consensus CTVs. Thirty-three of 270 (12%) had extrapelvic PSMA-11-positive lesions, and 19 of 270 (7%) had PSMA-11-positive lesions within the pelvis but not covered by the consensus CTVs. The 2 most common 68Ga-PSMA-11-positive lesion locations outside the consensus CTVs were bone (23/52, 44%) and perirectal lymph nodes (16/52, 31%). Conclusion: Post hoc analysis of 68Ga-PSMA-11 PET/CT implied a major impact on SRT planning in 52 of 270 patients (19%) with PCa early BCR (PSA < 1.0 ng/mL). This finding justifies a randomized imaging trial of SRT with or without 68Ga PSMA-11 PET/CT investigating its potential benefit on clinical outcome. PMID- 29123014 TI - PET Using a GRPR Antagonist 68Ga-RM26 in Healthy Volunteers and Prostate Cancer Patients. AB - This study was designed to analyze the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR) antagonist PET tracer, 68Ga-RM26; to assess its clinical diagnostic value in prostate cancer patients; and to perform a direct comparison between GRPR antagonist 68Ga-RM26 and agonist 68Ga-BBN. Methods: Five healthy volunteers were enrolled to validate the safety of 68Ga-RM26 and calculate dosimetry. A total of 28 patients with prostate cancer (17 newly diagnosed and 11 posttherapy) were recruited and provided written informed consent. All the cancer patients underwent PET/CT at 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga RM26. Among them, 22 patients (11 newly diagnosed and 11 posttherapy) underwent 68Ga-BBN PET/CT for comparison within 1 wk. 99mTc-MDP (methylene diphosphonate) bone scans were obtained within 2 wk for comparison. GRPR immunohistochemical staining of tumor samples was performed. Results: The administration of 68Ga-M26 was well tolerated by all subjects, with no adverse symptoms being noticed or reported during the procedure and at 2-wk follow-up. The total effective dose equivalent and effective dose were 0.0912 +/- 0.0140 and 0.0657 +/- 0.0124 mSv/MBq, respectively. In the 17 patients with newly diagnosed prostate cancer, 68Ga-RM26 PET/CT showed positive prostate-confined findings in 15 tumors with an SUVmax of 6.49 +/- 2.37. In the 11 patients who underwent prostatectomy or brachytherapy with or without androgen deprivation therapy, 68Ga-RM26 PET/CT detected 8 metastatic lymph nodes in 3 patients with an SUVmax of 4.28 +/- 1.25 and 21 bone lesions in 8 patients with an SUVmax of 3.90 +/- 3.07. Compared with 68Ga-RM26 PET/CT, GRPR agonist 68Ga-BBN PET/CT detected fewer primary lesions and lymph node metastases as well as demonstrated lower tracer accumulation. There was a significant positive correlation between SUV derived from 68Ga-RM26 PET and the expression level of GRPR (P < 0.001). Conclusion: This study indicates the safety and significant efficiency of GRPR antagonist 68Ga-RM26. 68Ga-RM26 PET/CT would have remarkable value in detecting both primary prostate cancer and metastasis. 68Ga-RM26 is also expected to be better than GRPR agonist as an imaging marker to evaluate GRPR expression in prostate cancer. PMID- 29123016 TI - The Use of Hyperbaric Oxygen for the Prevention and Management of Osteoradionecrosis of the Jaw: A Dana-Farber/Brigham and Women's Cancer Center Multidisciplinary Guideline. PMID- 29123017 TI - Benign pleural schwannoma presenting with a large, blood-stained pleural effusion. PMID- 29123018 TI - Aortic rupture involving matrix metalloproteinases 8 and 9 during Staphylococcus aureus pneumonia. PMID- 29123019 TI - Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. AB - Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at alpha-amino sp3 carbon hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand binding assays and absorption, distribution, metabolism, and excretion studies. PMID- 29123020 TI - Reducing the stochasticity of crystal nucleation to enable subnanosecond memory writing. AB - Operation speed is a key challenge in phase-change random-access memory (PCRAM) technology, especially for achieving subnanosecond high-speed cache memory. Commercialized PCRAM products are limited by the tens of nanoseconds writing speed, originating from the stochastic crystal nucleation during the crystallization of amorphous germanium antimony telluride (Ge2Sb2Te5). Here, we demonstrate an alloying strategy to speed up the crystallization kinetics. The scandium antimony telluride (Sc0.2Sb2Te3) compound that we designed allows a writing speed of only 700 picoseconds without preprogramming in a large conventional PCRAM device. This ultrafast crystallization stems from the reduced stochasticity of nucleation through geometrically matched and robust scandium telluride (ScTe) chemical bonds that stabilize crystal precursors in the amorphous state. Controlling nucleation through alloy design paves the way for the development of cache-type PCRAM technology to boost the working efficiency of computing systems. PMID- 29123021 TI - A generic interface to reduce the efficiency-stability-cost gap of perovskite solar cells. AB - A major bottleneck delaying the further commercialization of thin-film solar cells based on hybrid organohalide lead perovskites is interface loss in state-of the-art devices. We present a generic interface architecture that combines solution-processed, reliable, and cost-efficient hole-transporting materials without compromising efficiency, stability, or scalability of perovskite solar cells. Tantalum-doped tungsten oxide (Ta-WO x )/conjugated polymer multilayers offer a surprisingly small interface barrier and form quasi-ohmic contacts universally with various scalable conjugated polymers. In a simple device with regular planar architecture and a self-assembled monolayer, Ta-WO x -doped interface-based perovskite solar cells achieve maximum efficiencies of 21.2% and offer more than 1000 hours of light stability. By eliminating additional ionic dopants, these findings open up the entire class of organics as scalable hole transporting materials for perovskite solar cells. PMID- 29123023 TI - Young adult smokers' perceptions of plain packs, numbered packs and pack inserts in Turkey: a focus group study. AB - INTRODUCTION: The Turkish Government's 'National Tobacco Control Program 2015 2018' included plans to introduce plain packaging and also a ban on brand names on cigarette packs, allowing only assigned numbers on packs. We explored perceptions of these proposed measures, and also pack inserts with cessation messages, another novel way of using the packaging to communicate with consumers. METHODS: Eight focus groups were conducted with 47 young adult smokers in Manisa and Kutahya (Turkey) in December 2016. Participants were shown three straight edged plain cigarette packs, as required in Australia, and then three bevelled edged plain packs, as permitted in the UK. They were then shown plain packs with numbers rather than brand names, and finally three pack inserts with messages encouraging quitting or offering tips on how to do so. Participants were asked about their perceptions of each. RESULTS: Plain packs were considered unappealing and off-putting, although the bevelled-edged packs were viewed more favourably than the straight-edged packs. Numbered packs were thought by some to diminish the appeal created by the brand name and potentially decrease interest among never smokers and newer smokers. Pack inserts were thought to have less of an impact than the on-pack warnings, but could potentially help discourage initiation and encourage cessation. CONCLUSIONS: That bevelled-edged plain packs were perceived more positively than straight-edged plain packs is relevant to countries planning to introduce plain packaging. The study provides a first insight into smokers' perceptions of a ban on brand names, which was perceived to reduce appeal among young people. PMID- 29123024 TI - The Convention on the Rights of Persons with Disabilities as a tobacco control tool in the mental health setting. AB - BACKGROUND: Smoking rates remain high among people with mental health conditions, even though smoking contributes to negative mental health outcomes and is a leading cause of mortality. Many mental health facilities are not covered by smoke-free laws or do not encourage smoking cessation, and people with mental health conditions are often targeted in tobacco industry promotions. OBJECTIVE: To analyse how the Convention on the Rights of Persons with Disabilities (CRPD), to which most countries are a Party, obliges State Parties to review policies and practices for tobacco control in the mental health setting. METHOD: Analysis of CRPD Articles relevant to smoking and mental health. RESULTS: The CRPD contains several provisions that oblige State Parties to address the issue of smoking and mental health, particularly in relation to quit services, smoke-free policies in mental health facilities, health education focused on correcting misperceptions about smoking and mental health, and protecting people with mental health conditions from tobacco industry targeting. CONCLUSIONS: The CRPD is a potentially powerful tool to promote tobacco control in the mental health context. PMID- 29123025 TI - Mitogen-activated protein kinase (MAPK) dynamics determine cell fate in the yeast mating response. AB - In the yeast Saccharomyces cerevisiae, the exposure to mating pheromone activates a prototypic mitogen-activated protein kinase (MAPK) cascade and triggers a dose dependent differentiation response. Whereas a high pheromone dose induces growth arrest and formation of a shmoo-like morphology in yeast cells, lower pheromone doses elicit elongated cell growth. Previous population-level analysis has revealed that the MAPK Fus3 plays an important role in mediating this differentiation switch. To further investigate how Fus3 controls the fate decision process at the single-cell level, we developed a specific translocation based reporter for monitoring Fus3 activity in individual live cells. Using this reporter, we observed strikingly different dynamic patterns of Fus3 activation in single cells differentiated into distinct fates. Cells committed to growth arrest and shmoo formation exhibited sustained Fus3 activation. In contrast, most cells undergoing elongated growth showed either a delayed gradual increase or pulsatile dynamics of Fus3 activity. Furthermore, we found that chemically perturbing Fus3 dynamics with a specific inhibitor could effectively redirect the mating differentiation, confirming the causative role of Fus3 dynamics in driving cell fate decisions. MAPKs mediate proliferation and differentiation signals in mammals and are therapeutic targets in many cancers. Our results highlight the importance of MAPK dynamics in regulating single-cell responses and open up the possibility that MAPK signaling dynamics could be a pharmacological target in therapeutic interventions. PMID- 29123026 TI - The KLF14 transcription factor regulates hepatic gluconeogenesis in mice. AB - Kruppel-like factor 14 (KLF14) is a member of the Cys2/His2 zinc-finger DNA binding proteins. Despite strong evidence showing that a polymorphism in the Klf14 gene is closely linked to the development of type 2 diabetes, the physiological and metabolic functions of KLF14 still remain unclear. In the present study, we investigated the role of KLF14 in the regulation of hepatic gluconeogenesis. Adenoviruses expressing KLF14 (Ad-Klf14) or KLF14-specific shRNAs (Ad-shKlf14) were injected into normal C57BL/6J, db/db diabetic, or high fat diet-induced obese (DIO) mice. Gene expression, hepatic glucose production, glucose tolerance, and insulin resistance were tested in C57BL/6J, db/db, and DIO mice and primary hepatocytes. Our results demonstrate that KLF14 expression is induced in the livers of normal C57BL/6J mice upon fasting and significantly up regulated in the livers of db/db mice, suggesting a physiological link between KLF14 and gluconeogenesis. Adenovirus-mediated overexpression of KLF14 in primary hepatocytes increased both the mRNA and protein levels of peroxisome proliferator activated receptor-gamma coactivator 1alpha (Pgc-1alpha, also known as Ppargc1a), thereby stimulating cellular glucose production. Conversely, knockdown of KLF14 expression led to a reduction in PGC-1alpha, subsequently inhibiting glucose output in primary hepatocytes. Finally, forced expression of KLF14 in the livers of normal mice increased the plasma glucose levels and impaired glucose tolerance; in contrast, KLF14 knockdown in diabetic mouse livers improved glucose tolerance. Taken together, our data strongly indicate that KLF14 modulates hepatic gluconeogenesis. PMID- 29123027 TI - Dynamic energy dependency of Chlamydia trachomatis on host cell metabolism during intracellular growth: Role of sodium-based energetics in chlamydial ATP generation. AB - Chlamydia trachomatis is an obligate intracellular human pathogen responsible for the most prevalent sexually-transmitted infection in the world. For decades C. trachomatis has been considered an "energy parasite" that relies entirely on the uptake of ATP from the host cell. The genomic data suggest that C. trachomatis respiratory chain could produce a sodium gradient that may sustain the energetic demands required for its rapid multiplication. However, this mechanism awaits experimental confirmation. Moreover, the relationship of chlamydiae with the host cell, in particular its energy dependence, is not well understood. In this work, we are showing that C. trachomatis has an active respiratory metabolism that seems to be coupled to the sodium-dependent synthesis of ATP. Moreover, our results show that the inhibition of mitochondrial ATP synthesis at an early stage decreases the rate of infection and the chlamydial inclusion size. In contrast, the inhibition of the chlamydial respiratory chain at mid-stage of the infection cycle decreases the inclusion size but has no effect on infection rate. Remarkably, the addition of monensin, a Na+/H+ exchanger, completely halts the infection. Altogether, our data indicate that chlamydial development has a dynamic relationship with the mitochondrial metabolism of the host, in which the bacterium mostly depends on host ATP synthesis at an early stage, and at later stages it can sustain its own energy needs through the formation of a sodium gradient. PMID- 29123028 TI - The cell adhesion molecule BT-IgSF is essential for a functional blood-testis barrier and male fertility in mice. AB - The Ig-like cell adhesion molecule (IgCAM) BT-IgSF (brain- and testis-specific Ig superfamily protein) plays a major role in male fertility in mice. However, the molecular mechanism by which BT-IgSF supports fertility is unclear. Here, we found that it is localized in Sertoli cells at the blood-testis barrier (BTB) and at the apical ectoplasmic specialization. The absence of BT-IgSF in Sertoli cells in both global and conditional mouse mutants (i.e. AMHCre and Rosa26CreERT2 lines) resulted in male infertility, atrophic testes with vacuolation, azoospermia, and spermatogenesis arrest. Although transcripts of junctional proteins such as connexin43, ZO-1, occludin, and claudin11 were up-regulated in the absence of BT-IgSF, the functional integrity of the BTB was impaired, as revealed by injection of a BTB-impermeable component into the testes under in vivo conditions. Disruption of the BTB coincided with mislocalization of connexin43, which was present throughout the seminiferous epithelium and not restricted to the BTB as in wild-type tissues, suggesting impaired cell-cell communication in the BT-IgSF-KO mice. Because EM images revealed a normal BTB structure between Sertoli cells in the BT-IgSF-KO mice, we conclude that infertility in these mice is most likely caused by a functionally impaired BTB. In summary, our results indicate that BT-IgSF is expressed at the BTB and is required for male fertility by supporting the functional integrity of the BTB. PMID- 29123029 TI - Phenotypic dissection of the mouse Ren1d knockout by complementation with human renin. AB - Normal renin synthesis and secretion is important for the maintenance of juxtaglomerular apparatus architecture. Mice lacking a functional Ren1d gene are devoid of renal juxtaglomerular cell granules and exhibit an altered macula densa morphology. Due to the species-specificity of renin activity, transgenic mice are ideal models for experimentally investigating and manipulating expression patterns of the human renin gene in a native cellular environment without confounding renin-angiotensin system interactions. A 55-kb transgene encompassing the human renin locus was crossed onto the mouse Ren1d-null background, restoring granulation in juxtaglomerular cells. Correct processing of human renin in dense core granules was confirmed by immunogold labeling. After stimulation of the renin-angiotensin system, juxtaglomerular cells contained rhomboid protogranules with paracrystalline contents, dilated rough endoplasmic reticulum, and electron lucent granular structures. However, complementation of Ren1d-/- mice with human renin was unable to rescue the abnormality seen in macula densa structure. The juxtaglomerular apparatus was still able to respond to tubuloglomerular feedback in isolated perfused juxtaglomerular apparatus preparations, although minor differences in glomerular tuft contractility and macula densa cell calcium handling were observed. This study reveals that the human renin protein is able to complement the mouse Ren1d-/- non-granulated defect and suggests that granulopoiesis requires a structural motif that is conserved between the mouse Ren1d and human renin proteins. It also suggests that the altered macula densa phenotype is related to the activity of the renin-1d enzyme in a local juxtaglomerular renin-angiotensin system. PMID- 29123030 TI - The nonproton ligand of acid-sensing ion channel 3 activates mollusk-specific FaNaC channels via a mechanism independent of the native FMRFamide peptide. AB - The degenerin/epithelial sodium channel (DEG/ENaC) superfamily of ion channels contains subfamilies with diverse functions that are fundamental to many physiological and pathological processes, ranging from synaptic transmission to epileptogenesis. The absence in mammals of some DEG/ENaCs subfamily orthologues such as FMRFamide peptide-activated sodium channels (FaNaCs), which have been identified only in mollusks, indicates that the various subfamilies diverged early in evolution. We recently reported that the nonproton agonist 2-guanidine-4 methylquinazoline (GMQ) activates acid-sensing ion channels (ASICs), a DEG/ENaC subfamily mainly in mammals, in the absence of acidosis. Here, we show that GMQ also could directly activate the mollusk-specific FaNaCs. Differences in ion selectivity and unitary conductance and effects of substitutions at key residues revealed that GMQ and FMRFamide activate FaNaCs via distinct mechanisms. The presence of two activation mechanisms in the FaNaC subfamily diverging early in the evolution of DEG/ENaCs suggested that dual gating is an ancient feature in this superfamily. Notably, the GMQ-gating mode is still preserved in the mammalian ASIC subfamily, whereas FMRFamide-mediated channel gating was lost during evolution. This implied that GMQ activation may be essential for the functions of mammalian DEG/ENaCs. Our findings provide new insights into the evolution of DEG/ENaCs and may facilitate the discovery and characterization of their endogenous agonists. PMID- 29123031 TI - Structure-function characterization of three human antibodies targeting the vaccinia virus adhesion molecule D8. AB - Vaccinia virus (VACV) envelope protein D8 is one of three glycosaminoglycan adhesion molecules and binds to the linear polysaccharide chondroitin sulfate (CS). D8 is also a target for neutralizing antibody responses that are elicited by the smallpox vaccine, which has enabled the first eradication of a human viral pathogen and is a useful model for studying antibody responses. However, to date, VACV epitopes targeted by human antibodies have not been characterized at atomic resolution. Here, we characterized the binding properties of several human anti D8 antibodies and determined the crystal structures of three VACV-mAb variants, VACV-66, VACV-138, and VACV-304, separately bound to D8. Although all these antibodies bound D8 with high affinity and were moderately neutralizing in the presence of complement, VACV-138 and VACV-304 also fully blocked D8 binding to CS A, the low affinity ligand for D8. VACV-138 also abrogated D8 binding to the high affinity ligand CS-E, but we observed residual CS-E binding was observed in the presence of VACV-304. Analysis of the VACV-138- and VACV-304-binding sites along the CS-binding crevice of D8, combined with different efficiencies of blocking D8 adhesion to CS-A and CS-E allowed us to propose that D8 has a high- and low affinity CS-binding region within its central crevice. The crevice is amenable to protein engineering to further enhance both specificity and affinity of binding to CS-E. Finally, a wild-type D8 tetramer specifically bound to structures within the developing glomeruli of the kidney, which express CS-E. We propose that through structure-based protein engineering, an improved D8 tetramer could be used as a potential diagnostic tool to detect expression of CS-E, which is a possible biomarker for ovarian cancer. PMID- 29123032 TI - Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice. AB - The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease. However, the molecular mechanism of PXR mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wildtype (WT) and Pxr-null mice, we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) up-regulated Pxr mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, Cyp2b10 (220-fold), in a PXR dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty-acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNFalpha (3.0-fold), whereas the expression of peroxisome proliferator-activated receptor alpha target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes, including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1, and catalase, as well as the microsomal triglyceride transfer protein, involved in regulating lipid output were higher in Pxr-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy. PMID- 29123035 TI - Comment on "The extent of forest in dryland biomes". AB - The study by Bastin et al (Reports, 12 May 2017, p. 635) is based on an incomplete delimitation of dry forest distribution and on an old and incorrect definition of drylands. Its sampling design includes many plots located in humid ecosystems and ignores critical areas for the conservation of dry forests. Therefore, its results and conclusions may be unreliable. PMID- 29123034 TI - The virulence-associated protein HsvA from the fire blight pathogen Erwinia amylovora is a polyamine amidinotransferase. AB - Studies of virulence determinants in the bacterial phytopathogen Erwinia amylovora, the cause of devastating fire blight disease in apple and pear, have shown that HsvA, a putative amidinotransferase enzyme located in the Hrp pathogenicity island, is required for systemic infection in apple. However, the mechanism by which HsvA contributes to virulence is unclear. To investigate the role of HsvA in virulence, we carried out a series of biochemical and structural studies to characterize the amidinotransferase activity of HsvA. We found that HsvA displays a preference for linear aliphatic polyamines as the amidino acceptor substrate, especially for spermidine and putrescine (Km values of 33 MUm and 3.9 mm, respectively). The three-dimensional structure, determined at 2.30 A resolution using X-ray crystallography, revealed that the overall architecture of HsvA is similar to that of the human arginine-glycine amidinotransferase in the creatine biosynthesis pathway. The active site is located in the core of the protein at the base of a long, narrow substrate access channel. Specific amino acids near the entrance of the channel may serve as major determinants of the substrate specificity, including a glutamate residue at the rim of the channel entrance that appears to be positioned to interact with the distal primary amine in the putrescine substrate as well as the internal and distal amines in the spermidine substrate. These results suggest potential in vivo functions for HsvA as a virulence factor in fire blight and may also provide a basis for strategies to control fire blight by inhibiting HsvA activity. PMID- 29123033 TI - Inactivation of the MDM2 RING domain enhances p53 transcriptional activity in mice. AB - The MDM2 RING domain harbors E3 ubiquitin ligase activity critical for regulating the degradation of tumor suppressor p53, which controls many cellular pathways. The MDM2 RING domain also is required for an interaction with MDMX. Mice containing a substitution in the MDM2 RING domain, MDM2C462A, disrupting MDM2 E3 function and the MDMX interaction, die during early embryogenesis that can be rescued by p53 deletion. To investigate whether MDM2C462A, which retains p53 binding, has p53-suppressing activity, we generated Mdm2C462A/C462A ;p53ER/- mice, in which we replaced the endogenous p53 alleles with an inducible p53ER/- allele, and compared survival with that of similarly generated Mdm2-/-;p53ER/- mice. Adult Mdm2-null mice died ~7 days after tamoxifen-induced p53 activation, indicating that in the absence of MDM2, MDMX cannot suppress p53. Surprisingly, Mdm2C462A/C462A ;p53ER/- mice died ~5 days after tamoxifen injection, suggesting that p53 activity is higher in the presence of MDM2C462A than in the absence of MDM2. Indeed, in MDM2C462A-expressing mouse tissues and embryonic fibroblasts, p53 exhibited higher transcriptional activity than in those expressing no MDM2 or no MDM2 and MDMX. This observation indicated that MDM2C462A not only is unable to suppress p53 but may have gained the ability to enhance p53 activity. We also found that p53 acetylation, a measure of p53 transcriptional activity, was higher in the presence of MDM2C462A than in the absence of MDM2. These results reveal an unexpected role of MDM2C462A in enhancing p53 activity and suggest the possibility that compounds targeting MDM2 RING domain function could produce even more robust p53 activation. PMID- 29123037 TI - Science for global understanding. PMID- 29123036 TI - Response to Comment on "The extent of forest in dryland biomes". AB - De la Cruz et al question the reliability of our results, claiming that we do not refer to the most appropriate spatial extent of drylands. In our response, we explain why we chose an existing and internationally recognized delineation of drylands among several options, and why our findings are due to a difference of remote sensing technique and not to the definition of drylands we have selected. PMID- 29123039 TI - North Atlantic right whale faces extinction. PMID- 29123040 TI - Giant radio telescope lends a hand in Puerto Rico relief. PMID- 29123041 TI - New tools offer clues to how the human brain takes shape. PMID- 29123042 TI - Genomes rewrite cholera's global story. PMID- 29123043 TI - Polarizing head of House science panel to retire. PMID- 29123044 TI - Medical centers spearhead China's pharma push. PMID- 29123046 TI - The perfect wave. PMID- 29123045 TI - Brain implant trials spur ethical discussions. PMID- 29123047 TI - Killer clones. PMID- 29123048 TI - Cell cycle proteins moonlight in multiciliogenesis. PMID- 29123049 TI - Linking smell to metabolism and aging. PMID- 29123050 TI - Tricks for noncovalent catalysis. PMID- 29123051 TI - A record of ice sheet demise. PMID- 29123052 TI - The need to regulate replication fork speed. PMID- 29123053 TI - Plant invasions in the Anthropocene. PMID- 29123054 TI - Small media, big impact. PMID- 29123055 TI - Canada fails to protect its caribou. PMID- 29123056 TI - North Atlantic right whales in danger. PMID- 29123057 TI - Let experts judge research potential. PMID- 29123058 TI - Natural and engineered perovskites. PMID- 29123059 TI - Perovskite in Earth's deep interior. AB - Silicate perovskite-type phases are the most abundant constituent inside our planet and are the predominant minerals in Earth's lower mantle more than 660 kilometers below the surface. Magnesium-rich perovskite is a major lower mantle phase and undergoes a phase transition to post-perovskite near the bottom of the mantle. Calcium-rich perovskite is proportionally minor but may host numerous trace elements that record chemical differentiation events. The properties of mantle perovskites are the key to understanding the dynamic evolution of Earth, as they strongly influence the transport properties of lower mantle rocks. Perovskites are expected to be an important constituent of rocky planets larger than Mars and thus play a major role in modulating the evolution of terrestrial planets throughout the universe. PMID- 29123060 TI - Promises and challenges of perovskite solar cells. AB - The efficiencies of perovskite solar cells have gone from single digits to a certified 22.1% in a few years' time. At this stage of their development, the key issues concern how to achieve further improvements in efficiency and long-term stability. We review recent developments in the quest to improve the current state of the art. Because photocurrents are near the theoretical maximum, our focus is on efforts to increase open-circuit voltage by means of improving charge selective contacts and charge carrier lifetimes in perovskites via processes such as ion tailoring. The challenges associated with long-term perovskite solar cell device stability include the role of testing protocols, ionic movement affecting performance metrics over extended periods of time, and determination of the best ways to counteract degradation mechanisms. PMID- 29123061 TI - Properties and potential optoelectronic applications of lead halide perovskite nanocrystals. AB - Semiconducting lead halide perovskites (LHPs) have not only become prominent thin film absorber materials in photovoltaics but have also proven to be disruptive in the field of colloidal semiconductor nanocrystals (NCs). The most important feature of LHP NCs is their so-called defect-tolerance-the apparently benign nature of structural defects, highly abundant in these compounds, with respect to optical and electronic properties. Here, we review the important differences that exist in the chemistry and physics of LHP NCs as compared with more conventional, tetrahedrally bonded, elemental, and binary semiconductor NCs (such as silicon, germanium, cadmium selenide, gallium arsenide, and indium phosphide). We survey the prospects of LHP NCs for optoelectronic applications such as in television displays, light-emitting devices, and solar cells, emphasizing the practical hurdles that remain to be overcome. PMID- 29123062 TI - Perovskites in catalysis and electrocatalysis. AB - Catalysts for chemical and electrochemical reactions underpin many aspects of modern technology and industry, from energy storage and conversion to toxic emissions abatement to chemical and materials synthesis. This role necessitates the design of highly active, stable, yet earth-abundant heterogeneous catalysts. In this Review, we present the perovskite oxide family as a basis for developing such catalysts for (electro)chemical conversions spanning carbon, nitrogen, and oxygen chemistries. A framework for rationalizing activity trends and guiding perovskite oxide catalyst design is described, followed by illustrations of how a robust understanding of perovskite electronic structure provides fundamental insights into activity, stability, and mechanism in oxygen electrocatalysis. We conclude by outlining how these insights open experimental and computational opportunities to expand the compositional and chemical reaction space for next generation perovskite catalysts. PMID- 29123063 TI - Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. AB - Small-molecule dual hydrogen-bond (H-bond) donors such as ureas, thioureas, squaramides, and guanidinium ions enjoy widespread use as effective catalysts for promoting a variety of enantioselective reactions. However, these catalysts are only weakly acidic and therefore require highly reactive electrophilic substrates to be effective. We introduce here a mode of catalytic activity with chiral H bond donors that enables enantioselective reactions of relatively unreactive electrophiles. Squaramides are shown to interact with silyl triflates by binding the triflate counterion to form a stable, yet highly Lewis acidic, complex. The silyl triflate-chiral squaramide combination promotes the generation of oxocarbenium intermediates from acetal substrates at low temperatures. Enantioselectivity in nucleophile additions to the cationic intermediates is then controlled through a network of noncovalent interactions between the squaramide catalyst and the oxocarbenium triflate. PMID- 29123064 TI - Observation of mean path length invariance in light-scattering media. AB - The microstructure of a medium strongly influences how light propagates through it. The amount of disorder it contains determines whether the medium is transparent or opaque. Theory predicts that exciting such a medium homogeneously and isotropically makes some of its optical properties depend only on the medium's outer geometry. Here, we report an optical experiment demonstrating that the mean path length of light is invariant with respect to the microstructure of the medium it scatters through. Using colloidal solutions with varying concentration and particle size, the invariance of the mean path length is observed over nearly two orders of magnitude in scattering strength. Our results can be extended to a wide range of systems-however ordered, correlated, or disordered-and apply to all wave-scattering problems. PMID- 29123065 TI - How the news media activate public expression and influence national agendas. AB - We demonstrate that exposure to the news media causes Americans to take public stands on specific issues, join national policy conversations, and express themselves publicly-all key components of democratic politics-more often than they would otherwise. After recruiting 48 mostly small media outlets, we chose groups of these outlets to write and publish articles on subjects we approved, on dates we randomly assigned. We estimated the causal effect on proximal measures, such as website pageviews and Twitter discussion of the articles' specific subjects, and distal ones, such as national Twitter conversation in broad policy areas. Our intervention increased discussion in each broad policy area by ~62.7% (relative to a day's volume), accounting for 13,166 additional posts over the treatment week, with similar effects across population subgroups. PMID- 29123066 TI - Cordilleran Ice Sheet mass loss preceded climate reversals near the Pleistocene Termination. AB - The Cordilleran Ice Sheet (CIS) once covered an area comparable to that of Greenland. Previous geologic evidence and numerical models indicate that the ice sheet covered much of westernmost Canada as late as 12.5 thousand years ago (ka). New data indicate that substantial areas throughout westernmost Canada were ice free prior to 12.5 ka and some as early as 14.0 ka, with implications for climate dynamics and the timing of meltwater discharge to the Pacific and Arctic oceans. Early Bolling-Allerod warmth halved the mass of the CIS in as little as 500 years, causing 2.5 to 3.0 meters of sea-level rise. Dozens of cirque and valley glaciers, along with the southern margin of the CIS, advanced into recently deglaciated regions during the Bolling-Allerod and Younger Dryas. PMID- 29123067 TI - Genomic history of the seventh pandemic of cholera in Africa. AB - The seventh cholera pandemic has heavily affected Africa, although the origin and continental spread of the disease remain undefined. We used genomic data from 1070 Vibrio cholerae O1 isolates, across 45 African countries and over a 49-year period, to show that past epidemics were attributable to a single expanded lineage. This lineage was introduced at least 11 times since 1970, into two main regions, West Africa and East/Southern Africa, causing epidemics that lasted up to 28 years. The last five introductions into Africa, all from Asia, involved multidrug-resistant sublineages that replaced antibiotic-susceptible sublineages after 2000. This phylogenetic framework describes the periodicity of lineage introduction and the stable routes of cholera spread, which should inform the rational design of control measures for cholera in Africa. PMID- 29123069 TI - A neural algorithm for a fundamental computing problem. AB - Similarity search-for example, identifying similar images in a database or similar documents on the web-is a fundamental computing problem faced by large scale information retrieval systems. We discovered that the fruit fly olfactory circuit solves this problem with a variant of a computer science algorithm (called locality-sensitive hashing). The fly circuit assigns similar neural activity patterns to similar odors, so that behaviors learned from one odor can be applied when a similar odor is experienced. The fly algorithm, however, uses three computational strategies that depart from traditional approaches. These strategies can be translated to improve the performance of computational similarity searches. This perspective helps illuminate the logic supporting an important sensory function and provides a conceptually new algorithm for solving a fundamental computational problem. PMID- 29123068 TI - Integrated view of Vibrio cholerae in the Americas. AB - Latin America has experienced two of the largest cholera epidemics in modern history; one in 1991 and the other in 2010. However, confusion still surrounds the relationships between globally circulating pandemic Vibrio cholerae clones and local bacterial populations. We used whole-genome sequencing to characterize cholera across the Americas over a 40-year time span. We found that both epidemics were the result of intercontinental introductions of seventh pandemic El Tor V. cholerae and that at least seven lineages local to the Americas are associated with disease that differs epidemiologically from epidemic cholera. Our results consolidate historical accounts of pandemic cholera with data to show the importance of local lineages, presenting an integrated view of cholera that is important to the design of future disease control strategies. PMID- 29123070 TI - Redox-sensitive alteration of replisome architecture safeguards genome integrity. AB - DNA replication requires coordination between replication fork progression and deoxynucleotide triphosphate (dNTP)-generating metabolic pathways. We find that perturbation of ribonucleotide reductase (RNR) in humans elevates reactive oxygen species (ROS) that are detected by peroxiredoxin 2 (PRDX2). In the oligomeric state, PRDX2 forms a replisome-associated ROS sensor, which binds the fork accelerator TIMELESS when exposed to low levels of ROS. Elevated ROS levels generated by RNR attenuation disrupt oligomerized PRDX2 to smaller subunits, whose dissociation from chromatin enforces the displacement of TIMELESS from the replisome. This process instantly slows replication fork progression, which mitigates pathological consequences of replication stress. Thus, redox signaling couples fluctuations of dNTP biogenesis with replisome activity to reduce stress during genome duplication. We propose that cancer cells exploit this pathway to increase their adaptability to adverse metabolic conditions. PMID- 29123072 TI - Fighting for my Dream. PMID- 29123073 TI - Moderate iodine deficiency among pregnant women in Hong Kong: revisit the problem after two decades. AB - INTRODUCTION: A survey conducted during 2005 to 2007 by the Centre for Food Safety in Hong Kong suggested that only 5% of the local population had a sufficient dietary intake of iodine. The study, however, was limited as biochemical data (ie urinary iodine concentration) were lacking. Pregnant women are vulnerable to iodine deficiency because of their increased requirement. Recent studies have shown that iodine deficiency in early pregnancy is associated with poorer cognitive development in early childhood. This study reports the iodine status of women during early gestation at an obstetric unit in Hong Kong. METHODS: Healthy pregnant women with no history of hyperemesis gravidarum were enrolled into a study when they first made a booking in an antenatal clinic of a public hospital to investigate their iodine status during early pregnancy. All subjects were asked to collect their morning urine for measurement of iodine and creatinine levels. Daily dietary intake of iodine was assessed in a subgroup of participants by structured interview using a standard food frequency questionnaire. RESULTS: A total of 600 pregnant women were enrolled at a median of 7.0 weeks of gestation. The median urinary iodine concentration and urinary iodine-to-creatinine ratio were 100 MUg/L and 98 MUg/g, respectively; 429 (71.5%) participants had iodine insufficiency according to the World Health Organization classification. Daily dietary intake of iodine was assessed in 146 participants. The median daily intake of iodine was 69.5 MUg and 122 (83.6%) participants had an intake below the 250 MUg recommended during pregnancy by the World Health Organization. CONCLUSIONS: Local pregnant women continue to have an inadequate dietary intake of iodine and remain iodine-deficient. PMID- 29123071 TI - SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. AB - mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 MUM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling. PMID- 29123074 TI - The first case series of Chinese patients in Hong Kong with familial Alzheimer's disease compared with those with biomarker-confirmed sporadic late-onset Alzheimer's disease. AB - INTRODUCTION: Patients with familial Alzheimer's disease are being increasingly reported in Hong Kong. The objectives of this study were to report the clinical features of these patients, and to compare them with those with biomarker confirmed sporadic late-onset Alzheimer's disease. METHODS: All symptomatic Chinese patients with familial Alzheimer's disease who attended Queen Mary Hospital, Memory Clinic between January 1998 and December 2016 were included. Information about clinical features, baseline Mini-Mental State Examination score, and presenting cognitive symptoms or atypical clinical features were collected. Their clinical features were compared with those of 12 patients with sporadic late-onset Alzheimer's disease with cerebrospinal fluid biomarker evidence of Alzheimer's disease and 14 patients with late-onset Alzheimer's disease and positive amyloid loading on Pittsburgh compound B imaging. RESULTS: There were three families with familial Alzheimer's disease among whom eight family members were affected. The mean (+/- standard deviation) age of onset and the Mini-Mental State Examination score were 48.4 +/- 7.7 years and 7.9 +/- 9.2, respectively. Compared with the sporadic late-onset Alzheimer's disease patients, those with familial Alzheimer's disease had an earlier age of onset and presentation (both P<0.001) and received the correct diagnosis later (median [interquartile range], 7.5 [5.3-14.5] vs 2 [1.0-3.3] years; P<0.001). Patients with familial disease had a lower Mini-Mental State Examination score at presentation than those having late-onset Alzheimer's disease (mean, 7.9 +/- 9.2 vs 17.6 +/- 7.2; P=0.01). They also had fewer delusions, and less dysphoria and irritability (0% vs 41.7%, 0% vs 50% and 0% vs 54.2%; P=0.04, 0.01 and 0.01, respectively). There was a trend of less frequent amnesia among patients with familial Alzheimer's disease compared with those having late-onset Alzheimer's disease (75% vs 100%; P=0.05). CONCLUSION: Clinical features differ for patients with familial Alzheimer's disease compared with those with late-onset Alzheimer's disease. There is a delay in diagnosis. Promotion of public awareness of familial Alzheimer's disease is much needed. PMID- 29123075 TI - Evaluation of the awareness of, attitude to, and knowledge about fertility preservation in cancer patients among clinical practitioners in Hong Kong. AB - INTRODUCTION: Individuals can be exposed to gonadotoxic agents in the course of treatment for cancers and other medical conditions. Fertility preservation refers to strategies that aim to preserve fertility by protecting it against the damage inflicted by gonadotoxic treatment. Many young patients are prescribed gonadotoxic treatment without prior counselling. This study aimed to study the awareness of, attitude to, and knowledge about fertility preservation among clinicians in Hong Kong. METHODS: This was a cross-sectional study carried out between June and December 2016 using a self-administered questionnaire. The questionnaires were sent to clinicians in the departments of Clinical Oncology, Haematology, Obstetrics and Gynaecology, Paediatrics, and Surgery in various public hospitals of Hong Kong. RESULTS: In this survey, 36.5% (167 of 457) of clinicians responded. Of the respondents, only 45.6% were familiar with fertility preservation. The factors considered most important for referral were, in decreasing order of importance, prognosis of the patient, patient's desire to have children, time available before commencing gonadotoxic treatment, type of cancer, and type of gonadotoxic treatment. The majority of clinicians did not refer their patients for fertility preservation due to a lack of available time before treatment, considerable risk of recurrence, poor prognosis, financial constraints, need for cancer treatment as top priority at the time, and lack of awareness of such service. Almost all agreed that a dedicated centre should be set up for fertility preservation and 76.5% agreed that fertility preservation should be provided as a public service. CONCLUSION: Awareness among clinical practitioners of fertility preservation remains weak. Education of clinicians and the establishment of a dedicated fertility preservation centre are required. PMID- 29123076 TI - An efficient soil penetration strategy for explorative robots inspired by plant root circumnutation movements. AB - This paper presents a comparative analysis in terms of energy required by an artificial probe to penetrate soil implementing two different strategies: a straight penetration movement and a circumnutation, which is an oscillatory movement performed by plant roots. The role of circumnutations in plant roots is still debated. We hypothesized that circumnutation movements can help roots in penetrating soil, and validated our assumption by testing the probe at three distinct soil densities and using various combinations of circumnutation amplitudes and periods for each soil. The comparison was based on the total work done by the system while circumnutating at its tip level with respect to that shown by the same system in straight penetration. The total energy evaluation confirmed an improvement obtained by circumnutations up to 33%. We also proposed a fitting model for our experimental data that was used to estimate energy needed by the probe to penetrate soil at different dimensions and circumnutation amplitudes. Results showed the existence of a trade-off among penetration velocity, circumnutation period, and amplitude toward an energy consumption optimization, expressed by the lead angle of the helical path that should stay in the range between 46 degrees and 65 degrees . Moreover, circumnutations with appropriate amplitude (~10 degrees ) and period (~80 s) values were more efficient than straight penetration also at different probe tip dimensions, up to a threshold diameter (from 2 mm to 55 mm). Based on the obtained results, we speculated that circumnutations can represent a strategy used by plant roots to reduce the pressure and energy needed to penetrate soil. The translation of this biological feature in robotic systems will allow improving their energetic efficiency in digging tasks, and thus open new scenarios for use in search and rescue, environmental monitoring, and soil exploration. PMID- 29123077 TI - Effect and Outcome of Intraoperative Fluid Restriction in Living Liver Donor Hepatectomy. AB - BACKGROUND The purpose of this study was to evaluate the effect and outcome of intraoperative fluid restriction in living liver donor hepatectomy, regarding changes in intraoperative CVP levels, blood loss, and postoperative renal function. MATERIAL AND METHODS The charts of 167 patients were reviewed and analyzed retrospectively. Intraoperative central venous pressure levels, blood loss, fluids infused, and urine output per hour, before and after the liver allograft procurement, were calculated. Perioperative renal functions were also analyzed. RESULTS Fluid infused before and after liver allograft procurement was 3.21+/-1.5 and 9.0+/-3.9 mL/Kg/h and urine output was 1.5+/-0.7 and 1.8+/-1.4 mL/Kg/h, respectively. Intraoperative estimated blood loss was 91.3+/-78.9 mL. No patients required blood transfusion. Their preoperative and postoperative hemoglobin were 12.3+/-2.7 and 11.7+/-1.7 g/dL. CVP levels decreased gradually from 10.4+/-3.0 to a low of 8.1+/-1.9 mmHg at the time of transection of the liver parenchyma. Renal functions were not significantly affected based on the determination of BUN and creatinine levels. CONCLUSIONS The methods used to lower CVP are moderate and slow, with 2 main goals achieved: minimal blood loss (91.3+/ 78.9 ml) and no blood transfusion. Furthermore, it did not have any negative effect on renal function. PMID- 29123078 TI - High Performance Liquid Chromatography-Mass Spectrometry (LC-MS) Based Quantitative Lipidomics Study of Ganglioside-NANA-3 Plasma to Establish Its Association with Parkinson's Disease Patients. AB - BACKGROUND It is well known that, pathologically, Parkinson's disease is a common neurodegenerative disorder. In Parkinson's disease, the protein which is abundant in the human brain, alpha-synuclein, accumulates inside the nerve cells. In this situation, dysregulation of lipid metabolism performs a crucial role; however, its association with Parkinson's disease is has not yet been explored. MATERIAL AND METHODS We performed a high-performance liquid chromatography-mass spectrometry-derived quantitative lipidomics study to analyze the profile of lipidomic plasma obtained from 170 PD patients and 120 controls, taken from our hospital. A logistic regression model was used for analysis in each of the lipid species having all major classes of glycerolipids, sterols, sphingolipids, and glycerophospholipids. RESULTS We observed that there are differences in the plasma concentrations of 2 lipid subclasses, triacylglycerides and ganglioside NANA-3, between control and Parkinson's disease participants. The most significant difference between both the participants was observed in the case of ganglioside-NANA-3 plasma concentration (1.293+/-0.029 pmol/ul versus 1.488+/ 0.041 pmol/ul, respectively) after normalizing it with respect to total lipid. Further, a group of 22 glucosylceramide and ganglioside-NANA-3 species concentration was used for receiver operating characteristic curve analysis after normalizing it with respect to total lipid. The results were quite consistent with previously reported biomarker results. CONCLUSIONS Our results show that there is quite good association between high concentration of ganglioside-NANA-3 species and Parkinson's disease. Interestingly, the same metabolic pathway of glucosylceramide, which is a substrate of the enzyme glucocerebrosidase, has been linked with Parkinson's disease, which is at last followed by ganglioside-NANA-3. These results are supported by earlier works in which lower glucocerebrosidase activity has led to risk of the disease. PMID- 29123079 TI - A Case of Round Ligament Varices Presenting in Pregnancy. AB - BACKGROUND Round ligament varices (RLV) are rare and are almost exclusively seen in pregnant women. RLV may clinically resemble an inguinal hernia, inguinal mass, or other pathology involving the inguinal canal and round ligament. Ultrasound imaging is important to make the diagnosis of RLV. CASE REPORT A 34-year-old Hispanic woman, gravida 1 para 0, at 34 weeks gestation, presented to our outpatient department with a complaint of a small, painless, reducible right inguinal mass. Gray-scale sonography showed an asymmetric right inguinal anechoic mass composed of multiple serpentine tubular channels, which became more prominent when the patient performed a Valsalva maneuver. Color Doppler ultrasound imaging showed a hyper vascular structure with a venous flow pattern, consistent with RLV. The patient was treated conservatively and had an uneventful vaginal delivery at 38 weeks gestation. At two weeks postpartum, the RLV spontaneously regressed and her symptoms completely resolved. CONCLUSIONS RLV is a rare condition that should be recognized and diagnosed promptly to prevent patients from undergoing unnecessary surgical exploration. Ultrasound is the diagnostic imaging procedure of choice for the diagnosis of RLV, as well as for patient follow-up and to exclude possible complications associated with RLV. PMID- 29123080 TI - Organocatalytic enantio- and diastereoselective cycloetherification via dynamic kinetic resolution of chiral cyanohydrins. AB - Enantioselective approaches to synthesize six-membered oxacycles with multiple stereogenic centres are in high demand to enable the discovery of new therapeutic agents. Here we present a concise organocatalytic cycloetherification for the highly enantio- and diastereoselective synthesis of tetrahydropyrans involving simultaneous construction of two chiral centres, one of which is fully substituted. This method involves dynamic kinetic resolution of reversibly generated chiral cyanohydrins. A chiral bifunctional organocatalyst selectively recognizes a specific chair-like conformation of the intermediate, in which the small steric effect of the linear cyano group as well as its anomeric effect play important roles in controlling stereoselectivity. The products offer additional utility as synthetic intermediates because the cyano group can be further transformed into a variety of important functional groups. This strategy provides a platform to design efficient approaches to obtain a wide range of optically active tetrahydropyrans, which are otherwise synthetically challenging materials. PMID- 29123081 TI - Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes. AB - Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Here we use the autochthonous TiRP melanoma model, which recapitulates the tumoral resistance signature observed in human melanomas. TiRP tumors resist immunotherapy based on checkpoint blockade, cancer vaccines or adoptive T-cell therapy. TiRP tumors recruit and activate tumor-specific CD8+ T cells, but these cells then undergo apoptosis. This does not occur with isogenic transplanted tumors, which are rejected after adoptive T-cell therapy. Apoptosis of tumor-infiltrating lymphocytes can be prevented by interrupting the Fas/Fas ligand axis, and is triggered by polymorphonuclear-myeloid-derived suppressor cells, which express high levels of Fas-ligand and are enriched in TiRP tumors. Blocking Fas-ligand increases the anti-tumor efficacy of adoptive T-cell therapy in TiRP tumors, and increases the efficacy of checkpoint blockade in transplanted tumors. Therefore, tumor-infiltrating lymphocytes apoptosis is a relevant mechanism of immunotherapy resistance, which could be blocked by interfering with the Fas/Fas-ligand pathway. PMID- 29123082 TI - Supramammillary glutamate neurons are a key node of the arousal system. AB - Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake-sleep regulatory system. PMID- 29123083 TI - Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease. AB - Cerebrovascular changes occur in Alzheimer's disease (AD). Using in vivo phage display, we searched for molecular markers of the neurovascular unit, including endothelial cells and astrocytes, in mouse models of AD. We identified a cyclic peptide, CDAGRKQKC (DAG), that accumulates in the hippocampus of hAPP-J20 mice at different ages. Intravenously injected DAG peptide homes to neurovascular unit endothelial cells and to reactive astrocytes in mouse models of AD. We identified connective tissue growth factor (CTGF), a matricellular protein that is highly expressed in the brain of individuals with AD and in mouse models, as the target of the DAG peptide. We also showed that exogenously delivered DAG homes to the brain in mouse models of glioblastoma, traumatic brain injury, and Parkinson's disease. DAG may potentially be used as a tool to enhance delivery of therapeutics and imaging agents to sites of vascular changes and astrogliosis in diseases associated with neuroinflammation. PMID- 29123084 TI - Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. AB - Interleukin-12 (IL-12) has emerged as one of the most potent agents for anti tumor immunotherapy. However, potentially lethal toxicity associated with systemic administration of IL-12 precludes its clinical application. Here we redesign the molecule in such a way that its anti-tumor efficacy is not compromised, but toxic effects are eliminated. Deletion of the N-terminal signal peptide of IL-12 can effect such a change by preventing IL-12 secretion from cells. We use a newly designed tumor-targeted oncolytic adenovirus (Ad-TD) to deliver non-secreting (ns) IL-12 to tumor cells and examine the therapeutic and toxic effects in Syrian hamster models of pancreatic cancer (PaCa). Strikingly, intraperitoneal delivery of Ad-TD-nsIL-12 significantly enhanced survival of animals with orthotopic PaCa and cured peritoneally disseminated PaCa with no toxic side effects, in contrast to the treatment with Ad-TD expressing unmodified IL-12. These findings offer renewed hope for development of IL-12-based treatments for cancer. PMID- 29123085 TI - Airway surface liquid pH is not acidic in children with cystic fibrosis. AB - Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans. In order to address this deficiency, ASL pH was measured in vivo in children using a novel luminescent technology integrated with fibre-optic probes. Here we show that ASL pH in children with CF is similar to that of children without CF. Findings were supported by highly controlled direct pH measurements in primary human airway epithelial cell culture models, which also suggest that the potential ASL pH gradient produced by defective apical ion transport is balanced out by paracellular shunting of acid/base. Thus, reduced baseline ASL pH is unlikely to be an important pathobiological factor in early CF lung disease. PMID- 29123086 TI - Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling. AB - Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria worldwide. Its safety and efficacy have been extensively demonstrated in clinical trials; however, its performance in routine health care settings, where adherence to drug treatment is unsupervised and therefore may be suboptimal, is less well characterised. Here we develop a within-host modelling framework for estimating the effects of sub optimal adherence to AL treatment on clinical outcomes in malaria patients. Our model incorporates the data on the human immune response to the parasite, and AL's pharmacokinetic and pharmacodynamic properties. Utilising individual-level data of adherence to AL in 482 Tanzanian patients as input for our model predicted higher rates of treatment failure than were obtained when adherence was optimal (9% compared to 4%). Our model estimates that the impact of imperfect adherence was worst in children, highlighting the importance of advice to caregivers. PMID- 29123087 TI - Live imaging molecular changes in junctional tension upon VE-cadherin in zebrafish. AB - Forces play diverse roles in vascular development, homeostasis and disease. VE cadherin at endothelial cell-cell junctions links the contractile acto-myosin cytoskeletons of adjacent cells, serving as a tension-transducer. To explore tensile changes across VE-cadherin in live zebrafish, we tailored an optical biosensor approach, originally established in vitro. We validate localization and function of a VE-cadherin tension sensor (TS) in vivo. Changes in tension across VE-cadherin observed using ratio-metric or lifetime FRET measurements reflect acto-myosin contractility within endothelial cells. Furthermore, we apply the TS to reveal biologically relevant changes in VE-cadherin tension that occur as the dorsal aorta matures and upon genetic and chemical perturbations during embryonic development. PMID- 29123088 TI - A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer. AB - Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2' position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity. PMID- 29123090 TI - Global patterns of nitrate storage in the vadose zone. AB - Global-scale nitrogen budgets developed to quantify anthropogenic impacts on the nitrogen cycle do not explicitly consider nitrate stored in the vadose zone. Here we show that the vadose zone is an important store of nitrate that should be considered in future budgets for effective policymaking. Using estimates of groundwater depth and nitrate leaching for 1900-2000, we quantify the peak global storage of nitrate in the vadose zone as 605-1814 Teragrams (Tg). Estimates of nitrate storage are validated using basin-scale and national-scale estimates and observed groundwater nitrate data. Nitrate storage per unit area is greatest in North America, China and Europe where there are thick vadose zones and extensive historical agriculture. In these areas, long travel times in the vadose zone may delay the impact of changes in agricultural practices on groundwater quality. We argue that in these areas use of conventional nitrogen budget approaches is inappropriate. PMID- 29123089 TI - Tsg101 chaperone function revealed by HIV-1 assembly inhibitors. AB - HIV-1 replication requires Tsg101, a component of cellular endosomal sorting complex required for transport (ESCRT) machinery. Tsg101 possesses an ubiquitin (Ub) E2 variant (UEV) domain with a pocket that can bind PT/SAP motifs and another pocket that can bind Ub. The PTAP motif in the viral structural precursor polyprotein, Gag, allows the recruitment of Tsg101 and other ESCRTs to virus assembly sites where they mediate budding. It is not known how or even whether the UEV Ub binding function contributes to virus production. Here, we report that disruption of UEV Ub binding by commonly used drugs arrests assembly at an early step distinct from the late stage involving PTAP binding disruption. NMR reveals that the drugs form a covalent adduct near the Ub-binding pocket leading to the disruption of Ub, but not PTAP binding. We conclude that the Ub-binding pocket has a chaperone function involved in bud initiation. PMID- 29123091 TI - Effect of nitrogen atom positioning on the trade-off between emissive and photocatalytic properties of carbon dots. AB - Carbon dots (CDs) are a versatile nanomaterial with attractive photoluminescent and photocatalytic properties. Here we show that these two functionalities can be easily tuned through a simple synthetic means, using a microwave irradiation, with citric acid and varying concentrations of nitrogen-containing branched polyethyleneimine (BPEI) as precursors. The amount of BPEI determines the degree of nitrogen incorporation and the different inclusion modes within the CDs. At intermediate levels of BPEI, domains grow containing mainly graphitic nitrogen, producing a high photoluminescence yield. For very high (and very low) BPEI content, the nitrogen atoms are located primarily at the edge sites of the aromatic domains. Accordingly, they attract photogenerated electrons, enabling efficient charge separation and enhanced photocatalytic hydrogen generation from water. The ensuing ability to switch between emissive and photocatalytic behavior of CDs is expected to bring substantial improvements on their efficiency for on demand light emission or energy conversion applications. PMID- 29123092 TI - Natural variation of YELLOW SEEDLING1 affects photosynthetic acclimation of Arabidopsis thaliana. AB - Exploiting genetic variation for more efficient photosynthesis is an underexplored route towards new crop varieties. This study demonstrates the genetic dissection of higher plant photosynthesis efficiency down to the genomic DNA level, by confirming that allelic sequence variation at the Arabidopsis thaliana YELLOW SEEDLING1 (YS1) gene explains natural diversity in photosynthesis acclimation to high irradiance. We use a genome-wide association study to identify quantitative trait loci (QTLs) involved in the Arabidopsis photosynthetic acclimation response. Candidate genes underlying the QTLs are prioritized according to functional clues regarding gene ontology, expression and function. Reverse genetics and quantitative complementation confirm the candidacy of YS1, which encodes a pentatrico-peptide-repeat (PPR) protein involved in RNA editing of plastid-encoded genes (anterograde signalling). Gene expression analysis and allele sequence comparisons reveal polymorphisms in a light responsive element in the YS1 promoter that affect its expression, and that of its downstream targets, resulting in the variation in photosynthetic acclimation. PMID- 29123093 TI - Prevalence and detection of low-allele-fraction variants in clinical cancer samples. AB - Accurate detection of genomic alterations using high-throughput sequencing is an essential component of precision cancer medicine. We characterize the variant allele fractions (VAFs) of somatic single nucleotide variants and indels across 5095 clinical samples profiled using a custom panel, CancerSCAN. Our results demonstrate that a significant fraction of clinically actionable variants have low VAFs, often due to low tumor purity and treatment-induced mutations. The percentages of mutations under 5% VAF across hotspots in EGFR, KRAS, PIK3CA, and BRAF are 16%, 11%, 12%, and 10%, respectively, with 24% for EGFR T790M and 17% for PIK3CA E545. For clinical relevance, we describe two patients for whom targeted therapy achieved remission despite low VAF mutations. We also characterize the read depths necessary to achieve sensitivity and specificity comparable to current laboratory assays. These results show that capturing low VAF mutations at hotspots by sufficient sequencing coverage and carefully tuned algorithms is imperative for a clinical assay. PMID- 29123094 TI - Human sperm steer with second harmonics of the flagellar beat. AB - Sperm are propelled by bending waves traveling along their flagellum. For steering in gradients of sensory cues, sperm adjust the flagellar waveform. Symmetric and asymmetric waveforms result in straight and curved swimming paths, respectively. Two mechanisms causing spatially asymmetric waveforms have been proposed: an average flagellar curvature and buckling. We image flagella of human sperm tethered with the head to a surface. The waveform is characterized by a fundamental beat frequency and its second harmonic. The superposition of harmonics breaks the beat symmetry temporally rather than spatially. As a result, sperm rotate around the tethering point. The rotation velocity is determined by the second-harmonic amplitude and phase. Stimulation with the female sex hormone progesterone enhances the second-harmonic contribution and, thereby, modulates sperm rotation. Higher beat frequency components exist in other flagellated cells; therefore, this steering mechanism might be widespread and could inspire the design of synthetic microswimmers. PMID- 29123095 TI - Thermal crumpling of perforated two-dimensional sheets. AB - Thermalized elastic membranes without distant self-avoidance are believed to undergo a crumpling transition when the microscopic bending stiffness is comparable to kT, the scale of thermal fluctuations. Most potential physical realizations of such membranes have a bending stiffness well in excess of experimentally achievable temperatures and are therefore unlikely ever to access the crumpling regime. We propose a mechanism to tune the onset of the crumpling transition by altering the geometry and topology of the sheet itself. We carry out extensive molecular dynamics simulations of perforated sheets with a dense periodic array of holes and observe that the critical temperature is controlled by the total fraction of removed area, independent of the precise arrangement and size of the individual holes. The critical exponents for the perforated membrane are compatible with those of the standard crumpling transition. PMID- 29123096 TI - ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1. AB - ATR kinase activity slows replication forks and prevents origin firing in damaged cells. Here we describe proteomic analyses that identified mechanisms through which ATR kinase inhibitors induce unscheduled origin firing in undamaged cells. ATR-Chk1 inhibitor-induced origin firing is mediated by Cdc7 kinase through previously undescribed phosphorylations on GINS that induce an association between GINS and And-1. ATR-Chk1 inhibitor-induced origin firing is blocked by prior exposure to DNA damaging agents showing that the prevention of origin firing does not require ongoing ATR activity. In contrast, ATR-Chk1 inhibitor induced origins generate additional replication forks that are targeted by subsequent exposure to DNA damaging agents. Thus, the sequence of administration of an ATR kinase inhibitor and a DNA damaging agent impacts the DNA damage induced by the combination. Our experiments identify competing ATR and Cdc7 kinase-dependent mechanisms at replication origins in human cells. PMID- 29123097 TI - Polymorphic regenerated silk fibers assembled through bioinspired spinning. AB - A variety of artificial spinning methods have been applied to produce regenerated silk fibers; however, how to spin regenerated silk fibers that retain the advantages of natural silks in terms of structural hierarchy and mechanical properties remains challenging. Here, we show a bioinspired approach to spin regenerated silk fibers. First, we develop a nematic silk microfibril solution, highly viscous and stable, by partially dissolving silk fibers into microfibrils. This solution maintains the hierarchical structures in natural silks and serves as spinning dope. It is then spun into regenerated silk fibers by direct extrusion in the air, offering a useful route to generate polymorphic and hierarchical regenerated silk fibers with physical properties beyond natural fiber construction. The materials maintain the structural hierarchy and mechanical properties of natural silks, including a modulus of 11 +/- 4 GPa, even higher than natural spider silk. It can further be functionalized with a conductive silk/carbon nanotube coating, responsive to changes in humidity and temperature. PMID- 29123098 TI - Phospholipid flippase ATP11C is endocytosed and downregulated following Ca2+ mediated protein kinase C activation. AB - We and others showed that ATP11A and ATP11C, members of the P4-ATPase family, translocate phosphatidylserine (PS) and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflets at the plasma membrane. PS exposure on the outer leaflet of the plasma membrane in activated platelets, erythrocytes, and apoptotic cells was proposed to require the inhibition of PS-flippases, as well as activation of scramblases. Although ATP11A and ATP11C are cleaved by caspases in apoptotic cells, it remains unclear how PS-flippase activity is regulated in non-apoptotic cells. Here we report that the PS-flippase ATP11C, but not ATP11A, is sequestered from the plasma membrane via clathrin-mediated endocytosis upon Ca2+-mediated PKC activation. Importantly, we show that a characteristic di leucine motif (SVRPLL) in the C-terminal cytoplasmic region of ATP11C becomes functional upon PKC activation. Moreover endocytosis of ATP11C is induced by Ca2+ signaling via Gq-coupled receptors. Our data provide the first evidence for signal-dependent regulation of mammalian P4-ATPase. PMID- 29123099 TI - Spatio-temporally separated cortical flows and spindle geometry establish physical asymmetry in fly neural stem cells. AB - Asymmetric cell division, creating sibling cells with distinct developmental potentials, can be manifested in sibling cell size asymmetry. This form of physical asymmetry occurs in several metazoan cells, but the underlying mechanisms and function are incompletely understood. Here we use Drosophila neural stem cells to elucidate the mechanisms involved in physical asymmetry establishment. We show that Myosin relocalizes to the cleavage furrow via two distinct cortical Myosin flows: at anaphase onset, a polarity induced, basally directed Myosin flow clears Myosin from the apical cortex. Subsequently, mitotic spindle cues establish a Myosin gradient at the lateral neuroblast cortex, necessary to trigger an apically directed flow, removing Actomyosin from the basal cortex. On the basis of the data presented here, we propose that spatiotemporally controlled Myosin flows in conjunction with spindle positioning and spindle asymmetry are key determinants for correct cleavage furrow placement and cortical expansion, thereby establishing physical asymmetry. PMID- 29123101 TI - Symmetry control of nanorod superlattice driven by a governing force. AB - Nanoparticle self-assembly promises scalable fabrication of composite materials with unique properties, but symmetry control of assembled structures remains a challenge. By introducing a governing force in the assembly process, we develop a strategy to control assembly symmetry. As a demonstration, we realize the tetragonal superlattice of octagonal gold nanorods, breaking through the only hexagonal symmetry of the superlattice so far. Surprisingly, such sparse tetragonal superstructure exhibits much higher thermostability than its close packed hexagonal counterpart. Multiscale modeling reveals that the governing force arises from hierarchical molecular and colloidal interactions. This force dominates the interactions involved in the assembly process and determines the superlattice symmetry, leading to the tetragonal superlattice that becomes energetically favorable over its hexagonal counterpart. This strategy might be instructive for designing assembly of various nanoparticles and may open up a new avenue for realizing diverse assembly structures with pre-engineered properties. PMID- 29123100 TI - DNA methylation at enhancers identifies distinct breast cancer lineages. AB - Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression, we apply genome-wide expression-methylation quantitative trait loci (emQTL) analysis between DNA methylation and gene expression. On a whole genome scale, in cis and in trans, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association in three breast cancer cohorts (n = 104, n = 253 and n = 277). The expression-methylation quantitative trait loci associations form two main clusters; one relates to tumor infiltrating immune cell signatures and the other to estrogen receptor signaling. In the estrogen related cluster, using ChromHMM segmentation and transcription factor chromatin immunoprecipitation sequencing data, we identify transcriptional networks regulated in a cell lineage-specific manner by DNA methylation at enhancers. These networks are strongly dominated by ERalpha, FOXA1 or GATA3 and their targets were functionally validated using knockdown by small interfering RNA or GRO-seq analysis after transcriptional stimulation with estrogen. PMID- 29123102 TI - Semisynthetic fluorescent pH sensors for imaging exocytosis and endocytosis. AB - The GFP-based superecliptic pHluorin (SEP) enables detection of exocytosis and endocytosis, but its performance has not been duplicated in red fluorescent protein scaffolds. Here we describe "semisynthetic" pH-sensitive protein conjugates with organic fluorophores, carbofluorescein, and Virginia Orange that match the properties of SEP. Conjugation to genetically encoded self-labeling tags or antibodies allows visualization of both exocytosis and endocytosis, constituting new bright sensors for these key steps of synaptic transmission. PMID- 29123103 TI - In situ real-time gravimetric and viscoelastic probing of surface films formation on lithium batteries electrodes. AB - It is generally accepted that solid-electrolyte interphase formed on the surface of lithium-battery electrodes play a key role in controlling their cycling performance. Although a large variety of surface-sensitive spectroscopies and microscopies were used for their characterization, the focus was on surface species nature rather than on the mechanical properties of the surface films. Here we report a highly sensitive method of gravimetric and viscoelastic probing of the formation of surface films on composite Li4Ti5O12 electrode coupled with lithium ions intercalation into this electrode. Electrochemical quartz-crystal microbalance with dissipation monitoring measurements were performed with LiTFSI, LiPF6, and LiPF6 + 2% vinylene carbonate solutions from which structural parameters of the surface films were returned by fitting to a multilayer viscoelastic model. Only a few fast cycles are required to qualify surface films on Li4Ti5O12 anode improving in the sequence LiPF6 < LiPF6 + 2% vinylene carbonate << LiTFSI. PMID- 29123104 TI - A Prospective, Randomized Trial of Two Mucin Secretogogues for the Treatment of Dry Eye Syndrome in Office Workers. AB - The purpose of the study was to compare the two mucin secretogogues, diquafosol (DQS) and rebamipide (RBM), for the treatment of dry eye syndrome (DES) in office workers. Dry eye patients using computers for >4 h/day were randomly assigned treatment with either DQS or RBM. Main outcomes measures included changes in tear film break-up time (TBUT) and subjective symptoms assessed by the Dry Eye-Related Quality of Life Score (DEQS). The subjects had scheduled examinations at 0 and 4 weeks, and the examinations at 2 and 8 weeks were optional. Changes in keratoconjunctival fluorescein score and a patient satisfaction questionnaire were also recorded. Both groups showed significant improvements in the DEQS scores at 2, 4, and 8 weeks following the initiation of the study. Both groups showed significant increases in the TBUT at 2 and 4 weeks. No significant difference was found between the DQS and RBM groups at any time periods. Patients reported more comfort with the use of DQS compared with the use of RBM. No local or systemic side effects were noted. The results of the present study indicated that both DQS and RBM were effective for the treatment of DES in office workers. PMID- 29123105 TI - Total morphosynthesis of biomimetic prismatic-type CaCO3 thin films. AB - Biomimetic mineralization can lead to advanced crystalline composites with common chemicals under ambient conditions. An exceptional example is biomimetic nacre with its superior fracture toughness. The synthesis of the prismatic layer with stiffness and wear resistance nonetheless remains an elusive goal. Herein, we apply a biomimetic mineralization method to grow prismatic-type CaCO3 thin films, mimicking their biogenic counterparts found in mollusk shells with a three-step pathway: coating a polymer substrate, deposition of a granular transition layer, and mineralization of a prismatic overlayer. The synthetic prismatic overlayers exhibit structural similarity and comparable hardness and Young's modulus to their biogenic counterparts. Furthermore, employment of a biomacromolecular soluble additive, silk fibroin, in fabrication of the prismatic thin films leads to micro-/nano-textures with enhanced toughness and emerging under-water superoleophobicity. This study highlights the crucial role of the granular transition layer in promoting competition growth of the prismatic layer. PMID- 29123107 TI - Erratum: Resonant microwave fields and negative magnetic response, induced by displacement currents in dielectric rings: theory and the first experiments. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29123106 TI - Developmental diet regulates Drosophila lifespan via lipid autotoxins. AB - Early-life nourishment exerts long-term influences upon adult physiology and disease risk. These lasting effects of diet are well established but the underlying mechanisms are only partially understood. Here we show that restricting dietary yeast during Drosophila development can, depending upon the subsequent adult environment, more than double median lifespan. Developmental diet acts via a long-term influence upon the adult production of toxic molecules, which we term autotoxins, that are shed into the environment and shorten the lifespan of both sexes. Autotoxins are synthesised by oenocytes and some of them correspond to alkene hydrocarbons that also act as pheromones. This study identifies a mechanism by which the developmental dietary history of an animal regulates its own longevity and that of its conspecific neighbours. It also has important implications for the design of lifespan experiments as autotoxins can influence the regulation of longevity by other factors including diet, sex, insulin signalling and population density. PMID- 29123108 TI - Depleted depletion drives polymer swelling in poor solvent mixtures. AB - Establishing a link between macromolecular conformation and microscopic interaction is a key to understand properties of polymer solutions and for designing technologically relevant "smart" polymers. Here, polymer solvation in solvent mixtures strike as paradoxical phenomena. For example, when adding polymers to a solvent, such that all particle interactions are repulsive, polymer chains can collapse due to increased monomer-solvent repulsion. This depletion induced monomer-monomer attraction is well known from colloidal stability. A typical example is poly(methyl methacrylate) (PMMA) in water or small alcohols. While polymer collapse in a single poor solvent is well understood, the observed polymer swelling in mixtures of two repulsive solvents is surprising. By combining simulations and theoretical concepts known from polymer physics and colloidal science, we unveil the microscopic, generic origin of this collapse swelling-collapse behavior. We show that this phenomenon naturally emerges at constant pressure when an appropriate balance of entropically driven depletion interactions is achieved. PMID- 29123109 TI - Label-free automated three-dimensional imaging of whole organs by microtomy assisted photoacoustic microscopy. AB - Three-dimensional (3D) optical imaging of whole biological organs with microscopic resolution has remained a challenge. Most versions of such imaging techniques require special preparation of the tissue specimen. Here we demonstrate microtomy-assisted photoacoustic microscopy (mPAM) of mouse brains and other organs, which automatically acquires serial distortion-free and registration-free images with endogenous absorption contrasts. Without tissue staining or clearing, mPAM generates micrometer-resolution 3D images of paraffin- or agarose-embedded whole organs with high fidelity, achieved by label-free simultaneous sensing of DNA/RNA, hemoglobins, and lipids. mPAM provides histology like imaging of cell nuclei, blood vessels, axons, and other anatomical structures, enabling the application of histopathological interpretation at the organelle level to analyze a whole organ. Its deep tissue imaging capability leads to less sectioning, resulting in negligible sectioning artifact. mPAM offers a new way to better understand complex biological organs. PMID- 29123110 TI - Site of asteroid impact changed the history of life on Earth: the low probability of mass extinction. AB - Sixty-six million years ago, an asteroid approximately 9 km in diameter hit the hydrocarbon- and sulfur-rich sedimentary rocks in what is now Mexico. Recent studies have shown that this impact at the Yucatan Peninsula heated the hydrocarbon and sulfur in these rocks, forming stratospheric soot and sulfate aerosols and causing extreme global cooling and drought. These events triggered a mass extinction, including dinosaurs, and led to the subsequent macroevolution of mammals. The amount of hydrocarbon and sulfur in rocks varies widely, depending on location, which suggests that cooling and extinction levels were dependent on impact site. Here we show that the probability of significant global cooling, mass extinction, and the subsequent appearance of mammals was quite low after an asteroid impact on the Earth's surface. This significant event could have occurred if the asteroid hit the hydrocarbon-rich areas occupying approximately 13% of the Earth's surface. The site of asteroid impact, therefore, changed the history of life on Earth. PMID- 29123111 TI - Electromagnetic scattering laws in Weyl systems. AB - Wavelength determines the length scale of the cross section when electromagnetic waves are scattered by an electrically small object. The cross section diverges for resonant scattering, and diminishes for non-resonant scattering, when wavelength approaches infinity. This scattering law explains the colour of the sky as well as the strength of a mobile phone signal. We show that such wavelength scaling comes from the conical dispersion of free space at zero frequency. Emerging Weyl systems, offering similar dispersion at non-zero frequencies, lead to new laws of electromagnetic scattering that allow cross sections to be decoupled from the wavelength limit. Diverging and diminishing cross sections can be realized at any target wavelength in a Weyl system, providing the ability to tailor the strength of wave-matter interactions for radiofrequency and optical applications. PMID- 29123112 TI - Supramolecular networks stabilise and functionalise black phosphorus. AB - The limited stability of the surface of black phosphorus (BP) under atmospheric conditions is a significant constraint on the exploitation of this layered material and its few layer analogue, phosphorene, as an optoelectronic material. Here we show that supramolecular networks stabilised by hydrogen bonding can be formed on BP, and that these monolayer-thick films can passivate the BP surface and inhibit oxidation under ambient conditions. The supramolecular layers are formed by solution deposition and we use atomic force microscopy to obtain images of the BP surface and hexagonal supramolecular networks of trimesic acid and melamine cyanurate (CA.M) under ambient conditions. The CA.M network is aligned with rows of phosphorus atoms and forms large domains which passivate the BP surface for more than a month, and also provides a stable supramolecular platform for the sequential deposition of 1,2,4,5-tetrakis(4-carboxyphenyl)benzene to form supramolecular heterostructures. PMID- 29123113 TI - TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis. AB - Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator like effector nucleases (TALENs). Targeted insertion of a codon-optimized CSF2RA cDNA driven by the hybrid cytomegalovirus (CMV) early enhancer/chicken beta actin (CAG) promoter into the AAVS1 locus resulted in robust expression of the CSF2RA gene in gene-edited herPAP-iPSCs as well as thereof derived macrophages. These macrophages displayed typical morphology, surface phenotype, phagocytic and secretory activity, as well as functional CSF2RA expression verified by STAT5 phosphorylation and GM-CSF uptake studies. Thus, our study provides a proof-of concept, that TALEN-mediated integration of the CSF2RA gene into the AAVS1 safe harbor locus in patient-specific iPSCs represents an efficient strategy to generate functionally corrected monocytes/macrophages, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of herPAP. PMID- 29123114 TI - Structural basis for Ragulator functioning as a scaffold in membrane-anchoring of Rag GTPases and mTORC1. AB - Amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) is mediated by Rag GTPases, which are recruited to the lysosome by the Ragulator complex consisting of p18, MP1, p14, HBXIP and C7orf59; however, the molecular mechanism is elusive. Here, we report the crystal structure of Ragulator, in which p18 wraps around the MP1-p14 and C7orf59-HBXIP heterodimers and the interactions of p18 with MP1, C7orf59, and HBXIP are essential for the assembly of Ragulator. There are two binding sites for the Roadblock domains of Rag GTPases: helix alpha1 of p18 and the two helices side of MP1-p14. The interaction of Ragulator with Rag GTPases is required for their cellular co localization and can be competitively inhibited by C17orf59. Collectively, our data indicate that Ragulator functions as a scaffold to recruit Rag GTPases to lysosomal membrane in mTORC1 signaling. PMID- 29123115 TI - Gas sensors boosted by two-dimensional h-BN enabled transfer on thin substrate foils: towards wearable and portable applications. AB - The transfer of GaN based gas sensors to foreign substrates provides a pathway to enhance sensor performance, lower the cost and extend the applications to wearable, mobile or disposable systems. The main keys to unlocking this pathway is to grow and fabricate the sensors on large h-BN surface and to transfer them to the flexible substrate without any degradation of the performances. In this work, we develop a new generation of AlGaN/GaN gas sensors with boosted performances on a low cost flexible substrate. We fabricate 2-inch wafer scale AlGaN/GaN gas sensors on sacrificial two-dimensional (2D) nano-layered h-BN without any delamination or cracks and subsequently transfer sensors to an acrylic surface on metallic foil. This technique results in a modification of relevant device properties, leading to a doubling of the sensitivity to NO2 gas and a response time that is more than 6 times faster than before transfer. This new approach for GaN-based sensor design opens new avenues for sensor improvement via transfer to more suitable substrates, and is promising for next-generation wearable and portable opto-electronic devices. PMID- 29123116 TI - India Is Overtaking China as the World's Largest Emitter of Anthropogenic Sulfur Dioxide. AB - Severe haze is a major public health concern in China and India. Both countries rely heavily on coal for energy, and sulfur dioxide (SO2) emitted from coal-fired power plants and industry is a major pollutant contributing to their air quality problems. Timely, accurate information on SO2 sources is a required input to air quality models for pollution prediction and mitigation. However, such information has been difficult to obtain for these two countries, as fast-paced changes in economy and environmental regulations have often led to unforeseen emission changes. Here we use satellite observations to show that China and India are on opposite trajectories for sulfurous pollution. Since 2007, emissions in China have declined by 75% while those in India have increased by 50%. With these changes, India is now surpassing China as the world's largest emitter of anthropogenic SO2. This finding, not predicted by emission scenarios, suggests effective SO2 control in China and lack thereof in India. Despite this, haze remains severe in China, indicating the importance of reducing emissions of other pollutants. In India, ~33 million people now live in areas with substantial SO2 pollution. Continued growth in emissions will adversely affect more people and further exacerbate morbidity and mortality. PMID- 29123118 TI - Substrate Microarchitecture Shapes the Paracrine Crosstalk of Stem Cells with Endothelial Cells and Osteoblasts. AB - We examined the hypothesis that substrate microarchitecture regulates the crosstalk between human mesenchymal stem cells (hMSC) and cell types involved in bone regeneration. Compared with polyester flat substrates having uniformly distributed homogenous pores (2D), three-dimensional polystyrene substrates with randomly oriented and interconnected pores of heterogeneous size (3D) stimulated the stromal secretion of IGF-1 while lessened the production of VEGFR-1, MCP-1 and IL-6. The medium conditioned by hMSC cultured in 3D substrates stimulated tube formation by human endothelial cells (hEC) to a higher extent than medium from 2D cultures. 3D co-cultures of hMSC and hEC contained higher secreted levels of IGF-1, EGF and FGF-2 than 2D co-cultures, resulting in increased hEC proliferation and migration. Substrate microarchitecture influenced the secretion of factors related to bone remodeling as the ratio RANKL to OPG, and the levels of M-CSF and IL-6 were higher in 3D co-cultures of hMSC and human osteoblasts (hOB) than in 2D co-cultures. Cytokine microenvironment in 3D co-cultures stimulated osteoblast matrix reorganization while demoted the late steps of osteoblastic maturation. Altogether, data in this study may unveil a new role of scaffold microarchitecture during bone regeneration, as modulator of the paracrine relationships that hMSC establish with hEC and hOB. PMID- 29123117 TI - A glimpse of gluons through deeply virtual compton scattering on the proton. AB - The internal structure of nucleons (protons and neutrons) remains one of the greatest outstanding problems in modern nuclear physics. By scattering high energy electrons off a proton we are able to resolve its fundamental constituents and probe their momenta and positions. Here we investigate the dynamics of quarks and gluons inside nucleons using deeply virtual Compton scattering (DVCS)-a highly virtual photon scatters off the proton, which subsequently radiates a photon. DVCS interferes with the Bethe-Heitler (BH) process, where the photon is emitted by the electron rather than the proton. We report herein the full determination of the BH-DVCS interference by exploiting the distinct energy dependences of the DVCS and BH amplitudes. In the regime where the scattering is expected to occur off a single quark, measurements show an intriguing sensitivity to gluons, the carriers of the strong interaction. PMID- 29123119 TI - Acupuncture points can be identified as cutaneous neurogenic inflammatory spots. AB - Acupuncture, a traditional medical procedure practised for over 2000 years in Asia, stimulates specific but poorly defined sites called acupoints. To date, no unique anatomical acupoint structures have been found. However, noxious sensory signals from visceral organs produce hypersensitive spots on the skin (neurogenic spots), caused by cutaneous neurogenic inflammation, in the dermatome that overlaps with visceral afferent innervations. Here, we show that an acupoint is one form of neurogenic inflammation on the skin. Various studies have demonstrated that acupoints show mechanical hypersensitivity and have high electrical conductance. Stimulation of acupoints produces needling sensations caused by the activation of small diameter afferent nerve fibres and therapeutic effects on the associated visceral organs, which is likely due to the release of endogenous opioids. The present study provides experimental evidence that neurogenic spots exhibit all the characteristics of the acupoints listed above. In addition, the stimulation of neurogenic spots by electrical, mechanical, or chemical means alleviated pathological conditions in rat colitis and hypertension models via the endogenous opioid system. Our results suggest that acupoints associated with internal organs may be identical to neurogenic inflammatory spots on the skin, which are produced by activation of somatic afferents in abnormal conditions of visceral organs. PMID- 29123121 TI - The photoelastic coefficient P12 of H+ implanted GaAs as a function of defect density. AB - The photoelastic phenomenon has been widely investigated as a fundamental elastooptical property of solids. This effect has been applied extensively to study stress distribution in lattice-mismatched semiconductor heterostructures. GaAs based optoelectronic devices (e.g. solar cells, modulators, detectors, and diodes) used in space probes are subject to damage arising from energetic proton (H+) irradiation. For that reason, the effect of proton irradiation on photoelastic coefficients of GaAs is of primary importance to space applied optoelectronics. However, there yet remains a lack of systematic studies of energetic proton induced changes in the photoelastic properties of bulk GaAs. In this work, the H+ energy and fluence chosen for GaAs implantation are similar to that of protons originating from the radiation belts and solar flares. We present the depth-dependent photoelastic coefficient P 12 profile in non-annealed H+ implanted GaAs obtained from the analysis of the time-domain Brillouin scattering spectra. The depth-dependent profiles are found to be broader than the defect distribution profiles predicted by Monte Carlo simulations. This fact indicates that the changes in photoelastic coefficient P 12 depend nonlinearly on the defect concentrations created by the hydrogen implantation. These studies provide insight into the spatial extent to which defects influence photoelastic properties of GaAs. PMID- 29123120 TI - Membrane curvature induced by proximity of anionic phospholipids can initiate endocytosis. AB - The plasma membrane is uniquely enriched in phosphatidylserine (PtdSer). This anionic phospholipid is restricted almost exclusively to the inner leaflet of the plasmalemma. Because of their high density, the headgroups of anionic lipids experience electrostatic repulsion that, being exerted asymmetrically, is predicted to favor membrane curvature. We demonstrate that cholesterol limits this repulsion and tendency to curve. Removal of cholesterol or insertion of excess PtdSer increases the charge density of the inner leaflet, generating foci of enhanced charge and curvature where endophilin and synaptojanin are recruited. From these sites emerge tubules that undergo fragmentation, resulting in marked endocytosis of PtdSer. Shielding or reduction of the surface charge or imposition of outward membrane tension minimized invagination and PtdSer endocytosis. We propose that cholesterol associates with PtdSer to form nanodomains where the headgroups of PtdSer are maintained sufficiently separated to limit spontaneous curvature while sheltering the hydrophobic sterol from the aqueous medium. PMID- 29123122 TI - Identification of low oxygen-tolerating bacteria in prostate secretions of cancer patients and discussion of possible aetiological significance. AB - The microaerophylic organism Propionibacterium acnes has shown consistent association with prostate cancer (PC). Studies linking circumcision with reduced PC further support anaerobes involvement as circumcision reduces anaerobe colonisation on the glans penis. A 1988 study linked anaerobes with PC but considered them as opportunists in necrotic tumour. A hypothesis that a "Helicobacter-like" process causes PC justified this pilot study. Active surveillance patients were enrolled. Post-prostate massage urine samples were screened using the Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) technique for bacterial identification after culture in anaerobic and aerobic conditions. 8 out of 18 patients (41%) had either obligate anaerobic (n = 5) or microaerophilic (n = 4, one of whom also had anaerobes) organisms identified. None of 10 control samples contained obligate anaerobes. Although mean PSA was 63% higher in those with low oxygen tolerating bacteria, two high outliers resulted in this difference being non-significant. Given the substantially higher proportion of PC patients with organisms growing in a low concentration of oxygen when combined with previous studies compared to controls, the degree of significance was as high as smoking 5-9 cigarettes a day and needs further investigation. Translational research in trials combining Vitamin D and aspirin have begun as part of such investigation. PMID- 29123123 TI - Observation of transverse spin Nernst magnetoresistance induced by thermal spin current in ferromagnet/non-magnet bilayers. AB - Electric generation of spin current via spin Hall effect is of great interest as it allows an efficient manipulation of magnetization in spintronic devices. Theoretically, pure spin current can be also created by a temperature gradient, which is known as spin Nernst effect. Here, we report spin Nernst effect-induced transverse magnetoresistance in ferromagnet/non-magnetic heavy metal bilayers. We observe that the magnitude of transverse magnetoresistance in the bilayers is significantly modified by heavy metal and its thickness. This strong dependence of transverse magnetoresistance on heavy metal evidences the generation of thermally induced pure spin current in heavy metal. Our analysis shows that spin Nernst angles of W and Pt have the opposite sign to their spin Hall angles. Moreover, our estimate implies that the magnitude of spin Nernst angle would be comparable to that of spin Hall angle, suggesting an efficient generation of spin current by the spin Nernst effect. PMID- 29123124 TI - Hall sensors batch-fabricated on all-CVD h-BN/graphene/h-BN heterostructures. AB - The two-dimensional (2D) material graphene is highly promising for Hall sensors due to its potential of having high charge carrier mobility and low carrier concentration at room temperature. Here, we report the scalable batch-fabrication of magnetic Hall sensors on graphene encapsulated in hexagonal boron nitride (h BN) using commercially available large area CVD grown materials. The all-CVD grown h-BN/graphene/h-BN van der Waals heterostructures were prepared by layer transfer technique and Hall sensors were batch-fabricated with 1D edge metal contacts. The current-related Hall sensitivities up to 97 V/AT are measured at room temperature. The Hall sensors showed robust performance over the wafer scale with stable characteristics over six months in ambient environment. This work opens avenues for further development of growth and fabrication technologies of all-CVD 2D material heterostructures and allows further improvements in Hall sensor performance for practical applications. PMID- 29123125 TI - Purcell-enhanced quantum yield from carbon nanotube excitons coupled to plasmonic nanocavities. AB - Single-walled carbon nanotubes (SWCNTs) are promising absorbers and emitters to enable novel photonic applications and devices but are also known to suffer from low optical quantum yields. Here we demonstrate SWCNT excitons coupled to plasmonic nanocavity arrays reaching deeply into the Purcell regime with Purcell factors (F P) up to F P = 180 (average F P = 57), Purcell-enhanced quantum yields of 62% (average 42%), and a photon emission rate of 15 MHz into the first lens. The cavity coupling is quasi-deterministic since the photophysical properties of every SWCNT are enhanced by at least one order of magnitude. Furthermore, the measured ultra-narrow exciton linewidth (18 MUeV) reaches the radiative lifetime limit, which is promising towards generation of transform-limited single photons. To demonstrate utility beyond quantum light sources we show that nanocavity coupled SWCNTs perform as single-molecule thermometers detecting plasmonically induced heat at cryogenic temperatures in a unique interplay of excitons, phonons, and plasmons at the nanoscale. PMID- 29123126 TI - The self-healing of defects induced by the hydriding phase transformation in palladium nanoparticles. AB - Nanosizing can dramatically alter material properties by enhancing surface thermodynamic contributions, shortening diffusion lengths, and increasing the number of catalytically active sites per unit volume. These mechanisms have been used to explain the improved properties of catalysts, battery materials, plasmonic materials, etc. Here we show that Pd nanoparticles also have the ability to self-heal defects in their crystal structures. Using Bragg coherent diffractive imaging, we image dislocations nucleated deep in a Pd nanoparticle during the forward hydriding phase transformation that heal during the reverse transformation, despite the region surrounding the dislocations remaining in the hydrogen-poor phase. We show that defective Pd nanoparticles exhibit sloped isotherms, indicating that defects act as additional barriers to the phase transformation. Our results resolve the formation and healing of structural defects during phase transformations at the single nanoparticle level and offer an additional perspective as to how and why nanoparticles differ from their bulk counterparts. PMID- 29123127 TI - A mechanism for FtsZ-independent proliferation in Streptomyces. AB - The central player in bacterial cell division, FtsZ, is essential in almost all organisms in which it has been tested, with the most notable exception being Streptomyces. Streptomycetes differ from many bacteria in growing from the cell tip and undergoing branching, similar to filamentous fungi. Here we show that limited cell damage, either mechanical or enzymatic, leads to near complete destruction of mycelial microcolonies of a Streptomyces venezuelae ftsZ mutant. This result is consistent with a lack of ftsZ-dependent cross-walls and may be inconsistent with a recently proposed role for membrane structures in the proliferation of ftsZ mutants in other Streptomyces species. Rare surviving fragments of mycelium, usually around branches, appear to be the preferred sites of resealing. Restoration of growth in hyphal fragments of both wild-type and ftsZ mutant hyphae can occur at multiple sites, via branch-like outgrowths containing DivIVA protein at their tips. Thus, our results highlight branching as a means of FtsZ-independent cell proliferation. PMID- 29123129 TI - Effect of Substrate symmetry on the dendrite morphology of MoS2 Film synthesized by CVD. AB - In van der Waals epitaxial growth, the substrate plays a particularly important role in the crystal morphology. Here, we synthesized MoS2 by chemical vapour deposition on silicon carbide (SiC). The obtained MoS2 dendritic crystals show six-fold symmetry, which are different from the conventional triangular shapes on SiO2 substrate and from those with three-fold symmetry on SrTiO3 substrate. Interestingly, these MoS2 dendritic crystals on SiC exhibit an average fractal dimension 1.76, which is slightly larger than the classical Diffusion-limited Aggregation fractal dimension 1.66. The first principle calculation indicates that the six-fold symmetry of the dendritic MoS2 is determined by the lattice symmetry of SiC. To further demonstrating the substrate effect, we break the natural six-fold lattice symmetry of SiC (0001) into groove arrays through etching the substrate. And then we successfully synthesized cross-type dendritic crystal MoS2 with two-fold symmetry. Its average fractal dimension 1.83 is slightly larger than the fractal dimension 1.76 of the previous MoS2 dendrite with six-fold symmetry. In a word, the symmetry of SiC substrate determined the symmetry and the fractal dimension of the dendritic MoS2. This work provides one possibility of inducing the growth orientation of dendritic crystals through controlling the substrate surface symmetry artificially. PMID- 29123128 TI - PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. AB - Mutations in PTEN-induced kinase 1 (PINK1) result in a recessive familial form of Parkinson's disease (PD). PINK1 loss is associated with mitochondrial Ca2+ mishandling, mitochondrial dysfunction, as well as increased neuronal vulnerability. Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro. Phosphorylated LETM1 or the phospho mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. Expression of LETM1-T192E but not LETM1-wild type (WT) rescues mitochondrial calcium mishandling in PINK1 deficient neurons. Expression of both LETM1-WT and LETM1-T192E protects neurons against MPP+-MPTP-induced neuronal death in PINK1 WT neurons, whereas only LETM1 T192E protects neurons under conditions of PINK1 loss. Our findings delineate a mechanism by which PINK1 regulates mitochondrial Ca2+ level through LETM1 and suggest a model by which PINK1 loss leads to deficient phosphorylation of LETM1 and impaired mitochondrial Ca2+ transport.. PMID- 29123130 TI - Binding of mycotoxins to proteins involved in neuronal plasticity: a combined in silico/wet investigation. AB - We have applied a combined computational procedure based on inverse and direct docking in order to identify putative protein targets of a panel of mycotoxins and xenobiotic compounds that can contaminate food and that are known to have several detrimental effects on human health. This procedure allowed us to identify a panel of human proteins as possible targets for aflatoxins, gliotoxin, ochratoxin A and deoxynivalenol. Steady-state fluorescence and microscale thermophoresis experiments allowed us to confirm the binding of some of these mycotoxins to acetylcholinesterase and X-linked neuroligin 4, two proteins involved in synapse activity and, particularly for the second protein, neuronal plasticity and development. Considering the possible involvement of X-linked neuroligin 4 in the etiopathogenesis of autism spectrum syndrome, this finding opens up a new avenue to explore the hypothetical role of these xenobiotic compounds in the onset of this pathology. PMID- 29123132 TI - Rupturing Giant Plasma Membrane Vesicles to Form Micron-sized Supported Cell Plasma Membranes with Native Transmembrane Proteins. AB - Being able to directly obtain micron-sized cell blebs, giant plasma membrane vesicles (GPMVs), with native membrane proteins and deposit them on a planar support to form supported plasma membranes could allow the membrane proteins to be studied by various surface analytical tools in native-like bilayer environments. However, GPMVs do not easily rupture on conventional supports because of their high protein and cholesterol contents. Here, we demonstrate the possibility of using compression generated by the air-water interface to efficiently rupture GPMVs to form micron-sized supported membranes with native plasma membrane proteins. We demonstrated that not only lipid but also a native transmembrane protein in HeLa cells, Aquaporin 3 (AQP3), is mobile in the supported membrane platform. This convenient method for generating micron-sized supported membrane patches with mobile native transmembrane proteins could not only facilitate the study of membrane proteins by surface analytical tools, but could also enable us to use native membrane proteins for bio-sensing applications. PMID- 29123131 TI - Influenza virus genome reaches the plasma membrane via a modified endoplasmic reticulum and Rab11-dependent vesicles. AB - Transport of neo-synthesized influenza A virus (IAV) viral ribonucleoproteins (vRNPs) from the nucleus to the plasma membrane involves Rab 11 but the precise mechanism remains poorly understood. We used metal-tagging and immunolabeling to visualize viral proteins and cellular endomembrane markers by electron microscopy of IAV-infected cells. Unexpectedly, we provide evidence that the vRNP components and the Rab11 protein are present at the membrane of a modified, tubulated endoplasmic reticulum (ER) that extends all throughout the cell, and on irregularly coated vesicles (ICVs). Some ICVs are found very close to the ER and to the plasma membrane. ICV formation is observed only in infected cells and requires an active Rab11 GTPase. Against the currently accepted model in which vRNPs are carried onto Rab11-positive recycling endosomes across the cytoplasm, our findings reveal that the endomembrane organelle that is primarily involved in the transport of vRNPs is the ER. PMID- 29123133 TI - AIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor. AB - Pituitary tumors are frequently associated with mutations in the AIP gene and are sometimes associated with hypersecretion of growth hormone. It is unclear whether other factors besides an enlarged pituitary contribute to the hypersecretion. In a genetic screen for suppressors of reduced neurotransmitter release, we identified a mutation in Caenorhabditis elegans AIPR-1 (AIP-related-1), which causes profound increases in evoked and spontaneous neurotransmitter release, a high frequency of spontaneous calcium transients in motor neurons and an enlarged readily releasable pool of vesicles. Calcium bursts and hypersecretion are reversed by mutations in the ryanodine receptor but not in the voltage-gated calcium channel, indicating that these phenotypes are caused by a leaky ryanodine receptor. AIPR-1 is physically associated with the ryanodine receptor at synapses. Finally, the phenotypes in aipr-1 mutants can be rescued by presynaptic expression of mouse AIP, demonstrating that a conserved function of AIP proteins is to inhibit calcium release from ryanodine receptors. PMID- 29123134 TI - Divergent proliferation patterns of distinct human hair follicle epithelial progenitor niches in situ and their differential responsiveness to prostaglandin D2. AB - Human scalp hair follicles (hHF) harbour several epithelial stem (eHFSC) and progenitor cell sub-populations organised into spatially distinct niches. However, the constitutive cell cycle activity of these niches remains to be characterized in situ. Therefore, the current study has studied these characteristics of keratin 15+ (K15), CD200+ or CD34+ cells within anagen VI hHFs by immunohistomorphometry, using Ki-67 and 5-ethynyl-2'-deoxyuridine (EdU). We quantitatively demonstrate in situ the relative cell cycle inactivity of the CD200+/K15+ bulge compared to other non-bulge CD34+ and K15+ progenitor compartments and found that in each recognized eHFSC/progenitor niche, proliferation associates negatively with eHFSC-marker expression. Furthermore, we also show how prostaglandin D2 (PGD2), which is upregulated in balding scalp, differentially impacts on the proliferation of distinct eHFSC populations. Namely, 24 h organ-cultured hHFs treated with PGD2 displayed reduced Ki-67 expression and EdU incorporation in bulge resident K15+ cells, but not in supra/proximal bulb outer root sheath K15+ progenitors. This study emphasises clear differences between the cell cycle behaviour of spatially distinct stem/progenitor cell niches in the hHF, and demonstrates a possible link between PGD2 and perturbed proliferation dynamics in epithelial stem cells. PMID- 29123135 TI - High yield matrix-free ionization of biomolecules by pulse-heating ion source. AB - Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry has been widely used for biomolecular analysis. However, with conventional MALDI, it is difficult to analyse low-molecular-weight compounds because of the interference of matrix ion signals. Here, we report a matrix-free on-chip pulse-heating desorption/ionization (PHDI) method for a wide range of biomolecules ranging from low molecular-weight substances such as glycine (75.7 Da) to large species such as alpha-lactalbumin (14.2 kDa). Compared with the conventional MALDI, the matrix free PHDI method affords high yields of singly charged ions with very less fragmentation and background using only one-pulse without light (laser). We believe that this new technique for matrix-free biomolecules analysis would overcome the limitations of the conventional MALDI. PMID- 29123136 TI - Benchmarking integrated linear-optical architectures for quantum information processing. AB - Photonic platforms represent a promising technology for the realization of several quantum communication protocols and for experiments of quantum simulation. Moreover, large-scale integrated interferometers have recently gained a relevant role in quantum computing, specifically with Boson Sampling devices and the race for quantum supremacy. Indeed, various linear optical schemes have been proposed for the implementation of unitary transformations, each one suitable for a specific task. Notwithstanding, so far a comprehensive analysis of the state of the art under broader and realistic conditions is still lacking. In the present work we fill this gap, providing in a unified framework a quantitative comparison of the three main photonic architectures, namely the ones with triangular and square designs and the so-called fast transformations. All layouts have been analyzed in presence of losses and imperfect control over the internal reflectivities and phases, showing that the square design outperforms the triangular scheme in most operational conditions. Our results represent a further step ahead towards the implementation of quantum information protocols on large-scale integrated photonic devices. PMID- 29123137 TI - High-fraction brookite films from amorphous precursors. AB - Structure-specific synthesis processes are of key importance to the growth of polymorphic functional compounds such as TiO2, where material properties strongly depend on structure as well as chemistry. The robust growth of the brookite polymorph of TiO2, a promising photocatalyst, has been difficult in both powder and thin-film forms due to the disparity of reported synthesis techniques, their highly specific nature, and lack of mechanistic understanding. In this work, we report the growth of high-fraction (~95%) brookite thin films prepared by annealing amorphous titania precursor films deposited by pulsed laser deposition. We characterize the crystallization process, eliminating the previously suggested roles of substrate templating and Na helper ions in driving brookite formation. Instead, we link phase selection directly to film thickness, offering a novel, generalizable route to brookite growth that does not rely on the presence of extraneous elements or particular lattice-matched substrates. In addition to providing a new synthesis route to brookite thin films, our results take a step towards resolving the problem of phase selection in TiO2 growth, contributing to the further development of this promising functional material. PMID- 29123139 TI - Direct catalytic hydrogenation of CO2 to formate over a Schiff-base-mediated gold nanocatalyst. AB - Catalytic transformation of CO2 to formate is generally realized through bicarbonate hydrogenation in an alkaline environment, while it suffers from a thermodynamic sink due to the considerable thermodynamic stability of the bicarbonate intermediate. Here, we devise a route for the direct catalytic conversion of CO2 over a Schiff-base-modified gold nanocatalyst that is comparable to the fastest known nanocatalysts, with a turnover number (TON) of up to 14,470 over 12 h at 90 degrees C. Theoretical calculations and spectral analysis results demonstrate that the activation of CO2 can be achieved through a weakly bonded carbamate zwitterion intermediate derived from a simple Lewis base adduct of CO2. However, this can only occur with a hydrogen lacking Lewis base center in a polar solvent. This finding offers a promising avenue for the direct activation of CO2 and is likely to have considerable implications in the fields of CO2 conversion and gold catalytic chemistry. PMID- 29123138 TI - Chemical and cellular oxidant production induced by naphthalene secondary organic aerosol (SOA): effect of redox-active metals and photochemical aging. AB - Exposure to air pollution is a leading global health risk. Secondary organic aerosol (SOA) constitute a large portion of ambient particulate matter (PM). In this study, the water-soluble oxidative potential (OP) determined by dithiothreitol (DTT) consumption and intracellular reactive oxygen and nitrogen species (ROS/RNS) production was measured for SOA generated from the photooxidation of naphthalene in the presence of iron sulfate and ammonium sulfate seed particles. The measured intrinsic OP varied for aerosol formed using different initial naphthalene concentrations, however, no trends were observed between OP and bulk aerosol composition or seed type. For all experiments, aerosol generated in the presence of iron-containing seed induced higher ROS/RNS production compared to that formed in the presence of inorganic seed. This effect was primarily attributed to differences in aerosol carbon oxidation state [Formula: see text]. In the presence of iron, radical concentrations are elevated via iron redox cycling, resulting in more oxidized species. An exponential trend was also observed between ROS/RNS and [Formula: see text] for all naphthalene SOA, regardless of seed type or aerosol formation condition. This may have important implications as aerosol have an atmospheric lifetime of a week, over which [Formula: see text] increases due to continued photochemical aging, potentially resulting in more toxic aerosol. PMID- 29123140 TI - Effects of atomic-level nano-structured hydroxyapatite on adsorption of bone morphogenetic protein-7 and its derived peptide by computer simulation. AB - Hydroxyapatite (HA) is the principal inorganic component of bones and teeth and has been widely used as a bone repair material because of its good biocompatibility and bioactivity. Understanding the interactions between proteins and HA is crucial for designing biomaterials for bone regeneration. In this study, we evaluated the effects of atomic-level nano-structured HA (110) surfaces on the adsorption of bone morphogenetic protein-7 (BMP-7) and its derived peptide (KQLNALSVLYFDD) using molecular dynamics and density functional theory methods. The results indicated that the atomic-level morphology of HA significantly affected the interaction strength between proteins and HA substrates. The interactions of BMP-7 and its derived peptide with nano-concave and nano-pillar HA surfaces were stronger than those with flat or nano-groove HA surfaces. The results also revealed that if the groove size of nano-structured HA surfaces matched that of residues in the protein or peptide, these residues were likely to spread into the grooves of the nano-groove, nano-concave, and nano-pillar HA, further strengthening the interactions. These results are helpful in better understanding the adsorption behaviors of proteins onto nano-structured HA surfaces, and provide theoretical guidance for designing novel bioceramic materials for bone regeneration and tissue engineering. PMID- 29123141 TI - New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels. AB - One of the most challenging problems in the development of new anticancer drugs is the very high attrition rate. The so-called "drug repositioning process" propose to find new therapeutic indications to already approved drugs. For this, new analytic methods are required to optimize the information present in large scale pharmacogenomics datasets. We analyzed data from the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia studies. We focused on common cell lines (n = 471), considering the molecular information, and the drug sensitivity for common drugs screened (n = 15). We propose a novel classification based on transcriptomic profiles of cell lines, according to a biological network driven gene selection process. Our robust molecular classification displays greater homogeneity of drug sensitivity than cancer cell line grouped based on tissue of origin. We then identified significant associations between cell line cluster and drug response robustly found between both datasets. We further demonstrate the relevance of our method using two additional external datasets and distinct sensitivity metrics. Some associations were still found robust, despite cell lines and drug responses' variations. This study defines a robust molecular classification of cancer cell lines that could be used to find new therapeutic indications to known compounds. PMID- 29123143 TI - Martensite phase stress and the strengthening mechanism in TRIP steel by neutron diffraction. AB - Two TRIP-aided multiphase steels with different carbon contents (0.2 and 0.4 mass%) were analyzed in situ during tensile deformation by time-of-flight neutron diffraction to clarify the deformation induced martensitic transformation behavior and its role on the strengthening mechanism. The difference in the carbon content affected mainly the difference in the phase fractions before deformation, where the higher carbon content increased the phase fraction of retained austenite (gamma). However, the changes in the relative fraction of martensitic transformation with respect to the applied strain were found to be similar in both steels since the carbon concentrations in gamma were similar regardless of different carbon contents. The phase stress of martensite was found much larger than that of gamma or bainitic ferrite since the martensite was generated at the beginning of plastic deformation. Stress contributions to the flow stress were evaluated by multiplying the phase stresses and their phase fractions. The stress contribution from martensite was observed increasing during plastic deformation while that from bainitic ferrite hardly changing and that from gamma decreasing. PMID- 29123144 TI - Pinning and hysteresis in the field dependent diameter evolution of skyrmions in Pt/Co/Ir superlattice stacks. AB - We have imaged Neel skyrmion bubbles in perpendicularly magnetised polycrystalline multilayers patterned into 1 um diameter dots, using scanning transmission x-ray microscopy. The skyrmion bubbles can be nucleated by the application of an external magnetic field and are stable at zero field with a diameter of 260 nm. Applying an out of plane field that opposes the magnetisation of the skyrmion bubble core moment applies pressure to the bubble and gradually compresses it to a diameter of approximately 100 nm. On removing the field the skyrmion bubble returns to its original diameter via a hysteretic pathway where most of the expansion occurs in a single abrupt step. This contradicts analytical models of homogeneous materials in which the skyrmion compression and expansion are reversible. Micromagnetic simulations incorporating disorder can explain this behaviour using an effective thickness modulation between 10 nm grains. PMID- 29123142 TI - Genomic and epidemiological characterisation of a dengue virus outbreak among blood donors in Brazil. AB - Outbreaks caused by Dengue, Zika and Chikungunya viruses can spread rapidly in immunologically naive populations. By analysing 92 newly generated viral genome sequences from blood donors and recipients, we assess the dynamics of dengue virus serotype 4 during the 2012 outbreak in Rio de Janeiro. Phylogenetic analysis indicates that the outbreak was caused by genotype II, although two isolates of genotype I were also detected for the first time in Rio de Janeiro. Evolutionary analysis and modelling estimates are congruent, indicating a reproduction number above 1 between January and June, and at least two thirds of infections being unnoticed. Modelling analysis suggests that viral transmission started in early January, which is consistent with multiple introductions, most likely from the northern states of Brazil, and with an increase in within-country air travel to Rio de Janeiro. The combination of genetic and epidemiological data from blood donor banks may be useful to anticipate epidemic spread of arboviruses. PMID- 29123145 TI - Well-being, problematic alcohol consumption and acute subjective drug effects in past-year ayahuasca users: a large, international, self-selecting online survey. AB - Ayahuasca is a natural psychedelic brew, which contains dimethyltryptamine (DMT). Its potential as a psychiatric medicine has recently been demonstrated and its non-medical use around the world appears to be growing. We aimed to investigate well-being and problematic alcohol use in ayahuasca users, and ayahuasca's subjective effects. An online, self-selecting, global survey examining patterns of drug use was conducted in 2015 and 2016 (n = 96,901). Questions were asked about: use of ayahuasca, lysergic acid diethylamide (LSD) and magic mushrooms; demographics, current well-being and past-year problematic alcohol use of past year ayahuasca users and comparison drug users; and subjective effects of ayahuasca and comparison drugs. Ayahuasca users (n = 527) reported greater well being than both classic psychedelic users (n = 18,138) and non-psychedelic drug using respondents (n = 78,236). Ayahuasca users reported less problematic drinking than classic psychedelic users, although both groups reported greater problematic drinking than the other respondents. Ayahuasca's acute subjective effects usually lasted for six hours and were most strongly felt one hour after consumption. Within our online, self-selecting survey, ayahuasca users reported better well-being than comparison groups and less problematic drinking than classic psychedelic users. Future longitudinal studies of international samples and randomised controlled trials are needed to dissect the effects of ayahuasca on these outcomes. PMID- 29123146 TI - Productivity benefits of warming at regional scale could be offset by detrimental impacts on site level hydrology. AB - Climate change affects the distribution and persistence of wildlife. Broad scale studies have demonstrated that climate change shifts the geographic ranges and phenology of species. These findings are influential for making high level strategies but not practical enough to guide site specific management. In this study, we explored the environment factors affecting the population of Bar-headed Goose in the key breeding site of Qinghai using generalized additive mixed model (GAMM). Our results showed that 1) there were significant increasing trends in climate variables and river flows to the Qinghai Lake; 2) NDVI in the sites decreased significantly despite the regional positive trend induced by the warmer and wetter climate; 3) NDVI at site scale was negatively correlated to lake water level; and 4) the abundance of Bar-headed Goose decreased significantly at all sites. While the abundance was positively related to NDVI at breeding sites, the GAMM revealed an opposite relationship at foraging areas. Our findings demonstrated the multi-facet effects of climate change on population dynamics; and the effect at global/regional scale could be complicated by site level factors. PMID- 29123147 TI - Enzymatic degradation of organophosphorus insecticides decreases toxicity in planarians and enhances survival. AB - Organophosphorus insecticides (OPs) are toxic compounds used for agricultural purposes and responsible for severe types of contamination worldwide. OPs may also induce chronic deleterious effects and developmental disruption. Finding remediation strategies is a major concern to diminish their impact on environment and human health. Enzymes have emerged as a promising eco-friendly route for decontaminating OPs. The enzyme SsoPox from the archaea Sulfolobus solfataricus has been particularly studied, considering both its tremendous stability and phosphotriesterase activity. However, the toxicity of the degradation products generated through enzyme hydrolysis has been poorly investigated. To address both neurotoxicity and developmental perturbation, freshwater planarians from Platyhelminthes were considered to evaluate the impact of OP and degradation product exposure. Planarians have a large proportion of stem cells that give them an unconventional capacity for regeneration. OPs were found to be highly toxic to planarians and enzyme decontamination drastically enhanced survival rate. Although not completely innocuous, the degradation products were found to be less toxic than insecticides and reduced poisoning effects by increasing NOEC values by up to eight-fold. SsoPox also limited detrimental consequences on planarian mobility and enabled them to recover a non-exposed type regeneration process suggesting that enzymatic decontamination is a promising alternative to bioremediation. PMID- 29123148 TI - Radiological Investigation of High Background Radiation Areas. AB - In this paper, we used the Hyper-Pure Germanium (HPGe) detector to measure 30 samples which are collected from north of Nile Delta near Rosetta beach in Egypt. The activity of primordial radionuclides, such as 238U, 235U, 232Th, and 40K was estimated. Concentrations ranged between 36.5-177.4, 50-397.5 and 56.1-168.9 Bq.kg-1 for 238U, 232Th and 40K respectively. Activity concentration of 235U and the variation in uranium isotopic ratio 235U/238U was calculated. External hazard indices (Hex) (or radium equivalent activity Raeq), activity concentration indices (I), alpha index (Ialpha), absorbed outdoor gamma dose rate (Dout), effective outdoor gamma dose rate (Eout) and Excess Lifetime Cancer Risk (ELCR) due to different samples are estimated. External hazard indices (Hex) are ranged between 0.32-2.04, radium equivalent activity (Raeq) are ranged between 118.67 753.91, the activity concentration indices (I) are 0.42-2.61, and alpha index (Ialpha) are 0.18-0.89. External hazard indices (Hex) in some samples more than unity then it exceeds the upper limit of exposure. Also, the radium equivalent activities (Raeq) are higher than the exemption limits (370 Bq.kg-1). PMID- 29123149 TI - IL-6/IL-12 Cytokine Receptor Shuffling of Extra- and Intracellular Domains Reveals Canonical STAT Activation via Synthetic IL-35 and IL-39 Signaling. AB - IL-35 and IL-39 are recently discovered shared members of the IL-6- and IL-12 type cytokine family with immune-suppressive capacity. IL-35 has been reported to induce the formation of four different receptor complexes: gp130:IL-12beta2, gp130:gp130, IL-12beta2:IL-12beta2, and IL-12beta2:WSX-1. IL-39 was proposed to form a gp130:IL-23R receptor complex. IL-35, but not IL-39, has been reported to activate non-conventional STAT signaling, depending on the receptor complex and target cell. Analyses of IL-35 and IL-39 are, however, hampered by the lack of biologically active recombinant IL-35 and IL-39 proteins. Therefore, we engineered chimeric cytokine receptors to accomplish synthetic IL-35 and IL- 39 signaling by shuffling the extra- and intracellular domains of IL-6/IL-12-type cytokine receptors, resulting in biological activity for all previously described IL-35 receptor complexes. Moreover, we found that the proposed IL-39 receptor complex is biologically active and discovered two additional biologically active synthetic receptor combinations, gp130/IL-12Rbeta1 and IL-23R/IL-12Rbeta2. Surprisingly, synthetic IL-35 activation led to more canonical STAT signaling of all receptor complexes. In summary, our receptor shuffling approach highlights an interchangeable, modular domain structure among IL-6- and IL-12-type cytokine receptors and enabled synthetic IL-35 and IL-39 signaling. PMID- 29123150 TI - Lung Clearance Index and Quantitative Computed Tomography of Post-Infectious Bronchiolitis Obliterans in Infants. AB - Post-infectious bronchiolitis obliterans (BO) could be diagnosed via spirometry and chest computed tomography (CT); however, these tests are limited in infants. We aimed to evaluate the utility of lung clearance index (LCI) and air-trapping lung volume from chest CT in infants. This prospective study included 20 infants (mean age, 10.9 +/- 6.3 months) diagnosed with post-infectious BO between 2009 and 2016. All subjects underwent multiple breath washout tests. For quantitative analysis of chest CT, the mean lung area attenuation value was used as an individual cutoff to determine the air-trapping lung volume. The mean cutoff lung attenuation value was -659 Hounsfield units, the mean total lung volume was 265 ml, and the mean air-trapping lung volume percentage was 22.9%. Functional residual capacity correlated with total lung volume and normal attenuation lung volume (p < 0.02). LCI (p < 0.02) and moment ratio (MR) 1 (p < 0.05) correlated with the air-trapping lung volume percentage. The concordance indices of LCI (0.659, p = 0.025) and MR1 (0.642, p = 0.046) were significantly correlated with the air-trapping lung volume percentage from CT. LCI and quantitative air trapping lung volume from chest CT are feasible, complimentary tools for assessing infants with post-infectious BO. PMID- 29123151 TI - Polymer Nanodiscs: Discoidal Amphiphilic Block Copolymer Membranes as a New Platform for Membrane Proteins. AB - Lipid nanodiscs are playing increasingly important roles in studies of the structure and function of membrane proteins. Development of lipid nanodiscs as a membrane-protein-supporting platform, or a drug targeting and delivery vehicle in general, is undermined by the fluidic and labile nature of lipid bilayers. Here, we report the discovery of polymer nanodiscs, i.e., discoidal amphiphilic block copolymer membrane patches encased within membrane scaffold proteins, as a novel two-dimensional nanomembrane that maintains the advantages of lipid nanodiscs while addressing their weaknesses. Using MsbA, a bacterial ATP-binding cassette transporter as a membrane protein prototype, we show that the protein can be reconstituted into the polymer nanodiscs in an active state. As with lipid nanodiscs, reconstitution of detergent-solubilized MsbA into the polymer nanodiscs significantly enhances its activity. In contrast to lipid nanodiscs that undergo time- and temperature-dependent structural changes, the polymer nanodiscs experience negligible structural evolution under similar environmental stresses, revealing a critically important property for the development of nanodisc-based characterization methodologies or biotechnologies. We expect that the higher mechanical and chemical stability of block copolymer membranes and their chemical versatility for adaptation will open new opportunities for applications built upon diverse membrane protein functions, or involved with drug targeting and delivery. PMID- 29123152 TI - Neural-specific deletion of mitochondrial p32/C1qbp leads to leukoencephalopathy due to undifferentiated oligodendrocyte and axon degeneration. AB - Mitochondrial dysfunction is a critical step in the pathogenesis of many neurodegenerative diseases. The p32/ C1qbp gene functions as an essential RNA and protein chaperone in mitochondrial translation, and is indispensable for embryonic development. However, little is known about the consequences of mitochondrial dysfunction of p32 deletion in the brain development. Here, we found that mice lacking p32 in the central nervous system (p32cKO mice) showed white matter degeneration accompanied by progressive oligodendrocyte loss, axon degeneration and vacuolation in the mid brain and brain stem regions. Furthermore, p32cKO mice died within 8 weeks of birth. We also found that p32 deficient oligodendrocytes and neurons showed reduced oligodendrocyte differentiation and axon degeneration in primary culture. We show that mitochondrial disruption activates an adaptive program known as the integrated stress response (ISR). Mitochondrial respiratory chain function in oligodendrocytes and neurons is, therefore, essential for myelination and axon maintenance, respectively, suggesting that mitochondrial respiratory chain dysfunction in the central nervous system contributes to leukoencephalopathy. PMID- 29123153 TI - A genome-wide association study links small-vessel ischemic stroke to autophagy. AB - Genome-wide association studies (GWAS) can serve as strong evidence in correlating biological pathways with human diseases. Although ischemic stroke has been found to be associated with many biological pathways, the genetic mechanism of ischemic stroke is still unclear. Here, we performed GWAS for a major subtype of stroke-small-vessel occlusion (SVO)-to identify potential genetic factors contributing to ischemic stroke. GWAS were conducted on 342 individuals with SVO stroke and 1,731 controls from a Han Chinese population residing in Taiwan. The study was replicated in an independent Han Chinese population comprising an additional 188 SVO stroke cases and 1,265 controls. Three SNPs (rs2594966, rs2594973, rs4684776) clustered at 3p25.3 in ATG7 (encoding Autophagy Related 7), with P values between 2.52 * 10-6 and 3.59 * 10-6, were identified. Imputation analysis also supported the association between ATG7 and SVO stroke. To our knowledge, this is the first GWAS to link stroke and autophagy. ATG7, which has been implicated in autophagy, could provide novel insights into the genetic basis of ischemic stroke. PMID- 29123154 TI - Modification of single-nucleotide polymorphism in a fully humanized CYP3A mouse by genome editing technology. AB - Cytochrome P450, family 3, subfamily A (CYP3A) enzymes metabolize approximately 50% of commercially available drugs. Recently, we developed fully humanized transchromosomic (Tc) CYP3A mice with the CYP3A cluster including CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Our humanized CYP3A mice have the CYP3A5*3 (g.6986G) allele, resulting in the almost absence of CYP3A5 protein expression in the liver and intestine. To produce model mice for predicting CYP3A5's contribution to pharmacokinetics, we performed a single-nucleotide polymorphism (SNP) modification of CYP3A5 (g.6986G to A, *3 to *1) on the CYP3A cluster using genome editing in both mouse ES cells and fertilized eggs, and produced humanized CYP3A5*1 mice recapitulating the CYP3A5*1 carrier phenotype in humans. The humanized CYP3A mouse with CYP3A5*1 is the first Tc mouse for predicting the SNP effect on pharmacokinetics in humans. The combination of Tc technology and genome editing enables the production of useful humanized models that reflect humans with different SNPs. PMID- 29123155 TI - Large-scale in vitro production, refolding and dimerization of PsbS in different microenvironments. AB - Plants adapt to fluctuating light conditions by a process called non photochemical quenching (NPQ), where membrane protein PsbS plays a crucial role and transforms a change in the pH-gradient across the thylakoid membrane under excess light conditions into a photoprotective state, leading to de-excitation of antenna chlorophylls. The PsbS activation mechanism is elusive and has been proposed to involve a monomerization step and protonation of specific residues. To elucidate its function, it is essential to produce PsbS in large quantities, stabilize PsbS in a membrane-mimicking environment and analyze its pH-dependent conformational structure. We present an approach for large-scale in-vitro production and spectroscopic characterization of PsbS under controlled, non crystalline conditions. We produced PsbS of the moss Physcomitrella patens in milligram quantities in E. coli, refolded PsbS in several detergent types and analyzed its conformation at neutral and low pH by Dynamic Light Scattering and NMR spectroscopy. Our results reveal that at both pH conditions, PsbS exist as dimers or in apparent monomer-dimer equilibria. Lowering of the pH induces conformational changes, destabilizes the dimer state and shifts the equilibria towards the monomeric form. In vivo, a similar response upon thylakoid lumen acidification may tune PsbS activity in a gradual manner. PMID- 29123156 TI - Universal glass-forming behavior of in vitro and living cytoplasm. AB - Physiological processes in cells are performed efficiently without getting jammed although cytoplasm is highly crowded with various macromolecules. Elucidating the physical machinery is challenging because the interior of a cell is so complex and driven far from equilibrium by metabolic activities. Here, we studied the mechanics of in vitro and living cytoplasm using the particle-tracking and manipulation technique. The molecular crowding effect on cytoplasmic mechanics was selectively studied by preparing simple in vitro models of cytoplasm from which both the metabolism and cytoskeletons were removed. We obtained direct evidence of the cytoplasmic glass transition; a dramatic increase in viscosity upon crowding quantitatively conformed to the super-Arrhenius formula, which is typical for fragile colloidal suspensions close to jamming. Furthermore, the glass-forming behaviors were found to be universally conserved in all the cytoplasm samples that originated from different species and developmental stages; they showed the same tendency for diverging at the macromolecule concentrations relevant for living cells. Notably, such fragile behavior disappeared in metabolically active living cells whose viscosity showed a genuine Arrhenius increase as in typical strong glass formers. Being actively driven by metabolism, the living cytoplasm forms glass that is fundamentally different from that of its non-living counterpart. PMID- 29123157 TI - The NOD2 receptor is crucial for immune responses towards New World Leishmania species. AB - American Tegumentary Leishmaniasis is a chronic infection caused by Leishmania protozoan. It is not known whether genetic variances in NOD-like receptor (NLR) family members influence the immune response towards Leishmania parasites and modulate intracellular killing. Using functional genomics, we investigated whether genetic variants in NOD1 or NOD2 influence the production of cytokines by human PBMCs exposed to Leishmania. In addition, we examined whether recognition of Leishmania by NOD2 contributes to intracellular killing. Polymorphisms in the NOD2 gene decreased monocyte- and lymphocyte-derived cytokine production after stimulation with L. amazonensis or L. braziliensis compared to individuals with a functional NOD2 receptor. The phagolysosome formation is important for Leishmania induced cytokine production and upregulation of NOD2 mRNA expression. NOD2 is crucial to control intracellular infection caused by Leishmania spp. NOD2 receptor is important for Leishmania recognition, the control of intracellular killing, and the induction of innate and adaptive immune responses. PMID- 29123158 TI - Inhibition of Phosphatidylinositol 3-kinease suppresses formation and progression of experimental abdominal aortic aneurysms. AB - Accumulating evidence suggests an important role of Phosphatidylinositol 3 kinease (PI3K) pathway in inflammatory cells infiltration. Given the essential role of inflammatory cells infiltration during the formation and progression of abdominal aortic aneurysm (AAA), to investigate the possibility of preventing AAA formation and progression via targeting PI3K is anticipated. Here, experimental AAAs was created in rats by transient intraluminal porcine pancreatic elastase (PPE) infusion into the infrarenal aorta firstly. AAAs rats were administrated with vehicle or Wortmannin during the period of day 0 to day 28 after PPE infusion. The aortic diameter of rats treated with Wortmannin was significantly smaller than those treated with vehicle. Meanwhile, Elastin destruction score and SMC destruction score were significantly decreased in rats treated with Wortmannin. Furthermore, histological analysis revealed infiltration of inflammatory cells were significantly reduced in rats treated with Wortmannin. Finally, the mRNA expression of PI3K and protein expression of pAKT in human abdominal aneurismal aorta tissues was elevated as compare to normal aorta. Our study revealed that PI3K inhibitor suppresses experimental AAAs formation and progression, through mechanisms likely related to impairing inflammation cells infiltration and median elastin degradation. These findings indicated that PI3K inhibitor may hold substantial translation value for AAA diseases. PMID- 29123159 TI - Zinc is a critical regulator of placental morphogenesis and maternal hemodynamics during pregnancy in mice. AB - Zinc is an essential micronutrient in pregnancy and zinc deficiency impairs fetal growth. We used a mouse model of moderate zinc deficiency to investigate the physiological mechanisms by which zinc is important to placental morphogenesis and the maternal blood pressure changes during pregnancy. A 26% reduction in circulating zinc (P = 0.005) was exhibited in mice fed a moderately zinc deficient diet. Zinc deficiency in pregnancy resulted in an 8% reduction in both near term fetal and placental weights (both P < 0.0001) indicative of disrupted placental development and function. Detailed morphological analysis confirmed changes to the placental labyrinth microstructure. Continuous monitoring of maternal mean arterial pressure (MAP) revealed a late gestation decrease in the zinc-deficient dams. Differential expression of a number of regulatory genes within maternal kidneys supported observations on MAP changes in gestation. Increased MAP late in gestation is required to maintain perfusion of multiple placentas within rodent pregnancies. Decreased MAP within the zinc-deficient dams implies reduced blood flow and nutrient delivery to the placenta. These findings show that adequate zinc status is required for correct placental morphogenesis and appropriate maternal blood pressure adaptations to pregnancy. We conclude that insufficient maternal zinc intake from before and during pregnancy is likely to impact in utero programming of offspring growth and development largely through effects to the placenta and maternal cardiovascular system. PMID- 29123160 TI - InsuTAG: A novel physiologically relevant predictor for insulin resistance and metabolic syndrome. AB - The aim of this study was to investigate whether a novel physiologically relevant marker, InsuTAG (fasting insulin * fasting triglycerides) can predict insulin resistance (IR) and metabolic syndrome (MetS). Data of 618 participants from the Retirement Health and Lifestyle Study (RHLS) were evaluated for the current study. IR was defined by homeostatic model assessment (HOMA-IR) scores. Pearson correlations were used to examine the associations of InsuTAG with HOMA-IR and other markers. Predictions of IR from InsuTAG were evaluated using multiple regression models. Receiver operating characteristic curves (ROC) were constructed to measure the sensitivity and specificity of InsuTAG values and to determine the optimum cut-off point for prediction of IR. InsuTAG was positively correlated with HOMA-IR (r = 0.86; p < 0.0001). InsuTAG is a strong predictor of IR accounting for 65.0% of the variation in HOMA-IR values after adjusting for potential confounders. Areas under the ROC curve showed that InsuTAG (0.93) has higher value than other known lipid markers for predicting IR, with a sensitivity and specificity of 84.15% and 86.88%. Prevalence of MetS was significantly (p < 0.0001) higher in subjects with InsuTAG values greater than optimal cut-off value of 11.2. Thus, InsuTAG appears to be a potential feasible marker of IR and metabolic syndrome. PMID- 29123161 TI - Clinically Meaningful Improvements in LUTS/BPH Severity in Men Treated with Silodosin Plus Hexanic Extract of Serenoa Repens or Silodosin Alone. AB - To assess the rate and predictors of clinically meaningful improvements (CMI) in patients with lower urinary tract symptoms (LUTS) treated with either silodosin (SIL) alone or with a combination of SIL+ serenoa repens (Ser) hexanic lipidosterolic extract for >=12 months. Data from 186 patients were collected. Patients completed the International Prostatic Symptoms Score (IPSS) at baseline and at follow-up assessment. Descriptive statistics and logistic regression models tested rates and predictors of CMI. Two CMI were assessed: 1) >3 points improvement in total IPSS from baseline to end (CMI#1); 2) >25% IPSS improvement from baseline to end (CMI#2). Overall, 93 (50%) patients were treated with SIL and SIL+ Ser, respectively. At a mean 13.5-mos follow-up [range: 12-20], mean IPSS scores were significantly lower in patients treated with SIL + Ser compared to those after SIL (p = 0.002). SIL + Ser patients more frequently achieved CMI#1 (69.9% vs. 30.1%, p = 0.001) and CMI#2 (68.8% vs. 31.2%, p < 0.001) compared SIL men. At multivariable analyses, younger age, IPSS severity and SIL + Ser (all p < 0.03) were independent predictors of CMI#1 and CMI#2. In conclusion, SIL + Ser therapy was more effective than SIL alone in improving IPSS scores in men with LUTS. SIL + Ser treatment led to CMIs in up to seven out of ten men. PMID- 29123162 TI - LPPtiger software for lipidome-specific prediction and identification of oxidized phospholipids from LC-MS datasets. AB - Oxidized phospholipids (oxPLs) have been recently recognized as important mediators of various and often controversial cellular functions and stress responses. Due to the low concentrations in vivo, oxPL detection is mostly performed by targeted mass spectrometry. Although significantly improving the sensitivity, this approach does not provide a comprehensive view on oxPLs required for understanding oxPL functional activities. While capable of providing information on the diversity of oxPLs, the main challenge of untargeted lipidomics is the absence of bioinformatics tools to support high-throughput identification of previously unconsidered, oxidized lipids. Here, we present LPPtiger, an open-source software tool for oxPL identification from data dependent LC-MS datasets. LPPtiger combines three unique algorithms to predict oxidized lipidome, generate oxPL spectra libraries, and identify oxPLs from tandem MS data using parallel processing and a multi-scoring identification workflow. PMID- 29123163 TI - Imidacloprid and chlorpyrifos insecticides impair migratory ability in a seed eating songbird. AB - Birds that travel long distances between their wintering and breeding grounds may be particularly susceptible to neurotoxic insecticides, but the influence of insecticides on migration ability is poorly understood. Following acute exposure to two widely used agricultural insecticides, imidacloprid (neonicotinoid) and chlorpyrifos (organophosphate), we compared effects on body mass, migratory activity and orientation in a seed-eating bird, the white-crowned sparrow (Zonotrichia leucophrys). During spring migration, sparrows were captured, held and dosed by gavage daily for 3 days with either the vehicle control, low (10% LD50) or high (25% LD50) doses of imidacloprid or chlorpyrifos and tested in migratory orientation trials pre-exposure, post-exposure and during recovery. Control birds maintained body mass and a seasonally appropriate northward orientation throughout the experiment. Imidacloprid dosed birds exhibited significant declines in fat stores and body mass (mean loss: -17% low, -25% high dose) and failed to orient correctly. Chlorpyrifos had no overt effects on mass but significantly impaired orientation. These results suggest that wild songbirds consuming the equivalent of just four imidacloprid-treated canola seeds or eight chlorpyrifos granules per day over 3 days could suffer impaired condition, migration delays and improper migratory direction, which could lead to increased risk of mortality or lost breeding opportunity. PMID- 29123164 TI - Study on the characteristics of future precipitation in response to external changes over arid and humid basins. AB - The simulation abilities of the Coupled Model Inter-comparison Project Phase 5 (CMIP5) models to the arid basin (the Tarim River Basin, TRB) and humid basin (the Yangtze River Basin, YRB) were evaluated, determining the response of precipitation to external changes over typical basins. Our study shows that the future temporal and spatial variation characteristics of precipitation are different in different regions with the CMIP5. The annual and seasonal changes in precipitation were analyzed for the RCP2.6, RCP4.5 and RCP8.5 during 2021~2100 compared to those during 1961~2005. Precipitation shows an increasing trend in the TRB, but which decreases and then increases in the YRB, with a turning point in the middle of twenty-first Century. The ranges in annual precipitation increase with the increase in the scenario emissions in the future. Note that the Tarim River Basin is more vulnerable to the impact of emissions, especially for annual or spring and winter precipitation. Based on the uncertainty of CMIP5 data, the links between future precipitation changes and the elevation and relief amplitude were evaluated. The change of precipitation decreases with elevation, relief amplitude in the TRB, while it increases with elevation but decreases with relief amplitude in the YRB. PMID- 29123165 TI - Deep sequencing and analyses of miRNAs, isomiRs and miRNA induced silencing complex (miRISC)-associated miRNome in primary human chondrocytes. AB - MicroRNAs, a group of small, noncoding RNAs that post-transcriptionally regulate gene expression, play important roles in chondrocyte function and in the development of osteoarthritis. We characterized the dynamic repertoire of the chondrocyte miRNome and miRISC-associated miRNome by deep sequencing analysis of primary human chondrocytes. IL-1beta treatment showed a modest effect on the expression profile of miRNAs in normal and osteoarthritis (OA) chondrocytes. We found a number of miRNAs that showed a wide range of sequence modifications including nucleotide additions and deletions at 5' and 3' ends; and nucleotide substitutions. miR-27b-3p showed the highest expression and miR-140-3p showed the highest number of sequence variations. AGO2 RIP-Seq analysis revealed the differential recruitment of a subset of expressed miRNAs and isoforms of miRNAs (isomiRs) to the miRISC in response to IL-1beta, including miR-146a-5p, miR-155 5p and miR-27b-3p. Together, these results reveal a complex repertoire of miRNAs and isomiRs in primary human chondrocytes. Here, we also show the changes in miRNA composition of the miRISC in primary human chondrocytes in response to IL 1beta treatment. These findings will provide an insight to the miRNA-mediated control of gene expression in the pathogenesis of OA. PMID- 29123166 TI - A temperature sensitive Mycobacterium paragordonae induces enhanced protective immune responses against mycobacterial infections in the mouse model. AB - Recently, we introduced a temperature sensitive Mycobacterium spp., Mycobacterium paragordonae (Mpg). Here, we checked its potential as a candidate for live vaccination against Mycobacterium tuberculosis and Mycobacterium abscessus. Intravenous infections of mice with Mpg led to lower colony forming units (CFUs) compared to infection with BCG, suggesting its usefulness as a live vaccine. The analyses of immune responses indicated that the highly protective immunity elicited by Mpg was dependent on effective dendritic maturation, shift of cytokine patterns and antibody production toward a Th1 phenotype, and enhanced cytotoxic T cell response. Compared to BCG, Mpg showed a more effective protective immune response in the vaccinated mice against challenges with 2 different mycobacterial strains, M. tuberculosis H37Ra or M. abscessus Asan 50594. Our data suggest that a temperature sensitive Mpg may be a potentially powerful candidate vaccine strain to induce enhanced protective immune responses against M. tuberculosis and M. abscessus. PMID- 29123167 TI - Ordered and Disordered Phases in Mo1-xWxS2 Monolayer. AB - With special quasirandom structure approach and cluster expansion method combined with first-principle calculations, we explore the structure and electronic properties of monolayer Mo1-xWxS2 alloy with disordered phase and ordered phase. The phase transition from ordered phase to disordered phase is found to happen at 41 K and 43 K for x = 1/3 and x = 2/3, respectively. The band edge of VBM is just related with the composition x, while the band edge of CBM is sensitive to the degree of order, besides the concentration of W. Near the CBM band edge, there are two bands with the Mo-character and W-character, respectively. It is found that in disordered phase the Mo-character band is mixed with the W-character band, while the opposite happens in ordered phase. This result leads to that the splitting of two bands near CBM in ordered phase is larger than in disordered phase and gives rise to the smaller band gap in ordered phase compared to the disordered phase. The electron effective mass in ordered phase is smaller than in disordered phase, while the heavy hole effective mass in ordered phase is larger than that in disordered phase. PMID- 29123168 TI - Clinical Parameters and Gut Microbiome Changes Before and After Surgery in Thoracic Aortic Dissection in Patients with Gastrointestinal Complications. AB - Thoracic aortic dissection (TAAD) is one of the most common types of aortic diseases. Although surgery remains the main method of treatment, the high rate of postoperative gastrointestinal complications significantly influences the effects of surgery and the recovery process. Moreover, the mechanisms underlying this disease remain unclear. To address these problems, we examined changes in the gut microbiota in 40 thoracic aortic dissection patients with abdominal complications after surgery. Levels of white blood cells (WBC), neutrophile granulocytes (NE), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were higher in all patients after surgery. Levels of inflammatory cytokines, including interleukin (IL)-2, IL-6, IL-8, and IL-10, were also higher after surgery. A metagenome analysis revealed that levels of Oscillibacter, Anaerotruncus, Alistipes, and Clostridium difficile were higher after the operation. The abundance of functional genes, such as the spermidine/putrescine transport system permease protein, the flagellar motor switch protein, and branched-chain amino acid transport system proteins, was also higher post-surgery. These changes likely contribute to diarrhea, bloating, gastrointestinal bleeding, and other abdominal complications after surgery, and our research opens up new treatment possibilities for patients suffering from abdominal complications after surgical treatment. PMID- 29123169 TI - Plasmonic Chromatic Electrode with Low Resistivity. AB - We report on the optical and electrical properties of a novel plasmonic chromatic electrode (PCE). The PCE was composed of a metallic nano-hole array and ITO layer as a dielectric for electrical property. The structure design was optimized to obtain the matched condition between surface plasmon modes at the top and bottom metal-dielectric interfaces for high transmittance. The fabricated PCEs have high transmittance of 25~40% and low resistivity (level of 10-5 Omegacm) compared to conventional electrodes. Due to the multi-functionality and simple structure of PCEs, we predict the PCEs can be applied for advanced industrial use such as, high resolution, flexible, and stretchable devices. PMID- 29123170 TI - Establishment and phenotyping of disease model cells created by cell-resealing technique. AB - Cell-based assays are growing in importance for screening drugs and investigating their mechanisms of action. Most of the assays use so-called "normal" cell strain because it is difficult to produce cell lines in which the disease conditions are reproduced. In this study, we used a cell-resealing technique, which reversibly permeabilizes the plasma membrane, to develop diabetic (Db) model hepatocytes into which cytosol from diabetic mouse liver had been introduced. Db model hepatocytes showed several disease-specific phenotypes, namely disturbance of insulin-induced repression of gluconeogenic gene expression and glucose secretion. Quantitative image analysis and principal component analysis revealed that the ratio of phosphorylated Akt (pAkt) to Akt was the best index to describe the difference between wild-type and Db model hepatocytes. By performing image based drug screening, we found pioglitazone, a PPARgamma agonist, increased the pAkt/Akt ratio, which in turn ameliorated the insulin-induced transcriptional repression of the gluconeogenic gene phosphoenolpyruvate carboxykinase 1. The disease-specific model cells coupled with image-based quantitative analysis should be useful for drug development, enabling the reconstitution of disease conditions at the cellular level and the discovery of disease-specific markers. PMID- 29123171 TI - Axion dark matter detection by laser induced fluorescence in rare-earth doped materials. AB - We present a detection scheme to search for QCD axion dark matter, that is based on a direct interaction between axions and electrons explicitly predicted by DFSZ axion models. The local axion dark matter field shall drive transitions between Zeeman-split atomic levels separated by the axion rest mass energy m a c 2. Axion related excitations are then detected with an upconversion scheme involving a pump laser that converts the absorbed axion energy (~hundreds of MUeV) to visible or infrared photons, where single photon detection is an established technique. The proposed scheme involves rare-earth ions doped into solid-state crystalline materials, and the optical transitions take place between energy levels of 4f N electron configuration. Beyond discussing theoretical aspects and requirements to achieve a cosmologically relevant sensitivity, especially in terms of spectroscopic material properties, we experimentally investigate backgrounds due to the pump laser at temperatures in the range 1.9 - 4.2 K. Our results rule out excitation of the upper Zeeman component of the ground state by laser-related heating effects, and are of some help in optimizing activated material parameters to suppress the multiphonon-assisted Stokes fluorescence. PMID- 29123172 TI - Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans. AB - High fat feeding impairs skeletal muscle metabolic flexibility and induces insulin resistance, whereas exercise training exerts positive effects on substrate handling and improves insulin sensitivity. To identify the genomic mechanisms by which exercise ameliorates some of the deleterious effects of high fat feeding, we investigated the transcriptional and epigenetic response of human skeletal muscle to 9 days of a high-fat diet (HFD) alone (Sed-HFD) or in combination with resistance exercise (Ex-HFD), using genome-wide profiling of gene expression and DNA methylation. HFD markedly induced expression of immune and inflammatory genes, which was not attenuated by Ex. Conversely, Ex markedly remodelled expression of genes associated with muscle growth and structure. We detected marked DNA methylation changes following HFD alone and in combination with Ex. Among the genes that showed a significant association between DNA methylation and gene expression changes were PYGM, which was epigenetically regulated in both groups, and ANGPTL4, which was regulated only following Ex. In conclusion, while short-term Ex did not prevent a HFD-induced inflammatory response, it provoked a genomic response that may protect skeletal muscle from atrophy. These epigenetic adaptations provide mechanistic insight into the gene specific regulation of inflammatory and metabolic processes in human skeletal muscle. PMID- 29123173 TI - Effect of vitamin D supplementation on inflammation and nuclear factor kappa-B activity in overweight/obese adults: a randomized placebo-controlled trial. AB - In-vitro studies suggest that vitamin D reduces inflammation by inhibiting nuclear factor kappa-B (NFkappaB) activity. Yet, no trials have examined the effects of vitamin D supplementation on NFkappaB activity in-vivo in humans. We conducted a double-blind randomized trial (RCT) examining effects of vitamin D supplementation on inflammatory markers and NFkappaB activity in peripheral blood mononuclear cells (PBMCs). Sixty-five overweight/obese, vitamin D-deficient (25 hydroxyvitamin D [25(OH)D] <= 50 nmol/L) adults were randomized to a single 100,000 IU bolus followed by 4,000 IU daily cholecalciferol or matching placebo for 16 weeks. We measured BMI, % body fat, serum 25(OH)D, high-sensitivity C reactive protein (hsCRP), tumour necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), interferon-gamma (IFN-gamma), several interleukins, and NFkappaB activity in PBMCs. Fifty-four participants completed the study. Serum 25(OH)D concentrations increased with vitamin D supplementation compared to placebo (p < 0.001). Vitamin D and placebo groups did not differ in any inflammatory markers or NFkappaB activity (all p > 0.05). Results remained non significant after adjustment for age, sex, and % body fat, and after further adjustment for sun exposure, physical activity, and dietary vitamin D intake. Although in-vitro studies report anti-inflammatory effects of vitamin D, our RCT data show no effect of vitamin D supplementation on inflammatory markers or NFkappaB activity in-vivo in humans. PMID- 29123174 TI - D-Cateslytin, a new antimicrobial peptide with therapeutic potential. AB - The rise of antimicrobial resistant microorganisms constitutes an increasingly serious threat to global public health. As a consequence, the efficacy of conventional antimicrobials is rapidly declining, threatening the ability of healthcare professionals to cure common infections. Over the last two decades host defense peptides have been identified as an attractive source of new antimicrobials. In the present study, we characterized the antibacterial and mechanistic properties of D-Cateslytin (D-Ctl), a new epipeptide derived from L Cateslytin, where all L-amino acids were replaced by D-amino acids. We demonstrated that D-Ctl emerges as a potent, safe and robust peptide antimicrobial with undetectable susceptibility to resistance. Using Escherichia coli as a model, we reveal that D-Ctl targets the bacterial cell wall leading to the permeabilization of the membrane and the death of the bacteria. Overall, D Ctl offers many assets that make it an attractive candidate for the biopharmaceutical development of new antimicrobials either as a single therapy or as a combination therapy as D-Ctl also has the remarkable property to potentiate several antimicrobials of reference such as cefotaxime, amoxicillin and methicillin. PMID- 29123175 TI - Structure constrained by metadata in networks of chess players. AB - Chess is an emblematic sport that stands out because of its age, popularity and complexity. It has served to study human behavior from the perspective of a wide number of disciplines, from cognitive skills such as memory and learning, to aspects like innovation and decision-making. Given that an extensive documentation of chess games played throughout history is available, it is possible to perform detailed and statistically significant studies about this sport. Here we use one of the most extensive chess databases in the world to construct two networks of chess players. One of the networks includes games that were played over-the-board and the other contains games played on the Internet. We study the main topological characteristics of the networks, such as degree distribution and correlations, transitivity and community structure. We complement the structural analysis by incorporating players' level of play as node metadata. Although both networks are topologically different, we show that in both cases players gather in communities according to their expertise and that an emergent rich-club structure, composed by the top-rated players, is also present. PMID- 29123176 TI - Acoustic Mapping of Thermohaline Staircases in the Arctic Ocean. AB - Although there is enough heat contained in inflowing warm Atlantic Ocean water to melt all Arctic sea ice within a few years, a cold halocline limits upward heat transport from the Atlantic water. The amount of heat that penetrates the halocline to reach the sea ice is not well known, but vertical heat transport through the halocline layer can significantly increase in the presence of double diffusive convection. Such convection can occur when salinity and temperature gradients share the same sign, often resulting in the formation of thermohaline staircases. Staircase structures in the Arctic Ocean have been previously identified and the associated double diffusive convection has been suggested to influence the Arctic Ocean in general and the fate of the Arctic sea ice cover in particular. A central challenge to understanding the role of double diffusive convection in vertical heat transport is one of observation. Here, we use broadband echo sounders to characterize Arctic thermohaline staircases at their full vertical and horizontal resolution over large spatial areas (100 s of kms). In doing so, we offer new insight into the mechanism of thermohaline staircase evolution and scale, and hence fluxes, with implications for understanding ocean mixing processes and ocean-sea ice interactions. PMID- 29123177 TI - Liprotides kill cancer cells by disrupting the plasma membrane. AB - HAMLET (human alpha-lactalbumin made lethal to tumour cells) is a complex of alpha-lactalbumin (aLA) and oleic acid (OA) which kills transformed cells, while leaving fully differentiated cells largely unaffected. Other protein-lipid complexes show similar anti-cancer potential. We call such complexes liprotides. The cellular impact of liprotides, while intensely investigated, remains unresolved. To address this, we report on the cell-killing mechanisms of liprotides prepared by incubating aLA with OA for 1 h at 20 or 80 degrees C (lip20 and lip80, respectively). The liprotides showed similar cytotoxicity against MCF7 cells, though lip80 acts more slowly, possibly due to intermolecular disulphide bonds formed during preparation. Liprotides are known to increase the fluidity of a membrane and transfer OA to vesicles, prompting us to focus on the effect of liprotides on the cell membrane. Extracellular Ca2+ influx is important for activation of the plasma membrane repair system, and we found that removal of Ca2+ from the medium enhanced the liprotides' killing effect. Liprotide cytotoxicity was also increased by knockdown of Annexin A6 (ANXA6), a protein involved in plasma membrane repair. We conclude that MCF7 cells counteract liprotide-induced membrane permeabilization by activating their plasma membrane repair system, which is triggered by extracellular Ca2+ and involves ANXA6. PMID- 29123178 TI - A nanobody-based tracer targeting DPP6 for non-invasive imaging of human pancreatic endocrine cells. AB - There are presently no reliable ways to quantify endocrine cell mass (ECM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. To address this unmet need, we coupled RNA sequencing of human pancreatic islets to a systems biology approach to identify new biomarkers of the endocrine pancreas. Dipeptidyl-Peptidase 6 (DPP6) was identified as a target whose mRNA expression is at least 25-fold higher in human pancreatic islets as compared to surrounding tissues and is not changed by proinflammatory cytokines. At the protein level, DPP6 localizes only in beta and alpha cells within the pancreas. We next generated a high-affinity camelid single-domain antibody (nanobody) targeting human DPP6. The nanobody was radiolabelled and in vivo SPECT/CT imaging and biodistribution studies were performed in immunodeficient mice that were either transplanted with DPP6 expressing Kelly neuroblastoma cells or insulin-producing human EndoC-betaH1 cells. The human DPP6-expressing cells were clearly visualized in both models. In conclusion, we have identified a novel beta and alpha cell biomarker and developed a tracer for in vivo imaging of human insulin secreting cells. This provides a useful tool to non-invasively follow up intramuscularly implanted insulin secreting cells. PMID- 29123179 TI - Association of long noncoding RNAs expression levels and their gene polymorphisms with systemic lupus erythematosus. AB - Increasing evidence has demonstrated the association between long noncoding RNAs (lncRNAs) and multiple autoimmune diseases. To explore four lncRNAs (GAS5, lnc DC, linc0597 and linc0949) expression levels and gene polymorphisms in systemic lupus erythematosus (SLE), a two stage design was applied. In the first stage, 85 SLE patients and 71 healthy controls were enrolled to investigate the lncRNAs expression levels. Then, 1260 SLE patients and 1231 healthy controls were included to detect the single nucleotide polymorphisms (SNPs) in the differentially expressed lncRNAs identified in the first stage. Linc0597, lnc-DC and GAS5 expression levels were significantly lower in SLE patients than healthy controls (P < 0.001, P < 0.001, P = 0.003 respectively). Association of five SNPs (rs10515177, rs2070107, rs2632516, rs2877877, rs2067079) with SLE risk were analyzed. No significant association was observed between these gene polymorphisms and susceptibility to SLE (all P > 0.010), and we did not find significant association between any genotypes at five SNPs and their respective lncRNAs expression in SLE (all P > 0.010). In summary, the expression levels of linc0597, lnc-DC and GAS5 are decreased in SLE patients, but their gene polymorphisms are not associated with SLE risk, and do not influence their expression levels. PMID- 29123180 TI - The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models. AB - Many neurological disorders of gluten-related diseases (GRD), not directly referable to the gastrointestinal tract, have been reported in association with celiac disease (CD), including ataxia, neuropathy and epilepsy. In particular, people with epilepsy diagnosed with CD seems to be characterized by intractable seizure. In these patients, gluten restriction diet has resulted in a reduction of both seizure frequency and antiepileptic medication. Many hypotheses have been suggested, however, molecular mechanisms that associates GRD and epileptogenesis are yet unknown. In this study, we examined the effects of the toxic gliadin peptide 31-43 in in vivo and in vitro models of kainate-induced-epilepsy. We observed that p31-43 exacerbates kainate neurotoxicity in epilepsy models, through the involvement of the enzymatic activity of transglutaminases. Moreover, electrophysiological recordings in CA3 pyramidal neurons of organotypic hippocampal slices show that p31-43 increases the inward current induced by kainate, the average sEPSC amplitude and the total number of evoked action potentials when applicated alone, thus suggesting that p31-43 is able to influence CA3-CA1 neurotransmission and can potentiate postsynaptic kainate receptors. Our results suggest a possible mechanism underlying the relationship between GRD and epilepsy through a potentiation of kainate-induced neurotoxicity and links the toxic effects of gluten to epilepsy. PMID- 29123182 TI - Identification of a novel cAMP dependent protein kinase A phosphorylation site on the human cardiac calcium channel. AB - The "Fight or Flight" response is elicited by extrinsic stress and is necessary in many species for survival. The response involves activation of the beta adrenergic signalling pathway. Surprisingly the mechanisms have remained unresolved. Calcium influx through the cardiac L-type Ca2+ channel (Cav1.2) is absolutely required. Here we identify the functionally relevant site for PKA phosphorylation on the human cardiac L-type Ca2+ channel pore forming alpha1 subunit using a novel approach. We used a cell free system where we could assess direct effects of PKA on human purified channel protein function reconstituted in proteoliposomes. In addition to assessing open probability of channel protein we used semi-quantitative fluorescent phosphoprotein detection and MS/MS mass spectrometry analysis to demonstrate the PKA specificity of the site. Robust increases in frequency of channel openings were recorded after phosphorylation of the long and short N terminal isoforms and the channel protein with C terminus truncated at aa1504. A protein kinase A anchoring protein (AKAP) was not required. We find the novel PKA phosphorylation site at Ser1458 is in close proximity to the Repeat IV S6 region and induces a conformational change in the channel protein that is necessary and sufficient for increased calcium influx through the channel. PMID- 29123183 TI - Flexible Fe3O4@Carbon Nanofibers Hierarchically Assembled with MnO2 Particles for High-Performance Supercapacitor Electrodes. AB - Increasing use of wearable electronic devices have resulted in enhanced demand for highly flexible supercapacitor electrodes with superior electrochemical performance. In this study, flexible composite membranes with electrosprayed MnO2 particles uniformly anchored on Fe3O4 doped electrospun carbon nanofibers (Fe3O4@CNFMn) have been prepared as flexible electrodes for high-performance supercapacitors. The interconnected porous beaded structure ensures free movement of electrolyte within the composite membranes, therefore, the developed supercapacitor electrodes not only offer high specific capacitance of ~306 F/g, but also exhibit good capacitance retention of ~85% after 2000 cycles, which certify that the synthesized electrodes offer high and stable electrochemical performance. Additionally, the supercapacitors fabricated from our developed electrodes well maintain their performance under flexural stress and exhibit a very minute change in specific capacitance even up to 180 degrees bending angle. The developed electrode fabrication strategy integrating electrospinning and electrospray techniques paves new insights into the development of potential functional nanofibrous materials for light weight and flexible wearable supercapacitors. PMID- 29123181 TI - Carnosol controls the human glioblastoma stemness features through the epithelial mesenchymal transition modulation and the induction of cancer stem cell apoptosis. AB - A high cell proliferation rate, invasiveness and resistance to chemotherapy are the main features of glioblastoma (GBM). GBM aggressiveness has been widely associated both with a minor population of cells presenting stem-like properties (cancer stem-like cells, CSCs) and with the ability of tumor cells to acquire a mesenchymal phenotype (epithelial-mesenchymal transition, EMT). Carnosol (CAR), a natural inhibitor of MDM2/p53 complex, has been attracted attention for its anti cancer effects on several tumor types, including GBM. Herein, the effects of CAR on U87MG-derived CSC viability and stemness features were evaluated. CAR decreased the rate of CSC formation and promoted the CSC apoptotic cell death through p53 functional reactivation. Moreover, CAR was able to control the TNF alpha/TGF-beta-induced EMT, counteracting the effects of the cytokine on EMT master regulator genes (Slug, Snail, Twist and ZEB1) and modulating the activation of miR-200c, a key player in the EMT process. Finally, CAR was able to increase the temozolomide (TMZ) anti-proliferative effects. These findings demonstrate that CAR affected the different intracellular mechanism of the complex machinery that regulates GBM stemness. For the first time, the diterpene was highlighted as a promising lead for the development of agents able to decrease the stemness features, thus controlling GBM aggressiveness. PMID- 29123184 TI - Urinary peptidomics analysis reveals proteases involved in diabetic nephropathy. AB - Mechanisms underlying the onset and progression of nephropathy in diabetic patients are not fully elucidated. Deregulation of proteolytic systems is a known path leading to disease manifestation, therefore we hypothesized that proteases aberrantly expressed in diabetic nephropathy (DN) may be involved in the generation of DN-associated peptides in urine. We compared urinary peptide profiles of DN patients (macroalbuminuric, n = 121) to diabetic patients with no evidence of DN (normoalbuminuric, n = 118). 302 sequenced, differentially expressed peptides (adjusted p-value < 0.05) were analysed with the Proteasix tool predicting proteases potentially involved in their generation. Activity change was estimated based on the change in abundance of the investigated peptides. Predictions were correlated with transcriptomics (Nephroseq) and relevant protein expression data from the literature. This analysis yielded seventeen proteases, including multiple forms of MMPs, cathepsin D and K, kallikrein 4 and proprotein convertases. The activity of MMP-2 and MMP-9, predicted to be decreased in DN, was investigated using zymography in a DN mouse model confirming the predictions. Collectively, this proof-of-concept study links urine peptidomics to molecular changes at the tissue level, building hypotheses for further investigation in DN and providing a workflow with potential applications to other diseases. PMID- 29123185 TI - Hybrid Interference Induced Flat Band Localization in Bipartite Optomechanical Lattices. AB - The flat band localization, as an important phenomenon in solid state physics, is fundamentally interesting in the exploration of exotic ground property of many body system. Here we demonstrate the appearance of a flat band in a general bipartite optomechanical lattice, which could have one or two dimensional framework. Physically, it is induced by the hybrid interference between the photon and phonon modes in optomechanical lattice, which is quite different from the destructive interference resulted from the special geometry structure in the normal lattice (e.g., Lieb lattice). Moreover, this novel flat band is controllable and features a special local density of states (LDOS) pattern, which makes it is detectable in experiments. This work offers an alternative approach to control the flat band localization with optomechanical interaction, which may substantially advance the fields of cavity optomechanics and solid state physics. PMID- 29123186 TI - The biomechanical coordination during oropharyngeal swallowing: an evaluation with a non-invasive sensing system. AB - Swallowing is a very important and complex physiological behaviour. The dynamic of swallowing has created great interest as any procedural abnormality will result in dysphagia and even lower quality of life. However, a non-invasive evaluation of biomechanical coordination during oropharyngeal swallowing, which includes the activities of the tongue, the hyoid and swallowing-related muscles, has not yet been achieved. In the present study, we recruited fifteen subjects, and a non-invasive sensing system composed of a pressure sensor, a bend sensor, surface electrodes and a microphone was created to simultaneously monitor tongue pressure, hyoid motion, and surface EMG of swallowing-related muscles, as well as take sound recordings, when the subjects swallowed 5 ml of water. In addition to obtaining the durations of certain motor events, the considerable time (beginning, peak and ending time) of tongue pressure production, suprahyoid and infrahyoid muscle activity and hyoid motion were successfully measured. Moreover, the significant correlations between swallowing-related muscles, tongue pressure, and the hyoid were confirmed. These findings suggest that the non-invasive sensing system has potential as a good candidate for monitoring and evaluating the oropharyngeal process of swallowing, which may be useful in clinical work involving dysphagia evaluation and rehabilitation. PMID- 29123187 TI - Grazing exclusion by fencing non-linearly restored the degraded alpine grasslands on the Tibetan Plateau. AB - Resilience is an important aspect of the non-linear restoration of disturbed ecosystems. Fenced grassland patches on the northern Tibetan Plateau can be used to examine the resistance and resilience of degraded alpine grasslands to grazing and to a changing climate. To examine the non-linearity of restoration, we used moderate resolution imaging spectroradiometer (MODIS) normalized difference vegetation index (NDVI) as a proxy for productivity during a ten-year restoration by fencing. Degraded alpine grasslands exhibited three restoration trajectories: an equilibrium in meadows, a non-linear increase across steppes, and an abrupt impulse in desert-steppes following a slight increase in productivity. Combined with weather conditions, the ten-year grazing exclusion has successfully enhanced the NDVI on the most degraded steppes, but did not do so efficiently on either meadows or desert-steppes. Warming favors the NDVI enhancement of degraded meadows, but higher temperatures limited the restoration of degraded steppes and desert-steppes. Precipitation is necessary to restore degraded alpine grasslands, but more precipitation might be useless for meadows due to lower temperatures and for desert-steppes due to limitations caused by the small species pool. We suggest that detailed field observations of community compositional changes are necessary to better understand the mechanisms behind such non-linear ecological restorations. PMID- 29123188 TI - Spatio-temporal trends in crop damage inform recent climate-mediated expansion of a large boreal herbivore into an agro-ecosystem. AB - Large-scale climatic fluctuations have caused species range shifts. Moose (Alces alces) have expanded their range southward into agricultural areas previously not considered moose habitat. We found that moose expansion into agro-ecosystems is mediated by broad-scale climatic factors and access to high-quality forage (i.e., crops). We used crop damage records to quantify moose presence across the Canadian Prairies. We regressed latitude of crop damage against North Atlantic Oscillation (NAO) and crop area to test the hypotheses that NAO-mediated wetland recharge and occurrence of more nutritious crop types would result in more frequent occurrences of crop damage by moose at southerly latitudes. We examined local-scale land use by generating a habitat selection model to test our hypothesis that moose selected for areas of high crop cover in agro-ecosystems. We found that crop damage by moose occurred farther south during dry winters and in years with greater coverage of oilseeds. The results of our analyses support our hypothesis that moose movement into cropland is mediated by high-protein crops, but not by thermoregulatory habitat at the scale examined. We conclude that broad-scale climate combined with changing land-use regimes are causal factors in species' range shifts and are important considerations when studying changing animal distributions. PMID- 29123189 TI - A common neonicotinoid pesticide, thiamethoxam, alters honey bee activity, motor functions, and movement to light. AB - Honey bees provide key ecosystem services. To pollinate and to sustain the colony, workers must walk, climb, and use phototaxis as they move inside and outside the nest. Phototaxis, orientation to light, is linked to sucrose responsiveness and the transition of work from inside to outside the nest, and is also a key component of division of labour. However, the sublethal effects of pesticides on locomotion and movement to light are relatively poorly understood. Thiamethoxam (TMX) is a common neonicotinoid pesticide that bees can consume in nectar and pollen. We used a vertical arena illuminated from the top to test the effects of acute and chronic sublethal exposures to TMX. Acute consumption (1.34 ng/bee) impaired locomotion, caused hyperactivity (velocity: +109%; time moving: +44%) shortly after exposure (30 min), and impaired motor functions (falls: +83%; time top: -43%; time bottom: +93%; abnormal behaviours: +138%; inability to ascend: +280%) over a longer period (60 min). A 2-day chronic exposure (field relevant daily intakes of 1.42-3.48 ng/bee/day) impaired bee ability to ascend. TMX increased movement to light after acute and chronic exposure. Thus, TMX could reduce colony health by harming worker locomotion and, potentially, alter division of labour if bees move outside or remain outdoors. PMID- 29123190 TI - Feeding capability in the extinct giant Siamogale melilutra and comparative mandibular biomechanics of living Lutrinae. AB - At 50 kg in estimated weight, the extinct Siamogale melilutra is larger than all living otters, and ranks among the largest fossil otters. The biomechanical capability of S. melilutra jaws as related to their large size is unknown but crucial to reconstructing the species' potentially unique ecological niche. Here we compare the mandibular biomechanics of S. melilutra using engineering-based performance measures against ten extant otter biomechanical models. Despite a wide range of feeding preferences from durophagy to piscivory, living otter species exhibit a linear relationship between mandible stiffness and volume, as expected in isometric model scaling. In contrast, S. melilutra models exhibit a six-fold increase in stiffness from expected stiffness-volume relationships calculated from extant species models. Unlike stiffness, mechanical efficiency of biting is conserved among living otters and in S. melilutra. These findings indicate that although similar to living bunodont otters in morphology and biting efficiency, jaw strength in S. melilutra far surpasses molluscivores such as sea otters and Cape clawless otters, even after accounting for size. Therefore, Siamogale represents a feeding ecomorphology with no living analog, and its giant size and high mandibular strength confer shell-crushing capability matched only by other extinct molluscivores such as the marine bear Kolponomos. PMID- 29123191 TI - A spot laser modulated resistance switching effect observed on n-type Mn-doped ZnO/SiO2/Si structure. AB - In this work, a spot laser modulated resistance switching (RS) effect is firstly observed on n-type Mn-doped ZnO/SiO2/Si structure by growing n-type Mn-doped ZnO film on Si wafer covered with a 1.2 nm native SiO2, which has a resistivity in the range of 50-80 Omega?cm. The I-V curve obtained in dark condition evidences the structure a rectifying junction, which is further confirmed by placing external bias. Compared to the resistance state modulated by electric field only in dark (without illumination), the switching voltage driving the resistance state of the structure from one state to the other, shows clear shift under a spot laser illumination. Remarkably, the switching voltage shift shows a dual dependence on the illumination position and power of the spot laser. We ascribe this dual dependence to the electric filed produced by the redistribution of photo-generated carriers, which enhance the internal barrier of the hetero junction. A complete theoretical analysis based on junction current and diffusion equation is presented. The dependence of the switching voltage on spot laser illumination makes the n-type Mn-doped ZnO/SiO2/Si structure sensitive to light, which thus allows for the integration of an extra functionality in the ZnO-based photoelectric device. PMID- 29123193 TI - Characterization of mammary-specific disruptions for Tph1 and Lrp5 during murine lactation. AB - Serotonin is a homeostatic regulator of the mammary gland during lactation. The contribution of mammary-derived serotonin to circulating serum serotonin concentrations was previously unknown. We have developed mice with mammary specific disruptions of tryptophan hydroxylase 1 (Tph1) or low-density lipoprotein receptor-related protein 5 (Lrp5) that are induced during late pregnancy and lactation via use of the whey acidic protein (WAP)-Cre cre-lox system. Our objective was to characterize dams with a lactation- and mammary specific disruption of Lrp5 (WAP-Cre * Lrp5 FL/FL) or Tph1 (WAP-Cre * Tph1 FL/FL). Milk yield and pup weights were recorded throughout lactation. Dams were euthanized on d10 postpartum and mammary glands and duodenal tissue were harvested. WAP-Cre * Lrp5 FL/FL dams had elevated serotonin concentrations in both the mammary gland and circulation compared to controls. In contrast, WAP-Cre * Tph1 FL/FL dams had decreased mammary gland and serum serotonin concentrations compared to controls. Alveolar morphology, milk yield, and pup weights were similar. Mammary-derived serotonin makes a significant contribution to circulating serotonin concentrations during lactation, with no effect on milk yield or alveolar morphology. These transgenic models can and should be confidently used in future lactation studies to further elucidate the contribution of serotonin to the maintenance of lactation. PMID- 29123194 TI - Net primary productivity and its partitioning in response to precipitation gradient in an alpine meadow. AB - The dynamics of net primary productivity (NPP) and its partitioning to the aboveground versus belowground are of fundamental importance to understand carbon cycling and its feedback to climate change. However, the responses of NPP and its partitioning to precipitation gradient are poorly understood. We conducted a manipulative field experiment with six precipitation treatments (1/12 P, 1/4 P, 1/2 P, 3/4 P, P, and 5/4 P, P is annual precipitation) in an alpine meadow to examine aboveground and belowground NPP (ANPP and BNPP) in response to precipitation gradient in 2015 and 2016. We found that changes in precipitation had no significant impact on ANPP or belowground biomass in 2015. Compared with control, only the extremely drought treatment (1/12 P) significantly reduced ANPP by 37.68% and increased BNPP at the depth of 20-40 cm by 80.59% in 2016. Across the gradient, ANPP showed a nonlinear response to precipitation amount in 2016. Neither BNPP nor NPP had significant relationship with precipitation changes. The variance in ANPP were mostly due to forbs production, which was ultimately caused by altering soil water content and soil inorganic nitrogen concentration. The nonlinear precipitation-ANPP relationship indicates that future precipitation changes especially extreme drought will dramatically decrease ANPP and push this ecosystem beyond threshold. PMID- 29123192 TI - Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes. AB - Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D); (ii) MitoQ (DMitoQ;0.6 mg/kg/day); (iii) Ramipril (DRam;3 mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db/db mice for 12 weeks (n = 11-13/group). Non-diabetic (C) db/m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown. PMID- 29123195 TI - Specific Light-Up System for Protein and Metabolite Targets Triggered by Initiation Complex Formation. AB - Gene regulation systems are mimicked by simple quantitative detection of non nucleic acid molecular targets such as protein and metabolite. Here, we describe a one-tube, one-step real-time quantitative detection methodology for isothermal signal amplification of those targets. Using this system, real-time quantitative detection of thrombin and streptomycin, which were used as examples for protein and metabolite targets, was successfully demonstrated with detection limits of at most 50 pM and 75 nM, respectively. Notably, the dynamic range of target concentrations could be obtained for over four orders of magnitude. Thus, our method is expected to serve as a point-of-care or on-site test for medical diagnosis and food and environmental hygiene. PMID- 29123196 TI - Identification of selection signals by large-scale whole-genome resequencing of cashmere goats. AB - Inner Mongolia and Liaoning cashmere goats are two outstanding Chinese multipurpose breeds that adapt well to the semi-arid temperate grassland. These two breeds are characterized by their soft cashmere fibers, thus making them great models to identify genomic regions that are associated with cashmere fiber traits. Whole-genome sequencing of 70 cashmere goats produced more than 5.52 million single-nucleotide polymorphisms and 710,600 short insertions and deletions. Further analysis of these genetic variants showed some population specific molecular markers for the two cashmere goat breeds that are otherwise phenotypically similar. By analyzing F ST and thetapi outlier values, we identified 135 genomic regions that were associated with cashmere fiber traits within the cashmere goat populations. These selected genomic regions contained genes, which are potential involved in the production of cashmere fiber, such as FGF5, SGK3, IGFBP7, OXTR, and ROCK1. Gene ontology enrichment analysis of identified short insertions and deletions also showed enrichment in keratinocyte differentiation and epidermal cell differentiation. These findings demonstrate that this genomic resource will facilitate the breeding of cashmere goat and other Capra species in future. PMID- 29123198 TI - Detection and quantification of offal content in ground beef meat using vibrational spectroscopic-based chemometric analysis. AB - As less consumed animal by-product, beef and pork offal have chances to sneak into the authentic ground beef meat products, and thus a rapid and accurate detection and quantification technique is highly required. In this study, Fourier transformed-infrared (FT-IR) spectroscopy was investigated to develop an optimized protocol for analyzing ground beef meat potentially adulterated with six types of beef and pork offal. Various chemometric models for classification and quantification were constructed for the collected FT-IR spectra. Applying optimized chemometric models, FT-IR spectroscopy could differentiate authentic beef meat from adulterated samples with >99% accuracy, to identify the type of offal in the sample with >80% confidence, and to quantify five types of offal in an accurate manner (R 2 > 0.81). An optimized protocol was developed to authenticate ground beef meat as well as identify and quantify the offal adulterants using FT-IR spectroscopy coupled with chemometric models. This protocol offers a limit of detection <10% w/w of offal in ground beef meat and can be applied by governmental laboratories and food industry to rapidly monitor the integrity of ground beef meat products. PMID- 29123197 TI - A Microdevice Platform Recapitulating Hypoxic Tumor Microenvironments. AB - Hypoxia plays a central role in cancer progression and resistance to therapy. We have engineered a microdevice platform to recapitulate the intratumor oxygen gradients that drive the heterogeneous hypoxic landscapes in solid tumors. Our design features a "tumor section"-like culture by incorporating a cell layer between two diffusion barriers, where an oxygen gradient is established by cellular metabolism and physical constraints. We confirmed the oxygen gradient by numerical simulation and imaging-based oxygen sensor measurement. We also demonstrated spatially-resolved hypoxic signaling in cancer cells through immunostaining, gene expression assay, and hypoxia-targeted drug treatment. Our platform can accurately generate and control oxygen gradients, eliminates complex microfluidic handling, allows for incorporation of additional tumor components, and is compatible with high-content imaging and high-throughput applications. It is well suited for understanding hypoxia-mediated mechanisms in cancer disease and other biological processes, and discovery of new therapeutics. PMID- 29123199 TI - Detection of genomic loci associated with chromosomal recombination using high density linkage mapping in Setaria. AB - Meiotic recombination is essential to sexual reproduction and the generation of genetic diversity. Variation in recombination rates is presently of particular interest due to efforts being made to increase the rate of genetic gain in agricultural crops by breaking up large linkage disequilibrium blocks containing both beneficial and detrimental alleles. Here, a high-density genetic linkage map of Setaria was constructed using tunable genotyping by sequencing (tGBS) analysis of a population of recombinant inbred lines (RILs). Several regions of the Setaria genome exhibited significant levels of segregation distortion (SD), and recombination crossovers (COs) were also detected. The regions with high SD generally tended to have fewer COs, particularly for pericentromeric chromosomal areas. Recombination crossovers detected in Setaria were unevenly distributed across the genome and occurred more often in intergenic regions. Quantitative trait loci (QTLs) contributing towards the recombination frequency (Type I) and occurrence of COs in designated loci (Type II) were identified, and Type II QTLs garnered higher statistical power. The result of this study suggest that QTLs analysis of Type II traits using RILs might provide an opportunity to further understand meiotic recombination using high throughput genome sequencing and genotyping technologies. PMID- 29123200 TI - Discordancy Partitioning for Validating Potentially Inconsistent Pharmacogenomic Studies. AB - The Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) are two major studies that can be used to mine for therapeutic biomarkers for cancers of a large variety. Model validation using the two datasets however has proved challenging. Both predictions and signatures do not consistently validate well for models built on one dataset and tested on the other. While the genomic profiling seems consistent, the drug response data is not. Some efforts at harmonizing experimental designs has helped but not entirely removed model validation difficulties. In this paper, we present a partitioning strategy based on a data sharing concept which directly acknowledges a potential lack of concordance between datasets and in doing so, also allows for extraction of reproducible novel gene-drug interaction signatures as well as accurate test set predictions. We demonstrate these properties in a re-analysis of the GDSC and CCLE datasets. PMID- 29123201 TI - Insecticidal effects of dsRNA targeting the Diap1 gene in dipteran pests. AB - The Drosophila melanogaster (fruit fly) gene Diap1 encodes a protein referred to as DIAP1 (D rosophila Inhibitor of Apoptosis Protein 1) that acts to supress apoptosis in "normal" cells in the fly. In this study we investigate the use of RNA interference (RNAi) to control two dipteran pests, Musca domestica and Delia radicum, by disrupting the control of apoptosis. Larval injections of 125-500 ng of Diap1 dsRNA resulted in dose-dependent mortality which was shown to be attributable to down-regulation of target mRNA. Insects injected with Diap1 dsRNA have approx. 1.5-2-fold higher levels of caspase activity than controls 24 hours post injection, providing biochemical evidence that inhibition of apoptotic activity by the Diap1 gene product has been decreased. By contrast adults were insensitive to injected dsRNA. Oral delivery failed to induce RNAi effects and we suggest this is attributable to degradation of ingested dsRNA by intra and extracellular RNAses. Non-target effects were demonstrated via mortality and down regulation of Diap1 mRNA levels in M. domestica larvae injected with D. radicum Diap1 dsRNA, despite the absence of 21 bp identical sequence regions in the dsRNA. Here we show that identical 15 bp regions in dsRNA are sufficient to trigger non-target RNAi effects. PMID- 29123202 TI - Potential damaging mutation in LRP5 from genome sequencing of the first reported chimpanzee with the Chiari malformation. AB - The genus Pan is the closest related to humans (Homo sapiens) and it includes two species: Pan troglodytes (chimpanzees) and Pan paniscus (bonobos). Different characteristics, some of biomedical aspect, separate them from us. For instance, some common human medical conditions are rare in chimpanzees (menopause, Alzheimer disease) although it is unclear to which extent longevity plays an active role in these differences. However, both humans and chimpanzees present similar pathologies, thus, understanding traits in chimpanzees can help unravel the molecular basis of human conditions. Here, we sequenced the genome of Nico, a central chimpanzee diagnosed with a particular biomedical condition, the Chiari malformation. We performed a variant calling analysis comparing his genome to 25 whole genomes from healthy individuals (bonobos and chimpanzees), and after predicting the effects of the genetic variants, we looked for genes within the OMIM database. We found a novel, private, predicted as damaging mutation in Nico in LRP5, a gene related to bone density alteration pathologies, and we suggest a link between this mutation and his Chiari malformation as previously shown in humans. Our results reinforce the idea that a comparison between humans and chimpanzees can be established in this genetic frame of common diseases. PMID- 29123203 TI - Respiratory Syncytial Virus Exacerbates OVA-mediated asthma in mice through C5a C5aR regulating CD4+T cells Immune Responses. AB - Asthma exacerbation could be induced by respiratory syncytial virus (RSV), and the underlying pathogenic mechanism is related to complement activation. Although complement might regulate CD4+T cells immune responses in asthma model, this regulation existed in RSV-induced asthma model remains incompletely characterrized. In this study, we assessed the contribution of C5a-C5aR to CD4+T cell immune responses in RSV-infected asthma mice. Female BALB/C mice were sensitized and challenged with ovalbumin (OVA) while treated with RSV infection and C5a receptor antagonist (C5aRA) during challenge period. RSV enhanced lung damage, airway hyperresponsiveness, and C5aR expressions in asthma mice, while C5aRA alleviated these pathologic changes. The percentages of Th1, Th2 and Th17 cells were increased, while the percentage of Treg cells was decreased in RSV infected asthma mice compared with asthma mice. IFN-gamma, IL-4, IL-10 and IL-17A levels have similar trend with Th1, Th2, Th17 and Treg cells. Notably, above changes of CD4+T cells and their related cytokines were reversed by C5aRA. Together, the data indicates that RSV infection could apparently increase C5a and C5aR expression in the pathogenesis of RSV-infected asthma mice, meanwhile C5aRA prevents some of the CD4+T cells immune changes that are induced by RSV. PMID- 29123205 TI - 1000-Year Quasi-Periodicity of Weak Monsoon Events in Temperate Northeast Asia since the Mid-Holocene. AB - The Holocene variability in the East Asian summer monsoon (EASM) based on speleothem delta18O records has inconsistencies in timing, duration, and expression of millennial-scale events among nearby regions, and even within the same cave. Here, we present another stalagmite delta18O record with multi-decadal time resolution from the temperate Korean Peninsula (KP) for the last 5500 years in order to compare with Holocene millennial-scale EASM events from Southeast Asia. Based on our new stalagmite delta18O record, millennial-scale events since the mid-Holocene were successfully identified in the KP, representing a noticeable cyclic pattern with a periodicity of around 1000 years. We propose that the Holocene millennial-scale events are common hydroclimatic phenomena at least in the East Asian monsoon system. Meanwhile, the shorter periodicity of millennial-scale events than that of the North Atlantic region is likely to decouple the EASM system from the North Atlantic climate system. This observation suggests that weak EASM and North Atlantic Bond events may have been induced independently by direct solar activity (and then possible feedback) and ocean-ice sheet dynamics, respectively, rather than simple propagation from the North Atlantic to the EASM regions. PMID- 29123204 TI - Structural insights into DNA cleavage activation of CRISPR-Cas9 system. AB - CRISPR-Cas9 technology has been widely used for genome engineering. Its RNA guided endonuclease Cas9 binds specifically to target DNA and then cleaves the two DNA strands with HNH and RuvC nuclease domains. However, structural information regarding the DNA cleavage-activating state of two nuclease domains remains sparse. Here, we report a 5.2 A cryo-EM structure of Cas9 in complex with sgRNA and target DNA. This structure reveals a conformational state of Cas9 in which the HNH domain is closest to the DNA cleavage site. Compared with two known HNH states, our structure shows that the HNH active site moves toward the cleavage site by about 25 and 13 A, respectively. In combination with EM-based molecular dynamics simulations, we show that residues of the nuclease domains in our structure could form cleavage-compatible conformations with the target DNA. Together, these results strongly suggest that our cryo-EM structure resembles a DNA cleavage-activating architecture of Cas9. PMID- 29123206 TI - A Solution-Processable, Nanostructured, and Conductive Graphene/Polyaniline Hybrid Coating for Metal-Corrosion Protection and Monitoring. AB - A smart and effective anticorrosive coating consisting of alternating graphene and polyaniline (PANI) layers was developed using top-down solution processing. Graphite was exfoliated using sonication assisted by polyaniline to produce a nanostructured, conductive graphene/polyaniline hybrid (GPn) in large quantities (>0.5 L of 6 wt% solution in a single laboratory-scale process). The GPn was coated on copper and exhibited excellent anticorrosion protection efficiencies of 46.6% and 68.4% under electrochemical polarization in 1 M sulfuric acid and 3.5 wt% sodium chloride solutions, chosen as chemical and seawater models, respectively. Impedance measurements were performed in the two corrosive solutions, with the variation in charge transfer resistance (R ct) over time indicating that the GPn acted as an efficient physical and chemical barrier preventing corrosive species from reaching the copper surface. The GPn-coated copper was composed of many PANI-coated graphene planes stacked parallel to the copper surface. PANI exhibits redox-based conductivity, which was facilitated by the high conductivity of graphene. Additionally, the GPn surface was found to be hydrophobic. These properties combined effectively to protect the copper metal against corrosion. We expect that the GPn can be further applied for developing smart anticorrosive coating layers capable of monitoring the status of metals. PMID- 29123207 TI - Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4. AB - Atropine is a clinically relevant anticholinergic drug, which blocks inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia. However, many cardiac effects of atropine cannot be adequately explained solely by its antagonism at muscarinic receptors. In isolated mouse ventricular cardiomyocytes expressing a Forster resonance energy transfer (FRET)-based cAMP biosensor, we confirmed that atropine inhibited acetylcholine-induced decreases in cAMP. Unexpectedly, even in the absence of acetylcholine, after G-protein inactivation with pertussis toxin or in myocytes from M2- or M1/3-muscarinic receptor knockout mice, atropine increased cAMP levels that were pre-elevated with the beta-adrenergic agonist isoproterenol. Using the FRET approach and in vitro phosphodiesterase (PDE) activity assays, we show that atropine acts as an allosteric PDE type 4 (PDE4) inhibitor. In human atrial myocardium and in both intact wildtype and M2 or M1/3-receptor knockout mouse Langendorff hearts, atropine led to increased contractility and heart rates, respectively. In vivo, the atropine-dependent prolongation of heart rate increase was blunted in PDE4D but not in wildtype or PDE4B knockout mice. We propose that inhibition of PDE4 by atropine accounts, at least in part, for the induction of tachycardia and the arrhythmogenic potency of this drug. PMID- 29123208 TI - Differential T Cell Signaling Pathway Activation by Tacrolimus and Belatacept after Kidney Transplantation: Post Hoc Analysis of a Randomised-Controlled Trial. AB - Pharmacokinetic immunosuppressive drug monitoring poorly correlates with clinical outcomes after solid organ transplantation. A promising method for pharmacodynamic monitoring of tacrolimus (TAC) in T cell subsets of transplant recipients might be the measurement of (phosphorylated) p38MAPK, ERK1/2 and Akt (activated downstream of the T cell receptor) by phospho-specific flow cytometry. Here, blood samples from n = 40 kidney transplant recipients (treated with either TAC-based or belatacept (BELA)-based immunosuppressive drug therapy) were monitored before and throughout the first year after transplantation. After transplantation and in unstimulated samples, p-p38MAPK and p-Akt were inhibited in CD8+ T cells and p-ERK in CD4+ T cells but only in patients who received TAC based therapy. After activation with PMA/ionomycin, p-p38MAPK and p-AKT were significantly inhibited in CD4+ and CD8+ T cells when TAC was given, compared to pre-transplantation. Eleven BELA-treated patients had a biopsy-proven acute rejection, which was associated with higher p-ERK levels in both CD4+ and CD8+ T cells compared to patients without rejection. In conclusion, phospho-specific flow cytometry is a promising tool to pharmacodynamically monitor TAC-based therapy. In contrast to TAC-based therapy, BELA-based immunosuppression does not inhibit key T cell activation pathways which may contribute to the high rejection incidence among BELA-treated transplant recipients. PMID- 29123209 TI - Chromatin Protamination and Catsper Expression in Spermatozoa Predict Clinical Outcomes after Assisted Reproduction Programs. AB - Identification of parameters predicting assisted reproductive technologies (ARTs) success is a major goal of research in reproduction. Quality of gametes is essential to achieve good quality embryos and increase the success of ARTs. We evaluated two sperm parameters, chromatin maturity and expression of the sperm specific calcium channel CATSPER, in relation to ART outcomes in 206 couples undergoing ARTs. Chromatin maturity was evaluated by Chromomycin A3 (CMA3) for protamination and Aniline Blue (AB) for histone persistence and CATSPER expression by a flow cytometric method. CMA3 positivity and CATSPER expression significantly predicted the attainment of good quality embryos with an OR of 6.6 and 14.3 respectively, whereas AB staining was correlated with fertilization rate. In the subgroup of couples with women <=35 years, CATSPER also predicted achievement of clinical pregnancy (OR = 4.4). Including CMA3, CATSPER and other parameters affecting ART outcomes (female age, female factor and number of MII oocytes), a model that resulted able to predict good embryo quality with high accuracy was developed. CMA3 staining and CATSPER expression may be considered two applicable tools to predict ART success and useful for couple counseling. This is the first study demonstrating a role of CATSPER expression in embryo development after ARTs programs. PMID- 29123211 TI - Effects of Cement Paste Enhanced with Iron-Based Magnetic Particles on an Embedded Small Resonator Antenna. AB - Small resonator antennas, such as metaresonator antennas, have narrow bandwidths, which limits their effective range of frequencies. When they are used as embedded antennas in building materials, their performance is affected more than other types of antennas, as typical building materials have a shielding effectiveness (SE) of 80 dB to 100 dB. Adding magnetic and/or metallic particles to cement mixes changes the properties of the concrete, which can improve the performance of antennas. Specifically, enhancing a cement paste with iron-based magnetic particles improves the bandwidth and S11 of embedded antennas. This report investigates the impact of two different iron-based magnetic particle sizes (micro- and nanosized particles) to determine the effects that they have on the S11 and S21 characteristics of the metaresonator antenna array embedded in enhanced cement pastes. Results show that compared to cement paste only sample, cement paste with micro-sized iron-based magnetic particles had the greatest improvement of performance of a metaresonator antenna array in terms of a small shift in the resonance frequency and an increase of bandwidth. Particularly for a cement paste enhanced with micro-sized iron (III) oxide particles, the S21 curve was improved over the cement paste only sample by as much as 10 dB. PMID- 29123210 TI - Plasticity of the inner cell mass in mouse blastocyst is restricted by the activity of FGF/MAPK pathway. AB - In order to ensure successful development, cells of the early mammalian embryo must differentiate to either trophectoderm (TE) or inner cell mass (ICM), followed by epiblast (EPI) or primitive endoderm (PE) specification within the ICM. Here, we deciphered the mechanism that assures the correct order of these sequential cell fate decisions. We revealed that TE-deprived ICMs derived from 32 cell blastocysts are still able to reconstruct TE during in vitro culture, confirming totipotency of ICM cells at this stage. ICMs isolated from more advanced blastocysts no longer retain totipotency, failing to form TE and generating PE on their surface. We demonstrated that the transition from full potency to lineage priming is prevented by inhibition of the FGF/MAPK signalling pathway. Moreover, we found that after this first restriction step, ICM cells still retain fate flexibility, manifested by ability to convert their fate into an alternative lineage (PE towards EPI and vice versa), until peri-implantation stage. PMID- 29123212 TI - Influence of Precipitation and Crop Germination on Resource Selection by Mule Deer (Odocoileus hemionus) in Southwest Colorado. AB - Mule deer (Odocoileus hemionus) populations in the western United States provide many benefits to local economies but can also cause considerable damage to agriculture, particularly damage to lucrative crops. Limited information exists to understand resource selection of mule deer in response to annual variation in crop rotation and climatic conditions. We tested the hypothesis that mule deer select certain crops, and in particular sunflower, based on annual climatic variability. Our objective was to use movements, estimates of home range, and resource selection analysis to identify resources selected by mule deer. We used annually-derived crop-specific datasets along with Global Positioning System collars to monitor 14 mule deer in an agricultural area near public lands in southwestern Colorado, USA. We estimated home ranges for two winter seasons that ranged between 7.68 and 9.88 km2, and for two summer seasons that ranged between 5.51 and 6.24 km2. Mule deer selected areas closer to forest and alfalfa for most periods during 2012, but selected areas closer to sunflower in a majority of periods during 2013. Considerable annual variation in climate patterns and precipitation levels appeared to influence selection by mule deer because of variability in crop rotation and success of germination of specific crops. PMID- 29123213 TI - Detecting abnormality in heart dynamics from multifractal analysis of ECG signals. AB - The characterization of heart dynamics with a view to distinguish abnormal from normal behavior is an interesting topic in clinical sciences. Here we present an analysis of the Electro-cardiogram (ECG) signals from several healthy and unhealthy subjects using the framework of dynamical systems approach to multifractal analysis. Our analysis differs from the conventional nonlinear analysis in that the information contained in the amplitude variations of the signal is being extracted and quantified. The results thus obtained reveal that the attractor underlying the dynamics of the heart has multifractal structure and the variations in the resultant multifractal spectra can clearly separate healthy subjects from unhealthy ones. We use supervised machine learning approach to build a model that predicts the group label of a new subject with very high accuracy on the basis of the multifractal parameters. By comparing the computed indices in the multifractal spectra with that of beat replicated data from the same ECG, we show how each ECG can be checked for variations within itself. The increased variability observed in the measures for the unhealthy cases can be a clinically meaningful index for detecting the abnormal dynamics of the heart. PMID- 29123214 TI - Evolution of facial color pattern complexity in lemurs. AB - Interspecific variation in facial color patterns across New and Old World primates has been linked to species recognition and group size. Because group size has opposite effects on interspecific variation in facial color patterns in these two radiations, a study of the third large primate radiation may shed light on convergences and divergences in this context. We therefore compiled published social and ecological data and analyzed facial photographs of 65 lemur species to categorize variation in hair length, hair and skin coloration as well as color brightness. Phylogenetically controlled analyses revealed that group size and the number of sympatric species did not influence the evolution of facial color complexity in lemurs. Climatic factors, however, influenced facial color complexity, pigmentation and hair length in a few facial regions. Hair length in two facial regions was also correlated with group size and may facilitate individual recognition. Since phylogenetic signals were moderate to high for most models, genetic drift may have also played a role in the evolution of facial color patterns of lemurs. In conclusion, social factors seem to have played only a subordinate role in the evolution of facial color complexity in lemurs, and, more generally, group size appears to have no systematic functional effect on facial color complexity across all primates. PMID- 29123216 TI - A facile hydrothermal approach for the density tunable growth of ZnO nanowires and their electrical characterizations. AB - Controlling properties of one-dimensional (1D) semiconducting nanostructures is essential for the advancement of electronic devices. In this work, we present a low-temperature hydrothermal growth process enabling density control of aligned high aspect ratio ZnO nanowires (NWs) on seedless Au surface. A two order of magnitude change in ZnO NW density is demonstrated via careful control of the ammonium hydroxide concentration (NH4OH) in the solution. Based on the experimental observations, we further, hypothesized the growth mechanism leading to the density controlled growth of ZnO NWs. Moreover, the effect of NH4OH on the electrical properties of ZnO NWs, such as doping and field-effect mobility, is thoroughly investigated by fabricating single nanowire field-effect transistors. The electrical study shows the increase of free charge density while decrease of mobility in ZnO NWs with the increase of NH4OH concentration in the growth solution. These findings show that NH4OH can be used for simultaneous tuning of the NW density and electrical properties of the ZnO NWs grown by hydrothermal approach. The present work will guide the engineers and researchers to produce low-temperature density controlled aligned 1D ZnO NWs over wide range of substrates, including plastics, with tunable electrical properties. PMID- 29123215 TI - Observer's anxiety facilitates magnocellular processing of clear facial threat cues, but impairs parvocellular processing of ambiguous facial threat cues. AB - Facial expression and eye gaze provide a shared signal about threats. While a fear expression with averted gaze clearly points to the source of threat, direct gaze fear renders the source of threat ambiguous. Separable routes have been proposed to mediate these processes, with preferential attunement of the magnocellular (M) pathway to clear threat, and of the parvocellular (P) pathway to threat ambiguity. Here we investigated how observers' trait anxiety modulates M- and P-pathway processing of clear and ambiguous threat cues. We scanned subjects (N = 108) widely ranging in trait anxiety while they viewed fearful or neutral faces with averted or directed gaze, with the luminance and color of face stimuli calibrated to selectively engage M- or P-pathways. Higher anxiety facilitated processing of clear threat projected to M-pathway, but impaired perception of ambiguous threat projected to P-pathway. Increased right amygdala reactivity was associated with higher anxiety for M-biased averted-gaze fear, while increased left amygdala reactivity was associated with higher anxiety for P biased, direct-gaze fear. This lateralization was more pronounced with higher anxiety. Our findings suggest that trait anxiety differentially affects perception of clear (averted-gaze fear) and ambiguous (direct-gaze fear) facial threat cues via selective engagement of M and P pathways and lateralized amygdala reactivity. PMID- 29123217 TI - Measuring the Conformational Distance of GPCR-related Proteins Using a Joint based Descriptor. AB - Joint-based descriptor is a new level of macroscopic descriptor for protein structure using joints of secondary structures as a basic element. Here, we propose how the joint-based descriptor can be applied to examine the conformational distances or differences of transmembrane (TM) proteins. Specifically, we performed three independent studies that measured the global and conformational distances between GPCR A family and its related structures. First, the conformational distances of GPCR A family and other 7TM proteins were evaluated. This provided the information on the distant and close families or superfamilies to GPCR A family and permitted the identification of conserved local conformations. Second, computational models of GPCR A family proteins were validated, which enabled us to estimate how much they reproduce the native conformation of GPCR A proteins at global and local conformational level. Finally, the conformational distances between active and inactive states of GPCR proteins were estimated, which identified the difference of local conformation. The proposed macroscopic joint-based approach is expected to allow us to investigate structural features, evolutionary relationships, computational models and conformational changes of TM proteins in a more simplistic manner. PMID- 29123218 TI - Identification of a Neurocognitive Mechanism Underpinning Awareness of Chronic Tinnitus. AB - Tinnitus (ringing in the ears) is a common auditory sensation that can become a chronic debilitating health condition with pervasive effects on health and wellbeing, substantive economic burden, and no known cure. Here we investigate if impaired functioning of the cognitive control network that directs attentional focus is a mechanism erroneously maintaining the tinnitus sensation. Fifteen people with chronic tinnitus and 15 healthy controls matched for age and gender from the community performed a cognitively demanding task known to activate the cognitive control network in this functional magnetic resonance imaging study. We identify attenuated activation of a core node of the cognitive control network (the right middle frontal gyrus), and altered baseline connectivity between this node and nodes of the salience and autobiographical memory networks. Our findings indicate that in addition to auditory dysfunction, altered interactions between non-auditory neurocognitive networks maintain chronic tinnitus awareness, revealing new avenues for the identification of effective treatments. PMID- 29123219 TI - Band Gap Engineering of Hexagonal SnSe2 Nanostructured Thin Films for Infra-Red Photodetection. AB - We, for the first time, provide the experimental demonstration on the band gap engineering of layered hexagonal SnSe2 nanostructured thin films by varying the thickness. For 50 nm thick film, the band gap is ~2.04 eV similar to that of monolayer, whereas the band gap is approximately ~1.2 eV similar to that of bulk for the 1200 nm thick film. The variation of the band gap is consistent with the the theoretically predicted layer-dependent band gap of SnSe2. Interestingly, the 400-1200 nm thick films were sensitiveto 1064 nm laser iradiation and the sensitivity increases almost exponentiallly with thickness, while films with 50 140 nm thick are insensitive which is due to the fact that the band gap of thinner films is greater than the energy corresponding to 1064 nm. Over all, our results establish the possibility of engineering the band gap of SnSe2 layered structures by simply controlling the thickness of the film to absorb a wide range of electromagnetic radiation from infra-red to visible range. PMID- 29123221 TI - Unlocking the biomineralization style and affinity of Paleozoic fusulinid foraminifera. AB - Fusulinids are the most diverse, abundant and geographically widespread Paleozoic foraminifera which are widely considered to possess a "homogeneously microgranular" test microstructure composed of subangular grains of several micrometers in size. However, this texture appears to be a diagenetic artifact. Here we describe well-preserved Devonian calcareous fusulinids (Nanicella) from the Holy Cross Mountains (HCM) in central Poland. Foraminifera from Poland in which the primary nature of tests have not been masked by diagenesis are composed of low magnesium calcite spherical grains up to about 100 nanometers in diameter, identical to those observed in Recent and fossil hyaline foraminifera (Rotaliida, Globothalamea). These data call the paradigm of microgranular test microstructure of Foraminifera into question, and suggest a possible phylogenetic relationship between globothalamids and some fusulinids. PMID- 29123220 TI - Significance of dopamine D1 receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells. AB - Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, we tried to elucidate the steroidogenic differentiation processes using hiPSC-derived intermediate mesoderm (IM) that is known to be the origin of the human adrenal cortex and gonads. We first performed chemical screening to identify small molecules that induce steroidogenic differentiation of IM cells expressing Odd-skipped related 1 (OSR1), an early IM marker. We identified cabergoline as an inducer of 3beta-hydroxysteroid dehydrogenase, an essential enzyme for adrenogonadal steroidogenesis. Although cabergoline is a potent dopamine D2 receptor agonist, additional experiments showed that cabergoline exerted effects as a low-affinity agonist of D1 receptors by increasing intracellular cyclic AMP. Further analysis of OSR1+ cells transfected with steroidogenic factor-1/adrenal 4 binding protein revealed that D1 receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These results suggest the importance of dopamine D1 receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs. PMID- 29123222 TI - The independent effects of vitamin D deficiency and house dust mite exposure on lung function are sex-specific. AB - Vitamin D deficiency is increasing around the world and has been associated with the development of asthma. This study aims to evaluate the effect of dietary vitamin D deficiency at different life stages on lung function using a murine model of allergic airways disease. BALB/c mice were challenged intranasally with HDM or saline alone for 10 days. Twenty four hours after the last challenge, mice were anesthetized and lung function was measured using the forced oscillation technique (FOT). Mice were euthanized for assessment of inflammation in the bronchoalveolar lavage (BAL) and total collagen content in lung homogenates by ELISA. Vitamin D deficiency impaired lung function in both male and female mice, increasing tissue damping and elastance, however had no effect on HDM induced inflammation. The impact of vitamin D deficiency was more evident in females. HDM also decreased airway distensibility, but only in females and this response was not altered by vitamin D deficiency. Our data suggest that vitamin D deficiency and HDM exposure have independent effects on lung mechanics and that females are more susceptible to these effects. Vitamin D deficiency may exacerbate lung function deficits by having a direct, but independent, effect on parenchymal mechanics. PMID- 29123223 TI - Structural basis of small molecule ATPase inhibition of a human mitotic kinesin motor protein. AB - Kinesin microtubule motor proteins play essential roles in division, including attaching chromosomes to spindles and crosslinking microtubules for spindle assembly. Human kinesin-14 KIFC1 is unique in that cancer cells with amplified centrosomes are dependent on the motor for viable division because of its ability to cluster centrosomes and form bipolar spindles, but it is not required for division in almost all normal cells. Screens for small molecule inhibitors of KIFC1 have yielded several candidates for further development, but obtaining structural data to determine their sites of binding has been difficult. Here we compare a previously unreported KIFC1 crystal structure with new structures of two closely related kinesin-14 proteins, Ncd and KIFC3, to determine the potential binding site of a known KIFC1 ATPase inhibitor, AZ82. We analyze the previously identified kinesin inhibitor binding sites and identify features of AZ82 that favor binding to one of the sites, the alpha4/alpha6 site. This selectivity can be explained by unique structural features of the KIFC1 alpha4/alpha6 binding site. These features may help improve the drug-like properties of AZ82 and other specific KIFC1 inhibitors. PMID- 29123224 TI - Structure and photoluminescence properties of red-emitting apatite-type phosphor NaY9(SiO4)6O2:Sm3+ with excellent quantum efficiency and thermal stability for solid-state lighting. AB - A novel red-emitting phosphor NaY9(SiO4)6O2:Sm3+ (NYS:Sm3+) was synthesized and the X-ray diffraction and high-resolution TEM testified that the NYS compound belongs to the apatite structure which crystallized in a hexagonal unit cell with space group P63/m. The novel phosphor boasts of such three advantageous properties as perfect compatible match with the commercial UV chips, 73.2% quantum efficiency and 90.9% thermal stability at 150 degrees C. Details are as follows. NYS:Sm3+ phosphor showed obvious absorption in the UV regions centered at 407 nm, which can be perfectly compatible with the commercial UV chips. The property investigations showed that NYS:Sm3+ phosphor emitted reddish emission with CIE coordination of (0.563, 0.417). The optimum quenching concentration of Sm3+ in NYS phosphor was about 10%mol, and the corresponding concentration quenching mechanism was verified to be the electric dipole-dipole interaction. Upon excitation at 407 nm, the composition-optimized NYS:0.10Sm3+ exhibited a high quantum efficiency of 73.2%, and its luminescence intensity at 150 degrees C decreased simply to 90.9% of the initial value at room temperature. All of the results indicated that NYS:Sm3+ is a promising candidate as a reddish-emitting UV convertible phosphor for application in white light emitting diodes (w-LEDs). PMID- 29123225 TI - Archaea and the origin of eukaryotes. AB - Woese and Fox's 1977 paper on the discovery of the Archaea triggered a revolution in the field of evolutionary biology by showing that life was divided into not only prokaryotes and eukaryotes. Rather, they revealed that prokaryotes comprise two distinct types of organisms, the Bacteria and the Archaea. In subsequent years, molecular phylogenetic analyses indicated that eukaryotes and the Archaea represent sister groups in the tree of life. During the genomic era, it became evident that eukaryotic cells possess a mixture of archaeal and bacterial features in addition to eukaryotic-specific features. Although it has been generally accepted for some time that mitochondria descend from endosymbiotic alphaproteobacteria, the precise evolutionary relationship between eukaryotes and archaea has continued to be a subject of debate. In this Review, we outline a brief history of the changing shape of the tree of life and examine how the recent discovery of a myriad of diverse archaeal lineages has changed our understanding of the evolutionary relationships between the three domains of life and the origin of eukaryotes. Furthermore, we revisit central questions regarding the process of eukaryogenesis and discuss what can currently be inferred about the evolutionary transition from the first to the last eukaryotic common ancestor. PMID- 29123226 TI - Evolution and genome architecture in fungal plant pathogens. AB - This corrects the article DOI: 10.1038/nrmicro.2017.76. PMID- 29123228 TI - Host response: Granzyme B's roundhouse kick against bacteria. PMID- 29123229 TI - A flourishing field: going back to the roots of the Archaea. PMID- 29123230 TI - Environmental microbiology: Geographic coordinates guide natural product discovery. PMID- 29123227 TI - The enigmatic archaeal virosphere. AB - One of the most prominent features of archaea is the extraordinary diversity of their DNA viruses. Many archaeal viruses differ substantially in morphology from bacterial and eukaryotic viruses and represent unique virus families. The distinct nature of archaeal viruses also extends to the gene composition and architectures of their genomes and the properties of the proteins that they encode. Environmental research has revealed prominent roles of archaeal viruses in influencing microbial communities in ocean ecosystems, and recent metagenomic studies have uncovered new groups of archaeal viruses that infect extremophiles and mesophiles in diverse habitats. In this Review, we summarize recent advances in our understanding of the genomic and morphological diversity of archaeal viruses and the molecular biology of their life cycles and virus-host interactions, including interactions with archaeal CRISPR-Cas systems. We also examine the potential origins and evolution of archaeal viruses and discuss their place in the global virosphere. PMID- 29123231 TI - Synergistic combinations of short high-voltage pulses and long low-voltage pulses enhance irreversible electroporation efficacy. AB - Irreversible electroporation (IRE) uses ~100 MUs pulsed electric fields to disrupt cell membranes for solid tumor ablation. Although IRE has achieved exciting preliminary clinical results, implementing IRE could be challenging because of volumetric limitations at the ablation region. Combining short high voltage (SHV: 1600V, 2 MUs, 1 Hz, 20 pulses) pulses with long low-voltage (LLV: 240-480 V, 100 MUs, 1 Hz, 60-80 pulses) pulses induces a synergistic effect that enhances IRE efficacy. Here, cell cytotoxicity and tissue ablation were investigated. The results show that combining SHV pulses with LLV pulses induced SKOV3 cell death more effectively, and compared to either SHV pulses or LLV pulses applied alone, the combination significantly enhanced the ablation region. Particularly, prolonging the lag time (100 s) between SHV and LLV pulses further reduced cell viability and enhanced the ablation area. However, the sequence of SHV and LLV pulses was important, and the LLV + SHV combination was not as effective as the SHV + LLV combination. We offer a hypothesis to explain the synergistic effect behind enhanced cell cytotoxicity and enlarged ablation area. This work shows that combining SHV pulses with LLV pulses could be used as a focal therapy and merits investigation in larger pre-clinical models and microscopic mechanisms. PMID- 29123232 TI - Failure to Replicate an Association of a LINE-1 Element in ERI1 Exoribonuclease Family Member 3 (ERI3) with Schizophrenia. PMID- 29123233 TI - Steven H Ferris. PMID- 29123234 TI - Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status. AB - This corrects the article DOI: 10.1038/npp.2017.74. PMID- 29123235 TI - Irwin J Kopin. PMID- 29123236 TI - Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle beta2-adrenergic receptor but not by AMPK. AB - Leptin increases glucose uptake and fatty acid oxidation (FAO) in red-type skeletal muscle. However, the mechanism remains unknown. We have investigated the role of beta2-adrenergic receptor (AR), the major beta-AR isoform in skeletal muscle, and AMPK in leptin-induced muscle glucose uptake of mice. Leptin injection into the ventromedial hypothalamus (VMH) increased 2-deoxy-D-glucose (2DG) uptake in red-type skeletal muscle in wild-type (WT) mice accompanied with increased phosphorylation of the insulin receptor (IR) and Akt as well as of norepinephrine (NE) turnover in the muscle. Leptin-induced 2DG uptake was not observed in beta-AR-deficient (beta-less) mice despite that AMPK phosphorylation was increased in the muscle. Forced expression of beta2-AR in the unilateral hind limb of beta-less mice restored leptin-induced glucose uptake and enhancement of insulin signalling in red-type skeletal muscle. Leptin increased 2DG uptake and enhanced insulin signalling in red-type skeletal muscle of mice expressing a dominant negative form of AMPK (DN-AMPK) in skeletal muscle. Thus, leptin increases glucose uptake and enhances insulin signalling in red-type skeletal muscle via activation of sympathetic nerves and beta2-AR in muscle and in a manner independent of muscle AMPK. PMID- 29123237 TI - Coevolution of Vertex Weights Resolves Social Dilemma in Spatial Networks. AB - In realistic social system, the role or influence of each individual varies and adaptively changes in time in the population. Inspired by this fact, we thus consider a new coevolution setup of game strategy and vertex weight on a square lattice. In detail, we model the structured population on a square lattice, on which the role or influence of each individual is depicted by vertex weight, and the prisoner's dilemma game has been applied to describe the social dilemma of pairwise interactions of players. Through numerical simulation, we conclude that our coevolution setup can promote the evolution of cooperation effectively. Especially, there exists a moderate value of delta for each epsilon that can warrant an optimal resolution of social dilemma. For a further understanding of these results, we find that intermediate value of delta enables the strongest heterogeneous distribution of vertex weight. We hope our coevolution setup of vertex weight will provide new insight for the future research. PMID- 29123238 TI - Reconstructing Yeasts Phylogenies and Ancestors from Whole Genome Data. AB - Phylogenetic studies aim to discover evolutionary relationships and histories. These studies are based on similarities of morphological characters and molecular sequences. Currently, widely accepted phylogenetic approaches are based on multiple sequence alignments, which analyze shared gene datasets and concatenate/coalesce these results to a final phylogeny with maximum support. However, these approaches still have limitations, and often have conflicting results with each other. Reconstructing ancestral genomes helps us understand mechanisms and corresponding consequences of evolution. Most existing genome level phylogeny and ancestor reconstruction methods can only process simplified real genome datasets or simulated datasets with identical genome content, unique genome markers, and limited types of evolutionary events. Here, we provide an alternative way to resolve phylogenetic problems based on analyses of real genome data. We use phylogenetic signals from all types of genome level evolutionary events, and overcome the conflicting issues existing in traditional phylogenetic approaches. Further, we build an automated computational pipeline to reconstruct phylogenies and ancestral genomes for two high-resolution real yeast genome datasets. Comparison results with recent studies and publications show that we reconstruct very accurate and robust phylogenies and ancestors. Finally, we identify and analyze the conserved syntenic blocks among reconstructed ancestral genomes and present yeast species. PMID- 29123239 TI - The liver protection of propylene glycol alginate sodium sulfate preconditioning against ischemia reperfusion injury: focusing MAPK pathway activity. AB - Hepatic ischemia reperfusion (IR) injury contributes to the morbidity and mortality associated with liver surgery. This study investigated the protective function and mechanism of propylene glycol alginate sodium sulfate (PSS), a sulfated polysaccharide, in a mouse hepatic IR injury model. PSS (25 or 50 mg/kg) or saline were injected intraperitoneally to male Balb/c mice 1 h before 45 min of 70% warm hepatic ischemia and 2, 8, and 24 h of reperfusion. Serum and liver tissue samples were collected for evaluation of hepatocellular damage, liver histology, and assay of inflammatory cytokines, apoptosis- and autophagy-related proteins, and proteins in the mitogen-activated protein kinase (MAPKs). Histological injury and release of transaminases, and inflammatory cytokine production were significantly reduced by PSS pretreatment. The expression of apoptosis- and autophagy-related proteins, and the activation of MAPK signal, including jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and P38 were all affected by PSS treatment compared with IR model controls. PSS protected the liver from IR injury by suppressing the MAPK signaling and down-regulating inflammation, apoptosis, and autophagy. PMID- 29123240 TI - DNA methylation regulates TMEM16A/ANO1 expression through multiple CpG islands in head and neck squamous cell carcinoma. AB - ANO1 is a calcium-activated chloride channel that is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and other cancers. While ANO1 expression negatively correlates with survival in several cancers, its epigenetic regulation is poorly understood. We analyzed HNSCC samples from TCGA and a separate dataset of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples to identify differentially methylated regions. E6 and E7 transfected normal oral keratinocytes (NOK) were used to induce hypermethylation of the ANO1 promoter. We found three CpG islands that correlated with ANO1 expression, including two positively correlated with expression. Using two HNSCC datasets with differential expression of ANO1, we showed hypermethylation of positively correlated CpG islands potentiates ANO1 expression. E7 but not E6 transfection of NOK cells led to hypermethylation of a positively correlated CpG island without a change in ANO1 expression. ANO1 promoter methylation was also correlated with patient survival. Our results are the first to show the contribution of positively correlated CpG's for regulating gene expression in HNSCC. Hypermethylation of the ANO1 promoter was strongly correlated with but not sufficient to increase ANO1 expression, suggesting methylation of positively correlated CpG's likely serves as an adjunct to other mechanisms of ANO1 activation. PMID- 29123241 TI - Toxoplasma gondii tachyzoite-extract acts as a potent immunomodulator against allergic sensitization and airway inflammation. AB - Epidemiological and experimental studies have shown an inverse relationship between infections with certain parasites and a reduced incidence of allergic diseases. We and others have shown that infection with Toxoplasma gondii prevents the development of allergy in mice. To establish whether this beneficial effect could be recapitulated by soluble products of this parasite, we tested an extract derived from T. gondii tachyzoites. Immunization of BALB/c mice with tachyzoites lysate antigen (TLA) elicited mixed Th1/Th2 responses. When TLA was applied together with the sensitizing ovalbumin (OVA), the development of allergic airway inflammation was reduced, with decreased airway hyperresponsiveness associated with reduced peribronchial and perivascular cellular infiltration, reduced production of OVA-specific Th2 cytokines in lungs and spleens and reduced levels of serum OVA-specific IgG1 as well as IgE-dependent basophil degranulation. Of note, TLA retained its immunomodulatory properties, inducing high levels of IL-6, TNFalpha, IL-10 and IL-12p70 in bone marrow-derived dendritic cells after heat inactivation or proteinase K-treatment for disruption of proteins, but not after sodium metaperiodate-treatment that degrades carbohydrate structures, suggesting that carbohydrates may play a role in immunomodulatory properties of TLA. Here we show that extracts derived from parasites may replicate the benefits of parasitic infection, offering new therapies for immune-mediated disorders. PMID- 29123242 TI - Field-relevant doses of the systemic insecticide fipronil and fungicide pyraclostrobin impair mandibular and hypopharyngeal glands in nurse honeybees (Apis mellifera). AB - Global decreases in bee populations emphasize the importance of assessing how environmental stressors affect colony maintenance, especially considering the extreme task specialization observed in honeybee societies. Royal jelly, a protein secretion essential to colony nutrition, is produced by nurse honeybees, and development of bee mandibular glands, which comprise a reservoir surrounded by secretory cells and hypopharyngeal glands that are shaped by acini, is directly associated with production of this secretion. Here, we examined individual and combined effects of the systemic fungicide pyraclostrobin and insecticide fipronil in field-relevant doses (850 and 2.5 ppb, respectively) on mandibular and hypopharyngeal glands in nurse honeybees. Six days of pesticide treatment decreased secretory cell height in mandibular glands. When pyraclostrobin and fipronil were combined, the reservoir volume in mandibular glands also decreased. The total number of acini in hypopharyngeal glands was not affected, but pesticide treatment reduced the number of larger acini while increasing smaller acini. These morphological impairments appeared to reduce royal jelly secretion by nurse honeybees and consequently hampered colony maintenance. Overall, pesticide exposure in doses close to those experienced by bees in the field impaired brood-food glands in nurse honeybees, a change that could negatively influence development, survival, and colony maintenance. PMID- 29123243 TI - Immunohistochemical Detection of Propionibacterium acnes in the Retinal Granulomas in Patients with Ocular Sarcoidosis. AB - The etiology of sarcoidosis is still obscure; however, Mycobacteria and Propionibacterium acnes are considered the most implicated etiological agent for sarcoidosis. To investigate whether P. acnes is an etiological agent for sarcoid uveitis, we analyzed the frequency of P. acnes detected within the biopsied retinas from patients with ocular sarcoidosis by immunohistochemistry with a P. acnes-specific monoclonal antibody (PAB antibody). Eleven patients (12 eyes) with sarcoid uveitis were enrolled in this study. Eight patients with rhegmatogenous retinal detachment, two patients with non-sarcoid uveitis, and two patients with vitreoretinal lymphoma were enrolled as controls. In the sarcoidosis group, granulomas were mainly observed in the inner retinal layer filled with CD4+ cells and CD68+ cells, indicating the Th1 immune response. P. acnes, identified as round bodies that reacted with the PAB antibody, were present in 10/12 samples (83%) from 9/11 patients (82%) with sarcoidosis. These round bodies were scattered within the retinal granulomas mainly in the inner retinal layer. In the control group, no round bodies were detected. Our results suggested that P. acnes could be associated with sarcoid uveitis. We hypothesize that sarcoid granulomas may be formed by a Th1 immune response to P. acnes hematogenously transmitted to the retina. PMID- 29123245 TI - Small-cell lung cancer: what we know, what we need to know and the path forward. AB - This corrects the article DOI: 10.1038/nrc.2017.87. PMID- 29123244 TI - Tumour suppressors: Digging deeper into p53's functions. PMID- 29123247 TI - Tumour angiogenesis: Controlling nerves. PMID- 29123248 TI - Engineering 'cell robots' for parallel and highly sensitive screening of biomolecules under in vivo conditions. AB - Cells are capable of rapid replication and performing tasks adaptively and ultra sensitively and can be considered as cheap "biological-robots". Here we propose to engineer cells for screening biomolecules in parallel and with high sensitivity. Specifically, we place the biomolecule variants (library) on the bacterial phage M13. We then design cells to screen the library based on cell phage interactions mediated by a specific intracellular signal change caused by the biomolecule of interest. For proof of concept, we used intracellular lysine concentration in E. coli as a signal to successfully screen variants of functional aspartate kinase III (AK-III) under in vivo conditions, a key enzyme in L-lysine biosynthesis which is strictly inhibited by L-lysine. Comparative studies with flow cytometry method failed to distinguish the wild-type from lysine resistance variants of AK-III, confirming a higher sensitivity of the method. It opens up a new and effective way of in vivo high-throughput screening for functional molecules and can be easily implemented at low costs. PMID- 29123249 TI - Crickets alter wind-elicited escape strategies depending on acoustic context. AB - Acoustic signals trigger various behaviours in insects such as courtship or escape from predators. However, it remains unknown whether insects utilize acoustic signals to recognize environmental contexts. The cricket is a prominent model insect for neuroethological studies on acoustic behaviour because female crickets exhibit positive phonotaxis in response to male calling songs, and flying crickets display avoidance behaviour for high-frequency sounds such as echolocation call of bats. The carrier frequency of these sounds is a major factor in determining whether they initiate these acoustic behaviours. Here, we examined the impacts of different frequencies of tone sounds on cercal-mediated escape behaviour, using a 5-kHz tone corresponding to the calling song and a 15 kHz tone serving as a trigger of avoidance behaviours. Neither frequency elicited a response in the standing cricket by itself, but they had different impacts on walking responses to airflow stimuli. While the 15-kHz tone reduced response probability, extended moving distance, and enhanced turn-angle variability, the 5 kHz tone had no effect. Although both frequencies of tones facilitated walking backward, the 15-kHz tone had a larger effect than the 5-kHz tone. These frequency dependencies of behavioural modulation suggest that crickets can recognize acoustic contexts and alter their escape strategy accordingly. PMID- 29123246 TI - Transport of drugs from blood vessels to tumour tissue. AB - The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed. PMID- 29123250 TI - Parkinson disease: What goes around comes around: cognitive impairment as prodromal parkinsonism? PMID- 29123251 TI - Alzheimer disease: PINK1 rescues pathology in Alzheimer disease. PMID- 29123252 TI - Surgical Management and Prognostic Prediction of Adenocarcinoma of Jejunum and Ileum. AB - We conducted a retrospective study based on the Surveillance, Epidemiology, and End Results Program (SEER) database to establish a novel nomogram prognostic prediction system and to estimate the association between overall survival and prognostic factors, as well as to explore surgical treatment strategies for adenocarcinoma of the jejunum and ileum. A total of 883 patients from the SEER database were included in this study. Eight potential prognostic factors were included in a nomogram model and discriminatory power and accuracy were examined using the Harrell's C-index and Akaike Information Criterion (AIC) index. In comparison with the AJCC TNM staging system, the nomogram prediction system was more accurate and homogeneous (Harrell's C-index, 0.731 vs. 0.667; AIC index, 4852.9 vs. 4913.723). For surgical management, resection of more than 12 local lymph nodes could improve the likelihood of survival. This study demonstrates that our nomogram model is more accurate and homogeneous than the traditional AJCC TNM staging system, and proper surgical strategies for mesenteric lymphadenectomy improve overall survival. PMID- 29123253 TI - The gene fmt, encoding tRNAfMet-formyl transferase, is essential for normal growth of M. bovis, but not for viability. AB - Mycobacterium tuberculosis is a major health threat, necessitating novel drug targets. Protein synthesis in bacteria uses initiator tRNAi charged with formylated methionine residue. Deletion of the formylase gene, tRNAfMet-formyl transferase (fmt), causes severe growth-retardation in E. coli and in S. pneumoniae, but not in P. aeruginosa or S. aureus. fmt was predicted to be essential in M. tuberculosis by transposon library analysis, but this was never formally tested in any mycobacteria. We performed a targeted deletion of fmt in M. smegmatis as well as Mtb-complex (M. bovis). In both cases, we created a mero diploid strain, deleted the native gene by two-step allelic exchange or specialized-phage transduction, and then removed the complementing gene to create full deletion mutants. In M. smegmatis a full deletion strain could be easily created. In contrast, in M. bovis-BCG, a full deletion strain could only be created after incubation of 6 weeks, with a generation time ~2 times longer than for wt bacteria. Our results confirm the importance of this gene in pathogenic mycobacteria, but as the deletion mutant is viable, validity of fmt as a drug target remains unclear. Our results also refute the previous reports that fmt is essential in M. tuberculosis-complex. PMID- 29123255 TI - Clinicopathological factors influencing outcome in metastatic colorectal cancer patients treated with fluoropyrimidine and bevacizumab maintenance treatment vs observation: an individual patient data meta-analysis of two phase 3 trials. AB - BACKGROUND: The CAIRO3 and AIO 0207 trials demonstrated the efficacy of fluoropyrimidine plus bevacizumab (FP+Bev) maintenance treatment in metastatic colorectal cancer (mCRC) patients. In this individual patient data meta-analysis with updated follow-up, we aim to provide more precise estimates of treatment effects and to identify subgroups that benefit most from maintenance treatment or observation. METHODS: In 871 patients, randomised to FP+Bev maintenance treatment or observation, we investigated whether treatment effect was modified by sex, age, performance status, response to induction treatment, primary tumour location, number of metastatic sites, disease stage and primary tumour resection, serum LDH, platelet count, CEA, and RAS/BRAF mutation status. Primary end point was time to second progression after reintroduction of the induction regimen (PFS2). Secondary end points were first progression-free survival (PFS1) and overall survival (OS). RESULTS: At a median follow-up of 68.5 months (IQR 54.6 87.0 months), maintenance treatment was more effective compared with observation in PFS1 (HR 0.40(95% CI 0.34-0.47)) and PFS2 (HR 0.70(0.60-0.81)). No subgroups were identified that did not benefit from maintenance treatment in PFS1 and PFS2; no clinically relevant subgroup effects were observed. Regarding OS, pooled results were not significant (HR 0.91(0.78-1.05)), and the trials showed marked heterogeneity in overall treatment effect and subgroup effects. CONCLUSIONS: FP+Bev maintenance treatment is effective in all patients, regardless of the investigated subgroups. PMID- 29123256 TI - Favourable prognostic role of histological regression in stage III positive sentinel lymph node melanoma patients. AB - BACKGROUND: Sentinel lymph node (SLN)-positive melanoma patients are a heterogeneous group of patients with survival rates ranging from ~20 to over 80%. No data are reported concerning the role of histological regression on survival in stage III melanoma. METHODS: The study included 365 patients with positive SLN from two distinct hospitals. The model was developed on patients from 'AOU Citta della Salute e della Scienza di Torino', and externally validated on patients from IRCCS of Candiolo. Survival analyses were carried out according to the presence of regression and adjusted for all other prognostic factors. RESULTS: Among patients followed at 'AOU Citta della Salute e della Scienza di Torino' (n=264), the median follow-up time to death or censoring (whatever two events occurred earlier) was 2.7 years since diagnosis (interquartile range: 1.3-5.8). In all, 79 patients died from melanoma and 11 from other causes. Histological regression (n=43) was associated with a better prognosis (sub-HR=0.34, CI 0.12 0.92), whereas the other factors above showed an inverse association. In the external validation, the concordance index was 0.97 at 1 year and decreased to 0.66 at 3 years and to 0.59 at 5 years. Adding histological regression in the prognostic model increased the discriminative ability to 0.75 at 3 years and to 0.62 at 5 years. Finally, using a cutoff of 20% for the risk of death led to a net re-classification improvement of 15 and 11% at 3 and 5 years after diagnosis, respectively. CONCLUSIONS: Histological regression could lead to an improvement in prognostic prediction in patients with stage III-positive SLN melanoma. PMID- 29123257 TI - Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression. AB - BACKGROUND: We investigated the role of prostaglandin receptors (e.g. prostaglandin E2 receptor 2 (EP2), EP4) and the efficacy of celecoxib in urothelial tumourigenesis and cancer progression. METHODS: We performed immunohistochemistry in bladder cancer (BC) tissue microarrays, in vitro transformation assay in a normal urothelial SVHUC line, and western blot/reverse transcription-polymerase chain reaction/cell growth assays in BC lines. RESULTS: EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those who were resistant to cisplatin-based neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumours or positivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality, respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene considerably increased and decreased the expression of EP2/EP4 and phosphatase and tensin homologue (PTEN), respectively. Treatment with selective EP2/EP4 antagonist or celecoxib also resulted in prevention in 3-methylcholanthrene-induced neoplastic transformation of SVHUC cells. In BC lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression. Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines. CONCLUSIONS: EP2/EP4 activation correlates with induction of urothelial cancer initiation and outgrowth, as well as chemoresistance, presumably via downregulating PTEN expression. PMID- 29123254 TI - Implications of aging and the endoplasmic reticulum unfolded protein response on the molecular modality of breast cancer. AB - The endoplasmic reticulum (ER) is an important subcellular organelle that is involved in numerous activities required to achieve and maintain functional proteins in addition to its role in the biosynthesis of lipids and as a repository of intracellular Ca2+. The inability of the ER to cope with protein folding beyond its capacity causes disturbances that evoke ER stress. Cells possess molecular mechanisms aimed at clearing unwanted cargo from the ER lumen as an adaptive response, but failing to do so navigates the system towards cell death. This systemic approach is called the unfolded protein response. Aging insults cells through various perturbations in homeostasis that involve curtailing ER function by mitigating the expression of its resident chaperones and enzymes. Here the unfolded protein response (UPR) cannot protect the cell due to the weakening of its protective arm, which exacerbates imbalanced homeostasis. Aging predisposed breast malignancy activates the UPR, but tumor cells maneuver the mechanistic details of the UPR, favoring tumorigenesis and thereby eliciting a treacherous condition. Tumor cells exploit UPR pathways via crosstalk involving various signaling cascades that usher tumor cells to immortality. This review aims to present a collection of data that can delineate the missing links of molecular signatures between aging and breast cancer. PMID- 29123258 TI - Prognostic impact and concordance of TERT promoter mutation and protein expression in matched primary and metastatic cutaneous melanoma. AB - BACKGROUND: TERT promoter mutations are frequent in melanoma. Here we analysed the concordance and prognostic impact of TERT mutation and telomerase reverse transcriptase (TERT) protein expression in a large melanoma series. METHODS: In 194 primary nodular melanomas with 72 matched loco-regional metastases, TERT promoter mutation status was assessed by Sanger sequencing and TERT protein expression by immunohistochemistry. RESULTS: TERT mutations were found in 68% of primary melanomas and 64% of metastases, and the mutation status was discordant between primary tumour and metastasis in 24% of the cases. 6 of the 10 cases with discordant and wild-type metastases were also TERT wild type when re-tested in other intra-tumour regions, whereas 4 cases were mutation positive. TERT-mutated tumours tended to be thicker, have a higher mitotic count and higher patient age than TERT wild-type cases, but there was no significant association with reduced survival. TERT protein expression did not correlate with mutation status, but showed a similar discordancy between the primary and first metastatic lesion, and was significantly associated with reduced survival. CONCLUSIONS: TERT promoter mutations showed inter- and intra-tumoural discordancy, whereas only expression of TERT protein was associated with reduced patient survival. PMID- 29123259 TI - Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. AB - BACKGROUND: Inflammation and immune characteristics of the tumour microenvironment have therapeutic significance. The aim of this study was to investigate the clinical impact on disease progression in human extrahepatic cholangiocarcinoma (ECC). METHODS: A total of 114 consecutive ECC patients with curative resection between 2000 and 2014 were enrolled. Tumour infiltrating CD66b+ neutrophils (TANs; tumour associated neutrophils), CD163+ M2 macrophages (TAMs; tumour associated macrophages), CD8+ T cells, and FOXP3+ regulatory T cells (Tregs) were assayed by immunohistochemistry, and their relationships with patient clinicopathological characteristics and prognosis were evaluated. RESULTS: Tumour associated neutrophils were inversely correlated with CD8+ T cells (P=0.0001) and positively correlated with Tregs (P=0.001). High TANs (P=0.01), low CD8+ T cells (P=0.02), and high Tregs (P=0.04) were significantly associated with poor overall survival (OS). A high-risk signature, derived from integration of intratumoural inflammatory and immune cells, was significantly associated with poor recurrence-free survival (P=0.01) and OS (P=0.0008). A high risk signature was correlated with postoperative distant metastases. Furthermore, a high-risk signature was related to the resistance to gemcitabine-based chemotherapy used after recurrence. CONCLUSIONS: Our data showed that tumour infiltrating inflammatory and immune cells may play a pivotal role in ECC progression and a high-risk signature predicted poor prognosis in ECC patients. PMID- 29123262 TI - Morphomolecular pathology: setting the framework for a new generation of pathologists. PMID- 29123261 TI - A new panel of pancreatic cancer biomarkers discovered using a mass spectrometry based pipeline. AB - BACKGROUND: Pancreatic carcinoma (PC) is an aggressive malignancy that lacks strategies for early detection. This study aimed to develop a coherent, high throughput and non-discriminatory pipeline for the novel clinical biomarker discovery of PC. METHODS: We combined mass spectrometry (MS)-intensive methods such as isobaric tags for relative and absolute quantitation with two-dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS), 1D-targeted LC MS/MS, prime MRM (P-MRM) and stable isotope dilution-based MRM (SID-MRM) to analyse serum samples from healthy people (normal control, NC), patients with benign diseases (BD) and PC patients to identify novel biomarkers of PC. RESULTS: On the basis of the newly developed pipeline, we identified >1000 proteins, verified 142 differentially expressed proteins and finally targeted four proteins for absolute quantitation in 100 serum samples. The novel biomarker panel of apolipoprotein E (APOE), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), apolipoprotein A-I (APOA1), apolipoprotein L1 (APOL1), combining with CA19-9, statistically-significantly improved the sensitivity (95%) and specificity (94.1%), outperforming CA19-9 alone, for the diagnosis of PC. CONCLUSIONS: We developed a highly efficient pipeline for biomarker discovery, verification and validation, with each step systematically informing the next. A panel of proteins that might be clinically relevant biomarkers for PC was found. PMID- 29123260 TI - Combining DNA damaging therapeutics with immunotherapy: more haste, less speed. AB - The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity. PMID- 29123265 TI - IGF-1R: SUMO-ing its weight in chemoresistant colorectal cancer. PMID- 29123264 TI - Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma? AB - BACKGROUND: Irrespective of the underlying aetiology, 90% of hepatocellular carcinomas arise and progress on a background of chronic inflammation. We have explored the independent prognostic value of circulating inflammatory cells. METHODS: Peripheral blood count data sets from 583 consecutive patients presenting to a single UK centre (2000-2010) were analysed for associations with tumour stage, liver function, performance status (PST) and survival. Validation was in an independent Hong Kong cohort (585 patients; 2007-2013). RESULTS: In both UK and Hong Kong cohorts, neutrophils, platelets, lymphocytes, the neutrophil/lymphocyte ratio (NLR) and the Systemic Immune-Inflammation Index (SII) correlated stepwise, either increasing or decreasing (lymphocytes), with tumour node metastasis (TNM) and Childs-Pugh stage, PST and consequently with the combined Barcelona Clinic for Liver Cancer stage. Survival analyses confirmed the NLR and SII as highly significant prognostic biomarkers. Focused on individual cell types, only the neutrophil count was independently associated with both TNM stage and PST, as well as being significantly and independently associated with poorer survival. CONCLUSIONS: In this study of 1168 patients, neutrophils alone, rather than lymphocytes or platelets, were independently associated with outcome. These data support further characterisation of a potentially distinctive role for neutrophils as facilitators of tumour progression and deteriorating performance. PMID- 29123266 TI - Sox5 contributes to prostate cancer metastasis and is a master regulator of TGF beta-induced epithelial mesenchymal transition through controlling Twist1 expression. AB - BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is one of the main contributors to the death of prostate cancer patients. To date, the detailed molecular mechanisms underlying mCRPC are unclear. Given the crucial role of epithelial-mesenchymal transition (EMT) in cancer metastasis, we aimed to analyse the expression and function of Transforming growth factor-beta (TGF-beta) signal associated protein named Sox5 in mCRPC. METHODS: The protein expression levels were analysed by western blot, immunohistochemistry and immunofluorescence. Luciferase reporter assays and chromatin immunoprecipitation were employed to validate the target of Sox5. The effect of Smad3/Sox5/Twist1 on PCa progression was investigated in vitro and in vivo. RESULTS: Here, we found that TGF-beta induced EMT was accompanied by increased Sox5 expression. Interestingly, knockdown of Sox5 expression attenuated EMT induced by TGF-beta signalling. Furthermore, we demonstrated that Smad3 could bind to the promoter of Sox5 and regulate its expression. Mechanistically, Sox5 could bind to Twist1 promoter and active Twist1, which initiated EMT. Importantly, knockdown of Sox5 in prostate cancer cells resulted in less of the mesenchymal phenotype and cell migration ability. Furthermore, targeting Sox5 could inhibit prostate cancer progression in a xenograft mouse model. In clinic, patients with high Sox5 expression were more likely to suffer from metastases, and high Sox5 expression also has a lower progression-free survival and cancer specific-survival in clinic database. CONCLUSIONS: Therefore, we propose a new mechanism in which Smad3/Sox5/Twist1 promotes EMT and contributes to PCa progression. PMID- 29123268 TI - Special feature: 'We need to get the fundamentals right'. PMID- 29123263 TI - Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer. AB - BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance. PMID- 29123269 TI - Case report: Oral medicine: Diagnostic overshadowing. PMID- 29123271 TI - New guidance on dementia-friendly dentistry. PMID- 29123270 TI - Patient safety: Paraffin-based products. PMID- 29123267 TI - BPIFB1 (LPLUNC1) inhibits migration and invasion of nasopharyngeal carcinoma by interacting with VTN and VIM. AB - BACKGROUND: Bactericidal/Permeability-increasing-fold-containing family B member 1 (BPIFB1, previously termed LPLUNC1) is highly expressed in the nasopharynx, significantly downregulated in nasopharyngeal carcinoma (NPC), and associated with prognosis in NPC patients. Because metastasis represents the primary cause of NPC-related death, we explored the role of BPIFB1 in NPC migration and invasion. METHODS: The role of BPIFB1 in NPC metastasis was investigated in vitro and in vivo. A co-immunoprecipitation assay coupled with mass spectrometry was used to identify BPIFB1-binding proteins. Additionally, western blotting, immunofluorescence, and immunohistochemistry allowed assessment of the molecular mechanisms associated with BPIFB1-specific metastatic inhibition via vitronectin (VTN) and vimentin (VIM) interactions. RESULTS: Our results showed that BPIFB1 expression markedly inhibited NPC cell migration, invasion, and lung-metastatic abilities. Additionally, identification of two BPIFB1-interacting proteins, VTN and VIM, showed that BPIFB1 reduced VTN expression and the formation of a VTN integrin alphaV complex in NPC cells, leading to inhibition of the FAK/Src/ERK signalling pathway. Moreover, BPIFB1 attenuated NPC cell migration and invasion by inhibiting VTN- or VIM-induced epithelial-mesenchymal transition. CONCLUSIONS: This study represents the first demonstration of BPIFB1 function in NPC migration, invasion, and lung metastasis. Our findings indicate that re expression of BPIFB1 might represent a useful strategy for preventing and treating NPC. PMID- 29123273 TI - In-vivo imaging of the microvasculature of the soft tissue margins of osteonecrotic jaw lesions. AB - Introduction Given the increasing incidence of medication-related jaw osteonecrosis, and recognition of the mucosal blood supply's importance, we have developed a non-invasive Real Time Optical Vascular Imaging (RTOVI) instrument. Imaging the red blood cells within the sub-mucosal capillary networks demonstrates the microcirculatory anatomy. We report a small trial, demonstrating the technique's viability, examining mucosal microcirculatory changes adjacent to osteonecrotic lesions.Aims Imaging the microvasculature of soft tissue margins of patients' exposed necrotic bone lesions in situ was intended to provide unique observational as well as quantitative data, using an image analysis routine, based on ImageJ software. Our interest was to evaluate whether this could offer valuable information for complex wound margin management.Methods Four osteoradionecrosis and four medication-related osteonecrosis patients (M:F 1:1 mean 68.25 years) were enrolled under the NRES Ethics 11/LON/0354 and KCL Research Ethics Committee (REC) BDM/14/15-14 approvals. Microvascular images from mucosal margins of exposed mandibular osteonecrosis lesions were compared with equivalent images from both uninvolved contralateral mucosa and similar mucosal sites in four healthy subjects.Results We demonstrated narrow hypo-vascularised oedematous lesion margins surrounded by a concentric inflammatory band and normal mucosa beyond. Parameters reporting individual capillary shape, via mean percentage of occupancy per capillary per field of view and capillary loop aspect ratio, differed significantly between groups (ANOVA, p = 0.0002 and p = 0.04 respectively). Values reporting capillary number and area showed expected changes but did not reach statistical significance.Conclusion This pilot study demonstrated the feasibility of mucosal microvascular imaging in assessing the microvascular changes found in the soft tissues at the margins of osteonecrotic lesions, with potential to inform therapeutic interventions and clinical decisions to continue or modify regime strategies at the earliest opportunity. Given the increasing incidence of medication-related jaw osteonecrosis, and the recognition of the importance of mucosal blood supply, we developed a non invasive instrument demonstrating microcirculation anatomy by imaging transiting red blood cells. PMID- 29123274 TI - Oral health: Asthma and oral candidiasis. PMID- 29123279 TI - Dentistry - as was. PMID- 29123280 TI - Funding fair for potential PhD students. PMID- 29123281 TI - Free resources on oral health during pregnancy. PMID- 29123282 TI - Diagnosis and management of oral candidosis. AB - Candida is a fungus (yeast) that is generally regarded as a normal and harmless member of the oral microbiome in humans. Should host defences against these commensals be compromised in any way then Candida can cause clinical signs and symptoms, which manifest as distinct forms of oral candidosis (candidiasis). Candida albicans is the most frequently isolated candidal species from the oral cavity, although a range of non-C. albicans Candida species are being increasingly encountered. The basic principle of the management of candidosis is to identify and eliminate any underlying host predisposing factor. However, in many cases, antifungal therapy will also be required as part of initial management. This article will provide an overview of the isolation, identification and pathogenicity of Candida species encountered within the mouth and relate these to clinical management of oral candidosis. PMID- 29123290 TI - Oral medicine. PMID- 29123291 TI - A dentist's life: 'This is the first disruptive oral health product to come out for a long time'. PMID- 29123293 TI - Dental history: Teeth as reliquaries. PMID- 29123302 TI - Eclectic patients. PMID- 29123296 TI - Oral manifestations of systemic disease. AB - While the majority of disorders of the mouth are centred upon the direct action of plaque, the oral tissues can be subject to change or damage as a consequence of disease that predominantly affects other body systems. Such oral manifestations of systemic disease can be highly variable in both frequency and presentation. As lifespan increases and medical care becomes ever more complex and effective it is likely that the numbers of individuals with oral manifestations of systemic disease will continue to rise. The present article provides a succinct review of oral manifestations of systemic disease. In view of this article being part of a wider BDJ themed issue on the subject of oral medicine, this review focuses upon oral mucosal and salivary gland disorders that may arise as a consequence of systemic disease. PMID- 29123299 TI - Alternative sugars: Yacon syrup (nectar). PMID- 29123304 TI - Cosmetic dentistry: An excellent review. PMID- 29123305 TI - The development and implementation of a biopsy safety strategy for oral medicine. AB - The development and implementation of a biopsy safety strategy is described in this article. Analysis of previous adverse incidents relating to biopsies acted as a catalyst to review our biopsy pathway at Liverpool University Dental Hospital. Input from all staff involved enabled us to develop a biopsy safety strategy which was divided into five stages: preoperative assessment of patient and procedure, team briefings, biopsy surgical safety checklist, surgical removal and handling of biopsy specimens, and post-biopsy follow-up. It is hoped that other clinical teams will take the opportunity to review their own biopsy processes, in the light of our experience. PMID- 29123309 TI - Oral dryness and Sjogren's: an update. AB - Oral dryness is a very common condition presenting to a general dental practitioner or hospital specialist. The most common cause of oral dryness is drug related, however, patients with Sjogren's syndrome, a multisystem autoimmune condition, may present to their dentist rather than their GP complaining of dry mouth and dry eyes. This update article explores the causes of oral dryness and how to manage it. The update on Sjogren's syndrome explains the latest relevant diagnostic criteria, presenting signs, symptoms, investigations and management principles. PMID- 29123310 TI - Worldwide pattern of antibiotic prescription in endodontic infections. AB - Antibiotic prescribing practices are frequently inappropriate in endodontic therapy. PMID- 29123312 TI - Anaesthesia and sedation: No such thing. PMID- 29123314 TI - Retraction Note: Socket preservation. PMID- 29123313 TI - Case report: Oral surgery: Bone exposure. PMID- 29123316 TI - Do patients at risk of infective endocarditis need antibiotics before dental procedures? AB - Individual risk assessment is needed for each patient at risk of infective endocarditis. PMID- 29123317 TI - Antibiotic resistance. AB - New antibiotics and further education about prescribing are needed. PMID- 29123318 TI - Diagnostic adjuncts on oral cancer and precancer: an update for practitioners. AB - A variety of devices and techniques are now available to aid the clinician in visualising clinical changes that may be found in the oral cavity. These techniques can now be applied at chairside to characterise these changes and many offer a real time result at the point of care. They may assist in a practitioner referring a case earlier to a specialist to undertake further investigations. The translational value of the research published so far has been limited as these technologies have not been adapted for routine use in primary care. This review aims to examine the utility of these adjunctive aids in clinical practice based on the current available evidence. PMID- 29123319 TI - Help shape the future of oral and dental health research. PMID- 29123322 TI - Hypoxia-induced reactive oxygen species mediate N-cadherin and SERPINE1 expression, EGFR signalling and motility in MDA-MB-468 breast cancer cells. AB - One of the hallmarks of the tumour microenvironment is hypoxia resulting from increased oxygen consumption by proliferative cancer cells and altered vasculature. Hypoxic tension initiates various cellular signals and can drive epithelial to mesenchymal transition (EMT), a process important in cancer progression. In this study, using the antioxidant N-acetylcysteine (NAC), we show that hypoxia-induced reactive oxygen species (ROS) in MDA-MB-468 breast cancer cells, selectively regulate hypoxia-induced increases in N-cadherin and SERPINE1, two proteins involved in cell adhesion. Treatment of cells with NAC also attenuated hypoxia-mediated activation of EGFR, but did not have any effect on hypoxia-mediated induction of HIF1alpha. Exogenous hydrogen peroxide phenocopied the effects of hypoxia on N-cadherin and SERPINE1 expression and EGFR activation, suggesting its possible involvement in these hypoxia-mediated events. Reflective of their effect on cell adhesion proteins and EGFR (associated with migratory phenotypes), NAC also reduced cell migration under hypoxic conditions, a crucial event in metastasis. Our findings suggest a selective role for redox signalling in the regulation of specific components of the responses to hypoxia and induction of EMT in breast cancer cells. This study provides new evidence supporting the potential of targeting ROS as a therapeutic strategy for the control of breast cancer metastasis. PMID- 29123323 TI - Enamel Resistance to Demineralization After Bracket Debonding Using Fluoride Varnish. AB - The aim of this study was to evaluate the elemental content and morphology of enamel subjected to demineralization cycles after bracket debonding, adhesive remnant removal, and application of a fluoride varnish. 125 bovine teeth were divided into five groups (n = 25): 1) Intact enamel; 2) Intact enamel + demineralization cycles (DC); 3) Enamel after adhesive removal; 4)Enamel after adhesive removal + DC; 5) Enamel after adhesive removal + Profluorid + DC. The weight percentages of calcium (Ca), phosphorous (P) and fluoride (F) were calculated using energy dispersive X-ray spectroscopy (EDX). Samples were observed under scanning electron microscopy (SEM). Data were analyzed using Kruskal-Wallis and Mann-Whitney test. The weight percentages of Ca and P in Group 1 were significantly higher than Groups 2, 4, and 5. The weight percentages of Ca and P in Group 2 were significantly higher than Groups 4 and 5. Group 3 presented significantly higher percentages of Ca and P than Group 4. Group 5 showed a significantly higher percentage of Ca than Group 4. The presence of F was detected in Group 5. SEM images showed more signs of demineralization in Group 4 than Group 5. Fluoride varnish application may protect enamel from demineralization after bracket debonding. PMID- 29123324 TI - Three decades of Landsat-derived spring surface water dynamics in an agricultural wetland mosaic; Implications for migratory shorebirds. AB - Satellite measurements of surface water offer promise for understanding wetland habitat availability at broad spatial and temporal scales; reliable habitat is crucial for the persistence of migratory shorebirds that depend on wetland networks. We analyzed water extent dynamics within wetland habitats at a globally important shorebird stopover site for a 1983-2015 Landsat time series, and evaluated the effect of climate on water extent. A range of methods can detect open water from imagery, including supervised classification approaches and thresholds for spectral bands and indices. Thresholds provide a time advantage; however, there is no universally superior index, nor single best threshold for all instances. We used random forest to model the presence or absence of water from >6200 reference pixels, and derived an optimal water probability threshold for our study area using receiver operating characteristic curves. An optimized mid-infrared (1.5-1.7 MUm) threshold identified open water in the Sacramento Valley of California at 30-m resolution with an average of 90% producer's accuracy, comparable to approaches that require more intensive user input. SLC off Landsat 7 imagery was integrated by applying a customized interpolation that mapped water in missing data gaps with 99% user's accuracy. On average we detected open water on ~26000 ha (~3% of the study area) in early April at the peak of shorebird migration, while water extent increased five-fold after the migration rush. Over the last three decades, late March water extent declined by ~1300 ha per year, primarily due to changes in the extent and timing of agricultural flood-irrigation. Water within shorebird habitats was significantly associated with an index of water availability at the peak of migration. Our approach can be used to optimize thresholds for time series analysis and near real-time mapping in other regions, and requires only marginally more time than generating a confusion matrix. PMID- 29123325 TI - Personality Correlates of Risky Health Outcomes: Findings from a Large Internet Study. AB - Numerous studies have documented the effects of personality on health outcomes. However, which traits are most relevant to health, and the precise magnitude of their effects, is inconsistent across studies. The present study used a large sample (N=460,172) to replicate and extend the relations between the Big Five and three health-related outcomes: self-reported health, body mass index, and substance use. Low Conscientiousness predicted all outcomes, indicating that individuals who are less responsible and less self-controlled tend to report poorer health, be more overweight, and engage in more substance use. In addition, individuals who were more emotionally unstable (high Neuroticism) reported poorer health, and individuals prone to seek out social experiences and rewards (high Extraversion) engaged in more frequent substance use. PMID- 29123326 TI - Vibrations transmitted from human hands to upper arm, shoulder, back, neck, and head. AB - : Some powered hand tools can generate significant vibration at frequencies below 25 Hz. It is not clear whether such vibration can be effectively transmitted to the upper arm, shoulder, neck, and head and cause adverse effects in these substructures. The objective of this study is to investigate the vibration transmission from the human hands to these substructures. Eight human subjects participated in the experiment, which was conducted on a 1-D vibration test system. Unlike many vibration transmission studies, both the right and left hand arm systems were simultaneously exposed to the vibration to simulate a working posture in the experiment. A laser vibrometer and three accelerometers were used to measure the vibration transmitted to the substructures. The apparent mass at the palm of each hand was also measured to help in understanding the transmitted vibration and biodynamic response. This study found that the upper arm resonance frequency was 7-12 Hz, the shoulder resonance was 7-9 Hz, and the back and neck resonances were 6-7 Hz. The responses were affected by the hand-arm posture, applied hand force, and vibration magnitude. The transmissibility measured on the upper arm had a trend similar to that of the apparent mass measured at the palm in their major resonant frequency ranges. The implications of the results are discussed. Relevance to industry: Musculoskeletal disorders (MSDs) of the shoulder and neck are important issues among many workers. Many of these workers use heavy-duty powered hand tools. The combined mechanical loads and vibration exposures are among the major factors contributing to the development of MSDs. The vibration characteristics of the body segments examined in this study can be used to help understand MSDs and to help develop more effective intervention methods. PMID- 29123327 TI - A New Test Bench System for Hammer Drills: Validation for Handle Vibration. AB - Workers' can be exposed to high levels of hand vibration when drilling into concrete or rock using hammer drills; exposures that can cause hand arm vibration syndrome. Exposure levels may be reduced by different drill and bit designs and drilling methods, but these interventions have not been systematically evaluated. The purpose of this project was to develop a robotic test bench system for measuring handle vibration on drills in order to compare differences in drill designs, power sources, bit designs and drilling methods. The test bench is a departure from the ISO method for measuring drill handle vibration (ISO 28927 10), which requires drilling by humans. The test bench system was designed to repeatedly drill into concrete blocks under force control while productivity and handle vibration were measured. Handle vibration levels with different drills and bit sizes were similar to those collected following ISO methods. A new robotic test bench system for measuring handle vibration is presented and validated against ISO methods and demonstrates dynamic properties similar to human drilling. PMID- 29123328 TI - Induced defence to grazing by vertebrate herbivores: uncommon or under investigated? AB - There are many examples of macroalgae inducing defence in response to small invertebrate herbivores like amphipods, isopods, and gastropods but few cases of induction in response to vertebrate macrograzers like herbivorous fishes. This may be because larger grazers rapidly consume large quantities of seaweed before induction can occur, thus selecting for constitutive rather than induced defences. Alternatively, the pattern could occur because induction due to feeding by macrograzers is less commonly investigated. In Fiji, field assays with the brown macroalga Sargassum polycystum demonstrated that thalli growing in marine protected areas (MPAs) with abundant herbivorous fishes were significantly less palatable than those growing in adjacent fished areas (non-MPAs) with few herbivorous fishes. This significant preference occurred in 11 of 13 trials over 5 time periods and across 3 pairs of MPAs and spatially associated non-MPAs. This preference was not positively associated with algal nitrogen content or with the toughness of algal fronds. When S. polycystum ramets were taken from the non-MPA and half were partially grazed by fishes while the other half were protected from grazing, new growth from the controls was strongly preferred to new growth from the previously grazed ramets although these fronds originated from the same holdfast. This suggests that S. polycystum upregulates defences (probably chemical) in response to grazing by herbivorous fishes. This is one of the few published examples of induction of macroalgal defence in response to feeding by large, mobile grazers. It is unclear whether induced defences against fishes are rare or just under-investigated. PMID- 29123329 TI - Automatic Image Registration of Multi-Modal Remotely Sensed Data with Global Shearlet Features. AB - Automatic image registration is the process of aligning two or more images of approximately the same scene with minimal human assistance. Wavelet-based automatic registration methods are standard, but sometimes are not robust to the choice of initial conditions. That is, if the images to be registered are too far apart relative to the initial guess of the algorithm, the registration algorithm does not converge or has poor accuracy, and is thus not robust. These problems occur because wavelet techniques primarily identify isotropic textural features and are less effective at identifying linear and curvilinear edge features. We integrate the recently developed mathematical construction of shearlets, which is more effective at identifying sparse anisotropic edges, with an existing automatic wavelet-based registration algorithm. Our shearlet features algorithm produces more distinct features than wavelet features algorithms; the separation of edges from textures is even stronger than with wavelets. Our algorithm computes shearlet and wavelet features for the images to be registered, then performs least squares minimization on these features to compute a registration transformation. Our algorithm is two-staged and multiresolution in nature. First, a cascade of shearlet features is used to provide a robust, though approximate, registration. This is then refined by registering with a cascade of wavelet features. Experiments across a variety of image classes show an improved robustness to initial conditions, when compared to wavelet features alone. PMID- 29123330 TI - Markov Logic Networks for Adverse Drug Event Extraction from Text. AB - Adverse drug events (ADEs) are a major concern and point of emphasis for the medical profession, government, and society. A diverse set of techniques from epidemiology, statistics, and computer science are being proposed and studied for ADE discovery from observational health data (e.g., EHR and claims data), social network data (e.g., Google and Twitter posts), and other information sources. Methodologies are needed for evaluating, quantitatively measuring, and comparing the ability of these various approaches to accurately discover ADEs. This work is motivated by the observation that text sources such as the Medline/Medinfo library provide a wealth of information on human health. Unfortunately, ADEs often result from unexpected interactions, and the connection between conditions and drugs is not explicit in these sources. Thus, in this work we address the question of whether we can quantitatively estimate relationships between drugs and conditions from the medical literature. This paper proposes and studies a state-of-the-art NLP-based extraction of ADEs from text. PMID- 29123331 TI - Aptamer-functionalized hydrogel for self-programmed protein release via sequential photoreaction and hybridization. AB - A dynamic hydrogel that sequentially responds to two independent but interrelated physical and biomolecular signals was reported in this work. Once hit by an external light signal, an immobilized internal molecular signal is activated and freed via photoreaction; and subsequently the freed molecular signal works as a self-programming factor of the hydrogel to induce the dissociation of a biomolecular complex to release protein via hybridization reaction. Notably, pulsatile external light input can be converted to periodical protein output from the hydrogel to regulate cell migration. Thus, this hydrogel holds potential as a self-programming platform for biological and biomedical applications such as controlled release of bioactive substances. PMID- 29123332 TI - Target-or-Clear Zirconium-89 Labeled Silica Nanoparticles for Enhanced Cancer Directed Uptake in Melanoma: A Comparison of Radiolabeling Strategies. AB - Designing a nanomaterials platform with high target-to-background ratios has long been one of the major challenges in the field of nanomedicine. Here, we introduce a "target-or-clear" multifunctional nanoparticle platform that demonstrates high tumor-targeting efficiency and retention while minimizing off-target effects. Encouraged by the favorable preclinical and clinical pharmacokinetic profiles derived after fine-tuning surface chemical properties of radioiodinated (124I, t1/2 = 100.2 h) ultrasmall cRGDY-conjugated fluorescent silica nanoparticles (C dots), we sought to investigate how the biological properties of these radioconjugates could be influenced by the conjugation of radiometals such as zirconium-89 (89Zr, t1/2 = 78.4 h) using two different strategies: chelator-free and chelator-based radiolabeling. The attachment of 89Zr to newer, surface aminated, integrin-targeting C' dots using a two-pot synthesis approach led to favorable pharmacokinetics and clearance profiles as well as high tumor uptake and target-to-background ratios in human melanoma models relative to biological controls while maintaining particle sizes below the effective renal glomerular filtration size cutoff <10 nm. Nanoconjugates were also characterized in terms of their radiostability and plasma residence half-lives. Our 89Zr-labeled ultrasmall hybrid organic-inorganic particle is a clinically promising positron emission tomography tracer offering radiobiological properties suitable for enhanced molecularly targeted cancer imaging applications. PMID- 29123333 TI - Cognitive Profiles Associated With Responsiveness to Fraction Intervention. AB - This study examined differences in cognitive processing between 4th-grade students who respond adequately, as opposed to inadequately, to intervention on 3 fraction outcomes: number-line estimation, calculation, and word problems. Students were assessed on 7 cognitive processes and on the 3 fraction outcomes. Students were grouped as adequate or inadequate responders, using as the cut point the control-group mean on pre-to-post improvement on the relevant measure. Between-group differences identified reasoning, concept formation, and listening comprehension related to all 3 fraction outcomes. On the number-line outcome, within-group profile analysis indicated that inadequate responders experienced low reasoning ability relative to their other forms of cognitive processing. PMID- 29123334 TI - alpha-VINYLLYSINE AND alpha-VINYLARGININE ARE TIME-DEPENDENT INHIBITORS OF THEIR COGNATE DECARBOXYLASES. AB - (+/-)-alpha-Vinyllysine and (+/-)-alpha-vinylarginine display time-dependent inhibition of L-lysine decarboxylase from B. cadaveris, and L-arginine decarboxylase from E. coli, respectively. A complete Kitz-Wilson analysis has been performed using a modification of the Palcic continuous UV assay for decarboxylase activity. PMID- 29123335 TI - Retracted: Treadmill Training Increases SIRT-1 and PGC-1alpha Protein Levels and AMPK Phosphorylation in Quadriceps of Middle-Aged Rats in an Intensity-Dependent Manner. AB - [This retracts the article DOI: 10.1155/2014/987017.]. PMID- 29123336 TI - The Indian College of Palliative Medicine: A Concept in Evolution. PMID- 29123337 TI - Effect of Aerobic Exercise on Cancer-related Fatigue. AB - Background: Fatigue is the most common side effect of cancer treatment with chemotherapy and/or radiation therapy, selected biologic response modifiers. The main purpose of this study is to evaluate the effects of aerobic exercise on cancer-related fatigue in patients of the solid tumor after chemotherapy and radiotherapy. Methods: After screening for cancer-related fatigue, 34 patients fulfilled the inclusive criteria and were assigned into two groups (n = 17 recruited in the intervention group and n = 17 in control group). The intervention group received aerobic exercise program which included treadmill walking with low to moderate intensity (50%-70% of maximum heart rate), for 20-40 min/day for 5 days/week. Control group were taught stretching exercises of hamstrings, gastrocnemius, and soleus (to be done at home) and were encouraged to remain active. Outcome measures such as brief fatigue inventory (BFI), 6-min walk test, and functional assessment of cancer therapy-general (FACT-G) were taken at baseline and after 6-weeks. Results: The data were analyzed using the Wilcoxon matched-pairs signed rank test for within group and Mann-Whitney U-test for between group comparisons. The results of this study showed that there was a significant reduction in cancer-related fatigue BFI score (P < 0.0001,), also there was significant improvement in the physical performance as in 6-min walk distance (P < 0.0001) and quality of life, FACT-G score (P = 0.0001). Conclusion: Aerobic exercise for 6 weeks has beneficial effects on cancer-related fatigue in patients with solid tumor after chemotherapy and/or radiotherapy. PMID- 29123338 TI - Commentary. PMID- 29123339 TI - Hospital Workers' Confidence for End-of-Life Decisions in their Family: A Multicenter Study. AB - Aims: To study whether health-care workers feel capable of making resuscitation decisions for their own families, the confidence in their family to represent their own preferences, and if some health-care workers feel greater confidence in their ability to undertake such decisions for their family than others. Methods: An anonymous survey conducted among health-care workers of nine institutions in North and Central America. The self-administered questionnaire included demographic and professional characteristics, attitudes, personal preferences, and value judgments on the topic of resuscitation. Results: Eight hundred and fifty-eight surveys were completed; 21.1% by physicians, 37.2% by nurses, and 41.7% by other health-care. Most of the health-care workers (83.5%) stated that they should be unable to determine their own code status and they would allow their family or spouse/significant other to make this decision for themselves. Physicians felt significantly more capable of making a decision regarding the code status of a close family member than other hospital workers (P = 0.019). Professionals who chose to not undergo cardiopulmonary resuscitation were less likely to feel capable of determining the code status of their family. Conclusions: Most of the health-care workers feel capable of making code status decisions for a close family member and most feel equally comfortable having their family or spouse/significant other represent their code status preference should they be incapacitated. There is considerable reciprocity between the two situations. Physicians feel more confident in their ability to make code status decisions for their loved ones than other health-care workers. Regardless of profession, a personal preference for do not attempt resuscitation status is related to less confidence. PMID- 29123340 TI - The Palliative Performance Scale Predicts Survival among Emergency Department Patients, Minia, Egypt. AB - Background: Emergency department (ED) physicians provide care to patients with a wide range of prognoses, and must develop care plans that anticipate patient's survival. However, the tools available to guide care planning had limited data to support their use. There is a new concern to understand if palliative care (PC) should be offered in the ED and the Palliative Performance Scale (PPS), a screening tool used in other settings in PC, has been little used in the ED. Aim: The aim of this study is to assess the prognostic value of the PPS in predicting 1, 3 and 6 months survival in patients admitted through the ED. Design: This was a prospective, cohort study. Subjects and Methods: We evaluated 147 patients at the age of 35 years and more admitted through the ED of Minia University hospital from May 1, 2016 to June 31, 2016. Each patient's PPS score was evaluated initially in the ED, with follow-up assessments of survival at 1, 3, and 6 months. Results: Baseline PPS for the 147 patients was 50. The PPS score was a strong predictor of survival (Log-rank test of Kaplan-Meir P < 0.0001). Patients with an initial PPS score of 40 or less were less likely to survive at 6 months. Conclusion: The PPS score may predict survival in patients admitted to the hospital through the ED. The ease of use holds promise that the use of the PPS in the ED may help ED physicians predict survival and plan for a better decision. PMID- 29123341 TI - Effect of Expressed Breast Milk versus Swaddling versus Oral Sucrose Administration on Pain Associated with Suctioning in Preterm Neonates on Assisted Ventilation: A Randomized Controlled Trial. AB - Objective: The objective of our study was to assess the pain associated with suctioning in preterm neonates on assisted ventilation and comparing the use of expressed breast milk (EBM), sucrose, and swaddling to alleviate pain. Methods: Study design: A randomized controlled clinical trial. Inclusion Criteria: Preterm neonates on assisted ventilation. Exclusion Criteria: Major congenital anomalies and severe encephalopathy. Study Duration and Site: 6 months in level III neonatal Intensive Care Unit. In the first phase, we used premature infant pain profile (PIPP) score to assess pain associated with suctioning in preterm neonates on assisted ventilation. In the second phase, the effect of EBM, swaddling, and sucrose on pain relief during suctioning in neonates on assisted ventilation was assessed. Results: There was a significant increase in pain associated with suctioning in preterm neonates on assisted ventilation (preprocedure PIPP score 7.90 +/- 2.50; procedural PIPP score 13.63 +/- 2.57; P < 0.05). The postintervention mean procedural PIPP score was not significantly different between the EBM, swaddling, and sucrose groups (P = 0.24). Conclusions: Suctioning is painful for preterm neonates on assisted ventilation. There was no difference between EBM, swaddling, and sucrose in relieving pain associated with suctioning. PMID- 29123342 TI - Palliative Care for Children with Cancer in the Middle East: A Comparative Study. AB - Introduction: High incidence rates of childhood cancer and the consequent deaths in the Middle East is one of the major reasons for the need for palliative care in these countries. Using the experiences and innovations of the other countries can provide a pattern for the countries of the region and lead to the development of palliative care in children. Therefore, the aim of this study is to compare the status of pediatric palliative care in Egypt, Lebanon, Jordan, Turkey, and Iran. Materials and Methods: This is a comparative study in which the information related to pediatric palliative care system in the target countries (from 2000 to 2016) has been collected, summarized, and classified by searching in databases, such as "PubMed, Scopus, Google scholar, Ovid, and science direct." Results: Palliative care in children in the Middle East is still in its early stages and there are many obstacles to its development, namely, lack of professional knowledge, inadequate support of policy-makers, and lack of access to opioids and financial resources. Despite these challenges, providing services at the community level, support of nongovernmental organizations (NGOs), using trained specialists and multi-disciplinary approach is an opportunity in some countries. Conclusion: Considering the necessity of the development of pediatric palliative care in the region, solutions such as training the human resources, integrating palliative care programs into the curriculum of the related fields, establishing facilitating policies in prescription and accessibility of opioids, providing the necessary support by policy-makers, doing research on assessment of palliative care quality, as well as NGOs' participation and public education are suggested. PMID- 29123343 TI - Multiple Nutritional Deficiencies in Cerebral Palsy Compounding Physical and Functional Impairments. AB - Introduction: Cerebral palsy (CP) refers to a spectrum of disorders causing physical and intellectual morbidity. Macro and micro nutrient deficiencies often contribute to the subnormal physical and mental capabilities of them. Objectives: To assess the growth, nutritional status, physical and functional ability and quality of life in cerebral palsy children and to determine any relation with their gross motor and functional capabilities. Method: The study was conducted at a Tertiary Care Centre, with the participants in the age group 1-16 years. A pretested evaluation tool was prepared which included Anthropometric measurements, tests for hemoglobin and Vitamin D estimation, evidence of micronutrient deficiencies, Dietary patterns, Epidemiological factors, Functional assessment using GMFM (Gross Motor Function Measure ) and FIM (Functional Independent Measurement) scales and Quality of life (QOL) assessment. The data was statistically analyzed. Results: Out of the 41 children, 30 had quadriplegia, 3 had hemiplegia and 8 had spastic diplegia. 34 (82.9%) were severely underweight, 35 (85.4%) had severe stunting and 38 (92.7%) had severe wasting. Micronutrient deficiencies were noted like vitamin B complex deficiency in 37 (90.2%), vitamin A deficiency in 31 (75.6%), low vitamin D levels in 27 (65.9%) and insufficient levels in 9 (22%), severe anemia in 5 (12.2%) and moderate anemia in 26 (63.4%). The gross motor and functional scores were suboptimum in the majority of patients and the care givers had significant impairment in the quality of life. Conclusion: Majority of children with cerebral palsy had multiple nutritional deficiencies, gross motor and functional disabilities. QOL of the children and their care givers were suboptimum. A comprehensive package that address dietary intake, correction of micronutrient deficiencies especially anemia and vitamin D deficiency, physical and emotional support is recommended for the wellbeing of the affected children. PMID- 29123344 TI - Parents' Knowledge and Attitude Regarding Their Child's Cancer and Effectiveness of Initial Disease Counseling in Pediatric Oncology Patients. AB - Objective: To examine parent's knowledge, attitude and psychosocial response regarding their child's cancer and treatment after initial disease counseling by doctor. Materials and Methods: Structured questionnaire based study of 43 mothers of newly diagnosed pediatric cancer patients undergoing treatment in pediatric oncology division. Mothers received initial counseling regarding their child's cancer and treatment from the doctor. Questionnaire was administered 2-6 months after initial counseling and mothers self-reported their responses. Results: 83% mothers had school level education only and 84% belonged to lower and middle socio-economic status. More than 80% mothers knew the name of their child's cancer, type of treatment received by child and approximate duration of treatment. 93% knew regarding painful procedures and 84% mothers reported knowledge about chemotherapy side effects. Hope of cure and satisfaction with treatment were reported by 90% mothers. 81% mothers reported high levels of anxiety and 66% worried regarding painful procedures. As high as 60% of parents were afraid to send their child outside to play and 40% were afraid to send their child to school. 40% mothers wanted more information regarding child's higher education, married life & fertility. On statistical analysis, mother's age, educational status or family background did not influence their knowledge and attitude. Conclusion: Relevant information about child's cancer and treatment can be imparted effectively even to mothers with school level education. This knowledge helps to instill hopeful attitude, confidence and satisfaction in parents. Anxiety and fear related to cancer persists in mothers even after the initial stress period is over. Pain related to injections and procedures is a major concern in parents. Involvement of counselor in the treating team is desirable to overcome these problems. PMID- 29123345 TI - Effect of Supportive Psychotherapy on Mental Health Status and Quality of Life of Female Cancer Patients Receiving Chemotherapy for Recurrent Disease. AB - Context: Cancer patients receiving chemotherapy for their recurrent disease often report the presence of anxiety and depression. Aims: In the study, we intended to find out the mental health status and overall quality of life (QOL) of such patients and to identify the effect of supportive psychotherapy. Subjects and Methods: Forty cancer patients undergoing second or subsequent line chemotherapy(CCT) were selected for psychotherapy session. Pre- and post psychotherapy evaluation of anxiety and depression was determined by hospital anxiety depression scale. The QOL was measured before and after psychotherapy sessions by using WHO QOL-BREF scale. Statistical Analysis Used: Statistical analysis was done by paired t-test, using SPSS V.20. Results: Among 40 patients, 17 patients had breast cancer, and the remaining had ovarian cancer. All breast cancer and 19 ovarian cancer patients were receiving 2nd line CCT. Four ovarian cancer patients were undergoing 3rd line CCT. Results indicated that mean scores (+/- standard deviation) of anxiety 13.95 (+/-4) and depression 15.5 (+/-4.4) both exceeded the cut-off score of 11 and mean score of QOL physical health 29.77 (+/-10.1), psychological health 31.3 (+/-10.1), social relationship 35.1 (+/ 9.6), and environmental condition 25.9 (+/-9.9) was below cut-off score of 60. After psychotherapy, there was significant reduction in anxiety (P < 0.01), depression (P < 0.01) and improvement on QOL physical heath (P = 0.02), psychological health (P < 0.01), environmental condition (P < 0.01), and social relationship (P < 0.01). Conclusions: Supportive psychotherapy helps to reduce the level of anxiety, depression, and increase the QOL. Therefore, psychotherapeutic intervention should be encouraged along with chemotherapy to promote positive mental health and to obtain full benefit of their physical treatment. PMID- 29123346 TI - Estimation of Need for Palliative Care among Noncancer Patients Attending a Tertiary Care Hospital. AB - Context: Palliative care services, until recently, were mainly restricted to cancer patients with incurable diseases. Hence, evaluative studies of palliative care are sparse in areas other than oncology. Aims: To estimate what proportion of patients attending the Departments of Neurology, Cardiology, and Nephrology of Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, required palliative care and to identify the palliative care needs of those patients. Settings and Design: This was an exploratory descriptive study conducted in the three departments of JIPMER. Materials and Method: There was no predetermined sample size for the study. The participants were all adult inpatients and outpatients who were in need of palliative care in the departments of Cardiology, Nephrology, and Neurology on the day of study. Statistical Analysis: Percentage distribution was used to analyze the categorical variables such as education, gender, age, patients in need of palliative care, and their needs. Results: The study showed that one in ten non-cancer patients in tertiary care hospitals may require palliative care services. Apart from issues in physical domain, a substantial proportion of participants also had issues in the psychological, emotional, and financial domains. Conclusion: This study highlights the need for incorporation and initiation of palliative care services in other non-cancer specialties in tertiary care hospitals to ensure holistic management of such cases. Counseling service has also to be rendered as part of palliative care since a good share of the patients had psychological and emotional issues. PMID- 29123347 TI - Referral Patterns of Gynecological Cancer Patients to a Palliative Medicine Unit: A 2 Years Retrospective Analysis. AB - Introduction: Patients with advanced gynecological malignancies often present with a high burden of symptoms endangering their quality of life. Objective: This study aims at assessing the symptom prevalence in patients with gynecological malignancies referred to palliative care and identify factors that predict high symptom burden. Methodology: This was a retrospective data analysis of gynecological cancer patients referred to palliative medicine department. We reviewed the electronic medical records of patients to obtain data on (1) demography (age, residence); (2) clinical information (diagnosis, stage of cancer, the reason for referral to palliative care service, symptoms, and performance status). The data were reported as frequency and percentages and analysis performed using Chi-square. P < 0.05 was considered to be statistically significant. Results: We analyzed 196 patients with advanced gynecological cancers presenting to palliative medicine department. The pain was the most common symptoms (70.04%) followed by anorexia (34.13%), constipation (28.57%), and fatigue (28.06%). There was a trend toward higher symptom burden in patients younger than 60 years. Among cancer diagnosis, patients with cervical cancer had a higher prevalence of pain (76.66%) followed by ovarian (70.79%) and endometrium (60.97%). Anorexia was the next commonly prevalent symptoms in ovarian (40.45%), endometrium (29.27%), and cervical cancer (28.33%). Conclusion: Considering the high symptom burden among advanced gynecological cancer patients it becomes imperative that patients receive adequate screening for symptoms and appropriate palliative care referral be offered to ensure overall well-being of the patients. PMID- 29123348 TI - Symptom Prevalence in Patients with Advanced, Incurable Illness in Bangladesh. AB - Context: There is a significant need for palliative care for patients living in low- and middle-income countries. The presence and intensity of physical symptoms is a major factor influencing the suffering of patients at the end of life. Objectives: The primary aim of this study was to determine the prevalence and characteristics of common physical symptoms experienced by patients with advanced, incurable illness in a developing country. Method: This study used semi structured interviews in patients with advanced cancer or HIV/AIDS in Bangladesh. Results: Pain was the most common symptom (70.6%) and was frequently reported to be severe (62.6%). Very few patients received strong opioids to treat their pain (13.7%). Other frequent symptoms included loss of appetite (23.5%) and fever (19.9%). The average number of physical symptoms reported was 3 (range: 0-23). The majority of patients rated their most recent symptom (excluding pain) as severe (64.3%), with 35.8% continuing to have severe symptom intensity despite treatment. Conclusions: This study reveals the significant burden of symptoms, and the associated suffering for patients living with incurable illness, in a developing country. Very few patients received strong opioids, despite frequently having severe pain. Frequently, the treatments that patients received did not alleviate their symptoms. Palliative care is vital for the relief of suffering for patients with advanced and incurable diseases, especially in low- and middle income countries where access to curative treatments may be limited and patients often present to medical personnel when their illness is in an advanced stage or incurable. PMID- 29123350 TI - Evaluation of Community-based Palliative Care Services: Perspectives from Various Stakeholders. AB - Background: As a part of Memorandum of Understanding with Tamil Nadu Institute of Palliative Medicine, community-based palliative care services have been initiated 2 years back in our urban field practice areas. Aim: The aim of this study was to evaluate the home care service, a major component of our community-based palliative care, with a view to identify the unmet needs of the services rendered for decision-making about the program. Materials and Methods: It was a descriptive qualitative design carried out by the authors trained in qualitative research methods. In-depth interviews were done among four patients, seven caregivers, two social workers, six nursing staffs, and six medical interns for a minimum of 20 min. Interviews were audiorecorded, transcribed verbatim, and content analysis was done manually. Ethical principles were adhered throughout the study. Results: Descriptive coding of the text information was done; later, similar codes were merged together to form the categories. Five categories under the theme of strengths and five codes under the theme of challenges of the home care services emerged out. Categories under strengths were physical management, psychological care, social support, efficient teamwork, and acceptance by the community. Codes for felt challenges were interdisciplinary collaboration, volunteer involvement, training enhancement, widening the services, and enhancing the community support. Conclusions: This review revealed the concerns of various stakeholders. There is a need for more interprofessional collaborations, where team members understand each other's roles for effective teamwork, as evident from the framework analysis. PMID- 29123349 TI - The Psychometric Properties and Factor Structure of Persian Version of Edmonton Symptom Assessment Scale in Cancer Patients. AB - Context: Edmonton Symptom Assessment Scale (ESAS) was developed to assess objective and subjective symptoms in patients with cancer in all stages of their disease. Aim: The aim of the study was to translate and determine the psychometric properties of ESAS in an Iranian population. Materials and Methods: The current study was carried out to determine reliability and validity of ESAS using 246 patients with cancer in Imam Khomeini Hospital, Ardabil, Iran. After translating the instrument to Persian, content and face validity, discriminant validity, internal consistency, and test-retest were done to determine psychometric properties of ESAS. Furthermore, the construct validity was determined using confirmatory factor analysis to evaluate factor structure of the tool in two models: single factor and three factor. Results: With regard to goodness of fit indices including comparative fit index, incremental fit index, and normed fit index, factor structure of ESAS was confirmed with one factor and nine items. Because the values of average variance extracted of each dimension were less than the square of correlation coefficients between the three dimensions of ESAS, three-factor model was not confirmed. Discriminant validity was confirmed by finding significant differences between the two groups, patients with good general and critically ill conditions. Cronbach's alpha for the overall ESAS was 0.88, and correlation between test-retest with 4-6 h interval was 0.86 (r = 0.86 P < 0001). Conclusions: This study showed that Persian version of ESAS with same factor structure mentioned in the original version is an applicable tool for assessing objective and subjective symptoms in Iranian patients with cancer. PMID- 29123351 TI - The Effect of Aromatherapy with the Essential Oil of Orange on Pain and Vital Signs of Patients with Fractured Limbs Admitted to the Emergency Ward: A Randomized Clinical Trial. AB - Background and Objective: Pain is an emotional and unpleasant experience associated with actual or potential tissue damage. The literature shows no study on the effect of aromatherapy with the essential oil of orange on unpleasant feelings of patients with fractured limbs. In this regard, this paper aims at studying the effect of aromatherapy with the essential oil of orange on patients with fractured limbs admitted to the emergency ward. Methods: Sixty patients admitted to the emergency ward of Vali-e-Asr Hospital were selected by purposive sampling method and then were divided into two groups of control and experiment by block method. This study was done in one shift work (morning or afternoon). Four drops of the orange oil were poured on a pad and were pinned with a plastic pin to the patient's collar, about 20 cm distant from head. The old pad was replaced by the new one every 1 h. The patients' pain and vital signs were checked every 1 h for at last 6 h. The data were analyzed by SPSS Version 21. Results: Forty (66.7%) patients were male and twenty (33.3%) were female. Their age average was 37.93 +/- 18.19 years old. The most fractured cases were in the scapular (11 patients [18.3%]). Friedman test showed that pain in the experiment group (P = 0.0001) decreased significantly rather than the control group (0.339). However, in vital signs, there could be found that no significant change between the two groups was seen. Conclusion: Aromatherapy with orange oil can relieve pain in patients with fractured limbs but has no effect on their vital signs. Therefore, aromatherapy with orange oil can be used as a complementary medicine in these patients. PMID- 29123352 TI - Spiritual Needs and Quality of Life of Patients with Cancer. AB - Background and Aim: Information about spiritual needs and quality of life (QoL) is limited in Iranian cancer patients. This study was conducted to determine the relationship between spiritual needs and QoL among cancer patients in Iran. Methods: This correlational study included a convenience sample of 150 eligible cancer patients who were hospitalized in the oncology wards and outpatient clinics. Using two questionnaires; the spiritual needs survey and the European Organization for Research and Treatment of Cancer QoL Questionnaire-C30 data were collected. The data were analyzed by SPSS software version 19. Results: Our findings showed that the total mean score of spiritual needs was (64.32 +/- 22.22). Among the categories, the lowest score belonged to "morality and ethics" component (2.18 +/- 1.64), and the highest score belonged to "positivity/gratitude/hope/peace" component (15.95 +/- 5.47). The mean score of QoL was (79.28 +/- 19.20). Among the categories, the lowest score belonged to "global health status" component (8.44 +/- 3.64), and the highest score belonged to "functional" component (36.57 +/- 10.28). Pearson correlation coefficient showed that spiritual needs score positively correlated with QoL (r = 0.22; P = 0.006). Conclusion: The results of the present study suggest that information about the relationship between spiritual needs and QoL in patients with cancer. It should be improve QoL to meet spiritual need of these patients. In addition, the continuous and in-service education of cancer patients and nurses who work with them can be helpful in this area. PMID- 29123353 TI - Quality of Life among Cancer Patients. AB - Introduction: Cancer is a leading cause of death. People living with cancer experience a variety of symptoms. Quality of life (QOL) is a major concern of patients with terminal cancer. Symptoms affect their QOL. Management of symptoms improves distress and QOL. Objective: The objective of the study was to assess the QOL among cancer patients. Materials and Methods: A survey was conducted among 768 cancer patients selected by a convenient sampling technique. Data was collected from cancer patients by interview technique using structured and validated interviewed schedule. Results: Out of 768 cancer patients, 30.2% patients were in the age group of 51-60 years, majority with head-and-neck cancer (40.1%), and 57.7% had stage III disease. QOL of majority of patients was influenced by their symptoms. 82.3% of them had low QOL scores. Conclusion: Cancer patients experienced many symptoms that affected their QOL. There is a need to develop interventions for effective management of symptoms that will empower the patients to have a greater sense of control over their illness and treatment and to improve the QOL. PMID- 29123354 TI - Profile of Patients Opting for Palliative Care in India. AB - Introduction: Understanding the profile of end users is a key input for designing a service. Centers that provide full-scale palliative care are few and far between in our country, and there is a need to open more centers to extend the services to a larger percentage of patients. Methods: Patient data from the inception of the center till January 2016 have been stored in a database. The data were mined, exported to Excel, and analyzed. Results: The data of 11,258 patients revealed the profile of patients, including their age, gender distribution, marital status, symptomology, and outcome. The present paper describes the profile of patients opting for palliative care in our country. Conclusions: The profile of patients registered at this center validates certain assumptions while debunking others. It is hoped that this profile gives some guidance to those desirous of setting up palliative care services. PMID- 29123355 TI - Economics of Palliative and End-of-Life Care in India: A Concept Paper. AB - Only a few studies have assessed the economic outcomes of palliative care in India. The major areas of interest include hospice care, the process and structure of care, symptom management, and palliative chemotherapy compared to best supportive care. At present, there is no definite health-care system followed in India. Medical bankruptcy is common. In situations where patients bear most of the costs, medical decision-making might have significant implications on economics of health care. Game theory might help in deciphering the underlying complexities of decision-making when considered as a two person nonzero sum game. Overall, interdisciplinary communication and cooperation between health economists and palliative care team seem necessary. This will lead to enhanced understanding of the challenges faced by each other and hopefully help develop ways to create meaningful, accurate, and reliable health economic data. These results can then be used as powerful advocacy tools to convince governments to allocate more funds for the cause of palliative care. Eventually, this will save overall costs and avoid unnecessary health-care spending. PMID- 29123356 TI - Translational Research in Oncology: Implications for Palliative Care. AB - The label "translational research" (TR) has become ever more popular in the biomedical domain in recent years. It is usually presented as an attempt to bridge a supposed gap between knowledge produced at the laboratory bench and its use at the clinical bedside. This is claimed to help society harvest the benefits of its investments in scientific research. The past decade has witnessed a remarkable acceleration in the pace of translational cancer medicine - genome sequencing of various human cancers has been broadly deployed in drug discovery programs, diagnostic tests have been developed to predict molecularly targeted anticancer agents, advent of cancer immunotherapies, an enhanced appreciation of the complex interactions that exist between tumor cells and their microenvironment have revolutionized the management of cancers. Treatment for cancer and palliative care (PC) go hand in hand and the role of TR in PC can no longer be ignored. This paper discusses about the scientific discourse of TR in cancer care and its implications for the practice of PC. It starts with a brief reconstruction of the history of the concept and subsequently unravels how the label is used in clinical/research practice. In conclusion, TR seems to be driven by a changed relationship between science and society. "Translation" has become important because society is thought to deserve a tangible return in terms of health and quality of life on its investment in basic biomedical science. PMID- 29123358 TI - Chronic Cancer Pain: Diagnostic Dilemma and Management Challenges. AB - A 32-year-old female, diagnosed case of neuroendocrine tumor of pancreas, was admitted to the pain and palliative care unit with complaints of diffuse abdominal pain which was severe in intensity with score on numerical rating scale 9/10. Pain was not relieved even after taking tablet morphine immediate release 360 mg every 4 hourly, paracetamol 500 mg 6 hourly, and gabapentin 300 mg 8 hourly. She had undergone distal pancreatectomy with splenectomy and also received multiple lines of chemotherapy. After making a diagnosis of opioid induced hyperalgesia, opioid rotation from morphine to fentanyl was done. This case report reflects various conditions where strong opioids fail to relieve cancer pain, and a multimodal approach is needed for its management. PMID- 29123359 TI - Reversal of Opioid-Induced Toxicity. AB - Opioids are commonly used for pain control in palliative care setting. Accumulation of active metabolites of opioids can cause a well-recognized toxidrome including respiratory depression (RD), decreased conscious level, pinpoint pupils, and drop in blood pressure. Opioid toxicity is often associated with amount ingested and its speed of absorption in the body. This can have life threatening effects on various body systems. Naloxone is an opioid antagonist that competitively binds to opioid receptors and reverses all their effects. The indication for use is RD because of known or suspected opioid overdose. This article presents a case report of 61-year-old female, a case of advanced pancreatic cancer, progressed on disease-modifying treatments and referred to palliative care for best supportive care. She developed features of morphine toxicity that was promptly identified and managed with use of naloxone and other supportive measures. PMID- 29123357 TI - Complementary Therapies for Symptom Management in Cancer Patients. AB - Cancer patients are often poly-symptomatic which distressingly affects their quality of lives (QOLs). Alhough, conventional management provides adequate symptom control, yet is coupled with some limitations. Complementary therapies (CTs) have shown beneficial effects in cancer patients for symptomatic relief. The aim of this article is to provide evidence-based review of commonly used CTs for symptom management in cancer care. Hypnosis has promising evidence to be used for managing symptoms such as pain, chemotherapy-induced nausea/vomiting, distress, fatigue, and hot flashes. Guided imagery increases comfort and can be used as a psycho-supportive therapy. Meditation substantially improves psychological function, mental health, and QOL. Cognitive behavioral therapies effectively reduce pain, distress, fatigue, anxiety, and depression; and improve subjective sleep outcomes along with mood and QOL. Yoga has short term beneficial effects for anxiety, depression, fatigue, perceived stress, QOL, and well-being. T'ai Chi and qigong are beneficial adjunctive therapies for supportive cancer care, but their role in reducing cancer pain is not well proven. Acupuncture is effective for reducing treatment related side-effects, pain and fatigue. Other therapies such as massage techniques, energy therapies, and spiritual interventions have also demonstrated positive role in managing cancer-related symptoms and improve overall well-being. However, the clinical effectiveness of these therapies for symptom management in cancer patients cannot be concluded due to poor strength of evidence. Nonetheless, these are relatively free from risks and hence can be given along with conventional treatments. Only by tailoring these therapies as per patient's beliefs and preferences, optimal patient centered holistic care can be provided. PMID- 29123361 TI - Personalized Learning in Medical Education: Designing a User Interface for a Dynamic Haptic Robotic Trainer for Central Venous Catheterization. AB - While Virtual Reality (VR) has emerged as a viable method for training new medical residents, it has not yet reached all areas of training. One area lacking such development is surgical residency programs where there are large learning curves associated with skill development. In order to address this gap, a Dynamic Haptic Robotic Trainer (DHRT) was developed to help train surgical residents in the placement of ultrasound guided Internal Jugular Central Venous Catheters and to incorporate personalized learning. In order to accomplish this, a 2-part study was conducted to: (1) systematically analyze the feedback given to 18 third year medical students by trained professionals to identify the items necessary for a personalized learning system and (2) develop and experimentally test the usability of the personalized learning interface within the DHRT system. The results can be used to inform the design of VR and personalized learning systems within the medical community. PMID- 29123360 TI - Understanding the relationship between religiosity and caregiver-adolescent communication about sex within African-American families. AB - Caregiver-adolescent communication about sex plays a critical role in the sexual socialization of youth. Many caregivers, however, do not engage their youth in such conversations, potentially placing them at risk for negative sexual health outcomes. Lack of caregiver-adolescent communication about sex may be particularly harmful for rural African American youth, as they often report early sex initiation and are disproportionately impacted by STIs. Moreover, sexual communication may be particularly challenging for families with strong religious backgrounds, potentially affecting the occurrence and breadth of topics covered during communication. Study aims were to: determine whether there was a relationship between caregiver religiosity and type of topics covered during communication about sex (e.g., general sexual health vs. positive aspects of sexuality) among 435 caregivers of early adolescent, African American youth; and if so, identify factors that might explain how religiosity affects communication about sex. Results indicated that caregiver religiosity was positively associated with communication about general, but not positive aspects of sexuality for caregivers of males. Attitudes towards communication about sex and open communication style mediated the relationship. There was no association between religiosity and communication about sex for caregivers of females. The findings from this study could provide a base to better understand and support the sexual socialization process within religious, African American families. PMID- 29123362 TI - Lessons from Practice: Designing Tools to Facilitate Individualized Support for Quitting Smoking. AB - Many health care providers, with a variety of trainings, counsel clients on quitting smoking on a day-to-day basis. In their clinical practice, they draw from and adapt guidelines and research-based strategies to fit individual client situations and challenges. Designers of technologies to support quitting smoking can learn from these real world practices to create tools that better adapt to individual differences. We present findings from interviews with 28 providers with diverse experiences in smoking cessation counselling. Through analysis of their individualization strategies, challenges, and perceptions of technology, we find that providers: (1) individualize context appropriate coping strategies by involving clients in brainstorming, (2) emphasize the need to support nicotine withdrawal in clients, (3) mitigate social triggers and mediate social support for clients, and (4) need to navigate dependencies with other providers for managing medications and comorbid health conditions of clients. With this empirical understanding, we extend the discussion on the design of technology to support quitting smoking, highlight current barriers to individualization, and suggest future opportunities to address these barriers. PMID- 29123363 TI - WHATCH'EM: A Weather-Driven Energy Balance Model for Determining Water Height and Temperature in Container Habitats for Aedes aegypti. AB - The mosquito virus vector Aedes (Ae.) aegypti exploits a wide range of containers as sites for egg laying and development of the immature life stages, yet the approaches for modeling meteorologically sensitive container water dynamics have been limited. This study introduces the Water Height and Temperature in Container Habitats Energy Model (WHATCH'EM), a state-of-the-science, physically based energy balance model of water height and temperature in containers that may serve as development sites for mosquitoes. The authors employ WHATCH'EM to model container water dynamics in three cities along a climatic gradient in Mexico ranging from sea level, where Ae. aegypti is highly abundant, to ~2100 m, where Ae. aegypti is rarely found. When compared with measurements from a 1-month field experiment in two of these cities during summer 2013, WHATCH'EM realistically simulates the daily mean and range of water temperature for a variety of containers. To examine container dynamics for an entire season, WHATCH'EM is also driven with field-derived meteorological data from May to September 2011 and evaluated for three commonly encountered container types. WHATCH'EM simulates the highly nonlinear manner in which air temperature, humidity, rainfall, clouds, and container characteristics (shape, size, and color) determine water temperature and height. Sunlight exposure, modulated by clouds and shading from nearby objects, plays a first-order role. In general, simulated water temperatures are higher for containers that are larger, darker, and receive more sunlight. WHATCH'EM simulations will be helpful in understanding the limiting meteorological and container-related factors for proliferation of Ae. aegypti and may be useful for informing weather-driven early warning systems for viruses transmitted by Ae. aegypti. PMID- 29123365 TI - Political and medical role in the last Ebola outbreak. PMID- 29123366 TI - New approach for promoting HPV vaccination in college men based on multi-theory model (MTM) of health behavior change. PMID- 29123364 TI - Corneal lenticule storage before reimplantation. AB - Purpose: To explore the optimal lenticule storage conditions that maintain lenticule integrity and clarity. Methods: A total of 99 lenticules obtained from myopic patients undergoing small incision lenticule extraction (SMILE) were divided into four combinations for short-term storage conditions: PBS, Dulbecco's Modified Eagle's Medium (DMEM), Optisol GS, or anhydrous glycerol. Two thirds of the lenticules were further stored for 4 weeks under eight different conditions. Clarity evaluation with transmittance measurements, cell-death assays with terminal deoxynucleotidyl transferase-mediated nick end labeling assay (TUNEL), collagen fibril spacing and necrotic response assessed with transmission electron microscopy (TEM), and immunohistochemistry analysis for human leukocyte antigens (HLAs) and CD45 for immunogenicity, and matrix metalloproteinase (MMP)-2 for keratocyte response, were undertaken at baseline, 48 h (short term), and 4 weeks (long term). Results: The TUNEL and immunogenicity results were comparable among the groups. The mean percentage of TUNEL-positive cells across all groups was 24.3% +/- 11.8% and 62.9% +/- 20.7% at the 48 h and 4 week time points, respectively. HLA-ABC+, HLA-DR+, and CD45+ cells were extremely rare, and MMP-2 expression ranged from non-detectable to minimal, under all conditions at all time points. Transmittance at 4 weeks was significantly different among groups with the greatest maintenance of clarity seen in the lenticules stored initially in DMEM at 4 degrees C for 48 h followed by cryopreservation in serum-free medium or glycerol at 4 degrees C followed by storage at room temperature. At TEM analysis at 4 weeks, the lenticules cryopreserved in liquid nitrogen, regardless of storage solutions, had significantly narrower inter-fibrillar distance than controls, while glycerol-preserved lenticules, at either room temperature or -80 degrees C, maintained the inter-fibrillar distance. Conclusions: Clarity, structural integrity, and low immunogenicity under various conditions, at 4 degrees C or room temperature for short-term storage, offer encouragement for lenticule storage. It can be undertaken without access to s specialized and potentially expensive laboratory setup at least within the first 48 h before transportation to larger facilities for long-term storage. PMID- 29123367 TI - Epidemiological HIV infection surveillance among subjects with risk behaviours in the city of Messina (Sicily) from 1992 to 2015. AB - Introduction: Epidemiological studies are a key element in determining the evolution and spread of HIV infection among the world population. Knowledge of the epidemiological dynamics improves strategies for prevention and monitoring. Methods: We examined 2,272 subjects who voluntarily underwent HIV testing from January 1992 to December 2015. For each subject, an anonymous form was completed to obtain information on personal data, sexual habits and exposure to risk factors. Results: The number of subjects undergoing the screening test has increased over the years and the average age of the tested subjects has decreased over time. The main motivation for undergoing HIV testing is unprotected sex. Although heterosexual subjects taking the test were more numerous than homosexuals in this study, an increase in the latter over time should be highlighted. Conclusions: Although the number of tests performed has increased over the years, the persistence of unprotected sex shows an inadequate perception of risk. Therefore, it is necessary to implement programmes to increase the general awareness of HIV infection. It is also essential to undertake constant monitoring of behaviour, risk perception and the application of the screening test via surveillance systems in order to implement effective and efficient prevention. PMID- 29123368 TI - Atherosclerosis is associated with a higher risk of hepatic steatosis in HIV infected patients. AB - Introduction: Cardiovascular Diseases (CD) have emerged as a leading cause of morbidity and mortality in HIV population. Some studies have reported higher carotid Intima Media Thickness (c-IMT), a measure of subclinical atherosclerosis (AT), in this cohort of patients. Methods: Here, we evaluate the role of Hepatic Steatosis (HS) as likely marker for AT in 128 HIV-infected patients without hepatitis C infection. c-IMT has been detected non-invasively by carotid ultrasonography to assess the progression of AT. HS has been evaluated using a process based on vibration-controlled transient elastography (Fibroscan) by a novel ultrasonic controlled attenuation parameter (CAP). The cut-off value for defining the presence of significant HS was CAP > 259 dBm-1. Results: AT has been detected in 26 patients (20.3%), whereas steatosis of grade 2 (S2) in 31 (24.2%). The variables statistically related to AT were age, obesity, diabetes, hypertension and S2. In the multivariate analysis, AT was only associated (p < 0.001) with age and S2. The optimal cut-off value indicated by ROC curve for predicting AT was CAP > 250 dB/m-1. Discussion: Our results highlight the presence of AT in HIVinfected persons and its association with fatty liver disease; therefore, HS assessment in HIV population results crucial to predict AT and CD. PMID- 29123369 TI - Universal proposal strategies of anti-HPV vaccination for adolescents: comparative analysis between school-based and clinic immunization programs. AB - Introduction: A promising approach to increase teenager's adherence to immunization against HPV is the administration of vaccinations within the school facilities. The Local Health Unit of Taranto experienced two different vaccine strategy proposals in the twelve-year-olds: the first one was the usual active call strategy in the outpatient clinic, while the second one provided the involvement of the schools in the area. The aim of the study is to evaluate the results of the proposed vaccination strategies in both sexes and in towns of different sizes in order to identify an effective path for achieving vaccine coverage improvement. Methods: To estimate the number of anti-HPV vaccine doses administered in adolescents of the 2003 cohort, we used the computerized vaccination system data of the Apulia Region. Then, once analyzed, the data for anti-HPV vaccine were broken down by gender, vaccine strategy and size of the town of residence. Analyses performed by using STATA SE 14. Results: The multiple logistic regression points out that, females (OR = 3.2; p < 0.01), living in small towns (OR = 1.3; p < 0.01) and school vaccination strategy (OR = 2; p < 0.01) increase the likelihood of completing the anti-HPV vaccine cycle in adolescents. The comparative assessment of anti-HPV coverage strategies, suggests that school vaccination has resulted in significantly better outcomes than outpatient clinic one, for all the groups considered (overall 72.3% vs 55.6%). Conclusions: The involvement of school institutes can define a winning organizational model to get a wider adolescent's adherence to immunization programs, especially in bigger towns. The school vaccination strategy could improve anti-HPV vaccine adherence also in males, who perceives a lower HPV related diseases risk than females. PMID- 29123370 TI - Assessing hand hygiene compliance among healthcare workers in six Intensive Care Units. AB - Introduction: Healthcare associated infections (HAIs) are a cause of high morbidity, disability and reduced quality of life, as well as mortality and rising costs for health systems. Preventing the HAI risk by planning and implementing effective preventive strategies is important to safeguard patient health. Methods: The study aimed to evaluate the presence of procedures and protocols for infection control, to assess the adhesion to the different aspects of hand hygiene (HH) and hand washing technique by healthcare workers in six ICUs. A perspective observational study was conducted in six ICUs. In each ICU, the adherence by health care workers to both hand hygiene practices and standard precautions was assessed, as well as the presence of procedures and written protocols. Results: The findings showed that in all the involved ICUs, 73 of 142 required protocols and procedures were available. Specifically, 59 of 79 were available for general measure of risk control, 12 of 15 for hand hygiene, and 24 of 48 for standard precautions and isolation measures. Also, the results showed highly variable levels of adherence to the best hygiene practices in all the ICUs involved in the study, with compliance rates ranging from 3% to 100%, and 73 of 142 required protocols were available at the study time. Conclusions: Overall, the involved ICUs showed low levels of adherence to best hygiene practices. This suggests the need to implement immediate strategies for infection control in the ICUs. A multidisciplinary intervention could be effective in preventing and control the HAI risk.score was reached only by the third year students with regard to the proper HH. The level of knowledge about HAI was inadequate.A periodically check of nursing students' knowledge would be advisable in order to fill any gaps, improve training, reduce HAI and increase prevention measures compliance. PMID- 29123371 TI - Monitoring biodiversity in libraries: a pilot study and perspectives for indoor air quality. AB - Indoor Air Quality (IAQ) in libraries is influenced by the presence of specific factors which can impact on both paper storage as well as people health. Microclimatic conditions induce and support a biodiversity pattern involving environmental and anthropic microorganisms. We used a multidisciplinary monitoring model to characterize microflora biodiversity by Next Generation Sequencing (NGS). Biodiversity indexes were adapted to evaluate anthropic vs environmental pollution by combining Shannon mean index (H), species representativeness (EH), human/environmental pollution ratio (SA) to better characterize the NGS output and acquire synthetic information on Indoor Air Microbial Biodiversity (IAMB). Results indicate a frequently low microbial load (IGCM/m3 < 1000) characterized by different species (n = 102), including several cellulose metabolizing bacteria. Workers and visitors appeared a relevant source of microbial contamination. Air biodiversity assayed by NGS seems a promising marker for studying IAQ. PMID- 29123372 TI - The effect of musculoskeletal problems on fatigue and productivity of office personnel: a cross-sectional study. AB - Introduction: Work-related Musculoskeletal Disorders (WMSDs) can impact on fatigue and productivity of office workers. This study aimed to investigate the effect of musculoskeletal problems on fatigue and productivity among office personnel. Methods: This study was performed on 101 Iranian office workers. Data were gathered through a demographic questionnaire, Nordic Musculoskeletal Questionnaire, Numeric Rating Scale, Persian version of Multidimensional Assessment of Fatigue Scale, and Persian version of Health and Work Questionnaire. Results: The results revealed that the highest prevalence rates of musculoskeletal symptoms in the past week were related to neck (41.6%), lower back (41.6%), and shoulders (40.6%). The mean score of discomfort/pain was 1.67, 1.55, and 1.31 in the neck, lower back, and shoulders, respectively. Additionally, the severity of discomfort/pain in neck, shoulders, lower back, and thighs was correlated to total fatigue. The severity of discomfort/pain in neck, lower back, buttock, and thighs was also correlated to the concentration/focus subscale of productivity. Conclusions: Improvement of working conditions is suggested to reduce musculoskeletal problems and fatigue and enhance productivity. PMID- 29123373 TI - The Structure and Flexural Properties of Typha Leaves. AB - The Typha leaf has a structure of lightweight cantilever beam, exhibiting excellent mechanical properties with low density. Especially, the leaf blade evolved high strength and low density with high porosity. In this paper, the structure of Typha leaf was characterized by microcomputed tomography (Micro-CT) and scanning electron microscopy (SEM), and the relationship with flexural properties was analyzed. The three-point bending test was performed on leaves to examine flexural properties, which indicated that the flexural properties vary from the base to the apex in gradient. The cross-sectional geometry shape of the leaf blade presented a strong influence on the optimized flexural stiffness. The load carrying capacity of the leaf depended on the development level of the epidermal tissue, the vascular bundle, the mechanical tissue, and the geometric properties. The investigation can be the basis for lightweight structure design and the application in the bionic engineering field. PMID- 29123374 TI - Anti-CD20 Cell Therapies in Multiple Sclerosis-A Fixed Dosing Schedule for Ocrelizumab is Overkill. AB - Anti-CD 20 therapies have found significant uses in multiple sclerosis (MS). Based singularly on the accumulated evidence with the use of rituximab (RTX; Rituxan, Genentech, and Biogen) in neuroimmunological diseases, ocrelizumab (OCR; Ocrevus, Genentech) was developed as a treatment option for MS and selectively targets CD20 B cells, a cell surface antigen found on pre-B cells, mature, and memory B cells, but not on lymphoid stem cells and plasma cells. On the basis of indirect evidence, elimination of the antigen-presenting capabilities and antigen nonspecific immune functions of B cells appear to be central to the therapeutic efficacy of anti-CD20 B-cell therapies. An important question is this-Why does the drug need to be dosed at fixed intervals and not based on a measurable endpoint, such as tracking peripheral CD20 cell counts? There is minimal scientific validity in infusing the drug every 6 months particularly if CD20 cell counts are negligible in the peripheral blood. In this analysis, a case is made for following CD19 cell populations as a surrogate for CD20 cells on a monthly basis to guide OCR redosing parameters and does not follow a scheduled dosing parameter. PMID- 29123375 TI - Sequential Keraring implantation and corneal cross-linking for the treatment of keratoconus in children with vernal keratoconjunctivitis. AB - Purpose: The purpose of this study was to assess the safety and efficacy of femtosecond laser-assisted Keraring implantation followed by transepithelial accelerated corneal collagen cross-linking (CXL) for the treatment of keratoconus in children with vernal keratoconjunctivitis (VKC). Study design: This is a prospective interventional non-comparative case series. Patients and methods: Eighteen eyes of 11 children with keratoconus and VKC were included in this study. All the cases were treated with femtosecond laser-assisted Keraring implantation followed after 2 weeks by transepithelial accelerated CXL, and the patients were followed up for 1 year. Results: The preoperative mean uncorrected visual acuity (UCVA) was 1.01+/-0.2 (logMAR), whereas the postoperative mean UCVA was 0.6+/-0.2. The preoperative mean best-corrected visual acuity (BCVA) was 0.6+/-0.1, whereas the postoperative mean BCVA was 0.40+/-0.2. The preoperative average keratometry was 50.3+/-2.7 D, whereas the postoperative average keratometry was 45.8+/-3.1 D. Conclusion: The results of this study suggest that femtosecond laser-assisted Keraring implantation followed by CXL is safe and effective in the management of keratoconus in children with VKC. However, studies with a longer follow-up period are needed. PMID- 29123376 TI - Intracameral ketorolac concentration at the beginning and end of cataract surgery following preoperative topical ketorolac administration. AB - Purpose: To evaluate the intracameral concentration of ketorolac tromethamine (ketorolac) at the beginning and end of cataract surgery following preoperative topical administration. Setting: Santa Barbara Surgery Center, Santa Barbara, CA, USA. Design: This was a pre-post, interventional, single-arm study. Patients and methods: Patients undergoing cataract extraction and lens replacement (CELR) were eligible. Written informed consent was obtained from 14 patients who were prescribed topical ophthalmic ketorolac according to the surgeon's usual practice beginning the day prior to surgery. The surgeon withdrew 100 MUL of aqueous humor from the operative eye immediately prior to the initial surgical incision and again just prior to final anterior chamber reinflation and wound closure. Ketorolac concentrations in the intracameral fluid samples were measured. Results: Thirteen of 14 patients used four doses of ketorolac the day prior to surgery as directed, and one patient used three doses. On the day of surgery, all 14 patients administered one drop of topical ketorolac on awakening and one drop after arriving at the surgery center. Preoperative ketorolac concentrations for the 12 patients from whom samples were collected ranged from 4.9 to 369 ng/mL. End-of-procedure sample concentrations ranged from <1.0 (the lower limit of quantification [LLOQ]) to 6.32 ng/mL, with eight of 12 patients having ketorolac levels below the LLOQ. Conclusion: At-home compliance with topical ketorolac was good, with 92.9% of patients using it as directed. Following CELR, levels of ketorolac in the aqueous humor were low, and 66.7% of patients had undetectable levels. PMID- 29123377 TI - Parents' views on their children's use of eye drops and willingness to accept a new sustained-release subconjunctival injection. AB - Aim: The objectives of this study were to explore parents' views about their children's use of regular eye drops and whether they would consider a sustained release subconjunctival injection as a replacement for daily drops. Methods: A survey was conducted with 134 parents of children with chronic eye diseases at the Singapore National Eye Centre. Parents were asked their views about their children's use of eye drops and were then presented with a discrete choice experiment that, via a series of trade-off tasks, allowed for estimating demand for a series of hypothetical subconjunctival injections that varied along product features, including interval between administrations, risk of complications, out of-pocket cost and whether it is recommended by the patient's treating physician. Results: Results showed that the vast majority of parents did not find administration of eye drops to be inconvenient (78%) nor did children complain about using daily eye drops (78%). Furthermore, only about half of parents whose child missed doses stated concerns about the consequences of non-compliance. The discrete choice experiment revealed that only one in five parents would consider a subconjunctival injection for their children. These parents tended to be more concerned about the consequences of non-compliance with eye drops, had children who administered the drops themselves or had other chronic disease requiring regular medication. Among these parents, risk of complications had the largest effect on injection uptake. Conclusion: This study shows that parents do not find administration of daily eye drops to be a significant burden. As a result, most would not consider a subconjunctival injection unless risk of complications was extremely small. PMID- 29123379 TI - Guideline development for the management of gout: role of combination therapy with a focus on lesinurad. AB - The aim of this review was to summarize the evidence for combination therapy to achieve serum urate (SUA) target levels in gout. Within this overarching aim, a second aim was to evaluate the evidence for a new uricosuric agent lesinurad, which inhibits urate transport in the kidney. In summary, this review indicates that there are a number of ways to approach patients who do not achieve a target serum urate with allopurinol (APL) monotherapy. These include higher doses of APL up to 600-800 mg/d, switching to febuxostat, or adding in a uricosuric. For the latter option, controlled supporting evidence is available for benzbromarone, probenecid, and lesinurad. All options appear similar in terms of success rates, so the choice of option comes down to physician and patient choice, cost, experience, and strength of the evidence base. Increasing the dose of APL is the cheapest option, while febuxostat is consistently superior to standard doses of APL. The strongest evidence for the uricosuric option is available for lesinurad as trials of other agents are either nonexistent or based on small single-centre trials. It is suggested that guidelines should be expanded to consider all of these evidence-based options in the not-uncommon occurrence of APL inadequate response. PMID- 29123378 TI - 10H-3,6-Diazaphenothiazine induces G2/M phase cell cycle arrest and caspase dependent apoptosis and inhibits cell invasion of A2780 ovarian carcinoma cells through the regulation of NF-kappaB and (BIRC6-XIAP) complexes. AB - The asymptomatic properties and high treatment resistance of ovarian cancer result in poor treatment outcomes and high mortality rates. Although the fundamental chemotherapy provides promising anticancer activities, it is associated with severe side effects. The derivative of phenothiazine, namely, 10H 3,6-diazaphenothiazine (PTZ), was synthesized and reported with ideal anticancer effects in a previous paper. In this study, detailed anticancer properties of PTZ was examined on A2780 ovarian cancer cells by investigating the cytotoxicity profiles, mechanism of apoptosis, and cell invasion. Research outcomes revealed PTZ-induced dose-dependent inhibition on A2780 cancer cells (IC50 =0.62 uM), with significant less cytotoxicity toward HEK293 normal kidney cells and H9C2 normal heart cells. Generation of reactive oxygen species (ROS) and polarization of mitochondrial membrane potential (DeltaPsim) suggests PTZ-induced cell death through oxidative damage. The RT2 Profiler PCR Array on apoptosis pathway demonstrated PTZ-induced apoptosis via intrinsic (mitochondria-dependent) and extrinsic (cell death receptor-dependent) pathway. Inhibition of NF-kappaB and subsequent inhibition of (BIRC6-XIAP) complex activities reduced the invasion rate of A2780 cancer cells penetrating through the MatrigelTM Invasion Chamber. Lastly, the cell cycle analysis hypothesizes that the compound is cytostatic and significantly arrests cell proliferation at G2/M phase. Hence, the exploration of the underlying anticancer mechanism of PTZ suggested its usage as promising chemotherapeutic agent. PMID- 29123380 TI - Development of beta-cyclodextrin-based hydrogel microparticles for solubility enhancement of rosuvastatin: an in vitro and in vivo evaluation. AB - The aim of this study was to enhance the solubility of rosuvastatin (RST) calcium by developing beta-cyclodextrin-g-poly(2-acrylamido-2-methylpropane sulfonic acid [AMPS]) hydrogel microparticles through aqueous free-radical polymerization technique. Prepared hydrogel microparticles were characterized for percent entrapment efficiency, solubility studies, Fourier transform infrared spectroscopy, differential scanning calorimetry, thermal gravimetric analysis, powder X-ray diffraction, scanning electron microscopy, zeta size and potential, swelling and release studies. Formulations (HS1-HS9) have shown entrapment efficiency between 83.50%+/-0.30% and 88.50%+/-0.25%, and optimum release was offered by formulation HS7 at both pH levels, ie, 1.2 (89%) and 7.4 (92%). The majority of microparticles had a particle size of less than 500 um and zeta potential of -37 mV. Similarly, optimum solubility, ie, 10.66-fold, was determined at pH 6.8 as compared to pure RST calcium, ie, 7.30-fold. In vivo studies on fabricated hydrogel microparticulate system in comparison to pure drug were carried out, and better results regarding pharmacokinetic parameters were seen in the case of hydrogel microparticles. A potential approach for solubility enhancement of RST calcium and other hydrophobic moieties was successfully developed. PMID- 29123381 TI - High-dose dexamethasone induced LPS-stimulated rat alveolar macrophages apoptosis. AB - Prolonged administration of an excessive dose of corticosteroids proved to be harmful for patients with acute lung injury (ALI). A previous study has found that repeated administration of an excessive dose of methylprednisolone reduced alveolar macrophages (AMs) in bronchoalveolar lavage fluid (BALF) with an unknown mechanism. This study aimed to investigate the effect of excessive use of dexamethasone (Dex) on BALF AMs in vitro. Transmission electron microscopy and DNA fragmentation analysis demonstrated that 10-4 and 10-5 M Dex induced lipopolysaccharide-stimulated rat AMs apoptosis with downregulation of tumor necrosis factor-alpha, interleukin (IL)-12 and upregulation of IL-10, transforming growth factor-beta. These results indicated that apoptosis might be a novel contribution involved in the detrimental effect of excessive dose of Dex clinically used to treat ALI. PMID- 29123382 TI - In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors. AB - In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX)-loaded novel cell-penetrating peptide (CPP)-modified pH sensitive liposomes (CPPL) (referred to as CPPL(DOX)) with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG) derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate) was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p<0.01) and resulted in more cell apoptosis as a result of DNA disruption as well as a relatively lower tumor growth ratio (T/C%). Histological examination did not show any signs of necrosis or inflammation in normal tissues, but large cell dissolving areas were found in tumors following the treatment of animals with CPPL(DOX). Our findings provide important and detailed information regarding the distribution of CPPL(DOX) in vivo and reveal their abilities of tumor penetration and potential for the treatment of breast cancer. PMID- 29123383 TI - Internal consistency and item-total correlation of patient-reported outcome instruments and hemophilia joint health score v2.1 in US adult people with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P FiQ) study. AB - Background: The Pain, Functional Impairment, and Quality of Life study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adult people with hemophilia (PWH) of any severity in the USA who experience joint pain and/or bleeding. Objective: To assess internal consistency (IC) and item-total correlation (ITC) of assessment tools used in the Pain, Functional Impairment, and Quality of Life study. Methods: Participants completed 5 patient-reported outcome instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL]) and underwent an optional physiotherapist administered musculoskeletal exam (Hemophilia Joint Health Score v2.1) during routine visits. Reliability assessment included IC and ITC of each instrument. Results: A total of 381 adult PWH (median age, 34 years) were enrolled. Participants were predominantly white/non-Hispanic (69.2%); 75% had congenital hemophilia A, and 70.5% had severe hemophilia. A total of 310 subjects reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]). IC was generally high across the instruments employed (Cronbach's alpha 0.79-0.98) with the exception of HAL use of transportation (0.58) and IPAQ total physical activity (0.51). ITC was high (Pearson's product-moment correlation coefficient >0.20) for all items except the "vigorous intensity activities" item of IPAQ, which was applicable to less than one-third of participants. The ITCs were generally highest in domains/scores that measured the functional consequences of hemophilic arthropathy on mobility and pain. Conclusion: The demonstrated reliability (IC/ITC) of the patient-reported outcome instruments and Hemophilia Joint Health Score v2.1 support a role for these instruments in evaluating adult PWH in US clinical and research settings. PMID- 29123384 TI - Functional outcomes by age after inpatient stroke rehabilitation in Saudi Arabia. AB - Background: Among various risk factors, age has been identified as a nonmodifiable risk factor for stroke that influences functional outcomes after inpatient stroke rehabilitation in the developed world as well as in Saudi Arabia (SA). The demand for inpatient stroke rehabilitation services increases with population aging and stroke incidence; however, these services are limited in SA. Objective: To examine functional outcomes by age after inpatient stroke rehabilitation in SA. Patients and methods: Data from 418 patients with stroke who underwent inpatient stroke rehabilitation at the King Fahad Medical City Rehabilitation Hospital, Riyadh, SA, between November 2008 and December 2014 were collected from electronic medical records. According to the patients' age, we classified participants into two groups: adults, aged <65 years (n=255), and older adults, aged >=65 years (n=163). All patients' functional statuses at admission and discharge from inpatient stroke rehabilitation were assessed using the functional independence measure (FIM) scale. Results: The mean age was 59.9 years (SD =9.4). Older adults had significantly smaller changes in functional outcome from admission to discharge on both the total FIM (23 [SD =15.9]) and the motor FIM (21 [SD =15.4]), and they were significantly less independent (36%) compared to adults. In the adjusted models, older adults had significantly lower scores than adults, by 11 points (p<0.0001) for the total FIM score and by 10 points (p<0.0001) for the motor FIM subscale score. There was no significant change with age in the cognitive FIM subscale score. Conclusion: After inpatient stroke rehabilitation, older adults had limited functional outcomes or were less independent than adults. However, the clinical relevance of this finding is questionable, so there is currently no justification to deny patients access to intensive stroke rehabilitation solely because of advanced age. Future large scale research is needed to confirm rehabilitation outcomes by including confounders such as social support, socioeconomics, comorbidities, and the patient's opinion after rehabilitation. PMID- 29123385 TI - Clostridium difficile infection in the elderly: an update on management. AB - The burden of Clostridium difficile infection (CDI) is profound and growing. CDI now represents a common cause of health care-associated diarrhea, and is associated with significant morbidity, mortality, and health care costs. CDI disproportionally affects the elderly, possibly explained by the following risk factors: age-related impairment of the immune system, increasing antibiotic utilization, and frequent health care exposure. In the USA, recent epidemiological studies estimate that two out of every three health care associated CDIs occur in patients 65 years or older. Additionally, the elderly are at higher risk for recurrent CDI. Existing therapeutic options include metronidazole, oral vancomycin, and fidaxomicin. Choice of agent depends on disease severity, history of recurrence, and, increasingly, the drug cost. Bezlotoxumab, a recently approved monoclonal antibody targeting C. difficile toxin B, offers an exciting advancement into immunologic therapies. Similarly, fecal microbiota transplantation is gaining popularity as an effective option mainly for recurrent CDI. The challenge of decreasing CDI burden in the elderly involves adopting preventative strategies, optimizing initial treatment, and decreasing the risk of recurrence. Expanded strategies are certainly needed to improve outcomes in this high-risk population. This review considers available data from prospective and retrospective studies as well as case reports to illustrate the merits and gaps in care related to the management of CDI in the elderly. PMID- 29123386 TI - Geroprotectors as a therapeutic strategy for COPD - where are we now? AB - Although current therapies in chronic obstructive pulmonary disease (COPD) improve the quality of life, they do not satisfactorily reduce disease progression or mortality. There are still many gaps in knowledge about the cellular, molecular, and genetic mechanisms contributing to pathobiology of this disease. However, increasing evidence suggests that accelerated aging, chronic systemic inflammation, and oxidative stress play major roles in pathogenesis in COPD, thus opening new opportunities in therapy. Therefore, the aim of our review was to describe and discuss some of the most widely used therapeutics that affect the root cause of aging and oxidative stress (metformin, melatonin, sirolimus, statins, vitamin D, and testosterone) in context of COPD therapy. PMID- 29123387 TI - Longitudinal change of COPD assessment test (CAT) in a telehealthcare cohort is associated with exacerbation risk. AB - Background: There are only scarce data regarding the evolution of the chronic obstructive pulmonary disease (COPD) assessment test (CAT) over time. Our aim was to investigate the evolution of the CAT in a telehealthcare (THC) cohort and to evaluate its potential to predict exacerbations. Patients and methods: The CAT was measured weekly over up to 1 year in 40 COPD patients undergoing a THC intervention. The evolution of the CAT was analyzed using linear regression. The association between this evolution and the occurrence of exacerbations was evaluated using the Andersen-Gill formulation of the Cox proportional hazards model for the analysis of recurrent time-to-event data with time-varying predictors. Results: The median CAT at inclusion was 17 (interquartile range 13 22) points. During the study, 25% of patients had a significant negative slope (median -7 points per year [ppy]), 38% were stable (median +0 ppy) and 38% had a significant positive slope (median +6 ppy). The median slope of the CAT in the overall cohort was +1 (interquartile range -3 to +6) ppy. A significant positive association was found between the change in CAT scores and the risk of exacerbations (hazard ratio =1.08, 95% CI: 1.03-1.13; p<0.001). There was an 8% increase of the risk of exacerbation per unit increase in CAT. We detected a significant learning effect in filling out the CAT in 18.4% of patients with a median learning phase of five filled questionnaires. Conclusion: Sixty-three percent of the COPD patients monitored by THC experienced a stable or improved CAT during 1-year follow-up. We found a significant positive association between the evolution of the CAT over time and the risk of exacerbations. In about one fifth of patients, there was a significant learning effect in filling out the CAT, before reliable results could be obtained. The evolution of the CAT could help to assess the risk for future exacerbations. PMID- 29123388 TI - Upregulated pneumococcal adhesion molecule (platelet-activating factor receptor) may predispose COPD patients to community-acquired pneumonia. PMID- 29123389 TI - Alveolar-capillary reserve during exercise in patients with chronic obstructive pulmonary disease. AB - Background: Factors limiting exercise in patients with COPD are complex. With evidence for accelerated pulmonary vascular aging, destruction of alveolar capillary bed, and hypoxic pulmonary vasoconstriction, the ability to functionally expand surface area during exercise may become a primary limitation. Purpose: To quantify measures of alveolar-capillary recruitment during exercise and the relationship to exercise capacity in a cohort of COPD patients. Methods: Thirty-two subjects gave consent (53% male, with mean +/- standard deviation age 66+/-9 years, smoking 35+/-29 pack-years, and Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification of 0-4: 2.3+/-0.8), filled out the St George's Respiratory Questionnaire (SGRQ) to measure quality of life, had a complete blood count drawn, and underwent spirometry. The intrabreath (IB) technique for lung diffusing capacity for carbon monoxide (IBDLCO) and pulmonary blood flow (IBQc, at rest) was also performed. Subsequently, they completed a cycle ergometry test to exhaustion with measures of oxygen saturation and expired gases. Results: Baseline average measures were 44+/-21 for SGRQ score and 58+/-11 for FEV1/FVC. Peak oxygen consumption (VO2) was 11.4+/-3.1 mL/kg/min (49% predicted). The mean resting IBDLCO was 9.7+/-5.4 mL/min/mmHg and IBQc was 4.7+/ 0.9 L/min. At the first workload, heart rate (HR) increased to 92+/-11 bpm, VO2 was 8.3+/-1.4 mL/kg/min, and IBDLCO and IBQc increased by 46% and 43%, respectively, compared to resting values (p,0.01). The IBDLCO/Qc ratio averaged 2.0+/-1.1 at rest and remained constant during exercise with marked variation across subjects (range: 0.8-4.8). Ventilatory efficiency plateaued at 37+/-5 during exercise, partial pressure of mix expired CO2/partial pressure of end tidal CO2 ratio ranged from 0.63 to 0.67, while a noninvasive index of pulmonary capacitance, O2 pulse * PetCO2 (GxCap) rose to 138%. The exercise IBDLCO/Qc ratio was related to O2 pulse (VO2/HR, r=0.58, p<0.01), and subjects with the highest exercise IBDLCO/Qc ratio or the greatest rise from rest had the highest peak VO2 values (r=0.65 and 0.51, respectively, p<0.05). Of the noninvasive gas exchange measures of pulmonary vascular function, GxCap was most closely associated with DLCO, DLCO/Qc, and VO2 peak. Conclusion: COPD patients who can expand gas exchange surface area as assessed with DLCO during exercise relative to pulmonary blood flow have a more preserved exercise capacity. PMID- 29123390 TI - Hyperinflated lungs compress the heart during expiration in COPD patients: a new finding on dynamic-ventilation computed tomography. AB - Purpose: The aims of this study were to evaluate dynamic changes in heart size during the respiratory cycle using four-dimensional computed tomography (CT) and to understand the relationship of these changes to airflow limitation in smokers. Materials and methods: A total of 31 smokers, including 13 with COPD, underwent four-dimensional dynamic-ventilation CT during regular breathing. CT data were continuously reconstructed every 0.5 s, including maximum cross-sectional area (CSA) of the heart and mean lung density (MLD). Concordance between the cardiac CSA and MLD time curves was expressed by cross-correlation coefficients. The CT based cardiothoracic ratio at inspiration and expiration was also calculated. Comparisons of the CT indices between COPD patients and non-COPD smokers were made using the Mann-Whitney test. Spearman rank correlation analysis was used to evaluate associations between CT indices and the forced expiratory volume in 1 s (FEV1.0) relative to the forced vital capacity (FVC). Results: Cardiac CSA at both inspiration and expiration was significantly smaller in COPD patients than in non-COPD smokers (P<0.05). The cross-correlation coefficient between cardiac CSA and MLD during expiration significantly correlated with FEV1.0/FVC (rho=0.63, P<0.001), suggesting that heart size decreases during expiration in COPD patients. The change in the cardiothoracic ratio between inspiration and expiration frames was significantly smaller in COPD patients than in non-COPD smokers (P<0.01). Conclusion: Patients with COPD have smaller heart size on dynamic-ventilation CT than non-COPD smokers and have abnormal cardiac compression during expiration. PMID- 29123391 TI - Surface-enhanced Raman scattering investigation of targeted delivery and controlled release of gemcitabine. AB - Advanced and metastatic cancer forms are extremely difficult to treat and require high doses of chemotherapeutics, inadvertently affecting also healthy cells. As a result, the observed survival rates are very low. For instance, gemcitabine (GEM), one of the most effective chemotherapeutic drugs used for the treatment of breast and pancreatic cancers, sees only a 20% efficacy in penetrating cancer tissue, resulting in <5% survival rate in pancreatic cancer. Here, we present a method for delivering the drug that offers mitigation of side effects, as well as a targeted delivery and controlled release of the drug, improving its overall efficacy. By modifying the surface of gold nanoparticles (AuNPs) with covalently bonded thiol linkers, we have immobilized GEM on the nanoparticle (NP) through a pH-sensitive amide bond. This bond prevents the drug from being metabolized or acting on tissue at physiological pH 7.4, but breaks, releasing the drug at acidic pH, characteristic of cancer cells. Further functionalization of the NP with folic acid and/or transferrin (TF) offers a targeted delivery, as cancer cells overexpress folate and TF receptors, which can mediate the endocytosis of the NP carrying the drug. Thus, through the modification of AuNPs, we have been able to produce a nanocarrier containing GEM and folate/TF ligands, which is capable of targeted controlled-release delivery of the drug, reducing the side effects of the drug and increasing its efficacy. Here, we demonstrate the pH dependent GEM release, using an ultrasensitive surface-enhanced Raman scattering spectroscopy to monitor the GEM loading onto the nanocarrier and follow its stimulated release. Further in vitro studies with model triple-negative breast cancer cell line MDA-MB-231 have corroborated the utility of the proposed nanocarrier method allowing the administration of high drug doses to targeted cancer cells. PMID- 29123392 TI - Self-assembled albumin nanoparticles for combination therapy in prostate cancer. AB - Resistance to regular treatment strategies is a big challenge in the treatment of castration-resistant prostate cancer. Combination of photothermal and photodynamic therapy (PTT/PDT) with chemotherapy offers unique advantages over monotherapy alone. However, free drugs, such as photosensitizers and chemotherapeutic agents, lack tumor-targeted accumulation and can be easily eliminated from the body. Moreover, most of the PTT drugs are hydrophobic and their organic solvents have in vivo toxicity, thereby limiting their potential in clinical translation. Herein, simple multifunctional nanoparticles (NPs) using IR780 (a near-infrared dye) and docetaxel (DTX)-loaded nanoplatform based on human serum albumin (HSA) (HSA@IR780@DTX) was developed for targeted imaging and for PTT/PDT with chemotherapy for the treatment of castration-resistant prostate cancer treatment. In this platform, HSA is a biocompatible nanocarrier that binds to both DTX and IR780. DTX and IR780, as hydrophobic drug, can induce the self assembly of HSA proteins. Transmission electron microscopic imaging showed that NPs formed by self-assembly are spherical with a smooth surface with a hydrodynamic diameter of 146.5+/-10.8 nm. The cytotoxicity of HSA@IR780@DTX NPs with or without laser irradiation in prostate cancer cells (22RV1) was determined via CCK-8 assay. The antitumor effect of HSA@IR780@DTX plus laser irradiation was better than either HSA@IR780@DTX without laser exposure or single PTT heating induced by HSA@IR780 NPs under near-infrared laser, suggesting a significant combined effect in comparison to monotherapy. Near-infrared fluorescence imaging showed that HSA@IR780@DTX NPs could preferentially accumulate in tumors. In vivo therapeutic efficacy experiment showed that xenografted prostate tumors on mice treated with HSA@IR780@DTX plus near-infrared laser irradiation were completely inhibited, whereas tumors on mice treated with chemotherapy alone (HSA@DTX and HSA@IR780@DTX without laser) or PTT/PDT alone (HSA@IR780 with laser) showed moderate growth inhibition. Overall, HSA@IR780@DTX NPs showed notable targeting and theranostic potential for the treatment of castration-resistant prostate cancer. PMID- 29123393 TI - Antioxidant and hepatoprotective role of selenium against silver nanoparticles. AB - Silver nanoparticles (AgNPs) have attracted the most interest in terms of their potential biomedical and industrial applications. However, these nanoparticles have shown their toxic behavior toward environment, living tissues, and organisms. Selenium (Se), an essential trace element, is necessary for various metabolic processes, including protection against oxidative stress and immune function. The present study was undertaken to evaluate the effect of Se against AgNP-induced hepatic oxidative stress. AgNPs were synthesized and then prepared nanoparticles were characterized using various analytical techniques such as UV visible spectroscopy, X-ray diffraction, and transmission electron microscopy. Rats were administered AgNPs intraperitoneally (5 mg/kg/day) and Se (0.2 mg/kg) was given by gavage. AgNP administration induced hepatic damage as indicated by the serum marker enzymes with reduction in levels of glutathione, and decrease in activities of SOD, CAT, and GSH-peroxidase (P<0.05). Decrease in levels of total antioxidant capacity (TAC) and increase in level of C-reactive protein (CRP) was also observed in AgNP-treated group compared to control group. However, Se markedly attenuated AgNP-induced biochemical alterations, levels of TAC, CRP, and serum transaminases (AST, ALT) (P<0.05). Taken together, these findings suggest that administration of AgNPs produces hepatotoxicity in rats, whereas Se supplementation attenuates these effects. PMID- 29123394 TI - Quercetin nanoparticle complex attenuated diabetic nephropathy via regulating the expression level of ICAM-1 on endothelium. AB - The purpose of the study was to reveal the therapeutic effect of quercetin (QUE) nanoparticle complex on diabetic nephropathy (DN) by regulating the expression of intercellular adhesion molecular-1 (ICAM-1) on endothelium as compared to free QUE. QUE 10 mg/kg as a single abdominal subcutaneous injection daily for 8 weeks continuously in diabetic rats and 10 mg/kg QUE nanoparticle complex as a single abdominal subcutaneous injection every 5 days, continuously administered for 8 weeks to diabetic rats. Blood and left kidneys were collected; pathological change of kidney, renal function, oxidative stress level, blood glucose level, serum lipid, urine protein, and albumin/creatinine ratio were measured; and neutrophil adhesion, ICAM-1 expression, and CD11b+ cells infiltration were observed. Both QUE and QUE nanoparticle complex preconditioning ameliorated the pathological damage of kidney and improved renal function, alleviated renal oxidative stress injury, restricted inflammatory cells infiltration, and downregulated the ICAM-1 expression as compared to DN group, while QUE nanoparticle complex significantly alleviated this effect. PMID- 29123395 TI - A magnetically responsive nanocomposite scaffold combined with Schwann cells promotes sciatic nerve regeneration upon exposure to magnetic field. AB - Peripheral nerve repair is still challenging for surgeons. Autologous nerve transplantation is the acknowledged therapy; however, its application is limited by the scarcity of available donor nerves, donor area morbidity, and neuroma formation. Biomaterials for engineering artificial nerves, particularly materials combined with supportive cells, display remarkable promising prospects. Schwann cells (SCs) are the absorbing seeding cells in peripheral nerve engineering repair; however, the attenuated biologic activity restricts their application. In this study, a magnetic nanocomposite scaffold fabricated from magnetic nanoparticles and a biodegradable chitosan-glycerophosphate polymer was made. Its structure was evaluated and characterized. The combined effects of magnetic scaffold (MG) with an applied magnetic field (MF) on the viability of SCs and peripheral nerve injury repair were investigated. The magnetic nanocomposite scaffold showed tunable magnetization and degradation rate. The MGs synergized with the applied MF to enhance the viability of SCs after transplantation. Furthermore, nerve regeneration and functional recovery were promoted by the synergism of SCs-loaded MGs and MF. Based on the current findings, the combined application of MGs and SCs with applied MF is a promising therapy for the engineering of peripheral nerve regeneration. PMID- 29123396 TI - Use of magnetic nanoparticles as a drug delivery system to improve chlorhexidine antimicrobial activity. AB - Nanotechnology offers new tools for developing therapies to prevent and treat oral infections, particularly biofilm-dependent disorders, such as dental plaques and endodontic and periodontal diseases. Chlorhexidine (CHX) is a well characterized antiseptic agent used in dentistry with broad spectrum activity. However, its application is limited due to inactivation in body fluid and cytotoxicity toward human cells, particularly at high concentrations. To overcome these limitations, we synthesized nanosystems composed of aminosilane-coated magnetic nanoparticles functionalized with chlorhexidine (MNP@CHX). In the presence of human saliva, MNPs@CHX displayed significantly greater bactericidal and fungicidal activity against planktonic and biofilm-forming microorganisms than free CHX. In addition, CHX attached to MNPs has an increased ability to restrict the growth of mixed-species biofilms compared to free CHX. The observed depolarization of mitochondria in fungal cells treated with MNP@CHX suggests that induction of oxidative stress and oxidation of fungal structures may be a part of the mechanism responsible for pathogen killing. Nanoparticles functionalized by CHX did not affect host cell proliferation or their ability to release the proinflammatory cytokine, IL-8. The use of MNPs as a carrier of CHX has great potential for the development of antiseptic nanosystems. PMID- 29123397 TI - Highly sensitive protein detection via covalently linked aptamer to MoS2 and exonuclease-assisted amplification strategy. AB - Molybdenum disulfide (MoS2) has shown highly attractive superiority as a platform for sensing. However, DNA physisorption on the surface of MoS2 was susceptible to nonspecific probe displacement and false-positive signals. To solve these problems, we have developed a novel MoS2-aptamer nanosheet biosensor for detecting thrombin using a covalently linked aptamer to the MoS2 nanosheet. Ten percent Tween 80 was used to prevent thrombin from nonspecific binding and to rapidly form thiol-DNA/gold nanoparticle (AuNP) conjugates. Furthermore, an MoS2 and exonuclease coassisted signal amplification strategy was developed to improve the detection limit for thrombin. We used the hybridization of the aptamer molecules and the matched strand with a 5' terminal thiol to immobilize the aptamer molecules on the surface of AuNPs in AuNPs@MoS2 nanocomposites. Exonuclease digested the single-strand aptamer and released the thrombin, which was then detected in the next recycle. With the coassisted amplification strategy, a 6 fM detection limit was achieved, showing that this method has higher sensitivity than most reported methods for thrombin detection. The results presented in this work show that this method of covalently attaching the aptamer and using the coassisted amplification is a promising technique for the detection of protein in medical diagnostics. PMID- 29123398 TI - Triclosan resistance reversion by encapsulation in chitosan-coated-nanocapsule containing alpha-bisabolol as core: development of wound dressing. AB - The use of nanoparticles may be particularly advantageous in treating bacterial infections due to their multiple simultaneous mechanisms of action. Nanoencapsulation is particularly useful for lipophilic drugs. In this scenario, triclosan is considered a good candidate due to its lipophilicity, broad-spectrum activity, and safety. In the present study, we have developed and characterized an antimicrobial suspension of triclosan and alpha-bisabolol against pathogenic strains that are resistant (Pseudomonas aeruginosa) and susceptible (Escherichia coli, Staphylococcus aureus, and Candida albicans) to triclosan. We also aimed to determine the minimum inhibitory concentration, using serial microdilution adapted from a CLSI methodology (Clinical and Laboratory Standards Institute). Challenge test was used to confirm the antimicrobial effectiveness of the nanocapsule formulation, as well as after its incorporation into a commercial wound dressing (Veloderm(r)). The zeta potential of P. aeruginosa before and after contact with cationic nanocapsules and the ratio between the number of nanocapsules per colony forming unit (CFU) were determined to evaluate a possible interaction between nanocapsules and bacteria. The results showed that nanoencapsulation has improved the antimicrobial activity when tested with two different methodologies. The number of nanocapsules per CFU was high even in great dilutions and the zeta potential was reverted after being in contact with the cationic nanocapsules. The nanocapsules were able to improve the activity of triclosan, even when tested within 28 days and when dried in the wound dressing. PMID- 29123399 TI - Multifunctional gold nanorods and docetaxel-encapsulated liposomes for combined thermo- and chemotherapy. AB - Personalized and precise nanomedicines are highly demanded for today's medical needs. Liposomes are ideal candidates for the construction of multifunctional drug delivery systems. In this study, a liposome was used to improve the clinical issues of docetaxel (Doc), a potent antimitotic chemotherapy for prostate cancer (PC). RLT, a low-density lipoprotein receptor (LDLR)-binding peptide, and PEG were conjugated to the liposomes, and gold nanorods (GNRs) were also incorporated into the liposomes. The GNRs/Doc-liposome-RLT (GNRs/DocL-R) was tested in PC-3 cells and in PC-3 tumor-bearing nude mice. Results showed that GNRs/DocL-R possessed a diameter approximately 163.15+/-1.83 nm and a zeta potential approximately -32.8+/-2.16 mV. GNRs/DocL-R showed enhanced intracellular entrance, increased accumulation in the implanted tumor region, and the highest tumor inhibition in vitro and in vivo. Therefore, the multifunctional GNRs/DocL-R was a potential cancer treatment via combined chemo- and thermotherapy. PMID- 29123400 TI - Comparison of spontaneous brain activity revealed by regional homogeneity in AQP4 IgG neuromyelitis optica-optic neuritis versus MOG-IgG optic neuritis patients: a resting-state functional MRI study. AB - Objective: Many previous studies have demonstrated that neuromyelitis optica (NMO) patients have abnormalities of brain anatomy and function. However, differences in spontaneous brain activity between myelin oligodendrocyte glycoprotein (MOG)-IgG ON and aquaporin 4(AQP4)-neuromyelitis optica-optic neuritis (ON) remain unknown. In the current study, we investigated the brain neural homogeneity in MOG-IgG ON versus AQP4-IgG NMO-ON subjects by regional homogeneity (ReHo) method using magnetic resonance imaging (MRI). Patients and methods: A total of 32 NMO-ON and ON subjects (21 with AQP4-IgG+NMO-ON and 11 with MOG-IgG+ON) and 34 healthy controls (HCs) closely matched for age were recruited, and scans were performed for all subjects. A one-way analysis of variance (ANOVA) was performed to determine the regions in which the ReHo was different across the three groups. NMO-ON and ON subjects were distinguished from HCs by a receiver operating characteristic (ROC) curve. The relationship between the mean ReHo in many brain regions and clinical features in NMO subjects was calculated by Pearson correlation analysis. Results: Compared with HCs, MOG IgG+ON subjects had significantly decreased ReHo values in the posterior lobe of the left cerebellum and increased ReHo values in the left inferior frontal gyrus, right prefrontal gyrus, and left precentral/postcentral gyrus. AQP4-IgG+NMO-ON subjects showed higher ReHo values in the left inferior frontal gyrus and right middle temporal/occipital gyrus. Compared with MOG-IgG+ON subjects, AQP4-IgG+NMO ON subjects had lower ReHo values in the posterior lobe of the right cerebellum. AQP4-Ig+NMO-ON subjects showed higher ReHo values in the left precentral/postcentral gyrus and right superior temporal gyrus. Conclusion: AQP4 IgG+NMO-ON and MOG-IgG+ON subjects showed abnormal synchronized neuronal activity in many brain regions, which is consistent with deficits in visual, motor, and cognitive function. Furthermore, different patterns of synchronized neuronal activity occurred in the AQP4-IgG+NMO-ON and MOG-IgG+ON. PMID- 29123401 TI - Psychosocial intervention for patients with type 2 diabetes mellitus and comorbid depression: a meta-analysis of randomized controlled trials. AB - Background: The efficacy of psychosocial intervention has been proven in treatment of diabetic patients with depression in some studies. This meta analysis was conducted to explore the efficacy as well as additional effects of this method during diabetic management in patients with type 2 diabetes mellitus (T2DM) and comorbid depression. Methods: Electronic databases were searched from March 2000 to March 2017 for randomized controlled trials (RCTs) studying the effects of psychosocial intervention on T2DM patients with depression. There was no language limitation. Outcome measurements were symptoms of depression and anxiety, as well as glycemic control. A random effects model was conducted. Results: In total, 31 RCTs composed of 2,616 patients were eligible for this analysis. The psychosocial intervention was effective for depression symptoms with pooled standardized mean difference (SMD) of -1.50 (95% CI =-1.83, -1.18) and anxiety symptoms with SMD of -1.18 (95% CI =-1.50, -0.85). Meanwhile, the additional effects indicated a better improvement of glycemic control, including the fasting blood-glucose with SMD of -0.93 (95% CI =-1.15, -0.71), 2-hour postprandial plasma glucose with SMD of -0.84 (95% CI =-1.13, -0.56), and hemoglobin A1c with SMD of -0.81 (95% CI =-1.10, -0.53). Conclusion: These results demonstrate that the psychosocial intervention is very effective in treating T2DM patients with depression. PMID- 29123403 TI - Effects of short-term piano training on measures of finger tapping, somatosensory perception and motor-related brain activity in patients with cerebral palsy. AB - Playing a musical instrument demands the integration of sensory and perceptual information with motor processes in order to produce a harmonic musical piece. The diversity of brain mechanisms involved and the joyful character of playing an instrument make musical instrument training a potential vehicle for neurorehabilitation of motor skills in patients with cerebral palsy (CP). This clinical condition is characterized by motor impairments that can affect, among others, manual function, and limit severely the execution of basic daily activities. In this study, adolescents and adult patients with CP, as well as a group of typically developing children learned to play piano for 4 consecutive weeks, having completed a total of 8 hours of training. For ten of the participants, learning was supported by a special technical system aimed at helping people with sensorimotor deficits to better discriminate fingers and orient themselves along the piano keyboard. Potential effects of piano training were assessed with tests of finger tapping at the piano and tests of perception of vibratory stimulation of fingers, and by measuring neuronal correlates of motor learning in the absence of and after piano training. Results were highly variable especially among participants with CP. Nevertheless, a significant effect of training on the ability to perceive the localization of vibrations over fingers was found. No effects of training on the performance of simple finger tapping sequences at the piano or on motor-associated brain responses were registered. Longer periods of training are likely required to produce detectable changes. PMID- 29123402 TI - Transient global amnesia: current perspectives. AB - Transient global amnesia (TGA) is a clinical syndrome characterized by the sudden onset of an extraordinarily large reduction of anterograde and a somewhat milder reduction of retrograde episodic long-term memory. Additionally, executive functions are described as diminished. Although it is suggested that various factors, such as migraine, focal ischemia, venous flow abnormalities, and epileptic phenomena, are involved in the pathophysiology and differential diagnosis of TGA, the factors triggering the emergence of these lesions are still elusive. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a pivotal part in the pathophysiological cascade, leading to an impairment of hippocampal function during TGA. In this review, we discuss clinical aspects, new imaging findings, and recent clinical-epidemiological data with regard to the phenotype, functional anatomy, and putative cellular mechanisms of TGA. PMID- 29123404 TI - Effects of dopaminergic drug adjustment on executive function in different clinical stages of Parkinson's disease. AB - Background: Effects of dopaminergic medication on executive function in patients with Parkinson's disease (PD) are inconsistent. Objective: We examined the effect of dopaminergic medication on executive function in 24 drug-naive PD patients (de novo group) and in 21 PD patients on chronic dopaminergic medication (chronic medication group). Methods: PD patients without dementia were included in this study. For the de novo group patients, dopaminergic medication was initiated, and the dose was increased to improve motor symptoms. For the chronic medication group patients, dopaminergic medication was adjusted to relieve clinical problems. All participants were tested prior to and at 4-7 months after the drug initiation/adjustment. Executive function was assessed by using the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Motor function was assessed by using the Unified Parkinson's Disease Rating Scale (UPDRS; part III). Improvement in executive function was compared with a simultaneous change in levodopa equivalent doses (LED) of dopaminergic medication and with improvement in motor functions. Results: The mean standardized BADS scores showed no significant improvement in both the groups. In the de novo group, percent improvement in the standardized BADS scores showed a significant positive correlation with the LED, but not with percent improvement in UPDRS part III. In the chronic medication group, percent improvement in the standardized BADS scores was negatively correlated with change in the LED, but not with percent improvement in UPDRS part III. Multiple regression analysis using improvement in the standardized BADS score as a dependent variable and patient's background factors (ie, age, education, disease duration, and motor and executive assessments at baseline) as independent variable showed that improvement in the executive assessment is significantly correlated with the LED only in the de novo group. Conclusion: Effects of dopaminergic drug adjustment on executive function differ according to the patient's clinical stage and depend on LED in de novo stage. PMID- 29123405 TI - Contrast media-induced nephropathy: how has Italy contributed in the past 30 years? A systematic review. AB - Background and objective: The use of contrast media in Italy has exponentially increased in the past 3 decades. However, it is unknown whether there has been an increase in clinical research evaluating the risks associated with contrast media usage, especially regarding contrast-induced nephropathy. To fill this gap in knowledge, we performed a systematic review. Study eligibility criteria: Meta analyses, observational studies, and clinical trials assessing contrast media induced nephropathy as the safety outcome, in which at least one author was affiliated with an Italian university/health care structure, were eligble. Data sources: Ovid MEDLINE, Ovid Embase, Cochrane Methodology Register, and Web of Science were screened. Participants: Men and women exposed to contrast media. Results: In total, 60 original articles were retrieved with an incremental trend between 1990 and 2017. Cohort studies were the most common study design represented. In total, 45 of 60 (75.0%) studies were monocenter studies and 41 of 60 (68.3%) received no funding. In all, 91.7% of studies disclosed no conflicts of interest and 81.7% had no external collaboration. Most of the studies provided a level of evidence of III-2 (32/60; 53.3%) and II (23/60; 38.3%). In total, 50 of 60 studies (83.3%) were published in a scientific journal ranked in the first quartile of their subject area. Conclusion: There was an increased number of studies evaluating contrast-induced nephropathy in Italy during the last three decades. These studies covered procedures to prevent contrast-induced nephropathy or aimed to identify risk factors, biomarkers, and scores, and their related prognosis. PMID- 29123406 TI - Prophylactic Iron Supplementation in Pregnancy: A Controversial Issue. AB - In our world today, iron deficiency (ID) is the most frequent nutritional deficiency and it is being considered as an epidemic public health crisis. Women of reproductive age and infants are at particular risk of ID, especially in underdeveloped countries. During pregnancy, iron deficiency anemia is a specific risk factor associated with negative maternal and perinatal outcomes. Many countries have iron supplementation (IS) programs-as recommended by the World Health Organization-during pregnancy; however, IS clinical benefits and risks are unclear. This review aims to discuss the threats and benefits of routine IS on maternal and infant outcomes. PMID- 29123407 TI - Association of PTEN expression with biochemical recurrence in prostate cancer: results based on previous reports. AB - Purpose: Among men, prostate cancer (PCa) is one of the most commonly diagnosed cancers and the leading cause of cancer death worldwide. Phosphatase and tension homolog (PTEN) acts as a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/Akt pathway and suppresses tumor progression. Meanwhile, PTEN is frequently deleted in PCa. Identifying the specific molecular markers of biochemical recurrence (BCR) in PCa patients is critical in clinical practice. Our systematic review summarizes the evidence about the PTEN expression and BCR rate in PCa patients. Methods: To clarify the impact of PTEN expression on the PCa BCR rate, a systematic review and meta-analysis was performed by searching the PubMed, Embase, and Web of Science databases, to identify the relevant literature. The analysis of pooled data was performed with Stata 12. The combined odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were evaluated by the fixed-effects or random-effects models. The combined sensitivity and publication bias were also estimated. Results: In total, nine articles containing ten independent cohort studies, including 2,154 cases with positive expression of PTEN and 1,006 PTEN deletion cases, were deemed eligible for the meta-analysis. Overall, the positive expression of PTEN was associated with a significantly lower BCR rate (OR =0.521, 95% CI: 0.431-0.630). Subgroup analysis stratified by race revealed that in multiple races (OR =0.215, 95% CI: 0.072 0.648) and Caucasian (OR =0.469, 95% CI: 0.373-0.591) races, positive expression of PTEN showed a significant association with lower BCR rate. Subgroup analysis also showed the significant result in different sample sizes. Conclusion: PTEN deletion has a relationship with a higher BCR rate in PCa compared with positive expression of PTEN. PMID- 29123409 TI - Preventive effect of kampo medicine (hangeshashin-to, TJ-14) plus minocycline against afatinib-induced diarrhea and skin rash in patients with non-small cell lung cancer. AB - Purpose: Diarrhea and oral mucositis induced by afatinib can cause devastating quality of life issues for patients undergoing afatinib treatment. Several studies have shown that hangeshashin-to (TJ-14) might be useful for chemotherapy induced diarrhea and oral mucositis. In this study, we investigated the prophylactic effects of TJ-14 for afatinib-induced diarrhea and oral mucositis and minocycline for afatinib-induced skin rash. Patients and methods: First- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have become the standard first-line treatment in patients with EGFR mutated non-small cell lung cancer. The incidence of diarrhea was higher with afatinib than with gefitinib, and we conducted a single-arm Phase II study with afatinib. Patients who had previously undergone treatment with afatinib were ineligible. Both TJ-14 (7.5 g/day) and minocycline (100 mg/day) were administered simultaneously from the start of afatinib administration. The primary end point was the incidence of >= grade 3 (G3) diarrhea (increase of >=7 stools/day over baseline) during the first 4 weeks of treatment. The secondary end points were the incidence of >= G3 oral mucositis (severe pain interfering with oral intake) and $ G3 skin toxicity (severe or medically significant but not immediately life threatening). Results: A total of 29 patients (nine men and 20 women; median age, 66 years; performance status, 0/1/2: 18/10/1) were enrolled from four centers. Four patients had undergone prior treatment with chemotherapy, including gefitinib or erlotinib. In all, 20 (68.9%) patients and one (3.4%) patient had diarrhea of any grade and >= G3, respectively. One (3.4%) patient had >= G3 oral mucositis; no patients had >= G3 skin rash. A total of 18 (62%) of the 29 patients achieved a partial response. Conclusion: The present study indicated a trend in which TJ-14 reduced the risk of afatinib-induced diarrhea and minocycline reduced the risk of afatinib-induced skin rash. PMID- 29123408 TI - The matrix metalloproteinase and insulin-like growth factor system in oral cancer - a prospective clinical study. AB - Aim: The absence of reliable single serum biomarkers for oral premalignant lesion (OPL) and oral squamous cell carcinoma (OSCC) limits early diagnosis, monitoring of advanced disease, and prediction of prognosis. Methods: In this prospective study, serum levels of matrix metalloproteinase (MMP)-2, MMP-3, MMP-13, insulin like growth factor (IGF)-1, and IGF-binding protein (IGFBP)-3 were measured in 81 untreated OSCC patients, 49 healthy subjects, and 75 individuals with OPLs, and correlated with clinicopathological parameters. Results: Serum levels of MMP-3 were significantly higher in OSCC patients compared to healthy subjects (p=0.004). Mean IGF-1 and IGFBP-3 levels in OSCC patients were significantly lower in healthy subjects (p=0.001 and p<0.001). OSCC patients with an IGF-1 serum value <130 ng/mL (median) showed a significantly lower survival rate compared to >=130 ng/mL (p=0.049). Combined use of IGF-1 (<130 ng/mL) and IGFBP-3 (<3.1 MUg/mL) resulted in a significantly lower 12-month cumulative survival compared to the complementary set (78.5% vs 93.8%; p=0.031). There was a significantly positive correlation between IGF-1 and IGFBP-3 serum values (rs =0.625, p<0.001). Conclusion: This study shows that IGF-1 and IGFBP-3 have a vital role in the pathogenesis of OSCC and indicates for the first time that IGF 1 and IGFBP-3 in combination may be applied as potential tools for prognosis of OSCC. PMID- 29123410 TI - Long noncoding RNA and mRNA profiling in MDA-MB-231 cells following RNAi-mediated knockdown of SIRT7. AB - Breast cancer is one of the most common malignant cancers among women and a major clinical obstacle. Although studies have reported the abnormal expression of SIRT7 in breast cancer, whether the function of SIRT7 regulates the expression of long noncoding RNAs (lncRNAs) in breast cancer remains unknown. We aimed to determine the differential expressions of mRNAs and lncRNAs associated with SIRT7 and understand the regulatory mechanism of SIRT7 in breast cancer. RNA sequencing was performed to explore the transcriptome in MDA-MB-231 cells after SIRT7 depletion, and a total of 50,634 different transcripts were identified. In comparison with the negative control, siSIRT7 groups showed 240 differentially expressed mRNAs and 26 differentially expressed lncRNAs. Gene ontology analysis revealed that the differentially expressed mRNAs mainly regulated DNA replication, CXCR chemokine receptor binding, and maturation of large subunit rRNA from tricistronic rRNA transcript, nucleoplasm, mitochondrion, and NAD+ ADP ribosyltransferase activity. Kyoto Encyclopedia of Genes and Genomes analysis showed that the differentially expressed mRNAs were mainly involved in pathways associated with MAPK signaling pathway, tumor necrosis factor signaling pathway, hepatitis B, and cancer. Moreover, the target genes of the differentially expressed lncRNAs mainly regulated the carboxylic acid metabolic processes and were involved in glycolysis pathway. The mRNA-lncRNA coexpression network comprised 186 mRNAs and 23 lncRNAs. Our results provide essential data regarding differentially expressed lncRNAs and mRNAs after the depletion of SIRT7 in breast cancer cells, which may be useful to elucidate the role of SIRT7 in breast cancer development. PMID- 29123411 TI - Increased histone deacetylase 6 expression serves as a favorable prognostic factor for diffuse large B-cell lymphoma. AB - Objective: This study aims to investigate ectopic expression of histone deacetylase 6 (HDAC6) in diffuse large B-cell lymphoma (DLBCL). Methods: This study analyzed patients with DLBCL (n=132) and reactive lymph node hyperplasia (n=32) diagnosed in our hospital from December 2007 to May 2016. Correlation between HDAC6 expression and clinical pathologic features was analyzed by chi2 test. The significant differences between the 5-year overall survival (OS) or progression-free survival (PFS) and high HDAC6 expression as well as DLBCL clinic pathological features including age, International Prognostic Index (IPI) score, Eastern Cooperative Oncology Group score, lactate dehydrogenase (LDH), and germinal center B-cell-like were assessed by univariate and multivariate analyses. Results: HDAC6 high-expression percentage in DLBCL was significantly higher than that in the control group. The proportion of IPI score of 0-2, 5-year OS, and PFS in the high-expression group, which had lower percentage of patients with increased LDH and beta2-microglobulin, were significantly higher than those in the low-expression group. Moreover, HDAC6 mRNA expression in HDAC6 protein low expression was markedly lower than that in protein high expression. The multivariate analysis demonstrated that HDAC6 high expression was an independent prognostic factor for patients with DLBCL. Conclusion: HDAC6 high expression might be a prognostic factor for DLBCL. PMID- 29123413 TI - Overexpression of MPC1 inhibits the proliferation, migration, invasion, and stem cell-like properties of gastric cancer cells. AB - Invasion and metastasis are major malignant characteristics of human gastric cancer (GC), but the molecular mechanisms underlying the invasion and metastasis of GC cells remain elusive. MPC1, a key factor that controls pyruvate transportation through the inner mitochondrial membrane, was reported to be downregulated and correlated with poor prognosis in several cancers. However, the effects of MPC1 on human GC have not been illustrated. In this study, we investigated the potential role of MPC1 in the proliferation, migration, invasion, and stem cell-like properties of human GC cells and evaluated its prognostic significance for patients with GC. We found that MPC1 protein and mRNA levels were significantly decreased in GC tissues and cell lines. Low MPC1 expression was associated with tumor T stage, N stage, and advanced tumor node metastasis stage. Decreased MPC1 expression was an independent prognostic marker and correlated with poor overall survival of patients with GC. Furthermore, overexpression of MPC1 inhibited the proliferation, migration, invasion, and stem cell-like properties of GC cells. These findings suggest that MPC1 may be a novel prognostic marker and a potential therapeutic target in human GC. PMID- 29123412 TI - LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR-21-5p/SOX7 axis. AB - Background: Long noncoding RNAs (lncRNAs) have been revealed to play essential role in drug resistance of multiple cancers. LncRNA MEG3 was previously reported to be associated with cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC) cells. However, the molecular mechanism of MEG3 affecting DDP resistance in NSCLC remains to be further illustrated. In this study, we attempted to discuss whether MEG3 also could function as a competing endogenous RNA to regulate DDP resistance in NSCLC. Materials and methods: The expression of MEG3, miR-21-5p, and sex-determining region Y-box 7 (SOX7) in NSCLC tissues or cells was examined by quantitative real-time polymerase chain reaction (qRT-PCR). 3 (4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and caspase-3 activity analysis were applied to assess the DDP sensitivity of NSCLC cells. The interaction between MEG3, miR-21-5p, and SOX7 was explored by luciferase reporter assay, RNA immunoprecipitation (RIP) assay, qRT-PCR, and Western blot. Mouse NSCLC transplanted tumor was established to verify the functional role of MEG3 in DDP resistance in vivo. Results: MEG3 was downregulated in DDP-resistant NSCLC cells. Overexpression of MEG3 enhanced DDP sensitivity of NSCLC cells in vitro. MEG3 directly interacted with miR-21-5p and suppressed its expression. miR-21-5p significantly abolished the effects of MEG3 on DDP resistance via modulating cell proliferation and apoptosis. SOX7 was identified as a direct target of miR-21-5p and MEG3 positively regulated SOX7 expression by suppressing miR-21-5p. Moreover, MEG3 knockdown-induced pro proliferative and anti-apoptotic effects were reversed in DDP-resistant NSCLC cells by upregulating SOX7. Furthermore, upregulation of MEG3 induced sensitivity of NSCLC cells to DDP in vivo. Conclusion: MEG3 overexpression induced DDP sensitivity of NSCLC cells by regulating miR-21-5p/SOX7 axis, shedding light on the molecular mechanism of MEG3 involved in the development of DDP resistance of NSCLC cells. PMID- 29123414 TI - Low-grade central osteosarcoma in proximal humerus: a rare entity. AB - Low-grade central osteosarcoma is a rare subtype of tumor with low-grade malignancy. Currently, wide resection with negative resection margin is the standard treatment for this disease. The role of neoadjuvant chemotherapy in low grade central osteosarcoma was controversial and was mostly considered for tumors containing high-grade focal areas. Local tumor recurrences often exhibited a tumor with higher histologic grade or differentiation with the potential for metastases. In low-grade central osteosarcoma, timely wide resection after definite diagnosis can result in 5-year survival for almost 90%. However, the relatively nonspecific radiological and pathological findings make diagnosis very difficult. MDM2 and CDK4 are specific and provide sensitive markers for the diagnosis of low-grade central osteosarcoma, helping to differentiate low-grade central osteosarcoma from some benign lesions, including fibrous dysplasia, bone giant cell tumor, and chondrosarcoma. Here, we report the case of a 19-year-old woman with low-grade central osteosarcoma located at the proximal humerus. The affected site was rare, but the sensitive biomarkers CDK4 and MDM2 were positive. The patient recovered well after wide tumor resection following a proximal humerus endoprosthesis replacement. Our case highlighted the management strategies in low-grade central osteosarcoma. Being familiar with radiographic features, understanding the biological characteristics, and mastering diagnostic biomarkers can help oncologists avoid embarrassing situations in treatment when this rare tumor is highly suspected, even when located at an uncommon site. The discussion in this report focuses on radiographic and pathological features, advances of biomarkers that help in differential diagnosis, and current treatment options in low-grade central osteosarcoma. PMID- 29123415 TI - Impact of hypertrophic pulmonary osteoarthropathy on patients with lung cancer. AB - Purpose: Hypertrophic pulmonary osteoarthropathy (HPOA) is a rare disease that most commonly occurs secondary to lung cancer. However, the clinical significance of HPOA remains unclear. The aim of this study was to evaluate the impact of HPOA on patients with lung cancer in Taiwan. Patients and methods: Data regarding lung cancer patients who demonstrated findings of HPOA on bone scintigraphy between 2010 and 2016 were retrospectively analyzed. Pathological confirmation of cases was conducted at Chiayi and Kaohsiung Chang Gang Memorial Hospital. Clinical characteristics, including gender, smoking status, histology subtype, clinical stage, and epidermal growth factor receptor (EGFR) status were investigated. Results: We identified 69 lung cancer patients with typical HPOA findings on bone scintigraphy. Among them, 56 were male (81.2%) and 51 were ex-smokers or current smokers (73.9%). Adenocarcinoma was the most common histology subtype (n=42, 60.9%). Of 34 patients subjected to EGFR mutation analysis, only 4 (11.8%) had EGFR-tyrosine kinase inhibitor (EGFR-TKI)-sensitive mutations. Conclusion: Male, smoking, and adenocarcinoma were the most common clinical characteristics of lung cancer patients with HPOA in our cohort. However, the proportion of EGFR-TKI sensitive mutation cases was extremely low. PMID- 29123416 TI - Frequency and clinical relevance of EGFR mutations and EML4-ALK translocations in octogenarians with non-small cell lung cancer. AB - Background: Tyrosine kinase inhibitors (TKIs) have improved response rates in some patients with non-small cell lung cancer (NSCLC), and testing for EGFR mutation and ALK translocation is recommended for all patients with advanced lung adenocarcinoma. The frequency of driver mutations in elderly and very elderly patients has not been described. Patients and methods: We reviewed EGFR and ALK in patients over the age of 70 years diagnosed and treated at our center in 2015 (subgroups: 70-74, 75-79 and >80 years). We then assessed a second cohort, including all patients with lung cancer over the age of 80 years diagnosed in 2014. We also analyzed smoking history, treatment and response. Results: In the 2015 cohort of 179 patients, 16 were 80 years or older at diagnosis. Six of eight (75%) octogenarians with non-squamous NSCLC were EGFR or ALK positive. The 2014 cohort confirmed the high rate of driver alterations in octogenarians. Of 334 patients, 32 were 80 years or older and, of these, 10 had non-squamous histology and were tested for driver alterations (four of 10 [40%] EGFR or ALK positive). Rates of genetic drivers were somewhat lower in patients with non-squamous NSCLC aged 70-74 years (27.0%) and 75-79 years (26.7%). When treated with a TKI, octogenarians had high response rates and progression-free survival. Most octogenarians with lung adenocarcinoma were never smokers, with an inverse correlation of pack-years smoked to age at diagnosis. Conclusion: Very elderly patients with non-squamous NSCLC show high rates of driver alterations in EGFR and ALK. This, often frail and comorbid, population may not be fit for treatment with cytotoxic chemotherapy and may benefit from targeted treatments. Testing for EGFR and ALK alterations should not be restricted to younger patients. The biology of lung cancer in the very elderly may differ from that of moderately elderly patients, as longevity may select for individuals more resistant to, or with little exposure to, environmental carcinogens. PMID- 29123417 TI - The expression profile and clinical significance of circRNA0003906 in colorectal cancer. AB - Colorectal cancer (CRC) remains a major health problem worldwide and the detailed mechanisms of CRC still need further understanding. Circular RNAs (circRNAs), a special class of endogenous RNAs, have emerged recently as a new potential player in governing fundamental biological process and cancer progression. In this study, we chose circRNA0003906 as a targeted circRNA to evaluate its expression pattern and clinical value in CRC patients. circRNA0003906 expression level in 6 CRC cell lines and 122 paired CRC tissues was measured by quantitative real-time polymerase chain reaction. Then, the potential correlation between circRNA0003906 expression level and clinicopathological factors of CRC patients was analyzed. Additionally, a receiver operating characteristic curve was built to evaluate the diagnostic value of circRNA0003906. Our results showed that circRNA0003906 expression level was dramatically downregulated in both CRC tissues and cell lines. Moreover, the downregulation of circRNA0003906 level significantly correlated with lymphatic metastasis and poor differentiation. In addition, the area under the receiver operating characteristic curve of circRNA0003906 for CRC was 0.818 (P<0.001). Taking consideration of all of these results, circRNA0003906 may be potentially involved in the colorectal cancerogenesis and serve as a potential biomarker for the diagnosis and treatment of CRC. PMID- 29123418 TI - Evaluating the cost-effectiveness of afatinib after platinum-based therapy for the treatment of squamous non-small-cell lung cancer in France. AB - Background and aims: Lung cancer has the highest mortality rate of all cancers worldwide. Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers and has an extremely poor prognosis. Afatinib is an irreversible ErbB family blocker designed to suppress cellular signaling and inhibit cellular growth and is approved in Europe after platinum-based therapy for squamous NSCLC. The objective of the present analysis was to evaluate the cost-effectiveness of afatinib after platinum-based therapy for squamous NSCLC in France. Methods: The study population was based on the LUX-Lung 8 trial that compared afatinib with erlotinib in patients with squamous NSCLC. The analysis was performed from the perspective of all health care funders and affected patients. A partitioned survival model was developed to evaluate cost-effectiveness based on progression free survival and overall survival in the trial. Life expectancy, quality adjusted life expectancy and direct costs were evaluated over a 10-year time horizon. Future costs and clinical benefits were discounted at 4% annually. Deterministic and probabilistic sensitivity analyses were performed. Results: Model projections indicated that afatinib was associated with greater life expectancy (0.16 years) and quality-adjusted life expectancy (0.094 quality adjusted life years [QALYs]) than that projected for erlotinib. The total cost of treatment over a 10-year time horizon was higher for afatinib than erlotinib, EUR12,364 versus EUR9,510, leading to an incremental cost-effectiveness ratio of EUR30,277 per QALY gained for afatinib versus erlotinib. Sensitivity analyses showed that the base case findings were stable under variation of a range of model inputs. Conclusion: Based on data from the LUX-Lung 8 trial, afatinib was projected to improve clinical outcomes versus erlotinib, with a 97% probability of being cost-effective assuming a willingness to pay of EUR70,000 per QALY gained, after platinum-based therapy in patients with squamous NSCLC in France. PMID- 29123419 TI - Encephalitis treatment - a case report with long-term follow-up of EBV PCR in cerebrospinal fluid. AB - Background: Epstein-Barr virus (EBV) has been found to cause infectious mononucleosis multiple times, but has been associated rarely with EBV encephalitis. Also, whenever it is diagnosed, it is always treated symptomatically. Case report: A case of confirmed EBV encephalitis is presented, which was treated with antiviral therapy resulting in complete clearance of the virus in cerebrospinal fluid and minimal neurologic symptoms after hospital discharge. Conclusion: The Infectious Diseases Society of America guidelines state that intravenous acyclovir is not recommended for EBV-related encephalitis. But we reviewed the literature and found similar cases, and we believe that antiviral therapy should be recommended for EBV encephalitis because it is a potentially fatal disease and if left untreated, can lead to raised intracranial pressure, craniotomy and even death. PMID- 29123420 TI - Concurrent musculoskeletal and soft tissue pain in the upper extremity can affect the treatment and prognosis of carpal tunnel syndrome: redefining a common condition. AB - Objective: To demonstrate the importance of recognizing and separating nonmedian nerve-related symptoms from those related to median nerve compression at the carpal tunnel. Methods: The records of 80 patients, aged 31-82 years (39 males and 41 females), who had undergone median nerve decompression using open and endoscopic release surgery, were reviewed. Peripheral electrodiagnostic studies were performed in all patients prior to surgery. Those whose nonmedian nerve related symptoms, also known as musculoskeletal and soft tissue pain and tenderness, persisted postoperatively, were referred to another electrodiagnostic study to reassess the median nerve function at the carpal tunnel. Peripheral electrodiagnostic studies were deemed unnecessary for patients with exclusively median nerve-related symptoms who improved dramatically following surgery. Included from the study were cases whose presenting symptoms were primarily referrable to median nerve dysfunction with or without associated musculoskeletal pain. Cases that were excluded were those whose symptoms were related to various primary conditions. Outcome of surgery was reviewed and correlated with symptoms related to median nerve compression and musculoskeletal irritation, and with electrodiagnostic abnormalities. Results: Complete resolution of symptoms, following surgery, occurred in patients with clinical and electrophysiologic signs of median nerve compression but without significant symptoms of musculoskeletal irritation. Those with concurrent and prominent musculoskeletal and soft tissue pain had variable results, both favorable and unfavorable, including three who developed signs and symptoms of complex regional pain syndrome. Conclusion: The symptoms related to median nerve compression at the carpal tunnel and the symptoms related to musculoskeletal and soft tissue irritation are two different symptom complexes that have important diagnostic and therapeutic considerations. We would like to propose that "true carpal tunnel syndrome" symptoms, those that are exclusively median nerve related, should be considered a distinct entity. When musculoskeletal and soft tissue pain is more prominent and dominates the overall clinical presentation, the term "mechanical stress syndrome" is more appropriate. PMID- 29123421 TI - LncRNA expression in the spinal cord modulated by minocycline in a mouse model of spared nerve injury. AB - Neuropathic pain is a common and refractory chronic pain that affects millions of people worldwide. Its underlying mechanisms are still unclear, but they may involve long noncoding RNAs (lncRNAs), which play crucial roles in a variety of biological functions, including nociception. We used microarrays to investigate the possible interactions between lncRNAs and neuropathic pain and identified 22,213 lncRNAs and 19,528 mRNAs in the spinal cord in a mouse model of spared nerve injury (SNI)-induced neuropathic pain. The abundance levels of 183 lncRNAs and 102 mRNAs were significantly modulated by both SNI and administration of minocycline. A quantitative real-time polymerase chain reaction analysis validated expression changes in three lncRNAs (NR_015491, ENSMUST00000174263, and ENSMUST00000146263). Class distribution analysis of differentially expressed lncRNAs revealed intergenic lncRNAs as the largest category. Functional analysis indicated that SNI-induced gene regulations might be involved in the activities of cytokines (IL17A and IL17F) and chemokines (CCL2, CCL5, and CCL7), whereas minocycline might exert a pain-alleviating effect on mice through actin binding, thereby regulating nociception by controlling the cytoskeleton. Thus, lncRNAs might be responsible for SNI-induced neuropathic pain and the attenuation caused by minocycline. Our study could implicate lncRNAs as potential targets for future treatment of neuropathic pain. PMID- 29123423 TI - High expression of eIF3d is associated with poor prognosis in patients with gastric cancer. AB - Background: Eukaryotic initiation factor 3 subunit d (eIF3d) is the largest subunit of eIF3, which is shown to promote protein synthesis in cancer cells. Increased expression of eIF3d has been shown in some types of cancers, but has not been previously studied in gastric cancer (GC). Thus, the aim of this study was to analyze eIF3d expression in GC. Patients and methods: Expression of eIF3d was detected by immunohistochemistry in GC tissues and adjacent noncancerous (ANC) tissues. Samples were obtained from 210 patients with GC who had received curative gastrectomy. Clinicopathological features and survival rate were also analyzed. Results: Expression rates of eIF3d in GC and ANC were 45.2% and 21.0%, respectively. High expression of eIF3d protein was significantly related to tumor stage, as determined by lymph node metastasis and depth of invasion (p<0.05). The Kaplan-Meier survival curves showed that patients with high eIF3d expression had a significantly poor overall survival (p=0.005). Multivariate Cox regression analyses showed that the level of eIF3d was an independent predictive factor of poor prognosis for GC (p=0.017). Conclusion: Expression of eIF3d was upregulated in GC. High expression of eIF3d was determined as an independent poor prognostic factor in GC. It is suggested that eIF3d could be a good biomarker in GC. PMID- 29123422 TI - Neutrophil-Derived Interleukin 16 in Premetastatic Lungs Promotes Breast Tumor Cell Seeding. AB - The premetastatic niche in distant organs prior to metastatic cell arrival emerged as an important step in the metastatic cascade. However, molecular mechanisms underlying this process are still poorly understood. In particular, whether neutrophil recruitment at a premetastatic stage promotes or inhibits metastatic cell seeding has to be clarified. We aimed at unraveling how neutrophil infiltration in lung parenchyma induced by the distant primary tumor influences the establishment of lung metastasis. Elevated neutrophil counts and IL-16 levels were found in premetastatic lungs in a syngenic mouse model using 4T1 tumor cells. 4T1 cell-derived soluble factors stimulated IL-16 secretion by neutrophils. The functional contribution of IL-16 is supported by metastasis burden reduction in lungs observed on instillation of an IL-16 neutralizing antibody. Moreover, IL-16 promotes in vitro 4T1 cell adhesiveness, invasiveness, and migration. In conclusion, at a premetastatic stage, neutrophil-derived IL-16 favors tumor cell engraftment in lung parenchyma. PMID- 29123424 TI - Liver-related morbidity and mortality in patients with chronic hepatitis C and cirrhosis with and without sustained virologic response. AB - Background: Chronic hepatitis C (CHC) causes liver cirrhosis in 5%-20% of patients, leading to increased morbidity and mortality. This study aimed to estimate liver-related morbidity and mortality among patients with CHC and cirrhosis in Denmark with and without antiviral treatment and sustained virologic response (SVR). Furthermore we aimed to estimate the rate of hepatocellular carcinoma (HCC) and decompensation associated with certain prognostic factors. Materials and methods: Patients with CHC and cirrhosis registered in the Danish Database for Hepatitis B and C were eligible. Cirrhosis was based on liver biopsy, transient elastography, and clinical cirrhosis. Data were extracted from nationwide registries. The study period was from 2002 until 2013. Results: Of 1,038 patients included, 716 (69%) were male and the median age was 52 years. Median follow-up was 3.8 years, 360 patients died, and 233 of 519 treated patients achieved SVR. Alcohol overuse and hepatitis C virus genotype 3 were associated with an increased incidence rate (IR) of HCC, whereas diabetes and alcohol overuse were associated with increased IRs of decompensation. Achieving SVR reduced all-cause mortality (adjusted mortality rate ratio 0.68 [95% CI 0.43 1.09]) and liver-related mortality (mortality rate ratio 0.6 [95% CI 0.36-1]), as well as liver-related morbidity with adjusted IR ratios of 0.37 (95% CI 0.22 0.62) for HCC and 0.31 (95% CI 0.17-0.57) for decompensation. The IRs of HCC and decompensation remained elevated in patients with alcohol overuse after SVR. Conclusion: Alcohol overuse, hepatitis C genotype 3, and diabetes were associated with liver-related morbidity in patients with CHC and cirrhosis. SVR markedly reduced liver-related morbidity and mortality; however, special attention to patients with alcohol overuse should continue after SVR. PMID- 29123425 TI - Long-term safety profile of tolvaptan in autosomal dominant polycystic kidney disease patients: TEMPO Extension Japan Trial. AB - Aim: The aim of this trial (ClinicalTrials.gov identifier: NCT01280721) was to investigate the long-term safety profile of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: This open-label multicenter trial was conducted to examine adverse drug reactions (ADRs) related to tolvaptan up to an additional 3 years in 135 Japanese patients who participated in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial at doses of 60-120 mg/d. Blood samples were collected at baseline; at weeks 1, 2, and 3; at month 3; and every 3 months thereafter. Results: In total, 134/135 (>99%) patients experienced ADRs. The most frequent ADRs were thirst (77.0%), pollakiuria (57.0%), polyuria (37.8%), and hyperuricemia (14.8%). Any unexpected ADRs were not reported in this trial. Most ADRs occurred early during treatment. Fourteen patients (10.4%) experienced hepatic events, and 8 (5.9%) experienced >3 fold increases above the upper limits of normal in serum alanine aminotransferase or aspartate aminotransferase levels between 3 and 9 months following tolvaptan initiation, which recovered after drug interruption. Of the 8 patients, 7 (5.2%) were previously allocated to the placebo arm in the TEMPO 3:4 trial and 4 (3.0%) discontinued due to the hepatic events. One patient (0.7%) was previously allocated to tolvaptan and experienced similar events in the TEMPO 3:4 trial. None of the hepatic ADRs met Hy's Law laboratory criteria. Conclusion: ADRs observed in this extension trial were similar to those identified in the TEMPO 3:4 trial and hepatic events were not progressive. PMID- 29123426 TI - Language and HIV communication. PMID- 29123427 TI - Effect of age and estrogen on biochemical markers of bone turnover in postmenopausal women: a population-based study from Nepal. AB - Background: Osteoporosis, a common disease worldwide, is characterized by low bone mass and architectural deterioration of bone tissue, leading to enhanced bone fragility and increase in fracture risks. Both menopause and aging are related factors leading to greater risk of bone disease, particularly among postmenopausal women. Hence, the main purpose of this study was to investigate the differences in biochemical markers of bone turnover and to evaluate the association of hormones and age-related factors with biochemical markers between pre- and postmenopausal women. Methods: A descriptive cross-sectional study was conducted over a period of 6 months among the female population of Dholahity community, Lalitpur, Nepal. A total of 496 healthy women were selected based on the questionnaire strategy. Among them, 244 were premenopausal and 252 were postmenopausal women. Different bone markers were evaluated as per the guideline provided by the reagent manufacturer, and hormonal assay, particularly estradiol level assessment, was performed by chemiluminescence immunoassay-based technique. Results: A significant decrease in serum calcium level and estradiol level was observed in postmenopausal women as compared to premenopausal women, whereas a significant increase in serum phosphorus and alkaline phosphatase (ALP) levels was seen among postmenopausal (p<0.001). Age was significantly correlated with bone markers (ALP and calcium) in postmenopausal group (p<0.005), while there was no significant correlation in premenopausal group. In addition, there was significant positive correlation between calcium and estradiol in postmenopausal women, while ALP was negatively correlated with estradiol in that group. Further, no significant correlation was demonstrated between estradiol and bone markers in postmenopausal women in body mass index and age-adjusted partial correlation analysis. Conclusion: Timely diagnosis of osteoporosis in women would be of significant benefit for effective care for required populations and help to minimize mortality rate and financial burden of our country. PMID- 29123428 TI - Hematopoietic stem cell transplantation in a severe refractory Crohn's disease patient with intestinal stoma: a case report. AB - Background: Hematopoietic stem cell transplantation (HSCT) can be used in the treatment of patients with refractory Crohn's disease (CD) when no alternative treatment is available. However, HSCT increases the risk of infections, in particular during the aplasia of mobilization and conditioning. Moreover, intestinal stomas in CD augment the risk of morbidity in immunocompromised patients and under aplastic conditions. The objective of this report was to describe the results of the first year after HSCT in a CD patient with an intestinal stoma. Methods: The patient was assessed in respect to disease symptoms and endoscopic findings before the procedure and 30, 90, 180, and 365 days after HSCT. Results: No complications were observed during mobilization and conditioning with sufficient CD34+ cells being harvested in just one apheresis session. Toxicity was restricted to the hematological series. Scores of all the CD indexes and the quality of life of the patient improved. However, two of three endoscopic scores remained unchanged even though improvements were found in the appearance of the lesions. Conclusion: HSCT may be an alternative treatment for refractory CD in patients with an intestinal stoma, and a priori, carefully selected patients with stomas should not be excluded as candidates for this procedure. PMID- 29123429 TI - Assessment of prescribed medications and pattern of distribution for potential drug-drug interactions among chronic kidney disease patients attending the Nephrology Clinic of Lagos University Teaching Hospital in Sub-Saharan West Africa. AB - Introduction: Life expectancy has increased significantly among chronic kidney disease (CKD) patients due to the extensive use of polypharmacy practice for medication prescriptions. This predisposes them to potential drug-drug interactions (DDIs), which can lead to an increase in morbidity, mortality, length of hospital stay, and health care cost. Methods: This was a 30-month retrospective study that reviewed the medical case records of consenting adult CKD patients from January 2014 to June 2016. The Medscape drug reference database was used to evaluate patients' medications for potential DDIs. Results: This study involved 123 adult CKD patients (63 [51.22%] males and 60 [48.78%] females) with a mean age of 53.81+/-16.03 years. The most common comorbid conditions were hypertension (112 [91.10%]) and diabetes mellitus (45 [36.60%]). Regarding the form of nephrological interventions being offered, the majority of the respondents - 66 (53.66%) were on maintenance dialysis, followed by 53 (43.09%) respondents on conservative care, while 4 (3.25%) respondents were on renal transplantation. A total of 1264 prescriptions were made, and the mean number of prescribed medications per patient was 10.28+/-3.85. The most frequently prescribed medications were furosemide (88 [71.6%]), heparin (67 [54.47%]), lisinopril (65 [52.9%]), oral calcium carbonate (CaCO3) (63 [51.2%]), alpha calcidol (62 [50.4%]), and erythropoietin (61 [49.6%]). A total number of 1851 potential DDIs were observed among 118 patients. The prevalence of potential DDIs in this study was 78.0%, while the mean DDI per prescription was 1.50. Among the potential DDIs observed, the severity was mild in 639 (34.5%) patients, moderate in 1160 (62.7%) patients, and major in 51 (2.8%) patients and only 1 (0.1%) patient was of contraindicated drug combination. The most frequent DDIs' pattern observed was between oral CaCO3 and oral ferrous sulfate. There was a statistically significant association between the number of prescribed medications and the estimated glomerular filtration rate (eGFR; pre-ESRD and ESRD staging) with a P-value of 0.00000119. This implies that the number of prescribed medications increases as the eGFR declines in advance CKD stage patients. Conclusion: Most of these interactions have moderate severity and delayed onset, hence the need to follow-up these patients after prescription in order to reduce associated morbidity, mortality, length of hospital stay, and health care cost. Physicians and clinical pharmacists should utilise available interaction software to avoid harmful DDIs in these patients. PMID- 29123430 TI - The use of InvosTM somatic oximetry to measure variations in placental tissue oxygenation in laboring healthy term parturients with epidural analgesia: an observational study. AB - Purpose: Near-infrared spectroscopy provides a non-invasive continuous real-time monitoring of tissue oxygen saturation. As uterine contractions during labor may be associated with a transient uteroplacental hypoperfusion, this prospective, observational study investigates the ability of near-infrared spectroscopy to detect variation in uteroplacental oximetry during uterine contractions. Patients and methods: Four InvosTM oximetry probes (Medtronic(r), Minneapolis, MN, USA) per subjects were applied on the placental surface (PLA), the abdomen (MYO), the forearm (ARM) and the leg (LEG), of twenty healthy laboring parturients with epidural analgesia. Measurements of mean tissue oxygen saturation and area under the curve (AUC) were made during 60 minutes. The primary outcome was the difference of the AUC measurements between the PLA probe and the MYO probe. Results: The AUC values for the PLA and MYO probes were not different. The mean saturation values recorded by the PLA probe were not different from the other probes. Conclusion: The Invos monitor was unable to detect variations in uteroplacental saturation during labor in healthy parturients. PMID- 29123431 TI - Comparative quality measures of emergency care: an outcome cockpit proposal to survey clinical processes in real life. AB - Background: Benchmarking of real-life quality of care may improve evaluation and comparability of emergency department (ED) care. We investigated process management variables for important medical diagnoses in a large, well-defined cohort of ED patients and studied predictors for low quality of care. Methods: We prospectively included consecutive medical patients with main diagnoses of community-acquired pneumonia, urinary tract infection (UTI), myocardial infarction (MI), acute heart failure, deep vein thrombosis, and COPD exacerbation and followed them for 30 days. We studied predictors for alteration in ED care (treatment times, satisfaction with care, readmission rates, and mortality) by using multivariate regression analyses. Results: Overall, 2986 patients (median age 72 years, 57% males) were included. The median time to start treatment was 72 minutes (95% CI: 23 to 150), with a median length of ED stay (ED LOS) of 256 minutes (95% CI: 166 to 351). We found delayed treatment times and longer ED LOS to be independently associated with main medical admission diagnosis and time of day on admission (shortest times for MI and longest times for UTI). Time to first physician contact (-0.01 hours, 95% CI: -0.03 to -0.02) and ED LOS (-0.01 hours, 95% CI: -0.02 to -0.04) were main predictors for patient satisfaction. Conclusion: Within this large cohort of consecutive patients seeking ED care, we found time of day on admission to be an important predictor for ED timeliness, which again predicted satisfaction with hospital care. Older patients were waiting longer for specific treatment, whereas polymorbidity predicted an increased ED LOS. PMID- 29123432 TI - A pictorial Sleepiness and Sleep Apnoea Scale to recognize individuals with high risk for obstructive sleep apnea syndrome. AB - Purpose: The aim of this study was to evaluate the validity of a new pictorial form of a screening test for obstructive sleep apnea syndrome (OSAS) - the pictorial Sleepiness and Sleep Apnoea Scale (pSSAS). Validation was performed in a sample of patients admitted to sleep clinics in the UK and Switzerland. Patients and methods: All study participants were investigated with objective sleep tests such as full-night-attended polysomnography or polygraphy. The pSSAS was validated by taking into account the individual result of the sleep study, sleep-related questionnaires and objective parameters such as body mass index (BMI) or neck circumference. Different scoring schemes of the pSSAS were evaluated, and an internal validation was undertaken. Results: The full data set consisted of 431 individuals (234 patients from the UK, 197 patients from Switzerland). The pSSAS showed good predictive performance for OSAS with an area under the curve between 0.77 and 0.81 depending on which scoring scheme was used. The subscores of the pSSAS had a moderate-to-strong correlation with widely used screening questionnaires for OSAS or excessive daytime sleepiness as well as with BMI and neck circumference. Conclusion: The pSSAS can be used to select patients with a high probability of having OSAS. Due to its simple pictorial design with short questions, it might be suitable for screening in populations with low health literacy and in non-native English or German speakers. PMID- 29123433 TI - Real-world practice patterns for patients with advanced non-small cell lung cancer: multicenter retrospective cohort study in Japan. AB - Background: Recommended therapies for advanced/metastatic non-small cell lung cancer (NSCLC) have changed with the advent of targeted therapies. The objectives of this retrospective chart review study were to describe treatment patterns, biomarker testing practices, and health care resource use for advanced NSCLC at 5 sites in Japan. Patients and methods: We studied anonymized medical record data of patients aged >=18 years who initiated systemic therapy for newly diagnosed stage IIIB or IV NSCLC from January 2011 through June 2013. Data were analyzed descriptively by histology and mutation status. Overall survival was estimated using the Kaplan-Meier method. Results: We studied 175 patients, including 43 (25%), 129 (74%), and 3 (2%) with squamous, nonsquamous, and unknown NSCLC histology, respectively; 83% had stage IV NSCLC. Overall, 123 patients (70%) were male; the median age was 70 years (range, 47-86); and 33 (19%) were never smokers. In the nonsquamous cohort, 105 (81%) and 25 (19%) of patients were tested for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, respectively; 44 (42%) had EGFR-positive NSCLC and 2 (8%) had ALK-positive NSCLC, including 26/46 (57%) women and 21/46 (46%) never-smokers. In the squamous cohort, 17 (40%) and 4 (9%), respectively, were tested; 1 EGFR-positive tumor was detected. After first-line therapy, 105 (60%) patients received second-line, and 54/105 (51%; or 31% overall) received third-line therapy. EGFR tyrosine kinase inhibitors were most commonly prescribed for EGFR-positive NSCLC across all lines. In the nonsquamous EGFR/ALK negative/unknown cohort, most received first-line platinum combinations, particularly younger patients (78% >=75 years vs 93% <75 years old). The average hospitalization was 21 days/admission. The median (95% CI) overall survival from start of first-line therapy was 9.9 months (7.6-11.7) for all patients and 17.9 months (9.9-24.4) for patients with EGFR/ALK-positive status. Conclusion: Biomarker testing is common for nonsquamous NSCLC at the 5 Japanese study sites. Treatment is personalized by mutation status and age, per guideline recommendations. PMID- 29123434 TI - The prevalence of abnormal leukocyte count, and its predisposing factors, in patients with sickle cell disease in Saudi Arabia. AB - Introduction: High white blood cell (WBC) count is an indicator of sickle cell disease (SCD) severity, however, there are limited studies on WBC counts in Saudi Arabian patients with SCD. The aim of this study was to estimate the prevalence of abnormal leukocyte count (either low or high) and identify factors associated with high WBC counts in a sample of Saudi patients with SCD. Methods: A cross sectional and retrospective chart review study was carried out on 290 SCD patients who were routinely treated at King Fahad Hospital in Hofuf, Saudi Arabia. An interview was conducted to assess clinical presentations, and we reviewed patient charts to collect data on blood test parameters for the previous 6 months. Results: Almost half (131 [45.2%]) of the sample had abnormal leukocyte counts: low WBC counts 15 (5.2%) and high 116 (40%). High WBC counts were associated with shortness of breath (P=0.022), tiredness (P=0.039), swelling in hands/feet (P=0.020), and back pain (P=0.007). The mean hemoglobin was higher in patients with normal WBC counts (P=0.024), while the mean hemoglobin S was high in patients with high WBC counts (P=0.003). After adjustment for potential confounders, predictors of high WBC counts were male gender (adjusted odds ratio [aOR]=3.63) and patients with cough (aOR=2.18), low hemoglobin (aOR=0.76), and low heart rate (aOR=0.97). Conclusion: Abnormal leukocyte count was common: approximately five in ten Saudi SCD patients assessed in this sample. Male gender, cough, low hemoglobin, and low heart rate were associated with high WBC count. Strategies targeting high WBC count could prevent disease complication and thus could be beneficial for SCD patients. PMID- 29123435 TI - Early Infantile Leigh-like SLC19A3 Gene Defects Have a Poor Prognosis: Report and Review. AB - Solute carrier family 19 (thiamine transporter), member 3 (SCL19A3) gene defect produces an autosomal recessive neurodegenerative disorder associated with different phenotypes and acronyms. One of the common presentations is early infantile lethal Leigh-like syndrome. We report a case of early infantile Leigh like SLC19A3 gene defects of patients who died at 4 months of age with no response to a high dose of biotin and thiamine. In addition, we report a novel mutation that was not reported previously. Finally, we review the literature regarding early infantile Leigh-like SLC19A3 gene defects and compare the literature with our patient. PMID- 29123436 TI - Development and Retrospective Clinical Assessment of a Patient-Specific Closed Form Integro-Differential Equation Model of Plasma Dilution. AB - A closed-form integro-differential equation (IDE) model of plasma dilution (PD) has been derived which represents both the intravenous (IV) infusion of crystalloid and the postinfusion period. Specifically, PD is mathematically represented using a combination of constant ratio, differential, and integral components. Furthermore, this model has successfully been applied to preexisting data, from a prior human study, in which crystalloid was infused for a period of 30 minutes at the beginning of thyroid surgery. Using Euler's formula and a Laplace transform solution to the IDE, patients could be divided into two distinct groups based on their response to PD during the infusion period. Explicitly, Group 1 patients had an infusion-based PD response which was modeled using an exponentially decaying hyperbolic sine function, whereas Group 2 patients had an infusion-based PD response which was modeled using an exponentially decaying trigonometric sine function. Both Group 1 and Group 2 patients had postinfusion PD responses which were modeled using the same combination of hyperbolic sine and hyperbolic cosine functions. Statistically significant differences, between Groups 1 and 2, were noted with respect to the area under their PD curves during both the infusion and postinfusion periods. Specifically, Group 2 patients exhibited a response to PD which was most likely consistent with a preoperative hypovolemia. Overall, this IDE model of PD appears to be highly "adaptable" and successfully fits clinically-obtained human data on a patient-specific basis, during both the infusion and postinfusion periods. In addition, patient-specific IDE modeling of PD may be a useful adjunct in perioperative fluid management and in assessing clinical volume kinetics, of crystalloid solutions, in real time. PMID- 29123437 TI - Analysis of Age Distribution and Disease Presentation of 1269 Patients with Sarcoidosis. AB - Objective: While the incidence of sarcoidosis peaks between 20 and 39 years, it is comparatively low in elderly subjects. We sought to determine whether there are age-dependent differences in the demographic and laboratory characteristics of patients with sarcoidosis. Materials and Methods: We retrospectively collected information from our database using the International Classification of Disease (ICD) diagnostic code D86 between 2008 and 2014. Patients were divided into three groups: 20-39 years old (Group 1), 40-59 years old (Group 2), and 60-80 years old (Group 3). Results: A total of 3988 patients with code of D86 were included in the study. After the exclusion of non-eligible patients, the number of cases in Groups 1, 2, and 3 were 276, 641, and 352, respectively. The groups were compared according to demographic characteristics, ICD diagnostic codes, and laboratory parameters. The ratio of female patients was significantly higher in Group 3 than in Groups 1 and 2 (p=0.000). There was no difference in diagnostic codes of the ICD subgroups between groups (p=0.19). While the level of blood-urea nitrogen was significantly higher in Group 3 patients than in other groups (p=0.000), serum angiotensin-converting enzyme (ACE) values were found to be significantly low in Group 3 (p=0.010). The mean ACE values did not differ between females and males (50.8+/-39.3 and 59.1+/-45.5 mg/dL, respectively) (p=0.18). Conclusion: The majority of patients with sarcoidosis were female in all age groups and pulmonary sarcoidosis was the most common presentation of the disease. Elderly patients (>=60 years) with sarcoidosis had lower serum ACE levels than younger patients. PMID- 29123438 TI - Intravitreal Infliximab Injection to Treat Experimental Endophthalmitis. AB - Objective: The purpose of this study was to compare the use of an intravitreal injection of infliximab and of dexamethasone combined with vancomycin to treat experimental endophthalmitis induced by Staphylococcus epidermidis. Materials and Methods: The study was conducted between March 25 and April 13, 2012. Twenty-five six-month-old healthy rabbits were used, each weighing 2.5-3 kg. The rabbits were randomized into five groups with five animals per group. Endophthalmitis was induced by 0.1 mL (103 colony-forming units) S. epidermidis in all groups. In group 1, injection was not implemented after the occurrence of endophthalmitis. In groups 2, 3, and 4, the following intravitreal injections were given 24 h after the occurrence of endophthalmitis: group 2, 0.1 mg/0.1 mL vancomycin; group 3, 1 mg/0.1 mL vancomycin and 1 mg/0.1 mL dexamethasone; and group 4, 1 mg/0.1 mL vancomycin and 2 mg/0.1 mL infliximab. Group 5 was the control/uninfected group. The rabbits were clinically assessed each day for seven days. On day 9, a histopathologic evaluation was performed after enucleation. Results: After a clinical evaluation, no statistically significant difference was found between the vancomycin+infliximab and vancomycin+dexamethasone groups (p>0.05). The difference was significant when both groups were compared with the vancomycin group (p<0.001). After the histopathologic evaluation, no statistically significant difference was found among the three groups (p>0.05). Conclusion: An intravitreal injection of infliximab and of dexamethasone combined with vancomycin have similar clinical and histopathologic effects. To supplement the antibiotic treatment of endophthalmitis, infliximab in a safe dose range can be used as an alternative to dexamethasone to suppress inflammation and prevent ocular damage. PMID- 29123439 TI - Thoracoscopic Treatment of Pulmonary Hydatid Cysts May Have a High Morbidity Risk in Children: Retrospective Analysis. AB - Objective: Thoracoscopic treatment of pulmonary hydatid cyst (PHC) has been considered to be a good treatment option in both children and adults for nearly 25 years. However, there have been very few pediatric studies published during this period. Our goal is to review our results and evaluate the efficiency of thorascopy in pediatric patients. Materials and Methods: The medical records of patients with PHC who were surgically treated between 2005 and 2015 were reviewed. As all cysts larger than 5 cm in diameter were surgically removed, cysts less than 5 cm in diameter were medically treated and were not included in the study. Demographics, cyst characteristics, and operative/postoperative data were compared between patients who underwent thorascopy (thoracoscopy group) and patients who underwent thoracotomy (thoracotomy group). Chi-square and t-test were used for statistical analysis where appropriate. Results: There were 26 consecutive children (14 girls, 12 boys; mean age 9.4+/-2.7) included in the study. Except for 2 incidentally diagnosed patients, all were symptomatic, 4 had multifocal lesions, and multiorgan involvement was detected in 11 patients. Thoracoscopy was performed in 10 patients, and conversion was necessary in 2 patients due to unsuccessful fistula ligation attempts. The thoracoscopy group included 8 thoracoscopically treated patients, and remaining patients constituted the thoracotomy group (n=18). Comparison of preoperative characteristics of the groups was insignificant, whereas the overall complication rate (residual bronchial fistula, prolonged air leak, pneumothorax, and localized air cyst) and median hospital stay were significantly higher in the thoracoscopy group. There was no mortality and no recurrence at the postoperative follow-up after 37.4 months. Conclusion: The thoracoscopic approach to PHC may have a high risk of conversion and postoperative complication rate. Thoracotomy in children still seems to be the approach of choice for PHC larger than 5 cm. Routine thoracoscopic hydatid cyst treatment is yet far from being the gold standard, whereas thoracoscopy may be preferred in selected patients. PMID- 29123440 TI - Eosinophil Chemokines and Clara Cell Protein 16 Production in Nasal Mucosa of Patients with Persistent Allergic Rhinitis. AB - Objective: Eotaxin-2 and regulated on activation normal T cell expressed and secreted (RANTES) are involved in the eosinophil trafficking in patients with persistent allergic rhinitis (PAR). Clara cell protein 16 (CC16) is an anti inflammatory protein mainly produced by the epithelial non-ciliated Clara cells. The aim of this study was to investigate the production of CC16 and chemokines eotaxin-2 and RANTES in nasal mucosa of patients with PAR. Materials and Methods: Twenty-one PAR patients and 20 healthy participants were included. CC16, eotaxin 2, and RANTES concentrations were measured in nasal secretions. PAR patients were administered fluticasone furoate nasal spray (220 MUg daily for 14 days). We performed nasal cytology, symptom score assessment, and inflammatory mediator detection before and after the therapy. Results: The level of CC16 in patients with PAR was lower than in the healthy subjects (p=0.023). The eosinophil counts and local concentrations of eotaxin-2 and RANTES were higher in patients with PAR in comparison with controls (p=0.008, p=0.001, p=0.031, respectively). We also found a negative correlation between the CC16 and eotaxin-2 levels in nasal secretions of PAR patients (r=-0.492, p=0.023). After corticosteroid therapy, the patients with PAR had lower nasal symptoms, eosinophil counts, eotaxin-2, and RANTES levels and higher levels of CC16 (p<0.001 for all parameters). Conclusion: Our results suggest the presence of a negative correlation in production of CC16 and eotaxin-2 in nasal mucosa of patients with PAR. Intranasal corticosteroids have a suppressive effect on mucosal eosinophilic inflammation and a stimulating effect on local CC16 production. PMID- 29123441 TI - Evaluation of the BACTEC MGIT 960 SL DST Kit and the GenoType MTBDRsl Test for Detecting Extensively Drug-resistant Tuberculosis Cases. AB - Objective: The present study aimed to evaluate the performances of the BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl test for detecting second-line antituberculosis drug resistance in Multidrug-resistant TB (MDR-TB) cases. Materials and Methods: Forty-six MDR-TB strains were studied. Second-line antituberculosis drug resistances were detected using the BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl test. The Middlebrook 7H10 agar proportion method was used as the reference test. Results: The sensitivity and specificity values for the BACTEC MGIT 960 SL DST kit were both 100% for amikacin, kanamycin, capreomycin (4 ug/mL), and ofloxacin; 100% and 95.3%, respectively, for capreomycin (10 ug/mL); and 85.7% and 100%, respectively, for moxifloxacin (0.5 ug/mL). The sensitivity and specificity values for the GenoType MTBDRsl test to detect fluoroquinolone and aminoglycoside/cyclic peptide resistance were 88.9% and 100%, respectively, for ofloxacin and 85.7% and 94.9%, respectively, for moxifloxacin (0.5 ug/mL). The accuracy of the GenoType MTBDRsl assay for kanamycin, capreomycin, ofloxacin, and moxifloxacin was lower than that of the BACTEC MGIT 960 SL DST. Conclusion: The BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl were successful in detecting second-line antituberculosis drug resistance. Preliminary results of the GenoType MTBDRsl are very valuable for early treatment decisions, but we still recommend additional BACTEC MGIT 960 SL DST kit usage in the routine evaluation of drug-resistant tuberculosis. PMID- 29123442 TI - Functional Effects of Alagebrium (ALT-711)-Isolated Rat Carotid Artery. AB - Objective: In our study, the effects of glycosylated protein cross-link breaker, alagebrium was investigated on isolated rat carotid artery using myography. Alagebrium showed vasodilator effect on carotid artery rings; particularly, this effect was significantly increased in endothelium-intact rings. Materials and Methods: To clarify the vasodilator mechanism of alagebrium, different antagonists such as N(G)-Nitro-L-arginine methyl ester (L-NAME), glibenclamide, indomethacin, metoprolol, propranolol, tetraethylammonium, and calcium channel activator BAYK-8644 were used to reverse this effect. Results: Relaxation% responses to alagebrium were more significantly increased in intact endothelium than in denuded arteries. Blocking vasodilation related to channels (K-ATP, PGI2, BKca) and receptors (beta1, beta2) did not reverse the relaxation response to alagebrium. Vasodilator response to alagebrium was only slightly decreased after L-NAME incubation and significantly decreased after BAYK-8644 incubation. Conclusion: Results of present study suggest that the mechanism of alagebrium induced vasodilator effect may include the blockage of L-type calcium channels and partially of the nitric oxide synthase enzyme. PMID- 29123443 TI - Plasma Atherogenic Index is an Independent Indicator of Subclinical Atherosclerosis in Systemic Lupus Erythematosus. AB - Objective: Systemic lupus erythematosus (SLE) is characterized by chronic inflammation. Plasma atherogenic index (PAI) is a valuable marker for the cardiovascular disease and cardiac risk. The aim of this study was to evaluate the role and clinical use of PAI in atherosclerosis and the cardiac risk in SLE patients. Materials and Methods: We included 56 female SLE patients who were selected according to the American College of Rheumatology (1997) diagnosis criteria. Furthermore, we selected age-and body mass index (BMI)-matched 56 female healthy individuals. PAI was measured as a logarithmic value of triglyceride to high-density cholesterol ratio. We used carotid intima media thickness (cIMT) as an inflammatory marker because of its widespread use. The lipid and other biochemical parameters of patient and control groups were examined. Results: The PAI and cIMT values of SLE patients were 0.04+/-0.23 and 0.78+/-0.18 mm, respectively. Besides, for the control group, the PAI value was 0.09+/-0.20 and cIMT value was 0.50+/-0.15 mm (p=0.002, p<0.001; respectively). There was a strong correlation between cIMT and PAI (r=0.273, p=0.003). According to the multiple logistic regression analysis, we found that PAI value is an independent factor for cIMT in SLE patients (odds ratio: 2.6, 95 % confidence interval; 1.506-4.374; p=0.029). Conclusions: We determined that PAI can be used as an independent indicator for subclinical atherosclerosis in SLE patients. PMID- 29123444 TI - Imaging Findings of the Unusual Presentations, Associations and Clinical Mimics of Acute Appendicitis. AB - There are many kinds of unusual presentations or associations and clinical mimics of acute appendicitis, and definitive diagnosis requires knowledge of the imaging findings in some cases. The unusual presentations and associations of acute appendicitis included in this study are perforated appendicitis, acute appendicitis occurring in hernias, acute appendicitis with cystic endosalpingiosis, intussusception of appendix, and acute appendicitis with pregnancy. We also present uncommon gastrointestinal, urinary and gynecologic clinical mimics of acute appendicitis including anomalous congenital band, duplication cysts, giant Meckel's diverticulitis, inflammatory fibroid polyp, renal artery thrombosis, spontaneous urinary extravasation and OHVIRA syndrome. Familiarity with these entities may improve diagnostic accuracy and enable the quickest and most appropriate clinical management. PMID- 29123446 TI - Ankylosing Spondylitis and Balance. AB - Ankylosing spondylitis is a chronic inflammatory disease that mainly affects axial joints and the changes in the vertebrae cause typical kyphotic posture. In patients with ankylosing spondylitis, the postural changes, including cervical flexion, decreased lumbar lordosis, posterior rotation of pelvis, hip extension, knee flexion, and plantar flexion of ankle along with kyphosis, may occur in the upcoming terms of the disease and may negatively affect balance. Joint and eye involvements; muscular, vestibular and proprioceptional changes can also affect balance. This review evaluates the ankylosing spondylitis-equilibrium relationship together with posture and other parameters of balance. PMID- 29123445 TI - Acute Exacerbation of Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is the most common cause of chronic diffuse parenchymal disease of unknown cause. However, IPF patients sometimes develop acute exacerbation (AE), which is a life-threatening condition. The cause of AE of IPF remains unknown. The new criteria for AE of IPF have been proposed last year, wherein both idiopathic and triggered AE were proposed. Triggered AE includes infection, post-procedure and post-operation, drug toxicity, and aspiration. Therefore, detailed history taking is crucial. In this review, the definition, clinical symptoms, chest imaging, management, and prognosis for AE of IPF are described. PMID- 29123447 TI - Endovascular Stent Graft Repair of Localized Acute Aortic Intramural Hematoma: A Case Report and Literature Review. AB - Aortic intramural hematoma (IMH) is a variant of acute aortic syndrome, which can be life-threatening. Ascending aorta IMHs, particularly accompanied by penetrating aortic ulcer (PAU), can cause dissection, rupture, and cardiac tamponade. Therefore, early surgical treatment is recommended for IMHs of the ascending aorta. Herein, we present the case of a 60-year-old male patient who was on warfarin sodium treatment and in whom an IMH localized to the arcus aorta was detected incidentally via computed tomography, with the suspicion of pulmonary embolism, and an endovascular stent graft was inserted into the arcus aorta. This case highlights the importance of following ulcerated aortic plaques and suggests that IMH can be successfully treated with endovascular stent grafting. PMID- 29123448 TI - New Case of Endotipsitis: Urgent Need for Clinical Practice Guidelines. AB - Transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive procedure used for the decompression of portal pressure since the early 1990s. Bacteremia with an infection of the TIPS or endotipsitis is a serious complication with 32% mortality. To date and including the present case, only 56 cases have been reported in the literature. There are concerns regarding underdiagnosis. We report a case of a patient with endotipsitis and recurrent bacteremia treated successfully in our institution. In addition, previous reported cases were reviewed regarding microbiological data and mortality. Clinical practice guidelines including uniform disease definition, prophylaxis, and treatment of this nosocomial prosthetic-related infection are urgently needed. PMID- 29123450 TI - Cobblestone Appearance of the Nasopharyngeal Mucosa. PMID- 29123449 TI - Fracture With Urethral Injury: Evaluation by Retrograde Urethrogram. AB - Penile fracture is a rare condition. It primarily involves the rupture of the corpus cavernosum during erection, which may also affect the corpus spongiosum and urethra. We describe the case of a 35-year-old man who presented with acute penile pain, penile swelling, and a hematuria after a blunt trauma during sexual intercourse. The emergency retrograde urethrogram revealed a rare condition, extravasation of the opaque material from the penile urethra into the cavernous structure. The partial rupture of the corpus cavernosum with urethral disruption was repaired surgically. At the 3-month postoperative follow-up control, no complications were reported by the patient who has had both normal erectile and voiding functions. In cases of penile fracture with suspected urethral injury, retrograde urethrogram can be used for definitive diagnosis. PMID- 29123451 TI - A Giant Sciatic Hernia. PMID- 29123452 TI - Mechanical Extraction of a Refluxed Onyx Piece from the Sigmoid Sinus Using a Solitaire AB Stent for Treating a Dural Arteriovenous Fistula: technical report. PMID- 29123453 TI - Efficiency of Hyperbaric Oxygen Therapy in the Treatment of Carbon Monoxide Toxicity. PMID- 29123454 TI - Vitamin D- the Best Thing Under the Sun? PMID- 29123455 TI - Surgery on the Eye with Uveitis. PMID- 29123456 TI - A Guide to Time Lag and Time Lag Shortening Strategies in Oncology-Based Drug Development. AB - One of the ongoing challenges for academic, biotech and pharma organizations involved in oncology-related research and development is how to help scientists be more effective in transforming new scientific ideas into products that improve patients' lives. Decreasing the time required between bench work and translational study would allow potential benefits of innovation to reach patients more quickly. In this study, the time required to translate cancer related biomedical research into clinical practice is examined for the most common cancer cases including breast, lung and prostate cancer. The calculated "time lag" typically of 10 years for new oncology treatments in these areas can create fatal delays in a patient's life. Reasons for the long "time lag" in cancer drug development were examined in detail, and key opinion leaders were interviewed, to formulate suggestions for helping new drugs reach from bench to bed side more quickly. PMID- 29123457 TI - Survival benefit of postoperative radiation in papillary meningioma: Analysis of the National Cancer Data Base. AB - Aim/Background: Papillary meningioma represents a rare subset of World Health Organization (WHO) Grade III meningioma that portends an overall poor prognosis. There is relatively limited data regarding the benefit of postoperative radiation therapy (PORT). We used the National Cancer Data Base (NCDB) to compare overall survival (OS) outcomes of surgically resected papillary meningioma cases undergoing PORT compared to post-operative observation. Materials and methods: The NCDB was queried for patients with papillary meningioma, diagnosed between 2004 and 2013, who underwent upfront surgery with or without PORT. Overall survival (OS) was determined using the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) analyses were performed. Results: In total, 190 patients were identified; 89 patients underwent PORT, 101 patients were observed. Eleven patients received chemotherapy (6 with PORT, 5 without). 2-Year OS was significantly improved with PORT vs. no PORT (93.0% vs. 74.4%), as was 5-year OS (78.5% vs. 62.5%) (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27 0.85; p = 0.01). On MVA, patients receiving PORT had improved OS compared to observation (HR, 0.41; 95% CI, 0.22-0.76; p = 0.005). On subset analysis by age group, the benefit of PORT vs. no PORT was significant in patients <=18 years (n = 13), with 2-year OS of 85.7% vs. 50.0% (HR, 0.08; 95% CI, 0.01-0.80; p = 0.032) and for patients >18 years (n = 184), with 2-year OS of 94.7% vs. 76.1% (HR, 0.55; 95% CI, 0.31-1.00; p = 0.049), respectively. Conclusions: In this large contemporary analysis, PORT was associated with improved survival for both adult and pediatric patients with papillary meningioma. PORT should be considered in those who present with this rare, aggressive tumor. PMID- 29123458 TI - Comparison of MRI sequences in ideal fiducial maker-based radiotherapy for prostate cancer. AB - Aim: Prostate contouring using CT alone is difficult. To overcome the uncertainty, CT/MRI registration using a fiducial marker is generally performed. However, visualization of the marker itself can be difficult with MRI. This study aimed to determine the optimal MRI pulse sequence for defining the marker as well as the prostate outline among five sequences. Materials and methods: A total of 21 consecutive patients with prostate cancer were enrolled. Two gold fiducial markers were placed before CT/MRI examination. We used the following five sequences: T1-weighted spin-echo (T1WI; TR/TE, 400-650/8 ms); T2-weighted fast spin-echo (T2WI; 4000/80); T2*-2D-weighted gradient echo (T2*2D; 700/18); T2*-3D weighted gradient echo (T2*3D; TR/TE1/deltaTE, 37/14/7.3); and contrast-enhanced T1-weighted spin-echo (CE-T1WI; 400-650/8). Qualitative image analysis of the sequences was performed by three observers. These observers subjectively scored all images on a scale of 1-3 (1 = unclear, 2 = moderate, 3 = well visualized). A higher score indicated better visualization. Results: T2WI was significantly superior to the other sequences in terms of prostate definition. T2*2D and T2*3D were strongly superior to the other sequences and were significantly superior in terms of fiducial marker definition. Conclusions: T2*2D and T2*3D are superior to the other sequences for prostate contouring and marker identification. Therefore, we recommend initial T2*3D and T2*2D examinations. PMID- 29123459 TI - Wearable Sensing of Cardiac Timing Intervals from Cardiogenic Limb Vibration Signals. AB - In this paper we describe a new method to measure aortic valve opening (AVO) and closing (AVC) from cardiogenic limb vibrations (i.e., wearable ballistocardiogram [BCG] signals). AVO and AVC were detected for each heartbeat with accelerometers on the upper arm (A), wrist (W), and knee (K) of 22 subjects following isometric exercise. Exercise-induced changes were recorded with impedance cardiography. The method, Filter BCG, detects peaks in distal vibrations after filtering with individually-tuned bandpass filters. In agreement with recent studies, we did not find peaks at AVO and AVC in limb vibrations directly. Interestingly, distal vibrations filtered with FilterBCG yielded reliable peaks at AVO (r2 = 0.95 A, 0.94 W, 0.77 K) and AVC (r2= 0.92 A, 0.89 W, 0.68 K). FilterBCG measures AVO and AVC accurately from arm, wrist, and knee vibrations, and it outperforms the standard R-J interval method. PMID- 29123460 TI - FledFold: A Novel Software for RNA Secondary Structure Prediction. AB - Background: RNA secondary structure is essential to understand the mechanism of RNAs. Method: In this paper, fledFold, a novel software for RNA secondary structure prediction, is introduced. It combines both thermodynamic and kinetic factors of RNA secondary structures and can predict RNA secondary structures from their primary sequences with local personal computers. Results: FledFold is implemented in C++ under Windows 7 and could run on windows 7 or later version with at least 2 GB of RAM. Fledfold is user friendly and could output results with multiple formats. Conslusion: FledFold will be a valuable tool for RNA researches and it could be downloaded freely from http://www.jlucomputer.com/fledfold.php. PMID- 29123462 TI - Characterization of a New Allelic Variant of Triosephosphate Isomerase from the LNCaP Human Prostate Cancer Cell Line: Enzyme Inhibition and Spectroscopic Studies. AB - Background: The glycolytic pathway plays an important role in tumor cells. Triosephosphate isomerase (TIM) catalyzes the reversible isomerization of D glyceraldehyde-3-phosphate (GAP) to dihydroxyacetone phosphate (DHAP) in the glycolysis. Proteomics of a human prostate adenocarcinoma cell line revealed the presence of the G233D TIM variant, a new allelic type whose biochemical properties have not been reported [1]. Objective: Provide the first biochemical and biophysical characterization of the allelic variant G233D of TIM. Methods: The Michaelis-Menten curves using both substrates of TIM were obtained. Also the effect of the competitive inhibitor phosphoenolpyruvate (PEP) was assessed in presence of GAP and DHAP. The thermal stability in absence and presence of PEP was analyzed by circular dichroism spectroscopy. For comparison purposes, all the measurements were carried out on the wild type TIM and variant G233D. Results: The G233D variant exhibited a kcat value 4-fold lower than that of the WT enzyme in the GAP isomerization to DHAP, which is the reverse reaction of the glycolytic pathway. The G233D variant exhibited Ki and IC50 values of 120 MUM and 356 MUM in the presence of several concentrations of GAP and 0.3 mM DHAP, respectively. These inhibition parameters are similar to those exhibited by the WT enzyme. The thermal unfolding cooperativity of G233D variant was significantly increased upon PEP binding, suggesting that the ligand-bound enzyme was trapped in a rigid conformation. Conclusion: We suggest that the flow of GAP through glycolysis could be enhanced by the decreased activity of the G233D variant in the formation of DHAP. PMID- 29123461 TI - Intestinal Absorption and Factors Influencing Bioavailability of Magnesium-An Update. AB - Background: Information on the bioavailability of the essential mineral Mg2+ is sparse. Objective/Method: Evaluation of the present knowledge on factors influencing the bioavailability and intestinal absorption of Mg2+. Results: Mg2+ is absorbed via a paracellular passive and a transcellular active pathway that involves TRPM6/7 channel proteins. The bioavailability of Mg2+ varies within a broad range, depending on the dose, the food matrix, and enhancing and inhibiting factors. Dietary factors impairing Mg2+ up-take include high doses of other minerals, partly fermentable fibres (e.g., hemicellulose), non-fermentable fibres (e.g., cellulose, lignin), phytate and oxalate, whereas proteins, medium-chain triglycerides, and low- or indigestible carbohydrates (e.g., resistant starch, oligosaccharides, inulin, mannitol and lactulose) enhance Mg2+ uptake. The Mg2+ dose is a major factor controlling the amount of Mg2+ absorbed. In principle, the relative Mg2+ uptake is higher when the mineral is in-gested in multiple low doses throughout the day compared to a single, large intake of Mg2+. The type of Mg2+ salt appears less relevant than is often thought. Some studies demonstrated a slightly higher bioavailability of organic Mg2+ salts compared to inorganic compounds under standardized conditions, whereas other studies did not. Conclusion: Due to the lack of standardized tests to assess Mg2+ status and intestinal absorption, it remains unclear which Mg2+ binding form produces the highest bioavailability. The Mg2+ intake dose combined with the endogenous Mg2+ status is more important. Because Mg2+ cannot be stored but only retained for current needs, a higher absorption is usually followed by a higher excretion of the mineral. PMID- 29123463 TI - Switchgrass PvDREB1C plays opposite roles in plant cold and salt tolerance in transgenic tobacco. AB - Background: The C-repeat-binding factors/DRE-binding factors (CBF/DREBs) comprise a key transcription factor family involved in plant stress tolerance. Yet, there is limited information about switchgrass DREB genes and their functional roles. Results: In this study, four cold-inducible PvDREB1s were identified from switchgrass (Panicum virgatum), among which PvDREB1C was the one responded to cold stress later than the other three PvDREB1s. Yet, ectopic overexpression of PvDREB1C led to significantly compromised, instead of improved cold tolerance in transgenic tobacco. On the other hand, PvDREB1C was transcriptionally down regulated in response to salt stress, but overexpression of PvDREB1C improved plant salt tolerance in transgenic tobacco. The improved salt tolerance was associated with increased K+/Na+ ratio and Ca2+ content, higher cellular osmotic potential, and activation of stress-related functional genes in the leaves of transgenic plants under salt stress. Conclusions: The current results implied that PvDREB1C played opposite roles in plant cold and salt tolerance. Although DREB1s were known as positive stress regulators, particular attentions shall be paid to their potential negative regulatory role(s). PMID- 29123464 TI - Pattern Separation: A Potential Marker of Impaired Hippocampal Adult Neurogenesis in Major Depressive Disorder. AB - Adult neurogenesis involves the generation of new neurons, particularly in the dentate gyrus of the hippocampus. Decreased hippocampal neurogenesis has been implicated in both animal models of depression and in patients with major depressive disorder (MDD), despite some inconsistency in the literature. Here, we build upon current models to generate a new testable hypothesis, linking impaired neurogenesis to downstream psychological outcomes commonly observed in MDD. We contend that disruption in adult neurogenesis impairs pattern separation, a hippocampus-dependent function requiring the careful discrimination and storage of highly similar, but not identical, sensory inputs. This, in turn, can affect downstream processing and response selection, of relevance to emotional wellbeing. Specifically, disrupted pattern separation leads to misperceived stimuli (i.e., stimulus confusion), triggering the selection and deployment of established responses inappropriate for the actual stimuli. We speculate that this may be akin to activation of automatic thoughts, described in the Cognitive Behavior Theory of MDD. Similarly, this impaired ability to discriminate information at a fundamental sensory processing level (e.g., impaired pattern separation) could underlie impaired psychological flexibility, a core component of Acceptance and Commitment Therapy of MDD. We propose that research is needed to test this model by examining the relationship between cognitive functioning (e.g., pattern separation ability), psychological processes (e.g., perseveration and psychological inflexibility), and neurogenesis, taking advantage of emerging magnetic resonance spectroscopy-based imaging that measures neurogenesis in-vivo. PMID- 29123465 TI - Autoimmunity as a Driving Force of Cognitive Evolution. AB - In the last decades, increasingly robust experimental approaches have formally demonstrated that autoimmunity is a physiological process involved in a large range of functions including cognition. On this basis, the recently enunciated "brain superautoantigens" theory proposes that autoimmunity has been a driving force of cognitive evolution. It is notably suggested that the immune and nervous systems have somehow co-evolved and exerted a mutual selection pressure benefiting to both systems. In this two-way process, the evolutionary-determined emergence of neurons expressing specific immunogenic antigens (brain superautoantigens) has exerted a selection pressure on immune genes shaping the T cell repertoire. Such a selection pressure on immune genes has translated into the emergence of a finely tuned autoimmune T-cell repertoire that promotes cognition. In another hand, the evolutionary-determined emergence of brain autoreactive T-cells has exerted a selection pressure on neural genes coding for brain superautoantigens. Such a selection pressure has translated into the emergence of a neural repertoire (defined here as the whole of neurons, synapses and non-neuronal cells involved in cognitive functions) expressing brain superautoantigens. Overall, the brain superautoantigens theory suggests that cognitive evolution might have been primarily driven by internal cues rather than external environmental conditions. Importantly, while providing a unique molecular connection between neural and T-cell repertoires under physiological conditions, brain superautoantigens may also constitute an Achilles heel responsible for the particular susceptibility of Homo sapiens to "neuroimmune co pathologies" i.e., disorders affecting both neural and T-cell repertoires. These may notably include paraneoplastic syndromes, multiple sclerosis as well as autism, schizophrenia and neurodegenerative diseases. In the context of this theoretical frame, a specific emphasis is given here to the potential evolutionary role exerted by two families of genes, namely the MHC class II genes, involved in antigen presentation to T-cells, and the Foxp genes, which play crucial roles in language (Foxp2) and the regulation of autoimmunity (Foxp3). PMID- 29123466 TI - Neuroprotective Effect of beta-Caryophyllene on Cerebral Ischemia-Reperfusion Injury via Regulation of Necroptotic Neuronal Death and Inflammation: In Vivo and in Vitro. AB - Necrotic cell death is a hallmark feature of ischemic stroke and it may facilitate inflammation by releasing intracellular components after cell-membrane rupture. Previous studies reported that beta-caryophyllene (BCP) mitigates cerebral ischemia-reperfusion (I/R) injury, but the underlying mechanism remains unclear. We explored whether BCP exerts a neuroprotective effect in cerebral I/R injury through inhibiting necroptotic cell death and inflammation. Primary neurons with and without BCP (0.2, 1, 5, 25 MUM) treatment were exposed to oxygen glucose deprivation and re-oxygenation (OGD/R). Neuron damage, neuronal death type and mixed lineage kinase domain-like (MLKL) protein expression were assessed 48 h after OGD/R. Furthermore, mice underwent I/R procedures with or without BCP (8, 24, 72 mg/kg, ip.). Neurologic dysfunction, cerebral infarct volumes, cell death, cytokine levels, necroptosis core molecules, and HMGB1-TLR4 signaling were determined at 48 h after I/R. BCP (5 MUM) significantly reduced necroptotic neurons and MLKL protein expression following OGD/R. BCP (24, 72 mg/kg, ip.) reduced infarct volumes, neuronal necrosis, receptor-interaction protein kinase-1 (RIPK1), receptor-interaction protein kinase-3 (RIPK3) expression, and MLKL phosphorylation after I/R injury. BCP also decreased high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) levels. Thus, BCP alleviates ischemic brain damage potentially by inhibiting necroptotic neuronal death and inflammatory response. This study suggests a novel application for BCP as a neuroprotective agent. PMID- 29123468 TI - A Model-Based Approach for Separating the Cochlear Microphonic from the Auditory Nerve Neurophonic in the Ongoing Response Using Electrocochleography. AB - Electrocochleography (ECochG) is a potential clinically valuable technique for predicting speech perception outcomes in cochlear implant (CI) recipients, among other uses. Current analysis is limited by an inability to quantify hair cell and neural contributions which are mixed in the ongoing part of the response to low frequency tones. Here, we used a model based on source properties to account for recorded waveform shapes and to separate the combined signal into its components. The model for the cochlear microphonic (CM) was a sinusoid with parameters for independent saturation of the peaks and the troughs of the responses. The model for the auditory nerve neurophonic (ANN) was the convolution of a unit potential and population cycle histogram with a parameter for spread of excitation. Phases of the ANN and CM were additional parameters. The average cycle from the ongoing response was the input, and adaptive fitting identified CM and ANN parameters that best reproduced the waveform shape. Test datasets were responses recorded from the round windows of CI recipients, from the round window of gerbils before and after application of neurotoxins, and with simulated signals where each parameter could be manipulated in isolation. Waveforms recorded from 284 CI recipients had a variety of morphologies that the model fit with an average r2 of 0.97 +/- 0.058 (standard deviation). With simulated signals, small systematic differences between outputs and inputs were seen with some variable combinations, but in general there were limited interactions among the parameters. In gerbils, the CM reported was relatively unaffected by the neurotoxins. In contrast, the ANN was strongly reduced and the reduction was limited to frequencies of 1,000 Hz and lower, consistent with the range of strong neural phase-locking. Across human CI subjects, the ANN contribution was variable, ranging from nearly none to larger than the CM. Development of this model could provide a means to isolate hair cell and neural activity that are mixed in the ongoing response to low frequency tones. This tool can help characterize the residual physiology across CI subjects, and can be useful in other clinical settings where a description of the cochlear physiology is desirable. PMID- 29123467 TI - The Role of SDF-1/CXCR4/CXCR7 in Neuronal Regeneration after Cerebral Ischemia. AB - Stromal cell-derived factor-1 is a chemoattractant produced by bone marrow stromal cell lines. It is recognized as a critical factor in the immune and central nervous systems (CNSs) as well as exerting a role in cancer. SDF-1 activates two G protein-coupled receptors, CXCR4 and CXCR7; these are expressed in both developing and mature CNSs and participate in multiple physiological and pathological events, e.g., inflammatory response, neurogenesis, angiogenesis, hematopoiesis, cancer metastasis, and HIV infection. After an ischemic stroke, SDF-1 levels robustly increase in the penumbra regions and participate in adult neural functional repair. Here we will review recent findings about SDF-1 and its receptor, analyse their functions in neurogeneration after brain ischemic injury: i.e., how the system promotes the proliferation, differentiation and migration of neural precursor cells and mediates axonal elongation and branching. PMID- 29123469 TI - Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels. AB - The development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism remains unclear. Here we report that deleting Kv3.1-the channel with the highest 4-AP sensitivity reduces clinical signs in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In Kv3.1 knockout (KO) mice, EAE lesions in sensory and motor tracts of spinal cord were markedly reduced, and radial astroglia were activated with increased expression of brain derived neurotrophic factor (BDNF). Kv3.3/Kv3.1 and activated BDNF receptors were upregulated in demyelinating axons in EAE and MS lesions. In spinal cord myelin coculture, BDNF treatment promoted myelination, and neuronal firing via altering channel expression. Therefore, suppressing Kv3.1 alters neural circuit activity, which may enhance BNDF signaling and hence protect axons from inflammatory insults. PMID- 29123470 TI - Regulation of AMPA Receptor Trafficking by Protein Ubiquitination. AB - The molecular mechanisms underlying plastic changes in the strength and connectivity of excitatory synapses have been studied extensively for the past few decades and remain the most attractive cellular models of learning and memory. One of the major mechanisms that regulate synaptic plasticity is the dynamic adjustment of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor content on the neuronal plasma membrane. The expression of surface AMPA receptors (AMPARs) is controlled by the delicate balance between the biosynthesis, dendritic transport, exocytosis, endocytosis, recycling and degradation of the receptors. These processes are dynamically regulated by AMPAR interacting proteins as well as by various post-translational modifications that occur on their cytoplasmic domains. In the last few years, protein ubiquitination has emerged as a major regulator of AMPAR intracellular trafficking. Dysregulation of AMPAR ubiquitination has also been implicated in the pathophysiology of Alzheimer's disease. Here we review recent advances in the field and provide insights into the role of protein ubiquitination in regulating AMPAR membrane trafficking and function. We also discuss how aberrant ubiquitination of AMPARs contributes to the pathogenesis of various neurological disorders, including Alzheimer's disease, chronic stress and epilepsy. PMID- 29123471 TI - VGLUT2 Trafficking Is Differentially Regulated by Adaptor Proteins AP-1 and AP-3. AB - Release of the major excitatory neurotransmitter glutamate by synaptic vesicle exocytosis depends on glutamate loading into synaptic vesicles by vesicular glutamate transporters (VGLUTs). The two principal isoforms, VGLUT1 and 2, exhibit a complementary pattern of expression in adult brain that broadly distinguishes cortical (VGLUT1) and subcortical (VGLUT2) systems, and correlates with distinct physiological properties in synapses expressing these isoforms. Differential trafficking of VGLUT1 and 2 has been suggested to underlie their functional diversity. Increasing evidence suggests individual synaptic vesicle proteins use specific sorting signals to engage specialized biochemical mechanisms to regulate their recycling. We observed that VGLUT2 recycles differently in response to high frequency stimulation than VGLUT1. Here we further explore the trafficking of VGLUT2 using a pHluorin-based reporter, VGLUT2 pH. VGLUT2-pH exhibits slower rates of both exocytosis and endocytosis than VGLUT1-pH. VGLUT2-pH recycling is slower than VGLUT1-pH in both hippocampal neurons, which endogenously express mostly VGLUT1, and thalamic neurons, which endogenously express mostly VGLUT2, indicating that protein identity, not synaptic vesicle membrane or neuronal cell type, controls sorting. We characterize sorting signals in the C-terminal dileucine-like motif, which plays a crucial role in VGLUT2 trafficking. Disruption of this motif abolishes synaptic targeting of VGLUT2 and essentially eliminates endocytosis of the transporter. Mutational and biochemical analysis demonstrates that clathrin adaptor proteins (APs) interact with VGLUT2 at the dileucine-like motif. VGLUT2 interacts with AP 2, a well-studied adaptor protein for clathrin mediated endocytosis. In addition, VGLUT2 also interacts with the alternate adaptors, AP-1 and AP-3. VGLUT2 relies on distinct recycling mechanisms from VGLUT1. Abrogation of these differences by pharmacological and molecular inhibition reveals that these mechanisms are dependent on the adaptor proteins AP-1 and AP-3. Further, shRNA-mediated knockdown reveals differential roles for AP-1 and AP-3 in VGLUT2 recycling. PMID- 29123472 TI - Taurine as an Essential Neuromodulator during Perinatal Cortical Development. AB - A variety of experimental studies demonstrated that neurotransmitters are an important factor for the development of the central nervous system, affecting neurodevelopmental events like neurogenesis, neuronal migration, programmed cell death, and differentiation. While the role of the classical neurotransmitters glutamate and gamma-aminobutyric acid (GABA) on neuronal development is well established, the aminosulfonic acid taurine has also been considered as possible neuromodulator during early neuronal development. The purpose of the present review article is to summarize the properties of taurine as neuromodulator in detail, focusing on the direct involvement of taurine on various neurodevelopmental events and the regulation of neuronal activity during early developmental epochs. The current knowledge is that taurine lacks a synaptic release mechanism but is released by volume-sensitive organic anion channels and/or a reversal of the taurine transporter. Extracellular taurine affects neurons and neuronal progenitor cells mainly via glycine, GABA(A), and GABA(B) receptors with considerable receptor and subtype-specific affinities. Taurine has been shown to directly influence neurogenesis in vitro as well as neuronal migration in vitro and in vivo. It provides a depolarizing signal for a variety of neuronal population in the immature central nervous system, thereby directly influencing neuronal activity. While in the neocortex, taurine probably enhance neuronal activity, in the immature hippocampus, a tonic taurinergic tone might be necessary to attenuate activity. In summary, taurine must be considered as an essential modulator of neurodevelopmental events, and possible adverse consequences on fetal and/or early postnatal development should be evaluated for pharmacological therapies affecting taurinergic functions. PMID- 29123474 TI - Brain Interleukin-1 Facilitates Learning of a Water Maze Spatial Memory Task in Young Mice. AB - The proinflammatory cytokine interleukin-1 (IL-1) is produced by many types of cells, including immune cells in the periphery and glia and neurons in the brain. The type I IL-1 receptor (IL-1r1) is primarily responsible for transmitting the inflammatory effects of IL-1 and mediates several biological functions by binding to either IL-1alpha or IL-1beta. IL-1beta activation is associated with hippocampus-dependent memory tasks. Although IL-1beta impairs spatial memory under certain pathophysiological conditions, IL-1beta may be required for the normal physiological regulation of hippocampal plasticity and memory. In addition, brain IL-1beta levels are thought to change in the hippocampus in an age-dependent manner. These findings suggest that IL-1beta may have a beneficial, temporary effect on learning and memory in young mice, but the matter remains unclear. Therefore, we hypothesized that hippocampal IL-1beta has a beneficial effect on spatial learning and memory in young mice via IL-1r1, which is diminished in adults. We investigated the performance of young (3-month-old) and adult (6-month-old) wild-type mice, IL-1beta knockout mice (IL-1betako) and IL 1r1 knockout mice (IL-1r1ko) in learning a spatial memory task with a fixed platform in a water maze (WM) and measured the levels of IL-1beta and IL-1alpha in the hippocampus and cortex of adult and young mice by using homogeneous time resolved fluorescence (HTRF). Learning was significantly impaired in the training trials of the WM spatial memory task in young IL-1betako and IL-1r1ko mice but not in adult IL-1betako and IL-1r1ko mice. Moreover, young IL-1r1ko mice but not IL-1betako mice showed an impairment in long-term memory extinction, suggesting that IL-1alpha might facilitate memory extinction. In this study, the cytokine assay using HTRF did not indicate a higher expression of hippocampal IL-1 in young mice but cortical IL-1beta and IL-1alpha were significantly increased in adult mice. We need to investigate the role of cortical IL-1 and the local IL-1 expression in the hippocampal neurons in the future. PMID- 29123473 TI - Neurobehavioral Abnormalities Associated with Executive Dysfunction after Traumatic Brain Injury. AB - Objective: This article will address how anomalies of executive function after traumatic brain injury (TBI) can translate into altered social behavior that has an impact on a person's capacity to live safely and independently in the community. Method: Review of literature on executive and neurobehavioral function linked to cognitive ageing in neurologically healthy populations and late neurocognitive effects of serious TBI. Information was collated from internet searches involving MEDLINE, PubMed, PyscINFO and Google Scholar as well as the authors' own catalogs. Conclusions: The conventional distinction between cognitive and emotional-behavioral sequelae of TBI is shown to be superficial in the light of increasing evidence that executive skills are critical for integrating and appraising environmental events in terms of cognitive, emotional and social significance. This is undertaken through multiple fronto-subcortical pathways within which it is possible to identify a predominantly dorsolateral network that subserves executive control of attention and cognition (so-called cold executive processes) and orbito-frontal/ventro-medial pathways that underpin the hot executive skills that drive much of behavior in daily life. TBI frequently involves disruption to both sets of executive functions but research is increasingly demonstrating the role of hot executive deficits underpinning a wide range of neurobehavioral disorders that compromise relationships, functional independence and mental capacity in daily life. PMID- 29123475 TI - Cerebello-Cortical Differences in Effective Connectivity of the Dominant and Non dominant Hand during a Visuomotor Paradigm of Grip Force Control. AB - Structural and functional differences are known to exist within the cortical sensorimotor networks with respect to the dominant vs. non-dominant hand. Similarly, the cerebellum, a key structure in the sensorimotor network with its cerebello-cortical connections, has been reported to respond differently when using the dominant vs. non-dominant hand. Several groups have already investigated causal interactions during diverse motor paradigms using effective connectivity but few have studied the larger visuomotor network, including key structures such as the parietal cortex and the cerebellum, with both hands. Moreover, the effect of force level on such interactions is still unclear. We therefore sought to determine the hemispheric asymmetries in the cerebello cortical sensorimotor network in right-handers at two force levels (5% and 10% maximum voluntary contraction) for both hands. Cerebello-cortical modulations were investigated in 28 healthy, right-handed volunteers by determining the effective connectivity during a visuomotor task at two force levels under fMRI. A network was built consisting of the left and right primary motor (M1), ventral premotor (PMv) and posterior parietal cortices (PPC), in addition to the supplementary motor area (SMA), and the ipsilateral cerebellum (Cer) to the hand performing the motor task. Task performance (precision of isometric grip force tracking) did not differ between hands, nor did task-related activations in the sensorimotor areas apart from the contralateral primary motor cortex. However, during visuomotor control of the non-dominant hand, connectivity analysis revealed causal modulations between (i) the ipsilateral cerebellum and SMA, and (ii) the ipsilatearl cerebellum and contralateral PPC, which was not the case when using the dominant hand. These cerebello-cortical modulations for the non dominant hand were more present at the higher of the two force levels. We conclude that precision force generation executed with the non-dominant hand, compared to the dominant hand, may require enhanced cerebello-cortical interaction to ensure equivalent left-right task performance. PMID- 29123477 TI - The Effects of Medium Spiny Neuron Morphologcial Changes on Basal Ganglia Network under External Electric Field: A Computational Modeling Study. AB - The damage of dopaminergic neurons that innervate the striatum has been considered to be the proximate cause of Parkinson's disease (PD). In the dopamine denervated state, the loss of dendritic spines and the decrease of dendritic length may prevent medium spiny neuron (MSN) from receiving too much excitatory stimuli from the cortex, thereby reducing the symptom of Parkinson's disease. However, the reduction in dendritic spine density obtained by different experiments is significantly different. We developed a biological-based network computational model to quantify the effect of dendritic spine loss and dendrites tree degeneration on basal ganglia (BG) signal regulation. Through the introduction of error index (EI), which was used to measure the attenuation of the signal, we explored the amount of dendritic spine loss and dendritic trees degradation required to restore the normal regulatory function of the network, and found that there were two ranges of dendritic spine loss that could reduce EI to normal levels in the case of dopamine at a certain level, this was also true for dendritic trees. However, although these effects were the same, the mechanisms of these two cases were significant difference. Using the method of phase diagram analysis, we gained insight into the mechanism of signal degradation. Furthermore, we explored the role of cortex in MSN morphology changes dopamine depletion-induced and found that proper adjustments to cortical activity do stop the loss in dendritic spines induced by dopamine depleted. These results suggested that modifying cortical drive onto MSN might provide a new idea on clinical therapeutic strategies for Parkinson's disease. PMID- 29123476 TI - Multi-Scale Computational Models for Electrical Brain Stimulation. AB - Electrical brain stimulation (EBS) is an appealing method to treat neurological disorders. To achieve optimal stimulation effects and a better understanding of the underlying brain mechanisms, neuroscientists have proposed computational modeling studies for a decade. Recently, multi-scale models that combine a volume conductor head model and multi-compartmental models of cortical neurons have been developed to predict stimulation effects on the macroscopic and microscopic levels more precisely. As the need for better computational models continues to increase, we overview here recent multi-scale modeling studies; we focused on approaches that coupled a simplified or high-resolution volume conductor head model and multi-compartmental models of cortical neurons, and constructed realistic fiber models using diffusion tensor imaging (DTI). Further implications for achieving better precision in estimating cellular responses are discussed. PMID- 29123478 TI - Neural Synchronization from the Perspective of Non-linear Dynamics. PMID- 29123479 TI - Knowledge on Alzheimer's Disease among Public Hospitals and Health Clinics Pharmacists in the State of Selangor, Malaysia. AB - The prevalence of Alzheimer's disease (AD) has increased with the fast growing of aging population, thereby posing great challenges to provision of care for AD patients. Pharmacists play a vital role in the management of AD; this includes recognizing early symptoms of AD, providing medication counseling to AD patients and their caretakers, and identifying potential adverse drug reactions. A comprehensive understanding of the disease progression, as well as the pharmacological therapy, is essential to provide effective care to AD patients. The level of knowledge about AD among the pharmacists, however, remains unknown. Hence, this study aimed to assess the knowledge on AD among the pharmacists in public hospitals and health clinics and its correlates. A clear picture of the characteristics associated with different levels of knowledge could facilitate the targeted re-training of pharmacists. The 30-item validated Alzheimer disease knowledge scale (ADKS) tool was pilot-tested and used in this cross-sectional study. All pharmacists, from nine public hospitals and seven public health clinics in the State of Selangor, Malaysia, were invited to participate in this cross-sectional survey. The ADKS score was computed and compared across demographics characteristics. A total of 445 pharmacists responded to the survey. These pharmacists had a moderate overall score in ADKS; nevertheless, high scores were recorded in the domains of treatment management and care giving. No difference in AD knowledge was found among pharmacists worked in public hospitals and health clinics, except for the domain of care giving (p = 0.033). Ethnicity and age group were independent predictors of ADKS score in the current study. The pharmacists in the current study had moderate AD knowledge. On-going education and training programme on AD, in particular the domains other than treatment management and care giving, should be provided to the pharmacists to ensure delivery of quality care to AD patients. PMID- 29123480 TI - Impairment of Mitochondrial Biogenesis and Dynamics Involved in Isoniazid-Induced Apoptosis of HepG2 Cells Was Alleviated by p38 MAPK Pathway. AB - Isoniazid (INH), a widely used first-line antitubercular drug, has been noted to be associated with hepatotoxicity. In spite of extensive researches over many decades, the mechanism of INH-induced hepatotoxicity still remains poorly understood. Recently, mitochondrial toxicity has been emerging as a new paradigm for INH-induced hepatotoxicity. In this study, we showed that INH impaired mitochondrial biogenesis and dynamics in human hepatocarcinoma HepG2 cells. INH reduced mitochondrial membrane potential (MMP) and induced mitochondria swelling. INH also inhibited the protein expressions of three major mitochondrial biogenesis regulators, SIRT1, PGC1alpha and NRF1, along with increased acetylation of PGC1alpha. Meanwhile, INH decreased the number of mitochondria, accompanied by decreased expression of mitochondrial protein COX IV. INH caused mitochondrial fragmentation involving decreased levels of the fusion protein MFN2 as well as the fission protein DRP1. INH-reduced DRP1 expression was associated with the increase of apoptosis, suggesting the existence of pro-survival fission and its involvement in mitochondrial quality control. INH activated p38 MAPK, whereas inhibition of p38 MAPK aggravated INH-induced decreases of SIRT1, PGC1alpha, NRF1, COX IV and DRP1 expressions. P38 MAPK inhibition also further up regulated the acetylation of PGC1alpha and exacerbated INH-induced MMP loss, mitochondrial swelling and apoptosis. Taken together, INH-activated p38 MAPK induced mitochondrial biogenesis to alleviate apoptosis through partly recovering SIRT1-PGC1alpha pathway activation. In the meantime, p38 MAPK activation by INH promoted protective mitochondrial fission to alleviate apoptosis by partial recovery of DRP1 expression. PMID- 29123481 TI - Development in Assay Methods for in Vitro Antimalarial Drug Efficacy Testing: A Systematic Review. AB - The emergence and spread of drug resistance are the major challenges in malaria eradication mission. Besides various strategies laid down by World Health Organization, such as vector management, source reduction, early case detection, prompt treatment, and development of new diagnostics and vaccines, nevertheless the need for new and efficacious drugs against malaria has become a critical priority on the global malaria research agenda. At several screening stages, millions of compounds are screened (1,000-2,000,000 compounds per screening campaign), before pre-clinical trials to select optimum lead. Carrying out in vitro screening of antimalarials is very difficult as different assay methods are subject to numerous sources of variability across different laboratories around the globe. Despite this, in vitro screening is an essential part of antimalarial drug development as it enables to resource various confounding factors such as host immune response and drug-drug interaction. Therefore, in this article, we try to illustrate the basic necessity behind in vitro study and how new methods are developed and subsequently adopted for high-throughput antimalarial drug screening and its application in achieving the next level of in vitro screening based on the current approaches (such as stem cells). PMID- 29123482 TI - Anticancer Activities of Surfactin and Potential Application of Nanotechnology Assisted Surfactin Delivery. AB - Surfactin, a cyclic lipopeptide biosurfactant produced by various strains of Bacillus genus, has been shown to induce cytotoxicity against many cancer types, such as Ehrlich ascites, breast and colon cancers, leukemia and hepatoma. Surfactin treatment can inhibit cancer progression by growth inhibition, cell cycle arrest, apoptosis, and metastasis arrest. Owing to the potent effect of surfactin on cancer cells, numerous studies have recently investigated the mechanisms that underlie its anticancer activity. The amphiphilic nature of surfactin allows its easy incorporation nano-formulations, such as polymeric nanoparticles, micelles, microemulsions, liposomes, to name a few. The use of nano-formulations offers the advantage of optimizing surfactin delivery for an improved anticancer therapy. This review focuses on the current knowledge of surfactin properties and biosynthesis; anticancer activity against different cancer models and the underlying mechanisms involved; as well as the potential application of nano-formulations for optimal surfactin delivery. PMID- 29123483 TI - Impact of Vortioxetine on Synaptic Integration in Prefrontal-Subcortical Circuits: Comparisons with Escitalopram. AB - Prefrontal-subcortical circuits support executive functions which often become dysfunctional in psychiatric disorders. Vortioxetine is a multimodal antidepressant that is currently used in the clinic to treat major depressive disorder. Mechanisms of action of vortioxetine include serotonin (5-HT) transporter blockade, 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, and 5-HT1D, 5-HT3, and 5-HT7 receptor antagonism. Vortioxetine facilitates 5-HT transmission in the medial prefrontal cortex (mPFC), however, the impact of this compound on related prefrontal-subcortical circuits is less clear. Thus, the current study examined the impact of systemic vortioxetine administration (0.8 mg/kg, i.v.) on spontaneous spiking and spikes evoked by electrical stimulation of the mPFC in the anterior cingulate cortex (ACC), medial shell of the nucleus accumbens (msNAc), and lateral septal nucleus (LSN) in urethane-anesthetized rats. We also examined whether vortioxetine modulated afferent drive in the msNAc from hippocampal fimbria (HF) inputs. Similar studies were performed using the selective 5-HT reuptake inhibitor [selective serotonin reuptake inhibitors (SSRI)] escitalopram (1.6 mg/kg, i.v.) to enable comparisons between the multimodal actions of vortioxetine and SSRI-mediated effects. No significant differences in spontaneous activity were observed in the ACC, msNAc, and LSN across treatment groups. No significant impact of treatment on mPFC-evoked responses was observed in the ACC. In contrast, vortioxetine decreased mPFC evoked activity recorded in the msNAc as compared to parallel studies in control and escitalopram treated groups. Thus, vortioxetine may reduce mPFC-msNAc afferent drive via a mechanism that, in addition to an SSRI-like effect, requires 5-HT receptor modulation. Recordings in the LSN revealed a significant increase in mPFC-evoked activity following escitalopram administration as compared to control and vortioxetine treated groups, indicating that complex modulation of 5 HT receptors by vortioxetine may offset SSRI-like effects in this region. Lastly, neurons in the msNAc were more responsive to stimulation of the HF following both vortioxetine and escitalopram administration, indicating that elevation of 5-HT tone and 5-HT receptor modulation may facilitate excitatory hippocampal synaptic drive in this region. The above findings point to complex 5-HT receptor-dependent effects of vortioxetine which may contribute to its unique impact on the function of prefrontal-subcortical circuits and the development of novel strategies for treating mood disorders. PMID- 29123484 TI - Zolpidem Administration and Risk of Hepatocellular Carcinoma: A Case-Control Study in Taiwan. AB - Background/Objectives: Previous studies showed that zolpidem use could be associated with increased cancer risk, but the role of zolpidem on hepatocellular carcinoma (HCC) risk remains undetermined. The study purpose was to examine the association between HCC risk and zolpidem use in Taiwan. Methods: Using the database from the Taiwan National Health Insurance Program, we designed a case control study which consisted of 77986 subjects aged 20 years or older with newly diagnosed HCC as the case group, and 77986 subjects without HCC as the control group, from 2000 to 2011. Ever use of zolpidem was defined as a subject who had at least a prescription for zolpidem before the index date. Never use was defined as a subject who did not have a prescription for zolpidem before the index date. The association between HCC risk and zolpidem use was determined by the odds ratio (OR) and 95% confidence interval (CI) in a multivariable logistic regression model. Results: After adjustment for confounding factors, the adjusted OR of HCC was 1.05 (95% CI 0.97, 1.13) for subjects with ever use of zolpidem, compared with never use of zolpidem. The adjusted OR of HCC was 1.01 for subjects with increasing cumulative duration of zolpidem use for every 1 year (95% CI 0.99, 1.03), compared with never use of zolpidem. Conclusion: There is no significant association between HCC risk and zolpidem use. There is no duration dependent effect of zolpidem use on HCC risk. PMID- 29123485 TI - Intensifying Functional Task Practice to Meet Aerobic Training Guidelines in Stroke Survivors. AB - Objective: To determine whether stroke survivors could maintain workloads during functional task practice that can reach moderate levels of cardiometabolic stress (i.e., >=40% oxygen uptake reserve ([Formula: see text]O2R) for >=20 min) without the use of ergometer-based exercise. Design: Cross-sectional study using convenience sampling. Setting: Research laboratory in a tertiary rehabilitation hospital. Participants: Chronic hemiparetic stroke survivors (>6-months) who could provide consent and walk with or without assistance. Intervention: A single bout of intermittent functional training (IFT). The IFT protocol lasted 30 min and involved performing impairment specific multi-joint task-oriented movements structured into circuits lasting ~3 min and allowing 30-45 s recovery between circuits. The aim was to achieve an average heart rate (HR) 30-50 beats above resting without using traditional ergometer-based aerobic exercise. Outcome measures: Attainment of indicators for moderate intensity aerobic exercise. Oxygen uptake ([Formula: see text]O2), carbon dioxide production ([Formula: see text]CO2), and HR were recorded throughout the 30 min IFT protocol. Values were reported as percentage of [Formula: see text]O2R, HR reserve (HRR) and HRR calculated from predicted maximum HR (HRRpred), which were determined from a prior maximal graded exercise test. Results: Ten (3-female) chronic (38 +/- 33 months) stroke survivors (70% ischemic) with significant residual impairments (NIHSS: 3 +/- 2) and a high prevalence of comorbid conditions (80% >= 1) participated. IFT significantly increased all measures of exercise intensity compared to resting levels: [Formula: see text]O2 (Delta 820 +/- 290 ml min-1, p < 0.001), HR (Delta 42 +/- 14 bpm, p < 0.001), and energy expenditure (EE; Delta 4.0 +/- 1.4 kcal min-1, p < 0.001). Also, mean values for percentage of [Formula: see text]O2R (62 +/- 19), HRR (55 +/- 14), and HRRpred (52 +/- 18) were significantly higher than the minimum threshold (40%) indicating achievement of moderate intensity aerobic exercise (p = 0.004, 0.016, and 0.043, respectively). Conclusion: Sufficient workloads to achieve moderate levels of cardiometabolic stress can be maintained in chronic stroke survivors using impairment-focused functional movements that are not dependent on ergometers or other specialized equipment. PMID- 29123488 TI - Wearing Compression Tights on the Thigh during Prolonged Running Attenuated Exercise-Induced Increase in Muscle Damage Marker in Blood. AB - Purpose: To examine the effects of wearing a lower-body compression garment with different body coverage areas during prolonged running on exercise performance and muscle damage. Methods: Thirty male subjects were randomly assigned to one of three groups: (1) wearing a compression tights with 15 mmHg to thigh [n = 10, CT group], (2) wearing a compression socks with 15 mmHg to calf [n = 10, CS group], and (3) wearing a lower-body garment with < 5 mmHg to thigh and calf [n = 10, CON group]. The exercise consisted of 120 min of uphill running at 55% of [Formula: see text]O2max. Heart rate (HR), rate of perceived exertion (RPE), and running economy (evaluated by VO2) were monitored during exercise every 10 min. Changes in maximum voluntary contraction (MVC) of knee extension and plantar flexion, height of counter movement jump (CMJ) and drop jump (DJ), and scores of subjective feelings of muscle soreness and fatigue were evaluated before exercise, and 60 and 180 min after exercise. Blood samples were collected to determine blood glucose, lactate, serum free fatty acid, myoglobin (Mb), high sensitivity C-reactive protein, and plasma interleukin-6 concentrations before exercise (after 20 min of rest), at 60 min of exercise, immediately after exercise, and 60 and 180 min after exercise. Results: Changes in HR, RPE, and running economy during exercise did not differ significantly among the three groups. MVC of knee extension and plantar flexion, and DJ decreased significantly following exercise, with no difference among groups. The serum Mb concentration increased significantly with exercise in all groups, whereas the area under the curve for Mb concentration during 180 min post-exercise was significantly lower in the CT group (13,833 +/- 1,397 pg/mL 180 min) than in the CON group (24,343 +/ 3,370 pg/mL 180 min, P = 0.03). Conclusion: Wearing compression garment on the thigh significantly attenuated the increase in serum Mb concentration after exercise, suggesting that exercise-induced muscle damage was attenuated. PMID- 29123486 TI - Are We Reaching the Limits of Homo sapiens? AB - Echoing scientific and industrial progress, the Twentieth century was an unprecedented period of improvement for human capabilities and performances, with a significant increase in lifespan, adult height, and maximal physiological performance. Analyses of historical data show a major slow down occurring in the most recent years. This triggered large and passionate debates in the academic scene within multiple disciplines; as such an observation could be interpreted as our upper biological limits. Such a new phase of human history may be related to structural and functional limits determined by long term evolutionary constraints, and the interaction between complex systems and their environment. In this interdisciplinary approach, we call into question the validity of subsequent forecasts and projections through innovative and related biomarkers such as sport, lifespan, and height indicators. We set a theoretical framework based on biological and environmental relevance rather than using a typical single-variable forecasting approach. As demonstrated within the article, these new views will have major social, economical, and political implications. PMID- 29123487 TI - Hypertrophy Stimulation at the Onset of Type I Diabetes Maintains the Soleus but Not the EDL Muscle Mass in Wistar Rats. AB - Diabetes mellitus induces a reduction in skeletal muscle mass and strength. Strength training is prescribed as part of treatment since it improves glycemic control and promotes increase of skeletal muscle mass. The mechanisms involved in overload-induced muscle hypertrophy elicited at the establishment of the type I diabetic state was investigated in Wistar rats. The purpose was to examine whether the overload-induced hypertrophy can counteract the hypotrophy associated to the diabetic state. The experiments were performed in oxidative (soleus) or glycolytic (EDL) muscles. PI3K/Akt/mTOR protein synthesis pathway was evaluated 7 days after overload-induced hypertrophy of soleus and of EDL muscles. The mRNA expression of genes associated with different signaling pathways that control muscle hypertrophy was also evaluated: mechanotransduction (FAK), Wnt/beta catenin, myostatin, and follistatin. The soleus and EDL muscles when submitted to overload had similar hypertrophic responses in control and diabetic animals. The increase of absolute and specific twitch and tetanic forces had the same magnitude as muscle hypertrophic response. Hypertrophy of the EDL muscle from diabetic animals mostly involved mechanical loading-stimulated PI3K/Akt/mTOR pathway besides the reduced activation of AMP-activated protein kinase (AMPK) and decrease of myostatin expression. Hypertrophy was more pronounced in the soleus muscle of diabetic animals due to a more potent activation of rpS6 and increased mRNA expression of insulin-like growth factor-1 (IGF-1), mechano-growth factor (MGF) and follistatin, and decrease of myostatin, MuRF-1 and atrogin-1 contents. The signaling changes enabled the soleus muscle mass and force of the diabetic rats to reach the values of the control group. PMID- 29123489 TI - Plasmapheresis Responsive Rapid Onset Dementia with Predominantly Frontal Dysfunction in the Context of Hashimoto's Encephalopathy. AB - Background: Hashimoto's encephalopathy (HE) is a rare immunological neuropsychiatric disorder characterized by increased antithyroid antibodies and mixed neurological and psychiatric symptoms. HE has been previously discussed as a differential diagnosis for rapid progressive dementia. However, most of these patients suffered from additional neurological symptoms, like ataxia or seizures. Case presentation: Here, we present the case of a 59-year-old female patient suffering rapid onset dementia with salient frontal executive dysfunction. She developed rapid onset symptoms, including apathy, verbal depletion up to a stuporous state, severe working memory deficits, evidence of primitive reflexes, disturbed Luria's three-step test, and micturition disorder. Analysis of her cerebrospinal fluid was normal. The serum analyses showed increased antithyroid (antithyroid peroxidase and antithyroglobulin) antibodies. In the cerebral magnetic resonance imaging, supratentorial deep and peripheral white matter lesions were found; the electroencephalography showed intermittent slowing, and the [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) depicted medial and superior dorsolateral frontal hypometabolism. Several different psychopharmacological therapeutic approaches with various neuroleptics, antidepressants, and high doses of lorazepam were unsuccessful. Due to the organic alterations, including increased antithyroid antibodies, HE was suspected. Against expectations, treatment with high-dose corticosteroids proved to be ineffective and was associated with worsening symptoms. However, escalated treatment with plasmapheresis over 5 days led to significant improvement in all reported symptoms and in psychometric testing. The neuropsychological improvement was stable over a 6-month follow-up period, and the FDG-PET normalized. Conclusion: This case report reveals that (1) HE can mimic rapid onset dementia with predominantly frontal dysfunction; (2) this syndrome can be successfully treated in the context of HE; and (3) plasmapheresis can be effective in such a disease constellation. The detection of the immunological causes of rapid onset dementia and other psychiatric syndromes is important because it opens opportunities for new, innovative immunosuppressive treatment options. PMID- 29123490 TI - Avoidance of Novelty Contributes to the Uncanny Valley. AB - A hypothesis suggests that objects with a high degree of visual similarity to real humans trigger negative impressions (i.e., the uncanny valley). Previous studies have suggested that difficulty in object categorization elicits negative emotional reactions to enable the avoidance of potential threats. The present study further investigated this categorization-difficulty hypothesis. In an experiment, observers categorized morphed images of photographs and human doll faces as "photograph" or "doll" and evaluated the perceived eeriness of the images. Additionally, we asked the observers to answer questionnaires on behavioral inhibition systems (BIS). The results indicated that individual differences in the BIS score were associated with enhanced eeriness in the objects with a specific human likeness. These findings suggest that the tendency to avoid a potentially threatening novel experience contributes to promoting the perceived eeriness of objects with some degree of visual similarity to real humans. PMID- 29123491 TI - The Experimental School in Bonneuil-sur-Marne...with Commentary from a North American Context. PMID- 29123492 TI - The Adolescent's Competency for Interacting with Alcohol as a Determinant of Intake: The Role of Self-Regulation. AB - The competency for interacting with alcohol is a highly useful Educational Psychology model for preventing and for understanding the different behavioral levels of this interaction. Knowledge of facts, concepts and principles about alcohol use, self-regulated behavior, and attitudes toward alcohol are predictive of adequate interaction with alcohol. The objective of this study was to empirically evaluate this postulated relationship. A total of 328 Spanish adolescents participated, between the ages of 12 and 17. All were enrolled in 1st 4th year of compulsory secondary education, in the context of the ALADO Program for prevention of alcohol intake in adolescents. An ex post facto design was used, with inferential analyses and SEM analyses. Results show an interdependence relationship, with significant structural prediction between the behavioral levels defined and the level of alcohol intake, with principles, self-regulating control and attitudes carrying more weight. Analyses are presented, as are implications for psychoeducational intervention using preventive programs based on this competency model. PMID- 29123493 TI - Transcranial Direct Current Stimulation of the Medial Prefrontal Cortex Affects Judgments of Moral Violations. AB - Previous studies show that neural activities in the medial prefrontal cortex (mPFC) are correlated with moral processing during picture viewing tasks. In this study, we applied transcranial direct current stimulation (tDCS) to determine whether this non-invasive brain stimulation technique could modulate the evaluation of moral violations. Sixty-four subjects were randomly recruited, separated into different groups and tested with 42 pairs of pictures depicting moral violations. Each subject was required to rate the pictures two separate times, i.e., before and after tDCS intervention. We found that anodal tDCS (atDCS) increases cortical excitability over the mPFC (between the Fpz and Fp1 positions) as well as the sense of morality and emotional arousal of the subjects. In conclusion, this study indicated that the mPFC plays an important role in moral judgments while modulating ratings of moral violations under tDCS intervention conditions. PMID- 29123494 TI - The Ambiguity of Artworks -A Guideline for Empirical Aesthetics Research with Artworks as Stimuli. AB - The aim of this work is to provide researchers from the field of aesthetics with a guideline on working with artworks as stimuli. Empirical aesthetics research is complicated by the uncertainty of the object of research. There is no way to unquestionably tell whether an object is an artwork or not. However, although the extension of the term artwork (i.e., the range of objects to which this concept applies) remains vague, the different intensions of the term artwork (i.e., the internal concept that constitutes a formal definition) are well defined. Here, I review the various concepts of artworks (i.e., intensions) that scientists from different fields use in current research in empirical aesthetics. The selection of stimuli is often not explained and/or does not match the focus of the study. An application of two or more intensions within one study leads to an indeterminacy of the stimuli and, thus, to systematic problems concerning the interpretation and comparability of the experimental results. Based on these intensions and the Pleasure-Interest Model of Aesthetic Liking (Graf and Landwehr, 2015), I compiled a decision tree in order to provide researchers with an instrument that allows a better control over their stimuli. PMID- 29123495 TI - Likability's Effect on Interpersonal Motor Coordination: Exploring Natural Gaze Direction. AB - Although existing studies indicate a positive effect of interpersonal motor coordination (IMC) on likability, no consensus has been reached as for the effect of likability back onto IMC. The present study specifically investigated the causal effect of likability on IMC and explored, by tracking the natural gaze direction, the possible underlying mechanisms. Twenty-two participants were engaged in an interpersonal finger-tapping task with a confederate in three likability conditions (baseline, likable, and unlikable), while wearing an eye tracker. They had to perform finger tapping at their comfort tempo with the confederate who tapped at the same or 1.5 times of the participant's preferred frequency. Results showed that when tapping at the same frequency, the effect of likability on IMC varied with time. Participants coordinated at a higher level in the baseline condition at the beginning of the coordination task, and a facilitative effect of likability on IMC was revealed in the last session. As a novelty, our results evidenced a positive correlation between IMC and the amount of gaze onto the coordination partner's movement only in the likable condition. No effect of likability was found when the confederate was tapping at 1.5 times of the participant's preferred frequency. Our research suggests that the psychosocial property of the coordinating partner should be taken into consideration when investigating the performance of IMC and that IMC is a parameter that is sensitive to multiple factors. PMID- 29123496 TI - Positive Education for Young Children: Effects of a Positive Psychology Intervention for Preschool Children on Subjective Well Being and Learning Behaviors. AB - Despite the flourishing in recent years in applications of positive psychology in the field of education, there is a paucity of research investigating positive psychology interventions for preschool children. The present study examined the effects of a positive psychology-based intervention conducted in Israel on children's subjective well-being, mental health and learning behaviors. Twelve preschool classrooms of 3-6.5 year-olds were randomly assigned to a positive psychology intervention condition or a wait-list control condition. In the intervention condition, during one school year, 160 children experienced eight modules of basic concepts in positive psychology that were adapted to the developmental characteristics of young children and were compared to 155 children in demographically similar control classrooms. Children were administered a pre test and post-test of subjective well-being measures. In addition, children's mental health and emotional well-being were measured by parental questionnaires. Preschool teachers completed questionnaires concerning children's learning behaviors. The findings showed significant increases in subjective well-being and positive learning behaviors among the intervention participants, with no significant changes in the control group. The results highlight the potential of positive psychology interventions for increasing subjective well-being and a positive approach to learning at young ages. PMID- 29123497 TI - Leadership and Presenteeism among Scientific Staff: The Role of Accumulation of Work and Time Pressure. AB - The present study examines the joint roles of leadership and stressors for presenteeism of scientific staff. Leaders may have an impact on employees' health, both directly through interpersonal interactions and by shaping their working conditions. In the field of science, this impact could be special because of the mentoring relationships between the employees (e.g., PhD students) and their supervisors (e.g., professors). Based on the job demands-resources framework (JD-R), we hypothesized that the pressure to be present at the workplace induced by supervisors (supervisorial pressure) is directly related to employees' presenteeism as well as indirectly via perceptions of time pressure. The conservation of resources theory (COR) states that resource loss resulting from having to deal with job demands weakens the resource pool and therefore the capacity to deal with other job demands. Thus, we hypothesized that accumulation of work moderates the relationship between supervisorial pressure and time pressure, such that the relationship is stronger when accumulation of work is high compared to if accumulation of work is low. Cross-sectional data were obtained from 212 PhD students and postdocs of 30 scientific institutions in Germany. Analysis was performed using the SPSS macro PROCESS (Hayes, 2013). Supervisorial pressure was directly associated with higher presenteeism of employees and indirectly through increased time pressure. Moreover, supervisorial pressure and accumulation of work interacted to predict time pressure, but in an unexpected way. The positive relationship between supervisorial pressure and time pressure is stronger when accumulation is low compared to if accumulation of work is high. It seems possible that job stressors do not accumulate but substitute each other. Threshold models might explain the findings. Moreover, specific patterns of interacting job demands for scientific staff should be considered in absence management. PMID- 29123499 TI - Gait and Cognition in Parkinson's Disease: Cognitive Impairment Is Inadequately Reflected by Gait Performance during Dual Task. AB - Introduction: Cognitive and gait deficits are common symptoms in Parkinson's disease (PD). Motor-cognitive dual tasks (DTs) are used to explore the interplay between gait and cognition. However, it is unclear if DT gait performance is indicative for cognitive impairment. Therefore, the aim of this study was to investigate if cognitive deficits are reflected by DT costs of spatiotemporal gait parameters. Methods: Cognitive function, single task (ST) and DT gait performance were investigated in 67 PD patients. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) followed by a standardized, sensor-based gait test and the identical gait test while subtracting serial 3's. Cognitive impairment was defined by a MoCA score <26. DT costs in gait parameters [(DT - ST)/ST * 100] were calculated as a measure of DT effect on gait. Correlation analysis was used to evaluate the association between MoCA performance and gait parameters. In a linear regression model, DT gait costs and clinical confounders (age, gender, disease duration, motor impairment, medication, and depression) were correlated to cognitive performance. In a subgroup analysis, we compared matched groups of cognitively impaired and unimpaired PD patients regarding differences in ST, DT, and DT gait costs. Results: Correlation analysis revealed weak correlations between MoCA score and DT costs of gait parameters (r/rSp <= 0.3). DT costs of stride length, swing time variability, and maximum toe clearance (|r/rSp| > 0.2) were included in a regression analysis. The parameters only explain 8% of the cognitive variance. In combination with clinical confounders, regression analysis showed that these gait parameters explained 30% of MoCA performance. Group comparison revealed strong DT effects within both groups (large effect sizes), but significant between-group effects in DT gait costs were not observed. Conclusion: These findings suggest that DT gait performance is not indicative for cognitive impairment in PD. DT effects on gait parameters were substantial in cognitively impaired and unimpaired patients, thereby potentially overlaying the effect of cognitive impairment on DT gait costs. Limits of the MoCA in detecting motor-function specific cognitive performance or variable individual response to the DT as influencing factors cannot be excluded. Therefore, DT gait parameters as marker for cognitive performance should be carefully interpreted in the clinical context. PMID- 29123498 TI - Vestibular Deficits in Neurodegenerative Disorders: Balance, Dizziness, and Spatial Disorientation. AB - The vestibular system consists of the peripheral vestibular organs in the inner ear and the associated extensive central nervous system projections-from the cerebellum and brainstem to the thalamic relays to cortical projections. This system is important for spatial orientation and balance, both of critical ecological importance, particularly for successful navigation in our environment. Balance disorders and spatial disorientation are common presenting features of neurodegenerative diseases; however, little is known regarding central vestibular processing in these diseases. A ubiquitous aspect of central vestibular processing is its promiscuity given that vestibular signals are commonly found in combination with other sensory signals. This review discusses how impaired central processing of vestibular signals-typically in combination with other sensory and motor systems-may account for the impaired balance and spatial disorientation in common neurodegenerative conditions. Such an understanding may provide for new diagnostic tests, potentially useful in detecting early disease while a mechanistic understanding of imbalance and spatial disorientation in these patients may enable a vestibular-targeted therapy for such problems in neurodegenerative diseases. Studies with state of the art central vestibular testing are now much needed to tackle this important topic. PMID- 29123500 TI - Efficacy and the Safety of Granulocyte Colony-Stimulating Factor Treatment in Patients with Muscular Dystrophy: A Non-Randomized Clinical Trial. AB - Introduction: The current standard treatment for patients with Duchenne muscular dystrophy (DMD) involves corticosteroids. Granulocyte colony-stimulating factor (G-CSF) induces the proliferation of satellite cells and myoblasts and, in turn, muscle regeneration. Beneficial effects of G-CSF were also described for skeletal muscle disorders. Aim: We assessed the safety and effects of using G-CSF to promote muscle strength in patients with DMD. Materials and methods: Inclusion criteria were as follows: patients aged 5-15 years with diagnosed with DMD confirmed by genetic test or biopsy. Fourteen patients were treated with steroids, and their use was not changed in this study. Diagnoses were confirmed by genetic tests: deletions were detected in 11 patients and duplications in 5 patients. Nineteen 5- to 15-year-old patients diagnosed with DMD-9 were in wheelchairs, whereas 10 were mobile and independent-completed an open study. Participants received a clinical examination and performed physiotherapeutic and laboratory tests to gage their manual muscle strength, their isometric force using a hand dynamometer, and aerobic capacity [i.e., 6-min walk test (6MWT)] before and after therapy. Each participant received G-CSF (5 ug/kg/body/day) subcutaneously for five consecutive days during the 1st, 2nd, 3rd, 6th, and 12th month. Laboratory investigations that included full blood count and biochemistry were performed. Side effects of G-CSF treatment were assessed during each visit. During each cycle of G-CSF administration in the hospital, rehabilitation was also applied. All patients received regular ambulatory rehabilitation. Results: The subcutaneous administration of G-CSF improved muscle strength in participants. We recorded a significant increase in the distance covered in the 6MWT, either on foot or in a wheelchair, increased muscle force in isometric force, and a statistically significant decrease in the activity of the muscle enzyme creatine kinase after nearly every cycle of treatment. We observed no side effects of treatment with G-CSF. Conclusion: Our findings suggest that G-CSF increases muscle strength in patients with DMD, who demonstrated that G-CSF therapy is safe and easily tolerable. PMID- 29123501 TI - Gonadotropin-Releasing Hormone (GnRH) Receptor Structure and GnRH Binding. AB - Gonadotropin-releasing hormone (GnRH) regulates reproduction. The human GnRH receptor lacks a cytoplasmic carboxy-terminal tail but has amino acid sequence motifs characteristic of rhodopsin-like, class A, G protein-coupled receptors (GPCRs). This review will consider how recent descriptions of X-ray crystallographic structures of GPCRs in inactive and active conformations may contribute to understanding GnRH receptor structure, mechanism of activation and ligand binding. The structures confirmed that ligands bind to variable extracellular surfaces, whereas the seven membrane-spanning alpha-helices convey the activation signal to the cytoplasmic receptor surface, which binds and activates heterotrimeric G proteins. Forty non-covalent interactions that bridge topologically equivalent residues in different transmembrane (TM) helices are conserved in class A GPCR structures, regardless of activation state. Conformation-independent interhelical contacts account for a conserved receptor protein structure and their importance in the GnRH receptor structure is supported by decreased expression of receptors with mutations of residues in the network. Many of the GnRH receptor mutations associated with congenital hypogonadotropic hypogonadism, including the Glu2.53(90) Lys mutation, involve amino acids that constitute the conserved network. Half of the ~250 intramolecular interactions in GPCRs differ between inactive and active structures. Conformation-specific interhelical contacts depend on amino acids changing partners during activation. Conserved inactive conformation-specific contacts prevent receptor activation by stabilizing proximity of TM helices 3 and 6 and a closed G protein-binding site. Mutations of GnRH receptor residues involved in these interactions, such as Arg3.50(139) of the DRY/S motif or Tyr7.53(323) of the N/DPxxY motif, increase or decrease receptor expression and efficiency of receptor coupling to G protein signaling, consistent with the native residues stabilizing the inactive GnRH receptor structure. Active conformation-specific interhelical contacts stabilize an open G protein-binding site. Progress in defining the GnRH-binding site has recently slowed, with evidence that Tyr6.58(290) contacts Tyr5 of GnRH, whereas other residues affect recognition of Trp3 and Gly10NH2. The surprisingly consistent observations that GnRH receptor mutations that disrupt GnRH binding have less effect on "conformationally constrained" GnRH peptides may now be explained by crystal structures of agonist-bound peptide receptors. Analysis of GPCR structures provides insight into GnRH receptor function. PMID- 29123502 TI - Anaplastic Thyroid Cancer in Sicily: The Role of Environmental Characteristics. AB - Background: Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive cancer of the thyroid, contributing up to 30-40% of thyroid cancer-specific mortality. We analyzed ATC characteristics and survival rates in Sicily to evaluate the possible influence of environmental factors. With this aim, data regarding ATC incidences in urban/rural and industrial, iodine-deficient, and volcanic vs control areas were compared in Sicily as well as ATC data from Sicily and USA. Methods: Using the Sicilian Register of Thyroid Cancer (SRTC) database incidence, age, gender, tumor size and histotype, extrathyroidal extension, stage, and coexistence with pre-existing differentiated thyroid cancer (DTC) were evaluated in different areas of Sicily and also compared with Surveillance Epidemiology and End Results data in USA. Results: Forty-three ATCs were identified in Sicily in the period 2002-2009. In our series only age <70 years at diagnosis (p = 0.01), coexistence with DTC (p = 0.027) and tumor size <=6 cm (p = 0.012) were significant factors for increased survival at univariate analysis (only age at multivariate analysis). No difference in ATC incidence was found in urban vs rural areas and in iodine-deficient and industrial vs control areas. By contrast, in the volcanic area of Sicily, where DTC incidence is doubled relative to the rest of the island, also ATC incidence was increased. ATC data in Sicily were similar to those reported in the same period in the USA where overall survival rate at 6 and 12 months, however, was smaller. Conclusion: The similar ATC data observed in Sicily and USA (having different genetic background and lifestyle) and the increased ATC incidence in the volcanic area of Sicily paralleling the increased incidence of papillary thyroid cancer are compatible with the possibility that casual additional mutations, more frequent in a background of increased cell replication like DCT, are the major causes of ATC rather than genetic background and/or direct environmental influences. PMID- 29123503 TI - Hyperleptinemia in Neonatally Overfed Female Rats Does Not Dysregulate Feeding Circuitry. AB - Neonatal overfeeding during the first weeks of life in male rats is associated with a disruption in the peripheral and central leptin systems. Neonatally overfed male rats have increased circulating leptin in the first 2 weeks of life, which corresponds to an increase in body weight compared to normally fed counterparts. These effects are associated with a short-term disruption in the connectivity of neuropeptide Y (NPY), agouti-related peptide (AgRP), and pro opiomelanocortin (POMC) neurons within the regions of the hypothalamus responsible for control of energy balance and food intake. Female rats that are overfed during the first weeks of their life experience similar changes in circulating leptin levels as well as in their body weight. However, it has not yet been studied whether these metabolic changes are associated with the same central effects as observed in males. Here, we hypothesized that hyperleptinemia associated with neonatal overfeeding would lead to changes in central feeding circuitry in females as it does in males. We assessed hypothalamic NPY, AgRP, and POMC gene expression and immunoreactivity at 7, 12, or 14 days of age, as well as neuronal activation in response to exogenous leptin in neonatally overfed and control female rats. Neonatally overfed female rats were hyperleptinemic and were heavier than controls. However, these metabolic changes were not mirrored centrally by changes in hypothalamic NPY, AGRP, and POMC fiber density. These findings are suggestive of sex differences in the effects of neonatal overfeeding and of differences in the ability of the female and male central systems to respond to changes in the early life nutritional environment. PMID- 29123504 TI - The Minimum Biological Energy Quantum. AB - Some anaerobic archaea and bacteria live on substrates that do not allow the synthesis of one mol of ATP per mol of substrate via substrate level phosphorylation (SLP). Energy conservation in these cases is only possible by a chemiosmotic mechanism that involves the generation of an electrochemical ion gradient across the cytoplasmic membrane that then drives ATP synthesis via an ATP synthase. The minimal amount of energy required for ATP synthesis is thus dependent on the magnitude of the electrochemical ion gradient, the phosphorylation potential in the cell and the ion/ATP ratio of the ATP synthase. It was always thought that the minimum biological energy quantum is defined as the amount of energy required to translocate one ion across the cytoplasmic membrane. We will discuss the thermodynamics of the reactions involved in chemiosmosis and describe the limitations for ion transport and ATP synthesis that led to the proposal that at least -20 kJ/mol are required for ATP synthesis. We will challenge this hypothesis by arguing that the enzyme energizing the membrane may translocate net less than one ion: By using a primary pump connected to an antiporter module a stoichiometry below one can be obtained, implying that the minimum biological energy quantum that sustains life is even lower than assumed to date. PMID- 29123505 TI - Staphylococcus aureus in Some Brazilian Dairy Industries: Changes of Contamination and Diversity. AB - Staphylococcus aureus, a major food-poisoning pathogen, is a common contaminant in dairy industries worldwide, including in Brazil. We determined the occurrence of S. aureus in five dairies in Brazil over 8 months. Of 421 samples, 31 (7.4%) were positive for S. aureus and prevalence varied from 0 to 63.3% between dairies. Sixty-six isolates from the 31 samples were typed by Multi-Locus Sequence Typing to determine if these isolates were persistent or continuously reintroduced. Seven known sequence types (STs), ST1, ST5, ST30, ST97, ST126, ST188 and ST398, and four new ST were identified, ST3531, ST3540, ST3562 and ST3534. Clonal complex (CC) 1 (including the four new ST), known as an epidemic clone, was the dominant CC. However, there were no indications of persistence of particular ST. The resistance toward 11 antibiotic compounds was assessed. Twelve profiles were generated with 75.8% of strains being sensitive to all antibiotic classes and no Methicillin-resistant S. aureus (MRSA) strains were found. The enterotoxin-encoding genes involved in food-poisoning, e.g., sea, sed, see, and seg were targeted by PCR. The two toxin-encoding genes, sed and see, were not detected. Only three strains (4.5%) harbored seg and two of these also harbored sea. Despite the isolates being Methicillin-sensitive S. aureus (MSSA), the presence of CC1 clones in the processing environment, including some harboring enterotoxin encoding genes, is of concern and hygiene must have high priority to reduce contamination. PMID- 29123507 TI - Utilizing Biotinylated Proteins Expressed in Yeast to Visualize DNA-Protein Interactions at the Single-Molecule Level. AB - Much of our knowledge in conventional biochemistry has derived from bulk assays. However, many stochastic processes and transient intermediates are hidden when averaged over the ensemble. The powerful technique of single-molecule fluorescence microscopy has made great contributions to the understanding of life processes that are inaccessible when using traditional approaches. In single molecule studies, quantum dots (Qdots) have several unique advantages over other fluorescent probes, such as high brightness, extremely high photostability, and large Stokes shift, thus allowing long-time observation and improved signal-to noise ratios. So far, however, there is no convenient way to label proteins purified from budding yeast with Qdots. Based on BirA-Avi and biotin-streptavidin systems, we have established a simple method to acquire a Qdot-labeled protein and visualize its interaction with DNA using total internal reflection fluorescence microscopy. For proof-of-concept, we chose replication protein A (RPA) and origin recognition complex (ORC) as the proteins of interest. Proteins were purified from budding yeast with high biotinylation efficiency and rapidly labeled with streptavidin-coated Qdots. Interactions between proteins and DNA were observed successfully at the single-molecule level. PMID- 29123508 TI - Ecology of Alpine Macrofungi - Combining Historical with Recent Data. AB - Historical datasets of living communities are important because they can be used to document creeping shifts in species compositions. Such a historical data set exists for alpine fungi. From 1941 to 1953, the Swiss geologist Jules Favre visited yearly the region of the Swiss National Park and recorded the occurring fruiting bodies of fungi >1 mm (so-called "macrofungi") in the alpine zone. Favre can be regarded as one of the pioneers of alpine fungal ecology not least because he noted location, elevation, geology, and associated plants during his numerous excursions. However, some relevant information is only available in his unpublished field-book. Overall, Favre listed 204 fungal species in 26 sampling sites, with 46 species being previously unknown. The analysis of his data revealed that the macrofungi recorded belong to two major ecological groups, either they are symbiotrophs and live in ectomycorrhizal associations with alpine plant hosts, or they are saprotrophs and decompose plant litter and soil organic matter. The most frequent fungi were members of Inocybe and Cortinarius, which form ectomycorrhizas with Dryas octopetala or the dwarf alpine Salix species. The scope of the present study was to combine Favre's historical dataset with more recent data, either with the "SwissFungi" database or with data from major studies of the French and German Alps, and with the data from novel high throughput DNA sequencing techniques of soils from the Swiss Alps. Results of the latter application revealed, that problems associated with these new techniques are manifold and species determination remains often unclear. At this point, the fungal taxa collected by Favre and deposited as exsiccata at the "Conservatoire et Jardin Botaniques de la Ville de Geneve" could be used as a reference sequence dataset for alpine fungal studies. In conclusion, it can be postulated that new improved databases are urgently necessary for the near future, particularly, with regard to investigating fungal communities from alpine regions using new techniques. PMID- 29123506 TI - Challenges and Advances for Genetic Engineering of Non-model Bacteria and Uses in Consolidated Bioprocessing. AB - Metabolic diversity in microorganisms can provide the basis for creating novel biochemical products. However, most metabolic engineering projects utilize a handful of established model organisms and thus, a challenge for harnessing the potential of novel microbial functions is the ability to either heterologously express novel genes or directly utilize non-model organisms. Genetic manipulation of non-model microorganisms is still challenging due to organism-specific nuances that hinder universal molecular genetic tools and translatable knowledge of intracellular biochemical pathways and regulatory mechanisms. However, in the past several years, unprecedented progress has been made in synthetic biology, molecular genetics tools development, applications of omics data techniques, and computational tools that can aid in developing non-model hosts in a systematic manner. In this review, we focus on concerns and approaches related to working with non-model microorganisms including developing molecular genetics tools such as shuttle vectors, selectable markers, and expression systems. In addition, we will discuss: (1) current techniques in controlling gene expression (transcriptional/translational level), (2) advances in site-specific genome engineering tools [homologous recombination (HR) and clustered regularly interspaced short palindromic repeats (CRISPR)], and (3) advances in genome-scale metabolic models (GSMMs) in guiding design of non-model species. Application of these principles to metabolic engineering strategies for consolidated bioprocessing (CBP) will be discussed along with some brief comments on foreseeable future prospects. PMID- 29123509 TI - Isolation of Antagonistic Endophytes from Banana Roots against Meloidogyne javanica and Their Effects on Soil Nematode Community. AB - Banana production is seriously hindered by Meloidogyne spp. all over the world. Endophytes are ideal candidates compared to pesticides as an environmentally benign agent. In the present study, endophytes isolated from banana roots infected by Meloidogyne spp. with different disease levels were tested in vitro, and in sterile and nature banana monoculture soils against Meloidogyne javanica. The proportion of antagonistic endophytes were higher in the roots of middle and high disease levels. Among those, bacteria were dominant, and Pseudomonas spp., Bacillus spp. and Streptomyces spp. showed more abundant populations. One strain, named as SA, with definite root inner-colonization ability was isolated and identified as Streptomyces sp. This strain showed an inhibiting rate of >50% in vitro and biocontrol efficiency of 70.7% in sterile soil against Meloidogyne javanica, compared to the control. Greenhouse experiment results showed that the strain SA exhibits excellent biological control ability for plant-parasites both in roots and in root-knot nematode infested soil. SA treatment showed a higher number of bacterivores, especially Mesorhabditis and Cephalobus. The maturity index was significantly lower, while enrichment index (EI) was significantly higher in the SA treatment. In conclusion, this study presents an important potential application of the endophytic strain Streptomyces sp. for the control of plant-parasitic nematodes, especially Meloidogyne javanica, and presents the effects on the associated variation of the nematode community. PMID- 29123510 TI - Upregulation of the PatAB Transporter Confers Fluoroquinolone Resistance to Streptococcus pseudopneumoniae. AB - We characterized the mechanism of fluoroquinolone-resistance in two isolates of Streptococcus pseudopneumoniae having fluoroquinolone-efflux as unique mechanism of resistance. Whole genome sequencing and genetic transformation experiments were performed together with phenotypic determinations of the efflux mechanism. The PatAB pump was identified as responsible for efflux of ciprofloxacin (MIC of 4 MUg/ml), ethidium bromide (MICs of 8-16 MUg/ml) and acriflavine (MICs of 4-8 MUg/ml) in both isolates. These MICs were at least 8-fold lower in the presence of the efflux inhibitor reserpine. Complete genome sequencing indicated that the sequence located between the promoter of the patAB operon and the initiation codon of patA, which putatively forms an RNA stem-loop structure, may be responsible for the efflux phenotype. RT-qPCR determinations performed on RNAs of cultures treated or not treated with subinhibitory ciprofloxacin concentrations were performed. While no significant changes were observed in wild-type Streptococcus pneumoniae R6 strain, increases in transcription were detected in the ciprofloxacin-efflux transformants obtained with DNA from efflux-positive isolates, in the ranges of 1.4 to 3.4-fold (patA) and 2.1 to 2.9-fold (patB). Ciprofloxacin-induction was related with a lower predicted free energy for the stem-loop structure in the RNA of S. pseudopneumoniae isolates (-13.81 and -8.58) than for R6 (-15.32 kcal/mol), which may ease transcription. The presence of these regulatory variations in commensal S. pseudopneumoniae isolates, and the possibility of its transfer to Streptococcus pneumoniae by genetic transformation, could increase fluoroquinolone resistance in this important pathogen. PMID- 29123511 TI - A High Grain Diet Dynamically Shifted the Composition of Mucosa-Associated Microbiota and Induced Mucosal Injuries in the Colon of Sheep. AB - This study investigated the dynamic shifts in mucosa-associated microbiota composition and mucosal morphology in the colon of sheep fed a high grain (HG) diet. A total of 20 male sheep were randomly assigned to four groups (n = 5 for each). The sheep in first group received hay diet. The animals in other 3 groups were fed an HG diet for 7 (HG7), 14 (HG14), or 28 (HG28) days, respectively. Colonic digesta samples were collected to determine the pH and the concentrations of volatile fatty acid (VFA) and lactate. The colonic mucosa was sampled to characterize the bacterial communities using Illumina MiSeq sequencing and to determine mRNA expression levels of cytokines and tight junction protein genes using quantitative real-time PCR. As time advanced, results revealed that colonic pH linearly decreased (P = 0.007), and the concentrations of total VFA linearly increased (P < 0.001). Microbial analysis showed that an HG diet linearly reduced (P < 0.050) the diversity and richness of the colonic microbiota. The principal coordinate analysis results showed that the colonic mucosa-associated bacterial communities of the four groups significantly shifted with number of days fed an HG diet. At the genus level, HG feeding significantly increased the relative abundance of some taxa including Prevotella, Coprococcus, Roseburia, and Clostridium_sensu_stricto_1, and decreased the proportion of Treponema, and the percentage of these taxa was not affected by days fed an HG diet. The microscopic examination showed that HG feeding caused the mucosal epithelial injury. The RT PCR results showed that the mRNA expression of claudin-1 (P = 0.038), IL-1beta (P = 0.045), IL-6 (P = 0.050), and TNF-alpha (P = 0.020) increased linearly with number of days fed an HG diet. The correlation analysis revealed significant correlation between the colonic mucosal mRNA expression of cytokines and mucosal bacterial composition. Generally, HG feeding increased colonic fermentation and altered colonic mucosal bacterial communities, which eventually caused colonic mucosal damage and led to colonic dysfunction, and these changes occurred gradually over at least 4 weeks. PMID- 29123513 TI - Seroepidemiology and Risk Factors of Toxoplasma gondii Infection among the Newly Enrolled Undergraduates and Postgraduate Students in China. AB - Toxoplasma gondii is an obligate intracellular zoonotic parasite, infecting warm blood animals including humans. Previous serological surveys of T. gondii infection have focused on people of different occupations and special groups, such as slaughterhouse workers, AIDS patients and pregnant women. To investigate the potential impact of T. gondii infection on the health of young students, the prevalence of T. gondii infection and associated risk factors among the newly enrolled undergraduates and postgraduate students were investigated. A total of 3,569 newly enrolled students (age range: 15- to 37-years-old, median 26 years) from various regions of China were recruited in this study. The serum samples were tested for the presence of T. gondii specific IgG by the modified agglutination test (MAT). Questionnaires were used to collect information on risk factors for T. gondii infection. Sixty-five (1.82%) out of 3,569 participants were seropositive for IgG antibodies to T. gondii by MAT (titer>=1:20). Four variables were found to be positively associated with T. gondii infection, including primary geographical location, living in rural areas, gardening or agriculture, and drinking unboiled water by the univariate logistic regression, and only gardening or agriculture was the independent risk factor for T. gondii positivity by using multivariate logistic regression in this study, which may provide information to guide future research and control policies. PMID- 29123512 TI - Alternative Growth Promoters Modulate Broiler Gut Microbiome and Enhance Body Weight Gain. AB - Antibiotic growth promoters (AGPs) are frequently used to enhance weight-gain in poultry production. However, there has been increasing concern over the impact of AGP on the emergence of antibiotic resistance in zoonotic bacterial pathogens in the microbial community of the poultry gut. In this study, we adopted mass spectrophotometric, phylogenetic, and shotgun-metagenomic approaches to evaluate bioactive phenolic extracts (BPE) from blueberry (Vaccinium corymbosum) and blackberry (Rubus fruticosus) pomaces as AGP alternatives in broilers. We conducted two trials with 100 Cobb-500 broiler chicks (in each trial) in four equal groups that were provided water with no supplementation, supplemented with AGP (tylosin, neomycin sulfate, bacitracin, erythromycin, and oxytetracycline), or supplemented with 0.1 g Gallic acid equivalent (GAE)/L or 1.0 g GAE/L (during the last 72 h before euthanasia) of BPE for 6 weeks. When compared with the control group (water only), the chickens supplemented with AGP and 0.1 g GAE/L of BPE gained 9.5 and 5.8% more body weight, respectively. The microbiomes of both the AGP- and BPE-treated chickens had higher Firmicutes to Bacteroidetes ratios. AGP supplementation appeared to be associated with higher relative abundance of bacteriophages and unique cecal resistomes compared with BPE supplementation or control. Functional characterization of cecal microbiomes revealed significant animal-to-animal variation in the relative abundance of genes involved in energy and carbohydrate metabolism. These findings established a baseline upon which mechanisms of plant-based performance enhancers in regulation of animal growth can be investigated. In addition, the data will aid in designing alternate strategies to improve animal growth performance and consequently production. PMID- 29123514 TI - Assessment of the Combined Effect of Epstein-Barr Virus and Plasmodium falciparum Infections on Endemic Burkitt Lymphoma Using a Multiplex Serological Approach. AB - Epstein-Barr virus (EBV) is a necessary cause of endemic Burkitt lymphoma (eBL), while the role of Plasmodium falciparum in eBL remains uncertain. This study aimed to generate new hypotheses on the interplay between both infections in the development of eBL by investigating the IgG and IgM profiles against several EBV and P. falciparum antigens. Serum samples collected in a childhood study in Malawi (2005-2006) from 442 HIV-seronegative children (271 eBL cases and 171 controls) between 1.4 and 15 years old were tested by quantitative suspension array technology against a newly developed multiplex panel combining 4 EBV antigens [Z Epstein-Barr replication activator protein (ZEBRA), early antigen diffuse component (EA-D), EBV nuclear antigen 1, and viral capsid antigen p18 subunit (VCA-p18)] and 15 P. falciparum antigens selected for their immunogenicity, role in malaria pathogenesis, and presence in different parasite stages. Principal component analyses, multivariate logistic models, and elastic net regressions were used. As expected, elevated levels of EBV IgG (especially against the lytic antigens ZEBRA, EA-D, and VCA-p18) were strongly associated with eBL [high vs low tertile odds ratio (OR) = 8.67, 95% confidence interval (CI) = 4.81-15.64]. Higher IgG responses to the merozoite surface protein 3 were observed in children with eBL compared with controls (OR = 1.29, 95% CI = 1.02 1.64), showing an additive interaction with EBV IgGs (OR = 10.6, 95% CI = 5.1 22.2, P = 0.05). Using elastic-net regression models, eBL serological profile was further characterized by lower IgM levels against P. falciparum preerythrocytic stage antigen CelTOS and EBV lytic antigen VCA-p18 compared with controls. In a secondary analysis, abdominal Burkitt lymphoma had lower IgM to EBV and higher IgG to EA-D levels than cases with head involvement. Overall, this exploratory study confirmed the strong role of EBV in eBL and identified differential IgG and IgM patterns to erythrocytic vs preerythrocytic P. falciparum antigens that suggest a more persistent/chronic malaria exposure and a weaker IgM immune response in children with eBL compared with controls. Future studies should continue exploring how the malaria infection status and the immune response to P. falciparum interact with EBV infection in the development of eBL. PMID- 29123515 TI - Dietary Intervention with beta-Lactoglobulin-Derived Peptides and a Specific Mixture of Fructo-Oligosaccharides and Bifidobacterium breve M-16V Facilitates the Prevention of Whey-Induced Allergy in Mice by Supporting a Tolerance-Prone Immune Environment. AB - Cow's milk allergy (CMA) prevails in infants and brings increased risk of developing other allergic diseases. Oral administration of specific beta lactoglobulin (BLG)-derived peptides (PepMix) and a specific blend of short- and long-chain fructo-oligosaccharides and Bifidobacterium breve M-16V (FF/Bb) was found to partially prevent CMA development in mice. In this study, we aimed to expand the knowledge on the preventive potential and the underlying mechanisms of this approach. Three-week-old female C3H/HeOuJ mice were orally exposed to PepMix+/-FF/Bb prior to a 5-week oral sensitization with whole whey and cholera toxin as an adjuvant. The acute allergic skin response was determined after an intradermal challenge with whole whey protein. Following an oral challenge with whey, regulatory T cells (Tregs) in the small intestine lamina propria (SI-LP) and mRNA expression of immune markers in the Peyer's patches (PP) were investigated. The early impact of PepMix and FF/Bb interventions on the immune system during the oral tolerance (OT) induction phase was investigated after the last OT administration. Pre-exposing mice to PepMix+FF/Bb partially prevented the acute allergic skin response compared to PBS and increased Tregs and activated T cells in the SI-LP compared to sham-sensitized mice. It also increased the mRNA expression of Tbet over GATA3 in the PP of whey-sensitized mice. Directly upon the 6-day OT phase, FF/Bb intervention enhanced cecal content levels of propionic and butyric acid in PepMix-fed mice and the former was positively correlated with Foxp3+ cell numbers in the colon. In the PP of PepMix+FF/Bb-exposed mice, IL-22 mRNA expression increased and IL-10 followed the same tendency, while the Foxp3 expression was increased over GATA3 and RorgammaT. In the colon, the Tbet mRNA expression increased over GATA3, while IL-22 decreased. In addition, the Foxp3+/GATA3+ and regulatory/effector T cell ratios in the mesenteric lymph nodes and the CD11b+/CD11b- conventional dendritic cells ratio in the SI-LP were increased. In conclusion, the FF/Bb diet facilitates the capacity of the specific BLG-peptides to partially prevent the allergic response after sensitization to whole whey protein, possibly by creating a tolerance-prone environment during the OT phase. Such a dietary intervention might contribute to tailoring successful strategies for CMA prevention. PMID- 29123516 TI - Avidity and Bystander Suppressive Capacity of Human Regulatory T Cells Expressing De Novo Autoreactive T-Cell Receptors in Type 1 Diabetes. AB - The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt beta-cell destruction. We generated human Tregs expressing a high-affinity GAD555-567 reactive TCR (clone R164), as well as the lower affinity clone 4.13 specific for the same peptide. We demonstrated that de novo Treg avatars potently suppress antigen-specific and bystander responder T-cell (Tresp) proliferation in vitro in a process that requires Treg activation (P < 0.001 versus unactivated Tregs). When Tresp were also glutamic acid decarboxylase (GAD)-reactive, the high affinity R164 Tregs exhibited increased suppression (P < 0.01) with lower Tresp division index (P < 0.01) than the lower affinity 4.13 Tregs. These data demonstrate the feasibility of rapid expansion of antigen-specific Tregs for applications in attenuating beta-cell autoimmunity and emphasize further opportunities for engineering cellular specificities, affinities, and phenotypes to tailor Treg activity in adoptive cell therapies for the treatment of type 1 diabetes. PMID- 29123517 TI - Neutrophils in Gliomas. AB - Neutrophils are the most abundant white blood cells and are the first recruited to inflammatory sites. Neutrophils are an important component of the tumor stroma and can exert both anti-tumoral and pro-tumoral activities, depending on their maturation and activation state. In human gliomas, the number of circulating and infiltrating neutrophils correlates with the severity of the disease, indicating a prognostic and possible pro-tumoral role for these leukocytes. In glioma preclinical models, neutrophils promote tumor growth and orchestrate the resistance to anti-angiogenic therapies. Nevertheless, recent data indicate that neutrophils can be activated to directly kill tumor cells or to orchestrate the anti-tumoral response. Here, we review current knowledge about the role of neutrophils in glioma and their possible involvement in new strategies to improve current cancer therapies. PMID- 29123519 TI - Two Distinct Myeloid Subsets at the Term Human Fetal-Maternal Interface. AB - During pregnancy, immune cells infiltrate the placenta at different stages of fetal development. NK cells and macrophages are the most predominant cell types. These immune cells play pleiotropic roles, as they control spiral artery remodeling to ensure appropriate blood supply and maintain long-term tolerance to a true allograft; yet, they must be able to mount appropriate immune defenses to pathogens that may threaten the fetus. Whether the same cell type accomplishes all these tasks or if there are dedicated subsets remains controversial. Here, we identify and characterize two distinct subsets of myeloid cells that differ in their pro-inflammatory/regulatory capacity. While one subset predominantly produces the immune-modulating cytokine IL-10, the second subset has superior capacity to secrete pro-inflammatory mediators, such as IL-1beta and IL-6. The putative regulatory myeloid cells also express high levels of inhibitory receptors and their ligands, including programmed cell death 1 (PD1) ligands. Importantly, a large fraction of CD8 and CD4 cells in normal term human placenta are PD1 positive, suggesting that the PD1/PD1 ligands axis might be critical to maintain tolerance during pregnancy. PMID- 29123518 TI - Human Primary Macrophages Derived In Vitro from Circulating Monocytes Comprise Adherent and Non-Adherent Subsets with Differential Expression of Siglec-1 and CD4 and Permissiveness to HIV-1 Infection. AB - Macrophages are a major target for human immunodeficiency virus type 1 (HIV-1) infection. However, macrophages are largely heterogeneous and may exhibit differences in permissiveness to HIV-1 infection. This study highlights the interplay of macrophage heterogeneity in HIV-1 pathogenesis. We show that monocyte-derived macrophages (MDMs) could be divided into two distinct subsets: CD14+Siglec-1hiCD4+ (non-adherent MDM) and CD14+Siglec-1LoCD4- (adherent MDM). The CD14+Siglec-1hiCD4+MDM subset represented the smaller proportion in the macrophage pool, and varied among different donors. Fractionation and subsequent exposure of the two MDM subsets to HIV-1 revealed opposite outcomes in terms of HIV-1 capture and infection. Although the CD14+Siglec-1hiCD4+MDM captured significantly more HIV-1, infection was significantly higher in the CD14+Siglec 1LoCD4-MDM subset. Thus, CD14+Siglec-1hiCD4+MDM were less permissive to infection. Depletion of CD14+Siglec-1hiCD4+MDM or a decrease in their percentage, resulted in increased infection of MDM, suggestive of a capacity of these cells to capture and sequester HIV-1 in an environment that hinders its infectivity. Increased expression of innate restriction factors and cytokine genes were observed in the non-adherent CD14+Siglec-1hiCD4+MDM, both before and after HIV-1 infection, compared to the adherent CD14+Siglec-1LoCD4-MDM. We speculate that the differential expression of gene expression profiles in the two macrophage subsets may provide an explanation for the differences observed in HIV-1 infectivity. PMID- 29123520 TI - DExD/H-Box Helicase 36 Signaling via Myeloid Differentiation Primary Response Gene 88 Contributes to NF-kappaB Activation to Type 2 Porcine Reproductive and Respiratory Syndrome Virus Infection. AB - DExD/H-box helicase 36 (DHX36) is known to be an ATP-dependent RNA helicase that unwinds the guanine-quadruplexes DNA or RNA, but emerging data suggest that it also functions as pattern recognition receptor in innate immunity. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has been devastating the swine industry worldwide. Interstitial pneumonia is considered to be one of the most obvious clinical signs of PRRSV infection, suggesting that the inflammatory response plays an important role in PRRSV pathogenesis. However, whether DHX36 is involved in PRRSV-induced inflammatory cytokine expression remains unclear. In this study, we found that PRRSV infection increased the expression of DHX36. Knockdown of DHX36 and its adaptor myeloid differentiation primary response gene 88 (MyD88) by small-interfering RNA in MARC 145 cells significantly reduced NF-kappaB activation and pro-inflammatory cytokine expression after PRRSV infection. Further investigation revealed that PRRSV nucleocapsid protein interacted with the N-terminal quadruplex binding domain of DHX36, which in turn augmented nucleocapsid protein-induced NF-kappaB activation. Taken together, our results suggest that DHX36-MyD88 has a relevant role in the recognition of PRRSV nucleocapsid protein and in the subsequent activation of pro-inflammatory NF-kappaB pathway. PMID- 29123521 TI - Good Manufacturing Practice-Compliant Production and Lot-Release of Ex Vivo Expanded Regulatory T Cells As Basis for Treatment of Patients with Autoimmune and Inflammatory Disorders. AB - In recent years, the exploration of regulatory T cell (Treg)-based cellular therapy has become an attractive strategy to ameliorate inflammation and autoimmunity in various clinical settings. The main obstacle to the clinical application of Treg in human is their low number circulating in peripheral blood. Therefore, ex vivo expansion is inevitable. Moreover, isolation of Treg bears the risk of concurrent isolation of unwanted effector cells, which may trigger or deteriorate inflammation upon adoptive Treg transfer. Here, we present a protocol for the GMP-compliant production, lot-release and validation of ex vivo expanded Tregs for treatment of patients with autoimmune and inflammatory disorders. In the presented production protocol, large numbers of Treg, previously enriched from a leukapheresis product by using the CliniMACS(r) system, are ex vivo expanded in the presence of anti-CD3/anti-CD28 expander beads, exogenous IL-2 and rapamycin during 21 days. The expanded Treg drug product passed predefined lot release criteria. These criteria include (i) sterility testing, (ii) assessment of Treg phenotype, (iii) assessment of non-Treg cellular impurities, (iv) confirmation of successful anti-CD3/anti-CD28 expander bead removal after expansion, and (v) confirmation of the biological function of the Treg product. Furthermore, the Treg drug product was shown to retain its stability and suppressive function for at least 1 year after freezing and thawing. Also, dilution of the Treg drug product in 0.9% physiological saline did not affect Treg phenotype and Treg function for up to 90 min. These data indicate that these cells are ready to use in a clinical setting in which a cell infusion time of up to 90 min can be expected. The presented production process has recently undergone on site GMP-conform evaluation and received GMP certification from the Bavarian authorities in Germany. This protocol can now be used for Treg-based therapy of various inflammatory and autoimmune disorders. PMID- 29123522 TI - Transcriptome Analysis of Circulating Immune Cell Subsets Highlight the Role of Monocytes in Zaire Ebola Virus Makona Pathogenesis. AB - Existing models of Ebola virus disease (EVD) suggest antigen-presenting cells are initial targets of Zaire ebolavirus (ZEBOV). In vitro studies have shown that ZEBOV infection of monocytes and macrophages results in the production of inflammatory mediators, which may cause lymphocyte apoptosis. However, these findings have not been corroborated by in vivo studies. In this study, we report the first longitudinal analysis of transcriptional changes in purified monocytes, T-cells, and B-cells isolated from cynomolgus macaques following infection with ZEBOV-Makona. Our data reveal monocytes as one of the major immune cell subsets that supports ZEBOV replication in vivo. In addition, we report a marked increase in the transcription of genes involved in inflammation, coagulation, and vascular disease within monocytes, suggesting that monocytes contribute to EVD manifestations. Further, genes important for antigen presentation and regulation of immunity were downregulated, potentially subverting development of adaptive immunity. In contrast, lymphocytes, which do not support ZEBOV replication, showed transcriptional changes limited to a small number of interferon-stimulated genes (ISGs) and a failure to upregulate genes associated with an antiviral effector immune response. Collectively, these data suggest that ZEBOV-infected monocytes play a significant role in ZEBOV-Makona pathogenesis and strategies to suppress virus replication or modify innate responses to infection in these cells should be a priority for therapeutic intervention. PMID- 29123523 TI - Identification of an Evolutionarily Conserved Ankyrin Domain-Containing Protein, Caiap, Which Regulates Inflammasome-Dependent Resistance to Bacterial Infection. AB - Many proteins contain tandemly repeated modules of several amino acids, which act as the building blocks that form the underlying architecture of a specific protein-binding interface. Among these motifs and one of the most frequently observed is ankyrin repeats (ANK), which consist of 33 amino acid residues that are highly conserved. ANK domains span a wide range of functions, including protein-protein interactions, such as the recruitment of substrate to the catalytic domain of an enzyme, or the assembly of stable multiprotein complexes. Here, we report the identification of an evolutionarily conserved protein, that we term Caiap (from CARD- and ANK-containing Inflammasome Adaptor Protein), which has an N-terminal CARD domain and 16 C-terminal ANK domains and is required for the inflammasome-dependent resistance to Salmonella Typhimurium in zebrafish. Intriguingly, Caiap is highly conserved from cartilaginous fish to marsupials but is absent in placental mammals. Mechanistically, Caiap acts downstream flagellin and interacts with catalytic active Caspa, the functional homolog of mammalian caspase-1, through its ANK domain, while its CARD domain promotes its self oligomerization. Our results therefore point to ANK domain-containing proteins as key inflammasome adaptors required for the stabilization of active caspase-1 in functionally stable, high molecular weight complexes. PMID- 29123524 TI - Vertebrate Adaptive Immunity-Comparative Insights from a Teleost Model. AB - The channel catfish (Ictalurus punctatus) and the ciliated protozoan parasite Ichthyophthirius multifiliis are used to study pathogen-specific protective immunity. In this review, we briefly describe this host-parasite system and discuss the comparative insights it provides on the adaptive immune response of vertebrates. We include studies related to cutaneous mucosal immunity, B cell memory responses, and analyses of alphabeta T cell receptor (TCR) repertoires. This host-parasite model has played an important role in elucidating host protective responses to parasite invasion and for comparative studies of vertebrate immunity. Recent findings from bioinformatics analyses of TCR beta repertoires suggest that channel catfish preferentially expand specific clonotypes that are stably integrated in the genome. This finding could have broad implications related to diversity in lymphocyte receptors of early vertebrates. PMID- 29123525 TI - Identification of New Features from Known Bacterial Protective Vaccine Antigens Enhances Rational Vaccine Design. AB - With many protective vaccine antigens reported in the literature and verified experimentally, how to use the knowledge mined from these antigens to support rational vaccine design and study underlying design mechanism remains unclear. In order to address the problem, a systematic bioinformatics analysis was performed on 291 Gram-positive and Gram-negative bacterial protective antigens with experimental evidence manually curated in the Protegen database. The bioinformatics analyses evaluated included subcellular localization, adhesin probability, peptide signaling, transmembrane alpha-helix and beta-barrel, conserved domain, Clusters of Orthologous Groups, and Gene Ontology functional annotations. Here we showed the critical role of adhesins, along with subcellular localization, peptide signaling, in predicting secreted extracellular or surface exposed protective antigens, with mechanistic explanations supported by functional analysis. We also found a significant negative correlation of transmembrane alpha-helix to antigen protectiveness in Gram-positive and Gram negative pathogens, while a positive correlation of transmembrane beta-barrel was observed in Gram-negative pathogens. The commonly less-focused cytoplasmic and cytoplasmic membrane proteins could be potentially predicted with the help of other selection criteria such as adhesin probability and functional analysis. The significant findings in this study can support rational vaccine design and enhance our understanding of vaccine design mechanisms. PMID- 29123526 TI - Toll-Like Receptor Ligands and Interferon-gamma Synergize for Induction of Antitumor M1 Macrophages. AB - Tumor-associated macrophages may either promote or suppress tumor growth depending on their activation status. Interferon-gamma (IFN-gamma) has been identified as a key factor for inducing tumoricidal M1 phenotype in macrophages. However, it remains unclear whether IFN-gamma is sufficient or if additional stimuli are required. Here, we tested IFN-gamma and a panel of toll-like receptor (TLR) agonists for the ability to activate murine macrophages toward a tumoricidal M1 phenotype. The following TLR ligands were used: TLR1/TLR2 agonist Pam3CSK4, TLR2/TLR6 agonist lipotechoic acid, TLR3 agonist poly(I:C), TLR4 agonist lipopolysaccharide (LPS), TLR5 agonist flagellin, TLR7 agonist CL264, and TLR9 agonist CpG. We used an in vitro growth inhibition assay to measure both cytotoxic and cytostatic activity of mouse macrophages against Lewis lung carcinoma (LLC) and MOPC315 plasmacytoma tumor cells. Production of nitric oxide (NO) and cytokines by activated macrophages was quantified. We found that IFN gamma alone was not able to render macrophages tumoricidal. Similarly, macrophage activation with single TLR agonists was inefficient. In sharp contrast, IFN-gamma was shown to synergize with TLR agonists for induction of macrophage tumoricidal activity and production of both NO and pro-inflammatory cytokines (TNF-alpha, IL 12p40, and IL-12p70). Furthermore, IFN-gamma was shown to suppress macrophage IL 10 secretion induced by TLR agonists. NO production was necessary for macrophage tumoricidal activity. We conclude that two signals from the microenvironment are required for optimal induction of antitumor M1 macrophage phenotype. Combination treatment with IFN-gamma and TLR agonists may offer new avenues for macrophage based cancer immunotherapy. PMID- 29123527 TI - Erythropoietin Increases Myelination in Oligodendrocytes: Gene Expression Profiling Reveals Early Induction of Genes Involved in Lipid Transport and Metabolism. AB - Several studies have shown that erythropoietin (EPO) has neuroprotective or neuroreparative actions on diseases of the nervous system and that improves oligodendrocyte (OL) differentiation and myelination in vivo and in vitro. This study aims at investigating the early molecular mechanisms for the pro myelinating action of EPO at the gene expression level. For this purpose, we used a differentiating OL precursor cell line, rat central glia-4 cells. Cells were differentiated or not, and then treated with EPO for 1 or 20 h. RNA was extracted and changes in the gene expression profile were assessed using microarray analysis. Experiments were performed in biological replicates of n = 4. Differentiation alone changed the expression of 11% of transcripts (2,663 out of 24,272), representing 2,436 genes, half of which were upregulated and half downregulated. At 20 h of treatment, EPO significantly affected the expression of 99 genes that were already regulated by differentiation and of 150 genes that were not influenced by differentiation alone. Analysis of the transcripts most upregulated by EPO identified several genes involved in lipid transport (e.g., Cd36) and lipid metabolism (Ppargc1a/Pgc1alpha, Lpin1, Pnlip, Lpin2, Ppard, Plin2) along with Igf1 and Igf2, growth factors known for their pro-myelinating action. All these genes were only induced by EPO and not by differentiation alone, except for Pnlip which was highly induced by differentiation and augmented by EPO. Results were validated by quantitative PCR. These findings suggest that EPO might increase remyelination by inducing insulin-like growth factors and increasing lipid metabolism. PMID- 29123528 TI - Janus-Faced Neutrophil Extracellular Traps in Periodontitis. AB - Periodontitis is characterized by PMN infiltration and formation of neutrophil extracellular traps (NETs). However, their functional role for periodontal health remains complex and partially understood. The main function of NETs appears to be evacuation of dental plaque pathogen-associated molecular patterns. The inability to produce NETs is concomitant with aggressive periodontitis. But in cases with exaggerated NET production, NETs are unable to maintain periodontal health and bystander damages occur. This pathology can be also demonstrated in animal models using lipopolysaccharide as PMN activator. The progress of periodontitis appears to be a consequence of the formation of gingival pockets obstructing the evacuation of both pathogen-associated and damage-associated molecular patterns, which are responsible for the self-perpetuation of inflammation. Thus, besides the pathogenic effects of the periodontal bacteria, the dysregulation of PMN activation appears to play a main role in the periodontal pathology. Consequently, modulation of PMN activation might be a useful approach to periodontal therapy. PMID- 29123529 TI - T Cell-Mediated Chronic Inflammatory Diseases Are Candidates for Therapeutic Tolerance Induction with Heat Shock Proteins. AB - Failing immunological tolerance for critical self-antigens is the problem underlying most chronic inflammatory diseases of humans. Despite the success of novel immunosuppressive biological drugs, the so-called biologics, in the treatment of diseases such rheumatoid arthritis (RA) and type 1 diabetes, none of these approaches does lead to a permanent state of medicine free disease remission. Therefore, there is a need for therapies that restore physiological mechanisms of self-tolerance. Heat shock proteins (HSPs) have shown disease suppressive activities in many models of experimental autoimmune diseases through the induction of regulatory T cells (Tregs). Also in first clinical trials with HSP-based peptides in RA and diabetes, the induction of Tregs was noted. Due to their exceptionally high degree of evolutionary conservation, HSP protein sequences (peptides) are shared between the microbiota-associated bacterial species and the self-HSP in the tissues. Therefore, Treg mechanisms, such as those induced and maintained by gut mucosal tolerance for the microbiota, can play a role by targeting the more conserved HSP peptide sequences in the inflamed tissues. In addition, the stress upregulated presence of HSP in these tissues may well assist the targeting of the HSP induced Treg specifically to the sites of inflammation. PMID- 29123530 TI - Human Cardiac-Derived Stem/Progenitor Cells Fine-Tune Monocyte-Derived Descendants Activities toward Cardiac Repair. AB - Cardiac repair following MI relies on a finely regulated immune response involving sequential recruitment of monocytes to the injured tissue. Monocyte derived cells are also critical for tissue homeostasis and healing process. Our previous findings demonstrated the interaction of T and natural killer cells with allogeneic human cardiac-derived stem/progenitor cells (hCPC) and suggested their beneficial effect in the context of cardiac repair. Therefore, we investigated here whether monocytes and their descendants could be also modulated by allogeneic hCPC toward a repair/anti-inflammatory phenotype. Through experimental in vitro assays, we assessed the impact of allogeneic hCPC on the recruitment, functions and differentiation of monocytes. We found that allogeneic hCPC at steady state or under inflammatory conditions can incite CCL-2/CCR2-dependent recruitment of circulating CD14+CD16- monocytes and fine-tune their activation toward an anti-inflammatory profile. Allogeneic hCPC also promoted CD14+CD16- monocyte polarization into anti-inflammatory/immune-regulatory macrophages with high phagocytic capacity and IL10 secretion. Moreover, hCPC bended the differentiation of CD14+CD16- monocytes to dendritic cells (DCs) toward anti inflammatory macrophage-like features and impaired their antigen-presenting function in favor of immune-modulation. Collectively, our results demonstrate that allogeneic hCPC could reshape monocytes, macrophages as well as DCs responses by favoring their anti-inflammatory/tolerogenic activation/polarization. Thereby, therapeutic allogeneic hCPC might also contribute to post-infarct myocardial healing by modeling the activities of monocytes and their derived descendants. PMID- 29123531 TI - Chronic Obstructive Pulmonary Disease-Derived Circulating Cells Release IL-18 and IL-33 under Ultrafine Particulate Matter Exposure in a Caspase-1/8-Independent Manner. AB - Chronic obstructive pulmonary disease (COPD) is considered the fourth-leading causes of death worldwide; COPD is caused by inhalation of noxious indoor and outdoor particles, especially cigarette smoke that represents the first risk factor for this respiratory disorder. To mimic the effects of particulate matter on COPD, we isolated peripheral blood mononuclear cells (PBMCs) and treated them with combustion-generated ultrafine particles (UFPs) obtained from two different fuel mixtures, namely, pure ethylene and a mixture of ethylene and dimethylfuran (the latter mimicking the combustion of biofuels). UFPs were separated in two fractions: (1) sub-10 nm particles, named nano organic carbon (NOC) particles and (2) primarily soot particles of 20-40 nm and their agglomerates (200 nm). We found that both NOC and soot UFPs induced the release of IL-18 and IL-33 from unstable/exacerbated COPD-derived PBMCs. This effect was associated with higher levels of mitochondrial dysfunction and derived reactive oxygen species, which were higher in PBMCs from unstable COPD patients after combustion-generated UFP exposure. Moreover, lower mRNA expression of the repairing enzyme OGG1 was associated with the higher levels of 8-OH-dG compared with non-smoker and smokers. It was interesting that IL-18 and IL-33 release from PBMCs of unstable COPD patients was not NOD-like receptor 3/caspase-1 or caspase-8-dependent, but rather correlated to caspase-4 release. This effect was not evident in stable COPD-derived PBMCs. Our data suggest that combustion-generated UFPs induce the release of caspase-4-dependent inflammasome from PBMCs of COPD patients compared with healthy subjects, shedding new light into the biology of this key complex in COPD. PMID- 29123533 TI - Identifying Developmental Zones in Maize Lateral Root Cell Length Profiles using Multiple Change-Point Models. AB - The identification of the limits between the cell division, elongation and mature zones in the root apex is still a matter of controversy when methods based on cellular features, molecular markers or kinematics are compared while methods based on cell length profiles have been comparatively underexplored. Segmentation models were developed to identify developmental zones within a root apex on the basis of epidermal cell length profiles. Heteroscedastic piecewise linear models were estimated for maize lateral roots of various lengths of both wild type and two mutants affected in auxin signaling (rtcs and rum-1). The outputs of these individual root analyses combined with morphological features (first root hair position and root diameter) were then globally analyzed using principal component analysis. Three zones corresponding to the division zone, the elongation zone and the mature zone were identified in most lateral roots while division zone and sometimes elongation zone were missing in arrested roots. Our results are consistent with an auxin-dependent coordination between cell flux, cell elongation and cell differentiation. The proposed segmentation models could extend our knowledge of developmental regulations in longitudinally organized plant organs such as roots, monocot leaves or internodes. PMID- 29123534 TI - Viral Diagnostics in Plants Using Next Generation Sequencing: Computational Analysis in Practice. AB - Viruses cause significant yield and quality losses in a wide variety of cultivated crops. Hence, the detection and identification of viruses is a crucial facet of successful crop production and of great significance in terms of world food security. Whilst the adoption of molecular techniques such as RT-PCR has increased the speed and accuracy of viral diagnostics, such techniques only allow the detection of known viruses, i.e., each test is specific to one or a small number of related viruses. Therefore, unknown viruses can be missed and testing can be slow and expensive if molecular tests are unavailable. Methods for simultaneous detection of multiple viruses have been developed, and (NGS) is now a principal focus of this area, as it enables unbiased and hypothesis-free testing of plant samples. The development of NGS protocols capable of detecting multiple known and emergent viruses present in infected material is proving to be a major advance for crops, nuclear stocks or imported plants and germplasm, in which disease symptoms are absent, unspecific or only triggered by multiple viruses. Researchers want to answer the question "how many different viruses are present in this crop plant?" without knowing what they are looking for: RNA sequencing (RNA-seq) of plant material allows this question to be addressed. As well as needing efficient nucleic acid extraction and enrichment protocols, virus detection using RNA-seq requires fast and robust bioinformatics methods to enable host sequence removal and virus classification. In this review recent studies that use RNA-seq for virus detection in a variety of crop plants are discussed with specific emphasis on the computational methods implemented. The main features of a number of specific bioinformatics workflows developed for virus detection from NGS data are also outlined and possible reasons why these have not yet been widely adopted are discussed. The review concludes by discussing the future directions of this field, including the use of bioinformatics tools for virus detection deployed in analytical environments using cloud computing. PMID- 29123535 TI - Trait and Marker Associations in Oryza nivara and O. rufipogon Derived Rice Lines under Two Different Heat Stress Conditions. AB - Wild species and derived introgression lines (ILs) are a good source of genes for improving complex traits such as heat tolerance. The effect of heat stress on 18 yield traits was studied in four treatments in two seasons, under field conditions by subjecting 37 ILs and recurrent parents Swarna and KMR3, N22 mutants, and wild type and 2 improved rice cultivars to heat stress using polycover house method in wet season and late sowing method in dry season. Normal grown unstressed plants were controls. Both correlation and path coefficient analysis showed that the major contributing traits for high yield per plant (YPP) under heat stress conditions were tiller number, secondary branches in panicle, filled grain number, and percent spikelet fertility. Three ILs, K-377-24, K-16-3, and S-148 which gave the highest YPP of 12.30-32.52 g under heat stress in both the seasons were considered the most heat tolerant. In contrast, K-363-12, S-75, and Vandana which gave the least YPP of 5.36-10.84 g were considered heat susceptible. These lines are a good genetic resource for basic and applied studies on heat tolerance in rice. Genotyping using 49 SSR markers and single marker analysis (SMA) revealed 613 significant marker- trait associations in all four treatments. Significantly, nine markers (RM243, RM517, RM225, RM518, RM525, RM195, RM282, RM489, and RM570) on chromosomes 1, 2, 3, 4, 6, and 8 showed association with six traits (flag leaf spad, flag leaf thickness, vegetative leaf temperature, plant height, panicle number, and tiller number) under heat stress conditions in both wet and dry seasons. Genes such as heat shock protein binding DnaJ, Hsp70, and temperature-induced lipocalin-2 OsTIL-2 close to these markers are candidates for expression studies and evaluation for use in marker assisted selection for heat tolerance. PMID- 29123532 TI - Food Legumes and Rising Temperatures: Effects, Adaptive Functional Mechanisms Specific to Reproductive Growth Stage and Strategies to Improve Heat Tolerance. AB - Ambient temperatures are predicted to rise in the future owing to several reasons associated with global climate changes. These temperature increases can result in heat stress- a severe threat to crop production in most countries. Legumes are well-known for their impact on agricultural sustainability as well as their nutritional and health benefits. Heat stress imposes challenges for legume crops and has deleterious effects on the morphology, physiology, and reproductive growth of plants. High-temperature stress at the time of the reproductive stage is becoming a severe limitation for production of grain legumes as their cultivation expands to warmer environments and temperature variability increases due to climate change. The reproductive period is vital in the life cycle of all plants and is susceptible to high-temperature stress as various metabolic processes are adversely impacted during this phase, which reduces crop yield. Food legumes exposed to high-temperature stress during reproduction show flower abortion, pollen and ovule infertility, impaired fertilization, and reduced seed filling, leading to smaller seeds and poor yields. Through various breeding techniques, heat tolerance in major legumes can be enhanced to improve performance in the field. Omics approaches unravel different mechanisms underlying thermotolerance, which is imperative to understand the processes of molecular responses toward high-temperature stress. PMID- 29123536 TI - Response of Summer Maize Photosynthate Accumulation and Distribution to Shading Stress Assessed by Using 13CO2 Stable Isotope Tracer in the Field. AB - Maize is one of the most important crops globally that provides food, feed, and bioenergy. However, shading stress threatens maize production. In this study, we investigated the effects of shading on photosynthate accumulation and distribution of summer maize in the field. Zhengdan958 (ZD958) and Denghai 605 (DH605) were used as experimental materials in a field experiment running from 2013 to 2015. Shading treatments were applied over different growth stages: from the tassel stage (VT) to physiological maturity (R6) (S1), from the six-leaf stage (V6) to VT (S2), and from emergence stage (VE) to R6 (S3). The effects of shading on plant photosynthesis, photosynthate accumulation and distribution, and yield were evaluated in comparison to ambient sunlight. Shading significantly decreased the leaf area, SPAD value, net photosynthetic rate, dry matter accumulation, and grain yield. During the 3-year experimental period, grain yields of ZD958 and DH605 were reduced by 83.4%, 34.2%, 53.1% and 79.3%, 24.2%, 57.6% as compared to the CK by treatments S3, S2, and S1, respectively. 13CO2 stable isotope tracing revealed that shading differentially affected the photosynthate transfer rate in different stages; photosynthates were transferred from top to bottom plant parts, in the order control > S2 > S1 > S3. We conclude that shading clearly disrupted photosynthate metabolism, and reduced the photosynthate accumulation in the grain, resulting in a yield reduction. PMID- 29123537 TI - Association Mapping of Ferrous, Zinc, and Aluminum Tolerance at the Seedling Stage in Indica Rice using MAGIC Populations. AB - Excessive amounts of metal are toxic and severely affect plant growth and development. Understanding the genetic control of metal tolerance is crucial to improve rice resistance to Fe, Zn, and Al toxicity. The multi-parent advanced generation inter-cross (MAGIC) populations were genotyped using a 55 K rice SNP array and screened at the seedling stage for Fe, Zn, and Al toxicity using a hydroponics system. Association analysis was conducted by implementing a mixed linear model (MLM) for each of the five MAGIC populations double cross DC1 (founders were SAGC-08, HHZ5-SAL9-Y3-Y1, BP1976B-2-3-7-TB-1-1, PR33282-B-8-1-1-1 1-1), double cross DC2 (founders of double cross were FFZ1, CT 16658-5-2-2SR-2-3 6MP, IR 68, IR 02A127), eight parents population 8way (founders were SAGC-08, HHZ5-SAL9-Y3-Y1, BP1976B-2-3-7-TB-1-1, PR33282-B-8-1-1-1-1-1, FFZ1, CT 16658-5-2 2SR-2-3-6MP, IR 68, IR 02A127), DC12 (DC1+DC2) and rice multi-parent recombinant inbred line population RMPRIL (DC1+DC2+8way). A total of 21, 30, and 21 QTL were identified for Fe, Zn, and Al toxicity tolerance, respectively. For multi tolerance (MT) as Fe, Zn, and Al tolerance-related traits, three genomic regions, MT1.1 (chr.1: 35.4-36.3 Mb), MT1.2 (chr.1: 35.4-36.3 Mb), and MT3.2 (chr.3: 35.4 36.2 Mb) harbored QTL. The chromosomal regions MT2.1 (chr.2: 2.4-2.8 Mb), MT2.2 (chr.2: 24.5-25.8 Mb), MT4 (chr.4: 1.2 Mb Mb), MT8.1 (chr.8: 0.7-0.9 Mb), and MT8.2 (chr.8: 2.2-2.4 Mb) harbored QTL for Fe and Zn tolerance, while MT2.3 (chr.2: 30.5-31.6 Mb), MT3.1 (chr.3: 12.5-12.8 Mb), and MT6 (chr.6: 2.0-3.0 Mb) possessed QTL for Al and Zn tolerance. The chromosomal region MT9.1 (chr.9: 14.2 14.7 Mb) possessed QTL for Fe and Al tolerance. A total of 11 QTL were detected across different MAGIC populations and 12 clustered regions were detected under different metal conditions, suggesting that these genomic regions might constitute valuable regions for further marker-assisted selection (MAS) in breeding programs. PMID- 29123538 TI - Sex-Specific Response to Stress in Populus. AB - Populus is an effective model for genetic studies in trees. The genus Populus includes dioecious species, and the differences exhibited in males and females have been intensively studied. This review focused on the distinctions between male and female poplar and aspen plants under stress conditions, such as drought, salinity, heavy metals, and nutrient deficiency on morphological, physiological, proteome, and gene expression levels. In most studies, males of Populus species were more adaptive to the majority of the stress conditions and showed less damage, better growth, and higher photosynthetic capacity and antioxidant activity than that of the females. However, in two recent studies, no differences in non-reproductive traits were revealed for male and female trees. This discrepancy of the results could be associated with experimental design: different species and genotypes, stress conditions, types of plant materials, sampling sizes. Knowledge of sex-specific differences is crucial for basic and applied research in Populus species. PMID- 29123539 TI - The AP2/ERF Transcription Factor DRNL Modulates Gynoecium Development and Affects Its Response to Cytokinin. AB - The gynoecium is the female reproductive system in flowering plants. It is a complex structure formed by different tissues, some that are essential for reproduction and others that facilitate the fertilization process and nurture and protect the developing seeds. The coordinated development of these different tissues during the formation of the gynoecium is important for reproductive success. Both hormones and genetic regulators guide the development of the different tissues. Auxin and cytokinin in particular have been found to play important roles in this process. On the other hand, the AP2/ERF2 transcription factor BOL/DRNL/ESR2/SOB is expressed at very early stages of aerial organ formation and has been proposed to be a marker for organ founder cells. In this work, we found that this gene is also expressed at later stages during gynoecium development, particularly at the lateral regions (the region related to the valves of the ovary). The loss of DRNL function affects gynoecium development. Some of the mutant phenotypes present similarities to those observed in plants treated with exogenous cytokinins, and AHP6 has been previously proposed to be a target of DRNL. Therefore, we explored the response of drnl-2 developing gynoecia to cytokinins, and found that the loss of DRNL function affects the response of the gynoecium to exogenously applied cytokinins in a developmental-stage dependent manner. In summary, this gene participates during gynoecium development, possibly through the dynamic modulation of cytokinin homeostasis and response. PMID- 29123540 TI - Divergence and Conservative Evolution of XTNX Genes in Land Plants. AB - The Toll-interleukin-1 receptor (TIR) and Nucleotide-binding site (NBS) domains are two major components of the TIR-NBS-leucine-rich repeat family plant disease resistance genes. Extensive functional and evolutionary studies have been performed on these genes; however, the characterization of a small group of genes that are composed of atypical TIR and NBS domains, namely XTNX genes, is limited. The present study investigated this specific gene family by conducting genome wide analyses of 59 green plant genomes. A total of 143 XTNX genes were identified in 51 of the 52 land plant genomes, whereas no XTNX gene was detected in any green algae genomes, which indicated that XTNX genes originated upon emergence of land plants. Phylogenetic analysis revealed that the ancestral XTNX gene underwent two rounds of ancient duplications in land plants, which resulted in the formation of clades I/II and clades IIa/IIb successively. Although clades I and IIb have evolved conservatively in angiosperms, the motif composition difference and sequence divergence at the amino acid level suggest that functional divergence may have occurred since the separation of the two clades. In contrast, several features of the clade IIa genes, including the absence in the majority of dicots, the long branches in the tree, the frequent loss of ancestral motifs, and the loss of expression in all detected tissues of Zea mays, all suggest that the genes in this lineage might have undergone pseudogenization. This study highlights that XTNX genes are a gene family originated anciently in land plants and underwent specific conservative pattern in evolution. PMID- 29123541 TI - Rice Seed Germination Underwater: Morpho-Physiological Responses and the Bases of Differential Expression of Alcoholic Fermentation Enzymes. AB - The water-, energy-, and labor-intensive system of transplanted puddled rice (Oryza sativa) is steadily being replaced by direct seeding due to the progressive scarcity of these resources. However, the alternate dry direct seeding leads to competition with weeds and poor establishment when soils are flooded. Direct seeded rice capable of anaerobic germination (germination in flooded soil, AG) is ideal, which under rainfed ecosystems would also overcome waterlogging during germination. AG tolerance is associated with faster germination and faster elongation of coleoptiles, with the activities of alcoholic fermentation enzymes replacing aerobic respiration as a source of energy. To better understand the variability in the morpho-physiological responses and in the nature of the alcoholic fermentation enzymes during AG, 21 rice genotypes were studied. The genotypes Khao Hlan On (KHO) and IR42 were used as the tolerant and susceptible checks, respectively. KHO exhibited faster germination, with 82.5% of the coleoptiles emerging out of 10 cm of water within 8 days, whereas IR42 exhibited 20% germination and limited coleoptile growth. Among the test genotypes, four performed well, including two that are drought tolerant. Increased content and activity of the alcoholic fermentation enzymes, alcohol dehydrogenase (ADH1) and acetaldehyde dehydrogenase (ALDH2a and ALDH2b), was noted in KHO under anaerobic than under aerobic conditions and also in comparison with IR42 under AG. Gene transcripts for these enzymes were also more in KHO undergoing AG. However, no major differences were observed between KHO and IR42 in the critical cis-acting regulatory elements, such as the auxin, light, and sugar response elements, in the promoters of ADH1, ALDH2a, and ALDH2b genes. Post-transcriptional and post-translational regulatory mechanisms were implicated for the increased transcript and protein content/activity of the enzymes in KHO by observing four different transcripts of ALDH2a and a unique non-glycosylated form of ADH1 under AG. IR42 lacked the non-glycosylated ADH1 and contained only a truncated form of ALDH2a, which lacked the active site. Additionally, KHO exhibited increased activity and more isoforms for reactive oxygen species detoxifying enzymes under AG compared to IR42. These results highlight the need for a deeper functional understanding of the critical enzymes involved in AG. PMID- 29123542 TI - Effects of Diet and Genetics on Growth Performance of Pigs in Response to Repeated Exposure to Heat Stress. AB - Heat stress (HS) is one of the costliest issues in the U.S. pork industry. Aims of the present study were to determine the consequences of repeated exposure to HS on growth performance, and the effects of a high fiber diet, the genetic potential for high lean tissue accretion, and the genetic potential for residual feed intake (RFI) on resilience to HS. Barrows (n = 97) from three genetic lines (commercial, high RFI, low RFI) where subjected three times to a 4-day HS treatment (HS1, HS2, and HS3) which was preceded by a 9-day neutral (TN) adaptation period (TN1) and alternated by 7-day periods of neutral temperatures (TN2, TN3, and TN4). Body weight gain (BWG), feed intake (FI), feed conversion efficiency (FCE), RFI, and the drop in BWG and FI between TN and HS were estimated for each period, and slaughter traits were measured at the end of TN4. Commercial pigs had lower FI when fed a high fiber diet compared to a regular diet (2.70 +/- 0.08 vs. 2.96 +/- 0.08 kg/d; P < 0.05), while no differences were found for BWG, RFI or FCE. HS reduced FI, BWG, and FCE, increased RFI, and resulted in leaner pigs that generate smaller carcasses at slaughter. In TN, commercial pigs grew faster than the low and high RFI pigs (1.22 +/- 0.06 vs. 0.720 +/- 0.05 and 0.657 +/- 0.07; P < 0.001) but growth rates were not significantly different between the lines during HS. Growth rates for the low RFI and high RFI pigs were similar both during TN and during HS. Pigs of interest for genetic improvement are those that are able to maintain growth rates during HS. Our results show that response in growth to HS was repeatable over subsequent 4-d HS cycles, which suggests the potential for including this response in the breeding index. The best performing animals during HS are likely those that are not highly superior for growth in TN. PMID- 29123543 TI - Can We Validate the Results of Twin Studies? A Census-Based Study on the Heritability of Educational Achievement. AB - As for most phenotypes, the amount of variance in educational achievement explained by SNPs is lower than the amount of additive genetic variance estimated in twin studies. Twin-based estimates may however be biased because of self selection and differences in cognitive ability between twins and the rest of the population. Here we compare twin registry based estimates with a census-based heritability estimate, sampling from the same Dutch birth cohort population and using the same standardized measure for educational achievement. Including important covariates (i.e., sex, migration status, school denomination, SES, and group size), we analyzed 893,127 scores from primary school children from the years 2008-2014. For genetic inference, we used pedigree information to construct an additive genetic relationship matrix. Corrected for the covariates, this resulted in an estimate of 85%, which is even higher than based on twin studies using the same cohort and same measure. We therefore conclude that the genetic variance not tagged by SNPs is not an artifact of the twin method itself. PMID- 29123546 TI - On the Accuracy and Parallelism of GPGPU-Powered Incremental Clustering Algorithms. AB - Incremental clustering algorithms play a vital role in various applications such as massive data analysis and real-time data processing. Typical application scenarios of incremental clustering raise high demand on computing power of the hardware platform. Parallel computing is a common solution to meet this demand. Moreover, General Purpose Graphic Processing Unit (GPGPU) is a promising parallel computing device. Nevertheless, the incremental clustering algorithm is facing a dilemma between clustering accuracy and parallelism when they are powered by GPGPU. We formally analyzed the cause of this dilemma. First, we formalized concepts relevant to incremental clustering like evolving granularity. Second, we formally proved two theorems. The first theorem proves the relation between clustering accuracy and evolving granularity. Additionally, this theorem analyzes the upper and lower bounds of different-to-same mis-affiliation. Fewer occurrences of such mis-affiliation mean higher accuracy. The second theorem reveals the relation between parallelism and evolving granularity. Smaller work depth means superior parallelism. Through the proofs, we conclude that accuracy of an incremental clustering algorithm is negatively related to evolving granularity while parallelism is positively related to the granularity. Thus the contradictory relations cause the dilemma. Finally, we validated the relations through a demo algorithm. Experiment results verified theoretical conclusions. PMID- 29123544 TI - Non-coding RNAs in Mesenchymal Stem Cell-Derived Extracellular Vesicles: Deciphering Regulatory Roles in Stem Cell Potency, Inflammatory Resolve, and Tissue Regeneration. AB - Extracellular vesicles (EVs) are heterogeneous populations of nano- and micro sized vesicles secreted by various cell types. There is mounting evidence that EVs have widespread roles in transporting proteins, lipids, and nucleic acids between cells and serve as mediators of intercellular communication. EVs secreted from stem cells could function as paracrine factors, and appear to mimic and recapitulate several features of their secreting cells. EV-mediated transport of regulatory RNAs provides a novel source of trans-regulation between cells. As such, stem cells have evolved unique forms of paracrine mechanisms for recapitulating their potencies with specialized functions by transporting non coding RNAs (ncRNAs) via EVs. This includes the dissemination of stem cell derived EV-ncRNAs and their regulatory effects elicited in differentiation, self renewal, pluripotency, and the induction of reparative programs. Here, we summarize and discuss the therapeutic effects of mesenchymal stem cell-derived EV ncRNAs in the induction of intrinsic regenerative programs elicited through regulating several mechanisms. Among them, most noticeable are the EV-mediated enrichment of ncRNAs at the injury sites contributing the regulation of matrix remodeling, epithelial mesenchymal transitions, and attraction of fibroblasts. Additionally, we emphasize EV-mediated transmission of anti-inflammatory RNAs from stem cells to injury site that potentially orchestrate the resolution of the inflammatory responses and immune alleviation to better facilitate healing processes. Collectively, this knowledge indicates a high value and potential of EV-mediated RNA-based therapeutic approaches in regenerative medicine. PMID- 29123545 TI - Identification and Characterization of MicroRNAs in the Goat (Capra hircus) Rumen during Embryonic Development. AB - The rumen is an important digestive organ in ruminants. Numerous regulatory factors including microRNAs (miRNAs) are involved in embryonic organ development. In the present study, miRNAs expressed in the rumens of goats (Capra hircus) and their potential roles in the pathways involved in rumen development were identified using high-throughput sequencing. Histological morphology revealed a distinct difference in each layer of rumen during the period from embryonic day 60 (E60) to embryonic day 135 (E135). We determined the expression profiles of miRNAs in the goat rumen, and identified 423 known miRNAs and 559 potentially novel miRNAs in the E60 and E135 embryonic rumen, respectively. Bioinformatics analysis annotated the 42 differentially expressed miRNAs and the top 10 most highly expressed miRNAs of the two libraries to 48 and 38 gene ontology categories, as well as to 168 and 71 Kyoto Encyclopedia of Genes and Genomes pathways, respectively. The expression patterns of eight randomly selected miRNAs were validated by stem-loop quantitative reverse transcription PCR, suggesting that the sequencing data were reliable. We profiled the genome-wide expression of rumen-expressed miRNAs at different prenatal stages of rumen tissues, revealing that a subset of miRNAs might play important roles in the formation of the rumen layers. Taken together, these findings will aid the investigation of dominant rumen-related miRNA sets and help understand the genetic control of rumen development in goats. PMID- 29123548 TI - The Hazard Content of Cadmium, Lead, and Other Trace Elements in Some Medicinal Herbs and Their Water Infusions. AB - 54 samples belonging to 23 herbal species (15 individuals and 8 mixtures) were analyzed for their contents of heavy metals in the raw materials and in their water infusions. Trace and toxic elements in these samples were determined by using inductively coupled plasma-atomic emission spectrometry (ICP-OES) following acid digestion. The order of decreasing mean metal concentrations in raw materials (mg/kg) was found to be as follows: Fe (440) > Mn (162) > Zn (45.8) > Cu (12) > Pb (10.4) > Ni (5.4) > Cr (2.9) > Co (0.91) > Cd (0.5). It was found that 21% of the analyzed samples contain both Cd and Pb above their permissible limits. However, the infusions produced from these plants were found to contain fewer amounts of metals than the raw materials. Studied metals had the following mass transfer percentages to the infusion solutions (Fe: 3.5%, Cd: 14%, Cr: 15%, Pb: 20%, Co: 29%, Ni: 31%, Zn: 36%, Cu: 48%, and Mn: 53%). The estimated daily intake calculated for the toxic elements Pb and Cd through the consumption of herbal infusions was far below the tolerable daily intake set by the World Health Organization (WHO). PMID- 29123547 TI - Quercetin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy by Inhibiting ERK/NF-kappaB Pathway. AB - Background: Hepatic ischemia reperfusion (IR) injury is a common phenomenon in transplantation or trauma. The aim of the present study was to determine the protective effect of quercetin (QE) on hepatic IR injury via the ERK/NF-kappaB pathway. Methods: Mice were randomized into the sham, IR, QE100 + IR, and QE200 + IR groups. Quercetin was administered intragastrically daily at two doses (100 mg/kg and 200 mg/kg) for 5 days prior to IR injury. The expression levels of liver enzymes, inflammatory cytokines, and other marker proteins were determined at 2, 8, and 24 hours after IR. And they were compared among these groups. Results: Compared with the IR group, the treatment of QE reduced the release of cytokines, leading to inhibition of apoptosis and autophagy via downregulation of the ERK/NF-kappaB pathway in this model of hepatic IR injury. Conclusion: Apoptosis and autophagy caused by hepatic IR injury were inhibited by QE following a reduction in the release of inflammatory cytokines, and the relationship between the two may be associated with inactivation of the ERK/NF kappaB pathway. PMID- 29123549 TI - Isolation and Physiomorphological Characterization of Escherichia coli O157:H7 Infecting Bacteriophages Recovered from Beef Cattle Operations. AB - Bacteriophages, recovered from beef cattle environment and specifically targeting Escherichia coli O157:H7, were examined for their physiological and morphological characteristics. Degree of bacterial lysis and host range of isolated bacteriophages was determined against 55 isolates of E. coli O157:H7. Morphology of phages was examined under transmission electron microscope. Phage growth parameters, particularly rate of adsorption, rise period, latent period, and burst size were also determined. The stability of isolated phages was tested at acidic and alkaline pH, at high temperatures, and in cold storage. A total of 7 phages were isolated which showed lytic activity against 50 out of 55 isolates of E. coli O157:H7. Based on the morphology, phages were classified into Myoviridae or Siphoviridae family. Phages had a rise period between 19 and 40 min, a short latent period between 12 and 30 min, and a large burst size (89-631 virions per infected cell), indicating high lytic activity. Phages remained stable for 24 h at a wide pH (1-11) and temperature range (40-60 degrees C) and for 90 d in cold storage. Characterization of bacteriophages, with a diverse host range of E. coli O157:H7, could aid in the development of effective biocontrol strategies for this pathogen in the food industry. PMID- 29123552 TI - Pairwise Multiple Comparison Adjustment Procedure for Survival Functions with Right-Censored Data. AB - The aim of this study is to propose a new pairwise multiple comparison adjustment procedure based on Genz's numerical computation of probabilities from a multivariate normal distribution. This method is applied to the results of two sample log-rank and weighted log-rank statistics where the survival data contained right-censored observations. We conducted Monte Carlo simulation studies not only to evaluate the familywise error rate and power of the proposed procedure but also to compare the procedure with conventional methods. The proposed method is also applied to the data set consisting of 815 patients on a liver transplant waiting list from 1990 to 1999. It was found that the proposed method can control the type I error rate, and it yielded similar power as Tukey's and high power with respect to the other adjustment procedures. In addition to having a straightforward formula, it is easy to implement. PMID- 29123553 TI - This month in JICS. PMID- 29123551 TI - Discovery of Antimalarial Drugs from Streptomycetes Metabolites Using a Metabolomic Approach. AB - Natural products continue to play an important role as a source of biologically active substances for the development of new drug. Streptomyces, Gram-positive bacteria which are widely distributed in nature, are one of the most popular sources of natural antibiotics. Recently, by using a bioassay-guided fractionation, an antimalarial compound, Gancidin-W, has been discovered from these bacteria. However, this classical method in identifying potentially novel bioactive compounds from the natural products requires considerable effort and is a time-consuming process. Metabolomics is an emerging "omics" technology in systems biology study which integrated in process of discovering drug from natural products. Metabolomics approach in finding novel therapeutics agent for malaria offers dereplication step in screening phase to shorten the process. The highly sensitive instruments, such as Liquid Chromatography-Mass Spectrophotometry (LC-MS), Gas Chromatography-Mass Spectrophotometry (GC-MS), and Nuclear Magnetic Resonance (1H-NMR) spectroscopy, provide a wide range of information in the identification of potentially bioactive compounds. The current paper reviews concepts of metabolomics and its application in drug discovery of malaria treatment as well as assessing the antimalarial activity from natural products. Metabolomics approach in malaria drug discovery is still new and needs to be initiated, especially for drug research in Malaysia. PMID- 29123550 TI - Mesenchymal Stem Cells for Cartilage Regeneration of TMJ Osteoarthritis. AB - Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease, characterized by progressive cartilage degradation, subchondral bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical treatments have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In recent years, stem cell-based therapy has raised much attention as an alternative approach towards tissue repair and regeneration. Mesenchymal stem cells (MSCs), derived from the bone marrow, synovium, and even umbilical cord, play a role as seed cells for the cartilage regeneration of TMJ OA. MSCs possess multilineage differentiation potential, including chondrogenic differentiation as well as osteogenic differentiation. In addition, the trophic modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impaired function of TMJ. In this review, we will briefly discuss the pathogenesis of cartilage degeneration in TMJ OA and emphasize the potential sources of MSCs and novel approaches for the cartilage regeneration of TMJ OA, particularly focusing on the MSC-based therapy and tissue engineering. PMID- 29123554 TI - Psychological burnout and the intensive care practitioner: A practical and candid review for those who care. PMID- 29123555 TI - Meritocracy? Ask yourself. AB - Meritocracy refers to a governmental or other administrative system wherein appointments and responsibilities are assigned to individuals based on their merits, which are determined through objective evaluations or examinations. Merit can be earned by either intellectual or manual labour, as each person has his or her own talents. Nevertheless, there is no absolute definition of merit because both intelligence and skill are relative. In our current society, individuals can, theoretically, reach any goal in a meritocratic system. Indeed, merit should be the basis on which resources are allocated. This said, personal beliefs, bureaucratic complications, national regulations, and other human characteristics obscure the obvious superiority of this approach. Members of groups, including societies, often support and follow an individual who adheres to the group's norms rather than one who may be more deserving of such loyalty but who does not adhere to the shared rules. Individuals in a meritocratic system feel valued, believe their abilities are recognised, and have incentives to improve their professional performance. In such a context, individuals experience their environment as fair and feel more confident about themselves, others, and their work. Individuals working under such conditions are very likely to have higher levels of motivation, engage in more collaborative behaviour, show greater flexibility and experience enhanced well being compared with those operating in a system that is perceived as not based on merit. This paper presents an integrated discussion of meritocracy and poses seven questions that may improve our understanding of this concept. PMID- 29123556 TI - Oxygen therapy and the Goldilocks principle. PMID- 29123557 TI - Defining fluid removal in the intensive care unit: A national and international survey of critical care practice. AB - Design and objectives: To identify and compare how intensive care unit specialists in the United Kingdom and Australia and New Zealand self-reportedly define, assess and manage fluid overload in critically ill patients using a structured online questionnaire. Results: We assessed 219 responses. Australia and New Zealand and United Kingdom intensive care unit specialists reported using clinical examination findings, bedside tools and radiological features to assess fluid status, diagnose fluid overload and initiate fluid removal in the critically ill. An elevated central venous pressure is not regarded as helpful in diagnosing fluid overload and targeting a clinician-set fluid balance is the most popular management strategy. Renal replacement therapy is used ahead of more diuretic therapy in patients who are oligo/anuric, or when diuretic therapy has not generated an adequate response. Conclusions: This self-reported account of practice by United Kingdom and Australia and New Zealand intensivists demonstrates that fluid overload remains poorly defined with variability in both management and practice. PMID- 29123558 TI - Predictors of post-traumatic stress disorder following critical illness: A mixed methods study. AB - Purpose: Post-traumatic stress disorder has been reported in survivors of critical illness. The aim of this study was to investigate the predictors of post traumatic stress disorder in survivors of critical illness. Materials and methods: Patients attending the intensive care unit (ICU) follow-up clinic completed the UK-Post-Traumatic Stress Syndrome 14-Questions Inventory and data was collected from their medical records. Predictors investigated included age, gender, Apache II score, ICU length of stay, pre-illness psychopathology; delirium and benzodiazepine administration during ICU stay and delusional memories of the ICU stay following discharge. Results: A total of 198 patients participated, with 54 (27%) patients suffering with post-traumatic stress disorder. On multivariable logistic regression, the significant predictors of post-traumatic stress disorder were younger age, lower Apache II score, pre illness psychopathology and delirium during the ICU stay. Conclusions: The predictors of post-traumatic stress disorder in this study concur with previous research however a lower Apache II score has not been previously reported. PMID- 29123559 TI - Factors associated with success in the oral part of the European Diploma in Intensive Care. AB - Introduction: The oral part of European Diploma in Intensive Care diploma examinations changed in 2013 into an objective structured clinical examination type exam. This step was undertaken to provide a fair and reproducible clinical exam. All candidates face identical questions with predefined correct answers simultaneously in seven high throughput exam centres on the same day. We describe the factors that are associated with success in part 2 European Diploma in Intensive Care exam. Methods: We prospectively collected self-reported data from all candidates sitting European Diploma in Intensive Care part 2 in 2015, namely demographics, professional background and attendance to a European Diploma in Intensive Care part 2 or generic objective structured clinical examination preparatory courses. After testing association with success (with cutoff at p < 0.10) and co-linearity of these factors as independent variables, we performed a multivariate logistical analysis, with binary exam outcome (pass/fail) as the dependent variable. Structural equation modelling was used to gain further insight into relations among determinants of success in the oral part of the European Diploma in Intensive Care. Results: Out of 427 candidates sitting the exam, completed data from 341 (80%) were available for analysis. The following candidates' factors were associated with increased chance of success: English as native language (odds ratio 4.3 (95% CI 1.7-10.7)), use of Patient-centred Acute Care Training e-learning programme module (odds ratios 2.0 (1.2-3.3)), working in an EU country (odds ratios 2.5 (1.5-4.3)), and better results in the written part of the European Diploma in Intensive Care (for each additional SD of 6.1 points odds ratios 1.9 (1.4-2.4)). Chance of success in the European Diploma in Intensive Care 2 decreased with increased candidates 'age (for each additional SD of 5.5 years odds ratios 0.67 (0.51-0.87)). Exam centres (7 in total) could be clustered into 3 groups with similar success rates. There were significant differences in exam outcomes among these 3 groups of exam centres even after adjustment to known candidates' factors (G1 vs G2 odds ratios 2.4 (1.4-4.1); G1 vs G3 odds ratios 9.7 (4.0-23.1) and G2 vs G3 odds ratios 3.9 (1.7-9.2)). A short data collection period (only one year) and 20% of missing candidates' data are the main limitations of this study. Conclusions: Younger age, English as native language, better results in written part of the exam, working at a European country and the use of PACT for preparation, were factors associated with success in the oral part of the European Diploma in Intensive Care exam. Despite the limitations of this study, the differences in outcome among the exam centres will need further investigation. PMID- 29123560 TI - Outcomes in patients with acute kidney injury reviewed by Critical Care Outreach: What is the role of the National Early Warning Score? AB - Introduction: This study investigated outcomes in critically unwell acute kidney injury patients and the role of the National Early Warning Score and other factors in identifying patients who experience negative outcomes. Methods: Retrospective cohort study investigating 64 patients seen by Critical Care Outreach between November 2014 and February 2015. Mortality at one year was analysed using multivariate regression; all other statistical tests were non parametric. Results: Forty-four per cent of patients required escalation to higher level care, 56% failed to survive beyond one year and 30% of those who did survive had a deterioration in renal function. Previous acute kidney injury significantly predicted mortality but the National Early Warning Score did not. A subgroup of patients developed Stage 3 acute kidney injury before a rise in National Early Warning Score. Conclusions: Acute kidney injury in the Critical Care Outreach patient population is associated with high morbidity and mortality. Previous acute kidney injury and acute kidney injury stage may be superior to the National Early Warning Score at identifying patients in need of Critical Care Outreach review. PMID- 29123561 TI - Mortality prediction in status epilepticus with the APACHE II score. AB - A retrospective study was performed of adults admitted to the intensive care unit in order to determine the utility of the Acute Physiology and Chronic Health Evaluation II (APACHE II) score in predicting in-hospital mortality in intensive care unit patients with non-cardiac status epilepticus. The cohort consisted of 104 subjects, 50 (48.1%) male, 39 (37.5%) aged >=65 years, with a mean APACHE II score of 17.88. Four models of the APACHE II system were assessed: numerical score, adjusted score mortality, category, and category mortality. All models demonstrated poor calibration and discrimination, even after adjustment for significantly different covariates. There were independent associations between mortality and acute or toxic-metabolic seizure etiologies, myoclonic seizures, and postoperative status. After multivariate adjustment, only the association with toxic-metabolic seizure etiologies remained. The APACHE II score is a poor predictor of mortality in intensive care unit patients with status epilepticus. Further investigation is warranted to develop better measures of acute physiological disease severity in status epilepticus and its impact on mortality. PMID- 29123562 TI - The role of occupational and physiotherapy in multi-modal approach to tackling delirium in the intensive care. AB - The presence of delirium within critical care remains a long-standing challenge for patients and clinicians alike. A myriad of pre-disposing and precipitating factors lead to this patient cohort being high risk for developing delirium during their critical care stay. Until now, non-pharmacological management of these patients usually encompasses a 'bundle' of principles to reduce delirium days. These bundles have limited focus on the entire multi-disciplinary team (including occupational therapists and physiotherapists) who could assist with the reduction of delirium. The purpose of this analysis is to review the current literature and develop a mnemonic, which may help facilitate collaborative working for patients with delirium. Electronic databases were searched for non pharmacological managements of delirium within intensive care settings, after 2006. Critical appraisal using Critical Appraisal Skills Programme methodology was completed by the author. Multi-intervention approaches and bundles are successful at reducing delirium days, and in some cases, reducing hospital length of stay. The key components of these bundles include spontaneous breathing trials, daily sedation holds, addressing pain relief, early mobilisation and to a small extent normalisation of a daily routine. There is limited research into the role of therapy within this patient group, but there is a role for cognitive therapy, functional tasks, and a greater rehab emphasis within other patient populations such as stroke and elderly care. The critical care population have similar rehabilitation needs to these groups, and therefore would benefit from similar treatment plans. Critical care patients with delirium may benefit from a range of additional therapeutic activities to reduce the duration of delirium. The D.E.L.I.R.I.U.M mnemonic has been developed to encompass all the key elements of current delirium research in a simplistic memorable fashion. Further work is needed to trial the usefulness of the mnemonic in clinical practice to enable the entire multi-disciplinary team work collaboratively to reduce delirium with the intensive care. PMID- 29123563 TI - The lives and works of John Cheyne (1777-1836) and William Stokes (1804-1878). AB - Cheyne-Stokes respiration - an abnormal pattern of breathing, oscillating between hyperventilation and apnoea - was first described in the 19th century by Dr John Cheyne and Dr William Stokes. Although primarily known for this condition, both men contributed a lot more to the understanding and practice of medicine than this eponym. PMID- 29123564 TI - Critically appraised topic: Effect of noninvasive ventilation delivered by helmet vs. face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome. PMID- 29123565 TI - Lemierre's Syndrome - A rare cause of disseminated sepsis requiring multi-organ support. AB - Lemierre's syndrome is a rare complication of acute pharyngitis characterised by septicaemia with infective thrombophlebitis of the internal jugular vein, most commonly due to Fusobacterium necrophorum. It characteristically affects healthy young adults causing persistent pyrexia and systemic sepsis presenting several days after an initial pharyngitis. Septic emboli seed via the bloodstream to distant sites including the lung, joints, skin, liver, spleen and brain. Prolonged antimicrobial therapy is required and admission to intensive care common. This once rare condition is increasing in incidence but awareness amongst clinicians is low. We present a classic case in a young man who developed multi organ failure requiring intensive care support and describe the epidemiology, pathophysiology, microbiology, clinical features and management of the disease. PMID- 29123566 TI - Consideration of underlying causes of pneumothoraces in patients presenting with their first pneumothorax. AB - We report a case of cardiac arrest secondary to pneumothorax. The patient failed to improve, and further investigation showed an underlying condition predisposing the patient to the development of pneumothoraces - lymphangioleiomyomatosis. This highlights the importance of follow-up and investigation in patients presenting with their first pneumothorax. PMID- 29123567 TI - Neurological effects of fat embolism syndrome: A case report. AB - Fat embolism syndrome is a serious multi-system pathology which classically affects the respiratory system, neurological system and causes a petechial rash. We present the case of a 20-year-old farmer who developed fat embolism syndrome following a traumatic femoral fracture. Features developed within 24 h of injury and necessitated a prolonged stay in Intensive Care. He exhibited significant signs of cerebral fat embolism syndrome including coma and seizures but went on to make full functional recovery. Magnetic resonance imaging is the recommended imaging modality for patients with suspected cerebral fat embolism. In this case, computerised tomography was inconclusive, but magnetic resonance imaging demonstrated the "starfield pattern" of multiple high signal foci on a dark background. Supportive treatment of fat embolism syndrome is required in an appropriate setting, such as High Dependency or Intensive Care, for patients at risk of hypoxia or neurological deterioration. Despite major neurological involvement of fat embolism syndrome, full recovery is described by several cases including ours. PMID- 29123568 TI - The use of veno-venous extracorporeal membrane oxygenation following thrombolysis for massive pulmonary embolism. AB - A 59-year-old man was diagnosed with a massive pulmonary embolism. Despite thrombolysis there were two episodes of cardiac arrest and following recovery of spontaneous circulation profound cardiorespiratory failure ensued. An extracorporeal membrane oxygenation retrieval team initiated veno-venous extracorporeal membrane oxygenation on site to facilitate transfer to the extracorporeal membrane oxygenation centre. An excellent outcome is reported in the short term. This represents one of the few published cases of veno-venous extracorporeal membrane oxygenation for a massive pulmonary embolism following thrombolysis. PMID- 29123569 TI - Diagnostic dilemma: Severe thrombotic microangiopathy in pregnancy. AB - A diagnostic dilemma occurred when thrombotic microangiopathy developed during pregnancy. The diagnostic criteria of thrombotic microangiopathy include thrombocytopenia (platelets <100) and microangiopathic haemolytic anaemia (including thrombotic thrombocytopenic purpura and haemolytic-uraemic syndrome). An urgent interdisciplinary approach is required to treat thrombotic microangiopathy in pregnancy to differentiate between thrombotic microangiopathy and HELLP syndrome (haemolysis, elevated liver enzymes, low platelets).1 This case presented with the pentad of thrombotic thrombocytopenic purpura: severe thrombocytopenia (platelets 9 * 109/L), microangiopathic haemolytic anaemia (reticular count 245 * 109/L (20-110)), LDH >5000 U/L (<425)), neurological abnormalities (Glasgow Coma Scale 10/15), renal failure (creatinine 140 umol/L (<97)), fever (37.7C). A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, member 13 (ADAMTS13) activity of less than 5% and anti-ADAMTS13 antibodies retrospectively confirmed the diagnosis of acquired idiopathic thrombotic thrombocytopenic purpura in pregnancy. The immediate management in the Emergency Department with an interdisciplinary team of Consultant Nephrologists, Intensivists, Haematologists and Obstetricians facilitated prompt diagnosis resulting in immediate plasma exchange (PEX) and coordination of semi-elective delivery of the foetus. PMID- 29123570 TI - Cyclophosphamide and regional citrate anticoagulation: A sour combination? AB - We present a case of a woman in her 70 s, on cyclophosphamide for multiple myeloma, who was admitted to critical care with grade III acute kidney injury. Renal replacement therapy with regional citrate anticoagulation was commenced. Shortly thereafter her systemic-ionised calcium levels fell and remained stubbornly low until post-filter calcium return was doubled. Her total-to-ionised calcium ratio gradually increased and so, to avoid further accumulation of citrate, anticoagulation was changed to heparin. Cyclophosphamide, which accumulates in renal failure, is known to interfere with key enzymes involved in the tricarboxylic acid cycle. We postulate that cyclophosphamide interfered with her citrate metabolism, resulting in persistent systemic chelation of calcium. PMID- 29123571 TI - Case on caffeine toxicity and learning points. PMID- 29123572 TI - Doctors teaching pilots: What is good for the goose.... PMID- 29123573 TI - Conformity Index and Homogeneity Index of the Postoperative Whole Breast Radiotherapy. AB - BACKGROUND: The treatment of breast cancer involves a multidisciplinary approach in which radiotherapy plays a key role. AIM: The conformity index and the homogeneity index are two analysis tools of a treatment plan using conformal radiotherapy. The purpose of this article is an analysis of these two parameters in the assessment of the treatment plans in 58 patients undergoing postoperative radiotherapy of the whole breast. MATERIALS AND METHODS: All 58 patients participating in the study had a conservatively treated early-stage breast cancer. The treatment was performed using a standard regimen of fractionation in 25 fractions up to a total dose of 50 Gy. Dose-volume histograms were generated for both plans with and without segmental fields. RESULTS: Pair samples t-test was used. The technique with segmental fields allowed us more homogeneity distribution when compared to standard two tangential field techniques. The HI values were 1.08 +/- 0.01 and 1.09 +/- 0.01 for segment and technique with two tangential fields (p < 0.001). The DHI values were 0.92 +/- 0.02 and 0.901 +/- 0.01 for segment and technique with two tangential fields (p < 0.001). The CI values were 1.38 +/- 0.02 and 1.43 +/- 0.3 for segment and technique with two tangential fields (p = 0.0018). CONCLUSION: The results showed that the conformity and the homogeneity index are important tools in the analysis of the treatment plans during radiation therapy in patients with early-stage breast cancer. Adding segment fields in the administration of radiotherapy in patients with conservatively treated breast cancer can lead to improved dosage homogeneity and conformity. PMID- 29123574 TI - Sentinel Lymph Node Detection in Colorectal Cancer - First Experience. AB - BACKGROUND: Colorectal cancer (CRC) is the second commonest cancer in women, the third in men, being the fourth commonest cause of cancer death. The most important factor for prognosis and staging in CRC patients is the status of the regional lymph nodes (LN). AIM: To implement the method for sentinel lymph node (SLN) detection in CRC patients using radiocolloid, and test its detection rate, sensitivity, accuracy, negative predictive value and the possibility for upstaging. MATERIAL AND METHODS: The study included 40 CRC patients, age 63 +/- 14 years, without LNs detected on CT or MRI. SLN detection was performed after endoscopically peri- and intratumoral injection of 99mTc-SENTISCINT. All patients underwent resection with systemic lymphadenectomy, and the SLNs were detected ex vivo. Pathohistology was performed to all resected LNs. RESULTS: The identification rate was 95%, the accuracy of the procedure was 92.1%, the negative predictive value was 86.95%, the sensitivity was 83.3%, and the upstage was 22.5%. CONCLUSION: Identification of SLNs in CRC patients with this method is possible and the detection rate, negative predictive value, accuracy and sensitivity are reliable. We expect to contribute in the upstaging of stage II CRC patients and the selection of appropriate oncology treatment protocols. PMID- 29123575 TI - Systemic sclerosis and the gastrointestinal tract. AB - Systemic sclerosis (SSc) is an autoimmunological disease of unknown origin with complex pathogenesis and multiple organ involvement. It is characterised by vascular and immunological abnormalities leading to fibrosis of the skin and internal organs. It is a rather rare disease with a prevalence of around 20 per 100,000. The disease results in heterogeneous clinical findings and different courses. Systemic sclerosis usually begins with the onset of Raynaud's phenomenon (RP), followed by skin sclerosis and internal organ involvement, although it may appear synchronously with RP. Gastrointestinal involvement is a serious and prevalent complication of SSc, and the oesophagus is the most frequently affected organ. Both limited and diffuse cutaneous SSc involve internal organs, with the involvement of the gastrointestinal tract as a leading cause of morbidity. At present, treatment is mainly symptomatic with no disease-modifying drugs. PMID- 29123576 TI - The efficacy and safety of the biosimilar product (Inflectra(r)) compared to the reference drug (Remicade(r)) in rescue therapy in adult patients with ulcerative colitis. AB - Introduction: The biosimilar product Inflectra(r) has been approved by the European Medicine Agency (EMA) for the same indications as its reference drug, infliximab, based on studies in patients with rheumatic diseases. Thus far, there have not been enough data regarding its efficacy and safety in ulcerative colitis (UC). Aim: To assess the efficacy and safety of the biosimilar product Inflectra(r) in comparison with its reference biological agent (Remicade(r)) in rescue therapy in adult patients presenting with severe exacerbation of UC, as well as to evaluate recurrence rate during a 6-month observation after finish of treatment. Material and methods: In a single-centre retrospective study, a cohort of 83 adult patients with severe UC treated at the Department of Gastroenterology with Inflammatory Bowel Diseases Subdivision of the Central Clinical Hospital of MSWiA, Warsaw was investigated. All patients received three induction doses of Remicade(r) (28 individuals) or Inflectra(r) (55 individuals) based on the same criteria of the National Health Fund (NFZ) Therapeutic Program (total Mayo score > 6). Activity of the disease was evaluated on the Mayo scale at qualification, after finishing the rescue treatment (after 14 weeks), and after a 6-month observation period. In all patients, sigmoidoscopy was performed at qualification and after induction (after three doses). Results: The studied groups were similar with respect to age and sex distribution, duration of the disease, extent of the disease (left-sided type, pancolitis), additional pharmacotherapy, and smoking. Clinical response following three induction doses was noted in 81% of patients receiving Remicade(r) compared to 77% receiving the biosimilar product, Inflectra(r) (NS); while clinical remission was observed in 42% receiving Remicade(r) and 32% receiving Inflectra(r) (NS), respectively. Endoscopic remission assessed as 0 on the Mayo scale was achieved in 4 (15%) patients on Remicade(r) and in 7 (13%) patients on Inflectra(r) (p = 0.45). Relapse occurred in 68% of all patients, while 51% presented with exacerbation of the disease 3 months after finishing biological treatment. In 93%, exacerbation occurred within 12 months. The recurrence rate was similar in both groups (75% with Remicade(r), 64% with Inflectra(r), respectively). Side effects occurred with similar frequency in both groups. Conclusions: In the study, it was established that the biosimilar drug (Inflectra(r)) has a similar efficacy and safety as the reference biological agent (Remicade(r)), not only in rescue therapy, but also during a 6 month observation period in adult patients with severe UC. Low mucosal healing rate in both groups and high recurrence rate of the disease soon after finishing induction treatment indicate the need for prolonged therapy with infliximab in patients with severe UC. PMID- 29123577 TI - ABO blood grouping in Egyptian children with rotavirus gastroenteritis. AB - Introduction: Rotavirus gastroenteritis is an important public health problem all over the world, causing a notable economic burden in both developing and developed countries. Aim: To explore the relationship between blood group typing, rotavirus gastroenteritis, and its severity in Egyptian children. Material and methods: A cross sectional case control study was conducted on 231 cases of acute gastroenteritis attending the outpatient clinic of Al-Zahraa University Hospital. Full history taking, clinical examination, and clinical data collection were done. Blood samples were collected for an ABO grouping. Stool samples were tested for viral gastroenteritis agents. Results: Rota positive cases of GE were significantly more prevalent among cases with blood group A (p < 0.05) and significantly less among cases with blood group B (p < 0.05). The rate of hospitalisation was highly significantly greater among cases with group A (p < 0.005), and significantly lower among cases with group AB and O (p < 0.05). As regards the degree of dehydration, moderate and severe cases were highly significant in groups A and O (p < 0.005). Rota-positive gastroenteritis showed significant positive correlations with indicators of severity such as hospitalisation, degree of dehydration, and duration of fever (p < 0.005). Conclusions: Blood group A is highly associated with paediatric rotavirus gastroenteritis. This could highlight an important risk factor, which could play a significant role for the pathogenesis of rotavirus gastroenteritis and severity as well. Furthermore, more intervention care could be needed for blood group A paediatric patients, if gastroenteritis especially rotavirus affect this group to avoid comorbidities. PMID- 29123578 TI - The role of adhesion molecules in inflammatory bowel disease in children. Assessment of the possible risk of cardiovascular complications. AB - Introduction: Inflammatory bowel diseases (IBD) are chronic diseases that proceed with exacerbation and remission phases. Adhesion molecules play a significant role in inflammatory processes. The same adhesion molecules play an important role in atherogenesis. Aim: To assess the risk of atherosclerosis in IBD in children. Material and methods: The study included 40 patients with IBD (25 with Crohn's disease - CD and 15 with ulcerative colitis - UC) aged 4-17 years. In the study group, concentrations of selected adhesion molecules (intracellular adhesion molecule - ICAM, vascular cell adhesion molecule - VCAM, E-selectin) and selected parameters of lipid metabolism in serum were assessed. Results: No statistically significant differences between CD and UC patients and in the control group, in mean values of selected adhesins were obtained. Average variable VCAM was significantly lower in patients with CD than in patients with UC in the active stage of the diseases. Significantly higher average levels of triglycerides (TG) and high density lipoproteins (HDL) were found in the control group than in patients with CD. Significantly higher levels of total cholesterol (CHL) and HDL were noticed in the control group patients than in the patients with UC. The HDL/CHL was significantly higher in controls than in patients with UC. Conclusions: No increased risk of developing atherosclerosis was found in children with IBD. Decreased risk in patients during exacerbation of inflammatory bowel disease was revealed, which may result from malnutrition typical for acute disease phase. PMID- 29123579 TI - Blood serum levels of E-cadherin in patients with colorectal cancer. AB - Introduction: Colorectal cancer is the second most common cancer in terms of incidence in Poland. It is also the second most common cause of cancer deaths in men and the third women. In 75-80% of cases, depending on sources, it is of an occasional nature, and in the remaining 20-25% it has a hereditary character. Aim: To compare the levels of E-cadherin in blood serum with some histopathological and clinical features. E-cadherin is an adhesion molecule, loss of function of which is suspected to influence both cancer progression and metastasis. Material and methods: The study group comprised 48 patients diagnosed with colorectal cancer treated surgically in the Second Department of General and Gastroenterological Surgery, Medical University Hospital in Bialystok. Results: As has been shown here, there is no statistically significant relationship between the levels of E-cadherin in blood serum and the possible prognosis to the progression of colorectal cancer. However, it was indicated that there appears to be a statistically significant relationship between blood serum E-cadherin levels and the levels of alanine aminotransferase and aspartate aminotransferase in patients with colorectal cancer. Conclusions: The authors suggest that this significance may require further study. PMID- 29123580 TI - The impact of age and sex on the occurrence of pathology in the wall of the upper gastrointestinal tract. AB - Introduction: The growing incidence of gastrointestinal diseases forces to improve both imaging techniques and the identification of the population with a greater risk of a disease. Identification of lesions located inside the wall of intestinal tract or in close proximity often was not possible using endoscopy or computed tomography. Aim: The study was a retrospective evaluation of the occurrence of submucosal lesions (SML) and thickened wall (TW) of the upper gastrointestinal tract (UGIT) depending on age and sex. Material and methods: Out of 20012 gastroscopies during the 4-year follow-up study, we enrolled 199 patients with pathological lesions in the wall of the UGIT. All patients underwent computed tomography and endoscopic ultrasound (EUS). Results: We analysed a total of 122 (78 males, 44 females, age: 64.0 +/-12.9 years) out of 187 patients. 23.91% of SML in the oesophagus, 56.52% in the stomach, and 19.57% in the duodenum. A higher number of SMLs was found in men than in women (57.14% vs. 40.45%, p = 0.023), and the difference was greater over 50 years of age (85.71% vs. 40.00%, p = 0.031). We found less malignant SMLs compared to benign (35.87% vs. 64.13%, p = 0.026), especially in women (22.86% vs. 47.46%, p = 0.006). 26.67% of TW were in the oesophagus, 66.67% in the stomach, and 6.67% in the duodenum. There was a tendency towards increased incidence of TW over 50 years of age (8.58% vs. 18.30%, p = 0.074), which concerned men in particular (24.10% vs. 11.43%, p = 0.043). Until 65 years of age, these differences were significant for the oesophagus (27.27% vs. 0.00%, p = 0.044) and the stomach (25.93% vs. 4.00%, p = 0.029). As many as 70% of TW pathologies were malignant. Conclusions: Submucosal lesions and TW of the upper gastrointestinal tract account for 0.61% of performed gastroscopies. They occur in men and usually over 50 years of age. PMID- 29123581 TI - Surgical treatment of hepatic Echinococcus granulosus. AB - Introduction: Infections caused by metacestode stage of the Echinococcus granulosus in humans result in disease named cystic echinococcosis. Aim: To present the outcomes of patients treated surgically for cystic echinococcosis of the liver. Material and methods: One hundred and nineteen patients treated in the period between 1989 and 2014 due to E. granulosus infection in the Department of General, Transplant, and Liver Surgery, Medical University of Warsaw were selected for this retrospective study. Diagnostic protocol included imaging examinations, i.e. ultrasonography and computed tomography of the abdomen. Blood samples where used to proceed sequential enzyme-linked immunosorbent assay (ELISA) using Em2plus antigen as well as polymerase chain reaction (PCR) to detect E. granulosus. Results: Surgery was the choice for treatment for almost all of the patients (98.3%). In 40 (34.2%) patients right hemihepatectomy, in 19 (16.2%) patients left hemihepatectomy, and in 21 (17.9%) patients bisegementectomy were performed. Postoperative complications occurred in 4 (3.4%) patients. In 3 patients biliary fistula requiring endoscopic treatment was observed, and 1 patient had subdiaphragmatic abscess successfully treated with drainage under ultrasound guidance. None of the patients died in the postoperative period, and the 1-, 5-, and 10-year survival rates were 100.0%, 90.9%, and 87.9%, respectively. Conclusions: Surgical treatment of the symptomatic cystic echinococcosis is the modality of choice for E. granulosus infection of the liver. Despite substantial development of diagnostic methods and new management opportunities, echinococcal infection still presents a challenge for epidemiologists, pharmacologists, and clinicists. PMID- 29123582 TI - High serum N-terminal propeptide of procollagen type III concentration is associated with liver diseases. AB - Introduction: N-terminal propeptide of procollagen type III (PIIINP) is generated during the synthesis of type III collagen. PIIINP can be measured in the serum as an indicator of liver fibrosis and cirrhosis. Aim: To evaluate the effect of liver diseases of different aetiologies and clinical severity of liver cirrhosis on the serum level of PIIINP. Material and methods: Patients with alcoholic cirrhosis (AC) - 63 subjects, non-alcoholic cirrhosis (NAC) - 31 and toxic hepatitis (HT) - 33 were studied. Cirrhotic patients were classified according to the Child-Pugh scale. The samples were analysed using the ELISA method. Results: The level of PIIINP was significantly higher in patients with alcoholic cirrhosis, non-alcoholic cirrhosis, and toxic hepatitis in comparison to the control group. There were no significant differences in the serum PIIINP levels between liver diseases and according to the severity of liver cirrhosis. PIIINP has the highest diagnostic power for the diagnosis of toxic hepatitis. The highest sensitivity was reached in alcoholic cirrhosis, but other diagnostic values (specificity, positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy (ACC)) in alcoholic cirrhosis were lower than that in toxic hepatitis. In the diagnosis of non-alcoholic cirrhosis PIIINP has low sensitivity, specificity, PPV, NPV, and ACC. Conclusions: The serum PIIINP shows the alterations in liver diseases in comparison to healthy controls, but not between diseases. Taking the above into account we can suggest that PIIINP may be a useful test for the detection of liver diseases. PMID- 29123583 TI - Medullary colonic carcinoma with microsatellite instability has lower survival compared with conventional colonic adenocarcinoma with microsatellite instability. AB - Introduction: Colorectal medullary carcinoma (MC) is a rare subtype of poorly differentiated adenocarcinoma (PDA) with unclear prognostic significance. Microsatellite instable (MSI) colorectal carcinomas have demonstrated better prognosis in clinical stage II. Aim: To analyze the survival and clinicopathological characteristics of MCs versus PDAs with MSI in clinical stage III. Material and methods: We studied 22 cases of PDAs with MSI versus 10 MCs. Results: Of the 10 MCs, 7 patients were men; the mean age was 57.8 +/-5.6 years. The mean tumor size was 9.6 +/-4.1 cm, and the primary site was the right colon in 9; 7 patients showed lymph node metastases (LNM) and lymphovascular invasion (LVI). Of the 22 PDA cases, 12 (54.5%) were women with a mean age of 75 +/-16.1 years. The mean tumor size was 6.4 +/-3.2 cm. Twelve (54.5%) presented in the right colon, 21 (95.5%) showed LNM and 7 (31.8%) LVI. Follow-up was 32 +/-8 months, with a 5-year overall survival of 42.9% for MCs and 76.6% for PDAs (p = 0.048). Univariate analysis found local recurrence (p = 0.001) and medullary subtype (p = 0.043) associated with lower survival. Conclusions: Medullary carcinomas were of greater tumor size and associated with more LVI and worse survival versus PDAs with MSI in stage III. PMID- 29123584 TI - Analysis of postoperative morbidity and mortality following surgery for gastric cancer. Surgeon volume as the most significant prognostic factor. AB - Introduction: Surgical resection is the only potentially curative modality for gastric cancer and it is associated with substantial morbidity and mortality. Aim: To determine risk factors for postoperative morbidity and mortality following major surgery for gastric cancer. Material and methods: Between 1.08.2006 and 30.11.2014 in the Department of Oncological Surgery of Gdynia Oncology Centre 162 patients underwent gastric resection for adenocarcinoma. All procedures were performed by 13 surgeons. Five of them performed at least two gastrectomies per year (n = 106). The remaining 56 resections were done by eight surgeons with annual volume lower than two. Perioperative mortality was defined as every in-hospital death and death within 30 days after surgery. Causes of perioperative deaths were the matter of in-depth analysis. Results: Overall morbidity was 23.5%, including 4.3% rate of proximal anastomosis leak. Mortality rate was 4.3%. Morbidity and mortality were not dependent on: age, gender, body mass index, tumour location, extent of surgery, splenectomy performance, or pTNM stage. The rates of morbidity (50% vs. 21.3%) and mortality (16.7% vs. 3.3%) were significantly higher in cases of tumour infiltration to adjacent organs (pT4b). Perioperative morbidity and mortality were 37.5% and 8.9% for surgeons performing less than two gastrectomies per year and 16% and 0.9% for surgeons performing more than two resections annually. The differences were statistically significant (p = 0.002, p = 0.003). Conclusions: Annual surgeon case load and adjacent organ infiltration (pT4b) were significant risk factors for morbidity and mortality following major surgery for gastric cancer. The most common complications leading to perioperative death were cardiac failure and proximal anastomosis leak. PMID- 29123585 TI - Cause of mortality in aortoesophageal fistula: oesophageal sepsis. A case report. PMID- 29123586 TI - Long-term evolution of squamous-cell cancer in Plummer-Vinson syndrome. PMID- 29123587 TI - Local recurrence of sporadic mesenteric fibromatosis following radical surgery attacking the proximal jejunum. PMID- 29123588 TI - Infliximab treatment in a paediatric patient with ulcerative colitis, who developed acute pancreatitis due to azathioprine during follow-up. PMID- 29123589 TI - Measuring the impact of CPJ on pharmacy practice. PMID- 29123590 TI - Is it time to stop counselling patients to "finish the course of antibiotics"? PMID- 29123592 TI - Medical cannabis Q&A. PMID- 29123591 TI - Primary care of cancer patients: A pharmacy student's perspective. PMID- 29123593 TI - Part 5: Future vision for the pharmacy profession. PMID- 29123594 TI - Innovative pharmacy practice: Cathy Biggs. PMID- 29123595 TI - Community pharmacist-led telephone follow-up enabled close management of everolimus-induced adverse events in an outpatient with metastatic breast cancer. PMID- 29123596 TI - A scoping review of community pharmacists and patients at risk of suicide. AB - Background: Medications are commonly used in suicide attempts. Pharmacists are inextricably linked to medications and may have roles in helping those at risk of suicide. We conducted a scoping review to characterize the existing literature and make recommendations about future research. Methods: We used a 6-step approach based on an existing scoping review methodological framework, including identifying the research question; identifying relevant studies and other literature; study and literature selection; data charting; collating, summarizing and reporting results; and dissemination of results. We searched electronic databases, various grey literature sources and mobile app stores. Results: Thirty five articles were included following screening of 1013 database citations. Of 1085 results from grey literature searches, we included 12. Most publications were opinion pieces (n = 22), followed by survey studies (n = 9), primarily assessing pharmacists' knowledge and attitudes. Themes included education and training to impact knowledge and attitudes, gatekeeping of medication supply, collaboration and integration, and role perception. Public perspectives on pharmacists' roles were limited. Conclusions: Research regarding pharmacists' roles in the care of people at risk for suicide is limited. The areas that have dominated the literature include legal liability, especially with respect to gatekeeping medications, ethical decision making and education and training. Research is needed to determine what methods, outcomes and measures are required to best serve in building the evidence base for policy and practice decisions in this area. PMID- 29123597 TI - Review of the top 5 cardiology studies of 2015-16. PMID- 29123598 TI - Ready or not? Pharmacist perceptions of a changing injection scope of practice before it happens. AB - Background: Since 2012, Ontario pharmacists have been authorized to administer the influenza vaccine. In April 2016, the Ontario College of Pharmacists (OCP) proposed to expand the Pharmacy Act to allow pharmacists to vaccinate against 13 additional conditions. The OCP held an online public consultation and invited pharmacists, members of the public and organizations to weigh in on the proposed changes. Our objective was to explore the factors influencing how Ontario pharmacists may adopt or reject an expanding scope of practice, using data from the public consultation. Methods: We coded the responses to the public consultation in 2 ways: 1) sentiment analysis and 2) an integrative approach to coding using Rogers's diffusion of innovations theory across 5 domains: relative advantage, compatibility, complexity, trialability and observability. Results: Responses from pharmacists, the public and organizations were moderately positive on average. Pharmacists most commonly mentioned relative advantages, including benefits for patients, pharmacists, physicians and the health system. Positive responses focused on accessibility for patients, improved vaccine coverage, lower health care spending and freed physician time but cited lack of prescribing privileges as a barrier to the proposed changes. Negative responses focused on increased workload, patient safety concerns and the complexity of travel medicine. Conclusions: The expanded immunization services are likely to be well received by most pharmacists. Convenience and accessibility for patients were commonly cited benefits, but the changes will be only a slight improvement over the current system unless pharmacists can prescribe these vaccines. Although employers responded positively, the question remains whether they will support pharmacists in a way that aligns with pharmacists' values and expectations. Decision makers must pay close attention to the pharmacy infrastructure and how this will affect uptake of these services. Recognition of this, combined with pharmacists' positive perceptions of the expanded scope, will facilitate smooth integration of this legislation into Ontario pharmacy practice. PMID- 29123599 TI - Patient satisfaction with chronic HIV care provided through an innovative pharmacist/nurse-managed clinic and a multidisciplinary clinic. AB - Background: Pharmacist/nurse-led clinics are an established model for many chronic diseases but not yet for HIV. At our centre, patients with HIV are seen by a multidisciplinary team (physician, nurse, pharmacist, social worker) at least yearly. Some attend an HIV-specialist pharmacist/nurse clinic (or "nonphysician clinic," NPC) for alternate biannual visits. Our objective was to assess patient satisfaction with care received through both clinics. Methods: The Patient Satisfaction Survey for HIV Ambulatory Care (assesses satisfaction with access to care, clinic visits and quality of care) was administered by telephone to adults who attended either clinic between January and July 2014. Descriptive statistics described patient characteristics and satisfaction scores. Fisher's exact test compared satisfaction scores between the NPC and multidisciplinary clinic (MDC). Multivariate logistic regression examined associations between overall satisfaction with care and clinic type and patient characteristics (e.g., age, disease duration). Results: Respondents were very satisfied with the overall quality of HIV care in both the NPC and MDC (89% vs 93%, respectively, p = 0.6). Patients from both clinics expressed satisfaction with access to care, treatment plan input, their provider's knowledge of the newest developments in HIV care and explanation of medication side effects, with no significant differences noted. Significantly more MDC patients reported being asked about housing/finances, alcohol/drug use and whether they needed help disclosing their status. Patient characteristics were not significantly associated with satisfaction with overall quality of care. Conclusion: Patients are satisfied with both clinics, supporting NPC as an innovative model for chronic HIV care. Comparison of outcomes between clinics is needed to ensure high-quality care. PMID- 29123600 TI - Activities performed by pharmacists integrated in family health teams: Results from a web-based survey. AB - Objectives: Family health teams (FHTs), an interprofessional primary care practice model, were established in Ontario in 2005. As of October 2014, 191 FHT organizations were in operation, and 111 (58%) included one or several pharmacists. The objective of this study was to document the focus of pharmacist activities in FHTs. Approach: We invited all 155 known FHT pharmacists to a web based survey. The survey was constructed using information obtained from previously done semi-structured telephone interviews with pharmacists working in FHTs. The survey consisted of a list of activities, grouped into 5 main categories, and participants were asked to estimate time spent on each category. Free-text response questions allowed participants to identify activities not listed. Survey results were analyzed using descriptive statistics and content analysis for open-ended responses. Results: Seventy (45%) pharmacists completed the survey. The mean respondent age was 43 years, and the average length of time working in an FHT was 4 years. All pharmacists reported being engaged in some form of direct patient care, including managing single therapeutic issues (96%), conducting general medication reviews (70%) and medication reconciliation after hospitalization (63%). Most reported providing education and drug information (83%). Pharmacists felt their work would increase patient medication adherence (94%) and physician adherence to recommended guidelines (86%), as well as reduce inappropriate prescribing (93%), polypharmacy (90%), emergency room and hospital utilization (70%-81%). Conclusion: Pharmacists in FHTs are strongly focused on direct patient care activities, managing specific medication issues and unstructured drug information to physicians. The majority of pharmacists reported that their activities had a substantial impact on patient medication use and health. The findings from this survey can assist pharmacists new to FHT practice, health policy planning and health research to assess associations between pharmacist activities and measures of health and health care system performance. PMID- 29123601 TI - Education in cardiopulmonary resuscitation in Russia: A systematic review of the available evidence. AB - BACKGROUND: To summarise and appraise cumulative published scientific evidence relevant to cardiopulmonary resuscitation (CPR) education in Russia. DATA RESOURCES: We searched Medline, Scopus, Science Direct and Russian Science Citation Index databases from December 1991 to December 2016 to identify studies pertaining to the field of CPR education that were carried out by Russian researchers and/or investigated the topic of interest for Russia/Russian population. Reference lists of eligible publications, contents pages of relevant Russian journals and Google Scholar were also searched. There was no limitation based on publication language or study design. RESULTS: Of 7 964 unique citations identified, 22 studies were included. All studies were published from 2009 to 2016, mainly in Russian. Only three studies were reported to be randomized controlled. Non-medical individuals constituted 17% of studied populations. Most of the studies aimed to assess effects of CPR educational interventions, generally suggesting positive influence of the training conducted. The studies were highly heterogeneous as for methodological approaches, structure and duration of educational interventions, evaluation methods and criteria being used. Methodological quality was generally poor, with >40% publications not passing quality screening and only 2 studies meeting the criteria of moderate high quality. CONCLUSION: The results suggest paucity, low population coverage, high thematic and methodological heterogeneity and low quality of the studies addressing CPR education, which were carried out in the Russian Federation. There is a critical need in conducting methodologically consistent, large-scale, randomized, controlled studies evaluating and comparing efficiency of educational interventions for teaching CPR in different population categories of Russia. PMID- 29123602 TI - Rehabilitation of vulnerable groups in emergencies and disasters: A systematic review. AB - BACKGROUND: Natural and man-made disasters, especially those occurring in large scales not only result in human mortality, but also cause physical, psychological, and social disabilities. Providing effective rehabilitation services in time can decrease the frequency of such disabilities. The aim of the current study was to perform a systematic review related to rehabilitation of vulnerable groups in emergencies and disasters. METHODS: The systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The key words "recovery", "rehabilitation", "reconstruction", "transformation", "transition", "emergency", "disaster", "crisis", "hazard", "catastrophe", "tragedy", "mass casualty incident", "women", "female", "children", "pediatric", "disable", "handicap", "elder", "old" and "vulnerable" were used in combination with Boolean operators OR and AND. ISI Web of Science, PubMed, Scopus, Science Direct, Ovid, ProQuest, Wiley, Google Scholar were searched. RESULTS: In this study a total of 11 928 articles were considered and 25 articles were selected for final review of rehabilitation of vulnerable groups based on the objective of this study. Twenty five studies including six qualitative, sixteen cross-sectional and three randomized controlled trials were reviewed for rehabilitation of vulnerable groups in emergencies and disasters. Out of the selected papers, 23 were studied based on rehabilitation after natural disasters and the remaining were man-made disasters. Most types of rehabilitation were physical, social, psychological and economic. CONCLUSION: The review of the papers showed different programs of physical, physiological, economic and social rehabilitations for vulnerable groups after emergencies and disasters. It may help health field managers better implement standard rehabilitation activities for vulnerable groups. PMID- 29123603 TI - Paediatric-appropriate facilities in emergency departments of community hospitals in Ontario: A cross-sectional study. AB - BACKGROUND: We assessed whether the paediatric-appropriate facilities were available at Emergency Departments (ED) in community hospitals in a Canadian province. METHODS: We conducted a cross-sectional survey of EDs in community hospitals in Ontario, Canada that had inpatient paediatric facilities and a neonatal intensive care unit. Key informants were ED chiefs, clinical educators, or managers. The survey included questions about paediatric facilities related to environment, triage, training, and staff in EDs. RESULTS: Of 52 hospitals, 69% (n=36) responded to our survey. Of them, 14% EDs (n=5) had some separated spaces available for paediatric patients. About 53% (n=19) of EDs lacked children activities, e.g., toys. Only 11% (n=4) EDs were using paediatric triage scales and 42% (n=15) had a designated paediatric resuscitation bay. Only half of the ED (n=18) required from their staff to update paediatric life support training. Only 31% (n=11) had a designated liaison paediatrician for the ED. Paediatric social worker was present in only 8% (n=3) of EDs in community hospitals. CONCLUSION: Most of the Ontario community hospital EDs included in this survey had inadequate facilities for paediatric patients such as specific waiting and treatment areas. PMID- 29123604 TI - Factors behind not using child restrain(t) among hospital employees and general population: A case control study. AB - BACKGROUND: Motor vehicle crash (MVC) related injury has been identified as a major public health concern. Child restrain (CR) seat belts can minimize the mortality and morbidity from MVC. The use for seat belts is substantially low in developing countries like Pakistan even though its use has been shown to decrease morbidity and mortality by a significant extent. METHODS: This was a case control study with cases from the general population (GP) and controls from the Aga Khan University (AKU) employees in a 3:1 ratio. The study questionnaire was based on parameters like gender, education level, awareness and presence of CR and also assessed the frequency of usage, reasons for not using CR and the source of knowledge regarding CR use. RESULTS: Out of 848 respondents, 212 were from AKU and 636 were from the GP. 96.7% from AKU had at least a bachelor's degree while less than half (42.6%) of those from the GP were graduate or above (P<0.001). A statistically significant difference was found between the two groups with drivers from AKU being generally more aware about CR and its use. 81.1% of the group from AKU compared to 59.7% from the general population were found to be aware of child restraint use (P<0.001). Media (40.6%) was found to be the most common source of information amongst the AKU employees. CONCLUSION: Most motor vehicle related injuries in children can be prevented or their severity may be reduced by the use of appropriate child restraint seat belts. PMID- 29123605 TI - Evaluation of modified Alvarado scoring system and RIPASA scoring system as diagnostic tools of acute appendicitis. AB - BACKGROUND: Acute appendicitis is the most common surgical condition presented in emergency departments worldwide. Clinical scoring systems, such as the Alvarado and modified Alvarado scoring systems, were developed with the goal of reducing the negative appendectomy rate to 5%-10%. The Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) scoring system was established in 2008 specifically for Asian populations. The aim of this study was to compare the modified Alvarado with the RIPASA scoring system in Kuwait population. METHODS: This study included 180 patients who underwent appendectomies and were documented as having "acute appendicitis" or "abdominal pain" in the operating theatre logbook (unit B) from November 2014 to March 2016. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, predicted negative appendectomy and receiver operating characteristic (ROC) curve of the modified Alvarado and RIPASA scoring systems were derived using SPSS statistical software. RESULTS: A total of 136 patients were included in this study according to our criteria. The cut-off threshold point of the modified Alvarado score was set at 7.0, which yielded a sensitivity of 82.8% and a specificity of 56%. The PPV was 89.3% and the NPV was 42.4%. The cut-off threshold point of the RIPASA score was set at 7.5, which yielded a 94.5% sensitivity and an 88% specificity. The PPV was 97.2% and the NPV was 78.5%. The predicted negative appendectomy rates were 10.7% and 2.2% for the modified Alvarado and RIPASA scoring systems, respectively. The negative appendectomy rate decreased significantly, from 18.4% to 10.7% for the modified Alvarado, and to 2.2% for the RIPASA scoring system, which was a significant difference (P<0.001) for both scoring systems. CONCLUSION: Based on the results of this study, the RIPASA score is a simple scoring system with better sensitivity and specificity than the modified Alvarado scoring system in Asian populations. It consists of 14 clinical parameters that can be obtained from a good patient history, clinical examination and laboratory investigations. The RIPASA scoring system is more accurate and specific than the modified Alvarado scoring system for Kuwait population. PMID- 29123606 TI - Evaluation of a point of care ultrasound curriculum for Indonesian physicians taught by first-year medical students. AB - BACKGROUND: The purpose of this study was to assess the short-term efficacy of a 4-week ultrasound curriculum taught by American first-year medical students to general practitioners working in public health care clinics, or puskesmas, in Bandung, Indonesia. METHODS: We performed a prospective, observational study of Indonesian health care practitioners from public clinics in Bandung, Indonesia. These practitioners were enrolled in a 4-week ultrasound training course taught by first-year American medical students. A total of six sessions were held comprising of 38 ultrasound milestones. A pre-course and post-course written exam and practical exam was taken by each participant. RESULTS: We enrolled 41 clinicians in the course. The average pre-course exam score was 35.2% with a 2.4% pass rate, whereas the average post-course exam score was 82.0% with a 92.7% pass rate. The average practical score at the completion of the course was 83.2% (SD=0.145) with 82.9% of the class passing (score above 75.0%). CONCLUSION: Our data suggests that first-year medical students can effectively teach ultrasound to physicians in Indonesia using a 4-week intensive ultrasound training course. Future studies are needed to determine the amount of training required for proficiency and to evaluate the physicians' perceptions of the student instructors' depth of knowledge and skill in point of care ultrasound. PMID- 29123611 TI - Vulvar inflammation as a manifestation of Crohn's disease. PMID- 29123608 TI - The effects of microRNA-34a regulating Notch-1/NF-kappaB signaling pathway on lipopolysaccharide-induced human umbilical vein endothelial cells. AB - BACKGROUND: Notch-1/NF-kappaB signaling plays a key role in the cecal ligation and puncture (CLP)-induced sepsis. This study aims to investigate the intervention effects of microRNA-34a (miR-34a) lentivirus regulating Notch-1/NF kappaB signaling pathway on lipopolysaccharide (LPS)-induced human umbilical vein endothelial cells (HUVEC). METHODS: HUVEC were divided into four groups as the following: they were infected with negative control lentivirus (NC group) or miR 34a lentivirus (OE group); LPS (1 MUg/mL) was added on the third day on the basis of NC group and OE group for 24 hours (NC+LPS group or OE+LPS group). The levels of TNF-alpha, IL-1beta, IL-6, and IL-10 in the cell supernatants, and the mRNA and protein expression of Notch-1 and NF-kappaB in the HUVEC were evaluated. RESULTS: After 24 hours, the levels of TNF-alpha, IL-1beta, IL-6 in the cell supernatants and the protein expression of NF-kappaB from NC+LPS group were significantly higher than those of NC group, but IL-10 level and the protein expression of Notch-1 in NC+LPS group were the opposite. After intervention of miR-34a lentivirus, the cell supernatants TNF-alpha and the protein expression of NF-kappaB in OE+LPS group after 24 hours markedly decreased compared to NC+LPS group. While the cell supernatants IL-1beta and IL-6 and the mRNA expression of NF-kappaB slightly decreased in OE+LPS group, IL-10 and the mRNA and protein expression of Notch-1 were the opposite. CONCLUSION: miR-34a regulating Notch 1/NF-kappaB signaling pathway can reduce the HUVEC damage caused by LPS stimulation. PMID- 29123607 TI - Procedural simulation: medical student preference and value of three task trainers for ultrasound guided regional anesthesia. AB - BACKGROUND: Ultrasound guided regional anesthesia is widely taught using task trainer models. Commercially available models are often used; however, they can be cost prohibitive. Therefore, alternative "homemade" models with similar fidelity are often used. We hypothesize that professional task trainers will be preferred over homemade models. The purpose of this study is to determine realism, durability and cleanliness of three different task trainers for ultrasound guided nerve blocks. METHODS: This was a prospective observational study using a convenience sample of medical student participants in an ultrasound guided nerve block training session on January 24th, 2015. Participants were asked to perform simulated nerve blocks on three different task trainers including, 1 commercial and 2 homemade. A questionnaire was then given to all participants to rate their experiences both with and without the knowledge on the cost of the simulator device. RESULTS: Data was collected from 25 participants. The Blue Phantom model was found to have the highest fidelity. Initially, 10 (40%) of the participants preferred the Blue Phantom model, while 10 (40%) preferred the homemade gelatin model and 5 (20%) preferred the homemade tofu model. After cost awareness, the majority, 18 (72%) preferred the gelatin model. CONCLUSION: The Blue Phantom model was thought to have the highest fidelity, but after cost consideration the homemade gelatin model was preferred. PMID- 29123612 TI - Paradoxical brain embolism followed by percutaneous atrial septal closure: Stroke in a patient's thirties highlighting some issues surrounding brain stroke in an emergency setting. PMID- 29123610 TI - 'Runs' from a run: A case of exercise induced ischemic colitis. PMID- 29123609 TI - Anticholinergic syndrome induced by toxic plants. PMID- 29123613 TI - Case of morphine-induced ventricular fibrillation. PMID- 29123617 TI - What the P values really tell us. PMID- 29123616 TI - Corrigendum to "Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through PI3K/Akt Signaling and Limits Ventilator-Induced Lung Injury". AB - [This corrects the article DOI: 10.1155/2017/3715037.]. PMID- 29123614 TI - The Roles of ROS in Cancer Heterogeneity and Therapy. AB - Cancer comprises a group of heterogeneous diseases encompassing high rates of morbidity and mortality. Heterogeneity, which is a hallmark of cancer, is one of the main factors related to resistance to chemotherapeutic agents leading to poor prognosis. Heterogeneity is profoundly affected by increasing levels of ROS. Under low concentrations, ROS may function as signaling molecules favoring tumorigenesis and heterogeneity, while under high ROS concentrations, these species may work as cancer modulators due to their deleterious, genotoxic or even proapoptotic effect on cancer cells. This double-edged sword effect represented by ROS relies on their ability to cause genetic and epigenetic modifications in DNA structure. Antitumor therapeutic approaches may use molecules that prevent the ROS formation precluding carcinogenesis or use chemical agents that promote a sudden increase of ROS causing considerable oxidative stress inside tumor mass. Therefore, herein, we review what ROS are and how they are produced in normal and in cancer cells while providing an argumentative discussion about their role in cancer pathophysiology. We also describe the various sources of ROS in cancer and their role in tumor heterogeneity. Further, we also discuss some therapeutic strategies from the current landscape of cancer heterogeneity, ROS modulation, or ROS production. PMID- 29123618 TI - Practical statistics in pain research. AB - Pain is subjective, while statistics related to pain research are objective. This review was written to help researchers involved in pain research make statistical decisions. The main issues are related with the level of scales that are often used in pain research, the choice of statistical methods between parametric or nonparametric statistics, and problems which arise from repeated measurements. In the field of pain research, parametric statistics used to be applied in an erroneous way. This is closely related with the scales of data and repeated measurements. The level of scales includes nominal, ordinal, interval, and ratio scales. The level of scales affects the choice of statistics between parametric or non-parametric methods. In the field of pain research, the most frequently used pain assessment scale is the ordinal scale, which would include the visual analogue scale (VAS). There used to be another view, however, which considered the VAS to be an interval or ratio scale, so that the usage of parametric statistics would be accepted practically in some cases. Repeated measurements of the same subjects always complicates statistics. It means that measurements inevitably have correlations between each other, and would preclude the application of one-way ANOVA in which independence between the measurements is necessary. Repeated measures of ANOVA (RMANOVA), however, would permit the comparison between the correlated measurements as long as the condition of sphericity assumption is satisfied. Conclusively, parametric statistical methods should be used only when the assumptions of parametric statistics, such as normality and sphericity, are established. PMID- 29123619 TI - Vitamin D and fibromyalgia: a meta-analysis. AB - Vitamin D is a cofactor responsible for autoimmune disorders. There is no agreement in the studies investigating the association between vitamin D and fibromyalgia. This study aims to combine the conflicting results of the primary studies which compared these patients with control groups regarding the serum concentration of vitamin D. This meta-analysis has been designed based on PRISMA guidelines. Relevant keywords were searched in PubMed, Science direct, Scopus, Cochrane, and Google scholar and primary studies were selected. After screening the eligible studies according to inclusion/exclusion criteria, we investigated the risk of bias in the selected studies and also the heterogeneity between the primary results using Cochrane (Q) and I-squared (I2) indices. The primary results were combined using inverse variance method and Cohen statistics as well as a random effects model. Publication bias was assessed using Egger test. Sensitivity analysis was applied to investigate the influence of each primary study on the final result of the meta-analysis. Suspected factors in the heterogeneity were assessed using meta-regression models. We entered 12 eligible studies in the meta-analysis including 851 cases compared with 862 controls. The standardized mean difference of Vitamin D between the two groups was -0.56 (95% confidence interval: -1.05, -0.08). Our meta-analysis showed that vitamin D serum levels of patients with fibromyalgia was significantly lower than that of control group. PMID- 29123615 TI - The Combination of Physical Exercise with Muscle-Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10. AB - Sarcopenia represents an increasing public health risk due to the rapid aging of the world's population. It is characterized by both low muscle mass and function and is associated with mobility disorders, increased risk of falls and fractures, loss of independence, disabilities, and increased risk of death. Despite the urgency of the problem, the development of treatments for sarcopenia has lagged. Increased reactive oxygen species (ROS) production and decreased antioxidant (AO) defences seem to be important factors contributing to muscle impairment. Studies have been conducted to verify whether physical exercise and/or AOs could prevent and/or delay sarcopenia through a normalization of the etiologically relevant ROS imbalance. Despite the strong rationale, the results obtained were contradictory, particularly with regard to the effects of the tested AOs. A possible explanation might be that not all the agents included in the general heading of "AOs" could fulfill the requisites to counteract the complex series of events causing/accelerating sarcopenia: the combination of the muscle-directed antioxidants creatine and coenzyme Q10 with physical exercise as a biomedical rationale for pleiotropic prevention and/or treatment of sarcopenia is discussed. PMID- 29123620 TI - The effects of regular exercise on capsaicin-induced pulpal pain and pain-induced changes in passive avoidance learning and memory in rats. AB - Background: Pulpal pain is one of the most common and severe orofacial pain conditions with considerable adverse effects on physiological processes including learning and memory. Regular exercise is known to be effective on cognitive function as well as pain processing in the central nervous system. Here, the possible effects of regular exercise on pulpal pain response as well as pain induced changes in learning and memory efficiency in rats were investigated. Methods: Twenty-four male Wistar rats were randomly assigned to the control, capsaicin, exercise, and exercise plus capsaicin groups. Rats in exercise groups were forced to run on a treadmill with a moderate exercise protocol for 4 weeks. Capsaicin was used to induce dental pulp pain. Passive avoidance learning and memory performance was assessed by using a shuttle box apparatus. Results: According to the results, regular exercise could decrease the time course of capsaicin-induced pulpal pain (P < 0.001). Moreover, in capsaicin-treated rats, passive avoidance acquisition was impaired as compared to the control (P < 0.05) and exercise (P < 0.001) groups. Additionally, regular exercise before capsaicin injection could attenuate capsaicin-induced memory impairments (P < 0.05). Conclusions: Taken together, the present data showed that regular exercise has inhibitory effects on capsaicin-induced pulpal pain as well as pain-induced cognitive dysfunction in rats. PMID- 29123621 TI - A hybrid cardiac rehabilitation is as effective as a hospital-based program in reducing chest pain intensity and discomfort. AB - Background: Health care services effort to provide alternative cardiac rehabilitation (CR) models to serve patients according to their preferences and needs. So, the present study aimed to assess and compare the effects of hospital based and hybrid CR programs on chest pain intensity and discomfort in cardiac surgery patients. Methods: In this prospective study, 110 cardiac surgery patients were invited to the CR department of a hospital in the western part of Iran between March and July 2016. Patients were divided into two groups: hospital based and hybrid CR. The hospital-based program included 26 sessions, and the hybrid program included 10 training sessions and exercise. The Brief Pain Inventory and Pain Discomfort Scale were used as research instrument, and data were analyzed using the paired t-test and ANCOVA. Results: The results indicated that both hospital-based and hybrid CR are effective in reducing the chest pain intensity and discomfort of cardiac surgery patients (P < 0.05). In addition, the comparison of scores before and after treatment using ANCOVA shows that no significant differences were observed between the two programs (P > 0.05). Conclusions: Traditional hospital-based CR delivery is still the first choice for treatment in developing countries. However, hybrid CR is as effective as a hospital-based program in reducing pain components and it includes only 38% of the total cost in comparison to hospital-based delivery. So, we recommend using hybrid CR according with the recommendations of American Heart Association about using CR for the management of angina symptoms. PMID- 29123622 TI - Retrospective analysis of the financial break-even point for intrathecal morphine pump use in Korea. AB - Background: The high cost of intrathecal morphine pump (ITMP) implantation may be the main obstacle to its use. Since July 2014, the Korean national health insurance (NHI) program began paying 50% of the ITMP implantation cost in select refractory chronic pain patients. The aims of this study were to investigate the financial break-even point and patients' satisfaction in patients with ITMP treatment after the initiation of the NHI reimbursement. Methods: We collected data retrospectively or via direct phone calls to patients who underwent ITMP implantation at a single university-based tertiary hospital between July 2014 and May 2016. Pain severity, changes in the morphine equivalent daily dosage (MEDD), any adverse events, and patients' satisfaction were determined. We calculated the financial break-even point of ITMP implantation via investigating the patient's actual medical costs and insurance information. Results: During the studied period, 23 patients received ITMP implantation, and 20 patients were included in our study. Scores on an 11-point numeric rating scale (NRS) for pain were significantly reduced compared to the baseline value (P < 0.001). The MEDD before ITMP implantation was 0.59 [IQR: 0.55-0.82]. The total MEDD increased steadily to 0.77 [IQR: 0.53-1.08] at 1 year, which was 126% of the baseline (P < 0.001). More than a half (60%) responded that the ITMP therapy was somewhat satisfying. The financial break-even point was 28 months for ITMP treatment after the NHI reimbursement policy. Conclusions: ITMP provided effective chronic pain management with improved satisfaction and reasonable financial break-even point of 28 months with 50% financial coverage by NHI program. PMID- 29123623 TI - Effect of epidural corticosteroid injection on magnetic resonance imaging findings. AB - Background: Magnetic resonance imaging (MRI) of the spine is the preferred diagnostic tool for pathologic conditions affecting the spine. However, in patients receiving epidural corticosteroid injection (ESI) for treatment of spinal diseases, there is a possibility of misreading of MR images because of air or fluid in the epidural space after the injection. Therefore, we defined the characteristics of abnormal changes in MRI findings following an ESI in patients with low back pain. Methods: We reviewed the medical records of 133 patients who underwent MRI of the lumbar spine within 7 days after ESI between 2006 and 2015.All patients were administered an ESI using a 22-gauge Tuohy needle at the lumbar spine through the interlaminar approach. The epidural space was identified by the loss of resistance technique with air. Results: The incidences of abnormal changes in MRI findings because of ESI were 54%, 31%, and 25% in patients who underwent MRI at approximately 24 h, and 2 and 3 days after ESI, respectively. Abnormal MRI findings included epidural air or fluid, needle tracks, and soft tissue changes. Epidural air, the most frequent abnormal finding (82%), was observed in 41% of patients who underwent MRI within 3 days after injection. Abnormal findings due to an ESI were not observed in MR images acquired 4 days after ESI or later. Conclusions: Pain physicians should consider the possibility of abnormal findings in MR images acquired after epidural injection using the interlaminar approach and the loss of resistance technique with air at the lumbar spine. PMID- 29123624 TI - State of education regarding ultrasound-guided interventions during pain fellowships in Korea: a survey of recent fellows. AB - Background: Recently, the use of ultrasound (US) techniques in regional anesthesia and pain medicine has increased significantly. However, the current extent of training in the use of US-guided pain management procedures in Korea remains unknown. The purpose of the present study was to assess the current state of US training provided during Korean Pain Society (KPS) pain fellowship programs through the comparative analysis between training hospitals. Methods: We conducted an anonymous survey of 51 pain physicians who had completed KPS fellowships in 2017. Items pertained to current US practices and education, as well as the types of techniques and amount of experience with US-guided pain management procedures. Responses were compared based on the tier of the training hospital. Results: Among the 51 respondents, 14 received training at first- and second-tier hospitals (Group A), while 37 received training at third-tier hospitals (Group B). The mean total duration of pain training during the 1-year fellowship was 7.4 months in Group A and 8.4 months in Group B. Our analysis revealed that 36% and 40% of respondents in Groups A and B received dedicated US training, respectively. Most respondents underwent US training in patient-care settings under the supervision of attending physicians. Cervical root, stellate ganglion, piriformis, and lumbar plexus blocks were more commonly performed by Group B than by Group A (P < 0.05). Conclusions: Instruction regarding US-guided pain management interventions varied among fellowship training hospitals, highlighting the need for the development of educational standards that mandate a minimum number of US-guided nerve blocks or injections during fellowships in interventional pain management. PMID- 29123625 TI - Relationship between paravertebral muscle twitching and long-term effects of radiofrequency medial branch neurotomy. AB - Background: To achieve a prolonged therapeutic effect in patients with lumbar facet joint syndrome, radiofrequency medial branch neurotomy (RF-MB) is commonly performed. The purpose of this study was to evaluate the prognostic value of paravertebral muscle twitching when performing RF-MB in patients with lumbar facet joint syndrome. Methods: We collected and analyzed data from 68 patients with confirmed facet joint syndrome. Sensory stimulation was performed at 50 Hz with a 0.5 V cut-off value. Patients were divided into 3 groups according to the twitching of the paravertebral muscle during 2 Hz motor stimulation: 'Complete', when twitching was observed at all needles; 'Partial', when twitching was present at 1 or 2 needles; and 'None', when no twitching was observed. The relationship between the long-term effects of RF-MB and paravertebral muscle twitching was analyzed. Results: The mean effect duration of RF-MB was 4.6, 5.8, and 7.0 months in the None, Partial, and Complete groups, respectively (P = 0.47). Although the mean effect duration of RF-MB did not increase significantly in proportion to the paravertebral muscle twitching, the Complete group had prolonged effect duration (> 6 months) than the None group in subgroup analysis. (P = 0.03). Conclusions: Paravertebral muscle twitching while performing lumbar RF-MB may be a reliable predictor of long-term efficacy when sensory provocation under 0.5 V is achieved. However, further investigation may be necessary for clarifying its clinical significance. PMID- 29123626 TI - Treatment of hemifacial spasm in patient with hemifacial atrophy using combination therapy (ultrasound therapy and TENS): a case report. AB - A 19-year-old male patient presented with facial hemi-atrophy with unilateral spasms of the masseter and temporalis muscles. Ultrasound therapy and Transcutaneous Electric Nerve Stimulation therapy, known as combination therapy, were given on alternate days for 2 weeks. At the end of 2 weeks of combination therapy the patient reported a drastic reduction in the number of episodes of muscle spasm. The visual analog scale score for tenderness of the masseter and temporalis was also markedly reduced. No one has previously used combination therapy for the treatment of facial hemi-atrophy with hemi-facial spasms. The encouraging results of the combination therapy has prompted us to document this study. PMID- 29123627 TI - Abdominal wall myofascial pain: still an unrecognized clinical entity. PMID- 29123630 TI - Development of Temperature Distribution and Light Propagation Model in Biological Tissue Irradiated by 980 nm Laser Diode and Using COMSOL Simulation. AB - Introduction: The purpose of this project is to develop a mathematical model to investigate light distribution and study effective parameters such as laser power and irradiated time to get the optimal laser dosage to control hyperthermia. This study is expected to have a positive impact and a better simulation on laser treatment planning of biological tissues. Moreover, it may enable us to replace animal tests with the results of a COMSOL predictive model. Methods: We used in this work COMSOL5 model to simulate the light diffusion and bio-heat equation of the mouse tissue when irradiated by 980 nm laser diode and the effect of different parameters (laser power, and irradiated time) on the surrounding tissue of the tumor treatment in order to prevent damage from excess heat Results: The model was applied to study light propagation and several parameters (laser power, irradiated time) and their impact on light-heat distribution within the tumor in the mouse back tissue The best result is at laser power 0.5 W and time irradiation 0.5 seconds in order to get the maximum temperature hyperthermia at 52 degrees C. Conclusion: The goal of this study is to simulate a mouse model to control excess heating of tissue and reduce the number of animals in experimental research to get the best laser parameters that was safe for use in living animals and in human subjects. PMID- 29123631 TI - Comparison Between (311-312 nm) Narrow Band Ultraviolet-B Phototherapy and (308 nm) Monochromatic Excimer Light Phototherapy in Treatment of Vitiligo: A Histopathological Study. AB - Introduction: Recently, the monochromatic excimer light (MEL) of 308 nm wavelength has shown some advantages in comparison to narrow band ultraviolet B (NB-UVB) for the treatment of vitiligo. To histopathologically compare the early effects of NB-UVB and 308-nm MEL phototherapy on vitiliginous patches using H&E and HMB-45. Methods: Thirty subjects with non-segmental vitiligo lesions were treated twice a week for 6 weeks with 308-nm MEL, while NB-UVB was used to treat lesions contra laterally. Skin biopsies were taken from lesional areas before and after 6 weeks of treatment by either modality. It was prepared for light microscopy and immunohistochemical study (HMB-45). This study was performed as a clinical trial (Trial registration: http://www.pactr.org; Identifier: PACTR201705002279419) Results: All lesions before treatment had labeling index (number of pigmented cells/non-pigmented cells) of 0.0 (0%). After treatment the LI for MEL was 4.2 +/- 2.6, while for NB-UVB LI it was 0.3 +/- 0.7. MEL showed higher statistical significance regarding increase of basal pigmented cells, and significant decrease in vacuolated keratinocytes and basal membrane thickness than NB-UVB. Conclusion: Although NB-UVB is considered as treatment of choice for vitiligo, MEL is acknowledged as an effective treatment modality for vitiliginous lesions that induces more repigmentation than NB-UVB, and more rapidly, as confirmed by our study. PMID- 29123628 TI - Evaluation of Different Types of Lasers in Surface Conditioning of Porcelains: A Review Article. AB - To achieve proper bond strength for porcelains, adequate surface roughness is essential, which is traditionally gained by sandblasting or acid etching with hydrofluoric (HF) acid. Nowadays with the development of laser systems, serious efforts were made to apply this new instrument for surface etching of porcelains due to easy usage, safety, and more efficiency. There are different kinds of lasers and porcelains, so choosing the ones which will be good match for each other is crucial. Besides that, changing the irradiation setting can be beneficial as well. This article reviewed 33 related studies and summarized results of etching accomplished by Nd:YAG, Er:YAG, Er,Cr:YSGG and CO2 lasers on different types of porcelains considering different laser settings and evaluation methods to bring a comprehensive insight. PMID- 29123629 TI - Effect of Low-Level Laser Therapy and Strength Training Protocol on Hand Grip by Dynamometry. AB - Introduction: The purpose of this study was to investigate the effect of low level laser therapy (LLLT) - 660 nm and 904 nm - before grip strength protocol in healthy subjects. Methods: The study included 45 healthy volunteers with an average age of 22.7 (+/-1.4) years, subdivided into the following groups, control group: grip strength training associated with placebo LLLT; 660 nm group: LLLT (660 nm, 20 J/cm2, power of 30 mW, and beam area of 0.06 cm2, continuous, energy 1.2 J, and exposure time 40 seconds per point) before grip strength training and 904 nm group: LLLT (904 nm, 10 J/cm2, peak power of 70 W and 0.13 cm2 beam area, with pulsed beam 9.500 Hz and 30 seconds of exposure time per point and emitted energy 1.2 J) before grip strength training. The LLLT was timed to contact 10 points located in the region of the superficial and deep flexor muscles of the fingers, with a total energy of 12.0 J per session. For the strength training protocol, the volunteer exercised their fingers with the dominant hand on a small table, elbow flexed at 90 degrees , forearm in neutral, using a light extension handle. The Oxford protocol was performed during four weeks. The grip strength was assessed using a dynamometer (JamarTM). The data were evaluated by the analysis of variance (ANOVA) statistical method. Results: In the comparison of intragroup evaluation, only the 904 nm group showed a difference compared to the baseline assessment after 4 weeks (P < 0.05), in the final intergroup evaluation, a difference was observed in the comparison between the control and 904 nm groups Conclusion: In conclusion, LLLT (904 nm) applied before resistance training was effective in gaining grip strength when compared to LLLT (660 nm) and isolated strength training after 4 weeks. PMID- 29123633 TI - Efficiency of a New Combined Laser Therapy in Patients With Trophic Ulcers of Lower Extremities and Chronic Venous Insufficiency. AB - Introduction: Treating patients with trophic ulcers (TUs) of venous etiology (VE) is a complicated socio-medical and economic problem. One of the ways to increase treatment efficiency can be a complex therapy, including combined laser action. Methods: The objective of this study was a comparative evaluation of the efficiency of traditional treatment methods in patients with chronic venous diseases of C6 class, and combined laser therapy (LT) according to a new method by LASMIK(r) device. External exposure was conducted on the 1-4 affected area during one session for 2 minutes per zone (pulsed mode, light pulse duration of 100-130 ns, wavelength 635 nm, by a matrix emitter consisting of eight laser diodes with a surface area of 8 cm2, at a distance of up to 7 cm, pulsed power 40 W). Intravenous laser blood illumination (ILBI) was conducted in continuous mode with a wavelength of 365-405 nm (UV-spectrum) and 520-525 nm (green spectrum) alternately, during 12 daily sessions, according to a special scheme. Results: The new method reduces time periods for wound surface cleansing from purulo necrotic masses, stimulates proliferation and epithelialization processes by 2 2.7 times, compared with the conventional method. Conclusion: The high efficiency of a new combined LT has been demonstrated in the treatment of TU of VE in combination with traditional methods of patients' medical treatment. PMID- 29123632 TI - Management of Post Endodontic Retreatment Pain With Low Level Laser Therapy. AB - Introduction: Pharmacotherapy with analgesics and non-steroidal anti-inflammatory drugs has been traditionally used to relief post-operative pain of endodontic treatments. However, due to the side effects reported for these drugs, some efforts have been made to decrease the post-operative pain of the endodontic treatments through laser irradiation. The present study aimed to evaluate the effects of low level laser therapy (LLLT) on the reduction of pain after root canal retreatment. Methods: In this clinical trial, 61 patients requiring endodontic retreatments in posterior teeth were selected. A single visit endodontic retreatment was performed. After biomechanical preparation, low level laser was irradiated to the buccal and lingual mucosa overlying the apices of the target tooth in the experimental group. In the control group patients received placebo laser to eliminate the probable psychological effects of laser. Laser irradiation was done with a single dose of 808 nm wavelength (Whitening Lase II- Laser DMC, Samsung, Korea) with 100 mW power, and dose of 70 J/cm2 for 80 seconds. Pain severity was recorded before, immediately after and 4, 8, 12, 24 and 48 hours after the treatment by visual analogue scale (VAS). The pain scores were statistically analyzed by chi-square test between 2 groups. The effects of different variables on the post-operative pain experience were also studied by means of Logistic regression. Results: Pain scores decreased significantly through time until 48 hours after treatment. No significant differences were observed between the 2 modalities regarding pain scores at any time. According to regression analysis, pain severity scores were lower in the laser-irradiated specimens than control groups (OR = 5.69); however, this difference was not statistically significant. Consumption of analgesics after the treatment had significant effect in decreasing post-operative pain experience (OR = 56) while factors of age, gender, laser irradiation, pre-treatment pain scores and education level did not. Conclusion: Low level laser irradiation had limited effects to decrease pain associated with the endodontic retreatments in the first and second molars; however, more studies are required to assess the effects of different parameters of low level laser in this regard. PMID- 29123634 TI - Evaluation of Effectiveness of Photodynamic Therapy With Low-level Diode Laser in Nonsurgical Treatment of Peri-implantitis. AB - Introduction: Side effects related to antibiotic therapy for peri-implantitis are rare in laser therapy (LT); therefore, the aim of this study was to evaluate the effectiveness of LT and photodynamic therapy (PDT) on patients with primary peri implantitis. Methods: In this randomized clinical trial, 40 implants presenting primary peri-implantitis in 20 patients with a mean age of 52.6 years old were included using the simple sampling technique. Periodontal treatment comprising scaling and root planing (SRP) was accomplished for the whole mouth while mechanical debridement with titanium curettes and air polishing with sodium bicarbonate powder was accomplished around the implants. The implants were randomly divided into two groups and treated with LT (control) and PDT (test). The clinical indices were measured at baseline, 6 weeks and 3 months after treatment. Real-time polymerase chain reaction (PCR) was used for analysis of microbial samples at baseline and 3-month follow-up. Data were analyzed with SPSS 20, using repeated-measures analysis of variance (ANOVA) and Friedman's and Mann Whitney tests (alpha = 0.05). Results: Both groups showed statistically significant improvements in terms of bleeding on probing (P < 0.001), probing pocket depth (PPD) (P = 0.006) and modified plaque index (P < 0.001), with no significant differences between the 2 groups (P > 0.05). The number of Aggregatibacter actinomycetemcomitans (P = 0.022), Tannerella forsythia (P = 0.038) and Porphyromonas gingivalis (P = 0.05) in the test group and Porphyromonas gingivalis (P = 0.015) in the control group significantly decreased. Conclusion: The results suggested that LT and PDT have significant short-term benefits in the treatment of primary peri-implantitis. PMID- 29123636 TI - Management of Oral Lichen Planus by 980 nm Diode Laser. AB - Introduction: Oral lichen planus (OLP) is a mucocutaneous disease with uncertain etiology. As the etiology is unknown standard treatment modalities are not available. The traditional and common treatment relies on corticosteroids whether topical or systemic. In recent years, development of lasers made a proper path to use this instrument for treatment of the diseases which are refractory to conventional treatments. Previous studies in this field used CO2, ND:YAG, Excimer and some wavelength of diode lasers for the treatment of different types of lichen planus. Case Report: In this study, we present an OLP case which is treated using 980 nm diode laser. The result was measured by visual analogue scale (VAS) and clinical assessment; as a result, symptoms including pain and soreness started to decrease within a week, and by the end of a month completely subsided; the lesion disappeared totally as well. No recurrence was observed after a month and no side-effect was reported. Conclusion: 980 nm diode laser can be successfully used for treatment of patients with OLP. PMID- 29123635 TI - Er:YAG Laser and Cyclosporin A Effect on Cell Cycle Regulation of Human Gingival Fibroblast Cells. AB - Introduction: Periodontitis is a set of inflammatory disorders characterized by periodontal attachment loss and alveolar bone resorption. Because of deficiency in periodontitis mechanical therapy, this study was aimed to explore the molecular influence of the erbiumdoped: yttrium aluminum garnet (Er:YAG) laser and cyclosporin A (CsA) on human gingival fibroblasts (HGFs) for improvement in periodontal diseases therapy. Methods: We focused on articles that studied the proteome profiles of HGFs after treatment with laser irradiation and application of CsA. The topological features of differentially expressed proteins were analyzed using Cytoscape Version 3.4.0 followed by module selection from the protein-protein interaction (PPI) network using Cluster ONE plugin. In addition, we performed gene ontology (GO) enrichment analysis for the densely connected region and key proteins in both PPI networks. Results: Analysis of PPI network of Er:YAG laser irradiation on HGFs lead to introducing YWHAZ, VCP, HNRNPU, YWHAE, UBA52, CLTC, FUS and IGHG1 as key proteins while similar analysis revealed that ACAT1, CTSD, ALDOA, ANXA2, PRDX1, LGALS3, ARHGDI and EEF1A1 are the crucial proteins related to the effect of drug. GO enrichment analysis of hubbottleneck proteins of the 2 networks showed the different significant biological processes and cellular components. The functional enrichments of module of Er:YAG laser network are included as fatty acid transmembrane transport, cytokinesis, regulation of RNA splicing and asymmetric protein localization. There are not any significant clusters in network of HGF treated by CsA. Conclusion: The results indicate that there are 2 separate biomarker panels for the 2 treatment methods. PMID- 29123640 TI - Evolution of Godoy & Godoy manual lymph drainage. Technique with linear Movements. PMID- 29123637 TI - Diode Laser Assisted Excision and Low Level Laser Therapy in the Management of Mucus Extravasation Cysts: A Case Series. AB - Introduction: Mucus extravasation cyst is a commonly occurring lesion in oral cavity that may result from traumatic severance of a salivary gland duct with subsequent extravasation of mucus into fibrous connective tissue. After a conventional excision or marsupialization, recurrence is not uncommon. Diode laser offers an effective modality for management of such lesions. Case Reports: Four patients were referred with painless fluctuant swellings on labial and buccal mucosa. After recording history and clinical examination, provisional diagnosis of mucocele was made. All the lesions were excised with a diode laser and biopsy was performed. Surgical wounds were treated with low-level laser therapy (LLLT). Results: Uneventful healing was observed in all 4 cases. Significant reduction in postoperative discomfort was recorded after application of LLLT. Histopathological findings were suggestive of mucus extravasation cysts. Conclusion: Diode laser appears to be a good alternative to conventional modalities for the management of mucus extravasation cysts. PMID- 29123639 TI - The application of preoperative computed tomography angiogram for hemispherectomy. PMID- 29123638 TI - Panoramic radiographs for detecting osteopenia: A pilot study. PMID- 29123646 TI - First de novo draft genome sequence of Oryza coarctata, the only halophytic species in the genus Oryza. AB - Oryza coarctata plants, collected from Sundarban delta of West Bengal, India, have been used in the present study to generate draft genome sequences, employing the hybrid genome assembly with Illumina reads and third generation Oxford Nanopore sequencing technology. We report for the first time that more than 85.71 % of the genome coverage and the data have been deposited in NCBI SRA, with BioProject ID PRJNA396417. PMID- 29123645 TI - BeerDeCoded: the open beer metagenome project. AB - Next generation sequencing has radically changed research in the life sciences, in both academic and corporate laboratories. The potential impact is tremendous, yet a majority of citizens have little or no understanding of the technological and ethical aspects of this widespread adoption. We designed BeerDeCoded as a pretext to discuss the societal issues related to genomic and metagenomic data with fellow citizens, while advancing scientific knowledge of the most popular beverage of all. In the spirit of citizen science, sample collection and DNA extraction were carried out with the participation of non-scientists in the community laboratory of Hackuarium, a not-for-profit organisation that supports unconventional research and promotes the public understanding of science. The dataset presented herein contains the targeted metagenomic profile of 39 bottled beers from 5 countries, based on internal transcribed spacer (ITS) sequencing of fungal species. A preliminary analysis reveals the presence of a large diversity of wild yeast species in commercial brews. With this project, we demonstrate that coupling simple laboratory procedures that can be carried out in a non professional environment, with state-of-the-art sequencing technologies and targeted metagenomic analyses, can lead to the detection and identification of the microbial content in bottled beer. PMID- 29123647 TI - Tools for annotation and comparison of structural variation. AB - The impact of structural variants (SVs) on a variety of organisms and diseases like cancer has become increasingly evident. Methods for SV detection when studying genomic differences across cells, individuals or populations are being actively developed. Currently, just a few methods are available to compare different SVs callsets, and no specialized methods are available to annotate SVs that account for the unique characteristics of these variant types. Here, we introduce SURVIVOR_ant, a tool that compares types and breakpoints for candidate SVs from different callsets and enables fast comparison of SVs to genomic features such as genes and repetitive regions, as well as to previously established SV datasets such as from the 1000 Genomes Project. As proof of concept we compared 16 SV callsets generated by different SV calling methods on a single genome, the Genome in a Bottle sample HG002 (Ashkenazi son), and annotated the SVs with gene annotations, 1000 Genomes Project SV calls, and four different types of repetitive regions. Computation time to annotate 134,528 SVs with 33,954 of annotations was 22 seconds on a laptop. PMID- 29123643 TI - COINSTAC: Decentralizing the future of brain imaging analysis. AB - In the era of Big Data, sharing neuroimaging data across multiple sites has become increasingly important. However, researchers who want to engage in centralized, large-scale data sharing and analysis must often contend with problems such as high database cost, long data transfer time, extensive manual effort, and privacy issues for sensitive data. To remove these barriers to enable easier data sharing and analysis, we introduced a new, decentralized, privacy enabled infrastructure model for brain imaging data called COINSTAC in 2016. We have continued development of COINSTAC since this model was first introduced. One of the challenges with such a model is adapting the required algorithms to function within a decentralized framework. In this paper, we report on how we are solving this problem, along with our progress on several fronts, including additional decentralized algorithms implementation, user interface enhancement, decentralized regression statistic calculation, and complete pipeline specifications. PMID- 29123644 TI - RNAi targeting Caenorhabditis elegans alpha-arrestins marginally affects lifespan. AB - Background: alpha-arrestins are a family of proteins that are implicated in multiple biological processes, including metabolism and receptor desensitization. Methods: Here, we sought to examine the roles of alpha-arrestins in the longevity of Caenorhabditis elegans through an RNA interference screen. Results: We found that knocking down each of 24 out of total 29 C. elegans alpha-arrestins had small or no effects on lifespan. Thus, individual C. elegans alpha-arrestins may have minor effects on longevity. Conclusions: This study will provide useful information for future research on the functional role of alpha-arrestins in aging and longevity. PMID- 29123641 TI - Systematically linking tranSMART, Galaxy and EGA for reusing human translational research data. AB - The availability of high-throughput molecular profiling techniques has provided more accurate and informative data for regular clinical studies. Nevertheless, complex computational workflows are required to interpret these data. Over the past years, the data volume has been growing explosively, requiring robust human data management to organise and integrate the data efficiently. For this reason, we set up an ELIXIR implementation study, together with the Translational research IT (TraIT) programme, to design a data ecosystem that is able to link raw and interpreted data. In this project, the data from the TraIT Cell Line Use Case (TraIT-CLUC) are used as a test case for this system. Within this ecosystem, we use the European Genome-phenome Archive (EGA) to store raw molecular profiling data; tranSMART to collect interpreted molecular profiling data and clinical data for corresponding samples; and Galaxy to store, run and manage the computational workflows. We can integrate these data by linking their repositories systematically. To showcase our design, we have structured the TraIT-CLUC data, which contain a variety of molecular profiling data types, for storage in both tranSMART and EGA. The metadata provided allows referencing between tranSMART and EGA, fulfilling the cycle of data submission and discovery; we have also designed a data flow from EGA to Galaxy, enabling reanalysis of the raw data in Galaxy. In this way, users can select patient cohorts in tranSMART, trace them back to the raw data and perform (re)analysis in Galaxy. Our conclusion is that the majority of metadata does not necessarily need to be stored (redundantly) in both databases, but that instead FAIR persistent identifiers should be available for well-defined data ontology levels: study, data access committee, physical sample, data sample and raw data file. This approach will pave the way for the stable linkage and reuse of data. PMID- 29123642 TI - Supporting evidence-based analysis for modified risk tobacco products through a toxicology data-sharing infrastructure. AB - The US FDA defines modified risk tobacco products (MRTPs) as products that aim to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products. Establishing a product's potential as an MRTP requires scientific substantiation including toxicity studies and measures of disease risk relative to those of cigarette smoking. Best practices encourage verification of the data from such studies through sharing and open standards. Building on the experience gained from the OpenTox project, a proof-of-concept database and website ( INTERVALS) has been developed to share results from both in vivo inhalation studies and in vitro studies conducted by Philip Morris International R&D to assess candidate MRTPs. As datasets are often generated by diverse methods and standards, they need to be traceable, curated, and the methods used well described so that knowledge can be gained using data science principles and tools. The data-management framework described here accounts for the latest standards of data sharing and research reproducibility. Curated data and methods descriptions have been prepared in ISA-Tab format and stored in a database accessible via a search portal on the INTERVALS website. The portal allows users to browse the data by study or mechanism (e.g., inflammation, oxidative stress) and obtain information relevant to study design, methods, and the most important results. Given the successful development of the initial infrastructure, the goal is to grow this initiative and establish a public repository for 21 st-century preclinical systems toxicology MRTP assessment data and results that supports open data principles. PMID- 29123648 TI - Novel therapeutic approaches to simultaneously target rhinovirus infection and asthma/COPD pathogenesis. AB - Rhinoviruses are exclusive respiratory pathogens and the etiological agents of the common cold. These viruses are increasingly reported to cause exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Here, we review the role of rhinovirus infections in the pathogenesis of asthma and COPD and we discuss the current and potential future treatments. We propose that, in order to prevent exacerbations, the design of novel therapeutics should focus on directly acting antivirals but also include the design of drugs that simultaneously inhibit viral replication and alleviate symptoms of asthma and COPD. PMID- 29123650 TI - Transcellular communication at the immunological synapse: a vesicular traffic mediated mutual exchange. AB - The cell's ability to communicate with the extracellular environment, with other cells, and with itself is a crucial feature of eukaryotic organisms. In the immune system, T lymphocytes assemble a specialized structure upon contact with antigen-presenting cells bearing a peptide-major histocompatibility complex ligand, known as the immunological synapse (IS). The IS has been extensively characterized as a signaling platform essential for T-cell activation. Moreover, emerging evidence identifies the IS as a device for vesicular traffic-mediated cell-to-cell communication as well as an active release site of soluble molecules. Here, we will review recent advances in the role of vesicular trafficking in IS assembly and focused secretion of microvesicles at the synaptic area in naive T cells and discuss the role of the IS in transcellular communication. PMID- 29123649 TI - The gamma c family of cytokines: fine-tuning signals from IL-2 and IL-21 in the regulation of the immune response. AB - Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on the sharing of a receptor component, the common cytokine receptor gamma chain, gamma c, which is encoded by the gene mutated in humans with X-linked severe combined immunodeficiency (XSCID). Together, these cytokines play critical roles in lymphoid development, differentiation, growth, and survival as well as mediating effector function. Here, we provide an overview of the main actions of members of this cytokine family but then primarily focus on IL-2 and IL-21, discussing their dynamic interplay and contributions to a fine-tuned immune response. Moreover, we discuss the therapeutic utility of modulating their actions, particularly for autoimmunity and cancer. PMID- 29123651 TI - Recent advances in managing and understanding enuresis. AB - Enuresis, particularly in children during sleep, can be a debilitating condition, affecting the quality of life of the child and his or her family. The pathophysiology of nocturnal enuresis, though not clear, revolves around the inter-related mechanisms of overactive bladder, excessive nocturnal urine production, and sleep fragmentation. The first mechanism is more related to isolated nocturnal voiding, whereas the latter two are more related to nocturnal enuresis, in which circadian variations in arginine vasopressin hormone play a key role. A successful treatment would depend upon appropriately addressing the key factors precipitating nocturnal enuresis, necessitating an accurate diagnosis. Thus, advancements in diagnostic tools and treatment options play a key role in achieving overall success. This review summarizes recent advances in understanding the pathophysiology of nocturnal enuresis, diagnostic tools, and treatment options which can be explored in the future. PMID- 29123652 TI - Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. AB - Autoimmune lymphoproliferative syndrome (ALPS) is an inherited syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and autoimmune pathology, most commonly, autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis. PMID- 29123654 TI - A prospective cohort study on comparison of early outcome of classical Ponseti and modified Ponseti post tenotomy in clubfoot management. AB - Introduction: Ponseti method has become the main treatment modality for the management of clubfoot producing good long-term results. However, variation in cast application post tenotomy has not been evaluated. Methods: A prospective cohort study involving 40 patients with 67 clubfeet were randomized into two groups: 32 above knee cast (AKC) and 35 below knee cast (BKC) after percutaneous tenotomy. All had foot abduction brace after post tenotomy cast. The median age was 21 weeks (range: 1-104 weeks) and 1.9:1 male/female ratio. 27 (67.5%) patients had bilateral clubfoot and unilateral in 13 (32.5%). Patients were followed-up for 6 months with documentation of the Pirani Score and the cost of treatment. Results: No significant difference between AKC and BKC mean Pirani score before treatment (p = 0.550) and after treatment (p = 0.702). However, mean Pirani score at 6 months was significantly different (p = 0.038). Overall mean number of casting was 6.4 in AKC group and 4.7 in BKC group (p = 0.003). There was recurrence in 2 feet before completion of treatment (6.3%) among AKC and none among BKC group. However, there was no recurrence at 6 months after treatment in both groups. The mean cost for AKC and BKC were ?10,427.34 (52.33 US dollars) and ?7021.54 (35.24 US dollars) respectively (p = 0.002). Conclusion: Early results of below knee cast after tenotomy were comparable to the classical above knee cast after tenotomy in Ponseti treatment protocol for clubfoot. There was also reduction in cost of treatment in the modified Ponseti compared to the classical Ponseti. Long-term result will be desirable. PMID- 29123653 TI - Chloride in intensive care units: a key electrolyte. AB - Over the past few years, chloride has joined the league of essential electrolytes for critically ill patients. Dyschloremia can occur secondary to various etiologic factors before and during patient admission in the intensive care unit. Some cases are disease-related; others, treatment-related. Chloride abnormalities were shown in animal models to have adverse effects on arterial blood pressure, renal blood flow, and inflammatory markers, which have led to several clinical investigations. Hyperchloremia was studied in several settings and correlated to different outcomes, including death and acute kidney injury. Baseline hypochloremia, to a much lesser extent, has been studied and associated with similar outcomes. The chloride content of resuscitation fluids was also a subject of clinical research. In this review, we describe the effect of dyschloremia on outcomes in critically ill patients. We review the major studies assessing the chloride content of resuscitation fluids in the critically ill patient. PMID- 29123655 TI - Does surgeon volume affect the outcome of total knee arthroplasties in a developing country? - A retrospective cohort study. AB - Introduction: Recent studies have shown that in addition to patient factors, surgeon volume has influenced total knee arthroplasty (TKA) outcomes greatly. With recent propositions of regionalization of arthroplasties to higher volume centers, the need for further evidence is warranted. Materials and methods: Retrospective Cohort Study done at Aga Khan University Hospital, Pakistan from January 2007 to December 2015. High Volume (HV) group was set as at least 50 TKAs/year and Low Volume (LV) was set as at most 25 TKAs/year. A total of 615 patients undergoing a unilateral or bilateral TKA were included in our study. Results: LV group was associated with a higher length of stay (LOS) as compared to HV group in patients undergoing a bilateral TKA after adjusted logistic regression [OR 2.395 (1.47,3.91)]. We found no association between surgeon volume and postoperative complications. Conclusion: Patients getting a bilateral TKA by LV surgeons were twice more likely to have a longer LOS as compared to HV group. Further research is warranted comparing all aspects and possible confounders to different variables before a conclusion can be made. PMID- 29123656 TI - Off-label use of adipose-derived stem cells. AB - Background: Adipose-derived stem cells (ASCs) have a broad range of clinical applications. The ease of cell harvest and high yield with minimal donor-site morbidity makes adipose tissue an ideal source of stem cells. Further, the multi lineage potential of these cells present significant opportunities within the field of tissue engineering, with studies successfully demonstrating their ability to produce a range of tissue types. Materials and methods: Literature review of publications on the use of ASCs, in the context of current European and US regulations. Results: According to European and US regulations, many clinical trials reported in literature to date could be considered off-label. Conclusion: In Europe, clinical trials involving cultured ASCs and/or the use of collagenase, which causes changes in the structural and functional properties of stem cells, and/or ASCs application in non-homologous tissue, should be considered off-label. ASCs should be non-cultured, isolated mechanically, and used only in the subcutaneous tissue. PMID- 29123657 TI - Pain after surgery. PMID- 29123658 TI - The puzzle of chronic post-surgical pain: collaborative problem solving at its best? PMID- 29123660 TI - Does perioperative ketamine have a role in the prevention of chronic postsurgical pain: the ROCKet trial. AB - Identifying operations and individuals with an increased risk of chronic postsurgical pain (CPSP) has led to significant interest in interventions with the potential to achieve primary prevention of this condition. Pharmacological prevention remains controversial with a Cochrane review identifying perioperative ketamine administration as the only intervention with possible benefit although, with only small, heterogeneous studies, the authors called for a large randomised controlled trial (RCT) to confirm the validity of this result. In response to these data, a group of researchers from Australia and Hong Kong designed the ROCKet trial - Reduction Of Chronic Post-surgical Pain with Ketamine, endorsed by the Australian and New Zealand College of Anaesthetists (ANZCA) Clinical Trials Network (CTN). PMID- 29123659 TI - 'Why me?' The problem of chronic pain after surgery. AB - Chronic postsurgical pain (CPSP) has become a health priority and is scheduled to be included in the upcoming version of the International Classification of Diseases, 11th Revision (ICD-11). Recent studies on CPSP show unchanged prevalence despite progress made in fundamental research about underlying pathophysiological mechanisms. Nevertheless, clinical research has allowed better understanding of some CPSP aspects such as the development of neuropathic CPSP. Actually, some improvements are ongoing such as a refined definition and the assessment of CPSP in vulnerable populations, for example, paediatric patients. Pain after surgery, its resolution or its transition to CPSP is a dynamic process that reinforces the necessity of longitudinal assessment and management. In other words, CPSP can be called 'perioperative medicine'. PMID- 29123661 TI - The psychology of chronic post-surgical pain: new frontiers in risk factor identification, prevention and management. AB - In an era of considerable advances in anaesthesiology and pain medicine, chronic pain after major surgery continues to be problematic. This article briefly reviews the known psychological risk and protective factors associated with the development of chronic postsurgical pain (CPSP). We begin with a definition of CPSP and then explain what we mean by a risk/protective factor. Next, we summarize known psychological risk and protective factors for CPSP. Psychological interventions that target risk factors and may impact postsurgical pain are reviewed, including the acceptance and commitment therapy (ACT)-based approach to CPSP prevention and management we use in the Transitional Pain Service (TPS) at the Toronto General Hospital. Finally, we conclude with recommendations for research in risk factor identification and psychological interventions to prevent CPSP. Several pre-surgical psychological risk factors for CPSP have been consistently identified in recent years. These include negative affective constructs, such as anxiety symptoms, depressive symptoms, pain catastrophizing and general psychological distress. In contrast, relatively few studies have examined psychological protective factors for CPSP. Psychological interventions that target known psychological risk factors while enhancing protective psychological factors may reduce new incidence of CPSP. The primary goal of our ACT intervention is to teach patients a mindful way of responding to their postsurgical pain that empowers them to interrupt the negative cycle of pain, distress, behavioural avoidance and escalating opioid use that can limit functioning and quality of life while paradoxically amplifying pain over time. Early clinical outcome data suggest that patients who receive care from TPS physicians reduce their pain and opioid use, yet patients who also receive our ACT intervention have a larger decrease in daily opioid dose while reporting less pain interference and lower depression scores. PMID- 29123663 TI - The role of intraoperative interventions to minimise chronic postsurgical pain. AB - Chronic postsurgical pain (CPSP) is the most common complication following surgery, with increasing evidence of both its prevalence and severity. While awareness of the various risk factors for this long-term condition is also increasing, effective prevention remains elusive. In this review, we describe the increasing evidence for preventive or 'protective' strategies. Controversies and conflicting human data are presented along with suggestions for improved future study. PMID- 29123664 TI - Chronic post-amputation pain: peri-operative management - Review. AB - Study design: Narrative review. Method: Eight bibliographic databases were searched for studies published in the (last five years up until Feb 2017). For the two database searches (Cochrane and DARE), the time frame was unlimited. The review involved keyword searches of the term 'Amputation' AND 'chronic pain'. Studies selected were interrogated for any association between peri-operative factors and the occurrence of chronic post amputation pain (CPAP). Results: Heterogeneity of study populations and outcome measures prevented a systematic review and hence a narrative synthesis of results was undertaken. The presence of variation in two gene alleles (GCH1 and KCNS1) may be relevant for development of CPAP. There was little evidence to draw conclusions on the association between age, gender and CPAP. Pre-operative anxiety and depression influenced pain intensity post operatively and long-term post amputation pain (CPAP). The presence of pre-amputation pain is correlated to the development of acute and chronic post amputation pain while evidence for the association of post-operative pain with CPAP is modest. Regional anaesthesia and peri-neural catheters improve acute postoperative pain relief but evidence on their efficacy to prevent CPAP is limited. A suggested whole system pathway based on current evidence to optimize peri-operative amputation pain is described. Conclusion: The current evidence suggests that optimized peri-operative analgesia reduces the incidence of acute peri-operative pain but no firm conclusion can be drawn on reducing risk for CPAP. PMID- 29123662 TI - Chronic postsurgical pain: is there a possible genetic link? AB - Persistent or chronic postsurgical pain (CPSP) has been defined as 'pain persisting beyond 2 months'. The cut-off limit of 2 months has been controversial, and some researchers argue for a 3-month period for the definition of CPSP. Multiple mechanisms, including both patient and surgical, have been shown to influence this transition. Patient factors include age, gender, anxiety, depression, somatisation, catastrophising, pre-existing pain anywhere and pain at the site of surgery. The various surgical factors include site and nature of surgery, infection, inflammation and repeat surgery. There is evidence that pre- or post-op chemotherapy and radiotherapy can also contribute towards the chronification of pain after surgery. The question of why pain following surgery or trauma persists long after the normal healing time is not yet fully explained by current evidence. This is frustrating to healthcare providers and intensely disappointing to the patients, many of whom suffer in silence for years. Genetics is now being shown to influence both the onset and the perpetuation of chronic pain in the susceptible patient. The main mechanisms are believed to be 'single nucleotide polymorphisms' (SNPs) and 'epigenetics', both of which will be discussed, with current and ongoing research and evidence, in this review. The influence of SNPs has not been replicated in recent studies and researchers advise caution in interpreting past studies. More research is needed to demonstrate the involvement of epigenetics as well as linking SNPs to the susceptible patient's journey. PMID- 29123666 TI - Multi-modality imaging of a left atrial myxoma. AB - Objectives: Although echocardiography has traditionally been used to diagnose myxoma, invasive or non-invasive coronary angiography can be useful diagnostic tool before surgery. Methods: We present a case of an angiographically detected left atrial myxoma feeding from the left circumflex coronary artery. Results: The patient underwent open-heart surgery to remove the left atrial myxoma. After ligation of feeding artery, the mass was successfully excised. Conclusion: Preoperative coronary angiography can offer additional valuable information moreover detecting coronary artery disease. Because, there is sudden death risk from embolization during invasive coronary angiography, preoperative cardiac computed tomography angiography should be considered to plan the surgery of myxoma. PMID- 29123665 TI - The characterisation of unexplained pain after knee replacement. AB - Background: The aims of this study were to characterise the pain experienced by patients with chronic pain after knee replacement (KR), in whom no apparent 'orthopaedic' problem could be identified, and to establish how many have pain sensitisation problems (including neuropathic pain). Methods: A total of 44 patients were prospectively evaluated at a multidisciplinary tertiary referral clinic by an orthopaedic surgeon, pain specialist, rheumatologist and physiotherapist. These patients had been pre-screened by an orthopaedic surgeon to remove cases where there was an obvious cause of pain that could be treated with revision surgery. They were then followed up to find out whether any subsequent interventions had occurred. Results: The mean time since surgery was 29 months (range: 3-108 months), and 18% were revision KR. Patients were evaluated for symptoms of nociceptive pain, allodynia, pains elsewhere and psychosocial factors. The patients were categorised into nociceptive pain 43% (n = 19), pain sensitisation 25% (n = 11) and mixed pain 32% (n = 14). Mean Visual Analogue Score (VAS) pain scores were 6.7/10 with high scores for both constant (66%) and intermittent (70%) pain elements, and pain caused high levels of interference with life. Fifty percent suffered depression and 25% suffered widespread pains (more than three pains elsewhere in the body). Patients with widespread pains suffered more pain (p = 0.01) and higher rates of both pain sensitisation (p = 0.07) and thermal allodynia (p < 0.04). Conclusion: Patients after KR can experience severe pain that interferes with their lives, depression and many have pain sensitisation problems rather than any local, nociceptive cause. We advocate screening patients with unexplained pain after KR for pain sensitisation problems, pains at other sites and depression. Appropriate further treatment and multidisciplinary interventions can then be arranged. PMID- 29123667 TI - Paternal obesity: how bad is it for sperm quality and progeny health? AB - There is substantial evidence that paternal obesity is associated not only with an increased incidence of infertility, but also with an increased risk of metabolic disturbance in adult offspring. Apparently, several mechanisms may contribute to the sperm quality alterations associated with paternal obesity, such as physiological/hormonal alterations, oxidative stress, and epigenetic alterations. Along these lines, modifications of hormonal profiles namely reduced androgen levels and elevated estrogen levels, were found associated with lower sperm concentration and seminal volume. Additionally, oxidative stress in testis may induce an increase of the percentage of sperm with DNA fragmentation. The latter, relate to other peculiarities such as alteration of the embryonic development, increased risk of miscarriage, and development of chronic morbidity in the offspring, including childhood cancers. Undoubtedly, epigenetic alterations (ie, DNA methylation, chromatin modifications, and small RNA deregulation) of sperm related to paternal obesity and their consequences on the progeny are poorly understood determinants of paternal obesity-induced transmission. In this review, we summarize and discuss the data available in the literature regarding the biological, physiological, and molecular consequences of paternal obesity on male fertility potential and ultimately progeny health. PMID- 29123671 TI - Theoretical prediction of strain tuneable quaternary spintronic Heusler compounds. AB - Heusler materials have attracted a large amount of attention in the development of spintronic technologies. In this issue, Wang et al. [IUCrJ (2017), 4, 758-768] show how strain can be used to tune the band structure of these materials. PMID- 29123670 TI - Crystal engineering: structure, property and beyond. AB - Crystal engineering, which was considered to be crystal structure engineering, is now transforming into crystal property engineering. The same or similar crystal structures could have different properties while different crystal structures could have similar properties. PMID- 29123669 TI - CdS Aerogels as Efficient Photocatalysts for Degradation of Organic Dyes under Visible Light Irradiation. AB - Synthesis of efficient photocatalysts based on CdS nanomaterials for oxidative decomposition of organic effluents typically focuses on (a) enhancement of surface area of the catalysts and (b) promotion of the separation of photogenerated electron-hole pairs. CdS aerogel, which are synthesized by simple sol-gel assembly of discrete nanocrystals (NCs) into a porous network followed by supercritical drying, could provide higher surface area for photocatalytic reactions along with facile charge separation due to direct contact between NCs via covalent bonding. We evaluated the efficiency of CdS aerogel materials for degradation of organic dyes using methylene blue (MB) and methyl orange (MO) as test cases. CdS aerogel materials exhibited remarkable photocatalytic activity for dye degradation compared to typical, ligand-capped CdS NCs. The catalytic efficiency of CdS aerogels was further improved by decreasing the chain-length and extent of surface organics, leading to higher, and more hydrophilic, accessible surface area. The use of porous, chalcogenide-based solid state architectures for photocatalysis enables easy separation of catalyst while ensuring a high-interfacial surface area for analyte reactivity and visible light activation. PMID- 29123672 TI - The science is in the data. AB - Understanding published research results should be through one's own eyes and include the opportunity to work with raw diffraction data to check the various decisions made in the analyses by the original authors. Today, preserving raw diffraction data is technically and organizationally viable at a growing number of data archives, both centralized and distributed, which are empowered to register data sets and obtain a preservation descriptor, typically a 'digital object identifier'. This introduces an important role of preserving raw data, namely understanding where we fail in or could improve our analyses. Individual science area case studies in crystallography are provided. PMID- 29123673 TI - Cryo-EM reconstruction of the chlororibosome to 3.2 A resolution within 24 h. AB - The introduction of direct detectors and the automation of data collection in cryo-EM have led to a surge in data, creating new opportunities for advancing computational processing. In particular, on-the-fly workflows that connect data collection with three-dimensional reconstruction would be valuable for more efficient use of cryo-EM and its application as a sample-screening tool. Here, accelerated on-the-fly analysis is reported with optimized organization of the data-processing tools, image acquisition and particle alignment that make it possible to reconstruct the three-dimensional density of the 70S chlororibosome to 3.2 A resolution within 24 h of tissue harvesting. It is also shown that it is possible to achieve even faster processing at comparable quality by imposing some limits to data use, as illustrated by a 3.7 A resolution map that was obtained in only 80 min on a desktop computer. These on-the-fly methods can be employed as an assessment of data quality from small samples and extended to high-throughput approaches. PMID- 29123675 TI - The potential of hexatungstotellurate(VI) to induce a significant entropic gain during protein crystallization. AB - The limiting factor in protein crystallography is still the production of high quality crystals. In this regard, the authors have recently introduced hexatungstotellurate(VI) (TEW) as a new crystallization additive, which proved to be successful within the liquid-liquid phase separation (LLPS) zone. Presented here are comparative crystal structure analyses revealing that protein-TEW binding not only induces and stabilizes crystal contacts, but also exhibits a significant impact on the solvent-driven crystallization entropy, which is the driving force for the crystallization process. Upon the formation of TEW-mediated protein-protein contacts, the release of water molecules from the hydration shells of both molecules, i.e. TEW and the protein, causes a reduced solvent accessible surface area, leading to a significant gain in solvent entropy. Based on the crystal structures of aurone synthase (in the presence and absence of TEW), insights have also been provided into the formation of a metastable LLPS, which is caused by the formation of protein clusters, representing an ideal starting point in protein crystallization. The results strongly encourage the classification of TEW as a valuable crystallization additive. PMID- 29123678 TI - Rare earth-based quaternary Heusler compounds MCoVZ (M = Lu, Y; Z = Si, Ge) with tunable band characteristics for potential spintronic applications. AB - Magnetic Heusler compounds (MHCs) have recently attracted great attention since these types of material provide novel functionalities in spintronic and magneto electronic devices. Among the MHCs, some compounds have been predicted to be spin filter semiconductors [also called magnetic semiconductors (MSs)], spin-gapless semiconductors (SGSs) or half-metals (HMs). In this work, by means of first principles calculations, it is demonstrated that rare earth-based equiatomic quaternary Heusler (EQH) compounds with the formula MCoVZ (M = Lu, Y; Z = Si, Ge) are new spin-filter semiconductors with total magnetic moments of 3 uB. Furthermore, under uniform strain, there are physical transitions from spin filter semiconductor (MS) -> SGS -> HM for EQH compounds with the formula LuCoVZ, and from HM -> SGS -> MS -> SGS -> HM for EQH compounds with the formula YCoVZ. Remarkably, for YCoVZ EQH compounds there are not only diverse physical transitions, but also different types of spin-gapless feature that can be observed with changing lattice constants. The structural stability of these four EQH compounds is also examined from the points of view of formation energy, cohesive energy and mechanical behaviour. This work is likely to inspire consideration of rare earth-based EQH compounds for application in future spintronic and magneto-electronic devices. PMID- 29123677 TI - In vivo analysis of the Escherichia coli ultrastructure by small-angle scattering. AB - The flagellated Gram-negative bacterium Escherichia coli is one of the most studied microorganisms. Despite extensive studies as a model prokaryotic cell, the ultrastructure of the cell envelope at the nanometre scale has not been fully elucidated. Here, a detailed structural analysis of the bacterium using a combination of small-angle X-ray and neutron scattering (SAXS and SANS, respectively) and ultra-SAXS (USAXS) methods is presented. A multiscale structural model has been derived by incorporating well established concepts in soft-matter science such as a core-shell colloid for the cell body, a multilayer membrane for the cell wall and self-avoiding polymer chains for the flagella. The structure of the cell envelope was resolved by constraining the model by five different contrasts from SAXS, and SANS at three contrast match points and full contrast. This allowed the determination of the membrane electron-density profile and the inter-membrane distances on a quantitative scale. The combination of USAXS and SAXS covers size scales from micrometres down to nanometres, enabling the structural elucidation of cells from the overall geometry down to organelles, thereby providing a powerful method for a non-invasive investigation of the ultrastructure. This approach may be applied for probing in vivo the effect of detergents, antibiotics and antimicrobial peptides on the bacterial cell wall. PMID- 29123676 TI - Merging single-shot XFEL diffraction data from inorganic nanoparticles: a new approach to size and orientation determination. AB - X-ray free-electron lasers (XFELs) provide new opportunities for structure determination of biomolecules, viruses and nanomaterials. With unprecedented peak brilliance and ultra-short pulse duration, XFELs can tolerate higher X-ray doses by exploiting the femtosecond-scale exposure time, and can thus go beyond the resolution limits achieved with conventional X-ray diffraction imaging techniques. Using XFELs, it is possible to collect scattering information from single particles at high resolution, however particle heterogeneity and unknown orientations complicate data merging in three-dimensional space. Using the Linac Coherent Light Source (LCLS), synthetic inorganic nanocrystals with a core-shell architecture were used as a model system for proof-of-principle coherent diffractive single-particle imaging experiments. To deal with the heterogeneity of the core-shell particles, new computational methods have been developed to extract the particle size and orientation from the scattering data to assist data merging. The size distribution agrees with that obtained by electron microscopy and the merged data support a model with a core-shell architecture. PMID- 29123674 TI - Characterization of temporal coherence of hard X-ray free-electron laser pulses with single-shot interferograms. AB - Temporal coherence is one of the most fundamental characteristics of light, connecting to spectral information through the Fourier transform relationship between time and frequency. Interferometers with a variable path-length difference (PLD) between the two branches have widely been employed to characterize temporal coherence properties for broad spectral regimes. Hard X-ray interferometers reported previously, however, have strict limitations in their operational photon energies, due to the specific optical layouts utilized to satisfy the stringent requirement for extreme stability of the PLD at sub angstrom scales. The work presented here characterizes the temporal coherence of hard X-ray free-electron laser (XFEL) pulses by capturing single-shot interferograms. Since the stability requirement is drastically relieved with this approach, it was possible to build a versatile hard X-ray interferometer composed of six separate optical elements to cover a wide photon energy range from 6.5 to 11.5 keV while providing a large variable delay time of up to 47 ps at 10 keV. A high visibility of up to 0.55 was observed at a photon energy of 10 keV. The visibility measurement as a function of time delay reveals a mean coherence time of 5.9 +/- 0.7 fs, which agrees with that expected from the single-shot spectral information. This is the first result of characterizing the temporal coherence of XFEL pulses in the hard X-ray regime and is an important milestone towards ultra high energy resolutions at micro-electronvolt levels in time-domain X-ray spectroscopy, which will open up new opportunities for revealing dynamic properties in diverse systems on timescales from femto-seconds to nanoseconds, associated with fluctuations from angstrom to nanometre spatial scales. PMID- 29123680 TI - Hit detection in serial femtosecond crystallography using X-ray spectroscopy of plasma emission. AB - Serial femtosecond crystallography is an emerging and promising method for determining protein structures, making use of the ultrafast and bright X-ray pulses from X-ray free-electron lasers. The upcoming X-ray laser sources will produce well above 1000 pulses per second and will pose a new challenge: how to quickly determine successful crystal hits and avoid a high-rate data deluge. Proposed here is a hit-finding scheme based on detecting photons from plasma emission after the sample has been intercepted by the X-ray laser. Plasma emission spectra are simulated for systems exposed to high-intensity femtosecond pulses, for both protein crystals and the liquid carrier systems that are used for sample delivery. The thermal radiation from the glowing plasma gives a strong background in the XUV region that depends on the intensity of the pulse, around the emission lines from light elements (carbon, nitrogen, oxygen). Sample hits can be reliably distinguished from the carrier liquid based on the characteristic emission lines from heavier elements present only in the sample, such as sulfur. For buffer systems with sulfur present, selenomethionine substitution is suggested, where the selenium emission lines could be used both as an indication of a hit and as an aid in phasing and structural reconstruction of the protein. PMID- 29123683 TI - Thermomechanical effect in molecular crystals: the role of halogen-bonding interactions. AB - The design and synthesis of mechanically responsive materials is interesting because they are potential candidates to convert thermal energy into mechanical work. Reported in this paper are thermosalient effects in a series of halogen derivatives of salinazids. The chloro derivative, with higher electronegativity and a weaker inter-halogen bond strength (Cl?Cl) exhibits an excellent thermal response, whereas the response is weaker in the iodo derivative with stronger I?I halogen bonding. 3,5-Di-chloro-salinazid (Compound-A) exists in three polymorphic forms, two room-temperature polymorphs (Forms I and II) and one high-temperature modification (Form III). The transformation of Form I to Form III upon heating at 328-333 K is a reversible thermosalient transition, whereas the transformation of Form II to Form III is irreversible and non-thermosalient. 3,5-Di-bromo- (Compound-B) and 3-bromo-5-chloro- (Compound-C) salinazid are both dimorphic: the Form I to Form II transition in Compound-B is irreversible, whereas Compound-C shows a reversible thermosalient effect (362-365 K). In the case of 3,5-di-iodo salinazid (Compound-D) and 3,5-di-fluoro-salinazid (Compound-E), no phase transitions or thermal effects were observed. The thermosalient behaviour of these halosalinazid molecular crystals is understood from the anisotropy in the cell parameters (an increase in the a axis and a decrease in the b and c axes upon heating) and the sudden release of accumulated strain during the phase transition. The di-halogen salinazid derivatives (chlorine to iodine) show a decrease in thermal effects with an increase in halogen-bond strength. Interestingly, Compound-B shows solid-state photochromism in its polymorphs along with the thermosalient effect, wherein Form I is cyan and Form II is light orange. PMID- 29123681 TI - Lifetimes and spatio-temporal response of protein crystals in intense X-ray microbeams. AB - Serial synchrotron-based crystallography using intense microfocused X-ray beams, fast-framing detectors and protein microcrystals held at 300 K promises to expand the range of accessible structural targets and to increase overall structure pipeline throughputs. To explore the nature and consequences of X-ray radiation damage under microbeam illumination, the time-, dose- and temperature-dependent evolution of crystal diffraction have been measured with maximum dose rates of 50 MGy s-1. At all temperatures and dose rates, the integrated diffraction intensity for a fixed crystal orientation shows non-exponential decays with dose. Non exponential decays are a consequence of non-uniform illumination and the resulting spatial evolution of diffracted intensity within the illuminated crystal volume. To quantify radiation-damage lifetimes and the damage state of diffracting crystal regions, a revised diffraction-weighted dose (DWD) is defined and it is shown that for Gaussian beams the DWD becomes nearly independent of actual dose at large doses. An apparent delayed onset of radiation damage seen in some intensity-dose curves is in fact a consequence of damage. Intensity fluctuations at high dose rates may arise from the impulsive release of gaseous damage products. Accounting for these effects, data collection at the highest dose rates increases crystal radiation lifetimes near 300 K (but not at 100 K) by a factor of ~1.5-2 compared with those observed at conventional dose rates. Improved quantification and modeling of the complex spatio-temporal evolution of protein microcrystal diffraction in intense microbeams will enable more efficient data collection, and will be essential in improving the accuracy of structure factors and structural models. PMID- 29123682 TI - Analysis of XFEL serial diffraction data from individual crystalline fibrils. AB - Serial diffraction data collected at the Linac Coherent Light Source from crystalline amyloid fibrils delivered in a liquid jet show that the fibrils are well oriented in the jet. At low fibril concentrations, diffraction patterns are recorded from single fibrils; these patterns are weak and contain only a few reflections. Methods are developed for determining the orientation of patterns in reciprocal space and merging them in three dimensions. This allows the individual structure amplitudes to be calculated, thus overcoming the limitations of orientation and cylindrical averaging in conventional fibre diffraction analysis. The advantages of this technique should allow structural studies of fibrous systems in biology that are inaccessible using existing techniques. PMID- 29123679 TI - Mix-and-diffuse serial synchrotron crystallography. AB - Unravelling the interaction of biological macromolecules with ligands and substrates at high spatial and temporal resolution remains a major challenge in structural biology. The development of serial crystallography methods at X-ray free-electron lasers and subsequently at synchrotron light sources allows new approaches to tackle this challenge. Here, a new polyimide tape drive designed for mix-and-diffuse serial crystallography experiments is reported. The structure of lysozyme bound by the competitive inhibitor chitotriose was determined using this device in combination with microfluidic mixers. The electron densities obtained from mixing times of 2 and 50 s show clear binding of chitotriose to the enzyme at a high level of detail. The success of this approach shows the potential for high-throughput drug screening and even structural enzymology on short timescales at bright synchrotron light sources. PMID- 29123685 TI - Leukocyte deformability is a novel biomarker to reflect sepsis-induced disseminated intravascular coagulation. AB - Aim: Sepsis-induced disseminated intravascular coagulopathy is associated with a high mortality rate. The function and deformability of polymorphonuclear leukocytes change in patients with sepsis. The goal of this study was to characterize the changes in polymorphonuclear leukocyte deformability in patients with sepsis-induced disseminated intravascular coagulopathy and to evaluate the relationship between the severity of disseminated intravascular coagulopathy and the deformability of polymorphonuclear leukocytes. Methods: Thirty-five patients with sepsis-induced disseminated intravascular coagulopathy at our department were enrolled in this study. These patients were diagnosed with severe sepsis and an acute disseminated intravascular coagulopathy score >= 4. Blood samples were obtained from these patients on days 1, 3, and 7. Polymorphonuclear leukocyte deformability was measured with a microchannel flow analyzer, and polymorphonuclear leukocyte activity, represented as CD11b, was measured by flow cytometry. In contrast, 14 patients who fulfilled with sepsis criteria but without complicated disseminated intravascular coagulopathy were also entered in this study. Results: In patients with sepsis-induced disseminated intravascular coagulopathy, there was a significant correlation between their Japanese Association for Acute Medicine disseminated intravascular coagulopathy score and polymorphonuclear leukocyte deformability, and CD11b expression. Polymorphonuclear leukocytes became more stiffened and CD11b expression was higher in patients with sepsis-induced disseminated intravascular coagulopathy compared to patients without the condition. Conclusion: Polymorphonuclear leukocyte deformability correlated with the severity of sepsis-induced disseminated intravascular coagulopathy and the response to treatment. PMID- 29123684 TI - Descending necrotizing mediastinitis: 5 years of published data in Japan. AB - Descending necrotizing mediastinitis implies infection originating from the neck, most commonly an oropharyngeal or odontogenic focus, that spreads in the cervical fascial spaces and descends into the mediastinum. Early diagnosis is essential because descending necrotizing mediastinitis can rapidly progress to septic shock and organ failure. A comprehensive review of the current data of descending necrotizing mediastinitis in Japan was carried out using PubMed and ICHUSHI from the last 5 years. The symptoms, origins, comorbid conditions, treatment modalities, complications, and survival rates were analyzed. Tonsillar and pharyngeal origin was more identified compared to odontogenic origin. More than one-third of patients were diabetic and 28% of them were not identified as having any comorbidity. Streptococcus sp. and anaerobes were most isolated, reflecting the microflora of the oral cavity. Of the broad antibiotics, carbapenem was the most used as treatment, and clindamycin was the most co-given. Mediastinal drainage approach varied widely and the optimal approach is controversial. Twenty one patients were treated with video-assisted thoracic surgical drainage and 15 cases by percutaneous catheter drainage, whereas transcervical approach was applied in 25 patients and thoracotomy was carried out in 21 patients. The overall mortality was 5.6%. Many authors advocated that the most effective management tool is a high degree of clinical suspicion followed by prompt and adequate drainage with intensive care including hemodynamic and nutritional support and repeat computer tomographic monitoring. PMID- 29123688 TI - Relationship between systolic blood pressures measured in emergency department and outcomes in patients with subarachnoid hemorrhage. AB - Aim: High blood pressure is observed frequently in patients with subarachnoid hemorrhage who present to the emergency department. Although extremely high blood pressure is known to predict poor outcomes in patients with spontaneous intracerebral hemorrhage, the relationship between high blood pressure and outcomes has been studied less frequently in patients with subarachnoid hemorrhage. Methods: A retrospective study was carried out to evaluate whether high blood pressure observed in the emergency department was predictive of poor outcomes in patients with subarachnoid hemorrhage. Three-hundred and twelve subarachnoid hemorrhage patients who were admitted to our institution were quadrichotomized based on their initial systolic blood pressure: <140 mmHg (n = 60), 140-184 mmHg (n = 144), 185-219 mmHg (n = 64), and >=220 mmHg (n = 44). Demographics including subarachnoid hemorrhage severity (World Federation of Neurosurgical Societies grade) and outcome variables evaluated with the modified Rankin scale 30 days after admission were compared among the four blood pressure groups. Furthermore, an effort was made to delineate a threshold value of systolic blood pressure predictive of outcomes by receiver operating characteristic curve analysis. Results: The frequency of grade V subarachnoid hemorrhage in the >=220 mmHg group (55%) was significantly higher than in the other three blood pressure groups. The frequency of patients scoring 5-6 on the modified Rankin scale in the >=220 mmHg group (54%) was significantly higher than in the other three blood pressure groups. The cut-off systolic blood pressure value predicting poor outcomes (modified Rankin scale 5-6) determined by receiver operating characteristic curve analysis was 189 mmHg. Conclusions: The higher proportion of grade V patients may be responsible for the worse outcomes in the group with systolic blood pressure >=220 mmHg. Initial systolic blood pressure >=220 mmHg may be a crude indicator of poor outcomes in patients with subarachnoid hemorrhage. PMID- 29123687 TI - Hypothermia does not hasten death during uncontrolled hemorrhagic shock presenting as the "triad of death" in rats. AB - Aim: The aim of this study was to investigate the effect of hypothermia on survival and coagulopathy in hemorrhagic shock presenting as the "triad of death". Methods: Sixteen rats were lightly anesthetized with halothane while maintaining spontaneous breathing. The triad of death was simulated by inducing hypothermia (32.0 degrees C) with surface body cooling and hemodilution with replacement of 20 mL blood with 50 mL normal saline. Then, rats were randomly assigned to one of two rectal temperature groups (n = 8/group: group 1, rewarming to 37.0 degrees C; group 2, maintenance at 32.0 degrees C) and subjected to hemorrhagic shock initiated by amputation of the tail at 75% of its length. The rats were then observed for survival time without fluid resuscitation. Blood coagulability with Sonoclot analysis was also assessed. Results: The triad of death status was considered as being induced at a rectal temperature of 32 degrees C, arterial pH of 7.22, and deteriorating coagulating values. At 45 min after randomization, Sonoclot analysis revealed prolonged activated clotting times of 355 +/- 131 s and "time to peak" of 23 +/- 9 min in group 2, compared to 228 +/- 64 s and 12 +/- 1 min (P < 0.05) in group 1, respectively. Kaplan-Meier curves showed longer survival in group 2 than group 1 (P = 0.06). Conclusions: Compared to rewarming, hypothermia aggravates coagulation parameters, but does not hasten death during untreated hemorrhagic shock presenting as the triad of death. PMID- 29123668 TI - NanoEHS beyond Toxicity - Focusing on Biocorona. AB - The first phase of environmental health and safety of nanomaterials (nanoEHS) studies has been mainly focused on evidence-based investigations that probe the impact of nanoparticles, nanomaterials and nano-enabled products on biological and ecological systems. The integration of multiple disciplines, including colloidal science, nanomaterial science, chemistry, toxicology/immunology and environmental science, is necessary to understand the implications of nanotechnology for both human health and the environment. While strides have been made in connecting the physicochemical properties of nanomaterials with their hazard potential in tiered models, fundamental understanding of nano-biomolecular interactions and their implications for nanoEHS is largely absent from the literature. Research on nano-biomolecular interactions within the context of natural systems not only provides important clues for deciphering nanotoxicity and nanoparticle-induced pathology, but also presents vast new opportunities for screening beneficial material properties and designing greener products from bottom up. This review highlights new opportunities concerning nano-biomolecular interactions beyond the scope of toxicity. PMID- 29123691 TI - Refractory status epilepticus, circulatory collapse after cardiac arrest, and acute respiratory distress syndrome caused by severe isolated fluvoxamine poisoning: a case report. AB - Case: A 30-year-old female ingested 21.75 g fluvoxamine in a suicide attempt. She presented with grand mal seizures and vomiting on admission to our Emergency Center, with a fluvoxamine serum concentration of 4.58 MUg/mL. The patient was diagnosed with status epilepticus, which could not be fully suppressed with the maximum dosage of benzodiazepines. The patient also developed circulatory collapse after resuscitation for sudden cardiac arrest and acute respiratory distress syndrome, believed to be secondary to aspiration. Outcome: With venoarterial extracorporeal membrane oxygenation, a massive infusion of propofol successfully suppressed status epilepticus, and both the circulatory collapse and acute respiratory distress syndrome gradually improved; venoarterial extracorporeal membrane oxygenation and propofol treatments were then terminated, and the patient was discharged without further disabilities. Conclusion: Compared to all other reported clinical cases of fluvoxamine poisoning, the patient in this study ingested the highest dose and developed the most severe symptoms, but was successfully treated without any disabilities. PMID- 29123693 TI - An unexpected prolonged coma due to a pharmacobezoar formed from Vegetamine A(r) tablet ingestion. AB - Case: A 49-year-old man ingested massive quantities of Vegetamine A(r) tablets that contain two anticholinergic agents in addition to phenobarbital. The patient remained in an unexpectedly prolonged coma 4 days post-hospitalization. An acute gastroscopy revealed a pinkish-white pharmacobezoar on the lesser curvature of the stomach, which was extracted using a net. Direct hemoperfusion and treatment with multiple-dose activated charcoal was then initiated. Phenobarbital serum concentrations eventually decreased, resulting in complete recovery of the patient. Outcome: On day 30, the patient was transferred to the Psychiatric Department. Conclusion: An intragastric pharmacobezoar should be suspected in patients with promoted and prolonged toxicity or if high serum concentrations of agents indicate their continuous absorption. PMID- 29123694 TI - Lemierre syndrome involving external jugular vein. AB - Case: A 74-year-old woman with a week-long history of cold symptoms was diagnosed with Lemierre syndrome that involved her left external jugular vein. Outcome: The patient was successfully treated with 4 weeks of antibiotics and anticoagulant treatment. Typical cases of Lemierre syndrome involve only the internal jugular vein. The external jugular vein is anatomically distant from the pharyngolaryngeal space and usually does not receive blood or lymphatic flow from there. Thus, Lemierre syndrome ordinarily does not involve the external jugular vein and clinical characteristics of external jugular vein-involving Lemierre syndrome have not been uncovered, mainly due to its rarity. Based on our review, it would not much differ from those of typical cases. Conclusion: Considering the potential severity and mortality, more attention should be paid to this potentially fatal disease that may demonstrate atypical manifestation, as shown in this case. Accumulation of cases would be needed for further understanding. PMID- 29123690 TI - Portable system for monitoring of regional cerebral oxygen saturation during prehospital cardiopulmonary resuscitation: a pilot study. AB - Aim: We aimed to create a system for monitoring of regional cerebral oxygen saturation (rSO 2) in patients with prehospital cardiopulmonary arrest and clarify the changes in rSO 2 during cardiopulmonary resuscitation. Methods: We measured rSO 2 in cardiopulmonary arrest patients who were transferred by the emergency response vehicle of Nagasaki University Hospital. We developed a portable rSO 2 monitor (HAND ai TOS), which is small enough to carry during prehospital treatment. The sensor is attached to the forehead of the patient and monitors rSO 2 continuously during treatment and transfer. Results: No difficulties were experienced in monitoring rSO 2 during patient treatment and transfer. Median time (interquartile range) from the emergency medical service call to emergency response vehicle arrival was 15.0 min (11.0-19.5 min). Median rSO 2 on emergency response vehicle arrival at the scene was 46.3% (44.0-48.2%) (n = 9; median age, 74.0 years; four men, five women). Median rSO 2 showed significant increase within 5 min after return of spontaneous circulation (n = 6, 46.6% versus 58.7%, P < 0.05). There was no significant increase in rSO 2 during prehospital cardiopulmonary resuscitation until return of spontaneous circulation was established. Conclusions: We developed an rSO 2 monitoring system for use during prehospital cardiopulmonary resuscitation. The monitoring system showed a significant increase in rSO 2 after return of spontaneous circulation, whereas there was no significant increase in rSO 2 during cardiopulmonary resuscitation after intubation but before return of spontaneous circulation. PMID- 29123689 TI - Vasodilating prostaglandin E1 does not reproduce interleukin-1beta-induced oxygen metabolism abnormalities in rabbits. AB - Background: We have reported that administration of recombinant human interleukin (IL)-1beta induced circulatory shock in rabbits by causing overproduction of vasodilating prostaglandin(s) and simultaneously impaired oxygen metabolism by causing an abnormal dependence of oxygen consumption (VO2) on oxygen delivery (DO2). The present study was carried out to compare the effect of administration of exogenous PGE1 with that of IL-1beta on oxygen metabolism. Methods: Sixteen rabbits were assigned to one of three groups and given a single injection of 10 MUg/kg IL-1beta (IL-1beta group, n = 5), continuous infusion of 1 MUg/kg/min PGE1 (PGE1 group, n = 6), or saline (control group, n = 5). All rabbits were subjected to stepwise cardiac tamponade to decrease DO2 by inflating a balloon placed into the pericardial sac. The VO2/DO2 relation was analyzed by the dual-line method. Results: Both IL-1beta and PGE1 decreased the baseline value of mean arterial pressure by approximately 25% without inducing significant alteration of the cardiac index. With respect to the VO2/DO2 relation, the slope of the supply independent line was significantly increased in the IL-1beta group (y = 0.13x + 6.4), but not in the PGE1 group (y = 0.01x + 10.0) compared to that in the control group (y = 0.05x + 8.7). Conclusion: These results indicate that simple vasodilation and hypotension induced by administration of PGE1 are insufficient to account for the abnormal oxygen metabolism induced by IL-1beta. PMID- 29123686 TI - Impact of serum glucose levels on disease severity and outcome in patients with severe sepsis: an analysis from a multicenter, prospective survey of severe sepsis. AB - Aim: To determine whether glycemic abnormality and pre-existing diabetes are associated with disease severity and mortality in patients with severe sepsis. Methods: Six hundred and nineteen patients with severe sepsis were grouped into four categories according to their blood glucose levels (<100, 100-199, 200-299, and >=300 mg/dL). We compared disease severity and mortality between glycemic categories. In addition, we examined whether there was any relationship with pre existing diabetes status. Results: There were no significant differences in disseminated intravascular coagulation, Sequential Organ Failure Assessment, or Acute Physiology and Chronic Health Evaluation II scores and mortality rates between patients with or without pre-existing diabetes. However, in patients without pre-existing diabetes, those with blood glucose level <100 mg/dL had higher disseminated intravascular coagulation, Sequential Organ Failure Assessment, and Acute Physiology and Chronic Health Evaluation II scores than those with levels of 100-299 mg/dL. In addition, those with level >=300 mg/dL had a higher hospital mortality rate than those with levels of 100-199 mg/dL (odds ratio = 4.837). Multivariate logistic regression analysis revealed that a blood glucose level >=300 mg/dL is an independent predictor of hospital mortality in these patients. In contrast, no significant differences among severity scores or mortality were observed in patients with pre-existing diabetes. Conclusions: In patients with severe sepsis, the impact of glycemic abnormality on disease severity and hospital mortality depends on the pre-existing diabetes status. Specifically, a blood glucose level >=300 mg/dL may be associated with increased mortality in patients without pre-existing diabetes. PMID- 29123697 TI - What constitutes the wealth of an academic field?: ~ Ease in obtaining information and rich exchange of knowledge ~. PMID- 29123695 TI - Hemostasis with emergently modified application of intra-aortic balloon occlusion in a patient with impending cardiac arrest following blunt proximal thigh amputation. AB - Case: A 30-year-old woman had her left thigh run over by a train. We tried to compress the left femoral area to control the arterial bleeding, but bleeding continued from the stump and injured soft tissue. The application of a tourniquet bandage also failed because of the limited remaining thigh. She developed impending cardiac arrest. As the left femoral arterial pulsation was still palpable, we inserted an intra-aortic balloon occlusion catheter percutaneously. The hemorrhage from the stump region decreased rapidly. She was transferred to an operating room to carry out surgical hemostasis, and it was confirmed with deflation of the balloon in the common iliac artery. Outcome: There was no complication of the skin or soft tissue at the surgical site caused by impaired circulation, and her consciousness fully recovered. Conclusion: We report the successful control of bleeding by the emergently modified application of intra aortic balloon occlusion in the left common iliac artery. PMID- 29123696 TI - Ambulance transfer of extremely old patients in Nagoya, Japan. PMID- 29123692 TI - Anti-NMDAR encephalitis: case report and diagnostic issues. AB - Case: A 20-year-old woman developed acute psychotic symptoms and altered level of consciousness. She presented with neck stiffness, tremulous arms, facial dyskinesia, and distension of the lower abdomen. Pelvic magnetic resonance imaging showed bilateral ovarian teratomas. Anti-N-methyl-D-aspartate receptor antibodies were detected in her cerebrospinal fluid. Outcome: Resection of the tumors and immunotherapy were carried out. She gradually recovered and was discharged with few neurological deficits on the 105th day of hospitalization. Conclusion: Our survey of 63 previous reports describing 92 cases revealed that 21.7% of the patients were sent to emergency departments and 59.8% of the patients were managed in intensive care units. Emergency physicians and intensivists should be aware of this disorder, as they may encounter undiagnosed disorders in patients with epileptic attacks, acute psychotic signs, dyskinesia, or hypoventilation in the course of the illness. PMID- 29123701 TI - Independent risk factors for a complicated hospital course in intensive care unit overdose patients. AB - Aim: The purpose of the present study was to identify risk factors associated with a complicated hospital course in overdose patients admitted to the intensive care unit. Methods: A total of 335 overdose patients were retrospectively studied in the surgical and medical intensive care unit of an academic tertiary hospital. Factors possibly associated with a complicated hospital course were evaluated. Complicated hospital course was defined as the occurrence of pneumonia, rhabdomyolysis, decubitus ulcer, nerve palsy, prolonged intubation, prolonged hospitalization, or death. Results: Of the 335 overdose patients, 93 (27.8%) had a complicated hospital course. Complicated hospital course was found to be associated with a high number of ingested pills (median, 135 [interquartile range, 78-240] versus 84 [53-134] tablets, P < 0.0001), low Glasgow Coma Scale score on admission (7 [3-11] versus 13 [8-15], P < 0.0001), and a high serum lactate level on admission (1.8 [1.0-3.0] versus 1.4 [0.9-2.0] mg/dL, P < 0.01) on univariate analysis of these factors in patients with and without a complicated hospital course. The independent risk factors for a complicated hospital course identified on multivariate analysis were a high number of ingested pills (>=100 tablets), low admission Glasgow Coma Scale score (<9), and high serum lactate on admission (>=2.0 mg/dL). The probability of a complicated hospital course for patients with 0, 1, 2, or all 3 independent risk factors were 7%, 22%, 40%, and 81%, respectively. Conclusion: The total number of ingested pills, admission Glasgow Coma Scale score, and serum lactate level on admission are predictive of a complicated hospital course in overdose patients admitted to the intensive care unit. PMID- 29123702 TI - Effects of obligatory training and prior training experience on attitudes towards performing basic life support: a questionnaire survey. AB - Aim: To determine the effect of Japanese obligatory basic life support training for new driver's license applicants on their willingness to carry out basic life support. Methods: We distributed a questionnaire to 9,807 participants of basic life support courses in authorized driving schools from May 2007 to April 2008 after the release of the 2006 Japanese guidelines. The questionnaire explored the participants' willingness to perform basic life support in four hypothetical scenarios: cardiopulmonary resuscitation on one's own initiative; compression only cardiopulmonary resuscitation following telephone cardiopulmonary resuscitation; early emergency call; and use of an automated external defibrillator. The questionnaire was given at the beginning of the basic life support course in the first 6-month term and at the end in the second 6-month term. Results: The 9,011 fully completed answer sheets were analyzed. The training significantly increased the proportion of respondents willing to use an automated external defibrillator and to perform cardiopulmonary resuscitation on their own initiative in those with and without prior basic life support training experience. It significantly increased the proportion of respondents willing to carry out favorable actions in all four scenarios. In multiple logistic regression analysis, basic life support training and prior training experiences within 3 years were associated with the attitude. The analysis of reasons for unwillingness suggested that the training reduced the lack of confidence in their skill but did not attenuate the lack of confidence in detection of arrest or clinical judgment to initiate a basic life support action. Conclusions: Obligatory basic life support training should be carried out periodically and modified to ensure that participants gain confidence in judging and detecting cardiac arrest. PMID- 29123703 TI - Calcium channel blocker attenuated opioid withdrawal syndrome. AB - Case: A 61-year-old woman was diagnosed with deep cervical abscess and enlarged mediastinal abscess. These required a protracted period of mechanical ventilation and neck and thoracic drainage surgery with daily wound lavage, necessitating the administration of large amounts of fentanyl and dexmedetomidine. After extubation, fentanyl was discontinued but dexmedetomidine was continued, and she developed hypertension, tachycardia, tachypnea, and hyperthermia within several hours; therefore, she was diagnosed with opioid withdrawal syndrome. Her symptoms failed to improve with either an increased dexmedetomidine dose or a diltiazem infusion for symptomatic management. Ultimately, 20 mg nifedipine was given through a nasogastric tube, which led to a resolution of withdrawal symptoms. Outcome: This is the first case of calcium channel blockers attenuating opioid withdrawal syndrome symptoms in a human. Conclusion: Calcium channel blockers might be alternative therapy to refractory opioid withdrawal syndrome. Case accumulation in the future is expected. PMID- 29123704 TI - Severe hypothermia secondary to spinal cord injury without radiographic abnormality. AB - Case: A 64-year-old female was found lying by a river. She was unconscious and her lower body was under water. The patient was transported to the emergency room of our hospital. On arrival, her rectal temperature was 24.6 degrees C. We immediately started rewarming and artificial respiration. Five days after admission, rewarming was completed and she became conscious and could communicate. Initially, she had been injured and examination showed paraplegia. Magnetic resonance imaging of her cervical spine showed no findings indicating bony or ligament injury, but there was a T2 high intensity area at C5/6 and C6/7 levels. The patient was diagnosed with spinal cord injury without radiological abnormality. Outcome: At 5 months post-injury, the patient was able to walk without crutches. Conclusion: Spinal cord injury might be missed if there are no radiographic abnormalities. Spinal cord injury without radiological abnormality should be considered as a differential diagnosis of accidental hypothermia. PMID- 29123700 TI - Effects of the elective introduction of extracorporeal membrane oxygenation on outcomes in pediatric myocarditis cases. AB - Aim: To investigate the necessary indicators to diagnose pediatric myocarditis and choose appropriate candidates for extracorporeal membrane oxygenation therapy. Methods: We retrospectively reviewed the medical records of children aged <16 years of age who were diagnosed with myocarditis and admitted to the pediatric intensive care unit in a Japanese children's hospital from 2002 to 2013. We collected demographic data and symptoms and signs during the entire clinical course, investigated the survival and neurological outcomes, and identified the predictors of death. Results: Twenty-nine patients (median age, 5 years) met the inclusion criteria. Fever and gastrointestinal symptoms occurred in approximately 80% of the patients as initial symptoms and central nervous system symptoms were the most frequent symptom on emergency presentation (41%). Extracorporeal membrane oxygenation was administered to 16 patients; of these, five died. Of the 24 surviving patients, 23 achieved favorable neurological outcomes. Four of eight patients died following cardiopulmonary resuscitation triggered extracorporeal membrane oxygenation, and one of eight died following elective extracorporeal membrane oxygenation. Multivariate analysis using stepwise logistic regression analysis revealed creatinine level as an independent predictor of death. Conclusion: It is important to consider myocarditis when evaluating children with gastrointestinal or central nervous system symptoms. The elective introduction of extracorporeal membrane oxygenation before the completion of end-organ dysfunction has a positive effect on outcomes in pediatric myocarditis cases. Transfer to an institution that can initiate extracorporeal membrane oxygenation support should be promptly considered when managing pediatric myocarditis. PMID- 29123705 TI - Treatment of lethal acetylsalicylic acid poisoning without hemodialysis. AB - Case: A woman aged in her 20s ingested approximately 99 g acetylsalicylic acid, and was transported to our hospital 2 h later. She was lucid, but complained of hearing loss and tinnitus. We performed gastric lavage and gave her activated charcoal several times. We attempted to maintain the urinary pH at 7.5 and output above 100 mL/h while preparing for urgent hemodialysis. Outcome: It was revealed after discharge that the blood concentration of acetylsalicylic acid was 103.8 mg/dL on admission (lethal dose level) and had decreased to 35.4 mg/dL by the next morning. The half-life was 8.5 h. Conclusion: Hemodialysis is strongly recommended for patients who take a lethal dose of acetylsalicylic acid. However, by carefully evaluating the vital signs and urinary output and pH, while preparing for emergency hemodialysis, we consider that it is possible to treat acetylsalicylic acid poisoning by alkaline diuresis and critical supportive care. PMID- 29123698 TI - Determination of beta-d-glucan and endotoxin levels in Kampo extracts. AB - Aims: Kampo medicine is based on the use of established formulations combining natural extracts with no "brand-name" products or corresponding "generic" formulation. Due to differences in manufacturing practices, products of different pharmaceutical companies may contain different concentrations of beta-d-glucan and endotoxins. The aim of this study was to compare the concentrations of beta-d glucan and endotoxins in five Kampo extracts from four pharmaceutical companies. Methods: Packages of Kampo extracts were dissolved in distilled water. beta-d Glucan and endotoxin concentrations were measured using high-sensitivity kinetic turbidimetric Limulus assay. Results: All Kampo extracts examined in this study were found to contain detectable concentrations of beta-d-glucan and endotoxins. Significant differences in the concentration of beta-d-glucan and endotoxins (P = 0.0024 and P = 0.0013, respectively) were observed between products of different pharmaceutical companies. Conclusions: High beta-d-glucan and endotoxin contents were detected in Kampo extracts, with a large variability in the concentrations of both beta-d-glucan and endotoxins among extracts from different pharmaceutical companies. PMID- 29123699 TI - A simple predictive formula for the blood requirement in patients with high energy blunt injuries transferred within one hour post-trauma. AB - Aims: To recognize patients who require massive transfusion at the early stage of blunt trauma, we retrospectively investigated patients with high-energy blunt injuries transferred within 1 h post-trauma. Methods: Between August 2007 and July 2011, 233 trauma patients were: (i) injured by a high-energy blunt mechanism with Injury Severity Score >=9; (ii) not dead on arrival; (iii) older than 9 years; and (iv) at our center within 1 h after injury. The findings for 113 of those patients were analyzed, including those produced by ultrasonography, computed tomography, and arterial blood gas analyses. Results: Of 113 patients, 33 underwent massive transfusion (>=6 units) within 8 h of arrival. A logistic regression analysis revealed that an arterial lactate level >=28 mg/dL (P < 0.001; odds ratio, 105.11; 95% confidence interval, 12.58-2,718.84) and a flat ratio of the inferior vena cava on computed tomography >=3 (P < 0.001; odds ratio, 32.50; 95% confidence interval, 4.44-714.44) were significant independent predictors for a massive transfusion within 8 h. In a receiver operating curve analysis, the area under the curve of the need for massive transfusion was 0.956, with a sensitivity of 0.94 and a specificity of 0.90. A linear predictive formula for the probability (P) of receiving a massive transfusion was generated as P = 2 * lactate (mg/dL) + 15 * the flat ratio of inferior vena cava - 103. Using another 52 trauma patients, the formula was validated. Conclusions: An elevated level of arterial lactate and the flat ratio of inferior vena cava were significant predictors for identifying the patients who would require a massive transfusion in the early stage after high-energy blunt trauma. PMID- 29123706 TI - Potentially fatal coagulopathy secondary to yamakagashi (Rhabdophis tigrinus) bites that completely recovered with antivenom treatment. AB - Case: A healthy 40-year-old man was admitted with severe coagulopathy that developed after Rhabdophis tigrinus bites. On admission, he showed significantly elevated levels of thrombin-antithrombin III complex (60 ng/mL), plasmin-alpha 2 plasmin inhibitor complex (22.3 MUg/mL), and fibrinogen degradation products (592 MUg/mL). He subsequently developed severe hypofibrinogenemia (50 mg/dL). Outcome: Antivenom was given 28 h after the patient was bitten, following which his hemorrhagic symptoms resolved. By day 3 of admission, scabs had formed over the bite wounds. Furthermore, his fibrinogen levels increased to >100 mg/dL, while his thrombin-antithrombin III complex, plasmin-alpha 2-plasmin inhibitor complex, and fibrinogen degradation product levels normalized. He was discharged on day 6 of admission. Conclusion: Rhabdophis tigrinus bites induced disseminated intravascular coagulation with a fibrinolytic phenotype, which completely recovered with antivenom treatment. PMID- 29123707 TI - Traumatic vertebral artery dissection and cerebral infarction following head and neck injury with a lucid interval. AB - Cases: Two patients with cerebral infarction following head and neck injury who showed a lucid interval are presented. Outcome: A 70-year-old male showed infarctions in the cerebellum bilaterally and the right hypothalamus on the sixth day after an injury with no fracture of the cervical spine, and bilateral dissection of the vertebral arteries was diagnosed. A 74-year-old male showed infarctions in the territory of the right posterior cerebral artery and posterior inferior cerebellar artery 2 days after injury with fractures of the cervical spine (C2 and C3) and was diagnosed as having artery-to-artery embolism based on dissection of the right vertebral artery. Conclusion: Head and neck injury is a very common presentation in the emergency department. Three-dimensional computed tomography angiography is an effective screening imaging method for vertebral artery dissection that should be carried out on arrival in every patient with fracture of the cervical spine, and even considered in doubtful cases with no fracture. PMID- 29123708 TI - Delayed visceral ischemia induced by type B aortic dissection. AB - Case: A 56-year-old man presented with a sudden severe abdominal pain 13 days after the onset of type B acute aortic dissection. Chest computed tomography revealed type B aortic dissection, and the true lumen was narrowed by the expanding false lumen. Blood flow through the celiac trunk, superior mesenteric artery, and left renal artery was reduced. Blood flow through the distal abdominal aorta and bilateral femoral arteries was clearly recognized. Laboratory findings such as transaminases were rapidly worsening. Outcome: The patient underwent emergency fenestration of the abdominal aorta and recovered without organ failure. Conclusions: Rapidly worsening laboratory findings led us to emergency operation with successful results. Serial monitoring of laboratory findings is the key for adequate timing of operation. PMID- 29123709 TI - Comparison of positional shift of supraglottic devices resulting from chest compressions: simulation using a manikin and automated chest compression system. AB - Background: The American Heart Association 2010 Guidelines for Resuscitation suggest the use of supraglottic devices as an alternative to tracheal intubation during cardiopulmonary resuscitation. This study aimed to evaluate supraglottic device displacement and the effect of tape fixation by simulation with a manikin and automated chest compression system. Methods: We placed eight supraglottic devices (ProSeal, i-gel, Classic, Soft Seal, Fastrack, Supreme, Ambu-aura-i, air Q) into an advanced life support simulator, and compared no fixation and Durapore tape fixation conditions. After 5 min of automated chest compressions, positional shift of the supraglottic devices was measured. A total of five trials were carried out in each setting. Statistical analysis was carried out with two-way repeated measures anova. P < 0.05 was considered significant. Results: Positional shift after 5 min of chest compressions were as follows: ProSeal, 0.68 +/- 0.26 cm; i-gel, 0.50 +/- 0.16 cm; Classic, 0.36 +/- 0.15 cm; Soft Seal, 0.32 +/- 0.08 cm; Fastrack, 0.20 +/- 0.07 cm; Supreme, 0.20 +/- 0.07 cm; Ambu-aura-i, 0.18 +/- 0.08 cm; and air-Q, 0.12 +/- 0.04 cm. Positional shift was larger with the ProSeal and i-gel compared with any of the other six supraglottic devices (P < 0.05). Conversely, positional shift was significantly smaller with the air-Q than the other supraglottic devices (P < 0.05). Tape fixation reduced positional shift for all supraglottic devices, with a significant reduction observed with ProSeal, i-gel, Classic, and Soft Seal. Conclusion: Simulation analysis revealed that positional shift of air-Q by chest compressions is smaller than those of seven other supraglottic devices. PMID- 29123711 TI - Evaluation of an alternative chest compression technique: a manikin study. PMID- 29123710 TI - Comparison of the conventional Macintosh laryngoscope, the Pentax Airwayscope, and the McGrath MAC video laryngoscope under restricted cervical motion: a manikin study. AB - Aim: We compared the utility of the conventional Macintosh laryngoscope, the Pentax Airway Scope, and the McGrath MAC video laryngoscope under restricted cervical motion using a manikin. Methods: We recruited 36 participants into the simulation study. The manikin's cervical motion was restricted with a cervical collar and a head immobilizer, as occurs in trauma cases. We recorded the time to intubation and the success rate of the intubations. Results: Data are medians and ranges. The time to intubation under normal and restricted cervical motion were 22.5 (10-78) and 23 (9-119) s with the Macintosh laryngoscope, 13.5 (5-50) and 14 (7-119) s with the Airway Scope, and 13 (6-32) and 18 (7-80) s with the McGrath MAC video laryngoscope. The differences in the time to intubation between normal and restricted cervical motion were significant only with the McGrath MAC (P = 0.0008). With restricted cervical motion, the times to intubation in the Airway Scope attempts were significantly shorter than those in the Macintosh laryngoscope (P = 0.0005) and McGrath MAC (P = 0.0282) attempts. The success rates under normal and restricted cervical motion were 100% and 80.6% with the Macintosh laryngoscope (P = 0.0054), 100% and 100% with the Airway Scope, and 100% and 97.2% with the McGrath MAC, respectively. Conclusion: In the present study, the Airway Scope was the best among the three devices. However, the differences between the Airway Scope and the McGrath MAC video laryngoscope may not be serious in a clinical situation. Data were gathered using a manikin, and further studies will be necessary. PMID- 29123712 TI - Swallow syncope. PMID- 29123713 TI - Acute and emergency care for thyrotoxicosis and thyroid storm. AB - Thyroid hormones affect all organ systems and, in excess, can cause increased metabolic rate, heart rate, ventricle contractility, and gastrointestinal motility as well as muscle and central nervous system excitability. Thyroid storm is the extreme manifestation of thyrotoxicosis with an estimated incidence of 0.20 per 100,000 per year among hospitalized patients in Japan. The mortality of thyroid storm without treatment ranges from 80% to 100%; but with treatment, the mortality rate is between 10% and 50%. The diagnostic strategy for thyroid storm may take into consideration Burch-Wartofsky scoring or Akamizu's diagnostic criteria. Multiple treatment aims need to be addressed in managing thyroid storm effectively. This paper puts together all aspects to be considered for the management of hyperthyroidism and thyroid storm during the acute and emergency phase as well as consideration of special populations. PMID- 29123714 TI - Model for predicting the injury severity score. AB - Aim: To determine the formula that predicts the injury severity score from parameters that are obtained in the emergency department at arrival. Methods: We reviewed the medical records of trauma patients who were transferred to the emergency department of Gunma University Hospital between January 2010 and December 2010. The injury severity score, age, mean blood pressure, heart rate, Glasgow coma scale, hemoglobin, hematocrit, red blood cell count, platelet count, fibrinogen, international normalized ratio of prothrombin time, activated partial thromboplastin time, and fibrin degradation products, were examined in those patients on arrival. To determine the formula that predicts the injury severity score, multiple linear regression analysis was carried out. The injury severity score was set as the dependent variable, and the other parameters were set as candidate objective variables. IBM spss Statistics 20 was used for the statistical analysis. Statistical significance was set at P < 0.05. To select objective variables, the stepwise method was used. Results: A total of 122 patients were included in this study. The formula for predicting the injury severity score (ISS) was as follows: ISS = 13.252-0.078(mean blood pressure) + 0.12(fibrin degradation products). The P-value of this formula from analysis of variance was <0.001, and the multiple correlation coefficient (R) was 0.739 (R2 = 0.546). The multiple correlation coefficient adjusted for the degrees of freedom was 0.538. The Durbin-Watson ratio was 2.200. Conclusions: A formula for predicting the injury severity score in trauma patients was developed with ordinary parameters such as fibrin degradation products and mean blood pressure. This formula is useful because we can predict the injury severity score easily in the emergency department. PMID- 29123715 TI - Oxidative stress and heart rate variability in patients with vertigo. AB - Aims: Peripheral vertigo has been reported to result from oxidative stress or autonomic nervous dysfunction. Recently, heart rate variability has been used to evaluate autonomic nervous activity. Parasympathetic nervous dysfunction is associated with peripheral vertigo; however, the relationships between vertigo, oxidative stress, and autonomic nervous activity have not been investigated. The aim of this study was to elucidate the changes in oxidative stress and autonomic nervous activity in vertigo patients compared with healthy volunteers. Methods: Oxidative stress was assessed by evaluating biological antioxidant potential and reactive oxygen metabolites, and heart rate variability was measured to evaluate autonomic nervous activity. Thirty-four patients who complained of peripheral vertigo and were treated in our emergency department between January and August 2011 were enrolled in study 1. Oxidative stress and heart rate variability were measured and compared with those of healthy volunteers (n = 23). In study 2, oxidative stress in 18 vertigo patients and heart rate variability in 41 vertigo patients were measured between January and August 2012 before and after conventional treatment of vertigo to evaluate the effect of the treatment on oxidative stress and autonomic nervous activity. Results: Reactive oxygen metabolites were higher in vertigo patients than in healthy volunteers. Parasympathetic nervous activity was lower and the sympathetic/parasympathetic nervous activity ratio (autonomic nervous activity ratio) was higher in vertigo patients than in healthy volunteers. After treatment of vertigo, reactive oxygen metabolites decreased significantly and the autonomic nervous activity ratio became similar to that observed in healthy volunteers. Conclusions: Bedside monitoring of oxidative stress and heart rate variability may be useful for the diagnosis of vertigo and evaluation of the effect of treatment. PMID- 29123716 TI - Calcium-overloaded sympathetic preganglionic neurons in a case of severe sepsis with anorexia nervosa. AB - Aim: We aimed to show the status of intracellular elements in sympathetic preganglionic neurons in an autopsy case of a 55-year-old woman with severe sepsis and cardiac dysfunction with anorexia nervosa. Methods: Our methods include a case report and pathological examinations of autopsied tissues using synchrotron-generated microbeam X-ray fluorescence analysis. Results: A case report of severe sepsis and myocardial dysfunction. The patient had sudden short cardiac arrest without arrhythmia and sequelae, and echocardiogram showed negative inotropic change. The X-ray fluorescence analysis of autopsied tissues indicated an unusually high concentration of cytosolic calcium in sympathetic preganglionic neurons. However, there were no significant pathological findings of damage in the heart or the cardiovascular autonomic nuclei in the central nervous system. Conclusion: The data indicate that dysfunction of the sympathetic preganglionic neurons exists in a patient of severe sepsis and cardiac dysfunction with anorexia nervosa. PMID- 29123717 TI - Development of a prompt model for predicting neurological outcomes in patients with return of spontaneous circulation from out-of-hospital cardiac arrest. AB - Aim: Early prediction of the neurological outcomes of patients with out-of hospital cardiac arrest is important to select the optimal clinical management. We hypothesized that clinical data recorded at the site of cardiopulmonary resuscitation would be clinically useful. Methods: This retrospective cohort study included patients with return of spontaneous circulation after cardiopulmonary resuscitation who were admitted to our university hospital between January 2000 and November 2013 or two affiliated hospitals between January 2006 and November 2013. Clinical parameters recorded on arrival included age (A), arterial blood pH (B), time from cardiopulmonary resuscitation to return of spontaneous circulation (C), pupil diameter (D), and initial rhythm (E). Glasgow Outcome Scale was recorded at 6 months and a favorable neurological outcome was defined as a score of 4-5 on the Glasgow Outcome Scale. Multiple logistic regression analysis was carried out to derive a formula to predict neurological outcomes based on basic clinical parameters. Results: The regression equation was derived using a teaching dataset (total, n = 477; favourable outcome, n = 55): EP = 1/(1 + e-x ), where EP is the estimated probability of having a favorable outcome, and x = (-0.023 * A) + (3.296 * B) - (0.070 * C) - (1.006 * D) + (2.426 * E) - 19.489. The sensitivity, specificity, and accuracy were 80%, 92%, and 90%, respectively, for the validation dataset (total, n = 201; favourable outcome, n = 25). Conclusion: The 6-month neurological outcomes can be predicted in patients resuscitated from out-of-hospital cardiac arrest using clinical parameters that can be easily recorded at the site of cardiopulmonary resuscitation. PMID- 29123719 TI - Predictors of prolonged laparoscopic cholecystectomy in the treatment of low grade acute cholecystitis: a single-center, retrospective, observational study. AB - Aim: Laparoscopic cholecystectomy is frequently used to treat low-grade acute cholecystitis. Improvements in technical skills have reduced the rate of conversion from laparoscopic to open surgery. In this study, we sought to identify factors that might predict the surgical time of laparoscopic cholecystectomy as possible markers for surgical difficulty. Methods: We carried out a single-center retrospective analysis of a Japanese medical insurance database. Data were retrieved for 87 patients with acute cholecystitis. The analyzed factors included age, sex, body mass index, medical history, blood laboratory data, computed tomography findings, and time from disease onset to surgery. Multiple regression analysis was used to identify factors associated with surgical time. Results: Edema of the gallbladder wall on computed tomography, neutrophil sequestration, body mass index, and history of acute cholangitis were significantly associated with surgical time (P = 0.014, 0.027, 0.043, and 0.047, respectively). The conversion rate from laparoscopic surgery to open surgery was 2%. Conclusions: Our results suggest that edema of the gallbladder wall on computed tomography, neutrophil sequestration, body mass index, and history of acute cholangitis are associated with surgical time of laparoscopic cholecystectomy in the treatment of acute cholecystitis in our hospital. PMID- 29123718 TI - Factors affecting layperson confidence in performing resuscitation of out-of hospital cardiac arrest patients in Japan. AB - Aim: Bystander cardiopulmonary resuscitation including automated external defibrillator use increases the chance of survival after out-of-hospital cardiac arrest. However, bystanders may be distressed by witnessing out-of-hospital cardiac arrest and may hesitate to initiate cardiopulmonary resuscitation. The present study examined factors associated with layperson confidence in carrying out resuscitation of out-of-hospital cardiac arrest patients. Methods: We carried out a cross-sectional survey in February 2012. Laypeople were asked about background characteristics, whether they had performed cardiopulmonary resuscitation, had received cardiopulmonary resuscitation training, were aware of the location of the neighborhood automated external defibrillator, and felt confident in performing resuscitation, and their potential emotional distress if a resuscitation attempt were to prove unsuccessful. Results: Participants comprised 4,853 respondents. Of these, 2,372 (49%) had received cardiopulmonary resuscitation training, and 3,607 (74%) knew where the neighborhood automated external defibrillator was located. Confidence in performing chest compressions was reported by 2,667 (55%), confidence in performing rescue breathing by 2,498 (52%), and confidence in using an automated external defibrillator by 2,822 (58%). Potential emotional distress if a resuscitation attempt proved unsuccessful was reported by 4,247 (88%). Multivariate regression analysis showed that having carried out cardiopulmonary resuscitation, having received cardiopulmonary resuscitation training, and awareness of the neighborhood automated external defibrillator location were significantly associated with confidence in performing cardiopulmonary resuscitation. Conclusions: Our results suggest that more extensive cardiopulmonary resuscitation training and information regarding neighborhood automated external defibrillator locations may increase layperson confidence in initiating resuscitation. PMID- 29123720 TI - Press-through package mis-swallowing: Usefulness of computed tomography. AB - Case: An 88-year-old female with Alzheimer's-type dementia who mis-swallowed a press-through package visited our emergency department. Outcome: Plain radiography detected no foreign bodies, whereas plain computed tomography showed an elliptical body with a high density in the lower esophagus. The press-through package containing a tablet in the esophagogastric junction was successfully removed without severe complications using the endoscopic protector hood. In cases of press-through package mis-swallowing, it is important for emergency physicians to make an early and correct diagnosis of the location of the package, which shows high radiolucency. Based on the results of this case, we hypothesize that carrying out early computed tomography examinations is useful for identifying swallowed press-through packages. Our retrospective investigation showed that computed tomography has a sensitivity of 100% for detecting press through packages. Conclusion: We experienced a case of press-through package mis swallowing diagnosed on computed tomography. We recommend performing computed tomography examinations, especially in patients with an uncertain history and unclear symptoms. PMID- 29123721 TI - Acute calcific prevertebral tendinitis: rare cause of neck pain. AB - Case: We report a case of acute calcific prevertebral tendinitis and discuss the clinical signs, symptoms, and radiologic findings of the disease. Outcome: This 47-year-old man suffered from neck pain, odynophagia, and sore throat for 2 days. Acute calcific prevertebral tendinitis was noted. This disease, brought on by prolonged minor repetitive tendon injury, is an often overlooked cause of acute neck pain. The typical radiologic appearances of the disease include the calcification of the anterior surface of the C1-C2 spine and smooth soft tissue swelling over the retropharyngeal space. Conclusion: Generally this disease is benign and may be misdiagnosed as deep neck infection. Drainage on this patient would be considered malpractice. PMID- 29123722 TI - Multidetector computed tomography to detect ingested press-through packages: utility of multiplanar reconstruction imaging in the emergency department. AB - Case: We investigated the usefulness of multidetector computed tomography during examination in the emergency department to detect the location of press-through packages that had been inadvertently swallowed. In three patients, four press through packages were detected on multi-planar reconstruction of multidetector computed tomography images, with three lodged in the esophagus and one in the stomach. Outcome: The multidetector computed tomography detection rate of press through packages was 100% in patients who realized they had swallowed the packages by mistake. After diagnosis, press-through packages in the esophagus were immediately removed endoscopically. Conclusion: There are few reports on the usefulness of multi-planar reconstruction images by multidetector computed tomography during examinations in the emergency department for the diagnosis of foreign bodies in patients who have mistakenly swallowed press-through packages. Detecting the location of the packages provided useful information regarding the strategy for their removal. Therefore, proactive multidetector computed tomography use in the emergency department could be beneficial for patients who have inadvertently swallowed press-through packages. PMID- 29123723 TI - Delayed perforation of the sigmoid colon after endoscopic reduction of sigmoid volvulus. AB - Case: An 81-year-old woman was diagnosed with sigmoid volvulus. As there were no signs of peritoneal irritation, emergency endoscopic reduction was attempted and achieved successfully. Although she remained stable on the following day, she suddenly developed perforative pan-peritonitis 35 h after the procedure. Outcome: Emergency laparotomy revealed a 10-mm-diameter perforation at the anti-mesenteric wall of the top of the sigmoid loop, and sigmoid resection with Hartmann's procedure was carried out. Pathological examination revealed ischemic necrosis around the perforation site. She recovered well with intensive care, and was discharged 32 days later. Conclusion: Delayed sigmoid perforation after endoscopic reduction of sigmoid volvulus is a rare but important and life threatening pitfall, and should always be considered by acute care physicians. To prevent this dangerous complication, evaluation of the viability of the entire sigmoid by direct vision and semi-emergency operation as soon as the patient's condition is optimized after endoscopic reduction may be essential. PMID- 29123724 TI - Healthy baby delivered vaginally from a brain-dead mother. AB - Case: A pregnant (20 gestational weeks) 32-year-old woman was found in cardiac arrest. Spontaneous circulation returned after 15 min. She became brain dead on the 13th hospital day. The patient was in stable circulatory condition under nasal desmopressin and 20-30 mg/day of hydrocortisone. On the 92nd hospital day at gestational week 33 + 3 days, natural labor began and a healthy 2,130-g girl (Apgar 6/8) was delivered vaginally with minimum assistance. Outcome: The baby was discharged 40 days after birth and followed up regularly. Conclusion: Brain death remains a hopeless condition for patients, but a brain-dead woman may still be able to naturally deliver a healthy baby. PMID- 29123725 TI - Paralytic ileus induced by glyphosate intoxication successfully treated using Kampo medicine. AB - Case: A 65-year-old woman ingested glyphosate-surfactant herbicide in an attempt to commit suicide. She experienced glyphosate intoxication associated with multiple organ failure and developed a paralytic ileus. Daijokito, a traditional Japanese Kampo medicine was given to the patient to improve constipation and psychological symptoms. Next, rikkunshito was given to increase her gastric motility. Finally, daikenchuto was given to improve overall digestive peristalsis. Outcome: All abdominal symptoms ultimately improved after treatment with daikenchuto. Conclusion: Kampo medicines may help improve abdominal symptoms associated with glyphosate intoxication in cases where modern medical treatment alone proves inadequate. PMID- 29123726 TI - Intrahospital transport of mechanically ventilated intensive care patients using new equipment attached to a transfer board. AB - Aim: Multiple lines and tubes often complicate bed transfer in critically ill patients. To solve this problem, the authors developed medical equipment attached to a transfer board ("transfer board tree") that integrates the patient, transfer board, and medical equipment. The objective of this study was to evaluate the efficiency and safety of the transfer board tree. Methods: Forty mechanically ventilated patients (20 transfer board tree, 20 conventional) in the intensive care unit who were transported for computed tomography were enrolled. Transfer times and adverse events were recorded. Results: Transfer board tree patients had significantly shorter transfer times. There were two adverse events only in the conventional group. Conclusions: The transfer board tree enables rapid intrahospital transport of intensive care patients with sufficient monitoring. PMID- 29123727 TI - Severe hyponatremia associated with sildenafil (Viagra). PMID- 29123729 TI - Ileosigmoidal knotting, an unusual form of acute intestinal obstruction. AB - Aim: Ileosigmoidal knotting is an unusual form of acute intestinal obstruction characterized by closed-loop obstruction of both ileum and sigmoid colon. We present 36 cases of ileosigmoidal knotting. Methods: A retrospective analysis was designed to examine preoperative, operative, and postoperative findings of the 36 patients with ileosigmoidal knotting who were surgically treated in Necmettin Erbakan University's Meram Medical Faculty (Konya, Turkey) throughout a 26-year period. Results: The mean age was 55 (range, 47-61) years. The most common symptoms were abdominal pain, distention, obstipation, and vomiting, and the most common signs were abdominal tenderness and distention. The preoperative diagnosis was acute obstructed bowel in all patients. After resuscitation, all patients underwent emergency laparotomy. The most common type of ileosigmoidal knotting was type IA, in which the active ileum encircled the passive sigmoid in a clockwise manner. There was gangrene in both ileum and sigmoid colon in all patients. All ischemic bowels including ileum and sigmoid colon were resected and the continuity was carried out using primary anastomosis or Hartmann's procedure. Conclusions: Ileosigmoidal knotting is a rare disease but its preoperative diagnosis is difficult. In cases of knotting there is no form of conservative treatment. Resective surgery is absolutely necessary. PMID- 29123728 TI - Changes in pre- and in-hospital management and outcomes for out-of-hospital cardiac arrest between 2002 and 2012 in Kanto, Japan: the SOS-KANTO 2012 Study. AB - Aim: The current study compares pre- and in-hospital management and outcomes of out-of-hospital cardiac arrest cases between 2002 and 2012 in the Kanto region of Japan. Methods: We compared the data collected for the SOS-KANTO study project in 2002 and 2012. We included adult patients (aged >18 years) who experienced bystander-witnessed out-of-hospital cardiac arrest of cardiac etiology. The outcomes were as follows: proportion of favorable neurological outcomes at 1 month, bystander cardiopulmonary resuscitation provision, and pre- and postresuscitation treatment administration. Results: Of 4,171 patients (1,982 in SOS-KANTO in 2002 and 2,189 in 2012), the proportion of those with favorable neurological outcomes at 1 month (4.8% versus 9.0%, P < 0.001), and bystander cardiopulmonary resuscitation rates increased significantly between 2002 and 2012 (24.5% versus 38.9%, P < 0.001). Although none were documented in 2002, 118 cases (5.4%) of layperson use of an automated external defibrillator were recorded in 2012. Relative to 2002, use of an i.v. line to provide fluid was more frequently attempted and carried out successfully by emergency medical service providers in 2012. Among cases in which return of spontaneous circulation was achieved, more postresuscitation treatment was provided in 2012 (13.3% versus 43.8%, P < 0.001) relative to that provided in 2002. Conclusions: Proportions of bystander cardiopulmonary resuscitation, layperson use of automated external defibrillator, provision of prehospital adrenaline and postresuscitation treatment, and favorable neurological outcomes at 1 month increased significantly over 10 years in the Kanto region of Japan. PMID- 29123730 TI - Characteristics and trends of emergency patients with drug overdose in Osaka. AB - Aim: Drug overdose is an important issue in emergency medicine. However, studies covering overdose patients transported by ambulance have not been sufficiently carried out. We attempted to clarify problems of suspected drug overdose patients transported by ambulance. Methods: This is a prospective population-based cohort study. Data were collected by emergency medical service crews in Osaka City, Japan, between January 1998 and December 2010. Results: Drug overdose cases increased annually from 1,136 in 1998 to 1,822 in 2010 (P < 0.0001 for trend). In these cases, the dominant age range was between 16 and 40 years and the age distribution did not change over time. The age of non-overdose cases increased (P < 0.0001 for trend), with patients aged >=66 years becoming most common in recent years, reflecting the aging of society. Males comprised most non-overdose patients, but the percentage of females increased annually (P < 0.0001 in trend). Females comprised approximately 70% in overdose cases annually throughout the study period. The duration from the emergency call to the arrival at the hospital for overdose patients has increased markedly in recent years. It also takes more time to obtain acceptance from hospitals to care for patients of suspected overdose. Conclusion: The characteristics of drug overdose patients are clearly different from those of non-overdose patients. Recent trends of drug overdose patients indicate the accelerated burden on emergency medical services system. PMID- 29123731 TI - Reduction of unexpected serious adverse events after introducing medical emergency team. AB - Aim: To assess the clinical benefits of introducing a medical emergency team system for early medical intervention in hospital care. Methods: This prospective analysis included all cases of medical emergency team activation during the first year after the introduction of the medical emergency team system at Chiba University Hospital (Chiba, Japan) in February 2011. The rates of in-hospital mortality and unexpected events before and after introduction of the medical emergency team system were compared. Results: The total number of medical emergency team activation calls was 83 (4.9 per 1,000 admissions). The activation of the medical emergency team system was requested most frequently from the general ward (56.6%) and by a physician (57.8%), with the most important reasons for activation being cardiac arrest (37.3%), breathing abnormality (33.7%), and impaired consciousness (32.5%). The most frequent medical interventions by the medical emergency team were intubation (43.3%) and oxygen inhalation (41.0%). Approximately one-half of the patients requiring activation of the medical emergency team system were critically ill and needed subsequent intensive care unit admission. Although no significant difference was observed between the pre- and post- medical emergency team in-hospital mortalities (2.1% versus 2.0%, respectively), the incidence rate of serious events significantly decreased (12.4% versus 6.8%, respectively; P = 0.015). Conclusion: Most patients requiring activation of the medical emergency team system were critically ill and needed emergency treatment at the location of the medical emergency team activation, with subsequent critical care. Although the introduction of the medical emergency team system did not affect the in-hospital mortality rate, it reduced the incidence of unexpected serious adverse events, suggesting that it may be clinically useful. PMID- 29123732 TI - Cardiopulmonary arrest during the Nuss procedure: case report and review. AB - Case: The Nuss procedure is an established and widely approved minimally invasive technique for the correction of pectus excavatum. However, patients undergoing the procedure are at increased risk of cardiac arrest. It has not been established whether cardiopulmonary resuscitation is possible in patients who have received the Nuss procedure. We present here the case of a 14-year-old boy with pectus excavatum who underwent minimally invasive pectus repair but later had a fatal cardiac event before pectus bar removal. Outcome: Bystander cardiopulmonary resuscitation was carried out immediately but resuscitation failed. Conclusion: In patients who have undergone the Nuss procedure for pectus excavatum, it is important to manage perioperative events such as arrhythmia, develop measures for managing emergency situations in patients' areas of residence, and carry out continuing research and development of medical supply materials that can be used to manufacture Nuss bars. PMID- 29123733 TI - Iatrogenic subcutaneous emphysema and pneumomediastinum following a high-speed air drill dental treatment procedure. AB - Case: A patient was transported to our hospital with swelling in his right face and neck after restorative dental treatment. Subcutaneous emphysema and pneumomediastinum were discovered using computed tomography scans. Outcome: The patient had no severe symptoms. We prescribed prophylactic antibiotics and he recovered uneventfully. Conclusions: Clinicians must keep this pathology in mind because prompt diagnosis and treatment contribute to early improvement. Otherwise, patients may face life-threatening complications. PMID- 29123734 TI - Combination of blunt cardiac and pericardial injury presenting a massive hemothorax without hemopericardium. AB - Case: A 64-year-old man was injured after falling from a height of 5 m and was transported to our institution. On presentation, his hemodynamic state was unstable, and both focused assessment with sonography for trauma and enhanced computed tomography imaging revealed massive left pleural effusion, but no pericardial effusion. He went into cardiopulmonary arrest just before surgery, so an urgent left anterolateral thoracotomy followed by open chest cardiac massage and aortic clamping were carried out. By performing an additional right anterior thoracotomy, a left pleuropericardial laceration and a perforation measuring 1 cm in diameter at the left ventricle were found. The patient's dynamic state stabilized following the restoration of hemostasis by suturing the rupture site. Outcome: The patient's postoperative course was favorable, and he was discharged after 20 days of hospitalization. Conclusion: Blunt cardiac and pericardial injury rarely causes massive hemothorax with no hemopericardium, resulting in hemorrhagic shock. PMID- 29123735 TI - Diagnosis and long-term management of hydrolyzed wheat protein wheat-dependent exercise-induced anaphylaxis. AB - Case: A 37-year-old woman was admitted to the emergency room with bilateral periorbital edema, hypotension, and expiratory stridor that developed 30 min after starting to hang out washing following consumption of a jam bun. Despite no food allergies or similar episodes, she had recently developed facial wheals after bathing. Outcome: She was immediately and repeatedly administered adrenalin and succinic acid hydrocortisone sodium for wheat-dependent exercise-induced anaphylaxis. On the third hospital day, radioallergosorbent testing reactions to wheat, gluten, and omega-5 gliadin were mildly positive; skin-prick tests for hydrolyzed wheat protein and a face-wash challenge were positive. Therefore, we diagnosed hydrolyzed wheat protein wheat-dependent exercise-induced anaphylaxis. Despite advising her about hyposensitization, the episode recurred and an adrenalin auto-injector was prescribed. Conclusion: Differentiating hydrolyzed wheat protein wheat-dependent exercise-induced anaphylaxis from conventional wheat-dependent exercise-induced anaphylaxis is important owing to their severity and similarities. Each requires long-term management of patients' etiological conditions by advising them about hyposensitization and prescribing adrenalin auto-injectors. PMID- 29123736 TI - Simulation study of nasotracheal and orotracheal fiberoptic intubation with the Aintree Intubation Catheter. AB - Aim: Fiber-optic tracheal intubation is an essential technique to secure the airway for difficult airway and cervical cord injury victims. However, there is an anxiety about the vocal cord passage of tracheal tubes because of the potential of collision with the surroundings of the vocal cords. This study aimed to examine the utility of the Aintree Intubation Catheter in nasotracheal and orotracheal intubation. Methods: Participants were 21 anesthesiologists with more than 2 years of experience in clinical anesthesia. Participants attempted fiber optic tracheal intubation through the oral or nasal cavity with or without the Aintree Intubation Catheter in random order. The success rate of tracheal intubation, intubation time, and collision with the glottis were recorded. Participants also evaluated the subjective difficulty of the entire intubation process and passing the tracheal tube through the glottis using a Visual Analogue Scale. Results: There were no significant differences in intubation time or Visual Analogue Scale scores for passing the tracheal tube through the glottis between nasal and oral intubation, regardless of the use of the Aintree Intubation Catheter. However, the catheter significantly reduced the number of collisions with the glottis in both routes (nasal, P = 0.026; oral, P = 0.017). Conclusion: Our findings that the Aintree Intubation Catheter is effective in reducing collisions with the glottis during nasal and oral fiber-optic intubation suggest that Aintree Intubation Catheter use may reduce the risk of mechanical injury related to airway obstruction. PMID- 29123737 TI - Abnormal ranges of vital signs in children in Japanese prehospital settings. AB - Aim: The revised Fire Service Law obliges each prefectural government in Japan to establish a prehospital acuity scale. The Foundation for Ambulance Service Development (FASD) created an acuity scale for use as a reference. Our preliminary survey revealed that 32 of 47 prefectures directly applied the FASD scale for children. This scale shows abnormal ranges of heart rate and respiratory rate in young children. This study aimed to evaluate the validity of the abnormal ranges on the FASD scale to assess its overall performance for triage purposes in paediatric patients. Methods: We evaluated the validity of the ranges by comparing published centile charts for these vital signs with records of 1,296 ambulance patients. Results: A large portion of the abnormal ranges on the scale substantially overlapped with the normal centile charts. Triage decisions using the FASD scale of vital signs properly classified 22% (n = 287) of children. The sensitivity and specificity for high urgency were as high as 91% (95% confidence interval, 82-96%) and as low as 18% (95% confidence interval, 16 20%). Conclusion: We found there is room for improvement of the abnormal ranges on the FASD scale. PMID- 29123738 TI - Take with a pinch of salt! Wild plants labeled "edible" may be poisonous. PMID- 29123739 TI - Crowned dens syndrome. PMID- 29123740 TI - Horse kick injury mimicking a handle bar injury or a hidden speared injury. AB - A 16-year-old male was transported to our emergency department after he was kicked in the abdomen by a horse. He was diagnosed with injury of the liver and abdominal rectus muscle, and was cured by observational treatment. An Ichushi search was undertaken to identify articles published from 1983 to 2013 using the key words "horse" and "trauma". We found 13 cases that described horse-related injuries and summarized these cases, including our case. There were 10 males, three females and one patient of an undescribed sex. The patients ranged in age from 16 to 58 years old, with an average age of 33 years. The injured sites were predominantly the face (mandible) and upper abdomen, indicating that a projecting part of the body may be more likely to be injured. Cardiac rupture, aortic head injury, or lethality induced by a horse kick have not been reported in Japan, but such injuries have been reported in other countries. Ten of 15 cases (67%) required surgical treatment for severe injuries. Horse kick injuries tend to be severe, because the transfer of energy from the end of the hoof, with a small cross-sectional area, to a small field, leads to internal organic injuries that are more severe than predicted, similar to a handlebar injury. Accordingly, we advocate the close observation of patients with horse kick injuries, which may be regarded as being similar to blunt stab wounds or hidden speared injuries. PMID- 29123741 TI - Pediatric brain death in a Japanese pediatric hospital. AB - Aim: The Organ Transplantation Act was revised in Japan in 2010, which permitted the organs of children younger than 15 years to be donated after brain death. As of August 2012, 2 years after the Act was revised, only two children had become brain dead donors.In our hospital, we used a basic determination of brain death in order to predict the neurological outcome. We evaluated the incidence and characteristics of pediatric brain death treated at our hospital in order to investigate why there are so few pediatric brain deaths in Japan. Methods: We evaluated the characteristics of patients undergoing a basic determination of brain death and the procedure for the determination was compared retrospectively by reviewing their medical records. We enrolled 3,721 patients aged younger than 15 years who were admitted to the pediatric intensive care unit between 2008 and 2012. Results: A basic determination of brain death had been enacted in 35 patients. Many of the patients undergoing the determination were admitted after resuscitation (pre-group / post-group, 50%/74%) and many of them had been transferred from the emergency department (94%/89%). After revision of the Act, only three children were deemed to be brain dead in our hospital, which was 0.1% of total pediatric intensive care unit admissions and 7% of total pediatric intensive care unit deaths. Conclusions: The low incidence of pediatric brain death in Japan may be due to differences in exclusion criteria for determination of brain death and personal views regarding life and death compared with other countries. PMID- 29123742 TI - Evaluation of patients with hepatic portal venous gas who can be treated with conservative therapy. AB - Aim: Hepatic portal venous gas is an indication for emergency surgery and reportedly has a high mortality rate. However, these days, cases of hepatic portal venous gas associated with milder disease are increasing. In this report, we compared two groups to investigate whether there were any objective indicators for selecting conservative therapy. Methods: From July 2007 to August 2011, 19 patients with hepatic portal venous gas were evaluated at our hospital. The condition was diagnosed by computed tomography imaging. Vital signs, laboratory test results, and physical examination findings were compared. Results: The A group included 12 patients who could be treated with conservative therapy. The B group included 7 patients who could not be treated with conservative therapy. The combined mortality rate was 31.5% (6/19 patients). There was a significant difference in the pulse rate and shock index. In the A group, none of the patients had signs of peritoneal irritation. However, in the B group, physical examination revealed signs of peritoneal irritation in all patients. Conclusion: Conservative therapy may be possible in patients with hepatic portal venous gas, depending on the cause. Evaluation of vital signs and serial changes on physical examination are important. PMID- 29123743 TI - Contrast-enhanced multidetector-row computed tomography can predict pathological findings of acute appendicitis in children. AB - Aims: To retrospectively evaluate the correlation between multidetector-row computed tomography findings of acute appendicitis and the pathological status of acute appendicitis, and evaluate the capability of multidetector-row computed tomography to predict the pathological status of acute appendicitis in children. Methods: The presence of a distended appendix (>6 mm in transverse diameter) was used as a primary sign to indicate the presence of appendiceal inflammation. The presence of appendiceal wall thickening (>1 mm) and enhanced appendiceal wall continuity were also used as predictive findings to reflect the degree of progression of acute appendicitis on multidetector-row computed tomography findings. The findings of each individual case were classified into four grades. The final pathological diagnosis was classified into four groups: normal findings, only mucosal inflammation, inflammation with intramural spreading, and gangrenous. The relationship between the pathological grades and computed tomography grades was analyzed using Spearman's rank correlation test. Results: Four of six cases in Grade 0 reflected normal appendiceal findings (66.7%) and 3 of 5 cases in Grade I reflected only mucosal inflammation status (60.0%). Forty four of 51 cases in Grade II reflected intramural inflammation status (86.3%), and 40 of 57 cases in Grade III reflected gangrenous status (70.2%). The multidetector-row computed tomography grade was significantly correlated to the pathological grade with Spearman's rank correlation coefficient of 0.689 (P < 0.001). Conclusions: There was a close relationship between the multidetector-row computed tomography imaging findings and the pathological findings. This preoperative information is extremely useful for decision-making in the treatment strategy for acute appendicitis in children. PMID- 29123744 TI - Analysis of the clinical backgrounds of patients who developed respiratory acidosis under high-flow oxygen therapy during emergency transport. AB - Aim: High-flow oxygen is often administered to patients during emergency transport and can sometimes cause respiratory acidosis with disturbed consciousness, thereby necessitating mechanical ventilation. Although oxygen titration in chronic obstructive pulmonary disease patients during emergency transport reduces mortality rates, the clinical risk factors for respiratory acidosis in emergency settings are not fully understood. Therefore, we analyzed the clinical backgrounds of patients who developed respiratory acidosis during pre-hospital transport. Methods: This was a retrospective study of patients who arrived at our hospital by emergency transport in 2010 who received high-flow oxygen while in transit. Respiratory acidosis was defined by the following arterial blood gas readings: pH, <=7.35; PaCO 2, >=45 mmHg; and HCO 3-, >=24 mmol/L. The risk factors were identified using multivariable logistic regression analysis. Results: In 765 study patients, 66 patients showed respiratory acidosis. The following risk factors for respiratory acidosis were identified: age, >=65 years (odds ratio [OR] 1.4; 95% confidence interval [CI], 0.7-2.8); transportation time, >=10 min (OR 2.0; 95% CI, 1.1-3.7); three digits on the Japan Coma Scale (OR 3.1; 95% CI, 1.7-5.8); percutaneous oxygen saturation, <=90% (OR 1.6; 95% CI, 0.8-3.0); tuberculosis (OR 4.5; 95% CI, 1.4-15.1); asthma (OR 1.8; 95% CI, 0.6-5.3); pneumonia (OR 1.5; 95% CI, 0.7-3.1); and lung cancer (OR 3.9; 95% CI, 1.5-10.1). These underlying diseases as risk factors included both comorbid diseases and past medical conditions. Conclusions: The factors identified may contribute to the development of respiratory acidosis. Further studies on preventing respiratory acidosis will improve the quality of emergency medical care. PMID- 29123745 TI - Metallo-beta-lactamase-producing Klebsiella pneumoniae infection in a non hospital environment. AB - Case: A 92-year-old female resident at a nursing home was transported to the emergency department unconscious, hypotensive, and febrile. Chest X-rays and computed tomography revealed a permeation shadow in the right lung. The patient was diagnosed with sepsis due to pneumonia. At the time of admission, she had not received antibiotics or treatment using medical devices over the past 6 months. Two sets of samples were taken for blood and sputum cultures, and Klebsiella pneumoniae was isolated from all cultures. The strain was identified as metallo beta-lactamase-producing K. pneumoniae, and the patient was successfully treated with tazobactam-piperacillin. This case indicates that metallo-beta-lactamase producing K. pneumoniae infection occurred in a non-hospital environment. Outcome: After tazobactam-piperacillin treatment, the patient was transferred to another hospital. Conclusion: Emergency physicians should be aware of multidrug resistant bacterial infection even in a non-hospital setting. PMID- 29123746 TI - Successful treatment of a case with concurrent ingestion of carbamazepine overdose and grapefruit juice. AB - Case: We report a case with concurrent ingestion of carbamazepine (CBZ) overdose and grapefruit juice. A 23-year-old man, with a history of epilepsy, was admitted to our emergency department 2 h after ingesting 10 g CBZ with 1 L grapefruit juice. On arrival, the patient's Glasgow Coma Scale score was 9 and he showed signs of restlessness. Grapefruit juice-like gastric fluid, with tablet residue, was observed in his stomach after we inserted a gastric tube. Our initial test detected a blood CBZ level of 41.5 mg/L. Outcome: We treated the patient with gastric lavage, activated charcoal, and charcoal hemoperfusion. His blood CBZ level began to decrease after gastrointestinal decontamination, and he was discharged without any sequelae on day 9. Conclusion: Gastric lavage or aspiration may be considered in cases where drug residue is found in the stomach, especially if materials are involved that might exacerbate the drug's toxicity. PMID- 29123747 TI - Hemorrhagic shock due to ruptured left and right gastric artery aneurysm. AB - Case: We report a case of hemorrhagic shock due to a ruptured gastric artery aneurysm successfully treated with transarterial embolization. A 72-year-old woman with cholangitis presented with hemoperitoneum following a ruptured aneurysm of the gastric artery. Outcome: Emergent computed tomography and angiography were carried out and the patient was found to have spontaneous bleeding from both branches of the left and right gastric arteries. Transcatheter embolization was carried out at the distal branch of both gastric arteries with a coil. The patient recovered well with no recurrent bleeding. Conclusions: Although rare, visceral artery rupture should be considered in the differential diagnosis of unexplained hemorrhagic shock with abrupt onset of hemoperitoneum. Computed tomography and angiography are useful tools for obtaining prompt and accurate localization of the bleeding points. PMID- 29123748 TI - Posterior mediastinal hematoma after a simple fall in a patient with normal coagulation. AB - Case: A 77-year-old woman presented with neck swelling and odynophagia following a fall from standing height. She had no history of antiplatelet or anticoagulant use. Computed tomography of the chest showed an isodense to hypodense soft tissue mass in the bilateral carotid space, retropharyngeal space, and posterior mediastinum. With no airway obstruction symptoms, the patient was placed on bed rest under close observation. Outcome: The mass decreased in size spontaneously over the 10 days following symptom onset, accompanied by overall clinical improvement. The patient was diagnosed with a posterior mediastinal hematoma. Conclusion: This is the first reported case of posterior mediastinal hematoma caused by a neck hyperextension injury secondary to a simple fall in a patient with normal coagulation. The outcome was good; however, emergency physicians should be aware that hematomas necessitating airway management may occur after a fall. PMID- 29123749 TI - Three cases of heparin-induced thrombocytopenia associated with polytrauma. AB - Case: We present three cases in which patients that had suffered polytrauma developed heparin-induced thrombocytopenia after the start of heparin treatment for thrombosis. All three patients had high injury severity scores and required major surgery. They all started receiving unfractionated heparin for deep venous thrombosis with or without an asymptomatic pulmonary embolism. The patients were clinically diagnosed with heparin-induced thrombocytopenia after their platelet counts fell or exhibited a delayed recovery. Outcome: Heparin-induced thrombocytopenia and the associated thromboses were successfully treated by discontinuing all forms of heparin treatment and administering argatroban followed by warfarin. Conclusion: Early recognition and clinical diagnosis of heparin-induced thrombocytopenia is necessary for clinicians in cases in which severely injured trauma patients show reductions or delayed recovery in their platelet counts in combination with thrombosis after starting heparin treatment. PMID- 29123750 TI - Complications of non-occlusive mesenteric ischaemia. AB - Case: A 65-year-old arteriopath with a history of myocardial infarction 5 months previously presented with classical signs of mesenteric infarction that led to a right hemicolectomy with an end ileostomy. Outcome: Postoperative complications occurred due to unusually large volume ileostomy output in the subsequent 4 weeks, resulting in severe volume depletion and the sequelae that required intensive care support. These were triggered and prolonged by two episodes of intra-abdominal sepsis. Conclusions: Sepsis-induced high ileostomy output following intestinal resection for non-occlusive mesenteric ischaemia is a serious complication. Early restoration of intestinal continuity following bowel resection for established infarction may prevent this complication. PMID- 29123751 TI - Efficacy of cardiac magnetic resonance for the qualitative diagnosis of blunt cardiac injury. AB - Case: A 47-year-old man was admitted after a car collision in shock with cardiac tamponade. After his circulation was stabilized by pericardial drainage, we treated him conservatively. Abnormal laboratory data and initial electrocardiogram (ECG) were suggestive of myocardial injury. However, echocardiography and cardiac computed tomography could not reveal the cause of the tamponade or the site of cardiac injury. ECG-gated cardiac magnetic resonance images were acquired. Outcome: The cardiac magnetic resonance black-blood T2 weighted images showed hyperintense signals in the interventricular septum, whereas the late gadolinium enhancement images showed no enhancement in this region. We could accurately diagnose cardiac contusion of the anteroseptal area, which would explain the initial ECG abnormality seen in this patient. Conclusion: Cardiac magnetic resonance imaging may be especially useful in the evaluation of non-operative management of blunt cardiac injury and could explain the initial ECG abnormality seen in our patient. PMID- 29123752 TI - Mobitz type 1 second-degree atrioventricular block by triazolam and brotizolam overdose. PMID- 29123753 TI - Preventing contrast-induced acute kidney injury in the emergency room. PMID- 29123754 TI - Strategies to improve cardiac arrest survival: a time to act. PMID- 29123755 TI - Emergency medicine as a specialty in Asia. AB - Aim: We aim to examine the similarities and differences in areas of EM development, workload, workforce, and capabilities and support in the Asia region. Emerging challenges faced by our EM community are also discussed. Methods: The National Societies for Emergency Medicine of Hong Kong, India, Japan, Malaysia, Philippines, Singapore, South Korea, Taiwan, Thailand and Turkey participated in the joint Japanese Association of Acute Medicine (JAAM) and Asian Conference of Emergency Medicine (ACEM) Special Symposium held in October 2013 at Tokyo, Japan. The findings are reviewed in this paper. Results: Emergency medicine (EM) has over the years evolved into a distinct and recognized medical discipline requiring a unique set of cognitive, administrative and technical skills for managing all types of patients with acute illness or injury. EM has contributed to healthcare by providing effective, safe, efficient and cost effective patient care. Integrated systems have developed to allow continuity of emergency care from the community into emergency departments. Structured training curriculum for undergraduates, and specialty training programs for postgraduates are in place to equip trainees with the knowledge and skills required for the unique practice of EM. Conclusion: The practice of EM still varies among the Asian countries. However, as a region, we strive to continue in our efforts to develop the specialty and improve the delivery of EM. PMID- 29123757 TI - Thoracotomy for blunt chest trauma: is chest tube output a useful criterion? AB - Aim: The aim of this study was to determine whether the traditional criteria of chest tube output are useful indicators for urgent thoracotomy in patients with blunt chest trauma. Methods: Data were collected retrospectively from our trauma registry of 542 blunt chest trauma patients (Chest Abbreviated Injury Scale score of 3 or greater) over a 10-year period (2000-2010). The 1-h chest tube output was calculated from chest tube output and time after admission, and the results were compared between patients who underwent thoracotomy for hemorrhage and those who did not. Results: Data were available for 24 patients who underwent thoracotomy for hemorrhage and 93 patients who did not undergo thoracotomy. The 1-h chest tube output between the groups was significantly different (708.0 +/- 258.3 mL versus 108.9 +/- 222.9 mL). Receiver operating characteristic curve analysis of the predictive value of 1-h chest tube output for thoracotomy was conducted. The area under the receiver operating characteristic curve was 0.98, and the cutoff 1 h chest tube output value for predicting thoracotomy was 404 mL (sensitivity, 87.5%; specificity, 96.8%). Conclusions: The 1-h chest tube output of patients who underwent thoracotomy was lower than the thresholds traditionally reported as indications for urgent thoracotomy. High chest tube output as a traditional indicator for thoracotomy may not apply to patients with blunt chest trauma. PMID- 29123756 TI - Analysis of seasonal differences in emergency department attendance in Shiga Prefecture, Japan between 2007 and 2010. AB - Aim: Emergency department overcrowding is problematic. Some emergency departments have established a triage system to prevent overcrowding; however, effective management of a triage system requires knowledge of factors that influence emergency department attendance. Therefore, we investigated the effect of ambient temperature on emergency department attendance, as well as the types of patients that may have been affected. Methods: Data on emergency department attendance at Shiga University of Medical Science Hospital (Otsu, Japan) were retrospectively collected from 1 April, 2007 to 31 March, 2010. Attendance was classified into eight categories based on a combination of symptoms (trauma or non-trauma), transport (by ambulance or walk-in), and severity (serious or non-serious). Results: A total of 7,755 patients (4,120 [53.1%] men and 3,635 [46.9%] women) attended the emergency department during the study period. Statistically significant seasonal differences were observed in emergency department attendance in walk-in and non-serious groups of both trauma and non-trauma patients (P < 0.01), with the smallest differences occurring during winter. In a linear regression model, the mean ambient temperature had a positive correlation with emergency department attendance only in the walk-in and non-serious group of non trauma patients during the summer (y = 0.092 * [mean ambient temperature] - 0.565). Conclusion: In the walk-in and non-serious group of non-trauma patients, emergency department attendance significantly increased with the increase in mean ambient temperature during summer. In emergency department triage systems, it may be more effective to evaluate non-trauma and walk-in patients during summer, especially on hot days. PMID- 29123758 TI - Cervical spinal cord injuries associated with resuscitation from fatal circulatory collapse. AB - Introduction: Fatal cervical spinal cord injury (SCI) associated with collapse of the circulatory and/or respiratory system usually consists of high cervical SCI caused by high-energy trauma. As the elderly population grows, however, the etiology of fatal SCI may be changing. The aim of the present study was to understand the current clinical features of fatal SCI. Methods: Retrospective analysis was performed on 73 consecutive patients with acute cervical SCI between 2007 and 2013. Fourteen (19%) of them presented in a state of coma due to severe circulatory collapse after cardiac arrest (CA, n = 11) or respiratory arrest (RA, n = 3), and were resuscitated at the scene or hospital. The clinical features and radiological findings of these 14 patients were compared with those of the other 59. Results: Eleven of the 14 fatal SCI patients were injured by minor traumas. Computed tomography revealed C1-2 fractures or dislocations in 11 patients and subaxial injuries in three patients. Eleven patients showed some kind of ossification of the spinal column ligaments. In a univariate analysis, the predictive factors associated with fatal circulatory collapse were age (P = 0.02), estimated C1/2 injury (P < 0.0001), and complete tetraplegia (P < 0.0001). In a multiple regression model for fatality, the odds ratios (OR) for C1/2 injury and ASIA impairment score (AIS) A were 20.58 (P = 0.006) and 151.97 (P = 0.002). Conclusions: A state of unconsciousness with fatal circulatory collapse was significantly associated with C1/2 injury and AIS A. Moreover, our data show that fatal SCI can occur due to minor trauma in elderly people. PMID- 29123759 TI - Use and effectiveness of prothrombin complex concentrate in an emergency department: a review of 15 cases. AB - Aim: Hemostatic management of patients on oral anticoagulant therapy with critical bleeding continues to be a major challenge. The present study aimed to validate the efficacy, safety, and optimal dosage of prothrombin complex concentrate for rapidly normalizing elevated international normalized ratio (INR) values and achieving control of hemorrhage at an emergency department in Japan. Methods: We retrospectively collected data from all patients who were treated with PCC at our emergency department between January 2013 and September 2014. We used a commercially available prothrombin complex concentrate. Results: Fifteen patients (male / female, 7/8; average, 71.4 years) received prothrombin complex concentrate (14 for bleeding, including trauma-related bleeding, and one for invasive intervention) without complications. All but one patient received warfarin and the INR value declined in all patients with 500 IU (average, 8.98 IU/kg) prothrombin complex concentrate (average INR value before and after treatment: 2.20 versus 1.26). Although two patients died because of multiple organ failure, a relatively satisfactory hemostatic response was obtained in at least 11/15 patients. However, patients with a baseline INR value above 2.5 never achieved an optimal response (INR value < 1.35). Conclusion: A single dose of 500 IU prothrombin complex concentrate is insufficient for normalization of INR value, especially in patients with prolonged INR values. Administration strategies for trauma, the ideal dose (e.g., higher than 500 IU/patient), target optimal INR values, as well as the confirmation of safety should be addressed in the future. Further clinical trials are warranted to confirm this preliminary report. PMID- 29123760 TI - Utility of blood lactate level in triage. AB - Aim: Simple Triage and Rapid Treatment (START) is commonly used at disaster scenes. The Canadian Emergency Department Triage and Acuity Scale (CTAS) is used in urban and rural emergency departments (ED). However, triage is not always accurate or appropriate. The blood lactate level (BLL) is a major biomarker of physical status. We measured BLL using the Lactate Pro-1710 Test Meter in all patients transported to our ED and assessed their correlation with the triage level determined using START and the CTAS. Methods: This retrospective study included 510 patients admitted to our ED between January 2011 and July 2012 whose BLL was measured. The patients were classified into triage divisions (green, yellow, red, and black) according to vital signs and chief complaints, and correlations among BLL, triage level, and prognosis were assessed in all groups. Results: Of the total, 62 patients had cardiopulmonary arrest (CPA), 262 had internal pathologies, and 186 had external pathologies. Significant correlations were observed between BLL and both START and CTAS triage. Also BLL was significantly higher in severe patients categorized with START and CTAS (P < 0.0001), especially in the death group when the patients were divided into two groups according to prognosis (P < 0.0001). Two patients categorized yellow with START died during the hospitalization, however BLL of these two patients were high on admission at the ED. Conclusion: BLL could be used to correct the triage level, and decide the priority of treatment and transportation even within the same triage level, thereby avoiding under-triage. PMID- 29123761 TI - Polypharmacy as a risk factor for hospital admission among ambulance-transported old-old patients. AB - Aim: The aim of this study was to analyze the relationship between polypharmacy and hospital admission in ambulance-transported old-old patients. Methods: A retrospective cohort study was conducted of consecutive old-old patients (aged >= 85 years) transported by ambulance to a community teaching hospital between April and December of 2013. Patients with out-of-hospital cardiopulmonary arrest were excluded. Data were collected from the computerized records on the demographics, chief complaints, vital signs, and level of consciousness at arrival, final diagnoses at discharge, and polypharmacy (>=5 medications). The primary outcome was requirement of hospital admission. We also analyzed symptomatic adverse drug events (ADEs). Results: Of the 3,084 adults (aged >= 18 years) transported to the hospital during the study period, 381 (13%) were old-old patients. Of those, 233 (61%) were women, and 261 (69%) were admitted to the hospital. The mean number of their baseline medications was 6.8 +/- 3.9, and 250/347 patients (72%) were suffering from polypharmacy. Twenty-seven of the patients (7%) had symptomatic ADEs. Although the ADEs were not related to polypharmacy (P = 0.437), logistic regression adjustments for age, sex, and vital signs at arrival showed that patients with polypharmacy were more likely to be admitted to the hospital than were patients without (odds ratio: 2.12 [95% CI, 1.03-4.43]; P = 0.042). Conclusions: Symptomatic ADEs due to polypharmacy were one of the most preventable causative factors leading to hospital admission of old-old patients. Polypharmacy could be a major risk for emergency admission to hospital. PMID- 29123762 TI - Effect of pre-injury anticoagulant and antiplatelet agents on blood loss in elderly patients with severe trauma. AB - Aim: It has been widely reported that pre-injury use of anticoagulant and antiplatelet agents can affect traumatic brain injury and the associated risk of mortality, however, the effect of these agents on non-head injury site-related blood loss remains unclear. Therefore, we investigated the effects of pre-injury anticoagulant and antiplatelet agents on the transfusion amount and the need for massive transfusion in elderly patients with severe trauma. Methods: We retrospectively reviewed a cohort of elderly patients with severe trauma (age, >=65 years; Injury Severity Score, >=16) between September 2006 and March 2014. The selected patients were subsequently divided into patients who were: only taking warfarin, aspirin, or clopidogrel; taking various combinations of these agents; and a control group who were not taking any of these agents. Results: During the study period, 67 patients (20%) were taking anticoagulant and antiplatelet agents and 272 patients were included in the control group. Among these patients, 10 were receiving only warfarin, 28 were receiving only aspirin, 14 were receiving only clopidogrel, and 13 were receiving various combinations of these medications. The amount of red cell concentrate and need for massive transfusions were only significantly increased in the warfarin group (P < 0.05). Furthermore, the warfarin group had a significantly higher risk of needing a massive transfusion with multivariate logistic regression analysis (odds ratio, 5.03; 95% confidence interval, 1.25-20.20; P < 0.05). Conclusion: Patients who were receiving only warfarin before their injury had an increased risk of bleeding due to non-head injuries. PMID- 29123763 TI - Comparative analysis of mamushi (Gloydius blomhoffii) bite patients indicates that creatinine kinase levels/white blood cell count trends reflect severity. AB - Aim: There has been no indicator that allows an early quantitative evaluation of the severity of a mamushi snake (Gloydius blomhoffii) bite. Because the number of severe mamushi bite cases is much fewer than non-severe cases, a formal case control study is difficult. Therefore, we tried to generate a preliminary quantitative, real-time index for its severity by referring to published reports of severe mamushi bite cases. Methods: We enrolled patients who presented with a mamushi bite and visited our outpatient clinic. Severe cases were collected from published works. Creatinine kinase levels and white blood cell counts of non severe and severe cases were compared and analyzed. Results: There was a lag time of 10 h before the creatinine kinase level began to rise. The speed of the increase was higher in severe cases than in non-severe cases, and severe cases were recognized as those showing speeds of above 250 IU/L/h. White blood cell counts increased earlier than creatinine kinase levels without any lag time. Severe cases were recognized as those with the counts of over 1,000 * (h) + 6,000 [/MUL] before 5 h and 300 * (h) + 10,000 [/MUL] after 5 h. Conclusion: We herein present the creatinine kinase level and white blood cell count trends and demonstrate preliminary cut-off equations. The trends for both parameters serve as quantitative indicators of the severity of a mamushi bite until a large scale case-control study is achieved. PMID- 29123764 TI - Negative pressure wound therapy-assisted dermatotraction for the closure of large open wounds in a patient with non-clostridial gas gangrene. AB - Case: A 53-year-old woman developed septic shock associated with non-clostridial gas gangrene. She presented to the emergency department with two large open wounds on both thighs and in her sacral region. Non-enhanced computed tomography showed air density in contact with the right iliopsoas, which extended to the posterior compartment of the thigh. We made repeated efforts at surgical debridement of the wound with resection of necrotic tissues. Outcome: Using negative pressure wound therapy-assisted dermatotraction, the pus pockets and the wound dehiscence decreased in size. Using this method we were successful in achieving delayed closure without skin grafts. Conclusion: Negative pressure wound therapy can be an effective treatment for large and infected open contoured wounds. Negative pressure wound therapy-assisted dermatotraction might be beneficial for poorly healing, large, open wounds in patients in poor condition and with insufficient reserve to tolerate reconstructive surgery. PMID- 29123765 TI - Hemodialysis for removal of dabigatran in a patient with gastric hemorrhage. AB - Case: An 82-year-old man taking dabigatran was admitted with syncope. Computed tomography showed extravasation from the stomach. Laboratory data revealed renal insufficiency and prolonged activated partial thromboplastin time. The gastric endoscopy showed a gastric ulcer with an exposed vessel. However, an endoscopic hemostatic procedure failed to completely stop the bleeding. The patient experienced cardiac arrest from hypotensive shock. Spontaneous circulation returned after 5 min of resuscitation. After endoscopy, computed tomography showed a gastric perforation. For dabigatran removal, the patient underwent a 6-h hemodialysis session. Thrombin activity and thrombin-antithrombin complex increased during hemodialysis, while activated partial thromboplastin time decreased. Outcome: Good recovery was observed after dialysis and the following gastrectomy. Conclusion: Hemodialysis should be considered for dabigatran removal in cases of life-threatening hemorrhage. The thrombin-antithrombin complex may be useful for monitoring the plasma dabigatran level. PMID- 29123766 TI - Concomitant fat embolism syndrome and pulmonary embolism in a patient with a femoral shaft fracture. AB - Case: A 22-year-old man was injured in a traffic accident and developed respiratory distress on his first day of admission. On postadmission day 3, he developed serious respiratory distress with a suddenly altered mental status. Chest computed tomography revealed a pulmonary embolism that had not been evident when he was admitted. The patient was intubated and a continuous heparin infusion was started to treat the pulmonary embolism. Palpebral conjunctival petechiae were noticed the following day, at which point the patient fulfilled Gurd's criteria for fat embolism syndrome. Within a few days, his respiratory status was improved. Brain magnetic resonance imaging also provided evidence of fat embolism syndrome. His femoral shaft fracture was repaired on day 20. Outcome: The patient was discharged home on postadmission day 63. Conclusion: Concomitant fat embolism syndrome and pulmonary embolism, although very rare, should be considered when a trauma patient's respiratory status worsens. PMID- 29123767 TI - Postmortem diagnosis of massive gastrointestinal bleeding in a patient with aberrant right subclavian artery-esophageal fistula. AB - Case: Aberrant right subclavian artery-esophageal fistula is a rare, but fatal, complication. A 55-year-old febrile man with a nasogastric feeding tube developed sudden massive hematemesis and shock. Outcome: Upper endoscopy revealed an intragastric hematoma with no active bleeding observed except for oozing from an esophageal tear. Enhanced computed tomography scan detected aberrant right subclavian artery but was unable to determine the bleeding source. Repeat endoscopy carried out on day 2 confirmed hemostasis and the disappearance of the intragastric hematoma. However, the patient suddenly developed recurrent massive hematemesis with refractory shock on day 4 and died. Postmortem computed tomography revealed endoscopic clips in contiguity with aberrant right subclavian artery; a final diagnosis of aberrant right subclavian artery-esophageal fistula was made. Conclusion: Our case demonstrates aberrant right subclavian artery esophageal fistula may present with transient spontaneous hematemesis in a state of shock, possibly related to fever of unknown origin, and is challenging to diagnose by repeated endoscopy once hematemesis develops. PMID- 29123768 TI - Systemic emphysema accompanying marked undernutrition. AB - Case: A 38-year-old mentally retarded woman was transported to the emergency room for marked undernutrition. Two months prior, she had developed tooth decay and her food intake decreased severely. Over 2 months, her weight decreased from 47 to 31 kg (-16 kg). Computed tomography (CT) revealed extensive subcutaneous, mediastinal, and retroperitoneal emphysema. She was hospitalized and treatment with central venous hyperalimentation and antibiotics was initiated. CT performed 3 weeks after hospitalization showed that the systemic emphysema had completely disappeared. Outcome: She progressed favorably and was transferred to a specialized psychiatric hospital for further treatment. Conclusion: Regardless of the cause, this rare complication must be taken into account when treating patients suffering from long-term starvation or undernutrition. Whole-body management including nutritional management and careful follow-up observations are appropriate for treating this condition. PMID- 29123769 TI - Successful conservative management of a case of caustic esophagitis based on computed tomography assessment. AB - Case: We describe the case of a female patient who ingested approximately 100 mL of toilet bowl cleaner containing 9.5% hydrochloric acid in a suicide attempt. Upon admission for hematemesis and epigastric pain, she was alert and oriented with stable vital signs. Initial contrast-enhanced computed tomography (CT) demonstrated edematous changes with no evidence of upper gastrointestinal tract perforation. Endoscopy was not performed owing to the high risk of perforation. We managed this patient conservatively. Repeat contrast-enhanced CT revealed mediastinal emphysema on day 2, which resolved by day 6. The patient was subsequently discharged with no apparent strictures of the upper gastrointestinal tract. Outcome: Surgical interventions are frequently required following the ingestion of large amounts of highly concentrated hydrochloric acid; however, this patient was successfully managed conservatively. Conclusion: Contrast enhanced CT is useful in the assessment of the respiratory and digestive systems and the prediction of potential complications. PMID- 29123770 TI - Ascitic fluid with ammonia odor as a symptom of bladder rupture. AB - Case: An 88-year-old woman presented with abdominal pain, massive ascites, and acute kidney injury. She was clinically hypervolemic and the computed tomography attenuation value of the ascites was near that of water. Subsequent abdominocentesis revealed ammonia-smelling ascites fluid, leading to a suspicion of urinary tract injury, and a conclusive diagnosis of spontaneous bladder rupture was achieved using cystography. Outcome: The patient was managed conservatively with antibiotics, percutaneous drainage, and bladder catheter. As a result, she was discharged with normal renal function. Conclusion: The diagnosis of bladder rupture is difficult, and is rarely confirmed in the absence of a diagnostic suspicion. This case indicates that ascitic fluid odor, patient volume status, and the computed tomography attenuation value of ascites are potential indicators of bladder rupture. PMID- 29123771 TI - Crowned dens syndrome: reports of six cases and review of the literature. AB - Case: We have reported six cases of Crowned dens syndrome (CDS) diagnosed by computed tomography (CT). Presenting cases were three male and three female, aged from 45 to 89 (averaged in 72). Outcome: All cases showed calcification around the dens of axis in CTs. Neck pain in all cases relieved within at least 10 days, treated by non-steroidal anti-inflammatory drugs (NSAIDs) in five cases, and one by acetaminophens. Conclusion: Bouvet et al. first reported CDS in 1985, as acute pseudogout of the neck, which causes neck pain. CDS is a radioclinical syndrome defined by the radiographic calcifications in a crown-like configuration around the odontoid process, accompanied clinically by acute neck pain, often with neck stiffness, fevers and raised inflammatory markers. CDS is thought to be a rare condition; however, it is frequently misdiagnosed. CDS is an important differential diagnosis in patients presenting with acute neck pain. PMID- 29123772 TI - Ventricular fibrillation by anaphylaxis following consumption of blue_skinned fish. AB - Case: Approximately 4_h after eating mackerel sushi, a 65_year_old man developed generalized itchiness and redness, after which he became unresponsive. He went into a state of ventricular fibrillation but after he was defibrillated twice, his heartbeat returned. The electrocardiogram obtained immediately after hospitalization showed some ST_segment depression, but a subsequent electrocardiogram showed improvement. Coronary CT showed no obvious stenosis or plaque in the coronary artery. Outcome: Results of an IgE_RAST test confirmed that the level of allergen_specific IgE for mackerel measured <0.10_UA/mL, while the level for anisakis was 1.91_UA/mL. Conclusions: As for the mechanism leading to cardiac arrest, it is thought that the histamines and leukotrienes released from cardiac mast cells caused a coronary artery spasm (Kounis syndrome). This anaphylactic shock is considered to be a result of anisakis allergy, but in general cases of anaphylaxis resulting from consumption of blue_skinned fish. PMID- 29123773 TI - Severe pancreatoduodenal injury. AB - Case: A 30-year-old male involved in a traffic accident was brought to our hospital. He was in shock with a rigid abdomen, and a computed tomography scan showed severe pancreatoduodenal injury. He was successfully treated with damage control surgery consisting of peripancreatic packing at the initial surgery followed by a two-stage pancreaticoduodenectomy. Outcome: The postoperative course was complicated by a hepatic abscess, but there were no pancreaticoduodenectomy-related complications. The patient was transferred to a local hospital on postoperative day 55. Conclusion: Three step strategy consisting of peripancreatic packing followed by a two-stage pancreaticoduodenectomy is an effective treatment strategy for severe pancreatoduodenal injury. PMID- 29123774 TI - Successful treatment of non-convulsive status epilepticus diagnosed using bedside monitoring by a combination of amplitude-integrated and two-channel simplified electroencephalography. AB - Case: A 66-year-old man developed disturbed consciousness and right hemiparesis with transient convulsions in the right arm. Bedside monitoring using a combination of amplitude-integrated electroencephalography and two-channel simplified electroencephalography revealed intermittent episodes of 1-3 Hz delta waves lasting for approximately 5 min, consistent with non-convulsive status epilepticus. Fosphenytoin (22.5 mg/kg/day) and levetiracetam (1,000 mg) prevented right arm convulsions but did not restore consciousness. The two-channel simplified electroencephalography also showed an intermittent periodic delta wave pattern in the Fp1-C3 channel. Conventional electroencephalography revealed a polymorphic delta activity that was abolished by 2.5 mg diazepam, thus confirming the diagnosis of non-convulsive status epilepticus. Outcome: The patient recovered completely with the antiepileptic drug combination. Conclusion: Immediate initiation of bedside monitoring using amplitude-integrated electroencephalography and two-channel simplified electroencephalography allows early detection of non-convulsive status epilepticus in patients with disturbed consciousness, which considerably improves the prognosis. PMID- 29123775 TI - Early initiation of steroid pulse therapy for neuromyelitis optica in an emergency room setting. AB - Case: A 40-year-old man presented to the emergency room with visual impairment, dysesthesia of lower legs, and urinary retention. Two days before admission, he was consulted to the neurology department due to bilateral optic neuritis and scheduled the magnetic resonance imaging of spine. However, the urinary retention deteriorated acutely and he came to the emergency room. On arrival, the plain magnetic resonance image of his spine showed diffuse hyperintensity signals of the spinal cord in T2-weighted images. He was diagnosed with neuromyelitis optica and steroid pulse therapy was initiated. Outcome: We began treatment immediately in the emergency room, cooperating with the neurology team. After admission, plasmapheresis was added for his fluctuating symptoms. On hospital day 7, he was discharged without complication. Conclusion: It is important to understand the various clinical manifestations of neuromyelitis optica. In emergency settings, immediate steroid therapy is necessary for better outcomes. PMID- 29123776 TI - Severe heatstroke complicated with Takotsubo cardiomyopathy. AB - Case: A 69 year-old female with history of schizophrenia was transported to our hospital by ambulance due to coma. On arrival, she was hypotensive and tachycardic with a Glasgow coma scale score of 3 and a rectal core temperature of 40 degrees C. Heatstroke was strongly suspected as the cause of the coma and hypotension. Active external cooling with an electric fan and cooled IV fluid administration were started. Her electrocardiogram (EKG) showed ST elevation in V2-6, II, III and aVF. Echocardiography revealed apical ballooning, which indicated Takotsubo cardiomyopathy. Coronary angiography indicated normal coronary arteries. Outcome: After admission to the intensive care unit, her cardiovascular status gradually improved and she was transferred to the psychiatric ward on day 36. Conclusion: Heatstroke and Takotsubo cardiomyopathy can share the same pathophysiology. Close evaluation of hemodynamic status and myocardial damage is critical for survival. PMID- 29123777 TI - Ileum perforation due to cytomegalovirus infection in a patient with adult T-cell leukemia. AB - Case: A 73-year-old woman was transferred to our department due to severe abdominal pain with peritonitis. Her laboratory data showed that her white blood cell count was elevated to more than 50,000/mm3. Antibodies to HTLV-I were positive and we made the diagnosis of adult T-cell leukemia (ATL). Outcome: Emergency laparotomy was performed and revealed two separate small perforations of the ileum, requiring bowel resection. Immunohistochemistry for cytomegalovirus (CMV) antigen revealed positive staining in the intestinal stromal cells. Despite surgery and antiviral therapy with ganciclovir, she died after 28 days. Conclusion: Adult T-cell leukemia patients may present acute abdominal pain due to intestinal perforation caused by CMV infection. We should be aware of CMV infection as one of the pathogens causing acute abdominal crises such as massive hemorrhage or visceral perforation. PMID- 29123778 TI - Simultaneous operation for cancer-related sigmoid colon perforation and abdominal aortic aneurysm of 76 mm in diameter. AB - Case: A 92-year-old woman was emergently admitted to our hospital for peritonitis caused by sigmoid colon cancer perforation, with a coexistent abdominal aortic aneurysm of 76 mm in diameter. Outcome: A 92-year-old woman was admitted to the hospital with a complaint of abdominal pain and fever of 24-h duration. On physical examination, severe tenderness with muscular defense and a palpable, pulsating mass were detected in the upper abdomen. The patient was diagnosed as having panperitonitis caused by sigmoid colon perforation. Computed tomography also revealed an infrarenal abdominal aortic aneurysm of 76 mm in diameter. We performed endovascular aneurysm repair to prevent aneurysmal rupture in the perioperative period and simultaneously performed intra-abdominal drainage and Hartmann's operation. The patient's postoperative course was uneventful. Conclusion: Simultaneous endovascular aneurysm repair and operation for peritonitis is considered a possible treatment strategy for patients at high risk of abdominal aortic aneurysm rupture. PMID- 29123779 TI - H1N1 influenza-associated pneumonia with severe obesity: successful management with awake veno-venous extracorporeal membrane oxygenation and early respiratory physical therapy. AB - Case: We report a case of H1N1 influenza-associated respiratory failure with severe obesity. Outcome: A 54-year-old man was admitted to our intensive care unit (ICU) because of H1N1 influenza-associated severe respiratory failure. He was severely obese, having a body mass index of 37.2. His respiratory condition remained severe under mechanical ventilation. We started veno-venous extracorporeal membrane oxygenation immediately. Awake management was started on ICU Day 6, and the patient's respiratory physical therapy began the following day. His respiratory condition showed excellent improvement immediately following the initiation of respiratory physical therapy. The patient was successfully decannulated on ICU Day 9, and he was discharged from the ICU on Day 11. He was discharged from the hospital with no severe disability on disease Day 60. Conclusion: Awake extracorporeal membrane oxygenation management with early respiratory physical therapy can be useful in the treatment of morbidly obese patients who present with severe respiratory failure. PMID- 29123780 TI - Rabbit syndrome after taking herbicide containing 2-(4-chloro2 methylphenoxypropionic) acid. AB - Case: A 48-year-old woman attempted to commit suicide by ingesting a herbicide containing 4-chloro-2-methylphenoxypropionic acid. She was transferred to the emergency center. During this time, involuntary movements of her lips at approximately 5 Hz were observed, mimicking the chewing movements of a rabbit. Outcome: The symptom resolved in concert with the decrease in her blood concentration of the herbicide. Conclusion: It was suspected that the ingestion of 4-chloro-2-methylphenoxypropionic acid may have been associated with development of the rabbit syndrome. PMID- 29123781 TI - Successfully treated life-threatening upper gastrointestinal bleeding from fistula between gastroduodenal artery pseudoaneurysm and duodenum. AB - Case: An 85-year-old man was admitted to the hospital, underwent laparotomy, and was diagnosed with diffuse peritonitis due to perforation of gastric ulcer. Omental patch repair was carried out. After surgery, he suddenly vomited blood and manifested hypovolemic shock. An emergency upper gastrointestinal endoscopy was carried out immediately. However, the bleeding source was not visible. Dynamic-enhanced abdominal computed tomography showed a pseudoaneurysm of the gastroduodenal artery-communicating duodenal lumen with extravasation. Next, the patient underwent angiography for embolization. However, selective arterial embolization was not successful. Outcome: Finally, duodenotomy was carried out. The fistula between the pseudoaneurysm and duodenal lumen was directly ligated. An aneurysm could be clearly identified by previous findings. Conclusions: Gastroduodenal artery aneurysms are very uncommon but possibly lethal if they rupture. This life-threatening condition requires rapid diagnosis and treatment. Minimally invasive treatment is the preferred therapy for gastroduodenal artery aneurysm; however, acute care surgery should be considered without hesitation when conditions are critical. PMID- 29123782 TI - Temporal intrailiac balloon occlusion for the treatment of intractable pelvic fracture hemorrhage. AB - Case: A 48-year-old schizophrenic man sustained multiple injuries following a fall. Unstable pelvic fractures were diagnosed in the emergency department. The patient's hemodynamic status was stabilized following bilateral internal iliac artery embolization using a gelatin sponge. However, recurrent bleeding and an expanding retroperitoneal hemorrhage occurred 1 h after transcatheter arterial embolization. Outcome: Using temporal intrailiac balloon occlusion, with preperitoneal gauze packing, the patient's hemodynamic status was stabilized in the intensive care unit. No complications were observed following transcatheter arterial embolization and balloon occlusion. Conclusions: Temporary intrailiac balloon occlusion is a rapid and safe treatment for refractory pelvic hemorrhage, which can be administered simultaneously with other treatments including preperitoneal gauze packing and external fixation. PMID- 29123783 TI - Profuse bleeding from a pseudoaneurysm of the right superior thyroid artery after tracheostomy. AB - Case: A 70-year-old man was brought to our hospital emergency department with accidental thermal burns. Surgical tracheostomy was carried out on day 8 after admission, followed by several profuse bleeding episodes from the orifice. Contrast-enhanced computed tomography of the neck revealed a small nodule with arterial phase enhancement that was suspected to be a pseudoaneurysm. During emergency angiography, the nodule was revealed to be a pseudoaneurysm arising from the right superior thyroid artery with contrast medium extravasation. Outcome: The patient underwent transcatheter arterial embolization, which resolved bleeding from the tracheostomy orifice. Conclusion: Pseudoaneurysm of the superior thyroid artery is an extremely rare and life-threatening tracheostomy complication. All clinicians certified to perform tracheostomy should be acquainted with the various complications and methods for managing life threatening post-tracheostomy complications. PMID- 29123784 TI - Blunt pancreatic duct injury in children. AB - Case: A 10-year-old boy sustained a blunt injury to the pancreatic neck with complete transection of the main pancreatic duct. Because endoscopic catheterization across the rupture site was not possible, an endoscopic nasopancreatic drain was inserted through the proximal pancreatic duct into the retroperitoneum. An emergency laparotomy was carried out, during which time the tube was used as a guide for identifying disrupted pancreatic ducts. Damaged tissue was removed, the proximal pancreatic duct was ligated, and a Roux-en-Y distal pancreaticojejunostomy was carried out. Outcome: The patient was discharged 49 days after surgery. Conclusion: Preoperative catheterization of the transected pancreatic duct is an option for detecting a disrupted main pancreatic duct. PMID- 29123785 TI - Surgical treatment of gastrointestinal hereditary hemorrhagic telangiectasia. AB - Case: A 48-year-old man with a history of gastrointestinal bleeding from Osler Weber-Rendu disease presented with recurrent hematemesis and tarry stool. He received repeated endoscopic therapy, but profound component therapy was still needed. Because repeated gastrointestinal bleeding was caused by same bleeder, tattoo-assisted laparoscopic gastric wedge resection was carried out. Outcome: The pathology showed vascular abnormalities that involved gastric mucosal and submucosal layers. After surgery, the blood transfusion for the patient is not seen. Conclusion: Osler-Weber-Rendu is a hereditary disease characterized by vascular abnormalities of the nose, skin, lung, brain, and gastrointestinal tract. Management of gastrointestinal bleeding requires medical treatment first, and there are rare reports of surgical treatment. Our pathology findings showed a transmucosal vessel lesion, which had poor response to endoscopic treatment. Surgical intervention may be considered in the patient with gastrointestinal bleeding refractory to endoscopic therapy. PMID- 29123786 TI - Usefulness of prothrombin complex concentrate for cardiac injury in patients receiving oral anticoagulant therapy. PMID- 29123787 TI - Ditch-related falls: Need for preventive educational campaigns. PMID- 29123788 TI - Cardiac tamponade after extracorporeal cardiopulmonary resuscitation. PMID- 29123790 TI - Clinical and toxicological findings of acute intoxication with synthetic cannabinoids and cathinones. AB - Aim: Reporting of the analytical and clinical findings of synthetic cannabinoids and cathinones is essential in carrying out a complete clinical assessment of new psychoactive substances. Methods: From 2012 to 2014, we examined synthetic cathinone and cannabinoid poisoning in six patients aged 22-42 years old. Analyses of these compounds were carried out using liquid chromatography-tandem mass spectrometry. Results: The observed clinical symptoms were similar to those reported for intoxication with synthetic cathinones and cannabinoids. In cases of intoxication with synthetic cathinones, the psychiatric and neurological symptoms were long-lasting, and these compounds were detected in serum for 15-48 h after use. Although the clinical symptoms induced by the synthetic cannabinoids disappeared within several hours after use, the range of serum concentrations of these compounds was <=5 ng/mL for 1-3 h after use. In one fatal case, in which high serum concentrations of synthetic cathinones and cannabinoids were detected, the most plausible cause of death was heart failure due to overdose with these drugs. The long-lasting symptoms induced by synthetic cathinones correlated with the long detection window in serum, whereas the early disappearance of symptoms induced by synthetic cannabinoids corresponded to the short detection window in serum. Conclusions: This study shows that the profiles of synthetic cathinones and cannabinoids in serum are closely related to the duration of the toxic symptoms and that concomitant use of two psychoactive drugs with different pharmacological actions may have the potential for fatal cardiotoxicity. PMID- 29123789 TI - The retroperitoneal interfascial planes: current overview and future perspectives. AB - Recently, the concept of interfascial planes has become the prevalent theory among radiologists for understanding the retroperitoneal anatomy, having replaced the classic tricompartmental theory. However, it is a little known fact that the concept remains incomplete and includes embryological errors, which have been revised on the basis of our microscopic study. We believe that the concept not only provides a much clearer understanding of the retroperitoneal anatomy, but it also allows further development for diagnosis and treatment of retroperitoneal injuries and diseases, should it become an accomplished theory. We explain the history and outline of the concept of interfascial planes, correct common misunderstandings about the concept, explain the unconsciously applied therapeutic procedures based on the concept, and present future perspectives of the concept using our published and unpublished data. This knowledge could be essential to acute care physicians and surgeons sometime soon. PMID- 29123791 TI - Comparison of the efficacy of continuous i.v. infusion versus continuous regional arterial infusion of nafamostat mesylate for severe acute pancreatitis. AB - Aim: Continuous regional arterial infusion (CRAI) of protease inhibitors may be effective in the treatment of severe acute pancreatitis (SAP), but it is more invasive than i.v. infusion. The purpose of this study was to examine the effectiveness of continuous i.v. infusion (CIVI) for SAP compared with CRAI by unifying the dose and the administration period of nafamostat mesylate. Methods: This study comprised 32 patients with SAP who were divided into two groups: the CRAI group and the CIVI group. The protease inhibitor, nafamostat mesylate, was continuously infused at a rate of 200 mg/day for 5 days in both groups. Clinical outcomes including in-hospital mortality were examined. Results: There were no significant between-group differences in in-hospital mortality and 90-day mortality. The duration from admission to treatment was significantly shorter in the CIVI group (median, 7 h vs. 2 h, P = 0.0001; CRAI group vs. CIVI group). The rate of mechanical ventilation was significantly less in the CIVI group than in the CRAI group (93% vs. 47%, P = 0.007). The CIVI group showed a tendency toward decreased length of intensive care unit stay (median, 13 days vs. 4 days, P = 0.085) and hospital stay (median, 19 days vs. 11 days, P = 0.072). Total costs during hospitalization were significantly lower in the CIVI group (median, $18,320 vs. $11,641, P = 0.049). Conclusion: The effectiveness of CIVI with early nafamostat mesylate treatment after the development of SAP could be equivalent to, or better than, that of CRAI. PMID- 29123792 TI - Red cell and platelet distribution widths in patients with angina pectoris and acute myocardial infarction. AB - Aim: We aimed to determine the relationship of red cell and platelet distribution widths with the onset of acute myocardial infarction, to enable the early detection and prevention of acute myocardial infarction. Methods: Red cell and platelet distribution widths were retrospectively determined in 46 patients with stable angina pectoris and 140 patients with acute myocardial infarction who were brought to the emergency department of our institution. Red cell and platelet distribution widths were determined with an automatic blood cell analyzer, and the results were compared between the acute myocardial infarction and angina pectoris groups. Results: Both red cell and platelet distribution width values obtained at onset were significantly higher in the acute myocardial infarction group than in the angina pectoris group (red cell distribution widths, 46.4 +/- 0.51% versus 44.5 +/- 0.59%; mean difference -1.91 [95% confidence interval (CI), -3.79 to -0.34]; platelet distribution widths, 12.1 +/- 0.22 fL versus 11.1 +/- 0.17 fL; mean difference -1.03 [95% CI, -1.58 to -0.47]). The red cell distribution widths before onset was not different between the acute myocardial infarction and angina pectoris groups; however, the platelet distribution widths before onset was higher in the acute myocardial infarction group (red cell distribution widths, 46.5 +/- 0.85% versus 45.9 +/- 0.59%; mean difference -0.71 [95% CI, -2.74 to 1.30]; platelet distribution widths, 11.4 +/- 0.39 fL versus 10.6 +/- 0.21 fL; mean difference -0.83 [95% CI, -1.66 to 0.11]). Conclusion: Red cell distribution widths and especially platelet distribution widths may contribute to the early detection of acute myocardial infarction. PMID- 29123794 TI - Continuous veno-venous hemodialysis and filtration for extensive burn with severe hypernatremia. AB - Case: A 51-year-old man presented with severe burns, with a burn index of 33.5. Relaxation incisions were made in the trunk and right arm. Ringer's solution (12,000 mL) was used as initial fluid therapy for the first 24 h. The patient's serum Na level gradually increased to 170 mEq/L; infusion was carried out to correct the hypernatremia. Continuous veno-venous hemodialysis and filtration succeeded in maintaining the serum Na level at approximately 145 mEq/L. Outcome: After the initiation of continuous veno-venous hemodialysis and filtration, the skin graft survival rate improved markedly with the normalization of the Na level, and the patient recovered smoothly. He was discharged on foot. Conclusion: Hypernatremia, frequently observed in patients with extensive burns, is considered to be markedly disadvantageous for the survival of skin grafts. Continuous veno-venous hemodialysis and filtration may be one of the options for the treatment of refractory hypernatremia in severe burns. PMID- 29123796 TI - Refractory paroxysmal sympathetic hyperactivity following brain injury in a pregnant woman that dramatically improved after delivery. AB - Case: A 16-year-old primiparous girl in the 11th week of gestation presented to our hospital with a traumatic brain injury suffered during a motorcycle accident. She was comatose on arrival to the hospital and was admitted to the intensive care unit. From day 2, she developed intermittent episodes of tachycardia with tachypnea, fever, profuse sweating, and extensor posturing. She was diagnosed with paroxysmal sympathetic hyperactivity (PSH) and treated with morphine. However, paroxysmal sympathetic hyperactivity could not be controlled and her general condition deteriorated. Intrauterine fetal death was confirmed in the 16th week of gestation, on day 37 of hospitalization. P paroxysmal sympathetic hyperactivity increased each day until delivery and dramatically improved after delivery. Outcome: The patient gradually regained consciousness and was discharged to a rehabilitation hospital on day 117 after hospitalization. Conclusion: Pregnancy is a risk factor for paroxysmal sympathetic hyperactivity exacerbation, and delivery can result in resolution of the condition. PMID- 29123795 TI - Management of inadvertent vertebral artery injury due to central venous catheterization in a coagulopathic patient. AB - Case: A 72-year-old man was admitted to the intensive care unit for severe pancreatitis with coagulopathy. He underwent hemodialysis catheter insertion into the internal jugular vein that subsequently leaked arterial blood; vertebral artery cannulation was suspected following a computed tomography scan. Outcome: Under angiographic guidance, the catheter was removed, and an arteriovenous fistula was identified. The patient was successfully treated with endovascular embolization of the affected vertebral artery with detachable coils and N-butyl-2 cyanoacrylate. Conclusion: Despite ultrasound guidance, vertebral cannulation can occur, which can result in serious complications. Prompt management is needed to prevent further sequelae. Endovascular embolization with detachable coils and N butyl-2-cyanoacrylate appears to be an effective option for vertebral artery injury in patients with coagulopathy. PMID- 29123793 TI - Investigation and treatment of pulmonary embolism as a potential etiology may be important to improve post-resuscitation prognosis in non-shockable out-of hospital cardiopulmonary arrest: report on an analysis of the SOS-KANTO 2012 study. AB - Background: The prognosis of non-shockable out-of-hospital cardiac arrest is worse than that of shockable out-of-hospital cardiac arrest. We investigated the associations between the etiology and prognosis of non-shockable out-of-hospital cardiac arrest patients who experienced the return of spontaneous circulation after arriving at hospital. Methods and Results: All subjects were extracted from the SOS-KANTO 2012 study population. The subjects were 3,031 adults: (i) who had suffered out-of-hospital cardiac arrest, (ii) for whom there were no pre-hospital data on ventricular fibrillation/pulseless ventricular tachycardia until arrival at hospital, (iii) who experienced the return of spontaneous circulation after arriving at hospital. We compared the patients' prognosis after 1 and 3 months between various etiological and presumed cardiac factors. The proportion of the favorable brain function patients that developed pulmonary embolism or incidental hypothermia was significantly higher than that of the patients with presumed cardiac factors (1 month, P < 0.0001 and P < 0.0001, respectively; 3 months, P = 0.0018 and P < 0.0001, respectively). In multiple logistic regression analysis, pulmonary embolism and incidental hypothermia were found to be significant independent prognostic factors for 1- and 3-month survival and the favorable brain function rate. Conclusions: In patients who suffer non-shockable out-of hospital cardiac arrest, but who experience the return of spontaneous circulation after arriving at hospital, the investigation and treatment of pulmonary embolism as a potential etiology may be important for improving post-resuscitation prognosis. PMID- 29123797 TI - Double traction method-an easy and safe reduction method for anterior shoulder dislocations, even for non-orthopedic surgeons. AB - Cases: Forty-three male and 27 female patients with anterior shoulder dislocation, with an average age of 45 years, were treated with the "double traction method". The reduction is carried out by two operators, with the patient in a supine position. The first operator holds the patient's wrist and pulls gently longitudinally. After the patient's muscle spasm adequately subsides, the second operator tows the humerus head laterally by using a towel wrapped around the proximal arm. Outcome: Reduction was successful in 63 patients (90%). No iatrogenic fracture or neurovascular deficit occurred. Conclusion: Movement of the patient's arm position causes pain-related muscle spasm. The double traction method is distinctive compared to other manual relocation maneuvers in that the patient's arm is kept at the same position throughout the whole procedure. This maneuver is an easy and safe reduction method for anterior shoulder dislocations, even for non-orthopedic surgeons. It should be an option worth considering for closed reduction in shoulder dislocations. PMID- 29123798 TI - Revascularization for acute blunt popliteal artery injury. AB - Case: A 45-year-old man was brought to our hospital in pre-shock after falling from a motorcycle. As we diagnosed him with open fracture of the right femur with leg ischemia, we performed revascularization of injured popliteal artery and treated the leg. The pathological findings showed fragmentation and decrease of elastic fibers and fragmentation of collagen fibers, but no inflammatory cells or intimal hyperplasia, and no dissection. Outcome: Unfortunately, amputation had to be carried out on the 29th postoperative day due to infection and leg dysfunction. The postoperative course was uneventful. The patient could walk with an artificial leg and was discharged approximately 5 months after popliteal artery replacement. Conclusions: We report a case of revascularization involving a patient with open fracture of the right femur due to acute blunt popliteal artery injury. PMID- 29123800 TI - Acute pancreatitis and necrotizing colitis following extensive burn injury. AB - Case: We describe a patient with severe pancreatitis and ischemic colitis after extensive burn injury. An 81-year-old man presented with a 55% total body surface area burn with inhalation injury. A low-density area was detected in the pancreas on the abdominal computed tomography scan on admission. The clinical course of the patient was good until 28 days after injury when he complained of abdominal pain and distension. Abdominal computed tomography revealed acute pancreatitis and ischemic colitis. Outcome: The patient died 59 days after burn injury. Conclusions: Extensive burn injury can cause acute pancreatitis. Further work-up is necessary to identify pancreatic complications after severe burn injury. PMID- 29123799 TI - Septic shock due to infected giant venous malformation complicated by massive bleeding. AB - Case: A 19-year-old man with a hemangioma that extended from the left arm to the axillary region had deteriorated due to shock, and no improvement was observed after fluid resuscitation. His status on arrival led to complications of hemorrhagic and septic shock with his left arm swollen and deep purple in color. Left arm amputation to control the source of bleeding and infection was thought to be indicated, however, the coagulation system had collapsed. Therefore, initial reduction of the blood flow to the hemangioma with angiographic endovascular treatment was carried out. Thereafter, continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter against hypercytokinemia was introduced in the intensive care unit for damage control, which resulted in success. Outcome: We completed the arm amputation, and subsequently carried out a latissimus dorsi muscle flap transfer on the amputated stump. The patient achieved an ambulatory discharge. Conclusions: We successfully treated the very rare case of massive venous malformation with shock due to hemorrhage and infection by performing damage control. PMID- 29123801 TI - Genuine splenic artery aneurysm rupture treated by N-butyl cyanoacrylate and metallic coils under resuscitative endovascular balloon occlusion of the aorta. AB - Case: A 66 year-old woman who presented with sudden lower abdominal pain was transferred to our emergency room. Vital signs were stable on arrival at the hospital, but immediately became unstable. Systolic/diastolic blood pressure and heart rate were 66/33 mmHg and 70 b.p.m., respectively. Computed tomography scanning showed splenic artery aneurysm rupture and extravasation. The patient was treated non-operatively and definitively by endovascular therapy comprising resuscitative endovascular occlusion of the aorta for hemodynamic control, N butyl cyanoacrylate, and metallic coils as an embolization material. Outcome: On admission day 3, she was enrolled in another department and admission day 54, she was discharged. Conclusion: Although resuscitative endovascular occlusion of the aorta and N-butyl cyanoacrylate is known to be effective, the use of resuscitative endovascular occlusion of the aorta with transcatheter arterial embolization and N-butyl cyanoacrylate for non-traumatic bleeding has not previously been reported. By combining and adapting these devices, their applications in endovascular management may be increased. PMID- 29123803 TI - Analysis of consumption of medical resources in terms of intensive care unit/hospital stay and severity using Japan Trauma Data Bank. AB - Aim: We analyzed the length of intensive care unit or hospital stay of trauma patients to assess the consumption of medical resources using the Japan Trauma Data Bank. Methods: We classified 60,580 cases registered between 2004 and 2010 in the Japan Trauma Data Bank by hospital ward on emergency admission. Results: A total of 9,564 intensive care patients could be moved to the general ward before hospital transfer or discharge; 6,217 cases were transferred to another hospital and 9,444 cases were discharged directly from the intensive care unit. The length of intensive care unit or hospital stay correlated with the injury severity score. There were 5,856 patients (68%) from the non-survivors who died within 3 days of admission. Conclusion: Based on the Japan Trauma Data Bank data for many trauma patients, there are numerous cases of long-term stay >=15 days in intensive care in patients who could not be transferred to a general ward and who consumed the medical resources in the critical care department. PMID- 29123802 TI - Lactate, a useful marker for disease mortality and severity but an unreliable marker of tissue hypoxia/hypoperfusion in critically ill patients. AB - Early aggressive hemodynamic resuscitation using elevated plasma lactate as a marker is an essential component of managing critically ill patients. Therefore, measurement of blood lactate is recommended to stratify patients based on the need for fluid resuscitation and the risks of multiple organ dysfunction syndrome and death. Hyperlactatemia is common among critically ill patients, and lactate levels and their trend may be reliable markers of illness severity and mortality. Although hyperlactatemia has been widely recognized as a marker of tissue hypoxia/hypoperfusion, it can also result from increased or accelerated aerobic glycolysis during the stress response. Additionally, lactate may represent an important energy source for patients in critical condition. Despite its inherent complexity, the current simplified view of hyperlactatemia is that it reflects the presence of global tissue hypoxia/hypoperfusion with anaerobic glycolysis. This review of hyperlactatemia in critically ill patients focuses on its pathophysiological aspects and recent clinical approaches. Hyperlactatemia in critically ill patients must be considered to be related to tissue hypoxia/hypoperfusion. Therefore, appropriate hemodynamic resuscitation is required to correct the pathological condition immediately. However, hyperlactatemia can also result from aerobic glycolysis, unrelated to tissue dysoxia, which is unlikely to respond to increases in systemic oxygen delivery. Because hyperlactatemia may be simultaneously related to, and unrelated to, tissue hypoxia, physicians should recognize that resuscitation to normalize plasma lactate levels could be over-resuscitation and may worsen the physiological status. Lactate is a reliable indicator of sepsis severity and a marker of resuscitation; however, it is an unreliable marker of tissue hypoxia/hypoperfusion. PMID- 29123804 TI - Self-inflicted injuries are an important cause of penetrating traumatic injuries in Japan. AB - Aim: Japan has a low crime rate, but a high suicide rate. The aim of this study is to review the causes of penetrating traumatic injuries in a tertiary care emergency center in Japan. Methods: We retrospectively reviewed all admissions for traumatic injuries over a 3-year period, and calculated the proportion of patients with penetrating traumatic injuries. Weapon used, age, gender, Injury Severity Score, cause of injury, and site of injury in all patients with penetrating injuries were reviewed. The proportion of patients with penetrating injuries among patients with all types of traumatic injuries requiring surgical intervention was calculated. Results: Of 1,321 patients admitted over 3 years, 65 patients (5%) suffered from penetrating injuries. Most were stab wounds, with only one gunshot (2%). The most common site of injury was an extremity (48%). The most common cause of penetrating injury was self-inflicted (38%). The abdomen is the most common site injured among self-inflicted injuries. Of patients with all types of traumatic injuries requiring surgical intervention, penetrating injuries accounted for 23%. Conclusion: Penetrating injuries represent 23% of all patients with traumatic injuries who required surgical intervention. Self-inflicted penetrating injuries were most common, supporting the need for preventive services. Acute care surgeons must be familiar with the surgical management of penetrating traumatic injuries, even in a country with a low crime rate. PMID- 29123805 TI - A national survey examining recognition, demand for antivenom, and overall level of preparedness for redback spider bites in Japan. AB - Aim: Redback spiders are rapidly becoming a nationwide problem in Japan. The domestic production of antivenom for redback spider bites has been started because of extremely low supply. The purpose of this study was to investigate the ability of emergency physicians to recognize redback spider bites and to examine the demand for antivenom and identify the ideal choice for storage. Methods: Questionnaires examining the ability to recognize redback spider bites, the demand for antivenom, and overall level of preparedness were sent to 271 emergency medical service centers in Japan in March 2015. Results: Completed questionnaires were returned by 156 medical institutions (58%). Only 25% of the institutes correctly answered regarding the recognition of redback spider bites. A demand for the new, domestically produced antivenom was reported by 55% of the institutes. Antivenom demand was high and increased with the ability to recognize redback spider bites (0 correct answers, n = 24 [42.9%]; 1-2 answers, n = 32 [55.2%]; three answers, n = 28 [71.8%]; P = 0.02). The storage of antivenom within their prefectures or regions was the best option for initial supply planning. Approximately 90% of the emergency centers showed an ability to use the antivenom safely. Conclusion: The recognition of redback spider bites was low; however, the demand for antivenom was high. The storage of antivenom within their own prefectures or regions was considered to be the best option for initial supply planning. Emergency medical service centers are also good candidates for storage and safe use of antivenom. PMID- 29123806 TI - A retrospective study of in-hospital cardiac arrest. AB - Aim: In-hospital cardiac arrest is an important issue in health care today. Data regarding in-hospital cardiac arrest in Japan is limited. In Australia and the USA, the Rapid Response System has been implemented in many institutions and data regarding in-hospital cardiac arrest are collected to evaluate the efficacy of the Rapid Response System. This is a multicenter retrospective survey of in hospital cardiac arrest, providing data before implementing a Rapid Response System. Methods: Ten institutions planning to introduce a Rapid Response System were recruited to collect in-hospital cardiac arrest data. The Institutional Review Board at each participating institution approved this study. Data for patients admitted at each institution from April 1, 2011 until March 31, 2012 were extracted using the three keywords "closed-chest compression", "epinephrine", and "defibrillation". Patients under 18 years old, or who suffered cardiac arrest in the emergency room or the intensive care unit were excluded. Results: A total of 228 patients in 10 institutions were identified. The average age was 73 +/- 13 years. Males represented 64% of the patients (82/146). Overall survival after in-hospital cardiac arrest was 7% (16/228). Possibly preventable cardiac arrests represented 15% (33/228) of patients, with medical safety issues identified in 8% (19/228). Vital sign abnormalities before cardiac arrest were observed in 63% (138/216) of patients. Conclusions: Approximately 60% of patients had abnormal vital signs before cardiac arrest. These patients may have an improved clinical outcome by implementing a Rapid Response System. PMID- 29123807 TI - Sarcopenia is a predictive factor for prolonged intensive care unit stays in high energy blunt trauma patients. AB - Aim: Sarcopenia has been increasingly reported as a prognostic factor for outcome in settings such as cirrhosis, liver transplantation, and emergent surgery. We aimed to elucidate the significance of sarcopenia in severe blunt trauma patients. Methods: We retrospectively analyzed 84 patients emergently admitted to the intensive care unit at Kyushu University Hospital (Fukuoka, Japan) from May 2012 to April 2015. We assessed the amount of skeletal muscle present according to computed tomography and its relevance to ventilation-free days, patients' length of stay in the intensive care unit, and 28-day mortality. Results: Twenty five (29.7%) patients were defined as sarcopenic. Sixteen (19.7%) patients required 15 days or more in the intensive care unit. The major reason was a prolonged ventilation requirement due to flail chest (n = 7) or pneumonia (n = 3). Sarcopenic patients' stays in intensive care were significantly longer than those of non-sarcopenic patients (18.7 versus 6.4 days, respectively; P < 0.001). Univariate and multivariate analyses showed sarcopenia to be a significant risk factor for prolonged intensive care unit stay. Conclusion: Sarcopenia is a risk factor that predicts prolonged intensive care unit stay in high-energy blunt trauma patients. PMID- 29123808 TI - Characteristics of patients who fell into open drains: a report from a single emergency center in East Shizuoka: Epidemiology of patients who fell into open drains in East Shizuoka. AB - Aim: To clarify the characteristics of injuries caused by falling into an open drain. Methods: A medical chart review was retrospectively carried out of all patients in East Shizuoka, Japan, who were injured due to falling into an open drain, and who were subsequently transported to hospital by ambulance or a physician-staffed helicopter, between January 2013 and December 2014. The patients were divided into two groups, those treated as outpatients and those who were admitted to hospital. Results: During the investigation period, there were 33 patients who had accidentally fallen into an open drain. The ages of the subjects ranged from 10 to 90 years, with an average age of 58.8 years. The average age of the subjects, the ratio of female patients, and the average injury severity score in the admission group were higher than that of the outpatient group. One patient in the admission group who had cardiac arrest due to a cervical cord injury eventually died. Conclusion: Falls into open drains are especially frequent in elderly people and female patients, and older patients tend to more frequently require admission due to severe injury. To prevent injuries of this type, some measures are required to improve the safety of open drains. PMID- 29123809 TI - Splenic volume in severe sepsis is associated with disease severity and pneumococcal infection. AB - Aim: A small spleen, which is occasionally found in patients with pneumococcal sepsis, may increase pneumococcal susceptibility because of splenic malfunction. However, a small spleen may also originate from severe disease. We carried out a retrospective study to evaluate the association between splenic volume and severe pneumococcal sepsis or disease severity. Methods: We reviewed the medical records of 23 patients with severe pneumococcal sepsis treated at our institution between January 2004 and September 2015 (pneumococcal group) and 61 patients with severe non-pneumococcal bacteremia treated between April 2011 and September 2015 (control group). Splenic volume measured by abdominal computed tomography on admission was compared between the two groups. Correlations between Acute Physiology and Chronic Health Evaluation (APACHE) II scores and splenic volume on admission and the change in splenic volume from the non-septic state to admission were also determined. Results: Splenic volume on admission was significantly smaller (P = 0.001) and a small spleen was more frequent (P < 0.001) in the pneumococcal group. The APACHE II score was negatively correlated with splenic volume on admission (r = -0.46, P < 0.001) and the change in splenic volume (r = 0.44, P = 0.004). Pneumococcal infection (odds ratio 13.1, 95% confidence interval 2.6-65.7; P = 0.002) and APACHE II score (odds ratio 1.2, 95% confidence interval 1.1-1.3; P = 0.002) were independently associated with small spleen. Conclusion: Splenic volume decreased with increasing severity of severe sepsis. A small spleen was also associated with severe pneumococcal infection. PMID- 29123810 TI - Outcomes of abdominal trauma patients with hemorrhagic shock requiring emergency laparotomy: efficacy of intra-aortic balloon occlusion. AB - Aim: The aims of this study were to investigate outcomes of abdominal trauma in patients with hemorrhagic shock requiring emergency laparotomy and clarify the beneficial effects of intra-aortic balloon occlusion (IABO) for intra-abdominal hemorrhage in patients with critically uncontrollable hemorrhagic shock (CUHS). Methods: We reviewed 44 hemorrhagic shock patients who underwent emergency laparotomy for intra-abdominal hemorrhage over a 6-year period. Of these patients, we examined data for 19 subjects who underwent IABO during initial resuscitation to control massive intra-abdominal bleeding leading to CUHS. Results: The average Injury Severity Score and probability of survival (Ps) of the 44 patients were 27.6 +/- 15.4 and 0.735 +/- 0.304, respectively, and the overall survival rate was 77.3%. The differences in the Glasgow Coma Scale, lactate level, prothrombin time - international normalized ratio, and Ps between the two groups (21 responders and 23 non-responders) were statistically significant (P < 0.05). Intra-aortic balloon occlusion was attempted in 19 of 23 patients (82.6%) with CUHS, and there were no statistically significant differences in presenting Glasgow Coma Scale, body temperature, lactate, prothrombin time - international normalized ratio, or Revised Trauma Score between the survivors (n = 12) and non-survivors (n = 7). The only significant differences between these two groups were observed in Injury Severity Score (P = 0.047) and Ps (P = 0.007). In all patients, the balloons were successfully placed in 8.1 +/- 3.3 min in the thoracic aorta, and a significant increase in systolic blood pressure was observed immediately after IABO. Conclusion: The IABO procedure can be life-saving in the management of patients with CUHS arising from intra-abdominal hemorrhage, permitting transport to surgery. PMID- 29123811 TI - CPR related thoracic injury: a comparison of CPR guidelines between 2005 and 2010. AB - Aim: The objective of this study was to investigate the incidence and characteristics of thoracic injuries associated with cardiopulmonary resuscitation (CPR) performed under the 2005 and the 2010 guidelines. Methods: We evaluated patients who had an out-of-hospital cardiac arrest in 2010 (2005 group) and 2012 (2010 group). We analyzed the incidence and characteristics of rib fractures and pneumothoraces received during CPR as determined by medical records and image studies. Results: Two hundred and ninety-two patients in the 2005 group and 243 in the 2010 group were enrolled. The number of patients with rib fractures was greater in the 2010 group than in the 2005 group (123 [42.1%] versus 167 [68.7%], P < 0.001), and the number of pneumothorax patients with rib fractures was also higher (8 [2.7%] versus 21 [8.6%], P = 0.004). Of the 21 patients, four had a tension pneumothorax. The anterior-posterior diameter of the chest (APD) was smaller in patients with a pneumothorax and rib fractures than those without the injuries (166.0 mm [standard deviation 22.8] versus 176.2 mm [standard deviation 21.0], P = 0.04), and the APD for patients of Japanese descent was smaller than that of patients of European descent by more than 50 mm. Conclusion: The number of rib fractures and pneumothoraces received during CPR increased significantly under the 2010 guidelines when compared with the 2005 guidelines. As the APD for patients of Japanese descent is smaller than that of patients of European descent, Japanese medical facilities need to be prepared for possible fatal adverse events associated with CPR under the current international guidelines. PMID- 29123812 TI - Targeted age, device deployment, and problems associated with pediatric defibrillation in pediatric prehospital emergency medical care settings in Japan. AB - Aim: The use of automated external defibrillators was expanded to include infants according to the 2010 cardiopulmonary resuscitation guidelines in Japan. However, deployment has been slower for pediatric patients in Japan, because there are fewer appropriate pediatric patients for automated external defibrillators than adults. This study aimed to investigate the targeted age range for pediatric defibrillation and device deployment of defibrillators for pediatric patients in prehospital emergency medical care settings in Japan, and present the issues associated with automated external defibrillators. Methods: We administered a web based survey to the fire defense headquarters in Japan regarding prehospital emergency medical care for pediatric patients in June 2013. We extracted and analyzed some parts of the data related to pediatric defibrillation. Results: Eighty-eight percent of the fire defense headquarters responded to the survey. Sixty-two percent of the fire defense headquarters applied the expanded indication protocol for pediatric defibrillation, which included infants. Forty three percent of the fire defense headquarters replied that their emergency medical service personnel were using semi-automatic defibrillators without a pediatric mode, whereas 21% of them were using automated external defibrillators that were not equipped with pediatric attenuators. Moreover, many of the semi automatic defibrillators are not designed for pediatric defibrillation in patients aged <8 years. Conclusions: Pediatric prehospital emergency medical care in Japan is inadequately equipped for pediatric defibrillation. It will be necessary to use age-appropriate defibrillators as the targeted age range for automated external defibrillators rapidly expands to include infants. PMID- 29123813 TI - Practices and perceived barriers regarding pain management among Emergency Department physicians: a nationwide multicenter survey in Moroccan hospitals. AB - Aim: To describe pain management practices in Moroccan emergency departments, and to identify perceived barriers among emergency department physicians regarding pain management. Methods: Eleven Moroccan emergency departments participated in the study. A nationwide survey was administered to physicians. The questionnaire covered physicians' characteristics, practices regarding pain management, and the perceived barriers to pain control. Results: A total of 86 questionnaires were analyzed. The participants' mean age was 41+/-7 years and 59.3% had more than 10 years working experience in emergency departments. The majority of participants were general physicians (87.2%) with no pain education (73.3%). Pain assessment in emergency departments was carried out by 59.3% of the physicians. Simple interrogatory assessment was the main tool (88.3%) with poor use of algometric scales (11.7%). Pain assessment results were not recorded in clinical charts in 93% of cases. Pain reassessment after treatment was carried out by 23.2% of respondents. Physicians had opiophobia in 80.2% of cases. None of the Moroccan emergency departments participating in the study have a written protocol for pain management. Barriers relating to medical staff and the health care system were the most commonly encountered hindrances that preclude emergency department physicians from proper pain management. Conclusions: Despite the availability of international guidelines, pain management practices are still sub-optimal in Moroccan emergency departments. PMID- 29123814 TI - Spontaneous isolated left gastric artery dissection: unusual visceral artery dissection. AB - Case: A 51-year-old woman visited our emergency department complaining of acute onset of upper abdominal pain and nausea. Abdominal contrast-enhanced computed tomography showed an isolated left gastric artery dissection and pseudoaneurysm. After conservative management for 6 days, endovascular embolization was carried out for treatment of the pseudoaneurysm. Spontaneous dissection of a visceral artery rarely occurs in the case of a left gastric artery. Outcome: Contrast enhanced computed tomography is essential to make an accurate diagnosis and establish a therapeutic strategy. Conclusion: We should consider the occurrence of minor visceral artery dissection if a patient has acute abdominal pain without other obvious causes. PMID- 29123815 TI - Ventricular septal perforation after blunt chest trauma due to blows from a fist. AB - Case: A 40-year-old man received fist blows to his chest and abdomen. He presented with external jugular vein distention and facial congestion. Chest X ray showed bilateral pulmonary congestion. A Levine V/VI holosystolic murmur was audible. Echocardiography showed left-to-right shunt flow across the perimembranous region of the ventricular septum. The diameter of the hole was approximately 13 mm. We diagnosed ventricular septal perforation, started an infusion, and administered vasopressors. However, circulatory dynamics could not be maintained. The ventricular septal perforation was repaired directly with mattress sutures through the right ventricle. A small residual ventricular septal perforation was detected, which was repaired with a patch sutured through the left ventricle. Outcome: The patient was discharged without cardiovascular complications 43 days after admission. Conclusion: Ventricular septal perforation following blunt chest trauma is a rare form of cardiac trauma. It is important to consider the timing of the operation and the best method to ensure cardiac repair. PMID- 29123816 TI - Complete cervical tracheal transection due to blunt trauma. AB - Case: A 31-year-old man was caught up in the rotor of a snow-removing truck. He was diagnosed with tension pneumothorax and managed with tube thoracostomy in the ambulance. But he was left with respiratory discomfort. Computed tomography scan suggested the diagnosis of complete cervical tracheal transection. Outcome: The endotracheal tube was advanced distal to the transection site under bronchoscopic guidance, which stabilized the patient's cardiopulmonary condition. The tracheal injury healed well after emergent surgical repair. Conclusion: Complete cervical tracheal transection is rare and requires a high index of suspicion for timely diagnosis. It is important to secure the airway, which can be done by fiberoptic bronchoscopy. PMID- 29123817 TI - Rupture of gastrointestinal stromal tumor presenting with sudden onset chest and back pain and accompanied by gastric dilatation. AB - Case: A 72-year-old man with hypertension was admitted with acute-onset chest and back pain followed by epigastralgia. He was transported by helicopter due to suspected acute aortic dissection. Systolic blood pressures were equal in both arms. Physical examination showed epigastric tenderness without rebound. Blood tests showed leukocytosis. Electrocardiogram and echocardiogram were normal. Abdominal radiography showed acute gastric dilatation with an air-outlined large mass-like shadow. Abdominal computed tomography revealed a 6-cm exophytic mass and large intramural hematoma in the lesser curvature of the gastric body. Outcome: The patient underwent urgent laparotomy with total gastrectomy. The resected tumor showed positivity for CD117 and CD34 but negativity for S100, indicating a gastrointestinal stromal tumor. Fourteen days after the surgery, the patient was uneventfully discharged. Conclusion: Intramural bleeding of submucosal tumors including gastrointestinal stromal tumor should be considered in cases of acute gastric dilatation. Abdominal radiography may be a clue regarding the presence of this condition. PMID- 29123818 TI - Prolonged hypotension induced by ingesting a topical minoxidil solution: analysis of minoxidil and its metabolites. AB - Case: A 47-year-old man ingested 60 mL of a topical solution (3,000 mg minoxidil) and presented with prolonged hypotension. Treatment with dopamine hydrochloride and noradrenaline provided blood pressure control. Serum unchanged minoxidil concentrations at 4 and 16 h after ingestion were 4,994 and 33.9 ng/mL, respectively. Urine concentrations of unchanged minoxidil, minoxidil-O glucuronide, and minoxidil-N-O-sulfate at 16 h after ingestion were 360.4, 1,953, and 104.5 ng/mL, respectively. Outcome: The serum unchanged minoxidil concentration rapidly decreased over a short interval. However, the patient needed to receive vasopressor support for the first 4 days after being admitted to the hospital. The urine minoxidil-O-glucuronide concentration was higher than the concentrations of unchanged minoxidil and minoxidil-N-O-sulfate. Conclusion: Although the serum concentration of unchanged minoxidil rapidly decreased, ingesting large amounts of a topical minoxidil solution can have serious and prolonged cardiovascular effects. Analyzing the minoxidil-O-glucuronide concentration in urine is useful for diagnosing minoxidil poisoning. PMID- 29123819 TI - Cardiac arrest due to massive hemorrhage from uterine adenomyosis with leiomyoma successfully treated with damage control resuscitation. AB - Case: A 57-year-old woman was transferred to our emergency department by ambulance with cardiopulmonary arrest caused by massive genital bleeding. Cardiopulmonary resuscitation, including massive transfusion, was carried out and the return of spontaneous circulation was achieved. A giant uterine tumor was considered the source of the bleeding. Although hysterectomy was necessary to achieve definitive hemostasis, the patient was unable to tolerate the operation because of hemodynamic instability, acidosis, and coagulopathy. Therefore, we undertook vaginal gauze packing and uterine artery embolization to attain temporary hemostasis, which resulted in hemodynamic stabilization. Abdominal hysterectomy for definitive hemostasis was carried out 10 h after the embolization. Outcome: The patient made a good post-surgical recovery without any complications. Conclusion: In treating hemorrhagic shock due to uterine leiomyoma, damage-control resuscitation may be useful as a bridge prior to definitive hemostasis through hysterectomy. PMID- 29123820 TI - Vitamin K, fresh frozen plasma, and platelet transfusion used to arrest progression of intracranial hemorrhage after traumatic brain injury in a patient taking anticoagulant and antiplatelet agents. AB - Case: An 89-year-old man fell from stairs and sustained head trauma. He was taking warfarin and aspirin. Upon arrival at our hospital, his Glasgow Coma Scale score was 14. Initial head computed tomography showed small acute subdural hematoma. We immediately administered vitamin K and ordered fresh-frozen plasma. Repeat computed tomography 3 and 6 h after trauma revealed the acute subdural hematoma had increased to 14 and 20 mm, respectively, and there were several new intracranial hemorrhages. Fresh-frozen plasma and platelet transfusion were initiated. Outcome: Follow-up computed tomography revealed no further progression of intracranial hemorrhages, and the patient's consciousness did not deteriorate further. Conclusion: Appropriate administration of vitamin K, fresh-frozen plasma, and platelets successfully arrested progression of traumatic intracranial hemorrhages in this patient taking anticoagulant/antiplatelet agents and may have averted brain surgery. PMID- 29123821 TI - Recurrent convulsions, hypocalcemia, and hypoparathyroidism related to delayed diagnosis of 22q11.2 deletion syndrome in a middle-aged man. AB - Case: A 49-year-old man had idiopathic epilepsy with recurrent convulsions and history of cleft palate, mental retardation, schizophrenia, and cataract. He had convulsions the day before and on the day of admission. Fosphenytoin was given i.v.; his convulsion stopped, but he lost consciousness 2 h later and was admitted. Glasgow Coma Scale score on arrival was 3. Cerebral computed tomography showed bilateral calcification in the basal ganglia. Laboratory tests showed decreased serum calcium and albumin and increased creatine kinase. He regained consciousness after i.v. calcium gluconate administration. Additionally, he showed decreased parathyroid hormone and 1,25(OH)2 vitamin D. Suspecting hypoparathyroidism, i.v. calcium gluconate was changed to oral vitamin D. His medical history and physical appearance suggested 22q11.2 deletion syndrome, confirmed by chromosomal analysis. Outcome: The patient was discharged after 29 days and remains convulsion-free. Conclusion: Hypocalcemia due to hypoparathyroidism should be considered in the differential diagnosis of adult recurrent convulsions. PMID- 29123822 TI - Infected iliac artery aneurysm with aortocaval fistula. AB - Case: We report a case of an infected iliac artery aneurysm complicated by an aortocaval fistula. Outcome: A 74-year-old-man was admitted with fever, chills, general fatigue, and appetite loss. The patient was diagnosed with an infected iliac artery aneurysm, which was controlled with antibiotics preoperatively. During hospitalization, deep vein thrombosis developed with a pulmonary embolism resulting from an aortocaval fistula. The patient was successfully operated on with in situ autologous vein graft reconstruction. Conclusion: An infected iliac artery aneurysm with aortocaval shunt has rarely been reported. We successfully treated the patient with a combination of appropriate i.v. antibiotics and surgical resection. PMID- 29123823 TI - Diverticulitis-induced pylephlebitis possibly misdiagnosed as biliary duct obstruction. AB - Case: A 59-year-old Asian man presented to our emergency department with hypogastrium pain, loss of appetite, and diarrhea. On admission, he was hypotensive and jaundiced. Laboratory test results revealed thrombocytopenia, hypercreatininemia, and hyperbilirubinemia. Color Doppler sonography showed no blood flow in the right and left branches of the portal vein, which seemed similar to biliary obstruction. Enhanced computed tomography showed portal vein thrombi, consistent with pylephlebitis; a broad-spectrum antibiotic and an anticoagulant were administered. Outcome: The patient died of multiple organ failure 22 h post-admission. An autopsy revealed suppurative thrombi in the portal vein, multiple liver abscesses, and diverticulitis in the sigmoid colon. Conclusion: Pylephlebitis, a rare complication of intra-abdominal infections, is associated with high rates of morbidity and mortality. Ultrasonography findings mimic those of biliary obstruction. Enhanced computed tomography is useful for diagnosing this condition. PMID- 29123824 TI - Life-threatening urethral hemorrhage after placement of a Foley catheter in a patient with uroseptic disseminated intravascular coagulation due to chronic urinary retention induced by untreated benign prostatic hyperplasia. AB - Case: A 77-year-old man with severe septic disseminated intravascular coagulation following urinary infection was transported to our hospital. He had developed urinary retention induced by untreated prostatic hyperplasia. Immediate drainage with a Foley catheter was successfully carried out, but the hematuria progressed to life-threatening hemorrhage. Outcome: Complete hemostasis was impossible by surgical treatment because the tissue around the prostatic urethra was very fragile and hemorrhagic. Organized treatments (continuous hemodiafiltration combined with polymyxin-B immobilized fiber column hemoperfusion and systemic treatment with antibiotics and coagulation factors) were commenced soon after the operation. The patient eventually recovered from the septic disseminated intravascular coagulation. Conclusion: This case report illustrates the risk of placement of Foley catheters in patients with severe septic disseminated intravascular coagulation. PMID- 29123825 TI - Controlled normothermia for a cerebral air embolism complicating computed tomography-guided transthoracic needle biopsy of the lung. AB - Case: A 74-year-old woman underwent computed tomography-guided transthoracic needle biopsy of a small lung mass. Immediately after the procedure, she lost consciousness. After resuscitation, her brain computed tomography scan confirmed a cerebral air embolism. Outcome: As hyperbaric oxygenation was unavailable, she received controlled normothermia for neuroprotection. No cerebral symptoms were observed following treatment. Conclusion: Air embolisms are rare, but fatal, complications of computed tomography-guided transthoracic needle biopsy. Therefore, clinicians should be familiar with early diagnosis and prompt treatment. Preventing hyperthermia might be effective for treating hypoxic brain injury caused by cerebral air embolisms. PMID- 29123826 TI - Emergent transcatheter arterial embolization for norovirus-associated life threatening ulcer bleeding to achieve successful hemostasis in 2-year-old boy. AB - Case: We report a 2-year-old boy with duodenal ulcer with active bleeding that occurred as a result of norovirus gastroenteritis. On admission, the patient presented with shock accompanied with vomiting and melena. Abdominal contrast enhanced computed tomography scan showed signs of duodenal bleeding. Outcome: He was successfully treated with emergent transcatheter arterial embolization. After the treatment, endoscopic examination revealed duodenal ulcer and the stool norovirus antigen test was found to be positive. The patient recovered completely without any sequelae. Conclusion: Life-threatening duodenal ulcer bleeding in children can be caused by viral gastroenteritis. When endoscopic therapy is unsuccessful or difficult, in cases of small children, angiographic intervention can be a safe alternative treatment option of gastrointestinal bleeding. PMID- 29123827 TI - Ornithine transcarbamylase deficiency that developed at the age of 19 years with acute brain edema. AB - Case: A 19-year-old man had nausea, diarrhea, and general malaise the day before requesting emergency transport to his former primary physician. The patient became restless and had tonic seizures after admission. The patient was transferred to our hospital as there had been no improvement in his level of consciousness. On arrival, cranial computed tomography showed generalized swelling, and blood ammonia concentration was >=500 MUg/dL. After admission, seizures recurred continually despite careful monitoring and increased doses of sedatives and antiseizure drugs. Dilated pupils and a flat electroencephalogram were evident on day 4 of admission, and the patient died on day 11. Ornithine transcarbamylase deficiency was diagnosed at postmortem based on fractionation of blood and urine amino acids and orotic acid. Outcome: Urea cycle disorders need to be treated urgently to prevent irreversible neurological damage when accompanied by hyperammonemia. Conclusion: In cases of hyperammonemia, early dialysis should be considered to reduce the ammonia level. PMID- 29123828 TI - Central venous access training simulator that enables dilator or catheter insertion. PMID- 29123829 TI - Respiratory failure with hydrothorax due to acute onset pleuroperitoneal communication after upper endoscopy. PMID- 29123830 TI - Delivering bad news in emergency care medicine. AB - Forecasting is a strategy for delivering bad news and is compared to two other strategies, stalling and being blunt. Forecasting provides some warning that bad news is forthcoming without keeping the recipient in a state of indefinite suspense (stalling) or conveying the news abruptly (being blunt). Forecasting appears to be more effective than stalling or being blunt in helping a recipient to "realize" the bad news because it involves the deliverer and recipient in a particular social relation. The deliverer of bad news initiates the telling by giving an advance indication of the bad news to come; this allows the recipient to calculate the news in advance of its final presentation, when the deliverer confirms what the recipient has been led to anticipate. Thus, realization of bad news emerges from intimate collaboration, whereas stalling and being blunt require recipients to apprehend the news in a social vacuum. Exacerbating disruption to recipients' everyday world, stalling and being blunt increase the probability of misapprehension (denying, blaming, taking the situation as a joke, etc.) and thereby inhibit rather than facilitate realization. Particular attention is paid to the "perspective display sequence", a particular forecasting strategy that enables both confirming the recipient's perspective and using that perspective to affirm the clinical news. An example from acute or emergency medicine is examined at the close of the paper. PMID- 29123831 TI - Online Commentary in Primary Care and Emergency Room Settings. AB - This paper describes a communication practice called "online commentary" that is in widespread use in primary care in the USA. Online commentary is talk by a clinician that describes what he or she is finding in the course of the physical examination of the patient. The paper reviews the primary features of online commentary, with a special focus on its role in forecasting the likely results of the physical examination during the examination itself. It also describes patient outcomes that are associated with this use. It then uses data from an emergency room in the western USA to extend the notion of online commentary from primary care to the emergency setting. It proposes that online commentary facilitates effective teamwork by forecasting next actions, allowing members of the emergency team to anticipate probable next steps in the investigation and treatment of patient injuries. PMID- 29123832 TI - Pupil diameter for confirmation of brain death in adult organ donors in Japan. AB - Aim: The criteria for brain death in Japan include a bilateral pupil diameter of >=4 mm. We evaluated the appropriateness of a 4-mm pupil diameter in adult brain dead donors in Japan. Methods: We retrospectively reviewed the records of 148 consecutive adult brain-dead donors with an average age of 46 years. All records were anonymously registered to the Japanese Ministry of Health, Labour and Welfare (the Japanese Ministry of Health and Welfare before 2001) from the various designated emergency institutes that performed organ donation under brain death from 1999 to 2012 in Japan. Results: All donors had a Glasgow Coma Scale score of 3, absence of all seven brain stem reflexes, an isoelectric electroencephalogram for >30 min, and apnea as tested by the standard method. All of these examinations were repeated approximately 6 h later for confirmation. The pupil diameter (average +/- standard deviation) was 6.1 +/- 1.1 mm at the first assessment and 6.4 +/- 1.1 mm approximately 6 h later. The 95% probability distribution as calculated by statistical analysis was 3.93-8.30 mm in the left eye and 3.88-8.28 mm in the right eye in the first assessment, and 4.25-8.58 mm in the left eye and 4.32-8.43 mm in the right eye approximately 6 h later. Conclusion: Despite the various original causes of brain death, we conclude that a pupil diameter of >=4 mm is a reasonable criterion for brain death in adults. PMID- 29123833 TI - Clinical characteristics of non-convulsive status epilepticus diagnosed by simplified continuous electroencephalogram monitoring at an emergency intensive care unit. AB - Aim: The present study aimed to elucidate the clinical characteristics of non convulsive status epilepticus (NCSE) in patients with altered mental status (AMS). Methods: This single-center retrospective study comprised 149 patients who were hospitalized between March 1, 2015 and September 30, 2015 at the emergency intensive care unit (ICU) of the Kagawa University Hospital (Kagawa, Japan). The primary outcome was NCSE incidence. The secondary outcome was the comparison of duration of ICU stay, hospital stay, and a favorable neurological outcome, as assessed using the modified Rankin Scale score, at discharge from our hospital between patients with and without NCSE. Favorable neurological outcome and poor neurological outcome were defined as modified Rankin Scale scores of 0-2 and 3-6, respectively. Results: Simplified continuous electroencephalogram was used to monitor 36 patients (median age, 68 years; 69.4% males) with acute AMS; among them, NCSE was observed in 11 (30.1%) patients. Rates of favorable neurological outcome, duration of ICU stay, and hospital stay were not significantly different between the NCSE and non-NCSE groups (P = 0.45, P = 0.30, and P = 0.26, respectively). Conclusion: Approximately 30% of the patients with AMS admitted to emergency ICUs developed NCSE. The outcomes of AMS patients with and without NCSE did not differ significantly when appropriate medical attention and antiepileptic drugs were initiated. Simplified continuous electroencephalogram monitoring may be recommended in patients with AMS in emergency ICU to obtain early detection of NCSE followed by appropriate intervention. PMID- 29123834 TI - Inhaled hydrogen ameliorates endotoxin-induced bowel dysfunction. AB - Aim: Gastrointestinal dysmotility frequently occurs during sepsis and multiple organ failure, remaining a major cause of morbidity and mortality in critically ill patients. Previous studies have shown that hydrogen, a new therapeutic gas, can improve various organ damage associated with sepsis. In this study, we investigated the protective efficacies of inhaled hydrogen against lipopolysaccharide (LPS)-induced ileus. Methods: Sepsis was induced in rats and mice by a single i.p. injection of LPS at 15 mg/kg for mice and 5 mg/kg for rats. Four groups of rats and mice including sham/air, sham/hydrogen, LPS/air, and LPS/hydrogen were analyzed. Hydrogen (1.3%) was inhaled for 25 h beginning at 1 h prior to LPS treatment. Gastrointestinal transit was quantified and cytokine levels, as well as neutrophil extravasation, in the intestinal muscularis propria were determined. Results: Lipopolysaccharide challenge remarkably delayed gastrointestinal transit of non-absorbable dextran, associated with increased leukocyte recruitment and upregulation of pro-inflammatory cytokine mRNA expressions in the muscularis propria. Hydrogen significantly prevented LPS induced bowel dysmotility and reduced leukocyte extravasation, as well as inhibition of inflammatory cytokine expression. In vitro analysis of cytokine levels after LPS treatment of cultured macrophages showed an increase of interleukin-10 by hydrogen regardless of the presence of nitric oxide. Conclusions: This study showed the protective effects of hydrogen inhalation on LPS-induced septic ileus through inhibition of inflammation in the muscularis propria. These inhibitory effects on the pro-inflammatory response may be partially derived from anti-inflammatory cytokine interleukin-10 induction. PMID- 29123835 TI - Ambulance dispatches to schools during a 5-year period in Fukui Prefecture. AB - Aim: To determine the characteristics and trends of medical emergencies during school activities by analyzing information provided by fire departments. Methods: During a 5-year period from January 2009 to December 2013, all nine fire departments in Fukui Prefecture handled 850 emergencies at schools. We investigated the 850 cases with the age range of 0-63 years. Results: It was found that 21.5% of ambulance dispatches to schools were on weekends and there were more dispatches for non-faculty members of all age groups on weekends than on weekdays. The percentage of weekend dispatches was particularly high for students aged >=19 years. Emergency calls for junior high school students and younger students accounted for the majority of weekday calls. There were a total of 524 ambulance dispatches for the three categories "sprains, contusions, dislocations, and fractures" (n = 245), "seizures, epilepsy, and syncope" (n = 171), and "cuts, bruises, lacerations, trauma, amputations, and burns" (n = 108), with dispatches for these three categories accounting for 61.6% of all dispatches. Almost all dispatches for "heat stroke and dehydration" were during school hours and were concentrated between the months of July and September. Heat stroke was most common among high school students and most often occurred during the summer/fall season and on weekends. Conclusion: Heat stroke was the fourth most frequent condition that required an ambulance dispatch after the above three conditions. Heat stroke is predictable, indicating that it is necessary to prevent heat stroke during high school club activities. PMID- 29123836 TI - A survival prediction logistic regression models for blunt trauma victims in Japan. AB - Aim: This research aimed to propose a logistic regression model for Japanese blunt trauma victims. Methods: We tested whether the logistic regression model previously created from data registered in the Japan Trauma Data Bank between 2005 and 2008 is still valid for the data from the same data bank between 2009 and 2013. Additionally, we analyzed whether the model would be highly accurate even when its coefficients were rounded off to two decimal places. Results: The model was proved to be highly accurate (94.56%) in the recent data (2009-2013). We also showed that the model remains valid without respiratory rate data and the simplified model would maintain high accuracy. Conclusion: We propose the equation of survival prediction of blunt trauma victims in Japan to be Ps = 1/(1+e-b), where b = -0.76 + 1.03 * Revised Trauma Score - 0.07 * Injury Severity Score - 0.04 * age. PMID- 29123837 TI - Effectiveness of cadaver-based educational seminar for trauma surgery: skills retention after half-year follow-up. AB - Aim: In Japan, trauma surgery training remains insufficient, and on-the-job training has become increasingly difficult because of the decreasing number of severe trauma patients and the development of non-operative management. Therefore, we assessed whether a 1-day cadaver-based seminar is effective for trauma surgery training. Methods: Data were collected from 11 seminars carried out from January 2013 to March 2014, including a 10-point self-assessment of confidence levels (SACL) for 21 surgical skills and an evaluation of the contents before, just after, and a half-year after the seminar. Statistical analysis was undertaken using the paired t-test at P < 0.0167. Results: A total of 135 participants were divided into three groups based on experience and clinical careers. The SACL improved in all skills between before and just after the seminar, however, they decreased between just after and a half-year after the seminar. The SACL did not change significantly in all skills between just after and a half-year after the seminar in highly experienced and experienced group members belonging to an emergency center. Conclusions: A cadaver-based seminar provided more self-confidence just after the seminar for participants at all experience levels. This effect was not maintained after a half-year, except in participants who can practice the skills at an emergency center. Practicing and participating in the seminar repeatedly is suggested to be effective for skills retention in trauma surgery. PMID- 29123838 TI - Prehospital triage for endovascular clot removal in acute stroke patients. AB - Aim: To establish prehospital triage in accordance with the new guidelines for endovascular therapy, we retrospectively analyzed the monitoring data of the city wide transportation system using the Maria Prehospital Stroke Scale (MPSS), a novel prehospital stroke scale for emergency medical technicians (EMTs) to predict the likelihood of thrombolytic therapy after transportation. Methods: Kawasaki City, Japan, has six comprehensive stroke centers (CSCs) and six primary stroke centers (PSCs). In CSCs, endovascular therapy can be carried out 24 h a day, 7 days a week, but not in PSCs. There is no "drip and ship" protocol for further endovascular therapy from PSCs to CSCs. We determined the predictive value of MPSS scoring by the EMTs for the performance of endovascular therapy after transportation. Results: There were 2031 patients (mean age, 71.1 +/- 13.3 years) registered from April 2012 to March 2015. Multivariate logistic regression analysis indicated that the MPSS score and type of stroke center were independent predictors for performance of endovascular therapy. In particular, the odds ratio (OR) for endovascular therapy was significant for MPSS score 3 (OR, 2.914; 95% confidence interval (CI), 1.152-7.372; P = 0.024), MPSS score 4 (OR, 5.474; 95%CI, 2.300-13.029; P = 0.000), and MPSS score 5 (OR, 11.459; 95%CI, 4.334 30.296; P = 0.000) when MPSS score 1 was set as a reference. The diagnostic accuracy of the MPSS score evaluated by EMTs was 0.689 (95%CI, 0.627-0.751). Conclusions: Prehospital triage using MPSS scores evaluated by EMTs can predict the likelihood of performance of endovascular therapy after transportation, and may become a tool offering a flexible solution for designing a new transportation protocol. PMID- 29123839 TI - Relationship between nitrogen loss and blood urea nitrogen concentrations in patients requiring continuous renal replacement therapy. AB - Aim: It is well known that continuous renal replacement therapy (CRRT) produces some amount of nitrogen loss, but there are few tools that are easily applied to measure it. This study aimed to evaluate nitrogen loss using blood urea nitrogen (BUN) measurement in patients receiving CRRT. Methods: The subjects were 28 patients who received CRRT (except for liver failure) between 2010 and 2012. Nutrition data and nitrogen excretion in dialysate and urine were measured. Results: The median age of the patients was 61 years, with an Acute Physiology and Chronic Health Evaluation score of 27 points and a Sequential Organ Failure Assessment score of 12 points. All-cause hospital mortality was 50%. Median protein intake was 40 g/day. The daily urinary volume was 245 mL and volume of dialysate was 26,000 mL/day. The median amount of nitrogen loss was 10.58 g/day, with BUN showing a strong correlation (r = 0.804, P < 0.0001). There was a poor relation between protein intake (g/kg body weight) and nitrogen balance (r = 0.322, P = 0.002). Conclusions: In patients receiving CRRT, the nitrogen loss showed a positive correlation with BUN but not with protein intake. According to the guidelines, recommended protein intake was 1.5-2.0 g/kg/day, but we should be careful to avoid elevating BUN at the same time. The results showed that BUN might be a useful marker to check nitrogen balance in the nutritional management of patients receiving CRRT. PMID- 29123840 TI - A system of delivering medical staff members by helicopter to manage severely wounded patients in an area where medical resources are limited. AB - Aim: We review the case of a severely injured patient to evaluate the system of delivering medical staff by helicopter in areas with limited medical resources. Methods: The patient's chart was reviewed, summarized, and presented. Results: A 22-year-old woman attempted a suicidal fall after using a knife to stab herself. She was transported to a local hospital. A radiological study revealed fractures to the patient's face and the base of her skull, pneumocephalus, traumatic subarachnoid hemorrhage, stab wounds to the neck and chest, pneumothorax, unstable pelvic fracture, and right femoral shaft fracture. Her circulation status became unstable. We sent medical staff members to the local hospital by doctor helicopter. The patient underwent tracheal intubation and the insertion of a chest drain, and was evacuated by doctor helicopter. After aggressive intensive treatments in our hospital, the patient finally obtained social rehabilitation. Conclusion: In an area where medical resources are limited, sending trained physicians to a referring hospital to appropriately prepare a severely wounded patient for transportation might be the key for the patient to maximize his or her chance of survival. PMID- 29123841 TI - Post-traumatic hypopituitarism: report of a child case. AB - Case: We report a case of post-traumatic hypopituitarism in a 9-year-old boy who was injured in a car accident. Outcome: Post-traumatic hypopituitarism might be caused by moderate to severe head trauma, and while this possibility has recently drawn attention in adults, few reports are available regarding children. Our patient experienced head and facial injury, resulting in post-traumatic hypopituitarism. Six hours after injury he suffered from diabetes insipidus and hormone replacement therapy was started. On day 12 he underwent facial fracture reduction under general anesthesia. On day 24 he was discharged from the hospital. One year after the injury, secretory function and water dehydration tests suggested the possibility of post-traumatic hypopituitarism. Conclusion: We experienced a child case of post-traumatic hypopituitarism. Emergency physicians should pay attention to the possibility of post-traumatic hypopituitarism in cases of traumatic brain injury. PMID- 29123842 TI - Severe sepsis caused by Capnocytophaga canimorsus complicated by thrombotic microangiopathy in an immunocompetent patient. AB - Case: A 61-year-old man with an unremarkable medical history was admitted with fever 7 days after being bitten by his dog. On day 3, he showed altered mental status, and laboratory data showed progressive hemolytic anemia, thrombocytopenia, hyperbilirubinemia, renal dysfunction, coagulopathy, and schistocytosis. Severe sepsis complicated with thrombotic microangiopathy caused by Capnocytophaga canimorsus was suspected. Outcome: Plasma exchange was applied to treat the thrombotic microangiopathy and resulted in platelet count increase and improved renal function, hyperbilirubinemia, and schistocytosis. Blood culture results confirmed the presence of C. canimorsus. The patient was discharged in good condition. Conclusion: Capnocytophaga canimorsus is rare cause of severe sepsis, and should be suspected even in immunocompetent patients with dog-bite history. Capnocytophaga canimorsus infection may be complicated by thrombotic microangiopathy, for which plasma exchange should be considered prior to definitive diagnosis of thrombotic microangiopathy. PMID- 29123843 TI - Self-penile glans amputation: a report of two cases. AB - Case: Self-penile amputation, especially at the glans, has rarely been reported. Most reported cases of self-amputation were performed at the proximal or peripubic area, and there only one case of self-amputation at the glans has been reported in Japan. We report two cases of self-penile amputation at the glans. Case 1: A 31-year-old man with no psychiatric disease completely amputated his penis at the glans. He underwent a stump plasty under spinal anesthesia. Case 2: A 46-year-old man with schizophrenia amputated his penis at the glans. Surgery and the post-surgical course were almost the same as described in Case 1. Outcome: Both patients experienced few functional problems except for slight urinary stream disorders. Conclusion: A stump plasty is a good procedure to treat self-penile amputation at the glans. It is simple, quick, does not require special technical skills, and is not associated with serious complications. PMID- 29123844 TI - Primary aortoduodenal fistula with a history of distal gastrectomy. AB - Case: A 69-year-old man was transferred to our hospital because of an aortoduodenal fistula with hematemesis and pre-shock vital signs. He had a history of alcoholism, malnutrition, and distal gastrectomy and Billroth I reconstruction. Endovascular aneurysm repair was successfully carried out; however, the presence of comorbidities affected further radical treatment. Outcome: The patient survived for 2 months postoperatively. Conclusion: Endovascular aneurysm repair is a useful first-line treatment for high-risk aortoduodenal fistula patients; however, it requires improvement for long-term outcomes in complicated high-risk cases. PMID- 29123845 TI - Cortical blindness induced by hepatic encephalopathy: case report and review of published case reports. AB - Case: Cortical blindness induced by hepatic encephalopathy is an extremely rare complication and its epidemiology has not been studied in great detail. We report a 63-year-old man with liver cirrhosis who developed sudden bilateral visual impairment. Outcome: On arrival at hospital, the patient had orientation disturbance, slurred speech, and mild disturbance of consciousness with impaired vision (light sense). He had no focal neurological deficits except for bilateral blindness. Cerebral stroke was suspected, but imaging and ophthalmological examination did not reveal major abnormalities. An increased concentration of ammonia in blood suggested hepatic encephalopathy; a diagnosis of cortical blindness was proposed. His vision returned gradually with relief of hepatic encephalopathy. Conclusion: Cortical blindness can be an initial symptom of hepatic encephalopathy without severe disturbance of consciousness, and can be misdiagnosed as cerebral stroke. Cortical blindness induced by hepatic encephalopathy has been reported in only 10 cases, including our patient, and merits further evaluation. PMID- 29123846 TI - Two cases of cryptogenic life-threatening hemoptysis - identification and management of bleeding point. AB - Cases: Case 1: A 63-year-old woman was referred for coughing blood. Although cardiorespiratory dynamics were stabilized by artificial respiration under sedation, severely poor ventilation developed from asphyxia associated with massive respiratory tract hemorrhage. One-lung ventilation was temporarily secured by endotracheal tube insertion into the left main bronchus just prior to cardiopulmonary arrest.Case 2: A 72-year-old man was referred for massive hemoptysis after coughing, then intubated and placed on a respirator. During angiography, blood clots collected with bronchoscopy confirmed extravascular leakage into the right main bronchus. Outcomes: Both showed no hemoptysis recurrence after bronchial artery embolization and were discharged. Case 1 required intensive treatment for 6 days, including artificial respiratory management. Conclusion: Emergency one-lung ventilation was required for asphyxia in Case 1, and we had difficulties with bleeding point identification and hemostatic therapy. From that experience, we noted hemoptysis during angiography using bronchoscopy in Case 2, enabling prompt bronchial artery embolization. PMID- 29123847 TI - Unilateral cardiogenic pulmonary edema associated with acute mitral regurgitation. AB - Case: Two cases of cardiogenic unilateral pulmonary edema are reported. Both patients presented to the emergency department with dyspnea, and chest radiography revealed unilateral infiltration, which mimics pulmonary disease. However, the patients were diagnosed with cardiogenic pulmonary edema, because echocardiography showed severe mitral regurgitation with an eccentric jet. Outcome: The patients underwent mitral valve replacement and were discharged without complications. Conclusion: Unilateral cardiogenic pulmonary edema is rare, and early diagnosis and treatment are difficult. Delayed treatment leads to high mortality. The major cause of unilateral pulmonary edema is acute mitral regurgitation, and the direction of the jet is suggested as a mechanism of laterality. PMID- 29123848 TI - A case of type 2 diabetes mellitus with metformin-associated lactic acidosis initially presenting the appearance of a sulfonylurea-related hypoglycemic attack. AB - Case: A 64-year-old Japanese woman with diabetes mellitus was admitted for hypoglycemia. Her diabetes had been under good control with glimepiride, voglibose, exenatide, and metformin for a few years. Although overt proteinuria was observed, the serum creatinine values were within normal range during the routine outpatient follow-up. Hypoglycemic attack caused by glimepiride and loss of appetite by urinary tract infection were diagnosed. Then, metformin-associated lactic acidosis with acute renal failure caused by dehydration was detected. Outcome: Her condition was improved by continuous veno-venous hemodiafiltration and hemodialysis, known to be useful to remove metformin. Conclusion: We reported a case of metformin-associated lactic acidosis with hypoglycemia during routine treatment of diabetes that was successfully rescued by early renal replacement therapy. PMID- 29123849 TI - A case report of systemic embolic events associated with atrial fibrillation. AB - Case: An 82-year-old woman who had atrial fibrillation was found unconscious and was brought to the emergency department by ambulance. Her Glasgow Coma Scale score was 3, and an electrocardiogram showed ST segment elevation in V3 and V4. Cardiac ultrasonography showed left ventricular asynergy in the anterior wall, septum, and apex. Although dissection of the aorta was suspected, contrast computed tomography showed multiple arterial thromboses, including bilateral common carotid arteries and poor contrast in the left ventricle. Diffusion weighted images of magnetic resonance imaging showed a diffuse high-intensity area in both cerebral cortices. Outcome: The diagnosis was multiple arterial thromboembolisms associated with atrial fibrillation. There was no available treatment because of massive multiple lesions and the patient died within 24 h of presentation. Conclusion: Extracranial systemic embolic events other than cerebral embolism could be critical complications associated with atrial fibrillation. PMID- 29123850 TI - Delayed massive epistaxis from traumatic intracranial aneurysm after blunt facial injury. AB - Cases: Traumatic intracranial aneurysm following blunt head injury is uncommon but can be induced by extension of skull base fracture and causes unexpected hemorrhagic complications. We present two cases of traumatic intracranial aneurysm in the paraclinoid area that was revealed by delayed massive epistaxis. Lack of initial neurological deficits omitted screening for cerebrovascular injury. Outcome: Internal trapping was carried out using endovascular techniques in both cases, with extracranial-intracranial bypass in one case. No recurrent bleeding occurred in either case. Conclusion: To prevent unexpected delayed life threatening hemorrhagic accidents, careful assessment of skull-base fracture is prerequisite, even in cases of mild facial injury. PMID- 29123851 TI - A lethal case of mamushi (Gloydius blomhoffii) bite: severe bowel symptoms as a lethal sign. AB - Case: We report a lethal case of a mamushi (Gloydius blomhoffii) bite. An 84-year old woman was bitten by a mamushi snake on her right elbow. She was initially treated at another hospital, however, because the swelling expanded and her renal function worsened, she was transferred to our hospital. Compartment syndrome, thrombocytopenia, respiratory arrest, and elevated creatinine kinase and lactose dehydrogenase levels were seen; renal failure progressed, and ileus and peritonitis due to colon perforation occurred. Outcome: The patient died 35 days after the bite. An autopsy revealed widespread necrosis of the ileum, colon, and liver. Conclusion: This report supplies useful clinical information on the treatment of severe mamushi bite cases, and severe abdominal symptoms, such as ileus and melena, may be a lethal sign. PMID- 29123852 TI - Enteral nutrient gel causes formation of a huge gastric bezoar. PMID- 29123853 TI - High-grade traumatic torso visceral injury with hemodynamic instability: effectiveness of transarterial embolization using n-butyl cyanoacrylate. AB - Trauma patients with uncontrolled hemorrhage encountering coagulopathy are often associated with poor outcome. Recently, the concept of damage control interventional radiology, which focuses on "speedy stoppage of bleeding" by interventional radiology among trauma patients with hemodynamic instability and acute traumatic coagulopathy, was proposed as an alternative to damage control surgery. N-butyl cyanoacrylate (NBCA) has been used as a liquid embolic agent in various non-traumatic situations, where it has been shown to have a high technical success rate and low recurrent bleeding rate, especially in patients with coagulopathy. In this case, we treated a young patient with hemodynamic instability caused by a high-grade hepatic injury, who underwent arterial embolization (AE) using NBCA assisted with resuscitative endovascular balloon occlusion of the aorta and achieved successful hemostasis. A review of published works using PUBMED was carried out, and 10 published reports involving 23 trauma patients who underwent AE using NBCA were identified. Among them, only four reports involving five trauma patients with torso visceral injuries were identified. Three of five patients who were hemodynamically unstable underwent AE using NBCA, resulting in the stabilization of hemodynamics. We concluded that AE with resuscitative endovascular balloon occlusion of the aorta as a damage control interventional radiology procedure might be acceptable for the hemodynamically unstable hepatic injury, and NBCA could be one of the effective hemostatic agents for this purpose, in cases of trauma-induced coagulopathy. PMID- 29123854 TI - Local anesthetic toxicity: acute and chronic management. AB - Local anesthetics are commonly used medicines in clinical settings. They are used for pain management during minor interventional treatments, and for postoperative care after major surgeries. Cocaine is the well-known origin of local anesthetics, and the drug and related derivatives have long history of clinical usage for more than several centuries. Although illegal use of cocaine and its abuse are social problem in some countries, other local anesthetics are safely and effectively used in clinics and hospitals all over the world. However, still this drug category has several side-effects and possibilities of rare but serious complications. Acute neurotoxicity and cardiac toxicity are derived from unexpected high serum concentration. Allergic reactions are observed in some cases, especially following the use of ester structure drugs. Chronic toxicity is provoked when nerve fibers are exposed to local anesthetics at a high concentration for a long duration. Adequate treatments for acute toxic reactions can secure complete recovery of patients, and careful use of drugs prevents long lasting neurological complications. In addition to respiratory and circulatory management, effectiveness of lipid rescue in the acute toxicity treatment has been certified in many clinical guidelines. Prevention of the use of high concentration of local anesthetics is also validated to be effective to decrease the possibility of nerve fiber damage. PMID- 29123855 TI - Inter-rater reliability of the American Society of Anesthesiologists physical status rating for emergency gastrointestinal surgery. AB - Aim: The American Society of Anesthesiologists Physical Status (ASA-PS) classification system is used worldwide and has also been incorporated into various prediction rules. However, concerns have been raised regarding inter rater agreement in various surgical fields. Although emergency gastrointestinal surgery is relatively common and associated with high postoperative mortality, a reliability study has not yet been undertaken in this field. The aim of the present study was to investigate the inter-rater reliability of ASA-PS for emergency gastrointestinal surgery. Methods: Three sets of scenarios were generated for each ASA-PS class (2E, 3E, and 4E) in emergency gastrointestinal surgery, resulting in nine scenarios. These scenarios described the preoperative profiles of patients in one hospital. Two or three anesthesiologists from 18 other hospitals provided scores for ASA-PS for each scenario. Results: Fifty anesthesiologists scored the ASA-PS class. Between 66% and 90% of these anesthesiologists assigned the same ratings as the reference ratings for the individual scenarios. Inter-rater reliability was assessed using Fleiss' kappa (95% confidence interval) of 0.55 (0.54-0.56, P < 0.001) and an intraclass correlation coefficient (95% confidence interval) of 0.79 (0.63-0.93, P < 0.001). Conclusion: The results of the present study revealed the consistency of ASA-PS ratings between anesthesiologists for emergency gastrointestinal surgery. The ASA PS may serve as a reliable variable in the prediction rules for this field. PMID- 29123856 TI - Accidental falls related to clearing heavy snow on rooftops in a rural heavy snow area in Japan. AB - Aim: The purpose of this study is to describe our experience with patients who fell from rooftops while clearing snow. The falls occurred in rural areas that receive heavy snowfall and are undergoing depopulation and an increasing proportion of elderly residents. Methods: A retrospective observational chart review was carried out at the sole hospital providing emergency services in a rural heavy snow area in Japan. Results: A total of 70 patients were enrolled during four winter seasons between December 2009 and March 2013. Their mean age was 61 years, and 90% were male. The mean vertical height of falls was 4.1 m. A total of 174 injuries was observed, averaging 2.5 injuries per patient. Fractures accounted for 78% of all injuries, and main fractures included vertebra with lower extremities or rib fractures; 86% of patients sustained a maximum abbreviated injury scale score of 2-3. Conclusions: In a rural heavy snow area in Japan, the incidence of accidental falls related to clearing snow was high, and the victims were elderly. Fractures accounted for 78% of all injuries, and most patients suffered from moderate to serious injuries. PMID- 29123857 TI - Importance of respiratory rate for the prediction of clinical deterioration after emergency department discharge: a single-center, case-control study. AB - Aim: The purpose of the present study was to investigate the predictors of clinical deterioration soon after emergency department (ED) discharge. Methods: We undertook a case-control study using the ED database of the Nagano Municipal Hospital (Nagano, Japan) from January 2012 to December 2013. We selected adult patients with medical conditions who revisited the ED with deterioration within 2 days of ED discharge (deterioration group). The deterioration group was compared with a control group. Results: During the study period, 15,724 adult medical patients were discharged from the ED. Of these, 170 patients revisited the ED because of clinical deterioration within 2 days. Among the initial vital signs, respiratory rate was less frequently recorded than other vital signs (P < 0.001 versus all other vital signs in each group). The frequency of recording each vital sign did not differ significantly between the groups. Overall, patients in the deterioration group had significantly higher respiratory rates than those in the control group (21 +/- 5/min versus 18 +/- 5/min, respectively; P = 0.002). A binary logistic regression analysis revealed that respiratory rate was an independent risk factor for clinical deterioration (unadjusted odds ratio, 1.15; 95% confidence interval, 1.04-1.26; adjusted odds ratio, 1.15; 95% confidence interval, 1.01-1.29). Conclusions: An increased respiratory rate is a predictor of early clinical deterioration after ED discharge. Vital signs, especially respiratory rate, should be carefully evaluated when making decisions about patient disposition in the ED. PMID- 29123858 TI - Development of new equipment for intra-arrest brain cooling that uses cooled oxygen in the lungs: volunteer study. AB - Aims: Many experimental studies have reported that intra-arrest cooling during cardiac arrest is a promising treatment to mitigate brain injury. However, there is no clinically established method for cooling the brain during cardiac arrest. We hypothesized that, as blood flow in the lungs must be very slow during cardiopulmonary resuscitation, the blood could be cooled by ventilating the lungs with cooled oxygen like a radiator, and that this cooled blood would in turn cool the brain. The aim of this study was to develop equipment to cool oxygen for this purpose and to confirm its safety on a group of volunteers. Methods: We developed new equipment that cools oxygen by running it through a vinyl chloride coil submerged in a bottle of water and frozen at -80 degrees C. Using this equipment, seven volunteers were given oxygen by mask, and their blood pressure, heart rate, and peripheral saturation of oxygen were measured. The temperature in the mask was also measured. Results: This equipment was able to decrease the temperature in the mask to -5 degrees C at the Jackson Rees circuit for an oxygen flow of 10 L/min. Among the volunteer group, vital signs were unchanged and the temperature in the mask decreased from 30.1 +/- 2.6 degrees C (mean +/- standard deviation) to 15.9 +/- 9.6 degrees C. No adverse effects were observed in the volunteers after experimentation. Conclusion: We successfully developed new equipment to cool oxygen and established its safety in a volunteer study. PMID- 29123859 TI - Non-traumatic bladder rupture showing less than 10 Hounsfield units of ascites. AB - Aim: Bladder ruptures are commonly misdiagnosed as gastrointestinal perforations or intestinal ischemia. If a diagnosis is made preoperatively, conservative treatment is a safe and effective option. We evaluated the validity of using the attenuation value of ascites, measured by non-contrast computed tomography (CT), to identify patients with bladder ruptures. Methods: A retrospective search of our hospital database identified 7 patients with confirmed bladder ruptures between 2007 and 2013. We also enrolled 18 patients with gastrointestinal perforations and 10 patients with intestinal ischemia with detectable ascites on abdominal CT that had undergone emergency exploratory laparotomy between 2007 and 2013. Between-group comparisons of attenuation values of ascites as obtained by non-contrast CT were evaluated. Results: All attenuation values were less than 10 Hounsfield units (HU) in bladder rupture patients. Moreover, the attenuation value of ascites in cases of bladder rupture (median, 5.7; range, 3.1-6.1) was significantly lower than in cases of gastrointestinal perforation (median, 14.7; range, 4.7-25.4) and intestinal ischemia (median, 13.3; range, 6.0-18.1) (P = 0.004 for both comparisons). Conclusion: Bladder rupture mimics gastrointestinal perforation and intestinal ischemia with acute kidney injury. Therefore, the diagnosis of bladder rupture using the attenuation value of ascites on non contrast CT is both useful and highly significant. We suggest that bladder rupture be considered in the differential diagnosis of patients presenting with acute abdominal pain and attenuation values of ascites of less than 10 Hounsfield units. PMID- 29123860 TI - Diagnostic accuracy of radiographs for detecting supraglottitis: a systematic review and meta-analysis. AB - Aim: To assess the diagnostic performance of lateral radiograph of the neck for supraglottitis in adults and children. Methods: Electronic database searches (including PubMed, EMBASE, CINAHL, Web of Science, and WHO International Clinical Trials Registry Platform) were carried out through July 2014. Citations of included studies and recent narrative reviews were searched. Studies that compared lateral radiograph of the neck with a reference standard of direct/indirect laryngoscopy were included. Two reviewers independently assessed the methodological quality of included studies by Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Results: Of 2,088 potentially relevant citations, two single-gate (cohort) studies and six two-gate (case-control) studies were identified. These included studies of design are at the moderate or high risk of bias in QUADAS-2. The pooled sensitivity from bivariate random effects regression was 92.9% (95% confidence interval [CI], 88.5-95.9%) and the pooled specificity was 89.2% (95% CI, 85.9-91.9%), but the diagnostic value would be overestimated because of selection bias in the six two-gate studies. The sensitivity and specificity of the single-gate studies were 100.0% (95% CI, 92.2 100.0%) and 30.6% (95% CI, 15.5-35.6%) in children and 81.0% (95% CI, 78.2-93.2%) and 85.7% specificity (95% CI, 78.2-93.2%) in adults. Conclusion: This study determines that there are insufficient studies of lateral neck radiograph for detecting supraglottitis. Lateral radiograph of the neck seems to have moderate accuracy for detecting supraglottitis. Further approximately unbiased studies are needed to obtain more valid and reliable estimates of test accuracy. PMID- 29123861 TI - An adult case of laryngopharyngeal burn by drinking hot water. AB - Case: A 61-year-old man who was hospitalized with schizophrenia in a psychiatric hospital drank hot water estimated to be 90 degrees C. Eight hours after injury, laryngopharynx edema gradually progressed, and his breathing deteriorated. Upon arrival at our emergency room, we secured his respiratory tract by nasal intubation under a bronchoscope. Outcome: The edema gradually improved after peaking at hospital day 2, and he was extubated on hospital day 18. There were no apparent respiratory or esophageal problems, and he was discharged back to the psychiatric hospital on day 28. Conclusion: These types of laryngopharynx burns caused by ingesting hot foods or drinks have been rarely reported for adults. In cases of adults, when the patient is in a special situation such as having a psychiatric disorder, it is necessary to assume that the laryngopharynx burns might be aggravated. PMID- 29123862 TI - Management of maternal anaphylaxis in pregnancy: a case report. AB - Case: A 26-year-old woman (gravida 2, para 1) at 25 weeks' gestation was brought to the emergency department because of anaphylactic symptoms. She reported eating Japanese soba and developed symptoms of dyspnea, generalized itchy rash, abdominal pain, and severe uterine contractions within 15-30 min of eating. She was immediately treated by normal saline infusion, two injections of epinephrine (intramuscularly), and a nebulized short-acting beta2-receptor agonist, followed by H1-antihistamine and methylprednisolone. Obstetrical management was undertaken by an obstetrician. Outcome: The patient recovered rapidly without a biphasic reaction of anaphylaxis. After 11 weeks, a healthy, neurologically intact baby was born. Conclusion: Management of anaphylaxis in pregnant patients is basically the same of that in non-pregnant ones. Treatment should commence immediately to prevent further development of the anaphylaxis reaction and fetal neurological deficiency. PMID- 29123863 TI - Successful non-operative management of traumatic extrahepatic portal venous injury without intraperitoneal hemorrhage: a case report. AB - Case: A 52-year-old woman was admitted to our hospital with hypotension after falling from the fifth floor of an apartment building. Contrast-enhanced computed tomography showed liver injury with extravasation of contrast material from the hepatic artery, and extrahepatic portal venous injury with extravasation and pseudoaneurysm. Intra-abdominal hemorrhage was not observed, and bleeding was confined to the retroperitoneal space. Hepatic arteriography showed extravasation, while portal venography showed pseudoaneurysm but no extravasation. After transarterial embolization, the patient's vital signs improved. Non-operative management was selected for the portal venous injury. Outcome: Computed tomography on the 58th hospital day revealed disappearance of the portal venous pseudoaneurysm. The patient was discharged on the 90th hospital day without any complications. Conclusion: This case shows that non-operative management can be selected for portal venous injury when there is no retroperitoneal injury and bleeding is confined to the retroperitoneal space. PMID- 29123864 TI - Right-sided Bochdalek hernia in an elderly patient: a case review of adult Bochdalek hernias from 1982 to 2015 in Japan. AB - Case: An 89-year-old woman was admitted to our hospital because of dyspnea following abdominal pain and vomiting. According to chest computed tomography findings, a diagnosis of acute respiratory failure due to right-sided Bochdalek hernia was made. Outcome: Emergency laparotomy revealed that a bowel loop from the terminal ileum to the transverse colon had herniated into the right thoracic cavity through the foramen of Bochdalek. The herniated organs were reduced to the abdominal cavity and the foramen was repaired by direct suturing. The patient had good recovery and was discharged 78 days later. Conclusion: Bochdalek hernias in elderly patients are rare, but may be complicated by strangulation of the herniated organ. This should be taken into account by acute care physicians. To prevent this fatal complication, regardless of symptoms, surgical treatment may be essential as soon as a diagnosis of adult Bochdalek hernia is made. PMID- 29123865 TI - A case of tetanus treated with Kampo medicines such as Kakkonto and Shakuyakukanzoto. AB - Case: A 74-year-old man developed tetanus 3 days after working with cow and poultry manure. Kakkonto and shakuyakukanzoto, traditional Japanese herbal medicines that are effective for the relief of pain primarily related to muscle contraction, were given to control the trismus and painful contracture of the neck. Generalized convulsions were controlled without the use of muscle relaxants. Outcome: After 30 days, the patient was discharged from the hospital without any sequelae. Conclusion: Kakkonto and shakuyakukanzoto may be useful for the control of muscle spasms resulting from generalized tetanus. PMID- 29123866 TI - Pulmonary edema following tonic-clonic seizure. PMID- 29123867 TI - The qSOFA requires validation as a promptly applicable clinical criterion. PMID- 29123869 TI - Drug-induced anaphylaxis in the emergency room. AB - Anaphylaxis is a life-threatening, systemic allergic reaction that presents unique challenges for emergency care practitioners. Anaphylaxis occurs more frequently than previously believed. Therefore, proper knowledge regarding the epidemiology, mechanisms, symptoms, diagnosis, and treatment of anaphylaxis is essential. In particular, the initial treatment strategy, followed by correct diagnosis, in the emergency room is critical for preventing fatal anaphylaxis, although making a diagnosis is not easy because of the broad and often atypical presentation of anaphylaxis. To this end, the clinical criteria proposed by the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network are useful, which, together with a differential diagnosis, could enable a more accurate diagnosis. Additional in vitro tests, such as plasma histamine and tryptase measurements, are also helpful. It should be emphasized that adrenaline is the only drug recommended as first-line therapy in all published national anaphylaxis guidelines. Most international anaphylaxis guidelines recommend injecting adrenaline by the intramuscular route in the mid anterolateral thigh, whereas i.v. adrenaline is an option for patients with severe hypotension or cardiac arrest unresponsive to intramuscular adrenaline and fluid resuscitation. In addition to the route of administration, choosing the appropriate dose of adrenaline is essential, because serious adverse effects can potentially occur after an overdose of adrenaline. Furthermore, to avoid future recurrence of anaphylaxis, providing adrenaline auto-injectors and making an etiological diagnosis, including confirmation of the offending trigger, are recommended for patients at risk of anaphylaxis before their discharge from the emergency room. PMID- 29123870 TI - Characteristic of the acute drug intoxication conveyed by Kanagawa helicopter emergency medical service. AB - Aim: Various critical cases have been transported since the use of the Kanagawa Helicopter Emergency Medical Service (HEMS) started at Tokai University Hospital (Isehara, Japan) in 2002, including cases of acute poisoning. We analyzed the characteristics of acute poisoning cases conveyed by the HEMS. Methods: Kanagawa HEMS conveyed 3,814 cases from July 2002 to March 2013, and acute drug and poison intoxication was diagnosed in 131 of these cases. We undertook a descriptive statistical study of these cases. Results: The causative agent was found to be psychiatric prescription drugs in 39.7% of cases, pesticides in 29.7%, alcohol in 8.4%, analgesics in 5.3%, detergent or bleach in 6.1%, oil, natural gas, or thinner in 4.6%, and others in 6.1%. At HEMS contact, systolic blood pressure was less than 90 mmHg in 18.3% of cases, and 40.2% were in coma. Endotracheal intubation was carried out in 44.5% of cases, and 6.9% died within 24 h of hospital admission. The cases of poisoning that we transported in the HEMS were often in shock and/or coma on arrival at the field, and rapid endotracheal intubation was required in nearly half of them, as many were in a serious condition. Conclusion: We believe that outcomes were more likely to be improved by appropriate early treatment by the HEMS. It will be necessary to further compare the ambulance service with the HEMS to evaluate their efficacy in the future. PMID- 29123868 TI - Cardiocerebral and cardiopulmonary resuscitation - 2017 update. AB - Sudden cardiac arrest is a major public health problem in the industrialized nations of the world. Yet, in spite of recurrent updates of the guidelines for cardiopulmonary resuscitation and emergency cardiac care, many areas have suboptimal survival rates. Cardiocerebral resuscitation, a non-guidelines approach to therapy of primary cardiac arrest based on our animal research, was instituted in Tucson (AZ, USA) in 2002 and subsequently adopted in other areas of the USA. Survival rates of patients with primary cardiac arrest and a shockable rhythm significantly improved wherever it was adopted. Cardiocerebral resuscitation has three components: the community, the pre-hospital, and the hospital. The community component emphasizes bystander recognition and chest compression only resuscitation. Its pre-hospital or emergency medical services component emphasizes: (i) urgent initiation of 200 uninterrupted chest compressions before and after each indicated single defibrillation shock, (ii) delayed endotracheal intubation in favor of passive delivery of oxygen by a non rebreather mask, (iii) early adrenaline administration. The hospital component was added later. The national and international guidelines for cardiopulmonary resuscitation and emergency medical services are still not optimal, for several reasons, including the fact that they continue to recommend the same approach for two entirely different etiologies of cardiac arrest: primary cardiac arrest, often caused by ventricular fibrillation, where the arterial blood oxygenation is little changed at the time of the arrest, and secondary cardiac arrest from severe respiratory insufficiency, where the arterial blood is severely desaturated at the time of cardiac arrest. These different etiologies need different approaches to therapy. PMID- 29123871 TI - Comparison of quality of human serum albumin preparations in two pharmaceutical products. AB - Aim: Human serum albumin (HSA) is known for its multiple functions, such as maintenance of colloid osmotic pressure, transport of endogenous and exogenous substances, and antioxidation. The aim of this study was to measure the redox state and concentrations of beta-d-glucan and endotoxin to compare the quality of 5% HSA preparations from two different manufacturers. Methods: The quality of 5% HSA preparations in two different pharmaceutical products (groups A and B) was compared in terms of the percentage of reduced and oxidized albumin and the contaminant level of beta-d-glucan and endotoxin. Results: The percentage of human mercaptoalbumin in group A was significantly higher than that in group B (P < 0.01), whereas that of human non-mercaptoalbumin-2 in group A was significantly lower (P < 0.01). The concentration of beta-d-glucan in group A was significantly lower than in group B (P < 0.01). Conclusions: The present findings indicate the need for quality control of HSA preparations in applications involving the use of large volumes. PMID- 29123872 TI - Serum levels of interleukin-6 may predict organ dysfunction earlier than SOFA score. AB - Aim: To investigate the clinical utility of interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) as predictive markers in consideration of the time-course changes in critically ill patients with organ dysfunction. Methods: Serum levels of IL-6, PCT, CRP, and Sequential Organ Failure Assessment (SOFA) scores were measured sequentially in 92 patients during their initial 5 days following admission to the intensive care unit. Maximum values were analyzed. Patients were assigned to a low ( <= 8), intermediate ( > 8 and <= 16), or high ( > 16 and <= 24) SOFA score group. Results: There were significant differences in the maximum serum levels of IL-6 and PCT among the three SOFA score groups (IL-6, P < 0.0001; PCT, P = 0.0004). Specifically, comparisons between the groups revealed significant differences in IL-6 levels (low versus intermediate, P = 0.0007; intermediate versus high, P = 0.0010). The probability of patients with the maximum value was greatest on day 1 (56.5%) for IL-6, on day 1 (39.1%) or day 2 (38.0%) for PCT, on day 3 (39.1%) for CRP, and on day 1 (43.5%) for SOFA score. The median (interquartile range) peak day of IL-6 was day 1 (1-2), which was significantly earlier than that of SOFA score at day 2 (1-3) (P = 0.018). Conclusion: Serum levels of IL-6 reflected the severity of organ dysfunction in critically ill patients most accurately compared to PCT and CRP. Interleukin-6 elevated soonest from the insult and reached its peak earlier than SOFA score. PMID- 29123873 TI - A study of the effect of introduction of JTAS in the emergency room. AB - Aim: The purpose of this study was to better understand the effects of introducing the Japan Triage and Acuity Scale (JTAS) in the emergency room for walk-in patients. Methods: A simple triage was used in Term A (from April 2006 to December 2010, 4 years and 9 months) and the JTAS was introduced in Term B (from January 2011 to September 2015, 4 years and 9 months). The number of patients who had a sudden turn for the worse after arrival in the emergency room and the time between attendance and emergency catheterization (TBAEC) due to acute coronary syndrome were reviewed. Results: There were 653 patients in Term A and 626 patients in Term B who were finally diagnosed as having serious causes. There was no significant difference in the frequency of a sudden turn for the worse between the two terms. There were 182 patients in Term A and 167 patients in Term B who underwent emergency catheterization due to acute coronary syndrome. When ST elevation was recognized in the first electrocardiogram, the median time between attendance and medical attention during Term B improved significantly, by 4.5 min. However, there was no significant difference in medians for TBAEC. When ST elevation was not recognized, there was no significant difference between the two terms, neither in terms of median time between attendance and medical attention, nor TBAEC. Conclusion: The data suggests that the effects of introducing the JTAS in the emergency room were restrictive in these two aspects. PMID- 29123874 TI - Early administration of fibrinogen concentrates improves the short-term outcomes of severe pelvic fracture patients. AB - Aim: Hemorrhage from pelvic fracture is a major cause of mortality after blunt trauma. Several studies have suggested that early fibrinogen supplementation improves outcomes of traumatic hemorrhage. Thus, we revised our massive transfusion protocol (MTP) in April 2013 to include early off-label administration of fibrinogen concentrate. The objective of this study was to evaluate the impact of the revision on the short-term outcomes of pelvic fracture patients. Methods: This was a single-center, retrospective, cohort study. A total of 224 consecutive pelvic fracture patients hospitalized in Saitama Medical Center (Saitama, Japan), 115 before the revision (Group E) and 109 after (Group L), were enrolled. Characteristics of the patients were compared between the groups. Impacts of the revision were evaluated by hazard ratios adjusted for characteristics, injury severity, and coagulation status using Cox's multivariate proportional hazard model. The impact was also evaluated by log-rank test and relative risk of 28-day mortality between the groups. Results: The characteristics were equivalent between the groups. The multivariate analysis revealed that the revision of MTP was significantly related to improved survival with an adjusted hazard ratio (95% confidence interval) of 0.45 (0.07-0.97). The log-rank test gave chi2-test values of 5.2 (P = 0.022) and 6.7 (P = 0.009), and the relative risks were 0.37 (0.15-0.91) and 0.33 (0.13-0.84), in patients with all Injury Severity Scores and Injury Severity Score >=21, respectively. Conclusion: The revision of MTP to include aggressive off-label treatment with fibrinogen concentrate was related to improved short-term outcomes of severe pelvic fracture patients. However, due to the limitations of the study, the improvement could not be attributed totally to the revision. PMID- 29123875 TI - Indications of early intubation for patients with inhalation injury. AB - Aim: For patients with inhalation injury, the indications for early intubation are diverse. The purpose of this study was to identify the most reliable symptoms, physical findings, and medical examinations with which to determine the indications for early intubation in patients with inhalation injury. Methods: We retrospectively collected patient data from medical records. Collected data included age, sex, burn size, symptoms, physical findings, carboxyhemoglobin levels (COHb), and bronchial wall thickness (BWT) determined from chest computed tomography images. We analyzed the relationships between these findings and the early intubation. We performed fiberoptic bronchoscopy in all patients, and analyzed the relationships between bronchoscopic severity and other findings. Results: Of the 205 patients, 80 patients were diagnosed as having inhalation injury, and 34 patients were intubated. Burn size, facial burns, neck burns, use of accessory respiratory muscles, and COHb seemed to be related with intubation, whereas singed nasal hair was not. If the patients suffered >=27% total body surface area burn and BWT >=3.5 mm, the positive predictive value for early intubation was 1.00. If the patients suffered smaller cutaneous burn without neck burn, and their COHb <4.0%, the negative predictive value for early intubation was 0.97. Fiberoptic bronchoscopy findings from above the glottis were mainly related with patients' symptoms. Findings from below the glottis were mainly related with BWT and COHb. Conclusions: Patients' symptoms, especially use of accessory respiratory muscles, are reliable, and BWT and COHb are also useful tools, for determining the indication for early intubation. PMID- 29123876 TI - Do not attempt resuscitation order in Japan. AB - Aim: In Japan, the do not attempt resuscitation (DNAR) order is practised routinely even though no related laws or guidelines exist. This study aimed to clarify the current status of DNAR, reveal existing DNAR-related issues, and improve the application of DNAR. Methods: A questionnaire survey of medical institutions in Kanagawa Prefecture (total population, 9,120,000) about the current status of DNAR was carried out. Results: The results showed that DNAR has been practised at approximately 90% of the hospitals surveyed, but only about 30% have developed in-hospital DNAR guidelines. Approximately 80% of the hospitals do not involve patients in the decision on their own DNAR orders. Because the DNAR order has not been legislated, it is often unclear whether to resuscitate patients when a request for an ambulance is made for a cardiac arrest at home. Conclusion: It is necessary for prefectures, municipalities, and local medical control authorities to take the initiative in establishing an ordinance on DNAR orders and developing guidelines. PMID- 29123877 TI - Performance review of regional emergency medical service pre-arrival cardiopulmonary resuscitation with or without dispatcher instruction: a population-based observational study. AB - Background: To investigate variations in emergency medical service (EMS) pre arrival cardiopulmonary resuscitation (CPR), including both bystander CPR without dispatch assistance and dispatch-assisted CPR (DACPR). Methods: We carried out an observational study by implementing EMS pre-arrival CPR reports in three fire agencies. We included adult, non-traumatic, and non-EMS witnessed out-of-hospital cardiac arrests. This reporting system comprised the dispatch instruction process and bystander CPR quality based on evaluations by EMS crews who arrived on the scene. Bystander CPR was categorized as "ongoing CPR" if the bystander was performing CPR when the EMS reached the patient's side and "good-quality CPR" if the CPR was performed proficiently. We compared the frequencies of ongoing and good-quality CPR in the bystander CPR already started without dispatch assistance (CPR in progress) group and DACPR group. Results: Of 688 out-of-hospital cardiac arrests, CPR was already started in 150 cases (CPR in progress group). Dispatcher CPR instruction was provided in 368 cases. Among these, callers started chest compressions in 162 cases (DACPR group). Ongoing CPR was performed in 220 cases and was more frequent in the DACPR group (128/162 [79.0%] versus 92/150 [61.3%], P < 0.001). Good-quality CPR was more frequent in the CPR in progress group, but the difference was not statistically significant (36/92 [39.1%] versus 42/128 [29.0%], P = 0.888). Conclusions: Ongoing CPR and good-quality CPR were not frequent in EMS pre-arrival CPR. Detailed analysis of dispatch instructions and bystander CPR can contribute to improvement in EMS pre-arrival CPR. PMID- 29123878 TI - Investigation of Japan Disaster Medical Assistance Team response guidelines assuming catastrophic damage from a Nankai Trough earthquake. AB - Aim: Transporting critically ill patients outside of disaster-affected areas for treatment is an important activity of Japan Disaster Medical Assistance Teams (DMATs). We investigated whether this activity is possible after possible catastrophic damage from a Nankai Trough earthquake. Methods: Japan was divided into three areas based on the level of predicted damage (definitely, possibly, and non-affected areas). A survey of DMATs and the locations of emergency base hospitals and intensive care units (ICUs) in each area was carried out, and the ability to support disaster areas was investigated. Next, a survey of wide-area medical transport by Self-Defense Force aircraft and the medical transport abilities of helicopter ambulances was carried out. The numbers of ICU beds in each area were compared, and the capacity to accept patients was investigated. Finally, subjects for further study were examined. Results: The number of DMATs that could be sent from non-affected areas was insufficient. The number of patients that can be transported by Self-Defense Force aircraft and helicopter ambulance during the first 3 days was determined to be 1,443. The number of patients that can be accepted by ICUs in non-affected areas was insufficient. A system needs to be developed to provide medical treatment for critically ill patients within disaster areas during the acute phase. This will require DMAT operational reforms and the creation of logistics systems such as the supply of resources for earthquake-reinforced hospitals. Conclusion: In addition to patient transport, systems to provide medical care inside disaster-affected areas are needed. PMID- 29123879 TI - Direct intrahepatic portocaval shunt for refractory hepatic hydrothorax: a case report. AB - Case: A 64-year-old man with complaints of dyspnea and orthopnea secondary to a hepatic hydrothorax refractory to diuretic medication underwent the transjugular intrahepatic portosystemic shunt (TIPS) procedure to decrease the portal vein pressure. The TIPS procedure failed due to severe liver stiffness. Direct intrahepatic portocaval shunt (DIPS), a modified TIPS procedure that directly inserts a stent from the inferior vena cava to the portal vein, was successfully carried out. Outcome: The DIPS procedure significantly decreased the patient's pleural effusion and respiratory symptoms. Conclusion: No other medical treatment is available to control refractory pleural effusion caused by portal hypertension; however, the TIPS (or DIPS) procedure can be successfully carried out in patients <60 years old with a Model of End-Stage Liver Disease score <15. PMID- 29123880 TI - Efficacy of direct hemoperfusion with a polymyxin B-immobilized fiber column in miliary tuberculosis. AB - Case: A 75-year-old woman presented with a 10-day history of intermittent fever, general fatigue, and progressive dyspnea. Although she had a low PaO2/FIO2 ratio, the cause of acute respiratory distress syndrome was not clear until day 9 in hospital. Outcome: We treated the patient with direct hemoperfusion with a polymyxin B-immobilized fiber column incidentally; the PaO2/FIO2 ratio improved following this therapy. Acid-fast bacilli, which were not seen in the sputum on admission, were detected in cultures from sputum, urine, bone marrow, liver biopsy, and blood samples, with a real-time polymerase chain reaction assay confirming tuberculosis. She was immediately transferred to a specialized tuberculosis hospital, and after a 3-month treatment, was discharged. Conclusion: Treatment with polymyxin B-immobilized fiber column may provide good results for pulmonary oxygenation in acute respiratory distress syndrome caused by tuberculosis. PMID- 29123881 TI - Unexpected complications immediately after cranioplasty. AB - Case: An 84-year-old man with subarachnoid hemorrhage underwent craniotomy and clipping with external decompression. Perfusion magnetic resonance imaging showed subclinical sinking skin flap syndrome, and he underwent cranioplasty on postoperative day 58. No problems occurred during the operation, but cerebral edema and hemorrhage were recognized on immediate postoperative computed tomography. Edema continued to progress, but edema and bleeding eventually improved without additional surgery. Outcome: Neurological symptoms improved to presurgical baseline and stabilized. Conclusion: Causes of cerebral edema and hemorrhage immediately after cranioplasty include reperfusion, reduction of automatic adjustment function, sinking skin flap syndrome, negative pressure due to s.c. drain, venous stasis, vascular damage following restoration of midline shift, and allergic reaction. Although cranioplasty itself is a relatively minor surgery, the fatality rate for this complication is high. Most complications are due to infection, convulsions, or epidural hematoma, but brain edema and hemorrhage also occur. It is necessary to elucidate the etiology before corrective surgery. PMID- 29123882 TI - A case of circumferential type A aortic dissection with intimal intussusception diagnosed using repeat transthoracic echocardiography examination. AB - Case: Sometimes it is difficult to diagnose circumferential aortic dissection with enhanced computed tomography alone. A 58-year-old woman presented with sudden-onset chest discomfort and loss of consciousness. Transthoracic echocardiogram showed mild aortic regurgitation. Enhanced computed tomography scans showed no obvious intimal tear or flap at the proximal ascending aorta, but an intimal flap was observed from the aortic arch to both common iliac arteries. Stanford type B dissection was tentatively diagnosed. Repeat detailed transthoracic echocardiography examination showed an intimal tear and flap at the ascending aorta; prolapse into the left ventricle caused severe aortic regurgitation. Type A aortic dissection was definitively diagnosed; emergent operation showed a circumferential intimal tear originating from the ascending aorta. Outcome: The ascending aorta was replaced; aortic regurgitation disappeared. The patient was discharged in a good condition 58 days postoperatively. Conclusion: Dynamic evaluations with transthoracic echocardiography should be carried out to diagnose circumferential aortic dissection. PMID- 29123883 TI - Delayed autonomic neuropathy in a patient with diethylene glycol poisoning: a case report. AB - Case: A 72-year-old man presented to our hospital after ingesting insecticide containing approximately 2 mL/kg diethylene glycol, which exceeded the lethal dose of 1 mL/kg. The patient recovered from critical symptoms on acute phase until day 3, but received artificial ventilation for muscle weakness secondary to sensorimotor neuropathy on days 11-54. Outcome: Even after marked improvement from sensorimotor neuropathy, the patient continued to complain of orthostatic hypotension. Autonomic neuropathy was identified by positive result of a head-up tilt test, and reduction in coefficient of variation of R-R intervals and cardiac iodine-123-metaiodobenzylguanidine uptake for the assessment of cardiac sympathetic activity. The patient's symptoms fully recovered 2 years after the exposure to diethylene glycol. Conclusion: This case shows the first report of delayed autonomic neuropathy after recovery from severe sensorimotor neuropathy, and suggests the importance of continuous monitoring for late-onset neurological complications. PMID- 29123884 TI - A case of cerebral tuberculoma mimicking neurocysticercosis. AB - Case: A 42-year-old Peruvian woman residing in Japan for 11 years with a family history of neurocysticercosis presented to our intensive care unit with fever and intense headache.Computed tomography indicated multiple micronodular lesions in the brain parenchyma, and cerebral tuberculoma and neurocysticercosis were considered in the differential diagnosis. Neurocysticercosis was initially suspected, and oral praziquantel was initiated. However, because of a high adenosine deaminase level in the cerebrospinal fluid and positive peripheral blood interferon gamma release test result, cerebral tuberculoma was subsequently considered. Outcome: Antituberculous drugs with steroids were initiated on day 10, after which the symptoms gradually resolved; the patient was discharged on day 29. Gadolinium-contrast magnetic resonance imaging 8 months later showed reduced nodular shadows, confirming cerebral tuberculoma. Conclusion: Immediate diagnosis and treatment are imperative for cerebral tuberculoma, a lethal infection. Considering the recent increases in immigration worldwide, increased cases of tuberculoma mimicking neurocysticercosis are expected. PMID- 29123885 TI - Cardiac arrest caused by sibutramine obtained over the Internet: a case of a young woman without pre-existing cardiovascular disease successfully resuscitated using extracorporeal membrane oxygenation. AB - Case: Sibutramine is a weight loss agent that was withdrawn from the market in the USA and European Union because it increases adverse events in patients with cardiovascular diseases. However, non-prescription weight loss pills containing sibutramine can be still easily purchased over the Internet. : A 21-year-old woman without history of cardiovascular diseases developed cardiac arrest. She was a user of a weight loss pills, containing sibutramine and hypokalemia inducing agents, imported from Thailand over the Internet. Outcome: She was successfully resuscitated without any neurological deficits by using extracorporeal membrane oxygenation for refractory ventricular fibrillation. Conclusion: This case indicates that sibutramine can cause cardiac arrest even in subjects without pre-existing cardiovascular disease when combined with agents that promote QT prolongation. PMID- 29123886 TI - Sudden cerebral depression detected by bispectral index monitoring in cryptococcal meningitis with elevated near-fatal cerebrospinal fluid pressure. AB - Case: An increase in cerebrospinal fluid pressure (CSFP) is usually prominent in cryptococcal meningitis, which has a high mortality rate, so aggressive management to control CSFP is crucial. In this case, a 40-year-old-man survived cryptococcal meningitis treated with continuous spinal drainage under bispectral index (BIS) monitoring. He unexpectedly showed hypertension, went into a coma, and even loss his light reflexes due to CSFP elevation. His BIS values had abruptly dropped before developing these symptoms, but dramatically recovered after lumbar puncture drainage, suggesting that BIS monitoring could reflect cerebral function changes due to CSFP alternations. Outcome: Inducing continuous spinal drainage to control CSFP provided stable control of blood pressure and brain activity, which was continuously monitored by BIS, enabling us to provide prompt treatment. Conclusion: Cerebral depressions due to elevated CSFP may suddenly develop, so continuous spinal drainage is needed for preventing catastrophic events. Bispectral index could be useful for detecting early changes from CSFP elevation in meningitis cases with intracranial hypertension. PMID- 29123887 TI - Two cases of life-threatening arrhythmia induced by risperidone: evaluation of risperidone and 9-hydroxy-risperidone concentrations. AB - Cases: Case 1: A 20-year-old woman suffering a suspected overdose was transported to the hospital. She presented bradycardia with wide QRS waves and QT prolongation, followed by cardiac arrest. Extracorporeal cardiopulmonary resuscitation was implemented, improving circulation. Risperidone and 9OH-RIS levels were 9.6 ng/mL and 127.6 ng/mL, respectively. Case 2: A 54-year-old woman was hospitalized for femoral fracture and underwent surgery. Her electrocardiogram showed bradycardia and complete AV block. Risperidone and 9OH RIS levels were 3.2 ng/mL and 61.4 ng/mL, respectively. Outcome: In both cases, only serum concentration of 90H-RIS were elevated. Conclusion: Arrhythmia related to risperidone has proven rare but sometimes fatal. Serum concentrations of risperidone and the metabolite 9-hydroxy-risperidone (9OH-RIS) during these events are seldom documented. As 9OH-RIS shows pharmacological activity equivalent to risperidone, it may induce life-threatening arrhythmia (regardless of the intake dosage). It is critical to evaluate the serum concentration of 9OH RIS in suspected risperidone toxicity. PMID- 29123888 TI - Cardiac arrest caused by rapidly increasing ascites in a patient with TAFRO syndrome: a case report. AB - Case: Thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a newly defined systemic inflammatory disorder with gradual progression of symptoms. A 59-year-old man with fever and ascites of unknown cause developed sudden-onset shock and respiratory failure in the general ward. Cardiac arrest immediately followed. Although he was resuscitated, frequent administration of adrenaline was required to maintain his blood pressure. His circulation was most effectively stabilized by drainage of fluid from his distended abdomen. The volume of discharged ascites reached 4,000 mL at that time, and several liters continued to be discharged for >1 month. The diagnosis of TAFRO syndrome was based on the clinical features and laboratory and histological findings. Outcome: The ascites volume and concentrations of inflammatory parameters decreased with treatment using several immunosuppressive agents. Conclusion: The newly defined TAFRO syndrome may be life-threatening. Patients should be monitored for progression to shock and cardiac arrest, especially those with rapidly increasing ascites. PMID- 29123889 TI - A case of non-cardiogenic pulmonary edema provoked by intravenous acetazolamide. AB - Case: A 61-year-old man was diagnosed with severe chest trauma after a car accident and had had difficulty in weaning from a ventilator because of flail chest and dilated cardiomyopathy. On the 17th day in the intensive care unit, he received i.v. acetazolamide to increase urine output. One hour after the injection, he suddenly developed severe hypoxia. Chest radiography revealed a butterfly shadow. He received other diuretics and a vasodilator, which seemed slowly to resolve the respiratory failure. Five days later, acetazolamide was again given and he experienced the same deterioration. Outcome: We concluded that the episodes were attributed to pulmonary edema provoked by acetazolamide. Conclusion: Acute non-cardiogenic pulmonary edema is an uncommon and lethal adverse effect of acetazolamide. Careful attention may be warranted when administering acetazolamide to critically ill patients. PMID- 29123891 TI - A case series of pelvic fracture patients who developed lower urinary tract symptoms after transarterial embolization of bilateral internal iliac arteries. AB - Cases: Transarterial embolization of bilateral internal iliac arteries (TAE) is a useful hemostatic method for the management of pelvic fracture patients, but its effects on urinary functions remain unclear. In this study, we evaluated the impact of TAE on lower urinary tract symptoms (LUTS) in 10 pelvic fracture patients. Outcomes: Lower urinary tract symptoms before and after hospitalization were evaluated by International Prostate Symptoms Score, Overactive Bladder Symptoms Score, and Quality Of Life score. All scores showed significant worsening. The changes did not correlate with sex, age, injury severity score, or durations of unstable hemodynamics or urethral catheterization. Changes of International Prostate Symptoms Score and Quality Of Life score showed significant positive correlations with intervals between the evaluations. Conclusion: Pelvic fracture patients treated with TAE showed significant worsening of LUTS. Risk for exacerbation of LUTS should be taken into consideration when deciding to use TAE. PMID- 29123890 TI - Efficacy of isoproterenol for treating amlodipine overdose resulting in bradycardia. AB - Case: Amlodipine predominantly affects vascular smooth muscle cells. Amlodipine overdose usually presents with vasodilatory shock, accompanied by reflex tachycardia rather than bradycardia.An 81-year-old woman presented with impaired consciousness 8 h after ingesting 50 5-mg amlodipine tablets with suicidal intent. On admission, her blood pressure was 50/40 mmHg and her heart rate was 45 b.p.m. Serum amlodipine level was extremely high (474.4 ng/mL), causing refractory bradycardia. She remained hypotensive despite fluid resuscitation, and therefore was administered dopamine and norepinephrine. She was also administered glucagon and calcium gluconate, and underwent high-dose insulin euglycemic therapy. Outcome: Although her blood pressure improved, bradycardia progressively worsened and isoproterenol infusion was initiated, which resulted in an improvement in her heart rate. The patient discharged on day 14 without any complications. Conclusion: Isoproterenol is effective for treating bradycardia after amlodipine overdose. PMID- 29123892 TI - A case of panspinal epidural abscess that presented with meningeal irritation. AB - Case: In rare cases, spinal epidural abscess involves the entire spine and can lead to neurological deficits and sepsis if treatment is delayed or suboptimal. A 65-year-old man was admitted with a diagnosis of bacterial meningitis. After admission, magnetic resonance imaging showed a spinal epidural abscess from the cervical to lumbar spine. Blood culture revealed Staphylococcus aureus. The patient was initially treated medically because he had no neurological deficits. Repeat blood culture remained positive and abscesses were found in the mediastinum and bilateral psoas muscles. Outcome: Surgery was carried out and the patient's postoperative course was satisfactory. Conclusion: Spinal epidural abscess can extensively affect the spine and may present with the symptoms of bacterial meningitis. It is essential to examine the entire spine and paraspinal regions and to treat early in cases of spinal epidural abscess. PMID- 29123893 TI - A case of omental herniation through the esophageal hiatus successfully treated by laparoscopic surgery. AB - Case: We report a rare case of omental herniation through the esophageal hiatus. A 46-year-old man visited our emergency department complaining of epigastralgia. Abdominal examination revealed muscular defense and rebound tenderness in his upper abdomen. A computed tomography scan showed a fat density mass in the posterior mediastinum. A laparoscopic operation was carried out under the diagnosis of omental herniation through the esophageal hiatus. Outcome: Abdominal pain disappeared dramatically after the operation. The postoperative course was uneventful. Conclusion: Although a fat density mass in the posterior mediastinum is likely to be diagnosed as a lipomatous tumor, omental herniation through the esophageal hiatus should be taken into consideration as a possible diagnosis for acute abdominal pain in the emergency department. PMID- 29123894 TI - Differences in coagulofibrinolytic changes between post-cardiac arrest syndrome of cardiac causes and hypoxic insults: a pilot study. PMID- 29123895 TI - Microsurgical replantation of an amputated ear. AB - We report a case of successful microsurgical reattachment of an amputated ear. Microsurgical reattachment should be considered whenever possible. PMID- 29123896 TI - Superior mesenteric artery syndrome leading to reversible mucosal gangrene. AB - We describe a case in which gastrointestinal distention due to superior mesenteric artery syndrome (SMAS) developed into membranous gangrene, which in turn led to septic shock in a 60-year-old woman with cerebral palsy and cachexia. The association with SMAS and septic shock is considered extremely rare, it is important to consider this combination especially in cachectic patients with gastric distension accompanying refractory shock unknown etiology. PMID- 29123897 TI - A review of the history of the origin of triage from a disaster medicine perspective. AB - We usually associate triage with the Simple Triage and Rapid Treatment method, but much of its origin is still unknown. Therefore, French studies and the origin of triage shown in domestic and foreign published works have been investigated and its significance reaffirmed. The etymology of the word "triage" means "to break into three pieces." It was suggested by a literature review that the rise of Napoleon led to military tactical changes, and that the prototype of triage arose from the experience gained in the difficult campaign in Egypt and Syria. Subsequently, triage was refined by Napoleon's military surgeon, D. J. Larrey, who created the ambulance transport system. Although there is a clash between the ruthless and philanthropic aspects of triage, triage is in accordance with the primary purpose of evacuation or treatment. We should choose the triage method that is consistent with the purpose of each disaster situation. PMID- 29123898 TI - Better documentation in electronic medical records would lead to an increased use of lower extremity venous ultrasound in the inpatient setting: a retrospective study. AB - Aim: We hypothesized that the quality of the assessment of abnormal laboratory data in the emergency department (ED) could affect the hospital-attending physicians' decision-making after a patient's hospitalization. To test this hypothesis, we investigated how patients with a positive D-dimer result were reported by ED physicians in electronic medical records, and measured whether lower extremity venous ultrasonography examination was undertaken during hospitalization by the hospital-attending physicians. Methods: In an urban tertiary acute care general hospital in Japan, between January 2012 and December 2013, we included patients hospitalized after a positive D-dimer measurement (>=1.0 MUg/mL) that was taken in the emergency department. We retrospectively measured the quality of ED physician assessments. Then we examined whether that affected the decisions of attending physicians to order lower extremity venous ultrasonography examinations during hospitalization. The exposure variable was the quality of the ED physicians' assessment of patients with positive D-dimer results. The outcome was whether a lower extremity venous ultrasonography examination was ordered by the attending physician during hospitalization. Results: When assessments were described by ED physicians for patients with positive D-dimer results, the attending physicians frequently ordered lower extremity venous ultrasonography (odds ratio, 10.74; 95% confidence interval, 5.92-19.50), even if the assessments only contained "copied and pasted" laboratory data (odds ratio, 1.68; 95% confidence interval, 2.10-2.40). Conclusions: Better documentation by ED physicians, regarding patients with positive D-dimer results, strongly affected the decisions made by attending physicians to order lower extremity venous ultrasonography examination. PMID- 29123899 TI - Venous thromboembolism in major trauma patients: a single-center retrospective cohort study of the epidemiology and utility of D-dimer for screening. AB - Aim: Venous thromboembolism (VTE) can be a life-threatening complication after major trauma. The aim of this study was to investigate the epidemiology of VTE and to assess the usefulness of D-dimer for screening for VTE in major trauma cases among the Japanese population. Methods: We examined a single-center retrospective cohort of severely injured trauma patients who had been admitted to the emergency intensive care unit at Okayama University Hospital (Okayama, Japan) from April 2013 through to March 2016. Venous thromboembolism was confirmed by computed tomography angiography and computed tomography venography, which was determined based on the attending physician monitoring daily D-dimer levels. Independent risk factors for VTE were determined by multiple logistic regression analysis. D-dimer levels were evaluated using area under the receiver operating characteristic curve (AUROC) to predict VTE. Results: The study cohort consisted of 204 trauma patients (median Injury Severity Score, 20). Of the 204 patients, 65 (32%) developed VTE. The median time from admission to VTE diagnosis was 10 days. In multiple logistic regression analysis, higher Injury Severity Score and the presence of lower extremity fractures were revealed to be a risk factor for VTE. D-dimer levels at day 10 showed moderate accuracy, of which the AUROC was 0.785 (95% confidence interval, 0.704-0.866; P < 0.001). The cut-off that maximized the Youden index was 12.45 MUg/mL. Conclusions: At least one of every three major trauma patients had potential development of VTE at a median of 10 days following admission to the intensive care unit. D-dimer levels on day 10 can be a useful predictor of VTE. PMID- 29123900 TI - Evaluation of factors associated with the difficulty in finding receiving hospitals for traffic accident patients at the scene treated by emergency medical services: a population-based study in Osaka City, Japan. AB - Aim: Although the prolongation of the time between injury and hospital arrival of traffic accident patients can influence their prognosis, factors associated with the difficulty in hospital acceptance of these patients have not been sufficiently evaluated in Japan. Methods: We retrospectively analyzed the population-based ambulance records of all traffic accident patients for whom the Osaka Municipal Fire Department (Osaka City, Japan) dispatched an ambulance in 2013. We defined "cases with difficulty in hospital acceptance" as cases that required >=4 calls by emergency medical service personnel at the scene before receiving hospital acceptance. We included patient characteristics (age, sex, coma status, and trauma severity judged by emergency medical service personnel), time factors (day/night or weekday/holiday and weekends), and accident location for multivariable logistic regression analysis to assess factors associated with the difficulty in hospital acceptance. Results: Among 13,427 traffic accident patients, 2,033 (15.1%) were cases with difficulty in hospital acceptance. Pediatric patients (adjusted odds ratio [OR], 1.265; 95% confidence interval [CI], 1.060-1.509), male sex (adjusted OR, 1.260; 95% CI, 1.135-1.398), moderate grade trauma (adjusted OR, 2.241; 95% CI, 1.972-2.547), severe-grade trauma (adjusted OR, 2.057; 95% CI, 1.249-3.388), holidays and weekends (adjusted OR, 1.702; 95% CI, 1.539-1.882), and night-time (adjusted OR, 2.720; 95% CI, 2.443 3.027) were positively associated with difficulty in hospital acceptance. Conclusions: Using population-based ambulance records from a large urban community in Japan, we showed that the difficulty in hospital acceptance of patients at the scene of traffic accidents was positively associated with several prehospital factors. PMID- 29123901 TI - Respiratory extracorporeal membrane oxygenation for severe sepsis and septic shock in adults: a propensity score analysis in a multicenter retrospective observational study. AB - Aim: This multicenter retrospective observational study aimed to evaluate the efficacy of extracorporeal membrane oxygenation (ECMO) support for septic patients with severe respiratory failure using propensity score analyses. Methods: The data of severe sepsis patients from 42 intensive care units between January 2011 and December 2013 were retrospectively collected. Propensity score matching analyses were undertaken for severe respiratory failure patients with/without veno-venous ECMO support. The main outcome was in-hospital all-cause mortality. Results: Of 3195 patients with severe sepsis, 570 had severe respiratory failure. Forty patients in the ECMO group were matched with 150 patients in the control group. A survival time analysis revealed no difference in the in-hospital survival (hazard ratio, 0.854; 95% confidence interval, 0.531 1.373; P = 0.515). Two-hundred and eighty-five patients had severe respiratory failure induced by lung infection. Twenty-five ECMO group patients were matched with 89 patients in the control group. In the ECMO group, the survival time was longer than in the control group (hazard ratio, 0.498; 95% confidence interval, 0.279-0.889; P = 0.018). The number of renal replacement therapy- and vasopressor free days improved. The ECMO group received more red blood cells transfused than the control group, but there was no significant difference in the rate of severe bleeding complications between the groups. Conclusions: There was no difference in the in-hospital survival between the ECMO group and control group among overall septic patients with severe respiratory failure. However, in sepsis patients with severe respiratory failure induced by lung infection, ECMO support may improve their survival time. PMID- 29123902 TI - Influence of body position during Heimlich maneuver to relieve supralaryngeal obstruction: a manikin study. AB - Aim: : To study the most effective body position for Heimlich maneuver. Methods: A choking simulation manikin was connected to a laryngeal model of a child or an adult, and a differential pressure transducer recorded the airway pressure and waveform during the maneuver. A konjac jelly was placed on the larynx to mimic complete supralaryngeal obstruction. The maneuver (five successive compressions) was carried out six times each in standing, prone, and supine positions. For cases of children, we added a supine position with a pillow under the back. Results: In the adult model, airway obstruction was more frequently relieved in the supine and prone positions than in the standing position (P < 0.001). In the child model, airway obstruction was more frequently relieved in the supine position, with a pillow, and in the prone position, than in the standing position (P < 0.001). Without relief, successive Heimlich maneuvers made the airway pressure increasingly negative (adult, from -21.9 +/- 6.5 cmH2O to -31.5 +/- 9.1 cmH2O in the standing position [P < 0.001]; child, from -15.0 +/- 9.5 cmH2O to 30.0 +/- 9.2 cmH2O in the standing position [P < 0.001] and from -35.0 +/- 17.4 cmH2O to -47.3 +/- 25.1 cmH2O in the supine position without a pillow [P = 0.002]). Conclusions: The Heimlich maneuver was more effective in the supine and prone positions. In children, the prone position may be most effective. Successive Heimlich maneuvers may be harmful when the airway is not relieved after the first compression. PMID- 29123904 TI - Comparison of registry and government evaluation data to ascertain severe trauma cases in Japan. AB - Aims: Accurate evaluation of health care quality requires high-quality data, and case ascertainment (confirming eligible cases and deaths) is a foundation for accurate data collection. This study examined the accuracy of case ascertainment from two Japanese data sources. Methods: Using hospital-level data, we investigated the concordance in ascertaining trauma cases between a nationwide trauma registry (the Japan Trauma Data Bank) and annual government evaluations of tertiary hospitals between April 2012 and March 2013. We compared the median values for trauma case volumes, numbers of deaths, and case fatality rates from both data sources, and also evaluated the variability in discrepancies for the intrahospital differences of these outcomes. Results: The analyses included 136 hospitals. In the registry and annual evaluation data, the median case volumes were 120.5 cases and 180.5 cases, respectively; the median numbers of deaths were 11 and 12, respectively; and the median case fatality rates were 8.1% and 6.4%, respectively. There was broad variability in the intrahospital differences in these outcomes. Conclusions: The observed discordance between the two data sources implies that these data sources may have inaccuracies in case ascertainment. Measures are needed to evaluate and improve the accuracy of data from these sources. PMID- 29123903 TI - Early evaluation of severity in patients with severe sepsis: a comparison with "septic shock" - subgroup analysis of the Japanese Association for Acute Medicine Sepsis Registry (JAAM-SR). AB - Aim: The purpose of this subgroup analysis of a Japanese multicenter registry, the Japanese Association for Acute Medicine Sepsis Registry Advanced (JAAM-SR Advanced), was to identify early outcome indicators for severe sepsis that are useful and more objective than "septic shock." Methods: Among 624 patients with severe sepsis registered in JAAM-SR-Advanced, 554 with valid serum lactate data were retrospectively studied. Hypotension before and after fluid resuscitation and the highest lactate values over the initial 24 h were compared for their ability to predict in-hospital mortality. Results: Of the study group, 155 (28.0%) patients were non-survivors and had significantly lower systolic blood pressures and higher lactate peaks. The mortality of 364 patients with initial hypotension was higher than those patients without it (32.7% versus 19.1%, P < 0.01). Patients with the worst lactate values >=4 mmol/L had much higher mortality than other patients (P < 0.001). In an attempt to predict outcomes, we combined initial hypotension and the worst lactate values. The patient group with initial hypotension and the worst lactate values >=4 mmol/L (183 patients, 33.0%) had a significantly higher mortality rate of 48.6% than the other groups (P < 0.01). Conclusion: The novel combined criterion of initial hypotension and the worst lactate values >=4 mmol/L within the initial 24 h is potentially useful as a single outcome predictor for severe sepsis. PMID- 29123905 TI - Effectiveness of dispatcher training in increasing bystander chest compression for out-of-hospital cardiac arrest patients in Japan. AB - Aim: The Japanese government has developed a standardized training program for emergency call dispatchers to improve their skills in providing oral guidance on chest compression to bystanders who have witnessed out-of-hospital cardiac arrests (OHCAs). This study evaluated the effects of such a training program for emergency call dispatchers in Japan. Methods: The analysis included all consecutive non-traumatic OHCA patients transported to hospital by eight emergency medical services, where the program was implemented as a pilot project. We compared the provision of oral guidance and the incidence of chest compression applications by bystanders in the 1-month period before and after the program. Data collection was undertaken from October 2014 to March 2015. Results: The 532 non-traumatic OHCA cases were used for analysis: these included 249 cases before and 283 after the guidance intervention. Most patients were over 75 years old and were men. After the program, provision of oral guidance to callers slightly increased from 63% of cases to 69% (P = 0.13) and implementation of chest compression on patients by bystanders significantly increased from 40% to 52% (P = 0.01). Appropriate chest compression also increased from 34% to 47% (P = 0.01). In analysis stratified by the provision of oral guidance, increased chest compressions were observed only under oral guidance. Conclusions: We found increased provision of oral guidance by dispatchers and increased appropriate chest compressions by bystanders after the training program for dispatchers had been rolled out. Long-term observation and further data analysis, including patient outcomes, are needed. PMID- 29123906 TI - Two cases with intra-aortic balloon pumping use for severe septic cardiomyopathy. AB - Cases: Septic cardiomyopathy is defined as a reversible left ventricular systolic dysfunction. Patients with severe septic cardiomyopathy have a high mortality rate, even if they receive conventional therapy. For those patients, previous reports showed intra-aortic balloon pump (IABP) efficacy. We report two rare cases with IABP introduction leading them to drastic improvement, and survival from severe septic cardiomyopathy. Case 1 is a 78-year-old woman diagnosed with renal calculus pyelonephritis, septic shock, and septic cardiomyopathy. Case 2 is a 62-year-old man diagnosed with pneumonia, septic shock, and septic cardiomyopathy. Outcome: In both cases, despite conventional therapy for cardiomyopathy, including high-dose catecholamine therapy, shock was not reversed, and the IABP was inserted. Circulatory status was improved after the introduction of the IABP. Conclusion: Our findings suggest that an IABP can be useful for salvaging patients with septic cardiomyopathy who do not respond to conventional therapy. PMID- 29123907 TI - Endoscopic hematoma evacuation for acute subdural hematoma in a young patient: a case report. AB - Case: The standard treatment for acute subdural hematoma (ASDH) is large craniotomy; decompressive craniectomy may also be carried out, if needed, to prevent secondary brain damage. Recently, an endoscopic procedure for elderly patients with ASDH was carried out and reported; its safety and effectiveness were emphasized because of minimal invasiveness. We report a young case and discuss its difficulties and tips.A 31-year-old man was found to be in a state of general convulsion. At the time of admission, we observed severe consciousness disturbance, anisocoria, and left hemiparesis. Computed tomography showed a massive subdural hematoma with marked midline shift. Outcome: Osmotherapy and emergency trepanation improved anisocoria. An endoscopic procedure under local anesthesia was sequentially selected. After surgery, the patient's symptoms clearly improved. Conclusion: Although the standard treatment for ASDH is craniotomy, endoscopic surgery may be useful in some cases. PMID- 29123908 TI - A case of disseminated cryptococcosis with necrotizing fasciitis in a non-HIV patient. AB - Case: Disseminated cryptococcosis is a well-recognized condition among HIV patients, but it also occurs in non-HIV patients. Necrotizing fasciitis caused by cryptococcus is rare. An 81-year-old man who had received steroid therapy presented with erythema and pain in his right thigh. After the rapid progression of symptoms and a failure to respond to antibiotic therapy, a clinical diagnosis of necrotizing fasciitis was made. We performed debridement, and yeasts were detected using a Gram stain of the fascia. We treated the patient with liposomal amphotericin B. On day 3, he developed meningitis. Cryptococcus neoformans was detected in the blood, fascia, and cerebrospinal fluid. Flucytosine was added to liposomal amphotericin B. Outcome: Despite the antifungal treatment, new regions of dissemination to the skin developed, and the patient died of multiple organ failure. Conclusion: A diagnosis of disseminated cryptococcosis should be considered in a differential diagnosis of necrotizing fasciitis among immunocompromised patients, regardless of their HIV status. PMID- 29123909 TI - Basi-parallel anatomical scanning-magnetic resonance imaging for the diagnosis of reversible cerebral vasoconstriction syndrome of the basilar artery: a case report. AB - Case: Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized and important cause of thunderclap headache. Delays in diagnosis may cause deterioration of symptoms and concomitant unnecessary investigations. However, the diagnosis of RCVS in the acute stage remains difficult.A 41-year-old man was admitted to the emergency department for severe, recurrent occipital headaches. The results of initial computed tomography and magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid analysis were normal. Magnetic resonance angiography (MRA) showed multisegmental luminal stenosis of the basilar artery. Basi-parallel anatomical scanning (BPAS)-MRI, illustrating the outer contour of the vertebrobasilar artery, also showed multisegmental stenosis. Outcome: The patient was speculated as having RCVS and was treated with oral lomerizine hydrochloride. Repeat MRA and BPAS-MRI 2 months later showed resolution, confirming RCVS. Conclusion: Combined with MRA, BPAS-MRI is an effective and non-invasive imaging method for diagnosis of RCVS of the basilar artery. PMID- 29123910 TI - Management of pediatric 'cannot intubate, cannot oxygenate'. AB - Case: "Cannot intubate, cannot oxygenate" (CICO) is a rare, life-threatening situation. We describe a pediatric case of CICO and highlight some educational points.A 3-year-old boy who collapsed in the bathtub came to our emergency department. On admission, he went into cardiac arrest probably because of an airway obstruction. We judged his condition as CICO and carried out an emergent tracheostomy after several attempts to perform a cricothyroidotomy failed. We continued resuscitation; however, circulation did not return spontaneously. Outcome: The child died, and the autopsy showed an airway obstruction caused by idiopathic anaphylaxis or acquired angioedema. Conclusion: This case highlights that it can be anatomically difficult to perform a percutaneous cannula cricothyroidotomy and scalpel cricothyroidotomy safely in pediatric CICO cases. An emergent tracheostomy using the scalpel-finger-bougie technique on the proximal trachea should be considered in such cases. PMID- 29123911 TI - Perimortem cesarean delivery and subsequent emergency hysterectomy: new strategy for maternal cardiac arrest. AB - Cases: Perimortem cesarean delivery (PMCD) is the only way to resuscitate pregnant women in cardiac arrest, and has been found to increase maternal resuscitation rate by increasing circulating plasma volume. However, many obstetricians have not experienced a case of PMCD, as situations requiring it are rare. We report our strategy for cases of maternal cardiac arrest, on the basis of a review of published work, and present two case reports from our medical center. Outcomes: In case 1, PMCD led to death by massive bleeding. In case 2, PMCD and hysterectomy were carried out after the introduction of venoarterial extracorporeal membrane oxygenation, and both mother and baby survived. Conclusion: We find that rapid hysterectomy as a damage control surgery following PMCD can be life-saving for both mother and baby. PMID- 29123912 TI - Delayed sensorimotor neuropathy and renal failure: an additional report in a patient with diethylene glycol poisoning. PMID- 29123913 TI - Sex Hormone Status in Women With Chronic Kidney Disease: Survey of Nephrologists' and Renal Allied Health Care Providers' Perceptions. AB - Background: Chronic kidney disease (CKD) in reproductive-age women is accompanied by menstrual and fertility disorders and premature menopause. Objective: We sought to determine nephrologists' and allied health care providers' perceptions on management of sex hormone status in women with CKD. Methods: An anonymous, Internet-based survey was sent to nephrology society members from Canada, Australia, New Zealand, and the United Kingdom, and the Canadian Association of Nephrology Nurses and Technologists (February-November 2015). We assessed reported perceptions and management of sex hormone status in women with CKD. Results: One hundred seventy-five nephrologists (21% response rate) and 121 allied health care providers (30%; 116 nurses, 5 pharmacists) responded. Sixty eight percent of nephrologists and 46% of allied providers were between the ages of 30 and 50 years, and 38% of nephrologists and 89% of allied workers were female. Ninety-five percent of nephrologists agreed that kidney function impacts sex hormone status, although only a minority of nephrologists reported often discussing fertility (35%, female vs male nephrologists, P = .06) and menstrual irregularities with their patients (15%, female vs male nephrologists,P = .02). Transplant nephrologists reported discussing fertility more often than did nontransplant nephrologists (53% vs 30%, P = .03). Physicians were more likely to report discussing fertility (33% vs 7.5%, P < .001) and menstrual irregularities (15% vs 9%, P = .04) with patients than allied health care providers. Forty-three percent of physicians reported uncertainty about the role for postmenopausal hormone therapy in women with CKD. Conclusion: Nephrologists and allied health care providers recognize an impact of CKD on sex hormones in women but report not frequently discussing sex hormone-related issues with patients. Our international survey highlights an important knowledge gap in nephrology. PMID- 29123914 TI - Persistent pit viper envenomation in a cat. AB - Case summary: A 4-year-old female spayed, indoor/outdoor domestic mediumhair cat presented with multiple bleeding puncture wounds and hemorrhagic shock. The cat was diagnosed with suspected pit viper envenomation based on the location and appearance of the bite wounds, as well as the presence of severe coagulopathy with prolonged activated coagulation time (762 s), which responded to antivenom administration. The clinical course of the cat was unique owing to the prolonged clinical signs of envenomation that appeared as intermittent coagulopathy and hemorrhage over a 2 week period. Five vials of antivenom were administered and three units of packed red blood cells were transfused over a 7 day period. The cat made a complete recovery with cessation of hemorrhage and normalization of clotting times. Relevance and novel information: This is the first report of persistent pit viper venom-induced coagulopathy in the feline veterinary literature. PMID- 29123915 TI - Global cerebral ischemia with subsequent respiratory arrest in a cat after repeated use of a spring-loaded mouth gag. AB - Case summary: A 10-year-old neutered male domestic shorthair cat was evaluated because of signs of stertorous breathing and reverse sneezing of 8 months' duration. A CT scan performed 1 week before evaluation indicated nasopharyngeal stenosis or collapse. Increased respiratory effort, stertorous breathing, coughing, reverse sneezing, bilateral black ocular discharge and mucoid left nasal discharge were noted. Rhinoscopy suggested possible nasopharyngeal stenosis. Balloon dilation was attempted but unsuccessful. Ventral rhinotomy was performed the following day using a spring-loaded mouth gag to access the surgical site. After rhinotomy, the patient had neurologic signs attributed to global cerebral ischemia that progressed to respiratory arrest, subsequently resulting in euthanasia. Relevance and novel information: While ischemic brain injury has been associated with the use of a spring-loaded mouth gag in cats, to our knowledge this is the first reported instance where use resulted in respiratory arrest culminating in euthanasia. PMID- 29123916 TI - Erratum to: Pilot and Feasibility Studies, Vol. 4. AB - [This corrects the article DOI: 10.1186/s40814-017-0145-8.][This corrects the article DOI: 10.1186/s40814-017-0149-4.][This corrects the article DOI: 10.1186/s40814-017-0151-x.][This corrects the article DOI: 10.1186/s40814-017 0155-6.][This corrects the article DOI: 10.1186/s40814-017-0148-5.][This corrects the article DOI: 10.1186/s40814-017-0147-6.][This corrects the article DOI: 10.1186/s40814-017-0159-2.][This corrects the article DOI: 10.1186/s40814-017 0150-y.][This corrects the article DOI: 10.1186/s40814-017-0153-8.][This corrects the article DOI: 10.1186/s40814-017-0156-5.][This corrects the article DOI: 10.1186/s40814-017-0154-7.][This corrects the article DOI: 10.1186/s40814-017 0164-5.][This corrects the article DOI: 10.1186/s40814-017-0152-9.][This corrects the article DOI: 10.1186/s40814-017-0162-7.][This corrects the article DOI: 10.1186/s40814-017-0163-6.][This corrects the article DOI: 10.1186/s40814-017 0157-4.][This corrects the article DOI: 10.1186/s40814-017-0160-9.][This corrects the article DOI: 10.1186/s40814-017-0165-4.][This corrects the article DOI: 10.1186/s40814-017-0158-3.][This corrects the article DOI: 10.1186/s40814-017 0171-6.][This corrects the article DOI: 10.1186/s40814-017-0170-7.][This corrects the article DOI: 10.1186/s40814-017-0169-0.][This corrects the article DOI: 10.1186/s40814-017-0166-3.][This corrects the article DOI: 10.1186/s40814-017 0161-8.][This corrects the article DOI: 10.1186/s40814-017-0167-2.][This corrects the article DOI: 10.1186/s40814-017-0168-1.]. PMID- 29123918 TI - Whole genome sequencing identifies a novel homozygous exon deletion in the NT5C2 gene in a family with intellectual disability and spastic paraplegia. AB - Hereditary spastic paraplegias are a rare group of clinically and genetically heterogeneous neurodegenerative diseases, with upper motor neuron degeneration and progressive lower limb spasticity as their main phenotypic features. Despite that 76 distinct loci have been reported and some casual genes identified, most of the underlying causes still remain unidentified. Moreover, a wide range of clinical manifestations is present in most hereditary spastic paraplegias subtypes, adding further complexity to their differential clinical diagnoses. Here, we describe the first exon rearrangement reported in the SPG45/SPG65 (NT5C2) loci in a family featuring a complex hereditary spastic paraplegias phenotype. This study expands both the phenotypic and mutational spectra of the NT5C2-associated disease. PMID- 29123917 TI - The telomere bouquet facilitates meiotic prophase progression and exit in fission yeast. AB - During meiotic prophase, chromosome arrangement and oscillation promote the pairing of homologous chromosomes for meiotic recombination. This dramatic movement involves clustering of telomeres at the nuclear membrane to form the so called telomere bouquet. In fission yeast, the telomere bouquet is formed near the spindle pole body (SPB), which is the microtubule organising centre, functionally equivalent to the metazoan centrosome. Disruption of bouquet configuration impedes homologous chromosome pairing, meiotic recombination and spindle formation. Here, we demonstrate that the bouquet is maintained throughout meiotic prophase and promotes timely prophase exit in fission yeast. Persistent DNA damages, induced during meiotic recombination, activate the Rad3 and Chk1 DNA damage checkpoint kinases and extend the bouquet stage beyond the chromosome oscillation period. The auxin-inducible degron system demonstrated that premature termination of the bouquet stage leads to severe extension of prophase and consequently spindle formation defects. However, this delayed exit from meiotic prophase was not caused by residual DNA damage. Rather, loss of chromosome contact with the SPB caused delayed accumulation of CDK1-cyclin B at the SPB, which correlated with impaired SPB separation. In the absence of the bouquet, CDK1-cyclin B localised near the telomeres but not at the SPB at the later stage of meiotic prophase. Thus, bouquet configuration is maintained throughout meiotic prophase, by which this spatial organisation may facilitate local and timely activation of CDK1 near the SPB. Our findings illustrate that chromosome contact with the nuclear membrane synchronises meiotic progression of the nucleoplasmic chromosomes with that of the cytoplasmic SPB. PMID- 29123921 TI - A prospective evaluation of 3-D laparoscopic transperitoneal radical nephrectomy for large renal tumors (clinical stage T2N0M0): A single-centre, single-surgeon experience. PMID- 29123920 TI - A prospective study comparing whole-body skeletal X-ray survey with 18F-FDG PET/CT, 18F-NaF-PET/CT and whole-body MRI in the detection of bone lesions in multiple myeloma patients. AB - Background: For decades, the most widely used imaging technique for myeloma bone lesions has been a whole-body skeletal X-ray survey (WBXR), but newer promising imaging techniques are evolving. Purpose: To compare WBXR with the advanced imaging techniques 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT), 18F-sodium fluoride (NaF) PET/CT and whole-body magnetic resonance imaging (WB-MRI) in the detection of myeloma bone lesions. Material and Methods: Fourteen patients with newly diagnosed multiple myeloma were prospectively enrolled. In addition to WBXR, all patients underwent FDG PET/CT, NaF-PET/CT, and WB-MRI. Experienced specialists performed blinded readings based on predefined anatomical regions and diagnostic criteria. Results: In a region-based analysis, a two-sided ANOVA test showed that the extent of detected skeletal disease depends on the scanning technique (P < 0.0001). Tukey's multiple comparison test revealed that WB-MRI on average detects significantly more affected regions than WBXR (P < 0.005), FDG-PET/CT (P < 0.0001), and NaF PET/CT (P < 0.05). In a patient-based analysis, a Cochran's Q test showed that there are no significant differences in the proportion of patients with bone disease detected by the different scanning techniques (P = 0.23). Determination of intrareader variability resulted in Kappa coefficients corresponding to moderate (FDG-PET/CT) and substantial agreement (WB-MRI, WBXR, NaF-PET/CT). Conclusion: WB-MRI detects on average significantly more body regions indicative of myeloma bone disease compared to WBXR, FDG-PET/CT, and NaF-PET/CT. The lack of significance in the patient-based analysis is most likely due to the small number of study participants. PMID- 29123919 TI - T2 mapping and post-contrast T1 (dGEMRIC) of the patellar cartilage: 12-year follow-up after patellar stabilizing surgery in childhood. AB - Background: Cartilage degeneration has been reported after recurrent patellar dislocation. However, effects of surgical stabilization in childhood have not yet been described. Purpose: To examine the cartilage quality in very young adults operated with a patellar stabilizing procedure due to recurrent patellar dislocation in childhood, and evaluate if cartilage quality correlates with clinical parameters and patient-reported outcomes. Material and Methods: Seventeen patients were investigated >= 5 years (mean = 11.6 years) after patellar stabilizing surgery in childhood. Pre-contrast T2 relaxation times were analyzed in four superficial and four deep patellar cartilage regions of both knees. Two hours after 0.2 mM/kg Gd-DTPA2 i.v., post-contrast T1 (T1(Gd)) was analyzed in the same regions. Patient-reported outcomes (KOOS, Kujala, and Tegner scores) and recurrence rates were evaluated. Results: Comparing operated to healthy side, neither T2 nor dGEMRIC differed between the operated and the reference knee regarding the superficial half of the cartilage. In the deep half of the cartilage, T1(Gd) was shorter in the central part of the cartilage, whereas T2 was longer medially (P < 0.05). A low score in the KOOS subscales Symptom and Sports & Recreation, was correlated to the degenerative changes detected by T1(Gd) (r = 0.5, P = 0.041). Conclusion: In general, our findings demonstrate good cartilage quality 12 years after patellar stabilizing surgery during childhood. The subtle changes in T2 and T1(Gd) in the deep cartilage layer may be a result of altered biomechanics, although very early degenerative changes cannot be excluded. The short T1(Gd) centrally may reflect lower glycosaminoglycan content, whereas the increase in T2 medially indicates increased cartilage hydration. PMID- 29123922 TI - Robotic management of a duplicated ureter during intracoporeal urinary diversion following robotic cystectomy. PMID- 29123923 TI - Root-Securing and Brain-Fortifying Liquid Upregulates Caveolin-1 in Cell Model with Alzheimer's Disease through Inhibiting Tau Phosphorylation. AB - In order to explore the effect of root-securing and brain-fortifying Liquid- (RSBFL-) mediated caveolin-1 (CAV-1) on phosphorylation of Tau protein and to uncover underlying mechanisms of RSBFL for the prevention and treatment of Alzheimer's disease (AD), hippocampal neurons isolated from neonatal SD rats and cultured in DMEM-F12 medium were induced by exogenous Abeta1-42 to establish a cell model with AD. Meanwhile, pEGFP-C1-CAV1 and CAV1-shRNA plasmids were transfected into hippocampal neurons for CAV-1 overexpression and silence, respectively. The serum containing RSBFL was prepared for the intervention of AD model cells. The expression of CAV-1, GSK-3beta, and p-Tau in normal hippocampal neurons and AD model cells in the presence of serum containing RSBFL was evaluated. The model hippocampal neurons with AD induced by Abeta1-42 revealed an obvious CAV-1 inhibition, enhanced GSK-3beta activity, and abnormal Tau phosphorylation. In contrast, the treatment with serum containing RSBFL could upregulate CAV-1 in AD hippocampal neurons (P < 0.05) with improved p-GSK 3betaSer9 and reduced p-GSK-3betaTyr216 (P < 0.01), as well as suppressed abnormal phosphorylation of Tau protein. Therefore, RSBFL has an excellent protective effect on hippocampal neurons through increasing CAV-1 expression, inhibiting GSK-3beta activity, and reducing excessive abnormal phosphorylation of Tau protein. PMID- 29123925 TI - Corrigendum to "Interrelationship between Sleep and Exercise: A Systematic Review". AB - [This corrects the article DOI: 10.1155/2017/1364387.]. PMID- 29123924 TI - In Vitro Evaluation of Essential Oils Derived from Piper nigrum (Piperaceae) and Citrus limonum (Rutaceae) against the Tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - The present research aimed to study the chemical composition and acaricidal activity of Citrus limonum and Piper nigrum essential oils against the cattle tick Rhipicephalus microplus. GC-MS analysis of C. limonum essential oil showed limonene (50.3%), beta-pinene (14.4%), and gamma-terpinene (11.7%) as the major components; P. nigrum oil was mainly composed of beta-caryophyllene (26.2%), sigma-ocymene (5.8%), and alpha-pinene (5.5%). Acaricide activity was evaluated at concentrations of 2.5, 5.0, and 10.0% (v/v) of each plant oil, as well as 1 : 1 combination of both oils (5% : 5%, 2.5% : 2.5%, and 1.25% : 1.25% each), by immersing engorged R. microplus females for one minute. The LC90 of oils from C. limonum, P. nigrum, and the combination were 4.9%, 14.8%, and 5.1%, respectively. C. limonum essential oil caused 100% mortality of engorged females at the highest concentration (10%). P. nigrum essential oil inhibited egg-laying by up to 96% in a concentration-dependent manner, suggesting it reduces tick fecundity. When combined, the oils presented toxicity as to C. limonum oil alone, but with stronger inhibition of oviposition (5% : 5%), indicating a possible additive effect against R. microplus. The present data provide support for further investigation of novel natural products to control bovine tick infestations. PMID- 29123926 TI - Spinal Excitability Changes after Transspinal and Transcortical Paired Associative Stimulation in Humans. AB - Paired associative stimulation (PAS) produces enduring neuroplasticity based on Hebbian associative plasticity. This study established the changes in spinal motoneuronal excitability by pairing transcortical and transspinal stimulation. Transcortical stimulation was delivered after (transspinal-transcortical PAS) or before (transcortical-transspinal PAS) transspinal stimulation. Before and after 40 minutes of each PAS protocol, spinal neural excitability was assessed based on the amplitude of the transspinal-evoked potentials (TEPs) recorded from ankle muscles of both legs at different stimulation intensities (recruitment input output curve). Changes in TEPs amplitude in response to low-frequency stimulation and paired transspinal stimuli were also established before and after each PAS protocol. TEP recruitment input-output curves revealed a generalized depression of TEPs in most ankle muscles of both legs after both PAS protocols that coincided with an increased gain only after transcortical-transspinal PAS. Transcortical-transspinal PAS increased and transspinal-transcortical PAS decreased the low-frequency-dependent TEP depression, whereas neither PAS protocol affected the TEP depression observed upon paired transspinal stimuli. These findings support the notion that transspinal and transcortical PAS has the ability to alter concomitantly cortical and spinal synaptic activity. Transspinal and transcortical PAS may contribute to the development of rehabilitation strategies in people with bilateral increased motoneuronal excitability due to cortical or spinal lesions. PMID- 29123928 TI - Neuroplasticity and Healthy Lifestyle: How Can We Understand This Relationship? PMID- 29123929 TI - Palpitations and Asthenia Associated with Venlafaxine in a CYP2D6 Poor Metabolizer and CYP2C19 Intermediate Metabolizer. AB - Cardiotoxicity has been extensively reported in venlafaxine (VEN) overdoses. Asthenia is also among the common side effects described for this antidepressant. VEN is metabolized mainly by CYP2D6 and to a minor extent by CYP2C19 to the major active metabolite O-desmethylvenlafaxine (ODV). Altered pharmacokinetic parameters in patients with polymorphisms in the CYP2D6 and CYP2C19 genes that result in decreased enzymatic activity have been documented. Here we describe a patient case of VEN associated palpitations and asthenia. The patient takes VEN extended release 150 mg twice daily. Genotyping confirmed the patient is a poor metabolizer for CYP2D6 and an intermediate metabolizer for CYP2C19. We propose that the palpitations and asthenia are related to sustained VEN exposure due to reduced metabolism. PMID- 29123930 TI - Chronic Myeloid Leukemia with an e6a2 BCR-ABL1 Fusion Transcript: Cooperating Mutations at Blast Crisis and Molecular Monitoring. AB - A minority of chronic myeloid leukemia patients (CML) express a variety of atypical BCR-ABL1 fusion variants and, of these, the e6a2 BCR-ABL1 fusion is generally associated with an aggressive disease course. Progression of CML to blast crisis is associated with acquisition of additional somatic mutations yet these events have not been elucidated in patients with the e6a2 BCR-ABL1 genotype. Moreover, molecular monitoring is only sporadically performed in CML patients with atypical BCR-ABL1 fusion transcripts due to lack of consensus approaches or standardization. A case of CML is described in which comprehensive molecular analysis, including targeted next-generation sequencing, revealed a single ASXL1 mutation cooperating with an e6a2 BCR-ABL1 fusion transcript at blast crisis. A quantitative molecular monitoring approach was devised and adopted that reflected the disease response from initial treatment through allogeneic stem cell transplantation which resulted in undetectable e6a2 BCR-ABL1 transcripts. This case emphasizes the requirement for molecular monitoring in CML patients with atypical BCR-ABL1 fusion transcripts and emphasizes that comprehensive sequencing has the potential to identify targets for novel therapies in CML patients with advanced disease. PMID- 29123927 TI - Locus Coeruleus and Dopamine-Dependent Memory Consolidation. AB - Most everyday memories including many episodic-like memories that we may form automatically in the hippocampus (HPC) are forgotten, while some of them are retained for a long time by a memory stabilization process, called initial memory consolidation. Specifically, the retention of everyday memory is enhanced, in humans and animals, when something novel happens shortly before or after the time of encoding. Converging evidence has indicated that dopamine (DA) signaling via D1/D5 receptors in HPC is required for persistence of synaptic plasticity and memory, thereby playing an important role in the novelty-associated memory enhancement. In this review paper, we aim to provide an overview of the key findings related to D1/D5 receptor-dependent persistence of synaptic plasticity and memory in HPC, especially focusing on the emerging evidence for a role of the locus coeruleus (LC) in DA-dependent memory consolidation. We then refer to candidate brain areas and circuits that might be responsible for detection and transmission of the environmental novelty signal and molecular and anatomical evidence for the LC-DA system. We also discuss molecular mechanisms that might mediate the environmental novelty-associated memory enhancement, including plasticity-related proteins that are involved in initial memory consolidation processes in HPC. PMID- 29123931 TI - Rapid Ascending Sensorimotor Paralysis, Hearing Loss, and Fatal Arrhythmia in a Multimorbid Patient due to an Accidental Overdose of Fluoxetine. AB - Background: Common side effects of selective serotonin reuptake inhibitors (SSRIs) include tachycardia, drowsiness, tremor, nausea, and vomiting. Although SSRIs have less toxic side effects compared to more traditional antidepressants, serious and life threatening cases of SSRI overdose have been reported. We describe a 24-year-old multimorbid female who presented to the emergency department with rapid onset ascending sensorimotor paralysis, complicated by respiratory and cardiac arrest, found to have fatal levels of fluoxetine by toxicological analysis, not taken in a suicidal act. Results: Autopsy was performed at the Los Angeles County Medical Examiner's Office of a female with no evidence of traumatic injury. Toxicological analysis revealed lethal levels of fluoxetine, toxic levels of diphenhydramine, and multiple other coingested substances at nontoxic levels. Neuropathological examination of the brain and spinal cord revealed no evidence of Guillain-Barre paralysis. Conclusions: Lethal levels of fluoxetine and multiple potential drug-to-drug interactions in our patient likely contributed to her unique signs and symptoms. This is the first case reporting neurologic signs and symptoms consisting of rapid onset ascending sensorimotor paralysis, hearing loss, respiratory failure, cardiac arrest, and death in a patient with lethal levels of fluoxetine. PMID- 29123932 TI - Hyperphosphatemic Tumoral Calcinosis after Total Knee Arthroplasty. AB - We report a case of hyperphosphatemic tumoral calcinosis (TC) that occurred after total knee arthroplasty. A 64-year-old Japanese man presented with painful swellings in both shoulders, the left elbow, and the right hip that developed after he underwent total knee arthroplasty (TKA). The pathology of the patient's bone at the time of TKA included a thick osteoid seam with calcareous deposition at the margin of the trabecular bone, which is not generally seen in osteoarthritis. Computed tomography scans of the swollen joints demonstrated leaflet and amorphous calcification masses around the joints. We diagnosed the patient with TC. The present case highlights that TC lesions are rare but should be considered in the differential diagnosis of subcutaneous soft and hard masses around the joint. PMID- 29123933 TI - Hemoptysis following Talc Pleurodesis in a Pneumothorax Patient. AB - The purpose of this article is to report a case of hemoptysis occurring in combination with secondary spontaneous pneumothorax following chemical pleurodesis by talc. A Japanese male with cancer of renal pelvis was found with the left pneumothorax and multiple lung metastases. A computed-tomography scan revealed severe emphysema throughout the lungs. Talc pleurodesis was employed to arrest air leakage. The patient developed hemoptysis 45 minutes after talc injection into the thorax. This is the first report of hemoptysis following talc pleurodesis. The agent could induce severe inflammation in capillary vessels of the lung following visceral pleura infiltration. PMID- 29123935 TI - Symptomatic Bochdalek Hernia in Pregnancy: A Rare Case Report. AB - Introduction: Symptomatic Bochdalek hernia in pregnancy is quite rare. To the best of our knowledge, there are a total of 44 cases reported in the literature between 1959 and 2016 (Hernandez-Aragon et al., 2015; Koca et al., 2016). Difficulty and delay in diagnosis may lead to life-threatening complications. Case Report: We report a case of Bochdalek hernia during the 30 gestational weeks' pregnancy in whom pregnancy continued after surgical repair which resulted in term birth. Discussion: Bochdalek hernia is diagnosed with an incidence of 1 in 2200-12500 live births, while symptomatic diaphragm hernia is much less in adults. The actual incidence of diaphragmatic hernias during pregnancy is still unknown. Symptoms may include abdominal distension, recurrent abdominal pain, nausea, vomiting, inability to defecate, dyspnea, and chest pain. The patient with diaphragmatic hernia may be asymptomatic until the late weeks of gestation, as in our case, or herniation may occur during advanced gestational weeks with increased intraabdominal pressure. Conclusion: In conclusion, diagnosis of the diaphragm hernia during pregnancy is very rare. Diagnosis is rarer in symptomatic patients due to its rarity and the duration of diagnosis may, therefore, be delayed. Diaphragm hernia should be kept in mind in symptomatic patients due to its high maternal and fetal mortality rates. PMID- 29123934 TI - Symptomatic Patent Foramen Ovale with Hemidiaphragm Paralysis. AB - Dyspnea accounts for more than one-fourth of the hospital admissions from Emergency Department. Chronic conditions such as Chronic Obstructive Pulmonary Disease, Congestive Heart Failure, and Asthma are being common etiologies. Less common etiologies include conditions such as valvular heart disease, pulmonary embolism, and right-to-left shunt (RLS) from patent foramen ovale (PFO). PFO is present in estimated 20-30% of the population, mostly a benign condition. RLS via PFO usually occurs when right atrium pressure exceeds left atrium pressure. RLS can also occur in absence of higher right atrium pressure. We report one such case that highlights the importance of high clinical suspicion, thorough evaluation, and percutaneous closure of the PFO leading to significant improvement in the symptoms. PMID- 29123936 TI - Reconstruction of a Damaged Lower Polar Artery for Kidney Transplantation Using Tubularised Donor Aorta. AB - Introduction: Live donors, extended donor criteria, and the maximum usage of organs with anatomical variants are some of the mechanisms used to increase the number of organs available. Case: We present the case of a kidney transplant, in which the organ had an iatrogenic injury to a lower pole arterial branch during retrieval. The donor was a 35-year-old male (DCD, Maastricht III). The right kidney was accepted; it had three veins in a single cava patch and three renal arteries, the main artery with aorta patch that is 8 cm long. A small lower pole artery was sectioned during retrieval surgery at approximately 1 cm from its origin as well as a third small mid-lower pole artery. The lower pole damaged artery was reconstructed using tubularised aorta patch to a total length of 5 cm. No additional donor vessels had been sent. After construction of the tubulised aorta, E-E anastomosis to the damaged polar artery was done with interrupted 7-0 Prolene sutures. Conclusion: While the waiting list for a kidney continues to rise and we continue to have organ shortness, vascular retrieval injury should not be an absolute contraindication for transplant. PMID- 29123937 TI - A Systematic Review of the Causes and Management of Ischaemic Stroke Caused by Nontissue Emboli. AB - Introduction: The inadvertent or purposeful introduction of foreign bodies or substances can lead to cerebral infarction if they embolize to the brain. Individual reports of these events are uncommon but may increase with the increased occurrences of their risk factors, for example, intra-arterial procedures. Method: We searched EMBASE and MEDLINE for articles on embolic stroke of nontissue origin. 1889 articles were identified and screened and 216 articles were ultimately reviewed in full text and included in qualitative analysis. Articles deemed relevant were assessed by a second reviewer to confirm compatibility with the inclusion criteria. References of included articles were reviewed for relevant publications. We categorized the pathology of the emboli into the following groups: air embolism (141 reports), other arterial gas embolisms (49 reports), missiles and foreign bodies (16 reports), and others, including drug embolism, cotton wool, and vascular sclerosant agents. Conclusion: Air and gaseous embolism are becoming more common with increased use of interventional medical procedures and increased popularity of sports such as diving. There is increasing evidence for the use of hyperbaric oxygen for such events. Causes of solid emboli are diverse. More commonly reported causes include bullets, missiles, and substances used in medical procedures. PMID- 29123938 TI - Uninformative Biological Variability Elimination in Apple Soluble Solids Content Inspection by Using Fourier Transform Near-Infrared Spectroscopy Combined with Multivariate Analysis and Wavelength Selection Algorithm. AB - Uninformative biological variability elimination methods were studied in the near infrared calibration model for predicting the soluble solids content of apples. Four different preprocessing methods, namely, Savitzky-Golay smoothing, multiplicative scatter correction, standard normal variate, and mean normalization, as well as their combinations were conducted on raw Fourier transform near-infrared spectra to eliminate the uninformative biological variability. Subsequently, robust calibration models were established by using partial least squares regression analysis and wavelength selection algorithms. Results indicated that the partial least squares calibration models with characteristic variables selected by CARS method coupled with preprocessing of Savitzky-Golay smoothing and multiplicative scatter correction had a considerable potential for predicting apple soluble solids content regardless of the biological variability. PMID- 29123939 TI - Assessment of Availability and Human Health Risk Posed by Arsenic Contaminated Well Waters from Timis-Bega Area, Romania. AB - Mobilization of As from geological materials into ground and drinking water sources may represent an important threat to human health. The objective of this study was to assess the As concentration and availability in underground water used as drinking water sources. Water samples were collected from public and private wells in Timis-Bega area of Pannonian Basin, West Romania. Total dissolved As measured after "classical" filtration of water samples was in the range of 0.10-168 MUg L-1, thus exceeding the guideline value in majority of the samples. The aim of this study was also to assess the "truly dissolved" concentrations of As considered as available concentrations, in well waters, after passive sampling by Diffusive Gradients in Thin-films (DGT). The results showed that over 70% of total-dissolved As is in available forms. The obtained data were used to evaluate the risks of using the wells as drinking water source. Hazard quotients for ingestion and dermal pathways and hazard index (HI) for exposure to As were calculated. The HI values > 1 found that majority of samples indicated a health risk for local residents. PMID- 29123940 TI - Influence of Digestion Procedure and Residual Carbon on Manganese, Copper, and Zinc Determination in Herbal Matrices by Atomic Absorption Spectrometry. AB - Mineralization to the complete oxidation of sample carbon component does not always assure the best analyte recovery. Particular attention should be paid to the presence of silicon in the investigated plant sample and especially in the certified reference material for which Si content is scarcely given by the providers. During mineralization without addition of the hydrofluoric acid, the residual carbon may block silica surfaces and increase availability of an analyte for its spectral determination in the solution. This issue is of particular relevance because standard protocols for digestion of plant matrices often do not support hydrofluoric acid addition. Several procedures recommended for decomposition of herbal plants were applied for the respective certified reference material and examined in detail. Manganese, copper, and zinc contents were analyzed in all samples by the flame atomic absorption spectrometry. Additionally, the residual carbon was determined in all mineralizates. Silicon content was analyzed by the X-ray fluorescence method. The best recoveries were observed for samples characterized by relatively high residual carbon. PMID- 29123941 TI - Bile acids as global regulators of hepatic nutrient metabolism. AB - Bile acids (BA) are synthesized from cholesterol in the liver. They are essential for promotion of the absorption of lipids, cholesterol, and lipid-soluble vitamins from the intestines. BAs are hormones that regulate nutrient metabolism by activating nuclear receptors (farnesoid X receptor (FXR), pregnane X receptor, vitamin D) and G protein-coupled receptors (e.g., TGR5, sphingosine-1-phosphate receptor 2 (S1PR2)) in the liver and intestines. In the liver, S1PR2 activation by conjugated BAs activates the extracellular signal-regulated kinase 1/2 and AKT signaling pathways, and nuclear sphingosine kinase 2. The latter produces sphingosine-1-phosphate (S1P), an inhibitor of histone deacetylases 1/2, which allows for the differential up-regulation of expression of genes involved in the metabolism of sterols and lipids. We discuss here the emerging concepts of the interactions of BAs, FXR, insulin, S1P signaling and nutrient metabolism. PMID- 29123942 TI - Mode of Managing Nutrient Solution Based on N Use Efficiency for Lettuce (Lactuca sativa L.). AB - In aeroponic cultivation the nutrient solution is an essential component to achieve good production results. And nitrogen is the main constituent element of the nutrient solution and essential element in plant nutrition. Therefore, the management and monitoring nutrient solution and existing nitrogen is fundamental. The experiment shows that three modes of replacing the nutrient solution and three initial pH values and their interaction significantly influenced the fresh weight and dry matter of lettuce. The highest values of fresh and dry weight were recorded in the fifth treatment where there is an interaction between pH 6 and the mode of replacing half of the nutrient solution. The consumption rate of nitrate nitrogen (NO3-N), ammonium nitrogen (NH4-N) and gross nitrogen (GN) was higher during stage 1 (10 days after transplanting), especially for the mode of complete replacing nutrient solution. PMID- 29123943 TI - Telemedicine Enables Broader Access to Movement Disorders Curricula for Medical Students. AB - Background: The impact of tele-education for movement disorders on medical students is unknown. The present study had three objectives. First, to create a tele-education program for medical students in regions with limited access to movement disorders curricula. Second, to analyze the feasibility, satisfaction, and improvement of medical knowledge. Third, to assess the main reasons of medical students for attending this course. Methods: In 2016, a program was piloted in a low-middle income (Cameroon) and a middle-high income (Argentina) country. Medical students were offered a free movement disorder tele-education program (four medical schools in Argentina, and 1 medical school in Cameroon). Six real-time videoconferences covering hyperkinetic and hypokinetic movement disorders were included. Evaluations included attendance, pre- and post-medical knowledge, and satisfaction questionnaires. Results: The study included 151 undergraduate medical students (79.4% from Argentina, 20.6% from Cameroon). Feasibility was acceptable with 100% and 85.7% of the videoconferences completed in Argentina and Cameroon, respectively. Attendance was higher in Argentina compared to Cameroon (75% vs. 33.1%). According to student reports, the topics and innovative educational environment were the main reasons for attendance. Both groups ranked satisfaction as moderate to high, and medical knowledge improved similarly in both countries. Discussion: Tele-education can improve movement disorders knowledge in medical schools in high-middle and low-middle income countries lacking access to other educational opportunities. PMID- 29123944 TI - Hypothyroidism-induced Reversible Encephalopathy as a Cause of Aggravation of Parkinsonism and Myoclonus in Parkinson's Disease. AB - Background: Myoclonus and encephalopathy are unusual in patients with Parkinson's disease (PD). Case report: We describe the case of a 59-year-old male with PD who developed myoclonus and encephalopathy. Underlying hypothyroidism was revealed after admission and treated with levothyroxine. Myoclonus and encephalopathy were completely resolved following thyroid hormone replacement. Discussion: Hypothyroidism can cause reversible myoclonus and encephalopathy along with unusual aggravation of parkinsonism symptoms in patients with PD. PMID- 29123946 TI - Tumor cell death by pattern-sensing of exogenous RNA: Tumor cell TLR3 directly induces necroptosis by poly(I:C) in vivo, independent of immune effector-mediated tumor shrinkage. AB - Poly(I:C) acts on dendritic cells to induce potent antitumor effects through the production of cytokines/interferons, activation of natural killer cells and proliferation of cytotoxic T lymphocytes. In some tumor or myeloid lineages, poly(I:C) seemed to induce necroptosis in concert with a pan-caspase inhibitor by directly acting on toll-like receptor (TLR) 3 in both in vivo and in vitro models. PMID- 29123945 TI - The Anatomical Basis for Dystonia: The Motor Network Model. AB - Background: The dystonias include a clinically and etiologically very diverse group of disorders. There are both degenerative and non-degenerative subtypes resulting from genetic or acquired causes. Traditionally, all dystonias have been viewed as disorders of the basal ganglia. However, there has been increasing appreciation for involvement of other brain regions including the cerebellum, thalamus, midbrain, and cortex. Much of the early evidence for these other brain regions has come from studies of animals, but multiple recent studies have been done with humans, in an effort to confirm or refute involvement of these other regions. The purpose of this article is to review the new evidence from animals and humans regarding the motor network model, and to address the issues important to translational neuroscience. Methods: The English literature was reviewed for articles relating to the neuroanatomical basis for various types of dystonia in both animals and humans. Results: There is evidence from both animals and humans that multiple brain regions play an important role in various types of dystonia. The most direct evidence for specific brain regions comes from animal studies using pharmacological, lesion, or genetic methods. In these studies, experimental manipulations of specific brain regions provide direct evidence for involvement of the basal ganglia, cerebellum, thalamus and other regions. Additional evidence also comes from human studies using neuropathological, neuroimaging, non-invasive brain stimulation, and surgical interventions. In these studies, the evidence is less conclusive, because discriminating the regions that cause dystonia from those that reflect secondary responses to abnormal movements is more challenging. Discussion: Overall, the evidence from both animals and humans suggests that different regions may play important roles in different subtypes of dystonia. The evidence so far provides strong support for the motor network model. There are obvious challenges, but also advantages, of attempting to translate knowledge gained from animals into a more complete understanding of human dystonia and novel therapeutic strategies. PMID- 29123947 TI - Translational nanoparticle engineering for cancer vaccines. AB - Conventional cancer treatments remain insufficient to treat many therapy resistant tumors.1 Cancer vaccines attempt to overcome this resistance by activating the patient's immune system to eliminate tumor cells without the toxicity of systemic chemotherapy and radiation. Nanoparticles (NPs) are promising as customizable, immunostimulatory carriers to protect and deliver antigen. Although many NP vaccines have been investigated in preclinical settings, a few have advanced into clinical application, and still fewer have demonstrated clinical benefit. This review incorporates observations from NP vaccines that have been evaluated in early phase clinical trials to make recommendations for the next generation of NP-based cancer vaccines. PMID- 29123949 TI - Targeting IL-5Ralpha with antibody-conjugates reveals a strategy for imaging and therapy for invasive bladder cancer. AB - Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor alpha-subunit (IL-5Ralpha) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Ralpha as a target for antibody conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Ralpha immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Ralpha and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 (64Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64Cu-A14 treatments. Our findings suggest that although IL-5Ralpha protein expression is preferentially increased in MIBC, it is rapid IL-5Ralpha-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64Cu-A14 to detect MIBC tumors in vivo. This is the first report to elucidate the potential of IL-5Ralpha as an attractive MIBC target for antibody-conjugate applications. PMID- 29123948 TI - No patient left behind: The promise of immune priming with epigenetic agents. AB - Checkpoint inhibitors, monoclonal antibodies that inhibit PD-1 or CTLA-4, have revolutionized the treatment of multiple cancers. Despite the enthusiasm for the clinical successes of checkpoint inhibitors, and immunotherapy, in general, only a minority of patients with specific tumor types actually benefit from treatment. Emerging evidence implicates epigenetic alterations as a mechanism of clinical resistance to immunotherapy. This review presents evidence for that association, summarizes the epi-based mechanisms by which tumors evade immunogenic cell death, discusses epigenetic modulation as a component of an integrated strategy to boost anticancer T cell effector function in relation to a tumor immunosuppression cycle and, finally, makes the case that the success of this no-patient-left behind strategy critically depends on the toxicity profile of the epigenetic agent(s). PMID- 29123950 TI - Immune evasion mechanisms and immune checkpoint inhibition in advanced merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD 1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell-mediated clearance. Unlike chemotherapy, treatment with anti-PD-L1 (avelumab) or anti-PD-1 (pembrolizumab) antibodies leads to durable responses in MCC, in both virus-positive and virus-negative tumors. As many tumors are established through the evasion of infiltrating immune-cell clearance, the lessons learned in MCC may be broadly relevant to many cancers. PMID- 29123952 TI - Mevalonate metabolism governs cancer immune surveillance. AB - The metabolic reprogramming that drives immunity engages the mevalonate pathway for cholesterol biosynthesis and protein prenylation. The importance of tight regulation of this metabolic route is reflected by the fact that too low activity impairs cellular function and survival, whereas hyperactivity can lead to malignant transformation. Here, we first address how mevalonate metabolism drives immunity and then highlight ways of the immune system to respond to both, limited and uncontrolled flux through the mevalonate pathway. Immune responses elicited by mevalonate pathway dysregulation may be harnessed to increase the clinical efficacy of current cancer therapy regimens. PMID- 29123951 TI - Characterization of a switchable chimeric antigen receptor platform in a pre clinical solid tumor model. AB - The universal modular chimeric antigen receptor (UniCAR) platform redirects CAR-T cells using a separated, soluble targeting module with a short half-life. This segregation allows precise controllability and flexibility. Herein we show that the UniCAR platform can be used to efficiently target solid cancers in vitro and in vivo using a pre-clinical prostate cancer model which overexpresses prostate stem cell antigen (PSCA). Short-term administration of the targeting module to tumor bearing immunocompromised mice engrafted with human UniCAR-T cells significantly delayed tumor growth and prolonged survival of recipient mice both in a low and high tumor burden model. In addition, we analyzed phenotypic and functional changes of cancer cells and UniCAR-T cells in association with the administration of the targeting module to reveal potential immunoevasive mechanisms. Most notably, UniCAR-T cell activation induced upregulation of immune inhibitory molecules such as programmed death ligands. In conclusion, this work illustrates that the UniCAR platform mediates potent anti-tumor activity in a relevant in vitro and in vivo solid tumor model. PMID- 29123953 TI - PD-1 blockade augments anti-neuroblastoma immune response induced by anti-GD2 antibody ch14.18/CHO. AB - Immunotherapy with anti-GD2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients and is mainly based on GD2-specific Ab dependent cellular cytotoxicity (ADCC). Strategies to further enhance the efficacy are important and currently explored in prospective clinical trials randomizing ch14.18/CHO +/- IL-2. Recently, expression of programmed death 1 (PD 1) inhibitory receptor by effector cells and its ligand (PD-L1) by tumor cells has been shown. Here, we report for the first time effects of PD-1 blockade on ch14.18/CHO-based immunotherapy and mechanisms involved. Expression of PD-1 and PD-L1 on NB and effector cells was analyzed by RT-PCR and flow cytometry in the presence of ch14.18/CHO and/or IL-2. The effect of PD-1 blockade on ch14.18/CHO mediated anti-NB immune response was evaluated using anti-PD-1 Ab both in vitro (Nivolumab) and in a syngeneic PD-L1+/GD2+ NB mouse model (anti-mouse PD-1). Culture of NB cells LA-N-1 (low PD-L1 baseline expression) with leukocytes and subtherapeutic ch14.18/CHO concentrations for 24 h induced strong upregulation of PD-L1, which was further increased by IL-2 resulting in complete inhibition of ch14.18/CHO-mediated ADCC. Importantly, blockade with Nivolumab reversed the PD L1-dependent inhibition of ADCC. Similarly, co-incubation with anti-CD11b Ab abrogated the PD-L1 upregulation and restored ADCC. Mice treated with ch14.18/CHO in combination with PD-1 blockade showed a strong reduction of tumor growth, prolonged survival and the highest cytotoxicity against NB cells. In conclusion, ch14.18/CHO-mediated effects upregulate the inhibitory immune checkpoint PD-1/PD L1, and combination of ch14.18/CHO with PD-1 blockade results in synergistic treatment effects in mice representing a new effective treatment strategy against GD2-positive cancers. PMID- 29123954 TI - Exogenous lipid uptake induces metabolic and functional reprogramming of tumor associated myeloid-derived suppressor cells. AB - Myeloid-derived suppressor cells (MDSC) promote tumor growth by blocking anti tumor T cell responses. Recent reports show that MDSC increase fatty acid uptake and fatty acid oxidation (FAO) to support their immunosuppressive functions. Inhibition of FAO promoted a therapeutic T cell-mediated anti-tumor effect. Here, we sought to determine the mechanisms by which tumor-infiltrating MDSC increase the uptake of exogenous lipids and undergo metabolic and functional reprogramming to become highly immunosuppressive cells. The results showed that tumor-derived cytokines (G-CSF and GM-CSF) and the subsequent signaling through STAT3 and STAT5 induce the expression of lipid transport receptors with the resulting increase in the uptake of lipids present at high concentrations in the tumor microenvironment. The intracellular accumulation of lipids increases the oxidative metabolism and activates the immunosuppressive mechanisms. Inhibition of STAT3 or STAT5 signaling or genetic depletion of the fatty acid translocase CD36 inhibits the activation of oxidative metabolism and the induction of immunosuppressive function in tumor-infiltrating MDSC and results in a CD8+ T cell-dependent delay in tumor growth. Of note, human tumor-infiltrating and peripheral blood MDSC also upregulate the expression of lipid transport proteins, and lipids promote the generation of highly suppressive human MDSC in vitro. Our data therefore provide a mechanism by which tumor-derived factors and the high lipid content in the tumor microenvironment can cause the profound metabolic and functional changes found in MDSC and suggest novel approaches to prevent or reverse these processes. These results could further enhance the efficacy of cancer immunotherapy. PMID- 29123955 TI - Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: A systematic review and meta-analysis. AB - Background: With the rising use of immune checkpoint inhibitors (ICI) across varying tumors types, immune-related colitis is an increasingly encountered, serious adverse event requiring appropriate management. The incidence across ICI treatment regimens and tumor types is unclear. Objective: To characterize the incidence of immune-related colitis among various ICI regimens and tumor types. Methods: Thirty-four original studies of prospective ICI trials were identified based on a PubMed search completed on November 1st, 2016. Seventeen studies compared incidences across tumor types. The incidences of all-grade, grade 3-4 (severe) colitis, and grade 3-4 (severe) diarrhea were collected. Results: Thirty four studies containing 8863 patients were included in the meta-analysis. The overall incidence during ipilimumab monotherapy was 9.1% for all-grade colitis, 6.8% for severe colitis, and 7.9% for severe diarrhea. The incidence was lowest during PD-1/PD-L1 inhibitor monotherapy with 1.3% for all-grade colitis, 0.9% for severe colitis and 1.2% for severe diarrhea, while combination ipilimumab and nivolumab resulted in the highest incidences of all-grade colitis (13.6%), severe colitis (9.4%) and severe diarrhea (9.2%) among ICIs. Among melanoma, NSCLC, RCC patients, incidences of colitis and diarrhea with PD-1/PD-L1 inhibitor monotherapy did not significantly differ. Severe colitis incidence was similar with ipilimumab monotherapy at 3 mg/kg and 10 mg/kg (7.1% vs 5.1%, respectively), but significantly higher for severe diarrhea with 10mg/kg (11.5% vs 5.2%). Conclusions: The incidence of immune-related colitis and severe diarrhea was higher with ipilimumab-containing regimens compared with PD-1/PD-L1 inhibitors. There was no significant difference in immune-related colitis between different tumor types with PD-1/L1 inhibitors. PMID- 29123956 TI - Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis. AB - Myelofibrosis (MF) is a clonal neoplasia associated with chronic inflammation due to aberrant cytokine production. Mutations in Janus Kinase-2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia protein (MPL) genes have been recently associated to MF and they all activate the JAK/STAT signaling pathway. Since this pathway is essential in shaping the immune response, we investigated the role of circulating immune subsets and cytokines in 38 patients (20 carrying JAK2(V617F),13 exon-9 CALR mutation and 5 triple negative). In comparison to healthy donors, patients presented a reduced amount of circulating dendritic cells (DCs) associated with a defective ability of monocytes in differentiating into DCs. In addition, we found a reduction in circulating T-helper (Th)1 and Th17 and hypo-functional innate lymphoid cells (ILC). Results analyzed according to the mutational status showed that patients carrying JAK2(V617F) mutation had a reduction in Th17, myeloid-DCs and effector Tregs as well as increased ILC1 and cytokine producing Tregs. The CALR mutated patients revealed high ILC3 levels, reduced Th1 and their monocytes had a reduced capacity to mature in vitro into fully committed DCs. Their Tregs were also less effective in inhibiting the proliferation of autologous effector T-cells due to an increased proliferative status induced by CALR mutation. Triple negative patients presented a reduced amount of total circulating CD3, effectors Tregs and Th1 with increased ILC1. Overall, we have demonstrated that in MF different mutations lead to phenotypic and functional alterations in different immune subsets that may have a potential role in disease progression and susceptibility to infections. PMID- 29123957 TI - Labeling of cell therapies: How can we get it right? AB - Labeling cells for non-invasive tracking in vivo using magnetic resonance imaging (MRI) is an emerging hot topic garnering ever increasing attention, yet it is fraught with numerous methodological challenges, which merit careful attention. Several of the current procedures used to label cells for tracking by MRI take advantage of the intrinsic phagocytic nature of cells to engulf nanoparticles, though cells with low intrinsic phagocytic capacity are also commonly studied. Before we take the next steps towards administering such cells in vivo, it is essential to understand how the nanolabel is recognized, internalized, trafficked and distributed within the specific host cell. This is even more critical when contemplating labeling of cells that may ultimately be applied in vivo to patients in a therapeutic context. PMID- 29123958 TI - Expression of CD94 by ex vivo-differentiated NK cells correlates with the in vitro and in vivo acquisition of cytotoxic features. AB - The administration of ex vivo-expanded Natural Killer (NK) cells in leukemia therapy is still challenging, in part due to the difficulty to generate in sufficient quantities fully mature and functional NK cells and Identification of surface markers indicative of NK maturation and functionality is therefore needed. Here, based on the analysis of surface receptors of ex vivo-expanded NK cells, we identified CD94 as a surface marker correlating with high lytic potential against leukemic cell lines and immunological synapse formation. CD94 positive ex vivo-expanded NK cells displayed higher expression of NKG2 receptors and the adhesion molecule LFA-1, as compared with their CD94-negative counterparts. We also tested the in vivo anti-leukemic capacity of ex vivo expanded NK cells against patient-derived acute myeloid leukemia cells. Although no anti-leukemic effect was detected, we noticed that only CD94-positive ex vivo expanded NK cells were detected in leukemic mice at the end of the 2-week treatment. Moreover, flow cytometry analysis showed a subpopulation harboring CD94 (NK) and CD34 (leukemic cells) double staining, indicative of conjugate formation. Therefore surface expression of CD94 on ex vivo-differentiated NK cells emerged as an indicator of in vitro and in vivo killer cell functionality. PMID- 29123959 TI - Immunological efficacy of glypican-3 peptide vaccine in patients with advanced hepatocellular carcinoma. AB - We have previously conducted a phase I trial to test the efficacy of a glypican-3 (GPC3) peptide vaccine in patients with advanced hepatocellular carcinoma (HCC); however, its immunological mechanism of action remains unclear. Here, we report a pilot study conducted to evaluate the immunological mechanisms of action of this GPC3 peptide vaccine (UMIN-CTR number 000005093). Eleven patients with advanced HCC were vaccinated with the GPC3 peptide in this trial. The primary end point was GPC3 peptide-specific immune response induced by the GPC3 peptide vaccination. The secondary endpoints were clinical and biologic outcomes. We demonstrated that the present vaccine induced GPC3 peptide-specific cytotoxic T lymphocytes (CTLs), which were found to infiltrate into the tumor. Moreover, we established GPC3 peptide-specific CTL clones from a biopsy specimen: these cells exhibited GPC3 peptide-specific cytokine secretion and cell cytotoxicity. The plasma GPC3 level tended to decrease temporarily at least once during the follow up period. The GPC3-specific CTL frequency after vaccination was correlated with overall survival. The degree of skin reactions at the injection site correlated with the GPC3 peptide-specific CTLs. Furthermore, we sequenced the T cell receptors (TCRs) of tumor-infiltrating lymphocyte (TIL) clones, and confirmed the existence of this TCR repertoire in both tumor tissue and PBMCs. In response to these data, we are developing TCR-engineered T cell therapy using TCR sequences obtained from GPC3 peptide-specific CTL clones for improved efficacy in patients with advanced HCC. PMID- 29123960 TI - The STING agonist DMXAA triggers a cooperation between T lymphocytes and myeloid cells that leads to tumor regression. AB - Regressing tumors are usually associated with a large immune infiltrate, but the molecular and cellular interactions that govern a successful anti-tumor immunity remain elusive. Here, we have triggered type I Interferon (IFN) signaling in a breast tumor model (MMTV-PyMT) using 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a ligand of the STimulator of Interferon Genes, STING. The 2 main events rapidly triggered by DMXAA in transplanted PyMT tumors are 1) the disruption of the tumor vasculature, followed by hypoxia and cell death; 2) the release of chemokines. Both events converged to trigger the recruitment of 2 waves of immune cells: a swift, massive recruitment of neutrophils, followed by a delayed rise in monocytes and CD8 T cells in the tumor mass. Depletion experiments in vivo revealed that myeloid cell subsets and T cells need to cooperate to achieve full blown recruitment and activation at the tumor site and to induce effective secondary cell death leading to tumor regression (Illustration 1). Altogether, our study highlights that the tumor regression induced by the STING agonist DMXAA results from a cascade of events, with an initial vessel destruction followed by several infiltration waves of immune cells which have to cooperate to amplify and sustain the initial effect. We thus provide the first global and detailed kinetic analysis of the anti-tumoral effect of DMXAA and of its different articulated steps. PMID- 29123961 TI - Soluble NKG2D ligands limit the efficacy of immune checkpoint blockade. PMID- 29123962 TI - Distinctive features of tumor-infiltrating gammadelta T lymphocytes in human colorectal cancer. AB - gammadelta T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating gammadelta T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of gammadelta T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a highly variable rate of TILs (5-90%) and 4% gammadelta T cells on average, with the majority expressing Vdelta1. Most Vdelta1 and Vdelta2 T cells showed a predominant effector memory phenotype and had reduced production of IFN- gamma which was likely due to yet unidentified inhibitory molecules present in cancer stem cell secretome. Transcriptome analyses revealed that patients containing abundant gammadelta T cells had significantly longer 5-year disease free survival rate, suggesting their efficacy in controlling tumor at very early stage. PMID- 29123963 TI - Blocking C5aR signaling promotes the anti-tumor efficacy of PD-1/PD-L1 blockade. AB - Anti-PD-1/PD-L1 therapy has achieved great success in the clinic; however, only a small fraction of cancer patient benefit from PD-1/PD-L1 blockade therapy, and overcoming resistance to PD-1/PD-L1 blockade has thus become a primary priority. In this study, we demonstrated that administration of PD-1/PD-L1 antibodies resulted in the activation of the complement system and massive generation of C5a. Generation of C5a did not change the accumulation of MDSCs in either the tumor or spleen but enhanced their inhibitory potential. In addition, blockade of C5a-C5aR signaling in combination with PD-1/PD-L1 antibodies greatly enhanced the anti-tumor efficacy of PD-1/PD-L1 antibodies. Overall, these data indicate an immunosuppressive role of C5a in the context of PD-1/PD-L1 blockade therapy and provide a strong incentive to clinically explore combination therapies using a C5a antagonist. PMID- 29123964 TI - A novel bifunctional anti-PD-L1/TGF-beta Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. AB - Mesenchymalization is a cellular and molecular program in which epithelial cells progressively lose their well-differentiated phenotype and adopt mesenchymal characteristics. Tumor mesenchymalization occurs during the progression of cancer to metastatic disease, and is also associated with resistance to multiple therapeutics, including killing by cytotoxic immune cells. Furthermore, tumor cells can evade immune destruction by upregulating the checkpoint molecule PD-L1, and emerging research has found higher PD-L1 expression in mesenchymalized tumors. Here, the association between TGF-beta1-mediated mesenchymalization and PD-L1 was investigated in non-small cell lung cancer cells (NSCLC). TGF-beta1 was found to upregulate PD-L1 gene transcription in a Smad2-dependent manner, and a positive association between PD-L1 and phosphorylated Smad2 was found in NSCLC tumors. The potential to target these 2 negative immune regulators with a single agent was investigated using M7824, a novel clinical-stage bifunctional agent that targets both PD-L1 and TGF-beta. Treatment of NSCLC cells with M7824 in vitro and in vivo attenuated features of TGF-beta1-mediated mesenchymalization, including mesenchymal marker expression, proliferation suppression, and chemoresistance. These findings demonstrate that upregulation of tumor cell PD-L1 is a novel mechanism of TGF-beta1-induced immunosuppression in NSCLC, and that treatment with M7824 has the potential to simultaneously block both tumor mesenchymalization and PD-L1-dependent immunosuppression. PMID- 29123965 TI - Ig-like transcript 2 (ILT2) suppresses T cell function in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is associated with a profound dysregulation of the immune system. Loss of T cell function is frequently caused in cancer by sustained signaling of inhibitory receptors. Here, we analyzed the role of the novel inhibitory receptor Ig-like transcript 2 (ILT2) in the pathogenesis of CLL. We observed that ILT2 expression was markedly reduced on leukemic cells, whereas it was increased on CD8 and CD4 T cells from CLL patients, particularly in those patients harboring chromosome 11q deletion, which includes the ATM gene. A deep dysregulation of ILT2 ligands expression in leukemia cells was also observed. ILT2 impaired the activation and proliferation of CD4 and CD8 T cells in CLL patients, but it had no effect in leukemic cells. ILT2 downregulated the production of IL-2 by CD4 T cells of CLL patients and induced the expression of cytokines that promote the survival of leukemic cells, such as IFN-gamma, by T cells. Importantly, ILT2 blockade restored the activation, proliferation and cytokine production of T cells. In conclusion, we describe a novel immune inhibitory pathway that is upregulated in CLL and delineate a new potential target to be explored in this disease. PMID- 29123966 TI - PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody. AB - Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy. In immunocompetent mice TA99 treatment strongly increased the fraction of CD8 and CD4 effector T cells in the tumor compared with isotype control, highlighting the specific immune modulation of the tumor microenvironment by TA99. However, in most mice, TA99 immunotherapy could not prevent immune effector exhaustion and the recruitment of regulatory CD4 T cells and consequently tumor escape from immune surveillance. Remarkably, anti-PD-1 treatment at the time of tumor emergence restored the Th1 effector functions of CD4 and CD8 T cells as well as of natural killer and gammadeltaT cells, which translated into a significant slow down of tumor progression and extended survival. Our findings provide the first evidence that PD-1 blockade at the time of tumor emergence can efficiently boost the host anti-tumor immune response initiated several weeks before by the TA targeting mAb. These results are promising for the design of combined therapies to sensitize non-responder or resistant patients. PMID- 29123968 TI - Corrigendum. AB - [This corrects the article DOI: 10.1080/2162402X.2017.1319028.]. PMID- 29123967 TI - Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. AB - Immunotherapy clinical trials targeting the programmed-death ligand axis (PD-1/PD L1) show that most head and neck squamous cell carcinoma (HNSCC) patients are resistant to PD-1/PD-L1 inhibition. We investigated whether local radiation to the tumor can transform the immune landscape and render poorly immunogenic HNSCC tumors sensitive to PD-L1 inhibition. We used the first novel orthotopic model of HNSCC with genetically distinct murine cell lines. Tumors were resistant to PD-L1 checkpoint blockade, harbored minimal PD-L1 expression and tumor infiltrating lymphocytes at baseline, and were resistant to radiotherapy. The combination of radiation and PD-L1 inhibition significantly enhanced tumor control and improved survival. This was mediated in part through upregulation of PD-L1 on tumor cells and increased T-cell infiltration after RT, resulting in a highly inflamed tumor. Depletion of both CD4 and CD8 T-cells completely abrogated the effect of anti PD L1 with radiation on tumor growth. Our findings provide evidence that radiation to the tumor can induce sensitivity to PD-L1 checkpoint blockade in orthotopic models of HNSCC. These findings have direct relevance to high risk HNSCC patients with poorly immunogenic tumors and who may benefit from combined radiation and checkpoint blockade. PMID- 29123969 TI - Corrigendum. AB - [This corrects the article DOI: 10.1080/2162402X.2017.1342024.]. PMID- 29123970 TI - Physiological Markers of Interpersonal Stress Generation in Depression. AB - Abnormalities in parasympathetic nervous system activity have been linked to depression, but less is known about processes underlying this relationship. The present study evaluated resting and stress-reactive respiratory sinus arrhythmia (RSA) to a laboratory stressor as predictors of daily interpersonal stress generation and depressive symptoms, whether stress generation mediated the relationship between RSA and depressive symptoms, and potential sex differences. A sample of formerly depressed 102 emerging adults (18-22 years; 78% female) completed a laboratory stressor and daily assessments of stressors and depressive symptoms over two weeks. Multilevel modeling revealed that: 1) lower resting RSA predicted daily depressive symptoms; 2) less RSA reactivity predicted interpersonal stress generation, 3) interpersonal dependent stressors mediated the relationship between RSA reactivity and daily depressive symptoms, and 4) sex differences occurred in the resting RSA-depression relationship. These findings highlight the importance of resting RSA and RSA reactivity in the examination of depression and interpersonal processes. PMID- 29123971 TI - Concepts of Genomics in Kidney Transplantation. AB - Purpose of review: Identification of genetic variants to aid in individualized treatment of solid organ allograft recipients would improve graft survival. We will review the current state of knowledge for associations of variants with transplant outcomes. Recent findings: Many studies have yet to exhibit robust and reproducible results, however, pharmacogenomic studies focusing on cytochrome P450 (CYP) enzymes, transporters and HLA variants have shown strong associations with outcomes and have relevance towards drugs used in transplant. Genome wide association study data for the immunosuppressant tacrolimus have identified multiple variants in the CYP3A5 gene associated with trough concentrations. Additionally, APOL1 variants had been shown to confer risk to the development of end stage renal disease in African Americans. Summary: The field is rapidly evolving and new technology such as next generation sequencing, along with larger cohorts, will soon be commonly applied in transplantation to understand genetic association with outcomes and personalized medicine. PMID- 29123972 TI - How does early adulthood arrest alter substance use behavior? Are there differential effects by race/ethnicity and gender? AB - Purpose: Much criminal justice research has ignored racial/ethnic and gender differences in substance use subsequent to criminal justice involvement. This paper investigated how early adulthood arrest (i.e., 18 to 21 years of age) influences individuals' subsequent transitions from non-substance use to substance use, and substance use to non-substance use through age 30. We also consider if these relationships differ by race/ethnicity and gender. Processes proscribed by labeling theory subsequent to getting arrested are considered. Methods: We analyzed 15 waves of data from the National Longitudinal Survey of Youth 1997. Multinomial logistic regressions were performed using Stata software version 14. Results: We found racial/ethnic differences in the effect of arrest on subsequent substance use, particularly marijuana. Being arrested was associated with shifting non-binge drinkers and non-marijuana users into binge drinking and marijuana use; as well as shifting binge drinkers and marijuana users into non-use. This pattern was most evident among White and Black men. For Black men, the association between arrest and both becoming a binge drinker and becoming a non-binge drinker was experienced most strongly during their early twenties. Women's patterns in substance use transitions following an arrest were less clear than for the men. Conclusion: Some results, particularly transitioning into marijuana use, offer qualified support for processes proscribed through labeling theory. Findings that arrest shifts individuals into non-marijuana use suggest that factors not accounted for by labeling theory - arrest serving as a teachable moment for those using substances - may be at play. PMID- 29123973 TI - Cholera toxin B subunit induces local curvature on lipid bilayers. AB - The B subunit of the bacterial cholera toxin (CTxB) is responsible for the toxin binding to the cell membrane and its intracellular trafficking. CTxB binds to the monosialotetrahexosyl ganglioside at the plasma membrane of the target cell and mediates toxin internalization by endocytosis. CTxB induces a local membrane curvature that is essential for its clathrin-independent uptake. Using all-atom molecular dynamics, we show that CTxB induces local curvature, with the radius of curvature around 36 nm. The main feature of the CTxB molecular structure that causes membrane bending is the protruding alpha helices in the middle of the protein. Our study points to a generic protein design principle for generating local membrane curvature through specific binding to their lipid anchors. PMID- 29123974 TI - Expression profiles of BrMYB transcription factors related to glucosinolate biosynthesis and stress response in eight subspecies of Brassica rapa. AB - Brassica rapa is a polyploid species with phenotypically diverse cultivated subspecies. Glucosinolates (GSLs) are secondary metabolites that contribute to anticarcinogenic activity and plant defense in Brassicaceae. Previously, complete coding sequences of 13 BrMYB transcription factors (TFs) related to GSL biosynthesis were identified in the B. rapa genome. In the present study, we investigated GSL content and expression levels of these BrMYB TFs in 38 accessions belonging to eight subspecies of B. rapa. Twelve identified GSLs were detected and were classified into three chemical groups based on patterns of GSL content and expression profiles of the BrMYB TFs. GSL content and BrMYB TF expression levels differed among genotypes, including B. rapa subspecies pekinensis, chinensis and rapa. BrMYB28.3, BrMYB51.1 and BrMYB122.2 positively regulated GSL content in 38 accessions. Furthermore, expression levels of BrMYB28s and BrMYB34.3 increased under most abiotic and biotic stress treatments. The three BrMYB51 paralogs also showed drastically increased expression levels after infection with Pectobacterium carotovorum. The results of the present study improve our understanding of the functional diversity of these 13 BrMYB TFs during the evolution of polyploid B. rapa. PMID- 29123976 TI - Advanced glycation end products reduce the calcium transient in cardiomyocytes by increasing production of reactive oxygen species and nitric oxide. AB - Advanced glycation end products (AGE) are central to the development of cardiovascular complications associated with diabetes mellitus. AGE may alter cellular function through cross-linking of cellular proteins or by activating the AGE receptor (RAGE). However, the signalling molecules involved during AGE stimulation in cardiomyocytes remain unclear. Here, we investigated the effects of AGE treatment on intracellular calcium homeostasis of isolated cardiomyocytes and studied the activation of signalling molecules involved in this process. Treatment of cardiomyocytes with AGE for 24 h resulted in a dose-dependent reduction in calcium transient amplitude, reaching a maximum 50% reduction at a dose of 1 mg.mL-1. This was accompanied with a 32% reduction in sarcoplasmic reticulum calcium content but without any detectable changes in the expression of major calcium channels. Mechanistically, we observed a significant increase in the production of reactive oxygen species (ROS) in AGE-treated cardiomyocytes and enhancement of NADPH oxidase activity. This was accompanied with activation of p38 kinase and nuclear translocation of NF-kappaB, and subsequently induction of inducible NO synthase (iNOS) expression, leading to excessive nitric oxide production. Overall, our data reveal the molecular signalling that may underlie the alteration of intracellular calcium homeostasis in cardiac myocytes due to AGE stimulation. This may provide new insights into the pathophysiological mechanisms of the development of diabetic cardiomyopathy. PMID- 29123977 TI - Sodium hydrosulfide attenuates cerebral ischemia/reperfusion injury by suppressing overactivated autophagy in rats. AB - Ischemic stroke is a leading cause of death and disability worldwide, and autophagy may be involved in the pathological process of cerebral ischemia/reperfusion injury. Hydrogen sulfide (H2S) is an endogenous gasotransmitter with protective effects against multiple diseases. Here, we tested the effect of H2S on cerebral ischemia/reperfusion injury in rats. Sodium hydrosulfide (NaHS), an H2S donor, improved neurological function and reduced the size of the infarcts induced by transient middle cerebral artery occlusion (MCAO) followed by reperfusion in rats. NaHS treatment reduced the lactate dehydrogenase (LDH) activity in the serum (a marker of cellular membrane integrity) and the expression of cleaved caspase-3 (a marker for apoptosis) in the brains of MCAO rats. We also found that autophagy was overactivated in the brains of MCAO rats, as indicated by an increased ratio of LC3 II to I, decreased expression of p62, and transmission electron microscope detection. NaHS treatment significantly inhibited the autophagic activity in the brains of MCAO rats. Furthermore, PC12 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic MCAO in vitro. We found that NaHS treatment reduced cellular injury and suppressed overactivated autophagy induced by OGD/R in PC12 cells. An autophagy stimulator (rapamycin) eliminated the protective effect of NaHS against LDH release and caspase-3 activity induced by OGD/R in PC12 cells. An autophagy inhibitor (3-methyladenine, 3-MA) also reduced the cellular injury induced by OGD/R in PC12 cells. In conclusion, the results indicate that overactivated autophagy accelerates cellular injury after MCAO in rats and that exogenous H2S attenuates cerebral ischemia/reperfusion injury via suppressing overactivated autophagy in rats. PMID- 29123975 TI - Distribution of Lewis and Secretor polymorphisms and corresponding CA19-9 antigen expression in a Chinese population. AB - The Lewis (FUT3) and Secretor (FUT2) genes, corresponding to secretion of Lewis ABO (H) histo-blood group antigen CA19-9, are highly polymorphic with differences between populations. In this study, the FUT3 and FUT2 genes in 316 Chinese participants were sequenced to detect polymorphisms, and the associated CA19-9 antigen secretion was also measured. In total, 14 genotypes of FUT3 and 10 genotypes of FUT2 were verified. Le/Le, Le/le59,508 and Le/le59 were the main genotypes of FUT3 with frequencies of 53.2%, 10.7% and 3.5%, respectively. Se/Se, Se/se385 and se385/se385 were the main genotypes of FUT2, with frequencies of 21.4%, 18.6% and 16.2%, respectively. The alleles le1067 and le508 were found extensively in the Chinese population, and the frequency of allele se385 was shown to be higher than previously reported. Phenotype analysis revealed that 9.8% of individuals were the Lewis-negative type and 22.5% were the secretor negative type. Combined phenotypes showed that 3.2% of participants were of 'double-negative' phenotype (le, se) and 19.3% were of single dominant non secretor phenotype (Le, se). Serum Lewis antigen CA19-9 levels were significantly different between subgroups and consistent with the defined phenotype. Our study revealed the unique distribution of Lewis and Secretor polymorphisms in a large Chinese population, and decoded the combined genotypes of the two CA19-9-related genes. PMID- 29123978 TI - Deep sequencing and comprehensive expression analysis identifies several molecules potentially related to human poorly differentiated hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) that is graded histologically as poorly differentiated has a high recurrence, metastasis and poor prognosis. We sought to determine the regulatory mechanisms of HCC tumorigenesis and to identify molecules closely related to poorly differentiated HCC. High-throughput sequencing was used to construct microRNA (miRNA) and mRNA expression profiles for poorly differentiated HCC tissues and adjacent tissues. Network analysis was carried out to study miRNA-target interactions. Integrating the miRNA and mRNA data of HCC with four tumor grades from The Cancer Genome Atlas (TCGA) portal enabled the identification of potential closely related molecules for early diagnosis of poorly differentiated HCC. Electronic validation of RNA-seq data and survival analysis was also performed. In total, 1051 differentially expressed genes and 165 differentially expressed miRNAs were identified between HCC tumor and paired non-tumorous tissue. Based on 3718 miRNA-target interactions, we established an miRNA-target interaction network; the target genes were mainly involved in bile acid biosynthesis and bile secretion. Integrating expression data of HCC from TCGA indicated that two proteins, TM4SF1 and ANXA2, are convincing indicators for initial diagnosis of poorly differentiated HCC. According to the survival analysis, three proteins, ANXA2, C8orf33 and IGF2BP3, were identified as being associated with the survival time of HCC patients. Moreover, we suggest that hsa-miR-1180 may be an effective biomarker for poorly differentiated HCC. Three molecules, TM4SF1, ANXA2 and C8orf33, are potential biomarkers for distinguishing poorly differentiated from well-differentiated HCC. PMID- 29123979 TI - Inhibition of nonenzymatic depurination of nucleic acids by polycations. AB - DNA base depurination is one of the most common forms of DNA damage in vivo and in vitro, and the suppression of depurination is very important for versatile applications of DNA in biotechnology and medicine. In this work, it was shown that the polycations chitosan (Cho) and spermine (Spm) strongly inhibit DNA depurination through the formation of polyion complexes with DNA molecules. The intramolecular electrostatic interaction of positively charged polycations with DNA efficiently suppresses the protonation of purine groups, which is the key step of depurination. Importantly, the optimal pH for Cho's inhibition of depurination is significantly different from that of Spm. Cho is very effective in the inhibition of depurination in highly acidic media (pH: 1.5-3), whereas Spm is found to suppress the chemical reaction near neutral pH, as well as in acidic solutions. This remarkable pH specificity of the two biorelevant polycations is attributed to the difference in the pKa values of the amino groups. The relevance of our results with the biological roles of biogenic polycations is also discussed. PMID- 29123980 TI - Dynamic integration and excision of filamentous phage XacF1 in Xanthomonas citri pv. citri, the causative agent of citrus canker disease. AB - Inovirus XacF1 (7325 nucleotides) is integrated into the genome of Xanthomonas citri pv. citri (Xcc) strains at the host dif site (attB) by the host XerC/D recombination system. The XacF1 attP sequence is located within the coding region of ORF12, a possible phage regulator. After integration, this open reading frame (ORF) is split into two pieces on the host genome. We examined dynamic integration/excision of XacF1 in Xcc strain MAFF 301080 and found that the integration started at 4 h postinfection (p.i.) and peaked at 12 h p.i. Thereafter, the ratio of integrated to free forms remained constant, suggesting equilibrium of integration and excision of XacF1 in the host genome. However, the integrated state became very unstable following a 5'-deletion of ORF12 in XacF1, suggesting that ORF12 plays a key role in the integration cycle of XacF1 in Xcc strains. PMID- 29123981 TI - Coculture of endothelial progenitor cells and mesenchymal stem cells enhanced their proliferation and angiogenesis through PDGF and Notch signaling. AB - The beneficial effects of combined use of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) on tissue repair and regeneration after injury have been demonstrated, but the underlying mechanism remains incompletely understood. This study aimed to investigate the effects of direct contact coculture of human bone marrow-derived EPCs (hEPCs)/human bone marrow-derived MSCs (hMSCs) on their proliferation and angiogenic capacities and the underlying mechanism. hEPCs and hMSCs were cocultured in a 2D mixed monolayer or a 3D transwell membrane cell-to-cell coculture system. Cell proliferation was determined by Cell Counting Kit-8. Angiogenic capacity was evaluated by in vitro angiogenesis assay. Platelet-derived growth factor-BB (PDGF-BB), PDGF receptor neutralizing antibody (AB-PDGFR), and DAPT (a gamma-secretase inhibitor) were used to investigate PDGF and Notch signaling. Cell proliferation was significantly enhanced by hEPCs/hMSCs 3D-coculture and PDGF-BB treatment, but inhibited by AB-PDGFR. Expression of cyclin D1, PDGFR, Notch1, and Hes1 was markedly enhanced by PDGF-BB but inhibited by DAPT. In vitro angiogenesis assay showed that hEPCs/hMSCs coculture and PDGF-BB significantly enhanced angiogenic capacity, whereas AB-PDGFR significantly reduced the angiogenic capacity. PDGF-BB increased the expression of kinase insert domain receptor (KDR, an endothelial marker) and activated Notch1 signaling in cocultured cells, while DAPT attenuated the promoting effect of PDGF-BB on KDR expression of hEPCs/hMSCs coculture. hEPCs/hMSCs coculture enhanced their proliferation and angiogenic capacities. PDGF and Notch signaling pathways participated in the promoting effects of hEPCs/hMSCs coculture, and there was crosstalk between these two signaling pathways. Our findings should aid understanding of the mechanism of beneficial effects of hEPCs/hMSCs coculture. PMID- 29123982 TI - Decreased grip strength, muscle pain, and atrophy occur in rats following long term exposure to excessive repetitive motion. AB - Work-related musculoskeletal disorders (WMSD) are caused by the overuse of muscles in the workplace. Performing repetitive tasks is a primary risk factor for the development of WMSD. Many workers in highly repetitive jobs exhibit muscle pain and decline in handgrip strength, yet the mechanisms underlying these dysfunctions are poorly understood. In our study, rats performed voluntary repetitive reaching and grasping tasks (Task group), while Control group rats did not perform these activities. In the Task group, grip strength and forearm flexor withdrawal threshold declined significantly from week 2 to week 6, compared with these values at week 0 (P < 0.05). Relative muscle weight and muscle fiber cross sectional area of flexor digitorum superficialis (FDS) muscles decreased significantly in the Task group, compared with the Control group, at 6 weeks (P < 0.05 and P < 0.01, respectively). Nerve growth factor, glial cell line-derived neurotrophic factor, and tumor necrosis factor alpha-expression in FDS muscles were not significantly different in Control and Task groups at 3 and 6 weeks. At 6 weeks, the Task group had elevated MuRF1 protein levels (P = 0.065) and significant overexpression of the autophagy-related (Atg) proteins, Beclin1 and Atg5-Atg12, compared with in the Control group (both P < 0.05). These data suggested that long-term exposure to excessive repetitive motion causes loss of grip strength, muscle pain, and skeletal muscle atrophy. Furthermore, this exposure may enhance protein degradation through both the ubiquitin-proteasome and autophagy-lysosome systems, thereby decreasing skeletal muscle mass. PMID- 29123983 TI - Evaluation of Sox2 binding affinities for distinct DNA patterns using steered molecular dynamics simulation. AB - Transcription factors (TFs) are gene expression regulators that bind to DNA in a sequence-specific manner and determine the functional characteristics of the gene. It is worthwhile to study the unique characteristics of such specific TF binding pattern in DNA. Sox2 recognizes a 6- to 7-base pair consensus DNA sequence; the central four bases of the binding site are highly conserved, whereas the two to three flanking bases are variable. Here, we attempted to analyze the binding affinity and specificity of the Sox2 protein for distinct DNA sequence patterns via steered molecular dynamics, in which a pulling force is employed to dissociate Sox2 from Sox2-DNA during simulation to study the behavior of a complex under nonequilibrium conditions. The simulation results revealed that the first two stacking bases of the binding pattern have an exclusive impact on the binding affinity, with the corresponding mutant complexes showing greater binding and longer dissociation time than the experimental complexes do. In contrast, mutation of the conserved bases tends to reduce the affinity, and mutation of the complete conserved region disrupts the binding. It might pave the way to identify the most likely binding pattern recognized by Sox2 based on the affinity of each configuration. The alpha2-helix of Sox2 was found to be the key player in the Sox2-DNA association. The characterization of Sox2's binding patterns for the target genes in the genome helps in understanding of its regulatory functions. PMID- 29123984 TI - Transmembrane thioredoxin-related protein TMX1 is reversibly oxidized in response to protein accumulation in the endoplasmic reticulum. AB - Numerous secretory and membrane proteins undergo post-translational modifications in the endoplasmic reticulum (ER), and the formation of disulfide bonds is a modification that is critical for proper protein folding. The mammalian ER contains a large family of oxidoreductases that are considered to catalyze thiol/disulfide exchange and ensure the maintenance of a redox environment within the ER. Disruption of ER homeostasis causes an accumulation of misfolded and unfolded proteins, a condition termed ER stress. Despite advances in our understanding of the ER stress response and its downstream signaling pathway, it remains unclear how ER redox balance is controlled and restored in the stressed ER. In this study, we determined that brefeldin A (BFA)-induced protein accumulation in the ER triggers reversible oxidation of transmembrane thioredoxin related protein 1 (TMX1). Conversion of TMX1 to the oxidized state preceded the induction of immunoglobulin-binding protein, a downstream marker of ER stress. Oxidized TMX1 reverted to the basal reduced state after BFA removal, and our results suggest that glutathione is involved in maintaining TMX1 in the reduced form. These findings provide evidence for a redox imbalance caused by protein overload, and demonstrate the existence of a pathway that helps restore ER homeostasis during poststress recovery. PMID- 29123985 TI - Covalent bonding of heme to protein prevents heme capture by nontypeable Haemophilus influenzae. AB - Nontypeable Haemophilus influenzae (NTHi) are Gram-negative pathogens that contribute to a variety of diseases, including acute otitis media and chronic obstructive pulmonary disease. As NTHi have an absolute requirement for heme during aerobic growth, these bacteria have to scavenge heme from their human hosts. These heme sources can range from free heme to heme bound to proteins, such as hemoglobin. To test the impact of heme structural factors on heme acquisition by NTHi, we prepared a series of heme sources that systematically vary in heme exposure and covalent binding of heme to peptide/protein and tested the ability of NTHi to use these sources to support growth. Results from this study suggest that NTHi can utilize protein-associated heme only if it is noncovalently attached to the protein. PMID- 29123986 TI - Expression of a urokinase-type plasminogen activator during tumor growth leads to angiogenesis via galanin activation in tumor-bearing mice. AB - Small-cell lung carcinoma releases progalanin. The released progalanin is activated via a nonclassical processing pathway, being processed into an active form of galanin (1-20) by plasmin in extracellular components. Plasmin is produced from plasminogen activators. To clarify the regulation of progalanin via plasminogen activation by urokinase and tissue-plasminogen activator (t-PA), we investigated the regulation mechanism for urokinase and t-PA expression and their effect on galanin activation. Additionally, we studied the effect of activated galanin on angiogenesis. To determine the effect of cell density, we measured the expression levels of urokinase and t-PA using real-time PCR and plasminogen/gelatin zymography in a cell culture. The urokinase expression increased under both high cell density and presence of cell membrane fractions. However, urokinase increments induced by conditioned medium were low. These results indicate that expression of plasminogen activators is regulated by cell membrane factors. We used tumor-bearing mice to clarify the expression of plasminogen activators and galanin activation. Real-time PCR showed that urokinase was substantially higher in the central parts of tumors compared to the periphery, and this was confirmed by plasminogen/gelatin zymography. To evaluate the biological effect of plasminogen activators on tumor growth, we used tranexamic acid as a plasminogen inhibitor. Tranexamic acid decreased galanin (1 20) and the hemoglobin content of tumors and suppressed tumor growth. Additionally, galanin had no effect on the hemoglobin content of tumors derived from cells lacking GALR2. These results demonstrate the regulation of urokinase expression in tumors through progalanin activation in extracellular compartments, and confirm that galanin plays a role in angiogenesis. PMID- 29123987 TI - Jun dimerization protein 2 controls hypoxia-induced replicative senescence via both the p16Ink4a-pRb and Arf-p53 pathways. AB - The main regulators of replicative senescence in mice are p16Ink4a and Arf, inhibitors of cell cycle progression. Jun dimerization protein 2 (JDP2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence through recruitment of the Polycomb repressive complexes 1 and 2 to the promoter of the gene that encodes p16Ink4a and inhibits the methylation of lysine 27 of the histone H3 locus. However, whether or not JDP2 is able to regulate the chromatin signaling of either p16Ink4a-pRb or Arf-p53, or both, in response to oxidative stress remains elusive. Thus, this study sought to clarify this point. We demonstrated that the introduction of JDP2 leads to upregulation of p16Ink4a and Arf and decreases cell proliferation in the presence of environmental (20% O2), but not in low (3% O2) oxygen. JDP2-mediated growth suppression was inhibited by the downregulation of both p16Ink4a and Arf. Conversely, the forced expression of p16Ink4a or Arf inhibited cell growth even in the absence of JDP2. The downregulation of both the p53 and pRb pathways, but not each individually, was sufficient to block JDP2-dependent growth inhibition. These data suggest that JDP2 induces p16Ink4a and Arf by mediating signals from oxidative stress, resulting in cell cycle arrest via both the p16Ink4a-pRb and Arf-p53 pathways. PMID- 29123988 TI - Genetically encoding thioacetyl-lysine as a non-deacetylatable analog of lysine acetylation in Escherichia coli. AB - Reversible lysine acetylation is one of the most widely distributed post translational modifications; it is involved in a variety of biological processes and can be found in all three domains of life. Acetyltransferases and deacetylases work coordinately to control levels of protein acetylation. In this work, we applied the genetic code expansion strategy to site-specifically incorporate Nepsilon-thioacetyl-l-lysine (TAcK) as an analog of Nepsilon-acetyl-l lysine (AcK) into green fluorescent protein and malate dehydrogenase in Escherichia coli. We showed that TAcK could serve as an ideal functional mimic for AcK. It could also resist the bacterial sirtuin-type deacetylase CobB. Thus, genetic incorporation of TAcK as a non-deacetylatable analog of AcK into proteins will facilitate in vivo studies of protein acetylation. PMID- 29123990 TI - The skeletal-related events of denosumab versus zoledronic acid in patients with bone metastases: A meta-analysis of randomized controlled trials. AB - Objective: The meta-analysis was used to evaluate the skeletal-related events (SREs) and efficacy of denosumab versus zoledronic acid (ZA) in patients with bone metastases. Methods: The data of this meta-analysis study were searched from PUBMED, EMBASE, Cochrane Library, Web of Science with Conference Proceedings, Elsevier and China National Knowledge Infrastructure (CNKI) databases till August 2017. Two independent reviewers reviewed the reference lists of relevant articles. The fixed-effects model and random-effects model were used to summarize relative estimates and 95% confidence intervals (CIs) according to the heterogeneity of the included studies. Results: Three randomized controlled trials (RCTs) including 4050 patients were identified in this meta-analysis study. The pooled analysis showed that denosumab could significantly reduce SREs, series SREs [Odds Ratio (OR) = 0.84; 95% CI, 0.74-0.95, I2 = 0%, P = 0.008] in patients with bone metastases as compared with ZA. Similar results of spinal cord compression SRE and surgery to bone SRE were obtained with (OR = 0.84; 95% CI, 0.70-1.01, I2 = 0%, P = 0.07) and (OR = 0.92; 95% CI, 0.78-1.08, I2 = 0%, P = 0.28) separately, radiation to bone SRE (OR = 0.72; 95% CI, 0.46-1.10, I2 = 11%, P = 0.13) and pathological fracture SRE (OR = 0.78; 95% CI, 0.35-1.73, I2 = 25%, P = 0.54) showed similar results, there were no significant difference between denosumab and ZA in patients with bone metastases. Conclusion: Denosumab was more effective than ZA in reducing the incidence of SRE in patients with bone metastases. PMID- 29123989 TI - FRET analysis of HIV-1 Gag and GagPol interactions. AB - The Gag protein of HIV multimerizes to form viral particles. The GagPol protein encoding virus-specific enzymes, such as protease, reverse transcriptase, and integrase, is incorporated into HIV particles via interactions with Gag. The catalytically active forms of these enzymes are dimeric or tetrameric. We employed Forster resonance energy transfer (FRET) assays to evaluate Gag-Gag, Gag GagPol, and GagPol-GagPol interactions and investigated Gag and Pol interdomains tolerant to fluorescent protein insertion for FRET assays. Our data indicated that the matrix (MA)-capsid (CA) domain junction in the Gag region and the Gag C terminus were equally available for Gag-Gag and Gag-GagPol interaction assays. For GagPol dimerization assays, insertion at the MA-CA domain junction was most favorable. PMID- 29123992 TI - Prevalence of oral tori and exostosis in Malaysian population - A cross-sectional study. AB - Introduction: Oral tori and exostosis are non-pathological bony protuberances seen on the alveolar surfaces of the jaw bones. These are commonly seen on the palatal surfaces of the maxilla [torus palatinus (TP)] and around the premolars in the lingual surface of the mandible [torus mandibularis (TM)]. The aim of this cross-sectional study was to determine the prevalence of tori/exostosis in the Malaysian population. Methodology: A total of 2666 patients were examined for the presence of tori and exostosis in the maxilla and mandible and were categorized into TP, TM, and exostosis (facial/labial). Collected data was analysed for obtaining descriptive statistics. Results: 882 subjects were noticed with oral tori/exostosis among the population studied with a prevalence rate of 33%. TP was seen more in females (35%), compared to males (20%), and this difference was statistically significant (p value < 0.001). Highest prevalence of TP was seen in Malays (43%), followed by Chinese (31%) and Indians (21%), which was statistically significant (p value < 0.00). Discussion: High prevalence of tori and exostosis was seen in the population studied. Though harmless, in certain circumstances, their presence necessitates changes in the denture design during fabrication of prosthesis, which the dentist should be mindful. PMID- 29123991 TI - The use of Synthes MatrixWAVE bone anchored arch bars for closed treatment of multiple concurrent mandibular fractures. AB - Background: Maxillomandibular fixation (MMF) is an important tool in the treatment of facial fractures and bone-anchored arch bar systems have emerged as treatment options. This study illustrates our experience with the Synthes MatrixWAVE MMF system and the novel application in closed treatment of patients with multiple concurrent mandibular fractures. Methods: We enrolled eight patients with concurrent mandibular fractures and treated them with the MatrixWAVE MMF system. The malleable arch bars were fitted and then secured using 6-8 mm screws. The arch bar was and either stretched or compressed to ensure optimal positioning. 24-gauge interdental fixation wiring was placed using the fish loop technique on either side of the fracture to achieve stabilization of the mandible fractures. Results: All eight patients were retained in MMF until stable occlusion was achieved with clinical evidence of healing, approximately 4 6 weeks. Post-operative Panorex scans did not reveal any evidence of damage to tooth roots. None of the screws became overly embedded in the mucosa secondary to overgrowth; the arch bars were successfully removed in an outpatient setting without local anesthesia. Conclusions: The Synthes MatrixWAVE MMF system has unique features such as prominent screw anchor heads and horizontal malleability unique from other bone anchored arch bars. These features allow for completely closed treatment of patients with multiple concurrent mandible fractures. PMID- 29123993 TI - Prevalence of areca nut chewing habit among high school children of Parsa district of Nepal. AB - Aim: Consumption of areca nut products among school going children has become very common social evil in some areas of Nepal especially adjoining the Indian subcontinent. The aim of this study was to assess the prevalence of areca nut chewing habit among high school children in Terai belt of Nepal. The use of areca nut has become indigenous in this part and is being used by itself and in various formulations. The regular use of areca nut has been recognized as being carcinogenic to humans. Materials and methods: Data on areca nut chewing habit among high school children was collected from 1359 students of age group 14-18 years from 13 schools of Parsa district of Nepal by random selection and the information was obtained from self administered questionnaire. Results: The results from this study shows that the areca nut chewing habit is significant among the students of Parsa district (30.4%) and the frequency of chewing plain Supari was reported to be high (81.6%) followed by pan masala (10.4%) and gutkha (08.0%) and the habit increased with age. Conclusion: It is mandatory to motivate the children not to initiate the habit and to enable the adolescent children to realize the potential health risk of areca nut products. PMID- 29123994 TI - Pattern of invasion in squamous cell carcinomas of the lower lip and oral cavity. AB - Background: A number of factors may be responsible for the differences in the biologic behaviors of oral and lower lip squamous cell carcinomas (SCCs). Immunohistochemical invasion profiles have been used to detect invasion patterns like epithelial-mesenchymal-transition (EMT) and collective-cell-invasion (CCI), which have not been investigated in lower lip neoplasms. The aim of the present study was to compare the invasive phenotypes of SCCs of the lower lip and oral cavity. Method: A total of 44 OSCCs and 37 lower lip SCCs were immunostained with E-Cadherin, N-Cadherin, and podoplanin. Based on their expression patterns, tumors were allocated to EMT, CCI or non-EMT/non-CCI categories. Results: None of the oral SCCs showed EMT; while 5 lower lip SCCs demonstrated this phenotype. CCI was observed in 12 oral SCCs and 4 lower lip SCCs. The third group included 32 and 28 cases of oral and lower lip tumors, respectively. A significant difference in invasive phenotype was found between the two locations (P = 0.009). Conclusion: Oral cavity and lip tumors differ in various aspects and according to our results; the pattern of invasion may be added to these features. Between the two major invasion patterns, EMT was more prevalent in lip tumors while CCI was observed more commonly in oral neoplasms. The significance of the different expression patterns of the non-EMT/non-CCI category requires further investigation. PMID- 29123996 TI - Herbal combat against E. faecalis - An in vitro study. AB - Background: Herbs have renewed importance in this modern era for their antimicrobial properties and fewer side effects. So a novel idea to use these herbs for pulpectomy; was implemented. There are chances of failure of pulpectomy due to inefficient removal of microbial load. Thus, for a successful endodontic treatment, obturating material with optimum antimicrobial properties is advocated in the present study. Aim: To compare and evaluate the antibacterial efficacy of zinc oxide eugenol, zinc oxide with tulsi extract and zinc oxide with aloe vera as obturating materials against E. faecalis bacteria. Materials and methods: Antimicrobial efficacy of zinc oxide eugenol as control, zinc oxide with tulsi extract and zinc oxide with aloe vera as experimental groups were assessed by using agar diffusion method. The statistical analysis was done. Results: Intergroup comparison revealed significant difference amongst all the groups except between zinc oxide eugenol and zinc oxide with tulsi extract. Zinc oxide eugenol had significantly higher zone of inhibition among all the groups. Conclusion: According to results obtained from the present study can be summarized as follows: Zinc oxide eugenol > Zinc oxide with tulsi extract > Zinc oxide with aloe vera. PMID- 29123995 TI - Nodal involvement in Oral Squamous Cell Carcinoma (SCC) patients with and without Oral Sub Mucous Fibrosis (OSMF): A Comparative Study. AB - Aim: The aim of the study is to compare and evaluate neck node status of oral cancer patients with and without Oral Sub Mucous Fibrosis (OSMF) treated surgically. Methodology: A total of 50 patients of Indian origin who were diagnosed with Squamous Cell Carcinoma (SCC) of oral cavity and had not taken any prior treatment were included in the study. Clinical examination and metastatic workup was done for all patients. Patients diagnosed with resectable primary and without distant metastasis were taken up for surgery. For all patients, resected specimens were sent for radical histopathological examination. Result: The differences in nodal involvement in T1, T2 & T3 sized lesions were non significant, while in T4 sized lesions, a statistically significant lower incidence of nodal involvement in patients with-OSMF as compared to patients without OSMF was observed. Conclusion: Presence of N0 neck in T4 lesions in oral SCC patients with OSMF has potential implications on the present pattern of spread and treatment protocols, leading to need for further research with OSMF as independent risk factor for nodal involvement. PMID- 29123997 TI - Noise levels and sound pollution associated with various operative procedures and equipments in a pediatric dental environment-A clinical study. AB - Aim: To analyse sound levels and sound pollution in a Pediatric Dental Clinic and to analyse whether the levels are significant to the extent of being a health hazard. Methods: Noise levels were measured in a Pediatric dental clinic in an institutional setting with a precision noise level meter ((HTC 1350). Recordings were taken at different times of the day, at the centre, chair-side, reception, play area and four corners of the department keeping the microphone at a distance of 6 in. from the operator's ear. The noise levels of various equipments i.e. suction, micromotor, airotor were measured with the equipments turned on and during cutting operations with the microphone placed at a distance of 6 in. from the sound source. The sound levels for the laboratory equipments were taken at a distance of 6 in. and 2 m. Results: The highest mean sound levels were recorded at the reception, play area and chair-side area with least mean sound levels recorded at 9:00am which increased at 11:30am & 2:00pm and reduced again at 3:30pm The maximum sounds were produced by the lathe trimmer, airotor and scaler. Conclusion: Noise levels in a pediatric clinic approach the level of risk of hearing loss [85 db(A)]. This would have a serious effect on both providers and patients and a concerted effort would be required to control the noise levels and thus avoid the potential health hazards that it poses. PMID- 29123998 TI - Feasibility of Dentascan in planning of implant surgery in posterior maxilla and mandible. AB - Objectives: The present evaluate the feasibility of Computed tomography (Dentascan), in assessment of the implant site in posterior maxilla & mandible. Material and Methods: data of total 11 patients with 20 implant sites were involved in the present study. Out of the 20 implant sites selected 10 were in posterior maxilla and 10 in posterior mandible. All the patients were routinely examined by panoramic radiography and CT. All images obtained i.e., conventional panoramic radiograph, and film based Dentascan MPR- CT images were evaluated for the detectability of mandibular canal at the mental foramen, 1 cm, 2 cm, and 3 cm posterior to mental foramen. The judgments were then compared by using the four point grading score. Results: Both the statistical analysis and radiographic observation showed that Dentascan MPR CT gives significantly clearer images at the mental foramen and 1 cm, 2 cm , 3 cm posterior to it. Dentascan also provides significantly better visualization of the vital structures along with the bone density. The panoramic and Dentascan MPR CT images did not show a significant difference in visualization of the crest of alveolar ridge in both maxillary as well as the mandibular arch. Conclusion: The Dentascan MPR- CT images revealed significantly clearer images as well as better visualization of the vital structures than conventional panoramic radiography. Apart from providing clearer images Dentascan also gives the buccopalatal/buccolingual dimension at the implant site, along with the density of the available bone. PMID- 29123999 TI - Inflammation related genes are upregulated in surgical margins of advanced stage oral squamous cell carcinoma. AB - Aims: Advanced stage of oral squamous cell carcinoma (OSCC) exhibits different properties compared with the early stage for example an invasion ability. The present study investigated a differential gene expression of surgical margin between advanced and early stage of OSCC. Methods: Gene Expression Omnibus dataset (GSE31056) was downloaded and re-analyzed. Surgical margin samples were categorized into 2 groups; early stage and late stage. Differential gene expression analysis was performed. Dysregulated genes were further analyzed for gene ontology, enriched pathway, and disease association using a network-based analysis tools. Results: Eighty-five dysregulated genes were identified in margin of late stage OSCC. Metabolic process and biological regulation were the main gene ontology of dysregulated genes. Genes involved in Jak-STAT signaling pathway were upregulated in late stage of surgical margin samples. In addition, seven upregulated genes in late stage group, namely CEBPB, S1PR1, IL6, CEBPD, CHI3L1, PTX3, and SOCS3, were categorized in acute phase reaction and inflammation categories of disease association analysis. Conclusion: The differential expressed genes in surgical margin of late stage OSCC could be further employed to understand cancer's behavior and to identify target pathway to prevent OSCC invasion. PMID- 29124000 TI - Human papillomavirus associated head and neck squamous cell carcinoma: Controversies and new concepts. AB - High-risk human papillomavirus (HR-HPV) is a causative agent for an increasing subset of oropharyngeal squamous cell carcinoma. HPV 16 accounts for 90% of cases. The chance for malignant transformation due to infection with high-risk HPV is proportional to the expression of the viral oncogene products E6 and E7, which inactivate p53 and retinoblastoma (Rb) tumor suppressor functions. P16 is a surrogate marker of HPV associated HNSCC and 2+/3+ expression in more than 75% cells is diagnostic. Molecular demonstration of integrated virus by in situ hybridization is specific but has low sensitivity. HPV associated oropharyngeal carcinomas classically arise in the tonsillar crypts and commonly have basaloid morphology with a prominent lymphocytic repsonse and minimal despmoplastic reaction. In situ vs invasive carcinomas may be difficult to distinguish in histology. The HPV postitivity overrides traditional prognostic indicators such as tumour grade and histological subtype. Small cell morphology carries a poorer prognosis as does marked tumour anaplasia and multinucleation. Lymph node metastasis is extensive and frequently cystic however extranodal extension, laterality or nodal sizes do not carry prognostic implications as in conventional OSCC and OPSCC. Stage IV is reserved for distant metastasis. HPV-16-positive patients had significantly reduced overall and disease-specific mortality rates and an improved 3-year overall survival (OS) and disease-free survival (DFS) compared to patients with HPV negative tumors. Surgical treatment is the main option for primary and secondary HNSCC. Targeted therapies including drugs targeting EGFR and PIK3CA and have shown some promising results. HPV pathway expressing tumors are less aggressive and may receive adequate curative intent therapy from a reduced radiation or chemotherapy dose revision. OSCC however fails to show a distinct difference between HPV associated and tobaccco associated cancer and prognostic differences do not clearly exist. PMID- 29124001 TI - Ameloblastoma: A retrospective analysis of 31 cases. AB - Aims and objective: To evaluate the surgical treatment given and do a regular follow up to study the recurrence rate and complications of ameloblastoma in our institution. Materials and methods: A total of 31 cases of various subtypes of ameloblastoma, treated with different modalities, in the Department of OMFS, were recalled for a follow up & radiographs were taken along with the clinical examination for any recurrence or complications such as fracture/exposure of the reconstruction plate, loosening of the screw, infection of the graft, any draining sinus/signs of infection. Results: Two of our patients had fractured reconstruction plate, one patient developed infection, one patient complained of screw exposure and two other patients had infection of the iliac graft. Conclusion: We conclude that an adequate resection with a safe margin could be a treatment option and can be undertaken depending on the extent, location of the lesion and histopathologic variant. PMID- 29124002 TI - Three dimensional reconstruction of late post traumatic orbital wall defects by customized implants using CAD-CAM, 3D stereolithographic models: A case report. AB - Aim: Purpose of this case report is to highlight the precision and accuracy obtained with patient specific implants for orbital reconstruction designed on the basis of volumetric analysis of orbital computed tomographic scan (CT) scans using virtual planning, computerised designing and manufacturing and stereolithographic models to correct late post-traumatic orbital deformities such as enophthalmos and diplopia. Material and methods: This case report describes a patient who visited our outpatient clinic for correction of enophthalmos and persistent diplopia in upward gaze, seven months post trauma. Three dimensional (3D) virtual treatment planning was carried out by using the 3D CT data. The unaffected orbit of the contralateral side was superimposed on the deformed orbit to highlight the defect and a customized implant was designed in the desired size and shape on the virtual model using computer aided designing and manufacturing (CAD-CAM) and milled in titanium mesh for precise anatomic orbital reconstruction. Results: There was a marked improvement in both the diplopia in upward gaze and enophthalmos post surgery when the customized patient specific orbital implant was used. Conclusion: The concept of using customized implant with the help of 3D virtual treatment planning, 3D stereolithographic models and CAD-CAM greatly improves the correction of extremely difficult late post traumatic orbital deformities. PMID- 29124003 TI - Inflammatory myofibroblastic tumour: A case report and a clinical update. AB - The Inflammatory myofibroblastic tumor (IMT) is a heterogeneous group of rare lesions consisting predominantly of inflammatory cells and myofibroblastic spindle cells. Head and neck IMTs account for 14 to 18% of extra-pulmonary IMTs [lungs being the most commonly affected regions]. On account of its ambiguous clinical presentation, an IMT needs to be differentiated from other infectious, granulomatous, autoimmune and neoplastic lesions on the basis of histopathologic findings and immunohistochemical analysis. In this article, we report a case of IMT that presented in the anterior mandible that was treated by peripheral resection. Follow-up at 1 year showed satisfactory healing and no signs of recurrence. A special emphasis has been placed on the disputed nosology of this lesion and the latest therapeutic modalities. PMID- 29124004 TI - Papillary cystadenocarcinoma of the sublingual gland. AB - A 68-year-old Caucasian gentleman presented with a 6-month history of a left sided Level I/II neck swelling involving the floor of mouth. MRI revealed a large cystic lesion and histology confirmed a diagnosis of primary papillary cystadenocarcinoma of the sublingual gland. Papillary cystadenocarcinoma was first described in 1991 by the World Health Organisation [WHO], and is a rare malignant neoplasm characterised by cysts and papillary endo-cystic projections. Papillary cystadenocarcinoma arising from the sublingual glands is extremely rare and has the potential to metastasise to cervical lymph nodes. This patient we report was therefore treated with surgical excision and post-operative radiotherapy. PMID- 29124005 TI - Massive hemoptysis from Rasmussen's aneurysm in active pulmonary tuberculosis; A case report of successful treatment with bronchial artery embolization. AB - Rasmussen's aneurysm, a very rare complication of active pulmonary tuberculosis (TB), is a pulmonary artery aneurysm adjacent to or within a tuberculous cavity. It may lead to rupture and life threatening massive hemoptysis, an uncommon but challenging medico-surgical emergency. This complication warrants attention in view of the resurgence of tuberculosis and increasing occurrence of multi-drug resistant TB, especially in resource-poor, high-TB burden countries like India. We present a case of an elderly man who presented to the emergency room with low grade fever, cough and hemoptysis. Thoracic Multidetector row Computed Tomographic Angiography (MDCTA) showed left upper lobe consolidation with thick walled cavitary lesions and aneurysm along the apical segmental branch of left upper lobar pulmonary artery. Hemoptysis was successfully controlled with systemic artery embolization using polyvinyl alcohol (PVA) particles. He was treated with antitubercular chemotherapy and was followed for more than a year without further recurrence of hemoptysis. PMID- 29124006 TI - Selective pulmonary artery occlusion to treat hemoptysis associated with pulmonary venous obstruction. AB - Hemoptysis may occur in patients with pulmonary venous obstruction and prominent decompressing vessels in the airways adjacent to the affected pulmonary veins. The options for treatment of hemoptysis are limited, particularly when efforts to alleviate pulmonary venous obstruction have failed. Here we describe a patient with hemoptysis associated with stenosis of the central left upper pulmonary vein and occlusion of the central left lower pulmonary vein. The left upper pulmonary vein was dilated with balloon catheters and a vascular plug was placed in the left lower pulmonary artery. Vascular engorgement regressed in the left bronchus and hemoptysis has not recurred for 4 years despite recurrence of left upper pulmonary vein stenosis. Selective occlusion of branch pulmonary arteries may be an effective option for the treatment of hemoptysis from bleeding in lung segments with inoperable pulmonary venous obstruction. PMID- 29124007 TI - Immunotherapy "Shock" with vitiligo due to nivolumab administration as third line therapy in lung adenocarcinoma. AB - Non-small cell lung cancer is still diagnosed at late stage due to the lack of early symptoms and methods of diagnostic prevention. In the past ten years several targeted therapies have been introduced or explored. Tyrosine kinase inhibitors and immunotherapy are currently considered the most effective and safe therapies in comparison to the non-specific cytotoxic agents. Regarding tyrosine kinase inhibitors the adverse effects have been fully explored, however; on the other hand for immunotherapy there are still several issues to be clarified. We report a rare case of a patient with lung cancer adenocarcinoma who developed vitiligo throughout his body after nivolumab administration. PMID- 29124008 TI - Rare complicated parapneumonic effusion, Mycoplasma pneumoniae with new-onset lupus flare: Case report and literature review. AB - Mycoplasma pneumoniae has been associated with respiratory tract infections. Mycoplasma pneumoniae pneumonia-related pleural effusion is rarely reported. Extra-pulmonary abnormalities such as encephalitis, myocarditis, glomerulonephritis, and myringitis have been reported. However pulmonary manifestations in systemic lupus erythematosus include pneumonitis, pleurisy, interstitial lung disease, and thromboembolic disease. We present the case of a 26-year-old male who came for evaluation of fever, cough, and shortness of breath with right-sided chest pain. He was found to have right-side loculated complicated parapneumonic effusion and underwent drainage with a pleural catheter followed by fibrinolytic therapy. He was then found to have new-onset systemic lupus erythematosus concomitant with Mycoplasma pneumonia, leading to lupus flare and lupus nephritis. He responded well to levofloxacin, steroids, hydroxychloroquine, and mycophenolate, with complete resolution of loculated pleural effusion and symptom improvement. Our case describes the rare combination of Mycoplasma pneumoniae pneumonia, parapneumonic pleural effusion, and lupus flare with lupus nephritis. Early identification and treatment can lead to better out come in young patients. PMID- 29124009 TI - Small RNAome sequencing delineates the small RNA landscape of pluripotent adult stem cells in the planarian Schmidtea mediterranea. AB - Small noncoding RNAs play a pivotal role in the regulation of gene expression, and are key regulators of animal development. Freshwater planarian exhibits an extraordinary ability to regenerate any missing body parts, representing an emerging model for studying mechanism underlying stem cell regulation and tissue regeneration. Here, we utilized next-generation sequencing (NGS) to identify small RNAs that are expressed in planarian adult stem cells, and are implicated in tissue regeneration. We profiled microRNAs (miRNAs), piwi-interacting RNA (piRNAs), small rDNA-derived RNAs (srRNAs) and endogenous interfering RNAs (endo siRNAs) population from size 18-30 nt, measured the expression of 244 conserved miRNAs, and identified 41 novel miRNAs and 64 novel endo-siRNAs. Expression profiling analyses revealed that most piRNAs and srRNAs are up-regulated during regeneration, and that the most abundantly expressed srRNAs are from 5.8s and 28s rRNA. Furthermore, a target prediction method was adopted to investigate the anti correlation of small RNAs and mRNA expression. We built up a gene regulatory network based on the genes that are targeted by dynamically changed small RNAs. These results expand the known small RNA repertoire in planarian, and provide valuable insights and a rich resource for understanding the small RNAs landscape in stem cell-mediated regeneration. PMID- 29124010 TI - Positive fecal occult blood test as a diagnostic cue for Schistosoma mansoni infection in a developed country. AB - The rise in eco-tourism and travel off the beaten track have increased numbers of tourists with schistosomiasis which is seldom seen in developed countries, although this disease is considered a neglected tropical disease especially in poor communities. A Guinean male living in Japan was seen complaining of severe constipation. He was positive for fecal occult blood (FOB) and underwent colonoscopy. Colonoscopy showed petechiae of the rectal mucosa, with pathologic examination of biopsy tissue showing calcified eggs of the genus Schistosoma. Direct examination of eggs in feces and antibody tests of serum confirmed the diagnosis of schistosomiasis. The patient was administered Praziquantel (400 mg/day for 2 days) and FOB and fecal ova tests were negative after treatment. FOB tests have been reported as a useful assessment of morbidities associated with intestinal schistosomiasis. In developed countries, positive FOB result, which is used as a main examination for bowel malignant disease, are not recognized as being due to schistosomiasis. As this tropical disease is rarely present in developed countries, it may be under-diagnosed. Schistosomiasis should be included in the differential diagnosis of patients with positive FOB tests. PMID- 29124011 TI - Varicella-zoster virus myeloencephalitis. PMID- 29124012 TI - Necrotizing soft tissue infection of the thigh associated with retroperitoneal abscess in a patient with locally advanced ascending colon cancer: A case report. AB - Necrotizing soft tissue infection (NSTI) is a rare but rapidly progressing soft tissue infection. Few reports of NSTI caused by colon cancer have been published. We present a rare case of NSTI of the thigh associated the retroperitoneal spread of ascending colon cancer. A 64-year-old man had noticed right hip pain since 3 months before admission, he felt pain in the right thigh which was reddening, and he had difficulty in walking. He was referred to Yokosuka general hospital Uwamachi. Anterolateral aspect of his right thigh was reddening and swelling. The patient was diagnosed with a psoas abscess and a NSTI of the right thigh caused by penetration of ascending colon tumor. The patient underwent debridement of severely necrotized tissue in the right thigh, diverting ileostomy and subsequently a right hemicolectomy with reversal of the ileostomy were performed. He was discharged 70 days after the first surgery. Colon cancer can be a cause of retroperitoneal abscess accompanied by NSTI of the thigh. Two-stage surgery was an efficient option in this patient with NSTI of the thigh associated with locally advanced ascending colon cancer. PMID- 29124013 TI - Fibroblast growth-factor-21 is currently a weak biomarker for identifying mitochondrial and non-mitochondrial inborn errors of metabolism. PMID- 29124014 TI - A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. AB - Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, which results in the accumulation of glycogen in lysosomes in multiple tissues, including cardiac, skeletal, and smooth muscle cells. Thus far, 558 sequence variants of the GAA gene have been published in the Pompe Disease Mutation Database, and some mutations appear with considerable frequency in particular ethnic groups, such as Caucasians, Taiwanese, Chinese, and Koreans. However, the GAA mutation pattern in Japanese patients remains poorly understood. We analyzed the relationship between the genetic and clinical features of 38 mostly Japanese patients with Pompe disease from 35 unrelated families. We identified 28 different GAA gene mutations, including 7 novel mutations, by a GAA gene analysis. c.546G > T (22.9%) and c.1857C > G (14.3%) were the most common mutations and accounted for 37.1% of the total mutant alleles. In the six patients with infantile-onset Pompe disease (IOPD), c.1857C > G was also the most common mutation. In addition, there were 13 homozygotes (5 with the c.546G > T) among the 35 families, which is the highest frequency reported thus far. Regarding the initial symptoms, cardiomegaly was the most common (3/6 = 50%) in IOPD patients, while muscle weakness was observed the most frequently in patients with late-onset Pompe disease (LOPD) (15/30 = 50%). Notably, all IOPD patients who showed respiratory distress at the time of onset require respiratory assistance at present (4/4 = 100%). Regarding the presenting symptoms, cardiomegaly (6/6 = 100%) and hepatomegaly (4/6 = 66.7%) were more commonly seen in IOPD, and muscle weakness (24/29 = 82.7%) was observed more frequently in LOPD. Respiratory assistance is required at present in 33.3% of IOPD patients and 50% of LOPD patients, and 20% of IOPD patients and 29.6% of LOPD patients are wheelchair users. These individual clinical courses may be influenced by the timing of the diagnosis and treatment; for example, in 2007, an ERT orphan drug for treatment of Pompe disease, Alglucosidase alfa, was made available in Japan, and there were 5 (5/6 = 83.3%) wheelchair users diagnosed from 2008 to 2009 (cases 32-38) and 4 (4/27 = 14.8%) from 2010 to 2015 (cases 1-31). These findings underscore the importance of the early diagnosis and treatment. PMID- 29124015 TI - The influence of parental food preference and neophobia on children with phenylketonuria (PKU). AB - Background: In a previous case-control study, we demonstrated that children with PKU and non-PKU controls preferred sweet foods. Additionally, children with PKU exhibited food neophobia, with no preference for bitter tasting foods associated with the taste of phenylalanine (Phe)-free L-amino acid supplements. Objective: In an observational extension study, we evaluated the influence of parental food choice and neophobia on their children's taste preferences and food neophobia. Methods: Male and female parents/caregivers of 35 children with PKU and 35 control parents, completed a neophobia and food frequency questionnaire for comparison using the same questionnaires that they completed for their children. Results: Both groups of children (PKU and non PKU control) were rated as more food neophobic and exhibited more neophobic behaviour than parents, although children with PKU more so than non-PKU controls (PKU food neophobia p < 0.0001vs control 0.001; PKU general neophobia p = 0.003 vs control p = 0.04). Both groups of children ate significantly more sweets, sweetened drinks and potato fries than their parents but differences were greater for children with PKU who also consumed more high carbohydrate (low protein) staple foods such as bread and pasta, and more sweet snacks such as biscuits than their parents. Non-PKU control children's food choices were closer to their parent's choices. Conclusions: In PKU, parental food choices and their food neophobia have limited influence on their children's eating habits. Food neophobia in children with PKU may be associated with fear of eating unfamiliar foods potentially containing a source of protein or aspartame. Their preference for sweet foods may be influenced by limited food choices and habitual consumption of artificially sweetened L-amino acid supplements. PMID- 29124016 TI - Chemically synthesized biofuels from agricultural waste: Optimization operating parameters with surface response methodology (CCD). AB - Bioethanol is one of the most important alternative renewable energy sources that substitute the fossil fuels. Sugarcane bagasse has a content of cellulose and hemicelluloses, which make it suitable as fermentation substrate when hydrolyzed. The objective of work is ethanol production from sugarcane bagasse (SCB) by the fermentation process. Eight laboratory experiments were conducted to produce bioethanol from sugarcane bagasse. By using Design Expert, it was formulated the dilute acid hydrolysis step to investigate the effects of hydrolysis parameters on a yield of ethanol and optimum condition. All the three hydrolysis parameters were significant variables for the yield of ethanol. The optimum combinations of the three factors maximum ethanol yield were 10.86 ml at 50 g sample, 92.59 degrees C hydrolysis temperature, 30 min hydrolysis time and 1%v/v acid concentration. From this study following point were concluded: *Lignocellulosic containing material are sustainable for clean energy production*Production of bioethanol from waste sugarcane baggage's is possible*Operating parameters (time, temperature and acid concentration) can be optimized by surface response methodology.*Process parameters hydrolysis, fermentation and distillation have significant role on bioethanol yield. PMID- 29124018 TI - Improved high-throughput quantification of luminescent microplate assays using a common Western-blot imaging system. AB - Common Western-blot imaging systems have previously been adapted to measure signals from luminescent microplate assays. This can be a cost saving measure as Western-blot imaging systems are common laboratory equipment and could substitute a dedicated luminometer if one is not otherwise available. One previously unrecognized limitation is that the signals captured by the cameras in these systems are not equal for all wells. Signals are dependent on the angle of incidence to the camera, and thus the location of the well on the microplate. Here we show that: *The position of a well on a microplate significantly affects the signal captured by a common Western-blot imaging system from a luminescent assay.*The effect of well position can easily be corrected for.*This method can be applied to commercially available luminescent assays, allowing for high throughput quantification of a wide range of biological processes and biochemical reactions. PMID- 29124019 TI - A protocol for gene expression analysis of chondrocytes from bovine osteochondral plugs used for biotribological applications. AB - RNA isolation from human or animal cartilage tissue is necessary when performing mechanical or biotribological applications. Despite no influence on the cells and no alterations in gene expression patterns, enzymatic digestion of tissues should be avoided as it's known that the expression of collagen 2 can be effected (Hayman et al., 2006 [1]). After mechanical or biotribological tests alternative options with an immediate disruption of the tissue should be contemplated. To obtain RNA, different tissue homogenization and disruption methods are available on the market (Yu et al., 2004 [2]), but not everyone is suitable for cartilage. Some of them neither homogenize the cartilage, while others are producing a lot of foam during disruption process. After trying some of the currently available methods, we chose the MagNA Lyser Instrument from Roche to disrupt the cartilage and further isolate RNA by using the Fibrous Tissue Kit from Qiagen. After RNA isolation, cDNA synthesis was performed by additionally adding RNA from bacteriophage MS2 for stabilization purposes. For the RTqPCR bovine primers were designed and tested for efficiency to confirm that the whole gene expression analysis is working. Our protocol explains a whole method to perform gene expression analysis from bovine cartilage, but can also be used for human or any other animal tissue. PMID- 29124017 TI - Optimization of an in vitro assay methodology for competitive binding of thyroidogenic xenobiotics with thyroxine on human transthyretin and albumin. AB - Thyroid hormones (THs) are involved in the regulation of many physiological processes in vertebrates. Competition for TH binding sites on serum transport proteins can interfere with delivery of THs to target tissues, and this is a potential mechanism of action of exogenous thyroidogenic substances. To date, detailed accounts of in vitro methods for competitive binding with THs on TH transport proteins (human or wildlife) are sparse. In the limited number of published studies on in vitro radio-labelled TH-TH transport protein interactions, method descriptions were brief and with insufficient details for successful replication. Furthermore, upon review of these methodologies, we identified several opportunities for optimization. The present study addresses the methodological deficiencies and describes, in detail, a fully optimized and validated competitive T4 radio-ligand binding assay with human transthyretin (TTR) and albumin (ALB). *Significant improvements were made over previous methods, including better maintenance of protein stability and enhanced measurement of competition between different ligands.*Sample size was reduced to allow use of small pre-packed size exclusion chromatography columns, which eliminates the rinsing step during the separation procedure.*The assay was parameterized for use with T4 and human TTR and ALB. PMID- 29124020 TI - Mutual effects of stratification and mixed convection on Williamson fluid flow under stagnation region towards an inclined cylindrical surface. AB - We have found that few attempts are reported on Williamson fluid flow yields by an inclined cylindrical surface. To be more specific, Williamson fluid flow regime characteristics under stagnation point region especially when it is manifested with mutual interaction of double stratification and mixed convection effects are not proposed as yet. Therefore, we have considered stagnation point mixed convection Williamson fluid flow brought by an inclined cylinder in the presence of temperature and concentration stratification phenomena. Further, the fluid flow is entertained through no slip condition i-e the velocity of particles is directly related to velocity of cylindrical surface due to stretching. The physical situation within the real concerned constraints is translated in terms of differential equations as a boundary value problem. To make implementation of computational algorithm possible, following steps are taken into account *The PDE's are transformed into ODE's by using suitable transformation.*The resulting boundary value problem is converted into an initial value problem.*These constructed ordinary differential equations are solved computationally by shooting technique charted with Runge-Kutta scheme.*The effect logs of an involved physical flow parameters are explored by way of graphical outcomes and tabular values. PMID- 29124021 TI - Allele specific LAMP- gold nanoparticle for characterization of single nucleotide polymorphisms. AB - Due to their relevance as disease biomarkers and for diagnostics, screening of single nucleotide polymorphism (SNPs) requires simple and straightforward strategies capable to provide results in medium throughput settings. Suitable approaches relying on isothermal amplification techniques have been evolving to substitute the cumbersome and highly specialized PCR amplification detection schemes. Nonetheless, identification of an individual's genotype still requires sophisticated equipment and laborious methods. Here, we present a low-cost and reliable approach based on the allele specific loop-mediated isothermal amplification (AS-LAMP) coupled to ssDNA functionalized gold nanoparticle (Au nanoprobe) colorimetric sequence discrimination. The Au-nanoprobe integration allows for the colorimetric detection of AS-LAMP amplification product that can be easily interpreted in less than 15 min. We targeted a clinical relevant SNP responsible for lactose intolerance (-13910C/T dbSNP rs#: 4988235) to demonstrate its proof of concept and full potential of this novel approach. PMID- 29124022 TI - Outcomes of Extracorporeal Membrane Oxygenation in Children: An 11-Year Single Center Experience in Korea. AB - Background: Extracorporeal membrane oxygenation (ECMO) has become an important treatment modality in pediatric patients with cardiopulmonary failure, but few studies have been conducted in Korea. Methods: We conducted a retrospective review of pediatric patients younger than 18 years who were placed on ECMO between January 2004 and December 2014 at Samsung Medical Center. Results: We identified 116 children on ECMO support. The overall rate of successful weaning was 51.7%, and the survival to discharge rate was 37.1%. There were 39, 61, and 16 patients on ECMO for respiratory, cardiac, and extracorporeal cardiopulmonary resuscitation, respectively. The weaning rate in each group was 48.7%, 55.7%, and 43.8%, respectively. The survival rate was 43.6%, 36.1%, and 25.0%, respectively. Sixteen patients on ECMO had functional single ventricle physiology; in this group, the weaning rate was 43.8% and the survival rate was 31.3%. Ten patients were on ECMO as a bridge to transplantation (8 for heart and 2 for lung). In patients with heart transplantation, the rate of survival to transplantation was 50.0%, and the overall rate of survival to discharge was 37.5%. Conclusion: An increasing trend in pediatric ECMO utilization was observed. The outcomes were favorable considering the early experiences that were included in this study and the limited supply of specialized equipment for pediatric patients. PMID- 29124023 TI - Resection for Pancreatic Cancer Lung Metastases. AB - Background: Pancreatic cancer is a highly aggressive solid tumor. Patients with metastases from pancreatic cancer have poor survival rates. Here, we report the outcomes of 6 patients for whom resection of lung metastases was performed after a pancreatectomy to treat pancreatic cancer. Methods: We retrospectively reviewed the perioperative clinical data of patients with lung metastases resulting from primary pancreatic cancer who were treated with lung resection between 2008 and 2015. We report 6 cases where lung resection was performed to treat lung metastases after a pancreatectomy. Results: The number of lung metastases was 1 in 5 cases and 2 in 1 case. The surgical procedures performed to treat the lung metastases included 4 wedge resections and 2 lobectomies. The cell type of the primary tumor and metastases was tubular adenocarcinoma in 5 cases and intraductal papillary-mucinous carcinoma in 1 case. All 6 patients survived with a mean follow-up period of 65.6 months, although the disease recurred in 2 patients. Conclusion: Resection of lung metastases resulting from primary pancreatic cancer may lengthen survival, provided the patient can tolerate surgery. PMID- 29124024 TI - Patterns and Prognostic Significance of Cervical Lymph Node Metastasis and the Efficacy of Cervical Node Dissection in Esophageal Cancer. AB - Background: The clinical value of 3-field lymph node dissection (3FLND) in esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to identify the patterns and prognostic significance of cervical lymph node metastasis (CLNM) in ESCC. Methods: A retrospective review of 77 patients with ESCC who underwent esophagectomy and 3FLND between 2002 and 2016 was conducted. For each cervical node level, the efficacy index (EI), overall survival, recurrence rate, and complication rate were compared. Results: CLNM was identified in 34 patients (44.2%) who underwent 3FLND. Patients with CLNM had a significantly lower overall survival rate (22.7% vs. 58.2%) and a higher recurrence rate (45.9% vs. 16.3%) than patients without CLNM. CLNM was an independent predictor of recurrence in ESCC patients. Moreover, in patients with pathologic N3 tumors, the odds ratio of CLNM was 10.8 (95% confidence interval, 2.0 to 57.5; p= 0.005). Level IV dissection had the highest EI, and level IV metastasis was significantly correlated with overall survival (p=0.012) and recurrence (p=0.001). Conclusion: CLNM was a significant prognostic factor for ESCC patients and was more common among patients with advanced nodal stages. Level IV exhibited the highest risk of metastasis, and dissection at level IV may be crucial when performing 3FLND, especially in advanced nodal stage disease. PMID- 29124025 TI - Efficacy of Single-Port Video-Assisted Thoracoscopic Surgery Lobectomy Compared with Triple-Port VATS by Propensity Score Matching. AB - Background: In recent years, single-port video-assisted thoracoscopic surgery (VATS) for lobectomy in non-small cell lung cancer (NSCLC) patients has become increasingly common. The objective of this study was to compare the feasibility and safety of single-port and triple-port VATS lobectomy. Methods: A total of 73 patients with NSCLC who underwent VATS lobectomy from December 2011 to August 2016 were retrospectively reviewed, including 47 in the triple-port group and 26 in the single-port group. Statistical analysis was performed after propensity score matching. Patients were matched on a 1-to-1 basis. Results: Operative time and intraoperative blood loss in the triple-port group and the single-port group were similar (189.4+/-50.8 minutes vs. 205.4+/-50.6 minutes, p=0.259; 286.5+/ 531.0 mL vs. 314.6+/-513.1 mL, p=0.813). There were no cases of morbidity or mortality. No significant differences in complications or the total number of dissected lymph nodes were found between the 2 groups. In the single-port group, more mediastinal lymph nodes were dissected than in the triple-port group (1.7+/ 0.6 vs. 1.2+/-0.5, p=0.011). Both groups had 1 patient with bronchopleural fistula. Chest tube duration and postoperative hospital stay were shorter in the single-port group than in the triple-port group (8.7+/-5.1 days vs. 6.2+/-6.6 days, p=0.130; 11.7+/-6.1 days vs. 9.5+/-6.4 days, p=0.226). However, the differences were not statistically significant. In the single-port group, the rate of conversion to multi-port VATS lobectomy was 11.5% (3 of 26). The rates of conversion to open thoracotomy in the triple-port and single-port groups were 7.7% and 3.8%, respectively (p=1.000). Conclusion: In comparison with the triple port group, single-port VATS lobectomy showed similar results in safety and efficacy, indicating that single-port VATS lobectomy is a feasible and safe option for lung cancer patients. PMID- 29124026 TI - Risk Factors for Pneumonia in Ventilated Trauma Patients with Multiple Rib Fractures. AB - Background: Ventilator-associated pneumonia (VAP) is a common disease that may contribute to morbidity and mortality among trauma patients in the intensive care unit (ICU). This study evaluated the associations between trauma factors and the development of VAP in ventilated patients with multiple rib fractures. Methods: We retrospectively and consecutively evaluated 101 patients with multiple rib fractures who were ventilated and managed at our hospital between January 2010 and December 2015, analyzing the associations between VAP and trauma factors in these patients. Trauma factors included sternal fracture, flail chest, diaphragm injury, traumatic aortic dissection, combined cardiac injury, pulmonary contusion, pneumothorax, hemothorax, hemopneumothorax, abbreviated injury scale score, thoracic trauma severity score, and injury severity score. Results: Forty six patients (45.5%) had at least 1 episode of VAP, 10 (21.7%) of whom died in the ICU. Of the 55 (54.5%) patients who did not have pneumonia, 9 (16.4%) died in the ICU. Using logistic regression analysis, we found that VAP was associated with severe lung contusion (odds ratio, 3.07; 95% confidence interval, 1.12 to 8.39; p=0.029). Conclusion: Severe pulmonary contusion (pulmonary lung contusion score 6-12) is an independent risk factor for VAP in ventilated trauma patients with multiple rib fractures. PMID- 29124028 TI - Inter-Facility Transport on Extracorporeal Life Support: Clinical Outcomes and Comparative Analysis with In-house Patients. AB - Background: Extracorporeal life support (ECLS) is widely used in refractory heart or lung failure, and the demand for inter-facility transportation on ECLS is expanding. However, little is known about post-transportation outcomes, the clinical safety of such transportation, or the characteristics of the transported patients. Methods: This was a retrospective review of a 3-year, single institution experience with inter-facility ECLS transport, as well as a comparative analysis of clinical outcomes with those of in-house patients. We also analyzed the risk factors for hospital mortality in the entire ECLS population using univariate and multivariate analyses to investigate the effects of transport. Results: All 44 patients were safely transported without adverse events. The average travel distance was 178.7 km, with an average travel time of 74.0 minutes. Early survival of the transported group seemed to be better than that of the in-house group, but the difference was not statistically significant (70.5% vs. 56.6%, p=0.096). The incidence of complications was similar between the 2 groups, except for critical limb ischemia, which was significantly more common in the transported group than in the in-house group (25.0% vs. 8.1%, p=0.017). After adjusting for confounders, being part of the transported group was not a predictor of early death (adjusted odds ratio, 0.689; p=0.397). Conclusion: Transportation of patients on ECLS is relatively safe, and the clinical outcomes of transported patients are comparable to those of in-house ECLS patients. Although matched studies are required, our study demonstrates that transporting patients on ECLS did not increase their risk of hospital mortality after adjustment for other factors. PMID- 29124027 TI - Risk Factors of On-Pump Conversion during Off-Pump Coronary Artery Bypass Graft. AB - Background: Off-pump coronary artery bypass grafting (OPCABG) procedures can avoid the complications of an on-pump bypass. However, some cases unexpectedly require conversion to cardiopulmonary bypass during OPCABG. The risk factors associated with a sudden need for cardiopulmonary bypass were analyzed. Methods: This retrospective study included 283 subjects scheduled for OPCABG from 2001 to 2010. These were divided into an OPCABG group and an on-pump conversion group. Preoperative, operative, and postoperative variables were compared between the 2 groups. Results: Of the 283 patients scheduled for OPCABG, 47 (16%) were switched to on-pump coronary artery bypass grafting (CABG). The mortality of the both the OPCABG and on-pump conversion groups was not significantly different. The major risk factors for conversion to on-pump CABG were congestive heart failure (CHF) (odds ratio [OR], 3.5; p=0.029), ejection fraction (EF) <35% (OR, 4.4; p=0.012), and preoperative beta-blocker (BB) administration (OR, 0.3; p=0.007). The use of intraoperative (p=0.007) and postoperative (p=0.021) inotropics was significantly higher in the conversion group. The amount of postoperative drainage (p<0.001) and transfusion (p<0.001) also was significantly higher in the conversion group. There were no significant differences in stroke or cardiovascular complications between the groups over the course of short-term and long-term follow-up. Conclusion: Patients who undergo OPCABG and have CHF or a lower EF (<35%) are more likely to undergo on-pump conversion, while preoperative BB administration could help prevent conversions from OPCABG to on-pump CABG. PMID- 29124029 TI - Femoro-Supragenicular Popliteal Bypass with a Bridging Stent Graft in a Diffusely Diseased Distal Target Popliteal Artery: Alternative to Below-Knee Popliteal Polytetrafluoroethylene Bypass. AB - Background: Lesions in distal target arteries hinder surgical bypass procedures in patients with peripheral arterial occlusive disease. Methods: Between April 2012 and October 2015, 16 patients (18 limbs) with lifestyle-limiting claudication (n=12) or chronic critical limb ischemia (n=6) underwent femoral above-knee (AK) polytetrafluoroethylene (PTFE) bypass grafts with a bridging stent graft placement between the distal target popliteal artery and the PTFE graft. Ring-supported PTFE grafts were used in all patients with no available vein for graft material. Follow-up evaluations assessed clinical symptoms, the ankle-brachial index, ultrasonographic imaging and/or computed tomography angiography, the primary patency rate, and complications. Results: All procedures were successful. The mean follow-up was 12.6 months (range, 11 to 14 months), and there were no major complications. The median baseline ankle-brachial index of 0.4 (range, 0.2 to 0.55) significantly increased to 0.8 (range, 0.5 to 1.0) at 12 months (p<0.01). The primary patency rate at 12 months was 83.3%. The presenting symptoms resolved within 2 weeks. Conclusion: In AK bypasses with a diffusely diseased distal target popliteal artery or when below-knee (BK) bypass surgery is impossible, this procedure could be clinically effective and safe when used as an alternative to femoral-BK bypass surgery. PMID- 29124030 TI - Large Atrial Septal Defect Closure in a Patient with Severe Pulmonary Arterial Hypertension. AB - Patients with an atrial septal defect (ASD) and severe pulmonary arterial hypertension (PAH) are considered ineligible for defect closure surgery because of the risk of right ventricular decompensation and death after the operation. We report the case of a patient with large ASD and severe PAH who was able to undergo defect closure surgery successfully following long-term use of combined oral sildenafil and beraprost. PMID- 29124031 TI - Successful Lung Transplantation in a Patient with Myasthenia Gravis. AB - A 47-year-old man with myasthenia gravis (MG) was admitted for a lung transplant. He had bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation due to acute myeloid leukemia. MG developed after stem cell transplantation. Bilateral sequential lung transplantations and a total thymectomy were performed. The patient underwent right diaphragmatic plication simultaneously due to preoperatively diagnosed right diaphragmatic paralysis. A tracheostomy was performed and bilevel positive airway pressure (BiPAP) was applied on postoperative days 8 and 9, respectively. The patient was transferred to the general ward on postoperative day 12, successfully weaned off BiPAP on postoperative day 18, and finally discharged on postoperative day 62. PMID- 29124032 TI - Birt-Hogg-Dube Syndrome Manifesting as Spontaneous Pneumothorax: A Novel Mutation of the Folliculin Gene. AB - Birt-Hogg-Dube syndrome (BHDS) is a rare disease with autosomal dominant inheritance that manifests through skin tumors, pulmonary cystic lesions, and renal tumors. A mutation of FLCN located on chromosome 17p11.2, which encodes a tumor-suppressor protein (folliculin), is responsible for the development of BHDS. We report the case of a patient presenting with spontaneous pneumothorax, in whom a familial genetic study revealed a novel nonsense mutation: p.(Arg379*) in FLCN. PMID- 29124033 TI - Intraoperative Recurrent Laryngeal Nerve Monitoring in a Patient with Contralateral Vocal Fold Palsy. AB - Recurrent laryngeal nerve injury can develop following cervical or thoracic surgery; however, few reports have described intraoperative recurrent laryngeal nerve monitoring. Consensus regarding the use of this technique during thoracic surgery is lacking. We used intraoperative recurrent laryngeal nerve monitoring in a patient with contralateral vocal cord paralysis who was scheduled for completion pneumonectomy. This case serves as an example of intraoperative recurrent laryngeal nerve monitoring during thoracic surgery and supports this indication for its use. PMID- 29124034 TI - Internal Drainage of an Esophageal Perforation in a Patient with a High Surgical Risk. AB - A 71-year-old man presented with a productive cough and fever, and he was diagnosed as having an esophageal perforation and a mediastinal abscess. He had a history of traumatic hemothorax and pleural drainage for empyema in the right chest and was considered unable to tolerate thoracic surgery because of sepsis and progressive aspiration pneumonia. In order to aggressively drain the mediastinal contamination, we performed internal drainage by placing a Levin tube into the mediastinum through the perforation site. This procedure, in conjunction with controlling sepsis and providing sufficient postpyloric nutrition, allowed the esophageal injury to completely heal. PMID- 29124035 TI - Successful Tractotomy Technique for a Penetrating Lung Injury in a Patient with One Lung. AB - We report the case of a patient with penetrating chest trauma (right chest) who had undergone a left pneumonectomy due to pulmonary tuberculosis 24 years ago. We performed an emergent thoracotomy, finding an opening of the penetrating wound in a lower-lobe basal segment of the right lung. A stapled tractotomy was performed along the tract. Bleeding control and air-leakage control was done easily and rapidly. The patient was discharged without any complications on the seventh day of admission. Tractotomy can be a good option for treating penetrating lung injuries in patients with limited lung function who need emergent surgery. PMID- 29124036 TI - Surgical Repair of a Traumatic Tracheobronchial Injury in a Pediatric Patient Assisted with Venoarterial Extracorporeal Membrane Oxygenation. AB - Tracheobronchial rupture due to blunt chest trauma is a rare but life-threatening injury in the pediatric population. Computed tomography (CT) is not always reliable in the management of these patients. An additional concern is that ventilation may be disrupted during surgical repair of these injuries. This report presents the case of a 4 -year-old boy with an injury to the lower trachea and carina due to blunt force trauma that was missed on the initial CT scan. During surgery, he was administered venoarterial extracorporeal membrane oxygenation (ECMO). Although ECMO is not generally used in children, this case demonstrated that the short-term use of ECMO during pediatric surgery is safe and can prevent intraoperative desaturation. PMID- 29124037 TI - Chylothorax after Blunt Chest Trauma: A Case Report. AB - Traumatic chylothorax after blunt chest trauma alone is considered rare. Our patient was a 27-year-old female who was in a motorcycle accident and sustained blunt thoracic and traumatic thoracic aortic injuries with T1-T2 vertebral subluxation. She underwent thoracic endovascular aortic repair from T4 to T9 without any thoracic or spinal surgery. On postoperative day 7, the drainage from her left chest turned into a milky-white fluid indicative of chyle leakage. The patient was treated conservatively for 2 weeks and then the chest drain was safely removed. The results show that traumatic chylothorax can be successfully managed with conservative treatment. PMID- 29124038 TI - Intraoperative Radiation for Breast Cancer with IntrabeamTM: Factors Associated with Decreased Operative Times in Patients Having IORT for Breast Cancer. AB - Introduction: Intraoperative radiation with IntrabeamTM (IORT) for breast cancer is a newer technology recently implemented into the operating room (OR). This procedure requires time and coordination between the surgeon and radiation oncologist, who both perform their treatments in a single operative setting. We evaluated the surgeons at our center, who perform IORT and their OR times to examine changes in OR times following implementation of this new surgical procedure. We hypothesized that IORT is a technique for which timing could be improved with the increasing number of cases performed. Methods: A prospectively maintained IRB approved database was queried for OR times (incision and close) in patients who underwent breast conserving surgery (BCS), sentinel lymph node biopsy with and without IORT using the IntrabeamTM system at our institution from 2011 to 2015. The total OR times were compared for each surgeon individually and over time. Next, the OR times of each surgeon were compared to each other. Continuous variables were summarized and then a prediction model was created using IORT time, OR time, surgeon, and number of cases performed. Results: There were five surgeons performing IORT at our institution during this time period with a total of 96 cases performed. There was a significant difference observed in baseline surgeon-specific OR time for BSC (p = 0.03) as well as for BCS with IORT (p < 0.05), attributable to surgeon experience. The average BCS times were faster than the BCS plus IORT procedure times for all surgeons. The overall mean OR time for the entire combined surgical and radiation procedure was 135.5 min. The most common applicator sizes used were the 3.5 and 4 cm, yielding an average 21 min IORT time. Applicator choice did not differ over time (p = 0.189). After adjusting for IORT time and surgeon, the prediction model estimated that surgeons decreased the total BCS plus IORT OR time at a rate of -4.5 min per each additional 10 cases performed. Conclusion: Surgeon experience and applicator size are related to OR times for performing IORT for breast cancer. OR time for IORT in breast cancer treatment can be improved over time, even among experienced surgeons. PMID- 29124039 TI - Surgical Management of Stage IIIA Non-Small Cell Lung Cancer. AB - According to the eighth edition of the tumor-node-metastasis classification, stage III non-small cell lung cancer is subdivided into stages IIIA, IIIB, and IIIC. They represent a heterogeneous group of bronchogenic carcinomas with locoregional involvement by extension of the primary tumor and/or ipsilateral or contralateral lymph node involvement. Surgical indications have not been definitely established but, in general, long-term survival is only obtained in those patients in whom a complete resection is obtained. This mini-review mainly focusses on stage IIIA disease comprising patients with locoregionally advanced lung cancers. Different subcategories of N2 involvement exist, which range from unexpected N2 disease after thorough preoperative staging or "surprise" N2, to bulky N2 involvement, mostly treated by chemoradiation, and finally, the intermediate category of potentially resectable N2 disease treated with a combined modality regimen. After induction therapy for preoperative N2 involvement, best surgical results are obtained with proven mediastinal downstaging when a lobectomy is feasible to obtain a microscopic complete resection. However, no definite, universally accepted guidelines exist. A relatively new entity is salvage surgery applied for recurrent disease after full dose chemoradiation when no other therapeutic options exist. Equally, only a small subset of patients with T4N0-1 disease qualify for surgical resection after thorough discussion within a multidisciplinary tumor board on the condition that a complete resection is feasible. Targeted therapies and immunotherapy have recently become part of our therapeutic armamentarium, and it might be expected that they will be incorporated in current regimens after careful evaluation in randomized clinical trials. PMID- 29124040 TI - Cold-Shock Domain Family Proteins (Csps) Are Involved in Regulation of Virulence, Cellular Aggregation, and Flagella-Based Motility in Listeria monocytogenes. AB - Cold shock-domain family proteins (Csps) are highly conserved nucleic acid binding proteins regulating the expression of various genes including those involved in stress resistance and virulence in bacteria. We show here that Csps are involved in virulence, cell aggregation and flagella-based extracellular motility of Listeria monocytogenes. A L. monocytogenes mutant deleted in all three csp genes (DeltacspABD) is attenuated with respect to human macrophage infection as well as virulence in a zebrafish infection model. Moreover, this mutant is incapable of aggregation and fails to express surface flagella or exhibit swarming motility. An evaluation of double csp gene deletion mutant (DeltacspBD, DeltacspAD and DeltacspAB) strains that produce single csp genes showed that there is redundancy as well as functional differences among the three L. monocytogenes Csps in their contributions to virulence, cellular aggregation, flagella production, and swarming motility. Protein and mRNA expression analysis further showed impaired expression of key virulence and motility genes in the csp mutants. Our observations at protein and mRNA level suggest Csp-dependent expression regulation of these genes at transcriptional and post-transcriptional levels. In a mutant lacking all csp genes (DeltacspABD) as well as those possessing single csp genes (DeltacspBD, DeltacspAD, and DeltacspAB) we detected reduced levels of proteins or activity as well as transcripts from the prfA, hly, mpl, and plcA genes suggesting a Csp-dependent transcriptional regulation of these genes. These csp mutants also had reduced or completely lacked ActA proteins and cell surface flagella but contained elevated actA and flaA mRNA levels compared to the parental wild type strain suggesting Csp involvement in post-transcriptional regulation of these genes. Overall, our results suggest that Csps contribute to the expression regulation of virulence and flagella-associated genes thereby promoting host pathogenicity, cell aggregation and flagella-based motility processes in L. monocytogenes. PMID- 29124042 TI - E. fischeriana Root Compound Dpo Activates Antiviral Innate Immunity. AB - E. fischeriana has long been used as a traditional Chinese medicine. Recent studies reported that some compounds of E. fischeriana exhibited antimicrobial and immune enhance activity. Innate immune system is essential for the immune surveillance of inner and outer threats, initial host defense responses and immune modulation. The role of natural drug compounds, including E. fischeriana, in innate immune regulation is largely unknown. Here we demonstrated that E. fischeriana compound Dpo is involved in antiviral signaling. The genome wide RNA seq analysis revealed that the induction of ISGs by viral infection could be synergized by Dpo. Consistently, Dpo enhanced the antiviral immune responses and protected the mice from death during viral infection. Dpo however was not able to rescue STING deficient mice lethality caused by HSV-1 infection. The enhancement of ISG15 by Dpo was also impaired in STING, IRF3, IRF7, or ELF4 deficient cells, demonstrating that Dpo activates innate immune responses in a STING/IRFs/ELF4 dependent way. The STING/IRFs/ELF4 axis is therefore important for Dpo induced ISGs expression, and can be used by host to counteract infection. PMID- 29124043 TI - Activities of daily living measured by the Harvard Automated Phone Task track with cognitive decline over time in non-demented elderly. AB - Background: Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer's disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed. The Harvard Automated Phone Task, a novel performance-based activities of daily living instrument, has the potential to fill this gap. Objective: To further validate the Harvard Automated Phone Task by assessing its longitudinal relationship to global cognition and specific cognitive domains in clinically normal elderly and individuals with mild cognitive impairment. Design: In a longitudinal study, the Harvard Automated Phone Task was associated with cognitive measures using mixed effects models. The Harvard Automated Phone Task's ability to discriminate across diagnostic groups at baseline was also assessed. Setting: Academic clinical research center. Participants: Two hundred and seven participants (45 young normal, 141 clinically normal elderly, and 21 mild cognitive impairment) were recruited from the community and the memory disorders clinics at Brigham and Women's Hospital and Massachusetts General Hospital. Measurements: Participants performed the three tasks of the Harvard Automated Phone Task, which consist of navigating an interactive voice response system to refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). The 3 tasks were scored based on time, errors, repetitions, and correct completion of the task. The primary outcome measure used for each of the tasks was total time adjusted for correct completion. Results: The Harvard Automated Phone Task discriminated well between young normal, clinically normal elderly, and mild cognitive impairment participants (APT-Script: p<0.001; APT PCP: p<0.001; APT-Bank: p=0.04). Worse baseline Harvard Automated Phone Task performance or worsening Harvard Automated Phone Task performance over time tracked with overall worse performance or worsening performance over time in global cognition, processing speed, executive function, and episodic memory. Conclusions: Prior cross-sectional and current longitudinal analyses have demonstrated the utility of the Harvard Automated Phone Task, a new performance based activities of daily living instrument, in the assessment of early changes in complex activities of daily living in non-demented elderly at risk for Alzheimer's disease. Future studies will focus on cross-validation with other sensitive activities of daily living tests and Alzheimer's disease biomarkers. PMID- 29124041 TI - Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5 Fluorouracil Induced Intestinal Mucositis. AB - Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5 Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-kappaB and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis. PMID- 29124045 TI - Dietary Diversity Score and Its Related Factors among Employees of Kermanshah University of Medical Sciences. AB - Dietary diversity score (DDS) is known as an indicator of food quality. Dietary diversity can promote health status. The aim of this study was determined DDS and its related factors in Kermanshah University of Medical Sciences (KUMS) employees. This cross-sectional study was conducted on 190 employees of KUMS in 2015. According to the population of KUMS centers which were selected randomly (Paramedical, Public Health faculties, Imam Reza Hospital and province health center), subjects were selected by convenience sampling method. Food frequency questionnaire (FFQ) was used to calculate DDS. Foods were divided into 5 main groups: grains, vegetables, fruits, meat, and dairy products. The main groups had 23 subgroups. Total DDS divided to 4 quartiles: less than 3.0, 3.0-5.5, 5.6-8.5, and more than 8.5. Anthropometric parameters including: weight, height, waist circumference (WC), and hip circumference were measured. Data were analyzed by Kolmogorov-Smirnov test, chi2 test, and analysis of variance (ANOVA) test with SPSS 20 software (IBM Corp., Chicago, IL, USA). The mean +/- standard deviation of DDS and body mass index (BMI) were 5.68 +/- 1.73 and 25.1 +/- 3.42 kg/m2, respectively. The average of the waist-to-hip ratio (WHR) in men and women was 0.92 +/- 0.04 and 0.86 +/- 0.06, respectively. There was statistically significant difference between DDS and self-reported economic status (p < 0.022). No significant difference was observed between DDS and BMI or WC. However, significant negative correlation was observed between DDS and WHR in men (p < 0.019). This study showed that DDS had a negative correlation with the WHR. Therefore, dietary diversity may improve health status by effect on fat distribution in body. PMID- 29124044 TI - Index-Based Dietary Patterns and the Risk of Prostate Cancer. AB - Prostate cancer is the second leading cause for cancer incidence in male. Although this high incidence is due to prostate specific antigen screening, other risk-factors, such as diet, might also be involved. The results of previous studies on the association between prostate cancer risk and individual dietary components have been conflicting. Thus, evaluation by dietary pattern analysis rather than individual dietary factors is suggested. The purpose of this study was to review the association of prostate cancer with a priori dietary indices, which are less studied and reviewed to date compared to a posteriori indices. Studies reviewed in this research were published from January 1997 to March 2017. Seventeen studies with nine indices were selected. In Mediterranean Diet Score (MDS), all four studies were non-significant. In Dietary Inflammatory Index (DII), 3 out of 4 studies significantly increased risk by 1.33-2.39 times, suggesting that a higher pro-inflammatory diet may be a possible prostate cancer risk factor. In Oxidative Balance Score (OBS), 2 out of 5 studies had decreased risk by 0.28 and 0.34 times, whereas 1 study had increased risk by 1.17 times. Among other indices, Healthy Eating Index (HEI) and prostate cancer dietary index were associated with decreased risk, while the results from 2 studies of Low Carbohydrate, High Protein Diet (LCHP) score were conflicting. In conclusion, we observed that it is insufficient to support the association between a priori indices and prostate cancer risk, except for MDS and DII, which had relatively constant results among studies. Therefore, further studies are required to identify consistent criteria for each a priori index, and should be conducted actively in various populations. PMID- 29124046 TI - The Analysis of a Diet for the Human Being and the Companion Animal using Big Data in 2016. AB - The purpose of this study was to investigate the diet tendencies of human and companion animals using big data analysis. The keyword data of human diet and companion animals' diet were collected from the portal site Naver from January 1, 2016 until December 31, 2016 and collected data were analyzed by simple frequency analysis, N-gram analysis, keyword network analysis and seasonality analysis. In terms of human, the word exercise had the highest frequency through simple frequency analysis, whereas diet menu most frequently appeared in the N-gram analysis. companion animals, the term dog had the highest frequency in simple frequency analysis, whereas diet method was most frequent through N-gram analysis. Keyword network analysis for human indicated 4 groups: diet group, exercise group, commercial diet food group, and commercial diet program group. However, the keyword network analysis for companion animals indicated 3 groups: diet group, exercise group, and professional medical help group. The analysis of seasonality showed that the interest in diet for both human and companion animals increased steadily since February of 2016 and reached its peak in July. In conclusion, diets of human and companion animals showed similar tendencies, particularly having higher preference for dietary control over other methods. The diets of companion animals are determined by the choice of their owners as effective diet method for owners are usually applied to the companion animals. Therefore, it is necessary to have empirical demonstration of whether correlation of obesity between human being and the companion animals exist. PMID- 29124047 TI - Adiponectin Concentration in Gestational Diabetic Women: a Case-Control Study. AB - Gestational diabetes mellitus (GDM) is an impaired fasting glucose condition during pregnancy. Adiponectin is a polypeptide hormone that is extensively released by adipocytes which regulates energy homeostasis and carbohydrate and lipid metabolism. In addition, adiponectin has antidiabetic and anti-inflammatory properties. The aim of our research was to study about the relationship of adiponectin levels to GDM and glucose intolerance. We selected 25 GDM women and 35 healthy pregnant subjects (18-46 years) who were screened between 24 and 28 weeks of gestation based on the result of oral glucose tolerance test (OGTT). We designed a case-control study and measured the concentrations of serum adiponectin and compared the concentrations between the groups. Serum adiponectin concentration was measured using enzyme-linked immunosorbent assay (ELISA). Sociodemographic data were collected by personal interview. Serum adiponectin concentrations were significantly lower in the subjects with GDM (5.10 +/- 2.15 ng/mL vs. 7.86 +/- 3.52 ng/mL, p = 0.001) than in healthy pregnant subjects. The mean concentration of fasting blood glucose was considerably lower in control subjects (86.9 +/- 9.0 mg/dL vs. 175.9 +/- 20.1 mg/dL, p < 0.001) in comparison to GDM subjects. Our findings showed that serum concentrations of adiponectin were significantly lower in gestational diabetic women and this may help to predict the risk of GDM. PMID- 29124048 TI - Breastfeeding for One Month or Longer is Associated with Higher Risk of Osteoarthritis in Older Adults: NHANES 1999-2012. AB - Breastfeeding is associated with many health benefits to the mother but the association between osteoarthritis (OA) is not known. Menopause, a state of rapid estrogen loss, is associated with OA. To test whether lactation, another physiological state of low estrogen status, is associated with OA, a nationally representative dataset National Health and Nutrition Examination Survey (NHANES) 1999-2012 was analyzed. Information of OA diagnosis history and lactation for at least one month was self-reported by women 50 years and older that had given birth to at least one child. Women that breastfed for less than one month had a higher proportion of those that were 60 years and older, Hispanic (than non Hispanic Black), and higher current/self-reported greatest body mass index. Women that breastfed for one month or longer had a higher proportion of those that had 3 or more children, higher poverty-income ratio, were post-menopausal and performed vigorous physical activity. Weighted percentage of OA patients was 22%, and did not differ between the two groups. However, when logistic regression was performed adjusting for multiple covariates, lactation for one month or longer was positively associated with OA. Women that breastfed for one month or longer had an adjusted odds ratio of 1.21 (95% confidence interval, 1.05-1.40) for OA compared to those that breastfed for less than one month. The results indicate that women that breastfed for at least one month have a higher risk of OA than women that delivered a child but breastfed for less than one month. PMID- 29124049 TI - Effect of Personalized Nutritional Counseling on the Nutritional Status of Hemodialysis Patients. AB - This study set out to evaluate the impact of personalized nutritional counseling (PNC) on the nutritional status of hemodialysis (HD) patients. This was an intervention study for 10 months at 2 hospitals. Anthropometric, biochemical, dietary, and body composition parameters were measured at baseline and after 3 and 6 months of PNC. A total of 42 patients (23 men and 19 women) were included. Intake of dietary protein, serum albumin, and cholesterol levels had increased significantly from baseline to month 6 (p < 0.05). Among the bioelectrical impedance analysis (BIA) parameters, both the body cell mass (BCM) and the fat free mass (FFM) had significantly reduced at month 3 compared to baseline (p < 0.05). However, there was no difference between baseline and month 6. We assessed the nutritional status of the subjects using the malnutrition inflammation score (MIS), and divided them into an adequately nourished (AN) and a malnourished (MN) group at baseline. In the subgroup analysis, serum levels of albumin and cholesterol had increased significantly, particularly from baseline to month 6 in the MN group (p < 0.05). This study suggests that consecutive PNC contributed to the improvement of the protein intake, serum levels of albumin, cholesterol and to the delay of muscle wasting, which could also have a positive impact on the nutritional status, particularly in malnourished patients receiving HD treatment. PMID- 29124050 TI - Association between Healthy Eating Index-2010 and Fetuin-A Levels in Patients with Type 2 Diabetes: a Case-Control Study. AB - The Healthy Eating Index-2010 (HEI-2010) assesses compliance with the 2010 Dietary Guidelines for Americans. Studies suggest that adherence to the HEI-2010 is related to lower the risk of type 2 diabetes (T2D). Fetuin-A, a novel biomarker for T2D, may play a linking role in the inverse association between HEI 2010 and T2D. Thus, a case-control analysis involving 107 patients with T2D and107 healthy subjects was conducted to determine the association between HEI 2010 and serum fetuin-A levels. The results of simple regression analysis showed that fetuin-A levels were positively associated with full name of body mass index (BMI) (p < 0.001), waist circumference (WC) (p < 0.001), fasting blood glucose (FBG) (p < 0.001), triglycerides (TG) (p = 0.003), gamma-glutamyl transferase (GGT) (p < 0.001), and homeostasis model assessment of insulin resistance (HOMA IR) (p =0.001) and negatively associated with physical activity (PA) (p < 0.001), high-density lipoprotein (HDL) (p = 0.022), and HEI-2010 (p < 0.001) in all subjects. After controlling for confounders, the inverse association between fetuin-A and HEI-2010 remained significant in the subjects with T2D (beta = 0.386; p < 0.001), 107 healthy controls (beta = -0.237; p = 0.028), and all subjects (beta = -0.298; p < 0.001). In conclusion, the present results suggested that higher quality diet assessed by HEI-2010 associates with lower serum fetuin A levels in people with and without T2D. More studies are needed to confirm these findings. PMID- 29124051 TI - Continuation of Enteral Nutrition and Relief from Vomiting by Administration of a New Formula: a Case Report. AB - Gastro-esophageal reflux (GER) is a common and serious complication in patients receiving enteral nutrition, making continuation of enteral nutrition difficult. Semi-solid enteral nutrients were developed to prevent feeding-related GER. Semi solid enteral nutrients have high viscosity and, therefore, are typically administered through a large-diameter percutaneous endoscopic gastrostomy (PEG) tube. Recently, a new formula (Mermed(r), Mermed Plus(r)) was introduced that uses alginate, which behaves like a gelatin in acidic conditions. This formula improved GER during enteral feedings. Our case report shows that this new formula enables the continuation of enteral nutrition via a nasogastric tube (NGT) in patients with difficulty tolerating enteral nutrition secondary to vomiting. An 86-year-old woman with an atherothrombotic cerebral infarction vomited during tube feeding, resulting in aspiration pneumonia. After 1 week, we introduced a viscosity regulator and restarted enteral feeding using a 100 mL liquid diet, but vomiting persisted. Because of the continued difficulty in tolerating enteral nutrition, the patient was transferred to our hospital. From hospital day 4, Mermed Plus(r) (300 mL/225 kcal, administered for 1 hour, 3 times a day) was started, eventually increasing to 535 mL/400 kcal at hospital day 5. After this, vomiting ceased. Mermed Plus(r) was easily administered via NGT, and its effects were immediate. This treatment appeared to improve the patient's quality of life while reducing the burden on medical staff. PMID- 29124052 TI - Thirty Years of Sweat Chloride Testing at One Referral Center. AB - Objective: To conduct a descriptive analysis of the sweat test (ST), associating ST results with epidemiological data, CFTR (cystic fibrosis transmembrane conductance regulator) mutations and reasons to indicate the ST, as well as correlating sweat sodium and sweat chloride concentrations in subjects. Methods: Retrospective survey and descriptive analysis of 5,721 ST at a university referral center. Results: The inclusion of the subjects was based on clinical data related with cystic fibrosis (CF) phenotype. The samples were grouped by (i) sweat chloride concentrations (mEq/L): <30: 3,249/5,277 (61.6%); >=30 to <60: 1,326/5,277 (25.1%); >=60: 702/5,277 (13.3%) and (ii) age: (Group A--GA) 0 to <6 months; (Group B--GB) >=6 months to <18 years; (Group C--GC) >=18 years. Digestive symptoms showed higher prevalence ratio for the CF diagnosis as well as association between younger age and higher values of sweat chloride, sweat sodium, and chloride/sodium ratio. The indication of ST due to respiratory symptoms was higher in GB and associated with greater age, lower values of sweat chloride, sweat sodium, and chloride/sodium ratio. There was higher prevalence of ST with sweat chloride levels <30 mEq/L in GB, >=60 mEq/L in GC, and with borderline level in GB. There was positive correlation between sweat sodium and sweat chloride. Sweat chloride/sweat sodium and sweat sodium-sweat chloride indexes showed association with sex, reason for ST indication, and CFTR mutations. Sex alters some values presented in the ST. The number of ST/year performed before and after the newborn screening implementation was the same; however, we observed a higher number of borderlines values. A wide spectrum of CFTR mutation was found. Severe CFTR mutations and F508del/F508del genotype were associated with highest probability of ST chloride levels >=60 mEq/L, and the absence of CFTR mutations identified was associated with borderline ST and respiratory symptoms. Conclusions: ST data showed wide variability dependent on age, sex, reason for examination indication, CFTR mutations, and weight of the collected sweat sample. Sweat sodium concentration is directly correlated with sweat chloride levels and it could be used as a quality parameter. PMID- 29124053 TI - Contextual Factors and Mastery Motivation in Young Children with and without Cerebral Palsy: A Systematic Review. AB - Background: Mastery motivation is the driving force behind children's desire to explore the surrounding world and their comprehensive development. However, disease factors may lower a child's motivation and hamper development. The aim of this review is to examine mastery motivation in preschool children with cerebral palsy (CP) and the impact of contextual factors on mastery motivation. Methods: Six electronic databases were searched (PubMed, ScienceDirect, Scopus, PsycINFO, Medline, and Airiti Library) using the keywords "Activity," "Cerebral Palsy," "Preschool," "Motivation," "Mastery motivation," "Gross motor," and "Toddler." We reviewed six observational studies and one interventional study for the following features: (1) participants' characteristics; (2) assessment, observation, and intervention methods; (3) findings. Results: Of the seven studies, three were individual cohort studies and four were individual case-control studies. There were two types of motivation-related measures, standardized measurements and observations of structured tasks or free play. Three studies showed no significant difference in mastery motivation between children with and those without CP when given mental-age-appropriate tasks of moderate difficulty. However, environmental factors including social experience, family interaction, and caregivers' perceptions may affect motivation in preschool children with CP. Conclusion: Current studies on mastery motivation in preschool children with CP are very limited, and the lack of a universal, theory-based definition of mastery motivation and common assessment frameworks makes it difficult to draw clear conclusions on mastery motivation in children with CP. Future studies should investigate mastery motivation with rigorous study designs to identify ideal activities and environments for preschool children with CP. PMID- 29124054 TI - A Method for the Analysis of AP Foot Convexity: Insights into Smooth Muscle Biophysics. AB - Action potential (AP) profiles vary based on the cell type, with cells of the same type typically producing APs with similar shapes. But in certain syncytial tissues, such as the smooth muscle of the urinary bladder wall, even a single cell is known to exhibit APs with diverse profiles. The origin of this diversity is not currently understood, but is often attributed to factors such as syncytial interactions and the spatial distribution of parasympathetic nerve terminals. Thus, the profile of an action potential is determined by the inherent properties of the cell and influenced by its biophysical environment. The analysis of an AP profile, therefore, holds potential for constructing a biophysical picture of the cellular environment. An important feature of any AP is its depolarization to threshold, termed the AP foot, which holds information about the origin of the AP. Currently, there exists no established technique for the quantification of the AP foot. In this study, we explore several possible approaches for this quantification, namely, exponential fitting, evaluation of the radius of curvature, triangulation altitude, and various area based methods. We have also proposed a modified area-based approach (CX,Y) which quantifies foot convexity as the area between the AP foot and a predefined line. We assess the robustness of the individual approaches over a wide variety of signals, mimicking AP diversity. The proposed (CX,Y) method is demonstrated to be superior to the other approaches, and we demonstrate its application on experimentally recorded AP profiles. The study reveals how the quantification of the AP foot could be related to the nature of the underlying synaptic activity and help shed light on biophysical features such as the density of innervation, proximity of varicosities, size of the syncytium, or the strength of intercellular coupling within the syncytium. The work presented here is directed toward exploring these aspects, with further potential toward clinical electrodiagnostics by providing a better understanding of whole-organ biophysics. PMID- 29124055 TI - Regulatory and Scientific Advancements in Gene Therapy: State-of-the-Art of Clinical Applications and of the Supporting European Regulatory Framework. AB - Advanced therapy medicinal products (ATMPs) have a massive potential to address existing unmet medical needs. Specifically, gene therapy medicinal products (GTMPs) may potentially provide cure for several genetic diseases. In Europe, the ATMP regulation was fully implemented in 2009 and, at this point, the Committee for Advanced Therapies was created as a dedicated group of specialists to evaluate medicinal products requiring specific expertise in this area. To date, there are three authorized GTMPs, and the first one was approved in 2012. Broad research has been conducted in this field over the last few decades and different clinical applications are being investigated worldwide, using different strategies that range from direct gene replacement or addition to more complex pathways such as specific gene editing or RNA targeting. Important safety risks, limited efficacy, manufacturing hurdles, or ethical conflicts may represent challenges in the success of a candidate GTMP. During the development process, it is fundamental to take such aspects into account and establish overcoming strategies. This article reviews the current European legal framework of ATMPs, provides an overview of the clinical applications for approved and investigational GTMPs, and discusses critical challenges in the development of GTMPs. PMID- 29124056 TI - Microbial Therapeutics Designed for Infant Health. AB - Acknowledgment of the gut microbiome as a vital asset to health has led to multiple studies attempting to elucidate its mechanisms of action. During the first year of life, many factors can cause fluctuation in the developing gut microbiome. Host genetics, maternal health status, mode of delivery, gestational age, feeding regime, and perinatal antibiotic usage, are known factors which can influence the development of the infant gut microbiome. Thus, the microbiome of vaginally born, exclusively breastfed infants at term, with no previous exposure to antibiotics, either directly or indirectly from the mother, is to be considered the "gold standard." Moreover, the use of prebiotics as an aid for the development of a healthy gut microbiome is equally as important in maintaining gut homeostasis. Breastmilk, a natural prebiotic source, provides optimal active ingredients for the growth of beneficial microbial species. However, early life disorders such as necrotising enterocolitis, childhood obesity, and even autism have been associated with an altered/disturbed gut microbiome. Subsequently, microbial therapies have been introduced, in addition to suitable prebiotic ingredients, which when administered, may aid in the prevention of a microbial disturbance in the gastrointestinal tract. The aim of this mini-review is to highlight the beneficial effects of different probiotic and prebiotic treatments in early life, with particular emphasis on the different conditions which negatively impact microbial colonisation at birth. PMID- 29124057 TI - Radiation-Induced Cardiovascular Disease: A Clinical Perspective. AB - Cancer survival has improved dramatically, and this has led to the manifestation of late side effects of multimodality therapy. Radiation (RT) to the thoracic malignancies results in unintentional irradiation of the cardiac chambers. RT induced microvascular ischemia leads to disruption of capillary endothelial framework, and injury to differentiated myocytes results in deposition of collagen and fibrosis. Coexistence of risk factors of metabolic syndrome and preexisting atherosclerosis in addition to RT exposure results in accelerated occurrence of major coronary events. Hence, it becomes pertinent to understand the underlying pathophysiology and clinical manifestations of RT-induced cardiovascular disease to devise optimal preventive and surveillance strategies. PMID- 29124058 TI - Implementation of a Regional Training Program on African Swine Fever As Part of the Cooperative Biological Engagement Program across the Caucasus Region. AB - A training and outreach program to increase public awareness of African swine fever (ASF) was implemented by Defense Threat Reduction Agency and the Ministries of Agriculture in Armenia, Georgia, Kazakhstan, and Ukraine. The implementing agency was the company SAFOSO (Switzerland). Integration of this regional effort was administered by subject matter experts for each country. The main teaching effort of this project was to develop a comprehensive regional public outreach campaign through a network of expertise and knowledge for the control and prevention of ASF in four neighboring countries that experience similar issues with this disease. Gaps in disease knowledge, legislation, and outbreak preparedness in each country were all addressed. Because ASF is a pathogen with bioterrorism potential and of great veterinary health importance that is responsible for major economic instability, the project team developed public outreach programs to train veterinarians in the partner countries to accurately and rapidly identify ASF activity and report it to international veterinary health agencies. The project implementers facilitated four regional meetings to develop this outreach program, which was later disseminated in each partner country. Partner country participants were trained as trainers to implement the outreach program in their respective countries. In this paper, we describe the development, execution, and evaluation of the ASF training and outreach program that reached more than 13,000 veterinarians, farmers, and hunters in the partner countries. Additionally, more than 120,000 booklets, flyers, leaflets, guidelines, and posters were distributed during the outreach campaign. Pre- and post-ASF knowledge exams were developed. The overall success of the project was demonstrated in that the principles of developing and conducting a public outreach program were established, and these foundational teachings can be applied within a single country or expanded regionally to disseminate disease information across borders; overall, this method can be modified to raise awareness about many other diseases. PMID- 29124059 TI - Evaluation of Three Hydration Strategies in Detection Dogs Working in a Hot Environment. AB - Physical activity in hot environments can increase the risk of heat stress or heat stroke in dogs. Heat tolerance is influenced by acclimatization to the environment, physical fitness, and hydration state. Three common strategies to promote hydration in working dogs are free access to water (W), oral electrolyte solutions (OESs), and administration of subcutaneous fluids (SQs). None of these methods have been compared for safety or efficacy in a working environment. In a cross-over design, seven vehicle-screening canines were randomly assigned to each of the three hydration strategies during working shifts at the Sarita, TX checkpoint. Physical, behavioral, and biochemical parameters were collected before, during, and after a work shift (mean 5.7 +/- 0.8 h). Dogs were given 10 mL/kg oral W, 10 mL/kg chicken flavored OES, or 15 mL/kg of SQs initially followed by controlled access to W or OES. The dogs drank 15.61 +/- 4.47 mL/kg/h of W and OES when in the OES group, compared to 7.04 +/- 3.42 and 5.56 +/- 4.40 mL of W, for the W and SQ groups, respectively. The median environmental temperature was 84.8 degrees F (29.3 degrees C). The median humidity was 70%. Based on mixed effects linear modeling, dogs in the OES and SQ groups had significantly higher total CO2, and lower packed cell volume and total plasma protein at the end of the day. Creatinine increased a small but significant amount in the SQ group and decreased in the OES group. Searching behaviors were independent of hydration strategy but highly related to the dog specific factors of sex, breed, and activity level. Under conditions of controlled activity in moderate heat and humidity, dogs accustomed to the work and the environment were more likely to increase fluid consumption and hydration when provided a flavored OES. Potential benefits of OES and SQ were indirect and no adverse effects were documented for any of the hydration strategies tested. PMID- 29124060 TI - Avian Influenza Virus Surveillance in South-Central Spain Using Fecal Samples of Aquatic Birds Foraging at Landfills. AB - Aquatic wild birds have been intensively studied to better understand their role in avian influenza virus (AIV) maintenance and spread. To date, AIV surveillance has primarily focused on natural aquatic environments where different bird species aggregate and viral survival is enhanced. However, artificial habitats such as landfills are attracting substantial numbers of wild birds, AIV reservoir species included. The use of landfills as a predictable food source has significantly influenced population size, migratory traits, and feeding behavior of white storks (Ciconia ciconia) and black-headed gulls (Chroicocephalus ridibundus) among others. Considering the proximity of landfills to urban settlements and frequently poultry-farms, targeted monitoring of AIV in bird species that forage at landfills but are known to also frequent urban and agricultural habitats could be a useful means for monitoring of AIV, especially during periods of bird aggregation. During the wintering season 2014-2015, the prevalence of AIV in five avian species at two landfills in South-Central Spain was explored by rRT-PCR and species related temporal variation in AIV prevalence determined. We collected and tested 1,186 fresh fecal samples from white storks (N = 689), cattle egrets (Bubulcus ibis, N = 116) and mixed flocks of gulls (N = 381) as well as cloacal and oral swabs from five birds found dead. Seven samples contained AIV, five from gulls and one each from a stork and a cattle egret. Overall, AIV prevalence was 0.60%. No significant temporal variation was observed in AIV prevalence. Prevalence differed significantly among the sampled taxonomic groups, being highest in gulls (1.31%). H16N3 subtype was detected from a cattle egret and H11N9 subtype from a white stork, whereas gulls harbored both subtypes in addition to H11N3 subtype. H16 subtype detection in a cattle egret evidences its host range may not be restricted to gulls. Our results indicate that wild birds foraging at landfills may carry different LPAIV subtypes. PMID- 29124061 TI - Diagnostics of Thyroid Malignancy and Indications for Surgery in the Elderly and Younger Counterparts: Comparison of 3,749 Patients. AB - Background: It seems valuable for clinicians to know if diagnostics of thyroid malignancy (TM) and indications for surgery in the elderly patients differ from these in younger counterparts. Materials and Methods: Retrospective analysis of the medical records of 3,749 patients surgically treated for thyroid tumor. Data of patients with histopathology confirmed TM (n = 309) were studied. Results: The rate of cytological prediction to malignancy was more than three times higher in elderly women. Compression was a main reason for surgery in the elderly (p < 0.0001). The final diagnosis of malignancy was significantly higher in older women (p = 0.002). Clinical suspicion of malignancy was positively correlated with histopathological diagnosis in total group of women (r = 0.543, p < 0.001) and total group of men (r = 0.560, p < 0.001). The subgroup of the eldest TM patients included a significantly higher number of subjects with advanced cancer and primary tumor progression (p < 0.0001). Distant metastases were significantly more presented among the elderly patients (p = 0.032). Conclusions: The rate of cytological prediction to malignancy in elderly women is high. Tracheal compression is a common surgical indication in the elderly patients. The final diagnoses of malignancy predominate in elderly women. The oldest TM patients present a higher number of advanced thyroid tumors and distant metastases. PMID- 29124062 TI - Beating Heart Motion Accurate Prediction Method Based on Interactive Multiple Model: An Information Fusion Approach. AB - Robot-assisted motion compensated beating heart surgery has the advantage over the conventional Coronary Artery Bypass Graft (CABG) in terms of reduced trauma to the surrounding structures that leads to shortened recovery time. The severe nonlinear and diverse nature of irregular heart rhythm causes enormous difficulty for the robot to realize the clinic requirements, especially under arrhythmias. In this paper, we propose a fusion prediction framework based on Interactive Multiple Model (IMM) estimator, allowing each model to cover a distinguishing feature of the heart motion in underlying dynamics. We find that, at normal state, the nonlinearity of the heart motion with slow time-variant changing dominates the beating process. When an arrhythmia occurs, the irregularity mode, the fast uncertainties with random patterns become the leading factor of the heart motion. We deal with prediction problem in the case of arrhythmias by estimating the state with two behavior modes which can adaptively "switch" from one to the other. Also, we employed the signal quality index to adaptively determine the switch transition probability in the framework of IMM. We conduct comparative experiments to evaluate the proposed approach with four distinguished datasets. The test results indicate that the new proposed approach reduces prediction errors significantly. PMID- 29124063 TI - A Review of the Combination Therapy of Low Frequency Ultrasound with Antibiotics. AB - Single antimicrobial therapy has been unable to resist the global spread of bacterial resistance. Literatures of available in vitro and in vivo studies were reviewed and the results showed that low frequency ultrasound (LFU) has a promising synergistic bactericidal effect with antibiotics against both planktonic and biofilm bacteria. It also can facilitate the release of antibiotics from medical implants. As a noninvasive and targeted therapy, LFU has great potential in treating bacterial infections. However, more in-depth and detailed studies are still needed before LFU is officially applied as a combination therapy in the field of anti-infective treatment. PMID- 29124064 TI - Effect of Calcium Channel Blockers on Lower Urinary Tract Symptoms: A Systematic Review. AB - Background: Numerous medications are known to be associated with the development of lower urinary tract symptoms (LUTS). One such medication group is calcium channel blockers (CCB). Objective: To critically examine the literature regarding the involvement of CCB in manifestation of LUTS in humans. Methods: A systematic literature search was conducted on PubMed, SciELO, Scopus, and OpenGrey databases to find all potentially relevant research studies before August 2016. Results: Five studies met the inclusion criteria and were included in this review. Three out of five studies stated that CCB were involved in either precipitation or exacerbation of LUTS. As for the remaining two studies, one study found out that only the monotherapy of CCB was associated with increased prevalence of nocturia and voiding symptoms in young females, whereas the other study reported an inverse association of CCB with LUTS. The methodological quality of studies was considered high for four studies and low for one study. Conclusion: Healthcare providers should make efforts for an earlier identification of the individuals at risk of LUTS prior to the commencement of CCB therapy. Moreover, patients should be counselled to notify their healthcare provider if they notice urinary symptoms after the initiation of CCB. PMID- 29124066 TI - Corrigendum to "Expression of HIF-2alpha and VEGF in Cervical Squamous Cell Carcinoma and Its Clinical Significance". AB - [This corrects the article DOI: 10.1155/2016/5631935.]. PMID- 29124065 TI - Concentration-Response Relationship between PM2.5 and Daily Respiratory Deaths in China: A Systematic Review and Metaregression Analysis of Time-Series Studies. AB - The association between the particulate matters with aerodynamic diameter <= 2.5 MUm (PM2.5) and daily respiratory deaths, particularly the concentration-response pattern, has not been fully examined and established in China. We conducted a systematic review of time-series studies to compile information on the associations between PM2.5 concentration and respiratory deaths and used metaregression to assess the concentration-response relationship. Out of 1,957 studies screened, eleven articles in English and two articles in Chinese met the eligibility criteria. For single-day lags, per 10 MUg/m3 increase in PM2.5 concentration was associated with 0.30 [95% confidence interval (CI): 0.10, 0.50] percent increase in daily respiratory deaths; for multiday lags, the corresponding increase in respiratory deaths was 0.69 (95% CI: 0.55, 0.83) percent. Difference in the effects was observed between the northern cities and the south cities in China. No statistically significant concentration-response relationship between PM2.5 concentrations and their effects was found. With increasingly wider location coverage for PM2.5 data, it is crucial to further investigate the concentration-response pattern of PM2.5 effects on respiratory and other cause-specific mortality for the refinement and adaptation of global and national air quality guidelines and targets. PMID- 29124067 TI - Labor Induction with Orally Administrated Misoprostol: A Retrospective Cohort Study. AB - Introduction: One great challenge in obstetric care is labor inductions. Misoprostol has advantages in being cheap and stable at room temperature and available in resource-poor settings. Material and Methods: Retrospective cohort study of 4002 singleton pregnancies with a gestational age >=34 w at Sodersjukhuset, Stockholm, during 2009-2010 and 2012-2013. Previously used methods of labor induction were compared with misoprostol given as a solution to drink, every second hour. Main outcome is as follows: Cesarean Section (CS) rate, acid-base status in cord blood, Apgar score < 7,5', active time of labor, and blood loss > 1500 ml (PPH). Results: The proportion of CS decreased from 26% to 17% when orally given solution of misoprostol was introduced at the clinic (p < 0.001). No significant difference in the frequency of low Apgar score (p = 0.3), low aPh in cord blood (p = 0.1), or PPH (p = 0.4) between the different methods of induction was studied. After adjustment for different risk factor for CS the only method of induction which was associated with CS was dinoproston** (Propess(r)) (aor = 2.9 (1.6-5.2)). Conclusion: Induction of labor with misoprostol, given as an oral solution to drink every second hour, gives a low rate of CS, without affecting maternal or fetal outcome. PMID- 29124068 TI - Effects of Variety and Postharvest Handling Practices on Microbial Population at Different Stages of the Value Chain of Fresh Tomato (Solanum lycopersicum) in Western Terai of Nepal. AB - Background. Fresh vegetables such as tomato should have low microbial population for safe consumption and long storage life. The aerobic bacterial count (ABC) and coliform bacterial count (CBC), yeast, and mold population are the most widely used microbial indicators in fresh vegetables which should be lower than 4 log CFU g-1 for safe consumption. The stages of the supply chain, postharvest handling methods, and crop varieties had significant effects on microbial population. ABC, CBC, yeast, and mold population were significantly highest (P < 0.05) at retail market (5.59, 4.38, 2.60, and 3.14 log CFU g-1, resp.), followed by wholesale market (4.72, 4.71, 2.43, and 2.44 log CFU g-1, resp.), and were least at farm gate (3.89, 3.63, 2.38, and 2.03 log CFU g-1, resp.). Improved postharvest practices (washing in clean water and grading and packaging in clean plastic crate) helped to reduce ABC, CBC, and mold population by 2.51, 32.70, and 29.86 percentage as compared to the conventional method (no washing and no grading and packaging in mud plastered bamboo baskets). Among varieties, Pusa ruby had the lowest microbial load of 2.58, 4.53, 0.96, and 1.77 log CFU g-1 for ABC, CBC, yeast, and mold count, respectively. Significantly negative correlation (P < 0.05) was observed between fruit pH & ABC and pH & mold count. Although the microbial quality of fresh tomato is safe in the local market of western Terai of Nepal both in conventional and in improved practices however still it is essential to follow improved postharvest handling practices in production and marketing of newly introduced tomato cultivars (high-pH cultivars) for ensuring the safe availability of fresh tomato in the market. PMID- 29124069 TI - Sodium Fluorescein-Guided Resection under the YELLOW 560 nm Surgical Microscope Filter in Malignant Gliomas: Our First 38 Cases Experience. AB - Objective: Sodium fluorescein (FL) had been safely used in fluorescence-guided microsurgery for imaging various brain tumors. Under the YELLOW 560 nm surgical microscope filter, low-dose FL as a fluorescent dye helps in visualization. Our study investigated the safety and efficacy of this innovative technique in malignant glioma (MG) patients. Patients and Method: 38 patients suffering from MGs confirmed by pathology underwent FL-guided resection under YELLOW 560 nm surgical microscope filter. We retrospectively analyzed the clinical characters, microsurgery procedure, extent of resection, pathology of MGs, progression-free survival (PFS), and overall survival (OS). Results: Thirty-eight patients had MGs (10 WHO grade III, 28 WHO grade IV). With YELLOW 560 nm surgical microscope filter combined with neuronavigation, sodium fluorescein-guided gross total resection (GTR) was achieved in 35 (92.1%) patients and subtotal resection in 3 (7.69%). The sensitivity and specificity of FL were 94.4% and 88.6% regardless of radiographic localization. Intraoperatively, 10 biopsies (10/28 FL[+]) showed "low" or "high" fluorescence in non-contrast-enhancement region and are also confirmed by pathology. Our data showed 6-month PFS of 92.3% and median survival of 11 months. Conclusion: FL-guided resection of MGs under the YELLOW 560 nm surgical microscope filter combined with neuronavigation was safe and effective, especially in non-contrast-MRI regions. It is feasible for improving the extent of resection in MGs especially during emergency cases. PMID- 29124071 TI - Erratum to "Effect of High Dietary Tryptophan on Intestinal Morphology and Tight Junction Protein of Weaned Pig". AB - [This corrects the article DOI: 10.1155/2016/2912418.]. PMID- 29124070 TI - Exclusive Enteral Nutrition Induces Remission in Pediatric Crohn's Disease via Modulation of the Gut Microbiota. AB - Exclusive enteral nutrition (EEN) has been proven to be effective and safe in treating pediatric Crohn's disease (CD). EEN induces pediatric CD remission possibly through three pathways: (1) direct anti-inflammatory effects, (2) improved epithelial barrier function, and (3) modulation of the gut microbiota. Recent studies have demonstrated that modulation of the gut microbiota plays a major role in EEN-induced remission. Variations of microbial components, which directly influence the diversity and metabolic functions of the gut microbiota, are closely associated with the immunological conditions of the gut and the susceptibility to diseases. The reduction of proinflammatory microbial components and harmful microbial metabolites after EEN treatment greatly decreases the inflammatory injuries of the gut. PMID- 29124073 TI - First Necrotizing Fasciitis Caused by Haemophilus influenza Serotype a. AB - Necrotizing fasciitis (NF) is an infrequently encountered skin infection that has high morbidity and mortality, even with prompt medical and surgical intervention. We describe the case of a 67-year-old male presenting with significant NF in his left lower extremity, despite aggressive surgical intervention, and included multiple surgical debridements, ACell Matrix, split-thickness, and negative wound VAC therapy. Ultimately, this patient required a below the knee amputation. This is the first documented case of Haemophilus influenza type a causing NF. PMID- 29124072 TI - Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation. AB - The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (MDS) can potentially confer a growth advantage to individual cellular clones. Currently, the recommended treatment for patients with high-risk MDS is the methylation agent decitabine (DAC), a drug that can induce the reexpression of silenced tumor suppressor genes. We investigated the effects of DAC treatment on the myeloid MDS cell line SKM-1 and investigated the role of FOXO3A, a potentially tumor-suppressive transcription factor, by silencing its expression prior to DAC treatment. We found that FOXO3A exists in an inactive, hyperphosphorylated form in SKM-1 cells, but that DAC both induces FOXO3A expression and reactivates the protein by reducing its phosphorylation level. Furthermore, we show that this FOXO3A activation is responsible for the DAC induced differentiation of SKM-1 cells into monocytes, as well as for SKM-1 cell cycle arrest, apoptosis, and autophagy. Collectively, these results suggest that FOXO3A reactivation may contribute to the therapeutic effects of DAC in MDS. PMID- 29124074 TI - Rare Case of Duodenal Metastasis From Pulmonary Squamous Cell Carcinoma. AB - Pulmonary squamous cell carcinoma is the second most common non-small cell malignancy of the lung. It commonly metastasizes to the adrenal glands, bone, liver, brain, and kidneys. Most occurrences of metastatic squamous cell carcinoma involving the gastrointestinal tract originate from primary lung tumors. Metastasis to the duodenum, however, is exceedingly rare, with very few cases of stomach or duodenal involvement described in the literature. We report the case of a patient with stage IV pulmonary squamous cell carcinoma metastasizing to the duodenum with an uncommon presentation to add to the paucity of literature available regarding this rare finding. PMID- 29124076 TI - Clinical Outcomes of Hip Arthroscopic Surgery in Patients With Femoral Retroversion: A Matched Study to Patients With Normal Femoral Anteversion. AB - Background: Femoral retroversion has been noted as a possible risk factor for poor clinical results after hip arthroscopic surgery. Purpose: To compare the outcomes of the arthroscopic treatment of hip abnormalities in patients with femoral retroversion to patients with femoral anteversion between 10 degrees and 20 degrees . Study Design: Cohort study; Level of evidence, 3. Methods: Between November 2011 and September 2013, 790 hip arthroscopic procedures were performed at a single institution. Of these, 59 hips (7.5%) were located in patients with femoral version <=0 degrees , calculated using preoperative magnetic resonance imaging. These patients were pair matched, based on body mass index +/-5 kg/m2, age +/-5 years, and Tonnis grade, with 59 patients with femoral anteversion between 10 degrees and 20 degrees . Exclusion criteria included Perthes disease, inflammatory arthritis, slipped capital femoral epiphysis, previous hip surgery, abductor repair, lateral center-edge angle <20 degrees , Tonnis grade >1, and acetabular profunda or protrusio. Patient-reported outcomes (PROs) were recorded preoperatively, at 3 months postoperatively, and annually thereafter. The PROs utilized were the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), and Hip Outcome Score-Sports-Specific Subscale (HOS-SSS). The visual analog scale (VAS) was collected to assess the patients' pain; patient satisfaction scores (0-10) were also collected. Radiographs were collected at the above time intervals as well. Results: Two patients from the control group and 1 patient from the retroverted group required total hip arthroplasty at a mean 19.5 and 26.3 months, respectively. Both groups demonstrated significant improvement from their preoperative state in all PRO and VAS scores (P < .001). No differences in preoperative, postoperative, or change in PRO and VAS scores between the groups were noted. Conclusion: Patients with femoral retroversion reported similar outcomes compared to patients with normal femoral version when undergoing hip arthroscopic surgery. Both groups had similar improvements from the preoperative state. PMID- 29124075 TI - The Role of Lateral Extra-articular Tenodesis in Primary Anterior Cruciate Ligament Reconstruction: A Systematic Review With Meta-analysis and Best-Evidence Synthesis. AB - Background: The role of lateral extra-articular tenodesis (LEAT) to augment primary anterior cruciate ligament reconstruction (ACLR) remains controversial. Purpose: To determine whether the addition of LEAT to primary ACLR provides greater control of rotational laxity and improves clinical outcomes compared with ACLR alone and to assess the impact of early versus delayed ACLR. Study Design: Systematic review; Level of evidence, 3. Methods: Two reviewers independently searched 7 databases for randomized and nonrandomized clinical studies comparing ACLR plus LEAT versus ACLR alone. Animal, cadaveric, and biomechanical studies; revision or repair procedures; and studies using synthetic ligaments and multiligamentous-injured knees were excluded. Risk of bias was assessed with a modified Downs and Black checklist. The primary outcome was postoperative pivot shift. These data were pooled by use of a fixed-effects meta-analysis model. The studies were divided into delayed (>12 months) and early (<=12 months) reconstruction groups for meta-analysis. A best-evidence synthesis was performed on the remaining outcome measures. Results: Of 387 titles identified, 11 articles were included (5 of high quality). Meta-analysis of postoperative pivot shift in 3 studies of delayed primary ACLR showed a statistically significant difference for the pivot-shift test in favor of ACLR with LEAT (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.24-0.81; P = .008; I2 = 0). Meta-analysis of 5 studies of early primary ACLR found no statistically significant difference with the addition of LEAT (OR, 0.60; 95% CI, 0.33-1.09; P = .10; I2 = 33%). Insufficient evidence was available to determine whether the addition of LEAT had any effect on clinical, objective, subjective, and functional outcomes. Conclusion: In primary ACLR, no evidence is available showing additional benefit of LEAT in reducing the postoperative pivot shift in early reconstructions (<=12 months); however, LEAT may have a role in delayed ACLR. Strong evidence exists that a combined ACLR and LEAT reduces lateral femoral translation, but there is insufficient evidence to identify any benefit for other clinical outcomes. PMID- 29124077 TI - Can a Clinical Examination Demonstrate Intramuscular Tendon Involvement in Acute Hamstring Injuries? AB - Background: Involvement of the intramuscular (central) tendon in acute hamstring injuries, as detected on magnetic resonance imaging (MRI), may prolong recovery times. To date, it is unclear whether hamstring injuries exhibiting intramuscular tendon involvement can be identified though routine clinical examinations that assess flexibility and strength. Purpose: To test whether MRI-detected intramuscular tendon involvement could be identified by a clinical assessment of muscle strength and flexibility. Study Design: Case-control study; Level of evidence, 3. Methods: Participants were drawn from a multicenter randomized controlled trial on the effect of platelet-rich plasma in acute hamstring injuries. Clinical parameters assessed within 5 days of injury were active knee extension and passive straight-leg raise for hamstring flexibility and isometric knee flexion force with 15 degrees and 90 degrees of knee flexion. Also, 1.5-T MRI of the thigh was performed within 5 days of injury and was evaluated for the presence of different types of intramuscular tendon involvement. One-way analysis of variance was used to determine whether clinical parameters could discriminate injuries with intramuscular tendon involvement from those without such involvement. Results: A total of 74 acute hamstring injuries were included, with 52 (70.3%) injuries affecting the myotendinous junction. Injuries exhibiting intramuscular tendon discontinuity on MRI had an increased mean absolute flexibility deficit for active knee extension (20.4 degrees +/- 14.9 degrees vs 10.7 degrees +/- 9.0 degrees , respectively; P = .006) and decreased mean strength at 15 degrees (62.2 +/- 26.7 N vs 76.6 +/- 22.5 N, respectively; P = .05) compared with injuries without intramuscular tendon discontinuity. Flexibility and strength showed major overlap and variance among injuries with and without intramuscular tendon involvement. Conclusion: Hamstring flexibility and strength cannot be used to discriminate the presence of intramuscular tendon involvement. PMID- 29124078 TI - Demineralized Bone Matrix to Augment Tendon-Bone Healing: A Systematic Review. AB - Background: Following injury to the rotator cuff and anterior cruciate ligament, a direct enthesis is not regenerated, and healing occurs with biomechanically inferior fibrous tissue. Demineralized bone matrix (DBM) is a collagen scaffold that contains growth factors and is a promising biological material for tendon and ligament repair because it can regenerate a direct fibrocartilaginous insertion via endochondral ossification. Purpose: To provide a comprehensive review of the literature investigating the use of DBM to augment tendon-bone healing in tendon repair and anterior cruciate ligament reconstruction (ACLR). Study Design: Systematic review. Methods: Electronic databases (MEDLINE and EMBASE) were searched for preclinical and clinical studies that evaluated the use of DBM in tendon repair and ACLR. Search terms included the following: ("demineralized bone matrix" OR "demineralized cortical bone") AND ("tissue scaffold" OR "tissue engineering" OR "ligament" OR "tendon" OR "anterior cruciate ligament" OR "rotator cuff"). Peer-reviewed articles written in English were included, and no date restriction was applied (searches performed February 10, 2017). Methodological quality was assessed with peer-reviewed scoring criteria. Results: The search strategy identified 339 articles. After removal of duplicates and screening according to inclusion criteria, 8 studies were included for full review (tendon repair, n = 4; ACLR, n = 4). No human clinical studies were identified. All 8 studies were preclinical animal studies with good methodological quality. Five studies compared DBM augmentation with non-DBM controls, of which 4 (80%) reported positive findings in terms of histological and biomechanical outcomes. Conclusion: Preclinical evidence indicates that DBM can improve tendon-bone healing, although clinical studies are lacking. A range of animal models of tendon repair and ACLR showed that DBM can re-create a direct fibrocartilaginous enthesis, although the animal models are not without limitations. Before clinical trials are justified, research is required that determines the best source of DBM (allogenic vs xenogenic) and the best form of DBM (demineralized cortical bone vs DBM paste) to be used in them. PMID- 29124079 TI - Identifying more reliable parameters for the detection of change during the follow-up of mild to moderate keratoconus patients. AB - Background: Reaching a consensus on which parameters are most reliable at detecting progressive keratoconus patients with serial topography imaging is not evident. The aim of the study was to isolate the parameters best positioned to detect keratoconus progression using the Pentacam HR(r) measures based on the respective limits of repeatability and range of measurement. Method: Using the Pentacam HR(r), a tolerance index was calculated on anterior segment parameters in healthy and keratoconic eyes. The tolerance index provides a scale from least to most affected parameters in terms of measurement noise relative to that observed in healthy eyes. Then, based on the "number of increments" from no disease to advanced disease, a relative utility (RU) score was also calculated. RU values close to 1 indicate parameters best positioned to detect a change in keratoconic eyes. Results: The tolerance index values indicated that 36% of ocular parameters for keratoconic eyes had repeatability limits which were wider than normative limits (worse), but 28% of the ocular parameters were narrower than normative limits (better). Considering only those parameters with a RU greater than 0.95, a small number of parameters were within this range, such as corneal curvature and asphericity indices. Conclusions: This study demonstrates that measurement error in keratoconic eyes is significantly greater than healthy eyes. Indices implemented here provide guidance on the levels of expected precision in keratoconic eyes relative to healthy eyes to aid clinicians in distinguishing real change from noise. Importantly maximal keratometry (Kmax), central corneal thickness (CCT) and thinnest corneal thickness (TCT) were highlighted as problematic indices for the follow-up of keratoconus in terms of repeatability. PMID- 29124080 TI - Demographic and Mental Health Characteristics of Individuals Who Present to Community Health Clinics With Substance Misuse. AB - Introduction: Community health clinics (CHCs) are an opportune setting to identify and treat substance misuse. This study assessed the characteristics of patients who presented to a CHC with substance misuse. Methods: Personnel at a large CHC administered a 5-question screener to patients between June 3, 2014, and January 15, 2016, to assess past 3-month alcohol use, prescription opioid misuse, or illicit drug use. We stratified screen-positive patients into 4 diagnostic groups: (1) probable alcohol use disorder (AUD) and no comorbid opioid use disorder (OUD); (2) probable heroin use disorder; (3) probable prescription OUD, with or without comorbid AUD; and (4) no probable substance use disorder. We describe substance use and mental health characteristics of screen-positive patients and compare the characteristics of patients in the diagnostic groups. Results: Compared to the clinic population, screen-positive patients (N = 733) included more males (P < .0001) and had a higher prevalence of probable bipolar disorder (P < .0001) and schizophrenia (P < .0001). Eighty-seven percent of screen-positive patients had probable AUD or OUD; only 7% were currently receiving substance use treatment. The prescription opioid and heroin groups had higher rates of past bipolar disorder and consequences of mental health conditions than the alcohol only or no diagnosis groups (P < .0001). Conclusions: Patients presenting to CHCs who screen positive for alcohol or opioid misuse have a high likelihood of having an AUD or OUD, with or without a comorbid serious mental illness. Community health clinics offering substance use treatment may be an important resource for addressing unmet need for substance use treatment and comorbid mental illness. PMID- 29124081 TI - An Uncommon Cause of Severe Upper Airway Obstruction in a Toddler. PMID- 29124082 TI - Is osteoporosis an autoimmune mediated disorder? AB - The last two decades have marked a growing understanding of the interaction occurring between bone and immune cells. The chronic inflammation and immune system dysfunction commonly observed to occur during the ageing process and as part of a range of other pathological conditions, commonly associated with osteoporosis has led to the recognition of these processes as important determinants of bone disease. This is further supported by the recognition that the immune and bone systems in fact share regulatory mechanisms and progenitor molecules. Research into this complex synergy has provided a better understanding of the immunopathogenesis underlying bone diseases such as osteoporosis. However, existing research has largely focussed on delineating the role played by inflammation in pathogenic bone destruction, despite increasing evidence implicating autoantibodies as important drivers of osteoporosis. This review shall attempt to provide a comprehensive overview of existing research examining the role played by autoantibodies in osteoporosis in order to determine the potential for further research in this area. Autoantibodies represent promising targets for the improved treatment and diagnosis of inflammatory bone loss. PMID- 29124083 TI - Osteoprotegerin autoantibodies do not predict low bone mineral density in middle aged women. AB - Purpose: Autoantibodies against osteoprotegerin (OPG) have been associated with osteoporosis. The aim was to develop an immunoassay for OPG autoantibodies and test their diagnostic usefulness of identifying women general population with low bone mineral density. Methods: Included were 698 women at mean age 55.1 years (range 50.4-60.6) randomly selected from the general population. Measurement of wrist bone mineral density (g/cm2) was performed of the non-dominant wrist by dual-energy X-ray absorptiometry (DXA). A T-score < - 2.5 was defined as having a low bone mineral density. Measurements of OPG autoantibodies were carried by radiobinding assays. Cut-off levels for a positive value were determined from the deviation from normality in the distribution of 398 healthy blood donors representing the 99.7th percentile. Results: Forty-five of the 698 (6.6%) women were IgG-OPG positive compared with 2 of 398 (0.5%) controls (p < 0.0001) and 35 of the 698 (5.0%) women had a T-score < - 2.5. There was no difference in bone mineral density between IgG-OPG positive (median 0.439 (range 0.315-0.547) g/cm2) women and IgG-OPG negative (median 0.435 (range 0.176-0.652) g/cm2) women (p = 0.3956). Furthermore, there was neither a correlation between IgG-OPG levels and bone mineral density (rs = 0.1896; p = 0.2068) nor T-score (rs = 0.1889; p = 0.2086). Diagnostic sensitivity and specificity of IgG-OPG for low bone mineral density were 5.7% and 92.9%, and positive and negative predictive values were 7.4% and 90.8%, respectively. Conclusion: Elevated OPG autoantibody levels do not predict low bone mineral density in middle-aged women selected from the general population. PMID- 29124084 TI - Second-harmonic generation imaging of collagen in ancient bone. AB - Second-harmonic generation imaging (SHG) captures triple helical collagen molecules near tissue surfaces. Biomedical research routinely utilizes various imaging software packages to quantify SHG signals for collagen content and distribution estimates in modern tissue samples including bone. For the first time using SHG, samples of modern, medieval, and ice age bones were imaged to test the applicability of SHG to ancient bone from a variety of ages, settings, and taxa. Four independent techniques including Raman spectroscopy, FTIR spectroscopy, radiocarbon dating protocols, and mass spectrometry-based protein sequencing, confirm the presence of protein, consistent with the hypothesis that SHG imaging detects ancient bone collagen. These results suggest that future studies have the potential to use SHG imaging to provide new insights into the composition of ancient bone, to characterize ancient bone disorders, to investigate collagen preservation within and between various taxa, and to monitor collagen decay regimes in different depositional environments. PMID- 29124085 TI - Quantum capacitance, electrostatic potential, electronic and structural data for bare and functionalized niobium carbide MXenes. AB - The data reported in this article are structural and physicochemical properties for bare and F, O, OH and CH3O-functionalized Nb n+1C n (n = 1, 2, 3 and 4) MXenes. The structural properties are presented as top views and side views from the X direction of the optimal structures of studied MXenes. The physicochemical properties include quantum capacitances, electrostatic potentials and electronic properties such as the projected density of states (PDOS) and band structures. Further interpretation and discussion of these data can be obtained from the article entitled "Possibility of bare and functionalized niobium carbide MXenes for electrode materials of supercapacitors and field emitters" (Xin and Yu, 2017) [1]. PMID- 29124086 TI - The Pediatric Ependymoma Protein Database (PEPD). AB - Proteomics, through application of modern high-end mass spectrometric (MS) approaches, offers the advantage of in-depth analysis of cancer tissues regarding their protein composition. Pediatric brain tumor malignancies are scarcely approached by modern holistic technologies (e.g. genomics, proteomics) due to rarity of samples and most importantly difficulty in their collection. Ependymoma, is the third most common tumor in children and is thought to arise from ependymal cells in the wall of the cerebral ventricles or the spinal canal. Due to the heterogeneity of the disease its biological characteristics remain largely unknown and prognostic factors are basically based on clinical and histological criteria. Through application of a modified nanoLC-MS/MS analysis experimental approach we achieved, for the first time, the in-depth examination of the pediatric ependymoma tissue proteome. In the present article we report on the construction of a high-confidence database; the Pediatric Ependymoma Protein Database (PEPD), including 4,157 protein groups originating from the identification and analysis of more than 15,000 peptides. The PEPD offers a first step towards targeted protein validation of the protein content of this specific devastating disease affecting the young population. PMID- 29124087 TI - Annotating and quantifying pri-miRNA transcripts using RNA-Seq data of wild type and serrate-1 globular stage embryos of Arabidopsis thaliana. AB - The genome annotation for the model plant Arabidopsis thaliana does not include the primary transcripts from which MIRNAs are processed. Here we present and analyze the raw mRNA sequencing data from wild type and serrate-1 globular stage embryos of A. thaliana, ecotype Columbia. Because SERRATE is required for pri miRNA processing, these precursors accumulate in serrate-1 mutants, facilitating their detection using standard RNA-Seq protocols. We first use the mapping of the RNA-Seq reads to the reference genome to annotate the potential primary transcripts of MIRNAs expressed in the embryo. We then quantify these pri-miRNAs in wild type and serrate-1 mutants. Finally, we use differential expression analysis to determine which are up-regulated in serrate-1 compared to wild type, to select the best candidates for bona fide pri-miRNAs expressed in the globular stage embryos. In addition, we analyze a previously published RNA-Seq dataset of wild type and dicer-like 1 mutant embryos at the globular stage [1]. Our data are interpreted and discussed in a separate article [2]. PMID- 29124088 TI - Considerations and code for partial volume correcting [18F]-AV-1451 tau PET data. AB - [18F]-AV-1451 is a leading tracer used with positron emission tomography (PET) to quantify tau pathology. However, [18F]-AV-1451 shows "off target" or non-specific binding, which we define as binding of the tracer in unexpected areas unlikely to harbor aggregated tau based on autopsy literature [1]. Along with caudate, putamen, pallidum and thalamus non-specific binding [2], [3], we have found binding in the superior portion of the cerebellar gray matter, leading us to use inferior cerebellar gray as the reference region. We also addressed binding in the posterior portion of the choroid plexus. PET signal unlikely to be associated with tau also occurs in skull, meninges and soft tissue (see e.g. [4]). We refer to [18F]-AV-1451 binding in the skull and meninges as extra-cortical hotspots (ECH) and find them near lateral and medial orbitofrontal, lateral occipital, inferior and middle temporal, superior and inferior parietal, and inferior cerebellar gray matter. Lastly, the choroid plexus also shows non-specific binding that bleeds into hippocampus. We are providing the code (http://www.runmycode.org/companion/view/2798) used to create different regions of interest (ROIs) that we then used to perform Partial Volume Correction (PVC) using the Rousset geometric transfer matrix method (GTM, [5]). This method was used in the companion article, "Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's Disease" ([6], DOI 10.1016/j.neuroimage.2017.05.058). PMID- 29124089 TI - Data on the chemical properties of commercial fish sauce products. AB - This data article reports on the chemical properties of commercial fish sauce products associated with the fish sauce taste and flavor. All products were analyzed in triplicate. Dried solid content was analyzed by moisture analyzer. Fish sauce salinity was determined by a salt meter. pH was measured using a pH meter. The acidity was determined using a titration assay. Amino nitrogen and total nitrogen were evaluated using a titration assay and Combustion-type nitrogen analyzer, respectively. The analyzed products originated from Japan, Thailand, Vietnam, China, the Philippines, and Italy. Data on the chemical properties of the products are provided in table format in the current article. PMID- 29124090 TI - Practice variation amongst preventive child healthcare professionals in the prevention of child maltreatment in the Netherlands: Qualitative and quantitative data. AB - This article provides both qualitative and quantitative data on practice variation amongst preventive child healthcare professionals in the prevention of child maltreatment in the Netherlands. Qualitative data consist of topics identified during interviews with 11 experts (with quotes), resulting in an online survey. The quantitative data are survey responses from 1104 doctors and nurses working in 29 preventive child healthcare organizations. Additionally, the interview topic list, the qualitative data analysis methodology, the survey (in English and Dutch) and anonymized raw survey data (http://hdl.handle.net/10411/5LJOGH) are provided as well. This data-in-brief article accompanies the paper "Variation in prevention of child maltreatment by Dutch child healthcare professionals" by Simeon Visscher and Henk van Stel [1]. PMID- 29124091 TI - Real-time data for estimating a forward-looking interest rate rule of the ECB. AB - The purpose of the data presented in this article is to use it in ex post estimations of interest rate decisions by the European Central Bank (ECB), as it is done by Bletzinger and Wieland (2017) [1]. The data is of quarterly frequency from 1999 Q1 until 2013 Q2 and consists of the ECB's policy rate, inflation rate, real output growth and potential output growth in the euro area. To account for forward-looking decision making in the interest rate rule, the data consists of expectations about future inflation and output dynamics. While potential output is constructed based on data from the European Commission's annual macro-economic database, inflation and real output growth are taken from two different sources both provided by the ECB: the Survey of Professional Forecasters and projections made by ECB staff. Careful attention was given to the publication date of the collected data to ensure a real-time dataset only consisting of information which was available to the decision makers at the time of the decision. PMID- 29124092 TI - Dataset of the livability performance of the city of Birmingham, UK, as measured by its citizen wellbeing, resource security, resource efficiency and carbon emissions. AB - This data article presents the UK City LIFE1 data set for the city of Birmingham, UK. UK City LIFE1 is a new, comprehensive and holistic method for measuring the livable sustainability performance of UK cities. The Birmingham data set comprises 346 indicators structured simultaneously (1) within a four-tier, outcome-based framework in order to aid in their interpretation (e.g., promote healthy living and healthy long lives, minimize energy use, uncouple economic vitality from CO2 emissions) and (2) thematically in order to complement government and disciplinary siloes (e.g., health, energy, economy, climate change). Birmingham data for the indicators are presented within an Excel spreadsheet with their type, units, geographic area, year, source, link to secondary data files, data collection method, data availability and any relevant calculations and notes. This paper provides a detailed description of UK city LIFE1 in order to enable comparable data sets to be produced for other UK cities. The Birmingham data set is made publically available at http://epapers.bham.ac.uk/3040/ to facilitate this and to enable further analyses. The UK City LIFE1 Birmingham data set has been used to understand what is known and what is not known about the livable sustainability performance of the city and to inform how Birmingham City Council can take action now to improve its understanding and its performance into the future (see "Improving city-scale measures of livable sustainability: A study of urban measurement and assessment through application to the city of Birmingham, UK" Leach et al. [2]). PMID- 29124093 TI - Analysis of the conformations of the HIV-1 protease from a large crystallographic data set. AB - The HIV-1 protease performs essential roles in viral maturation by processing specific cleavage sites in the Gag and Gag-Pol precursor polyproteins to release their mature forms. Here the analysis of a large HIV-1 protease data set (containing 552 dimer structures) are reported. These data are related to article entitled "Conformations of the HIV-1 protease: a crystal structure data set analysis" (Palese, 2017) [1]. PMID- 29124094 TI - A novel reversible logic gate and its systematic approach to implement cost efficient arithmetic logic circuits using QCA. AB - Quantum-dot cellular automata, is an extremely small size and a powerless nanotechnology. It is the possible alternative to current CMOS technology. Reversible QCA logic is the most important issue at present time to reduce power losses. This paper presents a novel reversible logic gate called the F-Gate. It is simplest in design and a powerful technique to implement reversible logic. A systematic approach has been used to implement a novel single layer reversible Full-Adder, Full-Subtractor and a Full Adder-Subtractor using the F-Gate. The proposed Full Adder-Subtractor has achieved significant improvements in terms of overall circuit parameters among the most previously cost-efficient designs that exploit the inevitable nano-level issues to perform arithmetic computing. The proposed designs have been authenticated and simulated using QCADesigner tool ver. 2.0.3. PMID- 29124095 TI - Circular transcriptome sequencing of the middle silk gland and posterior silk gland in the Bombyx mori. AB - Circular transcriptome sequencing of the middle silk gland (MSG) and posterior silk gland (PSG) in the Bombyx mori are presented. The middle silk gland and posterior silk gland were collected from the third day of fifth-instar B.mori larvae. The circular RNAs enriched by using RNase R to degrade the linear RNA molecules, and circular RNA sequencing (circRNA-seq) was performed using an Illumina Hiseq. 2500 sequencing platform. Samples are described in the SRA portal (SRP100385) and FASTQ files have been deposited in Sequence Read Archive (accession numbers: SRX2577343 and SRX2577342). The interpretation of these data is presented in the following research article: "Identification of circular RNA in the Bombyx mori silk gland" [1] (Gan et al., 2017). PMID- 29124096 TI - Implicit Theory of Mind across the life span - Anticipatory looking data. AB - In this work, we present a collection of data from three replication studies of anticipatory looking false belief tasks measuring implicit Theory of Mind. Two paradigms, by Southgate & Senju and Surian & Geraci were replicated in two independent labs. Eye-tracking data was collected and processed in line with the original procedures to allow for an investigation of effects of false belief processing on looking times and first saccades. PMID- 29124097 TI - Safety data on single application of emu and macadamia nut oil on human skin. AB - This data article provides the results of skin sensitization testing for emu and macadamia nut oil on 20 participants (ages 22-59 years old), including 3 men and 17 women. The test was carried out by performing a standard patch test using a Finn Chamber on Scanpor tape. The oils were applied to the participant's back using the tape and left in place for 24 h. After 1- and 24-h from removal of the tape, the reaction of the participant's skin was judged based on a scoring method recommended by Japanese Patch Test Research Group. Results are shown in table format. PMID- 29124098 TI - Forest harvest dataset for northern Colorado Rocky Mountains (1984-2015) generated from a Landsat time series and existing forest harvest records. AB - This dataset provides a shapefile containing approximately 3500 polygons with the location, extent, size, and year of clearcut harvest events occurring between 1984 and 2015 in forested areas of the northern Colorado, Landsat WRS-2 scene Path 034, Row 032. Harvest events were modeled and mapped using a 32 year time series of Landsat imagery, the LandTrendr algorithm, and ancillary datasets. The dataset also conveys information on the elevation, aspect, ownership, distance to roads, and the watershed where each harvest event occurred. PMID- 29124099 TI - Data on the expression and insulin-stimulated phosphorylation of IRS-1 by miR-96 in L6-GLUT4myc myocytes. AB - Diets containing a high saturated fatty acid (SFA) increase the risk of metabolic diseases, and microRNAs (miRNAs) induced by SFA have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. In a previous report, miR 96 is found to be upregulated by SFA and involved in the suppression of insulin signaling intermediates, leading to insulin resistance in hepatocytes (Yang et al., 2016) [1]. This article presents the accompanying data collected from L6 GLUT4myc myocytes to determine the effects of miR-96 on insulin signaling in skeletal muscle cells. The transfection of miR-96 decreased the expression of IRS 1 in myocytes. Accordingly, miR-96 inhibited the insulin-stimulated phosphorylation of IRS-1, which led to an impairment of insulin signaling. More detailed analysis and understanding of the roles of miR-96 in diet-induced insulin resistance can be found in "Induction of miR-96 by dietary saturated fatty acids exacerbates hepatic insulin resistance through the suppression of INSR and IRS-1" (Yang et al., 2016) [1]. PMID- 29124100 TI - Data on conceptual design of cryogenic energy storage system combined with liquefied natural gas regasification process. AB - This paper describes data of an integrated process, cryogenic energy storage system combined with liquefied natural gas (LNG) regasification process. The data in this paper is associated with the article entitled "Conceptual Design and Exergy Analysis of Combined Cryogenic Energy Storage and LNG Regasification Processes: Cold and Power Integration" (Lee et al., 2017) [1]. The data includes the sensitivity case study dataset of the air flow rate and the heat exchanging feasibility data by composite curves. The data is expected to be helpful to the cryogenic energy process development. PMID- 29124101 TI - Data set of proteomic analysis of food borne pathogens after treatment with the disinfectants based on pyridoxal oxime derivatives. AB - Food borne pathogens, namely the Gram-positive bacterium Bacillus subtilis and the Gram-negative bacterium Escherichia coli, were grown under the inhibition with four different disinfectants based on chloride and bromide salts of pyridinium oxime. Bacterial samples were subjected to the sequential extraction of proteins and the in-solution tryptic digestion of obtained extracts was performed prior to the identification of proteins with LC-ESI-MS/MS. Proteomic analysis identified up- and down-regulated proteins in these bacteria after treatment with each compound. The tables with differently expressed proteins are presented with this article. PMID- 29124102 TI - Predicting forest floor and woody fuel consumption from prescribed burns in southern and western pine ecosystems of the United States. AB - We present pre-burn biomass and consumption data from 60 prescribed burns in the southeastern and western United States. The datasets include pre-burn biomass in Mg/ha by fuel category: herbaceous fuels, shrubs, 1-hr, 10-hr, 100-hr, 1000-hr, 10,000-hr, and > 10,000-hr downed wood, litter and duff. Pre-burn depth (cm) and reduction (cm) are provided for litter and duff layers. Day-of-burn fuel moistures and weather are also listed by site. PMID- 29124103 TI - Data on the agitation of a viscous Newtonian fluid by radial impellers in a cylindrical tank. AB - In this paper, the data assembled concerning the agitation of a Newtonian fluid in a cylindrical vessel is disclosed. The stirred vessel is not provided with baffles and has a flat-bottom. The data presents some information on the characteristics of two impellers: a six-blade Rushton turbine and a six-blade paddle impeller. The flow patterns generated by both impellers are depicted and compared. Also, the power required when changing the impeller rotational speed is given. The data summarized here via three-dimensional calculations of velocities and viscous dissipation in the whole volume of the tank provides additional knowledge for the best choice of impellers for each industrial process. PMID- 29124104 TI - Built Environment and Active Commuting: Rural-Urban Differences in the U.S. AB - The purpose of this research was to investigate rural-urban differences in participation rates in three modes of active commuting (AC) and their built environmental correlates. The 2010 Census supplemented with other datasets were used to analyze AC rates in percent of workers age 16+ walking, biking, or taking public transportation to work in 70,172 Census tracts, including 12,844 rural and 57,328 urban. Random-intercept factional logit regressions were used to account for zero-inflated data and for clustering of tracts within counties. We found that the average AC rates were 3.44% rural and 2.77% urban (p<0.01) for walking to work, 0.40% rural and 0.58% urban (p<0.01) for biking to work, and 0.59% rural and 5.86% urban (p<0.01) for public transportation to work. Some environmental variables had similar relationships with AC in rural and urban tracts, such as a negative association between tract greenness and prevalence of walking to work. Others had opposite correlational directions for rural vs. urban, such as street connectivity for walking to work and population density for both walking to work and public transportation to work. We concluded that rurality is an important moderator in AC-environment relationships. In developing strategies to promote AC, attention needs to be paid to rural-urban differences to avoid unintended consequences. PMID- 29124105 TI - Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H. AB - Introduction: Brain distribution of synaptic vesicle protein 2A was measured with fluorine-18 UCB-H ([18F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume. Results: [18F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship. Discussion: The cerebral distribution of [18F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([11C]UCB-J). An accurate [18F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging. PMID- 29124106 TI - Gamma rhythm low field magnetic stimulation alleviates neuropathologic changes and rescues memory and cognitive impairments in a mouse model of Alzheimer's disease. AB - Introduction: The abnormal amyloid beta (Abeta) accumulation and Abeta-related neural network dysfunction are considered central to the pathogenesis of Alzheimer's disease (AD) at the early stage. Deep-brain reachable low field magnetic stimulation (DMS), a novel noninvasive approach that was designed to intervene the network activity in brains, has been found to alleviate stress related cognitive impairments. Methods: Amyloid precursor protein/presenilin-1 transgenic mice (5XFAD) were treated with DMS, and cognitive behavior and AD-like pathologic changes in the neurochemical and electrophysiological properties in 5XFAD mice were assessed. Results: We demonstrate that DMS treatment enhances cognitive performances, attenuates Abeta load, upregulates postsynaptic density protein 95 level, and promotes hippocampal long-term potentiation in 5XFAD mouse brain. Intriguingly, the gamma burst magnetic stimulation reverses the aberrant gamma oscillations in the transgenic hippocampal network. Discussion: This work establishes a solid foundation for the effectiveness of DMS in treating AD and proposes a future study of gamma rhythm stimulation on reorganizing rhythmic neural activity in AD brain. PMID- 29124107 TI - A general neurologist's perspective on the urgent need to apply resilience thinking to the prevention and treatment of Alzheimer's disease. AB - The goal of this article was to look at the problem of Alzheimer's disease (AD) through the lens of a socioecological resilience-thinking framework to help expand our view of the prevention and treatment of AD. This serious and complex public health problem requires a holistic systems approach. We present the view that resilience thinking, a theoretical framework that offers multidisciplinary approaches in ecology and natural resource management to solve environmental problems, can be applied to the prevention and treatment of AD. Resilience thinking explains a natural process that occurs in all complex systems in response to stressful challenges. The brain is a complex system, much like an ecosystem, and AD is a disturbance (allostatic overload) within the ecosystem of the brain. Resilience thinking gives us guidance, direction, and ideas about how to comprehensively prevent and treat AD and tackle the AD epidemic. PMID- 29124109 TI - The effect of diagnostic criteria on outcome measures in preclinical and prodromal Alzheimer's disease: Implications for trial design. AB - Introduction: We investigated the influence of different inclusion criteria for preclinical and prodromal Alzheimer's disease (AD) on changes in biomarkers and cognitive markers and on trial sample size estimates. Methods: We selected 522 cognitively normal subjects and 872 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative study. Compared inclusion criteria were (1) preclinical or prodromal AD (amyloid marker abnormal); (2) preclinical or prodromal AD stage-1 (amyloid marker abnormal, injury marker normal); and (3) preclinical or prodromal AD stage-2 (amyloid and injury markers abnormal). Outcome measures were amyloid, neuronal injury, and cognitive markers. Results: In both subjects with preclinical and prodromal AD stage-2, inclusion criteria resulted in the largest observed decline in brain volumetric measures on magnetic resonance imaging and cognitive markers. Discussion: Inclusion criteria influence the observed rate of worsening in outcome measures. This has implications for trial design. PMID- 29124108 TI - An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations. AB - Introduction: Frontotemporal lobar degeneration-causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. Methods: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. Results: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2 +/- 10.9% in plasma and -10.2 +/- 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. Discussion: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes. PMID- 29124110 TI - Characterization of APOE and TOMM40 allele frequencies in the Japanese population. AB - Introduction: Dementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ~15% of the elderly population has dementia. The apolipoprotein E (APOE) genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 (TOMM40) gene have been associated with the age of onset of AD. However, differences in allele frequencies of these markers in different ethnic populations are not well known. Methods: Whole blood samples were collected from 300 Japanese subjects, and genomic DNA was extracted to determine APOE alleles and TOMM40 rs10524523 genotypes. Results: Our results indicated that the APOE epsilon3-TOMM40'523 short haplotype is less frequent in Japanese subjects than in Caucasians, whereas the APOE epsilon3-TOMM40'523 long and APOE epsilon3-TOMM40'523 very long haplotypes are more frequent in Japanese subjects than in Caucasians. We also showed that the APOE epsilon4-TOMM40'523 short haplotype, which was noted to be frequently observed in African Americans, was also found in the Japanese population, although it is extremely rare in the Caucasian population. Discussion: A biomarker risk assignment algorithm, using a combination of APOE, TOMM40'523 genotype, and age, has been developed to assign near-term risk for developing the onset of mild cognitive impairment due to AD and is being used as an enrichment tool in an ongoing delay-of-onset clinical trial. Understanding the characterization of APOE and TOMM40 allele frequencies in the Japanese population is the first step in developing a risk algorithm for AD research and clinical applications for AD prevention in Japan. PMID- 29124111 TI - Potential implications of practice effects in Alzheimer's disease prevention trials. AB - Introduction: Practice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome. Methods: We investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline. Results: On average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design. Discussion: Assuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials. PMID- 29124112 TI - Concise informed consent to increase data and biospecimen access may accelerate innovative Alzheimer's disease treatments. AB - Introduction: Informed consent forms that restrict the distribution of data and samples have been an impediment to advancing Alzheimer's disease (AD) understandings and treatments. The Coalition Against Major Disease public-private partnership developed concise addenda to responsibly broaden data access of informed consent forms. Methods: Coalition Against Major Disease members identified key elements for ensuring data and biospecimen access, and patient privacy protection according to applicable US law. Collaboration with the Alzheimer's Association established the understandability and relevance of the addenda with AD patients and Care Partners. Results: Two key findings are (1) patients with dementia and Care Partners were shocked that their data and samples are not broadly shared and (2) with diverse feedback, two concise addenda were created to enable data and sample sharing both within and outside future sponsored studies (see Boxes). Discussion: Increasing the access of valuable anonymized patient-level clinical trial data has the potential to inform the foundational and regulatory science required to deliver innovative treatments for AD. PMID- 29124113 TI - Biomathematical screening of amyloid radiotracers with clinical usefulness index. AB - Introduction: To facilitate radiotracers' development, a screening methodology using a biomathematical model and clinical usefulness index (CUI) was proposed to evaluate radiotracers' diagnostic capabilities. Methods: A total of 31 amyloid positron emission tomography radiotracers were evaluated. A previously developed biomathematical model was used to simulate 1000 standardized uptake value ratios with population and noise simulations, which were used to determine the integrated receiver operating characteristics curve (Az), effect size (Es), and standardized uptake value ratio (Sr) of conditions-pairs of healthy control-mild cognitive impaired and mild cognitive impaired-Alzheimer's disease. CUI was obtained from the product of averaged [Formula: see text], [Formula: see text], and [Formula: see text]. Results: The relationships of [Formula: see text], [Formula: see text], and [Formula: see text] with CUI were different, suggesting that they assessed different radiotracer properties. The combination of Az, Es, and Sr complemented each other and resulted in CUI of 0.10 to 5.72, with clinically applied amyloid positron emission tomography radiotracers having CUI greater than 3.0. Discussion: The CUI rankings of clinically applied radiotracers were close to their reported clinical results, attesting to the applicability of the screening methodology. PMID- 29124114 TI - Impact of programs to reduce antipsychotic and anticholinergic use in nursing homes. AB - Introduction: Antipsychotics are used for managing behavioral and psychological symptoms of dementia (BPSD) but have risks. Anticholinergics can worsen outcomes in dementia. The Improving Antipsychotic Appropriateness in Dementia Patients educational program (IA-ADAPT) and Centers for Medicare and Medicaid Services Partnership to Improve Dementia Care (CMS Partnership) promote improved care for BPSD. The purpose of this study was to evaluate the impact of these programs on medication use and BPSD among nursing home residents. Methods: This quasi experimental longitudinal study used Medicare and assessment data for Iowa nursing home residents from April 2011 to December 2012. Residents were required to be eligible for six continuous months for inclusion. Antipsychotic use and anticholinergic use were evaluated on a monthly basis, and changes in BPSD were tracked using assessment data. Results are presented as odds ratios (ORs) per month after exposure to the IA-ADAPT or the start of the CMS Partnership. Results: Of 426 eligible Iowa nursing homes, 114 were exposed to the IA-ADAPT in 2012. Nursing home exposure to the IA-ADAPT was associated with reduced antipsychotic use (OR [95% CI] = 0.92 [0.89-0.95]) and anticholinergic use (OR [95% CI] = 0.95 [0.92-0.98]), reduced use of excessive antipsychotic doses per CMS guidance (OR [95% CI] = 0.80 [0.75-0.86]), increased odds of a potentially appropriate indication among antipsychotic users (OR [95% CI] = 1.04 [1.00 1.09]), and decreased documentation of verbal aggression (OR [95% CI] = 0.96 [0.94-0.99]). Facilities with two or more IA-ADAPT exposures had greater reductions in antipsychotic and anticholinergic use than those with only one. The CMS Partnership was associated with reduced antipsychotic use (OR [95% CI] = 0.96 [0.94-0.98]) and decreased documentation of any measured BPSD (OR [95% CI] = 0.98 [0.97-0.99]) as well as delirium specifically (OR [95% CI] = 0.98 [0.96-0.99]). Discussion: This study suggests that the IA-ADAPT and the CMS Partnership improved medication use with no adverse impact on BPSD. PMID- 29124116 TI - Toward common mechanisms for risk factors in Alzheimer's syndrome. AB - The global strategic goal of reducing health care cost, especially the prospects for massive increases due to expanding markets for health care services demanded by aging populations and/or people with a wide range of chronic disorders disabilities, is a complex and formidable challenge with many facets. Current projections predict marked increases in the demand for health driven by both the exponential climb in the prevalence of chronic disabilities and the increases in the absolute numbers of people in need of some form of health care. Thus, the looming predicament for the economics of health care systems worldwide mandates the formulation of a strategic goal to foster significant expansion of global R&D efforts to discover and develop wide-ranging interventions to delay and/or prevent the onset of chronic disabling conditions. The rationale for adopting such a tactical objective is based on the premise that the costs and prevalence of chronic disabling conditions will be reduced by half even if a modest delay of 5 years in the onset of disability is obtained by a highly focused multinational research initiative. Because of the recent history of many failures in drug trials, the central thesis of this paper is to argue for the exploration-adoption of novel mechanistic ideas, theories, and paradigms for developing wide range and/or types of interventions. Although the primary focus of our discussion has been on biological approaches to therapy, we recognize the importance of emerging knowledge on nonpharmacological interventions and their potential impact in reducing health care costs. Although we may not find a drug to cure or prevent dementia for a long time, research is starting to demonstrate the potential contributes of nonpharmacological interventions toward the economics of health care in terms of rehabilitation, promoting autonomy, and potential to delay institutionalization, thus promoting healthy aging and reductions in the cost of care. PMID- 29124115 TI - Study protocol of the Intense Physical Activity and Cognition study: The effect of high-intensity exercise training on cognitive function in older adults. AB - Introduction: Inconsistent results from previous studies of exercise and cognitive function suggest that rigorously designed randomized controlled trials are urgently needed. Here, we describe the design of the Intense Physical Activity and Cognition (IPAC) study, which will assess the impact of a 6-month high-intensity exercise intervention on cognitive function and biomarkers of dementia risk, compared with a 6-month moderate-intensity exercise intervention and control group (no study-related exercise). Methods: One-hundred and five cognitively healthy men and women aged between 60 and 80 years are randomized into a high-intensity exercise, moderate-intensity exercise, or control group. Individuals randomized to an exercise intervention undertake 6 months of cycle based exercise twice a week, at 50 minutes per session. All participants undergo comprehensive neuropsychological testing, blood sampling, brain magnetic resonance imaging, fitness testing, and a body composition scan at baseline, 6 months (immediately after intervention), and 18 months (12 months after intervention). Discussion: The IPAC study takes a multidisciplinary approach to investigating the role of exercise in maintaining a healthy brain throughout aging. Rigorous monitoring of exertion and adherence throughout the intervention, combined with repeated measures of fitness, is vital in ensuring an optimum exercise dose is reached. Results from the IPAC study will be used to inform a large-scale multicentre randomized controlled trial, with the ultimate aim of pinpointing the frequency, duration, and intensity of exercise that provides the most benefit to the brain, in terms of enhancing cognitive function and reducing dementia risk in older adults. PMID- 29124117 TI - Proton pump inhibitors and the risk of severe cognitive impairment: The role of posttraumatic stress disorder. AB - Introduction: Proton pump inhibitors (PPIs), a common treatment for gastroesophageal reflux disease (GERD), were recently associated with increased risk of dementia. However, severe or chronic stress including, for example, posttraumatic stress disorder (PTSD) was not accounted for. This study examined whether PPI use was associated with severe cognitive impairment (SCI) and whether PTSD explained this association in a cohort of World Trade Center (WTC) responders. Method: A prospective cohort study of 3779 WTC responders attending a university-based monitoring and treatment program. Prescriptions for PPIs and SCI determined using the Montreal Cognitive Assessment were the focus of the analysis. Results: Overall, 1451 (38.4%) responders were dispensed PPIs, and 83 (2.2%) had SCI. Bivariable analyses revealed significant associations between being-dispensed PPIs in relation to SCI. After adjusting for PTSD, major depressive disorder, WTC exposures, age, and sex, being-dispensed PPIs were significantly associated with odds of SCI (adjusted odds ratio = 1.67 95% confidence interval = 1.054-2.643). Conclusions: Being-dispensed PPIs were associated with SCI in this analysis of WTC responders. Results suggest that clinicians treating GERD seek to both understand patients' mental health history and monitor cognitive functioning when designing treatment routines. Overall, results confirmed that this is an important area of investigation with potential direct clinical implications. PMID- 29124118 TI - Chemical Analysis and Evaluation of Antioxidant, Antimicrobial, and Photoprotective Activities of Schinopsis brasiliensis Engl. (Anacardiaceae). AB - Schinopsis brasiliensis Engl. is a native plant of Caatinga which has high concentrations of compounds capable of absorbing ultraviolet light, suggesting its potential application for the development of sunscreen preparations. After its identification and collection, this vegetable drug was submitted to a physicochemical analysis through the preparation of ethanolic extract. The phytochemical screening and analysis of extracts were carried out by high performance liquid chromatography (HPLC) evaluation. The antioxidant activity of the extract was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and beta carotene bleaching test. Inhibitory hemolytic activity and morphological deformation of erythrocytes induced by H2O2 were also demonstrated and the antimicrobial activity was analyzed by the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) method. For the in vitro determination of the sun protection factor (SPF), the spectrophotometric method was used. From the analyses carried out with this species, this plant showed significant results for the antioxidant and antimicrobial activities, as well as sunscreen action. Important flavonoids were identified. These data are an important step for the development of new photoprotective cosmetic with Caatinga species, revealing importance and representing another incentive for the preservation of the species involved and analyzed in the study. PMID- 29124119 TI - Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis with a silicone-covered nitinol short bilaterally flared stent: a case series. AB - Background and study aim: Gallbladder drainage in patients with cholecystitis who are unsuitable for surgery may be performed by endoscopic ultrasound (EUS)-guided placement of specifically designed fully covered metal stents. We describe the first case series of patients treated with a silicone-covered nitinol stent with bilateral anchor flanges. Patients and methods: Data from consecutive patients with acute cholecystitis who were deemed unsuitable candidates for surgery were collected. The stent placement procedure was performed in two tertiary endoscopy centers by four experienced endoscopists. Technical and clinical success rates, as well as adverse events and clinical outcome at follow-up, were assessed. Results: EUS-guided drainage for cholecystitis was performed in 16 patients (mean age 84 years; nine males). Technical and clinical success rates were 100 % (16/16) and 94 % (15/16), respectively; an early failure due to stone impaction occurred in the remaining case and required placement of a new stent. Symptom relief occurred in 11/15 cases (73 %) within 1 day, and within 2 days in the remaining 4 patients. Bleeding occurred in two patients (13 %): in one patient intraprocedural bleeding was successfully stopped during endoscopy; and delayed bleeding occurred in one patient requiring arterial embolization for catastrophic bleeding (patient died 10 days later). No cases of cholecystitis recurrence or biliary obstruction were observed during a median follow-up of 112 days (range 49 - 180 days). Conclusions: Our data showed that EUS-guided gallbladder drainage with a specially designed stent is feasible and successful in patients with acute cholecystitis who are unfit for surgery. PMID- 29124120 TI - Potential of colonoscopy as a treatment for intussusception in children. AB - Background and study aims: Invagination, which can occur in any part of the intestine, usually affects children and is the second most common cause of intestinal obstruction after pyloric stenosis. The cause of these intussusceptions in children is usually unknown and they typically occur within the ileocolic region. Management of pediatric patients with the condition often consists of surgical intervention. However, this retrospective study from the University Hospital of the University of Sao Paulo, Brazil, reports a series of cases of intussusception in children in whom a colonoscopy was used to reverse the intussusception. Patients and methods: From April 2010 to January 2015, 30 pediatric patients underwent a colonoscopy as an noninvasive method for treatment of children's intestinal intussusception. Results: Overall, treatment with colonoscopy was successful in reversing invagination in 66.7 % of the patients. However, 33.3 % of patients required surgery to resolve the intussusception. Conclusion: Noninvasive colonoscopy is a potential treatment for intussusception in children. PMID- 29124121 TI - Patients' comorbidities reduce the clinical value of emergency colonoscopy: results of a retrospective cohort study. AB - Background and study aims: Urgent endoscopy is often used to diagnose and sometimes treat acute upper gastrointestinal syndromes (hemorrhage, toxic ingestion, and occlusion). However, its suitability concerning the management of lower gastrointestinal conditions in emergency circumstances is controversial. Patients and methods: We studied the role of emergency colonoscopy in diagnosis and treatment of all consecutive patients presenting with acute lower gastrointestinal symptoms referred to our hospital on an emergency basis. All patients were first managed by physicians from the emergency room and/or the intensive care unit (ICU); the treatments included fluid resuscitation, blood transfusion, and antibiotic or cardiotonic as needed. Bowel cleansing was performed to purge the colon of clots, stool, and blood when clinically possible; alternatively, a bowel enema was used. Patients only underwent a computed tomography (CT) scan prior to the colonoscopy in clinically relevant situations. Colonoscopy was performed within 6 - 36 hours after hospitalization or the beginning of the clinical symptoms (hemorrhage, sepsis, colon distension) or occlusion, as assessed by abdominal CT scan. Results: From 2010 to 2015, 603 patients underwent urgent colonoscopy; among them, 214 (36 %) presented with lower GI bleeding, while 264 (44 %) had symptoms suggestive of intestinal ischemia; almost half (49 %, n = 295) of the patients were hospitalized in the ICU. Patients received therapies, such as clips (15 %), epinephrine injections (5 %), bipolar coagulation (7 %), or devolvulation (3 %) using colonoscopy or antibiotic therapy when needed. No perforation was observed after colonoscopy and only three cases of hemorrhage recurrence were documented as complications after the procedure. Overall, 192 patients died within 1 month after colonoscopy due to four independent risk situations, as follows: septic shock, heart transplantation, multiorgan failure, and ischemic colitis. Only 67 (35 %) underwent urgent intestinal surgery when ischemic colitis was identified, and this did not have a significant effect on the mortality rate. Conclusions: Urgent bedside colonoscopy is feasible and safe for routine use. The highest advantage was observed in patients with red blood hemorrhage, diarrhea, and colon distension when symptoms were not associated with multiorgane failure, heart transplantation, or septic shock. As revealed by colonoscopy and pathological features, ischemic colitis is associated with a bad prognosis, and patients experience a higher rate of early mortality regardless of whether they undergo urgent colon surgery. PMID- 29124122 TI - Patient decision-making and clinical outcomes following endoscopic therapy or esophagectomy for Barrett's neoplasia. AB - Background and study aims: The objective of this study was to assess patient involvement in decision-making, decision confidence, and decision regret among patients who had undergone endoscopic eradication therapy (EET) or esophagectomy for Barrett's esophagus (BE) associated neoplasia. Patients and methods: Patients with BE high grade dysplasia or intramucosal (T1a) adenocarcinoma who had undergone EET or esophagectomy were invited to complete a survey. Results: The cohort included 50 subjects, 70 % (35/50) of whom had undergone EET and 30 % (15/50) of whom had undergone esophagectomy. Subjects who underwent esophagectomy were more likely to report post-treatment dysphagia (47 % vs 14 %, P = 0.03), post-treatment dietary modification (73 % vs 6 %, P < 0.0001), and were less likely to view their post-treatment health favorably. However, when asked whether they had selected the right treatment, a high degree of confidence was reported by both groups (mean 9.8 for EET vs 9.3 for esophagectomy on a 0 - 10 scale, P = 0.12). In fact, 97 % (34/35) of EET patients and 80 % (12/15) of esophagectomy patients indicated they would select the same treatment option ( P = 0.08). Conclusions: Patients who have undergone EET or surgery for BE neoplasia report a high degree of involvement in the decision-making process. Although EET patients report fewer symptom-specific outcomes, measures of decision confidence and decision regret do not differ between the two treatment groups. PMID- 29124123 TI - Endoscopic ultrasound in diagnosis of solid pancreatic lesions: Elastography or contrast-enhanced harmonic alone versus the combination. AB - Background and study aims : Endoscopic ultrasound (EUS) elastography (EUS-E) and contrast-enhanced harmonic EUS (CH-EUS) are useful methods for the diagnosis of pancreatic lesions. This study aims to compare the accuracy of combined EUS-E and CH-EUS with that of EUS-E or CH-EUS alone in the differential diagnosis of pancreatic solid lesions. Patients and methods: One hundred thirty-six patients with solid pancreatic lesions underwent EUS with both EUS-E and CH-EUS were included. Diagnoses were classified as adenocarcinoma, neuroendocrine tumor (NET), and inflammatory pseudotumor in 95, 22, and 19 patients, respectively. EUS records in each case were rearranged into 3 groups: EUS-E, CH-EUS, and combination. Each modality was randomly reviewed by 3 reviewers with different levels of clinical experience. Sensitivity, specificity, and accuracy of each modality according to each diagnosis group were evaluated. For the combined diagnosis populations, the proportions of correct diagnoses among the 3 modalities were compared by using the multivariate logistic regression analysis. Results : The accuracies of EUS-E, CH-EUS, and the combination of them were 68.4 %, 65.4 %, and 75.7 %, respectively, for adenocarcinoma group; 83.8 %, 82.4 %, and 86.8 % for NET group; 80.1 %, 78.7 %, and 81.6 % for inflammatory pseudotumor group. The multivariate logistic regression analysis for the combined diagnosis populations showed that the proportion of correct diagnoses when EUS-E and CH-EUS were combined was slightly higher than with the other 2 modalities, although the significant differences among them were not observed. Conclusion : EUS-E and CH EUS combined may improve differential diagnosis of solid pancreatic lesions compared with use of the individual modalities. PMID- 29124125 TI - No treatment for asymptomatic common bile ducts stones? PMID- 29124124 TI - Preliminary experience with pancreatic sphincterotomy as treatment for intraductal papillary mucinous neoplasm-associated recurrent pancreatitis. AB - Background and study aims: Pancreatic intraductal papillary mucinous neoplasms (IPMN) are cystic tumors of the pancreas characterized by a malignant potential. IPMN have been associated with recurrent pancreatitis (RP). Obstruction of the main pancreatic duct by thick mucus has been postulated to be the cause of pancreatitis. In a few isolated reports, pancreatic sphincterotomy (PS) has been reported to reduce the frequency of pancreatitis. The aim of this study was to assess the efficacy of PS in patients with IPMN-associated RP. Patients and methods: We retrospectively identified patients with RP and IPMN who underwent PS from June 2010 to December 2015. Patients were included in two different groups: (a) main duct/mixed type IPMN (MD-IPMN) and (b) branch duct IPMN (BD IPMN) with or without worrisome features/high risk stigmata. Other causes of RP were excluded. The number of pancreatitis episodes occurring during a comparable time period before and after PS was evaluated. Results: In total, 16 patients were analyzed (seven included in the MD-IPMN group and nine in the BD-IPMN group). The numbers of pancreatitis episodes occurring before and after PS were 3.5 +/- 2.32 and 0.56 +/- 1.03, respectively ( P < 0.0001). Mean follow-up was 27.4 months (range 6 - 63 months). Complete, partial (reduction of pancreatitis episodes > 50 %), and no response were obtained in 11 (68.7 %), 3 (18.7 %), and 2 patients (12.5 %), respectively. One (6.25 %) case of mild post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis was observed. No cancer was detected in resected patients. None of the BD-IPMN group patients had or developed worrisome features/high risk stigmata during follow-up. Conclusions: PS seems to be effective in reducing the number of episodes of IPMN-associated pancreatitis and should be considered as a treatment option in selected clinical settings. However, active surveillance should be continued considering the malignant potential of IPMN. Further prospective controlled studies are needed to confirm our results. PMID- 29124126 TI - Safe management of laparoscopic endoscopic cooperative surgery for superficial non-ampullary duodenal epithelial tumors. AB - Background and study aims Endoscopic submucosal dissection (ESD) for duodenal tumors results in a high delayed perforation rate due to the thinness of the duodenal wall. In most cases with perforation after duodenal ESD, additional surgery is needed due to severe peritonitis. A newly developed procedure, laparoscopic endoscopic cooperative surgery for duodenal tumors (D-LECS), may help to avoid perforation after ESD. In our institution, patients with superficial non-ampullary duodenal epithelial tumors (SNADET) smaller than 50 mm which could not have en-bloc resection by endoscopic mucosal resection were treated with D-LECS. After a laparoscopic exposure of anterior duodenal wall of second portion, ESD was performed. Laparoscopic suturing from the serosal side of ESD site was performed for reinforcement. There were neither postoperative leakage nor other complications. Therefore, D-LECS can be performed safely and prevent perforation after ESD for SNADET. D-LECS could be selected as a treatment for SNADET which can be cured by ESD. PMID- 29124127 TI - Effectiveness of TC-325 (Hemospray) for treatment of diffuse or refractory upper gastrointestinal bleeding - a single center experience. AB - Background and study aims: TC-325 (Hemospray, Cook Medical) is a powder agent for endoscopic hemostasis in patients with upper gastrointestinal bleeding (UGIB). Although most publications are based on case-reports and retrospective studies, data on efficacy are promising. Here we report our experience with TC 325 for diffuse or refractory UGIB. Patients and methods: Data on patients receiving TC-325 for endoscopic hemostasis from November 2013 to February 2017 at our center were analyzed retrospectively. Primary endpoints were technical success (successful immediate hemostasis) and clinical success (effective hemostasis and no recurrent bleeding). Secondary endpoints were recurrent bleeding within 3 and 7 days, hospital mortality and TC-325 associated complications. TC-325 was used for bleeding not amenable to standard endoscopic treatment (e. g. diffuse bleeding) or as salvage therapy after failure of conventional methods. Results: Fifty-two patients received TC-325 treatment. Most of the patients were treated for peptic ulcer bleeding (18/52 patients, 34.6 %) and post-interventional bleeding (13/52 patients, 25 %). Hemospray was used in 23/52 (44.2 %) patients as monotherapy and in 29/52 (55.8 %) patients as a salvage therapy. Application of the powder on the bleeding source was successful in all patients with no therapy-related adverse events (AEs). Immediate hemostasis was achieved in 51/52 (98.1 %) patients. Recurrent bleeding within 3 and 7 days was observed in 22/51 and 25/51 patients respectively (43.1 % and 49 %). The overall clinical success was 56.9 % on day 3 and 51 % on day 7. Total mortality was 15.4 % (8 patients), bleeding associated mortality was 3.8 % (2 patients). There were no therapy-related AEs. Conclusions: TC-325 showed a high technical success rate as monotherapy for bleeding sources not amenable to standard methods or as an "add-on" therapy after unsuccessful hemostasis. However, rebleeding was frequent in this cohort and further studies are warranted to exactly define a treatment algorithm for TC-325 use. PMID- 29124128 TI - Vascular Deformation Mapping (VDM) of Thoracic Aortic Enlargement in Aneurysmal Disease and Dissection. AB - Thoracic aortic aneurysm is a common and lethal disease that requires regular imaging surveillance to determine timing of surgical repair and prevent major complications such as rupture. Current cross-sectional imaging surveillance techniques, largely based on computed tomography angiography, are focused on measurement of maximal aortic diameter, although this approach is limited to fixed anatomic positions and is prone to significant measurement error. Here we present preliminary results showing the feasibility of a novel technique for assessing change in aortic dimensions, termed vascular deformation mapping (VDM). This technique allows quantification of 3-dimensional changes in the aortic wall geometry through nonrigid coregistration of computed tomography angiography images and spatial Jacobian analysis of aortic deformation. Through several illustrative cases we demonstrate that this method can be used to measure changes in the aortic wall geometry among patients with stable and enlarging thoracic aortic aneurysm and dissection. Furthermore, VDM results yield observations about the presence, distribution, and rate of aortic wall deformation that are not apparent by routine clinical evaluation. Finally, we show the feasibility of superposing patient-specific VDM results on a 3-dimensional aortic model using color 3D printing and discuss future directions and potential applications for the VDM technique. PMID- 29124129 TI - Subtle Microbiome Manipulation Using Probiotics Reduces Antibiotic-Associated Mortality in Fish. AB - Prophylactic antibiotics in the aquaculture and ornamental fish industry are intended to prevent the negative impacts of disease outbreaks. Research in mice and humans suggests that antibiotics may disturb microbiome communities and decrease microbiome-mediated disease resistance, also known as "colonization resistance." If antibiotics impact fish as they do mice and humans, prophylactic administrations on aquaculture farms may increase downstream disease susceptibility in target hosts, despite short-term pathogen control benefits. We tested the effects of antibiotics on mortality after a pathogen challenge in the Poecilia sphenops black molly and subsequently tested if probiotic inoculations could reverse any antibiotic-induced losses of disease resistance. We found that antibiotic treatment significantly increased fish mortality. We further found that our two candidate probiotic bacterial species, Phaeobacter inhibens S4Sm and Bacillus pumilus RI06-95Sm, were able to colonize black molly microbiomes and reverse the negative impacts of antibiotics. Despite the positive impact on survival, probiotic treatment did not influence overall microbiome community structure or diversity. Our results suggest that subtle manipulations of microbiome composition can have dramatic impacts on host phenotype. The results of this study have implications for how antibiotic-treated microbiomes can be restored and suggest that small-scale additions may be as effective as wholesale transplants. IMPORTANCE Prophylactic antibiotics are widespread in the aquaculture industry and are used where vaccination is impossible or overly expensive. If antibiotics impact fish as they do mice and humans, prophylactic administrations in aquaculture and ornamental fish farms may increase downstream disease susceptibility in target hosts, despite short-term pathogen control benefits. Recent research has suggested that their use exacerbates bacterial outbreaks by creating sterile, nutrient-rich environments for invading pathogens to colonize and could help to explain rising economic costs of bacterial outbreaks in aquaculture. Our findings suggest a long-term cost of prophylactic antibiotic use and demonstrate a probiotic-based solution that does not rely on full microbiome community transplantation. PMID- 29124130 TI - Aquaporin10 is a pseudogene in cattle and their relatives. AB - Background: Although AQP10 is mainly expressed in the human GI tract, its physiological role is unclear. In fact, we previously reported that mouse AQP10 is a pseudogene. It is possible that AQP10 is also a pseudogene in other animals. Methods: Genome databases were searched for AQP10 orthologs and the genomic DNA of each candidate pseudogene was sequenced to confirm its mutations. The expression of the AQP10 mRNA was examined by RT-PCR in the small intestine where human AQP10 is highly expressed. Results: The genomic database of some mammals had insertions and deletions in the exons of the AQP10 gene, including cattle (Bos taurus), sheep (Ovis aries) and goats (Capra hircus). In the bovine AQP10 gene, exon 1 and 5 had deletions resulting in a frame-shift or a premature termination, respectively, which were confirmed by the direct exon sequencing of the genomic DNA. In the RT-PCR experiments, the PCR primer sets for exon 1/2 and exon 4/5 failed to detect the bands for AQP10 mRNA in the duodenum and jejunum. Similar AQP10 gene mutations were also confirmed in the genomic DNA from sheep and goats. Although these animals were derived from porcine ancestors, the exons of the swine (Sus scrofa) AQP10 gene were complete without mutations. Therefore, AQP10 gene might have turned to a pseudogene around 65 million years before when cattle evolved from porcine ancestors. Conclusion: AQP10 of ruminantia which regurgitate and rechew their food may have lost its role possibly due to the redundant expression of other aquaglyceroporins. PMID- 29124131 TI - Structural and functional comparison of hexahistidine tagged and untagged forms of small multidrug resistance protein, EmrE. AB - EmrE is a member of the small multidrug resistance (SMR) protein family in Escherichia coli. EmrE confers resistance to a wide variety of quaternary cation compounds (QCCs) as an efflux transporter driven by proton motive force. The purification yield of most membrane proteins are challenging because of difficulties in over expressing, isolating and solubilizing them and the addition of an affinity tag often improves purification. The purpose of this study is to compare the structure and function of hexahistidinyl (His6) tagged (T-EmrE) and untagged (UT-EmrE) versions of EmrE. In vivo QCC resistance assays determined that T-EmrE demonstrated reduced resistance as compared to UT-EmrE. We isolated EmrE using the two different purification methods, an organic solvent extraction method used to isolate UT-EmrE and nickel affinity chromatography of T-EmrE. All proteins were solubilized in the same buffered n-dodecyl-beta-d-maltopyranoside (DDM) detergent and their conformations were examined in the presence/absence of different QCCs. In vitro analysis of protein multimerization using SDS-Tricine PAGE and dynamic light scattering analysis revealed that both proteins predominated as monomers, but the formation of dimers was more constant and uniform in T-EmrE compared to UT-EmrE. The aromatic residue conformations of both proteins indicate that T-EmrE form is more aqueous exposed than UT-EmrE, but UT EmrE appeared to have a more dynamic environment surrounding its aromatic residues. Using fluorescence to obtain QCC ligand-binding curves indicated that the two forms had differences in dissociation constants (Kd ) and maximum specific one-site binding (Bmax ) values for particular QCCs. In vitro analyses of both proteins demonstrated subtle but significant differences in multimerization and QCC binding. In vivo analysis indicates differences caused by the addition of the tag, we also observed differences in vitro that could be a result of the tag and/or the different purification methods. PMID- 29124133 TI - Deficiency of spermatogenesis and reduced expression of spermatogenesis-related genes in prefoldin 5-mutant mice. AB - MM-1alpha is a c-Myc-binding protein and acts as a transcriptional co-repressor in the nucleus. MM-1alpha is also PDF5, a subunit of prefoldin that is chaperon comprised of six subunits and prevents misfolding of newly synthesized nascent polypeptides. Prefoldin also plays a role in quality control against protein aggregation. It has been reported that mice harboring the missense mutation L110R of MM-1alpha/PFD5 exhibit neurodegeneration in the cerebellum and also male infertility, but the phenotype of infertility has not been fully characterized. In this study, we first analyzed morphology of the testis and epididymis of L110R of MM-1alpha mice. During differentiation of spermatogenesis, spermatogonia, spermatocytes and round spermatids were formed, but formation of elongated spermatids was compromised in L110R MM-1alpha mice. Furthermore, reduced number/concentration of sperm in the epididymis was observed. MM-1alpha was strongly expressed in the round spermatids and sperms with round spermatids, suggesting that MM-1alpha affects the differentiation and maturation of germ cells. Changes in expression levels of spermatogenesis-related genes in mice testes were then examined. The fatty-acid-binding protein (fabp4) gene was up regulated and three genes, including sperm-associated glutamate (E)-rich protein 4d (speer-4d), phospholipase A2-Group 3 (pla2g3) and phospholipase A2-Group 10 (pla2g10), were down-regulated in L110R MM-1alpha mice. L110R MM-1alpha and wild type MM-1alpha bound to regions of up-regulated and down-regulated genes, respectively. Since these gene products are known to play a role in maturation and motility of sperm, a defect of at least MM-1alpha transcriptional activity is thought to induce expressional changes of these genes, resulting in male infertility. PMID- 29124134 TI - Chromogenic assessment of the three molybdo-selenoprotein formate dehydrogenases in Escherichia coli. AB - Escherichia coli synthesizes three selenocysteine-dependent formate dehydrogenases (Fdh) that also have a molybdenum cofactor. Fdh-H couples formate oxidation with proton reduction in the formate hydrogenlyase (FHL) complex. The activity of Fdh-H in solution can be measured with artificial redox dyes but, unlike Fdh-O and Fdh-N, it has never been observed by chromogenic activity staining after non-denaturing polyacrylamide gel electrophoresis (PAGE). Here, we demonstrate that Fdh-H activity is present in extracts of cells from stationary phase cultures and forms a single, fast-migrating species. The activity is oxygen labile during electrophoresis explaining why it has not been previously observed as a discreet activity band. The appearance of Fdh-H activity was dependent on an active selenocysteine incorporation system, but was independent of the [NiFe] hydrogenases (Hyd), 1, 2 or 3. We also identified new active complexes of Fdh-N and Fdh-O during fermentative growth. The findings of this study indicate that Fdh-H does not form a strong complex with other Fdh or Hyd enzymes, which is in line with it being able to deliver electrons to more than one redox-active enzyme complex. PMID- 29124135 TI - Influence of chemical denaturants on the activity, fold and zinc status of anthrax lethal factor. AB - Anthrax lethal factor (LF) is a zinc-dependent endopeptidase which, through a process facilitated by protective antigen, translocates to the host cell cytosol in a partially unfolded state. In the current report, the influence of urea and guanidine hydrochloride (GdnHCl) on LF's catalytic function, fold and metal binding was assessed at neutral pH. Both urea and GdnHCl were found to inhibit LF prior to the onset of unfolding, with the inhibition by the latter denaturant being a consequence of its ionic strength. With the exception of demetallated LF (apoLF) in urea, unfolding, as monitored by tryptophan fluorescence spectroscopy, was found to follow a two-state (native to unfolded) mechanism. Analysis of the metal status of LF with 4-(2-pyridylazoresorcinol) (PAR) following urea or GdnHCl exposure suggests the enzyme to be capable of maintaining its metal ion passed the observed unfolding transition in a chelator-inaccessible form. Although an increase in the concentration of the denaturants eventually allowed the chelator access to the protein's zinc ion, such process is not correlated with the release of the metal ion. Indeed, significant dissociation of the zinc ion from LF was not observed even at 6 M urea, and only high concentrations of GdnHCl (>3 M) were capable of inducing the release of the metal ion from the protein. Hence, the current study demonstrates not only the propensity of LF to tightly bind its zinc ion beyond the spectroscopically determined unfolding transition, but also the utility of PAR as a structural probe. PMID- 29124136 TI - Novel acidic phospholipase A2 from Porthidium hyoprora causes inflammation with mast cell rich infiltrate. AB - Phospholipases A2 (PLA2) are a group of enzymes that hydrolyze phospholipids at the sn-2 position, being present in all nature. In venomous animals, these proteins assume a special role, being able to exert diverse pharmacological effects. In this work, authors identified a new isoform of PLA2 in the venom of Porthidium hyoprora, which was isolated through sequential chromatographic steps and named PhTX-III. The enzyme was characterized biochemically and structurally. Structural studies using mass spectrometry confirmed an acidic secretory PLA2, family IIA, with molecular mass of 13,620.9 Da and identification of 86% of its primary sequence. PhTX-III did not exhibit myotoxic, anticoagulant or antibacterial effects, often present in this class of enzymes. Although, it was capable of initiate inflammatory response, with local edema and release of cytokines IL-1alpha, IL-6 and TNF-alpha, probably due to mast cell degranulation. PMID- 29124132 TI - Intrinsically disordered proteins in the nucleus of human cells. AB - Intrinsically disordered proteins are known to perform a variety of important functions such as macromolecular recognition, promiscuous binding, and signaling. They are crucial players in various cellular pathway and processes, where they often have key regulatory roles. Among vital cellular processes intimately linked to the intrinsically disordered proteins is transcription, an intricate biological performance predominantly developing inside the cell nucleus. With this work, we gathered information about proteins that exist in various compartments and sub-nuclear bodies of the nucleus of the human cells, with the goal of identifying which ones are highly disordered and which functions are ascribed to the disordered nuclear proteins. PMID- 29124138 TI - Molten globule nature of Plasmodium falciparum P2 homo-tetramer. AB - The P2 protein in Plasmodium falciparum has a high tendency to oligomerize, which seems to drive many of its non-ribosomal functions. During nuclear division of the parasite inside RBC, P2 translocates to the RBC surface as a tetramer. From a systematic study using variety of biophysical techniques, NMR spectral characteristics and relaxation dispersion measurements under different conditions of pH and/or urea concentrations, we deduce that (i) PfP2, an almost entirely helical protein, forms a molten globule monomer at low pH, (ii) at physiological pH, and at micro-molar concentrations, PfP2 is a stable tetramer wherein two dimmers associate sideways with close packing of helices at the interface, and (iii) the molten globule characteristic of the monomer is preserved in the tetramer. This dynamism in the structure of PfP2 may have functional implications since it is known that different kinds of oligomers are transiently formed in the parasite. PMID- 29124139 TI - Editorial: Launch of Biochemistry and Biophysics Reports. PMID- 29124137 TI - Model structures of inactive and peptide agonist bound C5aR: Insights into agonist binding, selectivity and activation. AB - C5a receptor (C5aR) is one of the major chemoattractant receptors of the druggable proteome that binds C5a, the proinflammatory polypeptide of complement cascade, triggering inflammation and SEPSIS. Here, we report the model structures of C5aR in both inactive and peptide agonist (YSFKPMPLaR; a=D-Ala) bound meta active state. Assembled in CYANA and evolved over molecular dynamics (MD) in POPC bilayer, the inactive C5aR demonstrates a topologically unique compact heptahelical bundle topology harboring a beta-hairpin in extracellular loop 2 (ECL2), derived from the atomistic folding simulations. The peptide agonist bound meta-active C5aR deciphers the "site2" at an atomistic resolution in the extracellular surface (ECS), in contrast to the previously hypothesized inter helical crevice. With estimated Ki~2.75 MUM, the meta-active C5aR excellently rationalizes the IC50 (0.1-13 MUM) and EC50 (0.01-6 MUM) values, displayed by the peptide agonist in several signaling studies. Moreover, with Ki~5.3*105 MUM, the "site2" also illustrates selectivity, by discriminating the stereochemical mutant peptide (YSFkPMPLaR; k=D-Lys), known to be inert toward C5aR, up to 1 mM concentration. Topologically juxtaposed between the structures of rhodopsin and CXCR1, the C5aR models also display excellent structural correlations with the other G-protein coupled receptors (GPCRs). The models elaborated in the current study unravel many important structural insights previously not known for regulating the agonist binding and activation mechanism of C5aR. PMID- 29124140 TI - Probing the role of aromatic residues in the self-assembly of Abeta(16-22) in fluorinated alcohols and their aqueous mixtures. AB - The Abeta(16-22) sequence KLVFFAE spans the hydrophobic core of the Abeta peptide and plays an important role in its self-assembly. Apart from forming amyloid fibrils, Abeta(16-22) can self-associate into highly ordered nanotubes and ribbon like structures depending on the composition of solvent used for dissolution. The Abeta(16-22) sequence which has FF at the 19th and 20th positions would be a good model to investigate peptide self-assembly in the context of aromatic interactions. In this study, self-assembly of Abeta(16-22) and its aromatic analogs obtained by replacement of F19, F20 or both by Y or W was examined after dissolution in fluorinated alcohols and their aqueous mixtures in solvent cluster forming conditions. The results indicate that the presence of aromatic residues Y and W and their position in the sequence plays an important role in self assembly. We observe the formation of amyloid fibrils and other self-assembled structures such as spheres, rings and beads. Our results indicate that 20% HFIP is more favourable for amyloid fibril formation as compared to 20% TFE, when F is replaced with Y or W. The dissolution of peptides in DMSO followed by evaporation of solvent and dissolution in water appears to greatly influence peptide conformation, morphology and cross-beta content of self-assembled structures. Our study shows that positioning of aromatic residues F, Y and W have an important role in directing self-assembly of the peptides. PMID- 29124141 TI - A novel binding of GTP stabilizes the structure and modulates the activities of human phosphoglucose isomerase/autocrine motility factor. AB - Phosphoglucose isomerase (PGI) catalyzes the interconversion between glucose 6 phosphate and fructose 6-phosphate in the glycolysis pathway. In mammals, the enzyme is also identical to the extracellular proteins neuroleukin, tumor secreted autocrine motility factor (AMF) and differentiation and maturation mediator for myeloid leukemia. Hereditary deficiency of the enzyme causes non spherocytic hemolytic anemia in human. In the present study, a novel interaction between GTP and human PGI was corroborated by UV-induced crosslinking, affinity purification and kinetic study. GTP not only inhibits the isomerization activity but also compromises the AMF function of the enzyme. Kinetic studies, including the Yonetani-Theorell method, suggest that GTP is a competitive inhibitor with a Ki value of 63 MUM and the GTP-binding site partially overlaps with the catalytic site. In addition, GTP stabilizes the structure of human PGI against heat- and detergent-induced denaturation. Molecular modelling and dynamic simulation suggest that GTP is bound in a syn-conformation with the gamma-phosphate group located near the phosphate-binding loop and the ribose moiety positioned away from the active-site residues. PMID- 29124142 TI - High efficiency reduction capability for the formation of Fab' antibody fragments from F(ab)2 units. AB - Antibodies have widespread applications in areas ranging from therapeutics to chromatography and protein microarrays. Certain applications require only the fragment antigen-binding (Fab) units of the protein. This study compares the cleavage efficacy of dithiothreitol (DTT), mercaptoethylamine (MEA), and dithiobutylamine (DTBA) - a relatively new reducing agent synthesized in 2012. Pseudo-first order kinetic analyses show DTBA to be ~213 times faster than DTT and ~71 times faster than MEA in the formation of Fab' antibody fragments from polyclonal rabbit antibodies. Monoclonal mouse antibodies were also used to show the feasibility of the reduction process on antibodies from a different species and with a different clonality. DTBA cleaved the monoclonal mouse F(ab)2 units most efficiently, ~2 times faster than DTT ~10 times faster than MEA. Due to the extremely quick reactivity of all the reducing agents in the first five minutes of monoclonal antibody reductions as well as for the DTBA reductions of the polyclonal rabbit antibodies, the pseudo-first order kinetic analyses should be interpreted qualitatively for these results. Nucleophilic sulfides on Fab' fragments are preserved in the DTBA reduction process, demonstrated by their reactivity with Ellman's reagent. Degradation of the Fab' fragments was observed with the monoclonal mouse antibodies after reduction with DTBA or DTT. In conclusion, DTBA is the more efficient reducing agent compared to DTT and MEA, however, the reduction process should be optimized as degradation of the Fab' fragments is possible. PMID- 29124143 TI - Effects of deficient of the Hoogsteen base-pairs on the G-quadruplex stabilization and binding mode of a cationic porphyrin. AB - Background: In stabilization of the G-quadruplex, formation of a Hoogsteen base pair between the guanine (G) bases is essential. However, the contribution of each Hoogsteen base-pair at different positions to whole stability of the G quadruplex has not been known. In this study, the effect of a deficiency of the Hoogsteen type hydrogen bond in the G-quadruplex stability was investigated. Spectral properties of meso-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) associated with various G-quadruplexes were also examined. Methods: The thermal stability of the thrombin-binding DNA aptamer 5'G1G2TTG5G6TG8TG10G11TTG14G15 G quadruplex, in which the guanine (G) base at 1, 2, 5, 6 and 8th positions was replaced with an inosine (I) base, one at a time, was investigated by circular dichroism (CD). The absorption, CD and fluorescence decay curve for the G quadruplex associated TMPyP were also measured. Results: The transition from the G-quadruplex to a single stranded form was endothermic and induced by an increase in entropy. The order in stability was 0>8>6>2>5>1, where the numbers denote the position of the replacement and 0 represents no replacements of the G base, suggesting the significant contribution of the G1 base in the stability of the G quadruplex. Alteration in the spectral property of TMPyP briefly followed the order in thermal stability. Conclusions: Replacement of a G base with an I base resulted in destabilization of the G-quadruplex. The missing hydrogen bond at position 1 destabilized the G-quadruplex most efficiently. TMPyP binds near the I base-replaced location namely, the side of the G-quadruplex. General significance: The Hoogsteen base-pairing is confirmed to be essential in stabilization of G-quadruplex. When G is replaced with I, the latter base is mobile to interact with cationic porphyrin. PMID- 29124144 TI - Noninvasive cross-sectional observation of three-dimensional cell sheet-tissue fabrication by optical coherence tomography. AB - Cell sheet engineering allows investigators/clinicians to prepare cell-dense three-dimensional (3-D) tissues, and various clinical trials with these fabricated tissues have already been performed for regenerating damaged tissues. Cell sheets are easily manipulated and 3-D tissues can be rapidly fabricated by layering the cell sheets. This study used optical coherence tomography (OCT) to noninvasively analyze the following processes: (1) adhesions between layered cell sheets, and (2) the beating and functional interaction of cardiac cell sheet tissues for fabricating functional thicker 3-D tissues. The tight adhesions and functional couplings between layered cell sheets could be observed cross sectionally and in real time. Importantly, the noninvasive and cross-sectional analyses of OCT make possible to fabricate 3-D tissues by confirming the adherence and functional couplings between layered cell sheets. OCT technology would contribute to cell sheet engineering and regenerative medicine. PMID- 29124145 TI - Membrane perturbations induced by the interactions of zinc ions with band 3 in human erythrocytes. AB - Of group 12 metals, zinc is an essential element to maintain our life, but other metals such as cadmium and mercury are toxic in cellular activities. Interactions of these metals with biomembranes are important to understand their effects on our living cells. Here, we describe the membrane perturbations induced by these metals in human erythrocytes. Of these metals, Zn2+ ions only induced the erythrocyte agglutination. Histidine residues in extracellular domains of band 3 participated in Zn2+-induced agglutination. Interestingly, it was found that band 3-cytoskeleton interactions play an important role in Zn2+-induced agglutination. In contrast with Hg2+ and Cd2+ ions, Zn2+ ions greatly suppressed pressure induced hemolysis by cell agglutination. Such a suppression was removed upon dissociation of agglutinated erythrocytes by washing, indicating the reversible interactions of Zn2+ ions with erythrocyte membranes. Excimer fluorescence of pyrene indicated that spectrin is denatured by a pressure of 200 MPa irrespective of hemolysis suppression. Taken together, these results suggest that the agglutination of erythrocytes due to the interactions of Zn2+ ions with band 3 is stable under pressure, but spectrin, cytoskeletal protein, is denatured by pressure. PMID- 29124146 TI - Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Ialpha, a new auto-antigen in Sjogren's syndrome patients, in salivary duct epithelial cells. AB - The regenerating gene, Reg, was originally isolated from a rat regenerating islet cDNA library, and its human homolog was named REG Ialpha. Recently, we reported that REG Ialpha mRNA as well as its product were overexpressed in ductal epithelial cells in the minor salivary glands of Sjogren's syndrome (SS) patients. This study was undertaken to elucidate the role of cytokines and the subsequent intracellular mechanism for induction of REG Ialpha in the salivary glands of SS patients. We prepared a reporter plasmid containing REG Ialpha promoter (-1190/+26) upstream of a luciferase reporter gene. The promoter plasmid was introduced by lipofection into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with interleukin (IL)-6, IL-8, and a combination of the two. Thereafter transcriptional activity of REG Ialpha was measured by luciferase assay. We found that IL-6 stimulation, but not IL-8, significantly enhanced the REG Ialpha promoter activity in salivary ductal cells. Deletion analysis revealed that the region of -141 to -117 of the REG Ialpha gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transduction and activation of transcription (STAT). The introduction of siRNA for human STAT3 abolished IL-6-induced REG Ialpha transcription. These results showed that IL-6 stimulation induced REG Ialpha transcription through STAT3 activation and binding to the consensus sequence of REG Ialpha promoter in salivary ductal cells. This IL-6/STAT dependent REG Ialpha induction might play a role in the pathogenesis of SS. PMID- 29124147 TI - Insights into the inhibitory mechanism of triazole-based small molecules on phosphatidylinositol-4,5-bisphosphate binding pleckstrin homology domain. AB - Background: Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is an important regulator of several cellular processes and a precursor for other second messengers which are involved in cell signaling pathways. Signaling proteins preferably interact with PI(4,5)P2 through its pleckstrin homology (PH) domain. Efforts are underway to design small molecule-based antagonist, which can specifically inhibit the PI(4,5)P2/PH-domain interaction to establish an alternate strategy for the development of drug(s) for phosphoinositide signaling pathways. Methods: Surface plasmon resonance, molecular docking, circular dichroism, competitive Forster resonance energy transfer, isothermal titration calorimetric analyses and liposome pull down assay were used. Results: In this study, we employed 1,2,3-triazol-4-yl methanol containing small molecule (CIPs) as antagonists for PI(4,5)P2/PH-domain interaction and determined their inhibitory effect by using competitive-surface plasmon resonance analysis (IC50 ranges from 53 to 159 nM for PI(4,5)P2/PLCdelta1-PH domain binding assay). We also used phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], PI(4,5)P2 specific PH-domains to determine binding selectivity of the compounds. Various physicochemical analyses showed that the compounds have weak affect on fluidity of the model membrane but, strongly interact with the phospholipase C delta1 (PLCdelta1)-PH domains. The 1,2,3-triazol-4-yl methanol moiety and nitro group of the compounds are essential for their exothermic interaction with the PH-domains. Potent compound can efficiently displace PLCdelta1-PH domain from plasma membrane to cytosol in A549 cells. Conclusions: Overall, our studies demonstrate that these compounds interact with the PIP-binding PH-domains and inhibit their membrane recruitment. General significance: These results suggest specific but differential binding of these compounds to the PLCdelta1-PH domain and emphasize the role of their structural differences in binding parameters. These triazole based compounds could be directly used/further developed as potential inhibitor for PH domain-dependent enzyme activity. PMID- 29124149 TI - HaCaT anchorage blockade leads to oxidative stress, DNA damage and DNA methylation changes. AB - Cell adhesion plays an important role in neoplastic transformation. Thus, anchorage-independent growth and epithelial-mesenchymal transition, which are features associated to anoikis-resistance, are vital steps in cancer progression and metastatic colonization. Cell attachment loss may induce intracellular oxidative stress, which triggers DNA damage as methylation changes. HaCaT lineage cells were submitted to periods of 1, 3, 5 and 24 h of anchorage blockage with the purpose of study of oxidative stress effect on changes in the DNA methylation pattern, derived from attachment blockade. Through this study, HaCaT anchorage blockage-induced oxidative stress was reported to mediate alterations in global DNA methylation changes and into TP53 gene promoter pattern during anoikis resistance acquisition. Furthermore, at the first experimental time-periods (1, 3 and 5 h), genome hypermethylation was found; however, genome hypomethylation was observed in later time-periods (24 h) of attachment impediment. The TP 53 methylation analyses were performed after 24 h of replated anoikis-resistance cells and same methylation pattern was observed, occurring an early (1 and 3 h) hypermethylation that was followed by late (5 and 24 h) hypomethylation. However, LINE-1, a marker of genomic instability, was perceived in time-dependent hypomethylation. The mRNA levels of the DNMTs enzymes were influenced by cell attachment blockage, but non-conclusive results were obtained in order to match DNMTs transcription to pattern methylation results. In conclusion, DNA damage was found, leaded by oxidative stress that has come up from HaCaT anchorage blockade, which rises a global genome hypomethylation tendency as consequence, which might denote genomic instability. PMID- 29124148 TI - Model of ribosomal translocation coupled with intra- and inter-subunit rotations. AB - The ribosomal translocation involves both intersubunit rotations between the small 30S and large 50S subunits and the intrasubunit rotations of the 30S head relative to the 30S body. However, the detailed molecular mechanism on how the intersubunit and intrasubunit rotations are related to the translocation remains unclear. Here, based on available structural data a model is proposed for the ribosomal translocation, into which both the intersubunit and intrasubunit rotations are incorporated. With the model, we provide quantitative explanations of in vitro experimental data showing the biphasic character in the fluorescence change associated with the mRNA translocation and the character of a rapid increase that is followed by a slow single-exponential decrease in the fluorescence change associated with the 30S head rotation. The calculated translation rate is also consistent with the in vitro single-molecule experimental data. PMID- 29124150 TI - Analysis of ent-kaurenoic acid by ultra-performance liquid chromatography-tandem mass spectrometry. AB - ent-Kaurenoic acid (KA) is a key intermediate connected to a phytohormone gibberellin. To date, the general procedure for quantifying KA is by using traditional gas chromatography-mass spectrometry (GC-MS). In contrast, gibberellins, which are more hydrophilic than KA, can be easily quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, we have established a new method to quantify KA by LC-MS/MS by taking advantage of a key feature of KA, namely the lack of fragmentation that occurs in MS/MS when electrospray ionization (ESI) is in the negative mode. Q1 and Q3 were adopted as identical channels for the multiple reaction monitoring of KA. The method was validated by comparing with the results obtained by selected ion monitoring in GC MS. This new method could be applicable for the quantification of other hydrophobic compounds. PMID- 29124151 TI - Isolation and immobilization of alkaline protease on mesoporous silica and mesoporous ZSM-5 zeolite materials for improved catalytic properties. AB - Alkaline protease from brinjal leaf (Solanum melongena) having milk clotting activity has been purified to 9.44 fold to a final specific activity of 45.71 U/mg. SDS-PAGE of the final preparation revealed a single protein band of approx 14 kDa. Purified enzyme was characterized and was successfully immobilized into the amorphous mesoporous silica (SBA-15) and crystalline mesoporous zeolite (Nano ZSM-5) using entrapment method. Maximum immobilization of 63.5% and 79.77% was obtained with SBA-15 and Nano-ZSM-5, respectively. This protocol serves as a novel approach for bioprocesses, mainly as milk coagulant for local dairy products and particularly, cheese making, and opens the new dimension of further research and other innovation. PMID- 29124152 TI - Construction of P-glycoprotein incorporated tethered lipid bilayer membranes. AB - To investigate drug-membrane protein interactions, an artificial tethered lipid bilayer system was constructed for the functional integration of membrane proteins with large extra-membrane domains such as multi-drug resistance protein 1 (MDR1). In this study, a modified lipid (i.e., 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[amino (polyethylene glycol)-2000] (DSPE-PEG)) was utilized as a spacer molecule to elevate lipid membrane from the sensor surface and generate a reservoir underneath. Concentration of DSPE-PEG molecule significantly affected the liposome binding/spreading and lipid bilayer formation, and 0.03 mg/mL of DSPE-PEG provided optimum conditions for membrane protein integration. Further, the incorporation of MDR1 increased the local rigidity on the platform. Antibody binding studies showed the functional integration of MDR1 protein into lipid bilayer platform. The platform allowed to follow MDR!-statin-based drug interactions in vitro. Each binding event and lipid bilayer formation was monitored in real-time using Surface Plasmon Resonance and Quartz Crystal Microbalance-Dissipation systems, and Atomic Force Microscopy was used for visualization experiments. PMID- 29124154 TI - Psoriasis pathogenesis - Pso p27 constitutes a compact structure forming large aggregates. AB - Psoriasis is a chronic inflammatory skin disease. The absence of microbial organisms as potential causal agents has given rise to the hypothesis that the inflammation is due to an autoimmune reaction. The defined inflamed areas of the skin lesions argue for an immunological disease with a local production of a causal antigen. Pso p27 is a protein generated in mast cells in psoriatic plaques, but not in uninvolved skin. We recently demonstrated that the Pso p27 is generated by cleavage of SerpinB3 (SCCA1) in the presence of mast cell associated chymase. In this communication we demonstrate by X-ray crystallographic analysis that the cleavage products associate into a complex similar to SCCA1, but with the reactive centre loop inserted into a 5-stranded central beta-sheet. Native gel electrophoresis show that these Pso p27 complexes form large aggregates which may be of significance with respect to an immunogenic role of Pso p27. PMID- 29124153 TI - Human retinal pigment epithelial cell proliferation by the combined stimulation of hydroquinone and advanced glycation end-products via up-regulation of VEGF gene. AB - Although recent research showed that advanced glycation endproduct (AGE) and hydroquinone (HQ) are related to the pathogenesis of age-related macular degeneration (AMD), the mechanism how AGE and HQ induce or accelerate AMD remains elusive. In the present study, we examined the effects of AGE and HQ on changes of human retinal pigment epithelial (RPE) cell numbers and found that the viable cell numbers were markedly reduced by HQ by apoptosis and that AGE prevented the decreases of HQ-treated cell numbers by increased replicative DNA synthesis of RPE cells without changing apoptosis. Real-time RT-PCR revealed that vascular endothelial growth factor (VEGF)-A mRNA was increased by HQ treatment and the addition of HQ+AGE resulted in a further increment. The increase of VEGF secretion was confirmed by ELISA, and inhibition of VEGF signaling by chemical inhibitors and small interfering RNA decreased the HQ+AGE-induced increases in RPE cell numbers. The deletion analysis demonstrated that -102 to -43 region was essential for the VEGF-A promoter activation. Site-directed mutaions of specificity protein 1 (SP1) binding sequences in the VEGF-A promoter and RNA interference of SP1 revealed that SP1 is an essential transcription factor for VEGF-A expression. These results indicate that HQ induces RPE cell apoptosis, leading to dry AMD, and suggest that AGE stimulation in addition to HQ enhances VEGF-A transcription via the AGE-receptor for AGE pathway in HQ-damaged cells. As a result, the secreted VEGF acts as an autocrine/paracrine growth factor for RPE and/or adjacent vascular cells, causing wet AMD. PMID- 29124155 TI - Liposomal delivery of a phosphodiesterase 3 inhibitor rescues low oxygen-induced ATP release from erythrocytes of humans with type 2 diabetes. AB - ATP release from erythrocytes in response to low oxygen tension requires an increase in cAMP, the level of which is regulated by phosphodiesterase 3 (PDE3). Such release is defective in erythrocytes of humans with type 2 diabetes (DM2). This study tested a hypothesis that direct delivery of the clinically useful PDE3 inhibitor, cilostazol, to erythrocytes of humans with type 2 diabetes using liposomes would restore low-oxygen tension-induced ATP release. Cilostazol was incorporated into liposomes prepared from dimyristoylphosphatidylcholine (DMPC). Liposome-delivery of cilostazol restored ATP release from DM2 erythrocytes to levels which were not different from that released from non-cilostazol treated healthy erythrocytes under the same conditions. There were no observed adverse effects of the liposomes on either healthy or DM2 erythrocytes. The directed liposomal delivery of PDE inhibitors to erythrocytes may help prevent or slow the development of peripheral vascular disease in individuals with DM2 by restoring an important physiological controller of microvascular perfusion while minimizing side effects associated with systemic delivery of some of these inhibitors. PMID- 29124156 TI - Chromatin structure analysis enables detection of DNA insertions into the mammalian nuclear genome. AB - Background: Genetically modified organisms (GMOs) have numerous biomedical, agricultural and environmental applications. Development of accurate methods for the detection of GMOs is a prerequisite for the identification and control of authorized and unauthorized release of these engineered organisms into the environment and into the food chain. Current detection methods are unable to detect uncharacterized GMOs, since either the DNA sequence of the transgene or the amino acid sequence of the protein must be known for DNA-based or immunological-based detection, respectively. Methods: Here we describe the application of an epigenetics-based approach for the detection of mammalian GMOs via analysis of chromatin structural changes occurring in the host nucleus upon the insertion of foreign or endogenous DNA. Results: Immunological methods combined with DNA next generation sequencing enabled direct interrogation of chromatin structure and identification of insertions of various size foreign (human or viral) DNA sequences, DNA sequences often used as genome modification tools (e.g. viral sequences, transposon elements), or endogenous DNA sequences into the nuclear genome of a model animal organism. Conclusions: The results provide a proof-of-concept that epigenetic approaches can be used to detect the insertion of endogenous and exogenous sequences into the genome of higher organisms where the method of genetic modification, the sequence of inserted DNA, and the exact genomic insertion site(s) are unknown. General significance: Measurement of chromatin dynamics as a sensor for detection of genomic manipulation and, more broadly, organism exposure to environmental or other factors affecting the epigenomic landscape are discussed. PMID- 29124157 TI - The constituents of licorice (Glycyrrhiza uralensis) differentially suppress nitric oxide production in interleukin-1beta-treated hepatocytes. AB - Licorice (Glycyrrhizae radix) is the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linnaeus in the Japanese Pharmacopoeia. Glycyrrhizae radix has been widely used as a sweetener and a traditional medicine. A Glycyrrhizae radix extract contains many constituents and has antispasmodic, antitussive, anti-ulcer, and anti-inflammatory effects. However, reports comparing the anti-inflammatory effects of these constituents are very few. Here, we purified several constituents from the roots and stolons of G. uralensis and examined and compared their anti-inflammatory effects by monitoring the levels of the inflammatory mediator, nitric oxide (NO), in interleukin (IL) 1beta-treated rat hepatocytes. From the G. uralensis extract, we purified the main constituent glycyrrhizin and the constituents that are characteristic of G. uralensis (chalcones and flavanones). These constituents suppressed NO production in IL-1beta-treated rat hepatocytes, and isoliquiritigenin showed the greatest suppression activity. Isoliquiritigenin, isoliquiritin, and liquiritigenin significantly decreased both protein and mRNA for the inducible nitric oxide synthase. These constituents reduced the levels of mRNAs encoding tumor necrosis factor alpha and IL-6. In contrast, although glycyrrhizin is abundant, it showed a 100-fold lower potency in NO suppression. Therefore, both glycyrrhizin and the minor constituents (isoliquiritigenin, isoliquiritin, and liquiritigenin) may be responsible for the anti-inflammatory effects of G. uralensis. It is also implied that these constituents may have a therapeutic potential for inflammatory hepatic disorders. PMID- 29124158 TI - The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops. AB - HIV-1 protease (PR) is a 99 amino acid protein responsible for proteolytic processing of the viral polyprotein - an essential step in the HIV-1 life cycle. Drug resistance mutations in PR that are selected during antiretroviral therapy lead to reduced efficacy of protease inhibitors (PI) including darunavir (DRV). To identify the structural mechanisms associated with the DRV resistance mutation L33F, we performed X-ray crystallographic studies with a multi-drug resistant HIV 1 protease isolate that contains the L33F mutation (MDR769 L33F). In contrast to other PR L33F DRV complexes, the structure of MDR769 L33F complexed with DRV reported here displays the protease flaps in an open conformation. The L33F mutation increases noncovalent interactions in the hydrophobic pocket of the PR compared to the wild-type (WT) structure. As a result, L33F appears to act as a molecular anchor, reducing the flexibility of the 30s loop (residues 29-35) and the 80s loop (residues 79-84). Molecular anchoring of the 30s and 80s loops leaves an open S1/S1' subsite and distorts the conserved hydrogen-bonding network of DRV. These findings are consistent with previous reports despite structural differences with regards to flap conformation. PMID- 29124159 TI - Functional identification of organic cation transporter 1 as an atenolol transporter sensitive to flavonoids. AB - Atenolol, a beta1-adrenergic receptor blocker, is administered orally and its intestinal absorption has recently been indicated to be mediated by carrier protein and reduced markedly by ingestion of some fruit juices, such as apple and orange juices. This could be postulated to be a problem arising from the interaction of some components of fruit juices with atenolol at a transporter involved in its intestinal uptake, but the responsible transporter and its interacting components have not been identified yet. In an attempt to examine that possibility, we could successfully find that human organic cation transporter 1 (OCT1/SLC22A1), which is suggested to be expressed at the brush border membrane of enterocytes, is highly capable of transporting atenolol. In this attempt, OCT1 was stably expressed in Madin-Darby canine kidney II cells and the specific uptake of atenolol by the transporter was found to be saturable, conforming to the Michaelis-Menten kinetics with the maximum transport rate (Vmax) of 4.00 nmol/min/mg protein and the Michaelis constant (Km) of 3.08 mM. Furthermore, the OCT1-specific uptake was found to be inhibited by various flavonoids, including those contained in fruit juices that have been suggested to interfere with intestinal atenolol absorption. Particularly, phloretin and quercetin, which are major components of apple juice, were potent in inhibiting OCT1-mediated atenolol transport with the inhibition constants of 38.0 and 48.0 uM, respectively. It is also notable that the inhibition by these flavonoids was of the noncompetitive type. These results indicate that OCT1 is an atenolol transporter that may be involved in intestinal atenolol uptake and sensitive to fruit juices, although its physiological and clinical relevance remains to be further examined. PMID- 29124160 TI - The double mutation of cytochrome P450's and fatty acid desaturases affect lipid regulation and longevity in C. elegans. AB - An imbalance between energy uptake and energy expenditure can lead to obesity and increase the risk of coronary heart disease, high blood pressure, stroke, type II diabetes and some cancers. Given that key elements of the energy pathway are evolutionary conserved, invertebrate research is an attractive alternative that overcomes the many legislative, financial and experimental hurdles typical of research with higher metazoan animals. Recent studies have suggested that some members of the cytochrome P450 superfamily are involved in lipid metabolism in addition to the traditional xenobiotic activity. To investigate this notion in more detail, the present study aimed to pinpoint phenotypic, genetic and genomic level responses of Caenorhabditis elegans using selected deletion mutants including fat-5 (a member of the Delta9 desaturases) and cyp-35A2 (a member of the cytochrome P450 family). The creation of a fat-5(tm420);cyp-35A2(gk317) mutant uncovered that the deletion of both genes resulted in a strain which is marked by an extended lifespan. Furthermore, it diminished the overall level of Nile Red positive compartments, which is indicative of a change in lipid metabolism. Comprehensive transcriptomics revealed that several genes involved in aging and lipid transport/homeostasis were modulated following the double deletion of fat-5 and cyp-35A2. Taken together, the results suggest the presence of a putative correlation between longevity and lipid regulation and given that both genes have human homologs, this finding may offer a new lead to investigate in higher organisms. PMID- 29124161 TI - Comparative gene expression profiles in pancreatic islets associated with agouti yellow mutation and PACAP overexpression in mice. AB - In diabetes mellitus, pituitary adenylate cyclase-activating polypeptide (PACAP) has insulinotropic and glucose-lowering properties. We previously demonstrated that transgenic mice overexpressing PACAP in pancreatic beta-cells (PACAP-Tg) show attenuated pancreatic islet hyperplasia and hyperinsulinemia in type 2 diabetic models. To explore the underlying mechanisms, here we crossed PACAP-Tg mice with lethal yellow agouti (KKAy) diabetic mice, and performed gene chip analysis of laser capture microdissected pancreatic islets from four F1 offspring genotypes (wild-type, PACAP-Tg, KKAy, and PACAP-Tg:KKAy). We identified 1371 probes with >16-fold differences between at least one pair of genotypes, and classified the probes into five clusters with characteristic expression patterns. Gene ontology enrichment analysis showed that genes involved in the terms ribosome and intracellular organelles such as ribonucleoprotein complex, mitochondrion, and chromosome organization were significantly enriched in clusters characterized by up-regulated genes in PACAP-Tg:KKAy mice compared with KKAy mice. These results may provide insight into the mechanisms of diabetes that accompany islet hyperplasia and amelioration by PACAP. PMID- 29124162 TI - The effect of the cytoplasmic tail of influenza C virus CM2 protein on its biochemical properties and intracellular processing. AB - CM2 is an integral membrane protein encoded by the influenza C virus M gene. To examine the effects of the cytoplasmic tail of CM2 on its biochemical properties, deletion and substitution mutations were introduced into CM2 cytoplasmic tail at residues 47-115, and the expressed CM2 mutants were investigated. Although the cytoplasmic tail is not essential for the oligomerization of CM2, it may affect the degree of oligomerization. The residues 47-48, 67-69, 73-90 and 113-115 were all required for the proper expression of CM2. Pulse-chase experiments suggest that residues 47-48, 67-69, 73-75 and 79-87 stabilize CM2, thereby affecting CM2 expression. The C-terminal region at residues 61-115 is not essential for CM2 transport to the cell surface, and a 14-amino-acid, but not an 11-amino-acid, cytoplasmic tail is sufficient for the cell surface expression of CM2. These results suggest that either certain amino acid sequences or the length of the CM2 cytoplasmic tail are necessary for the proper conformational maturation, stability, expression level and intracellular transport of CM2. PMID- 29124163 TI - Surfaceome and exoproteome of a clinical sequence type 398 methicillin resistant Staphylococcus aureus strain. AB - For many years Staphylococcus aureus has been recognized as an important human pathogen. In this study, the surfacome and exoproteome of a clinical sample of MRSA was analyzed. The C2355 strain, previously typed as ST398 and spa-t011 and showing a phenotype of multiresistance to antibiotics, has several resistance genes. Using shotgun proteomics and bioinformatics tools, 236 proteins were identified in the surfaceome and 99 proteins in the exoproteome. Although many of these proteins are related to basic cell functions, some are related to virulence and pathogenicity like catalase and isdA, main actors in S. aureus infection, and others are related to antibiotic action or eventually resistance like penicillin binding protein, a cell-wall protein. Studying the proteomes of different subcellular compartments should improve our understanding of this pathogen, a microorganism with several mechanisms of resistance and pathogenicity, and provide valuable data for bioinformatics databases. PMID- 29124164 TI - Structural insight into activation of homoserine dehydrogenase from the archaeon Sulfolobus tokodaii via reduction. AB - Homoserine dehydrogenase (HSD; 305 amino acid residues) catalyzes an NAD(P) dependent reversible reaction between l-homoserine and aspartate 4-semialdehyde and is involved in the aspartate pathway. HSD from the hyperthermophilic archaeon Sulfolobus tokodaii was markedly activated (2.5-fold) by the addition of 0.8 mM dithiothreitol. The crystal structure of the homodimer indicated that the activation was caused by cleavage of the disulfide bond formed between two cysteine residues (C303) in the C-terminal regions of the two subunits. PMID- 29124165 TI - alpha-Amylase immobilization onto functionalized graphene nanosheets as scaffolds: Its characterization, kinetics and potential applications in starch based industries. AB - alpha-Amylase is imperative for starch and its deriviatized industries. Functionalized graphene sheets were tailored and optimized as scaffold for alpha amylase immobilization using Response Surface Methodology based on Box-Behnken design, with an overall immobilization efficiency of 85.16%. Analysis of variance provided adequacy to the mathematical model for further studies. Native and immobilized functionalized graphene were characterized using transmission and scanning electron microscopy, followed by Fourier transform infrared (FTIR) spectroscopy. Wheat alpha-amylase conjugated with functionalized graphene sheets were visually evident on transmission and scanning micrographs while the FTIR spectra showed interplay of various chemical interactions and bonding, during and after immobilization. Optimum pH and optimum temperature for immobilized enzyme though remained unchanged but showed broader range whereas Km showed a slight decrease (1.32 mg/mL). It also showed enhanced thermal and storage stability and retained 73% residual activity after 10 uses. These ensemble of properties and non-toxic nature of functionalized graphene, makes it viable to be absorbed commercially in starch processing industries. PMID- 29124166 TI - Kinesin family member 14 in human oral cancer: A potential biomarker for tumoral growth. AB - Kinesin family member 14 (KIF14), a microtubule-based motor protein, plays an important role in chromosomal segregation, congression, and alignment. Considerable evidence indicates that KIF14 is involved in cytokinesis, although little is known about its role in oral squamous cell carcinomas (OSCCs). In the current study, we functionally and clinically investigated KIF14 expression in patients with OSCC. Quantitative reverse transcriptase-polymerase chain reaction and immunoblotting analyses were used to assess the KIF14 regulatory mechanism in OSCC. Immunohistochemistry (IHC) was performed to analyze the correlation between KIF14 expression and clinical behavior in 104 patients with OSCC. A KIF14 knockdown model of OSCC cells (shKIF14 cells) was used for functional experiments. KIF14 expression was up-regulated significantly (P<0.05) in OSCCs compared with normal counterparts in vitro and in vivo. In addition, shKIF14 cells inhibited cellular proliferation compared with control cells by cell-cycle arrest at the G2/M phase through up-regulation of G2 arrest-related proteins (p Cdc2 and cyclin B1). As expected, IHC data from primary OSCCs showed that KIF14 positive patients exhibited significantly (P<0.05) more larger tumors compared with KIF14-negative patients. The current results suggest for the first time that KIF14 is an indicator of tumoral size in OSCCs and that KIF14 might be a potential therapeutic target for development of new treatments for OSCCs. PMID- 29124167 TI - Anti-prion activity found in beetle grub hemolymph of Trypoxylus dichotomus septentrionalis. AB - No remedies for prion disease have been established, and the conversion of normal to abnormal prion protein, a key event in prion disease, is still unclear. Here we found that substances in beetle grub hemolymph, after they were browned by aging for a month or heating for hours, reduced abnormal prion protein (PrP) levels in RML prion-infected cells. Active anti-prion components in the hemolymph were resistant to protease treatment and had molecular weights larger than 100 kDa. Aminoguanidine treatment of the hemolymph abolished its anti-prion activity, suggesting that Maillard reaction products are enrolled in the activity against the RML prion. However, levels of abnormal PrP in RML prion-infected cells were not decreased by incubation with the Maillard reaction products formed by amino acids or bovine serum albumin. The anti-prion components in the hemolymph modified neither cellular or cell-surface PrP levels nor lipid raft or autophagosome levels. The anti-prion activity was not observed in cells infected with 22 L prion or Fukuoka-1 prion, suggesting the anti-prion action is prion strain-dependent. Although the active components of the hemolymph need to be further evaluated, the present findings imply that certain specific chemical structures in the hemolymph, but not chemical structures common to all Maillard reaction products, are involved in RML prion formation or turnover, without modifying normal PrP expression. The anti-prion components in the hemolymph are a new tool for elucidating strain-dependent prion biology. PMID- 29124168 TI - A single conserved basic residue in the potassium channel filter region controls KCNQ1 insensitivity toward scorpion toxins. AB - Although many studies concerning the sensitivity mechanism of scorpion toxin potassium channel interactions have been reported, few have explored the biochemical insensitivity mechanisms of potassium channel receptors toward natural scorpion toxin peptides, such as the KCNQ1 channel. Here, by sequence alignment analyses of the human KCNQ1 channel and scorpion potassium channel MmKv2, which is completely insensitive to scorpion toxins, we proposed that the insensitivity mechanism of KCNQ1 toward natural scorpion toxins might involve two functional regions, the turret and filter regions. Based on this observation, a series of KCNQ1 mutants were constructed to study molecular mechanisms of the KCNQ1 channel insensitivity toward natural scorpion toxins. Electrophysiological studies of chimera channels showed that the channel filter region controls KCNQ1 insensitivity toward the classical scorpion toxin ChTX. Interestingly, further residue mutant experiments showed that a single basic residue in the filter region determined the insensitivity of KCNQ1 channels toward scorpion toxins. Our present work showed that amino acid residue diversification at common sites controls the sensitivity and insensitivity of potassium channels toward scorpion toxins. The unique insensitivity mechanism of KCNQ1 toward natural scorpion toxins will accelerate the rational design of potent peptide inhibitors toward this channel. PMID- 29124169 TI - A method of gentle hydration to prepare oil-free giant unilamellar vesicles that can confine enzymatic reactions. AB - We report a new and improved method to prepare, by gentle hydration of lipid films, oil-free giant unilamellar vesicles (GUVs), in which enzymatic reactions can be encapsulated. The traditional method of gentle hydration requires very low concentrations of metal ions, whereas enzymatic reactions generally require mono- and divalent metal ions at physiological concentrations. In order to improve the production of oil-free GUVs that can confine enzymatic reactions, we developed a novel method also based on gentle hydration, but in which the precursor lipid film was doped with both 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethylene glycol)-2000] (PEGylated lipid) and sugar. Close examination of the size, shape, and lamellarity of vesicles prepared in this manner demonstrated that the process improves the production of oil-free GUVs even at low temperatures and physiological salt concentrations. PEGylated lipid and sugar were found to synergistically improve GUV formation. Finally, we demonstrate the successful enzymatic synthesis of RNA within oil-free GUVs that were prepared on ice. PMID- 29124170 TI - The histone deacetylase inhibitor cambinol prevents acidic pHe-induced anterograde lysosome trafficking independently of sirtuin activity. AB - Common features of the solid tumor microenvironment, such as acidic extracellular pH and growth factors, are known to induce the redistribution of lysosomes from a perinuclear region to a position near the plasma membrane. Lysosome/plasma membrane juxtaposition facilitates invasion by allowing for the release of lysosomal proteases, including cathepsin B, which contribute to matrix degradation. In this study we identified the sirtuin 1/sirtuin 2 (SIRT1/2) inhibitor cambinol acts as a drug that inhibits lysosome redistribution and tumor invasion. Treatment of cells with cambinol resulted in a juxtanuclear lysosome aggregation (JLA) similar to that seen upon treatment with the PPARgamma agonist, troglitazone (Tro). Like Tro, cambinol required the activity of ERK1/2 in order to induce this lysosome clustering phenotype. However, cambinol did not require the activity of Rab7, suggesting that this drug causes JLA by a mechanism different from what is known for Tro. Additionally, cambinol-induced JLA was not a result of autophagy induction. Further investigation revealed that cambinol triggered JLA independently of its activity as a SIRT1/2 inhibitor, suggesting that this drug could have effects in addition to SIRT1/2 inhibition that could be developed into a novel anti-cancer therapy. PMID- 29124171 TI - Effect of methionine-35 oxidation on the aggregation of amyloid-beta peptide. AB - Aggregation of Abeta peptides into amyloid plaques is considered to trigger the Alzheimer's disease (AD), however the mechanism behind the AD onset has remained elusive. It is assumed that the insoluble Abeta aggregates enhance oxidative stress (OS) by generating free radicals with the assistance of bound copper ions. The aim of our study was to establish the role of Met35 residue in the oxidation and peptide aggregation processes. Met35 can be readily oxidized by H2O2. The fibrillization of Abeta with Met35 oxidized to sulfoxide was three times slower compared to that of the regular peptide. The fibrils of regular and oxidized peptides looked similar under transmission electron microscopy. The relatively small inhibitory effect of methionine oxidation on the fibrillization suggests that the possible variation in the Met oxidation state should not affect the in vivo plaque formation. The peptide oxidation pattern was more complex when copper ions were present: addition of one oxygen atom was still the fastest process, however, it was accompanied by multiple unspecific modifications of peptide residues. Addition of copper ions to the Abeta with oxidized Met35 in the presence of H2O2, resulted a similar pattern of nonspecific modifications, suggesting that the one-electron oxidation processes in the peptide molecule do not depend on the oxidation state of Met35 residue. Thus, it can be concluded that Met35 residue is not a part of the radical generating mechanism of Abeta Cu(II) complex. PMID- 29124172 TI - The intronic region of Fbxl12 functions as an alternative promoter regulated by UV irradiation. AB - The ubiquitin ligases, SCF complexes, consist of Cul1, Skp1, Rbx1 and the substrate recognition components F-box proteins. Previous studies have reported that one of these F-box proteins, Fbl12, which is produced by Fbxl12 gene, regulates both cell cycle and differentiation. In this paper, we show that the intronic region of Fbxl12 gene acts as an alternative promoter and induces expression of a short form of Fbl12 that lacks F-box domain (Fbl12DeltaF). We also found that UV irradiation increases Fbl12DeltaF mRNA in cells. Finally, Fbl12DeltaF may promote the subcellular localization of Fbl12 from nucleus to cytoplasm through their binding. Our data provide the possibility that Fbl12DeltaF induced by alternative promoter controls the SCFFbl12 activity in response to UV stimulation. PMID- 29124173 TI - The stability of the TIM-barrel domain of a psychrophilic chitinase. AB - Chitinase 60 from the psychrophilic bacterium Moritella marina (MmChi60) is a four-domain protein whose structure revealed flexible hinge regions between the domains, yielding conformations in solution that range from fully extended to compact. The catalytic domain is a shallow-grooved TIM-barrel. Heat-induced denaturation experiments of the wild-type and mutants resulting from the deletions of the two-Ig-like domains and the chitin binding domain reveal calorimetric profiles that are consistent with non-collaborative thermal unfolding of the individual domains, a property that must be associated to the "hinge-regions". The calorimetric measurements of the (beta/alpha)8 catalytic domain reveal that the thermal unfolding is a slow-relaxation transition exhibiting a stable, partially structured intermediate state. Circular dichroism provides evidence that the intermediate exhibits features of a molten globule i.e., loss of tertiary structure while maintaining the secondary structural elements of the native. GdnHCl-induced denaturation studies of the TIM-barrel demonstrate an extraordinarily high resistance to the denaturant. Slow-relaxation kinetics characterize the unfolding with equilibration times exceeding six days, a property that is for the first time observed for a psychrophilic TIM barrel. On the other hand, the thermodynamic stability is DeltaG=6.75+/-1.3 kcal/mol, considerably lower than for structural-insertions-containing barrels. The mutant E153Q used for the crystallographic studies of MmChi60 complexes with NAG ligands has a much lower stability than the wild-type. PMID- 29124174 TI - Oxidative stress-mediated antitumor activity of erythorbic acid in high doses. AB - Intravenous (iv) infusion of high-dose ascorbic acid (AA) has been used as a treatment for cancer patients. The tumoricidal action of AA occurs due to its prooxidant effect. Erythorbic acid (EA), one of the AA epimers, has reduced vitamin C activity, while the antioxidant activity of EA is similar to that of AA. Currently, other physiological and pharmacological functions of EA are not well known. We examined the cytotoxicity of EA to murine colon carcinoma (colon 26) cells and the antitumor activity of EA in tumor-bearing mice. Cytotoxic activity of EA to colon-26 cells was evaluated by using the calcein-AM assay. EA showed the same cytotoxic activity to colon-26 cells as that of AA. The cytotoxicity of EA was shown to be caused by oxidative stress. Next, colon-26 tumor-bearing mice were iv administered EA and AA on alternate days for 4 times, and tumor growth rates were measured. Tumor growth was significantly inhibited by administration of high-dose EA in vivo as well as AA. Finally, the in vivo biodistribution and clearance of EA and AA were investigated in tumor-bearing mice. Endogenous AA in the tumor was consumed to resist oxidative stress caused by reactive oxygen species that was generated by administered EA. These results indicated that the oxidative stress-mediated antitumor activity is one of the pharmacological functions of high-dose iv EA. PMID- 29124175 TI - Transthyretin chemical chaperoning by flavonoids: Structure-activity insights towards the design of potent amyloidosis inhibitors. AB - Background: Many polyphenols have been proposed as broad-spectrum inhibitors of amyloid formation. To investigate structure-activity relationships relevant for the interaction of flavonoids with transthyretin (TTR), the protein associated with familial amyloid polyneuropathy (FAP), we compared the effects of major tea catechins and their larger polymers theaflavins, side-by-side, on TTR amyloid formation process. Methods: Interaction of flavonoids with TTR and effect on TTR stability were assessed through binding assays and isoelectric focusing in polyacrylamide gel. TTR aggregation was studied, in vitro, by dynamic light scattering (DLS), transmission electron microscopy (TEM) and in cell culture, through cytotoxicity assays. Results: Tested flavonoids bound to TTR and stabilized the TTR tetramer, with different potencies. The flavonoids also inhibited in vitro formation of TTR small oligomeric species and in cell culture inhibited pathways involving caspase-3 activation and ER stress that are induced by TTR oligomers. In all assays performed the galloyl esters presented higher potency to inhibit aggregation than the non-gallated flavonoids tested. Conclusions: Our results highlight the presence of gallate ester moiety as key structural feature of flavonoids in chemical chaperoning of TTR aggregation. Upon binding to the native tetramer, gallated flavonoids redirect the TTR amyloidogenic pathway into unstructured nontoxic aggregation assemblies more efficiently than their non-gallated forms. General significance: Our findings suggest that galloyl moieties greatly enhance flavonoid anti-amyloid chaperone activity and this should be taken into consideration in therapeutic candidate drug discovery. PMID- 29124176 TI - The polyglutamine-expanded androgen receptor has increased DNA binding and reduced transcriptional activity. AB - Expansion of a polyglutamine-encoding trinucleotide CAG repeat in the androgen receptor (AR) to more than 37 repeats is responsible for the X-linked neuromuscular disease spinal and bulbar muscular atrophy (SBMA). Here we evaluated the effect of polyglutamine length on AR function in Xenopus oocytes. This allowed us to correlate the nuclear AR concentration to its capacity for specific DNA binding and transcription activation in vivo. AR variants with polyglutamine tracts containing either 25 or 64 residues were expressed in Xenopus oocytes by cytoplasmic injection of the corresponding mRNAs. The intranuclear AR concentration was monitored in isolated nuclei and related to specific DNA binding as well as transcriptional induction from the hormone response element in the mouse mammary tumor virus (MMTV) promoter. The expanded AR with 64 glutamines had increased capacity for specific DNA binding and a reduced capacity for transcriptional induction as related to its DNA binding activity. The possible mechanism behind these polyglutamine-induced alterations in AR function is discussed. PMID- 29124177 TI - Activities of 20 aminoacyl-tRNA synthetases expressed in a reconstituted translation system in Escherichia coli. AB - A significant challenge in the field of in vitro synthetic biology is the construction of a self-reproducing cell-free translation system, which reproduces its components, such as translation proteins, through translation and transcription by itself. As a first step for such construction, in this study we expressed and evaluated the activity of 20 aminoacyl-tRNA synthetases (aaRSs), a major component of a translation system, in a reconstituted translation system (PURE system). We found that 19 aaRS with the exception of phenylalanyl-tRNA synthetase (PheRS) are expressed as soluble proteins and their activities are comparable to those expressed in Escherichia coli . This study provides basic information on the properties of aaRSs expressed in the PURE system, which will be helpful for the future reconstitution of a self-reproducing translation system. PMID- 29124178 TI - A pirin-like protein from Pseudomonas stutzeri and its quercetinase activity. AB - A pirin-like protein from a marine denitrifying bacterium, Pseudomonas stutzeri Zobell has been heterologously expressed in E. coli and purified to homogeneity with metal-affinity and gel filtration chromatographies. The recombinant pirin like protein has exhibited quercetinase activities upon the incorporation of a divalent metal ion, while its biological role remains unclear. In the case of Cu2+ the holo-protein demonstrated the highest activities and spectroscopic properties typical of type II Cu protein. A 3D-structual model constructed using the crystal structure of human pirin as temperate indicated that the metal biding site is constructed with 3His1Glu located in the consensus sequences in the N terminal domain. PMID- 29124179 TI - Electrospun bioactive mats enriched with Ca-polyphosphate/retinol nanospheres as potential wound dressing. AB - Background: While electrospun materials have been frequently used in tissue engineering no wound dressings exist that significantly improved wound healing effectively. Methods: We succeeded to fabricate three-dimensional (3D) electrospun poly(D,l-lactide) (PLA) fiber mats into which nanospheres, formed from amorphous calcium polyphosphate (polyP) nanoparticles (NP) and encapsulated retinol ("retinol/aCa-polyP-NS" nanospheres [NS]), had been incorporated. Results: Experiments with MC3T3-E1 cells revealed that co-incubation of the cells with Ca-polyP together with retinol (or incubation with retinol/aCa-polyP-NS) resulted in a significant synergistic effect on cell growth compared with particle-free polyP complexed with Ca2+ or amorphous Ca-polyP NPs and retinol alone. Incubation of the cells in the presence of the retinol/aCa-polyP NSs also caused a significant increase of the expression levels of the genes encoding for the fatty acid binding protein 4 (FABP4), as well as of the genes encoding for leptin and the leptin receptor. In contrast, the single components, soluble Na polyP, complexed to Ca2+, or retinol-free aCa-polyP NPs, and retinol, had no significant effect on the expression of these genes. Conclusions: These results indicate that the PLA fibers, supplemented with aCa-polyP-NP or retinol/aCa-polyP NS, elicit morphogenetic activity, suggesting that these fiber mats, along with the antibacterial effect of polyP, have a beneficial potential as wound dressings combining antimicrobial and regenerative (wound healing) properties. General significance: The PLA-based fiber mats, containing retinol and polyP nanoparticles, provide promising bioactive meshes that are urgently needed as dressings for chronic wounds. PMID- 29124180 TI - Conservation of structure and function in vertebrate c-FLIP proteins despite rapid evolutionary change. AB - Cellular FLICE-like inhibitory protein (c-FLIP, gene symbol CFLAR) was first identified as a negative regulator of death receptor-mediated apoptosis in mammals. To understand the ubiquity and diversity of the c-FLIP protein subfamily during evolution, c-FLIP orthologs were identified from a comprehensive range of vertebrates, including birds, amphibians, and fish, and were characterized by combining experimental and computational analysis. Predictions of three dimensional protein structures and molecular phylogenetic analysis indicated that the conserved structural features of c-FLIP proteins are all derived from an ancestral caspase-8, although they rapidly diverged from the subfamily consisting of caspases-8, -10, and -18. The functional role of the c-FLIP subfamily members is nearly ubiquitous throughout vertebrates. Exogenous expression of non mammalian c-FLIP proteins in cultured mammalian cells suppressed death receptor mediated apoptosis, implying that all of these proteins possess anti-apoptotic activity. Furthermore, non-mammalian c-FLIP proteins induced NF-kappaB activation much like their mammalian counterparts. The CFLAR mRNAs were synthesized during frog and fish embryogenesis. Overexpression of a truncated mutant of c-FLIP in the Xenopus laevis embryos by mRNA microinjection caused thorax edema and abnormal constriction of the abdomen. Depletion of cflar transcripts in zebrafish resulted in developmental abnormalities accompanied by edema and irregular red blood cell flow. Thus, our results demonstrate that c-FLIP/CFLAR is conserved in both protein structure and function in several vertebrate species, and suggest a significant role of c-FLIP in embryonic development. PMID- 29124182 TI - The affinity of yeast and bacterial SCO proteins for CU(I) and CU(II). A capture and release strategy for copper transfer. AB - SCO (Synthesis of Cytochrome c Oxidase) proteins are present in prokaryotic and eukaryotic cells, and are often required for efficient synthesis of the respiratory enzyme cytochrome c oxidase. The Bacillus subtilis version of SCO (i.e., BsSCO) has much greater affinity for Cu(II) than it does for Cu(I) (Davidson and Hill, 2009), and this has been contrasted to mitochondrial SCO proteins that are characterized as being specific for Cu(I) (Nittis, George and Winge, 2001). This differential affinity has been proposed to reflect the different physiological environments in which these two members of the SCO protein family reside. In this study the affinity of mitochondrial SCO1 from yeast is compared directly to that of BsSCO in vitro. We find that the yeast SCO1 protein has similar preference for Cu(II) over Cu(I), as does BsSCO. We propose a mechanism for SCO function which would involve high-affinity binding to capture Cu(II), and relatively weak binding of Cu(I) to facilitate copper transfer. PMID- 29124181 TI - Role of gabra2, GABAA receptor alpha-2 subunit, in CNS development. AB - gabra2 gene codes for the alpha-2 subunit of the GABAA receptor, one of the ionotropic receptors which has been related to anxiety, depression and other behavioural disorders, including drug dependence and schizophrenia. GABAergic signalling also plays a role during development, by promoting neural stem cell maintenance and renewal. To investigate the role of gabra2 in CNS development, gabra2 deficient zebrafish were generated. The pattern of proliferation during the embryonic development was disrupted in morphant embryos, which also displayed an increase in the number of apoptotic nuclei mainly at the mid- and hindbrain regions. The expression of several genes (notch1, pax2, fgf8 and wnt1) known to contribute to the development of the central nervous system was also affected in gabra2 morpholino-injected embryos, although no changes were found for pax6a and shh a expression. The transcriptional activity of neuroD (a proneural gene involved in early neuronal determination) was down-regulated in gabra2 deficient embryos, and the expression pattern of gad1b (GABA-synthesising enzyme GAD67) was clearly reduced in injected fish. I propose that gabra2 might be interacting with those signalling pathways that regulate proliferation, differentiation and neurogenesis during the embryonic development; thus, gabra2 might be playing a role in the differentiation of the mesencephalon and cerebellum. Given that changes in GABAergic circuits during development have been related to several psychiatric disorders, such as autism and schizophrenia, this work might be helpful to understand the role of neurotransmitter systems during CNS development and to assess the developmental effects of several GABAergic drugs. PMID- 29124183 TI - Predicting CK2 beta-dependent substrates using linear patterns. AB - CK2 is a constitutively active Ser/Thr protein kinase deregulated in cancer and other pathologies, responsible for about the 20% of the human phosphoproteome. The holoenzyme is a complex composed of two catalytic (alpha or alpha') and two regulatory (beta) subunits, with individual subunits also coexisting in the cell. In the holoenzyme, CK2beta is a substrate-dependent modulator of kinase activity. Therefore, a comprehensive characterization of CK2 cellular function should firstly address which substrates are phosphorylated exclusively when CK2beta is present (class-III or beta-dependent substrates). However, current experimental constrains limit this classification to a few substrates. Here, we took advantage of motif-based prediction and designed four linear patterns for predicting class III behavior in sets of experimentally determined CK2 substrates. Integrating high-throughput substrate prediction, functional classification and network analysis, our results suggest that beta-dependent phosphorylation might exert particular regulatory roles in viral infection and biological processes/pathways like apoptosis, DNA repair and RNA metabolism. It also pointed, that human beta dependent substrates are mainly nuclear, a few of them shuttling between nuclear and cytoplasmic compartments. PMID- 29124184 TI - Solution structure of variant H2A.Z.1 nucleosome investigated by small-angle X ray and neutron scatterings. AB - Solution structures of nucleosomes containing a human histone variant, H2A.Z.1, were measured by small-angle X-ray and neutron scatterings (SAXS and SANS). SAXS revealed that the outer shape, reflecting the DNA shape, of the H2A.Z.1 nucleosome is almost the same as that of the canonical H2A nucleosome. In contrast, SANS employing a contrast variation technique revealed that the histone octamer of the H2A.Z.1 nucleosome is smaller than that of the canonical nucleosome. The DNA within the H2A.Z.1 nucleosome was more susceptible to micrococcal nuclease than that within the canonical nucleosome. These results suggested that the DNA is loosely wrapped around the histone core in the H2A.Z.1 nucleosome. PMID- 29124185 TI - Post-translational activation of non-selenium glutathione peroxidase of Chlamydomonas reinhardtii by specific incorporation of selenium. AB - Glutathione peroxidase (GPX) plays a pivotal role in the protection of cells against oxidative damage. The green alga Chlamydomonas reinhardtii expresses both selenocysteine-containing GPX and the non-selenium GPX homolog (GPXH). We previously reported that supplementation of selenium to algal culture induces GPXH to exhibit GPX activity. Here we investigated the incorporation of selenium into GPXH and its causal relationship with the upregulation of the enzymatic activity. GPXH was purified from algal cells grown with selenium and proteolytically digested into four fragments. Selenium content analysis for these proteolytic fragments confirmed that GPXH-incorporated selenium is predominantly enriched in a fragment that carries the putative catalytic residue Cys-38. We next constructed three kinds of engineered GPXH proteins by substituting Ser for one of three Cys residues in native GPXH, Cys-38, -66, and -84, using a bacterial overexpression system, resulting in Cys38Ser, Cys66Ser, and Cys84Ser derivatives, respectively. Of these, the Cys66Ser and Cys84Ser derivatives exhibited the same level of selenium-dependent GPX activity as the normal recombinant GPXH, whereas the Cys38Ser mutant GPXH not only lost its activity completely but also demonstrated severely impaired incorporation of selenium. These findings strongly suggest that selenium is post-translationally assimilated into the Cys-38 of the GPXH protein, thereby enhancing its enzymatic activity. PMID- 29124186 TI - Application of termite hindgut metagenome derived carboxyl ester hydrolases in the modification of cephalosporin substrates. AB - In the pharmaceutical industry, de-acetylated cephalosporins are highly valuable starting materials for producing semi-synthetic beta-lactam antibiotics. In this study a fosmid metagenome library from termite hindgut symbionts was screened for carboxyl ester hydrolases capable of de-acetylating cephalosporins. Recombinant Escherichia coli clones with esterolytic phenotypes on tributyrin agar plates were selected and further tested for de-acetylating activity against Cephalothin and 7-aminocephalosporanic acid (7-ACA). Two clones displaying de-acetylating activity were sequenced and the corresponding two carboxyl ester hydrolase encoding genes (axeA and axeB) belonging to the carbohydrate esterase family 7 (CE7) were identified. The primary structure of both the axeA and axeB revealed the presence of G-X-S-X-G sequence motif and respective subunit molecular masses of 40 kDa. In addition to de-acetylating cephalosporin based molecules, the two enzymes were also shown to be true esterases based on their preferences for short chain length fatty acid esters. PMID- 29124187 TI - Xanthophylls lutein and zeaxanthin modify gene expression and induce synthesis of hyaluronan in keratinocyte model of human skin. AB - Background: Clinical trials report benefits of the xanthophylls lutein and zeaxanthin for skin health. Here a keratinocyte culture was used to investigate the effects of in vitro xanthophyll treatment on gene expression and biochemical pathways. Methods: We employed the EpiDerm tissue model, Affymetrix Human Genome Array U113, bioinformatics analyses, qPCR validation and biochemical assays for glycosaminoglycans. Results: We discovered 176 genes were significantly (p<0.05) down-regulated (log 2FC>2) and 47 genes were significantly up-regulated. Among the down-regulated genes we validated by qPCR marked reduction in expression of peptidase inhibitors. Bioinformatic analysis of the up-regulated genes implicated biosynthetic pathways for glycosaminoglycans. We assayed but found no increase in production of sulfated glycosaminoglycans, however there was a significant increase in biosynthesis of hyaluronic acid, a non-sulfated glycan. Conclusions: The pattern of xanthophyll-regulated genes and the resulting biochemical responses can be linked with the responses observed in clinic trials. General significance: Skin health benefits from xanthophyll supplementation and this study reveals molecular mechanisms for some of the effects. PMID- 29124189 TI - Association of lamin A/C with muscle gene-specific promoters in myoblasts. AB - The A-type and B-type lamins form a filamentous meshwork underneath the inner nuclear membrane called the nuclear lamina, which is an important component of nuclear architecture in metazoan cells. The lamina interacts with large, mostly repressive chromatin domains at the nuclear periphery. In addition, genome-lamina interactions also involve dynamic association of lamin A/C with gene promoters in adipocytes. Mutations in the human lamin A gene cause a spectrum of hereditary diseases called the laminopathies which affect muscle, cardiac and adipose tissues. Since most mutations in lamin A/C affect skeletal muscle, we investigated lamin-chromatin interactions at promoters of muscle specific genes in both muscle and non-muscle cell lines by ChIP-qPCR. We observed that lamin A/C was specifically associated with promoter regions of muscle genes in myoblasts but not in fibroblasts. Lamin A/C dissociated from the promoter regions of the differentiation specific MyoD, myogenin and muscle creatine kinase genes when myoblasts were induced to differentiate. In the promoter regions of the myogenin and MyoD genes, the binding of lamin A/C in myoblasts inversely correlated with the active histone mark, H3K4me3. Lamin A/C binding on muscle genes was reduced and differentiation potential was enhanced on treatment of myoblasts with a histone deacetylase inhibitor. These findings suggest a role for lamina-chromatin interactions in muscle differentiation and have important implications for the pathological mechanisms of striated muscle associated laminopathies. PMID- 29124188 TI - Enzymatic attributes of an l-isoaspartyl methyltransferase from Candida utilis and its role in cell survival. AB - Backgrounds: Spontaneous deamidation and isoaspartate (IsoAsp) formation contributes to aging and reduced longevity in cells. A protein-l-isoaspartate (d aspartate) O-methyltransferase (PCMT) is responsible for minimizing IsoAsp moieties in most organisms. Methods: PCMT was purified in its native form from yeast Candida utilis. The role of the native PCMT in cell survival and protein repair was investigated by manipulating intracellular PCMT levels with Oxidized Adenosine (AdOx) and Lithium Chloride (LiCl). Proteomic Identification of possible cellular targets was carried out using 2-dimensional gel electrophoresis, followed by on-Blot methylation and mass spectrometric analysis. Results: The 25.4 kDa native PCMT from C. utilis was found to have a Km of 3.5 uM for AdoMet and 33.36 uM for IsoAsp containing Delta Sleep Inducing Peptide (DSIP) at pH 7.0. Native PCMT comprises of 232 amino acids which is coded by a 698 bp long nucleotide sequence. Phylogenetic comparison revealed the PCMT to be related more closely with the prokaryotic homologs. Increase in PCMT levels in vivo correlated with increased cell survival under physiological stresses. PCMT expression was seen to be linked with increased intracellular reactive oxygen species (ROS) concentration. Proteomic identification of possible cellular substrates revealed that PCMT interacts with proteins mainly involved with cellular housekeeping. PCMT effected both functional and structural repair in aged proteins in vitro. General significance: Identification of PCMT in unicellular eukaryotes like C. utilis promises to make investigations into its control machinery easier owing to the familiarity and flexibility of the system. PMID- 29124190 TI - Weak electric fields serve as guidance cues that direct retinal ganglion cell axons in vitro. AB - Growing axons are directed by an extracellular electric field in a process known as galvanotropism. The electric field is a predominant guidance cue directing retinal ganglion cell (RGC) axons to the future optic disc during embryonic development. Specifically, the axons of newborn RGCs grow along the extracellular voltage gradient that exists endogenously in the embryonic retina (Yamashita, 2013 [8]). To investigate the molecular mechanisms underlying galvanotropic behaviour, the quantification of the electric effect on axon orientation must be examined. In the present study, a culture system was built to apply a constant, uniform direct current (DC) electric field by supplying an electrical current to the culture medium, and this system also continuously recorded the voltage difference between the two points in the medium. A negative feedback circuit was designed to regulate the supplied current to maintain the voltage difference at the desired value. A chick embryo retinal strip was placed between the two points and cultured for 24 h in an electric field in the opposite direction to the endogenous field, and growing axons were fluorescently labelled for live cell imaging (calcein-AM). The strength of the exogenous field varied from 0.0005 mV/mm to 10.0 mV/mm. The results showed that RGC axons grew in the reverse direction towards the cathode at voltage gradients of >=0.0005 mV/mm, and straightforward extensions were found in fields of >=0.2-0.5 mV/mm, which were far weaker than the endogenous voltage gradient (15 mV/mm). These findings suggest that the endogenous electric field is sufficient to guide RGC axons in vivo. PMID- 29124191 TI - Characterization of acetohydroxyacid synthase from the hyperthermophilic bacterium Thermotoga maritima. AB - Acetohydroxyacid synthase (AHAS) is the key enzyme in branched chain amino acid biosynthesis pathway. The enzyme activity and properties of a highly thermostable AHAS from the hyperthermophilic bacterium Thermotoga maritima is being reported. The catalytic and regulatory subunits of AHAS from T. maritima were over expressed in Escherichia coli. The recombinant subunits were purified using a simplified procedure including a heat-treatment step followed by chromatography. A discontinuous colorimetric assay method was optimized and used to determine the kinetic parameters. AHAS activity was determined to be present in several Thermotogales including T. maritima. The catalytic subunit of T. maritima AHAS was purified approximately 30-fold, with an AHAS activity of approximately 160+/ 27 U/mg and native molecular mass of 156+/-6 kDa. The regulatory subunit was purified to homogeneity and showed no catalytic activity as expected. The optimum pH and temperature for AHAS activity were 7.0 and 85 degrees C, respectively. The apparent Km and Vmax for pyruvate were 16.4+/-2 mM and 246+/-7 U/mg, respectively. Reconstitution of the catalytic and regulatory subunits led to increased AHAS activity. This is the first report on characterization of an isoleucine, leucine, and valine operon (ilv operon) enzyme from a hyperthermophilic microorganism and may contribute to our understanding of the physiological pathways in Thermotogales. The enzyme represents the most active and thermostable AHAS reported so far. PMID- 29124192 TI - Immobilization of Bacillus subtilis oxalate decarboxylase on a Zn-IMAC resin. AB - Oxalate decarboxylase, a bicupin enzyme coordinating two essential manganese ions per subunit, catalyzes the decomposition of oxalate into carbon dioxide and formate in the presence of oxygen. Current efforts to elucidate its catalytic mechanism are focused on EPR studies of the Mn. We report on a new immobilization strategy linking the enzyme's N-terminal His6-tag to a Zn-loaded immobilized metal affinity resin. Activity is lowered somewhat due to the expected crowding effect. High-field EPR spectra of free and immobilized enzyme show that the resin affects the coordination environment of the active site Mn ions only minimally. The immobilized preparation was used to study the effect of varying pH on the same sample. Repeated freeze-thaw cycles lead to break down of the resin beads and some enzyme loss from the sample. However, the EPR signal increases due to higher packing efficiency on the sample column. PMID- 29124193 TI - Fibroblast growth factor-2 did not restore plasminogen system activity in endothelial cells on glycated collagen. AB - People with diabetes experience morbidity and mortality from unregulated microvascular remodeling, which may be linked to hyperglycemia. Elevated glucose leads to extracellular matrix collagen glycation, which delays endothelial capillary-like tube formation in vitro. Glucose also increases endothelial cell fibroblast growth factor-2 (FGF-2) release and extracellular matrix storage, which should increase tube formation. In this study, we determined if FGF-2 could restore plasminogen system activity and angiogenic function in endothelial cells on glycated collagen. Human umbilical vein endothelial cells cultured on native or glycated collagen substrates were stimulated with FGF-2. Plasminogen system activity, cell migration, and capillary-like tube formation were measured, along with plasminogen system protein and mRNA levels. Glycated collagen decreased endothelial cell plasminogen system activity, cell migration, and tube length. FGF-2 did not restore plasminogen system activity or tube formation in cells on glycated collagen, despite decreasing plasminogen activator inhibitor-1 (PAI-1) protein level. We now show that PAI-1 binds to glycated collagen, which may localize PAI-1 to the extracellular matrix. These data suggest that FGF-2 may not restore angiogenic functions in endothelial cells on glycated collagen due to PAI 1 bound to glycated collagen. PMID- 29124195 TI - Low-mass molecular dynamics simulation for configurational sampling enhancement: More evidence and theoretical explanation. AB - It has been reported recently that classical, isothermal-isobaric molecular dynamics (NTP MD) simulations at a time step of 1.00 fs of the standard-mass time (Deltat=1.00 fssmt) and a temperature of <=340 K using uniformly reduced atomic masses by tenfold offers better configurational sampling than standard-mass NTP MD simulations at the same time step. However, it has long been reported that atomic masses can also be increased to improve configurational sampling because higher atomic masses permit the use of a longer time step. It is worth investigating whether standard-mass NTP MD simulations at Deltat=2.00 or 3.16 fssmt can offer better or comparable configurational sampling than low-mass NTP MD simulations at Deltat=1.00 fssmt. This article reports folding simulations of two beta-hairpins showing that the configurational sampling efficiency of NTP MD simulations using atomic masses uniformly reduced by tenfold at Deltat=1.00 fssmt is statistically equivalent to and better than those using standard masses at Deltat=3.16 and 2.00 fssmt, respectively. The results confirm that, relative to those using standard masses at routine Deltat=2.00 fssmt, the low-mass NTP MD simulations at Deltat=1.00 fssmt are a simple and generic technique to enhance configurational sampling at temperatures of <=340 K. PMID- 29124196 TI - Binding and structural studies of the complexes of type 1 ribosome inactivating protein from Momordica balsamina with cytosine, cytidine, and cytidine diphosphate. AB - The type 1 ribosome inactivating protein from Momordica balsamina (MbRIP1) has been shown to interact with purine bases, adenine and guanine of RNA/DNA. We report here the binding and structural studies of MbRIP1 with a pyrimidine base, cytosine; cytosine containing nucleoside, cytidine; and cytosine containing nucleotide, cytidine diphosphate. All three compounds bound to MbRIP1 at the active site with dissociation constants of 10-4 M-10-7 M. As reported earlier, in the structure of native MbRIP1, there are 10 water molecules in the substrate binding site. Upon binding of cytosine to MbRIP1, four water molecules were dislodged from the substrate binding site while five water molecules were dislodged when cytidine bound to MbRIP1. Seven water molecules were dislocated when cytidine diphosphate bound to MbRIP1. This showed that cytidine diphosphate occupied a larger space in the substrate binding site enhancing the buried surface area thus making it a relatively better inhibitor of MbRIP1 as compared to cytosine and cytidine. The key residues involved in the recognition of cytosine, cytidine and cytidine diphosphate were Ile71, Glu85, Tyr111 and Arg163. The orientation of cytosine in the cleft is different from that of adenine or guanine indicating a notable difference in the modes of binding of purine and pyrimidine bases. Since adenine containing nucleosides/nucleotides are suitable substrates, the cytosine containing nucleosides/nucleotides may act as inhibitors. PMID- 29124194 TI - Metabolic remodeling in human colorectal cancer and surrounding tissues: alterations in regulation of mitochondrial respiration and metabolic fluxes. AB - The aim of the work was to evaluate whether or not there is glycolytic reprogramming in the neighboring cells of colorectal cancer (CRC). Using postoperative material we have compared the functional capacity of oxidative phosphorylation (OXPHOS) in CRC cells, their glycolytic activity and their inclination to aerobic glycolysis, with those of the surrounding and healthy colon tissue cells. Experiments showed that human CRC cannot be considered a hypoxic tumor, since the malignancy itself and cells surrounding it exhibited even higher rates of OXPHOS than healthy large intestine. The absence of acute hypoxia in colorectal carcinomas was also confirmed by their practically equal glucose-phosphorylating capacity as compared with surrounding non-tumorous tissue and by upregulation of VEGF family and their ligands. Studies indicated that human CRC cells in vivo exert a strong distant effect on the energy metabolism of neighboring cells, so that they acquire the bioenergetic parameters specific to the tumor itself. The growth of colorectal carcinomas was associated with potent downregulation of the creatine kinase system. As compared with healthy colon tissue, the tumor surrounding cells display upregulation of OXPHOS and have high values of basal and ADP activated respiration rates. Strong differences between the normal and CRC cells in the affinity of their mitochondria for ADP were revealed; the corresponding Km values were measured as 93.6+/-7.7 uM for CRC cells and 84.9+/-9.9 uM for nearby tissue; both these apparent Km (ADP) values were considerably (by almost 3 times) lower in comparison with healthy colon tissue cells (256+/-34 uM). PMID- 29124197 TI - Characterization of the retinal pigment epithelium in Friedreich ataxia. AB - We assessed structural elements of the retina in individuals with Friedreich ataxia (FRDA) and in mouse models of FRDA, as well as functions of the retinal pigment epithelium (RPE) in FRDA using induced pluripotent stem cells (iPSCs). We analyzed the retina of the FRDA mouse models YG22R and YG8R containing a human FRATAXIN (FXN) transgene by histology. We complemented this work with post-mortem evaluation of eyes from FRDA patients. Finally, we derived RPE cells from patient FRDA-iPSCs to assess oxidative phosphorylation (OXPHOS) and phagocytosis. We showed that whilst the YG22R and YG8R mouse models display elements of retinal degeneration, they do not recapitulate the loss of retinal ganglion cells (RGCs) found in the human disease. Further, RPE cells differentiated from human FRDA iPSCs showed normal OXPHOS and we did not observe functional impairment of the RPE in Humans. PMID- 29124198 TI - A simple and ultra-low cost homemade seamless ligation cloning extract (SLiCE) as an alternative to a commercially available seamless DNA cloning kit. AB - The seamless ligation cloning extract (SLiCE) method is a novel seamless DNA cloning tool that utilizes homologous recombination activities in Escherichia coli cell lysates to assemble DNA fragments into a vector. Several laboratory E. coli strains can be used as a source for the SLiCE extract; therefore, the SLiCE method is highly cost-effective.The SLiCE has sufficient cloning ability to support conventional DNA cloning, and can simultaneously incorporate two unpurified DNA fragments into vector. Recently, many seamless DNA cloning kits have become commercially available; these are generally very convenient, but expensive. In this study, we evaluated the cloning efficiencies between a simple and highly cost-effective SLiCE-method and a commercial kit under various molar ratios of insert DNA fragments to vector DNA. This assessment identified that the SLiCE from a laboratory E. coli strain yielded 30-85% of the colony formation rate of a commercially available seamless DNA cloning kit. The cloning efficiencies of both methods were highly effective, exhibiting over 80% success rate under all conditions examined. These results suggest that SLiCE from a laboratory E. coli strain can efficiently function as an effective alternative to commercially available seamless DNA cloning kits. PMID- 29124199 TI - Biophysical and enzymatic properties of aminoglycoside adenylyltransferase AadA6 from Pseudomonas aeruginosa. AB - The gene coding for the aminoglycoside adenylyltransferase (aadA6) from a clinical isolate of Pseudomonas aeruginosa was cloned and expressed in Escherichia coli strain BL21(DE3)pLysS. The overexpressed enzyme (AadA6, 281 amino-acid residues) and a carboxy-terminal truncated variant molecule ([1 264]AadA6) were purified to near homogeneity and characterized. Light scattering experiments conducted under low ionic strength supported equilibrium between monomeric and homodimeric arrangements of the enzyme subunits. Circular Dichroism spectropolarimetry indicated a close structural relation to adenylate kinases. Both forms modified covalently the aminoglycosides streptomycin and spectinomycin. The enzyme required at least 5 mM MgCl2 for normal Michaelis Menten kinetics. Streptomycin exhibited a strong substrate inhibition effect at 1 mM MgCl2. The truncated 17 residues at the C-terminus have little influence on protein folding, whereas they have a positive effect on the enzymic activity and stabilize dimers at high protein concentrations (>100 MUM). Homology modelling and docking based on known crystal structures yielded models of the central ternary complex of monomeric AadA6 with ATP and streptomycin or spectinomycin. PMID- 29124200 TI - Bax and caspases regulate increased production of mitochondria-derived reactive species in neuronal apoptosis: LACK of A role for depletion of cytochrome c from the mitochondrial electron transport chain. AB - A Bax-dependent increase of reactive oxygen species (ROS) and other reactive species (RS) occurs after withdrawing NGF from mouse sympathetic neurons in cell culture. Possible mechanisms underlying the increased ROS/RS are leakage of electrons from the mitochondrial electron transport chain secondary to caspase cleavage of respiratory complexes or leakage secondary to depletion of cytochrome c from the chain. We previously demonstrated that deletion of Bax or caspase 3 from these cells reduces ROS/RS production to near baseline levels indicating a central role for both Bax and caspase 3 in generating the ROS/RS. Here we depleted cytochrome c to a similar level in neurons from wild type and bax hemizygous or knockout mice by NGF withdrawal or treatment with H2O2. Death was prevented with a caspase inhibitor that caused a partial reduction of ROS/RS levels but did not completely prevent the ROS/RS increase. ROS/RS was highest in bax wild-type cells, lowest in bax knockout cells, and at an intermediate level in the bax hemizygous cells. These and our previous findings indicate that Bax and caspase 3 are necessary for the increased ROS/RS after withdrawing NGF from these cells and that little or none of the increased ROS/RS are secondary to a depletion of cytochrome c from the electron transport chain. PMID- 29124201 TI - Basal cells express functional TRPV4 channels in the mouse nasal epithelium. AB - Basal cells in the nasal epithelium (olfactory and airway epithelia) are stem/progenitor cells that are capable of dividing, renewing and differentiating into specialized cells. These stem cells can sense their biophysical microenvironment, but the underlying mechanism of this process remains unknown. Here, we demonstrate the prominent expression of the transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca2+-permeable channel that is known to act as a sensor for hypo-osmotic and mechanical stresses, in the basal cells of the mouse nasal epithelium. TRPV4 mRNA was expressed in the basal portions of the prenatal mouse nasal epithelium, and this expression continued into adult mice. The TRPV4 protein was also detected in the basal layers of the nasal epithelium in wild-type but not in TRPV4-knockout (TRPV4-KO) mice. The TRPV4-positive immunoreactions largely overlapped with those of keratin 14 (K14), a marker of basal cells, in the airway epithelium, and they partially overlapped with those of K14 in the olfactory epithelium. Ca2+ imaging analysis revealed that hypo osmotic stimulation and 4alpha-phorbol 12,13 didecanoate (4alpha-PDD), both of which are TRPV4 agonists, caused an increase in the cytosolic Ca2+ concentration in a subset of primary epithelial cells cultured from the upper parts of the nasal epithelium of the wild-type mice. This response was barely noticeable in cells from similar parts of the epithelium in TRPV4-KO mice. Finally, there was no significant difference in BrdU-labeled proliferation between the olfactory epithelia of wild-type and TRPV4-KO mice under normal conditions. Thus, TRPV4 channels are functionally expressed in basal cells throughout the nasal epithelium and may act as sensors for the development and injury-induced regeneration of basal stem cells. PMID- 29124202 TI - Carbenoxolone-sensitive and cesium-permeable potassium channel in the rod cells of frog taste discs. AB - The rod cells in frog taste discs display the outward current and maintain the negative resting potential in the condition where internal K+ is replaced with Cs+. We analyzed the properties of the Cs+-permeable conductance in the rod cells. The current-voltage (I/V) relationships obtained by a voltage ramp were bell-shaped under Cs+ internal solution. The steady state I/V relationships elicited by voltage steps also displayed the bell-shaped outward current. The activation of the current accelerated with the depolarization and the inactivation appeared at positive voltage. The gating for the current was maintained even at symmetric condition (Cs+ external and internal solutions). The wing cells did not show the properties. The permeability for K+ was a little larger than that for Cs+. Internal Na+ and NMDG+ could not induce the bell-shaped outward current. Carbenoxolone inhibited the bell-shaped outward Cs+ current dose dependently (IC50 : 27 MUM). Internal arachidonic acid (20 MUM) did not induce the linear current-voltage (I-V) relationship which is observed in two-pore domain K+ channel (K2P). The results suggest that the resting membrane potentials in the rod cells are maintained by the voltage-gated K+ channels. PMID- 29124203 TI - Recovery of extracellular matrix components by enalapril maleate during the repair process of ultraviolet B-induced wrinkles in mouse skin. AB - The renin-angiotensin system is known to be involved in skin remodeling and inflammation. Previously, we reported that ultraviolet B (UVB) irradiation enhanced angiotensin-converting enzyme (ACE) expression and angiotensin II levels in hairless mouse skin, and an ACE inhibitor, enalapril maleate (EM), accelerated repair of UVB-induced wrinkles. In this study, we analyzed gene expression profiles by DNA microarray and protein distribution patterns using an immunofluorescence method to clarify the process of EM-accelerated wrinkle repair in UVB-irradiated hairless mouse skin. In the microarray analysis, we detected EM induced up-regulation of various extracellular matrix (ECM)-related genes in the UVB-irradiated skin. In the immunofluorescence, we confirmed that type I collagen alpha1 chain, fibrillin 1, elastin and dystroglycan 1 in the skin decreased after repeated UVB irradiation but staining for these proteins was improved by EM treatment. In addition, ADAMTS2 and MMP-14 also increased in the EM-treated skin. Although the relationship between these molecules and wrinkle formation is not clear yet, our present data suggest that the molecules are involved in the repair of UVB-induced wrinkles. PMID- 29124204 TI - Knockdown of aquaporin-8 induces mitochondrial dysfunction in 3T3-L1 cells. AB - Background: Aquaporin-8 (AQP8), a member of the aquaporin water channel family, is expressed in various tissue and cells, including liver, testis, and pancreas. AQP8 appears to have functions on the plasma membrane and/or on the mitochondrial inner membrane. Mitochondrial AQP8 with permeability for water, H2O2 and NH3 has been expected to have important role in various cells, but its information is limited to a few tissues and cells including liver and kidney. In the present study, we found that AQP8 was expressed in the mitochondria in mouse adipose tissues and 3T3-L1 preadipocytes, and investigated its role by suppressing its gene expression. Methods: AQP8-knocked down (shAQP8) cells were established using a vector expressing short hairpin RNA. Cellular localization of AQP8 was examined by western blotting and immunocytochemistry. Mitochondrial function was assessed by measuring mitochondrial membrane potential, oxygen consumption and ATP level measurements. Results: In 3T3-L1 cells, AQP8 was expressed in the mitochondria. In shAQP8 cells, mRNA and protein levels of AQP8 were decreased by about 75%. The shAQP8 showed reduced activities of complex IV and ATP synthase; it is probable that the impaired mitochondrial water handling in shAQP8 caused suppression of the electron transport and ADP phosphorylation through inhibition of the two steps which yield water. The reduced activities of the last two steps of oxidative phosphorylation in shAQP8 cause low routine and maximum capacity of respiration and mitochondrial hyperpolarization. Conclusion: Mitochondrial AQP8 contributes to mitochondrial respiratory function probably through maintenance of water homeostasis. General significance: The AQP8-knocked down cells we established provides a model system for the studies on the relationships between water homeostasis and mitochondrial function. PMID- 29124206 TI - Conformational changes on ligand binding in wild-type and mutants from Spodoptera frugiperda midgut trehalase. AB - Trehalase specifically hydrolyses trehalose into two glucose units and is most important in insects and fungi. Previous evidence suggested that Spodoptera frugiperda midgut trehalase (wild type, WT) has substantial conformational changes on binding different substances. Our goal is to understand this mobility. For this, two deletion mutants were produced, lacking regions supposed to be the cause of mobility [(102 residues from the N-terminus (NT) and this portion plus 31 residues from the C-terminus (NCT)]. Circular dichroism spectra before and after denaturation of the enzymes support the assertion that they are appropriately folded. The overall results show that the removal of 102 or 133 amino acids does not greatly change the interaction with the substrate and competitive inhibitors, but leads to a considerable decrease in kcat/Km values from WT 74,500 M-1 s-1 to NT 647 M-1 s-1 and NCT 1,044 M-1 s-1. Diethyl pyrocarbonate His modification only occurs in wild and truncated trehalases in the presence of some ligands. Looking for changes in folding WT, NT, and NCT were incubated with different compounds in the presence of Sypro Orange, that binds to hydrophobic regions increasing its fluorescence. The dye fluorescence is affected by 2 compounds when WT is present, and at least by 5 compounds when NT or NCT are present, suggesting that conformational changes caused by ligand binding occur only in the vicinity of the active site. These data provide physical evidence in favor of a change in folding around the active site caused by ligand binding, in agreement to prior chemical modification and other kinetic data and challenging the hypothesis that N- and C-terminal are the mobile regions. PMID- 29124205 TI - Fluvoxamine alleviates paclitaxel-induced neurotoxicity. AB - Paclitaxel (Px) is an effective chemotherapeutic agent for the treatment of various cancers. However, it is often associated with neurological side effects, including chemotherapy-associated cognitive impairment (CACI), such as "chemobrain". Previously, we reported that endoplasmic reticulum (ER) stress is involved in Px-induced neurotoxicity, and immunoglobulin heavy chain binding protein (BiP) inducer X (BIX) alleviates Px-induced neurotoxicity. However, BIX has not been used in clinical practice yet. We recently reported that fluvoxamine (Flv) alleviates ER stress via induction of sigma-1 receptor (Sig-1R). The purpose of this study was to investigate whether Flv could alleviate Px-induced neurotoxicity in vitro. SK-N-SH cells were pre-treated for 12 h with or without 10 MUg/ml Flv followed by treatment with 1 MUM Px with or without co-existence of 10 MUg/ml Flv for 24 h. To investigate the involvement of Sig-1R in alleviation effect on Px-induced neurotoxicity,1 MUM NE100, an antagonist of Sig-1R, was added for 24 h. Neurotoxicity was assessed using the MTS viability assay and ER stress-mediated neurotoxicity was assessed by evaluating the expression of C/EBP homologous protein (CHOP), cleaved caspase 4, and cleaved caspase 3. Pre treatment with Flv significantly alleviated the induction of CHOP, cleaved caspase 4, and cleaved caspase 3 in SK-N-SH cells. At the same time, pre treatment with Flv significantly induced Sig-1R in SK-N-SH cells. In addition, viability was significantly higher in Flv-treated cells than in untreated cells, which was reversed by treatment with NE100. Our results suggest that Flv alleviates Px-induced neurotoxicity in part through the induction of Sig-1R. Our findings should contribute to one of the novel approaches for the alleviation of Px-induced neurotoxicity, including chemobrain. PMID- 29124207 TI - Lipocalin-type prostaglandin D2 synthase reduces glucagon secretion in alpha TC-1 clone 6 cells via the DP1 receptor. AB - Diabetes is associated with disturbances in the normal levels of both insulin and glucagon, both of which play critical roles in the regulation of glycemia. Recent studies have found lipocalin-type prostaglandin D2 synthase (l-PGDS) to be an emerging target involved in the pathogenesis of type-2 diabetes. This study focused on the effect of l-PGDS on glucagon secretion from cultured pancreatic Alpha TC-1 Clone 6 cells. When cells were treated with various concentrations of l-PGDS (0, 10, 50, and 100 ug/ml) for 2 h in 1 mM glucose; glucagon secretion decreased to 670+/-45, 838+/-38, 479+/-11, and 437+/-45 pg/ml, respectively. In addition, pancreatic islets were isolated from C57BL/6 mice and stained for prostaglandin D2 receptors, DP1 and DP2, using immunohistochemistry. Our results showed that these islets express only the DP1 receptor. Pancreatic islets were then stained for alpha and beta cells, as well as DP1, to find the primary location of the receptor within the islets using immunofluorescence. Interestingly, DP1 receptor density was found primarily in alpha cells rather than in beta cells. Our study is the first to report a correlation between l-PGDS and glucagon secretion in alpha cells. Based on our obtained results, it can be concluded that higher concentrations of l-PGDS significantly reduced the secretion of glucagon in alpha cells, which may contribute to the pathogenesis of diabetes as well as offer a novel therapeutic site for the treatment of diabetes. PMID- 29124208 TI - Life equations for the senescence process. AB - The Gompertz law of mortality quantitatively describes the mortality rate of humans and almost all multicellular animals. However, its underlying kinetic mechanism is unclear. The Gompertz law cannot explain the mortality plateau at advanced ages and cannot give an explicit relationship between temperature and mortality. In this study a reaction kinetics model with a time dependent rate coefficient is proposed to describe the survival and senescence processes. A temperature-dependent mortality function was derived. The new mortality function becomes the Gompertz mortality function with the same relationship of parameters prescribed by the Strehler-Mildvan correlation when age is smaller than a characteristic value delta, and reaches the mortality plateau when age is greater than delta. A closed-form analytical expression for describing the relationship of average lifespan with temperature and other equations are derived from the new mortality function. The derived equations can be used to estimate the limit of average lifespan, predict the maximal longevity, calculate the temperature coefficient of lifespan, and explain the tendency of the survival curve. This prediction is consistent with the most recently reported mortality trajectories for single-year birth cohorts. This study suggests that the senescence process results from the imbalance between damaging energy and protecting energy for the critical chemical substance in the body. The rate of senescence of the organism increases while the protecting energy decreases. The mortality plateau is reached when the protecting energy decreases to its minimal levels. The decreasing rate of the protecting energy is temperature-dependent. This study is exploring the connection between the biochemical mechanism and demography. PMID- 29124209 TI - Novel pH-dependent regulation of human cytosolic sialidase 2 (NEU2) activities by siastatin B and structural prediction of NEU2/siastatin B complex. AB - Human cytosolic sialidase (Neuraminidase 2, NEU2) catalyzes the removal of terminal sialic acid residues from glycoconjugates. The effect of siastatin B, known as a sialidase inhibitor, has not been evaluated toward human NEU2 yet. We studied the regulation of NEU2 activity by siastatin B in vitro and predicted the interaction in silico. Inhibitory and stabilizing effects of siastatin B were analyzed in comparison with DANA (2-deoxy-2,3-dehydro-N-acetylneuraminic acid) toward 4-umbelliferyl N-acetylneuraminic acid (4-MU-NANA)- and alpha2,3 sialyllactose-degrading activities of recombinant NEU2 produced by E. coli GST fusion gene expression. Siastatin B exhibited to have higher competitive inhibitory activity toward NEU2 than DANA at pH 4.0. We also revealed the stabilizing effect of siastatin B toward NEU2 activity at acidic pH. Docking model was constructed on the basis of the crystal structure of NEU2/DANA complex (PDB code: 1VCU). Molecular docking predicted that electrostatic neutralization of E111 and E218 residues of the active pocket should not prevent siastatin B from binding at pH 4.0. The imino group (1NH) of siastatin B can also interact with D46, neutralized at pH 4.0. Siastatin B was suggested to have higher affinity to the active pocket of NEU2 than DANA, although it has no C7-9 fragment corresponding to that of DANA. We demonstrated here the pH-dependent affinity of siastatin B toward NEU2 to exhibit potent inhibitory and stabilizing activities. Molecular interaction between siastatin B and NEU2 will be utilized to develop specific inhibitors and stabilizers (chemical chaperones) not only for NEU2 but also the other human sialidases, including NEU1, NEU3 and NEU4, based on homology modeling. PMID- 29124210 TI - The leukotriene B4 receptor BLT1 is stabilized by transmembrane helix capping mutations. AB - In this study, we introduced structure-based rational mutations in the guinea pig leukotriene B4 receptor (gpBLT1) in order to enhance the stabilization of the protein. Elements thought to be unfavorable for the stability of gpBLT1 were extracted based on the stabilization elements established in soluble proteins, determined crystal structures of G-protein-coupled receptors (GPCRs), and multiple sequence alignment. The two unfavorable residues His832.67 and Lys883.21, located at helix capping sites, were replaced with Gly (His83Gly2.67 and Lys88Gly3.21). The modified protein containing His83Gly2.67/Lys88Gly3.21 was highly expressed, solubilized, and purified and exhibited improved thermal stability by 4 degrees C in comparison with that of the original gpBLT1 construct. Owing to the double mutation, the expression level increased by 6-fold (Bmax=311 pmol/mg) in the membrane fraction of Pichia pastoris. The ligand binding affinity was similar to that of the original gpBLT1 without the mutations. Similar unfavorable residues have been observed at helix capping sites in many other GPCRs; therefore, the replacement of such residues with more favorable residues will improve stabilization of the GPCR structure for the crystallization. PMID- 29124211 TI - Continuous degradation of maltose by enzyme entrapment technology using calcium alginate beads as a matrix. AB - Maltase from Bacillus licheniformis KIBGE-IB4 was immobilized within calcium alginate beads using entrapment technique. Immobilized maltase showed maximum immobilization yield with 4% sodium alginate and 0.2 M calcium chloride within 90.0 min of curing time. Entrapment increases the enzyme-substrate reaction time and temperature from 5.0 to 10.0 min and 45 degrees C to 50 degrees C, respectively as compared to its free counterpart. However, pH optima remained same for maltose hydrolysis. Diffusional limitation of substrate (maltose) caused a declined in Vmax of immobilized enzyme from 8411.0 to 4919.0 U ml-1 min-1 whereas, Km apparently increased from 1.71 to 3.17 mM ml-1. Immobilization also increased the stability of free maltase against a broad temperature range and enzyme retained 45% and 32% activity at 55 degrees C and 60 degrees C, respectively after 90.0 min. Immobilized enzyme also exhibited recycling efficiency more than six cycles and retained 17% of its initial activity even after 6th cycles. Immobilized enzyme showed relatively better storage stability at 4 degrees C and 30 degrees C after 60.0 days as compared to free enzyme. PMID- 29124212 TI - Enhancing hypothiocyanite production by lactoperoxidase - mechanism and chemical properties of promotors. AB - Background: The heme enzyme lactoperoxidase is found in body secretions where it significantly contributes to the humoral immune response against pathogens. After activation the peroxidase oxidizes thiocyanate to hypothiocyanite which is known for its microbicidal properties. Yet several pathologies are accompanied by a disturbed hypothiocyanite production which results in a reduced immune defense. Methods: The results were obtained by measuring enzyme-kinetic parameters using UV-vis spectroscopy and a standardized enzyme-kinetic test system as well as by the determination of second order rate constants using stopped-flow spectroscopy. Results: In this study we systematically tested thirty aromatic substrates for their efficiency to promote the lactoperoxidase-mediated hypothiocyanite production by restoring the native ferric enzyme state. Thereby hydrophobic compounds with a 3,4-dihydroxyphenyl partial structure such as hydroxytyrosol and selected flavonoids emerged as highly efficient promotors of the (pseudo )halogenating lactoperoxidase activity. Conclusions: This study discusses important structure-function relationships of efficient aromatic LPO substrates and may contribute to the development of new agents to promote lactoperoxidase activity in secretory fluids of patients. Significance: This study may contribute to a better understanding of the (patho-)physiological importance of the (pseudo )halogenating lactoperoxidase activity. The presented results may in future lead to the development of new therapeutic strategies which, by reactivating lactoperoxidase-derived hypothiocyanite production, promote the immunological activity of this enzyme. PMID- 29124213 TI - Photocontrol of the GTPase activity of the small G protein K-Ras by using an azobenzene derivative. AB - The small G protein Ras is a central regulator of cellular signal transduction processes, functioning as a molecular switch. Switch mechanisms utilizing conformational changes in nucleotide-binding motifs have been well studied at the molecular level. Azobenzene is a photochromic molecule that undergoes rapid and reversible isomerization between the cis and trans forms upon exposure to ultraviolet and visible light irradiation, respectively. Here, we introduced the sulfhydryl-reactive azobenzene derivative 4-phenylazophenyl maleimide (PAM) into the nucleotide-binding motif of Ras to regulate the GTPase activity by photoirradiation. We prepared four Ras mutants (G12C, Y32C, I36C, and Y64C) that have a single reactive cysteine residue in the nucleotide-binding motif. PAM was stoichiometrically incorporated into the cysteine residue of the mutants. The PAM modified mutants exhibited reversible alterations in GTPase activity, nucleotide exchange rate, and interaction between guanine nucleotide exchange factor and Ras, accompanied by photoisomerization upon exposure to ultraviolet and visible light irradiation. The results suggest that incorporation of photochromic molecules into its nucleotide-binding motif enables photoreversible control of the function of the small G protein Ras. PMID- 29124215 TI - Two-headed outer- and inner-arm dyneins of Leishmania sp bear conserved IQ-like motifs. AB - Dyneins are high molecular weight microtubule based motor proteins responsible for beating of the flagellum. The flagellum is important for the viability of trypanosomes like Leishmania. However, very little is known about dynein and its role in flagellar motility in such trypanosomatid species. Here, we have identified genes in five species of Leishmania that code for outer-arm dynein (OAD) heavy chains alpha and beta, and inner-arm dynein (IAD) heavy chains 1alpha and 1beta using BLAST and MSA. Our sequence analysis indicates that unlike the three-headed outer-arm dyneins of Chlamydomonas and Tetrahymena, the outer-arm dyneins of the genus Leishmania are two-headed, lacking the gamma chain like that of metazoans. N-terminal sequence analysis revealed a conserved IQ-like calmodulin binding motif in the outer-arm alpha and inner-arm 1alpha dynein heavy chain in the five species of Leishmania similar to Chlamydomonas reinhardtii outer-arm gamma. It was predicted that both motifs were incapable of binding calmodulin. Phosphorylation site prediction revealed conserved serine and threonine residues in outer-arm dynein alpha and inner-arm 1alpha as putative phosphorylation sites exclusive to Leishmania but not in Trypanosoma brucei suggesting that regulation of dynein activity might be via phosphorylation of these IQ-like motifs in Leishmania sp. PMID- 29124214 TI - Gene replacement and quantitative mass spectrometry approaches validate guanosine monophosphate synthetase as essential for Mycobacterium tuberculosis growth. AB - Guanosine monophosphate synthetase (GMPS), encoded by guaA gene, is a key enzyme for guanine nucleotide biosynthesis in Mycobacterium tuberculosis. The guaA gene from several bacterial pathogens has been shown to be involved in virulence; however, no information about the physiological effect of direct guaA deletion in M. tuberculosis has been described so far. Here, we demonstrated that the guaA gene is essential for M. tuberculosis H37Rv growth. The lethal phenotype of guaA gene disruption was avoided by insertion of a copy of the ortholog gene from Mycobacterium smegmatis, indicating that this GMPS protein is functional in M. tuberculosis. Protein validation of the guaA essentiality observed by PCR was approached by shotgun proteomic analysis. A quantitative method was performed to evaluate protein expression levels, and to check the origin of common and unique peptides from M. tuberculosis and M. smegmatis GMPS proteins. These results validate GMPS as a molecular target for drug design against M. tuberculosis, and GMPS inhibitors might prove to be useful for future development of new drugs to treat human tuberculosis. PMID- 29124216 TI - Identification of potential novel interaction partners of the sodium-activated potassium channels Slick and Slack in mouse brain. AB - The sodium-activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) are paralogous channels of the Slo family of high-conductance potassium channels. Slick and Slack channels are widely distributed in the mammalian CNS and they play a role in slow afterhyperpolarization, generation of depolarizing afterpotentials and in setting and stabilizing the resting potential. In the present study we used a combined approach of (co)-immunoprecipitation studies, Western blot analysis, double immunofluorescence and mass spectrometric sequencing in order to investigate protein-protein interactions of the Slick and Slack channels. The data strongly suggest that Slick and Slack channels co assemble into identical cellular complexes. Double immunofluorescence experiments revealed that Slick and Slack channels co-localize in distinct mouse brain regions. Moreover, we identified the small cytoplasmic protein beta-synuclein and the transmembrane protein 263 (TMEM 263) as novel interaction partners of both, native Slick and Slack channels. In addition, the inactive dipeptidyl-peptidase (DPP 10) and the synapse associated protein 102 (SAP 102) were identified as constituents of the native Slick and Slack channel complexes in the mouse brain. This study presents new insights into protein-protein interactions of native Slick and Slack channels in the mouse brain. PMID- 29124217 TI - Production, in Pichia pastoris, of a recombinant monomeric mapacalcine, a protein with anti-ischemic properties. AB - Mapacalcine is a small homodimeric protein of 19 kDa with 9 disulfide bridges extracted from the Cliona vastifica sponge (Red Sea). It selectively blocks a calcium current insensitive to most calcium blockers. Specific receptors for mapacalcine have been described in a variety of tissues such as brain, smooth muscle, liver, and kidney. Previous works achieved on hepatocytes and nervous cells demonstrated that this protein selectively blocks a calcium influx triggered by an ischemia/reperfusion (I/R) shock and efficiently protects cells from death after I/R. The aim of this work was to produce the recombinant mapacalcine in the yeast Pichia pastoris. Mass spectrometry, light scattering analysis and biological characterization demonstrated that the recombinant mapacalcine obtained was a monomeric form with 4 disulfide bridges which retains the biological activity of the natural protein. PMID- 29124218 TI - Characterisation of the flavin adenine dinucleotide binding region of Myxococcus xanthus protoporphyrinogen oxidase. AB - Protoporphyrinogen oxidase (PPOX), the penultimate enzyme in the haem biosynthetic pathway catalysers the six electron oxidation of protoporphyrinogen IX to protoporphyrin-IX, in the presence of flavin adenine dinucleotide (FAD) and oxygen. In humans, partial defects in PPOX result in variegate porphyria. In this study, the FAD binding region in Myxococcus xanthus PPOX was analysed by engineering and characterising a selection of mutant proteins. Amino acid residues which interact with FAD via their side chains were selected for study. Mutants were characterised and compared with wild type protein. Characterisation included FAD quantitation, analysis of FAD spectra and kinetic assay. Results revealed that Serine 20 mutants could still bind FAD, but polarity in this position is favourable, yet not essential for the integrity of FAD binding. Study of Glutamate 39 mutants suggest that a negative charge at position 39 is clearly favoured for interaction with the ribose ring of FAD, as all non-conservative replacements could not bind sufficient FAD. Asparagine 441 appears not to be directly involved in FAD binding but rather in stabilizing the FAD, and polarity in this position appears important. Tryptophan 408 may play a role in orientating or stabilizing the bound substrate during catalysis, and a non-polar (or slightly polar) residue is favoured at this position; however, aromaticity in this position appears not to be critical. Overall this study sheds further light on how M. xanthus PPOX interacts with FAD. PMID- 29124219 TI - 1-Amino-4-hydroxy-9,10-anthraquinone - An analogue of anthracycline anticancer drugs, interacts with DNA and induces apoptosis in human MDA-MB-231 breast adinocarcinoma cells: Evaluation of structure-activity relationship using computational, spectroscopic and biochemical studies. AB - The X-ray diffraction and spectroscopic properties of 1-amino-4-hydroxy-9,10 anthraquinone (1-AHAQ), a simple analogue of anthracycline chemotherapeutic drugs were studied by adopting experimental and computational methods. The optimized geometrical parameters obtained from computational methods were compared with the results of X-ray diffraction analysis and the two were found to be in reasonably good agreement. X-ray diffraction study, Density Functional Theory (DFT) and natural bond orbital (NBO) analysis indicated two types of hydrogen bonds in the molecule. The IR spectra of 1-AHAQ were studied by Vibrational Energy Distribution Analysis (VEDA) using potential energy distribution (PED) analysis. The electronic spectra were studied by TDDFT computation and compared with the experimental results. Experimental and theoretical results corroborated each other to a fair extent. To understand the biological efficacy of 1-AHAQ, it was allowed to interact with calf thymus DNA and human breast adino-carcinoma cell MDA-MB-231. It was found that the molecule induces apoptosis in this adinocarcinoma cell, with little, if any, cytotoxic effect in HBL-100 normal breast epithelial cell. PMID- 29124220 TI - Antimicrobial activity of the toxin VdTX-I from the spider Vitalius dubius (Araneae, Theraphosidae). AB - Background: Currently there is an urgent need to develop new classes of antimicrobial agents with different mechanisms of action from conventionally antibiotics used for the control of pathogenic microorganisms. The acylpolyamine called VdTX-I was isolated from the venom of the tarantula Vitalius dubius, and first described with activity as an antagonist of nicotinic cholinergic receptors. The main objective of this study was to investigate the antimicrobial activity found in the venom of the spider, with emphasis on the toxin VdTX-I. Methods: Antimicrobial assays were performed in 96 well plates culture against 14 micro-organisms (fungi, yeasts and bacteria), which were tested concentrations from 0.19 to 100 MUM of VdTX-I. After qualitative analysis, dose-response curve assays were performed in bacterial kill curve using MTT reagent and hemolytic assay. Results: The antimicrobial activity of the VdTX-I toxin was observed in 12 tested species of Candida, Trichosporiun, Staphylococcus and Micrococcus. The toxicity had a dose-response at 3.12 uM - 100 MUM in Candida albicans, Candida guillermondii, Micrococcus luteus and Escherichia coli. VdTX-I took about 5 min to inhibit bacterial growth, which was faster than streptomycin. The toxin showed no hemolytic activity between 0.19 and 100 MUM. At 2.5 ug/mL of toxin it was observed no growth inhibition against a mammalian cell lineage. Conclusions: The VdTX-I toxin has a significant antimicrobial activity, with broad spectrum, and is experimentally inert to mammalian blood cells. General Significance: This paper explores the antimicrobial potential of the spider toxin VdTX-I, which can provide a new model to design new antimicrobial drugs. PMID- 29124221 TI - Study of rabies virus by Differential Scanning Calorimetry. AB - Differential Scanning Calorimetry (DSC) has been used in the past to study the thermal unfolding of many different viruses. Here we present the first DSC analysis of rabies virus. We show that non-inactivated, purified rabies virus unfolds cooperatively in two events centered at approximately 62 and 73 degrees C. Beta-propiolactone (BPL) treatment does not alter significantly viral unfolding behavior, indicating that viral inactivation does not alter protein structure significantly. The first unfolding event was absent in bromelain treated samples, causing an elimination of the G-protein ectodomain, suggesting that this event corresponds to G-protein unfolding. This hypothesis was confirmed by the observation that this first event was shifted to higher temperatures in the presence of three monoclonal, G-protein specific antibodies. We show that dithiothreitol treatment of the virus abolishes the first unfolding event, indicating that the reduction of G-protein disulfide bonds causes dramatic alterations to protein structure. Inactivated virus samples heated up to 70 degrees C also showed abolished recognition of conformational G-protein specific antibodies by Surface Plasmon Resonance analysis. The sharpness of unfolding transitions and the low standard deviations of the Tm values as derived from multiple analysis offers the possibility of using this analytical tool for efficient monitoring of the vaccine production process and lot to lot consistency. PMID- 29124223 TI - Optimizing hyaluronidase dose and plasmid DNA delivery greatly improves gene electrotransfer efficiency in rat skeletal muscle. AB - Transfection of rat skeletal muscle in vivo is a widely used research model. However, gene electrotransfer protocols have been developed for mice and yield variable results in rats. We investigated whether changes in hyaluronidase pre treatment and plasmid DNA delivery can improve transfection efficiency in rat skeletal muscle. We found that pre-treating the muscle with a hyaluronidase dose suitable for rats (0.56 U/g b.w.) prior to plasmid DNA injection increased transfection efficiency by >200% whereas timing of the pre-treatment did not affect efficiency. Uniformly distributing plasmid DNA delivery across the muscle by increasing the number of plasmid DNA injections further enhanced transfection efficiency whereas increasing plasmid dose from 0.2 to 1.6 ug/g b.w. or vehicle volume had no effect. The optimized protocol resulted in ~80% (CI95%: 79-84%) transfected muscle fibers with a homogenous distribution. We also show that transfection was stable over five weeks of regular exercise or inactivity. Our findings show that species-specific plasmid DNA delivery and hyaluronidase pre treatment greatly improves transfection efficiency in rat skeletal muscle. PMID- 29124222 TI - Dynamic miRNA-mRNA paradigms: New faces of miRNAs. AB - More and more evidences suggested that the flow of genetic information can be spatially and temporally regulated by non-coding RNAs (ncRNAs), such as microRNAs (miRNAs). Although biogenesis and function of miRNAs have been well detailed, elucidation of the dynamic interplays between miRNAs and mRNAs have just begun. Here, we highlighted that the miRNA-mRNA interactions which could take place in different cellular locations. During dynamic interactions, miRNA binding sites included not only 3'UTRs, but also 5'UTRs and CDSs. Under different physiological or pathological conditions, miRNAs could switch from translational inhibition to activation. Dynamic miRNA-mRNA paradigms which suggested a novel tip of the iceberg beneath the gene regulation network will provide clues for function studies of other ncRNAs. PMID- 29124224 TI - Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells. AB - Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is currently incurable. SMA is caused by decreased levels of the survival motor neuron protein (SMN), as a result of loss or mutation of SMN1. Although the SMN1 homolog SMN2 also produces some SMN protein, it does not fully compensate for the loss or dysfunction of SMN1. Salbutamol, a beta2-adrenergic receptor agonist and well-known bronchodilator used in asthma patients, has recently been shown to ameliorate symptoms in SMA patients. However, the precise mechanism of salbutamol action is unclear. We treated SMA fibroblast cells lacking SMN1 and HeLa cells with salbutamol and analyzed SMN2 mRNA and SMN protein levels in SMA fibroblasts, and changes in SMN protein ubiquitination in HeLa cells. Salbutamol increased SMN protein levels in a dose-dependent manner in SMA fibroblast cells lacking SMN1, though no significant changes in SMN2 mRNA levels were observed. Notably, the salbutamol-induced increase in SMN was blocked by a protein kinase A (PKA) inhibitor and deubiquitinase inhibitor, respectively. Co-immunoprecipitation assay using HeLa cells showed that ubiquitinated SMN levels decreased in the presence of salbutamol, suggesting that salbutamol inhibited ubiquitination. The results of this study suggest that salbutamol may increase SMN protein levels in SMA by inhibiting ubiquitin-mediated SMN degradation via activating beta2-adrenergic receptor-PKA pathways. PMID- 29124225 TI - Novel curcumin derivatives as potent inhibitors of amyloid beta aggregation. AB - Modulation of abnormal amyloid beta (Abeta) aggregation is considered to be a potential therapeutic target for Alzheimer's disease (AD). Recent in vitro and in vivo experiments suggest that inhibition of Abeta aggregation by curcumin would exert favorable effects for preventing or treating AD. We have previously synthesized a series of novel curcumin derivatives. In this study, we investigated the effects of our curcumin derivatives on Abeta aggregation and the cell toxicities of Abeta aggregates. According to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) profiles, 14 of 41 compounds showed a significant increase in the densities of the bands of Abeta (1-42) by incubation during the aggregation process relative to those of Abeta (1-42) prepared in the presence of the vehicle control. Of the 14 compounds, four compounds additionally reduced cell toxicity of the Abeta aggregates by incubation during the aggregation process. A significant positive correlation was observed between the cell viability and densities of the bands at ranges of 15 20, 20-37, 37-75, and 75-200 kDa in SDS-PAGE. On the basis of these results, we propose four curcumin derivatives with potential for preventing AD. These curcumin derivatives exhibited high inhibitory effects on Abeta aggregation and induced the formation of lower molecular size Abeta species that have weaker cell toxicity. These compounds may exert therapeutic effects on AD in future in vivo studies. PMID- 29124226 TI - The gene transfer agent-like particle of the marine phototrophic bacterium Rhodovulum sulfidophilum. AB - Gene transfer agents (GTAs) are shaped like bacteriophage particles but have many properties that distinguish them from bacteriophages. GTAs play a role in horizontal gene transfer in nature and thus affect the evolution of prokaryotic genomes. In the course of studies on the extracellular production of designed RNAs using the marine bacterium Rhodovulum sulfidophilum, we found that this bacterium produces a GTA-like particle. The particle contains DNA fragments of 4.5 kb, which consist of randomly fragmented genomic DNA from the bacterium. This 4.5-kb DNA production was prevented while quorum sensing was inhibited. Direct observation of the particle by transmission electron microscopy revealed that the particle resembles a tailed phage and has a head diameter of about 40 nm and a tail length of about 60 nm. We also identified the structural genes for the GTA in the genome. Translated amino acid sequences and gene positions are closely related to those of the genes that encode the Rhodobacter capsulatus GTA. This is the first report of a GTA-like particle from the genus Rhodovulum. However, gene transfer activity of this particle has not yet been confirmed. The differences between this particle and other GTAs are discussed. PMID- 29124227 TI - Structure-based pKa prediction provides a thermodynamic basis for the role of histidines in pH-induced conformational transitions in dengue virus. AB - pH-induced conformational changes in dengue virus (DENV) are critical to its ability to infect host cells. The envelope protein heterodimers that make up the viral envelope shift from a dimer to a trimer conformation at low-pH during membrane fusion. Previous studies have suggested that the ionization of histidine residues at low-pH is central to this pH-induced conformational change. We sought out to use molecular modeling with structure-based pKa prediction to provide a quantitative basis for the role of histidines in pH-induced conformational changes and identify which histidine residues were primarily responsible for this transition. We combined existing crystallographic and cryo-electron microscopy data to construct templates of the dimer and trimer conformations for the mature and immature virus. We then generated homology models for the four DENV serotypes and carried out structure-based pKa prediction using Rosetta. Our results showed that the pKa values of a subset of conserved histidines in DENV successfully capture the thermodynamics necessary to drive pH-induced conformational changes during fusion. Here, we identified the structural determinants underlying these pKa values and compare our findings with previous experimental results. PMID- 29124228 TI - IL-38: A new factor in rheumatoid arthritis. AB - The newly characterized cytokine IL-38 (IL-1F10) belongs to the IL-1 family of cytokines. Previous work has demonstrated that IL-38 inhibited Candida albicans induced IL-17 production from peripheral blood mononuclear cells. However, it is still unclear whether IL-38 is an inflammatory or an anti-inflammatory cytokine. We generated anti-human IL-38 monoclonal antibodies in order to perform immunohistochemical staining and an enzyme-linked immunosorbent assay. While human recombinant IL-38 protein was not cleaved by recombinant caspase-1, chymase, or PR3 in vitro, overexpression of IL-38 cDNA produced a soluble form of IL-38 protein. Furthermore, immunohistochemical analysis showed that synovial tissues obtained from RA patients strongly expressed IL-38 protein. To investigate the biological role of IL-38, C57BL/6 IL-38 gene-deficient (-/-) mice were used in an autoantibody-induced rheumatoid arthritis (RA) mouse model. As compared with control mice, IL-38 (-/-) mice showed greater disease severity, accompanied by higher IL-1beta and IL-6 gene expression in the joints. Therefore, IL-38 acts as an inhibitor of the pathogenesis of autoantibody-induced arthritis in mice and may have a role in the development or progression of RA in humans. PMID- 29124229 TI - Comprehensive analysis of the dynamic structure of nuclear localization signals. AB - Most transcription and epigenetic factors in eukaryotic cells have nuclear localization signals (NLSs) and are transported to the nucleus by nuclear transport proteins. Understanding the features of NLSs and the mechanisms of nuclear transport might help understand gene expression regulation, somatic cell reprogramming, thus leading to the treatment of diseases associated with abnormal gene expression. Although many studies analyzed the amino acid sequence of NLSs, few studies investigated their three-dimensional structure. Therefore, we conducted a statistical investigation of the dynamic structure of NLSs by extracting the conformation of these sequences from proteins examined by X-ray crystallography and using a quantity defined as conformational determination rate (a ratio between the number of amino acids determining the conformation and the number of all amino acids included in a certain region). We found that determining the conformation of NLSs is more difficult than determining the conformation of other regions and that NLSs may tend to form more heteropolymers than monomers. Therefore, these findings strongly suggest that NLSs are intrinsically disordered regions. PMID- 29124230 TI - Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-kappaB signaling pathways. AB - Recent reports have shown that antibiotics such as macrolide, aminoglycoside, and tetracyclines have immunomodulatory effects in addition to essential antibiotic effects. These agents may have important effects on the regulation of cytokine and chemokine production. However, the precise mechanism is unknown. This time, we used Multi Plex to measure the production of cytokines and chemokines following tetracycline treatment of lipopolysaccharide (LPS)-induced THP-1 cells. The signaling pathways were investigated with Western blotting analysis. Three tetracyclines significantly suppressed the expression of cytokines and chemokines induced by LPS. Minocycline (50 MUg/ml), tigecycline (50 MUg/ml), or doxycycline (50 MUg/ml) were added after treatment with LPS (10 MUg/ml). Tumor necrosis factor-alpha was downregulated to 16%, 14%, and 8%, respectively, after 60 min compared to treatment with LPS without agents. Interleukin-8 was downregulated to 43%, 32%, and 26% at 60 min. Macrophage inflammatory protein (MIP)-1alpha was downregulated to 23%, 33%, and 16% at 120 min. MIP-1beta was downregulated to 21%, 11%, and 2% at 120 min. Concerning about signaling pathways, the mechanisms of the three tetracyclines might not be the same. Although the three tetracyclines showed some differences in the time course, tetracyclines modulated phosphorylation of the NF-kappaB pathway, p38 and ERK1/2/MAPK pathways, resulting in inhibition of cytokine and chemokine production. In addition, SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor) significantly suppressed the expression of TNF-alpha and IL-8 in LPS-stimulated THP-1 cells. And further, the NF-kappaB inhibitor, BAY11-7082, almost completely suppressed LPS-induced these two cytokines production. Thus, more than one signaling pathway may be involved in tetracyclines downregulation of the expression of LPS-induced cytokines and chemokines in THP-1 cells. And among the three signaling pathways, NF-kappaB pathway might be the dominant pathway on tetracyclines modification the LPS induced cytokines production in THP-1 cells. In general, minocycline and doxycycline suppressed the production of cytokines and chemokines in LPS stimulated THP-1 cell lines via mainly the inhibition of phosphorylation of NF kappaB pathways. Tigecycline has the same structure as the other tetracyclines, however, it showed the different properties of cytokine modulation in the experimental time course. PMID- 29124231 TI - Curcumin, bisdemethoxycurcumin and dimethoxycurcumin complexed with cyclodextrins have structure specific effect on the paracellular integrity of lung epithelia in vitro. AB - The phytochemical curcumin may improve translocation of the cystic fibrosis transmembrane regulatory (CFTR) protein in lung epithelium and therefore be helpful in the treatment of cystic fibrosis (CF) symptoms. However, previous studies often use commercial curcumin that is a combination of curcumin, demethoxycurcumin and bisdemethoxycurcumin which could affect the investigated cells differently. In the present study, we investigated the potential difference between curcumin, bisdemethoxycurcumin and dimethoxycurcumin on the epithelial tight junction complex, in the bronchial epithelial cell line VA10, by measuring transepithelial electrical resistance (TER), immunofluorescence and western blotting of tight junction proteins. The curcuminoids were complexed with hydroxypropyl-gamma-cyclodextrin for increased solubility and stability. Curcumin (10 ug/ml) increased the TER significantly after 24 h of treatment while four times higher concentration of bisdemethoxycurcumin was required to obtain similar increase in TER as curcumin. Interestingly, dimethoxycurcumin did not increase TER. Curcumin clearly affected the F-actin structures both apically and basolaterally. These results begin to define possible effects of curcuminoids on healthy bronchial epithelia and shows that difference in the phenyl moiety structure of the curcuminoids influences the paracellular epithelial integrity. PMID- 29124232 TI - Catalase from larvae of the camel tick Hyalomma dromedarii. AB - Catalase plays a major role in protecting cells against toxic reactive oxygen species. Here, Catalase was purified from larvae of the camel tick Hyalomma dromedarii and designated TLCAT. It was purified by ammonium sulfate precipitation and chromatography on DEAE-cellulose, Sephacryl S-300 and CM cellulose columns. Gel filtration and SDS-PAGE of the purified TLCAT indicated that the protein has a native molecular weight of 120 kDa and is most likely a homodimer with a subunit of approximately 60 kDa. The Km value of TLCAT is 12 mM H2O2 and displayed its optimum activity at pH 7.2. CaCl2, MgCl2, MnCl2 and NiCl2 increased the activity of TLCAT, while FeCl2, CoCl2, CuCl2 and ZnCl2 inhibited the activity of TLCAT. Sodium azide inhibited TLCAT competitively with a Ki value of 0.28 mM. The presence of TLCAT in cells may play a role in protecting H. dromedarii ticks against oxidative damage. This finding will contribute to our understanding of the physiology of these ectoparasites and the development of untraditional methods to control them. PMID- 29124234 TI - Permeability, strength and electrochemical studies on ceramic multilayers for solid-state electrochemical cells. AB - An electrochemical reactor can be used to purify flue gasses. Such a reactor can be a multilayer structure consisting of alternating layers of porous electrodes and electrolytes (a porous cell stack). In this work optimization of such a unit has been done by changing the pore former composition and the electrode powder pre-treatment. The effect on permeability, mechanical strength and electrochemical behavior was studied in this work. The effects were evaluated by measuring the pressure difference over the samples in relation to the flow through the sample, by the ball on ring method and by electrochemical impedance spectroscopy in air at temperatures between 300 and 450 degrees C. The resulting structures were also evaluated with scanning electron microscopy. The work showed a dependence on the pore former composition and electrode powder pre-treatment resulting in variations in porosity, strength and flow resistance. A higher porosity gives a lower backpressure. The electrochemical performance shows that both thickness and amount of pore former in the electrolyte is important, but almost no dependence of electrode composition on the polarization resistances within the tested compositions. PMID- 29124233 TI - Tea polyphenols ameliorate fat storage induced by high-fat diet in Drosophila melanogaster. AB - Background: Polyphenols in tea are considered beneficial to human health. However, many such claims of their bioactivity still require in vitro and in vivo evidence. Results: Using Drosophila melanogaster as a model multicellular organism, we assess the fat accumulation-suppressing effects of theaflavin (TF), a tea polyphenol; epitheaflagallin (ETG), which has an unknown function; and epigallocatechin gallate (EGCg), a prominent component of green tea. Dietary TF reduced the malondialdehyde accumulation related to a high-fat diet in adult flies. Other physiological and genetic responses induced by the high-fat diet, such as lipid accumulation in the fat body and expression of lipid metabolism related genes, were ameliorated by the addition of TF, ETG, and EGCg, in some cases approaching respective levels without high-fat diet exposure. Continuous ingestion of the three polyphenols resulted in a shortened lifespan. Conclusion: We provide evidence in Drosophila that tea polyphenols have a fat accumulation suppressing effect that has received recent attention. We also suggest that tea polyphenols can provide different desirable biological activities depending on their composition and the presence or absence of other chemical components. PMID- 29124235 TI - In vivo XCT bone characterization of lattice structured implants fabricated by additive manufacturing. AB - Several cylindrical specimens and dental implants, presenting diagonal lattice structures with different cell sizes (600, 900 and 1200 MUm) were additively manufactured by selective laser melting process. Then they were implanted for two months in a sheep. After removal, they were studied by Archimedes' method as well as X-ray computed tomography in order to assess the penetration of bone into the lattice. We observed that the additive manufactured parts were geometrically conformed to the theoretical specifications. However, several particles were left adhering to the surface of the lattice, thereby partly or entirely obstructing the cells. Nevertheless, bone penetration was clearly visible. We conclude that the 900 MUm lattice cell size is more favourable to bone penetration than the 1200 MUm lattice cell size, as the bone penetration is 84% for 900 MUm against 54% for 1200 MUm cell structures. The lower bone penetration value for the 1200 MUm lattice cell could possibly be attributed to the short residence time in the sheep. Our results lead to the conclusion that lattice implants additively manufactured by selective laser melting enable better bone integration. PMID- 29124236 TI - IMPLEMENTATION, RECRUITMENT AND BASELINE CHARACTERISTICS: A RANDOMIZED TRIAL OF COMBINED TREATMENTS FOR SMOKING CESSATION AND WEIGHT CONTROL. AB - Background: Two-thirds of treatment-seeking smokers are obese or overweight. Most smokers are concerned about gaining weight after quitting. The average smoker experiences modest post-quit weight gain which discourages many smokers from quitting. Although evidence suggests that combined interventions to help smokers quit smoking and prevent weight gain can be helpful, studies have not been replicated in real world settings. Methods: This paper describes recruitment and participant characteristics of the Best Quit Study, a 3-arm randomized controlled trial testing tobacco cessation treatment alone or combined with simultaneous or sequential weight management. Study participants were recruited via tobacco quitlines from August 5, 2013 to December 15, 2014. Results: Statistical analysis on baseline data was conducted in 2015/2016. Among 5,082 potentially eligible callers to a tobacco quitline, 2,540 were randomized (50% of eligible). Compared with individuals eligible but not randomized, those randomized were significantly more likely to be female (65.7% vs 54.5%, p<.01), overweight or obese (76.3% vs 62.5%, p<.01), more confident in quitting (p<.01), more addicted (first cigarette within 5 minutes: 50.0% vs 44.4%, p<.01), and have a chronic disease (28.6% vs. 24.4%, p<.01). Randomized groups were not statistically significantly different on demographics, tobacco or weight variables. Two-thirds of participants were female and white with a mean age of 43. Conclusions: Adding weight management interventions to tobacco cessation quitlines was feasible and acceptable to smokers. If successful for cessation and weight outcomes, a combined intervention may provide a treatment approach for addressing weight gain with smoking cessation through tobacco quitlines. PMID- 29124238 TI - The future prospects of supply and demand for urologists in Korea. AB - Purpose: The purpose of this study was to forecast the future supply and demand for urologists and to discuss the possible policy implications. Materials and Methods: A demographic utilization-based model was used to calculate the total urologist requirements for Korea. Utilization rates for ambulatory and inpatient genitourinary specialty services were estimated according to age, sex, and insurance status. These rates were used to estimate genitourinary specialty specific total service utilization expressed in patient care minutes for future populations and converted to genitourinary physician requirements by applying per genitourinary-physician productivity estimates. An in-and-out movement model for urologist supply was used. Results: Depending on assumptions about data at each step in the method, the supply of urologic surgeons is expected to exceed the demand by 2025 under the current enrollment rate of specialists (43.5% in 2012) when comparing the results of the projections under demand scenarios 3 and 4. However, if the current enrollment rate persists, the imbalance in supply and demand will be not severe by 2030. The degree of imbalance can be alleviated by 2030 by maintaining the current occupancy rate of urologic residents of 43.5%. Conclusions: This study shows that the number of residents needs to be reduced according to the supply and demand for urologic surgeons. Moreover, a policy should be established to maintain the current occupancy rate of residents. The factors affecting the supply and demand of urologic surgeons are complicated. Thus, comprehensive policies encompassing these factors should be established with appropriate solutions. PMID- 29124237 TI - Oxidation-reduction potential as a new marker for oxidative stress: Correlation to male infertility. AB - Male infertility affects men worldwide. Oxidative stress (OS), characterized by an overabundance of reactive oxygen species (ROS) or a deficiency of antioxidants, is one of the major causes of male infertility. OS causes damage at the molecular level, which impairs lipids, proteins, and DNA. The cyclic cascade of redox reactions weakens sperm function which leads to poor semen parameters and eventual sterility. There is a need for advanced diagnostic tests that can quickly and accurately detect OS. Most commonly used assays can only measure single constituents of OS. However, the MiOXSYS System introduces a new strategy to detect OS by measuring the oxidation-reduction potential (ORP)--a direct evaluation of the redox balance between ROS and antioxidants. The MiOXSYS System has shown promise as a diagnostic tool in the evaluation of male infertility. This review explores the concept of ORP, details the principle of the MiOXSYS System, and summarizes the findings in clinical studies that support ORP measurement in semen. PMID- 29124239 TI - Impact of preoperative proteinuria on renal functional outcomes after open partial nephrectomy in patients with a solitary kidney. AB - Purpose: To assess the impact of proteinuria on postoperative renal function after open partial nephrectomy (OPN) in patients with a solitary kidney and analyze predictive factors for developing chronic kidney disease (CKD) stage IV or higher. Materials and Methods: Patients with a solitary kidney who underwent OPN at Tokyo Women's Medical University Hospital between 1986 and 2016 were the subjects of this study. The patients were divided into 2 groups according to the presence of preoperative proteinuria. The development rate of stage IV CKD or higher was analyzed by the Kaplan-Meier method to compare the postoperative renal function of the 2 groups. Multivariate regression analysis was used to demonstrate predictive factors for postoperative CKD progression. Results: A total of 96 patients, including 73 without proteinuria and 23 with proteinuria, were included in this study. Patients with proteinuria were more likely to be men (95.6% vs. 64.3%, p<0.01), had a higher body mass index (25.7 kg/m2 vs. 23.5 kg/m2, p<0.01), and had a higher incidence of hypertension (69.5% vs. 39.7%, p=0.01). Patients with proteinuria had a higher probability of developing stage IV CKD or higher (p=0.0002). Lower preoperative eGFR (p<0.0001) and positive proteinuria (p=0.04) were independent predictors for CKD stage progression on multivariate analysis. Conclusions: Preoperative proteinuria and eGFR were independent predictors for developing stage IV CKD or higher after OPN. Meanwhile, surgical factors including ischaemia time and tumor size had no significant effect. This suggests that assessment of preoperative CKD stage could help stratify patients according to their risk of renal function exacerbation. PMID- 29124240 TI - Lymph node yield in node-negative patients predicts cancer specific survival following radical cystectomy for transitional cell carcinoma. AB - Purpose: To determine the oncological implications of increased nodal dissection in node-negative bladder cancer during radical cystectomy in a contemporary Australian series. Materials and Methods: We performed a multicenter retrospective study, including more than 40 surgeons across 5 sites over a 10 year period. We identified 353 patients with primary bladder cancer undergoing radical cystectomy. Extent of lymphadenectomy was defined as follows; limited pelvic lymph node dissection (PLND) (perivesical, pelvic, and obturator), standard PLND (internal and external iliac) and extended PLND (common iliac). Multivariable cox proportional hazards and logistic regression models were used to determine LNY effect on cancer-specific survival. Results: Over the study period, the extent of dissection and lymph node yield increased considerably. In node-negative patients, lymph node yield (LNY) conferred a significantly improved cancer-specific survival. Compared to cases where LNY of 1 to 5 nodes were taken, the hazard ratio (HR) for 6 to 15 nodes harvested was 0.78 (95% confidence interval [CI], 0.43-1.39) and for greater than 15 nodes the HR was 0.31 (95% CI, 0.17-0.57), adjusted for age, sex, T stage, margin status, and year of surgery. The predicted probability of cancer-specific death within 2 years of cystectomy was 16% (95% CI, 13%-19%) with 10 nodes harvested, falling to 5.5% (95% CI, 0% 12%) with 30 nodes taken. Increasing harvest in all PLND templates conferred a survival benefit. Conclusions: The findings of the current study highlight the improved oncological outcomes with increased LNY, irrespective of the dissection template. Further prospective research is needed to aid LND data interpretation. PMID- 29124242 TI - Growth kinetics of small renal mass: Initial analysis of active surveillance registry. AB - Purpose: To evaluate the clinical safety and natural history of active surveillance (AS) for incidentally diagnosed small renal mass (SRM). Materials and Methods: We analyzed prospective data for patients who underwent AS for SRM. From 2010 to 2016, 37 SRMs of less than 3 cm were registered. Computed tomography (CT) and magnetic resonance imaging were used for initial diagnosis and CT, ultrasonography, and chest CT were performed at 6-month intervals. If there was no change in size during 2 years, follow-ups were performed annually. If the growth rate was more than 0.5 cm/y, if the diameter was more than 4 cm, or if clinical progression was observed, we regarded it as progression of SRM and recommended active treatment. We compared the growth rate and clinical course of SRM between patients who remained on surveillance and those who had progressed disease. Results: The mean age was 63 years (range, 30-86 years) and the mean diameter was 1.8 cm (range, 0.6-2.8 cm) at diagnosis. The mean follow-up period was 27.3 months (range, 6-80 months) and the average growth rate was 0.2 cm/y (range, 0-1.9 cm/y). Six patients (16.2%) showed progression of SRM. Three patients wanted continuous observation, and partial nephrectomy was performed on 3 other patients. None of the patients had clinical progression, including metastasis. Conclusions: We could delay active treatment for patients with an SRM with scheduled surveillance if the SRM grew relatively slowly. If more long-term AS results are documented for more patients, AS could be an alternative treatment modality for SRM. PMID- 29124241 TI - US Preventive Services Task Force prostate-specific antigen screening guidelines result in higher Gleason score diagnoses. AB - Purpose: To evaluate the impact that the 2012 US Preventive Services Task Force (USPSTF) prostate-specific antigen (PSA) screening guidelines have had on the diagnosis of prostate cancer, we compared the incidence and distribution of new cases diagnosed in 2011-before the USPSTF PSA screening recommendations versus 2014 at which time the guidelines were widely adopted. Materials and Methods: We identified all prostate biopsies performed by a large urology group practice utilizing a centralized pathology lab. We examined total biopsies performed, percentage of positive biopsies, and for those with positive biopsies examined for differences in patient age, PSA, and Gleason score. Results: A total of 4,178 biopsies were identified - 2,513 in 2011 and 1,665 in 2014. The percentage of positive biopsies was 27% in 2011 versus 34% in 2014 (p<0.0001). Among patients with positive biopsies, we found statistically significant differences between the 2 cohorts in the median ages and Gleason scores. Patients were about 1 year younger in 2014 compared to 2011 (t-test; p=0.043). High Gleason scores (8-10) were diagnosed in 19% of the 2014 positive biopsies versus 9% in the 2011 positive biopsies (chi square; p<0.0001). Conclusions: After the widespread implementation of the 2011 USPTF PSA screening guidelines, 34% fewer biopsies were performed with a 29% increase in positive biopsy rates. We found a significantly higher incidence of high grade disease in 2014 compared with 2011. The percentage of patients with positive biopsies having Gleason scores 8-10 more than doubled in 2014. The higher incidence of these more aggressive cancers must be part of the discussion regarding PSA screening. PMID- 29124243 TI - Establishment of Korean prostate cancer database by the Korean Urological Oncology Society. AB - Purpose: Despite the necessity, to date, no detailed database of prostate cancer, especially one that includes clinicopathological data, has been created in Korea. For that reason, the Korean Urological Oncology Society (KUOS) decided to create the Korean Prostate Cancer Database (KPCD). Materials and Methods: The KPCD program was introduced in 2010. After considering regional distribution, a total of 20 hospitals participated in the KPCD. The Database consists of 4 domains (demographic, pretreatment, treatment, and follow-up data) and 135 variables. Results: In total, 7,608 men with prostate cancer between 2000 and 2010 were registered in the KPCD. The mean age at the time of diagnosis was 67.6+/-7.7 years. The mean PSA at diagnosis was 74.0+/-366.9 ng/mL, and the proportions of patients with Gleason scores of <=6, 7, and 8-10 were 37.0%, 26.7%, and 34.2%, respectively. At diagnosis, 62.3% of the patients had localized tumors, 14.6% had regional, 12.8% had distant, and 10.4% cases were from unknown diseases. With regards to the initial treatment modality employed, 1.3% of patients were managed with active surveillance, 62.1% underwent surgery, 4.3% underwent radiotherapy, 27.1% had androgen deprivation therapy, and 5.2% underwent unknown therapies. The 5-year cancer-specific survival rate of patients in the KPCD was 98.6% in the localized stage, 94.8% in the regional stage, 74.7% in the distant stage, and 86.9% in the unknown stage. Conclusions: The KUOS created a relatively successful database of patients with prostate cancer in Korea. The KPCD will continue to improve the availability of data regarding prostate cancer. PMID- 29124244 TI - Impact of loop-tail ureteral stents on ureteral stent-related symptoms immediately after ureteroscopic lithotripsy: Comparison with pigtail ureteral stents. AB - Purpose: To evaluate urination-related quality of life (QoL) in patients with an indwelling ureteral stent immediately after ureteroscopic lithotripsy (URSL) for upper urinary calculi. We compared the effects of loop-tail and pigtail ureteral stents on urination-related QoL. Materials and Methods: Of 135 patients who underwent URSL between May 2014 and March 2015 at our hospital, we retrospectively analyzed the records of 70 patients (42 men, 28 women; median age, 63 years) in whom the stent tail was positioned inside the bladder without crossing the midline and who completed the core lower urinary tract symptoms score (CLSS) questionnaire pre- and postoperatively. Results: There were significant differences in incomplete emptying (p=0.048) and bladder pain (p=0.041) between patients with loop-tail versus pigtail ureteral stents after URSL. In the multivariate analysis, stent type had a stronger association with incomplete emptying (p=0.022) and bladder pain (p=0.018) than age, sex, body mass index, stent side, operation time, diameter of ureteral access sheath, and stent type. Conclusions: Patients with loop-tail ureteral stents had better urination related QoL in the immediate post-URSL stage than patients with pigtail stents. PMID- 29124246 TI - Validation of APACHE II scoring system at 24 hours after admission as a prognostic tool in urosepsis: A prospective observational study. AB - Purpose: Urosepsis implies clinically evident severe infection of urinary tract with features of systemic inflammatory response syndrome (SIRS). We validate the role of a single Acute Physiology and Chronic Health Evaluation II (APACHE II) score at 24 hours after admission in predicting mortality in urosepsis. Materials and Methods: A prospective observational study was done in 178 patients admitted with urosepsis in the Department of Urology, in a tertiary care institute from January 2015 to August 2016. Patients >18 years diagnosed as urosepsis using SIRS criteria with positive urine or blood culture for bacteria were included. At 24 hours after admission to intensive care unit, APACHE II score was calculated using 12 physiological variables, age and chronic health. Results: Mean+/ standard deviation (SD) APACHE II score was 26.03+/-7.03. It was 24.31+/-6.48 in survivors and 32.39+/-5.09 in those expired (p<0.001). Among patients undergoing surgery, mean+/-SD score was higher (30.74+/-4.85) than among survivors (24.30+/ 6.54) (p<0.001). Receiver operating characteristic (ROC) analysis revealed area under curve (AUC) of 0.825 with cutoff 25.5 being 94.7% sensitive and 56.4% specific to predict mortality. Mean+/-SD score in those undergoing surgery was 25.22+/-6.70 and was lesser than those who did not undergo surgery (28.44+/-7.49) (p=0.007). ROC analysis revealed AUC of 0.760 with cutoff 25.5 being 94.7% sensitive and 45.6% specific to predict mortality even after surgery. Conclusions: A single APACHE II score assessed at 24 hours after admission was able to predict morbidity, mortality, need for surgical intervention, length of hospitalization, treatment success and outcome in urosepsis patients. PMID- 29124245 TI - Thermo-expandable prostatic stents for bladder outlet obstruction in the frail and elderly population: An underutilized procedure? AB - Purpose: To report our outcomes with the use of a thermo-expandable metallic intraprostatic stent (Memokath) for patients with bladder outlet obstruction (BOO) secondary to prostatic obstruction, and to assess it is a feasible option for many frail and elderly men unsuitable for surgery. Materials and Methods: We reviewed patients who underwent insertion of a Memokath stent for BOO over 17 years (January 1999 to December 2015) at one regional center over a long follow up period (median, 7 years). Patients were selected if they had obstructive urinary symptoms or urinary retention with an indwelling catheter in situ, and were ineligible for transurethral resection of the prostate (TURP) under general or spinal anesthesia. Primary outcomes assessed were the improvement in urinary symptoms and voiding parameters, as well as the ability to void spontaneously if catheterized, along with complications. Results: One hundred forty-four patients who presented with BOO or urinary retention had a Memokath stent inserted. Ninety patients (62.5%) had a successful stent insertion with a significant difference between the median preoperative (550 mL) and postoperative residual volume (80 mL, p<0.0001). Nearly two-thirds of men (64%) returned to unassisted voiding with no increased risk of complications over time. Fifty-four patients (37.5%) experienced stent failure. Main complications requiring stent removal or repositioning were migration, occlusion, refractory urinary retention and irritative voiding symptoms. Conclusions: In elderly and frail men with BOO deemed unsuitable to undergo TURP, prostatic stent is a safe and practical alternative to long-term catheterization. PMID- 29124248 TI - Circumcision-incision orchidopexy: A novel technique for palpable, low inguinal undescended testis. AB - Given that both orchidopexy and circumcision are commonly done in a single operative setting, we adopted a technique of combined orchidopexy and circumcision using a single circumcision incision. We applied this new technique to boys with palpable, low inguinal cryptorchidism. Here we describe a case series of 7 boys who underwent concurrent orchidopexy via the circumcision site. We present this novel technique and discuss our preliminary outcomes, including the anatomic basis and feasibility. The technique appears to be an alternative for concurrent circumcision and cryptorchid cases with palpable, low inguinal testes. PMID- 29124249 TI - Relating coccidioidomycosis (valley fever) incidence to soil moisture conditions. AB - Coccidioidomycosis (also called Valley fever) is caused by a soilborne fungus, Coccidioides spp., in arid regions of the southwestern United States. Though some who develop infections from this fungus remain asymptomatic, others develop respiratory disease as a consequence. Less commonly, severe illness and death can occur when the infection spreads to other regions of the body. Previous analyses have attempted to connect the incidence of coccidioidomycosis to broadly available climatic measurements, such as precipitation or temperature. However, with the limited availability of long-term, in situ soil moisture data sets, it has not been feasible to perform a direct analysis of the relationships between soil moisture levels and coccidioidomycosis incidence on a larger temporal and spatial scale. Utilizing in situ soil moisture gauges throughout the southwest from the U.S. Climate Reference Network and a model with which to extend those estimates, this work connects periods of higher and lower soil moisture in Arizona and California between 2002 and 2014 to the reported incidence of coccidioidomycosis. The results indicate that in both states, coccidioidomycosis incidence is related to soil moisture levels from previous summers and falls. Stated differently, a higher number of coccidioidomycosis cases are likely to be reported if previous bands of months have been atypically wet or dry, depending on the location. PMID- 29124247 TI - Chlamydia trachomatis versus common uropathogens as a cause of chronic bacterial prostatitis: Is there any difference? Results of a prospective parallel-cohort study. AB - Purpose: The role of Chlamydia trachomatis (CT) infection in chronic bacterial prostatitis (CBP) is well known. What is unclear is whether there are any differences in the course or clinical outcome of the disease when the cause is CT or other uropathogens. Materials and Methods: A series of 311 patients affected by CBP due to CT (cohort A) was compared with a group of 524 patients affected by CBP caused by common uropathogen bacteria (cohort B). All participants completed the following questionnaires: National Institutes of Health Chronic Prostatitis Symptom Index, International Prostate Symptom Score, International Index of Erectile Function-15 erectile function domain (IIEF-15-EFD), Premature Ejaculation Diagnostic Tool (PEDT), and the Short Form 36 (SF-36) Health Survey. All patients were followed with clinical and microbiological evaluations. Results: After a mean follow-up time of 42.3 months, the number of symptomatic episodes was significantly higher in patients in cohort A than in cohort B (4.1+/ 1.1 vs. 2.8+/-0.8, p<0.001), and the mean time to first symptomatic recurrence was shorter in cohort A than in cohort B (3.3+/-2.3 months vs. 5.7+/-1.9 months, p<0.001). Moreover, scores on the SF-36 tool were significantly lower in cohort A (96.5+/-1.0 vs. 99.7+/-1.9, p<0.001) at the first symptomatic recurrence. Cohort A also showed significantly lower scores on the IIEF-15-EFD and PEDT questionnaires at the end of the follow-up period (26.8+/-2.9 vs. 27.3+/-3.3, p=0.02 and 11.5+/-2.3 vs. 4.5+/-2.8, p<0.001, respectively). Conclusions: Patients affected by CBP due to CT infection have a higher number of symptomatic recurrences with a more severe impact on quality of life. PMID- 29124250 TI - Impaired Rab7 and Dynamin2 Block Fat Turnover by Autophagy in Alcoholic Fatty Livers. PMID- 29124251 TI - TRAIL Deletion Prevents Liver, but Not Adipose Tissue, Inflammation during Murine Diet-Induced Obesity. AB - Background & Aim: TNF-related apoptosis-inducing ligand (TRAIL) and its cognate receptor(s) are upregulated in human and murine nonalcoholic steatohepatitis (NASH). However, the consequence of this enhanced expression on NASH pathogenesis remains unclear. TRAIL may either accentuate liver injury by promoting hepatic steatosis and inflammation, or it may mitigate the disease process by improving systemic insulin resistance and averting hepatic fibrosis. Herein, we investigated the role of TRAIL in an obesity-induced murine model of NASH. Methods: C57BL/6 wild-type (WT) mice and Trail-/- mice were placed on a 20-week standard chow or FFC (high fat, fructose, and cholesterol) diet which induces obesity, insulin resistance and NASH. Metabolic phenotype, liver injury, inflammation and fibrosis, and adipose tissue homeostasis were examined. Results: FFC diet-fed Trail-/- mice displayed no difference in weight gain and metabolic profile when compared to WT mice on the same diet. All FFC-fed mice developed significant hepatic steatosis, which was attenuated in Trail-/- mice. TRAIL deficiency also significantly decreased FFC diet-induced liver injury as manifest by reduced serum ALT values, hepatic TUNEL-positive cells and macrophage associated inflammation. FFC diet-associated hepatic stellate cell activation and hepatic collagen deposition were also abrogated in Trail-/- mice. In contrast to the liver, TRAIL deletion did not improve FFC diet-induced adipose tissue injury and inflammation, and actually aggravated insulin resistance. In conclusion, these observations employing genetic TRAIL inactivation suggest that NASH pathogenesis may be dissociated from other features of the metabolic syndrome and liver-targeted inhibition of TRAIL signaling may be salutary. PMID- 29124252 TI - Bone Loss at the Hip and Subsequent Mortality in Older Men: The Osteoporotic Fractures in Men (MrOS) Study. AB - Low bone mineral density (BMD) is associated with increased mortality risk, yet the impact of BMD loss on mortality is relatively unknown. We hypothesized that greater BMD loss is associated with increased mortality risk in older men. Change in femoral neck BMD was assessed in 4400 Osteoporotic Fractures in Men (MrOS) study participants with two to three repeat dual-energy X-ray absorptiometry scans over an average of 4.6 +/- 0.4 (mean +/- SD) years. Change in femoral neck BMD was estimated using mixed effects models; men were grouped into three categories of BMD change: maintenance (n = 1087; change >= 0 g/cm2); expected loss (n = 2768; change between 0 g/cm2 and <1 SD below mean change [>-0.034 g/cm2]); and accelerated loss (n = 545; change 1 SD below mean change or worse [<=-0.034 g/cm2]). Multivariate proportional hazards models adjusted for potential confounders estimated the risk of all-cause mortality over 8.1 +/- 2.8 years following visit 2. Mortality was centrally adjudicated by physician review of death certificates. At visit 1, mean age was 72.9 +/- 5.5 years. Men who maintained BMD were less likely to die during the subsequent follow-up period (33.7%) than men who had accelerated BMD loss (60.6%) (p < 0.001). Compared to men who had maintained BMD, those who had accelerated BMD loss had a 44% greater risk of mortality in multivariate-adjusted models (HR, 1.44; 95% CI, 1.23 to 1.68). Compared to men who had maintained BMD, there was no significant difference in mortality risk for men with expected loss of BMD (36.9% died) (multivariate HR, 1.00; 95% CI, 0.89 to 1.13). Further adjustment for visit 1 or visit 2 BMD measurement did not substantially alter these associations. Results for total hip BMD were similar. In conclusion, accelerated loss of BMD at the hip is a risk factor for mortality in men that is not explained by comorbidity burden, concurrent change in weight, or physical activity. PMID- 29124253 TI - Exploring Gyral Patterns of Infant Cortical Folding based on Multi-view Curvature Information. AB - The human cortical folding is intriguingly complex in its variability and regularity across individuals. Exploring the principal patterns of cortical folding is of great importance for neuroimaging research. The term-born neonates with minimum exposure to the complicated environments are the ideal candidates to mine the postnatal origins of principal cortical folding patterns. In this work, we propose a novel framework to study the gyral patterns of neonatal cortical folding. Specifically, first, we leverage multi-view curvature-derived features to comprehensively characterize the complex and multi-scale nature of cortical folding. Second, for each feature, we build a dissimilarity matrix for measuring the difference of cortical folding between any pair of subjects. Then, we convert these dissimilarity matrices as similarity matrices, and nonlinearly fuse them into a single matrix via a similarity network fusion method. Finally, we apply a hierarchical affinity propagation clustering approach to group subjects into several clusters based on the fused similarity matrix. The proposed framework is generic and can be applied to any cortical region, or even the whole cortical surface. Experiments are carried out on a large dataset with 600+ term-born neonates to mine the principal folding patterns of three representative gyral regions. PMID- 29124254 TI - Developmental Patterns Based Individualized Parcellation of Infant Cortical Surface. AB - The human cerebral cortex develops dynamically during the early postnatal stage, reflecting the underlying rapid changes of cortical microstructures and their connections, which jointly determine the functional principles of cortical regions. Hence, the dynamic cortical developmental patterns are ideal for defining the distinct cortical regions in microstructure and function for neurodevelopmental studies. Moreover, given the remarkable inter-subject variability in terms of cortical structure/function and their developmental patterns, the individualized cortical parcellation based on each infant's own developmental patterns is critical for precisely localizing personalized distinct cortical regions and also understanding inter-subject variability. To this end, we propose a novel method for individualized parcellation of the infant cortical surface into distinct and meaningful regions based on each individual's cortical developmental patterns. Specifically, to alleviate the effects of cortical measurement errors and also make the individualized cortical parcellation comparable across subjects, we first create a population-based cortical parcellation to capture the general developmental landscape of the cortex in an infant population. Then, this population-based parcellation is leveraged to guide the individualized parcellation based on each infant's own cortical developmental patterns in an iterative manner. At each iteration, the individualized parcellation is gradually updated based on 1) the prior information of the population-based parcellation, 2) the individualized parcellation at the previous iteration, and also 3) the developmental patterns of all vertices. Experiments on fifteen healthy infants, each with longitudinal MRI scans acquired at six time points (i.e., 1, 3, 6, 9, 12 and 18 months of age), show that our method generates a reliable and meaningful individualized cortical parcellation based on each infant's own developmental patterns. PMID- 29124255 TI - A microdialysis-based analytical system for dynamic monitoring of arsenic transformation under microbial activity. AB - In this study, a microdialysis (MD) technique was combined with high-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC-ICP-MS) for continuous monitoring of the dynamic variations of arsenic species in a microbe-inoculated culture broth. After optimizing the analytical system, retrodialysis was applied to assess the probe recovery and analytical performance of the proposed method. The mean probe recoveries of four arsenic species were in the range from 57.0 to 81.8%. The limit of detection (LOD) for arsenic was in the range of 0.6-1.8 ng mL-1 and 0.032 MUM for MDA, respectively. The accuracy was assessed by an addition/recovery test with a satisfactory value of 98.07-109.08% for arsenic species and 93.57-108.15% for MDA, respectively. To evaluate the practical applicability of this method, we monitored, continuously for 72 h, the dynamic variations of the concentrations of the four arsenic species in a standardized bacterial sample (ATCC 25922). After adding the arsenic species into the bacteria-inoculated broth, we found that the concentration of As3+ decreased over time, whereas As5+ increased in concentration. In addition, malondialdehyde (MDA) was also monitored to evaluate the effect of oxidative damage of the arsenic species on the studied microbial system. Our analyses revealed that the dynamic variations of the arsenic species and MDA could be observed continuously during the microbial growth period. This economical and eco-friendly method might also be helpful for monitoring the transformations of other metal species, oxidation processes, and the bioremediation ability of microbial systems. PMID- 29124256 TI - Highly selective adsorption of p-xylene over other C8 aromatic hydrocarbons by Co CUK-1: a combined experimental and theoretical assessment. AB - High quality crystalline Co-CUK-1 can be synthesized rapidly and efficiently by a microwave-assisted method. The resulting microporous coordination material is a highly effective adsorbent for the separation of xylene isomers and ethylbenzene, as demonstrated here through sorption isotherm analysis, Ideal Adsorbed Solution Theory (IAST) calculations, and grand canonical Monte Carlo (GCMC) simulations. Co-CUK-1 showed high sorption capacity and high adsorption selectivity for p xylene over the corresponding m- and o-isomers, and ethylbenzenes. According to the data obtained from IAST and GCMC simulations, the Co-CUK-1 is found to strongly favour p-xylene adsorption because p-xylene molecules undergo well defined molecular packing in the 1-D channels; by comparison, the packing efficiencies of o-xylene, m-xylene and ethylbenzene are significantly lower, as is evidenced by lower saturation capacities. PMID- 29124257 TI - Adsorption dynamics of polyatomic molecules on planar surfaces. AB - This is a comparative study of the adsorption dynamics of increasingly longer polyatomic molecules on a planar surface. We perform kinetic Monte Carlo simulations of the gas uptake to identify the molecular mechanisms and parameters that govern the evolution of the adsorbed film to its final equilibrium state. We also develop an analytical model for the adsorption dynamics of mono-atomic gases that demonstrates a direct correlation between the strength of the gas-gas interaction and the adsorption rate dependence with coverage. When this is added to the effect of the orientational freedom of polyatomic molecules, we are able to explain the change in the adsorption rate dependence observed experimentally for longer molecules. PMID- 29124259 TI - Correction: A metal-free fluorescence turn-on molecular probe for detection of nucleoside triphosphates. AB - Correction for 'A metal-free fluorescence turn-on molecular probe for detection of nucleoside triphosphates' by Debabrata Maity et al., Chem. Commun., 2017, 53, 208-211. PMID- 29124258 TI - An acoustic on-chip goniometer for room temperature macromolecular crystallography. AB - This paper describes the design, development and successful use of an on-chip goniometer for room-temperature macromolecular crystallography via acoustically induced rotations. We present for the first time a low cost, rate-tunable, acoustic actuator for gradual in-fluid sample reorientation about varying axes and its utilisation for protein structure determination on a synchrotron beamline. The device enables the efficient collection of diffraction data via a rotation method from a sample within a surface confined droplet. This method facilitates efficient macromolecular structural data acquisition in fluid environments for dynamical studies. PMID- 29124260 TI - Biomimetic superwettable materials with structural colours. AB - Structural colours and superwettability are of great interest due to their unique characteristics. However, the application of materials with either structural colours or superwettability is limited. Moreover, materials possessing both structural colours and superwettability are crucial for many practical applications. The combination of structural colours and superwettability can result in materials for use various applications, such as in sensors, detectors, bioassays, anti-counterfeiting, and liquid actuators, by controlling surfaces to repel or absorb liquids. Regarding superwettability and structural colours, surface texture and chemical composition are two factors for the construction of materials with superwettable structural colours. This review aims at offering a comprehensive elaboration of the mechanism, recent biomimetic research, and applications of biomimetic superwettable materials with structural colours. Furthermore, this review provides significant insight into the design, fabrication, and application of biomimetic superwettable materials with structural colours. PMID- 29124261 TI - Regioselective phosphinylation of coumarins under green LED irradiation and its mechanism. AB - The regioselective synthesis of 3-phosphinylated coumarins in moderate to excellent yields was developed via an EY/BPO-mediated cross-dehydrogenative coupling (CDC) reaction under green LED irradiation. The results of control experiments showed that the active intermediate, a P-centered radical, might be obtained through energy transfer and electron transfer processes. PMID- 29124262 TI - Ni-Catalyzed cross-coupling reactions of N-acylpyrrole-type amides with organoboron reagents. AB - The catalytic conversion of amides to ketones is highly desirable yet challenging in organic synthesis. We herein report the first Ni/bis-NHC-catalyzed cross coupling of N-acylpyrrole-type amides with arylboronic esters to obtain diarylketones. This method is facilitated by a new chelating bis-NHC ligand. The reaction tolerates diverse functional groups on both arylamide and arylboronic ester partners including sensitive ester and ketone groups. PMID- 29124263 TI - Photoinduced electron transfer reaction in mitochondria for spatiotemporal selective photo-oxidation of lipids by donor/acceptor linked molecules. AB - Donor-acceptor-linked molecules have been synthesized and utilized to induce the rapid and site-selective lipid-oxidation in mitochondria by utilizing a photoinduced intermolecular electron transfer reaction. Two water-soluble donor acceptor molecules (1 and 2) were designed and synthesized for this purpose. 2 was prepared to modulate its affinity to cell membrane in mitochondria. Confocal laser microscopy experiments revealed that 1 and 2 possess high localization abilities in mitochondria. By the photoinduced electron transfer, 2 exhibited the remarkable oxidation ability of lipids, mainly cardiolipin. In HeLa cells, 2 triggered mitochondrial lipid oxidation, which was followed by apoptotic cell death, under illumination within a few seconds. These results show that the present molecular system is highly promising to utilize the photoinduced intermolecular electron transfer reaction in a precise spatiotemporal manner in a cell by using light. PMID- 29124264 TI - Laser-structured Janus wire mesh for efficient oil-water separation. AB - We report here the fabrication of a Janus wire mesh by a combined process of laser structuring and fluorosilane/graphene oxide (GO) modification of the two sides of the mesh, respectively, toward its applications in efficient oil/water separation. Femtosecond laser processing has been employed to make different laser-induced periodic surface structures (LIPSS) on each side of the mesh. Surface modification with fluorosilane on one side and GO on the other side endows the two sides of the Janus mesh with distinct wettability. Thus, one side is superhydrophobic and superoleophilic in air, and the other side is superhydrophilic in air and superoleophobic under water. As a proof of concept, we demonstrated the separation of light/heavy oil and water mixtures using this Janus mesh. To realize an efficient separation, the intrusion pressure that is dominated by the wire mesh framework and the wettability should be taken into account. Our strategy may open up a new way to design and fabricate Janus structures with distinct wettability; and the resultant Janus mesh may find broad applications in the separation of oil contaminants from water. PMID- 29124270 TI - Experimental and theoretical investigation of fluorescence solvatochromism of dialkoxyphenyl-pyrene molecules. AB - We investigated the fluorescence properties of dialkoxyphenyl-pyrene molecules experimentally as well as theoretically. Our experiments confirmed fluorescence solvatochromism in 2,5-dimethoxyphenyl-pyrene and, in contrast there was no significant solvent-effect on the emission properties of the isomers, 3,5- and 2,6-dimethoxyphenyl-pyrene. This clear difference in the solvent-dependence would reflect the difference in character of the excited-state between the isomers, which differ only in the substitution positions of the two methoxy groups. The positional effects of the di-substituted molecules are successfully explained theoretically by the topologies of the highest occupied molecular orbital of the phenyl group that are governed by the relative positions of the two substituents, though it is somewhat contradictory to the meta-effect for the mono-substituted molecules. Theoretical calculations were also used to analyze the character of the excited states; 2,5-dimethoxyphenyl-pyrene alone exhibited an intramolecular charge transfer character for the excited state, which was responsible for the solvatochromism effect. The dynamics of the excited states were analyzed using time-resolved fluorescence measurements, in which a characteristic increase of the fluorescence intensity was observed for 2,5-dialkoxyphenyl-pyrene; this observation was supported by the theoretical calculations as well. PMID- 29124271 TI - Defects by design: synthesis of palladium nanoparticles with extended twin defects and corrugated surfaces. AB - Recent catalytic work has highlighted the importance of grain boundaries in the design of highly active catalyst materials due to the high energy of atoms at strained defect sites. In addition, undercoordinated atoms have long been known to contribute to the catalytic performance of metal nanoparticles. In this work, we describe a method for deliberately increasing the coverage of defect boundaries and undercoordinated atoms at the surfaces of well-defined, symmetric palladium nanoparticles. Careful control of the competitive interactions of chloride and bromide ions with the surface of twinned palladium nanoparticles is used to drive the growth of fin-like structures to extend the area of exposed twin boundaries while also inducing corrugation at the particle surface to add further undercoordinated sites. Mechanistic studies show surface passivation by bromide and etching by chloride in the presence of a low concentration of surfactant to be the key factors that tailor the surface of these nanoparticles, while the internal defect structure is controlled by reaction kinetics. Importantly, these basic principles of competition between surface passivation and etching as well as kinetic control of twin structure are not unique to palladium, and thus this method has the potential to be extended to the enhancement of surface defect density for nanoparticles composed of other catalytically relevant metals. PMID- 29124272 TI - Lithiation-assisted exfoliation and reduction of SnS2 to SnS decorated on lithium integrated graphene for efficient energy storage. AB - Low reversion of lithium sulfide and defects causing irreversible capacity loss are the primary causes of low Coulombic efficiency in tin sulfide/graphene-based composites. Herein, we synthesized a SnS/graphene composite via a novel lithiation-assisted exfoliation and reduction method using SnS2, n-butyllithium, and graphene oxide as raw materials. The experimental results reveal that lithium from the insertion agent combine with the oxygen-containing groups on graphene oxide; this can help in the reduction of hexagonal SnS2 to orthorhombic SnS during calcination and simultaneous pre-occupancy of the edge and defect sites of graphene; thus, additional lithium ion consumption during the initial several lithiation processes is diminished. Microstructural characterizations indicate that the exfoliated SnS nanosheets with a dramatically decreased lateral size (50 100 nm) are uniformly decorated on the surface of lithium-integrated graphene sheets. Consequently, the as-prepared SnS/graphene composite exhibits a significantly high SnS ultilization with a 77.5% initial Coulombic efficiency, which is the highest value reported in the current literature. Moreover, an excellent reversibility of conversion reaction (SnS + 2Li+ + 2e- <-> Sn + Li2S) and a high reversible capacity of 1016.4 mA h g-1 after 100 cycles are expressed in this composite electrode, demonstrating its importance as an anode material for energy storage. PMID- 29124273 TI - Reduced invasive and muscle-sparing operative approaches to the posterolateral chest wall provide an excellent accessibility for the operative stabilization! : Minimized approaches to the posterolateral chest wall. AB - PURPOSE: Stabilizing techniques for flail chest injuries are described through wide surgical approaches to the chest wall, especially in the most affected posterior and lateral regions. Severe morbidity due to these invasive approaches needs to be considered due to dissection of the scapular guiding muscles and the risk of injuries to neurovascular bundles. This study discusses possibilities for minimized approaches to the posterior and lateral regions. METHOD: Ten fresh frozen cadavers in lateral decubitus position were observed on both sides. Each surgical arm was kept mobile during the procedure. Approaches were performed following a standard protocol with muscle-sparing incisions starting with 5 cm in length and extending to 10 and 15 cm. The accessible surface comparing the extensions was measured. Visible ribs were counted. In a next step, MatrixRib(r) Plates were fixed to those ribs to prove the feasibility of rib stabilization through limited approaches. RESULTS: Combinations of the posterior and lateral minimized approaches allow surgical fixation of 6-9 and 7-11 ribs through 5 and 10 cm incisions, respectively. In the case of an extreme expansion of a rib fracture series, an access extension can be made to 15 cm to be able to adequately supply the entire hemithorax using two approaches. CONCLUSION: Extensive invasive surgical approaches to the thoracic wall can be replaced by reduced invasive and muscle-sparing access combinations. A free-moving positioning of the arm and an accurate preoperative plan for minimizing approaches are essential. Minimally invasive plate techniques are very helpful adjuncts. PMID- 29124274 TI - [Psycho-oncology care in rural areas : Results from a cross-sectional survey on the utilisation of community-based psychosocial support services]. AB - BACKGROUND: Clinically relevant distress and unmet psychosocial needs frequently occur in the course of cancer diseases. Particularly for thinly populated rural areas in Germany rates of distressed patients and uptake of community-based psycho-oncology services are unknown. OBJECTIVES: Determination of a) the proportion of cancer patients with psychosocial distress and unmet needs and b) the utilisation of community-based psycho-oncology services in thinly populated rural areas. MATERIALS AND METHODS: Prospective cross-sectional study of 229 cancer patients (colon, breast, prostate cancer) living in thinly populated rural areas. Indicators for clinically relevant distress and utilisation of psychosocial services were assessed by applying screening instruments. We conducted descriptive and multivariate analyses. RESULTS: More than one third of all cancer patients (39.3%) in thinly populated areas exhibited clinically relevant distress. However, only 15.6% of distressed patients consulted community based psycho-oncology services. Most frequently, medical or psychological psychotherapists were contacted. Information deficits of patients and attending physicians alongside dispositional factors emerged as the main reasons for non utilisation. DISCUSSION: This study presents first data on psycho-oncology care in rural areas in Germany stratifying the degree of urbanisation in line with the standards of the European Commission. Concerning limitations, we only accounted for structural service coverage, leaving aside other indicators for socio-spatial deprivation. PMID- 29124276 TI - ? PMID- 29124275 TI - [The role of MDK in the German reimbursement system for intensive care medicine]. AB - The experts of Medizinischer Dienst der Krankenversicherung (MDK) assess services from different areas of the health care sector, including checks of hospital invoicing. MDK assessors are only employed after being commissioned by a statutory health or nursing insurance. The assessment of intensive medical treatment is made difficult by uncertainties and indistinctness in the regulations, especially the procedure codes for complex intensive care treatment. PMID- 29124277 TI - ? PMID- 29124278 TI - Targeted Gene Editing in Human Pluripotent Stem Cells Using Site-Specific Nucleases. AB - Introduction of induced pluripotent stem cell (iPSC) technology and site-directed nucleases brought a major breakthrough in the development of regenerative therapies and biomedical research. With the advancement of ZFNs, TALENs, and the CRISPR/Cas9 technology, straightforward and precise manipulation of the genome of human pluripotent stem cells (PSC) became possible, allowing relatively easy and fast generation of gene knockouts, integration of transgenes, or even introduction of single nucleotide changes for correction or introduction of disease-specific mutations. We review current applications of site-specific nucleases in human PSCs and focus on trends and challenges for efficient gene editing and improvement of targeting strategies. Graphical Abstract. PMID- 29124279 TI - Up-front PET/CT changes treatment intent in patients with head and neck squamous cell carcinoma. AB - PURPOSE: In patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), we wanted to examine the differences in overall treatment decisions, i.e. curative versus palliative treatment intent, reached by a multidisciplinary team conference (MDTC) based on 18F-fluoro-deoxy-glucose-positron emission tomography/computed tomography (PET/CT) or chest X-ray + MRI of the head and neck (CXR/MRI). PATIENTS AND METHODS: This was a prospective blinded cohort study based on paired data. Consecutive patients with histologically verified primary HNSCC were invited to participate. All included patients underwent CXR/MRI and PET/CT before diagnostic biopsy. An ordinary MDTC using all available imaging was conducted as per standard practice. After at least 3 months (to eliminate recall bias in the team), the first project MDTC was conducted, based on either CXR/MRI or PET/CT, and the tumor board drew conclusions regarding treatment. After an additional 3 months, a second project MDTC was conducted using the complementary imaging modality. RESULTS: A total of 307 patients were included. Based on CXR/MRI, 303 patients (99%) were recommended for curative treatment and only four patients (1%) for palliative treatment. Based on PET/CT, the MDTC concluded that 278 (91%) patients were suitable for curative treatment and 29 (9%) patients for palliative treatment. The absolute difference of 8% was statistically significant (95% CI: 4.8%-11.5%, p < 0.001). CONCLUSIONS: A PET/CT-based imaging strategy significantly changed the decisions regarding treatment intent made by a MDTC for patients diagnosed with HNSCC, when compared with the standard imaging strategy of CXR/MRI. PMID- 29124280 TI - 18F-fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment. AB - PURPOSE: Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed to evaluate the performance of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) for predicting tumour progression during sorafenib treatment. METHODS: We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing 18F-FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured. RESULTS: Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR >= 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR >= 2.9 (hazard ratio [HR] = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR >= 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis. CONCLUSION: Pretreatment tumour metabolic activity assessed by 18F-FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment. PMID- 29124281 TI - Absolute number of new lesions on 18F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab. AB - PURPOSE: Evaluation of response to immunotherapy is a matter of debate. The aim of the present study was to evaluate the response of metastatic melanoma to treatment with ipilimumab by means of 18F-FDG PET/CT, using the patients' clinical response as reference. METHODS: The final cohort included in the analyses consisted of 41 patients with metastatic melanoma who underwent 18F-FDG PET/CT before and after administration of ipilimumab. After determination of the best clinical response, the PET/CT scans were reviewed and a separate independent analysis was performed, based on the number and functional size of newly emerged 18F-FDG-avid lesions, as well as on the SUV changes after therapy. RESULTS: The median observation time of the patients after therapy was 21.4 months (range 6.3 41.9 months). Based on their clinical response, patients were dichotomized into those with clinical benefit (CB) and those without CB (No-CB). The CB group (31 patients) included those with stable disease, partial remission and complete remission, and the No-CB group (10 patients) included those with progressive disease. The application of a threshold of four newly emerged 18F-FDG-avid lesions on the posttherapy PET/CT scan led to a sensitivity (correctly predicting CB) of 84% and a specificity (correctly predicting No-CB) of 100%. This cut-off was lower for lesions with larger functional diameters (three new lesions larger than 1.0 cm and two new lesions larger than 1.5 cm). SUV changes after therapy did not correlate with clinical response. Based on these findings, we developed criteria for predicting clinical response to immunotherapy by means of 18F-FDG PET/CT (PET Response Evaluation Criteria for Immunotherapy, PERCIMT). CONCLUSION: Our results show that a cut-off of four newly emerged 18F-FDG-avid lesions on posttherapy PET/CT gives a reliable indication of treatment failure in patients under ipilimumab treatment. Moreover, the functional size of the new lesions plays an important role in predicting the clinical response. Validation of these results in larger cohorts of patients is warranted. PMID- 29124282 TI - Development of a complete set of wheat-barley group-7 Robertsonian translocation chromosomes conferring an increased content of beta-glucan. AB - KEY MESSAGE: A complete set of six compensating Robertsonian translocation chromosomes involving barley chromosome 7H and three chromosomes of hexaploid wheat was produced. Grain beta-glucan content increased in lines containing 7HL. Many valuable genes for agronomic performance, disease resistance and increased yield have been transferred from relative species to wheat (Triticum aestivum L.) through whole-arm Robertsonian translocations (RobT). Although of a great value, the sets of available translocations from barley (Hordeum vulgare L.) are limited. Here, we present the production of a complete set of six compensating RobT chromosomes involving barley chromosome 7H and three group-7 chromosomes of wheat. The barley group-7 long-arm RobTs had a higher grain beta-glucan content compared to the wheat control. The beta-glucan levels varied depending on the temperature and were higher under hot conditions. Implicated in this increase, the barley cellulose synthase-like F6 gene (CslF6) responsible for beta-glucan synthesis was physically mapped near the centromere in the long arm of barley chromosome 7H. Likewise, wheat CslF6 homoeologs were mapped near the centromere in the long arms of all group-7 wheat chromosomes. With the set of novel wheat barley translocations, we demonstrate a valuable increase of beta-glucan, along with a resource of genetic stocks that are likely to carry many other important genes from barley into wheat. PMID- 29124283 TI - Semi-rational engineering of CYP153A35 to enhance omega-hydroxylation activity toward palmitic acid. AB - CYP153A35 from Gordonia alkanivorans was recently characterized as fatty acid omega-hydroxylase. To enhance the catalytic activity of CYP153A35 toward palmitic acid, site-directed saturation mutagenesis was attempted using a semi-rational approach that combined structure-based computational analysis and subsequent saturation mutagenesis. Using colorimetric high-throughput screening (HTS) method based on O-demethylation activity of P450, CYP153A35 D131S and D131F mutants were selected. The best mutant, D131S, having a single mutation on BC-loop, showed 13- and 17-fold improvement in total turnover number (TTN) and catalytic efficiency (k cat/K M) toward palmitic acid compared to wild-type, respectively. However, in whole-cell reaction, D131S mutant showed only 50% improvement in omega hydroxylated palmitic acid yield compared to the wild type. Docking simulation studies explained that the effect of D131S mutation on the catalytic activity would be mainly caused by the binding pose of fatty acids in the substrate access tunnel of the enzyme. This effect of D131S mutation on the catalytic activity is synergistic with that of the mutations in the active site previously reported. PMID- 29124284 TI - Ca2+/nuclear factor of activated T cells signaling is enriched in early-onset rectal tumors devoid of canonical Wnt activation. AB - : Our previous extensive analysis revealed a significant proportion of early onset colorectal tumors from India to be localized to the rectum in younger individuals and devoid of deregulated Wnt/beta-catenin signaling. In the current study, we performed a comprehensive genome-wide analysis of clinically well annotated microsatellite stable early-onset sporadic rectal cancer (EOSRC) samples. Results revealed extensive DNA copy number alterations in rectal tumors in the absence of deregulated Wnt/beta-catenin signaling. More importantly, transcriptome profiling revealed a (non-Wnt/beta-catenin, non-MSI) genetic signature that could efficiently and specifically identify Wnt- rectal cancer. The genetic signature included a significant representation of genes belonging to Ca2+/NFAT signaling pathways that were validated in additional samples. The validated NFAT target genes exhibited significantly higher expression levels than canonical Wnt/beta-catenin targets in Wnt- samples, an observation confirmed in other CRC expression data sets as well. We confirmed the validated genes to be transcriptionally regulated by NFATc1 by (a) evaluating their respective transcript levels and (b) performing promoter-luciferase and chromatin immunoprecipitation assays following ectopic expression as well as knockdown of NFATc1 in CRC cells. NFATc1 and its targets RUNX2 and GSN could drive increased migration in CRC cells. Finally, the validated genes were associated with poor survival in the cancer genome atlas CRC expression data set. This study is the first comprehensive molecular characterization of EOSRC that appears to be driven by noncanonical tumorigenesis pathways. KEY MESSAGES: Early-onset sporadic rectal cancer exhibits DNA gain and loss without Wnt activation. Ca2+/NFAT signaling appears to be activated in the absence of Wnt activation. An eight-gene genetic signature distinguishes Wnt+ and Wnt- rectal tumors. NFAT and its target genes regulate tumorigenic properties in CRC cells. PMID- 29124285 TI - Kinematics and arthrokinematics in the chronic ACL-deficient knee are altered even in the absence of instability symptoms. AB - PURPOSE: To analyze the in vivo kinematics and arthrokinematics of chronic ACL deficient (ACL-D) and unaffected contralateral knees during level walking and downhill running using dynamic biplane radiography. It was hypothesized that ACL D knees would demonstrate increased anterior translation and internal rotation, and that ACL-deficiency would alter the tibiofemoral contact paths in comparison to the unaffected contralateral side. METHODS: Eight participants with unilateral chronic ACL-D without instability symptoms were recruited. The contralateral unaffected knee was considered as control. Kellgren-Lawrence (K-L) grades were determined from ACL-D and unaffected knees. Dynamic knee motion was determined from footstrike through the early-stance phase (20-25% of gait cycle) using a validated volumetric model-based tracking process that matched subject-specific CT bone models to dynamic biplane radiographs. Participants performed level walking at 1.2 m/s and downhill running at 2.5 m/s while biplane radiographs were collected at 100 and 150 images per second, respectively. Tibiofemoral kinematics and arthrokinematics (the path of the closest contact point between articulating subchondral bone surfaces) were determined and compared between ACL-D and unaffected knees. A two-way repeated measures analysis of variance was used to identify differences between ACL-D and unaffected knees at 5% increments of the gait cycle. RESULTS: Anterior-posterior translations were significantly larger in ACL-D than unaffected knees during level walking (all p < 0.001) and downhill running (all p <= 0.022). Internal rotation showed no significant difference between ACL-D and unaffected knees during level walking and downhill running. Closest contact points on the femur in ACL-D knees were consistently more anterior in the lateral compartment during downhill running (significant from 10 to 20% of the gait cycle, all p <= 0.044), but not during level walking. No differences in medial compartment contact paths were identified. Half of the participants had asymmetric K-L grades, with all having worse knee OA in the involved knee. Only 2 relatively young individuals had not progressed beyond stage 1 in either knee. CONCLUSION: The results suggest that anterior translation and knee joint contact paths are altered in ACL-D knees even in the absence of instability symptoms. The clinical relevance is that ACL-D patients who do not report symptoms of instability likely still demonstrate altered knee kinematics and arthrokinematics compared to their uninvolved limb. LEVEL OF EVIDENCE: Case control study, Level III. PMID- 29124287 TI - Medial stabilized and posterior stabilized TKA affect patellofemoral kinematics and retropatellar pressure distribution differently. AB - PURPOSE: Patellofemoral kinematics and retropatellar pressure distribution change after total knee arthroplasty (TKA). It was hypothesized that different TKA designs will show altered retropatellar pressure distribution patterns and different patellofemoral kinematics according to their design characteristics. METHODS: Twelve fresh-frozen knee specimens were tested dynamically in a knee rig. Each specimen was measured native, after TKA with a posterior stabilized design (PS) and after TKA with a medial stabilized design (MS). Retropatellar pressure distribution was measured using a pressure sensitive foil which was subdivided into three areas (lateral and medial facet and patellar ridge). Patellofemoral kinematics were measured by an ultrasonic-based three-dimensional motion system (Zebris CMS20, Isny Germany). RESULTS: Significant changes in patellofemoral kinematics and retropatellar pressure distribution were found in both TKA types when compared to the native situation. Mean retropatellar contact areas were significantly smaller after TKA (native: 241.1 +/- 75.6 mm2, MS: 197.7 +/- 74.5 mm2, PS: 181.2 +/- 56.7 mm2, native vs. MS p < 0.001; native vs. PS p < 0.001). The mean peak pressures were significantly higher after TKA. The increased peak pressures were however seen in different areas: medial and lateral facet in the PS-design (p < 0.001), ridge in the MS design (p < 0.001). Different patellofemoral kinematics were found in both TKA designs when compared to the native knee during flexion and extension with a more medial patella tracking. CONCLUSION: Patellofemoral kinematics and retropatellar pressure change after TKA in different manner depending on the type of TKA used. Surgeons should be aware of influencing the risks of patellofermoral complications by the choice of the prosthesis design. PMID- 29124286 TI - Adjustable loop ACL suspension devices demonstrate less reliability in terms of reproducibility and irreversible displacement. AB - PURPOSE: The aim of this study was to perform a comprehensive biomechanical examination of frequently applied femoral cortical suspension devices, comparing the properties of both fixed and adjustable fixation mechanisms. It was hypothesized that adjustable loop devices demonstrate less consistent fixation properties with increased variability compared to fixed loop devices. METHODS: Nine frequently applied fixation button types were tested, six adjustable and three rigid loop devices. Six samples of each device type were purchased. Each device was installed in a servo-hydraulic mechanical testing machine, running a 2000 cycle loading protocol at force increments between 50 and 500 N. Irreversible displacement in mm was measured for all of the tested samples of each implant. Ultimately, maximum load to failure was applied and measured in Nm. An irreversible displacement of 3 mm was considered failure of the implant. RESULTS: Three of the six adjustable devices (GraftMaxTM, TightRope(r) ToggleLocTM) demonstrated a median displacement above the threshold of clinical failure before completion of the cycles. All adjustable loop devices showed a wide intragroup variation in terms of irreversible displacement, compared to fixed-loop devices. Fixed-loop devices provided consistent reproducible results with narrow ranges and significantly lower irreversible displacement (p < 0.05), the maximum being 1.4 mm. All devices withstood an ultimate force of more than 500 N. CONCLUSION: Adjustable loop devices still show biomechanical inferiority and demonstrate heterogeneity of fixation properties with wide- and less reproducible displacement ranges resultant to the mechanism of adjustment, denoting less reliability. However, three adjustable devices (RIGIDLOOPTM Adjustable, Ultrabutton ?, ProCinchTM) demonstrate fixation capacities within the margins of clinical acceptance. RIGIDLOOPTM Adjustable provides the most comparable fixation properties to fixed loop devices. PMID- 29124288 TI - The medial tibial joint line elevation over 5 mm restrained the improvement of knee extension angle in unicompartmental knee arthroplasty. AB - PURPOSE: The purpose of this study was to examine the relationship between medial tibial joint line elevation and the improvement of range of motion (ROM) in unicompartmental knee arthroplasty (UKA). The hypothesis was that limited elevation of tibial joint line will improve knee range of motion in UKA. METHODS: Forty-six consecutive medial UKAs were enrolled in this study. Medial tibial joint line elevation was defined as the polyethylene insert and tibial tray thickness minus the tibial osteotomy and sawblade thickness. Positive values indicated an elevation of the tibial joint line. A component gap between the femoral trial prosthesis and the medial tibial osteotomy surface was also examined. Joint loosening was also calculated based on the joint component gap minus insert and tibial tray thickness. The correlation of the medial tibial joint line elevation with joint looseness and postoperative range of motion were analyzed. RESULTS: The mean medial tibial joint line elevation was 4.9 +/- 1.1 mm. The medial tibial joint line elevation reduced the improvement of knee extension (R = - 0.43, p < 0.01). The medial tibial joint line elevation was also correlated with reduced loosening of the joint knee extension (R = - 0.42, p < 0.01). This, in turn, resulted in limited improvement of the knee extension angle. Moreover, joint line elevation under 5 mm significantly improved knee extension angle compared to joint line elevation over 5 mm. CONCLUSIONS: The medial joint line elevation of the tibia in UKA reduced the improvement of knee extension angle, due to a reduced joint looseness at knee extension. A tibial joint line elevation greater than 5 mm in UKA should be avoided to prevent postoperative flexion contracture. For the clinical relevance, this study clarified that the medial joint line of the tibia is an important factor to prevent postoperative flexion contracture in UKA. LEVEL OF EVIDENCE: II. PMID- 29124289 TI - Peak stresses shift from femoral tunnel aperture to tibial tunnel aperture in lateral tibial tunnel ACL reconstructions: a 3D graft-bending angle measurement and finite-element analysis. AB - PURPOSE: To investigate the effect of tibial tunnel orientation on graft-bending angle and stress distribution in the ACL graft. METHODS: Eight cadaveric knees were scanned in extension, 45 degrees , 90 degrees , and full flexion. 3D reconstructions with anatomically placed anterior cruciate ligament (ACL) grafts were constructed with Mimics 14.12(r). 3D graft-bending angles were measured for classic medial tibial tunnels (MTT) and lateral tibial tunnels (LTT) with different drill-guide angles (DGA) (45 degrees , 55 degrees , 65 degrees , and 75 degrees ). A pivot shift was performed on 1 knee in a finite-element analysis. The peak stresses in the graft were calculated for eight different tibial tunnel orientations. RESULTS: In a classic anatomical ACL repair, the largest graft bending angle and peak stresses are seen at the femoral tunnel aperture. The use of a different DGA at the tibial side does not change the graft-bending angle at the femoral side or magnitude of peak stresses significantly. When using LTT, the largest graft-bending angles and peak stresses are seen at the tibial tunnel aperture. CONCLUSION: In a classic anatomical ACL repair, peak stresses in the ACL graft are found at the femoral tunnel aperture. When an LTT is used, peak stresses are similar compared to classic ACL repairs, but the location of the peak stress will shift from the femoral tunnel aperture towards the tibial tunnel aperture. CLINICAL RELEVANCE: the risk of graft rupture is similar for both MTTs and LTTs, but the location of graft rupture changes from the femoral tunnel aperture towards the tibial tunnel aperture, respectively. LEVEL OF EVIDENCE: I. PMID- 29124290 TI - Predicting psychiatric readmission: sex-specific models to predict 30-day readmission following acute psychiatric hospitalization. AB - PURPOSE: Psychiatric readmission is a common negative outcome. Predictors of readmission may differ by sex. This study aimed to derive and internally validate sex-specific models to predict 30-day psychiatric readmission. METHODS: We used population-level health administrative data to identify predictors of 30-day psychiatric readmission among women (n = 33,353) and men (n = 32,436) discharged from all psychiatric units in Ontario, Canada (2008-2011). Predictor variables included sociodemographics, health service utilization, and clinical characteristics. Using derivation data sets, multivariable logistic regression models were fit to determine optimal predictive models for each sex separately. Results were presented as adjusted odds ratios (aORs) and 95% confidence intervals (CI). The multivariable models were then applied in the internal validation data sets. RESULTS: The 30-day readmission rates were 9.3% (women) and 9.1% (men). Many predictors were consistent between women and men. For women only, personality disorder (aOR 1.21, 95% CI 1.03-1.42) and positive symptom score (aOR 1.41, 95% CI 1.09-1.82 for score of 1 vs. 0; aOR 1.44, 95% CI 1.26 1.64 for >= 2 vs. 0) increased odds of readmission. For men only, self-care problems at admission (aOR 1.20, 95% CI 1.06-1.36) and discharge (aOR 1.44, 95% CI 1.26-1.64 for score of 1 vs. 0; aOR 1.79, 95% CI 1.17-2.74 for 2 vs. 0), and mild anxiety rating (score of 1 vs. 0: aOR 1.30, 95% CI 1.02-1.64, derivation model only) increased odds of readmission. Models had moderate discriminative ability in derivation and internal validation samples for both sexes (c statistics 0.64-0.65). CONCLUSIONS: Certain key predictors of psychiatric readmission differ by sex. This knowledge may help to reduce psychiatric hospital readmission rates by focusing interventions. PMID- 29124291 TI - Self-reported discriminatory and positive behaviours towards people with mental health problems: findings from an Australian national survey. AB - OBJECTIVE: The aim of the study was to explore self-reported avoidance, discrimination, and positive treatment by members of the public towards people with mental health problems. METHODS: In 2014, telephone interviews were carried out with 5220 Australians aged 18 +. Respondents were asked if they had known an adult with a mental health problem over the previous 12 months. If they had, they were asked further questions about the person's age, gender, relationship to the respondent, and their mental health problem. Respondents were then asked if they had avoided, discriminated against or treated the person more positively and, if so, some details about what happened. RESULTS: 19.9% of respondents reported avoiding someone with a mental health problem, with the most common reasons being difficulty tolerating the person's behaviour and needing time out. However, respondents were more likely to report treating the person with mental health problems more positively (73.0%) than avoiding or discriminating against them (4.7%). The most common positive behaviours were non-specific support and maintaining or increasing contact. Avoidance was less likely from friends and those aged 60 +. Discrimination was more likely from family members and spouses and less likely from respondents aged 60 +. Positive treatment was more likely from people who had experienced a mental health problem. CONCLUSIONS: This study provides insight into the reasons why people avoid others with mental health problems. The results can provide input into the design of anti-discrimination interventions and further empower people with mental health problems as they advocate for change in the area of discrimination. PMID- 29124292 TI - Homelessness as a predictor of mortality: an 11-year register-based cohort study. AB - PURPOSE: The purpose of this study was to examine the association between homelessness and psychiatric disorders, including substance use disorders, on one hand, and cause-specific and all-cause mortality on the other in a high-income country. METHODS: A historical nationwide register-based cohort study of the Danish population from 15 years of age between 2000 and 2011 was conducted. The association between homelessness, psychiatric disorders, and mortality was analysed by Poisson Regression adjusting for important confounders. Standardised mortality ratios (SMRs) were calculated for people with a history of homelessness compared with the general population using direct age-standardisation. RESULTS: During 51,892,324 person-years of observation, 656,448 died. People with at least one homeless shelter contact accounted for 173,592 person-years with 4345 deaths. The excess mortality in the population experiencing homelessness compared with the general population was reduced by 50% after adjusting for psychiatric diagnoses, including substance use disorders (mortality rate ratio (MRR) for men 3.30, 95% CI 3.18-3.41; women 4.41, 95% CI 4.14-4.71). Full adjustment including physical comorbidity and socioeconomic factors in a sub-cohort aged 15-29 years resulted in an MRR of 3.94 (95% CI 3.10-5.02) compared with the general population. The excess mortality associated with homelessness differed according to psychiatric diagnosis, sex, and cause of death. CONCLUSIONS: A mental health or a substance use disorder combined with homelessness considerably increases the risk of death. However, homelessness is also independently associated with high mortality. Differences in the association between homelessness and mortality in men and women suggest the need for sex-tailored interventions. PMID- 29124293 TI - Identification of major depressive disorder among the long-term unemployed. AB - PURPOSE: Depression is a common mental health disorder among the unemployed, but research on identifying their depression in health care is scarce. The present study aimed to explore the identification of major depressive disorder (MDD) in health care on long-term unemployed and find out if the duration of unemployment correlates with the risk for unidentified MDD. METHODS: The study sample consisted the patient files of long-term unemployed people (duration of unemployment 1-35 years, median 11 years), who in a screening project diagnosed with MDD (n = 243). The MDD diagnosis was found in the health care records of 101. Binomial logistic regression models were used to explore the effect of the duration of unemployment, as a discrete variable, to the identification of MDD in health care. RESULTS: MDD was appropriately identified in health care for 42% (n = 101) of the participants with MDD. The odds ratio for unidentified MDD in health care was 1.060 (95% confidence interval 1.011; 1.111, p = 0.016) per unemployment year. When unemployment had continued, for example, for five years the odds ratio for having unidentified MDD was 1.336. The association remained significant throughout adjustments for the set of background factors (gender, age, occupational status, marital status, homelessness, criminal record, suicide attempts, number of health care visits). CONCLUSIONS: This study among depressed long-term unemployed people indicates that the longer the unemployment period has lasted, the more commonly these people suffer from unidentified MDD. Health services should be developed with respect to sensitivity to detect signs of depression among the long-term unemployed. PMID- 29124294 TI - The relationship between financial difficulty and childhood symptoms of attention deficit/hyperactivity disorder: a UK longitudinal cohort study. AB - PURPOSE: Attention deficit/hyperactivity disorder (ADHD) is associated with socioeconomic status (SES), in that children who grow up in low SES families are at an increased risk of ADHD symptoms and diagnosis. The current study explores whether different levels of ADHD symptoms are associated with prior changes in the SES facet of financial difficulty. METHODS: Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined symptoms of ADHD measured by the Strengths and Difficulties Questionnaire (SDQ) hyperactivity subscale in relation to parent-reported changes in financial difficulty, grouped into four repeated measures at four time points across childhood; (n = 6416). A multilevel mixed effects linear regression model with an unstructured covariance matrix was used to test whether different patterns of financial difficulty were associated with subsequent changes in ADHD symptoms. RESULTS: Families who had no financial difficulty had children with a lower average ADHD symptom score than groups who experienced financial difficulty. Children whose families stayed in financial difficulty had higher mean ADHD symptom scores than all other groups (No difficulty mean SDQ hyperactivity 3.14, 95% CI 3.07, 3.21, In difficulty mean SDQ hyperactivity 3.39, 95% CI 3.28, 3.45, p < 0.001). Increasing or decreasing financial difficulty predicted mean symptom scores lower than those of the in difficulty group and higher than the no difficulty group. CONCLUSIONS: Our findings contribute to the building evidence that SES may influence the severity and/or impairment associated with the symptoms of ADHD, however the effects of SES are small and have limited clinical significance. PMID- 29124295 TI - [Novel concepts for eradication of biofilms on implants]. PMID- 29124296 TI - [Diagnostics and treatment of posterior shoulder instability]. AB - Posterior shoulder instability has a markedly lower incidence than anterior shoulder instability. It has a wide spectrum of clinical symptom manifestations and the overwhelming number of patients lack a traumatic primary dislocation. In addition to a detailed medical history, a specific clinical examination with the help of standardized provocation tests is essential for the diagnostics. For the detection of structural posterior capsule and labral lesions in cases of chronic courses, magnetic resonance imaging (MRI) should be used with an intra-articular contrast agent. Relevant bony defects of the humeral head (reverse Sachs-Hill lesion) are frequent, whereas critical posterior defects of glenoid cavity are relatively rare. Both lesions should be quantified using 3D computed tomography. The choice of therapeutic procedure should be based on the underlying pathology of the defect. Conservative therapy is useful in patients with scapular dyskinesis, voluntary dislocation and pathological muscle patterning. In isolated soft tissue pathologies, arthroscopic labrum fixation and capsule plication are the standard treatment. In the case of insufficient soft tissue relations or critical posterior glenoid defects, bony stabilization of the glenoid using an iliac crest bone graft is the recommended therapy. PMID- 29124297 TI - Complete resolution and remodeling of chronic recurrent multifocal osteomyelitis on MRI and radiographs. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition thought to be under-diagnosed, with a true prevalence of more than the 1 in 10,000 estimated. It is a condition that is classically described as polyostotic with a relapsing and remitting course, preferentially affecting the metaphyses of tubular bones in the pediatric population. Lesions have characteristic appearances of cortical hyperostosis and mixed lytic/sclerotic medullary appearances radiographically, with active osteitis and periostitis best seen with fluid-sensitive sequences on magnetic resonance imaging (MRI). There are reports of lesions resolving on follow-up radiographs and MRI scans, but no supporting images. In particular, although the marrow appearances and degree of osteitis have been shown to improve on MRI, complete resolution and remodeling back to normal has never been demonstrated. We present a case of a lesion that has completely healed and remodeled back to normal appearances on both radiographs and MRI, and consider this the standard for the often loosely used terms "normalization" and "resolution". We discuss the implications of this for our understanding of the natural history of CRMO, and how this adds weight to the condition being significantly under-diagnosed. It provides a "gold standard" to be aimed for when assessing treatments for CRMO, and the optimal outcomes that are possible. It also provides further insight into the potential of pediatric bone to recover and remodel when affected by inflammatory conditions. PMID- 29124298 TI - Can FDG-PET/CT replace blind bone marrow biopsy of the posterior iliac crest in Ewing sarcoma? AB - OBJECTIVE: To determine and compare the value of 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) to blind bone marrow biopsy (BMB) of the posterior iliac crest in detecting metastatic bone marrow involvement in newly diagnosed Ewing sarcoma. MATERIALS AND METHODS: This retrospective study included 20 patients with newly diagnosed Ewing sarcoma who underwent pretreatment FDG-PET/CT and a total of 38 blind BMBs (two unilateral and 18 bilateral) of the posterior iliac crest. FDG-PET/CT scans were evaluated for bone marrow involvement, both in the posterior iliac crest and other sites, and compared to blind BMB results. RESULTS: FDG-PET/CT was positive for bone marrow involvement in 7/38 posterior iliac crests, whereas BMB was positive in 5/38 posterior iliac crests. FDG-PET/CT and BMB results in the posterior iliac crest agreed in 36/38 cases (94.7%, 95% confidence interval [CI]: 82.7-98.5%). On a patient level, FDG-PET/CT was positive for bone marrow involvement in 4/20 patients, whereas BMB of the posterior iliac crest was positive in 3/20 patients. On a patient level, FDG-PET/CT and BMB results agreed in 19/20 patients (95.0%, 95% CI: 76.4-99.1%). The only discrepancies between FDG-PET/CT and BMB were observed in two BMBs of one patient. Both BMBs in this patient were negative, whereas FDG-PET/CT indicated bilateral posterior iliac crest involvement and also extensive bone marrow involvement elsewhere. CONCLUSIONS: FDG-PET/CT appears to be a valuable method for metastatic bone marrow assessment in newly diagnosed Ewing sarcoma. The routine use of blind BMB of the posterior iliac crest should be reconsidered when FDG-PET/CT is available. PMID- 29124299 TI - ? PMID- 29124301 TI - [Correction: Dyspnea]. PMID- 29124300 TI - Xanthoceraside modulates NR2B-containing NMDA receptors at synapses and rescues learning-memory deficits in APP/PS1 transgenic mice. AB - RATIONALE: Alzheimer's disease (AD) is characterized by memory loss and synaptic damage. Previous studies suggested that xanthoceraside decreases glutamate induced PC12 cell death, ameliorates memory deficits, and increases the number of dendritic spines in AD mice. These results indicated that xanthoceraside might have activities that protect synaptic plasticity. Herein, we detected the effect of xanthoceraside on synaptic function. MATERIALS AND METHODS: Three-month-old APP/PS1 transgenic mice were orally treated with xanthoceraside (0.02, 0.08, or 0.32 mg/kg) once daily for 4 months and then behavioral tests were performed. LTP and Fluo-4/AM were carried out in vivo and in vitro, respectively. CaMKII-GluR1 and NR2B-associated proteins on synapses were measured. RESULTS: Xanthoceraside administration alleviated learning-memory deficits and increased the LTP in APP/PS1 transgenic mice. Meanwhile, xanthoceraside increased the expression of pT286-CaMKII in synaptic and extrasynaptic pools and CaMKII, pS831-GluR1, and GluR1 in synaptic pools. In addition, xanthoceraside increased the total pY1472 NR2B and NR2B expression and increased the levels of pY1472-NR2B in synaptic and extrasynaptic pools and NR2B in synaptic pools. However, NR2B was decreased in extrasynaptic pools, which might be associated with decreased expression of STEP61 and pY531-Fyn. In vitro studies showed that xanthoceraside inhibited intracellular calcium overload and increased the number of and extended the length of dendrites in primary hippocampal neurons compared with the Abeta25-35 group. CONCLUSIONS: The mechanism of xanthoceraside on ameliorating learning memory deficits might be related to decrease intracellular calcium overload, increase CaMKII-GluR1 proteins, and up-regulate trafficking of pY1472-NR2B at synapse, thereby improving LTP in APP/PS1 transgenic mice. PMID- 29124302 TI - Metallothionein Induction as Indicator of Low Level Metal Exposure to Aquatic Macroinvertebrates from a Relatively Unimpacted River System in South Africa. AB - The Marico River is relatively unaffected by anthropogenic activities. However, metal concentrations-mainly from natural sources-occasionally exceed environmental quality guidelines. Macroinvertebrates are capable to react to these metals through processes such as the induction of metallothioneins (MTs). The aims of this study were to determine whether the induction of MTs can be used as indicator of natural metal exposure in not anthropogenically impacted systems and whether there are relationships between metal concentrations in water, sediment and macroinvertebrates and concomitant MT levels. Positive correlations were found between metals in sediment and macroinvertebrates, while there were no correlations between metal concentrations in water and macroinvertebrates. Even in a not anthropogenically impacted system, a positive correlation existed between trace metal bioaccumulation (e.g. Ni, Pb, Zn) in macroinvertebrates and the induction of MTs. There were, however, no correlations between MTs and bioaccumulation of earth metals (e.g. Al, Fe, Mn, Ti). PMID- 29124303 TI - Journals' TOP guidelines transparency level should be disclosed. PMID- 29124304 TI - Modeling coverage gaps in haplotype frequencies via Bayesian inference to improve stem cell donor selection. AB - Regardless of sampling depth, accurate genotype imputation is limited in regions of high polymorphism which often have a heavy-tailed haplotype frequency distribution. Many rare haplotypes are thus unobserved. Statistical methods to improve imputation by extending reference haplotype distributions using linkage disequilibrium patterns that relate allele and haplotype frequencies have not yet been explored. In the field of unrelated stem cell transplantation, imputation of highly polymorphic human leukocyte antigen (HLA) genes has an important application in identifying the best-matched stem cell donor when searching large registries totaling over 28,000,000 donors worldwide. Despite these large registry sizes, a significant proportion of searched patients present novel HLA haplotypes. Supporting this observation, HLA population genetic models have indicated that many extant HLA haplotypes remain unobserved. The absent haplotypes are a significant cause of error in haplotype matching. We have applied a Bayesian inference methodology for extending haplotype frequency distributions, using a model where new haplotypes are created by recombination of observed alleles. Applications of this joint probability model offer significant improvement in frequency distribution estimates over the best existing alternative methods, as we illustrate using five-locus HLA frequency data from the National Marrow Donor Program registry. Transplant matching algorithms and disease association studies involving phasing and imputation of rare variants may benefit from this statistical inference framework. PMID- 29124305 TI - Dummy-surface molecularly imprinted polymers as a sorbent of micro-solid-phase extraction combined with dispersive liquid-liquid microextraction for determination of five 2-phenylpropionic acid NSAIDs in aquatic environmental samples. AB - A highly binding dummy template surface of molecularly imprinted polymers (MWNTs MIPs) was synthesized on multi-walled carbon nanotubes surface using 2 phenylpropionic acid as dummy template, 4-vinylpyridine as the functional monomer, ethylene glycol dimethacrylate as the cross-linker, and DMF as porogen by precipitation polymerization method. MIPs were characterized by FT-IR spectroscopy, scanning electron microscope, thermo-gravimetric analysis, and nitrogen adsorption-desorption experiment. Adsorption and selectivity experiments of MIPs and non-imprinted polymers (NIPs) verified that the MIPs had a good selectivity and adsorption properties for five 2-phenylpropionic acid nonsteroidal anti-inflammatory drugs (NSAIDs). Imprinted polymer was used as a sorbent material for MUSPE in current work and MUSPE-DLLME method was selected for pretreatment of water samples. The MUSPE-DLLME method was successfully used for the pre-concentration of five non-steroidal anti-inflammatory drugs in different environmental water samples prior to ultra-high performance liquid chromatography-tandem mass spectrometry. Efficiencies of MUSPE and DLLME were thoroughly investigated and optimized in this study. The optimal results were obtained by using 3 mL of 1% formic acid-acetonitrile as elution solvent and dichloroethane and acetonitrile as extractant and disperser solvent, respectively. Limits of detection and quantification of five NSAIDs for different water matrices varied from 0.50 to 1.10 ng L-1 and 0.93 to 2.20 ng L-1, respectively. Each target analyte had a good linearity in its corresponding concentration range. Enrichment factors of target analytes ranged from 91 to 215. Recoveries of the target analytes were between 72.43 and 113.99% at the concentration levels of 0.02, 0.1, and 0.5 MUg L-1. The developed method was successfully applied to extraction and analysis of NSAIDs in different water samples with satisfactory results which could help us better understand their environmental fate and risk to ecological health. Graphical abstract Dummy surface molecularly imprinted polymers as a sorbent of micro-solid-phase extraction combined with dispersive liquid-liquid microextraction for determination of five 2-phenylpropionic acid NSAIDs in aquatic environmental samples. PMID- 29124306 TI - A new strategy for metal labeling of glycan structures in antibodies. AB - Quantitative analysis of complex proteins is a challenging task in modern bioanalytical chemistry. Commonly available isotope labels are still suffering from limitations and drawbacks, whereas new metal labels open numerous possibilities in mass spectrometric analyses. In this work, we have developed a new metal labeling strategy to tag glycan structures of proteins, more particularly antibodies. The oligosaccharide glycans were selectively trimmed to the last N-acetylglucosamine to which an artificial azide containing galactose residue was bound. This azide can be used for subsequent cycloaddition of an alkyne. Therefore, we developed a lanthanide-containing macrocyclic reagent to selectively connect to this azido galactose. In summary, the glycan structures of an antibody can be labeled with a metal functionality using this approach. Furthermore, the functionality of the antibodies can be fully maintained by labeling the Fc glycans instead of using labeling reagents that target amino or thiol groups. This approach enables the possibility of using elemental, besides molecular mass spectrometry, for quantitative analyses or imaging experiments of antibodies in complex biological samples. Graphical abstract Antibody labeling at sugar moieties with rare earth elements to enable application in elemental mass spectrometry. PMID- 29124308 TI - The beta6/beta7 region of the Hsp70 substrate-binding domain mediates heat-shock response and prion propagation. AB - Hsp70 is a highly conserved chaperone that in addition to providing essential cellular functions and aiding in cell survival following exposure to a variety of stresses is also a key modulator of prion propagation. Hsp70 is composed of a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). The key functions of Hsp70 are tightly regulated through an allosteric communication network that coordinates ATPase activity with substrate-binding activity. How Hsp70 conformational changes relate to functional change that results in heat shock and prion-related phenotypes is poorly understood. Here, we utilised the yeast [PSI +] system, coupled with SBD-targeted mutagenesis, to investigate how allosteric changes within key structural regions of the Hsp70 SBD result in functional changes in the protein that translate to phenotypic defects in prion propagation and ability to grow at elevated temperatures. We find that variants mutated within the beta6 and beta7 region of the SBD are defective in prion propagation and heat-shock phenotypes, due to conformational changes within the SBD. Structural analysis of the mutants identifies a potential NBD:SBD interface and key residues that may play important roles in signal transduction between domains. As a consequence of disrupting the beta6/beta7 region and the SBD overall, Hsp70 exhibits a variety of functional changes including dysregulation of ATPase activity, reduction in ability to refold proteins and changes to interaction affinity with specific co-chaperones and protein substrates. Our findings relate specific structural changes in Hsp70 to specific changes in functional properties that underpin important phenotypic changes in vivo. A thorough understanding of the molecular mechanisms of Hsp70 regulation and how specific modifications result in phenotypic change is essential for the development of new drugs targeting Hsp70 for therapeutic purposes. PMID- 29124307 TI - Mouse models for human intestinal microbiota research: a critical evaluation. AB - Since the early days of the intestinal microbiota research, mouse models have been used frequently to study the interaction of microbes with their host. However, to translate the knowledge gained from mouse studies to a human situation, the major spatio-temporal similarities and differences between intestinal microbiota in mice and humans need to be considered. This is done here with specific attention for the comparative physiology of the intestinal tract, the effect of dietary patterns and differences in genetics. Detailed phylogenetic and metagenomic analysis showed that while many common genera are found in the human and murine intestine, these differ strongly in abundance and in total only 4% of the bacterial genes are found to share considerable identity. Moreover, a large variety of murine strains is available yet most of the microbiota research is performed in wild-type, inbred strains and their transgenic derivatives. It has become increasingly clear that the providers, rearing facilities and the genetic background of these mice have a significant impact on the microbial composition and this is illustrated with recent experimental data. This may affect the reproducibility of mouse microbiota studies and their conclusions. Hence, future studies should take these into account to truly show the effect of diet, genotype or environmental factors on the microbial composition. PMID- 29124310 TI - Combined Effects of Dissolved Nutrients and Oxygen on Plant Litter Decomposition and Associated Fungal Communities. AB - Aquatic ecosystems worldwide have been substantially altered by human activities, which often induce changes in multiple factors that can interact to produce complex effects. Here, we evaluated the combined effects of dissolved nutrients (nitrogen [N] and phosphorus [P]; three levels: concentration found in oligotrophic streams in the Cerrado biome, 10* and 100* enriched) and oxygen (O2; three levels: hypoxic [4% O2], depleted [55% O2], and saturated [96% O2]) on plant litter decomposition and associated fungal decomposers in laboratory microcosms simulating stream conditions under distinct scenarios of water quality deterioration. Senescent leaves of Maprounea guianensis were incubated for 10 days in an oligotrophic Cerrado stream to allow microbial colonization and subsequently incubated in microcosms for 21 days. Leaves lost 1.1-3.0% of their initial mass after 21 days, and this was not affected either by nutrients or oxygen levels. When considering simultaneous changes in nutrients and oxygen concentrations, simulating increased human pressure, fungal biomass accumulation, and sporulation rates were generally inhibited. Aquatic hyphomycete community structure was also affected by changes in nutrients and oxygen availability, with stronger effects found in hypoxic treatments than in depleted or saturated oxygen treatments. This study showed that the effects of simultaneous changes in the availability of dissolved nutrients and oxygen in aquatic environments can influence the activity and composition of fungal communities, although these effects were not translated into changes in litter decomposition rates. PMID- 29124309 TI - Gain of function of TMEM16E/ANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia. AB - Mutations in the human TMEM16E (ANO5) gene are associated both with the bone disease gnathodiaphyseal dysplasia (GDD; OMIM: 166260) and muscle dystrophies (OMIM: 611307, 613319). However, the physiological function of TMEM16E has remained unclear. We show here that human TMEM16E, when overexpressed in mammalian cell lines, displayed partial plasma membrane localization and gave rise to phospholipid scrambling (PLS) as well as non-selective ionic currents with slow time-dependent activation at highly depolarized membrane potentials. While the activity of wild-type TMEM16E depended on elevated cytosolic Ca2+ levels, a mutant form carrying the GDD-causing T513I substitution showed PLS and large time-dependent ion currents even at low cytosolic Ca2+ concentrations. Contrarily, mutation of the homologous position in the Ca2+-activated Cl- channel TMEM16B paralog hardly affected its function. In summary, these data provide the first direct demonstration of Ca2+-dependent PLS activity for TMEM16E and suggest a gain-of-function phenotype related to a GDD mutation. PMID- 29124311 TI - Impacts of Projected Climate Warming and Wetting on Soil Microbial Communities in Alpine Grassland Ecosystems of the Tibetan Plateau. AB - Climate change is projected to have impacts on precipitation and temperature regimes in drylands of high elevation regions, with especially large effects in the Qinghai-Tibetan Plateau. However, there was limited information about how the projected climate change will impact on the soil microbial community and their activity in the region. Here, we present results from a study conducted across 72 soil samples from 24 different sites along a temperature and precipitation gradient (substituted by aridity index ranging from 0.079 to 0.89) of the Plateau, to assess how changes in aridity affect the abundance, community composition, and diversity of bacteria, ammonia-oxidizers, and denitrifers (nirK/S and nosZ genes-containing communities) as well as nitrogen (N) turnover enzyme activities. We found V-shaped or inverted V-shaped relationships between the aridity index (AI) and soil microbial parameters (gene abundance, community structures, microbial diversity, and N turnover enzyme activities) with a threshold at AI = 0.27. The increasing or decreasing rates of the microbial parameters were higher in areas with AI < 0.27 (alpine steppes) than in mesic areas with 0.27 < AI < 0.89 (alpine meadow and swamp meadow). The results indicated that the projected warming and wetting have a strong impact on soil microbial communities in the alpine steppes. PMID- 29124312 TI - Anaerobic Benzene Mineralization by Nitrate-Reducing and Sulfate-Reducing Microbial Consortia Enriched From the Same Site: Comparison of Community Composition and Degradation Characteristics. AB - Benzene mineralization under nitrate-reducing conditions was successfully established in an on-site reactor continuously fed with nitrate and sulfidic, benzene-containing groundwater extracted from a contaminated aquifer. Filling material from the reactor columns was used to set up anoxic enrichment cultures in mineral medium with benzene as electron donor and sole organic carbon source and nitrate as electron acceptor. Benzene degradation characteristics and community composition under nitrate-reducing conditions were monitored and compared to those of a well-investigated benzene-mineralizing consortium enriched from the same column system under sulfate-reducing conditions. The nitrate reducing cultures degraded benzene at a rate of 10.1 +/- 1.7 MUM d-1, accompanied by simultaneous reduction of nitrate to nitrite. The previously studied sulfate reducing culture degraded benzene at similar rates. Carbon and hydrogen stable isotope enrichment factors determined for nitrate-dependent benzene degradation differed significantly from those of the sulfate-reducing culture (LambdaH/C nitrate = 12 +/- 3 compared to LambdaH/C sulfate = 28 +/- 3), indicating different benzene activation mechanisms under the two conditions. The nitrate reducing community was mainly composed of Betaproteobacteria, Ignavibacteria, and Anaerolineae. Azoarcus and a phylotype related to clone Dok59 (Rhodocyclaceae) were the dominant genera, indicating an involvement in nitrate-dependent benzene degradation. The primary benzene degrader of the sulfate-reducing consortium, a phylotype belonging to the Peptococcaceae, was absent in the nitrate-reducing consortium. PMID- 29124313 TI - Simultaneous occurrence of two distinct leukemic clones with PML-RARalpha and RUNX1-RUNX1T1 in a case of acute myeloid leukemia. PMID- 29124314 TI - Prophylactic DNA vaccine targeting Foxp3+ regulatory T cells depletes myeloid derived suppressor cells and improves anti-melanoma immune responses in a murine model. AB - Regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) are the two important and interactive immunosuppressive components of the tumor microenvironment that hamper anti-tumor immune responses. Therefore, targeting these two populations together might be beneficial for overcoming immune suppression in the tumor microenvironment. We have recently shown that prophylactic Foxp3 DNA/recombinant protein vaccine (Foxp3 vaccine) promotes immunity against Treg in tumor-free conditions. In the present study, we investigated the immune modulatory effects of a prophylactic regimen of the redesigned Foxp3 vaccine in the B16F10 melanoma model. Our results indicate that Foxp3 vaccination continuously reduces Treg population in both the tumor site and the spleen. Surprisingly, Treg reduction was associated with a significant decrease in the frequency of MDSC, both in the spleen and in the tumor environment. Furthermore, Foxp3 vaccination resulted in a significant reduction of arginase-1(Arg-1)-induced nitric oxide synthase (iNOS), reactive oxygen species (ROS) and suppressed MDSC activity. Moreover, this concurrent depletion restored production of inflammatory cytokine IFN-gamma and enhanced tumor specific CTL response, which subsequently resulted in the reduction of tumor growth and the improved survival rate of vaccinated mice. In conclusion, our results revealed that Foxp3 vaccine promotes an immune response against tumor by targeting both Treg and MDSC, which could be exploited as a potential immunotherapy approach. PMID- 29124315 TI - The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy. AB - Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. Mocetinostat upregulated PD-L1 and antigen presentation genes including class I and II human leukocyte antigen (HLA) family members in a panel of NSCLC cell lines in vitro. Mocetinostat target gene promoters were occupied by a class I HDAC and exhibited increased active histone marks after mocetinostat treatment. Mocetinostat synergized with interferon gamma (IFN-gamma) in regulating class II transactivator (CIITA), a master regulator of class II HLA gene expression. In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. In ex vivo assays, patient-derived, mocetinostat-treated Tregs also showed significant down regulation of FOXP3 and HELIOS. The combination of mocetinostat and a murine PD-L1 antibody antagonist demonstrated increased anti-tumor activity compared to either therapy alone in two syngeneic tumor models. Together, these data provide evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy. PMID- 29124316 TI - Potential role of IgM-enriched immunoglobulin as adjuvant treatment for invasive meningococcal disease. PMID- 29124317 TI - Early application of airway pressure release ventilation in acute respiratory distress syndrome: a therapy for all? PMID- 29124318 TI - Does a 1-h rest after a successful spontaneous breathing trial really improve extubation outcome? : Discussion on whether reconnection to mechanical ventilation for 1 h after a successful spontaneous breathing trial reduces reintubation in critically ill patients: a multicenter randomized controlled trial. PMID- 29124319 TI - Is organizational justice climate at the workplace associated with individual level quality of care and organizational affective commitment? A multi-level, cross-sectional study on dentistry in Sweden. AB - PURPOSE: The aim of this study is to investigate whether organizational justice climate at the workplace level is associated with individual staff members' perceptions of care quality and affective commitment to the workplace. METHODS: The study adopts a cross-sectional multi-level design. Data were collected using an electronic survey and a response rate of 75% was obtained. Organizational justice climate and affective commitment to the workplace were measured by items from Copenhagen Psychosocial Questionnaire and quality of care by three self developed items. Non-managerial staff working at dental clinics with at least five respondents (n = 900 from 68 units) was included in analyses. A set of Level 2 random intercept models were built to predict individual-level organizational affective commitment and perceived quality of care from unit-level organizational justice climate, controlling for potential confounding by group size, gender, age, and occupation. RESULTS: The results of the empty model showed substantial between-unit variation for both affective commitment (ICC-1 = 0.17) and quality of care (ICC-1 = 0.12). The overall results showed that the shared perception of organizational justice climate at the clinical unit level was significantly associated with perceived quality of care and affective commitment to the organization (p < 0.001). CONCLUSIONS: Organizational justice climate at work unit level explained all variation in affective commitment among dental clinics and was associated with both the individual staff members' affective commitment and perceived quality of care. These findings suggest a potential for that addressing organizational justice climate may be a way to promote quality of care and enhancing affective commitment. However, longitudinal studies are needed to support causality in the examined relationships. Intervention research is also recommended to probe the effectiveness of actions increasing unit-level organizational justice climate and test their impact on quality of care and affective commitment. PMID- 29124320 TI - Recipe for IBD: can we use food to control inflammatory bowel disease? AB - The mucosal immune system and the microbiota in the intestinal tract have recently been shown to play a key role in the pathogenesis of inflammatory bowel disease (IBD). Both of these can be influenced by food. Thus, we propose dietary intervention as a therapeutic option for IBD. In this review, we discuss the interaction of the intestinal mucosal immune system and the intestinal microbiota in the context of IBD. In addition, we discuss the impact of food components on immune responses in IBD. Finally, we address the current evidence of how this interaction (i.e., immune system-microbiota) can be modulated by food components, pre/probiotics, and fecal microbiota transplantation (FMT) and how these approaches can support intestinal homeostasis. By gathering the vast amount of literature available on the impact of food on IBD, we aim to distinguish between scientifically sound data and theories, which have not been included in this review. PMID- 29124322 TI - Air-breathing changes the pattern for temperature-induced pH regulation in a bimodal breathing teleost. AB - It is well established that ectothermic vertebrates regulate a lower arterial pH when temperature increases. Typically, water-breathers reduce arterial pH by altering plasma [HCO3-], whilst air-breathers rely on ventilatory adjustments to modulate arterial PCO2. However, no studies have investigated whether the shift from water- to air-breathing within a species changes the mechanisms for temperature-induced pH regulation. Here, we used the striped catfish Pangasianodon hypophthalmus to examine how pH regulation is affected by water- versus air-breathing, since P. hypophthalmus can accommodate all gas exchange by its well-developed gills in normoxic water, but achieves the same metabolic rate with aerial oxygen uptake using its the swim-bladder when exposed to aquatic hypoxia. We, therefore, measured arterial acid-base status in P. hypophthalmus as temperature changed between 20 and 35 degrees C in either normoxic or severely hypoxic water. In normoxic water, where P. hypophthalmus relied entirely on branchial gas exchange, P. hypophthalmus exhibited the typical teleost reduction in plasma [HCO3-] and arterial pH when temperature rose. However, when forced to increase air-breathing in hypoxic water, arterial PCO2 fell due to a branchial hyperventilation, but it increased with temperature most likely due to passive CO2 retention. We propose that the rise in arterial PCO2 reflects a passive consequence of the progressive transition to air breathing at higher temperatures, and that this response fortuitously matches the new regulated pHa, relieving the requirement for branchial ion exchange. PMID- 29124323 TI - [Goodpasture syndrome: ocular manifestation in a young man]. AB - Goodpasture syndrome (GS) is a rare organ-specific autoimmune disease that may consist of glomerulonephritis and pulmonary hemorrhage. Only few case reports have been published on ocular symptoms in the context of GS. This is a case report of a 22-year-old male with GS who was referred to our practice because of visual disturbances. The anamnesis revealed pulmonary hemorrhage, acute renal failure and nephrotic syndrome, which was treated by immunosuppressive therapy with additional plasmapheresis. Ophthalmoscopically, bilateral cotton wool spots were found along the vessels and bilateral retinal hemorrhages predominantly at the posterior pole. By intensifying the existing antihypertensive therapy the eyesight showed significant improvement. Although infrequently seen in Goodpasture syndrome it is important to be aware of ocular symptoms as they may be the initial signs of GS. PMID- 29124321 TI - Vaccine responses in newborns. AB - Immunisation of the newborn represents a key global strategy in overcoming morbidity and mortality due to infection in early life. Potential limitations, however, include poor immunogenicity, safety concerns and the development of tolerogenicity or hypo-responsiveness to either the same antigen and/or concomitant antigens administered at birth or in the subsequent months. Furthermore, the neonatal immunological milieu is polarised towards Th2-type immunity with dampening of Th1-type responses and impaired humoral immunity, resulting in qualitatively and quantitatively poorer antibody responses compared to older infants. Innate immunity also shows functional deficiency in antigen presenting cells: the expression and signalling of Toll-like receptors undergo maturational changes associated with distinct functional responses. Nevertheless, the effectiveness of BCG, hepatitis B and oral polio vaccines, the only immunisations currently in use in the neonatal period, is proof of concept that vaccines can be successfully administered to the newborn via different routes of delivery to induce a range of protective mechanisms for three different diseases. In this review paper, we discuss the rationale for and challenges to neonatal immunisation, summarising progress made in the field, including lessons learnt from newborn vaccines in the pipeline. Furthermore, we explore important maternal, infant and environmental co-factors that may impede the success of current and future neonatal immunisation strategies. A variety of approaches have been proposed to overcome the inherent regulatory constraints of the newborn innate and adaptive immune system, including alternative routes of delivery, novel vaccine configurations, improved innate receptor agonists and optimised antigen-adjuvant combinations. Crucially, a dual strategy may be employed whereby immunisation at birth is used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. Similarly, potent non-specific immunomodulatory effects may be elicited when challenged with unrelated antigens, with the potential to reduce the overall risk of infection and allergic disease in early life. PMID- 29124324 TI - The effect of mental fatigue on critical power during cycling exercise. AB - PURPOSE: Time to exhaustion (TTE) tests used in the determination of critical power (CP) and curvature constant (W') of the power-duration relationship are strongly influenced by the perception of effort (PE). This study aimed to investigate whether manipulation of the PE alters the CP and W'. METHODS: Eleven trained cyclists completed a series of TTE tests to establish CP and W' under two conditions, following a mentally fatiguing (MF), or a control (CON) task. Both cognitive tasks lasted 30 min followed by a TTE test. Ratings of PE and heart rate (HR) were measured during each TTE. Blood lactate was taken pre and post each TTE test. Ratings of perceived mental and physical fatigue were taken pre- and post-cognitive task, and following each TTE test. RESULTS: Perceived MF significantly increased as a result of the MF task compared to baseline and the CON task (P < 0.05), without a change in perceived physical fatigue (P > 0.05). PE was significantly higher during TTE in the MF condition (P < 0.05). Pre-post blood lactate accumulation was significantly lower after each TTE in MF condition (P < 0.05). HR was not significant different between conditions (P > 0.05). Neither cognitive task induced any change in CP (MF 253 +/- 51 vs. CON 247 +/- 58W; P > 0.05), although W' was significantly reduced in the MF condition (MF 22.8 +/- 4.5 vs. CON 29.3 +/- 6.3 kJ; P < 0.01). CONCLUSION: MF has no effect of CP, but reduces the W' in trained cyclists. Lower lactate accumulation during TTE tests following MF suggests that cyclists were not able to fully expend W' even though they exercised to volitional exhaustion. PMID- 29124327 TI - A phase II study of biweekly gemcitabine and carboplatin in completely resected stage IB-IIIA non-small cell lung cancer. AB - PURPOSE: We conducted a prospective study to evaluate the efficacy and safety of biweekly gemcitabine and carboplatin combination treatment in patients with resected non-small cell lung cancer (NSCLC). METHODS: Patients with completely resected stage IB to IIIA NSCLC were treated with four cycles of gemcitabine (1000 mg/m2, days 1 and 15) plus carboplatin [area under the time-concentration curve (AUC) 5 mg/mL/min, day 1] every 4 weeks as adjuvant chemotherapy. RESULTS: Forty-three patients were enrolled in this study. The median number of treatment cycles was four. The completion rate of chemotherapy was 79.1%. Major grade 3/4 hematological adverse events included leukocytopenia (27.9%) and neutropenia (53.5%), whereas non-hematological toxicities were generally mild. Ten patients (23.3%) required chemotherapy treatment schedule delay, and one patient required one dose level reduction because of drug fever. Median disease-free survival was 78.6 months [95% confidence interval (CI) 39.5-not reached (NA)] and median overall survival was not reached (95% CI 83.7-NA). CONCLUSIONS: Biweekly administration of gemcitabine and carboplatin is effective and well tolerated for patients with completely resected NSCLC as an adjuvant chemotherapy. PMID- 29124325 TI - Changes in fat oxidation in response to various regimes of high intensity interval training (HIIT). AB - Increased whole-body fat oxidation (FOx) has been consistently demonstrated in response to moderate intensity continuous exercise training. Completion of high intensity interval training (HIIT) and its more intense form, sprint interval training (SIT), has also been reported to increase FOx in different populations. An explanation for this increase in FOx is primarily peripheral adaptations via improvements in mitochondrial content and function. However, studies examining changes in FOx are less common in response to HIIT or SIT than those determining increases in maximal oxygen uptake which is concerning, considering that FOx has been identified as a predictor of weight gain and glycemic control. In this review, we explored physiological and methodological issues underpinning existing literature concerning changes in FOx in response to HIIT and SIT. Our results show that completion of interval training increases FOx in approximately 50% of studies, with the frequency of increased FOx higher in response to studies using HIIT compared to SIT. Significant increases in beta-HAD, citrate synthase, fatty acid binding protein, or FAT/CD36 are likely responsible for the greater FOx seen in these studies. We encourage scientists to adopt strict methodological procedures to attenuate day-to-day variability in FOx, which is dramatic, and develop standardized procedures for assessing FOx, which may improve detection of changes in FOx in response to HIIT. PMID- 29124328 TI - Efficacy of combination chemotherapy using irinotecan and nedaplatin for patients with recurrent and refractory endometrial carcinomas: preliminary analysis and literature review. AB - PURPOSE: We aimed to retrospectively evaluate the efficacy and toxicity of an irinotecan hydrochloride (CPT) and nedaplatin (N) combination therapy for recurrent and refractory endometrial carcinoma, administered based on UGT1A1 genotype. METHODS: Between 2009 and 2017, 21 patients who received CPT-N therapy for recurrent endometrial carcinoma as second- or third-line chemotherapy at our hospital were identified. The CPT-N regimen included 40-70 mg/m2 of CPT-11 on days 1, 8, and 15, and 50 mg/m2 of nedaplatin on day 1, q4 weeks. RESULTS: The median patient age was 63 years. The number of prior chemotherapeutic regimens ranged from 1 to 2. Two patients had prior pelvic irradiation. The response rate [ratio of complete remission (CR) to partial remission (PR)] of CPT-N therapy was 3 of 21 (14.3%), and clinical benefit rate (CBR) [the combined percentages of CR, PR, and stable disease (SD)] was 9 of 21 (42.8%). Toxicities included grade 3 neutropenia [4 (19.0%) cases], grade 3 febrile neutropenia [2 (9.5%) cases], and grade 3 diarrhea [3 (14.3%) cases]; all resolved with conservative treatment. Patients with a wild-type UGT1A1 status received higher doses of CPT-11 (p = 0.048) and had similar RR and CBR compared to those with a UGT1A1*6 and *28 status. There were no significant differences in frequencies of hematological or non-hematological toxicities, regardless of UGT1A1 status. CONCLUSIONS: The CPT-N regimen for recurrent and refractory endometrial carcinoma had tolerable side effects and significant efficacy. This regimen is a viable treatment option for endometrial carcinoma. PMID- 29124326 TI - Impact of two arbuscular mycorrhizal fungi on Arundo donax L. response to salt stress. AB - MAIN CONCLUSION: AM symbiosis did not strongly affect Arundo donax performances under salt stress, although differences in the plants inoculated with two different fungi were recorded. The mechanisms at the basis of the improved tolerance to abiotic stresses by arbuscular mycorrhizal (AM) fungi have been investigated mainly focusing on food crops. In this work, the potential impact of AM symbiosis on the performance of a bioenergy crop, Arundo donax, under saline conditions was considered. Specifically, we tried to understand whether AM symbiosis helps this fast-growing plant, often widespread in marginal soils, withstand salt. A combined approach, involving eco-physiological, morphometric and biochemical measurements, was used and the effects of two different AM fungal species (Funneliformis mosseae and Rhizophagus irregularis) were compared. Results indicate that potted A. donax plants do not suffer permanent damage induced by salt stress, but photosynthesis and growth are considerably reduced. Since A. donax is a high-yield biomass crop, reduction of biomass might be a serious agronomical problem in saline conditions. At least under the presently experienced growth conditions, and plant-AM combinations, the negative effect of salt on plant performance was not rescued by AM fungal colonization. However, some changes in plant metabolisms were observed following AM-inoculation, including a significant increase in proline accumulation and a trend toward higher isoprene emission and higher H2O2, especially in plants colonized by R. irregularis. This suggests that AM fungal symbiosis influences plant metabolism, and plant-AM fungus combination is an important factor for improving plant performance and productivity, in presence or absence of stress conditions. PMID- 29124330 TI - [Cystic tumors of the pancreas]. PMID- 29124331 TI - Cannabidiol as a treatment for epilepsy. PMID- 29124329 TI - Recruitment to and pilot results of the PACES randomized trial of physical exercise during adjuvant chemotherapy for colon cancer. AB - PURPOSE: We report the recruitment rate, reasons for and factors influencing non participation, and descriptive results of a randomized controlled trial of two different exercise programs for patients with colon cancer undergoing adjuvant chemotherapy. METHODS: Participants were randomized to a low-intensity, home based program (Onco-Move), a moderate- to high-intensity, combined supervised resistance and aerobic exercise program (OnTrack), or Usual Care. Non participants provided reasons for non-participation and were asked to complete a questionnaire assessing behavioral and attitudinal variables. Trial participants completed performance-based and self-reported outcome measures prior to randomization, at the end of chemotherapy, and at the 6-month follow-up. RESULTS: Twenty-three of 63 referred patients agreed to participate in the trial. All 40 non-participants provided reasons for non-participation. Forty-five percent of the non-participants completed the questionnaire. Those who did not want to exercise had higher fatigue scores at baseline and a more negative attitude toward exercise. Compliance to both programs was high and no adverse events occurred. On average, the colon cancer participants were able to maintain or improve their physical fitness levels and maintain or decrease their fatigue levels during chemotherapy and follow-up. CONCLUSIONS: Recruitment of patients with colon cancer to a physical exercise trial during adjuvant chemotherapy proved to be difficult, underscoring the need to develop more effective strategies to increase participation rates. Both home-based and supervised programs are safe and feasible in patients with colon cancer undergoing chemotherapy. Effectiveness needs to be established in a larger trial. TRIAL REGISTRATION: Netherlands Trial Register - NTR2159. PMID- 29124332 TI - Sexually transmitted infections of the lower gastrointestinal tract. AB - The World Health Organization estimates that there is greater than one million new cases of sexually transmitted infections (STIs) every day. In many countries, STIs are at an unprecedented high, including the USA, where nearly 20 million new cases were reported in 2016. Although morbidity associated with STIs is usually seen in the context of genitourinary disease, these pathogens may also affect the gastrointestinal tract and cause anal pain, abdominal pain, or diarrhea. It is important to recognize patterns of injury associated with these pathogens, especially those that may mimic other gastrointestinal diseases, such as idiopathic inflammatory bowel disease (IBD). This review focuses upon STIs of the lower gastrointestinal tract, organized by the most common site of involvement: the anus, rectum, and colon. PMID- 29124333 TI - Assessment of hepatotoxicity of first-line anti-tuberculosis drugs on Wistar rats. AB - Adverse drug reactions are inevitable risk factors associated with use of modern medicines. First-line anti-tuberculosis drugs contribute to diverse pathological complications, and hepatotoxicity is one of them. This study investigated the effects of anti-TB drugs in combination (rifampicin [RIF] + isoniazid [INH] + pyrazinamide [PZA]) on Wistar rats. Rats were grouped as control group (saline), toxicant group that was given (30.85 mg/kg b.wt., INH + 61.7 mg/kg b.wt., RIF + 132.65 mg/kg b.wt. PZA in dosage extrapolated from dose that is used in human). Different anti-oxidant enzymes were measured in the liver along with histopathology, hematology, genotoxic effect on bone marrow chromosomes, and DNA fragmentation. In addition, gene and protein expression of CYP2E1, NR1I2, NAT, and CYP7A1 was measured by qPCR and western blot. After administration of anti-TB drugs to Wistar rats for 28 days, there was an increase in thiobarbituric acid reactive substances and a decrease in anti-oxidant enzymes. Marked changes in histopathology, hematology, DNA fragmentation, chromosomes, and in gene expression were observed. Results of the study proved increased hepatotoxicity due to combinational treatment of anti-TB drugs and also that CYP2E1, NR1I2, NAT, and CYP7A1 genes play a vital role in anti-TB drug-induced hepatotoxicity. PMID- 29124334 TI - Production of (3-hydroxybutyrate-co-3-hydroxyhexanoate) copolymer from coffee waste oil using engineered Ralstonia eutropha. AB - Polyhydroxyalkonate (PHA) is a type of polymer that has the potential to replace petro-based plastics. To make PHA production more economically feasible, there is a need to find a new carbon source and engineer microbes to produce a commercially valuable polymer. Coffee waste is an inexpensive raw material that contains fatty acids. It can act as a sustainable carbon source and seems quite promising with PHA production in Ralstonia eutropha, which is a well-known microbe for PHA accumulation, and has the potential to utilize fatty acids. In this study, to make poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (P(HB-co-HHx)), which has superior properties in terms of biodegradability, biocompatibility, and mechanical strength, engineered strain Ralstonia eutropha Re2133 overexpressing (R)-specific enoyl coenzyme-A hydratase (phaJ) and PHA synthetase (phaC2) with deletion of acetoacetyl Co-A reductases (phaB1, phaB2, and phaB3) was used to produce PHA from coffee waste oil. At a coffee oil concentration of 1.5%, and C/N ratio of 20, the R. eutropha Re2133 fermentation process results in 69% w/w of DCW PHA accumulation and consists of HB (78 mol%) and HHx (22 mol%). This shows the feasibility of using coffee waste oil for P(HB-co-HHx) production, as it is a low-cost fatty acid enriched waste material. PMID- 29124335 TI - Rhamnosidase activity of selected probiotics and their ability to hydrolyse flavonoid rhamnoglucosides. AB - Bioavailability of flavonoids is low, especially when occurring as rhamnoglucosides. Thus, the hydrolysis of rutin, hesperidin, naringin and a mixture of narcissin and rutin (from Cyrtosperma johnstonii) by 14 selected probiotics was tested. All strains showed rhamnosidase activity as shown using 4 nitrophenyl alpha-L-rhamnopyranoside as a substrate. Hesperidin was hydrolysed by 8-27% after 4 and up to 80% after 10 days and narcissin to 14-56% after 4 and 25 97% after 10 days. Rutin was hardly hydrolysed with a conversion rate ranging from 0 to 5% after 10 days. In the presence of narcissin, the hydrolysis of rutin was increased indicating that narcissin acts as an inducer. The rhamnosidase activity as well as the ability to hydrolyse flavonoid rhamnoglucosides was highly strain specific. Naringin was not hydrolysed by rhamnosidase from probiotics, not even by the purified recombinant enzyme, only by fungal rhamnosidase. In conclusion, rhamnosidases from the tested probiotics are substrate specific cleaving hesperidin, narcissin and to a small extent rutin, but not naringin. PMID- 29124337 TI - Warmed Winter Water Temperatures Alter Reproduction in Two Fish Species. AB - We examined the spawning success of Fathead Minnows (Pimephales promelas) and Johnny Darters (Etheostoma nigrum) exposed to elevated winter water temperatures typical of streams characterized by anthropogenic thermal inputs. When Fathead Minnows were exposed to temperature treatments of 12, 16, or 20 degrees C during the winter, spawning occurred at 16 and 20 degrees C but not 12 degrees C. Eggs were deposited over 9 weeks before winter spawning ceased. Fathead Minnows from the three winter temperature treatments were then exposed to a simulated spring transition. Spawning occurred at all three temperature treatments during the spring, but fish from the 16 degrees and 20 degrees C treatment had delayed egg production indicating a latent effect of warm winter temperatures on spring spawning. mRNA analysis of the egg yolk protein vitellogenin showed elevated expression in female Fathead Minnows at 16 and 20 degrees C during winter spawning that decreased after winter spawning ceased, whereas Fathead Minnows at 12 degrees C maintained comparatively low expression during winter. Johnny Darters were exposed to 4 degrees C to represent winter temperatures in the absence of thermal inputs, and 12, 16, and 20 degrees C to represent varying degrees of winter thermal pollution. Johnny Darters spawned during winter at 12, 16, and 20 degrees C but not at 4 degrees C. Johnny Darters at 4 degrees C subsequently spawned following a simulated spring period while those at 12, 16, and 20 degrees C did not. Our results indicate elevated winter water temperatures common in effluent-dominated streams can promote out-of-season spawning and that vitellogenin expression is a useful indicator of spawning readiness for fish exposed to elevated winter temperatures. PMID- 29124336 TI - Application of age assessment based on the radiographic visibility of the root pulp of lower third molars in a northern Chinese population. AB - The purpose of the present study was to explore the potential application of radiographic visibility of the root pulp in lower third molars in a northern Chinese population, in order to determine if this methodology can be used to prove whether a person has surpassed the thresholds of 18 and 21 years of age. A total of 1300 orthopantomograms comprising equal numbers of females and males evenly distributed between the ages of 15 and 40 years were analyzed. The radiographic visibility of the root pulp of the lower third molars was assessed using the stages described by Olze et al. (2010). Stage 1 first appeared at 19.25 years in males and at 20.73 years in females. The earliest appearance of stage 2 happened at 22.33 years in males and at 22.41 years in females. Stage 3 was achieved first at 26.45 years in males and at 27.66 years in females. It was concluded that stages 1, 2, and 3 can be used to show that a person is over 18 years of age. If stages 2 or 3 are determined, it is possible to prove that an individual has already attained the age of 21 years. PMID- 29124338 TI - Japanese medicine and Berlin: a very special and successful relationship. AB - We describe a unique interaction between the very advanced German medicine and the ambitious Japanese medicine at the end of the 19th century and some of their protagonists. The Japanese sent some of their brightest young doctors to Germany where they not only studied medicine but also contributed to medical progress in Germany. Most went to Berlin, but before coming to Germany, in Japan they had to learn not only the German language but also German medicine as students of prominent German doctors in Japan. Both groups complemented each other in this cooperation to the benefit of all. PMID- 29124339 TI - Accuracy of screw fixation using the O-arm(r) and StealthStation(r) navigation system for unstable pelvic ring fractures. AB - PURPOSE: Screw fixation for unstable pelvic ring fractures is generally performed using the C-arm. However, some studies reported erroneous piercing with screws, nerve injuries, and vessel injuries. Recent studies have reported the efficacy of screw fixations using navigation systems. The purpose of this retrospective study was to investigate the accuracy of screw fixation using the O-arm(r) imaging system and StealthStation(r) navigation system for unstable pelvic ring fractures. METHODS: The participants were 10 patients with unstable pelvic ring fractures, who underwent screw fixations using the O-arm StealthStation navigation system (nine cases with iliosacral screw and one case with lateral compression screw). We investigated operation duration, bleeding during operation, the presence of complications during operation, and the presence of cortical bone perforation by the screws based on postoperative CT scan images. We also measured the difference in screw tip positions between intraoperative navigation screen shot images and postoperative CT scan images. RESULTS: The average operation duration was 71 min, average bleeding was 12 ml, and there were no nerve or vessel injuries during the operation. There was no cortical bone perforation by the screws. The average difference between intraoperative navigation images and postoperative CT images was 2.5 +/- 0.9 mm, for all 18 screws used in this study. CONCLUSION: Our results suggest that the O-arm StealthStation navigation system provides accurate screw fixation for unstable pelvic ring fractures. PMID- 29124340 TI - Discovering the stacking landscape of a pyridine-pyridine system. AB - Extremely extensive calculations of potential energy surfaces for the parallel displaced configuration of pyridine dimer systems have been carried out using a dispersion-corrected density functional. Instead of focusing on stationary geometries these calculations provide much deeper insight into the "landscape" of the interaction energies of the particular systems-one can learn how the pyridine dimer stability changes along with various geometrical parameters. Other calculations such as natural bond orbital and energy decomposition have also been applied. The interplay of two significant factors, electrostatic forces and electron correlation effects, have been evaluated. The role of pi...pi interactions in the stacked pyridine systems has also been confirmed, and surprisingly, this happened to be true even for the geometries where the formation of C-H...pi interactions might be proposed instead. The combination of many different methods has revealed the complexity of the stacking interactions. Apart from providing a "literal new look" into pyridine interaction patterns another picture has emerged. A stacking interaction in a pyridine dimer system is perceived as a combination of many different sources of the interaction energy, including orbital ones, and this is true for many different geometries. PMID- 29124341 TI - Phytophagy of omnivorous predator Macrolophus pygmaeus affects performance of herbivores through induced plant defences. AB - Plants possess various inducible defences that result in synthesis of specialized metabolites in response to herbivory, which can interfere with the performance of herbivores of the same and other species. Much less is known of the effects of plant feeding by omnivores. We found that previous feeding of the omnivorous predator Macrolophus pygmaeus on sweet pepper plants significantly reduced reproduction of the two-spotted spider mite Tetranychus urticae and western flower thrips Frankliniella occidentalis on the same plants, also on leaves that had not been exposed to the omnivore. In contrast, no effect was found on the reproduction of the green peach aphid Myzus persicae. Juvenile survival and developmental time of T. urticae and M. persicae, and larval survival of F. occidentalis were not affected by plant feeding by M. pygmaeus. Larvae of F. occidentalis feeding on leaves previously exposed to M. pygmaeus required longer to develop into adults. Defence-related plant hormones were produced locally and systemically after exposure to M. pygmaeus. The concentrations of 12-oxo phytodienoic acid and jasmonic acid-isoleucine in the attacked leaves were significantly higher than in the corresponding leaves on the uninfested plants, and jasmonic acid concentrations showed the same trend, suggesting that jasmonic acid-related defence pathways were activated. In contrast, similar concentrations of salicylic acid were found in the attacked leaves of M. pygmaeus-infested plants and uninfested plants. Our results show that plant feeding by omnivorous predators decreases the performance of herbivores, suggesting that it induces plant defences. PMID- 29124342 TI - Connections between radial and ulnar nerve at high humeral level in cadavers: incidence, topography, and literature review. AB - PURPOSE: Although communications between branches and cords of the brachial plexus have been extensively published, there is a scarcity of reports concerning radial and ulnar nerve (RN-UN) communication in the arm. The current study aims to demonstrate the incidence, topography, and length of communicating branches between RN and UN. Any additional coexisted variations were also recorded. MATERIALS AND METHODS: Two hundred and sixty-six upper limbs collected from one hundred and thirty-three (81 males and 52 females) Greek cadavers were dissected. RESULTS: Three out of one hundred and thirty-three cadavers, accounting for an incidence of up to 2.3%, were found to have an atypical communicating branch originating at a high humeral level from RN towards UN. In two cadavers, communicating branches were detected on the left side and in one cadaver bilaterally. CONCLUSIONS: The study of atypical communications between RN and UN attracts great attention for its clinical importance, mainly in cases of peripheral neuropathies with diagnostic dilemma or upper limb nerve injury producing an otherwise unexpected symptomatology due to the aberrant nerve supply. Familiarity with these variations is crucial in avoiding misdiagnosis and preserving valuable communicating branches, thus achieving an uneventful outcome in cases of upper limb nerve injury repair. PMID- 29124344 TI - Three-dimensional computed tomography angiography reconstruction of the origin of the uterine artery and its clinical significance. AB - PURPOSE: In women, the uterine artery is the main branch of the internal iliac artery, vascularizing most of the uterus. Knowledge of its origin and variations is essential during extensive gynaecological surgery and interventional radiological procedures. We aimed to investigate its origin and explore its anatomical variations by three-dimensional (3D) reconstructed computed tomography (CT) angiography. METHODS: This was a retrospective, monocentric observational study involving CT scans of the abdomen and lower limbs of women < 50 years old with 3D reconstructed CT images of the internal and external iliac arterial axes. RESULTS: Between 01 January 2014 and 31 December 2015, among 986 cases of CT scans performed in women, for all indications, 3D reconstructed images for 43 women could be analysed. The uterine artery originated from a common trunk with the umbilical artery in 62.7% of cases, from a direct branch of the internal iliac artery in 25.6% of cases, directly from the superior gluteal artery in 9.3% of cases and from the internal pudendal artery in 2.3%. CONCLUSIONS: Three dimensional(3D) reconstructed CT angiography can detect the point of origin of the uterine artery. Therefore, it can be used as a mapping tool of the pelvic arterial tree. Our study corroborates data from the literature that the uterine artery most often originates from a common trunk with the umbilical artery. However, surgeons and intervention radiologists must be aware of the variability of its origin to facilitate the safety of the patients during procedures. PMID- 29124343 TI - Anatomical landmarks of mandibular interforaminal region related to dental implant placement with 3D CBCT: comparison between edentulous and dental mandibles. AB - BACKGROUND: Anterior mandibular (interforaminal) region is important in implant applications as it serves a basis for neurovascular bedding and holds the prosthesis for patients. Treatment planning for dental implant patients is often complicated by the unknown extent of the anterior loop of the neurovascular bundle. Anatomical structures including mandibular incisive canal (MIC) and lingual foramen (LF) should also be examined as part of the detailed analysis for their neurovascular structures. This study aimed to detect the positions of LF and MIC as well as the prolongation of interforaminal region in Anatolian population to supply the reference data of the surgical safe zone in chin for the clinicians. MATERIALS AND METHODS: Mandibles of 70 adult specimens (35 edentulous + 35 dentate) were retrieved from the Department of Anatomy, Ege University. Images of the dry mandibles were obtained using a cone beam computed tomography unit applying a standardized exposure protocol. Afterwards, mandibles were sawn into vertical sections according to the respective tomographic cross-sections. Images were evaluated for the absence/presence of the MIC, its dimensions and antero-posterior length for both edentulous and dentate groups. In addition; the presence, number, location, labial canal and LF diameter and height of the LF were determined for both groups. RESULTS: The MIC was observed in 80 and 68.6% of the dentate and edentulous groups, consecutively (p > 0.05). The MIC continued towards the incisor region in a slightly downward direction. The LF was observed in all dentate mandibles (100%), while it was present in 94.3% of the edentulous mandibles (p > 0.05). For the dentate group, 62.9% of the specimens had two foramens and 20% had three foramens in the mandibular midline. Mean length of the MIC in dentate groups and edentulous groups was measured as 2.55 +/- 0.809 and 3.08 +/- 1.745 mm, respectively. Well-defined MIC mean diameter in dentate groups and edentulous groups were measured as 2.44 +/- 0.702 and 2.35 +/- 0.652 mm, respectively. Significant difference was found between dentate and edentulous group in most of the parameters except for the LF and the diameter of the MIC (p > 0.05). The correlation between observers' measurements ranged between 0.742 and 0.993 for all anatomical landmarks and mandible groups. CONCLUSION: The MIC and LF are associated with neurovascular bundle variations in number, location and size. Therefore, clinicians should determine each of these anatomical structures on a case-by-case basis to recognize their presence and to take measures for the possible implications of various treatment options. These guidelines included leaving a 2 mm safety zone between an implant and the coronal aspect of the neurovascular bundle. To avoid neurovascular injury during surgery in the interforaminal area, guidelines were developed with respect to validating the presence of an anterior loop of the neurovascular bundle. PMID- 29124345 TI - A rare anatomic variation of the superficial palmar branch of the radial artery causing pain. AB - BACKGROUND: The superficial palmar branch of the radial artery (SPBRA) normally pierces through the thenar muscles and unites with the ulnar artery to form the superficial palmar arch. Rarely, a subcutaneous course of the SPBRA is described in which the artery lies superficial to the thenar muscles. CASE REPORT: We report about a 17-year-old female patient with pain at the thenar eminence due to a unique course of the SPBRA. Duplex sonography and magnetic resonance angiography revealed a subcutaneous course of the artery over the thenar muscles. Arterial transposition by splitting of the abductor pollicis brevis muscle was performed. At 12-month follow-up, the patient is still free of symptoms. Duplex sonography confirmed patency of the SPBRA. CONCLUSION: While a subcutaneous course of the SPBRA has been described before, we present an adolescent patient with this anatomical variation causing pain. Our specifically tailored treatment strategy consisting of arterial transposition by splitting of the abductor pollicis brevis muscle was efficient and feasible in our patient and hand surgeons should be aware of this anatomical variation. PMID- 29124346 TI - Live surgery: highly educational or harmful? AB - PURPOSE: Live surgery (LS) is considered a useful teaching opportunity. The benefits must be balanced with patient safety concerns. To evaluate the rate of complications of a series of urologic LS performed by experts during the Congress Challenge in Laparoscopy and Robotics (CILR). METHODS: We present a large, multi institution, multi-surgeon database that derives from 12 CILR events, from 2004 to 2015 with a total of 224 cases. Radical prostatectomy (RP) was the most common procedure and a selection of complex cases was noted. The primary measure was postoperative complications and use of a Postoperative Morbidity Index (PMI) to allow quantitative weighing of postoperative complications. RESULTS: From 12 events, the number of cases increased from 11 in 2004 to 27 in 2015 and a total of 27 surgeons. Of 224 cases (164 laparoscopic and 60 robotic), there were 26 (11.6%) complications: 5 grade I, 5 grade II, 3 grade IIIa, 12 grade IIIb and 1 grade V, the latter from laparoscopic cystectomy. Analysis of PMI was 23 times higher from cystectomy compared to RP. CONCLUSIONS: In the setting of live surgery, the overall rate of complications is low considering the complexity of surgeries. The PMI is not higher in more complex procedures, whereas RP seems very safe. PMID- 29124348 TI - Super-, perfect-, ultra-, micro-, mini-, ...: does anybody benefit from miniaturized percutaneous nephrolithotomy? PMID- 29124347 TI - The effect of onabotulinumtoxinA according to site of injection in patients with overactive bladder: a systematic review and meta-analysis. AB - PURPOSE: This study assessed the efficacy and safety of onabotulinumtoxinA according to injection site for treatment of overactive bladder. METHODS: A systematic literature review located randomized controlled trials of onabotulinumtoxinA treatment for neurogenic detrusor overactive bladder and idiopathic overactive bladder in adults. We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Register using the Ovid platform. Meta-analysis was based on Cochrane Review Methods. RESULTS: Eight studies (419 participants) were included. Trigone-including injection demonstrated a significant improvement in symptom score (SMD = - 0.53, 95% CI - 1.04 to - 0.02, P = 0.04, I 2 = 78%), higher complete dryness rates (OR = 2.19 patients, 95% CI 1.32-3.63, P = 0.002, I 2 = 41%), and lower frequency of incontinence episodes (WMD = - 0.85 per day, 95% CI - 1.55 to - 0.16, P = 0.02, I 2 = 87%) in patients. Comparing trigone including injection to trigone-sparing injection, lower detrusor pressure (WMD = 2.55 cm H2O, 95% CI - 4.16 to - 0.95, P = 0.002, I 2 = 0%) and higher volume at first desire to void (WMD = 17.54 ml, 95% CI 1.00-34.07, P = 0.04, I 2 = 0%) were observed with trigone-including injection. Between intradetrusor and suburothelial injection sites, there were no differences in efficacy or safety regarding the incidence of vesicoureteral reflux, hematuria, general weakness, bladder discomfort, large post-void residual, and urinary tract infection. CONCLUSION: Trigone-including onabotulinumtoxinA injection has superior efficacy to trigone-sparing injection without increased complications. The depth of injection does not influence the efficacy or safety of onabotulinumtoxinA. PMID- 29124350 TI - Role of TRH/UCN3 neurons of the perifornical area/bed nucleus of stria terminalis region in the regulation of the anorexigenic POMC neurons of the arcuate nucleus in male mice and rats. AB - Two anorexigenic peptides, thyrotropin-releasing hormone (TRH) and urocortin 3 (UCN3), are co-expressed in a continuous neuronal group that extends from the perifornical area to the bed nucleus of stria terminalis, raising the possibility that this cell group may be involved in the regulation of energy homeostasis. In this study, therefore, we tested the hypothesis that the TRH/UCN3 neurons regulate food intake by influencing feeding-related neuropeptide Y (NPY) and/or proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). Triple-labeled immunofluorescent preparations demonstrated that only very few NPY neurons (4.3 +/- 1.3%) were contacted by double-labeled TRH/UCN3 axons in the ARC. In contrast, more than half of the POMC neurons (52.4 +/- 8.5%) were contacted by double-labeled axons. Immuno-electron microscopy demonstrated that the UCN3 axons established asymmetric synapses with POMC neurons, indicating the excitatory nature of these synaptic specializations. Patch clamp electrophysiology revealed that TRH and UCN3 have antagonistic effects on the POMC neurons. While UCN3 depolarizes and increases the firing rate of POMC neurons, TRH prevents these effects of UCN3. These data demonstrate that TRH/UCN3 neurons in the perifornical/BNST region establish abundant synaptic associations with the POMC neurons in the ARC and suggest a potentially important role for these neurons in the regulation of food intake through an antagonistic interaction between TRH and UCN3 on the electrophysiological properties of POMC neurons. PMID- 29124352 TI - Brain waves from an "isolated" cortex: contribution of the anterior insula to cognitive functions. AB - Using two independent electrical neuroimaging techniques (BESA and sLORETA), we tested a fMRI-seeded source modeling indicating that in visual discriminative tasks the anterior insula (aIns) participates in the generation of three prefrontal ERP components: the pN1 (at 115 ms), the pP1 (at 170 ms), and the pP2 (at 300 ms). This latter component represented the focus of the present study. Results showed that the pP2 had different activation profiles across hemispheres. The left aIns activity peaked at 420 ms (30 ms before the response) for both Go and No-go trials, that is independently from the ultimate choice (response or inhibition). The right aIns activity started at about 250 ms and progressively increased for a time interval extending after the motor response; its amplitude was larger in case of Go than No-go stimuli. We suggest that the activation of the left aIns reflected the timing of the decision, and the right aIns the categorization and the performance monitoring processes. A control experiment requiring simple (not discriminative) motor response revealed that the pP2 and the aIns activity were nearly absent after the 250 ms; this result confirmed that the aIns activity at this stage is associated with the decisional processes, and not with the motor response per se. The present investigation shed new lights on the insular contribution to perceptual decision-making, and opens to the possibility of assessing the aIns activity via ERP analysis. PMID- 29124351 TI - NeuroSeg: automated cell detection and segmentation for in vivo two-photon Ca2+ imaging data. AB - Two-photon Ca2+ imaging has become a popular approach for monitoring neuronal population activity with cellular or subcellular resolution in vivo. This approach allows for the recording of hundreds to thousands of neurons per animal and thus leads to a large amount of data to be processed. In particular, manually drawing regions of interest is the most time-consuming aspect of data analysis. However, the development of automated image analysis pipelines, which will be essential for dealing with the likely future deluge of imaging data, remains a major challenge. To address this issue, we developed NeuroSeg, an open-source MATLAB program that can facilitate the accurate and efficient segmentation of neurons in two-photon Ca2+ imaging data. We proposed an approach using a generalized Laplacian of Gaussian filter to detect cells and weighting-based segmentation to separate individual cells from the background. We tested this approach on an in vivo two-photon Ca2+ imaging dataset obtained from mouse cortical neurons with differently sized view fields. We show that this approach exhibits superior performance for cell detection and segmentation compared with the existing published tools. In addition, we integrated the previously reported, activity-based segmentation into our approach and found that this combined method was even more promising. The NeuroSeg software, including source code and graphical user interface, is freely available and will be a useful tool for in vivo brain activity mapping. PMID- 29124354 TI - Parathyroid, Thyroid and Recurrent Laryngeal Nerve Anatomy in an Indian Rhinoceros (Rhinoceros unicornis). AB - INTRODUCTION: The parathyroid gland was first identified in the Indian rhinoceros in 1849 by Sir Richard Owen. We performed a necropsy in an Indian rhinoceros, recapitulating Owen's dissection and display what appear to be the initial identification of the recurrent laryngeal nerve in situ and the anatomy and histology of the largest rhinoceros parathyroid glands yet identified. MATERIALS AND METHODS: Patrick T. Rhino, a 41-year-old Indian rhinoceros was born in 1974. His early years were unremarkable. In 2006, he was donated to White Oak Conservation in Yulee, Florida, where he bred and sustained minor injuries. In his geriatric years, he developed a cataract and degenerative joint disease (DJD). At age 41, he developed progressive ataxia and lameness and was euthanized to minimize suffering when he was unable to stand. ROS, FH, SH and medication history were unremarkable. Physical exam was age and species appropriate. Pre mortem serum demonstrated: creat 1.8 mg/dL (0.8-2.1), calcium 10.6 mg/dL (9.7 13.1), phos 3.8 mg/dL (2.5-6.7), alk phos 69 U/L (26-158) and intact PTH 44.1 pg/mL (rhinoceros reference range: unknown). Necropsy revealed intervertebral DJD with thoracic spondylosis, which combined with osteoporosis, resulted in thoracic myelopathy and ataxia. The neck block was sent in formalin to the Yale University School of Medicine. RESULTS: Detailed dissection was performed under loupe magnification. Presumed structures were photographed in situ and biopsied. The thyroid was identified deep to the strap muscles, received its blood supply from the inferior and superior thyroid arteries and was blue in color. The right recurrent laryngeal nerve, identified and photographed in situ for the first time in the rhinoceros, was deep to the inferior thyroid artery and was traced throughout its cervical course. Single parathyroid glands identified on the lateral thyroid lobes received their blood supply from the inferior thyroid arteries and were confirmed histologically. They appear to be the largest parathyroids yet identified in the rhinoceros with estimated weights of 6,280 and 11,000 mg, respectively. Although the etiology of the parathyroid gland enlargement is unknown, the specimen has been preserved recapitulating the dissection performed by Sir Richard Owen. CONCLUSION: The parathyroids, thyroid and recurrent laryngeal nerve were identified in an Indian rhinoceros. This appears to be the first display of the rhinoceros recurrent laryngeal nerve in situ, and the parathyroid glands are the largest yet identified in the rhinoceros. PMID- 29124353 TI - Oligomer-prone E57K-mutant alpha-synuclein exacerbates integration deficit of adult hippocampal newborn neurons in transgenic mice. AB - In the adult mammalian hippocampus, new neurons are constantly added to the dentate gyrus. Adult neurogenesis is impaired in several neurodegenerative mouse models including alpha-synuclein (a-syn) transgenic mice. Among different a-syn species, a-syn oligomers were reported to be the most toxic species for neurons. Here, we studied the impact of wild-type vs. oligomer-prone a-syn on neurogenesis. We compared the wild-type a-syn transgenic mouse model (Thy1-WTS) to its equivalent transgenic for oligomer-prone E57K-mutant a-syn (Thy1-E57K). Transgenic a-syn was highly expressed within the hippocampus of both models, but was not present within adult neural stem cells and neuroblasts. Proliferation and survival of newly generated neurons were unchanged in both transgenic models. Thy1-WTS showed a minor integration deficit regarding mushroom spine density of newborn neurons, whereas Thy1-E57K exhibited a severe reduction of all spines. We conclude that cell-extrinsic a-syn impairs mushroom spine formation of adult newborn neurons and that oligomer-prone a-syn exacerbates this integration deficit. Moreover, our data suggest that a-syn reduces the survival of newborn neurons by a cell-intrinsic mechanism during the early neuroblast development. The finding of increased spine pathology in Thy1-E57K is a new pathogenic function of oligomeric a-syn and precedes overt neurodegeneration. Thus, it may constitute a readout for therapeutic approaches. PMID- 29124355 TI - A Multi-institutional Comparison of Adrenal Venous Sampling in Patients with Primary Aldosteronism: Caution Advised if Successful Bilateral Adrenal Vein Sampling is Not Achieved. AB - INTRODUCTION: In patients with primary aldosteronism (PA), adrenal venous sampling (AVS) is recommended to differentiate between unilateral (UNI) or bilateral (BIL) adrenal disease. A recent study suggested that lateralization could be predicted, based on the ratio of aldosterone/cortisol levels (A/C) between the left adrenal vein (LAV) and inferior vena cava (IVC), with a 100% positive predictive value (PPV). This study aimed to validate those findings utilizing a larger, multi-institutional cohort. METHODS: A retrospective review was performed of patients with PA who underwent AVS from 2 tertiary-care institutions. Laterality was predicted by an A/C ratio of >3:1 between the dominant and non-dominant adrenal. AVS results were compared to LAV/IVC ratios utilizing the published criteria (Lt >= 5.5; Rt <= 0.5). RESULTS: Of 222 patients, 124 (57%) had UNI and 98 (43%) had BIL disease based on AVS. AVS and LAV/IVC findings were concordant for laterality in 141 (64%) patients (69 UNI, 72 BIL). Using only the LAV/IVC ratio, 54 (24%) patients with UNI disease on AVS who underwent successful surgery would have been assumed to have BAH unless AVS was repeated, and 24 (11%) patients with BIL disease on AVS may have been incorrectly offered surgery (PPV 70%). Based on median LAV/IVC ratios (left 5.26; right 0.31; BIL 2.84), no LAV/IVC ratio accurately predicted laterality. DISCUSSION: This multi-institutional study of patients with both UNI and BIL PA failed to validate the previously reported PPV of LAV/IVC ratio for lateralization. Caution should be used in interpreting incomplete AVS data to differentiate between UNI versus BIL disease and strong consideration given to repeat AVS prior to adrenalectomy. PMID- 29124357 TI - ? PMID- 29124359 TI - Letter to the editor on the article "Saccular measurements in routine MRI can predict hydrops in Meniere's disease" by Simon F et al. PMID- 29124356 TI - Low Lifetime Risk of Contralateral Breast Cancer in a Middle-Income Asian Country: Evidence to Guide Post-treatment Surveillance. AB - BACKGROUND: The rate of contralateral risk-reducing mastectomy (CRRM) is increasing in the West with controversial evidence of improved survival in early breast cancer patients. Although uptake of CRRM in Asia appears low, the trends may rise, and there is currently an urgent need to provide evidence for informed decision-making in clinical practice. This study aims to determine the risk of contralateral breast cancer (CBC) and its associated factors in an Asian setting. METHOD: A total of 2937 newly diagnosed patients with stage I and stage II breast cancer in University Malaya Medical Centre between Jan 1993 to Dec 2012 were included in the study. Multinomial logistic regression analysis allowing death to compete with CBC as a study outcome was used; patients with unilateral breast cancer who were alive were taken as reference. A stepwise backward regression analysis including age at diagnosis, ethnicity, family history of breast cancer, TNM stage, hormonal receptor status, HER2 status, chemotherapy, radiotherapy, and hormone therapy was conducted. RESULTS: Fifty women developed CBC, over a median follow-up of 6 years. The 5- and 10-year cumulative risk of contralateral breast cancer was 1.0% (95% CI 0.6-1.4%) and 2.8% (95% CI 2.0-3.6%), respectively. Young age at diagnosis of first cancer, positive family history, and stage I disease were independent predictors of CBC. DISCUSSION: The current study suggests that the risk of CBC is very low in a Southeast Asian setting. Any recommendations or practice of CRRM should be reviewed with caution and patients must be counseled appropriately. PMID- 29124360 TI - Continuum theory: presbyphagia to dysphagia? Functional assessment of swallowing in the elderly. AB - OBJECTIVES: To investigate whether disclosed symptoms (coughing, choking and throat clearing) can be used as early predictors of swallowing disorders in non hospitalized elderly population. In addition, to determine the presence of early findings of swallowing disorders through fiber optic endoscopic evaluation of swallowing (FEES). MATERIALS AND METHODS: One hundred subjects older than 60 years were recruited from local community social meetings for seniors, they fulfilled inclusion criteria, and were given an oral interview and underwent FEES, with findings classified as: (1) saliva stasis; (2) pharyngeal residue; (3) penetration; (4) aspiration; (5) laryngeal sensitivity. RESULTS: Twenty-one percent of subjects declared previous choking, 10% coughing, and 7% throat clearing, 39% had pharyngeal residue; 6% saliva stasis; 9% penetration; 2% aspiration; and 92% laryngeal sensitivity present. Thirty-three percent showed pharyngeal residue without saliva stasis, while only 6% showed positivity for both (p = 0.003). CONCLUSIONS: Our data suggest that health care professionals should be aware that among an apparently healthy population, some subjects may have swallowing disorders without clinical complaints and that a nasolaryngoscopy exam may not be enough to predict dysphagia. We suggest that FEES should be performed to look for surrogate of dysphagia such as pharyngeal residue, laryngeal penetration, and aspiration. PMID- 29124361 TI - Involvement of C-terminal amino acids of a hyperthermophilic serine racemase in its thermostability. AB - Pyrobaculum islandicum is a hyperthermophilic archaeon that grows optimally at 95 100 degrees C. In the previous study, we extensively purified a serine racemase from this organism and cloned the gene for overexpression in Escherichia coli (Ohnishi et al. 2008). This enzyme also exhibits highly thermostable L-serine/L threonine dehydratase activity. In the present study, we aimed to elucidate the molecular mechanisms underlying the high thermostability of this enzyme. A recombinant variant of this enzyme, PiSRvt, constructed by truncating the C terminal 72 amino acids, was compared with the native enzyme, PiSR. The dehydratase activity of PiSR and PiSRvt was found to owe to a homotrimer and a monomer, respectively, that demonstrated high and moderate thermostability, respectively. These observations reveal that the C-terminal region contributes to monomer trimerization that provides the extreme thermostability. PMID- 29124363 TI - Reduced joint-awareness in bicruciate-retaining total knee arthroplasty compared to cruciate-sacrificing total knee arthroplasty. AB - PURPOSE: There is rising impact of patient-reported outcome (PRO) measurement in joint arthroplasty over the past years. Bicruciate-retaining implants have shown more physiologic knee kinematics and provide superior proprioceptive capacities. The aim of this study was to evaluate if the functional properties of this new implant design lead to improved PRO results after total knee arthroplasty (TKA). METHODS: This prospective, controlled trial compares PRO of bicruciate-retaining total knee arthroplasty (BCR-TKA) to unicondylar knee arthroplasty (UKA) and standard posterior-stabilized total knee arthroplasty (PS-TKA). We evaluated 102 patients (34 patients in each group) 18 months postoperatively after knee arthroplasty. Primary outcome measure was the Forgotten Joint Score (FJS). RESULTS: The BCR-group showed the same level of joint awareness as the UKA-group (p = 0.999). The second control group of PS-TKA patients had a lower mean score value in the FJS compared to the BCR-group (p = 0.035) and UKA-group (p = 0.031). There was no correlation of age, gender, body mass index (BMI) and the FJS. No relevant floor- or ceiling effects occurred. CONCLUSIONS: This study found reduced joint awareness for BCR-TKA compared to a standard total knee arthroplasty. The score values of the BCR-group were equal to the UKA-group. Further prospective, randomized studies to investigate long-term survivorship of bicruciate-retaining implants are needed. LEVEL OF EVIDENCE: Level II. PMID- 29124362 TI - Arthroscopic one-tunnel transosseous foveal repair for triangular fibrocartilage complex (TFCC) peripheral tear. AB - PURPOSE: Arthroscopic repair of a peripheral triangular fibrocartilage complex (TFCC) tear is a promising, minimally invasive surgical technique, especially in patients with symptomatic distal radioulnar joint (DRUJ) instability. The purpose of this study was to evaluate the clinical result of arthroscopic one-tunnel transosseous foveal repair for peripheral TFCC tears. METHODS: Sixteen patients who underwent TFCC foveal repair were retrospectively evaluated. The mean follow up period was 31.1 months. The torn TFCC of all patients was repaired with the arthroscopic one-tunnel transosseous foveal repair technique. Postoperative outcomes were evaluated using the visual analogue scale (VAS) for pain, wrist range of motion, grip strength, Mayo wrist score, Quick Disabilities of the Arm, Shoulder and Hand (Quick DASH) score, and postoperative complications. RESULTS: On arthroscopic examination, all 16 patients showed Palmer 1B type peripheral TFCC tears with foveal disruption. Among them, 13 patients had a proximal component TFCC tear (Atzei class 3) and 3 patients had a complete TFCC tear (Atzei class 2). At the final follow-up, the mean range of the pronation supination arc (P = 0.03) and grip strength (P = 0.001) was significantly increased. Twelve patients had normal stability of the DRUJ and six patients showed mild laxity compared with the contralateral side. The mean VAS for pain perception decreased from 3.7 to 0.8 (P = 0.001). The modified Mayo wrist (P = 0.001) and Quick DASH (P = 0.001) scores showed significant functional improvement. No surgery-related complications occurred. CONCLUSIONS: The present study shows that arthroscopic one-tunnel transosseous repair is a good treatment strategy for TFCC foveal tears in terms of reliable pain relief, functional improvement, and re-establishment of DRUJ stability. PMID- 29124364 TI - Sagittal magnetic resonance imaging-scan orientation significantly influences accuracy of femoral posterior condylar offset measurement. AB - BACKGROUND: In total knee arthroplasty the femoral posterior condylar offset (PCO) may serve as a potential branch for correct femoral component positioning. The technique of adjusting the sagittal magnetic resonance imaging (MRI)-scan on which it is measured has not been investigated in previous literature, but may be subject to variances due to knee joint positioning or axial localizer scan angulation. The purpose of this study was to investigate the effect of simulated femur rotation on the accuracy of PCO measurement. MATERIALS AND METHODS: Ten asymptomatic knee joints underwent MRI investigations. A sagittal plane perpendicular to the transepicondylar axis was defined as the true-sagittal plane (tsP). Sagittal images were reformatted in the tsP and angulated by 5 degrees and - 5 degrees in medial and lateral direction. In total each knee received three scans in 0 degrees , 5 degrees and - 5 degrees axial localizer scan angulation. Medial and lateral PCO measurement was performed in each MRI-scan angulation. RESULTS: Simulated external rotation decreased medial PCO size by 1.7 mm (95% CI 0.5994-3.127) (p = 0.012), and simulated internal rotation increased medial PCO size by 2.1 mm (95% CI 1.142-2.994) (p = 0.001). Lateral PCO size increased by 1.9 mm (95% CI 0.5660-3.412) and decreased by 2.1 mm (95% CI 1.142 2.994) with simulated external and internal rotation, respectively (p = 0.011; p = 0.0007). CONCLUSION: This study shows the high sensitivity of medial and lateral PCO measurements to small changes of MRI axial localizer scan angulations simulating minor degrees of internal or external femur rotation. Thus, absolute PCO values should be interpreted with caution if the sagittal image acquisition is not standardized. PMID- 29124365 TI - Change in reimbursement and costs in German oncological head and neck surgery over the last decade: ablative tongue cancer surgery and reconstruction with split-thickness skin graft vs. microvascular radial forearm flap. AB - OBJECTIVES: Defects after ablative tongue cancer surgery can be reconstructed by split-thickness skin grafts or free microvascular flaps. The different surgical options may influence costs, reimbursement, and therefore possible profits. Our goal was to analyze the development of these parameters for different procedures in head and neck reconstruction in Germany over the last decade. MATERIALS AND METHODS: After tumor resection and neck dissection of tongue cancer, three different scenarios were chosen to calculate costs, reimbursement, length of stay (LoS), and profits. Two options considered were reconstruction by split-thickness skin graft with (option Ia) and without (option Ib) tracheotomy. In addition, we analyzed microvascular reconstruction with radial forearm flap (option II). Furthermore, unsatisfactory results after options Ia and Ib may make secondary tongue plastic with split-thickness skin grafting necessary (option I+). The calculations were performed considering the German Diagnosis Related Group (DRG) system and compared to the specific DRG cost data of 250 German reference hospitals. RESULTS: The overall average length of stay (aLoS) declined from 16.7 to 12.8 days with a reduction in every option. Until 2011, all options showed similar accumulated DRG reimbursement. From 2012 onwards, earnings almost doubled for option II due to changes in the DRG allocation. As was expected, the highest costs were observed in option II. Profits (reimbursement minus costs) were also highest for option II (mean 2052 ?, maximum 3630 Euros in 2015) followed by options Ia (765 ?) and Ib/I+ (681 ?). Average profits over time would be 17 to 19% higher if adjusted for inflation. CONCLUSIONS: We showed the development of the DRG allocation of two commonly used methods of reconstruction after ablative tongue cancer surgery and the associated LoS, reimbursement, costs, and profits. As expected, the highest values were found for microvascular reconstruction. Microvascular reconstruction may also be the primary choice of treatment from a medical point of view. However, prolonged operation times, intensive care, and hospital stay in connection with complex microvascular operations can easily turn profits into losses as opposed to the results of simple, reliable, and fast split thickness skin grafting. The inflation rate influences profits in reimbursement systems where costs are based on a previous period of time. CLINICAL RELEVANCE: Surgeons find themselves daily in an area of conflict between economic interests and medical decision-making. Due to its multidimensional aspects, the choice of the reconstructive technique should be primarily based on the best medical care for the patient. But there should also be awareness of the economic risk of all three surgical procedures. PMID- 29124366 TI - Interannual water quality changes at the head of a tropical estuary. AB - Waters entering the small estuaries of the Brazilian north-east originate from drainage basins that cross semi-arid and tropical rainforest areas at various levels of use and conservation. Such rivers are often under heavy demand for water supply and other services, such as effluent dilution. The present study examines four consecutive years (2006-2009) of water quality-monitoring data divided by season (rainy and dry) just before the Goiana River enters its estuary. The environmental variables are largely controlled by rainfall patterns. The water temperatures are consistently above 25 degrees C, which impairs dissolved oxygen levels (3.1 to 6.7 mg L-1) and may suggest eutrophication. By contrast, biochemical oxygen demand, percentage O2 saturation and total phosphorous (which are eutrophication indicators) do not show non-compliant levels, according to local legislation. Although the monitoring stations surround a municipal centre, the estuary is downstream from this area, the main uses of which are artisanal fisheries, nature conservation, leisure and aquaculture. Therefore, continuous monitoring and long-term analysis of the resulting water quality are important. PMID- 29124369 TI - Exploring the regioselectivity in the cycloaddition of azides to alkynes catalyzed by dinuclear copper clusters (Cu2AAC reaction) using the topologies of ?2 rho (r) and ??2 rho (r). AB - The regioselectivity of the dinuclear-Cu(I)-catalyzed version of the Huisgen reaction, abbreviated in this paper to Cu2AAC, was analyzed using quantum topological methods in order to study how the electronic charge distribution evolved along different reaction paths. Electronic densities were computed at the LC-wPBE/6-311++G(2d,2p)//LC-wPBE/6-311++G(d,p) level. The presence of two copper ions in the catalyst was found to lead to an electrophilic site in the external alkyne carbon that, in a generalized Sharpless-type mechanism, undergoes an initial donor-acceptor interaction with the azide molecule, but with an inverted electrophile-nucleophile pattern when compared with the corresponding mononuclear process (CuAAC). Differences between the two competitive dinuclear-Cu(I) catalyzed pathways, 1,4-Cu2AAC and 1,5-Cu2AAC, arise mainly from the presence of secondary interactions in the 1,5-Cu2AAC pathway and because different nitrogen atoms are involved in the formation of the second N...C bond. Overall descriptions of both processes are provided. PMID- 29124367 TI - Saccharomyces cerevisiae proteinase A excretion and wine making. AB - Proteinase A (PrA), the major protease in Saccharomyces cerevisiae, plays an essential role in zymogen activation, sporulation, and other physiological processes in vivo. The extracellular secretion of PrA often occurs during alcoholic fermentation, especially in the later stages when the yeast cells are under stress conditions, and affects the quality and safety of fermented products. Thus, the mechanism underlying PrA excretion must be explored to improve the quality and safety of fermented products. This paper briefly introduces the structure and physiological function of PrA. Two transport routes of PrA, namely, the Golgi-to-vacuole pathway and the constitutive Golgi-to-plasma membrane pathway, are also discussed. Moreover, the research history and developments on the mechanism of extracellular PrA secretion are described. In addition, it is briefly discussed that calcium homeostasis plays an important role in the secretory pathway of proteins, implying that the regulation of PrA delivery to the plasma membrane requires the involvement of calcium ion. Finally, this review focuses on the effects of PrA excretion on wine making (including Chinese rice wine, grape wine, and beer brewage) and presents strategies to control PrA excretion. PMID- 29124370 TI - Popular Weight Loss Strategies: a Review of Four Weight Loss Techniques. AB - PURPOSE OF REVIEW: The purpose of this paper is to review the epidemiology of obesity and the most recent literature on popular fad diets and exercise regimens that are used for weight loss. The weight loss plans that will be discussed in this article include juicing or detoxification diets, intermittent fasting, the paleo diet, and high intensity training. RECENT FINDINGS: Despite the growing popularity of fad diets and exercise plans for weight loss, there are limited studies that actually suggest these particular regimens are beneficial and lead to long-term weight loss. Juicing or detoxification diets tend to work because they lead to extremely low caloric intake for short periods of time, however tend to lead to weight gain once a normal diet is resumed. Both intermittent fasting and the paleo diet lead to weight loss because of overall decreased caloric intake as well. Lastly, studies on short bursts of high intensity training have shown remarkable weight loss and improvements in cardiovascular health. Review of the literature does suggest that some fad diets and exercise plans do lead to weight loss; however, the studies are quite limited and are all based on the concept of caloric restriction. PMID- 29124371 TI - Rare earth and precious elements in the urban sewage sludge and lake surface sediments under anthropogenic influence in the Republic of Benin. AB - Nowadays, sewage sludge and water bodies are subjected to heavy pollution due to rapid population growth and urbanization. Heavy metal pollution represents one of the main challenges threatening our environment and the ecosystem. The present work aims to evaluate the contamination state of the sewage sludge and lake sediments in the Republic of Benin. Twenty metallic elements including 15 rare earth elements (Eu, Sb, Cs, Nd, Pr, Gd, La, Ce, Tb, Sm, Dy, Ho, Eu, Yb, and Lu) and five precious elements (Ag, Au, Pd, Pt, and Ru) were investigated using inductive plasma-mass spectrometry. Results showed broad range concentrations of the elements. Ce, La, and Nd were present in both sediments and sewage sludge at concentrations ranging 5.80-41.30 mg/kg dry matter (DM), 3.23-15.60 mg/kg DM, and 2.74-19.26 mg/kg DM, respectively. Pr, Sm, Gd, Tb, Dy, Eu, Er, Yb, Cs, Ho, and Tm concentrations were lower (0.02-5.94 mg/kg DM). Among precious elements, Ag was detected at the highest concentration in all sites (0.43-4.72 mg/kg DM), followed by Pd (0.20-0.57 mg/kg DM) and Au (0.01-0.57 mg/kg DM). Ru and Pt concentrations were < 0.20 mg/kg DM in all samples. Pollution indices and enrichment factor indicated a strong to severe enrichment of the elements, mainly Ce and precious elements in both sediments and sewage sludge. This revealed a growing anthropogenic input which was also implied by principal component analysis. The evaluation of pollution loading index (PLI) indicated a moderate to strong contamination (0.12 <= PLI <= 0.58; 37 <= PLI <= 114, respectively, for rare earth elements and precious elements), while the degree of contamination indicated a moderate polymetallic contamination for rare earth elements and significant contamination for precious elements. PMID- 29124372 TI - Optimal Silicon Doping Layers of Quantum Barriers in the Growth Sequence Forming Soft Confinement Potential of Eight-Period In0.2Ga0.8N/GaN Quantum Wells of Blue LEDs. AB - The features of eight-period In0.2Ga0.8N/GaN quantum wells (QWs) with silicon (Si) doping in the first two to five quantum barriers (QBs) in the growth sequence of blue light-emitting diodes (LEDs) are explored. Epilayers of QWs' structures are grown on 20 pairs of In0.02Ga0.98N/GaN superlattice acting as strain relief layers (SRLs) on patterned sapphire substrates (PSSs) by a low pressure metal-organic chemical vapor deposition (LP-MOCVD) system. Temperature dependent photoluminescence (PL) spectra, current versus voltage (I-V) curves, light output power versus injection current (L-I) curves, and images of high resolution transmission electron microscopy (HRTEM) of epilayers are measured. The consequences show that QWs with four Si-doped QBs have larger carrier localization energy (41 meV), lower turn-on (3.27 V) and breakdown (- 6.77 V) voltages, and higher output power of light of blue LEDs at higher injection current than other samples. Low barrier height of QBs in a four-Si-doped QB sample results in soft confinement potential of QWs and lower turn-on and breakdown voltages of the diode. HRTEM images give the evidence that this sample has relatively diffusive interfaces of QWs. Uniform spread of carriers among eight QWs and superior localization of carriers in each well are responsible for the enhancement of light output power, in particular, for high injection current in the four-Si-doped QB sample. The results demonstrate that four QBs of eight In0.2Ga0.8N/GaN QWs with Si doping not only reduce the quantum-confined Stark effect (QCSE) but also improve the distribution and localization of carriers in QWs for better optical performance of blue LEDs. PMID- 29124373 TI - "The Chignon Mastopexy": A Double Glandular Suspended Flaps for an Auto Augmentation Effect. AB - BACKGROUND: Many mastopexy techniques have been described in the literature focusing on the new nipple areolar complex position and the breast deflation treatment, but only few of them detailed the glandular volume redistribution to avoid the use of implants. We describe a mastopexy procedure that brings the maximum of the volume to the central part of the breast. We compare the procedure to a "chignon" hair style way to vulgarize the technique and simplify its comprehension. METHODS: Breast volume is reshaped by the use of a vertical mastopexy and two deepithelized glandular flaps sutured for the first one to the pectoralis major fascia and for the second one to the contralateral flap. A lateral release of two fasciocutaneous flaps allows the final vertical suture. RESULTS: From January 2011 to January 2016, 30 patients, between 85 operated on for ptotic breasts, were treated with this technique. The follow-up period is from 6 months to 5 years. Esthetic improvement in the breast shape and its projection were achieved in 90%. The illusion of augmentation of the final volume was noticed in 70% of the cases. No complications were noticed during this study. CONCLUSION: We describe an easy and reliable technique for breast lift, based on a mastopexy method that changes the architecture of the breast to bring the maximum of its volume to the central part. The technique is rewarding for moderate volumes when the ptosis is more related to a glandular sagging than to a cutaneous looseness and breast deflation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or Online Instructions to Authors www.springer.com/00266 . PMID- 29124374 TI - Complications and Treatment Strategy After Breast Augmentation by Polyacrylamide Hydrogel Injection: Summary of 10-Year Clinical Experience. AB - From 1997 to 2006, polyacrylamide hydrogel (PAAG) was approved for use in China as a permanent filler for breast augmentation, and it is estimated that 200,000 women have undergone PAAG injection since then. After injection, complications such as pain, mass, hematoma, asymmetry, migration, infection, and even cancer continue to emerge. Because of the potential toxicity and unstable nature of the material and the nonstandardized injection layers, complications after PAAG injection breast augmentation are often complex and difficult to treat. The only treatment for these complications is debridement surgery, which includes PAAG evacuation, capsule remove, lesion excision, and mastectomy. Currently, although there are a variety of surgical methods for complications after PAAG injection, there is a lack of consensus regarding the diagnosis and treatment. We systematically review the literature and summarize our experience of diagnosis and treatment of complications after PAAG injection in our hospital over the past 10 years. To date, this is the first attempt to propose a diagnostic classification for PAAG injection breast augmentation and to set out a treatment strategy based on this classification. Although the China Food and Drug Administration withdrew its approval in 2006, PAAG is still being used illegally in some areas, and the patient population is widespread. This study aims to provide a more comprehensive understanding of PAAG complications to drive the standard diagnosis and treatment based on clinical classification, and to provide references for the future development of safer injectable products. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29124375 TI - Reductive Augmentation of the Breast. AB - AIM: Although breast reduction surgery plays an invaluable role in the correction of macromastia, it almost always results in a breast lacking in upper pole fullness and/or roundness. We present a technique of breast reduction combined with augmentation termed "reductive augmentation" to solve this problem. The technique is also extremely useful for correcting breast asymmetry, as well as revising significant pseudoptosis in the patient who has previously undergone breast augmentation with or without mastopexy. METHODS: An evolution of techniques has been used to create a breast with more upper pole fullness and anterior projection in those patients desiring a more round, higher-profile appearance. Reductive augmentation is a one-stage procedure in which a breast augmentation is immediately followed by a modified superomedial pedicle breast reduction. Often, the excision of breast tissue is greater than would normally be performed with breast reduction alone. RESULTS: Thirty-five patients underwent reductive augmentation, of which 12 were primary surgeries and 23 were revisions. There was an average tissue removal of 255 and 227 g, respectively, per breast for the primary and revision groups. Six of the reductive augmentations were performed for gross asymmetry. Fourteen patients had a previous mastopexy, and 3 patients had a previous breast reduction. The average follow-up was 26 months. CONCLUSIONS: Reductive augmentation is an effective one-stage method for achieving a more round-appearing breast with upper pole fullness both in primary breast reduction candidates and in revisionary breast surgery. This technique can also be applied to those patients with significant asymmetry. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29124376 TI - An Alternative Rhinoplasty Technique: Rotational Spreader Flap ("Rabbit Flap"). AB - BACKGROUND: In modern rhinoplasty, septal cartilage is the most commonly used graft material. It is a big challenge if septal cartilage is insufficient. We present an alternative technique named the "rabbit flap," created from the cephalic portion of the lower lateral cartilage to show its effectiveness on nasolabial angle, nasal axis deviation, and nasal dorsal line. METHODS: An alternative flap, called a "rabbit flap," is constituted from the cephalic portion of the lower lateral cartilage (LLC). The key for this flap's success is in not cutting the connection between the lateral and medial crus of the alar cartilage. The flap is rotated and placed between the upper lateral cartilage and the septum to ensure a spreader graft effect; it can also be moved forward and backward to adjust the nasal tip rotation. Patients whose minimum width of LLC was 12 mm were included in this study. We subjectively evaluated the results of this technique for 24 patients who completed the rhinoplasty outcomes evaluation (ROE) questionnaire and objectively by measuring the nasal axis and nasolabial angles in the preoperative and postoperative first-year periods. RESULTS: There were significant improvements in ROE, nasal axis deviation, and nasolabial angle scores when preoperative and postoperative first-year controls were compared (p < 0.001). We also observed no complications. CONCLUSIONS: With this technique, we can correct both a nasal tip rotation and a mild nasal axis deviation. Moreover, we can achieve a proper nasal dorsal line and prevent an inverted V deformity. By expanding the internal nasal valve, a functionally effective surgery can be performed. However, the LLC must be strong enough to avoid alar collapse. In light of our results, we believe that the technique we call the "rabbit flap" can be used as an alternative rhinoplasty technique. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29124378 TI - Usefulness of Cross-Linked Human Acellular Dermal Matrix as an Implant for Dorsal Augmentation in Rhinoplasty. AB - BACKGROUND: Asian noses are relatively small and flat compared to Caucasians; therefore, rhinoplasty procedures often focus on dorsal augmentation and tip projection rather than reduction in the nasal framework. Various autologous and alloplastic implant materials have been used for dorsal augmentation. Recently, human acellular dermal matrices have been introduced as an implant material for dorsal augmentation, camouflaging autologous implants without an additional donor site. Here, we introduce a cross-linked human acellular dermal matrix as an implant material in augmentation rhinoplasty and share the clinical experiences. METHODS: Eighteen patients who underwent augmentation rhinoplasty using acellular dermal matrix from April 2014 to November 2015 were reviewed retrospectively. Clinical outcomes and complications were assessed at the outpatient clinic during the follow-up period ranging from 8 to 38 months. Contour changes were assessed through comparison of preoperative and postoperative photographs by two independent plastic surgeons. Patient satisfaction was assessed at the outpatient clinic by six questions regarding aesthetic and functional aspects. RESULTS: Postoperative photographs demonstrated the height of the nasal dorsum did not decrease over time except two patients whose ADM was grafted into a subperiosteal pocket. Others who underwent supraperiosteal implantation showed acceptable maintenance of dorsal height. No major complication was reported. Overall, patient satisfaction scored 81.02 out of 100. CONCLUSIONS: Cross-linked human ADM has advantages of both autogenous and alloplastic materials. The surgical results remain stable without complications. Therefore, it is a suitable alternative implant material for dorsal augmentation in rhinoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29124377 TI - Trendy Tattoos-Maybe a Serious Health Risk? AB - BACKGROUND: The literature reports many cases of cutaneous malignancy in the setting of skin tattoos. In this study, we review the reported incidence of and risk factors for tattoo-associated skin cancer. METHODS: A PubMed literature review was performed for all cases of tattoo-associated skin cancer, including squamous cell carcinoma, basal cell carcinoma, malignant melanoma, keratoacanthoma, and other rare skin malignancies (source: PubMed/until June 2017). RESULTS: The authors identified 51 publications and 63 total cases of tattoo-associated skin cancer. We also report on a single new case of tattoo associated skin cancer observed at one of our co-authors' institutions. Among these 64 total cases, 58% were associated with black and blue inks and 34% were associated with red ink. CONCLUSIONS: Overall, while the strength of association remains unclear, the literature reports many cases of tattoo-associated skin cancer. Among these cases, black, blue, and red inks were particularly worrisome for their carcinogenic potential. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29124379 TI - Use of the BREAST-QTM Survey in the Prospective Evaluation of Reduction Mammaplasty Outcomes. AB - INTRODUCTION: BREAST-QTM is a patient-reported outcomes survey instrument with a specific module that evaluates breast reduction surgery. It allows assessment of patient's satisfaction with received treatment and evaluates the impact of surgery on different aspects of the patient's quality of life. This article aims to assess the satisfaction and quality of life of patients who underwent reduction mammaplasty. MATERIALS AND METHODS: Women aged between 18 and 60 years, with a body mass index ranging from 19 to 30 kg/m2, who were already scheduled for reduction mammaplasty, were included in the study. The Brazilian version of the BREAST-QTM Reduction/Mastopexy Module (preoperative 1.0 and postoperative 1.0 versions) was self-applied preoperatively and 1 and 6 months after the operation. RESULTS: One hundred and seven patients were included in the study and completed the 6-month follow-up. The median age was 33 years, and the median preoperative body mass index was 25 kg/m2. The superomedial pedicle was used in 96.3% of the cases, and the total median weight of the resected breast was 1115 g. There was a significant improvement in the scores of the scales: Psychosocial well-being, Sexual well-being, Physical well-being, and Satisfaction with the breasts compared to the preoperative assessment (p < 0.0001). The scales Satisfaction with the NAC and Satisfaction with the outcome, available only in the postoperative version, demonstrated high satisfaction rates at the two postoperative periods evaluated. CONCLUSION: Reduction mammaplasty improved the quality of life and provided high levels of patient satisfaction with outcomes 1 and 6 months postoperatively. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29124380 TI - Chemoembolisation for hepatocellular carcinoma with bile duct invasion: is preprocedural biliary drainage mandatory? AB - PURPOSE: To determine the necessity of preprocedural biliary drainage prior to chemoembolisation for hepatocellular carcinoma (HCC) with bile duct invasion. MATERIALS AND METHODS: The study included 52 patients who received chemoembolisation for unresectable HCC invading bile duct and causing hyperbilirubinemia (>3 mg/dL). Patients were divided into three groups according to biliary drainage and its effect: effective drainage (n=21), ineffective drainage (n=17), and non-drainage (n=14). Thirty-day mortality, length of hospitalisation, adverse events recorded using Common Terminology Criteria for Adverse Events (CTCAE), survival, and tumour response was compared among three groups. RESULTS: Thirty-day mortality rates were 14.3% (n=3), 17.6% (n=3), and 7.1% (n=1) for effective, ineffective, and non-drainage groups, respectively, and did not differ significantly among groups (p=0.780). The mean length of hospitalisation was shorter in non-drainage group compared to ineffective drainage group (12.1+/-11.4 vs 34.1+/-29.6 days, p=0.012). Mean differences in CTCAE grade for laboratory parameters before and after chemoembolisation were not significantly different among three groups. Survival among three groups was not significantly different (p=0.239-0.825). The tumour response was also not significantly different among three groups (p=0.679). CONCLUSION: Biliary drainage may not be mandatory prior to chemoembolisation in patients with HCC invading the bile duct. KEY POINTS: * Chemoembolisation without biliary drainage can be performed for icteric HCC. * Chemoembolisation without biliary drainage is not accompanied by increased adverse events. * Preprocedural biliary drainage may not be mandatory for chemoembolisation for icteric HCC. PMID- 29124381 TI - Intraprocedural 3D perfusion measurement during chemoembolisation with doxorubicin-eluting beads in liver metastases of malignant melanoma. AB - OBJECTIVES: To study feasibility and validity of a new software application for intraprocedural assessment of perfusion during chemoembolisation of melanoma metastases. METHODOLOGY: In a prospective phase-II trial, ten melanoma patients with liver-only metastases underwent chemoembolisation with doxorubicin-eluting beads (DEBDOX-TACE). Tumour perfusion was evaluated immediately before and after treatment at cone beam computer tomography (CBCT) using a new software application. For control and comparison, patients underwent perfusion measurement via contrast-enhanced multidetector CT (MDCT) before and after treatment. RESULTS: CBCT showed 94.7 % reduction in perfusion in metastases after DEBDOX TACE, whereas MDCT showed 96.8 %. Reduction in perfusion after treatment was statistically significant (p < 0.01) for both methods. The additional time needed for data acquisition during treatment was 5 min per case or less; the post processing data analysis was 10 min or less. Perfusion imaging was associated with additional contrast agent and patient exposure to radiation (dose-length product [DLP]): 18 ml and 394 mGy*cm in CBCT and 100 ml and 446 mGy*cm in MDCT, respectively. CONCLUSIONS: Reduction in perfusion of melanoma metastases after DEBDOX-TACE can be reliably assessed during the intervention via perfusion software at CBCT. Data acquisition and analysis require additional time but can be easily performed during the treatment. KEY POINTS: * Tumour perfusion of melanoma metastases can be assessed at cone beam CT. * The software shows a significant decrease of tumour perfusion after DEBDOX-TACE. * Data acquisition and analysis require an acceptable additional time during the procedure. * CBCT requires less radiation exposure and contrast for perfusion study than MSCT. * This software can monitor the course of DEBDOX-TACE in melanoma metastases. PMID- 29124382 TI - Use of whole body CT to detect patterns of CPR-related injuries after sudden cardiac arrest. AB - AIMS AND OBJECTIVES: We have recently implemented a dedicated sudden cardiac arrest (SCA) - whole-body computed tomography (WBCT) protocol to evaluate SCA patients with return of spontaneous circulation (ROSC) following cardiopulmonary resuscitation (CPR). The aim of this study is to evaluate the number and pattern of CPR-related injuries in ROSC patients with SCA-WBCT. METHODS AND MATERIALS: Single-centre retrospective review of 39 patients (13 female; 20 male, mean age 51.8 years) with non-traumatic, out-of-hospital SCA and ROSC and evaluation with dedicated SCA-WBCT over a 10-month period. RESULTS: In-hospital mortality was 54%. CPR-related injuries were detected in 85% (33/39). Chest injuries were most common on WBCT: 85% (33) subjects had rib fractures (mean of 8.5 fractures/subject); 31% (12) sternal fractures; 13% (5) mediastinal haematoma; 10% (4) pneumothorax; 8% (3) pneumomediastinum and 3% (1) haemothorax. Three subjects (8%) had abdominal injuries on WBCT, including one hepatic haematoma with active haemorrhage. CONCLUSION: CPR-related injuries on WBCT after ROSC are common, with serial rib fractures detected most commonly. An unexpectedly high rate of abdominal injuries was detected on SCA-WBCT. Radiologists need to be attuned to the spectrum of CPR-related injuries in WBCT, including abdominal injuries and subtle rib fractures. KEY POINTS: * CPR frequently causes injuries. * Radiologists should be aware of the spectrum of CPR related injuries. * Rib fractures are frequent and radiologic findings often subtle. * Clinically unexpected abdominal injuries may be present. PMID- 29124383 TI - Medial temporal lobe atrophy ratings in a large 75-year-old population-based cohort: gender-corrected and education-corrected normative data. AB - OBJECTIVES: To find cut-off values for different medial temporal lobe atrophy (MTA) measures (right, left, average, and highest), accounting for gender and education, investigate the association with cognitive performance, and to compare with decline of cognitive function over 5 years in a large population-based cohort. METHODS: Three hundred and ninety 75-year-old individuals were examined with magnetic resonance imaging of the brain and cognitive testing. The Scheltens's scale was used to assess visually MTA scores (0-4) in all subjects. Cognitive tests were repeated in 278 of them after 5 years. Normal MTA cut-off values were calculated based on the 10th percentile. RESULTS: Most 75-year-old individuals had MTA score <=2. Men had significantly higher MTA scores than women. Scores for left and average MTA were significantly higher in highly educated individuals. Abnormal MTA was associated with worse results in cognitive test and individuals with abnormal right MTA had faster cognitive decline. CONCLUSION: At age 75, gender and education are confounders for MTA grading. A score of >=2 is abnormal for low-educated women and a score of >=2.5 is abnormal for men and high-educated women. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later. KEY POINTS: * Gender and education are confounders for MTA grading. * We suggest cut-off values for 75 year-olds, taking gender and education into account. * Males have higher MTA scores than women. * Higher MTA scores are associated with worse cognitive performance. PMID- 29124385 TI - Tea and coffee consumption in relation to glioma: a case-control study. AB - PURPOSE: Data on the link between tea and coffee consumption and risk of glioma are controversial. We aimed to examine the association between tea and coffee consumption and glioma in Iranian adults. METHODS: In this hospital-based case control study, we enrolled 128 pathologically confirmed new cases of glioma and 256 age- and sex-matched controls. Dietary intakes of study participants including tea and coffee consumption was assessed using the validated Block format 123-item semi-quantitative FFQ. Participants were categorized based on tertiles of tea and coffee consumption. Data on potential confounders were also collected through the use of pre-tested questionnaire. RESULTS: Individuals with the greatest tea consumption were less likely to have glioma compared with those with the lowest consumption (0.36; 0.20-0.68). This inverse association was not changed after controlling for energy intake. The association remained statistically significant even after taking other potential confounders, including dietary intakes of red and processed meats, legumes and nuts, fruits, salt and mutual effects of tea and coffee consumption, into account (0.33; 0.13 0.86). Additional adjustments for BMI did not alter the association. After controlling for potential confounders, including dietary intakes and BMI, coffee consumption was inversely associated with odds of glioma; such that individuals in the top category of coffee consumption were 91% less likely to have glioma compared with those in the bottom category (0.09; 0.03-0.24). Considering coffee and tea intake combined, those in the highest tertile were 65% less likely to have glioma compared with those in the lowest tertile (0.35; 0.15-0.83). CONCLUSION: We found an inverse association between tea and coffee consumption and odds of glioma, even after controlling for a wide range of confounders. PMID- 29124384 TI - Diagnostic performance of computed tomography angiography in the detection of coronary artery in-stent restenosis: evidence from an updated meta-analysis. AB - OBJECTIVES: To evaluate the performance of computed tomography angiography (CTA) >=64 slices for detecting coronary in-stent restenosis (ISR) and determine the influence of separate characteristics on diagnostic accuracy. METHODS: We searched the PubMed, EMBASE and Cochrane databases for studies of CTA >=64 slices in diagnosing ISR. We pooled data on bivariate modelling, and subgroup analysis was also performed. RESULTS: A total of 35 studies involving 4131 stents were included. The pooled positive likelihood ratio (LR+) and the negative likelihood ratio (LR-) were 14.0 and 0.10, for CTA in diagnosis-significant ISR >=50%. LR+ and LR- were similar between CTA >64 slices versus 64 slices (both P > 0.99). LR- (0.10) was good for ruling out suspected ISR for <3-mm diameter. Time between CTA and stent implantation >6 months did not affect the ability of CTA for the high LR+ (12.3) and the LR- (0.10). Thick-strut stents >=100 MUm or bifurcation stenting demonstrated inferior accuracy, which was unfavourable for stent imaging. CONCLUSIONS: With the high LR+ and LR- of CTA, patients with ISR may be appropriate for non-invasive angiographic follow-up. However, CTA imaging seems unsuitable for patients with characteristics unfavourable for stent imaging, such as thick-strut stents or bifurcation stenting. KEY POINTS: * CTA may provide accurate information on characteristics of in-stent restenosis lesions. * Using CTA, ISR patients may be appropriate for non-invasive angiographic follow-up. * Stent diameter and the number of slices do not influence CTA. * CTA seems unsuitable for patients with thick-strut stents or bifurcation stenting. PMID- 29124386 TI - Olive oil consumption and 10-year (2002-2012) cardiovascular disease incidence: the ATTICA study. AB - PURPOSE: Olive oil, being rich in mono-unsaturated fatty acids and anti inflammatory compounds, may have protective effects against cardiovascular disease (CVD). The aim of the present work was to examine the association of olive oil consumption with the 10-year CVD incidence in adults without pre existing CVD. METHODS: The ATTICA Study is a prospective, population-based study conducted in the greater metropolitan area of Athens (Attica, Greece). During 2001-2002, 3042 CVD-free adults (1514 men and 1528 women) were voluntarily recruited to the ATTICA study. Among various dietary habits, consumption of olive oil and other fats/oils was assessed at baseline; participants were classified into three groups (no use; mixed use; and exclusive use of olive oil). In 2011 2012, the 10-year study follow-up was performed, recording the fatal/non-fatal CVD incidence in 2020 participants (mean follow-up duration: 8.41 years). RESULTS: After controlling for various covariates, an inverse association between exclusive olive oil use and the risk of developing CVD was observed (relative risk 0.07, 95% CI: 0.01-0.66) compared to those not consuming olive oil. Further adjustment for fibrinogen plasma levels (among various inflammatory markers) showed a significant mediation effect on the previous association. CONCLUSIONS: These findings support exclusive olive oil consumption, a key component of the Mediterranean diet, for the primary CVD prevention, in adults without pre existing disease. Circulating fibrinogen levels appear to play a mediating role in this relationship. PMID- 29124387 TI - Effects of Lactobacillus coryniformis K8 CECT5711 on the immune response to influenza vaccination and the assessment of common respiratory symptoms in elderly subjects: a randomized controlled trial. AB - PURPOSE: Elderly people are particularly vulnerable to seasonal influenza. Therefore, vaccination is strongly recommended. However, the vaccine efficacy is lower in the elderly, owing to immunosenescence. The objective of the present study was to evaluate the ability of the probiotic strain Lactobacillus coryniformis K8 CECT5711 to enhance the immune response to the influenza vaccine in the elderly and to assess the effects on symptoms related to respiratory infections. METHODS: A randomized, double-blind, placebo-controlled trial was conducted between November 2015 and April 2016. A total of 98 nursing home residents, more than 65 years of age were randomly assigned to receive L. coryniformis K8 CECT5711 (3 * 109 CFU/day) or a placebo for 2 weeks before influenza vaccination. The primary outcome was the percentage of seroconversion. The secondary outcomes were the incidence of influenza-like illness (ILI) and respiratory symptoms associated with respiratory infections during the 5-month follow-up period. The serum cytokine and immunoglobulin levels were also evaluated. RESULTS: The percentage of responders to vaccination was higher in the probiotic group than in the control group (p = 0.036). L. coryniformis ingestion was associated with a significantly lower incidence of respiratory symptoms commonly associated with respiratory infections (p = 0.007) and lower consumption of analgesics (p = 0.008). CONCLUSION: The administration of L. coryniformis K8 CECT5711 to an elderly population increased the immune response against the influenza vaccine and decreased symptoms associated with respiratory infections. Probiotic administration may be a natural and safe strategy to improve the efficacy of vaccines and to protect against common respiratory infections in susceptible populations. PMID- 29124388 TI - Measuring the impact of olive pomace enriched biscuits on the gut microbiota and its metabolic activity in mildly hypercholesterolaemic subjects. AB - PURPOSE: Olive pomace is a major waste product of olive oil production but remains rich in polyphenols and fibres. We measured the potential of an olive pomace-enriched biscuit formulation delivering 17.1 +/- 4.01 mg/100 g of hydroxytyrosol and its derivatives, to modulate the composition and metabolic activity of the human gut microbiota. METHODS: In a double-blind, controlled parallel dietary intervention 62 otherwise healthy hypercholesterolemic (total plasma cholesterol 180-240 mg/dl) subjects were randomly assigned to eat 90 g of olive pomace-enriched biscuit (olive-enriched product, OEP) or an isoenergetic control (CTRL) for 8 weeks. Fasted blood samples, 24-h urine and faecal samples were collected before and after dietary intervention for measurement of microbiota, metabolites and clinical parameters. RESULTS: Consumption of OEP biscuits did not impact on the diversity of the faecal microbiota and there was no statistically significant effect on CVD markers. A trend towards reduced oxidized LDL cholesterol following OEP ingestion was observed. At the genus level lactobacilli and Ruminococcus were reduced in OEP compared to CTRL biscuits. A trend towards increased bifidobacteria abundance was observed after OEP ingestion in 16S rRNA profiles, by fluorescent in situ hybridization and by qPCR. Targeted LC-MS revealed significant increases phenolic acid concentrations in 24-h urine following OEP ingestion and 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid, derivatives of hydroxytyrosol, were elevated in blood. A sex effect was apparent in urine small phenolic acid concentrations, and this sex effect was mirrored by statistically significant differences in relative abundances of faecal bacteria between men and women. CONCLUSION: Ingestion of OEP biscuits led to a significant increase in the metabolic output of the gut microbiota with an apparent sex effect possibly linked to differences in microbiota makeup. Increased levels of homovanillic acid and DOPAC, thought to be involved in reducing oxidative LDL cholesterol, were observed upon OEP ingestion. However, OEP did not induce statistically significant changes in either ox-LDL or urinary isoprostane in this study. PMID- 29124389 TI - Dry-field maneuver for controlling the massive intraventricular bleeding during neuroendoscopic procedures. AB - PURPOSE: Massive hemorrhages pose a significant problem in intraventricular endoscopic surgeries. These hemorrhages have the potential to cause mortality and morbidity, particularly in excisional surgeries. Often, the bleeding can be controlled only by cauterization and liquid irrigation, due to the incongruity of the use of antihemorrhagic agents in the fluid. The final option to stop the massive bleeding is the dry-field maneuver. In this study, the effects and clinical results of the dry-field maneuver in bleeding control of a massive bleeding were investigated. METHODS: Dry-field maneuver was retrospectively studied in a patient population that had massive bleeding during intraventricular endoscopic procedures. RESULTS: Dry-field maneuver was used in seven patients. Four of these patients underwent some excisional surgery. The other two patients were operated for an endoscopic third ventriculostomy and one for intraventricular hemorrhage evacuation. It was observed that the hemorrhage in patients stopped rapidly after the dry-field maneuver. Moreover, there was no need for an antihemorrhagic material. CONCLUSION: Dry-field maneuver is an option for providing hemostasis, particularly, for a massive hemorrhage. It also has the potential to be used in elective surgeries because it improves the visual quality. PMID- 29124390 TI - The Liebau phenomenon: a translational approach to new paradigms of CSF circulation and related flow disturbances. AB - PURPOSE: The aim of the study is to provide a comparison between Liebau's effect, underlying the working principles of impedance pumps, and the cerebrospinal fluid (CSF) circulation. METHODS: Gerhard Liebau was a cardiologist with a specific interest in severe aortic regurgitation. Such interest drew his scientific attention to the flow-driven efficiency of valveless pumps. During one of his experiments, he assembled two rubber tubes of different sizes and documented how water could be aspirated against gravity when the tube of larger diameter underwent rhythmic compression. He subsequently tested an elastic tube connected to glass pipes of the same size on both ends, immersed in a water bucket. When the elastic tube was periodically pumped with a finger, a net flow could be observed in both directions; depending on the pumping site on the elastic tube, the flow was directed towards the most closely connected glass tube. The principles of a hydraulic system of different elasticity and compliance were also recently applied to the physiology and fluid dynamics of embryonic hearts. RESULTS: Impedance pumps and the CSF dynamics model are both valveless systems and can both be activated by the effects of the cardiac cycle. The novel hydraulic model of impedance pumps was the foundation for the development of modern valveless micropumps and contributes to explain how the embryonic valveless tubular heart is capable of generating blood flow. CONCLUSIONS: Liebau's effect and the mechanism of impedance pumps can enlighten some of the aspects of CSF dynamics and related flow disturbances. PMID- 29124391 TI - Implementing a digital real-time Hydrocephalus and Shunt Registry to evaluate contemporary pattern of care and surgical outcome in pediatric hydrocephalus. AB - OBJECTIVE: Treatment monitoring and outcome evaluation in pediatric hydrocephalus require gapless documentation regarding surgical and clinical follow-up data beginning from day 1 of treatment in order to apply high quality of care. Endoscopic procedures, shunt insertion and revision surgeries, and individual modifications of valve hardware or pressure settings during follow-up as well as established outcome measurements are highly relevant for complete illustration of the patient's hydrocephalus histories. A digital tool to capture, organize, and analyze comprehensive treatment-related data was estimated long overdue, consequentially developed, and implemented in daily pediatric neurosurgical routine. METHODS: We established a self-contained, network-capable database application to supply and back up clinical information of complete surgical treatment history with implant status and follow up for all institutional pediatric hydrocephalus patients from 1995 to date. The application content has been prospectively complemented since 2012 during daily pediatric neurosurgical routine. Beside surgical data, neurological outcome and quality of life assessment were integrated according to validated scales to be recordable 2, 3, and 5 years after initial surgical intervention for prospective administration. The application is in continuous and problem-free use since implementation offering homogeneous and structured real-time information of surgical and corresponding neurological hydrocephalus-related data. By using an automatized data extraction tool, an exemplary surgical outcome evaluation reviewing institutional ventriculo-peritoneal shunt (VPS) treatment in infants over a period of more than 20 years was performed. To validate applicability, the Registry was successfully implemented in an external institution under identical conditions continuously serving for the same purpose until today. RESULTS: Upon completion of the developing process, the application was successfully implemented into routine clinical workflow of our institution. In total, 579 pediatric hydrocephalus patients entered into the Registry with collectively 1874 corresponding hydrocephalus-related surgeries (9% neuro-endoscopic procedures, 18% temporary CSF-diversions, 73% shunt surgeries) so far. For exemplary surgical outcome analysis, the total volume of complex data sets could easily be reduced stepwise in regard to requested inclusion criteria. The selection process generated conclusive data of 256 institutional pediatric VPS patients providing a median follow-up of 8.5 years. Surgical outcome was evaluated in regard to hydrocephalus etiology, applied valve design, valve augmentation, cause of initial malfunction, time to initial shunt revision, and number of total revisions. CONCLUSION: The pediatric hydrocephalus registry application delivers easy access to contemporary and up-to-date clinical information during daily clinical routine and proves comprehensive value for various scientific purposes. Institutional hydrocephalus etiologies, treatment modalities, and surgical outcome could be reviewed for a selected pediatric patient collective during an interval of more than 20 years and confirmed initial shunt treatment within the first year of age, communicating hydrocephalus and a history of prematurity as significant variables for unfavorable shunt survival and long-term revision rate. At our institution, the Registry emerged to an essential and sustainable tool to capture, organize, and analyze patterns of care in pediatric hydrocephalus patients of all etiologies and treatment modalities. Because of its adaptable and reliable predicate, a prospective multi-center utilization is currently in preparation. PMID- 29124392 TI - Tracking the evolutionary pathway of sex chromosomes among fishes: characterizing the unique XX/XY1Y2 system in Hoplias malabaricus (Teleostei, Characiformes). AB - The Neotropical fish, Hoplias malabaricus, is one of the most cytogenetically studied fish taxon with seven distinct karyomorphs (A-G) comprising varying degrees of sex chromosome differentiation, ranging from homomorphic to highly differentiated simple and multiple sex chromosomes. Therefore, this fish offers a unique opportunity to track evolutionary mechanisms standing behind the sex chromosome evolution and differentiation. Here, we focused on a high-resolution cytogenetic characterization of the unique XX/XY1Y2 multiple sex chromosome system found in one of its karyomorphs (G). For this, we applied a suite of conventional (Giemsa-staining, C-banding) and molecular cytogenetic approaches, including fluorescence in situ hybridization FISH (with 5S and 18S rDNAs, 10 microsatellite motifs and telomeric (TTAGGG) n sequences as probes), comparative genomic hybridization (CGH), and whole chromosome painting (WCP). In addition, we performed comparative analyses with other Erythrinidae species to discover the evolutionary origin of this unique karyomorph G-specific XY1Y2 multiple sex chromosome system. WCP experiments confirmed the homology between these multiple sex chromosomes and the nascent XX/XY sex system found in the karyomorph F, but disproved a homology with those of karyomorphs A-D and other closely related species. Besides, the putative origin of such XY1Y2 system by rearrangements of several chromosome pairs from an ancestral karyotype was also highlighted. In addition, clear identification of a male-specific region on the Y1 chromosome suggested a differential pattern of repetitive sequences accumulation. The present data suggested the origin of this unique XY1Y2 sex system, revealing evidences for the high level of plasticity of sex chromosome differentiation within the Erythrinidae. PMID- 29124393 TI - The systemic environment: at the interface of aging and adult neurogenesis. AB - Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche mediated mechanisms. PMID- 29124395 TI - Non-invasive detection of HPV DNA in exfoliative samples from ophthalmic pterygium: a feasibility study. AB - PURPOSE: The evaluation of a non-invasive detection method for human papilloma virus (HPV) in ophthalmic pterygia. METHODS: Cotton swab samples and corresponding tissue specimens were collected from 21 ophthalmic pterygia of 21 patients. HPV detection and typing were performed by real-time PCR. Discrepancies in HPV detection between swab and tissue samples as well as clinical correlations of findings were examined. RESULTS: HPV DNA was detected in 9 (42.86%) tissue specimens and 8 (38.09%) respective swab specimens. HPV genotypes 33, 39, 45, 56, 59 and 66 were identified in the examined specimens, while more than one strain's HPV type was detected in 2 specimens. HPV presence was significantly correlated with the female gender whereas other clinical associations were not statistically significant. CONCLUSIONS: Findings imply that PCR-mediated HPV detection and typing in exfoliative swab specimens may be employed as a non-invasive diagnostic tool in the management of ophthalmic pterygia. PMID- 29124394 TI - Influence of hippocampal niche signals on neural stem cell functions during aging. AB - The genesis of new neurons from neural stem cells in the adult brain offers the hope that this mechanism of plasticity can be harnessed for the treatment of brain injuries and diseases. However, neurogenesis becomes impaired during the normal course of aging; this is also the primary risk factor for most neurodegenerative diseases. The local microenvironment that regulates the function of resident neural stem cells (the "neurogenic niche") is a particularly complex network of various signaling mechanisms, rendering it especially challenging for the dissection of the control of these cells but offering the potential for the advancement of our understanding of the regulation/misregulation of neurogenesis. In this review, we examine the factors that control neurogenesis in an age-dependent manner, and we define these signals by the extrinsic mechanism through which they are presented to the neural stem cells. Secreted signals, cell-contact-dependent signals, and extracellular matrix cues all contribute to the regulation of the aging neurogenic niche and offer points of therapeutic intervention. PMID- 29124397 TI - Long-term glucocorticoid treatment in patients with polymyalgia rheumatica, giant cell arteritis, or both diseases: results from a national rheumatology database. AB - The objective of this study was to evaluate glucocorticoid (GC) use in patients with polymyalgia rheumatica (PMR), giant cell arteritis (GCA) or both diseases (PMR + GCA) under rheumatological care. Data from patients with PMR (n = 1420), GCA (n = 177) or PMR + GCA (n = 261) from the National Database of the German Collaborative Arthritis Centers were analyzed regarding GCs and related comorbidities (osteoporosis, diabetes and cardiovascular disease), stratified by disease duration (DD). Longitudinal data were analyzed for all patients with a DD <= 2 years at database entry (n = 1397). Three-year data were available for 256 patients. Predictors of GC use >= 3 years were examined by logistic regression analyses. A total of 76% received GCs, and 19% (PMR) to 40% (GCA) received methotrexate. Median GC doses were 12.5 mg (PMR), 11.3 mg (GCA), and 20.0 mg/day (PMR + GCA) in a 0-6-month DD. Median GC doses <= 5 mg/day were reached at a 13 18-month DD in PMR patients and at a 19-24-month DD in GCA or PMR + GCA patients. In the multivariate analysis, baseline methotrexate (OR 2.03, [95% CI 1.27 3.24]), GCs > 10 mg/day (OR 1.65, [1.07-2.55]), higher disease activity (OR 1.12, [1.02-1.23]) (median 0.6 years DD), and female sex (OR 1.63 [1.09-2.43]) were predictive for GC therapy at >= 3 years. Of the examined comorbidities, only osteoporosis prevalence increased within 3 years. GC use for >= 3 years was reported in one-fourth of all the patients. A difficult-to-control disease activity within the first year was a good predictor of long-term GC need. PMID- 29124396 TI - Infections and the risk of psoriatic arthritis among psoriasis patients: a systematic review. AB - Psoriasis and psoriatic arthritis (PsA) are related inflammatory diseases with some shared genetic and environmental risk factors. It has been suggested that environmental factors, including infections, can trigger the development of PsA among psoriasis patients. The aim of this review was to systematically examine available data evaluating the effect of infections on the risk of developing PsA. A systematic search of the Cochrane Library, PubMed, Scopus, and Web of Science was conducted on March 16 2017, in accordance with the PRISMA statement. The following search terms were used along with "psoriatic arthritis": "infections", "risk", "bacteria", and "virus". Abstracts were reviewed and publications meeting the following criteria included: (1) Observational studies on psoriasis and PsA patients, including case-control, cohort, or ecologic studies and (2) presenting original data on the association between infections and PsA. The protocol for this systematic review was registered on PROSPERO (ID: 79432). Twenty-seven original studies presenting data on infections among PsA patients were included. Eight studies showed a statistically significant association between infections and PsA. In addition, seven studies reported mixed result with some statistically significant associations and five studies did not find statistically significant associations. This included studies of bacterial as well as viral pathogens and those of infections in general. The remaining seven studies lacked data to determine statistical significance. Out of all included studies, the total number of included patients was 933 PsA patients and 1611 controls. While the studies summarized did not all provide evidence supporting an association between infections and PsA certain trends emerged. The available data are inconsistent and further studies are needed to verify or refute this purported association. In particular, laryngeal infections and infections involving streptococci should be studied more carefully. PMID- 29124398 TI - Patient perceptions of glucocorticoids in anti-neutrophil cytoplasmic antibody associated vasculitis. AB - Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) are multisystem diseases of small blood vessels, collectively known as the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). This study explores the patient's perspective on the use of glucocorticoids, which are still a mainstay of treatment in AAV. Patients with AAV from the UK, USA, and Canada were interviewed, using purposive sampling to include a range of disease manifestations and demographics. The project steering committee, including patient partners, designed the interview prompts and cues about AAV, its treatment, and impact on health-related quality of life. Interviews were transcribed and analysed to establish themes grounded in the data. A treatment related code was used to focus analysis of salient themes related to glucocorticoid therapy. Fifty interviews were conducted. Individual themes related to therapy with glucocorticoids emerged from the data and were analysed. Three overarching themes emerged: (1) Glucocorticoids are effective at the time of diagnosis and during relapse, and withdrawal can potentiate a flare, (2) glucocorticoids are associated with salient emotional, physical, and social effects (depression, anxiety, irritation, weight gain and change in appearance, diabetes mellitus, effect on family and work); and (3) patient perceptions of balancing the risks and benefits of glucocorticoids. Patients identified the positive aspects of treatment with glucocorticoids; they are fast-acting and effective, but, they voiced concerns about adverse effects and the uncertainty of the dose-reduction process. These results may be informative in the development of novel glucocorticoid-sparing regimens. PMID- 29124399 TI - Length of exposure to antiphospholipid antibodies, rather than age, is a risk factor for thrombosis: a retrospective single-centre observational study. AB - To investigate the association of age and other factors with thrombosis risk in antiphospholipid antibody (aPL) carriers, a retrospective observational study was conducted in a cohort of patients with medium-high aPL titres recruited in a tertiary care hospital. Assuming an age difference of 9.8 years between patients with and without thrombosis, we estimated that a sample size of 70 participants was required. Several variables besides age including gender, vascular risk factors, inherited thrombophilias, non-thrombotic clinical manifestations, laboratory parameters, aPL profile, length of aPL exposure, antithrombotic drugs and partial aPL score were assessed by univariate analysis followed by multivariate logistic regression. Outcomes were analysed by whether thromboses occurred before (model 1) or after (model 2) aPL detection. Seventy patients [50 females; median (interquartile range) baseline age: 46.99 (39.39-66.20) years] were followed for 2.59 (0.67-5.86) years. Overall, 18 and 5 thromboses were diagnosed applying models 1 and 2, respectively. Time to thrombosis after aPL detection was 2.10 (1.03-8.24) years. Age did not differ between patients with and without thrombosis using models 1 (p = 0.92) or 2 (p = 0.67). Instead, we identified other predictors of thrombosis, namely, lack of thromboprophylaxis [odds ratio (OR) 13.50, 95% confidence interval (95% CI) 1.02-178.05, p = 0.048] and length of aPL exposure (OR 1.41, 95% CI 1.04-1.92, p = 0.026) in model 2, while lupus anticoagulant showed a tendency to increase the risk (OR 7.10, 95% CI 0.86-58.78, p = 0.069) in model 1. Unlike age, lack of thromboprophylaxis, prolonged aPL exposure and lupus anticoagulant may increase the risk of thrombosis in aPL carriers. PMID- 29124400 TI - Characterization of M1 and M2 polarization of macrophages in vascularized human dermo-epidermal skin substitutes in vivo. AB - AIMS AND OBJECTIVES: Vascularized bio-engineered human dermo-epidermal skin substitutes (vascDESS) hold promise for treating burn patients, including those with severe full-thickness wounds. We have previously shown that vascDESS promote wound healing by enhanced influx of macrophages and granulocytes. Immediately following transplantation, macrophages infiltrate the graft and differentiate into a pro-inflammatory (M1) or a pro-healing M2 phenotype. The aim of this study was to characterize the activation state of macrophages infiltrating skin transplants at distinct time points following transplantation. METHODS: Keratinocytes and the stromal vascular fraction (SVF) were derived from human skin or adipose tissue, respectively. Human SVF containing both endothelial and mesenchymal/stromal cells was used to generate vascularized dermal component in vitro, which was subsequently covered with human keratinocytes. Finally, vascDESS were transplanted on the back of immuno-incompetent rats, excised, and analyzed after 1 and 3 weeks using immunohistological techniques. RESULTS: A panel of markers of macrophage M1 (nitric oxide synthase: iNOS) and M2 (CD206) subclass was used. All skin grafts were infiltrated by both M1 and M2 rat macrophages between 1-3 weeks post-transplantation. CD68 (PG-M1) was used as a pan-macrophage marker. The number of CD68+CD206+ M2-polarized macrophages was higher in 3-week transplants as compared to early-stage transplants (1 week). In contrast, the number of CD68+iNOS+ M1 cells was markedly decreased in later stages in vivo. CONCLUSIONS: Macrophages exhibit a heterogeneous and temporally regulated polarization during skin wound healing. Our results suggest that the phenotype of macrophages changes during healing from a more pro-inflammatory (M1) profile in early stages after injury, to a less inflammatory, pro-healing (M2) phenotype in later phases in vivo. PMID- 29124401 TI - Bronchoscopic assessments and clinical outcomes in pediatric patients with tracheomalacia and bronchomalacia. AB - BACKGROUND: Tracheomalacia and bronchomalacia (TM/BM) are one of the serious causes of airway obstruction in infants and children. This study reviewed our bronchoscopic assessments and clinical outcomes in pediatric patients with TM/BM, and investigated risk factors of surgical intervention for TM/BM. METHODS: Fifty seven consecutive patients who were diagnosed as TM/BM by bronchoscopy between 2009 and 2013 were reviewed retrospectively. They were divided into two groups according to the presence (group E, n = 26) or absence (group N, n = 31) of acute life-threatening events and extubation failure (ALTE/EF). The severity of TM/BM was evaluated by Oblateness Index which was obtained from bronchoscopic images. RESULTS: Oblateness Index was significantly higher in Group E than in Group N. Patients in Group E underwent surgical intervention for TM/BM more frequently, and had significantly longer intubation period and hospital stay. Clinical symptoms of ALTE/EF, Oblateness Index >= 0.70, and multiple malacic lesions were significant risk factors indicating surgical events in patients with TM/BM. CONCLUSIONS: Patients with TM/BM who had ALTE/EF had more severe malacic lesions indicating surgical intervention, and worse clinical outcomes. Oblateness Index is a simple and semi-quantitative index for bronchoscopic assessment of TM/BM, and can be one of the prognostic tools to predict clinical severity of pediatric TM/BM. PMID- 29124402 TI - Presence of viable germ cells in testicular regression syndrome remnants: Is routine excision indicated? A systematic review. AB - There is no consensus in the literature about the necessity for excision of testicular remnants in the context of surgery for an impalpable testis and testicular regression syndrome (TRS). The incidence of germ cells (GCs) within these nubbins varies between 0 and 16% in previously published series. There is a hypothetical potential future malignancy risk, although there has been only one previously described isolated report of intratubular germ-cell neoplasia. Our aim was to ascertain an accurate incidence of GCs and seminiferous tubules (SNTs) within excised nubbins and hence guide evidence-based practice. The systematic review protocol was designed according to the PRISMA guidelines, and subsequently published by the PROSPERO database after review (CRD42013006034). The primary outcome measure was the incidence of GCs and the secondary outcome was the incidence of SNTs. The comprehensive systematic review included articles published between 1980 and 2016 in all the relevant databases using specific search parameters and terms. Strict inclusion and exclusion criteria were ultilised to identify articles relevant to the review questions. Twenty-nine paediatric studies with a total of 1455 specimens were included in the systematic review. The mean age of the patients undergoing nubbin resection was 33 months and the TRS specimen was more commonly excised from the left (68%). The incidence of SNTs was 10.7% (156/1455) and the incidence of GCs, 5.3% (77/1455). Histological analysis excluding the presence of either SNTs or GCs was consistent with TRS, fibrosis, calcification or haemosiderin deposits. There is limited evidence on subset analysis that GCs and SNTs may persist with increasing patient age. This systematic review has identified that 1 in 20 of resected testicular remnants has viable GCs and 1 in 10 has SNTs present. There is insufficiently strong evidence for the persistence of GCs and SNTs with time or future malignant potential. Intra-abdominal TRS specimens may contain more elements and, therefore, require excision, although this is based on limited evidence. However, there is no available strong evidence to determine that a TRS specimen requires routine excision in an inguinal or scrotal position. PMID- 29124403 TI - Esophagoesophagopexy technique for assisted fistulization of esophageal atresia. AB - PURPOSE: We describe our experience using a modified suture fistula technique for addressing tension in longer gap esophageal atresia (EA). Esophagoesophagopexy (EEP) is the tacking of the proximal and distal ends of esophageal pouches without formal anastomosis. In this retrospective cohort, we review the outcomes of patients with EA after EEP. METHODS: We reviewed the operative reports of EA cases treated at our institution from 1997 to 2016 and identified all patients described as having EEP. RESULTS: Of 129 EA cases, five patients underwent EEP. Formal anastomosis was not done due to patient's instability, prematurity, or long gap. Median birth weight was 1.4 kg (0.6-2.2 kg), and median gestational age at birth was 29 weeks (25-34 weeks). Age at time of EEP ranged 0-5 months. Esophagoesophageal fistula was confirmed in three patients. All three had strictures requiring weekly dilations. One of these patients died. The two surviving patients underwent fundoplication. CONCLUSION: We describe an alternative technique for esophageal anastomosis in patients for whom a standard anastomosis is not possible. EEP can lead to a functional anastomosis through fistulization and avoid the morbidity of multiple thoracotomies and lengthening procedures. Families should be educated on the potential need for dilations and antireflux procedures. PMID- 29124404 TI - Pediatric patients receiving naloxone within 48 h of anesthesia: a case-control study. AB - PURPOSE: Excessive narcotization in pediatric surgical patients has not been well characterized. This report describes the use of postoperative naloxone in pediatric patients. METHODS: Pediatric surgical patients from January 1, 2010, through June 30, 2016, who underwent general anesthesia and received naloxone within 48 h postoperatively were identified and matched 1:1 with controls by age, sex, and procedure. Cases and controls underwent retrospective chart review. RESULTS: Forty-seven patients received naloxone, with a rate of 2.0 (95% CI 1.5 2.7) per 1000 anesthetics. Indications were respiratory depression (n = 19), facilitating extubation (n = 15), and reversing sedation (n = 13), and 44 cases received naloxone in a monitored environment. The median (interquartile range) naloxone dose was 4.0 (2.0-23.5) mcg/kg, and five patients (11%) later required subsequent naloxone treatments. Their characteristics were similar to controls, including opioid medications, except cases that had signs of respiratory depression before naloxone administration. The outcomes were similar, although more cases were admitted to the intensive care unit before naloxone administration. One patient died 13 days postoperatively of unrelated causes. CONCLUSION: Postoperative naloxone administration in pediatric patients is rare. The observation that most administrations occurred in a monitored setting implies that at-risk patients had been appropriately identified and kept under closer surveillance. PMID- 29124406 TI - Selective lateral pelvic lymph node dissection: a comparative study of the robotic versus laparoscopic approach. AB - BACKGROUND: Lateral pelvic lymph node dissection (LPND) is a challenging procedure due to its technical difficulty and higher incidence of surgical morbidity. We compared short-term outcomes between laparoscopic and robotic LPND in patients with rectal cancer. METHODS: Between May 2006 and December 2014, prospectively collected data from consecutive patients undergoing robotic or laparoscopic total mesorectal excision (TME) with LPND were retrospectively compared. Patients' demographics, perioperative outcomes, functional results, and initial oncologic outcomes were analyzed. RESULTS: Fifty and 35 patients underwent robotic or laparoscopic TME with LPND, respectively. Bilateral LPND was performed in 10 patients (20%) in the robotic group and 6 (17.1%) in the laparoscopic group. For unilateral pelvic dissection, the mean operative time was not significantly different between groups (robotic vs. laparoscopic group, 41.0 +/- 15.8 min vs. 35.3 +/- 13.4 min; P = 0.146), but the EBL was significantly lower in the robotic group (34.6 +/- 21.9 mL vs. 50.6 +/- 23.8 mL; P = 0.002). Two patients (4.0%) in the robotic group and 7 (20.0%) in the laparoscopic group underwent Foley catheter reinsertion for urinary retention postoperatively (P = 0.029). The mean number of harvested lateral pelvic lymph nodes (LPNs) was 6.6 (range 0-25) in the robotic group and 6.4 (range 1-14) in the laparoscopic group. Pathologic LPN metastatic rate was not different between groups (robotic vs. laparoscopic group, 28.0 vs. 41.2%; P = 0.243). During the median follow-up of 26.3 months, overall recurrence rate was not different between groups (robotic vs. laparoscopic group, 30.0 vs. 31.2%; P = 0.850). Three patients (6.0%) in the robotic group and 4 (11.4%) in the laparoscopic group developed local recurrence (P = 0.653). CONCLUSIONS: Robotic TME with LPND is safe and feasible with favorable short-term surgical outcomes. PMID- 29124405 TI - LigaSure versus CUSA for parenchymal transection during laparoscopic hepatectomy in hepatocellular carcinoma patients with cirrhosis: a propensity score-matched analysis. AB - BACKGROUND: LigaSure has been reported as a safe and effective approach for parenchymal transection in open hepatectomy; however, its roles in laparoscopic hepatectomy (LH) with liver cirrhosis have not been evaluated. The aim of this study was to compare the outcomes of LigaSure vs. Cavitron Ultrasonic Surgical Aspirator (CUSA) for LH in hepatocellular carcinoma (HCC) patients with cirrhosis. METHODS: We retrospectively reviewed the medical records of 135 HCC patients with background cirrhosis who underwent pure LH using CUSA (n = 55) or LigaSure (n = 80) for parenchymal transection between January 2015 and May 2017 at West China Hospital of Sichuan University. We performed 1:1 propensity score matching between the LigaSure and CUSA groups. Subsequently, 48 patients were included in each group. RESULTS: The mean parenchymal transection time (74.3 +/- 23.6 vs. 86.3 +/- 25.8 min, P = 0.019) in the LigaSure group was obviously shorter than that in the CUSA group. The LigaSure did not increase the intraoperative blood loss or blood transfusion requirement when compared with CUSA. Moreover, the degree of postoperative reperfusion injury and complications were not significantly different between the two groups. Furthermore, there were no significant differences between the two groups regarding 2-year overall survival rate or disease-free survival rate. In addition, the total hospitalization costs (P = 0.032) and intraoperative costs (P = 0.006) per case were significantly lower in the LigaSure group than those in the CUSA group. CONCLUSION: The two devices were safe and effective for LH in patients with cirrhosis. The LigaSure method may be a simple, feasible, and cost-effective surgical technique for LH in selected HCC patients with cirrhosis. PMID- 29124407 TI - Educational system based on the TAPP checklist improves the performance of novices: a multicenter randomized trial. AB - BACKGROUND: Despite recent developments in surgical education, obstacles including inadequate budget, limited human resources, and a scarcity of time have limited its widespread adoption. To provide systematic training for laparoscopic inguinal hernia repair, we had previously developed and validated a checklist to evaluate the recorded performance of transabdominal preperitoneal (TAPP) repair. We had also developed an educational system that included didactic materials based on the TAPP checklist and incorporated remote evaluation and feedback system. The aim of this study was to evaluate the educational impact of the TAPP education system on novice surgeons. METHODS: Residents and surgeons from participating hospitals, who had performed 0 or 1 TAPP procedure, were randomly assigned to the intervention group (IG), who trained using this new educational tool, and the control group (CG), who trained using the conventional system. Their surgical videos were rated by blinded raters. All participants performed their first case prior to randomization. The primary outcome was improvement of TAPP checklist score from the first to the third case. RESULTS: Eighteen participants from 9 institutes were recruited for this study. Seven participants in the IG and 5 participants in the CG were included in the final analysis. The participants in the IG demonstrated significant improvement in their TAPP performance (p = 0.044) from their first case to their third case, whereas their counterparts in the CG failed to make any significant progress during the same period (p = 0.581). CONCLUSION: The new TAPP educational system was effective in improving the TAPP performance of novice surgeons. PMID- 29124408 TI - MS-CASPT2 study of the ground and low lying states of CsH. AB - Correlated ab initio methods [CASPT2 and R-CCSD(T)] in conjunction with the ANO RCC basis sets in large contraction were used to calculate potential energy curves (PECs) of the ground and excited electronic states of CsH+ (doublets and quartets) with the inclusion of the scalar relativistic effects and spin-orbit interaction. The ground X2Sigma+ state is a rather fragile van der Waals molecular ion. The binding energy of this X2Sigma+ state provided by both computational methods is estimated to be 0.02-0.04 eV, and is compared with the reported experimental binding energy (0.51-0.77 eV). This large binding energy can be attributed to the A2Sigma+ state, and can thus explain the apparent disagreement between theory and experiment. The spectroscopic constants of all bound states were calculated from the PECs and compared with previous published data for X2Sigma+ and A2Sigma+ states. Graphical abstract Low-lying Omega states of cesium hydride cation. PMID- 29124409 TI - Activated Carbon Fibers "Thickly Overgrown" by Ag Nanohair Through Self-Assembly and Rapid Thermal Annealing. AB - Anisotropic nanomaterial-modified carbon fibers attract increasing attention because of their superior properties over traditional ones. In this study, activated carbon fibers (ACFs) "thickly overgrown" by Ag nanohair were prepared through self-assembly and rapid thermal annealing. Viscose fibers with well dispersed silver nanoparticles (AgNPs) on surfaces were first prepared through self-assembly of hyperbranched poly(amino-amine) (HBPAA)-capped AgNPs on viscose surfaces. HBPAA endowed the AgNP surfaces with negative charges and abundant amino groups, allowing AgNPs to monodispersively self-assemble to fiber surfaces. Ag nanohair-grown ACFs were prepared by sequential pre-oxidation and carbonization. Because the carbonization furnace was open-ended, ACFs are immediately transferrable to the outside of the furnace. Therefore, the Ag liquid adsorbed by ACF pores squeezed out to form Ag nanowires through thermal contraction. FESEM characterization indicated that Ag nanohairs stood on ACF surface and grew from ACF caps. XPS and XRD characterization showed that Ag successfully assembled to fiber surfaces and retained its metallic state even after high-temperature carbonization. TG analysis suggested that Ag nanohair grown ACFs maintained their excellent thermal stabilities. Finally, the fabricated ACFs showed excellent and durable antibacterial activities, and the developed method may provide a potential strategy for preparing metal nanowire grown ACFs. PMID- 29124410 TI - Absence of haemosporidian parasite infections in the long-lived Cory's shearwater: evidence from molecular analyses and review of the literature. AB - The apparent scarcity or absence of blood parasites in some avian groups, such as seabirds, has been related to intrinsic and extrinsic factors including host immunological capacity, host-parasite assemblage, and ecological parameters, but also to reduced sensitivity of some methods to detect low parasite prevalence/intensities of infection. Here, we examined the haemosporidian parasite prevalence in a breeding population of Cory's shearwater Calonectris diomedea borealis, a long-distance migrant seabird, nesting in the Macaronesian region, in the Eastern Atlantic. Previous studies on Calonectris diomedea complex were based on small sample sizes providing weak evidence for a lack of infections by haemoparasites. Here, we investigated the presence of both parasite infections in C. d. borealis and larvae of potential mosquito vectors on the area. By employing a PCR-based assay, we extensively examined the prevalence of blood parasites belonging to the genera Plasmodium, Haemoproteus, and Leucocytozoon in 286 individuals from different life stages (i.e., chicks, immatures, sabbatical, and breeding adults), facing their specific energetic trade-offs (immunological functions vs. life history activities). We sampled immatures and adult shearwaters, of different sexes, ages, and migratory origins, from two sub colonies. None of the sampled individuals were infected by these parasites, supporting the hypothesis that there was no in situ or ex situ transmission of vector-borne parasites in marine habitats irrespective of host's life stage and in spite of the presence of the potential Plasmodium vector Culiseta longiareolata breeding in the area. These results suggest that the lack of transmission of haemosporidian parasites on Selvagem Grande may be related to the lack of suitable dipteran vectors at the study sites, which may result from the geographic isolation of this area. PMID- 29124411 TI - Reply to the Letter to the Editor of Mr. Frank Eertmans, Oystershell Laboratories, Drongen, Belgium. PMID- 29124412 TI - Evaluation of a short formation on the performance of point-of-care renal ultrasound performed by physicians without previous ultrasound skills: prospective observational study. AB - BACKGROUND: Point-of-Care Ultrasound (PoCUS) is recommended by emergency medicine societies for the detection of hydronephrosis. Training of certified Emergency Physicians (EP) without prior ultrasound experience remains debated. We investigate performance of a brief training session for the detection of hydronephrosis with PoCUS performed by EP without previous ultrasound experience. PATIENTS AND METHODS: This was a prospective observational study of a convenience sample of patients older than 18 years with presumed renal colic, acute pyelonephritis or documented acute renal failure. Exclusion criteria were pregnancy and documented end of life.After inclusion and informed consent, a PoCUS was performed. A radiologist's renal ultrasound (RRUS) was then conducted, the radiologist being blind to PoCUS result.The objective was to determine the diagnostic performance of PoCUS performed by EP for the detection of hydronephrosis using RRUS as gold standard. RESULTS: Six EP participated in this study. 55 patients were included, five secondary excluded for lack of RRUS. Age was 47 +/- 22 years, sex ratio 1. Hydronephrosis prevalence was 38% (CI 95% [26 52%]). Sensitivity of PoCUS was 100% (CI 95% [82-100%]) while its specificity was 71% (CI 95% [52-86%]) with a NPV of 100% (CI 95% [85-100%]) and a 68% (CI 95% [48 84%]) PPV. Kappa coefficient was 0.65 (CI 95% [0.45-0.85]). DISCUSSION: We demonstrated that a short training program enables EP without previous ultrasound skills to rule out hydronephrosis with satisfactory performances. The main limitation was the absence of collection of the number of PoCUS by EP. After this didactic course, an experiential phase must be carried out. PMID- 29124413 TI - Assessment of bacterial diversity in Hyalomma aegyptium, H. marginatum and H. excavatum ticks through tag-encoded pyrosequencing. AB - Ticks are among the most significant human-biting ectoparasites and they play a major role in transmission of many pathogenic agents to humans. In the present study, three species of Hyalomma ticks, Hyalomma aegyptium, H. marginatum and H. excavatum, were examined for the presence of zoonotic bacteria, both male and female ticks alike. Examination of microbial diversity with tag-encoded pyrosequencing indicates that H. marginatum and H. excavatum were more diversity rich than H. aegyptium. Although numerous pathogenic and non-pathogenic bacterial genera were detected, including Acidovorax, Bacillus, Bacteroides, Bdellovibrio, Clostridium, Curvibacter, Escherichia, Flavobacterium, Limnohabitans, Paenibacillus, Ralstonia, Sarcina, Sediminibacterium, Segetibacter Stenotrophomonas and Variovorax, the predominant zoonotic bacteria represented in these ticks were genera Borrelia, Francisella, and Rickettsia. To the authors' knowledge, this work represents the first detection of Yersinia enterocolitica in the tick H. excavatum, raising questions regarding the vector competency of this tick, as well as associations of different disease representations perhaps through previously unforeseen routes of pathogen introduction. Likewise, similar questions are related to the presence of Legionella pneumophila in one H. excavatum sample. PMID- 29124414 TI - Synergistic Effects of Ag Nanoparticles/BiV1-xMoxO4 with Enhanced Photocatalytic Activity. AB - In recent years, BiVO4 has drawn much attention as a novel photocatalyst given its excellent ability to absorb visible light. This work reports the development of Ag-modified BiV1-xMoxO4 composites through a facile hydrothermal synthesis with the subsequent photoinduced reduction of Ag+ at almost neutral pH conditions. Metallic Ag nanoparticles were deposited on the (040) facet of Mo doped BiVO4 powders. The crystal structure and morphology of the as-prepared samples were studied by XRD and SEM analyses. Moreover, the photocatalytic performance of BiVO4, Ag/BiVO4, and Ag-modified BiV1-xMoxO4 were evaluated by the degradation of rhodamine B (RhB). The Ag/BiV0.9925Mo0.0075O4 composite exhibited the most efficient photocatalytic performance. The present work provides greater insight into the application of BiVO4 in the field of photocatalysis. PMID- 29124415 TI - Spatial and temporal distribution of carbon dioxide gas using GOSAT data over IRAN. AB - CO2 concentration (XCO2) shows the spatial and temporal variation in Iran. The major purpose of this investigation is the assessment of the spatial distribution of carbon dioxide concentration in the different seasons of 2013 based on the Thermal And Near Infrared Sensor for Carbon Observation-Fourier Transform Spectrometer (TANSO-FTS) level 2 GOSAT data by implementing the ordinary kriging (OK) method. In this study, the Land Surface Temperature (LST), Normalized Difference Vegetation Index (NDVI) data from the MODerate resolution Imaging Spectroradiometer (MODIS), and metrological parameters (temperature and precipitation) were used for the analysis of the spatial distribution of CO2 over Iran in 2013. The spatial distribution maps of XCO2 show the highest concentration of this gas in the south and south-east and the lowest concentration in the north and north-west. These results indicate that the concentration of carbon dioxide decreased with the increase of LST and temperature and a decrease of NDVI and humidity in the study area. Therefore, the existence of vegetation has an effective role in capturing carbon from the atmosphere by photosynthesis phenomena, and sustainable land management can be effective for carbon absorption from the atmosphere and mitigation of climate change in arid and semi-arid regions. PMID- 29124416 TI - Prevalence and correlates of health information-seeking among Hispanic and non Hispanic childhood cancer survivors. AB - PURPOSE: Childhood cancer survivors (CCS) report high unmet information needs. This study examined the prevalence of cancer-related information-seeking among CCS and investigated associations between information-seeking behavior and positive health outcomes such as follow-up care. METHODS: Participants (n = 193) were young adult CCS diagnosed with cancer in Los Angeles County, 54% of Hispanic ethnicity, with a mean age of 19.87, in remission, and at least 2 years from completion of treatment. CCS were asked where they accessed health information related to their cancer with response options categorized into four information domains: hospital resources, social media, other survivors, and family members. Multivariable logistic regression was used to assess variables associated with each information domain, including sociodemographics, post-traumatic growth (i.e., reporting positive changes since cancer diagnosis), health care engagement, level of education, and health insurance status. RESULTS: Hospital resources were the most commonly accessed information domain (65.3%), and CCS of Hispanic ethnicity (vs. non-Hispanic) were more likely to access this source. Seeking information from other cancer survivors was positively associated with follow-up care and post-traumatic growth. Hispanic CCS were marginally less likely to seek information from other survivors and family than non-Hispanics. CONCLUSIONS: While CCS obtain information from a variety of sources, hospital resources are an important site for access, particularly for individuals of Hispanic ethnicity. Information sharing between survivors may promote positive health care engagement; however, Hispanic CCS may be less likely to utilize this resource and may face barriers in information sharing with other cancer survivors. PMID- 29124417 TI - Oncology navigators' perceptions of cancer-related financial burden and financial assistance resources. AB - INTRODUCTION: As the cost of cancer treatment continues to rise, many patients are faced with significant emotional and financial burden. Oncology navigators guide patients through many aspects of care and therefore may be especially aware of patients' financial distress. Our objective was to explore navigators' perception of their patients' financial burden and their role in addressing financial needs. MATERIALS AND METHODS: We conducted a real-time online survey of attendees at an oncology navigators' association conference. Participants included lay navigators, oncology nurse navigators, community health workers, and social workers. Questions assessed perceived burden in their patient population and their role in helping navigate patients through financial resources. Answers to open-ended questions are reported using identified themes. RESULTS: Seventy eight respondents participated in the survey, reporting that on average 75% of their patients experienced some degree of financial toxicity related to their cancer. Only 45% of navigators felt the majority of these patients were able to get some financial assistance, most often through assistance with medical costs (73%), subsidized insurance (36%), or non-medical expenses (31%). Commonly identified barriers for patients obtaining assistance included lack of resources (50%), lack of knowledge about resources (46%), and complex/duplicative paperwork (20%). CONCLUSION: Oncology navigators reported a high burden of financial toxicity among their patients but insufficient knowledge or resources to address this need. This study underscores the importance of improved training and coordination for addressing financial burden, and the need to address community and system-level barriers. PMID- 29124418 TI - The effect of pre-transplant pain and chronic disease self-efficacy on quality of life domains in the year following hematopoietic stem cell transplantation. AB - PURPOSE: Pain is common for hematopoietic stem cell transplant (HSCT) patients and may be experienced pre-transplant, acutely post-transplant, and for months or years following transplant. HSCT patients with persistent pain may be at risk for poor quality of life following transplant; however, the impact of pre-transplant pain on quality of life post-transplant is not well understood. Self-efficacy for chronic disease management is associated with quality of life among cancer patients and may impact quality of life for HSCT patients. The primary aim was to examine the effect of pre-transplant pain and self-efficacy on quality of life domains in the year following transplant. METHODS: One hundred sixty-six HSCT patients completed questionnaires providing information on pain, self-efficacy, and quality of life prior to transplant, at discharge, and 3-, 6-, and 12-months post-transplant as part of a longitudinal, observational study. Linear mixed modeling examined the trajectories of these variables and the effect of pre transplant pain and self-efficacy on post-transplant quality of life. RESULTS: Pain and social and emotional quality of life remained stable in the year following transplant while self-efficacy and physical and functional quality of life improved. Pre-transplant pain was significantly related to lower physical well-being post-transplant. Lower pre-transplant self-efficacy was related to lower quality of life across all domains post-transplant. CONCLUSION: Above and beyond the effect of pre-transplant pain, self-efficacy for managing chronic disease is important in understanding quality of life following transplant. Identifying patients with pain and/or low self-efficacy pre-transplant may allow for early intervention with self-management strategies. PMID- 29124419 TI - A systematic review to assess the management of patients with cerebral metastases secondary to colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) rarely metastasizes to the brain. The incidence of cerebral metastases (CM) is estimated between 1 and 3%. Given the improved survival from advanced CRC as a result of surgical and oncological advances, it is anticipated that the incidence of patients with CM from CRC will rise over the next few years. The aim of this article was to systematically review the treatment options and outcome of patients with CM from CRC. METHODS: PubMed and Medline databases were examined using the search words or MESH headings "colorectal" "cancer/carcinoma/adenocarcinoma", "cerebral"/"brain" and "metastases/metastasis". RESULTS: CM from CRC are diagnosed on average 28.3 months after the primary tumour. The median survival time following diagnosis is 5.3 months. Surgery (with or without associated radiotherapy), stereotactic radiosurgery, whole brain radiotherapy and best supportive care result in median survival of 10.3, 6.4, 4.4 and 1.8 months, respectively. On average, the 1-year overall survival rate for patients with CM from CRC regardless of the treatment modality is estimated to be around 24%. CONCLUSIONS: The prognosis of patients with CM from CRC is dismal. Surgery may increase survival, but the additional benefit of perioperative radiotherapy cannot be ascertained due to paucity of data. Further studies are required to identify the role of the different oncological and surgical therapies and identify those patients likely to benefit most. Identification of patients who are at higher risk of developing brain metastases may be another important area for future research. PMID- 29124421 TI - If You Film It Will They Watch? Factors Associated with Willingness to View Safer Sex Messaging in Internet-Based Sexually Explicit Media. AB - Research on the association between viewing condomless sex in sexually explicit media (SEM) and engaging in risk behavior suggests the need for SEM-based safer sex messaging (e.g., PrEP, condom use), though few studies have considered viewer willingness to watch SEM containing HIV/STI prevention messages. Online survey data from a racially diverse sample of 859 men and women were used to investigate factors associated with willingness to watch SEM with safer sex messaging. Analyses were conducted separately for three groups: heterosexual men and other men who only report sex with women, heterosexual women and other women who only report sex with men, and gay, bisexual, and other men who have sex with men. All three groups expressed some willingness to view safer sex messages in SEM and a majority viewed the SEM industry as having some responsibility to provide this type of messaging. Factors associated with greater willingness varied across the three groups. These findings have implications for the design and implementation of safer sex messaging in SEM. PMID- 29124420 TI - Mixed-Method Evaluation of Social Media-Based Tools and Traditional Strategies to Recruit High-Risk and Hard-to-Reach Populations into an HIV Prevention Intervention Study. AB - Men who have sex with men and transgender women are hard-to-reach populations for research. Social media-based tools may overcome certain barriers in accessing these groups and are being tested in an ongoing study exploring HIV home-test kit use to reduce risk behavior. We analyzed pre-screening responses about how volunteers learned about the study (n = 896) and demographic data from eligible participants who came for an initial study visit (n = 216) to determine the strengths and weaknesses of recruitment strategies. Social media-based strategies resulted in the highest number of individuals screened (n = 444, 26% eligible). Dating sites/apps reached large numbers of eligible participants. White-Hispanics and African-Americans were more likely to be recruited through personal contacts; community events successfully reached Hispanic volunteers. Incorporating recruitment queries into pre-screening forms can help modify recruitment strategies for greater efficacy and efficiency. Findings suggest that recruitment strategies need to be tailored to reach specific target populations. PMID- 29124422 TI - Perifoveal interdigitation zone loss in hydroxychloroquine toxicity leads to subclinical bull's eye lesion appearance on near-infrared reflectance imaging. AB - PURPOSE: To characterize the ultrastructural and functional correlates of hydroxychloroquine (HCQ)-induced subclinical bull's eye lesion seen on near infrared reflectance (NIR) imaging. METHODS: An asymptomatic 54-year-old male taking HCQ presented with paracentral ring-like scotoma, abnormal multifocal electroretinography (mfERG) and preserved ellipsoid zone on optical coherence tomography (OCT). Dense raster OCT was performed to create en face reflectivity maps of the interdigitation zone. Macular Integrity Assessment (MAIA) microperimetry and mfERG findings were compared with NIR imaging, en face OCT, retinal thickness profiles and wave-guiding cone density maps derived from flood illumination adaptive optics (AO) retinal photography. RESULTS: The bull's eye lesion is an oval annular zone of increased reflectivity on NIR with an outer diameter of 1450 um. This region corresponds exactly to an area of preserved interdigitation zone reflectivity in en face OCT images and of normal cone density on AO imaging. Immediately surrounding the bull's eye lesion is an annular zone (3 degrees -12 degrees eccentricity) of depressed retinal sensitivity on MAIA and reduced amplitude density on mfERG. Wave-guiding cone density at 2 degrees temporal was 25,400 per mm2. This declined rapidly to 12,900 and 1200 per mm2 at 3 degrees and 4 degrees . CONCLUSION: Multimodal imaging illustrated pathology in the area surrounding the NIR bull's eye, characterized by reduced reflectance, wave-guiding cone density and retinal function. Further studies are required to investigate whether the bull's eye on NIR imaging and en face OCT is prominent or consistent enough for diagnostic use. PMID- 29124423 TI - Effects of mutual intercropping on the cadmium accumulation in accumulator plants Stellaria media, Malachium aquaticum, and Galium aparine. AB - Intercropping affects heavy-metal uptake in plants. In this study, three cadmium (Cd)-accumulator species (Stellaria media, Malachium aquaticum, and Galium aparine) were intercropped together in Cd-contaminated soil to study the effects of intercropping on co-remediation. Mutual intercropping significantly increased the biomasses of S. media, M. aquaticum, and G. aparine compared with their respective monocultures. The photosynthetic pigment contents of three species were not significantly affected by mutual intercropping. Mutual intercropping did not increase the Cd contents in roots and shoots of G. aparine, but it increased the Cd contents in roots of S. media and M. aquaticum. It also decreased the Cd contents in shoots of S. media and M. aquaticum. Only G. aparine intercropped with M. aquaticum and three-species intercropping increased Cd-accumulation levels in whole plants of each species. Only S. media intercropped with M. aquaticum and three-species intercropping increased the Cd accumulation at the whole plant level in every plant in a single pot, with S. media intercropped with M. aquaticum showing the greatest increase. Therefore, S. media intercropped with M. aquaticum and three-species intercropping may improve the efficiency of phytoremediation of Cd-contaminated soil, with S. media intercropped with M. aquaticum representing the best combination. PMID- 29124424 TI - Effects of gravel-sand mulching on soil bacterial community and metabolic capability in the semi-arid Loess Plateau, China. AB - Gravel and sand mulching is an indigenous technology used for the crop yield for at least 300 years in the loess area of northwest China; however, little is known about the changes of soil bacterial community and metabolic capability under the mulching. In this study, we investigated the soil microbial community structure and metabolic functional diversity during mulching using Illumina MiSeq sequencing and Biolog ECO method. Totally, 9417 OTUs were classified at 97% similarity level for soil samples after 0 (control), 4, 7, and 10 years of mulching. Dendrogram result indicated that mulching affected the soil bacterial community; and the higher richness and diversity of bacterial community were detected in mulching samples. The average abundance of soil bacteria (such as Proteobacteria, Actinobacteria, Firmicutes and Nitrospirae) in mulching samples was higher than samples without mulching. Besides, some microbial communities (such as Rhodobacteraceae, Phenylobacterium, Pseudonocardia, Nonomuraea and Aeromicrobium) were only present in the mulched soil samples. However, the lower metabolic capability was observed in mulching samples based on Biolog method, which the main reason for the opposite result might be that the soil objects detected by the two methods are different. In conclusion, these results demonstrated that gravel and sand mulching affected the structure and metabolic capability of bacterial community and was one reason for crop yield. PMID- 29124425 TI - Steroid hormones in environmental matrices: extraction method comparison. AB - The U.S. Environmental Protection Agency (EPA) has developed methods for the analysis of steroid hormones in water, soil, sediment, and municipal biosolids by HRGC/HRMS (EPA Method 1698). Following the guidelines provided in US-EPA Method 1698, the extraction methods were validated with reagent water and applied to municipal wastewater, surface water, and municipal biosolids using GC/MS/MS for the analysis of nine most commonly detected steroid hormones. This is the first reported comparison of the separatory funnel extraction (SFE), continuous liquid liquid extraction (CLLE), and Soxhlet extraction methods developed by the U.S. EPA. Furthermore, a solid phase extraction (SPE) method was also developed in house for the extraction of steroid hormones from aquatic environmental samples. This study provides valuable information regarding the robustness of the different extraction methods. Statistical analysis of the data showed that SPE based methods provided better recovery efficiencies and lower variability of the steroid hormones followed by SFE. The analytical methods developed in-house for extraction of biosolids showed a wide recovery range; however, the variability was low (<= 7% RSD). Soxhlet extraction and CLLE are lengthy procedures and have been shown to provide highly variably recovery efficiencies. The results of this study are guidance for better sample preparation strategies in analytical methods for steroid hormone analysis, and SPE adds to the choice in environmental sample analysis. PMID- 29124427 TI - Rhabdomyolysis-associated acute kidney injury: Questions. PMID- 29124426 TI - Molecular chaperones involved in mitochondrial iron-sulfur protein biogenesis. AB - Iron-sulfur (FeS) clusters are prosthetic groups critical for the function of many proteins in all domains of life. FeS proteins function in processes ranging from oxidative phosphorylation and cofactor biosyntheses to DNA/RNA metabolism and regulation of gene expression. In eukaryotic cells, mitochondria play a central role in the process of FeS biogenesis and support maturation of FeS proteins localized within mitochondria and in other cellular compartments. In humans, defects in mitochondrial FeS cluster biogenesis lead to numerous pathologies, which are often fatal. The generation of FeS clusters in mitochondria is a complex process. The [2Fe-2S] cluster is first assembled on a dedicated scaffold protein (Isu1) by the action of protein factors that interact with Isu1 to form the "assembly complex". Next, the FeS cluster is transferred onto a recipient apo-protein. Genetic and biochemical evidence implicates participation of a specialized J-protein co-chaperone Jac1 and its mitochondrial (mt)Hsp70 chaperone partner, and the glutaredoxin Grx5 in the FeS cluster transfer process. Finally, various specialized ISC components assist in the generation of [4Fe-4S] clusters and cluster insertion into specific target apoproteins. Although a framework of protein components that are involved in the mitochondrial FeS cluster biogenesis has been established based on genetic and biochemical studies, detailed molecular mechanisms involved in this important and medically relevant process are not well understood. This review summarizes our molecular knowledge on chaperone proteins' functions during the FeS protein biogenesis. PMID- 29124428 TI - Rhabdomyolysis-associated acute kidney injury: Answers. PMID- 29124430 TI - Oversensing of the wearable cardioverter defibrillator during bipolar ventricular stimulation. AB - The wearable cardioverter defibrillator (WCD) is a temporary treatment option for patients with potentially reversible risk of sudden cardiac death. This case demonstrates a pitfall during WCD usage in a pacemaker-dependent patient as well as a possible solution allowing continuation of WCD therapy. Bipolar stimulation may lead to double counting of the WCD detection algorithm resulting in false alarm or inappropriate therapy. PMID- 29124431 TI - The Coupling Effects of Surface Plasmon Polaritons and Magnetic Dipole Resonances in Metamaterials. AB - We numerically investigate the coupling effects of surface plasmon polaritons (SPPs) and magnetic dipole (MD) resonances in metamaterials, which are composed of an Ag nanodisk array and a SiO2 spacer on an Ag substrate. The periodicity of the Ag nanodisk array leads to the excitation of SPPs at the surface of the Ag substrate. The near-field plasmon interactions between individual Ag nanodisks and the Ag substrate form MD resonances. When the excitation wavelengths of SPPs are tuned to approach the position of MD resonances by changing the array period of Ag nanodisks, SPPs and MD resonances are coupled together into two hybridized modes, whose positions can be well predicted by a coupling model of two oscillators. In the strong coupling regime of SPPs and MD resonances, the hybridized modes exhibit an obvious anti-crossing, resulting into an interesting phenomenon of Rabi splitting. Moreover, the magnetic fields under the Ag nanodisks are greatly enhanced, which may find some potential applications, such as magnetic nonlinearity. PMID- 29124432 TI - Regional disparities in medical equipment distribution in the Slovak Republic - a platform for a health policy regulatory mechanism. AB - BACKGROUND: This study aims to examine the localisation of selected parameters in the deployment and use of medical equipment in the Slovak Republic and to verify potential regional disparities. The study evaluates the benefits of an analytical platform for regulatory mechanisms in the healthcare system. METHODS: The correspondence analysis is applied to the entire data set containing information regarding medical equipment distribution and mortality. RESULTS: The results highlight regional differences in the use of medical equipment throughout the analysed period from 2008 to 2014. The total amount of medical equipment increased slightly to 9192 devices during the time span. In 2014, there was a significant decrease of 16.44%. Disparities are found in the frequencies and structure of medical equipment. In some regions, medical equipment is not present or is present in low numbers. CONCLUSIONS: The results regarding regional disparities demonstrate the regional development of the amount of medical equipment. The deployment of medical equipment is not proportional, and not all of the analysed devices are available in each region. The tests also indicate the appropriateness of the amount of medical equipment and create a platform for further investigation. The results of the analysis suggest the unsuitable distribution of medical equipment throughout the Slovak regions, where there are significant regional disparities. These findings can serve as a monitoring platform to evaluate the accessibility and efficiency of medical equipment usage. TRIAL REGISTRATION: No human participants were involved in the research. PMID- 29124429 TI - What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection? AB - PURPOSES: Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. METHODS: We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. RESULTS: A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. CONCLUSIONS: This study revealed eight risk factors for fatal AEIP. PMID- 29124433 TI - Positive association between serum uric acid and bone mineral density in Chinese type 2 diabetes mellitus stratified by gender and BMI. AB - Accumulating evidence has demonstrated that serum uric acid (UA), a natural powerful antioxidant, plays a beneficial role in bone health in the general population. However, few reports are available on the association between serum UA and bone in patients with type 2 diabetes mellitus (T2DM). We therefore investigated whether the benefit of serum UA for bone health was still present in those patients. 626 males and 609 postmenopausal females with T2DM were enrolled in this cross-sectional study. Serum UA concentrations and bone mineral density (BMD) measured at lumbar spine, femoral neck and total hip by dual-energy X-ray absorptiometry were obtained from all subjects. Meanwhile, data on osteoporosis prevalence, glucose metabolism, bone turnover markers and other serum biochemical indexes were collected. After adjustment for potential confounders, the results suggested that serum UA was positively associated with BMD in patients with normal weight, but this positive association varied by gender and skeletal sites in overweight T2DM patients [body mass index (BMI) >= 25 kg/m2]. Moreover, significantly lower odds ratios (ORs) for osteoporosis were found in postmenopausal patients with the highest UA tertile and male patients with medium UA tertile [adjusted OR 0.315, 95% confidence interval (CI) 0.170-0.581 for postmenopausal patients; adjusted OR 0.464, 95% CI 0.225-0.955 for male patients]. The positive association between serum UA and BMD found in Chinese T2DM patients may imply that relatively high UA is a protective factor for bone in these patients. Large intervention studies are needed to further confirm the outcomes and provide possible explanations. PMID- 29124434 TI - Effect of prednisone treatment for 30 and 90 days on bone metabolism in collagen induced arthritis (CIA) rats. AB - Glucocorticoids (GCs) are often prescribed to treat rheumatoid arthritis (RA) in the long term, but there is still controversy in the administration of GCs, mainly because of the adverse reactions such as osteoporosis. Numerous studies have demonstrated that osteoporosis could be induced by GCs in normal rats. However, few experiments have focused on whether osteoporosis could be induced or aggravated by GCs in collagen induced arthritis (CIA) rats. We have investigated bone changes in CIA rats treated with prednisone at 4.5 mg/kg/day for 30 and 90 days by bone histomorphometry, bone mineral density (BMD), micro-CT, biomechanical test, and enzyme-linked immunosorbant assay. We found that high bone turnover osteoporosis was shown in CIA rats. Prednisone treatment for 30 and 90 days improved articular structure and decelerated the degeneration of the femur in CIA rats, but did not improve BMD and bone biomechanics. We conclude that osteoporosis was not aggravated in CIA rats treated with prednisone for 30 and 90 days. On the contrary, prednisone treatment for 30 and 90 days could prevent bone loss of the femur in CIA rats. There was a negative effect on bone metabolism in CIA rats treated with prednisone for 90 days. PMID- 29124435 TI - Vitamin D deficiency: an unrecognized cause of flank pain. AB - Loin pain is frequently not associated with any urinary abnormality. Musculoskeletal abnormalities are not uncommon as alternative cause of flank pain. Osteomalacia of the ribs was infrequently encountered as the cause of flank pain. Vitamin D deficiency has been reported as a common problem worldwide with special predilection to the Middle East area. In this study, we looked for vitamin D deficiency in patients with flank pain associated with tenderness over the tips of the lowermost ribs. Out of 783 patients presenting with unilateral or bilateral flank pain to a single center over a period of 3 years, 316 did not have a definite urologic cause (group B). One hundred and eighty-seven of these patients had distinct tenderness over the costal margin (group B1) that could not be explained by history and radiology. All patients of group B were tested for serum levels of 25(OH) vitamin D. Very low serum levels of 25(OH) vitamin D was detected in all cases of group B1 and in only in only 26.4% of the remaining cases of group B (group B2). Relief of flank pain was noticed within 2 months in 55.1% of vitamin D deficient cases. In patients presenting with flank pain, the existence of tenderness of the last ribs instead of the renal angle proper should alert to a possible cause in the rib cage. Estimation of serum vitamin D level should be performed in these cases. PMID- 29124436 TI - Postnatal deletion of beta-catenin in osterix-expressing cells is necessary for bone growth and intermittent PTH-induced bone gain. AB - wnt/beta-catenin signaling has been shown to influence bone homeostasis and is important for parathyroid hormone (PTH)-induced bone gain. To further understand the role of beta-catenin in the early stages of osteoblastic lineage cells for postnatal bone homeostasis and the anabolic actions of PTH on bone, we examined mice with postnatal disruption of beta-catenin in osterix-expressing cells (beta catenin KO mice) by mating floxed beta-catenin mice with transgenic mice expressing cre under the control of the osterix promoter suppressible by doxycycline. After withdrawal of doxycycline, beta-catenin KO mice developed progressive bone loss, ectopic cartilage formation, accumulation of mesenchymal stromal cells, and bone marrow adiposity. The beta-catenin-defective osteoblasts sorted by flow cytometry from beta-catenin KO mice exhibited decreased EdU incorporation, increased annexin V activity, and profound alterations in gene expression including wnt target genes, osteoclast regulators, and osteoblast markers. A dramatic increase in osteoclasts was observed in both neonatal and postnatal beta-catenin KO mice. Intermittent administration of PTH for 4 weeks significantly increased bone mass in control mice; however, this anabolic effect of PTH was substantially blunted in beta-catenin KO mice. Our data indicate that beta-catenin in osterix-expressing cells is required for postnatal osteoblast differentiation, osteoblast proliferation, and bone resorption, and is essential for the anabolic actions of PTH in bone. PMID- 29124437 TI - Optimal vitamin D intake for preventing serum 25-hydroxyvitamin D insufficiency in young Japanese women. AB - Populations of East Asian countries have been known to have low calcium intakes and low serum 25(OH)D concentrations, suggesting that Ca and vitamin D (VitD) deficiencies are commonly observed. These nutritional imbalances may lead to low peak bone mass (PBM). The low PBM seen in Ca/VitD-deficient individuals may lead to osteoporosis, as well as an increased risk of fracture. A survey was conducted in young Japanese women (n = 296, 21.2 +/- 2.3 years old) on their Ca/VitD intakes and serum 25(OH)D levels, which demonstrated a significant positive correlation between VitD intake and serum 25(OH)D levels (R 2 = 0.020, P = 0.016), and the proportion with serum 25(OH)D over 20 ng/mL was significantly increased with VitD intake (P = 0.013). Serum 25(OH)D was negatively correlated to serum intact parathyroid hormone (R 2 = 0.053, P < 0.001). On receiver operating characteristic curve analysis, the VitD intake threshold for maintaining 25(OH)D levels at 20 ng/mL or higher was 11.6 MUg/day or greater. It was suggested that the recommended VitD intake allowance, defined in the Adequate Intakes as 5.5 MUg/day, may not be sufficient to maintain serum 25(OH)D levels for bone health. PMID- 29124438 TI - Reorganization of sensory input at brainstem in hemifacial spasm and postparalytic facial syndrome. AB - We hypothesized the filtering of sensory input from face and hand at brainstem may reorganize in hemifacial spasm (HFS) and postparalytic facial syndrome (PFS). Thus, we examined the prepulse inhibition of blink reflex (BR-PPI) in HFS and PFS. We included 12 healthy subjects, 13 patients with HFS, and 11 patients with PFS. Baseline BR, BR recovery at interstimulus interval (ISI) of 300 ms and BR PPI at ISI of 100 ms were performed on the right sides of healthy subjects and on both sides of patients. Within-subject analysis showed baseline BR and BR-PPI were similar between asymptomatic and symptomatic sides of patients with HFS whereas BR recovery was higher on the symptomatic side. In the PFS group, latency of R2 during baseline BR recording was longer (p = 0.022) and R2 amplitude (p = 0.046) was reduced on the symptomatic side compared to asymptomatic side. Reduction of R2 area in BR-PPI recordings was also the lowest in HFS compared to other two groups (p = 0.000); however, it was also lower in patients with PFS compared to healthy subjects (p = 0.018). BR-PPI was decreased on both sides of patients. The mean R2 recovery was higher on both sides of patients with HFS and PFS (p = 0.007). Filtering of facial sensory input is decreased probably to monitor and to correct the sequence of facial movements in these disorders. PMID- 29124440 TI - Orbital myositis as a manifestation of primary antiphospholipid syndrome. PMID- 29124439 TI - Lennox-Gastaut syndrome: a comprehensive review. AB - Lennox-Gastaut syndrome (LGS) is considered an epileptic encephalopathy and is defined by a triad of multiple drug-resistant seizure types, a specific EEG pattern showing bursts of slow spike-wave complexes or generalized paroxysmal fast activity, and intellectual disability. The prevalence of LGS is estimated between 1 and 2% of all patients with epilepsy. The etiology of LGS is often divided into two groups: identifiable (genetic-structural-metabolic) in 65 to 75% of the patients and LGS of unknown cause in others. Lennox-Gastaut syndrome may be considered as secondary network epilepsy. The seizures in LGS are usually drug resistant, and complete seizure control with resolution of intellectual and psychosocial dysfunction is often not achievable. Reduction in frequency of the most incapacitating seizures (e.g., drop attacks and tonic-clonic seizures) should be the major objective. Valproate, lamotrigine, and topiramate are considered to be the first-line drugs by many experts. Other effective antiepileptic drugs include levetiracetam, clobazam, rufinamide, and zonisamide. The ketogenic diet is an effective and well-tolerated treatment option. For patients with drug resistance, a further therapeutic option is surgical intervention. Corpus callosotomy is a palliative surgical procedure that aims at controlling the most injurious seizures. Finally, vagus nerve stimulation offers reasonable seizure improvement. The long-term outcome for patients with LGS is generally poor. This syndrome is often associated with long-term adverse effects on intellectual development, social functioning, and independent living. PMID- 29124441 TI - Bulbar paralysis associated with Miller-Fisher syndrome and its overlaps in Chinese patients. AB - The study aimed to determine the incidence and the onset time of bulbar paralysis (BP) associated with Miller-Fisher syndrome (MFS) and its overlaps, to better understand the clinical characteristics among patients with MFS and its overlaps. Medical records from 48 patients with MFS and its overlaps were divided into two groups based on the presence (MFS-BP+) or absence (MFS-BP-) of BP. Their clinical features, laboratory and electrophysiological findings, neuroimaging data, and treatment plan were analyzed and compared between two groups. The incidence of BP associated with MFS and its overlaps was 48%. Eighty-two percent of the patients developed BP within 1 week after the onset of MFS and its overlaps. The cerebrospinal fluid (CSF) protein level in patients was higher in MFS-BP+ than in MFS-BP- group (67.69 +/- 26.59 vs. 50.15 +/- 20.44 mg/dl; P < 0.05). Frequencies of severe limb weakness, hypoglossal paralysis, disturbance of consciousness, and tracheal intubation required were also significantly higher in MFS-BP+ than in MFS-BP- group. Positive results of anti-GQ1b and anti-GT1b antibodies were all found in MFS-BP+ group. The prevalence of BP in MFS and its overlap was higher, the majority of BP occurred within 7 days after the onset of the disease, and early diagnosis of BP concurrence is helpful to decide the treatment plan. PMID- 29124442 TI - Neuropsychological profile in parents of adult phenylketonuria patients. AB - Phenylketonuria (PKU) is a disorder caused by an inborn error of metabolism, causing cognitive and behavioral disorders when not treated. Heterozygotes (i.e., patients' parents) were described with low verbal intelligence quotient, but no study systematically investigated cognitive functions in PKU parents. To obtain a neuropsychological profile in heterozygotes, we compared cognitive performance of heterozygotes and healthy controls (HC) on cognitive battery. Twelve heterozygotes and 14 HCs underwent standardized neuropsychological tasks assessing frontal/executive functions, memory, and visuospatial abilities. No significant difference between heterozygotes and HC was found on demographic aspects. Heterozygotes performed worse than HC on immediate verbal recall, on test assessing set-shifting, divided attention, and sensitivity to processing speed. No difference was found on the remaining cognitive tests.In conclusions, we observed less efficient control/executive functions in heterozygotes when compared to HCs. Further studies in large sample of heterozygotes should be performed to confirm our results. PMID- 29124444 TI - Risk factors for unplanned pregnancy in women with mental illness living in a developing country. AB - Pregnant women in general are at an increased risk of experiencing symptoms of mental illness, and those living in a developing country are even more vulnerable. Research points towards a causal relationship between unplanned pregnancy and perinatal mental illness and suggests that pregnancy planning can aid in reducing the negative impact of mental illness on a woman, her unborn baby, and the rest of the family. In this quantitative, descriptive study, we investigated both socio-demographic factors and variables relating to mental illness itself that may place women at an increased risk of experiencing unplanned pregnancy. Data was gathered at two maternal mental health clinics in Cape Town by means of semi-structured interviews. Univariate analyses of the data revealed five independent key risk factors for unplanned pregnancy: lower levels of education, unmarried status, belonging to the Colored ethnic population, substance use, and having a history of two or more suicide attempts. Some of these factors overlap with findings of similar studies, but others are unique to the specific population (women with mental illness within a developing country). Screening of women based on these risk predictors may pave the way for early interventions and reduce the incidence of unplanned pregnancy and the negative consequences thereof in the South African population. PMID- 29124443 TI - Identification of CDC42BPG as a novel susceptibility locus for hyperuricemia in a Japanese population. AB - Chronic kidney disease and hyperuricemia are serious global health problems. Recent genome-wide association studies have identified various genetic variants related to these disorders. However, most studies have been conducted in a cross sectional manner. To identify novel susceptibility loci for chronic kidney disease or hyperuricemia, we performed longitudinal exome-wide association studies (EWASs), using ~ 244,000 genetic variants and clinical data of Japanese individuals who had undergone annual health checkups for several years. After establishing quality controls, the association of renal function-related traits in 5648 subjects (excluding patients with dialysis and population outliers) with 24,579 single nucleotide variants (SNVs) for three genetic models (P < 3.39 * 10- 7) was tested using generalized estimating equation models. The longitudinal EWASs revealed novel relations of five SNVs to renal function-related traits. Cross-sectional data for renal function-related traits in 7699 Japanese subjects were examined in a replication study. Among the five SNVs, rs55975541 in CDC42BPG was significantly (P < 4.90 * 10- 4) related to the serum concentration of uric acid in the replication cohort. We also examined the SNVs detected in our longitudinal EWASs with the information on P values in GKDGEN meta-analysis data. Four SNVs in SLC15A2 were significantly associated with the estimated glomerular filtration rate in European ancestry populations, although these SNVs were related to the serum concentration of uric acid with borderline significance in our longitudinal EWASs. Our findings indicate that CDC42BPG may be a novel susceptibility locus for hyperuricemia. PMID- 29124446 TI - Towards better healthcare for migrant and refugee children in Europe. PMID- 29124447 TI - Psychiatric screening and interventions for minor refugees in Europe: an overview of approaches and tools. AB - : Currently hundreds of thousands of minor refugees entered Europe. This group has been exposed to traumatic events pre-, during, and post-migration and is at increased risk of developing psychiatric disorders. In this article, we describe the results of our literature search on screening and interventions for post traumatic stress disorder (PTSD) in minor refugees, in order to make recommendations for clinical practice. Results show that studies on diagnostic accuracy of assessment instruments and efficacy of mental healthcare interventions in this population are lacking. Traumatic experiences pre-flight, during the flight and at resettlement, superimposed by parental PTSD, and other contextual factors, might lead to more than 25% of minor refugees developing PTSD. CONCLUSION: To enhance the number of minor refugees recognized with PTSD, we recommend the use of a brief screening instrument. A public health approach, focusing on environmental supportive factors is the first step in treatment for this group, followed by short-term psychological group interventions focusing on psycho-education and stress reduction. Minor refugees with no improvement in PTSD symptoms by these interventions need referral to specialized mental health care services. Mental health providers should be culturally competent. What is Known: * Post-traumatic stress disorder, anxiety, sleeping problems, and depression are the most common psychiatric disorders in minor refugees. * Evidence based methods on screening and interventions in minor refugees with psychiatric disorders are lacking. What is New: * In the absence of validated screening tools a best practice reliable, quick and child-friendly tool is presented. * A layered system for mental health care and psychosocial support in minor refugees is explained. PMID- 29124448 TI - The Photocatalytic Application of Semiconductor Stibnite Nanostructure Synthesized via a Simple Microwave-Assisted Approach in Propylene Glycol for Degradation of Dye Pollutants and its Optical Property. AB - Stibnite (Sb2S3) semiconducting material was successfully synthesized by a rapid and facile microwave route using antimony chloride (SbCl3) and sodiumthiosulfate (Na2S2O3) dissolved in propylene glycol (PG) containing different hydroxyethyl cellulose (HEC) masses. The phase identification, morphology, and elemental composition of products were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), field- emission scanning electron microscopy (FE-SEM), energy dispersive X-ray (EDX) spectroscopy, and Fourier transform infrared spectroscopy (FTIR). The results revealed the orthorhombic phase of Sb2S3 single crystal-forming sheaf-like nanostructure, and a possible formation mechanism was proposed and discussed. Its direct band gap calculated from UV-visible absorption is 1.60 eV. In this research, the photocatalytic activities of Sb2S3 nanostructure were investigated through the degradation of methyl orange (MO) and methylene blue (MB) under visible light irradiation. The as-obtained 0.30 g HEC-added solution (0.3 HEC-Sb2S3) photocatalyst exhibited better photocatalytic activity than the other products, which degraded 91% of MO within 300 min and 90% of MB within 240 min under the Xe-lamp irradiation. The first-order plot was fitted with this experiment which the rate constant (k) of 0.3 HEC-Sb2S3 for MO and MB degradation are 0.0085 and 0.0098 min-1, respectively. Therefore, the new experience with a novel and simple synthetic procedure of Sb2S3 photocatalyst that exhibits the characteristics of a highly effective photocatalyst under visible light irradiation was discovered. PMID- 29124449 TI - The evolution of public health ethics frameworks: systematic review of moral values and norms in public health policy. AB - Given the evolution of the public health (PH) and the changes from the phenomenon of globalization, this area has encountered new ethical challenges. In order to find a coherent approach to address ethical issues in PH policy, this study aimed to identify the evolution of public health ethics (PHE) frameworks and the main moral values and norms in PH practice and policy. According to the research questions, a systematic search of the literature, in English, with no time limit was performed using the main keywords in databases Web of Science (ISI) and PubMed. Finally, the full text of 56 papers was analyzed. Most of the frameworks have common underpinning assumptions and beliefs, and the need to balance PH moral obligation to prevent harm and health promotion with respect for individual autonomy has been specified. As such, a clear shift from liberal values in biomedical ethics is seen toward the community's collective values in PHE. The main moral norms in PH practice and policy included protecting the population against harm and improving PH benefits, utility and evidenced-based effectiveness, distributive justice and fairness, respect for all, privacy and confidentiality, solidarity, social responsibility, community empowerment and participation, transparency, accountability and trust. Systematic review of PHE frameworks indicates utilization of the aforementioned moral norms through an practical framework as an ethical guide for action in the PH policy. The validity of this process requires a systematic approach including procedural conditions. PMID- 29124450 TI - Stepwise strategy for monitoring toxic cyanobacterial blooms in lentic water bodies. AB - Climate change has been causing the increase in frequency, severity, and duration of harmful algal blooms, which makes the establishment of water management strategies indispensable. For cyanobacteria, several methods are currently used in monitoring programs. However, these methods are time-consuming and require specialists, and results are usually not provided within an adequate timeframe for taking timely mitigation actions. This work proposes a strategy for a faster, easier, and more cost-effective monitoring of cyanobacterial blooms, using a stepwise approach based on fluorometric determination of phycocyanin at an early stage. Complementary parameters (chlorophyll a, enumeration of dominant cyanobacterial species and cyanotoxin potential and quantification) are determined when necessary, thus progressively allocating human and financial resources within the monitoring program. This strategy was applied and validated using nine lentic eutrophic freshwater bodies prone to the occurrence of cyanobacterial blooms. Samples were sequentially evaluated, and the study ended up with two samples that showed high health risks. However, according to WHO guidelines, eight of the nine samples would be classified as having "moderate risk of adverse health effects" and could lead to preventive measures that would have an important regional economic impact. Therefore, the present approach proved to be a promising alternative to increase the effectiveness and accuracy of the risk assessment process in water bodies where cyanobacterial blooms occur. PMID- 29124451 TI - Current treatment concepts for iatrogenic ventriculitis: a nationwide survey in Germany. AB - BACKGROUND: Iatrogenic ventriculitis is a common complication of the external ventricular drainage. While the procedure and indications for external ventricular drains (EVD) are highly standardized, the treatment of ventriculitis is not clearly defined. OBJECTIVE: To depict the treatment of iatrogenic ventriculitis currently performed in German hospitals. METHODS: A standardized questionnaire consisting of 18 multiple choice questions, each with the ability to provide additional individual answers, covering the diagnosis and treatment of iatrogenic ventriculitis as well as general handling of EVDs, was sent to 121 neurosurgical hospitals registered in the German Society for Neurosurgery (DGNC). RESULTS: Thirty-three out of 121 hospitals returned the questionnaire. While diagnostics are performed similarly in most hospitals, the treatment varies remarkably. Ten of the 33 (30%) units never applied antibiotics intrathecally and 12 (36%) only in selected (1-20%) cases, while 7 (21%) do this routinely, and the remaining 4 centers vary their treatment. While the targeted systemic therapy after pathogen identification and resistance testing is similar, the choice of empiric antibiotics varies as does the type of drug used for intrathecal therapy. Among the applied systemic antibiotics, vancomycin [n = 23 (70%)] and meropenem [n = 22 (67%)] were the most common, but many others, including ceftriaxone, metronidazol, linezolid, piperacillin/tazobactam, fosfomycin and ceftazidim, are used. There is no standard practice regarding EVD handling. Twelve (36%) hospitals do not replace the EVD after a new diagnosis of ventriculitis, 13 (39%) do so once after the diagnosis, and 8 (24%) regularly switch EVDs after a defined time span (7-20 days), even without signs of infection. CONCLUSION: Treatment concepts for iatrogenic ventriculitis are very heterogeneous. Thus, there is an urgent need for generating outcome data and defining a standard treatment algorithm with the recently published practice guideline being an important first step. PMID- 29124452 TI - Aboveground biomass estimation at different scales for subtropical forests in China. AB - BACKGROUND: The accurate estimation of forest biomass at different scales is the critical step in the assessment of forest carbon stocks. We used three models at increasing scales: allometric model at ecoregional scale (model 1), dummy variable allometric model at both ecoregion and regional scales (model 2), and allometric model at regional scale (model 3) to estimate the aboveground biomass of six subtropical forests in China. Furthermore, we also tested whether wood density can improve the accuracy of the allometric model at regional scale. RESULTS: Aboveground biomass estimates for six subtropical forests were significantly affected by the ecoregions (p < 0.05). Model 1 and model 2 had good fitness with higher values of R 2, lower RSE (residual standard error) and MPSE (mean percent standard error) than model 3. The values of MPSE for model 1, model 2, and model 3 ranged from 2.79 to 30.40%, 5.15 to 40.94%, and 13.25 to 80.81% at ecoregion scale, respectively. At regional scale, MPSE of model 2 was very similar to that of model 1, and was less than model 3. New allometric models with wood density had greater R 2, lower RSE and MPSE than the traditional allometric models without wood density variable for six subtropical forests at regional scale. CONCLUSION: The dummy variable allometric models have better performances to estimate aboveground biomass for six subtropical forests in China, which provided an effective approach to improve the compatibility of forest biomass estimations from different scales. New allometric models with wood density substantially improved accuracies of aboveground biomass estimation for subtropical forests at regional scale. PMID- 29124453 TI - A Machine Learning Ensemble Classifier for Early Prediction of Diabetic Retinopathy. AB - The main complication of diabetes is Diabetic retinopathy (DR), retinal vascular disease and it leads to the blindness. Regular screening for early DR disease detection is considered as an intensive labor and resource oriented task. Therefore, automatic detection of DR diseases is performed only by using the computational technique is the great solution. An automatic method is more reliable to determine the presence of an abnormality in Fundus images (FI) but, the classification process is poorly performed. Recently, few research works have been designed for analyzing texture discrimination capacity in FI to distinguish the healthy images. However, the feature extraction (FE) process was not performed well, due to the high dimensionality. Therefore, to identify retinal features for DR disease diagnosis and early detection using Machine Learning and Ensemble Classification method, called, Machine Learning Bagging Ensemble Classifier (ML-BEC) is designed. The ML-BEC method comprises of two stages. The first stage in ML-BEC method comprises extraction of the candidate objects from Retinal Images (RI). The candidate objects or the features for DR disease diagnosis include blood vessels, optic nerve, neural tissue, neuroretinal rim, optic disc size, thickness and variance. These features are initially extracted by applying Machine Learning technique called, t-distributed Stochastic Neighbor Embedding (t-SNE). Besides, t-SNE generates a probability distribution across high-dimensional images where the images are separated into similar and dissimilar pairs. Then, t-SNE describes a similar probability distribution across the points in the low-dimensional map. This lessens the Kullback-Leibler divergence among two distributions regarding the locations of the points on the map. The second stage comprises of application of ensemble classifiers to the extracted features for providing accurate analysis of digital FI using machine learning. In this stage, an automatic detection of DR screening system using Bagging Ensemble Classifier (BEC) is investigated. With the help of voting the process in ML-BEC, bagging minimizes the error due to variance of the base classifier. With the publicly available retinal image databases, our classifier is trained with 25% of RI. Results show that the ensemble classifier can achieve better classification accuracy (CA) than single classification models. Empirical experiments suggest that the machine learning-based ensemble classifier is efficient for further reducing DR classification time (CT). PMID- 29124454 TI - Evaluating the Effectiveness of Community and Hospital Medical Record Integration on Management of Behavioral Health in the Emergency Department. AB - This study evaluated the correlation of an emergency department embedded care coordinator with access to community and medical records in decreasing hospital and emergency department use in patients with behavioral health issues. This retrospective cohort study presents a 6-month pre-post analysis on patients seen by the care coordinator (n=524). Looking at all-cause healthcare utilization, care coordination was associated with a significant median decrease of one emergency department visit per patient (p < 0.001) and a decrease of 9.5 h in emergency department length of stay per average visit per patient (p<0.001). There was no significant effect on the number of hospitalizations or hospital length of stay. This intervention demonstrated a correlation with reducing emergency department use in patients with behavioral health issues, but no correlation with reducing hospital utilization. This under-researched approach of integrating medical records at point-of-care could serve as a model for better emergency department management of behavioral health patients. PMID- 29124455 TI - Measuring and understanding adherence in a home-based exercise intervention during chemotherapy for early breast cancer. AB - PURPOSE: Ensuring and measuring adherence to prescribed exercise regimens are fundamental challenges in intervention studies to promote exercise in adults with cancer. This study reports exercise adherence in women who were asked to walk 150 min/week throughout chemotherapy treatment for early breast cancer. Participants were asked to wear a FitbitTM throughout their waking hours, and Fitbit steps were uploaded directly into study computers. METHODS: Descriptive statistics are reported, and both unadjusted and multivariable linear regression models were used to assess associations between participant characteristics, breast cancer diagnosis, treatment, chemotherapy toxicities, and patient-reported symptoms with average Fitbit steps/week. RESULTS: Of 127 women consented to the study, 100 had analyzable Fitbit data (79%); mean age was 48 and 31% were non-white. Mean walking steps were 3956 per day. Nineteen percent were fully adherent with the target of 6686 steps/day and an additional 24% were moderately adherent. In unadjusted analysis, baseline variables associated with fewer Fitbit steps were: non-white race (p = 0.012), high school education or less (p = 0.0005), higher body mass index (p = 0.0024), and never/almost never drinking alcohol (p = 0.0048). Physical activity variables associated with greater Fitbit steps were: pre-chemotherapy history of vigorous physical activity (p = 0.0091) and higher self-reported walking minutes/week (p < 0.001), and higher outcome expectations from exercise (p = 0.014). Higher baseline anxiety (p = 0.03) and higher number of chemotherapy-related symptoms rates "severe/very severe" (p = 0.012) were associated with fewer steps. In multivariable analysis, white race was associated with 12,146 greater Fitbit steps per week (p = 0.004), as was self-reported walking minutes prior to start of chemotherapy (p < 0.0001). CONCLUSIONS: Inexpensive commercial-grade activity trackers, with data uploaded directly into research computers, enable objective monitoring of home-based exercise interventions in adults diagnosed with cancer. Analysis of the association of walking steps with participant characteristics at baseline and toxicities during chemotherapy can identify reasons for low/non-adherence with prescribed exercise regimens. PMID- 29124456 TI - Serial immunological parameters in a phase II trial of exemestane and low-dose oral cyclophosphamide in advanced hormone receptor-positive breast cancer. AB - BACKGROUND AND PURPOSE: Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets. METHODS: This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy (ClinicalTrials.gov: NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3+Helios+) and other immune cell subsets were monitored during treatment and compared with healthy controls. RESULTS: Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2 48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0-76.0%); median PFS was 4.23 months (95% CI 2.8-11.7). No treatment related decrease in Tregs was observed. However, elevated baseline levels of Naive Tregs [greater than 2.5 (the median of the naive Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32-56.5)]. In addition, the baseline levels of Naive Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of %CD4 + Naive T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40). CONCLUSION: Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naive Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients. PMID- 29124457 TI - When Does Premature Treatment Termination Occur? Examining Session-by-Session Dropout Among Clients with Gambling Disorder. AB - Premature termination challenges the successful outcomes of psychological treatments for gambling disorder. To date, research has primarily identified clients who are at particular risk for dropping out of treatment. A smaller but growing body of literature has investigated when dropout occurs. Typically, those studies have not considered improvement in psychological distress within their operationalizations of dropout and therefore may have misrepresented when dropout occurs. The current study examined when dropout occurs using an operationalization based on the criteria of attaining reliable change in a naturalistic sample of clients with gambling disorder, and the classification rates yielded from that operationalization were compared to the rates from a more common operationalization. Participants (n = 334) were clients meeting diagnostic criteria for gambling disorder at an outpatient private practice who completed a measure of psychological distress at baseline and prior to each subsequent treatment session. A survival analysis was conducted to determine temporal patterns of treatment dropout (i.e., clients who discontinued treatment before realizing reliable changes in psychological distress) and completion (i.e., clients who discontinued treatment after realizing reliable changes in distress) at each treatment session. Forty-nine percent of clients were classified as dropouts, and the majority of those clients did so in the first few sessions. The more common operationalization of dropout classified clients as dropouts when they had improved in their distress and clients as completers when they had not improved in their distress. Discussion centers on the implications of dropout occurring at various stages of treatment and future directions. PMID- 29124458 TI - Pitfalls of cannulation for extracorporeal life support: review of the literature and illustrative case presentation. AB - Extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) are an increasingly established advanced therapy for emerging severe lung and/or cardiocirculatory dysfunction or failure. Several reports have provided evidence for a potential benefit in prognosis by ECLS in cases of cardiogenic shock including cardiopulmonary resuscitation. Routine use in specialized centers reduces the incidence of negative side effects (e.g., vascular/ischemic, embolic, hemorrhagic, hemolytic and, furthermore, septic). Vascular complications like not only limb ischemia but also hypoxia proximal to the cannulation site up to complete sectorial hypoxia called "harlequin phenomenon" could refer to be a major adverse event in ECLS which, therefore, should be limited primarily to cardiocirculatory indications. Here we report on a case with "harlequin phenomenon" after ECLS implementation as a relevant complication of the mode of cannulation and review benefits and risks of commonly used variants of vascular access. PMID- 29124459 TI - Differences in clotting parameters between species for preclinical large animal studies of cardiovascular devices. AB - Several species of domestic animals are used in preclinical studies evaluating the safety and feasibility of medical devices; however, the relevance of animal models to human health is often not clear. The purpose of this study was to compare the clotting parameters of animal models to determine which animals most adequately mimic human clotting parameters. The clotting parameters of the different species were assessed in whole blood by in vitro thromboelastography using the clotting activators, such as tissue factor (extrinsic clotting screening test, EXTEM(r)) and partial thromboplastin phospholipid (intrinsic clotting screening test, IINTEM(r)). The measurements were performed using normal blood samples from humans (n = 13), calves (n = 18), goats (n = 56) and pigs (n = 8). Extrinsic clotting time (CT) and the intrinsic CT were significantly prolonged in calves compared to humans (249.9 +/- 91.3 and 376.4 +/- 124.4 s vs. 63.5 +/- 11.8 and 192.5 +/- 29.0 s, respectively, p < 0.01). The maximum clot firmness (MCF) in domestic animals (EXTEM(r): 77-87 mm, IINTEM(r): 66-78 mm) was significantly higher than that of humans (EXTEM(r): 59.1 +/- 6.0 mm, IINTEM(r): 58.8 +/- 1.5 mm, p < 0.01), and calves and goats exhibited longer time to MCF (MCF-t) than did humans and pigs (p < 0.01). Our results show that there are relevant differences in the four species' extrinsic and intrinsic clotting parameters. These cross-comparisons indicate that it is necessary to clarify characteristics of clotting properties in preclinical animal studies. PMID- 29124460 TI - Medical egg freezing: the importance of a patient-centered approach to fertility preservation. AB - PURPOSE: This binational qualitative study of medical egg freezing (MEF) examined women's motivations and experiences, including their perceived needs for patient centered care in the midst of fertility- and life-threatening diagnoses. METHODS: Forty-five women who had undertaken MEF were interviewed in the USA (33 women) and in Israel (12 women) between June 2014 and August 2016. Interviews lasted approximately 1 h and were conducted by two senior medical anthropologists, one in each country. Women were recruited from four American IVF clinics (two academic, two private) and two Israeli clinics (both academic) where MEF is being offered to cancer patients and women with other fertility-threatening medical conditions. RESULTS: Women who undertake MEF view their fertility and future motherhood as important components of their identities and recovery and, thus, are grateful for the opportunity to pursue fertility preservation. However, women who undergo MEF have special needs, given that they tend to be a "vulnerable" population of young (age < 30), unmarried, resource-constrained women, who are facing not only fertility loss but also the "double jeopardy" of cancer. Through in-depth, qualitative interviews, these women's MEF stories reveal 10 dimensions of care important to fertility preservation, including five "system factors" (information, coordination and integration, accessibility, physical comfort, cost) and five "human factors" (adolescent issues, male partner involvement, family involvement, egg disposition decisions, emotional support). Together, these dimensions of care constitute an important framework that can be best described as "patient-centered MEF." CONCLUSIONS: Women pursuing MEF have special medical needs and concerns, which require particular forms of patient-centered care. This study outlines 10 dimensions of patient-centered fertility preservation that are appropriate for MEF patients. This approach may help IVF clinics to be better prepared for delivering top-quality care to mostly young, single women facing the daunting prospect of fertility loss and life-threatening medical diagnoses. PMID- 29124461 TI - Improvement of pregnancy outcome by extending embryo culture in IVF-ET during clinical application. AB - PURPOSE: The purpose of this study is to investigate the application value of the extended embryo culture for 7-8 h in day 3 morning during IVF-ET process. METHODS: Embryos were retrospectively assessed during 08:00-09:00 on the morning of day 3 in the control group, and were assessed once again at 16:00 in the afternoon in the extended culture (EC) group. The embryos with good developmental potential were preferentially selected to transfer. The cumulative pregnancy outcomes were analyzed in one oocyte retrieval cycle. RESULTS: Similar proportions were found in the rates of cumulative clinical pregnancy, cumulative live birth, and the perinatal/neonatal outcomes per oocyte retrieval cycle (P > 0.05). But higher total clinical pregnancy rate, higher total implantation rate, and lower total abortion rate were obtained in the EC group (P < 0.05). After EC, 53.58% of the embryos were able to continue to develop. The transferred embryos were mainly composed of >= 8-cell embryos (75.90%) in the EC group and <= 8-cell embryos (82.92%) in the control group. Interestingly, the implantation rates were increasingly improved with the increasing blastomere number up to 56.31% at the morula stage in the EC group, while they were limited to 32.33% at 8-cell stage in the control group. CONCLUSIONS: The extended culture of day 3 embryos for 7-8 h not only reduced the risk of IVF-ET treatment compared to blastocyst culture through another 2-3 days, but also improved the clinical outcomes and the efficiency of every transferred cycle and every transferred embryo. PMID- 29124462 TI - Polymorphisms of mitochondrial DNA control region are associated to endometriosis. AB - PURPOSE: Polymorphisms in the control region of mitochondrial DNA (mtDNA) can affect generation of reactive oxygen species and impact in the pathogenesis of endometriosis. This study investigated the association of mtDNA polymorphisms with endometriosis. METHODS: Patients were divided in two groups: endometriosis (n = 90) and control (n = 92). Inclusion criteria were as follows: women between 18 and 50 years, with histological diagnosis and surgical staging of endometriosis (endometriosis group) or undergoing gynecological surgery for tubal ligation, leiomyoma, or ovarian cysts, with no evidence of endometriosis (control group). DNA extraction was performed from peripheral blood. Sanger sequencing of mtDNA control region was performed, and polymorphisms were determined comparing the sequences obtained with the Cambridge Reference Sequence. RESULTS: The frequency of polymorphisms T16217C (14.4 and 5.4% of endometriosis and control group, respectively; p = 0.049) and G499A (13.3 vs. 4.3%; p = 0.038) was higher in the endometriosis group, while T146C (32.6 vs. 18.9%; p = 0.042) and 573.2C (5.6 vs. 29.3%; p < 0.001) were lower. No difference was observed in haplogroups between groups. CONCLUSION: mtDNA polymorphisms T16217C and G499A were associated with endometriosis, while T416C and 573.2C were shown to be associated with an absence of disease. PMID- 29124463 TI - Contamination levels, toxicity profiles, and emission sources of polycyclic aromatic hydrocarbons (PAHs) in the soils of an emerging industrial town and its environs in the Southeastern Nigeria. AB - Polycyclic aromatic hydrocarbon (PAH) concentrations in Nnewi and its environs were determined. Soil samples were extracted by sonication using hexane:dichloromethane (3:1) mixture and determined by gas chromatography-flame ionization detection. The total PAHs concentrations (MUg/kg) were 16.681 to 46.815, being three orders of magnitude lower than the maximum permissible level recommended by the Agency for Toxic Substances and Disease Registry (ATSDR). These concentrations followed this order: industrial ? farmlands ? commercial ? residential. Industrialized areas showed higher concentrations (p ? 0.05) than the other areas. Diagnostic ratios show that the major source of PAHs was the open burning of industrial and agricultural wastes, as shown by the occurrence of highest concentrations in the industrial areas, followed by agricultural areas. Benzo[a]pyrene equivalent values showed non-pollution and very low toxicity. Nevertheless, it was clear that industrialization has had some impact on the PAHs levels in soils and the total environment in this area and could be problematic with time, except with proper environmental management. PMID- 29124464 TI - Linezolid-Associated Hypoglycemia. AB - Our case describes a 77-year-old, African American male who was experiencing recurrent hypoglycemic episodes, which resulted in two emergency department (ED) visits and a subsequent inpatient admission during his second ED visit. He was prescribed linezolid 600 mg twice daily for 14 days for the treatment of a Staphylococcus hominis urinary tract infection. Nine and a half days into therapy, the patient began having recurrent hypoglycemic episodes. These episodes persisted despite repeated intravenous dextrose boluses. The patient's linezolid was discontinued during the second day of his inpatient admission. After a brief lag period after the final linezolid administration, the patient's blood glucose level stabilized within normal limits. He was later discharged home. The Naranjo scale scores the causality of this reaction between 4 and 8, indicating possible to probable causality. The patient had a follow-up appointment with his primary care physician 2 weeks after discharge, with no noted blood glucose complications. Two months after discharge, he entered hospice care for his advancing heart failure and later expired due to causes unrelated to blood glucose complications. PMID- 29124465 TI - The origin of wild populations of Toxicodendron succedaneum on mainland Japan revealed by genetic variation in chloroplast and nuclear DNA. AB - Toxicodendron succedaneum: (L.) Kuntze is a tree cultivated for the production of sumac wax, which is extracted from the mesocarp. There are several hypotheses regarding the origin of T. succedaneum on mainland Japan. In this study, the geographical distribution of genetic variation in 13 wild populations on Honshu, Shikoku, Kyushu, and Ryukyu Islands, Japan was investigated and compared with that of individuals from continental Asia. Seven chloroplast DNA haplotypes of T. succedaneum were observed in Japan and could be divided into three lineages based on relatedness between haplotypes. One of these lineages was also observed in continental Asia, and the others were genetically distant from the haplotypes that originated on the continent, with one considered to have originated on the Ryukyu Islands, and the other on mainland Japan. The genetic diversity of both chloroplast and nuclear DNA was lower in populations from Ryukyu Islands than in populations from mainland Japan. Bayesian clustering based on nuclear genotypes showed a clear difference between the groups from Ryukyu Islands and mainland Japan. Based on approximate Bayesian computation analysis of polymorphic data for both genomes, it was inferred that wild populations of T. succedaneum on mainland Japan consist of both lineages with natural distribution on mainland Japan and those introduced from Ryukyu Islands and continental Asia. PMID- 29124466 TI - Antifungal activity of avocado rhizobacteria against Fusarium euwallaceae and Graphium spp., associated with Euwallacea spp. nr. fornicatus, and Phytophthora cinnamomi. AB - Plant rhizobacteria have been successfully used as biocontrol agents against fungal phytopathogens. However, their potential to control two important avocado diseases, namely Fusarium dieback (FD) and Phytophthora root rot (PRR), has been poorly studied. FD is an emerging disease triggered by fungi associated with two ambrosia beetle species (Euwallacea fornicatus species complex), while PRR is caused by Phytophthora cinnamomi, a soil-borne oomycete. In the present work, the antifungal activity of bacteria isolated from avocado rhizosphere was tested in dual culture assays against Fusarium euwallaceae, Graphium euwallaceae and Graphium sp., causal agents of FD, and against P. cinnamomi. In 2015, rhizosphere soil samples of FD infested and non-infested avocado trees were collected from a commercial avocado orchard in Escondido, California. In an initial screening, 72 of the 168 assessed bacterial isolates reduced mycelial growth of F. euwallaceae by up to 46%. Eight bacterial isolates showing inhibition percentages larger than 40% were then selected for further antagonism assays against the other fungal pathogens. Five bacterial isolates, determined by 16S rDNA sequencing to belong to the Bacillus subtilis/Bacillus amyloliquefaciens species complex, successfully inhibited the mycelial growth of both Graphium species by up to 30%. The same isolates and an additional isolate identified as Bacillus mycoides, inhibited the growth of P. cinnamomi by up to 25%. This is the first report of avocado rhizobacteria with antifungal activity against pathogens responsible for FD and PRR in avocado. PMID- 29124467 TI - Spathaspora piracicabensis f. a., sp. nov., a D-xylose-fermenting yeast species isolated from rotting wood in Brazil. AB - Two strains of a novel yeast species were isolated from rotting wood of an ornamental tree (purple quaresmeira, Tibouchina granulosa, Melastomataceae) in an Atlantic Rainforest area in Brazil. Analysis of the sequences of the internal transcribed spacer (ITS-5.8S) region and the D1/D2 domains of the large subunit rRNA gene showed that this species belongs to the Spathaspora clade, and is phylogenetically related to Spathaspora brasiliensis, Candida materiae and Sp. girioi. The novel species ferments D-xylose, producing ethanol, with amounts between 3.37 and 3.48 g L-1 ethanol from 2% D-xylose. Ascospores were not observed from this new species. The name Spathaspora piracicabensis f. a., sp. nov. is proposed to accommodate these isolates. The type strain is UFMG-CM-Y5867T (= CBS 15054T = ESALQ-I54T). The MycoBank number is MB 822,320. PMID- 29124468 TI - Mortality following benign sacral insufficiency fracture and associated risk factors. AB - : This study demonstrated increased mortality following sacral insufficiency fractures as with other major osteoporotic fractures. The 6-month mortality rate was 9.8%, the 1-year mortality rate was 17.5%, and the 3-year mortality rate was 25.5%. Sex- and age-adjusted standardized mortality ratio increased after fractures. INTRODUCTION: There are no data about mortality after sacral insufficiency fractures. The purposes of this study were to investigate the mortality rate among sacral insufficiency fracture patients and to identify risk factors associated with mortality. METHODS: This is a retrospective cohort study of patients diagnosed with sacral insufficiency fracture via radiological exam in a single institute from 2001 to 2014, excluding patients with pathological sacral fracture due to metastasis or primary tumor. Mortality and its predisposing factors were analyzed based on a review of electronic medical records and mortality data provided by the Korean Statistical Information Service. Kaplan Meier survival analysis and Cox regression analysis were used for statistical analysis. RESULTS: A total of 325 patients were included (275 women and 50 men). The mean age at the time of diagnosis was 69.4 years. One hundred and forty patients (43.1%) had a history of malignancy, and 71 patients (21.8%) had undergone pelvic radiation therapy before fracture diagnosis. Twenty-one patients (6.5%) underwent sacroplasty, and the others underwent conservative management after fracture diagnosis. The mean follow-up was 51.5 months, and a total of 101 patients died at the final follow-up. The 6-month mortality rate was 9.8%, the 1 year mortality rate was 17.5%, and the 3-year mortality rate was 25.5%. Sex- and age-adjusted standardized mortality ratio (SMR) increased after fractures. The overall SMR is 8.9 at 3 months decreasing to 4.5 at 2 years. Multivariable Cox regression analysis showed that significant factors associated with increased mortality were male gender, malignancy history, lumbosacral fusion with distal fusion level S1, stroke history, low total femur bone mineral density score, and low body mass index. CONCLUSIONS: Like other types of osteoporotic fractures, sacral insufficiency fractures are associated with increased mortality. PMID- 29124469 TI - Protocolization, Standardization and the Need for Adaptive Expertise in our Medical Systems. PMID- 29124470 TI - Relation of presystolic wave on doppler examination to syntax score in patients with acute myocardial infarction. AB - BACKGROUND: There are few reports demonstrating a relationship between presystolic wave (PSW) and left ventricular function. The aim of the present study was to investigate the associations between PSW and angiographic and echocardiographic characteristics of patients with acute myocardial infarction (AMI). METHODS: We studied 348 consecutive patients with AMI. Pulsed Doppler echocardiography was used to assess the both diastolic functions and presence of PSW from left ventricular outflow tract. Patients were divided into two groups by the presence or absence of PSW. The Syntax score (SXscore) was calculated from baseline angiograms to assess the complexity and severity of coronary artery disease. RESULTS: The overall prevalence of PSW was 51.1%. Compared to patients without PSW, patients with PSW presence had greater left ventricular ejection fraction (LVEF), greater septal a' velocity, lower mitral E and septal e' velocity and lower E/A and e'/a' ratios. Also, median SXscore were significantly lower in the PSW presence group compared to PSW absence group [1 (6-14) vs. 12 (7 18), P = 0.013]. In addition, the number of patients with high-SXscore (> 16) was significantly lower in PSW presence group (24 vs. 42), (P = 0.006). In multiple logistic regression analysis, absence of PSW found independent predictor of high SXscore (OR 2.297 95% CI 1.235-4.272; P = 0.009). CONCLUSIONS: We found that the presence of PSW was related with higher LVEF, lower SXscore and lower stage diastolic dysfunction in patients with AMI. PSW may be used in prediction of the coronary artery disease complexity and it could help risk stratification in patients with AMI. PMID- 29124471 TI - Clinical outcome and functional characteristics of patients with asymptomatic low flow low-gradient severe aortic stenosis with preserved ejection fraction are closer to high-gradient severe than to moderate aortic stenosis. AB - Asymptomatic "paradoxic" severe low-flow low-gradient aortic stenosis with preserved ejection fraction (PAS) constitutes a challenging condition where the optimal management and follow-up remain elusive. We evaluated the clinical outcome in patients with PAS as compared to asymptomatic patients with moderate (MAS) or classical severe aortic stenosis (CAS). Consecutive asymptomatic moderate or severe aortic stenosis patients without concomitant other heart or lung disease (n = 121) were invited. Participants (n = 74) were assigned to three subgroups with regard to degree of aortic stenosis: MAS (n = 25), CAS (n = 22) and PAS (n = 27). Echocardiographic parameters at baseline and clinical outcome data after > 3 years of follow-up time were obtained. Patients with PAS had the smallest stroke volumes and the highest relative wall thickness (p < 0.05). Left ventricular mass index was highest in subjects with CAS, followed closely by PAS and eventually MAS subjects. Whereas ejection fraction was similar amongst the subgroups, a stepwise decrease in global longitudinal left ventricular strain with increasing degree of aortic stenosis was observed, with CAS patients displaying the lowest mean global longitudinal strain, followed by PAS and MAS. A trend towards increasing mortality rate by increasing degree of stenosis was observed. Patients with CAS underwent aortic valve replacement surgery more frequently than both PAS and MAS (p < 0.001). These data suggest that echocardiographic parameters and clinical outcome in patients with PAS bear closer resemblance to CAS than to MAS, but management of PAS is more conservative than in CAS. PMID- 29124472 TI - Anxiety in Williams Syndrome: The Role of Social Behaviour, Executive Functions and Change Over Time. AB - Anxiety is a prevalent mental health issue for individuals with Williams syndrome (WS). Relatively little is known about the developmental course of anxiety, or how it links with core features of WS, namely social and executive functioning (EF). In this study, parent-reports of anxiety were compared across a 4-year period (N = 17), and links between anxiety, social and EF were explored from concurrent parent-reports (N = 26). Results indicated that high anxiety persisted over time, and anxiety was related to impairments in both social and executive functioning. Importantly, results indicated that impairments in EFs may drive the links between anxiety and social functioning. This timely investigation provides new insights into anxiety in WS and highlights potential areas for intervention. PMID- 29124473 TI - Severity and predictive factors of adverse events in pemetrexed-containing chemotherapy for non-small cell lung cancer. AB - Pemetrexed is a key anticancer agent for treatment of advanced non-small cell lung cancer (NSCLC). Pemetrexed is generally well tolerated, but individual patient differences exist in severity of adverse events. Our study aimed to characterize the adverse events of pemetrexed that result in discontinuation of chemotherapy and to identify risk factors associated with those adverse events. We retrospectively studied the incidence of adverse events in 257 patients with NSCLC who received pemetrexed (P) with or without bevacizumab (B) and/or carboplatin (C): P, PB, CP, or CPB. Patients whose chemotherapy was discontinued were divided into two groups according to adverse events and disease progression. Grade 2/3 nausea, fatigue with P and PB, and rash with CP and CPB occurred more frequent in the adverse events group than in the disease progression group. Multivariate analysis indicated that grade 2/3 nausea [odds ratio (OR) 9.94; 95% confidence interval (CI) 1.46-67.37; p = 0.01] and fatigue (OR 10.62; CI 1.60 70.20; p = 0.01) with P or PB, and rash (OR 6.12; CI 1.34-27.88; p = 0.01) with CP or CPB, were independent risk factors for discontinuation of chemotherapy. Administration of dexamethasone at doses less than 4 mg after the day of pemetrexed administration was associated with nausea following P or PB (OR 11.08; 95% CI 1.02-119.95; p = 0.04). Grade 2/3 nausea and fatigue with P or PB, and rash with CP or CPB, were associated with discontinuation of chemotherapy. PMID- 29124474 TI - Growth, chain formation, and toxin production by southern Brazilian Pseudo nitzschia isolates under laboratory conditions. AB - Pseudo-nitzschia is a diatom genus capable of producing the neurotoxin domoic acid (DA), which has been related to mortalities of marine vertebrates, and the amnesic shellfish poisoning (ASP) in human consumers of contaminated bivalves. This study reports DA production among Pseudo-nitzschia strains isolated from shellfish farming areas in southern Brazil. Twenty-seven cultures of potentially toxigenic Pseudo-nitzschia species were established. Growth, stepped-chain formation, and DA production were evaluated in static, intermittently illuminated (12:12 photoperiod) batch cultures for 12 selected strains, and under continuous light and/or turbulence for a single Pseudo-nitzschia calliantha strain. Growth rate ranged from 0.16 to 0.39 day-1 among the 12 strains. Only P. calliantha and P. cf. multiseries yielded detectable levels of intracellular DA, reaching up to 0.054 fg cell-1 in late exponential and 0.15 pg cell-1 in early stationary phase, respectively. Continuous light impaired cell growth, and turbulence enhanced step chain formation by threefold during exponential growth phase, but no DA production was detected under both conditions. The effect of turbulence on chain formation should be further evaluated in the field, once particle size is expected to affect the ingestion of toxic cells and thus toxin accumulation by certain DA vectors. The low cell toxicity revealed herein under laboratory conditions is in accordance with the low frequency of DA contamination episodes in south Brazilian waters. Nevertheless, monitoring of Pseudo-nitzschia abundance and DA presence in farming areas is continuously required to assure the quality of local shellfish products. PMID- 29124475 TI - Pre-oxidation of low-density polyethylene (LDPE) by ultraviolet light (UV) promotes enhanced degradation of LDPE in soil. AB - Polyethylene represents nearly 64% of all the synthetic plastics produced and are mainly used for domestic and industrial applications. Their extensive use poses a serious environmental threat because of their non-biodegradable nature. Among all the polyethylene remediation strategies, in situ bioremediation happens to be the safest and efficient one. In the current study, efforts had been given to compare the extent of LDPE degradation under UV-treated and UV-untreated conditions by soil microcosm. Landfill soil was collected and UV-treated and UV-untreated LDPE were added separately to the soil following incubation under similar conditions. Electron microscopic images as well as the weight loss and the tensile strength results clearly revealed that UV-treated LDPE showed better degradation than the non-treated ones in soil. To elucidate the mechanism of this enhanced biodegradation, the bond spectra of differentially treated LDPE were analyzed by FTIR. The results obtained from bond spectra studies revealed that UV treatment increases both carbonyl and terminal double-bond index of the LDPE, thereby making it highly susceptible for microbial degradation. Moreover, incubation of UV-treated LDPE with soil favors better adherence of metabolically active and significantly higher number of microorganisms on it. Taken together, all these results demonstrate the higher microbial association and their better metabolic potential to the UV-treated LDPE that lead to enhanced degradation of the LDPE by the soil microorganisms. PMID- 29124476 TI - Aligned Chemically Etched Silver Nanowire Monolayer as Surface-Enhanced Raman Scattering Substrates. AB - Silver nanowires (AgNWs) were chemically etched to significantly increase the surface roughness and then self-assembled on the liquid/gas interfaces via the interfacial assembly method to obtain aligned chemically etched silver nanowire films. The as-fabricated silver nanowire films were used as novel surface enhanced Raman scattering (SERS) substrates. The morphologies and plasmon characteristics of the substrates were investigated using multiple measurement methods. The performance of as-fabricated substrates was measured using rhodamine B as a probe. The detection limitation can be as low as 10-11 M. The greatly improved plasmonic properties are attributed to the efficient light coupling and larger electromagnetic field enhancement. The novel set of SERS substrates of aligned chemically etched AgNWs is believed to be important for efficient, homogeneous, and ultrasensitive SERS sensing applications. PMID- 29124477 TI - Correction to: Drug Delivery from an Innovative LAMA/LABA Co-suspension Delivery Technology Fixed-Dose Combination MDI: Evidence of Consistency, Robustness, and Reliability. AB - This article was originally published Online First without open access. After publication it was discovered that the author had ordered open access during the production process. The incorrect license was assigned to this paper due to a technical error. PMID- 29124479 TI - Study on the computer-aided design of high energetic compounds based on the 1,2,3,4-tetrazine-1,3-dioxide frame. AB - In order to discover more potential high energy compounds, five computer-aided design methods were founded, and 20 high energetic compounds based on the 1,2,3,4 tetrazine-1,3-dioxide frame were designed. The first step of computer-aided design methods was to design new frame M. Three combination rules were invented, they were simple double-points rule, complicated double-points rule, and complicated multi-points rule. The second step of computer-aided design methods was to design 1,2,3,4-tetrazine 1,3-dioxides derivants by connecting M to 1,2,3,4 tetrazine-1,3-dioxides. Two combination rules were invented, they were simple single-points rule and double-points rule. All the structures are ring-fused or caged compounds including 1,2,3,4-tetrazine-1,3-dioxide. In these compounds, almost half of them have positive or zero oxygen balances, and the nitrogen contents of 17 compounds are over 40%. The densities and detonation velocities of all compounds are over 1.98 g cm-3 and 9500 m s-1 respectively. -N = N- group and -NO2 group have a major contribution to enthalpy of formation, detonation heat, and power index. -O- group and -ONO2 group have the main contribution to density, detonation velocity, and detonation pressure. PMID- 29124480 TI - A case of napsin A-positive metastatic lung cancer originating from the colon. AB - BACKGROUND: We report a case of napsin A-positive metastatic lung cancer originating from the colon. No cases of napsin A-positive metastatic lung tumors originating from colorectal cancer have been reported previously. CASE PRESENTATION: Computed tomography identified a small lung nodule in a 70-year-old male patient, 18 months after resection for rectal cancer. The size of the lung tumor increased from 1.8 to 2.1 cm in 6 months and metastasis from the rectal cancer was suspected. Resection of the lung tumor was performed, and the histological features of the lung tumor revealed findings typical of colorectal adenocarcinoma and resembled those of the original rectal cancer. Furthermore, the metastasis stained positive for napsin A and thyroid transcription factor-1 (TTF-1) on immunohistochemical evaluation, and immunohistochemical analysis identified the same results in the rectal specimen. CONCLUSIONS: These findings led us to believe that this was a rare case of napsin A-positive metastatic lung cancer originating in the colon. The patient was treated with chemotherapy for recurrent rectal cancer, and no other metastases were found after the lung resection. This is the first report of napsin A-positive colorectal cancer metastasizing to the lung. PMID- 29124478 TI - The role of RNA-binding protein tristetraprolin in cancer and immunity. AB - RNA-binding protein tristetraprolin (TTP) plays a fundamental role in various physiological and pathological processes including differentiation, reprogramming, metabolism, proliferation, pluripotency, tumorigenesis and immunity. Due to its ability to bind and target ARE-containing mRNAs for rapid degradation, TTP down-regulates the expression of a mass of critical genes, thereby functioning as cancer suppressor gene. The loss of TTP has been reported in several human cancers and is relevant to poor prognosis. Recent research shows that TTP also has an emerging significant role in immunity. The aim of this paper is to provide an overview of various roles of TTP in human cancers and immunity. We summarize TTP deficiency in several cancers and discuss that the lack of TTP can influence tumor progression at different aspects such as promoting cancer cell proliferation; accelerating cell cycle; improving survivability and resisting cell death; inducing angiogenesis; activating invasion and metastasis; inducing epithelial-mesenchymal transition; and deregulating cellular energetics. We also pay attention to novel understanding of the relationship between TTP and immunity. Finally, due to its vital role, the disorder of TTP in both cancer and immune cells receives increasing attention and we overview current thinking about regulatory mechanisms of TTP itself expression. This knowledge may contribute to TTP becoming a diagnostic marker for cancer or immune-related diseases and a possible therapeutic target. PMID- 29124481 TI - Improved Antitumor Efficacy and Pharmacokinetics of Bufalin via PEGylated Liposomes. AB - Bufalin was reported to show strong pharmacological effects including cardiotonic, antiviral, immune-regulation, and especially antitumor effects. The objective of this study was to determine the characterization, antitumor efficacy, and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity, which were prepared by FDA-approved pharmaceutical excipients. Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high-pressure homogenization method. Their mean particle sizes were 127.6 and 155.0 nm, mean zeta potentials were 2.24 and - 18.5 mV, and entrapment efficiencies were 76.31 and 78.40%, respectively. In vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that in bufalin-loaded liposomes. The cytotoxicity of blank liposomes has been found within acceptable range, whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity. In vivo pharmacokinetics indicated that bufalin-loaded PEGylated liposomes could extend or eliminate the half-life time of bufalin in plasma in rats. The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma. PMID- 29124483 TI - Stochastic integer programming for multi-disciplinary outpatient clinic planning. AB - Scheduling appointments in a multi-disciplinary clinic is complex, since coordination between disciplines is required. The design of a blueprint schedule for a multi-disciplinary clinic with open access requirements requires an integrated optimization approach, in which all appointment schedules are jointly optimized. As this currently is an open question in the literature, our research is the first to address this problem. This research is motivated by a Dutch hospital, which uses a multi-disciplinary cancer clinic to communicate the diagnosis and to explain the treatment plan to their patients. Furthermore, also regular patients are seen by the clinicians. All involved clinicians therefore require a blueprint schedule, in which multiple patient types can be scheduled. We design these blueprint schedules by optimizing the patient waiting time, clinician idle time, and clinician overtime. As scheduling decisions at multiple time intervals are involved, and patient routing is stochastic, we model this system as a stochastic integer program. The stochastic integer program is adapted for and solved with a sample average approximation approach. Numerical experiments evaluate the performance of the sample average approximation approach. We test the suitability of the approach for the hospital's problem at hand, compare our results with the current hospital schedules, and present the associated savings. Using this approach, robust blueprint schedules can be found for a multi-disciplinary clinic of the Dutch hospital. PMID- 29124484 TI - Four-Dimensional Computed Tomography: Clinical Impact for Patients with Primary Hyperparathyroidism. PMID- 29124485 TI - Comment on: External Validation of the Simplified Preoperative Assessment for Low Grade Mucinous Adenocarcinoma of the Appendix. PMID- 29124482 TI - ApoCIII as a Cardiovascular Risk Factor and Modulation by the Novel Lipid Lowering Agent Volanesorsen. AB - PURPOSE OF REVIEW: Apolipoprotein CIII (ApoCIII) is now recognized as a key regulator in severe hypertriglyceridemia, chylomicronemia, and conditions of triglyceride-rich lipoprotein (TRL) remnant excess due to its inhibition of lipoprotein lipase (LPL) and hepatic lipase, leading to decreased hepatic reuptake of TRLs, as well as enhanced synthesis and secretion of VLDL from the liver. ApoCIII gain-of-function mutations are associated with atherosclerosis and coronary heart disease (CHD), and contribute to the development of cardiometabolic syndrome, hypertriglyceridemia, and type 2 diabetes mellitus. Conversely, loss-of-function mutations in ApoCIII are associated with lower levels of plasma triglycerides (TG), attenuation of vascular inflammatory processes such as monocyte adhesion and endothelial dysfunction, and potentially, a reduction in the incidence and progression of atherosclerosis and cardioprotection. RECENT FINDINGS: Evidence is now emerging that volanesorsen, a second-generation antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in decreases in TG in patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and metabolic dyslipidemia with type 2 diabetes giving support to the hypothesis that ApoCIII is a powerful inhibitor of LPL, and when reduced, endogenous clearance of TRLs can result in substantial reductions in TG levels. Discovery of the ApoCIII inhibitor volanesorsen opens a new era of lipid-lowering drugs for reduction in TG and potentially for reduction in LDL-C. Herein, this review will provide an update on the pathophysiology of ApoCIII linked atherosclerosis and the development of the first drug to target ApoCIII, volanesorsen, as a promising lipid-lowering agent. PMID- 29124486 TI - Importance of Platelet Indices in Hepatocellular Carcinoma Prognosis. PMID- 29124487 TI - Yes-Associated Protein (YAP) is a Key Factor for Improving the Management of Cancer Treatments. PMID- 29124488 TI - T-Helper 1 Immune Response in Metastatic Lymph Nodes of Pancreatic Ductal Adenocarcinoma: A Marker For Prolonged Survival. AB - BACKGROUND: Although lymph node (LN) metastases is considered a grave prognostic sign in pancreatic ductal adenocarcinoma (PDAC), patients with positive lymph nodes (PLN) constitute a heterogeneous group. Our purpose was to identify morphological and immune parameters in the primary tumor and in PLN of resected PDAC patients, which could further stratify these patients to different subgroups. METHODS: We retrospectively evaluated histological and immunohistochemical characteristics of 66 patients with PDAC who were operated at our institution. These were subsequently correlated to clinical outcome. RESULTS: Mean patient age and number of LN harvested was 65.5 +/- 10.3 and 12.3 +/- 6.5 years, respectively. Tumor size (T stage) and perineural invasion had no effect on clinical outcome. High-grade tumor was associated with decreased survival [overall survival (OS) = 19.6 +/- 2.7 months for poorly differentiated PDAC vs. 31.2 +/- 4 for well and moderately differentiated, p = 0.03]. Patients with >= 8 PLN had significantly worse outcome (OS = 7.3 +/- 0.8 months for PLN >= 8 vs. OS = 30.1 +/- 3.2 months for PLN < 8, p < 0.0001). T helper (Th) 1 immune response was measured both by its effector cells (CD8+) and expression of its main transcription factor, T-bet. CD8+ high patients had significantly increased OS compared with CD8+ low (OS = 36.8 +/- 5.3 months for CD8 + high vs. OS = 24.3 +/- 3.5 for CD8 + low, p = 0.03) Similarly, Th1 predominant immune response measured by T-bet expression was associated with improved OS compared with non-Th1 (OS = 32.8 +/- 3.2 vs. OS = 19.5 +/- 2.9, p < 0.0001). CONCLUSIONS: Our data indicate an association between Th1-type immune response and increased survival. Future research is needed to exploit Th1 immune response as a biological marker for immunotherapy. PMID- 29124489 TI - Reply to: Importance of Platelet Indices in Hepatocellular Carcinoma Prognosis. PMID- 29124490 TI - Nerve Blocks in Pediatric and Adolescent Headache Disorders. AB - PURPOSE OF REVIEW: Peripheral nerve blocks of the scalp, mainly greater occipital nerve blocks, have received a renewed interest amongst pediatric providers as they offer an alternate option to provide both acute and chronic relief from the suffering of children with difficult to treat headaches. This narrative review will provide an in-depth discussion of the published pediatric-specific studies exploring the utility of nerve blocks for pediatric headache disorders. RECENT FINDINGS: A total of seven pediatric publications have been reported to date and reveal excellent therapeutic effectiveness of bilateral greater occipital nerve blocks on primary chronic headaches and post-traumatic headaches. Lidocaine is the preferred anesthetic choice and the value-added of concomitant steroids remains to be elucidated. It is important to ensure complete paresthesia of the blocked nerves to maximize effectiveness. The available studies suggest that peripheral nerve blocks of the scalp are an excellent tool that frontline clinicians can add to their armamentarium in treating pediatric headaches. PMID- 29124491 TI - From the laboratory to the clinic: sharing BRCA VUS reclassification tools with practicing genetics professionals. AB - Despite ongoing research efforts to reclassify BRCA variant of uncertain significance (VUS), results for strategies to disseminate findings to genetic counselors are lacking. We disseminated results from a study on reclassification of BRCA VUS using a mailed reclassification packet including a reclassification guide, patient education aid, and patient letter template for patients/families with BRCA VUS. This study reports on genetic counselors' responses to the dissemination materials. Eligible participants (n = 1015) were identified using mailing lists from professional genetics organizations. Participants were mailed a BRCA VUS reclassification packet and a return postcard to assess responses to the materials. Closed-ended responses were analyzed using descriptive statistics, and thematic analysis was conducted on open-ended responses. In response to the mailing, 128 (13.0%) genetic counselors completed and returned postcards. The majority of respondents (n = 117; 91.4%) requested the patient letter template and patient education guides as PDFs (n = 122; 95.3%). The majority (n = 123; 96.9%) wanted an updated reclassification guide upon availability. Open-ended responses demonstrate the material was well-received; some specified they would tailor the patient letter to fit their practice and patients' needs. Participants requested additional patient and provider educational materials for use in practice. Materials communicating BRCA VUS reclassification updates were liked and were likely to be used in practice. To achieve the benefits of VUS reclassification in clinical practice, ongoing efforts are needed to continuously and effectively disseminate findings to providers and patients. PMID- 29124492 TI - Biogenesis of Selenium Nanoparticles Using Green Chemistry. AB - Selenium binds some enzymes such as glutathione peroxidase and thioredoxin reductase, which may be activated in biological infections and oxidative stress. Chemical and physical methods for synthesizing nanoparticles, apart from being expensive, have their own particular risks. However, nanoparticle synthesis through green chemistry is a safe procedure that different biological sources such as bacteria, fungi, yeasts, algae and plants can be the catalyst bed for processing. Synthesis of selenium nanoparticles (SeNPs) by macro/microorganisms causes variation in morphology and shape of the particles is due to diversity of reduction enzymes in organisms. Reducing enzymes of microorganisms by changing the status of redox convert metal ions (Se2-) to SeNPs without charge (Se0). Biological activity of SeNPs includes their protective role against DNA oxidation. Because of the biological and industrial properties, SeNPs have wide applications in the fields of medicine, microelectronic, agriculture and animal husbandry. SeNPs can show strong antimicrobial effects on the growth and proliferation of microorganisms in a dose-dependent manner. The objective of this review is to consider SeNPs applications to various organisms. PMID- 29124493 TI - Genotype phenotype correlation in Asian Indian von Hippel-Lindau (VHL) syndrome patients with pheochromocytoma/paraganglioma. AB - The data in genotype-phenotype correlation in Indian von Hippel-Lindau (VHL) patients is limited. We have retrospectively studied 31 genetically proven VHL patients with pheochromocytoma/paraganglioma (PCC/PGL) from families and have reviewed the World literature on PCC/PGL in patients with large VHL deletions. Three patients had large deletions and 28 patients had other mutations [missense mutations in 25, 3 bp deletion in 2 and single bp duplication in one]. Unilateral PCC were significantly more common in patients with large VHL deletions whereas multiple PCC (bilateral PCC or PCC + sympathetic PGL) were significantly more common in those with other mutations. World literature review confirmed the rarity of PCC/PGL in patients with large deletions and we report the first definitive case of PCC associated with complete VHL deletion. Pancreatic neuroendocrine tumours were more common, often metastatic and the most common cause of death in our cohort. Our study had eight parent off-spring pairs from five families. The off-springs were significantly younger at presentation and had significantly higher number of PCC/PGL. In conclusion, PCC/PGL are rare in patients with large VHL deletions and if occur are most likely to be solitary. Patients with bilateral PCC or multifocal PCC/PGL are least likely to have large VHL deletions. Our study also provides additional evidence for existence of the phenomenon of anticipation in VHL syndrome. PMID- 29124494 TI - Information and support needs of young women regarding breast cancer risk and genetic testing: adapting effective interventions for a novel population. AB - Young women from hereditary breast and ovarian cancer (HBOC) families face a unique set of challenges in managing their HBOC risk, where obtaining essential information to inform decision making is key. Previous work suggests that this need for specific health information also comes at a time of heightened distress and greater individuation from family. In this report, we describe our adaptation of a previously-studied behavioral intervention for this population, utilizing a systematic approach outlined by the Centers for Disease Control and Prevention. First, we assessed the information needs and levels of distress in this population and correlates of this distress. These data then were used to inform the adaptation and piloting of a three-session telephone-based peer coaching intervention. One hundred young women (M age = 25 years) who were first or second degree relatives of BRCA1/2 mutation carriers participated. Sixty-three percent of the sample endorsed unmet HBOC information needs and they, on average, reported moderate levels of cancer-related distress (M = 21.9, SD = 14.6). Greater familial disruption was associated with greater cancer-related distress in multivariable models (p < .05). Ten women who participated in the survey completed the intervention pilot. They reported lower distress from pre- to post- (15.8 vs. 12.0), as well as significantly lower decisional conflict (p < .05) and greater endorsement of an array of healthy coping strategies (i.e., active coping, instrumental coping, positive reframing, planning, p's < .05). Our survey results suggest that young adult women from HBOC families have unmet cancer genetic information and support needs. Our pilot intervention was able to reduce levels of decisional conflict and promote the use of effective coping strategies. This approach needs to be further tested in a larger randomized trial. PMID- 29124495 TI - Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer. AB - Patients synchronously or metachronously presenting with ovarian and colon cancer can pose diagnostic challenges. A primary colon carcinoma can metastasize to one or both ovaries, two independent primary tumors can arise or an ovarian carcinoma can metastasize to the colon. Clinical and immunohistochemical characterization can aid the diagnosis. Recently, we reported that in difficult cases finding pathogenic APC variants supports a colonic origin.In this case report we describe the clinical history of a female patient suspected for Lynch syndrome. She was diagnosed with a bilateral ovarian cancer at age 44, followed by the detection of a colon carcinoma 12.5 months later. Lesions of both sites showed a DNA mismatch repair deficiency with immunohistochemical loss of MLH1 and PMS2 expression without MLH1 promoter hypermethylation. In absence of germline MMR gene variants identical somatic MLH1 and CTNNB1 gene variants were found, indicating a clonal relation. MMR germline mosaicism was made unlikely by ultra deep sequencing of the MLH1 variant in DNA isolated from normal mucosa, blood, urine and saliva. Although initially being suspect for Lynch syndrome it was eventually concluded that a metachronously diagnosed colon carcinoma that metastasized to both ovaries was most likely. PMID- 29124496 TI - Biological activity of Entada phaseoloides and Entada rheedei. AB - The aim of our study is to find functional compounds from natural resources. We focus on plants grown in tropical areas, especially Madagascar and Thailand, because they have unique flora and are expected to contain interesting compounds. We review the functional compounds of the seed kernels of Entada phaseoloides and E. rheedei and their biological activities such as anti-proliferation and melanogenesis inhibitory properties, etc. PMID- 29124497 TI - Parent-Child Endorsement Discrepancies among Youth at Chronic-Risk for Depression. AB - Depression is one of the most common mental health problems among U.S. adolescents, particularly among Latinos. Parent-child ratings of the presence and severity of child depressive symptoms show only low-to-moderate agreement. However, research has failed to examine discrepancies in populations with the highest levels of unmet need and little is known about patterns and predictors of parent-child agreement in ratings of depressive symptoms among ethnic minority families in community settings. Using a sample of 184 low-income, predominantly Latino, 5th through 7th grade students (63.6% female) at chronic risk for depression, this study utilized exploratory Latent Class Analysis (LCA) to uncover patterns of parent-child endorsement of core diagnostic depressive symptoms. Overall, children reported higher levels of core (i.e., depressed mood, anhedonia, irritability) and secondary (e.g., sleep disturbances) depressive symptoms relative to their parents. The three latent classes identified include a low endorsement and high agreement class (LH), high endorsement and high agreement class (HH), and high child endorsement and low agreement class (HCL). Multinomial regression models revealed that previous mental health service use and higher externalizing problems were associated with HH class membership, relative to HCL class membership. Findings provide evidence that a substantial number of children may have depressive symptoms that go undetected by their parents. Access to services among children at-risk for depression may be increased with psychoeducation to improve parental awareness and stigma reduction. PMID- 29124498 TI - Effects of a 9-month resistance training intervention on quality of life, sense of coherence, and depressive symptoms in older adults: randomized controlled trial. AB - PURPOSE: (1) To determine the effects of a 9-month resistance training intervention on quality of life, sense of coherence, and depressive symptoms in older adults, and (2) to compare effects between different training frequencies. METHODS: Men and women aged 65-75 (N = 106) were randomized to four groups according to training frequency: training groups RT1 (n = 26), RT2 (n = 27), and RT3 (n = 28) and non-training control group (n = 25). All training groups attended supervised resistance training twice a week for 3 months. For the following 6 months, they continued training with different frequencies (1, 2 or 3 times per week). Psychological functioning was measured by quality of life (WHOQOL-Bref), sense of coherence (Antonovsky's SOC-13), and depressive symptoms (Beck's Depression Inventory II). Measurements were conducted at baseline and 3 and 9 months after baseline. The effects of the intervention were analyzed using generalized estimating equations (GEE). RESULTS: After 3 months, there was an intervention effect on environmental quality of life (group * time p = .048). Between 3 and 9 months, environmental quality of life decreased among RT1 compared to RT2 and RT3 (group * time p = .025). Between baseline and 9 months, environmental quality of life increased in RT2 compared to all other groups (group * time p = .011). Sense of coherence increased in RT2 compared to the control group and RT3 (group * time p = .032). CONCLUSION: Resistance training is beneficial for environmental quality of life and sense of coherence. Attending resistance training twice a week seems to be the most advantageous for these aspects of psychological functioning. PMID- 29124500 TI - Internet-Based Self-Help Intervention for ICD-11 Adjustment Disorder: Preliminary Findings. AB - Adjustment disorder is one of the most diagnosed mental disorders. However, there is a lack of studies of specialized internet-based psychosocial interventions for adjustment disorder. We aimed to analyze the outcomes of an internet-based unguided self-help psychosocial intervention BADI for adjustment disorder in a two armed randomized controlled trial with a waiting list control group. In total 284 adult participants were randomized in this study. We measured adjustment disorder as a primary outcome, and psychological well-being as a secondary outcome at pre-intervention (T1) and one month after the intervention (T2). We found medium effect size of the intervention for the completer sample on adjustment disorder symptoms. Intervention was effective for those participants who used it at least one time in 30-day period. Our results revealed the potential of unguided internet-based self-help intervention for adjustment disorder. However, high dropout rates in the study limits the generalization of the outcomes of the intervention only to completers. PMID- 29124501 TI - Quality and Clinical Outcomes Associated with a Gentamicin Use System Change for Managing Chorioamnionitis. AB - Chorioamnionitis is an intra-amniotic infection with serious maternal and neonatal complications. Clinical studies suggest antibiotic administration before delivery reduces the risk of complications compared to after delivery. Our center implemented a standardized intrapartum gentamicin computerized provider order entry and dosage form dispensing system intended to improve treatment initiation efficiency in hospitalized obstetric patients. The primary objective of this retrospective study was to determine if these system changes were associated with decreased time from gentamicin ordering to administration in patients with chorioamnionitis. A secondary objective was to compare clinical outcomes before and after system changes. Classification and regression tree (CART) analyses was applied to identify key predictors. Results demonstrated a trend towards reduced time to administration in the post-implementation group. Clinical outcomes were not altered. CART analysis revealed that post-implementation assignment and length of membrane rupture predicted shorter time to gentamicin initiation. This study suggests that the specific system changes we implemented were safe and improved efficiency, but additional changes are needed to have a clinically significant impact. PMID- 29124502 TI - Facilitators and Barriers for Advance Care Planning Among Ethnic and Racial Minorities in the U.S.: A Systematic Review of the Current Literature. AB - Growing evidence suggests a low engagement in advance care planning (ACP) among ethnic minorities in the U.S. The purpose of this study was to synthesize findings from prior research about ACP among ethnic minorities. An extensive literature search was conducted using multiple electronic databases. After applying inclusion criteria, 26 studies were included. Four categories of facilitators and barriers to ACP were identified: (1) Socio-demographic factors, (2) health status, literacy and experiences, (3) cultural values, and (4) spirituality. Socio-demographic factors showed inconsistent findings regarding their association with ACP engagement. Worse health status and knowledge about ACP are common facilitators across ethnic minority groups, whereas mistrust toward the health care system was a barrier only for Blacks. Collectivistic cultural values influenced ACP engagement among Latinos and Asian Americans; however, spirituality/religion played an important role among Blacks. The implications for culturally competent approaches to promote ACP and future research directions are discussed. PMID- 29124499 TI - Association between social support and health-related quality of life among Chinese rural elders in nursing homes: the mediating role of resilience. AB - PURPOSE: This study aims to confirm the relationship between social support and health-related quality of life (HRQOL) among rural Chinese elders in nursing homes, and to examine the mediating role of resilience in the impact of social support on HRQOL. METHODS: A cross-sectional survey of 205 elders aged 60 and above was conducted in five rural public nursing homes. Sociodemographic characteristics, the SF-36 questionnaire, and information about social support and resilience were collected. The researchers administered the questionnaires to the participants in a face-to-face setting. Descriptive analysis and a correlation matrix were used to indicate characteristics of the participants and bivariate correlations, respectively. The mediation analyses, composed of regression analysis and PROCESS analysis, were preformed to test both direct and indirect effects of social support on HRQOL, namely the mediating role of resilience. RESULTS: Social support was positively related to HRQOL (beta = 0.303, p < 0.001) among Chinese rural elders in nursing homes. The mediating role of resilience in the relationship between social support and HRQOL was confirmed (a*b bootstrapped 95% confidence interval = [0.098, 0.257]), which revealed that social support had an indirect effect on HRQOL through resilience. CONCLUSIONS: Resilience partially mediates the relationship between social support and HRQOL. The mediation model provides a better understanding of how social support and resilience work together to affect HRQOL, and it could guide the interventions in health care for promoting HRQOL among Chinese rural elders in nursing homes. PMID- 29124503 TI - Urological dysfunction in synucleinopathies: epidemiology, pathophysiology and management. AB - OBJECTIVE: Parkinson's disease (PD) and multiple system atrophy (MSA) are major neurogenerative diseases characterized pathologically by abnormal alpha-synuclein aggregation. PD and MSA are clinically characterized by motor disorder and bladder dysfunction (mainly urinary urgency and frequency, also called overactive bladder). However, few literatures are available concerning bladder dysfunction in PD or MSA. METHOD: A systematic review. RESULTS: The bladder dysfunction in MSA is more severe than that in PD for large post-void residual or urinary retention. These bladder dysfunctions presumably reflect the different nervous system pathologies. Overactive bladder in PD reflects lesions in the brain, e.g., in the prefrontal-nigrostriatal D1 dopaminergic bladder-inhibitory pathway. Overactive bladder in MSA reflects lesions similar to PD and the cerebellum (bladder-inhibitory), and the urinary retention in MSA presumably reflects lesions in the pontine micturition center and the sacral intermediolateral nucleus of the spinal cord (bladder-facilitatory). Bladder dysfunction not only impairs an individual's quality of life, it can also cause emergency hospitalizations due to acute retention and early institutionalization. Anticholinergics are the first-line treatment for bladder dysfunction in PD and MSA patients, but care should be taken for the management of bladder dysfunction particularly in MSA patients due to the high prevalence of difficult emptying, which needs clean, intermittent catheterization. CONCLUSIONS: This review summarizes the epidemiology, pathophysiology, and management of bladder dysfunction in individuals with PD or MSA. PMID- 29124504 TI - Variable synaptic strengths controls the firing rate distribution in feedforward neural networks. AB - Heterogeneity of firing rate statistics is known to have severe consequences on neural coding. Recent experimental recordings in weakly electric fish indicate that the distribution-width of superficial pyramidal cell firing rates (trial- and time-averaged) in the electrosensory lateral line lobe (ELL) depends on the stimulus, and also that network inputs can mediate changes in the firing rate distribution across the population. We previously developed theoretical methods to understand how two attributes (synaptic and intrinsic heterogeneity) interact and alter the firing rate distribution in a population of integrate-and-fire neurons with random recurrent coupling. Inspired by our experimental data, we extend these theoretical results to a delayed feedforward spiking network that qualitatively capture the changes of firing rate heterogeneity observed in in vivo recordings. We demonstrate how heterogeneous neural attributes alter firing rate heterogeneity, accounting for the effect with various sensory stimuli. The model predicts how the strength of the effective network connectivity is related to intrinsic heterogeneity in such delayed feedforward networks: the strength of the feedforward input is positively correlated with excitability (threshold value for spiking) when firing rate heterogeneity is low and is negatively correlated with excitability with high firing rate heterogeneity. We also show how our theory can be used to predict effective neural architecture. We demonstrate that neural attributes do not interact in a simple manner but rather in a complex stimulus-dependent fashion to control neural heterogeneity and discuss how it can ultimately shape population codes. PMID- 29124505 TI - Transitions between asynchronous and synchronous states: a theory of correlations in small neural circuits. AB - The study of correlations in neural circuits of different size, from the small size of cortical microcolumns to the large-scale organization of distributed networks studied with functional imaging, is a topic of central importance to systems neuroscience. However, a theory that explains how the parameters of mesoscopic networks composed of a few tens of neurons affect the underlying correlation structure is still missing. Here we consider a theory that can be applied to networks of arbitrary size with multiple populations of homogeneous fully-connected neurons, and we focus its analysis to a case of two populations of small size. We combine the analysis of local bifurcations of the dynamics of these networks with the analytical calculation of their cross-correlations. We study the correlation structure in different regimes, showing that a variation of the external stimuli causes the network to switch from asynchronous states, characterized by weak correlation and low variability, to synchronous states characterized by strong correlations and wide temporal fluctuations. We show that asynchronous states are generated by strong stimuli, while synchronous states occur through critical slowing down when the stimulus moves the network close to a local bifurcation. In particular, strongly positive correlations occur at the saddle-node and Andronov-Hopf bifurcations of the network, while strongly negative correlations occur when the network undergoes a spontaneous symmetry breaking at the branching-point bifurcations. These results show how the correlation structure of firing-rate network models is strongly modulated by the external stimuli, even keeping the anatomical connections fixed. These results also suggest an effective mechanism through which biological networks may dynamically modulate the encoding and integration of sensory information. PMID- 29124507 TI - Pre-performance Physiological State: Heart Rate Variability as a Predictor of Shooting Performance. AB - Heart rate variability (HRV) is commonly used in sport science for monitoring the physiology of athletes but not as an indicator of physiological state from a psychological perspective. Since HRV is established to be an indicator of emotional responding, it could be an objective means of quantifying an athlete's subjective physiological state before competition. A total of 61 sport shooters participated in this study, of which 21 were novice shooters, 19 were intermediate shooters, and 21 were advanced level shooters. HRV, self-efficacy, and use of mental skills were assessed before they completed a standard shooting performance task of 40 shots, as in a competition qualifying round. The results showed that HRV was significantly positively correlated with self-efficacy and performance and was a significant predictor of shooting performance. In addition, advanced shooters were found to have significantly lower average heart rate before shooting and used more self-talk, relaxation, imagery, and automaticity compared to novice and intermediate shooters. HRV was found to be useful in identifying the physiological state of an athlete before competing, and as such, coaches and athletes can adopt practical strategies to improve the pre performance physiological state as a means to optimize performance. PMID- 29124506 TI - Heart Rate Variability Biofeedback Does Not Substitute for Asthma Steroid Controller Medication. AB - Despite previous findings of therapeutic effects for heart rate variability biofeedback (HRVB) on asthma, it is not known whether HRVB can substitute either for controller or rescue medication, or whether it affects airway inflammation. Sixty-eight paid volunteer steroid naive study participants with mild or moderate asthma were given 3 months of HRVB or a comparison condition consisting of EEG alpha biofeedback with relaxing music and relaxed paced breathing (EEG+), in a two-center trial. All participants received a month of intensive asthma education prior to randomization. Both treatment conditions produced similar significant improvements on the methacholine challenge test (MCT), asthma symptoms, and asthma quality of life (AQOL). MCT effects were of similar size to those of enhanced placebo procedures reported elsewhere, and were 65% of those of a course of a high-potency inhaled steroid budesonide given to a sub-group of participants following biofeedback training. Exhaled nitric oxide decreased significantly only in the HRVB group, 81% of the budesonide effect, but with no significant differences between groups. Participants reported becoming more relaxed during practice of both techniques. Administration of albuterol after biofeedback sessions produced a large improvement in pulmonary function test results, indicating that neither treatment normalized pulmonary function as a potent controller medication would have done. Impulse oscillometry showed increased upper airway (vocal cord) resistance during biofeedback periods in both groups. These data suggest that HRVB should not be considered an alternative to asthma controller medications (e.g., inhaled steroids), although both biofeedback conditions produced some beneficial effects, warranting further research, and suggesting potential complementary effects. Various hypotheses are presented to explain why HRVB effects on asthma appeared smaller in this study than in earlier studies. Clinical Trial Registration NCT02766374. PMID- 29124508 TI - ? PMID- 29124509 TI - Evaluation of cancer rehabilitation in Austria. PMID- 29124510 TI - LPS ameliorates renal ischemia/reperfusion injury via Hsp27 up-regulation. AB - PURPOSE: We have recently reported lipopolysaccharide (LPS) pretreatment attenuated renal ischemia/reperfusion injury (IRI), but the exact mechanism remains to be well elucidated. It was reported that heat shock protein (Hsp) 27 was up-regulated after administration of LPS, but whether a direct link existed between Hsp27 up-regulation and LPS-induced protection against renal IRI is still unknown. METHODS: Mice were exposed to IRI or sham procedure, with pretreatment of LPS or not. Quercetin, an inhibitor of Hsp27 synthesis, was used, and an RNA interference with adenovirus vector using short hairpin RNA targeting Hsp27 was developed for inhibition of Hsp27 in mice. In addition, mice trans-infected with adenovirus vector encoding Hsp27 were used to testify the role of Hsp27 overexpression in LPS-induced renoprotection. Renal function, histological damage, inflammatory reaction, oxidative stress and apoptosis indices were measured. Western blot analysis was used to detect expression of Hsp27. RESULTS: We found LPS pretreatment stimulated renal up-regulation of Hsp27 and reduced renal IRI proven by less renal dysfunction, histological damage, inflammatory reaction, oxidative stress and apoptosis. It was observed that inhibition of Hsp27 synthesis by Quercetin abolished LPS-induced renoprotective effects. After renal knockdown of Hsp27, LPS-induced tolerance against renal IRI was largely removed. Mice with Hsp27 overexpression showed significantly improved renal function after IRI and LPS combined with Hsp27 overexpression had a synergistic effect on protection against renal IRI. CONCLUSION: Administration of LPS produces protective effects against renal IRI via Hsp27 up-regulation. Preconditional Hsp27 up-regulation might have a great potential for the treatment of renal IRI via ameliorating apoptosis. PMID- 29124511 TI - Effect of shear stress on the migration of hepatic stellate cells. AB - When the liver is damaged, hepatic stellate cells (HSCs) can change into an activated, highly migratory state. The migration of HSCs may be affected by shear stress due not only to sinusoidal flow but also by the flow in the space of Disse because this space is filled with blood plasma. In this study, we evaluated the effects of shear stress on HSC migration in a scratch-wound assay with a parallel flow chamber. At regions upstream of the wound area, the migration was inhibited by 0.6 Pa and promoted by 2.0 Pa shear stress, compared to the static condition. The platelet-derived growth factor (PDGF)-BB receptor, PDGFR-beta, was expressed in all conditions and the differences were not significant. PDGF increased HSC migration, except at 0.6 Pa shear stress, which was still inhibited. These results indicate that another molecular factor, such as PDGFR-alpha, may act to inhibit the migration under low shear stress. At regions downstream of the wound area, the migration was smaller under shear stress than under the static condition, although the expression of PDGFR-beta was significantly higher. In particular, the migration direction was opposite to the wound area under high shear stress; therefore, migration might be influenced by the intercellular environment. Our results indicate that HSC migration was influenced by shear stress intensity and the intercellular environment. PMID- 29124512 TI - Synthesis and antiproliferative and apoptosis-inducing activity of novel 3 substituted-3-hydroxy-2-oxindole compounds. AB - Anticancer role of oxindole compounds is well documented. Here, we synthesized new derivatives of 3-hydroxy-2-oxindole functionalized at position 3 (1a-f) which are expected to have antiproliferative activity in cancer cells. Human prostate cancer cell line (DU145) was treated with the synthesized derivatives at 40-MUM concentration for 24, 48, and 72 h. Compounds 1-ethyl-3-hydroxy-1,1',3,3' tetrahydro-2H,2'H-3,3'-biindole-2,2'-dione (1d), 5-bromo-1-ethyl-3-hydroxy 1,1',3,3'-2H,2'H-3,3'-biindole-2,2'-dione (1e), and 5-chloro-1-ethyl-3-hydroxy 1,1',3,3'-tetrahydro-2H,2'H-3,3'-biindole-2,2'-dione (1f) were found to significantly reduce DU145 cell viability at 48 and 72 h whereas no significant changes were observed up to 24 h. The compounds 1e and 1f showed the most cytotoxicity effect and had a similar antiproliferative activity on DU145 cell line. They have halogen and ethyl substitutions at positions 5 and 1, respectively. The IC50 of compound 1e for DU145 and A375 cells at 48 h was determined. The apoptotic effects and cell cycle progression of compound 1e at 1/2 * IC50 (55 MUM) concentration in DU145 cells were investigated by nuclei staining, comet assay, flow cytometry, and scanning electron microscopy (SEM). The results obtained showed that this compound increased the percentage of tail DNA, increased the occurrence of the sub-G1 phase, and induced G2M arrest and apoptosis in DU145 cells after exposure for 48 h to a 55-MUM concentration. The SEM images revealed cell contraction at 24 h, cell condensation, plasma membrane blebbing, and formation of apoptotic bodies at 48 and 72 h. These observations suggest that the antiproliferative activity of compound 1e may be to induce apoptosis in DU145 cells. PMID- 29124513 TI - Electrocoagulation of olive mill wastewaters to enhance biogas production. AB - OBJECTIVES: To assess the combination of electrocoagulation and anaerobic co digestion of olive mill wastewaters (OMWW) with other substrates, such as chicken manure, in a continuous stirred tank reactor for biogas production. RESULTS: Anaerobic digestion of OMWW treated by electrocoagulation allowed higher production of biogas, up to 0.74 l biogas g-1 COD introduced compared to untreated or diluted olive mill wastewaters (OMWW) (0.37 and 0.6 l biogas g-1 COD) respectively. Pretreated OMWW co-digested with chicken manure at different volumic ratios OMWW/manure in a continuous stirred tank reactor under mesophilic conditions revealed that OMWW/manure (7:3 v/v) was optimal for biogas production and process stability. CONCLUSION: Anaerobic digestion could achieve promising results in depollution and valorization of OMWW under a continuous stirred tank reactor. PMID- 29124515 TI - Gene expression studies of reference genes for quantitative real-time PCR: an overview in insects. AB - Whenever gene expression is being examined, it is essential that a normalization process is carried out to eliminate non-biological variations. The use of reference genes, such as glyceraldehyde-3-phosphate dehydrogenase, actin, and ribosomal protein genes, is the usual method of choice for normalizing gene expression. Although reference genes are used to normalize target gene expression, a major problem is that the stability of these genes differs among tissues, developmental stages, species, and responses to abiotic factors. Therefore, the use and validation of multiple reference genes are required. This review discusses the reasons that why RT-qPCR has become the preferred method for validating results of gene expression profiles, the use of specific and non specific dyes and the importance of use of primers and probes for qPCR as well as to discuss several statistical algorithms developed to help the validation of potential reference genes. The conflicts arising in the use of classical reference genes in gene normalization and their replacement with novel references are also discussed by citing the high stability and low stability of classical and novel reference genes under various biotic and abiotic experimental conditions by employing various methods applied for the reference genes amplification. PMID- 29124514 TI - Anaerobic microplate assay for direct microbial conversion of switchgrass and Avicel using Clostridium thermocellum. AB - OBJECTIVE: To develop and prototype a high-throughput microplate assay to assess anaerobic microorganisms and lignocellulosic biomasses in a rapid, cost-effective screen for consolidated bioprocessing potential. RESULTS: Clostridium thermocellum parent Deltahpt strain deconstructed Avicel to cellobiose, glucose, and generated lactic acid, formic acid, acetic acid and ethanol as fermentation products in titers and ratios similar to larger scale fermentations confirming the suitability of a plate-based method for C. thermocellum growth studies. C. thermocellum strain LL1210, with gene deletions in the key central metabolic pathways, produced higher ethanol titers in the Consolidated Bioprocessing (CBP) plate assay for both Avicel and switchgrass fermentations when compared to the Deltahpt strain. CONCLUSION: A prototype microplate assay system is developed that will facilitate high-throughput bioprospecting for new lignocellulosic biomass types, genetic variants and new microbial strains for bioethanol production. PMID- 29124516 TI - Purification of therapeutic proteins mediated by in vivo polyester immobilized sortase. AB - OBJECTIVES: To overcome laborious and costly procedures often associated with therapeutic protein production and purification, in vivo polyester immobilized sortase is explored for the production of human tumor necrosis factor alpha (TNFalpha) and human interferon alpha 2b (IFNalpha2b) by Escherichia coli. RESULTS: Hybrid genes encoding PhaC-Sortase-TNFalpha or PhaC-Sortase-IFNalpha2b fusions (with a LPETG recognition signal immediately before TNFalpha or IFNalpha2b), mediated intracellular production of polyester (polyhydroxyalkanoate, PHA) beads in Escherichia coli. Upon isolation of respective PHA beads, pure soluble TNFalpha or IFNalpha2b was released by activating sortase via addition of CaCl2 and triglycine. TNFalpha and IFNalpha2b each were recognized by corresponding conformational antibodies in an ELISA assay. CONCLUSIONS: In vivo polyester immobilized sortase could be exploited for production and purification of high-value therapeutic proteins without laborious and costly downstream processing. PMID- 29124517 TI - Characterization of L-rhamnose isomerase from Clostridium stercorarium and its application to the production of D-allose from D-allulose (D-psicose). AB - OBJECTIVE: To characterize L-rhamnose isomerase (L-RI) from the thermophilic bacterium Clostridium stercorarium and apply it to produce D-allose from D allulose. RESULTS: A recombinant L-RI from C. stercorarium exhibited the highest specific activity and catalytic efficiency (k cat/K m) for L-rhamnose among the reported L-RIs. The L-RI was applied to the high-level production of D-allose from D-allulose. The isomerization activity for D-allulose was maximal at pH 7, 75 degrees C, and 1 mM Mn2+ over 10 min reaction time. The half-lives of the L RI at 65, 70, 75, and 80 degrees C were 22.8, 9.5, 1.9, and 0.2 h, respectively. To ensure full stability during 2.5 h incubation, the optimal temperature was set at 70 degrees C. Under the optimized conditions of pH 7, 70 degrees C, 1 mM Mn2+, 27 U L-RI l-1, and 600 g D-allulose l-1, L-RI from C. stercorarium produced 199 g D-allose l-1 without by-products over 2.5 h, with a conversion yield of 33% and a productivity of 79.6 g l-1 h-1. CONCLUSION: To the best of our knowledge, this is the highest concentration and productivity of D-allose reported thus far. PMID- 29124518 TI - One pot simultaneous preparation of both enantiomer of beta-amino alcohol and vicinal diol via cascade biocatalysis. AB - OBJECTIVES: To investigate the efficiency of a new cascade biocatalysis system for the conversion of R, S-beta-amino alcohols to enantiopure vicinal diol and beta-amino alcohol. RESULTS: An efficient cascade biocatalysis was achieved by combination of a transaminase, a carbonyl reductase and a cofactor regeneration system. An ee value of > 99% for 2-amino-2-phenylethanol and 1-phenyl-1, 2 ethanediol were simultaneously obtained with 50% conversion from R, S-2-amino-2 phenylethanol. The generality of the cascade biocatalysis was further demonstrated with the whole-cell approaches to convert 10-60 mM R, S-beta-amino alcohol to (R)- and (S)-diol and (R)- and (S)-beta-amino alcohol in 90-99% ee with 50-52% conversion. Preparative biotransformation was demonstrated at a 50 ml scale with mixed recombinant cells to give both (R)- and (S)-2-amino-2 phenylethanol and (R)- and (S)-1-phenyl-1, 2-ethanediol in > 99% ee and 40-42% isolated yield from racemic 2-amino-2-phenylethanol. CONCLUSIONS: This cascade biocatalysis system provides a new practical method for the simultaneous synthesis of optically pure vicinal diol and an beta-amino alcohol. PMID- 29124520 TI - SEOM clinical guideline of diagnosis and management of low-grade glioma (2017). AB - Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk-benefit ratio of adjuvant treatment must be weighed for each individual. PMID- 29124521 TI - Successful peritoneal dialysis using a percutaneous tube for peritoneal drainage in an extremely low birth weight infant: a case report. AB - BACKGROUND: Peritoneal dialysis (PD) for acute kidney injury (AKI) of newborns has been performed safely. AKI occurs in 8 to 24% of extremely low birth weight (ELBW) infants. Although PD has only been used occasionally in ELBW infants, prognosis is poor for ELBW infants with AKI. Several reports have described successful PD in these infants, but no guideline-based evidence concerning indications for renal replacement therapy in ELBW infants are currently available. Here, we report on our experience with PD in an ELBW infant with AKI resulting from septic shock. CASE PRESENTATION: A male was born at 24 weeks and 3 days gestation weighing 264 g by emergency cesarean section due to complications of pregnancy in a patient with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. On day of life (DOL) 15, the inability to ventilate, along with cardiovascular dysfunction, acute kidney injury, and ascites under tension led to the tentative diagnosis of abdominal compartment syndrome (ACS). On DOL 17, placement of a percutaneous drainage tube immediately released compression of the tense abdomen. Although intra-abdominal pressure reduction with percutaneous drainage temporarily improved respiratory status, circulatory impairment persisted and infections were not well controlled. Finally, the patient developed anuria. On DOL 21, peritoneal dialysis (PD) was started by initially inserting a drainage tube. Although the patient had catheter-associated peritonitis, urine output improved by DOL 44 and PD was discontinued on DOL 53. On DOL 75, extubation was conducted without circulatory dysfunction. The patient was discharged on DOL 224. CONCLUSIONS: We emphasize that starting PD treatment before the onset of anuria is important in ELBW infants with AKI. Although the catheter used in our case was initially inserted for drainage of ascites, this type of catheter is sufficiently useful for PD in ELBW infants, and PD using a drainage tube may represent a safe, effective, and minimally invasive treatment for ELBW infants. To our knowledge, this is the first report to describe the use of a percutaneous tube to conduct successful PD for peritoneal drainage in an ELBW infant. This is the lowest-weight ELBW infant with successful PD reported to date. PMID- 29124519 TI - Prognostic and predictive role of the PI3K-AKT-mTOR pathway in neuroendocrine neoplasms. AB - Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K-AKT-mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials' design to identify potential predictive or prognostic biomarkers. PMID- 29124522 TI - Retraction Note to: Potential Start Codon Targeted (SCoT) and Interretrotransposon Amplified Polymorphism (IRAP) Markers for Evaluation of Genetic Diversity and Conservation of Wild Pistacia Species Population. AB - "This article has been retracted by the Publisher in agreement with the Editor-in Chief, because it contains portions of writings on the same topic already published and without sufficient attribution to these earlier works being given. The principal authors of the paper acknowledged that text from background sources was mistakenly used in this article without proper reference to the original source. Upon investigation carried out according to the Committee on Publication Ethics guidelines, it has been found that the authors have duplicated or rephrased parts from other articles of which the main sources. PMID- 29124523 TI - Assessing Mental Health Among Adults. AB - The aim of the study is to compare the knowledge of adults regarding mental health. Public understanding regarding mental health and illnesses among general population is usually a lacking aspect. Understanding mental illness plays a paramount role in the prevention and treatment of mental diseases and also rehabilitation of individual. Mental health is considered to be the foundation for effective functioning for an individual and also for a community. Despite all of these facts, mental health is still deliberated as a luxury. The misinterpretations on which such views are formulated are now becoming vibrant than they were in the past. In addition, WHO and other international organizations aiming to identify the enhancement of mental health as a priority concern for low and middle income countries especially in India. A comparative study involving urban and rural areas with selected 400 adults. A structured knowledge questionnaire was cast-off to assess and compare the knowledge of adults regarding mental health, residing in urban and rural areas. Majority of adults residing in urban areas were having good level of knowledge regarding mental health as compared to rural areas. Based on the study findings it was unwavering that adults in urban have good level of understanding regarding mental health which eventually help them to supports mental illness in their community settings. PMID- 29124524 TI - High comorbidity, measured by the Charlson Comorbidity Index, associates with higher 1-year mortality risks in elderly patients experiencing a first acute heart failure hospitalization. AB - BACKGROUND: Comorbidity is related to poor health results in chronic heart failure (HF). AIMS: The purpose of the study was to assess whether a high Charlson Comorbidity Index score (CCI) relates to 1 year mortality after a first hospitalization for acute HF (AHF). METHODS: We reviewed the medical records of 897 patients > 65 years of age admitted within a two-year period because of a first episode of AHF. We analyzed two groups: low (CCI <= 2) and high (CCI > 2) comorbidity. RESULTS: Patients' mean CCI was 2.2 +/- 1.7; 344 patients (38.35%) had a CCI > 2. 1-year all-cause mortality rate in the high comorbidity group was 32.6%, worse than that among low comorbidity group patients (23.7%, p = 0.002). Cox multivariate analysis identified a CCI > 2 as an independent risk factor for 1-year mortality (p = 0.002; HR: 1.525; CI 95% 1.161-2.003), along with older age, history of arterial hypertension, and higher admission heart rate and serum potassium values. Analyzing CCI as a continuous variable, the association remained is also significant (p = 0.0001; HR 1.145; CI 95% 1.069-1.854). CONCLUSIONS: Higher global comorbidity (CCI > 2) at the time of a first hospitalization because of AHF is an independent predictor of mid-term post discharge mortality among elderly HF patients. PMID- 29124526 TI - What Makes Research Useful for Public School Educators? AB - In this study, we explored the extent to which educators discuss and prioritize Rogers' (Diffusion of innovations, The Free Press: New York, 1995) five attributes of innovations-relative advantage, compatibility, complexity, observability, and trialability-in the context of research use. Using a directed content analysis of 54 semi-structured interviews and exemplar quotes, we describe how educators mentioned compatibility most frequently, but also commonly invoked observability and complexity in their discussions of research use. Our results also revealed key differences between educators in executive and non executive roles. We discuss the implications of our findings for closing the research-practice gap in school-based mental health services and psychosocial interventions. PMID- 29124525 TI - Heterogeneity in retinoblastoma: a tale of molecules and models. AB - Retinoblastoma, an intraocular pediatric cancer, develops in the embryonic retina following biallelic loss of RB1. However, there is a wide range of genetic and epigenetic changes that can affect RB1 resulting in different clinical outcomes. In addition, other transformations, such as MYCN amplification, generate particularly aggressive tumors, which may or may not be RB1 independent. Recognizing the cellular characteristics required for tumor development, by identifying the elusive cell-of-origin for retinoblastoma, would help us understand the development of these tumors. In this review we summarize the heterogeneity reported in retinoblastoma on a molecular, cellular and tissue level. We also discuss the challenging heterogeneity in current retinoblastoma models and suggest future platforms that could contribute to improved understanding of tumor initiation, progression and metastasis in retinoblastoma, which may ultimately lead to more patient-specific treatments. PMID- 29124527 TI - Stepped Care Interpersonal Psychotherapy Treatment for Depressed Adolescents: A Pilot Study in Pediatric Clinics. AB - Adolescents with depression are at risk for negative long-term consequences and recurrence of depression. Many do not receive nor access treatment, especially Latino youth. New treatment approaches are needed. This study examined the feasibility and acceptability of a stepped collaborative care treatment model (SCIPT-A) for adolescents with depression utilizing interpersonal psychotherapy for adolescents (IPT-A) and antidepressant medication (if needed) compared to Enhanced Treatment as Usual (E-TAU) in urban pediatric primary care clinics serving primarily Latino youth. Results suggest the SCIPT-A model is feasible, acceptable and potentially beneficial for urban Latino adolescents. Clinicians delivered the SCIPT-A model with fidelity using supervision successfully implemented in a community setting. PMID- 29124528 TI - Systematic review of economic burden of heart failure. AB - The aim of this study is to perform a systematic review of the costing methodological approaches adopted by published cost-of-illness (COI) studies. A systematic review was performed to identify cost-of-illness studies of heart failure published between January 2003 and September 2015 via computerized databases such as Pubmed, Wiley Online, Science Direct, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Costs reported in the original studies were converted to 2014 international dollars (Int$). Thirty five out of 4972 studies met the inclusion criteria. Nineteen out of the 35 studies reported the costs as annual cost per patient, ranging from Int$ 908.00 to Int$ 84,434.00, while nine studies reported costs as per hospitalization, ranging from Int$ 3780.00 to Int$ 34,233.00. Cost of heart failure increased as condition of heart failure worsened from New York Heart Association (NYHA) class I to NYHA class IV. Hospitalization cost was found to be the main cost driver to the total health care cost. The annual cost of heart failure ranges from Int$ 908 to Int$ 40,971 per patient. The reported cost estimates were inconsistent across the COI studies, mainly due to the variation in term of methodological approaches such as disease definition, epidemiological approach of study, study perspective, cost disaggregation, estimation of resource utilization, valuation of unit cost components, and data sources used. Such variation will affect the reliability, consistency, validity, and relevance of the cost estimates across studies. PMID- 29124531 TI - Identification of Peptide AEDG in the Polypeptide Complex of the Pineal Gland. AB - The polypeptide complex of the epiphysis and the peptide AEDG, constructed on the basis of its amino acid analysis, exert similar biological effects. Both bioregulators normalize melatonin synthesis in the pineal gland, functioning of the brain, eye retina, cardiovascular, endocrine, and immune systems; they also act as antioxidants, stress-protectors, and geroprotectors. Within the epiphysis polypeptide complex, free amino acids (3.26%), dipeptides (23.19%), tripeptides (50.72%), tetrapeptides (22.10%), and pentapeptides (0.72%) were revealed by mass spectrometry and HPLC. Peptide AEDG was detected among the tetrapeptides of the epiphysis polypeptide complex by selective reaction monitoring method. The biological effects of the epiphysis polypeptide complex are determined by the effect of its component AEDG. PMID- 29124529 TI - EEG indices correlate with sustained attention performance in patients affected by diffuse axonal injury. AB - The aim of this study is to assess the ability of EEG-based indices in providing relevant information about cognitive engagement level during the execution of a clinical sustained attention (SA) test in healthy volunteers and DAI (diffused axonal injury)-affected patients. We computed three continuous power-based engagement indices (P beta /P alpha , 1/P alpha , and P beta / (P alpha + P theta )) from EEG recordings in a control group (n = 7) and seven DAI-affected patients executing a 10-min Conners' "not-X" continuous performance test (CPT). A correlation analysis was performed in order to investigate the existence of relations between the EEG metrics and behavioral parameters in both the populations. P beta /P alpha and 1/P alpha indices were found to be correlated with reaction times in both groups while P beta / (P alpha + P theta ) and P beta /P alpha also correlated with the errors rate for DAI patients. In line with previous studies, time course fluctuations revealed a first strong decrease of attention after 2 min from the beginning of the test and a final fading at the end. Our results provide evidence that EEG-derived indices extraction and evaluation during SA tasks are helpful in the assessment of attention level in healthy subjects and DAI patients, offering motivations for including EEG monitoring in cognitive rehabilitation practice. Graphical abstract Three EEG derived indices were computed from four electrodes montages in a population of seven healthy volunteers and a group of seven DAI-affected patients. Results show a significant correlation between the time course of the indices and behavioral parameters, thus demonstrating their usefulness in monitoring mental engagement level during a sustained attention task. PMID- 29124530 TI - Fungus-Farming Termites Selectively Bury Weedy Fungi that Smell Different from Crop Fungi. AB - Mutualistic associations such as the fungal farms of insects are prone to parasitism and are consequently vulnerable to attack by weeds and pests. Therefore, efficient farm management requires quick detection of weeds for their elimination. Furthermore, if the available weedicides are non-specific, then the ability of insects to discriminate between crop and weeds becomes essential for targeted application of such compounds. Here, we demonstrate for the first time in fungus-farming insects, that worker castes of the fungus-growing termite Odontotermes obesus discriminate between their crop (Termitomyces) and the weedy (Pseudoxylaria) fungi, even if exposed to only fungal scents. Termites respond to the presence of fungal mycelium or scent alone, by burying the weed with the offered material such as soil or agar, possibly anointing the weed with chemicals in the process. The scent profiles of crop and weedy fungi are distinct and the differences are likely exploited by termites to selectively mount their defences. Sesquiterpene compounds such as aristolene and viridiflorol, which are absent from crop odours, may constitute the "weedy scent". Our results provide a general mechanism of how other fungus-farming insects could avoid indiscriminate application of non-specific fungicides which could lead to poisoning their crops, and have bearing on the stability of the mutualism between termites and their crop fungus in the face of parasitism by weedy fungi. PMID- 29124532 TI - Acetylsalicylic Acid Produces Different Effects on the Production of Active Oxygen Species by Activated Platelets in Different Inflammatory Diseases. AB - We studied the effect of acetylsalicylic acid on ROS generation by platelets in patients after surgical interventions and in patients with bronchial asthma was studied. Platelets stimulated with platelet-activating factor are characterized by weak luminol-enhanced chemiluminescence in healthy people and patients after operations with laparoscopic incisions. Addition of platelet activation factor to platelet samples from patients after open abdominal surgery caused intensive chemiluminescence that was suppressed after platelet incubation with acetylsalicylic acid. At the same time, platelets of patients with aspirin sensitive asthma did not respond to addition of platelet activating factor, but after incubation with acetylsalicylic acid, an intensive burst of chemiluminescence was detected with a maximum in 5-10 sec after the addition of a platelet-activating factor. In patients with bronchial asthma tolerant to aspirin, platelet activation factor did not induce chemiluminescence irrespective of incubation with acetylsalicylic acid. PMID- 29124533 TI - Syngeneic and Xenogeneic Transplantations of Mesenchymal Stromal Cells Modify the Production of Reactive Oxygen Species by Blood Mononuclears of Mice. AB - In vivo modifying effects of bone marrow mesenchymal stromal cells of humans and laboratory mice on ROS production by mouse blood mononuclears are studied by luminol-dependent zymosan-induced chemiluminescence after syngeneic and xenogeneic transplantation into systemic blood flow. The chemiluminescent activity of mouse blood mononuclears has increased early (1 day) after syngeneic (mouse mesenchymal stromal cells) and xenogeneic (human mesenchymal stromal cells) transplantation. Later, 7-21 days after syngeneic and xenogeneic transplantation, the chemiluminescent activity of mouse mononuclears is suppressed. The probable mechanisms of involvement of the transplanted mesenchymal stromal cells in reprogramming of the blood mononuclear phagocytes from proinflammatory (M1) to anti-inflammatory (M2) phenotype under conditions of their in vivo interactions are discussed; a frequent manifestation of this reprogramming is transition of the phase of activation into inhibition of ROS producing activity of macrophages. PMID- 29124534 TI - Anterograde Amnesia Induced by Disruption of Consolidation or Reconsolidation of Long-Term Memory. AB - Mechanisms of amnesia caused by impairment of consolidation or reconsolidation of conditioned food aversion memory with protein synthesis inhibitor cycloheximide were studied in Helix lucorum. Cycloheximide injection during training or memory reconsolidation in trained snails produced amnesia. In both cases, repeated training 10 days after amnesia induction led to short-term memory formation, while long-term memory was not formed, despite the fact that the number of conditioned and reinforcing stimuli combinations was higher than during initial training. The possibility of formation of short-term memory not transforming into long-term memory is one of the key characteristics of anterograde amnesia. Our findings data and experimental model can be used for analysis of specific molecular mechanisms of anterograde amnesia. PMID- 29124535 TI - Peculiarities of the Development of the Myocardial Infarction in ISIAH Rats. AB - We studied peculiarities of the development of myocardial infarction in rats with inherited stress-induced arterial hypertension (ISIAH rats). The control group consisted of Wistar rats. Occlusion of the left coronary artery (30 min) followed by reperfusion (120 min) was performed. The infarct size was determined relative to the risk zone by staining with 1% triphenyltetrazolium. BP, blood filling, and blood flow in the caudal vessels were measured. The infarct size was 31.5+/-3.0% of the risk zone in Wistar rats and 47.9+/-4.4% in ISIAH rats (p=0.026). No correlations of infarction size and BP or HR were found at the study stages. In ISIAH rats, local 30-min ischemia followed by 120-min reperfusion caused greater myocardial infarction that did not depend on BP or HR. PMID- 29124536 TI - Study of the Association of Polymorphisms of p53 and p21 with the Risk of Development of Stomach Cancer. AB - A real-time PCR with hybridization and fluorescent detection was used to analyze the distribution of p53 G215C, p21A1026G, and G369C gene polymorphisms in patients with stomach cancer and healthy subjects. It was found that allele C, genotypes of CC and GC of G215C p53, and G369C p21 polymorphisms and allele A and AA and GA genotypes of A1026G p21 polymorphism are significantly associated with the risk of stomach cancer development. PMID- 29124537 TI - Pathogenetic Mechanisms of Outbreak and Development of Cardiac Autonomic Neuropathy in Patients with Metabolic Syndrome. AB - A cross-sectional study of universe sample of patients (N=135; mean age -49.7+/ 0.8 years) with metabolic syndrome yielded the incidence of cardiac autonomic neuropathy of 37.5%. The pathogenetic peculiarities were revealed for the onset and development of this neuropathy. At the early stages, the progress of cardiac autonomic neuropathy closely correlated with elevation of blood glucose, while endothelial dysfunction progressing at the later period against the background of persistent hyperglycemia is viewed as an extra factor contributing to the development of this disease. PMID- 29124538 TI - Effect of Acorus calamus L. Polysaccharide on CD274 and CD326 Expression by Lewis Lung Carcinoma Cells in Mice. AB - Tumor cells can maintain their growth via immunosuppression and escape from host antitumor immunity by controlling the PD-1/PD-L1 system. Expression of PD-L1 (CD274) is an inhibitory signal for T cells, while the increase in CD326 expression in the tumor tissue correlates with metastasis development. The experimental preparation on the basis of alpha(1,2)-L-rhamno-alpha(1,4)-D galactopyranosyluronan from Acorus calamus L. produces an antitumor effect: it reduces tumor node size and the number and area of metastases after transplantation of Lewis lung carcinoma. Using flow cytometry, we demonstrated a decrease in the population of tumor cells expressing surface CD274 (PD-L1) and CD326 antigens after 20-day course of alpha(1,2)-L-rhamno-alpha(1,4)-D galactopyranosyluronan. PMID- 29124539 TI - Stably Fluorescent Cell Line of Human Ovarian Epithelial Cancer Cells SK-OV-3ip red. AB - Stable red fluorescing line of human ovarian epithelial cancer cells SK-OV-3ip red was generated expressing gene coding for protein TurboFP635 (Katushka) fluorescing in the far-red spectrum region with excitation and emission peaks at 588 and 635 nm, respectively. Fluorescence of SK-OV-3ip-red line remained high during long-term cell culturing and after cryogenic freezing. The obtained cell line SK-OV-3ip-red can serve a basis for a model of a scattered tumor with numerous/extended metastases and used both for testing anticancer drugs inhibiting metastasis growth and for non-invasive monitoring of the growth dynamics with high precision. PMID- 29124540 TI - Oligonucleotide Microchip for the Identification of Infectious Agents of Reproductive System with Simultaneous Analysis of Determinants of Resistance to Antimicrobial Substances. AB - We developed a multiplexed DNA microarray-based assay allowing identification of 12 causative agents of reproductive tract infections with the simultaneous detection of 47 genetic determinants of resistance to antimicrobial substances. The microarray was tested on 93 isolates of Neisseria gonorrhoeae, 32 isolates of Treponema pallidum and 29 samples of Ureaplasma spp./Mycoplasma spp. The N. gonorrhoeae isolates had multiple mutations in the penA, ponA, rpsJ, gyrA, parC, and mtrR genes; their prognostic value significantly increased when combinations of mutations were detected. In the analyzed T. pallidum isolates, single A2058G substitution in the 23S rRNA gene responsible for macrolide resistance was found. DNA sequences of Ureaplasma spp./Mycoplasma spp. were determined as wild type, which was not fully consistent with the results of analysis of their antimicrobial susceptibility. PMID- 29124541 TI - HIV Acquisition and Transmission Potential Among African American Men Who Have Sex with Men and Women in Three U.S. Cities. AB - Black men who have sex with men and women (BMSMW) are at increased HIV risk, but few efficacious interventions meet their unique needs. Three HIV prevention interventions were evaluated with a common protocol. Baseline data were pooled to describe sexual behavior involving transmission risk with male, female, and male to-female transgender partners and identify factors associated with transmission risk. BMSMW from Los Angeles, Philadelphia, and Chicago who reported sexual risk and bisexual behavior in the past year were recruited via modified chain referral sampling and community recruitment. Baseline assessments were conducted via audio computer-assisted interview and sexual behaviors assessed over the past 3 months. From December 2010 to November 2012, 584 BMSMW were enrolled across the three cities. More than half (55%) were recruited by other participants. Overall, the mean age was 43 years. Seventy-five percent reported an annual income <$10,000 and selling sex was prevalent (31%). Three-quarters identified as bisexual. Thirty-nine percent were HIV-positive. Among HIV-positive participants, 46% reported sex without condoms with HIV-negative or unknown male partners and 45% with HIV-negative or unknown female partners. Overall, factors associated with sex without condoms included network size, education, income, sexual orientation identification, HIV status, exchange sex, homonegativity, and social support. Findings support the need for enhanced HIV prevention efforts for this population. Future studies should examine contextual factors in addition to individual risk behaviors to inform the development and implementation of promising strategies to prevent HIV and promote the overall health and wellness of BMSMW and their sexual partners. PMID- 29124542 TI - Uptake of HPV testing and extended cervical cancer screening intervals following cytology alone and Pap/HPV cotesting in women aged 30-65 years. AB - OBJECTIVE: To evaluate the adoption of HPV testing and recommended extended cervical cancer screening intervals in clinical practice, we described yearly uptake of Pap/HPV cotesting and estimated length of time between normal screens by patient characteristics. METHODS: We examined 55,575 Pap/HPV records from 27,035 women aged 30-65 years from the Johns Hopkins Hospital Pathology Data System between 2006 and 2013. Cotest uptake and median times to next screening test for cotests and cytology only were calculated. Adjusted hazard ratios were estimated using Cox proportional hazards models, with random effects adjustment for clustering within clinic. RESULTS: Cotest usage increased from < 10% in 2006 to 78% in 2013. The median time to next screening test following normal cytology alone remained constant around 1.5 years. Screening intervals following a dual negative cotest increased from 1.5 years in 2006/2007 to 2.5 years in 2010, coincident with increases in the proportion of women cotested. Intervals following a dual negative cotest were longer among Medicare patients (3 years) compared with privately insured women (2.5 years), and shorter among black (2 years) compared with white women (2.8 years). CONCLUSION: By mid-2013 we observed broad adoption of Pap/HPV cotesting in routine screening in a large academic medical center. Increased screening intervals were observed only among cotested women, while those screened by cytology alone continued to be screened almost annually. The influence of different combinations of race and insurance on screening intervals should be further evaluated to ensure balance of screening risks and benefits in the U.S. POPULATION: PMID- 29124545 TI - A framework to understand diet, physical activity, body weight, and cancer risk. PMID- 29124544 TI - Reproductive risk factor associations with lobular and ductal carcinoma in the Carolina Breast Cancer Study. AB - BACKGROUND: Invasive lobular breast tumors display unique reproductive risk factor profiles. Lobular tumors are predominantly Luminal A subtype, and it is unclear whether reported risk factor associations are independent of molecular subtype. METHODS: Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between risk factors and histologic subtype [ductal (n = 2,856), lobular (n = 326), and mixed ductal-lobular (n = 473)] in the Carolina Breast Cancer Study (1993-2013). Three marker immunohistochemical clinical subtypes were defined as Luminal A (ER+ or PR+/HER2-), Luminal B (ER+ or PR+/HER2+), Triple Negative (ER-/PR-/HER2-), and HER2+ (ER-/PR-/HER2+). RESULTS: In case-case analyses compared to ductal, lobular tumors were significantly associated with lactation duration > 12 months [OR 1.86, 95% CI (1.33-2.60)], age at first birth >= 26 years [OR: 1.35, 95% CI: (1.03-1.78)], and current oral contraceptive use [OR: 1.86, 95% CI: (1.08-3.20)]. Differences in risk factor associations between ductal and lobular tumors persisted after restricting to Luminal A subtype. CONCLUSIONS: Lobular tumors were associated with older age at first birth, increased lactation duration, and current oral contraceptive use. Etiologic heterogeneity by histology persisted after restricting to Luminal A subtype, suggesting both tumor histology and intrinsic subtype play integral parts in breast cancer risk. PMID- 29124543 TI - Determinants of prolactin in postmenopausal Chinese women in Singapore. AB - PURPOSE: Mechanistic and observational data together support a role for prolactin in breast cancer development. Determinants of prolactin in Asian populations have not been meaningfully explored, despite the lower risk of breast cancer in Asian populations. METHODS: Determinants of plasma prolactin were evaluated in 442 postmenopausal women enrolled in the Singapore Chinese Health Study, a population based prospective cohort study. At baseline all cohort members completed an in person interview that elicited information on diet, menstrual and reproductive history, and lifestyle factors. One year after cohort initiation we began collecting blood samples. Quantified were plasma concentrations of prolactin, estrone, estradiol, testosterone, androstenedione, and sex hormone-binding globulin (SHBG). Analysis of covariance method was used for statistical analyses with age at blood draw, time since last meal, and time at blood draw as covariates. RESULTS: Mean prolactin levels were 25.1% lower with older age at menarche (p value = 0.001), and 27.6% higher with greater years between menarche and menopause (p value = 0.009). Prolactin levels were also positively associated with increased sleep duration (p value = 0.005). The independent determinants of prolactin were years from menarche to menopause, hours of sleep, and the plasma hormones estrone and SHBG (all p values < 0.01). CONCLUSION: The role of prolactin in breast cancer development may involve reproductive and lifestyle factors, such as a longer duration of menstrual cycling and sleep patterns. PMID- 29124546 TI - Fast Neural Dynamics of Proactive Cognitive Control in a Task-Switching Analogue of the Wisconsin Card Sorting Test. AB - One common assumption has been that prefrontal executive control is mostly required for target detection (Posner and Petersen in Ann Rev Neurosci 13:25-42, 1990). Alternatively, cognitive control has also been related to anticipatory updating of task-set (contextual) information, a view that highlights proactive control processes. Frontoparietal cortical networks contribute to both proactive control and reactive target detection, although their fast dynamics are still largely unexplored. To examine this, we analyzed rapid magnetoencephalographic (MEG) source activations elicited by task cues and target cards in a task-cueing analogue of the Wisconsin Card Sorting Test. A single-task (color sorting) condition with equivalent perceptual and motor demands was used as a control. Our results revealed fast, transient and largely switch-specific MEG activations across frontoparietal and cingulo-opercular regions in anticipation of target cards, including (1) early (100-200 ms) cue-locked MEG signals at visual, temporo parietal and prefrontal cortices of the right hemisphere (i.e., calcarine sulcus, precuneus, inferior frontal gyrus, anterior insula and supramarginal gyrus); and (2) later cue-locked MEG signals at the right anterior and posterior insula (200 300 ms) and the left temporo-parietal junction (300-500 ms). In all cases larger MEG signal intensity was observed in switch relative to repeat cueing conditions. Finally, behavioral restart costs and test scores of working memory capacity (forward digit span) correlated with cue-locked MEG activations at key nodes of the frontoparietal network. Together, our findings suggest that proactive cognitive control of task rule updating can be fast and transiently implemented within less than a second and in anticipation of target detection. PMID- 29124548 TI - Development of an Experimental and Digital Cardiovascular Arterial Model for Transient Hemodynamic and Postural Change Studies: "A Preliminary Framework Analysis". AB - The ultimate goal of the present work is to aid in the development of tools to assist in the treatment of cardiovascular disease. Gaining an understanding of hemodynamic parameters for medical implants allow clinicians to have some patient specific proposals for intervention planning. In the present work an experimental and digital computational fluid dynamics (CFD) arterial model consisting of a number of major arteries (aorta, carotid bifurcation, cranial, femoral, jejunal, and subclavian arteries) were fabricated to study: (1) the effects of local hemodynamics (flow parameters) on global hemodynamics (2) the effects of transition from bedrest to upright position (postural change) on hemodynamics, and (3) diffusion of dye (medical drug diffusion simulation) in the arterial system via experimental and numerical techniques. The experimental and digital arterial models used in the present study are the first 3-D systems reported in literature to incorporate the major arterial vessels that deliver blood from the heart to the cranial and femoral arteries. These models are also the first reported in literature to be used for flow parameter assessment via medical drug delivery and orthostatic postural change studies. The present work addresses the design of the experimental and digital arterial model in addition to the design of measuring tools used to measure hemodynamic parameters. The experimental and digital arterial model analyzed in the present study was developed from patient specific computed tomography angiography (CTA) scans and simplified geometric data. Segments such as the aorta (ascending and descending) and carotid bifurcation arteries of the experimental and digital arterial model was created from online available patient-specific CTA scan data provided by Charite' Clinical and Research Hospital. The cranial and coronary arteries were simplified arterial geometries developed from dimensional specification data used in previous work. For the patient specific geometries, a MATLAB code was written to upload the CTA scans of each artery, calculate the centroids, and produce surface splines at each discrete cross section along the lumen centerline to create the patient specific arterial geometries. The MATLAB code worked in conjunction with computer aided software (CAD) Solidworks to produce solid models of the patient specific geometries and united them with the simplified geometries to produce the full arterial model (CAD model). The CAD model was also used as a blueprint to fabricate the experimental model which was used for flow visualization via particle imaging velocimetry (PIV) and postural change studies. A custom pulse duplicator (pulsatile pump) was also designed and developed for the present work. The pulse duplicator is capable of producing patient-specific volumetric waveforms for inlet flow to the experimental arterial model. A simple fluid structure interaction (FSI) study was also conducted via optical techniques to establish the magnitude of vessel diameter change due to the pulsatile flow. A medical drug delivery (dye dispersion and tracing) case was simulated via a dye being dispersed into the pulsatile flow stream to measure the transit time of the dye front. Pressure waveforms for diseased cases (hypertension & stenotic cases) were also obtained from the experimental arterial model during postural changes from bedrest (0 degrees ) to upright position (90 degrees ). The postural changes were simulated via attaching the experimental model to a tile table the can transition from 0 degrees to 90 degrees . The PIV results obtained from the experimental model provided parametric data such as velocity and wall shear stress data. The medical drug delivery simulations (experimental and numerical) studies produce time dependent data which is useful for predicting flow trajectory and transit time of medical drug dispersion. In the case of postural change studies, pressure waveforms were obtained from the common carotid artery and the femoral sections to yield pressure difference data useful for orthostatic hypotension analysis. Flow parametric data such as vorticity (flow reversal), wall shear stress, normal stress, and medical drug transit data was also obtained from the digital arterial model CFD simulations. Although the present work is preliminary work, the experimental and digital models proves to be useful in providing flow parametric data of interest such as: (1) normal stress which is useful for predicting the magnitude of forces which could promote arterial rupture or dislodging of medical implants, (2) wall shear stress which is useful for analyzing the magnitude of drug transport at the arterial wall, (3) vorticity which is useful for predicting the magnitude of flow reversal, and (4) arterial compliance in the case of the experimental model which could be useful in the efforts of developing FSI numerical simulations that incorporates compliance which realistically models the flow in the arterial system. PMID- 29124547 TI - Online Reduction of Artifacts in EEG of Simultaneous EEG-fMRI Using Reference Layer Adaptive Filtering (RLAF). AB - Simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) allow us to study the active human brain from two perspectives concurrently. Signal processing based artifact reduction techniques are mandatory for this, however, to obtain reasonable EEG quality in simultaneous EEG-fMRI. Current artifact reduction techniques like average artifact subtraction (AAS), typically become less effective when artifact reduction has to be performed on the-fly. We thus present and evaluate a new technique to improve EEG quality online. This technique adds up with online AAS and combines a prototype EEG-cap for reference recordings of artifacts, with online adaptive filtering and is named reference layer adaptive filtering (RLAF). We found online AAS + RLAF to be highly effective in improving EEG quality. Online AAS + RLAF outperformed online AAS and did so in particular online in terms of the chosen performance metrics, these being specifically alpha rhythm amplitude ratio between closed and opened eyes (3-45% improvement), signal-to-noise-ratio of visual evoked potentials (VEP) (25-63% improvement), and VEPs variability (16-44% improvement). Further, we found that EEG quality after online AAS + RLAF is occasionally even comparable with the offline variant of AAS at a 3T MRI scanner. In conclusion RLAF is a very effective add-on tool to enable high quality EEG in simultaneous EEG-fMRI experiments, even when online artifact reduction is necessary. PMID- 29124549 TI - Benefit of Surgical Resection of the Primary Tumor in Patients Undergoing Chemotherapy for Stage IV Colorectal Cancer with Unresected Metastasis. AB - PURPOSE: Resection of the primary tumor in patients with unresected metastatic colorectal cancer is controversial, and often performed only for palliation of symptoms. Our goal was to determine if resection of the primary tumor in this patient population is associated with improved survival. METHODS: This is a retrospective cohort study of the National Cancer Data Base from 2004 to 2012. The study population included all patients with synchronous metastatic colorectal adenocarcinoma who were treated with systemic chemotherapy. The study groups were patients who underwent definitive surgery for the primary tumor and those who did not. Patients were excluded if they had surgical intervention on the sites of metastasis or pathology other than adenocarcinoma. Primary outcome was overall survival. RESULTS: Of the 65,543 patients with unresected stage IV colorectal adenocarcinoma undergoing chemotherapy, 55% underwent surgical resection of the primary site. Patients who underwent surgical resection of the primary tumor had improved median survival compared to patients treated with chemotherapy alone (22 vs 13 months, p < .0001). The surgical survival benefit was present for patients who were treated with either multi-agent or single-agent chemotherapy (23 vs 14 months, p < 0.001; 19 vs 9 months, p < 0.001). Surgical resection of the primary tumor was also associated with improved survival when using multivariate analysis with propensity score matching (OR = 0.863; 95% CI [0.805-.924]; HR = 0.914; 95% CI [0.888-0.942]). CONCLUSIONS: Our results show that in patients with synchronous unresected stage IV colorectal adenocarcinoma undergoing single- or multi-agent chemotherapy, after adjusting for confounding variables, definitive resection of the primary site was associated with improved overall survival. Large randomized controlled trials are needed to determine if there is a causal relationship between surgery and increased overall survival in this patient population. PMID- 29124550 TI - Gastrectomy with Extended Lymphadenectomy: a North American Perspective. AB - PURPOSE: Despite evidence of oncologic benefits from extended (D2) lymphadenectomy in gastric cancer from many East Asian studies, there is persistent debate over its use in the West, mainly due to perceived high rates of morbidity and mortality. This study evaluates the safety and efficacy of D2 dissection in a high-volume North American center. METHODS: A prospectively entered database of all patients undergoing gastrectomy for cancer at a North American referral center from 2005 to 2016 was reviewed. Wedge resections, thoracoabdominal approach, emergency surgery, palliative operations, and non adenocarcinoma cases were excluded. RESULTS: Of 366 non-bariatric gastrectomies over this period, 175 met the inclusion criteria. Median age was 73 years and 69% were male. One hundred forty-one patients (80%) underwent D2 dissection, the rest having D1. There was no difference in postoperative complications (D1 = 44%: D2 = 42%), anastomotic leaks (D1 = 6%: D2 = 5%), and same-admission or 30-day mortality (D1 = 6%: D2 = 2%). D2 dissection was associated with higher pathological stage (72% > stage 1 vs 38% > stage 1; p < 0.05) and median lymph node yield (30 vs 14; p < 0.05), with no difference in complete resection (R0) rate (D1 = 98% vs D2 = 92%). Laparoscopic approach was employed in 34% (45/141) of D2 cases, resulting in shorter median length of stay (6 days vs 9; p < 0.05) and equivalent oncologic outcomes compared to open D2. CONCLUSION: This study supports the use of D2 lymphadenectomy, by either open or laparoscopic approach, in high-volume North American centers as a safe and effective oncologic procedure for gastric cancer, with equivalent complication rates and superior lymph node yield to traditional D1 dissection. PMID- 29124552 TI - ? PMID- 29124551 TI - Mechanical Characterization and Material Modeling of Diabetic Aortas in a Rabbit Model. AB - Diabetes has been recognized as a major risk factor to cause macrovascular diseases and plays a key role in aortic wall remodeling. However, the effects of diabetes on elastic properties of aortas remain largely unknown and quantitative mechanical data are lacking. Thirty adult rabbits (1.6-2.2 kg) were collected and the type 1 diabetic rabbit model was induced by injection of alloxan. A total of 15 control and 15 diabetic rabbit (abdominal) aortas were harvested. Uniaxial and biaxial tensile tests were performed to measure ultimate tensile strength and to characterize biaxial mechanical behaviors of the aortas. A material model was fitted to the biaxial experimental data to obtain constitutive parameters. Histological and mass fraction analyses were performed to investigate the underlying microstructure and dry weight percentages of elastin and collagen in the control and the diabetic aortas. No statistically significant difference was found in ultimate tensile strength between the control and the diabetic aortas. Regarding biaxial mechanical responses, the diabetic aortas exhibited significantly lower extensibility and significantly higher tissue stiffness than the control aortas. Notably, tissue stiffening occurred in both circumferential and axial directions for the diabetic aortas; however, mechanical anisotropy does not change significantly. The material model was able to fit biaxial experimental data very well. Histology showed that a number of isolated foam cells were embedded in the diabetic aortas and hyperplasia of collagen was identified. The dry weight percentages of collagen within the diabetic aortas increased significantly as compared to the control aortas, whereas no significant change was found for that of elastin. Our data suggest that the diabetes impairs elastic properties and alters microstructure of the aortas and consequently, these changes may further contribute to complex aortic wall remodeling. PMID- 29124553 TI - Intolerance of uncertainty in children with attention-deficit/hyperactivity disorder. AB - Intolerance of uncertainty (IU) has often been studied in the context of internalizing disorders, but no studies to our knowledge have explored the relation between IU and externalizing disorders. Given the proposed link between IU and emotion regulation, the current study sought to examine levels of IU in an externalizing clinical population with known emotion regulation difficulties attention-deficit/hyperactivity disorder (ADHD). IU levels in this population were compared to a clinical population known to experience elevated levels of IU. Participants in present study were ninety-three children (36 anxiety disorder, 28 ADHD, 29 unaffected children) ages 7-13, who completed the Intolerance of Uncertainty Scale-Short Version (IUS). Responses on the IUS were converted to total IU, prospective IU, and inhibitory IU. A linear mixed model analysis of covariance was conducted while controlling for age, sex, and ADHD medications. A significant interaction was observed between diagnostic status and IU scale. Planned contrasts indicated that children with anxiety disorders and ADHD reported significantly higher levels of IU relative to unaffected children, and children with ADHD reported comparable levels of inhibitory IU relative to children with anxiety disorders. The current results contribute to a growing literature on the link between IU and psychopathology. IU appears to be a transdiagnostic construct present among children with internalizing and externalizing disorders, and may be broadly associated with emotion regulation deficits rather than specific disorder symptoms. PMID- 29124554 TI - Trend analysis of cancer incidence and mortality in China. PMID- 29124555 TI - Kawasaki Disease Presenting as Acute Scrotum. PMID- 29124556 TI - Chronic Bleeding Following Duhamel Procedure Due to Staple Line Ulcers. PMID- 29124557 TI - Baseline predictors of DMT reinitiation among patients with multiple sclerosis following an MI-CBT intervention. AB - Patients with multiple sclerosis (MS) are often nonadherent to their disease modifying therapy (DMT). While recent studies demonstrate enhanced DMT adherence following intervention grounded in motivational interviewing (MI), little is known about how to address DMT reinitiation among MS patients who have prematurely discontinued DMT against medical advice and do not intend to reinitiate. We examined baseline predictors of DMT reinitiation among patients with MS who discontinued medications against medical advice following a telephone based MI and Cognitive Behavioral Therapy (MI-CBT) intervention. Following MI-CBT intervention, 66 patients reported whether or not they opted to reinitiate DMT. Rate of disease progression (beta = 0.295) and perceived personal control (beta = - 0.131) emerged as unique significant predictors of DMT reinitiation following intervention. Clinical characteristics and health-related beliefs may be used to prospectively identify patients most likely to reinitiate DMT following MI-CBT intervention, furthering the goal of preserving brain health and preventing neurologic decline in MS via appropriate DMT utilization. Further study is warranted to delineate potential mediators and moderators of DMT reinitiation outcomes. PMID- 29124558 TI - Development of a simple device enabling percutaneous flow regulation for a small vascular graft for a Blalock-Taussig shunt capable of flow regulation: complete translation of an original article originally published in Pediatric Cardiology and Cardiac Surgery (154-159, 2016: vol. 32). AB - OBJECTIVES: The Blalock-Taussig shunt (BTS) operation is a cornerstone as initial palliative surgery for congenital heart disease with severely reduced pulmonary blood flow (PBF). The ideal PBF provided by BTS is crucial for an uneventful postoperative course, since excess PBF results in acute distress of the systemic circulation and insufficient PBF requires another BTS surgery. Therefore, the goal of this study was to develop a simple device to control the shunt graft flow percutaneously using a constrictor balloon connected to a subcutaneous port. METHODS: The device consists of a cylindrical balloon and an anti-bending structure extension connected to the balloon center. A PTFE vascular graft wrapped by the device was connected to a simulated closed circuit to measure the relationship between pressure and blood flow while changing the inner volume of the balloon. In a beagle model of replacement of the right carotid artery, blood flow velocity was measured in the carotid artery after saline injection into the balloon. The blood flow velocity before and after balloon inflation was compared immediately after implantation of the device and at 3 months after implantation. RESULTS: The device provided good flow control by inflating and deflating the balloon ex vivo and in vivo for up to 3 months in a canine model with a small graft wrapped with the device. CONCLUSIONS: The simple device developed in this study may enable regulation of PBF through a small vascular graft and help to prevent severe morbidity and mortality in the clinical setting of BTS. PMID- 29124559 TI - Hungry bone syndrome two weeks after starting cinacalcet: a call for caution. AB - Cinacalcet is an effective and safe alternative to parathyroidectomy in end stage renal disease (ESRD) patients with secondary hyperparathyroidism. Hypocalcemia is a known complication of treatment that is usually readily reversible upon discontinuation of the drug. It rarely manifests severely and symptomatically requiring hospital admission. We present the case of a 55 year old man with severe, symptomatic and prolonged hypocalcemia that occurred 2 weeks after starting cinacalcet. Cinacalcet induced a state of pharmacological parathyroidectomy with subsequent hungry bone syndrome. Serum calcium returned to normal range after 4 weeks of stopping the drug while receiving high doses of elemental calcium and vitamin D receptor activation therapy (VDRA). PMID- 29124560 TI - Maintenance treatment using the purine-synthesis inhibitor mizoribine in a patient with relapsing thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening disease. Although plasma exchange (PE) therapy and corticosteroids are standard remission induction and maintenance therapies, some patients are easily refractory and frequently relapse under treatment with this therapy, and require additional treatment. However, there are limited data about additional treatment interventions. We report a case of 56-year-old man who was hospitalized for fever, general fatigue and hemoglobinuria. Owing to the symptoms and the laboratory findings of hemolysis, he was diagnosed with TTP. He was treated with PE therapy and corticosteroids, and the TTP went into remission. However, his TTP relapsed and remission induction was attempted again. As a remission maintenance treatment, we used combination therapy with the purine-synthesis inhibitor mizoribine (MZR) and corticosteroids. The administration of MZR maintained disease activity with no adverse event for long periods and allowed us to gradually reduce the corticosteroids dose. Hence, we propose that MZR is an effective treatment for TTP maintenance. PMID- 29124561 TI - Technology III: in-line vaporizer with reflector. AB - As the clinical advantages of vapor anesthesia (VA) for sedation of patients in ICU become more apparent, the ergonomics, economy and safety issues need to be better addressed. Here we describe the use of a new commercial digital in-line anesthetic vaporizer that can be attached to the inspiratory limb of a ventilator. If used with a simple, and easily assembled secondary circuit and anesthetic reflector, the circuit remains remote from the patient, the VA consumption approaches a physical minimum, VA level is controlled and monitored, and the tidal volume size is not limited. PMID- 29124562 TI - Video-based heart rate monitoring across a range of skin pigmentations during an acute hypoxic challenge. AB - The robust monitoring of heart rate from the video-photoplethysmogram (video-PPG) during challenging conditions requires new analysis techniques. The work reported here extends current research in this area by applying a motion tolerant algorithm to extract high quality video-PPGs from a cohort of subjects undergoing marked heart rate changes during a hypoxic challenge, and exhibiting a full range of skin pigmentation types. High uptimes in reported video-based heart rate (HRvid) were targeted, while retaining high accuracy in the results. Ten healthy volunteers were studied during a double desaturation hypoxic challenge. Video PPGs were generated from the acquired video image stream and processed to generate heart rate. HRvid was compared to the pulse rate posted by a reference pulse oximeter device (HRp). Agreement between video-based heart rate and that provided by the pulse oximeter was as follows: Bias = - 0.21 bpm, RMSD = 2.15 bpm, least squares fit gradient = 1.00 (Pearson R = 0.99, p < 0.0001), with a 98.78% reporting uptime. The difference between the HRvid and HRp exceeded 5 and 10 bpm, for 3.59 and 0.35% of the reporting time respectively, and at no point did these differences exceed 25 bpm. Excellent agreement was found between the HRvid and HRp in a study covering the whole range of skin pigmentation types (Fitzpatrick scales I-VI), using standard room lighting and with moderate subject motion. Although promising, further work should include a larger cohort with multiple subjects per Fitzpatrick class combined with a more rigorous motion and lighting protocol. PMID- 29124563 TI - Excellence in the treatment of patients with pituitary tumors. PMID- 29124564 TI - Encapsulation of Probiotics: Proper Selection of the Probiotic Strain and the Influence of Encapsulation Technology and Materials on the Viability of Encapsulated Microorganisms. AB - Probiotic encapsulation is an entire system that not only involves but also depends on many factors. Elements such as the encapsulation method itself, materials, environmental conditions, and last, but not least, the strain; all play an important role in the encapsulation process. The current paper focuses on the right selection of probiotics, the various stress factors that impact the survival capacity of probiotics during and after encapsulation, and the rational selection of appropriate protection strategies to overcome these factors and achieve the highest possible encapsulation efficiency under optimal conditions. This review discusses the effects of temperature, moisture content, and water activity as well as pH, oxygen, and pressure on the viabilities of microorganisms. The effect of the surface and structure of the capsules on the encapsulated microorganisms and the impact of the materials used for the encapsulation are discussed as well. Last, but not least, the importance of choosing the right bacteria is reviewed. PMID- 29124565 TI - Glycosaminoglycans from fish swim bladder: isolation, structural characterization and bioactive potential. AB - The swim bladder of fish is an internal gas-filled organ that allows fish to control their buoyancy and swimming depth. Fish maws (the dried swim bladders of fish) have been used over many centuries as traditional medicines, tonics and a luxurious gourmet food in China and Southeast Asia. Little is known about the structural information of polysaccharides comprising this important functional material of fish tissue. In the present study, the total glycosaminoglycan (GAG) from fish maw was characterized. Two GAGs were identified, chondroitin sulfate (CS, having a molecular weight of 18-40 kDa) and heparan sulfate (HS), corresponding to 95% and 5% of the total GAG, respectively. Chondroitinase digestion showed that the major CS GAG was composed of DeltaUA-1 -> 3-GalNAc4S (59.7%), DeltaUA-1 -> 3-GalNAc4,6S (36.5%), DeltaUA-1 -> 3-GalNAc6S (2.2%) and DeltaUA-1 -> 3-GalNAc (1.6%) disaccharide units. 1H-NMR analysis and degradation with specific chondroitinases, both CS-type A/C and CS-type B were present in a ratio of 1.4:1. Analysis using surface plasmon resonance showed that fibroblast growth factor (FGF)-2 bound to the CS fraction (KD = 136 nM). These results suggest that this CS may be involved in FGF-signal pathway, mediating tissue repair, regeneration and wound healing. The CS, as the major GAG in fish maw, may have potential pharmacological activity in accelerating wound healing. PMID- 29124566 TI - Zinc Potentiates Lipopolysaccharide-induced Nitric Oxide Production in Cultured Primary Rat Astrocytes. AB - Zn2+ plays a crucial role in the CNS where it accumulates in synaptic vesicles and is released during neurotransmission. Synaptically released Zn2+ is taken up by neurons and astrocytes. The majority of previous work has focused on neuronal damage caused by excess Zn2+. However, its effect on astrocyte function is not well understood. We examined the effect of extracellularly applied Zn2+ on nitric oxide (NO) production in primary cultured rat astrocytes, which were experimentally activated by lipopolysaccharide (LPS). Zn2+, at a concentration up to 125 MUM, augmented LPS-induced NO production without affecting cell viability. LPS induced expression of both mRNA and protein of inducible NO synthase; this expression was enhanced by 125 uM Zn2+. Zn2+ also increased LPS-induced production of intracellular reactive oxygen species. Zn2+ enhanced the phosphorylation of p38-mitogen-activated protein kinase (MAPK) at 1-6 h after LPS treatment. The LPS-induced nuclear factor-kappaB (NFkappaB) activation was sustained for 6 h by Zn2+. Intracellular Zn2+ chelation with N,N,N',N'-tetrakis(2 pyridylmethyl)ethylenediamine (TPEN) or inhibition of p38-MAPK diminished the Zn2+ enhancement of LPS-induced NO production. These findings suggest that activation of MAPK and NFkappaB is important for mediating Zn2+enhancement of LPS induced NO production in astrocytes. Such changes may exacerbate glial and neuronal damage during neuroinflammation. PMID- 29124568 TI - PknG supports mycobacterial adaptation in acidic environment. AB - Mycobacterium tuberculosis (Mtb), causative agent of human tuberculosis (TB), has the remarkable ability to adapt to the hostile environment inside host cells. Eleven eukaryotic like serine-threonine protein kinases (STPKs) are present in Mtb. Protein kinase G (PknG) has been shown to promote mycobacterial survival inside host cells. A homolog of PknG is also present in Mycobacterium smegmatis (MS), a fast grower, non-pathogenic mycobacterium. In the present study, we have analyzed the role of PknG in mycobacteria during exposure to acidic environment. Expression of pknG in MS was decreased in acidic medium. Recombinant MS ectopically expressing pknG (MS-G) showed higher growth in acidic medium compared to wild type counterpart. MS-G also showed higher resistance upon exposure to 3.0 pH and better adaptability to acidic pH. Western blot analysis showed differential threonine but not serine phosphorylation of cellular proteins in MS at acidic pH which was restored by ectopic expression of pknG in MS. In Mtb H37Ra (Mtb-Ra), expression of pknG was increased at acidic pH. We also observed decreased expression of pknG in MS during infection in macrophages while the expression of pknG in Mtb-Ra was increased in similar conditions. Taken together, our data strongly suggests that pknG regulates growth of mycobacteria in acidic environment and is differentially transcribed in MS and Mtb under these conditions. PMID- 29124567 TI - Dimethyl Fumarate Modulates Oxidative Stress and Inflammation in Organs After Sepsis in Rats. AB - Sepsis is defined as life-threatening organ dysfunction induced by a disrupted host response to infecting pathogens. Evidences suggest that oxidative stress is intrinsically related to sepsis progression. Dimethyl fumarate (DMF) is a novel oral therapeutic agent with anti-oxidant properties which exerts protective effects through activation of nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2). Thus, the aim of this study is to evaluate the effect of DMF in different organs of rats submitted to an animal model of sepsis. Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) procedure and sham operated rats was considered control group. The experimental groups were divided into sham + vehicle, sham + DMF, sham + NAC, CLP + vehicle, CLP + DMF, and CLP + NAC. Rats were treated by oral gavage with DMF immediately after and 12 h after surgery, or NAC (s.c.) at 3, 6, and 12 h after surgery. Twenty-four hours after sepsis induction, neutrophil infiltration, nitrite/nitrate concentrations, oxidative damage to lipids and proteins, superoxide dismutase (SOD), and catalase (CAT) activities were evaluated in the heart, liver, lung, and kidney. Septic animals presented increased neutrophil infiltration, NO metabolism, oxidative damage to lipids and proteins, and decreases of SOD and CAT activities, mainly in the heart, liver, and lung, while DMF-treated animals showed significant reduction in neutrophil infiltration, NO metabolism, and oxidative damage followed by increased SOD and CAT activities. DMF is effective in preventing oxidative stress and inflammation in rats 24 h after sepsis induction. PMID- 29124570 TI - Acquisition and retention of conditioned aversions to context and taste in laboratory mice. AB - We compared the rate of acquisition and strength of retention of conditioned context aversion (CCA) with conditioned taste aversion (CTA) using pigmented, genetically heterogeneous mice (derived from Large and Small strains). Extending previous findings, in Experiment 1, mice accustomed to drinking from large glass bottles in the colony room learned to avoid graduated tubes after a single conditioning trial when drinking from these novel tubes was paired with injections of LiCl. The results also showed that CCA could be developed even when there was a 30-minute delay between conditioned stimulus and unconditioned stimulus. Retention of the aversion lasted for 4 weeks in both Immediate and Delay groups. Studies of conditioned saccharin aversion were conducted in Experiment 2. CTA acquisition was very similar to that observed in CCA and duration of aversion retention was similar in the CCA and CTA Delay groups, although at least 2 weeks longer in the Immediate group. Thus, CCA acquisition and retention characteristics are closer to those seen for CTA than has previously been reported. In Experiment 3, we examined whether albino mice (which are known to have weaker visual abilities compared to pigmented mice) would develop CCA comparable to those of pigmented mice. The development of conditioned aversion and its duration of retention was similar in albinos and pigmented mice. Nonspecific aversion emerged as an important contributor to strength of aversion during retention trials in both CCA and CTA paradigms with pigmented (but not albino) mice and deserves additional scrutiny in this field of inquiry. PMID- 29124571 TI - ? PMID- 29124569 TI - Running-based pica and taste avoidance in rats. AB - Running in an activity wheel generates pica behavior (kaolin clay intake) in rats. Wheel running also results in Pavlovian conditioned avoidance of the taste solution consumed immediately before the running. Since pica has been considered a behavioral marker of nausea in rats, these findings suggest that wheel running induces nausea, which is the underlying physiological state for establishing taste avoidance. This article reports a replication of running-based pica in rats (Experiment 1) and concurrent demonstrations of running-based pica and taste avoidance in the same animals (Experiments 2 and 3). Also shown is that pica does not alleviate running-based taste avoidance (Experiment 3). Another finding is that pica is generated by a nausea-inducing lithium chloride injection but not by a pain-inducing hypertonic saline injection (Experiment 4). These results, when taken together, support the hypothesis that pica behavior generated by wheel running reflects nausea in rats. PMID- 29124573 TI - ? PMID- 29124574 TI - ? PMID- 29124572 TI - ? PMID- 29124575 TI - ? PMID- 29124576 TI - [Monoclonal antibodies for targeted migraine prevention]. PMID- 29124577 TI - [How to deal with increased liver markers]. PMID- 29124578 TI - [Meralgia paraesthetica (Bernhardt-Roth syndrome)]. PMID- 29124579 TI - [What can peat therapy achieve?] PMID- 29124581 TI - ? PMID- 29124580 TI - [Targeted injections can relieve pain]. PMID- 29124582 TI - [Male urinary incontinence - causes and therapeutic approaches for male stress incontinence]. PMID- 29124583 TI - [Urinary incontinence in women]. PMID- 29124584 TI - ? PMID- 29124586 TI - ? PMID- 29124585 TI - ? PMID- 29124587 TI - ? PMID- 29124588 TI - ? PMID- 29124589 TI - ? PMID- 29124590 TI - ? PMID- 29124591 TI - ? PMID- 29124592 TI - ? PMID- 29124593 TI - ? PMID- 29124594 TI - ? PMID- 29124595 TI - ? PMID- 29124596 TI - ? PMID- 29124597 TI - ? PMID- 29124598 TI - ? PMID- 29124599 TI - ? PMID- 29124600 TI - ? PMID- 29124601 TI - ? PMID- 29124602 TI - ? PMID- 29124603 TI - ? PMID- 29124604 TI - ? PMID- 29124605 TI - ? PMID- 29124607 TI - ? PMID- 29124606 TI - ? PMID- 29124608 TI - ? PMID- 29124609 TI - ? PMID- 29124611 TI - ? PMID- 29124610 TI - ? PMID- 29124612 TI - ? PMID- 29124614 TI - ? PMID- 29124613 TI - ? PMID- 29124615 TI - ? PMID- 29124618 TI - ? PMID- 29124616 TI - ? PMID- 29124619 TI - ? PMID- 29124621 TI - ? PMID- 29124620 TI - ? PMID- 29124622 TI - Medicinal plants with antithrombotic property in Persian medicine: a mechanistic review. AB - Thrombosis is one of the major causes of morbidity and mortality in a wide range of vessels diseases. Due to the high prevalence of thromboembolic disorders investigations are being carried out on new antithrombotic agents with limited adverse side effects in which herbal medicines are considered as alternative remedies. Persian medicine (PM) as a traditional medicine has a good potential for pharmacotherapy based on its own principles and development of drugs via investigating PM literature. In PM manuscripts there are some concepts that express the management of blood clots and antithrombotic properties. This study reviewed the pharmacological effects of medicinal plants mentioned in PM literature for blood clot management in light of current knowledge. Plants mentioned in PM for management of blood clot belong to 12 families in which Apiaceae, Lamiaceae and Compositae were the most repeated ones. Among the proposed plants Allium sativum, Rosmarinus officinalis, Boswellia serrata, Sesamum indicum, Matricaria chamomilla and Carthamus tinctorius have been the most researched plants in modern antithrombotic studies while for some plants such as Helichrysum stoechas, Dracocephalum kotschi, Carum carvi, Bunium persicum and Lagoecia cuminoides no evidence could be found. One of the interesting notes in clot management in PM texts was introducing the target organ for some of the recommended herbs like Carum carvi and Bunium persicum for dissolving blood clot in stomach and Commiphora mukul for thrombosed hemorrhoid. It seems review of PM recommendations can help to design future researches for antithrombotic drugs discovering with more effectiveness and safety. PMID- 29124623 TI - Removal of ligand-bound liposomes from cell surfaces by microbubbles exposed to ultrasound. AB - Gas-filled microbubbles attached to cell surfaces can interact with focused ultrasound to create microstreaming of nearby fluid. We directly observed the ultrasound/microbubble interaction and documented that under certain conditions fluorescent particles that were attached to the surface of live cells could be removed. Fluorescently labeled liposomes that were larger than 500 nm in diameter were attached to the surface of endothelial cells using cRGD targeting to alphavbeta3 integrin. Microbubbles were attached to the surface of the cells through electrostatic interactions. Images taken before and after the ultrasound exposure were compared to document the effects on the liposomes. When exposed to ultrasound with peak negative pressure of 0.8 MPa, single microbubbles and groups of isolated microbubbles were observed to remove targeted liposomes from the cell surface. Liposomes were removed from a region on the cell surface that averaged 33.1 MUm in diameter. The maximum distance between a single microbubble and a detached liposome was 34.5 MUm. Single microbubbles were shown to be able to remove liposomes from over half the surface of a cell. The distance over which liposomes were removed was significantly dependent on the resting diameter of the microbubble. Clusters of adjoining microbubbles were not seen to remove liposomes. These observations demonstrate that the fluid shear forces generated by the ultrasound/microbubble interaction can remove liposomes from the surfaces of cells over distances that are greater than the diameter of the microbubble. PMID- 29124624 TI - Maternal Hypertension, Antihypertensive Medication Use, and Small for Gestational Age Births in the National Birth Defects Prevention Study, 1997-2011. AB - Background Small for gestational age (SGA) birth is associated with poor long term health outcomes. It is unclear whether maternal antihypertensive medication increases risk of SGA independently of maternal hypertension. Methods We analyzed associations between maternal hypertension and antihypertensive medication use and SGA among non-malformed singleton controls in the National Birth Defects Prevention Study. We defined SGA as birthweight < 10th percentile for a given gestational age, sex, race/ethnicity, and parity. We included 1045 SGA and 10,019 non-SGA births. We used logistic regression to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs). We assessed interaction between hypertension, antihypertensive use, and maternal race/ethnicity and age. Results Overall, 122 (11.7%) SGA and 892 (8.9%) non-SGA mothers reported hypertension and 21 (2.0%) SGA and 154 (1.5%) non-SGA mothers reported antihypertensive use. The most commonly reported medications were centrally-acting antiadrenergics, beta blockers, calcium channel blockers, and diuretics. Compared to normotensive pregnancies, maternal hypertension, regardless of treatment (AOR, 1.49 [95% CI, 1.20, 1.86]), and untreated maternal hypertension [AOR, 1.46 (95% CI, 1.15, 1.86)] were associated with SGA. We observed a positive, but not significant, association between antihypertensive use and SGA. SGA risk varied by maternal race/ethnicity, being highest among Hispanic mothers, and age, being highest among mothers >= 35 years, but statistical tests for interaction were not significant. Conclusions Consistent with the literature, our findings suggest that maternal hypertension slightly increases SGA risk. We did not observe an appreciably increased SGA risk associated with antihypertensive medication use beyond that of the underlying maternal hypertension. PMID- 29124625 TI - Maternal Health Behaviors and Outcomes in a Nomadic Tibetan Population. AB - Introduction Despite significant global improvements in maternal health, large disparities persist. In China, rural women and women who live in western regions experience lower rates of maternal healthcare utilization and higher rates of maternal mortality than women elsewhere in the country. This paper examines maternal health care-seeking among nomadic Tibetan women in rural western China, a particularly understudied group. Methods Secondary data analysis was conducted with survey data collected in 2014 in Qinghai Province, China. Participants (rural, nomadic, adult women) provided birth histories and information on care received during antenatal, intrapartum and/or postpartum period(s). Using bivariate and multivariable logistic regression models, these outcomes were explored in relation to maternal characteristics (e.g., educational attainment and parity), use of health insurance, and time. Results Approximately half of all women had ever used antenatal care, institutional delivery, and/or skilled birth attendance. The utilization of these services has increased over time, from 10% of births prior to the year 2000, to approximately 50% since 2000. Utilization increased by year (odds ratios ranging from 1.1 to 1.3) even after controlling for covariates. Women with health insurance coverage were significantly more likely to use these services than women without insurance, although less than 20% of women reported that insurance paid for any antenatal and/or childbirth care. Discussion Utilization of maternal care is improving among this population but rates remain low in comparison to other women in rural, western China. Further targeted interventions may be needed to reach and adequately address the maternal health needs of this unique population. PMID- 29124626 TI - Examining Delivery Method and Infant Feeding Intentions between Women in Traditional and Non-Traditional Prenatal Care. AB - Introduction The purpose of the study is to evaluate delivery method and breastfeeding initiation in women enrolled in group prenatal care (CenteringPregnancy) and in traditional prenatal care. Methods Data were obtained from medical records of a hospital-based midwifery practice in south central Connecticut that offered both types of prenatal care programs. Medical information from 307 women enrolled in this practice was included in the analysis. Out of the 307, 80 were enrolled in group prenatal care. Socio demographic, lifestyle, and previous and current obstetrical information from medical records formed the basis of comparison. Bivariate and logistic regression analyses were carried out. Results Women in Centering had fewer planned cesarean sections (1.3 vs. 12.8%) and had a higher breastfeeding initiation (88.7 vs. 80.0%). However, Centering women were found to have a higher portion of unplanned cesarean sections (27.5 vs. 11.0%). Both the unadjusted and the adjusted odds ratios of having a cesarean planned delivery were lower in the group care. Women in Centering had 2.44 (95% CI 1.05, 5.66) times the odds of breastfeeding initiation compared to the odds for women in traditional prenatal care after adjusting for maternal age, smoking status, gestation and race. Discussion CenteringPregnancy can have positive impact for the woman and baby. This program implementation saw lower rates of elective cesarean sections and increased breastfeeding compared to women in traditional care. PMID- 29124627 TI - Laboring Until Labor: The Prevalence and Correlates of Antenatal Maternity Leave in the United States. AB - Introduction Most women in the U.S. are employed during pregnancy and work until the month of childbirth. For many, working throughout pregnancy poses little threat to their health; however, women experiencing difficult pregnancies and/or working in strenuous or inflexible jobs may benefit from taking time from work as they approach childbirth, but almost no empirical evidence examines antenatal leave (ANL). Methods Using a national survey of English-speaking women, this paper offers the first national description of ANL and examines state policy predictors of uptake. Results Thirty-seven percent of employed women worked until the week their baby was due. After controlling for characteristics of women and their jobs, living in a state with any or multiple leave laws increased the probability of ANL by 14 and 23% points, respectively. Women living in states with multiple leave laws stopped work almost 2 weeks earlier than women in states without a policy. Discussion Paid leave policies currently being considered at the federal, state, and local levels should consider the potential impact on antenatal leave, in addition to postnatal leave, and how they influence population health. PMID- 29124628 TI - Chronic intermittent hypoxia exposure induces kidney injury in growing rats. AB - OBJECTIVE: The objectives of this paper are to examine the effect of chronic intermittent hypoxia (CIH) on the morphological changes in the kidney of growing rats and to explore the mechanisms underlying the CIH-induced renal damage. METHODS: Forty Sprague-Dawley rats were randomly divided into two groups: 2 and 4 weeks CIH groups (2IH, 4IH), and in the control group 2 and 4 weeks air stimulated groups (2C, 4C), with 10 rats in each group. Pathological changes of renal tissue were observed by HE staining, PAS staining, and Masson staining. Real-time PCR method was used to detect the mRNA expression of HIF-1alpha, CuZnSOD/ZnSOD, and MnSOD in renal tissue. RESULTS: (1) Intermittent hypoxia (IH) caused morphological damage in the kidney. Hypertrophy of epithelial cells in the kidney tubules and dilation in the glomeruli were observed under light microscope in HE and PAS stain, especially in 4IH group. Masson staining showed no significant fibrotic response in the IH groups. (2) Compared with the corresponding control groups, the levels of serum SOD were significantly lower in CIH groups, and especially in 4IH group. The mRNA expression of Cu/ZnSOD and MnSOD in CIH groups decreased significantly as compared to control groups. The mRNA levels of HIF-1alpha in the kidney were significantly higher in CIH groups than those in the corresponding control groups. CONCLUSION: Oxidative stress played a critical role in renal damage by up-regulating HIF-1alpha transcription and down-regulating Cu/ZnSOD and MnSOD transcription after chronic intermittent hypoxia exposure in growing rats. PMID- 29124629 TI - The role of education in the self-compilation of Epworth sleepiness scale questionnaire in patients with suspected obstructive sleep apnea. PMID- 29124630 TI - Effectiveness of inspiratory muscle training on sleep and functional capacity to exercise in obstructive sleep apnea: a randomized controlled trial. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of inspiratory muscle training (IMT) on sleep and functional capacity to exercise in subjects with obstructive sleep apnea (OSA). METHODS: This is a controlled, randomized, double-blind study conducted in 16 OSA patients divided into two groups: training (IMT: n = 8) and placebo-IMT (P-IMT: n = 8). IMT was conducted during 12 weeks with a moderate load (50-60% of maximal inspiratory pressure-MIP), while P-IMT used a load < 20% of MPI. Total daily IMT time for both groups was 30 min, 7 days per week, twice a day. RESULTS: There was no difference comparing IMT to P-IMT group after training for lung function (p > 0.05) and respiratory muscle strength (p > 0.05). Maximal oxygen uptake (VO2Max) was not significantly different between IMT and P-IMT group (mean difference - 1.76, confidence interval (CI) - 7.93 to 4.41, p = 0.71). The same was observed for the other ventilatory and cardiometabolic variables measured (p > 0.05). A significant improvement in sleep quality was found when Pittsburgh Sleep Quality Index (PSQI) values of IMT and P IMT group after training were compared (mean difference: 3.7, confidence interval 95% (CI95%) 0.6 to 6.9, p = 0.02) but no significant changes were seen in daytime sleepiness between both groups after the intervention (mean difference: 3.4, CI 95%: - 3.3 to 10.0; p = 0.29). CONCLUSION: According to these results, 12 weeks of moderate load IMT resulted in improved sleep quality, but there were no significant repercussions on functional capacity to exercise or excessive daytime sleepiness. PMID- 29124631 TI - Sensitive Fluorescent Determination of Cobalt by Microwave Assisted Synthesized TPTZ Functionalized Carbon Dots. AB - Novel fluorescent carbon dots (CDs) for cobalt ions sensing were synthesized from 2,4,6-tris(2'-pyridyl)-s-triazine (TPTZ) and citric acid by microwave-assisted method in one pot. This sensor was water soluble, simple, sensitive and cheap. The size of the CDs was determined from transmission electron microscope image and was in the range of 10 nm. Under optimized experimental conditions, this luminescent system had stable response for Co (II) over a concentration range from 0.4 to 50 uM with a detection limit as low as 230 nM. The proposed method showed good sensitivity and selectivity with respect to interference ions. Finally, this system was used for Co (II) determination in tap water, river water and mineral water and B12 ampoule samples. PMID- 29124632 TI - Revealed and Stated Preferences of Decision Makers for Priority Setting in Health Technology Assessment: A Systematic Review. AB - BACKGROUND: There is much interest from stakeholders in understanding how health technology assessment (HTA) committees make national funding decisions for health technologies. A growing literature has analysed past decisions by committees (revealed preference, RP studies) and hypothetical decisions by committee members (stated preference, SP studies) to identify factors influencing decisions and assess their importance. OBJECTIVES: A systematic review of the literature was undertaken to provide insight into committee preferences for these factors (after controlling for other factors) and the methods used to elicit them. METHODS: Ovid Medline, Embase, Econlit and Web of Science were searched from inception to 11 May 2017. Included studies had to have investigated factors considered by HTA committees and to have conducted multivariate analysis to identify the effect of each factor on funding decisions. Factors were classified as being important based on statistical significance, and their impact on decisions was compared using marginal effects. RESULTS: Twenty-three RP and four SP studies (containing 42 analyses) of 14 HTA committees met the inclusion criteria. Although factors were defined differently, the SP literature generally found clinical efficacy, cost-effectiveness and equity factors (such as disease severity) were each important to the Pharmaceutical Benefits Advisory Committee (PBAC), the National Institute for Health and Care Excellence (NICE) and the All Wales Medicines Strategy Group. These findings were supported by the RP studies of the PBAC, but not the other committees, which found funding decisions by these and other committees were mostly influenced by the acceptance of the clinical evidence and, where applicable, cost-effectiveness. Trust in the evidence was very important for decision makers, equivalent to reducing the incremental cost-effectiveness ratio (cost per quality-adjusted life-year) by A$38,000 (Australian dollars) for the PBAC and L15,000 for NICE. CONCLUSIONS: This review found trust in the clinical evidence and, where applicable, cost-effectiveness were important for decision makers. Many methodological differences likely contributed to the diversity in some of the other findings across studies of the same committee. Further work is needed to better understand how competing factors are valued by different HTA committees. PMID- 29124633 TI - An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems. AB - New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous Worldwide Integrated Assessment (WIA) in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little new information has been gathered on soil organisms. The impact on marine and coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal class (neonicotinoids and fipronil), with the potential to greatly decrease populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds, and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates and their deleterious impacts on growth, reproduction, and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota, and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015). PMID- 29124634 TI - Analysis of factors controlling soil phosphorus loss with surface runoff in Huihe National Nature Reserve by principal component and path analysis methods. AB - Phosphorus (P) loss with surface runoff accounts for the P input to and acceleration of eutrophication of the freshwater. Many studies have focused on factors affecting P loss with surface runoff from soils, but rarely on the relationship among these factors. In the present study, rainfall simulation on P loss with surface runoff was conducted in Huihe National Nature Reserve, in Hulunbeier grassland, China, and the relationships between P loss with surface runoff, soil properties, and rainfall conditions were examined. Principal component analysis and path analysis were used to analyze the direct and indirect effects on P loss with surface runoff. The results showed that P loss with surface runoff was closely correlated with soil electrical conductivity, soil pH, soil Olsen P, soil total nitrogen (TN), soil total phosphorus (TP), and soil organic carbon (SOC). The main driving factors which influenced P loss with surface runoff were soil TN, soil pH, soil Olsen P, and soil water content. Path analysis and determination coefficient analysis indicated that the standard multiple regression equation for P loss with surface runoff and each main factor was Y = 7.429 - 0.439 soil TN - 6.834 soil pH + 1.721 soil Olsen-P + 0.183 soil water content (r = 0.487, p < 0.01, n = 180). Soil TN, soil pH, soil Olsen P, and soil water content and the interactions between them were the main factors affecting P loss with surface runoff. The effect of physical and chemical properties of undisturbed soils on P loss with surface runoff was discussed, and the soil water content and soil Olsen P were strongly positive influences on the P loss with surface runoff. PMID- 29124635 TI - Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro. AB - PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners. PMID- 29124636 TI - Green-fabrication of gold nanomaterials using Staphylococcus warneri from Sundarbans estuary: an effective recyclable nanocatalyst for degrading nitro aromatic pollutants. AB - Microbial synthesis of gold nanoparticles (GNPs) has attracted considerable attention in recent times due to their exceptional capability for the bioremediation of industrial wastes and also for the treatment of wastewater. A bacterial strain Staphylococcus warneri, isolated from the estuarine mangroves of Sundarbans region produced highly stable GNPs by reducing hydrogen auric chloride (HAucl4) salt using intracellular protein extract. The nanoparticles were characterized utilizing ultraviolet-visible spectrophotometry, transmission electron microscopy, scanning electron microscopy, atomic force microscopy, X-ray diffraction, and surface enhanced Raman scattering. Highly dispersed, spherically shaped GNPs varied around 15-25 nm in size and were highly crystalline with face centered cubic structures. Recyclable catalytic activity of as-synthesized GNPs was evidenced by complete degradation of nitro aromatic pollutants like 2 nitroaniline, 4-nitroaniline, 2-nitrophenol and 4-nitrophenol. Our GNPs show excellent and efficient catalytic activity with significantly high rate constant (10-1 order) and high turnover frequency (103 order) in recyclable manner up to three times. To our knowledge, this is the first report of Staphylococcus warneri in the production of gold nanoparticles. This green technology for bioremediation of toxic nitro aromatic pollutants is safe and economically beneficial to challenge the development and sustainability issue. PMID- 29124637 TI - Large-scale geographic patterns of mercury contamination in Morocco revealed by freshwater turtles. AB - Mercury (Hg) is a toxic contaminant present in most aquatic ecosystems. High concentrations pose serious threats to organisms and to human health. Because previous studies focused on few countries, environmental hazard due to Hg contamination remains obscure in many geographic areas, and for example limited information is available in North Africa. We examined total Hg contamination in 13 sites in Morocco (12 rivers and one lake) spread over a large area, 400 km north-south and 350 km west-east, that encompasses different biogeographic zones separated by the Atlas Mountains. Due to their longevity and sedentary habits, we used freshwater turtles as biological probes to monitor Hg exposure. Keratinized tissues reflect long-term Hg exposure; thus, we assayed Hg concentration in the claws of > 200 individuals and supplemented these data with blood Hg concentrations of > 60 individuals (a tissue that provides shorter term Hg exposure integration). The results provide the first large-scale picture of Hg contamination in the aquatic freshwater systems of Morocco. Comparisons with previous studies revealed that some of the sites were highly contaminated (e.g. mean Hg concentrations were above 5 MUg g-1, a very high level in keratinized tissues) whereas other sites presented moderate or baseline levels. Unexpectedly, all highly contaminated sites were found in less densely populated areas, while more densely urbanized northern sites, even the sewers of large cities, were not highly contaminated. We hypothesize that silver mining activities in the southern High Atlas and in the Anti-Atlas contaminate rivers of the catchment basins over long distances. These findings indicate that fish, water consumption and contamination levels in local people should be further scrutinized. PMID- 29124638 TI - Foliar application with nano-silicon reduced cadmium accumulation in grains by inhibiting cadmium translocation in rice plants. AB - Nano-silicon (Si) may be more effective than regular fertilizers in protecting plants from cadmium (Cd) stress. A field experiment was conducted to study the effects of nano-Si on Cd accumulation in grains and other organs of rice plants (Oryza sativa L. cv. Xiangzaoxian 45) grown in Cd-contaminated farmland. Foliar application with 5~25 mM nano-Si at anthesis stage reduced Cd concentrations in grains and rachises at maturity stage by 31.6~64.9 and 36.1~60.8%, respectively. Meanwhile, nano-Si application significantly increased concentrations of potassium (K), magnesium (Mg), and iron (Fe) in grains and rachises, but imposed little effect on concentrations of calcium (Ca), zinc (Zn), and manganese (Mn) in them. Uppermost nodes under panicles displayed much higher Cd concentration (4.50~5.53 mg kg-1) than other aerial organs. After foliar application with nano Si, translocation factors (TFs) of Cd ions from the uppermost nodes to rachises significantly declined, but TFs of K, Mg, and Fe from the uppermost nodes to rachises increased significantly. High dose of nano-Si (25 mM) was more effective than low dose of nano-Si in reducing TFs of Cd from roots to the uppermost nodes and from the uppermost nodes to rachises. These findings indicate that nano-Si supply reduces Cd accumulation in grains by inhibiting translocation of Cd and, meanwhile, promoting translocation of K, Mg, and Fe from the uppermost nodes to rachises in rice plants. PMID- 29124639 TI - The variation of cloud amount and light rainy days under heavy pollution over South China during 1960-2009. AB - The ground observation data was used to analyze the variation of cloud amount and light precipitation over South China during 1960-2009. The total cloud cover (TCC) decreases in this period, whereas the low cloud cover (LCC) shows the obvious opposite change with increasing trends. LCP defined as low cloud cover/total cloud cover has increased, and small rainy days (< 10 mm day-1) decreased significantly (passing 0.001 significance level) during the past 50 years, which is attributed to the enhanced levels of air pollution in the form of anthropogenic aerosols. The horizontal visibility and sunshine duration are used to depict the anthropogenic aerosol loading. When horizontal visibility declines to 20 km or sunshine duration decreases to 5 h per day, LCC increases 52% or more and LCP increases significantly. The correlation coefficients between LCC and horizontal visibility or sunshine duration are - 0.533 and - 0.927, and the values between LCP and horizontal visibility or sunshine duration are - 0.849 and - 0.641, which pass 0.001 significance level. The results indicated that aerosols likely impacted the long-term trend of cloud amount and light precipitation over South China. PMID- 29124640 TI - Comparison between snowmelt-runoff and rainfall-runoff nonpoint source pollution in a typical urban catchment in Beijing, China. AB - As a climate-driven event, nonpoint source (NPS) pollution is caused by rainfall- or snowmelt-runoff processes; however, few studies have compared the characteristics and mechanisms of these two kinds of NPS processes. In this study, three factors relating to urban NPS, including surface dust, snowmelt, and rainfall-runoff processes, were analyzed comprehensively by both field sampling and laboratory experiments. The seasonal variation and leaching characteristics of pollutants in surface dust were explored, and the runoff quality of snowmelt NPS and rainfall NPS were compared. The results indicated that dusts are the main sources of urban NPS and more pollutants are deposited in dust samples during winter and spring. However, pollutants in surface dust showed a low leaching ratio, which indicated most NPS pollutants would be carried as particulate forms. Compared to surface layer, underlying snow contained higher chemical oxygen demand, total suspended solids (TSS), Cu, Fe, Mn, and Pb concentrations, while the event mean concentration of most pollutants in snowmelt tended to be higher in roads. Moreover, the TSS and heavy metal content of snowmelt NPS was always higher than those of rainfall NPS, which indicated the importance of controlling snowmelt pollution for effective water quality management. PMID- 29124642 TI - Bootstrap rolling window estimation approach to analysis of the Environment Kuznets Curve hypothesis: evidence from the USA. AB - This study aims to examine the validity of inverted U-shaped Environmental Kuznets Curve by investigating the relationship between economic growth and environmental pollution for the period from 1966 to 2013 in the USA. Previous studies based on the assumption of parameter stability and obtained parameters do not change over the full sample. This study uses bootstrap rolling window estimation method to detect the possible changes in causal relations and also obtain the parameters for sub-sample periods. The results show that the parameter of economic growth has increasing trend in 1982-1996 sub-sample periods, and it has decreasing trend in 1996-2013 sub-sample periods. Therefore, the existence of inverted U-shaped Environmental Kuznets Curve is confirmed in the USA. PMID- 29124641 TI - The mineralization of oxalic acid and bio-treated coking wastewater by catalytic ozonation using nickel oxide. AB - Coking wastewater after biological treatment still possesses potential environmental risk and should be mineralized further. This work focused on the mineralization of bio-treated coking wastewater using catalytic ozonation by NiO. First, oxalic acid, the typical by-product of advanced oxidation process (AOPs), was used to test the catalytic performance of NiOs, prepared by modified hydrothermal methods upon addition of different surfactants. This demonstrated that NiO upon addition of hexadecyltrimethylammonium (CTAB) had the best catalytic activity, due to its high concentration surface hydroxyl density and strong stability. Moreover, the best NiO was applied for the catalytic ozonation of bio-treated coking wastewater. Under our experimental conditions, the total organic carbon (TOC) removal reached 100% after 420 min. In addition, the spectroscopic analysis suggested that compounds with conjugated structures could be significantly removed by both ozonation and catalytic ozonation. Some of these substances were transformed into by-products with aliphatic C-C and O=C-O groups such as organic acids that can inhibit further mineralization. PMID- 29124643 TI - Characteristics of radiocesium contaminations in mushrooms after the Fukushima nuclear accident: evaluation of the food monitoring data from March 2011 to March 2016. AB - The monitoring inspection of food after the Fukushima nuclear accident (2011) was essential for ensuring food safety in Japan and reducing the adverse health effects due to incorporation of inacceptable amounts of radionuclides, in particular radiocesium (134Cs and 137Cs). In this study, the mushroom fraction of the governmental data set of the first 5 years after the accident has been analyzed for contamination levels in mushrooms, in particular time trends and radioecological characteristics as well as associated health risks. The analyses show that mycorrhiza mushrooms are much more sensitive for radionuclide uptake than saprobiontic mushrooms (the latter of which include the very popular shiitake mushrooms (Lentinula edodes)). The maximum value reached 31,000 Bq/kg in a sample of apricot milkcaps in 2012. Analysis of the origin of the samples revealed that the origin (in terms of prefecture) of the mushrooms was a less determining factor for the contamination level than the type of mushrooms, as most exceedances in 2012 and thereafter were found outside Fukushima Prefecture. Several dose models were applied to the data to evaluate both worst case and realistic effective committed dose scenarios. The doses were generally rather low due to low consumption rates in the Japanese food basket. In any case, the analysis proved that the food monitoring campaign was highly effective in cutting doses to the public by more than a factor of 10 compared with a hypothetical scenario in which no monitoring had been conducted. PMID- 29124644 TI - Spatial trends and pollution assessment for mercury in the surface soils of the Nansi Lake catchment, China. AB - Surface soil samples collected from Nansi Lake catchment were analyzed for mercury (Hg) to determine its spatial trends and environmental impacts. Results showed that the average soil Hg contents were 0.043 mg kg-1. A positive correlation was shown between TOC and soil Hg contents. The main type of soil with higher TOC contents and lower pH values showed higher soil Hg contents. Soil TOC contents and CV values were both higher in the eastern catchment. The eastern part of the catchment, where the industry is developed, had relatively high soil Hg contents and a banding distribution of high Hg contents was corresponded with the southwest-northeast economic belt. Urban soils had higher Hg contents than rural soils. The urbanization pattern that soil Hg contents presented a decreasing trend from city center to suburb was shown clearly especially in the three cities. Soil Hg contents in Jining City showed a good consistency with the urban land expansion. The spatial trends of soil Hg contents in the catchment indicated that the type and the intensity of human activities have a strong influence on the distribution of Hg in soils. Calculated risk indices showed that the western part of the catchment presented moderately polluted condition and the eastern part of the catchment showed moderate to strong pollution level. The area with high ecological risk appeared mainly along the economic belt. PMID- 29124645 TI - Environmental impacts the of production and use of biodiesel. AB - Biodiesel as renewable, environmental friendly, less toxic, and biodegradable is an attractive alternative to fossil fuels and is produced mainly from vegetable oils and animal fats. It is expected, globally, that the use of renewable biofuels, in general, will increase rapidly in the near future. The growing biodiesel production and usage have encouraged assessment of its impact on the environment. The present paper reviews various aspects of biodiesel production using commercial processing technology and biodiesel use through evaluation and analysis of the studies concerning environmental impacts of biodiesel. As a general conclusion, it can be said that biodiesel has the potential to offer a series of perceived benefits such as political, economical, and agricultural, as well as environmental (due to its biodegradability, less toxicity, renewability) and health (greenhouse gas-saving, less harmful exhaust emissions). PMID- 29124646 TI - Metal availability, soil nutrient, and enzyme activity in response to application of organic amendments in Cd-contaminated soil. AB - The study investigated the effects of organic amendments: green tea amendment (GTA) and oil cake amendment (OCA) on Cd bioavailability, soil nutrients, and soil enzyme activity in Cd-contaminated soil. The amendments were added to the soil at the doses of 1, 3, and 5% and were incubated for 45 days. Then, pakchoi cabbage was planted to test the remediation effect of the above two organic amendments. The diethylenetriaminepentaacetic acid (DTPA)-extractable Cd in GTA and OCA treatments was reduced by 14.69-27.51 and 13.75-68.77%, respectively, compared to no amendment-applied treatment. The application of GTA and OCA notably decreased the proportion of exchangeable fraction of Cd, but increased the percentage of oxide and organic-bound fraction of Cd, thereby suppressing the uptake by pakchoi cabbage. Cd concentration of aboveground parts decreased by 8.21-18.05 and 7.77-35.89% in GTA and OCA treatments, respectively. Relative to the no amendment-applied treatment, both GTA and OCA had enhanced soil nutrients and enzyme activities largely. Redundancy analysis showed that organic matter, total P, available N, and DTPA-extractable Cd significantly affected the enzyme activities. Furthermore, the application of OCA at the dose of 5% was more effective in reducing bioavailable Cd, enhancing soil available nutrients and urease and catalase activities in contaminated soil. These results indicated that oil cake should be used to immobilize metal and improve fertility and quality of Cd-contaminated soil. PMID- 29124648 TI - A case of esophageal actinomycosis with a unique morphology presenting as a refractory ulcer. AB - A 60-year-old man presented with odynophagia after bronchial artery infusion chemotherapy for pulmonary metastasis of hepatocellular carcinoma. Esophagogastroduodenoscopy (EGD) revealed an esophageal ulcer in the middle thoracic esophagus. An esophageal biopsy demonstrated no malignancy. However, the symptoms had not improved after a month. EGD was performed again and showed a white cord lump at the bottom of the same esophageal ulcer identified before, showing no improving tendency. A repeated biopsy of the lump revealed actinomycosis, and the symptoms were improved by the oral administration of ampicillin. We herein report a case in which esophageal actinomycosis with a unique morphology of refractory esophageal ulcer was rapidly improved by the administration of antibiotics. PMID- 29124647 TI - Improvement of semen parameters after antibiotic therapy in asymptomatic infertile men infected with Mycoplasma genitalium. AB - OBJECTIVES: To elucidate the association between asymptomatic infections caused by Mycoplasma genitalium and male infertility, and evaluate the role of antibiotic therapy in treatment of this failure. METHODS: A total of 165 infertile males having abnormal semen parameters (study group) and 165 healthy fertile men (control group) were included. Semen samples were taken from all participants and after analyzing for semen parameters, undergone real-time PCR, microbial culture, and reactive oxygen species (ROS), as well as total antioxidant capacity (TAC) assays. Infected individuals of study group were treated with antibiotic. One month after the treatment completion, second semen samples were taken and subjected to all the tests mentioned. The data were analyzed using SPSS statistical software, version 22.0. RESULTS: The frequency of M. genitalium was significantly higher in the infertile men compared with the fertile ones (9.7% vs. 1.2%; p = 0.001). Mean cycle threshold (C t) value was lower in infected infertile than infected fertile men (p < 0.001). All semen parameters, except volume, pH, and viscosity, were improved (p < 0.05), most of which reached their normal range; leukocytes in seminal fluid decreased (p = 0.02), the level of TAC was elevated (p = 0.002), and ROS level as well as ROS/TAC ratio reduced after antibiotic treatment (p = 0.03). Wives of seven infected infertile men (43.8%) became pregnant 4 months after the treatment completion. CONCLUSIONS: Asymptomatic infection caused by M. genitalium is correlated with male infertility and antibiotic therapy can improve the semen quality and be used to treat male infertility. PMID- 29124649 TI - Angiotensin receptor blockade: a novel approach for symptomatic radiation necrosis after stereotactic radiosurgery. AB - Preclinical evidence suggests angiotensin blockade therapy (ABT) decreases late radiation toxicities. This study aims to investigate the association between ABT and symptomatic radiation necrosis (SRN) following stereotactic radiosurgery (SRS). Resected brain metastases (rBM) and arteriovenous malformation (AVM) patients treated with SRS from 2002 to 2015 were identified. Patients in the ABT cohort were on therapy during SRS and at 1-month follow up. Kaplan Meier method and cumulative incidence model were used to analyze overall survival (OS) and intracranial outcomes. 228 consecutive patients were treated with SRS: 111 with rBM and 117 with AVM. Overall, 51 (22.4%) patients were in the ABT group: 32 (28.8%) in the rBM and 19 (16.2%) in AVM cohorts. Baseline characteristics were similar, except for higher Graded Prognostic Analysis (3-4) in the rBM (ABT: 25.0% vs. non-ABT: 49.0%, p = 0.033) and median age in the AVM (ABT: 51.4 vs. non ABT: 35.4, p < 0.001) cohorts. In both populations, OS and intracranial efficacy (rBM-local control; AVM-obliteration rates) were statistically similar between the cohorts. ABT was associated with lower 1-year SRN rates in both populations: rBM, 3.1 versus 25.3% (p = 0.003); AVM, 6.7 vs. 14.6% (p = 0.063). On multivariate analysis, ABT was a significant predictive factor for rBM (HR: 0.17; 95% CI 0.03-0.88, p = 0.035), but did not reach statistical significance for AVM (HR: 0.36; 95% CI 0.09-1.52, p = 0.165). ABT use appears to be associated with a reduced risk of SRN following SRS, without detriment to OS or intracranial efficacy. A prospective trial to validate these findings is warranted. PMID- 29124651 TI - Novel quantitative insights into carbon sources for synthesis of poly hydroxybutyrate in Synechocystis PCC 6803. AB - Many freshwater cyanobacteria accumulate polyhydroxybutyrate (PHB) under nitrogen or phosphorus deprivation. While prior literature has shed lights on transcriptomic and metabolomic changes in the model cyanobacterium Synechocystis PCC 6803 cells, the quantitative contributions of the newly fixed carbon following nitrogen deprivation or the externally added acetate to PHB synthesis are not clear. Similarly, it is not clear how photomixotrophy affects precursor contributions. In this study, we show that (i) the pre-growth mode (photoautotrophic or photomixotrophic), while significantly impacting glycogen levels, does not have any significant effect on PHB levels, (ii) the carbon fixed following nitrogen deprivation contributes 26% of C for PHB synthesis in photoautotrophically pre-grown cells and its contribution to the PHB synthesis goes down with the addition of acetate at the resuspension phase or with photomixotrophic pre-growth, (iii) the acetate added at the start of nitrogen deprivation, doubles the intracellular PHB levels and contributes 44-48% to PHB synthesis and this value is not greatly affected by how the cells were pre-grown. Indirectly, the labeling studies also show that the intracellular C recycling is the most important source of precursors for PHB synthesis, contributing about 74 87% of the C for PHB synthesis in the absence of acetate. The addition of acetate significantly reduces its contribution. In photoautotrophic pre-growth followed by acetate addition under nitrogen starvation, the contribution of intracellular C reduces to about 34%. Thus, our study provides several novel quantitative insights on how prior nutritional status affects the precursor contributions for PHB synthesis. PMID- 29124652 TI - Red shift in the spectrum of a chlorophyll species is essential for the drought induced dissipation of excess light energy in a poikilohydric moss, Bryum argenteum. AB - Some mosses are extremely tolerant of drought stress. Their high drought tolerance relies on their ability to effectively dissipate absorbed light energy to heat under dry conditions. The energy dissipation mechanism in a drought tolerant moss, Bryum argenteum, has been investigated using low-temperature picosecond time-resolved fluorescence spectroscopy. The results are compared between moss thalli samples harvested in Antarctica and in Japan. Both samples show almost the same quenching properties, suggesting an identical drought tolerance mechanism for the same species with two completely different habitats. A global target analysis was applied to a large set of data on the fluorescence quenching dynamics for the 430-nm (chlorophyll-a selective) and 460-nm (chlorophyll-b and carotenoid selective) excitations in the temperature region from 5 to 77 K. This analysis strongly suggested that the quencher is formed in the major peripheral antenna of photosystem II, whose emission spectrum is significantly broadened and red-shifted in its quenched form. Two emission components at around 717 and 725 nm were assigned to photosystem I (PS I). The former component at around 717 nm is mildly quenched and probably bound to the PS I core complex, while the latter at around 725 nm is probably bound to the light harvesting complex. The dehydration treatment caused a blue shift of the PS I emission peak via reduction of the exciton energy flow to the pigment responsible for the 725 nm band. PMID- 29124653 TI - Salt stress effects on the photosynthetic electron transport chain in two chickpea lines differing in their salt stress tolerance. AB - The main objective of this study was to evaluate the effects of salt stress on the photosynthetic electron transport chain using two chickpea lines (Cicer arietinum L.) differing in their salt stress tolerance at the germination stage (AKN 87 and AKN 290). Two weeks after sowing, seedlings were exposed to salt stress for 2 weeks and irrigated with 200 ml of 200 mM NaCl every 2 days. The polyphasic OJIP fluorescence transient and the 820-nm transmission kinetics (photosystem I) were used to evaluate the effects of salt stress on the functionality of the photosynthetic electron transport chain. It was observed that a signature for salt stress was a combination of a higher J step (VJ), a smaller IP amplitude, and little or no effect on the primary quantum yield of PSII (phiPo). We observed for AKN 290 a shorter leaf life cycle, which may represent a mechanism to cope with salt stress. For severely salt-stressed leaves, an inhibition of electron flow between the PQ pool and P700 was found. The data also suggest that the properties of electron flow beyond PSI are affected by salt stress. PMID- 29124654 TI - Meta-analysis of Microbial Fuel Cells Using Waste Substrates. AB - Microbial fuel cell experimentation using waste streams is an increasingly popular field of study. One obstacle to comparing studies has been the lack of consistent conventions for reporting results such that meta-analysis can be used for large groups of experiments. Here, 134 unique microbial fuel cell experiments using waste substrates were compiled for analysis. Findings include that coulombic efficiency correlates positively with volumetric power density (p < 0.001), negatively with working volume (p < 0.05), and positively with percentage removal of chemical oxygen demand (p < 0.005). Power density in mW/m2 correlates positively with chemical oxygen demand loading (p < 0.005), and positively with maximum open-circuit voltage (p < 0.05). Finally, single-chamber versus double chamber reactor configurations differ significantly in maximum open-circuit voltage (p < 0.005). Multiple linear regression to predict either power density or maximum open-circuit voltage produced no significant models due to the amount of multicollinearity between predictor variables. Results indicate that statistically relevant conclusions can be drawn from large microbial fuel cell datasets. Recommendations for future consistency in reporting results following a MIAMFCE convention (Minimum Information About a Microbial Fuel Cell Experiment) are included. PMID- 29124650 TI - Correction to: Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study. AB - The members of the PERNO Study Group were not individually captured in the metadata of the original publication. They are included in the metadata of this publication. PMID- 29124655 TI - Enhanced Bioactivity of the Anti-LOX-1 scFv Engineered by Multimerization Strategy. AB - Single-chain variable fragment (scFv) antibodies as therapeutic agents have the potential to reduce the production cost and immunogenicity relative to monoclonal antibodies, but their monovalency and lack of a fragment crystallizable region can lead to reduced function. Multimerization is one strategy for recovering the function; however, their application is limited by the production of multimeric proteins. In our previous study, an anti-lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) scFv showed potential use in diagnosis and therapy of atherosclerotic diseases, but is limited by its inherent low antigen-binding activity. In this study, to improve the efficacy of the anti-LOX-1 scFv, we constructed the anti-LOX-1 scFv multimers by modifying the linker length between the variable domains of the scFv or by fusing the scFv with self-merization domains and expressed these scFv multimers in Brevibacillus choshinensis hosts. After optimization, all of the scFv multimers obtained efficient secretion expression. Compared with the scFv monomer, the multimers that are successfully fractionated displayed increased neutralization activity and showed elevated antigen-binding avidity, especially the tetramer, which improved the antigen avidity by two orders of magnitude. Moreover, the scFv dimer and the tetramer both displayed better stability and longer half-life in serum, which can be attractive candidates for the next-generation anti-LOX-1 therapeutic antibody. PMID- 29124656 TI - Enzymatic Activation of the Emerging Drug Resveratrol. AB - The plant originated stilbene "resveratrol" (3,4',5-trans-trihydroxystilbene) is well known for its diverse health benefits including anti-tumor, anti inflammatory, anti-microbial, and anti-oxidant properties. Besides a significant amount of reports on different aspects of its application as prodrug in the last 50 years, still, a strategy leading to the production of the active drug is missing. The aim of this work was to evaluate the enzymatic activation of prodrug resveratrol to the effective drug piceatannol, without engaging expensive cofactors. Five different heme proteins were analyzed for the transformation of resveratrol. Kinetic parameters of resveratrol transformation and analysis of the transformed products were conducted through HPLC and GC-MS. Effect of pH and organic solvent on the transformation process had also been evaluated. Among all tested heme proteins, only a variant of cytochrome P450BM3 from Bacillus megaterium (CYPBM3F87A) was found suitable for piceatannol production. The most suitable pH for the reaction conditions was 8.5, while organic solvents did not show any effect on transformation. For resveratrol transformation, the turnover rate (k cat) was 21.7 (+/- 0.6) min-1, the affinity constant (K M) showed a value of 55.7 (+/- 16.7) MUM for a catalytic efficiency (k cat/K M) of 389 min-1 mM-1. GC-MS analysis showed that the only product from resveratrol transformation by cytochrome P450BM3 is the biologically active piceatannol. The enzymatic transformation of resveratrol, an emerging compound with medical interest, to active product piceatannol by a variant of cytochrome P450BM3 in the absence of expensive NADPH cofactor is demonstrated. This enzymatic process is economically attractive and can be scaled up to cover the increasing medical demand for piceatannol. PMID- 29124657 TI - Thank You! PMID- 29124658 TI - Atypical HRCT manifestations of pulmonary sarcoidosis. AB - PURPOSE: To present our experience of cases of pulmonary sarcoidosis with atypical HRCT patterns found during 2016 focusing on the differential diagnosis to contribute to the difficult role of the radiologist in the disease identification and to help the clinicians to reach the diagnosis. MATERIALS AND METHODS: The HRCT examinations of 47 patients with sarcoidosis were studied retrospectively. All patients had a histopathological confirm of the disease. 29 (61.7%) show a typical pulmonary pattern and 18 (38.3%) an atypical pattern. The latter were evaluated by three experienced radiologists dedicated to thoracic disease to radiologically define the predominant pattern of presentation. RESULTS: In the 18 patients (38.3%) with atypical sarcoidosis, the following parenchymal patterns were observed: four patients (22.2%) had interstitial fibrotic alterations, three patients (16.6%) with reticular pattern with inter intralobular septal thickening, two patients (11.1%) with small-airway involvement with mosaic oligoemia, two patients (11.1%) with pleural involvement (pneumothorax and pleural plaques), one patient (5.5%) with fibrocystic changes, 1 (5.5%) with halo-sign, 1 (5.5%) with diffuse bilateral ground-glass opacities, and 1 (5.5%) with isolated lung mass; in addition, three patients (16.6%) with atypical lymph node pattern were also found. CONCLUSIONS AND DISCUSSION: The atypical pulmonary alterations found in CT examination can be confused with other lung diseases and they are always a challenge even for the most experienced radiologist. In our experience, cases with atypical pulmonary sarcoidosis patterns evaluated in the study are consistent with similar cases described in the literature, both in lymph node and atypical parenchymal involvement. All the atypical characteristics of the work should alert the radiologist to consider sarcoidosis among the possible differential diagnoses, always correlating the results of the computed tomography examination with appropriate clinical laboratory evaluations. PMID- 29124659 TI - Varilactones and wortmannilactones produced by Penicillium variabile cultured with histone deacetylase inhibitor. AB - Seven polyketides, including four new ones named as varilactones A-B (1-2) and wortmannilactones M-N (3-4), as well as three biogenetically related known wortmannilactones E, F and H (5-7), were isolated from the fungus Penicillium variabile HXQ-H-1, cultivated in potato-based medium with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Their structures (1-7) were established by analysis of NMR and MS data, and the absolute configuration of oxabicyclo[2.2.1]heptane unit was deduced from 1H-NMR analyses on MPA esters after chemical reduction reaction. Among them, varilactones A and B (1 and 2), features a novel skeleton with a triene unit linking an oxabicyclo[2.2.1]heptane and an oxabicyclo[3.3.0]octane rings. PMID- 29124660 TI - Anti-inflammatory activity of caffeic acid derivatives isolated from the roots of Salvia miltiorrhiza Bunge. AB - Ten caffeic acid derivatives (1-10) were isolated from the roots of Salvia miltiorrhiza by using various chromatographic methods and their chemical structures were spectroscopically elucidated. The absolute configurations of chiral centers were determined by comparison with reported coupling constants, optical rotation values, and CD techniques. Anti-inflammatory activities were evaluated using nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 inhibition assays, and by determining the expression of heme oxygenase (HO)-1. Two new caffeic acid derivatives, 8-epiblechnic acid 9 methyl ester (4) and 8-epiblechnic acid 9'-methyl ester (5), and eight known derivatives, caffeic acid methyl ester (1), shimobashiric acid B (2), rosmarinic acid methyl ester (3), salvianolic acid C (6), methyl salvianolate C (7), lithospermic acid monomethyl ester (8), lithospermic acid dimethyl ester (9), and dimethyl lithospermate B (10), were isolated from the ethyl acetate fraction of S. miltiorrhiza. All caffeic acid derivatives were evaluated for their inhibitory effect on NO production. Compounds 2 and 3 inhibited NO production with IC50 values of 1.4 and 0.6 MUM, respectively. These compounds also strongly inhibited the production of iNOS and COX-2. In addition, compound 3 induced the expression HO-1 in a concentration-dependent manner at 0.1, 0.3, and 1.0 MUM. PMID- 29124661 TI - Valsartan regulates TGF-beta/Smads and TGF-beta/p38 pathways through lncRNA CHRF to improve doxorubicin-induced heart failure. AB - This study investigated the interaction among valsartan (VAL), TGF-beta pathways, and long non-coding RNA (lncRNA) cardiac hypertrophy-related factor (CHRF) in doxorubicin (DOX)-induced heart failure (HF), and explored their roles in DOX induced HF progression. HF mice models in vivo were constructed by DOX induction. The expression of CHRF and TGF-beta1 in hearts was detected, along with cardiac function, caspase-3 activity, and cell apoptosis. Primary myocardial cells were pretreated with VAL, followed by DOX induction in vitro for functional studies, including the detection of cell apoptosis with terminal deoxynucleotidyl transferase dUTP nick-end labeling and the expression of proteins associated with TGF-beta1 pathways. HF models were established in vivo and in vitro. Expression of CHRF and TGF-beta1 was up-regulated, and cell apoptosis and caspase-3 activity were increased in the hearts and cells of the HF models. VAL supplementation alleviated the cardiac dysfunction and injury in the HF process. Moreover, overexpressed CHRF up-regulated TGF-beta1, promoted myocardial cell apoptosis, and reversed VAL's cardiac protective effect, while interference of CHRF (si CHRF) did the opposite. Down-regulation of CHRF reversed the increased expression of TGF-beta1 and the downstream proteins induced by pcDNA-TGF-beta1 in HL-1 cells, while overexpression of CHRF reversed the VAL's cardiac protective effect in vivo. In conclusion, VAL regulates TGF-beta pathways through lncRNA CHRF to improve DOX-induced HF. PMID- 29124662 TI - Dopamine agonist withdrawal in hyperprolactinemia: when and how. PMID- 29124663 TI - Residual flow in false lumen of chronic descending aortic dissection. PMID- 29124665 TI - Evaluation of 'Definite' Anaphylaxis Drug Allergy Alert Overrides in Inpatient and Outpatient Settings. AB - INTRODUCTION: Drug-allergy interaction (DAI) alerts are generated when a known adverse sensitivity-inducing substance is prescribed. A recent study at our institution showed that providers overrode most DAI alerts, including those that warned against potentially life-threatening 'anaphylaxis'. OBJECTIVE: The aim of this study was to determine the rate of anaphylaxis overrides, the reasons for these overrides, whether the overrides were appropriate, and if harm occurred from overrides. METHODS: All DAI alerts, with a reaction of 'anaphylaxis', were analysed for inpatients and outpatients within our health system between January 2009 and December 2011. Only alerts that were triggered by 'definite' alerts (i.e. same ordered medication as documented allergen) were included. Patient charts were reviewed to assess the appropriateness of overrides and potential harm, according to a predetermined set of criteria. RESULTS: A total of 202 inpatient and 16 outpatient alerts met the inclusion criteria. The rate of overrides for 'definite' anaphylaxis DAI alerts was high (inpatient: n = 93, 46.0%; outpatient: n = 11, 68.8%) but appropriate for most overrides in the inpatient (n = 78, 83.9%) and outpatient settings (n = 11, 100%). The most common override reasons in the inpatient and outpatient settings were 'administer per desensitization protocol' (n = 64, 31.7%) and 'patient does not have this allergy' (n = 7, 63.6%), respectively. No harm was associated with overrides in either setting, particularly because many medications were not administered. CONCLUSIONS: Overrides of 'definite' anaphylaxis DAI alerts were common and often appropriate. Most overrides were due to desensitizations. Allergy reconciliation for patients could further improve critical decision support. PMID- 29124664 TI - Downhill exercise alters immunoproteasome content in mouse skeletal muscle. AB - Content of the immunoproteasome, the inducible form of the standard proteasome, increases in atrophic muscle suggesting it may be associated with skeletal muscle remodeling. However, it remains unknown if the immunoproteasome responds to stressful situations that do not promote large perturbations in skeletal muscle proteolysis. The purpose of this study was to determine how an acute bout of muscular stress influences immunoproteasome content. To accomplish this, wild type (WT) and immunoproteasome knockout lmp7 -/- /mecl1 -/- (L7M1) mice were run downhill on a motorized treadmill. Soleus muscles were excised 1 and 3 days post exercise and compared to unexercised muscle (control). Ex vivo physiology, histology and biochemical analyses were used to assess the effects of immunoproteasome knockout and unaccustomed exercise. Besides L7M1 muscle being LMP7/MECL1 deficient, no other major biochemical, histological or functional differences were observed between the control muscles. In both strains, the downhill run shifted the force-frequency curve to the right and reduced twitch force; however, it did not alter tetanic force or inflammatory markers. In the days post-exercise, several of the proteasome's catalytic subunits were upregulated. Specifically, WT muscle increased LMP7 while L7M1 muscle instead increased beta5. These findings indicate that running mice downhill results in subtle contractile characteristics that correspond to skeletal muscle injury, yet it does not appear to induce a significant inflammatory response. Interestingly, this minor stress activated the production of specific immunoproteasome subunits that if knocked out were replaced by components of the standard proteasome. These data suggest that the immunoproteasome may be involved in maintaining cellular homeostasis. PMID- 29124666 TI - Study Design and Evaluation of Risk Minimization Measures: A Review of Studies Submitted to the European Medicines Agency for Cardiovascular, Endocrinology, and Metabolic Drugs. AB - INTRODUCTION: Studies measuring the effectiveness of risk minimization measures (RMMs) submitted by pharmaceutical companies to the European Medicines Agency are part of the post-authorization regulatory requirements and represent an important source of data covering a range of medicinal products and safety-related issues. Their objectives, design, and the associated regulatory outcomes were reviewed, and conclusions were drawn that may support future progress in risk minimization evaluation. METHODS: Information was obtained from risk management plans, study protocols, clinical study reports, and assessment reports of 157 medicinal products authorized for cardiovascular, endocrinology, and metabolic indications. We selected observational studies measuring, as outcomes of interest, the relationship between the RMMs in place and (1) implementation measures, such as clinical knowledge or physicians' compliance to recommendations contained in the RMMs; and (2) occurrence or reduced severity of the adverse drug reactions for which the RMMs were required. RESULTS: Of 59 eligible studies (24 completed, 35 ongoing), 44 assessed implementation measures, whereas only 15 assessed safety outcomes (1 study as a single endpoint and 14 studies with other endpoints). Fifty-one studies used non-experimental designs and 25 studies employed electronic healthcare databases for analysis. Of the 24 completed studies, 17 were considered satisfactory and supported immediate regulatory decision making, 6 were considered inconclusive and required new evaluations, and 1 was terminated early because new safety restrictions were required, thereby necessitating a new evaluation. Compliance with agreed deadlines was considered acceptable in 21 of 24 completed studies; the average time for a submission was 37 months (standard deviation +/- 17), with differences observed by type of data source employed. CONCLUSIONS: Three important gaps in the evaluation plans of RMMs were identified: lack of early feedback on implementation, limited evaluation of safety outcomes, and inability to provide information on the effectiveness from an integrated measurement of different elements of a set of risk minimization tools. More robust evidence is needed to advance regulatory science and support more rapid adjustment of risk minimization strategies as needed. PMID- 29124667 TI - Improving survival in ACLF: growing evidence for use of G-CSF. PMID- 29124668 TI - The Application of CGRP(r) Monoclonal Antibodies in Migraine Spectrum: Needs and Priorities. AB - Migraine is among the highest impact illnesses in the global population. Its negative ramifications are personal, social, economic and work related. Research on the development of new preventative migraine therapies has been idle for decades. The introduction, shortly, of an innovative pharmacological class useful for migraine prevention, namely monoclonal antibodies towards calcitonin gene related peptide or its receptor, opens a new, immense therapeutic scenario. The necessity to manage the chronic and refractory forms of migraine must not take our attention away from the target of the pre-chronic forms. This is the most important target in every study. Indeed, by reducing the evolution towards chronic and consequently refractory chronic migraine, we will reduce complications caused by pharmacological abuse, the serious disability of these devastating chronic states, and the healthcare expenses needed to manage chronicity, abuse and consequent pathologies. We will, lastly, be able to rehabilitate these patients to achieve a quality working and social life, and facilitate their reintegration into daily normality. PMID- 29124669 TI - Shunt occlusion for portosystemic shunt syndrome related refractory hepatic encephalopathy-A single-center experience in 21 patients from Kerala. AB - INTRODUCTION: Large spontaneous portosystemic shunts (SPSS) are seen in a subset of patients with liver disease and medically refractory recurrent/persistent hepatic encephalopathy (MRHE). Shunt occlusion has been shown to improve clinical outcomes. METHODS: We retrospectively analyzed patient characteristics, SPSS attributes, procedural features, baseline clinical and investigational parameters, neurological outcomes, adverse effects (procedure and portal hypertension related), and risk factors predicting outcomes in liver disease patients undergoing shunt occlusion procedure for MRHE. RESULTS: Between October 2016 and July 2017, 21 patients (Child-Pugh score, CTP 6 to 13) with mean model of end-stage liver disease (MELD) and MELD-sodium scores 15.7 and 19.3 respectively with MRHE [3-cirrhotic Parkinsonism (CP)] were diagnosed to have single or multiple large SPSSs. A total of 29 shunts were occluded (1 surgical, 20 non-surgical). Recurrent and persistent HE and CP markedly improved in the short (n=20, 1 to 3 months), intermediate (n=12, 3 to 6 months), and long (n=7, 6 to 9 months) follow up. None had spontaneous or persistent HE at a median follow up 105 (30 to 329) days (p<0.05). Motor, speech, sleep abnormalities, daily activities of living, and liver disease severity scores improved significantly on follow up. Baseline arterial ammonia showed a statistically significant reduction in all time periods of follow up after shunt occlusion (p<0.05). CTP >11 predicted mortality post shunt occlusion (p=0.04). Embolization of large SPSS in liver disease patients with MRHE and modestly preserved liver function is safe and efficacious and associated with improved quality of life and can function as a bridge to liver transplantation in accurately selected patients. PMID- 29124670 TI - Visual working memory can selectively reset a subset of its representations. AB - The visual working memory (VWM) resetting process is triggered when the mapping between an object in the environment and its corresponding VWM representation becomes irrelevant. Resetting involves discarding the no longer relevant representations, and encoding novel representations and mappings. We examined how resetting operates on VWM's contents. Specifically, we tested whether losing only part of the encoded mappings led to resetting all of the VWM representations. Subjects monitored moving polygons for an abrupt shape-change. Occasionally, a polygon separated into two halves that continued to move independently, making the original single mapping irrelevant. This loss of mapping triggered a resetting process, producing a performance cost: subjects missed shape-changes when they occurred during resetting, but not when the changes occurred before or after resetting. Critically, the cost was (1) specific to the separated item, (2) larger when more mappings were lost, and (3) unaffected by the set-size. This suggests that resetting is a "local" process: VWM removes only the representations whose mappings are lost. PMID- 29124673 TI - Failure to accurately identify the number of diseased coronary arteries: A weakness of SPECT MPI. PMID- 29124671 TI - Mutations of N-Methyl-D-Aspartate Receptor Subunits in Epilepsy. AB - Epilepsy is one of the most common neurological diseases. Of all cases, 70%-80% are considered to be due to genetic factors. In recent years, a large number of genes have been identified as being involved in epilepsy. Among them, N-methyl-D aspartate receptor (NMDAR) subunit-encoding genes represent a large proportion, suggesting an important role for NMDARs in epilepsy. In this review, we summarize and analyze the genotypes, functional alterations, and clinical aspects of NMDAR subunit mutations/variants identified from patients with epilepsy. These data will help to throw light upon the pathogenicity of these NMDAR mutations and advance our understanding of the subtle and complicated role of NMDARs in epilepsy. It will also offer new insights into precision therapy for this disorder. PMID- 29124674 TI - The cognitive loci of the display and task-relevant set size effects on distractor interference: Evidence from a dual-task paradigm. AB - The congruency effect of a task-irrelevant distractor has been found to be modulated by task-relevant set size and display set size. The present study used a psychological refractory period (PRP) paradigm to examine the cognitive loci of the display set size effect (dilution effect) and the task-relevant set size effect (perceptual load effect) on distractor interference. A tone discrimination task (Task 1), in which a response was made to the pitch of the target tone, was followed by a letter discrimination task (Task 2) in which different types of visual target display were used. In Experiment 1, in which display set size was manipulated to examine the nature of the display set size effect on distractor interference in Task 2, the modulation of the congruency effect by display set size was observed at both short and long stimulus-onset asynchronies (SOAs), indicating that the display set size effect occurred after the target was selected for processing in the focused attention stage. In Experiment 2, in which task-relevant set size was manipulated to examine the nature of the task-relevant set size effect on distractor interference in Task 2, the effects of task relevant set size increased with SOA, suggesting that the target selection efficiency in the preattentive stage was impaired with increasing task-relevant set size. These results suggest that display set size and task-relevant set size modulate distractor processing in different ways. PMID- 29124672 TI - Radio Electric Asymmetric Conveyer Technology Modulates Neuroinflammation in a Mouse Model of Neurodegeneration. AB - In this study, the effects of Radio Electric Asymmetric Conveyer (REAC), a non invasive physical treatment, on neuroinflammatory responses in a mouse model of parkinsonism induced by intoxication with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), were investigated in vivo. We found that the REAC tissue optimization treatment specific for neuro-regenerative purposes (REAC TO RGN-N) attenuated the inflammatory picture evoked by MPTP-induced nigro-striatal damage in mice, decreasing the levels of pro-inflammatory molecules and increasing anti-inflammatory mediators. Besides, there was a significant reduction of both astrocyte and microglial activation in MPTP-treated mice exposed to REAC TO-RGN-N. These results indicated that REAC TO-RGN-N treatment modulates the pro-inflammatory responses and reduces neuronal damage in MPTP induced parkinsonism. PMID- 29124675 TI - Pim-2 Cooperates with Downstream Factor XIAP to Inhibit Apoptosis and Intensify Malignant Grade in Prostate Cancer. AB - To find the exact downstream effector of Pim-2 pathway in prostate cancer cells, and to determine the means by which it affects prostate cancer. XIAP, Pim-2 and p eIF4B expressions were detected in PCA and BPH tissues. Then the Pim-2 and XIAP expressions were manipulated using transfection or RNAi in prostatic cells. Finally, Pim-2/eIF4B/XIAP levels were examined in PCA tissues with different clinicopathologic features. XIAP was significantly higher in PCA than in BPH tissues. When Pim-2 was transfected into noncancerous prostate epithelial cells RWPE-1, Pim-2, p-eIF4B and XIAP were all significantly increased and the apoptosis rate was significantly decreased. When XIAP was transfected into RWPE-1 cells, XIAP was significantly increased with no impact on Pim-2, p-eIF4B and the apoptosis rate. When Pim-2 SiRNA was transfected into prostate cancer cells PC-3, Pim-2, p-eIF4B and XIAP were significantly decreased and the apoptosis rate was significantly increased. When XIAP SiRNA was transfected into PC-3 cells, XIAP was significantly decreased with no impact on Pim-2, p-eIF4B and apoptosis rate. Pim-2, p-eIF4B and XIAP were all significantly higher in PCA tissues with GS >=8 than those with GS <=7. XIAP is the downstream factor of Pim-2 pathway in prostate cancer cells. Pim-2 and XIAP cooperate in inhibiting the apoptosis of prostate cancer cells. The activation of Pim-2 pathway may predict higher GS in prostate cancer. PMID- 29124676 TI - Cost-Effectiveness Analysis of the Gonadotropin Treatments HP-hMG and rFSH for Assisted Reproductive Technology in France: A Markov Model Analysis. AB - OBJECTIVES: The objectives of this study were to assess (1) the expected cost of a live birth (LB) after in vitro fertilization with two different gonadotropin treatments [high purified human menopausal gonadotropin (HP-hMG) and recombinant follicle-stimulating hormone (rFSH)] as the single cost variable, and (2) the cost effectiveness of HP-hMG relative to rFSH in the context of the routine practice of assisted reproductive technology (ART) in France. METHODS: A Markov model was developed to simulate the therapeutic management, the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) courses, and the effects of complications in hypothetical cohorts of 30,000 patients undergoing IVF/ICSI with fresh embryo transfer (up to four attempts) using data from the MERIT and MEGASET clinical trials or from French routine ART practice. RESULTS: The cost per LB was estimated at ?12,145 and at ?14,247 with HP-hMG and rFSH, respectively, using efficacy data from published clinical trials. The resulting incremental cost-effectiveness ratio (ICER) was - ?11,616 per LB. HP-hMG was less expensive by around ?15.0 million and more effective by 1289 additional LBs. Using French clinical data, the cost per LB was ?16,415 and ?18,7531 with HP-hMG and rFSH, respectively. The ICER for HP-hMG versus rFSH was estimated at - ?7,719 per LB with a saving of about ?8.54 million and 1097 additional LBs. Deterministic sensitivity analyses showed that the main ICER drivers were the LB rate, followed by the total gonadotropin doses. The probabilistic sensitivity analysis indicated that HP-hMG was the dominant strategy in 71.2% of cases using the clinical trial data and in 50.2% of cases using the French data. CONCLUSION: This analysis indicates that compared with rFSH, HP-hMG is less costly for IVF/ICSI management from the French healthcare payer's viewpoint. The results of the present Markov model analysis are consistent with previous findings in other European countries. PMID- 29124677 TI - Scale Effects and Expected Savings from Consolidation Policies of Italian Local Healthcare Authorities. AB - BACKGROUND: Consolidation is often considered by policymakers as a means to reduce service delivery costs and enhance accountability. OBJECTIVE: The aim of this study was to estimate the potential cost savings that may be derived from consolidation of local health authorities (LHAs) with specific reference to the Italian setting. METHODS: For our empirical analysis, we use data relating to the costs of the LHAs as reported in the 2012 LHAs' Income Statements published within the New Health Information System (NSIS) by the Ministry of Health. With respect to the previous literature on the consolidation of local health departments (LHDs), which is based on ex-post-assessments on what has been the impact of the consolidation of LHDs on health spending, we use an ex-ante evaluation design and simulate the potential cost savings that may arise from the consolidation of LHAs. RESULTS: Our results show the existence of economies of scale with reference to a particular subset of the production costs of LHAs, i.e. administrative costs together with the purchasing costs of goods (such as drugs and medical devices) as well as non-healthcare-related services. CONCLUSIONS: The research findings of our paper provide practical insight into the concerns and challenges of LHA consolidations and may have important implications for NHS organisation and for the containment of public healthcare expenditure. PMID- 29124679 TI - Fear of fat and restrained eating: negative body talk between female friends as a moderator. AB - PURPOSE: This study examined whether engagement in negative body talk would moderate the association between fear of fat and restrained eating among female friend dyads. METHODS: Female friends (N pairs = 130) were recruited from a Midwestern university in the United States. The dyadic data were examined with an Actor-Partner Interdependence Model (APIM). RESULTS: Results showed that women's fear of fat was significantly related to their own restrained eating behaviors. In contrast, women's fear of fat was not significantly related to their friends' restrained eating behaviors. Negative body talk was significantly related to restrained eating, as reported by both friends. The interaction between negative body talk and women's own fear of fat was found to be significant. Although women with less fear of fat showed less restrained eating, engaging in more negative body talk with a friend increased their engagement in restrained eating. Women with more fear of fat engaged in more restrained eating, regardless of their engagement in negative body talk. CONCLUSION: Given the detrimental role of body talk between fear of fat and restrained eating, interventions may target reducing body talk among young women. NO LEVEL OF EVIDENCE FOR: Basic science, Animal study, Cadaver study, and Experimental study articles. PMID- 29124678 TI - High adherence to Mediterranean diet, but not individual foods or nutrients, is associated with lower likelihood of being obese in a Mediterranean cohort. AB - PURPOSE: The aim of the present study was to evaluate the association between the Mediterranean diet and obesity in a Mediterranean cohort. METHODS: The study population of MEAL (Mediterranean Healthy Eating, Ageing, and Lifestyle) study comprised 1814 men and women (18 + years) recruited in the city of Catania, southern Italy. Food intake was evaluated through a validated food frequency questionnaire and the Mediterranean diet adherence was assessed through the MEDI LITE score. RESULTS: Individuals highly adherent to the Mediterranean diet (highest quartile of the score) were less likely to be obese (OR 0.53, 95% CI 0.32, 0.89) despite there was no significant associations when considering men and women separately. The dietary profile of obese and non-obese individuals did not significantly differ, except for vitamin E, processed meat, and alcohol more consumed among non-obese ones. Among the food groups characterizing this dietary pattern, only satisfaction of the criterion for dairy products (< 1 serving/day) was significantly associated with lower odds of being obese. Among other covariates, current smoking was associated with obesity, while high physical activity and regular alcohol drinking were inversely associated. Some differences between men and women in the highest category of occupational status occurred, as the former were less likely, while the latter were more likely to be obese. CONCLUSIONS: Higher adherence to the Mediterranean diet as a whole dietary pattern, rather than its individual components, is associated with less likelihood of being obese. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study. PMID- 29124680 TI - The Antiepileptic Drug Levetiracetam Protects Against Quinolinic Acid-Induced Toxicity in the Rat Striatum. AB - Levetiracetam (LVT) is a relatively novel antiepileptic drug (AED) known to act through binding with the synaptic vesicular 2A (SV2A) protein, thus modulating the presynaptic neurotransmitter release. The tryptophan metabolite quinolinic acid (QUIN) acts as an excitotoxin when its brain concentrations reach toxic levels under pathological conditions. Since increased neuronal excitability induced by QUIN recruits degenerative events in the brain, and novel AED is also expected to exert neuroprotective effects in their pharmacological profiles, in this work the effect of LVT (54 mg/kg, i.p., administered for seven consecutive days) was tested as a pretreatment against the toxicity evoked by the bilateral intrastriatal injection of QUIN (60 nmol/MUl) to adult rats. QUIN increased the striatal levels of peroxidized lipids and carbonylated proteins as indexes of oxidative damage 24 h after its infusion. In addition, in synaptosomal fractions isolated from QUIN-lesioned rats 24 h after the toxin infusion, gamma aminobutyric acid (GABA) release was decreased, whereas glutamate (Glu) release was increased. QUIN also decreased motor activity and augmented the rate of cell damage at 7 days post-lesion. All these alterations were significantly prevented by pretreatment of rats with LVT. The results of this study show a neuroprotective role and antioxidant action of LVT against the brain damage induced by excitotoxic events. PMID- 29124682 TI - Nonacog Beta Pegol: A Review in Haemophilia B. AB - Nonacog beta pegol [Refixia(r) (EU)] is an intravenously-administered, glycoPEGylated recombinant factor IX (FIX), with an extended terminal half-life. It is approved in the EU for the treatment and prophylaxis of bleeding in patients aged >= 12 years with haemophilia B. The therapeutic efficacy and safety of nonacog beta pegol was demonstrated in the phase 3 Paradigm trials in previously treated adolescents and adults with haemophilia B. In Paradigm 2, nonacog beta pegol showed good haemostatic effects when treating bleeds on demand, and reduced annualized bleeding rates when used as a once-weekly prophylaxis. It also improved some health-related quality of life measures in adult patients. The longer-term efficacy of nonacog beta pegol was demonstrated in the open-label extension Paradigm 4 trial. In Paradigm 3, nonacog beta pegol effectively maintained intraoperative and postoperative haemostasis. Nonacog beta pegol was well tolerated in phase 3 clinical trials in patients with haemophilia B, with no evidence of FIX inhibitor formation, allergic reactions or thromboembolic complications. In conclusion, nonacog beta pegol is effective and well tolerated in the on-demand, prophylaxis and perioperative settings in adolescent and adults with haemophilia B. Its extended half-life allows for once weekly prophylaxis. Therefore, nonacog beta pegol is a useful additional treatment option for patients with haemophilia B. PMID- 29124681 TI - Synergistic Toxicity of the Neurometabolites Quinolinic Acid and Homocysteine in Cortical Neurons and Astrocytes: Implications in Alzheimer's Disease. AB - The brain of patients affected by Alzheimer's disease (AD) develops progressive neurodegeneration linked to the formation of proteins aggregates. However, their single actions cannot explain the extent of brain damage observed in this disorder, and the characterization of co-adjuvant involved in the early toxic processes evoked in AD is essential. In this line, quinolinic acid (QUIN) and homocysteine (Hcy) appear to be involved in the AD neuropathogenesis. Herein, we investigate the effects of QUIN and Hcy on early toxic events in cortical neurons and astrocytes. Exposure of primary cortical cultures to these neurometabolites for 24 h induced concentration-dependent neurotoxicity. In addition, QUIN (25 MUM) and Hcy (30 MUM) triggered ROS production, lipid peroxidation, diminished of Na+,K+-ATPase activity, and morphologic alterations, culminating in reduced neuronal viability by necrotic cell death. In astrocytes, QUIN (100 MUM) and Hcy (30 MUM) induced caspase-3-dependent apoptosis and morphologic alterations through oxidative status imbalance. To establish specific mechanisms, we preincubated cell cultures with different protective agents. The combined toxicity of QUIN and Hcy was attenuated by melatonin and Trolox in neurons and by NMDA antagonists and glutathione in astrocytes. Cellular death and morphologic alterations were prevented when co-culture was treated with metabolites, suggesting the activation of protector mechanisms dependent on soluble factors and astrocyte and neuron communication through gap junctions. These findings suggest that early damaging events involved in AD can be magnified by synergistic toxicity of the QUIN and Hcy. Therefore, this study opens new possibilities to elucidate the molecular mechanisms of neuron-astrocyte interactions and their role in neuroprotection against QUIN and Hcy. PMID- 29124683 TI - The 21st Century Cures Act Implications for the Reduction of Racial Health Disparities in the US Criminal Justice System: a Public Health Approach. AB - Past drug epidemics have disproportionately criminalized drug addiction among African Americans, leading to disparate health outcomes, increased rates of HIV/AIDS, and mass incarceration. Conversely, the current opioid addiction crisis in the USA focuses primarily on white communities and is being addressed as a public health problem. The 21st Century Cures Act has the potential to reduce racial health disparities in the criminal justice system through the Act's public health approach to addiction and mental health issues. The 21st Century Cures Act is a progressive step in the right direction; however, given the historical context of segregation and the criminalization of drug addiction among African Americans, the goals of health equity are at risk of being compromised. This paper discusses the implications of this landmark legislation and its potential to decrease racial health disparities, highlighting the importance of ensuring that access to treatment and alternatives to incarceration must include communities of color. In this paper, the authors explain the key components of the 21st Century Cures Act that are specific to criminal justice reform, including a key objective, which is treatment over incarceration. We suggest that without proper attention to how, and where, funding mechanisms are distributed, the 21st Century Cures Act has the potential to increase racial health disparities rather than alleviate them. PMID- 29124685 TI - Mitochondrial Trifunctional Protein Deficiency: Severe Cardiomyopathy and Cardiac Transplantation. AB - We describe mitochondrial trifunctional protein deficiency (MTPD) in two male siblings who presented with severe cardiomyopathy in infancy. The first sibling presented in severe cardiac failure at 6 months of age and succumbed soon after. The second sibling came to attention after newborn screening identified a possible fatty acid oxidation defect. Dietary therapy and carnitine supplementation commenced in the neonatal period. Despite this the second child required cardiac transplantation at 3 years of age after a sudden and rapid decline in cardiac function. The outcome has been excellent, with no apparent extra-cardiac manifestations of a fatty acid oxidation disorder at the age of 7. Pathogenic HADHA mutations were subsequently identified via genome wide exome sequencing. This is the first reported case of MTPD to undergo cardiac transplantation. We suggest that cardiac transplantation could be considered in the treatment of cardiomyopathy in MTPD. PMID- 29124684 TI - Racial/Ethnic Disparities: a Longitudinal Study of Growth Trajectories Among US Kindergarten Children. AB - BACKGROUND/OBJECTIVES: While previous studies have documented racial/ethnic disparities in childhood obesity, less is known about when disparities emerge, how they evolve, and the most appropriate early childhood period for targeted interventions. We examined racial/ethnic differences in growth trajectories among US kindergarten-aged children followed from birth and identified sensitive periods at which disparities emerge. SUBJECTS AND METHODS: This is a longitudinal study design using Early Childhood Longitudinal Study Birth Cohort data. We employed random effects growth curves to model trajectories of mean BMI z-scores by race/ethnicity and sex. To visualize sensitive periods for emergence of disparities, we used locally estimated smoothing spline curves to graph the relationship between age and BMI z-score within each racial group. RESULTS: Unweighted baseline sample size included ~ 7200 children. Overall, 54.6% of children were white, 23.1% Hispanic, 15.7% African-American, 3.4% Asian, 2.8% American-Indian, and 0.4% Pacific-Islander. Mean BMI z-scores for Hispanic boys and American-Indian boys and girls were already significantly higher by 24 months than their white peers and remained higher through kindergarten entry. African American and Asian children started with significantly lower birth-weights compared to whites, but Asian girls' growth trajectory remained slow, while African-American girls experienced steeper increases in BMI z-scores and ultimately overtook their white and Asian peers over time. By kindergarten entry, disparities were present across all racial/ethnic groups. CONCLUSION: Racial/ethnic disparities in US children's weight status and growth trajectories emerge at different ages for different racial groups, but they are generally well established by kindergarten age. Our findings indicate that interventions designed to prevent early childhood overweight/obesity should be implemented early in the life course. PMID- 29124686 TI - History of UV Lamps, Types, and Their Applications. AB - The use of ultraviolet (UV) light, for the treatment of skin conditions, dates back to the early 1900s. It is well known that sunlight can be of therapeutic value, but it can also lead to deleterious effects such as burning and carcinogenesis. Extensive research has expanded our understanding of UV radiation and its effects in human systems and has led to the development of man-made UV sources that are more precise, safer, and more effective for the treatment of wide variety of dermatologic conditions. PMID- 29124687 TI - Ultraviolet Light Induced Generation of Reactive Oxygen Species. AB - As ultraviolet (UV) radiation is naturally and ubiquitously emitted by the sun, almost everyone is exposed to it on a daily basis, and it is necessary for normal physiological function. Human exposure to solar UV radiation thus has important health implications. The generation of reactive oxygen species (ROS) by UV radiation is one of the mechanisms through which UV light can manifest its possible detrimental effects on health. When an imbalance develops due to ROS generation exceeding the body's antioxidant defence mechanisms, oxidative stress can develop. Oxidative stress can lead to cellular damage (e.g. lipid peroxidation and DNA fragmentation), apoptosis and cell death. Broadly UV can induce ROS by affecting the cellular components directly or by means of photosensitization mechanisms. More specifically UV light can induce ROS by affecting the enzyme catalase and up-regulating nitric oxide synthase (NOS) synthesis. It may also cause a decrease in protein kinase C (PKC) expression leading to increased ROS production. UVR is capable of modifying DNA and other chromophores resulting in elevated ROS levels. The effects of raised ROS levels can vary based on the intracellular oxidant status of the cell. It is therefore important to protect yourself against the potentially harmful effects of UV light as it can lead to pathological UV-induced ROS production. PMID- 29124688 TI - UV-Induced Molecular Signaling Differences in Melanoma and Non-melanoma Skin Cancer. AB - There are three major types of skin cancer: melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC and SCC are often referred to as non melanoma skin cancer (NMSC). NMSCs are relatively non-lethal and curable by surgery, hence are not reportable in most cancer registries all over the world. Melanoma is the deadliest skin cancer. Its incidence rate (case number) is about 1/10th of that for NMSC, yet its death toll is ~8 fold higher than NMSC.Melanomas arise from melanocytes which are normally located on the basement membrane with dendrites extending into the epidermal keratinocytes. A major known function of melanocytes is to produce pigments which are enclosed by lipid membrane (termed melanosomes) and distribute them into keratinocytes, thus give different shade of skin colors. BCCs arise from basal cells, which are a layer of cells located at the deepest part of epidermis. Basal cells are recently considered to be skin stem cells as they are constantly proliferating and generating keratinocytes which are continuously pushed to the surface and eventually become a dead layer of stratum corneum. Squamous cells are the keratinocytes which resembles fish scale shape, ie, those initiated from basal cells and differentiated into squamous cells. Both basal cells and squamous cells belong to keratinocytes, therefore sometimes BCC and SCC are termed keratinocyte cancer.These three types of cancer share many characteristics, yet they are very different from etiology to progression. One shared characteristic of skin cancer is that, according to the current views, they all are caused by solar or artificial ultraviolet radiation (UVR). UVA and UVB from solar UVR are the major UV bands reaching the earth surface. Both UV types cause DNA damage and immune suppression which play crucial roles in skin carcinogenesis. UVB can be directly absorbed by DNA molecules and thus causes UV-signature DNA damages; UVA, on the other hand, may function through inducing cellular ROS which then causes oxidative DNA damages [1 4]. This chapter will discuss the molecular signaling differences of UVR in melanoma and NMSC. PMID- 29124689 TI - Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation. AB - The sensitivity of Xeroderma pigmentosa (XP) patients to sunlight has spurred the discovery and genetic and biochemical analysis of the eight XP gene products (XPA XPG plus XPV) responsible for this disorder. These studies also have served to elucidate the nucleotide excision repair (NER) process, especially the critical role played by the XPA protein. More recent studies have shown that NER also involves numerous other proteins normally employed in DNA metabolism and cell cycle regulation. Central among these is ataxia telangiectasia and Rad3-related (ATR), a protein kinase involved in intracellular signaling in response to DNA damage, especially DNA damage-induced replicative stresses. This review summarizes recent findings on the interplay between ATR as a DNA damage signaling kinase and as a novel ligand for intrinsic cell death proteins to delay damage induced apoptosis, and on ATR's regulation of XPA and the NER process for repair of UV-induced DNA adducts. ATR's regulatory role in the cytosolic-to-nuclear translocation of XPA will be discussed. In addition, recent findings elucidating a non-NER role for XPA in DNA metabolism and genome stabilization at ds-ssDNA junctions, as exemplified in prematurely aging progeroid cells, also will be reviewed. PMID- 29124690 TI - Impact of Ultraviolet Light on Vitiligo. AB - Vitiligo is a disorder of the melanocytes that results in a dynamic spectrum of skin depigmentation. Its etiology is complex and multifactorial, with data supporting several different hypotheses. Given its prominent phenotype, vitiligo has a significant negative impact on quality of life. Coupled with the chronic and incurable nature of the disease, this presents a formidable treatment challenge. Several treatment modalities have been instituted over the years, with varying efficacy. This chapter focuses on the use of ultraviolet light in vitiligo as an established therapeutic option. PMID- 29124691 TI - Polymorphous Light Eruption. AB - Polymorphous light eruption (PLE) is the commonest immuno-mediated photodermatosis. It occurs after solar or artificial UV-light exposure and affects only the sun-exposed areas with preference of the V-area of the chest, of arms and forearms, legs, upper part of the back, and rarely the face. The lesions are itching or burning, and vary morphologically from erythema to papules, vesico papules and occasionally blisters, plaques, sometimes erythema multiforme-like, insect bite-like wheals and purpura. The clinical manifestations befall within a few hours to days from light exposure, last a few days, and subside in about a week without sequelae. Its diagnosis is based on history, morphology and phototests. PLE is considered as a delayed hypersensitivity response to newly UV induced, but still unidentified, antigen(s). Usually, MED is normal, but the provocative phototests with UVA or UVB reproduce the spontaneous lesions in about 50% of the patients. Broad spectrum sunscreens and antioxidants, photohardening with PUVA or narrow band UVB may be beneficial to prevent the disease. Therapy is based mainly on topical or systemic corticosteroids. PMID- 29124692 TI - Ultraviolet Radiations: Skin Defense-Damage Mechanism. AB - UV-radiations are the invisible part of light spectra having a wavelength between visible rays and X-rays. Based on wavelength, UV rays are subdivided into UV-A (320-400 nm), UV-B (280-320 nm) and UV-C (200-280 nm). Ultraviolet rays can have both harmful and beneficial effects. UV-C has the property of ionization thus acting as a strong mutagen, which can cause immune-mediated disease and cancer in adverse cases. Numbers of genetic factors have been identified in human involved in inducing skin cancer from UV-radiations. Certain heredity diseases have been found susceptible to UV-induced skin cancer. UV radiations activate the cutaneous immune system, which led to an inflammatory response by different mechanisms. The first line of defense mechanism against UV radiation is melanin (an epidermal pigment), and UV absorbing pigment of skin, which dissipate UV radiation as heat. Cell surface death receptor (e.g. Fas) of keratinocytes responds to UV-induced injury and elicits apoptosis to avoid malignant transformation. In addition to the formation of photo-dimers in the genome, UV also can induce mutation by generating ROS and nucleotides are highly susceptible to these free radical injuries. Melanocortin 1 receptor (MC1R) has been known to be implicated in different UV-induced damages such as pigmentation, adaptive tanning, and skin cancer. UV-B induces the formation of pre-vitamin D3 in the epidermal layer of skin. UV-induced tans act as a photoprotection by providing a sun protection factor (SPF) of 3-4 and epidermal hyperplasia. There is a need to prevent the harmful effects and harness the useful effects of UV radiations. PMID- 29124693 TI - Ultraviolet Photobiology in Dermatology. AB - The effects of ultraviolet radiation on human skin have been studied for years, and both its harmful and therapeutic effects are well known. Exposure to UV light can lead to sunburn, immunosuppression, skin aging, and carcinogenesis, and photoprotection is strongly advocated. However, when used under controlled conditions, UV radiation can also be helpful in the diagnosis and treatment of many skin conditions. PMID- 29124694 TI - Ultraviolet A-1 in Dermatological Diseases. AB - The exposure to ultraviolet radiations and visible light, or phototherapy, is a well-known therapeutic tool available for the treatment of many dermatological disorders. The continuos medical and technological progresses, of the last 50 years, have involved the field of phototherapy, which evolved from UVA and PUVA in its various forms, to the development of narrowband UVB (NB-UVB) and NB-UVB micro-focused phototherapies. Further advances in technology have now permitted the introduction of a new device emitting UVA-1 radiations. PMID- 29124695 TI - Photodermatoses in the Pigmented Skin. AB - Skin colour (specifically in relation to its melanin content and composition) has a marked influence on its interaction with ultraviolet light. Eumelanin has mainly photoprotective properties while pheomelanin has the ability to cause formation of reactive oxygen species. This difference is responsible for the difference in incidence and presentation of various idiopathic photodermatoses in dark skinned patients compared to those with lighter skin types. Certain conditions are peculiar to darker skins including pin point popular variant of polymorphous light eruption. These differences are discussed in this chapter while also highlighting the challenges faced in performing phototesting in patients with dark skin. PMID- 29124696 TI - Psycho-Neuro-Endocrine-Immunology: A Psychobiological Concept. AB - Psycho-Neuro-Endocrine-Immunology (P.N.E.I.) is a scientific field of study that investigates the link between bidirectional communications among the nervous system, the endocrine system, and the immune system and the correlations of this cross-talk with physical health. The P.N.E.I. innovative medical approach represents a paradigm shift from a strictly biomedical view of health and disease taken as hermetically sealed compartments to a more interdisciplinary one. The key element of P.N.E.I. approach is represented by the concept of bidirectional cross-talk between the psychoneuroendocrine and immune systems. The Low Dose Medicine is one of the most promising approaches able to allow the researchers to design innovative therapeutic strategies for the treatment of skin diseases based on the rebalance of the immune response. PMID- 29124697 TI - Ultraviolet B Radiation: The Vitamin D Connection. AB - Vitamin D is known as the sunshine vitamin. During exposure to sunlight the skin transforms 7-dehydrocholesterol into vitamin D3. Throughout evolution vitamin D3 has played a pivotal role in the evolution of vertebrates. Vitamin D is not only critically important for bone health but has a multitude of other biologic functions to help reduce chronic illnesses. This Chapter reviews how vitamin D is produced in the skin, factors that affect its production and a prospective on how to obtain vitamin D from sensible sun exposure. PMID- 29124698 TI - Role of Vitamin D in Rheumatoid Arthritis. AB - Vitamin D is a fat soluble hormone, with a well described role in bone health and calcium/phosphate metabolism. Recent evidences have related vitamin D to other physiological functions and pathological conditions. Specifically, vitamin D has widely proven activities on immune system and evidences suggest that it may be implicated in the pathogenesis of rheumatoid arthritis (RA). The relationship between vitamin D and RA is complex, also because a deficitary vitamin D status, which is very common in RA patients, can contribute to the increased risk of osteoporosis typical of RA. In this chapter, will be described and discussed the main aspects of the relationship between RA and vitamin D. PMID- 29124699 TI - Asthma and Allergy "Epidemic" and the Role of Vitamin D Deficiency. AB - The increase in asthma and allergies prevalence that has been recorded in many countries during the last decades, and the reemergence of vitamin D (VD) deficiency in many populations worldwide, renders fairly plausible the assumption of an underlying association between these two conditions and justifies the research effort invented in this issue. Indeed, there is growing body of evidence from epidemiological, laboratory, and clinical studies, suggesting that such an association does exist. The hypothesis of low levels of VD leading to compromised fetal programming and impairment of various immune functions involved in asthma and allergic disorders, stands as the most credible explanation of this presumed association. However, the evidence is not yet definite and there are some conflicting results among studies. As a consequence, no safe conclusions can be drawn yet, and more research is required in order to fully clarify the involvement of VD deficiency in the pathogenesis of asthma and allergies, and decide if VD has a role to play in the prevention and therapy of these disorders. PMID- 29124700 TI - Vitamin D Metabolism and the Implications for Atherosclerosis. AB - Vitamin D levels and metabolism may play a role in the pathogenesis and treatment of atherosclerosis and subsequent cardiovascular health. Herein, we discuss both normal and disordered vitamin D metabolism as it pertains to atherosclerosis, and we review major clinical trials regarding vitamin D levels and effects of supplementation. Although there are no official recommendations for vitamin D as it applies to atherosclerosis, it is clear that these two entities are linked. Further study of the complex association between vitamin D and atherosclerosis, as well as the effects of supplementation, are recommended. PMID- 29124701 TI - Vitamin D and Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus (T2DM) has become a significant global health care problem and its reported incidence is increasing at an alarming rate. Despite the improvement in therapy and development of new drugs, treatment still remains insufficient especially due to the associated side effects of most available drugs. Efforts are continuing toward disease prevention and search for safer drugs. Conflicting evidence is associating low levels of vitamin D in the body to T2DM and as such studies have been conducted to test the effect of vitamin D levels on incidence of diabetes, diabetic control as well as diabetic complications.Despite the conflicting evidence, vitamin D replacement seems to have some beneficial effect on the many aspects of diabetes: incidence, control and complications. Further long term and more convincing controlled trials are required in order to draw firmer conclusions on this beneficial role of vitamin D treatment on T2DM. PMID- 29124702 TI - Impact of UV Radiation on Genome Stability and Human Health. AB - Gradual depletion of the atmospheric ozone layer during the past few years has increased the incidence of solar UV radiation specifically the UV-C on earth's surface is one of the major environmental concerns because of the harmful effects of this radiation in all forms of life. The solar UV radiation including the harmful wavelength range of UV-B (280-320 nm) represents a significant climatic stress for both animals and plants, causing damage to the fundamental biomolecules such as DNA, proteins and lipids, thus activating genotoxic stress and induces genome instability. When DNA absorbs UV-B light, energy from the photon causes covalent linkages to form between adjacent pyrimidine bases, creating photoproducts, primarily cyclobutane pyrimidine dimers (CPDs) and pyrimidine-6,4-pyrimidinone photoproduct (6,4PPs). Pyrimidine dimers create distortions in the DNA strands and therefore can inhibit DNA replication as well transcription. Lack of efficient repair of UV-induced DNA damage may induce the formation of DNA double stand breaks (DSBs), one of the serious forms of damage in DNA double helix, as well as oxidative damage. Unrepaired DSBs in the actively dividing somatic cells severely affect cell growth and development, finally results in loss of cell viability and development of various diseases, such as cancer in man.This chapter mainly highlights the incidence of solar UV-radiation on earth's surface along with the formation of major types of UV-induced DNA damage and the associated repair mechanisms as well as methods of detecting DNA damage and finally our present understanding on the impact on solar UV radiation on human health. PMID- 29124704 TI - Biofilms: Microbial Strategies for Surviving UV Exposure. AB - Biofilm communities are an ingenious form of protection of microbial cells which have been evolving for billion of years. In general, ultraviolet (UV) radiation presents poor penetration in the matrix of biofilms and only the first few top layers of microbial cells are exposed to its deleterious effects. For further protection against UV radiation, exposed cells can produce specialized compounds such as mycosporine-like amino acids and carotenoid pigments. In this chapter, the adaptation mechanisms presented by biofilms against UV radiation are presented, as well as the application of UV light to monitor and destroy biofilms in man made surfaces. PMID- 29124703 TI - Vitamin D, Cardiovascular Disease and Risk Factors. AB - Observational studies have suggested a possible protective role of vitamin D on the cardiovascular system. The available evidence does not support either cardiovascular benefits or harms of vitamin D supplementation. This chapter provides an overview and discussion of the current knowledge of vitamin D effects from a cardiovascular health perspective. It focuses on vitamin D in relation to cardiovascular disease, i.e. ischemic heart disease, and stroke; the traditional cardiovascular risk factors hypertension, abnormal blood lipids, obesity; and the emerging risk factors hyperparathyroidism, microalbuminuria, chronic obstructive pulmonary diseases, and non-alcoholic fatty liver disease. Meta-analyses of observational studies have largely found vitamin D levels to be inversely associated with cardiovascular risk and disease. However, Mendelian randomization studies and randomized, controlled trials (RCTs) have not been able to consistently replicate the observational findings. Several RCTs are ongoing, and the results from these are needed to clarify whether vitamin D deficiency is a causal and reversible factor to prevent cardiovascular disease. PMID- 29124705 TI - UV Induced Mutagenicity in Water: Causes, Detection, Identification and Prevention. AB - At first it seemed that UV processes for disinfection and advanced oxidation were "harmless", as they didn't involve the addition of "dangerous" chemicals nor seemed to result in the formation of toxic byproducts. However, recently it has become clear that also during UV processes mutagentic/genotoxic byproducts may be formed. It was found that these are nitrogen containing aromatic compounds, which are formed by the reaction of photolysis products of nitrate with (photolysis products of) natural organic matter. Now more has become clear on the formation process of these compounds, it is possible to limit or even prevent their formation during e.g. UV/H2O2 processes. Besides, it appears to be possible to remove such byproducts by means of filtration processes. Thus, UV based processes can safely be applied in water treatment. PMID- 29124706 TI - Role of Ultraviolet Disinfection in the Prevention of Surgical Site Infections. AB - The role of the environment in surgical site infections is surprisingly understudied. UV disinfection holds promise for reducing the level of contamination in operating rooms and thereby lowering the risk of infection for patients. Issues such as the frequency, amount and locations for UV disinfection to have an impact on the risk of surgical site infection are recently emerging in the literature. As technologies and knowledge improve, UV disinfection will have a role to play in operating rooms in the future. PMID- 29124707 TI - UV Disinfection of Wastewater and Combined Sewer Overflows. AB - Municipal wastewater contains bacteria, viruses, and other pathogens that adversely affect the environment, human health, and economic activity. One way to mitigate these effects is a final disinfection step using ultraviolet light (UVL). The advantages of UVL disinfection, when compared to the more traditional chlorine, include no chlorinated by-products, no chemical residual, and relatively compact size. The design of most UV reactors is complex. It involves lamp selection, power supply design, optics, and hydraulics. In general, medium pressure lamps are more compact, powerful, and emit over a wider range of light than the more traditional low pressure lamps. Low pressure lamps, however, may be electrically more efficient. In UV disinfection, the fraction of surviving organisms (e.g. E. coli) will decrease exponentially with increasing UV dose. However, the level of disinfection that can be achieved is often limited by particle-associated organisms. Efforts to remove or reduce the effects of wastewater particles will often improve UV disinfection effectiveness. Regrowth, photoreactivation, or dark repair after UV exposure are sometimes cited as disadvantages of UV disinfection. Research is continuing in this area, however there is little evidence that human pathogens can photoreactivate in environmental conditions, at doses used in wastewater treatment. The UV disinfection of combined sewer overflows, a form of wet weather pollution, is challenging and remains largely at the research phase. Pre-treatment of combined sewer overflows (CSOs) with a cationic polymer to induce fast settling, and a low dose of alum to increase UV transmittance, has shown promise at the bench scale. PMID- 29124708 TI - Phototherapy in Atopic Dermatitis. AB - Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. Currently management of AD includes avoidance of triggering factors, skin care aiming to compensate the skin barrier defects, anti-inflammatory therapy (mostly topical corticosteroids and topical calcineurin inhibitors). When these first-line approaches are unsuccessful, systemic treatment or phototherapy ought to be carried out as next line of defence. Current phototherapy modalities for AD include broadband UVB (290-320 nm), narrowband UVB (311-313 nm), UVA-1 therapy (340-400 nm), UVA therapy plus 8-methoxypsoralens (PUVA), 308 nm excimer laser (EL) and Full spectrum light (FSL). PMID- 29124709 TI - Phototherapy of Psoriasis, a Chronic Inflammatory Skin Disease. AB - Phototherapy is an effective treatment modality for several skin diseases which has been in use from the era of the Egyptians. Insight into its mode of action has gradually accumulated over the past decades. A crucial biological effect of ultraviolet radiation is the induction of apoptosis in T lymphocytes and in keratinocytes in the epidermis. Via this mechanism inflammation-induced pathological changes characteristic of psoriasis are counteracted.Phototherapy remains the only therapeutic option for certain patient groups where modification of the systemic immune reactions is contraindicated, such as by HIV, internal malignancy or pregnancy. UVB treatment is highly cost-effective, which is important in this age of increasing health care costs. PMID- 29124710 TI - Ultraviolet Irradiation of Blood: "The Cure That Time Forgot"? AB - Ultraviolet blood irradiation (UBI) was extensively used in the 1940s and 1950s to treat many diseases including septicemia, pneumonia, tuberculosis, arthritis, asthma and even poliomyelitis. The early studies were carried out by several physicians in USA and published in the American Journal of Surgery. However with the development of antibiotics, UBI use declined and it has now been called "the cure that time forgot". Later studies were mostly performed by Russian workers and in other Eastern countries and the modern view in Western countries is that UBI remains highly controversial.This chapter discusses the potential of UBI as an alternative approach to current methods used to treat infections, as an immune modulating therapy and as a method for normalizing blood parameters. No resistance of microorganisms to UV irradiation has been reported, and multi antibiotic resistant strains are as susceptible as their wild-type counterparts. Low and mild doses of UV kill microorganisms by damaging the DNA, while any DNA damage in host cells can be rapidly repaired by DNA repair enzymes. However the use of UBI to treat septicemia cannot be solely due to UV-mediated killing of bacteria in the blood-stream, as only 5-7% of blood volume needs to be treated with UV to produce the optimum benefit. UBI may enhance the phagocytic capacity of various phagocytic cells (neutrophils and dendritic cells), inhibit lymphocytes, and oxidize blood lipids. The oxidative nature of UBI may have mechanisms in common with ozone therapy and other oxygen therapies. There may be some similarities to extracorporeal photopheresis (ECP) using psoralens and UVA irradiation. However there are differences between UBI and ECP in that UBI tends to stimulate the immune system, while ECP tends to be immunosuppressive. With the recent emergence of bacteria that are resistant to all known antibiotics, UBI should be more investigated as an alternative approach to infections, and as an immune-modulating therapy. PMID- 29124712 TI - Safety and Efficacy of Phototherapy in the Management of Eczema. AB - Atopic Dermatitis (AD), a common skin disease, can occur in patients of all age, gender and ethnicity. It is an inflammatory affection, characterized by chronic and highly debilitating behavior. First-line interventions against AD include environmental measures and topical emollients, corticosteroids or calcineurin inhibitors. When these measures are not sufficient, phototherapy represents an efficient second-line option of treatment; it can be administered on its own, or in the most severe cases combined with systemic medicaments such as corticosteroids.Different types of light therapy, including photochemotherapy, have been tested in the past and in recent years for AD: in particular, ultraviolet A1 (UVA1) and narrow band ultraviolet B (NB-UVB) have been reported in the literature as the most effective resources, respectively for acute and chronic AD. However, to date, no guidelines have been realized concerning the use of phototherapy for AD, as no light form has been defined superior to the others. The most reliable protocols and dosimetry are standardized within the American Academy of Dermatology (AAD) psoriasis guidelines.In adults and children over 12 years (8 years for NB-UVB) phototherapy is recommended with strength B and level of evidence II (excluding home phototherapy, which is recommended with strength C and level of evidence III). It is usually safe and well tolerated; however its short- and long-term adverse effects are the same as those observed when light therapy is performed for other pathologic conditions. Erythema and photodamage are in particular quite frequent; moreover it has not been clarified whether UV radiation may induce neoplastic cellular transformation. For all these reasons, the use of phototherapy must be chosen only after a comprehensive and careful evaluation of the patient's features and compliance, as well as of the limitations of the procedure due to costs and availability. PMID- 29124711 TI - From UV Protection to Protection in the Whole Spectral Range of the Solar Radiation: New Aspects of Sunscreen Development. AB - Sunscreens have been constantly improving in the past few years. Today, they provide an efficient protection not only in the UVB but also in the UVA spectral region of the solar radiation. Recently it could be demonstrated that 50% of all free radicals induced in the skin due to solar radiation are formed in the visible and infrared spectral region. The good protective efficacy of sunscreens in the UV region prompts people to stay much longer in the sun than if they had left their skin unprotected. However, as no protection in the visible and infrared spectral region is provided, high amounts of free radicals are induced here that could easily exceed the critical radical concentration. This chapter describes how the effect of sunscreens can be extended to cover also the visible and infrared spectral region of the solar radiation by adding pigments and antioxidants with high radical protection factors to the sunscreen formulations. PMID- 29124713 TI - UV Driven Tanning Salons: Danger on Main Street. AB - Appearing in the early 1980s, at a time when UVA was considered as relatively safe, the tanning industry has substantially developed in occidental countries, especially in Northern European countries. In Europe, the erythemally-weighted irradiance of a modern sunbed should not exceed 0.3 W/m2, equivalent to an UV index of 12, i.e. to a tropical midday sun, but increased in recent years, the UV spectrum emitted by sunbeds had evolved towards higher UVA irradiance and solariums UV had become even less similar to natural sun. PMID- 29124714 TI - Dose Quantification in UV Phototherapy. AB - Ultraviolet light has long been used to alleviate a number of skin conditions, and its efficacy is well known. However, over-exposure to ultraviolet radiation has a number of detrimental effects and thus it is vital to maintain a dose to skin within the therapeutic window. To maximise treatment gain whilst circumventing potential side-effects of over-exposure requires accurate determination of irradiance and skin-dose. This is complicated by the fact that ultraviolet radiation is essentially absorbed at the skin surface, which means that changing orientation of the patient and source can modulate dose received. In addition, irregular patient shapes mean dose must be carefully calibrated. This chapter focuses on methods of determination of dose, clinical protocols for quantifying radiation dose received and mathematical models for estimating these quantities. PMID- 29124716 TI - Applying cognitive acuity theory to the development and scoring of situational judgment tests. AB - The theory of cognitive acuity (TCA) treats the response options within items as signals to be detected and uses psychophysical methods to estimate the respondents' sensitivity to these signals. Such a framework offers new methods to construct and score situational judgment tests (SJT). Leeds (2012) defined cognitive acuity as the capacity to discern correctness and distinguish between correctness differences among simultaneously presented situation-specific response options. In this study, SJT response options were paired in order to offer the respondent a two-option choice. The contrast in correctness valence between the two options determined the magnitude of signal emission, with larger signals portending a higher probability of detection. A logarithmic relation was found between correctness valence contrast (signal stimulus) and its detectability (sensation response). Respondent sensitivity to such signals was measured and found to be related to the criterion variables. The linkage between psychophysics and elemental psychometrics may offer new directions for measurement theory. PMID- 29124715 TI - The Relationship Between Psychological Distress and Perception of Emotional Support in Medical Students and Residents and Implications for Educational Institutions. AB - OBJECTIVE: Psychological distress is pervasive among medical students and residents (MSR) and is associated with academic under-performance, decreased empathy, burnout, and suicidal ideation. To date, there has been little examination of how demographic and socioeconomic factors influence trainee's psychological distress levels, despite suggestion that financial concerns are a common source of stress. Recent Canadian studies examining the prevalence of distress, burnout, and resilience in MSR are limited. METHODS: Undergraduate and postgraduate medical trainees attending a Canadian university were surveyed. The questionnaire included standardized instruments to evaluate psychological distress, burnout, and resilience. Additional items explored MSR living and domestic circumstances, and anticipated debt upon training completion. Ordinary least squares regression models determined predictors of psychological distress, risk for burnout, and resiliency. Logistic regression of psychological distress predicted risk of MSR contemplating dropping out of their training program. RESULTS: Feeling emotionally/psychologically unsupported while attending university was a key predictor of psychological distress and burnout, while feeling supported reduces this risk. Risk for burnout increased with each year of medical training. Psychologically distressed MSR were at significantly greater odds of contemplating dropping out of their medical training program. CONCLUSIONS: Our results point to the important opportunity universities and medical schools have promoting MSR well-being by reducing institutional stressors, as well as teaching and promoting self-care and burnout avoidance techniques, instituting wellness interventions, and developing programs to identify and support at risk and distressed students. PMID- 29124717 TI - Semantic ambiguity effects on traditional Chinese character naming: A corpus based approach. AB - Words are considered semantically ambiguous if they have more than one meaning and can be used in multiple contexts. A number of recent studies have provided objective ambiguity measures by using a corpus-based approach and have demonstrated ambiguity advantages in both naming and lexical decision tasks. Although the predictive power of objective ambiguity measures has been examined in several alphabetic language systems, the effects in logographic languages remain unclear. Moreover, most ambiguity measures do not explicitly address how the various contexts associated with a given word relate to each other. To explore these issues, we computed the contextual diversity (Adelman, Brown, & Quesada, Psychological Science, 17; 814-823, 2006) and semantic ambiguity (Hoffman, Lambon Ralph, & Rogers, Behavior Research Methods, 45; 718-730, 2013) of traditional Chinese single-character words based on the Academia Sinica Balanced Corpus, where contextual diversity was used to evaluate the present semantic space. We then derived a novel ambiguity measure, namely semantic variability, by computing the distance properties of the distinct clusters grouped by the contexts that contained a given word. We demonstrated that semantic variability was superior to semantic diversity in accounting for the variance in naming response times, suggesting that considering the substructure of the various contexts associated with a given word can provide a relatively fine scale of ambiguity information for a word. All of the context and ambiguity measures for 2,418 Chinese single-character words are provided as supplementary materials. PMID- 29124718 TI - The Bangor Voice Matching Test: A standardized test for the assessment of voice perception ability. AB - Recognising the identity of conspecifics is an important yet highly variable skill. Approximately 2 % of the population suffers from a socially debilitating deficit in face recognition. More recently the existence of a similar deficit in voice perception has emerged (phonagnosia). Face perception tests have been readily available for years, advancing our understanding of underlying mechanisms in face perception. In contrast, voice perception has received less attention, and the construction of standardized voice perception tests has been neglected. Here we report the construction of the first standardized test for voice perception ability. Participants make a same/different identity decision after hearing two voice samples. Item Response Theory guided item selection to ensure the test discriminates between a range of abilities. The test provides a starting point for the systematic exploration of the cognitive and neural mechanisms underlying voice perception. With a high test-retest reliability (r=.86) and short assessment duration (~10 min) this test examines individual abilities reliably and quickly and therefore also has potential for use in developmental and neuropsychological populations. PMID- 29124719 TI - MorphoLex: A derivational morphological database for 70,000 English words. AB - Most of the new words a reader will find are morphologically complex. Also, theoretical models of language processing propose that morphology plays an important role in visual word processing. Nevertheless, studies on the subject show contradicting results that are difficult to reconcile. One factor that may explain this is the lack of a sizeable and reliable morphological database. As a consequence, there are enormous methodological differences in the way the values for morphological variables are calculated across studies. We present a sizeable and freely available database with six new variables for affixes and three for roots for 68,624 words from the English Lexicon Project. We further studied by means of regression models the influence of these new variables on the lexical decision latencies of 4,724 morphologically complex nouns that included one root and one suffix. Results showed that root frequency and suffix length had a facilitatory effect, whereas the percentage of more frequent words in the morphological family of the suffix had an inhibitory effect on latencies. After controlling for collinearity, root family size, suffix family size, suffix P*, and suffix frequency also had facilitatory effects. These results shed new light on the importance of suffix length and the frequency of the lexical competitors of the family of a suffix. This database represents a valuable resource for studies on the effect of morphology in visual word processing in English and can be found at https://github.com/hugomailhot/MorphoLex-en . PMID- 29124720 TI - THE MEDICAL TREATMENT OF MILD ENDOMETRIOSIS. AB - Minor degrees of endometriosis have often been regarded as being of no import and hence remain untreated, but a study of the natural history of endometriosis has demonstrated that 47% (95% confidence limits, 23-71%) of patients (n=35) given placebo in a double-blind, randomized controlled trial showed progression of the disease when assessed before and after treatment by laparoscopy. The active agent, the progestogen gestrinone, was given at a dose of 2.5 mg twice weekly and resulted in an improvement of the disease (p <0.004). Furthermore, follow-up over 12 months showed no significant difference between those patients treated with active agent or placebo, and none between those with persistent disease and those in whom it had been obliterated. These data suggest that a diagnosis of mild endometriosis should be followed by treatment to prevent progressive disease, but that the treatment does not influence subsequent fertility. They indicate that expectant treatment has no place and that even if fertility is not an immediate requirement, active treatment should be instituted, and that the new gestogen, gestrinone is efficacious. Other treatments, such as danazol or luteinizing hormone releasing hormone (LHRH) agonists, or the older contraceptive or pseudopregnancy regimens, must be set against spontaneous improvement (in 5 of 17 patients i.e. 29%) or elimination (in 4 of 17 patients i.e. 24%) in the placebo group. Infertile patients with mild endometriosis have disorders of follicular and luteal function, and in vitro fertilization suggests a reduced fertilization rate. Nevertheless, these patients require active treatment if these problems are not to be compounded by adhesions, possibly leading to ovarian enclosure, that would further reduce the untreated cumulative conception rate. PMID- 29124721 TI - LAPAROSCOPIC TREATMENT OF ENDOMETRIOSIS. AB - Adequate management of endometriosis by laparoscopy included 3 steps: a laparoscopic diagnosis with peritoneal fluid sampling for cytologic examination and biopsies of implants and of peritoneum to assure a correct diagnosis, a laparoscopic evaluation of extension with the American Fertility Society (AFS) 85 scoring system in order to classify the severity of the disease, and a laparoscopic treatment with the following strategy: drainage of the ovarian endometrioma and careful peritoneal washing, treatment of peritoneal implants, ovariolysis, treatment of the ovarian cysts, hemostasis and peritoneal lavage. Treatment of peritoneal implants is very easily performed by CO2 laser vaporization using a suprapubic puncture. Ovarian endometriomas are treated by laparoscopic cystectomy using a transparietal cystectomy or an intraperitoneal cystectomy. Laser vaporization is used only in case of small ovarian cysts or after an incomplete resection of a large cyst. Results of laparoscopic treatment of endometriosis compare favorably with those obtained with surgical procedures performed by laparotomy with the well known advantage of a laparoscopic approach. PMID- 29124722 TI - STEROIDAL DRUGS IN ENDOMETRIOSIS. AB - Progestins, including medroxyprogesterone acetate (MPA), danazol and gestrinone, are used in the medical management of endometriosis. Danazol and gestrinone, by inducing progestin-like effects, closely resemble MPA in their actions on intrauterine endometrium. Ectopic endometrium, on the other hand, does not respond to these hormonal stimuli (as determined by estrogen and progestin receptor assays and 17beta-hydroxysteroid dehydrogenase activity measurements), indicating that the therapeutic effects of steroidal drugs may not be entirely due to an action on the endometrium. At therapeutic doses, these drugs also prevent the midcycle elevation in gonadotropic hormone secretion and suppress ovarian activity (as evidenced by follicular arrest and low and stable estrogen and progesterone secretion). These indirect actions of progestins are probably more important than their direct actions on the endometrium in the treatment of endometriosis. These steroidal drugs also have androgenic effects, though the increase in the free androgen index caused by danazol is significantly larger than that induced by gestrinone or by MPA. In a study involving treatment with danazol (200 mg three times a day), high-dose MPA (100 mg/day) or placebo for 6 months, danazol and MPA were found to have equal clinical efficacy (as judged by relief of symptoms and disappearance of lesions). Danazol therapy, however, caused more androgenic and metabolic side-effects. Those patients who were infertile were also examined at 30 months. The cumulative pregnancy rate in these patients over the duration of the trial was danazol 33%, MPA 42% and placebo 46%, with no significant difference between treatments. Hormonal therapy delayed conception by approximately 8 months. Steroidal drugs of this type, which are useful in the treatment of both the lesion and symptoms of endometriosis, are not in general the treatment of choice for infertility associated with endometriosis. PMID- 29124723 TI - THE RATIONALE FOR ENDOCRINE THERAPY. AB - There are three major types of peritoneal endometriotic implant as distinguished by their laparoscopic and morphological characteristics; the microscopic or epithelial-type plaque, the vesicular and papular type and the fibrotic, nodular type. Fluctuations in hormone levels during the menstrual cycle and throughout hormonal therapy have differential effects on the three types of implant. After only a short period of treatment with gestrinone the active types of peritoneal endometriotic implant exhibit inactivity and involutionary changes. Regressive changes in the implants may explain the abolition of the symptoms. PMID- 29124724 TI - PATHOGENESIS, DIAGNOSIS AND TREATMENT OF GENITAL ENDOMETRIOSIS. AB - The etiology of genital endometriosis remains unclear, but it is evident that persisting endometriotic foci are stimulated by ovarian steroid hormones. Many cases are treated by surgery either via laparotomy or pelviscopy. Endocrine treatments with testosterone, gestagens, danazol and gestrinone have also been used to some effect. Recently developed analogs of gonadotropin-releasing hormone (GnRH) have demonstrated the high binding capacities of receptors involved in the down-regulation of the normal cycle which result in atrophy of the endometrium. These agents could therefore be used in the treatment of endometriosis. To date, 924 patients with pelvic endometriosis have been treated in our department with conventional endocrine therapies, 40 patients were treated with buserelin (D-Ser (Bu)6 luteinizing hormone-releasing hormone monopeptide-ethylamide), 900 MUg/day intranasally, and 50 patients with goserelin depot, a GnRH analog of D-Ser (Bu)6 Azegly10 -GnRH, with depot applications (3.6 mg per 4 weeks). The stage of development of endometriosis was determined using the endoscopic endometriosis classification prior to and after endocrine treatment. A complete check of the pelvis was carried out each time and a careful revision of the endometriotic foci undertaken. Endocrine treatment of endometriosis allowed 60% of previously sterile patients to become pregnant. Ovarian function in these patients was normal. The analogs proved to be clinically effective, safe and were well tolerated. Gestrinone proved to be the endocrine treatment of preference. PMID- 29124725 TI - GESTRINONE IN THE TREATMENT OF MYOMAS. AB - In a study involving over 300 women, gestrinone has been found to induce regression of uterine myomas. Gestrinone was given in doses of 2.5-5 mg (orally or by vaginal pessary), two or three times weekly. The treatment regimen depended upon tumor size and tumor age. Patients with small tumors, i.e. uterine volumes of less than 200 cm3 , were treated for 6 months, whereas those with uterine volumes of 200-300 cm3 were treated for 1 year. In severe cases where uterine volumes were greater than 400 cm3 , the patients were treated for 2 years. Large myomas of 300 cm3 or more required higher doses of steroid. During the first 6 months of treatment there was a marked reduction in uterine volume, but subsequently the rate of tumor regression was slower. Following discontinuation of treatment, reactivation of tumor growth was slow in most patients. Gestrinone caused amenorrhea in all patients and in most women it lasted throughout therapy. The abdominal discomfort, dyspareunia and dysuria which resulted from the myoma were progressively alleviated during treatment. Most patients experienced at least some side-effects associated with the mild androgenicity of gestrinone. These included weight gain, seborrhea and acne (which developed in most patients). Hirsutism, hoarseness and increase in libido were less common, affecting 10-20% of patients, depending on the dose and duration of treatment. All side effects were reversible. PMID- 29124726 TI - The relation between cortisol and functional connectivity in people with and without stress-sensitive epilepsy. AB - OBJECTIVE: The most common reported seizure-precipitant is stress. We recently showed a biologic basis for stress sensitivity of seizures: cortisol levels in people with stress-sensitive epilepsy correlated with focal interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Here we aimed to determine whether the effect of cortisol on the epileptic brain is global or focal, and whether cortisol affects all brains or just those of stress-sensitive people. Because epilepsy is associated with changes in functional brain connectivity, we studied the relationship between cortisol and changes in global and focal (node-centered) functional connectivity measures for individuals with stress-sensitive and non-stress-sensitive epilepsy. METHODS: Seventeen people with epilepsy underwent long-term (>24 h) EEG recording. During the first 5 h after waking, saliva was collected every 15 min for cortisol measurements. Theta band functional connectivity was assessed for every 15 min of the recording. We calculated the average phase-lag index (PLI) between all channels as a measure of global functional connectivity. We used network Strength, the averaged PLI per channel, as focal functional connectivity measure. We correlated cortisol, global, and focal functional connectivity (Strength) with IED frequency using linear mixed models. Analyses were split for people with and without stress sensitivity of seizures. RESULTS: Cortisol was negatively correlated with global functional connectivity in people with stress-sensitive seizures (estimate 0.0020; P < .01), whereas not in those without stress-sensitivity (estimate 0.0003; P = .46). This relationship occurred irrespective of the presence of IEDs on a channel (channels without IEDs and stress-sensitivity: estimate -0.0019; P < .01, non-stress-sensitive -0.0003; P = .41). Global and focal functional connectivity were negatively correlated with IED frequency, irrespective of stress sensitivity of seizures or channel type. SIGNIFICANCE: People with stress sensitive epilepsy have a whole-brain neuronal response to cortisol that is different from that of people with non-stress-sensitive epilepsy. This offers a basis for understanding seizure genesis in stress-sensitive epilepsy, which might require a different treatment approach. PMID- 29124727 TI - Untargeted antifungal therapy in adult patients with complicated intra-abdominal infection: a systematic review. AB - BACKGROUND: Systematic reviews comparing untargeted antifungal treatment with placebo or no treatment in critically ill patients have provided conflicting results. We aimed to assess patient-important benefits and harms of untargeted antifungal therapy vs. placebo or no treatment in adult patients with complicated intra-abdominal infection. METHODS: We conducted a systematic review with meta analysis and trial sequential analysis of randomised clinical trials assessing untargeted antifungal therapy compared to placebo or no treatment in adults with complicated intra-abdominal infection. We used the Cochrane and GRADE methodologies and exclusively assessed patient-important outcomes. Two independent authors screened trials for eligibility, extracted data and assessed risk of bias. We performed conventional meta-analyses, including sensitivity and subgroup analyses, and trial sequential analysis to assess the risk of random errors and to estimate trial sequential analysis adjusted confidence intervals. RESULTS: We included six trials (1,067 patients) in the review, and four trials reported data on the predefined outcome measures and were included in the meta analysis. Three of the four trials had high risk of bias. We observed no statistically significant difference in mortality (relative risk 0.58, 95% confidence interval 0.24-1.39) or in any of the other patient-important outcomes between untargeted antifungal treatment and placebo or no treatment (low/very low quality of evidence). Trial sequential analysis demonstrated lack of data and high risk of random errors. CONCLUSIONS: The quantity and quality of evidence supporting untargeted antifungal treatment in adult patients with complicated intra-abdominal infection are low to very low with no firm evidence for benefit or harm. PMID- 29124728 TI - Generating new evidence, improving clinical practice and developing research capacity: the benefits of recruiting to the U.K. Dermatology Clinical Trials Network's STOP GAP and BLISTER trials. AB - Clinical trials may benefit clinical practice in three ways: firstly, clinicians may change their practice according to the new trial evidence; secondly, clinical processes can improve when working on a trial; and thirdly, research capacity is increased. We held a meeting to present and discuss the results of two large multicentre randomized controlled trials delivered through the U.K. Dermatology Clinical Trials Network. Investigators gave reflections on how the trials had changed their clinical practice. The STOP GAP trial showed that prednisolone and ciclosporin are equally effective as first-line systemic treatment for pyoderma gangrenosum. The final decision of which treatment to use should be based on the different adverse event profiles of the two drugs in relation to comorbidities, along with age, disease severity and patient preference. The BLISTER trial showed that starting people with pemphigoid on doxycycline produces acceptable short term effectiveness and a superior safety profile to oral corticosteroids. Recruiting to these trials has led to the development of new specialist clinics with improved documentation. It has increased the profile of participating departments and embedded research in the department's activities. Helping to design and run these trials has also allowed trial staff to develop new skills in research design, which has been beneficial for career development. These and other benefits of recruiting to the trials are summarized here. We hope that these reflections will inspire wider involvement in clinical research. PMID- 29124730 TI - Inaugural JAGS "Mini-Focus" Issue: Cardiovascular Disease. PMID- 29124729 TI - Courses and Conferences. PMID- 29124731 TI - Cardiovascular Risk Burden and Future Risk of Walking Speed Limitation in Older Adults. AB - OBJECTIVES: To explore the association between cardiovascular risk factor (CRF) burden and limitation in walking speed, balance, and chair stand and to verify whether these associations vary according to age and cognitive status. DESIGN: Longitudinal population-based study. SETTING: Urban area of Stockholm, Sweden. PARTICIPANTS: Individuals aged 60 and older who participated in the Swedish National Study on Aging and Care in Kungsholmen and were free of limitations in walking speed (n = 1,441), balance (n = 1,154), or chair stands (n = 1,496) at baseline (2001-04). MEASUREMENTS: At baseline, data on demographic characteristics, CRFs, other lifestyle factors, C-reactive protein, and cognitive function were collected. CRF burden was measured using the Framingham general cardiovascular risk score (FRS). Limitations in walking speed (<0.8 m/s), balance (<5 seconds), and chair stand (inability to rise 5 times) were determined at 3-, 6-, and 9-year follow-up. Data were analyzed using Cox proportional hazards models stratified according to age (<78, >=78). RESULTS: During follow-up, 326 persons developed limitations in walking speed, 303 in balance, and 374 in chair stands. An association between the FRS and walking speed limitation was evident only in adults younger than 78 (for each 1-point increase in FRS: hazard ratio (HR) = 1.09, 95% confidence interval (CI) = 1.02-1.17) after controlling for potential confounders including cognitive function (correspondingly, in adults aged >=78: HR = 0.98, 95% CI = 0.92-1.03). Also, higher FRS was significantly associated with faster decline in walking speed (P < .001). CONCLUSION: A higher FRS is associated with greater risk of subsequent development of walking speed limitation in adults younger than 78, independent of cognitive function. Interventions targeting multiple CRFs in younger-old people may help in maintaining mobility function. PMID- 29124733 TI - A Veterans Day Salute: Honoring Veterans as They Age. PMID- 29124732 TI - Erratum. PMID- 29124735 TI - Perioperative fluid administration and effect on physiology and biochemistry of patients undergoing neurosurgical procedures. PMID- 29124736 TI - Response to 'Providing dermatological care in resource-limited settings: barriers and potential solutions'. PMID- 29124737 TI - The Health of Older Americans: A Primer on Medicare and a Local Perspective. AB - Our work with older adults, particularly those with limited incomes, has provided significant insight into the complexities of Medicare and the U.S. healthcare system. This article provides a brief history and overview of Medicare; describes the array of insurance choices Medicare beneficiaries face; and considers the effect of income, race, and health literacy on an individual's ability to navigate Medicare. We discuss how health is more than healthcare service delivery and that it takes community efforts to ensure that older adults not only understand their insurance, but also have access to other important resources that influence their health such as safe, affordable housing; food security; and transportation. PMID- 29124734 TI - Evolution of a Geriatric Syndrome: Pathophysiology and Treatment of Heart Failure with Preserved Ejection Fraction. AB - The majority of older adults who develop heart failure (HF), particularly older women, have a preserved left ventricular ejection fraction (HFpEF). The prevalence of this syndrome is increasing, and the prognosis is not improving, unlike that of HF with reduced ejection fraction (HFrEF). Individuals with HFpEF have severe symptoms of effort intolerance, poor quality of life, frequent hospitalizations, and greater likelihood of death. Despite the importance of HFpEF, there are numerous major gaps in our understanding of its pathophysiology and management. Although it was originally viewed as a disorder due solely to abnormalities in left ventricular diastolic function, our understanding has evolved such that HFpEF is now understood as a systemic syndrome involving multiple organ systems, and it is likely that it is triggered by inflammation and other as-yet-unidentified circulating factors, with important contributions of aging and multiple comorbidities, features generally typical of other geriatric syndromes. We present an update on the pathophysiology, diagnosis, management, and future directions in this disorder in older persons. PMID- 29124738 TI - Transcripts immunoprecipitated with Sxl protein in primordial germ cells of Drosophila embryos. AB - In Drosophila, Sex lethal (Sxl), an RNA binding protein, is required for induction of female sexual identity in both somatic and germline cells. Although the Sxl-dependent feminizing pathway in the soma was previously elucidated, the downstream targets for Sxl in the germline remained elusive. To identify these target genes, we selected transcripts associated with Sxl in primordial germ cells (PGCs) of embryos using RNA immunoprecipitation coupled to sequencing (RIP seq) analysis. A total of 308 transcripts encoded by 282 genes were obtained. Seven of these genes, expressed at higher levels in PGCs as determined by microarray and in situ hybridization analyses, were subjected to RNAi-mediated functional analyses. Knockdown of Neos, Kap-alpha3, and CG32075 throughout germline development caused gonadal dysgenesis in a sex-dependent manner, and Su(var)2-10 knockdown caused gonadal dysgenesis in both sexes. Moreover, as with knockdown of Sxl, knockdown of Su(var)2-10 in PGCs gave rise to a tumorous phenotype of germline cells in ovaries. Because this phenotype indicates loss of female identity of germline cells, we consider Su(var)2-10 to be a strong candidate target of Sxl in PGCs. Our results represent a first step toward elucidating the Sxl-dependent feminizing pathway in the germline. PMID- 29124739 TI - Psychological stress and psoriasis: a systematic review and meta-analysis. AB - BACKGROUND: Psychological stress has long been linked with the exacerbation/onset of psoriasis. OBJECTIVES: To determine if antecedent psychological stress is associated with the exacerbation/onset of psoriasis. METHODS: A search of the PubMed, PsycINFO, Cochrane library and ClinicalTrials.gov databases was performed. Surveys evaluating beliefs about stress reactivity were analysed separately. Suitable studies were meta-analysed. RESULTS: Thirty-nine studies (32 537 patients) were included: 19 surveys, seven cross-sectional studies, 12 case control studies and one cohort study. Forty-six per cent of patients believed their disease was stress reactive and 54% recalled preceding stressful events. Case-control studies evaluating stressful events rates prior to the exacerbation (n = 6) or onset (n = 6) of psoriasis varied in time lag to recollection (<= 9 months to >= 5 years). Pooling five studies evaluating stressful events preceding onset of psoriasis gave an odds ratio (OR) of 3.4 [95% confidence interval (CI) 1.8-6.4; I2 = 87%]; the only study evaluating a documented stress disorder diagnosis reported similar rates between patients and controls (OR 1.2, 95% CI 0.8-1.8). Four studies evaluating stressful events prior to psoriasis exacerbation reported comparable rates with controls, whereas two found more frequent/severe preceding events among patients with psoriasis. A small prospective cohort study reported a modest association between stress levels and exacerbation of psoriasis (r = 0.28, P < 0.05). CONCLUSIONS: The association between preceding stress and exacerbation/onset of psoriasis is based primarily on retrospective studies with many limitations. No convincing evidence exists that preceding stress is strongly associated with exacerbation/onset of psoriasis. PMID- 29124740 TI - Organizing activity of Fgf8 on the anterior telencephalon. AB - The anterior part of the embryonic telencephalon gives rise to several brain regions that are important for animal behavior, including the frontal cortex (FC) and the olfactory bulb. The FC plays an important role in decision-making behaviors, such as social and cognitive behavior, and the olfactory bulb is involved in olfaction. Here, we show the organizing activity of fibroblast growth factor 8 (Fgf8) in the regionalization of the anterior telencephalon, specifically the FC and the olfactory bulb. Misexpression of Fgf8 in the most anterior part of the mouse telencephalon at embryonic day 11.5 (E11.5) by ex utero electroporation resulted in a lateral shift of dorsal FC subdivision markers and a lateral expansion of the dorsomedial part of the FC, the future anterior cingulate and prelimbic cortex. Fgf8-transfected brains had lacked ventral FC, including the future orbital cortex, which was replaced by the expanded olfactory bulb. The olfactory region occupied a larger area of the FC when transfection efficiency of Fgf8 was higher. These results suggest that Fgf8 regulates the proportions of the FC and olfactory bulb in the anterior telencephalon and has a medializing effect on the formation of FC subdivisions. PMID- 29124742 TI - Lactate improves SAPS 3 prognostication. AB - INTRODUCTION: Lactate concentration is known to be a strong predictor of mortality, but is not included in any of the major intensive care scorings systems such as the Simplified Acute Physiology Score (SAPS 3). The objective of this study was to investigate the prognostic value of lactate concentration when combined with SAPS 3. MATERIALS AND METHODS: In the period of 2008 to June 2017 the general intensive care unit at Skane University Hospital in Lund, Sweden had 5141 first-time admissions. Of these, 3039 patients had lactate concentrations analysed within 1 h of admission. RESULTS: As expected, lactate concentration was found to be strongly related to 30-day mortality. Lactate concentration was found to be a SAPS 3 independent predictor of mortality (odds ratio 1.08, 95% confidence interval 1.05-1.11, P < 0.001), but did not improve the area under the receiver operating characteristic curve (AUC) (AUC 78.9% vs. 78.7%, P = 0.053). However, we found that lactate added prognostic value to SAPS 3 for patients with cardiac arrest (AUC 79.6% vs. 76.4%, P = 0.0082) and sepsis (AUC 75.1% vs. 72.7%, P = 0.033). CONCLUSION: Even compared to our current prognostication model, SAPS 3, lactate concentration was found to be an independent predictor for all diagnoses, cardiac arrest and sepsis. The addition of lactate concentration level improved the AUC for cardiac arrest and sepsis, but not for all diagnoses. PMID- 29124741 TI - Veterans Experiencing Elder Abuse: Improving Care of a High-Risk Population About Which Little Is Known. AB - At least 10% of older adults experience abuse, neglect, or exploitation annually in the United States, and this problem is expected to grow as our population ages. Little is known about the prevalence and characteristics of elder abuse of veterans, but it is likely that this population is at high risk based on established elder abuse risk factors. Veterans who receive their care through the Veterans Health Administration (VHA) have a higher prevalence of poor psychological health, poor physical health, functional impairment, cognitive impairment, and social isolation than the general population. As the largest integrated healthcare system in the United States, the VHA has long been a leader in the development of innovative, integrated care programs for older adults. The VHA has another opportunity to lead by promoting research, clinical care, and education on elder abuse, furthering their mission of serving those who served. This article outlines the rationale for developing a research agenda for elder abuse in the VHA, as well as potential first steps toward understanding more about this complex problem affecting veterans. PMID- 29124743 TI - A novel germline mutation in CDK4 codon 24 associated to familial melanoma. PMID- 29124745 TI - Medication Access in America and Medicare Part D: Prescription Shopping Saves but May Be Costly. AB - This article is a reflection of some of the changes we have witnessed in pharmacy over the years, including the rise in medication use and prices and the transformation of how medicines are paid for in the United States, with growing concern over pricing transparency. We discuss the complex Medicare Part D prescription drug benefit, how enrollees can save by comparing plans annually, and the influence of preferred pharmacies. We review options for medication assistance other than Part D and share our belief that, although Medicare Part D has dramatically improved access to medicines, more needs to be done to decrease Medicare's and individuals' out-of-pocket spending and, as importantly, to ensure that medicines are doing more good than harm. PMID- 29124746 TI - GROWTH HORMONE IN HUMAN PREGNANCY: Maternal 24-hour Serum Profiles and Experimental Effects of Continuous GH Secrection. AB - Growth hormone (GH) concentrations in serum were recorded in healthy women at different stages of normal pregnancy. Using a non-thrombogenic venous catheter and a portable pump, blood samples were collected at 30 min intervals for a period of 24 h. Growth hormone serum profiles were also established in non pregnant women, women undergoing legal abortion and cesarean section and during spontaneous labor. A dramatic change in growth hormone secretion was demonstrated during late pregnancy when compared with the non-pregnant state. The pulsatile pattern, with intermittent high peaks and low or undetectable levels between peaks, characteristic of normal men and non-pregnant women, was completely suppressed. During late pregnancy, all investigated women evidenced increased, very stable serum levels of GH and there was no evidence of pulsatile activity. Two monoclonal antibodies directed against different epitopes on the GH-molecule were used in radio-immunoassays to distinguish the pituitary 22K-GH from other circulating GH variants. During the second half of pregnancy, a continuous secretion of a new placental GH variant and a concommitant suppression of the pulsatile pituitary GH secretion was demonstrated. The progressive transformation of GH secretion from a pulsatile into a stable, continuous pattern started at the end of the first trimester. After placental removal at cesarean section in late pregnancy there was a rapid fall in serum GH concentration, whereas levels were unaffected after legal abortion in the first trimester. These results and simultaneous measurements of hPL and hCG support the concept that a placental GH variant is produced during pregnancy. Studies on the diurnal variations of thyrotropin, prolactin and cortisol indicate that human pregnancy is associated with selective alterations in the secretion of pituitary hormones. The biological impact of continuous GH secretion was elucidated in two experimental systems in the rat. The pregnancy-associated murine protein-1 (PAMP-1) in rodents was previously believed to be regulated by sex steroids. However, a continuous infusion of hGH was found to increase the plasma concentration of PAMP-1 in non pregnant, hypophysectomized female rats. On the other hand, intermittent hGH administration or estrogen treatment had no effect on this seemingly 'steroid sensitive' protein. Steroid sulfatase activity in rat liver microsomes is another sexually differentiated function. Likewise, this system was found to be regulated by the mode of GH administration. A continuous GH secretion during human pregnancy can alter maternal liver metabolism and have important implications for the physiological adjustment to gestation. PMID- 29124747 TI - Medicare and Medication Access Basics for Providers and Patients. PMID- 29124748 TI - Is epilepsy the cause of comorbidities in Dravet syndrome? PMID- 29124749 TI - Prediction of bleeding and thrombosis by standard biochemical coagulation variables in haematological intensive care patients. AB - PURPOSE: We assessed the value of standard biochemical coagulation parameters in predicting bleeding, thrombosis and mortality in adult Intensive Care Unit (ICU) patients with haematological malignancies. METHODS: We screened all patients with acute leukaemia and myelodysplastic syndrome admitted to a university hospital ICU during 2008-2012. Data were obtained from the clinical chemistry laboratory database and patient files. We graded bleeding according to the World Health Organisation (WHO)-system within 24-h, within 5-days and during the whole ICU stay. We analysed the predictive values of laboratory parameters using multiple logistic regression and receiver operator characteristics (ROC) curves. As we previously have established that platelet count at admission was associated with bleeding, we focused on International Normalised Ratio (INR), activated pro thrombin time (APTT), anti-thrombin, D-dimer and fibrinogen, and markers of infection (C-reactive protein, pro-calcitonin), kidney function (creatinine) and tissue damage (lactate dehydrogenase (LDH)). RESULTS: We included 116 patients; 66 (57%) had at least one bleeding episode and 11 (9%) patients had at least one thrombotic event. The differences in coagulation values when bleeding compared to baseline values were minor. INR was the only variable we found associated with subsequent bleeding within 24 h from admission to ICU (odds ratio 2.91, 95% CI: 1.01-8.43, P = 0.048). ROC analyses did not show predictive value of any of the other variables with regards to bleeding and none of the variables were associated with thrombosis in adjusted analyses. Increased levels of LDH at admission were associated with increased 7-day and 30-day mortality. CONCLUSIONS: Increased INR at admission was associated with a higher rate of bleeding in ICU patients with haematological malignancies. No other biochemical coagulation or other parameter had any association with bleeding, thrombosis or mortality except increased LDH, which at ICU admission was associated with increased 30-day mortality. PMID- 29124744 TI - Usefulness of knockout mice to clarify the role of the opioid system in chronic pain. AB - : Several lines of knockout mice deficient in the genes encoding each component of the endogenous opioid system have been used for decades to clarify the specific role of the different opioid receptors and peptide precursors in many physiopathological conditions. The use of these genetically modified mice has improved our knowledge of the specific involvement of each endogenous opioid component in nociceptive transmission during acute and chronic pain conditions. The present review summarizes the recent advances obtained using these genetic tools in understanding the role of the opioid system in the pathophysiological mechanisms underlying chronic pain. Behavioural data obtained in these chronic pain models are discussed considering the peculiarities of the behavioural phenotype of each line of knockout mice. These studies have identified the crucial role of specific components of the opioid system in different manifestations of chronic pain and have also opened new possible therapeutic approaches, such as the development of opioid compounds simultaneously targeting several opioid receptors. However, several questions still remain open and require further experimental effort to be clarified. The novel genetic tools now available to manipulate specific neuronal populations and precise genome editing in mice will facilitate in a near future the elucidation of the role of each component of the endogenous opioid system in chronic pain. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc. PMID- 29124750 TI - Response to 'Providing dermatological care in resource-limited settings: barriers and potential solutions' - reply from authors. PMID- 29124751 TI - Detailed characterization of human Mycobacterium tuberculosis specific HLA-E restricted CD8+ T cells. AB - HLA-E presented antigens are interesting targets for vaccination given HLA-Es' essentially monomorphic nature. We have shown previously that Mycobacterium tuberculosis (Mtb) peptides are presented by HLA-E to CD8+ effector T cells, but the precise phenotype and functional capacity of these cells remains poorly characterized. We have developed and utilized in this study a new protocol combining HLA-E tetramer with intracellular staining for cytokines, transcription factors and cytotoxic molecules to characterize these cells in depth. We confirm in this study the significantly increased ex vivo frequency of Mtb-peptide/HLA-E TM+ CD8+ T cells in the circulation of patients with active tuberculosis (TB). HLA-E restricted CD8+ T cells from TB patients produced more IL-13 than cells from controls or subjects with latent tuberculosis infection (LTBI). Compared to total CD8+ T cells, HLA-E restricted cells produced more IFNgamma, IL-4, IL-10, and granulysin but less granzyme-A. Moreover, compared to "classical" Mtb specific HLA-A2 restricted CD8+ T cells, HLA-E restricted CD8+ T cells produced less TNFalpha and perforin, but more IL-4. In conclusion, HLA-E restricted- Mtb specific cells can produce Th2 cytokines directly. PMID- 29124753 TI - Erratum. PMID- 29124752 TI - Extending the seductive allure of neuroscience explanations effect to popular articles about educational topics. AB - BACKGROUND: The seductive allure of neuroscience explanations (SANE) is the finding that people overweight psychological arguments when framed in terms of neuroscience findings. AIM: This study extended this finding to arguments concerning the application of psychological findings to educational topics. SAMPLE: Participants (n = 320) were recruited from the general public, specifically among English-speaking Amazon Mechanical Turk workers residing in the United States. METHODS: We developed eight articles that orthogonally varied two processes (learning vs. development) with two disciplines (cognitive vs. affective psychology). We increased neuroscience framing across four levels: psychological finding alone, with an extraneous neuroscience finding (verbal), with an extraneous neuroscience finding (verbal) and graph, and with an extraneous neuroscience finding (verbal) and brain image. Participants were randomly assigned to one level of neuroscience framing and rated the credibility of each article's argument. RESULTS: Seductive allure of neuroscience explanations effects were not ubiquitous. Extraneous verbal neuroscience framings, either alone or accompanied by graphs, did not influence the credibility of the application of psychological findings to educational topics. However, there was a SANE effect when educational articles were accompanied by both extraneous verbal neuroscience findings and brain images. This effect persisted even after controlling for individual differences in familiarity with education, attitude towards psychology, and knowledge of neuroscience. CONCLUSION: The results suggest that there is a SANE effect for articles about educational topics among the general public when they are accompanied by both extraneous verbal neuroscience findings and brain images. PMID- 29124754 TI - Clouding Jolt Accentuation by Cloudy Clinical Setting for Lumbar Puncture. PMID- 29124757 TI - A Review of HIV and Headache: A Cross-Sectional Study. PMID- 29124756 TI - Post-Dengue New Daily Persistent Headache: Comment. PMID- 29124758 TI - Combination of NSAID and Triptan in Migraine Treatment and Cardiovascular Risk: Is It Safe? PMID- 29124759 TI - Editorial: Nutraceuticals and Occipital Nerve Blocks. PMID- 29124760 TI - Indications and methodology for video-electroencephalographic studies in the epilepsy monitoring unit. AB - Although the epilepsy and neurology communities have position papers on a number of topics pertaining to epilepsy diagnosis and management, no current paper exists for the rationale and appropriate indications for epilepsy monitoring unit (EMU) evaluation. General neurologists, hospital administrators, and insurers also have yet to fully understand the role this type of testing has in the diagnosis and management of individuals with paroxysmal neurologic symptoms. This review outlines the indications for long-term video-electroencephalography (VEEG) for typical elective admissions to a specialized inpatient setting. The common techniques used in EMUs to obtain diagnostic information are reviewed. The added benefit of safety measures and clinical testing above that available for routine or long-term ambulatory electroencephalography is also discussed. The indications for admission to the EMU include differential diagnosis of paroxysmal spells, characterization of seizure types, presurgical epilepsy evaluations, seizure quantification, monitoring medication adjustment in a safe setting, and differentiation between seizures and side effects. We conclude that the appropriate use of this specialized testing can lead to an early and correct diagnosis in a variety of clinical circumstances. The EMU evaluation is considered the gold standard test for the definitive diagnosis of epilepsy and seizure-like spells. PMID- 29124762 TI - Evolution in the design of a low sheath-flow interface for CE-MS and application to biological samples. AB - Although several interfaces for CE-MS hyphenation are commercially available, the development of new versatile, simple and yet efficient and sensitive alternatives remains an important field of research. In a previous work, a simple low sheath flow interface was developed from inexpensive parts. This interface features a design easy to build, maintain, and adapt to particular needs. The present work introduces an improved design of the previous interface. By reducing the diameter of the separation capillary and the emitter, a smaller Taylor cone is spontaneously formed, minimizing the zone dispersion while the analytes go through the interface and leading to less peak broadening associated to the ESI process. Numerical modeling allowed studying the mixing and diffusion processes taking place in the Taylor cone. The analytical performance of this new interface was tested with pharmaceutically relevant molecules and endogenous metabolites. The interface was eventually applied to the analysis of neural cell culture samples, allowing the identification of a panel of neurotransmission-related molecules. An excellent migration time repeatability was obtained (intra-day RSD <0.5% for most compounds, and <3.0% for inter-day precision). Most metabolites showed S/N ratios >10 with an injected volume of 6.7 nL of biological extract. PMID- 29124763 TI - Neuronal expression of brain derived neurotrophic factor in the injured telencephalon of adult zebrafish. AB - The reparative ability of the central nervous system varies widely in the animal kingdom. In the mammalian brain, the regenerative mechanisms are very limited and newly formed neurons do not survive longer, probably due to a non-suitable local environment. On the opposite, fish can repair the brain after injury, with fast and complete recovery of damaged area. The brain of zebrafish, a teleost fish widely used as vertebrate model, also possesses high regenerative properties after injury. Taking advantage of this relevant model, the aim of the present study was to investigate the role of brain-derived neurotrophic factor (BDNF) in the regenerative ability of adult brain, after stab wound telencephalic injury. BDNF is involved in many brain functions and plays key roles in the repair process after traumatic brain lesions. It has been reported that BDNF strengthens the proliferative activity of neuronal precursor cells, facilitates the neuronal migration toward injured areas, and shows survival properties due to its anti apoptotic effects. BDNF mRNA levels, assessed by quantitative PCR and in situ hybridization at 1, 4, 7, and 15 days after the lesion, were increased in the damaged telencephalon, mostly suddenly after the lesion. Double staining using in situ hybridization and immunocytochemistry revealed that BDNF mRNA was restricted to cells identified as mature neurons. BDNF mRNA expressing neurons mostly increased in the area around the lesion, showing a peak 1 day after the lesion. Taken together, these results highlight the role of BDNF in brain repair processes and reinforce the value of zebrafish for the study of regenerative neurogenesis. PMID- 29124761 TI - Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe *PS1Deltae9 transgenic mouse model of Alzheimer's disease. AB - There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD); however, its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, there is a need to investigate neuroinflammation in both health and disease. Here, we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APPswe *PS1Deltae9 transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [18 F]DPA-714 positron emission tomography and myo-inositol levels using 1 H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N acetylaspartate (NAA), choline-containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12 m of age in the TG mice as assessed by working memory tests . A significant increase in [18 F]DPA-714 uptake was seen in the hippocampus and cortex of 18 m-old TG mice when compared to age matched WT mice and 6 m-old TG mice. No overall effect of gene was seen on metabolite levels; however, a significant reduction in NAA was observed in 18 m old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore, we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in ageing. PMID- 29124764 TI - Flank spot number and its significance for systematics, taxonomy and conservation of the near-threatened Mediterranean trout Salmo cettii: evidence from a genetically pure population. AB - The number of spots on the flank of the Mediterranean trout Salmo cettii population from Tellesimo Stream in Sicily, Italy, varied between seven and 37, with a median and mode of 21, numbers much lower than those reported in the literature and different from those of other Italian trout populations. This finding could be ascribed to the phenotypic plasticity of the species or, alternatively, could provide evidence to support the different origin of Sicilian autochthonous trout. Given the ease of use of this character for the identification of native fish, it could be particularly important for conservation and management purposes. PMID- 29124765 TI - Lipocalin-type prostaglandin D synthase-derived PGD2 attenuates malignant properties of tumor endothelial cells. AB - Endothelial cells (ECs) are a key component of the tumor microenvironment. They have abnormal characteristics compared to the ECs in normal tissues. Here, we found a marked increase in lipocalin-type prostaglandin D synthase (L-PGDS) mRNA (Ptgds) expression in ECs isolated from mouse melanoma. Immunostaining of mouse melanoma revealed expression of L-PGDS protein in the ECs. In situ hybridization also showed L-PGDS (PTGDS) mRNA expression in the ECs of human melanoma and oral squamous cell carcinoma. In vitro experiments showed that stimulation with tumor cell-derived IL-1 and TNF-alpha increased L-PGDS mRNA expression and its product prostaglandin D2 (PGD2 ) in human normal ECs. We also investigated the contribution of L-PGDS-PGD2 to tumor growth and vascularization. Systemic or EC specific deficiency of L-PGDS accelerated the growth of melanoma in mice, whereas treatment with an agonist of the PGD2 receptor, DP1 (BW245C, 0.1 mg/kg, injected intraperitoneally twice daily), attenuated it. Morphological and in vivo studies showed that endothelial L-PGDS deficiency resulted in functional changes of tumor ECs such as accelerated vascular hyperpermeability, angiogenesis, and endothelial to-mesenchymal transition (EndMT) in tumors, which in turn reduced tumor cell apoptosis. These observations suggest that tumor cell-derived inflammatory cytokines increase L-PGDS expression and subsequent PGD2 production in the tumor ECs. This PGD2 acts as a negative regulator of the tumorigenic changes in tumor ECs. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29124766 TI - Direct costs of transfusion reactions - an expert judgement approach. AB - BACKGROUND AND OBJECTIVES: Despite increasingly meticulous haemovigilance reporting throughout the world, a systematic assessment of the cost of transfusion reactions is still lacking. This is partly caused by the fact that such an assessment requires a subjective expert assessment of the additional costs linked to the adverse reaction. Data on the cost of transfusion reactions could support decision-making regarding blood transfusion safety measures. MATERIALS AND METHODS: Thirteen experts from nine hospitals were asked to estimate the additional care required following various types of transfusion reactions. Additional care was quantified as the proportion of reactions requiring care, and the amount of care required (e.g. hospitalization days, additional physician's time). Experts were also asked to provide, per type of transfusion reaction, an estimate of the proportion of transfusion reactions preventable. Structured quantitative expert elicitation methods were applied to obtain and combine expert estimates. RESULTS: The estimated annual in-hospital cost of transfusion reactions in the Netherlands is ?933 356 per year (?1.52 per transfusion). Two-thirds (64%) of these are incurred by non-serious transfusion reactions. Circulatory overload, TRALI and anaphylaxis clearly dominate the costs of serious adverse transfusion reactions (66% in total); non-haemolytic transfusion reactions incur 46% of the cost of non-serious transfusion reactions. Additional safety measures targeting circulatory overload and new antibody formation potentially offer the highest cost reduction. CONCLUSION: In-hospital costs of transfusion reactions are substantial but contribute to less than 1% of the total cost of transfusion in the Netherlands. A considerable part of these costs (24%) might be preventable. PMID- 29124767 TI - Adenylate control contributes to thermal acclimation of sugar maple fine-root respiration in experimentally warmed soil. AB - We investigated the occurrence of and mechanisms responsible for acclimation of fine-root respiration of mature sugar maple (Acer saccharum) after 3+ years of experimental soil warming (+4 to 5 degrees C) in a factorial combination with soil moisture addition. Potential mechanisms for thermal respiratory acclimation included changes in enzymatic capacity, as indicated by root N concentration; substrate limitation, assessed by examining nonstructural carbohydrates and effects of exogenous sugar additions; and adenylate control, examined as responses of root respiration to a respiratory uncoupling agent. Partial acclimation of fine-root respiration occurred in response to soil warming, causing specific root respiration to increase to a much lesser degree (14% to 26%) than would be expected for a 4 to 5 degrees C temperature increase (approximately 55%). Acclimation was greatest when ambient soil temperature was warmer or soil moisture availability was low. We found no evidence that enzyme or substrate limitation caused acclimation but did find evidence supporting adenylate control. The uncoupling agent caused a 1.4 times greater stimulation of respiration in roots from warmed soil. Sugar maple fine-root respiration in warmed soil was at least partially constrained by adenylate use, helping constrain respiration to that needed to support work being performed by the roots. PMID- 29124768 TI - The peripheral nervous system of the ascidian tadpole larva: Types of neurons and their synaptic networks. AB - Physical and chemical cues from the environment are used to direct animal behavior through a complex network of connections originating in exteroceptors. In chordates, mechanosensory and chemosensory neurons of the peripheral nervous system (PNS) must signal to the motor circuits of the central nervous system (CNS) through a series of pathways that integrate and regulate the output to motor neurons (MN); ultimately these drive contraction of the tail and limb muscles. We used serial-section electron microscopy to reconstruct PNS neurons and their hitherto unknown synaptic networks in the tadpole larva of a sibling chordate, the ascidian, Ciona intestinalis. The larva has groups of neurons in its apical papillae, epidermal neurons in the rostral and apical trunk, caudal neurons in the dorsal and ventral epidermis, and a single tail tip neuron. The connectome reveals that the PNS input arises from scattered groups of these epidermal neurons, 54 in total, and has three main centers of integration in the CNS: in the anterior brain vesicle (which additionally receives input from photoreceptors of the ocellus), the motor ganglion (which contains five pairs of MN), and the tail, all of which in turn are themselves interconnected through important functional relay neurons. Some neurons have long collaterals that form autapses. Our study reveals interconnections with other sensory systems, and the exact inputs to the motor system required to regulate contractions in the tail that underlie larval swimming, or to the CNS to regulate substrate preference prior to the induction of larval settlement and metamorphosis. PMID- 29124769 TI - Introgression from Populus balsamifera underlies adaptively significant variation and range boundaries in P. trichocarpa. AB - Introgression can be an important source of adaptive phenotypes, although conversely it can have deleterious effects. Evidence for adaptive introgression is accumulating but information on the genetic architecture of introgressed traits lags behind. Here we determine trait architecture in Populus trichocarpa under introgression from P. balsamifera using admixture mapping and phenotypic analyses. Our results reveal that admixture is a key driver of clinal adaptation and suggest that the northern range extension of P. trichocarpa depends, at least in part, on introgression from P. balsamifera. However, admixture with P. balsamifera can lead to potentially maladaptive early phenology, and a reduction in growth and disease resistance in P. trichocarpa. Strikingly, an introgressed chromosome 9 haplotype block from P. balsamifera restores the late phenology and high growth parental phenotype in admixed P. trichocarpa. This epistatic restorer block may be strongly advantageous in maximizing carbon assimilation and disease resistance in the southernmost populations where admixture has been detected. We also confirm a previously demonstrated case of adaptive introgression in chromosome 15 and show that introgression generates a transgressive chlorophyll content phenotype. We provide strong support that introgression provides a reservoir of genetic variation associated with adaptive characters that allows improved survival in new environments. PMID- 29124770 TI - Characterization of the gut microbiota in early life stages of pikeperch Sander lucioperca. AB - This study characterized the gastrointestinal microbiome of nine juvenile farmed pikeperch Sander lucioperca using a metagenomics approach based on bacterial 16S rRNA gene sequencing. Potential changes in the gut microbiota during 2 months of S. lucioperca juvenile life were investigated. Results revealed that gut microbiota was dominated by Proteobacteria (95-92%), while other phyla Firmicutes (1-1.5%) and Actinobacteria (0.9-1.5%) were less abundant. At the family level, fish-gut microbiota were dominated by Enterobacteriaceae, which constituted c. 83% of all DNA sequence reads. Such a situation was present in all of the examined fish except one, which showed a different proportion of particular microbial taxa than the other fish. In this fish, a higher relative abundance (%) of Fusobacteria (21.0%), Bacteroidetes (9.5%) and Firmicutes (7.5%) was observed. There were no significant differences in the gut microbiome structure at different stages of development in the examined fish. This may indicate that Proteobacteria inhabiting the gut microbiota at an early stage of life are a necessary component of the pikeperch microbiome that may support proper nutrition of the fish. The information obtained on the gut microbiome could be useful in determining juvenile S. lucioperca health and improving rearing conditions by welfare monitoring in aquaculture. PMID- 29124771 TI - Near-infrared hyperspectral imaging for detection and quantification of azodicarbonamide in flour. AB - BACKGROUND: The present study aimed to establish a method for the detection and quantification of azodicarbonamide (ADC) in flour using hyperspectral imaging technology. Hyperspectral images of pure flour, pure ADC and flour-ADC mixtures with different concentrations of ADC were collected. F-values of one-way analysis of variance for all possible wavebands within the spectra of the flour and ADC were calculated, and the maximum value indicated that the two wavebands have more significant differences, i.e. the optimal two wavebands. Threshold segmentation was used for band ratio images of two wavebands to create a binary image. This allowed visual identification of ADC-rich pixels in the mixtures. RESULTS: The two wavebands with the largest difference between flour and ADC were 2039 nm and 1892 nm. Using the binary image construction method, different concentrations of ADC in flour were identified. The minimum detected concentration was 0.2 g kg-1 . In the mixtures, the number of ADC-rich pixels detected had a good linear relationship with the ADC concentrations, with a correlation coefficient of 0.9845. CONCLUSION: This study indicated that the band ratio algorithm combination with threshold segmentation for hyperspectral images provides a non destructive method for detecting and quantifying of ADC in flour. (c) 2017 Society of Chemical Industry. PMID- 29124772 TI - Morphology of P2X3-immunoreactive nerve endings in the rat tracheal mucosa. AB - Nerve endings with immunoreactivity for the P2X3 purinoreceptor (P2X3) in the rat tracheal mucosa were examined by immunohistochemistry of whole-mount preparations with confocal scanning laser microscopy. P2X3 immunoreactivity was observed in ramified endings distributed in the whole length of the trachea. The myelinated parent axons of P2X3-immunoreactive nerve endings ramified into several branches that extended two-dimensionally in every direction at the interface between the epithelial layer and lamina propria. The axonal branches of P2X3-immunoreactive endings branched off many twigs located just beneath the epithelium, and continued to intraepithelial axon terminals. The axon terminals of P2X3 immunoreactive endings were beaded, rounded, or club-like in shape and terminated between tracheal epithelial cells. Flat axon terminals sometimes partly ensheathed neuroendocrine cells with immunoreactivity for SNAP25 or CGRP. Some axons and axon terminals with P2X3 immunoreactivity were immunoreactive for P2X2, while some terminals were immunoreactive for vGLUT2. Furthermore, a retrograde tracing method using fast blue (FB) revealed that 88.4% of FB-labeled cells with P2X3 immunoreactivity originated from the nodose ganglion. In conclusion, P2X3 immunoreactive nerve endings in the rat tracheal mucosa have unique morphological characteristics, and these endings may be rapidly adapting receptors and/or irritant receptors that are activated by mucosal irritant stimuli. PMID- 29124773 TI - Consumption of orange fermented beverage improves antioxidant status and reduces peroxidation lipid and inflammatory markers in healthy humans. AB - BACKGROUND: Alcoholic fermentation of fruits has generated novel products with high concentrations of bioactive compounds and moderate alcohol content. The aim of this study was to evaluate the potential effect on cardiovascular risk factors of the regular consumption by healthy humans of a beverage obtained by alcoholic fermentation and pasteurization of orange juice. RESULTS: Thirty healthy volunteers were enrolled in a randomized controlled study. The experimental group (n = 15) drank 500 mL orange beverage (OB) per day for 2 weeks (intervention phase), followed by a 3-week washout phase. Blood samples were collected at baseline (E-T0) and at the end of the intervention (E-T1) and washout (E-T2) phases. Controls (n = 15) did not consume OB during a 2-week period. OB intake significantly increased oxygen radical absorbance capacity (43.9%) and reduced uric acid (-8.9%), catalase (CAT) (-23.2%), thiobarbituric acid reactive substances (TBARS) (-30.2%) and C-reactive protein (-2.1%) (E-T1 vs. E-T0). These effects may represent longer-term benefits, given the decreased uric acid ( 8.9%), CAT (-34.6%), TBARS (-48.4%) and oxidized low-density lipoprotein (-23.9%) values recorded after the washout phase (E-T2 vs. E-T0). CONCLUSION: The regular consumption of OB improved antioxidant status and decreased inflammation state, lipid peroxidation and uric acid levels. Thus OB may protect the cardiovascular system in healthy humans and be considered a novel functional beverage. (c) 2017 Society of Chemical Industry. PMID- 29124774 TI - Early drug and anti-infliximab antibody levels for prediction of primary nonresponse to infliximab therapy. AB - BACKGROUND: Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined. AIM: To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse. METHODS: A retrospective observational case-control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre-infusion infliximab and antibodies to infliximab (ATI) levels were measured by our previously described drug-tolerant ELISA assay. RESULTS: Thirty-five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2 MUg/mL vs 13.5, 9.5 MUg/mL, P = .0019, P < .0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, P = .0004) and at higher levels in nonresponders compared to responders (week 2, 6: median ATI 7.3, 10.8 MUg/mL-eq vs 3.8, 4.4 MUg/mL-eq, P = .005, P = .008 respectively). Moreover, week 2 infliximab levels <6.8 MUg/mL (AUC = 0.68, P = .002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3 MUg/mL-eq (AUC = 0.78, P = .0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease-related surgeries were also associated with an increased risk of primary nonresponse. CONCLUSIONS: Infliximab levels below 6.8 MUg/mL and antibodies to infliximab levels above 4.3 MUg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients. PMID- 29124775 TI - Capillary-HPLC with tandem mass spectrometry in analysis of alkaloid dyestuffs - a new approach. AB - Development of the identification method of alkaloid compounds in Amur cork tree as well as not examined so far Oregon grape and European Barberry shrubs are presented. The novel approach to separation of alkaloids was applied and the capillary-high-performance liquid chromatography (capillary-HPLC) system was used, which has never previously been reported for alkaloid-based dyestuffs analysis. Its optimization was conducted with three different stationary phases (unmodified octadecylsilane-bonded silica, octadecylsilane modified with polar groups and silica-bonded pentaflourophenyls) as well as with different solvent buffers. Detection of the isolated compounds was carried out using diode-array detector (DAD) and tandem mass spectrometer with electrospray ionization (ESI MS/MS). The working parameters of ESI were optimized, whereas the multiple reactions monitoring (MRM) parameters of MS/MS detection were chosen based on the product ion spectra of the quasi-molecular ions. Calibration curve of berberine has been estimated (y = 1712091x + 4785.03 with the correlation coefficient 0.9999). Limit of detection and limit of quantification were calculated to be 3.2 and 9.7 ng/mL, respectively. Numerous alkaloids (i.e., berberine, jatrorrhizine and magnoflorine, as well as phellodendrine, menisperine and berbamine) were identified in the extracts from alkaloid plants and silk and wool fibers dyed with these dyestuffs, among them their markers. PMID- 29124776 TI - Field findings about milk ethanol stability: a first report of interrelationship between alpha-lactalbumin and lactose. AB - BACKGROUND: Milk ethanol stability is not only associated with microbiological acidification, but is a phenomenon with many variables that influence the balance of soluble salts, mainly calcium ion activity. On this basis, we wanted to find out more about milk ethanol stability by studying its relationship with milk protein fractions and others major components. The influence of milk composition on ethanol stability was assessed through a predictive model comprising 180 individual raw milk samples. An additional model was used to assess the ethanol stability status as a response to the proteins fractions quantified by electrophoresis. RESULTS: Of the total samples, 68% were classified as stable and 32% as unstable to alcohol. Milk ethanol instability increased at low values of lactose content and high values of ash percentage. alpha-Lactalbumin (alpha-La) was also associated with ethanol stability, and the higher the alpha-La percentage the lower were the chances of ethanol instability. CONCLUSION: The lower values of alpha-La in unstable milk samples might be related to lower content of lactose, as alpha-La promotes lactose synthesis, a key component for the osmotic balance of milk and thus its ethanol stability. This is the first field report linking ethanol stability indirectly with alpha-La. (c) 2017 Society of Chemical Industry. PMID- 29124777 TI - Coherence in the Visual Imagination. AB - An incoherent visualization is when aspects of different senses of a word (e.g., the biological "mouse" vs. the computer "mouse") are present in the same visualization (e.g., a visualization of a biological mouse in the same image with a computer tower). We describe and implement a new model of creating contextual coherence in the visual imagination called Coherencer, based on the SOILIE model of imagination. We show that Coherencer is able to generate scene descriptions that are more coherent than SOILIE's original approach as well as a parallel connectionist algorithm that is considered competitive in the literature on general coherence. We also show that co-occurrence probabilities are a better association representation than holographic vectors and that better models of coherence improve the resulting output independent of the association type that is used. Theoretically, we show that Coherencer is consistent with other models of cognitive generation. In particular, Coherencer is a similar, but more cognitively plausible model than the C3 model of concept combination created by Costello and Keane (2000). We show that Coherencer is also consistent with both the modal schematic indices of perceptual symbol systems theory (Barsalou, 1999) and the amodal contextual constraints of Thagard's (2002) theory of coherence. Finally, we describe how Coherencer is consistent with contemporary research on the hippocampus, and we show evidence that the process of making a visualization coherent is serial. PMID- 29124778 TI - Giving versus acting: Using latent profile analysis to distinguish between benevolent and activist support for global poverty reduction. AB - There are a variety of ways that people can respond to inequality. This article considers the distinction between collective giving and collective acting, but also adopts a focus on the people who engage in those behaviours. Benevolent supporters engage in efforts to alleviate suffering through the transfer of money or provision of goods ('giving'), while activist supporters engage in actions that aim to challenging an underlying injustice or exploitation ('acting'). Using samples obtained through anti-poverty non-governmental organizations (N = 2,340), latent profile analysis suggested two qualitatively different forms of support for global poverty reduction: a benevolent supporter profile (defined by moderate levels of charitable support) and an activist supporter profile (defined by engagement in a suite of socio-political actions). The two forms of support are predicted by different appraisals for, emotional reactions to (outrage v sympathy), and social change beliefs about, global injustice. Results highlight the theoretical and practical importance of considering subgroup differences in how social justice is pursued. PMID- 29124779 TI - Prenatal diethylstilbestrol exposure and cancer risk in women. AB - In the Diethylstilbestrol [DES] Combined Cohort Follow-up, the age- and calendar year specific standardized incidence ratio [SIR] for clear cell adenocarcinoma [CCA] was 27.6 (95% confidence interval [CI] 7.51-70.6) for the exposed women. The SIR for breast cancer was 1.17 (95% CI 1.01-1.36) and the hazard ratio [HR] adjusted for birth year and cohort for comparison with the unexposed was 1.05 (95% CI 0.79-1.41). The SIR for pancreatic cancer was 2.43 (95% CI 1.21-4.34) and the adjusted HR for comparison with unexposed women was 7.16 (95% CI 0.84-61.5). There was little evidence of excess risk for other sites. There appeared to be a deficit in risk for endometrial cancer among the exposed (SIR 0.61; 95% CI 0.35 0.98), and an excess in the unexposed (SIR 1.55; 95% CI 0.95-2.40); the adjusted HR was 0.45 (95% CI 0.22-0.93) for the internal comparison. There was no overall excess cancer risk in exposed women compared with general population rates (1.06; 95% CI 0.95-1.17) or with unexposed participants (adjusted HR 1.03; 95% CI 0.84 1.25). These data do not support the suggestion that there is a diathesis of cancers in DES exposed female offspring The excess risk of breast and pancreatic cancers that we observed is concerning and warrants continued follow-up and mechanistic investigation. Environ. Mol. Mutagen, 2017. Published 2017. This article is a US Government work and is in the public domain in the USA. PMID- 29124780 TI - Refractive error and vision correction in a general sports-playing population. AB - PURPOSE: To evaluate, in an amateur sports-playing population, the prevalence of refractive error, the type of vision correction used during sport and attitudes toward different kinds of vision correction used in various types of sports. METHOD: A questionnaire was used for people engaging in sport and data was collected from sport centres, gyms and universities that focused on the motor sciences. RESULTS: One thousand, five hundred and seventy-three questionnaires were collected (mean age 26.5 +/- 12.9 years; 63.5 per cent male). Nearly all (93.8 per cent) subjects stated that their vision had been checked at least once. Fifty-three subjects (3.4 per cent) had undergone refractive surgery. Of the remainder who did not have refractive surgery (n = 1,519), 580 (38.2 per cent) reported a defect of vision, 474 (31.2 per cent) were myopic, 63 (4.1 per cent) hyperopic and 241 (15.9 per cent) astigmatic. Logistic regression analysis showed that the best predictors for myopia prevalence were gender (p < 0.001) and location of sport practice (p < 0.001). Sports that present higher prevalence of outdoor activity have lower prevalence of myopia. Contact lens penetration over the study sample was 18.7 per cent. Contact lenses were the favourite system of correction among people interviewed compared to spectacles and refractive surgery (p < 0.001). CONCLUSIONS: This study showed that sport was not associated with different levels of myopia prevalence in the adult population. However, subjects engaging in outdoor sports had lower rates of myopia prevalence. Penetration of contact lens use in sport was four times higher than the overall adult population. Contact lenses were the preferred system of correction in sports compared to spectacles or refractive surgery, but this preference was affected by the type of sport practised and by the age and level of sports activity for which the preference was required. PMID- 29124781 TI - Vascular input function correction of inflow enhancement for improved pharmacokinetic modeling of liver DCE-MRI. AB - PURPOSE: To propose a simple method to correct vascular input function (VIF) due to inflow effects and to test whether the proposed method can provide more accurate VIFs for improved pharmacokinetic modeling. METHODS: A spoiled gradient echo sequence-based inflow quantification and contrast agent concentration correction method was proposed. Simulations were conducted to illustrate improvement in the accuracy of VIF estimation and pharmacokinetic fitting. Animal studies with dynamic contrast-enhanced MR scans were conducted before, 1 week after, and 2 weeks after portal vein embolization (PVE) was performed in the left portal circulation of pigs. The proposed method was applied to correct the VIFs for model fitting. Pharmacokinetic parameters fitted using corrected and uncorrected VIFs were compared between different lobes and visits. RESULTS: Simulation results demonstrated that the proposed method can improve accuracy of VIF estimation and pharmacokinetic fitting. In animal study results, pharmacokinetic fitting using corrected VIFs demonstrated changes in perfusion consistent with changes expected after PVE, whereas the perfusion estimates derived by uncorrected VIFs showed no significant changes. CONCLUSION: The proposed correction method improves accuracy of VIFs and therefore provides more precise pharmacokinetic fitting. This method may be promising in improving the reliability of perfusion quantification. Magn Reson Med 79:3093-3102, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29124782 TI - The effect of cigarette smoking on human seminal parameters, sperm chromatin structure and condensation. AB - Considerable debate still exists regarding the effects of cigarette smoking on male fertility. This work aimed to explore effects of cigarette smoking on semen parameters and DNA fragmentation on 95 infertile patients who were divided into infertile male nonsmokers (45) and infertile male smokers (50). Smokers were subdivided according to a number of cigarettes smoked per day into mild (<=10), moderate (11-20) and heavy smokers (>=21). Semen analysis, sperm chromatin condensation integrity with aniline blue staining and sperm viability were compared between the study groups. A significant decrease has been shown in sperm count (p = .006), progressive motility (p = <.001), percentage of normal forms (p = <.001) and viability (p = .002) between infertile nonsmoker and infertile smokers. The percentage of abnormal sperm chromatin condensation was significantly higher in smokers compared to nonsmokers (p = <.001). A linear correlation was detected between the extent of cigarette smoking and the degree of worsening in progressive motility (p = .001), total motility (p < .001), viability (p < .001) and normal morphology (p < .001). These results indicate that cigarette smoking has detrimental effects on semen parameters. It negatively affected all conventional semen parameters in addition to sperm chromatin condensation and sperm viability. These abnormalities were also proportional to the number of cigarettes smoked per day and to the duration of smoking. PMID- 29124783 TI - A key role for Rac and Pak signaling in neutrophil extracellular traps (NETs) formation defines a new potential therapeutic target. AB - NET formation in mice (NETosis) is supported by reactive oxygen species (ROS) production by NADPH oxidase and histone hypercitrullination by peptidylarginine deiminase 4 (PAD4). Rac1 and Rac2, expressed in polymorphonuclear neutrophils (PMNs), regulate the cytoskeleton, cell shape, adhesion, and migration and are also essential components of the NADPH oxidase complex. We aimed to explore the role of the Rac signaling pathway including the upstream guanosine exchange factor (GEF) activator, Vav, and a downstream effector, the p21-activated kinase, Pak, on NETosis in PMNs using a previously described flow-cytometry-based assay. Rac2-/- PMNs showed reduced levels of citrullinated histone H3 (H3Cit)-positive cells and defective NETosis. Rac1Delta/Delta ; Rac2-/- PMNs demonstrated a further reduction in PMA-induced H3Cit levels and a more profound impairment of NETosis than deletion of Rac2 alone, suggesting an overlapping role of these two highly related proteins. Genetic knockouts of Vav1, or Vav2, did not impair H3Cit response to phorbol myristate ester (PMA) or NETosis. Combined, Vav1 and Vav3 deletions decreased H3Cit response and caused a modest but significant impairment of NETosis. Pharmacologic inhibition of Pak by two inhibitors with distinct mechanisms of action, led to reduced H3Cit levels after PMA stimulation, as well as significant inhibition of NETosis. We validated the importance of Pak using Pak2Delta/Delta PMNs, which demonstrated significantly impaired histone H3 citrullination and NETosis. These data confirm and more comprehensively define the key role of the Rac signaling pathway in PMN NETosis. The Rac signaling cascade may represent a valuable target for inhibition of NETosis and related pathological processes. PMID- 29124785 TI - Time to address gender inequalities against female physicians. AB - Although the health care system depends heavily on female physicians, it discriminates against women and tends to concentrate female physicians' work in lower status occupations. Gender discrimination has structural, social, and cultural dimensions. Such discrimination is perceived differently by various stakeholders and the public. In addition, there is reluctance to publicly acknowledge gender discrimination, especially in the culturally conservative Middle East region. Gender discrimination leads to underrepresentation of female physicians in leadership roles and certain specialties and hence leads to less attention and understanding of the working conditions of female physicians and their roles in the health care system. The lack of accessible data in the region regarding gender discrimination among physicians leads to stakeholders failing to recognize the existence and magnitude of this type of discrimination. This article takes up the relatively neglected issue of gender discrimination in the health care workforce among the stakeholders of the Ministry of Health and Prevention of the United Arab Emirates. Future research should explore the extent of gender discrimination among physicians and the gender remuneration gap, together with other sorts of discrimination, perception of equal opportunity, and dominant stereotypes of men and women working in health care in relation to job obligation, promotion, retention, remuneration, and education. PMID- 29124784 TI - Dysfunction in emotion processing underlies functional (psychogenic) dystonia. AB - OBJECTIVE: We sought to determine whether abnormalities in emotion processing underlie functional (psychogenic) dystonia, one of the most common functional movement disorders. METHODS: Motor and emotion circuits were examined in 12 participants with functional dystonia, 12 with primary organic dystonia, and 25 healthy controls using functional magnetic resonance imaging at 4T and a finger tapping task (motor task), a basic emotion-recognition task (emotional faces task), and an intense-emotion stimuli task. RESULTS: There were no differences in motor task activation between groups. In the faces task, when compared with the other groups, functional dystonia patients showed areas of decreased activation in the right middle temporal gyrus and bilateral precuneus and increased activation in the right inferior frontal gyrus, bilateral occipital cortex and fusiform gyrus, and bilateral cerebellum. In the intense-emotion task, when compared with the other groups, functional dystonia patients showed decreased activation in the left insular and left motor cortices (compared to organic dystonia, they showed an additional decrease in activation in the right opercular cortex and right motor cortex) and increased activation in the left fusiform gyrus. CONCLUSIONS: Functional dystonia patients exhibited stimulus-dependent altered activation in networks involved in motor preparation and execution, spatial cognition, and attentional control. These results support the presence of network dysfunction in functional dystonia. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29124786 TI - Schwann cell precursors in health and disease. AB - Schwann cell precursors (SCPs) are frequently regarded as neural crest-derived cells (NCDCs) found in contact with axons during nerve formation. Nevertheless, cells with SCPs properties can be found up to the adulthood. They are well characterized with regard to both gene expression profile and cellular behavior for instance, proliferation, migratory capabilities and survival requirements-. They differ in origin regarding their anatomic location: even though most of them are derived from migratory NCCs, there is also contribution of the boundary cap neural crest cells (bNCCs) to the skin and other tissues. Many functions are known for SCPs in normal development, including nerve fasciculation and target innervation, arterial branching patterning and differentiation, and other morphogenetic processes. In addition, SCPs are now known to be a source of many neural (glia, endoneural fibroblasts, melanocytes, visceral neurons, and chromaffin cells) and non-neural-like (mesenchymal stromal cells, able e.g., to generate dentine-producing odontoblasts) cell types. Until now no reports of endoderm-like derivatives were reported so far. Interestingly, in the Schwann cell lineage only early SCPs are likely able to differentiate into melanocytes and bone marrow mesenchymal stromal cells. We have also herein discussed the literature regarding their role in repair as well as in disease mechanisms, such as in diverse cancers. Moreover, many caveats in our knowledge of SCPs biology are highlighted all through this article. Future research should expand more into the relevance of SCPs in pathologies and in other regenerative mechanisms which might bring new unexpected clinically-relevant knowledge. PMID- 29124787 TI - Reduced tubular degradation of glomerular filtered plasma albumin is a common feature in acute and chronic kidney disease. AB - Tubular epithelial cells take up and degrade plasma albumin filtered by the glomerulus. Tubular damage resulting in reduced albumin uptake or degradation has been suggested as one mechanism contributing to albuminuria in kidney disease. This study investigated whether tubular albumin uptake or degradation is altered in acute and chronic glomerular disease. Mouse models of acute glomerular injury (anti-GBM disease and LPS-induced albuminuria) and chronic disease (streptozotocin-induced diabetes and db/db mice) were examined. Mice were injected intravenously with Alexa-albumin plus DQ-albumin and killed 20 minutes later. Tubular uptake of albumin (Alexa-albumin) and albumin degradation (Dye Quenched (DQ)-albumin) was assessed in tissue sections via confocal microscopy. Tubular uptake of Alexa-albumin in the models of diabetic nephropathy was not different to normal mice. However, the fluorescence signal resulting from degradation of DQ-albumin was significantly reduced in db/db mice, and the ratio of degraded to intact albumin was reduced in both models. The ratio of degraded to intact albumin in tubules was also reduced in the anti-GBM model. In the LPS model, both tubular uptake and degradation of albumin were significantly reduced, with a substantial reduction in the ratio of degraded to intact albumin in tubules. LPS stimulation of cultured tubular epithelial cells inhibited albumin uptake, indicating a direct role for LPS in modifying tubular handling of albumin. In conclusion, reduced degradation of filtered albumin in the proximal tubule is a common feature of glomerular diseases. This may be a general mechanism whereby tubular dysfunction contributes to the development of albuminuria. PMID- 29124788 TI - Need for multiscale planning for conservation of urban bats. AB - For over a century there have been continual efforts to incorporate nature into urban planning. These efforts (i.e., urban reconciliation) aim to manage and create habitats that support biodiversity within cities. Given that species select habitat at different spatial scales, understanding the scale at which urban species respond to their environment is critical to the success of urban reconciliation efforts. We assessed species-habitat relationships for common bat species at 50-m, 500-m, and 1 km spatial scales in the Chicago (U.S.A.) metropolitan area and predicted bat activity across the greater Chicago region. Habitat characteristics across all measured scales were important predictors of silver-haired bat (Lasionycteris noctivagans) and eastern red bat (Lasiurus borealis) activity, and big brown bat (Eptesicus fuscus) activity was significantly lower at urban sites relative to rural sites. Open vegetation had a negative effect on silver-haired bat activity at the 50-m scale but a positive effect at the 500-m scale, indicating potential shifts in the relative importance of some habitat characteristics at different scales. These results demonstrate that localized effects may be constrained by broader spatial patterns. Our findings highlight the importance of considering scale in urban reconciliation efforts and our landscape predictions provide information that can help prioritize urban conservation work. PMID- 29124789 TI - What would James Parkinson think? A virtual dialogue on factors influencing the development of Parkinson's disease. PMID- 29124791 TI - Impact of different intensities of intermittent theta burst stimulation on the cortical properties during TMS-EEG and working memory performance. AB - Intermittent theta burst stimulation (iTBS) is a noninvasive brain stimulation technique capable of increasing cortical excitability beyond the stimulation period. Due to the rapid induction of modulatory effects, prefrontal application of iTBS is gaining popularity as a therapeutic tool for psychiatric disorders such as depression. In an attempt to increase efficacy, higher than conventional intensities are currently being applied. The assumption that this increases neuromodulatory may be mechanistically false for iTBS. This study examined the influence of intensity on the neurophysiological and behavioural effects of iTBS in the prefrontal cortex. Sixteen healthy participants received iTBS over prefrontal cortex at either 50, 75 or 100% resting motor threshold in separate sessions. Single-pulse TMS and concurrent electroencephalography (EEG) was used to assess changes in cortical reactivity measured as TMS-evoked potentials and oscillations. The n-back task was used to assess changes in working memory performance. The data can be summarised as an inverse U-shape relationship between intensity and iTBS plastic effects, where 75% iTBS yielded the largest neurophysiological changes. Improvement in reaction time in the 3-back task was supported by the change in alpha power, however, comparison between conditions revealed no significant differences. The assumption that higher intensity results in greater neuromodulatory effects may be false, at least in healthy individuals, and should be carefully considered for clinical populations. Neurophysiological changes associated with working memory following iTBS suggest functional relevance. However, the effects of different intensities on behavioural performance remain elusive in the present healthy sample. PMID- 29124792 TI - Nitromethane Bridged Bis(1,3,4-oxadiazoles): Trianionic Energetic Salts with Low Sensitivities. AB - Trianionic energetic salts based on one nitromethylene and two dinitromethyl anions were designed and synthesized. Interestingly, the unstable dinitromethylene group of diethyl 2,2'-((dinitromethylene)bis(1,3,4-oxadiazole 5,2-diyl))bis(2,2-dinitroacetate) (2) was changed to a mononitromethylene group by an aminolysis reaction to form triammonium ((nitromethanidylene)bis(1,3,4 oxadiazole-5,2-diyl))bis(dinitromethanide) (3), whereas in (dinitrobis(5 (trinitromethyl)-1,3,4-oxadiazol-2-yl)methan) 8 it was hydrolyzed to a carbonyl group resulting in (bis(5-(trinitromethyl)-1,3,4-oxadiazol-2-yl)methanone) 9. All the new compounds were fully characterized by infrared, multinuclear NMR spectra, and elemental analysis. The structures of triammonium ((nitromethanidylene)bis(1,3,4-oxadiazole-5,2-diyl))bis(dinitromethanide) dihydrate (3?2 H2 O) and bis(2-dinitromethyl-1,3,4-oxadiazole-5-yl)methanone (9) were further confirmed by single-crystal X-ray diffraction analysis. Based on their different physical and detonation properties, some of the energetic salts were found to exhibit good energetic performance and low sensitivity. PMID- 29124794 TI - Effect of Home Bleaching on the Translucency of CAD/CAM Systems. AB - PURPOSE: To evaluate the effect of a home bleaching agent (Opalescence PF) on the translucency of CAD/CAM ceramic systems. MATERIALS AND METHODS: The 28 sintered ceramic specimens (IPS Empress CAD and IPS e.max CAD; 15 mm long, 10 mm wide, 1 mm thick) were divided into two subgroups as control and bleaching groups (n = 7). Carbamide peroxide (CP), 16%, home bleaching agent was applied onto the surface of each specimen for 6 hours per day for 7 days. A spectrophotometer (VITA Easyshade Advance) was used to measure the CIE L* a* b* coordinates and the reflectance value (Y) of the specimens on white and black backgrounds. The translucency parameter (TP), contrast ratio (CR), and opalescence parameter (OP) of the specimens were calculated. The data were statistically analyzed using Kolmogorov-Smirnov, one-way ANOVA, Tukey's test, and Pearson's correlation. RESULTS: Statistically significant differences in the TP values after 16% CP bleaching treatment were observed (p ? 0.05); however, no significant differences were found in the OP and CR values after the surface treatment (p ? 0.05). CONCLUSIONS: According to our study, patients who have all-ceramic restorations in their mouths should be careful when using home bleaching agents, because whitening agents can affect the translucency of all-ceramic restorations such as e.max CAD and Empress CAD. PMID- 29124790 TI - Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature. AB - Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3). Findings from autopsies of heterozygous mutation carriers of genes that are traditionally considered recessively inherited are also discussed. Lewy bodies may be present in syndromes clinically distinctive from PD (eg, MPAN-related neurodegeneration) and absent in patients with clinical PD syndrome (eg, LRRK2-PD or Parkin-PD). Therefore, the authors can conclude that the presence of Lewy bodies are not specific to the diagnosis of PD and that PD can be diagnosed even in the absence of Lewy body pathology. Interventions that reduce alpha-synuclein load may be more justified in SNCA-PD or GBA-PD than in other genetic forms of PD. The number of reported genetic PD autopsies remains small, and there are limited genotype clinical-pathological-phenotype studies. Therefore, larger series of autopsies from genetic PD patients are required. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29124793 TI - Evidence for allosteric effects on p53 oligomerization induced by phosphorylation. AB - p53 is a tetrameric protein with a thermodynamically unstable deoxyribonucleic acid (DNA)-binding domain flanked by intrinsically disordered regulatory domains that control its activity. The unstable and disordered segments of p53 allow high flexibility as it interacts with binding partners and permits a rapid on/off switch to control its function. The p53 tetramer can exist in multiple conformational states, any of which can be stabilized by a particular modification. Here, we apply the allostery model to p53 to ask whether evidence can be found that the "activating" C-terminal phosphorylation of p53 stabilizes a specific conformation of the protein in the absence of DNA. We take advantage of monoclonal antibodies for p53 that measure indirectly the following conformations: unfolded, folded, and tetrameric. A double antibody capture enzyme linked-immunosorbent assay was used to observe evidence of conformational changes of human p53 upon phosphorylation by casein kinase 2 in vitro. It was demonstrated that oligomerization and stabilization of p53 wild-type conformation results in differential exposure of conformational epitopes PAb1620, PAb240, and DO12 that indicates a reduction in the "unfolded" conformation and increases in the folded conformation coincide with increases in its oligomerization state. These data highlight that the oligomeric conformation of p53 can be stabilized by an activating enzyme and further highlight the utility of the allostery model when applied to understanding the regulation of unstable and intrinsically disordered proteins. PMID- 29124795 TI - Proteomic analysis of lysine acetylation provides strong evidence for involvement of acetylated proteins in plant meiosis and tapetum function. AB - Protein lysine acetylation (KAC) is a dynamic and reversible post-translational modification that has important biological roles in many organisms. Although KAC has been shown to affect reproductive development and meiosis in yeast and animals, similar studies are largely lacking in flowering plants, especially proteome-scale investigations for particular reproductive stages. Here, we report results from a proteomic investigation to detect the KAC status of the developing rice anthers near the time of meiosis (RAM), providing strong biochemical evidence for roles of many KAC-affected proteins during anther development and meiosis in rice. We identified a total of 1354 KAC sites in 676 proteins. Among these, 421 acetylated proteins with 629 KAC sites are novel, greatly enriching our knowledge on KAC in flowering plants. Gene Ontology enrichment analysis showed chromatin silencing, protein folding, fatty acid biosynthetic process and response to stress to be over-represented. In addition, certain potentially specific KAC motifs in RAM were detected. Importantly, 357 rice meiocyte proteins were acetylated; and four proteins genetically identified to be important for rice tapetum and pollen development were acetylated on 14 KAC sites in total. Furthermore, 47 putative secretory proteins were detected to exhibit acetylated status in RAM. Moreover, by comparing our lysine acetylome with the RAM phosphoproteome we obtained previously, we proposed a correlation between KAC and phosphorylation as a potential modulatory mechanism in rice RAM. This study provides the first global survey of KAC in plant reproductive development, making a promising starting point for further functional analysis of KAC during rice anther development and meiosis. PMID- 29124796 TI - Resolving conflicts of interests: the need for reflection. PMID- 29124798 TI - Studies on the effectiveness of flipped classrooms: are we comparing apples to apples? PMID- 29124799 TI - The certainty of uncertainty: can we teach a constructive response? PMID- 29124801 TI - Responses to clinical uncertainty in Australian general practice trainees: a cross-sectional analysis. AB - CONTEXT: Tolerance for ambiguity is essential for optimal learning and professional competence. General practice trainees must be, or must learn to be, adept at managing clinical uncertainty. However, few studies have examined associations of intolerance of uncertainty in this group. OBJECTIVES: The aim of this study was to establish levels of tolerance of uncertainty in Australian general practice trainees and associations of uncertainty with demographic, educational and training practice factors. METHODS: A cross-sectional analysis was performed on the Registrar Clinical Encounters in Training (ReCEnT) project, an ongoing multi-site cohort study. Scores on three of the four independent subscales of the Physicians' Reaction to Uncertainty (PRU) instrument were analysed as outcome variables in linear regression models with trainee and practice factors as independent variables. RESULTS: A total of 594 trainees contributed data on a total of 1209 occasions. Trainees in earlier training terms had higher scores for 'Anxiety due to uncertainty', 'Concern about bad outcomes' and 'Reluctance to disclose diagnosis/treatment uncertainty to patients'. Beyond this, findings suggest two distinct sets of associations regarding reaction to uncertainty. Firstly, affective aspects of uncertainty (the 'Anxiety' and 'Concern' subscales) were associated with female gender, less experience in hospital prior to commencing general practice training, and graduation overseas. Secondly, a maladaptive response to uncertainty (the 'Reluctance to disclose' subscale) was associated with urban practice, health qualifications prior to studying medicine, practice in an area of higher socio-economic status, and being Australian-trained. CONCLUSIONS: This study has established levels of three measures of trainees' responses to uncertainty and associations with these responses. The current findings suggest differing 'phenotypes' of trainees with high 'affective' responses to uncertainty and those reluctant to disclose uncertainty to patients. More research is needed to examine the relationship between clinical uncertainty and clinical outcomes, temporal changes in tolerance for uncertainty, and strategies that might assist physicians in developing adaptive responses to clinical uncertainty. PMID- 29124802 TI - Response to: 'Professional identity in clinician-scientists: brokers between care and science'. PMID- 29124803 TI - Shifting discourses of widening access from 'why not you?' to 'we want you': only one part of the solution. PMID- 29124804 TI - Sleep is just part of the picture. PMID- 29124808 TI - Replies to the Letter to the editor. PMID- 29124807 TI - Combining anti-IgE with oral immunotherapy? PMID- 29124805 TI - Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes. AB - Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes-cleft lip alone (CL) and CL plus cleft palate (CLP)-are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 * 10-8 ). We also identified significant evidence of gene-gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. PMID- 29124809 TI - Kearns-Sayre syndrome in the absence of a mtDNA deletion? PMID- 29124810 TI - Environment learning from virtual exploration in individuals with down syndrome: the role of perspective and sketch maps. AB - BACKGROUND: Spatial knowledge about an environment is an important determinant of ability to move effectively within it and of personal autonomy. Individuals with Down's syndrome (DS) have difficulty managing configural visuospatial information. METHOD: Twenty-nine individuals with DS and 29 typically developing (TD) children, matched for mental age, learned about environments through virtual exploration using a route or survey view. A sketch map of the environment was or was not presented before exploration. Then the acquisition of configural knowledge (landmark locations) and route retracing were tested. RESULTS: Individuals with DS were able to acquire configural knowledge through virtual exploration in all presentation conditions, and generally performed no worse than matched TD children. However, they were not able to benefit from the conditions that facilitated acquisition of configural knowledge in TD children, that is, seeing a sketch map before exploring and exploring in survey (rather than route) view. As regards route retracing, individuals with DS paused more often than controls and tended to travel longer paths, which made them slower overall. CONCLUSIONS: DS reduces children's ability to benefit from additional survey information and may be related to difficulty in elaborating configural/simultaneous information. PMID- 29124811 TI - The end of one era and the beginning of another. PMID- 29124812 TI - Dartintinnus alderae n. g., n. sp., a Brackish Water Tintinnid (Ciliophora, Spirotrichea) with Dual-ended Lorica Collapsibility. AB - A tintinnid ciliate isolated from waters of the Thames River (Connecticut, USA) is described through combined in vivo observation, protargol impregnation, and phylogenetic analysis. The novel genus Dartintinnus and its type species, D. alderae are distinct from established tintinnid taxa by a lorica that collapses on both anterior and posterior ends. Dartintinnus is placed in the family Eutintinnidae based on a hyaline, elongated lorica opened at both ends, a ciliary pattern including a ventral kinety, at least one dorsal kinety, and right, left and lateral fields, and a sister relationship with Eutintinnus in gene trees. Main differences between D. alderae and Eutintinnus species include a 5.5-6.5% divergence in the small subunit rRNA gene, the geometry of the lorica (resembling an isosceles tetrahedron when collapsed vs. a cylinder, respectively), the number of macronuclear nodules (two vs. four), and the number of dorsal kineties (one vs. usually two). Considering the features of the new genus, we improve the diagnosis of the family Eutintinnidae, including the presence of a lateral ciliary field that had been overlooked in some Eutintinnus species. This work exemplifies the potential for novel diversity, even in these relatively well studied protists, and the importance of an integrated approach for the description of tintinnid taxa. PMID- 29124813 TI - A Simplified Quantitative Method to Measure Brain Shifts in Patients with Middle Cerebral Artery Stroke. AB - BACKGROUND AND PURPOSE: A standardized and validated method to measure brain shifts in malignant middle cerebral artery (MCA) stroke with decompressive hemicraniectomy (DHC) could facilitate clinical decision making, prognostication, and comparison of results between studies. METHODS: We tested for reliability simplified methods to measure transcalvarial herniation, midline brain shift, and the contralateral cerebral ventricular atrium in malignant MCA stroke after DHC. Multiple raters measured brain shifts on post-DHC computed tomography (CT) scans with aligned and unaligned slice orientations in 25 patients. We compared the simplified measurements to previously reported more meticulous measurements. RESULTS: The simplified measurements correlate well with the more meticulous measurements on both aligned and unaligned CTs (intraclass correlation coefficients .72-.89). CONCLUSIONS: These simplified and expedient methods of measuring brain shifts in malignant MCA stroke after DHC correlate well with the more meticulous methods. PMID- 29124814 TI - Validation of an updated Associative Transcriptomics platform for the polyploid crop species Brassica napus by dissection of the genetic architecture of erucic acid and tocopherol isoform variation in seeds. AB - An updated platform was developed to underpin association genetics studies in the polyploid crop species Brassica napus (oilseed rape). Based on 1.92 * 1012 bases of leaf mRNAseq data, functional genotypes, comprising 355 536 single-nucleotide polymorphism markers and transcript abundance were scored across a genetic diversity panel of 383 accessions using a transcriptome reference comprising 116 098 ordered coding DNA sequence (CDS) gene models. The use of the platform for Associative Transcriptomics was first tested by analysing the genetic architecture of variation in seed erucic acid content, as high-erucic rapeseed oil is highly valued for a variety of applications in industry. Known loci were identified, along with a previously undetected minor-effect locus. The platform was then used to analyse variation for the relative proportions of tocopherol (vitamin E) forms in seeds, and the validity of the most significant markers was assessed using a take-one-out approach. Furthermore, the analysis implicated expression variation of the gene Bo2g050970.1, an orthologue of VTE4 (which encodes a gamma-tocopherol methyl transferase converting gamma-tocopherol into alpha-tocopherol) associated with the observed trait variation. The establishment of the first full-scale Associative Transcriptomics platform for B. napus enables rapid progress to be made towards an understanding of the genetic architecture of trait variation in this important species, and provides an exemplar for other crops. PMID- 29124815 TI - Diluted seawater affects phytohormone receptors and maintains the protonema stage in Physcomitrella patens. AB - Due to its highly efficient homologous recombination ability and unusual evolutionary position, the moss Physcomitrella patens has begun to attract more attention in genetic and evolutionary studies. Protonema, the filament stage of the gametophyte, is of great significance in P. patens protoplast isolation. Moreover, protonema is widely used in genetic engineering. However, difficulties in the induction and state maintenance of protonema restrict its wider application. In this work, protonema was induced efficiently in a diluted seawater medium, and the filamentous state was maintained without further cell differentiation. The developmental process of the protonema resumed, progressing to bud assembly and gametophore formation after transfer to freshwater medium. In addition, a transcriptome analysis showed that plant hormone signal transduction pathways were downregulated when protonema was grown in diluted seawater medium. Consistent with the transcriptome results, the protonema failed to respond to the addition of indole-3-acetic acid and 6-benzylaminopurine to the diluted seawater medium. Based on these results, we concluded that diluted seawater medium blocks the differentiation of protonema. This result could provide a novel insight to benefit future protonema production. PMID- 29124816 TI - The Cannabis Abuse Screening Test and the DSM-5 in the general population: Optimal thresholds and underlying common structure using multiple factor analysis. AB - The Cannabis Abuse Screening Test (CAST) aims at screening the problematic use of cannabis. It has never been validated against the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and its relationships with this latter have never been studied. We used a probabilistic telephone survey collected in 2014 (1351 past-year cannabis users aged 15-64) implementing the CAST and a DSM-5 adaptation of the Munich Composite International Diagnostic Interview assessing cannabis use disorders. Data were weighted, and CAST items were considered categorical. Factorial structures were assessed with confirmatory factor analyses; the relationships between the instruments were studied with multiple factor analysis (MFA). One factor for the DSM-5 and two correlated factors for the CAST were the best confirmatory factor analyses solutions. The CAST thresholds for screening moderate/severe and severe cannabis use disorders were 5 (sensitivity = 78.2% and specificity = 79.6%) and 8 (sensitivity = 86.0% and specificity = 86.7%), respectively. The MFA identified two orthogonal dimensions: The first was equally shared by both instruments; the second was the second CAST dimension (extreme frequencies of use before midday and alone, memory problems, and reproaches from friends/family). The CAST structure and screening properties were confirmed. The MFA explains its screening performances by its first dimension and identified the problematic patterns (the second dimension) that are not captured by the DSM-5. PMID- 29124818 TI - Diagnosis and management of patients with enhanced myometrial vascularity associated with retained products of conception. AB - OBJECTIVES: To assess the complication rate, including estimated amount of blood loss, in patients undergoing dilation and curettage (D&C) for the treatment of retained products of conception with markedly enhanced myometrial vascularity mimicking arteriovenous malformation. METHODS: This was a retrospective medical records review study of patients with retained products of conception with enhanced myometrial vascularity presenting to our ultrasound unit between August 2015 and August 2017. Color/power Doppler imaging was used subjectively to identify the degree and extent of vascularity. All patients underwent D&C, and their operative reports and medical records were reviewed to see if ultrasound guidance was used, to ascertain estimated blood loss and to identify complications during or after the procedure. RESULTS: The study group included 31 patients, of whom seven had retained products of conception after a vaginal delivery and 24 had retained products of conception after a first-trimester termination or miscarriage. The largest dimension of the region of enhanced myometrial vascularity ranged from 10 mm to 53 mm, with 14/31 having a width of >= 20 mm. Fifteen patients underwent a standard D&C procedure, 13 an ultrasound guided procedure and three hysteroscopy. Estimated operative blood loss varied from negligible to a maximum of 400 mL. There were no intraoperative complications, although one patient was treated for presumed endometritis. CONCLUSIONS: An increasing number of studies describe the enhanced myometrial vascularity associated with retained products of conception as 'acquired arteriovenous malformation', with some recommending management with uterine artery embolization. Our study demonstrates that the enhanced myometrial vascularity is associated with retained products of conception, and surgical removal by D&C, possibly with the aid of ultrasound guidance or hysteroscopy, is a safe treatment option. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29124817 TI - Why the Flavin Adenine Dinucleotide (FAD) Cofactor Needs To Be Covalently Linked to Complex II of the Electron-Transport Chain for the Conversion of FADH2 into FAD. AB - A covalently bound flavin cofactor is predominant in the succinate-ubiquinone oxidoreductase (SQR; Complex II), an essential component of aerobic electron transport, and in the menaquinol-fumarate oxidoreductase (QFR), the anaerobic counterpart, although it is only present in approximately 10 % of the known flavoenzymes. This work investigates the role of this 8alpha-N3-histidyl linkage between the flavin adenine dinucleotide (FAD) cofactor and the respiratory Complex II. After parameterization with DFT calculations, classical molecular dynamics simulations and quantum-mechanics calculations for Complex II:FAD and Complex II:FADH2 , with and without the covalent bond, were performed. It was observed that the covalent bond is essential for the active-center arrangement of the FADH2 /FAD cofactor. Removal of this bond causes a displacement of the isoalloxazine group, which influences interactions with the protein, flavin solvation, and possible proton-transfer pathways. Specifically, for the noncovalently bound FADH2 cofactor, the N1 atom moves away from the His-A365 and His-A254 residues and the N5 atom moves away from the glutamine-62A residue. Both of the histidine and glutamine residues interact with a chain of water molecules that cross the enzyme, which is most likely involved in proton transfer. Breaking this chain of water molecules could thereby compromise proton transfer across the two active sites of Complex II. PMID- 29124819 TI - The limited role of differential fractionation in genome content variation and function in maize (Zea mays L.) inbred lines. AB - Maize is a diverse paleotetraploid species with considerable presence/absence variation and copy number variation. One mechanism through which presence/absence variation can arise is differential fractionation. Fractionation refers to the loss of duplicate gene pairs from one of the maize subgenomes during diploidization. Differential fractionation refers to non-shared gene loss events between individuals following a whole-genome duplication event. We investigated the prevalence of presence/absence variation resulting from differential fractionation in the syntenic portion of the genome using two whole-genome de novo assemblies of the inbred lines B73 and PH207. Between these two genomes, syntenic genes were highly conserved with less than 1% of syntenic genes being subject to differential fractionation. The few variably fractionated syntenic genes that were identified are unlikely to contribute to functional phenotypic variation, as there is a significant depletion of these genes in annotated gene sets. In further comparisons of 60 diverse inbred lines, non-syntenic genes were six times more likely to be variable than syntenic genes, suggesting that comparisons among additional genome assemblies are not likely to result in the discovery of large-scale presence/absence variation among syntenic genes. PMID- 29124820 TI - Anatomical and electrical remodeling with incomplete left atrial appendage ligation: Results from the LAALA-AF registry. PMID- 29124821 TI - Ring/Chain Morphology Control in Overall-Neutral, Internally Ion-Paired Supramolecular Polymers. AB - The self-assembly of internally ion-paired, neutral AA/BB-type supramolecular polymers composed of complementary di-ionizable homoditopic pairs of monomers is reported. Host-to-guest double-proton transfer mediates the recognition between bis-calix[5]arenedicarboxylic acids and alpha,omega-diaminoalkanes to yield cyclic, doughnut-shaped assemblies with morphologies (i.e., cyclic vs. linear) that can be controlled by means of external chemical stimuli. The behavior of these intriguing aggregates, both in solution and on surfaces, has been investigated by a combination of 1 H and DOSY NMR spectroscopy, light-scattering, and atomic force microscopy. PMID- 29124823 TI - Differences between child and adult large-scale functional brain networks for reading tasks. AB - Reading is an important high-level cognitive function of the human brain, requiring interaction among multiple brain regions. Revealing differences between children's large-scale functional brain networks for reading tasks and those of adults helps us to understand how the functional network changes over reading development. Here we used functional magnetic resonance imaging data of 17 adults (19-28 years old) and 16 children (11-13 years old), and graph theoretical analyses to investigate age-related changes in large-scale functional networks during rhyming and meaning judgment tasks on pairs of visually presented Chinese characters. We found that: (1) adults had stronger inter-regional connectivity and nodal degree in occipital regions, while children had stronger inter-regional connectivity in temporal regions, suggesting that adults rely more on visual orthographic processing whereas children rely more on auditory phonological processing during reading. (2) Only adults showed between-task differences in inter-regional connectivity and nodal degree, whereas children showed no task differences, suggesting the topological organization of adults' reading network is more specialized. (3) Children showed greater inter-regional connectivity and nodal degree than adults in multiple subcortical regions; the hubs in children were more distributed in subcortical regions while the hubs in adults were more distributed in cortical regions. These findings suggest that reading development is manifested by a shift from reliance on subcortical to cortical regions. Taken together, our study suggests that Chinese reading development is supported by developmental changes in brain connectivity properties, and some of these changes may be domain-general while others may be specific to the reading domain. PMID- 29124824 TI - Why artificial light at night should be a focus for global change research in the 21st century. AB - The environmental impacts of artificial light at night have been a rapidly growing field of global change science in recent years. Yet, light pollution has not achieved parity with other global change phenomena in the level of concern and interest it receives from the scientific community, government and nongovernmental organizations. This is despite the globally widespread, expanding and changing nature of night-time lighting and the immediacy, severity and phylogenetic breath of its impacts. In this opinion piece, we evidence 10 reasons why artificial light at night should be a focus for global change research in the 21st century. Our reasons extend beyond those concerned principally with the environment, to also include impacts on human health, culture and biodiversity conservation more generally. We conclude that the growing use of night-time lighting will continue to raise numerous ecological, human health and cultural issues, but that opportunities exist to mitigate its impacts by combining novel technologies with sound scientific evidence. The potential gains from appropriate management extend far beyond those for the environment, indeed it may play a key role in transitioning towards a more sustainable society. PMID- 29124825 TI - Addressing vulnerability: opening a new door to improved outcomes in acute heart failure. PMID- 29124826 TI - Comparing the behavioural impact of a nudge-based handwashing intervention to high-intensity hygiene education: a cluster-randomised trial in rural Bangladesh. AB - OBJECTIVE: To determine the impact of environmental nudges on handwashing behaviours among primary school children as compared to a high-intensity hygiene education intervention. METHODS: In a cluster-randomised trial (CRT), we compared the rates of handwashing with soap (HWWS) after a toileting event among primary school students in rural Bangladesh. Eligible schools (government run, on-site sanitation and water, no hygiene interventions in last year, fewer than 450 students) were identified, and 20 schools were randomly selected and allocated without blinding to one of four interventions, five schools per group: simultaneous handwashing infrastructure and nudge construction, sequential infrastructure then nudge construction, simultaneous infrastructure and high intensity hygiene education (HE) and sequential handwashing infrastructure and HE. The primary outcome, incidence of HWWS after a toileting event, was compared between the intervention groups at different data collection points with robust Poisson regression analysis with generalised estimating equations, adjusting for school-level clustering of outcomes. RESULTS: The nudge intervention and the HE intervention were found to be equally effective at sustained impact over 5 months post-intervention (adjusted IRR 0.81, 95% CI 0.61-1.09). When comparing intervention delivery timing, the simultaneous delivery of the HE intervention significantly outperformed the sequential HE delivery (adjusted IRR 1.58 CI 1.20 2.08), whereas no significant difference was observed between sequential and simultaneous nudge intervention delivery (adjusted IRR 0.75, 95% CI 0.48-1.17). CONCLUSION: Our trial demonstrates sustained improved handwashing behaviour 5 months after the nudge intervention. The nudge intervention's comparable performance to a high-intensity hygiene education intervention is encouraging. PMID- 29124822 TI - Concise Review: Advanced Cell Culture Models for Diamond Blackfan Anemia and Other Erythroid Disorders. AB - In vitro surrogate models of human erythropoiesis made many contributions to our understanding of the extrinsic and intrinsic regulation of this process in vivo and how they are altered in erythroid disorders. In the past, variability among the levels of hemoglobin F produced by adult erythroblasts generated in vitro by different laboratories identified stage of maturation, fetal bovine serum, and accessory cells as "confounding factors," that is, parameters intrinsically wired in the experimental approach that bias the results observed. The discovery of these factors facilitated the identification of drugs that accelerate terminal maturation or activate specific signaling pathways for the treatment of hemoglobinopathies. It also inspired studies to understand how erythropoiesis is regulated by macrophages present in the erythroid islands. Recent cell culture advances have greatly increased the number of human erythroid cells that can be generated in vitro and are used as experimental models to study diseases, such as Diamond Blackfan Anemia, which were previously poorly amenable to investigation. However, in addition to the confounding factors already identified, improvement in the culture models has introduced novel confounding factors, such as possible interactions between signaling from cKIT, the receptor for stem cell factor, and from the glucocorticoid receptor, the cell proliferation potential and the clinical state of the patients. This review will illustrate these new confounding factors and discuss their clinical translation potential to improve our understanding of Diamond Blackfan Anemia and other erythroid disorders. Stem Cells 2018;36:172-179. PMID- 29124828 TI - Extraordinarily Large Ferromagnetic Coupling (J>=150 cm-1 ) by Electron Delocalization in a Heterometallic Mo?Mo-Ni Chain Complex. AB - The new heterometallic chain compounds Mo2 Ni(dpa)4 Cl2 (1) and [Mo2 Ni(dpa)4 Cl2 ]OTf (2) (dpa=2,2'-dipyridylamine) have been prepared and studied by crystallography and magnetic susceptibility, among other methods. Oxidation of 1 to 2 removes an electron from the multiply bonded Mo2 unit, consistent with the formulation of 2 containing a (Mo2 )5+ ???(Ni)2+ core. While 1 contains an S=1, pseudo-octahedral NiII ion, 2 has an S=3/2 ground state, in which the two NiII unpaired electrons, one in a localized delta-orbital and one in a heavily delocalized sigmanb -orbital are joined by an unpaired electron in a Mo-Mo delta orbital. The S=3/2 ground state is persistent to 300 K, evidencing strong ferromagnetic coupling of the Mo2 and Ni spins with J>=150 cm-1 . This ferromagnetic interaction occurs via delocalization of a sigmanb -electron across all three metal atoms, forcing ferromagnetic alignment of electrons in orthogonal Ni and Mo2 delta-symmetry orbitals. We anticipate that this new means of coupling spins can be used as a design principle for the preparation of new compounds with high spin ground states. PMID- 29124829 TI - Anatomical and electrical remodeling with incomplete left atrial appendage ligation: Results from the LAALA-AF registry. PMID- 29124827 TI - Recovery from temporary endoplasmic reticulum stress in plants relies on the tissue-specific and largely independent roles of bZIP28 and bZIP60, as well as an antagonizing function of BAX-Inhibitor 1 upon the pro-adaptive signaling mediated by bZIP28. AB - The unfolded protein response (UPR) is an ancient signaling pathway that commits to life-or-death outcomes in response to proteotoxic stress in the endoplasmic reticulum (ER). In plants, the membrane-tethered transcription factor bZIP28 and the ribonuclease-kinase IRE1 along with its splicing target, bZIP60, govern the two cytoprotective UPR signaling pathways known to date. The conserved ER membrane-associated BAX inhibitor 1 (BI1) modulates ER stress-induced programmed cell death through yet-unknown mechanisms. Despite the significance of the UPR for cell homeostasis, in plants the regulatory circuitry underlying ER stress resolution is still largely unmapped. To gain insights into the coordination of plant UPR strategies, we analyzed the functional relationship of the UPR modulators through the analysis of single and higher order mutants of IRE1, bZIP60, bZIP28 and BI1 in experimental conditions causing either temporary or chronic ER stress. We established a functional duality of bZIP28 and bZIP60, as they exert partially independent tissue-specific roles in recovery from ER stress, but redundantly actuate survival strategies in chronic ER stress. We also discovered that BI1 attenuates the pro-survival function of bZIP28 in ER stress resolution and, differently to animal cells, it does not temper the ribonuclease activity of inositol-requiring enzyme 1 (IRE1) under temporary ER stress. Together these findings reveal a functional independence of bZIP28 and bZIP60 in plant UPR, and identify an antagonizing role of BI1 in the pro-adaptive signaling mediated by bZIP28, bringing to light the distinctive complexity of the unfolded protein response (UPR) in plants. PMID- 29124830 TI - Janus kinase inhibitors for the use of alopecia areata: A promising therapeutic of the future. PMID- 29124831 TI - A prospective observational study to compare efficacy of topical triamcinolone acetonide 0.1% oral paste, oral methotrexate, and a combination of topical triamcinolone acetonide 0.1% and oral methotrexate in moderate to severe oral lichen planus. AB - Topical corticosteroids are considered to be the most effective treatment for oral lichen planus (OLP). Methotrexate has been found to be effective in extensive cutaneous lichen planus. The objectives of the study were to evaluate the clinical efficacy and safety of topical triamcinolone 0.1% oral paste, oral methotrexate and a combination of these in symptomatic moderate-to- severe OLP. Forty-five patients were recruited and were allocated to three treatment arms with 15 patients in each treatment arm. They were treated for a period of 16 weeks or until complete clinical remission, whichever was earlier. The parameters assessed were clinical severity score, visual analogue score, and quality of life impairment questionnaire score. Forty-three patients completed the study. All three treatment modalities were effective. The patients in the combination group had significantly better reduction in the outcome parameters assessed compared to the other two groups. Nine patients achieved complete clinical remission, 6 in the combination group and 3 in the topical triamcinolone group. Systemic methotrexate, alone or in combination with topical triamcinolone, is effective in management of moderate to severe OLP. PMID- 29124832 TI - How should new orthopaedic implants be introduced: an example and recommendations for best practice. AB - Continued advancements in orthopaedics have led to the development of many new implants; many of these are being utilized in clinical practice with little or no evidence base for their safety or effectiveness. Highly publicized failures in orthopaedic technology have led to an increased awareness of this issue in both medical and non-medical circles. In most cases, the significant harm caused to the public could have been avoided by the appropriately staged implementation of new implants. This review comments on the current literature regarding the optimal practice for the introduction of new orthopaedic technology. The authors' experience with the failed ESKA Adapter Short-stem/Modular Hip is described; the methodology used for its evaluation is used as a basis to discuss what was successful about the process and also give warning on what could be improved upon. The ideal practice requires new orthopaedic implants to be evaluated by high-volume surgeons in specialist orthopaedic hospitals. These studies should include biomechanical studies, radiostereophotometric analysis, implant retrieval and outcome assessment. Results and complications should be reported early to the appropriate joint registry and regulatory body. Once a suitable evidence base has developed, the implant can be distributed into wider clinical practice or withdrawn. These recommendations aim to protect the patient and public from harm while allowing surgical innovation to still continue. PMID- 29124833 TI - A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3'UTR encoded, aggregation-inducing motif. AB - Single-nucleotide variants that abolish the stop codon ("nonstop" alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C-terminally extended protein depends on the absence or presence of a downstream in-frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized. In a family with autosomal dominant Charcot-Marie Tooth disease type 2, that is, an axonopathy affecting sensory neurons as well as lower motor neurons, we identified a heterozygous nonstop variant in REEP1. Mutations in this gene have classically been associated with the upper motor neuron disorder hereditary spastic paraplegia (HSP). We show that the C-terminal extension resulting from the nonstop variant triggers self-aggregation of REEP1 and of several reporters. Our findings support the recently proposed concept of 3'UTR-encoded "cryptic amyloidogenic elements." Together with a previous report on an aggregation-prone REEP1 deletion variant in distal hereditary motor neuropathy, they also suggest that toxic gain of REEP1 function, rather than loss of-function as relevant for HSP, specifically affects lower motor neurons. A search for similar correlations between genotype, phenotype, and effect of mutant protein may help to explain the wide clinical spectra also in other genetically determined disorders. PMID- 29124834 TI - Prevalence and characterisation of Staphylococcus aureus causing community acquired skin and soft tissue infections on Java and Bali, Indonesia. AB - OBJECTIVES: To define the role of Staphylococcus aureus in community settings among patients with skin and soft tissue infections (SSTI) in Indonesia. METHODS: Staphylococcus aureus were cultured from anterior nares, throat and wounds of 567 ambulatory patients presenting with SSTI. The mecA gene and genes encoding Panton Valentine leukocidin (PVL; lukF-PV and lukS-PV) and exfoliative toxin (ET; eta and etb) were determined by PCR. Clonal relatedness among methicillin-resistant S. aureus (MRSA) and PVL-positive S. aureus was analysed using multilocus variable-number tandem-repeat analysis (MLVA) typing, and multilocus sequence typing (MLST) for a subset of isolates. Staphylococcal cassette chromosome mec (SCCmec) was determined for all MRSA isolates. Moreover, determinants for S. aureus SSTI, and PVL/ET-positive vs PVL/ET-negative S. aureus were assessed. RESULTS: Staphylococcus aureus were isolated from SSTI wounds of 257 (45.3%) patients, eight (3.1%) of these were MRSA. Genes encoding PVL and ETs were detected in 21.8% and 17.5% of methicillin-susceptible S. aureus (MSSA), respectively. PVL-positive MRSA was not detected. Nasopharyngeal S. aureus carriage was an independent determinant for S. aureus SSTI (odds ratio [OR] 1.8). Primary skin infection (OR 5.4) and previous antibiotic therapy (OR 3.5) were associated with PVL-positive MSSA. Primary skin infection (OR 2.2) was the only factor associated with ET-positive MSSA. MLVA typing revealed two more prevalent MSSA clusters. One ST1-MRSA-SCCmec type IV isolate and a cluster of ST239-MRSA SCCmec type III were found. CONCLUSIONS: Community-acquired SSTI in Indonesia was frequently caused by PVL-positive MSSA, and the hospital-associated ST239-MRSA may have spread from the hospital into the community. PMID- 29124836 TI - Living Ab Initio Emulsion Polymerization of Methyl Methacrylate in Water Using a Water-Soluble Organotellurium Chain Transfer Agent under Thermal and Photochemical Conditions. AB - Ab initio emulsion polymerization of methyl methacrylate (MMA) using a water soluble organotellurium chain transfer agent in the presence of the surfactant Brij 98 in water is reported. Polymerization proceeded under both thermal and visible light-irradiation conditions, giving poly(methyl methacrylate) (PMMA) with controlled molecular weight and low dispersity (D<1.5). Despite the formation of an opaque latex, the photoactivation of the organotellurium dormant species took place efficiently, as demonstrated by the quantitative monomer conversion and temporal control. Control of polymer particle size (PDI<0.030) was also achieved using a semi-batch monomer addition process. The PMMA polymer in the particles retained high end-group fidelity and was successfully used for the synthesis of block copolymers. PMID- 29124835 TI - Clinical characteristics and outcomes of Castleman disease: A multicenter study of 185 Chinese patients. AB - Castleman disease (CD) is a rare lymphoproliferative disorder. To assess the clinical features, outcomes, and prognostic factors of this disease, we retrospectively analyzed 185 HIV-negative CD patients from four medical centers in southern China. The median age was 37 years. One hundred and twenty-one patients (65.4%) were classified as unicentric CD (UCD) and 64 patients (34.6%) were classified as multicentric CD (MCD). The histology subtype was hyaline vascular for 132 patients (71.4%), plasma cell for 50 patients (27%), and mixed type for 3 patients (1.6%). The 5-year overall survival (OS) of 185 CD cases was 80.3%. All UCD patients underwent surgical excision, whereas the treatment strategies of MCD patients were heterogeneous. The outcome for UCD patients was better than MCD patients, with 5-year OS rates of 93.6% and 51.2%, respectively. In further analysis of the MCD subgroup, a multivariate analysis using a Cox regression model revealed that age, splenomegaly and pretreatment serum albumin level were independent prognostic factors for OS. This multicenter study comprising the largest sample size to date suggested that MCD is a distinct entity from UCD with a significantly worse outcome. Older age (>=40 years), splenomegaly, and hypoalbuminemia were risk factors for poorer MCD prognosis. PMID- 29124837 TI - Synthetic Ion Channels and DNA Logic Gates as Components of Molecular Robots. AB - A molecular robot is a next-generation biochemical machine that imitates the actions of microorganisms. It is made of biomaterials such as DNA, proteins, and lipids. Three prerequisites have been proposed for the construction of such a robot: sensors, intelligence, and actuators. This Minireview focuses on recent research on synthetic ion channels and DNA computing technologies, which are viewed as potential candidate components of molecular robots. Synthetic ion channels, which are embedded in artificial cell membranes (lipid bilayers), sense ambient ions or chemicals and import them. These artificial sensors are useful components for molecular robots with bodies consisting of a lipid bilayer because they enable the interface between the inside and outside of the molecular robot to function as gates. After the signal molecules arrive inside the molecular robot, they can operate DNA logic gates, which perform computations. These functions will be integrated into the intelligence and sensor sections of molecular robots. Soon, these molecular machines will be able to be assembled to operate as a mass microrobot and play an active role in environmental monitoring and in vivo diagnosis or therapy. PMID- 29124838 TI - Protuberant heterotopic ossification following distal biceps tendon repair. PMID- 29124839 TI - Expanding the Scope of Sortase-Mediated Ligations by Using Sortase Homologues. AB - Sortase-catalyzed transacylation reactions are widely used for the construction of non-natural protein derivatives. However, the most commonly used enzyme for these strategies (sortase A from Staphylococcus aureus) is limited by its narrow substrate scope. To expand the range of substrates compatible with sortase mediated reactions, we characterized the in vitro substrate preferences of eight sortase A homologues. From these studies, we identified sortase A enzymes that recognize multiple substrates that are unreactive toward sortase A from S. aureus. We further exploited the ability of sortase A from Streptococcus pneumoniae to recognize an LPATS substrate to perform a site-specific modification of the N-terminal serine residue in the naturally occurring antimicrobial peptide DCD-1L. Finally, we unexpectedly observed that certain substrates (LPATXG, X=Nle, Leu, Phe, Tyr) were susceptible to transacylation at alternative sites within the substrate motif, and sortase A from S. pneumoniae was capable of forming oligomers. Overall, this work provides a foundation for the further development of sortase enzymes for use in protein modification. PMID- 29124840 TI - Electrochemistry of Metalloproteins Attached through Functional Self-Assembled Monolayers on Gold and Ferromagnetic Electrodes. AB - We report the experimental results of a study of the electron-transfer processes of redox-active metalloproteins bound to mixed self-assembled monolayers (SAMs) on magnetic (nickel or ultrathin gold-coated nickel) or nonmagnetic (gold) electrodes. Metalloproteins, such as hemoglobin (Hb), Cytochrome C (Cyt C), and Cyt C oxidase, are attached through electrostatic interactions to the free carboxylate or imidazole groups present in the mixed SAMs. The formation of both mixed SAMs and SAM/metalloprotein heterostructures were confirmed by using advanced surface analysis techniques, such as polarization modulation infrared reflection absorption spectroscopy and aqueous contact angle measurements. Electrochemical measurements indicated a stronger electronic coupling between Hb and Cyt C oxidase and the mixed-SAM-coated gold or gold-coated-nickel electrodes, whereas a weaker coupling was found between the protein and the pure nickel electrode. Surface coverage and the electron-transfer rate constant were estimated from the cyclic voltammetry data. PMID- 29124841 TI - Regulation of cysteine residues in LsrB proteins from Sinorhizobium meliloti under free-living and symbiotic oxidative stress. AB - The development of legume nitrogen-fixing nodules is regulated by reactive oxygen species (ROS) produced by symbionts. Several regulators from Rhizobium are involved in ROS sensing. In a previous study, we found that Sinorhizobium meliloti LsrB regulates lipopolysaccharide production and is associated with H2 O2 accumulation in alfalfa (Medicago sativa) nodules. However, its underlying regulatory mechanism remains unclear. Here, we report that the cysteine residues in LsrB are required for adaptation to oxidative stress, gene expression, alfalfa nodulation and nitrogen fixation. Moreover, LsrB directly activated the transcription of lrp3 and gshA (encoding gamma-glutamylcysteine synthetase, responsible for glutathione synthesis) and this regulation required the cysteine (Cys) residues in the LsrB substrate-binding domain. The Cys residues could sense oxidative stress via the formation of intermolecular disulfide bonds, generating LsrB dimers and LsrB-DNA complexes. Among the Cys residues, C238 is a positive regulatory site for the induction of downstream genes, whereas C146 and C275 play negative roles in the process. The lsrB mutants with Cys-to-Ser substitutions displayed altered phenotypes in respect to their adaptation to oxidative stress, nodulation and nitrogen fixation-related plant growth. Our findings demonstrate that S. meliloti LsrB modulates alfalfa nodule development by directly regulating downstream gene expression via a post-translational strategy. PMID- 29124843 TI - Splenic vessel preservation versus splenic vessel resection in laparoscopic spleen-preserving distal pancreatectomy. AB - BACKGROUND: Laparoscopic spleen-preserving distal pancreatectomy for low-grade malignant pancreas tumours was recently demonstrated and can be performed with splenic vessel preservation (SVP) or splenic vessel resection (SVR). Whether one approach is superior to another is still a matter of debate. METHODS: A systematic literature search (PubMed, Embase, Science Citation Index, Springer Link and Cochrane Central Register of Controlled Trials) was performed. Pooled intra- and post-operative outcomes were evaluated. Stratified and sensitivity analyses were performed to explore heterogeneity between studies and to assess the effects of the study qualities. RESULTS: A total of six studies were included. There was no significant difference for SVR and SVP in terms of overall post-operative complications and the pooled odds ratio (OR) was 0.87 (95% confidence interval (CI) 0.55-1.38, I2 = 25%). Meta-analysis on the pooled outcome of intraoperative operative time and blood loss favoured SVR; the mean differences were 18.64 min (95% CI 6.91-30.37 min, I2 = 21%) and 65.67 mL (95% CI 18.88-112.45 mL, I2 = 48%), respectively. Subgroup analysis showed a decrease incidences in perigastric varices (OR = 0.07, 95% CI 0.03-0.18, I2 = 29%) and splenic infarction (OR = 0.16, 95% CI 0.08-0.32, I2 = 0%) in SVP. CONCLUSION: For selected patients who underwent laparoscopic spleen-preserving distal pancreatectomy, an increased preference for the SVP technique should be suggested considering its short-term benefits. However, in case of large tumours that distort and compress vessel course, SVR could be applied with acceptable splenic ischaemia and perigastric varices. PMID- 29124844 TI - Influence of pulsed and continuous substrate inputs on freshwater bacterial community composition and functioning in bioreactors. AB - Aquatic environments are typically not homogenous, but characterized by changing substrate concentration gradients and nutrient patches. This heterogeneity in substrate availability creates a multitude of niches allowing bacteria with different substrate utilization strategies to hypothetically coexist even when competing for the same substrate. To study the impact of heterogeneous distribution of organic substrates on bacterioplankton, bioreactors with freshwater bacterial communities were fed artificial freshwater medium with acetate supplied either continuously or in pulses. After a month-long incubation, bacterial biomass and community-level substrate uptake rates were twice as high in the pulsed treatment compared to the continuously fed reactors even if the same total amount of acetate was supplied to both treatments. The composition of the bacterial communities emerging in the two treatments differed significantly with specific taxa overrepresented in the respective treatments. The higher estimated growth yield in cultures that received pulsed substrate inputs, imply that such conditions enable bacteria to use resources more efficiently for biomass production. This finding agrees with established concepts of basal maintenance energy requirements and high energetic costs to assimilate substrates at low concentration. Our results further imply that degradation of organic matter is influenced by temporal and spatial heterogeneity in substrate availability. PMID- 29124845 TI - Squamous cell carcinoma of unknown primary masquerading as multiple splenic abscesses. PMID- 29124842 TI - Porous Polyelectrolytes: The Interplay of Charge and Pores for New Functionalities. AB - The past decade has witnessed rapid advances in porous polyelectrolytes and there is tremendous interest in their synthesis as well as their applications in environmental, energy, biomedicine, and catalysis technologies. Research on porous polyelectrolytes is motivated by the flexible choice of functional organic groups and processing technologies as well as the synergy of the charge and pores spanning length scales from individual polyelectrolyte backbones to their nano /micro-superstructures. This Review surveys recent progress in porous polyelectrolytes including membranes, particles, scaffolds, and high surface area powders/resins as well as their derivatives. The focus is the interplay between surface chemistry, Columbic interaction, and pore confinement that defines new chemistry and physics in such materials for applications in energy conversion, molecular separation, water purification, sensing/actuation, catalysis, tissue engineering, and nanomedicine. PMID- 29124846 TI - Prevalence, mechanisms and genetic relatedness of the human pathogenic fungus Aspergillus fumigatus exhibiting resistance to medical azoles in the environment of Taiwan. AB - Emerging azole resistance in Aspergillus fumigatus poses a serious threat to human health. This nationwide surveillance study investigated the prevalence and molecular characteristics of azole-resistant A. fumigatus environmental isolates in Taiwan, an island country with increasing use of azole fungicides. Of the 2760 air and soil samples screened from 2014 to 2016, 451 A. fumigatus isolates were recovered from 266 samples and 34 isolates from 29 samples displayed resistance to medical azoles (itraconazole, voriconazole or posaconazole). The resistance prevalence was 10.9% and 7.5% in A. fumigatus-positive samples and isolates respectively. Most (29, 85.3%) azole-resistant isolates harboured TR34 /L98H mutations, which were widely distributed, clustered genetically with clinical isolates, and had growth rates that were similar to those of the wild-type isolates. Microsatellite genotyping revealed both the global spread of the TR34 /L98H isolates and the occurrence of TR34 /L98H/S297T/F495I isolates belonging to local microsatellite genotypes. AfuMDR3 and atrF, two efflux transporter genes, were constitutively upregulated in two individual resistant isolates without cyp51A mutations, highlighting their potential roles in azole resistance. These results emphasize the need for periodic environmental surveillance at the molecular level in regions in which azole fungicides are applied, and agricultural fungicide management strategies that generate less selective pressure should be investigated. PMID- 29124848 TI - Quantitative chemical biosensing by bacterial chemotaxis in microfluidic chips. AB - Whole-cell bacterial bioreporters are proposed as alternatives to chemical analysis of, for example, pollutants in environmental compartments. Commonly based on reporter gene induction, bioreporters produce a detectable signal within 30 min to a few hours after exposure to the chemical target, which is impractical for applications aiming at a fast response. In an attempt to attain faster readout but maintain flexibility of chemical targeting, we explored the concept for quantitative chemical sensing by bacterial chemotaxis. Chemotaxis was quantified from enrichment of cells across a 600 um-wide chemical gradient stabilized by parallel flow in a microfluidic chip, further supported by transport and chemotaxis steady state and kinetic modelling. As proof-of-concept, we quantified Escherichia coli chemotaxis towards serine, aspartate and methylaspartate as a function of attractant concentration and exposure time. E. coli chemotaxis enrichment increased sharply between 0 and 10 uM serine, before saturating at 100 uM. The chemotaxis accumulation rate was maximal at 10 uM serine, leading to observable cell enrichment within 5 min. The potential application for biosensing of environmental toxicants was investigated by quantifying chemotaxis of Cupriavidus pinatubonensis JMP134 towards the herbicide 2,4-dichlorophenoxyacetate. Our results show that bacterial chemotaxis can be quantified on a scale of minutes and may be used for developing faster bioreporter assays. PMID- 29124847 TI - Potassium iodide: A forgotten remedy for cutaneous cryptococcosis. PMID- 29124849 TI - Metaproteomics reveals major microbial players and their metabolic activities during the blooming period of a marine dinoflagellate Prorocentrum donghaiense. AB - Interactions between bacteria and phytoplankton during bloom events are essential for both partners, which impacts their physiology, alters ambient chemistry and shapes ecosystem diversity. Here, we investigated the community structure and metabolic activities of free-living bacterioplankton in different blooming phases of a dinoflagellate Prorocentrum donghaiense using a metaproteomic approach. The Fibrobacteres-Chlorobi-Bacteroidetes group, Rhodobacteraceae, SAR11 and SAR86 clades contributed largely to the bacterial community in the middle-blooming phase while the Pseudoalteromonadaceae exclusively dominated in the late-blooming phase. Transporters and membrane proteins, especially TonB-dependent receptors were highly abundant in both blooming phases. Proteins involved in carbon metabolism, energy metabolism and stress response were frequently detected in the middle-blooming phase while proteins participating in proteolysis and central carbon metabolism were abundant in the late-blooming phase. Beta-glucosidase with putative algicidal capability was identified from the Pseudoalteromonadaceae only in the late-blooming phase, suggesting an active role of this group in lysing P. donghaiense cells. Our results indicated that diverse substrate utilization strategies and different capabilities for environmental adaptation among bacteria shaped their distinct niches in different bloom phases, and certain bacterial species from the Pseudoalteromonadaceae might be crucial for the termination of a dinoflagellate bloom. PMID- 29124850 TI - The role of shame in the development and maintenance of psychological distress in adults with intellectual disabilities: A narrative review and synthesis. AB - BACKGROUND: The role of shame in the development and maintenance of psychological distress in adults with mild-to-moderate intellectual disabilities has been relatively under-researched. This study provides a review of diverse current research that has implicitly or explicitly investigated shame processes in this population in some form. METHODS: A narrative review of the literature was undertaken. An electronic search of four databases identified 17 studies that met the eligibility criteria. RESULTS: Findings indicate that individuals with mild to-moderate intellectual disabilities may experience difficulties with both external and internal shame, which appear to be related to increased psychological distress. Experiences of being shamed may significantly negatively impact on self-to-self and other self-relating, processes of social comparison, subsequent self-worth and emotional well-being. CONCLUSION: Shame may be a contributory factor in the development and maintenance of psychological distress and subsequent mental health issues in some adults with mild-to-moderate intellectual disabilities. PMID- 29124851 TI - Lower risk of pelvic metalware infection with operative repair of concurrent bladder rupture. AB - BACKGROUND: Patients with traumatic bladder rupture frequently have associated pelvic fracture. With increasing numbers of pelvic fractures fixed internally, there are concerns that conservative management of bladder rupture may increase the risk of pelvic metalware infection. This study aims to determine if operative repair of bladder rupture in comparison to conservative management with catheter drainage alone is associated with a lower rate of infection of internal fixation device for concurrent pelvic fracture. METHODS: This is a retrospective cohort study of level IV evidence. From July 2001 through June 2013, 45 multi-trauma patients at a level 1 trauma centre were identified to have sustained bladder rupture with concurrent pelvic fracture requiring internal fixation. Clinicopathological data were extracted from the TraumaNET database, medical records and health-coding database. Patients were stratified into two retrospective cohorts, management with surgical repair and management with catheter drainage alone. Fischer's exact test was used to determine whether the rate of pelvic metalware infection was different in the two cohorts. RESULTS: Of the 45 patients, 13 had intraperitoneal bladder rupture, 28 had extraperitoneal bladder rupture and four had combined intra-extraperitoneal bladder rupture. The median age for this cohort was 31. Bladder rupture was surgically repaired in 36 patients and managed conservatively with catheter drainage in nine patients. The rate of pelvic internal fixation device infection was lower in patients managed with surgical repair compared with conservative management (5.6% versus 33.3%, P = 0.047). CONCLUSION: Operative repair of bladder rupture is associated with a lower rate of pelvic orthopaedic hardware infection in the presence of concurrent pelvic fracture requiring internal fixation. PMID- 29124852 TI - Occurrence of chlorophyll allomers during virus-induced mortality and population decline in the ubiquitous picoeukaryote Ostreococcus tauri. AB - During viral infection and growth limitation of the picoeukaryote Ostreococcus tauri, we examined the relationship between membrane permeability, oxidative stress and chlorophyll allomers (oxidation products). Chlorophyll allomers were measured in batch-cultures of O. tauri in parallel with maximum quantum efficiency of photosystem II photochemistry (Fv /Fm ), carotenoids, and reactive oxygen species and membrane permeability using fluorescent probes (CM-H2 DCFDA and SYTOX-Green). Viral infection led to mass cell lysis of the O. tauri cells within 48 h. The concentration of the allomer hydroxychlorophyll a peaked with a 16-fold increase (relative to chlorophyll-a) just after the major lysis event. In contrast, cell death due to growth limitation resulted in a twofold increase in allomer production, relative to chl-a. Two allomers were detected solely in association with O. tauri debris after viral lysis, and unlike other allomers were not observed before viral lysis, or during cell death due to growth limitation. Conversely, the component chl-aP276 was found in the highest concentrations relative to chl-a, in exponentially growing O. tauri. The components described have potential as indicators of mode of phytoplankton mortality, and of population growth. PMID- 29124853 TI - Intracorporeal robot-assisted radical cystectomy, together with an enhanced recovery programme, improves postoperative outcomes by aggregating marginal gains. AB - OBJECTIVE: To assess the cumulative effect of an enhanced recovery after surgery (ERAS) pathway and minimally invasive robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) in comparison with open radical cystectomy (ORC) on length of hospital stay (LOS) and peri-operative outcomes. MATERIALS AND METHODS: Between February 2009 and October 2017, 304 radical cystectomy cases were performed at a single institution (ORC, n = 54; robot assisted radical cystectomy [RARC], n = 250). Data were prospectively collected. We identified 45 consecutive ORC cases performed without ERAS before the commencement of the RARC programme (Cohort A), 50 consecutive iRARC cases performed without ERAS (Cohort B) and 40 iRARC cases with ERAS (Cohort C). The primary outcome measure was LOS, while secondary outcome measures included peri operative 90-day complications and readmission rate. Complications were accessed using the Clavien-Dindo system. RESULTS: Patients in all cohorts were evenly matched with regard to age, sex, body mass index, neoadjuvant treatment, tumour stage, lymph node yield, previous pelvic radiotherapy and surgery, peri-operative anaemia, as well as physiological state. Patients who underwent iRARC with ERAS had a significantly higher American Society of Anesthesiologists score (III-IV) and were more likely to receive neobladder reconstruction. The median (interquartile range) LOS was shorter in the iRARC with ERAS group (7 [6-10]) days than in the iRARC without ERAS group (11 [8-15]) days and the ORC group (17 [14-21] days). In a propensity score-matched cohort of patients who underwent iRARC, patients who followed the ERAS pathway had significantly lower 90-day readmission rates. Additionally, implementing ERAS in an iRARC cohort resulted in a significantly lower 90-day all (P < 0.001) and gastrointestinal-related complications (P = 0.001). The ERAS pathway and younger patients were independently associated with an LOS of <=10 days on multinomial logistic regression. CONCLUSION: A comprehensive ERAS programme can significantly reduce LOS in patients undergoing iRARC without increasing 90-day readmission rates. An ERAS programme can augment the benefits of iRARC in improving peri-operative outcomes. In studies comparing ORC and RARC, the presence or absence of an ERAS programme will be a confounding factor and only level 1 evidence can be interpreted reliably. PMID- 29124854 TI - Thermoacclimation and genome adaptation of the membrane lipidome in marine Synechococcus. AB - The marine cyanobacteria of the genus Synechococcus are important primary producers, displaying a wide latitudinal distribution that is underpinned by diversification into temperature ecotypes. The physiological basis underlying these ecotypes is poorly known. In many organisms, regulation of membrane fluidity is crucial for acclimating to variations in temperature. Here, we reveal the detailed composition of the membrane lipidome of the model strain Synechococcus sp. WH7803 and its response to temperature variation. Unlike freshwater strains, membranes are almost devoid of C18, mainly containing C14 and C16 chains with no more than two unsaturations. In response to cold, we observed a rarely observed process of acyl chain shortening that likely induces membrane thinning, along with specific desaturation activities. Both of these mechanisms likely regulate membrane fluidity, facilitating the maintenance of efficient photosynthetic activity. A comprehensive examination of 53 Synechococcus genomes revealed clade-specific gene sets regulating membrane lipids. In particular, the genes encoding desaturase enzymes, which is a key to the temperature stress response, appeared to be temperature ecotype-specific, with some of them originating from lateral transfers. Our study suggests that regulation of membrane fluidity has been among the important adaptation processes for the colonization of different thermal niches by marine Synechococcus. PMID- 29124855 TI - Reconstructive options for large back free flap donor sites. AB - BACKGROUND: Reconstruction of posterior thoracic and trunk defects can prove challenging even to the most seasoned surgeons. Many commonly used techniques for closing back defects include primary closure and split skin grafts. Often times, however, other techniques are needed in order to give the patient the best aesthetic and functional outcome. In this study, we focus on and evaluate donor site closure techniques for defects in the back created by harvesting scapular and parascapular flaps. METHODS: Twenty patients were operated on to remove pathologically diagnosed sarcomas using a wide local excision. The defects, ranging from 5 to 22 cm in width, were closed using donor flaps from the scapular/parascapular region. Nine donor sites were then closed primarily with wide undermining, while 11 donor sites were closed using multiple techniques, such as large transposition flaps, large rotation advancement flaps, keystone neurovascular island flaps, latissimus dorsi advancement flap and large Y-V advancement flaps. RESULTS: All recipient and donor flaps survived with good aesthetic and functional outcome. Patient satisfaction was high and only two of 20 donor site flaps required further surgery due to wound dehiscence. No other complications were seen during the follow-up period. CONCLUSION: The proposed advanced techniques for donor site closure in back defects have shown that primary wound healing can be achieved with the use of a variety of different techniques and the avoidance of the complications of a skin graft. PMID- 29124856 TI - Comparison of anthropometrical parameters and dietary habits of young women with and without menstrual disorders. AB - AIM: The aim of this study was to assess the nutritional status and dietary habits of young women, in order to explore their relationship with the menstrual cycle and to determine the proportion of women with menstrual cycle irregularities. METHODS: A total of 348 young women aged 15-25 years (19.7 +/- 3.7 years) participated in the study and were assigned to a younger group (15-18 years; YG) or an older group (19-25 years; OG). Two subgroups were also distinguished: women with menstrual disorders (MD) and women with regular cycles (RC). Body mass, waist circumference, fat mass (FM), energy and nutrient intakes, and eating behaviour of the subjects were evaluated. RESULTS: In both age groups, women with menstrual cycle disorders were more likely to have higher body weight, higher body mass index, larger waist circumference and higher body FM. The daily diets of these women contained larger quantities of animal protein and fat, including saturated fat (in OG), but were poorer in vitamins B1 and B6 (in YG) and in iron. Disinhibition was significantly more common in the MD group. CONCLUSIONS: The results of this study suggest that nutritional habits and status can interfere with the course of the menstrual cycle in young women. PMID- 29124858 TI - High dark inorganic carbon fixation rates by specific microbial groups in the Atlantic off the Galician coast (NW Iberian margin). AB - Bulk dark dissolved inorganic carbon (DIC) fixation rates were determined and compared to microbial heterotrophic production in subsurface, meso- and bathypelagic Atlantic waters off the Galician coast (NW Iberian margin). DIC fixation rates were slightly higher than heterotrophic production throughout the water column, however, more prominently in the bathypelagic waters. Microautoradiography combined with catalyzed reporter deposition fluorescence in situ hybridization (MICRO-CARD-FISH) allowed us to identify several microbial groups involved in dark DIC uptake. The contribution of SAR406 (Marinimicrobia), SAR324 (Deltaproteobacteria) and Alteromonas (Gammaproteobacteria) to the dark DIC fixation was significantly higher than that of SAR202 (Chloroflexi) and Thaumarchaeota, in agreement with their contribution to microbial abundance. Q PCR on the gene encoding for the ammonia monooxygenase subunit A (amoA) from the putatively high versus low ammonia concentration ecotypes revealed their depth stratified distribution pattern. Taken together, our results indicate that chemoautotrophy is widespread among microbes in the dark ocean, particularly in bathypelagic waters. This chemolithoautotrophic biomass production in the dark ocean, depleted in bio-available organic matter, might play a substantial role in sustaining the dark ocean's food web. PMID- 29124857 TI - Mineral surface-reactive metabolites secreted during fungal decomposition contribute to the formation of soil organic matter. AB - Soil organic matter (SOM) constitutes the largest terrestrial C pool. An emerging, untested, view is that oxidation and depolymerization of SOM by microorganisms promote the formation of SOM-mineral associations that is critical for SOM stabilization. To test this hypothesis, we performed laboratory-scale experiments involving one ectomycorrhizal and one saprotrophic fungus that represent the two major functional groups of microbial decomposers in the boreal forest soils. Fungal decomposition enhanced the retention of SOM on goethite, partly because of oxidative modifications of organic matter (OM) by the fungi. Moreover, both fungi secreted substantial amounts (> 10% new biomass C) of aromatic metabolites that also contributed to an enhanced mineral retention of OM. Our study demonstrates that soil fungi can form mineral-stabilized SOM not only by oxidative conversion of the SOM but also by synthesizing mineral surface reactive metabolites. Metabolites produced by fungal decomposers can play a yet overlooked role in the formation and stabilization of SOM. PMID- 29124859 TI - Sympatric kelp species share a large portion of their surface bacterial communities. AB - Kelp forest ecosystems are biodiversity hotspots, providing habitat for dense assemblages of marine organisms and nutrients for marine and terrestrial food webs. The surfaces of kelps support diverse microbial communities that facilitate the transfer of carbon from algal primary production to higher trophic levels. We quantified the diversity of bacteria on the surfaces of eight sympatric kelp species from four sites in British Columbia. Kelp-associated bacterial communities are significantly different from their environment, even though 86% of their bacterial taxa are shared with seawater and 97% are shared with rocky substrate. This differentiation is driven by differences in relative abundance of the bacterial taxa present. Similarly, a large portion of bacterial taxa (37%) is shared among all eight kelp species, yet differential abundance of bacterial taxa underlies differences in community structure among species. Kelp-associated bacterial diversity does not track host phylogeny; instead bacterial community composition is correlated with the life-history strategy of the host, with annual and perennial kelps supporting divergent bacterial communities. These data provide the first community-scale investigation of kelp forest-associated bacterial diversity. More broadly, this study provides insight into mechanisms that may structure bacterial communities among closely related sympatric host species. PMID- 29124860 TI - Safety of single-incision laparoscopic cholecystectomy for acute cholecystitis. AB - BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) is a common procedure performed worldwide. In this study, we evaluated the safety and efficacy of SILC for acute cholecystitis. METHODS: Patients who underwent SILC between September 2012 and December 2016 were retrospectively enrolled and divided into acute and chronic groups. Demographic, operative and outcome data were obtained by reviewing medical records, physical examination and telephone follow-up. RESULTS: In total, 1435 patients were included in this study: 220 (15.3%) in the acute group and 1215 (84.7%) in the chronic group. The mean operative time was longer in the acute group than in the chronic group (44.7 +/- 21.6 versus 32.8 +/- 9.8 min; P < 0.001). Insertion of additional ports was performed in 17 patients: six in the acute group and 11 in the chronic group. Conversion to abdominal laparotomy was performed in eight patients: one in the acute group and seven in the chronic group. The mean post-operative hospital stay was 31.7 +/- 20.4 h in the acute group and 27.7 +/- 13.7 h in the chronic group. The complication rate was similar between the acute (n = 8, 3.6%) and chronic (n = 33, 2.7%) groups. CONCLUSION: SILC does not increase the complication rate and is a safe and feasible technique for both chronic and acute cholecystitis. PMID- 29124861 TI - Inhibiting bacterial quorum sensing arrests coral disease development and disease associated microbes. AB - Among the greatest threats to coral reefs are coral epizootics, which are increasing in frequency and severity across many reef ecosystems. In particular, white band disease (WBD) has devastated Caribbean acroporid populations since its initial outbreak in 1979. However, despite its widespread and damaging effects, the aetiology of WBD remains largely unresolved. Here, we examine the role of quorum sensing within bacterial communities associated with WBD-infected Acropora cervicornis. Microbial communities isolated from WBD-infected corals were exposed to quorum sensing inhibitor (QSI) - a N-acyl homoserine lactone autoinducer antagonist - and then dosed onto healthy test corals. WBD-associated bacteria supplemented with QSI lost the ability to establish disease, while healthy corals exposed to uninhibited WBD bacterial communities became infected within two days. Microbial 16S rRNA metagenomic sequencing analyses were then used to identify shifts in bacterial communities due to QSI exposure on WBD-associated bacterial communities. Our results demonstrated that Vibrionaceae and Flavobacteriaceae abundances were strongly inhibited by the addition of QSI to WBD-infected corals, whereas putative coral symbiont Endozoicomonas and Halomonadaceae abundances decrease dramatically in diseased corals. PMID- 29124862 TI - Catabolic task division between two near-isogenic subpopulations co-existing in a herbicide-degrading bacterial consortium: consequences for the interspecies consortium metabolic model. AB - Variovorax sp. WDL1 mediates hydrolysis of the herbicide linuron into 3,4 dichloroaniline (DCA) and N,O-dimethylhydroxylamine in a tripartite bacterial consortium with Comamonas testosteroni WDL7 and Hyphomicrobium sulfonivorans WDL6. Although strain WDL1 contains the dcaQTA1A2B operon for DCA oxidation, this conversion is mainly performed by WDL7. Phenotypic diversification observed in WDL1 cultures and scrutiny of the WDL1 genome suggest that WDL1 cultures consist of two dedicated subpopulations, i.e., a linuron-hydrolysing subpopulation (Lin + DCA-) and a DCA-oxidizing subpopulation (Lin-DCA+). Whole genome analysis of strains representing the respective subpopulations revealed that they are identical, aside from the presence of hylA (in Lin + DCA- cells) and the dcaQTA1A2B gene cluster (in Lin-DCA+ cells), and that these catabolic gene modules replace each other at exactly the same locus on a 1380 kb extra chromosomal element that shows plasmid gene functions including genes for transferability by conjugation. Both subpopulations proliferate in consortium biofilms fed with linuron, but Lin + DCA- cells compose the main WDL1 subpopulation. Our observations instigated revisiting the interactions within the consortium and suggest that the physical separation of two essential linuron catabolic gene clusters in WDL1 by mutually exclusive integration in the same mobile genetic element is key to the existence of WDL1 in a consortium mode. PMID- 29124863 TI - Interannual bumble bee abundance is driven by indirect climate effects on floral resource phenology. AB - Climate change can influence consumer populations both directly, by affecting survival and reproduction, and indirectly, by altering resources. However, little is known about the relative importance of direct and indirect effects, particularly for species important to ecosystem functioning, like pollinators. We used structural equation modelling to test the importance of direct and indirect (via floral resources) climate effects on the interannual abundance of three subalpine bumble bee species. In addition, we used long-term data to examine how climate and floral resources have changed over time. Over 8 years, bee abundances were driven primarily by the indirect effects of climate on the temporal distribution of floral resources. Over 43 years, aspects of floral phenology changed in ways that indicate species-specific effects on bees. Our study suggests that climate-driven alterations in floral resource phenology can play a critical role in governing bee population responses to global change. PMID- 29124864 TI - Corrigendum for Calcagno et al. (2014) DOI: 10.1111/ele.12379. PMID- 29124865 TI - How does CKD affect HbA1c? AB - HOW DOES CHRONIC KIDNEY DISEASE AFFECT HBA1C?: A number of factors determine HbA1c other than the level of glucose exposure alone. In an subset analysis of the Atherosclerosis Risk in Communities study of 941 diabetic people with varying degrees of chronic kidney disease (CKD), as well as 724 who did not have CKD, and mean age in the eighth decade, Jung et al. ask whether HbA1c is reliable as an indicator of glycemia in people with kidney disease (CKD) to the same degree as in those not having kidney disease, and, if not, whether measures of glycated serum proteins may be more useful. The only available measure of glycemia for comparison was a single fasting glucose level, and the authors acknowledge that this gives an incomplete measure, particularly in people with relatively mild diabetes, whose mean HbA1c was 6.4%, with most having levels of 7.5% or lower. In patients of this sort, postprandial glucose levels may better explain variations in mean HbA1c. Recognizing that the dataset may be limited, Jung et al. nevertheless give an intriguingly negative answer to the first question, of the reliability of HbA1c with kidney disease. Using Deming regression analysis, Jung et al. showed that the correlation between HbA1c and fasting glucose weakens as renal function worsens, and, moreover, that this appears particularly to be the case in people with anemia (hemoglobin <130 and <120 g/L for men and women, respectively), confirming earlier observations. Among those diabetic people with neither anemia nor CKD, the correlation coefficient between HbA1c and fasting glucose was r = 0.70, compared with r = 0.35 among those with both anemia and very severe CKD (estimated glomerular filtration rate [eGFR] <30 or <45 mL/min per 1.73 m2 with at least microalbuminuria, or eGFR <60 mL/min per 1.73 m2 with macroalbuminuria). As far as the second question, of whether the alternative measures, namely fructosamine and glycated albumin, may be more useful with CKD, Jung et al. found that these parameters are equally flawed with CKD. Intriguingly, this suggests that anemia affects indirect measures of glycemic exposure not only by its association with more rapid erythrocyte turnover, but, more generally, also as a marker of a catabolic state with altered plasma protein turnover. How, then, should we assess a given diabetic person's degree of glycemic control in the presence of CKD (or of anemia, which, per Jung et al., was, even without CKD, also associated with a reduction in the correlation between HbA1c and fasting glucose)? Jung et al. suggest the use of continuous glucose monitoring to estimate average glucose. Although becoming recognized as an important tool, this technology is not as generally available as the simpler self-monitoring of blood glucose (SMBG). In an earlier analysis of potential complexities of HbA1c as a measure of glycemic exposure, we showed that self monitored plasma glucose profiles suggest that approximately 10% of individuals with diabetes have HbA1c substantially above and another 10% have HbA1c substantially below those that may be anticipated based on mean glucose levels. In clinical practice, then, we should consider encouraging older people with diabetes and CKD to perform SMBG to more adequately interpret HbA1c results. PMID- 29124866 TI - Characterization of the toxin Plx2A, a RhoA-targeting ADP-ribosyltransferase produced by the honey bee pathogen Paenibacillus larvae. AB - The toxin Plx2A is an important virulence factor of Paenibacillus larvae, the etiological agent of American Foulbrood, the most destructive bacterial disease of honey bees. Biochemical and functional analyses as well as the crystal structure of Plx2A revealed that it belongs to the C3 mono-ADP-ribosylating toxin subgroup. RhoA was identified as the cellular target of Plx2A activity. The kinetic parameters (KM , kcat ) were established for both the transferase and glycohydrolase reactions. When expressed in yeast, Plx2A was cytotoxic for eukaryotic cells and catalytic variants confirmed that the cytotoxicity of Plx2A depends on its enzymatic activity. The crystal structure of Plx2A was solved to 1.65 A and confirmed that it is a C3-like toxin, although with a new molecular twist, it has a B-domain. A molecular model of the 'active' enzyme conformation in complex with NAD+ was produced by computational methods based on the recent structure of C3bot1 with RhoA. In murine macrophages, Plx2A induced actin cytoskeleton reorganization while in insect cells, vacuolization and the occurrence of bi-nucleated cells was observed. The latter is indicative of an inhibition of cytokinesis. All these cellular effects are consistent with Plx2A inhibiting the activity of RhoA by covalent modification. PMID- 29124867 TI - Acute Kidney Injury in Critically Ill Surgical Patients: Epidemiology, Risk Factors and Outcomes. AB - AIM: Acute kidney injury (AKI) is one of the most serious complications seen in intensive care units (ICUs). However, its epidemiology, risk factors and clinical outcomes in surgical critically ill patients remains unclear. METHODS: A prospective cohort study was conducted in surgical intensive care unit (ICU) of the university hospital in Bangkok, Thailand. AKI was diagnosed according to the KDIGO 2012 criteria. RESULTS: A total of 189 of the 400 patients enrolled in our study developed AKI (47.3%). The severity was: stage 1 = 29.6% of all AKI (56 cases), stage 2 = 30.7% (58 cases), and stage 3 = 39.7% (75 cases). Risk factors of AKI development included a higher BMI, a greater APACHE-II score, septic shock, use of mechanical ventilation, acute medical complications during surgical admission, and pre-existing chronic kidney disease. After adjustment for covariates, only the most severe stage of AKI (stage 3) was associated with increasing 28-day ICU mortality compared with no AKI stage, HR=7.75 (95% CI, 1.46 41.20, P=0.02). CONCLUSIONS: AKI is common and is associated with an increase in mortality in surgical ICU patients. There should be more focus on patients with AKI risk factors to prevent this deleterious event. PMID- 29124868 TI - Obligate sugar oxidation in Mesotoga spp., phylum Thermotogae, in the presence of either elemental sulfur or hydrogenotrophic sulfate-reducers as electron acceptor. AB - Mesotoga prima strain PhosAc3 is a mesophilic representative of the phylum Thermotogae comprising only fermentative bacteria so far. We show that while unable to ferment glucose, this bacterium is able to couple its oxidation to reduction of elemental sulfur. We demonstrate furthermore that M. prima strain PhosAc3 as well as M. prima strain MesG1 and Mesotoga infera are able to grow in syntrophic association with sulfate-reducing bacteria (SRB) acting as hydrogen scavengers through interspecies hydrogen transfer. Hydrogen production was higher in M. prima strain PhosAc3 cells co-cultured with SRB than in cells cultured alone in the presence of elemental sulfur. We propose that the efficient sugar oxidizing metabolism by M. prima strain PhosAc3 in syntrophic association with a hydrogenotrophic sulfate-reducing bacterium can be extrapolated to all members of the Mesotoga genus. Genome comparison of Thermotogae members suggests that the metabolic difference between Mesotoga and Thermotoga species (sugar oxidation versus fermentation) is mainly due to the absence of the bifurcating [FeFe] hydrogenase in the former. Such an obligate oxidative process for using sugars, unusual within prokaryotes, is the first reported within the Thermotogae. It is hypothesized to be of primary ecological importance for growth of Mesotoga spp. in the environments that they inhabit. PMID- 29124869 TI - Polydopamine Based Colloidal Materials: Synthesis and Applications. AB - Polydopamine is a synthetic analogue of natural melanin (eumelanin) produced from oxidative polymerization of dopamine. Owing to its strong adhesion ability, versatile chemical reactivity, biocompatibility and biodegradation, polydopamine is commonly applied as a versatile linker to synthesize colloidal materials with diverse structures, unique physicochemical properties and tunable functions, which allow for a broad scope of applications including biomedicine, sensing, catalysis, environment and energy. In this personal account, we discuss first about the different synthetic approaches of polydopamine, as well as its polymerization mechanism, and then with a comprehensive overview of recent progress in the synthesis and applications of polydopamine-based colloidal materials. Finally, we summarize this personal account with future perspectives. PMID- 29124870 TI - Defining a glycated haemoglobin (HbA1c) level that predicts increased risk of penile implant infection. AB - OBJECTIVES: To re-evaluate the role of diabetes mellitus (DM) as a risk factor for penile implant infection by exploring the association between glycated haemoglobin (HbA1c) levels and penile implant infection rates and to define a threshold value that predicts implant infection. PATIENTS AND METHODS: We conducted a multicentre prospective study including all patients undergoing penile implant surgery between 2009 and 2015. Preoperative, perioperative and postoperative management were identical for the entire cohort. Univariate analysis was performed to define predictors of implant infection. The HbA1c levels were analysed as continuous variables and sequential analysis was conducted using 0.5% increments to define a threshold level predicting implant infection. Multivariable analysis was performed with the following factors entered in the model: DM, HbA1C level, patient age, implant type, number of vascular risk factors (VRFs), presence of Peyronie's disease (PD), body mass index (BMI), and surgeon volume. A receiver operating characteristic (ROC) curve was generated to define the optimal HbA1C threshold for infection prediction. RESULTS: In all, 902 implant procedures were performed over the study period. The mean patient age was 56.6 years. The mean HbA1c level was 8.0%, with 81% of men having a HbA1c level of >6%. In all, 685 (76%) implants were malleable and 217 (24%) were inflatable devices; 302 (33.5%) patients also had a diagnosis of PD. The overall infection rate was 8.9% (80/902). Patients who had implant infection had significantly higher mean HbA1c levels, 9.5% vs 7.8% (P < 0.001). Grouping the cases by HbA1c level, we found infection rates were: 1.3% with HbA1c level of <6.5%, 1.5% for 6.5-7.5%, 6.5% for 7.6-8.5%, 14.7% for 8.6-9.5%, 22.4% for >9.5% (P < 0.001). Patient age, implant type, and number of VRFs were not predictive. Predictors defined on multivariable analysis were: PD, high BMI, and high HbA1c level, whilst a high-volume surgeon had a protective effect and was associated with a reduced infection risk. Using ROC analysis, we determined that a HbA1c threshold level of 8.5% predicted infection with a sensitivity of 80% and a specificity of 65%. CONCLUSION: Uncontrolled DM is associated with increased risk of infection after penile implant surgery. The risk is directly related to the HbA1c level. A threshold HbA1c level of 8.5% is suggested for clinical use to identify patients at increased infection risk. PMID- 29124871 TI - Low triglyceride as a marker for increased risk of cardiovascular diseases in patients with long-term type 2 diabetes: A cross-sectional survey in China. AB - BACKGROUND: There are inconsistent findings regarding associations between triglyceride levels and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM). This study aimed to test whether the association between triglycerides and CVD depends upon duration of diabetes. METHODS: From April 1, 2012, to June 30, 2012, we conducted a cross-sectional survey of 223 612 patients with T2DM from 630 hospitals in China. Cardiovascular disease was defined as having either prior coronary heart disease or stroke, or diabetic foot. Binary logistic regression was used to estimate odds ratios of triglyceride for CVD. Relative excess risk due to interaction, attributable proportion due to interaction, and synergy index were used to estimate effect size of additive interaction between low triglyceride, ie, <1.7 mmol/L, and duration of diabetes, ie, >=15 years. RESULTS: Among 223 612 T2DM patients, 31 898 (14.27%) suffered from CVD. A low level of triglyceride was associated with decreased risk of CVD (univariable OR, 0.91, 95% CI, 0.88-0.93; multivariable OR, 0.94, 95% CI, 0.92-0.97) among patients with <15 years of duration of diabetes but increased risk of CVD (univariable OR, 1.12, 95% CI, 1.04-1.21; multivariable OR, 1.18, 95% CI, 1.09 1.27) among those patients with 15 and more years of duration of diabetes with significant additive interactions (relative excess risk due to interaction, 0.39, 95% CI, 0.25-0.52; attributable proportion due to interaction, 0.20, 95% CI, 0.14 0.27; and synergy index, 1.80, 95% CI, 1.43-2.28). CONCLUSIONS: Whereas a high triglyceride level was associated with increased risk of CVD in short-term T2DM, low triglyceride was associated with increased CVD risk in long-term T2DM. Low triglyceride may be a marker of CVD risk in Chinese patients with long-term T2DM. PMID- 29124873 TI - Exposure to predicted precipitation patterns decreases population size and alters community structure of cyanobacteria in biological soil crusts from the Chihuahuan Desert. AB - Cyanobacteria typically colonize the surface of arid soils, building biological soil crust (biocrusts) that provide a variety of ecosystem benefits, ranging from fertilization to stabilization against erosion. We investigated how future scenarios in precipitation anticipated for the Northern Chihuahuan Desert affected abundance and composition of biocrust cyanobacteria in two grassland ecosystems. Scenarios included a decrease in precipitation and a delay of monsoon rainfall. After three years, both treatments negatively affected cyanobacteria, although the effects of monsoon delay were milder than those of decreased precipitation. Mature biocrusts in black grama grassland suffered severe losses in cyanobacterial biomass and diversity, but compositionally simpler biocrusts in blue grama-dominated grassland maintained biomass, only suffering diversity losses. This could be partially explained by the differential sensitivity of cyanobacterial taxa: nitrogen-fixing Scytonema spp. were the most sensitive, followed by phylotypes in the Microcoleus steenstrupii complex. Microcoleus vaginatus was the least affected in all cases, but is known to be very sensitive to warming. We predict that altered precipitation will tend to prevent biocrusts from reaching successional maturity, selecting for M. vaginatus over competing M. steenstrupii, among pioneer biocrust-formers. A shift towards heat-sensitive M. vaginatus could ultimately destabilize biocrusts when precipitation changes are combined with global warming. PMID- 29124874 TI - Important privacy considerations with electronic health record documentation. PMID- 29124876 TI - Trehalose, a temperature- and salt-induced solute with implications in pathobiology of Acinetobacter baumannii. AB - Acinetobacter baumannii is an opportunistic human pathogen that has become a global threat to healthcare institutions worldwide. A major factor contributing to success of this bacterium is its outstanding ability to survive on dry surfaces. The molecular basis for desiccation resistance is not completely understood. This study focused on growth under osmotic stress and aimed to identify the pool of compatible solutes synthesized in response to these low water activity conditions. A. baumannii produced mannitol as compatible solute, but in contrast to Acinetobacter baylyi, also trehalose was accumulated in response to increasing NaCl concentrations. The genome of A. baumannii encodes a trehalose-6-phosphate phosphatase (OtsB) and a trehalose-6-phosphate synthase (OtsA). Deletion of otsB abolished trehalose formation, demonstrating that otsB is essential for trehalose biosynthesis. Growth of the mutant was neither impaired at low salt nor at 500 mM NaCl, but it did not grow at high temperatures, indicating a dual function of trehalose in osmo- and thermoprotection. This led us to analyse temperature dependence of trehalose formation. Indeed, expression of otsB was not only induced by high osmolarity but also by high temperature. Concurrently, trehalose was accumulated in cells grown at high temperature. Taken together, these data point to an important role of trehalose in A. baumannii beyond osmoprotection. PMID- 29124878 TI - Preparation and characterization of a novel molecularly imprinted polymer for the separation of glycyrrhizic acid. AB - Molecularly imprinted polymers of glycyrrhizic acid were prepared by solution polymerization using glycyrrhizic acid as the template molecule, N vinypyrrolidone as functional monomer, N,N-methylene bisacrylamide as cross linker and ascorbic acid and hydrogen peroxide as initiators. Focused on the adsorption capacity and separation degree of the polymer to glycyrrhizic acid, the effects of the monomers, crosslinker and initiators were investigated and optimized. Finally, the structure of the polymer was characterized by using Fourier transform infrared spectroscopy and scanning electron microscopy. To obtain objective results, non-imprinted molecular polymers prepared under the same conditions were also characterized. The adsorption quantity of the polymer was measured by high-performance liquid chromatography. Under the optimum conditions, the maximum adsorption capacity of glycyrrhizic acid approached 15 mg/g, and the separation degree was as high as 2.5. The adsorption kinetics could be well described by a pseudo-first-order model, while the thermodynamics of the adsorption process could be described by the Langmuir model. PMID- 29124877 TI - Sporadic primary hyperparathyroidism and stone disease: a comprehensive metabolic evaluation before and after parathyroidectomy. AB - OBJECTIVES: To characterize the stone risk and the impact of parathyroidectomy on the metabolic profile of patients with primary hyperparathyroidism (PHPT) and urolithiasis. PATIENTS AND METHODS: We analysed the prospectively collected charts of patients treated at our stone clinic between January 2001 and January 2016 searching for patients with PHPT and urolithiasis. Imaging evaluation of the kidneys, bones and parathyroid glands was assessed. We analysed the demographic data, serum and urinary variables before and after parathyroidectomy. We used a paired t-test, Fisher's test, Spearman's test and anova in the statistical analysis. RESULTS: A total of 51 patients were included. The mean patient age was 57.1 +/- 12.1 years and 82.4% were women. Before parathyroidectomy, mean calcium and parathyroid hormone (PTH) levels were 11.2 +/- 1.0 mg/dL and 331 +/- 584 pg/dL, respectively. Hypercalcaemia was present in 84.3% of patients. All eight patients with normal calcium levels had elevated PTH levels. Only two patients did not have PTH above the normal range, although both had elevated calcium levels. The most common urinary disorders were low urinary volume (64.7%), hypercalciuria (60.8%), high urinary pH (41.2%) and hypocitraturia (31.4%). After parathyroidectomy, the number of patients with hypercalcaemia (n = 4; 7.8%), elevated PTH (n = 17; 33.3%) and hypophosphataemia (n = 3; 5.9%) significantly decreased (P < 0.001). The number of urinary abnormalities decreased and there was a reduction in urinary calcium (P < 0.001), pH (P = 0.001) and citrate levels (P = 0.003). CONCLUSION: Individuals with PHPT and nephrolithiasis frequently have elevated baseline PTH and calcium levels. Low volume, hypercalciuria, high urinary pH, and hypocitraturia are the most frequent urinary disorders. Parathyroidectomy is effective in normalizing serum calcium and PTH levels, although other urinary metabolic may persist. Patients should be monitored for the need for citrate supplementation. PMID- 29124879 TI - Hydrogenotrophic methanogenesis is the dominant methanogenic pathway in neotropical tank bromeliad wetlands. AB - Several thousands of tank bromeliads per hectare of neotropical forest create a unique wetland ecosystem that emits substantial amounts of CH4 . Tank bromeliads growing in the forest canopy (functional type-II tank bromeliads) were found to emit more CH4 than tank bromeliads growing on the forest floor (functional type-I tank bromeliads) but the reasons for this difference and the underlying microbial CH4 -cycling processes have not been studied. Therefore, we characterized archaeal communities in bromeliad tanks of the two different functional types in a neotropical montane forest of southern Ecuador using terminal-restriction fragment length polymorphism (T-RFLP) and performed tank-slurry incubations to measure CH4 production potential, stable carbon isotope fractionation and pathway of CH4 formation. The archaeal community composition was dominated by methanogens and differed between bromeliad functional types. Hydrogenotrophic Methanomicrobiales were the dominant methanogens and hydrogenotrophic methanogenesis was the dominant methanogenic pathway among all bromeliads. The relative abundance of aceticlastic Methanosaetaceae and the relative contribution of aceticlastic methanogenesis increased in type-I tank bromeliads probably due to more oxic conditions in type-I than in type-II bromeliads leading to the previously observed lower in situ CH4 emissions from type-I tank bromeliads but to higher CH4 production potentials in type-I tank bromeliad slurries. PMID- 29124875 TI - Emerging functions of the EGFR in cancer. AB - The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as 'noncanonical') functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand-induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress-induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications. PMID- 29124880 TI - Costus spiralis (Jacq.) Roscoe: A Novel Source of Flavones with alpha-Glycosidase Inhibitory Activity. AB - Costus spiralis, a plant used in traditional Brazilian medicine for the treatment of complications in diabetes, was investigated. Assay of hexane, ethyl acetate, methanol, and aqueous fractions obtained by partition of a crude methanol extract of dried leaves of C. spiralis revealed that AGI activity was confined to the ethyl acetate fraction. Purification of this fraction yielded schaftoside and isoschaftoside. The AGI activities of the two flavones were lower than, but comparable with, that of the anti-diabetic drug acarbose. In contrast, the IC50 value of the ethyl acetate fraction was 1.95-, 2.34-, and 2.22-fold higher than those of acarbose, schaftoside, and isoschaftoside, respectively. The results demonstrate for the first time that schaftoside and isoschaftoside are responsible, in part, for the AGI activity of C. spiralis. Our study suggests that further investigations into C. spiralis may lead to the discovery of additional compounds with antihyperglycemic activity. PMID- 29124882 TI - The prevalence of back pain in patients in one Australian tertiary hospital population. AB - OBJECTIVES: The aims of the present study were to provide back pain (BP) point prevalence data from inpatients at an Australian tertiary hospital on one day, and compare this with Australian non-hospitalized population prevalence data; to collect data around the development of BP throughout hospital admission; and to analyse the association between BP and past history of BP, gender, age, admission specialty and hospital length of stay (LOS). METHODS: This was a single-site, prospective, observational study of hospitalized inpatients on one day during 2016, with a subsequent survey over the following 11 days (unless discharge or death occurred sooner). RESULTS: Data were collected from 343 patients (75% of the hospitalized cohort). A third of patients (n = 108) reported BP on admission, and almost a fifth (n = 63) developed new BP during their hospitalization. Patients who described BP at any time during their hospital stay had a higher chance of having had a history of BP, with odds increasing after adjustment for age and gender (odds ratio 5.89; 95% confidence interval (CI) 3.0 to 11.6; p < 0.001). After adjusting for age and gender, those experiencing BP had a significantly longer LOS (median 13 days; CI 10.8 to 15.3) than those who did not (median 10 days; CI 8.4 to 11.6; p = 0.034). CONCLUSIONS: Hospital LOS for patients who complained of BP at any time during their admission was 3 days longer than those who had no BP, and a history of BP predicted a higher likelihood of BP during admission. Screening of patients on admission to identify any history of BP, and application of a package of care including early mobilization and analgesia may prevent the onset of BP and reduce LOS. PMID- 29124883 TI - Plant protection means used in organic farming throughout the European Union. AB - Following the obligatory implementation of integrated pest management in the European Union (EU), the plant protection means suitable for application in organic agriculture attracted the attention of quite a wide group of potential users. In spite of the common rules of organic production, as well as the uniform principles of placing plant protection products on the market, the availability of products that can be legally used in organic crop protection differs significantly among the Member States. There is a uniform list of 10 basic substances that can be used in the protection of organic crops throughout the entire EU. Twelve Member States have official registers of plant protection products for use in organic agriculture, and the total number of qualified products per country varies from 11 in Lithuania to 576 in Italy. Some products that improve plant vigour or resistance and may be of use in protection of organic crops are placed on the market as biostimulants. They fall under the law that governs fertilisers and the systems of their registration vary widely among the Member States. In addition, there exist a number of products that have been legally introduced onto the markets of some Member States without registration as a consequence of a loophole in the law. The use of unregistered products in organic agriculture raises some doubts, but currently it seems that there is no legal basis on which to explicitly prohibit the practice. (c) 2017 Society of Chemical Industry. PMID- 29124884 TI - Utility of Cremophor RH 40 as a micellar improvement for spectrofluorimetric estimation of sorafenib in pure form, commercial preparation, and human plasma. AB - An easy, quick, simple and accurate spectrofluorimetric method was recognized and validated for evaluation of sorafenib (SOR) in pure form and biologically in plasma. Cremophor RH 40 (Cr RH 40) used for enhancing the fluorescence activity of SOR in phosphate buffer (pH 7). Cr RH 40 improved the native fluorescence of SOR remarkably in water. The fluorescence spectrum of SOR was observed at 405 nm after excitation at 265 nm. The linearity appeared to be in the range of 5 to 600 ng ml-1 for pure and from 9 to 500 ng ml-1 for plasma using the protein precipitation (ppt) method while from 10 to 500 ng ml-1 for plasma using liquid liquid extraction method. The precisions and the accuracy of the estimated method gave satisfactory results. The recommended method was effectively applied for determination of SOR in human plasma with high recovery values. The results of some compounds that are possibly found in plasma were studied. The proposed method was also focused on real volunteers and a drug dissolution test. PMID- 29124881 TI - The implications of baseline bone-health assessment at initiation of androgen deprivation therapy for prostate cancer. AB - OBJECTIVES: To assess bone-density testing (BDT) use amongst prostate cancer survivors receiving androgen-deprivation therapy (ADT), and downstream implications for osteoporosis and fracture diagnoses, as well as pharmacological osteoporosis treatment in a national integrated delivery system. PATIENTS AND METHODS: We identified 17 017 men with prostate cancer who received any ADT between 2005 and 2014 using the Veterans Health Administration cancer registry and administrative data. We identified claims for BDT within a 3-year period of ADT initiation. We then used multivariable regression to examine the association between BDT use and incident osteoporosis, fracture, and use of pharmacological treatment. RESULTS: We found that a minority of patients received BDT (n = 2 502, 15%); however, the rate of testing increased to >20% by the end of the study period. Men receiving BDT were older at diagnosis and had higher-risk prostate cancer (both P < 0.001). Osteoporosis and fracture diagnoses, use of vitamin D +/ calcium, and bisphosphonates were all more common in men who received BDT. After adjustment, BDT, and to a lesser degree >=2 years of ADT, were both independently associated with incident osteoporosis, fracture, and osteoporosis treatment. CONCLUSIONS: BDT is rare amongst patients with prostate cancer treated with ADT in this integrated delivery system. However, BDT was associated with substantially increased treatment of osteoporosis indicating an underappreciated burden of osteoporosis amongst prostate cancer survivors initiating ADT. Optimising BDT use and osteoporosis management in this at-risk population appears warranted. PMID- 29124885 TI - Oleoylethanolamide: The role of a bioactive lipid amide in modulating eating behaviour. AB - Fatty acid ethanolamides are lipid mediators that regulate a plethora of physiological functions. One such bioactive lipid mediator, oleoylethanolamide (OEA), is a potent agonist of the peroxisome proliferator-activated receptor alpha (PPAR-alpha), which modulates increased expression of the fatty acid translocase CD36 that enables the regulation of feeding behaviour. Consumption of dietary fat rich in oleic acid activates taste receptors in the gut activating specific enzymes that lead to the formation of OEA. OEA further combines with PPAR-alpha to enable fat oxidation in the liver, resulting in enhanced energy production. Evidence suggests that sustained ingestion of a high-fat diet abolishes the anorexic signal of OEA. Additionally, malfunction of the enterocyte that transforms oleic acid produced during fat digestion into OEA might be responsible for reduced satiety and hyperphagia, resulting in overweight and obesity. Thus, OEA anorectic signalling may be an essential element of the physiology and metabolic system regulating dietary fat intake and obesity. The evidence reviewed in this article indicates that intake of oleic acid, and thereby the resulting OEA imparting anorexic properties, is dependent on CD36, PPAR-alpha, enterocyte fat sensory receptors, histamine, oxytocin and dopamine; leading to increased fat oxidation and enhanced energy expenditure to induce satiety and increase feeding latency; and that a disruption in any of these systems will cease/curb fat-induced satiety. PMID- 29124886 TI - CBX3/heterochromatin protein 1 gamma is significantly upregulated in patients with non-small cell lung cancer. AB - AIM: Lung cancer is typically categorized into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC comprises of the majority of lung cancer with a poor prognosis in advanced cases. Transcriptional profiling studies, including microarrays and RNA-sequencing studies, have significantly enriched our knowledge of gene expression patterns in NSCLC. A recent transcriptional profiling study identified high prevalence of CBX3/HP1-gamma upregulation in human NSCLC samples. CBX3/HP1-gamma is an isoform of the heterochromatin protein 1 family, which plays a role in heterochromatin formation and is linked to cancer. METHODS: We examined lung cancer samples from our hospital using immunohistochemistry for CBX3/HP1-gamma staining. We also analyzed publicly available databases of NSCLC transcriptional profiling to validate our results. RESULTS: We identified a high prevalence (77.2%) of samples with positive CBX3/HP1-gamma staining by immunohistochemistry in NSCLC patient samples. Independently, we queried a publicly available dataset (GSE40419) containing RNA-seq data from 77 patients. Upregulation of CBX3/HP1-gamma in tumor samples was present in 60.2% of the patients. A similar correlation was also observed in the The Cancer Genome Atlas (TCGA) database. Interestingly, we discovered a highly significant association between positive CBX3/HP1-gamma staining and EGFR mutation in our patient samples (40 of 42 patients, P < 0.001). Treatment of EGFR mutant NSCLC cell lines with the EGFR inhibitor gefitinib failed to yield a change in CBX/HP1-gamma expression, suggesting that CBX/HP1 gamma expression may be independent of EGFR downstream signaling. CONCLUSION: We report a significant upregulation of CBX3/HP1-gamma in NSCLC patients, and also a possible relationship between CBX3/HP1-gamma expression and EGFR mutation. PMID- 29124887 TI - Association between metabolic syndrome and gingival inflammation in obese children. AB - BACKGROUND AND OBJECTIVE: Our previous work showed a positive association between metabolic syndrome (MetS) and gingival crevicular fluid (GCF) tumour necrosis factor-alpha (TNF-alpha) in a sample of obese and non-obese children. However, whether this association persists among obese children is unknown. We aim to investigate the extent to which MetS is associated with GCF TNF-alpha level among obese children. METHODOLOGY: We performed a cross-sectional analysis using data from visit 1 of the QUebec Adipose and Lifestyle InvesTigation in Youth cohort. A total of 219 obese children aged 8-10 years, for whom data were available for both MetS and TNF-alpha, were included in our analysis. The independent variable, MetS, was defined according to the International Diabetes Federation recommendations. GCF samples were collected from the gingival sulcus using a paper strip, and the concentration of TNF-alpha was determined by enzyme-linked immunosorbent assay. Analyses included descriptive statistics and sex-specific linear regression analyses adjusting for potential confounders. RESULTS: In this sample comprising only obese children, 24 (10.9%) had MetS. Among obese boys, those with MetS had 44.9% higher GCF TNF-alpha (95% confidence interval: 16.5% 73.3%) compared to those without MetS. No such association was detected in obese girls. CONCLUSION: MetS was positively associated with GCF TNF-alpha concentration in obese boys. These results suggest that obese boys with MetS may have a worse gingival health profile compared to their obese counterpart without MetS. PMID- 29124888 TI - Differential oxidative stress tolerance of Streptococcus mutans isolates affects competition in an ecological mixed-species biofilm model. AB - Streptococcus mutans strongly influences the development of pathogenic biofilms associated with dental caries. Our understanding of S. mutans behaviour in biofilms is based on a few well-characterized laboratory strains; however, individual isolates vary widely in genome content and virulence-associated phenotypes, such as biofilm formation and environmental stress sensitivity. Using an ecological biofilm model, we assessed the impact of co-cultivation of several S. mutans isolates with Streptococcus oralis and Actinomyces naeslundii on biofilm composition following exposure to sucrose. The laboratory reference strain S. mutans UA159 and clinical isolates Smu44 (most aciduric), Smu56 (altered biofilm formation) and Smu81 (more sensitive to oxidative stress) were used. Our data revealed S. mutans isolates varied in their ability to compete and become dominant in the biofilm after the addition of sucrose, and this difference correlated with sensitivity to H2 O2 produced by S. oralis. Smu81 was particularly sensitive to H2 O2 and could not compete with S. oralis in mixed species biofilm, despite forming robust biofilms on its own. Thus, diminished oxidative stress tolerance in S. mutans isolates can impair their ability to compete in complex biofilms, even in the presence of sucrose, which could influence the progression of a healthy biofilm community to one capable of causing disease. PMID- 29124889 TI - The neurovascular structure-adjacent frozen-section examination (NeuroSAFE) approach to nerve sparing in robot-assisted laparoscopic radical prostatectomy in a British setting - a prospective observational comparative study. AB - OBJECTIVES: To evaluate the neurovascular structure-adjacent frozen-section examination (NeuroSAFE) technique in a British setting in men undergoing robot assisted laparoscopic radical prostatectomy (RALP) . PATIENTS AND METHODS: We retrospectively analysed our prospectively maintained database of patients who underwent RALP between November 2008 and February 2017. We examined preoperative pathological and functional parameters, intraoperative nerve sparing (NS), postoperative histology, as well as functional and oncological follow-up. We compared those who had a NeuroSAFE approach and those who had NS without NeuroSAFE. We also compared all the RALPs before and after the introduction of NeuroSAFE. Statistical analysis was done using the two-tailed t-test and chi squared analysis. RESULTS: This single surgeon series included 417 RALPs, including 120 NeuroSAFEs. The NeuroSAFE cohort had a greater proportion of D'Amico high-risk disease (30.8% vs 9.6%, P < 0.001), higher Gleason scores and higher pT stage compared to the non-NeuroSAFE NS cohort. After the introduction of NeuroSAFE, more preoperatively potent men underwent bilateral NS with pT2 disease (84.6% vs 66.3%, P = 0.002) and more overall NS were performed in patients with pT3 disease (65.1% vs 36.7%, P = 0.012). Overall positive surgical margin (PSM) rates were lower in the NeuroSAFE cohort compared to those who had NS without NeuroSAFE (9.2% vs 17.8%, P = 0.04). The 12-month potency rates were also higher in the NeuroSAFE cohort for both bilateral (77.3% vs 50.9%, P = 0.009) and unilateral (70.6% vs 40%, P = 0.04) NS. Pad-free continence was also higher in the NeuroSAFE group (85.7% vs 70.9%, P = 0.019), but there was no significant difference between those who were wearing <=1 safety pad. Although we only had short-term oncological follow-up, it did not significantly differ between the two groups. CONCLUSION: Adoption of NeuroSAFE allowed us to offer NS in higher risk patients, whilst reducing PSM rates and at the same time improving potency at 12 months. PMID- 29124892 TI - Abstracts, RCOG National Trainees Conference (NTC), Yorkshire, UK, 16-17 November 2017. PMID- 29124890 TI - New perspectives on telomerase RNA structure and function. AB - Telomerase is an ancient ribonucleoprotein (RNP) that protects the ends of linear chromosomes from the loss of critical coding sequences through repetitive addition of short DNA sequences. These repeats comprise the telomere, which together with many accessory proteins, protect chromosomal ends from degradation and unwanted DNA repair. Telomerase is a unique reverse transcriptase (RT) that carries its own RNA to use as a template for repeat addition. Over decades of research, it has become clear that there are many diverse, crucial functions played by telomerase RNA beyond simply acting as a template. In this review, we highlight recent findings in three model systems: ciliates, yeast and vertebrates, that have shifted the way the field views the structural and mechanistic role(s) of RNA within the functional telomerase RNP complex. Viewed in this light, we hope to demonstrate that while telomerase RNA is just one example of the myriad functional RNA in the cell, insights into its structure and mechanism have wide-ranging impacts. WIREs RNA 2018, 9:e1456. doi: 10.1002/wrna.1456 This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution. PMID- 29124893 TI - Ischaemic colitis: uncertainty in diagnosis, pathophysiology and management. AB - Ischaemic colitis is the most common form of gastrointestinal ischaemia, but may be confused with acute mesenteric ischaemia, inflammatory bowel disease or infectious colitis. This review article outlines the current classification, epidemiology and risk factors, as well as approaches about diagnosis and management to guide clinical practice. It also identifies areas for further research. PMID- 29124891 TI - The diagnostic value of tissue button technique for specimen accusation during endobronchial ultrasound-guided transbronchial fine-needle aspiration. AB - INTRODUCTION: The quality of tissue acquisition during endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is a major determinant of the diagnostic yield of the procedure. In the tissue button (TB) technique, the retrieved cellular specimen is fixed in ethanol and subsequently scraped from slide using surgical blade into formaldehyde and processed like ordinary tissue biopsy thus potentially increasing its diagnostic value. OBJECTIVES: To retrospectively evaluate the diagnostic yield of a TB technique in patients undergoing EBUS-TBNA for various malignant and benign conditions. METHODS: The diagnostic yield of specimen obtained by two methods (TB and traditional cell block technique) performed during the same procedure are outlined in 46 patients who underwent EBUS-TBNA (median age = 65, range 19-85 years). RESULTS: Overall, in both malignant and benign conditions, TB resulted in clear diagnostic material in 43/46 (93.4%) patients. Specifically, TB provided clear histological diagnosis of malignancy (either primary lung cancer or metastases from extra-thoracic cancer) in 30/46 (65.2%) patients and granulomatous inflammation in 11/46 (23.9%) of patients. Only in two patients TB did not provide diagnostic material. CONCLUSIONS: The newly introduced TB technique provides valuable histological diagnostic material during EBUS-TBNA both malignant and benign conditions. Given its simplicity and its high diagnostic yield, TB should be considered to be used as one of the preferred specimen acquisition modalities during EBUS-TBNA specimen processing. Direct comparison to alternative tissue processing techniques during EBUS-TBNA should be explored in further randomized prospective studies. PMID- 29124894 TI - Combined transcatheter arterial chemoembolization and radiofrequency ablation in single-session for solitary hepatocellular carcinoma larger than 7 cm. AB - AIMS: To evaluate technical feasibility and treatment results of combined transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in single-session for solitary hepatocellular carcinoma (HCC) larger than 7 cm in diameter. METHODS: Institutional review board approved this retrospective study. Written informed consent was obtained from all patients. Between June 2007 and July 2013, 87 patients (75 men, 12 women; mean age, 55.5 years +/- 15.0) with solitary HCC with a mean maximum diameter of 9.5 cm +/- 2.4 (range, 7.1-13.5 cm) not feasible for surgical resection underwent combined TACE and RFA in a single session. Immediately following TACE, RFA was performed under fluoroscopy and CB CT guidance. The primary endpoint was overall survival (OS). The secondary endpoints were technical safety and local tumor progression (LTP) rates. OS and time to progression (TTP) were analyzed with the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP. RESULTS: Technical success of combined TACE and RFA in a single session was achieved in all patients (100%). On 1-month follow-up MRI, complete response (CR) was observed in 76 of 87 patients (87.4 %), partial response (PR) in 8 and stable disease (SD) in 3 patients. The median follow-up period was 49.5 months (interquartile range, 30.0-70.0 months). The median OS was 39 months (range, 15-86 months). The cumulative OS rates at 1, 3 and 5 years were 100%, 65.5% and 47.5%, respectively. The estimated 1, 3 and 5 year LTP rates were 0 %, 29.9% and 55.2 %, respectively. Univariate and multivariate analyses showed a tumor larger than 10.0 cm (P < 0.05) and presence of portal vein branch invasion (P < 0.05) led to the worst prognosis. No major complications were noted. CONCLUSIONS: Combined use of TACE and RFA in single-session is a safe and effective option in the treatment of patients with solitary large HCC (> 7 cm) not amenable to surgery. PMID- 29124895 TI - Defining the core microbiome of the symbiotic dinoflagellate, Symbiodinium. AB - Dinoflagellates of the genus Symbiodinium underpin the survival and ecological success of corals. The use of cultured strains has been particularly important to disentangle the complex life history of Symbiodinium and their contribution to coral host physiology. However, these cultures typically harbour abundant bacterial communities which likely play important, but currently unknown, roles in Symbiodinium biology. We characterized the bacterial communities living in association with a wide phylogenetic diversity of Symbiodinium cultures (18 types spanning 5 clades) to define the core Symbiodinium microbiome. Similar to other systems, bacteria were nearly two orders of magnitude more numerically abundant than Symbiodinium cells and we identified three operational taxonomic units (OTUs) which were present in all cultures. These represented the alpha proteobacterium Labrenzia and the gamma-proteobacteria Marinobacter and Chromatiaceae. Based on the abundance and functional potential of bacteria harboured in these cultures, their contribution to Symbiodinium physiology can no longer be ignored. PMID- 29124896 TI - Beyond the response-High throughput behavioral analyses to link genome to phenome in Caenorhabditis elegans. AB - The development and application of methods for automated behavioral analysis have revolutionized behavioral genetics across model organisms. In this review we summarize the history of automated behavioral analysis in the nematode Caenorhabditis elegans. We highlight recent studies of learning and memory to exemplify just how complex the genetic and neural circuit mechanisms underlying a seemingly simple single behavioral response can be. We finish by looking forward at the exciting prospects of combing genomic technologies with connectomic and phenomic level measurements. PMID- 29124897 TI - Flow injection gas chromatography with sulfur chemiluminescence detection for the analysis of total sulfur in complex hydrocarbon matrixes. AB - A fast and reliable analytical technique for the determination of total sulfur levels in complex hydrocarbon matrices is introduced. The method employed flow injection technique using a gas chromatograph as a sample introduction device and a gas phase dual-plasma sulfur chemiluminescence detector for sulfur quantification. Using the technique described, total sulfur measurement in challenging hydrocarbon matrices can be achieved in less than 10 s with sample-to sample time <2 min. The high degree of selectivity and sensitivity toward sulfur compounds of the detector offers the ability to measure low sulfur levels with a detection limit in the range of 20 ppb w/w S. The equimolar response characteristic of the detector allows the quantitation of unknown sulfur compounds and simplifies the calibration process. Response is linear over a concentration range of five orders of magnitude, with a high degree of repeatability. The detector's lack of response to hydrocarbons enables direct analysis without the need for time-consuming sample preparation and chromatographic separation processes. This flow injection-based sulfur chemiluminescence detection technique is ideal for fast analysis or trace sulfur analysis. PMID- 29124898 TI - Impaired competence in flagellar mutants of Bacillus subtilis is connected to the regulatory network governed by DegU. AB - The competent state is a developmentally distinct phase, in which bacteria are able to take up and integrate exogenous DNA into their genome. Bacillus subtilis is one of the naturally competent bacterial species and the domesticated laboratory strain 168 is easily transformable. In this study, we report a reduced transformation frequency of B. subtilis mutants lacking functional and structural flagellar components. This includes hag, the gene encoding the flagellin protein forming the filament of the flagellum. We confirm that the observed decrease of the transformation frequency is due to reduced expression of competence genes, particularly of the main competence regulator gene comK. The impaired competence is due to an increase in the phosphorylated form of the response regulator DegU, which is involved in regulation of both flagellar motility and competence. Altogether, our study identified a close link between motility and natural competence in B. subtilis suggesting that hindrance in motility has great impact on differentiation of this bacterium not restricted only to the transition towards sessile growth stage. PMID- 29124899 TI - Simeprevir oxidative degradation product: Molecular modeling, in silico toxicity and resolution by synchronous spectrofluorimetry. AB - In this article, one of the potential degradation products of the novel antiviral drug simeprevir was isolated and characterized by means of infrared (IR) and mass spectrometry. Moreover, comparative molecular docking, ADMET (absorption, distribution, metabolism, excretion - toxicity) and insilico toxicity prediction studies were applied to evaluate the activity of simeprevir and its degradation product. Furthermore,a simple, accurate and selective second derivative synchronous spectrofluorimetric method was developed for the determination of simeprevir in the presence of its oxidative degradation product.The synchronous fluorescence spectra of both compounds were measured in ethanol at pH 2.0 usingDeltalambda of 140 nm and the peak amplitude of the second derivative spectra were measured at 442 nm. The method was rectilinear over the concentration range of 0.2 to 2.0 MUg/ml and validated according to the ICH (International Conference on Harmonization) guidelines. Moreover, the method was statistically compared to the reverse-phase high-performance liquid chromatography (RP-HPLC) method and good results were obtained. PMID- 29124900 TI - Unsatisfactory exfoliative anal cytology samples, 15-year experience with histologic, cytologic, and molecular follow-up. AB - BACKGROUND: The incidence of anal carcinoma has risen in recent decades. Exfoliative cytology screening of selected high risk patients is performed in many centers. Unsatisfactory cytology results are frustrating to patients, clinicians, and laboratorians. The aim of this study is to ascertain outcomes of patients with non-diagnostic anal cytology. METHODS: A retrospective review of anal cytology testing performed at the Cleveland Clinic between 01/01/2001 and 12/31/2015 was performed. All cases were received as liquid-based samples and processed as ThinPreps (Hologic, Marlborough, MA). Co-testing for HR-HPV DNA was performed using Hybrid Capture 2(r) (Qiagen, Germantown, MD) in the majority of patients. RESULTS: Of 1,276 ThinPrep anal cytology samples, 130 (10%) were deemed unsatisfactory. 77% of patients were HIV positive. 85% were males. Of the unsatisfactory cases, 116 (89%) were co-tested for HR-HPV DNA. Of those, 40 patients (34%) had a simultaneous positive HR-HPV DNA. Adequate follow up cytology within a one year and a two year period revealed that 18/130 (14%) and 26/130 (20%) of patients had ASC or SIL respectively. Histologic follow-up within one and two years showed 3 patients (2%) and 8 patients (6%) with HSIL or worse. CONCLUSIONS: High risk patients with unsatisfactory anal cytology are not "negative". At least one-third proved to be concomitantly HR-HPV DNA positive with one-fifth showing subsequent cytologic squamous abnormalities and with more than 5% being diagnosed with a high grade intraepithelial lesion within two years. Prompt repeat cytology and/or HR-HPV DNA is recommended for high risk patients with non-diagnostic cytology. PMID- 29124901 TI - Raccoon roundworm (Baylisascaris procyonis) as an occupational hazard: 1. Knowledge of B. procyonis and attitudes towards it and other zoonoses among wildlife rehabilitators. AB - Wildlife rehabilitators are at risk of zoonotic diseases because they often have prolonged contact with many species of wildlife and their bodily fluids. Raccoon roundworm (Baylisascaris procyonis) is a common zoonotic parasite of raccoons that has the potential to cause severe or fatal neurologic disease in a broad variety of hosts if the eggs within raccoon faeces are ingested. We administered an online survey to wildlife rehabilitators to assess their knowledge regarding aspects of transmission, biology and disease caused by B. procyonis, and also to evaluate attitudes towards wildlife diseases and B. procyonis as an occupational hazard. Knowledge was assessed using multiple choice and true-false questions; attitudes were measured using Likert-type items. A total of 659 complete or near complete responses (missing fewer than three knowledge or attitudes items and/or non-response to some demographic fields) were collected. The median knowledge score was 7/14 questions correct (range: 0-14 correct). Generally, individuals with higher levels of education and rehabilitation experience, veterinary professionals and those who are members of professional wildlife rehabilitation groups scored above the median significantly more often (p < .01). Significantly more rehabilitators who were located in the south-east and those with part-time or infrequent commitments scored below the median overall knowledge score. There was general agreement that B. procyonis is a health risk of rehabilitators and that measures should be taken to control transmission to people and animals. Some factors explaining differences in attitudes include setting of rehabilitation (home versus animal care facility), veterinary profession, region, membership in a wildlife rehabilitation group and rehabilitation of raccoons. Findings emphasize the importance of awareness and mentorship to inform rehabilitators on the potential risks of B. procyonis and other potential zoonoses within captive wildlife settings, and the important role of professional wildlife rehabilitator groups in disseminating educational materials. PMID- 29124903 TI - Relationship between the left ventricular size and the amount of trabeculations. AB - Contemporary imaging modalities offer noninvasive quantification of myocardial deformation; however, they make gross assumptions about internal structure of the cardiac walls. Our aim is to study the possible impact of the trabeculations on the stroke volume, strain, and capacity of differently sized ventricles. The cardiac left ventricle is represented by an ellipsoid and the trabeculations by a tissue occupying a fixed volume. The ventricular contraction is modeled by scaling the ellipsoid whereupon the measurements of longitudinal strain, end diastolic, end-systolic, and stroke volumes are derived and compared. When the trabeculated and nontrabeculated ventricles, having the same geometry and deformation pattern, contain the same amount of blood and contract with the same strain, we observed an increased stroke volume in our model of the trabeculated ventricle. When these ventricles contain and eject the same amount of blood, we observed a reduced strain in the trabeculated case. We identified that a trade off between the strain and the amount of trabeculations could be reached with a 0.35- to 0.41-cm dense trabeculated layer, without blood filled recesses (for a ventricle with end-diastolic volume of about 150 mL). A trabeculated ventricle can work at lower strains compared to a nontrabeculated ventricle to produce the same stroke volume, which could be a possible explanation why athletes and pregnant women develop reversible signs of left ventricular noncompaction, since the trabeculations could help generating extra cardiac output. This knowledge might help to assess heart failure patients with dilated cardiomyopathies who often show signs of noncompaction. PMID- 29124902 TI - T-cell responses against rhinovirus species A and C in asthmatic and healthy children. AB - BACKGROUND: Infections by rhinovirus (RV) species A and C are the most common causes of exacerbations of asthma and a major cause of exacerbations of other acute and chronic respiratory diseases. Infections by both species are prevalent in pre-school and school-aged children and, particularly for RV-C, can cause severe symptoms and a need for hospitalization. While associations between RV infection and asthma are well established, the adaptive immune-mechanisms by which RV infections influence asthma exacerbations are yet to be defined. OBJECTIVE: The aim of this study was to characterize and compare T-cell responses between RV-A and RV-C and to test the hypothesis that T-cell responses would differ between asthmatic children and healthy controls. METHODS: A multi parameter flow cytometry assay was used to characterize the in vitro recall T cell response against RV-A and RV-C in PBMCs from children with acute asthma (n = 22) and controls (n = 26). The responses were induced by pools of peptides containing species-specific VP1 epitopes of RV-A and RV-C. RESULTS: Regardless of children's clinical status, all children that responded to the in vitro stimulation (>90%) had a similar magnitude of CD4+ T-cell responses to RV-A and RV-C. However, asthmatic children had a significantly lower number of circulating regulatory T cells (Tregs), and healthy controls had significantly more Tregs induced by RV-A than RV-C. CONCLUSIONS AND CLINICAL RELEVANCE: The comparable recall memory T-cell responses in asthmatic and control children to both RV-A and RV-C show that differences in the antibody and inflammatory responses previously described are likely to be due to regulation, with a demonstrated candidate being reduced regulatory T-cells. The reduced Treg numbers demonstrated here could explain the asthmatic's inability to appropriately control immunopathological responses to RV infections. PMID- 29124904 TI - Mind the gaps in research on the control of gastrointestinal nematodes of farmed ruminants and pigs. AB - Gastrointestinal (GI) nematode control has an important role to play in increasing livestock production from a limited natural resource base and to improve animal health and welfare. In this synthetic review, we identify key research priorities for GI nematode control in farmed ruminants and pigs, to support the development of roadmaps and strategic research agendas by governments, industry and policymakers. These priorities were derived from the DISCONTOOLS gap analysis for nematodes and follow-up discussions within the recently formed Livestock Helminth Research Alliance (LiHRA). In the face of ongoing spread of anthelmintic resistance (AR), we are increasingly faced with a failure of existing control methods against GI nematodes. Effective vaccines against GI nematodes are generally not available, and anthelmintic treatment will therefore remain a cornerstone for their effective control. At the same time, consumers and producers are increasingly concerned with environmental issues associated with chemical parasite control. To address current challenges in GI nematode control, it is crucial to deepen our insights into diverse aspects of epidemiology, AR, host immune mechanisms and the socio-psychological aspects of nematode control. This will enhance the development, and subsequent uptake, of the new diagnostics, vaccines, pharma-/nutraceuticals, control methods and decision support tools required to respond to the spread of AR and the shifting epidemiology of GI nematodes in response to climatic, land-use and farm husbandry changes. More emphasis needs to be placed on the upfront evaluation of the economic value of these innovations as well as the socio-psychological aspects to prioritize research and facilitate uptake of innovations in practice. Finally, targeted regulatory guidance is needed to create an innovation-supportive environment for industries and to accelerate the access to market of new control tools. PMID- 29124908 TI - Review of transmission routes of 24 infectious diseases preventable by biosecurity measures and comparison of the implementation of these measures in pig herds in six European countries. AB - This study aimed to review the transmission routes of important infectious pig diseases and to translate these into biosecurity measures preventing or reducing the transmission between and within pig herds. Furthermore, it aimed to identify the level of implementation of these measures in different European countries and discuss the observed variations to identify potentials for improvement. First, a literature review was performed to show which direct and indirect transmission routes of 24 infectious pig diseases can be prevented through different biosecurity measures. Second, a quantitative analysis was performed using the Biocheck.UGentTM, a risk-based scoring system to evaluate biosecurity in pig herds, to obtain an insight into the implementation of these biosecurity measures. The database contained farm-specific biosecurity data from 574 pig farms in Belgium, Denmark, France, Germany, the Netherlands and Sweden, entered between January 2014 and January 2016. Third, a qualitative analysis based on a review of literature and other relevant information resources was performed for every subcategory of internal and external biosecurity in the Biocheck.UGentTM questionnaire. The quantitative analysis indicated that at the level of internal, external and overall biosecurity, Denmark had a significantly distinct profile with higher external biosecurity scores and less variation than the rest of the countries. This is likely due to a widely used specific pathogen-free (SPF) system with extensive focus on biosecurity since 1971 in Denmark. However, the observed pattern may also be attributed to differences in data collection methods. The qualitative analysis identified differences in applied policies, legislation, disease status, pig farm density, farming culture and habits between countries that can be used for shaping country-specific biosecurity advice to attain improved prevention and control of important pig diseases in European pig farms. PMID- 29124905 TI - Rapid and simple detection of foot-and-mouth disease virus: Evaluation of a cartridge-based molecular detection system for use in basic laboratories. AB - Highly contagious transboundary animal diseases such as foot-and-mouth disease (FMD) are major threats to the productivity of farm animals. To limit the impact of outbreaks and to take efficient steps towards a timely control and eradication of the disease, rapid and reliable diagnostic systems are of utmost importance. Confirmatory diagnostic assays are typically performed by experienced operators in specialized laboratories, and access to this capability is often limited in the developing countries with the highest disease burden. Advances in molecular technologies allow implementation of modern and reliable techniques for quick and simple pathogen detection either in basic laboratories or even at the pen-side. Here, we report on a study to evaluate a fully automated cartridge-based real time RT-PCR diagnostic system (Enigma MiniLab(r) ) for the detection of FMD virus (FMDV). The modular system integrates both nucleic acid extraction and downstream real-time RT-PCR (rRT-PCR). The analytical sensitivity of this assay was determined using serially diluted culture grown FMDV, and the performance of the assay was evaluated using a selected range of FMDV positive and negative clinical samples of bovine, porcine and ovine origin. The robustness of the assay was evaluated in an international inter-laboratory proficiency test and by deployment into an African laboratory. It was demonstrated that the system is easy to use and can detect FMDV with high sensitivity and specificity, roughly on par with standard laboratory methods. This cartridge-based automated real-time RT-PCR system for the detection of FMDV represents a reliable and easy to use diagnostic tool for the early and rapid disease detection of acutely infected animals even in remote areas. This type of system could be easily deployed for routine surveillance within endemic regions such as Africa or could alternatively be used in the developed world. PMID- 29124909 TI - Ameloblastic carcinoma with metastasis to the parotid gland. PMID- 29124910 TI - Missing pieces of the puzzle to effectively control digital dermatitis. AB - Since the first report of bovine digital dermatitis (DD) in 1974, there is a large body of the literature published; however, effective prevention and control of the disease remain elusive. Although many aspects of the pathogenesis of DD have been investigated, even some of the most basic questions such as the aetiology of this disease remain under debate. Treponema spp. have been strongly associated with DD lesions and occur in abundance in advanced lesions; however, efforts to induce disease with pure cultures of these organisms have been largely underwhelming and inconsistent. Furthermore, although the disease has been presented for several decades, there is limited scientific evidence regarding effective treatment of DD. Apparent discrepancies between effectiveness in vitro and in vivo have challenged the scientific community to identify new potential treatment options. With no treatment resulting in a 100% cure rate, the current expectation is manageable control, but prospects for the eradication of the disease are unlikely using current approaches. In order to develop more effective approaches to control DD on-farm, there is a critical need for a deeper understanding regarding the causation, ecology, transmission and treatment of this disease. In this article, we attempt to provide insights into specific research needs related to DD in order to assist the industry, researchers, pharmaceutical companies and research sponsors with decision-making and identified research gaps. PMID- 29124911 TI - First North American validation and head-to-head comparison of four preoperative nomograms for prediction of lymph node invasion before radical prostatectomy. AB - OBJECTIVES: To perform a head-to-head comparison of four nomograms; namely, the Cagiannos, the 2012-Briganti, the Godoy and the online-Memorial Sloan Kettering Cancer Center (MSKCC), for prediction of lymph node invasion (LNI) in a North American population. PATIENTS AND METHODS: A total of 19 775 patients with clinically localized prostate cancer (PCa) who had undergone radical prostatectomy and pelvic lymph node dissection (PLND) were identified within the Surveillance Epidemiology and End Results (SEER) database. All four nomograms were tested using Heagerty's concordance index (C-index), calibration plots and decision curve analysis (DCA). In addition, we examined specific nomogram-derived thresholds to compare the number of avoided PLNDs and missed LNI-positive cases. RESULTS: All nomograms were found to have highly comparable C-index values: the Cagiannos, 78.6%; the Godoy, 78.2%; the 2012-Briganti, 79.8%; and the MSKCC, 79.9%. The Cagiannos nomogram showed the best calibration, followed by the 2012 Briganti, the Godoy and the online-MSKCC. In DCA, the 2012-Briganti and the Cagiannos, in that order, provided the best results, followed by the Godoy and the online-MSKCC models. For each nomogram, the threshold associated with <=10% missed LNI cases avoided 8 693 (46.6%), 8 652 (46.4%), 8 461 (45.4%) and 8 590 (46.1%) PLNDs, respectively, with the use of the Cagiannos (2.6% threshold), the online-MSKCC (4.3% threshold), the Godoy (3.6% threshold) and the 2012-Briganti (4.6% threshold) nomograms. CONCLUSION: The Cagiannos and the 2012-Briganti nomograms exhibited the best calibrations and DCA results. Conversely, C-index values and ability to avoid unnecessary PLNDs were virtually the same for all four nomograms examined. PMID- 29124912 TI - Metastatic medullary thyroid carcinoma or calcitonin-secreting carcinoid tumor of lung? A diagnostic dilemma in a patient with lung mass and thyroid nodule. AB - Calcitonin-secreting neuroendocrine tumors are rare and have been reported in literature as case reports or case series in various organs including lung, pancreas, larynx, bladder, and ovary. These tumors have similar cytologic features and immunohistochemical profile to medullary thyroid carcinoma and thus it is difficult to distinguish them, especially when calcitonin-secreting neuroendocrine tumors are intermediate or higher grade and there is a mass lesion in the thyroid gland. Here, we report a rare case of calcitonin secreting atypical carcinoid tumor of the lung in a patient with thyroid nodule. However, after extensive ancillary studies on the thyroid gland, no tumor was detected and subsequent resection specimen revealed a pulmonary atypical carcinoid tumor with metastasis to level 11 lymph node. Being aware of this entity has significant clinical, diagnostic, and therapeutic implications and can prevent unnecessary thyroidectomies with subsequent possible morbidities. PMID- 29124914 TI - Experiences of using simulation in dementia education. AB - This article describes the development of a simulation training day for multidisciplinary teams (MDTs) working on acute adult wards with the aim of improving their confidence in supporting people with dementia who are distressed. Recommendations are made for those who may be interested in delivering simulation training in their area of practice. Registered nurses, non-registered support workers and occupational therapists experienced in dementia care took part in a one-day simulation training pilot session that included three 'skill stations' with three patient simulation scenarios. A session at the end of the day was used to generate qualitative feedback and develop a strategy to advance this style of teaching. Feedback highlighted the need for further development of the skill stations and scenarios. The pilot showed that simulation training works well from an MDT perspective, but the content requires careful consideration in terms of stretching participants' abilities without causing high levels of anxiety. PMID- 29124913 TI - Measurement of lying and standing blood pressure in hospital. AB - Measuring lying and standing blood pressure (BP) is an important clinical observation in older hospital inpatients. This is because a drop in BP on standing, known as orthostatic hypotension (OH) is common in older people and in acute illness and, therefore, in hospital patients. OH increases the risk of a fall in hospital. Simple measures such as changes in medication or rehydration can reduce this drop in BP and reduce the risk of falls. In a recent snapshot audit in England and Wales of 179 acute hospitals and 4,846 patients aged 65 years and over admitted with an acute illness, only 16% had a lying and standing BP recorded within 48 hours. A review of the literature showed that existing advice on how to measure and interpret lying and standing BP was often not appropriate for use on the ward with frail and unwell inpatients. An online survey of 275 clinicians' usual practice highlighted variation and the need for clarity and pragmatism. In the light of the survey findings, a clinical guide has been developed on when to measure lying and standing BP, how to measure it and what is considered a significant result. PMID- 29124915 TI - Views on ageing in place from relocated low-income housing residents in the US. AB - BACKGROUND: Ageing in place (AIP) is the ability to live in one's home and community independently, despite age, ability level or income. AIM: To elicit knowledge and feelings about AIP from low-income older adults relocated to low income housing. METHOD: Nursing students, supervised by nursing faculty trained in research, conducted semi-structured interviews about AIP with volunteer residents living in a low-income apartment complex in the southern US. FINDINGS: Seven participants discussed common fears and worries as well as needs for AIP in low-income housing. Mental health issues were prominent. CONCLUSION: Mental health warrants consideration along with physical, social and emotional well being in beginning to identify and address the needs of older people ageing anywhere, perhaps especially in relocated low-income older adults. This information could inform future interventions to encourage AIP in the US and potentially in other countries. PMID- 29124916 TI - How collaboration is improving acute hospital admission for people with dementia. AB - In November 2015 it became apparent that a person with dementia's journey through the acute hospital was not always as streamlined as it should have been. There was evidence of late and multiple inter-ward transfers for this patient group that could potentially have a detrimental effect on individuals' and carers' well being. The aim of this project was to examine current processes around patient flow and decision-making, explore any themes arising and identify opportunities for improving transitions of care. Collaborative working among various specialties has resulted in increased transfers before 8pm, a reduction in transfers after midnight and a reduction in inter-ward transfers. PMID- 29124917 TI - Oral hygiene and mouth care for older people in acute hospitals: part 1. AB - The oral health of older people in acute hospitals has rarely been studied. Hospital admission provides a prime opportunity for identification and rectification of problems, and oral health promotion. This two-part article explores oral hygiene and mouth care provision for older adults in acute hospitals. The first article presents the findings of a literature review exploring oral and dental disease in older adults, the importance of good oral health and mouth care, and the current situation. Searches of electronic databases and the websites of relevant professional health service bodies in the UK were undertaken to identify articles and guidelines. The literature shows a high prevalence of oro-dental disease in this population, with many known detrimental effects, combined with suboptimal oral hygiene and mouth care provision in acute hospitals. Several guidelines exist, although the emphasis on oral health is weaker than other aspects of hospital care. Older adults admitted to acute hospitals have a high burden of oro-dental disease and oral and mouth care needs, but care provision tends to be suboptimal. The literature is growing, but this area is still relatively neglected. Great potential exists to develop oral and mouth care in this context. The second part of this article explores clinical recommendations. PMID- 29124918 TI - Approaches to acute pain management in older people. AB - Pain is a diverse, individual experience and is associated with distress and suffering. Uncontrolled acute pain has been linked to delayed recovery and prolonged hospital stay. Nurses have a duty of care to their patients and acute pain management is integral to this. However, acute pain in older people can be difficult to manage, often because of under-reporting or difficulties in assessment. Older people have altered physiology often compounded by multiple co morbidities and polypharmacy, all of which affect the appropriateness of, and available, pharmacological pain management strategies. In addition, older people are at greater risk of adverse drug reactions, drug interactions and side effects from analgesia. Consequently, non-pharmacological strategies should also be integral to pain management. PMID- 29124919 TI - Location and expression of Juno in mice oocytes during maturation. AB - OBJECTIVE: Oocyte-sperm interaction is the essential step in fertilization. Juno, which has been known as Folate receptor 4, is the Izumo1 receptor expressed on the oocyte membrane. This study aims to investigate the location and expression of Juno in mice oocytes during maturation. METHODS: To confirm the stage at which Juno expression begins in the mice oocytes and its location pattern, we performed immunostaining methods. Next, we evaluated Juno mRNA expression by a half quantitative RT-PCR. Juno knockdown oocytes were generated by microinjecting siRNA into the germinal vesicle (GV) stage oocytes, and analyzed the maturation rate. RESULTS: Our results showed that Juno was expressed on the surface of the oocyte cytoplasmic membrane at the GV stage and it continues to be expressed at similar levels in the metaphase II (MII) stages of oocytes maturation. Interestingly, Juno is also expressed on the first polar body membrane at the MII stage. Fluorescence showing Juno expression was decreased in the oolemma of siRNA injected oocytes, but it was not completely disappearing in knock down oocytes. MII stage-rates of siRNA injected oocytes were not significantly different from sham controls. CONCLUSION: Juno was expressed in oocytes at the GV stage and it continues to be expressed at similar levels in later stages of oocytes maturation. Juno accumulation in oolemma during oocyte maturation is essential for fertilization, such as membrane recognition of both gametes. PMID- 29124920 TI - Nanocolloidosomes with Selective Drug Release for Active Tumor-Targeted Imaging Guided Photothermal/Chemo Combination Therapy. AB - Selective drug release is highly desirable for photothermal/chemo combination therapy when two or even more theranostic agents are encapsulated together within the same nanocarrier. A conventional nanocarrier can hardly achieve this goal. Herein, doxorubicin and indocyanine green (DOX/ICG)-loaded nanocolloidosomes (NCs), with selective drug release, were fabricated as a novel multifunctional theranostic nanoplatform for photothermal/chemo combination therapy. Templating from galactose-functionalized hydroxyethyl starch-polycaprolactone (Gal-HES-PCL) nanoparticles-stabilized Pickering emulsions, the resultant DOX/ICG@Gal-HES-PCL NCs had a diameter of around 140 nm and showed an outstanding tumor-targeting ability, preferable tumor penetration capability, and promotion of photothermal effect. Moreover, these NCs can be used for NIR fluorescence imaging and thus render real-time imaging of solid tumors with high contrast. Collectively, such NCs achieved the best in vivo antitumor efficacy combined with laser irradiation compared with DOX/ICG@HES-PCL NCs and DOX/ICG mixture. These NCs are valuable for active tumor-targeted imaging-guided combination therapy against liver cancer and potentially other diseases. PMID- 29124921 TI - Effect of Rubidium Incorporation on the Structural, Electrical, and Photovoltaic Properties of Methylammonium Lead Iodide-Based Perovskite Solar Cells. AB - We report the electrical properties of rubidium-incorporated methylammonium lead iodide ((RbxMA1-x)PbI3) films and the photovoltaic performance of (RbxMA1-x)PbI3 film-based p-i-n-type perovskite solar cells (PSCs). The incorporation of a small amount of Rb+ (x = 0.05) increases both the open circuit voltage (Voc) and the short circuit photocurrent density (Jsc) of the PSCs, leading to an improved power conversion efficiency (PCE). However, a high fraction of Rb+ incorporation (x = 0.1 and 0.2) decreases the Jsc and thus the PCE, which is attributed to the phase segregation of the single tetragonal perovskite phase to a MA-rich tetragonal perovskite phase and a RbPbI3 orthorhombic phase at high Rb fractions. Conductive atomic force microscopic and admittance spectroscopic analyses reveal that the single-phase (Rb0.05MA0.95)PbI3 film has a high electrical conductivity because of a reduced deep-level trap density. We also found that Rb substitution enhances the diode characteristics of the PSC, as evidenced by the reduced reverse saturation current (J0). The optimized (RbxMA1-x)PbI3 PSCs exhibited a PCE of 18.8% with negligible hysteresis in the photocurrent-voltage curve. The results from this work enhance the understanding of the effect of Rb incorporation into organic-inorganic hybrid halide perovskites and enable the exploration of Rb-incorporated mixed perovskites for various applications, such as solar cells, photodetectors, and light-emitting diodes. PMID- 29124922 TI - Catalyst-Controlled Stereoselective Synthesis Secures the Structure of the Antimalarial Isocyanoterpene Pustulosaisonitrile-1. AB - Three new isocyanoditerpenes (5-7) have been characterized from Australian specimens of the nudibranch Phyllidiella pustulosa. The planar structure and (3R,6S,7R) absolute configuration of pustulosaisonitrile-1 were deduced by spectroscopic analyses at 900 MHz informed by molecular modeling, DFT calculations, and computational NMR chemical shift predictions and by comparison of experimental electronic circular dichroism (ECD) data with TDDFT-ECD calculations for the truncated model compound 8. A catalyst-controlled enantio- and diastereoselective total synthesis of the two most likely diastereomeric candidates for the structure of 5 solidified its (3R,6S,7R,10S,11R,14R) absolute configuration. Three individual enantioselective methods provided stereochemical control at key positions, permitting an unambiguous final structural assignment. Isocyanide 5 and synthetic diastereomers 5a and 5c showed activity against Plasmodium falciparum malaria parasites (IC50 ~1 MUM). PMID- 29124923 TI - Palladium-Catalyzed Decarboxylative ortho-Acylation of Benzamides with alpha Oxocarboxylic Acids. AB - A palladium-catalyzed decarboxylative ortho-acylation of tertiary benzamides with alpha-oxocarboxylic acids by weak O-coordination has been described. This reaction proceeds smoothly with a high monoacylation selectivity, affording ortho acylated benzamides in moderate to good yields. When secondary benzamides are employed as the substrates, the formed ortho-acylated benzamides undergo further intramolecular cyclization to provide isoindolinone derivatives. In addition, several transformations of the synthesized ortho-acylated benzamides into a diversity of synthetically valuable products have been demonstrated. PMID- 29124924 TI - Controllable Synthesis of Tunable Microstructures of Self-Supporting Graphene Films from Opened Bubble to Cube via in Situ Template-Modulating. AB - Three-dimensional (3D) microstructured building units have replaced layer-to layer stacked designs in transparent graphene films to fully exploit the advantages of two-dimensional graphene. However, it is still challenging to precisely control the size and microstructures of these building blocks to develop multifunctional graphene-based materials that satisfy the performance requirements of diverse applications. In this study, we propose a controllable method to regulate the microstructures of building units to form structures ranging from opened bubbles and cubes, while the size decreased from 20 to 3 MUm, via an in situ template-modulating technology. NaCl was used as either a liquid or solid template by changing the dc bias. The reduced size and dense arrangement of the building units not only provide an improved mass loading for the transparent films but also build multiple pathways for fast ion/electron transmission, enhancing their promise for various practical applications. Generally, we provide a convenient protocol for finely regulating the microstructure and size of these building units, resulting in multifunctional films with a controllable transmittance, which enables the use of these graphene based architectures as transparent electrodes in various applications and extends the family of multifunctional materials that will present new possibilities for electronics and other devices. PMID- 29124925 TI - Organic Gas Sensor with an Improved Lifetime for Detecting Breath Ammonia in Hemodialysis Patients. AB - In this work, a TFB (poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-(4,4'-(N-(4-s butylphenyl)diphenylamine)]) sensor with a cylindrical nanopore structure exhibits a high sensitivity to ammonia in ppb-regime. The lifetime and sensitivity of the TFB sensor were studied and compared to those of P3HT (poly(3 hexylthiophene)), NPB (N,N'-di(1-naphthyl)-N,N'-diphenyl-(1,1'-biphenyl)-4,4' diamine), and TAPC (4,4'-cyclohexylidenebis[N,N-bis(4-methylphenyl) benzenamine]) sensors with the same cylindrical nanopore structures. The TFB sensor outstands the others in sensitivity and lifetime and it shows a sensing response (current variation ratio) of 13% to 100 ppb ammonia after 64 days of storage in air. A repeated sensing periods testing and a long-term measurement have also been demonstrated for the test of robustness. The performance of the TFB sensor is stable in both tests, which reveals that the TFB sensor can be utilized in our targeting clinical trials. In the last part of this work, we study the change of ammonia concentration in the breath of hemodialysis (HD) patients before and after dialysis. An obvious drop of breath ammonia concentration can be observed after dialysis. The reduction of breath ammonia is also correlated with the reduction of blood urea nitrogen (BUN). A correlation coefficient of 0.82 is achieved. The result implies that TFB sensor may be used as a real-time and low cost breath ammonia sensor for the daily tracking of hemodialysis patients. PMID- 29124926 TI - Thin and Flexible Fe-Si-B/Ni-Cu-P Metallic Glass Multilayer Composites for Efficient Electromagnetic Interference Shielding. AB - Thin and flexible materials that can provide efficient electromagnetic interference (EMI) shielding are urgently needed, especially if they can be easily processed and withstand harsh environments. Herein, layer-structured Fe-Si B/Ni-Cu-P metallic glass composites have been developed by simple electroless plating Ni-Cu-P coating on commercial Fe-Si-B metallic glasses. The 0.1 mm-thick composite shows EMI shielding effectiveness of 40 dB over the X-band frequency range, which is higher than those of traditional metals, metal oxides, and their polymer composites of larger thickness. Most of the applied electromagnetic waves are proved to be absorbed rather than bounced back. This performance originates from the combination of a superior soft magnetic property, excellent electrical conductivity, and multiple internal reflections from multilayer composites. In addition, the flexible composites also exhibit good corrosion resistance, high thermal stability, and excellent tensile strength, making them suitable for EMI shielding in harsh chemical or thermal environments. PMID- 29124927 TI - Integrated, Continuous Emulsion Creamer. AB - Automated and reproducible sample handling is a key requirement for high throughput compound screening and currently demands heavy reliance on expensive robotics in screening centers. Integrated droplet microfluidic screening processors are poised to replace robotic automation by miniaturizing biochemical reactions to the droplet scale. These processors must generate, incubate, and sort droplets for continuous droplet screening, passively handling millions of droplets with complete uniformity, especially during the key step of sample incubation. Here, we disclose an integrated microfluidic emulsion creamer that packs ("creams") assay droplets by draining away excess oil through microfabricated drain channels. The drained oil coflows with creamed emulsion and then reintroduces the oil to disperse the droplets at the circuit terminus for analysis. Creamed emulsion assay incubation time dispersion was 1.7%, 3-fold less than other reported incubators. The integrated, continuous emulsion creamer (ICEcreamer) was used to miniaturize and optimize measurements of various enzymatic activities (phosphodiesterase, kinase, bacterial translation) under multiple- and single-turnover conditions. Combining the ICEcreamer with current integrated microfluidic DNA-encoded library bead processors eliminates potentially cumbersome instrumentation engineering challenges and is compatible with assays of diverse target class activities commonly investigated in drug discovery. PMID- 29124928 TI - Contact Selectivity Engineering in a 2 MUm Thick Ultrathin c-Si Solar Cell Using Transition-Metal Oxides Achieving an Efficiency of 10.8. AB - In this paper, the integration of metal oxides as carrier-selective contacts for ultrathin crystalline silicon (c-Si) solar cells is demonstrated which results in an ~13% relative improvement in efficiency. The improvement in efficiency originates from the suppression of the contact recombination current due to the band offset asymmetry of these oxides with Si. First, an ultrathin c-Si solar cell having a total thickness of 2 MUm is shown to have >10% efficiency without any light-trapping scheme. This is achieved by the integration of nickel oxide (NiOx) as a hole-selective contact interlayer material, which has a low valence band offset and high conduction band offset with Si. Second, we show a champion cell efficiency of 10.8% with the additional integration of titanium oxide (TiOx), a well-known material for an electron-selective contact interlayer. Key parameters including Voc and Jsc also show different degrees of enhancement if single (NiOx only) or double (both NiOx and TiOx) carrier-selective contacts are integrated. The fabrication process for TiOx and NiOx layer integration is scalable and shows good compatibility with the device. PMID- 29124930 TI - Dual Internal Standards with Metals and Molecules for MALDI Imaging of Kidney Lipids. AB - The quest for internal standards useful in MALDI imaging studies goes on to get not only lateral distribution but also reliable relative quantitative information. We developed a method based on application of matrix and dual internal standards to allow intra- and intersample normalization of lipids intensities in kidney sections of control and cisplatin-treated Wistar rats. An inkjet printer was used to deposit a custom-prepared ink with DHB as MALDI matrix, a primary lipids-based internal standard, and a spiked lanthanide as a secondary internal standard. We applied different laser energy and varied the amounts of matrix-internal standards mixture to evaluate the normalization potential of the internal standards. Successful correction of intensity artifacts caused by instrumental drifts was possible, but not those resulting from uneven matrix application. ICP-MS absolute quantification of the lanthanide in the printed layer ensured the reproducibility of the matrix and internal standards application with RSD of 10-15%. Internal standard-normalized data allowed intrasample modification of the MALDI image to make it compatible with the optical image. Normalization to internal standards corrected a 2-fold difference in lipids intensity, which allowed a meaningful comparison of tissue lipids in control and cisplatin-treated kidneys. More importantly, normalization of lipid relative abundances based on the same adduct type (H+, Na+, and K+) for analyte and internal standard corrected for different ionization efficiencies showing a realistic signal level and enabling reliable comparison of different samples on relative quantitative basis. PMID- 29124929 TI - Injectable Polymeric Cytokine-Binding Nanowires Are Effective Tissue-Specific Immunomodulators. AB - Injectable nanomaterials that interact with the host immune system without surgical intervention present spatially anchored complements to cell transplantation and could offer improved pharmacokinetics compared to systemic cytokine therapy. Here we demonstrate fabrication of high aspect ratio polycaprolactone nanowires coupled with cytokine-binding antibodies that assemble into porous matrices when injected into the subcutaneous space. These structures are fabricated using a nanotemplating technique that allows for tunability of particle dimensions and utilize a straightforward maleimide conjugation chemistry to allow site-specific coupling to proteins. Nanowires are well tolerated in vivo and incite minimal inflammatory infiltrate. Nanowires conjugated with antibodies were designed to capture and potentiate endogenous interleukin-2 (IL-2), an important leukocyte activating cytokine. Together these nanowire-antibody matrices were capable of localizing endogenous IL-2 in the skin and activated targeted specific natural killer and T cell subsets, demonstrating both tissue- and cell-specific immune activation. These self-assembling nanowire matrices show promise as scaffolds to present engineered, local receptor-ligand interactions for cytokine-mediated disease. PMID- 29124931 TI - Influence of Homogenization and Thermal Processing on the Gastrointestinal Fate of Bovine Milk Fat: In Vitro Digestion Study. AB - Dairy lipids are an important source of energy and nutrients for infants and adults. The dimensions, aggregation state, and interfacial properties of fat globules in raw milk are changed by dairy processing operations, such as homogenization and thermal processing. These changes influence the behavior of fat globules within the human gastrointestinal tract (GIT). The gastrointestinal fate of raw milk, homogenized milk, high temperature short time (HTST) pasteurized milk, and ultrahigh temperature (UHT) pasteurized milk samples was therefore determined using a simulated GIT. The properties of particles in different regions of the GIT depended on the degree of milk processing. Homogenization increased the initial lipid digestion rate but did not influence the final digestion extent. Thermal processing of homogenized milk decreased the initial rate and final extent of lipid digestion, which was attributed to changes in interfacial structure. These results provide insights into the impact of dairy processing on the gastrointestinal fate of milk fat. PMID- 29124932 TI - Effects of Environmental Stresses and in Vitro Digestion on the Release of Tocotrienols Encapsulated Within Chitosan-Alginate Microcapsules. AB - Considering the health benefits of tocotrienols, continuous works have been done on the encapsulation and delivery of these compounds. In this study, we encapsulated tocotrienols in chitosan-alginate microcapsules and evaluated their release profile. Generally, these tocotrienols microcapsules (TM) displayed high thermal stability. When subjected to pH adjustments (pH 1-9), we observed that the release of tocotrienols was the highest (33.78 +/- 0.18%) under basic conditions. The TM were also unstable against the effect of ionic strength, with a high release (70.73 +/- 0.04%) of tocotrienols even at a low sodium chloride concentration (50 mM). As for the individual isomers, delta-tocotrienol was the most sensitive to pH and ionic strength. In contrast, beta-/gamma-tocotrienols were the most ionic-stable isomers but more responsive toward thermal treatment. Simulated gastrointestinal model showed that the chitosan-alginate-based TM could be used to retain tocotrienols in the gastric and subsequently release them in the intestines for possible absorption. PMID- 29124933 TI - Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga. AB - Polycavernosides A and B are glycosidic macrolide natural products isolated as the toxins causing fatal human poisoning by the edible red alga Gracilaria edulis (Polycavernosa tsudai). Total synthesis of polycavernosides A and B has been achieved via a convergent approach. The synthesis of the macrolactone core structure is highlighted by the catalytic asymmetric syntheses of the two key fragments using hetero-Diels-Alder reaction and Kiyooka aldol reaction as the key steps, their union through Suzuki-Miyaura coupling, and Keck macrolactonization. Finally, glycosylation with the l-fucosyl-d-xylose unit and construction of the polyene side chain through Stille coupling completed the total synthesis of polycavernosides A and B. PMID- 29124934 TI - Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors? AB - Reversible covalent inhibitors have many clinical advantages over noncovalent or irreversible covalent drugs. However, apart from selecting a warhead, substantial efforts in design and synthesis are needed to optimize noncovalent interactions to improve target-selective binding. Computational prediction of binding affinity for reversible covalent inhibitors presents a unique challenge since the binding process consists of multiple steps, which are not necessarily independent of each other. In this study, we lay out the relation between relative binding free energy and the overall reversible covalent binding affinity using a two-state binding model. To prove the concept, we employed free energy perturbation (FEP) coupled with lambda-exchange molecular dynamics method to calculate the binding free energy of a series of alpha-ketoamide analogues relative to a common warhead scaffold, in both noncovalent and covalent binding states, and for two highly homologous proteases, calpain-1 and calpain-2. We conclude that covalent binding state alone, in general, can be used to predict reversible covalent binding selectivity. However, exceptions may exist. Therefore, we also discuss the conditions under which the noncovalent binding step is no longer negligible and propose to combine the relative FEP calculations with a single QM/MM calculation of warhead to predict the binding affinity and binding kinetics. Our FEP calculations also revealed that covalent and noncovalent binding states of an inhibitor do not necessarily exhibit the same selectivity. Thus, investigating both binding states, as well as the kinetics will provide extremely useful information for optimizing reversible covalent inhibitors. PMID- 29124935 TI - Enzymatic and Chemoenzymatic Syntheses of Disialyl Glycans and Their Necrotizing Enterocolitis Preventing Effects. AB - Necrotizing enterocolitis (NEC) is one of the most common and devastating intestinal disorders in preterm infants. Therapies to meet the clinical needs for this special and highly vulnerable population are extremely limited. A specific human milk oligosaccharide (HMO), disialyllacto-N-tetraose (DSLNT), was shown to contribute to the beneficial effects of breastfeeding as it prevented NEC in a neonatal rat model and was associated with lower NEC risk in a human clinical cohort study. Herein, gram-scale synthesis of two DSLNT analogs previously shown to have NEC preventing effect is described. In addition, four novel disialyl glycans have been designed and synthesized by enzymatic or chemoenzymatic methods. Noticeably, two disialyl tetraoses have been produced by enzymatic sialylation of chemically synthesized thioethyl beta-disaccharides followed by removal of the thioethyl aglycon. Dose-dependent and single-dose comparison studies showed varying NEC-preventing effects of the disialyl glycans in neonatal rats. This study helps to refine the structure requirement of the NEC-preventing effect of disialyl glycans and provides important dose-dependent information for using DSLNT analogs as potential therapeutics for NEC prevention in preterm infants. PMID- 29124936 TI - In Vivo Computed Tomography/Photoacoustic Imaging and NIR-Triggered Chemo Photothermal Combined Therapy Based on a Gold Nanostar-, Mesoporous Silica-, and Thermosensitive Liposome-Composited Nanoprobe. AB - Safe multifunctional nanoplatforms that have multiple therapeutic functions integrated with imaging capabilities are highly desired for biomedical applications. In this paper, targeted chemo-photothermal synergistic therapy and photoacoustic/computed tomography imaging of tumors were achieved by one novel multifunctional nanoprobe (GMS/DOX@SLB-FA); it was composed of a gold nanostar core and a doxorubicin (DOX)-loaded mesoporous silica shell (GMS), which was coated with a folic acid (FA)-modified thermosensitively supported lipid bilayer (SLB-FA) as a gatekeeper. The multifunctional probe had perfect dispersion and stability; 2.1 nm mesoporous pores and 208 nm hydration particle sizes were obtained. In vitro studies indicated that the drug-loaded probe had excellent ability to control the release of DOX, with 71.98 +/- 2.52% cumulative release after laser irradiation, which was significantly higher than that of unirradiated control group. A survival rate of 72.75 +/- 4.37% of HeLa cells at 57.75 MUg/mL probe also demonstrated the low cytotoxicity of the targeted probe. Both in vitro and in vivo results showed that the probe could achieve targeted photoacoustic imaging of tumors because of the fact that the FA-modified probe could specifically recognize the overexpressed FA receptors on tumor cells; meanwhile, the probe could also achieve the chemo-photothermal synergistic therapy of tumors through controlling the drug release from mesoporous channels by a near-infrared laser. Therefore, the probe had great potential in the early diagnosis and treatment of cancer. PMID- 29124937 TI - An Implantable Transparent Conductive Film with Water Resistance and Ultrabendability for Electronic Devices. AB - Recently, instead of indium tin oxide, the random mesh pattern of metallic nanowires for flexible transparent conducting electrodes (FTCEs) has received a great amount of interest due to its flexibility, low resistance, reasonable price, and compliant processes. Mostly, nanowires for FTCEs are fabricated by spray or mayer coating methods. However, the metallic nanowire layer of FTCEs, which is fabricated by these methods, has a spiked surface roughness and low junction contact between the nanowires that lead to their high sheet resistance value. Also, the nanowires on FTCEs are easy to peel-off through exterior forces such as bending, twisting, or contact. To solve these problems, we demonstrate novel methods through which silver nanowires (AgNWs) are deposited onto a nanosize porous nitrocellulose (NC) substrate by electrophoretic deposition (EPD) and an opaque and porous substrate. Respectively, through dimethyl sulfoxide treatment, AgNWs on NC (AgNW/NC) is changed to the transparent and nonporous FTCEs. This enhances the junction contact of the AgNWs by EPD and also allows a permanent attachment of AgNWs onto the substrate. To show the mechanical strength of the AgNWs on the transparent nitrocellulose (AgNW/TNC), it is tested by applying diverse mechanical stress, such as a binding test (3M peel-off), compressing, bending, twisting, and folding. Next, we demonstrate that AgNW/TNC can be effectively implanted onto normal newspapers and papers. As paper electronics, light-emitting diodes, which are laminated onto paper, are successfully operated through a basic AgNW/TNC strip circuit. Finally, it is demonstrated that AgNW/TNC and AgNW/TNC on paper are water resistant for 15 min due to the insulation properties of the nonporous substrate. PMID- 29124939 TI - Subsecond-Resolved Molecular Measurements in the Living Body Using Chronoamperometrically Interrogated Aptamer-Based Sensors. AB - Electrochemical, aptamer-based (E-AB) sensors support the continuous, real-time measurement of specific small molecules directly in situ in the living body over the course of many hours. They achieve this by employing binding-induced conformational changes to alter electron transfer from a redox-reporter-modified, electrode-attached aptamer. Previously we have used voltammetry (cyclic, alternating current, and square wave) to monitor this binding-induced change in transfer kinetics indirectly. Here, however, we demonstrate the potential advantages of employing chronoamperometry to measure the change in kinetics directly. In this approach target concentration is reported via changes in the lifetime of the exponential current decay seen when the sensor is subjected to a potential step. Because the lifetime of this decay is independent of its amplitude (e.g., insensitive to variations in the number of aptamer probes on the electrode), chronoamperometrically interrogated E-AB sensors are calibration-free and resistant to drift. Chronoamperometric measurements can also be performed in a few hundred milliseconds, improving the previous few-second time resolution of E-AB sensing by an order of magnitude. To illustrate the potential value of the approach we demonstrate here the calibration-free measurement of the drug tobramycin in situ in the living body with 300 ms time resolution and unprecedented, few-percent precision in the determination of its pharmacokinetic phases. PMID- 29124940 TI - Core Levels, Band Alignments, and Valence-Band States in CuSbS2 for Solar Cell Applications. AB - The earth-abundant material CuSbS2 (CAS) has shown good optical properties as a photovoltaic solar absorber material, but has seen relatively poor solar cell performance. To investigate the reason for this anomaly, the core levels of the constituent elements, surface contaminants, ionization potential, and valence band spectra are studied by X-ray photoemission spectroscopy. The ionization potential and electron affinity for this material (4.98 and 3.43 eV) are lower than those for other common absorbers, including CuInxGa(1-x)Se2 (CIGS). Experimentally corroborated density functional theory (DFT) calculations show that the valence band maximum is raised by the lone pair electrons from the antimony cations contributing additional states when compared with indium or gallium cations in CIGS. The resulting conduction band misalignment with CdS is a reason for the poor performance of cells incorporating a CAS/CdS heterojunction, supporting the idea that using a cell design analogous to CIGS is unhelpful. These findings underline the critical importance of considering the electronic structure when selecting cell architectures that optimize open-circuit voltages and cell efficiencies. PMID- 29124938 TI - Quality Assessments of Long-Term Quantitative Proteomic Analysis of Breast Cancer Xenograft Tissues. AB - Clinical proteomics requires large-scale analysis of human specimens to achieve statistical significance. We evaluated the long-term reproducibility of an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomics strategy using one channel for reference across all samples in different iTRAQ sets. A total of 148 liquid chromatography tandem mass spectrometric (LC-MS/MS) analyses were completed, generating six 2D LC-MS/MS data sets for human-in-mouse breast cancer xenograft tissues representative of basal and luminal subtypes. Such large-scale studies require the implementation of robust metrics to assess the contributions of technical and biological variability in the qualitative and quantitative data. Accordingly, we derived a quantification confidence score based on the quality of each peptide-spectrum match to remove quantification outliers from each analysis. After combining confidence score filtering and statistical analysis, reproducible protein identification and quantitative results were achieved from LC-MS/MS data sets collected over a 7-month period. This study provides the first quality assessment on long-term stability and technical considerations for study design of a large scale clinical proteomics project. PMID- 29124941 TI - Graphdiyne as Electrode Material: Tuning Electronic State and Surface Chemistry for Improved Electrode Reactivity. AB - Graphdiyne (GDY) is recently synthesized two-dimensional carbon allotrope with hexagonal rings cross-linked by diacetylene through introducing butadiyne linkages (-C=C-C=C-) to form 18-C hexagons and is emerging to be fundamentally interesting and particularly useful in various research fields. In this study, we for the first time find that GDY can be used as an electrode material with reactivity tunable by electronic states and surface chemistry of GDY. To demonstrate this, GDY is oxidized into graphdiyne oxide (GDYO) that is then chemically and electrochemically reduced into chemically reduced GDYO (cr-GDYO) and electrochemically reduced GDYO (er-GDYO), respectively. Electrode reactivity of GDY and its derivatives (i.e., GDYO, cr-GDYO, and er-GDYO) is studied with hexaammineruthenium chloride ([Ru(NH3)6]Cl3) and potassium ferricyanide (K3Fe(CN)6) as redox probes. We find that electron transfer kinetics of the redox probes employed here at GDYs depends on the density of electronic state (DOS) and the synergetic effects of the surface chemistry as well as the hydrophilicity of the materials, and that the electron transfer kinetics at cr-GDYO and er-GDYO are faster than those at GDY and GDYO, and quite comparable with those at carbon nanotubes and graphene and its derivatives (i.e., GO, cr-GO, and er-GO). These properties, combined with the unique electronic and chemical structures of GDY, essentially enable GDY as a new kind of electrode material for fundamental studies on carbon electrochemistry and various electroanalytical applications. PMID- 29124942 TI - Quality of life after endovascular sclerotherapy of low-flow venous malformations: the efficacy of polidocanol compared with ethanol. AB - Background Limited information is available on mid-term results and quality of life (QOL) after endovascular sclerotherapy of venous malformations. Purpose To compare two agents-polidocanol and ethanol-with a focus on the influence on QOL after sclerotherapy. Material and Methods Forty-one consecutive patients with a venous malformation in the head and neck area or in the extremities were treated with polidocanol between 2008 and 2013. Pre- and post-treatment magnetic resonance imaging (MRI) scans were compared. All patients completed a self evaluation form on symptoms as well as a QOL questionnaire. The results were compared with previously obtained material during 1991-2001, comprising 44 consecutive, similarly located venous malformation patients subject to ethanol sclerotherapy. Results No significant clinical complications were observed. Subjectively, 19 (46%) of the patients benefitted from the treatment. QOL results showed that 85% of patients had an index < 39 - where 0 represents the highest and 100 the lowest QOL. Patients in the ethanol group had marginally better overall post-treatment QOL results. Post-treatment MRI in 35 patients showed the size of the malformation unchanged in 19 (54%) patients, in ten (29%) there was a decrease (<50%) while in six (17%) the decrease was more significant (>50%). Post treatment MRI results did not correlate with either subjective symptoms or QOL results. Conclusion Polidocanol sclerotherapy were found to be an effective, safe, and well tolerated treatment option for low flow venous malformations. Routine MRI for follow-up appears redundant and may be omitted. PMID- 29124943 TI - Simultaneous inter-arm and inter-leg systolic blood pressure differences to diagnose peripheral artery disease: a diagnostic accuracy study. AB - PURPOSE: Inter-arm systolic blood pressure differences (IASBPD) and inter-leg systolic blood pressure differences (ILSBPD) have arisen as potential tools to detect peripheral artery disease (PAD) and individuals at high cardiovascular risk. This study aims to evaluate the diagnostic accuracy of IASBPD and ILSBPD to detect PAD, and whether IASBPD or ILSBPD improves diagnostic accuracy of the oscillometric ankle-brachial index (ABI). MATERIALS AND METHODS: In this prospective study, eligible for inclusion were consecutive adults, with at least one of the following cardiovascular risk factors: diabetes, dyslipidemia, hypertension, smoking habit or age >=65. IASBPD, ILSBPD and ankle-brachial index (ABI) were measured in all participants through four-limb simultaneous oscillometric measurements and compared with Doppler ABI (reference test, positive cut-off: <= 0.9). RESULTS: Of 171 subjects included, PAD was confirmed in 23 and excluded in 148. Thirteen and 38 subjects had IASBPD and ILSBPD >=10 mmHg, respectively. Pearson correlation with Doppler ABI of IASBPD and ILSBPD was 0.073 (P = .343) and -0.628 (P < .001), respectively. Diagnostic accuracy of an ILSBPD >=10 mmHg to detect PAD was: sensitivity = 69.6% (95%CI = 48.6-90.5), specificity = 85.1% (79.1-91.2), diagnostic odds ratio (dOR) = 13.1 (4.8-35.5) and area under ROC curve (AUC) = 0.765 (0.616-0.915). IASBPD had an AUC = 0.532 (0.394-0.669), and oscillometric ABI had an AUC = 0.977 (0.950-1.000). The addition of ILSBPD to oscillometric ABI reduced dOR from 174.0 (38.3-789.9) to 34.4 (9.5-125.1). Similarly, the addition of IASBPD reduced dOR to 49.3 (14.6 167.0). CONCLUSIONS: In a Primary Care population with >=1 cardiovascular risk factors, ILSBPD showed acceptable diagnostic accuracy for PAD, whilst IASBPD accuracy was negligible. However, the combination of ILSBPD (or IASBPD) with oscillometric ABI did not improve the ability to detect PAD. Thus, oscillometer ABI seems to be preferable to detect PAD and individuals at high cardiovascular risk. ILSBPD could be uniquely recommended for the diagnosis of PAD when blood pressure measurements in upper limbs are not possible. PMID- 29124944 TI - Human rights of refugee-survivors of sexual and gender-based violence with communication disability. AB - Article 19 of the Universal Declaration of Human Rights (United Nations, 1948 ) states that all people have the right to seek, receive and impart information using any means. Ensuring that people with communication disability achieve this right is inherently challenging. For people with communication disability, who are refugee-survivors of sexual and gender-based violence (SGBV), additional human rights are challenged, including the right to education, protection from discrimination, a safe place to live, security of person and legal protection. Their experiences and needs, however, are poorly understood. This paper reports on a literature review of the intersectionality between SGBV, being a refugee and having a communication disability, and a preliminary investigation of the situation of refugee-survivors of SGBV with communication disability, in Rwanda. The project involved 54 participants, including 50 humanitarian and partner organisation staff and four carers of refugees with communication disabilities, from two locations (camp-based and urban refugees). Findings from both revealed that, for people with communication disability, barriers are likely to occur at each step of preventing and responding to SGBV. Moreover, stigmatisation of people with communication disability challenges SGBV prevention/support and people with communication disability may be targeted by SGBV perpetrators. SGBV service providers acknowledge their lack of knowledge and skills about communication disability, but wish to learn. Findings highlight the need for increased knowledge and skill development, in order to improve the situation for refugee-survivors of SGBV with communication disability. PMID- 29124945 TI - Protecting the human right to freedom of expression in international law. AB - Since its inclusion in Article 19 of the Universal Declaration of Human Rights, the right to freedom of opinion and expression has been protected in all of the relevant international human rights treaties. In international law, freedom to express opinions and ideas is considered essential at both an individual level, insofar as it contributes to the full development of a person, and being a foundation stone of democratic society. Free speech is a necessary precondition to the enjoyment of other rights, such as the right to vote, free assembly and freedom of association, and is essential to ensure press freedom. However, there is a clear and worrying global trend, including in western democracies, of governments limiting vibrant discussion and debate within civil society and among civil society, political leaders and government. Two examples illustrate this trend. First, anti-protest laws in Australia and the United States threaten the ability of people to stand together and express views on issues they care deeply about. Secondly, metadata retention laws jeopardise press freedom by undermining the confidentiality of journalists' sources and dissuading people from speaking freely on matters of public importance. PMID- 29124946 TI - Factors Affecting Life Satisfaction of Older Adults in Turkey. AB - This study aimed to examine the determinants of life satisfaction of older adults in Turkey. The sample consisted of 2,959 older adults over 65 years. The effects of psychological, daily life and instrumental activity, physical health and health status, and other important variables on life satisfaction were analyzed. The variables lessening life satisfaction for older adults included poverty, a lower self-reported health status, a decline in physical health, ability to chew, ability to do household activities, and an increase in feelings of depression and feeling social withdrawn. In contrast, being married, having a higher education level, and having an income-generating work increased life satisfaction among older adults. This study suggests the necessity of developing local and national policies that enable older adults to become more active in their communities. These policies should be coordinated under the framework of national aging policies that bridge health, social, and economic issues. PMID- 29124947 TI - Activity Preferences of persons with dementia: An examination of reports by formal and informal caregivers. AB - Objectives The aims of this study are (1) to describe the types of leisure activities preferred by persons with dementia in the past and present, as reported by family members and therapeutic recreation staff members, and (2) to examine the influence of demographic and functional abilities variables on the perceived current interest of persons with dementia. Method Family members of persons with dementia and therapeutic recreation staff involved in the care of those persons completed an activities preference assessment concerning the persons with dementia. Participants were recruited from a nursing home and a senior day center. Family members completed the assessment for the past and present, and staff members completed the assessment for the present. Results For present preferences, music was the most often preferred activity according to both family and staff, followed by reminiscence and reading, while the least desirable activity was cooking/baking according to family and trivia games according to the staff. Current preferences were significantly related to past preferences. Gender was also related to preference for some activities. A significant reduction in preference from the premorbid past to the present was found for music, reading, and cooking. Additionally, the number of activities persons preferred as reported by both caregiver groups was affected by dementia. Family members tended to report lower preference levels for the activities in the present in comparison to the staff, and they were also more likely to report not knowing the present level of preference than therapeutic recreation staff members. Conclusion The assessments by both therapeutic recreation staff members and family members shed light on leisure preferences of persons with dementia, while the varying reports reflect a possibly different perspective of the two caregiver groups. PMID- 29124948 TI - Tasigna (nilotinib) in chronic myeloid leukemia treatment-free remission after nearly 2 years: an interview with Adam Mead. AB - Dr Mead earned his medical degree from the University of Oxford and trained in hematology at St Bartholomew's Hospital and University College London. In 2007, he earned his PhD at UCL, which focused on the analysis of FLT3 mutations in acute myeloid leukemia. He is now Associate Professor of Hematology and MRC Senior Clinical Fellow at the WIMM, University of Oxford. His research group focuses on myeloid diseases and normal blood stem-cell biology. Dr Mead is the lead clinician for myeloproliferative neoplasms (MPN) and chronic myeloid leukemia in the Thames Valley Strategic Clinical Network and is the chief investigator for several chronic myeloid leukemia and MPN clinical trials. Additionally, Dr Mead has helped shape the diagnostic and treatment guidelines for MPNs in the UK and serves as the chair of the MPN clinical study subgroup of the National Cancer Research Institute. PMID- 29124949 TI - Reassessment of inclusion body-based production as a versatile opportunity for difficult-to-express recombinant proteins. AB - The production of recombinant proteins in the microbial host Escherichia coli often results in the formation of cytoplasmic protein inclusion bodies (IBs). Proteins forming IBs are often branded as difficult-to-express, neglecting that IBs can be an opportunity for their production. IBs are resistant to proteolytic degradation and contain up to 90% pure recombinant protein, which does not interfere with the host metabolism. This is especially advantageous for host toxic proteins like antimicrobial peptides (AMPs). IBs can be easily isolated by cell disruption followed by filtration and/or centrifugation, but conventional techniques for the recovery of soluble proteins from IBs are laborious. New approaches therefore simplify protein recovery by optimizing the production process conditions, and often include mild resolubilization methods that either increase the yield after refolding or avoid the necessity of refolding all together. For the AMP production, the IB-based approach is ideal, because these peptides often have simple structures and are easy to refold. The intentional IB production of almost every protein can be achieved by fusing recombinant proteins to pull-down tags. This review discusses the techniques available for IB-based protein production before considering technical approaches for the isolation of IBs from E. coli lysates followed by efficient protein resolubilization which ideally omits further refolding. The techniques are evaluated in terms of their suitability for the process-scale production and downstream processing of recombinant proteins and are discussed for AMP production as an example. PMID- 29124950 TI - Factors associated with dental caries, periodontitis and intra-oral lesions in individuals with HIV / AIDS. AB - This study aimed to investigate the factors associated with oral diseases in individuals with HIV/AIDS. A cross sectional study was carried out which included 312 individuals registered in the Specialized Care Services for HIV/AIDS in three municipalities of the State of Bahia: Feira de Santana, Santo Antonio de Jesus and Juazeiro, Brazil. Socioeconomic-demographic characteristics related to life style and to dental caries, periodontitis and intra-oral mucosal lesions were investigated in patients with HIV/AIDS infection. Prevalence Ratio with 95% Confidence Interval and significance level of 5% were employed for the statistical analysis. The majority of the individuals evaluated were male with a mean age (+/- standard deviation) of 41.5 +/- 11.3 years, and a mean time of HIV infection diagnosis (+/- standard deviation) of 5.2 +/- 4.4 years. The presence of dental caries was observed in 78.7% of the sample, periodontitis in 25.4% and 36.2% showed intra-oral lesions. Oral health status showed a statistically significant association with the following variables: gender, age, schooling level, current occupation, family income, past and current smoking, antiretroviral use time, latest viral burden dosage, latest CD4-positive T lymphocyte count, use of complete/partial dental prosthesis, need for dental prosthesis, and use of dental floss. With the exception of those factors directly related to HIV/AIDS i.e., antiretroviral use time, latest viral burden dosage and latest CD4-positive T lymphocyte count, the factors associated with oral diseases in this population were the same as those associated with oral diseases in the non-HIV/AIDS population. PMID- 29124951 TI - The role of serious mental illness in motivation, participation and adoption of health behavior change among obese/sedentary Latino adults. AB - OBJECTIVE: Serious mental illness (SMI; e.g. schizophrenia, schizoaffective disorder, delusional disorder, bipolar disorder, severe major depressive disorder, and psychotic disorders) and Latino ethnicity can produce a compounded health disparity, placing individuals at particularly high risk for excess morbidity and premature mortality. In this study we sought to identify the role of SMI in motivation, participation, and adoption of health behavior change among overweight Latino adults. DESIGN: Qualitative, semi-structured interviews were conducted with 20 overweight Latinos with SMI who were enrolled in a randomized trial evaluating the effectiveness of a motivational health promotion intervention adapted for persons with SMI, In SHAPE. The interviews explored the complicated role having an SMI had in the lives of the Latino participants. RESULTS: SMI had both positive and negative impact on Latino participants' health behaviors. The nature of their mental illness along with medication side effects (e.g. lethargy, weight gain, etc.) negatively impacted their ability to making lasting health behavior change. However, the regular appointments with various specialists provided them with structure that they otherwise would have lacked and gave them a reason to get out of the house. CONCLUSIONS: This exploratory research provides insight into the experience of overweight Latinos with SMI and the ways in which SMI impacts their participation in health behavior change. An understanding of the positive and negative effects of SMI on health behavior change will inform the development of health promotion interventions targeted at Latinos with SMI. PMID- 29124953 TI - Bilingualism, a human right in times of anxiety: Lessons from California. AB - Article 19 of the Universal Declaration of Human Rights refers to the individual's right of expression without interference, "through any media and regardless of frontiers". Currently, in some nations across the world, there is decreasing interest in cross-cultural interactions and a new interest in nationalism and assimilation, in communication within frontiers and in a specific medium: the national language. Speech-language pathologists (SLPs) advocate for individuals with communication disorders that interfere with their comprehension and expression. The profession promotes communication as a human right. Unfortunately, many clients and their families continue to report instances in which we, SLPs, limit their human right of expression by ignoring their home languages and recommending the exclusive use of the national language. Real progress requires reflection and action on language policy. In 1998, Californians passed Proposition 227, which eliminated bilingual public education. Then, in 2016, California voters approved Proposition 58 allowing the creation of multilingual and biliteracy programs. A discussion about the presentation of these two propositions to the public may hopefully help bilingual SLPs and advocates protect our multilingual clients' human right of expression in these times of anxiety. PMID- 29124952 TI - Current management and treatment of patients with stable coronary artery diseases presenting to cardiologists in different clinical contexts: A prospective, observational, nationwide study. AB - Background Stable coronary artery disease (CAD) is a leading cause of mortality worldwide. Few studies document the complete sequence of investigation of the overall stable CAD population during outpatient visits or hospitalisation. Aim To obtain accurate and up-to-date information on current management of patients with stable CAD. Methods START (STable coronary Artery diseases RegisTry) was a prospective, observational, nationwide study aimed at evaluating the presentation, management, treatment and quality of life of stable CAD patients presenting to cardiologists during outpatient visits or discharged from cardiology wards. Results Over a 3-month period, 5070 consecutive patients were enrolled in 183 participating centres: 72% managed by a cardiologist during outpatient or day hospital visits and 28% discharged from cardiology wards. The vast majority of patients (87%) received a coronary angiography (86% of patients managed during outpatient visits and 90% during hospitalisation; p < 0.0001). Outpatients more frequently received optimal medical therapy (OMT; i.e. aspirin or thienopyridine, beta-blockers and statins) compared to hospitalised patients (70.2% vs 67.1%; p = 0.03). A personalised diet was prescribed in 58% (60.5% in outpatients and 52.9% in those admitted to hospitals; p < 0.0001), physical activity programmes were suggested in 65% (69.4% and 54.3%; p < 0.0001) and smoking cessation was recommended in 71% of currently smoking patients (73.2% and 65.2%; p = 0.02). Conclusions In this large, contemporary registry, patients with stable CAD discharged from cardiology wards more commonly underwent diagnostic imaging procedures and less frequently received OMT or lifestyle modification programmes compared to patients manged by cardiologists during outpatient visits. PMID- 29124954 TI - Practicality of using the figure-of-eight bandage to prevent fatal wound dehiscence after spinal tumor surgery for upper thoracic metastasis. AB - OBJECT: Serious postoperative wound problems can frequently develop after surgery with perioperative RT for upper thoracic metastatic lesions. The figure-of-eight bandage can restrict excessive shoulder motion, which could prevent wound dehiscence. The purpose of this study was to describe the efficacy of using the figure-of-eight bandage to prevent postoperative wound dehiscence. METHODS: Between February 2005 and July 2015, we retrospectively evaluated the medical records of cancer patients who underwent surgery with or without RT for spinal metastasis involving the upper thoracic spine. From January 2009, all patients received figure-of-eight bandaging immediately postoperatively, which was then maintained for 2 months. The outcome measures were the incidence and successful management of wound dehiscence following application of the figure-of-eight bandage. RESULTS: One hundred and fifteen patients (71 men and 44 women) were enrolled in the present study. A figure-of-eight bandage in conjunction with a thoracolumbosacral orthosis (TLSO) was applied to 78 patients, while only TLSO was applied to 37 patients. The overall rate of wound dehiscence was 4.34% and the mean duration before wound dehiscence was 27.0 days (range, 22-31 days) after surgery. In the TLSO-only group, wound dehiscence occurred in four patients (10.81%), meanwhile there was only one case (1.33%) of wound dehiscence in the group that had received the figure-of-eight bandage with TLSO. Three of four patients with wound dehiscence in the TLSO only group died from unresolved wound problems and another patient was treated with wound closure followed by the application of the figure-of-eight bandage. The only patient with wound dehiscence among the patients who received both the figure-of-eight bandage and TLSO was managed by primary wound closure without further complication. CONCLUSION: Current study suggests that the figure-of-eight bandage could prevent wound dehiscence and be used to treat wound problems easily. PMID- 29124955 TI - Current issues of preoperative radio(chemo)therapy and its future evolution in locally advanced rectal cancer. AB - Neoadjuvant therapies are effective for local control and tumor downstaging. Up to date, preoperative long-course chemoradiotherapy and short-course radiotherapy are the two primary guideline-recommended neoadjuvant therapies for locally advanced rectal cancer patients. However, clinicians throughout the world are trying their best to further optimize the regimens and concepts of neoadjuvants. Hence, there is an urgent need to summarize evidence regarding indications of neaoadjuvant therapies and relative merits of current standard regimens. In addition, we also reviewed the optimized regimens mainly based on short-course radiotherapy with delayed surgery, consolidation chemotherapy, induction chemotherapy, chemotherapy alone without radiation and concepts in terms of organ preservation and personalized treatments to further explore the future evolution of neoadjuvant therapies in rectal cancer. PMID- 29124956 TI - A systematic review and development of a classification framework for factors associated with missing patient-reported outcome data. AB - BACKGROUND/AIMS: Missing patient-reported outcome data can lead to biased results, to loss of power to detect between-treatment differences, and to research waste. Awareness of factors may help researchers reduce missing patient reported outcome data through study design and trial processes. The aim was to construct a Classification Framework of factors associated with missing patient reported outcome data in the context of comparative studies. The first step in this process was informed by a systematic review. METHODS: Two databases (MEDLINE and CINAHL) were searched from inception to March 2015 for English articles. Inclusion criteria were (a) relevant to patient-reported outcomes, (b) discussed missing data or compliance in prospective medical studies, and (c) examined predictors or causes of missing data, including reasons identified in actual trial datasets and reported on cover sheets. Two reviewers independently screened titles and abstracts. Discrepancies were discussed with the research team prior to finalizing the list of eligible papers. In completing the systematic review, four particular challenges to synthesizing the extracted information were identified. To address these challenges, operational principles were established by consensus to guide the development of the Classification Framework. RESULTS: A total of 6027 records were screened. In all, 100 papers were eligible and included in the review. Of these, 57% focused on cancer, 23% did not specify disease, and 20% reported for patients with a variety of non-cancer conditions. In total, 40% of the papers offered a descriptive analysis of possible factors associated with missing data, but some papers used other methods. In total, 663 excerpts of text (units), each describing a factor associated with missing patient-reported outcome data, were extracted verbatim. Redundant units were identified and sequestered. Similar units were grouped, and an iterative process of consensus among the investigators was used to reduce these units to a list of factors that met the guiding principles. The list was organized on a framework, using an iterative consensus-based process. The resultant Classification Framework is a summary of the factors associated with missing patient-reported outcome data described in the literature. It consists of 5 components (instrument, participant, centre, staff, and study) and 46 categories, each with one or more sub-categories or examples. CONCLUSION: A systematic review of the literature revealed 46 unique categories of factors associated with missing patient-reported outcome data, organized into 5 main component groups. The Classification Framework may assist researchers to improve the design of new randomized clinical trials and to implement procedures to reduce missing patient reported outcome data. Further research using the Classification Framework to inform quantitative analyses of missing patient-reported outcome data in existing clinical trials and to inform qualitative inquiry of research staff is planned. PMID- 29124957 TI - Microwave-assisted synthesis of borneol esters and their antimicrobial activity. AB - Seventeen borneol esters (1-17) were synthesised by conventional and microwave assisted methodology using DIC/DMAP, and seven are described for the first time (8, 9, 10, 12, 13, 16 and 17). The microwave-assisted methodology was carried out without use of solvents, displayed short reaction times, and showed equal or higher yields for all the long-chain esters and three aromatic compounds (11, 12 and 14) when compared to the conventional approach. All the borneol esters were evaluated against the bacteria Streptococcus sanguinis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and the fungus Candida albicans. Compounds 12, 13 and 14 displayed promising antibacterial activity with a MIC equal to ampicilin (62.5 mg mL-1) for some microorganisms. In fact, bornyl 3',4' dimethoxybenzoate (13) was active against all tested bacteria and fungus. PMID- 29124958 TI - Streptomyces sp. is a powerful biotechnological tool for the biodegradation of HCH isomers: biochemical and molecular basis. AB - Actinobacteria are well-known degraders of toxic materials that have the ability to tolerate and remove organochloride pesticides; thus, they are used for bioremediation. The biodegradation of organochlorines by actinobacteria has been demonstrated in pure and mixed cultures with the concomitant production of metabolic intermediates including gamma-pentachlorocyclohexene (gamma-PCCH); 1,3,4,6-tetrachloro-1,4-cyclohexadiene (1,4-TCDN); 1,2-dichlorobenzene (1,2-DCB), 1,3-dichlorobenzene (1,3-DCB), or 1,4-dichlorobenzene (1,4-DCB); 1,2,3 trichlorobenzene (1,2,3-TCB), 1,2,4-trichlorobenzene (1,2,4-TCB), or 1,3,5 trichlorobenzene (1,3,5-TCB); 1,3-DCB; and 1,2-DCB. Chromatography coupled to mass spectrometric detection, especially GC-MS, is typically used to determine HCH-isomer metabolites. The important enzymes involved in HCH isomer degradation metabolic pathways include hexachlorocyclohexane dehydrochlorinase (LinA), haloalkane dehalogenase (LinB), and alcohol dehydrogenase (LinC). The metabolic versatility of these enzymes is known. Advances have been made in the identification of actinobacterial haloalkane dehydrogenase, which is encoded by linB. This knowledge will permit future improvements in biodegradation processes using Actinobacteria. The enzymatic and genetic characterizations of the molecular mechanisms involved in these processes have not been fully elucidated, necessitating further studies. New advances in this area suggest promising results. The scope of this paper encompasses the following: (i) the aerobic degradation pathways of hexachlorocyclohexane (HCH) isomers; (ii) the important genes and enzymes involved in the metabolic pathways of HCH isomer degradation; and (iii) the identification and quantification of intermediate metabolites through gas chromatography coupled to mass spectrometry (GC-MS). PMID- 29124959 TI - Speech therapy in adolescents with Down syndrome: In pursuit of communication as a fundamental human right. AB - PURPOSE: The achievement of speech intelligibility by persons with Down syndrome facilitates their participation in society. Denial of speech therapy services by virtue of low cognitive skills is a violation of their fundamental human rights as proclaimed in the Universal Declaration of Human Rights in general and in Article 19 in particular. Here, we describe the differential response of an adolescent with Down syndrome to three speech therapy interventions and demonstrate the use of a single subject randomisation design to identify effective treatments for children with complex communication disorders. METHOD: Over six weeks, 18 speech therapy sessions were provided with treatment conditions randomly assigned to targets and sessions within weeks, specifically comparing auditory-motor integration prepractice and phonological planning prepractice to a control condition that included no prepractice. All treatments involved high intensity practice of nonsense word targets paired with tangible referents. RESULT: A measure of generalisation from taught words to untaught real words in phrases revealed superior learning in the auditory-motor integration condition. CONCLUSION: The intervention outcomes may serve to justify the provision of appropriate supports to persons with Down syndrome so that they may achieve their full potential to receive information and express themselves. PMID- 29124961 TI - Mobilizing Mercy. A history of the Canadian Red Cross. PMID- 29124960 TI - Fostering human rights through TalkBank. AB - In accord with articles 19 and 27 of the Universal Declaration of Human Rights, people with speech and language disorders have the right to receive maximal benefit from academic research on speech and language acquisition and disorders. To evaluate the diverse nature of speech and language disorders, this research must have access to large datasets, as well as to refined tools for the systematic analysis of these datasets. The TalkBank system addresses this need by providing researchers with thousands of hours of open-access database archives of digital audio, video and transcript files documenting typical and disordered language use in dozens of languages and cultures. In this paper, we review the TalkBank system, with an emphasis on the AphasiaBank, PhonBank and FluencyBank databases. We describe how specialised assessment tools can be used to study issues in speech and language acquisition and disorders recorded within these databases. We then provide illustrations of how assessments support the needs of researchers, clinicians, developers, and educators, whose combined work contributes solutions for people with speech, language and language learning disorders worldwide. PMID- 29124962 TI - Effect of ultrasonic waves on crocin and safranal content and expression of their controlling genes in suspension culture of saffron (Crocus sativus L.). AB - The expression of biosynthesis controlling genes of crocin and safranal in saffron (Crocus sativus) can be influenced by ultrasonic waves. Sterilized saffron corms were cultured in a 1/2-MS medium supplemented by 2-4-D and BAP. Saffron callus cells were treated with ultrasonic waves in a cellular suspension culture under optimal growth conditions. The samples were collected at 24 and 72 hours after treatment in three replications. The secondary metabolites were measured by high-performance liquid chromatography and the gene expression was analysed by the real-time polymerase chain reaction. Results indicate that this elicitor can influence the expressions of genes CsBCH, CsLYC and CsGT-2; the ultrasonic waves acted as an effective mechanical stimulus to the suspension cultures. The analysis of variance of the ultrasonically produced amounts of safranal and crocin indicates that there is a significant difference between once and twice-treated samples in that the amount of safranal was the highest within the samples taken from the twice-treated suspension culture at 72 h after the ultrasound treatment, and the crocin was maximised after 24 h passed the twice applied ultrasound treatment. PMID- 29124963 TI - Relevance and bio-catalytic strategies for the kinetic resolution of ketoprofen towards dexketoprofen. AB - This review presents the most relevant investigations concerning the biocatalytic kinetic resolution of racemic ketoprofen to dexketoprofen for the last 22 years. The advantages related to the administration of the dex-enantiomer in terms of human health, the so called "chiral switch" in the pharmaceutical industry and the sustainability of biotransformations have been the driving forces to develop innovative technology to obtain dexketoprofen. In particular, the kinetic resolution of racemic ketoprofen through enantiomeric esterification and hydrolysis using lipases as biocatalysts are thoroughly revised and commented upon. In this context, the biocatalysts, acyl-acceptors (alcohols), reaction conditions, conversion, enantiomeric excess, and enantiomeric ratio among others are discussed. Moreover, the investigations concerning scaling up processes in order to obtain an optically pure enantiomer of the profen are presented. Finally, some guidelines about perspectives of the technology and research opportunities are given. PMID- 29124964 TI - The impact of anxiety on health care utilization among Hispanic and non-Hispanic youth. AB - This study examined differences in health service utilization among anxious and non-anxious youth primary care patients. We further examined the moderating role of Hispanic ethnicity on the relation between anxiety and service utilization. Past 4-year health care utilization was examined in a group of 6962 American youth (51.10% male; 53.10% Hispanic). Youth with an anxiety disorder had significantly more medical visits over the prior 4-year period than youth without an anxiety disorder. Hispanic youth utilized health care services at higher rates than non-Hispanic youth; however, ethnicity did not moderate the relation between youth anxiety and health care utilization. PMID- 29124965 TI - Perceived inequalities in care and support for older women from Black and minority ethnic backgrounds in Wales: findings from a survey exploring dignity from service providers' perspectives. AB - OBJECTIVE: As part of a large mixed-method study aimed at capturing understandings of dignity, and care expectations of community dwelling older women from Black and minority ethnic (BME) backgrounds living in Wales, the aim of this paper is to compare service providers' perceptions of their care and support provided to older people in general, and to older women from BME backgrounds in particular, with a focus on two dignity indicators: care and support needs, and effective communication. DESIGN: A survey design was used. RESULTS: A total of 124 responses from service providers in Wales were received. Perceived inequalities in care and support were found. Although most respondents reported that care and support provision was generally acceptable, more respondents believed that compared to older people in general, older women from BME backgrounds were seldom or never offered opportunities and support to express their needs, were involved in their own care, were provided appropriate information, had their key needs especially less visible needs (psychological and religious needs) been taken into account, or were communicated with effectively (all p < 0.05). In some cases, respondents tended to report more positively in areas related to their own practice. CONCLUSION: We suggest that learning from the views and perceptions of service providers, as well as older people and their families, remains key to developing services for the UK's increasingly diverse and ageing population. A better understanding of how inequalities may occur, their impact on older people and their families, and how they may be minimised can inform the development of high quality care for older people regardless of their ethnic and cultural backgrounds in Wales, other parts of the UK and beyond. PMID- 29124966 TI - Marine natural pigments as potential sources for therapeutic applications. AB - In recent years, marine natural pigments have emerged as a powerful alternative in the various fields of food, cosmetic, and pharmaceutical industries because of their excellent biocompatibility, bioavailability, safety, and stability. Marine organisms are recognized as a rich source of natural pigments such as chlorophylls, carotenoids, and phycobiliproteins. Numerous studies have shown that marine natural pigments have considerable medicinal potential and promising applications in human health. In this review, we summarize the marine natural pigments as potential sources for therapeutic applications, including: antioxidant, anticancer, antiangiogenic, anti-obesity, anti-inflammatory activities, drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), photoacoustic imaging (PAI), and wound healing. Marine natural pigments will offer a better platform for future theranostic applications. PMID- 29124967 TI - Inhibitory effect of biofilm-forming Lactobacillus kunkeei strains against virulent Pseudomonas aeruginosa in vitro and in honeycomb moth (Galleria mellonella) infection model. AB - Biofilms correspond to complex communities of microorganisms embedded in an extracellular polymeric matrix. Biofilm lifestyle predominates in Pseudomonas aeruginosa, an opportunistic Gram negative pathogen responsible for a wide spectrum of infections in humans, plants and animals. In this context, anti biofilm can be considered a key strategy to control P. aeruginosa infections, thereby more research in the field is required. On the other hand, Lactobacillus species have been described as beneficial due to their anti-biofilm properties and their consequent effect against a wide spectrum of pathogens. In fact, biofilm-forming Lactobacilli seem to be more efficient than their planktonic counterpart to antagonise pathogenic bacteria. In this work, we demonstrated that Lactobacillus kunkeei, a novel Lactobacillus species isolated from honeybee guts, can form biofilms in vitro. In addition, the L. kunkeei biofilm can, in turn, inhibit the formation of P. aeruginosa biofilms. Finally, we found that L. kunkeei strains attenuate infection of P. aeruginosa in the Galleria mellonella model, presumably by affecting P. aeruginosa biofilm formation and/or their stability. Since L. kunkeei presents characteristics of a probiotic, this work provides evidence arguing that the use of this Lactobacillus species in both animals (including insects) and humans could contribute to impair P. aeruginosa biofilm formation. PMID- 29124968 TI - Probiotic bacteria cell walls stimulate the activity of the intestinal epithelial cells and macrophage functionality. AB - The effect of oral administration of probiotic bacteria cell walls (PBCWs) in the stimulation of the immune system in healthy BALB/c mice was evaluated. We focused our investigation mainly on intestinal epithelial cells (IECs) which are essential for coordinating an adequate mucosal immune response and on the functionality of macrophages. The probiotic bacteria and their cell walls were able to stimulate the IECs exhibiting an important activation and cytokine releases. Supplementation with PBCWs promoted macrophage activation from peritoneum and spleen, indicating that the PBCWs oral administration was able to improve the functionality of the macrophages. In addition, the PBCWs increased immunoglobulin A (IgA)-producing cells in the gut lamina propria in a similar way to probiotic bacteria, but this supplementation did not have an effect on the population of goblet cells in the small intestine epithelium. These results indicate that the probiotic bacteria and their cell walls have an important immunoregulatory effect on the IECs without altering the homeostatic environment but with an increase in IgA+ producing cells and in the innate immune cells, mainly those distant from the gut such as spleen and peritoneum. These findings about the capacity of the cell walls from probiotic bacteria to stimulate key cells, such as IECs and macrophages, and to improve the functioning of the immune system, suggest that those structures could be applied as a new oral adjuvant. PMID- 29124969 TI - The gut mycobiome composition is linked to carotid atherosclerosis. AB - The mycobiotic component of the microbiota comprises an integral, yet under researched, part of the gastrointestinal tract. Here, we present a preliminary study of the possible contribution of gut mycobiota to sub-clinical atherosclerosis in a well-characterised group of obese and non-obese subjects in association with the Framingham Risk Score (FRS) and carotid intima-media thickness (cIMT). From all taxa identified, the relative abundance of the phylum Zygomycota, comprising the family Mucoraceae and genus Mucor, was negatively associated with cIMT and this association remained significant after controlling for false discovery rate. Obese subjects with detectable Mucor spp. had a similar cardiovascular risk profile as non-obese subjects. Interestingly, the relative abundance of Mucor racemosus was negatively associated both with FRS and cIMT. Partial least square discriminant analyses modelling, evaluating the potential relevance of gut mycobiota in patients stratified by mean values of cIMT, showed that even a 1 component model had a high accuracy (0.789), with a high R2 value (0.51). Variable importance in projection scores showed that M. racemosus abundance had the same impact in the model as waist-to-hip ratio, high-density lipoprotein-cholesterol, fasting triglycerides or fasting glucose, suggesting that M. racemosus relative abundance in the gut may be a relevant biomarker for cardiovascular risk. PMID- 29124970 TI - A review on the nucleic acid constituents in mushrooms: nucleobases, nucleosides and nucleotides. AB - Mushrooms have become increasingly important as a reliable food source. They have also been recognized as an important source of bioactive compounds of high nutritional and medicinal values. The nucleobases, nucleosides and nucleotides found in mushrooms play important roles in the regulation of various physiological processes in the human body via the purinergic and/or pyrimidine receptors. Cordycepin, a 3'-deoxyadenosine found in Cordyceps sinensis has received much attention as it possesses many medicinal values including anticancer properties. In this review, we provide a broad overview of the distribution of purine nucleobases (adenine and guanine); pyrimidine nucleobases (cytosine, uracil, and thymine); nucleosides (uridine, guanosine, adenosine and cytidine); as well as novel nucleosides/tides in edible and nonedible mushrooms. This review also discusses the latest research focusing on the successes, challenges, and future perspectives of the analytical methods used to determine nucleic acid constituents in mushrooms. Besides, the exotic taste and flavor of edible mushrooms are attributed to several nonvolatile and water-soluble substances, including the 5'-nucleotides. Therefore, we also discuss the total flavor 5'-nucleotides: 5'-guanosine monophosphate (5'-GMP), 5'-inosine monophosphate (5'-IMP), and 5'-xanthosine monophosphate (5'-XMP) in edible mushrooms. PMID- 29124971 TI - Motor learning from virtual reality to natural environments in individuals with Duchenne muscular dystrophy. AB - PURPOSE: To examine whether performance improvements in the virtual environment generalize to the natural environment. STUDY DESIGN: we had 64 individuals, 32 of which were individuals with DMD and 32 were typically developing individuals. METHODS: The groups practiced two coincidence timing tasks. In the more tangible button-press task, the individuals were required to 'intercept' a falling virtual object at the moment it reached the interception point by pressing a key on the computer. In the more abstract task, they were instructed to 'intercept' the virtual object by making a hand movement in a virtual environment using a webcam. RESULTS AND CONCLUSIONS: For individuals with DMD, conducting a coincidence timing task in a virtual environment facilitated transfer to the real environment. However, we emphasize that a task practiced in a virtual environment should have higher rates of difficulties than a task practiced in a real environment. IMPLICATIONS FOR REHABILITATION Virtual environments can be used to promote improved performance in ?real-world? environments. Virtual environments offer the opportunity to create paradigms similar ?real-life? tasks, however task complexity and difficulty levels can be manipulated, graded and enhanced to increase likelihood of success in transfer of learning and performance. Individuals with DMD, in particular, showed immediate performance benefits after using virtual reality. PMID- 29124972 TI - Perinatal and familial risk factors for irritable bowel syndrome in a Swedish national cohort. AB - OBJECTIVE: Studies of the importance of perinatal factors for the development of irritable bowel syndrome (IBS) are sparse. We conducted a large national cohort study to examine perinatal and familial risk factors for IBS. MATERIAL AND METHODS: A national cohort of 1,963,685 persons who were born in Sweden in 1973 1992 (identified from the Swedish Birth Registry) were followed up for adult (18 years and older) IBS incidence in the Swedish Patient Register through 2010 (maximum age 38 years). There were 24,633 IBS cases in 46,784,296 person-years of follow-up. RESULTS: After adjusting for potential confounders, significant risk factors for IBS included caesarean (HR = 1.10, 95% confidence interval [CI] 1.05 1.11, p < .001), low birth weight (<2500g) (HR = 1.11, 95%CI 1.01-1.22, p = .02), being second in birth order (HR = 1.04, 95%CI 1.01-1.08, p = .01), foetal growth >=1 SD (HR = 1.06, 95%CI 1.00-1.11, p = .05), young maternal age (<20 years) (HR= 1.09, 95%CI 1.02-1.17, p = .02), maternal marital status (divorced/widowed) (HR = 1.12, 95%CI 1.08-1.17, p < .001), maternal education of 10-11 years (HR = 1.04, 95%CI 1.01-1.08, p = .01), maternal education of 12-14 years (HR = 1.06, 95%CI 1.01-1.11, p = .03), parental history of IBS (HR = 1.54, 95%CI 1.42-1.66, p < .001), parental history of anxiety (HR = 1.21, 95%CI 1.17-1.26, p < .001) and parental history of depression (HR = 1.09, 95%CI 1.02-1.17, p = .02). Protective factors were male sex (HR = 0.36, 95%CI 0.35-0.37, p < .001) and old maternal at delivery (>=35 years) (HR = 0.95, 95%CI 0.90-1.00, p = .03). CONCLUSIONS: In this large cohort study, several perinatal and familial factors were associated with an increased risk of IBS independently, suggesting that perinatal and familial factors may play an important long-term role in the aetiology of IBS. PMID- 29124973 TI - Divergent hypersensitivity responses following topical application of the quaternary ammonium compound, didecyldimethylammonium bromide. AB - Didecyldimethylammonium bromide (DDAB) is a fourth generation dialkyl-quaternary ammonium compound (QAC) that is used in numerous products for its antimicrobial properties. While many QACs have been associated with allergic disease, the toxicity and sensitization of DDAB have not been thoroughly investigated. The purpose of these studies was to evaluate the irritancy and sensitization potential of DDAB following dermal application in a murine model. DDAB induced significant irritancy (0.0625-2%), evaluated by ear swelling in female BALB/c mice. Initial evaluation of the sensitization potential was conducted using the local lymph node assay (LLNA) at concentrations ranging from 0.0625% to 2%. A concentration-dependent increase in lymphocyte proliferation was observed with a calculated EC3 value of 0.057%. Immune cell phenotyping along with local and systemic IgE levels were evaluated following 4 and 14 days of dermal application. Phenotypic analyses revealed significant and dose-responsive increases in the absolute number of B-cells, CD4+ T-cells, CD8+ T-cells, and dendritic cells in the draining lymph nodes (DLNs) following 4 and 14 days of dermal exposure with significant increases in the number of activated B-cells and dendritic cells. However, increased activation of CD4+ T-cell and CD8+ T-cells was only observed following four days of DDAB exposure. Exposure to DDAB also induced increased production of IgE as evaluated by phenotypic analysis of DLN B-cells (IgE+ B cells) and measurement of total serum IgE levels following 14 days but not four days of dermal application. Significant increases in gene expression were observed in the DLN (Il-4, Il-10, and ox40l) and ear (tslp) following 4 and 14 days of DDAB exposure. These results demonstrate the potential for development of irritation and hypersensitivity responses to DDAB following dermal exposure and raise concerns about the effects of exposure duration on hypersensitivity responses. PMID- 29124974 TI - Media portrayal of elite athletes with disability - a systematic review. AB - BACKGROUND: The media plays an important role in shaping society's beliefs about disability and sport. The aim of this systematic review is to identify how elite athletes with disability are portrayed in the media. METHOD: Six electronic databases were searched from 2001 to March 2017 for quantitative or qualitative content analysis of media coverage of elite athletes with disability: SportsDiscus, CINAHL, PsychInfo, Medline 1996-, Embase, and Proquest. Quality assessment and data extraction were performed by two independent assessors. RESULTS: Seventeen moderate quality articles were included. Six themes emerged from the data such as frequency of articles and photos about elite athletes with disability; athlete gender; athlete nationality; disability; athleticism; and Olympic Games versus Paralympic Games. Our results show that elite athletes with disability are less visible in the media than their nondisabled counterparts; female athletes received less coverage than male; the media favored domestic athletes and certain types of disability; and, although there was a focus on athleticism, this was underpinned by a "supercrip" narrative and a medicalised description of disability. CONCLUSION: Although there has been a positive shift in the narrative around elite athletes with disability in media, relative absence and differing portrayal is present. Considering the power of media shaping society's perceptions of disability, further investigation is warranted. Implications for Rehabilitation Media has a role in how elite athletes with disability are portrayed and consequently perceived by the public. Elite athletes with disability rarely feature in media. Images of disability are minimized, and certain types of disabilities are favored. An athletic narrative is emerging; however, a medicalised description of athletes remains, shifting the focus from athleticism. "Supercrip" and "Superhuman" terms are commonly used, but may negatively impact the broader disability community. PMID- 29124975 TI - Ulnar artery pseudoaneurysm and compartment syndrome formation after snake bite to the left forearm. AB - OBJECTIVE: To report the outcome of a patient who developed pseudoaneurysms and compartment syndrome after a Deinagkistrodon acutus snakebite. CASE REPORT: A 61 year-old man, bitten by Deinagkistrodon acutus in his left forearm, came to the hospital eight hours after the bite. Despite the use of antivenom and supportive therapy, the patient developed compartment syndrome of the left forearm, the tissue pressure was elevated and fasciotomy was arranged. During the initial surgery, part of the necrotic tissues was removed. Moreover, two pseudoaneurysms of the ulnar artery were identified at the second debridement and the pseudoaneurysms were removed during this surgery. The patient went through a total of four surgeries, recovered and was eventually discharged from the hospital. CONCLUSION: A snake bite by Deinagkistrodon acutus may be accompanied by pseudoaneurysms and increased intracompartmental pressure. PMID- 29124976 TI - Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity. AB - INTRODUCTION: There is increasing evidence that the pathophysiological target of mercury is in fact selenium, rather than the covalent binding of mercury to sulfur in the body's ubiquitous sulfhydryl groups. The role of selenium in mercury poisoning is multifaceted, bidirectional, and central to understanding the target organ toxicity of mercury. METHODS: An initial search was performed using Medline/PubMed, Toxline, Google Scholar, and Google for published work on mercury and selenium. These searches yielded 2018 citations. Publications that did not evaluate selenium status or evaluated environmental status (e.g., lake or ocean sediment) were excluded, leaving approximately 500 citations. This initial selection was scrutinized carefully and 117 of the most relevant and representative references were selected for use in this review. Binding of mercury to thiol/sulfhydryl groups: Mercury has a lower affinity for thiol groups and higher affinity for selenium containing groups by several orders of magnitude, allowing for binding in a multifaceted way. The established binding of mercury to thiol moieties appears to primarily involve the transport across membranes, tissue distribution, and enhanced excretion, but does not explain the oxidative stress, calcium dyshomeostasis, or specific organ injury seen with mercury. Effects of mercury on selenium and the role this plays in the pathophysiology of mercury toxicity: Mercury impairs control of intracellular redox homeostasis with subsequent increased intracellular oxidative stress. Recent work has provided convincing evidence that the primary cellular targets are the selenoproteins of the thioredoxin system (thioredoxin reductase 1 and thioredoxin reductase 2) and the glutathione-glutaredoxin system (glutathione peroxidase). Mercury binds to the selenium site on these proteins and permanently inhibits their function, disrupting the intracellular redox environment. A number of other important possible target selenoproteins have been identified, including selenoprotein P, K, and T. Impairment of the thioredoxin and glutaredoxin systems allows for proliferation intracellular reactive oxygen species which leads to glutamate excitosis, calcium dyshomeostasis, mitochondrial injury/loss, lipid peroxidation, impairment of protein repair, and apoptosis. Methylmercury is a more potent inhibitor of the thioredoxin system, partially explaining its increased neurotoxicity. A second important mechanism is due to the high affinity of mercury for selenium and the subsequent depletion of selenium stores needed for insertion into de novo generation of replacement selenoproteins. This mercury induced selenium deficiency state inhibits regeneration of the selenoproteins to restore the cellular redox environment. The effects of selenium on mercury and the role this plays in biological response to mercury: Early research suggested selenium may provide a protective role in mercury poisoning, and with limitations this is true. The roles selenium plays in this reduction of mercury toxicity partially depends on the form of mercury and may be multifaceted including: 1) facilitating demethylation of organic mercury to inorganic mercury; 2) redistribution of mercury to less sensitive target organs; 3) binding to inorganic mercury and forming an insoluble, stable and inert Hg:Se complex; 4) reduction of mercury absorption from the GI tract; 5) repletion of selenium stores (reverse selenium deficiency); and 6) restoration of target selenoprotein activity and restoring the intracellular redox environment. There is conflicting evidence as to whether selenium increases or hinders mercury elimination, but increased mercury elimination does not appear to be a major role of selenium. Selenium supplementation has been shown to restore selenoprotein function and reduce the toxicity of mercury, with several significant limitations including: the form of mercury (methylmercury toxicity is less responsive to amelioration) and mercury dose. CONCLUSIONS: The interaction with selenium is a central feature in mercury toxicity. This interaction is complex depending on a number of features such as the form of mercury, the form of selenium, the organ and dose. The previously suggested "protective effect" of selenium against mercury toxicity may in fact be backwards. The effect of mercury is to produce a selenium deficiency state and a direct inhibition of selenium's role in controlling the intracellular redox environment in organisms. Selenium supplementation, with limitations, may have a beneficial role in restoring adequate selenium status from the deficiency state and mitigating the toxicity of mercury. PMID- 29124977 TI - Drug delivery for bioactive polysaccharides to improve their drug-like properties and curative efficacy. AB - Over several decades, natural polysaccharides (PSs) have been actively exploited for their wide bioactivities. So far, many PS-related reviews have been published; however, none focused on the delivery of bioactive PSs as therapeutic molecules. Herein, we summarized and discussed general pharmacokinetic properties of PSs and drug delivery systems (DDSs) developed for them, together with the challenges and prospects. Overall, most bioactive PSs suffer from undesirable pharmacokinetic attributes, which negatively affect their efficacy and clinical use. Various DDSs therefore have been being utilized to improve the drug-like properties and curative efficacy of bioactive PSs by means of improving oral absorption, controlling the release, enhancing the in vivo retention ability, targeting the delivery, exerting synergistic effects, and so on. Specifically, nano-sized insoluble DDSs were mainly applied to improve the oral absorption and target delivery of PSs, among which liposome was especially suitable for immunoregulatory and/or anti-ischemic PSs due to its synergistic effects in immunoregulation and biomembrane repair. Chemical conjugation of PSs was mainly utilized to improve their oral absorption and/or prolong their blood residence. With formulation flexibility, in situ forming systems alone or in combination with drug conjugation could be used to achieve day(s)- or month(s)-long sustained delivery of PSs per dosing. PMID- 29124979 TI - Mesoporous carbon nanomaterials in drug delivery and biomedical application. AB - Recent development of nano-technology provides highly efficient and versatile treatment methods to achieve better therapeutic efficacy and lower side effects of malignant cancer. The exploration of drug delivery systems (DDSs) based on nano-material shows great promise in translating nano-technology to clinical use to benefit patients. As an emerging inorganic nanomaterial, mesoporous carbon nanomaterials (MCNs) possess both the mesoporous structure and the carbonaceous composition, endowing them with superior nature compared with mesoporous silica nanomaterials and other carbon-based materials, such as carbon nanotube, graphene and fullerene. In this review, we highlighted the cutting-edge progress of carbon nanomaterials as drug delivery systems (DDSs), including immediate/sustained drug delivery systems and controlled/targeted drug delivery systems. In addition, several representative biomedical applications of mesoporous carbon such as (1) photo-chemo synergistic therapy; (2) delivery of therapeutic biomolecule and (3) in vivo bioimaging are discussed and integrated. Finally, potential challenges and outlook for future development of mesoporous carbon in biomedical fields have been discussed in detail. PMID- 29124978 TI - Sustained-release solid dispersion of pelubiprofen using the blended mixture of aminoclay and pH independent polymers: preparation and in vitro/in vivo characterization. AB - The present study aimed to develop the sustained-release oral dosage form of pelubiprofen (PEL) by using the blended mixture of 3-aminopropyl functionalized magnesium phyllosilicate (aminoclay) and pH-independent polymers. The sustained release solid dispersion (SRSD) was prepared by the solvent evaporation method and the optimal composition of SRSD was determined as the weight ratio of drug: Eudragit(r) RL PO: Eudragit(r) RS PO of 1:1:2 in the presence of 1% of aminoclay (SRSD(F6)). The dissolution profiles of SRSD(F6) were examined at different pHs and in the simulated intestinal fluids. The drug release from SRSD(F6) was limited at pH 1.2 and gradually increased at pH 6.8, resulting in the best fit to Higuchi equation. The sustained drug release from SRSD(F6) was also maintained in simulated intestinal fluid at fasted-state (FaSSIF) and fed-state (FeSSIF). The structural characteristics of SRSD(F6) were examined by using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR), indicating the change of drug crystallinity to an amorphous form. After oral administration in rats, SRSD(F6) exhibited the prolonged drug exposure in plasma. For both PEL and PEL-transOH (active metabolite), once a day dosing of SRSD(F6) achieved oral exposure (AUC) comparable to those from the multiple dosing (3 times a day) of untreated drug. In addition, the in vivo absorption of SRSD(F6) was well-correlated with the in vitro dissolution data, establishing a good level A in vitro/in vivo correlation. These results suggest that SRSD(F6) should be promising for the sustained-release of PEL, thereby reducing the dosing frequency. PMID- 29124980 TI - Prenatal Diagnosis and Molecular Analysis of a Large Novel Deletion (- -JS) Causing alpha0-Thalassemia. AB - alpha-Thalassemia (alpha-thal) is a very common single gene hereditary disease caused by large deletions or point mutations of the alpha-globin gene cluster in tropical and subtropical regions of the world. Here, we report for the first time, a novel large alpha-thal deletion in a Chinese family from Jiangsu Province, People's Republic of China (PRC), which removes almost the entire alpha2 and alpha1 genes from the alpha-globin gene cluster. Thus, it was named the Jiangsu deletion (- -JS) on the alpha-globin gene cluster causing alpha0 thal. Heterozygotes for this deletion showed an alpha-thal trait phenotype with reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (Hb) (MCH) levels. The sequencing results showed that a 2538 bp deletion (NG_000006.1: g.35801_38338) existed in this novel genotype on the basis of -alpha4.2 (leftward), indicating a deletion of about 6.8 kb from the alpha-globin cluster. In addition, a 29 bp sequence was inserted into the deletion during the recombination events that led to this deletion. Through pedigree analysis, we knew that the proband inherited the novel allele from his mother. PMID- 29124981 TI - Chitosan and its derivatives as vehicles for drug delivery. AB - Chitosan and its derivatives as vehicles for drug delivery can achieve the purpose of sustained release and controlled release for drugs, improve the stability of drugs, and reduce adverse drug reactions. So, the bioavailability of drugs can be enhanced. Therefore, chitosan and its derivatives have become a hotspot in the field of drug delivery. Their characteristics as drug delivery vectors were introduced, the types and applications were summarized. The development direction of chitosan and its derivatives in this field was also forecasted. PMID- 29124983 TI - Comparative toxicological evaluation of nonylphenol and nonylphenol polyethoxylates using human keratinocytes. AB - Nonylphenol polyethoxylates (NPEOs) are a major group of nonionic surfactants widely used in various detergents, cleaners, plastics, papers, and agro-chemical products. Nonylphenol (NP), which is a final degraded metabolite derived from NPEOs, has been reported as an endocrine disrupter, known to mimic or disturb reproductive hormone functions. Concern about the hazards of NP and NPEOs has generated legal restrictions and action plans worldwide. Considering the fact that NP and NPEOs are majorly used in the production of products such as detergents, shampoos, and cosmetics which frequently come into contact with the skin, we investigated the effects of NP and NPEOs on a human keratinocyte cell line (HaCaT). In this study, the toxicity of NP and NPEOs was screened in HaCaT cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide thiazolyl blue assay and Western blotting. The potential cytotoxicity of substitutes was assessed by dose-response assays, relative cell viability, and genotoxicity caused by specific alterations in DNA damage response proteins (including ataxia-telangiectasia mutated, p53, Chk1, Chk2, and Histone H2A.X). We demonstrated that NP and NPEOs are toxic to HaCaT cells, as revealed by the decreased cell viability after 24 h treatment. NPs and NPEOs also induced apoptosis and DNA damage as shown by the activation of Poly(ADP-ribose) polymerase, Caspase-3, and Histone H2A.X. PMID- 29124982 TI - Pre Gestational Thalassemia Screening in Mainland China: The First Two Years of a Preventive Program. AB - In this study, we report the experience of a pre gestational thalassemia screening program at a single center in Southern China. Free thalassemia screening, genetic counseling and prenatal diagnosis (PND) for couples planning pregnancy were implemented over a 2-year period. Among a total of 83,062 screened individuals (41,531 couples), the allele frequencies of beta-thalassemia (beta thal), - -SEA and - -THAI deletions were 3.79, 5.75 and 0.028%, respectively. Out of the 41,531 couples, 11,039 couples had at least one partner who had a positive screening test; of these, 455 at-risk couples (1.07%) were identified, including 68 (0.16%) for beta-thal, 162 (0.39%) for Hb Bart's (gamma4) hydrops fetalis, 190 (0.46%) for deletional Hb H (beta4) disease and 25 (0.06%) for nondeletional Hb H disease. Of the 455 at-risk couples, 90 were already pregnant and 66 underwent PND at 10-13 weeks' gestation, resulting in 15 affected fetuses. The remaining 355 at-risk couples were still preparing for pregnancy, and they were on the list for follow-up. There is considerable scope for facilitating timely PND through improved organization and screening strategy. The pre pregnancy screening is a feasible and effective approach to thalassemia prevention. PMID- 29124984 TI - Dendrimer-based contrast agents for PET imaging. AB - Positron emission tomography (PET) imaging offers physiological and biological information through the in vivo distribution of PET agents for disease diagnosis, therapy monitoring and prognosis evaluation. Due to the unique structural characteristics allowing for facile modification of targeting ligands and radionuclides, dendrimers can be served as a versatile scaffold to build up various PET imaging agents, and significant breakthroughs have been made in this field over the past decades. This review focuses on the recent advances in dendrimer-based contrast agents for PET imaging of cancer, cardiovascular and other diseases. In particular, radiolabeling strategies for different PET isotopes are described in detail. Several challenges involved in clinical translation of radiolabeled dendrimers are also discussed. PMID- 29124985 TI - Pharmacotherapy and motor recovery after stroke. AB - INTRODUCTION: Stroke is one of the most prevalent neurological diseases worldwide, especially among the elderly population. There are various mechanisms that enhance motor recovery after a stroke. In clinical practice, we have the opportunity to enhance plasticity by designing specific rehabilitation programs. Areas covered: There are a variety of drugs commonly administered to people after the acute phase of a stroke. These drugs may modify motor performance. Herein reviewed is the evidence concerning motor enhancement or decline in stroke patients, produced by drugs commonly used in rehabilitation settings. An extensive review of animal and human studies is performed. Expert commentary: Many of the clinical trials carried out were underpowered. Modest evidence supports the claim that there are agents that can affect motor rehabilitation after a stroke. Amphetamine-like agents, serotonin reuptake inhibitors, and levodopa might improve motor outcomes, while antipsychotics, some antiepileptic drugs, and GABAmimetic drugs could impair the recovery process. To draw definite recommendations, more comprehensive knowledge about the efficacy, long-term effects, and safety of these drugs is required. There are also other interesting molecules that open a promising field for basic and clinical research, in the search for new therapeutic options. PMID- 29124986 TI - Development of zolmitriptan transfersomes by Box-Behnken design for nasal delivery: in vitro and in vivo evaluation. AB - The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box-Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X1), amount of drug (X2) and amount of tween 80 (X3). The dependent responses were vesicle size (Y1), flexibility index (Y2) and regression coefficient of drug release kinetics (Y3). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74 mg of lecithin (X1), 98.37 mg of zolmitriptan (X2) and 32.2 mg of Tween 80 (X3) and had vesicle size of 93.3 nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1 um. The formulations were found to be physically stable upon storage at room temperature up to 2 months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist(r)). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect. PMID- 29124987 TI - Outcomes of treatment with sorafenib in Egyptian patients with hepatocellular carcinoma: a retrospective cohort study. AB - BACKGROUND: Sorafenib is the standard of care, first line treatment for advanced HCC. This study aims to evaluate real-life efficacy and safety of sorafenib in Egyptian patients with Hepatocellular carcinoma (HCC). METHODS: This retrospective cohort study was conducted in the medical oncology department at Maadi Armed Forces Medical Compound. Patients with advanced HCC who received sorafenib between January and December 2015 were included (130 patients). RESULTS: The median overall survival of patients with HCC treated with sorafenib was 5 months (CI: 4.166-5.834), and progression free survival was 4 months (CI: 3.479-4.521). Disease control rate was 45.44% with 2 patients experiencing complete remission (1.2%). The adverse events rate was 76.1% for toxicities of all grades; with hand and foot syndrome being the most common (32.3% of any grade) and liver dysfunction the most common grade III toxicity (13.8%). Treatment was stopped for radiological progression based on modified RECIST criteria in 47 patients (36.3%), 18 patients stopped the treatment for intolerable toxicity. At the end of treatment upon radiological progression, 51 patients (39.2%) were still classified as Child A class of cirrhosis. CONCLUSION: Sorafenib use should be limited to patients with Child A, PS 0-1, and low disease burden. PMID- 29124988 TI - Extracorporeal elimination of butalbital in acute aspirin-butalbital-caffeine codeine (Fiorinal with Codeine) poisoning. AB - BACKGROUND: Butalbital is a small molecule (approximately 220 Da), with 26% protein binding, a 0.8 L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after an overdose of aspirin 325 mg-butalbital 50 mg-caffeine 40 mg with codeine 30 mg (Fiorinal with Codeine). METHODS: This is a case report of a single patient. RESULTS: A 67-year-old female was admitted to the medical intensive care unit approximately 3 h after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function and a relatively low peak salicylate concentration at 46.4 mg/dL (3.4 mmol/L). Approximately 8 h after ingestion of 2000 mg of butalbital, our patient's serum concentration was 26.9 mg/L (normal <10 mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 233-300 mL/min. CONCLUSIONS: The extracorporeal clearance of butalbital observed in this case demonstrates the utility of dialysis to augment drug elimination in a Fiorinal with Codeine overdose. PMID- 29124989 TI - Perceived rather than actual overweight is associated with mental health problems in adolescence. AB - BACKGROUND: Overweight and perceived overweight are common among adolescents. The nature of the relationship between overweight/perceived overweight and mental health problems is still unclear. AIMS: The aim of this study was to examine whether actual overweight, perceived overweight or both are associated with internalizing and externalizing disorders among adolescents. METHODS: Data were collected by two similar school surveys in all Finnish-speaking secondary schools in Tampere (population 200,000) in the academic years 2002-2003 and 2012-2013. A total of 2775 acceptable responses were received. All the analyses were carried out separately for girls and boys. Mean age of the respondents was 15.6 years. RESULTS: In multivariate analyses perceived overweight, not actual weight, was significantly associated with higher risk of self-reported depression (OR: 4.3, 95% CI: 2.9-6.3, p < .001) and self-reported conduct disorder (OR: 2.3, 95% CI: 1.6-3.3, p < .001) in girls and with higher risk of self-reported depression (OR: 3.26, 95% CI: 1.65-6.4, p = .001) and self-reported social phobia (OR: 2.4, 95% CI: 1.0-5.6, p = .05) in boys. CONCLUSION: Perceived overweight rather than actual weight status is associated with both internalizing and externalizing mental health problems in adolescents. PMID- 29124990 TI - Yoga - a laborious way to well-being: patients' experiences of yoga as a treatment for hypertension in primary care. AB - OBJECTIVE: The aim of the study was to describe patients' experience of yoga as a treatment for hypertension, as well as their experience of living with hypertension. DESIGN: Qualitative interview study Method and materials: In 2013 2014, in southern Sweden, patients with hypertension from three health care centres were invited to participate in a randomised controlled trial on yoga for hypertension. After completion of the study, eight women and five men (aged 35 79), who had practiced the yoga intervention, were interviewed about their experiences. We used a semi-structured interview guide according to Kvale. Qualitative analysis was conducted by systematic text condensation inspired by Malterud. RESULTS: Two main themes emerged during the analysis process: Yoga - a laborious way to well-being and hypertension - a silent disease. The positive experiences of doing yoga were described in terms of tranquillity and increased agility. The drawbacks were mainly linked to the time required to perform the exercises. Living with high blood pressure and having to take medication can imply a stigma and cause concerns for future cardiovascular events. Most patients that we interviewed expressed a wish to find alternative ways to treat their high blood pressure. Participating in the yoga study was seen as a good possibility to try such an alternative way. CONCLUSIONS: Many patients with hypertension in Swedish primary care seem to be interested in trying alternative treatments to control blood pressure. The patients in our study experienced several benefits from doing yoga, but they also pointed out difficulties in implementing yoga as a regular and permanent lifestyle change. PMID- 29124991 TI - Similar treatment outcome in myofascial TMD patients with localized and widespread pain. AB - OBJECTIVE: To study the outcome of oral appliance treatment in myofascial Temporomandibular disorder (TMD) patients with and without comorbid pain using pain site drawings. MATERIAL AND METHODS: This randomized, controlled multicentre study comprised 65 myofascial TMD patients diagnosed according to the Research Diagnostic Criteria for Temporomandibular Disorders. Pain-site drawings were filled in at the baseline examination. The patients were treated with oral appliances. Treatment outcome was followed up for 1 year and analysed according to the recommendations by the Initiative on Methods, Measurement and Pain assessment in Clinical Trials (IMMPACT) on an intent-to-treat basis. The data were analysed for two pain profiles, localized pain (face and head, n = 26) versus widespread pain group (pain sites outside the face and head, n = 39). RESULTS: Statistically significant improvement was registered within both groups for all outcome variables (characteristic pain intensity, 30% pain reduction of worst reported pain, graded chronic pain, depression, and somatization scores) during the follow-up with only small differences between the groups. CONCLUSIONS: Oral appliance treatment had a positive effect on all outcome measures during the 1-year follow-up in patients suffering from myofascial TMD pain, regardless of whether the pain was localized or widespread. Multiple pain sites seemed to have surprisingly little influence on the outcome variables. However, some indications of more challenges when treating patients with widespread pain compared to local pain could be observed. Pain-site drawings seem to be useful in the clinical situation and could support the clinicians in decision-making regarding treatment planning. PMID- 29124993 TI - Increasing economic burden caused by nephro-geriatric patients. PMID- 29124992 TI - Efficacy of ketamine for postoperative pain following robotic thyroidectomy: A prospective randomised study. AB - : Objective Although robotic thyroidectomy (RoT) is a minimally invasive surgery, percutaneous tunneling causes moderate to severe pain immediately postoperatively. We evaluated the efficacy of ketamine for postoperative pain management in patients following RoT. Methods Sixty-four patients scheduled for RoT were randomly divided into two groups. In the ketamine group (n = 32), ketamine was infused from induction of anaesthesia until the end of the procedure (0.15-mg/kg bolus with continuous infusion at 2 ug/kg/min). In the control group (n = 32), the same volume of saline was infused. Visual analogue scale (VAS) scores for acute and chronic pain, the incidence of hypoesthesia, postoperative analgesic requirements, and complications related to opioids or ketamine were compared between the two groups. Results The VAS pain scores were significantly lower in the ketamine group up to 24 h postoperatively. The VAS pain score when coughing was significantly higher in the control group than in the ketamine group at 24 h postoperatively. A significantly greater proportion of patients in the control group required rescue analgesics. Complications were comparable in both groups. Conclusions Ketamine infusion decreased pain scores for 24 h postoperatively and reduced analgesic requirements without serious complications in patients following RoT. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01997801. PMID- 29124994 TI - A review on biosimilar infliximab, CT-P13, in the treatment of inflammatory bowel disease. AB - The introduction of biological agents has led to significant changes in the treatment of inflammatory bowel disease (IBD). The relatively high price of infliximab (IFX) and the expiration of the patents led to the introduction of biosimilar agents. CT-P13 was the first IFX biosimilar approved in the same indications as the reference product; however, the approval was based on randomized clinical trials conducted in patients with rheumatoid arthritis and ankylosing spondylitis. In the past 2-3 years, new findings from prospective observational studies supported the short-, medium- and long-term clinical efficacy and safety of CT-P13 in patients with IBD. This review summarized the clinical use and efficacy of the first biosimilar IFX, CT-P13, in the treatment of IBD. PMID- 29124995 TI - Peri-implant soft-tissue parameters and crestal bone levels among narghile smokers and nonsmokers. AB - This retrospective convenient sample case-control study investigated the peri implant soft-tissue inflammatory parameters and crestal bone loss (CBL) among narghile smokers (NS) (Group I) and nonsmoking controls (Group II). Demographic data were collected using a questionnaire. Peri-implant plaque index (PI), bleeding-on-probing (BOP) and pocket-depth (PD) were assessed; and peri-implant CBL was measured on standardized digital bite-wing radiographs. Sample-size was estimated and statistical analysis were done using Mann-Whitney U-test. Level of significance was set at p < .05. Seventy-two male individuals (35 in Group I and 37 in Group II) were included. The mean age of individuals in Groups I and II were 45.3 +/- 5.2 and 42.6 +/- 3.3 years, correspondingly. In Group 1, the duration and daily frequency of narghile smoking was 17.5 +/- 1.6 years and 6.3 +/- 0.5 times per day, respectively. The mean duration of each narghile smoking session was 28.5 +/- 0.6 min. The mean peri-implant PI (p < .05), PD (p < .05) and mesial (p < .05) and distal (p < .05) CBL were statistically significantly higher among individuals in Group I compared with Group II. BOP was significantly higher in Group II than Group I (p < .05). Narghile smoking increases peri implant soft-tissue inflammation and CBL. PMID- 29124996 TI - A 30-year mortality and respiratory morbidity study of refractory ceramic fiber workers. AB - AIM: Report mortality (n = 1119), cancer incidence (n = 1207) and radiographic (n = 1451) findings from a 30-year investigation of current and former refractory ceramic fiber (RCF) workers. METHODS: Cause of death, health and work histories, radiographs and spirometry were collected. Mortality and cancer incidence were analyzed. Logistic regression analysis investigated the associations of latency and cumulative fiber exposure (CFE) on radiographic changes. RESULTS: The mortality study showed no increase in standardized mortality rates (SMR) for lung cancer, but urinary cancers were significantly elevated in the higher exposed group (SMR = 3.62, 95% CI: 1.33-7.88) and leukemia in the total cohort (SMR = 2.51, 95% CI: 1.08-4.94). One death attributed to mesothelioma was identified (SMR = 2.86, 95% CI: 0.07-15.93) in a worker reporting some asbestos exposure. The overall rate of pleural changes was 6.1%, attaining 21.4% in the highest CFE category for all subjects (adjusted odds ratio (aOR) = 6.9, 95% CI: 3.6-13.4), and 13.0% for those with no reported asbestos exposure (OR= 9.1, 95% CI: 2.5 33.6). Prevalence for recent hires (>=1985) was similar to the background. Interstitial changes were not elevated. Localized pleural thickening was associated with small decreases in spirometry results. CONCLUSION: Increases in leukemia and urinary cancer but not lung cancer mortality were found. One death attributed to mesothelioma was observed in a worker with self-reported asbestos exposure and a work history where occupational asbestos exposure may have occurred, rendering uncertainties in assigning causation. Radiographic analyses indicated RCF exposure alone is associated with increased pleural but not interstitial changes. Reductions in RCF exposure should continue. The mortality study is ongoing. PMID- 29124998 TI - Evaluation of the presence of asbestos in cosmetic talcum products. AB - Talc has been used for over a century in a variety of cosmetic products. While pure cosmetic talc (free of asbestos) is not considered a risk factor for mesothelioma, it has been recently suggested that inhalation of cosmetic talc containing trace levels of asbestos is a risk factor for mesothelioma. Bulk analyses of cosmetic talcum products were performed in the 1960s and 1970s, however, the analytical methods used at that time were incapable of determining whether asbestos minerals were present in the asbestiform versus non-asbestiform habit. The distinction between these two mineral habits is critical, as non asbestiform amphibole minerals do not present an asbestos-related cancer risk via inhalation. As such, we evaluated six historical talcum powders using modern-era analytical methods to determine if asbestos is present, and if so, to identify the mineral habit (asbestiform versus non-asbestiform) of the asbestos. Based on their labels, the products were produced by four manufacturers and sold between 1940 and 1977. The products were analyzed in duplicate by two laboratories using standard protocols. Laboratory A analyzed samples using X-ray diffraction (XRD) and polarized light microscopy (PLM), and Laboratory B analyzed samples using PLM and transmission electron microscopy (TEM) with energy dispersive X-ray analysis (EDX) and selected area electron diffraction (SAED). No asbestiform minerals were found in any of the products. Nonetheless, even if some historical cosmetic talcum products contained trace amounts (<=0.1%) of asbestiform minerals, any resulting asbestos exposure would be expected to be exceedingly low, and comparable to exposures from breathing ambient air. PMID- 29124999 TI - Cervical myelitis presenting as occipital neuralgia. AB - AIM: Occipital neuralgia is a common form of headache that is characterized by paroxysmal severe lancinating pain in the occipital nerve distribution. METHODS: The exact pathophysiology is still not fully understood and occipital neuralgia often develops spontaneously. There are no specific guidelines for evaluation of patients with occipital neuralgia. RESULT: Cervical spine, spinal cord and posterior neck muscle lesions can induce occipital neuralgia. Brain and spine imaging may be necessary in some cases, according to the nature of the headache or response to treatment. DISCUSSION: We report a case of cervical myelitis presenting as occipital neuralgia. PMID- 29124997 TI - Perinatal exposure to environmental tobacco smoke is associated with changes in DNA methylation that precede the adult onset of lung disease in a mouse model. AB - Prenatal and early-life environmental tobacco smoke (ETS) exposure can induce epigenetic alterations associated with inflammation and respiratory disease. The objective of this study was to address the long-term epigenetic consequences of perinatal ETS exposure on latent respiratory disease risk, which are still largely unknown. C57BL/6 mice were exposed to prenatal and early-life ETS; offspring lung pathology, global DNA, and gene-specific methylation were measured at two adult ages. Significant alterations in global DNA methylation and promoter methylation of IFN-gamma and Thy-1 were found in ETS-exposed offspring at 10-12 and 20 weeks of age. These sustained epigenetic alterations preceded the onset of significant pulmonary pathologies observed at 20 weeks of age. This study suggests that perinatal ETS exposure induces persistent epigenetic alterations in global DNA, as well as IFN-gamma and Thy-1 promoter methylation that precede the adult onset of fibrotic lung pathology. These epigenetic findings could represent potential biomarkers of latent respiratory disease risk. PMID- 29125000 TI - Salivary evaluation in radioactive I131 treated patients with thyroid carcinoma. AB - BACKGROUND AND OBJECTIVE: radioiodine treatment (I131) used to treat thyroid carcinomas produces side effects (sialadenitis, xerostomia, dysphagia and caries susceptibility) reflecting in a poor patient quality of life. This study aimed to evaluate the effect of I131 on salivary function and possible oral impairment. MATERIAL AND METHODS: Thirty-seven patients undergoing I131 were submitted to oral examination, answer questions regarding xerostomia/hyposalivation and collect saliva at three moments (M1: 30-45 days before I131, M2: 1-2 days after I131 and M3: 7-10 days after treatment). Saliva was assayed for flow rate and calcium/phosphate concentrations. RESULTS AND CONCLUSIONS: significant difference in calcium/phosphate concentration was shown between M1 and M2, with evident decrease at M2. Flow rate reduced right after treatment with 41% of patients returning to previous rate at M3 (no statistical difference). A higher number of patients related xerostomia and difficulty in swallowing food at M2. The results showed that xerostomia/hyposalivation, dysphagia and calcium/phosphate concentration decrease may be considered early radioiodine side effects. PMID- 29125001 TI - Hypoxia due to positive pressure ventilation in Edwards' syndrome: A case report. AB - Edwards' syndrome also known as trisomy 18 is a congenital disorder associated with cardiovascular issues including ventricular septal defect (VSD), atrial septal defect (ASD) and patent duct arteriosus (PDA). An emergency colostomy was performed on a neonate born with an imperforate anus. Pre-operative transthoracic echocardiography showed presence of VSD, a patent foramen ovale (PFO) or ASD. Even though the baby had a good general condition and optimal peripheral oxygen saturation (SpO2), during positive pressure ventilation, she suffered severe hypoxia (50% SpO2). The cause of the hypoxia was thought to be the right-left shunt and so during a second attempt at anaesthesia a vasopressor (noradrenaline 0.03 ug/kg/min) was infused to increase systemic vascular resistance. Thereafter, SpO2 increased to 80-90% and the surgery was completed. The baby recovered without any neurological complications. Genetic testing post-partum showed she had Edwards' syndrome. PMID- 29125002 TI - Qualitative research thrives in primary care with the support of research training and mentoring. PMID- 29125003 TI - Improving bedside teaching feedback: A response to Aylward et al. PMID- 29125005 TI - Neurogenetics in Spain. PMID- 29125004 TI - Impact of the automated dose dispensing with medication review on geriatric primary care patients drug use in Finland: a nationwide cohort study with matched controls. AB - OBJECTIVE: In an automated dose dispensing (ADD) service, medicines are dispensed in unit-dose bags according to administration times. When the service is initiated, the patient's medication list is reconciled and a prescription review is conducted. The service is expected to reduce drug use. The aim of this national controlled study was to investigate whether the ADD service with medication review reduces drug use among geriatric primary care patients. DESIGN, SETTING AND PATIENTS: This is a nationwide cohort study with matched controls. The study group consisted of all primary care patients >=65 years enrolled in the ADD service in Finland during 2007 (n = 2073). Control patients (n = 2073) were matched by gender, age, area of patient's residence and number of the prescription drugs reimbursed. The data on all prescription drugs reimbursed during the 1 year periods before and after the ADD service enrollment were extracted from the Finnish National Prescription Register. Drug use was calculated as defined daily doses (DDD) per day. RESULTS: The studied 20 most used drugs covered 86% of all reimbursed drug use (in DDD) of the study group. The use of 11 out of these 20 active substances studied was reduced significantly (p < .001-.041) when the drug use was adjusted by the number of chronic diseases. Two of these drugs were hypnotics and six were cardiovascular system drugs. CONCLUSIONS: Drug use was decreased after initiation of the ADD service in primary care patients >=65 years compared to matched controls in this 1 year cohort study. Further studies should be conducted in order to explore the causality, assess the ADD service's impact on drug use quality and costs, as well as impact of accompanied prescription review on positive outcomes. PMID- 29125006 TI - Unilateral hippocampal wasting after combined-modality therapy for glioblastoma. PMID- 29125007 TI - The importance of design thinking in medical education. AB - Design thinking provides a creative and innovate approach to solve a complex problem. The discover, define, develop and delivery phases of design thinking lead to the most effective solution and this approach can be widely applied in medical education, from technology intervention projects to curriculum development. Participants in design thinking acquire essential transferable life long learning skills in dealing with uncertainty and collaborative team working. PMID- 29125008 TI - Does more favourable handling of the cerebrospinal fluid increase the diagnostic sensitivity of Borrelia burgdorferi sensu lato-specific PCR in Lyme neuroborreliosis? AB - BACKGROUND: Tests for direct detection of Borrelia burgdorferi sensu lato (Bb) in Lyme neuroborreliosis (LNB) are needed. Detection of Bb DNA using PCR is promising, but clinical utility is hampered by low diagnostic sensitivity. We aimed to examine whether diagnostic sensitivity can be improved by the use of larger cerebrospinal fluid (CSF) volumes and faster handling of samples. METHODS: Patients who underwent CSF examination for LNB were included. We collected two millilitres of CSF for PCR analysis, extracted DNA from the pellets within 24 h and analysed the eluate by two real-time PCR protocols (16S rRNA and OspA). Patients who fulfilled diagnostic criteria for LNB were classified as LNB cases and the rest as controls. RESULTS: Bb DNA in CSF was detected by PCR in seven of 28 adults with LNB. Two were Bb antibody negative. No Bb DNA was detected in CSF from 137 controls. Diagnostic sensitivity was 25% and specificity 100%. There was a non-significant trend towards larger CSF sample volume, faster handling of the sample, shorter duration of symptoms, and higher CSF cell count in the PCR positive cases. CONCLUSION: We did not find that optimized handling of CSF increased diagnostic sensitivity of PCR in adults with LNB. However, our case series is small and we hypothesize that the importance of these factors will be clarified in further studies with larger case series and altered study design. PCR for diagnosis of LNB may be useful in cases without Bb antibodies due to short duration of symptoms. PMID- 29125009 TI - Exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type. AB - PURPOSE: To explore exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type and to explore patient experiences of physiotherapy. METHODS: A cross sectional questionnaire survey design was used to collect quantitative and qualitative data from adult members of the Hypermobility Syndromes Association and Ehlers-Danlos Syndrome Support UK. Descriptive and inferential statistics were used to analyse the data. Qualitative data was analysed thematically. RESULTS: 946 questionnaires were returned and analysed. Participants who received exercise advice from a physiotherapist were 1.75 more likely to report high volumes of weekly exercise (odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.30-2.36, p < 0.001) than those with no advice. Participants who believed that exercise is important for long-term management were 2.76 times more likely to report a high volume of weekly exercise compared to the participants who did not hold this belief (OR = 2.76, 95% CI = 1.38-5.50, p = 0.004). Three themes emerged regarding experience of physiotherapy; physiotherapist as a partner, communication - knowledge, experience and safety. CONCLUSION: Pain, fatigue and fear are common barriers to exercise. Advice from a physiotherapist and beliefs about the benefits of exercise influenced the reported exercise behaviours of individuals with Ehlers Danlos syndrome - hypermobility type in this survey. Implications for rehabilitation Exercise is a cornerstone of treatment for Ehlers-Danlos syndrome/Ehlers-Danlos syndrome - hypermobility type. Pain, fatigue and fear of injury are frequently reported barriers to exercise. Advice from physiotherapists may significantly influence exercise behaviour. Physiotherapists with condition specific knowledge and good verbal and non-verbal communication facilitate a positive therapeutic experience. PMID- 29125010 TI - The genus Scrophularia: a source of iridoids and terpenoids with a diverse biological activity. AB - CONTEXT: Scrophularia genus (Scrophulariaceae) includes about 350 species commonly known as figwort. Many species of this genus grow wild in nature and have not been cultivated yet. However, some species are in danger of extinction. OBJECTIVE: This paper reviews the chemical compounds, biological activities and the ethnopharmacology of some Scrophularia species. MATERIALS AND METHODS: All information was obtained through reported data on bibliographic database such as Scopus, United States National Agricultural Library, Biological Abstracts, EMBASE, PubMed, MedlinePlus, PubChem and Springer Link (1934-2017). The information in different Pharmacopoeias on this genus was also gathered from 1957 to 2007. RESULTS: The structures of 204 compounds and their biological activity were presented in the manuscript: glycoside esters, iridoid glycosides and triterpenoids are the most common compounds in this genus. Among them, scropolioside like iridoids have shown potential for anti-inflammatory, hepatoprotective and wound healing activity. Among the less frequently isolated compounds, resin glycosides such as crypthophilic acids have shown potent antiprotozoal and antimicrobial activities. CONCLUSION: The Scrophularia genus seems to be a rich source of iridoids and terpenoids, but isolation and identification of its alkaloids have been a neglected area of scientific study. The diverse chemical compounds and biological activities of this genus will motivate further investigation on Scrophularia genus as a source of new therapeutic medications. PMID- 29125011 TI - Impact of TiO2 and ZnO nanoparticles on an aquatic microbial community: effect at environmentally relevant concentrations. AB - To investigate effects of engineered nanoparticles (ENPs) at environmentally relevant concentrations to aquatic microbial communities, TiO2 at 700 ug/L and ZnO at 70 ug/L were spiked to river water samples either separately or combined. Compared to controls where no ENPs were added, the addition of TiO2 ENPs alone at the tested concentration had no statistically significant effect on both the bacterial and eukaryotic communities. The presence of added ENPs: ZnO or ZnO + TiO2 led to significant shift of the microbial community structure and genus distribution. This shift was more obvious for the bacteria than the eukaryotes. Based on results from single particle - inductively coupled plasma - mass spectrometry (SP-ICP-MS), all ENPs aggregated rapidly in water and resulted in much larger particles sizes than the original counterparts. "Dissolved" (including particles smaller than the size detection limits and dissolved ions) concentrations of Ti and Zn increased, too in treatment groups vs. the controls. PMID- 29125012 TI - Optical assessment of the in vivo tympanic membrane status using a handheld optical coherence tomography-based otoscope. AB - OBJECTIVE: Conventional otoscopes and oto-endoscopes, which are used to examine the tympanic membrane (TM), do not provide tomographic information. Optical coherence tomography (OCT) non-invasively reveals the depth-resolved internal microstructure of the TM with very high spatial resolution. We designed this study to examine the TMs with middle ear diseases using a handheld otoscope employing 860 nm spectral domain (SD)-OCT, combined with video camera and to demonstrate the clinical applicability of this system. DESIGN: A total of 120 patients with otologic symptoms were enrolled. TM images were obtained using the handheld OCT-based otoscope (860 nm central wave length, 15 MUm axial resolution, 15 MUm lateral resolution, and 7 mm scanning range using relay lens). Both OCT and oto-endoscope images were compared according to the clinical characteristics such as perforation, retraction, and postoperative healing process. RESULTS: The objective grade about the thickness of perforation margins and the accurate information about the extent of TM retraction that was not distinguishable by oto endoscopic exam could be identified using this system. The postoperative healing process of TMs could be also followed using the OCT device. CONCLUSION: These analyses from the surgeon-oriented perspective suggest another useful application of the handheld OCT device. PMID- 29125013 TI - Diagnostic value of combined serum marker changes and quantitative MRI evaluation of cartilage volume of tibial plateau in a surgically-induced osteoarthritis dog model. AB - Objective To evaluate the combined diagnostic value of two serum osteoarthritis (OA) markers and quantitative magnetic resonance imaging (MRI) evaluation of the cartilage volume of the tibial plateau in a canine model of experimental OA. Methods A total of 18 male Beagle dogs were used in this longitudinal study. OA was surgically induced via anterior cruciate ligament transection (ACLT) of the right knee in 10 dogs. The remaining eight dogs formed the sham operation control group and underwent the same procedure without ACLT. At various times after surgery, enzyme-linked immunosorbent assay was used to measure serum C telopeptide of type II collagen (CTX-II) and type X collagen (ColX) levels. Quantitative evaluation of the tibial plateau volume was undertaken using MRI and ImageJ software. Results The serum CTX-II levels were significantly higher in the OA group at weeks 8, 12 and 16 after surgery, but not at week 4, compared with the control group. The serum ColX levels in the OA group were significantly higher than in the control group at weeks 8 and 12. The tibial plateau cartilage volumes in the OA group were significantly lower than in the control group at weeks 8 and 16. Conclusion Serum CTX-II and ColX levels combined with quantitative MRI evaluation of the tibial plateau cartilage volume in a canine model of OA demonstrated the potential to detect and monitor OA progression. PMID- 29125014 TI - Problematizing official narratives of HIV and AIDS education in Scotland and Zimbabwe. AB - When human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) are framed within an intersectional approach, they have the potential to transform understandings of social justice within the curriculum and education policy and practice in general. Yet, this transformative potential is often hampered by official narratives that fail to position HIV and AIDS as an integral component of overlapping systems of oppression, domination and discrimination. This article explores how official HIV and AIDS narratives tend to promote systemic injustice and inequality within education policy and practice in both Scotland and Zimbabwe, despite their good intents. We frame our argument within a transformative education discourse which seeks to create participatory and emancipatory HIV-related messages at school, tertiary and community levels. Using a narrative enquiry design, a Foucauldian theoretical lens was used to analyse the narratives derived from key informant responses, supplemented by analysis of key documents that deal with HIV and AIDS in both Scotland and Zimbabwe. Four broad narratives emerged: the 'Gay' Narrative; the Migration Narrative; the Conspiracy Narrative; and the Religious Narrative. We discuss how each of these narratives entrench stigma across both developed and developing world contexts, and propose how a more intersectional interpretation would contribute to a deeper and less stigmatizing understanding of HIV, thus offering more useful insights into related policy and educational practices. This article will thus contribute to the growing body of intersectional HIV and AIDS knowledge that is relevant for schools, teacher education, public health and community settings, not only in the countries studied, but the world over. PMID- 29125015 TI - Factors associated with return to work in patients with long-term disabilities due to neurological and neuropsychiatric disorders. AB - The current study explores factors predicting return to work in a sample of patients with neurological and neuropsychiatric disorders who have attended a prevocational readiness and social skills training programme many years after trauma. Participants were community-dwelling adults with long-term disabilities (N = 67). Results of univariate analyses followed by multivariate logistic regression analysis revealed that both pre-injury (prior) and post-injury (current) factors influenced the likelihood of employment in our sample: prior employment, current employment readiness, current cognitive competence (particularly memory and executive functioning) and emotional adjustment. Our findings demonstrate that both pre-trauma and current factors interact in predicting return to work not only for individuals with traumatic brain injury (TBI), but also for a broader group of patients with long-term disabilities due to a variety of neurological and neuropsychiatric conditions. Thus, our findings provide preliminary support for ongoing long-term management of individuals with long-term disabilities and warrant close attention of future investigators to potential benefits of cognitive remediation, psychotherapy and vocational rehabilitation in terms of maintenance of initial gains and increased probability of return to work many years after trauma. PMID- 29125016 TI - Open for business: a comparative study of websites selling autologous stem cells in Australia and Japan. AB - AIM: This article examines online marketing practices of Japanese and Australian clinics offering putative autologous stem cell treatments. MATERIALS & METHODS: We conducted google searches for keywords related to stem cell therapy and stem cell clinics in English and Japanese. RESULTS: We identified websites promoting 88 point-of-sale clinics in Japan and 70 in Australia. CONCLUSION: Our findings provide further evidence of the rapid global growth in clinics offering unproven stem cell interventions. We also show that these clinics adopt strategies to promote their services as though they are consistent with evidentiary and ethical standards of science, research and medicine. Unless addressed, these practices risk harming not only vulnerable patients but also undermining public trust in science and medicine. PMID- 29125017 TI - The effects of resistance training volume on osteosarcopenic obesity in older women. AB - The aim of this study was to analyze the effects of resistance training (RT) performed with 1 or 3 sets per exercise on osteosarcopenic obesity (OSO) syndrome parameters in older women. Sixty-two older women (68.0 +/- 4.3 years, 26.8 +/- 4.4 kg/m2) participated in a 12-week RT program. Participants were randomly assigned into one of the three groups: two training groups that performed either 1 set (G1S, n = 21) or 3 sets (G3S, n = 20) 3 times weekly, or a control group (CG, n = 21). Body composition was assessed by dual X-ray absorptiometry, strength was evaluated by 1 repetition maximum testing. The G3S presented significantly higher strength changes than G1S. The changes for percentage of body fat were higher for G3S compared to G1S. There was no difference in skeletal muscle mass between G3S and G1S, however both training groups displayed greater increases in this outcome compared to CG. There was no effect for bone mineral density. The overall analysis indicated higher (P < 0.05) positive changes for G3S than G1S (composed Z-score: G3S = 0.62 +/- 0.40; G1S = 0.11 +/- 0.48). The results suggest that a 12-week RT period is effective to improve the risk factors of OSO, and that 3 sets induce higher improvements than a single set. PMID- 29125018 TI - The Glasgow antipsychotic side-effects scale for clozapine in inpatients and outpatients with schizophrenia or schizoaffective disorder. AB - BACKGROUND: The inconsistency in clinician and patient ratings of clozapine induced side effects underscore the need to supplement clinician-based estimates of side effects with patient-reported ones. AIMS: The main aims of the study are validation of the Glasgow antipsychotic side-effects scale for clozapine (GASS-C) in Serbian inpatients/outpatients with schizophrenia or schizo-affective disorder and recommendations for its future use, based on common and rare clozapine associated side-effects. METHODS: The GASS-C was administered to 95 outpatients/inpatients diagnosed with schizophrenia, schizoaffective, or chronic psychotic disorder. RESULTS: The scale showed good overall reliability, with an internal consistency coefficient of alpha = 0.84, an average retest coefficient of rho = 0.76, and a Spearman-Brown coefficient of validity of 0.81. Side effects were absent or mild in 64.2% of the patients, moderate in 31.6%, severe in 4.2%; 14% of the subjects considered their symptoms distressing. The most commonly reported side-effects were drowsiness, thirst, frequent urination, and dry mouth. Women reported more side effects than men, and patients not in a relationship reported significantly fewer side effects than patients in a relationship. Results indicate a weak positive correlation (rho = 0.231; p = .025) between severity of side effects and clozapine dose. CONCLUSIONS: The GASS-C showed good psychometric characteristics in clinical population of patients on clozapine. In future studies, clozapine serum concentrations should be measured when using the GASS-C to monitor side effects. PMID- 29125019 TI - The loss of macular ganglion cells begins from the early stages of disease and correlates with brain atrophy in multiple sclerosis patients. AB - BACKGROUND: The importance of neurodegeneration in multiple sclerosis (MS) is increasingly well recognized. OBJECTIVES: To evaluate retinal pathology using optical coherence tomography (OCT) and to investigate possible associations between retinal layers' thickness and specific patterns of gray matter volume in patients with a new diagnosis of MS. METHODS: A total of 31 patients underwent OCT scans and brain magnetic resonance imaging. In total, 30 controls underwent the same OCT procedure. The association between focal cortical volume and OCT measurements was investigated with voxel-based morphometry (VBM). RESULTS: Compared to controls, patients' macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), and macular ganglion cell-inner plexiform layer (mGCIPL) thickness were significantly reduced ( p = 0.0009, p = 0.0003, p = 0.0049, and p = 0.0007, respectively). Peripapillary RNFL (pRNFL) and temporal sector pRNFL (T-pRNFL) did not show any significant changes, although there was a trend toward T-pRNFL thinning ( p = 0.0254). VBM analysis showed that mGCIPL and pRNFL were significantly correlated with the volume reduction of occipital-parietal cortex ( p < 0.005). CONCLUSION: mRNFL, mGCL, and mIPL are significantly reduced in MS patients without concomitant pRNFL thinning. These retinal changes show a significant association with cortical regions that are known to be important for visuospatial performance. PMID- 29125020 TI - Possible binding sites and interactions of propanidid and AZD3043 within the gamma-aminobutyric acid type A receptor (GABAAR). AB - Propanidid is an intravenous anesthetic with transient action and rapid recovery features, but it is clinically unacceptable due to its side effects. AZD-3043, an analog of propanidid with the methoxy group substituted by the ethoxy group, has become the focus of recent development efforts. Although propanidid and AZD-3043 are known to act by potentiating the gamma-aminobutyric acid type A receptors (GABAARs), their action sites and binding modes in the recognition of target proteins still remain unclear. In this study, molecular docking and ONIOM calculations were performed to explore the possible binding sites and binding modes of propanidid and AZD-3043 with the GABAAR. The predicted active region located in the transmembrane domain (TMD) of GABAAR was identified as the most favorable binding site for propanidid and AZD-3043, with the highest docking score (-39.69 and -39.44 kcal/mol, respectively) and the largest binding energy ( 88.478 and -78.439 kcal/mol, respectively). The important role of amino acids Asp245, Asp424, Asp425, Arg428, Phe307, and Ser308 in determining the binding modes of propanidid or AZD-3043 with GABAAR was revealed. The detailed molecular interactions between propanidid and AZD-3043 and the GABAAR were revealed for the first time. This could improve our understanding of the action mechanism of general anesthetics and will be helpful for the design of more potential lead like molecules. PMID- 29125021 TI - Organizational Policies and Programs to Reduce Job Stress and Risk of Workplace Violence Among K-12 Education Staff. AB - We examine strategies, programs, and policies that educators have developed to reduce work stressors and thus health risks. First, we review twenty-seven empirical studies and review papers on organizational programs and policies in K 12 education published from 1990 to 2015 and find some evidence that mentoring, induction, and Peer Assistance and Review programs can increase support, skill development, decision-making authority, and perhaps job security, for teachers and thus have the potential to reduce job stressors. Second, we describe efforts to reduce workplace violence in Oregon, especially in special education, including legislation, collective bargaining, research, and public awareness. We conclude that to reduce workplace violence, adequate resources are needed for staffing, training, equipment, injury/assault reporting, and investigation. Third, we discuss collective bargaining initiatives that led to mentoring and Peer Assistance and Review and state legislation on prevention of bullying and harassment of school staff. Finally, we present a research agenda on these issues. PMID- 29125022 TI - Number of days required for reliably estimating physical activity and sedentary behaviour from accelerometer data in older adults. AB - The purpose of the study was to examine the minimum number of monitoring days for reliably estimating physical activity (PA) and sedentary behaviour (SB) from accelerometer data in older adults. Forty-two older adults from a local senior centre participated in this study. Participants wore an ActiGraph wGT3X-BT on the right hip for 7 consecutive days. Accelerometer data were downloaded to a computer and converted to activity count data in 60s epochs. Time spent in SB and different PA intensity categories were estimated with commonly used activity count cut-points. Participants with at least 7 valid days of monitoring (>=10 h.day-1) were included in the analysis. Intraclass correlation coefficients (ICC) were calculated for determining single-day monitoring reliability. The Spearman Brown prophecy formula was used to estimate the minimum number of monitoring days required for achieving an ICC of 0.80. Single-day ICC values for time spent in SB and PA intensity categories ranged from 0.45 to 0.61. Minimum number of monitoring days required for achieving an ICC of 0.80 ranged from 2.5 to 4.9 days. In this study, a minimum of 5 consecutive days of monitoring was required for reliably estimating SB and PA from accelerometer data in older adults. PMID- 29125024 TI - Wingspan stent delivery catheter fracture and the TRAP technique for endovascular salvage. AB - Background Intracranial atherosclerotic disease may result in ischemic infarction and has a high rate of recurrent ischemic strokes despite medical therapy. Patients who fail medical therapy may undergo endovascular treatment with cerebral artery angioplasty and possible Wingspan stent placement. We present a unique case of Wingspan delivery microcatheter fracture that resulted in a retained foreign body and an endovascular salvage maneuver. Case description An elderly patient presented with an acute ischemic stroke due to a severe stenosis in the proximal left middle cerebral artery (MCA). The patient failed non invasive medical treatment and underwent endovascular treatment with angioplasty and Wingspan stent placement. Following Wingspan stent deployment, the stent delivery catheter fractured, and the retained catheter fragment resulted in MCA occlusion. The foreign body was retrieved by balloon catheter inflation within an intermediate catheter adjacent to the proximal end of the fractured catheter and removal of the entire construct (TRAP technique). Conclusions Wingspan delivery microcatheter fracture is a rare event. The TRAP technique may be used for successful retrieval of a retained foreign body. PMID- 29125025 TI - Choroid plexus AVM with anomalous origin of the capsulothalamic artery: A case report. AB - Background and importance Traditionally, it has been believed that the plexal segment of the anterior choroidal artery (AChoA) can be sacrificed safely. Here, we present a case of choroid plexus arteriovenous malformation (AVM) in which the capsulothalamic artery originated from distal plexal segment of the AChoA. Clinical presentation A 45-year-old man was diagnosed with arteriovenous malformation involving the left inferior horn in screening MRI. Preceding stereotactic radiosurgery, transarterial target embolization was performed. In this procedure, 20% n-butyl-2-cyanoacrylate (NBCA) was successfully injected from the lateral plexal branch of the AChoA. After embolization, right homonymous hemianopsia developed due to cerebral infarction on the left optic radiation. This infarction was considered to be within the territory of the capsulothalamic artery. Conclusion This anomalous capsulothalamic artery might be formed by hemodynamic compromise of the brain surrounding AVM in early gestation. We must be aware of this unusual anatomical variation to avoid ischemic complication in embolization of the AChoA. PMID- 29125026 TI - Delayed and incomplete treatment may result in dural fistula development in children with Vein of Galen malformation. AB - The association of dural arteriovenous fistulas (DAVF) in children with Vein of Galen malformation (VGM) has recently been reported for the first time. In a larger series of cases treated with transarterial NBCA embolization, 30% had DAVF. We wanted to analyze the development of DAVF in our cohort of children with VGM and to evaluate whether their occurrence depends on different treatment timing and embolic materials. We analyzed 43 VGM cases treated with a combined transarterial and transvenous approach between 2003 and 2016. In our early series until 2011, we used coils solely in 21 children. Since 2012, 22 children were treated with the combination of coils and Onyx. In the early series treated with coils solely, no case presented initially with or developed DAVF over time on follow-up angiograms. In our recent series we found four cases (9%) with DAVF. In two patients (5%), DAVF were found on the initial angiogram. Both patients presented at our department at age >2 years and were not treated elsewhere before. One patient (2%) presented at our department with too proximal occlusion of arterial feeders performed at another institution before. Only one patient (2%) developed DAVF in our department after the transarterial use of Onyx. Interestingly, this child did not develop DAVF as long as we used coils solely and his DAVF was localized exactly where an Onyx cast was identified. In conclusion, delayed and incomplete treatment may have a considerable impact on the occurrence of DAVF in VGM. PMID- 29125027 TI - Thromboembolic complications during endovascular treatment of ruptured cerebral aneurysms. AB - Background In cases of subarachnoid hemorrhage due to aneurysm rupture, the administration of an anticoagulant or antiplatelet agent involves the risk of rebleeding from the aneurysm. There is a possibility of inducing thromboembolic events during the endovascular embolization of ruptured cerebral aneurysms. Patients and methods From April 2006 to March 2017, we treated a total of 70 patients with ruptured cerebral aneurysms with an endovascular technique. Among them, five patients (7.1%) showed intra-arterial thrombus formation. The aneurysms were located at the anterior communicating artery and basilar artery in two patients each, and on the internal carotid artery at the bifurcation of the anterior choroidal artery (AChoA) in one. In these patients, the clinical course, radiological findings, and management were retrospectively reviewed. Results Thrombus formation was observed in the posterior cerebral artery, anterior cerebral artery (A2), AChoA, and middle cerebral artery. The timing of thrombus formation was during coil delivery in four cases, and guiding catheter advancement in one. As for thrombus management, for all patients, administrations of heparin and antiplatelet agents were performed. For four patients, urokinase injection into the affected arteries was added after the completion of embolization. Cerebral infarction was postoperatively identified in two patients, but no hemorrhage was noted. Conclusion Administrations of heparin and antiplatelet drugs should be performed appropriately during procedures, and close observation of the arterial condition on angiography is necessary. Once thromboembolism occurs during the endovascular embolization of ruptured cerebral aneurysms, adequate heparinization, and antiplatelet therapy should first be performed. PMID- 29125028 TI - Molecular Basis of Citrus sunki Susceptibility and Poncirus trifoliata Resistance Upon Phytophthora parasitica Attack. AB - Coevolution has shaped the molecular basis of an extensive number of defense mechanisms in plant-pathogen interactions. Phytophthora parasitica, a hemibiothrophic oomycete pathogen and the causal agent of citrus root rot and gummosis, interacts differently with Citrus sunki and Poncirus trifoliata, two commonly favored citrus rootstocks that are recognized as susceptible and resistant, respectively, to P. parasitica. The molecular core of these interactions remains elusive. Here, we provide evidence on the defense strategies employed by both susceptible and resistant citrus rootstocks, in parallel with P. parasitica deployment of effectors. Time course expression analysis (quantitative real-time polymerase chain reaction) of several defense-related genes were evaluated during i) plant disease development, ii) necrosis, and iii) pathogen effector gene expression. In C. sunki, P. parasitica deploys effectors, including elicitins, NPP1 (necrosis-inducing Phytophthora protein 1), CBEL (cellulose binding elicitor and lectin activity), RxLR, and CRN (crinkler), and, consequently, this susceptible plant activates its main defense signaling pathways that result in the hypersensitive response and necrosis. Despite the strong plant-defense response, it fails to withstand P. parasitica invasion, confirming its hemibiothrophic lifestyle. In Poncirus trifoliata, the effectors were strongly expressed, nevertheless failing to induce any immunity manipulation and disease development, suggesting a nonhost resistance type, in which the plant relies on preformed biochemical and anatomical barriers. PMID- 29125029 TI - Match-derived relative pitch area changes the physical and team tactical performance of elite soccer players in small-sided soccer games. AB - Small-sided games (SSGs) are used in training sessions to prepare for full-sized matches. For the same number of players, smaller pitch sizes result in decreased physical performance and shorter interpersonal distances. A relative pitch area derived from the full-sized match results in larger pitch sizes and this may increase the fit between SSGs and full-sized matches. This study aimed to investigate SSGs with a traditional small pitch and a match-derived relative pitch area in youth elite soccer players. Four age categories (under-13, under 15, under-17 and under-19) played 4 vs. 4 plus goalkeepers on a small (40x30m, 120m2 relative pitch area) and large pitch (68x47m, 320m2 relative pitch area). The number of games per age category ranged 15-30. Positional data (LPM-system) were collected to determine physical (total distance covered, high intensity distance and number of sprints) and team tactical (inter-team distance, LPW ratio, surface area, stretch indices, goalkeeper-defender distance) performance measures and tactical variability. On a large pitch, physical performance significantly increased, inter-team and intra-team distances were significantly larger and tactical variability of intra-team distance measures significantly increased. The match-derived relative pitch area is an important training manipulation and leads to changes in physical and tactical performance 4 vs. 4 plus goalkeepers. PMID- 29125030 TI - Exploring the effect of D61G mutation on SHP2 cause gain of function activity by a molecular dynamics study. AB - Noonan syndrome (NS) is a common autosomal dominant congenital disorder which could cause the congenital cardiopathy and cancer predisposition. Previous studies reported that the knock-in mouse models of the mutant D61G of SHP2 exhibited the major features of NS, which demonstrated that the mutation D61G of SHP2 could cause NS. To explore the effect of D61G mutation on SHP2 and explain the high activity of the mutant, molecular dynamic simulations were performed on wild type (WT) of SHP2 and the mutated SHP2-D61G, respectively. The principal component analysis and dynamic cross-correlation mapping, associated with secondary structure, showed that the D61G mutation affected the motions of two regions (residues Asn 58-Thr 59 and Val 460-His 462) in SHP2 from beta to turn. Moreover, the residue interaction networks analysis, the hydrogen bond occupancy analysis and the binding free energies were calculated to gain detailed insight into the influence of the mutant D61G on the two regions, revealing that the major differences between SHP2-WT and SHP2-D61G were the different interactions between Gly 61 and Gly 462, Gly 61 and Ala 461, Gln 506 and Ile 463, Gly 61 and Asn 58, Ile 463 and Thr 466, Gly 462 and Cys 459. Consequently, our findings here may provide knowledge to understand the increased activity of SHP2 caused by the mutant D61G. PMID- 29125031 TI - A rapidly expanding calvarial Langerhans cell histiocytosis with low Ki-67 in an adult: a challenging diagnosis on magnetic resonance imaging. AB - Langerhans cell histiocytosis may have a wide variety of clinical presentations. The growth of localised form is usually slow and it mainly involves bones such as the skull, femur, spine, ribs, mandible and pelvis in children. The spectrum of clinical manifestations and magnetic resonance imaging findings of the disease may sometimes mimic infections as well as benign and malignant tumours. In this report, we describe an unusual case of rapidly progressive calvarial Langerhans cell histiocytosis with a painful and tender mass in a 27-year-old man that created diagnostic and therapeutic challenges. We also discuss the relationship between Ki-67 proliferative index and the expansion of the disease. Magnetic resonance imaging studies revealed a bone defect on the left frontal bone with soft tissue components, showing a prominent expansion within a month. The clinical manifestation with the enhancement pattern of epidural soft tissue component on contrast-enhanced magnetic resonance imaging suggested an infection besides Langerhans cell histiocytosis. Immunohistochemical expression of Ki-67 antigen was 5%. The presence of a relatively low Ki-67 value indicates that the inflammatory response may have a more important role than local Langerhans cell proliferation in the aggressive clinical course and rapid expansion. PMID- 29125032 TI - B Cells Protect T Cell-deficient mice from Cryptococcal Brain Invasion. PMID- 29125033 TI - Medical costs in patients with heart failure after acute heart failure events: one-year follow-up study. AB - AIMS: This study investigated annual medical costs using real-world data focusing on acute heart failure. METHODS: The data were retrospectively collected from six tertiary hospitals in South Korea. Overall, 330 patients who were hospitalized for acute heart failure between January 2011 and July 2012 were selected. Data were collected on their follow-up medical visits for 1 year, including medical costs incurred toward treatment. Those who died within the observational period or who had no records of follow-up visits were excluded. Annual per patient medical costs were estimated according to the type of medical services, and factors contributing to the costs using Gamma Generalized Linear Models (GLM) with log link were analyzed. RESULTS: On average, total annual medical costs for each patient were USD 6,199 (+/-9,675), with hospitalization accounting for 95% of the total expenses. Hospitalization cost USD 5,904 (+/-9,666) per patient. Those who are re-admitted have 88.5% higher medical expenditure than those who have not been re-admitted in 1 year, and patients using intensive care units have 19.6% higher expenditure than those who do not. When the number of hospital days increased by 1 day, medical expenses increased by 6.7%. LIMITATIONS: Outpatient drug costs were not included. There is a possibility that medical expenses for AHF may have been under-estimated. CONCLUSION: It was found that hospitalization resulted in substantial costs for treatment of heart failure in South Korea, especially in patients with an acute heart failure event. Prevention strategies and appropriate management programs that would reduce both frequency of hospitalization and length of stay for patients with the underlying risk of heart failure are needed. PMID- 29125034 TI - The Memo Slide: An explorative study into a novel mechanical follow-the-leader mechanism. AB - Follow-the-leader propagation allows for the insertion of flexible surgical instruments along curved paths, reducing the access required for natural orifice transluminal endoscopic surgery. Currently, the most promising follow-the-leader instruments use the alternating memory method containing two mechanical memory banks for controlling the motion of the flexible shaft, which reduces the number of actuators to a minimum. These instruments do, however, require concentric structures inside the shaft, limiting its miniaturization. The goal of this research was, therefore, to develop a mechanism conforming the principles of the alternating memory method that could be located at the controller-side instead of inside the shaft of the instrument, which is positioned outside the patient and is therefore less restricted in size. First, the three-dimensional motion of the shaft was decoupled into movement in a horizontal and vertical plane, which allowed for a relatively simple planar alternating memory mechanism design for controlling planar follow-the-leader motion. Next, the planar movement of the alternating memory mechanism was discretized, increasing its resilience to errors. The resulting alternating memory mechanism was incorporated and tested in a proof-of-concept prototype called the Memo Slide. This prototype does not include a flexible shaft, but was fully focused on proving the function of the alternating memory mechanism. Evaluation of the Memo Slide shows the mechanism to work very well, being able to transfer any planar path that lays within its physical boundaries along the body of the mechanism without accumulating errors. PMID- 29125035 TI - Cone-beam computed tomography (CBCT) for adaptive image guided head and neck radiation therapy. AB - BACKGROUND: Adaptive (ART) and image guided radiation therapy (IGRT) can improve target coverage and reduce unnecessary irradiation of organs at risk (OAR). The purpose of this study is to report the results of using mid-course imaging and a novel workflow with cone-beam computed tomography (CBCT) surveillance of dose to OAR to trigger adaptive replanning in head and neck radiotherapy. MATERIAL AND METHODS: Impact of radiation therapist (RTT) managed match protocol and mid course imaging was assessed in two cohorts of consecutive patients receiving RT to the head and neck region, using computed tomography (CT) and CBCT-based dose verification respectively. In the CBCT cohort, patients at high risk of xerostomia received weekly dose surveillance, while low-risk patients received a mid-course CBCT review. For weekly surveillance, predicted total doses to parotid glands, spinal cord and brainstem were calculated. If predicted mean dose to parotid glands increased by >2 Gy or constraints to brainstem or spinal cord were exceeded, replanning was performed. RESULTS: None had replanning triggered by mid course imaging. In the CBCT cohort, weekly surveillance of 40 patients yielded minimal reduction in mean dose to parotid glands of 0.65 Gy (range0.4-1 Gy ) for three patients. Patients were surveilled averagely 4.5 times during treatment. Time consumption per CBCT/week was 22 min (range 17-38). Number of patients needed to see to achieve any dose reduction to parotid glands was 13 or the equivalent of 22 working-hours. CONCLUSION: The tested dose surveillance algorithm resulted in a minimal dose reduction ( <=1 Gy) to parotid glands for three of 40 patients. The proposed algorithm and workflow is thus not sustainable. Mid-course dose verification did not provide added benefit and can be safely omitted in the presence of closely monitored daily IGRT. Daily image guidance and match protocol is a safe and efficient method for identifying patients requiring adaptive replanning. PMID- 29125036 TI - Bivariate functional principal components analysis: considerations for use with multivariate movement signatures in sports biomechanics. AB - Sporting performance is often investigated through graphical observation of key technical variables that are representative of whole movements. The presence of differences between athletes in such variables has led to terms such as movement signatures being used. These signatures can be multivariate (multiple time-series observed concurrently), and also be composed of variables measured relative to different scales. Analytical techniques from areas of statistics such as Functional Data Analysis (FDA) present a practical alternative for analysing multivariate signatures. When applied to concurrent bivariate time-series multivariate functional principal components analysis (referred to as bivariate fPCA or bfPCA in this paper) has demonstrated preliminary application in biomechanical contexts. Despite this, given the infancy of bfPCA in sports biomechanics there are still necessary considerations for its use with non conventional or complex bivariate structures. This paper focuses on the application of bfPCA to the force-angle graph in on-water rowing, which is a bivariate structure composed of variables with different units. A normalisation approach is proposed to investigate and standardise differences in variability between the two variables. The results of bfPCA applied to the non-normalised data and normalised data are then compared. Considerations and recommendations for the application of bfPCA in this context are also provided. PMID- 29125037 TI - An audit of injuries in six english professional soccer academies. AB - Regulations now state that professional academies in the United Kingdom are required to substantially increase the volume of soccer training. This study assessed the current injury occurrence, providing an update to reports published prior to the introduction of the Elite Player Performance Plan (EPPP). 608 soccer players aged 11-18 years from six professional soccer clubs were prospectively monitored, recording injuries during the 2014-2015 season. An injury rate of 1.32 injuries per player/season was indicated with a mean time loss of 21.9 days per injury. The greatest time loss per injury was in the U14s-U15s, and the highest rate of severe injuries in the U15s. Strains and sprains were the most common injury type, with the knee and ankle the most frequently injured anatomical sites. Seasonal variation indicated two peaks in injury incidence, occurring in September and January. In comparison to a published audit prior to the inception of the EPPP, this study indicates that academy soccer players are three-times more likely to experience an injury. Given that time loss and injury severity also increased during periods that typically follow rapid growth, these players should be considered an important group for training load monitoring and injury prevention strategies. PMID- 29125038 TI - Melanotic neuroectodermal tumour of infancy: A case report and differential diagnosis. AB - Melanotic neuroectodermal tumour of infancy is an uncommon pigmented neoplasm of neural crest origin. It was first described in 1918 by Krompecher, known as congenital melanocarcinoma at that time. Although it is generally agreed upon that it is a benign entity, it is locally aggressive and has a significant recurrent risk, reported to be between 10-15%. There have also been prior reports of malignant behaviour in these tumours, although extremely rare. The majority of cases of this tumour (about 70%) arise from the maxilla and its occurrence in the cranial vault represents approximately 15.6% of cases. We describe a rare case of melanotic neuroectodermal tumour of infancy, with simultaneous involvement of the cranial vault and petrous temporal bone, in a four-month-old child, complicated by post-surgical pseudo-meningocele. This case illustrates the diagnostic dilemma in differentiating reactive osseous sclerosis from direct tumour infiltration, both of which can occur in the context of melanotic neuroectodermal tumour of infancy. The discussion places emphasis on differential diagnoses and useful radiological features to assist in clinching the diagnosis of melanotic neuroectodermal tumour of infancy. PMID- 29125039 TI - Astrocyte Autophagy Flux Protects Neurons Against Oxygen-Glucose Deprivation and Ischemic/Reperfusion Injury. AB - The role of autophagy varies with the type of acute brain injury. In general, autophagy mediates a clear neuroprotective effect in intoxication caused by various psychoactive agents, subarachnoid hemorrhage and spinal cord injury. In contrast, autophagic cell death has also been reported to actively contribute to neuronal loss in neonatal hypoxic ischemic encephalopathy. However, it still remains to be determined whether autophagy pays a cytoprotective or a cytotoxic role in stroke. Previous studies focused primarily on the role of neurons rather than the role of astrocytes in brain injury. Thus, it is unknown whether modulating the autophagy flux of astrocytes contributes to improving neuronal survival after stroke. In the current study, we investigated the time course of autophagy flux in vitro using cocultured astrocytes and neurons exposed to oxygen glucose deprivation/reoxygenation, which mimicked the process of ischemia/reperfusion. Autophagy flux of astrocytes was regulated by treatment with the autophagy inducer rapamycin, autophagy inhibitor 3-methyladenine, and the transduction of small interfering RNA against autophagy-related gene 5. In addition, AAV-GFAP-ATG7 was used to induce astrocyte autophagy flux in mice subjected to focal cerebral ischemia. We found that induction of autophagy flux of astrocytes in vitro enhanced the viability of neurons and decreased neuronal apoptosis. Furthermore, induction of astrocyte autophagy flux in mice improved neurological outcomes. In contrast, inhibition of autophagy flux in astrocytes decreased the viability of neurons and increased neuronal apoptosis. These results suggest that upregulation of autophagy flux in astrocytes may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke. PMID- 29125040 TI - Reliability of horizontal force-velocity-power profiling during short sprint running accelerations using radar technology. AB - Radar technology can be used to perform horizontal force-velocity-power profiling during sprint-running. The aim of this study was to determine the reliability of radar-derived profiling results from short sprint accelerations. Twenty-seven participants completed three 30 m sprints (intra-day analysis), and nine participants completed the testing session on four separate days (inter-day analysis). The majority of radar-derived kinematic and kinetic descriptors of short sprint performance had acceptable intra-day and inter-day reliability [intraclass correlation coefficient (ICC) >= 0.75 and coefficient of variation (CV) <= 10%], but split times over the initial 10 m and some variables that include a horizontal force component had only moderate relative reliability (ICC = 0.49-0.74). Comparing the average of two sprint trials between days resulted in acceptable reliability for all variables except the relative slope of the force velocity relationship (SFvrel; ICC = 0.74). Practitioners should average sprint test results over at least two trials to reduce measurement variability, particularly for outcome variables with a horizontal force component and for sprint distances of less than 10 m from the start. PMID- 29125041 TI - HIV risks among women who are married to men who have sex with men in India: a qualitative investigation. AB - In countries such as India, men who have same-sex partnerships may marry women due to cultural pressures regardless of their sexual desires and preferences. The wives of such men may be at risk for HIV but limited existing research addresses this issue. This qualitative study used in-depth interviews to investigate HIV related risk among married men who have sex with men (n = 34) and women who were aware of their husband's same-sex behaviour (n = 13) from six research sites in five states and a Union Territory in India: Delhi (Delhi), Visakhapatnam (Andhra Pradesh), Hyderabad (Telangana), Bengaluru (Karnataka), Chennai and Madurai (Tamil Nadu). Thematic analysis revealed that wives of men who have sex with men were at risk for HIV from their husbands' sexual practices, which are often hidden to avoid the potential consequences of stigmatisation, as well as from gender-based inequities that make husbands the primary decision-makers about sex and condom use, even when wives are aware of their husband's same-sex behaviour. Innovative interventions are needed to address HIV-related risk in couples where wives remain unaware of their husband's same-sex behaviour, and for wives who are aware but remain within these marriages. PMID- 29125043 TI - European Stroke Conference, Stockholm, Sweden. PMID- 29125042 TI - Molecular surveillance of chloroquine drug resistance markers (Pfcrt and Pfmdr1) among imported Plasmodium falciparum malaria in Qatar. AB - Imported malaria has been a great challenge for public health in Qatar due to influx of large number of migrant workers. Antimalarial drug resistance has emerged as one of the greatest challenges facing malaria control today. Monitoring parasite haplotypes that predict susceptibility to major antimalarial can guide treatment policies. This study aimed to determine molecular drug resistance pattern in imported malaria cases in Qatar. Blood samples from the uncomplicated P. falciparum malaria patients were collected at Hamad General Hospital, HMC, Doha, Qatar. The samples were further confirmed by nested polymerase chain reaction (PCR) for P. falciparum. Molecular markers of chloroquine (Pfcrt and Pfmdr1) were analyzed by using nested PCR- RFLP method to determine the key point mutations associated with chloroquine (CQ) drug resistance. A total 118 blood samples were positive for P. falciparum. Overall, by RFLP, 72% harboured wild type allele (N86) of Pfmdr1 gene. The prevalence of Pfcrt mutant (T76), WT (K76) and mixed alleles (K76T) was 63.6% (n = 75), 22.9% (n = 27) and 13.5% (n = 16), respectively. Mean parasitaemia level was higher among the wild type alleles of Pfcrt gene as compared to the mixed/mutant alleles whereas mixed alleles of Pfmdr1 gene having high parasitaemia. Molecular surveillance strategy based on imported malaria cases can be used to detect and track CQ drug-resistant malaria. The data presented here might be helpful for enrichment of molecular surveillance of antimalarial resistance and will be useful for developing and updating antimalarial guidance for non-immune imported cases in Qatar. PMID- 29125044 TI - Highlights of the 10th International Symposium on Thrombolysis and Acute Stroke Therapy, 21-23 September 2008, in Budapest. PMID- 29125046 TI - Conference Diary. PMID- 29125045 TI - Fourth National Congress of the Indian Stroke Association in Hyderabad. PMID- 29125047 TI - Extra-corporeal membrane oxygenation and outcomes in massive pulmonary embolism: Two eras at an urban tertiary care hospital. AB - Mortality associated with high-risk pulmonary embolism (PE) remains high. Extra corporeal membrane oxygenation (ECMO) allows for acute hemodynamic stabilization and potentially for administration of other disease process altering therapies. We sought to compare two eras: pre-ECMO and post-ECMO in relation to high-risk PE treatment and mortality. A single-center retrospective chart review was conducted of high-risk PE patients. High-risk PE was defined as acute PE and cardiac arrest or shock. A total of 60 patients were identified, 31 in the pre-ECMO era and 29 in the post-ECMO era. Mean age was 56.1+/-21.1 years and 51.7% were women. More patients in the post-ECMO era were identified with computed tomography (82.8% vs 51.6%, p=0.011) and more patients in the post-ECMO era had right ventricular dysfunction on echocardiography (96.4% vs 78.3%, p=0.045). No other differences were noted in baseline characteristics or clinical, laboratory and imaging data between the two groups. In total, ECMO was used in 13 (44.8%) patients in the post-ECMO era. There was greater utilization of catheter-directed therapies in the post-ECMO era compared to the pre-ECMO era ( n = 7 (24.1%) vs n = 1 (3.2%), p=0.024). Thirty-day survival increased from 17.2% in patients who presented in the pre-ECMO era to 41.4% in the post-ECMO era ( p=0.043). While more work is necessary to better identify those PE patients who stand to benefit from mechanical circulatory support, our findings have important implications for the management of such patients. PMID- 29125048 TI - Keeping up with the times at Memory. PMID- 29125049 TI - Pseudoaneurysm at M3 of the middle cerebral artery: Morphological changes on serial radiological examinations. AB - A 20-year-old man presented with consciousness disturbance and hemiparesis, and computed tomography demonstrated subarachnoid and intracerebral hemorrhage. Angiography on admission demonstrated a slight irregularity of the middle cerebral artery (MCA) branch. Angiography on the 12th day showed a suspicious lesion at M3 of the left MCA. Angiography performed 24 days after the onset disclosed an aneurysm at M3. The aneurysm was trapped and resected after superficial temporal artery-MCA bypass. Pathological examinations revealed that this distal aneurysm was a pseudoaneurysm without vascular components in its dome. Although a lesion that may cause subarachnoid or intracerebral hemorrhage was not detected on the initial angiography, repeated examinations revealed the atypical vascular lesion in distal MCA. PMID- 29125050 TI - Nano-fumed silica as a novel pollutant that inhibits the algicidal effect of p hydroxybenzoic acid on Microcystis aeruginosa. AB - Nanomaterials and/or contaminants are becoming more common in the developing world, but their effects on interspecific interactions are rarely reported, particularly in aquatic ecosystems. Thus, the present study determined the effects of the novel pollutant nano-fumed silica (NFS) on algal control by a macrophyte via the allelochemical p-hydroxybenzoic acid in a microcosm test. The allelochemical p-hydroxybenzoic acid caused significant decreases in chlorophyll a, but increased the amount of superoxide anion radicals ([Formula: see text]) and the electric conductivity in Microcystis aeruginosa. The 50% inhibitory concentration (IC50) for p-hydroxybenzoic acid was 0.919 mmol/L in microalga during the exponential phase. Interestingly, NFS at 100-1600 mg/L had clear stimulatory effects on M. aeruginosa. When NFS at 800 mg/L was combined with different concentrations of p-hydroxybenzoic acid, the IC50 for p-hydroxybenzoic acid was 1.045 mmol/L. Thus, NFS significantly reduced the algicidal effect exhibited by p-hydroxybenzoic acid on M. aeruginosa. Furthermore, NFS might act as a silicon nutrient and enhance allelopathic resistance in M. aeruginosa to inhibit the algicidal effects of macrophytes via allelopathy. These findings suggest that before algal control is considered using macrophyte allelopathy, it is essential to remove the pollutant NFS from polluted lakes. PMID- 29125051 TI - How to become proficient in performance of the resting ankle-brachial index: Results of the first randomized controlled trial. AB - The resting ankle-brachial index (ABI) is a first-line test to diagnose peripheral artery disease (PAD). No randomized controlled trial (RCT) has yet been conducted to determine the best teaching method to become proficient in the ABI procedure. We conducted a monocentric RCT to determine whether didactic learning alone or didactic learning combined with experiential learning improved proficiency in the ABI procedure. Medical students ( n = 30) received didactic learning, including (i) a presentation of the ABI guidelines and (ii) a video demonstration. Each student was then randomized into two groups ('no experiential learning group' and 'experiential learning group'). An initial evaluation was performed after the didactic learning and a final evaluation at the end of the intervention. A student was considered to be proficient when he or she performed a correct ABI procedure on a healthy individual and a patient. The correct procedure corresponds to (i) following guidelines and (ii) a difference in ABI measurement between a vascular specialist and a student of <= 0.15. No student was proficient at the initial evaluation. At the final evaluation, in the didactic learning group, the number of proficient students was not improved compared with the initial evaluation (0/10 vs 1/10). In the experiential learning group, the number of proficient students was significantly improved (0/20 vs 11/20; p < 0.05). At the final evaluation, there was a significant difference between the number of proficient students depending on their learning group. In conclusion, didactic learning alone is insufficient to gain proficiency in the ABI procedure. Combining didactic learning with experiential learning significantly improved the students' proficiency. PMID- 29125052 TI - Prevalence of extended-spectrum beta-lactamase and carbapenemase-producing bloodstream isolates of Klebsiella pneumoniae in a tertiary care hospital. AB - To improve prescribing of empiric therapy, the local molecular epidemiology of extended-spectrum beta-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs) in bloodstream isolates of K. pneumoniae were evaluated. Isolates resistant to third generation cephalosporins were screened phenotypically for ESBLs and carbapenemases, and subsequently confirmed by PCR for the presence of ESBL (blaTEM, blaSHV and blaCTX-M) and carbapenemase (blaKPC, blaVIM, blaNDM and blaOXA-48) genes. Hydrolytic activity (functional gene expression) was quantified using a nitrocefin degradation assay and correlated to ceftazidime or meropenem MIC. Clonality was assessed by repetitive element-based PCR. Beta-lactamases were functionally expressed in 13 isolates (15.5%); 7 (53.8%) harboured blaCTX-M-15 and 6 (46.2%) carried the blaKPC-2 gene. Correlation of hydrolytic activity to MIC yielded a coefficient of 98% for isolates expressing ESBLs alone and 56% for carbapenemase producers. Four unique ESBL-expressing clones and five carbapenem-resistant clones were identified. All 13 resistant isolates were susceptible to ceftazidime/avibactam (MIC <= 8/4 mg/L). PMID- 29125054 TI - Nitrogen and phosphorus release from organic wastes and suitability as bio-based fertilizers in a circular economy. AB - The drive to a more circular economy has created increasing interest in recycling organic wastes as bio-based fertilizers. This study screened 15 different manures, digestates, sludges, composts, industry by-products, and struvites. Nitrogen (N) and phosphorous (P) release was compared following addition to soil. Three waste materials were then 'upgraded' using heating and pressure (105 degrees C at 220 kPa), alkalinization (pH 10), or sonification to modify N and P release properties, and compared in a second soil incubation. Generally, maximum N release was negatively correlated with the CN ratio of the material (r = -0.6). Composted, dried, or raw organic waste materials released less N (mean of 10.8 +/ 0.5%, 45.3 +/- 7.2%, and 47.4 +/- 3.2% of total N added respectively) than digestates, industry-derived organic fertilizer products, and struvites (mean of 58.2 +/- 2.8%, 77.7 +/- 6.0%, and 100.0 +/- 13.1% of total N added respectively). No analyzed chemical property or processing type could explain differences in P release. No single upgrading treatment consistently increased N or P release. However, for one raw biosolid, heating at a low temperature (105 degrees C) with pressure did increase N release as a percentage of total N added to soil from 30% to 43%. PMID- 29125053 TI - Twenty minutes of normothermic cardiac arrest in a pig model: the role of short term hypothermia for neurological outcome. AB - INTRODUCTION: Cardiopulmonary resuscitation restores circulation, but with inconsistent blood-flow and pressures. Our recent approach using an extracorporeal life support system, named "controlled integrated resuscitation device" (CIRD), may lead to improved survival and neurological recovery after cardiac arrest (CA). The basic idea is to provide a reperfusion tailored to the individual patient by control of the conditions of reperfusion and the composition of the reperfusate. Hypothermia is one aspect of this concept. Here, we investigated the role of immediate short-term blood cooling after experimental CA and its influence on survival and neurological recovery. METHODS: Twenty-one pigs were exposed to 20 minutes of normothermic CA. Afterwards, CIRD was immediately started for 60 minutes in all animals and the heart was converted to a sinus rhythm. The pigs either received normothermic reperfusion (37 degrees C, n=11) or the temperature was maintained at 32 degrees C for the first 30 minutes (n=10). Thermometric, hemodynamic and serologic data were collected during the experiment. After weaning from CIRD, neurological recovery was assessed daily by a species-specific neurological deficit score (NDS; 0: normal; 500: brain death). RESULTS: One pig in each group could not be successfully resuscitated. Due to severe neurological deficits, only 6/11 animals in the normothermic group finished the observation time of seven days with an NDS of 37+/-34. In the hypothermic group, all nine surviving animals reached day seven with an NDS of 16+/-13. Analogous to the lower NDS, animals in the hypothermic group also showed lower neuron-specific enolase end values as a marker of brain injury. CONCLUSIONS: Within this experimental setting, immediate moderate and short-term hypothermia after CA improves survival and seems to result in statistically non significant better neurological recovery. PMID- 29125055 TI - Cerebral amyloid angiopathy, cerebral microbleeds and implications for anticoagulation decisions: The need for a balanced approach. AB - Cerebral amyloid angiopathy is a common hemorrhagic small vessel disease of the brain, often associated with high risk of spontaneous lobar intracerebral hemorrhage. When the suspicion of cerebral amyloid angiopathy is raised, clinicians are hesitant in prescribing oral anticoagulation in patients in whom it is otherwise indicated, including the case of non-valvular atrial fibrillation. This is one of the thorniest clinical dilemmas in the field currently. In this short Leading Opinion piece by an international panel of clinicians-researchers active in the field, we present our consistent approach and future outlook on oral anticoagulation post intracerebral hemorrhage and in the setting of clinical-radiologic evidence of cerebral amyloid angiopathy. We discuss recent advances and support a more balanced approach with implications for the wider neurological clinical community in regards to successful recruiting this patient population in ongoing and future randomized trials. PMID- 29125056 TI - Monosodium glutamate and treadmill exercise: Anxiety-like behavior and spreading depression features in young adult rats. AB - OBJECTIVES: The route of administration is an important factor in determining the action of some drugs. We previously demonstrated that subcutaneous monosodium glutamate (MSG) accelerated cortical spreading depression (CSD) in the rat and that treadmill exercise attenuated this effect. This study evaluated whether other routes of administration exert the same action by testing orogastric (gavage) and topical cortical MSG administration in treadmill-exercised and sedentary rats. Additionally, in the orogastric treatment we tested anxiety-like behavior. METHODS: Exercised and sedentary rats received per gavage water or MSG (1 or 2 g/kg) daily from postnatal (P) day 7 to 27. Behavioral tests (open field and elevated plus-maze) occurred at P53 +/- 3. At P56 +/- 3, we analyzed CSD parameters (velocity, amplitude, and duration of the negative potential change). Other three groups of rats received an MSG solution (25, 50 or 75 mg/ml) topically to the intact dura mater during CSD recording. RESULTS: MSG-gavage increased anxiety-like behavior and the CSD velocities compared with water treated controls (P < 0.05). Exercise decelerated CSD. In contrast to gavage, which accelerated CSD, topical MSG dose-dependently and reversibly impaired CSD propagation, reduced CSD amplitude and increased CSD duration (P < 0.05). CONCLUSIONS: The exercise-dependent attenuation of the effects of MSG confirms our previous results in rats treated subcutaneously with MSG. CSD results suggest two distinct mechanisms for gavage and topical MSG administration. Additionally, data suggest that exercise can help protect the developing and adult brain against the deleterious actions of MSG. PMID- 29125057 TI - Deoxynivalenol and its acetyl derivatives in bread and biscuits in Shandong province of China. AB - In the present study, 100 commercial breads and biscuits were investigated for the occurrence of deoxynivalenol (DON) and its acetylated derivatives 3 acetyldeoxynivalenol (3-Ac-DON) and 15-acetyldeoxynivalenol (15-Ac-DON). The target mycotoxins were determined by isotope dilution ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). DON was determined in 95% of the test samples with a mean value of 153.3 ug/kg. Compared with DON, 3 Ac-DON and 15-Ac-DON were far less frequently detected, with mean values of 1.14 and 0.37 ug/kg, respectively. The estimated daily intakes of the sum of DON and its derivatives in breads and biscuits were 0.0059 and 0.0313 ug/kg bw/day, respectively, which was within the group provisional tolerable daily intake of 1.0 ug/kg bw/day set by the Joint FAO/WHO Expert Committee on Food Additives. In the future, systematic monitoring programmes of DON and its derivatives in relevant foodstuffs are still necessary for food safety and human health. PMID- 29125059 TI - Corrigenda. PMID- 29125058 TI - Edaravone attenuates oxidative stress induced by chronic cerebral hypoperfusion injury: role of ERK/Nrf2/HO-1 signaling pathway. AB - Objectives The potential protective effects and mechanisms of edaravone have not been well elucidated in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH). The aim of this study was to investigate whether edaravone could improve cognitive damage in rats induced by CCH, and whether the effects of edaravone were associated with ERK/Nrf2/HO-1 signaling pathway. Methods CCH was induced by bilateral common carotid arteries occlusion (BCCAO). Sprague-Dawley (SD) rats were randomly divided into four groups: sham (sham-operated) group, vehicle (BCCAO + normal saline) group, edaravone3.0 group and edaravone6.0 group. The edaravone3.0 and edaravone6.0 group rats were provided 3.0 mg/kg and 6.0 mg/kg of edaravone, respectively, intraperitoneal (i.p.) injection twice daily following the first day after BCCAO. In this experiment, the spatial learning and memory were assessed using the Morris water maze. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the hippocampus were measured biochemically. And, the levels of total ERK1/2 (t-ERK1/2), Phospho ERK1/2 (p-ERK1/2), total Nrf2 (t-Nrf2), nuclear Nrf2 (n-Nrf2), and HO-1 were assessed by western blot. Results The results showed that the treatment with edaravone significantly improved CCH-induced cognitive damage, and boosted endogenous antioxidants SOD activity and HO-1 level, decreased MDA contents in the hippocampus by activating Nrf2 signaling pathway which was related to ERK1/2. We also found that the neuronal morphology of the hippocampal CA1 area significantly improved and the number of Nrf2 positive cells markedly increased in the edaravone treatment groups. Conclusion Our results demonstrated a neuroprotective effect of edaravone on hippocampus against oxidative stress and cognitive deficit induced by CCH. The mechanism may be related to the enhancement of antioxidant defense system by activating ERK/Nrf2/HO-1 signaling pathway. PMID- 29125062 TI - Drug delivery during pregnancy: how can nanomedicine be used? PMID- 29125060 TI - Dendritic polymers for dermal drug delivery. AB - Skin-mediated therapeutic delivery is a potential alternative to traditional drug delivery approaches. However, dermal drug delivery is limited to the molecules with optimal physico-chemical properties. To overcome this barrier for delivering 'nonideal' drug molecules across the skin, different drug carriers and penetration enhancement methods have been investigated. Conventional chemical and physical approaches for dermal drug delivery are limited by their skin irritation potential, complexity of application and poor patient compliance. In recent years, dendritic polymers have shown potential in improving the dermal delivery of various molecules. With minimal skin irritation potential and high drug loading capacity, dendrimers offer multiple advantages for improving delivery of drugs across the skin. The current review aims to provide an overview of dendritic polymers for dermal (topical and transdermal) drug delivery. [Formula: see text]. PMID- 29125063 TI - Implantable systems for drug delivery to the brain. AB - Most diseases and disorders of the brain require long-term therapy and a constant supply of drugs. Implantable drug-delivery systems provide long-term, sustained drug delivery in the brain. The present review discusses different type of implantable systems such as solid implants, in situ forming implants, in situ forming microparticles, depot formulations, polymeric-lipid implants, sucrose acetate isobutyrate and N-stearoyl L-alanine methyl ester systems for continuous drug delivery into brain for various brain diseases including glioblastomas, medulloblastoma, epilepsy, stroke, schizophrenia and Alzheimer's diseases. Implantable neural probes and microelectrode array systems for brain are also discussed in brief. PMID- 29125064 TI - Pulmonary aerosol delivery and the importance of growth dynamics. AB - Aerosols are dynamic systems, responding to variations in the surrounding environmental conditions by changing in size, composition and phase. Although, widely used in inhalation therapies, details of the processes occurring on aerosol generation and during inhalation have received little attention. Instead, research has focused on improvements to the formulation of the drug prior to aerosolization and the resulting clinical efficacy of the treatment. Here, we highlight the processes that occur during aerosol generation and inhalation, affecting aerosol disposition when deposited and, potentially, impacting total and regional doses. In particular, we examine the response of aerosol particles to the humid environment of the respiratory tract, considering both the capacity of particles to grow by absorbing moisture and the timescale for condensation to occur. [Formula: see text]. PMID- 29125065 TI - Virus-like nanoparticles: emerging tools for targeted cancer diagnostics and therapeutics. PMID- 29125066 TI - Autonomous self-navigating drug-delivery vehicles: from science fiction to reality. AB - Low efficacy of targeted nanomedicines in biological experiments enforced us to challenge the traditional concept of drug targeting and suggest a paradigm of 'addressed self-navigating drug-delivery vehicles,' in which affinity selection of targeting peptides and vasculature-directed in vivo phage screening is replaced by the migration selection, which explores ability of 'promiscuous' phages and their proteins to migrate through the tumor-surrounding cellular barriers, using a 'hub and spoke' delivery strategy, and penetrate into the tumor affecting the diverse tumor cell population. The 'self-navigating' drug-delivery paradigm can be used as a theoretical and technical platform in design of a novel generation of molecular medications and imaging probes for precise and personal medicine. [Formula: see text]. PMID- 29125067 TI - Evidence of size-dependent effect of silica micro- and nano-particles on basal and specialized monocyte functions. AB - AIM: To analyze the effect of silica particles on monocyte/macrophage functions. MATERIALS & METHODS: Silica micro- and nanoparticles were obtained by the Stober method. Their effect on monocyte/macrophage proliferation, activation, membrane integrity and metabolic activity were determined. RESULTS: Silica particles inhibit cell proliferation while 10 nm nanoparticles (NPs) did not affect it. Similarly, silica particles induced strong cell activation. However, 10 nm NPs do not alter IL-12 or nitrite levels. Furthermore, bigger NPs and microparticles increase cell membrane damage and reduce the number of living cells but smallest NPs (10 and 240 nm) did not. CONCLUSION: Cell activation properties of silica particles could be useful tools for immune stimulation therapy, while 10 nm NPs would be suitable for molecule transportation. PMID- 29125069 TI - World Stroke Day Celebrations: Report from India. PMID- 29125068 TI - Conference Diary. PMID- 29125071 TI - Clinical experience in idiopathic pulmonary fibrosis: a retrospective study. AB - Introduction Idiopathic pulmonary fibrosis (IPF) is a rare lung disease with an increased incidence since the last few years. Here, we report our eight-year clinical experience in CHU of Liege, Belgium. Methods We have studied retrospectively patients recruited from our ambulatory care polyclinic at CHU of Liege from 1 January 2009 to 1 January 2017. We have excluded all patients treated with a specific anti-fibrotic therapy due to incomplete follow-up. The diagnosis of IPF was made according to the ATS/ERS international recommendations (2015). Results Out of the 114 patients initially selected, 82 cases were found to be suitable for the analysis. The average age was 71.1 +/- 9.35 years with a male predominance. The median survival was 43.7 months (23.6-71.7) with a majority (45%) of patients in the group II of the GAP index. The median rate of annual decline in diffusion capacity of CO (DLCO) was 11%, whereas the sub analysis for group III (according to GAP index) showed a decrease annual rate of 30%. Conclusion Our results are in keeping with the literature. One of our major finding is that patients in GAP III exhibit an annual rate of mortality of 42% and a median annual decline in DLCO of 30%. This observation highlights the fact that this specific subgroup of patients presents a high risk of morbi-mortality. PMID- 29125072 TI - Predictors of dependence after MCA ischemic stroke submitted to thrombolysis. AB - OBJECTIVES: Stroke is one of the most common causes of disability-adjusted life years worldwide. The aim of this study is to identify variables associated with dependence at 3 months and also after the first 3 months after the first-ever ischemic stroke (IS) in middle cerebral artery (MCA) territory submitted to intravenous thrombolysis (IVT). METHODS: A single-center cohort study of patients with first-ever MCA IS treated with IVT at the Hospital de Clinicas, Universidade Federal do Parana, was followed over 5 years. Logistic regression was performed to determine predictors of early and late dependence. RESULTS: A total of 144 patients were included; 48.6% women, and 47.2% were dependent at 3 months after stroke. NIHSS at admission (OR = 1.3, 95%CI = 1.16-1.45, p < 0.001), large artery atherosclerosis (LAA) stroke (OR = 4.11, 95%CI = 1.31-12.85, p = 0.014) and pneumonia during hospitalization (OR = 9.17, 95%CI = 1.42-59.07, p = 0.019) were predictors for early dependence. For the late dependence analyses, 99 patients were included; 49.5% women and 39.4% were dependent after 3 months of stroke. NIHSS at admission (OR = 1.33, 95%CI = 1.15-1.54, p < 0.001), pneumonia during hospitalization (OR = 11.08, 95%CI = 1.45-84.73, p = 0.019) and seizure after discharge (OR = 5.82, 95%CI = 1.06-32.01, p = 0.040) were predictors for late dependence. DISCUSSION: .Dependence is an important indicator of the efficacy of stroke care. Besides it was not possible to evaluate rehabilitation, this is the first study on predictors of post-stroke dependence that focus exclusively on patients with first-ever MCA IS submitted to IVT. NIHSS, LAA stroke, in-hospital pneumonia and seizures after discharge were associated with dependence after first-ever MCA IS submitted to IVT. PMID- 29125073 TI - Erythrocyte Associated Amyloid-beta as Potential Biomarker to Diagnose Dementia. AB - BACKGROUND: Although it is known that Alzheimer's disease (AD) is associated with the progressive accumulation of amyloid beta-peptide (Abeta) in the human brain, its pathogenic role has to be completely clarified. Abeta moves from the bloodbrain barrier to the plasma and an increased Abeta production in brain could be associated with higher Abeta concentrations in blood. A recent study has evaluated Abeta40 and Abeta42 levels in human red blood cells (RBCs) with evidence of agedependent higher Abeta concentration in RBCs. OBJECTIVE: The aim of the study was to investigate if erythrocyte associated Abeta (iAbeta) levels could be different in subjects affected by dementia in comparison with controls and according to the patient's cognitive impairment or different dementia subtypes. METHOD: To answer these questions we assessed iAbeta40 and iAbeta42 levels in 116 patients: 32 healthy controls, 39 with diagnosis of vascular dementia (VaD), 14 mild cognitive impairment (MCI) and 31 AD. RESULTS: In this population we found significant differences in iAbeta42 between controls and cognitive impaired patients. Moreover, iAbeta42 significantly differed between dementia vs MCI. AD also showed different iAbeta42 levels as compared to VaD. Conversely, no differences were found for iAbeta40. All the analyses were adjusted for potential confounders like age, gender and Hb concentration. A direct correlation between increasing iAbeta42 concentration and the progression of the cognitive decline using the MMSE score as continuous variable was also found. CONCLUSION: Our findings support the evidence that iAbeta42 could be an instrument to early recognize dementia and predict cognitive impairment. PMID- 29125070 TI - Circulating Mitochondrial DNA at the Crossroads of Mitochondrial Dysfunction and Inflammation During Aging and Muscle Wasting Disorders. AB - Mitochondrial structural and functional integrity is maintained through the coordination of several processes (e.g., biogenesis, dynamics, mitophagy), collectively referred to as mitochondrial quality control (MQC). Dysfunctional MQC and inflammation are hallmarks of aging and are involved in the pathogenesis of muscle wasting disorders, including sarcopenia and cachexia. One of the consequences of failing MQC is the release of mitochondria-derived damage associated molecular patterns (DAMPs). By virtue of their bacterial ancestry, these molecules can trigger an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondria-derived DAMPs, especially cell-free mitochondrial DNA, have recently been associated with conditions characterized by chronic inflammation, such as aging and degenerative diseases. Yet, their actual implication in the aging process and muscle wasting disorders is at an early stage of investigation. Here, we review the contribution of mitochondria-derived DAMPs to age-related systemic inflammation. We also provide arguments in support of the exploitation of such signaling pathways for the management of muscle wasting conditions. PMID- 29125074 TI - [A soccer player with an unstable knee]. AB - A 19-year-old soccer player presented with instability of his left knee after a rotation trauma. Congenital absence of the anterior cruciate ligament was suspected because of leg length discrepancy and specific MRI findings. He regained stability after an anterior cruciate reconstruction. PMID- 29125075 TI - [Treatment of paracetamol intoxication: taking into consideration dosage, route of administration, and risk factors]. AB - - Paracetamol is the drug for which the Dutch Poisons Information Centre (DPIC) receives the most information requests.- The protocol for the treatment of single acute oral paracetamol intoxications is clear, however, ambiguity exists concerning the treatment of intoxications with repeated supratherapeutic doses of paracetamol.- Paracetamol intoxications with liquid preparations, extended release tablets, exposure routes other than oral, and repeated supratherapeutic ingestions require a tailored approach.- An increased risk of liver damage due to paracetamol intoxication has to be taken into account for patients who consume excessive levels of alcohol, are malnourished or have a pre-existing liver condition.- The decision tree of the DPIC is a helpful tool to swiftly attain a risk assessment and treatment plan for most types of paracetamol intoxication. PMID- 29125076 TI - [A 14-year-old Syrian refugee with neurobrucellosis]. AB - BACKGROUND: Neurobrucellosis is a rare complication of brucellosis, a bacterial zoonotic disease endemic in regions such as the Middle East. It is important to be alert for this imported disease in the Netherlands as well, especially among migrants. CASE DESCRIPTION: A 14-year-old boy from Syria presented with headache, vomiting and weight loss. Brucella melitensis was identified in the cerebrospinal fluid. The patient's condition deteriorated despite antibiotic treatment, particularly neurologically, and imaging revealed a newly developed hydrocephalus. The symptoms disappeared after placement of a temporary external ventricular drain. The patient made a complete recovery following 8 months of continual antibiotic therapy. CONCLUSION: Diagnosis and treatment were delayed, partly because there were no medical records available, previous treatment had been interrupted when the patient fled the country, and the language barrier. Knowledge of previous medical history and of the epidemiology of infectious diseases in the land of origin is particularly important when treating migrants. Treating brucellosis with antibiotics can lead to clinical deterioration due to a Jarisch-Herxheimer-like phenomenon. PMID- 29125077 TI - [A child with an abnormality in the pupil]. AB - A 19-year-old female had been treated conservatively for a pupillary abnormality in early childhood. At the age of 4, slit-lamp examination had shown a persistent pupillary membrane in the right eye. Now she presented with a visual acuity of 1/300 in the right eye. PMID- 29125078 TI - [From war to priority battle; blood transfusion as a medical innovation during World War I]. AB - The logistics system for blood transfusion was first developed on the Western Front during World War I. This article focuses on the people who played a major role in this development. It discusses the people who came up with the idea of preventing coagulation through addition of citrate and who discovered the stabilisation of blood by adding glucose. The inclusion of citrate can be regarded as having been simultaneously developed in several countries, while the stabilisation of erythrocytes was discovered by American researchers. As regards to the credit for being the first person to apply blood transfusion as a logistics system, this priority development was contested by an American and a Canadian, who coincidentally had the same surname - Robertson. The war induced both of them to start large-scale implementation of their discovery of blood transfusion. The Germans, however, generally continued with the traditional treatment for blood loss and shock by administering saline and gum arabic. PMID- 29125079 TI - [Relapse of chronic inflammatory demyelinating polyneuropathy following treatment with zoledronic acid]. AB - BACKGROUND: Zoledronic acid is a nitrogen-containing bisphosphonate that is frequently used in the treatment of osteoporosis. Many patients experience a so called acute-phase reaction during initial treatment; this is characterized by flu-like symptoms and fever. CASE DESCRIPTION: We describe a 61-year-old woman who suffered from chronic inflammatory demyelinating polyneuropathy (CIDP), and who was started on intravenous zoledronic acid treatment as adjuvant therapy for breast cancer. Within 24 hours of the initial treatment she developed cold shivers, extreme fatigue, muscle pain and headache. These symptoms resolved spontaneously in the course of the following days. At the same time, she also experienced a CIDP relapse, with a tingling sensation in her arms and legs and deterioration in her ability to walk. Considering the course of the symptoms and the absence of any other cause, CIDP relapse was very probably the result of the acute-phase reaction induced by zoledronic acid. CONCLUSION: Caution is warranted when using nitrogen-containing bisphosphonates such as zoledronic acid, particularly in patients with known neuromuscular disorders. PMID- 29125080 TI - [Organ-sparing treatment in oesophagus cancer: feasible and safe?] AB - In many countries, neoadjuvant chemoradiotherapy (nCRT) plus surgery is standard treatment for resectable oesophageal cancer. After nCRT, up to 30% of all patients have no residual disease in the resection specimen. Consequently, an active surveillance approach, in which patients undergo frequent clinical investigations after nCRT instead of standard oesophagectomy, is increasingly applied in selected patients. Here, we describe outcomes for three patients who underwent active surveillance. A 63-year old woman was considered unfit for surgery after nCRT. Four years after completion of nCRT, she still had no signs of disease recurrence. The second patient, a 57-year old woman, refused surgery when no residual disease was detectable after nCRT. One year following treatment, she developed a vertebral metastasis, in the absence of locoregional disease. The third patient concerned a 66-year old man with a clinically complete response after nCRT, who also refused surgery. During active surveillance, he developed a locoregional regrowth and underwent a radical oesophagectomy. PMID- 29125081 TI - [Metformin-associated lactic acidosis: an insufficiently recognised problem]. AB - Metformin-associated lactic acidosis (MALA) is a rare but potentially fatal condition that can easily be avoided. As metformin is known to facilitate the production of lactate, predisposing factors can accelerate this process. In situations of infection or dehydration, metformin can accumulate due to kidney failure, hereby increasing the risk of MALA. Despite controversy in the literature about the presence of a relationship between metformin and lactic acidosis, the severity of the condition is cause for concern and allows for preventive measurements. Awareness of this condition among patients and clinicians is insufficient, resulting in many patients continuing metformin in situations where there is an increased risk of developing MALA. Metformin can easily be discontinued temporarily without causing any harm. We emphasize the importance of temporarily discontinuing metformin in situations where the risk of lactic acidosis is increased, such as severe infection, dehydration and acute kidney insufficiency. This requires increased awareness and adequate counselling by clinicians as well as pharmacists. PMID- 29125082 TI - [Splenic abscess]. AB - Splenic abscess is a rare and potentially lethal clinical condition. The most common symptoms of a splenic abscess - abdominal pain, nausea and fever - are non specific. As a result, a splenic abscess is often not considered in the initial work-up. This might lead to a delay in diagnosis and treatment. In this case series we successively describe a 41-year-old female with a splenic abscess after Streptococcus milleri bacteraemia, a 78-year-old male with a splenic abscess caused by a colon carcinoma and a 52-year-old male with a splenic abscess resulting from a colosplenic fistula after bariatric surgery. By emphasizing the different aetiologies, the different clinical presentations and the different therapeutic options of a splenic abscess, we aim to create greater awareness of this rare clinical phenomenon. PMID- 29125083 TI - [Single embryo implantation per IVF cycle: the answer to every request for assisted reproduction?] AB - The Dutch eSET-policy is justifiable in case a healthy singleton is the main goal. However, patients who want to create a family of more children may for that reason welcome twins. PMID- 29125084 TI - [Going to the hospital or not? Limitations of the interpretation of treatment preferences in acute situations at home]. AB - When talking about 'advance care planning' (ACP), people regularly state that they do not want to go to the hospital any more. There are several reasons why this wish may be unclear in acute situations: preferred treatment is not always available or discussed, there may be different reasons for the 'no more hospital' statement and the emergency department is often insufficiently prepared for carrying out limited evaluations or treatments. To provide appropriate care, we recommend to (a) discuss the limitations of ACP, (b) evaluate preferences in the current context, (c) improve communication between primary and secondary care and to consider alternative options, (d) regularly evaluate current policies and (e) invest in local initiatives to prevent admission or long-term admission or to enable people to stay home. Treatment preferences, supported by earlier ACP discussions, always develop through the relationship between physicians and patients in specific situations. PMID- 29125085 TI - [The objective of advance care planning]. AB - This commentary reflects on a study to determine the efficacy of an advance care planning (ACP) website in increasing planning documentation. It is interesting to see that ACP is considered to be a regular intervention. ACP thus ceases to be something to believe in or not and becomes a normal intervention, the efficacy of which can be studied. The study also shows that ACP is a concept which can take many forms, that ACP in itself is almost an umbrella term and that physicians need not take the central role in ACP. The main point of critique of the study, however, is that the endpoint of the study is documentation. One can question whether that is the right objective of ACP as the worth of ACP would seem to lie more in the process of enabling a patient to reflect on treatment goals and personal values than in writing a living will. PMID- 29125086 TI - Effects of management practices on the welfare of dairy donkeys and risk factors associated with signs of hoof neglect. PMID- 29125087 TI - EXAMINING TEMPORAL SHIFTS IN THE PROXIMATE DETERMINANTS OF FERTILITY IN LOW- AND MIDDLE-INCOME COUNTRIES. AB - SummaryTargeting reductions in fertility remains a key development goal, as too high fertility hampers the economic and health prosperity of low- and middle income countries. However, critical to the success of gaining reductions in fertility is the ability to understand the factors that are shaping fertility, and to understand the factors that are acting to keep fertility levels high. To contribute to this understanding, this study applied the Bongaarts (2015) adjusted proximate determinants of fertility model to 33 low- and middle-income countries using data collected from the Demographic and Health Survey (DHS) programme between 2000 and 2016. Results from the analysis indicate that there has been a universal decrease in the duration of breast-feeding and postpartum abstinence, which has contributed to stalling and increasing fertility rates in countries of Central Africa. In other regions of the world, such as Southern Africa, Latin America & Caribbean and Asia, increased contraceptive use and increased age at marriage, or sexual debut, has been able to offset this, leading to substantial decreases in fertility rates. These findings should serve as a guide to where additional development policy and programmatic attention should focus to reduce too-high fertility in resource-poor settings. PMID- 29125088 TI - Cerebrospinal Fluid Biomarkers as Predictors of Shunt Response in Idiopathic Normal Pressure Hydrocephalus: A Systematic Review. AB - BACKGROUND: The widely accepted treatment for idiopathic normal-pressure hydrocephalus (iNPH) is a cerebrospinal fluid (CSF) diversion shunt procedure, to which approximately 80% of patients will respond. The purpose of this systematic review was to identify which CSF biomarkers have been investigated in predicting shunt responsiveness in iNPH patients, and to analyze the level of evidence for each. METHODS: To find all relevant articles, a comprehensive search of Medline, Embase, and PsycINFO was conducted. RESULTS: The literature search identified 344 unique citations, of which 13 studies satisfied the inclusion criteria and were analyzed in our review. These 13 studies reported on 37 unique biomarkers. CONCLUSIONS: The available studies suggest that there is evidence for the utility of CSF biomarkers in predicting shunt responsiveness in iNPH patients, though none have been shown to predict shunt response with both high sensitivity and specificity. We found that there is no available evidence for the use of Abeta38, Abeta40, Abeta43, APL1beta25, APL1beta27, APL1beta28, sAPP, aAPPalpha, sAPPbeta, TNF-alpha, MCP-1, sCD40L, sulfatide, MBP, L-PGDS, cystatin C, transthyretin, TGF beta2, or YKL-40 in predicting shunt response. There is minimal evidence for the use of TGF-beta1, TBR-II, homocysteine, and interleukins (particularly IL-1beta, IL-6, and IL-10). However, the available evidence suggests that these biomarkers warrant further investigation. Abeta42, tau, p-tau, NFL, and LRG have the greatest amount of evidence for their predictive value in determining shunt responsiveness in iNPH patients. Future research should be guided by, but not limited to, these biomarkers. PMID- 29125089 TI - The development of determiners in the context of French-English bilingualism: a study of cross-linguistic influence. AB - This paper reports the preliminary results of a study examining the role of structural overlap, language exposure, and language use on cross-linguistic influence (CLI) in bilingual first language acquisition. We focus on the longitudinal development of determiners in a corpus of two French-English children between the ages of 2;4 and 3;7. The results display bi-directional CLI in the rate of development, i.e., accelerated development in English and a minor delay in French. Unidirectional CLI from English to French was instead observed in the significantly higher rate of ungrammatical determiner omissions in plural and generic contexts than in singular specific contexts in French. These findings suggest that other language-internal mechanisms may be at play. They also lend support to the role of expressive abilities on the magnitude of this phenomenon. PMID- 29125090 TI - Distributional learning aids linguistic category formation in school-age children. AB - The goal of this study was to determine if typically developing children could form grammatical categories from distributional information alone. Twenty-seven children aged six to nine listened to an artificial grammar which contained strategic gaps in its distribution. At test, we compared how children rated novel sentences that fit the grammar to sentences that were ungrammatical. Sentences could be distinguished only through the formation of categories of words with shared distributional properties. Children's ratings revealed that they could discriminate grammatical and ungrammatical sentences. These data lend support to the hypothesis that distributional learning is a potential mechanism for learning grammatical categories in a first language. PMID- 29125091 TI - How children learn to produce appropriate referring expressions in narratives: the role of clarification requests and modeling. AB - Asking children to clarify themselves promotes their ability to uniquely identify objects in referential communication tasks. However, little is known about whether parents ask preschoolers for clarification during interactions and, if so, how. Study 1 explored how mothers clarify their preschoolers' ambiguous descriptions of the characters in their narratives, and whether clarification requests affect children's repairs of their ambiguous descriptions. Mothers were found to use different strategies, including signaling misunderstanding and modeling appropriate descriptions. Presence of these different strategies predicted children's ability to provide informative repairs. Study 2 tested the effect of children's experience with signaling misunderstanding and modeling on their ability to uniquely identify the characters of a story on a second narration. Experiencing modeling, but not misunderstandings, positively affected children's provision of appropriate descriptions during second narrations. Findings are discussed in terms of the role of imitation in driving referential development. PMID- 29125092 TI - Monitoring the South African population's salt intake: spot urine v. 24 h urine. AB - OBJECTIVE: The present study set out to determine whether morning spot urine samples can be used to monitor Na (and K) intake levels in South Africa, instead of the 'gold standard' 24 h urine sample. DESIGN: Participants collected one 24 h and one spot urine sample for Na and K analysis, after which estimations using three different formulas (Kawasaki, Tanaka and INTERSALT) were calculated. SETTING: Between 2013 and 2015, urine samples were collected from different population groups in South Africa. SUBJECTS: A total of 681 spot and 24 h urine samples were collected from white (n 259), black (n 315) and Indian (n 107) subgroups, mostly women. RESULTS: The Kawasaki and the Tanaka formulas showed significantly higher (P<=0.001) estimated Na values than the measured 24 h excretion in the whole population (5677.79 and 4235.05 v. 3279.19 mg/d). The INTERSALT formula did not differ from the measured 24 h excretion for the whole population. The Kawasaki formula seemed to overestimate Na excretion in all subgroups tested and also showed the highest degree of bias (-2242 mg/d, 95 % CI 10 659, 6175) compared with the INTERSALT formula, which had the lowest bias (161 mg/d, 95 % CI-4038, 4360). CONCLUSIONS: Estimations of Na excretion by the three formulas should be used with caution when reporting on Na intake levels. More research is needed to validate and develop a specific formula for the South African context with its different population groups. The WHO's recommendation of using 24 h urine collection until more studies are carried out is still supported. PMID- 29125093 TI - Interrelationship between food security status, home availability of variety of fruits and vegetables and their dietary intake among low-income pregnant women. AB - OBJECTIVE: To (i) determine differences in the availability of variety of fruits and vegetables (F&V) at home by food security status; and (ii) examine the inter associations between food security status, availability of variety of F&V at home and frequency of F&V intake, among low-income pregnant women. Design/Setting Participants were interviewed to collect food security status, home availability of variety of F&V and frequency of F&V intake. Bivariate analyses, multivariate regression and exploratory mediation analyses were conducted using IBM SPSS Statistics version 23.0 and the PROCESS macro. SUBJECTS: Low-income pregnant women (n 198) were interviewed if they were >=18 years of age, in the second trimester of pregnancy, and spoke English or Spanish. RESULTS: Low/very low food security was found among 43 % of participants. Compared with fully food-secure participants, very low food-secure participants reported a lower variety of fruits (P=0.028) and vegetables (P=0.058) available at home. Mediation analyses indicated that through home availability of variety of fresh F&V, food security status was associated with the daily intake of F&V (indirect effect (95 % CI): fresh fruits, -0.039 (-0.074, -0.013); fresh vegetables, -0.048 (-0.083, 0.023)). As food security worsened, the available variety of fresh F&V decreased, which was associated with lower intake. CONCLUSIONS: The study highlights the interlink between food security, home food environment and diet quality, and the importance of nutrition education intervention to promote a healthy home food environment and improved pregnancy outcomes among low-income women. PMID- 29125094 TI - Inferring individual cow effects, dairy system effects and feeding effects on latent variables underlying milk protein composition and cheese-making traits in dairy cattle. PMID- 29125095 TI - Social Comparison Orientation in Monozygotic and Dizygotic Twins. AB - Twin research has offered evidence that monozygotic (MZ) twins are more socially close than dizygotic (DZ) twins, but has not paid much attention to the way twins compare themselves with their co-twin. The few studies in this area suggest that 'horizontal comparisons' (social comparison motivated by solidarity or communion with others) matter more for MZ twins than for DZ twins, at least when the co twin is the social comparison standard. Consistent with this view, we predicted higher interest in MZ twins relative to DZ twins to select their co-twin rather than other people in general as the social comparison standard. The Social Comparison Orientation (SCO) scale, which measures the inclination to compare with others in a horizontal rather than vertical mode (comparing either upward or downward), was administered in 90 MZ pairs and 57 same-sex DZ pairs (63% female; average age 18.06 years) from the Netherlands Twin Register. MZ twin pairs showed significantly higher SCO scores than DZ twin pairs (with a large effect size) on the co-twin SCO, whereas the two groups did not differ from each other on the general SCO excluding the co-twin as social comparison standard. In MZ twin pairs, anxiety was associated with social comparison with others in general, not with their co-twin. For both scales, twin resemblance was explained by additive genetic variance. The present findings provide direct evidence that horizontal comparisons with the co-twin are of particular importance for MZ twins. PMID- 29125096 TI - Preliminary validation and piloting of a comprehensive measure of household food security in Australia. AB - OBJECTIVE: To investigate the psychometric properties, validity and reliability of a newly developed measure of food insecurity, the Household Food and Nutrition Security Survey (HFNSS), among an Australian population. DESIGN: Cross-sectional study. SETTING: Metropolitan areas of Melbourne, Australia, identified as very high, high or medium vulnerability in the 2008 Vulnerability Assessment for Mortgage, Petrol and Inflation Risks and Expenditure index. SUBJECTS: A convenience sample of 134 adults (117 females and fifteen males, aged over 18 years). RESULTS: Rasch modelling and factor analysis identified four items for exclusion. The remaining items yielded excellent reliability among the current sample and assessed three underlying components: the adult experience of food insecurity (component one), initial/periodic changes to children's food intakes (component two) and progressive/persistent decreases in children's food intakes (component three). Compared with the widely used US Department of Agriculture Food Security Survey Module, the HFNSS identified a significantly higher proportion of food insecurity; this is likely due to the HFNSS's identification of food insecurity due to reasons other than (and including) limited financial access. CONCLUSIONS: The HFNSS may be a valid and reliable tool for the assessment of food insecurity among the Australian population and provides a means of assessing multiple barriers to food security beyond poor financial access (which has been identified as a limitation of other existing tools). Future research should explore the validity and reliability of the tool among a more representative sample, as well as specifically among vulnerable population subgroups. PMID- 29125097 TI - Historical and contemporary aspects of maternal immunity in swine. AB - Maternal immunity plays a pivotal role in swine health and production because piglets are born agammaglobulinemic and with limited cell-mediated immunity, i.e. few peripheral lymphoid cells, immature lymphoid tissues, and no effector and memory T-lymphocytes. Swine do not become fully immunologically competent until about 4 weeks of age, which means that their compromised ability to respond to infectious agents during the first month of life must be supplemented by maternal immune components: (1) circulating antibodies derived from colostrum; (2) mucosal antibodies from colostrum and milk; and (3) immune cells provided in mammary secretions. Because maternal immunity is highly effective at protecting piglets against specific pathogens, strengthening sow herd immunity against certain diseases through exposure or vaccination is a useful management tool for ameliorating clinical effects in piglets and delaying infection until the piglets' immune system is better prepared to respond. In this review, we discuss the anatomy and physiology of lactation, the immune functions of components provided to neonatal swine in mammary secretion, the importance of maternal immunity in the prevention and control of significant pathogens. PMID- 29125099 TI - Single Nucleotide Polymorphisms of Paclitaxel-induced Peripheral Sensory Neuropathy in Chinese Han Population. AB - Objective To study the single nucleotide polymorphisms (SNPs)that predict a patient's risk of grade 2-3 paclitaxel-induced peripheral sensory neuropathy (PSN) in Chinese Han populations.Methods Totally 216 patients received paclitaxel in Peking Union Medical College Hospital from May 2014 to December 2016 were enrolled.DNA was isolated from peripheral blood.Genotyping for eight candidate SNPs was performed on Sequenom-MassARRARYiPLEX platform.Patients were followed up and PSN was assessed by trained physicians according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.Results A total of 209 patients entered the final analysis.Among the candidate SNPs,only rs4141404:A>C(LIMK2) was significantly associated with grade 2/3 PSN (OR:4.32,95%CI:2.37-7.89,P<0.0001).In multivariate logistic regression analysis,both rs4141404:A>C(LIMK2) and history of receiving platinum compound (OR:2.70,95%CI:1.32-5.51,P=0.007) were associated with grade 2/3 PSN.Conclusion rs4141404:A>C(LIMK2) may be the markers of risk of grade 2/3 PSN. PMID- 29125100 TI - Effects of Force and Inflammatory Factors on the Expressions of Osteogenesis Regulators in Human Periodontal Ligament Cells. AB - Objective To observe the effects of force signals and inflammatory cytokines on the expressions of functional proteins during the differentiation of periodontal ligament cells(PDLCs) into osteoclasts. Methods The caries-free premolars that needed to be removed for orthodontic treatment were collected,human periodontal ligament cells were cultured in vitro.Human PDLCs were exposed to inflammatory cytokines including interleukin(IL)-1beta,-6,-23,and tumor necrosis factor alpha(TNF-alpha). Cyclicmechanical tension with a maximum 5% elongation for different durations(0,2,4,8,12,and 24 hours) were applied. Then the expressions of signaling molecules related to osteoclastogenesis(OPG) and receptor activated nuclear factor kappaB ligand(RANKL) were determined at protein levels by Western blotting. Results Inflammatory cytokines improved the expressions of osteoclastgenesis regulators in hPDLCs,while cyclic-tension force reduced their expressions. However,the combined effect of inflammatory cytokines and cyclic tension force resulted in high expressions of osteoclastgenesis regulators. Conclusion Inflammatory cytokines can promote the expressions of the osteoclastgenic factors,which can not be offset by cyclic-tension force. PMID- 29125101 TI - PEI-Fe3O4 Nanoparticles for Human Amniotic Epithelial Cells Labeling AB - Objective To label human amniotic epithelial cells(hAECs) by using PEI-Fe3O4 nanoparticles. Methods The PEI-Fe3O4 nanoparticles were characterized by using transmission electron microscopy and dynamic light scattering. The primary cultured hAECs were labeled with the nanoparticles,and the labeling efficiency was evaluated by Prussian blue staining. The cell survival rate and viability were tested by using placenta blue staining and CCK-8 assay,respectively. Results The PEI-Fe3O4 nanoparticles were compact spheres with an average particle size of 13 nm,a hydrodynamic radius of 17.56 nm,and a zeta potential of+34.5 mV. The labeling efficiency of the nanoparticles on hAECs reached 91% when the concentrations were greater than 20 MUg/ml. When the concentrations of nanoparticles were at 50 MUg/ml(t=16.37,P<0.0001;t=10.39,P<0.0001) and 100 MUg/ml(t=29.89,P<0.0001;t=16.86,P<0.0001),the cell survival rates and cell viabilities were significantly reduced versus controls. Conclusion The PEI-Fe3O4 nanoparticles can be used for labeling hAECs without obvious cytotoxicity at its working concentration. PMID- 29125098 TI - Enterococci and Their Interactions with the Intestinal Microbiome. AB - The Enterococcus genus comprises over 50 species that live as commensal bacteria in the gastrointestinal (GI) tracts of insects, birds, reptiles, and mammals. Named "entero" to emphasize their intestinal habitat, Enterococcus faecalis and Enterococcus faecium were first isolated in the early 1900s and are the most abundant species of this genus found in the human fecal microbiota. In the past 3 decades, enterococci have developed increased resistance to several classes of antibiotics and emerged as a prevalent causative agent of health care-related infections. In U.S. hospitals, antibiotic use has increased the transmission of multidrug-resistant enterococci. Antibiotic treatment depletes broad communities of commensal microbes from the GI tract, allowing resistant enterococci to densely colonize the gut. The reestablishment of a diverse intestinal microbiota is an emerging approach to combat infections caused by antibiotic-resistant bacteria in the GI tract. Because enterococci exist as commensals, modifying the intestinal microbiome to eliminate enterococcal clinical pathogens poses a challenge. To better understand how enterococci exist as both commensals and pathogens, in this article we discuss their clinical importance, antibiotic resistance, diversity in genomic composition and habitats, and interaction with the intestinal microbiome that may be used to prevent clinical infection. PMID- 29125102 TI - Role of Methylprednisolone in Treatment of Spinal Cord Injured with Bone Marrow Mesenchymal Stem Cells Transplantation in Rats and Its Effect on the Expressions of Tumor Necrosis Factor-alpha and Interleukin-1beta. AB - Objective To investigate the role of methylprednisolone (MP) in treatment of spinal cord injured (SCI) with bone marrow mesenchymal stem cells (BMSCs) transplantation in rats and its effect on the expressions of tumor necrosis factor-alpha(TNF-alpha) and interleukin-1beta(IL-1beta) at the local tissues.Methods Forty male Sprague-Dawley(SD) rats were used to establish the models of SCI according to the modified Allen's contusion method and then divided into four groups (n=10 in each group) by using random numbers table:MP group,BMSCs group,BMSCs+MP group,and control group.MP was intravenously administrated immediately after SCI.BMSCs labeled by 5-bromo-2 deoxyuridine(BrdU)were transplanted into the injured sites of spinal cord after two hours of SCI.On the 1 st,7 th,and 14th days after SCI,when functional outcome measurements were evaluated by the Basso-Beattie-Bresnahan (BBB) score.On the 14th day after treatment,the spine cord tissues were harvested for the TNF alpha/IL-1beta immunohistochemistry,and Tunel staining method was used to detect cell apoptosis rate.BrdU-positive BMSCs were examined in BMSCs group and BMSCs+MP group.Results Functional recovery of hind limb in MP+BMSCs group was the best among the four group.On the 1 st day after injury,the BBB scores showed no significant difference among four group(chi2=1.0756,P=0.7829).On the 7th and 14th day,the BBB score of MP+BMSCs group was significantly higher than MP group (chi2=17.7186,P=0.0002;chi2= 24.7259,P<0.0001) and BMSCs group (chi2=15.8110,P=0.0024;chi2=25.6014,P<0.0001),respectively.The BBB score of the control group was significantly lower than MP group (chi2=8.3265,P=0.0325;chi2=13.5060,P=0.0062) and BMSCs group (chi2=14.1166,P=0.0036;chi2=8.9613,P=0.0299),respectively.On the 14th day,immunohistochemical staining presented that the TNF-alpha and IL-1beta positive cells in MP+BMSCs group were significantly lower than MP group (q=5.573,P=0.0004;q=4.596,P=0.0025) and BMSCs group (q=13.780,P<0.0001;q=8.456,P<0.0001),and control group was significantly higher than MP group (q=14.710,P<0.0001;q=6.710,P<0.0001) and BMSCs group (q=6.502,P=0.0001;q=2.849,P=0.0514).Tunel staining showed the apoptotic rate of spinal cord cells in four group were (48.47+/-5.70)%,(31.95+/-3.58)%,(41.39+/ 2.33)%,and (23.48+/-2.69)%.The number of apoptotic cells in MP+BMSCs group was least in four groups;compared with the control group,the apoptotic rate significantly decreased in MP group (q=14.840,P<0.0001) and BMSCs group (q=6.716,P=0.0002);compared with the MP+BMSCs group,the apoptotic rate was significantly increased in the MP group (q=7.332,P=0.0001) and BMSCs group (q=15.460,P<0.0001). BrdU staining revealed BrdU-positive rate in MP+BMSCs group [(9.3000+/-0.5175)%] was significantly higher than that in BMSCs group [(6.6000+/ 0.3399)%](t=4.361,P=0.0004).Conclusion MP can improve the function of the hind limbs of SCI rats treated with BMSCs transplantation and lower the expressions of TNF-alpha and IL-1beta in injured tissue. PMID- 29125103 TI - Effect of Calcium-sensing Receptor on the Apoptosis of Rat Spinal Cord Neurons in Anoxia/Reoxygenation Injury and Its Significance. AB - Objective To investigate the effect and significance of calcium-sensing receptor (CaSR) on the apoptosis of rat spinal cord neurons in anoxia/reoxygenation(A/R) injury. Methods The spinal cells were in ischemia and hypoxia environment for 1 h and in normal environment for 24 h to establish a model of A/R. After spinal A/R model was established,the spinal cells were divided into four groups randomly:the control group,A/R group,A/R+GdCl3 group,and A/R+NPS-2390 group. The expression of CaSR in each group was detected by immunofluorescence and Western blotting. The concentration of intracellular calcium was measured by laser confocal scanning microscopy. The expressions of Caspase-3,Bax,and Bcl-2 were detected by using Western blotting. The apoptotic rate of spinal cells was detected by Tunel assay. Results Compared to the control group, there was a significant increase in the level of CaSR (t=5.462, P=0.006), the concentration of intracellular calcium (t=8.573, P=0.001), the apoptotic rate (t=4.899, P=0.008), Caspase-3 (t=5.118, P=0.007), and Bax (t=10.930,P=0.001) in A/R group. Compared to the A/R group, there was a significant increase in the level of CaSR (t=4.975, P=0.008),the concentration of intracellular calcium (t=4.899, P=0.008), the apoptotic rate (t=7.746, P=0.002), Caspase-3 (t=4.776, P=0.009), and Bax (t=5.281, P=0.006) in A/R+GdCl3 group. Compared to the A/R group, there was a significant decrease in the level of CaSR (t=3.674,P=0.021), the concentration of intracellular calcium (t=3.846, P=0.018), the apoptotic rate (t=4.281,P=0.013), Caspase-3 (t=3.521, P=0.024), and Bax(t=3.473, P=0.026) in A/R+NPS-2390 group. However, compared to the control group, there was a significant decrease in the level of Bcl-2 (t=6.242,P=0.003) in A/R group. Compared to the A/R group, there was a significant decrease in the level of Bcl-2(t=3.028, P=0.004) in A/R+GdCl3 group. Compared to the A/R group, there was a significant increase in the level of Bcl-2 (t=2.840, P=0.047) in A/R+NPS-2390 group.Conclusion During the process of A/R injury in rat spinal cord neurons,the expression of calcium sensing receptor increases,along with increase in intracellular calcium and spinal neuron apoptosis. PMID- 29125104 TI - Polymorphisms of 23 Y-chromosome STR Loci in A Han Population in Jiangsu Province. AB - Objective To investigate the polymorphisms of 23 Y-STR loci in a Han population in Jiangsu province. Methods Blood samples were collected from 4821 unrelated healthy Han males in Jiangsu province. DNA templates were amplified by PowerPlex Y23 kit,and the amplification products were detected by 3500xL genetic analyzer. Then,we calculated the allele frequencies and gene diversities respectively,as well as the haplotype frequencies and haplotype diversities. Results The gene diversity of these 23 Y-STR loci ranged 0.4099-0.9696. A total of 4781 haplotypes were detected,of which 4743 were found once. The haplotype diversity was 0.99999812. Conclusion The 23 Y-STR loci used in this study are highly polymorphic in Han individuals in Jiangsu province and therefore suitable for population genetic study and forensic individual identification. PMID- 29125105 TI - Sequence Analysis and Comparison of the Key Genes of Domestic Live Attenuated Varicella Vaccine. AB - Objective To analyze the safety and consistency of domestic live attenuated varicella vaccines (LAVVs) at gene level.Methods The key genes (ORF38,ORF54,and ORF62) of LAVVs produced by four Chinese manufacturers were amplified by polymerase chain reaction (PCR) and sequenced.The sequencing results were compared with the sequences of Dumas,P-Oka,and V-Oka strains in GenBank and with the sequences of Varilrix (GSK) and Varivax (Merck).Results The ORF38 and ORF54 gene sequences of four domestic LAVVs were the same as each other and completely consistent with the sequences of V-Oka and Varilrix;however,it was different from Varivax (Merck) at one site.The ORF62 gene sequences of four domestic LAVVs were similar,and had individual nucleotide differences with V-Oka,Varilrix(GSK),and Varivax (Merck).Conclusions The sequences of ORF38,ORF54,and ORF62 of four domestic LAVVs are almost the same,showing good stability.They have small differences with V-Oka,Varilrix(GSK),and Varivax (Merck),without introducing new mutations. PMID- 29125107 TI - Meta-analysis of Influencing Factors of 18F-Fluorodeoxyglucose Uptake of Brown Adipose Tissue in PET/CT Imaging. AB - Objective To explore the influencing factors of 18F-Fluorodeoxyglucose(18F-FDG) uptake of brown adipose tissue(BAT) in PET/CT imaging by performing meta analysis.Methods Relevant articles published between 1980 and 2016 were searched in PubMed,EMBASE,Web of Science,CBM,WanFang Data,CNKI,and VIP.The factors of gender,season and age were extracted according to the inclusive criteria.Meta analysis was performed to analyze the factors.Results The merger OR value and 95% CI of 18F-FDG uptake of BAT with gender,age,season were 2.67 (2.30-3.11),2.17 (1.38-3.39),and 15.35 (4.72-49.95) respectively.The 18F-FDG uptake rate of BAT was 2.16 times in females as that in males,8.67 times in the minors as that in the adults,and 1.94 times in winter as that in summer.Conclusion Gender,season,and age are risk factors for 18F-FDG uptake of BAT. PMID- 29125106 TI - Follow-up Results and Clinical Significance of Magnetic Resonance Spectroscopy Combined with Fluorescence Microscopy in Resection of High Grade Supra-tentoria Gliomas. AB - Objective To investigate the clinical effectiveness of magnetic resonance spectroscopy (MRS) combined with sodium fluorescein(FL) in the treatment of high grade gliomas(HGG). Methods From August 2013 to 2015 November,the clinical data of 72 supratentorial HGG(WHO grade III-IV) patients who had received surgical treatment in our hospital were retrospectively studied,among whom 43 cases received MRS combined with intra-perative FL navigation(observation group),and 29 cases only received conventional surgery(control group). Post-operative radiotherapy and chemotherapy were applied for more than 3 months. Routine enhanced MRI were performed 24-48 hours after the operation to investigate the extent of tumor resection. Six months after the operation,the quality of life of patients was evaluated by using the Karnofsky score,and 1-year postoperative survival rate and progression-free survival(PFS) were observed. Results Postoperative MRI showed that the rate of gross total resection(GTR) in observation group was significantly higher than that in control group(72.09%vs.51.72%;chi2=23.88,P=0.001),and the GTR rate of WHO grade IV tumors was significantly higher than that of WHO grade III tumors in observation group(92.86% vs.62.07%;chi2=6.06,P=0.042). The postoperative Karnofsky score in the observation group was significantly higher than that in control group(MU=2.34,P=0.021). The mean time of follow-up was(16.4+/-2.4) months(8-21 months) and there was no statistical significant difference between observation group and control group in 1-year survival rate(74.07% vs.77.50%;chi2=4.90,P=0.165) and PFS [(13.2+/-1.2) months vs.(12.7+/-2.0) months;chi2=7.26,P=0.067]. In observation group,the PFS of WHO grade IV patients was significantly higher than that in control group [(14.2+/-0.3) months vs.(10.0+/-1.1) months;chi2=11.03,P=0.031]. There was also no statistical significant difference between WHO grade IV tumors in two groups in terms of 1 year survival rate(71.43% vs.72.54%;chi2=5.33,P=0.089),and there was no statistical significant difference between WHO grade III tumors in two groups in 1-year survival rate(75.86% vs. 72.22%;chi2=3.78,P=0.250) and in PFS [(13.7+/ 1.4) months vs.(12.4+/-0.8) months;chi2=4.85,P=0.083]. Conclusions MRS combined with intraoperative FL navigation technology can improve the resection rate and improve survival quality of patients,and there is no evidence that MRS combined with intraoperative FL navigation prolong the overall survival of patients with high-grade gliomas. Different outcome may be found with longer follow-up and increased simple size. PMID- 29125108 TI - Lipoic Acid Combined with Epalrestat versus Lipoic Acid in Treating Diabetic Peripheral Neuropathy:A Meta-analysis. AB - Objective To compare the clinical effectiveness of lipoic acid combined with epalrestat versus lipoic acid in treating diabetic peripheral neuropathy(DPN). Methods Randomized controlled trials(RCTs) and clinical controlled trials on lipoic acid versus epalrestat for DPN before February 2016 were searched through five databases:CNKI,CBM,VIP,Wanfang,and PubMed. The quality of the included trials were assessed using Cochrane software and Jadad scores. Data were analyzed with Review Manager 5.3 software. Results Nine studies were included in the analysis. Meta analysis showed that the lipoic aid monotherapy was significantly inferior to lipoic acid-epalerestat combination therapy [RR=0.58,95%Cl(0.47,0.71),P<0.00001]. Inferiority of the lipoic acid monotherapy was also shown in nerve conduction velocity with WMDs of-4.94 [95%Cl(-7.41, 2.46),P<0.0001] for median motor nerve conduction velocity(MNCV),-5.08 [95%Cl( 7.68,-2.49),P=0.0001] for peroneal MNCV,-4.24 [95%Cl(-6.20,-2.29),P<0.0001] for median sensory nerve conduction velocity(SNCV),and-3.66 [95%Cl(-5.02, 2.31),P<0.00001] for peroneal SNCV. Sensitivity analysis showed that the results were robust. However,the included trials were limited by simple design,few subjective indicators,and short follow-up time. Conclusions Lipoic acid combined with epalrestat is better than lipoic acid alone in the treatment of DPN,as well as the MNCV and SNCV of median or peroneal nerve. Due to the low quality of the included studies,high-quality RCTs are warranted to validate the results. PMID- 29125109 TI - Impact of Myocardial Bridge-mural Coronary Artery on Myocardial Functions. AB - Objective To study the impact of myocardial bridge (MB)-mural coronary artery (MCA) on myocardial functions.Methods Totally 82 patients presenting with chest tightness and chest pain who were diagnosed with the MB in the left anterior descending artery by CT coronary angiography were enrolled as the MB group,in which the thickness and length of MB and the systolic stenosis degree of MCA were measured.In addition,82 healthy subjects,as confirmed by health check-up,were set as the control group.The age,gender,body mass index (BMI),heart rate (HR),smoking history,interventricular septal thickness,left ventricular posterior wall thickness,diameter of left atrium,left ventricular end-diastolic diameter,left ventricular end-systolic diameter,left ventricular ejection fraction,and the cases of E'/A'<1 were compared between MB group and control group.The potential correlations among the thicken/length of MB,the systolic stenosis degree of MCA and early diastolic peak strain rate(SRe)/late diastolic peak strain rate(SRa) were analyzed.Results The age (t=0.97,P=0.65),gender (chi2=0.10,P=0.75),BMI (t=1.82,P=0.07),HR (t=0.87,P=0.39) and smoking history (chi2=0.43,P=0.51) were not significantly difference between these two group.The interventricular septal thickness (t=1.54,P=0.13),left ventricular posterior wall thickness (t=1.47,P=0.14),diameter of left atrium (t=1.62,P=0.11),left ventricular end diastolic diameter (t=0.49,P=0.63),left ventricular end-systolic diameter (t=1.29,P=0.20),and left ventricular ejection fraction (t=0.56,P=0.57) were also not significantly different between the normal and MB group.However,there was significant difference in the cases of E'/A'<1 (chi2=38.22,P=0.00).The SRe (r= 0.97,P=0.00;r=-0.93,P=0.00)and SRa (r=-0.89,P=0.00;r=-0.90,P=0.00) the left ventricular anterior wall were negatively correlated with the thickness of MB and the systolic stenosis degree of MCA and were not correlated with the length of MB (r=-0.09,P=0.76;r=-0.13,P=0.66).Conclusions MB is not correlated with myocardial systolic function,but can affect myocardial diastolic function.When the MB thickness increases,the systolic stenosis degree of MCA increases,the myocardial diastolic function gradually decreases,but the MB length is not related to myocardial systolic function. PMID- 29125110 TI - Perioperative Safety of Patients Undergoing Unilateral or Simultaneous Bilateral Total Knee Arthroplasty. AB - Objective To analyze the perioperative safety of patients undergoing unilateral or simultaneous bilateral total knee arthroplasty(TKA). Methods Totally 500 patients who had undergone unilateral or simultaneous bilateral TKA between December 2014 to December 2015 were retrospectively reviewed. They were divided into two groups:unilateral group(n=310)and bilateral group(n=190).The general data,perioperative transfusion,and complications were compared between these two groups. Results Patients in unilateral group had significantly higher ASA scores(chi2=8.344,P=0.015) and NYHA grade(chi2=7.537,P=0.023)than in bilateral group.Patients in bilateral group had significantly higher posterior drainage volume(t=44.984,P=0.000). Transfusion rate(chi2=42.896,P=0.000) was significantly higher and the lowest postoperative hemoglobin was significantly lower(t=0.006,P=0.000)in the bilateral group. The episodes of transfusion(chi2=1.025,P=0.599) and the amount of transfused packed red blood cells(chi2=3.836,P=0.429) were similar between two groups. There was no significant difference in the length of postoperative hospital stay(t=0.310,P=0.756),admission to intensive care unit(chi2=0.317,P=0.895),and incidences of complications(chi2=0.047,P=0.475). Conclusions For patients with low ASA scores and NYHA grade,simultaneous bilateral TKA is recommended. For older patients with high ASA score,poor cardiac function,and high incidences of complications,unilateral TKA is recommended. PMID- 29125111 TI - Comparison of Ultrasound Features of Primary Metastatic Papillary Thyroid Carcinoma and Recurrent/Persistent Metastatic Cervical Lymph Nodes. AB - Objective To explore the ultrasound features and levels of cervical lymph node metastases in primary and recurrent/persistent papillary thyroid cancer (PTC).Methods We retrospectively analyzed the clinical data of 2181 patients who underwent cervical lymph nodes dissection for PTC from January 1st 2015 to January 1st 2016.Totally 418 PTC patients (with 622 lymph nodes) who met the inclusion criteria entered the final analysis.Patients who had not received any prior thyroid treatment (surgery with or without radioactive iodine) were categorized as the primary group (352 patients with 527 metastatic lymph nodes),and patients who had received prior treatment (thyroidectomy with or without radioactive iodine) for PTC were categorized as recurrent/persistent group (66 patients with 95 metastatic lymph nodes).Pathological results from lymph node dissections were used as the gold standards by means of level-to-level analysis.Results The mean of the minimum axis diameter of the lymph nodes in the primary group was (6.7+/-3.6)mm,and that of the recurrent/persistent group was (6.6+/-3.1)mm (U=0.180,P=0.857).The proportion of metastasis in the central area of primary group was 40.0%,which was significantly higher than that in the recurrent/persistent group (12.6%);the proportion of metastasis in the lateral area was 60.6% in the primary group,which was significantly lower than that in the recurrent/persistent group (87.4%)(chi2=26.288,P<0.001).In lateral metastatic lymph nodes,III level was the most common place in both groups.Level V metastatic lymph was rare in both primary group and recurrent/persistent group.Calcifications (63.1% vs. 48.2%;chi2=7.207,P=0.007) and peripheral vascularity (81.1% vs. 59.4%;chi2= 16.147, P<0.001) were more common in the recurrent/persistent group.The round shape,absence of an echogenic hilum,hyperechogenicity,and cystic aspects were not significantly different between these two groups (all P>0.05).Conclusions Primary metastatic lymph nodes often occur in the central area of lymph nodes,while lateral metastatic lymph nodes are more common in recurrent/persistent PTC.For metastatic lymph nodes,calcifications and peripheral vascularity are more common in recurrent/persistent PTC. PMID- 29125112 TI - Clinical Values of Combined Diffused Optical Tomography and PET-CT in the Diagnosis of Breast Cancer. AB - Objective To investigate the clinical values of combined diffused optical tomography (DOT) combined positron emission tomography-computed tomography (PET CT) in the diagnosis of breast cancer. Methods We performed DOT and PET-CT examinations in 38 patients with 40 lesions and compared these images with the pathological results to analyze the sensitivity,specificity,accuracy,positive predictive value,and negative predictive value of these two techniques and their combination.Results The sensitivity,specificity,accuracy,positive predictive value,and negative predictive value in diagnosing breast cancer were 78.26%,76.47%,77.50%,72.22%,and 81.81% for DOT,86.96%,82.35%,85.00%,86.96%,and 82.35% for PET-CT,and 86.96%,94.12%,90.00%,95.23%,and 84.21% for the combination of PET-CT and DOT.Conclusions DOT and PET-CT are both effective diagnostic methods for breast cancer.Combined DOT and PET-CT can improve the diagnostic efficacy in terms of specificity,positive predictive value,and accuracy. PMID- 29125113 TI - Ultrasound-guided Selective Cervical Nerve Root Block Plus Superficial Cervical Plexus Block for Minimally Invasive Parathyroidectomy. AB - Objective To explore the efficacy and safety of ultrasound-guided cervical root block (CRB) in patients undergoing minimally invasive parathyroidectomy (MIP).Methods We enrolled 35 patients with hyperparathyroidism undergoing MIP in Peking Union Medical College Hospital.C4-7 nerve roots were identified in ultrasound imaging by the shape of the transverse process.A 50 mm insulated needle was gently introduced by an in-plane approach toward the posterior edge of the nerve root located at the inside of the posterior tubercle.After careful aspiration,a total of 3-4 ml of a mixture of 0.5% ropivacaine and 1% lidocaine was slowly injected.The superficial block was administered at the midpoint of the posterior border of the sternocleidomastoid by injecting 5-6 ml of the same mixture.The patients were administrated with dexmedetomidine during the surgery.All patients were assessed for sensory following the procedure and for pain after the surgery.Results Totally 35 patients successfully received MIP under ultrasound-guided CRB plus superficial block.There was no conversion to general anesthesia,no toxic reaction of local anesthetics,and no intravertebral injection.Hoarseness occurred in 6 patients (17.1%) and Horner syndrome occurred in 3 patients (8.6%).The median cold sensory visual analogue scale score was 1.2 [0,5] points at 10 minutes after the procedure.Patient's satisfaction score was 9.5 points.Conclusion Ultrasound-guided CRB plus superficial block can achieve accurate and safe anesthesia,and it provides lasting analgesic effect during and after MIP. PMID- 29125114 TI - Antenatal Sonographic Diagnosis and Clinical Significance of Placenta Previa Accreta after Cesarean Section. AB - Objective To investigate the clinical and antenatal sonographic characteristics of placenta previa accreta after cesarean section. Methods The data of 21 inpatients diagnosed as placenta previa accreta after cesarean section in PUMC Hospital from 2006 to 2016 were retrospectively reviewed. The clinical and ultrasound features were recorded and compared among three placental accreta groups,including placenta accrete group(n=5),increta group(n=12),and percreta group(n=4). The relationship between the placental thickness at the uterine anterior lower segment level and the blood loss of the following cesarean section was tested. Results Of 21 patients,placenta previa was diagnosed by ultrasound in 20 cases(95.2%) and placenta previa accreta was diagnosed in 9 cases(42.9%). Antenatal ultrasound findings included following signs:loss of "clear zone"(15/18,83.3%),myometrial thinning(12/18,66.7%),abnormal placental lacunae(12/19,63.2%),bladder wall interruption(2/18,11.1%),and uterovesical hypervascularity(4/9,44.4%). Myometrial thinning(J-T=64.000,P=0.036),abnormal placental lacunae(J-T=74.500,P=0.032) and the placental thickness at the uterine anterior lower segment level(U=83.000,P=0.010) showed significant difference among different placenta accreta groups. Placental thickness at the uterine anterior lower segment level showed linear correlation with the blood loss of the following cesarean section(r=0.669,P=0.002). The blood loss of the following cesarean section showed significant difference among different placenta accreta groups(U=118.500,P=0.000). Conclusions The clinical and sonographic manifestations of placenta previa accreta after cesarean section show a spectrum of demographic characteristics. The measurement of thickness of placenta at the anterior lower segment may help the evaluation of the clinical prognosis of this special pathology. PMID- 29125115 TI - Roles of Hypothalamic-Pituitary-Adrenal Axis and Hypothalamus-Pituitary-Ovary Axis in the Abnormal Endocrine Functions in Patients with Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome(PCOS) is a common reproductive endocrine disease in women of childbearing age. While it can be affected by a variety of factors,its pathophysiology remains unclear. Its clinical features mainly include anovulation,hyperandrogenism,and hyperinsulinemia,which are closely related with abnormal neuroendocrine system. Hypothalamic-pituitary-gonadal axis(HPG) plays a crucial regulatory role in various life activities in mammals. In particular,hypothalamic-pituitary-adrenal(HPA) axis and hypothalamus-pituitary ovary(HPO) axis can be abnormal in PCOS patients. The corresponding abnormalities include abnormal gonadotropin releasing hormone pulse frequency,increased luteinizing hormone/follicle-stimulating hormone ratio,and excessive excretion of adrenal and ovarian androgens. Meanwhile,insulin and leptin also play key roles in endocrine dysfunction in PCOS patients. This article systematically reviews the role of HPA axis and HPO axis in the neuroendocrine dysfunction in PCOS patients. PMID- 29125116 TI - Emerging Roles of Histidine Triad Nucleotide Binding Protein 1 in Neuropsychiatric Diseases. AB - The histidine triad nucleotide binding protein1(HINT1),which belongs to the histidine triad(HIT) enzyme superfamily,exerts its enzymic activities as hydrolase or transferase. Its physiological functions are still unclear. HINT1 protein is expressed in various tissues and plays an important role in transcription and signal transduction. Earlier studies have identified HINT1 as a haplo-insufficient tumor suppressor. Other evidences indicate that HINT1 is involved in a wide variety of physiological processes,some of which are irrelevant with its basic enzymic activities. Investigations recently suggest that HINT1 is closely related to many peripheral and central nervous system diseases,and plays a vital role in some of neuropsychiatric diseases such as inherited peripheral neuropathies,schizophrenia,mood disorder,drug addiction,and Down's syndrome. In this review,the role of HINT1 in above-mentioned neuropsychiatric disorders was summarised,and the research findings of HINT1 in each of the above diseases were summarized and analyzed,in order to provide some guidance for further research on this protein. PMID- 29125117 TI - Research Advances in the Neuroinflammation in Alzheimer's Disease. AB - Alzheimer's disease(AD) is a chronic degenerative disease of the nervous system,and the pathological change of AD is the formation of senile plaques containing amyloid beta(Abeta) and the neurofibrillary tangles. AD patients and animal models exhibit the over activation of microglia(MG) and astrocytes,causing neuroinflammation,leading to neuron death. Inhibition of MG activity can alleviate Abeta plaques. A growing number of studies have found that neuroinflammation is involved in the development and progression of AD. This article reviews the role of neuroinflammation induced by MG,astrocytes,T lymphocyte,and monocyte-derived macrophages in the mechanism of AD. PMID- 29125118 TI - Research Advances of Calcium-and Integrin-binding Protein 1 in Tumors. AB - Calcium-and integrin-binding protein 1(CIB1),a member of calcium binding protein containing EF-hand domain,has been shown to bind a variety of signaling proteins. Interaction of CIB1 with its various binding partners provides valuable insight into potential mechanisms by which CIB1 may regulate diverse tumors characteristic biological process that range from adhesion,migration,cell survival,proliferation,and angiogenesis. CIB1 has also been implicated in both the increase and decrease of cell proliferation.CIB1 promoted cell proliferation and survival by adjusted tumor-associated extracellular regulated protein kinases 1/2(ERK1/2),phosphatidylinositol 3 kinase(PI-3K)/v-akt murine thymoma viral oncogene homolog-dependent signaling pathway,or increased cell migration by activating Src family kinases,protein kinase C,PI-3K,and ERK 1/2-mediated signaling pathway.CIB1 inhibited cell proliferation through inhibiting polo-like kinases 3(PLK3) activity.It also inhibits cell migration by binding to and activating p21-activated kinase 1. Especially a large subset of triple-negative breast cancer may display non-oncogene addiction to CIB1,a phenomenon in which cancer cells require,or become 'addicted' to a non-mutated,non-overexpressed gene/protein that is nonetheless essential to maintain oncogenic signaling pathways,and implicate CIB1 as a novel drug target in tumors. Additionally,CIB1 plays a role in such pathological processes as cardiac hypertrophy,deafness,and male infertility. Research on CIB1 function has important clinical significance. In this review,we discussed current understanding of CIB1 in human tumors. PMID- 29125119 TI - Research Progress of the Differentiation of 3T3-L1 Preadipocytes into Mature Adipocytes. AB - Along with the increase in the prevalence of lipid metabolism disorders,in vitro research on the adipocytes has been a hot topic in recent years. 3T3-L1 preadipocyte line is one of the most commonly used cell line for establishing adipocytes models. However,for 3T3-L1 cell lines,the traditional method,known also as the "Cocktail" method,have disadvantages including low transformation rate and heterogeneous conversion. Therefore,many studies aimed to improving the induction method by changing the time of inducers or adding other new drugs have been performed(known as the improved method). The present study was to summarize the progress of the traditional methods and the improved methods for inducing 3T3 L1 cell lines to mature adipocytes. PMID- 29125120 TI - Canal to diaphysis ratio as a risk factor for hip fractures and hip fracture pattern. AB - INTRODUCTION: Osteoporosis and related fractures constitute a significant burden on modern healthcare. The standard method of diagnosing osteoporosis with a dual energy X-ray absorptiometry (DXA) scan is limited by accessibility and expense. The thickness of the cortex of the proximal femur on plain radiographs has been suggested to be a method for indicating osteoporosis and as a risk factor of hip fractures in the elderly. METHODS: A retrospective study was undertaken to assess the usefulness of the canal-diaphysis ratio (CDR) as a risk factor for developing a hip fracture, excluding patients presenting under 50 years old, following high energy trauma or pathological fractures. The CDR was measured in 84 neck of femur (NOF) fracture patients and 84 intertrochanteric hip fracture patients, and these were subsequently compared to the CDR of 84 patients without a hip fracture. Measurements were taken on two occasions by two members of the orthopaedic team, so as to assess the test's inter- and intraobserver reliability. RESULTS: In comparison to those without a fracture, there was a significant difference in the CDR of patients with a NOF fracture (P < 0.0001) and intertrochanteric fracture (P < 0.0001). Furthermore, the odds of having a CDR above 60.67 and 64.41 were significantly higher in the NOF (OR = 2.214, P = 0.0129) and intertrochanteric fracture (OR = 32.27, P < 0.0001) groups respectively, when compared to the non fractured group. The analysis of the test's inter- and intraobserver reliability showed strong levels of reproducibility. DISCUSSION: We concluded that a raised CDR was associated with an increased incidence of NOF and intertrochanteric hip fracture. Measuring the CDR can thus be considered as a reproducible and inexpensive method of identifying elderly patients at risk of hip fractures. PMID- 29125122 TI - Confronting the therapeutic misconception. PMID- 29125123 TI - Frameless stereotactic radiosurgery for brain metastases: a review of outcomes and prognostic scores evaluation. AB - INTRODUCTION: Stereotactic brain radiosurgery provides good local control in patients with limited brain metastases. A newly developed frameless system allows pain-free treatment. We reviewed the effectiveness of this frameless stereotactic brain radiosurgery and identified prognostic factors that may aid better patient selection. METHODS: Medical records of patients with brain metastases treated with linear accelerator-based frameless stereotactic brain radiosurgery between January 2010 and July 2015 in a university affiliated hospital in Hong Kong were reviewed. Outcomes including local and distant brain control rate, progression free survival, and overall survival were analysed. Prognostic factors were identified by univariable and multivariable analyses. Association of outcomes with four common prognostic scores was performed. RESULTS: In this study, 64 patients with 94 lesions were treated with a median dose of 18 Gy (range, 12-22 Gy) in a single fraction. The median follow-up was 11.5 months. One-year actuarial local and distant brain control rates were 72% and 71%, respectively. The median overall survival was 13.0 months. On multivariable analysis, Karnofsky performance status score (>50 vs <=50) and number of lesions (1-2 vs >=3) were found to associate significantly with distinct brain progression-free survival (P=0.022, hazard ratio=0.20, 95% confidence interval 0.05-0.80 and P=0.003, hazard ratio=0.31, 95% confidence interval 0.14-0.68, respectively). Overall survival was associated significantly with Basic Score for Brain Metastases (P=0.031), Score Index for Radiosurgery in Brain Metastases (P=0.007), and Graded Prognostic Assessment (P=0.003). Improvement in overall survival was observed in all groups of different prognostic scores. CONCLUSION: Frameless stereotactic brain radiosurgery is effective in patients with oligo-metastases of brain and should be increasingly considered in patients with favourable prognostic scoring. PMID- 29125121 TI - Structural basis of host recognition and biofilm formation by Salmonella Saf pili. AB - Pili are critical in host recognition, colonization and biofilm formation during bacterial infection. Here, we report the crystal structures of SafD-dsc and SafD SafA-SafA (SafDAA-dsc) in Saf pili. Cell adherence assays show that SafD and SafA are both required for host recognition, suggesting a poly-adhesive mechanism for Saf pili. Moreover, the SafDAA-dsc structure, as well as SAXS characterization, reveals an unexpected inter-molecular oligomerization, prompting the investigation of Saf-driven self-association in biofilm formation. The bead/cell aggregation and biofilm formation assays are used to demonstrate the novel function of Saf pili. Structure-based mutants targeting the inter-molecular hydrogen bonds and complementary architecture/surfaces in SafDAA-dsc dimers significantly impaired the Saf self-association activity and biofilm formation. In summary, our results identify two novel functions of Saf pili: the poly adhesive and self-associating activities. More importantly, Saf-Saf structures and functional characterizations help to define a pili-mediated inter-cellular oligomerizaiton mechanism for bacterial aggregation, colonization and ultimate biofilm formation. PMID- 29125124 TI - Predictable capability control scheme for oxygen-exchange blood flow regulation in an extracorporeal membrane oxygenation system. AB - Extracorporeal membrane oxygenation system is used for rescue treatment strategies for temporary cardiopulmonary function support to facilitate adequately oxygenated blood to return into the systemic and pulmonary circulation systems. Therefore, a servo flow regulator is used to adjust the roller motor speed, while support blood flow can match the sweep gas flow (GF) in a membrane oxygenator. A generalised regression neural network is designed as an estimator to automatically estimate the desired roller pump speed and control parameters. Then, the proportional-integral-derivative controller with tuning control parameters showed good performance to achieve speed regulation and speed tracking in the desired operating point. Given the pressure of carbon dioxide, drainage blood flow, and cannula size, the proposed predictable capability control scheme can be validated to meet the intended uses in clinical applications. PMID- 29125125 TI - Bogdanov-Takens bifurcation in a neutral BAM neural networks model with delays. AB - In this study, the authors first discuss the existence of Bogdanov-Takens and triple zero singularity of a five neurons neutral bidirectional associative memory neural networks model with two delays. Then, by utilising the centre manifold reduction and choosing suitable bifurcation parameters, the second-order and the third-order normal forms of the Bogdanov-Takens bifurcation for the system are obtained. Finally, the obtained normal form and numerical simulations show some interesting phenomena such as the existence of a stable fixed point, a pair of stable non-trivial equilibria, a stable limit cycles, heteroclinic orbits, homoclinic orbits, coexistence of two stable non-trivial equilibria and a stable limit cycles in the neighbourhood of the Bogdanov-Takens bifurcation critical point. PMID- 29125126 TI - Improving GRN re-construction by mining hidden regulatory signals. AB - Inferring gene regulatory networks (GRNs) from gene expression data is an important but challenging issue in systems biology. Here, the authors propose a dictionary learning-based approach that aims to infer GRNs by globally mining regulatory signals, known or latent. Gene expression is often regulated by various regulatory factors, some of which are observed and some of which are latent. The authors assume that all regulators are unknown for a target gene and the expression of the target gene can be mapped into a regulatory space spanned by all the regulators. Specifically, the authors modify the dictionary learning model, k-SVD, according to the sparse property of GRNs for mining the regulatory signals. The recovered regulatory signals are then used as a pool of regulatory factors to calculate a confidence score for a given transcription factor regulating a target gene. The capability of recovering hidden regulatory signals was verified on simulated data. Comparative experiments for GRN inference between the proposed algorithm (OURM) and some state-of-the-art algorithms, e.g. GENIE3 and ARACNE, on real-world data sets show the superior performance of OURM in inferring GRNs: higher area under the receiver operating characteristic curves and area under the precision-recall curves. PMID- 29125127 TI - Design of dynamic genetic memory. AB - In electronic systems, dynamic random access memory (DRAM) is one of the core modules in the modern silicon computer. As for a bio-computer, one would need a mechanism for storage of bio-information named 'data', which, in binary logic, has two levels, logical high and logical low, or in the normalised form, '1' and '0'. This study proposes a possible genetic DRAM based on the modified electronic configuration, which uses the biological reaction to fulfil an equivalent RC circuit constituting a memory cell. The authors implement fundamental functions of the genetic DRAM by incorporating a genetic toggle switch for data hold. The results of simulation verify that the basic function can be used on a bio-storage module for the future bio-computer. PMID- 29125128 TI - Action potential propagation: ion current or intramembrane electric field? AB - The established action potential propagation mechanisms do not satisfactorily explain propagation on myelinated axons given the current knowledge of biological channels and membranes. The flow across ion channels presents two possible effects: the electric potential variations across the lipid bilayers (action potential) and the propagation of an electric field through the membrane inner part. The proposed mechanism is based on intra-membrane electric field propagation, this propagation can explain the action potential saltatory propagation and its constant delay independent of distance between Ranvier nodes in myelinated axons. PMID- 29125129 TI - Left-right asymmetry in firing rate of extra-retinal photosensitive neurons in the crayfish. AB - The purpose of this paper is to explore the firing rate of the caudal photoreceptors (CPRs) from the sixth abdominal ganglion of the crayfish Cherax quadricarinatus. We use simultaneous extracellular recordings on left and right CPR in the isolated ganglion (n = 10). The CPRs showed an asymmetry in the spontaneous activity and light-induced response. In darkness, we observed one subgroup (70%) in which the left CPR (CPR-L) and right CPR (CPR-R) had spontaneous firing rates with a median of 18 impulses/s and 6 impulses/s, respectively. In another subgroup (20%), the CPR-R had a median of 15 impulses/s and the CPR-L had 8 impulses/s. In both groups, the differences were significant. Furthermore, the CPRs showed an asymmetrical photoresponse induced by a pulse of white light (700 Lux, 4 s). In one subgroup (30%), the CPR-L showed light-induced activity with a median of 73%, (interquartile range, IQR = 51), while the CPR-R had a median of 41%, (IQR = 47). In another subgroup (70%), the CPR-R showed a median of 56%, (IQR = 51) and the CPR-L had a median of 42%, (IQR = 46). In both groups, the differences were significant. Moreover, we observed a differential effect of temperature on CPR activity. These results suggest a functional asymmetry in both activities from left and right CPRs. These CPR activity fluctuations may modulate the processing of information by the nervous system. PMID- 29125130 TI - Acid sphingomyelinase inhibitors, imipramine and zoledronic acid, increase skeletal muscle tissue sensitivity to insulin action at old age. AB - Malfunction of skeletal muscles and dysregulated turnover of sphingolipids in the insulin responsive tissues have been determined at old age. Present article investigates the role of acid sphingomyelinase (SMase)-dependent ceramide accumulation in reduction of the skeletal muscle sensitivity to insulin action at old age. The 3-, 12- and 24-month-old Wistar male rats were used in the experiments. The progressive increase of ceramide content and ceramide/sphingomyeline (SM) ratio was determined in the extensor digitorum longus (EDL) muscle during aging of rats. The agedependent ceramide accumulation was followed by reduction of muscle tissue response to insulin action. The resistance of EDL to insulin action at old age can be imitated by exogenous natural N-palmitoyl-D-erythro-sphingosine (C16-ceramide) injection to adult rats, while imipramine or zoledronic acid treatment of old animals nullified dysregulation of SM turnover and improved the muscle tissue response to insulin action. Drugs significantly increased insulin-stimulated 2-D-[3H] glucose uptake by the EDL muscle of 24-month-old animals to the level close to that of 3-month old rats in both in vivo and in vitro experiments. Imipramine, as well as zoledronic acid significantly reduced acid SMase activity in the EDL of old animals. Thus, ceramide overproduction via acid SMase activation can be important for the development of EDL resistance to insulin action. Therefore, acid SMase inhibitors can possibly be used as therapeutic tools for improvement of muscle tissue sensitivity to insulin action at an old age. PMID- 29125131 TI - Polymer scaffolds for vascular tissue engineering fabricated by combined electrospinning and hot embossing. AB - Although tissue engineering has shown great advances in recent years, creating proper mechanical properties and cell growth microenvironments is still challenging. In this study, electrospun nanofibrous membranes were hot embossed to develop three-dimensional hierarchical micro/nanostructures that load and culture human umbilical-vein endothelial cells (HUVECs). The hot-embossed membranes exhibited not only superior mechanical properties (the tensile strength was 7.01 +/- 0.18 MPa and the tensile modulus was 166.91 +/- 15.54 MPa), but also better cell viability evaluated through a CCK-8 assay and fluorescent dye. The grating and well arrays of the micropatterned fibre mats encouraged the HUVECs to proliferate. Therefore, the approach proposed in this paper-combined electrospinning and hot embossing-has bright prospects in biomedical applications for the use of polymer scaffold in tissue engineering. PMID- 29125133 TI - Repair of articular cartilage defects with acellular cartilage sheets in a swine model. AB - Acellular cartilage sheets (ACSs) have been demonstrated as a good biomaterial for cartilage regeneration as a result of their natural cartilage matrix components, cartilage-specific structures, and good biocompatibility. However, it remains unknown whether allogeneic ACSs could promote cartilage regeneration and repair cartilage defects in a large animal model. The current study explored the feasibility of repairing articular cartilage defects using ACS scaffold with or without autologous bone marrow stromal cells (BMSCs) in a swine model. According to the current results, ACSs retained natural cartilage structure, primary cartilage matrices, and cartilage-specific growth factors. After cell seeding, ACSs presented good biocompatibility with BMSCs, which produced abundant extracellular matrix (ECM) proteins to cover the lacuna structures. In vivo results indicated that ACSs alone could induce endogenous host cells to regenerate cartilage and achieve generally satisfactory repair of cartilage defects at 6 months post-operation, including good interface integration and cartilage-specific ECM deposition. After combination with autologous BMSCs, BMSC ACS constructs achieved more satisfactory repair of cartilage defects even without in vitro pre-induction of chondrogenesis. More importantly, all defects in both BMSC-ACS and ACS-only groups showed enhanced cartilage regeneration compared with BMSC-polyglycolic acid and blank groups, which mainly exhibited fibrogenesis in defect areas. Collectively, the current results indicate that ACSs can efficiently repair articular cartilage defects by promoting chondrogenic differentiation of BMSCs or inducing endogenous chondrogenesis in situ, thus serving as a good cartilage regeneration scaffold for recovery of articular function. PMID- 29125134 TI - Implicit relevance feedback from electroencephalography and eye tracking in image search. AB - OBJECTIVE: Methods from brain-computer interfacing (BCI) open a direct access to the mental processes of computer users, which offers particular benefits in comparison to standard methods for inferring user-related information. The signals can be recorded unobtrusively in the background, which circumvents the time-consuming and distracting need for the users to give explicit feedback to questions concerning the individual interest. The obtained implicit information makes it possible to create dynamic user interest profiles in real-time, that can be taken into account by novel types of adaptive, personalised software. In the present study, the potential of implicit relevance feedback from electroencephalography (EEG) and eye tracking was explored with a demonstrator application that simulated an image search engine. APPROACH: The participants of the study queried for ambiguous search terms, having in mind one of the two possible interpretations of the respective term. Subsequently, they viewed different images arranged in a grid that were related to the query. The ambiguity of the underspecified search term was resolved with implicit information present in the recorded signals. For this purpose, feature vectors were extracted from the signals and used by multivariate classifiers that estimated the intended interpretation of the ambiguous query. MAIN RESULT: The intended interpretation was inferred correctly from a combination of EEG and eye tracking signals in 86% of the cases on average. Information provided by the two measurement modalities turned out to be complementary. SIGNIFICANCE: It was demonstrated that BCI methods can extract implicit user-related information in a setting of human computer interaction. Novelties of the study are the implicit online feedback from EEG and eye tracking, the approximation to a realistic use case in a simulation, and the presentation of a large set of photographies that had to be interpreted with respect to the content. PMID- 29125132 TI - Chitosan inhibits platelet-mediated clot retraction, increases platelet-derived growth factor release, and increases residence time and bioactivity of platelet rich plasma in vivo. AB - Platelet-rich plasma (PRP) has been used to treat different orthopedic conditions, however, the clinical benefits of using PRP remain uncertain. Chitosan (CS)-PRP implants have been shown to improve meniscus, rotator cuff and cartilage repair in pre-clinical models. The purpose of this current study was to investigate in vitro and in vivo mechanisms of action of CS-PRP implants. Freeze dried formulations containing 1% (w/v) CS (80% degree of deacetylation and number average molar mass 38 kDa), 1% (w/v) trehalose as a lyoprotectant and 42.2 mM calcium chloride as a clot activator were solubilized in PRP. Gravimetric measurements and molecular/cellular imaging studies revealed that clot retraction is inhibited in CS-PRP hybrid clots through physical coating of platelets, blood cells and fibrin strands by chitosan, which interferes with platelet aggregation and platelet-mediated clot retraction. Flow cytometry and ELISA assays revealed that platelets are activated and granules secreted in CS-PRP hybrid clots and that cumulative release of platelet-derived growth factor (PDGF-AB) and epidermal growth factor is higher from CS-PRP hybrid clots compared to PRP clots in vitro. Finally, CS-PRP implants resided for up to 6 weeks in a subcutaneous implantation model and induced cell recruitment and granulation tissue synthesis, confirming greater residency and bioactivity compared to PRP in vivo. PMID- 29125135 TI - Silk fibroin/amniotic membrane 3D bi-layered artificial skin. AB - Burn injuries have been reported to be an important cause of morbidity and mortality and they are still considered as unmet clinical need. Although there is a myriad of effective stem cells that have been suggested for skin regeneration, there is no one ideal scaffold. The aim of this study was to develop a three dimensional (3D) bi-layer scaffold made of biological decellularized human amniotic membrane (AM) with viscoelastic electrospun nanofibrous silk fibroin (ESF) spun on top. The fabricated 3D bi-layer AM/ESF scaffold was submerged in ethanol to induce beta-sheet transformation as well as to get a tightly coated and inseparable bi-layer. The biomechanical and biological properties of the 3D bi-layer AM/ESF scaffold were investigated. The results indicate significantly improved mechanical properties of the AM/ESF compared with the AM alone. Both the AM and AM/ESF possess a variety of suitable adhesion cells without detectable cytotoxicity against adipose tissue-derived mesenchymal stem cells (AT-MSCs). The AT-MSCs show increased expression of two main pro-angiogenesis factors, vascular endothelial growth factor and basic fibroblast growth factor, when cultured on the AM/ESF for 7 days, when comparing with AM alone. The results suggest that the AM/ESF scaffold with autologous AT-MSCs has excellent cell adhesion and proliferation along with production of growth factors which serves as a possible application in a clinical setting for skin regeneration. PMID- 29125136 TI - Mechanically stable surface-hydrophobilized chitosan nanofibrous barrier membranes for guided bone regeneration. AB - The use of chitosan based nanofiber membranes in guided bone regeneration (GBR) is limited by its uncontrolled swelling and mechanical instability in aqueous environments. This paper describes the significantly improved stability and properties of surface butyrylated chitosan nanofiber (BCSNF) membranes that greatly enhance their potential in GBR. The BCSNF membranes exhibited an overall degree of substitution of 1.61, an average diameter of 99.3 +/- 33.7 nm, and a 75% decrease in swelling with an approximate doubling in suture pull out strengths as compared to unmodified fibers in aqueous environment. In a five week phosphate-buffered saline-lysozyme degradation study, it was found that the remaining mass fraction of BCSNF membranes was 11.5% more than that of unmodified fibers. In vitro, the BCSNF membranes were found to support the adhesion and proliferation of fibroblasts and were cell occulusive. In vivo, the BCSNF membranes were found to significantly improve the regeneration of a rat calvarial critical size defect in a 12 week healing period and showed better barrier function than commercially available collagen membranes with little soft tissue penetration through the membranes. Taken together, these data provide strong scientific evidence for use of BCSNF membranes in GBR applications. PMID- 29125137 TI - Red blood cell distribution width, relative lymphocyte count, and type 2 diabetes predict all-cause mortality in patients with advanced heart failure. AB - INTRODUCTION Early identification of patients with advanced heart failure (HF) who are at higher risk of poor outcome is an important element of patient management, both from the medical and economic standpoint. OBJECTIVES We sought to determine the association between hematologic parameters assessed on admission and within a 3-year follow-up in consecutive patients with advanced HF. We also investigated the association between baseline demographic and clinical data and mortality. PATIENTS AND METHODS We analyzed the data of consecutive patients with advanced HF from the single-center registry COMMIT-HF. Patients with hematologic and autoimmune disorders, acute or chronic inflammatory diseases, malignant diseases, incomplete clinical and laboratory data, and those receiving glucocorticoids were excluded from the study. RESULTS We analyzed 785 patients with advanced HF out of the total number of 1798 patients included in the COMMIT-HF registry between 2009 and 2013. The mean (SD) age of the patients was 61.9 (12.4) years, and 76.8% of them were male. Diabetes (hazard ratio [HR], 1.46; 95% CI, 1.15-1.86; P = 0.002), elevated red blood cell distribution width (RDW; HR, 1.05; 95% CI, 1.04-1.07; P <0.0001), and a low relative lymphocyte count (RLC%; HR, 0.942; 95% CI, 0.928-0.956; P <0.0001) were shown to be independent predictors of death. CONCLUSIONS Our study showed that diabetes is a strong independent predictor of death in patients with advanced HF. RDW and RLC% are simple, accurate, and widely available markers predicting mortality at 3 years in patients with advanced HF. PMID- 29125138 TI - Detection accuracy for epithelial dysplasia using an objective autofluorescence visualization method based on the luminance ratio. AB - The autofluorescence visualization method (AVM) uses blue excitation light to assist in the diagnosis of epithelial dysplasia. It detects epithelial dysplasia as a black area, which is known as fluorescence visualization loss (FVL). In this study, we evaluated the detection accuracy for epithelial dysplasia of the tongue using the objective AVM and assessed its possible clinical utility. Seventy-nine tongue specimens clinically suspected to have leukoplakia or squamous cell carcinoma (SCC) were analyzed. First, the AVM was subjectively performed using the Visually Enhanced Lesion scope (VELscope), and the iodine-staining method was then performed. After biopsy, the histopathological results and the luminance ratio between the lesion and healthy tissue were compared, and a receiver operating characteristic curve was created. The cutoff value for the objective AVM was determined; the lesion was considered FVL-positive or -negative when the luminance ratio was higher or lower than the cutoff value, respectively. The histopathological diagnoses among the 79 specimens were SCC (n=30), leukoplakia with dysplasia (n=34), and leukoplakia without dysplasia (n=15). The cutoff value of the luminance ratio was 1.62, resulting in 66 FVL-positive and 13 FVL-negative specimens. The luminance ratio was significantly higher in the epithelial dysplasia-positive than -negative group (P<0.000 1). The objective AVM showed much higher consistency between histopathological results than did the two methods (kappa statistic=0.656). In conclusion, objective autofluorescence visualization has a potential as an auxiliary method for diagnosis of epithelial dysplasia. PMID- 29125141 TI - Corrigendum: Infrared light excites cells by changing their electrical capacitance. AB - This corrects the article DOI: 10.1038/ncomms1742. PMID- 29125140 TI - Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex. AB - Pluripotent stem cells (PSCs) harbor constitutive DNA replication stress during their rapid proliferation and the consequent genome instability hampers their applications in regenerative medicine. It is therefore important to understand the regulatory mechanisms of replication stress response in PSCs. Here, we report that mouse embryonic stem cells (ESCs) are superior to differentiated cells in resolving replication stress. Specifically, ESCs utilize a unique Filia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks, therefore maintaining genomic stability. The ESC-specific Filia-Floped complex resides on replication forks under normal conditions. Replication stress stimulates their recruitment to stalling forks and the serine 151 residue of Filia is phosphorylated in an ATR-dependent manner. This modification enables the Filia-Floped complex to act as a functional scaffold, which then promotes the stalling fork restart through a dual mechanism: both enhancing recruitment of the replication fork restart protein, Blm, and stimulating ATR kinase activation. In the Blm pathway, the scaffolds recruit the E3 ubiquitin ligase, Trim25, to the stalled replication forks, and in turn Trim25 tethers and concentrates Blm at stalled replication forks through ubiquitination. In differentiated cells, the recruitment of the Trim25-Blm complex to replication forks and the activation of ATR signaling are much less robust due to lack of the ESC-specific Filia-Floped scaffold. Thus, our study reveals that ESCs utilize an additional and unique regulatory layer to efficiently promote the stalled fork restart and maintain genomic stability. PMID- 29125142 TI - Bone: PPARgamma controls marrow adiposity. PMID- 29125144 TI - Bone: High-intensity exercise to prevent fractures - risk or gain? PMID- 29125143 TI - Metabolism: Metabolic effects of intermeal fasting. PMID- 29125139 TI - Salivary proteins and microbiota as biomarkers for early childhood caries risk assessment. AB - Early childhood caries (ECC) is a term used to describe dental caries in children aged 6 years or younger. Oral streptococci, such as Streptococcus mutans and Streptococcus sorbrinus, are considered to be the main etiological agents of tooth decay in children. Other bacteria, such as Prevotella spp. and Lactobacillus spp., and fungus, that is, Candida albicans, are related to the development and progression of ECC. Biomolecules in saliva, mainly proteins, affect the survival of oral microorganisms by multiple innate defensive mechanisms, thus modulating the oral microflora. Therefore, the protein composition of saliva can be a sensitive indicator for dental health. Resistance or susceptibility to caries may be significantly correlated with alterations in salivary protein components. Some oral microorganisms and saliva proteins may serve as useful biomarkers in predicting the risk and prognosis of caries. Current research has generated abundant information that contributes to a better understanding of the roles of microorganisms and salivary proteins in ECC occurrence and prevention. This review summarizes the microorganisms that cause caries and tooth-protective salivary proteins with their potential as functional biomarkers for ECC risk assessment. The identification of biomarkers for children at high risk of ECC is not only critical for early diagnosis but also important for preventing and treating the disease. PMID- 29125145 TI - The 2017 Doyne Lecture: the orbit as a window to systemic disease. AB - A very large number of disorders affect the orbit, and many of these occur in the setting of systemic disease. This lecture covers selected aspects of orbital diseases with systemic associations in which the author has a particular clinical or research interest. Spontaneous orbital haemorrhage often occurs in the presence of bleeding diatheses. Thrombosis of orbital veins and ischaemic necrosis of orbital and ocular adnexal tissues occur with thrombophilic disorders, vasculitis, and certain bacterial and fungal infections. Non infectious orbital inflammation commonly occurs with specific inflammatory diseases, including Graves' disease, IgG4-related disease, sarcoidosis, Sjogren's syndrome and granulomatosis with polyangiitis, all of which have systemic manifestations. IgG4-related ophthalmic disease is commoner than all these except Graves' orbitopathy. Some of these orbital inflammatory diseases are associated with an increased risk of B-cell lymphoma, usually marginal zone lymphoma of MALT type. Ocular adnexal lymphoma also has an association with infectious agents including Helicobacter pylori and Chlamydia psittaci. Orbital metastasis may be the first presentation of systemic malignancy. A number of orbital neoplasms occur in the setting of familial cancer syndromes, including Neurofibromatosis types 1 and 2. Study of the genetics and molecular biology of orbital diseases such as Graves' orbitopathy and idiopathic orbital inflammatory disease will yield useful information on their diagnosis and management. PMID- 29125146 TI - Genetics and genetic testing for age-related macular degeneration. AB - Considerable advances have been made in our understanding of age-related macular degeneration (AMD) genetics over the past decade. The genetic associations discovered to date are estimated to account for approximately half of AMD heritability, and functional studies of these variants have revealed new insights into disease pathogenesis, leading to the development of potential novel therapies. There is furthermore growing interest in genetic testing for predicting an individual's risk of AMD and offering personalised preventive or therapeutic treatments. We review the progress made so far in AMD genetics and discuss the possible applications for genetic testing. PMID- 29125147 TI - Retinal layers thickness changes following epiretinal membrane surgery. AB - PurposeTo evaluate the time course of changes in the thickness of retinal layers after epiretinal membrane (ERM) removal surgery.MethodsA retrospective cohort study of patients following surgery for idiopathic ERM. We used new specialized image analysis software to create a thickness map of each retinal layer and analyzed changes during one year follow-up. Healthy fellow eyes were used as negative controls and the retina prior to surgery as positive control.ResultsTwenty-one patients were included with a mean age of 68+/-13 years. Central macular thickness decreased steadily until 6 months after surgery (25% decrease, 516+/-76 to 386+/-73 MUm, P<0.001) with no further decrease between 6 and 12 months (386+/-73 to 390+/-73 MUm, P=0.291). The retinal nerve fiber layer (RNFL), and the ganglion cell and inner plexiform layer (GCIPL) were most affected (57%, P<0.001 and 27%, P=0.010, respectively). The thickest region showed a more abrupt decrease of 21% at first follow-up (504+/-61 to 399+/-58 MUm, P=0.001) with subsequent decrements of about 3%. Prior to surgery all retinal layers were thicker in study eyes compared with healthy control eyes (6 63%, all P<0.05).ConclusionsFollowing ERM surgery, in the course of 6 months, the macula gradually becomes thinner after which a stable state is reached. All layers appear to be affected, with the RNFL and GCIPL impacted the most. Our results provide a unique view on how the thickness of different retinal layers changes following ERM surgery. PMID- 29125148 TI - Role of pericytes in the retina. PMID- 29125149 TI - SIA-formula: an easy way to calculate surgically induced astigmatism. PMID- 29125150 TI - Contemporary management of men with high-risk localized prostate cancer in the United States. AB - This corrects the article DOI: 10.1038/pcan.2017.5. PMID- 29125151 TI - Transition metal-free N-fluoroalkylation of amines using cyanurate activated fluoroalcohols. AB - A novel and highly efficient method for N-fluoroalkylation of amines using 2,4,6 tris(fluoroalkoxy)-1,3,5-triazines was developed. This simple approach allowed the N-fluoroalkylation of amines under fast, mild and efficient reaction conditions, without using a transition metal as a catalyst. PMID- 29125153 TI - Metal-enhanced Forster resonance energy transfer (ME-FRET) in anthracene/tetracene-doped crystal systems. AB - Anthracene tetracene-doped crystals (TA) dispersed in a thin polymer film matrix have been reported as efficient down converting systems based on Forster Resonance Energy Transfer (FRET) which occurs efficiently from donor (anthracene) to acceptor (tetracene) molecules. In this work, we demonstrate that the efficiency of this system can be further improved by a metal-enhanced FRET, which is obtained by incorporating metal nanoparticles into the polymer matrix. We report on the preparation and optical responses of polymeric transparent thin films where dodecanethiol-capped silver or gold nanoparticles are dispersed with TA in a polymethylmethacrylate (PMMA) matrix. A maximum of 11-fold and 6.5-fold enhancement was achieved with silver and gold nanoparticles, respectively. Efficiency is discussed in terms of film morphology and plasmon resonance induced effects. PMID- 29125152 TI - Recent developments in transition-metal photoredox-catalysed reactions of carbonyl derivatives. AB - Single-electron reduction of C[double bond, length as m-dash]O and C[double bond, length as m-dash]N bonds of aldehydes, ketones, and imines results in the formation of ketyl and alpha-aminoalkyl anion radicals, respectively. These reactive intermediates are characterized by an altered electronic character with respect to their parent molecules and undergo a diverse range of synthetically useful transformations, which are not available to even-electron species. This Review summarizes the reactions of ketyl and alpha-aminyl radicals generated from carbonyl derivatives under transition-metal photoredox-catalysed conditions. We primarily focus on recent developments in the field, as well as give a brief overview of catalytic enantioselective transformations that provide a means to achieve precise stereocontrol over the reactivity of ion radicals. PMID- 29125154 TI - A naphthalimide-based solid state luminescent probe for ratiometric detection of aluminum ions: in vitro and in vivo applications. AB - A naphthalimide-based fluorescent probe 4 has been designed and synthesized that detects Al3+ ions in solution, solid state and in biological systems, including cells, tissues and nematodes. Further, a portable kit has been developed using probe 4 for the on-site detection of Al3+ ions. PMID- 29125155 TI - Formation of spherical ice-shells inside carbon fullerenes. AB - The structural and dynamic properties of encapsulated water inside fullerene cages, C60 to C320, were investigated employing classical molecular dynamics simulations. We find that the confined water forms single to multiple concentric, spherical shells as the size of the fullerene increases. This is possible due to the reduced number of hydrogen bonds per water molecule in the nanoscale liquid as compared to bulk water, allowing the encapsulated H2O molecules to imitate the shape of the confining boundary. These water-cluster shells exhibit solid-like behavior at temperatures as high as 500 K. Our current findings complement the existing literature on water confined by sp2-hybridized nanocarbon structures including one dimensional nanotubes and two dimensional graphene sheets. PMID- 29125156 TI - Vibrational states of nano-confined water molecules in beryl investigated by first-principles calculations and optical experiments. AB - Using quantum mechanical calculations within density functional theory, we provide a comprehensive analysis of infrared-active excitation of water molecules confined in nanocages of a beryl crystal lattice. We calculate infrared-active modes including the translational, librational, and mixed-type resonances of regular and heavy water molecules. The results are compared to the experimental spectra measured for the two principal polarizations of the electric field: parallel and perpendicular to the crystallographic c-axis. Good agreement is achieved between calculated and measured isotopic shifts of the normal modes. We analyze the vibrational modes in connection with the structural characteristics and arrangements of water molecules within the beryl crystal. Specific atomic displacements are assigned to each experimentally detected vibrational mode resolving the properties of nano-confined water on scales not accessible by experiments. Our results elucidate the applicability and efficiency of a combined experimental and computational approach for describing and an in-depth understanding of nano-confined water, and pave the way for future studies of more complex systems. PMID- 29125157 TI - 3D organic Na4C6O6/graphene architecture for fast sodium storage with ultralong cycle life. AB - Sodium-ion batteries (SIBs) have aroused increasing interest as one of the most promising replacements for lithium-ion batteries (LIBs). Here, a novel organic inorganic 3D Na4C6O6-graphene architecture was successfully fabricated from commercial Na2C6O6 and for the first time applied for sodium storage. Hence, the 3D Na4C6O6-graphene architecture exhibits a high reversible capacity, good cyclic performance and high-rate capability for sodium storage. PMID- 29125158 TI - Photodissociation of ethylphenylcobalamin antivitamin B12. AB - Biologically active forms of cobalamins are crucial cofactors in biochemical reactions and these metabolites can be inhibited by their structurally similar analogues known as antivitamins B12. Phenylethynylcobalamin (PhEtyCbl) or 4 ethylphenylcobalamin (EtPhCbl) exemplify recently synthesized and structurally characterized antivitamins B12. Herein, DFT and TD-DFT studies of EtPhCbl are provided to explore its photochemical behavior, which may lead to design of arylcobalamins that can be used as therapeutic agents in light activated drug applications. To understand the photolability of EtPhCbl, a potential energy surface (PES) for the photodissociation of the Co-C bond was constructed. The S1 PES contains two energy minima, one being metal-to-ligand charge transfer (MLCT) and another the ligand-field (LF) state. There are two possible pathways for photodissociation: the first pathway (path A) involves initially lengthening the Co-C bond from the MLCT minimum and then elongation of Co-NIm while the second pathway (path B) involves the lengthening of the Co-NIm bond through the MLCT region followed by the lengthening of the Co-C bond through the LF region. It is shown that photodissociation involving path A is not energetically favorable whereas preferable photodissociation of the Co-C bond involves path B. PMID- 29125159 TI - Development of luminescent sensors based on transition metal complexes for the detection of nitroexplosives. AB - The detection of chemical explosives is a major area of research interest and is essential for the military as well as homeland security to counter the catastrophic effects of global terrorism. In recent years, tremendous effort has been devoted to the development of luminescent materials for the detection of explosives in the vapor, solution, and solid states with a high degree of selectivity and sensitivity and a rapid response time. Apart from the wide range of organic fluorescent chemosensors, transition metal complexes play a prominent role in the sensing of nitroaromatic explosives owing to their rich photophysical characteristics. This review briefly summarizes the salient features of the design and preparation of transition metal (Zn(ii), Ir(iii), Pd(ii), Pt(ii), Re(i) and Ru(ii)) complexes/metallacycles/metallosupramolecules with emphasis on their photophysical properties, sensing behavior, mechanism of action, and the driving forces for detecting explosives and future prospects and challenges. Most of the probes that have been reported to date act as "turn-off" luminescent sensors because their emission (intensity, lifetime, and quantum yield) is eventually quenched upon sensing with nitroaromatic compounds (NACs) through photo-induced electron or energy transfer. These unique properties of transition metal complexes in response to explosives open up new vistas for the development of real world applications such as on-site detection, in-field security, forensic research, etc. PMID- 29125160 TI - The femtosecond-to-second photochemistry of red-shifted fast-closing anion channelrhodopsin PsACR1. AB - Anion channelrhodopsins (ACRs) are of great interest due to their ability to inhibit electrical signaling in optogenetic experiments. The photochemistry of ACRs is currently poorly understood and an improved understanding would be beneficial for rational design of ACRs with modified properties. Activation/deactivation of ACRs involves a series of photoreactions ranging from femtoseconds to seconds, thus real-time observation is essential to comprehend the full complexity of the photochemical processes. Here we investigate the photocycle of an ACR from Proteomonas sulcata (PsACR1), which is valuable for optogenetic applications due to the red-shifted absorption and action spectra compared to the prototype ACRs from Guillardia theta: GtACR1 and GtACR2, and the fast channel closing properties. From femto-to-submillisecond transient absorption spectroscopy, flash photolysis, and point mutations of acidic residues near the retinal Schiff base (RSB), E64, and D230, we found that the photoisomerization occurs in ~500 fs independent of the protonation state of E64. Notably, E64 is involved in the rearrangement of the hydrogen-bond network near the RSB after photoisomerization. Furthermore, we suggest that E64 works as a primary proton acceptor during deprotonation of the RSB as has been proposed for GtACR1. Our findings allow for a deeper understanding of the photochemistry on the activation/deactivation of ACRs. PMID- 29125161 TI - Dimer formation of GdDO3A-arylsulfonamide complexes causes loss of pH-dependency of relaxivity. AB - Gadolinium(iii) complexes with pH-dependent relaxivities have been proposed as responsive magnetic resonance imaging (MRI) contrast agents (CA) for mapping of pH value in living subjects. The latter is clinically relevant because hypoxia induced reduction of interstitial pH (acidosis) is a hallmark of tumor progression and resistance against chemotherapy. In order to obtain versatile building blocks for integration of a pH-responsive MRI-CA functionality into larger molecular assemblies, such as bioconjugates, micelles or nanoparticles, we equipped the structural motif GdDO3A-ethylene(arylsulfonic acid) with additional carboxylic acid moieties in the aromatic para-position. Two novel compounds were characterized concerning their pH-dependent relaxivity as well as by 17O NMR and 1H NMRD, augmented by determination of luminescence lifetimes of the respective Eu(iii) complexes and structural modelling by density functional theory (TPSSh/LCRECP/6-31G(d)). Unexpected involvement of the peripheral carboxylates into metal ion complexation effected self-assembly of the lanthanide(iii) complexes, resulting in dimeric species comprising two lanthanide ions, two symmetrically bridging ligands, and one coordinated water molecule per Gd(iii) (q = 1). These structures are stable even at low concentrations and in presence of competing anions like phosphate. The pH-sensitive sulfonamide moieties are not involved into Gd(iii) coordination, resulting in virtually constant relaxivities of r1 = 6.7 mM-1 s-1 (298 K, 20 MHz) over the biologically relevant pH range (4 to 9). Since further functionalisation on the peripheral carboxylates would effectively inhibit dimer formation, the compounds are nonetheless suited for the initially envisaged field of application. PMID- 29125162 TI - Controlled optical characteristics of lanthanide doped upconversion nanoparticles for emerging applications. AB - Lanthanide-doped upconversion nanoparticles (UCNPs) can convert long wavelength excitation radiation in the near-infrared region to higher energy emission radiation from ultraviolet to near-infrared. The anti-Stokes luminescence process will result in high tissue penetration depth, low background noise and low photo damage in bioimaging applications. Considering these excellent optical performances, UCNPs have been considered as the next generation of fluorescent probes for sensing and bioimaging based on near-infrared light stimulation. In this mini review, we highlight the recent advances of UCNPs in the field of emerging applications, such as dye sensitized UCNPs, photogene regulation, anti counterfeiting, and super-resolution imaging, which depend on the optical modulation. Finally, we discuss the challenges and opportunities in the development of these new applications. PMID- 29125163 TI - Chasing the agostic interaction in ligand assisted cyclometallation reactions of palladium(ii). AB - A 500 MHz NMR study of the reaction between 1-tetralone oxime and PdCl42- in CD3OD shows resonances attributable to a potential agostic intermediate prior to the formation of the insoluble cyclopalladated product which itself was characterised by X-ray crystallography. Calculated structural, spectroscopic, QTAIM, NBO and NCI analysis results obtained from density functional theory (DFT) calculations give a full description of the putative agostic intermediate [PdCl2(1-tetralone oxime)] (1) which is shown to include a previously unrecognised pi-electron density donation from the aromatic ring to the metal in close proximity to the agostic carbon atom. Changing the (N)-OH donor to (N)-OMe does not effect the magnitude of these interactions. (N)-OH and (N)-OMe acetophenone imines in which the aromatic ring has the potential to rotate show similar agostic and pi-electron donation to the alicyclic ring counterparts. 1 Tetralone which coordinates to the metal by a Pd-O bond that is much weaker than the Pd-N complexes has a slightly stronger agostic component and slightly weaker pi-electron donation than the oxime counterpart. PMID- 29125164 TI - Aminophosphine ligands as a privileged platform for development of antitumoral ruthenium(ii) arene complexes. AB - The rapid and modular synthesis of the aminophosphine core has been exploited as a tool for rapid development of antitumoral metallodrug candidates. Starting with a series of structurally diverse aminophosphines, all obtained in a single step from commercial amines, a family of Ru(ii)-cymene complexes have been generated and tested in vitro for anti-tumoral activity in a series of cell lines, including the platinum-resistant A2780R. Through this approach, Ru(ii) aminophosphine complexes have been identified with the IC50 value range as low as 10-0.8 MUM. Several biological assays were carried out to gain insight into the mechanism of action. Cell death by apoptosis and pH-independent action has been demonstrated. In addition, a selective cytotoxicity profile for tumoral cells over non-tumoral cells has been identified. Importantly, for the key candidates no loss of activity was observed when applied to the Pt-resistant A2780R, which highlights the potential utility of the bis-phospinoamine scaffold as an easily tunable auxiliary ligand core in both drug discovery and subsequently a logical design of new anticancer metal-containing drugs. The complexes are characterised by NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction. PMID- 29125165 TI - Syntheses and characterization of phosphonates and diphosphonates of molybdenum, A4[(MoO3)5(O3PR)2].xH2O, A2[Mo2O5(O3PR)2] and A2[Mo2O5(O3P-R-PO3)] (A = K, Rb, Cs, Tl, NH4). AB - Twenty new molybdenum phosphonates and diphosphonates have been synthesized and structurally characterized by single crystal and powder X-ray diffraction, CHN analyses, spectroscopic and thermal studies. Four of them are molecular phenyl- and benzyl-phosphonates containing discrete [(MoO3)5(O3PR)2]4- (R = Ph or CH2Ph) cyclic anions. The sixteen non-molecular compounds are layered isostructural phenylphosphonates, A2[Mo2O5(O3PPh)2] (A = NH4, Tl, Rb, Cs) and K1.5(H3O)0.5[Mo2O5(O3PPh)2] and the corresponding diphosphonate compounds with pillared anionic layers, A2[Mo2O5(O3P(CH2)3PO3)], A2[Mo2O5(O3P(CH2)4PO3)] and A2[Mo2O5(O3P(C6H4)PO3)]. The A+ ions reside in the interlayer region as well as in the cavities within the anionic layers. PMID- 29125166 TI - Applications and developments of on-chip biochemical sensors based on optofluidic photonic crystal cavities. AB - Photonic crystal (PC) cavities, which possess the advantages of compactness, flexible design, and suitability for integration in a lab-on-a-chip system, are able to distinguish slight variations in refractive index with only a small amount of analyte. Combined with the newly proposed optofluidic technology, PC cavity devices stimulate an emerging class of miniaturized and label-free biochemical sensors. In this review, an overview of optofluidic PC cavities based biochemical sensors is presented. First, the basic properties of the PC, as well as the sensing principle of the PC cavity, are discussed. Second, the applications of the sensors in detecting gas, liquid, and biomolecule concentrations are reviewed, with a focus on their structures, sensing principles, sensing properties, advantages, and disadvantages. Finally, the current challenges and future development directions of optofluidic PC-cavity based biochemical sensors are discussed. PMID- 29125167 TI - High-performance wearable strain sensors based on fragmented carbonized melamine sponges for human motion detection. AB - Strain sensors with a large strain sensing range and high sensitivity are in high demand due to their various potential applications ranging from human motion detection to soft robotics. In this study, high-performance strain sensors are developed by fragmenting carbonized melamine sponges that are commercially available. The strain sensors, based on fragmented carbonized melamine sponges (FCMS), demonstrate high sensitivity with a gauge factor (GF) of 18.7 at an FCMS density of 1.07 mg cm-2 and a large strain sensing range of up to 80%. As a comparison, the strain sensor based on unfragmented carbonized melamine sponges has only a GF of ~8.0 and limited stretchability (<7%). In situ tension tests indicate that the strain-response mechanism of the sensor is mainly ascribed to the reorientation of individual FCMS at low strains (<40%), while crack propagation dominates the strain-response behavior of the sensor at strains larger than 40%. The high sensitivity and large strain sensing range of the sensor, as well as the low-cost and scalable fabrication method, enable diverse applications. It can not only detect large-strain human arthrosis movements, but it also exhibits the capability to monitor subtle human physiological activity. PMID- 29125168 TI - Ferroelectric control of Rashba spin orbit coupling at the GeTe(111)/InP(111) interface. AB - GeTe is a prototypical compound of a new class of multifunctional materials, i.e., ferroelectric Rashba semiconductors (FRS). In the present work, by combining the first-principles calculations and Rashba model analysis, we reexamine Rashba spin-orbit coupling (SOC) in a GeTe(111) crystal and clarify its linear Rashba SOC strength. We further investigate Rashba SOC at the interface of a GeTe(111)/InP(111) superlattice and demonstrate the ferroelectric manipulation of Rashba SOC in detail. A large modulation of Rashba SOC is obtained, and surprisingly, we find that Rashba SOC does not monotonically increase with the increase of ferroelectric displacement, due to the parabola opening reversal of Rashba splitting bands. In addition, a reversal of the spin texture is realized by tuning the ferroelectric polarization. Our investigation provides a deep insight into the ferroelectric control of Rashba SOC, which is of great importance in FRS spin field effect transistors. PMID- 29125169 TI - Substrate-free copper nanoclusters exhibit super diamagnetism and surface based soft ferromagnetism. AB - Pure metallic copper nanoparticles free of any substrate were synthesized by the thermo-chemical reduction of copper acetate using triethanolamine as a reducing cum-protection agent. The structure and physical and magnetic properties of the Cu NPs were analysed physicochemically. Microscopic analysis reveals the formation of particles of size of 3-5 nm as seen by TEM but present as a large agglomeration as identified by SEM. A structure of Cu9 is predicted for the Cu NPs on the basis of investigations using XPS, MALDI, EPR, and magnetic measurements and supported by the prediction of DFT calculation from an earlier work. The most important findings come from magnetization studies which prove the existence of giant diamagnetism from the nanomer clusters of copper as well as the formation of two different ferromagnetic transitions at ~40 K and ~100 K, the latter two arising from the surface properties possibly due to thin films of CuO and/or the presence of TEOA giving rise to temperature dependent coercivity revealing them to be soft room temperature ferromagnets. The clusters of Cu NPs with the identified structure show temperature and field dependent giant diamagnetism which is about 29-39 times larger than the diamagnetism calculated from known and established atomic values. Though such enhanced diamagnetism has been predicted for noble metal clusters, experimental observation so far has been restricted to Au and Pt and this is probably the first report on substrate-free metallic copper clusters. PMID- 29125170 TI - Coupled flower-like Bi2S3 and graphene aerogels for superior sodium storage performance. AB - A hierarchically structured Bi2S3/graphene aerogel composite is constructed that shows excellent sodium storage properties. Specifically, the composite delivers a stable reversible capacity of 397 mA h g-1 at 100 mA g-1 after 50 cycles and 348 mA h g-1 at 1 A g-1 after 120 cycles. Furthermore, even at a high current density of 2 A g-1, a reversible capacity of 336 mA h g-1 is achieved. PMID- 29125171 TI - Nanomechanical clinical coagulation diagnostics and monitoring of therapies. AB - Clinical coagulation diagnostics often requires multiple tests. Coagulation times are a first indication of an abnormal coagulation process, such as a coagulation factor deficiency. To determine the specific deficient factor, additional immuno- and/or enzyme assays are necessary. Currently, every clinical laboratory has to normalize their assays (international normalized ratio, INR), and therefore, certain variability within the clinical analytics exists. We report a novel strategy for a quick, reliable and quantitative diagnosis of blood coagulation diseases (e.g. haemophilia) and for monitoring factor replacement and anticoagulant therapies (e.g. heparin treatment). We exploit nano-oscillations of microcantilevers for real-time measurements of the evolving blood plasma clot strength (viscosity). The sensors are oscillated at multiple high resonance mode numbers, in order to minimise the oscillation amplitude (a few nanometers), to provide direct internal control and to increase the quality factor. Along with the activated thromboplastin time (aPTT) and prothrombin time (PT) other parameters important for thrombosis diagnostics can be obtained, including the final clot strength and the fibrinolysis time. We demonstrate the dependence of the parameters on factor deficiencies and we diagnose a specific factor deficiency through an integrated and quantitative in situ immunoassay. This approach does not require continuous calibration since it delivers an absolute quantity (clot strength). The low sample volume required (a few MUl) and the ability to measure different parameters within the same test (PT, aPTT and global coagulation assay) make the presented technique a versatile point-of-care device for clinical coagulation diagnostics. PMID- 29125172 TI - Hierarchically interconnected porous scaffolds for phase change materials with improved thermal conductivity and efficient solar-to-electric energy conversion. AB - An ice-templating self-assembly strategy and a vacuum impregnation method were used to fabricate polyethylene glycol (PEG)/hierarchical porous scaffold composite phase change materials (PCMs). Hierarchically interconnected porous scaffolds of boron nitride (BN), with the aid of a small amount of graphene oxide (GO), endow the composite PCMs with high thermal conductivity, excellent shape stability and efficient solar-to-electric energy conversion. The formation of a three-dimensional (3D) thermally conductive pathway in the composites contributes to improving the thermal conductivity up to 2.36 W m-1 K-1 at a relatively low content of BN (ca. 23 wt%). This work provides a route for thermally conductive and shape-stabilized composite PCMs used as energy storage materials. PMID- 29125173 TI - alpha-Trifluoromethylated tertiary homoallylic amines: diastereoselective synthesis and conversion into beta-aminoesters, gamma- and delta-aminoalcohols, azetidines and pyrrolidines. AB - The diastereoselective addition of allyl zinc and allylindium derivatives to alpha-trifluoromethyl N-tert-butanesulfinyl hemiaminals, bench stable precursors of aryl and alkyl trifluoromethyl ketimines, allows the synthesis of homoallylic amines containing a tetrasubstituted carbon stereocentre bearing a trifluoromethyl group with good diastereoselectivities (up to dr > 99 : 1). This approach was also suitable for accessing chiral homoallylic amines bearing two contiguous stereocenters. The synthetic usefulness of N-tert-butanesulfinyl homoallylamines was illustrated by preparing various trifluoromethylated nitrogen containing bifunctional synthons (aminoesters, aminoalcohols) and small azaheterocycles (azetidines, pyrrolidines). PMID- 29125174 TI - Self-assembly of cubic colloidal particles at fluid-fluid interfaces by hexapolar capillary interactions. AB - Colloidal particles adsorbed at fluid-fluid interfaces can self-assemble, thanks to capillary interactions, into 2D ordered structures. Recently, it has been predicted by theoretical and numerical calculations [G. Soligno et al., Phys. Rev. Lett., 2016, 116, 258001] that cubes with smooth edges adsorbed at a flat fluid-fluid interface generate hexapolar capillary deformations that cause the particles to self-assemble into honeycomb and hexagonal lattices, at equilibrium and for Young's contact angle pi/2. Here we extend these results. Firstly, we show that capillary interactions induced by hexapolar deformations can drive the particles at the interface to form also thermodynamically-stable square lattices, in addition to honeycomb and hexagonal lattices. Then, we study the effects of tuning the particle shape on the particle self-assembly at the interface, considering, respectively, smooth-edge cubes, sharp-edge cubes, slightly truncated-edge cubes, and highly truncated-edge cubes. In our calculations, both capillary and hard-particle interactions are taken into account. We show that such variations in the particle shape significantly affect both qualitatively and quantitatively the self-assembly of the particles at the interface, and we sum up our results in the form of temperature-density phase diagrams. For example, using typical experimental parameters, our results show that only 4-to-5 nm sized sharp edge and smooth-edge cubes can self-assemble into a honeycomb lattice, while slightly and highly truncated-edge cubes can form a honeycomb lattice only if they have a 8-to-12 and 10-to-16 nm size, respectively, for the same experimental parameters. Also, our results show that the capillarity-induced square lattice phase is stable only for the smooth-edge and truncated-edge cubes, but not for the sharp-edge cubes. PMID- 29125175 TI - Short synthesis of polyfunctional sp3-rich threonine-derived morpholine scaffolds. AB - A convenient synthesis of novel complex morpholines was achieved by a two-step process involving a Petasis three-component coupling reaction of glycolaldehyde, organoboronic acid and different amines, followed by an acid- or base-mediated intramolecular cyclization. The use of threonine derivatives with glycolaldehyde in the Petasis reaction has been studied and successfully applied in the process, achieving morpholines with a higher fraction of sp3 carbon atoms compared to blockbuster drugs. PMID- 29125176 TI - HPLC-DAD-ESI-MS/MS analysis of fruits from Firmiana simplex (L.) and evaluation of their antioxidant and antigenotoxic properties. AB - OBJECTIVES: The secondary metabolites of the fruits of Firmiana simplex (L.) were analysed by LC-DAD-ESI-MS/MS; furthermore, we evaluated their antioxidant and antigenotoxic properties. METHODS: The antioxidant activity was investigated using the 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), the 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) and the ferric reducing antioxidant power (FRAP) assays. The antigenotoxic potential was determined via the comet assay. KEY FINDINGS: The ethyl acetate fraction (EtOAc) was analysed by LC-DAD-ESI-MS/MS: phenolic acids and flavonoids were the main polyphenols of the fruits. The EtOAc fraction yielded the highest content of polyphenols with 314.61 mg GAE/g extract, followed by 297.51, 153.75, 101.47, 97.19 for dichloromethane, butanol, methanol and water extracts, respectively. As expected, a strong correlation exists between the antioxidant activity of the investigated extracts and their total phenolic content. In the DPPH assay, the IC50 value of the most active EtOAc fraction was 6.79 MUg/ml, relative to 2.92 MUg/ml of the standard ascorbic acid. ABTS and FRAP assays supported the results of DPPH assay. Moreover, using the comet assay, we could show that the phenol rich EtOAc extract exhibits an antigenotoxic potential in human liver cancer cells (Hep-G2) treated with hydrogen peroxide (H2 O2 ) as a genotoxic agent. CONCLUSIONS: The fruits of Firmiana simplex may be a good natural source of antioxidant and antigenotoxic agents. PMID- 29125178 TI - Use of a light source to help identify the jugular vein in chelonians. PMID- 29125177 TI - Surgical management of impalement injuries to the trunk of dogs: a multicentre retrospective study. AB - OBJECTIVES: To review a large series of dogs referred for treatment of traumatic impalement injuries to the thorax and/or abdomen and to report aetiologies, injury characteristics, management and long-term outcomes. MATERIALS AND METHODS: Previously collected data on dogs that were surgically treated for impalement injuries to the trunk at six veterinary specialist referral institutions in the UK over an 11-year period were reviewed. Data included patient signalment, physiological variables, injury-specific variables, diagnostic imaging reports, surgical procedures undertaken, duration of hospitalisation, antibiotic use, complications and outcomes. Data were reported with summary statistics. RESULTS: Fifty-four dogs were included. Impalement occurred most frequently on wooden objects (n=34), and the thoracic cavity was most commonly penetrated (n=37). Computed tomography was sensitive and specific to identifying wooden material in 64% and 88% of cases (n=11), respectively. Thoracotomy was performed in 56%, coeliotomy in 20% and a foreign body or its fragments were retrieved during surgery in 37% of the cases. Complications occurred in 19 dogs (35%), and of these, 68% were minor and 32% major. The survival rate for thoracotomy cases was 93% (n=30). Overall long-term survival was 90%. CLINICAL SIGNIFICANCE: Despite the often dramatic presentation of impalement injuries, the majority of patients treated in the specialist referral setting can achieve excellent outcomes. These injuries require thorough diagnostic imaging and interpretation before adequate surgical exploration and management, augmented by anaesthesia and critical care during the peri- and postoperative periods; therefore stable patients should be referred to centres able to provide this type of care. PMID- 29125179 TI - The impact of sociodemography, diet, and body size on serum retinol in women 16 35 years of age: SANHANES-1. AB - To determine the current vitamin A status of a nationally representative sample of women aged 16-35 years, compare it with previous national data, and determine the impact of sociodemography, diet, and body size on vitamin A status, we performed secondary analysis of data on South African women who participated in the first South African National Health and Nutrition Examination Survey (SANHANES-1). Vitamin A status was assessed by serum retinol, and the findings are reported as means and prevalences with corresponding 95% confidence intervals. Overall, the age-standardized vitamin A deficiency prevalence was 11.7%, a decrease from previous national data, but serum retinol levels remained lower than in other developing countries. Overall, unweighted, multilevel, multivariate logistic regression showed that vitamin A deficiency was influenced by race only (odds ratio (OR) = 1.89, P = 0.031), while weighted multiple logistic regression for 16- to 18-year-olds showed that vitamin A deficiency was influenced by locality (OR = 9.83, P = 0.005) and household income (intermediate (OR = 0.2, P = 0.022) and upper (OR = 0.25, P = 0.049)). Despite the decreased prevalence, vitamin A deficiency remains a moderate public health problem in the country. Opportunities for targeted interventions have been identified. PMID- 29125181 TI - Acclimation of photosynthesis to lightflecks in tomato leaves: interaction with progressive shading in a growing canopy. AB - Plants in natural environments are often exposed to fluctuations in light intensity, and leaf-level acclimation to light may be affected by those fluctuations. Concurrently, leaves acclimated to a given light climate can become progressively shaded as new leaves emerge and grow above them. Acclimation to shade alters characteristics such as photosynthetic capacity. To investigate the interaction of fluctuating light and progressive shading, we exposed three-week old tomato (Solanum lycopersicum) plants to either lightflecks or constant light intensities. Lightflecks of 20 s length and 1000 MUmol m-2 s-1 peak intensity were applied every 5 min for 16 h per day, for 3 weeks. Lightfleck and constant light treatments received identical daily light sums (15.2 mol m-2 day-1 ). Photosynthesis was monitored in leaves 2 and 4 (counting from the bottom) during canopy development throughout the experiment. Several dynamic and steady-state characteristics of photosynthesis became enhanced by fluctuating light when leaves were partially shaded by the upper canopy, but much less so when they were fully exposed to lightflecks. This was the case for CO2 -saturated photosynthesis rates in leaves 2 and 4 growing under lightflecks 14 days into the treatment period. Also, leaf 2 of plants in the lightfleck treatment showed significantly faster rates of photosynthetic induction when exposed to a stepwise change in light intensity on day 15. As the plants grew larger and these leaves became increasingly shaded, acclimation of leaf-level photosynthesis to lightflecks disappeared. These results highlight continuous acclimation of leaf photosynthesis to changing light conditions inside developing canopies. PMID- 29125180 TI - Exosomes: biology, therapeutic potential, and emerging role in musculoskeletal repair and regeneration. AB - Exosomes are nanovesicles secreted from cells that play key roles in intercellular communication. They carry unique content derived from parental cells and are capable of transferring this cargo between cells. The role and function of exosomes largely depends on the origin and functional status of the parental cells. Emerging evidence indicates that exosomes are associated with biological processes and pathogenesis of certain diseases. These nanovesicles offer great potential as biomarkers, enabling the monitoring and diagnosis of various diseases in a noninvasive manner. Furthermore, as an efficient vehicle of biomolecular intercellular transfer, exosomes are under intensive investigation for their potential for drug delivery and carriers for gene therapy. Here, we first summarize the basic biology and function of exosomes, followed by a discussion of their clinical potential, including the use of exosomes for disease diagnosis, treatment, and drug delivery. The review will highlight the potential of exosomes derived from stem cells in regenerative medicine, with a focus on musculoskeletal tissues. We conclude by sharing our views on the challenges, opportunities, and future directions for the use of exosomes as a therapeutic treatment for the repair and regeneration of musculoskeletal tissues. PMID- 29125182 TI - Circulating microRNAs as potential biomarkers in myasthenia gravis patients. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that bind to specific mRNA targets and regulate a wide range of important biological processes within cells. Circulating miRNAs are released into the extracellular space and can be measured in most biofluids, including blood serum and plasma. Recently, circulating miRNAs have emerged as easily accessible markers in various body fluids with different profiles and quantities specific for different human disorders, including autoimmune diseases. In myasthenia gravis (MG), diagnostic tests such as titers of serum autoantibodies specific for either the acetylcholine receptor (AChR+ ) or muscle-specific tyrosine kinase (MuSK+ ) do not necessarily reflect disease progression, and there is a great need for reliable objective biomarkers to monitor the disease course and therapeutic response. Recent studies in AChR+ MG revealed elevated levels of the immuno-miRNAs miR-150-5p and miR-21-5p. Of particular importance, levels of miR-150-5p were lower in immunosuppressed patients and in patients with clinical improvement following thymectomy. In MuSK+ MG, another profile of circulating miRNAs was found, including upregulation of the let-7 family of miRNAs. Here, we summarize the potential role of circulating miRNAs as biomarkers in general and in MG, and highlight important considerations for the analysis of circulating miRNA. PMID- 29125183 TI - Ovarian surgery for symptom relief in women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine condition, affecting approximately one in 10 women. PCOS is defined by two of three features: oligo- or anovulation, clinical or biochemical hyperandrogenism or both, or polycystic ovaries.Women with PCOS can have a wide range of health problems, including infrequent and irregular periods, unwanted hair growth and acne, and subnormal fertility. Long-term health concerns include an increased risk of heart disease, diabetes and the development of precancerous disease of the womb. OBJECTIVES: To assess the effectiveness and harms of ovarian surgery as a treatment for symptomatic relief of hirsutism, acne and menstrual irregularity in PCOS. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL, MEDLINE, Embase and PsycINFO (from inception to 17 October 2016). We handsearched citation lists, registers of ongoing trials and conference proceedings. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of women undergoing ovarian drilling in comparison to no treatment, medical treatment, or other forms of surgical treatment for the symptoms of PCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary outcome measures were improvement in menstrual regularity and androgenic symptoms of PCOS (hirsutism, acne); the secondary outcome measures included harms, change of body mass index (BMI), waist circumference, androgen levels, metabolic measures and quality of life. We assessed the quality of the evidence using GRADE methods. MAIN RESULTS: We included 22 RCTs (2278 women analyzed) of participants with PCOS and symptoms of acne, hirsutism or irregular menstrual cycles, all of which included laparoscopic ovarian drilling (LOD) as an intervention.Two studies reported their funding source (Farquhar 2002 - supported in part by the Auckland Medical Research Foundation; Sarouri 2015 - the authors thank the Vice Chancellor for Research of Guilan University of Medical Sciences for funding this project).The quality of the evidence ranged from very low to moderate quality. The main limitations were imprecision associated with the low number of studies, inconsistency and risk of bias associated with the inability to blind participants. There were too few studies to assess risk of publication bias. Menstrual RegularityTwo studies compared LOD versus metformin (n=226) but no conclusions could be drawn with regard to menstrual regularity, as their findings were inconsistent and they were unsuitable for pooling. There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when LOD was compared with medical treatment including metformin + clomiphene (OR 1.02, 95% CI 0.64 to 1.64, 2 studies, 332 women, I2 = 13%, low-quality evidence), letrozole (OR 1.08, 95% CI 0.64 to 1.84, 1 study, 260 women, low-quality evidence), or metformin + letrozole (OR 0.95, 95% CI 0.49 to 1.81, 1 study, 146 women, low-quality evidence). However, one study reported that LOD was superior to gonadotrophin (OR 19.2, 95% CI 3.17 to 116.45, 1 study, 35 women, very low-quality evidence).There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when bilateral unipolar LOD was compared to unilateral LOD (OR 1.51, 95% CI 0.62 to 3.71, 2 studies, 104 women, I2 = 0%, moderate-quality evidence), transvaginal ultrasound-guided LOD (OR 1.23, 95% CI 0.64 to 2.37, 1 study, 147 women, low-quality evidence), LOD using adjusted thermal dose in accordance with the ovarian volume (OR 0.42, 95% CI 0.16 to 1.14, 1 study, 115 women, low-quality evidence) or bipolar LOD (OR 1.00, 95% CI 0.05 to 18.57, 1 study, 18 women, low-quality evidence).Four to five punctures per ovary may improve the rate of women reporting menstrual regularity compared with two or fewer (OR 16.04, 95% CI 4.19 to 61.34, 2 studies, 73 women, I2 = 0%, low-quality evidence). Androgenic SymptomsThere was probably little or no difference in improvement in androgenic symptoms when LOD was compared to metformin (OR 1.00, 95% CI 0.42 to 2.37, 1 study, 126 women, moderate-quality evidence) or gonadotrophins; acne (OR 3.20, 95% CI 0.33 to 30.94, 1 study, 25 women, low quality evidence), hirsutism (OR 2.31, 95% CI 0.22 to 23.89, 1 study, 25 women, low-quality evidence).There appeared to be little or no difference in improvement of androgenic symptoms when LOD was compared to transvaginal ultrasound-guided LOD, with respect to hirsutism (OR 1.09, 95% CI 0.30 to 3.91, 1 study, 39 women, low-quality evidence) or acne (OR 0.84, 95% CI 0.20 to 3.50, 1 study, 31 women, low-quality evidence). HarmsLOD was associated with fewer gastrointestinal side effects than metformin plus clomiphene (OR 0.05, 95% CI 0.01 to 0.36, 2 studies, 332 women, I2 = 0%, moderate-quality evidence). One study suggested little or no difference in rates of ovarian hyperstimulation syndrome between LOD and gonadotrophins (OR 0.08, 95% CI 0.00 to 1.61, 1 study, 33 women, low-quality evidence).There were fewer adhesions with transvaginal hydrolaparoscopy compared to LOD (OR 0.10, 95% CI 0.05 to 0.18, 1 study, 246 women, moderate-quality evidence). There appeared to be little or no difference in adhesions when variable energy LOD was compared with standard LOD (OR 0.96, 95% CI 0.32 to 2.88, 1 study, 64 women, low-quality evidence). Another study (44 women) reported that none of the women who returned for surgery following either traditional or unilateral LOD were found to have adhesions. AUTHORS' CONCLUSIONS: There was no clear evidence that LOD improves menstrual regularity or the androgenic symptoms of PCOS, compared to most of the medical treatments used in the included studies. LOD was associated with fewer gastrointestinal side effects compared to metformin and clomiphene.There was also no clear evidence of different effectiveness between types of LOD, except that LOD with four to five punctures per ovary may be more effective than two or fewer punctures. There was little evidence comparing LOD with different types of surgery, although one study concluded that transvaginal hydrolaparoscopy had a lower risk of adhesions than LOD.There was evidence from one small study of benefit from LOD compared to gonadotrophins for menstrual regulation. However, gonadotrophins are seldom used for this indication. PMID- 29125185 TI - Thymus involvement in early-onset myasthenia gravis. AB - It has long been established that the thymus plays a central role in autoimmune myasthenia gravis (MG) because of either thymoma or thymic hyperplasia of lymphoproliferative origin. In this review, we discuss thymic changes associated with thymic hyperplasia and their implications in the development of an autoimmune response against the acetylcholine receptor (AChR).The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development. As thymic epithelial cells or myoid cells express AChR, a specific antigen presentation can easily occur within the thymus in the presence of recruited peripheral cells, such as B cells and T follicular helper cells. How the thymus turns into a TLO is not known, but local inflammation seems mandatory. Interferon (IFN)-beta is overexpressed in MG thymus and could orchestrate thymic changes associated with MG. Knowledge about how IFN beta is induced in MG thymus and why its expression is sustained even long after disease onset would be of interest in the future to better understand the etiological and physiopathological mechanisms involved in autoimmune MG. PMID- 29125184 TI - Hepatic and hippocampal cytochrome P450 enzyme overexpression during spontaneous recurrent seizures. AB - OBJECTIVE: Available evidence points to a role of cytochrome P450 (Cyp) drug biotransformation enzymes in central nervous system diseases, including epilepsy. Deviations in drug pharmacokinetic profiles may impact therapeutic outcomes. Here, we ask whether spontaneous recurrent seizure (SRS) activity is sufficient to modulate the expression of major Cyp enzymes in the liver and brain. METHODS: Unilateral intrahippocampal (IH) kainic acid (KA) injections were used to elicit nonconvulsive status epilepticus (SE), epileptogenesis, and SRS, as monitored by video-electroencephalography. Intraperitoneal (IP) KA injection was used to trigger generalized tonic-clonic SE. KA-injected mice and sham controls were sacrificed at 24-72 hours and 1 week post-SE (IH or IP KA), and during the chronic stage (SRS; 6 weeks post-IH KA). Liver and brain tissues were processed for histology, real-time quantitative polymerase chain reaction, Western blot, or microsomal enzymatic assay. Cyp2e1, Cyp3a13, glial fibrillary acidic protein (GFAP), IBA1, xenobiotic nuclear receptors nr1i2 (PXR), nr1i3 (CAR) and nr3c1 (glucocorticoid receptor [GR]) expression was examined. Serum samples were obtained to assay corticosterone levels, a GR activator. RESULTS: A significant increase of Cyp3a13 and Cyp2e1 transcript level and protein expression was found in the liver and hippocampi during SRS, as compared to control mice. In the ipsilateral hippocampus, Cyp2e1 and Cyp3a protein upregulation during SRS positively correlated to GFAP expression. GFAP+ , and not IBA1+ , cells colocalized with Cyp2e1 or Cyp3a expression. In the liver, a trend increase in Cyp3a microsomal activity was found during SRS as compared to control mice. The transcript levels of the Cyp upstream regulators GR, xenobiotic nr1i2, and nr1i3 receptors were unchanged at SRS. Corticosterone levels, a GR ligand, were increased in the blood post-SE. SIGNIFICANCE: SRS modifies Cyp expression in the liver and the hippocampus. Nuclear receptors or inflammatory pathways are candidate mechanisms of Cyp regulation during seizures. PMID- 29125186 TI - Evolutionary dynamics of interactions between plants and their enemies: comparison of herbivorous insects and pathogens. AB - Plants colonized land over 400 million years ago. Shortly thereafter, organisms began to consume terrestrial plant tissue as a nutritional resource. Most plant enemies are plant pathogens or herbivores, and they impose natural selection for plants to evolve defenses. These traits generate selection pressures on enemies. Coevolution between terrestrial plants and their enemies is an important element of the evolutionary history of both groups. However, coevolutionary studies of plant-pathogen interactions have tended to focus on different research topics than plant-herbivore interactions. Specifically, studies of plant-pathogen interactions often adopt a "gene-for-gene" conceptual framework. In contrast, studies of plants and herbivores often investigate escalation or elaboration of plant defense and herbivore adaptations to overcome it. The main exceptions to the general pattern are studies that focus on small, sessile herbivores that share many features with plant pathogens, studies that incorporate both herbivores and pathogens into a single investigation, and studies that test aspects of Thompson's geographic mosaic theory for coevolution. We discuss the implications of these findings for future research. PMID- 29125187 TI - First analysis by MALDI-TOF MS technique of Chryseobacterium species relevant to aquaculture. PMID- 29125188 TI - The mouse passive-transfer model of MuSK myasthenia gravis: disrupted MuSK signaling causes synapse failure. AB - While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies against muscle-specific kinase (MuSK). MuSK is a transmembrane tyrosine kinase found in the postsynaptic membrane of the neuromuscular junction. During development, MuSK serves as a signaling hub, coordinating the alignment of the pre- and postsynaptic components of the synapse. Adult mice that received repeated daily injections of IgG from anti-MuSK+ myasthenia gravis patients developed muscle weakness, associated with neuromuscular transmission failure. MuSK autoantibodies are predominantly of the IgG4 type. They suppress the kinase activity of MuSK and the phosphorylation of target proteins in the postsynaptic membrane. Loss of postsynaptic acetylcholine receptors is the primary cause of neuromuscular transmission failure. MuSK autoantibodies also disrupt the capacity of the motor nerve terminal to adaptively increase acetylcholine release in response to the reduced postsynaptic responsiveness to acetylcholine. The passive IgG transfer model of MuSK myasthenia gravis has been used to test candidate treatments. Pyridostigmine, a first-line cholinesterase inhibitor drug, exacerbated the disease process, while 3,4-diaminopyridine and albuterol were found to be beneficial in this mouse model. PMID- 29125189 TI - Neoplasia in goldlined seabream, Rhabdosargus sarba (Forsskal, 1775). PMID- 29125190 TI - Lambert-Eaton myasthenic syndrome: mouse passive-transfer model illuminates disease pathology and facilitates testing therapeutic leads. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2-4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low. LEMS further reduces this low probability such that transmission is no longer effective at triggering a muscle contraction. The LEMS-mediated attack reduces the number of presynaptic calcium channels, disorganizes transmitter release sites, and results in the homeostatic upregulation of other calcium channel types. Symptomatic treatment is focused on increasing the probability of release from dysfunctional release sites. Current treatment uses the potassium channel blocker 3,4-diaminopyridine (DAP) to broaden the presynaptic action potential, providing more time for calcium channels to open. Current research is focused on testing new calcium channel gating modifiers that work synergistically with DAP. PMID- 29125191 TI - Dual-flow-RootChip reveals local adaptations of roots towards environmental asymmetry at the physiological and genetic levels. AB - Roots grow in highly dynamic and heterogeneous environments. Biological activity as well as uneven nutrient availability or localized stress factors result in diverse microenvironments. Plants adapt their root morphology in response to changing environmental conditions, yet it remains largely unknown to what extent developmental adaptations are based on systemic or cell-autonomous responses. We present the dual-flow-RootChip, a microfluidic platform for asymmetric perfusion of Arabidopsis roots to investigate root-environment interactions under simulated environmental heterogeneity. Applications range from investigating physiology, root hair development and calcium signalling upon selective exposure to environmental stresses to tracing molecular uptake, performing selective drug treatments and localized inoculations with microbes. Using the dual-flow RootChip, we revealed cell-autonomous adaption of root hair development under asymmetric phosphate (Pi) perfusion, with unexpected repression in root hair growth on the side exposed to low Pi and rapid tip-growth upregulation when Pi concentrations increased. The asymmetric root environment further resulted in an asymmetric gene expression of RSL4, a key transcriptional regulator of root hair growth. Our findings demonstrate that roots possess the capability to locally adapt to heterogeneous conditions in their environment at the physiological and transcriptional levels. Being able to generate asymmetric microenvironments for roots will help further elucidate decision-making processes in root-environment interactions. PMID- 29125193 TI - Exposure to a specific time-varying electromagnetic field inhibits cell proliferation via cAMP and ERK signaling in cancer cells. AB - Exposure to specific electromagnetic field (EMF) patterns can affect a variety of biological systems. We have shown that exposure to Thomas-EMF, a low-intensity, frequency-modulated (25-6 Hz) EMF pattern, inhibited growth and altered cell signaling in malignant cells. Exposure to Thomas-EMF for 1 h/day inhibited the growth of malignant cells including B16-BL6 mouse melanoma cells, MDA-MB-231, MDA MB-468, BT-20, and MCF-7 human breast cancer and HeLa cervical cancer cells but did not affect non-malignant cells. The Thomas-EMF-dependent changes in cell proliferation were mediated by adenosine 3',5'-cyclic monophosphate (cAMP) and extracellular-signal-regulated kinase (ERK) signaling pathways. Exposure of malignant cells to Thomas-EMF transiently changed the level of cellular cAMP and promoted ERK phosphorylation. Pharmacologic inhibitors (SQ22536) and activators (forskolin) of cAMP production both blocked the ability of Thomas-EMF to inhibit cell proliferation, and an inhibitor of the MAP kinase pathway (PD98059) was able to partially block Thomas-EMF-dependent inhibition of cell proliferation. Genetic modulation of protein kinase A (PKA) in B16-BL6 cells also altered the effect of Thomas-EMF on cell proliferation. Cells transfected with the constitutively active form of PKA (PKA-CA), which interfered with ERK phosphorylation, also interfered with the Thomas-EMF effect on cell proliferation. The non-malignant cells did not show any EMF-dependent changes in cAMP levels, ERK phosphorylation, or cell growth. These data indicate that exposure to the specific Thomas-EMF pattern can inhibit the growth of malignant cells in a manner dependent on contributions from the cAMP and MAP kinase pathways. Bioelectromagnetics. 39;217 230, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29125194 TI - Amyotrophic lateral sclerosis-A case report and mechanistic review of the association with toluene and other volatile organic compounds. AB - Unmasking of latent neurodegenerative disease has been reported following exposure to chemicals that share one or more mechanisms of action in common with those implicated in the specific disease. For example, unmasking of latent Parkinson's disease (PD) has been associated with exposure to anti-dopaminergic agents, while the progression of pre-existing mild cognitive impairment and unmasking of latent Alzheimer's disease has been associated with exposure to general anesthetic agents which promote Abeta protein aggregation. This literature review and clinical case report about a 45-year-old man with no family history of motor neuron disease who developed overt symptoms of a neuromuscular disorder in close temporal association with his unwitting occupational exposure to volatile organic compounds (VOCs) puts forth the hypothesis that exposure to VOCs such as toluene, which disrupt motor function and increase oxidative stress, can unmask latent ALS type neuromuscular disorder in susceptible individuals. PMID- 29125192 TI - Long-term outcomes among 2-year survivors of autologous hematopoietic cell transplantation for Hodgkin and diffuse large b-cell lymphoma. AB - BACKGROUND: Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL); however, long-term outcomes are not well described. METHODS: This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression free for >=2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years. RESULTS: The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4 fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population. CONCLUSIONS: Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications. Cancer 2018;124:816-25. (c) 2017 American Cancer Society. PMID- 29125195 TI - Molecular dynamics simulation of liquid water and ice nanoclusters using a new effective HFD-like model. AB - We have determined a new two-body interaction potential of water by the inversion of viscosity collision integrals of water vapor and fitted to achieve the Hartree fock dispersion-like (HFD-like) potential function. The calculated two-body potential generates the thermal conductivity, viscosity, and self-diffusion coefficient of water vapor in an excellent accordance with experimental data at wide temperature ranges. We have also used a new many-body potential as a function of temperature and density with the HFD-like pair-potential of water to improve the two-body properties better than the SPC, SPC/E, TIP3P, and TIP4P models. We have also used the new corrected potential to simulate the configurational energy and the melting temperatures of the (H2 O)500 , (H2 O)864 , (H2 O)2048 , and (H2 O)6912 ice nanoclusters in good agreement with the previous simulation data using the TIP4P model. The extrapolated melting point at the bulk limit is also in better agreement with the experimental bulk data. The self-diffusion coefficients for the ice nanoclusters also simulated at different temperatures. (c) 2017 Wiley Periodicals, Inc. PMID- 29125196 TI - An interacting quantum atom study of model SN 2 reactions (X- ...CH3 X, X = F, Cl, Br, and I). AB - The quantum chemical topology method has been used to analyze the energetic profiles in the X- + CH3 X -> XCH3 + X- SN 2 reactions, with X = F, Cl, Br, and I. The evolution of the electron density properties at the BCPs along the reaction coordinate has been analysed. The interacting quantum atoms (IQA) method has been used to evaluate the intra-atomic and interatomic energy variations along the reaction path. The different energetic terms have been examined by the relative energy gradient method and the ANANKE program, which enables automatic and unbiased IQA analysis. Four of the six most important IQA energy contributions were needed to reproduce the reaction barrier common to all reactions. The four reactions considered share many common characteristics but when X = F a number of particularities occur. (c) 2017 Wiley Periodicals, Inc. PMID- 29125197 TI - IEI-EMF provocation case studies: A novel approach to testing sensitive individuals. AB - The etiology of Idiopathic Environmental Intolerance attributed to Electromagnetic Fields (IEI-EMF) is controversial. While the majority of studies have indicated that there is no relationship between EMF exposure and symptoms reported by IEI-EMF sufferers, concerns about methodological issues have been raised. Addressing these concerns, the present experiment was designed as a series of individual case studies to determine whether there is a relationship between radiofrequency-electromagnetic field (RF-EMF) exposure and an IEI-EMF individual's self-reported symptoms. Three participants aged 44-64 were tested during a series of sham and active exposure trials (2 open-label trials; 12 randomized, double-blind, counterbalanced trials), where symptom severity and exposure detection were scored using 100 mm visual analogue scales. The RF-EMF exposure was a 902-928 MHz spread spectrum digitally modulated signal with an average radiated power output of 1 W (0.3 W/m2 incident power density at the participant). In the double-blind trials, no significant difference in symptom severity or exposure detection was found for any of the participants between the two conditions. Belief of exposure strongly predicted symptom severity score for all participants. Despite accounting for several possible limitations, the present experiment failed to show a relationship between RF-EMF exposure and an IEI-EMF individual's symptoms. Bioelectromagnetics. 39:132-143, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29125199 TI - Evaluation of MESSAGE communication strategy combined with group reminiscence therapy on elders with mild cognitive impairment in long-term care facilities. AB - OBJECTIVE: This study aims to evaluate combined effects of MESSAGE communication strategy and group reminiscence therapy (GRT) on elders with mild cognitive impairment (MCI) in long-term care facilities in Changchun, China. METHODS: This study is a nonrandomized controlled trial. Subjects included 60 elders with MCI. Participants were divided into intervention (MESSAGE communication strategy combined with GRT) and control groups (without any intervention). Primary outcomes comprised cognitive function and quality of life of elderly people, as measured by the Beijing version of the Montreal Cognitive Assessment and the Chinese (mainland) version of Short-Form 36 Health Survey assessment. RESULTS: We observed significant changes in cognitive function with mean difference of 1.962 after 12 weeks (P = .000; 95% confidence interval [CI] = 1.341, 2.582), delayed memory dimension of 1.115 (P = .003; 95% CI = 0.417, 1.813). The intervention group exhibited the following improvements: general health of 14.731 (P = .000; 95% CI = 8.511, 20.951), mental health of 21.038 (P = .000; 95% CI = 17.301, 24.776), role-emotional of 26.925 (P = .003; 95% CI = 10.317, 45.533), and vitality of 14.231 (P = .000; 95% CI = 10.084, 18.377). CONCLUSIONS: Using a sample of Chinese elderly people with MCI and residing in long-term care facilities, we concluded that application of MESSAGE communication strategy combined with GRT resulted in improved cognitive function and quality of life. PMID- 29125198 TI - Redox-Active Ligand-Assisted Two-Electron Oxidative Addition to Gallium(II). AB - The reaction of digallane (dpp-bian)Ga-Ga(dpp-bian) (2) (dpp-bian=1,2-bis[(2,6 diisopropylphenyl)imino]acenaphthene) with allyl chloride (AllCl) proceeded by a two-electron oxidative addition to afford paramagnetic complexes (dpp bian)Ga(eta1 -All)Cl (3) and (dpp-bian)(Cl)Ga-Ga(Cl)(dpp-bian) (4). Treatment of complex 4 with pyridine induced an intramolecular redox process, which resulted in the diamagnetic complex (dpp-bian)Ga(Py)Cl (5). In reaction with allyl bromide, complex 2 gave metal- and ligand-centered addition products (dpp bian)Ga(eta1 -All)Br (6) and (dpp-bian-All)(Br)Ga-Ga(Br)(dpp-bian-All) (7). The reaction of digallane 2 with Ph3 SnNCO afforded (dpp-bian)Ga(SnPh3 )2 (8) and (dpp-bian)(NCO)Ga-Ga(NCO)(dpp-bian) (9). Treatment of GaCl3 with (dpp-bian)Na in diethyl ether resulted in the formation of (dpp-bian)GaCl2 (10). Diorganylgallium derivatives (dpp-bian)GaR2 (R=Ph, 11; tBu, 14; Me, 15; Bn, 16) and (dpp bian)Ga(eta1 -All)R (R=nBu, 12; Cp, 13) were synthesized from complexes 3, 10, Bn2 GaCl, or tBu2 GaCl by salt metathesis. The salt elimination reaction between (dpp-bian)GaI2 (17) and tBuLi was accompanied by reduction of both the metal and the dpp-bian ligand, which resulted in digallane 2 as the final product. Similarly, the reaction of complex 10 with MentMgCl (Ment=menthyl) proceeded with reduction of the dpp-bian ligand to give the diamagnetic complex [(dpp-bian)GaCl2 ][Mg2 Cl3 (THF)6 ] (18). Compounds 11, 12, 13, 15, and 16 were thermally robust, whereas compound 14 decomposed when heated at reflux in toluene to give complex (dpp-bian-tBu)GatBu2 (19). Both complexes 7 and 19 contain R-substituted dpp-bian ligand: in the former compound the allyl group was attached to the imino-carbon atom, whereas in complex 19, the tBu group was situated on the naphthalene ring. Crystal structures of complexes 3, 8, 9, 10, 13, 14, 18, and 19 were determined by single-crystal X-ray analysis. The presence of dpp-bian radical anions in 3, 6, 8, and 10-16 was determined by ESR spectroscopy. PMID- 29125200 TI - Refreshing Rubbers as Customized Photothermal Conversion Materials through Post Darkening Modeling Production. AB - Organic conjugated polymers with low energy bandgaps are emerging as a particular class of near-infrared (NIR) photothermal conversion materials. However, these polymers routinely possess high phase transition temperatures due to the rigid skeleton and strong intermolecular interactions. Conjugated polymers can rarely be thermally processed at low temperature, especially below 100 degrees C. This work formulates a concept of post-darkening modeling production (p-DMP) by which the thermoplastic non-conjugated trans-polyisoprene (TPI) is refreshed into a photothermal conversion material with high light use efficiency. Two steps, including the customizable shaping at low temperature and iodine vapor-tailored "darkening", ensure the ease of preparing photothermal conversion devices with desirable topologies. A few characterizations, with the combination of density functional theory (DFT) calculations, provide reasonable explanations for understanding the "darkening" process of TPI in iodine atmosphere. In particular, the p-DMP is successfully extended to three-dimension (3D) printing, opening an avenue to fabricate personalized photothermal products, for example, a sunlight directed physiotherapy device for healthcare of articular tissues. PMID- 29125201 TI - Protein Recognition by Functionalized Sulfonatocalix[4]arenes. AB - The interactions of two mono-functionalized sulfonatocalix[4]arenes with cytochrome c were investigated by structural and thermodynamic methods. The replacement of a single sulfonate with either a bromo or a phenyl substituent resulted in altered recognition of cytochrome c as evidenced by X-ray crystallography. The bromo-substituted ligand yielded a new binding mode in which a self-encapsulated calixarene dimer contributed to crystal packing. This ligand also formed a weak halogen bond with the protein. The phenyl-substituted ligand was bound to Lys4 of cytochrome c, in a 1.7 A resolution crystal structure. A dimeric packing arrangement mediated by ligand-ligand contacts in the crystal suggested a possible assembly mechanism. The different protein recognition properties of these calixarenes are discussed. PMID- 29125202 TI - Catalyst- and Supporting-Electrolyte-Free Electrosynthesis of Benzothiazoles and Thiazolopyridines in Continuous Flow. AB - A catalyst- and supporting electrolyte-free method for electrochemical dehydrogenative C-S bond formation in continuous flow has been developed. A broad range of N-arylthioamides have been converted to the corresponding benzothiazoles in good to excellent yields and with high current efficiencies. This transformation is achieved using only electricity and laboratory grade solvent, avoiding degassing or the use of inert atmosphere. This work highlights three advantages of electrochemistry in flow, which is (i) a supporting electrolyte free reaction, (ii) an easy scale-up of the reaction without the need for a larger reactor and, (iii) the important and effective impact of having a good mixing of the reaction mixture, which can be achieved effectively with the use of flow systems. This clearly improves the reported methods for the synthesis of benzothiazoles. PMID- 29125204 TI - A Molecular Barium Hydrido Complex Stabilized by a Super-Bulky Hydrotris(pyrazolyl)borate Ligand. AB - Hydrogenolysis of the scorpionate-supported barium alkyl complex (TpAd,iPr )Ba[CH(SiMe3 )2 ](THF) (TpAd,iPr =hydrotris(3-adamantyl-5-isopropyl pyrazolyl)borate) afforded the dinuclear barium hydrido complex [(TpAd,iPr )Ba(MU H)]2 (2), which was characterized by NMR spectroscopy and single-crystal X-ray analysis. Exposure of 2 with 1 atm of CO resulted in a reductive coupling process to form the cis-ethendiolate dianion (3). Reaction of 2 with one equivalent of PhC=C-C=CPh gave barium 1,4-diphenyl-2-butyne-1,4-diyl complex {[(TpAd,iPr )Ba]2 (PhCH-C=C-CHPh) (4). PMID- 29125203 TI - Characterization of chalcogen bonding interactions via an in-depth conceptual quantum chemical analysis. AB - The chalcogen bond has been acknowledged as an influential noncovalent interaction (NCI) between an electron-deficient chalcogen (donor) and a Lewis base (acceptor). This work explores the main features of chalcogen bonding through a large-scale computational study on a series of donors and acceptors spanning a wide range in strength and character of this type of bond: (benzo)chalcogenadiazoles (with Ch = Te/Se/S) versus halides and neutral Lewis bases with O, N, and C as donor atoms. We start from Pearson's hard and soft acids and bases (HSAB) principle, where the hard nature of the chalcogen bond is quantified through the molecular electrostatic potential and the soft nature through the Fukui function. The sigma-holes are more pronounced when going down in the periodic table and their directionality matches the structural orientation of donors and acceptors in the complexes. The Fukui functions point toward an n >sigma*-type interaction. The initial conjectures are further scrutinized using quantum mechanical methods, mostly relating to the systems' electron density. A Ziegler-Rauk energy decomposition analysis shows that electrostatics plays a distinctly larger role for the soft halides than for the hard, uncharged acceptors, associated with the softness matching within the HSAB principle. The natural orbital for chemical valence analysis confirms the n->sigma* electron donation mechanism. Finally, the electron density and local density energy at the bond critical point in the quantum theory of atoms in molecules study and the position of the spikes in the reduced density gradient versus density plot in the NCI theory situate the chalcogen bond in the same range as strong hydrogen bonds. (c) 2017 Wiley Periodicals, Inc. PMID- 29125205 TI - Reconstructing pectoral appendicular muscle anatomy in fossil fish and tetrapods over the fins-to-limbs transition. AB - The question of how tetrapod limbs evolved from fins is one of the great puzzles of evolutionary biology. While palaeontologists, developmental biologists, and geneticists have made great strides in explaining the origin and early evolution of limb skeletal structures, that of the muscles remains largely unknown. The main reason is the lack of consensus about appendicular muscle homology between the closest living relatives of early tetrapods: lobe-finned fish and crown tetrapods. In the light of a recent study of these homologies, we re-examined osteological correlates of muscle attachment in the pectoral girdle, humerus, radius, and ulna of early tetrapods and their close relatives. Twenty-nine extinct and six extant sarcopterygians were included in a meta-analysis using information from the literature and from original specimens, when possible. We analysed these osteological correlates using parsimony-based character optimization in order to reconstruct muscle anatomy in ancestral lobe-finned fish, tetrapodomorph fish, stem tetrapods, and crown tetrapods. Our synthesis revealed that many tetrapod shoulder muscles probably were already present in tetrapodomorph fish, while most of the more-distal appendicular muscles either arose later from largely undifferentiated dorsal and ventral muscle masses or did not leave clear correlates of attachment in these taxa. Based on this review and meta-analysis, we postulate a stepwise sequence of specific appendicular muscle acquisitions, splits, and fusions that led from the ancestral sarcopterygian pectoral fin to the ancestral tetrapod forelimb. This sequence largely agrees with previous hypotheses based on palaeontological and comparative work, but it is much more comprehensive in terms of both muscles and taxa. Combined with existing information about the skeletal system, our new synthesis helps to illuminate the genetic, developmental, morphological, functional, and ecological changes that were key components of the fins-to-limbs transition. PMID- 29125206 TI - A comparative analysis and guide to virtual reality robotic surgical simulators. AB - BACKGROUND: Since the US Food and Drug Administration approved robotically assisted surgical devices for human surgery in 2000, the number of surgeries utilizing this innovative technology has risen. In 2015, approximately 650 000 robot-assisted procedures were performed worldwide. Surgeons must be properly trained to safely transition to using such innovative technology. Multiple virtual reality robotic simulators are now commercially available for educational and training purposes. There is a need for comparative evaluations of these simulators to aid users in selecting an appropriate device for their purposes. METHODS: We conducted a comparison of the design and capabilities of all dedicated simulators of the da Vinci robot - the da Vinci Skills Simulator (dVSS), dV-Trainer (dVT), Robotic Skills Simulators (RoSS) and the RobotiX Mentor. This paper provides the base specifications of the hardware and software, with an emphasis on the training capabilities of each system. RESULTS: Each simulator contains a large number of training exercises for skills development: dVSS n = 40, dVT n = 65, RoSS n = 52, RobotiX Mentor n = 31. All four offer 3D visual images but use different display technologies. The dVSS leverages the real robotic surgical console to provide visualization, hand controls and foot pedals. The dVT, RoSS and RobotiX Mentor created simulated versions of all of these control systems. Each includes systems management services that allow instructors to collect, export and analyze the scores of students using the simulators. CONCLUSIONS: This study provides comparative information on the four simulators' functional capabilities. Each device offers unique advantages and capabilities for training robotic surgeons. Each has been the subject of validation experiments, which have been published in the literature. But those do not provide specific details on the capabilities of the simulators, which are necessary for an understanding sufficient to select the one best suited for an organization's needs. This article provides comparative information to assist with that type of selection. PMID- 29125207 TI - Specificity of Donor Structures for endo-beta-N-Acetylglucosaminidase-Catalyzed Transglycosylation Reactions. AB - To demonstrate the structural specificity of the glycosyl donor for the transglycosylation reaction by using endo-beta-N-acetylglucosaminidase from Mucor hiemalis (endo-M), a series of tetrasaccharide oxazoline derivatives was synthesized. These derivatives correspond to the core structure of an asparagine linked glycoprotein glycan with a beta-mannose unit of a non-natural-type monosaccharide, including beta-glucose, beta-galactose, and beta-talose in place of the beta-mannose moiety. The transglycosylation activity of wildtype (WT) endo M and two mutants, N175Q and N175A, was examined by using these tetrasaccharide donors with p-nitrophenyl N-acetylglucosaminide (GlcNAc-pNp). The essential configuration of the hydroxy group for the transglycosylation reaction was determined. On the basis of these results, the transglycosylation reaction was investigated by using chemically modified donors, and transglycosylated products were successfully obtained. PMID- 29125208 TI - Understanding the distressed prostate cancer patient: Role of personality. AB - OBJECTIVE: To evaluate the relationship between personality and emotional distress in prostate cancer. Neuroticism and introversion were hypothesized to be associated with clinically significant symptoms of emotional distress, including depression, anxiety, and suicidal ideation. METHODS: Men with a history of prostate cancer (n = 212) completed an NIH-funded cross-sectional study using well-validated measures of personality, depression, anxiety, and suicidal ideation. Covariates were age, education, time since diagnosis, comorbidity, and presence of metastases. RESULTS: Emotional distress was reported by 37% of participants, including depression (23%), anxiety (15%), and suicidal ideation (10%). As hypothesized, men who were more neurotic were more likely to report emotional distress (44.5% vs 26.9%; OR = 2.78, P = .004), depression (31.9% vs 11.8%; OR = 4.23, P = .001), and suicidal ideation (29.4% vs 9.7%; OR = 4.15, P = .001). Introverts were more likely to report emotional distress (45.2% vs 28.7%; OR = 2.32, P = .012) and depression (30.8% vs 15.7%; OR = 2.57, P = .014). Men with metastases were more likely to report emotional distress (51.7% vs 31.2%; OR = 4.56, P < .001). CONCLUSIONS: Neuroticism and introversion were associated with clinically significant emotional distress in men with prostate cancer. Findings suggest that, in the context of treatment for prostate cancer, patient distress reflects disease characteristics (eg, metastases presence) as well as stable personality traits. Implications for clinical care are discussed. PMID- 29125209 TI - Corrigendum. PMID- 29125210 TI - Gastrointestinal: Cystic endosalpingiosis of the spleen: CT, MR, and US imaging. PMID- 29125211 TI - Gastrointestinal: Voluntary padlock ingestion. PMID- 29125212 TI - Hepatobiliary and Pancreatic: Management of bleeding colonic varices in liver disease. PMID- 29125213 TI - Gastrointestinal: Spray coagulation with snare tip as a rescue therapy to argon plasma coagulation for bleeding jejunal angioectasia. PMID- 29125214 TI - Treating multiple body parts for skin laxity and fat deposits using a novel focused radiofrequency device with an ultrasound component: Safety and efficacy study. AB - BACKGROUND AND OBJECTIVES: Growing demand for noninvasive skin tightening and reduction in fat results in an increasing pressure for devices with good clinical efficacy, consistency of results, and high patient comfort. The objective was to validate clinical efficacy and versatility of a novel device, which combines radiofrequency (RF) and ultrasound for treating skin laxity and fat deposits. METHODS: We treated 34 subjects with facial skin laxity and/or abundant body or arm fat deposits. Subjects were divided based on their indications. Ten subjects received treatments to the face, 7 subjects to arms, 8 subjects to thighs, and 9 subjects on abdomen. All patients received 4 treatments on a weekly basis. Photographs of patients were assessed by blinded evaluators to recognize the baseline images from the 3-month follow-up images. Patient comfort and satisfaction were evaluated using a 5-point Likert scale questionnaire. Any adverse events were recorded. RESULTS: Patient images were correctly recognized in >90% of cases in all study groups. Patient questionnaires showed overall satisfaction with the therapy course and results. On a scale of 1 to 5, the patients agreed (4.1) that they are satisfied with the results that the treatment is comfortable (4.1) and that they are satisfied with the treatment time (4.1). No adverse events were reported. CONCLUSIONS: Consistent clinical efficacy was confirmed across all the treated areas, together with high patient comfort and satisfaction. We conclude the device is a highly versatile solution that can deliver results across body parts and different indications. PMID- 29125215 TI - Additive Manufacturing: A Comparative Analysis of Dimensional Accuracy and Skin Texture Reproduction of Auricular Prostheses Replicas. AB - PURPOSE: The use of computer-aided design/computer-aided manufacturing (CAD/CAM) and additive manufacturing in maxillofacial prosthetics has been widely acknowledged. Rapid prototyping can be considered for manufacturing of auricular prostheses. Therefore, so-called prostheses replicas can be fabricated by digital means. The objective of this study was to identify a superior additive manufacturing method to fabricate auricular prosthesis replicas (APRs) within a digital workflow. MATERIALS AND METHODS: Auricles of 23 healthy subjects (mean age of 37.8 years) were measured in vivo with respect to an anthropometrical protocol. Landmarks were volumized with fiducial balls for 3D scanning using a handheld structured light scanner. The 3D CAD dataset was postprocessed, and the same anthropometrical measurements were made in the CAD software with the digital lineal. Each CAD dataset was materialized using fused deposition modeling (FDM), selective laser sintering (SLS), and stereolithography (SL), constituting 53 APR samples. All distances between the landmarks were measured on the APRs. After the determination of the measurement error within the five data groups (in vivo, CAD, FDM, SLS, and SL), the mean values were compared using matched pairs method. To this, the in vivo and CAD dataset were set as references. Finally, the surface structure of the APRs was qualitatively evaluated with stereomicroscopy and profilometry to ascertain the level of skin detail reproduction. RESULTS: The anthropometrical approach showed drawbacks in measuring the protrusion of the ear's helix. The measurement error within all groups of measurements was calculated between 0.20 and 0.28 mm, implying a high reproducibility. The lowest mean differences of 53 produced APRs were found in FDM (0.43%) followed by SLS (0.54%) and SL (0.59%)--compared to in vivo, and again in FDM (0.20%) followed by SL (0.36%) and SLS (0.39%)--compared to CAD. None of these values exceed the threshold of clinical relevance (1.5%); however, the qualitative evaluation revealed slight shortcomings in skin reproduction for all methods: reproduction of skin details exceeding 0.192 mm in depth was feasible. CONCLUSION: FDM showed the superior dimensional accuracy and best skin surface reproduction. Moreover, digital acquisition and CAD postprocessing seem to play a more important role in the outcome than the additive manufacturing method used. PMID- 29125216 TI - Evaluation of a sudden unexpected death in infancy intervention programme aimed at improving parental awareness of risk factors and protective infant care practices. AB - AIM: Sudden unexpected death in infancy (SUDI) rates for Maori and Pacific infants remain higher than for other ethnic groups in New Zealand and bed-sharing is a major risk factor when there is smoking exposure in pregnancy. Sleep space programmes of education and Pepi-Pod baby beds require evaluation. METHODS: Two hundred and forty Maori and Pacific women and infants were randomised 1:1, to the Pepi-Pod sleep space programme, or to a control group with 'usual care'. When infants were under 2 weeks of age, baseline interviews occurred, followed up by interviews at 2 and 4 months of age to assess safe sleep knowledge, infant care practices and Pepi-Pod use and acceptability. All participants were offered a New Zealand Standard approved portable cot. RESULTS: At baseline, 25% of babies did not have a baby bed. Knowledge of smoking and bed-sharing as SUDI risks improved at follow-up in both groups. One quarter regularly bed-shared at follow-up in both groups. Intention to bed-share was a strong predictor of subsequent behaviour. Pepi-Pods were regularly used by 46% at 2 months and 16% at 4 months follow-up. CONCLUSIONS: Bed-sharing and knowledge improvement were similar irrespective of group. It is likely that the impact of the intervention was reduced because the control group received better support than 'usual care' and all participants had a baby bed. New Zealand SUDI rates have declined since sleep space programmes have been available. Sleep space programmes should be prioritised for those with modifiable SUDI risk. PMID- 29125217 TI - An evaluation of the impact of FIFA World Cup on soccer emergency department injuries among Montreal adolescents. AB - AIM: The 'trickle-down effect', or how major sports events have a positive impact on sports participation, has been the subject of many studies, but none produced conclusive results. We took a different approach and rather than look at sports participation, we used injuries as a proxy and see if injuries increased, or remained the same, after the International Federation of Association Football World Cup. METHODS: Using a retrospective cohort design, we looked at the injuries suffered by males and females (13-16 years old) while playing team sports in Montreal, that occurred in May to July, from 1999 to 2014. Information reported by the Canadian Hospitals Injury Reporting Prevention Program (CHIRPP) was limited to the two CHIRPP centres in Montreal: the Montreal Children's Hospital and Hopital Sainte-Justine. RESULTS: In females, no significant trends were noticed. In males who played non-organised soccer, the percent changes between FIFA World Cup (WC) (June) and pre-FIFA WC (May) was always highest during FIFA WC years: 17.2% more injuries in years when FIFA WC was held compared to 1.3% less injuries during non-FIFA WC years. In non-organised soccer, male players suffered less strains/sprains (11.9% vs. 30.1%; P = 0.015), suffered more severe injuries (59.7% vs. 43.1%; P = 0.049) and more of their injuries were the results of direct contact with another player (26.8% vs. 13.3%; P = 0.028) during FIFA WC. CONCLUSION: FIFA WC seems to have an impact on the injuries of teenage boys when playing non-organised soccer. The impact was short-lived, only lasting during the FIFA WC event. PMID- 29125218 TI - Marijuana use and associated motives in Colorado university students. AB - BACKGROUND AND OBJECTIVES: Marijuana is the most commonly used illicit drug among college students, with heavy use leading to negative outcomes. Use of marijuana for medical and recreational purposes in select U.S. states has been controversial, with concerns surrounding increased prevalence rates and harm. The current exploratory study aimed to assess marijuana use in college students in Colorado, demographic differences in frequency of use, and motives for using. METHODS: College students (N = 300; 61% female) were recruited through introductory psychology courses and completed a series of questionnaires and a marijuana urine screen. RESULTS: Almost three-fourths of the sample reported lifetime use of marijuana. Sixty-five percent used marijuana within the last year and 29% tested positive on the urine screen. Hurdle Poisson regression models with a subset of participants (n = 117) showed non-Greek and freshman status were associated with increased number of days participants used marijuana in the last month. Problem marijuana use was positively associated with a range of motives-of note-motives focused on coping, boredom, alcohol, and food. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Prevalence rates of marijuana use were high in this sample of college students in a state with legal recreational marijuana use. Particular students (eg, students who use marijuana to cope) may be at higher risk for problem marijuana use. Developing effective, tailored interventions for university students is warranted. (Am J Addict 2017;26:830-837). PMID- 29125219 TI - Effects of a Grapevine Shoot Extract Containing Resveratrol and Resveratrol Oligomers on Intestinal Adenoma Development in Mice: In Vitro and In Vivo Studies. AB - SCOPE: Evidence suggests that the dietary consumption of plant extracts containing polyphenols might help prevent the onset of cancers of the gastrointestinal tract. In the present study, the chemopreventive and antiproliferative efficacy of a grapevine shoot extract (Vineatrol(r)30) containing resveratrol and resveratrol oligomers is investigated in vivo and in vitro. METHODS AND RESULTS: The in vivo study is performed using ApcMin mice on a high-fat diet, which represents a model of human adenomatous polyposis, while the potential of the extract as well as some of its isolated constituents to inhibit intestinal adenoma cell proliferation in vitro is investigated using APC10.1 cells derived from an ApcMin mouse. Vineatrol(r)30 at a low (2.3 mg kg-1 diet) or high dose (476 mg kg-1 diet) reduces the adenoma number in male and adenoma volume in female animals. Furthermore, Vineatrol(r)30 as well as resveratrol and two resveratrol tetramers compromise the expansion of APC10.1 cells by reducing cell number, inducing cell cycle arrest, cellular senescence, and apoptosis. However, except for the extract, none of the isolated resveratrol oligomers is more efficacious than resveratrol in these cells. CONCLUSION: Vineatrol(r)30 may merit further investigation as a potential dietary gastrointestinal cancer chemopreventive agent in humans. PMID- 29125220 TI - A dynamic power prior for borrowing historical data in noninferiority trials with binary endpoint. AB - Traditionally, noninferiority hypotheses have been tested using a frequentist method with a fixed margin. Given that information for the control group is often available from previous studies, it is interesting to consider a Bayesian approach in which information is "borrowed" for the control group to improve efficiency. However, construction of an appropriate informative prior can be challenging. In this paper, we consider a hybrid Bayesian approach for testing noninferiority hypotheses in studies with a binary endpoint. To account for heterogeneity between the historical information and the current trial for the control group, a dynamic P value-based power prior parameter is proposed to adjust the amount of information borrowed from the historical data. This approach extends the simple test-then-pool method to allow a continuous discounting power parameter. An adjusted alpha level is also proposed to better control the type I error. Simulations are conducted to investigate the performance of the proposed method and to make comparisons with other methods including test-then-pool and hierarchical modeling. The methods are illustrated with data from vaccine clinical trials. PMID- 29125221 TI - Site-Selective O-Arylation of Glycosides. AB - Direct and site-selective O-arylation of carbohydrates has been a challenge in synthesis. Herein we report a method based on copper-catalyzed O-arylation to address this challenge. Proper choice of the ancillary ligand on copper is critical for the efficiency and site selectivity of this transformation. This method features mild conditions, tolerates various functional groups, and demonstrates broad substrate scope. PMID- 29125222 TI - Total Synthesis and Antibacterial Study of Cyclohexapeptides Desotamide B, Wollamide B and Their Analogs. AB - As natural-product-derived antibiotics, desotamides A - D and wollamides exhibit growth inhibitory activity against Gram-posivite bacteria (IC50 0.6 - 7 MUm) and are noncytotoxic to mammalian cells (IC50 > 30 MUm). Herein we firstly report the total synthesis of above two cyclohexapeptides as well as a series of structural variants through solid phase peptide synthesis, of which 3 displayed a 2-fold increase of antibacterial activity when compared with the original peptide 1. This strategy may offer good improvements for the synthesis of other cyclic peptides. PMID- 29125223 TI - Perinatal nutrition interacts with genetic background to alter behavior in a parent-of-origin-dependent manner in adult Collaborative Cross mice. AB - Previous studies in animal models and humans have shown that exposure to nutritional deficiencies in the perinatal period increases the risk of psychiatric disease. Less well understood is how such effects are modulated by the combination of genetic background and parent-of-origin (PO). To explore this, we exposed female mice from 20 Collaborative Cross (CC) strains to protein deficient, vitamin D deficient, methyl donor enriched or standard diet during the perinatal period. These CC females were then crossed to a male from a different CC strain to produce reciprocal F1 hybrid females comprising 10 distinct genetic backgrounds. The adult F1 females were then tested in the open field, light/dark, stress-induced hyperthermia, forced swim and restraint stress assays. Our experimental design allowed us to estimate effects of genetic background, perinatal diet, PO and their interactions on behavior. Genetic background significantly affected all assessed phenotypes. Perinatal diet exposure interacted with genetic background to affect body weight, basal body temperature, anxiety-like behavior and stress response. In 8 of 9 genetic backgrounds, PO effects were observed on multiple phenotypes. Additionally, we identified a small number of diet-by-PO effects on body weight, stress response, anxiety- and depressive-like behavior. Our data show that rodent behaviors that model psychiatric disorders are affected by genetic background, PO and perinatal diet, as well as interactions among these factors. PMID- 29125224 TI - Normalize the response of EPID in pursuit of linear accelerator dosimetry standardization. AB - Normalize the response of electronic portal imaging device (EPID) is the first step toward an EPID-based standardization of Linear Accelerator (linac) dosimetry quality assurance. In this study, we described an approach to generate two dimensional (2D) pixel sensitivity maps (PSM) for EPIDs response normalization utilizing an alternative beam and dark-field (ABDF) image acquisition technique and large overlapping field irradiations. The automated image acquisition was performed by XML-controlled machine operation and the PSM was generated based on a recursive calculation algorithm for Varian linacs equipped with aS1000 and aS1200 imager panels. Cross-comparisons of normalized beam profiles and 1.5%/1.5 mm 1D Gamma analysis was adopted to quantify the improvement of beam profile matching before and after PSM corrections. PSMs were derived for both photon (6, 10, 15 MV) and electron (6, 20 MeV) beams via proposed method. The PSM-corrected images reproduced a horn-shaped profile for photon beams and a relative uniform profiles for electrons. For dosimetrically matched linacs equipped with aS1000 panels, PSM-corrected images showed increased 1D-Gamma passing rates for all energies, with an average 10.5% improvement for crossline and 37% for inline beam profiles. Similar improvements in the phantom study were observed with a maximum improvement of 32% for 15 MV and 22% for 20 MeV. The PSM value showed no significant change for all energies over a 3-month period. In conclusion, the proposed approach correct EPID response for both aS1000 and aS1200 panels. This strategy enables the possibility to standardize linac dosimetry QA and to benchmark linac performance utilizing EPID as the common detector. PMID- 29125225 TI - Baicalein Reduces Oxidative Stress in CHO Cell Cultures and Improves Recombinant Antibody Productivity. AB - Oxidative stress that naturally accumulates in the endoplasmic reticulum (ER) as a result of mitochondrial energy metabolism and protein synthesis can disturb the ER function. Because ER have a responsibility on the protein synthesis and quality control of the secreted proteins, ER homeostasis has to be well maintained. When H2 O2 , an oxidative stress inducer, is added to recombinant Chinese hamster ovary (rCHO) cell cultures, it reduced cell growth, monoclonal antibody (mAb) production, and galactosylated form of mAb in a dose-dependent manner. To find an effective antioxidant for rCHO cell cultures, six antioxidants (hydroxyanisole, N-acetylcysteine, baicalein, berberine chloride, kaempferol, and apigenin) with various concentrations are examined individually as chemical additives to rCHO cell cultures producing mAb. Among these antioxidants, baicalein shows the best mAb production performance. Addition of baicalein significantly reduced the expression level of BiP and CHOP along with reduced reactive oxygen species level, suggesting oxidative stress accumulated in the cells can be relieved using baicalein. As a result, addition of baicalein in batch cultures resulted in 1.7-1.8-fold increase in the maximum mAb concentration (MMC), while maintaining the galactosylation of mAb. Likewise, addition of baicalein in fed-batch culture resulted in 1.6-fold increase in the MMC while maintaining the galactosylation of mAb. Taken together, the results obtained here demonstrate that baicalein is an effective antioxidant to increase mAb production in rCHO cells. PMID- 29125226 TI - Loperamide cardiotoxicity: "A Brief Review". AB - Loperamide is a popular antidiarrheal medication that has been used for many years. It is currently gaining more attention among healthcare professionals due to its increasing potential for side effects. At present, it is considered safe enough to be sold over the counter. In contrast with other opioid agonists, loperamide is a peripherally acting MU-receptor agonist exerting its effects mainly on the myenteric plexus of the gastrointestinal longitudinal muscle layer. It decreases peristalsis and fluid secretion resulting in longer gastrointestinal transit time. The bioavailability of the drug is extremely low. Moreover, it is actively excluded from the central nervous system; hence, it lacks the central effects of euphoria and analgesia at the recommended dosages. Loperamide abuse has been steadily increasing in the United States. Abusers typically ingest high doses in desire to achieve a satisfactory central nervous system drug penetration. This has made it a potential over the counter substitute for self treating opioid withdrawal symptoms and achieving euphoric effects. PMID- 29125227 TI - Pichia pastoris Alcohol Oxidase 1 (AOX1) Core Promoter Engineering by High Resolution Systematic Mutagenesis. AB - Unravelling the core promoter sequence-function relationship is fundamental for engineering transcription initiation and thereby a feasible "tuning knob" for fine-tuning expression in synthetic biology and metabolic engineering applications. Here a systematic replacement studies of the core promoter and 5' untranslated region (5'UTR) of the exceptionally strong and tightly methanol regulated Komagataella phaffii (syn. Pichia pastoris) alcohol oxidase 1 (AOX1) promoter at unprecedented resolution is performed. Adjacent triplets of the 200 bp long core promoter are mutated at a time by changing the wild-type sequence into cytosine or adenine triplets, resulting in 130 variants that are cloned upstream of an eGFP reporter gene providing a library for expression fine-tuning. Mutations in the TATA box motif, regions downstream of the transcription start site or next to the start codon in the 5'UTR had a significant effect on the eGFP fluorescence. Surprisingly, mutations in most other regions are tolerated, indicating that yeast core promoters can show a high tolerance toward small mutations, supporting regulatory models of degenerate motifs, or redundant design. The authors exploited these neutral core promoter positions, not affecting expression, to introduce extrinsic sequence elements such as cloning sites (allowing targeted core promoter/5'UTR modifications) and bacterial promoters (applicable in multi host vectors). PMID- 29125228 TI - Routine follow-up of preterm infants in New Zealand. AB - AIM: To describe the routine follow-up of preterm infants by different District Health Boards (DHBs) in New Zealand (NZ), and to compare current practice with international guidelines. METHODS: A descriptive survey of the existing routine follow-up management of preterm infants in NZ. From November 2015 until January 2016, a questionnaire was sent out across NZ to one paediatrician (n = 24) and one Child Development Service (CDS) (n = 20) from each DHB. All paediatricians responded and 85% of the CDSs responded. Responses were collated and compared to recommendations from paediatric literature. RESULTS: There is tremendous variation across NZ of the eligibility criteria for routine preterm follow-up. Overall, a gestational age of <32 weeks and/or birthweight <1500 g was the most commonly used indication for routine preterm follow-up. The timing of visits and the assessments that were performed varied enormously. Respondents commonly reported that limited funding and resources prevented optimal follow-up management. CONCLUSION: There is regional disparity in the routine follow-up that preterm infants receive in NZ. A standardised approach to follow-up of preterm infants across NZ, as recommended in the literature, is difficult due to the lack of funding and resources. PMID- 29125229 TI - Observational review of paediatric intraosseous needle placement in the paediatric emergency department. AB - AIM: Intraosseous (IO) access is a life-saving option during resuscitations in the paediatric emergency department (PED). This study aimed to compare success rates and time to placement for Manual IO versus EZ-IO needles in PED patients <=8 and >8 kg. METHODS: This was a retrospective cross-sectional descriptive study of IO use in a single-centre tertiary PED from 2006 to 2014. Cases were identified through diagnosis codes for IO infusion, cardiopulmonary resuscitation and cardiac arrest and admissions to the intensive care unit. Categorical measures were compared with Z-test for comparison of two proportions and continuous with Student's t-tests. RESULTS: Of 1748 charts screened, 50 had an IO attempted. In patients <=8 kg, Manual IO had success rate of 55% (17/31) versus 47% (8/17) for EZ-IO (P = 0.61). In patients >8 kg, Manual had success rate of 100% (2/2) versus 93% (14/15) for EZ-IO (P = 0.71). Manual performance was no different for <=8 kg than >8 kg (P = 0.21), but EZ-IO was less successful for <=8 kg than >8 kg (P = 0.005). In patients <=8 kg, Manual IO had a shorter time to placement at 4.5 min versus 12.8 for EZ-IO (P = 0.02). CONCLUSION: We observed no difference in performance between Manual and EZ-IO devices in children <=8 kg, but the Manual IO were placed more quickly. We observed lower success rates with EZ-IO devices in children <=8 kg compared to >8 kg. Future investigations should focus specifically on training for IO placement in children <=8 kg. PMID- 29125230 TI - Revisiting fetal dose during radiation therapy: evaluating treatment techniques and a custom shield [JACMP, 17(5), 2016]. PMID- 29125232 TI - MBA degree is needed for leadership roles in Medical Physics profession. PMID- 29125231 TI - Navigating the medical physics education and training landscape. AB - PURPOSE: The education and training landscape has been profoundly reshaped by the ABR 2012/2014 initiative and the MedPhys Match. This work quantifies these changes and summarizes available reports, surveys, and statistics on education and training. METHODS: We evaluate data from CAMPEP-accredited program websites, annual CAMPEP graduate and residency program reports, and surveys on the MedPhys Match and Professional Doctorate degree (DMP). RESULTS: From 2009-2015, the number of graduates from CAMPEP-accredited graduate programs rose from 210 to 332, while CAMPEP-accredited residency positions rose from 60 to 134. We estimate that approximately 60% of graduates of CAMPEP-accredited graduate programs intend to enter clinical practice, however, only 36% of graduates were successful in acquiring a residency position in 2015. The maximum residency placement percentage for a graduate program is 70%, while the median for all programs is only 22%. Overall residency placement percentage for CAMPEP-accredited program graduates from 2011-2015 was approximately 38% and 25% for those with a PhD and MS, respectively. The disparity between the number of clinically oriented graduates and available residency positions is perceived as a significant problem by over 70% of MedPhys Match participants responding to a post-match survey. Approximately 32% of these respondents indicated that prior knowledge of this situation would have changed their decision to pursue graduate education in medical physics. CONCLUSION: These data reveal a substantial disparity between the number of residency training positions and graduate students interested in these positions, and a substantial variability in residency placement percentage across graduate programs. Comprehensive data regarding current and projected supply and demand within the medical physics workforce are needed for perspective on these numbers. While the long-term effects of changes in the education and training infrastructure are still unclear, available survey data suggest that these changes could negatively affect potential entrants to the profession. PMID- 29125233 TI - In vivo imaging xenograft models for the evaluation of anti-brain tumor efficacy of targeted drugs. AB - Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)-dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3-NTRK1 gene fusion. We investigated the efficacy of targeted drugs by comparison with their effect in extracranial models. In vitro, H1975 cells were sensitive to the third-generation epidermal growth factor receptor inhibitor osimertinib. Moreover, HGF stimulated the proliferation of NUGC4 cells, that was inhibited by crizotinib, which has anti-MET activity. KM12SM cells were sensitive to the tropomyosin-related kinase-A inhibitors crizotinib and entrectinib. In in vivo H1975 cell models, osimertinib inhibited the progression of both brain and subcutaneous tumors. Furthermore, in in vivo NUGC4 cell models, crizotinib remarkably delayed the progression of brain tumors, and that of peritoneal carcinomatosis. Interestingly, in in vivo KM12SM cell models, treatment with crizotinib delayed the progression of liver metastases, but not that of brain tumors. Conversely, treatment with entrectinib discernibly delayed the progression of both tumor types. Thus, the effect of targeted drugs against brain tumors can differ from the one reported in extracranial tumors. Moreover, the same multikinase inhibitory drug can display different efficacies in brain tumor models containing different drivers. Therefore, our in vivo imaging model for brain tumors may prove useful for preclinical drug screening against brain metastases. PMID- 29125234 TI - Evaluation of clinically applied treatment beams with respect to bunker shielding parameters for a Cyberknife M6. AB - Compared to a conventional linear accelerator, the Cyberknife (CK) is a unique system with respect to radiation protection shielding and the variety and number of non-coplanar beams are two key components regarding this aspect. In this work, a framework to assess the direction distribution and modulation factor (MF) of clinically applied treatment beams of a CyberKnife M6 is developed. Database filtering options allow studying the influence of different parameters such as collimator types, treatment sites or different bunker sizes. A distribution of monitor units (MU) is generated by projecting treatment beams onto the walls, floor and ceiling of the CyberKnife bunker. This distribution is found to be highly heterogeneous and depending, among other parameters, on the bunker size. For our bunker design, 10%-13% of the MUs are delivered to the right and left wall, each. The floor receives more than 64% of the applied MUs, while the wall behind the patient's head is not hit by primary treatment beams. Between 0% and 5% of the total MUs are delivered to the wall at the patient's feet. This number highly depends on the treatment site, e.g., for extracranial patients no beams hit that wall. Collimator choice was found to have minor influence on the distribution of MUs. On the other hand, the MF depends on the collimator type as well as on the treatment site. The MFs (delivered MU/prescribed dose) for all treatments, all MLC treatments, cranial and extracranial treatments are 8.3, 6.4, 7.7, and 9.9 MU/cGy, respectively. The developed framework allows assessing and monitoring important parameters regarding radiation protection of a CK-M6 using the actually applied treatment beams. Furthermore, it enables evaluating different clinical and constructional situations using the filtering options. PMID- 29125235 TI - Comparison of the mRNA expression profile of B-cell receptor components in normal CD5-high B-lymphocytes and chronic lymphocytic leukemia: a key role of ZAP70. AB - The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine kinases in B-CLL compared to that in normal CD5-high and CD5-low B lymphocytes remain unknown. In the current study, we measured the mRNA expression levels of CD79A, CD79B, LYN, SYK, SHP1, and ZAP70 in purified populations of CD5 high B-CLL cells, CD5-low B-cells from the peripheral blood of healthy donors, and CD5-high B-cells from human tonsils. Here, we report a clear separation in the B-CLL dataset between the ZAP70-high and ZAP70-low subgroups. Each subgroup has a unique expression profile of BCR signaling components that might reflect the functional status of the BCR signaling pathway. Moreover, the ZAP70-low subgroup does not resemble either CD5-high B-lymphocytes from the tonsils or CD5 low lymphocytes from PBMC (P < 0.05). We also show that ZAP70 is the only gene that is differentially expressed in CD5-high and CD5-low normal B-lymphocytes, confirming the key role of Zap-70 tyrosine kinase in BCR signaling alterations in B-CLL. PMID- 29125236 TI - Library of Norcoclaurine Synthases and Their Immobilization for Biocatalytic Transformations. AB - Norcoclaurine synthases (NCS), catalyzing a Pictet-Spengler reaction in plants as one of the first enzymes in the biosynthetic benzylisoquinoline pathway, are investigated for biocatalytic transformations. The library of NCS available is extended by two novel NCSs from Argemone mexicana (AmNCS1, AmNCS2) and one new NCS from Corydalis saxicola (CsNCS); furthermore, it is shown that the NCS from Papaver bracteatum (PbNCS) is a highly productive catalyst leading to the isoquinoline product with up to >99% e.e. Under certain conditions lyophilized whole Escherichia coli cells containing the various overexpressed NCS turned out to be suitable catalysts. The reaction using dopamine as substrate bears several challenges such as the spontaneous non-stereoselective background reaction and side reactions. The PbNCS enzyme is successfully immobilized on various carriers whereby EziG3 proved to be the best suited for biotransformations. Dopamine showed limited stability in solution resulting in the coating of the catalyst over time, which could be solved by the addition of ascorbic acid (e.g., 1 mg ml 1 ) as antioxidant. PMID- 29125237 TI - Toenail mineral concentration and risk of esophageal squamous cell carcinoma, results from the Golestan Cohort Study. AB - Studies conducted in China linked selenium deficiency to higher risk of esophageal squamous cell carcinoma (ESCC), but this has not been widely tested outside that selenium-deficient region. The aim of this study was to investigate the association between selenium and other mineral concentrations in toenails and risk of ESCC in a region with high incidence rates. In this nested case-control study, we identified 222 cases of ESCC from the Golestan Cohort Study, Iran, which has followed up 50,045 participants since enrollment (2004-2008). We randomly selected one control for each case matched by age and sex, using incidence density sampling. We used toenail samples collected at baseline to measure the concentration of selenium, zinc, chromium, mercury, and scandium using instrumental neutron activation analysis. Multivariate adjusted logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals. Median nail selenium, zinc, chromium, and mercury levels were 1.01, 74.59, 0.77, and 0.018 MUg/g in cases and 1.02, 75.71, 0.71, and 0.023 MUg/g in controls, respectively. The adjusted odds ratios comparing each fourth quartile of mineral status versus the first quartile were as follows: selenium = 0.78 (95% CI, 0.41-1.49); zinc=0.80 (95% CI, 0.42-1.53); chromium = 0.91 (95% CI, 0.46 1.80); and mercury=0.61 (95% CI, 0.27-1.38), and all trend tests were non significant. The nail selenium concentration in our controls reflects relatively high selenium status. No evidence of association between selenium or chromium concentrations in toenails and the risk of ESCC was detected in this population. PMID- 29125238 TI - LncRNA UCA1 promotes proliferation and cisplatin resistance of oral squamous cell carcinoma by sunppressing miR-184 expression. AB - Chemotherapy resistance has become the main obstacle for the effective treatment of human cancers. Long non-coding RNA urothelial cancer associated 1 (UCA1) is generally regarded as an oncogene in some cancers. However, the function and molecular mechanism of UCA1 implicated in cisplatin (CDDP) chemoresistance of oral squamous cell carcinoma (OSCC) is still not fully established. UCA1 expression in tumor tissues and cells was tested by qRT-PCR. MTT, flow cytometry and caspase-3 activity analysis were explored to evaluate the CDDP sensitivity in OSCC cells. Western blot analysis was used to measure BCL2, Bax and SF1 protein expression. Luciferase reporter assay was conducted to investigate the molecular relationship between UCA1, miR-184, and SF1. Nude mice model was used to confirm the functional role of UCA1 in CDDP resistance in vivo. UCA1 expression was upregulated in OSCC tissues, cell lines, and CDDP resistant OSCC cells. Function analysis revealed that UCA1 facilitated proliferation, enhanced CDDP chemoresistance, and suppressed apoptosis in OSCC cells. Mechanisms investigation indicated that UCA1 could interact with miR-184 to repress its expression. Rescue experiments suggested that downregulation of miR-184 partly reversed the tumor suppression effect and CDDP chemosensitivity of UCA1 knockdown in CDDP-resistant OSCC cells. Moreover, UCA1 could perform as a miR-184 sponge to modulate SF1 expression. The OSCC nude mice model experiments demonstrated that depletion of UCA1 further boosted CDDP-mediated repression effect on tumor growth. UCA1 accelerated proliferation, increased CDDP chemoresistance and restrained apoptosis partly through modulating SF1 via sponging miR-184 in OSCC cells, suggesting that targeting UCA1 may be a potential therapeutic strategy for OSCC patients. PMID- 29125239 TI - Hippocampal sparing approach in fractionated stereotactic brain VMAT radio therapy: A retrospective feasibility analysis. AB - Volumetric Modulated Arc Therapy (VMAT) techniques for fractioned stereotactic brain radiotherapy (FSBRT) can achieve highly conformal dose distribution to intracranial lesions. However, they can potentially increase the dose to hippocampus (H) causing neurocognitive toxicity during the first four months after irradiation. The purpose of this study was to assess the feasibility of hippocampal-sparing (HS) treatment plans in 22 patients with brain metastasis treated with VMAT technique. Firstly, we retrospectively analyzed hippocampal doses in all 22 VMAT original (not hippocampal-sparing, NHS) plans. Plans with hippocampal dose exceeding constraints (9 out of 22) were re-planned considering dose constraints on the hippocampus (H) and on hippocampal avoidance zone (HAZ) generated using 5 mm isotropic margin to the hippocampus. Conformity (CI) and homogeneity indexes (HI) on the target and MUs, were maintained as close as possible to the original plans. Mean CINHS and CIHS obtained were: 0.79 +/- 0.11 and 0.81 +/- 0.10, respectively (P = 0.75); mean HINHS and HIHS were 1.05 +/- 0.02 and 1.04 +/- 0.01 respectively (P = 0.72). In both sets of plans, the mean MU values were similar: 1033 +/- 275 and 1022 +/- 234 for NHS and HS respectively. In HS plans, the mean hippocampal dose was decreased by an average of 35%. After replanning, the Dmax (21.3 Gy) for HAZ and H was met by 45% (4/9) and 78% (7/9) of the NHS plans, respectively. The worst results were obtained for cases with target volumes extention closer than 12 mm to H, because of the difficulty to spare hippocampus without compromising target coverage. After replanning D40% constraint value (7.3 Gy) was met by all the 9 NHS plans. In conclusion, this study suggests that an hippocampal-sparing approach to FSBRT is feasible resulting in a decrease in the dose to the hippocampus without any loss in conformity or increase in treatment time. PMID- 29125242 TI - External female genitalia of six species of the genus Meccus (Hemiptera: Reduviidae: Triatominae). AB - Triatomine classification is based on morphological characteristics. Studies have been conducted to improve their identification by observing many characteristics. However, there are problems of differentiating among highly interrelated species and new criteria are required. The purpose of this study was to determine the morphological differences in the external female genitalia of M. pallidipennis, M. longipennis, M. picturatus, M. bassolsae, M. mazzottii, and M. phyllosomus in order to distinguish among species using scanning electron microscopy. Observations were made of the dorsal, posterior, lateral, and ventral views of the female external genitalia for each species. In the six species we studied, relevant differences were observed in the dorsal view of the X segment, as well as the IX, VIII, and VII tergites. In the posterior and lateral view, the most visible differences were registered in the gonocoxite size of the segments VIII, IX, and X. Finally, in the ventral view of the VII sternite, differences among species were observed in the size of the inflection in the top and upper corner. Our results show that it was possible to differentiate among the triatominae species for each of the four views by using a scanning electron microscope to analyze morphological characteristics of the VII, VIII, IX, and X abdomen segments. PMID- 29125241 TI - Seasonal dynamics of Anopheles species at three locations in the Republic of Korea. AB - Weekly changes in adult Anopheles species were monitored at Camp Humphreys (CH), Ganghwa Island (GH), and Warrior Base (WB), from May-October, 2009-2010 to explore the relationship between Plasmodium vivax development and vector dynamics in the Republic of Korea (ROK). Adult females were trapped and dissected to determine parity for estimating longevity, mortality, and birthrate. A degree-day (DD) method was used to estimate the extrinsic incubation period (EIP) of P. vivax and duration of the gonotrophic cycle and other life stages. Anopheles sinensis was the predominant species, with satellite data showing peak abundance occurring after the period of maximum greenness. Abundance peaks were location dependent, comprised nulliparous and parous females, and timing could not be fully explained by DD estimation. Parity showed synchronicity between locations and years and was highest for September and lowest during maximum greenness. Mosquito longevity was predicted to exceed the EIP (when malaria transmission is possible) during weeks 29, 31, 34, and near the end of the season. Area-wide changes in parity suggest a common cause; information on local larval habitat and agricultural practices may explain location-specific effects. DD estimates of EIP and parity could be used to predict when conditions are suitable for P. vivax transmission. PMID- 29125240 TI - Tumor-associated DNA mutation detection in individuals undergoing colonoscopy. AB - The majority of colorectal cancers (CRC) harbor somatic mutations and epigenetic modifications in the tumor tissue, and some of these mutations can be detected in plasma as circulating tumor DNA (ctDNA). Precancerous colorectal lesions also contain many of these same mutations. This study examined plasma for ctDNA from patients undergoing a screening or diagnostic colonoscopy to determine the sensitivity and specificity of the ctDNA panel for detecting CRC and precancerous lesions. Two hundred patients without a history of nonskin cancer had blood drawn before a colonoscopy. Plasma ctDNA was measured with a 96 mutation panel for nine cancer driver genes. The ctDNA results were correlated with the findings at colonoscopy. Of the 200 patients, 176 (88%) had wild-type DNA, 12 (6%) had mutations detected, and 12 (6%) had indeterminate results. Colonoscopy was normal in 80% of the patients and 20% were found to have polyps. No CRC was found in this study, precluding a determination of true-positive rate for CRC detection. Our ctDNA panel was positive in 13.2% of patients with colonic polyps found at colonoscopy, while 4.7% of patients with normal colonoscopy also had ctDNA detected, which may represent ctDNA released from a benign process, an occult tumor, or an acquired somatic mutation from clonal hematopoiesis. PMID- 29125243 TI - Wing morphology variations in a natural population of Phlebotomus tobbi Adler and Theodor 1930. AB - Cutaneous leishmaniasis (CL) is highly endemic in the Cukurova region, located on the crossroads of main refugee routes from the Middle East to Europe on the eastern Mediterranean part of Turkey. Our purpose was to investigate the phenotypic variation of Phlebotomus tobbi, the known vector of CL in the region, during one active season. Sand flies and microclimatic data were collected monthly from May to October, 2011, from five locations in six villages in the study area. A geometric morphometric approach was used to investigate wing morphology. Shape analyses revealed that males collected in May and June comprised one group, while specimens collected in August, September, and October formed a second group. Specimens from July were found to be distributed within these two groups. A similar distribution pattern was observed for females, but specimens from October were represented as the third district group. Significant size variation was detected for both sexes between months. Wing size and temperature were negatively correlated for females, but there was no temperature effect for males. Wing size of both sexes was increased in correlation to increasing relative humidity. Males were found to have smaller wings with increasing population density. PMID- 29125244 TI - Abundance and distribution of Anopheles mosquitoes in a malaria endemic area along the Thai-Lao border. AB - Malaria is an important public health problem in Thailand, especially along international borders. In this study, we conducted a longitudinal entomological survey in six villages and rubber plantation sites to address the spatio-temporal abundance and behavior of malaria vectors in Ubon Ratchathani Province along the Thailand-Laos border. Adult female mosquitoes were collected by human landing collections (indoor and outdoor) and by cattle bait collections twice per year, during rainy and dry seasons. Mosquitoes were morphologically identified and sibling species were determined by allele-specific PCR. Of the 10,024 Anopheles, 9,328 (93.1%) and 696 (6.9%) were collected during the rainy and dry seasons, respectively. A total of 9,769 (97.5%) and 255 (2.5%) was collected on cattle and human baits, respectively. Very few primary and secondary malaria vectors were collected, consisting of 12 specimens of An. dirus, eight An. minimus, and seven An. aconitus. Of the 152 specimens of the Maculatus Group, only three were identified to An sawadwongporni by molecular methods. The others were 112 An. rampae, a non-vector, that were not amplified or were misidentified as other non vectors. The very low density of primary malaria vectors found in the study villages suggests that entomological risk and malaria transmission is higher in neighboring forest areas. Further studies on malaria vector distribution, as well as human behaviors, are needed to understand malaria transmission dynamics in the province and to develop suitable vector control methods. PMID- 29125245 TI - First records of Ixodes lividus from sand martin (Riparia riparia) nests in Lithuania. AB - Ixodes lividus (Koch, 1844) ticks are specific parasites of the sand martin Riparia riparia (L.). The distribution range of I. lividus covers Europe (being absent from the Mediterranean area) and Asia. However, until now there have been no reports on the presence of this tick in Lithuania. A total of 47 nests were collected in three different colonies of sand martins in the central part of Lithuania and 46.8% of them were infested with ticks. In total, 2,770 ticks were found and identified as I. lividus based on morphological characteristics. Larvae were the predominant stage, representing 99.6% of all collected ticks. The taxonomic identification of I. lividus was confirmed by sequence analysis of the tick mitochondrial 16S rRNA gene. Phylogenetic analysis of 16S rRNA sequences indicates six genotypes of I. lividus transported by the sand martin in the Baltic region. The detection of genotypes like those reported from other European regions pointed to the importance of avian migratory connections, which are associated with the dispersal of I. lividus and the related tick-borne pathogens in the Baltic region. This study represents the first record of I. lividus from sand martin nests in Lithuania. PMID- 29125246 TI - History of the discovery of the mode of transmission of yellow fever virus. AB - This essay documents and examines the historical circumstances and events surrounding the discovery of the mode of transmission of yellow fever virus in Cuba. Close scrutiny of the articles published by Walter Reed and his colleagues in 1900, 1901 and 1902 reveals their limitations as historic documents. Fortunately, other sources of information from that period survive in letters and documents written by individuals involved in the quest for the mode of transmission. Examination and comparison of those sources of information unveiled a fascinating story which reveals that misunderstandings engendered by published articles accorded merit where it was not fully due. PMID- 29125247 TI - Forest canopy, water level, and biopesticide interact to determine oviposition habitat selection in Aedes albopictus. AB - Understanding how interacting abiotic and biotic factors influence colonization rates into different habitat types is critical for both conserving and controlling species. For example, the rapid global spread of Asian tiger mosquitoes, Aedes albopictus, has reduced native species abundances and produced disease outbreaks. Fortunately, bacterial endospores of two Bacillus species (biospesticide) are highly lethal to Ae. albopictus larvae and have been commercially developed to reduce populations. Oviposition habitat selection is the first defense Ae. albopictus females possess against any control substance added to breeding sites, and considerable variation exists in their response to biopesticides. In a field experiment, I crossed the presence/absence of biopesticides, with two canopy (open, closed) and water (high, low) levels at 64 breeding sites, to examine if these interacted to influence oviposition site choice. Avoidance of biopesticide was most pronounced in closed canopy sites and those with low water levels, as all main effects and two-way interactions influenced oviposition. Oviposition habitat selection represents a possible mechanism of resistance to biopesticides and other methods used to kill mosquito larvae. Future experiments examining how larval density and mortality modify these results should allow for more effective control of this highly invasive species. PMID- 29125248 TI - Effects of flash flooding on mosquito and community dynamics in experimental pools. AB - Pulsed disturbances of larval mosquito sites are likely to have a direct negative effect on mosquitoes but may also have indirect effects due to the alteration of community structure. These altered communities may become attractive to gravid mosquitoes searching for oviposition sites when the disturbances decrease the abundance of mosquito antagonists such as competitors, which often results in an increase in mosquito food resources. However, flash flood disturbances in intermittent riverbeds can also remove mosquito food resources such as algae, so that the net effect of flash floods could be either to increase or decrease mosquito abundance. We conducted an outdoor mesocosm experiment to assess the effects of flash floods on mosquito oviposition habitat selection and larval abundance during the post-disturbance period of community recovery. Mesocosms were artificially flooded. Mosquito oviposition, immature abundance, invertebrate species diversity, chlorophyll a, and abiotic parameters were monitored. Our results showed that the flash flood negatively affected phytoplankton and zooplankton, leading to a decrease of mosquito oviposition in flooded mesocosms compared to non-flooded mesocosms. More broadly, this study indicates how disturbances influence mosquito oviposition habitat selection due to the loss of food resources in ephemeral pools, and it highlights the importance of considering the effects of disturbances in management, habitat restoration, and biodiversity conservation in temporary aquatic habitats. PMID- 29125249 TI - First record of Aedes aegypti and Aedes albopictus in thirteen Panhandle region counties of Texas, U.S.A. PMID- 29125250 TI - Ecological characterization of Aedes aegypti larval habitats (Diptera: Culicidae) in artificial water containers in Girardot, Colombia. AB - The establishment of habitats for immature Ae. aegypti is regulated by biotic and abiotic factors and interactions between these factors. This study aimed to determine the effects of physico-chemical variables and planktonic algae on immature Ae. aegypti habitats in 101 water tanks (50 of them containing Ae. aegypti pupae and/or larvae) in Girardot, Colombia. Physical data were collected from the water tanks (volume, capacity, material, detritus, and location), along with the physico-chemical variables (temperature, pH, conductivity, redox potential, dissolved oxygen, percentage of oxygen saturation, nitrates, nitrites, and orthophosphates). The richness and abundance of the planktonic organisms were also measured. A chi-square test showed that the occurrence of detritus was greater and the container volume was smaller in the tanks that were positive for larvae. Only Cyanobacteria had a positive correlation with the abundance of immature-stage Ae. aegypti. The results could be important for understanding the vector ecology and envisaging its probable control in the domestic water tanks of Girardot. PMID- 29125251 TI - Morphological and morphometric analysis of scutella of six species and two subspecies of Triatoma (Hemiptera: Reduviidae) in Mexico. AB - Morphological characters can be used to distinguish the vast majority of triatomine species, but the existence of high levels of phenotypic plasticity and recently diverged species can lead to erroneous determinations. To approach this problem, we analyzed the male and female morphologies of the scutella of Triatoma barberi, T. dimidiata, T. lecticularia, T. mexicana, T. recurva, T. rubida, and two sub-species, T. protracta protracta and T. protracta nahuatlae. Scutellum samples were observed by scanning electron microscopy and subjected to morphological analysis and morphometric investigation using a canonical discriminant analysis. The results revealed differences primarily in central depression shape, posterior process, and vestiture. We observed clear dimension based differences in scutellum morphometry in all the taxa under study, providing sound evidence for species and subspecies differentiation. On the other hand, there is no difference between sexes in T. lecticularia, T. protracta protracta, and T. protracta nahuatlae. Our methodology can be implemented to differentiate species of the genus Triatoma. PMID- 29125253 TI - First report of the endobacteria Wolbachia in natural populations of Culex pipiens in Morocco. PMID- 29125252 TI - The distribution of mosquitoes across an altitudinal gradient in the Galapagos Islands. AB - An avian malaria parasite (genus Plasmodium) has been detected consistently in the Galapagos Penguin (Spheniscus mendiculus) and less frequently in some passerines. We sampled three resident mosquito species (Aedes taeniorhynchus, Culex quinquefasciatus, and Aedes aegypti) using CDC light and gravid traps on three islands in 2012, 2013, and 2014. We sampled along altitudinal gradients to ask whether there are mosquito-free refugia at higher elevations as there are in Hawaii. We captured both Ae. taeniorhynchus and Cx. quinquefasciatus at all sites. However, abundances differed across islands and years and declined significantly with elevation. Aedes aegypti were scarce and limited to areas of human inhabitation. These results were corroborated by two negative binomial regression models which found altitude, year, trap type, and island as categorized by human inhabitation to be significant factors influencing the distributions of both Ae. taeniorhynchus and Cx. quinquefasciatus. Annual differences at the highest altitudes in Isabela and Santa Cruz indicate the lack of a stable highland refuge if either species is found to be a major vector of a parasite, such as avian malaria in Galapagos. Further work is needed to confirm the vector potential of both species to understand the disease dynamics of avian malaria in Galapagos. PMID- 29125254 TI - Field cage insecticide resistance tests against Culex quinquefasciatus Say (Diptera: Culicidae) in Harris County, Texas, U.S.A. AB - The ground adulticiding program in densely populated Harris County has been employed on the basis of virus-positive mosquitoes almost exclusively using the 'rotation of chemicals best practices' stratagem. To evaluate its effectiveness, 15 comparative field cage testing events were conducted from 2011-2015 using seven wild population samples from repeatedly collected locations of Culex quinquefasciatus Say and a laboratory susceptible Sebring strain colony reared to adults. A 3 * 3 plot design was employed for exposure to ultra-low volume applications of malathion and synergized permethrin. No significant differences were found in mortality rate among testing dates, year, row placement, or relative humidity. Mortality was significantly different between adulticides (p<0.001) with mean mortality rates for malathion 96.42% (+/-7.95%) and permethrin 92.38% (+/-14.04). There was a significant temperature difference for permethrin (p<0.001) but none for malathion (p=0.644). Mosquito population mortality was statistically different by study operational area (p<0.011) and chemical (p<0.001). Susceptible colony adults used as positive controls downwind strongly aided determination of efficacy and resistance to each adulticide, providing evidence of individual application coverage, though comparative analysis was done with overall mortalities by normal methodology. PMID- 29125255 TI - Evaluation of sticky traps for adult Aedes mosquitoes in Malaysia: a potential monitoring and surveillance tool for the efficacy of control strategies. AB - The present study compared the performance of sticky traps in order to identify the most effective and practical trap for capturing Aedes aegypti and Aedes albopictus mosquitoes. Three phases were conducted in the study, with Phase 1 evaluating the five prototypes (Models A, B, C, D, and E) of sticky trap release and-recapture using two groups of mosquito release numbers (five and 50) that were released in each replicate. Similarly, Phase 2 compared the performance between Model E and the classical ovitrap that had been modified (sticky ovitrap), using five and 50 mosquito release numbers. Further assessment of both traps was carried out in Phase 3, in which both traps were installed in nine sampling grids. Results from Phase 1 showed that Model E was the trap that recaptured higher numbers of mosquitoes when compared to Models A, B, C, and D. Further assessment between Model E and the modified sticky ovitrap (known as Model F) found that Model F outperformed Model E in both Phases 2 and 3. Thus, Model F was selected as the most effective and practical sticky trap, which could serve as an alternative tool for monitoring and controlling dengue vectors in Malaysia. PMID- 29125256 TI - Decoupling of active and passive reasons for the invasion dynamics of Aedes albopictus Skuse (Diptera: Culicidae): Comparisons of dispersal history in the Apennine and Florida peninsulas. AB - Aedes albopictus is an important vector of several diseases including dengue- and Chikungunya fever and is a potential vector of Zika-fever. The invasion dynamics of Aedes albopictus was reconsidered by comparing the temperature-related development of the mosquito with the observed real geographical distribution in Florida and in Italy. The potential number of generations and the annual dispersal distances of the mosquito were calculated for the estimates. The estimated total dispersals are 3.6-4.6 km/year/generation in Italy and 4.6-5.3 km/year/generation in Florida, values that are at least five to six times higher than those derived from release and recapture studies and from the previously measured flying distances of female Asian tiger mosquitoes. Subtracting the calculated dispersal distances with the known active dispersal of female Ae. albopictus, the passive dispersal component of the total dispersal distances was found to be 2.8-4.1 km/year/generation in Italy and 3.8-4.8 km/year/generation in Florida. Our results confirm that the active dispersal of female mosquitoes plays a secondary role in determining the rate of areal expansion and, in contrast, passive factors may play a primary role. It was concluded, based on similar average values of the passive dispersal distances of the mosquito in Florida and Italy, that at large spatial scales the anthropogenic component can be well estimated. PMID- 29125257 TI - Improving door-to-needle times for patients with suspected neutropenic sepsis. AB - Neutropenic sepsis is a potentially life-threatening complication of chemotherapy and has an associated mortality of 2% to 21%. Patients can deteriorate rapidly and are usually advised to attend their local emergency department (ED) for urgent assessment and antibiotic therapy within one hour of arrival. Delivery of this emergency care is, however, inconsistent, and at times suboptimal, due to a lack of awareness of the condition and of clinical expertise. This article discusses a collaborative project between an acute oncology service and an ED, which has improved and sustained compliance with this standard through a range of initiatives, including revised and integrated sepsis guidelines, education, sepsis champions and a fast-track patient pathway. A transformational leadership approach, which embraced collaborative working and fostered motivation by creating ownership of the project by the ED team, has been instrumental in its success. PMID- 29125258 TI - Evaluation of a mental health liaison team. Part 1: background and literature review. AB - Hospitals and emergency departments (EDs) are caring for increasing numbers of patients who present with underlying mental health issues. Management of these patients can be challenging for clinical staff who often lack the specialist knowledge and skills required to provide appropriate care. In April 2015, a mental health liaison service was introduced in Rotherham Hospital as part of a two-year pilot scheme. The aim was to provide assessment and treatment of adults with mental health problems admitted to the hospital. An evaluation of the new service was undertaken to assess the effects of the service. This article, part one of two, reviews the literature, as well as outlining the background to, and method of, evaluation. Part two, which will be published in December, examines the themes revealed by analysis of the service participants' responses. PMID- 29125259 TI - Implementation of a model of emergency care in an Australian hospital. AB - AIM: Emergency departments are characterised by a fast-paced, quick turnover and high acuity workload, therefore appropriate staffing is vital to ensure positive patient outcomes. Models of care are frameworks in which safe and effective patient-to-nurse ratios can be ensured. The aim of this study was to implement a supportive and transparent model of emergency nursing care that provides structure - regardless of nursing staff profile, business or other demands; improvement to nursing workloads; and promotes individual responsibility and accountability for patient care. METHOD: A convergent parallel mixed-method approach was used. Quantitative data were analysed using descriptive statistics and the qualitative data used a thematic analysis to identify recurrent themes. RESULTS: Data post-implementation of the model of emergency nursing care indicate improved staff satisfaction in relation to workload, patient care and support structures. CONCLUSION: The development and implementation of a model of care in an emergency department improved staff workload and staff's perception of their ability to provide care. PMID- 29125260 TI - Liver allocation. AB - Liver allocation policies determine how those livers that are offered for transplantation are allocated to those who have met the criteria for liver transplantation and are fit enough to undergo the procedure. The goals of allocation policies are based on varying combinations of need (reducing mortality awaiting a graft), benefit (maximizing the outcomes of candidates on the list) or utility (maximizing the life-years gained). Improvement in quality of life is rarely included in the setting of allocation policies. Policies need to be complaint with legal and ethical standards, ensure equity, and provide transparency. Most jurisdictions have used two major categories: high-urgency (such as acute liver failure) and elective where candidates are ranked according to need. Need for these candidates is often measured by the MELD score (or its modifications): although there are many valid concerns about the model, it remains the most widely used. Some jurisdictions are developing models which allocate on the basis of transplant benefit. It is important that allocation models do not stifle innovation and research. Different jurisdictions have developed different approaches to respond to the variations in both donors and recipients, the geographical challenges, prevalence of liver disease and donor rates and how to include those whose prognosis is not assessed by the standard models. While there is a need to review and audit policies regularly, and revise if necessary, development of the ideal policy should not distract from approaches to increase donor rates, maximise the quality of offered organs and ensure all useable organs are indeed used. PMID- 29125261 TI - Hepatitis B and liver transplantation. AB - Liver transplantation (LT) is the only effective treatment for hepatitis B-virus (HBV) related end stage liver disease, even if the outcome of these patients, has significantly improved after introduction of effective and well tolerated nucleoside/nucleotide analogues (NUC). Pre-transplant therapy has been initially based on lamivudine, but entecavir and tenofovir represent the currently recommended first-line therapeutic option in patients with HBV decompensated cirrhosis. After LT, the development of hepatitis B immunoglobulin (HBIG) in the early 1990's dramatically changes the prognosis of these patients by reducing the incidence of HBV recurrence and increasing survival rate. Combination of HBIG and NUC is now considered as the standard of care for prophylaxis against HBV recurrence, however personalized therapeutic algorithms based on pre- and post transplant viral and host factors have been proposed. Finally, liver grafts from hepatitis B core antibody-positive donors and from hepatitis B antigen-positive donors can be safely used in selected patients. PMID- 29125262 TI - Mediterranean diet in liver steatosis: the role of polyphenols. PMID- 29125263 TI - Welfare-Enhancing Technological Change and the Growth of Obesity. PMID- 29125264 TI - Drug-coated balloons reduce the risk of recurrent restenosis in arteriovenous fistulas and prosthetic grafts for hemodialysis. AB - BACKGROUND: Aim of this study was to evaluate the early and mid-term outcomes of drug-coated balloons (DCBs) in hemodialysis patients with recurrent stenosis of arteriovenous fistula and previously treated with plain balloon angioplasty (PBA). METHODS: Between July 2013 and June 2016 38 hemodialysis patients with recurrent stenosis of arteriovenous fistula underwent endovascular treatment with a DCB at our center. All patients were previously treated at the target lesion with a PBA. The intervals in months between the standard PBA and the procedure with DCB (time PBA-DCB) and between the procedure with DCB and the restenosis at the target lesion (time DCB-restenosis) were evaluated and compared with T-test. Estimated outcomes at 2 years in terms of patient survival, primary patency, primary assisted patency, secondary patency, and freedom from target lesion restenosis were assessed with Kaplan-Meier curves. RESULTS: Intraprocedural technical success was obtained in 97.4% of the cases. During the follow-up (mean duration 14.3 months, range 2-33) 19 patients (50%) developed a restenotic lesion at the target lesion with an estimated 2-year freedom from target lesion restenosis of 32.8%. Mean time PBA-DCB was 6.4 months, and the mean time DCB restenosis was 7.9 months with a statistically significant difference at T-test (P<0.001). Estimated 2-year rates of primary patency, primary assisted patency, and secondary patency were 40.8%, 73.1%, and 82.5%, respectively. CONCLUSIONS: In our experience DCBs were safe and effective in the treatment of recurrent stenosis in patients with failing arteriovenous fistula. The time to restenosis at the target lesion was longer respect to that necessary to have a recurrent restenosis after PBA. PMID- 29125265 TI - The 1918 Influenza Pandemic and Subsequent Health Outcomes: An Analysis of SIPP Data. PMID- 29125267 TI - Treatment strategies of spinal arteriovenous fistulas and malformations: timing matters. AB - Spinal vascular malformations are a rare heterogeneous entity of spinal lesions with abnormal blood vessels. They may occur extra- and intradurally, peri- and intramedullary, with confined or complex configuration, and at various levels of the spine. Associated clinical symptoms are extremely variable and may range from diffuse pain, to progressive myelopathy, and even to acute hemorrhage with severe neurological deficits. Often, the patients present with significant spinal cord injury before the spinal arteriovenous lesions are diagnosed. Early recognition of the pathology is essential to cease potential disease progression and neurological deterioration. Therefore, the purpose of this review was to describe the current findings in spinal arteriovenous lesions focusing on the timing of treatment and treatment modality. PMID- 29125266 TI - Decision making in very severe traumatic brain injury (Glasgow Coma Scale 3-5): a literature review of acute neurosurgical management. AB - INTRODUCTION: Patients presenting with an early Glasgow Coma Scale (GCS) Score of 3-5 after blunt or penetrating skull-brain assaults are categorized as having sustained a very severe traumatic brain injury (vs-TBI). This category is often overlooked in literature. Impact on patients and families lives however is huge and the question "whether to surgically treat or not" frequently poses a dilemma to treating physicians. Little is known about mortality and outcome, compared to what is known for the group of severe TBI patients (s-TBI) (GCS 3-8). The main goal of this review was creating more awareness for the neurosurgical treatment of this patient group. EVIDENCE ACQUISITION: A literature search (2000-2017) was conducted discussing "severe TBI (GCS 3-8)", "(neuro)surgical management" and "outcome". Ultimately 45 out of 2568 articles were included for further analysis. EVIDENCE SYNTHESIS: Mortality rates and unfavorable outcome are high for s-TBI patients and as expected higher for vs-TBI patients. Mortality rates reach up to 100% for specific subgroups with GCS=3 and bilaterally fixed dilated pupils. Functional outcome was generally poor, but sometimes, although seldom, favorable in specific groups of vs-TBI patients after neurosurgical intervention. Factors like initial GCS, pupillary abnormalities and age seem to be associated with worse outcome. CONCLUSIONS: Overall this literature review showed high rates of unfavorable outcome and mortality for vs-TBI patients. However, some studies, reporting relatively low mortality rates, reported "good" outcome for specific groups of vs-TBI patients. It is concluded that clinical decision making, in particular those on treatment limitations, should never be taken based on the GCS alone. PMID- 29125268 TI - An Investigation of the Effects of Alcohol Consumption and Alcohol Policies on Youth Risky Sexual Behaviors. PMID- 29125269 TI - Direct oral anticoagulants use in elderly patients with non valvular atrial fibrillation: state of evidence. AB - Non-valvular atrial fibrillation (NVAF) increases the risk of stroke by three- to five-fold, especially in elderly patients, creating a huge burden on medical system as well as a negative impact on patients' lives. Balancing efficacy and bleeding risk is a challenge when considering anticoagulation therapy in elderly patients, because of their frequent high risk of both stroke and bleeding. Real world data reveal the underuse of anticoagulation in the elderly, especially due to physicians' fear of bleeding, often neglecting the thromboembolic risk. Care of elderly patients with NVAF is often complicated by factors including adherence, cognitive impairment, health literacy, risk of falling, adverse effects, involvement of caregivers, and patient-physician relationship. Therefore, shared decision making and conversations between clinicians and patients are crucial. In addition, elderly patients often suffer from multiple comorbidities, requiring multiple concomitant medications, with an increased risk of drug interactions. Four non-vitamin K antagonist oral anticoagulants, the so called direct oral anticoagulants (DOACs) - dabigatran, rivaroxaban, apixaban and edoxaban - have been approved for reducing the risk of stroke and systemic embolism in patients with NVAF. Clinical trials and real-world data show the advantages of this class of drugs compared to conventional anticoagulation in the treatment of elderly patients with NVAF and identify subgroups of older patients who may be more suitable candidates for particular agents. However, there are conflicting opinions on the absolute benefit of DOACs use in elderly patients. A key factor to consider is that elderly patients frequently suffer from renal impairment and therefore dose adjustments according to creatinine clearance are mandatory for DOACs. As each DOAC comes with its own unique advantages and safety profile, a personalized case by case approach should be adopted to decide on the appropriate anticoagulation regimen for elderly patients after weighing the overall risks and benefits of therapy. PMID- 29125270 TI - Alternative incision sutureless aortic valve replacement: propensity matched comparison between partial sternotomy and right anterior minithoracotomy. AB - BACKGROUND: Sutureless aortic valve prostheses have the potential to augment the adoption of alternative incision approaches for aortic valve replacement (AVR). Still, we lack the evidence on which surgical approach is best associated with sutureless AVR. METHODS: Data on 483 patients undergoing sutureless small incision AVR between 2010-2014 in two European institutions (207 with ministernotomy [MS] and 276 via right anterior minithoracotomy [RAMT]) have been retrospectively analyzed. After propensity score matching, 160 pairs of patients have been selected. RESULTS: No significant difference for in-hospital mortality was observed between MS and RAMT (P=0.12). Both perfusion and aortic cross clamping times were longer in RAMT group (P<0.0005). Lower incidence of third degree atrioventricular block requiring pacemaker implantation (P=0.04), shorter ventilation times (P<0.0005) and less requirement for pleural drainage/thoracentesis (P=0.007) have been registered in the RAMT group. Follow up was shorter for RAMT group (14.6 vs. 21.7 months, P<0.0005). Survival by Kaplan-Meier was comparable both for unmatched (P=0.79) and matched (P=0.90) cohorts. Cox regression analysis showed no statistically significant difference for mid-term survival between the two approaches (P=0.95 for intercohort comparison [MS vs. RAMT]). Mid-term survival by Cox multivariable proportional hazards regression model was associated with two independent predictors: preoperative left ventricular ejection fraction (P=0.021) and prolonged (>24 h) assisted ventilation (P=0.001). CONCLUSIONS: Small incision sutureless AVR through both partial sternotomy and right anterior minithoracotomy provides excellent clinical outcomes. Right anterior minithoracotomy, though associated with longer operative times compared to partial sternotomy, may result in less perioperative morbidity, with no difference in early and mid-term survival. PMID- 29125271 TI - The Neuroeconomics of Mind Reading and Empathy. PMID- 29125272 TI - The relationship between the hormone levels before transplantation and the outcomes of hormone replacement therapy frozen embryo transfer. AB - BACKGROUND: The aim of the present study was to analyze the relationship between the outcomes of hormone replacement therapy frozen embryo transfer (HRT-FET) and serum estradiol and progesterone levels on the day of endometrial transformation and before transplantation. METHODS: Clinical data of patients who underwent 426 cycles of HRT-FET were retrospectively analyzed and were divided into group according to estradiol and progesterone levels. Differences in embryo implantation rate and clinical pregnancy rate were compared, and relationship between estradiol levels and outcome of transplantation was analyzed. RESULTS: During the 426 cycles, clinical pregnancy rate was 49.77% and embryo implantation rate was 27.20%. Differences in estradiol and progesterone levels on the day of endometrial transformation and before transplantation between pregnant and non pregnant groups were not statistically significant. Furthermore, embryo implantation rate and clinical pregnancy rate among different levels of estradiol patients was not statistical different. On the day before transplantation, serum estradiol level decreased in 98.36% of patients. Differences in implantation rate and clinical pregnancy rate among patients with different extents of decrease in estradiol and different progesterone levels the day before transplantation were statistically significant (P<0.05). CONCLUSIONS: The extent of decrease in serum estradiol and progesterone levels on the day before transplantation may be associated with outcome of HRT-FET. PMID- 29125273 TI - Expression and clinical significance of EGF and TGF-alpha in chronic pancreatitis and pancreatic cancer. AB - BACKGROUND: The purpose of this project was to investigate the expression and clinical significance of epidermal growth factor (EGF) and the transforming growth factor-alpha (TGF-alpha) in the occurrence and development of chronic pancreatitis and pancreatic cancer. METHODS: We recruited 31 patients with chronic pancreatitis, 42 with pancreatic cancer, and 20 with normal pancreas in our hospital. Chronic pancreatitis, pancreatic cancer, and normal pancreas expressed EGF and TGF-alpha mRNAs as well as EGF and TGF-alpha proteins. RESULTS: Immunofluorescence showed that EGF and TGF-alpha were expressed in chronic pancreatitis and pancreatic cancer, but the expression levels for both proteins were higher in pancreatic cancer. Variance analysis indicated that the differences in the expression levels of EGF and TGF-alpha in chronic pancreatitis, pancreatic cancer, and normal pancreas were statistically significant. The abnormally elevated expression of EGF and TGF-alpha are closely associated with the occurrence and development of chronic pancreatitis and pancreatic cancer. CONCLUSIONS: EGF and TGF-alpha have important research value as indicators to assess the progression of these conditions and provide a new basis for the clinical diagnosis. PMID- 29125275 TI - Neuroeconomic Foundations of Trust and Social Preferences: Initial Evidence. PMID- 29125274 TI - Pseudohypoparathyroidism. AB - The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The phenotypes of Albright hereditary osteodystrophy (AHO), originally described as associated to the disease, and progressive osseous heteroplasia, can be associated to the endocrine manifestations of hormonal resistance. Genetic or epigenetic alterations in the complex imprinted GNAS locus, encoding the alpha subunit of the stimulatory G protein (GSalpha) and several other transcripts, give rise to the different forms oh PHP, which can be differentiated according to the phenotype, the response to PTH infusion and in vitro assays testing Gsalpha activity. Since PHP-related phenotypes are overlapping and other non GNAS dependent disorders mimicking AHO, such as acrodysostosis, have been genetically characterized, the term PHP is today considered obsolete and better referred to the more comprehensive "inactivating PTH/PTHrP signaling disorder (iPPSD)" as proposed in a recent classification. This broad term include all the congenital rare disorders due to impaired PTH/PTHrP cAMP pathway. Genetic and epigenetic analyses, although not necessary for diagnosis made on the basis of major and minor criteria according to clinical and biochemical signs, will let to differentiate among the different forms for proper therapeutic planning, counseling and follow-up. PMID- 29125276 TI - The Neuroeconomics of Distrust: Sex Differences in Behavior and Physiology. PMID- 29125277 TI - 3D-Printed Hierarchical Porous Frameworks for Sodium Storage. AB - Exploring 3D printing in the field of sodium-ion batteries is a great challenge since conventionally inks cause unavoidably compact filaments or frameworks, which significantly hamper the infiltration of electrolyte and diffusion of big size sodium ions (1.02 A), resulting in low reversible capacities. Here, new hierarchical porous frameworks are 3D printed for sodium storage by employing well-designed GO-contained inks. The resultant frameworks possess continuous filaments, hierarchical multihole gridding. Such distinct properties render these frameworks able to facilitate the fast transportation of both sodium ion and electron. As a result, 3D-printed hierarchical porous frameworks reveal the high specific capacity as well as rate performance and periodic steadiness for up to 900 cycles for sodium storage. PMID- 29125278 TI - Grafting Commercial Surfactants (Brij, CiEj) and PEG to Electrodes via Aryldiazonium Salts. AB - Grafting commercial surfactants appears to be a simple way to modify electrodes and conducting interfaces, avoiding the synthesis of complex organic molecules. A new surface functionalization route is presented to build surfactant coatings with monolayer thickness grafting molecules considered as nonreactive. A monolayer of -SO2Cl functions (from a p-benzenesulfonyl chloride) was first electrografted. It showed a high reactivity toward weak nucleophiles commonly found on surfactant end-moieties such as hydroxyl groups (-OH), and it was used to covalently graft the following: (1) nonionic diblock oligomers (Brij or CiEj, CxH2x + (OCH2CH2)nOH with x = 16 and n = 23 for Brij58, x = 16 and n = 10 for Brij C10, and x = 16 and n = 2 for Brij52); (2) poly(ethylene glycol) (PEG) short chains (PEO9 for (OCH2CH2)nOH with n = 9) and mixed formula. The surface modification due to these molecular coatings was investigated in terms of wetting properties and interfacial electrochemistry characteristics (charge transfer resistivity, capacity, and ions dynamics). Built on flat and transparent thin chromium films, Brij and PEO mixed coatings have been proven to be promising coatings for electrochemical biosensor application such as for stabilizing a partially tethered supported biomimetic membrane. PMID- 29125279 TI - Molecular Weight and Charge Density Effects of Guanidinylated Biodegradable Polycarbonates on Antimicrobial Activity and Selectivity. AB - Six guanidine functionalized aliphatic biodegradable polycarbonates with varying molecular weights and charge densities were synthesized via postsynthesis modification of alkyne containing polycarbonates using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) click chemistry. The concept of passive diluting group was to modify the cationic charge density of the polycarbonate without changing its hydrophilicity. Within the molecular weight range from 8000 to 30000 g mol-1, these guanidine polycarbonates exhibited broad-spectrum biocidal activity with low toxicity to red blood cells (RBCs). The lowest molecular weight homopolymer sample (PG-8k-100) showed the best antimicrobial activity (MIC = 40 MUg/mL against Escherichia coli and MIC = 20 MUg/mL against Staphylococcus epidermidis) and least RBC toxicity (0.6% hemolysis at MIC). Within the three guanidine charge densities from 20% to 70%, the low to medium dilution samples (PG-8k-7030 and PG-8k-5050) had no obvious loss in antimicrobial activities compared to the nondiluted control sample PG-8k-100. However, upon further dilution, PG-8k-2080 gave the lowest antimicrobial activity. PMID- 29125280 TI - Haptacyclic Carbazole-Based Ladder-Type Nonfullerene Acceptor with Side-Chain Optimization for Efficient Organic Photovoltaics. AB - In this research, a haptacyclic carbazole-based dithienocyclopentacarbazole (DTCC) ladder-type structure was formylated to couple with two 1,1 dicyanomethylene-3-indanone (IC) moieties, forming a new nonfullerene acceptor DTCCIC-C17 using a bulky branched 1-octylnonayl side chain at the nitrogen of the embedded carbazole and four 4-octylphenyl groups at the sp3-carbon bridges. The rigid and coplanar main-chain backbone of the DTCC core provides a broad light absorbing window and a higher-lying LUMO energy level, whereas the bulky flanked side chains reduce intermolecular interactions, making DTCCIC-C17 amorphous with excellent solution processability. The DTCCIC-C17 as an acceptor is combined with a medium band gap polymer poly[(2,6-(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl) benzo[1,2-b:4,5-b']dithiophene))-alt-(5,5-(1',3'-di-2-thienyl-5',7'-bis(2 ethylhexyl)benzo[1',2'-c:4',5'-c']dithiophene-4,8-dione))] (PBDB-T) as the donor in the active layer to obtain suitable highest occupied molecular orbital/lowest unoccupied molecular orbital energy alignments and complimentary absorption. The devices with an inverted configuration (ITO/ZnO/active layer/MoO3/Ag) without using an aqueous poly(3,4-ethylenedioxythiophene) polystyrene sulfonate layer were fabricated for better device stability. When the diiodooctane-treated PBDB T:DTCCIC-C17 active layer was thermally annealed at 50 degrees C for 10 min, the device achieved the highest efficiency of 9.48% with a high Voc of 0.98 V, a Jsc of 14.27 mA cm-2, and an FF of 0.68. PMID- 29125281 TI - Brushlike Cationic Polymers with Low Charge Density for Gene Delivery. AB - Using a combined synthesis approach comprising reversible addition-fragmentation transfer polymerization and ring opening reaction, a series of poly glycidyl methacrylate (polyGMA) polymers were designed and synthesized for gene delivery. These polymers characterized by low cationic charge respective to established gene delivery vectors such as PEI were studied to further elucidate the key structure-activity parameters that mediate efficient and biocompatible gene delivery. Compared to PEI, these brushlike polymers facilitated markedly improved safety and gene delivery efficiency. PMID- 29125282 TI - Smart Chiral Sensing Platform with Alterable Enantioselectivity. AB - A quinine (QN)-based chiral sensing platform with alterable enantioselectivity is constructed for electrochemical chiral recognition of tryptophan (Trp) isomers. The electrochemical signals of l- and d-Trp on the QN modified electrode depend closely on temperature, and more particularly are reversed at certain temperatures, which could be attributed to the temperature-sensitive H-bonds and pi-pi interactions between QN and the Trp isomers. The mechanisms of the reverse chiral recognition are investigated by density functional theory (DFT), variable temperature UV spectra, and variable-temperature 1H NMR spectra. In addition, the chiral recognition is highly specific to the isomers of Trp compared with other chiral amino acids. This study is the first example showing how temperature influences the reverse recognition of electrochemical chiral interfaces. PMID- 29125283 TI - High Lithium Storage Capacity and Long Cycling Life Fe3S4 Anodes with Reversible Solid Electrolyte Interface Films and Sandwiched Reduced Graphene Oxide Shells. AB - Increasing demands for lithium-ion batteries (LIBs) with high energy density and high power density require highly reversible electrochemical reactions to enhance the cyclability and capacities of electrodes. As the reversible formation/decomposition of the solid electrolyte interface (SEI) film during the lithiation/delithiation process of Fe3S4 could bring about a higher capacity than its theoretical value, in the present work, synthesized Fe3S4 nanoparticles are sandwich-wrapped with reduced graphene oxide (RGO) to fabricate highly reversible and long cycling life anode materials for high-performance LIBs. The micron-sized long slit between sandwiched RGO sheets effectively prevents the aggregation of intermediate phases during the discharge/charge process and thus increases cycling capacity because of the reversible formation/decomposition of the SEI film driven by Fe nanoparticles. Furthermore, the RGO sheets interconnect with each other by a face-to-face mode to construct a more efficiently conductive network, and the maximum interfacial oxygen bridge bonds benefit the fast electron hopping from RGO to Fe3S4, improving the depth of the electrochemical reactions and facilitating the highly reversible lithiation/delithiation of Fe3S4. Thus, the resultant Fe3S4/RGO hybrid shows a highly reversible charge capacity of 1324 mA h g-1 over 275 cycles at a current density of 100 mA g-1, even retains 480 mA h g-1 over 500 cycles at 1000 mA g-1, which are much higher than reported values. PMID- 29125284 TI - The Story behind "Synergy of Synthesis, Computation, and NMR Reveals Correct Baulamycin Structures". PMID- 29125286 TI - Bosonic Confinement and Coherence in Disordered Nanodiamond Arrays. AB - In the presence of disorder, superconductivity exhibits short-range characteristics linked to localized Cooper pairs which are responsible for anomalous phase transitions and the emergence of quantum states such as the bosonic insulating state. Complementary to well-studied homogeneously disordered superconductors, superconductor-normal hybrid arrays provide tunable realizations of the degree of granular disorder for studying anomalous quantum phase transitions. Here, we investigate the superconductor-bosonic dirty metal transition in disordered nanodiamond arrays as a function of the dispersion of intergrain spacing, which ranges from angstroms to micrometers. By monitoring the evolved superconducting gaps and diminished coherence peaks in the single quasiparticle density of states, we link the destruction of the superconducting state and the emergence of bosonic dirty metallic state to breaking of the global phase coherence and persistence of the localized Cooper pairs. The observed resistive bosonic phase transitions are well modeled using a series-parallel circuit in the framework of bosonic confinement and coherence. PMID- 29125285 TI - Nonswelling Thiol-Yne Cross-Linked Hydrogel Materials as Cytocompatible Soft Tissue Scaffolds. AB - A key drawback of hydrogel materials for tissue engineering applications is their characteristic swelling response, which leads to a diminished mechanical performance. However, if a solution can be found to overcome such limitations, there is a wider application for these materials. Herein, we describe a simple and effective way to control the swelling and degradation rate of nucleophilic thiol-yne poly(ethylene glycol) (PEG) hydrogel networks using two straightforward routes: (1) using multiarm alkyne and thiol terminated PEG precursors or (2) introducing a thermoresponsive unit into the PEG network while maintaining their robust mechanical properties. In situ hydrogel materials were formed in under 10 min in PBS solution at pH 7.4 without the need for an external catalyst by using easily accessible precursors. Both pathways resulted in strong tunable hydrogel materials (compressive strength values up to 2.4 MPa) which could effectively encapsulate cells, thus highlighting their potential as soft tissue scaffolds. PMID- 29125287 TI - Anion Recognition in Aqueous Media by Cyclopeptides and Other Synthetic Receptors. AB - Anion receptors often rely on coordinative or multiple ionic interactions to be active in water. In the absence of such strong interactions, anion binding in water can also be efficient, however, as demonstrated by a number of anion receptors developed in recent years. The cyclopeptide-derived receptors comprising an alternating sequence of l-proline and 6-aminopicolinic acid subunits are an example. These cyclopeptides are neutral and, at first sight, can only engage in hydrogen-bond formation with an anionic substrate. Nevertheless, they even interact with strongly solvated sulfate anions in water. The intrinsic anion affinity of these cyclopeptides can be related to structural aspects of their highly preorganized concave binding site, which comprises a wall of hydrophobic proline units arranged around the peptide NH groups at the cavity base. When anions are incorporated into this cavity they can engage in hydrogen bonding interactions to the NH groups, and complex formation also benefits from cavity dehydration. Formation of 1:1 complexes, in which an anion binds to a single cyclopeptide ring, is associated with only small stability constants, however, whereas significantly more stable complexes are formed if the anion is buried between two cyclopeptide molecules. A major contribution to the formation of these sandwich complexes derives from the addition of the second ring to the initially formed 1:1 cyclopeptide-anion complex. This step brings the apolar proline residues of both cyclopeptides in close proximity, which causes the resulting structure to be stabilized to a large extent by hydrophobic effects. Solvent dependent binding studies provided an estimate to which degree these solvent effects contribute to the overall complex stability. In these studies, bis(cyclopeptides) were used, featuring two cyclopeptide rings covalently connected via linkers that enable both rings to simultaneously interact with the anion. Bis(cyclopeptides) with additional solubilizing groups allowed binding studies in a wide range of solvents, including in water. The systematic analysis of the solvent dependence of anion affinity yielded a quantitative correlation between complex stability and parameters relating to the solvation of the anions and solvent properties, confirming that solvent effects contribute to anion binding. Interestingly, the thermodynamic signature of complex formation in water mirrors that of sulfate binding to a protein complex but is opposite to that of other recently described anion receptors, which also do not engage in ionic or coordinative interactions with the substrate. These receptors not only differ in terms of the thermodynamics of binding from the cyclopeptides but also possess a characteristically different anion selectivity in that they prefer to bind weakly coordinating anions but fail to bind sulfate. Solvent effects likely control the anion binding of both receptors types but their impact on complex formation and anion selectivity seems to be profoundly different. Future work in the area of anion coordination chemistry will benefit from the deeper understanding of these effects and how they can be controlled. PMID- 29125288 TI - Uptake, Translocation, and Biotransformation of Organophosphorus Esters in Wheat (Triticum aestivum L.). AB - The uptake, translocation and biotransformation of organophosphate esters (OPEs) by wheat (Triticum aestivum L.) were investigated by a hydroponic experiment. The results demonstrated that OPEs with higher hydrophobicity were more easily taken up by roots, and OPEs with lower hydrophobicity were more liable to be translocated acropetally. A total of 43 metabolites including dealkylated, oxidatively dechlorinated, hydroxylated, methoxylated, and glutathione-, and glucuronide- conjugated products were detected derived from eight OPEs, with diesters formed by direct dealkylation from the parent triesters as the major products, followed with hydroxylated triesters. Molecular interactions of OPEs with plant biomacromolecules were further characterized by homology modeling combined with molecular docking. OPEs with higher hydrophobicity were more liable to bind with TaLTP1.1, the most important wheat nonspecific lipid transfer protein, consistent with the experimental observation that OPEs with higher hydrophobicity were more easily taken up by wheat roots. Characterization of molecular interactions between OPEs and wheat enzymes suggested that OPEs were selectively bound to TaGST4-4 and CYP71C6v1 with different binding affinities, which determined their abilities to be metabolized and form metabolite products in wheat. This study provides both experimental and theoretical evidence for the uptake, accumulation and biotransformation of OPEs in plants. PMID- 29125289 TI - A Practical and High-Affinity Fluorescent Probe for Uridine Diphosphate Glucuronosyltransferase 1A1: A Good Surrogate for Bilirubin. AB - This study aimed to develop a practical and high-affinity fluorescent probe for uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), a key conjugative enzyme responsible for the elimination and detoxification of many potentially harmful compounds. Several substrates derived from N-butyl-4-phenyl-1,8 naphthalimide were designed and synthesized on the basis of the substrate preference of UGT1A1 and the principle of photoinduced electron transfer (PET). Following the preliminary screening, substrate 2 was found with a high specificity and high affinity toward UGT1A1, while such biotransformation brought remarkable changes in fluorescence emission. Both inhibition kinetic analyses and molecular docking simulations demonstrated that 2 could bind on UGT1A1 at the same ligand-binding site as bilirubin. Furthermore, this newly developed probe was successfully used for sensing UGT1A1 activities and the high-throughput screening of UGT1A1 modulators in complex biological samples. In conclusion, a practical and high-affinity fluorescent probe for UGT1A1 was designed and well characterized, which could serve as a good surrogate for bilirubin to investigate UGT1A1-ligand interactions. PMID- 29125290 TI - Effect of Ionic Functional Groups on the Oxidation State and Interfacial Binding Property of Catechol-Based Adhesive. AB - Adhesive hydrogels were prepared by copolymerizing dopamine methacrylamide with either acrylic acid (AAc) or N-(3-aminopropyl)methacrylamide hydrochloride (APMH). The effect of incorporating the anionic and cationic side chains on the oxidation state of catechol was characterized using the FOX assay to track the production of hydrogen peroxide byproduct generated during the autoxidation of catechol, and the interfacial binding property of the adhesive was determined by performing Johnson-Kendall-Roberts contact mechanics tests tested over a wide range of pH values (pH 3.0-9.0). The ionic species contributed to interfacial binding to surfaces with the opposite charge with measured work of adhesion values that were comparable to or in some cases higher than those of catechol. Addition of AAc minimized the oxidation of catechol even at a pH of 8.5 and correspondingly preserved the elevated adhesive property of catechol to both quartz and amine-functionalized surfaces. However, AAc lost its buffering capacity at pH 9.0, and catechol was oxidized at this pH. On the other hand, catechol formed a cohesive covalent bond with the network-bound amine side chain of APMH at basic pH, which interfered with the interfacial binding capability of APMH and the catechol. PMID- 29125292 TI - TfOH-Catalyzed Reaction between 3-Diazoindolin-2-imines and Electron-Rich Arenes: Access to 3-Aryl-2-aminoindoles. AB - TfOH-catalyzed reactions between 3-diazoindolin-2-imines and electron-rich arenes were disclosed. These metal-free reactions furnished 3-aryl-2-aminoindoles in moderate to excellent yields with the tolerance of a broad range of functional groups. PMID- 29125291 TI - Identification of a New Pyrazolo[1,5-a]quinazoline Ligand Highly Affine to gamma Aminobutyric Type A (GABAA) Receptor Subtype with Anxiolytic-Like and Antihyperalgesic Activity. AB - Compounds that can act on GABAA receptor subtype in a selective manner, without the side effects of classical benzodiazepine ligands, represent promising therapeutic tools in neurological disorder as well as for relief of pain or in comorbidity of anxiety states and depression. Continuing our research on GABAA receptor subtype ligands, here is reported the synthesis of a series of pyrazolo[1,5-a]quinazoline 3- and/or 8-substituted as 5-deaza analogues of previous reported pyrazolo[5,1-c][1,2,4]benzotriazine, already identified as selective GABAA receptor subtype ligands endowed with anxiolytic-like and antihyperalgesic action or enhancer cognition. Between the new compounds stands out 12b for its high affinity value (Ki = 0.27 nM) and for its anxiolytic-like and ability to relieve neuropathic painful conditions evaluated in CCI and STZ murine model. PMID- 29125293 TI - Oxidation of Wine Polyphenols by Secretomes of Wild Botrytis cinerea Strains from White and Red Grape Varieties and Determination of Their Specific Laccase Activity. AB - Processing of Botrytis cinerea-infected grapes leads to enhanced enzymatic browning reactions mainly caused by the enzyme laccase which is able to oxidize a wide range of phenolic compounds. The extent of color deterioration depends on the activity of the enzymes secreted by the fungus. The present study revealed significant differences in the oxidative properties of secretomes of several B. cinerea strains isolated from five grape varieties. The presumed laccase containing secretomes varied in their catalytic activity toward six phenolic compounds present in grapes. All strains led to identical product profiles for five of six substrates, but two strains showed deviating product profiles during gallic acid oxidation. Fast oxidation of caffeic acid, ferulic acid, and malvidin 3-O-glucoside was observed. Product formation rates and relative product concentrations were determined. The results reflect the wide range of enzyme activity and the corresponding different impact on color deterioration by B. cinerea. PMID- 29125294 TI - Transition Metal Doping Reveals Link between Electron T1 Reduction and 13C Dynamic Nuclear Polarization Efficiency. AB - Optimal efficiency of dissolution dynamic nuclear polarization (DNP) is essential to provide the required high sensitivity enhancements for in vitro and in vivo hyperpolarized 13C nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI). At the nexus of the DNP process are the free electrons, which provide the high spin alignment that is transferred to the nuclear spins. Without changing DNP instrumental conditions, one way to improve 13C DNP efficiency is by adding trace amounts of paramagnetic additives such as lanthanide (e.g., Gd3+, Ho3+, Dy3+, Tb3+) complexes to the DNP sample, which has been observed to increase solid-state 13C DNP signals by 100-250%. Herein, we have investigated the effects of paramagnetic transition metal complex R-NOTA (R = Mn2+, Cu2+, Co2+) doping on the efficiency of 13C DNP using trityl OX063 as the polarizing agent. Our DNP results at 3.35 T and 1.2 K show that doping the 13C sample with 3 mM Mn2+-NOTA led to a substantial improvement of the solid-state 13C DNP signal by a factor of nearly 3. However, the other transition metal complexes Cu2+-NOTA and Co2+-NOTA complexes, despite their paramagnetic nature, had essentially no impact on solid state 13C DNP enhancement. W-band electron paramagnetic resonance (EPR) measurements reveal that the trityl OX063 electron T1 was significantly reduced in Mn2+-doped samples but not in Cu2+- and Co2+-doped DNP samples. This work demonstrates, for the first time, that not all paramagnetic additives are beneficial to DNP. In particular, our work provides a direct evidence that electron T1 reduction of the polarizing agent by a paramagnetic additive is an essential requirement for the improvement seen in solid-state 13C DNP signal. PMID- 29125295 TI - Structure-Activity Relationships and Biological Characterization of a Novel, Potent, and Serum Stable C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonist. AB - In our ongoing pursuit of CXCR4 antagonists as potential anticancer agents, we recently developed a potent, selective, and plasma stable peptide, Ac-Arg-Ala-[d Cys-Arg-Phe-Phe-Cys]-COOH (3). Nevertheless, this compound was still not potent enough (IC50 ~ 53 nM) to enter preclinical studies. Thus, a lead-optimization campaign was here undertaken to further improve the binding affinity of 3 while preserving its selectivity and proteolytic stability. Specifically, extensive structure-activity relationships (SARs) investigations were carried out on both its aromatic and disulfide forming amino acids. One among the synthesized analogue, Ac-Arg-Ala-[d-Cys-Arg-Phe-His-Pen]-COOH (19), displayed subnanomolar affinity toward CXCR4, with a marked selectivity over CXCR3 and CXCR7. NMR and molecular modeling studies disclosed the molecular bases for the binding of 19 to CXCR4 and for its improved potency compared to the lead 3. Finally, biological assays on specific cancer cell lines showed that 19 can impair CXCL12-mediated cell migration and CXCR4 internalization more efficiently than the clinically approved CXCR4 antagonist plerixafor. PMID- 29125296 TI - Hydroxy-Assisted Regio- and Stereoselective Synthesis of Functionalized 4 Methylenepyrrolidine Derivatives via Phosphine-Catalyzed [3 + 2] Cycloaddition of Allenoates with o-Hydroxyaryl Azomethine Ylides. AB - In this work, we present a new strategy for the chemo-, regio-, and stereoselective synthesis of functionalized pyrrolidine derivatives via a hydroxy assisted phosphine-catalyzed reaction of allenoates or substituted allenoates with o-hydroxyaryl azomethine ylides that offers a wide variety of 4 methylenepyrrolidine derivatives in synthetically useful yields with high stereoselctivities under mild conditions. Remarkably, it is the first example of highly regio- and stereoselective phosphine-catalyzed [3 + 2] cycloaddition of allenoates with o-hydroxyaryl azomethine ylides. PMID- 29125297 TI - Identification of Protein-Ligand Binding Sites by Sequence Information and Ensemble Classifier. AB - Identifying protein-ligand binding sites is an important process in drug discovery and structure-based drug design. Detecting protein-ligand binding sites is expensive and time-consuming by traditional experimental methods. Hence, computational approaches provide many effective strategies to deal with this issue. Recently, lots of computational methods are based on structure information on proteins. However, these methods are limited in the common scenario, where both the sequence of protein target is known and sufficient 3D structure information is available. Studies indicate that sequence-based computational approaches for predicting protein-ligand binding sites are more practical. In this paper, we employ a novel computational model of protein-ligand binding sites prediction, using protein sequence. We apply the Discrete Cosine Transform (DCT) to extract feature from Position-Specific Score Matrix (PSSM). In order to improve the accuracy, Predicted Relative Solvent Accessibility (PRSA) information is also utilized. The predictor of protein-ligand binding sites is built by employing the ensemble weighted sparse representation model with random under sampling. To evaluate our method, we conduct several comprehensive tests (12 types of ligands testing sets) for predicting protein-ligand binding sites. Results show that our method achieves better Matthew's correlation coefficient (MCC) than other outstanding methods on independent test sets of ATP (0.506), ADP (0.511), AMP (0.393), GDP (0.579), GTP (0.641), Mg2+ (0.317), Fe3+ (0.490) and HEME (0.640). Our proposed method outperforms earlier predictors (the performance of MCC) in 8 of the 12 ligands types. PMID- 29125298 TI - Surface-Initiated Ring-Opening Metathesis Polymerization of Dicyclopentadiene from the Vapor Phase. AB - Surface-attached polydicyclopentadiene (pDCPD) films were prepared on gold and silicon substrates via surface-initiated ring-opening metathesis polymerization (SI-ROMP) of dicyclopentadiene (DCPD). The films were grown utilizing monomer in both the vapor phase and the solution phase with the former process exhibiting rapid kinetics, producing ~400-nm-thick pDCPD films in less than 1 min of polymerization. No significant differences in thickness were observed for films grown from monomer in the vapor phase with the different isomers (exo and endo) of DCPD. Decane was used as an inert additive to control the concentration of DCPD monomer in the vapor phase enabling the preparation of pDCPD films with thickness ranging from tens of nanometers to hundreds of nanometers. The thickness of pDCPD films polymerized using monomer in the vapor phase was enhanced by the presence of a rinse solvent on the surface of the ROMP-active gold substrates. The choice of ROMP catalyst was found to be an important consideration when SI-ROMP was conducted on different substrates. Electrochemical impedance spectroscopy was used to reveal that the films provide effective barriers to the diffusion of aqueous ions in excess of 1 * 106 Omega.cm2. The mechanical properties of the surface-tethered pDCPD films were quantified with AFM PeakForce quantitative nanomechanical mapping (QNM) with a measured reduced Young's modulus (Er) of 15 GPa. The measured Er was greater than that of a non cross-linked surface-tethered polymer, pNB, indicating that the pDCPD films are stiffer. PMID- 29125299 TI - Charge-Driven Fluorescence Blinking in Carbon Nanodots. AB - This study focuses on the mechanism of fluorescence blinking of single carbon nanodots, which is one of their key but less understood properties. The results of our single-particle fluorescence study show that the mechanism of carbon nanodots blinking has remarkable similarities with that of semiconductor quantum dots. In particular, the temporal behavior of carbon nanodot blinking follows a power law both at room and at cryogenic temperatures. Our experimental data suggest that static quenching via Dexter-type electron transfer between surface groups of a nanoparticle plays a major role in the transition of carbon nanodots to off or gray states, whereas the transition back to on states is governed by an electron tunneling from the particle's core. These findings advance our understanding of the complex mechanism of carbon nanodots emission, which is one of the key steps for their application in fluorescence imaging. PMID- 29125300 TI - Ultrafast Synthesis and Coating of High-Quality beta-NaYF4:Yb3+,Ln3+ Short Nanorods. AB - An ultrafast route to prepare up-converting single beta-phase NaYF4:Yb3+,Ln3+ (Ln: Er, Tm, or Tb) short nanorods (UCNRs) of high quality was developed. This new procedure affords reactive-surface nanorods that are easily coated by direct injection of suitable capping ligands. Thus highly crystalline nanorods with excellent UC fluorescence and good solvent-selective dispersion are obtained, which represents a significant advance in the field and enlarges their use for biomedical and other technological applications. Unlike other methodologies, the short reaction time provides a kinetic control over crystallization processes, and the beta-phase and rod morphology is preserved regardless of the optically active Ln3+ ion. The UC emission was finely tuned by using the most popular Yb3+/Tm3+ and Yb3+/Er3+ pairs. More importantly, UCNRs doped with the unusual Yb3+/Tb3+ pair, with no ladder-like energy levels, provided a nice emission upon near-infrared excitation, which constitutes the first example of phonon-assisted cooperative sensitization to date in pure beta-NaYF4 nanocrystals. PMID- 29125301 TI - Photon Antibunching Reveals Static and Dynamic Quenching Interaction of Tryptophan with Atto-655. AB - Fluorescence correlation spectroscopy (FCS) of photoinduced electron transfer (PET) between the dye Atto-655 and the amino acid tryptophan has been extensively used for studying fast conformational dynamics of small disordered peptides and proteins. However, a precise understanding of the quenching mechanism and its exact rates that would explain ensemble as well as single-molecule spectroscopy results is still lacking. In this contribution, a general unified model for intermolecular PET between Atto-655 and tryptophan is developed, which involves ground-state complex formation, quenching sphere of action, and dynamic quenching at the single-molecule level. We present measurements of fluorescence antibunching, fluorescence lifetime, and steady-state fluorescence intensity and absorbance and demonstrate that our model is capable to describe all results in a global and coherent manner. PMID- 29125302 TI - Molecular Materials for Nonaqueous Flow Batteries with a High Coulombic Efficiency and Stable Cycling. AB - This manuscript presents a working redox battery in organic media that possesses remarkable cycling stability. The redox molecules have a solubility over 1 mol electrons/liter, and a cell with 0.4 M electron concentration is demonstrated with steady performance >450 cycles (>74 days). Such a concentration is among the highest values reported in redox flow batteries with organic electrolytes. The average Coulombic efficiency of this cell during cycling is 99.868%. The stability of the cell approaches the level necessary for a long lifetime nonaqueous redox flow battery. For the membrane, we employ a low cost size exclusion cellulose membrane. With this membrane, we couple the preparation of nanoscale macromolecular electrolytes to successfully avoid active material crossover. We show that this cellulose-based membrane can support high voltages in excess of 3 V and extreme temperatures (-20 to 110 degrees C). These extremes in temperature and voltage are not possible with aqueous systems. Most importantly, the nanoscale macromolecular platforms we present here for our electrolytes can be readily tuned through derivatization to realize the promise of organic redox flow batteries. PMID- 29125303 TI - Position-Dependent Dynamics Explain Pore-Averaged Diffusion in Strongly Attractive Adsorptive Systems. AB - Using molecular simulations, we investigate the relationship between the pore averaged and position-dependent self-diffusivity of a fluid adsorbed in a strongly attractive pore as a function of loading. Previous work (Krekelberg, W. P.; Siderius, D. W.; Shen, V. K.; Truskett, T. M.; Errington, J. R. Connection between thermodynamics and dynamics of simple fluids in highly attractive pores. Langmuir 2013, 29, 14527-14535, doi: 10.1021/la4037327) established that pore averaged self-diffusivity in the multilayer adsorption regime, where the fluid exhibits a dense film at the pore surface and a lower density interior pore region, is nearly constant as a function of loading. Here we show that this puzzling behavior can be understood in terms of how loading affects the fraction of particles that reside in the film and interior pore regions as well as their distinct dynamics. Specifically, the insensitivity of pore-averaged diffusivity to loading arises from the approximate cancellation of two factors: an increase in the fraction of particles in the higher diffusivity interior pore region with loading and a corresponding decrease in the particle diffusivity in that region. We also find that the position-dependent self-diffusivities scale with the position-dependent density. We present a model for predicting the pore-average self-diffusivity based on the position-dependent self-diffusivity, which captures the unusual characteristics of pore-averaged self-diffusivity in strongly attractive pores over several orders of magnitude. PMID- 29125304 TI - Homogeneous Nucleation of Ice in Transiently-Heated, Supercooled Liquid Water Films. AB - We have investigated the nucleation and growth of crystalline ice in 0.24 MUm thick, supercooled water films adsorbed on Pt(111). The films were transiently heated with ~10 ns infrared laser pulses, which produced typical heating and cooling rates of ~109-1010 K/s. The crystallization of these water films was monitored with infrared spectroscopy. The experimental conditions were chosen to suppress ice nucleation at both the water/metal and water/vacuum interfaces. Furthermore, internal pressure increases due to curvature effects are precluded in these flat films. Therefore, the experiments were sensitive to the homogeneous ice nucleation rate from ~210 to 225 K. The experiments show that Jmax, the maximum for the homogeneous ice nucleation rate, J(T), needs to be >=1026 m-3 s-1 and is likely to be ~1029+/-2 m-3 s-1. We argue that such large nucleation rates are consistent with experiments on hyperquenched glassy water, which typically have crystalline fractions of ~1% or more. PMID- 29125305 TI - Role Transformation of Poly( N-isopropylacrylamide) Microgels from Stabilizer to Seed in Dispersion Polymerization by Controlling the Water Content in Methanol Water Mixture. AB - Poly( N-isopropylacrylamide) (PNIPAM)-based ionic microgels with different diameters were first prepared and then used as particulate stabilizer or seed in dispersion polymerization of styrene. The role of PNIPAM-based ionic microgels could be transformed from particulate stabilizer to seed by controlling the water content in methanol-water mixture. Generally, PNIPAM-based ionic microgels served as particulate stabilizer in methanol in the absence of water, leading to the formation of spherical polystyrene nanoparticles. However, they turned into seeds when water was added into the methanol solution, with the formation of octopus like nanoparticles. Further study demonstrated that the mechanism for this role transition was related to the special thermosensitivity of PNIPAM microgels in methanol-water mixture. They lost their thermosensitivity in pure methanol solution but restored their thermosensitivity when increasing the water content in methanol-water mixture. PMID- 29125306 TI - Unilateral Acute Respiratory Distress Syndrome with Contralateral Pulmonary Artery Agenesis. PMID- 29125308 TI - [Articles of the Hungarian Medical Journal from December, 1979]. PMID- 29125307 TI - [Articles of the Hungarian Medical Journal from October, 1978]. PMID- 29125309 TI - [Articles of the Hungarian Medical Journal from August, 1980]. PMID- 29125310 TI - [Articles of the Hungarian Medical Journal from July, 1978]. PMID- 29125311 TI - [Articles of the Hungarian Medical Journal from December, 1978]. PMID- 29125312 TI - [Articles of the Hungarian Medical Journal from April, 1978]. PMID- 29125313 TI - [Articles of the Hungarian Medical Journal from May, 1978]. PMID- 29125315 TI - [Articles of the Hungarian Medical Journal from March, 1978]. PMID- 29125314 TI - Associations of Calcium and Dairy Products with All-Cause and Cause-Specific Mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Prospective Cohort Study. AB - Associations of calcium and dairy product intakes with cardiovascular disease risk and cancer mortality are controversial. We investigated associations of calcium and dairy product intakes with mortality in the prospective REasons for Geographic and Racial Differences in Stroke study (n = 30,239). Of 2,966 total deaths, 32.3% were from CVD and 28.8% from cancer. For those in the upper relative to the lowest quintile of intakes, from Cox proportional hazards regression models, the multivariable-adjusted hazard ratios (HRs) for all-cause mortality were 1.13 (95% confidence intervals [CI] 0.95-1.35; P-trend 0.004) for whole milk, and 0.75 (CI 0.61-0.93; P-trend 0.001) for nonfat milk; for CVD mortality the corresponding HRs were 0.80 (CI 0.55-1.16; P-trend 0.80) and 0.72 (CI 0.49-1.05; P-trend 0.06); and for cancer mortality they were 1.56 (CI 1.17 2.08; P-trend 0.006) and 0.89 (CI 0.62-1.28; P-trend 0.86). Calcium (total, dietary, supplemental) and total dairy product intakes were not associated with all-cause, cardiovascular, or cancer mortality. These results suggest that whole milk consumption may be directly associated with cancer mortality; non-fat milk consumption may be inversely associated with all-cause and cardiovascular- and cancer-specific mortality; and calcium intake independent of milk product intakes may not be associated with mortality. PMID- 29125316 TI - 'It is nothing more than a senior moment': the moderating role of subjective age in the effect of change in memory on self-rated memory. AB - OBJECTIVE: The association between memory performance and self-rated memory is yet to be understood. More specifically, little is known about the factors that lie at the base of self-evaluations of memory in relation to actual changes in memory. In this study, we suggest that subjective age modifies the effect of objective change in memory on self-rated memory. METHOD: We used two waves of the Health and Retirement Study (N = 4624) to examine whether subjective age moderates the effect of experienced changes in memory between T1 and T2 on self rated memory at T2. RESULTS: Our results suggest that subjective age is a significant moderator of the effect of change in memory on self-rated memory. The effect is weaker among those with younger subjective age, and stronger for those with older subjective age. CONCLUSION: While preserving a young subjective age is usually considered an adaptive strategy, it also has potential negative effects, masking changes in memory performance. PMID- 29125317 TI - [Articles of the Hungarian Medical Journal from October, 1979]. PMID- 29125318 TI - [Articles of the Hungarian Medical Journal from September, 1978]. PMID- 29125319 TI - Perceptions of neighborhood safety and depressive symptoms among older minority urban subsidized housing residents: the mediating effect of sense of community belonging. AB - OBJECTIVES: Older minority subsidized housing residents represent a population that is particularly vulnerable to depression. Although research suggests that neighborhood characteristics influence older adults' mental health, it has not been explored in this target population. Drawing on social disorganization and social capital theories, this study's aim was to explore if perceptions of neighborhood safety are associated with depressive symptoms; and, whether a sense of community belonging has a mediating effect on this potential relationship. METHODS: The data are from interviews with 216 older adults (50% Black, 45% Latino/a) living in a U.S. urban subsidized housing development. RESULTS: Among participants, 80% identified feeling 'very safe' during the day while 63% expressed feeling 'very safe' at night in their neighborhood. Approximately 60% possessed a stronger sense of community belonging and 26% had clinically relevant depressive symptoms. Hierarchical regression analyses revealed that perceptions of feeling less safe in one's neighborhood were significantly associated with elevated levels of depressive symptoms; however, a greater sense of community belonging buffered (or had a significant mediating effect on) this relationship. CONCLUSION: The findings suggest the importance of continued exploration of the role of social capital in relation to feelings of safety in later life. PMID- 29125320 TI - Prenatal famine exposure and mental health in later midlife. AB - OBJECTIVES: Maternal malnutrition during pregnancy may have long-lasting effects on offspring's mental health. We investigate the effect of prenatal exposure to the Dutch famine (mid November 1944 to late April 1945) on mental health in later mid-life. METHODS: Data are from the Netherlands Kinship Panel Study (n = 642). We use difference-in-difference analyses to compare mental health in later midlife (measured with the MHI-5 index) across three cohorts ('pre-famine cohort', 'famine cohort', 'post-famine cohort') and across two regions (famine affected cities vs. rest of the country). RESULTS: In the affected cities, we find poorer mental health for the famine cohort than for the pre-famine and post famine cohorts. In the non-affected rest of the country, no significant mental health differences between birth cohorts were found. The mental health differences between birth cohorts differ significantly between the affected cities and the rest of the Netherlands. CONCLUSION: Our analyses link prenatal famine exposure to poorer mental health in later midlife. This suggests that in utero malnutrition has a long-lasting detrimental effect on mental health. PMID- 29125321 TI - Two Futures: Financial and Practical Realities for Parents of Living With a Life Limited Child. AB - Today more and more children are living with complex health care needs, many of these children are living with life limiting and/or threatening conditions, some are medically fragile. To live a childhood these children must live in communities and with their families. In most cases this means the child's carers, their parents, most often their mothers, are required to undertake a great deal of the child's care. During a project on parental coping I became aware of the ways in which parents were restructuring their working lives in order to meet the demands of the nursing and medical care needs of their children. In this paper I relate the stories we discovered in this qualitative study and discuss the tensions between parental and state's responsibility for children, carers and the political and cultural rights and responsibilities pertaining to children's care. I use Margret Urban Walker's ideas of expressive collaborative morality to argue that the care of life limited and life threatened children should be framed in a negotiation between the state and the carers, both informal and professional. That such an agreement should include a covenant to assist parents and siblings when a child dies to recover and adjust to their loss, in recognition of the work they have performed in caring for the child during their child's life and their death. PMID- 29125322 TI - Breastfeeding Is Associated with Decreased Childhood Maltreatment. AB - PURPOSE: Child maltreatment has serious implications for youth outcomes, yet its associations with early parenting practices are not fully understood. This study investigated whether breastfeeding practices are correlated with childhood maltreatment. MATERIALS AND METHODS: Data were utilized from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative and longitudinal study of adolescents. The analytic sample comprised 4,159 adolescents. The outcome variables included four subtypes of childhood maltreatment (neglect, inadequate supervision, physical abuse, and sexual abuse). The primary independent variable was breastfeeding duration. Covariates of the child, mother, and household were included in analyses. Logistic regression models were employed to predict odds of maltreatment subtypes from breastfeeding duration and covariates. RESULTS: Compared with adolescents never breastfed, adolescents breastfed 9 months or longer had a reduced odds of having experienced neglect (odds ratio [OR] = 0.54; 95% confidence interval [CI] = 0.35-0.83) and sexual abuse (OR = 0.47; 95% CI = 0.24-0.93) after controlling for covariates. CONCLUSIONS: Breastfeeding duration is significantly associated with decreased childhood neglect and sexual abuse. Breastfeeding practices should be explored as a consideration among clinicians when assessing maltreatment risk. Further research should examine whether a causal relationship exists between breastfeeding and decreased maltreatment. PMID- 29125323 TI - Examining the Effects of MTV's 16 and Pregnant on Adolescent Girls' Sexual Health: The Implications of Character Affinity, Pregnancy Risk Factors, and Health Literacy on Message Effectiveness. AB - Health communication strategies to decrease teen pregnancies include the employment of entertainment-education (E-E), which involves embedding health messages in an entertainment media vehicle that is relatable and attractive to the intended audience. MTV's 16 and Pregnant is an example of such an effort as an E-E documentary-style reality show that aimed to reduce the U.S. teen pregnancy rate. A pretest-posttest experiment was conducted with 147 adolescent girls (ages 14-18) to investigate the effectiveness of 16 and Pregnant on beliefs, attitudes, and intentions to avoid teen pregnancy. Among participants who reported the lowest levels of identification, parasocial relationship, and homophily, viewing 16 and Pregnant resulted in more negative attitudes toward teen pregnancy. Among participants who reported the highest level of homophily, viewing 16 and Pregnant resulted in more positive attitudes toward teen pregnancy. Levels of pregnancy risk and health literacy were examined but were not significant moderators. Results are discussed in light of E-E theory and research. PMID- 29125324 TI - Communication training interventions for family and professional carers of people living with dementia: a systematic review of effectiveness, acceptability and conceptual basis. AB - OBJECTIVES: To update previous reviews and provide a more detailed overview of the effectiveness, acceptability and conceptual basis of communication training interventions for carers of people living with dementia. METHOD: We searched CINAHL Plus, MEDLINE and PsycINFO using a specific search and extraction protocol, and PRISMA guidelines. Two authors conducted searches and extracted studies that reported effectiveness, efficacy or acceptability data regarding a communication training-intervention for carers of people living with dementia. Risk of bias was assessed using the Cochrane Collaboration guidelines. Quality of qualitative studies was also systematically assessed. RESULTS: Searches identified 450 studies (after de-duplication). Thirty-eight studies were identified for inclusion in the review. Twenty-two studies focused on professional carers; 16 studies focused mainly on family carers. Training interventions were found to improve communication and knowledge. Overall training interventions were not found to significantly improve behaviour that challenges and caregiver burden. Acceptability levels were high overall, but satisfaction ratings were found to be higher for family carers than professional carers. Although many interventions were not supported by a clear conceptual framework, person-centred care was the most common framework described. CONCLUSION: This review indicated that training-interventions were effective in improving carer knowledge and communication skills. Effective interventions involved active participation by carers and were generally skills based (including practicing skills and discussion). However, improvements to quality of life and psychological wellbeing of carers and people living with dementia may require more targeted interventions. PMID- 29125325 TI - Communicating Risk Information in Direct-to-Consumer Prescription Drug Television Ads: A Content Analysis. AB - Direct-to-consumer (DTC) television ads for prescription drugs are required to disclose the product's major risks in the audio or audio and visual parts of the presentation (sometimes referred to as the "major statement"). The objective of this content analysis was to determine how the major statement of risks is presented in DTC television ads, including what risk information is presented, how easy or difficult it is to understand the risk information, and the audio and visual characteristics of the major statement. We identified 68 DTC television ads for branded prescription drugs, which included a unique major statement and that aired between July 2012 and August 2014. We used subjective and objective measures to code 50 ads randomly selected from the main sample. Major statements often presented numerous risks, usually in order of severity, with no quantitative information about the risks' severity or prevalence. The major statements required a high school reading level, and many included long and complex sentences. The major statements were often accompanied by competing non risk information in the visual images, presented with moderately fast-paced music, and read at a faster pace than benefit information. Overall, we discovered several ways in which the communication of risk information could be improved. PMID- 29125326 TI - Young Schema Questionnaire - Short Form Version 3 (YSQ-S3): Preliminary validation in older adults. AB - OBJECTIVES: The aim of the current study was to establish the reliability and validity of one of the most used schema questionnaires, Young Schema Questionnaire Short Form Version 3 (YSQ-S3) in older adults. METHOD: 104 participants aged 60-84 years were recruited. They were administered a battery of questionnaires, including the YSQ-S3, Young-Atkinson Mode Inventory (YAMI), Germans (Personality) Screener, the Geriatric Depression Scale (GDS), The Geriatric Anxiety Inventory (GAI) and the Basic Psychological Needs Scale (BPNS). The YSQ-S3 was completed a second time by 83 participants a median of 12 days later. RESULTS: Satisfactory internal consistency reliability was found for 13 of the 18 early maladaptive schemas (EMS) of the YSQ-S3. Test-retest reliability was satisfactory for 17 of 18 EMS. Convergent validity was evident from significant correlations between the EMS of the YSQ-S3 and the vulnerable child and angry child schema modes from the YAMI. Congruent validity was evident from correlations of the majority of the EMS with the GDS, the GAI, German's (Personality) Screener and the BPNS measure. CONCLUSIONS: By and large the YSQ-S3 demonstrates internal and test re-test reliability in as well as congruent and convergent validity, in older adults. This suggests the YSQ-S3 may be of use in work establishing the utility of schema therapy in this population, and that schema therapy with older people warrants further exploration. Notwithstanding this some re-development of some EMS items appears to be required for the YSQ-S3 to be more relevant to older people. PMID- 29125329 TI - Digital breast tomosynthesis findings may be different in HER2 positive breast cancer patients according to hormone receptor status. PMID- 29125328 TI - Automated customized retrieval of radiotherapy data for clinical trials, audit and research. AB - OBJECTIVE: To enable fast and customizable automated collection of radiotherapy (RT) data from tomotherapy storage. METHODS: Human-readable data maps (TagMaps) were created to generate DICOM-RT (Digital Imaging and Communications in Medicine standard for Radiation Therapy) data from tomotherapy archives, and provided access to "hidden" information comprising delivery sinograms, positional corrections and adaptive-RT doses. RESULTS: 797 data sets totalling 25,000 scans were batch-exported in 31.5 h. All archived information was restored, including the data not available via commercial software. The exported data were DICOM compliant and compatible with major commercial tools including RayStation, Pinnacle and ProSoma. The export ran without operator interventions. CONCLUSION: The TagMap method for DICOM-RT data modelling produced software that was many times faster than the vendor's solution, required minimal operator input and delivered high volumes of vendor-identical DICOM data. The approach is applicable to many clinical and research data processing scenarios and can be adapted to recover DICOM-RT data from other proprietary storage types such as Elekta, Pinnacle or ProSoma. Advances in knowledge: A novel method to translate data from proprietary storage to DICOM-RT is presented. It provides access to the data hidden in electronic archives, offers a working solution to the issues of data migration and vendor lock-in and paves the way for large-scale imaging and radiomics studies. PMID- 29125327 TI - Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study. AB - RATIONALE: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood. OBJECTIVES: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. METHODS: Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid beta was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. MEASUREMENTS AND MAIN RESULTS: We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid beta42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB-mask (Alzheimer's disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively). CONCLUSIONS: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly. PMID- 29125330 TI - Benign and malignant enlarged chest nodes staging by diffusion-weighted MRI: an alternative to mediastinoscopy? AB - OBJECTIVE: To evaluate the accuracy of diffusion-weighted MRI with background suppression (DWIBS) in differentiating between malignant and benign mediastinal lymph-nodes. METHODS: Consecutive patients with enlarged mediastinal lymph-nodes underwent MRI DWIBS within 10 days prior to mediastinoscopy. Relative contrast ratios (RCRs) were computed on b800 and apparent diffusion coefficient (ADC) maps by dividing the node signal with the chest muscle signal, using manually drawn regions of interest (ROIs) by radiologists, blinded to pathology. Unpaired Student's t-tests were used to compare RCR-b800 and ADC between malignant and benign nodes. Receiver operating characteristic curves analyses were also performed. RESULTS: Six patients were excluded for poor image quality. Analysis was performed for 54 patients. Mean ADC values were significantly higher for benign (1740 +/- 401 * 10-6 mm2 s-1) compared with malignant nodes (1266 +/- 403 * 10-6 mm2 s-1, p = 0.0001). Mean RCR-b800 values were significantly lower for benign (2.64 +/- 1.07) compared with malignant nodes (6.44 +/- 3.47, p < 0.0001). Receiver operating characteristic analysis for RCR-b800 (cut-off of 3.6), showed a sensitivity of 90.9%, a specificity 83% and an accuracy 85% for differentiating benign from malignant nodes. For ADC (cut-off of 1285), the sensitivity was 68.2%, the specificity 84.6% and the accuracy 80.4%. CONCLUSION: DWIBS can accurately differentiate malignant from benign states in enlarged mediastinal lymph-nodes and represents an alternative method in aetiological work-up of mediastinal lymphadenopathies. Advances in knowledge: DWIBS may represent a useful adjunctive imaging modality, particularly for diagnosis of benign mediastinal lymph node, and thus may reduce the frequency of futile mediastinoscopy, which remains an invasive procedure. PMID- 29125331 TI - 18FDG-PET/CT is useful in the follow-up of surgically treated patients with oesophageal adenocarcinoma. AB - OBJECTIVE: The purpose of this study was to evaluate fludeoxyglucose-positron emission ;tomography/CT's (FDG-PET/CT) performance in the follow ;up of patients with surgically treated oesophageal adenocarcinoma. METHODS: The follow-up FDG PET/CT scans of 162 consecutive patients with surgically treated oesophageal adenocarcinoma were retrospectively reviewed. Histopathological and/or imaging examinations confirmed recurrent disease. The accuracy, sensitivity, specificity and negative and positive predictive values were calculated. RESULTS: Recurrence occurred in 71 (43%) patients, usually within the first year following surgery (60%) and in more than one site (76%). The sensitivity, specificity, positive predictive value, negative-predictive value and accuracy of FDG-PET/CT for anastomotic recurrence were 77, 76, 16, 98 and 76%; for regional nodal recurrence were 88, 85, 43, 97 and 86%; and for distant metastatic recurrence were: 97, 96, 91, 99 and 96%. In 5 of the 42 patients (12%) with distant metastases, the metastatic sites were outside the area covered by a conventional follow-up chest abdomen CT and in 4 patients (9%) metastases were barely perceptible on the CT component of the FDG-PET/CT and consequently were unlikely to be detected without the aid of the FDG uptake. CONCLUSION: FDG PET/CT is accurate in detecting oesophageal adenocarcinoma recurrence, especially within the first post-operative year when most recurrences occur, and is useful in identifying patients with a solitary metastasis. Advances in knowledge: FDG-PET/CT should be considered as a valuable tool in the routine follow ;up of surgically treated oesophageal cancer patients within the first 2 years after surgery. PMID- 29125332 TI - ABO blood group related venous thrombosis risk in patients with peripherally inserted central catheters. AB - OBJECTIVE: To investigate the association between ABO blood group and upper limb venous thrombosis (VT) risk in patients with peripherally inserted central catheters (PICC). METHODS: Single centre retrospective cohort study. A cohort of patients who underwent PICC insertion from September 2010 to August 2014 were followed up for symptomatic VT presentations diagnosed by ultrasound. Blood group status was identified from hospital information systems. RESULTS: 2270 participants had 3020 PICCs inserted. There were 124 cases of symptomatic VT, an incident rate of 4% [95% confidence interval, CI (3-5%)]. Univariate analysis adjusting for the clustered sample showed that having chemotherapy, two or more previous PICCs, a larger catheter size, a diagnosis of cancer and having a blood group B were all associated with an increased risk of a VT. In the multivariate analysis, PICC diameter, cancer diagnosis and blood group B were all independently associated with increased risk of VT. CONCLUSION: Patients undergoing PICC insertion with a blood group B appear to have a higher risk of VT, independent of risks attached to the PICC procedure and cancer diagnosis. Without any existing guidelines for PICC-related VT, this investigation creates a platform for further research to be conducted in order to establish guidelines. Advances in knowledge: Previous studies investigating VT risk associated with blood group status related to large heterogeneous populations. In this article, we look at patients specifically with PICC, which reduces the heterogeneity in the cohort. In addition, due to the substantial number of patients enrolled, we had a chance to perform multivariate analyses with statistical significance. PMID- 29125333 TI - Enhanced pre-operative axillary staging using intradermal microbubbles and contrast-enhanced ultrasound to detect and biopsy sentinel lymph nodes in breast cancer: a potential replacement for axillary surgery. AB - OBJECTIVE: To compare the experience of four UK Centres in the use of intradermal microbubbles and contrast enhanced ultrasound (CEUS) to pre-operatively identify and biopsy sentinel lymph nodes (SLN) in patients with breast cancer. METHODS: In all centres, breast cancer patients had a microbubble/CEUS SLN core biopsy prior to axillary surgery and patients in Centres 1 and 2 had a normal greyscale axillary ultrasound. Data were collected between 2010 and 2016; 1361 from Centre 1 (prospective, sequential), 376 from Centre 2 (retrospective, sequential), 121 from Centre 3 (retrospective, selected) and 48 from Centre 4 (prospective, selected). RESULTS: SLN were successfully core biopsied in 80% (Centre 1), 79.6% (Centre 2), 77.5% (Centre 3) and 88% (Centre 4). The sensitivities to identify all SLN metastases were 46.9% [95% confidence intervals (CI) (39.4-55.1)], 52.5% [95% CI (39.1-65.7)], 46.4% [95% CI (27.5-66.1)] and 45.5% [95% CI (16.7-76.6)], respectively. The specificities were 99.7% [95% CI (I98.9-100)], 98.1% [95% CI (94.5-99.6)], 100% [95% CI (93.2-100%)] and 96.3% [95% CI (81-99.9)], respectively.The negative predictive values were 87.0% [95% CI (84.3-89.3)], 84.5% [95% CI (78.4-89.5)], 86.9% [95% CI (82.4-90.3)] and 86.2% [95% CI (78.4 91.5)], respectively. At Centres 1 and 2, 12/730 (1.6%) and 7/181 (4%), respectively, of patients with a benign microbubble/CEUS SLN core biopsy had two or more lymph node (LN) macrometastases found at the end of primary surgical treatment. CONCLUSION: The identification and biopsy of SLN using CEUS is a reproducible technique. Advances in knowledge: In the era of axillary conservation, microbubble/CEUS SLN core biopsy has the potential to succeed surgical staging of the axilla. PMID- 29125334 TI - Submillisievert chest dual energy computed tomography: a pilot study. AB - OBJECTIVE: To assess if diagnostic dual energy CT (DECT) of the chest can be achieved at submillisievert (sub-mSv) doses. METHODS: Our IRB-approved prospective study included 20 patients who were scanned on dual-source multidector CT(MDCT). All patients gave written informed consent for acquisition of additional image series at reduced radiation dose on a dual-source MDCT (80/140 kV) within 10 s after the standard of care acquisition. Dose reduction was achieved by reducing the quality reference milliampere-second, with combined angular exposure control. Four readers, blinded to all clinical data, evaluated the image sets. Image noise, signal-to-noise and contrast-to-noise ratio were assessed. Volumetric CT dose index (CTDIvol), doselength product (DLP), size specific dose estimate, and effective dose were also recorded. RESULTS: The mean age and body mass index of the patients were 71 years +/- 9 and 24 kg m-2 +/- 3, respectively. Although images became noisier, overall image quality and image sharpness on blended images were considered good or excellent in all cases (20/20). All findings made on the reduced dose images presented with good demarcation. The intraobserver and interobserver agreements were kappa = 0.83 and 0.73, respectively. Mean CTDIvol, size specific dose estimate, DLP and effective dose for reduced dose DECT were: 1.3 +/- 0.2 mGy, 1.8 +/- 0.2 mGy, 51 +/- 9.9 mGy.cm and 0.7 +/- 0.1 mSv, respectively. CONCLUSION: Routine chest DECT can be performed at sub-mSv doses with good image quality and without loss of relevant diagnostic information. Advances in knowledge: (1) Contrast-enhanced DECT of the chest can be performed at sub-mSv doses, down to mean CTDIvol 1.3 mGy and DLP 51 mGy.cm in patients with body mass index <31 kg m-2. (2) To our knowledge, this is the first time that sub-mSv doses have been successfully applied in a patient study using a dual source DECT scanner. PMID- 29125335 TI - A review of mammographic positioning image quality criteria for the craniocaudal projection. AB - Detection of breast cancer is reliant on optimal breast positioning and the production of quality images. Two projections, the mediolateral oblique and craniocaudal (CC), are routinely performed. Determination of successful positioning and inclusion of all breast tissue is achieved through meeting stated image quality criteria. For the CC view, current image quality criteria are inconsistent. Absence of reliable anatomical markers, other than the nipple, further contribute to difficulties in assessing the quality of CC views. The aim of this paper was to explore published international quality standards to identify and find the origin of any CC positioning criteria which might provide for quantitative assessment. The pectoralis major (pectoral) muscle was identified as a key posterior anatomical structure to establish optimum breast tissue inclusion on mammographic projections. It forms the first two of the three main CC metrics that are frequently reported (1) visualization of the pectoral muscle, (2) measurement of the posterior nipple line and (3) depiction of retroglandular fat. This literature review explores the origin of the three metrics, and discusses three key publications, spanning 1992 to 1994, on which subsequent image quality standards have been based. The evidence base to support published CC metrics is sometimes not specified and more often, the same set of publications are cited, most often without critical evaluation. To conclude, there remains uncertainty if the metrics explored for the CC view support objective evaluation and reproducibility to confirm optimal breast positioning and quality images. PMID- 29125336 TI - A useful method for assessing differences of compensatory hypertrophy in the contralateral kidney before and after radical nephrectomy in patients with renal cell carcinoma: ellipsoid formula on computed tomography. AB - OBJECTIVE: To investigate the usefulness of the ellipsoid formula for assessing compensatory hypertrophy of the contralateral kidney on pre-operative and post operative CT in renal cell carcinoma (RCC) patients. METHODS: We retrospectively identified 389 patients who had radical nephrectomy for RCC between 2011 and 2015. Contrast-enhanced CT was performed within 3 months pre-operative and at 1 year post-operative. The kidney volumes were calculated from CT using the ellipsoid formula. We subdivided patients into three groups based on tumour size (I: <=4 cm, II: 4-7 cm, III: >7 cm). Volumetric renal parameters were compared and multivariate analyses were performed to determine predictors associated with pre-operative and post-operative compensatory hypertrophy. RESULTS: Kidney volume calculation using the ellipsoid method took a median of 51 s. Group III had a significantly larger median pre-operative contralateral renal volume than Groups I and II (I: 140.4, II: 141.6, III: 166.7 ml, p < 0.05). However, the median ratio of post-operative contralateral renal volume change was significantly higher in Groups I and II than Group III (I: 0.36, II: 0.23, III: 0.12, p < 0.001). On multivariate analysis, tumour size revealed the strongest positive association with pre-operative contralateral kidney volume (partial regression coefficient: beta = 30.8, >7 cm) and ratio of post-operative contralateral kidney volume change (beta = 0.214, I vs III; beta = 0.168, II vs III). CONCLUSION: Kidney volume calculation for assessing pre- and post-operative compensatory hypertrophy of the contralateral kidney in RCC patients can be easily and rapidly performed from CT images using the ellipsoid formula. Advances in knowledge: The ellipsoid formula allows reliable method for assessing pre operative and post-operative compensatory hypertrophy of the contralateral kidney in RCC. PMID- 29125338 TI - Providing high-quality care at the end of life: the role of education and guidance. AB - Palliative care in the UK has been ranked as the best in the world. So where did palliative care go so wrong that a 168-page document is required to inform staff how to care for dying patients if it has been going so well for so long? Those nearing the end of their life deserve to be given optimum care, attention, compassion and consideration, but this is not always the case. The Liverpool Care Pathway was a tool originally devised to help health professionals provide high quality end-of-life care to people in the final phase of life. This tool, when used in the correct way, could provide the 'gold standard' of end-of-life care for patients. However, a national review found that rather than a tick-box exercise, care of the dying should be centred around individualised care planning for the dying patient, as highlighted in the publication of the guidance: One Chance to Get It Right. Care of the dying is a complex skill that requires nurses to provide some of the most challenging care, and for which many nurses have received little or no training. The implementation of this guidance into practice will require thoughtful change management, abandoning an old way of working in order to ensure excellence and high-quality care for patients nearing the end of life. PMID- 29125339 TI - Patient safety at the crossroads. AB - John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses some important clinical negligence and patient safety themes arising from a number of recent reports. PMID- 29125337 TI - The value of superb microvascular imaging in differentiating benign renal mass from malignant renal tumor: a retrospective study. AB - OBJECTIVE: This study is to evaluate the value of superb microvascular imaging (SMI) in assessing renal tumour vascularity and in differentiating benign from malignant renal tumours. METHODS: Patients with pathologically confirmed renal mass who underwent colour Doppler flow imaging (CDFI) and SMI examination between October 2016 and March 2017 were retrospectively analysed. Patients were classified into benign renal mass group and malignant tumour group according to their pathological results. The vascularity, vascular distribution and vessel morphology obtained from the two scanning methods were analysed and compared between the two groups. RESULTS: 53 patients with renal tumour were enrolled into the study, including 11 cases of benign renal tumours and 42 cases of malignant ones. SMI showed significant difference in vascularity between the two groups; CDFI showed no statistical difference. Compared with CDFI, SMI showed significantly higher grade in malignant tumour (p < 0.001), and no significant difference (p = 0.421) in benign mass. According to CDFI, there is no statistical difference in vascular distribution and vessel morphology (p = 0.432, p = 0.122) between the two groups, while SMI method showed significant difference (p < 0.05) between the two groups. SMI was significantly more sensitive and accurate than CDFI. CONCLUSION: Comparing with CDFI, SMI could effectively detect vascularity, vascular characteristics and distribution and annular blood flow in renal tumour. SMI appears more sensitive and precise in distinguishing benign renal mass from malignant tumour. Advances in knowledge: SMI seems potentially valuable in evaluating renal tumour vascularity and in differentiating benign from malignant renal tumours. PMID- 29125340 TI - Liability for unsafe care and treatment. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, discusses the first time the Care Quality Commission has used its authority to prosecute a care provider and what this means for nurses and trusts. PMID- 29125341 TI - Evaluation of the economic impact of a national lymphoedema service in Wales. AB - Lymphoedema Network Wales has focused on maximising the impact of its service through the effective use of available resources to ensure high-quality and consistent care for people with lymphoedema across Wales. The aim of this evaluation was to estimate the economic impact of a national lymphoedema service on the NHS Wales budget. Work was undertaken to determine the care pathway within Lymphoedema Network Wales and develop a hypothetical 'world without' the service as a comparator. The four groups of patients that made up the pathways were group 0: 'at risk', group 1-2: 'uncomplicated lymphoedema', group 3: 'complicated/complex' and group 4: 'palliative care'. Overall resource utilisation between 6 months pre- and 6 months post-entry indicated that there were significant cost reductions to be seen after lymphoedema service entry for all patients in each group. This evaluation provides estimates that suggest that the service is likely to be cost saving when people with lymphoedema are managed within Lymphoedema Network Wales rather than in a 'world without' the service. PMID- 29125343 TI - Protection not prosecution. PMID- 29125342 TI - Learning from experience. PMID- 29125344 TI - Royal College of Nursing response to the draft standards for nurses. AB - Emeritus Professor Alan Glasper, University of Southampton, discusses the Royal College of Nursing's response to the Nursing and Midwifery Council consultation on standards to be finalised in spring 2018. PMID- 29125345 TI - Person-centred care: what nurses can learn from the patient perspective. AB - Janet Scammell, Associate Professor (Nursing), Bournemouth University, considers evidence from National Voices, a coalition of health and social care charities in England. PMID- 29125346 TI - Prevention and management of incontinence-associated dermatitis. AB - David Voegeli, Associate Professor of Nursing, Skin Health Research Group, Faculty of Health Sciences, University of Southampton, discusses the care of patients with incontinence-associated dermatitis and how to distinguish this condition from pressure ulcers. PMID- 29125347 TI - We owe our patients honesty. AB - Clare Price-Dowd, Senior Programme Lead, NHS Leadership Academy, discusses the importance of candour in her latest blog on the '6Cs of nursing', and the need for honesty and openness in patient care. PMID- 29125348 TI - COPD: a proposed multidisciplinary approach to psychological issues. AB - Patients with chronic obstructive pulmonary disease (COPD) form a sizeable part of the ill-health demographic, both internationally and nationally, impacting markedly on hospital admissions. While prevalence rates of psychological comorbidity vary, there appears to be a consistent presence of depression and anxiety, and additional COPD symptom-related psychological distress. The research evidence base is limited, with seemingly little potential for expansion. Based on the available evidence, this study proposes a multidisciplinary team working model to support the integration of psychological input into the care of inpatients with COPD. PMID- 29125349 TI - Florence Nightingale Foundation: supporting excellent leadership. PMID- 29125351 TI - Advancing urological nursing. PMID- 29125350 TI - A thoroughly productive partnership. PMID- 29125352 TI - In defence of care homes: a call to arms. PMID- 29125353 TI - Reflections on a life in nursing. PMID- 29125354 TI - The rise of the stoma care nurse. PMID- 29125355 TI - Improving organ donation in the UK. PMID- 29125356 TI - Caring for those who care. PMID- 29125357 TI - Great leaps forward in cancer nursing. PMID- 29125358 TI - Raising our voice: how nurses are changing the world. PMID- 29125359 TI - Working in the early days of the NHS. PMID- 29125360 TI - Promoting excellence in care: 25 years at the heart of nursing. AB - Emeritus Professor, University of Southampton, discusses the contribution of the British Journal of Nursing to enhancing contemporary nursing within the health service over the past quarter of a century. PMID- 29125361 TI - 25 years on, we're just getting started. PMID- 29125362 TI - Registration awaits, but what shape of NHS waits with it? AB - Duncan Hamilton, Third Year Student, Adult Nursing, University of Surrey, explores the challenges facing the nursing workforce and wonders what the future NHS will look like. PMID- 29125363 TI - After 25 years, BJN is still a 'steal'. PMID- 29125364 TI - Improving care for patients with dementia in the recovery room. AB - Caring for patients with dementia emerging from general anaesthesia in the recovery room can be very challenging. Sedation is sometimes necessary in order to nurse patients effectively and avoid any negative consequences of poor post anaesthetic care. No local or national guidelines could be found to suggest best nursing practice in this situation. Three small-scale innovations were introduced into the recovery room in one hospital as part of a quality improvement project to give alternatives to chemical restraint. These were: music and distraction therapy, maximising the use of the 'About Me' document and improved access to staff training. The simple innovations were well received by recovery room staff. Further research is needed to quantify the benefits of these innovations and further work is needed to develop use of the carer's passport in recovery. PMID- 29125365 TI - Assessing students' knowledge of healthcare-associated infections: a global perspective. AB - The aim of this review was to explore students' knowledge of healthcare associated infections (HCAIs) from a global perspective. HCAIs may be the result of treatment in or contact with healthcare or social care settings and have been shown to cause an increase in morbidity, mortality and increased length of hospital stay. Student placements may involve interactions between university students, patients and/or health professionals and this may be a source of cross contamination of the microbial agents that cause HCAIs. This situation may be exacerbated in some countries owing to variations in the levels of infrastructure development, knowledge, and economic status. A literature search was carried out, resulting in 12 studies selected for review. Findings were organised into two themes: nursing students' knowledge of HCAIs and students in other health-related subjects' knowledge of HCAIs. Nursing students' knowledge was adequate in some aspects of HCAIs, although poor in certain areas. Knowledge of HCAIs varied between students studying different health-related subjects. Curriculum differences between the student groups may account for this variation. A review of the curricula for healthcare students should ensure they include training and practical skills in the prevention of HCAIs, including modes of disease transmission, handwashing and disinfection techniques. PMID- 29125366 TI - The state of the nursing workforce today. AB - Sam Foster, Chief Nurse, Oxford University Hospitals, looks at threats to the nursing workforce and explores some of the ways in which these can be minimised. PMID- 29125367 TI - Recent advances in the management of pancreatic adenocarcinoma. AB - INTRODUCTION: Pancreatic cancer (PC) demonstrates very poor prognosis and its incidence continues to increase, despite developments in chemotherapy, radiotherapy, and targeted therapies. Surgical resection is currently the only curative approach for PC. The role of radiotherapy in adjuvant and locally advanced PC continues to be increasingly controversial. This review article aims to explore the current knowledge of pancreatic adenocarcinoma, focusing on diagnosis, treatment strategies, and the best supportive care. Areas covered: The current literature on pancreatic adenocarcinoma treatment modalities has been summarized, with a focus on clinical trials and reviews. New treatment strategies and their impact on clinical practice have also been discussed. Expert commentary: Despite many therapeutic developments, only modest improvements in survival rates have been achieved. There is an essential need to increase survival by developing more innovative treatment approaches for patients with PC. PMID- 29125368 TI - Societal burden of cluster headache in the United States: a descriptive economic analysis. AB - AIM: To estimate direct and indirect costs in patients with a diagnosis of cluster headache in the US. METHODS: Adult patients (18-64 years of age) enrolled in the Marketscan Commercial and Medicare Databases with >=2 non-diagnostic outpatient (>=30 days apart between the two outpatient claims) or >=1 inpatient diagnoses of cluster headache (ICD-9-CM code 339.00, 339.01, or 339.02) between January 1, 2009 and June 30, 2014, were included in the analyses. Patients had >=6 months of continuous enrollment with medical and pharmacy coverage before and after the index date (first cluster headache diagnosis). Three outcomes were evaluated: (1) healthcare resource utilization, (2) direct healthcare costs, and (3) indirect costs associated with work days lost due to absenteeism and short term disability. Direct costs included costs of all-cause and cluster headache related outpatient, inpatient hospitalization, surgery, and pharmacy claims. Indirect costs were based on an average daily wage, which was estimated from the 2014 US Bureau of Labor Statistics and inflated to 2015 dollars. RESULTS: There were 9,328 patients with cluster headache claims included in the analysis. Cluster headache-related total direct costs (mean [standard deviation]) were $3,132 [$13,396] per patient per year (PPPY), accounting for 17.8% of the all cause total direct cost. Cluster headache-related inpatient hospitalizations ($1,604) and pharmacy ($809) together ($2,413) contributed over 75% of the cluster headache-related direct healthcare cost. There were three sub-groups of patients with claims associated with indirect costs that included absenteeism, short-term disability, and absenteeism + short-term disability. Indirect costs PPPY were $4,928 [$4,860] for absenteeism, $803 [$2,621] for short-term disability, and $3,374 [$3,198] for absenteeism + disability. CONCLUSION: Patients with cluster headache have high healthcare costs that are associated with inpatient admissions and pharmacy fulfillments, and high indirect costs associated with absenteeism and short-term disability. PMID- 29125369 TI - Pregnancy and live birth after successful cancer treatment in young women: the need to improve fertility preservation and advice for female cancer patients. PMID- 29125371 TI - Telerehabilitation booster sessions and remote patient monitoring in the management of chronic low back pain: A case series. AB - BACKGROUND: Improvements in chronic low back pain (CLBP) seen in physical therapy do not appear to be retained over the long term. Booster sessions have been proposed, but barriers exist to their implementation. Telerehabilitation (TR) and remote patient monitoring (RPM) may be ways to circumvent these barriers. The purpose of this case series was to describe the implementation of TR booster sessions and RPM in three patients with CLBP. CASE SERIES: Three females with CLBP tracked their daily pain level and home exercise program adherence using a mobile phone application for 12 months following discharge from traditional face to-face physical therapy. Synchronous audio and video TR booster sessions were conducted at months 1, 3, 6, and 12. OUTCOMES: All patients met their individual goals. They demonstrated excellent home exercise program adherence and self efficacy. A temporary increase in pain was seen in all patients, but they managed solely with the TR booster sessions and without other healthcare resources. Satisfaction with the program was very high. CONCLUSIONS: This case series describes the use of TR booster sessions and RPM in three patients with CLBP. The positive results suggest this approach may be helpful in improving long-term management of patients with CLBP but demand further investigation. PMID- 29125372 TI - Matched increases in cerebral artery shear stress, irrespective of stimulus, induce similar changes in extra-cranial arterial diameter in humans. AB - The mechanistic role of arterial shear stress in the regulation of cerebrovascular responses to physiological stimuli (exercise and hypercapnia) is poorly understood. We hypothesised that, if shear stress is a key regulator of arterial dilation, then matched increases in shear, induced by distinct physiological stimuli, would trigger similar dilation of the large extra-cranial arteries. Participants ( n = 10) participated in three 30-min experimental interventions, each separated by >=48 h: (1) mild-hypercapnia (FICO2:~0.045); (2) submaximal cycling (EX; 60%HRreserve); or (3) resting (time-matched control, CTRL). Blood flow, diameter, and shear rate were assessed (via Duplex ultrasound) in the internal carotid and vertebral arteries (ICA, VA) at baseline, during and following the interventions. Hypercapnia and EX produced similar elevations in blood flow and shear rate through the ICA and VA ( p < 0.001), which were both greater than CTRL. Vasodilation of ICA and VA diameter in response to hypercapnia (5.3 +/- 0.8 and 4.4 +/- 2.0%) and EX (4.7 +/- 0.7 and 4.7 +/- 2.2%) were similar, and greater than CTRL ( p < 0.001). Our findings indicate that matched levels of shear, irrespective of their driving stimulus, induce similar extra cranial artery dilation. We demonstrate, for the first time in humans, an important mechanistic role for the endothelium in regulating cerebrovascular response to common physiological stimuli in vivo. PMID- 29125373 TI - Use of 1,3-beta-D-glucan in invasive fungal diseases in hematology patients. AB - INTRODUCTION: Invasive fungal diseases (IFD) remain a leading cause of morbidity and mortality in hematology patients. Within a diagnostic-driven approach, the use of the serum (1,3)-beta-D-glucan (BDG) test represents a valid tool for the early diagnosis and treatment of IFD. Areas covered: The available literature on the use of BDG in hematology patients was systematically retrieved. Then, it was reviewed and discussed, to identify key issues pertaining to a clinically oriented narrative presentation of the topic. Expert commentary: The use of BDG in hematology patients at risk for invasive aspergillosis (IA) is secondary to the use of galactomannan. However, since BDG is not specific for IA, it offers an advantage of diagnosing also other IFD, such as candidiasis and pneumocystosis. The limitations of BDG include high costs and lower sensitivity in hematology patients compared to other cohorts. The risk of false positive results is possibly lower in real life than in theory, since glucan-free equipment is available and modern dialysis membranes and blood products usually do not release BDG. Thus, in experienced hands and selected clinical situations, BDG is a useful diagnostic tool, particularly due to short turnover time to results and versatility in diagnosing different IFD. PMID- 29125374 TI - Interventions to improve utilization of cataract surgical services by girls: Case studies from Asia and Africa. AB - PURPOSE: Gender and blindness initiatives continue to make eye care personnel aware of the service utilization inequity strongly favouring men, yet interventions to reduce that inequity, particularly for girls, are under developed. METHODS: This descriptive study gathered quantitative data on the degree of gender equity at five Child Eye Health Tertiary Facilities (CEHTFs) in Asia and Africa and conducted in-depth interviews with eye care personnel to assess their strategies and capacity to reduce gender inequity. Cataract surgery was utilized to assess the degree of inequity and success of interventions to reduce inequity in case finding, service utilization, and follow-up. RESULTS: CEHTF administrative data showed significant gender inequity in cataract surgical services favouring boys in all settings. CEHTFs actively seek children through community and school-based outreach, yet do not have initiatives to reduce gender inequity. Little gender inequity was found among children receiving surgical and follow-up care, although two out of three children were boys. CEHTF staff, despite being aware, offered no effective means to reduce gender inequity involving cataract surgical services. Interventions that successfully increased service utilization by girls came from individual cases, involving extraordinary effort by a single eye care programme person. CONCLUSION: Community-based case finders such as Anganwadi workers in India, Female Community Health Volunteers (FCHVs) in Nepal, and Key Informants (KIs) in Africa are necessary to identify children in need of cataract services, but insufficient to increase service utilization by girls. Secondary, often extra-ordinary community-based interventions by eye care personnel are needed in all settings. PMID- 29125375 TI - ITGA2B and ITGB3 gene mutations associated with Glanzmann thrombasthenia. PMID- 29125376 TI - Extending julius seizure, a bang-sensitive gene, as a model for studying epileptogenesis: Cold shock, and a new insertional mutation. AB - The bang-sensitive (BS) mutants of Drosophila are an important model for studying epilepsy. We recently identified a novel BS locus, julius seizure (jus), encoding a protein containing two transmembrane domains and an extracellular cysteine-rich loop. We also determined that jussda iso7.8, a previously identified BS mutation, is an allele of jus by recombination, deficiency mapping, complementation testing, and genetic rescue. RNAi knockdown revealed that jus expression is important in cholinergic neurons and that the critical stage of jus expression is the mid-pupa. Finally, we found that a functional, GFP-tagged genomic construct of jus is expressed mostly in axons of the neck connectives and of the thoracic abdominal ganglia. In this Extra View article, we show that a MiMiC GFP-tagged Jus is localized to the same nervous system regions as the GFP-tagged genomic construct, but its expression is mostly confined to cell bodies and it causes bang-sensitivity. The MiMiC GFP-tag lies in the extracellular loop while the genomic construct is tagged at the C-terminus. This suggests that the alternate position of the GFP tag may disrupt Jus protein function by altering its subcellular localization and/or stability. We also show that a small subset of jus-expressing neurons are responsible for the BS phenotype. Finally, extending the utility of the BS seizure model, we show that jus mutants exhibit cold sensitive paralysis and are partially sensitive to strobe-induced seizures. PMID- 29125377 TI - Intraflagellar transport proteins are involved in thrombocyte filopodia formation and secretion. AB - Intraflagellar transport (IFT) proteins are vital for the genesis and maintenance of cilia. Our identification of ift122 transcripts in zebrafish thrombocytes that lack primary cilia was unexpected. IFT proteins serve transport in cilia, whose narrow dimensions may have necessitated the evolution of IFT from vesicular transport in ancestral eukaryotes. We hypothesized that IFTs might also facilitate transport within the filopodia that form when thrombocytes are activated. To test this possibility, we knocked down ift122 expression by injecting antisense Morpholino oligonucleotides (MOs) into zebrafish embryos. Laser-induced arterial thrombosis showed prolonged time to occlusion (TTO) of the vessel, as would be expected with defective thrombocyte function. Acute effects in adult zebrafish were evaluated by Vivo-Morpholino (Vivo-MO) knockdown of ift122. Vivo-MO morphants showed a prolonged time to thrombocyte aggregation (TTA) in the plate tilt assay after thrombocyte activation by the following agonists: ADP, collagen, PAR1 peptide, and epinephrine. A luminescence assay for ATP revealed that ATP secretion by thrombocytes was reduced in collagen-activated blood of Vivo-MO ift122 morphants. Moreover, DiI-C18 labeled morphant thrombocytes exposed to collagen showed reductions in filopodia number and length. Analysis of ift mutants, in which cilia defects have been noted, also showed prolongation of TTO in our arterial laser thrombosis assay. Additionally, collagen activation of wild-type thrombocytes led to a concentration of IFT122 both within and at the base of filopodia. Taken together these results, suggest that IFT proteins are involved in both the extension of filopodia and secretion of ATP, which are critical in thrombocyte function. PMID- 29125378 TI - Type of obstetric anesthesia administered and complications in women with preeclampsia in low- and middle-income countries: A systematic review. AB - BACKGROUND: Delivery is often expedited with cesarean section, necessitating anesthesia, to prevent complications in women with preeclampsia. Anesthesia associated risks in these women from low- and middle-income countries (LMICs) are not known. METHODS: We searched major databases (until February 2017) for studies on general vs. regional anesthesia in women with preeclampsia. We summarized the association between outcomes and type of anesthesia using a random effects model and reported as odds ratio (OR) with 95% confidence intervals (95% CIs). FINDINGS: We included 14 studies (10,411 pregnancies). General anesthesia was associated with an increase in the odds of maternal death sevenfold (OR 7.70, 95% CI 1.9 to 31.0, I2 = 58%) than regional anesthesia. The odds of pulmonary edema (OR 5.16, 95% CI 2.5 to 10.4, I2 = 0%), maternal intensive care unit admissions (OR 16.25, 95% CI 9.0 to 29.5, I2 = 65%), and perinatal death (OR 3.01, 95% CI 1.4 to 6.5, I2 = 56%) were increased with general vs. regional anesthesia. CONCLUSION: General anesthesia is associated with increased complications in women with preeclampsia undergoing cesarean section in LMIC. PMID- 29125379 TI - Bcl-xL/Bak interaction and regulation by miRNA let-7b in the intrinsic apoptotic pathway of stored platelets. AB - Bcl-2 family proteins play key roles in the intrinsic apoptosis pathway in platelets, with both pro- and antiapoptotic protein expressions regulating survival during ex vivo storage. We detected a significant decrease in antiapoptotic Bcl-xL and increase in proapoptotic Bak expression on the third day of storage and as a result the ratio of Bak:Bcl-xL also decreased. Moreover, we identified an interaction between Bcl-xL and Bak. These shifts corresponded with activation of the apoptotic pathway, suggesting these proteins might play an important role in platelet survival. We then performed bioinformatic analysis to gain insight into protein expression regulation during storage. This identified a potential binding site of the microRNA (miRNA) let-7b in the 3'-UTR of the Bcl-xL gene, which we confirmed by a dual-luciferase reporter assay. We also determined that let-7b was upregulated during platelet storage, and let-7b transfection influenced Bcl-xL and Bak protein, but not mRNA, expression. Together, these data suggest that only posttranscriptional mechanisms are available for regulating gene expression in anucleate platelets. PMID- 29125380 TI - Breathing pattern recordings using respiratory inductive plethysmography, before and after a physiotherapy breathing retraining program for asthma: A case report. AB - Breathing retraining (BR) improves symptoms, psychological well-being and quality of life in adults with asthma; but there remains uncertainty as to mechanism of effect. One of the intuitively logical theories is that BR works through altering breathing pattern. There is currently no evidence, however, that BR does result in measurable changes in breathing pattern. In this case report we describe the effects of physiotherapy BR on a 57-year-old female with a 10-year history of asthma. Data were collected before and after a physiotherapy BR program comprising three sessions over 18 weeks: breathing pattern (respiratory inductive plethysmography (RIP); physiology (end tidal carbon dioxide (ETCO2), heart rate, oxygen saturations, spirometric lung function); questionnaires (Asthma Control Questionnaire (ACQ), Hospital Anxiety and Depression Score, Nijmegen Questionnaire); and medication usage. After BR, the patient's symptoms improved. Her physiology was largely unchanged, although her FEV1 increased by 0.12L, peak flow by 21L/min. The patient reported using less Salbutamol, yet her asthma control improved (ACQ down 1.5). Her Nijmegen score dropped from positive to negative for hyperventilation (from 39 to 7). Her anxiety-depression levels both reduced into 'normal' ranges. The patient's expiratory time increased, with longer respiratory cycles and slower respiratory rate. No changes were seen in relative contributions of ribcage and abdomen. Controlled trials are now needed to determine the generalizability of these findings. PMID- 29125381 TI - Pleiotropy in Drosophila organogenesis: Mechanistic insights from Combgap and the retinal determination gene network. AB - Master regulatory transcription factors cooperate in networks to shepherd cells through organogenesis. In the Drosophila eye, a collection of master control proteins known as the retinal determination gene network (RDGN) switches the direction and targets of its output to choreograph developmental transitions, but the molecular partners that enable such regulatory flexibility are not known. We recently showed that two RDGN members, Eyes absent (Eya) and Sine oculis (So), promote exit from the terminal cell cycle known as the second mitotic wave (SMW) to permit differentiation. A search for co-factors identified the ubiquitously expressed Combgap (Cg) as a novel transcriptional partner that impedes cell cycle exit and interferes with Eya-So activity specifically in this context. Here, we argue that Cg acts as a flexible transcriptional platform that contributes to numerous gene expression outcomes by a variety of mechanisms. For example, Cg provides repressive activities that dampen Eya-So output, but not by recruiting Polycomb chromatin-remodeling complexes as it does in other contexts. We propose that master regulators depend on both specifically expressed co-factors that assemble the combinatorial code and broadly expressed partners like Cg that recruit the diverse molecular activities needed to appropriately regulate their target enhancers. PMID- 29125382 TI - Intra-sheath versus extra-sheath ultrasound guided corticosteroid injection for trigger finger: a triple blinded randomized clinical trial. AB - OBJECTIVE: The aim of this study is to compare clinical results of ultrasound guided corticosteroid injection, intra-sheath versus extra-sheath of the finger flexor tendon. METHODS: A total of 166 patients with trigger finger were evaluated in a triple blind randomized clinical trial study. All the patients were injected with 1ml of 40mg/ml methyl prednisolone acetate, under the guidance of ultrasound. Half the patients were injected extra sheath, while the other half were injected intra sheath at the level of first annular pulley. RESULTS: The two groups were comparable in baseline characteristics (age, gender, dominant hand, involved hand and finger, and the symptoms duration). No significant difference was observed in the two groups with regards to Quinnell grading. In the final visit, 94% of patients from each group were symptom free. CONCLUSION: Results of corticosteroid injection intra-sheath or extra-sheath of the finger flexor tendon under ultrasound guidance in patients with trigger finger are comparably alike. Extra-sheath injection at the level of A1 pulley is as effective as an Intra sheath administration. PMID- 29125383 TI - Depression and Substance Use: Towards the Development of an Emotion Regulation Model of Stigma Coping. AB - The comorbidity between depression and substance use problems is well-documented, yet little research has investigated how stigma associated with one's depression might relate to alcohol and drug use. The current study examined the association between depression-related stigma and substance use coping and considered the role of emotion dysregulation (i.e., difficulty in monitoring, evaluating, and modulating one's emotional reactions) as a mechanism underlying this association. A sample of individuals who self-identified as having current or remitted depression (N = 218) completed self-report measures of depression-related stigma, emotion dysregulation, and tendency to rely on alcohol or drugs to cope with psychological distress. Depression-related stigma was positively associated with emotion dysregulation, which was in turn associated with a greater tendency to engage in substance use coping. These findings provide initial support for the role of stigma as a contributor to maladaptive coping responses, such as substance use, among people living with depression. Further, they underscored the potential utility of targeting emotion dysregulation in stigma coping and substance abuse prevention intervention efforts. PMID- 29125384 TI - Is it necessary to perform prehabilitation exercise for patients undergoing total knee arthroplasty: meta-analysis of randomized controlled trials. AB - OBJECTIVES: This study was designed to test whether it is necessary to perform prehabilitation exercise for patients undergoing total knee arthroplasty (TKA). METHODS: Literatures were identified from Pubmed, Clinicaltrials, Cochrane library, and SpringerLink. All studies that compared a prehabilitation exercise group with control group before TKA were included. The primary outcome was length of hospital stay. Secondary outcomes were quadriceps strength and functional ability in short term (1.5 to 3 months) after TKA. RESULTS: There was significant difference in the length of hospital stay, knee range of motion (ROM) and sit-to stand test (P<0.05). No statistical differences were found in quadriceps strength, 6-minute walk, ROM, knee extension, knee flexion, WOMAC pain, WOMAC function, WOMAC stiffness between the two groups in short term after TKA (P>0.05). CONCLUSIONS: Our meta-analysis found that prehabilitation exercise was effective in reducing length of hospital stay. Importantly, it was an effective method for improving knee ROM and sit-to-stand test after TKA. However, there was no effect of prehabilitation exercise on the improvement of quadriceps strength, 6-minute walk, pain and functional recovery following TKA. PMID- 29125385 TI - Novel approaches to surgical site infections: what recommendations can be made? AB - INTRODUCTION: Surgical site infections (SSI) are one of the most frequent healthcare-associated infections worldwide, representing a substantial burden on the healthcare system and the individual patient. Various risk factors for SSI have been identified, which can be separated into patient-related, procedure related and other risk factors. Areas covered: Other risk factors relevant for SSI are the season in which surgery is performed, the volume of surgeries in a department, the working atmosphere in the operating room and the indications for surgery. Overall, the risk of SSI is higher during summertime. Higher-volume departments appear to be protective against SSI as does a calm working atmosphere. The frequency of certain types of surgery differs greatly among European countries. The decision to perform surgery appears to be dependent on the patient's condition as well as the healthcare system and financial incentives. Expert commentary: When possible, elective surgery should not be executed during summertime but during cooler times of year. Departments with a high volume of surgical procedures should be given preference. The establishment of a calm working atmosphere is beneficial to a surgeon's performance and can reduce SSI rates. The indications for performing surgery should be carefully reevaluated whenever possible. PMID- 29125386 TI - Investigating Uncertainty in Genetic Counseling Encounters: Managing Information About Genetic Cancer Risk. AB - The Theory of Motivated Information Management (TMIM) was used to investigate how individuals at increased risk of developing hereditary cancer seek information from genetic counselors. Results show the TMIM model fit the data well in predicting participants' intentions to seek information from genetic counselors. Participants felt an uncertainty discrepancy that elicited feelings of anxiety, which in turn negatively predicted both outcome expectancies and efficacy assessments. Efficacy assessments, but not anxiety, significantly predicted participants' intentions to seek information from a genetic counselor in the future. Findings showed no significant relationship between outcome expectancies and efficacy assessments. One implication for genetic counselors is the need to more closely monitor emotional response to genetic disease risk-whether that emotional response be positive or negative-as that response may influence information-seeking intentions. Further, genetic counselors might also pay more attention to building efficacy for themselves (making patients feel the counselor is more credible) and their patients (increasing patient ability to communicate effectively about genetic disease risk). Analysis also extends TMIM theory by showing that in a relationship where information exchange is the primary function the model still showed good fit. However, outcome expectancies functioned differently than in previous tests of the model. PMID- 29125387 TI - Significado de psicologas/os de atencion primaria de salud sobre la intervencion psicosocial de grupo en el tratamiento de la depresion en Chile. AB - En Chile, el tratamiento de la depresion en salud publica promueve la realizacion de Intervenciones Psicosociales en Grupo (IPG) para todos los casos diagnosticados, no obstante, se observa una baja implementacion de estas prestaciones. El presente articulo describe y caracteriza, desde el punto de vista de la disciplina psicologica, el significado de psicologas/os que trabajan en consultorios de atencion primaria de salud (APS) sobre las IPG en el tratamiento de la depresion. Se entrevistaron a ocho psicologas/os de los distintos Servicios de Salud de la Region Metropolitana de Santiago. Este estudio se baso en las premisas de la Teoria Fundamentada, utilizando sus estrategias de analisis. La categoria "los grupos no nos resultan" expone las principales barreras que impiden la realizacion de estas intervenciones. La carga laboral centrada en atenciones individuales, el escaso presupuesto destinado a su implementacion, y la falta de instalaciones adecuadas para realizar las IPG emergen como barreras institucionales. Asi mismo, la "poca fe" en la efectividad del trabajo en grupo, la figura de las/os psicologas/os como unicas/os profesionales capacitadas/os para trabajar con las emociones, la idea de que la baja adherencia al tratamiento no depende de su ejercicio laboral, y el hecho de que la implementacion de las IPG dependa del interes individual de algunas/os profesionales, emergen como las principales resistencias profesionales a su realizacion. Se discuten los alcances de estas barreras, y se proponen soluciones que favorezcan el cambio cultural necesario para que las/los profesionales e instituciones de salud puedan alinearse en plenitud con el modelo comunitario de salud propuesto por el Plan Nacional de Salud Mental y Psiquiatria (PNSMP). PMID- 29125388 TI - Conserved function of mediator in regulating nuclear hormone receptor activation between plants and animals. AB - Perception of the plant hormone jasmonoyl-isoleucine (JA-Ile) involves the formation of a co-receptor complex between COI1, the F-box subunit of a SCF-type E3 ubiquitin ligase, and its substrates, a group of jasmonate ZIM-domain (JAZ) transcriptional repressors. In recent studies, we show that MED25, a subunit of the Arabidopsis Mediator, physically and functionally interacts with COI1 and the master transcription factor MYC2 on MYC2 target promoters. Here we provide evidence that MED25 also physically interacts with a subset of JAZ proteins. Therefore, in term of their interaction with Mediator, the JA-Ile co-receptor complex SCFCOI1-JAZs together with the master transcription factor MYC2 resembles the nuclear hormone receptor system of metazoans. In addition, we show that the plant MED25 and its animal counterpart also cooperates with similar epigenetic regulators in distinct signaling pathways. Our study reveals a scenario that plants and animals have evolved distinct, yet largely similar, mechanism for nuclear hormone receptor activation at the level of transcriptional regulation. PMID- 29125389 TI - Training for vigilance on the move: a video game-based paradigm for sustained attention. AB - The capacity for superior vigilance can be trained by using knowledge of results (KR). Our present experiments demonstrate the efficacy of such training using a first-person perspective movement videogame-based platform in samples of students and Soldiers. Effectiveness was assessed by manipulating KR during a training phase and withdrawing it in a subsequent transfer phase. Relative to a no KR control condition, KR systematically improved performance for both Soldiers and students. These results build upon our previous findings that demonstrated that a video game-based platform can be used to create a movement-centred sustained attention task with important elements of traditional vigilance. The results indicate that KR effects in sustained attention extend to a first person perspective movement based paradigm, and that these effects occur in professional military as well as a more general population. Such sustained attention training can save lives and the present findings demonstrate one particular avenue to achieve this goal. Practitioner Summary: Sustained attention can be trained by means of knowledge of results using a videogame-based platform with samples of students and Soldiers. Four experiments demonstrate that a dynamic, first-person perspective video game environment can serve to support effective sustained attention training in professional military as well as a more general population. PMID- 29125390 TI - Responsiveness of voltage-gated calcium channels in SH-SY5Y human neuroblastoma cells on micropillar substrates. AB - In this study, poly-L-lactic acid micropillar substrates were fabricated to evaluate the influence of topographic substrates on cell morphological and functional characteristics, such as spreading area, voltage-gated calcium channels (VGCCs) and membrane potential. The proliferation, spreading area, perimeter and circularity of SH-SY5Y cells interfaced with different substrates were first investigated. In addition, the cytoskeleton and focal adhesion of a cell as important manifestations of cell morphology were analyzed by immunofluorescence. VGCC responsiveness was evaluated by measuring the dynamic changes in intracellular Ca2+ evoked by 50 mM extracellular K+. To determine study whether the differences in VGCC responsiveness were caused by the differences in VGCC gene expression, the expression of N/L- type VGCCs was determined by qPCR and fluorescence staining. Notably, improved measurement of the membrane potential with potentiometric fluorescent dye TMRM was applied to determine the membrane potential of SH-SY5Y cells. Results indicated that the SH SY5Y cells were deformed significantly to adapt to the substrates; however, no distinct effect on the proliferative ability of SH-SY5Y cells was observed. The micropillar substrates markedly influenced VGCC responsiveness, which correlated strongly with cell spreading but not with VGCC expression. The resting membrane potential of SH-SY5Y cells cultured on different substrates also changed, but no effect on responsiveness of VGCC was observed. These results suggest that the effect of the micropillar substrates on cell VGCC responsiveness may be attributed to changes in the functionality of the ion channel itself. Thus, topographic substrates can be used to engineer cell functionality in cell-based drug screening. PMID- 29125391 TI - Five Ways to Wellbeing: holistic narratives of public health programme participants. AB - This paper reports on a study which formed part of a qualitative process evaluation of a wellbeing programme in North West England. The study used the biographic narrative interpretive method (BNIM) to undertake and analyse data from interviews with six participants from diverse projects within the programme. This generated rich case studies and spotlighted cross-case commonalities, building understanding of how the programme achieved its effects. We present findings using the Five Ways to Wellbeing framework, presenting one abridged 'case' and summarising cross-cutting themes. We explore how BNIM gives insight into the psychosocial complexity of wellbeing, building understanding of its holistic and dynamic nature, and then highlight the flexibility, resonance and widespread appeal of Five Ways to Wellbeing. In concluding, we argue that by enabling participants to tell their own stories of participation in the different projects, we gain a more authentic understanding of the 'whole' story of how involvement has affected wellbeing. Such approaches are crucial as wellbeing becomes a central concept in global health policy and promotion. PMID- 29125392 TI - Medical costs for the treatment of cervical cancer at central hospitals in Vietnam. AB - Cervical cancer remains the second most common cancer amongst female aged 15 to 44 years old in Vietnam. We estimated medical costs for the treatment of cervical cancer patients. We employed the standard costing approach and health care provider perspective. We first computed the unit cost of 22 medical services related to cervical cancer treatments and then, based on standard cervical cancer treatment protocols, we estimated the cost of nine treatment scenarios for cervical cancer patients. We found that the medical costs for treatment of cervical cancers at central hospitals in Vietnam increased as the cancer progresses into later stages. PMID- 29125393 TI - Complementary Support from Facilitators and Peers for Promoting mHealth Engagement and Weight Loss. AB - This study investigates the effects of mHealth interventions on sustainable behavior change and weight loss, drawing on in-app user activity data and online survey data. Specifically, we focus on the interactions within mobile support groups in Noom, an mHealth application for obesity intervention, to delve into how social support from facilitators and peers may play differential roles in promoting health outcomes. The results of structural equation modeling (N = 301) demonstrated that (a) perceived facilitator support was positively associated with group members' health information acquisition such as fitness-themed article reading whereas perceived peer support was positively linked to group participation such as posting and responding; (b) perceived peer support was positively related to normative influence among group members, which subsequently increased group members' responses to others' posts; and (c) health information reading and in-group posting promoted weight loss; however, merely responding to others' posts did not lead to weight-loss success. The findings suggest that the complementary influences of facilitators and peers must be considered to enhance the efficacy of support group interventions. PMID- 29125394 TI - Knowledge Gained and Retained from a Video-Centered, Community-Based Intervention for Ebola Prevention, Congo. AB - There are few effective communication interventions to respond to Ebola Virus Disease (EVD) outbreaks, and their development is a continuing challenge. The largest outbreak of EVD was first recognized in 2014 and once again highlighted the need for health education communication campaigns. EVD emergence and transmission are associated with behaviors that increase exposure to infected individuals and infected wildlife. In 2008-2009, an educational video-centered intervention consisting of a film followed by a structured discussion was developed to improve EVD knowledge, attitudes, and behaviors (KABs) for prevention of EVD and care of infected people. The film was produced for a Congolese audience in local languages and features doctors and residents from the region. The objective of the study was to assess the effectiveness of this intervention to change KABs related to EVD. The intervention was conducted over 12 months and reached >60,000 people; 220 individuals were sampled before and immediately after the intervention, and a subsample of 53 who had received the intervention 1 year earlier were interviewed to assess changes in KABs related to EVD. Statistically significant improvements in EVD recognition, transmission, and mitigation of risk after the intervention were observed. This study also demonstrates significant retention of knowledge one year after the intervention. Overall, the intervention was effective in improving KABs among a limited literacy population and knowledge was retained for more than one year. The materials and approaches developed were used in 2014 as part of a social mobilization strategy in response to an Ebola outbreak in the Congo Basin. PMID- 29125395 TI - Microbiota of the ground air layers in natural and industrial zones of the Kola Arctic. AB - The fungi and bacteria number, as well as the species composition of the fungi in the ground air layer in the European Arctic region of Russia, primarily in the tundra (the Rybachy Peninsula), in the subzone of the northern taiga (the Pasvik State Nature Reserve) and in the industrial areas (the Copper-Nickel Plant "Pechenganickel," the Kandalaksha Aluminum Plant) have been studied. One hundred and ninety-two atmosphere air samples of various ecosystems have been analyzed. The sample collection took place in the summer-autumn period (June, July, September, in 2012-2015) with the aspirator, precipitating microorganisms on the surface of media. The number of microorganisms per 1 m3 of air was calculated. The portion of the airborne fungi in the ground air layer both in the tundra and in the taiga was higher in comparison with the bacteria, and amounted to 60-77% of the total number colony forming units (CFU). The least number of microorganisms in the investigated period was registered in the Barents Sea coastal atmospheric air, only 11-15 microbial CFU per 1 m3. The airborne fungi diversity in the taiga zone was richer than in the tundra. The fungi of the g. Penicillium predominated in both zones air. Bacteria gram-positive (the division Fermicutes) predominated within the bacterial biota. The species Penicillium decumbens, P. raistrickii prevailed in the air of the background tundra zone regions. The representatives of the genus Torula and Sterilia mycelia, P. raistrickii predominated in the taiga zone. Close by the Copper-Nickel Plant (about 3 km), the air bacterial contamination (100-600 CFU per 1 m3) was revealed, with prevailing bacteria gram-negative (the division Gracilicutes). The species Cladosporium oxysporum predominated in the air to the greatest possible extent of the contaminated region due to the emissions of the Kandalaksha Aluminum Plant. The species Gongronella butleri were uppermost due to the emissions of the Copper-Nickel Plant "Pechenganickel". The quantity of the dark pigmented fungi in the air for both zones amounted to 25% of the total amount within the emphasized species. The composition of the air industrial emissions stimulated the development of specific airborne fungi which are essentially different from those of the background regions. PMID- 29125396 TI - Therapies and mechanisms of opioid withdrawal. PMID- 29125397 TI - Oxytocin receptor genotype and low economic privilege reverses ventral striatum social anxiety association. AB - Oxytocin receptor gene (OXTR) polymorphisms, lower ventral striatum (VS) response to social stimuli, and lower economic privilege have been independently associated with depression and anxiety. However, the interactions between these risk factors are unknown. One hundred and fifty-seven healthy adult participants genotyped for OXTR rs237915 completed a common emotion-matching task during functional magnetic resonance imaging. Past economic privilege and depression and anxiety symptoms were concurrently assessed through validated self-report measures. The data revealed an interaction between rs237915 genotype and economic privilege on the neural response to negative faces. C-carriers showed decreased VS activation and increased connectivity between the VS and ventromedial prefrontal cortex with increased economic privilege. TT homozygotes showed the reverse pattern. Low VS response to negative faces predicted increased social anxiety, but only for those with either lower economic privilege or the C allele. For those with both, low VS response was associated with paradoxically lower social anxiety. Findings suggest that economic privilege and OXTR rs237915 genotype may calibrate social motivational neural systems for better or worse. While lower VS response to negative faces may generally constitute a risk factor for social anxiety, lower response to social cues may be a benefit for those with dual risk. PMID- 29125398 TI - The management of peri- and postprocedural pain in interventional radiology: a narrative review. AB - Interventional radiology encompasses a wide range of procedures and the degree of associated pain depends predominantly on the procedure being undertaken. Procedures may be painful during but not after the procedure, relatively painless during but painful after the procedure, or relatively painless during and after the procedure. However, there is a lack of good quality publications in interventional radiology that specifically address the subject of peri- and postprocedural pain management. Nevertheless, a variety of more or less complex protocols exist for intraprocedural sedation and for peri- and postprocedural analgesia. While weight-based protocols for procedural sedation have demonstrable benefit, protocols for postprocedural pain relief after major procedures have not been sufficiently rigorously evaluated. PMID- 29125399 TI - An analysis of variables affecting the duration of Pavlik harness treatment: Is it possible to predict the duration of treatment? AB - BACKGROUND: Pavlik harness is the initial treatment for the infants with developmental dysplasia of the hip who have not yet begun walking. OBJECTIVES: The present study evaluates the variables which affect the duration of PH treatment for patients successfully treated. STUDY DESIGN: Cross-sectional study. METHODS: Pavlik harness was employed for 140 hips of 87 patients with developmental dysplasia of the hip in our institution between 2010 and 2013. In all, 55 hips of 46 patients who were treated successfully with Pavlik harness were included in this study. According to Graf's sonographic classification, 23 hips were Type IIC, 26 were Type IID, and 6 were Type III. The studied variables were (1) alpha angle, (2) age at the start of treatment, (3) laterality, and (4) gender. The variables were compared with the duration of Pavlik harness treatment. RESULTS: A highly significant inverse correlation was observed between Pavlik harness application time and alpha angle at the start of the treatment ( r = -0.050; p < 0.001). Bilateral involvement has statistically longer duration, when compared with unilateral involvement ( r = 0.28; p = 0.036). No statistically significant difference was present between duration of treatment and age at the start of Pavlik harness treatment ( r = -0.034; p = 0.804). There was no statistical significance between gender and duration of Pavlik harness ( r = 0.201; p > 0.05). CONCLUSION: The duration of treatment was negatively correlated with the initial alpha angle. A change of 1 degree in alpha angle may alter the duration of treatment as 0.89 week calculated by the formula (Application time (Week) = 56.6 - 0.89 * alpha angle). Bilateral involvement may need longer Pavlik harness treatment. Clinical relevance Pavlik harnes generally is the first treatment method for the infants with DDH. This study suggest conclutions about how long time is the Pavlik harness should be kept on the infants? The main indicator is initial alfa angle which is negatively correlated with the duration of treatment. PMID- 29125400 TI - IJS Impact Factor Jumps to 2.871 in Only Five Years! PMID- 29125401 TI - Conference Diary. PMID- 29125402 TI - Adolescent internal condylar resorption (AICR) of the temporomandibular joint, part 1: A review for diagnosis and treatment considerations. AB - Background Adolescent internal condylar resorption (AICR) is a temporomandibular joint (TMJ) pathology that develops predominately in teenage females during pubertal growth (onset between ages 11 and 15 years), with a distinct clinical, radiographic, and magnetic resonance imaging (MRI) presentation. Clinical and imaging presentation The condition usually occurs bilaterally with: (1) Progressive retrusion of the mandible; (2) High occlusal plane angle facial morphology; (3) Worsening Class II occlusion; and (4) TMJ symptoms such as pain, headaches, noises, etc. MRI imaging demonstrates decreased condylar head size and anterior disc displacement. Treatment protocol AICR can be successfully treated when the condyles and discs are salvageable with the following surgical protocol: (1) Removal of bilaminar tissue surrounding the condyle; (2) Reposition the disc with the Mitek anchor technique; and (3) Orthognathic surgery to advance the maxillo-mandibular complex in a counterclockwise direction. Conclusion AICR can be successfully treated using the specific protocol presented herein to provide stable and predictable outcomes. PMID- 29125403 TI - Conference Diary. PMID- 29125404 TI - Comment on ITAIS. PMID- 29125405 TI - Cutibacterium (formerly Propionibacterium) acnes infections associated with implantable devices. AB - INTRODUCTION: Cutibacterium acnes (C. acnes), a Gram-positive biofilm-forming rod implicated in acne vulgaris, is increasingly recognized for its role in implant associated infections. The diagnosis of C. acnes implant-associated infections remains challenging. The optimal treatment is a combination of both surgical intervention and antibiotic therapy. Areas covered: In this review, we discuss the different types of implant-associated infections caused by C. acnes. We also highlight the clinical manifestations pertaining to the various sites of infection, and identify several risk factors previously reported in the literature. We then cover the diagnostic laboratory markers, such as IL-6 and AD 1, optimizing C. acnes recovery in culture, and the specific molecular techniques. Finally, we examine the various effective antibiotic regimens and identify some preventive methods against C. acnes infections. Expert commentary: Biomarkers such as IL-6 and AD-1 should be further investigated for the diagnosis of C. acnes implant-associated infections. The use of 16S rRNA gene sequencing and other molecular techniques should be further explored in this setting. Longer incubation periods should be requested whenever C. acnes infection is suspected. If the clinical suspicion is high, sonication of the excised implant should be encouraged. Research should focus on developing effective anti-biofilm agents. Finally, preventive methods such as hair removal prior to surgery should be further explored. PMID- 29125406 TI - Bruton's tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL). AB - INTRODUCTION: The BTK inhibitor ibrutinib is effective in both low- and high-risk CLL patients, achieving durable remissions with continuous therapy in the majority of patients. Ibrutinib lacks myelotoxicity and is generally well tolerated by older and unfit patients; however, side effects, such as atrial fibrillation or hemorrhage, can result in treatment interruption or discontinuation. Given the high efficacy and overall safety, ibrutinib is increasingly used in untreated and previously treated CLL patients. Second generation BTK inhibitors are being developed, with different and generally more BTK-selective kinase inhibition profiles, which may increase the safety and/or efficacy. Areas covered: We review key features of ibrutinib, along with problems of its use, discuss the potential and drawbacks of second generation molecules, and discuss combination therapies currently in development. Expert Opinion: BTK inhibitors have been a major therapeutic advance in older/unfit patients and those with high-risk and/or relapsed CLL, but require indefinite maintenance therapy and risk of developing treatment resistance or adverse events requiring treatment cessation increases over time. Novel combination strategies are currently being evaluated (e.g. the combination of ibrutinib with venetoclax), which may achieve greater depth of remission, remove the need for indefinite maintenance treatment and potentially replace chemoimmunotherapy in the first line setting. PMID- 29125408 TI - Improving stroke transitions: Development and implementation of a social work case management intervention. AB - Strokes impact over 800,000 people every year. Stroke care typically begins with inpatient care and then continues across an array of healthcare settings. These transitions are difficult for patients and caregivers, with psychosocial needs going unmet. Our team developed a case management intervention for acute stroke patients and their caregivers aimed at improving stroke transitions. The intervention focusses on four aspects of a successful care transition: support, preparedness, identifying and addressing unmet needs, and stroke education. This paper describes the development and implementation of this program, and is an example of the synergy created between neuroscience and clinical practice. PMID- 29125409 TI - Interdependence in decision-making by medical consultants: implications for improving the efficiency of inpatient physician services. AB - OBJECTIVES: Hospital administrators are seeking to improve efficiency in medical consultation services, yet whether consultants make decisions to provide more or less care is unknown. We examined how medical consultants account for prior consultants' care when determining whether to provide intensive consulting care or sign off in the treatment of complex surgical inpatients. We applied three distinct theoretical frameworks in the interpretation of our results. METHODS: We performed a retrospective cohort study of consultants' care intensity, measured alternately using a dummy variable for providing two or more days consulting (versus one) and a continuous measure of total days consulting, with 100% Medicare claims data from 2007-2010. Our analytic samples included consults for beneficiaries undergoing coronary artery bypass grafting (n = 61,785) or colectomy (n = 33,460) in general acute care hospitals. We compared the care intensity of consultants who observed different patterns of consulting care before their initial consults using ordinary least squares regression models at the patient-physician dyad level, controlling for patient comorbidity and many other patient- and physician-level factors as well as hospital region and year fixed effects. RESULTS: Consultants were less likely to provide intensive consulting care with each additional prior consultant on the case (1.2-1.7 percent) or if a prior consultant rendered intensive consulting care (20.6-21.5 percent) but more likely when prior consults were more concentrated across consultants (2.9-3.1 percent). Effects on consultants' total days consulting were similar. CONCLUSION: On average, consultants appeared to calibrate their care intensity for individual patients to maximize their value to all patients. Interventions for improving consulting care efficiency should seek to facilitate (not constrain) consultants' decision-making processes. PMID- 29125410 TI - Hemorrhage associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on a regimen of dual antiplatelet therapy: a retrospective analysis. AB - OBJECTIVE: Intracranial stenting and flow diversion require the use of dual antiplatelet therapy (DAPT) to prevent in-stent thrombosis. DAPT may significantly increase the risk of hemorrhagic complications in patients who require subsequent surgical interventions. In this study, the authors sought to investigate whether DAPT is a risk factor for hemorrhagic complications associated with ventriculoperitoneal (VP) shunt placement in patients with aneurysmal subarachnoid hemorrhage (aSAH). Moreover, the authors sought to compare VP shunt complication rates with respect to the shunt's location from the initial external ventricular drain (EVD) site. METHODS: Patients with aSAH who presented to the authors' institution from July 2009 through November 2016 and required VP shunt placement for persistent hydrocephalus were included. The rates of hemorrhagic complications associated with VP shunt placement were compared between patients who were on a regimen of DAPT (aspirin and clopidogrel) for use of a stent or flow diverter, and patients who underwent microsurgical clipping or coiling only and were not on DAPT using a backward stepwise multivariate analysis. Rates of radiographic hemorrhage and infection-related VP shunt revision were compared between patients who underwent VP shunt placement along the same track and those who underwent VP shunt placement at a different site (contralateral or posterior) from the initial EVD. RESULTS: A total of 443 patients were admitted for the management of aSAH. Eighty of these patients eventually required VP shunt placement. Thirty-two patients (40%) had been treated with stent-assisted coiling or flow diverters and required DAPT, whereas 48 patients (60%) had been treated with coiling without stents or surgical clipping and were not on DAPT at the time of VP shunt placement. A total of 8 cases (10%) of new hemorrhage were observed along the intracranial proximal catheter of the VP shunt. Seven of these hemorrhages were observed in patients on DAPT, and 1 occurred in a patient not on DAPT. After multivariate analysis, only DAPT was significantly associated with hemorrhage (OR 31.23, 95% CI 2.98-327.32; p = 0.0001). One patient (3%) on DAPT who experienced hemorrhage required shunt revision for hemorrhage-associated proximal catheter blockage. The remaining 7 hemorrhages were clinically insignificant. The difference in rates of hemorrhage between shunt placement along the same track and placement at a different site of 0.07 was not significant (6/47 vs 2/32, p = 0.46). The difference in infection related VP shunt revision rate was not significantly different (1/47 vs 3/32, p = 0.2978). CONCLUSIONS: This clinical series confirms that, in patients with ruptured aneurysms who are candidates for stent-assisted coiling or flow diversion, the risk of clinically significant VP shunt-associated hemorrhage with DAPT is low. In an era of evolving endovascular therapeutics, stenting or flow diversion is a viable option in select aSAH patients. PMID- 29125411 TI - Erratum. Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers. PMID- 29125412 TI - Stereotactic radiosurgery for jugular foramen schwannomas: an international multicenter study. AB - OBJECTIVE: For some jugular foramen schwannomas (JFSs), complete resection is possible but may be associated with significant morbidity. Stereotactic radiosurgery (SRS) is a minimally invasive alternative or adjunct to microsurgery for JFSs. The authors reviewed clinical and imaging outcomes of SRS for patients with these tumors. METHODS: Nine participating centers of the International Gamma Knife Research Foundation identified 92 patients who underwent SRS between 1990 and 2013. Forty-one patients had prior subtotal microsurgical resection. The median interval between previous surgery and SRS was 15 months (range 0.5-144 months). Eighty-four patients had preexisting cranial nerve (CN) symptoms and signs. The median tumor volume was 4.1 cm3 (range 0.8-22.6 cm3), and the median margin dose was 12.5 Gy (range 10-18 Gy). Patients with neurofibromatosis were excluded from this study. RESULTS: The median follow-up was 51 months (range 6 266 months). Tumors regressed in 47 patients, remained stable in 33, and progressed in 12. The progression-free survival (PFS) was 93% at 3 years, 87% at 5 years, and 82% at 10 years. In the entire series, only a dumbbell shape (extension extracranially via the jugular foramen) was significantly associated with worse PFS. In the group of patients without prior microsurgery (n = 51), factors associated with better PFS included tumor volume < 6 cm3 (p = 0.037) and non-dumbbell-shaped tumors (p = 0.015). Preexisting cranial neuropathies improved in 27 patients, remained stable in 51, and worsened in 14. The CN function improved after SRS in 12% of patients at 1 year, 24% at 2 years, 27% at 3 years, and 32% at 5 years. Symptomatic adverse radiation effects occurred in 7 patients at a median of 7 months after SRS (range 5-38 months). Six patients underwent repeat SRS at a median of 64 months (range 44-134 months). Four patients underwent resection at a median of 14 months after SRS (range 8-30 months). CONCLUSIONS: Stereotactic radiosurgery proved to be a safe and effective primary or adjuvant management approach for JFSs. Long-term tumor control rates and stability or improvement in CN function were confirmed. PMID- 29125413 TI - A computational fluid dynamics simulation framework for ventricular catheter design optimization. AB - In this research an optimization methodology and 3D computational fluid dynamics algorithm were coupled to reach an important design objective for ventricular catheters: uniform inlet flow distribution. The optimized catheter design presented significantly improves on previous designs explored in the literature and on standard catheter designs used clinically. The automated, iterative fluid simulation framework described in this work can be used to rapidly explore design parameter influence on other flow-related objectives in the future. PMID- 29125414 TI - Resection of gliomas deemed inoperable by neurosurgeons based on preoperative imaging studies. AB - OBJECTIVE Maximal safe resection is a primary objective in the management of gliomas. Despite this objective, surgeons and referring physicians may, on the basis of radiological studies alone, assume a glioma to be unresectable. Because imaging studies, including functional MRI, may not localize brain functions (such as language) with high fidelity, this simplistic approach may exclude some patients from what could be a safe resection. Intraoperative direct electrical stimulation (DES) allows for the accurate localization of functional areas, thereby enabling maximal resection of tumors, including those that may appear inoperable based solely on radiological studies. In this paper the authors describe the extent of resection (EOR) and functional outcomes following resections of tumors deemed inoperable by referring physicians and neurosurgeons. METHODS The authors retrospectively examined the cases of 58 adult patients who underwent glioma resection within 6 months of undergoing a brain biopsy of the same lesion at an outside hospital. All patients exhibited unifocal supratentorial disease and preoperative Karnofsky Performance Scale scores >= 70. The EOR and 6-month functional outcomes for this population were characterized. RESULTS Intraoperative DES mapping was performed on 96.6% (56 of 58) of patients. Nearly half of the patients (46.6%, 27 of 58) underwent an awake surgical procedure with DES. Overall, the mean EOR was 87.6% +/- 13.6% (range 39.0%-100%). Gross-total resection (resection of more than 99% of the preoperative tumor volume) was achieved in 29.3% (17 of 58) of patients. Subtotal resection (95%-99% resection) and partial resection (PR; < 95% resection) were achieved in 12.1% (7 of 58) and 58.6% (34 of 58) of patients, respectively. Of the cases that involved PR, the mean EOR was 79.4% +/- 12.2%. Six months after surgery, no patient was found to have a new postoperative neurological deficit. The majority of patients (89.7%, 52 of 58) were free of neurological deficits both pre- and postoperatively. The remainder of patients exhibited either residual but stable deficits (5.2%, 3 of 58) or complete correction of preoperative deficits (5.2%, 3 of 58). CONCLUSIONS The use of DES enabled maximal safe resections of gliomas deemed inoperable by referring neurosurgeons. With rare exceptions, tumor resectability cannot be determined solely by radiological studies. PMID- 29125415 TI - Letter to the Editor. Intraoperative brain relaxation using mannitol. PMID- 29125416 TI - Gamma oscillations in the somatosensory thalamus of a patient with a phantom limb: case report. AB - The amputation of an extremity is commonly followed by phantom sensations that are perceived to originate from the missing limb. The mechanism underlying the generation of these sensations is still not clear although the development of abnormal oscillatory bursting in thalamic neurons may be involved. The theory of thalamocortical dysrhythmia implicates gamma oscillations in phantom pathophysiology although this rhythm has not been previously observed in the phantom limb thalamus. In this study, the authors report the novel observation of widespread 38-Hz gamma oscillatory activity in spike and local field potential recordings obtained from the ventral caudal somatosensory nucleus of the thalamus (Vc) of a phantom limb patient undergoing deep brain stimulation (DBS) surgery. Interestingly, microstimulation near tonically firing cells in the Vc resulted in high-frequency, gamma oscillatory discharges coincident with phantom sensations reported by the patient. Recordings from the somatosensory thalamus of comparator groups (essential tremor and pain) did not reveal the presence of gamma oscillatory activity. PMID- 29125417 TI - Loss of mechanosensitive sclerostin may accelerate cranial bone growth and regeneration. AB - OBJECTIVE: Cranial defects can result from trauma, infection, congenital malformations, and iatrogenic causes and represent a surgical challenge. The current standard of care is cranioplasty, with either autologous or allogeneic material. In either case, the intrinsic vascularity of the surrounding tissues allows for bone healing. The objective of this study was to determine if mechanotransductive gene manipulation would yield non-weight-bearing bone regeneration in a critical size calvarial defect in mice. METHODS: A mouse model of Sost deletion in Sost knockout (KO) mice was created in which the osteocytes do not express sclerostin. A critical size calvarial defect (4 mm in diameter) was surgically created in the parietal bone in 8-week-old wild-type (n = 8) and Sost KO (n = 8) male mice. The defects were left undisturbed (no implant or scaffold) to simulate a traumatic calvariectomy model. Eight weeks later, the animals were examined at necropsy by planimetry, histological analysis of new bone growth, and micro-CT scanning of bone thickness. RESULTS: Defects created in wild-type mice did not fill with bone over the study period of 2 months. Genetic downregulation of sclerostin yielded animals that were able to regenerate 40% of the initial critical size defect area 8 weeks after surgery. A thin layer of bone covered a significant portion of the original defect in all Sost KO animals. A statistically significant increase in bone volume (p < 0.05) was measured in Sost KO mice using radiodensitometric analysis. Immunohistochemical analysis also confirmed that this bone regeneration occurred through the Wnt pathway and originated from the edge of the defect; BMP signaling did not appear to be affected by sclerostin. CONCLUSIONS: Mechanical loading is an important mechanism of bone formation in the cranial skeleton and is poorly understood. This is partially due to the fact that it is difficult to load bone in the craniomaxillofacial skeleton. This study suggests that modulation of the Wnt pathway, as is able to be done with monoclonal antibodies, is a potentially efficacious method for bone regeneration that requires further study. PMID- 29125418 TI - Self-plant perception via long-distance signaling. AB - Plant growth and development are influenced by the interactions with other organisms including bacteria, fungi, herbivores and neighboring plants. Plant density influences the phase transitions during the entire life cycle and root architecture through a mechanism involving auxin and MEDIATOR 25 in Arabidopsis thaliana, but the nature of the signals that are perceived in response to increasing number of neighbors remains elusive. Here, we report that plant-plant perception can occur distantly, since root growth and auxin response in Arabidopsis seedlings grown at high plant density into half-divided Petri plates, decreased both primary root growth and lateral root formation in comparison with single plants grown alone, which correlates with reduced auxin response at the primary root tip. It is possible that a diffusible, yet unidentified volatile can be perceived by neighbors to synchronize physiological and developmental behavior. PMID- 29125420 TI - Corrigendum. PMID- 29125419 TI - Editorial. PMID- 29125422 TI - Characteristics of morphologic macular abnormalities in neuroimmunology practice. AB - BACKGROUND: Morphologic macular abnormalities (MMAs) are frequently seen on macular optical coherence tomography (OCT) imaging in neuroimmunology practice, yet studies pragmatically assessing prevalence and risk factors of MMAs to date are limited. OBJECTIVE: To describe the characteristics of MMAs in a neuroimmunology-based academic practice. METHODS: Cross-sectional study of 1450 patients (2900 eyes) who underwent spectral-domain macular OCT between June 2010 and June 2012. The association between MMAs and demographic variables was analyzed using mixed-effects logistic regression. Odds ratios (ORs) were calculated per 5-year age increments. RESULTS: MMAs were observed in 338/2872 eyes (11.7%) of 232/1445 participants (16.1%). The most common abnormalities identified, included drusen (6.0%), epiretinal membrane (ERM; 5.5%), and microcystoid macular pathology (MMP; 1.9%). Overall, patients with MMAs were older (OR: 1.79, p = 5 * 10-5) and more likely to be males (OR: 2.45, p = 0.014). In particular, advancing age was associated with higher risk of drusen and ERM (OR: 1.80 and 4.26, p = 2 * 10-5 and 7 * 10-3, respectively). MMP prevalence declined with age (OR: 0.73, p = 0.015) and was associated with African-American ethnicity (OR: 15.0, p = 5 * 10-5). CONCLUSION: Unexpected or incidental MMAs are common in patients assessed with OCT in neuroimmunology practice, emphasizing the importance of comprehensive OCT image review for risk stratification and appropriate ophthalmology referral. PMID- 29125423 TI - Management of chronic neuropathic pain with single and compounded topical analgesics. AB - The goal of our review was to emphasize important aspects that physicians should take into consideration when prescribing topical analgesics as part of chronic neuropathic pain treatment. We discuss the dermatopharmacokinetics and microstructural components of the skin, differences between topical and transdermal drug delivery, and topical medication effects on peripheral neuropathy and central sensitization. Even though the US FDA approved topical analgesics are 8%-capsaicin and 5%-lidocaine patches for treating postherpetic neuralgia, there are many other studies conducted on the efficacy of topical ketamine cream, clonidine gel, topical gabapentin, topical baclofen and topical phenytoin for peripheral neuropathic pain, either alone or in combination with other formulations. Furthermore, we discuss new compounded topical analgesics that are becoming more popular and that are showing promising results in the management of chronic peripheral neuropathies. However, more studies are needed for elucidation of the role of topical analgesics and their effects, especially when combined with other treatments. PMID- 29125424 TI - Understanding Postdisaster Substance Use and Psychological Distress Using Concepts from the Self-Medication Hypothesis and Social Cognitive Theory. AB - This article applies constructs from the Self-Medication Hypothesis and Social Cognitive Theory to explain the development of substance use and psychological distress after a disaster. A conceptual model is proposed, which employs a sequential mediation model, identifying perceived coping self-efficacy, psychological distress, and self-medication as pathways to substance use after a disaster. Disaster exposure decreases perceived coping self-efficacy, which, in turn, increases psychological distress and subsequently increases perceptions of self-medication in vulnerable individuals. These mechanisms lead to an increase in postdisaster substance use. Last, recommendations are offered to encourage disaster researchers to test more complex models in studies on postdisaster psychological distress and substance use. PMID- 29125425 TI - Ethical and regulatory challenges of research using pervasive sensing and other emerging technologies: IRB perspectives. AB - Vast quantities of personal health information and private identifiable information are being created through mobile apps, wearable sensors, and social networks. While new strategies and tools for obtaining health data have expanded researchers' abilities to design and test personalized and adaptive health interventions, the deployment of pervasive sensing and computational techniques to gather research data is raising ethical challenges for Institutional Review Boards (IRBs) charged with protecting research participants. To explore experiences with, and perceptions about, technology-enabled research, and identify solutions for promoting responsible conduct of this research we conducted focus groups with human research protection program and IRB affiliates. Our findings outline the need for increased collaboration across stakeholders in terms of: (1) shared and dynamic resources that improve awareness of technologies and decrease potential threats to participant privacy and data confidentiality, and (2) development of appropriate and dynamic standards through collaboration with stakeholders in the research ethics community. PMID- 29125427 TI - The surgical treatment of metastatic spine tumors within the intramedullary compartment. AB - OBJECTIVE Metastasis to the spinal cord is rare, and optimal management of this disease is unclear. The authors investigated this issue by analyzing the results of surgical treatment of spinal intramedullary metastasis (IM) at a major cancer center. METHODS The authors retrospectively reviewed the medical records of 13 patients who underwent surgery for IM. Patients had renal cell carcinoma (n = 4), breast carcinoma (n = 3), melanoma (n = 2), non-small cell lung cancer (n = 1), sarcoma (n = 1), adenoid cystic carcinoma (n = 1), and cervical cancer (n = 1). Cerebrospinal fluid was collected before surgery in 11 patients, and was negative for malignant cells, as was MRI of the neuraxis. Eleven patients presented with neurological function equivalent to Frankel Grade D. RESULTS Radiographic gross total resection was achieved in 9 patients, and tumor eventually recurred locally in 3 of those 9 (33%). Leptomeningeal disease was diagnosed in 4 patients after surgery. In the immediate postoperative period, neurological function in 6 patients deteriorated to Frankel Grade C. At 2 months, only 2 patients remained at Grade C, 8 were at Grade D, and 1 had improved to Grade E. One patient developed postoperative hematoma resulting in Frankel Grade A. Radiotherapy was delivered in 8 patients postoperatively. The median survival after spine surgery was 6.5 months. Three patients are still living. CONCLUSIONS Surgery was performed as a last option to preserve neurological function in patients with IM. In most patients, neurological function returned during the immediate postoperative period and was preserved for the patients' remaining lifetime. The data suggest that surgery can be effective in preventing further decline in selected patients with progressive neurological deficit. PMID- 29125426 TI - Influence of catastrophizing, anxiety, and depression on in-hospital opioid consumption, pain, and quality of recovery after adult spine surgery. AB - OBJECTIVE Perception of perioperative pain is influenced by various psychological factors. The aim of this study was to determine the impact of catastrophizing, anxiety, and depression on in-hospital opioid consumption, pain scores, and quality of recovery in adults who underwent spine surgery. METHODS Patients undergoing spine surgery were enrolled in this study, and the preoperatively completed questionnaires included the verbal rating scale (VRS), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), and Oswestry Disability Index (ODI). Quality of recovery was assessed using the 40 item Quality of Recovery questionnaire (QoR40). Opioid consumption and pain scores according to the VRS were recorded daily until discharge. RESULTS One hundred thirty-nine patients were recruited for the study, and 101 completed the QoR40 assessment postoperatively. Patients with higher catastrophizing scores were more likely to have higher maximum pain scores postoperatively (estimate: 0.03, SE: 0.01, p = 0.02), without increased opioid use (estimate: 0.44, SE: 0.27, p = 0.11). Preoperative anxiety (estimate: 1.18, SE: 0.65, p = 0.07) and depression scores (estimate: 1.06, SE: 0.71, p = 0.14) did not correlate with increased postoperative opioid use; however, patients with higher preoperative depression scores had lower quality of recovery after surgery (estimate: -1.9, SE: 0.56, p < 0.001). CONCLUSIONS Catastrophizing, anxiety, and depression play important roles in modulating postoperative pain. Preoperative evaluation of these factors, utilizing a validated tool, helps to identify patients at risk. This might allow for earlier psychological intervention that could reduce pain severity and improve the quality of recovery. PMID- 29125428 TI - Schwann cells and mesenchymal stem cells in laminin- or fibronectin-aligned matrices and regeneration across a critical size defect of 15 mm in the rat sciatic nerve. AB - OBJECTIVE Artificial nerve guides are being developed to substitute for autograft repair after peripheral nerve injuries. However, the use of conduits is limited by the length of the gap that needs to be bridged, with the success of regeneration highly compromised in long gaps. Addition of aligned proregenerative cells and extracellular matrix (ECM) components inside the conduit can be a good strategy to achieve artificial grafts that recreate the natural environment offered by a nerve graft. The purpose of this study was to functionalize chitosan devices with different cell types to support regeneration in limiting gaps in the rat peripheral nerve. METHODS The authors used chitosan devices combined with proteins of the ECM and cells in a rat model of sciatic nerve injury. Combinations of fibronectin and laminin with mesenchymal stem cells (MSCs) or Schwann cells (SCs) were aligned within tethered collagen-based gels, which were placed inside chitosan tubes that were then used to repair a critical-size gap of 15 mm in the rat sciatic nerve. Electrophysiology and algesimetry tests were performed to analyze functional recovery during the 4 months after injury and repair. Histological analysis was performed at the midlevel and distal level of the tubes to assess the number of regenerated myelinated fibers. RESULTS Functional analysis demonstrated that SC-aligned scaffolds resulted in 100% regeneration success in a 15-mm nerve defect in this rat model. In contrast, animals that underwent repair with MSC-aligned constructs had only 90% regeneration success, and those implanted with acellular bridges had only 75% regeneration success. CONCLUSIONS These results indicate that the combination of chitosan conduits with ECM-enriched cellular gels represents a good alternative to the use of autografts for repairing long nerve gaps. PMID- 29125429 TI - Graft subsidence as a predictor of revision surgery following stand-alone lateral lumbar interbody fusion. AB - OBJECTIVE Lateral lumbar interbody fusion (LLIF) is a less invasive surgical option commonly used for a variety of spinal conditions, including in high-risk patient populations. LLIF is often performed as a stand-alone procedure, and may be complicated by graft subsidence, the clinical ramifications of which remain unclear. The aim of this study was to characterize further the sequelae of graft subsidence following stand-alone LLIF. METHODS A retrospective review of prospectively collected data was conducted on consecutive patients who underwent stand-alone LLIF between July 2008 and June 2015; 297 patients (623 levels) met inclusion criteria. Imaging studies were examined to grade graft subsidence according to Marchi criteria, and compared between those who required revision surgery and those who did not. Additional variables recorded included levels fused, DEXA (dual-energy x-ray absorptiometry) T-score, body mass index, and routine demographic information. The data were analyzed using the Student t-test, chi-square analysis, and logistic regression analysis to identify potential confounding factors. RESULTS Of 297 patients, 34 (11.4%) had radiographic evidence of subsidence and 18 (6.1%) required revision surgery. The median subsidence grade for patients requiring revision surgery was 2.5, compared with 1 for those who did not. Chi-square analysis revealed a significantly higher incidence of revision surgery in patients with high-grade subsidence compared with those with low-grade subsidence. Seven of 18 patients (38.9%) requiring revision surgery suffered a vertebral body fracture. High-grade subsidence was a significant predictor of the need for revision surgery (p < 0.05; OR 12, 95% CI 1.29-13.6), whereas age, body mass index, T-score, and number of levels fused were not. This relationship remained significant despite adjustment for the other variables (OR 14.4; 95% CI 1.30-15.9). CONCLUSIONS In this series, more than half of the patients who developed graft subsidence following stand-alone LLIF required revision surgery. When evaluating patients for LLIF, supplemental instrumentation should be considered during the index surgery in patients with a significant risk of graft subsidence. PMID- 29125430 TI - Cortical bone trajectory screw fixation versus traditional pedicle screw fixation for 2-level posterior lumbar interbody fusion: comparison of surgical outcomes for 2-level degenerative lumbar spondylolisthesis. AB - OBJECTIVE The cortical bone trajectory (CBT) screw technique is a new nontraditional pedicle screw (PS) insertion method. However, the biomechanical behavior of multilevel CBT screw/rod fixation remains unclear, and surgical outcomes in patients after 2-level posterior lumbar interbody fusion (PLIF) using CBT screw fixation have not been reported. Thus, the purposes of this study were to examine the clinical and radiological outcomes after 2-level PLIF using CBT screw fixation for 2-level degenerative lumbar spondylolisthesis (DS) and to compare these outcomes with those after 2-level PLIF using traditional PS fixation. METHODS The study included 22 consecutively treated patients who underwent 2-level PLIF with CBT screw fixation for 2-level DS (CBT group, mean follow-up 39 months) and a historical control group of 20 consecutively treated patients who underwent 2-level PLIF using traditional PS fixation for 2-level DS (PS group, mean follow-up 35 months). Clinical symptoms were evaluated using the Japanese Orthopaedic Association (JOA) scoring system. Bony union was assessed by dynamic plain radiographs and CT images. Surgery-related complications, including symptomatic adjacent-segment disease (ASD), were examined. RESULTS The mean operative duration and intraoperative blood loss were 192 minutes and 495 ml in the CBT group and 218 minutes and 612 ml in the PS group, respectively (p < 0.05 and p > 0.05, respectively). The mean JOA score improved significantly from 12.3 points before surgery to 21.1 points (mean recovery rate 54.4%) at the latest follow-up in the CBT group and from 12.8 points before surgery to 20.4 points (mean recovery rate 51.8%) at the latest follow-up in the PS group (p > 0.05). Solid bony union was achieved at 90.9% of segments in the CBT group and 95.0% of segments in the PS group (p > 0.05). Symptomatic ASD developed in 2 patients in the CBT group (9.1%) and 4 patients in the PS group (20.0%, p > 0.05). CONCLUSIONS Two-level PLIF with CBT screw fixation for 2-level DS could be less invasive and result in improvement of clinical symptoms equal to those of 2-level PLIF using traditional PS fixation. The incidence of symptomatic ASD and the rate of bony union were lower in the CBT group than in the PS group, although these differences were not significant. PMID- 29125431 TI - The timing of venous thromboembolic events after spine surgery: a single-center experience with 6869 consecutive patients. AB - OBJECTIVE Venous thromboembolic events (VTEs), including both deep venous thrombosis (DVT) and pulmonary embolism, are a major cause of morbidity and mortality after spine surgery. Prophylactic anticoagulation, or chemoprophylaxis, can prevent VTE. However, the timing of VTEs after spine surgery and the effect of chemoprophylaxis on VTE timing remain underinvestigated. METHODS The records of 6869 consecutive spine surgeries were retrospectively examined. Data on patient demographics, surgical variables, hospital course, and timing of VTEs were collected. Patients who received chemoprophylaxis were compared with those who did not. Appropriate regression models were used to examine selection for chemoprophylaxis and the timing of VTEs. RESULTS Age (OR 1.037, 95% CI 1.023 1.051; p < 0.001), longer surgery (OR 1.003, 95% CI 1.002-1.004; p < 0.001), history of DVT (OR 1.697, 95% CI 1.038-2.776; p = 0.035), and fusion surgery (OR 1.917, 95% CI 1.356-2.709; p < 0.001) predicted selection for chemoprophylaxis. Chemoprophylaxis patients experienced more VTEs (3.62% vs 2.03% of patients, respectively; p < 0.001), and also required longer hospital stays (5.0 days vs 1.0 days; HR 0.5107; p < 0.0001) and had a greater time to the occurrence of VTE (median 6.8 days vs 3.6 days; HR 0.6847; p = 0.0003). The cumulative incidence of VTEs correlated with the postoperative day in both groups (Spearman r = 0.9746, 95% CI 0.9457-0.9883, and p < 0.0001 for the chemoprophylaxis group; Spearman r = 0.9061, 95% CI 0.8065-0.9557, and p < 0.0001 for the nonchemoprophylaxis group), and the cumulative incidence of VTEs was higher in the nonchemoprophylaxis group throughout the 30-day postoperative period. Cumulative VTE incidence and postoperative day were linearly correlated in the first 2 postoperative weeks (R = 0.9396 and p < 0.0001 for the chemoprophylaxis group; R = 0.8190 and p = 0.0003 for the nonchemoprophylaxis group) and the remainder of the 30-day postoperative period (R = 0.9535 and p < 0.0001 for the chemoprophylaxis group; R = 0.6562 and p = 0.0058 for the nonchemoprophylaxis group), but the linear relationships differ between these 2 postoperative periods (p < 0.0001 for both groups). CONCLUSIONS Anticoagulation reduces the cumulative incidence of VTE after spine surgery. The cumulative incidence of VTEs rises linearly in the first 2 postoperative weeks and then plateaus. Surgeons should consider early initiation of chemoprophylaxis for patients undergoing spine surgery. PMID- 29125432 TI - Association between baseline cognitive impairment and postoperative delirium in elderly patients undergoing surgery for adult spinal deformity. AB - OBJECTIVE Postoperative delirium is common in elderly patients undergoing spine surgery and is associated with a longer and more costly hospital course, functional decline, postoperative institutionalization, and higher likelihood of death within 6 months of discharge. Preoperative cognitive impairment may be a risk factor for the development of postoperative delirium. The aim of this study was to investigate the relationship between baseline cognitive impairment and postoperative delirium in geriatric patients undergoing surgery for degenerative scoliosis. METHODS Elderly patients 65 years and older undergoing a planned elective spinal surgery for correction of adult degenerative scoliosis were enrolled in this study. Preoperative cognition was assessed using the validated Saint Louis University Mental Status (SLUMS) examination. SLUMS comprises 11 questions, with a maximum score of 30 points. Mild cognitive impairment was defined as a SLUMS score between 21 and 26 points, while severe cognitive impairment was defined as a SLUMS score of <= 20 points. Normal cognition was defined as a SLUMS score of >= 27 points. Delirium was assessed daily using the Confusion Assessment Method (CAM) and rated as absent or present on the basis of CAM. The incidence of delirium was compared in patients with and without baseline cognitive impairment. RESULTS Twenty-two patients (18%) developed delirium postoperatively. Baseline demographics, including age, sex, comorbidities, and perioperative variables, were similar in patients with and without delirium. The length of in-hospital stay (mean 5.33 days vs 5.48 days) and 30-day hospital readmission rates (12.28% vs 12%) were similar between patients with and without delirium, respectively. Patients with preoperative cognitive impairment (i.e., a lower SLUMS score) had a higher incidence of postoperative delirium. One- and 2 year patient reported outcomes scores were similar in patients with and without delirium. CONCLUSIONS Cognitive impairment is a risk factor for the development of postoperative delirium. Postoperative delirium may be associated with decreased preoperative cognitive reserve. Cognitive impairment assessments should be considered in the preoperative evaluations of elderly patients prior to surgery. PMID- 29125433 TI - A points-based algorithm for prognosticating clinical outcome of Chiari malformation Type I with syringomyelia: results from a predictive model analysis of 82 surgically managed adult patients. AB - OBJECTIVE Although various predictors of postoperative outcome have been previously identified in patients with Chiari malformation Type I (CMI) with syringomyelia, there is no known algorithm for predicting a multifactorial outcome measure in this widely studied disorder. Using one of the largest preoperative variable arrays used so far in CMI research, the authors attempted to generate a formula for predicting postoperative outcome. METHODS Data from the clinical records of 82 symptomatic adult patients with CMI and altered hindbrain CSF flow who were managed with foramen magnum decompression, C-1 laminectomy, and duraplasty over an 8-year period were collected and analyzed. Various preoperative clinical and radiological variables in the 57 patients who formed the study cohort were assessed in a bivariate analysis to determine their ability to predict clinical outcome (as measured on the Chicago Chiari Outcome Scale [CCOS]) and the resolution of syrinx at the last follow-up. The variables that were significant in the bivariate analysis were further analyzed in a multiple linear regression analysis. Different regression models were tested, and the model with the best prediction of CCOS was identified and internally validated in a subcohort of 25 patients. RESULTS There was no correlation between CCOS score and syrinx resolution (p = 0.24) at a mean +/- SD follow-up of 40.29 +/- 10.36 months. Multiple linear regression analysis revealed that the presence of gait instability, obex position, and the M-line-fourth ventricle vertex (FVV) distance correlated with CCOS score, while the presence of motor deficits was associated with poor syrinx resolution (p <= 0.05). The algorithm generated from the regression model demonstrated good diagnostic accuracy (area under curve 0.81), with a score of more than 128 points demonstrating 100% specificity for clinical improvement (CCOS score of 11 or greater). The model had excellent reliability (kappa = 0.85) and was validated with fair accuracy in the validation cohort (area under the curve 0.75). CONCLUSIONS The presence of gait imbalance and motor deficits independently predict worse clinical and radiological outcomes, respectively, after decompressive surgery for CMI with altered hindbrain CSF flow. Caudal displacement of the obex and a shorter M-line-FVV distance correlated with good CCOS scores, indicating that patients with a greater degree of hindbrain pathology respond better to surgery. The proposed points-based algorithm has good predictive value for postoperative multifactorial outcome in these patients. PMID- 29125436 TI - Stroke Diagnosis and Imaging: a Symbiotic Partnership. PMID- 29125435 TI - Health Literacy among Medically Underserved: The Role of Demographic Factors, Social Influence, and Religious Beliefs. AB - The current study examined the sociodemographic and psychosocial variables that predicted being at risk for low health literacy among a population of racially and ethnically diverse patients accessing primary care services at community based clinics. Participants (N = 416) were aged 50-75 years, currently not up-to date with colorectal cancer (CRC) screening, at average CRC risk, and enrolled in a randomized controlled trial (RCT) aimed at promoting CRC screening. Participants completed a baseline interview that assessed health literacy as measured by Rapid Estimate of Adult Literacy in Medicine-Revised, sociodemographic factors, and psychosocial variables (e.g., health beliefs) prior to randomization and receipt of an intervention. Thirty-six percent of the participants were found to be at risk for low health literacy. Sociodemographic and psychosocial variables were assessed as predictors of being at risk for low health literacy using logistic regression. In the final model, predictors were male gender, being from a racial/ethnic minority group, being unable to work, having higher social influence scores, and having higher religious belief scores. These findings suggest several patient characteristics that may be associated with low health literacy, and highlight the importance of supporting all patients through simplified and clear communications and information to improve understanding of CRC screening information. PMID- 29125438 TI - ICAS 2009: Intracranial Atherosclerosis from a to V. PMID- 29125437 TI - Conference Diary. PMID- 29125439 TI - Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis. AB - In the majority of relapsing multiple sclerosis patients, the disease can be quite easily controlled by already available, approved therapies. There are, however, some aggressive cases who continue to have clinical and magnetic resonance imaging (MRI) activity in spite of the treatment. These are the cases who may now receive benefit from intense immunosuppression followed by autologous haematopoietic stem cell transplantation (aHSCT). In this review, we describe the method and the rationale of aHSCT, the more recently published studies that demonstrate its efficacy in selected multiple sclerosis cases, the problems related to safety and the transplant-related mortality risk of the procedure. A description of the ideal patient who can take advantage of aHSCT is outlined and, finally, the ongoing studies which are near to completion or are close to starting are briefly reported. PMID- 29125440 TI - Long-term outcomes of primarily metastatic juvenile pilocytic astrocytoma in children. AB - OBJECTIVE Primarily metastatic juvenile pilocytic astrocytoma (JPA) is rare, likely representing 2%-3% of all cases of JPA. Due to the rarity of primarily metastatic JPA, there is currently no standard treatment paradigm and the long term outcomes are not fully known. The goal of this case series was to add to the current understanding of this disease process. METHODS The authors searched a comprehensive database of pediatric patients with brain and spinal cord tumors treated at Lucile Packard Children's Hospital from 1997 to 2016 and identified 5 patients with primarily metastatic JPA. A retrospective chart review was performed and details of the patients' treatment and clinical course were recorded for further analysis. RESULTS For the 5 patients with primarily metastatic JPA, the mean follow-up period was 12.3 years. All patients in our series had biopsies or subtotal resections and upfront treatment. Three patients were treated with chemotherapy alone, one was treated with chemotherapy and radiotherapy, and one was treated with radiotherapy alone. Four patients had stable disease after initial treatment, and one patient had multiple episodes of progressive disease but underwent successful salvage therapy and has had stable disease for 19 years. One patient died of an intracerebral hemorrhage 10 years following initial radiation treatment believed to be secondary to radiation vasculopathy. CONCLUSIONS Evaluation of the entire neuraxis should be performed in all instances of initial JPA diagnosis to properly assess for primarily metastatic disease. Many patients with primarily metastatic JPA will have stable disease after upfront treatment, although the higher rate of stable disease found in this series relative to other reports is likely secondary to the small sample size. PMID- 29125441 TI - Letter to the Editor. Propranolol for pediatric intracerebral cavernomas: unanswered questions. PMID- 29125442 TI - Long-term outcomes after surgical treatment of pediatric neurogenic thoracic outlet syndrome. AB - OBJECTIVE Neurogenic thoracic outlet syndrome (nTOS) is an uncommon compression syndrome of the brachial plexus that presents with pain, sensory changes, and motor weakness in the affected limb. The authors reviewed the clinical presentations and outcomes in their series of pediatric patients with surgically treated nTOS over a 6-year period. METHODS Cases of nTOS in patients age 18 years or younger were extracted for analysis from a prospective database of peripheral nerve operations. Baseline patient characteristics, imaging and neurophysiological data, operative findings, and outcomes and complications were assessed. RESULTS Twelve patients with 14 cases of nTOS surgically treated between April 2010 and December 2016 were identified. One-third of the patients were male, and 2 male patients underwent staged, bilateral procedures. Disabling pain (both local and radiating) was the most common presenting symptom (100%), followed by numbness (35.7%), then tingling (28.6%). The mean duration of symptoms prior to surgery was 15.8 +/- 6.6 months (mean +/- SD). Sports-related onset of symptoms was seen in 78.6% of cases. Imaging revealed cervical ribs in 4 cases, prominent C-7 transverse processes in 4 cases, abnormal first thoracic ribs in 2 cases, and absence of bony anomalies in 4 cases. Neurophysiological testing results were normal in 85.7% of cases. Conservative management failed in all patients, with 5 patients reporting minimal improvement in symptoms with physical therapy. With a mean follow-up after surgery of 22 +/- 18.3 months (mean +/- SD), pain relief was excellent (> 90%) in 8 cases (57.1%), and good (improved > 50%) in 6 cases (42.9%). On univariate analysis, patients who reported excellent pain resolution following surgery at long-term follow-up were found to be significantly younger, and to have suffered a shorter duration of preoperative symptoms than patients who had worse outcomes. Lack of significant trauma or previous surgery to the affected arm was also associated with excellent outcomes. There were 4 minor complications in 3 patients within 30 days of surgery: 1 patient developed a small pneumothorax that resolved spontaneously; 1 patient suffered a transient increase in pain requiring consultation, followed by hiccups for a period of 3 hours that resolved spontaneously; and 1 patient fell at home, with transient increased pain in the surgically treated extremity. There were no new neurological deficits, wound infections, deep vein thromboses, or readmissions. CONCLUSION Pediatric nTOS commonly presents with disabling pain and is more frequently associated with bony anomalies compared with adult nTOS. In carefully selected patients, surgical decompression of the brachial plexus results in excellent pain relief, which is more likely to be seen in younger patients who present for early surgical evaluation. PMID- 29125443 TI - Neurosurgical management in children with bleeding diathesis: auditing neurological outcome. AB - OBJECTIVE The aim of this study was to assess the outcome of neurosurgical treatment in children with bleeding diathesis and also to evaluate the current management plan applied in the authors' service. METHODS The authors retrospectively analyzed all cases in which neurosurgical procedures were performed in pediatric patients presenting with intracranial hematoma due to an underlying bleeding tendency over a 5-year period at their institution. They evaluated the patients' neurological symptoms from the initial referral, hematological abnormalities, surgical treatment, neurological outcome, and scores on the Pediatric Glasgow Outcome Scale-Extended (GOS-E Peds) obtained 1 year after the last operation. RESULTS Five patients with a bleeding diathesis who underwent surgery for intracranial hematoma were identified; the diagnosis was hemophilia A in 3 cases, idiopathic thrombocytopenic purpura in 1 case, and severe aplastic anemia in 1 case. Intracerebral hematoma (ICH) (n = 4) and acute subdural hematoma (n = 1) were confirmed on radiological investigations. In 2 of the 4 patients with ICH, the diagnosis of bleeding diathesis was made for the first time on presentation. Four patients (all male) were younger than 2 years; the patient with severe aplastic anemia and spontaneous ICH was 15 years old and female. The duration of symptoms varied from 24 hours to 5 days. Neurological examination at 1 year's follow-up showed complete recovery (GOS-E Peds score of 1) in 3 cases and mild weakness (GOS-E Peds score of 2) in 2 cases. CONCLUSIONS Neurosurgical management of patients with bleeding diathesis should be carried out in a tertiary-care setting with multidisciplinary team management, including members with expertise in neuroimaging and hematology, in addition to neurosurgery. Early diagnosis and prompt treatment of a bleeding diathesis is crucial for full neurological recovery. PMID- 29125444 TI - Online postconcussion return-to-play instructions. AB - OBJECTIVE The authors of recent concussion guidelines have sought to form a consensus on injury management, but it is unclear if they have been effective in conveying this information to the public. Many parents and athletes obtain medical recommendations via the Internet. This review is aimed at evaluating consistency between online resources and published guideline statements in postconcussion return-to-play (RTP) decisions. METHODS Five websites were selected through a Google search for RTP after concussion, including a federal government institution (Centers for Disease Control and Prevention) website, a national high school association (National Federation of State High School Associations) website, a popular nationally recognized medical website for patients (WebMD), a popular parent-driven website for parents of children who participate in sports (MomsTeam), and the website of a private concussion clinic (Sports Concussion Institute), along with a university hospital website (University of Michigan Medicine). Eight specific items from the Zurich Sport Concussion Consensus Statement 2012 were used as the gold standard for RTP recommendations. Three independent reviewers graded each website for each of the 8 recommendations (A = states guideline recommendations appropriately; B = mentions guideline recommendation; C = does not mention guideline recommendation; F = makes inappropriate recommendation). RESULTS A grade of A was assigned for 45.8% of the recommendations, B for 25.0%, C for 25.0%, and F for 4.2%. All the websites were assigned an A grade for the recommendation of no RTP on the day of injury. Only 1 website (WebMD) mentioned medication usage in conjunction with the Zurich statement, and only 2 websites (Sports Concussion Institute and University of Michigan Medicine) mentioned appropriate management of persistent symptoms. None of these websites commented correctly on all 8 guideline recommendations. CONCLUSIONS Online resources are inconsistent in relaying guideline recommendations for RTP and provide a potential source of confusion in the management of concussion for athletes and their parents, which can result in inappropriate RTP decisions. PMID- 29125445 TI - Morphometric and volumetric comparison of 102 children with symptomatic and asymptomatic Chiari malformation Type I. AB - OBJECTIVE Chiari malformation Type I (CM-I) is typically defined on imaging by a cerebellar tonsil position >= 5 mm below the foramen magnum. Low cerebellar tonsil position is a frequent incidental finding on brain or cervical spine imaging, even in asymptomatic individuals. Nonspecific symptoms (e.g., headache and neck pain) are common in those with low tonsil position as well as in those with normal tonsil position, leading to uncertainty regarding appropriate management for many patients with low tonsil position and nonspecific symptoms. Because cerebellar tonsil position is not strictly correlated with the presence of typical CM-I symptoms, the authors sought to determine if other 2D morphometric or 3D volumetric measurements on MRI could distinguish between patients with asymptomatic and symptomatic CM-I. METHODS The authors retrospectively analyzed records of 102 pediatric patients whose records were in the University of Michigan clinical CM-I database. All patients in this database had cerebellar tonsil position >= 5 mm below the foramen magnum. Fifty-one symptomatic and 51 asymptomatic patients were matched for age at diagnosis, sex, tonsil position, and tonsil morphology. National Institutes of Health ImageJ software was used to obtain six 2D anatomical MRI measurements, and a semiautomated segmentation tool was used to obtain four 3D volumetric measurements of the posterior fossa and CSF subvolumes on MRI. RESULTS No significant differences were observed between patients with symptomatic and asymptomatic CM-I related to tentorium length (50.3 vs 51.0 mm; p = 0.537), supraoccipital length (39.4 vs 42.6 mm; p = 0.055), clivus-tentorium distance (52.0 vs 52.1 mm; p = 0.964), clivus-torcula distance (81.5 vs 83.3 mm; p = 0.257), total posterior fossa volume (PFV; 183.4 vs 190.6 ml; p = 0.250), caudal PFV (152.5 vs 159.8 ml; p = 0.256), fourth ventricle volume to caudal PFV ratio (0.0140 vs 0.0136; p = 0.649), or CSF volume to caudal PFV ratio (0.071 vs 0.061; p = 0.138). CONCLUSIONS No clinically useful 2D or 3D measurements were identified that could reliably distinguish pediatric patients with symptoms attributable to CM-I from those with asymptomatic CM-I. PMID- 29125447 TI - Multiple echocardiography abnormalities associated with endoscopic third ventriculostomy failure. AB - OBJECTIVE Although endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) has gained increasing prominence in the management of hydrocephalus caused by intraventricular hemorrhage of prematurity, the rates of long-term shunt independence remain low. Furthermore, limited evidence is available to identify infants who might benefit from the procedure. The authors tested the hypothesis that elevated venous pressure that results from comorbid cardiac disease might predispose patients to ETV/CPC failure and shunt dependence. METHODS A retrospective analysis was performed on a consecutive series of 48 infants with hydrocephalus who underwent ETV/CPC and also underwent preoperative echocardiography between 2007 and 2014. Comorbid cardiac abnormalities that are known to result in elevated right heart pressure were reviewed. Associations between ETV/CPC success and the presence of pulmonary hypertension, right ventricular hypertrophy, left-to-right shunting, ventricular septal defect, or patent ductus arteriosus were determined using multivariate logistic regression analysis. RESULTS Of the 48 children who met the inclusion criteria, ETV/CPC failed in 31 (65%). In univariate analysis, no single echocardiogram abnormality was associated with shunt failure, but the presence of 2 or more concurrent echocardiogram abnormalities was associated with ETV/CPC failure (17 [85%] of 20 vs 14 [50%] of 28, respectively; p = 0.018). In multivariate logistic regression analysis, when the authors adjusted for the child's ETV success score, the presence of 2 abnormalities remained independently associated with poor outcome (2 or more echocardiogram abnormalities, OR 0.13, 95% CI 0.01-0.7, p = 0.032; ETV success score, OR 1.1, 95% CI 1-1.2, p = 0.05). CONCLUSIONS In this study, cardiac abnormalities were inversely associated with the success of ETV/CPC in infants with hydrocephalus of prematurity. ETV/CPC might not be as efficacious in patients with significant cardiac anomalies. These results provide a basis for future efforts to stratify surgical candidacy for ETV/CPC on the basis of comorbid abnormalities. Proper cardiac physiological pressure monitoring might help elucidate the relationship between cardiac abnormalities and hydrocephalus. PMID- 29125446 TI - Suprasellar and recurrent pediatric craniopharyngiomas: expanding indications for the extended endoscopic transsphenoidal approach. AB - OBJECTIVE The expanded endonasal endoscopic transsphenoidal approach has become increasingly used for craniopharyngioma surgery in the pediatric population, but questions still persist regarding its utility in younger children, in recurrent and irradiated tumors, and in masses primarily located in the suprasellar region. The narrow corridor, incomplete pneumatization, and fear of hypothalamic injury have traditionally relegated this approach to application in older children with mostly cystic craniopharyngiomas centered in the sella. The authors present a series of consecutive pediatric patients in whom the endonasal endoscopic approach was used to remove craniopharyngiomas from patients of varied ages, regardless of the location of the tumor and previous treatments or surgeries, to ascertain if the traditional concerns about limitations of this approach are worth reevaluating METHODS Eleven consecutive pediatric patients (age <= 18 years) underwent surgery via an endoscopic transsphenoidal approach at NewYork Presbyterian/Weill Cornell Medical Center from 2007 to 2016. The authors recorded the location, consistency, and size of the lesion, assessed for hypothalamic invasion radiographically, calculated skull base measurements, and assessed parameters such as extent of resection, visual function, endocrinological function, weight gain, and return-to-school status. RESULTS The average age at the time of surgery was 7.9 years (range 4-17 years) and the tumor sizes ranged from 1.3 to 41.7 cm3. Five cases were purely suprasellar, 5 had solid components, 4 were reoperations, and 5 had a conchal sphenoid aeration. Nevertheless, gross total resection was achieved in 45% of the patients and 50% of those in whom it was the goal of surgery, without any correlation with the location, tumor consistency, or the age of the patient. Near-total resection, subtotal resection, or biopsy was performed intentionally in the remaining patients to avoid hypothalamic injury. Anterior pituitary dysfunction occurred in 81.8% of the patients, and 63.3% developed diabetes insipidus . Two patients (18%) had a greater than 9% increase in body mass index. Visual function was stable or improved in 73%. All children returned to an academic environment, with 10 of them in the grade appropriate for their age. There was a single case of each of the following: CSF leak, loss of vision unilaterally, and abscess. CONCLUSIONS The endoscopic transsphenoidal approach is suitable for removing pediatric craniopharyngiomas even in young children with suprasellar tumors, conchal sphenoid sinus, recurrent tumors, and tumors with solid components. The extent of resection is dictated by intrinsic hypothalamic tumor invasiveness rather than the approach. The endoscopic transsphenoidal approach affords the ability to directly inspect the hypothalamus to determine invasion, which may help spare the patient from hypothalamic injury. Irrespective of approach, the rates of postoperative endocrinopathy remain high and the learning curve for the approach to a relatively rare tumor is steep. PMID- 29125449 TI - The Coming Year in Stroke: a Busy Schedule for 2010. PMID- 29125448 TI - Erratum. The addition of duraplasty to posterior fossa decompression in the surgical treatment of pediatric Chiari malformation Type I: a systematic review and meta-analysis of surgical and performance outcomes. PMID- 29125450 TI - Conference Diary. PMID- 29125452 TI - Prevalence and risk factors of vitamin D insufficiency and deficiency among 6-24 month-old underweight and normal-weight children living in an urban slum of Bangladesh. AB - OBJECTIVE: We quantified the prevalence of vitamin D status in 6-24-month-old underweight and normal-weight children and identified the socio-economic and dietary predictors for status. DESIGN: Cross-sectional, baseline data from a nutritional intervention study were analysed. Multinomial logistic regression was used to estimate the odds of being vitamin D deficient or insufficient with the reference being vitamin D sufficient. SETTING: Urban slum area of Mirpur field site, Dhaka, Bangladesh. SUBJECTS: Underweight (weight-for-age Z-score <-2.00) and normal-weight (weight-for-age Z-score >=-1.00) children aged 6-24 months. RESULTS: Among 468 underweight children, 23.1 % were sufficient, 42.3 % insufficient, 31.2 % deficient and 3.4 % severely vitamin D deficient. Among 445 normal-weight children, 14.8 % were sufficient, 39.6 % insufficient and 40.0 % deficient and 5.6 % severely deficient. With adjusted multinominal regression analysis, risk factors (OR (95 % CI)) for vitamin D deficiency in underweight children were: older age group (18-24 months old; 2.9 (1.5-5.7)); measurement of vitamin D status during winter (3.0 (1.4-6.4)) and spring (6.9 (3.0-16.1)); and maternal education (>=6 years of institutional education; 2.2 (1.0-4.9)). In normal-weight children, older age group (3.6 (1.2-10.6)) and living in the richest quintile (3.7 (1.1-12.5)) were found to be significantly associated with vitamin D insufficiency. CONCLUSIONS: The study demonstrates a significant burden of vitamin D insufficiency and deficiency in both underweight and normal-weight children <2 years of age from an urban slum of Bangladesh. Identification of risk factors may help in mitigating the important burden in such children. PMID- 29125453 TI - Vitamin D research and public health nutrition: a current perspective. PMID- 29125454 TI - Primary care research: does it defy definition? PMID- 29125455 TI - ICTV Virus Taxonomy Profile: Pleolipoviridae. AB - Members of the family Pleolipoviridae (termed pleolipoviruses) are pseudo spherical and pleomorphic archaeal viruses. The enveloped virion is a simple membrane vesicle, which encloses different types of DNA genomes of approximately 7-16 kbp (or kilonucleotides). Typically, virions contain a single type of transmembrane (spike) protein at the envelope and a single type of membrane protein, which is embedded in the envelope and located in the internal side of the membrane. All viruses infect extremely halophilic archaea in the class Halobacteria (phylum Euryarchaeota). Pleolipoviruses have a narrow host range and a persistent, non-lytic life cycle. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Pleolipoviridae which is available at www.ictv.global/report/pleolipoviridae. PMID- 29125456 TI - Microbacterium album sp. nov. and Microbacterium deserti sp. nov., two halotolerant actinobacteria isolated from desert soil. AB - Strains SYSU D8007T and SYSU D8014T were isolated from desert soil collected from Saudi Arabia. The two isolates were Gram-stain-positive, non-motile, aerobic and non-spore-forming. These strains were able to grow at 4-45 degrees C and in the presence of up to 8 % (w/v) NaCl. Strain SYSU D8007T could grow at pH 6.0-10.0, and strain SYSU D8014T at pH 5.0-10.0. They shared highest 16S rRNA gene sequence similarities with Microbacterium marinilacus YM11-607T and Microbacterium paludicola US15T. Menaquinones MK-11 and MK-12 were detected as the respiratory quinones. The polar lipid profiles of strains SYSU D8007T and SYSU D8014T consisted of diphosphatidylglycerol and phosphatidylglycerol, but differed in the number of unidentified glycolipids. Strain SYSU D8007T contained anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0 as the predominant fatty acids, while strain SYSU D8014T contained anteiso-C15 : 0 and anteiso-C17 : 0 as the major fatty acids (>10 %). While glucose, rhamnose and ribose were detected in strain SYSU D8007T as the whole-cell sugars, galactose, glucose and rhamnose were present in strain SYSU D8014T. The genomic DNA G+C content of strains SYSU D8007T and SYSU D8014T was 72.2 and 73.6 mol%, respectively. Based on phenotypic, genotypic and phylogenetic characteristics, it can be concluded that strains SYSU D8007T and SYSU D8014T represent two novel species of the genus Microbacterium, for which the names Microbacterium album sp. nov. and Microbacterium deserti sp. nov. are proposed, respectively. The type strains are SYSU D8007T (=CGMCC 1.15794T=KCTC 39990T) and SYSU D8014T (=CPCC 204619T=KCTC39991T). PMID- 29125457 TI - Emended description of the genus Phytobacter, its type species Phytobacter diazotrophicus (Zhang 2008) and description of Phytobacter ursingii sp. nov. AB - The species Phytobacter diazotrophicus and the associated genus Phytobacter were originally described by Zhanget al. [Arch Microbiol189 (2008), 431-439] on the basis of few endophytic nitrogen-fixing bacteria isolated from wild rice (Oryza rufipogon) in China. In this study, we demonstrate that a number of clinical isolates that were either described in the literature, preserved in culture collections, or obtained during a 2013 multi-state sepsis outbreak in Brazil also belong to the same genus. 16S rRNA gene sequencing, multilocus sequence analysis based on gyrB, rpoB, atpD and infB genes, as well as digital DNA-DNA hybridization support the existence of a second species within the genus Phytobacter. All isolates from the recent Brazilian outbreak, along with some older American clinical strains, were found to belong to the already described species Phytobacterdiazotrophicus, whereas three clinical strains retrieved in the USA over a time span of almost four decades, could be assigned to a new Phytobacter species. Implementation of an extended set of biochemical tests showed that the two Phytobacter species could phenotypically be discriminated from each other by the ability to utilize l-sorbose and d-serine. This feature was limited to the strains of the novel species described herein, for which the name Phytobacter ursingii sp. nov. is proposed, with ATCC 27989T (=CNCTC 5729T) as the designated type strain. An emended description of the species Phytobacter diazotrophicus and of the genus Phytobacter is also provided. PMID- 29125458 TI - Actinoplanes sediminis sp. nov., isolated from marine sediment. AB - An actinomycete strain M4I47T was isolated from sediment from Megas Gialos, Syros, Greece. The results of phylogenetic analysis of the 16S rRNA gene sequence of M4I47T indicated that the highest similarity was with Actinoplanes atraurantiacus Y16T (98.9 %), Actinoplanes deccanensis IFO 13994T (98.8 %), Actinoplanes digitatis IFO 12512T (98.1 %) and Actinoplanes abujensis A4029T (98.0 %). The cell wall of the novel isolate contained meso-diaminopimelic acid and the whole-cell sugars were xylose, arabinose and glucose. The predominant menaquinones were MK-9(H4), MK-9(H6) and MK-9(H2). The phospholipid profile comprised phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylinositol, phosphatidylinositol mannosides and an unknown phospholipid. The DNA G+C content was 71.5 mol%. Furthermore, a combination of DNA-DNA relatedness and some physiological and biochemical properties indicated that the novel strain could be readily distinguished from the most closely related species. On the basis of these phenotypic and genotypic data, M4I47T represents a novel species of the genus Actinoplanes, for which the name Actinoplanessediminis sp. nov. is proposed. The type strain is M4I47T (=CCTCC AA 2016022T=DSM 100965T). PMID- 29125459 TI - Pseudogracilibacillus endophyticus sp. nov., a moderately thermophilic and halophilic species isolated from plant root. AB - A Gram-stain-positive strain, designated DT7-02T, was isolated from the surface sterilized root of Oenotherabiennis (evening primrose) and subjected to taxonomic characterization. Cells of DT7-02T were slender rod-shaped, motile by means of flagella, and oxidase- and catalase-positive. The colonies were circular, pinkish yellow, opaque, glistering and 1-2 mm in diameter. The strain was moderately thermophilic and halophilic, as growth occurred at 20-44 degrees C (optimum 40 degrees C), pH 7-10 (optimum pH 8-9) and in the presence of 0-8 % of NaCl (optimum 4 %) in tryptic soy broth. The analysis of 16S rRNA gene sequences indicated that the strain represented a member of the genus Pseudogracilibacillus of the family Bacillaceae, and the sequence similarity was 96.5 % with Pseudogracilibacillus auburnensis P-207T and 95.9 % with Pseudogracilibacillus marinus NIOT-bflm-S4T. Other related taxa were Ornithinibacillus contaminans DSM 22953T and Sinibacillus soli KCTC 33117T, with 16S rRNA gene sequence similarities of 95.4 and 94.3 %, respectively. The major cellular fatty acids of DT7-02T were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The DNA G+C content was 35.1 mol%, and the respiratory quinone was MK-7. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. The combination of chemotaxonomic properties enabled differentiation of DT7-02T from the other two species of the genus Pseudogracilibacillus. The results of phylogenetic, phenotypic and chemotaxonomic analyses demonstrate that strain DT7-02T (=KCTC 33854T=JCM 31192T) merits recognition as representing a novel species of the genus Pseudogracilibacillus, for which the name Pseudogracilibacillusendophyticus sp. nov. is proposed. PMID- 29125460 TI - Nocardia rhizosphaerihabitans sp. nov., a novel actinomycete isolated from a coastal soil. AB - An actinomycete strain, designated KLBMP S0039T, was isolated from the rhizosphere soil of Lycium Linn., collected from the coastal region in Lianyungang, Jiangsu Province, eastern PR China, and was studied to determine its taxonomic position. The isolate showed a combination of morphological and chemotaxonomic properties typical of the members of the genus Nocardia. The cell wall contained meso-diaminopimelic acid as the diagnostic diamino acid and the whole-cell sugars were galactose, arabinose, glucose and ribose. The predominant menaquinone was identified as MK-8(H4omega-cycl). The diagnostic phospholipids were found to be diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and unknown lipids. The predominant cellular fatty acids were identified as C16 : 0, C18 : 0, C18 : 1omega9c, and 10-methyl C18 : 0 [tuberculostearic acid (TBSA)]. The G+C content of the genomic DNA was determined to be 68.2 mol%. The 16S rRNA gene sequence similarity indicated that KLBMP S0039T was most closely related to Nocardia neocaledoniensis NBRC 108232T (99.4 % 16S rRNA gene sequence similarity) and Nocardia asteroides NBRC 15531T (99.2 %), similarities to other type strains of species of the genus Nocardia were found to be less than 98.6 %. However, DNA-DNA relatedness values and phenotypic data indicated that KLBMP S0039T could be clearly distinguished from the closely related species of the genus Nocardia. On the basis of polyphasic taxonomic data, it is concluded that KLBMP S0039T represents a novel species of the genus Nocardia, for which the name Nocardiarhizosphaerihabitans sp. nov. is proposed. The type strain is KLBMP S0039T (=KCTC 39693T=CGMCC 4.7329T). PMID- 29125461 TI - Chemotaxis to self-generated AI-2 promotes biofilm formation in Escherichia coli. AB - Responses to the interspecies quorum-sensing signal autoinducer-2 (AI-2) regulate the patterns of gene expression that promote biofilm development. Escherichia coli also senses AI-2 as a chemoattractant, a response that requires the periplasmic AI-2-binding protein LsrB and the chemoreceptor Tsr. Here, we confirm, as previously observed, that under static conditions highly motile E. coli cells self-aggregate and form surface-adherent structures more readily than cells lacking LsrB and Tsr, or than DeltaluxS cells unable to produce AI-2. This difference is observed both at 37 and 30 degrees C. Cells deleted for the genes encoding the lsrACDBFG operon repressor (DeltalsrR), or the AI-2 kinase (DeltalsrK), or an AI-2 uptake channel protein (DeltalsrC), or an AI-2 metabolism enzyme (DeltalsrG) are also defective in biofilm formation. The Deltatsr and DeltalsrB cells are totally defective in AI-2 chemotaxis, whereas the other mutants show normal or near-normal chemotaxis to external gradients of AI-2. These data demonstrate that chemotaxis to external AI-2 is necessary but not sufficient to induce the full range of density-dependent behaviours that are required for optimal biofilm formation. We also demonstrate that, compared to other binding-protein-dependent chemotaxis systems in E. coli, low levels (on the order of ~250 molecules of periplasmic LsrB per wild-type cell and as low as ~50 molecules per cell in some mutants) are adequate for a strong chemotaxis response to external gradients of AI-2. PMID- 29125464 TI - Off-Policy Reinforcement Learning: Optimal Operational Control for Two-Time-Scale Industrial Processes. AB - Industrial flow lines are composed of unit processes operating on a fast time scale and performance measurements known as operational indices measured at a slower time scale. This paper presents a model-free optimal solution to a class of two time-scale industrial processes using off-policy reinforcement learning (RL). First, the lower-layer unit process control loop with a fast sampling period and the upper-layer operational index dynamics at a slow time scale are modeled. Second, a general optimal operational control problem is formulated to optimally prescribe the set-points for the unit industrial process. Then, a zero sum game off-policy RL algorithm is developed to find the optimal set-points by using data measured in real-time. Finally, a simulation experiment is employed for an industrial flotation process to show the effectiveness of the proposed method. PMID- 29125462 TI - Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. AB - We previously reported that Parkinson's disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2 phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies. PMID- 29125465 TI - Decoding Kinematics Using Task-Independent Movement-Phase-Specific Encoding Models. AB - Neural decoders of kinematic variables have largely relied on task-dependent (TD) encoding models of the neural activity. TD decoders, though, require prior knowledge of the tasks, which may be unavailable, lack scalability as the number of tasks grows, and require a large number of trials per task to reduce the effects of neuronal variability. The execution of movements involves a sequence of phases (e.g., idle, planning, and so on) whose progression contributes to the neuronal variability. We hypothesize that information about the movement phase facilitates the decoding of kinematics and compensates for the lack of prior knowledge about the task. We test this hypothesis by designing a task-independent movement-phase-specific (TI-MPS) decoding algorithm. The algorithm assumes that movements proceed through a consistent sequence of phases regardless of the specific task, and it builds one model per phase by combining data from different tasks. Phase transitions are detected online from neural data and, for each phase, a specific encoding model is used. The TI-MPS algorithm was tested on single-unit recordings from 437 neurons in the dorsal and ventral pre-motor cortices from two nonhuman primates performing 3-D multi-object reach-to-grasp tasks. The TI-MPS decoder accurately decoded kinematics from tasks it was not trained for and outperformed TD approaches (one-way ANOVA with Tukey's post-hoc test and -value <0.05). Results indicate that a TI paradigm with MPS models may help decoding kinematics when prior information about the task is unavailable and pave the way toward clinically viable prosthetics. PMID- 29125463 TI - Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3 A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX. Inhibition of NAMPT blocked P7C3-A20-mediated neuroprotection, whereas supplementation with the NAMPT substrate, nicotinamide, potentiated a subthreshold dose of P7C3-A20 to full efficacy. Importantly, P7C3-A20 blocked PTX-induced allodynia in tumored mice without reducing antitumoral efficacy. These findings identify enhancement of NAMPT activity as a promising new therapeutic strategy to protect against anticancer drug-induced peripheral neurotoxicity. PMID- 29125466 TI - The science in the p-value: need for a rethinking. PMID- 29125467 TI - Strain-induced enhancement of thermoelectric performance of TiS2 monolayer based on first-principles phonon and electron band structures. AB - Using first-principle calculations combined with Boltzmann transport theory, we investigate the biaxial strain effect on the electronic and phonon thermal transport properties of a 1 T (CdI2-type) structural TiS2 monolayer, a recent experimental two-dimensional (2D) material. It is found that the electronic band structure can be effectively modulated and that the band gap experiences an indirect-direct-indirect transition with increasing tensile strain. The band convergence induced by the tensile strain increases the Seebeck coefficient and the power factor, while the lattice thermal conductivity is decreased under the tensile strain due to the decreasing group velocity and the increasing scattering chances between the acoustic phonon modes and the optical phonon modes, which together greatly increase the thermoelectric performance. The figure of merit can reach 0.95 (0.82) at an 8 percent tensile strain for the p-type (n-type) doping, which is much larger than that without strain. The present work suggests that the TiS2 monolayer is a good candidate for 2D thermoelectric materials, and that biaxial strain is a powerful tool with which to enhance thermoelectric performance. PMID- 29125468 TI - A coarse-grained polarizable force field for the ionic liquid 1-butyl-3 methylimidazolium hexafluorophosphate. AB - We present a coarse-grained polarizable molecular dynamics force field for the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIm][PF6]). For the treatment of electronic polarizability, we employ the Drude model. Our results show that the new explicitly polarizable force field reproduces important static and dynamic properties such as mass density, enthalpy of vaporization, diffusion coefficients, or electrical conductivity in the relevant temperature range. In situations where an explicit treatment of electronic polarizability might be crucial, we expect the force field to be an improvement over non polarizable models, while still profiting from the reduction of computational cost due to the coarse-grained representation. PMID- 29125469 TI - A facile approach for reducing the working voltage of Au/TiO2/Au nanostructured memristor by enhancing the local electric field. AB - Memristor devices have attracted tremendous interest for their different applications from nonvolatile data storage to neuromorphic computing units. Exploring the role of surface roughness of bottom electrode (BE)/active layer interface provides useful guidelines for the optimization of the memristor switching performance. This study focussed on the effect of surface roughness of the BE electrode on the switching characteristics of Au/TiO2/Au three layer memristor device. An optimized wet-etching treatment conditions was found to modify the surface roughness of the Au BE where the measurment results indicate that the roughness of the Au BE is affected by both duration time and solution concentrations of the wet-etching process. Then we fabricated arrays of TiO2-based nanostructured memristors sandwiched between two sets of cross-bar Au electrode lines (junction area 900 um2). The results reaveled a reduction in the working voltages in current-voltage characteristic of the device performance with increasing the surface roughness at the Au(BE)/TiO2 active layer interface. The set voltage of the device (Vset) significantly decreased from 2.26 V to 1.93 V by increasing the interface roughness from 4.2 nm to 13.1 nm. The present work provides information for better understanding the switching mechanism of titanium dioxide based devices, and it can be inferred that enhancing the roughness of the Au BE/TiO2 active layer interface leads to a localized non-uniform electric field distribution that plays a vital role in the reducing the energy consumption of the device. PMID- 29125470 TI - Magnetic behavior of metastable Fe films grown on Ir(111). AB - We investigated the growth of ultra-thin Fe films on Ir(111) by means of in situ low energy electron diffraction and spin-resolved photoemission techniques. We observe a (1x1) diffraction pattern, characteristic of the fcc substrate, below 4 monolayers (ML). Then, a complex superstructure starts to develop, compatible with the formation of bcc-like Fe domains aligned with the substrate according to the Kourdjumov-Sachs orientation relationships. The analysis of the diffraction patterns reveals a progressive evolution towards a fully relaxed bcc lattice, characteristic of bulk Fe. Both photoemission (filled states) and inverse photoemission (empty states) results show characteristic features related to the contribution of the Fe layer, evolving towards those observed on the Fe (110) bcc surface. Spin resolution allows to detect a spectral polarization above 4 ML corresponding to the formation of bcc Fe, which gradually increases indicating the formation of an in-plane magnetized ferromagnetic layer in thick films. No in-plane net magnetization is detected in thinner films, independent of the sample temperature down to 30 K. Following recent investigations on the Fe/Ir(111) system with microscopy techniques, we link this observation to the stabilization of a non collinear spin structure yielding an overall nil magnetization. PMID- 29125471 TI - Carbon dot/polyvinylpyrrolidone hybrid nanofibers with efficient solid-state photoluminescence constructed using an electrospinning technique. AB - Carbon dots (CDs) are the promising candidates for application in optoelectronic and biological areas due to their excellent photostability, unique photoluminescence, good biocompatibility, low toxicity and chemical inertness. However, the self-quenching of photoluminescence as they are dried into the solid state dramatically limits their further application. Therefore, realizing efficient photoluminescence and large-scale production of CDs in the solid state is an urgent challenge. Herein, solid-state hybrid nanofibers based on CDs and polyvinylpyrrolidone (PVP) are constructed through an electrospinning process. The resulting solid-state hybrid PVP/CD nanofibers present much enhanced photoluminescence performance compared to the corresponding pristine colloidal CDs due to the decrease in non-radiative recombination of electron-holes. Owing to the suppressed self-quenching of CDs, the photoluminescence quantum yield is considerably improved from 42.9% of pristine CDs to 83.5% of nanofibers under the excitation wavelength of 360 nm. This has great application potential in optical or optoelectronic devices. PMID- 29125472 TI - Membrane vesiculation induced by proteins of the dengue virus envelope studied by molecular dynamics simulations. AB - Biological membranes are continuously remodeled in the cell by specific membrane shaping machineries to form, for example, tubes and vesicles. We examine fundamental mechanisms involved in the vesiculation processes induced by a cluster of envelope (E) and membrane (M) proteins of the dengue virus (DENV) using molecular dynamics simulations and a coarse-grained model. We show that an arrangement of three E-M heterotetramers (EM3) works as a bending unit and an ordered cluster of five such units generates a closed vesicle, reminiscent of the virus budding process. In silico mutagenesis of two charged residues of the anchor helices of the envelope proteins of DENV shows that Arg-471 and Arg-60 are fundamental to produce bending stress on the membrane. The fine-tuning between the size of the EM3 unit and its specific bending action suggests this protein unit is an important factor in determining the viral particle size. PMID- 29125473 TI - Superconducting properties of lithographic lead break junctions. AB - We have fabricated mechanically controlled break junction samples made of lead (Pb) by means of state-of-the-art nanofabrication methods: electron beam lithography and physical vapour deposition. The electrical and magnetic properties were characterized in a [Formula: see text] cryostat and showed a hard superconducting gap. Temperature and magnetic field dependence of tunnel contacts were compared and quantitatively described by including either thermal broadening of the density of states or pair breaking in the framework of a Skalski model, respectively. We show point contact spectra of few-atom contacts and present tunneling spectra exhibiting a superconducting double-gap structure. PMID- 29125474 TI - Indirect K-edge bimagnon resonant inelastic x-ray scattering spectrum of alpha FeTe. AB - We calculate the K-edge indirect bimagnon resonant inelastic x-ray scattering (RIXS) intensity spectra of the bicollinear antiferromagnetic order known to occur in the alpha-FeTe chalcogenide system. Utilizing linear spin wave theory for this large-S spin system we find that the bimagnon spectrum contains four scattering channels (two intraband and two interband). We find from our calculations that for suitable energy-momentum combination the RIXS spectra can exhibit a one-, two- or three- peak structure. The number of peaks provides a clue on the various bimagnon excitation processes that can be supported both in and within the acoustic and optical magnon branches of the bicollinear antiferromagnet. Unlike the RIXS response of the antiferromagnetic or the collinear antiferromagnetic spin ordering, the RIXS intensity spectrum of the bicollinear antiferromagnet does not vanish at the magnetic ordering wave vector [Formula: see text]. It is also sensitive to next-next nearest neighbor and biquadratic coupling interactions. Our predicted RIXS spectrum can be utilized to understand the role of multi-channel bimagnon spin excitations present in the alpha-FeTe chalcogenide. PMID- 29125475 TI - Control of active turbulence through addressable soft interfaces. AB - We present an experimental study of a kinesin/tubulin active nematic formed at different oil interfaces. By tuning the interfacial rheology of the contacting oil, we have been able to condition and control the seemingly chaotic motion that characterizes the self-sustained active flows in our preparations. The active nematic is inherently unstable and spontaneously develops defects from an initial homogeneous state. We show that the steady state and, in particular, the density and dynamics of the defects strongly depends on the rheology of the contacting oil. Using a smectic-A thermotropic liquid crystal as the oil phase, we pattern the interface thanks to the anisotropy of the shear viscosity in this material. The geometry of the active nematic adapts to the boundary conditions at the interface by changing from the so-called active turbulent regime to laminar flows along the easy flow directions. The latter can be either a lattice of self assembled circular paths or reconfigurable homogeneous orientations that can be addressed by means of an external magnetic field. We show that, under all confinement conditions, the spatiotemporal modes exhibited by the active liquid are consistent with a single intrinsic length scale, which can be tuned by the material parameters, and obey basic topological requirements imposed on the defects that drive the active flows. Future control strategies, including a tunable depleting agent, are discussed. PMID- 29125476 TI - Adrenalectomy was recommended for patients with subclinical Cushing's syndrome due to adrenal incidentaloma. AB - OBJECTIVE: To assess whether adrenalectomy may improve biochemical and metabolic impairment for patients with subclinical Cushing syndrome (SCS) due to adrenal incidentaloma (AI) compared with conservative management. METHODS: A total of 87 patients with SCS due to AI in Peking Union Medical College Hospital between September 2011 and January 2016 have been treated. Forty-eight patients underwent laparoscopic adrenalectomy (operative group), whereas 39 were managed conservatively (control group). RESULTS: The duration of follow-up was 32.5 +/- 10.6 months in operative group, and 30.1 +/- 13.1 months in control group, respectively. In the operative group, laboratory corticosteroid parameters normalized in all patients but not in the control group. In the operative group, BP of hypertensive patients improved or normalized (22 of 48); to the contrary, in the control group, cure or improvement was never achieved among the patients with hypertension, whereas a worsening was observed in 5 patients (P= 0.004). No significant difference was found in glycemic control and blood lipid change between the two groups. However, a decrease in triglyceridaemia and HBA1c was found in operative group compared with the control group (P= 0.011 and P= 0.017, respectively). Substitutive corticosteroid treatment was administered in 3 patients due to postoperative adrenal insufficiency during hospital stay, and the duration of treatment was 9 weeks, 10 weeks and 12 weeks, respectively. CONCLUSIONS: Laparoscopic adrenalectomy should be performed for patients with SCS due to AI. PMID- 29125477 TI - MicroRNA-186 suppresses lung cancer progression by targeting SIRT6. AB - MicroRNAs are a class of small non-coding RNA molecules that play crucial roles in the initiation and progression of lung cancer. This study was undertaken to investigate the expression and roles of miR-186 in lung cancer. Ectopic expression experiments demonstrated that miR-186 functions as a tumor suppressor. Bioinformatic predictions, a luciferase reporter assay, and protein expression analysis suggested that miR-186 could inhibit the protein levels of SIRT6, a purported tumor suppressor gene. Collectively, our results indicated that miR-186 could inhibit lung cancer progression through targeting SIRT6 and that miR-186 may be a therapeutic target for lung cancer. PMID- 29125478 TI - Utility of paraneoplastic antigens as biomarkers for surveillance and prediction of recurrence in ovarian cancer. AB - BACKGROUND: Ovarian cancer is frequently diagnosed at an advanced stage and 70% of patients experience recurrence months to years from initial diagnosis. The expression of paraneoplastic antigens can result in the occurrence of onconeural autoantibodies in ovarian cancer that may be associated with neurological disorders that are clinically manifested in patients before diagnosis of ovarian cancer. These paraneoplastic antigens can serve as excellent biomarkers not only for early detection but also for monitoring ovarian cancer recurrence. OBJECTIVE: To assess the immunoreactivity of our previous 3 biomarkers along with 3 paraneoplastic antigens, HARS, Ro52 and CDR2 for the evaluation of their sensitivity in predicting recurrence before the clinical relapse of the ovarian cancer. METHODS: Western blot immunoassays were performed to assess the immunoreactivity of 6 antigens with 21 recurrent ovarian cancer patients. RESULTS: The results indicated that antibodies to HARS, Ro52, CDR2 and 5H6 antigens predicted ovarian cancer recurrence 5.03 months before the clinical or symptomatic relapse in 21 ovarian cancer patients with a sensitivity of 90.5% when CA125 levels were below the standard cutoff (35 U/ml). CONCLUSION: Our study suggests that appearance of onconeural antibodies prior to the rise in CA125 during post treatment surveillance can be a useful diagnostic to predict ovarian cancer recurrence. PMID- 29125479 TI - Plasma 3,3',5-Triiodo-L-thyronine [T3] level mirrors changes in tumor markers in two cases of metastatic cancer of the breast and pancreas treated with exogenous L-T3. AB - Preclinical studies have attributed 3,3',5-triiodo-L-thyronine (T3) a direct negative effect on tumor progression, as well as chemosensitizing, differentiating and immunomodulatory properties. On the other hand, L-thyroxine (T4), via a thyroid hormone receptor on plasma membrane integrin alphavbeta3, promotes solid tumor growth and neoangiogenesis, therefore lowering endogenous T4 reduces tumor growth rate. We present the case of two patients with metastatic triple negative breast cancer and metastatic pancreatic cancer respectively, who benefit of the sole treatment with antithyroid drugs and exogenous administration of T3 (liothyronine). In these cases tumor growth was accompanied by T3 depletion in plasma, which may represent a novel marker for progression. PMID- 29125480 TI - Methods and significance of the combined detection of HER2 gene amplification and chemosensitivity in gastric cancer. AB - OBJECTIVE: This study aims to investigate the significance of combined detection of HER2 gene amplification and chemosensitivity in gastric cancer. METHODS: Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and fluorescence reverse-transcription polymerase chain reaction (RT-PCR) were used to analyze the expression of HER2 protein, HER2 gene amplification and the mRNA expression of ERCC1, TUBB3 and TYMS genes in 135 cases of gastric carcinoma. RESULTS: The expression rate of HER2 protein was 39.3% (53/135). Among these positive cases, patients with HER2 protein (3+) accounted for 9.6% (13/135), patients with HER2 protein (2+) accounted for 13.3% (18/135), and patients with HER2 protein (1+) accounted for 16.3% (22/135). The amplification rate of the HER2 gene was 35.8% (19/53). In the detection of the mRNA expression of ERCC1, TUBB3 and TYMS, 45 patients had low and moderate single gene expression, 50 patients had low and moderate double gene expression, 22 patients had low and moderate mRNA expression for ERCC1, TUBB3 and TYMS, and 18 patients had no low and moderate expression. Among the 53 patients with HER2 protein expression and 22 patients with low and moderate mRNA expression of ERCC1, TUBB3 and TYMS, 12 patients received chemotherapy and trastuzumab. Follow-up results revealed that HER2 gene status was positively correlated with the therapeutic effect of the combined treatment in patients with low mRNA expression of ERCC1, TUBB3 and TYMS. Among these patients, five patients with extensive HER2 (3+), HER2 cluster specific amplification, and low mRNA expression of ERCC1, TUBB3 and TYMS had a total survival of up to 19.1 months. CONCLUSIONS: The detection of HER2 in gastric cancer is highly heterogeneity, and the combined detection of HER2 protein expression, HER2 gene amplification and chemosensitivity can provide important reference markers for the benefit of antitumor drugs. PMID- 29125481 TI - Identification of serum miR-124 as a biomarker for diagnosis and prognosis in osteosarcoma. AB - BACKGROUND: It has been demonstrated that microRNAs (miRNAs) play an important role in the carcinogenesis of osteosarcoma. OBJECTIVE: The aim of the present study was to determine the diagnostic and prognostic value of serum miR-124 in osteosarcoma. METHODS: The serum miR-124 expression levels in 114 osteosarcoma patients, 40 periostitis patients and 50 normal controls were detected using real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The level of serum miR-124 was remarkably decreased in osteosarcoma patients when compared to periostitis patients and healthy controls (both p< 0.05). The serum miR-124 levels in osteosarcoma patients were significantly elevated after receiving surgical treatment (p< 0.01). Furthermore, the area under the receiver-operating characteristic (ROC) curve (AUC) for serum miR-124 was 0.846, combining with 79.8% sensitivity and 86.00% specificity. A significant correlation was detected between serum miR-124 expression and distant metastasis (p= 0.0256) as well as clinical stage (p= 0.0006). Similarly, serum miR-124 levels in patients with advanced clinical stage or positive distant metastasis were significantly decreased. Moreover, the Kaplan-Meier method with log-rank test showed that osteosarcoma patients with lower serum miR-124 levels had unfavorable 5 year overall survival and disease free survival rates. Finally, multivariate analysis revealed that serum miR-124 was an independent prognostic indicator for osteosarcoma. CONCLUSIONS: These findings suggested that serum miR-124 might be a promising biomarker with diagnostic and prognostic value for osteosarcoma. PMID- 29125482 TI - MiRNA373 induces cervical squamous cell carcinoma SiHa cell apoptosis. AB - OBJECTIVE: Cervical squamous cell carcinoma seriously threats to patient's life and health. MiRNAs have role of regulating cell growth, proliferation, and death. MiRNAs can promote or inhibit cell growth and proliferation. This study discussed the role of miRNA373 in regulating cervical squamous cell carcinoma growth, proliferation, and apoptosis. PATIENTS AND METHODS: MiRNA373 and scramble miRNA were synthetized and transfected to cervical squamous cell carcinoma SiHa cells by lipofectamine. IAPs plasmid and miRNA373 were sequentially transfected to SiHa cells. MTT assay, caspase-3 activity, and flow cytometry were applied to test miRNA373 and IAPs impacts on cell growth, proliferation, and apoptosis. Western blot was adopted to determine IAPs expression. RESULTS: MiRNA373 transfection obviously reduced SiHa cell growth, induced phosphatidylserine eversion and caspase-3 activation, and declined IAPs expression. IAPs interference significantly enhanced miRNA373 induced SiHa cell apoptosis. IAPs overexpression markedly restrained miRNA373 induced SiHa cell apoptosis. CONCLUSIONS: MiRNA373 transfection suppressed SiHa cell growth and proliferation. MiRNA373 induced SiHa cell apoptosis possibly through downregulating IAPs, suggesting that IAPs might be a target for cervical squamous cell carcinoma treatment. PMID- 29125483 TI - The targeted regulation of Gli1 by miR-361 to inhibit epithelia-mesenchymal transition and invasion of esophageal carcinoma cells. AB - Epithelia-mesenchymal transition (EMT) is critical for invasion and metastasis of esophageal carcinoma. Gli1, a transcriptional factor in Hedgehog pathway, is correlated with EMT, invasion and metastasis of tumors. However, its role in esophageal cancer is still unknown. Bioinformatics analysis revealed relationship between microRNA (miR)-361 and 3'-UTR of Gli1 gene. This study thus investigated the role of miR-361 and Gli1 in invasion and metastasis of esophageal cancer. Both tumor and adjacent tissues were collected from 58 esophageal cancer patients to test the expressions of miR-361 and Gli1, the relationship of which was confirmed by dual-luciferase reporter gene assay. Cultured esophageal cancer cells EC9706 were transfected with mimic NC, miR-361 mimic, si-NC, si-Gli1, miR 361 mimics+si-Glil, pQC or pQC-FU-Gli1. Transwell and colony formation assays were performed for cell invasion and attachment-independent growth. Expressions of Gli1, Snail, E-cadherin and N-cadherin proteins were revealed by Western blotting. The expression of Gli1 was significantly elevated in esophageal cancer tissues, along with lower miR-361 expression which was correlated with TNM stage. MiR-361 inhibited the expression of Gli1 via targeting on 3'-UTR of Gli1 gene. The transfection of miR-361 mimics and/or si-Gli1 significantly suppressed the growth of malignant cells. The over-expression of miR-361 and/or silencing of Gli1 decreased intracellular expression of Gli1, Snail and N-cadherin, and increased E-cadherin expression to suppress EMT and invasion of tumor cells while the opposite effects were obtained by over-expression of Gli1. Abnormal elevation of Gli1 and decrease of miR-361 were found in esophageal cancer tissues. MiR-361 weakened invasion of cancer cells and impeded EMT process via the inhibition of Gli1. PMID- 29125484 TI - General Practice Clinical Data Help Identify Dementia Hotspots: A Novel Geospatial Analysis Approach. AB - We have a poor understanding of whether dementia clusters geographically, how this occurs, and how dementia may relate to socio-demographic factors. To shed light on these important questions, this study aimed to compute a dementia risk score for individuals to assess spatial variation of dementia risk, identify significant clusters (hotspots), and explore their association with socioeconomic status. We used clinical records from 16 general practices (468 Statistical Area level 1 s, N = 14,746) from the city of west Adelaide, Australia for the duration of 1 January 2012 to 31 December 2014. Dementia risk was estimated using The Australian National University-Alzheimer's Disease Risk Index. Hotspot analyses were applied to examine potential clusters in dementia risk at small area level. Significant hotspots were observed in eastern and southern areas while coldspots were observed in the western area within the study perimeter. Additionally, significant hotspots were observed in low socio-economic communities. We found dementia risk scores increased with age, sex (female), high cholesterol, no physical activity, living alone (widow, divorced, separated, or never married), and co-morbidities such as diabetes and depression. Similarly, smoking was associated with a lower dementia risk score. The identification of dementia risk clusters may provide insight into possible geographical variations in risk factors for dementia and quantify these risks at the community level. As such, this research may enable policy makers to tailor early prevention strategies to the correct individuals within their precise locations. PMID- 29125486 TI - Putative Dementia Cases Fluctuate as a Function of Mini-Mental State Examination Cut-Off Points. AB - As the population ages, there is a growing need to quickly and accurately identify putative dementia cases. Many cognitive tests are available; among those commonly used are the Cognitive Dementia Rating (CDR) and the Mini-Mental Status Examination (MMSE). The aim of this work was to compare the validity and reliability of these cognitive tests in a primary care based cohort (pcb-Cohort). The MMSE and the CDR were applied to 568 volunteers in the pcb-Cohort. Distinct cut-off points for the MMSE were considered, namely MMSE 27, MMSE 24, and MMSE PT (adapted for the Portuguese population). The MMSE 27 identified the greatest number of putative dementia cases, and, as determined by the ROC curve, it was the most sensitive and specific of the MMSE cut-offs considered. Putative predictive or risk factors identified included age, literacy, depression, and diabetes mellitus (DM). DM has previously been indicated as a risk factor for dementia and Alzheimer's disease. Comparatively, the MMSE 27 cut-off has the greatest sensibility (94.9%) and specificity (66.3%) when compared to MMSE PT and MMSE 24. Upon comparing MMSE and CDR scores, the latter identified a further 146 putative dementia cases, thus permitting one to propose that in an ideal situation, both tests should be employed. This increases the likelihood of identifying putative dementia cases for subsequent follow up work, thus these cognitive tests represent important tools in patient care. Further, this is a significant study for Portuguese populations, where few of these studies have been carried out. PMID- 29125485 TI - Cognitive Variability Predicts Incident Alzheimer's Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker. AB - BACKGROUND: Alzheimer's disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture. OBJECTIVE: To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-beta 42 (Abeta42) peptide. METHODS: Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/Abeta42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n = 105) or diagnosed with MCI (n = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p tau181/Abeta42. RESULTS: When included in models alone or in combination with CSF p-tau181/Abeta42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83-4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03-5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models. CONCLUSIONS: These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers. PMID- 29125487 TI - Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A Familiar and Sporadic Alzheimer's Disease Brains. AB - Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains. PMID- 29125488 TI - Comparison between FCSRT and LASSI-L to Detect Early Stage Alzheimer's Disease. AB - BACKGROUND: The Free and Cued Selective Reminding Test (FCSRT) is the most accurate test for the diagnosis of prodromal Alzheimer's disease (AD). Recently, a novel cognitive test, the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), has been developed in order to provide an early diagnosis. OBJECTIVE: To compare the diagnostic accuracy of the FCSRT and the LASSI-L for the diagnosis of AD in its preclinical and prodromal stages using 18F fluorodeoxyglucose positron emission tomography (FDG-PET) as a reference. METHODS: Fifty patients consulting for subjective memory complaints without functional impairment and at risk for AD were enrolled and evaluated using FCSRT, LASSI-L, and FDG-PET. Participants were evaluated using a comprehensive neurological and neuropsychological protocol and were assessed with the FCSRT and LASSI-L. FDG-PET was acquired concomitantly and used for classification of patients as AD or non-AD according to brain metabolism using both visual and semi quantitative methods. RESULTS: LASSI-L scores allowed a better classification of patients as AD/non-AD in comparison to FCSRT. Logistic regression analysis showed delayed recall and failure to recovery from proactive semantic interference from LASSI-L as independent statistically significant predictors, obtaining an area under the curve of 0.894. This area under the curve provided a better discrimination than the best FCSRT score (total delayed recall, area under the curve 0.708, p = 0.029). CONCLUSIONS: The LASSI-L, a cognitive stress test, was superior to FCSRT in the prediction of AD features on FDG-PET. This emphasizes the possibility to advance toward an earlier diagnosis of AD from a clinical perspective. PMID- 29125489 TI - Word and Picture Version of the Free and Cued Selective Reminding Test (FCSRT): Is There Any Difference? AB - The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results. PMID- 29125490 TI - Plasma Proteomic Profiles of Cerebrospinal Fluid-Defined Alzheimer's Disease Pathology in Older Adults. AB - BACKGROUND: Cerebrospinal fluid (CSF) biomarkers of the beta-amyloid and microtubule associated protein tau metabolism have proven the capacity to improve classification of subjects developing Alzheimer's disease (AD). The blood plasma proteome was characterized to further elaborate upon the mechanisms involved and identify proteins that may improve classification of older adults developing an AD dementia. OBJECTIVE: Identify and describe plasma protein expressions that best classify subjects with CSF-defined presence of AD pathology and cerebral amyloidosis. METHODS: We performed a cross-sectional analysis of samples collected from community-dwelling elderly with (n = 72) or without (n = 48) cognitive impairment. CSF Abeta1-42, tau, and phosphorylated tau (P-tau181) were measured using ELISA, and mass spectrometry quantified the plasma proteomes. Presence of AD pathology was defined as CSF P-tau181/Abeta1-42 > 0.0779, and presence of amyloidosis was defined as CSF Abeta1-42 < 724 pg/mL. RESULTS: Two hundred and forty-eight plasma proteins were quantified. Plasma proteins did not improve classification of the AD CSF biomarker profile in the whole sample. When the analysis was separately performed in the cognitively impaired individuals, the diagnosis accuracy of AD CSF profile was 88.9% with 19 plasma proteins included. Within the full cohort, there were 16 plasma proteins that improved diagnostic accuracy of cerebral amyloidosis to 92.4%. CONCLUSION: Plasma proteins improved classification accuracy of AD pathology in cognitively-impaired older adults and appeared representative of amyloid pathology. If confirmed, those candidates could serve as valuable blood biomarkers of the preclinical stages of AD or risk of developing AD. PMID- 29125494 TI - Cognitive enhancing and antioxidant effects of tetrahydroxystilbene glucoside in Abeta1-42-induced neurodegeneration in mice. AB - Polyhydroxy stilbenes have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease (AD). Tetrahydroxystilbene glucoside is one of the major polyhydroxy stilbenes, which provides underlying therapeutic activities for neuroprotective actions in various experimental conditions. This study intends to investigate the impact of tetrahydroxystilbene glucoside remedy for cognitive disorder and oxidative stress in Abeta1-42-induced AD mice and to clarify the mechanisms of action through Keap1/Nrf2 pathway. It was found that The swimming time of Abeta1-42-induced mice which were treated by tetrahydroxystilbene glucoside (30, 60 and 120 mg/kg) was significantly increased in the target quadrant through the Morris water maze experiment and the number of avoidances was increased through the passive avoidance experiment. Moreover, tetrahydroxystilbene glucoside attenuated Abeta1 42-induced memory impairment, however, the locomotor and exploratory activity of the mice were not affected. Tetrahydroxystilbene glucoside obviously decreased the levels of MDA and GSSG in both hippocampus and cortex compared with the Abeta1-42-treated group, and obviously increased the level of GSH and activities of CAT and SOD in above tissues. The results of this study also demonstrated that tetrahydroxystilbene glucoside increased Nrf2 and HO-1 protein expression and decreased Keap1 protein expression in a concentration-dependent manner in Abeta1 42-treated mice, which involved in the Keap1/Nrf2 antioxidant pathway in hippocampus and cerebral cortex tissue. These results demonstrated that tetrahydroxystilbene glucoside as a natural drug might provide potential treatment for AD. PMID- 29125493 TI - Validation of Ultrasensitive Mutant Huntingtin Detection in Human Cerebrospinal Fluid by Single Molecule Counting Immunoassay. AB - BACKGROUND: The measurement of disease-relevant biomarkers has become a major component of clinical trial design, but in the absence of rigorous clinical and analytical validation of detection methodology, interpretation of results may be misleading. In Huntington's disease (HD), measurement of the concentration of mutant huntingtin protein (mHTT) in cerebrospinal fluid (CSF) of patients may serve as both a disease progression biomarker and a pharmacodynamic readout for HTT-lowering therapeutic approaches. We recently published the quantification of mHTT levels in HD patient CSF by a novel ultrasensitive immunoassay-based technology and here analytically validate it for use. OBJECTIVE: This work aims to analytically and clinically validate our ultrasensitive assay for mHTT measurement in human HD CSF, for application as a pharmacodynamic biomarker of CNS mHTT lowering in clinical trials. METHODS: The single molecule counting (SMC) assay is an ultrasensitive bead-based immunoassay where upon specific recognition, dye-labeled antibodies are excited by a confocal laser and emit fluorescent light as a readout. The detection of mHTT by this technology was clinically validated following established Food and Drug Administration and European Medicine Agency guidelines. RESULTS: The SMC assay was demonstrated to be accurate, precise, specific, and reproducible. While no matrix influence was detected, a list of interfering substances was compiled as a guideline for proper collection and storage of patient CSF samples. In addition, a set of recommendations on result interpretation is provided. CONCLUSIONS: This SMC assay is a robust and ultrasensitive method for the relative quantification of mHTT in human CSF. PMID- 29125495 TI - A dialogue on the issue of the "quantum brain" between consciousness and unconsciousness. AB - In this paper, we present some diverse points of view on the issue of the quantum brain.The paper is structured in the form of opening statements by each of the co authors followed by comments and critique presented by the other co-authors. The main focus of the discussion is on the interplay between the state of being alive and consciousness, both of which possess characteristics of quantum physical states. PMID- 29125496 TI - Consciousness in hibernation and synthetic torpor. AB - While human hibernation would provide many advantages for medical applications and space exploration, the intrinsic risks of the procedure itself, as well as those involved if the procedure were to be misused, need to be assessed. Moreover, the distinctive brain state that is present during a hibernation-like state raises questions regarding the state of consciousness of the subject. Since, in animal studies, the cortical activity of this state differs from that of sleep, coma, or even general anesthesia, and resembles a sort of "slowed wakefulness", it is uncertain whether residual consciousness may still be present. In this review, I will present a brief summary of the literature on hibernation and of the current state of the art in inducing a state of artificial hibernation (synthetic torpor); I will then focus on the brain changes that are observed during hibernation, on how these could modify the neural substrate of consciousness, and on the possible use of hibernation as a model for quantum biology. Finally, some ethical considerations on the use of synthetic torpor technology will be presented. PMID- 29125497 TI - Quantum brain theory and the appearing of world. AB - The appearing of world is approached via the dream world which has generally been thought to be merely derivative: a "composition" of memory traces from waking life, which are merged and fused into a dream world that in some instances can be indiscernable from the world of waking life. Two dreams are presented which challenge the composition theory of dream formation. An alternative unified theory of world appearance in both waking and dreaming is proposed, which makes use of developments in quantum brain dynamics. For this "monadological" proposal the wake world and the dream world are ontologically at parity. This surprising conclusion extends the quantum revolution to our very Existenz. PMID- 29125498 TI - Two pathways toward an integrative quantum psychophysics. PMID- 29125492 TI - Towards an Understanding of Energy Impairment in Huntington's Disease Brain. AB - This review systematically examines the evidence for shifts in flux through energy generating biochemical pathways in Huntington's disease (HD) brains from humans and model systems. Compromise of the electron transport chain (ETC) appears not to be the primary or earliest metabolic change in HD pathogenesis. Rather, compromise of glucose uptake facilitates glucose flux through glycolysis and may possibly decrease flux through the pentose phosphate pathway (PPP), limiting subsequent NADPH and GSH production needed for antioxidant protection. As a result, oxidative damage to key glycolytic and tricarboxylic acid (TCA) cycle enzymes further restricts energy production so that while basal needs may be met through oxidative phosphorylation, those of excessive stimulation cannot. Energy production may also be compromised by deficits in mitochondrial biogenesis, dynamics or trafficking. Restrictions on energy production may be compensated for by glutamate oxidation and/or stimulation of fatty acid oxidation. Transcriptional dysregulation generated by mutant huntingtin also contributes to energetic disruption at specific enzymatic steps. Many of the alterations in metabolic substrates and enzymes may derive from normal regulatory feedback mechanisms and appear oscillatory. Fine temporal sequencing of the shifts in metabolic flux and transcriptional and expression changes associated with mutant huntingtin expression remain largely unexplored and may be model dependent. Differences in disease progression among HD model systems at the time of experimentation and their varying states of metabolic compensation may explain conflicting reports in the literature. Progressive shifts in metabolic flux represent homeostatic compensatory mechanisms that maintain the model organism through presymptomatic and symptomatic stages. PMID- 29125499 TI - Mast cells in the brain - Old cells, new target. AB - Mast cells (MCs) are mainly known for their involvement on allergic reactions through degranulation and release of vasoactive, inflammatory and nociceptive mediators. Upon encountering an allergen, MCs are first responders, true sensors of the environment, actually they respond to a wide range of "danger" signals both immunological and non-immunological in rapid and selective manner. They secrete both preformed and newly synthesized mediators acting as effectors in relationship between nervous, vascular and immune systems. For this peculiarity, MCs are "master regulators" and key players of the immune system as well as important source of essential and beneficial mediators with crucial roles in the regulation of various physiological processes. MCs are unique cells with multiple capabilities. It has well known that MCs are critical for the pathogenesis of inflammatory disease. MCs exert their effect through alteration of vascular permeability and recruitment of inflammatory cells. While a functional involvement of peripheral MCs in inflammatory conditions is well established, the role of Central Nervous System MCs is not well understood yet. Increasing evidence indicate that in the brain, the inflammation is strongly involved in the pathogenesis of neurodegenerative and neuropsychiatric diseases. In this review, we discuss some aspects of the current knowledge of MCs role in the brain and their potential role as therapeutic emerging target for neural diseases. PMID- 29125500 TI - Bessel-like functional distributions in brain average evoked potentials. AB - Average evoked potential data recorded as impulse responses of brains to electric shocks show Bessel-like functional distributions which we analyze in terms of couples of damped/amplified oscillators. This reproduces results obtained in terms of ordinary differential equations (Freeman K-sets) and offers the possibility of a direct connection with the dissipative model of brain in the quantum gauge field theory paradigm. We study the control mechanism by fine tuning the model parameters and the brain property of discriminating between two similar behaviors or perceptions. We suggest that a similar control mechanism may be useful in security communication protocols. Finally, brain activity and mental activity is considered in the light of our results. PMID- 29125501 TI - Document of Trapani on animal consciousness and quantum brain function: A hypothesis. PMID- 29125502 TI - Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions. AB - Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromuscular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS. PMID- 29125503 TI - Patient Preferences for Treatments of Neuromuscular Diseases: A Systematic Literature Review. AB - BACKGROUND: Treatment decisions of neuromuscular diseases involve weighing clinical benefits and risks, as well as impact on patient social life, work status, other activities of daily living, and health-related quality of life. OBJECTIVE: To conduct a systemic literature review of patient preferences for treatments of neuromuscular diseases. METHODS: We searched Embase, Web of Science, and PubMed for full-text articles reporting results from studies of patient preferences for treatments of neuromuscular diseases. We excluded articles published before the year 2000, articles written in a language other than English, articles only reporting proxy-assessments of patient preferences, and studies reporting results for a sample comprising <5 patients. RESULTS: The search resulted in the identification of 305 unique publications. Of these, 275 were excluded following title and abstract screening and 23 following full-text review. Seven articles were included for data synthesis. Preference data were identified for a hypothetical treatment with pulmonary benefits of Duchenne muscular dystrophy and Becker muscular dystrophy, pathways for different routes of opioid drug administration in motor neuron disease, wheelchair features in amyotrophic lateral sclerosis (ALS), ankle foot orthoses in patients with Charcot Marie Tooth disease, and mechanical ventilation in ALS and a mixed cohort of patients with neuromuscular diseases. CONCLUSIONS: Despite considerable research into the development of new health technologies targeting neuromuscular diseases, little is known of patients' preferences for pharmacological interventions. More research is needed to help incorporate patient preferences in clinical decision making to improve treatment satisfaction, medication compliance, and health outcomes. PMID- 29125505 TI - Using non-nutritive sucking to support feeding development for premature infants: A commentary on approaches and current practice. AB - Non-nutritive sucking is often used with premature infants by either using a pacifier or an expressed breast nipple to support the introduction and development of early oral feeding. The pattern of non-nutritive sucking is distinct in that it involves two sucks per second in contrast to nutritive sucking which is one suck per second. Although some literature has identified that non-nutritive sucking has some benefit for the premature infant's feeding development, it is not entirely clear why such an approach is helpful as neurologically, activation of non-nutritive and nutritive skills are different. A summary is presented of the main approaches that use non-nutritive sucking with reference to the literature. This paper also considers other factors and beneficial approaches to managing the introduction of infant feeding. These are: the infant's toleration of enteral feeds pre oral trials, overall development and gestational age when introducing oral experiences, developing swallowing skills before sucking, physiological stability, health status, as well as the development and interpretation of infant oral readiness signs and early communication. PMID- 29125506 TI - Should the dose of folic acid be adjusted for Mexican population? The pilot prevention program implemented in Nuevo Leon, Mexico. AB - In 1980 Smithells et al. reported that the intake of folic acid (FA) prevents the recurrence of neural tube defects (NTDs) [1]. After this and several other studies were conducted, the intake of 400 micrograms of folic acid per day, at least three months before and three months during pregnancy for prevention of NTD, was proposed [2,3,4]. Other strategies were also developed to increase folate blood levels in woman of childbearing age such as promoting the consumption of folate rich foods and food fortification (flour and most recently rice) [5]. Nevertheless, results have not been as expected due to poor consumption of folic acid supplements [6]. As a result, in the year 2000, a novel strategy was developed in order to increase folate blood levels in Mexican women. The results of the strategy are presented, as well as, a discussion about how to personalize a program for different populations. PMID- 29125507 TI - Self-management and health care transition: Trials, tribulations and triumphs. AB - PURPOSE: The purpose of this article is to provide perspectives pertaining to the importance of fostering comprehensive self-management competencies of AEA-SHCN, with attention directed to AEA with spina bifida based upon the Health Care Transition Research Consortium Health Care Transition model. This article is based upon the plenary presentation given at the Spina Bifida 3rd World Congress, entitled, Self-Management and Health Care Transition: Trials, Tribulations and Triumphs. METHOD: A historical perspective of healthcare transition initiatives and best practice guidelines is provided that have influenced the field of research and practice. Relatively scant attention has been directed to the development and refinement of self-management competencies prior to the transfer of care and transition to adulthood. Against this backdrop of the predominant framework of care focused on the transfer of care, a discussion of our team's experience with the provision of healthcare transition services and the complexity of addressing the self-management needs of the adolescents and emerging adults (AEA) with spina bifida served in the Movin' On Up HCT program will be presented. RESULTS: Through our clinical and research healthcare transition experience, insights pertaining to self-management will be presented. CONCLUSION: The acquisition of self-management knowledge and skills is a complex process that extends far beyond learning the fundamental skills of daily condition management. PMID- 29125504 TI - Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database. AB - BACKGROUND: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. OBJECTIVE: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. METHODS: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. RESULTS: Loss of ambulation in non steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. CONCLUSIONS: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field. PMID- 29125508 TI - Urologic self-management through intermittent self-catheterization among individuals with spina bifida: A journey to self-efficacy and autonomy. AB - PURPOSE: To describe the age of independence in intermittent self-catheterization (ISC) in a diverse patient population and identify factors associated with ISC in individuals with spina bifida. METHODS: Two hundred patients with myelomeningocele or lipomyelomeningocele, who were ? 3 years of age and utilized catheterization for bladder management were included. Data regarding diagnosis, functional level of lesion, race, ethnicity, presence of shunt, method of catheterization, self-management skills, fine motor skills, and cognitive abilities were collected. RESULTS: Fifty-five percent of individuals were able to perform ISC with a mean age of 9.45 years (SD = 2.97) and 22.7% used a surgically created channel. Higher level of lesion and female gender were associated with a lower rate of ISC. Intellectual disability was present in 15% of the individuals able to perform ISC and in 40% of those not able to perform ISC (p= 0.0005). Existent self-efficacy regarding activities of daily living (i.e. dressing, bathing, skin care) were associated with ISC (p< 0.0001). CONCLUSIONS: The average age of ISC emerged as a target for culturally-appropriate educational interventions to stimulate greater early independence. Future research on factors that may foster an 'independent spirit' early in childhood leading to self management are warranted. PMID- 29125509 TI - Developing a community based service model for disability: Listening to the needs of all beneficiaries and providers. AB - PURPOSE: To inform the strategic and operational development of a community based service model at the Crann Centre, Cork, Ireland for SB children, adults, their families and providers. A needs assessment was conducted by gathering the views of multiple stakeholder perspectives within the SB community in the geographical region the Centre will serve. The intention is to create project deliverables that are responsive to the needs highlighted through this research. METHODS: The study used a multi method design with a participatory research approach to explore the needs of SB individuals, families and providers. This involved in depth interviews, focus groups and online surveys. RESULTS: One hundred and fifty nine respondents contributed to this qualitative needs assessment. The research established a range of psychosocial, clinical, vocational and educational issues causing ongoing difficulties for SB individuals and families. Providers highlighted supports that would benefit the social and clinical wellbeing of persons with SB. Collectively participants in the study reported that there was an absence of coordinated, continuous and comprehensive service delivery for the SB community in the region. This was amplified by geographical location of services and access to relevant supports. CONCLUSION: Consensus across stakeholders in this research pointed to the necessity for an innovative model of community based provision at the Crann Centre. This was described as offering a service with family at the core of an assets based model of practice. A key finding was the lack of importance placed on the social and emotional development of SB individuals. Traditionally participants described a singular focus on physical health through clinically defined treatment models. The desire for a social model of disability that informed health and wellbeing of SB individuals and families emerged as a prominent recommendation from the research. PMID- 29125510 TI - Regenerative medicine and spina bifida: Recent developments in induced fetal regeneration. AB - Regenerative medicine as it applies to spina bifida is a multi-pronged endeavor involving spinal cord repair, tissue engineering and fetal regeneration, all of which can mutually overlap to variable extents. The efforts involving spinal cord repair, whether they be cell-based or not, are virtually indistinguishable from the enormous body of work related to spinal cord recovery after traumatic injury. Tissue engineering, on the other hand, can involve a variety of structures besides constructs used for covering the spina bifida defect, for example the urinary bladder, bone, muscle and skin. This brief review will not delve into any of these two main areas, which actually can also involve fetal interventions within their respective realms, but rather be devoted to a very recent development making use of the uniquely enhanced ability of the fetus to repair, or regenerate areas of tissue damage, coined transamniotic stem cell therapy, or TRASCET. TRASCET is a still experimental therapeutic paradigm for the treatment of not only spina bifida, but also other birth defects, based on the principle of harnessing/enhancing the normal biological role of a select population of stem cells that naturally occur in the amniotic fluid, specifically amniotic fluid derived mesenchymal stem cells (afMSCs), for therapeutic benefit. PMID- 29125511 TI - Variation in bowel and bladder continence across US spina bifida programs: A descriptive study. AB - PURPOSE: Continence is low in individuals with spina bifida, but published prevalence varies markedly across studies. The objective of this study was to examine bladder and bowel continence among patients served by multidisciplinary clinics participating in the National Spina Bifida Patient Registry and to examine whether variation in prevalence exists across clinics. METHODS: Data were obtained from patients 5 years and older from March 2009 to December 2012. Data were gathered at clinic visits using standardized definitions. RESULTS: Data from 3252 individuals were included. Only 40.8% of participants were continent of urine; 43% were continent of stool. Bladder and bowel continence differed by spina bifida type, with those with myelomeningocele having significantly lower reported prevalence of continence than those with other forms of spina bifida. Bladder and bowel continence varied across registry sites. Adjustment based on demographic and condition-specific variables did not make substantive differences in prevalence observed. CONCLUSION: Less than half of spina bifida patients served in multidisciplinary clinics report bladder or bowel continence. Variability in prevalence was observed across clinics. Further research is needed to examine if clinic-specific variables (e.g., types of providers, types of interventions used) account for the observed variation. PMID- 29125512 TI - A chronic care model for spina bifida transition. AB - Providing comprehensive transition care for adolescents and young adults with spina bifida (AYASB) requires a structured approach to addressing chronic condition management, self-management, care coordination, and health care navigation that is adaptable to the various levels of cognitive ability, physical function, and family/community environments within the population. This commentary (1) highlights AYASB transition program needs identified in the literature and within a local community, (2) analyzes advantages and limitations of published AYASB transition care models in addressing these needs, (3) demonstrates how a spina bifida (SB) transition clinic used the Chronic Care Model (CCM) to develop a comprehensive AYASB transition program, and (4) examines the potential feasibility in adapting this model to other SB clinics. A SB specific transition clinic based on the CCM model facilitates the complex chronic care management and transition planning for AYASB. Further study is needed to evaluate health care outcomes using the CCM for SB transition. PMID- 29125513 TI - Effect of bladder augmentation on VP shunt failure rates in spina bifida. AB - PURPOSE: Most patients with spina bifida require ventriculoperitoneal (VP) shunt placement. Some also require bladder augmentation, which may increase the risk of VP shunt malfunction and/or failure. The aim of this study was to assess whether bladder augmentation affects the rate of VP shunt failure in this population. METHODS: Using the Pediatric Health Information System, we studied patients with spina bifida born between 1992 and 2014 who underwent VP shunt placement. Using conditional logistic regression, we compared age- and hospital-matched patients who did and did not undergo a bladder augmentation to determine their difference in rates of VP shunt failure. RESULTS: There were 4192 patients with spina bifida who underwent both surgical closure and VP shunt placement. Of these, 203 patients with bladder augmentation could be matched to 593 patients without bladder augmentation. VP shunt failure occurred within 2 years in 7.7% of patients, the majority of whom were in the group who underwent bladder augmentation (87%). After adjusting for confounders, undergoing bladder augmentation was independently associated with VP shunt failure (HR: 33.5, 95% CI: 13.15-85.44, p< 0.001). CONCLUSION: Bladder augmentation appears to be associated with VP shunt failure. Additional studies are necessary to better define this relationship and identify risk-reduction techniques. PMID- 29125514 TI - Crowdsourcing utility estimation for spina bifida in the general population. AB - INTRODUCTION: Cost-utility analyses (CUA) are useful when the treatment conditions depend on patient preferences that are in turn dependent on health state utility value. Spina bifida (SB) is an example of such a preference sensitive condition. Historically, the SB utility value for CUA has been gathered via a traditional face-to-face interview. However, due to funding and time constrains, utility estimation via online crowdsourcing has recently gained popularity. Our aim was to estimate the utility value for a generic SB health state using a validated online tool. METHODS: A cross-sectional survey of American adults was conducted using the time-trade-off (TTO) method. Participants were recruited from an online crowdsourcing interface, Amazon's Mechanical Turk (mTurk). Demographic information and prior knowledge of SB were assessed. Respondents were provided a written passage and an online video explaining SB and its potential associated comorbidities. Participants were queried on hypothetical ascending time-trades from a child-parent dyad perspective to determine the utility of a SB health state in an affected 6-year-old child. Respondents were also asked to indicate the percentage of time traded from their life in relation to their child's. Utility estimates were then calculated and compared using bivariate and multivariate analyses. RESULTS: We obtained 503 responses (85% response rate). Mean respondent age was 34 (+/- 11); 247 (49%) were female; 386 (77%) were white; 189 (38%) were married, and 234 (46%) had children. Mean proportion of longevity traded by participants in the dyadic interaction was 66% (+/- 27) from the parent's life. Only 51 respondents (9%) reported having "ample" prior knowledge of SB; 8 respondents (0.02%) had SB themselves. Few others had previous experience with SB or myelomeningocele either in a child (4, 1%), or friend/relative (28, 5%). Compared with a perfect health state of 1.0, we found mean utilities of 0.85 (+/- 0.20) for SB. CONCLUSIONS: Utility estimation for SB is feasible through crowdsourcing, and the resultant values are similar to previous estimates using traditional techniques. Subjects view the SB health state to be inferior to perfect health. PMID- 29125515 TI - Endoscopic Third Ventriculostomy to address hydrocephalus in Africa: A call for education and community-based rehabilitation. AB - PURPOSE: Endoscopic Third Ventriculostomy (ETV) and Choroid Plexus Cautery (CPC) are low-cost, safe, and promising interventions for spina bifida-associated hydrocephalus (SBHCP). The purpose of this review was to explore and describe these efforts in Africa in order to upscale surgical training and rehabilitation services. METHODS: A PubMed search for articles on ETV and CPC as management of SBHCP in Africa was performed. Two authors appraised the results for key themes in content: indications, technique, outcomes, complications, education, and rehabilitation. RESULTS: Twenty of 47 articles identified were included for appraisal. Twelve described indications, ten and seven outlined technique and complications, respectively, and four described predictors of operative success. Fourteen studies describe outcomes, including operative and neurodevelopmental outcomes. Only two outlined educational efforts. Half of the literature stems from a single site in Uganda; in total, only six countries were represented. No articles described significant post-operative rehabilitation services or related training. CONCLUSION: The experience of ETV and CPC in Africa is promising, however, efforts to train and empower local staff in surgical technique and methods to upscale post-operative community-based rehabilitation services remain as a key to long-term success. PMID- 29125516 TI - Evaluation of spina bifida transitional care practices in the United States. AB - PURPOSE: Recent studies have revealed that the lack of continuity in preparing patients with spina bifida to transition into adult-centered care may have detrimental health consequences. We sought to describe current practices of transitional care services offered at spina bifida clinics in the US. METHODS: Survey design followed the validated transitional care survey by the National Cystic Fibrosis center. Survey was amended for spina bifida. Face validity was completed. Survey was distributed to registered clinics via the Spina Bifida Association. Results were analyzed via descriptive means. RESULTS: Total of 34 clinics responded. Over 90 characteristics were analyzed per clinic. The concept of transition is discussed with most patients. Most clinics discuss mobility, bowel and bladder management, weight, and education plans consistently. Most do not routinely evaluate their process or discuss insurance coverage changes with patients. Only 30% communicate with the adult providers. Sexuality, pregnancy and reproductive issues are not readily discussed in most clinics. Overall clinics self-rate themselves as a 5/10 in their ability to provide services for their patients during transition. CONCLUSIONS: Characteristics of current transitional care services and formal transitional care programs at US clinics show wide variances in what is offered to patients and families. PMID- 29125517 TI - Genetic epidemiology of neural tube defects. AB - It has been estimated that 60-70% of neural tube defects (NTDs) have a genetic component, but few causative genes have been identified. The lack of information on genes associated with non-syndromic NTDs in humans is especially notable as the "genomic revolution" has led to new tools (e.g., genome-wide genotyping arrays, next-generation sequencing) that are helping to elucidate the full spectrum of genetic variation (from common to rare) contributing to complex traits, including structural birth defects. However, the application of modern genomic approaches to the study of NTDs has lagged behind that of some other common structural birth defects. This may be due to the difficulty of assembling large study cohorts for anencephaly or spina bifida. The purpose of this review is to outline the evolution of genetic studies of NTDs, from studies of familial aggregation to candidate gene and genome-wide association studies, through whole exome and whole-genome sequencing. Strategies for addressing gaps in NTD genetic research are also explored. PMID- 29125518 TI - A trauma-informed approach supports health and development in children and youth with spina bifida. AB - Children with developmental disabilities may be at greater risk for experiencing maltreatment and traumatic events, threats to their physical and psychological safety and well-being. Young children and youth with spina bifida benefit from being considered in light of this risk, and may be especially vulnerable given the complexity of their neurodevelopmental condition. A trauma-informed approach brings together evidence from the neurosciences, epidemiology and psychology to promote improved developmental, behavioral, physical and mental health status. Incorporating a trauma-informed approach strengthens a longitudinal, interdisciplinary and developmentally-oriented care model for children and youth with spina bifida. A case example further illustrates how using a trauma-informed approach and evidence-based interventions can foster the development and well being of youth with spina bifida who have been impacted by a traumatic event. PMID- 29125520 TI - Daily time management in children with spina bifida. AB - PURPOSE: Spina bifida (SB) often results in a complex disability and can also cause cognitive dysfunction. No previous study has investigated the ability to adapt to time in children with SB. This ability is crucial for an individual's possibility to develop autonomy in life. The purpose of this study was to investigate whether children aged 10-17 with SB have lower time-processing abilities than typically-developing children, and to describe the profile of time processing in children with SB. METHOD: Participants comprised a consecutive sample of 21 children (drawn from a geographical cohort of 45) aged 10-17 years (mean: 14 years, SD: 2 years); 13 were boys. The instruments used were KaTid-Y, Time-S, and Time-P. RESULTS: The children with SB had lower time-processing abilities than typically-developing children (52.4% under -2SD), particularly difficulties to orient to and to estimate objective time, to understand time perspectives and with time planning. They also self-rated low use of strategies to adapt to time. The parents rated their children as having extensive difficulties in daily time management. CONCLUSIONS: The low time-processing ability found in children with SB is likely to be an important contributing factor to low autonomy and independence. PMID- 29125519 TI - Advanced skeletal maturity in children and adolescents with myelomeningocele. AB - PURPOSE: Atypical skeletal development is common in youth with myelomeningocele (MM), though the underlying reasons have not been fully elucidated. This study assessed skeletal maturity in children and adolescents with MM and examined the effects of sex, age, sexual development, ethnicity, anthropometrics and shunt status. METHODS: Forty-three males and 35 females with MM, 6-16 years old, underwent hand radiographs for bone age determination. The difference between bone age and chronological age was evaluated using Wilcoxon sign rank tests. Relationships between age discrepancy (skeletal-chronological) and participant characteristics were assessed using multiple linear regression with forward selection. RESULTS: Overall, forty percent (31/78) of MM participants had an advanced bone age of 1 year or greater (median: 2.5 years), while 47% (37/78) were within 1 year above or below their chronological age (-0.001 years) and 13% (10/78) were delayed by more than 1 year (-1.4 years). Bone age was advanced compared to chronologic age in both males and females (p? 0.024). Advanced bone age was observed in early to late puberty and after maturation (p? 0.07), as well as in Hispanic participants (p= 0.003) and in those with a shunt (p= 0.0004). Advanced bone age was positively correlated with height, weight and body mass index (BMI) percentiles (p= 0.004). In multiple linear regression analysis, advanced bone age was most strongly associated with higher Tanner stage of sexual development, and higher weight, height or BMI percentile. CONCLUSIONS: Advanced skeletal maturity is common in children/adolescents with MM over 8 years of age who have reached puberty (65%), particularly those who are overweight (80%). Hormonal effects associated with adiposity and sexual maturity likely influence skeletal maturation. Clinicians may use Tanner stage and weight or BMI to gain insight into skeletal maturity. PMID- 29125522 TI - Sexual identity and orientation in adult men and women with spina bifida. AB - PURPOSE: Sexuality has received little attention in spina bifida (SB) care. The aim of this study was to assess sexual identity and orientation in adults with SB. METHODS: An international online survey to adults with SB was administered over 10-months (recruitment: SB clinics, SB organizations via social media). Collected data included demographics, sexual identity and orientation. Non parametric tests were used for analysis. RESULTS: Median age of 77 men and 119 women was 35 years old (52.0% shunted, 48.5% community ambulators, 42.3% outside United States). Most commonly, men identified as male (96.1%), while 1.3% each described themselves as female, transgender and other. All women reporting sexual identity identified as female (99.2%), 0.8% not providing an answer. Most men reported heterosexual orientation (89.6%), followed by gay (7.8%) and bisexual (2.6%). Most women reported heterosexual orientation (84.9%), followed by bisexual (10.4%), gay/lesbian (2.5%), asexual (0.8%) and other (1.7%). CONCLUSION: As in the general population, sexual identity typically coincides with biological gender. Sexual orientation of adults with SB mirrors the general population. Due to self-selection, these findings likely do not reflect exact prevalence in the SB population. PMID- 29125521 TI - Variation in surgical management of neurogenic bowel among centers participating in National Spina Bifida Patient Registry. AB - PURPOSE: Optimal management of neurogenic bowel in patients with spina bifida (SB) remains controversial. Surgical interventions may be utilized to treat constipation and provide fecal continence, but their use may vary among SB treatment centers. METHODS: We queried the National Spina Bifida Patient Registry (NSBPR) to identify patients who underwent surgical interventions for neurogenic bowel. We abstracted demographic characteristics, SB type, functional level, concurrent bladder surgery, mobility, and NSBPR clinics to determine whether any of these factors were associated with interventions for management of neurogenic bowel. Multivariable logistic regression with adjustment for selection bias was performed. RESULTS: We identified 5,528 patients with SB enrolled in the 2009-14 NSBPR. Of these, 1,088 (19.7%) underwent procedures for neurogenic bowel, including 957 (17.3%) ACE/cecostomy tube and 155 (2.8%) ileostomy/colostomy patients. Procedures were more likely in patients who were older, white, non ambulatory, with higher-level lesion, with myelomeningocele lesion, with private health insurance (all p< 0.001), and female (p= 0.006). On multivariable analysis, NSBPR clinic, older age (both p< 0.001), race (p= 0.002), mobility status (p= 0.011), higher lesion level (p< 0.001), private insurance (p= 0.002) and female sex (p= 0.015) were associated with increased odds of surgery. CONCLUSIONS: There is significant variation in rates of procedures to manage neurogenic bowel among NSBPR clinics. In addition to SB-related factors such as mobility status and lesion type/level, non-SB-related factors such as patient age, sex, race and treating center are also associated with the likelihood of undergoing neurogenic bowel intervention. PMID- 29125523 TI - The National Spina Bifida Patient Registry: Past, present, and future. AB - "The National Spina Bifida Patient Registry: Past, Present, and Future" was presented at the Spina Bifida World Congress, March 17, 2017, San Diego, California. This commentary provides a summary of registry activities including the reason for development, a description of the clinic participants and their patients who are participating, analytic works and publications. Two specific efforts that are related to the work of the registry, a urologic protocol to preserve renal function for newborns and young children, and a skin breakdown prevention bundle developed and implemented in registry clinics, are highlighted. PMID- 29125524 TI - Expectant use of CIC in newborns with spinal dysraphism: Report of clinical outcomes. AB - PURPOSE: Report urologic outcomes among newborns with spinal dysraphism managed within an expectant clean intermittent catheterization (CIC) program. METHODS: Newborns were followed clinically and with serial ultrasound (US). Urodynamics (UD) and dimercaptosuccinic acid (DMSA) renal scan were obtained at 3-6 months, 1 year, 3 years, then as needed. Patients with initial evaluation after 6 months were excluded. RESULTS: Median follow-up was 3.2 years. 11/102 began catheterization for continence (median 4.0 years) and 47/102 did not start CIC. Of these, 2/58 developed a DMSA abnormality. 44/102 began CIC early, often for elevated storage pressures and febrile urinary tract infection (UTI). Of these, 20/44 developed a DMSA abnormality including 9 who had abnormality detected prior to starting CIC. Being on CIC or starting immediately upon recognition of new hydronephrosis, reflux, elevated filling pressures, or febrile UTI was associated with lower chance of DMSA abnormalities (4/17, 24%) compared to delaying CIC (16/27, 60%) (p= 0.03). CONCLUSIONS: CIC can be deferred until continence in select infants with a low risk of significant DMSA abnormality. However, immediate initiation of CIC upon recognition of risk factors is recommended as this was associated with fewer DMSA abnormalities than delaying CIC. Recommendations for expectantly-managed patients include close follow-up, serial US and UD, and prompt initiation of CIC upon recognition of new hydronephrosis, reflux, elevated storage pressures, or febrile UTIs. PMID- 29125525 TI - Early postnatal bladder function in fetoscopic myelomeningocele repair patients. AB - PURPOSE: Prenatal repair of myelomeningocele (MMC) via hysterotomy has demonstrated neurosurgical and motor benefits, when compared to postnatal repairs. Urologic benefits, however, remain to be seen. The purpose of this study was to review early postnatal bladder function in patients undergoing a novel endoscopic approach for MMC repair using an exteriorized uterus. METHODS: A prospective urologic assessment of patients undergoing fetoscopic MMC repair and receiving subsequent care at our facility, was performed. Patients were managed and urodynamic studies risk-stratified according to the Centers for Disease Control and Prevention Urologic and Renal Protocol for the Newborn and Young Child with Spina Bifida. RESULTS: Fetoscopic MMC repair was performed in 14 patients. No patients had hydronephrosis or bladder thickening at birth. Detrusor overactivity was observed in nine (64.3%) patients. Impaired compliance was seen in eight (57.1%) patients. No patients had a detrusor leak point pressure of > 40 cm H2O or evidence of detrusor sphincter dyssynergia. Three (21.4%) patients had vesicoureteral reflux, seven (50.0%) had an open bladder neck, and none had trabeculated bladders. CONCLUSION: In this early experience with fetoscopic MMC repair, postnatal bladder function does not appear to be any worse than that of previously reported prenatal or postnatal closures. PMID- 29125526 TI - Bowel management and continence in adults with spina bifida: Results from the National Spina Bifida Patient Registry 2009-15. AB - INTRODUCTION: Advances in care have allowed most children with spina bifida (SB) to live to adulthood. The majority have neuropathic bowel dysfunction (NBD), resulting in constipation, incontinence, and diminished quality of life. We sought to 1) describe contemporary NBD management and continence outcomes of adults with SB; 2) describe differences from younger patients; and 3) assess for association with socio-economic factors. METHODS: We analyzed data on NBD management and continence from the National Spina Bifida Patient Registry (NSBPR). Patients were segregated into young children (5-11 years), adolescents (12-19 years), and adults (20 years and older). A strict definition of continence was utilized. Statistical analysis compared cohorts by gender, ethnicity, SB type, lesion level, insurance status, educational attainment, employment status, and continence. RESULTS: A total of 5209 SB patients were included, of whom 1370 (26.3%) were adults. Management and continence varied by age and SB type. Oral medication use did not differ between groups (5.2-6.6%). Suppositories and rectal enemas were used only by 11.5% of adults, which was significantly less than among school-aged children. Antegrade enemas were used by 17.7% of adults which was significantly less than among adolescents (27.2%). Adults were more likely to use digital stimulation or disimpaction or have undergone a colostomy. Bowel continence was reported by 58.3% of overall adult cohort: 55.6% of adults with myelomeningocele and 74.9% with non-myelomeningocele. Bowel continence was significantly associated with employment (p= 0.0002), private insurance (p= 0.0098), non-myelomeningocele type of SB (p= 0.0216) and educational attainment (p= 0.0324) on univariate analysis but only with employment on multivariable logistic regression (p= 0.0027). CONCLUSIONS: Bowel management techniques differed between adults and younger patients with SB. Bowel continence was reported by over half of SB adults and was associated with socio-economic factors. PMID- 29125528 TI - A non-invasive glucose level estimation in a multi-sensing health care monitoring system. AB - BACKGROUND AND OBJECTIVE: The treatment and care of patients with chronic diseases depends directly on the evolution of biomedical parameters. It is important to have a monitoring health care system that provides biomedical data at any time and place. Here, a multi-sensing health care monitoring system with a built-in non-invasive blood glucose level estimation method is presented. METHODS: Six biomedical parameters were obtained from 15 participants. Glucose levels were obtained using a computer vision approach. A standard glucose laboratory test was taken as a baseline, and a commercial glucometer as a secondary reference. The remaining parameters were also contrasted with a commercial vital signs monitor. RESULTS: In comparison to standard test, our proposal reported a better performance (RMSE of 9.811) than obtained with the commercial glucometer; the Mann-Whitney test found no significant differences. The remaining biomedical parameters exhibit similar results to the commercial vital signs monitor as validated by a cardiologist. CONCLUSION: The results suggest the proposed approach could be considered highly competitive regarding standard tests and validated with commercial health care monitoring systems. PMID- 29125529 TI - Cross-sectional evaluation of visuomotor tracking performance following subconcussive head impacts. AB - BACKGROUND: Repeated mild traumatic brain injury (mTBI) has been associated with increased risk of degenerative neurological disorders. While the effects of mTBI and repeated injury are known, studies have only recently started examining repeated subconcussive impacts, impacts that do not result in a clinically diagnosed mTBI. In these studies, repeated subconcussive impacts have been connected to cognitive performance and brain imaging changes. OBJECTIVE: Recent research suggests that performance on a visuomotor tracking (VMT) task may help improve the identification of mTBI. The goal of this study was to investigate if VMT performance is sensitive to the cumulative effect of repeated subconcussive head impacts in collegiate men's lacrosse players. METHODS: A cross-sectional, prospective study was completed with eleven collegiate men's lacrosse players. Participants wore helmet-mounted sensors and completed VMT and reaction time assessments. The relationship between cumulative impact metrics and VMT metrics were investigated. RESULTS: In this study, VMT performance correlated with repeated subconcussive head impacts; individuals approached clinically diagnosed mTBI-like performance as the cumulative rotational velocity they experienced increased. CONCLUSION: This suggests that repeated subconcussive impacts can result in measurable impairments and indicates that visuomotor tracking performance may be a useful tool for monitoring the effects of repeated subconcussive impacts. PMID- 29125530 TI - The impact of symptoms of anxiety and depression on subjective and objective outcome measures in individuals with vestibular disorders. AB - BACKGROUND: Anxiety and depression are common in individuals with vestibular disorders and anecdotally symptoms of these disorders have been associated with poorer scores on subjective outcome measures of dizziness and balance. It is unknown if symptoms of psychological distress impact individual outcomes with vestibular rehabilitation therapy (VRT). OBJECTIVE: To compare subjective and objective outcome measures in subjects with vestibular disorders who have symptoms of anxiety and/or depression to those who do not exhibit those symptoms. METHODS: A retrospective chart review was performed at two outpatient vestibular rehabilitation clinics. Data recorded included demographics, scores on the Positive and Negative Affective Scale (PANAS), and subjective and objective outcome measures of balance and gait. RESULTS: The PANAS scale was utilized to group subjects (N = 118) into two groups: Subjects with abnormal affect (SAA) (18.6%; N = 22) and subjects with normal affect (SNA) (81.4%; N = 96). Both groups demonstrated a statistically significant improvement in all outcome measures (p < 0.001) from evaluation to discharge. SAA subjects took longer than SNA subjects to achieve goals (p < 0.05). SAA subjects tended to have poorer outcome measure scores at both initial and final assessment, but this was not statistically significant (p > 0.05). CONCLUSIONS: Results from this study indicate that VRT is effective in treating vestibular disorders in individuals with symptoms of psychological distress such as anxiety and depression. However, individuals with these symptoms may not achieve as high of outcomes as those that do not report symptoms of psychological distress. PMID- 29125531 TI - Posturographic pattern of patients with chronic subjective dizziness before and after vestibular rehabilitation. AB - INTRODUCTION: Chronic subjective dizziness (CSD) is frequently encountered in neurotology clinics. This diagnosis is mainly clinical, but computerized dynamic posturography (CDP) could be a helpful instrumental tool in the identification of these patients and validation of the treatment. This study was aimed to look for a specific posturographic pattern among patients diagnosed with CSD, and to eventually visualize improvement after vestibular rehabilitation. METHODS: Single center, retrospective review from 2009 to 2014. We included patients diagnosed with CSD who underwent CDP in their neurotologic assessment. For those patients who benefited from vestibular rehabilitation, we compared their pre- and post rehabilitation posturographies. RESULTS: We included 114 patients, of whom 74% had known anxiety disorders and 33% a history of past vestibular disorder. 62% of the assessment posturographies were abnormal. The most affected sub-items were limit of stability, composite score of sensory organization tests and condition 5 in respectively 34%, 23% and 20% of the cases. In univariate analysis, only pathologic videonystagmography and history of unilateral vestibular dysfunction were significantly related to abnormal posturography. In the 42 patients who had vestibular rehabilitation and a post rehabilitation posturography, the proportion of abnormal posturography significantly dropped from 79% to 33% (p < 0.001). When it was assessed, 79% of the patients reported a subjective improvement. CONCLUSION: Patients with CSD have a high rate of abnormal posturography, but without a specific pattern. Vestibular rehabilitation is an effective tool in the therapeutic armamentarium. PMID- 29125532 TI - A New Whooping Cough Vaccine That May Prevent Colonization and Transmission. AB - This article is a Letter to the Editor. The major purpose of this Letter is to highlight the development of a new genetically altered whooping cough vaccine. Recently a baboon model has been used to show that this next generation pertussis vaccine can prevent colonization, as well as disease, and elicit antibodies against major pertussis antigens. Two phase I clinical trials have been performed, showing that this new vaccine is safe in humans, and a phase II trial will be performed in the US in 2018. PMID- 29125533 TI - Sequencing and De Novo Assembly of the Toxicodendron radicans (Poison Ivy) Transcriptome. AB - Contact with poison ivy plants is widely dreaded because they produce a natural product called urushiol that is responsible for allergenic contact delayed dermatitis symptoms lasting for weeks. For this reason, the catchphrase most associated with poison ivy is "leaves of three, let it be", which serves the purpose of both identification and an appeal for avoidance. Ironically, despite this notoriety, there is a dearth of specific knowledge about nearly all other aspects of poison ivy physiology and ecology. As a means of gaining a more molecular-oriented understanding of poison ivy physiology and ecology, Next Generation DNA sequencing technology was used to develop poison ivy root and leaf RNA-seq transcriptome resources. De novo assembled transcriptomes were analyzed to generate a core set of high quality expressed transcripts present in poison ivy tissue. The predicted protein sequences were evaluated for similarity to SwissProt homologs and InterProScan domains, as well as assigned both GO terms and KEGG annotations. Over 23,000 simple sequence repeats were identified in the transcriptome, and corresponding oligo nucleotide primer pairs were designed. A pan-transcriptome analysis of existing Anacardiaceae transcriptomes revealed conserved and unique transcripts among these species. PMID- 29125534 TI - Full-Body Locomotion Reconstruction of Virtual Characters Using a Single Inertial Measurement Unit. AB - This paper presents a method of reconstructing full-body locomotion sequences for virtual characters in real-time, using data from a single inertial measurement unit (IMU). This process can be characterized by its difficulty because of the need to reconstruct a high number of degrees of freedom (DOFs) from a very low number of DOFs. To solve such a complex problem, the presented method is divided into several steps. The user's full-body locomotion and the IMU's data are recorded simultaneously. Then, the data is preprocessed in such a way that would be handled more efficiently. By developing a hierarchical multivariate hidden Markov model with reactive interpolation functionality the system learns the structure of the motion sequences. Specifically, the phases of the locomotion sequence are assigned in the higher hierarchical level, and the frame structure of the motion sequences are assigned at the lower hierarchical level. During the runtime of the method, the forward algorithm is used for reconstructing the full body motion of a virtual character. Firstly, the method predicts the phase where the input motion belongs (higher hierarchical level). Secondly, the method predicts the closest trajectories and their progression and interpolates the most probable of them to reconstruct the virtual character's full-body motion (lower hierarchical level). Evaluating the proposed method shows that it works on reasonable framerates and minimizes the reconstruction errors compared with previous approaches. PMID- 29125535 TI - An Intelligent Cooperative Visual Sensor Network for Urban Mobility. AB - Smart cities are demanding solutions for improved traffic efficiency, in order to guarantee optimal access to mobility resources available in urban areas. Intelligent video analytics deployed directly on board embedded sensors offers great opportunities to gather highly informative data about traffic and transport, allowing reconstruction of a real-time neat picture of urban mobility patterns. In this paper, we present a visual sensor network in which each node embeds computer vision logics for analyzing in real time urban traffic. The nodes in the network share their perceptions and build a global and comprehensive interpretation of the analyzed scenes in a cooperative and adaptive fashion. This is possible thanks to an especially designed Internet of Things (IoT) compliant middleware which encompasses in-network event composition as well as full support of Machine-2-Machine (M2M) communication mechanism. The potential of the proposed cooperative visual sensor network is shown with two sample applications in urban mobility connected to the estimation of vehicular flows and parking management. Besides providing detailed results of each key component of the proposed solution, the validity of the approach is demonstrated by extensive field tests that proved the suitability of the system in providing a scalable, adaptable and extensible data collection layer for managing and understanding mobility in smart cities. PMID- 29125536 TI - Are Some of the Cigar Warnings Mandated in the U.S. More Believable Than Others? AB - Background: Text warnings are mandated on cigars sold in the United States (U.S.), however little published research has examined effectiveness of cigar warnings. This is the first study examining the believability of cigar warnings among adults in the U.S. Methods: Adults in the U.S. (n = 5014) were randomized in a phone survey to receive one of three cigar-specific mandated warning messages ("Cigar smoking can cause cancers of the mouth and throat, even if you do not inhale", "Cigar smoking can cause lung cancer and heart disease", and "Cigars are not a safe alternative to cigarettes") with one of four warning sources (no source, Surgeon General, CDC (Centers for Disease Control and Prevention), FDA (Food and Drug Administration)). Results: Most adults found the cigar warnings very believable (66.9%). Weighted logistic regression results indicate that the message "Cigar smoking can cause lung cancer and heart disease" was associated with higher odds of being very believable (AOR: 2.05, 95% CI: 1.55, 2.70) and the message "Cigars are not a safe alternative to cigarettes" was associated with lower odds of being very believable (AOR: 0.71, 95% CI: 0.55, 0.92) compared to the message "Cigar smoking can cause cancers of the mouth and throat, even if you do not inhale". Warning source had no impact on believability. Conclusions: We tested three of the currently mandated cigar warnings in the U.S. and found significant differences in believability between them. Further research on cigar warnings may improve communication to the public on cigar health risks, ultimately preventing uptake of cigars and promoting cessation among cigar users. PMID- 29125537 TI - Associations of Fasting Blood Glucose with Influencing Factors in Northeast China: A Quantile Regression Analysis. AB - Background: Diabetes mellitus (DM) has become a major public health problem in China. Although a number of researchers have investigated DM risk factors, little is known about the associations between values of fasting blood glucose (FBG) and influencing factors. This study aims to explore these associations by the quantile regression (QR) model. Methods: A cross-sectional survey based on a sample of 23,050 adults aged 18 to 79 years was conducted in Jilin in 2012, and some subjects were excluded due to missing values with respect to necessary variables or having glycemic control, in accordance with the purposes of this study. Finally, in total 14,698 people were included in this study. QR was performed to identify the factors influencing the level of FBG in different quantiles of FBG. Results: The distribution of FBG status was different between males and females (chi2 = 175.30, p < 0.001). The QR model provided more detailed views on the associations of FBG with different factors and revealed apparent quantile-related patterns separately for different factors. Body mass index (BMI) was positively associated with the low and middle quantiles of FBG. Waist circumference (WC) had a positive association with the high quantiles of FBG. Conclusions: FBG had a positive association with BMI in normal FBG, and a positive association with WC in high FBG. Diet and alcohol intake were associated with FBG in normal FBG. FBG was more likely to be elevated in the elderly, female workers, and people with family history of DM. PMID- 29125538 TI - Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction. AB - Cigarette smoke has been shown to trigger aberrant signaling pathways and pathophysiological processes; however, the regulatory mechanisms underlying smoke induced gene expression remain to be established. Herein, we observed that two smoke-responsive genes, HO-1 and CYP1A1, are robustly induced upon smoke by different mechanisms in human bronchial epithelia. CYP1A1 is mediated by aryl hydrocarbon receptor signaling, while induction of HO-1 is regulated by oxidative stress, and suppressed by N-acetylcysteine treatment. In light of a pivotal role of NRF2 and BACH1 in response to oxidative stress and regulation of HO-1, we examined if smoke-induced HO-1 expression is modulated through the NRF2/BACH1 axis. We demonstrated that smoke causes significant nuclear translocation of NRF2, but only a slight decrease in nuclear BACH1. Knockdown of NRF2 attenuated smoke-induced HO-1 expression while down-regulation of BACH1 had stimulatory effects on both basal and smoke-induced HO-1 with trivial influence on NRF2 nuclear translocation. Chromatin immunoprecipitation assays showed that smoke augments promoter-specific DNA binding of NRF2 but suppresses BACH1 binding to the HO-1 promoter ARE sites, two of which at -1.0 kb and -2.6 kb are newly identified. These results suggest that the regulation of NRF2 activator and BACH1 repressor binding to the ARE sites are critical for smoke-mediated HO-1 induction. PMID- 29125539 TI - Combined Proteomics/Genomics Approach Reveals Proteomic Changes of Mature Virions as a Novel Poxvirus Adaptation Mechanism. AB - DNA viruses, like poxviruses, possess a highly stable genome, suggesting that adaptation of virus particles to specific cell types is not restricted to genomic changes. Cowpox viruses are zoonotic poxviruses with an extraordinarily broad host range, demonstrating their adaptive potential in vivo. To elucidate adaptation mechanisms of poxviruses, we isolated cowpox virus particles from a rat and passaged them five times in a human and a rat cell line. Subsequently, we analyzed the proteome and genome of the non-passaged virions and each passage. While the overall viral genome sequence was stable during passaging, proteomics revealed multiple changes in the virion composition. Interestingly, an increased viral fitness in human cells was observed in the presence of increased immunomodulatory protein amounts. As the only minor variant with increasing frequency during passaging was located in a viral RNA polymerase subunit and, moreover, most minor variants were found in transcription-associated genes, protein amounts were presumably regulated at transcription level. This study is the first comparative proteome analysis of virus particles before and after cell culture propagation, revealing proteomic changes as a novel poxvirus adaptation mechanism. PMID- 29125540 TI - Is High Folic Acid Intake a Risk Factor for Autism?-A Review. AB - Folate is required for metabolic processes and neural development. Insuring its adequate levels for pregnant women through supplementation of grain-based foods with synthetic folic acid (FA) in order to prevent neural tube defects has been an ongoing public health initiative. However, because women are advised to take multivitamins containing FA before and throughout pregnancy, the supplementation together with natural dietary folates has led to a demographic with high and rising serum levels of unmetabolized FA. This raises concerns about the detrimental effects of high serum synthetic FA, including a rise in risk for autism spectrum disorder (ASD). Some recent studies have reported a protective effect of FA fortification against ASD, but others have concluded there is an increased risk for ASD and other negative neurocognitive development outcomes. These issues are accompanied by further health questions concerning high, unmetabolized FA levels in serum. In this review, we outline the reasons excess FA supplementation is a concern and review the history and effects of supplementation. We then examine the effects of FA on neuronal development from tissue culture experiments, review recent advances in understanding of metabolic functional blocks in causing ASD and treatment for these with alternative forms such as folinic acid, and finally summarize the conflicting epidemiological findings regarding ASD. Based on the evidence evaluated, we conclude that caution regarding over supplementing is warranted. PMID- 29125542 TI - Slowly Digestible Carbohydrate for Balanced Energy: In Vitro and In Vivo Evidence. AB - There is growing interest among consumers in foods for sustained energy management, and an increasing number of ingredients are emerging to address this demand. The SUSTRATM 2434 slowly digestible carbohydrate is a blend of tapioca flour and corn starch, with the potential to provide balanced energy after a meal. The aim of the study was to characterize this starch's digestion profile in vitro (modified Englyst assay) and in vivo (intact and cecectomized rooster study), and to determine its effects on available energy, by measuring post prandial glycemia in healthy adults (n = 14), in a randomized, double-blind, placebo-controlled, cross-over study, with two food forms: cold-pressed bar and pudding. The in vitro starch digestion yielded a high slowly digestible fraction (51%) compared to maltodextrin (9%). In the rooster digestibility model, the starch was highly digestible (94%). Consumption of slowly digestible starch (SDS), in an instant pudding or bar, yielded a significantly lower glycemic index compared to a control. At individual time points, the SDS bar and pudding yielded blood glucose levels with significantly lower values at 30-60 min and significantly higher values at 120-240 min, demonstrating a balanced energy release. This is the first study to comprehensively characterize the physiological responses to slowly digestible starch (tapioca and corn blend) in in vitro and in vivo studies. PMID- 29125541 TI - The Dark Side of the Epitranscriptome: Chemical Modifications in Long Non-Coding RNAs. AB - The broad application of next-generation sequencing technologies in conjunction with improved bioinformatics has helped to illuminate the complexity of the transcriptome, both in terms of quantity and variety. In humans, 70-90% of the genome is transcribed, but only ~2% carries the blueprint for proteins. Hence, there is a huge class of non-translated transcripts, called long non-coding RNAs (lncRNAs), which have received much attention in the past decade. Several studies have shown that lncRNAs are involved in a plethora of cellular signaling pathways and actively regulate gene expression via a broad selection of molecular mechanisms. Only recently, sequencing-based, transcriptome-wide studies have characterized different types of post-transcriptional chemical modifications of RNAs. These modifications have been shown to affect the fate of RNA and further expand the variety of the transcriptome. However, our understanding of their biological function, especially in the context of lncRNAs, is still in its infancy. In this review, we will focus on three epitranscriptomic marks, namely pseudouridine (Psi), N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We will introduce writers, readers, and erasers of these modifications, and we will present methods for their detection. Finally, we will provide insights into the distribution and function of these chemical modifications in selected, cancer related lncRNAs. PMID- 29125543 TI - A Mediated BOD Biosensor Based on Immobilized B. Subtilis on Three-Dimensional Porous Graphene-Polypyrrole Composite. AB - We have developed a novel mediated biochemical oxygen demand (BOD) biosensor based on immobilized Bacillus subtilis (B. subtilis) on three-dimensional (3D) porous graphene-polypyrrole (rGO-PPy) composite. The 3D porous rGO-PPy composite was prepared using hydrothermal method following with electropolymerization. Then the 3D porous rGO-PPy composite was used as a support for immobilizing negatively charged B. subtilis denoted as rGO-PPy-B through coordination and electrostatic interaction. Further, the prepared rGO-PPy-B was used as a microbial biofilm for establishing a mediated BOD biosensor with ferricyanide as an electronic acceptor. The indirect determination of BOD was performed by electrochemical measuring ferrocyanide generated from a reduced ferricyanide mediator using interdigited ultramicroelectrode array (IUDA) as the working electrode. The experimental results suggested a good linear relationship between the amperometric responses and BOD standard concentrations from 4 to 60 mg/L, with a limit detection of 1.8 mg/L (S/N >= 3). The electrochemical measurement of real water samples showed a good agreement with the conventional BOD5 method, and the good anti-interference as well as the long-term stability were well demonstrated, indicating that the proposed mediated BOD biosensor in this study holds a potential practical application of real water monitoring. PMID- 29125544 TI - Towards Optical Partial Discharge Detection with Micro Silicon Photomultipliers. AB - Optical detection is reliable in intrinsically characterizing partial discharges (PDs). Because of the great volume and high-level power supply of the optical devices that can satisfy the requirements in photosensitivity, optical PD detection can merely be used in laboratory studies. To promote the practical application of the optical approach in an actual power apparatus, a silicon photomultiplier (SiPM)-based PD sensor is introduced in this paper, and its basic properties, which include the sensitivity, pulse resolution, correlation with PD severity, and electromagnetic (EM) interference immunity, are experimentally evaluated. The stochastic phase-resolved PD pattern (PRPD) for three typical insulation defects are obtained by SiPM PD detector and are compared with those obtained using a high-frequency current transformer (HFCT) and a vacuum photomultiplier tube (PMT). Because of its good performances in the above aspects and its additional advantages, such as the small size, low power supply, and low cost, SiPM offers great potential in practical optical PD monitoring. PMID- 29125545 TI - Infection of a French Population of Aedes albopictus and of Aedes aegypti (Paea Strain) with Zika Virus Reveals Low Transmission Rates to These Vectors' Saliva. AB - Disease caused by the Zika virus (ZIKV) is a public health emergency of international concern. Recent epidemics have emerged in different regions of the world and attest to the ability of the virus to spread wherever its vector, Aedes species mosquitoes, can be found. We have compared the transmission of ZIKV by Ae. aegypti (PAEA strain originating from Tahiti) and by a French population of Ae. albopictus to better assess their competence and the potential risk of the emergence of ZIKV in Europe. We assessed the transmission of ZIKV by Ae. albopictus in temperatures similar to those in Southern France during the summer. Our study shows that the extrinsic incubation period of Ae. aegypti for transmission was shorter than that of Ae. albopictus. Both vectors were able to transmit ZIKV from 10 to 14 days post-infection. Ae. aegypti, however, had a longer transmission period than the French population of Ae. albopictus. Although the salivary glands of both vectors are highly infected, transmission rates of ZIKV to saliva remain relatively low. These observations may suggest that the risk of emergence of ZIKV in Europe could be low. PMID- 29125547 TI - Salt-Assisted Ultrasonicated De-Aggregation and Advanced Redox Electrochemistry of Detonation Nanodiamond. AB - Nanodiamond particles form agglomerates in the dry powder state and this poses limitation to the accessibility of their diamond-like core thus dramatically impacting their technological advancement. In this work, we report de agglomeration of nanodiamond (ND) by using a facile technique namely, salt assisted ultrasonic de-agglomeration (SAUD). Utilizing ultrasound energy and ionic salts (sodium chloride and sodium acetate), SAUD is expected to break apart thermally treated nanodiamond aggregates (~50-100 nm) and produce an aqueous slurry of de-aggregated stable colloidal nanodiamond dispersions by virtue of ionic interactions and electrostatic stabilization. Moreover, the SAUD technique neither has toxic chemicals nor is it difficult to remove impurities and therefore the isolated nanodiamonds produced are exceptionally suited for engineered nanocarbon for mechanical (composites, lubricants) and biomedical (bio labeling, biosensing, bioimaging, theranostic) applications. We characterized the microscopic structure using complementary techniques including transmission electron microscopy combined with selected-area electron diffraction, optical and vibrational spectroscopy. We immobilized SAUD produced NDs on boron-doped diamond electrodes to investigate fundamental electrochemical properties. They included surface potential (or Fermi energy level), carrier density and mapping electrochemical (re)activity using advanced scanning electrochemical microscopy in the presence of a redox-active probe, with the aim of understanding the surface redox chemistry and the interfacial process of isolated nanodiamond particles as opposed to aggregated and untreated nanoparticles. The experimental findings are discussed in terms of stable colloids, quantum confinement and predominantly surface effects, defect sites (sp2-bonded C and unsaturated bonds), inner core (sp3-bonded C)/outer shell (sp2-bonded C) structure, and surface functionality. Moreover, the surface electronic states give rise to midgap states which serve as electron donors (or acceptors) depending upon the bonding (or antibonding). These are important as electroanalytical platforms for various electrocatalytic processes. PMID- 29125548 TI - Liquid Biopsy and Therapeutic Targets: Present and Future Issues in Thoracic Oncology. AB - The practice of liquid biopsy (LB) has revolutionized the care of patients with metastatic lung cancer. Many oncologists now use this approach in daily practice, applying precise procedures for the detection of activating or resistance mutations in EGFR. These tests are performed with plasma DNA and have been approved as companion diagnostic test for patients treated with tyrosine kinase inhibitors. ALK is another important target in lung cancer since it leads to treatment of patients who are positive for a rearrangement in ALK identified with tumor tissue. By analogy with EGFR, LB for detection of genomic alterations in ALK (rearrangements or mutations) has been rapidly adopted in the clinic. However, this promising approach has some limitations and has not yet been disseminated as much as the blood test targeting EGFR. In addition to these two therapeutic targets LB can be used for evaluation of the genomic status of other genes of interest of patients with lung cancer (ROS1, RET, NTRK MET, BRAF, HER2, etc.). LB can be performed to evaluate a specific target or for a more or less complex panel of genes. Considering the number of potential targets for clinical trials, techniques of next-generation sequencing of circulating DNA are on the rise. This review will provide an update on the contribution of LB to care of patients with metastatic lung cancer, including the present limits of this approach, and will consider certain perspectives. PMID- 29125546 TI - Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update. AB - Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression. PMID- 29125550 TI - A New Maraging Stainless Steel with Excellent Strength-Toughness-Corrosion Synergy. AB - A new maraging stainless steel with superior strength-toughness-corrosion synergy has been developed based on an innovative concept of alloy design. The high strength-toughness combination is achieved by forming dispersive nano-sized intermetallic compounds in the soft lath martensitic matrix with a slight amount of residual austenite. The good corrosion resistance is guaranteed by exactly controlling the Co content based on understanding the synergistic effect between Co and Cr. The fine structure characteristics of two dominant strengthening precipitations including Ni3Ti and Mo-rich phases were finely characterized associated with transmission electron microscope (TEM) and atom probe tomography (APT) analyses. The relationship among microstructure, strength and toughness is discussed. The precipitation mechanism of different precipitates in the new maraging stainless steel is revealed based on the APT analysis. PMID- 29125549 TI - KLF2 in Regulation of NF-kappaB-Mediated Immune Cell Function and Inflammation. AB - KLF2 (Kruppel-like factor 2) is a member of the zinc finger transcription factor family, which critically regulates embryonic lung development, function of endothelial cells and maintenance of quiescence in T-cells and monocytes. It is expressed in naive T-cells and monocytes, however its level of expression decreases during activation and differentiation. KLF2 also plays critical regulatory role in various inflammatory diseases and their pathogenesis. Nuclear factor-kappaB (NF-kappaB) is an important inducer of inflammation and the inflammation is mediated through the transcription of several proinflammatory cytokines, chemokines and adhesion molecules. So, both transcriptional factors KLF2 and NF-kappaB are being associated with the similar cellular functions and their maintenance. It was shown that KLF2 regulates most of the NF-kappaB mediated activities. In this review, we focused on emphasizing the involvement of KLF2 in health and disease states and how they interact with transcriptional master regulator NF-kappaB. PMID- 29125551 TI - Assembly Modulated by Particle Position and Shape: A New Concept in Self Assembly. AB - In this communication we outline how the bespoke arrangements and design of micron-sized superparamagnetic shapes provide levers to modulate their assembly under homogeneous magnetic fields. We label this new approach, 'assembly modulated by particle position and shape' (APPS). Specifically, using rectangular lattices of superparamagnetic micron-sized cuboids, we construct distinct microstructures by adjusting lattice pitch and angle of array with respect to a magnetic field. Broadly, we find two modes of assembly: (1) immediate 2D jamming of the cuboids as they rotate to align with the applied field (rotation-induced jamming) and (2) aggregation via translation after their full alignment (dipole dipole assembly). The boundary between these two assembly pathways is independent on field strength being solely a function of the cuboid's dimensions, lattice pitch, and array angle with respect to field-a relationship which we capture, along with other features of the assembly process, in a 'phase diagram'. In doing so, we set out initial design rules to build custom made assemblies. Moreover, these assemblies can be made flexible thanks to the hinged contacts of their particle building blocks. This flexibility, combined with the superparamagnetic nature of the architectures, renders our assembly method particularly appropriate for the construction of complex actuators at a scale hitherto not possible. PMID- 29125553 TI - Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors. AB - The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A2A, and lately the A1 ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A1AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8 Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A2AAR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A2BAR, and the use of FEP as a tool for bioisosteric design on the A3AR. PMID- 29125552 TI - Transmission of Bacterial Endophytes. AB - Plants are hosts to complex communities of endophytic bacteria that colonize the interior of both below- and aboveground tissues. Bacteria living inside plant tissues as endophytes can be horizontally acquired from the environment with each new generation, or vertically transmitted from generation to generation via seed. A better understanding of bacterial endophyte transmission routes and modes will benefit studies of plant-endophyte interactions in both agricultural and natural ecosystems. In this review, we provide an overview of the transmission routes that bacteria can take to colonize plants, including vertically via seeds and pollen, and horizontally via soil, atmosphere, and insects. We discuss both well documented and understudied transmission routes, and identify gaps in our knowledge on how bacteria reach the inside of plants. Where little knowledge is available on endophytes, we draw from studies on bacterial plant pathogens to discuss potential transmission routes. Colonization of roots from soil is the best studied transmission route, and probably the most important, although more studies of transmission to aerial parts and stomatal colonization are needed, as are studies that conclusively confirm vertical transfer. While vertical transfer of bacterial endophytes likely occurs, obligate and strictly vertically transferred symbioses with bacteria are probably unusual in plants. Instead, plants appear to benefit from the ability to respond to a changing environment by acquiring its endophytic microbiome anew with each generation, and over the lifetime of individuals. PMID- 29125556 TI - Integration of GIS, Electromagnetic and Electrical Methods in the Delimitation of Groundwater Polluted by Effluent Discharge (Salamanca, Spain): A Case Study. AB - The present work envisages the possible geometry of a contaminated plume of groundwater near hospital facilities by combining GIS (Geographic Information System) and geophysical methods. The rock underlying the soil and thin sedimentary cover of the study area is moderately fractured quartzite, which makes aquifers vulnerable to pollution. The GIS methodology is used to calculate the area that would be affected by the effluent source of residual water, based on algorithms that consider ground surface mapping (slopes, orientations, accumulated costs and cost per distance). Geophysical methods (electromagnetic induction and electric resistivity tomography) use changes in the electrical conductivity or resistivity of the subsurface to determine the geometry of the discharge and the degree of contamination. The model presented would allow a preliminary investigation regarding potential corrective measures. PMID- 29125555 TI - Work Stress and Altered Biomarkers: A Synthesis of Findings Based on the Effort Reward Imbalance Model. AB - While epidemiological studies provide statistical evidence on associations of exposures such as stressful work with elevated risks of stress-related disorders (e.g., coronary heart disease or depression), additional information on biological pathways and biomarkers underlying these associations is required. In this contribution, we summarize the current state of the art on research findings linking stressful work, in terms of an established theoretical model-effort reward imbalance-with a broad range of biomarkers. Based on structured electronic literature search and recent available systematic reviews, our synthesis of findings indicates that associations of work stress with heart rate variability, altered blood lipids, and risk of metabolic syndrome are rather consistent and robust. Significant relationships with blood pressure, heart rate, altered immune function and inflammation, cortisol release, and haemostatic biomarkers were also observed, but due to conflicting findings additional data will be needed to reach a firm conclusion. This narrative review of empirical evidence supports the argument that the biomarkers under study can act as mediators of epidemiologically established associations of work stress, as measured by effort reward imbalance, with incident stress-related disorders. PMID- 29125554 TI - Antibody Competition Reveals Surface Location of HPV L2 Minor Capsid Protein Residues 17-36. AB - The currently available nonavalent human papillomavirus (HPV) vaccine exploits the highly antigenic L1 major capsid protein to promote high-titer neutralizing antibodies, but is limited to the HPV types included in the vaccine since the responses are highly type-specific. The limited cross-protection offered by the L1 virus-like particle (VLP) vaccine warrants further investigation into cross protective L2 epitopes. The L2 proteins are yet to be fully characterized as to their precise placement in the virion. Adding to the difficulties in localizing L2, studies have suggested that L2 epitopes are not well exposed on the surface of the mature capsid prior to cellular engagement. Using a series of competition assays between previously mapped anti-L1 monoclonal antibodies (mAbs) (H16.V5, H16.U4 and H16.7E) and novel anti-L2 mAbs, we probed the capsid surface for the location of an L2 epitope (aa17-36). The previously characterized L1 epitopes together with our competition data is consistent with a proposed L2 epitope within the canyons of pentavalent capsomers. PMID- 29125557 TI - Early Response Monitoring Following Radiation Therapy by Using [18F]FDG and [11C]Acetate PET in Prostate Cancer Xenograft Model with Metabolomics Corroboration. AB - We aim to characterize the metabolic changes associated with early response to radiation therapy in a prostate cancer mouse model by 2-deoxy-2-[18F]fluoro-d glucose ([18F]FDG) and [11C]acetate ([11C]ACT) positron emission tomography, with nuclear magnetic resonance (NMR) metabolomics corroboration. [18F]FDG and [11C]ACT PET were performed before and following irradiation (RT, 15Gy) for transgenic adenocarcinoma of mouse prostate xenografts. The underlying metabolomics alterations of tumor tissues were analyzed by using ex vivo NMR. The [18F]FDG total lesion glucose (TLG) of the tumor significant increased in the RT group at Days 1 and 3 post-irradiation, compared with the non-RT group (p < 0.05). The [11C]ACT maximum standard uptake value (SUVmax) in RT (0.83 +/- 0.02) and non-RT groups (0.85 +/- 0.07) were not significantly different (p > 0.05). The ex vivo NMR analysis showed a 1.70-fold increase in glucose and a 1.2-fold increase in acetate in the RT group at Day 3 post-irradiation (p < 0.05). Concordantly, the expressions of cytoplasmic acetyl-CoA synthetase in the irradiated tumors was overexpressed at Day 3 post-irradiation (p < 0.05). Therefore, TLG of [18F]FDG in vivo PET images can map early treatment response following irradiation and be a promising prognostic indicator in a longitudinal preclinical study. The underlying metabolic alterations was not reflected by the [11C]ACT PET. PMID- 29125558 TI - The Impact of a Multi-Level Multi-Component Childhood Obesity Prevention Intervention on Healthy Food Availability, Sales, and Purchasing in a Low-Income Urban Area. AB - The multifactorial causes of obesity require multilevel and multicomponent solutions, but such combined strategies have not been tested to improve the community food environment. We evaluated the impact of a multilevel (operating at different levels of the food environment) multicomponent (interventions occurring at the same level) community intervention. The B'more Healthy Communities for Kids (BHCK) intervention worked at the wholesaler (n = 3), corner store (n = 50), carryout (n = 30), recreation center (n = 28), household (n = 365) levels to improve availability, purchasing, and consumption of healthier foods and beverages (low-sugar, low-fat) in low-income food desert predominantly African American zones in the city of Baltimore (MD, USA), ultimately intending to lead to decreased weight gain in children (not reported in this manuscript). For this paper, we focus on more proximal impacts on the food environment, and measure change in stocking, sales and purchase of promoted foods at the different levels of the food system in 14 intervention neighborhoods, as compared to 14 comparison neighborhoods. Sales of promoted products increased in wholesalers. Stocking of these products improved in corner stores, but not in carryouts, and we did not find any change in total sales. Children more exposed to the intervention increased their frequency of purchase of promoted products, although improvement was not seen for adult caregivers. A multilevel food environment intervention in a low-income urban setting improved aspects of the food system, leading to increased healthy food purchasing behavior in children. PMID- 29125560 TI - Human Actions Analysis: Templates Generation, Matching and Visualization Applied to Motion Capture of Highly-Skilled Karate Athletes. AB - The aim of this paper is to propose and evaluate the novel method of template generation, matching, comparing and visualization applied to motion capture (kinematic) analysis. To evaluate our approach, we have used motion capture recordings (MoCap) of two highly-skilled black belt karate athletes consisting of 560 recordings of various karate techniques acquired with wearable sensors. We have evaluated the quality of generated templates; we have validated the matching algorithm that calculates similarities and differences between various MoCap data; and we have examined visualizations of important differences and similarities between MoCap data. We have concluded that our algorithms works the best when we are dealing with relatively short (2-4 s) actions that might be averaged and aligned with the dynamic time warping framework. In practice, the methodology is designed to optimize the performance of some full body techniques performed in various sport disciplines, for example combat sports and martial arts. We can also use this approach to generate templates or to compare the correct performance of techniques between various top sportsmen in order to generate a knowledge base of reference MoCap videos. The motion template generated by our method can be used for action recognition purposes. We have used the DTW classifier with angle-based features to classify various karate kicks. We have performed leave-one-out action recognition for the Shorin-ryu and Oyama karate master separately. In this case, 100 % actions were correctly classified. In another experiment, we used templates generated from Oyama master recordings to classify Shorin-ryu master recordings and vice versa. In this experiment, the overall recognition rate was 94.2 % , which is a very good result for this type of complex action. PMID- 29125559 TI - Endotoxin-Induced Inflammation Suppresses the Effect of Melatonin on the Release of LH from the Ovine Pars Tuberalis Explants-Ex Vivo Study. AB - The secretion of the hormone melatonin reliably reflects environmental light conditions. Among numerous actions, in seasonal breeders, melatonin may regulate the secretion of the gonadotropins acting via its corresponding receptors occurring in the Pars Tuberalis (PT). However, it was previously found that the secretory activity of the pituitary may be dependent on the immune status of the animal. Therefore, this study was designed to determine the role of melatonin in the modulation of luteinizing hormone (LH) secretion from the PT explants collected from saline- and endotoxin-treated ewes in the follicular phase of the oestrous cycle. Twelve Blackhead ewes were sacrificed 3 h after injection with lipopolysaccharide (LPS; 400 ng/kg) or saline, and the PTs were collected. Each PT was cut into 4 explants, which were then divided into 4 groups: I, incubated with 'pure' medium 199; II, treated with gonadotropin-releasing hormone (GnRH) (100 pg/mL); III, treated with melatonin (10 nmol/mL); and IV, incubated with GnRH and melatonin. Melatonin reduced (p < 0.05) GnRH-induced secretion of LH only in the PT from saline-treated ewes. Explants collected from LPS-treated ewes were characterized by lower (p < 0.05) GnRH-dependent response in LH release. It was also found that inflammation reduced the gene expression of the GnRH receptor and the MT1 melatonin receptors in the PT. Therefore, it was shown that inflammation affects the melatonin action on LH secretion from the PT, which may be one of the mechanisms via which immune/inflammatory challenges disturb reproduction processes in animals. PMID- 29125561 TI - Dimethyl Sulfoxide (DMSO) Decreases Cell Proliferation and TNF-alpha, IFN-gamma, and IL-2 Cytokines Production in Cultures of Peripheral Blood Lymphocytes. AB - Dimethylsulfoxide (DMSO) is an amphipathic molecule composed of a polar domain characterized by the sulfinyl and two nonpolar methyl groups, for this reason it is able to solubilize polar and nonpolar substances and transpose hydrophobic barriers. DMSO is widely used to solubilize drugs of therapeutic applications and studies indicated that 10% v/v concentration did not modify culture viability when used to treat human peripheral blood mononuclear cells (PBMC). However, some DMSO concentrations could influence lymphocyte activation and present anti inflammatory effects. Therefore, the objective of this study was to evaluate the effect of DMSO on lymphocyte activation parameters. Cell viability analysis, proliferation, and cytokine production were performed on PBMC from six healthy subjects by flow cytometry. The results indicated that 2.5% v/v DMSO concentrations did not modify lymphocytes viability. DMSO at 1% and 2% v/v concentrations reduced the relative proliferation index of lymphocytes and at 5% and 10% v/v concentrations reduced the percentage of total lymphocytes, cluster of differentiation 4+ (CD4+) T lymphocytes and CD8+ T lymphocytes interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL 2) producers. Thus, it was concluded that DMSO has an in vitro anti-inflammatory effect by reducing lymphocyte activation demonstrated with proliferation reduction and the decrease of cytokine production. PMID- 29125562 TI - A New Nortriterpenoid, a Sesquiterpene and Hepatoprotective Lignans Isolated from the Fruit of Schisandra chinensis. AB - A new nortriterpenoid, 19(R)-hydroxyl-wuweizidilactone H (1), and a sesquiterpene, (6R)-beta-chamigrenic acid (2), together with one known nortriterpenoid, wuweizidilactone H (3), and three known hepatoprotective lignans, micrantherin A (4), gomisin M2 (5) and schizandrin (6) were isolated from the fruit of Schisandra chinensis. Their structures were elucidated by UV, IR, HRESIMS, NMR spectra and X-ray analysis. Among them, the absolute configuration of 2 was confirmed for the first time. In vitro assays, compounds 4 6 (10 MUM) exhibited hepatoprotective activities (survival rate: 44%, 43% and 44%) against damage induced by N-acetyl-p-aminophenol (APAP) in human liver carcinoma (HepG2) cells. PMID- 29125563 TI - Effects of Resveratrol against Lung Cancer: In Vitro and In Vivo Studies. AB - Uncontrolled cell growth and resistance to apoptosis characterize cancer cells. These two main features are initiated in cancer cells through mutations in key signaling molecules, which regulate pathways that are directly involved in controlling cell proliferation and apoptosis. Resveratrol (RSV), a naturally occurring plant polyphenol, has been shown to have biological effects counteracting different diseases. It has been found to provide cardio-protective, neuro-protective, immuno-modulatory, and anti-cancer health benefits. RSV has been found to inhibit cancer cell proliferation, induce cell cycle arrest and apoptosis, and these anticancer effects may be due to its ability to modulate signaling molecules involved in these processes. The present review summarizes the existing in vitro and in vivo studies on resveratrol and its anti-lung cancer properties. PMID- 29125564 TI - Carbon-Based Nanomaterials in Biomass-Based Fuel-Fed Fuel Cells. AB - Environmental and sustainable economical concerns are generating a growing interest in biofuels predominantly produced from biomass. It would be ideal if an energy conversion device could directly extract energy from a sustainable energy resource such as biomass. Unfortunately, up to now, such a direct conversion device produces insufficient power to meet the demand of practical applications. To realize the future of biofuel-fed fuel cells as a green energy conversion device, efforts have been devoted to the development of carbon-based nanomaterials with tunable electronic and surface characteristics to act as efficient metal-free electrocatalysts and/or as supporting matrix for metal-based electrocatalysts. We present here a mini review on the recent advances in carbon based catalysts for each type of biofuel-fed/biofuel cells that directly/indirectly extract energy from biomass resources, and discuss the challenges and perspectives in this developing field. PMID- 29125565 TI - A Pneumatic Tactile Sensor for Co-Operative Robots. AB - Tactile sensors of comprehensive functions are urgently needed for the advanced robot to co-exist and co-operate with human beings. Pneumatic tactile sensors based on air bladder possess some noticeable advantages for human-robot interaction application. In this paper, we construct a pneumatic tactile sensor and apply it on the fingertip of robot hand to realize the sensing of force, vibration and slippage via the change of the pressure of the air bladder, and we utilize the sensor to perceive the object's features such as softness and roughness. The pneumatic tactile sensor has good linearity, repeatability and low hysteresis and both its size and sensing range can be customized by using different material as well as different thicknesses of the air bladder. It is also simple and cheap to fabricate. Therefore, the pneumatic tactile sensor is suitable for the application of co-operative robots and can be widely utilized to improve the performance of service robots. We can apply it to the fingertip of the robot to endow the robotic hand with the ability to co-operate with humans and handle the fragile objects because of the inherent compliance of the air bladder. PMID- 29125566 TI - Botulinum Toxin in Management of Limb Tremor. AB - Essential tremor is characterized by persistent, usually bilateral and symmetric, postural or kinetic activation of agonist and antagonist muscles involving either the distal or proximal upper extremity. Quality of life is often affected and one's ability to perform daily tasks becomes impaired. Oral therapies, including propranolol and primidone, can be effective in the management of essential tremor, although adverse effects can limit their use and about 50% of individuals lack response to oral pharmacotherapy. Locally administered botulinum toxin injection has become increasingly useful in the management of essential tremor. Targeting of select muscles with botulinum toxin is an area of active research, and muscle selection has important implications for toxin dosing and functional outcomes. The use of anatomical landmarks with palpation, EMG guidance, electrical stimulation, and ultrasound has been studied as a technique for muscle localization in toxin injection. Earlier studies implemented a standard protocol for the injection of (predominantly) wrist flexors and extensors using palpation and EMG guidance. Targeting of muscles by selection of specific activators of tremor (tailored to each patient) using kinematic analysis might allow for improvement in efficacy, including functional outcomes. It is this individualized muscle selection and toxin dosing (requiring injection within various sites of a single muscle) that has allowed for success in the management of tremors. PMID- 29125567 TI - Data Retention Characterization of Gate-Injected Gold-Nanoparticle Non-Volatile Memory with Low-Damage CF4-Plasma-Treated Blocking Oxide Layer. AB - Gold-nanoparticle (Au-NP) non-volatile memories (NVMs) with low-damage CF4 plasma treatment on the blocking oxide (BO) layer have been investigated to present the gate injection of the holes. These holes, injected from the Al gate with the positive gate bias, were explained by the bandgap engineering of the gradually fluorinated BO layer and the effective work function modulation of the Al gate. The Si-F complex in the BO layer was analyzed by X-ray photoelectron spectroscopy (XPS), while the depth of fluorine incorporation was verified using a secondary ion mass spectrometer (SIMS). In addition, the valence band modification of the fluorinated BO layer was examined by ultraviolet photoelectron spectroscopy (UPS) to support the bandgap engineering. The reactive power of the CF4 plasma treatment on the BO layer was modified to increase the electric field of the BO layer and raise the effective work function of the Al gate, leading to the hole injection from the gate. The injected holes are trapped at the interface between the gold-nanoparticles (Au-NPs) and the tunneling oxide (TO) layer, resulting in superior data retention properties such as an extremely low charge loss of 5.7% at 104 s and a nearly negligible increase in charge loss at 85 degrees C of the CF4-plasma-treated Au-NP NVMs, which can be applied in highly reliable consumer electronics. PMID- 29125568 TI - Chemical Composition of Herbal Macerates and Corresponding Commercial Essential Oils and Their Effect on Bacteria Escherichia coli. AB - This study addresses the chemical composition of some commercial essential oils (clove, juniper, oregano, and marjoram oils), as well as appropriate herbal extracts obtained in the process of cold maceration and their biological activity against selected Escherichia coli strains: E. coli ATTC 25922, E. coli ATTC 10536, and E. coli 127 isolated from poultry waste. On the basis of the gas chromatography-mass spectrometry (GCMS) analysis, it was found that the commercial essential oils revealed considerable differences in terms of the composition and diversity of terpenes, terpenoids and sesquiterpenes as compared with the extracts obtained from plant material. The commercial clove, oregano, and marjoram oils showed antibacterial properties against all the tested strains of E. coli. However, these strains were not sensitive to essential oils obtained from the plant material in the process of maceration. The tested strains of E. coli show a high sensitivity, mainly against monoterpenes (alpha-pinene, beta pinene, alpha,beta,gamma-terpinene, limonene) and some terpenoids (thymol, carvacrol). The commercial juniper oil contained mainly monoterpenes and monoterpenoids, while the extracts contained lower amounts of monoterpenes and high amounts of sesquiterpenes-the anti-microbiotic properties of the juniper herbal extract seem to be caused by the synergistic activity of mono- and sesquiterpenes. PMID- 29125569 TI - Rapid Determination of Major Compounds in the Ethanol Extract of Geopropolis from Malaysian Stingless Bees, Heterotrigona itama, by UHPLC-Q-TOF/MS and NMR. AB - A reliable, rapid analytical method was established for the characterization of constituents of the ethanol extract of geopropolis (EEGP) produced by Malaysian stingless bees-Heterotrigona itama-by combining ultra-high-performance liquid chromatography with quadruple time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). Based on known standards, the online METLIN database, and published literature, 28 compounds were confirmed. Phenolic acids, flavones, triterpenes and phytosterol were identified or tentatively identified using characteristic diagnostic fragment ions. The results indicated that terpenoids were the main components of EEGP, accompanied by low levels of phenolic acids, flavonoids, and phytosterol. Two major components were further purified by preparative high performance liquid chromatography (PHPLC) and identified by nuclear magnetic resonance (NMR) as 24(E)-cycloart-24-ene-26-ol-3-one and 20-hydroxy-24-dammaren-3 one. These two triterpenes, confirmed in this geopropolis for the first time, are potential chemical markers for the identification of geopropolis from Malaysian stingless bees, H. itama. PMID- 29125570 TI - Soft-Template Synthesis of Mesoporous Anatase TiO2 Nanospheres and Its Enhanced Photoactivity. AB - Highly crystalline mesoporous anatase TiO2 nanospheres with high surface area (higher than P25 and anatase TiO2) are prepared by a soft-template method. Despite the high specific surface area, these samples have three times lower equilibrium adsorption (<2%) than Degussa P25. The rate constant of the mesoporous anatase TiO2 (0.024 min-1) reported here is 364% higher than that of P25 (0.0066 min-1), for the same catalytic loading. The results of oxidation extraction photometry using several reactive oxygen species (ROS) scavengers indicated that mesoporous anatase TiO2 generates more ROS than P25 under UV-light irradiation. This significant improvement in the photocatalytic performance of mesoporous spherical TiO2 arises from the following synergistic effects in the reported sample: (i) high surface area; (ii) improved crystallinity; (iii) narrow pore wall thicknesses (ensuring the rapid migration of photogenerated carriers to the surface of the material); and (iv) greater ROS generation under UV-light. PMID- 29125571 TI - The Blood-Brain Barrier Permeability of Six Indole Alkaloids from Uncariae Ramulus Cum Uncis in the MDCK-pHaMDR Cell Monolayer Model. AB - Uncariae Ramulus Cum Uncis (URCU) is a widely used traditional Chinese medicine, and is reported to have various central nervous system effects. Alkaloids have been demonstrated to be the predominant pharmacological active components of URCU. In order to evaluate the blood-brain barrier (BBB) permeability and transport mechanism of six typical indole alkaloids from URCU, the MDCK-pHaMDR cell monolayer model was used as an in vitro surrogate model for BBB. The samples were analyzed by high-performance liquid chromatography, and the apparent permeability coefficients (Papp) were calculated. Among the six alkaloids, isorhynchophylline (2), isocorynoxeine (4), hirsutine (5) and hirsuteine (6) showed high permeability, with Papp values at 10-5 cm/s level in bidirectional transport. For rhynchophylline (1) and corynoxeine (3), they showed moderate permeability, with Papp values from the apical (AP) side to the basolateral (BL) side at 10-6 cm/s level and efflux ratio (Papp BL->AP/Papp AP->BL) above 2. The time- and concentration-dependency experiments indicated that the main mechanism for 2, 4, 5 and 6 through BBB was passive diffusion. The efflux mechanism involved in the transports of compounds 1 and 3 could be reduced significantly by verapamil, and molecular docking screening also showed that 1 and 3 had strong bindings to P-glycoprotein. This study provides useful information for predicting the BBB permeability for 1-6, as well as better understanding of their central nervous system pharmacological activities. PMID- 29125572 TI - Silybin, a Major Bioactive Component of Milk Thistle (Silybum marianum L. Gaernt.)-Chemistry, Bioavailability, and Metabolism. AB - Milk thistle (Silybum marianum) is a medicinal plant that has been used for thousands of years as a remedy for a variety of ailments. The main component of S. marianum fruit extract (silymarin) is a flavonolignan called silybin, which is not only the major silymarin element but is also the most active ingredient of this extract, which has been confirmed in various studies. This compound belongs to the flavonoid group known as flavonolignans. Silybin's structure consists in two main units. The first is based on a taxifolin, the second a phenyllpropanoid unit, which in this case is conyferil alcohol. These two units are linked together into one structure by an oxeran ring. Since the 1970s, silybin has been regarded in official medicine as a substance with hepatoprotective properties. There is a large body of research that demonstrates silybin's many other healthy properties, but there are still a lack of papers focused on its molecular structure, chemistry, metabolism, and novel form of administration. Therefore, the aim of this paper is a literature review presenting and systematizing our knowledge of the silybin molecule, with particular emphasis on its structure, chemistry, bioavailability, and metabolism. PMID- 29125574 TI - Coordination Polymers Containing 1,3-Phenylenebis-((1H-1,2,4-triazol-1 yl)methanone) Ligand: Synthesis and epsilon-Caprolactone Polymerization Behavior. AB - The reaction of isophthaloyl dichloride with 1H-1,2,4-triazole afforded the new ligand 1,3-phenylenebis(1,2,4-triazole-1-yl)methanone (1). A series of Co(II), Cu(II), Zn(II) and Ni(II) complexes were synthesized using 1 and then characterized by melting point analysis, elemental analysis, theoretical calculations, thermogravimetric analysis, X-ray powder diffraction, nuclear magnetic resonance, infrared and Raman spectroscopy. Experimental and computational studies predict the formation of coordination polymers (CPs). The cobalt and copper CPs and zinc(II) complex were found to be good initiators for the ring-opening polymerization of epsilon-caprolactone (CL) under solvent-free conditions. 1H-NMR analysis showed that the obtained polymers of CL were mainly linear and had terminal hydroxymethylene groups. Differential scanning calorimetry showed that the obtained polycaprolactones had high crystallinity, and TGA showed that they had decomposition temperatures above 400 degrees C. These results provide insight and guidance for the design of metal complexes with potential applications in the polymerization of CL. PMID- 29125576 TI - Application of the Taguchi Method for Optimizing the Process Parameters of Producing Lightweight Aggregates by Incorporating Tile Grinding Sludge with Reservoir Sediments. AB - This study aimed to apply the Taguchi optimization technique to determine the process conditions for producing synthetic lightweight aggregate (LWA) by incorporating tile grinding sludge powder with reservoir sediments. An orthogonal array L16(45) was adopted, which consisted of five controllable four-level factors (i.e., sludge content, preheat temperature, preheat time, sintering temperature, and sintering time). Moreover, the analysis of variance method was used to explore the effects of the experimental factors on the particle density, water absorption, bloating ratio, and loss on ignition of the produced LWA. Overall, the produced aggregates had particle densities ranging from 0.43 to 2.1 g/cm3 and water absorption ranging from 0.6% to 13.4%. These values are comparable to the requirements for ordinary and high-performance LWAs. The results indicated that it is considerably feasible to produce high-performance LWA by incorporating tile grinding sludge with reservoir sediments. PMID- 29125573 TI - Tailoring Nutritional Advice for Mexicans Based on Prevalence Profiles of Diet Related Adaptive Gene Polymorphisms. AB - Diet-related adaptive gene (DRAG) polymorphisms identified in specific populations are associated with chronic disorders in carriers of the adaptive alleles due to changes in dietary and lifestyle patterns in recent times. Mexico's population is comprised of Amerindians (AM) and Mestizos who have variable AM, European (EUR) and African genetic ancestry and an increased risk of nutrition-related chronic diseases. Nutritional advice based on the Mexican genome and the traditional food culture is needed to develop preventive and therapeutic strategies. Therefore, we aimed to provide a prevalence profile of several DRAG polymorphisms in the Mexican population, including Central West (CW) Mexico subpopulations. Geographic heat maps were built using ArcGIS10 (Esri, Redlands, CA, USA) software, based on the published data of the MTHFR C677T (rs1801133), ABCA1 Arg230Cys (rs9282541), APOE T388C (rs429358)/C526T (rs7412), LCT C-13910T (rs4988235) polymorphisms and AMY1 copy number variation (CNV). Also, new data obtained by allelic discrimination-real-time polymerase chain reaction (RT-PCR) assays for the MTHFR, ABCA1, and APOE polymorphisms as well as the AMY1 CNV in the CW Mexico subpopulations with different proportions of AM and EUR ancestry were included. In the CW region, the highest frequency of the MTHFR 677T, ABCA1 230C and APOE epsilon4 adaptive alleles was observed in the AM groups, followed by Mestizos with intermediate AM ancestry. The LCT-13910T allele frequency was highest in Mestizos-EUR but extremely low in AM, while the AMY1 diploid copy number was 6.82 +/- 3.3 copies. Overall, the heat maps showed a heterogeneous distribution of the DRAG polymorphisms, in which the AM groups revealed the highest frequencies of the adaptive alleles followed by Mestizos. Given these genetic differences, genome-based nutritional advice should be tailored in a regionalized and individualized manner according to the available foods and Mexican traditional food culture that may lead to a healthier dietary pattern. PMID- 29125575 TI - An Optimized and Sensitive Pharmacokinetic Quantitative Method of Investigating Gastrodin, Parishin, and Parishin B, C and E in Beagle Dog Plasma using LC-MS/MS after Intragastric Administration of Tall Gastrodia Capsules. AB - Gastrodia elata Blume, called Tianma in China, has been widely used to treat headaches, convulsions and epilepsy for thousands of years. In the present study, a series of optimizations were employed to develop a rapid, sensitive, and reliable high-performance liquid chromatography-triple quadrupole mass spectrometry method, which was then used for the simultaneous determination of gastrodin, parishin, parishin B, parishin C and parishin E in beagle dog plasma after intragastric administration of tall Gastrodia capsules (Tianma brand). The chromatographic separation was achieved on a C18 column with gradient elution by using a mixture of 0.4% formic acid aqueous solution and acetonitrile as the mobile phase at a flow rate of 0.15 mL/min. A tandem mass spectrometric detection was conducted using multiple-reaction monitoring (MRM) via electrospray ionization (ESI) source in negative ionization mode. Samples were pre-treated by a single-step protein precipitation with methanol, and bergenin was used as internal standard (IS). Under the optimized conditions, the lower limit of quantification (LLOQ) was 0.10 ng/mL for gastrodin, 0.40 ng/mL for parishin B, 0.02 ng/mL for parishin E and 0.20 ng/mL for parishin and parishin C, all of which previously were the highest levels of sensitivity. The methods were optimized for selectivity, calibration curves, accuracy and precision. Extraction recoveries, matrix effects and stability were within acceptable ranges. Pharmacokinetic parameters of the tested substances were also quantitatively determined. Finally, a possible metabolic pathway was induced based on correlations obtained from quantitative and qualitative data analysis in vivo. PMID- 29125577 TI - Anandins A and B, Two Rare Steroidal Alkaloids from a Marine Streptomyces anandii H41-59. AB - Anandins A (1) and B (2), two rare steroidal alkaloids, were isolated from the fermentative broth of a marine actinobacteria Streptomyces anandii H41-59. The gross structures of the two alkaloids were elucidated by spectroscopic methods including HR-ESI-MS, and NMR. Their absolute configurations were confirmed by single-crystal X-ray diffraction analysis and comparison of their experimental and calculated electronic circular dichroism spectra, respectively. Anandin A exhibited a moderate inhibitory effect against three human cancer cell lines MCF 7, SF-268, and NCI-H460 with IC50 values of 7.5, 7.9, 7.8 MUg/mL, respectively. PMID- 29125578 TI - An Insight into Sargassum muticum Cytoprotective Mechanisms against Oxidative Stress on a Human Cell In Vitro Model. AB - Sargassum muticum is a brown seaweed with strong potential to be used as a functional food ingredient, mainly due to its antioxidant properties. It is widely used in traditional oriental medicine for the treatment of numerous diseases. Nevertheless, few studies have been conducted to add scientific evidence on its effects as well as on the mechanisms of action involved. In this work, the human cell line MCF-7 was used as an in vitro cellular model to evaluate the capability of Sargassum muticum enriched fractions to protect cells on an oxidative stress condition. The concentration of the bioactive compounds was obtained by vacuum liquid chromatography applied on methanol (M) and 1:1 methanol:dichloromethane (MD) crude extracts, resulting in seven enriched fractions from the M extraction (MF2-MF8), and eight fractions from the MD extraction (MDF1-MDF8). All fractions were tested for cytotoxic properties on MCF 7 cells and the nontoxic ones were tested for their capacity to blunt the damaging effects of hydrogen peroxide-induced oxidative stress. The nontoxic effects were also confirmed in 3T3 fibroblast cells as a nontumor cell line. The antioxidant potential of each fraction, as well as changes in the cell's real time hydrogen peroxide production, in the mitochondrial membrane potential, and in Caspase-9 activity were evaluated. The results suggest that the protective effects evidenced by S. muticum can be related with the inhibition of hydrogen peroxide production and the inhibition of Caspase-9 activity. PMID- 29125579 TI - The Structure of Liquid and Amorphous Hafnia. AB - Understanding the atomic structure of amorphous solids is important in predicting and tuning their macroscopic behavior. Here, we use a combination of high-energy X-ray diffraction, neutron diffraction, and molecular dynamics simulations to benchmark the atomic interactions in the high temperature stable liquid and low density amorphous solid states of hafnia. The diffraction results reveal an average Hf-O coordination number of ~7 exists in both the liquid and amorphous nanoparticle forms studied. The measured pair distribution functions are compared to those generated from several simulation models in the literature. We have also performed ab initio and classical molecular dynamics simulations that show density has a strong effect on the polyhedral connectivity. The liquid shows a broad distribution of Hf-Hf interactions, while the formation of low-density amorphous nanoclusters can reproduce the sharp split peak in the Hf-Hf partial pair distribution function observed in experiment. The agglomeration of amorphous nanoparticles condensed from the gas phase is associated with the formation of both edge-sharing and corner-sharing HfO6,7 polyhedra resembling that observed in the monoclinic phase. PMID- 29125581 TI - Occurrence of Polychlorinated Dibenzo-p-Dioxins and Dibenzofurans and Polychlorinated Biphenyls in Fruit and Vegetables from the "Land of Fires" Area of Southern Italy. AB - The concentrations of polychlorinated dibenzo-p-concentrations dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) (PCDD/Fs), and polychlorinated biphenyls (PCBs) were determined in fruit and vegetables collected in farms located in the well-known "Land of Fires" area of Southern Italy, in an effort to learn more about the environmental pollution of this high-risk area due to illegal waste dumping and uncontrolled burning near cultivated fields. Concentrations were in the range 0.011-2.26 ng g-1 for the six "indicator" non-dioxin-like PCBs (NDL PCBs), and 0.0009-0.096 pg WHO toxic equivalent (TEQ) g-1 for the sum of dioxin like PCBs (DL-PCBs) and PCDD/Fs. Lacking maximum limits for these contaminants in fruit and vegetables, the concentration values found were compared with the action levels set out in the EU Recommendations. These levels were never exceeded in the examined samples. In the present study, the highest mean value for PCDD/Fs + DL-PCB corresponded to apricots, olives, and nuts, while the lowest values were observed in endive and green beans. The results showed also that NDL-PCB levels in apricots were much higher than in any other food, suggesting that they can accumulate PCBs: this fruit might be proposed as a "sentinel" of the presence of these contaminants in the environment. PMID- 29125580 TI - Structural Diversity, Biological Properties and Applications of Natural Products from Cyanobacteria. A Review. AB - Nowadays, various drugs on the market are becoming more and more resistant to numerous diseases, thus declining their efficacy for treatment purposes in human beings. Antibiotic resistance is one among the top listed threat around the world which eventually urged the discovery of new potent drugs followed by an increase in the number of deaths caused by cancer due to chemotherapy resistance as well. Accordingly, marine cyanobacteria, being the oldest prokaryotic microorganisms belonging to a monophyletic group, have proven themselves as being able to generate pharmaceutically important natural products. They have long been known to produce distinct and structurally complex secondary metabolites including peptides, polyketides, alkaloids, lipids, and terpenes with potent biological properties and applications. As such, this review will focus on recently published novel compounds isolated from marine cyanobacteria along with their potential bioactivities such as antibacterial, antifungal, anticancer, anti tuberculosis, immunosuppressive and anti-inflammatory capacities. Moreover, various structural classes, as well as their technological uses will also be discussed. PMID- 29125582 TI - Next Generation Sequencing of Chromosome-Specific Libraries Sheds Light on Genome Evolution in Paleotetraploid Sterlet (Acipenser ruthenus). AB - Several whole genome duplication (WGD) events followed by rediploidization took place in the evolutionary history of vertebrates. Acipenserids represent a convenient model group for investigation of the consequences of WGD as their representatives underwent additional WGD events in different lineages resulting in ploidy level variation between species, and these processes are still ongoing. Earlier, we obtained a set of sterlet (Acipenser ruthenus) chromosome-specific libraries by microdissection and revealed that they painted two or four pairs of whole sterlet chromosomes, as well as additional chromosomal regions, depending on rediploidization status and chromosomal rearrangements after genome duplication. In this study, we employed next generation sequencing to estimate the content of libraries derived from different paralogous chromosomes of sterlet. For this purpose, we aligned the obtained reads to the spotted gar (Lepisosteus oculatus) reference genome to reveal syntenic regions between these two species having diverged 360 Mya. We also showed that the approach is effective for synteny prediction at various evolutionary distances and allows one to clearly distinguish paralogous chromosomes in polyploid genomes. We postulated that after the acipenserid-specific WGD sterlet karyotype underwent multiple interchromosomal rearrangements, but different chromosomes were involved in this process unequally. PMID- 29125584 TI - Review of Recent Inkjet-Printed Capacitive Tactile Sensors. AB - Inkjet printing is an advanced printing technology that has been used to develop conducting layers, interconnects and other features on a variety of substrates. It is an additive manufacturing process that offers cost-effective, lightweight designs and simplifies the fabrication process with little effort. There is hardly sufficient research on tactile sensors and inkjet printing. Advancements in materials science and inkjet printing greatly facilitate the realization of sophisticated tactile sensors. Starting from the concept of capacitive sensing, a brief comparison of printing techniques, the essential requirements of inkjet printing and the attractive features of state-of-the art inkjet-printed tactile sensors developed on diverse substrates (paper, polymer, glass and textile) are presented in this comprehensive review. Recent trends in inkjet-printed wearable/flexible and foldable tactile sensors are evaluated, paving the way for future research. PMID- 29125583 TI - Occurrences of Organochlorine Pesticides along the Course of the Buffalo River in the Eastern Cape of South Africa and Its Health Implications. AB - Most organochlorine pesticides (OCPs) which are increasingly used in agriculture and industry are not biodegradable and thereby persist in the environment for a very long period of time. They are capable of negatively impacting the health of humans and biota when present in a higher concentration than recommended. This study evaluated the concentrations of 17 OCPs in surface water samples collected from six sampling sites along the course of the Buffalo River in Eastern Cape, South Africa, between December 2015 and May 2016. The samples were subjected to solvent extraction, followed by florisil clean up, and analyzed using gas chromatography coupled with an electron capture detector. The individual concentrations of OCPs detected ranged from 50%, one (6%) >30%, and one (6%) >20% of the values higher than the target value; one (6%) used the appearance of glycosuria. CONCLUSIONS: When evaluating RCTs which included criteria for pharmacologic GDM therapy dose adjustment, the most common criterion for diagnosis was the two-step test, and the most common used therapies were insulin and metformin. Regarding glucose monitoring, the most common frequency was four times per day, fasting and two hours after each main meal, using as target glucose values 95 and 120 mg/dL, respectively. Importantly, we found six different criteria for pharmacologic GDM therapy dose adjustment, with the majority using very tight criteria of either one or two values per week higher than the target values, of which two-thirds used only one value, and one-third used two values. PMID- 29125639 TI - Chemical, Physiochemical, and Microstructural Properties, and Probiotic Survivability of Fermented Goat Milk Using Polymerized Whey Protein and Starter Culture Kefir Mild 01. AB - : A set-type fermented goat milk (FGM) using polymerized whey protein (PWP) as main thickening agent and Kefir Mild 01 as starter culture was developed. The FGM with PWP (0.3%, w/v) and pectin (0.2%, w/v) had low syneresis (5.44 +/- 0.92%), desirable viscosity (952.86 +/- 61.52 mPa?s), and hardness (112.57 +/- 3.23 g), which were comparable to a fermented cow milk. Sensory evaluation data showed that the FGM with PWP and pectin had higher scores of both flavor (4.41 +/- 0.39) and taste (3.72 +/- 0.34) than the sample without PWP. Chemical composition of both fermented goat and cow milk were analyzed. The protein content of goat and cow milk samples were 3.50% +/- 0.12% and 3.28% +/- 0.09% (w/w), respectively. Lactobacillus acidophilus population in both FGM samples remained above 106 CFU/g during the 1st 4-wk storage. There was a slight but no significant (P > 0.05) decrease in pH and TA during storage. Scanning electron microscopy micrographs displayed a compact and homogeneous protein network of the FGM with PWP and pectin. Polymerized whey protein may be a novel protein-based thickening agent for formulation of a set-type FGM with starter culture Kefir Mild 01. PRACTICAL APPLICATION: Fermented goat milk is an increasingly popular dairy product in the world. However, it is difficult to make set type fermented goat milk due to the smaller size and lower content of casein micelles in goat milk. A fermented goat milk with PWP (0.3%, w/v) and pectin (0.2%, w/v) was successfully developed in this study. The product fermented by Kefir Mild 01 starter culture had a similar taste with Kefir but no yeast or alcoholic exists. The new product would be a promising food in the market. PMID- 29125640 TI - Characterization of Whole Grain Pasta: Integrating Physical, Chemical, Molecular, and Instrumental Sensory Approaches. AB - : The consumption of whole-grain food-including pasta-has been increasing steadily. In the case of whole-grain pasta, given the many different producers, it seems important to have some objective parameters to define its overall quality. In this study, commercial whole-grain pasta samples representative of the Italian market have been characterized from both molecular and electronic senses (electronic nose and electronic tongue) standpoint in order to provide a survey of the properties of different commercial samples. Only 1 pasta product showed very low levels of heat damage markers (furosine and pyrraline), suggesting that this sample underwent to low temperature dry treatment. In all samples, the furosine content was directly correlated to protein structural indices, since protein structure compactness increased with increasing levels of heat damage markers. Electronic senses were able to discriminate among pasta samples according to the intensity of heat treatment during the drying step. Pasta sample with low furosine content was discriminated by umami taste and by sensors responding to aliphatic and inorganic compounds. Data obtained with this multidisciplinary approach are meant to provide hints for identifying useful indices for pasta quality. PRACTICAL APPLICATION: As observed for semolina pasta, objective parameters based on heat-damage were best suited to define the overall quality of wholegrain pasta, almost independently of compositional differences among commercial samples. Drying treatments of different intensity also had an impact on instrumental sensory traits that may provide a reliable alternative to analytical determination of chemical markers of heat damage in all cases where there is a need for avoiding time-consuming procedures. PMID- 29125641 TI - Assessing the Impact of Germination and Sporulation Conditions on the Adhesion of Bacillus Spores to Glass and Stainless Steel by Fluid Dynamic Gauging. AB - : The adhesion of spores of 3 Bacillus species with distinctive morphologies to stainless steel and borosilicate glass was studied using the fluid dynamic gauging technique. Marked differences were observed between different species of spores, and also between spores of the same species prepared under different sporulation conditions. Spores of the food-borne pathogen B. cereus were demonstrated to be capable of withstanding shear stresses greater than 1500 Pa when adhered to stainless steel, in contrast to spores of Bacillus subtilis and Bacillus megaterium, which detached in response to lower shear stress. An extended DLVO model was shown to be capable of predicting the relative differences in spore adhesion between spores of different species and different culture conditions, but did not predict absolute values of force of adhesion well. Applying the model to germinating spores showed a significant reduction in adhesion force shortly after triggering germination, indicating a potential strategy to achieve enhanced removal of spores from surfaces in response to shear stress, such as during cleaning-in-place procedures. PRACTICAL APPLICATION: Spore forming bacteria are a concern to the food industry because they have the potential to cause food-borne illness and product spoilage, while being strongly adhesive to processing surfaces and resistant to cleaning-in-place procedures. This work is of significance to the food processors and manufacturers because it offers insight to the properties of spore adhesion and identifies a potential strategy to facilitate the removal of spores during cleaning procedures. PMID- 29125642 TI - Genistein Ameliorates Fat Accumulation Through AMPK Activation in Fatty Acid Induced BRL Cells. AB - : Genstein is the most abundant phytoestrogen in soybean that was reported to play positive roles in menopausal syndrome and metabolic syndrome. In the present study, we investigated the effects and potential mechanisms of genistein against progression of nonalcoholic fatty liver disease (NAFLD) in BRL cells treated with fatty acid mixture (oleate/palmitate, 2:1 ratio). Our data demonstrated that genistein remarkably improved fatty acid mixture-induced hepatocelluler fat accumulation, inhibited upregulation of genes expression related to fatty acid synthesis, and derepressed those associated with fatty acid oxidation. In addition, the results displayed that genistein promoted the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) suppressed by fatty acid, which were significantly weakened by compound C, an AMPK inhibitor. Taken all together, genistein is capable to ameliorate fat accumulation through regulation of fatty acid metabolism mediated by AMPK activation in BRL cells. Further investigations are needed to verify the protective effects of genistein on NAFLD model in in vivo animal study or in vitro human cell lines along with absorption, distribution, metabolism, and excretion studies of genistein. PRACTICAL APPLICATION: Genistein is able to ameliorate fat accumulation through regulation of fatty acid metabolism mediated by AMPK activation in vitro. PMID- 29125643 TI - Environmental variation partitioned into separate heritable components. AB - Trait variation is normally separated into genetic and environmental components, yet genetic factors also control the expression of environmental variation, encompassing plasticity across environmental gradients and within-environment responses. We defined four components of environmental variation: plasticity across environments, variability in plasticity, variation within environments, and differences in within-environment variation across environments. We assessed these components for cold tolerance across five rearing temperatures using the Drosophila melanogaster Genetic Reference Panel (DGRP). The four components were found to be heritable, and genetically correlated to different extents. By whole genome single marker regression, we detected multiple candidate genes controlling the four components and showed limited overlap in genes affecting them. Using the binary UAS-GAL4 system, we functionally validated the effects of a subset of candidate genes affecting each of the four components of environmental variation and also confirmed the genetic and phenotypic correlations obtained from the DGRP in distinct genetic backgrounds. We delineate selection targets associated with environmental variation and the constraints acting upon them, providing a framework for evolutionary and applied studies on environmental sensitivity. Based on our results we suggest that the traditional quantitative genetic view of environmental variation and genotype-by-environment interactions needs revisiting. PMID- 29125644 TI - Atomic Vacancies Control of Pd-Based Catalysts for Enhanced Electrochemical Performance. AB - Structure-engineered Pd-based catalysts at the atomic level can effectively improve the catalytic performance for oxygen or small organic molecules electrocatalysis, comparable to or even superior to that of commercial Pt/C. Here, PdCuCo anisotropic structure (AS) electrocatalysts are synthesized with abundant vacancy defects on the exterior surface, which is unambiguously verified by aberration-corrected transmission electron microscopy. The PdCuCo-AS with vacancy (v-PdCuCo-AS) shows excellent electrochemical activity toward oxygen reduction (ORR) and oxidation of alcohols. The mass activity of the v-PdCuCo-AS is 0.18 A mg-1 at 0.9 V versus reversible hydrogen electrode (RHE), which is 15.55 times larger than that of the commercial Pd/C catalyst in acidic electrolyte. According to the theoretical calculations, this significant improvement can be understood as a result of the promoted charge transfer by polarized electronic structures of the v-PdCuCo-AS in the processes of ORR. The synergistic effect of the correlated defects and the compressive strain caused by the doping Co and Cu atoms effectively improve the electrocatalysis activity for the ORR in acidic/alkaline electrolyte on the v-PdCuCo-AS stems. This approach provides a strategy to design other AS structures for improving their electrochemical performance. PMID- 29125645 TI - Advanced Plasmonic Materials for Dynamic Color Display. AB - Plasmonic structures exhibit promising applications in high-resolution and durable color generation. Research on advanced hybrid plasmonic materials that allow dynamically reconfigurable color control has developed rapidly in recent years. Some of these results may give rise to practically applicable reflective displays in living colors with high performance and low power consumption. They will attract broad interest from display markets, compared with static plasmonic color printing, for example, in applications such as digital signage, full-color electronic paper, and electronic device screens. In this progress report, the most promising recent examples of utilizing advanced plasmonic materials for the realization of dynamic color display are highlighted and put into perspective. The performances, advantages, and disadvantages of different technologies are discussed, with emphasis placed on both the potential and possible limitations of various hybrid materials for dynamic plasmonic color display. PMID- 29125646 TI - Epidural abscess caused by Schizophyllum commune: A rare case of rhinogenic cranial complication by a filamentous basidiomycete. AB - Central nervous system (CNS) infections due to filamentous basidiomycetes are extremely rare. We encountered a case of epidural abscess due to Schizophyllum commune that extended from sinusitis. A 53-year-old Japanese man presented at our hospital with a headache. Computed tomography (CT) of the cranium and sinuses showed ethmoid and sphenoid sinusitis with no intracranial abnormalities. The patient was diagnosed with acute sinusitis and underwent antibiotic treatment. However, the symptoms deteriorated, and the patient came to our hospital again with consciousness disturbance. CT scan of the cranium and sinuses showed no improvement of sinusitis after antibiotic therapy and an epidural abscess emerged in the middle cranial fossa. Therefore, emergency craniotomy and endoscopic sinus fenestration were performed. Filamentous fungal elements were observed in both rhinorrhoea and epidural abscess. The symptoms improved after the operation and administration of liposomal amphotericin B. The clinical isolate was identified as S. commune by a molecular-based method. To our knowledge, this is the first report of epidural abscess due to this fungus. Although rare, clinicians should be aware that S. commune could be a causative agent of CNS infections. PMID- 29125647 TI - Regio- and Enantioselective Allylic Amination of Aliphatic MBH Adducts with N Heteroaromatics. AB - Palladium-catalyzed regio- and enantioselective allylic amination of aliphatic Morita-Baylis-Hillman (MBH) adducts with N-heteroaromatic nucleophiles (e.g., benzimidazole, 4,5-diphenylimidazole, benzotriazole, and purines) was achieved by using a spiroketal-based diphosphine (SKP) ligand, and afforded a range of chiral, branched N-allyl products with high selectivity. PMID- 29125648 TI - Pharmacological effects of Zataria multiflora Boiss L. and its constituents focus on their anti-inflammatory, antioxidant, and immunomodulatory effects. AB - Zataria multiflora Boiss (Z. multiflora) belongs to the Lamiaceae family is used traditionally for culinary and medicinal purposes. Different pharmacological effects have been described for the plant including; bronchodilation, vasodilation, and effect on lung inflammation. The plant is also used as a remedy against cough in the traditional medicine. In this article, 'pharmacological effects of Z. multiflora and its constituents focusing on their anti inflammatory, antioxidant, and immunomodulatory properties were reviewed' by searching various databases until 'June' 2016. The anti-inflammatory effects of the plant such as decreased total white blood cell, neutrophils, and eosinophils counts were demonstrated. The sprotective effects of Z. multiflora on serum levels of phospholipase A2 and total protein were showed. In addition, constituents of the plant, such as flavonoids and carvacrol, also showed anti inflammatory effects. Z. multiflora also reduced oxidative stress by scavenging free radicals and can be used in the therapy of oxidative damage. Decreased level of malondialdehyde and protective effects of Z. multiflora on serum levels of nitric oxide were also shown. Improvement of the serum levels of IgE, reduction in pro-inflammatory cytokine (IL-4, TGF-beta, and IL-17), and increased anti inflammatory cytokines (IFN-gamma and FOXP3) were shown for Z. multiflora and its constituents, carvacrol and thymol. These results indicated that carvacrol and thymol could be used for treatment of inflammatory diseases as new anti inflammatory agents. Therefore, Z. multiflora showed anti-inflammatory, antioxidant, and immunomodulatory effects which could be used for treatment of inflammatory and immune dysregulation diseases or disorders associated with increased oxidative stress. PMID- 29125649 TI - Milker's nodule: an occupational infection and threat to the immunocompromised. AB - Milker's nodule virus, also called paravaccinia virus, is a DNA virus of the parapoxvirus genus transmitted from infected cows to humans. It results from contact with cattle, cattle by-products or fomites. Classified as an occupational disorder, those at risk of exposure include farmers, butchers and agricultural tourists. The viral infection begins 5-15 days after inoculation as an erythematous-purple, round nodule with a clear depressed centre and a surrounding erythematous ring. While familiar to those in farming communities, the presence of the nodule may be concerning to others, particularly the immunosuppressed. Milker's nodules are self-limited in immunocompetent individuals and heal without scarring within 8 weeks. Another member of the Parapoxvirus genus, the orf virus, is also transmitted from animals to humans by direct contact. While complications are rare, haematopoietic stem cell transplant recipients are at risk of graft versus-host disease, as the parapoxvirus may trigger these complications in immunocompromised individuals. In addition, paravaccinia may serve as the antigen source for the development of erythema multiforme. The unique structure and replication process of viruses in the Poxvirus family, while includes the Parapoxvirus genus, have been a focus for treatment of infections and cancer. Manipulation of these viruses has demonstrated promising therapeutic possibilities as vectors for vaccines and oncologic therapy. PMID- 29125650 TI - Combination of HPLC with organic and inorganic mass spectrometry to study the metabolic response of the clam Scrobicularia plana to arsenic exposure. AB - Arsenic is a toxic element extensively studied in the marine environment due to differential toxicological effects of inorganic and organic species. In the present work, the bivalve Scrobicularia plana was exposed to AsV (10 and 100 MUg/L) for 14 days to evaluate the metabolic perturbations caused by this element. Arsenic speciation and metabolomic analysis were performed in the digestive gland of the bivalve using two complementary analytical platforms based on inorganic and organic mass spectrometry. It has been observed the greater presence of the innocuous specie arsenobetaine produced in this organism as defense mechanism against arsenic toxicity, although significant concentrations of methylated and inorganic arsenic were also present, depending on the level of arsenic in aqueous media. Complementarily, a metabolomic study based on mass spectrometry and statistical discriminant analysis allows a good classification of samples associated to low and high As(V) exposure in relation to controls. About 15 metabolites suffer significant changes of expression by the presence of As(V): amino acids, nucleotides, energy-related metabolites, free fatty acids, phospholipids and triacylglycerides, which can be related to membrane structural and functional damage. In addition, perturbation of the methylation cycle, associated with the increase of homocysteine and methionine was observed, which enhance the methylation of toxic inorganic arsenic to less toxic dimethylarsenic. PMID- 29125652 TI - Mini-implants and narrow diameter implants as mandibular overdenture retainers: A systematic review and meta-analysis of clinical and radiographic outcomes. AB - This study reviews the clinical and radiographic outcomes of Mini-implants (MI) and Narrow Diameter Implants (NDI) as mandibular overdenture (MO) retainers. Six databases were consulted for clinical studies that evaluated implants with diameter <=3.5 mm. Data on the MI and NDI for survival and success rate and peri implant bone loss and were collected and submitted to meta-analysis. Thirty-six studies were included, 24 reporting MI performance and 12 describing NDI results. The MI group comprised data from 1 cross-sectional clinical study, 3 retrospective longitudinal (RL) clinical studies, 13 prospective longitudinal (PL) clinical studies and 7 randomised clinical trials (RCT) with follow-up periods ranging from 1 day to 7 years. Eight studies used conventional loading, thirteen used immediate loading, two studies used both loading types, and one study did not report. The NDI group comprised data from 3 RL clinical studies, 6 PL clinical studies and 3 RCT with follow-up ranging from 6 months to 10 years. Ten studies used conventional loading, 1 study used immediate loading, and 1 study did not report. The average survival rates of MI and NDI studies were 98% and 98%, respectively, while the average success rates were 93% and 96%, respectively. The average peri-implant bone loss after 12, 24 and 36 months was 0.89, 1.18 and 1.02 mm for MI and 0.18, 0.12 and -0.32 mm for NDI. Both MI and NDI showed adequate clinical behaviour as overdenture retainers. The NDI showed a better long-term predictability to retain OM with most studies adopting conventional loading. PMID- 29125651 TI - An Ideal Molecular Sieve for Acetylene Removal from Ethylene with Record Selectivity and Productivity. AB - Realization of ideal molecular sieves, in which the larger gas molecules are completely blocked without sacrificing high adsorption capacities of the preferred smaller gas molecules, can significantly reduce energy costs for gas separation and purification and thus facilitate a possible technological transformation from the traditional energy-intensive cryogenic distillation to the energy-efficient, adsorbent-based separation and purification in the future. Although extensive research endeavors are pursued to target ideal molecular sieves among diverse porous materials, over the past several decades, ideal molecular sieves for the separation and purification of light hydrocarbons are rarely realized. Herein, an ideal porous material, SIFSIX-14-Cu-i (also termed as UTSA-200), is reported with ultrafine tuning of pore size (3.4 A) to effectively block ethylene (C2 H4 ) molecules but to take up a record-high amount of acetylene (C2 H2 , 58 cm3 cm-3 under 0.01 bar and 298 K). The material therefore sets up new benchmarks for both the adsorption capacity and selectivity, and thus provides a record purification capacity for the removal of trace C2 H2 from C2 H4 with 1.18 mmol g-1 C2 H2 uptake capacity from a 1/99 C2 H2 /C2 H4 mixture to produce 99.9999% pure C2 H4 (much higher than the acceptable purity of 99.996% for polymer-grade C2 H4 ), as demonstrated by experimental breakthrough curves. PMID- 29125653 TI - Synthesis and Characterisation of a Paramagnetic [2]Rotaxane Based on a Crown Ether-Like Wheel Incorporating a Nitroxide Motif. AB - The synthesis of the new nitroxide crown ether 8 and its use as the wheel in a bistable [2]rotaxane, containing dialkylammonium and 4,4'-bipyridinium recognition sites, is reported. The synthesis of 8 was achieved by the sequential addition of substituted phenyl groups to a nitrone derivatives leading to the preferential formation of the cis stereoisomer. Due to charge-dipole interactions between the nitroxide unit and the bipyridinium moiety, it was possible to probe the movement of the macrocycle between the two molecular stations of the [2]rotaxane after addition of a base by measuring the nitrogen hyperfine splitting in the corresponding EPR spectra. The equilibrium constant for the complexation of dibenzyl viologen by the macrocycle 8 was also determined by EPR titration. PMID- 29125654 TI - Ternary Nonfullerene Polymer Solar Cells with 12.16% Efficiency by Introducing One Acceptor with Cascading Energy Level and Complementary Absorption. AB - A novel small-molecule acceptor, (2,2'-((5E,5'E)-5,5'-((5,5'-(4,4,9,9-tetrakis(5 hexylthiophen-2-yl)-4,9-dihydro-s-indaceno[1,2-b:5,6-b']dithiophene-2,7 diyl)bis(4-(2-ethylhexyl)thiophene-5,2-diyl))bis(methanylylidene)) bis(3-hexyl-4 oxothiazolidine-5,2-diylidene))dimalononitrile (ITCN), end-capped with electron deficient 2-(3-hexyl-4-oxothiazolidin-2-ylidene)malononitrile groups, is designed, synthesized, and used as the third component in fullerene-free ternary polymer solar cells (PSCs). The cascaded energy-level structure enabled by the newly designed acceptor is beneficial to the carrier transport and separation. Meanwhile, the three materials show a complementary absorption in the visible region, resulting in efficient light harvesting. Hence, the PBDB-T:ITCN:IT-M ternary PSCs possess a high short-circuit current density (Jsc ) under an optimal weight ratio of donors and acceptors. Moreover, the open-circuit voltage (Voc ) of the ternary PSCs is enhanced with an increase of the third acceptor ITCN content, which is attributed to the higher lowest unoccupied molecular orbital energy level of ITCN than that of IT-M, thus exhibits a higher Voc in PBDB-T:ITCN binary system. Ultimately, the ternary PSCs achieve a power conversion efficiency of 12.16%, which is higher than the PBDB-T:ITM-based PSCs (10.89%) and PBDB T:ITCN-based ones (2.21%). This work provides an effective strategy to improve the photovoltaic performance of PSCs. PMID- 29125655 TI - '25-Hydroxyvitamin D, Autoantigenic and Total Antibody Concentrations: Results from a Danish Case-control Study of Newly Diagnosed Patients with Childhood Type 1 Diabetes and their Healthy Siblings'. AB - B cells have recently entered the stage as an important accessory player in type 1 diabetes (T1D) etiopathogenesis. Experimental studies suggest regulatory functions of vitamin D on B cells. However, only a few human studies, with considerable methodological limitations, have been conducted within this field. Our objective was to investigate whether higher 25-hydroxyvitamin D (25(OH)D) concentrations were inversely associated with beta-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma-associated antigen-2A (IA 2A). Further, we also wanted to examine the relationship between 25(OH)D and total antibody concentrations. We randomly selected 500 patients with newly diagnosed T1D and 500 siblings for 25(OH)D, antibody and genetic analysis from the population-based Danish Registry of Childhood and Adolescent Diabetes. The relative change (RC) in the mean concentration of GADA, IA-2A and antibody isotypes by a 10 nmol/l increase in 25(OH)D concentration was modelled by a robust log-normal regression model. We found no association between 25(OH)D and GADA [adjusted RC per 10 nmol/l increase: 1.00; 95% confidence interval (CI): 0.98-1.02] and IA-2A [adjusted RC per 10 nmol/l increase: 0.92; CI: 0.76-1.12]. Further, 25(OH)D was not associated with the total concentration of antibody isotypes [immunoglobulin (Ig)A, IgE, IgG and IgM]. All null findings were unaltered after adjustment for genetic variation in the vitamin D pathway. Physiological concentrations of 25(OH)D are unlikely to have a clinically important effect on antibody concentrations in a paediatric population of newly diagnosed patients with T1D and their healthy siblings. PMID- 29125656 TI - A mechanically strengthened polyacrylamide gel matrix fully compatible with electrophoresis of proteins and nucleic acids. AB - Polyacrylamide gel electrophoresis is a universal tool in a biochemist's toolkit for protein and nucleic acid separation and subsequent visualisation and analysis. The standard formulation of polyacrylamide gels consists of acrylamide (ACM) monomer crosslinked with bisacrylamide (MBA) which creates a gel with excellent sieving properties but which is mechanically fragile and prone to tearing during post-electrophoresis manipulations involved in visualisation and analysis. By adding a poly(ethylene oxide) macro-crosslinker to the standard gel formulation, we have created a tough gel matrix that can be used to fractionate proteins and nucleic acids by polyacrylamide gel electrophoresis. The protein and nucleic acid resolving capabilities and performance during staining and electroblotting of the tough gel matrix rivals that of conventional acrylamide/bisacrylamide gels. The tough gel matrix is resistant to tear and remarkably elastic, capable of stretching to over four times its original length before breaking, and represents a significant improvement over standard polyacrylamide gel formulations. PMID- 29125657 TI - Bending-Tolerant Anodes for Lithium-Metal Batteries. AB - Bendable energy-storage systems with high energy density are demanded for conformal electronics. Lithium-metal batteries including lithium-sulfur and lithium-oxygen cells have much higher theoretical energy density than lithium-ion batteries. Reckoned as the ideal anode, however, Li has many challenges when directly used, especially its tendency to form dendrite. Under bending conditions, the Li-dendrite growth can be further aggravated due to bending induced local plastic deformation and Li-filaments pulverization. Here, the Li metal anodes are made bending tolerant by integrating Li into bendable scaffolds such as reduced graphene oxide (r-GO) films. In the composites, the bending stress is largely dissipated by the scaffolds. The scaffolds have increased available surface for homogeneous Li plating and minimize volume fluctuation of Li electrodes during cycling. Significantly improved cycling performance under bending conditions is achieved. With the bending-tolerant r-GO/Li-metal anode, bendable lithium-sulfur and lithium-oxygen batteries with long cycling stability are realized. A bendable integrated solar cell-battery system charged by light with stable output and a series connected bendable battery pack with higher voltage is also demonstrated. It is anticipated that this bending-tolerant anode can be combined with further electrolytes and cathodes to develop new bendable energy systems. PMID- 29125658 TI - A cross-sectional epidemiological study of hidradenitis suppurativa in an Irish population (SHIP). AB - BACKGROUND: Hidradenitis suppurativa (HS), a chronic inflammatory disease that affects apocrine gland-bearing skin, has a significant impact on patients' quality of life. Estimates of the epidemiologic prevalence of HS are highly variable, and clinical data on disease characteristics and patient burden of disease remain limited. OBJECTIVE: The primary objective of this study was to determine the number of patients with HS attending dermatology clinics in a hospital setting in Ireland (within a 6-month time period). Secondary objectives included the assessment of disease characteristics and the collection of patient responses on disease burden and work productivity. METHODS: This was an epidemiologic, non-interventional, cross-sectional study across four dermatology clinics in Ireland over a 6-month time period. The disease prevalence was estimated by calculating the percentage of total patients with a diagnosis of HS (the primary population) across the selected sites. Secondary analyses were performed using the full analysis set, which consisted of eligible adults (>=18 years of age) from the primary population who provided informed consent. Data from these analyses are presented as descriptive summary statistics, with the use of an analysis of covariance for continuous endpoints. RESULTS: The prevalence of HS across the four selected sites was estimated at 1.4% (95% CI, 1.24-1.62). One hundred and fifty eligible patients comprised the full analysis set. The majority of participants were white (95.3%), female (70.0%), cigarette smokers (56.0%) and overweight or obese (body mass index >=25 kg/m2 , 81.8%). Most patients for whom data were available presented with Hurley stage II (50.4%), and more than a third of the full analysis set had a relative with HS (34.7%). Questionnaire responses revealed a profound impact on quality of life, including diminished work productivity and various psychological comorbidities. CONCLUSION: This study offers insight into the clinical features and disease burden of hidradenitis suppurativa in an Irish population. PMID- 29125659 TI - Multiple consecutive recapture of rigid nanoparticles using a solid-state nanopore sensor. AB - Solid-state nanopore sensors have been used to measure the size of a nanoparticle by applying a resistive pulse sensing technique. Previously, the size distribution of the population pool could be investigated utilizing data from a single translocation, however, the accuracy of the distribution is limited due to the lack of repeated data. In this study, we characterized polystyrene nanobeads utilizing single particle recapture techniques, which provide a better statistical estimate of the size distribution than that of single sampling techniques. The pulses and translocation times of two different sized nanobeads (80 nm and 125 nm in diameter) were acquired repeatedly as nanobeads were recaptured multiple times using an automated system controlled by custom-built scripts. The drift-diffusion equation was solved to find good estimates for the configuration parameters of the recapture system. The results of the experiment indicated enhancement of measurement precision and accuracy as nanobeads were recaptured multiple times. Reciprocity of the recapture and capacitive effects in solid state nanopores are discussed. Our findings suggest that solid-state nanopores and an automated recapture system can also be applied to soft nanoparticles, such as liposomes, exosomes, or viruses, to analyze their mechanical properties in single-particle resolution. PMID- 29125660 TI - Primary prophylaxis of invasive fungal infections with posaconazole or itraconazole in patients with acute myeloid leukaemia or high-risk myelodysplastic syndromes undergoing intensive cytotoxic chemotherapy: A real world comparison. AB - This is an observational-retrospective study comparing the real-world outcomes associated with posaconazole vs itraconazole as prophylaxis treatments. Two hundred and ninety-three patient admissions attributable to 174 patients were included in the study. Patients were treated with itraconazole (n = 114 admissions; 39%) or posaconazole (n = 179; 61%). Antifungal prophylaxis failure (APF) due to treatment-related adverse events (in 34 out of 293 patient admissions; 11.6%) was more frequent in the posaconazole group (6.1% vs 15.1%; P = .024). There were 9 patient admissions for episodes of APF due to probable/proven breakthrough fungal infection (primary endpoint): 6 and 3 in the itraconazole and posaconazole group respectively (5.3% vs 1.7%; P = .095). All of them were associated with invasive pulmonary aspergillosis (IPA). APF was more frequent with itraconazole (65% vs 30%; P < .001), along with failure due to possible/probable/proven IPA (25% vs 10%; P = .002) and overall failure by any of the 3 different causes of prophylaxis failure (70% vs 38%; P < .001). In agreement with clinical trial data, this real-world evidence supports the use of posaconazole over itraconazole in AML or MDS patients undergoing intensive chemotherapy. PMID- 29125661 TI - Eyelid reanimation using crossface nerve graft: Relationship between surgical outcome and preoperative paralysis duration. AB - BACKGROUND: To reanimate the mimetic muscles, crossface nerve graft (CFNG) is an effective surgical option. However, muscle atrophy after facial paralysis may influence the surgical result. We analyzed the relationship between surgical result and preoperative paralysis duration. METHODS: We performed CFNG on 15 patients. The sural nerve was transferred between the affected and nonaffected sides of the zygomatic branch. Eyelid function and eyelid lid were evaluated using the modified House-Brackmann scale. The effects of age, sex, cause of facial paralysis, graft nerve length, and preoperative paralysis duration were evaluated. RESULTS: The mean follow up period was 9.3 +/- 3.3 (range 4-14) years. Eyelid closure was excellent in four patients, good in six, fair in one, and poor in four. Statistically, no significant difference was observed between those patients with excellent or good outcomes and fair or poor outcomes regarding age (40.9 +/- 11.0 years vs. 22.6 +/- 20.8; P = .067), sex (male/female = 2/8 vs. 3/2; P = .250), cause (tumor/trauma = 10/0 vs. 3/2; P = .095), and length of nerve graft (14.4 +/- 0.8 cm vs. 13.8 +/- 1.6 cm; P = .375). The average preoperative paralysis duration in the excellent/good patients was significantly shorter than that in the fair/poor patients (P = .005). All eight cases with preoperative paralysis of less than 6 months showed a marked excellent/good result. Two of the seven patients with preoperative paralysis was 6 months or longer marked fair/poor result. (P = .007). CONCLUSIONS: To achieve successful results with CFNG, surgery should be performed within 6 months of the onset of paralysis. PMID- 29125662 TI - How do Mediterranean shrub species cope with shade? Ecophysiological response to different light intensities. AB - Under natural conditions, light exposure for Mediterranean shrubs can be highly variable, especially during cloudy days or under a canopy, and can interfere with other environmental factors such as temperature and water availability. With the aim of decoupling the effect of radiation and temperature from water availability, we conducted an experiment where two perennial and three summer semi-deciduous shrub species were subjected to different levels of irradiation. In order to follow plant responses to light exposure, we measured gas exchange, photosystem II photochemical efficiency, photosynthetic pigments and leaf mass area in spring and summer. Results showed that all study species presented a plastic response to different light conditions, and that light-related traits varied in a coordinated manner. Summer semi-deciduous species exhibited a more opportunistic response, with higher photosynthesis rates in full sun, but under shade conditions, the two strategies presented similar assimilation rates. Stomatal conductance did not show such a drastic response as photosynthetsis, being related to changes in WUE. Daily cycles of Fv /Fm revealed a slight photoinhibitory response during summer, mainly in perennial species. In all cases photosynthetic pigments adjusted to the radiation level; leaves had lower chlorophyll content, higher pool of xanthophylls and higher proportion of the de epoxydaded state of xanthophylls under sun conditions. Lutein content increased in relation to the xanthophyll pool under shade conditions. Our results evidenced that radiation is an important driving factor controlling morphological and physiological status of Mediterranean shrub species, independently of water availability. Summer semi-deciduous species exhibit a set of traits with higher response variability, maximising their photosynthetic assimilation under different sun conditions. PMID- 29125663 TI - Biocatalytic Oxidative Cascade for the Conversion of Fatty Acids into alpha Ketoacids via Internal H2 O2 Recycling. AB - The functionalization of bio-based chemicals is essential to allow valorization of natural carbon sources. An atom-efficient biocatalytic oxidative cascade was developed for the conversion of saturated fatty acids to alpha-ketoacids. Employment of P450 monooxygenase in the peroxygenase mode for regioselective alpha-hydroxylation of fatty acids combined with enantioselective oxidation by alpha-hydroxyacid oxidase(s) resulted in internal recycling of the oxidant H2 O2 , thus minimizing degradation of ketoacid product and maximizing biocatalyst lifetime. The O2 -dependent cascade relies on catalytic amounts of H2 O2 and releases water as sole by-product. Octanoic acid was converted under mild conditions in aqueous buffer to 2-oxooctanoic acid in a simultaneous one-pot two step cascade in up to >99 % conversion without accumulation of hydroxyacid intermediate. Scale-up allowed isolation of final product in 91 % yield and the cascade was applied to fatty acids of various chain lengths (C6:0 to C10:0). PMID- 29125664 TI - Changes in nitric oxide levels and their relationship with callose deposition during the interaction between soybean and Soybean mosaic virus. AB - The present study aimed to investigate changes in nitric oxide (NO) level and its relationship with callose deposition during the interaction between soybean and Soybean mosaic virus (SMV). Soybean cv. 'Jidou 7' and SMV strains N3 and SC-8 were used to constitute incompatible and compatible combinations. Intracellular NO was labelled with the NO-specific fluorescence probe DAF-FM DA. Confocal laser scanning microscopy (CLSM) was then used to observe changes in NO production during SMV infection-induced defence responses in soybean. The results showed NO fluorescence increased rapidly at 2-72 h post-inoculation, peaked at 72 h and then decreased in the incompatible combination. However, in the compatible combination, extremely weak NO fluorescence appeared in the early stage (2-24 h) post-inoculation, but was not observed thereafter. Injections of the NO scavenger c-PTIO prior to inoculation postponed the onset of NO production to 48 or 72 h post-inoculation. The same occurred when injections of NR or NOS inhibitors were applied prior to inoculation. The observation of callose fluorescence in the incompatible combination revealed that either the elimination or reduction of NO in the early stage led to a delay in callose formation, enabling the virus to cause systemic infection. Together with our previous findings, this study indicates that viral infection could induce NO production and callose deposition during the incompatible interaction between soybean and SMV. The production of NO involves NR and NOS enzymatic pathways, and NO mediates the process of callose deposition at plasmodesmata. PMID- 29125665 TI - Firearms and Suicide: Finding the Right Words. PMID- 29125666 TI - Tenosynovitis caused by Mycobacterium malmoense in two kidney transplant recipients and review of the literature. AB - We report two unrelated cases of tenosynovitis caused by Mycobacterium malmoense in kidney transplant recipients. Both patients received immunosuppression and were referred to our tertiary hospital because of persisting complaints lasting >6 months not responding to corticosteroids or surgery. The mycobacterial cultures were positive for the slow-growing M. malmoense after several weeks of incubation. The patient in Case 1 was treated with a combination of surgical debridement and antibiotics, whereas the patient in Case 2 was only treated surgically. Both cases illustrate the doctor's delay in diagnosing mycobacterial infections, and remind us that nontuberculous mycobacterial infections should be part of the differential diagnosis of tenosynovitis, especially in immunocompromised patients. PMID- 29125667 TI - The Divergent Dimerization Behavior of N-Substituted Dicyanomethyl Radicals: Dynamically Stabilized versus Stable Radicals. AB - Herein, we demonstrate that the dimerization behavior of amine-substituted dicyanomethyl radicals can be switched from sigma- to pi-dimerization simply by varying the electron-donating substituents. For dicyanomethyl radicals with a 4,4'-ditolylamine (DT. ) or a phenothiazine (PT. ) substituent, the monomeric radical form and the corresponding dimer connected by a reversible C-C bond (sigma-dimer) are in equilibrium in solution. On the other hand, the radical with the julolidine skeleton (JD. ) does not undergo sigma-dimerization and was isolated as a stable radical in spite of the absence of bulky protecting groups. X-ray single-crystal analysis revealed that JD. forms the pi-dimer in the crystalline state, and variable-temperature spectroscopy showed that JD. is in equilibrium with the pi-dimer in toluene solution. DFT calculations point to the importance of electrostatic interactions as a driving force for the pi dimerization of JD. because of its polarized structure. PMID- 29125668 TI - Distribution and related factors of cardiometabolic disease stage based on body mass index level in Chinese adults-The National Diabetes and Metabolic Disorders Survey. AB - BACKGROUND: It is important to characterize distribution of cardiometabolic disease (CMD) based on different body mass index (BMI) levels in a population. This information remains scarce in China, so we investigated the proportions and related factors of cardiometabolic disease stages based on different BMI levels in Chinese adults. METHODS: We included 45 093 participants aged >=20 years from the National Diabetes and Metabolic Disorders Survey. Cardiometabolic disease (central obesity, elevated triglycerides, elevated blood pressure, elevated plasma glucose, reduced high-density lipoprotein cholesterol, and cardiovascular disease) was classified as stage 0 (no CMD), stage 1 (mild-to-moderate CMD), or stage 2 (severe CMD). Overweight/obesity was defined as BMI >=25 kg/m2 . RESULTS: The standardized proportions of stage 0, stage 1, and stage 2 were 32.6%, 36.4%, and 30.9% in normal-weight men, 29.9%, 42.5%, and 27.7% in normal-weight women, 4.9%, 31.7%, and 63.4% in overweight/obese men, and 6.9%, 31.4%, and 61.7% in overweight/obese women, respectively. Multinomial regression showed that regardless of gender or region, the probability of severe cardiometabolic disease rapidly increased with increasing BMI. Severe cardiometabolic disease risk was positively associated with ageing, family history of diabetes, hypertension, or cardiovascular disease, but was inversely associated with higher levels of education and increased physical activity. CONCLUSIONS: Of Chinese men and women with normal weight, more than one third had mild-to-moderate cardiometabolic disease, and less than one third had severe cardiometabolic disease, while of these with overweight or obesity, nearly one third had mild-to-moderate cardiometabolic disease, and nearly two thirds had severe cardiometabolic disease. PMID- 29125669 TI - The role of Arabidopsis thaliana RASD1 gene in ABA-dependent abiotic stress response. AB - Abiotic stress is one of the key parameters affecting plant productivity. Drought and soil salinity, in particular, challenge plants to activate various response mechanisms to withstand these adverse growth conditions. While the molecular events that take place are complex and to a large extent unclear, the plant hormone abscisic acid (ABA) is considered a major player in mediating the adaptation of plants to stress. Here we report the identification of an ABA insensitive mutant from Arabidopsis thaliana. A combination of molecular, genetic and physiology approaches were implemented, to characterise the AtRASD1 locus (RESPONSIVENESS TO ABA SALT AND DROUGHT 1) and to investigate its role in plant development. RASD1 is expressed predominantly in the vascular system of A. thaliana and encodes a peptide of unknown function with no similarity to any known sequence to date. The protein is localised in the nucleus and the cytoplasm, and RASD1-impaired plants are drought-intolerant and insensitive to exogenous ABA and NaCl during germination and root growth. Our data indicate that RASD1 is involved in ABA-dependent signal transduction pathways and therefore in enabling plants to activate response mechanisms related to seed germination and abiotic stress. PMID- 29125671 TI - First trimester pre-eclampsia screening: why delay implementation? PMID- 29125670 TI - Use of a hepatitis C virus (HCV) RNA-positive donor in a treated HCV RNA-negative liver transplant recipient. AB - The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA-positive donor organs are typically not given to patients who have cleared HCV. A 64-year-old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15 IU/mL by week 10. At week 18 of a planned 24-week treatment course, the patient underwent deceased-donor LT and received an organ from an anti-HCV-positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12 weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV-infected transplant patients. PMID- 29125672 TI - Reply. PMID- 29125673 TI - Overexpression of SDH confers tolerance to salt and osmotic stress, but decreases ABA sensitivity in Arabidopsis. AB - Sorbitol dehydrogenase (SDH) catalyses the reversible oxidation of sorbitol, xylitol and ribitol to their corresponding ketoses. In this study, we investigated the expression and role of Arabidopsis SDH in salt and osmotic stress tolerance, and abscisic acid (ABA) response. The expression patterns of SDH were investigated using transgenic Arabidopsis plants expressing beta glucuronidase (GUS) under control of the promoter with the first intron of SDH. qRT-PCR and histochemical assay of GUS activity were used to study SDH expression regulation by ABA, salt and osmotic stress. SDH-overexpression lines of Arabidopsis were used to investigate the role of SDH in salt and osmotic stress, and ABA response. Arabidopsis SDH was predominantly expressed in source organs such as green cotyledons, fully expanded leaves and sepals, especially in vascular tissues of theses organs. SDH expression was inhibited by NaCl and mannitol treatments. Seed germination and post-germination growth of SDH overexpressing lines exhibited decreased sensitivity to salt and osmotic stress compared to WT plants. The transcript of SDH was induced by ABA. Overexpression of SDH decreased sensitivity to ABA during seed germination and post-germination growth. Expression of AAO3 increased but ABI5 and MYB2 decreased in SDH overexpressing lines after ABA treatment. This study demonstrates that expression of SDH is regulated by ABA, salt and osmotic stress. SDH functions in plant tolerance to salt and osmotic stress, and ABA response via specific regulating gene expression of ABA synthesis and signalling in Arabidopsis. PMID- 29125674 TI - Women's preference for non-invasive prenatal DNA testing versus chromosomal microarray after screening for Down syndrome: a prospective study. AB - OBJECTIVE: To examine preferences for follow-up testing in women screened with high or intermediate risk for Down syndrome in the first or second trimester. DESIGN: Prospective cohort study. SETTING: Three public hospitals in Hong Kong, China. SAMPLE: Women with pregnancies termed as high risk (>=1:250; HR) or intermediate risk (1:251-1200; IR) for Down syndrome. METHODS: Women with pregnancies screened as HR were offered the choices of: (1) an invasive test plus chromosomal microarray (CMA) to obtain more detailed fetal genetic information; (2) non-invasive cell-free prenatal DNA screening (NIPT) to detect trisomies 13, 18 and 21, and to avoid procedure-related miscarriage; and (3) to decline any further testing. Women received standardised counselling informing them that the reporting times were identical, the procedure miscarriage risk was 0.1-0.2% and that there was no charge for screening. Women with IR pregnancies (1:251-1200) were offered NIPT as a secondary screening test. MAIN OUTCOME MEASURES: Uptake rate for NIPT. RESULTS: Three hundred and forty-seven women had pregnancies deemed as HR; 344 (99.1%) women opted for follow-up testing, 216 (62.2%) of whom chose NIPT. Five hundred and seven of 614 women (82.6%) with IR risk chose NIPT. Seven (21%) of 34 women with nuchal translucency >=3.5 mm opted for NIPT. CONCLUSION: In a setting where reporting times are similar and there is no cost difference between options, approximately 60% of women with pregnancies classed as HR would opt for NIPT, offering simple but limited aneuploidy assessment, over a diagnostic procedure with comprehensive and more detailed assessment. TWEETABLE ABSTRACT: 60% of pregnant Chinese women prefer NIPT over CMA when screened as high risk for Down syndrome. PMID- 29125675 TI - Simultaneous Application of Photothermal Therapy and an Anti-inflammatory Prodrug using Pyrene-Aspirin-Loaded Gold Nanorod Graphitic Nanocapsules. AB - Photothermal therapy (PTT) has been extensively developed as an effective approach against cancer. However, PTT can trigger inflammatory responses, in turn simulating tumor regeneration and hindering subsequent therapy. A therapeutic strategy was developed to deliver enhanced PTT and simultaneously inhibit PTT induced inflammatory response. 1-Pyrene methanol was utilize to synthesize the anti-inflammatory prodrug pyrene-aspirin (P-aspirin) with a cleavable ester bond and also facilitate loading the prodrug on gold nanorod (AuNR)-encapsulated graphitic nanocapsule (AuNR@G), a photothermal agent, through pi-pi interactions. Such AuNR@G-P-aspirin complexes were used for near-infrared laser-triggered photothermal ablation of solid tumor and simultaneous inhibition of PTT-induced inflammation through the release of aspirin in tumor milieu. This strategy showed excellent effects in vitro and in vivo. PMID- 29125676 TI - Decreasing mortality and disease severity in hepatitis C patients awaiting liver transplantation in the United States. AB - Hepatitis C virus (HCV) infection has been the leading indication for liver transplantation (LT) in the United States. Since 2013, interferon-free antiviral therapy has led to sustained virological response in many LT candidates. We compared the wait-list mortality of HCV patients with that of patients with other chronic liver diseases. Data for primary LT candidates were obtained from the Organ Procurement and Transplantation Network database. Adult wait-list registrants were divided into 3 cohorts: cohort 1 included patients on the waiting list as of January 1, 2004; cohort 2 as of January 1, 2009; and cohort 3 as of January 1, 2014. The primary outcome was wait-list mortality, and the secondary outcome was the rate of change in Model for End-Stage Liver Disease (MELD). Multivariate Cox proportional hazards analysis was performed to evaluate 12-month wait-list mortality. The cohorts included 7627 LT candidates with HCV and 13,748 patients without HCV. Compared with cohort 2, HCV patients in cohort 3 had a 21% lower risk of death (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.67-0.93). Among patients with non-HCV liver disease, no difference in mortality was seen between cohorts 2 and 3 (HR, 0.97; 95% CI, 0.86-1.09). Among HCV patients, the mean rate of change in MELD decreased from 2.35 per year for cohort 2 to 1.90 per year for cohort 3, compared with 1.90 and 1.66 in cohorts 2 and 3, respectively, among non-HCV patients. In this population-based study, wait list mortality and progression of disease severity decreased in recent HCV patients for whom direct-acting antiviral agents were available. Liver Transplantation 24 735-743 2018 AASLD. PMID- 29125677 TI - A dyadic analysis of stress processes in Latinas with breast cancer and their family caregivers. AB - OBJECTIVE: Breast cancer diagnosis and treatment negatively affect quality of life for survivors and their family caregivers. The stress process model has been useful for describing the cascade of social and psychological experiences that culminate in degraded quality of life for both survivors and their family caregivers. This study is designed to test theoretically specified predictors of negative psychosocial outcomes in a dyadic context. METHODS: Participants were 230 dyads composed of Latinas recently diagnosed with breast cancer and their primary family caregiver, who completed measures of socioeconomic status, stress, family conflict, depression, and anxiety. Data were analyzed following the Actor Partner Interdependence Mediation Model in structural equation modeling. RESULTS: For both survivors and caregivers, there were significant direct and indirect actor effects (through family conflict) of perceived stress on depression and anxiety. Several indirect partner effects were also evident in this sample. Specifically, caregivers' stress was predictive of survivors' depression and anxiety through survivors' increased perceptions of family conflict. CONCLUSIONS: As predicted by the stress process model, stress and family conflict were predictive of psychological distress in breast cancer survivors and their family caregivers. Significant partner effects in the Actor-Partner Interdependence Mediation Model suggest that there are some dyadic influences, particularly from caregivers' stress to survivors' perceptions of exacerbated family conflict. These findings show how strained family relationships can aggravate the well being of cancer survivors and their family caregivers through this challenging experience. PMID- 29125678 TI - Spata-13,17-diene Synthase-An Enzyme with Sesqui-, Di-, and Sesterterpene Synthase Activity from Streptomyces xinghaiensis. AB - A terpene synthase from the marine bacterium Streptomyces xinghaiensis has been characterised, including a full structure elucidation of its products from various substrates and an in-depth investigation of the enzyme mechanism by isotope labelling experiments, metal cofactor variations, and mutation experiments. The results revealed an interesting dependency of Mn2+ catalysis on the presence of Asp-217, a residue that is occupied by a highly conserved Glu in most other bacterial terpene synthases. PMID- 29125679 TI - Topical Tranexamic Acid Compared With Anterior Nasal Packing for Treatment of Epistaxis in Patients Taking Antiplatelet Drugs: Randomized Controlled Trial. AB - OBJECTIVE: We evaluated the efficacy of topical application of the injectable form of tranexamic acid (TXA) compared with anterior nasal packing (ANP) for the treatment of epistaxis in patients taking antiplatelet drugs (aspirin, clopidogrel, or both) who presented to the emergency department (ED). METHODS: A randomized, parallel-group clinical trial was conducted at two EDs. A total of 124 participants were randomized to receive topical TXA (500 mg in 5 mL) or ANP, 62 patients per group. The primary outcome was the proportion of patients in each group whose bleeding had stopped at 10 minutes. Secondary outcomes were the rebleeding rate at 24 hours and 1 week, ED length of stay (LOS), and patient satisfaction. RESULTS: Within 10 minutes of treatment, bleeding was stopped in 73% of the patients in the TXA group, compared with 29% in the ANP group (difference = 44%, 95% confidence interval, 26% to 57%; p < 0.001). Additionally, rebleeding was reported in 5 and 10% of patients during the first 24 hours in the TXA and the ANP groups, respectively. At 1 week, 5% of patients in the TXA group and 21% of patients in the ANP group had experienced recurrent bleeding (p = 0.007). Patients in the TXA group reported higher satisfaction scores (median [interquartile range {IQR}], 9 [8-9.25]) compared with the ANP group (median [IQR] = 4 [3-5]; p < 0.001). Discharge from the ED in <2 hours was achieved in 97% of patients in the TXA group versus 13% in the ANP group (p < 0.001). There were no adverse events reported in either group. CONCLUSIONS: In our study population, epistaxis treatment with topical application of TXA resulted in faster bleeding cessation, less rebleeding at 1 week, shorter ED LOS, and higher patient satisfaction compared with ANP. PMID- 29125680 TI - Carbon Dioxide Utilization Coming of Age. PMID- 29125682 TI - Low Temperature Synthesis of Large-Size Anatase TiO2 Nanosheets with Enhanced Photocatalytic Activities. AB - TiO2 nanosheets have continuously been intriguing due to their high surface activities as photocatalyst but still challenging to synthesis large-scale 2D nanostructures. A special microstructure evolution of TiO2 , ripening in aqueous solution at low temperature (~4 degrees C), is found for the first time, i.e., from the initial aperiodic atom-networks gradually into low crystallized continuous spongy structure with small crystal facets and ultimately forming large-size anatase nanosheets with exposed (101) and (200) facets. Based on this finding, the synthesized anatase TiO2 nanosheets possess monodispersed large scale 2D nanostructure so as to exhibit appreciable quantum size effects and remarkable enhanced optical absorption capacity. Using photocatalytic reduction of Cr (VI) to Cr (III) as the probe reaction to evaluate photocatalytic activities of the TiO2 nanosheets, the reductivity of Cr (VI) achieves 99.8% in 15 min under irradiation of 200-800 nm light. At the same time, an in situ Cr (III)-doping occurs spontaneously and triggers pronounced visible light driven photocatalysis, reducing 99% of Cr (VI) in 100 min under irradiation of 400-800 nm light. PMID- 29125681 TI - 2015/16 I-MOVE/I-MOVE+ multicentre case-control study in Europe: Moderate vaccine effectiveness estimates against influenza A(H1N1)pdm09 and low estimates against lineage-mismatched influenza B among children. AB - BACKGROUND: During the 2015/16 influenza season in Europe, the cocirculating influenza viruses were A(H1N1)pdm09 and B/Victoria, which was antigenically distinct from the B/Yamagata component in the trivalent influenza vaccine. METHODS: We used the test-negative design in a multicentre case-control study in twelve European countries to measure 2015/16 influenza vaccine effectiveness (VE) against medically attended influenza-like illness (ILI) laboratory-confirmed as influenza. General practitioners swabbed a systematic sample of consulting ILI patients and a random sample of influenza-positive swabs was sequenced. We calculated adjusted VE against influenza A(H1N1)pdm09, A(H1N1)pdm09 genetic group 6B.1 and influenza B overall and by age group. RESULTS: We included 11 430 ILI patients, of which 2272 were influenza A(H1N1)pdm09 and 2901 were influenza B cases. Overall VE against influenza A(H1N1)pdm09 was 32.9% (95% CI: 15.5-46.7). Among those aged 0-14, 15-64 and >=65 years, VE against A(H1N1)pdm09 was 31.9% (95% CI: -32.3 to 65.0), 41.4% (95% CI: 20.5-56.7) and 13.2% (95% CI: -38.0 to 45.3), respectively. Overall VE against influenza A(H1N1)pdm09 genetic group 6B.1 was 32.8% (95% CI: -4.1 to 56.7). Among those aged 0-14, 15-64 and >=65 years, VE against influenza B was -47.6% (95% CI: -124.9 to 3.1), 27.3% (95% CI: -4.6 to 49.4) and 9.3% (95% CI: -44.1 to 42.9), respectively. CONCLUSIONS: Vaccine effectiveness (VE) against influenza A(H1N1)pdm09 and its genetic group 6B.1 was moderate in children and adults, and low among individuals >=65 years. Vaccine effectiveness (VE) against influenza B was low and heterogeneous among age groups. More information on effects of previous vaccination and previous infection is needed to understand the VE results against influenza B in the context of a mismatched vaccine. PMID- 29125683 TI - Organellar Omics-A Reviving Strategy to Untangle the Biomolecular Complexity of the Cell. AB - A eukaryotic cell encompasses many membrane-enclosed organelles, each of these holding several types of biomolecules that exhibit tremendous diversity in terms of their localization and expression. Despite the development of increasingly sensitive analytical tools, the enormous biomolecular complexity that exists within a cell cannot yet be fully resolved as low abundant molecules often remain unrecognized. Moreover, a drawback of whole cell analysis is that it does not provide spatial information and therefore it is not capable of assigning distinct biomolecules to specific compartments or analyzing changes in the composition of these compartments. Reduction of the biomolecular complexity of a sample helps to identify low abundant molecules, but such a reductionist approach requires methods that enable proper isolation and purification of individual cellular organelles. Decades of research have led to the development of a plethora of isolation methods for a broad range of subcellular organelles; yet, in particular, intrinsically dynamic compartments belonging to the endocytic machinery, including the plasma membrane, remain difficult to isolate in a sufficiently pure fraction. In this review, we discuss various methods that are commonly used to isolate subcellular organelles from cells and evaluate their advantages and disadvantages. PMID- 29125684 TI - Magnesium boosts the memory restorative effect of environmental enrichment in Alzheimer's disease mice. AB - BACKGROUND: Environmental enrichment (EE) has been shown to enhance cognitive function in mouse models of Alzheimer's disease (AD). Magnesium-L-threonate (MgT) is a compound with a newly discovered effect to rescue learning and memory function in aging and AD mice. AIM: To study the additive therapeutic effect of EE combined with MgT (EM) and the potential mechanism underlying the effects. MATERIALS AND METHODS: APP/PS1 mice were treated with EE, MgT, or combination of EE and MgT (EM) and compared for restored memory function. RESULTS: EM was more effective in improving cognition and spatial memory than either treatment alone in either long-term (12 months, started at 3 months old, which was before disease manifestation) or short-term (3 months, started at 6 months old, which was after disease manifestation) treatment. The behavioral improvement has coincided with rescue of synaptic contacts in the hippocampal region of the AD mouse brain. Immunoblots also showed that EM but neither single treatment rescued the activity reduction in CaMKII and CREB, two important downstream molecules in the N-methyl D-aspartate receptor (NMDAR) pathway. CONCLUSION: Environmental enrichment and MgT may synergistically improve recognition and spatial memory by reducing synaptic loss and restoring the NMDAR signaling pathway in AD mice, which suggests that combination of EE and MgT may be a novel therapeutic strategy for AD. PMID- 29125685 TI - Low-Temperature and Rapid Growth of Large Single-Crystalline Graphene with Ethane. AB - Future applications of graphene rely highly on the production of large-area high quality graphene, especially large single-crystalline graphene, due to the reduction of defects caused by grain boundaries. However, current large single crystalline graphene growing methodologies are suffering from low growth rate and as a result, industrial graphene production is always confronted by high energy consumption, which is primarily caused by high growth temperature and long growth time. Herein, a new growth condition achieved via ethane being the carbon feedstock to achieve low-temperature yet rapid growth of large single-crystalline graphene is reported. Ethane condition gives a growth rate about four times faster than methane, achieving about 420 um min-1 for the growth of sub centimeter graphene single crystals at temperature about 1000 degrees C. In addition, the temperature threshold to obtain graphene using ethane can be reduced to 750 degrees C, lower than the general growth temperature threshold (about 1000 degrees C) with methane on copper foil. Meanwhile ethane always keeps higher graphene growth rate than methane under the same growth temperature. This study demonstrates that ethane is indeed a potential carbon source for efficient growth of large single-crystalline graphene, thus paves the way for graphene in high-end electronical and optoelectronical applications. PMID- 29125686 TI - Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease. AB - It was previously thought that neurons were phagocytosed only when dead or dying. However, it is increasingly clear that viable synapses, dendrites, axons and whole neurons can be phagocytosed alive (defined here as neurophagy), and this may contribute to a wide range of developmental, physiological and pathological processes. Phagocytosis of live synapses, dendrites and axons by glia contributes to experience-dependent sculpting of neuronal networks during development, but excessive phagocytosis of synapses may contribute to pathology in Alzheimer's disease, schizophrenia and ageing. Neurons can expose phosphatidylserine or calreticulin, which act as 'eat me' signals provoking phagocytosis via microglial receptors, whereas sialylation of neuronal surfaces acts as a 'don't eat me' signal that inhibits phagocytosis and desialylation can provoke phagocytosis. Opsonins, such as complement components and apolipoproteins, are released during inflammation and enhance engulfment. Phagocytosis of neurons is seen in multiple human diseases, but it is as yet unclear whether inhibition of phagocytosis will be beneficial in treating neurological diseases. Here we review the signals regulating glial phagocytosis of live neurons and synapses, and the involvement of this phagocytosis in development and disease. PMID- 29125687 TI - Con: Liver transplantation for expanded criteria malignant diseases. AB - Organ shortage requires policies and guidelines to aid organ allocation along the principles of urgency or utility. Identifying patients with significant benefit and withholding liver transplantation (LT) from patients too sick for transplantation are ongoing challenges, in particular in patients with malignancies. An arbitrary threshold of >50% 5-year overall survival (OS) is broadly considered a minimum standard for LT. In patients transplanted for intrahepatic cholangiocarcinoma (iCC), this was only achieved in select cases and when the tumor had a diameter of <2 cm. In patients with extrahepatic and hilar cholangiocarcinoma (CCC), strict selection criteria and combined preoperative radiotherapy/chemotherapy according to the Mayo protocol showed that acceptable longterm results can be achieved in a single high-volume center but are difficult to repeat elsewhere. Furthermore, only rigorously selected patients with neuroendocrine tumors (NETs) meeting the NET Milan criteria adopted by United Network for Organ Sharing can also have >50% 5-year OS. A prospective study in patients with unresectable colorectal cancer metastases in the liver has shown promising OS rates, but further prospective trials are warranted. Current evidence shows that none of the proposed expanded malignant criteria justify deviation of scarce donor organs to patients with hilar CCC, iCC > 2 cm, metastatic NET beyond NET Milan criteria, or metastatic colorectal cancer (CRC) outside clinical trials. Liver Transplantation 24 104-111 2018 AASLD. PMID- 29125688 TI - A Metal-Polyphenol Network Coated Nanotheranostic System for Metastatic Tumor Treatments. AB - As a characteristic trait of most tumor types, metastasis is the major cause of the death of patients. In this study, a photothermal agent based on gold nanorod is coated with metal (Gd3+ )-organic (polyphenol) network to realize combination therapy for metastatic tumors. This nanotheranostic system significantly enhances antitumor therapeutic effects in vitro and in vivo with the combination of photothermal therapy (PTT) and chemotherapy, also can remarkably prevent the invasion and metastasis due to the presence of polyphenol. After the treatment, an 81% decrease in primary tumor volumes and a 58% decrease in lung metastasis are observed. In addition, the good performance in magnetic resonance imaging, computerized tomography, and photothermal imaging of the nanotheranostic system can realize image-guided therapy. The multifunctional nanotheranostic system will find a great potential in diagnosis and treatment integration in tumor treatments, and broaden the applications of PTT treatment. PMID- 29125690 TI - Cancer and risk of cerebral venous thrombosis: a case-control study. AB - : Essentials The risk of cerebral venous thrombosis (CVT) in patients with cancer is not known. We performed a case-control study including 594 patients with CVT and 6278 controls. History of cancer increased the risk of CVT approximately 5 fold. The association was strongest with hematological cancer in the first year after diagnosis. SUMMARY: Background Cancer is an established risk factor for leg vein thrombosis and pulmonary embolism. Controlled studies assessing the risk of cerebral venous thrombosis (CVT) in patients with cancer have not been performed. Objective To assess whether cancer is a risk factor for CVT. Patients/Methods This was a case-control study. We assessed consecutive adult patients with CVT from three academic hospitals from 1987 to 2015, and control subjects from the Dutch MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis). We adjusted for age, sex and oral contraceptive use, and stratified for type of cancer and time since diagnosis of cancer. Results We included 594 cases and 6278 controls. In total, 53 cases (8.9%) and 160 controls (2.5%) had a history of cancer. Cases were younger (median 42 vs. 48 years), more often female (68% vs. 54%) and more often used oral contraceptives (55% vs. 23%) than controls. The risk of CVT was increased in patients with cancer compared with those without cancer (adjusted odds ratio [aOR], 4.86; 95% confidence interval [CI], 3.46-6.81). Patients with a hematological type of cancer had a higher risk of CVT (aOR, 25.14; 95% CI, 11.64-54.30) than those with a solid type of cancer (aOR, 3.07; 95% CI, 2.03-4.65). The association was strongest in the first year after diagnosis of cancer (hematological aOR, 85.57; 95% CI, 19.70 371.69; solid aOR, 10.50; 95% CI, 5.40-20.42). Conclusions Our study indicates that cancer is a strong risk factor for CVT, particularly within the first year of diagnosis and in patients with a hematological type of cancer. PMID- 29125689 TI - Resource utilization and cost of influenza requiring hospitalization in Canadian adults: A study from the serious outcomes surveillance network of the Canadian Immunization Research Network. AB - BACKGROUND: Consideration of cost determinants is crucial to inform delivery of public vaccination programs. OBJECTIVES: To estimate the average total cost of laboratory-confirmed influenza requiring hospitalization in Canadians prior to, during, and 30 days following discharge. To analyze effects of patient/disease characteristics, treatment, and regional differences in costs. METHODS: Study utilized previously recorded clinical characteristics, resource use, and outcomes of laboratory-confirmed influenza patients admitted to hospitals in the Serious Outcomes Surveillance (SOS), Canadian Immunization Research Network (CIRN), from 2010/11 to 2012/13. Unit costs including hospital overheads were linked to inpatient/outpatient resource utilization before and after admissions. RESULTS: Dataset included 2943 adult admissions to 17 SOS Network hospitals and 24 Toronto Invasive Bacterial Disease Network hospitals. Mean age was 69.5 years. Average hospital stay was 10.8 days (95% CI: 10.3, 11.3), general ward stays were 9.4 days (95% CI: 9.0, 9.8), and ICU stays were 9.8 days (95% CI: 8.6, 11.1) for the 14% of patients admitted to the ICU. Average cost per case was $14 612 CAD (95% CI: $13 852, $15 372) including $133 (95% CI: $116, $150) for medical care prior to admission, $14 031 (95% CI: $13 295, $14 768) during initial hospital stay, $447 (95% CI: $271, $624) post-discharge, including readmission within 30 days. CONCLUSION: The cost of laboratory-confirmed influenza was higher than previous estimates, driven mostly by length of stay and analyzing only laboratory confirmed influenza cases. The true per-patient cost of influenza-related hospitalization has been underestimated, and prevention programs should be evaluated in this context. PMID- 29125691 TI - Virtual Environment for Social Information Processing: Assessment of Children with and without Autism Spectrum Disorders. AB - : Social information processing (SIP) skills are critical for developing and maintaining peer relationships. Building on existing assessment techniques, Virtual Environment for SIP (VESIPTM ), a simulation-based assessment that immerses children in social decision-making scenarios, was developed. This study presents preliminary evidence of VESIP's usefulness for measuring SIP skills in children with and without autism spectrum disorders (ASD). Twenty-one children with ASD and 29 control children participated. It was hypothesized that (a) children (8-12 years old), with and without ASD, would understand and interact effectively with VESIP; (b) VESIP scores would be reliable in both populations; and (c) children with ASD would score lower on SIP domains than typically developing peers. Results supported these hypotheses. Finally, response bias was also evaluated, showing that children with ASD have different problem-solving strategies than their peers. VESIP has great potential as a scalable assessment of SIP strengths and challenges in children with and without ASD. Autism Res 2018, 11: 305-317. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Children with autism spectrum disorders (ASDs) often struggle interpreting and responding to social situations. The present study suggests that an animated, simulation-based assessment approach is an effective way to measure how children with or without ASDs problem-solve challenging social situations. VESIP is an easy-to-use assessment tool that can help practitioners understand a child's particular strengths and weaknesses. PMID- 29125692 TI - Does Contraceptive Use in the United States Meet Global Goals? AB - CONTEXT: The United Nations Sustainable Development Goals (SDGs) seek to achieve health equity, and they apply to all countries. SDG contraceptive use estimates for the United States are needed to contextualize U.S. performance in relation to that of other countries. METHODS: Data from the 2011-2013 and 2013-2015 waves of the National Survey of Family Growth were used to calculate three SDG indicators of contraceptive use for U.S. women aged 15-44: contraceptive prevalence, unmet need for family planning and demand for family planning satisfied by modern methods. These measures were calculated separately for married or cohabiting women and for unmarried, sexually active women; differences by sociodemographic characteristics were assessed using t tests from logistic regression analysis. Estimates for married women were compared with 2010-2015 estimates from 94 other countries, most of which were low- or middle-income. RESULTS: For married or cohabiting women, U.S. estimates for contraceptive prevalence, unmet need and demand satisfied by modern methods were 74%, 9% and 80%, respectively; for unmarried, sexually active women, they were 85%, 11% and 82%, respectively. Estimates varied by sociodemographic characteristics, particularly among married or cohabiting women. Five countries performed better than the United States on contraceptive prevalence, 12 on unmet need and four on both measures; seven performed better on demand satisfied by modern methods. CONCLUSIONS: There is a need to continue efforts to expand access to contraceptive care in the United States, and to monitor the SDG indicators so that improvement can be tracked over time. PMID- 29125693 TI - Current status of liver transplantation for cholangiocarcinoma. PMID- 29125694 TI - Impaired long contact white matter fibers integrity is related to depression in Parkinson's disease. AB - AIMS: Depression is one of the most common nonmotor symptoms in Parkinson's disease (PD). But the pathogenesis is still unclear. Studies have shown that depression in PD is closely related to the white matter abnormalities, but the number of studies is still very small and lack of whole brain white matter lesions study. METHODS: In this study, we investigated whole brain white matter integrity in 31 depressed PD patients and 37 nondepressed PD patients by diffusion tensor imaging. RESULTS: There was no difference in age, gender, age of onset, disease duration, Hoehn-Yahr scale, Unified Parkinson's Disease Rating Scale scores-III, and Mini-Mental State Examination scores between the two groups. The only difference was the Hamilton Depression Rating Scale. Depressed PD patients showed reduced fractional anisotropy values in the left anterior corona radiata, left posterior thalamic radiation, left cingulum, left superior longitudinal fasciculus, left sagittal stratum (including inferior longitudinal fasciculus and inferior fronto-occipital fasciculus), and left uncinate fasciculus. In patients with depression, the Hamilton Depression Rating Scale (HDRS) was negatively correlated with the FA value in the left cingulum (r = 0.712, P = .032) and left superior longitudinal fasciculus (r = -0.699, P = .025). CONCLUSIONS: This study suggested depression in PD was related to impaired white matter integrity especially the long contact fibers in the left hemisphere. These findings may be helpful for further understanding the potential mechanisms underlying depression in PD. PMID- 29125695 TI - Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm. AB - : Essentials The accuracy of the age-adjusted D-dimer in suspected venous thromboembolism is still debated. We assessed the performance of age-adjusted D dimer combined with the PALLADIO algorithm. The age-adjusted threshold can reduce the need for imaging tests compared to the fixed cut-off. The safety of this approach should be confirmed in large management studies. SUMMARY: Background Age adjusted D-dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned. Objectives To assess the diagnostic performance of age adjusted D-dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT). Methods PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D-dimer (using the manufacturer's cut-off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D-dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D-dimer underwent limited CUS (group 2); patients with likely PTP and positive D-dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3 month follow-up. In this post-hoc analysis we evaluated age-adjusted D-dimer cut off (defined as age times 10 MUg L-1 , or age times 5 MUg L-1 for D-dimers with a lower manufacturer's cut-off, in patients > 50 years). Results In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age-adjusted D-dimer, compared with the fixed cut-off, resulted in 5.1% (95% CI, 4.0-6.5%) reduction of CUS. The incidence of symptomatic VTE during follow-up was: 0.24% (95% CI, 0.04-1.37) in group 1; 1.12% (95% CI, 0.44-2.85) in group 2; and 1.89% (95% CI, 0.64-5.40) in group 3. Conclusions The PALLADIO algorithm using age-adjusted D-dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies. PMID- 29125697 TI - Vocal fold augmentation under local anaesthesia using autologous fascia. PMID- 29125696 TI - Detection of 13 mycotoxins in feed using modified QuEChERS with dispersive magnetic materials and UHPLC-MS/MS. AB - An analytical method for the simultaneous determination of 13 mycotoxins in feed by magnetic dispersive solid-phase extraction combined with ultra-high performance liquid chromatography and tandem mass spectrometry was developed. The samples were extracted with acetonitrile/water (80:20, v/v, containing 3% acetic acid), and separated by centrifugation after salting-out, and then treated with magnetic adsorbents to remove interferences. The separation of target mycotoxins was performed on an ACQUITY UPLC HSS T3 column using a mobile phase consisting of 1 mmol/L ammonium acetate with 0.1% formic acid and methanol by gradient elution. Good linearities for the 13 mycotoxins were achieved with correlation coefficients over 0.99, and the recoveries of mycotoxins were in the range of 89.3-112.6% at spiking at levels of 5, 20, and 100 MUg/kg, with relative standard deviations of 0.9-10.4%. Based on the functional magnetic materials (MDN@Fe3 O4 , PSA@Fe3 O4 , ZrO2@ Fe3 O4 ) applied in dispersive solid-phase extraction, the pretreatment process is more convenient and it is beneficial to reduce the experimental cost by reusing the recycled magnetic materials. It is a simple, rapid, and environmentally friendly analytical method for the determination of mycotoxins in feed. PMID- 29125698 TI - Engineering Potato Virus X Particles for a Covalent Protein Based Attachment of Enzymes. AB - Plant virus nanoparticles are often used to display functional amino acids or small peptides, thus serving as building blocks in application areas as diverse as nanoelectronics, bioimaging, vaccination, drug delivery, and bone differentiation. This is most easily achieved by expressing coat protein fusions, but the assembly of the corresponding virus particles can be hampered by factors such as the fusion protein size, amino acid composition, and post-translational modifications. Size constraints can be overcome by using the Foot and mouth disease virus 2A sequence, but the compositional limitations cannot be avoided without the introduction of time-consuming chemical modifications. SpyTag/SpyCatcher technology is used in the present study to covalently attach the Trichoderma reesei endoglucanase Cel12A to Potato virus X (PVX) nanoparticles. The formation of PVX particles is confirmed by western blot, and the ability of the particles to display Cel12A is demonstrated by enzyme-linked immunosorbent assays and transmission electron microscopy. Enzymatic assays show optimal reaction conditions of 50 degrees C and pH 6.5, and an increased substrate conversion rate compared to free enzymes. It is concluded that PVX displaying the SpyTag can serve as new scaffold for protein display, most notably for proteins with post-translational modifications. PMID- 29125699 TI - Prevalence of diabetes mellitus in people clinically diagnosed with periodontitis: A systematic review and meta-analysis of epidemiologic studies. AB - OBJECTIVES: Diabetes mellitus and periodontitis are complex chronic diseases with an established bidirectional relationship. This systematic review evaluated in subjects with professionally diagnosed periodontitis the prevalence and odds of having diabetes. METHODS: The MEDLINE-PubMed, CENTRAL and EMBASE databases were searched. Prevalence of diabetes mellitus among subjects with periodontitis was extracted or if possible calculated. RESULTS: From the 803 titles and abstracts that came out of the search, 27 papers met the initial criteria. Prevalence of diabetes was 13.1% among subjects with periodontitis and 9.6% among subjects without periodontitis. Based on subanalysis, for subjects with periodontitis, the prevalence of diabetes was 6.2% when diabetes was self-reported, compared to 17.3% when diabetes was clinically assessed. The highest prevalence of diabetes among subjects with periodontitis was observed in studies originating from Asian countries (17.2%, n = 18,002) and the lowest in studies describing populations from Europe (4.3%, n = 7,858). The overall odds ratio for patients with diabetes to be among subjects with periodontitis as compared to those without periodontitis was 2.27 (95% CI [1.90;2.72]). A substantial variability in the definitions of periodontitis, combination of self-reported and clinically assessed diabetes, lack of confounding for diabetes control in included studies introduces estimation bias. CONCLUSIONS: The overall prevalence and odds of having diabetes are higher within periodontitis populations compared to people without periodontitis. Self-reported diabetes underestimates the prevalence when compared to this condition assessed clinically. Geographical differences were observed: the highest diabetes prevalence among subjects with periodontitis was observed in studies conducted in Asia and the lowest in studies originating from Europe. PMID- 29125701 TI - Data-driven reduced-order model of microtubule mechanics. AB - A beam element is constructed for microtubules based upon data reduction of the results from atomistic simulation of the carbon backbone chain of alphabeta tubulin dimers. The database of mechanical responses to various types of loads from atomistic simulation is reduced to dominant modes. The dominant modes are subsequently used to construct the stiffness matrix of a beam element that captures the anisotropic behavior and deformation mode coupling that arises from a microtubule's spiral structure. In contrast to standard Euler-Bernoulli or Timoshenko beam elements, the link between forces and node displacements results not from hypothesized deformation behavior, but directly from the data obtained by molecular scale simulation. Differences between the resulting microtubule data driven beam model (MTDDBM) and standard beam elements are presented, with a focus on coupling of bending, stretch, shear deformations. The MTDDBM is just as economical to use as a standard beam element, and allows accurate reconstruction of the mechanical behavior of structures within a cell as exemplified in a simple model of a component element of the mitotic spindle. PMID- 29125700 TI - Bioavailability and Pharmacokinetics of TRPV1 Antagonist Mavatrep (JNJ-39439335) Tablet and Capsule Formulations in Healthy Men: Two Open-Label, Crossover, Single Dose Phase 1 Studies. AB - To improve room temperature stability and oral bioavailability of mavatrep (JNJ 39439335, a transient receptor potential vanilloid subtype-1 antagonist), various formulations were initially developed and evaluated in 2 phase 1 open-label, randomized, 3-way crossover studies in healthy participants. Study 1 evaluated 2 new overencapsulated tablet formulations (formulations B and C) relative to an overencapsulated early tablet formulation (formulation A), using mavatrep HCl salt form. Because these tablets were still not room-temperature stable, in study 2: two free-base solid dispersion amorphous formulations (formulations D and E) were evaluated relative to the best encapsulated formulation from study 1 (formulation C) and also food effect. Both studies had screening (~4 weeks), treatment (study 1: n = 18, 6-sequenced; formulations B and C [2 * 25 mg] versus A [2 * 25 mg]; study 2, part 1: n = 24, formulations D and E [2 * 12.5 mg] versus C [1 * 25 mg]; study 2, part 2: n = 16, best formulation from part 1 fed versus fasted, 2 * 12.5 mg) with a 21-day washout period and a follow-up. Mavatrep exhibited consistent pharmacokinetics across formulations. Following rapid absorption (median tmax , 1.5-6.5 hours), plasma concentrations declined multiexponentially (mean t1/2 , 67-104 hours). The new encapsulated tablet formulation (formulation C, capsule filler: poloxamer 407) was the best formulation (Cmax and AUC values 2-3-fold > than the other 2) from study 1. Using this as a reference in study 2, part 1, only small (<20%) differences in mean Cmax and AUC were observed between the 3 formulations (C, D, and E). Formulation E (gelatin capsule with amorphous solid dispersion [12.5 mg free base], hydroxypropyl methylcellulose, vitamin E polyethylene glycol succinate, silicified microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide) showed improved room-temperature stability and provided the best overall bioavailability with small variability. Small effects of a high-fat meal on oral bioavailability were observed for formulation E, but were not clinically meaningful. Mavatrep safety profiles were similar across formulations and under fasted and fed conditions. No new safety concerns were reported. PMID- 29125702 TI - Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology. AB - Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects. PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design. Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher Cmax and 1.3 fold higher AUC compared with the oromucosal spray. Tmax following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ~15-fold increase in Cmax and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray. PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications. PMID- 29125703 TI - Pharmacokinetics and Safety of Mavatrep (JNJ-39439335), a TRPV1 Antagonist in Healthy Japanese and Caucasian Men: A Double-Blind, Randomized, Placebo Controlled, Sequential-Group Phase 1 Study. AB - This single-center, double-blind, placebo-controlled, sequential-group phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of mavatrep (JNJ-39439335), a transient receptor potential vanilloid 1 antagonist, in healthy Japanese and caucasian subjects. In part 1, a single-ascending-dose study, 50 subjects (25 each healthy Japanese and caucasians) were enrolled and received a single oral dose of 10, 25, or 50 mg mavatrep. Caucasian subjects were matched to Japanese subjects with respect to age (+/-5 years) and body mass index (+/-5 kg/m2 ). In part 2, a multiple-ascending-dose study, 36 Japanese subjects were enrolled and received once-daily oral doses of 10, 25, or 50 mg of mavatrep for 21 days. The single-dose PK of mavatrep and its metabolites was similar in the Japanese and caucasian subjects after adjustment of body weight. Following multiple dosing in Japanese subjects, a steady-state condition was reached in approximately 14 days. M2 and M3 are major circulating metabolites with mean exposure > 10% of mavatrep. Nonrenal clearance was the major route of elimination for mavatrep, M2, and M3. Mavatrep exhibited a long half-life, ranging from 68 to 101 and 82-130 hours for Japanese and caucasian subjects, respectively. After single and multiple dosing, mavatrep was well tolerated. The most common adverse events observed were thermohypoesthesia, feeling cold, chills, and feeling hot. Mavatrep and its metabolites exhibited similar PK profiles after single ascending doses in healthy Japanese and caucasian men. PMID- 29125704 TI - Left atrial ejection force predicts the outcome after catheter ablation for paroxysmal atrial fibrillation. AB - INTRODUCTION: Left atrium (LA) systolic dysfunction is observed in the early stages of atrial fibrillation (AF) prior to LA anatomical change. We investigated whether LA systolic dysfunction predicts recurrent AF after catheter ablation (CA) in patients with paroxysmal AF. METHODS AND RESULTS: We studied 106 patients who underwent CA for paroxysmal AF. LA systolic function was assessed with the LA emptying volume = Maximum LA volume (LAVmax ) - Minimum LA volume (LAVmin ), LA emptying fraction = [(LAVmax - LAVmin )/LAVmax ] * 100, and LA ejection force calculated with Manning's method [LA ejection force = (0.5 * rho * mitral valve area * A2 )], where rho is the blood density and A is the late-diastolic mitral inflow velocity. Recurrent AF was detected in 35/106 (33%) during 14.6 +/- 9.1 months. Univariate analysis revealed reduced LA ejection force, decreased LA emptying fraction, larger LA diameter, and elevated brain natriuretic peptide as significant variables. On multivariate analysis, reduced LA ejection force and larger LA diameter were independently associated with recurrent AF. Moreover, patients with reduced LA ejection force and larger LA diameter had a higher risk of recurrent AF than preserved LA ejection force (log-rank P = 0.0004). CONCLUSIONS: Reduced LA ejection force and larger LA diameter were associated with poor outcome after CA for paroxysmal AF, and could be a new index to predict recurrent AF. PMID- 29125705 TI - Mycobacterium tuberculosis Mce3C promotes mycobacteria entry into macrophages through activation of beta2 integrin-mediated signalling pathway. AB - Establishment of infection by facultative intracellular pathogen Mycobacterium tuberculosis (Mtb) requires adherence to and internalisation by macrophages. However, the effector molecules exploited by Mtb for entry into macrophages remain to be fully understood. The mammalian cell entry (Mce) proteins play an essential role in facilitating the internalisation of mycobacteria into mammalian cells. Here, we characterized Mtb Mce3C as a new mycobacterial surface protein that could promote mycobacterial adhesion to and invasion of macrophages in an RGD motif-dependent manner. We then further demonstrated that beta2 integrin was required for Mce3C-mediated cell entry. In addition, we found that binding of Mce3C recruited beta2 integrin-dependent signalling adaptors and induced local actin rearrangement at the site of mycobacterial invasion. By using specific antibodies and pharmacological inhibitors, we further demonstrated the involvement of Src-family tyrosine kinases, spleen tyrosine kinase, Vav, Rho, and Rho-associated kinase in Mce3C-mediated mycobacterial invasion. Our results reveal a novel mechanism by which Mtb Mce3C exploits integrin-mediated signalling cascade for Mce, providing potential targets for the development of therapies against Mtb infection. PMID- 29125707 TI - Vascularized humeral periosteal flap to treat lateral humeral condyle nonunion: An anatomical study and report of two successfully-treated pediatric cases. AB - PURPOSE: Nonunion is a common complication of lateral condyle humeral (LCH) fractures in children. In situ fixation with a screw and bone grafting is the classically-recommended method of treatment. The purpose of this study is to analyze the feasibility of obtaining a vascularized periosteal flap obtained from the lateral humerus and based on the posterior collateral radial vessels (PCRV). Second, to report the results after the application in two pediatric cases. METHODS: Periosteal branches of PCRV were studied in ten upper limbs from fresh human cadavers. Then, two children with LCH nonunion were treated with this flap. RESULTS: The PCRV provided mean of 5.3 anterior periosteal branches (range 4-7) with a mean distance between them of 19.1 mm (range 5-29 mm) and 5.7 posterior periosteal branches (range 3-7) with a mean distance between them of 15.9 mm (range 6-33 mm. PCRV distally anastomosed to the interosseous recurrent artery and the radial recurrent artery, creating a vascular net over the lateral condyle and allowing for the design of a reverse vascularized humeral periosteal flap (VHPF). Abundant periosteal callus and rapid consolidation were achieved in both children. No bone fixation or grafting was necessary. CONCLUSIONS: VHPF might be considered a viable biological surgical option to promote bone healing in LCH nonunions in children, while avoiding the need for bone fixation and the donor morbidity associated with bone grafting. PMID- 29125706 TI - Enhancing the Quantum Anomalous Hall Effect by Magnetic Codoping in a Topological Insulator. AB - The quantum anomalous Hall (QAH) effect, which has been realized in magnetic topological insulators (TIs), is the key to applications of dissipationless quantum Hall edge states in electronic devices. However, investigations and utilizations of the QAH effect are limited by the ultralow temperatures needed to reach full quantization-usually below 100 mK in either Cr- or V-doped (Bi,Sb)2 Te3 of the two experimentally confirmed QAH materials. Here it is shown that by codoping Cr and V magnetic elements in (Bi,Sb)2 Te3 TI, the temperature of the QAH effect can be significantly increased such that full quantization is achieved at 300 mK, and zero-field Hall resistance of 0.97 h/e2 is observed at 1.5 K. A systematic transport study of the codoped (Bi,Sb)2 Te3 films with varied Cr/V ratios reveals that magnetic codoping improves the homogeneity of ferromagnetism and modulates the surface band structure. This work demonstrates magnetic codoping to be an effective strategy for achieving high-temperature QAH effect in TIs. PMID- 29125708 TI - Integration of dermoscopy and reflectance confocal microscopy for distinguishing melanomas from nevi of the breast area. AB - BACKGROUND: Nevi of special sites encompass a class of benign lesions characterized by the presence of atypical clinical and histopathological features that can be difficult to distinguish from melanoma. Dermoscopy and reflectance confocal microscopy may improve the clinical assessment of melanocytic lesions to avoid unnecessary excisions. OBJECTIVES: The aim of this study was to assess the value of specific dermoscopic and confocal criteria in distinguishing melanomas from nevi of the breast area. METHODS: Dermoscopic and confocal images from consecutive patients with at least one clinically and/or dermoscopically equivocal melanocytic skin lesion of the breast area were retrospectively evaluated. In this case-control study, only histopathologically proven melanomas (cases) and nevi (controls) were included. Spearman's coefficients were first calculated to flag significant correlation; then univariate and multivariate logistic regression analyses were performed to assess which factors were independently associated with the histopathological diagnosis. Finally, a mixed dermoscopic/confocal score was created to distinguish nevi from melanomas on the breast area. RESULTS: The study population included 55 skin lesions of the breast area, 34 (61.8%) nevi and 21 (38.2%) melanomas. Among dermoscopic criteria, atypical network and irregular pigmentation resulted independently associated with melanoma diagnosis (OR: 11.1; 95% CI 1.0-119.9; P:0.048 and OR: 6.5; 95% CI 1.1-37.5; P:0.037, respectively). Furthermore, on RCM examination, the presence of pagetoid cells was an independent positive predictor for melanoma (OR: 38.5; 95% CI 3.9-379.6; P:0.002). The mixed score showed high levels of sensitivity and specificity, 95.2% and 82.4%, respectively, which were higher than dermoscopic and confocal evaluations alone. CONCLUSION: The combined use of dermoscopy and confocal microscopy in the triage of pigmented lesions of the breast area may help in increasing the diagnostic accuracy and avoiding unnecessary excisions. PMID- 29125709 TI - Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study. AB - : Essentials The association between chronic kidney disease and bleeding is unknown. We followed 10 347 subjects at high cardiovascular risk for bleeding events. Chronic kidney disease was associated with a 1.5-fold increased bleeding risk. Especially albuminuria rather than decreased kidney function was associated with bleeding events. SUMMARY: Background There are indications that patients with chronic kidney disease have an increased bleeding risk. Objectives To investigate the association between chronic kidney disease and bleeding in patients at high cardiovascular risk. Methods We included 10 347 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2015 for an outpatient visit with classic risk factors for arterial disease or with symptomatic arterial disease (Second Manifestation of Arterial disease [SMART] cohort). Patients were staged according to the KDIGO guidelines, on the basis of estimated glomerular filtration rate (eGFR) and albuminuria, and were followed for the occurrence of major hemorrhagic events until March 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding were calculated with Cox proportional hazards analyses. Results The incidence rate for bleeding in subjects with chronic kidney disease was 8.0 per 1000 person-years and that for subjects without chronic kidney disease was 3.5 per 1000 person-years. Patients with chronic kidney disease (n = 2443) had a 1.5 fold (95% CI 1.2-1.9) increased risk of bleeding as compared with subjects without chronic kidney disease (n = 7904) after adjustment. Subjects with an eGFR of < 45 mL min-1 1.73 m-2 with albuminuria had a 3.5-fold (95% CI 2.3-5.3) increased bleeding risk, whereas an eGFR of < 45 mL min-1 1.73 m-2 without albuminuria was not associated with an increased bleeding risk (HR 1.3, 95% CI 0.7-2.5). Conclusion Chronic kidney disease is a risk factor for bleeding in patients with classic risk factors for arterial disease or with symptomatic arterial disease, especially in the presence of albuminuria. PMID- 29125710 TI - Thiazolidinedione therapy and breast cancer risk in diabetic women: A systematic review and meta-analysis. AB - Rising experimental evidence suggests that thiazolidinediones (TZDs) exert a protective effect on breast cancer. However, studies concerning this issue were inconsistent and limited. Hence, we performed a meta-analysis with data from currently available studies to evaluate the effect of TZDs on breast cancer risk among diabetic women. We comprehensively searched for all pertinent studies addressing TZDs use and breast cancer risk published before January 1, 2016, in PubMed, Clinical Trials, and Cochrane Library. Data synthesis was performed in a random-effects model using Stata version 12.0 (Stata Corp, College Station, Texas). Fourteen independent studies were eventually selected in this meta analysis, including 5 randomized controlled clinical trials (RCTs), 7 cohort studies, and 2 case-control studies. No significant associations of TZD use and risk of breast cancer were observed in the RCTs (pooled risk ratio [RR]: 0.77, 95% confidence interval (CI), 0.39-1.53, I2 = 26%) or case-control studies (pooled odds ratio, 0.99, 95% CI, 0.76-1.28, I2 = 31%). A 19% reduction in breast cancer risk (pooled RR: 0.81, 95% CI, 0.66-0.99, I2 = 72%) was found in the cohort studies. However, after removing the study with the smallest event number and the greatest effect size, the association became nonsignificant with greatly decreased heterogeneity (pooled RR: 0.94, 95% CI, 0.86-1.03, I2 = 16%). This meta-analysis did not find any significant association between TZDs use and risk of breast cancer among diabetic women. PMID- 29125711 TI - Direct Dehydroxytrifluoromethoxylation of Alcohols. AB - The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late-stage trifluoromethoxylation of complex small molecules. PMID- 29125712 TI - Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 hours of normothermic machine perfusion. AB - Normothermic machine perfusion (NMP) is an emerging technology to preserve liver allografts more effectively than cold storage (CS). However, little is known about the effect of NMP on steatosis and the markers indicative of hepatic quality during NMP. To address these points, we perfused 10 discarded human livers with oxygenated NMP for 24 hours after 4-6 hours of CS. All livers had a variable degree of steatosis at baseline. The perfusate consisted of packed red blood cells and fresh frozen plasma. Perfusate analysis showed an increase in triglyceride levels from the 1st hour (median, 127 mg/dL; interquartile range [IQR], 95-149 mg/dL) to 24th hour of perfusion (median, 203 mg/dL; IQR, 171-304 mg/dL; P = 0.004), but tissue steatosis did not decrease. Five livers produced a significant amount of bile (>=5 mL/hour) consistently throughout 24 hours of NMP. Lactate in the perfusate cleared to <3 mmol/L in most livers within 4-8 hours of NMP, which was independent of bile production rate. This is the first study to characterize the lipid profile and functional assessment of discarded human livers at 24 hours of NMP. Liver Transplantation 24 233-245 2018 AASLD. PMID- 29125713 TI - Outbreak of invasive aspergillosis in heart transplant recipients: The role of screening computed tomography scans in asymptomatic patients and universal antifungal prophylaxis. AB - BACKGROUND: Delays in diagnosing pulmonary invasive aspergillosis (IA), a significant cause of morbidity and mortality among heart transplant recipients (HTRs), may impact on successful treatment. The appropriate screening strategy for IA in these patients remains undefined, particularly in the setting of nosocomial outbreaks. We describe our experience employing chest computed tomography (CT) scans as a screening method for IA. In addition, we comment on antimicrobial prophylaxis in HTRs in the setting of an outbreak. METHODS: Screening CT scans of the chest and serum galactomannan (GM) were performed in HTRs during an outbreak that followed the index case of IA. Abnormal CT findings prompted a diagnostic workup. Antimicrobial prophylaxis for new transplants recipients included intravenous micafungin while hospitalized, followed by outpatient inhaled amphotericin B for up to 3 months. RESULTS: During a 10-month period, five cases of IA were identified among HTRs. Two additional asymptomatic patients were diagnosed with IA among 15 asymptomatic HTRs who underwent screening chest CT scans. Among the five cases of IA in HTRs, two of five (40%) had a partial response and the other three failed voriconazole therapy. Complete response to voriconazole therapy assessed at 12 weeks was achieved in these two asymptomatic HTRs diagnosed via screening CTs. Serum GM was positive only in one of the symptomatic cases. The negative predictive value of CT scans was 100% (95% confidence interval, 71.5%-100%). CONCLUSIONS: In an outbreak setting, screening CT scans of the chest may aid in early detection of asymptomatic HTRs with IA and improve outcome. PMID- 29125714 TI - Prognostic awareness and communication preferences among caregivers of patients with malignant glioma. AB - OBJECTIVE: Malignant glioma (MG) is a devastating neuro-oncologic disease with almost invariably poor prognosis, yet many families facing malignant glioma have poor prognostic awareness (PA), or the awareness of the patient's incurable disease and shortened life expectancy. Accurate PA is associated with favorable medical outcomes at end-of-life for patients and psychosocial outcomes for informal caregivers (ICs) through bereavement. To date, however, no study has specifically examined PA among MG ICs and the information they receive that shapes their awareness. METHODS: Thirty-two ICs of patients with malignant glioma completed a semi-structured assessment of their awareness of the incurability and life expectancy of their loved one's illness, and to understand their sources of prognostic information and preferences for communication of prognostic information. RESULTS: Twenty-two (69%) ICs had full PA-awareness of the incurability of malignant glioma and accurate estimates of their loved ones' life expectancy. Twenty-three (72%) felt that prognostic information was extremely or very important to possess, and 16 (50%) desired more prognostic information. The majority of ICs received prognostic information from physicians and the Internet. Qualitative analyses revealed that many ICs had difficulty navigating medical encounters in which they concurrently wanted to elicit prognostic information from physicians and protect patients from such information. CONCLUSIONS: Accurate and timely PA is necessary for ICs to serve as critical members of health care teams. Interventions are needed to foster ICs' skills in navigating prognostic communication with patients and health care providers and thereby improve their ability to advocate for their loved one's wishes. PMID- 29125715 TI - Two Phase 1, Open-Label, Single-Dose, Randomized, Crossover Studies to Assess the Pharmacokinetics, Safety, and Tolerability of Orally Administered Granules of Secnidazole (2 g) in Healthy Female Volunteers Under Different Administration Conditions. AB - Bacterial vaginosis (BV) is the most common vaginal infection in reproductive-age women and a significant risk factor for sexually transmitted diseases and pregnancy complications. Standard 5- to 7-day antimicrobial treatments for BV are associated with high rates of recurrence and adverse events. SYM-1219 is a novel granule formulation containing 2 g of secnidazole, developed as an oral, single dose BV treatment. Two phase 1, open-label, single-center, randomized, crossover trials (studies 102 and 103) assessed the pharmacokinetics and safety of SYM-1219 single doses (>=7-day washout between doses) in healthy, nonpregnant women aged 18 to 65 years inclusive. Study 102 compared SYM-1219 in applesauce in fasted vs fed states. Study 103 compared SYM-1219 (fasted) in pudding and yogurt vs applesauce. Studies 102 and 103 each dosed 24 subjects (mean [standard deviation] ages, 36 [1.8] and 40 [11.6] years, respectively). In both studies the 90% confidence intervals for all treatment comparisons of maximum plasma concentration, area under the concentration-time curve from 0 to last measurable concentration and to infinity, geometric mean ratios were within 80% to 125%, demonstrating bioequivalence. In both studies median fasted time to maximum plasma concentration was 4 hours (6 hours fed in study 102), and mean half-life ranged from 17 to 19 hours. Treatment-emergent adverse events occurred in 70.8% and 83.3% subjects in studies 102 and 103, respectively, most commonly headache (41.7% and 50.0%) and gastrointestinal treatment-emergent adverse events. The pharmacokinetics of SYM-1219 were similar in fed and fasted states and when administered in different foods. PMID- 29125716 TI - Novel Silicon Doped Tin Oxide-Carbon Microspheres as Anode Material for Lithium Ion Batteries: The Multiple Effects Exerted by Doped Si. AB - Silicon doped tin oxide embedded porous carbon microspheres (Siy Sn1-y Ox @C) are synthesized. It is found that the doped Si not only improves the reversibility of lithiation/delithiation reactions, but also prevents Sn from aggregation. In addition, the doped Si introduces extra defects into the carbon matrix and produces Li+ conductive Li4 SiO4 , which accelerates Li+ diffusion. Together with the conductive, porous carbon matrix that provides void space to accommodate the volume change of Sn during charge/discharge cycling, the novel Siy Sn1-y Ox @C exhibits excellent electrochemical performance. It shows a high initial columbic efficiency of 75.9%. A charge (delithiation) capacity of 880.32 mA h g-1 is retained after 150 cycles, i.e., 91% of the initial capacity. These results indicate that the as-synthesized Siy Sn1-y Ox @C is a promising anode material for lithium ion batteries. PMID- 29125717 TI - AFOB Special Issue on Industrial Biotechnology. PMID- 29125718 TI - Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator. AB - Ozanimod (RPC1063) is an oral selective modulator of the sphingosine-1-phosphate 1 and 5 receptors under development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. The effects of high-fat and low-fat meals on the pharmacokinetics (PK) of a single oral dose of ozanimod were evaluated in 24 healthy volunteers in a randomized, open-label crossover trial. Each subject received a 1-mg dose of ozanimod hydrochloride under 3 meal conditions (fasted, high-fat, and low-fat), each separated by 7 days. Mean plasma concentration-time profiles for ozanimod and its active metabolites (RP101988 [major], RP101075 [minor]) were similar under all 3 conditions. Moreover, all PK parameters for ozanimod, RP101988, and RP101075 were similar under the 3 meal conditions. The 90% confidence intervals (CIs) for the ratios of geometric least squares mean (fed/fasted) were within the equivalence limits of 0.80 to 1.25 for area under the concentration-time curve from time 0 to infinity (AUC0-infinity ) and maximum plasma concentration (Cmax ) for ozanimod, RP101988, and RP101075, except for the high-fat effect on RP101075 Cmax (90%CI, 0.76-0.88). Given this lack of a food effect on the exposure of ozanimod and its active metabolites, ozanimod can be taken without regard to meals. PMID- 29125719 TI - Safety, Pharmacokinetics, and Immunogenicity of Obiltoxaximab After Intramuscular Administration to Healthy Humans. AB - Inhalational anthrax is a highly lethal infection caused by Bacillus anthracis and a serious bioterrorism threat. Protective antigen (PA) is a critical component required for the virulence of Bacillus anthracis. Obiltoxaximab, a high affinity monoclonal antibody that neutralizes PA, is approved in the United States for intravenous use for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate. Here, we explored the safety, pharmacokinetics (PK), and immunogenicity of obiltoxaximab administered by intramuscular injection at doses of 4, 8, 16, 20, and 24 mg/kg in healthy humans. Systemic exposures were approximately dose proportional, maximum serum concentrations were observed after 6-9 days, and terminal half-life ranged from 16 to 23 days. Average absolute intramuscular bioavailability was 64%. Obiltoxaximab was well tolerated, and local tolerability was acceptable up to 24 mg/kg intramuscularly, up to 6 injections per dose, and up to 5 mL per injection. No injection-site abscesses or hypersensitivity reactions occurred; no subjects developed treatment-emergent antitherapeutic antibodies over the study period of 71 days. PMID- 29125720 TI - Charge Transfer from Carbon Nanotubes to Silicon in Flexible Carbon Nanotube/Silicon Solar Cells. AB - Mechanical fragility and insufficient light absorption are two major challenges for thin flexible crystalline Si-based solar cells. Flexible hybrid single-walled carbon nanotube (SWNT)/Si solar cells are demonstrated by applying scalable room temperature processes for the fabrication of solar-cell components (e.g., preparation of SWNT thin films and SWNT/Si p-n junctions). The flexible SWNT/Si solar cells present an intrinsic efficiency ~7.5% without any additional light trapping structures. By using these solar cells as model systems, the charge transport mechanisms at the SWNT/Si interface are investigated using femtosecond transient absorption. Although primary photon absorption occurs in Si, transient absorption measurements show that SWNTs also generate and inject excited charge carriers to Si. Such effects can be tuned by controlling the thickness of the SWNTs. Findings from this study could open a new pathway for designing and improving the efficiency of photocarrier generation and absorption for high performance ultrathin hybrid SWNT/Si solar cells. PMID- 29125722 TI - Management of New Onset Psychosis in the Postpartum Period. PMID- 29125723 TI - A Kidney Exchange Clearinghouse in New England. PMID- 29125721 TI - The Association Between Comorbid Autism Spectrum Disorders and Antipsychotic Treatment Failure in Early-Onset Psychosis: A Historical Cohort Study Using Electronic Health Records. AB - OBJECTIVE: In a sample of children and adolescents with first-episode psychosis, we investigated whether multiple treatment failure (MTF, defined as the initiation of a third trial of novel antipsychotic due to nonadherence, adverse effects, or insufficient response) was associated with comorbid autism spectrum disorders. METHODS: Data were from the electronic health records of 638 children (51% male) aged from 10 to 17 years with first-episode psychosis (per ICD-10 criteria) from January 1, 2008, to November 1, 2014, referred to mental health services in South London, United Kingdom; data were extracted using the Clinical Record Interactive Search (CRIS) system. The effect of autism spectrum disorder comorbidity on the development of MTF during a 5-year period was modeled using Cox regression. RESULTS: There were 124 cases of MTF prior to the age of 18 (19.4% of the sample). Comorbid autism spectrum disorders were significantly associated with MTF (adjusted hazard ratio = 1.99; 95% CI, 1.19-3.31; P = .008) after controlling for a range of potential confounders. Other factors significantly associated with MTF included higher age at first presentation (P = .001), black ethnicity (P = .03), and frequency of clinical contact (P < .001). No significant association between other comorbid neurodevelopmental disorders (hyperkinetic disorder or intellectual disability) and MTF was found. CONCLUSIONS: Children with first-episode psychosis and comorbid autism spectrum disorders at first presentation are less likely to have a beneficial response to antipsychotics. PMID- 29125724 TI - Mortality Reductions, Educational Attainment, and Fertility Choice. AB - This paper develops a model where reductions in mortality are the main force behind economic development. The model generates a pattern of changes similar to the demographic transition, where gains in life expectancy at birth are followed by reductions in fertility and increases in the rate of human capital accumulation. The onset of the transition is characterized by a critical level of life expectancy at birth, which marks the movement of the economy from a Malthusian equilibrium to an equilibrium with investments in human capital and the possibility of long-run growth. PMID- 29125725 TI - The Collapse of a Medical Labor Clearinghouse (and Why Such Failures Are Rare). PMID- 29125726 TI - How Do Hospitals Respond to Price Changes? AB - This paper examines hospital responses to changes in diagnosis-specific prices by exploiting a 1988 policy reform that generated large price changes for 43 percent of Medicare admissions. I find hospitals responded primarily by "upcoding" patients to diagnosis codes with the largest price increases. This response was particularly strong among for-profit hospitals. I find little evidence hospitals increased the volume of admissions differentially for diagnoses subject to the largest price increases, despite the financial incentive to do so. Neither did they increase intensity or quality of care in these diagnoses, suggesting hospitals do not compete for patients at the diagnosis level. PMID- 29125727 TI - Human Capital Formation, Life Expectancy, and the Process of Development. PMID- 29125728 TI - The Long-Term Impact of Military Service on Health: Evidence from World War II and Korean War Veterans. AB - During the World War II and Korean War era, the U.S. military freely distributed cigarettes to overseas personnel and provided low-cost tobacco products on domestic military bases. In fact, even today the military continues to sell subsidized tobacco products on its bases. Using a variety of instrumental variables approaches to deal with nonrandom selection into the military and into smoking, we provide substantial evidence that cohorts with higher military participation rates subsequently suffered more premature mortality. More importantly, we show that a large fraction, 35 to 79 percent, of the excess veteran deaths due to heart disease and lung cancer are attributable to military induced smoking. PMID- 29125729 TI - Economic Conditions Early in Life and Individual Mortality. PMID- 29125730 TI - Development of a Protease Biosensor Based on a Dimerization-Dependent Red Fluorescent Protein. AB - Dysregulated activity of the protease matriptase is a key contributor to aggressive tumor growth, cancer metastasis, and osteoarthritis. Methods for the detection and quantification of matriptase activity and inhibition would be useful tools. To address this need, we developed a matriptase-sensitive protein biosensor based on a dimerization-dependent red fluorescent protein (ddRFP) reporter system. In this platform, two adjoining protein domains, connected by a protease-labile linker, produce fluorescence when assembled and are nonfluorescent when the linker is cleaved by matriptase. A panel of ddRFP-based matriptase biosensor designs was created that contained different linker lengths between the protein domains. These constructs were characterized for linker specific cleavage, matriptase activity, and matriptase selectivity; a biosensor containing a RSKLRVGGH linker (termed B4) was expressed at high yields and displayed both high catalytic efficiency and matriptase specificity. This biosensor detects matriptase inhibition by soluble and yeast cell surface expressed inhibitor domains with up to a 5-fold dynamic range and also detects matriptase activity expressed by human cancer cell lines. In addition to matriptase, we highlight a strategy that can be used to create effective biosensors for quantifying activity and inhibition of other proteases of interest. PMID- 29125732 TI - Targeted Activation of Molecular Transportation by Visible Light. AB - Regulated transportation of nanoscale objects with a high degree of spatiotemporal precision is a prerequisite for the development of targeted molecular delivery. In vitro integration of the kinesin-microtubule motor system with synthetic molecules offers opportunities to develop controllable molecular shuttles for lab-on-a-chip applications. We attempted a combination of the kinesin-microtubule motor system with push-pull type azobenzene tethered inhibitory peptides (azo-peptides) through which reversible, spatiotemporal control over the kinesin motor activity was achieved locally by a single, visible wavelength. The fast thermal relaxation of the cis-isomers of azo-peptides offered us quick and complete resetting of the trans-state in the dark, circumventing the requirement of two distinct wavelengths for two-way switching of kinesin-driven microtubule motility. Herein, we report the manipulation of selected, single microtubule movement while keeping other microtubules at complete rest. The photoresponsive inhibitors discussed herein would help in realizing complex bionanodevices. PMID- 29125731 TI - Imaging PD-L1 Expression with ImmunoPET. AB - High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that 89Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy. Importantly, the concentration of antigen is beneath the detection limit of previously developed anti-PD-L1 radiotracers, including radiolabeled atezolizumab. We also show that 89Zr-C4 can specifically detect antigen in human NSCLC and prostate cancer models endogenously expressing a broad range of PD-L1. 89Zr-C4 detects mouse PD-L1 expression changes in immunocompetent mice, suggesting that endogenous PD-1/2 will not confound human imaging. Lastly, we found that 89Zr-C4 could detect acute changes in tumor expression of PD-L1 due to standard of care chemotherapies. In summary, we present evidence that low levels of PD-L1 in clinically relevant cancer models can be imaged with immunoPET using a novel recombinant human antibody. PMID- 29125734 TI - Entropically Driven Order in Crowded Solutions: From Liquid Crystals to Cell Biology. PMID- 29125733 TI - Dissolved Alkali Metals in Zeolites. PMID- 29125735 TI - Resveratrol Exerts Antioxidant Effects by Activating SIRT2 To Deacetylate Prx1. AB - Resveratrol is a promising chemical agent that treats multiple aging-related diseases and improves life span. While reactive oxygen species undoubtedly play ubiquitous roles in the aging process and resveratrol has been shown to be an effective antioxidant, the mechanism through which resveratrol acts against oxidative stress remains unknown. Here we show that resveratrol activates SIRT2 to deacetylate Prx1, leading to an increased H2O2 reduction activity and a decreased cellular H2O2 concentration. Knockdown of SIRT2 or Prx1 by RNA interference abrogates resveratrol's ability to reduce the H2O2 level in HepG2 cells. Using purified SIRT2 and a Prx1 mutant harboring acetyllysine at position 27 (Prx1-27AcK), we show that resveratrol enhances SIRT2's activity to deacetylate Prx1-27AcK, resulting in a significantly increased H2O2 reducing activity. Thus, SIRT2 and Prx1 are targets for modulating intracellular redox status in the therapeutic strategies for the treatment of aging-related disorders. PMID- 29125736 TI - pDeep: Predicting MS/MS Spectra of Peptides with Deep Learning. AB - In tandem mass spectrometry (MS/MS)-based proteomics, search engines rely on comparison between an experimental MS/MS spectrum and the theoretical spectra of the candidate peptides. Hence, accurate prediction of the theoretical spectra of peptides appears to be particularly important. Here, we present pDeep, a deep neural network-based model for the spectrum prediction of peptides. Using the bidirectional long short-term memory (BiLSTM), pDeep can predict higher-energy collisional dissociation, electron-transfer dissociation, and electron-transfer and higher-energy collision dissociation MS/MS spectra of peptides with >0.9 median Pearson correlation coefficients. Further, we showed that intermediate layer of the neural network could reveal physicochemical properties of amino acids, for example the similarities of fragmentation behaviors between amino acids. We also showed the potential of pDeep to distinguish extremely similar peptides (peptides that contain isobaric amino acids, for example, GG = N, AG = Q, or even I = L), which were very difficult to distinguish using traditional search engines. PMID- 29125737 TI - Room-Temperature Nanowelding of a Silver Nanowire Network Triggered by Hydrogen Chloride Vapor for Flexible Transparent Conductive Films. AB - High contact resistance between silver nanowires (AgNWs) is a key issue in widespread application of AgNW flexible transparent conductive films as a promising candidate to replace the brittle and expensive indium tin oxide. A facile, room-temperature nanowelding method of an AgNW network triggered by hydrogen chloride (HCl) vapor is demonstrated to reduce the sheet resistance of the AgNW network. Under the visible light, O2 and HCl vapor serving as an etching couple induced silver atoms to be transferred from the bottom AgNW at the junction to the top one, and then, these silver atoms epitaxially recrystallized at the contact position with the lattice of the top AgNW as the template, ultimately resulting in the coalescence of the junction between AgNWs. Polydimethylsiloxane (PDMS) was spin-coated onto the HCl-vapor-treated (HVT) AgNW network on the polyethylene terephthalate substrate to fabricate PDMS/HVT AgNW films. The fabricated film with low sheet resistance and high transmittance retained its conductivity after 4000 bending cycles. Furthermore, excellent heating performance, electromagnetic interference shielding effectiveness, and foldability were obtained in the PDMS/HVT AgNW film. Thus, the role of the simple nanowelding process is evident in enhancing the performance of AgNW transparent conductive films for emerging soft optoelectronic applications. PMID- 29125738 TI - Profiling of Protein O-GlcNAcylation in Murine CD8+ Effector- and Memory-like T Cells. AB - During an acute infection, antigenic stimulation leads to activation, expansion, and differentiation of naive CD8+ T cells, first into cytotoxic effector cells and eventually into long-lived memory cells. T cell antigen receptors (TCRs) detect antigens on antigen-presenting cells (APCs) in the form of antigenic peptides bound to major histocompatibility complex I (MHC-I)-encoded molecules and initiate TCR signal transduction network. This process is mediated by phosphorylation of many intracellular signaling proteins. Protein O-GlcNAc modification is another post-translational modification involved in this process, which often has either reciprocal or synergistic roles with phosphorylation. In this study, using a chemoenzymatic glycan labeling technique and proteomics analysis, we compared protein O-GlcNAcylation of murine effector and memory-like CD8+ T cells differentiated in vitro. By quantitative proteomics analysis, we identified 445 proteins that are significantly regulated in either effector- or memory-like T cell subsets. Furthermore, qualitative and quantitative analysis identified highly regulated protein clusters that suggest involvement of this post-translational modification in specific cellular processes. In effector-like T cells, protein O-GlcNAcylation is heavily involved in transcriptional and translational processes that drive fast effector T cells proliferation. During the formation of memory-like T cells, protein O-GlcNAcylation is involved in a more specific, perhaps more targeted regulation of transcription, mRNA processing, and translation. Significantly, O-GlcNAc plays a critical role as part of the "histone code" in both CD8+ T cells subgroups. PMID- 29125740 TI - Significant Enhancement of Thermal Conductivity in Nanofibrillated Cellulose Films with Low Mass Fraction of Nanodiamond. AB - High thermal conductive nanofibrillated cellulose (NFC) hybrid films based on nanodiamond (ND) were fabricated by a facile vacuum filtration technique. In this issue, the thermal conductivity (TC) on the in-plane direction of the NFC/ND hybrid film had a significant enhancement of 775.2% at a comparatively low ND content (0.5 wt %). The NFC not only helps ND to disperse in the aqueous medium stably but also plays a positive role in the formation of the hierarchical structure. ND could form a thermal conductive pathway in the hierarchical structures under the intermolecular hydrogen bonds. Moreover, the hybrid films composed of zero-dimensional ND and one-dimensional NFC exhibit remarkable mechanical properties and optical transparency. The NFC/ND hybrid films possessing superior TC, mechanical properties, and optical transparency can open applications for portable electronic equipment as a lateral heat spreader. PMID- 29125741 TI - Achieving Molecular Complexity via Stereoselective Multiple Domino Reactions Promoted by a Secondary Amine Organocatalyst. AB - In the last two decades, organocatalysis has emerged as an intensively investigated and rapidly growing area of research facilitating many known and many new transformations to provide efficient novel entries to complex molecules of high stereochemical purity. The organocatalysts have not only shown their efficiency for catalyzing the reactions in which one bond is formed, but they have also been effectively exploited in various versions of one-pot reactions. Domino reactions are one of the most important classes of one-pot reactions, where the target structure can be obtained in one pot without changing any reaction conditions while each reaction occurs as a consequence of the intermediates generated in previous steps. Owing to the synthetic importance and operational advantages associated with the use of organocatalysts and the development of domino reactions, various asymmetric transformations leading to a complex structure of choice have been explored. The early era of organocatalysis exhibits a limited growth in the development of asymmetric domino reactions with special emphasis on two reactions occurring one after the other. In 2006, our group made a step forward to develop more complex domino reactions catalyzed by a secondary amine organocatalyst, wherein three reactions take place in one pot to provide cyclohexene carbaldehydes bearing four stereogenic centers with excellent stereocontrol. This triggered our interest to develop new organocatalytic domino sequences, especially for multiple domino reactions. After our seminal contribution, domino reactions catalyzed by secondary amine organocatalysts not only became more popular, but they also could be catalyzed by other classes of organocatalysts, such as bifunctional hydrogen bonding catalysts, chiral Bronsted acids, and N-heterocyclic carbenes. The mode of activation in this triple domino reaction relied on the sequential generation of enamine and iminium intermediates using a proline-based chiral secondary amine organocatalyst. By employing this strategy, we have developed several triple domino reactions leading to the formation of carbo- and heterocyclic structures bearing multiple stereogenic centers with excellent levels of stereoselectivities. The applications of the secondary amine organocatalysts have been further extended to more complex quadruple domino sequences. Moreover, these multiple domino sequences have been combined successfully with other transformations in one pot to create densely functionalized polycyclic compounds. This Account gives an overview of our research in the area of organocatalytic asymmetric multiple domino reactions with special emphasis on the secondary amine catalyzed triple and quadruple domino reactions via a sequential generation of enamine and iminium intermediates. The multiple cascade reactions assisted by di- and tri-iminium and -enamine species as well as other types of organocatalysts have been excluded from the scope of this Account. PMID- 29125739 TI - Yield Improvement of the Anti-MRSA Antibiotics WAP-8294A by CRISPR/dCas9 Combined with Refactoring Self-Protection Genes in Lysobacter enzymogenes OH11. AB - The cyclic lipodepsipeptides WAP-8294A are antibiotics with potent activity against methicillin-resistant Staphylococcus aureus (MRSA). One member of this family, WAP-8294A2 (Lotilibcin), was in clinical trials due to its high activity and distinct chemistry. However, WAP-8294A compounds are produced in a very low yield by Lysobacter and only under very stringent conditions. Improving WAP-8294A yield has become very critical for research and application of these anti-MRSA compounds. Here, we report a strategy to increase WAP-8294A production. We first used the CRISPR/dCas9 system to increase the expression of five cotranscribed genes (orf1-5) in the WAP gene cluster, by fusing the omega subunit of RNA polymerase with dCas9 that targets the operon's promoter region. This led to the transcription of the genes increased by 5-48 folds in strain dCas9-omega3. We then refactored four putative self-protection genes (orf6, orf7, orf9 and orf10) by reorganizing them into an operon under the control of a strong Lysobacter promoter, PHSAF. The refactored operon was introduced into strain dCas9-omega3, and the transcription of the self-protection genes increased by 20-60 folds in the resultant engineered strains. The yield of the three main WAP-8294A compounds, WAP-8294A1, WAP-8294A2, and WAP-8294A4, increased by 6, 4, and 9 folds, respectively, in the engineered strains. The data also showed that the yield increase of WAP-8294A compounds was mainly due to the increase of the extracellular distribution. WAP-8294A2 exhibited potent (MIC 0.2-0.8 MUg/mL) and specific activity against S. aureus among a battery of clinically relevant Gram positive pathogens (54 isolates). PMID- 29125742 TI - Heterogeneous OH Oxidation, Shielding Effects, and Implications for the Atmospheric Fate of Terbuthylazine and Other Pesticides. AB - Terbuthylazine (TBA) is a widely used herbicide, and its heterogeneous reaction with OH radicals is important for assessing its potential to undergo atmospheric long-range transport and to affect the environment and public health. The apparent reaction rate coefficients obtained in different experimental investigations, however, vary by orders of magnitude depending on the applied experimental techniques and conditions. In this study, we used a kinetic multilayer model of aerosol chemistry with reversible surface adsorption and bulk diffusion (KM-SUB) in combination with a Monte Carlo genetic algorithm to simulate the measured decay rates of TBA. Two experimental data sets available from different studies can be described with a consistent set of kinetic parameters resolving the interplay of chemical reaction, mass transport, and shielding effects. Our study suggests that mass transport and shielding effects can substantially extend the atmospheric lifetime of reactive pesticides from a few days to weeks, with strong implications for long-range transport and potential health effects of these substances. PMID- 29125743 TI - Heterogeneous Rupturing Dendrimers. AB - Utilizing macromolecular scaffolds as templates for the production of small molecules that are distinctively different from the original monomer feedstock has many potential applications. Herein, as a proof-of-concept, a family of dendrimers displaying internally queued disulfide bridges were synthesized and exploited as flawless macromolecular templates that selectively rupture into a set of monomeric mercaptans. Disassembly was accomplished in a reducing environment, using DTT as an external stimulus, and the thiol constituents were successfully isolated. Their composition was dictated by three dendritic regions, i.e., (i) the symmetrical trithiol of the core (C3), (ii) the interior-asymmetric trithiols (CD2), and (iii) the periphery-asymmetric monothiols (DB2), in which B functionality is of an orthogonal nature. Taking into account the steady state between disulfides and thiols in all living cells, the collapse of the dendrimers to a multitude of smaller thiols was intracellularly assessed as a means to disrupt the balance of reactive oxygen species (ROS) often elevated in cancer cells. Indeed, the fragmentation induced a significant increase of ROS in human lung carcinoma A549 cells. These findings can potentially alter the perception of dendrimers being limited to carriers to being prodrugs for intracellular delivery of ROS with the potential to fight cancer. PMID- 29125745 TI - Fruit Seeds of the Rosaceae Family: A Waste, New Life, or a Danger to Human Health? AB - In fruit production seeds are mostly regarded as waste, but for plants they represent a beginning of new life. Seeds accumulate toxic or health-beneficial compounds, and the elucidation of their metabolic profile is especially important to people who consume the entire fruit, including the seeds. The present research quantifies the levels of bioactive compounds (phenolics and cyanogenic glycosides (CGG)) in fruit seeds of 35 cultivars belonging to 6 different fruit species. High-performance liquid chromatography and mass spectrophotometry were used to detect and identify the studied compounds. Significant differences in the content of individual bioactive compounds as well as their groups were recorded (p < 0.05). For the first time neoamygdalin and prunasin were detected in a number of fruit cultivars. All fruit seeds, except pears, accumulated from 2- to 46-fold higher levels of CGG than phenolics. On average, seeds contained from 75.46 to 1648.14 MUg/g phenolics and from 46.39 to 4374.31 MUg/g CGG. The study also clarifies the new lethal dose for cyanogenic glycosides. PMID- 29125744 TI - Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors. AB - N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a starting point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT. PMID- 29125746 TI - Selective Activation of Methane on Single-Atom Catalyst of Rhodium Dispersed on Zirconia for Direct Conversion. AB - Direct methane conversion into value-added products has become increasingly important. Because of inertness of methane, cleaving the first C-H bond has been very difficult, requiring high reaction temperature on the heterogeneous catalysts. Once the first C-H bond becomes activated, the remaining C-H bonds are successively dissociated on the metal surface, hindering the direct methane conversion into chemicals. Here, a single-atom Rh catalyst dispersed on ZrO2 surface has been synthesized and used for selective activation of methane. The Rh single atomic nature was confirmed by extended X-ray fine structure analysis, electron microscopy images, and diffuse reflectance infrared Fourier transform spectroscopy. A model of the single-atom Rh/ZrO2 catalyst was constructed by density functional theory calculations, and it was shown that CH3 intermediates can be energetically stabilized on the single-atom catalyst. The direct conversion of methane was performed using H2O2 in the aqueous solution or using O2 in gas phase as oxidants. Whereas Rh nanoparticles produced CO2 only, the single-atom Rh catalyst produced methanol in aqueous phase or ethane in gas phase. PMID- 29125747 TI - Alchemical Free Energy Calculations for Nucleotide Mutations in Protein-DNA Complexes. AB - Nucleotide-sequence-dependent interactions between proteins and DNA are responsible for a wide range of gene regulatory functions. Accurate and generalizable methods to evaluate the strength of protein-DNA binding have long been sought. While numerous computational approaches have been developed, most of them require fitting parameters to experimental data to a certain degree, e.g., machine learning algorithms or knowledge-based statistical potentials. Molecular dynamics-based free energy calculations offer a robust, system-independent, first principles-based method to calculate free energy differences upon nucleotide mutation. We present an automated procedure to set up alchemical MD-based calculations to evaluate free energy changes occurring as the result of a nucleotide mutation in DNA. We used these methods to perform a large-scale mutation scan comprising 397 nucleotide mutation cases in 16 protein-DNA complexes. The obtained prediction accuracy reaches 5.6 kJ/mol average unsigned deviation from experiment with a correlation coefficient of 0.57 with respect to the experimentally measured free energies. Overall, the first-principles-based approach performed on par with the molecular modeling approaches Rosetta and FoldX. Subsequently, we utilized the MD-based free energy calculations to construct protein-DNA binding profiles for the zinc finger protein Zif268. The calculation results compare remarkably well with the experimentally determined binding profiles. The software automating the structure and topology setup for alchemical calculations is a part of the pmx package; the utilities have also been made available online at http://pmx.mpibpc.mpg.de/dna_webserver.html . PMID- 29125748 TI - Optimization of Empirical Force Fields by Parameter Space Mapping: A Single-Step Perturbation Approach. AB - A general method for parametrizing atomic interaction functions is presented. The method is based on an analysis of surfaces corresponding to the difference between calculated and target data as a function of alternative combinations of parameters (parameter space mapping). The consideration of surfaces in parameter space as opposed to local values or gradients leads to a better understanding of the relationships between the parameters being optimized and a given set of target data. This in turn enables for a range of target data from multiple molecules to be combined in a robust manner and for the optimal region of parameter space to be trivially identified. The effectiveness of the approach is illustrated by using the method to refine the chlorine 6-12 Lennard-Jones parameters against experimental solvation free enthalpies in water and hexane as well as the density and heat of vaporization of the liquid at atmospheric pressure for a set of 10 aromatic-chloro compounds simultaneously. Single-step perturbation is used to efficiently calculate solvation free enthalpies for a wide range of parameter combinations. The capacity of this approach to parametrize accurate and transferrable force fields is discussed. PMID- 29125749 TI - LC-MS/MS Identification of Species-Specific Muscle Peptides in Processed Animal Proteins. AB - An innovative analytical strategy has been applied to identify signature peptides able to distinguish among processed animal proteins (PAPs) derived from bovine, pig, fish, and milk products. Proteomics was first used to elucidate the proteome of each source. Starting from the identified proteins and using a funnel based approach, a set of abundant and well characterized peptides with suitable physical-chemical properties (signature peptides) and specific for each source was selected. An on-target LC-ESI-MS/MS method (MRM mode) was set up using standard peptides and was then applied to selectively identify the PAP source and also to distinguish proteins from bovine carcass and milk proteins. We believe that the method described meets the request of the European Commission which has developed a strategy for gradually lifting the "total ban" toward "species to species ban", therefore requiring official methods for species-specific discrimination in feed. PMID- 29125750 TI - Contribution of Quinones and Ketones/Aldehydes to the Optical Properties of Humic Substances (HS) and Chromophoric Dissolved Organic Matter (CDOM). AB - The molecular basis of the optical properties of chromophoric dissolved organic matter (CDOM) and humic substances (HS) remains poorly understood and yet to be investigated adequately. This study evaluates the relative contributions of two broad classes of carbonyl-containing compounds, ketones/aldehydes versus quinones, to the absorption and emission properties of a representative suite of HS as well as a lignin sample. Selective reduction of quinones to hydroquinones by addition of small molar excesses of dithionite to these samples under anoxic conditions produced small or negligible changes in their optical properties; however, when measurable, these changes were largely reversible upon exposure to air, consistent with the reoxidation of hydroquinones to quinones. With one exception, estimates of quinone content based on dithionite consumption by the HS under anoxic conditions were in good agreement with past electrochemical measurements. In contrast, reduction of ketones/aldehydes to alcohols employing excess sodium borohydride produced pronounced and largely, but not completely, irreversible changes in the optical properties. The results demonstrate that (aromatic) ketones/aldehydes, as opposed to quinones, play a far more prominent role in the optical absorption and emission properties of these HS, consistent with these moieties acting as the primary acceptors in charge-transfer transitions within these samples. As a method, anoxic dithionite titrations may further allow additional insight into the content and impact of quinones/hydroquinones on the optical properties of HS and CDOM. PMID- 29125751 TI - Soft X-ray Absorption Spectroscopy of Liquids and Solutions. AB - X-ray absorption spectroscopy (XAS) is an electronic absorption technique for which the initial state is a deeply buried core level. The photon energies corresponding to such transitions are governed primarily by the binding energies of the initial state. Because the binding energies of core electrons vary significantly among atomic species, this makes XAS an element-selective spectroscopy. Proper interpretation of XA spectra can provide detailed information on the local chemical and geometric environment of the target atom. The introduction of liquid microjet and flow cell technologies into XAS experiments has enabled the general study of liquid samples. Liquids studied to date include water, alcohols, and solutions with relevance to biology and energy technology. This Review summarizes the experimental techniques employed in XAS studies of liquid samples and computational methods used for interpretation of the resulting spectra and summarizes salient experiments and results obtained in the XAS investigations of liquids. PMID- 29125752 TI - Hexalanthanide Complexes as Molecular Precursors: Synthesis, Crystal Structure, and Luminescent and Magnetic Properties. AB - Reaction of hexanuclear octahedral molecular precursors with a 3-chlorobenzoate ligand affords an unprecedented family of isostructural polylanthanide complexes via solvothermal and microwave-assisted syntheses in an acetonitrile medium. The general chemical formula of the compounds that constitute this series is {[Ln6(MU3-OH)2(H2O)2(NO3)2(3-cb)14].(CH3CN)4}, where 3-cb- stands for 3 chlorobenzoate and Ln = Eu, Tb, Dy, Ho, Er, or Y. The crystal structure, solubility, and magnetic and luminescent properties of these complexes have been studied. The luminescent properties evidence that the composition of the hexalanthanide precursor is preserved during the synthetic process that is of particular interest for cases in which heterolanthanide complexes are targeted. PMID- 29125753 TI - Current Advances on the Structure, Bioactivity, Synthesis, and Metabolic Regulation of Novel Ubiquinone Derivatives in the Edible and Medicinal Mushroom Antrodia cinnamomea. AB - In recent years, Antrodia cinnamomea has attracted great attention around the world as an extremely precious edible and medicinal mushroom. Ubiquinone derivatives, which are characteristic metabolites of A. cinnamomea, have shown great bioactivities. Some of them have been regarded as promising therapeutic agents and approved into clinical trial by the U.S. Food and Drug Administration. Although some excellent reviews have been published covering different aspects of A. cinnamomea, this review brings, for the first time, complete information about the structure, bioactivity, chemical synthesis, biosynthesis, and metabolic regulation of ubiquinone derivatives in A. cinnamomea. It not only advances our knowledge on the bioactive metabolites, especially the ubiquinone derivatives, in A. cinnamomea but also provides valuable information for the investigation on other edible and medicinal mushrooms. PMID- 29125754 TI - Localized Intrinsic Valence Virtual Orbitals as a Tool for the Automatic Classification of Core Excited States. AB - Accurate assignments of the unoccupied molecular orbitals involved in electronic excitations are crucial to the interpretation of experimental spectra. Here we present an automated approach to the orbital assignment of excited states by introducing a unique orbital basis known as localized intrinsic valence virtual orbitals (LIVVOs), which are a special case of the previously reported valence virtual orbitals. The LIVVOs are used to quantify the local contributions to particle orbitals from orthogonality-constrained density functional theory, providing an assignment with atomic-level/angular momentum shell specificity. This localized set also allows us to define the total valence character of an excited state. We highlight the utility of our approach by studying the local orbital changes in core-excited states at the sulfur K-edge of ethanethiol and benzenethiol as well as the oxygen K-edge spectrum of the water monomer and dimer. PMID- 29125755 TI - Super-Resolution Structured Illumination Microscopy. AB - Super-resolved structured illumination microscopy (SR-SIM) is among the most rapidly growing fluorescence microscopy techniques that can surpass the optical diffraction limit. The strength of SR-SIM is that it can be readily applied to samples prepared for conventional fluorescence microscopy, requiring no sophisticated sample preparation protocols. As an extension of wide-field fluorescence microscopy, it is inherently capable of multicolor imaging and optical sectioning and, with sufficiently fast implementations, permits live cell imaging. Image reconstruction, however, currently relies on sophisticated computational procedures, susceptible to reconstruction artifacts, requiring trained users to recognize and avoid them. Here, we review the latest developments in SR-SIM research. Starting from a historical overview of the development of SR-SIM, we review how this method can be implemented in various experimental schemes, we provide an overview of the important parameters involved in successful image reconstruction, we summarize recent biological applications, and we provide a brief outlook of the directions in which we believe SR-SIM is headed in the future. PMID- 29125757 TI - Correction to Formation of Low-Molecular-Weight Dissolved Organic Nitrogen in Predenitrification Biological Nutrient Removal Systems and Its Impact on Eutrophication in Coastal Waters. PMID- 29125756 TI - Hepatitis B Virus Capsid Completion Occurs through Error Correction. AB - Understanding capsid assembly is important because of its role in virus lifecycles and in applications to drug discovery and nanomaterial development. Many virus capsids are icosahedral, and assembly is thought to occur by the sequential addition of capsid protein subunits to a nucleus, with the final step completing the icosahedron. Almost nothing is known about the final (completion) step because the techniques usually used to study capsid assembly lack the resolution. In this work, charge detection mass spectrometry (CDMS) has been used to track the assembly of the T = 4 hepatitis B virus (HBV) capsid in real time. The initial assembly reaction occurs rapidly, on the time scale expected from low resolution measurements. However, CDMS shows that many of the particles generated in this process are defective and overgrown, containing more than the 120 capsid protein dimers needed to form a perfect T = 4 icosahedron. The defective and overgrown capsids self-correct over time to the mass expected for a perfect T = 4 capsid. Thus, completion is a distinct phase in the assembly reaction. Capsid completion does not necessarily occur by inserting the last building block into an incomplete, but otherwise perfect icosahedron. The initial assembly reaction can be predominently imperfect, and completion involves the slow correction of the accumulated errors. PMID- 29125758 TI - Probing the Impact of Solvation on Photoexcited Spin Crossover Complexes with High-Precision X-ray Transient Absorption Spectroscopy. AB - Investigating the photoinduced electronic and structural response of bistable molecular building blocks incorporating transition metals in solution phase constitutes a necessary stepping stone for steering their properties toward applications and performance optimizations. This work presents a detailed X-ray transient absorption (XTA) spectroscopy study of a prototypical spin crossover (SCO) complex [FeII(mbpy)3]2+ (where mbpy = 4,4'-dimethyl-2,2'-bipyridine) with an [FeIIN6] first coordination shell in water (H2O) and acetonitrile (CH3CN). The unprecedented data quality of the XTA spectra together with the direct fitting of the difference spectra in k space using a large number of scattering paths enables resolving the subtle difference in the photoexcited structures of an FeII complex in two solvents for the first time. Compared to the low spin (LS) 1A1 state, the average Fe-N bond elongations for the photoinduced high spin (HS) 5T2 state are found to be 0.181 +/- 0.003 A in H2O and 0.199 +/- 0.003 A in CH3CN. This difference in structural response is attributed to ligand-solvent interactions that are stronger in H2O than in CH3CN for the HS excited state. Our studies demonstrate that, although the metal center of [FeII(mbpy)3]2+ could have been expected to be rather shielded by the three bidentate ligands with quasi octahedral coordination, the ligand field strength in the HS excited state is nevertheless indirectly affected by solvation effects that modifies the charge distribution within the Fe-N covalent bonds. More generally, this work highlights the importance of including solvation dynamics in order to develop a generalized understanding of the spin-state switching at the atomic level. PMID- 29125759 TI - Highly Regio- and Enantioselective Copper-Catalyzed Reductive Hydroxymethylation of Styrenes and 1,3-Dienes with CO2. AB - Herein, we report a highly regio- and enantioselective copper-catalyzed reductive hydroxymethylation of styrenes and 1,3-dienes with 1 atm of CO2. Diverse important chiral homobenzylic alcohols were readily prepared from styrenes. Moreover, a variety of 1,3-dienes also were converted to chiral homoallylic alcohols with high yields and excellent regio-, enantio-, and Z/E-selectivities. The utility of this transformation was demonstrated by a broad range of styrenes and 1,3-dienes, facile product modification, and synthesis of bioactive compounds (R)-(-)-curcumene and (S)-(+)-ibuprofen. Mechanistic studies demonstrated the carboxylation of phenylethylcopper complexes with CO2 as one key step. PMID- 29125760 TI - Diastereo- and Enantioselective Synthesis of Bi- and Tricyclic N-Heterocycle Fused beta-Lactones. AB - The utility of the nucleophile-catalyzed (Lewis base) aldol lactonization (NCAL) process for the diastereo- and enantioselective synthesis of N-heterocycle-fused beta-lactones from N-linked ketoacids is described. A series of bi- and tricyclic, N-heterocycle-fused, beta-lactones were first synthesized in racemic fashion via the NCAL process with excellent diastereoselectivity (>19:1) utilizing 4-pyrrolidinopyridine as an effective achiral Lewis base. A catalytic, enantioselective version of this NCAL process using isothiourea catalysts provided access to bicyclic beta-lactone-fused, N-heterocycles in moderate to good yields (up to 80%) with high enantiocontrol (up to >99:1 er). An unusual diastereodivergent NCAL process was discovered that leads to two different products; a tricyclic N-heterocycle-fused beta-lactone and a bicyclic enamine derived from in situ decarboxylation of the diastereomeric tricyclic beta lactone. The reactivity of these adducts was briefly explored. PMID- 29125761 TI - Mixed Valency as a Strategy for Achieving Charge Delocalization in Semiconducting and Conducting Framework Materials. AB - The fundamentally important phenomenon of mixed valency has been discussed in detail over the past 50 years, predominantly in the context of dinuclear complexes, which are used as model systems for understanding electron delocalization in more complex biological and physical systems. Very recently, mixed valency has been shown to be an important mechanism for charge transfer, leading to delocalization and conductivity in two- and three-dimensional framework materials such as metal-organic frameworks and related systems including covalent organic frameworks and semicrystalline semiconducting metal organic graphenes. This Viewpoint provides a current perspective on the field of mixed-valence frameworks, where the property is either intrinsic or generated postsynthetically via an external stimulus. Aspects of the spectroscopy and applications of these materials are also discussed, highlighting the future potential for exploiting mixed valency in extended solid-state systems. PMID- 29125763 TI - Benzyl Alcohol-Treated CH3NH3PbBr3 Nanocrystals Exhibiting High Luminescence, Stability, and Ultralow Amplified Spontaneous Emission Thresholds. AB - We report the high yield synthesis of about 11 nm sized CH3NH3PbBr3 nanocrystals with near-unity photoluminescence quantum yield. The nanocrystals are formed in the presence of surface-binding ligands through their direct precipitation in a benzyl alcohol/toluene phase. The benzyl alcohol plays a pivotal role in steering the surface ligands binding motifs on the NC surface, resulting in enhanced surface-trap passivation and near-unity PLQY values. We further demonstrate that thin films from purified CH3NH3PbBr3 nanocrystals are stable >4 months in air, exhibit high optical gain (about 520 cm-1), and display stable, ultralow amplified spontaneous emission thresholds of 13.9 +/- 1.3 and 569.7 +/- 6 MUJ cm 2 at one-photon (400 nm) and two-photon (800 nm) absorption, respectively. To the best of our knowledge, the latter signifies a 5-fold reduction of the lowest reported threshold value for halide perovskite nanocrystals to date, which makes them ideal candidates for light-emitting and low-threshold lasing applications. PMID- 29125762 TI - Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores. AB - A series of potent and selective D3 receptor (D3R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds 11, 14, 15a, and 15c revealed favorable D3R affinity (Ki = 12-25.6 nM) and were highly selective for D3R vs D3R (ranging from 264- to 905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10-20 min benchtop C N cross-coupling methodology, affording a broad range of arylated diazaspiro precursors. PMID- 29125764 TI - Selective Acceleration of Crystal Growth of Indomethacin Polymorphs by Low Concentration Poly(ethylene oxide). AB - Physical stability of pharmaceutical amorphous solid dispersions is one of the critical attributes to the successful development of the formulation. Herein, we studied the impact of low-concentration poly(ethylene oxide) (PEO) on the crystallization rates of three polymorphs of indomethacin (IMC, gamma-, alpha-, and delta-form). We observed that the addition of 3% w/w PEO significantly increased the crystal growth rates of gamma-form and alpha-form of IMC, but had a negligible effect on the delta-form. The reduction of the activation energy for the crystal growth of IMC polymorphs after adding the PEO follows the order gamma form > alpha-form > delta-form, which is consistent with the trend toward the accelerating effects of PEO on the crystal growth rates of three polymorphs. With the addition of low-concentration PEO, there is an increase of molecular mobility of IMC as evidenced by the decreased structural relaxation times and viscosities. This study suggests that the substantially different effects of PEO on the crystal growth rates of IMC polymorphs are attributable to the different adsorption of PEO on the crystal surface of those polymorphs, which in turn exerts a selective accelerating effect on IMC molecules to organize into the different crystalline phases. These findings are relevant for understanding the crystallization behavior of amorphous solid dispersions containing polymorphic drugs. PMID- 29125765 TI - Trehalose-Functionalized Gold Nanoparticle for Inhibiting Intracellular Protein Aggregation. AB - Trehalose is a well-known antiamyloidogenic molecule that inhibits protein aggregation under the intracellular/extracellular condition, and recent work shows that the nanoparticle form of trehalose can further enhance this performance. Here we have designed a trehalose-functionalized Au nanoparticle that can inhibit the aggregation of a polyglutamine-containing mutant protein inside the neuronal cell. Designed nanoparticles have a 20-30 nm Au core with about 350 +/- 50 trehalose molecules per particle on the surface on average. They enter the cell, inhibit mutant protein aggregation, and enhance the cell survival against toxic protein aggregates. This work extends the application potential of trehalose for the understanding and treatment of different diseases involving protein aggregation. PMID- 29125766 TI - Highly Sensitive Ammonia Gas Sensor Based on Single-Crystal Poly(3 hexylthiophene) (P3HT) Organic Field Effect Transistor. AB - A highly sensitive organic field-effect transistor (OFET)-based sensor for ammonia in the range of 0.01 to 25 ppm was developed. The sensor was fabricated by employing an array of single-crystal poly(3-hexylthiophene) (P3HT) nanowires as the organic semiconductor (OSC) layer of an OFET with a top-contact geometry. The electrical characteristics (field-effect mobility, on/off current ratio) of the single-crystal P3HT nanowire OFET were about 2 orders of magnitude larger than those of the P3HT thin film OFET with the same geometry. The P3HT nanowire OFET showed excellent sensitivity to ammonia, about 3 times higher than that of the P3HT thin film OFET at 25 ppm ammonia. The ammonia response of the OFET was reversible and was not affected by changes in relative humidity from 45 to 100%. The high ammonia sensitivity of the P3HT nanowire OFET is believed to result from the single crystal nature and high surface/volume ratio of the P3HT nanowire used in the OSC layer. PMID- 29125767 TI - Simultaneous Analysis of Equilibrium Fluctuations at the Surface and in the Bulk of a Binary Liquid Mixture by Dynamic Light Scattering. AB - For the first time, we demonstrate that it is possible to simultaneously analyze microscopic fluctuations at the surface and in the bulk of a binary liquid mixture by dynamic light scattering in macroscopic thermodynamic equilibrium. For a model system containing n-octacosane and ethanol, three individual signals distinguishable in the time-resolved analysis of the scattered light intensity appear on different time scales. One oscillatory signal from surface fluctuations at the vapor-liquid interface in the short-time range and two exponential Rayleigh signals from fluctuations in temperature and concentration in the bulk of fluid in the long-time range could be associated with hydrodynamic modes. This microscopic information allows for a simultaneous determination of the macroscopic properties interfacial tension, kinematic viscosity, thermal diffusivity, and mutual diffusivity within a single experimental run. The presented approach represents a worthwhile strategy, for example, in the context of sensor development for an effective multiproperty determination of fluid systems. PMID- 29125768 TI - Self-Assembling Elastin-Like Hydrogels for Timolol Delivery: Development of an Ophthalmic Formulation Against Glaucoma. AB - This work focuses on improving the effectiveness of current therapies against glaucoma by incorporating self-assembled polymers into the ophthalmic formulation. To that end, we first studied the influence of the dispersing medium on the mechanical performance of self-assembling elastin-like (EL) and silk elastin-like (SEL) hydrogels by conducting rheological tests. These polymers were subsequently incorporated into the antiglaucoma formulation, which contains timolol maleate (TM) as active ingredient, and in vivo tests, namely adhesion tests and intraocular pressure measurements (IOP), were performed in New Zealand rabbits. An enhanced reduction in IOP due to the presence of the polymers was observed. Moreover, differences in the effectiveness between both EL- and SEL hydrogels, which can be explained on the basis of the different rheological properties displayed by these two systems, were also encountered. The results point to the potential of this system as a basis for the development of an ophthalmic formulation against glaucoma. PMID- 29125769 TI - Is Solute Rotation in an Ionic Liquid Influenced by the Addition of Glucose? AB - Fluorescence anisotropy measurements and molecular dynamics (MD) simulations have been performed to understand the specific interactions of two structurally similar nondipolar solutes, 2,5-dimethyl-1,4-dioxo-3,6-diphenylpyrrolo[3,4 c]pyrrole (DMDPP) and 1,4-dioxo-3,6-diphenylpyrrolo[3,4-c]pyrrole (DPP), with neat 1-butyl-3-methylimidazolium dicyanamide ([BMIM][N(CN)2]) and also in the presence of glucose. It has been observed that the measured reorientation times of DMDPP in neat [BMIM][N(CN)2] follow the predictions of the Stokes-Einstein Debye hydrodynamic theory with slip boundary condition. Addition of glucose (0.075 and 0.15 mole fraction) has no bearing on the rotational diffusion of the solute apart from the viscosity related effects. In contrast, the reorientation times of DPP in neat [BMIM][N(CN)2] obey stick boundary condition as the hydrogen bond donating solute experiences specific interactions with the dicyanamide anion. No influence of the additive can be noticed on the rotational diffusion of DPP at 0.075 mole fraction of glucose. However, at 0.15 mole fraction of glucose, the reorientation times of the solute at a given viscosity and temperature decrease by 15-40% compared to those obtained in the neat ionic liquid. MD simulations indicate that each DPP molecule hydrogen bonds with two dicyanamide anions in neat ionic liquid. The simulations also reveal that, at 0.15 mole fraction of glucose, the concentration of anions hydrogen bonded to glucose increases significantly; therefore, the percentage of solute molecules that can form hydrogen bonds with two dicyanamide anions decreases to 84, which leads to faster rotation of DPP. PMID- 29125770 TI - Comparison of RESP and IPolQ-Mod Partial Charges for Solvation Free Energy Calculations of Various Solute/Solvent Pairs. AB - The calculation of solvation free energies DeltaGsolv by molecular simulations is of great interest as they are linked to other physical properties such as relative solubility, partition coefficient, and activity coefficient. However, shortcomings in molecular models can lead to DeltaGsolv deviations from experimental data. Various studies have demonstrated the impact of partial charges on free energy results. Consequently, calculation methods for partial charges aimed at more accurate DeltaGsolv predictions are the subject of various studies in the literature. Here we compare two methods to derive partial charges for the general AMBER force field (GAFF), i.e. the default RESP as well as the physically motivated IPolQ-Mod method that implicitly accounts for polarization costs. We study 29 solutes which include characteristic functional groups of drug like molecules, and 12 diverse solvents were examined. In total, we consider 107 solute/solvent pairs including two water models TIP3P and TIP4P/2005. Comparison with experimental results yields better agreement for TIP3P, regardless of the partial charge scheme. The overall performance of GAFF/RESP and GAFF/IPolQ-Mod is similar, though specific shortcomings in the description of DeltaGsolv for both RESP and IPolQ-Mod can be identified. However, the high correlation between free energies obtained with GAFF/RESP and GAFF/IPolQ-Mod demonstrates the compatibility between the modified charges and remaining GAFF parameters. PMID- 29125771 TI - Seven Chromisms Associated with Dithizone. AB - Variations in the electromagnetic wavelengths of absorption and reflection of molecules do not only make life colorful but also are often of central importance in solar energy conversion and optoelectronic information processing and transfer. Dithizone and its derivatives and complexes are, to our knowledge, probably the most "colorful" compound, being responsive to no less than seven different external stimuli that effect color change. Apart from a more detailed discussion of the cyclic voltammetry and observed electrochromism in the SCH3 substituted free ligand and mercury complex, concentratochromism, solvatochromism, halochromism, thermochromism, and chronochromism in the ligand, and photochromism in the carboxy-functionalized phenylmercury(II) complex are also presented here. Color changes are either associated with proton transfer or loss, or isomerization. PMID- 29125772 TI - One-Step Synthesis of Fully Functionalized Pyrazolo[3,4-b]pyridines via Isobenzofuranone Ring Opening. AB - A novel series of fully substituted pyrazolo[3,4-b]pyridines 4 has been prepared in a regioselective manner by the microwave-assisted reaction between N substituted 5-aminopyrazoles 1 and 3-(3-oxo-2-benzofuran-1(3H)-ylidene)pentane 2,4-dione (2). This is the second reported example of a cyclocondensation reaction using substrate 2 as a 1,3-bis-electrophilic reagent. Remarkably, this synthesis offers functionalized products with acetyl and carboxyl groups in one step, in good yields, and with short reaction times. Additionally, the cyclization intermediate 3 was isolated, allowing us to postulate a mechanism for this reaction, which is initiated via isobenzofuranone ring opening of 2 in a Michael-type reaction. The structures of the products and regioselectivity of the reactions were determined on the basis of NMR measurements and X-ray diffraction. For this new reaction using substrate 2, the optimal reaction conditions and its scope were investigated. PMID- 29125773 TI - Large Scale Two-Dimensional Flux-Closure Domain Arrays in Oxide Multilayers and Their Controlled Growth. AB - Ferroelectric flux-closures are very promising in high-density storage and other nanoscale electronic devices. To make the data bits addressable, the nanoscale flux-closures are required to be periodic via a controlled growth. Although flux closure quadrant arrays with 180 degrees domain walls perpendicular to the interfaces (V-closure) have been observed in strained ferroelectric PbTiO3 films, the flux-closure quadrants therein are rather asymmetric. In this work, we report not only a periodic array of the symmetric flux-closure quadrants with 180 degrees domain walls parallel to the interfaces (H-closure) but also a large scale alternative stacking of the V- and H-closure arrays in PbTiO3/SrTiO3 multilayers. On the basis of a combination of aberration-corrected scanning transmission electron microscopic imaging and phase field modeling, we establish the phase diagram in the layer-by-layer two-dimensional arrays versus the thickness ratio of adjacent PbTiO3 films, in which energy competitions play dominant roles. The manipulation of these flux-closures may stimulate the design and development of novel nanoscale ferroelectric devices with exotic properties. PMID- 29125774 TI - A One-Pot Synthesis of Highly Functionalized Purines. AB - Highly substituted purines were synthesized in good to high yields through a one pot straightforward metal-free scalable method, using the Traube synthesis adapted to Vilsmeier-type reagents. From 5-amino-4-chloropyrimidines, new 9-aryl substituted chloropurines and intermediates for peptide nucleic acid synthesis were prepared. Variant procedures allowing a rapid synthesis of ribonucleosides and 7-benzylpurine from 5-amidino-6-aminopyrimidines are also reported to illustrate the high potential of this versatile toolbox. This route appears to be particularly interesting in the field of nucleic acids for a direct and rapid access to various new 8-alkylpurine nucleosides. PMID- 29125776 TI - Unique Trapped Dimer State of the Photogenerated Hole in Hybrid Orthorhombic CH3NH3PbI3 Perovskite: Identification, Origin, and Implications. AB - Revealing the innate character and transport of the photogenerated hole is essential to boost the high photovoltaic performance in the lead-based organohalide perovskite. However, knowledge at the atomic level is currently very limited. In this work, we systematically investigate the properties of the photogenerated hole in the orthorhombic CH3NH3PbI3 using hybrid functional PBE0 calculations with spin-orbit coupling included. An unexpected trapping state of the hole, localized as I2- (I dimer), is uncovered, which was never reported in photovoltaic materials. It is shown that this localized configuration is energetically more favorable than that of the delocalized hole state by 191 meV and that it can highly promote the diffusion of the hole with an energy barrier as low as 131 meV. Furthermore, the origin of I dimer formation upon trapping of the hole is rationalized in terms of electronic and geometric effects, and a good linear correlation is found between the hole trapping capacity and the accompanying structural deformation in CH3NH3PbX3 (X = Cl, Br, and I). It is demonstrated that good CH3NH3PbX3 materials for the hole diffusion should have small structural deformation energy and weak hole trapping capacity, which may facilitate the rational screening of superior photovoltaic perovskites. PMID- 29125775 TI - Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines. AB - Photochemical precursors that produce dA* and dG(N2-H)* are needed to investigate their reactivity. The synthesis of two 1,1-diphenylhydrazines (1, 2) and their use as photochemical sources of dA* and dG(N2-H)* is presented. Trapping studies indicate production of these radicals with good fidelity, and 1 was incorporated into an oligonucleotide via solid-phase synthesis. Cyclic voltammetric studies show that reduction potentials of 1 and 2 are lower than those of widely used "hole sinks", e.g., 8-oxodGuo and 7-deazadGuo, to investigate DNA-hole transfer processes. These molecules could be useful (a) as sources of dA* and dG(N2-H)* at specific sites in oligonucleotides and (b) as "hole sinks" for the study of DNA hole transfer processes. PMID- 29125777 TI - Quasi-Static Resonances in the Visible Spectrum from All-Dielectric Intermediate Band Semiconductor Nanocrystals. AB - The quest for materials with metal-like properties as alternatives to noble metals is an intense area of research that is set to lead to dramatic improvements in technologies based on plasmonics. Here, we present intermediate band (IB) semiconductor nanocrystals (NCs) as a class of all-dielectric nanomaterials providing quasi-static optical resonances. We show that IB NCs can display a negative permittivity in a broad range of visible wavelengths, enabling a metal-like optical response despite the absence of free carriers in the NC ground state. Using a combination of spectroscopy measurements and ab initio calculations, we hereby provide a theoretical model for both the linear and nonlinear optical properties of chalcopyrite CuFeS2 NCs, as a case study of IB semiconductor nanomaterials. Our results rationalize the high performance of IB nanomaterials as photothermal agents and suggest the use of IB semiconductors as alternatives to noble metals for technologies based on plasmonic materials. PMID- 29125778 TI - Isolation and molecular cytogenetic characterization of a wheat - Leymus mollis double monosomic addition line and its progenies with resistance to stripe rust. AB - A common wheat - Leymus mollis (2n = 4x = 28, NsNsXmXm) double monosomic addition line, M11003-4-3-8/13/15 (2n = 44 = 42T.a + L.m2 + L.m3), with stripe rust resistance was developed (where T.a represents Triticum aestivum chromosome, L.m represents L. mollis chromosome, and L.m2/3 represents L. mollis chromosome of homoeologous groups 2 and 3). The progenies of line M11003-4-3-8/13/15 were characterized by cytological observation, specific molecular markers, fluorescence in situ hybridization (FISH), and genomic in situ hybridization (GISH). Among the progenies, there existed five different types (I, II, III, IV, and V) of chromosome constitution, the formulas of which were 2n = 44 = 42T.a + 1L.m2 + 1L.m3, 2n = 43 = 42T.a + 1L.m2, 2n = 43 = 42T.a + 1L.m3, 2n = 42 = 42T.a, and 2n = 44 = 42T.a + 2L.m2, respectively. Field disease screening showed that types I and III showed high resistance to stripe rust, while types II, IV, and V were susceptible. Leymus mollis was almost immune to stripe rust, whereas the wheat parent, cultivar 7182, was susceptible. Therefore, we concluded that the stripe rust resistance originated from L. mollis. These various lines could be further fully exploited as important disease resistance materials to enrich wheat genetic resources. PMID- 29125779 TI - Outcomes of Recurrent Retinal Detachment Surgery following Pars Plana Vitrectomy for Rhegmatogenous Retinal Detachment. AB - AIM: To study the anatomical and functional outcomes of recurrent retinal detachment (RD) surgery following pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment. METHODS: Retrospective analysis of 133 consecutive cases of recurrent RD. INCLUSION CRITERIA: age >=18 years, recurrent RD following PPV +/- encircling band for rhegmatogenous RD. EXCLUSION CRITERIA: age <18 years, post endophthalmitis/tractional/exudative/combined RD, post-scleral buckle, primary surgery done at another institute. The final anatomical and functional outcomes, and their association with clinico-surgical factors, were analyzed. RESULTS: Proliferative vitreoretinopathy (PVR) >= Grade C in re-detached retina (OR, 2.49; 95% CI, 1.02-6.09; P = 0.045) and need for multiple resurgeries (OR, 6.48; 95% CI, 2.51-16.69; P < 0.0001) were significant risk factors for the final anatomical failure. Eyes with PVR >= Grade C (OR, 0.31, 95% CI, 0.12-0.80; P = 0.013) in primary RD, and with multiple breaks (OR, 0.24; 95% CI, 0.06-0.96; P = 0.044) at the time of recurrent RD, were less likely to have final BCVA >=20/200. The visual acuity at the time of recurrent RD had a moderately positive correlation (r = 0.454, P < 0.001), and the delay in recurrence of RD had a weakly positive correlation (r = 0.214, P = 0.046) with the final BCVA. CONCLUSIONS: PVR >= Grade C and multiple resurgeries are associated with higher incidence of anatomical failure in recurrent RD surgery. Multiple breaks are associated with a poorer visual outcome, whereas a better baseline visual acuity and delayed recurrence of RD after primary repair are associated with a better visual outcome. PMID- 29125781 TI - Shyness and Social Anxiety Assessed Through Self-Report: What Are We Measuring? AB - The distinction between shyness and social anxiety remains unclear in the literature. In an attempt to shed further light on this issue, our research evaluated whether shyness and social anxiety were the same construct underlying various measurement scales. Participants (N = 801, Mage = 36.21, range = 18-74, female = 53.10%) responded to 10 questionnaires assessing either shyness or social anxiety. Evidence indicated that the scales were highly correlated and loaded onto 1 factor. Confirmatory factor analysis corroborated this finding. A second exploratory factor analysis revealed that all the shyness and social anxiety items best loaded together onto 3 factors: one corresponding to fear of negative evaluation, embarrassment, self-consciousness, scrutiny, authority, interaction anxiety, and shyness (71.0%); a second comprised of primarily interaction anxiety and shyness (17.7%); and a third associated with performance anxiety (7.5%). All scales were similarly discriminated from sociability. Overall, the constructs of shyness and social anxiety were not differentiated from each other. Researchers should carefully consider what items are included in shyness and social anxiety scales if these constructs are to be distinguished from one another. PMID- 29125780 TI - Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments. AB - BACKGROUND: In 177Lu-DOTATATE treatments, bone marrow (BM) is one of the most important organs at risk. The authors previously developed an image-based two compartment method for BM dosimetry, showing a significant correlation between absorbed dose to BM and hematological toxicity in 177Lu-DOTATATE treatments. In the present study, they aimed to further evaluate this BM dosimetry method by finding optimal settings for dividing the whole body into two compartments; in terms of minimizing the coefficient of variation (CV) for the individual absorbed doses and studying its correlation to the BM response. The authors have also added specific absorbed fractions for male and female. Finally, they compare this two-compartment method with whole-body dosimetry. METHODS: This study included 46 patients with advanced neuroendocrine tumors treated with 177Lu-DOTATATE on two to five occasions at Sahlgrenska University Hospital. Planar gamma camera images were collected at four time points postinjection, and a segmentation tool using a normalized number of uptake foci (nNUF) to divide the whole body into high- and low-uptake compartments was used. The authors characterized the two-compartment model and compared it with whole-body dosimetry. RESULTS AND CONCLUSION: The dosimetry method was robust, with an optimal nNUF value of 0.1-0.2. Using an nNUF value of 0.15, the absorbed BM dose was estimated as 0.20 Gy/7.4 GBq, and the CV as 8.4%. Compared to whole-body dosimetry, stronger correlation was found between absorbed dose to BM and hematological response using the two-compartment method. The two-compartment method has potential as a valuable image-based alternative to blood-based BM dosimetry. PMID- 29125782 TI - Quality Improvement in Athletic Health Care. AB - CONTEXT: Quality improvement (QI) is a health care concept that ensures patients receive high-quality (safe, timely, effective, efficient, equitable, patient-centered) and affordable care. Despite its importance, the application of QI in athletic health care has been limited. OBJECTIVES: To describe the need for and define QI in health care, to describe how to measure quality in health care, and to present a QI case in athletic training. DESCRIPTION: As the athletic training profession continues to grow, a widespread engagement in QI efforts is necessary to establish the value of athletic training services for the patients that we serve. A review of the importance of QI in health care, historical perspectives of QI, tools to drive QI efforts, and examples of common QI initiatives is presented to assist clinicians in better understanding the value of QI for advancing athletic health care and the profession. Clinical and Research Advantages: By engaging clinicians in strategies to measure outcomes and improve their patient care services, QI practice can help athletic trainers provide high-quality and affordable care to patients. PMID- 29125784 TI - Identifying the Population with Serious Illness: The "Denominator" Challenge. AB - BACKGROUND: To ensure seriously ill people and their families receive high quality primary and specialty palliative care services, rigorous methods are needed to prospectively identify this population. OBJECTIVE: To define and operationalize a definition of serious illness for the purpose of identifying patients and caregivers who need primary or specialty palliative care services. DESIGN/SETTING: Two stages of work included (1) building expert consensus around a conceptual definition of serious illness and (2) using the National Health and Aging Trends Study linked to Medicare claims data to test a range of operational definitions composed of diagnoses, utilization, and markers of care needs. MEASUREMENTS: One-year outcomes included mean total Medicare costs, mortality, and percent hospitalized, as well as those reporting >=2 measures of need and functional impairment. Sensitivity, specificity, and c-statistics (unadjusted and adjusted for age, sex, race, and Medicaid status) were calculated for each definition across the outcomes. RESULTS: Conceptually, "Serious illness" is a health condition that carries a high risk of mortality AND either negatively impacts a person's daily function or quality of life, OR excessively strains their caregivers. The range of operational definitions simulated all had low sensitivity and high specificity across all outcomes. None of the definitions reached an unadjusted c-statistic >0.6 (or adjusted >0.7) for identifying a population with >=2 indicators of care needs. CONCLUSIONS: Standard administrative data are inadequate to identify this population. Defining the seriously ill denominator with high specificity, as described here, will focus efforts toward the highest-need segment of the population, who may indeed benefit most. PMID- 29125783 TI - Effectiveness of a smartphone app to increase parents' knowledge and empowerment in the MMR vaccination decision: A randomized controlled trial. AB - Researchers are trying to build evidence for mhealth effectiveness in various fields. However, no evidence yet is showing the effectiveness of mhealth on parents' attitudes and behavior with regard to recommended vaccination of their children. The aim of this study was to look into the effects of 2 smartphone based interventions targeting MMR vaccination knowledge and psychological empowerment respectively. The interventions used gamification features and videos in combination with text messages. We conducted a 2x2 between-subject factorial randomized controlled trial (absence/presence of knowledge intervention X absence/presence of empowerment intervention) with parents of young children in Italy. We randomly allocated 201 eligible participants to one of the 4 conditions. Data were collected by questionnaires at baseline and posttest. Primary outcomes were MMR vaccination knowledge, psychological empowerment, risk perception, and preferred decisional role; secondary outcomes included MMR vaccination intention, attitude, confidence, and recommendation intention. A significant gain in vaccination knowledge was reported by all experimental groups compared with the control (F(3,179) = 48.58, p < .000), while only those receiving both interventions reported a significant increase in their psychological empowerment (t(179) = -2.79, p = .006). Participants receiving the intervention targeting knowledge reported significantly higher intention to vaccinate (t(179) = 2.111; p = .03) and higher confidence in the decision (t(179) = 2.76; p = .006) compared with the control group. Parent-centered, gamified mobile interventions aimed at providing parents with vaccination-related information can be used to increase their knowledge, their intention to vaccinate as well as their confidence in the vaccination decision. PMID- 29125785 TI - Cytogenetic analysis and mapping of leaf rust resistance in Aegilops speltoides Tausch derived bread wheat line Selection2427 carrying putative gametocidal gene(s). AB - Leaf rust (Puccinia triticina) is a major biotic stress affecting wheat yields worldwide. Host-plant resistance is the best method for controlling leaf rust. Aegilops speltoides is a good source of resistance against wheat rusts. To date, five Lr genes, Lr28, Lr35, Lr36, Lr47, and Lr51, have been transferred from Ae. speltoides to bread wheat. In Selection2427, a bread wheat introgresed line with Ae. speltoides as the donor parent, a dominant gene for leaf rust resistance was mapped to the long arm of chromosome 3B (LrS2427). None of the Lr genes introgressed from Ae. speltoides have been mapped to chromosome 3B. Since none of the designated seedling leaf rust resistance genes have been located on chromosome 3B, LrS2427 seems to be a novel gene. Selection2427 showed a unique property typical of gametocidal genes, that when crossed to other bread wheat cultivars, the F1 showed partial pollen sterility and poor seed setting, whilst Selection2427 showed reasonable male and female fertility. Accidental co-transfer of gametocidal genes with LrS2427 may have occurred in Selection2427. Though LrS2427 did not show any segregation distortion and assorted independently of putative gametocidal gene(s), its utilization will be difficult due to the selfish behavior of gametocidal genes. PMID- 29125786 TI - Novel recombinant multiepitope proteins for the detection of anti-Cryptococcus antibodies. AB - AIM: To produce and test recombinant multiepitope proteins as an alternative assay for the serological diagnosis of cryptococcosis. MATERIALS & METHODS: Previously, synthetic peptides were used to detect anti-Cryptococcus antibodies, and in silico analyses showed that the union of peptides would improve the results. Here, the coding sequences of these peptides were assembled into synthetic genes. Four genes have been cloned and expressed in Escherichia coli, producing recombinant multiepitope proteins: proteins A, B, C and D. RESULTS: All constructs yielded good results; however, protein D showed the best results, with a sensitivity of 88.57% and specificity of 100%. CONCLUSION: The multiepitope proteins were shown to be potential antigens for the diagnosis of cryptococcosis in an attempt to detect anti-Cryptococcus antibodies. PMID- 29125787 TI - Being There in the Midst of the Story: How Immersive Journalism Affects Our Perceptions and Cognitions. AB - Immersive journalism in the form of virtual reality (VR) headsets and 360 degrees -video is becoming more mainstream and is much touted for inducing greater "presence" than traditional text. But, does this presence influence psychological outcomes of reading news, such as memory for story content, perceptions of credibility, and empathy felt toward story characters? We propose that two key technological affordances of VR (modality and interactivity) are responsible for triggering three presence-related cognitive heuristics (being-there, interaction, and realism), which influence news readers' memory and their perceptions of credibility, empathy, and story-sharing intentions. We report a 3 (storytelling medium: VR vs. 360 degrees -video vs. Text) * 2 (story: "The displaced" and "The click effect") mixed-factorial experiment, in which participants (N = 129) experienced two New York Times stories (that differed in their emotional intensity) using one of the three mediums (VR, 360 degrees -video, Text). Participants who experienced the stories using VR and 360 degrees -video outperformed those who read the same stories using text with pictures, not only on such presence-related outcomes as being-there, interaction, and realism, but also on perceived source credibility, story-sharing intention, and feelings of empathy. Moreover, we found that senses of being-there, interaction, and realism mediated the relationship between storytelling medium and reader perceptions of credibility, story recall, and story-sharing intention. These findings have theoretical implications for the psychology of virtual reality, and practical applications for immersive journalism in particular and interactive media in general. PMID- 29125788 TI - Internet-Related Disorders: Development of the Short Compulsive Internet Use Scale. AB - The addiction treatment system only reaches a small number of individuals suffering from Internet-related disorders. Therefore, it is important to improve case detection for preventive measures and brief interventions. Existing screening instruments are often time-consuming and rarely validated using clinical criteria. The aim of this study is to develop an optimized short screening for problematic Internet use and Internet addiction (IA). A regression analysis was conducted in random subsamples of a merged sample (N = 3,040; N = 1,209) to examine the item performance of the Compulsive Internet Use Scale (CIUS). Based on the results, a short version of the CIUS was developed and compared with the original CIUS. A fully structured diagnostic interview, covering the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for the Internet gaming disorder with a broader focus on all Internet activities, was conducted. A five-item version of the short screening performed best across the samples. Comparing the area under the curve (AUC) of the receiver operating characteristic between the Short CIUS and the original test revealed no significant difference (AUC = 0.968; 0.977). A cutoff point of 7 turned out to perform best for case detection and yielded a sensitivity of 0.95 and a specificity of 0.87, Cronbach's alpha was 0.77. The analysis showed that the performance of the Short CIUS is just as good in detecting problematical Internet use and IA as the performance of the original CIUS. The Short CIUS provides an economical and valid instrument for the assessment of problematic Internet use and IA. PMID- 29125789 TI - Video Game Acceptance: A Meta-Analysis of the Extended Technology Acceptance Model. AB - The current study systematically reviews and summarizes the existing literature of game acceptance, identifies the core determinants, and evaluates the strength of the relationships in the extended technology acceptance model. Moreover, this study segments video games into two categories: hedonic and utilitarian and examines player acceptance of these two types separately. Through a meta-analysis of 50 articles, we find that perceived ease of use (PEOU), perceived usefulness (PU), and perceived enjoyment (PE) significantly associate with attitude and behavioral intention. PE is the dominant predictor of hedonic game acceptance, while PEOU and PU are the main determinants of utilitarian game acceptance. Furthermore, we find that respondent type and game platform are significant moderators. Findings of this study provide critical insights into the phenomenon of game acceptance and suggest directions for future research. PMID- 29125791 TI - A Virtual Reality Game to Assess Obsessive-Compulsive Disorder. AB - The retrospective and subjective nature of clinical interviews is an important shortcoming of current psychiatric diagnosis. Consequently, there is a clear need for objective and standardized tools. Virtual reality (VR) can be used to achieve controlled symptom provocation, which allows direct assessment for the clinician. We developed a video VR game to provoke and assess obsessive-compulsive disorder (OCD) symptoms in a standardized and controlled environment. The first objective was to evaluate if the VR game is capable of provoking symptoms in OCD patients as opposed to healthy controls. The second objective was to evaluate the tolerability of the VR game in OCD patients. The VR game was created using a first-person perspective and confronted patients with 15 OCD-specific items, while simultaneously measuring OCD symptoms, including the number of compulsions, anxiety, tension, uncertainty, and urge to control. In this pilot study, eight patients and eight healthy controls performed the VR game. OCD patients performed significantly more compulsions (U = 5, p = 0.003) during the VR game. The anxiety, tension, uncertainty, and urge to control in response to the specific items were also higher for OCD patients, although significance was not yet reached because of the small sample. There were no substantial adverse effects. The results of this pilot study indicate that the VR game is capable of provoking a variety of OCD symptoms in OCD patients, as opposed to healthy controls, and is a potential valuable tool to objectify and standardize an OCD diagnosis. PMID- 29125792 TI - How Digital Anxieties Are Shaping the Next Generation's Mental Health. PMID- 29125794 TI - SR-B1: A Unique Multifunctional Receptor for Cholesterol Influx and Efflux. AB - The scavenger receptor, class B type 1 (SR-B1), is a multiligand membrane receptor protein that functions as a physiologically relevant high-density lipoprotein (HDL) receptor whose primary role is to mediate selective uptake or influx of HDL-derived cholesteryl esters into cells and tissues. SR-B1 also facilitates the efflux of cholesterol from peripheral tissues, including macrophages, back to liver. As a regulator of plasma membrane cholesterol content, SR-B1 promotes the uptake of lipid soluble vitamins as well as viral entry into host cells. These collective functions of SR-B1 ultimately affect programmed cell death, female fertility, platelet function, vasculature inflammation, and diet-induced atherosclerosis and myocardial infarction. SR-B1 has also been identified as a potential marker for cancer diagnosis and prognosis. Finally, the SR-B1-linked selective HDL-cholesteryl ester uptake pathway is now being evaluated as a gateway for the delivery of therapeutic and diagnostic agents. In this review, we focus on the regulation and functional significance of SR-B1 in mediating cholesterol movement into and out of cells. PMID- 29125795 TI - Impurities in Oligonucleotide Drug Substances and Drug Products. AB - This white paper, which is the 10th in a series intended to address issues associated with the development of therapeutic oligonucleotides, examines the subject of product-related impurities. The authors consider chemistry and safety aspects and advance arguments in favor of platform approaches to impurity identification and qualification. Reporting, identification, and qualification thresholds suitable for product-related impurities of therapeutic oligonucleotides are proposed. PMID- 29125796 TI - A Bold Goal: More Healthy Days Through Improved Community Health. AB - Humana, a large health care company, has set a goal of 20% improvement in health in the communities it serves by 2020. The metric chosen for the Bold Goal initiative was the HRQOL-4 version of the Centers for Disease Control and Prevention (CDC) Healthy Days survey. This paper presents the methods for measuring progress, reports results for the first year of tracking, and describes Humana's community-based interventions. Across 7 specially designated "Bold Goal" communities, mean unhealthy days declined from 10.98 in 2015 to 10.64 in 2016, which represented a 3.1% relative, or 0.34 absolute, decline. This compares with a 0.17 absolute unhealthy days decline in Humana's national population overall. The paper also describes how additional work identifying associations between social determinants of health (SDOH) and Healthy Days is influencing Humana's strategy. Lastly, a strategy of community engagement is illustrated through 2 case examples: San Antonio and Knoxville. In the San Antonio area, the community in which Humana has been involved the longest, unhealthy days dropped by 9.0% ( 0.95 absolute) from a mean 10.52 to 9.57 unhealthy days. In Knoxville, one of the newer areas of engagement, mean unhealthy days declined by 4.8% (-0.61 absolute), representing declines in both physically and mentally unhealthy days. Overall, results are encouraging, and Humana expects declines to accelerate over time as initiatives are launched and scaled in Bold Goal communities. PMID- 29125797 TI - Is reduction of symptoms in eating disorder patients after 1 year of treatment related to attachment security and mentalization? AB - In a sample of 38 eating disorder (ED) patients who received psychotherapeutic treatment, changes in attachment security, and mentalization in relation to symptoms reduction were investigated. Attachment security improved in 1 year but was unrelated to improvement of ED or comorbid symptoms. Mentalization did not change significantly in 1 year. Pretreatment mentalization was negatively related to the severity of ED symptoms, trait anxiety, psycho-neuroticism, and self injurious behavior after 1 year of treatment. We conclude that for ED patients, improving mentalization might increase the effect of treatment on core and comorbid symptoms. PMID- 29125799 TI - Body Growth and Rapid Hematological Development Support Breath Hold of Baby Belugas (Delphinapterus leucas) during Subice Transit. AB - Body size and oxygen stores in the blood and muscle set breath-hold limits in marine mammals, yet these characteristics are understudied in immature cetaceans. We examined body mass and hematology from birth through adulthood in beluga whales (Delphinapterus leucas). At birth, body mass was 8% and 6% of the maximum mass recorded for adult females and males, respectively. Body mass then increased rapidly, approaching an asymptote around 12 yr for females and 18 yr for males. Interestingly, red blood cell counts, hemoglobin content, and hematocrit levels decreased after birth; this neonatal anemia was reversed as levels increased after 2 mo postpartum. Mature levels were obtained at approximately 8, 9, and 11 mo postpartum, respectively. Neonatal mean corpuscular hemoglobin also increased with ontogeny; mature levels were achieved by approximately 13 mo after birth. In contrast, mean corpuscular volume and mean corpuscular hemoglobin concentration demonstrated a significant but subtle increase throughout ontogeny. Our results indicate that postnatal maturation was required and that maturation occurred far earlier than the age at weaning (i.e., 2-3 yr postpartum). This is atypical of marine mammals, which generally achieve mature hemoglobin levels at weaning. Hematological maturation before maternal independence undoubtedly supports the prolonged breath holds of young belugas transiting under sea ice. This assessment enhances our knowledge of cetacean physiology and provides important inputs for determining age-specific dive capacity, yielding insights into age-specific flexibility to alter underwater behaviors, as will be required for future regime shifts and disturbances. PMID- 29125800 TI - The trauma factor: Examining the relationships among different types of trauma, dissociation, and psychopathology. AB - Extensive research has reported a dose-response relationship between exposure to trauma and the severity of both dissociation and psychopathology. However, certain types of trauma may co-occur more frequently than others and specific combinations of traumatic experiences may relate differently to dissociative processes and psychiatric symptoms. In the current study, 359 adult participants completed questionnaires on traumatic experiences, dissociation, and psychopathology. A correlation network analysis showed that some types of trauma are more likely to co-occur and that especially traumatic experiences in attachment relationships during childhood were significantly associated with other trauma in life. A latent class analysis identified four classes of participants (namely, extremely traumatized, resilient to the impact of abuse, exposed to impersonal and social trauma, and reporting low levels of traumatization) who showed different profiles on trauma exposure, dissociation, and psychopathology. Mediation analyses further showed that dissociation partially mediated the relationship between different types of traumatic experiences and the severity of psychiatric symptoms. The findings of this study support the view that a comprehensive assessment of traumatic experiences and dissociation is needed in trauma research and clinical practice. PMID- 29125802 TI - Penalty-based approaches to evaluating multiplicity adjustments in clinical trials: Advanced multiplicity problems. AB - Given the importance of addressing multiplicity issues in confirmatory clinical trials, several recent publications focused on the general goal of identifying most appropriate methods for multiplicity adjustment in each individual setting. This goal can be accomplished using the Clinical Scenario Evaluation approach. This approach encourages trial sponsors to perform comprehensive assessments of applicable analysis strategies such as multiplicity adjustments under all plausible sets of statistical assumptions using relevant evaluation criteria. This two-part paper applies a novel class of criteria, known as criteria based on multiplicity penalties, to the problem of evaluating the performance of several candidate multiplicity adjustments. The ultimate goal of this evaluation is to identify efficient and robust adjustments for each individual trial and optimally select parameters of these adjustments. Part II focuses on advanced settings with several sources of multiplicity, for example, clinical trials with several endpoints evaluated at two or more doses of an experimental treatment. A case study is given to illustrate a penalty-based approach to evaluating candidate multiple testing procedures in advanced multiplicity problems. PMID- 29125801 TI - Laparoscopic Versus Open Restorative Proctocolectomy for Familial Adenomatous Polyposis. AB - PURPOSE: This study compared outcomes after laparoscopic (LAP) or conventional (open) total proctocolectomy with outcomes after ileal J-pouch anal anastomosis (IPAA) at a single institution. METHODS: Charts from 133 familial adenomatous polyposis patients (1997-2013) were reviewed. Demographic data (age, sex, color, American Society of Anesthesiologists [ASA] status, previous surgery, and body mass index) and surgical outcomes (length of stay, early and late morbidity, reoperation, and mortality rates) were compared among 63 patients undergoing IPAA. RESULTS: Demographic features were similar among patients (25 open and 38 LAP). Conversely, colorectal cancer at diagnosis prevailed in the open group (60% versus 31.6%; P = .02). Tumor stages (P = .65) and previous surgery index (20% versus 10.5%; P = .46) were similar. Surgical length was longer for LAP (374 versus 281 minutes, P = .003). Short-term complication rates (28% versus 28.9%), hospital stay (10.9 versus 8.9 days), and total long-term reoperations (28% versus 21%) were not statistically different. However, major late morbidity (16% versus 2.6%; P < .001) and late reoperation rates (16% versus 5.2%; P < .05) were greater among open patients. Both groups did not differ regarding pouch failure rates (8% versus 5.2%). There was no operative mortality in the present series. CONCLUSIONS: (1) LAP IPAA is a safe procedure associated with a low conversion rate, (2) short-term results showed no clear advantages for both approaches, and (3) a greater risk of major late complications and late reoperations should be expected after open procedures. PMID- 29125803 TI - Religiosity and the concept of god moderate the relationship between the type of trauma, posttraumatic cognitions, and mental health. AB - The aim of the study was to examine the role of religiosity as a moderator in the relationships between trauma, posttraumatic cognitions, and mental health. A one dimensional measure of religiosity and a multidimensional "concept of god" measure were used; sexual and nonsexual traumatic events were assessed and posttraumatic cognitions related to either sexual or nonsexual trauma were taken into account. A total of 337 females from Poland participated in the cross sectional study. It was predicted that the relationships between sexual trauma and mental health would be stronger in religious individuals - this hypothesis was supported in the case of negative mental health (PTSD, z = -1.88, p = .003). No significant effects were found for nonsexual trauma; overall, highly religious individuals who had recently experienced trauma showed higher levels of satisfaction with life than nonreligious participants. As for the posttraumatic cognitions, one-dimensional religiosity was not a significant factor, but the self-blame cognitions and the concept of severe god were positively linked. In the case of sexual trauma, this effect was significant among nonreligious individuals. Moreover, the relationship between self-blame and PTSD was stronger in individuals who had the severe god concept. The current study was conducted in a religious society, where the majority of the population is raised as Roman Catholics. It has been demonstrated that religiosity is an important factor in the processing of trauma. This does not apply to religious individuals only: the concept of god was also a significant factor in nonreligious women. PMID- 29125804 TI - Acceptance and perceived usefulness of robots to assist with activities of daily living and healthcare tasks. AB - As the number of older adults living with chronic conditions continues to rise, they will require assistance with activities of daily living (ADL) and healthcare tasks to continue living independently in their homes. One proposed solution to assist with the care needs of an aging population and a shrinking healthcare workforce is robotic technology. Using a cross-sectional survey design, we purposively sampled adults (>=18 years old) to assess generational acceptance and perceived usefulness of robots to assist with ADLs, healthcare tasks, and evaluate acceptance of robotic healthcare assistance across different settings. A total of 499 adults (age range [years] 18-98, Mean = 38.7, SD = 22.7) responded to the survey. Significant differences were found among young, middle-aged, and older adults on perceived usefulness of robots for cleaning, escorting them around town, acting as companionship, delivering meals, assessing sadness and calling for help, providing medical advice, taking vital sign assessments, and assisting with personal care (p < 0.05). The majority of younger adults reported that they would like a robot to provide healthcare assistance in the hospital, compared to middle-aged and older adults (p < 0.001). Results of this study can guide the design of robots to assist adults of all ages with useful tasks. PMID- 29125798 TI - Wnt/beta-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. AB - The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/beta-catenin pathway plays a role in almost every facet of liver biology. Furthermore, its aberrant activation is also a hallmark of various hepatic pathologies. In addition to its signaling function, beta-catenin also plays a role at adherens junctions. Wnt/beta-catenin signaling also influences the function of many different cell types. Due to this myriad of functions, Wnt/beta-catenin signaling is complex, context-dependent, and highly regulated. In this review, we discuss the Wnt/beta-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type-specific roles of Wnt/beta-catenin signaling as it relates to liver physiology and pathobiology. PMID- 29125805 TI - Association of Mass Media Communication with Contraceptive Use in Sub-Saharan Africa: A Meta-Analysis of Demographic and Health Surveys. AB - Literature abounds with evidence on the effectiveness of individual mass media interventions on contraceptive use and other health behaviors. There have been, however, very few studies summarizing effect sizes of mass media health communication campaigns in sub-Saharan Africa. In this study, we used meta analytic techniques to pool data from 47 demographic and health surveys conducted between 2005 and 2015 in 31 sub-Saharan African countries and estimate the prevalence of exposure to family planning-related mass media communication. We also estimated the average effect size of exposure to mass media communication after adjusting for endogeneity. We performed meta-regression to assess the moderating role of selected variables on effect size. On average, 44% of women in sub-Saharan Africa were exposed to family planning-related mass media interventions in the year preceding the survey. Overall, exposure was associated with an effect size equivalent to an odds ratio of 1.93. More recent surveys demonstrated smaller effect sizes than earlier ones, while the effects were larger in lower contraceptive prevalence settings than in higher prevalence ones. The findings have implications for designing communication programs, setting expectations about communication impact, and guiding decisions about sample size estimation for mass media evaluation studies. PMID- 29125806 TI - The Secret of Intrafamilial Child Sexual Abuse: Who Keeps It and How? AB - This article analyzes how women survivors of intrafamilial child sexual abuse perceive the family members who took part in keeping it secret and their tactics for doing so. Analysis of 20 in-depth interviews with Jewish Israeli women revealed unique ways of guarding the secret. These were attributed to the perpetrator, the mother and the family. Secret-keeping tactics included presenting a normative public identity or an unstable psychological identity, presenting multiple personas, reframing the abuse, concealing any trace of the secret after it was disclosed, as if the abuse had never happened, and making a monument of the abuser. These tactics are discussed in the context of silencing, the interpersonal relations orientation model, and the wider concepts of secrecy in society. Implications for professional practice and for society are considered, and new attitudes toward intrafamilial child sexual abuse secrecy are suggested. PMID- 29125807 TI - What are the preferred characteristics of a service robot for the elderly? A multi-country focus group study with older adults and caregivers. AB - This multi-perspective study focuses on how a service robot for the elderly should behave when interacting with potential users. An existing service robot and a scenario were used as a concrete case, which was discussed and analyzed during focus group sessions with older adults (n = 38), informal caregivers (n = 24), and professional caregivers (n = 35) in the Netherlands, France, and the United Kingdom. A total of seven topics-privacy, task execution, environment, appearance, behavior, visitors, and communication-were explored. The results showed that some of the characteristics mentioned were unique to a user group, but several were cross-cutting. Overall, potential users expected the service robot to be customizable in order to match the users' needs and preferences. Also, high expectations concerning its functioning and behavior were expressed, which sometimes could even be compared to the qualities of a human being. This emphasizes the complexity of service robot development for older adults, and highlights the need for a personalized and flexible solution. One size does not fit all, and specific attention should be paid to the development of the robot's social behavior and skills beyond a mere functional support for the person. PMID- 29125808 TI - Monocyte-Derived Procoagulant Microvesicles Induced by High Glucose Can Be Attenuated by the Antioxidant N-Acetyl-L-Cysteine, Partly Through the P38/MAPK Pathway. AB - BACKGROUND: Microvesicles (MVs) are small membrane vesicles that are derived from many different cell types by a process of exocytic budding of the plasma membrane. MVs may be associated with a higher incidence of vascular disease in diabetic patients, but the mechanism of this association is unclear. Diabetic patients also show hypercoagulability and platelet hyperaggregability. In this study, we investigated the generation and activity of high glucose (HG)-induced MVs from monocytes to elucidate the potential mechanism of such MVs in diabetes. METHODS: HG-induced MV generation from THP-1 monocytes before and after N-acetyl L-cysteine (NAC) treatment was examined by enzyme-linked immunosorbent assay. MV activity was measured by spectrophotometry. Apoptosis and generation of reactive oxidative species (ROS) from THP-1 cells were detected by flow cytometry. Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and P38/MAPK pathway components were also analyzed in treated monocytes. RESULTS: MVs were generated from THP-1 cells after 20 hr of exposure to HG (4.6 fold higher than untreated control cells), which was concomitant with a 3.3-fold increase in apoptosis (P < 0.01). The procoagulant activity (PCA) of the generated MVs was increased significantly by 4.1-fold (P < 0.01) relative to untreated cells. ROS levels peaked 2 hr after HG exposure. The frequency of MVs was greatly decreased after NAC treatment (P < 0.01). Both the ERK/MAPK and P38/MAPK pathway were activated after HG stimulation, whereas treatment with a P38 inhibitor decreased MV generation by 66% compared to untreated control. CONCLUSIONS: The generation of monocyte-derived MVs induced by HG was associated with PCA, concomitant with apoptosis and ROS generation. The P38/MAPK pathway was partly involved in this process as evidenced by the reduction in MV generation following treatment with a P38 inhibitor. Our results could provide insights into novel mechanisms of thrombogenicity in an HG state. PMID- 29125810 TI - Aspirin is safe and cost-effective in preventing venous thromboembolism prophylaxis in arthroplasty. PMID- 29125809 TI - Burden of hospitalized childhood community-acquired pneumonia: A retrospective cross-sectional study in Vietnam, Malaysia, Indonesia and the Republic of Korea. AB - BACKGROUND: Few studies describe the community-acquired pneumonia (CAP) burden in children in Asia. We estimated the proportion of all CAP hospitalizations in children from nine hospitals across the Republic of Korea (high-income), Indonesia, Malaysia (middle-income), and Vietnam (low/middle-income). METHODS: Over a one or two-year period, children <5 years hospitalized with CAP were identified using ICD-10 discharge codes. Cases were matched to standardized definitions of suspected (S-CAP), confirmed (C-CAP), or bacterial CAP (B-CAP) used in a pneumococcal conjugate vaccine efficacy study (COMPAS). Median total direct medical costs of CAP-related hospitalizations were calculated. RESULTS: Vietnam (three centers): 7591 CAP episodes were identified with 4.3% (95% confidence interval 4.2;4.4) S-CAP, 3.3% (3.2;3.4) C-CAP and 1.4% (1.3;1.4) B-CAP episodes of all-cause hospitalization in children aged <5 years. The B-CAP case fatality rate (CFR) was 1.3%. Malaysia (two centers): 1027 CAP episodes were identified with 2.7% (2.6;2.9); 2.6% (2.4;2.8); 0.04% (0.04;0.1) due to S-CAP, C CAP, and B-CAP, respectively. One child with B-CAP died. Indonesia (one center): 960 CAP episodes identified with 18.0% (17.0;19.1); 16.8% (15.8;17.9); 0.3% (0.2;0.4) due to S-CAP, C-CAP, and B-CAP, respectively. The B-CAP CFR was 20%. Korea (three centers): 3151 CAP episodes were identified with 21.1% (20.4;21.7); 11.8% (11.2;12.3); 2.4% (2.1;2.7) due to S-CAP, C-CAP, and B-CAP, respectively. There were no deaths. COSTS: CAP-related hospitalization costs were highest for B CAP episodes: 145.00 (Vietnam) to 1013.3 USD (Korea) per episode. CONCLUSION: CAP hospitalization causes an important health and cost burden in all four countries studied (NMRR-12-50-10793). PMID- 29125811 TI - Does leukocyte-poor or leukocyte-rich platelet-rich plasma applied with biopolymers have superiority to conventional platelet-rich plasma applications on chondrocyte proliferation? AB - OBJECTIVES: This study aims to investigate the possible effects of leukocyte concentration in the content of platelet-rich plasma (PRP) and the administration of PRP using a drug delivery system on chondrocyte proliferation in vitro conditions. PATIENTS AND METHODS: Blood from nine male patients (mean age 65 years; range 49 to 81 years) with advanced stage osteoarthritis who had not responded to medical or conservative treatments and underwent total knee arthroplasty was used to prepare two formulations: PRP with low concentration leukocytes (2000-4000 leukocytes/uL) was designated as pure PRP (P-PRP), whereas PRP with high concentration leukocytes (9000-11000 leukocytes/uL) as leukocyte rich PRP (L-PRP). Samples were divided into five groups as control group (group 1), chondrocyte cultures with P-PRP applied directly (group 2), chondrocyte cultures with L-PRP applied directly (group 3), chondrocytes co-cultured with P PRP applied hydrogel (group 4), and chondrocytes co-cultured with L-PRP applied hydrogel (group 5). In all groups; cell morphology, viability and proliferation were compared with the expression of stage-specific embryonic antigen-1 (SSEA-1), a precondrocyte marker. RESULTS: Maximum cell proliferation and SSEA-1 expression occurred in group 4, with a statistically significant correlation between SSEA-1 expression and cell proliferation. CONCLUSION: Our study showed the importance of leukocyte concentration of PRP and efficiency of delivery systems such as hydrogel and that L-PRP administered with a delivery system is more efficient than conventional applications of PRP in the treatment of cartilage damage. PMID- 29125812 TI - Is talon tibial intramedullary nailing clinically superior compared to conventional locked nailing? AB - OBJECTIVES: This study aims to compare the results of talon tibial intramedullary (IM) nailing with the results of conventional distal locked tibial IM nailing. PATIENTS AND METHODS: The study included 60 patients (37 males, 23 females; mean age 42.2 years; range 18 to 92 years) who underwent tibial IM nailing with the diagnosis of unilateral, closed or open (Gustilo-Anderson type 1) tibial diaphyseal fracture (Orthopaedic Trauma Association 42) between January 2013 and January 2016. Patients were separated into two groups as talon tibial IM nailing group (group 1, n=30) and distal locked tibial IM nailing group (group 2, n=30). All patients' operative and total radiation exposure times were recorded. At last control, American Orthopaedic Foot and Ankle Society and Tegner Lysholm scores were evaluated for clinical outcomes. All complications were recorded. RESULTS: Mean operative time was 43.8 minutes in group 1 and 50.2 minutes in group 2. Mean radiation exposure time in group 1 was 5.4 minutes, which was three times shorter than the time of group 2, which was 17.5 minutes. Mean time until union was 16.9 weeks in group 1 and 12.2 weeks in group 2. Statistically significant differences were present between two groups in operative, radiation exposure time and time until union (p=0.019, p=0.001, p=0.001, respectively). When American Orthopaedic Foot and Ankle Society and Tegner Lysholm scores were compared, there were no statistically significant differences (p=0.951 and p=0.896). CONCLUSION: Talon tibial IM nailing is an easier and safer alternative to conventional distal locked tibial IM nailing with shorter operative and radiation exposure times. However, it should be kept in mind that the time until radiographic union may be longer compared to conventional tibial IM nailing. PMID- 29125813 TI - The effect of metabolic syndrome on recurrence in patients who had undergone surgery for carpal tunnel syndrome. AB - OBJECTIVES: This study aims to investigate whether or not metabolic syndrome (MS) affects recurrence in patients who had undergone surgery for carpal tunnel syndrome (CTS). PATIENTS AND METHODS: The study included 86 hands of 78 patients (19 males, 59 females; mean age 52.0+/-8.2 years; range 36 to 78 years) who underwent CTS surgery. Patients were examined clinically and demographically for the presence of MS. Patients were also evaluated using a visual analog scale and the Boston Carpal Tunnel Syndrome Questionnaire. Diagnoses of recurrence were established using electromyography in patients with clinical CTS and Tinel and/or Phalen test positivity. The effect of MS on recurrent CTS was examined statistically by independent t-test. RESULTS: At the end of a mean follow-up period of 36.2+/-19.2 months (range 12 to 60 months), recurrence was identified in 31 (36%) of the 86 hands. Of these 31 hands, MS was present in 23 (74.2%). In the 55 hands (64%) without recurrence, MS was present in 10 (18.2%). According to these differences, the effect of MS on recurrent CTS was statistically significant (p<0.001). CONCLUSION: Our study indicated that MS affected recurrence in patients who had undergone CTS surgery. PMID- 29125814 TI - Carpometacarpal fracture dislocation of the fourth and fifth finger: mid-term results of 15 patients. AB - OBJECTIVES: This study aims to retrospectively evaluate and compare the mid-term clinical follow-up results of patients who were treated with open or closed reduction due to carpometacarpal (CMC) fracture dislocation. PATIENTS AND METHODS: Medical charts of 15 patients (1 male, 14 females; mean age 32.5+/-10.5 years; range 18 to 55 years) who were operated for fourth and fifth finger CMC fracture dislocations were examined. Patients were divided into two groups according to applied treatment as closed reduction and percutaneous pinning (CRPP, n=6) and open reduction and percutaneous pinning (ORPP, n=9). Patients were assessed by a hand therapist blinded to the treatment groups. Patients were compared in respect of visual analog scale (VAS), Quick Disabilities of the Arm, Shoulder and Hand (Q-DASH) scores, and grip strength. Complications were recorded. RESULTS: Mean VAS values of ORPP group and CRPP group were 2.33+/-0.50 and 1.67+/-0.52, respectively. Mean Q-DASH values of ORPP group and CRPP group were 13.63+/-3.21 and 9.05+/-2.36, respectively. Mean grip strength values of ORPP group and CRPP group were 65.78+/-3.70 and 75.17+/-6.11, respectively. Mean VAS and Q-DASH scores of ORPP group were statistically significantly higher compared to CRPP group. Mean grip strength value of CRPP group was statistically significantly higher compared to ORPP group. CONCLUSION: Treatment of fourth and fifth finger CMC fracture dislocations with CRPP results in statistically superior VAS, Q-DASH and grip strength values in the early post-injury period. PMID- 29125815 TI - Is the use of headless compression screws appropriate in arthroscopic ankle arthrodesis? AB - OBJECTIVES: This study aims to evaluate whether the use of headless compression screws is appropriate in arthroscopic ankle arthrodesis. PATIENTS AND METHODS: Twenty-two feet of 22 patients (12 males, 10 females; mean age 43.7 years; range 21 to 63 years) in whom we applied arthroscopic ankle arthrodesis were examined retrospectively. Mean follow-up duration was 59.3 months (range 36 to 92 months). Coronal and sagittal plane alignment and concomitant pathologies were evaluated on patients' radiographs. Assessments related to pain and functionality were performed by the American Orthopaedic Foot and Ankle Society (AOFAS) scoring. RESULTS: Radiographic union was achieved in 21 of the total 22 ankles (95.4%). Mean time to union was 10.3+/-3.5 weeks (range 6.6 to 13.8 weeks). Mean AOFAS pain score increased from 8.1+/-10.2 to 35.0+/-6.3 and functional score increased from 21.3+/-5.5 to 43.4+/-3.8 (p<0.001). On coronal plane, preoperative tibiotalar angle of 6.6+/-5.5 degrees decreased to 2.3+/-2.1 degrees postoperatively. On sagittal plane, while preoperative tibiotalar angle was 17+/ 4.9 degrees , it was 17+/-4.5 degrees postoperatively. One patient had subtalar pain and one patient had nonunion postoperatively. CONCLUSION: The use of headless compression screws is an appropriate choice in the ankle area owing to their advantages of providing successful fixation whilst not causing screw head irritation or pain. PMID- 29125816 TI - Intraobserver and interobserver reliability assessment of tibial plateau fracture classification systems. AB - OBJECTIVES: This study aims to assess the intra- and interobserver reliability of commonly used tibial plateau fracture classification systems. PATIENTS AND METHODS: This retrospective cohort study included computed tomography (CT) and plain radiographic images (lateral and anteroposterior X-rays) of 60 patients (40 males, 20 females; mean age 45.9 years; range 18 to 80 years) who presented to two orthopaedic clinics between January 2011 and January 2015 with unilateral tibial plateau fractures. All plain X-rays (XR) and CT images were evaluated by four observers on two separate occasions, 1.5 months apart. All fractures were classified according to the Arbeitsgemeinschaft fur Osteosynthesefragen Orthopaedic Trauma Association (AO-OTA), Schatzker, Hohl and Moore, Luo and revised Duparc systems. Intraobserver reliability was measured with Cohen's kappa (kappa) coefficient and interobserver reliability with Fleiss' kappa coefficient. RESULTS: When Schatzker classification was performed, interobserver reliability was in moderate level for (kappa=0.51) for XR and in substantial level for CT (kappa=0.61). When AO/OTA classification was used, interobserver reliability was in moderate level for both methods of diagnosis (kappaXR=0.43 and kappaCT=0.54, respectively). In the Hohl and Moore classification, the interobserver reliability was also moderate for both methods of diagnosis (kappaXR=0.45 and kappaCT=0.51, respectively). Revised Duparc classification showed the lowest interobserver reliability ranging from fair to moderate level (kappaXR=0.27-0.55 and kappaCT=0.44-0.61). Interobserver reliability for Luo classification was kappaCT=0.47. Intraobserver reliability for CT in Luo classification was in substantial level for observers 1, 2 and 3 (kappaCT=0.67-0.71) and in perfect level for observer 4 (kappaCT=0.84). Intraobserver reliability was in substantial level in Schatzker classification and in moderate level at the other classifications. CONCLUSION: Among the classification systems compared in this study, Schatzker was the most reliable particularly when CT was used. On the other hand, revised Duparc classification presented the worse reliability results due to its complexity and different morphological subtypes. PMID- 29125817 TI - Do peak torque angles of muscles change following anterior cruciate ligament reconstruction using hamstring or patellar tendon graft? AB - OBJECTIVES: This study aims to compare the effects of anterior cruciate ligament (ACL) reconstruction using autogenous hamstring or patellar tendon graft on the peak torque angle. PATIENTS AND METHODS: The study included 132 patients (103 males, 29 females; mean age 29+/-9 year) who were performed ACL reconstruction with autogenous hamstring or patellar tendon graft. The peak torque angles in the quadriceps and hamstring muscles were recorded using an isokinetic dynamometer. RESULTS: Angle of peak knee flexion torque occurred significantly earlier within the range of motion on the operated side than nonoperated side at 180 degrees /second in the hamstring tendon group. Angle of peak knee extension torque occurred significantly earlier within the range of motion on the operated side than nonoperated side at 180 degrees /second in the patellar tendon group. There were no statistically significant differences in the flexion and extension peak torque angles between the operated and nonoperated knees at 60 degrees /second in both groups. CONCLUSION: The angle of peak torque at relatively high angular velocities is affected after ACL reconstruction in patients with hamstring or patellar tendon grafts. The graft donor site directly influences this parameter. This finding may be important for clinicians in terms of preventing re-injury. PMID- 29125818 TI - [Does preoperative body weight affect early postoperative functional activities in patients with total hip arthroplasty?] AB - OBJECTIVES: This study aims to compare early postoperative functional activities of obese or non-obese patients who underwent total hip arthroplasty (THA). PATIENTS AND METHODS: The study included 45 patients (17 males, 28 females; mean age 64.6+/-8.6 years; range 45 to 78 years) who were operated due to coxarthrosis. Patients were assigned to two groups as obese (body mass index [BMI] >30 kg/m2, n=21) and non-obese (BMI <30 kg/m2, n=24) based on their preoperative BMI. Obese and non-obese patients' functional movements (lie-to-sit, sit-to-stand, ambulation, stair climbing) were assessed with Iowa Level of Assistance Scale while ambulation velocity was assessed with Iowa Ambulation Velocity Scale preoperatively, on postoperative second and sixth days and at discharge. RESULTS: While there was significant difference between non-obese patients' intragroup functional movement levels preoperatively and at discharge (p<0.05), there were no difference in the same intragroup values of obese patients (p>0.05). There was no significant difference between obese and non obese patients in terms of functional movements and ambulation velocities on postoperative second and sixth days and at discharge (p>0.05). CONCLUSION: According to our study findings, obesity has no effect in early postoperative period on functional activities in patients who underwent THA. PMID- 29125819 TI - How successful are Turkish orthopedists in complying with time limit in scientific presentations? AB - OBJECTIVES: This study aims to investigate the durations of scientific presentations and factors affecting the rates of exceeding the time limit in presentations at 26th Turkish National Congress of Orthopedics and Traumatology, which is one of Turkey's largest nationally organized orthopedics and traumatology meetings in terms of the numbers of speakers and participators. MATERIALS AND METHODS: Speech durations of Turkish orthopedists and the rates of these durations against the durations specified in the schedule were calculated. Any relationships between factors related to speakers who made presentations (age and place of work) and factors such as the day, auditorium, and hour of presentation with speech durations were investigated. Durations of sessions of sub-associations and branches were classified and statistically compared. RESULTS: Out of 480 speakers with a mean age of 47 years (range 28 to 71 years), only 171 (35.6%) completed their presentations within the time specified in the schedule. Speech durations statistically significantly increased as the age of the speakers increased. Rates of non-compliance with time limit were higher in presentations performed on the first day. There was no significant difference between meeting auditoriums and meeting hours with regards to compliance with time limit percentages. An analysis based on places of work of speakers revealed no significant difference in terms of time usage percentages. A significant difference was present between the given and used times in the sessions of Society of Bone and Soft Tissue Tumors, Sports Traumatology Branch, and Turkish Society of Orthopaedics and Traumatology. Rates of compliance with time limit were higher in the sessions of Foot and Ankle Surgery Branch, Turkish Society of Shoulder and Elbow Surgery, and Turkish Society of Orthopaedic Research. CONCLUSION: Turkish orthopedists are unsuccessful in complying with time limit in scientific presentations. Awareness should be raised on this subject and time discipline should be established with various measures and training. PMID- 29125820 TI - Rafting technique without bone grafting in reverse Hill-Sachs lesions. AB - In this article, we report a case of bilateral posterior shoulder instability, having reverse Hill-Sachs lesions of 25 to 50% of the articular surface on the right side, and of 50% on the left side. The defects were anatomically reconstructed after tuberculum minus osteotomy by elevation of the articular surface and buttressing with raft screws without graft usage. Early rehabilitation with pendulum shoulder exercises was started at third postoperative day. At postoperative sixth week, patient had full range of motion without instability and pain. At postoperative 18th month, the patient had normal physical examination and the constant shoulder score was 86, which was 92.4% of the age- and gender-matched population. Rafting technique without bone grafting may be a treatment alternative with satisfactory clinical results for medium to large sized reverse Hill-Sachs lesions of posterior shoulder instability. PMID- 29125821 TI - Proximal tibiofibular synostosis. AB - A 22-year-old male patient admitted to our clinic with mild pain in left knee. Pain had started 10 years ago and there was no history of trauma. Pain was increased with kneeling. No abnormality was detected on physical examination. Imaging results revealed proximal tibiofibular synostosis in left knee. PMID- 29125822 TI - Liposclerosing myxofibrous tumor: a rare tumor of proximal femur. AB - Liposclerosing myxofibrous tumor is a very rarely observed benign fibro-osseous lesion, which contains complex histological structures. It was first described in the year 1986. Histopathological examination of the lesion may show myxoid areas, osteoclastic activity, bone trabeculae similar to fibrous dysplasia, fat necrosis, ischemic ossification and rarely cartilage components. This lesion, which is particularly localized to the proximal femur, is thought to be associated with fibrous dysplasia. In this case report, we aim to present a liposclerosing myxofibrous tumor case, which was treated surgically, in light of the literature review. The patient who was treated with curettage, grafting and 95-degree dynamic condylar screw-plate system was asymptomatic at the 16th month control and recurrence was not detected. PMID- 29125823 TI - Failure of an expandable cage-plate cervical vertebral body replacement: case report of a device related complication. AB - Instabilities of the cervical spine after complete or incomplete corpectomy may be the result from resection due to stenosis induced myelopathy, tumors, infections or fractures. In this article, we report a 49-year-old female patient after surgical decompression and stabilization at C5/7 with permanent cervicobrachialgia due to cervical stenosis at C5/7. Corpectomy of C6 and stabilization of C5/7 were performed with a combination of cage and plate. At an outpatient control 16 months after reoperation, the patient complained of neck pain, while the control X-ray showed a fracture of the implant. Due to instability of the device, a revision was indicated, resulting in removal of all components with restabilization. Definitive stabilization was performed with a PINA(r) cage, discectomy and cage implantation at C4/5 and C7/Th1 and a plate from C4 to Th1 with screw fixation in C4/5/Th1. Postoperative course was complication free and the patient was without pain or neurological symptoms at follow-up after 12 months with all implants in radiologically regular position. To the best of our knowledge, this is the first case report to describe such a complication. PMID- 29125824 TI - Intraluminal valves: development, function and disease. AB - The circulatory system consists of the heart, blood vessels and lymphatic vessels, which function in parallel to provide nutrients and remove waste from the body. Vascular function depends on valves, which regulate unidirectional fluid flow against gravitational and pressure gradients. Severe valve disorders can cause mortality and some are associated with severe morbidity. Although cardiac valve defects can be treated by valve replacement surgery, no treatment is currently available for valve disorders of the veins and lymphatics. Thus, a better understanding of valves, their development and the progression of valve disease is warranted. In the past decade, molecules that are important for vascular function in humans have been identified, with mouse studies also providing new insights into valve formation and function. Intriguing similarities have recently emerged between the different types of valves concerning their molecular identity, architecture and development. Shear stress generated by fluid flow has also been shown to regulate endothelial cell identity in valves. Here, we review our current understanding of valve development with an emphasis on its mechanobiology and significance to human health, and highlight unanswered questions and translational opportunities. PMID- 29125825 TI - Understanding the aetiology and resolution of chronic otitis media from animal and human studies. AB - Inflammation of the middle ear, known clinically as chronic otitis media, presents in different forms, such as chronic otitis media with effusion (COME; glue ear) and chronic suppurative otitis media (CSOM). These are highly prevalent diseases, especially in childhood, and lead to significant morbidity worldwide. However, much remains unclear about this disease, including its aetiology, initiation and perpetuation, and the relative roles of mucosal and leukocyte biology, pathogens, and Eustachian tube function. Chronic otitis media is commonly modelled in mice but most existing models only partially mimic human disease and many are syndromic. Nevertheless, these models have provided insights into potential disease mechanisms, and have implicated altered immune signalling, mucociliary function and Eustachian tube function as potential predisposing mechanisms. Clinical studies of chronic otitis media have yet to implicate a particular molecular pathway or mechanism, and current human genetic studies are underpowered. We also do not fully understand how existing interventions, such as tympanic membrane repair, work, nor how chronic otitis media spontaneously resolves. This Clinical Puzzle article describes our current knowledge of chronic otitis media and the existing research models for this condition. It also identifies unanswered questions about its pathogenesis and treatment, with the goal of advancing our understanding of this disease to aid the development of novel therapeutic interventions. PMID- 29125826 TI - Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with few effective therapeutic options. Structural remodelling of the extracellular matrix [i.e. collagen cross-linking mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease pathogenesis and represent a therapeutic target. This study aimed to further our understanding of the mechanisms by which LO inhibitors might improve lung fibrosis. Lung tissues from IPF and non-IPF subjects were examined for collagen structure (second harmonic generation imaging) and LO gene (microarray analysis) and protein (immunohistochemistry and western blotting) levels. Functional effects (collagen structure and tissue stiffness using atomic force microscopy) of LO inhibitors on collagen remodelling were examined in two models, collagen hydrogels and decellularized human lung matrices. LOXL1/LOXL2 gene expression and protein levels were increased in IPF versus non-IPF. Increased collagen fibril thickness in IPF versus non-IPF lung tissues correlated with increased LOXL1/LOXL2, and decreased LOX, protein expression. beta-Aminoproprionitrile (beta-APN; pan-LO inhibitor) but not Compound A (LOXL2-specific inhibitor) interfered with transforming growth factor-beta-induced collagen remodelling in both models. The beta-APN treatment group was tested further, and beta-APN was found to interfere with stiffening in the decellularized matrix model. LOXL1 activity might drive collagen remodelling in IPF lungs. The interrelationship between collagen structural remodelling and LOs is disrupted in IPF lungs. Inhibition of LO activity alleviates fibrosis by limiting fibrillar collagen cross-linking, thereby potentially impeding the formation of a pathological microenvironment in IPF. PMID- 29125829 TI - Bee or Wasp Sting. AB - While jogging in a local park in Hong Kong, a 55-year-old, previously healthy man was stung on the ventral aspect of his right wrist. The tiny stinger was gently removed with nail cutters and examined under a microscope at 80x magni cation; plucking the stinger is ill- advised as this may inject more venom into the wounded site. Two days after stinging, the microscopic appearance of the stinger con rmed the diagnosis to be from a bee instead of a wasp or other insect. A simple method of con rming the nature of insect stings and an overview of Hymenoptera stings and their management are provided herein. PMID- 29125827 TI - Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia. AB - Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1alpha (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1alpha downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA. PMID- 29125828 TI - Comprehensive analysis of gene expression patterns in Friedreich's ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers. AB - Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients homozygous for GAA expansions have low FXN mRNA and protein levels when compared with heterozygous carriers or healthy controls. Frataxin is a mitochondrial protein involved in iron-sulfur cluster synthesis, and many FRDA phenotypes result from deficiencies in cellular metabolism due to lowered expression of FXN Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking. Peripheral tissues, including blood cells, buccal cells and skin fibroblasts, can readily be isolated from FRDA patients and used to define molecular hallmarks of disease pathogenesis. For instance, FXN mRNA and protein levels as well as FXN GAA-repeat tract lengths are routinely determined using all of these cell types. However, because these tissues are not directly involved in disease pathogenesis, their relevance as models of the molecular aspects of the disease is yet to be decided. Herein, we conducted unbiased RNA sequencing to profile the transcriptomes of fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Bioinformatic analyses revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins in FRDA fibroblasts. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in FRDA fibroblasts. Finally, comparison of genes differentially expressed in FRDA fibroblasts to three previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease. When performed on statistically meaningful sample group sizes, unbiased global profiling analyses utilizing peripheral tissues are critical for the discovery and validation of FRDA disease biomarkers. PMID- 29125830 TI - Inflammation, fever, and body temperature under febrile conditions. PMID- 29125831 TI - Nanoparticle radio-enhancement: principles, progress and application to cancer treatment. AB - Enhancement of radiation effects by high-atomic number nanoparticles (NPs) has been increasingly studied for its potential to improve radiotherapeutic efficacy. The underlying principle of NP radio-enhancement is the potential to release copious electrons into a nanoscale volume, thereby amplifying radiation-induced biological damage. While the vast majority of studies to date have focused on gold nanoparticles with photon radiation, an increasing number of experimental, theoretical and simulation studies have explored opportunities offered by other NPs (e.g. gadolinium, platinum, iron oxide, hafnium) and other therapeutic radiation sources such as ion beams. It is thus of interest to the research community to consolidate findings from the different studies and summarise progress to date, as well as to identify strategies that offer promising opportunities for clinical translation. This is the purpose of this Topical Review. PMID- 29125833 TI - Acceptability and use of a dapivirine vaginal ring in a phase III trial: Erratum. PMID- 29125832 TI - Minibeam radiotherapy with small animal irradiators; in vitro and in vivo feasibility studies. AB - Minibeam radiation therapy (MBRT) delivers an ultrahigh dose of x-ray (?100 Gy) in 200-1000 um beams (peaks), separated by wider non-irradiated regions (valleys) usually as a single temporal fraction. Preclinical studies performed at synchrotron facilities revealed that MBRT is able to ablate tumors while maintaining normal tissue integrity. The main purpose of the present study was to develop an efficient and accessible method to perform MBRT using a conventional x ray irradiator. We then tested this new method both in vitro and in vivo. Using commercially available lead ribbon and polyethylene sheets, we constructed a collimator that converted the cone beam of an industrial irradiator to 44 identical beams (collimator size ~ 4 * 10 cm). The dosimetry characteristics of the generated beams were evaluated using two different radiochromic films (beam FWHM = 246 +/- 32 um; center-to-center = 926 +/- 23 um; peak-to valley dose ratio = 24.35 +/- 2.10; collimator relative output factor = 0.84 +/- 0.04). Clonogenic assays demonstrated the ability of our method to induce radiobiological cell death in two radioresistant murine tumor cell lines (TRP = glioblastoma; B16-F10 = melanoma). A radiobiological equivalent dose (RBE) was calculated by evaluating the acute skin response to graded doses of MBRT and conventional radiotherapy (CRT). Normal mouse skin demonstrated resistance to doses up to 150 Gy on peak. MBRT significantly extended the survival of mice with flank melanoma tumors compared to CRT when RBE were applied (overall p < 0.001). Loss of spatial resolution deep in the tissue has been a major concern. The beams generated using our collimator maintained their resolution in vivo (mouse brain tissue) and up to 10 cm deep in the radiochromic film. In conclusion, the initial dosimetric, in vitro and in vivo evaluations confirmed the utility of this affordable and easy-to-replicate minibeam collimator for future preclinical studies. PMID- 29125834 TI - Analysis of a Screening System for Diabetic Cardiovascular Autonomic Neuropathy in China. AB - BACKGROUND The aim of this study was to create a screening system for diabetic cardiovascular autonomic neuropathy (DCAN) in diabetic patients. MATERIAL AND METHODS A Chinese cohort of 455 diabetic participants was recruited between 2011 and 2013. Short-term heart rate variability testing was used to evaluate cardiovascular autonomic function. A simple model was developed using multiple variable regression to include only significant risk factors that were simple and easily assessed. A DCAN score was determined based on the coefficients of the multiple variable model. This score was tested on the entire cohort of 455 diabetic patients and another independent, external cohort of 115 diabetic patients. RESULTS The screening system consisted of age, body mass index, duration of diabetes mellitus, and resting heart rate, and these factors were significantly (P<0.05) associated with DCAN. Receiver operating characteristic (ROC) curve analysis was done. The areas under the ROC curve were 0.798, 0.756, and 0.729 for the total sample, validation cohort, and external set, respectively. A cutoff DCAN score of 12 out of 25 produced optimal results for sensitivity (80.36%), specificity (58.27%), and percentage of patients that needed subsequent testing (43.55%) for the validation set. CONCLUSIONS The study concludes that a simple and practical DCAN screening can be applied for early intervention to delay or prevent the disease in the Chinese population. PMID- 29125835 TI - A large ongoing outbreak of hepatitis A predominantly affecting young males in Lazio, Italy; August 2016 - March 2017. AB - The hepatitis A virus (HAV) is mainly transmitted through the faecal-oral route. In industrialized countries HAV infection generally occurs as either sporadic cases in travelers from endemic areas, local outbreak within closed/semi-closed population and as foodborne community outbreak. Recently, an increasing number of HAV infection clusters have been reported among young men-who-have-sex-with-men (MSM). The Lazio Regional Service for the epidemiology and control for infectious diseases (SeRESMI) has noticed an increase of acute hepatitis A (AHA) since September 2016. Temporal analysis carried out with a discrete Poisson model using surveillance data between January 2016 and March 2017 evidenced an ongoing outbreak of AHA that started at the end of August. Molecular investigation carried out on 130 out of 513 cases AHA reported until March 2017 suggests that this outbreak is mainly supported by an HAV variant which is currently spreading within MSM communities across Europe (VRD_521_2016). The report confirms that AHA is an emerging issue among MSM. In addition through the integration of standard (case based) surveillance with molecular investigation we could discriminate, temporally concomitant but epidemiologically unrelated, clusters due to different HAV variants. As suggested by the WHO, in countries with low HAV circulation, vaccination programmes should be tailored on the local epidemiological patterns to prevent outbreaks among high risk groups and eventual spillover of the infection in the general population. PMID- 29125836 TI - A simple in vitro tumor chemosensitivity assay based on cell penetrating peptide tagged luciferase. AB - The analysis of intracellular ATP can reveal the response of cells to different treatments and is important for individualized medicine. In the present study, we developed a cell penetrating peptides (CPPs) tagged luciferase (TAT-LUC) for tumor chemosensitivity assay. The activity of recombinant TAT-LUC was evaluated using ATP standard solution and tumor cells. This recombinant TAT-LUC was then used for the analysis of sensitivity index (SI) of four strains of tumor cells. The results showed that TAT-LUC could detect less than 10 nM extracellular ATP with a strong correlation between the luminescence intensity and the ATP content (R2 = 0.994). Without cell lysis, the detection limit for intracellular ATP analysis was 40 tumor cells. Furthermore, chemosensitivity of four strains of tumor cells (Skov-3/DDP, A549/DDP, MDA-MB-231, Huh-7) was determined by this assay successfully. The cell penetration ability of TAT-LUC enables the assay not only to reflect drug resistance of tumor cells real-timely but also to minimize the test time, which can be a valuable aid for personalized cancer chemotherapy. PMID- 29125837 TI - Differences exist across insurance schemes in China post-consolidation. AB - BACKGROUND: In China, the basic insurance system consists of three schemes: the UEBMI (Urban Employee Basic Medical Insurance), URBMI (Urban Resident Basic Medical Insurance), and NCMS (New Cooperative Medical Scheme), across which significant differences have been observed. Since 2009, the central government has been experimenting with consolidating these schemes in selected areas. This study examines whether differences still exist across schemes after the consolidation. METHODS: A survey was conducted in the city of Suzhou, collecting data on subjects 45 years old and above with at least one inpatient or outpatient treatment during a period of twelve months. Analysis on 583 subjects was performed comparing subjects' characteristics across insurance schemes. A resampling-based method was applied to compute the predicted gross medical cost, OOP (out-of-pocket) cost, and insurance reimbursement rate. RESULTS: Subjects under different insurance schemes differ in multiple aspects. For inpatient treatments, subjects under the URBMI have the highest observed and predicted gross and OOP costs, while those under the UEBMI have the lowest. For outpatient treatments, subjects under the UEBMI and URBMI have comparable costs, while those under the NCMS have much lower costs. Subjects under the NCMS also have a much lower reimbursement rate. CONCLUSIONS: Differences still exist across schemes in medical costs and insurance reimbursement rate post-consolidation. Further investigations are needed to identify the causes, and interventions are needed to eliminate such differences. PMID- 29125838 TI - Nitrergic neurons of the dorsal raphe nucleus encode information about stress duration. AB - Nitrergic neurons of the dorsal raphe nucleus (DRN) may play a role in physiological stress responses. The caudal lateral wings (CLW) are unique compared to other rostral-caudal DRN sub-regions because they contain distinct nitric oxide (NO) synthase (NOS) populations that are independent of tryptophan hydroxylase (TPH). NOS neurons in the CLW are also highly activated during acute restraint stress. However, the effects of acute stress duration on NOS activation in the CLW are unclear. Here NADPH-d, an index of NOS activity, is used to show that sub-regions of the DRN have differential NOS activation in response to 6 hours of restraint stress in rats. We report increased NOS activity through 6 hours of restraint in the caudal lateral wings and ventromedial sub-regions. These data suggest that, NOS neurons may play a dynamic role in the response to stress duration. PMID- 29125839 TI - Csseverin inhibits apoptosis through mitochondria-mediated pathways triggered by Ca2 + dyshomeostasis in hepatocarcinoma PLC cells. AB - BACKGROUND: Numerous experimental and epidemiological studies have demonstrated a link between Clonorchis sinensis (C. sinensis) infestation and cholangiocarcinoma (CCA) as well as hepatocellular carcinoma (HCC). The underlying molecular mechanism involved in the malignancy of CCA and HCC has not yet been addressed. Csseverin, a component of the excretory/secretory products of C. sinensis (CsESPs), was confirmed to cause obvious apoptotic inhibition in the human HCC cell line PLC. However, the antiapoptotic mechanism is unclear. In the present study, we investigated the cellular features of the antiapoptotic mechanism upon transfection of the Csseverin gene. METHODS: In the present study, we evaluated the effects of Csseverin gene overexpression on the apoptosis of PLC cells using an Annexin PE/7-AAD assay. Western blotting was applied to quantify the activation of caspase-3 and caspase-9, the mitochondrial translocation of Bax and the release of Cyt c upon Csseverin overexpression in PLC cells. Laser scanning confocal microscopy was used to analyze the changes of intracellular calcium. Fluorescence assay and immunofluorescence assays were performed to observe the changes of the mitochondrial permeability transition pore (MPTP). RESULTS: The overexpression of Csseverin in PLC cells showed apoptosis resistance after the induction of apoptosis. Additionally, the activation of caspase-3 and caspase-9 was specifically weakened in Csseverin overexpression PLC cells. The overexpression of Csseverin reduced the increase in intracellular free Ca2+, thereby inhibiting MPTP opening in PLC cells. Moreover, Bax mitochondrial translocation and the subsequent release of Cyt c were downregulated in apoptotic Csseverin overexpression PLC cells. CONCLUSIONS: The present findings suggest that Csseverin, a component of CsESPs, confers protection from human HCC cell apoptosis via the inactivation of membranous Ca2+ channels. Csseverin might be involved in the process of HCC through C. sinensis infestation in affected patients. PMID- 29125840 TI - Are there physicochemical differences between allosteric and competitive ligands? AB - Previous studies have compared the physicochemical properties of allosteric compounds to non-allosteric compounds. Those studies have found that allosteric compounds tend to be smaller, more rigid, more hydrophobic, and more drug-like than non-allosteric compounds. However, previous studies have not properly corrected for the fact that some protein targets have much more data than other systems. This generates concern regarding the possible skew that can be introduced by the inherent bias in the available data. Hence, this study aims to determine how robust the previous findings are to the addition of newer data. This study utilizes the Allosteric Database (ASD v3.0) and ChEMBL v20 to systematically obtain large datasets of both allosteric and competitive ligands. This dataset contains 70,219 and 9,511 unique ligands for the allosteric and competitive sets, respectively. Physically relevant compound descriptors were computed to examine the differences in their chemical properties. Particular attention was given to removing redundancy in the data and normalizing across ligand diversity and varied protein targets. The resulting distributions only show that allosteric ligands tend to be more aromatic and rigid and do not confirm the increase in hydrophobicity or difference in drug-likeness. These results are robust across different normalization schemes. PMID- 29125841 TI - Correction: Error-Robust Modes of the Retinal Population Code. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005148.]. PMID- 29125842 TI - Evaluating the glucose raising effect of established loci via a genetic risk score. AB - Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (beta +/- SE: 0.024 +/- 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (beta +/- SE: 0.011 +/- 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: beta +/- SE: 0.019 +/- 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels. PMID- 29125843 TI - Increased sediment loads cause non-linear decreases in seagrass suitable habitat extent. AB - Land-based activities, including deforestation, agriculture, and urbanisation, cause increased erosion, reduced inland and coastal water quality, and subsequent loss or degradation of downstream coastal marine ecosystems. Quantitative approaches to link sediment loads from catchments to metrics of downstream marine ecosystem state are required to calculate the cost effectiveness of taking conservation actions on land to benefits accrued in the ocean. Here we quantify the relationship between sediment loads derived from landscapes to habitat suitability of seagrass meadows in Moreton Bay, Queensland, Australia. We use the following approach: (1) a catchment hydrological model generates sediment loads; (2) a statistical model links sediment loads to water clarity at monthly time steps; (3) a species distribution model (SDM) factors in water clarity, bathymetry, wave height, and substrate suitability to predict seagrass habitat suitability at monthly time-steps; and (4) a statistical model quantifies the effect of sediment loads on area of seagrass suitable habitat in a given year. The relationship between sediment loads and seagrass suitable habitat is non linear: large increases in sediment have a disproportionately large negative impact on availability of seagrass suitable habitat. Varying the temporal scale of analysis (monthly vs. yearly), or varying the threshold value used to delineate predicted seagrass presence vs. absence, both affect the magnitude, but not the overall shape, of the relationship between sediment loads and seagrass suitable habitat area. Quantifying the link between sediment produced from catchments and extent of downstream marine ecosystems allows assessment of the relative costs and benefits of taking conservation actions on land or in the ocean, respectively, to marine ecosystems. PMID- 29125844 TI - Significant associations between driver gene mutations and DNA methylation alterations across many cancer types. AB - Recent evidence shows that mutations in several driver genes can cause aberrant methylation patterns, a hallmark of cancer. In light of these findings, we hypothesized that the landscapes of tumor genomes and epigenomes are tightly interconnected. We measured this relationship using principal component analyses and methylation-mutation associations applied at the nucleotide level and with respect to genome-wide trends. We found that a few mutated driver genes were associated with genome-wide patterns of aberrant hypomethylation or CpG island hypermethylation in specific cancer types. In addition, we identified associations between 737 mutated driver genes and site-specific methylation changes. Moreover, using these mutation-methylation associations, we were able to distinguish between two uterine and two thyroid cancer subtypes. The driver gene mutation-associated methylation differences between the thyroid cancer subtypes were linked to differential gene expression in JAK-STAT signaling, NADPH oxidation, and other cancer-related pathways. These results establish that driver gene mutations are associated with methylation alterations capable of shaping regulatory network functions. In addition, the methodology presented here can be used to subdivide tumors into more homogeneous subsets corresponding to underlying molecular characteristics, which could improve treatment efficacy. PMID- 29125845 TI - Biosurfactants produced by Scheffersomyces stipitis cultured in sugarcane bagasse hydrolysate as new green larvicides for the control of Aedes aegypti, a vector of neglected tropical diseases. AB - Biosurfactants are microbial metabolites with possible applications in various industrial sectors that are considered ecofriendly molecules. In recent years, some studies identified these compounds as alternatives for the elimination of vectors of tropical diseases, such as Aedes aegypti. The major bottlenecks of biosurfactant industrial production have been the use of conventional raw materials that increase production costs as well as opportunistic or pathogenic bacteria, which restrict the application of these biomolecules. The present study shows the potential of hemicellulosic sugarcane bagasse hydrolysate as a raw material for the production of a crystalline glycolipidic BS by Scheffersomyces stipitis NRRL Y-7124, which resulted in an emulsifying index (EI24) of 70 +/- 3.4% and a superficial tension of 52 +/- 2.9 mN.m-1. Additionally, a possible new application of these compounds as biolarvicides, mainly against A. aegypti, was evaluated. At a concentration of 800 mg.L-1, the produced biosurfactant caused destruction to the larval exoskeletons 12 h after application and presented an letal concentration (LC50) of 660 mg.L-1. Thus, a new alternative for biosurfactant production using vegetal biomass as raw material within the concept of biorefineries was proposed, and the potential of the crystalline glycolipidic biosurfactant in larvicidal formulations against neglected tropical disease vectors was demonstrated. PMID- 29125846 TI - Characterization of the Lycium barbarum fruit transcriptome and development of EST-SSR markers. AB - Lycium barbarum, commonly known as goji, is important in Chinese herbal medicine and its fruit is a very important agricultural and biological product. However, the molecular mechanism of formation of its fruit and associated medicinal and nutritional components is unexplored. Moreover, this species lacks SSR markers due to lack of genomic and transcriptomic information. In this study, a total of 139,333 unigenes with average length of 1049 bp and N50 of 1579 bp are obtained by trinity assembly from Illumina sequencing reads. A total of 92,498 (66.38%) unigenes showed similarities in at least one database including Nr (46.15%), Nt (56.56%), KO (15.56%), Swiss-prot (33.34%), Pfam (33.43%), GO (33.62%) and KOG/COG (17.55%). Genes in flavonoid and taurine biosynthesis pathways were found and validated by RT-qPCR. A total of 50,093 EST-SSRs were identified from 38,922 unigenes, and 22,537 EST-SSR primer pairs were designed. Four hundred pairs of SSR markers were randomly selected to validate assembly quality, of which 352 (88%) were successful in PCR amplification of genomic DNA from 11 Lycium accessions and 210 produced polymorphisms. The polymorphic loci showed that the genetic similarity of the 11 Lycium accessions ranged from 0.50 to 0.99 and the accessions could be divided into 4 groups. These results will facilitate investigations of the molecular mechanism of formation of L. barbarum fruit and associated medicinal and nutritional components, and will be of value to novel gene discovery and functional genomic studies. The EST-SSR markers will be useful for genetic diversity evaluation, genetic mapping and marker-assisted breeding. PMID- 29125847 TI - A numerical investigation of the effect of surface wettability on the boiling curve. AB - Surface wettability is recognized as playing an important role in pool boiling and the corresponding heat transfer curve. In this work, a systematic study of pool boiling heat transfer on smooth surfaces of varying wettability (contact angle range of 5 degrees - 180 degrees ) has been conducted and reported. Based on numerical simulations, boiling curves are calculated and boiling dynamics in each regime are studied using a volume-of-fluid method with contact angle model. The calculated trends in critical heat flux and Leidenfrost point as functions of surface wettability are obtained and compared with prior experimental and theoretical predictions, giving good agreement. For the first time, the effect of contact angle on the complete boiling curve is shown. It is demonstrated that the simulation methodology can be used for studying pool boiling and related dynamics and providing more physical insights. PMID- 29125848 TI - Early decreased TLR2 expression on monocytes is associated with their reduced phagocytic activity and impaired maturation in a porcine polytrauma model. AB - In their post-traumatic course, trauma patients suffering from multiple injuries have a high risk for immune dysregulation, which may contribute to post-injury complications and late mortality. Monocytes as specific effector cells of the innate immunity play a crucial role in inflammation. Using their Pattern Recognition Receptors (PRRs), notably Toll-Like Receptors (TLR), the monocytes recognize pathogens and/or pathogen-associated molecular patterns (PAMPs) and organize their clearance. TLR2 is the major receptor for particles of gram positive bacteria, and initiates their phagocytosis. Here, we investigated the phagocytizing capability of monocytes in a long-term porcine severe trauma model (polytrauma, PT) with regard to their TLR2 expression. Polytrauma consisted of femur fracture, unilateral lung contusion, liver laceration, hemorrhagic shock with subsequent resuscitation and surgical fracture fixation. After induction of PT, peripheral blood was withdrawn before (-1 h) and directly after trauma (0 h), as well as 3.5 h, 5.5 h, 24 h and 72 h later. CD14+ monocytes were identified and the expression levels of H(S)LA-DR and TLR2 were investigated by flow cytometry. Additionally, the phagocytizing activity of monocytes by applying S. aureus particles labelled with pHrodo fluorescent reagent was also assessed by flow cytometry. Furthermore, blood samples from 10 healthy pigs were exposed to a TLR2 neutralizing antibody and subsequently to S. aureus particles. Using flow cytometry, phagocytizing activity was determined. P below 0.05 was considered significant. The number of CD14+ monocytes of all circulating leukocytes remained constant during the observational time period, while the percentage of CD14+H(S)LA-DR+ monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of TLR2+ expressing cells out of all monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of phagocytizing monocytes decreased immediately and remained lower during the first 3.5 h after trauma, but increased after 24 h. Antagonizing TLR2 significantly decreased the phagocytizing activity of monocytes. Both, decreased percentage of activated as well as TLR2 expressing monocytes persisted as long as the reduced phagocytosis was observed. Moreover, neutralizing TLR2 led to a reduced capability of phagocytosis as well. Therefore, we assume that reduced TLR2 expression may be responsible for the decreased phagocytizing capacity of circulating monocytes in the early post-traumatic phase. PMID- 29125849 TI - Effect of water, sanitation and hygiene interventions on active trachoma in North and South Wollo zones of Amhara Region, Ethiopia: A Quasi-experimental study. AB - BACKGROUND: Trachoma is chronic kerato conjunctivitis, which is caused by repeated infection with Chlamydia trachomatis bacterium. It is hyper endemic in many rural areas of Ethiopia. The objective of this study was to measure the effect of water, sanitation and hygiene interventions on active trachoma in selected woredas of North and South Wollo zones of Amhara Region, Ethiopia. METHODOLOGY: A community based quasi-experimental study was conducted from October 2014 to December 2015 among children aged 1-8 years at baseline and among one year older same children after intervention. A four-stage random cluster sampling technique was employed to select study participants. From each selected household, one child was clinically assessed for active trachoma. Structured questionnaire was used to collect socio demographic and behavioral data. MacNemar test was applied to compare the prevalence of active trachoma between baseline and after the intervention period at both intervention and non-intervention study areas. RESULTS: The prevalence of active trachoma was reduced from baseline prevalence of 26% to 18% after one-year intervention period in the intervention woredas (P<=0.001). MacNemar test result showed significant reduction of active trachoma prevalence after the intervention period in the intervention woredas compared to the non-intervention woredas (P<=0.001). Water, sanitation and hygiene related activities were significantly improved after the intervention period in the intervention woredas (P<0.05). CONCLUSIONS: There was a significant reduction of active trachoma prevalence between the baseline and after the intervention period in the intervention woredas, but not in the non-intervention ones. Improved water, sanitation and hygiene interventions contributed to the reduction of active trachoma. However, the magnitude of active trachoma prevalence observed after the intervention is still very high in the studied areas of North and South Wollo Zones communities. To achieve the global trachoma elimination target by the year 2020 as set by the WHO, continued WaSH interventions and periodic monitoring, evaluation and reporting of the impact of WaSH on active trachoma is warranted. PMID- 29125850 TI - 1.5 versus 3 versus 7 Tesla in abdominal MRI: A comparative study. AB - OBJECTIVES: The aim of this study was to investigate and compare the feasibility as well as potential impact of altered magnetic field properties on image quality and potential artifacts of 1.5 Tesla, 3 Tesla and 7 Tesla non-enhanced abdominal MRI. MATERIALS AND METHODS: Magnetic Resonance (MR) imaging of the upper abdomen was performed in 10 healthy volunteers on a 1.5 Tesla, a 3 Tesla and a 7 Tesla MR system. The study protocol comprised a (1) T1-weighted fat-saturated spoiled gradient-echo sequence (2D FLASH), (2) T1-weighted fat-saturated volumetric interpolated breath hold examination sequence (3D VIBE), (3) T1-weighted 2D in and opposed phase sequence, (4) True fast imaging with steady-state precession sequence (TrueFISP) and (5) T2-weighted turbo spin-echo (TSE) sequence. For comparison reasons field of view and acquisition times were kept comparable for each correlating sequence at all three field strengths, while trying to achieve the highest possible spatial resolution. Qualitative and quantitative analyses were tested for significant differences. RESULTS: While 1.5 and 3 Tesla MRI revealed comparable results in all assessed features and sequences, 7 Tesla MRI yielded considerable differences in T1 and T2 weighted imaging. Benefits of 7 Tesla MRI encompassed an increased higher spatial resolution and a non-enhanced hyperintense vessel signal at 7 Tesla, potentially offering a more accurate diagnosis of abdominal parenchymatous and vasculature disease. 7 Tesla MRI was also shown to be more impaired by artifacts, including residual B1 inhomogeneities, susceptibility and chemical shift artifacts, resulting in reduced overall image quality and overall image impairment ratings. While 1.5 and 3 Tesla T2w imaging showed equivalently high image quality, 7 Tesla revealed strong impairments in its diagnostic value. CONCLUSIONS: Our results demonstrate the feasibility and overall comparable imaging ability of T1-weighted 7 Tesla abdominal MRI towards 3 Tesla and 1.5 Tesla MRI, yielding a promising diagnostic potential for non-enhanced Magnetic Resonance Angiography (MRA). 1.5 Tesla and 3 Tesla offer comparably high-quality T2w imaging, showing superior diagnostic quality over 7 Tesla MRI. PMID- 29125851 TI - New evidence showing that the destruction of gut bacteria by antibiotic treatment could increase the honey bee's vulnerability to Nosema infection. AB - It has become increasingly clear that gut bacteria play vital roles in the development, nutrition, immunity, and overall fitness of their eukaryotic hosts. We conducted the present study to investigate the effects of gut microbiota disruption on the honey bee's immune responses to infection by the microsporidian parasite Nosema ceranae. Newly emerged adult workers were collected and divided into four groups: Group I-no treatment; Group II-inoculated with N. ceranae, Group III-antibiotic treatment, and Group IV-antibiotic treatment after inoculation with N. ceranae. Our study showed that Nosema infection did not cause obvious disruption of the gut bacterial community as there was no significant difference in the density and composition of gut bacteria between Group I and Group II. However, the elimination of gut bacteria by antibiotic (Groups III and IV) negatively impacted the functioning of the honey bees' immune system as evidenced by the expression of genes encoding antimicrobial peptides abaecin, defensin1, and hymenoptaecin that showed the following ranking: Group I > Group II > Group III > Group IV. In addition, significantly higher Nosema levels were observed in Group IV than in Group II, suggesting that eliminating gut bacteria weakened immune function and made honey bees more susceptible to Nosema infection. Based on Group IV having displayed the highest mortality rate among the four experimental groups indicates that antibiotic treatment in combination with stress, associated with Nosema infection, significantly and negatively impacts honey bee survival. The present study adds new evidence that antibiotic treatment not only leads to the complex problem of antibiotic resistance but can impact honey bee disease resistance. Further studies aimed at specific components of the gut bacterial community will provide new insights into the roles of specific bacteria and possibly new approaches to improving bee health. PMID- 29125852 TI - Processes affecting altitudinal distribution of invasive Ageratina adenophora in western Himalaya: The role of local adaptation and the importance of different life-cycle stages. AB - The spread of invasive plants along elevational gradients is considered a threat to fragile mountain ecosystems, but it can also provide the opportunity to better understand some of the basic processes driving the success of invasive species. Ageratina adenophora (Asteraceae) is an invasive plant of global importance and has a broad distribution along elevational gradients in the Western Himalayas. Our study aimed at understanding the role of evolutionary processes (e.g. local adaptation and clinal differentiation) and different life history stages in shaping the distribution pattern of the invasive plant along an elevational gradient in the Western Himalaya. We carried out extensive distributional surveys, established a reciprocal transplant experiment with common gardens at three elevational levels, and measured a suite of traits related to germination, growth, reproduction and phenology. Our results showed a lack of local adaptation, and we did not find any evidence for clinal differentiation in any measured trait except a rather weak signal for plant height. We found that seed germination was the crucial life-cycle transition in determining the lower range limit while winter mortality of plants shaped the upper range limit in our study area, thus explaining the hump shaped distribution pattern. Differences in trait values between gardens for most traits indicated a high degree of phenotypic plasticity. Possible causes such as apomixis, seed dispersal among sites, and pre adaptation might have confounded evolutionary processes to act upon. Our results suggest that the success and spread of Ageratina adenophora are dependent on different life history stages at different elevations that are controlled by abiotic conditions. PMID- 29125853 TI - Whole-genome DNA methylation characteristics in pediatric precursor B cell acute lymphoblastic leukemia (BCP ALL). AB - In addition to genetic alterations, epigenetic abnormalities have been shown to underlie the pathogenesis of acute lymphoblastic leukemia (ALL)-the most common pediatric cancer. The purpose of this study was to characterize the whole genome DNA methylation profile in children with precursor B-cell ALL (BCP ALL) and to compare this profile with methylation observed in normal bone marrow samples. Additional efforts were made to correlate the observed methylation patterns with selected clinical features. We assessed DNA methylation from bone marrow samples obtained from 38 children with BCP ALL at the time of diagnosis along with 4 samples of normal bone marrow cells as controls using Infinium MethylationEPIC BeadChip Array. Patients were diagnosed and stratified into prognosis groups according to the BFM ALL IC 2009 protocol. The analysis of differentially methylated sites across the genome as well as promoter methylation profiles allowed clear separation of the leukemic and control samples into two clusters. 86.6% of the promoter-associated differentially methylated sites were hypermethylated in BCP ALL. Seven sites were found to correlate with the BFM ALL IC 2009 high risk group. Amongst these, one was located within the gene body of the MBP gene and another was within the promoter region- PSMF1 gene. Differentially methylated sites that were significantly related with subsets of patients with ETV6-RUNX1 fusion and hyperdiploidy. The analyzed translocations and change of genes' sequence context does not affect methylation and methylation seems not to be a mechanism for the regulation of expression of the resulting fusion genes. PMID- 29125854 TI - RAAAF's office landscape The End of Sitting: Energy expenditure and temporary comfort when working in non-sitting postures. AB - An earlier study suggested that the activity-inviting office landscape called "The End of Sitting", designed by Rietveld Architecture Art Affordances (RAAAF), should be considered as an alternative working environment to prevent sedentary behavior. The End of Sitting lacks chairs and tables but consists instead of a myriad of sloped surfaces at different heights that afford workers to stand, lean or recline at different locations. In this study, we assessed the impact of four of its workspaces on physical intensity, temporary comfort and productivity of office work and compared the outcomes with sitting and standing behind a desk. Twenty-four participants worked for 10 minutes in each of the six test conditions. Energy expenditure, measured by indirect calorimetry, and heart rate were recorded. Questionnaires were used to assess the perceived comfort. The number of words found in the word search test was counted as a measure of productivity. The majority of The End of Sitting workspaces led to a significant increase in energy expenditure compared with sitting behind a desk (ps < .05). Average MET values ranged from 1.40 to 1.58 which is a modest rise in energy expenditure compared to sitting (1.32 METs) and not significantly different from standing (1.47 METs). The scores on the general comfort scale indicated that some workspaces were less comfortable than sitting (ps < .05), but the vast majority of participants reported that at least one of The End of Sitting workspaces was equally or more comfortable than sitting. No differences in productivity between the test conditions were found. Further long-term studies are required to assess the behavioral adaptations, productivity and the level of comfort when using The End of Sitting as a permanent office. PMID- 29125856 TI - Forecast horizon of multi-item dynamic lot size model with perishable inventory. AB - This paper studies a multi-item dynamic lot size problem for perishable products where stock deterioration rates and inventory costs are age-dependent. We explore structural properties in an optimal solution under two cost structures and develop a dynamic programming algorithm to solve the problem in polynomial time when the number of products is fixed. We establish forecast horizon results that can help the operation manager to decide the precise forecast horizon in a rolling decision-making process. Finally, based on a detailed test bed of instance, we obtain useful managerial insights on the impact of deterioration rate and lifetime of products on the length of forecast horizon. PMID- 29125855 TI - Functional classification of grasp strategies used by hemiplegic patients. AB - This study aimed to identify and qualify grasp-types used by patients with stroke and determine the clinical parameters that could explain the use of each grasp. Thirty-eight patients with chronic stroke-related hemiparesis and a range of motor and functional capacities (17 females and 21 males, aged 25-78), and 10 healthy subjects were included. Four objects were used (tissue packet, teaspoon, bottle and tennis ball). Participants were instructed to "grasp the object as if you are going to use it". Three trials were video-recorded for each object. A total of 456 grasps were analysed and rated using a custom-designed Functional Grasp Scale. Eight grasp-types were identified from the analysis: healthy subjects used Multi-pulpar, Pluri-digital, Lateral-pinch and Palmar grasps (Standard Grasps). Patients used the same grasps with in addition Digito-palmar, Raking, Ulnar and Interdigital grasps (Alternative Grasps). Only patients with a moderate or relatively good functional ability used Standard grasps. The correlation and regression analyses showed this was conditioned by sufficient finger and elbow extensor strength (Pluri-digital grasp); thumb extensor and wrist flexor strength (Lateral pinch) or in forearm supinator strength (Palmar grasp). By contrast, the patients who had severe impairment used Alternative grasps that did not involve the thumb. These strategies likely compensate specific impairments. Regression and correlation analyses suggested that weakness had a greater influence over grasp strategy than spasticity. This would imply that treatment should focus on improving hand strength and control although reducing spasticity may be useful in some cases. PMID- 29125858 TI - Temperature-dependent development and reproduction of rice leaffolder, Marasmia exigua (Lepidoptera: Pyralidae). AB - Marasmia exigua (Butler) (Lepidoptera: Pyralidae) is one of the major rice leaffolders negatively affecting the rice production in the world. The growth and development of M. exigua was studied at seven constant temperatures (10, 15, 20, 25, 27, 30 and 35 degrees C). The results showed that M. exigua eggs failed to hatch at 10 degrees C and the larvae could not complete development at 15 and 35 degrees C. The developmental times of each stage, survival rates of pre-adult, adult longevity, fecundities and oviposition days of M. exigua at 20, 25, 27 and 30 degrees C were investigated using age-stage, two-sex life table. The total pre adult development time decreased with the increase in temperature decreasing from 61.58 days at 20 degrees C to 28.94 days at 30 degrees C. The highest survival rate was observed at 25 degrees C (73%). Male adult longevities were generally longer than that of females, except at 30 degrees C. The highest mean fecundity, age-stage specific fecundity and age-specific fecundity peak values were all observed at 27 degrees C. The maximum intrinsic rate of increase r and finite rate of increase lambda were observed at 27 degrees C, while the maximum net reproduction rate R0 was observed at 25 degrees C. The longest mean generation time occurred at 20 degrees C and the shortest at 27 degrees C. These results provide better understanding on the development, reproduction and dynamic of M. exigua populations, their distribution, and might be utilized to forecast and manage M. exigua outbreaks in China. PMID- 29125857 TI - Phantom-based evaluation of dose exposure of ultrafast combined kV-MV-CBCT towards clinical implementation for IGRT of lung cancer. AB - PURPOSE: Combined ultrafast 90 degrees +90 degrees kV-MV-CBCT within single breath-hold of 15s has high clinical potential for accelerating imaging for lung cancer patients treated with deep inspiration breath-hold (DIBH). For clinical feasibility of kV-MV-CBCT, dose exposure has to be small compared to prescribed dose. In this study, kV-MV dose output is evaluated and compared to clinically established kV-CBCT. METHODS: Accurate dose calibration was performed for kV and MV energy; beam quality was determined. For direct comparison of MV and kV dose output, relative biological effectiveness (RBE) was considered. CT dose index (CTDI) was determined and measurements in various representative locations of an inhomogeneous thorax phantom were performed to simulate the patient situation. RESULTS: A measured dose of 20.5mGE (Gray-equivalent) in the target region was comparable to kV-CBCT (31.2mGy for widely-used, and 9.1mGy for latest available preset), whereas kV-MV spared healthy tissue and reduced dose to 6.6mGE (30%) due to asymmetric dose distribution. The measured weighted CTDI of 12mGE for kV-MV lay in between both clinical presets. CONCLUSIONS: Dosimetric properties were in agreement with established imaging techniques, whereas exposure to healthy tissue was reduced. By reducing the imaging time to a single breath-hold of 15s, ultrafast combined kV-MV CBCT shortens patient time at the treatment couch and thus improves patient comfort. It is therefore usable for imaging of hypofractionated lung DIBH patients. PMID- 29125859 TI - Insulin resistance enhances the mitogen-activated protein kinase signaling pathway in ovarian granulosa cells. AB - The ovary is the main regulator of female fertility. Granulosa cell dysfunction may be involved in various reproductive endocrine disorders. Here we investigated the effect of insulin resistance on the metabolism and function of ovarian granulosa cells, and dissected the functional status of the mitogen-activated protein kinase signaling pathway in these cells. Our data showed that dexamethasone-induced insulin resistance in mouse granulosa cells reduced insulin sensitivity, accompanied with an increase in phosphorylation of p44/42 mitogen activated protein kinase. Furthermore, up-regulation of cytochrome P450 subfamily 17 and testosterone and down-regulation of progesterone were observed in insulin resistant mouse granulosa cells. Inhibition of p44/42 mitogen-activated protein kinase after induction of insulin resistance in mouse granulosa cells decreased phosphorylation of p44/42 mitogen-activated protein kinase, downregulated cytochrome P450 subfamily 17 and lowered progesterone production. This insulin resistance cell model can successfully demonstrate certain mechanisms such as hyperandrogenism, which may inspire a new strategy for treating reproductive endocrine disorders by regulating cell signaling pathways. PMID- 29125860 TI - Autophagy pathway induced by a plant virus facilitates viral spread and transmission by its insect vector. AB - Many viral pathogens are persistently transmitted by insect vectors and cause agricultural or health problems. Generally, an insect vector can use autophagy as an intrinsic antiviral defense mechanism against viral infection. Whether viruses can evolve to exploit autophagy to promote their transmission by insect vectors is still unknown. Here, we show that the autophagic process is triggered by the persistent replication of a plant reovirus, rice gall dwarf virus (RGDV) in cultured leafhopper vector cells and in intact insects, as demonstrated by the appearance of obvious virus-containing double-membrane autophagosomes, conversion of ATG8-I to ATG8-II and increased level of autophagic flux. Such virus containing autophagosomes seem able to mediate nonlytic viral release from cultured cells or facilitate viral spread in the leafhopper intestine. Applying the autophagy inhibitor 3-methyladenine or silencing the expression of Atg5 significantly decrease viral spread in vitro and in vivo, whereas applying the autophagy inducer rapamycin or silencing the expression of Torc1 facilitate such viral spread. Furthermore, we find that activation of autophagy facilitates efficient viral transmission, whereas inhibiting autophagy blocks viral transmission by its insect vector. Together, these results indicate a plant virus can induce the formation of autophagosomes for carrying virions, thus facilitating viral spread and transmission by its insect vector. We believe that such a role for virus-induced autophagy is common for vector-borne persistent viruses during their transmission by insect vectors. PMID- 29125861 TI - Identification of hospitalized elderly patients at risk for adverse in-hospital outcomes in a university orthopedics and trauma surgery environment. AB - BACKGROUND: As a consequence of demographic changes, hospitals are confronted with increasing numbers of elderly patients, who are at high risk of adverse events during hospitalization. Geriatric risk screening followed by comprehensive geriatric assessment (CGA) and treatment has been requested by geriatric societies and task forces to identify patients at risk. Since empirical evidence on factors predisposing to adverse hospital events is scarce, we now prospectively evaluated implications of geriatric risk screening followed by CGA in a university hospital department of orthopedics and trauma surgery. METHODS: Three hundred and eighty-one patients >=75 years admitted to the Department of Orthopedics and Trauma Surgery of the University Hospital Essen received Identification of Seniors at Risk (ISAR) Screening followed by CGA via a geriatric liaison service in case of positive screening results. Associations between ISAR, CGA, comorbid risk factors and diseases, length of hospital stay, number of nursing and physiotherapy hours, and falls during hospital stay were analyzed. RESULTS: Of 381 ISAR screenings, 327 (85.8%) were positive, confirming a high percentage of patients at risk of adverse events. Of these, 300 CGAs revealed 82.7% abnormal results, indicating activities of daily living impairment combined with cognitive, emotional or mobility disturbances. Abnormal CGA resulted in a longer hospital stay (14.0+/-10.3 days in ISAR+/CGA abnormal compared with 7.6+/-7.0 days in ISAR+/CGA normal and 8.1+/-5.4 days in ISAR-, both p<0.001), increased nursing hours (3.4+/-1.1 hours/day in ISAR+/CGA abnormal compared with 2.5+/-1.0 hours/day in ISAR+/CGA normal and 2.2+/-0.8 hours/day in ISAR-, both p<0.001), and increased falls (7.3% in ISAR+/CGA abnormal, 0% in ISAR+/CGA normal, 1.9% in ISAR-). Physiotherapy hours were only significantly increased in ISAR+/CGA abnormal (3.0+/-2.7 hours) compared with in ISAR+/CGA normal (1.6+/-1.4 hours, p<0.001) whereas the comparison with ISAR- (2.4+/-2.4 hours) did not reach significance (p = 0.368). In multivariable regressions, the CGA domains activities of daily living impairment (assessed by Barthel-Index) and signs of depression (assessed by geriatric depression scale) predicted longer length of hospital stay. High ISAR score, and impairment in activities of daily living and cognition (assessed by mini-mental state examination and clock-drawing test) predicted increased nursing hours, and impairment in activities of daily living and mobility predicted increased physiotherapy hours. CONCLUSIONS: An abnormal geriatric screening and assessment is associated with longer hospital stay, more nursing and physiotherapy hours, and more falls. PMID- 29125862 TI - Peptidergic control in a fruit crop pest: The spotted-wing drosophila, Drosophila suzukii. AB - Neuropeptides play an important role in the regulation of feeding in insects and offer potential targets for the development of new chemicals to control insect pests. A pest that has attracted much recent attention is the highly invasive Drosophila suzukii, a polyphagous pest that can cause serious economic damage to soft fruits. Previously we showed by mass spectrometry the presence of the neuropeptide myosuppressin (TDVDHVFLRFamide) in the nerve bundle suggesting that this peptide is involved in regulating the function of the crop, which in adult dipteran insects has important roles in the processing of food, the storage of carbohydrates and the movement of food into the midgut for digestion. In the present study antibodies that recognise the C-terminal RFamide epitope of myosuppressin stain axons in the crop nerve bundle and reveal peptidergic fibres covering the surface of the crop. We also show using an in vitro bioassay that the neuropeptide is a potent inhibitor (EC50 of 2.3 nM) of crop contractions and that this inhibition is mimicked by the non-peptide myosuppressin agonist, benzethonium chloride (Bztc). Myosuppressin also inhibited the peristaltic contractions of the adult midgut, but was a much weaker agonist (EC50 = 5.7 MUM). The oral administration of Bztc (5 mM) in a sucrose diet to adult female D. suzukii over 4 hours resulted in less feeding and longer exposure to dietary Bztc led to early mortality. We therefore suggest that myosuppressin and its cognate receptors are potential targets for disrupting feeding behaviour of adult D. suzukii. PMID- 29125863 TI - Lectins identify distinct populations of coelomocytes in Strongylocentrotus purpuratus. AB - Coelomocytes represent the immune cells of echinoderms, but detailed knowledge about their roles during immune responses is very limited. One major challenge for studying coelomocyte biology is the lack of reagents to identify and purify distinct populations defined by objective molecular markers rather than by morphology-based classifications that are subjective at times. Glycosylation patterns are known to differ significantly between cell types in vertebrates, and furthermore they can vary depending on the developmental stage and activation states within a given lineage. Thus fluorescently labeled lectins that recognize distinct glycan structures on cell surface proteins are routinely used to identify discrete cell populations in the vertebrate immune system. Here we now employed a panel of fifteen fluorescently-labeled lectins to determine differences in the glycosylation features on the surface of Strongylocentrotus purpuratus coelomocytes by fluorescence microscopy and flow cytometry. Eight of the lectins (succinylated wheat germ agglutinin, Len culinaris lectin, Pisum sativum agglutinin, Saphora japonica agglutinin, Solanum tuberosum lectin, Lycopersicon esculentum lectin, Datura stramonium lectin, Vicia villosa lectin) showed distinct binding patterns to fixed and live cells of three major coelomocyte classes: phagocytic cells, red spherule cells, and vibratile cells. Importantly, almost all lectins bound only to a subgroup of cells within each cell type. Lastly, we established fluorescently-labeled lectin-based fluorescence activated cell sorting as a strategy to purify distinct S. purpuratus coelomocyte (sub-)populations based on molecular markers. We anticipate that this will become a routine approach in future studies focused on dissecting the roles of different coelomocytes in echinoderm immunity. PMID- 29125864 TI - Psychological stress in aged female mice causes acute hypophagia independent of central serotonin 2C receptor activation. AB - Sex differences exist in the activation of the hypothalamic-pituitary-adrenal axis following exposure to stress, and the stress response is further affected by aging. This study was conducted to elucidate the mechanism of hypophagia in aged female mice exposed to stress. Immediately after a stress load, aged female mice exhibited acute hypophagia and a rise in plasma corticosterone levels. The administration of a serotonin 2C receptor (5-HT2CR) antagonist suppressed plasma corticosterone but did not affect the reduction in food intake. In contrast, an endogenous ghrelin enhancer, rikkunshito (RKT), significantly inhibited the reduction in food intake. An increase in peripheral acylated ghrelin levels during fasting, which occurs in young mice, was not observed in aged female mice. Moreover, in these mice, significantly increased levels of ghrelin and gastric preproghrelin mRNA expression were observed in the fed status. Moreover, plasma ghrelin levels were elevated by RKT and not by the 5-HT2CR antagonist. In female mice, the hypothalamic non-edited (INI) and partially edited mRNA 5-HT2CR isoforms (VNV, VNI, VSV or VSI) decreased with age, while in male mice, the editing isoform was unchanged by aging or stress. Estrogen receptor alpha (ERalpha)-positive cell counts in the arcuate nucleus of young male mice exposed to stress and control aged male mice were increased compared with those in young control mice. In aged male mice exposed to stress, the number of ERalpha expressing cells in the paraventricular nucleus were significantly increased compared with those in aged control mice; in female mice, there was no increase in the number of ERalpha-positive cells. Hypophagia in aged female mice exposed to stress may be independent of 5-HT2CR activation. It seems likely that the mechanisms may be caused by sex dependent, differential regulation in 5-HT2CR mRNA expression, peripheral acylated ghrelin secretion and/or hypothalamic ERalpha expression. PMID- 29125865 TI - Membrane order in the plasma membrane and endocytic recycling compartment. AB - The cholesterol content of membranes plays an important role in organizing membranes for signal transduction and protein trafficking as well as in modulating the biophysical properties of membranes. While the properties of model or isolated membranes have been extensively studied, there has been little evaluation of internal membranes in living cells. Here, we use a Nile Red based probe, NR12S, and ratiometric live cell imaging, to analyze the membrane order of the plasma membrane and endocytic recycling compartment. We find that after a brief incubation to allow endocytosis, NR12S is distributed between the plasma membrane and the endocytic recycling compartment. The NR12S reports that the endocytic recycling compartment is more highly ordered than the plasma membrane. We also find that the plasma membrane and the endocytic recycling compartment are differentially affected by altering cellular cholesterol levels. The membrane order of the plasma membrane, but not the endocytic recycling compartment, is altered significantly when cellular cholesterol content is increased or decreased by 20%. These results demonstrate that changes in cellular cholesterol differentially alter membrane order within different organelles. PMID- 29125866 TI - Inconsistent selection of outcomes and measurement devices found in shoulder arthroplasty research: An analysis of studies on ClinicalTrials.gov. AB - INTRODUCTION: Recent evidence suggests a lack of standardization of shoulder arthroplasty outcomes. This issue is a limiting factor in systematic reviews. Core outcome set (COS) methodology could address this problem by delineating a minimum set of outcomes for measurement in all shoulder arthroplasty trials. METHODS: A ClinicalTrials.gov search yielded 114 results. Eligible trials were coded on the following characteristics: study status, study type, arthroplasty type, sample size, measured outcomes, outcome measurement device, specific metric of measurement, method of aggregation, outcome classification, and adverse events. RESULTS: Sixty-six trials underwent data abstraction and data synthesis. Following abstraction, 383 shoulder arthroplasty outcomes were organized into 11 outcome domains. The most commonly reported outcomes were shoulder outcome score (n = 58), pain (n = 33), and quality of life (n = 15). The most common measurement devices were the Constant-Murley Shoulder Outcome Score (n = 38) and American Shoulder and Elbow Surgeons Shoulder Score (n = 33). Temporal patterns of outcome use was also found. CONCLUSION: Our study suggests the need for greater standardization of outcomes and instruments. The lack of consistency across trials indicates that developing a core outcome set for shoulder arthroplasty trials would be worthwhile. Such standardization would allow for more effective comparison across studies in systematic reviews, while at the same time consider important outcomes that may be underrepresented otherwise. This review of outcomes provides an evidence-based foundation for the development of a COS for shoulder arthroplasty. PMID- 29125867 TI - Effects of cognate, non-cognate and synthetic CXCR4 and ACKR3 ligands on human lung endothelial cell barrier function. AB - Recent evidence suggests that chemokine CXCL12, the cognate agonist of chemokine receptors CXCR4 and ACKR3, reduces thrombin-mediated impairment of endothelial barrier function. A detailed characterization of the effects of CXCL12 on thrombin-mediated human lung endothelial hyperpermeability is lacking and structure-function correlations are not available. Furthermore, effects of other CXCR4/ACKR3 ligands on lung endothelial barrier function are unknown. Thus, we tested the effects of a panel of CXCR4/ACKR3 ligands (CXCL12, CXCL11, ubiquitin, AMD3100, TC14012) and compared the CXCR4/ACKR3 activities of CXCL12 variants (CXCL12alpha/beta, CXCL12(3-68), CXCL121, CXCL122, CXCL12-S-S4V, CXCL12-R47E, CXCL12-K27A/R41A/R47A) with their effects on human lung endothelial barrier function in permeability assays. CXCL12alpha enhanced human primary pulmonary artery endothelial cell (hPPAEC) barrier function, whereas CXCL11, ubiquitin, AMD3100 and TC14012 were ineffective. Pre-treatment of hPPAEC with CXCL12alpha and ubiquitin reduced thrombin-mediated hyperpermeability. CXCL12alpha-treatment of hPPAEC after thrombin exposure reduced barrier function impairment by 70% (EC50 0.05-0.5nM), which could be antagonized with AMD3100; ubiquitin (0.03-3MUM) was ineffective. In a human lung microvascular endothelial cell line (HULEC5a), CXCL12alpha and ubiquitin post-treatment attenuated thrombin-induced hyperpermeability to a similar degree. CXCL12(3-68) was inefficient to activate CXCR4 in Presto-Tango beta-arrestin2 recruitment assays; CXCL12-S-S4V, CXCL12 R47E and CXCL12-K27A/R41A/R47A showed significantly reduced potencies to activate CXCR4. While the potencies of all proteins in ACKR3 Presto-Tango assays were comparable, the efficacy of CXCL12(3-68) to activate ACKR3 was significantly reduced. The potencies to attenuate thrombin-mediated hPPAEC barrier function impairment were: CXCL12alpha/beta, CXCL121, CXCL12-K27A/R41A/R47A > CXCL12-S-S4V, CXCL12-R47E > CXCL122 > CXCL12(3-68). Our findings indicate that CXCR4 activation attenuates thrombin-induced lung endothelial barrier function impairment and suggest that protective effects of CXCL12 are dictated by its CXCR4 agonist activity and interactions of distinct protein moieties with heparan sulfate on the endothelial surface. These data may facilitate development of compounds with improved pharmacological properties to attenuate thrombin-induced vascular leakage in the pulmonary circulation. PMID- 29125868 TI - Local thoracic therapy improve prognosis for stage IV non-small cell lung cancer patients combined with chemotherapy: A Surveillance, Epidemiology, and End Results database analysis. AB - Patients with stage IV non-small cell lung cancer (NSCLC) comprise a heterogeneous group, and the optimal treatment for this group of patients is complex and debatable. We aimed to assess the effect of local thoracic therapy combined with chemotherapy on cancer specific survival (CSS). To evaluate the CSS of four subgroups of patients with stage IV NSCLC according to four different treatment modalities: combined modality of Chemotherapy, Surgery, and Radiation (Chem+Sur+RT), Chemotherapy and Radiation (Chem+RT), Chemotherapy and Surgery (Chem+Sur), and Chemotherapy only (Chem Only) by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of survival outcomes and risk factors. The 3-year CSS was 33.5% in "Chem+Sur+RT" group, 9.3% in "Chem+RT" group, 42.7% in "Chem+Sur" group and 11.8% in "Chem Only" group, which had significant difference in univariate log-rank test (P<0.001) and multivariate Cox regression (P<0.001). Moreover, we observed significant survival benefits in "Chem+Sur" group in all stage of T/N categories, including stage I, stage II, stage IIIa and stage IIIb (all P<0.001). Multimodality therapy, especially combined thoracic surgery and chemotherapy is associated with dramatically improved prognosis for patients with stage IV NSCLC. PMID- 29125869 TI - Monitoring the treatment of hepatitis C with directly acting antivirals by serological and molecular methods. AB - AIM: To evaluate the potential value of using a serological assay to quantitate the hepatitis C virus core antigen (HCV-Ag) when monitoring patients with chronic hepatitis C being treated with direct-acting antivirals (DAAs). METHODS: Ninety six patients treated with DAAs, either alone (91) or in combination with PEG interferon (5), were tested for HCV-RNA and for HCV-Ag at baseline and at weeks 2, 4, 8 and 12 during treatment and 12 weeks after completion. The concordance and correlation between the viral parameters as well as the respective kinetics during and after treatment were evaluated. RESULTS: A sustained viral response (SVR) was achieved in 82 patients (91%), whereas 11 relapsed (R) and 1 showed a virological breakthrough while receiving treatment. HCV-RNA and HCV-Ag showed good concordance (kappa = 0.62) and correlation. No significant differences between SVR and R was observed in either assay at 2 and 4 weeks after the start of treatment. At 8 weeks, HCV-Ag showed higher accuracy than HCV-RNA (AUC: 0.74 vs. 0.55) and there was a significantly greater decrease from baseline in SVR than in R (4.01 vs. 3.36 log10; p<0.05). CONCLUSIONS: Monitoring during treatment with DAAs by using either HCV-RNA or HCV-Ag has only a limited predictive value for SVR. Since those assays are equivalent for identifying a virological relapse, HCV-Ag may be preferred from an economical and organizational perspective. PMID- 29125870 TI - Comparison of ancient and modern Chinese based on complex weighted networks. AB - In this study, we compare statistical properties of ancient and modern Chinese within the framework of weighted complex networks. We examine two language networks based on different Chinese versions of the Records of the Grand Historian. The comparative results show that Zipf's law holds and that both networks are scale-free and disassortative. The interactivity and connectivity of the two networks lead us to expect that the modern Chinese text would have more phrases than the ancient Chinese one. Furthermore, by considering some of the topological and weighted quantities, we find that expressions in ancient Chinese are briefer than in modern Chinese. These observations indicate that the two languages might have different linguistic mechanisms and combinatorial natures, which we attribute to the stylistic differences and evolution of written Chinese. PMID- 29125871 TI - Does ownership of improved dairy cow breeds improve child nutrition? A pathway analysis for Uganda. AB - The promotion of livestock production is widely believed to support enhanced diet quality and child nutrition, but the empirical evidence for this causal linkage remains narrow and ambiguous. This study examines whether adoption of improved dairy cow breeds is linked to farm-level outcomes that translate into household level benefits including improved child nutrition outcomes in Uganda. Using nationwide data from Uganda's National Panel Survey, propensity score matching is used to create an unbiased counterfactual, based on observed characteristics, to assess the net impacts of improved dairy cow adoption. All estimates were tested for robustness and sensitivity to variations in observable and unobservable confounders. Results based on the matched samples showed that households adopting improved dairy cows significantly increased milk yield-by over 200% on average. This resulted in higher milk sales and milk intakes, demonstrating the potential of this agricultural technology to both integrate households into modern value chains and increase households' access to animal source foods. Use of improved dairy cows increased household food expenditures by about 16%. Although undernutrition was widely prevalent in the study sample and in matched households, the adoption of improved dairy cows was associated with lower child stunting in adopter household. In scale terms, results also showed that holding larger farms tends to support adoption, but that this also stimulates the household's ability to achieve gains from adoption, which can translate into enhanced nutrition. PMID- 29125872 TI - Impaired placental autophagy in placental malaria. AB - BACKGROUND: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. METHODS: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis. Western blotting and immunofluorescence staining coupled with advanced image analysis were used to quantify the expression of autophagic markers (LC3-II, LC3-I, Rab7, ATG4B and p62) and the density of autophagosomes (LC3-positive puncta) and lysosomes (LAMP1 positive puncta). RESULTS: Placental malaria with intervillositis was associated with higher LC3-II:LC3-I ratio, suggesting increased autophagosome formation. We found higher density of autophagosomes and lysosomes in the syncytiotrophoblast of malaria-infected placentas with intervillositis. However, there appear to be no biologically relevant increase in LC3B/LAMP1 colocalization and expression of Rab7, a molecule involved in autophagosome/lysosome fusion, was lower in placental malaria with intervillositis, indicating a block in the later stage of autophagy. ATG4B and p62 expression showed no significant difference across histological groups suggesting normal autophagosome maturation and loading of cargo proteins into autophagosomes. The density of autophagosomes and lysosomes in the syncytiotrophoblast was negatively correlated with placental amino acid uptake. CONCLUSIONS: Placental malaria-associated intervillositis is associated with dysregulated autophagy that may impair transplacental amino acid transport, possibly contributing to poor fetal growth. PMID- 29125874 TI - Pulmonary immune responses to Mycobacterium tuberculosis in exposed individuals. AB - BACKGROUND: Blood based Interferon-(IFN)-gamma release assays (IGRAs) have a poor predictive value for the development of tuberculosis. This study aimed to investigate the correlation between IGRAs and pulmonary immune responses in tuberculosis contacts in Germany. METHODS: IGRAs were performed on bronchoalveolar lavage (BAL) cells and peripheral blood from close healthy contacts of patients with culturally confirmed tuberculosis. Cellular BAL composition was determined by flow cytometry. BAL cells were co-cultured with three strains of Mycobacterium tuberculosis (Mtb) and Mtb derived antigens including Purified Protein Derivative (PPD), 6 kD Early Secretory Antigenic Target (ESAT-6) and 10 kD Culture Filtrate Protein (CFP-10). Levels of 29 cytokines and chemokines were analyzed in the supernatants by multiplex assay. Associations and effects were examined using linear mixed-effects models. RESULTS: There were wide variations of inter-individual cytokine levels in BAL cell culture supernatants. Mycobacterial infection and stimulation with PPD showed a clear induction of several macrophage and lymphocyte associated cytokines, reflecting activation of these cell types. No robust correlation between cytokine patterns and blood IGRA status of the donor was observed, except for slightly higher Interleukin-2 (IL-2) responses in BAL cells from IGRA positive donors upon mycobacterial infection compared to cells from IGRA-negative donors. Stronger correlations were observed when cytokine patterns were stratified according to BAL IGRA status. BAL cells from donors with BAL IGRA positive responses produced significantly more IFN-gamma and IL-2 upon PPD stimulation and mycobacterial infection than cells from BAL IGRA-negative individuals. Correlations between BAL composition and basal cytokine release from unstimulated cells were suggestive of pre-activated lymphocytes but impaired macrophage activity in BAL IGRA-positive donors, in contrast to BAL IGRA-negative donors. CONCLUSIONS: In vitro BAL cell cytokine responses to M. tuberculosis antigens or infection do not reflect blood IGRA status but do correlate with stronger cellular responses in BAL IGRA-positive donors. The cytokine patterns observed suggest a pre-activated state of lymphocytes and suppressed macrophage responsiveness in BAL cells from BAL IGRA-positive individuals. PMID- 29125873 TI - U6 snRNA expression prevents toxicity in TDP-43-knockdown cells. AB - Depletion of amyotrophic lateral sclerosis (ALS)-associated transactivation response (TAR) RNA/DNA-binding protein 43 kDa (TDP-43) alters splicing efficiency of multiple transcripts and results in neuronal cell death. TDP-43 depletion can also disturb expression levels of small nuclear RNAs (snRNAs) as spliceosomal components. Despite this knowledge, the relationship between cell death and alteration of snRNA expression during TDP-43 depletion remains unclear. Here, we knocked down TDP-43 in murine neuroblastoma Neuro2A cells and found a time lag between efficient TDP-43 depletion and appearance of cell death, suggesting that several mechanisms mediate between these two events. The amount of U6 snRNA was significantly decreased during TDP-43 depletion prior to increase of cell death, whereas that of U1, U2, and U4 snRNAs was not. Downregulation of U6 snRNA led to cell death, whereas transient exogenous expression of U6 snRNA counteracted the effect of TDP-43 knockdown on cell death, and slightly decreased the mis-splicing rate of Dnajc5 and Sortilin 1 transcripts, which are assisted by TDP-43. These results suggest that regulation of the U6 snRNA expression level by TDP-43 is a key factor in the increase in cell death upon TDP-43 loss-of-function. PMID- 29125875 TI - Drug abusers have impaired cerebral oxygenation and cognition during exercise. AB - BACKGROUND: Individuals with Substance Use Disorder (SUD) have lower baseline metabolic activity of the prefrontal cortex (PFC) associated with impairment of cognitive functions in decision-making and inhibitory control. Aerobic exercise has shown to improve PFC function and cognitive performance, however, its effects on SUD individuals remain unclear. PURPOSE: To verify the cognitive performance and oxygenation of the PFC during an incremental exercise in SUD individuals. METHODS: Fourteen individuals under SUD treatment performed a maximum graded exercise test on a cycle ergometer with continuous measurements of oxygen consumption, PFC oxygenation, and inhibitory control (Stroop test) every two minutes of exercise at different intensities. Fifteen non-SUD individuals performed the same protocol and were used as control group. RESULTS: Exercise increased oxyhemoglobin (O2Hb) and total hemoglobin (tHb) by 9% and 7%, respectively. However, when compared to a non-SUD group, this increase was lower at high intensities (p<0.001), and the inhibitory cognitive control was lower at rest and during exercise (p<0.007). In addition, PFC hemodynamics during exercise was inversely correlated with inhibitory cognitive performance (reaction time) (r = -0.62, p = 0.001), and a lower craving perception for the specific abused substance (p = 0.0189) was reported immediately after exercise. CONCLUSION: Despite SUD individuals having their PFC cerebral oxygenation increased during exercise, they presented lower cognition and oxygenation when compared to controls, especially at elevated intensities. These results may reinforce the role of exercise as an adjuvant treatment to improve PFC function and cognitive control in individuals with SUD. PMID- 29125876 TI - Psychometric properties of the Resilience Scale for Adults (RSA) and its relationship with life-stress, anxiety and depression in a Hispanic Latin American community sample. AB - Resilience is a multi-dimensional construct associated with health and well being. At present, we do not yet have a valid, scientific instrument that is designed to evaluate adult resilience in Spanish-speaking countries and that accounts for family, social and individual components. This study aimed at investigating the construct and cross-cultural validity of the Resilience Scale for Adults (RSA) by combining Confirmatory Factor Analysis (CFA), Multidimensional Scaling (MDS) and Hierarchical Regression models in a Hispanic Latin-American group. A community sample of 805 adults answered the RSA, Spanish Language Stressful Life-Events checklist (SL-SLE), and the Hopkins Symptom Checklist-25 (HSCL-25). First-order CFA verified the six factors structure for the RSA (RMSEA = .037, SRMR = .047, CFI = .91, TLI = .90). Five RSA scales and total score have good internal consistency (scales alpha > .70; total score alpha = .90). Two second-order CFA verified the intrapersonal and interpersonal dimensions of the protector factors of resilience, as well as their commonality and uniqueness with affective symptoms (anxiety and depression). An exploratory MDS reproduced the relations of RSA items and factors at first and second-order levels against random simulated data, thereby providing initial evidence of its cross-cultural validity in a Spanish-speaking group. The Four-steps hierarchical model showed that the RSA scales are the strongest predictors of anxiety and depression-greater than gender, age, education and stressful life-events. Three RSA scales are significant unique predictors of affective symptoms. In addition, similar to findings in diverse cultural settings, resilience is positively associated with age but not with education. Women report higher scores of Social Resources and Social Competence and lower scores of Perception of the Self. In conclusion, this study demonstrates the construct and criterion-related validity of the RSA in broad, diverse and Spanish speaking sample. PMID- 29125877 TI - Impact of tumor burden on prognostic prediction for patients with terminal stage hepatocellular carcinoma: A nomogram study. AB - BACKGROUND: The recently proposed nomogram of Barcelona Clinic Liver Cancer (BCLC) lacks predictive accuracy for patients with stage D hepatocellular carcinoma (HCC). Tumor burden is crucial in prognostic prediction but is not included in the criteria of stage D HCC. This study aims to develop a nomogram with tumor burden as the core element for BCLC stage D patients. METHODS: A total of 386 patients were randomly grouped into derivation and validation sets (1:1 ratio). The multivariate Cox proportional hazards model was used to select factors with significant prognostic effect and generate the nomogram. Concordance indices and calibration plots were used to evaluate the performance of nomogram. RESULTS: Overall survival of study patients was significantly associated with tumor burden as well as hepatitis B, serum alpha-fetoprotein level, cirrhosis and performance status in multivariate Cox regression (all p<0.05). Beta-coefficients of these variables in derivation set were used to generate the nomogram. Each patient was assigned with a total nomogram point that predicted individualized 6 month and 1-year survival. The derivation and validation sets had a c-index of 0.759 (95% confidence interval [CI]: 0.552-0.923) and 0.741 (95% CI: 0.529 0.913), respectively. The calibration plots were close to the 45-degree line for 6-month and 1-year survival prediction for all quarters of patients in both derivation and validation sets. CONCLUSION: Tumor burden is significantly associated with the outcome for patients with stage D HCC. The tumor burden incorporated nomogram may serve as a feasible and easy-to-use tool in predicting survival on an individual level. PMID- 29125879 TI - Spironolactone is effective in treating hypokalemia among peritoneal dialysis patients. AB - BACKGROUND: Hypokalemia is common in peritoneal dialysis (PD) patients and is associated with increased cardiovascular and all-cause mortality. The management approach for such patients routinely includes spironolactone at our centre. We undertook this study to assess the efficacy of spironolactone for the treatment of hypokalemia in PD patients. METHODS: Retrospective chart review of PD patients at a single centre. Serum potassium was compared prior to initiation of spironolactone and two months afterwards. Indication for spironolactone and changes in blood pressure (BP), weight, and serum creatinine were also recorded. RESULTS: The chart review identified 53 patients who fit our selection criteria. The mean age was 64 +/- 15 years and the majority was treated with continuous cyclic peritoneal dialysis. Serum potassium rose from 3.7 +/- 0.5 to 4.2 +/- 0.5 mmol/L (P<0.0001) after 2 months with a mean dose of spironolactone of 28.5+/ 15.2 mg (median dose 25 mg). A significant reduction in systolic BP was observed from 150+/- 18 to 137 +/-24 (P = 0.002); a non- significant reduction in diastolic BP was also observed. The rise in potassium was constant in the range of 0.4 to 0.5 mmol/L regardless of whether spironolactone was initiated for hypokalemia, diuresis, or as an antihypertensive. There was no change in serum creatinine or body weight two months after introduction of spironolactone. CONCLUSIONS: Spironolactone is safe and effective in treating hypokalemia in PD patients. It is also an effective antihypertensive agent and merits further study in the PD population. PMID- 29125878 TI - Insight into the interactions, residue snorkeling, and membrane disordering potency of a single antimicrobial peptide into different lipid bilayers. AB - Pardaxin, with a bend-helix-bend-helix structure, is a membrane-active antimicrobial peptide that its membrane activity depends on the lipid bilayer composition. Herein, all-atom molecular dynamics (MD) simulations were performed to provide further molecular insight into the interactions, structural dynamics, orientation behavior, and cationic residues snorkeling of pardaxin in the DMPC, DPPC, POPC, POPG, POPG/POPE (3:1), and POPG/POPE (1:3) lipid bilayers. The results showed that the C-terminal helix of the peptide was maintained in all six types of the model-bilayers and pardaxin was tilted into the DMPC, DPPC, and POPG/POPE mixed bilayers more than the POPC and POPG bilayers. As well as, the structure of zwitterionic membranes was more affected by the peptide than the anionic bilayers. Taken together, the study demonstrated that the cationic residues of pardaxin snorkeled toward the interface of lipid bilayers and all phenylalanine residues of the peptide played important roles in the peptide membrane interactions. We hope that this work will provide a better understanding of the interactions of antimicrobial peptides with the membranes. PMID- 29125881 TI - Chemical and cultural control of Tropilaelaps mercedesae mites in honeybee (Apis mellifera) colonies in Northern Thailand. AB - At least two parasitic mites have moved from Asian species of honeybees to infest Apis mellifera. Of these two, Varroa destructor is more widespread globally while Tropilaelaps mercedesae has remained largely in Asia. Tropilaelaps mites are most problematic when A. mellifera is managed outside its native range in contact with Asian species of Apis. In areas where this occurs, beekeepers of A. mellifera treat aggressively for Tropilaelaps and Varroa is either outcompeted or is controlled as a result of the aggressive treatment regime used against Tropilaelaps. Many mite control products used worldwide may in fact control both mites but environmental conditions differ globally and thus a control product that works well in one area may be less or ineffective in other areas. This is especially true of volatile compounds. In the current research we tested several commercial products known to control Varroa and powdered sulfur for efficacy against Tropilaelaps. Additionally, we tested the cultural control method of making a hive division to reduce Tropilaelaps growth in both the parent and offspring colony. Making a split or nucleus colony significantly reduced mite population in both the parent and nucleus colony when compared to un-manipulated control colonies. The formic acid product, Mite-Away Quick Strips(r), was the only commercial product that significantly reduced mite population 8 weeks after initiation of treatment without side effects. Sulfur also reduced mite populations but both sulfur and Hopguard(r) significantly impacted colony growth by reducing adult bee populations. Apivar(r) (amitraz) strips had no effect on mite or adult bee populations under the conditions tested. PMID- 29125880 TI - MAVS activates TBK1 and IKKepsilon through TRAFs in NEMO dependent and independent manner. AB - Mitochondrial antiviral-signaling protein (MAVS) transmits signals from RIG-I like receptors after RNA virus infections. However, the mechanism by which MAVS activates downstream components, such as TBK1 and IKKalpha/beta, is unclear, although previous work suggests the involvement of NEMO or TBK1-binding proteins TANK, NAP1, and SINTBAD. Here, we report that MAVS-mediated innate immune activation is dependent on TRAFs, partially on NEMO, but not on TBK1-binding proteins. MAVS recruited TBK1/IKKepsilon by TRAFs that were pre-associated with TBK1/IKKepsilon via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKKepsilon. TRAF2-/-3-/-5-/-6-/- cells completely lost RNA virus responses. TRAFs' E3 ligase activity was required for NEMO activation by synthesizing ubiquitin chains that bound to NEMO for NF-kappaB and TBK1/IKKepsilon activation. NEMO-activated IKKalpha/beta were important for TBK1/IKKepsilon activation through IKKalpha/beta-mediated TBK1/IKKepsilon phosphorylation. Moreover, individual TRAFs differently mediated TBK1/IKKepsilon activation and thus fine-tuned antiviral immunity under physiological conditions. PMID- 29125882 TI - MiR-137 inhibited inflammatory response and apoptosis after spinal cord injury via targeting of MK2. AB - Spinal cord injuries are common and troublesome disorder, which is mediated by various signal pathways and mechanisms. MK2 is also involved in numerous inflammatory diseases including spinal cord injury. The role of microRNA-137 (miR 137) and its detailed working mechanism in spinal cord injuries remain unclear. In the present study, we found that an elevated MK2 but a decreased miR-137 was expressed in serum specimens of patients with spinal cord injury and in hydrogen peroxide-treated C8-D1A and C8-B4 cells. Meanwhile, we suggested that upregulation of miR-137 could inhibit the expression of TNF-alpha and IL-6, two markers of inflammatory response after SCI, and apoptosis in hydrogen peroxide treated C8-D1A and C8-B4 cells. Furthermore, we verified that MK2 was a direct target of miR-137 thorough a constructed luciferase assay. Even further, we elucidated that miR-137 could suppress the inflammatory response and apoptosis via negative regulation of MK2. Finally, through an animal model trial performed using mice, we demonstrated the protective effect of how miR-137 works on inflammatory response and apoptosis after spinal cord injury. Considering all the forementioned, our findings revealed that miR-137 inhibited inflammatory response and apoptosis after spinal cord injury via the targeting of MK2. The outcomes of the present study might indicate a new target in molecular treatment of SCI. PMID- 29125883 TI - A genetic variant of miR-335 binding site in the ERBB4 3'-UTR is associated with prognosis of ovary cancer. AB - Ovarian cancer is one of the leading gynecologic malignancies globally, the 5 year survival rate for patients with advanced stage ovarian cancer is very low. Our objective was to test the hypothesis that miR-335 was associated with the survival of patients with ovarian cancer. Bioinformatics tools and luciferase report assay were used to select the target of miR-335, and real-time PCR was used to detect the expression of miR-335 and ERBB4 in different genotype groups. Finally, Cox regression and Kaplan-Meier analyses were used to assess the relationship of ERBB4 genotype and survival of ovary cancer. Firstly, individuals carried ERBB4 rs186724 GG genotype had poorer overall survival compared with those carried CC/CT genotypes in ovarian cancer, while the participants with rs1836724 GA genotype had the same overall survival with that in participants with rs1836724 AA genotype in accordance with the result of Cox regression and Kaplan-Meier analyses. Then according to result of the in-silicon analysis, ERBB4 was the target of miR-335, and rs1836724 was located on 3'UTR of ERBB4, the binding site of miR-335, and miR-335 inhibited the expression of ERBB4 and this regulation was more suppressed when the G allele replaced by the variant A allele. Finally, miR-335 was similar among GG, GA, and AA groups, and ERBB4 level was higher in GG group. Finally, malignant grade is apparently higher in GG group than the other group. The data indicated that the ERBB4 rs1836724 polymorphism was associated with the survival of ovarian cancer. PMID- 29125884 TI - Comparative characterization of CD271+ and CD271- subpopulations of CD34+ human adipose-derived stromal cells. AB - Adipose-derived stromal/stem cells (ASCs) are promising candidates for cell-based therapies. However, the lack of markers able to unequivocally identify these cells, the differential expression of cell surface molecules among stromal progenitors from different tissues and cellular alterations caused by culture are phenomena that need to be comprehensively addressed in order to improve ASC purification and consequently refine our knowledge about their function and therapeutic efficiency. In this study, we investigated the potential of CD271, a marker used for purification of bone marrow-derived mesenchymal stem cells, on enriching ASCs from CD34+ stromal cells of human adipose tissue. Putative ASC populations were sorted based on CD271 expression (CD45- CD31- CD34+ CD271+ and CD45- CD31- CD34+ CD271- cells) and compared regarding their clonogenic efficiency, proliferation, immunophenotypic profile, and multilineage potential. To shed light on their native identity, we also interrogated the expression of key perivascular cell markers in freshly isolated cells. CD271- cells displayed twofold higher clonogenic efficiency than CD271+ cells. Upon culture, the progeny of both populations displayed similar immunophenotypic profile and in vitro adipogenic and chondrogenic potentials, while CD271+ cells produced more calcified extracellular matrix. Interestingly, uncultured freshly isolated CD271+ cells displayed higher expression of pericyte-associated markers than CD271- cells and localized in the inner region of the perivascular wall. Our results demonstrate that cells with in vitro ASC traits can be obtained from both CD271+ and CD271- stromal populations of human adipose tissue. In addition, gene expression profiling and in situ localization analyses indicate that the CD271+ population displays a pericytic phenotype. PMID- 29125885 TI - MiR 376c inhibits osteoblastogenesis by targeting Wnt3 and ARF-GEF-1 -facilitated augmentation of beta-catenin transactivation. AB - Wnt signaling pathway plays important role in all aspects of skeletal development which include chondrogenesis, osteoblastogenesis, and osteoclastogenesis. Induction of the Wnt-3 signaling pathway promotes bone formation while inactivation of the pathway leads to bone related disorders like osteoporosis. Wnt signaling thus has become a desired target to treat osteogenic disorders. MicroRNAs (miRNAs) represent an important category of elements that interact with Wnt signaling molecules to regulate osteogenesis. Here, we show that miR-376c, a well-characterized tumor suppressor which inhibits cell proliferation and invasion in osteosarcoma by targeting to transforming growth factor-alpha, suppresses osteoblast proliferation, and differentiation. Over-expression of miR 376c inhibited osteoblast differentiation, whereas inhibition of miR-376c function by antimiR-376c promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay along with qRT-PCR identified Wnt-3 and ARF-GEF-1 as direct targets of miR-376c. It was seen that over-expression of miR-376c leads to repression of canonical Wnt/beta-catenin signaling. Our overall results suggest that miR-376c targets Wnt 3 and ARF-GEF-1 suppresses ARF-6 activation which prevents the release of beta catenin and its transactivation thereby inhibiting osteoblast differentiation. Although miR-376c is known to be a tumor repressor; we have identified a second complementary function of miR-376c where it inhibits Wnt-3-mediated osteogenesis and promotes bone loss. PMID- 29125886 TI - MTA1 promotes viability and motility in nasopharyngeal carcinoma by modulating IQGAP1 expression. AB - Nasopharyngeal carcinoma (NPC) is frequently seen in Chinese, especially the population that resides in southeast China. Metastasis-associated protein 1 (MTA1) is a chromatin modifier and plays a role in tumor cell metastasis. IQGAP1 is a ubiquitously expressed protein that contributes to cytoskeleton remodeling. This study aimed to investigate the role of MTA1 and IQGAP1 in NPC malignant transformation. MTA1 and IQGAP1 expression in NPC (n = 43) and control tissues (n = 31) were detected using qRT-PCR, immunoblot, and immunohistochemistry. MTA1 was overexpressed in CNE-1 and CNE-2 cell line by pcDNA3.1/MTA1 transfection. Dominant-negative p53 was transfected to inhibit p53 activity. si-IQGAP1 or dominant-negative IQGAP1 (IQGAP1DeltaGRD) was used to suppress IQGAP1 activity. Cell proliferation was measured by CKK-8 assay. Cell migration was evaluated by Transwell assay. The results showed that MTA1 and IQGAP1 were highly expressed in NPC tissues compared with the controls. Forced expression of MTA1 accelerated cell proliferation and migration and upregulated IQGAP1 expression in a p53 independent way. Knockdown of IQGAP1 or transfection of dominant-negative IQGAP1 impeded tumor cell proliferation and migration as well as PI3K/Akt signaling induced by MTA1. In conclusion, MTA1 participates in NPC malignant transformation via regulating IQGAP1 expression and PI3K/Akt signaling pathway. PMID- 29125887 TI - From Knowing to Doing: Guidelines for Socioculturally Attuned Family Therapy. AB - Family therapists know that clinical concerns are not separate from larger sociopolitical contexts. Attunement to clients' sociocultural experience is foundational to good practice, yet few guidelines integrate attention to the larger societal processes or address social equity. The purpose of this article is to help therapists move from knowing about sociocontextual issues to doing socioculturally attuned practice. We offer an overarching framework that returns to Bateson and the roots of family therapy through a call for third order transformation. The approach is responsive to societal context and an analysis of power while working through enduring concepts of major family therapy models. Transtheoretical guidelines that can be integrated across practice models to promote third order change are illustrated with case examples. PMID- 29125888 TI - Circular RNA hsa_circ_0003221 (circPTK2) promotes the proliferation and migration of bladder cancer cells. AB - Emerging studies have shown that circular RNAs could be ideal biomarkers and even potential therapeutic targets for some tumors, including bladder cancer. However, only a few studies have investigated the circular RNAs in human bladder cancer. The key circular RNA molecules are closely related to bladder cancer and their roles remain largely unknown. Here, we investigated a novel circular RNA molecule, hsa-circ-0003221(circPTK2), which is differentially expressed in bladder carcinoma. Significant differential expression levels of circPTK2 were confirmed with quantitative PCR in 40 pairs of tissue and blood samples from patients with bladder carcinoma. Moreover, circPTK2 levels both in tissue and blood were significantly correlated with several clinicopathologic characteristics, including poor differentiation (P = 0.0103 in tissue, P = 0.024 in blood), N2-N3 lymph node metastasis (P = 0.0065 in tissue, P = 0.016 in blood), and T(II-III-IV) stage (P = 0.008 in tissue, P = 0.0003 in blood). Quantitative PCR results confirmed that circPTK2 is highly expressed in migrated cells separated by Transwell assay and in metastatic lymph nodes of tumors transplanted in nude mice. In vitro silence of circPTK2 by small interfering RNA inhibited the proliferation and migration of bladder cancer cells. On the contrary, circPTK2 overexpression promoted proliferation and migration. This study showed that circPTK2 promotes proliferation and migration of cells and may be a novel potential biomarker and therapeutic target for bladder cancer diagnosis and therapy. PMID- 29125889 TI - Pterostilbene down-regulates hTERT at physiological concentrations in breast cancer cells: Potentially through the inhibition of cMyc. AB - Human telomerase reverse transcriptase (hTERT) encodes the catalytic subunit of telomerase, which has been shown to be upregulated in many cancers. Pterostilbene is a naturally occurring stilbenoid and phytoalexin found primarily in blueberries that exhibits antioxidant activity and inhibits the growth of various cancer cell types. Therefore, the aim of this study was to determine whether treatment with pterostilbene, at physiologically achievable concentrations, can inhibit the proliferation of breast cancer cells and down-regulate the expression of hTERT. We found that pterostilbene inhibits the cellular proliferation of MCF 7 and MDA-MB-231 breast cancer cells in both a time- and dose-dependent manner, without significant toxicity to the MCF10A control cells. Pterostilbene was also shown to increase apoptosis in both breast cancer cell lines. Dose-dependent cell cycle arrest in G1 and G2/M phase was observed after treatment with pterostilbene in MCF-7 and MDA-231 cells, respectively. hTERT expression was down-regulated after treatment in both a time- and dose-dependent manner. Pterostilbene also reduced telomerase levels in both cell lines in a dose-dependent manner. Moreover, cMyc, a proposed target of the pterostilbene-mediated inhibition of hTERT, was down-regulated both transcriptionally and posttranscriptionally after treatment. Collectively, these findings highlight a promising use of pterostilbene as a natural, preventive, and therapeutic agent against the development and progression of breast cancer. PMID- 29125890 TI - Up-regulated WDR5 promotes gastric cancer formation by induced cyclin D1 expression. AB - Gastric cancer (GC) is the fourth common cancer and second leading cause of cancer-related mortality in the world. WD repeat domain 5 (WDR5) has been identified that its functions as an important role in various biological functions through the epigenetic regulation of gene transcription. However, the oncogenic effect of WDR5 in gastric cancer remains largely unknown. In this study, we investigated the role of WDR5 in gastric cancer genesis. We found that WDR5 expression is increased in gastric cancer patients. Through survival analysis, we found that high expression of WDR5 is associated with high risk gastric cancer; patients who with WDR5 high expression have poor survival rate compared with those who with WDR5 low expression. To make further investigation, we identified that WDR5 is targeted for cell cycle arrest by the Cyclin D1 in a process that is regulated by H3K4me3. Moreover, over-expression of WDR5 promotes cell proliferation, induces S/G2/M arrest in cell cycle, and promotes the expression of WDR5 targets, as well as that of H3K4me3 on the promoter of its targets. Inversely, WDR5 knockdown by shRNA inhibits cell proliferation, reverses S/G2/M arrest in cell cycle, and suppresses the expression of WDR5 targets, as well as that of H3K4me3. We also observed the positive correlation of WDR5 expression with its target in the cohort study of gastric patients. Taken together, our data reveal that WDR5 may have oncogenic effect and WDR5-mediated H3K4 methylation plays an important role in gastric cancer. PMID- 29125891 TI - Profiling Response to Tumor Necrosis Factor Inhibitor Treatment in Axial Spondyloarthritis. AB - OBJECTIVE: Lack of response to tumor necrosis factor inhibitor (TNFi) agents is not uncommon, encountered during the treatment of axial spondyloarthritis (SpA) patients, and it can be classified as primary lack of response (PLR) or secondary lack of response (SLR). The primary aim of this study was to evaluate factors associated with TNFi failure types and their characteristics in axial SpA. METHODS: Adult axial SpA patients who were TNFi naive at the time of baseline evaluation and started receiving their first biologics for active axial disease were identified. Based on the clinical response to the first TNFi, patients were then stratified into 3 groups: PLR, SLR, and responders. Clinical, demographic, and laboratory data were collected and analyzed. RESULTS: There was a total of 249 axial SpA patients in the study (70.7% male, mean +/- SD age 37.3 +/- 12.4 years), which included PLR (n = 62), SLR (n = 93), and responders (n = 94). PLR patients tended to be older, with a lower HLA-B27 rate, a higher percentage of nonresponder axial SpA patients, and a higher baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score compared to SLR patients or responders. In multiple regression analysis, increasing age, negative HLA-B27, higher baseline BASDAI, and treatment with the soluble TNF receptor protein were the independent predictors of PLR. CONCLUSION: PLR accounted for nearly 40% of the TNFi failures in axial SpA patients. Older age, negative HLA-B27, higher baseline disease activity, and treatment with soluble TNF receptors were the independent predictors of the primary nonresponse to TNFi. PMID- 29125892 TI - Lewis Acid-Assisted Photoinduced Intermolecular Coupling between Acylsilanes and Aldehydes: A Formal Cross Benzoin-Type Condensation. AB - Intermolecular carbon-carbon bond-forming reaction between readily available acylsilanes and aldehydes was achieved under photoirradiation conditions with assistance of a catalytic amount of Lewis acid. Nucleophilic addition of photochemically generated siloxycarbenes to aldehydes followed by 1,4-silyl migration afforded synthetically useful alpha-siloxyketones. Electrophilic activation of aldehydes by Lewis acid is highly important to realize this reaction efficiently, otherwise the yield of the desired coupling products were significantly decreased. Noteworthy is that a formal cross benzoin-type reaction using acylsilanes was achieved under Lewis acidic conditions. This is the first example of Lewis acid-catalyzed reaction of photochemically generated siloxycarbenes with electrophiles. PMID- 29125893 TI - Mesenchymal stem cells for the prevention and treatment of bronchopulmonary dysplasia in preterm infants. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a major complication of prematurity and currently lacks efficient treatments. Mesenchymal stem/stromal cells (MSCs) have been extensively explored as a potential therapy in several preclinical and clinical settings. Human and animal MSCs have been shown to prevent and treat lung injury in various preclinical models of lung diseases, including experimental BPD. OBJECTIVES: To determine if MSCs, administered intravenously or endotracheally, are safe and effective in preventing or treating BPD, or both, in preterm infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 10), MEDLINE via PubMed (1966 to 6 November 2016), Embase (1980 to 6 November 2016), and CINAHL (1982 to 6 November 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We considered RCTs and quasi-RCTs investigating prevention or treatment of BPD, or both, in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality according to prespecified criteria. MAIN RESULTS: We found no RCTs or quasi-RCTs addressing the use of MSCs for prevention or treatment of BPD in premature infants. Two RCTs are currently registered and ongoing. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the safety and efficacy of MSCs in the treatment or prevention of BPD in premature infants. The results of the ongoing trials addressing this issue are expected in the near future. PMID- 29125894 TI - The Stabilization of Glycosyl Cations Through Cooperative Noncovalent Interactions: A Theoretical Perspective. AB - A systematic study of the stabilization of glycosyl cations on aromatic rings is reported at the B3LYP, M06-2X and M11 levels of theory. In particular, pi-acidic arenes such as fluorobenzenes or naphthalenediimides efficiently stabilize these cations acting cooperatively as sandwich-type ternary cation-pi-anion systems. The stabilization and cooperativity in polar (both protic and aprotic) and non polar solvents has been also evaluated by using the polarizable continuum model. In addition, the role of the protecting group at the C-2 position (methyl, acetyl, benzyl, and pivaloyl) for this noncovalent stabilization has been explored, as well as the behaviour of the corresponding 2-deoxy glycosyl cation. PMID- 29125895 TI - Impact of preserved collateral veins on small-for-size grafts in living donor liver transplantation. AB - AIM: Graft size is a critical issue in living donor liver transplantation (LDLT). We hypothesized that too much portal flow could possibly be diverted into pre existing collateral veins, alleviating small-for-size syndrome (SFSS) in LDLT. This study evaluated the impact of the preserved collateral veins in the outcomes of LDLT using a small-for-size graft. METHODS: For patient safety, a graft-to recipient weight ratio (GRWR) <0.8% was strictly confined to patients with collateral veins (group A), and the patient group was compared in a 1:3 ratio to a matched group of patients with GRWR >=0.8% (group B) using propensity score analysis. RESULTS: Forty and 120 patients were included in group A and B, respectively. No significant differences in baseline patient characteristics were observed between the two groups except for graft weight and GRWR. The lowest GRWR was 0.4%. The graft portal inflow showed no significant differences for 7 days after graft implantation, ranging from 1668 to 5100 mL/min. Small-for-size syndrome occurred in no patients (0.0%) in group A and in 10 (8.3%) in group B (P = 0.067). Overall survival rates at 1, 3, and 5 years were not different between the two groups (85.0%, 82.5%, and 82.5% vs. 92.5%, 86.7%, and 85.0%, respectively; P = 0.670). CONCLUSION: Pre-existing collateral veins saved during surgery may have a reserve buffer for excessive portal flow to obviate SFSS in LDLT. PMID- 29125896 TI - An in situ Dynamic Continuum of Supramolecular Phosphoglycopeptides Enables Formation of 3D Cell Spheroids. AB - Higher-order assemblies of proteins, with a structural and dynamic continuum, is an important concept in biology, but these insights have yet to be applied in designing biomaterials. Dynamic assemblies of supramolecular phosphoglycopeptides (sPGPs) transform a 2D cell sheet into 3D cell spheroids. A ligand-receptor interaction between a glycopeptide and a phosphopeptide produces sPGPs that form nanoparticles, which transform into nanofibrils upon partial enzymatic dephosphorylation. The assemblies form dynamically and hierarchically in situ on the cell surface, and interact with the extracellular matrix molecules and effectively abolish contact inhibition of locomotion (CIL) of the cells. Integrating molecular recognition, catalysis, and assembly, these active assemblies act as a dynamic continuum to disrupt CIL, thus illustrating a new kind of biomaterial for regulating cell behavior. PMID- 29125897 TI - Image analysis of neural stem cell division patterns in the zebrafish brain. AB - Proliferating stem cells in the adult body are the source of constant regeneration. In the brain, neural stem cells (NSCs) divide to maintain the stem cell population and generate neural progenitor cells that eventually replenish mature neurons and glial cells. How much spatial coordination of NSC division and differentiation is present in a functional brain is an open question. To quantify the patterns of stem cell divisions, one has to (i) identify the pool of NSCs that have the ability to divide, (ii) determine NSCs that divide within a given time window, and (iii) analyze the degree of spatial coordination. Here, we present a bioimage informatics pipeline that automatically identifies GFP expressing NSCs in three-dimensional image stacks of zebrafish brain from whole mount preparations. We exploit the fact that NSCs in the zebrafish hemispheres are located on a two-dimensional surface and identify between 1,500 and 2,500 NSCs in six brain hemispheres. We then determine the position of dividing NSCs in the hemisphere by EdU incorporation into cells undergoing S-phase and calculate all pairwise NSC distances with three alternative metrics. Finally, we fit a probabilistic model to the observed spatial patterns that accounts for the non homogeneous distribution of NSCs. We find a weak positive coordination between dividing NSCs irrespective of the metric and conclude that neither strong inhibitory nor strong attractive signals drive NSC divisions in the adult zebrafish brain. (c) 2017 International Society for Advancement of Cytometry. PMID- 29125898 TI - Biodiversity impact assessment (BIA+) - methodological framework for screening biodiversity. AB - For the past 20 years, the life cycle assessment (LCA) community has sought to integrate impacts on biodiversity into the LCA framework. However, existing impact assessment methods still fail to do so comprehensively because they quantify only a few impacts related to specific species and regions. This paper proposes a methodological framework that will allow LCA practitioners to assess currently missing impacts on biodiversity on a global scale. Building on existing models that seek to quantify the impacts of human activities on biodiversity, the herein proposed methodological framework consists of 2 components: a habitat factor for 14 major habitat types and the impact on the biodiversity status in those major habitat types. The habitat factor is calculated by means of indicators that characterize each habitat. The biodiversity status depends on parameters from impact categories. The impact functions, relating these different parameters to a given response in the biodiversity status, rely on expert judgments. To ensure the applicability for LCA practitioners, the components of the framework can be regionalized on a country scale for which LCA inventory data is more readily available. The weighting factors for the 14 major habitat types range from 0.63 to 1.82. By means of area weighting of the major habitat types in a country, country-specific weighting factors are calculated. In order to demonstrate the main part of the framework, examples of impact functions are given for the categories "freshwater eutrophication" and "freshwater ecotoxicity" in 1 major habitat type. The results confirm suitability of the methodological framework. The major advantages are the framework's user-friendliness, given that data can be used from LCA databases directly, and the complete inclusion of all levels of biodiversity (genetic, species, and ecosystem). It is applicable for the whole world and a wide range of impact categories. Integr Environ Assess Manag 2018;14:282-297. (c) 2017 SETAC. PMID- 29125899 TI - Demographic and Clinical Factors Associated With Nonsurgical Osteoarthritis Treatment Among Patients in Outpatient Clinics. AB - OBJECTIVE: To identify patient demographic and clinical characteristics associated with osteoarthritis (OA) treatment use. METHODS: This was a secondary data analysis of 3 clinical trials among patients with hip or knee OA conducted in Duke Primary Care practices, the Durham Veterans Affairs (VA) Health Care System, and the University of North Carolina-Chapel Hill (UNC). At baseline, participants reported sociodemographic characteristics, OA-related pain and function, and OA treatment use, including oral analgesics, topical creams, joint injections, and physical therapy. Separate, multivariable logistic models (adjusted for clustering of clinics and providers for the Duke and VA cohorts) were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between participant characteristics and each type of OA treatment. RESULTS: Oral analgesic use was reported by 70-82% of participants across the 3 cohorts. Physical therapy, knee injections, and topical creams were used by 39-52%, 55-60%, and 25-39% of Duke, VA, and UNC participants, respectively. In multivariable models, worse pain, stiffness, and function, per 5 unit increase, were associated with greater odds of using any oral analgesic for the cohorts from Duke (OR 1.18 [95% CI 1.08-1.28]) and UNC (OR 1.14 [95% CI 1.05 1.24]), but not for the VA cohort (OR 1.04 [95% CI 0.95-1.14]). For all 3 cohorts, nonwhites had higher odds of using topical creams compared to whites. CONCLUSION: Results suggest potential underutilization of therapies other than oral analgesics. Patient characteristics may affect OA treatment use, and understanding the relationship between these factors and OA treatment preferences may improve adherence to OA treatment guidelines. PMID- 29125900 TI - Association of Comorbidities in Spondyloarthritis With Poor Function, Work Disability, and Quality of Life: Results From the Assessment of SpondyloArthritis International Society Comorbidities in Spondyloarthritis Study. AB - OBJECTIVE: Comorbidities add to the burden of disease and its complexity, and may prevent the achievement of treat-to-target goals. The objective of this study was to study the relationship between comorbidities and key disease outcomes in spondyloarthritis (SpA), namely function, work ability, and quality of life. METHODS: Patients from the multinational (22 countries), cross-sectional Assessment in SpondyloArthritis international Society (ASAS) Comorbidities in Spondyloarthritis study were included in the analysis, provided they fulfilled the ASAS criteria. Data on comorbidities based on both self- and physician-report were collected through questionnaires and were subsequently used to compute the Rheumatic Disease Comorbidity Index (RDCI). Univariable and multivariable (adjusted for relevant confounders) multilevel (with country as a random effect) linear or logistic (as appropriate) regression analyses were conducted to investigate the relationship between the RDCI and functional ability, work ability, and quality of life. RESULTS: In total, 3,370 of 3,984 recruited patients (85%) fulfilled the ASAS criteria: 66% were male, mean +/- SD age was 43 +/- 14 years, mean +/- SD disease duration was 8.4 +/- 9.5 years, and mean +/- SD RDCI was 0.7 +/- 1.1. At least 1 comorbidity was reported in 51% of patients; 9% had >=3 comorbidities. RDCI was independently associated with a higher Bath Ankylosing Spondylitis Functional Index score (beta = 0.37, 95% confidence interval [95% CI] 0.30, 0.43), lower EuroQol 5-domain questionnaire (beta = 0.03, 95% CI -0.04, -0.02), less work employment (odds ratio [OR] 0.83, 95% CI 0.76, 0.91), higher absenteeism (OR 1.18, 95% CI 1.04, 1.34), and higher presenteeism (OR 1.42, 95% CI 1.26, 1.61). CONCLUSION: Comorbidities in SpA adversely influence physical function, work ability, and quality of life and are important to take into account in daily clinical practice. PMID- 29125901 TI - Efficacy of Hydroxychloroquine in Hand Osteoarthritis: A Randomized, Double Blind, Placebo-Controlled Trial. AB - OBJECTIVE: To determine the symptom-modifying effect of hydroxychloroquine (HCQ) in hand osteoarthritis (OA). METHODS: In this randomized, double-blind, multicenter trial, patients with symptomatic hand OA received either HCQ 400 mg once a day or placebo during 24 weeks. The primary outcome was change of pain measured on a 100-mm visual analog scale (VAS) at 24 weeks. Secondary outcomes included decrease of pain at weeks 6 and 12 and change in Australian Canadian Hand Osteoarthritis Index (AUSCAN) and Arthritis Impact Measurement Scale 2 short form (AIMS2-SF) total scores. RESULTS: A total of 196 patients was included (placebo n = 98, HCQ n = 98). Mean +/- SD age was 58.0 +/- 7.6 years, and 86% were female. Baseline mean +/- SD pain VAS was 44.9 +/- 22.9 mm in the placebo group and 43.2 +/- 22.3 mm in the HCQ group. At 24 weeks, change in pain VAS was not significantly different between both groups (imputed mean VAS 42.7 in the HCQ group versus 45.3 in the placebo group after 24 weeks), as was the case in pain VAS at weeks 6 and 12. Changes in AUSCAN total score and AIMS2-SF total score in both groups were similar between the groups. In total, 24 patients in the placebo group and 21 patients in the HCQ group reported >=1 adverse event. In the HCQ group, 3 patients reported a severe allergic reaction. Fifteen patients withdrew from the study (5 placebo, 10 HCQ group) due to adverse events. CONCLUSION: Treatment with HCQ at 24 weeks is not effective in reducing the symptoms of hand OA compared to placebo. PMID- 29125902 TI - Asthma in Children of Mothers With Systemic Lupus Erythematosus and the Role of Preterm Birth. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) and asthma share inheritable IgE related pathophysiology, but the association between maternal SLE and asthma in the offspring has not been explored. Our aim was to investigate the association between maternal SLE during pregnancy and childhood asthma and examine the role of preterm birth as a mediator of the association using Swedish register data. METHODS: Information on 12,000 singleton live births (2001-2013) was collected from the Medical Birth Register. Childhood asthma was defined as at least 1 International Classification of Diseases-coded visit in the National Patient Register. Prevalent maternal SLE at delivery was identified from the Medical Birth Register and the National Patient Register. Risk ratios for asthma were estimated while controlling for confounders. Mediation analysis was used to estimate what percentage of the total effect can be explained by preterm birth (defined as either <34 or <37 weeks of gestation). RESULTS: We compared 775 children born to mothers with SLE with 11,225 born to mothers without SLE. Ninety seven children of mothers with SLE (13%) were diagnosed with asthma, compared to 1,211 in the unexposed group (11%). The risk ratio for childhood asthma was 1.46 (95% confidence interval 1.16-1.84). In mediation analysis, 20-29% of the total effect of SLE was explained by preterm birth. CONCLUSION: Prevalent maternal SLE during pregnancy is associated with an increased risk of asthma in the offspring. While preterm birth can explain a fair proportion of this association, additional unidentified mechanisms also likely play a role. PMID- 29125903 TI - A Young Woman With Sudden Urinary Retention and Sensory Deficits. PMID- 29125904 TI - Early Rheumatoid Arthritis Presentation, Treatment, and Outcomes in Aboriginal Patients in Canada: A Canadian Early Arthritis Cohort Study Analysis. AB - OBJECTIVE: Health inequities exist in chronic diseases for Aboriginal people. This study compared early rheumatoid arthritis (RA) presentation, treatment, and outcomes between Aboriginal and white patients in a large Canadian cohort study. METHODS: Longitudinal data from the Canadian Early Arthritis Cohort, a prospective multicenter early RA study, were analyzed for participants who self identified as Aboriginal or white ethnicity. Disease characteristics at presentation, prognostic factors, frequency of remission, and disease-modifying therapy strategies were contrasted between population groups. Linear mixed models were used to estimate rates of change for disease activity measures over a 5-year period. RESULTS: At baseline, 2,173 participants (100 Aboriginal and 2,073 white) had similar mean +/- SD symptom duration (179 +/- 91 days), 28-joint Disease Activity Scores (DAS28; 4.87 +/- 1.48), and Health Assessment Questionnaire (0.88 +/- 0.68) scores. Factors associated with poor prognosis were more frequently present in Aboriginal participants, but disease-modifying therapy selection and frequency of therapy escalation was similar between the 2 groups. DAS28 remission was achieved less frequently in Aboriginal than in white participants (adjusted odds ratio 0.39 [95% confidence interval 0.25-0.62]). Results were primarily driven by slower improvement in swollen joint counts and nonsignificant improvement in patient global scores in Aboriginal participants. Pain levels remained higher in Aboriginal patients. CONCLUSION: Aboriginal early RA patients experienced worse disease outcomes than their white counterparts. This may reflect unmeasured biologic differences and/or disparities in prognostic factors informed by inequities in determinants of health. The appropriateness of current treatment strategies applied in different contexts should be considered. PMID- 29125905 TI - Arthritis After Cancer Immunotherapy: Symptom Duration and Treatment Response. AB - OBJECTIVE: Musculoskeletal manifestations of immune-related adverse events (irAEs) after checkpoint inhibitor immunotherapy for cancer remain incompletely characterized and poorly understood. A recently published case series suggested that immunotherapy-induced arthritis is an aggressive process requiring high-dose corticosteroids. METHODS: This was a retrospective chart review of all patients with musculoskeletal irAEs first seen by one of the authors between 2014 and 2016. All patients had been treated for a malignancy with immune checkpoint inhibitors targeting PD-1 (nivolumab, pembrolizumab), PD-L1 (durvalumab), and/or CTLA-4 (ipilimumab, tremelimumab) at Memorial Sloan Kettering Cancer Center. RESULTS: We identified 10 patients with a mean +/- SD age of 63.2 +/- 9.7 years. Seven were treated with a combination of checkpoint inhibitors and 3 with nivolumab monotherapy. Four patients developed inflammatory polyarthritis, 4 oligoarthritis, and 2 tenosynovitis. Six were antinuclear antibody positive and 2 had anti-cyclic citrullinated peptide antibodies. Mean +/- SD time from the first dose of immunotherapy until joint involvement was 6.3 +/- 4.3 months. All 10 patients were treated with systemic corticosteroids, but 6 of 10 required <=20 mg per day of prednisone. Five patients received steroid-sparing agents. Mean +/- SD time until resolution of joint symptoms after the last dose of immunotherapy was 9.2 +/- 6.1 months. CONCLUSION: Musculoskeletal irAEs can manifest as a rheumatoid arthritis-like polyarthritis, oligoarthritis, tenosynovitis, or polymyalgia rheumatica. Musculoskeletal symptoms can last more than a year, but they can generally be managed with low to moderate doses of corticosteroids. PMID- 29125906 TI - Narrative Review of the Educational, Vocational, and Financial Needs of Adolescents and Young Adults with Cancer: Recommendations for Support and Research. AB - Adolescents and young adults (AYAs) with cancer have unique needs around education and vocation during and after treatment. This narrative review series aims at documenting the unique needs of AYAs from the current literature and at providing recommendations to inform an update of the Australian National Service Delivery Framework for AYAs with Cancer. AYAs with cancer may experience impairments to cognitive, physical, and psychological functioning and health, which can adversely affect their academic grades, peer relationships, and likelihood of entering the workforce. Treatment expenses and time off work can stifle AYAs' financial independence from their parents. The combined effect of disrupted education, vocation, and financial dependence can reduce AYAs' sense of identity. Although support is available in some countries, support efficacy is yet to be clearly established. Continued research is required to deliver successful education and work reintegration programs that build the confidence of AYAs with cancer to achieve their best. Educational and vocational support, as well as financial advice, may improve AYAs' financial security and quality of life during survivorship. PMID- 29125907 TI - Risk of Type 2 Diabetes Mellitus Development in the Native Population of Low- and High-Altitude Regions of Kyrgyzstan: Finnish Diabetes Risc Score Questionnaire Results. AB - : Moldobaeva, Marina S., Anastasiya V. Vinogradova, and Marina K. Esenamanova. Risk of type 2 diabetes mellitus development in the native population of low- and high-altitude regions of Kyrgyzstan: Finnish Diabetes Risc Score questionnaire results. High Alt Med Biol. 18:428-435, 2017. OBJECTIVE: The number of patients with diabetes is steadily growing, but likely only half of all cases are ever identified. The Kyrgyz, native inhabitants of Central Asia, live in the mountainous area and have a particular lifestyle and nutrition. However, the risk of type 2 diabetes mellitus (T2DM) in our population is not well defined. Therefore, we aimed at determining the risk of T2DM development in the Kyrgyz population residing in low- and high-altitude (HAlt) regions by using the Finnish Diabetes Risc Score (FINDRISC) questionnaire. METHODS: We included in the study 3190 randomly selected participants, including 1780 low-altitude (LAlt) residents (Chu region, 500-1200 m) and 1410 HAlt residents (Naryn region, 2000-4500 m), among whom there were 1207 men and 1983 women. Assessment of T2DM development was conducted by using the FINDRISC questionnaire and risk stratification was performed by region of residency, gender, and age. RESULTS: An irregular intake of vegetables and fruits, increased waist circumference (WC), and increased body mass index (BMI) were identified as leading risk factors of T2DM development in native residents of Chu and Naryn regions of Kyrgyzstan. The 10-year risk stratification of T2DM development revealed the absence of a very high-risk group; high-risk status was more frequently identified among residents of the LAlt Chu district (4.7% of women and 2.1% of men), as compared with the HAlt population (1.9% of women and 1% of men) (p = 0.0018 for women and p = 0.09 for men). CONCLUSIONS: In the Kyrgyz population, a 10-year high risk of T2DM development is greater among residents of LAlts as compared with HAlts, irrespective of gender. No very high-risk group was detected in residents of low or HAlts. The leading composites of FINDRISC score are increased WC and BMI, possibly due to irregular intake of vegetables and fruits that are dependent on the altitude of residence and age. PMID- 29125908 TI - Transgender Medicare Beneficiaries and Chronic Conditions: Exploring Fee-for Service Claims Data. AB - PURPOSE: Data on the health and well-being of the transgender population are limited. However, using claims data we can identify transgender Medicare beneficiaries (TMBs) with high confidence. We seek to describe the TMB population and provide comparisons of chronic disease burden between TMBs and cisgender Medicare beneficiaries (CMBs), thus laying a foundation for national level TMB health disparity research. METHODS: Using a previously validated claims algorithm based on ICD-9-CM codes relating to transsexualism and gender identity disorder, we identified a cohort of TMBs using Medicare Fee-for-Service (FFS) claims data. We then describe the demographic characteristics and chronic disease burden of TMBs (N = 7454) and CMBs (N = 39,136,229). RESULTS: Compared to CMBs, a greater observed proportion of TMBs are young (under age 65) and Black, although these differences vary by entitlement. Regardless of entitlement, TMBs have more chronic conditions than CMBs, and more TMBs have been diagnosed with asthma, autism spectrum disorder, chronic obstructive pulmonary disease, depression, hepatitis, HIV, schizophrenia, and substance use disorders. TMBs also have higher observed rates of potentially disabling mental health and neurological/chronic pain conditions, as well as obesity and other liver conditions (nonhepatitis), compared to CMBs. CONCLUSION: This is the first systematic look at chronic disease burden in the transgender population using Medicare FFS claims data. We found that TMBs experience multiple chronic conditions at higher rates than CMBs, regardless of Medicare entitlement. TMBs under age 65 show an already heavy chronic disease burden which will only be exacerbated with age. PMID- 29125910 TI - Real Time Care. PMID- 29125909 TI - Calcium Phosphate Microspheres as a Delivery Vehicle for Tooth-Bleaching Agents. AB - Bleaching of vital teeth has become common practice in cosmetic dentistry today. Tooth sensitivity and demineralization of the enamel are, however, common side effects associated with hydrogen and carbamide peroxide bleaching. This study investigated if calcium phosphate microspheres, which have remineralizing properties, could be used as an additive without hindering the diffusion of the bleaching agent and if the spheres could be used as a carrier for carbamide peroxide. A remineralizing agent could increase the safety of bleaching and decrease the severity of its side effects. Comparisons between current hydrogen peroxide diffusion studies and previously published work are difficult since many studies include challenging-to-replicate conditions or lack reporting of important parameters. Hence, a diffusion model was designed by Wu Lab (School of Dentistry, University of California, Los Angeles) to measure the diffusion flux and determine the diffusivity of hydrogen peroxide. Physical parameters (e.g., diffusivity) could then be used for direct comparison to the results obtained by future studies. Three whitening gels with increasing amounts of spheres were formulated and tested with 2 commercially available whitening gels. The flux of hydrogen peroxide through 1-mm discs of bovine enamel was measured at steady state conditions, and the diffusivity was calculated. The results showed that the spheres could be used as a carrier for carbamide peroxide and that the amount of spheres did not affect the diffusivity of peroxide through the enamel discs. Hence, the microspheres are considered promising as an additive to minimize side effects in bleaching gel formulation. PMID- 29125911 TI - 5-Lipoxygenase Knockout Aggravated Apical Periodontitis in a Murine Model. AB - 5-Lipoxygenase (5-LO) plays a vital role in the host innate immune response, including bacteria-induced inflammation. Apical periodontitis (AP) is due to immune disorders caused by imbalances between bacterial invasion and subsequent host defense response. In this work, we investigated the role of 5-lipoxygenase in AP by using 5- lo knockout mice (5- lo-/- mice). Results showed that 5- lo-/- mice had greater periapical bone loss and more osteoclasts positive for tartrate resistant acid phosphatase staining than did wild-type mice, as determined by micro-computed tomography and histologic staining. The inflammation- and osteoclastogenesis-related factors IL-1beta, TNF-alpha, RANK, and RANKL were also significantly elevated in 5- lo-/- mice, whereas osteoprotegerin was reduced. Furthermore, peritoneal macrophages from 5- lo-/- mice revealed an obviously impaired ability to phagocytose the AP pathogenic bacteria Fusobacterium nucleatum. In vivo experiments confirmed that 5- lo knockout led to decreased macrophage recruitment and increased F. nucleatum infection around the periapical area due to decreased leukotriene B4 and LXA4 production. All these results showed that 5- lo knockout impaired the host innate immune system to promote the release of bone resorption-related factors. Therefore, 5- lo deficiency aggravated AP in an experimental murine AP model. PMID- 29125912 TI - An In Vitro Examination of the Effects of Altitude on Dry Powder Inhaler Performance. AB - BACKGROUND: The effects of altitude on dry powder inhaler (DPI) performance remain understudied. As existing standardized testing methodologies do not consider altitude, inhalation devices may be used in environments in which their performance has not been sufficiently characterized. METHODS: Six DPIs spanning a range of device resistances were examined in vitro in an environmental chamber mimicking a high-altitude environment equivalent to an altitude of 4200 m, with controls established at an altitude of 700 m. Deposition and size distribution data were quantified by using an Alberta Idealized Throat coupled to a Next Generation Impactor, operated by using a square inhalation profile. Controls were established for two cases, one with a standard pressure drop and the other with a minimal efficacious flowrate. Experiments at simulated altitude were performed first by using a matched volumetric flowrate and second with a matched pressure drop, corresponding to values obtained in the controls. In vitro results were input into a lung deposition model to examine the relationship between particle size distributions, inhalation flowrates, and regional deposition in the respiratory tract. RESULTS AND CONCLUSIONS: Simulated altitude caused statistically significant effects in some DPIs, but effects were variable, device dependent, and relatively minor. Medium-high resistance devices were more affected by the flowrate used to establish the control than by any effects of altitude. Patients able to generate sufficient inspiratory efforts can expect relatively consistent device performance at altitudes up to 4200 m for the devices examined here. PMID- 29125913 TI - Standardized Kaempferia parviflora Extract Enhances Exercise Performance Through Activation of Mitochondrial Biogenesis. AB - Exercise enhances mitochondrial biogenesis in skeletal muscle. Increased mitochondrial function and content can contribute to the improvement in skeletal muscle function and the benefits of exercise by increasing the response to energy demands. The effect of standardized Kaempferia parviflora extract (KPE) on exercise performance was accessed in L6 myotubes and C57BL/6J mice. KPE significantly activated peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and increased mitochondrial density in L6 myotubes. KPE also upregulated the expression of transcription factors for mitochondrial biogenesis (estrogen-related receptor-alpha [ERRalpha], nuclear respiratory factor-1 [NRF-1], and mitochondrial transcription factor A [Tfam]) through activation of PGC-1alpha in L6 myotubes. In vivo models including normal diet mice and high-fat diet obese mice showed that KPE effectively enhanced running endurance and increased the skeletal muscle weight/body weight ratio. Furthermore, these observations were associated with a significant upregulation of mitochondrial biogenesis regulatory genes in skeletal muscle tissue. KPE enhanced the protein expression of the sirtuin 1 (SIRT1)/adenosine monophosphate (AMP)-activated protein kinase (AMPK)/PGC-1alpha/peroxisome proliferator activated receptor-delta (PPARdelta) signaling pathway components in vitro and in vivo, acting as an exercise metabolism regulator. These results suggest that KPE has the potential to enhance exercise performance through mitochondrial biogenesis and the SIRT1/AMPK/PGC-1alpha/PPARdelta signaling pathways. PMID- 29125914 TI - Putting Culture in the Middle in Judging Scholarly Merit. AB - I discuss the critical importance of putting culture in the middle in judging scholarly merit in psychological science. I describe the challenges in evaluating cultural research, pointing out the various ways that ethnocentric judgments undermine the scientific merit of cultural research and the consequences of the marginalization of culture in psychological science and practice. In spite of the obstacles, cultural psychologists have made major scientific contributions and achieved scientific eminence. I further suggest that we raise the bar by including a broad, cultural approach to research as one basis for judging scientific contributions. I propose that to put culture in the middle, the evaluation of scholarly merit in psychological science should (a) consider the integration of cultural perspectives in research as a critical indicator, (b) take into consideration the international visibility of scholarship, PMID- 29125915 TI - A pilot study investigating reactive oxygen species production in capillary blood after a marathon and the influence of an antioxidant-rich beetroot juice. AB - We report that reactive oxygen species (ROS), as measured in capillary blood taken from the finger-tip, increased after a marathon (+128% P < 0.01; effect size = 1.17), indicating that this collection method might be useful for measuring ROS in field settings. However, mitochondrial DNA damage remained unchanged. Beetroot juice, taken before and after exercise, was unable to mitigate exercise-induced ROS production, questioning its use an antioxidant-rich food. PMID- 29125917 TI - Silent Soundings: Hearing the Hospice Call. PMID- 29125918 TI - In Vitro Characterization of the eFlow Closed System Nebulizer with Glycopyrrolate Inhalation Solution. AB - BACKGROUND: Glycopyrrolate administered by a novel, investigational eFlow(r) Closed System (CS) nebulizer (eFlow CS) is being evaluated for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The eFlow CS is a hand held, vibrating membrane nebulizer optimized to deliver 1 mL of glycopyrrolate solution into the lung in <3 minutes. Clinical studies have shown improvements in lung function of subjects treated with nebulized glycopyrrolate. METHODS: The aerosol performance of the eFlow CS nebulizer was characterized by delivered dose, aerodynamic droplet size distribution and nebulization time. Simulated use nebulizer performance over 60 days was assessed by volume median diameter (VMD), nebulized amount, and nebulization time. Nebulization outputs were assayed to ensure adequate delivery of glycopyrrolate with an acceptable impurity profile. Aerosol condensates were analyzed for glycopyrrolate concentration and impurities by ultra-high-performance liquid chromatography and compared with non-nebulized samples. RESULTS: The mean mass median aerodynamic diameter, geometric standard deviation, and fine particle fraction were 3.7 MUm, 1.7, and 72%, respectively, and independent of formulation strength (25 and 50 MUg/mL). Delivered dose was 88% of the nominal dose for both formulation strengths. The mean delivered dose, assessed by breathing simulation, was 56.8% for 25 MUg/mL and 62.6% for 50 MUg/mL. Nebulization times were 1-2.5 minutes with no apparent increasing trend with use over a 60-day period. The nebulized amount showed no significant changes, whereas the VMD showed a slight, but not pharmaceutically relevant, increase (0.1-0.2 MUm) after 60-day simulated use. Glycopyrrolate concentration and impurity levels of nebulized samples were statistically similar to those of non-nebulized samples. CONCLUSION: The eFlow CS generates glycopyrrolate aerosols with high delivered dose, short treatment time, and small droplet size with narrow size distribution suitable for central and peripheral airway deposition. The unit dose vial mitigates medication misuse and ensures dose uniformity. Results support the use of glycopyrrolate/eFlow CS for the treatment of COPD. PMID- 29125919 TI - Autologous Chondrocyte Implantation "Sandwich" Technique Compared With Autologous Bone Grafting for Deep Osteochondral Lesions in the Knee. AB - BACKGROUND: Treating symptomatic osteochondral defects is challenging, especially in young adults with deep (>8-10 mm) empty defects after osteochondritis dissecans (OCD) or collapsed condyles secondary to avascular necrosis (AVN). For this population, osteoarthritis (OA) is inevitable if articular congruence is not restored. PURPOSE: To describe the autologous chondrocyte implantation (ACI) "sandwich" technique with autologous bone grafting (ABG) and compare it with ABG alone for restoration of the osteochondral unit. The midterm to long-term outcomes in patients after the treatment for OCD and AVN will be reported and compared. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The outcomes for a consecutive cohort of 24 patients who underwent combined ABG with the ACI sandwich technique between 2001 and 2013 (ACI sandwich group) was compared with a historical control group of 17 consecutive patients who underwent ABG alone between 1995 and 2002 (ABG group) by a single surgeon for symptomatic deep (>8 mm) osteochondral lesions. Patients who were followed up with a minimum of 2 years were included in this study. The modified Cincinnati Knee Rating System, the Western Ontario and McMaster Universities Osteoarthritis Index, a visual analog scale (VAS), the Short Form-36, and a patient satisfaction survey were used to evaluate clinical outcomes. Survival analysis was performed using the Kaplan-Meier method, with no clinical improvement, graft failure, or conversion to prosthetic arthroplasty as the endpoint (failure). Kellgren-Lawrence (K-L) grading to assess OA progression was also performed. RESULTS: In the ABG group, 13 of 17 patients (76%) were available with a mean follow-up of 15.7 years postoperatively (range, 5-21 years). In the ACI sandwich group, all 24 patients were available with a mean follow-up of 7.8 years postoperatively (range, 2-15 years). No significant differences were observed between the groups in terms of age, sex, side of the operated knee, body mass index, lesion type, lesion size, lesion depth, lesion location, or the need for realignment osteotomy. Eight patients (62%) were considered failures in the ABG group, while 3 patients (13%) were considered failures in the ACI sandwich group. The survival rate was significantly better in the ACI sandwich group than the ABG group (87% vs 54% at 5 years, respectively; P = .0025). All functional scores in patients with retained grafts significantly improved in the ACI sandwich group, whereas only the VAS score showed significant improvement in the ABG group. The patient satisfaction survey showed a very high satisfaction rate in the ACI sandwich group, with over 90% of patients reporting their knees as good or excellent and being satisfied with the procedure. In the ACI sandwich group, K-L grading demonstrated no significant OA progression from preoperatively to a mean 5.1 years postoperatively. CONCLUSION: Our study showed that the ACI sandwich technique provided excellent and superior survival rates compared to ABG alone and significant improvements over midterm to long-term follow-up. This unique treatment offers native joint preservation for conditions that naturally will progress to OA and eventually require prosthetic arthroplasty. PMID- 29125916 TI - Histomorphological and Molecular Assessments of the Fixation Times Comparing Formalin and Ethanol-Based Fixatives. AB - The lack of standardization of tissue handling and processing hinders the development and validation of new biomarkers in research and clinical settings. We compared the histomorphology and the quality and quantity of biomolecules in paraffin-embedded mouse tissues, followed by fixation with neutral buffered formalin (NBF), 70% ethanol, and buffered ethanol (BE70) fixative. The quality of the histomorphology and immunohistochemistry in BE70 was relatively time independent, whereas those in NBF rapidly decreased after 1 week of fixation. Protein recovered from tissue fixed in 70% ethanol and BE70 was compatible with Western blot and protein array using AKT and GAPDH antibodies, regardless of the fixation time. In addition, the quality and quantity of RNA extracted from tissue in ethanol-based fixative showed minimal changes from 4 hr to 6 months, whereas NBF had a dramatic detrimental change in RNA quality after 1 week of fixation. Furthermore, ethanol-based fixative offers a superior DNA template for PCR amplification-based molecular assays than NBF. In conclusion, coagulative, ethanol-based fixatives show a broader time spectrum than the aldehyde crosslinking fixative NBF in their histomorphological features and the quantity and quality of the biomolecules from paraffin-embedded tissue, and they may facilitate the use of fixative-fixed paraffin-embedded tissues in research and clinical laboratories, avoiding overfixation. PMID- 29125920 TI - Frontal Plane Knee Mechanics and Early Cartilage Degeneration in People With Anterior Cruciate Ligament Reconstruction: A Longitudinal Study. AB - BACKGROUND: Abnormal frontal plane gait mechanics are known risk factors for knee osteoarthritis, but their role in early cartilage degeneration after anterior cruciate ligament reconstruction (ACLR) is not well understood. Hypothesis/Purpose: The objective was to evaluate the association of frontal plane gait mechanics with medial knee cartilage magnetic resonance (MR) relaxation times over 1 year in patients with ACLR and controls. It was hypothesized that (1) there will be an increase in frontal plane medial knee loading and medial knee MR relaxation times over time in the patients with ACLR, and (2) increases in frontal plane medial knee loading will be associated with an increase in medial knee MR relaxation times. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Patients with ACLR (n = 37) underwent walking gait analyses and bilateral quantitative MR imaging (MRI) before surgery and at 6 and 12 months after ACLR. Healthy control participants (n = 13) were evaluated at baseline and 12 months. Gait variables included peak knee adduction moment (KAM), KAM impulse, and peak knee adduction angle. MRI variables included medial femur and medial tibia whole compartment and subregional T1rho and T2 relaxation times. Statistical analyses included a comparison of changes over time for gait and MRI variables, correlations between changes in gait and MRI variables over time, and differences in change in MRI variables in patients who showed an increase versus decrease in KAM impulse. RESULTS: There were significant increases in medial T1rho (Delta 4%-11%) and T2 (Delta 2%-10%) relaxation times from baseline to 6 months for both knees in the ACLR group and in KAM (Delta 13%) for the injured knee. From baseline to 6 months, patients who had an increase in KAM impulse in the injured knee had a greater increase in medial T1rho and T2 relaxation times as compared with those who did not have an increase in KAM impulse. Longitudinal changes for the control group were not significant. CONCLUSION: There is an increase in medial knee relaxation times over the first 6 months after ACLR. People with an increase in medial knee loading show an increase in medial knee relaxation times when compared with those who do not have an increase in medial knee loading over the first 6 months. PMID- 29125921 TI - Management of Anticoagulation in Patients With Prostate Cancer Receiving Enzalutamide. AB - Enzalutamide, a novel, oral androgen receptor antagonist used for the treatment of metastatic, castration-resistant prostate cancer, has been shown to improve overall and progression-free survival, prolong time to initiation of chemotherapy, reduce skeletal-related events, and carry a favorable adverse effect profile. Metastatic prostate cancer is a disease of older men, a population with an increased incidence of medical comorbidities warranting anticoagulation. Prostate cancer itself, along with some of its therapies, is also prothrombotic. Enzalutamide interacts with several anticoagulants through various mechanisms, making their concurrent use clinically challenging. As such, complex decisions about anticoagulation in these patients are frequently encountered by treating physicians. In this review, we describe the potential interactions between enzalutamide and various anticoagulants, and suggest management paradigms based on the current body of knowledge for patients with atrial fibrillation, venous thromboembolism, and mechanical heart valves. PMID- 29125922 TI - Is Prophylactic Cranial Irradiation the Standard of Care for Extensive-Stage Small-Cell Lung Cancer? PMID- 29125923 TI - Prophylactic Cranial Irradiation for Extensive Small-Cell Lung Cancer. AB - Small-cell lung cancer (SCLC) has a high predilection for metastasizing to the brain after chemotherapy. This has been blamed on the blood-brain barrier, which prevents chemotherapy from penetrating into the brain, thus creating a sanctuary site. It has been estimated that up to three quarters of patients with SCLC will eventually develop brain metastases. This led investigators to administer prophylactic cranial irradiation (PCI) to decrease this risk. Several trials were performed in patients with SCLC after initial therapy (chemotherapy with or without thoracic radiotherapy) that compared the outcomes of PCI versus no PCI. Early trials generally found that PCI significantly decreased the risk of brain metastases but did not significantly improve survival. These trials were re evaluated in two larger meta-analyses that included patients with either limited stage SCLC or extensive-stage SCLC (ESCLC). Both meta-analyses reported that PCI significantly decreased brain metastases and improved survival in patients who had a complete response following initial therapy. These studies were performed before the advent of modern imaging with computed tomography or magnetic resonance imaging (MRI). There have been two modern trials of PCI versus no PCI in patients with ESCLC and both found that PCI decreases brain metastases. The first did not include brain MRI before registration and found that PCI improved survival, whereas the second study did include MRI before registration and at frequent intervals thereafter. That trial found that PCI did not confer a survival advantage. This review will examine the evidence and provide recommendations regarding the role of PCI for patients with ESCLC. PMID- 29125924 TI - Anticoagulants Could Be a Victim of Enzalutamide. PMID- 29125925 TI - Errata. PMID- 29125926 TI - Anticoagulation and Enzalutamide: Caution Over Convenience. PMID- 29125927 TI - Errata. PMID- 29125928 TI - The Tippy Barstool of Prophylactic Cranial Irradiation. PMID- 29125929 TI - Effects of Low-Level Laser Therapy With a Herbal Extract on Alveolar Bone Healing. AB - PURPOSE: This study investigated the effect of a gallium-aluminum-arsenide (GaAlAs) diode laser used in low-level laser therapy (LLLT) with the application of Mecsina Hemostopper on mandibular alveolar bone healing. MATERIALS AND METHODS: Standard semispherical bone defects were created in left mandibular diastema sites of 32 female Long-Evans rats. Experimental animals were allocated to 1 of 4 groups: control group (no treatment), laser group (GaAlAs LLLT), Mecsina group, and laser-Mecsina combination group. Liquid Mecsina 0.01 mL was applied to the bone defects. Laser treatment was performed for 7 days after surgery at an energy dose of 10 J/cm2. All animals were sacrificed to observe hard tissue healing histologically, immunohistochemically, and radiologically at 30 days after surgery. RESULTS: Histologic assessment showed significantly more calcified tissue areas and significantly more osteoblast cells in the laser and laser-Mecsina groups than in the other groups (P < .01). Qualitative morphologic assessment showed that more bone tissue was present in the laser-Mecsina group than in the other groups. CONCLUSION: This study showed that LLLT, Mecsina application, and combined treatments were effective in healing alveolar bone among all tested treatment modalities. PMID- 29125930 TI - Primary Xanthoma of the Mandible-A Case Report. AB - Xanthomas are common cutaneous and subcutaneous lesions that occur due to altered metabolic or endocrinal function. They are found on skin and around tendon sheaths in individuals with dyslipidemias. In extremely rare cases, they can present as isolated intrabony lesions in otherwise healthy individuals. The isolated intrabony lesions are referred to as primary xanthomas. This report describes a case of an incidentally found primary xanthoma, its management, and follow-up in an otherwise healthy patient. PMID- 29125931 TI - Outcome Analysis and Unexpected-Scenario Prediction in 2-Stage Orthodontic Lower Third Molar Extraction. AB - PURPOSE: We propose a 2-stage orthodontic lower third molar extraction procedure to reduce iatrogenic inferior alveolar nerve injury. We tested our hypothesis that there are factors that can predict both dislodgement of the root portion and limited traction distances. PATIENTS AND METHODS: Fifteen patients (mean age, 25.7 years; age range, 17 to 65 years) with 20 lower third molars were enrolled. Panoramic films and cone beam computed tomography were analyzed. Dislodgement of the root portion, traction distance, duration of the orthodontic phase, and postoperative complications were documented. The predictive factors were analyzed and discussed. RESULTS: Three teeth had dislodgements of the root portion. The mean traction duration was 59.2 days (range, 33 to 77 days), and the mean traction distance was 2.60 mm (range, 0.27 to 5.20 mm). Root apex cortical bone indentation and root curvature were significantly associated with traction distance. Pulpitis symptoms were documented in 1 tooth, and no postoperative nerve disturbances occurred. CONCLUSIONS: Our proposed 2-stage orthodontic lower third molar extraction procedure reduced iatrogenic inferior alveolar nerve injury. Cortical bone indentation and root curvature predicted dislodgement of the root portion and limited traction distances. PMID- 29125932 TI - Pathogenesis of Cleft Palate in Robin Sequence: Observations From Prenatal Magnetic Resonance Imaging. AB - PURPOSE: The etiology of the palatal cleft in Robin sequence (RS) is unknown. The purpose of this study was to assess the position of the fetal tongue at prenatal magnetic resonance imaging (MRI) and to suggest a potential relation between tongue position and development of the cleft palate seen in most patients with RS. MATERIALS AND METHODS: This is a retrospective case-and-control study including fetuses with prenatal MRIs performed in the authors' center from 2002 to 2017. Inclusion criteria were 1) prenatal MRI of adequate quality, 2) liveborn infant, and 3) postnatal diagnosis of RS (Robin group) or cleft lip and palate (CLP group). Patients with postnatal RS without a palatal cleft were excluded. A control group with normal facial morphology was matched by gestational age. The outcome variable was tongue position at fetal MRI, described as within the cleft, along the floor of the mouth (normal), other, or indeterminate. RESULTS: One hundred twenty-two patients with mean gestational age at MRI of 25.8 +/- 4.9 weeks were included (Robin, n = 21 [17%]; CLP, n = 47 [39%]; control, n = 54 [44%]). The tongue was visualized within the palatal cleft in 76.2% of the Robin group and 4.3% of the CLP group. The tongue was found along the floor of the mouth (normal) in the remainder of the Robin and CLP groups and in 100% of the control group. CONCLUSION: These findings suggest a relation between in utero tongue position and the development of cleft palate in RS. PMID- 29125933 TI - Can Use of Rigid Fixation After Consolidation Increase Stability in Cleft Patients Following Distraction Osteogenesis? AB - PURPOSE: The stability of distraction osteogenesis (DO) is an important issue in maxillary advancement for patients with cleft lip and palate (CLP). The aim of this study was to evaluate postoperative stability in patients with and without internal fixation after removing maxillary distraction devices. MATERIALS AND METHODS: This randomized clinical trial assessed patients with CLP who needed maxillary advancement greater than 6 mm; they were randomly assigned to 1 of 2 groups. In group 1, distraction devices were removed 3 months after distraction and then 4 L miniplates were placed bilaterally in the maxilla. In group 2 (controls), no miniplates were placed after removing the distraction devices. Lateral cephalograms taken on 3 occasions (preoperatively, immediately after removing the distraction device, and after 18 months) were used to determine vertical and horizontal changes at the A point. RESULTS: Twenty-two patients (n = 11 per group) were included. There was no significant difference between groups for horizontal relapse (P = .79). The results showed no significant difference for vertical relapse between the 2 groups (P = .11). The Pearson correlation test showed a correlation between the amount of advancement and horizontal relapse at the A point in group 1 (P = .01) and group 2 (P = .001). In group 1, for every 1 mm maxillary advancement, a 0.36-mm relapse was seen (B = 0.36, P = .01). In group 2, for every 1-mm maxillary advancement, a 0.43-mm relapse was seen (B = 0.43, P = .001). CONCLUSION: According to these results, rigid fixation after consolidation did not increase stability in patients with CLP after DO. PMID- 29125934 TI - Bringing urban governance back in: Neighborhood conflicts and depression. AB - Urban governance and its impact on contentious politics have received remarkably little attention in existing studies on mental health. Drawing on a measure of neighborhood conflicts developed in a survey of thirty-nine urban neighborhoods in Guangzhou, China, this article investigates the potential link between urban governance and mental health. Net of sociodemographic, relational, and environmental measures, it finds that among residents' conflicts with different entities of urban governance, only those with local/grassroots governments are significantly associated with more depressive symptoms. Moreover, these subgroups of government-oriented conflicts associated with more depressive symptoms are related to neighborhood planning and communal properties, reflecting a dilemma in the Chinese model of urban governance. By offering a relational interpretation of neighborhood conflicts, this study not only challenges the previous view that community building in China improves mental health, but calls attention to the significance of urban governance in research on mental health. PMID- 29125935 TI - Going viral in PNG - Exploring routes and circumstances of entry of a rabies infected dog into Papua New Guinea. AB - In this qualitative study implemented in November 2016, we elicited narratives about fictional rabies incursions from key employees (n = 16) of the National Agriculture and Quarantine Inspection Authority in Papua New Guinea (PNG) to explore the potential circumstances and routes of entry of a rabies-infected dog, and direct rabies preparedness. Although PNG is rabies free, proximity to rabies endemic Indonesia poses a risk of introduction and it is expected that an outbreak in PNG would have devastating human health impacts consistent with other countries with similarly low human development indices and abundant free-roaming dogs. Participants used their local and professional knowledge to create plausible narratives in response to contextual, but fictitious, newspaper stories. An ethnographic content analysis was used to extract themes and interpret the narratives. Themes were assessed in the context of their potential influence on rabies preparedness in PNG against the social and political background of PNG and relevant, published literature. Consistent themes included the ubiquity of trade and the complexity of routes between Indonesia and PNG. Dog ownership seemed pragmatic - actors in the narratives readily and rationally involved dogs in transactions in response to trade, exchange or gifting opportunities. Consequently, dogs changed ownership frequently. The findings of this study have important implications for rabies preparedness in PNG; there is potential for wide geographic dissemination of rabies in dogs before outbreak detection. However, common patterns of travel - trade of dogs via Papuan towns and use of traditional trade routes - do provide opportunity for targeted surveillance and response in the event of an incursion. PMID- 29125937 TI - Novel Specificity of IDO Enzyme Involved in the Biosynthesis of Mating Pheromone in the Ciliate Blepharisma stoltei. AB - Mating pheromones (gamone 1 and gamone 2) in the ciliate Blepharisma are biologically active substances that trigger sexual reproduction (conjugation) under starvation conditions. Gamone 1 is a glycoprotein secreted by type I cells, and gamone 2 is a tryptophan (Trp)-derivative compound secreted by type II cells. Both gamones stimulate complementary mating type cells to promote each gamone production and induce pair formation. To elucidate the biosynthetic pathway of gamone 2, we investigated the enzymes involved in the pathway and the specificity of the enzymes. An RNA-seq analysis revealed that Blepharisma stoltei (Heterotrichea) possesses four indoleamine 2,3-dioxygenase (IDO) genes showing distinct expression patterns. Along with results from real-time PCR, these findings demonstrated that each IDO gene has different expression patterns that depend on the cellular conditions. Expression of IDO-I was correlated with the intensity of gamone 2 expression, and the recombinant IDO-I protein showed catalytic activity for 5-hydroxy-L-Trp (5-HTP) but very weak activity for L-Trp. Our results indicate that IDO-I is an enzyme evolutionary specialized to gamone 2 production in Blepharisma, and that the biosynthetic pathway for gamone 2 uses 5 HTP as an intermediate. PMID- 29125938 TI - New aspects of RNA-based regulation by Hfq and its partner sRNAs. AB - Hfq, an RNA chaperone, promotes the pairing of small RNAs (sRNAs) to target mRNAs, mediating post-transcriptional regulation of mRNA stability and translation. This regulation contributes to bacterial adaptation during stress and pathogenesis. Recent advances in sequencing techniques demonstrate the presence of sRNAs encoded not only in intergenic regions but also from the 3' and 5' UTRs of mRNAs, expanding sRNA regulatory networks. Additional layers of regulation by Hfq and its associated RNAs continue to be found. Newly identified RNA sponges modulate the activity of some sRNAs. A subset of sRNAs are proving to be bifunctional, able to pair with targets and also encoding small ORFs or binding other RNA binding proteins, such as CsrA. In addition, there are accumulating examples of Hfq inhibiting mRNA translation in the absence of sRNAs. PMID- 29125936 TI - A ravenous defense: canonical and non-canonical autophagy in immunity. AB - While classically considered a survival mechanism employed during nutrient scarcity, the autophagy pathway operates in multiple scenarios wherein a return to homeostasis or degradative removal of an invader is required. Now recognized as a pathway with vast immunoregulatory power, autophagy can no longer serve as a 'one size fits all' term, as its machinery can be recruited to different pathogens, at different times, with different outcomes. Both canonical autophagy and the molecularly related, yet divergent pathways non-canonical autophagy are key players in proper host defense and allow us an opportunity to tailor infectious disease intervention and treatment to its specific pathway. PMID- 29125939 TI - Regulation of microbial growth by turgor pressure. AB - Rapid changes in environmental osmolarity are a natural aspect of microbial lifestyles. The change in turgor pressure resulting from an osmotic shock alters the mechanical forces within the cell envelope, and can impact cell growth across a range of timescales, through a variety of mechanical mechanisms. Here, we first summarize measurements of turgor pressure in various organisms. We then review how the combination of microfluidic flow cells and quantitative image analysis has driven discovery of the diverse ways in which turgor pressure mechanically regulates bacterial growth, independent of the effect of cytoplasmic crowding. In Gram-positive, rod-shaped bacteria, reductions in turgor pressure cause decreased growth rate. Moreover, a hypoosmotic shock, which increases turgor pressure and membrane tension, leads to transient inhibition of cell-wall growth via electrical depolarization. By contrast, Gram-negative Escherichia coli is remarkably insensitive to changes in turgor. We discuss the extent to which turgor pressure impacts processes such as cell division that alter cell shape, in particular that turgor facilitates millisecond-scale daughter-cell separation in many Actinobacteria and eukaryotic fission yeast. This diverse set of responses showcases the potential for using osmotic shocks to interrogate how mechanical perturbations affect cellular processes. PMID- 29125940 TI - Overcoming the energetic limitations of syngas fermentation. AB - The fermentation of synthesis gas (including carbon monoxide, carbon dioxide, and hydrogen) with anaerobic acetogens is an established biotechnological process that has recently been transferred to a commercial scale. The natural product spectrum of acetogens is natively restricted to acetate, ethanol, and 2,3 butanediol but is rapidly expanding to heterologous products. Syngas fermentation can achieve high carbon-efficiencies; however, the underlying metabolism is operating at a thermodynamic limit. This necessitates special enzymatic properties for energy conservation by acetogens. Therefore, the availability of cellular energy is considered to restrain the efficient production of energy intense products with complex production pathways. The optimization of the feed gas composition and other process parameters, genetic engineering, and integration with other biotechnologies is required to overcome this limitation. PMID- 29125941 TI - Epitranscriptomics: regulation of mRNA metabolism through modifications. AB - Cellular RNAs can be modified post-transcriptionally with dynamic and reversible chemical modifications. These modifications can alter the structure and metabolism of mRNA, but only recent methodological and conceptual advances allowed systematic mapping and functional analysis to unfold the role they play in mRNA biology. Mapping the most common internal mRNA modification, N6 methyladenosine (m6A), paved the way for the deciphering of other types of mRNA modifications, such as N1-methyladenosine (m1A). RNA methylation provides dynamic regulation to the processing, export, translation and stability of mRNA molecules, thereby influencing fundamental biological and pathological processes such as differentiation, cellular response to stress and tumorigenesis. This review summarizes the key methods and the recent discoveries in the field of epitranscriptomics through the prism of post-transcriptional mRNA methylation in eukaryotes. PMID- 29125943 TI - Effects of chilled and frozen storage conditions on the lamb M. longissimus lumborum fatty acid and lipid oxidation parameters. AB - This study investigated the effects of chilled and frozen storage conditions on the fatty acid profile and lipid oxidation in lamb M. longissimus lumborum (LL). Muscle LL (n=360) were randomly selected at 24h post-mortem from a commercial Australian abattoir and maintained chilled for five periods (0, 2, 4, 6 and 8weeks) followed by frozen for six periods (0, 4, 8, 12, 24 and 52weeks) at -12 degrees C or -18 degrees C. Samples were analysed for fatty acid profile and lipid oxidative parameters (TBARS, oxidation-reduction potential and peroxidase activity). Health-claimable polyunsaturated fatty acids (EPA and DHA) were unaffected by neither storage period nor temperature. TBARS levels did not exceed rancidity thresholds recommended in the literature, with these and other lipid peroxidation parameters showing broad increases in concentration with more 'long term' chilled and frozen storage periods. Combined, the results suggest nutritional and eating quality were maintained across the various chilled and frozen storage conditions applied in this study. PMID- 29125942 TI - Conditions for addressing environmental determinants of health behavior in intersectoral policy networks: A fuzzy set Qualitative Comparative Analysis. AB - Improving health requires changes in the social, physical, economic and political determinants of health behavior. For the realization of policies that address these environmental determinants, intersectoral policy networks are considered necessary for the pooling of resources to implement different policy instruments. However, such network diversity may increase network complexity and therefore hamper network performance. Network complexity may be reduced by network management and the provision of financial resources. This study examined whether network diversity - amidst the other conditions - is indeed needed to address environmental determinants of health behavior. We included 25 intersectoral policy networks in Dutch municipalities aimed at reducing overweight, smoking, and alcohol/drugs abuse. For our fuzzy set Qualitative Comparative Analysis we used data from three web-based surveys among (a) project leaders regarding network diversity and size (n = 38); (b) project leaders and project partners regarding management (n = 278); and (c) implementation professionals regarding types of environmental determinants addressed (n = 137). Data on budgets were retrieved from project application forms. Contrary to their intentions, most policy networks typically addressed personal determinants. If the environment was addressed too, it was mostly the social environment. To address environmental determinants of health behavior, network diversity (>50% of the actors are non public health) was necessary in networks that were either small (<16 actors) or had small budgets ( micronutrients > macronutrients. In particular, the spring area showed high K concentrations, as well as high concentrations of several micronutrients and toxic elements. A generalized Zn contamination and a progressive macronutrient (above all Ca and P), micronutrient (above all Ni, Cu and Fe) and toxic element (above all Cr and Pb) accumulation toward the mouth was related to pollution from agricultural and urban activities. Industrial sources, especially tanneries along the Solofrana tributary, accounted for high Mn concentrations, whereas the volcanic origin of the substrate accounted for a generalized V contamination. PMID- 29125956 TI - Ecotoxic potential of a presumably non-toxic azo dye. AB - Microbes have potential to convert non-toxic azo dyes into hazardous products in the environment. However, the role of microbes in biotransforming such presumably non-toxic dyes has not been given proper attention, thereby, questions the environmental safety of such compounds. The present study assessed salinity driven microbial degradation of an unregulated azo dye, Acid orange 7 (AO7), under moderately halophilic conditions of textile effluent. The halophilic microbial consortium from effluent decolorized ~97% AO7 (50-500mgL-1). The consortium efficiently decolorized the dye at different pH (5-8) and salinity (5 18% NaCl). The 16S rRNA sequence analyses confirmed the presence of Halomonas and Escherichia in the consortium. The FTIR and GC-MS analyses suggested microbial consortium degrade AO7 following symmetric and asymmetric cleavage and yield carcinogenic/mutagenic aromatic byproducts viz. aniline, 1-amino-2-naphthol, naphthalene, and phenyldiazene. In contrast to AO7, the biodegraded products caused molecular, cellular and organism level toxicity. The degraded products significantly reduced: radicle length in root elongation assay; shoot length/biomass in plant growth assays; and caused chromosomal abnormalities and reduced mitotic index in Allium cepa bioassay. We demonstrated that under saline conditions of textile effluent, halophilic microbes convert a presumably non toxic azo dye into hazardous products. The study calls to review the current toxicity classification of azo dyes and develop environmentally sound regulatory policies by incorporating the role of environmental factors in governing dye toxicity, for environmental safety. PMID- 29125957 TI - A network perspective on comorbid depression in adolescents with obsessive compulsive disorder. AB - People with obsessive-compulsive disorder [OCD] frequently suffer from depression, a comorbidity associated with greater symptom severity and suicide risk. We examined the associations between OCD and depression symptoms in 87 adolescents with primary OCD. We computed an association network, a graphical LASSO, and a directed acyclic graph (DAG) to model symptom interactions. Models showed OCD and depression as separate syndromes linked by bridge symptoms. Bridges between the two disorders emerged between obsessional problems in the OCD syndrome, and guilt, concentration problems, and sadness in the depression syndrome. A directed network indicated that OCD symptoms directionally precede depression symptoms. Concentration impairment emerged as a highly central node that may be distinctive to adolescents. We conclude that the network approach to mental disorders provides a new way to understand the etiology and maintenance of comorbid OCD-depression. Network analysis can improve research and treatment of mental disorder comorbidities by generating hypotheses concerning potential causal symptom structures and by identifying symptoms that may bridge disorders. PMID- 29125958 TI - Investigation of brain science and neurological/psychiatric disorders using genetically modified non-human primates. AB - Although mice have been the most frequently used experimental animals in many research fields due to well-established gene manipulation techniques, recent evidence has revealed that rodent models do not always recapitulate pathophysiology of human neurological and psychiatric diseases due to the differences between humans and rodents. The recent developments in gene manipulation of non-human primate have been attracting much attention in the biomedical research field, because non-human primates have more applicable brain structure and function than rodents. In this review, we summarize recent progress on genetically-modified non-human primates including transgenic and knockout animals using genome editing technology. PMID- 29125959 TI - Proximity labeling: spatially resolved proteomic mapping for neurobiology. AB - Understanding signaling pathways in neuroscience requires high-resolution maps of the underlying protein networks. Proximity-dependent biotinylation with engineered enzymes, in combination with mass spectrometry-based quantitative proteomics, has emerged as a powerful method to dissect molecular interactions and the localizations of endogenous proteins. Recent applications to neuroscience have provided insights into the composition of sub-synaptic structures, including the synaptic cleft and inhibitory post-synaptic density. Here we compare the different enzymes and small-molecule probes for proximity labeling in the context of cultured neurons and tissue, review existing studies, and provide technical suggestions for the in vivo application of proximity labeling. PMID- 29125961 TI - Search strategies in practice: Influence of information and task constraints. AB - The practice of a motor task has been conceptualized as a process of search through a perceptual-motor workspace. The present study investigated the influence of information and task constraints on the search strategy as reflected in the sequential relations of the outcome in a discrete movement virtual projectile task. The results showed that the relation between the changes of trial-to-trial movement outcome to performance level was dependent on the landscape of the task dynamics and the influence of inherent variability. Furthermore, the search was in a constrained parameter region of the perceptual motor workspace that depended on the task constraints. These findings show that there is not a single function of trial-to-trial change over practice but rather that local search strategies (proportional, discontinuous, constant) adapt to the level of performance and the confluence of constraints to action. PMID- 29125960 TI - Neural lineage tracing in the mammalian brain. AB - Delineating the lineage of neural cells that captures the progressive steps in their specification is fundamental to understanding brain development, organization, and function. Since the earliest days of embryology, lineage questions have been addressed with methods of increasing specificity, capacity, and resolution. Yet, a full realization of individual cell lineages remains challenging for complex systems. A recent explosion of technical advances in genome-editing and single-cell sequencing has enabled lineage analysis in an unprecedented scale, speed, and depth across different species. In this review, we discuss the application of available as well as future genetic labeling techniques for tracking neural lineages in vivo in the mammalian nervous system. PMID- 29125962 TI - Retrospective evaluation of Project Envision: A community mobilization pilot program to prevent sexual violence in New York City. AB - Sexual violence is a public health problem associated with short- and long-term physical and mental health consequences. Most interventions that aim to prevent sexual violence before it occurs target individual-level change or promote bystander training. Community-level interventions, while increasingly recommended in the sexual violence prevention field, are rarely documented in peer-reviewed literature. This paper is a targeted process evaluation of Project Envision, a 6 year pilot initiative to address social norms at the root of sexual violence through coalition building and community mobilization in three New York City neighborhoods, and reflects the perspectives of those charged with designing and implementing the program. Evaluation methods included a systematic literature review, archival source document review, and key informant interviews. Three themes emerged from the results: community identity and implications for engagement; capacity and readiness for community mobilization and consequences for implementation; and impacts on participants. Lessons learned include the limitations of using geographic boundaries to structure community interventions in urban settings; carefully considering whether communities should be mobilized around an externally-identified issue; translating theoretical frameworks into concrete tasks; assessing all coalition partners and organizations for readiness; critically evaluating available resources; and recognizing that community organizing is a skill that requires investment from funders. We conclude that Project Envision showed promise for shifting institutional norms towards addressing root causes of sexual violence in addition to providing victim services. PMID- 29125963 TI - A capillary electrophoresis method for identifying forensically relevant body fluids using miRNAs. AB - Body fluid identification (BFID) can provide crucial information during the course of an investigation. In recent years, microRNAs (miRNAs) have shown considerable body fluid specificity, are able to be co-extracted with DNA, and their small size (18-25 nucleotides) make them ideal for analyzing highly degraded forensic samples. In this study, we designed a preliminary 8-marker system for BFID including an endogenous reference gene (let-7g) to differentiate between venous blood (miR-451a and miR-142-3p), menstrual blood (miR-141-3p and miR-412-3p), semen (miR-891a and miR-10b), and saliva (miR-205) using a capillary electrophoresis approach. This panel uses a linear primer system in order to incorporate additional miRNA markers by forming a multiplex system. The miRNA system was able to distinguish between venous blood, menstrual blood, semen, and saliva using a rudimentary data interpretation strategy. All STR amplifications from co-extracted DNA yielded complete profiles from human identification purposes. PMID- 29125964 TI - Null alleles and sequence variations at primer binding sites of STR loci within multiplex typing systems. AB - Rare variants are widely observed in human genome and sequence variations at primer binding sites might impair the process of PCR amplification resulting in dropouts of alleles, named as null alleles. In this study, 5 cases from routine paternity testing using PowerPlex(r)21 System for STR genotyping were considered to harbor null alleles at TH01, FGA, D5S818, D8S1179, and D16S539, respectively. The dropout of alleles was confirmed by using alternative commercial kits AGCU Expressmarker 22 PCR amplification kit and AmpFlSTR(r). Identifiler(r) Plus Kit, and sequencing results revealed a single base variation at the primer binding site of each STR locus. Results from the collection of previous reports show that null alleles at D5S818 were frequently observed in population detected by two PowerPlex(r) typing systems and null alleles at D19S433 were mostly observed in Japanese population detected by two AmpFlSTRTM typing systems. Furthermore, the most popular mutation type appeared the transition from C to T with G to A, which might have a potential relationship with DNA methylation. Altogether, these results can provide helpful information in forensic practice to the elimination of genotyping discrepancy and the development of primer sets. PMID- 29125965 TI - Death by self-mutilation after oral cannabis consumption. AB - Major self-mutilation (amputation, castration, self-inflicted eye injuries) is frequently associated with psychiatric disorders and/or substance abuse. A 35 year-old man presented with behavioral disturbances of sudden onset after oral cannabis consumption and major self-mutilation (attempted amputation of the right arm, self-enucleation of both eyes and impalement) which resulted in death. During the enquiry, four fragments of a substance resembling cannabis resin were seized at the victim's home. Autopsy confirmed that death was related to hemorrhage following the mutilations. Toxicological findings showed cannabinoids in femoral blood (tetrahydrocannabinol (THC) 13.5 ng/mL, 11-hydroxy tetrahydrocannabinol (11-OH-THC) 4.1 ng/mL, 11-nor-9-carboxy-THC (THC-COOH) 14.7 ng/mL, cannabidiol (CBD) 1.3 ng/mL, cannabinol (CBN) 0.7 ng/mL). Cannabinoid concentrations in hair (1.5 cm brown hair strand/1 segment) were consistent with concentrations measured in chronic users (THC 137 pg/mg, 11-OH-THC 1 pg/mg, CBD 9 pg/mg, CBN 94 pg/mg). Analysis of the fragments seized confirmed that this was cannabis resin with high levels of THC (31-35%). We discuss the implications of oral consumption of cannabis with a very high THC content. PMID- 29125966 TI - Stopping and slowing manual and spoken responses: Similar oscillatory signatures recorded from the subthalamic nucleus. AB - Response control in the forms of stopping and slowing responses is thought to be implemented by a frontal-subcortical network, which includes the subthalamic nucleus (STN). For manual control, stopping is linked to STN beta (13-30 Hz) and slowing responses are linked to lower frequencies (<12 Hz). Whether similar STN oscillatory activities are associated with the control of spoken responses is not clear. We studied 16 patients with STN LFP recordings during manual and vocal stop signal tasks in two experiments. We found increased beta activities for stopping spoken responses, similar to manual stopping. However, unlike manual stopping, stopping spoken responses elicited a right-lateralized beta power increase, which may be related to previously reported hyperactivity of right sided motor control regions in stuttering. We additionally studied STN power changes associated with slowing responses in the same stop-signal tasks by comparing slower vs. faster go trials. Now, rather than beta, there was an alpha power increase after Go cues, which remained elevated only in slower Go trials in both the vocal and manual tasks. These data show that different types of response control are generalizable across effectors and relate to different frequencies recorded from the STN. PMID- 29125967 TI - VDMOSFET as a prospective dosimeter for radiotherapy. AB - Performance of a commercial p-channel power vertical-double-diffusion metal-oxide semiconductor field-effect transistors (VDMOSFETs) as a gamma-radiation dosimeters were studied. The devices were irradiated with 60Co to 10-50Gy at the gate biases ranging from 0 to 5V, and subsequent dosimetric signal fading was monitored during room-temperature storage without a gate bias for 100 days. A linear relationship was found between the threshold voltage shift and the radiation dose for all values of the gate bias. Furthermore, a power-law relationship between the radiation sensitivity and the gate bias during the irradiation was revealed. The radiation sensitivity of these devices is higher than that of RADFETs with 100-nm-thick oxide gate layers manufactured by the Tyndall National Institute in Cork, Ireland. Room-temperature signal fading for VDMOSFETs is similar to that for RADFETs, i.e., the threshold voltage shift decreases slowly. A continuous annealing of VDMOSFETs at 150 degrees C for 27 days results in a significant decrease of the threshold voltage shift, especially during the first 7 days. PMID- 29125968 TI - The prevalence of anxiety and associated factors in persons with multiple sclerosis. AB - BACKGROUND: The prevalence of anxiety and its association with sociodemographic and clinical factors is not well characterized in those with multiple sclerosis (MS). We aimed to estimate the prevalence and examine associated factors of anxiety in persons with MS. METHODS: A cross-sectional analysis was conducted utilizing data from 244 participants from the Neurological Disease and Depression study. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS). Descriptive statistics and multiple logistic regression was used to examine anxiety and associated factors. RESULTS: Nearly 30.0% of participants had anxiety according to the HADS. The most prevalent symptom of anxiety was "worrying thoughts" (26.6%). After adjustment for various confounders, depression (OR: 7.31 95% CI 3.29-16.26) was found to be associated with higher odds of anxiety, while lower odds of anxiety were associated with higher education (OR: 0.51, 95% CI 0.28-0.94). Furthermore, anxiety was strongly associated with decreased quality of life. CONCLUSION: Anxiety represents a substantial burden for those with MS and is associated with a variety of adverse outcomes including decreased quality of life. Our results further emphasize the importance of understanding the impact of anxiety in this population. PMID- 29125969 TI - Psychiatric comorbidities and suicidality among patients with neuromyelitis optica spectrum disorders in Argentina. AB - BACKGROUND: Neuromyelitis optica is a relapsing inflammatory, secondarily demyelinating astrocytopathy that most commonly affects the optic nerves and the spinal cord. OBJECTIVE: This study aimed to evaluate the psychopathological profile, presence of current depression, and suicidality in patients with neuromyelitis optica spectrum disorders (NMOSD) in an Argentinean cohort, and compare these parameters to those in patients with multiple sclerosis (MS) and in healthy controls (HCs). METHODS: Twenty patients with NMOSD, 18 with MS, and 20 healthy controls were included. The presence and grade of current depression were assessed using Beck's depression inventory (BDI), while psychiatric disease and suicidality were assessed using the Mini-International Neuropsychiatric Interview. RESULTS: The prevalence of psychiatric disease in the NMOSD group was 45%, significantly higher than in the MS group (16%, p = 0.06) and the HCs (5%, p = 0.008). Recurrent major depressive disorder was the most frequent psychiatric disease and was diagnosed in four (20%) patients in the NMOSD group and in two (11%) patients in the MS group. In the NMOSD group, two (10%) patients were diagnosed with past manic episodes, one (5%) with current dysthymic disorder, one (5%) with lifetime psychotic disorder, and one (5%) with bulimia nervosa. One patient (5.5%) in the MS group and one in the HC (5%) were diagnosed with current generalized anxiety disorder. Ten patients (50%) in the NMOSD group had current depressive symptoms versus five (28%) patients in the MS group (p = 0.16) and two (10%) in the HC group (p = 0.02). Six (30%) patients with NMOSD versus only one (5.5%) patient with MS had attempted suicide at least once, this difference was statistically significant (p = 0.05). Current suicide risk was high in patients with NMOSD (8, 40%) and moderate in patients with MS (4, 22%). CONCLUSIONS: Our study shows that the prevalence of psychiatric comorbidities in patients with NMOSD is significantly higher than in patients with MS and healthy controls. Given the high frequency of suicidality, assessment of pertinent psychiatric disorders in such patients to optimize monitoring and comprehensive treatment is required. PMID- 29125970 TI - Chemical characterization of cytotoxic indole acetic acid derivative from mulberry fruit (Morus alba L.) against human cervical cancer. AB - The fruit of the white mulberry tree (Morus alba L.) is a multiple fruit with a sweet flavor commonly consumed around the world. Chemical investigation of the fruits led to the isolation of two indole acetic acid derivatives (1 -2) including a new compound, which turned out to be an isolation artifact, 3S-(beta D-glucopyranosyloxy)-2,3-dihydro-2-oxo-1H-indole-3-acetic acid butyl ester (1), along with five known compounds (3 -7). Compounds 2 and 7 were newly identified from mulberry fruit. The new isolation artifact (1) exhibited cytotoxic effect on human cervical cancer Hela cells in a dose-dependent manner. Compound 1 activated caspase-8, caspase-9, and caspase-3, followed by cleavage of PARP, a substrate of caspase-3, in a dose-dependent manner. Simultaneous alterations in protein expression of mitochondrial factors Bax, BID and Bcl-2 were also observed. A comparison between compounds 1 and 2 led to a structure-activity relationship analysis of the cytotoxic effect. These results suggest that compound 1 could be beneficial in human cervical cancer treatment, and provide a theoretical basis for further application of compound 1. PMID- 29125971 TI - 5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones: As potent urease inhibitors; synthesis, in vitro screening, and molecular modeling study. AB - 5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones 1-43 were synthesized in a "one-pot" three component reaction and structurally characterized by various spectroscopic techniques such as 1H, 13C NMR, EI-MS, HREI-MS, and IR. All compounds were evaluated for their in vitro urease inhibitory activity. It is worth mentioning that except derivatives 1, 11, 12, and 14, all were found to be more potent than the standard thiourea (IC50 = 21.25 +/- 0.15 uM) and showed their urease inhibitory potential in the range of IC50 = 3.70 +/- 0.5-20.14 +/- 0.1 uM. Structure-activity relationship (SAR) was rationalized by looking at the varying structural features of the molecules. However, molecular modeling study was performed to confirm the binding interactions of the molecules (ligand) with the active site of enzyme. PMID- 29125972 TI - A biolayer interferometry-based enzyme-linked aptamer sorbent assay for real-time and highly sensitive detection of PDGF-BB. AB - Accurate, fast and sensitive detection of disease-specific protein biomarkers, especially in blood, urine, or other bodily fluids, is an important approach to achieve early disease diagnosis. Platelet-derived growth factor-BB (PDGF-BB), a widely used biomarker, is involved in a substantial number of serious diseases, such as hepatic fibrosis, atherosclerosis, age-related macular degeneration and diabetic eye disease and is often over-expressed in human malignant tumors. Therefore, the development of sensitive and specific detection methods for PDGF BB is of great importance for the early diagnosis of disease and assessments of patient recovery. In the current study, a biolayer interferometry-based enzyme linked aptamer sorbent assay (BLI-ELASA) was successfully established for rapid (20-25min), high-throughput (8 or 16 samples) and real-time monitoring of PDGF-BB in clinical samples. The method exhibited a broad detection range from 0.5 to 1000ng/mL of PDGF-BB (good linear range from 0.5 to 10ng/mL), with a low detection limit of 0.08ng/mL. Moreover, BLI-ELASA was applied to the detection of PDGF-BB in spiked serum and urine samples and showed a high degree of selectivity for PDGF-BB, good reproducibility, and stability. We believe that the methodology in this work can be easily adapted to detect other biomolecules in clinical samples, including viruses, pathogens and toxins, in a rapid, sensitive, high throughput and real-time manner. PMID- 29125973 TI - Creation of antifouling microarrays by photopolymerization of zwitterionic compounds for protein assay and cell patterning. AB - Nonspecific binding or adsorption of biomolecules presents as a major obstacle to higher sensitivity, specificity and reproducibility in microarray technology. We report herein a method to fabricate antifouling microarray via photopolymerization of biomimetic betaine compounds. In brief, carboxybetaine methacrylate was polymerized as arrays for protein sensing, while sulfobetaine methacrylate was polymerized as background. With the abundant carboxyl groups on array surfaces and zwitterionic polymers on the entire surfaces, this microarray allows biomolecular immobilization and recognition with low nonspecific interactions due to its antifouling property. Therefore, low concentration of target molecules can be captured and detected by this microarray. It was proved that a concentration of 10ngmL-1 bovine serum albumin in the sample matrix of bovine serum can be detected by the microarray derivatized with anti-bovine serum albumin. Moreover, with proper hydrophilic-hydrophobic designs, this approach can be applied to fabricate surface-tension droplet arrays, which allows surface directed cell adhesion and growth. These light controllable approaches constitute a clear improvement in the design of antifouling interfaces, which may lead to greater flexibility in the development of interfacial architectures and wider application in blood contact microdevices. PMID- 29125974 TI - Investigations of trace and toxic elements of kidney stones from two different Sudanese areas by u-PIXE using Nuclear Microprobe (NMP). AB - In this study 14 kidney stones (oxalate and phosphate stones) collected from two Sudanese hospitals Particle Induced X ray Emission (u-PIXE). This technique was used to investigate the matrix as well as the trace element compositions of kidney stones on a microscopic scale using 1.5MeV proton energy. Significant differences in elements content across the groups were found by applying statistical methods. Trace elements such as P,Ca, Fe, Ni, Cu, Zn, Se, Sr, Br, and Pb showed a possible linear relationship of the mean profile for trace elements for each group of stones. This study shows that micro analysis of urinary stones can provide complementary information on patients' exposure to epidemiological risk factors such as geography, diet and drinking water. PMID- 29125975 TI - Prospective prediction of arrests for driving under the influence from relationship patterns with family and friends in adolescence. AB - Driving under the influence (DUI) is dangerous and costly, yet there are few prospective studies on modifiable risk and protective processes that would inform prevention. Middle adolescence, when most individuals are first learning to drive and first using alcohol, may be a particularly salient period for family and friendship influences on DUI risk. In the present study, youth's family and friendship environments were observed and measured at age 16 in a diverse community sample (n=999), and then court records were used to document arrest for DUI through the age of 32years. We first examined the univariate effects of family and friendship variables on later DUI and then fit more comprehensive structural equation models to test predictive effects on the level of construct (e.g., parental monitoring) and environment (e.g., family). Results indicate that parental monitoring (Odds Ratio [OR]=0.77), positive family relations (OR=0.84), prosocial peer affiliation (OR=0.77), and deviant peer affiliation (OR=1.43) at age 16 were individually predictive of arrests for DUI from ages 16 to 32, even after controlling for both teen and parent alcohol use. The comprehensive, multivariate models indicated that the friendship environment was most predictive of arrests for DUI during the follow-up period. Together, these results are consistent with a model in which attenuated family ties contribute to substance use-based friendships at age 16, which in turn contribute to an increased likelihood of arrest for DUI in later adolescence and early adulthood. Implications for prevention are discussed. PMID- 29125977 TI - Windows of opportunity: timing in neurodevelopmental disorders. AB - Developmental processes disrupted in neurodevelopmental disorders occur rapidly and with temporal precision. During development, individual gene activity can dynamically engage different signaling networks; thus genetic mutations can lead to different functional changes at different times. Interpretation of phenotypes can be further complicated if initial functional changes trigger compensatory mechanisms. Examining genetic mouse models of neurodevelopmental disorders reveals cellular phenotypes that change over the course of development and exist long before behavioral deficits are assessed. Correspondingly, earlier genetic interventions in these disorder models have often been more effective at improving behavioral deficits than late interventions. The restricted period of effective intervention demonstrates that identifying a target window is an essential component of treatment. PMID- 29125976 TI - Trends in self-efficacy to quit and smoking urges among homeless smokers participating in a smoking cessation RCT. AB - INTRODUCTION: In the U.S., approximately 73% of homeless adults smoke cigarettes and they experience difficulty quitting. Homeless smokers report low self efficacy to quit and that smoking urges are a barrier to quitting. Self-efficacy to quit and smoking urges are dynamic and change throughout smoking cessation treatment. This study examines changes in self-efficacy to quit and smoking urges throughout a smoking cessation intervention among the homeless and identifies predictors of change in these characteristics. METHODS: Homeless smokers (n=430) participating in a smoking cessation randomized controlled trial in the U.S. completed surveys at baseline, and weeks 1, 2, 4, 6, 8, and 26 on demographic and smoking characteristics (i.e., confidence to quit, self-efficacy to refrain from smoking, and smoking urges). A growth curve analysis was conducted by modeling change in the smoking characteristics over time and examining the variability in the change in smoking characteristics by demographic characteristics and treatment group. RESULTS: Among the full sample, self-efficacy to refrain from smoking increased linearly over time, confidence to quit increased until the midpoint of treatment but subsequently decreased, and smoking urges decreased until the midpoint of treatment but subsequently increased. There were race differences in these trajectories. Racial minorities experienced significantly greater increases in self-efficacy to refrain from smoking than Whites and Blacks had higher confidence to quit than Whites. CONCLUSIONS: White participants experienced less increase in self-efficacy to refrain from smoking and lower confidence to quit and therefore may be a good target for efforts to increase self-efficacy to quit as part of homeless-targeted smoking cessation interventions. Sustaining high confidence to quit and low smoking urges throughout treatment could be key to promoting higher cessation rates among the homeless. PMID- 29125978 TI - Decoding hidden messages in neurons: insights from epitranscriptome-controlled and specialized ribosome-controlled translation. AB - Activity-regulated protein synthesis, especially in the restricted synaptic domains, is critical to maintaining connections and communication between neurons. Accumulating evidence has linked dysregulated translation to various neurodevelopmental or neurodegenerative diseases. In the past 3 decades, after finding ribosomes and specific mRNAs localized around synapses, a significant amount of work has furthered our understanding of how the genetic sequences in mRNAs and their cognate RNA-binding proteins are coordinated to build up synaptic proteomes. Recent exciting findings of various RNA modifications, specialized ribosomes, and their regulatory roles in translation have led to emerging needs to unravel how synaptic ribosomes interpret these hidden codes to regulate molecular connectomes. PMID- 29125979 TI - Synaptic plasticity may underlie l-DOPA induced dyskinesia. AB - l-DOPA provides highly effective treatment for Parkinson's disease, but l-DOPA induced dyskinesia (LID) is a very debilitating response that eventually is presented by a majority of patients. A central issue in understanding the basis of LID is whether it is due to a response to chronic l-DOPA over years of therapy, and/or due to synaptic changes that follow the loss of dopaminergic neurotransmission and then triggered by acute l-DOPA administration. We review recent work that suggests that specific synaptic changes in the D1 dopamine receptor-expressing direct pathway striatal projection neurons due to loss of dopamine in Parkinson's disease are responsible for LID. Chronic l-DOPA may nevertheless modulate LID through priming mechanisms. PMID- 29125980 TI - Molecular insights into cortico-striatal miscommunications in Huntington's disease. AB - Huntington's disease (HD), a dominantly inherited neurodegenerative disease, is defined by its genetic cause, a CAG-repeat expansion in the HTT gene, its motor and psychiatric symptomology and primary loss of striatal medium spiny neurons (MSNs). However, the molecular mechanisms from genetic lesion to disease phenotype remain largely unclear. Mouse models of HD have been created that exhibit phenotypes partially recapitulating those in the patient, and specifically, cortico-striatal disconnectivity appears to be a shared pathogenic event shared by HD mouse models and patients. Molecular studies have begun to unveil converging molecular and cellular pathogenic mechanisms that may account for cortico-striatal miscommunication in various HD mouse models. Systems biological approaches help to illuminate synaptic molecular networks as a nexus for HD cortio-striatal pathogenesis, and may offer new candidate targets to modify the disease. PMID- 29125981 TI - The clinical development of vaccines for HER2+ breast cancer: Current landscape and future perspectives. AB - Human epidermal growth factor receptor 2 (HER2) is a tumor associated antigen over-expressed in 20-30% of cases of breast cancer. Passive immune therapy with HER2-directed monoclonal antibodies (mabs) has changed the natural history of this subset of breast tumors both in the localized and metastatic settings. The safety and efficacy of HER2 vaccines have been assessed in early phase clinical trials but to date clinically relevant results in late phase trials remain an elusive target. Here, we review the recent translational discoveries related to the interactions between the adaptive immune system and the HER2 antigen in breast cancer, results of published clinical trials, and future directions in the field of HER2 vaccine treatment development. PMID- 29125982 TI - Disability in activities of daily living among adults with cancer: A systematic review and meta-analysis. AB - INTRODUCTION: People with cancer frequently report limitation in Activities of Daily Living (ADLs); essential activities required to live independently within society. Although several studies have assessed ADL related disability, variability in assessment, setting, and population means evidence is difficult to interpret. We aimed to determine the prevalence of ADL related disability, overall and by setting, and the most commonly affected ADLs in people living with cancer. METHODS: We searched twelve databases to June 2016 for observational studies assessing ADL disability in adults with cancer. Data on study design, population, ADL instruments and disability (difficulty with or requiring assistance in >=1 activity) were extracted, summarised, and pooled to estimate disability prevalence with 95% confidence intervals (95% CI) overall and by setting. RESULTS: Forty-three studies comprising 19,246 patients were included. Overall, 36.7% (95% CI 29.8-44.3, 18 studies) and 54.6% (95% CI 46.5-62.3, 15 studies) of patients respectively reported disability relating to basic and instrumental ADLs. Disability was marginally more prevalent in inpatient compared to outpatient settings. The Katz Index (18 studies) and Lawton IADL Scale (11 studies) were the most commonly used instruments. Across the activities studied, the most frequently affected basic ADLs were personal hygiene, walking and transfers, and instrumental ADLs were housework, shopping and transportation. CONCLUSIONS: About one-third and half of adults with cancer respectively have difficulty or require assistance to perform basic and instrumental ADLs. These findings highlight the need for rehabilitation focused on functional independence, and underscore the importance of professionals skilled in occupational assessment and therapy within cancer services. PMID- 29125983 TI - Functional differences between healthy and diabetic endothelial cells on topographical cues. AB - The endothelial lining of blood vessels is severely affected in type II diabetes. Yet, there is still a paucity on the use of diabetic endothelial cells for study and assessment of implantable devices targeting vascular disease. This critically impairs our ability to determine appropriate topographical cues to be included in implantable devices that can be used to maintain or improve endothelial cell function in vivo. Here, the functional responses of healthy and diabetic human coronary arterial endothelial cells were studied and observed to differ depending on topography. Gratings (2 MUm) maintained normal endothelial functions such as adhesiveness, angiogenic capacity and cell-cell junction formation, and reduced immunogenicity of healthy cells. However, a significant and consistent effect was not observed in diabetic cells. Instead, diabetic endothelial cells cultured on the perpendicularly aligned multi-scale hierarchical gratings (250 nm gratings on 2 MUm gratings) drastically reduced the uptake of oxidized low-density lipoprotein, decreased immune activation, and accelerated cell migration. Concave microlens (1.8 MUm diameter) topography was additionally observed to overwhelmingly deteriorate diabetic endothelial cell function. The results of this study support a new paradigm and approach in the design and testing of implantable devices and biomedical interventions for diabetic patients. PMID- 29125984 TI - Ultraviolet germicidal efficacy as a function of pulsed radiation parameters studied by spore film dosimetry. AB - Disinfection by pulsed ultraviolet (UV) radiation is a commonly used method, e.g. in industry or medicine and can be carried out either with lasers or broadband UV radiation sources. Detrimental effects to biological materials depending on parameters such as pulse duration tau or pulse repetition frequency fp are well understood for pulsed coherent UV radiation, however, relatively little is known for its incoherent variant. Therefore, within this work, it is the first time that disinfection rates of pulsed and continuous (cw) incoherent UV radiation studied by means of spore film dosimetry are presented, compared with each other, and in a second step further investigated regarding two pulse parameters. After analyzing the dynamic range of the Bacillus subtilis spore films with variable cw radiant exposures H=5-100Jm-2 a validation of the Bunsen-Roscoe law revealed its restricted applicability and a 28% enhanced detrimental effect of pulsed compared to cw incoherent UV radiation. A radiant exposure H=50Jm-2 and an irradiance E=0.5Wm-2 were found to be suitable parameters for an analysis of the disinfection rate as a function of tau=0.5-10ms and fp=25-500Hz unveiling that shorter pulses and lower frequencies inactivate more spores. Finally, the number of applied pulses as well as the experiment time were considered with regard to spore film disinfection. PMID- 29125985 TI - Cadmium toxicity and its amelioration by kinetin in tomato seedlings vis-a-vis ascorbate-glutathione cycle. AB - The supplementation of plant hormones may enhance the tolerance capacity of plants against certain environmental stresses by increasing their physiological functioning and detoxification capacity. To answer the question that whether a phytohormone 'kinetin' (KN, 6-furfuylaminopurine), one of the artificial cytokinins could ameliorate the cadmium induced toxicity in tomato seedlings, the effect of KN was assessed in differentially cadmium (Cd1: 3mgkg-1 sand and Cd2: 9mgkg-1 sand) intoxicated tomato seedlings by estimating the changes in reactive oxygen species (ROS, viz. superoxide radical and H2O2 generation) and probable alteration in photosystem II photochemistry, ascorbate-glutathione cycle enzymes and their metabolites. Accumulation of Cd in tomato seedlings increased the production of ROS by negatively impacting PS II photochemistry (decrease in Fv/Fm (phiP0), Psi0, phiE0 and PIABS and increase in energy fluxes per reaction centre: ABS/RC, ET0/RC, TR0/RC and DI0/RC) manifested by lowered fresh mass despite the accelerated activity of AsA-GSH cycle enzymes (viz. ascorbate peroxidase, APX; glutathione reductase, GR; dehydroascorbate reductase, DHAR and monodehydroascorbate reductase; MDHAR). Simultaneous application of kinetin (10MUM) alleviated the negative effects on the fresh mass and lowered the ROS level by positively affecting PS II photochemistry and further rise in AsA-GSH cycle enzymes and their metabolites. PMID- 29125986 TI - Gating of visual processing by physiological need. AB - Physiological need states and associated motivational drives can bias visual processing of cues that help meet these needs. Human neuroimaging studies consistently show a hunger-dependent, selective enhancement of responses to images of food in association cortex and amygdala. More recently, cellular resolution imaging combined with circuit mapping experiments in behaving mice have revealed underlying neuronal population dynamics and enabled tracing of pathways by which hunger circuits influence the assignment of value to visual objects in visual association cortex, insular cortex, and amygdala. These experiments begin to provide a mechanistic understanding of motivation-specific neural processing of need-relevant cues in healthy humans and in disease states such as obesity and other eating disorders. PMID- 29125987 TI - Contextual modulation of sound processing in the auditory cortex. AB - In everyday acoustic environments, we navigate through a maze of sounds that possess a complex spectrotemporal structure, spanning many frequencies and exhibiting temporal modulations that differ within frequency bands. Our auditory system needs to efficiently encode the same sounds in a variety of different contexts, while preserving the ability to separate complex sounds within an acoustic scene. Recent work in auditory neuroscience has made substantial progress in studying how sounds are represented in the auditory system under different contexts, demonstrating that auditory processing of seemingly simple acoustic features, such as frequency and time, is highly dependent on co occurring acoustic and behavioral stimuli. Through a combination of electrophysiological recordings, computational analysis and behavioral techniques, recent research identified the interactions between external spectral and temporal context of stimuli, as well as the internal behavioral state. PMID- 29125988 TI - Quantification of nitrogenous bases, DNA and Collagen type I for the estimation of the postmortem interval in bone remains. AB - Estimating the postmortem interval (PMI) is an important goal in forensic medicine and continues to be one of the most difficult tasks of the forensic investigator. Few accurate methods exist to determine the time since death of skeletonized human remains due to the great number of intrinsic and external factors that may alter the normal course of postmortem change. The purpose of this research was to assess the usefulness of various biochemical parameters, such as nitrogenous bases (adenine, guanine, purines, cytosine, thymine, pyrimidines, hypoxanthine and xanthine), DNA and Collagen Type I peptides to estimate PMI. These parameters were analysed in cortical bone for the establishment of data in a total of 80 long bones of 80 corpses (50 males, 30 females) with a mean age of 68.31 years (S.D.=18.021, range=20-97). The bones were removed from the cement niches of a cemetery in Murcia (south-eastern Spain), where they had lain for between 5 and 47 years (mean time 23.83 years, S.D.=10.85). Our results show a significant decrease in adenine (p=0.0004), guanine (p=0.0001), purines (p=0.0001), cytosine (p=0.0001), thymine (p=0.0226), pyrimidines (p=0.0002) and the number of peptides of Collagen type I (p=0.0053) in those with a PMI>=20 years. In a curvilinear regression analysis the results show that 30.6% of the variable PMI could be explained by guanine concentration, in bones with a PMI<20 years, while in cases of a PMI>=20 years, the variable that best explained membership of this group was adenine (38.0%). In the discriminant analysis applied to the all the variables as a function of PMI when two groups were established, 86.7% of the cases were correctly classified. These results show that the quantification of Collagen type I proteins and nitrogenous bases could be used as a complementary tool, together with other analyses, in the estimation of PMI. PMID- 29125989 TI - Prediction of mortality risk in victims of violent crimes. AB - BACKGROUND: To predict mortality risk in victims of violent crimes based on individual injury diagnoses and other information available in health care registries. METHODS: Data from the Swedish hospital discharge registry and the cause of death registry were combined to identify 15,000 hospitalisations or prehospital deaths related to violent crimes. The ability of patient characteristics, injury type and severity, and cause of injury to predict death was modelled using conventional, Lasso, or Bayesian logistic regression in a development dataset and evaluated in a validation dataset. RESULTS: Of 14,470 injury events severe enough to cause death or hospitalization 3.7% (556) died before hospital admission and 0.5% (71) during the hospital stay. The majority (76%) of hospital survivors had minor injury severity and most (67%) were discharged from hospital within 1day. A multivariable model with age, sex, the ICD-10 based injury severity score (ICISS), cause of injury, and major injury region provided predictions with very good discrimination (C-index=0.99) and calibration. Adding information on major injury interactions further improved model performance. Modeling individual injury diagnoses did not improve predictions over the combined ICISS score. CONCLUSIONS: Mortality risk after violent crimes can be accurately estimated using administrative data. The use of Bayesian regression models provides meaningful risk assessment with more straightforward interpretation of uncertainty of the prediction, potentially also on the individual level. This can aid estimation of incidence trends over time and comparisons of outcome of violent crimes for injury surveillance and in forensic medicine. PMID- 29125990 TI - Structural characterization of the new synthetic cannabinoids CUMYL-PINACA, 5F CUMYL-PINACA, CUMYL-4CN-BINACA, 5F-CUMYL-P7AICA and CUMYL-4CN-B7AICA. AB - Synthetic cannabinoids are a group of new psychoactive compounds (NPS) that act as agonists at the cannabinoid receptor. First reported in 2008, they currently represent one of the largest groups of NPS that are monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Five samples (4 from the European RESPONSE project and one from daily casework) containing different synthetic cannabinoids were analyzed by a complex of analytical methods including gas chromatography-electron ionization mass spectrometry (GC-EI-MS), liquid chromatography-high resolution mass spectrometry (LC-HRMS), infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR). Five new synthetic cannabinoids containing a cumyl moiety as a linked group were identified: CUMYL PINACA, 5F-CUMYL-PINACA, CUMYL-4CN-BINACA, 5F-CUMYL-P7AICA, CUMYL-4CN-B7AICA. 5F CUMYL-PINACA and 5F-CUMYL-P7AICA as well as CUMYL-4CN-BINACA and CUMYL-4CN-B7AICA are constitutional isomers and only differ in the position of a nitrogen atom. The article contains all analytical data for a proper identification and differentiation of the five cumyl compounds. PMID- 29125991 TI - Effects of quercetin combined with anticancer drugs on metastasis-associated factors of gastric cancer cells: in vitro and in vivo studies. AB - Chemotherapy is essential to most patients with gastric cancer and the anticancer drug, irinotecan (CPT-11), and its metabolite, SN-38, an inhibitor of DNA topoisomerase I, are first-line chemotherapies for gastric cancer. Quercetin, a flavonoid that is widely found in various vegetables and fruits, has the ability to potentiate the efficacy of anticancer drugs. The purpose of this study was to investigate the therapeutic effect of quercetin combined with irinotecan/SN-38 in the AGS human gastric cancer cell line in vitro and in vivo. The in vitro study evaluated the efficacy of high-dose SN-38 and quercetin combined with low-dose SN 38 on cell viability, apoptosis, and beta-catenin expression. Results showed that cell viability and the percentage of apoptosis in combined treatments with quercetin and SN-38 were comparable to treatment with high-dose SN-38 alone. AGS cells treated with a high dose of SN-38 exhibited up-regulation of beta-catenin protein expression, whereas quercetin-treated cells (either quercetin alone or combined with low-dose SN-38) exhibited lower protein levels of beta-catenin. In the AGS xenograft mouse model, gene expression of cyclooxygenase-2 and epithelial mesenchymal transition-related markers, such as Twist1 and ITGbeta6, were lower in combined treatments with quercetin and low-dose irinotecan than high-dose irinotecan alone. Furthermore, the concentration of angiogenesis-associated factors (vascular endothelial growth factor (VEGF)-A and VEGF-receptor 2) and percentage of Tie2-expressing monocytes was significantly down-regulated in combined treatments with quercetin and irinotecan. These results suggest that quercetin may enhance the efficacy of irinotecan/SN-38 in the human AGS cell line. PMID- 29125992 TI - Phenol-enriched olive oils improve HDL antioxidant content in hypercholesterolemic subjects. A randomized, double-blind, cross-over, controlled trial. AB - At present, high-density lipoprotein (HDL) function is thought to be more relevant than HDL cholesterol quantity. Consumption of olive oil phenolic compounds (PCs) has beneficial effects on HDL-related markers. Enriched food with complementary antioxidants could be a suitable option to obtain additional protective effects. Our aim was to ascertain whether virgin olive oils (VOOs) enriched with (a) their own PC (FVOO) and (b) their own PC plus complementary ones from thyme (FVOOT) could improve HDL status and function. Thirty-three hypercholesterolemic individuals ingested (25 ml/day, 3 weeks) (a) VOO (80 ppm), (b) FVOO (500 ppm) and (c) FVOOT (500 ppm) in a randomized, double-blind, controlled, crossover trial. A rise in HDL antioxidant compounds was observed after both functional olive oil interventions. Nevertheless, alpha-tocopherol, the main HDL antioxidant, was only augmented after FVOOT versus its baseline. In conclusion, long-term consumption of phenol-enriched olive oils induced a better HDL antioxidant content, the complementary phenol-enriched olive oil being the one which increased the main HDL antioxidant, alpha-tocopherol. Complementary phenol-enriched olive oil could be a useful dietary tool for improving HDL richness in antioxidants. PMID- 29125993 TI - Substrate and mechanotransduction influence SERCA2a localization in human pluripotent stem cell-derived cardiomyocytes affecting functional performance. AB - Physical cues are major determinants of cellular phenotype and evoke physiological and pathological responses on cell structure and function. Cellular models aim to recapitulate basic functional features of their in vivo counterparts or tissues in order to be of use in in vitro disease modeling or drug screening and testing. Understanding how culture systems affect in vitro development of human pluripotent stem cell (hPSC)-derivatives allows optimization of cellular human models and gives insight in the processes involved in their structural organization and function. In this work, we show involvement of the mechanotransduction pathway RhoA/ROCK in the structural reorganization of hPSC derived cardiomyocytes after adhesion plating. These structural changes have a major impact on the intracellular localization of SERCA2 pumps and concurrent improvement in calcium cycling. The process is triggered by cell interaction with the culture substrate, which mechanical cues drive sarcomeric alignment and SERCA2a spreading and relocalization from a perinuclear to a whole-cell distribution. This structural reorganization is mediated by the mechanical properties of the substrate, as shown by the process failure in hPSC-CMs cultured on soft 4kPa hydrogels as opposed to physiologically stiff 16kPa hydrogels and glass. Finally, pharmacological inhibition of Rho-associated protein kinase (ROCK) by different compounds identifies this specific signaling pathway as a major player in SERCA2 localization and the associated improvement in hPSC-CMs calcium handling ability in vitro. PMID- 29125994 TI - Enhanced human somatic cell reprogramming efficiency by fusion of the MYC transactivation domain and OCT4. AB - The development of human induced pluripotent stem cells (iPSCs) holds great promise for regenerative medicine. However the iPSC induction efficiency is still very low and with lengthy reprogramming process. We utilized the highly potent transactivation domain (TAD) of MYC protein to engineer the human OCT4 fusion proteins. Applying the MYC-TAD-OCT4 fusion proteins in mouse iPSC generation leads to shorter reprogramming dynamics, with earlier activation of pluripotent markers in reprogrammed cells than wild type OCT4 (wt-OCT4). Dramatic enhancement of iPSC colony induction efficiency and shortened reprogramming dynamics were observed when these MYC-TAD-OCT4 fusion proteins were used to reprogram primary human cells. The OCT4 fusion proteins induced human iPSCs are pluripotent. We further show that the MYC Box I (MBI) is dispensable while both MBII and the linking region between MBI/II are essential for the enhanced reprogramming activity of MYC-TAD-OCT4 fusion protein. Consistent with an enhanced transcription activity, the engineered OCT4 significantly stimulated the expression of genes specifically targeted by OCT4-alone, OCT4/SOX2, and OCT4/SOX2/KLF4 during human iPSC induction, compared with the wt-OCT4. The MYC TAD-OCT4 fusion proteins we generated will be valuable tools for studying the reprogramming mechanisms and for efficient iPSC generation for humans as well as for other species. PMID- 29125995 TI - A human iPS cell myogenic differentiation system permitting high-throughput drug screening. AB - Muscular dystrophy is a disease characterized by progressive muscle weakness and degeneration. There are currently no available treatments for most muscular diseases, such as muscular dystrophy. Moreover, current therapeutics are focused on improving the quality of life of patients by relieving the symptoms or stress caused by the disease. Although the causative genes for many muscular diseases have been identified, the mechanisms underlying their pathogenesis remain unclear. Patient-derived induced pluripotent stem cells (iPSCs) have become a powerful tool for understanding the pathogenesis of intractable diseases, as well as for phenotype screening, which can serve as the basis for developing new drugs. However, it is necessary to develop an efficient and reproducible myogenic differentiation system. Previously, we reported a tetracycline-inducible MyoD overexpression model of myogenic differentiation using human iPSCs (hiPSCs). However, this model has certain disadvantages that limit its use in various applications, such as a drug screening. In this study, we developed an efficient and reproducible myogenic differentiation system by further modifying our previous protocol. The new protocol achieves efficient differentiation of feeder free hiPSCs to myogenic cells via small-scale culture in six-well microplates to large-scale culture in 384-well microplates for high-throughput applications. PMID- 29125996 TI - Characterization of wear debris released from alumina-on-alumina hip prostheses: Analysis of retrieved femoral heads and peri-prosthetic tissues. AB - We analyzed by SEM three alumina-on-alumina femoral heads obtained from three patients who underwent revision for an aseptic loosening of the acetabular component. In parallel, the peri-prosthetic tissues were analyzed histologically in search of wear debris coming from the ceramic. Stripe wears, abrasive streaks, craters, and areas with extensive biomaterial removal were evidenced on the three femoral heads by SEM. In the altered area, the structure of the ceramic composed of minute polyhedric grains packed together was evidenced. In the peri-prosthetic tissues, the alumina particles were present in different forms: larges particles appeared transparent and birefringent, small particles engulfed by the macrophages had a light brown tint and were not birefringent. Large particles corresponded to the grains observed by SEM. EDS microanalysis confirmed the presence of aluminum oxide in these particles. Alumina debris are difficult to identify microscopically due to their pleomorphism. PMID- 29125997 TI - Non suicidal self-injury, emotional eating and insomnia after child sexual abuse: Are those symptoms related to emotion regulation? AB - OBJECTIVE: The aim of this article was to assess the effects of child sexual abuse (CSA) on emotion regulation (ER) in adolescents and to evaluate the relationships between non suicidal self-injury (NSSI), emotional eating, insomnia and emotion disregulation (ED). METHOD: Fifty two adolescents, aged 10-18 years, without who weren't diagnosed a psychiatric disease before abuse and completed 6 months of follow-up after abuse included the study. Control group consisted of 33 healthy voluntary participants without any known psychiatric disorders. Patients and volunteers who participated in the study were assessed with the Inventory of Statements About Self-injury (ISAS), Dutch Eating Behavior Questionnaire (DEBQ), Pittsburgh Sleep Quality Index (PSQI), Insomnia severity index (ISI), and the Difficulties in Emotion Regulation Scale (DERS). RESULTS: In our study, PSQI scores, DERS total scores and DEBQ emotional eating subscores were significantly higher in the CSA victims (In orderly; p = 0,034, p < 0.001, p = 0,023). 55.7% of the CSA victims reported self-injurious behavior, while 15.5% of healthy voluntary participants reporting self-injurious behavior. The CSA victims reporting NSSI had higher DERS scores than CSA victims without NSSI. (p = 0.024). The CSA victims with post-traumatic stress disorder (PTSD) and CSA victims without PTSD had a positive correlation between DEBQ emotional eating subscores and DERS total scores (In orderly: r = 0.762, p = 0.031; r = 0.872, p < 0.001). There was a positive correlation between the PSQI scores and DERS scores in the CSA victims with PTSD (r = 0.827, p = 0.023). CONCLUSION: Further studies are needed to assess the relationship between self-injury, emotional eating, insomnia and ED, and to determine how sexual abuse effect the ER in a clinical sample of CSA. PMID- 29125998 TI - Suicides by hanging and its association with meteorological conditions in Sao Paulo. AB - The main goal of this study was to evaluate the association between daily cases of hanging suicides and meteorological conditions in Sao Paulo, Brazil. We considered a retrospective observational study based on the analysis of all necroscopic medical-expert reports available in digital form from the central unit of the Instituto Medico Legal (Medical Legal Institute) of Sao Paulo between July 1, 2006 and June 31, 2007. The meteorological variables were combined via Principal Components Analysis. In order to explain their association with the frequency of suicides, Poisson regression models were employed. The analysis suggests that hotter and brighter days are associated with higher incidence of hanging suicides. PMID- 29125999 TI - Preclinical evaluation of heat-denatured [18F]FDG-labeled red blood cells for detecting splenic tissues with PET in rats. AB - INTRODUCTION: Heat-denatured 99mTc-labeled red blood cells (RBCs) are used for detecting splenic tissues with scintigraphy. The present study aimed to evaluate the feasibility of using heat-denatured [18F]fluorodeoxyglucose ([18F]FDG) labeled RBCs in detecting splenic tissues using positron emission tomography (PET) in rats. METHODS: RBCs were washed with phosphate buffered saline, labeled with [18F]FDG at 38 degrees C, and heat-denatured at 50 degrees C for 15 min. In vitro stability was assessed by measuring extracellular radioactivity during the 0-180 min incubation at 37 degrees C. Thin layer chromatography (TLC) of the extracellular fluid was performed. The autologous RBCs were intravenously injected in four rats and PET scanning was simultaneously performed for 30 min. Time-activity curves of several organs, including the spleen, were analyzed on the PET images. RESULTS: Labeling efficiency was 92%. Low levels of radioactivity were released from the labeled RBCs for 180 min. TLC revealed that 80% of the released radioactivity was due to [18F]FDG-6-phosphate. Whole body images showed strong uptake of heat-denatured [18F]FDG-labeled RBCs in the spleen soon after injection in all four rats. Time-activity curves revealed that the splenic uptake continued to increase for 30 min and the amount of radioactivity in the other organs, except the urinary bladder, decreased after the initial surge. CONCLUSIONS: Heat-denatured [18F]FDG-labeled RBCs are suitable spleen-specific agents for PET. This method is clinically relevant as an alternative for heat denatured 99mTc-labeled RBC scintigraphy. PMID- 29126000 TI - Direct PCR amplification of DNA from human bloodstains, saliva, and touch samples collected with microFLOQ(r) swabs. AB - Previous studies have shown that nylon flocked swabs outperform traditional fiber swabs in DNA recovery due to their innovative design and lack of internal absorbent core to entrap cellular materials. The microFLOQ(r) Direct swab, a miniaturized version of the 4N6 FLOQSwab(r), has a small swab head that is treated with a lysing agent which allows for direct amplification and DNA profiling from sample collection to final result in less than two hours. Additionally, the microFLOQ(r) system subsamples only a minute portion of a stain and preserves the vast majority of the sample for subsequent testing or re analysis, if desired. The efficacy of direct amplification of DNA from dilute bloodstains, saliva stains, and touch samples was evaluated using microFLOQ(r) Direct swabs and the GlobalFilerTM Express system. Comparisons were made to traditional methods to assess the robustness of this alternate workflow. Controlled studies with 1:19 and 1:99 dilutions of bloodstains and saliva stains consistently yielded higher STR peak heights than standard methods with 1ng input DNA from the same samples. Touch samples from common items yielded single source and mixed profiles that were consistent with primary users of the objects. With this novel methodology/workflow, no sample loss occurs and therefore more template DNA is available during amplification. This approach may have important implications for analysis of low quantity and/or degraded samples that plague forensic casework. PMID- 29126001 TI - A robust heteronuclear dipolar recoupling method comparable to TEDOR for proteins in magic-angle spinning solid-state NMR. AB - In this letter, we propose a robust heteronuclear dipolar recoupling method for proteins in magic-angle spinning (MAS) solid-state NMR. This method is as simple, robust and efficient as the well-known TEDOR in the aspect of magnetization transfer between 15N and 13C. Deriving from our recent band-selective dual back to-back pulses (DBP) (Zhang et al., 2016), this method uses new phase-cycling schemes to realize broadband DBP (Bro-DBP). For broadband 15N-13C magnetization transfer (simultaneous 15N->13C' and 15N->13Calpha), Bro-DBP has almost the same 15N->13Calpha efficiency while offers 30-40% enhancement on 15N->13C' transfer, compared to TEDOR. Besides, Bro-DBP can also be used as a carbonyl (13C') selected method, whose 15N->13C' efficiency is up to 1.7 times that of TEDOR and is also higher than that of band-selective DBP. The performance of Bro-DBP is demonstrated on the N-formyl-[U-13C,15N]-Met-Leu-Phe-OH (fMLF) peptide and the U 13C, 15N labeled beta1 immunoglobulin binding domain of protein G (GB1) microcrystalline protein. Since Bro-DBP is as robust, simple and efficient as TEDOR, we believe it is very useful for protein studies in MAS solid-state NMR. PMID- 29126002 TI - A thiourea-appended rhodamine chemodosimeter for mercury(II) and its bioimaging application. AB - A rhodamine-thiourea conjugate RTP with an o-phenylenediamine linker was developed as a fluorogenic chemodosimeter for Hg2+ detection. In the presence of Hg2+, a colorless solution of RTP turned pink with a maximum absorption band at 555nm and with a 62-fold fluorescence enhancement at 578nm (Phi=0.34). RTP is highly selective to Hg2+ among other metal ions with a detection limit of 1.6nM (0.3ppb). A similar rhodamine analog with a flexible ethylenediamine spacer was less selective and less sensitive than RTP. Hg2+ induced cyclic guanylation to yield a benzimidazole moiety and a subsequent ring-opening of the spirolactam unit resulted in chromogenic and fluorogenic changes. The membrane-permeable RTP probe was successfully demonstrated in monitoring of Hg2+ in cultured HeLa cells. PMID- 29126003 TI - Ethanol- and trifluoroethanol-induced changes in phase states of DPPC membranes. Prodan emission-excitation fluorescence spectroscopy supported by PARAFAC analysis. AB - It has been shown that Prodan emission-excitation fluorescence spectroscopy supported by Parallel Factor (PARAFAC) analysis is a fast, simple and sensitive method used in the study of the phase transition from the noninterdigitated gel (Lbeta') state to the interdigitated gel (LbetaI) phase, triggered by ethanol and 2,2,2-trifluoroethanol (TFE) molecules in dipalmitoylphosphatidylcholines (DPPC) membranes. The relative contribution of lipid phases with spectral characteristics of each pure phase component has been presented as a function of an increase in alcohol concentration. It has been stated that both alcohol molecules can induce a formation of the LbetaI phase, but TFE is over six times stronger inducer of the interdigitated phase in DPPC membranes than ethanol molecules. Moreover, in the TFE-mixed DPPC membranes, the transition from the Lbeta' to LbetaI phase is accompanied by a formation of the fluid phase, which most probably serves as a boundary phase between the Lbeta' and LbetaI regions. Contrary to the three phase-state model of TFE-mixed DPPC membranes, in ethanol mixed DPPC membranes only the two phase-state model has been detected. PMID- 29126004 TI - Photovoltaic characteristics of natural light harvesting dye sensitized solar cells. AB - In this work of research, anthocyanin as a natural dye obtained from raspberry fruits, was used and tested as a photon harvesting/electron donating dye in titanium dioxide nanoparticle-based DSSCs. A working photoelectrode made from TiO2 nanoparticles with an average particle size (10-40nm) that is coated on Florine doped tin-oxide substrate, was prepared via a simple and low cost hydrothermal method. A detailed structural and morphological analysis of the TiO2 photoactive electrode was investigated by X-ray diffraction (XRD), diffuse reflectance spectrometer, transmission electron microscope (TEM) and scanning electron microscope (SEM). Complete photovoltaic characteristics including (current, voltage, outpower, and responsivity) of the natural anthocyanin based dye sensitized solar cell have been investigated under different illumination intensity ranging from 10 to 100mW.cm-2. The cell responsivity and efficiency of the fabricated solar cell under different illumination intensity were found to be in the range (R=15.6-23.8mA.W-1 and eta=0.13-0.25) at AM=1.5 conditions. This study is important for enhancing the future applications of the promising DSSC technology. PMID- 29126005 TI - Colorimetric recognition of 6-benzylaminopurine in environmental samples by using thioglycolic acid functionalized silver nanoparticles. AB - A simple and selective colorimetric sensor thioglycolic acid capped silver nanoparticles (TGA-AgNPs) was developed for the detection of 6-benzylaminopurine (6-BAP). The synthesized TGA-AgNPs were characterized by UV-vis spectroscopy, dynamic light scattering (DLS), and transmission electron microscopic (TEM) techniques. The TGA-AgNPs as a sensor for binding 6-BAP through hydrogen-bonding and pi-pi bonding that causes large conjugate clusters, resulting in a color change from yellow to reddish orange. The surface plasmon resonance (SPR) band of TGA-AgNPs at 397nm is red-shifted to 510nm, which confirms that 6-BAP induces the aggregation of TGA-AgNPs. Under the optimized conditions, a linear relationship between the absorption ratio (A510nm/A397nm) and 6-BAP concentration was found in the range of 4-26MUM. The detection limit of 6-BAP was 0.2MUM, which is lower than the other analytical techniques. Moreover, the proposed sensor was successfully applied for the detection of 6-BAP in environmental samples with good recoveries. The proposed assay provides a simple and cost-effective method for the analysis of 6-BAP in vegetable and water samples. PMID- 29126006 TI - A multispectroscopic and molecular docking investigation of the binding interaction between serum albumins and acid orange dye. AB - The interaction of Acid Orange 10 (AO10) with bovine serum albumin (BSA) was investigated comparatively with that of human serum albumin (HSA) using multispectroscopic techniques for understanding their toxic mechanism. Further, density functional theory calculations and docking studies have been carried out to gain more insights into the nature of interactions existing between AO10 and serum albumins. The fluorescence results suggest that AO10 quenched the fluorescence of BSA through the combination of static and dynamic quenching mechanism. The same trend was followed in the interaction of AO10 with HSA. In addition to the type of quenching mechanism, the fluorescence spectroscopic results suggest that the binding occurs near the tryptophan moiety of serum albumins and the binding. AO10 has more binding affinity towards BSA than HSA. An AO10-Trp model has been created to explicitly understand the CHpi interactions from Bader's quantum theory of atoms in molecules analysis which confirmed that AO10 bind more strongly with BSA than that of HSA due to the formation of three hydrogen bonds with BSA whereas it forms two hydrogen bonds in the case of HSA. These obtained results provide an in-depth understanding of the interaction of the acid azo dye AO10 with serum albumins. This interaction study provides insights into the underlying reasons for toxicity of AO10 relevant to understand its effect on bovids and humans during the blood transportation process. PMID- 29126007 TI - Quantitative monitoring of sucrose, reducing sugar and total sugar dynamics for phenotyping of water-deficit stress tolerance in rice through spectroscopy and chemometrics. AB - In the present investigation, the changes in sucrose, reducing and total sugar content due to water-deficit stress in rice leaves were modeled using visible, near infrared (VNIR) and shortwave infrared (SWIR) spectroscopy. The objectives of the study were to identify the best vegetation indices and suitable multivariate technique based on precise analysis of hyperspectral data (350 to 2500nm) and sucrose, reducing sugar and total sugar content measured at different stress levels from 16 different rice genotypes. Spectral data analysis was done to identify suitable spectral indices and models for sucrose estimation. Novel spectral indices in near infrared (NIR) range viz. ratio spectral index (RSI) and normalised difference spectral indices (NDSI) sensitive to sucrose, reducing sugar and total sugar content were identified which were subsequently calibrated and validated. The RSI and NDSI models had R2 values of 0.65, 0.71 and 0.67; RPD values of 1.68, 1.95 and 1.66 for sucrose, reducing sugar and total sugar, respectively for validation dataset. Different multivariate spectral models such as artificial neural network (ANN), multivariate adaptive regression splines (MARS), multiple linear regression (MLR), partial least square regression (PLSR), random forest regression (RFR) and support vector machine regression (SVMR) were also evaluated. The best performing multivariate models for sucrose, reducing sugars and total sugars were found to be, MARS, ANN and MARS, respectively with respect to RPD values of 2.08, 2.44, and 1.93. Results indicated that VNIR and SWIR spectroscopy combined with multivariate calibration can be used as a reliable alternative to conventional methods for measurement of sucrose, reducing sugars and total sugars of rice under water-deficit stress as this technique is fast, economic, and noninvasive. PMID- 29126008 TI - A novel NBD-based fluorescent turn-on probe for the detection of cysteine and homocysteine in living cells. AB - Biothiols, such as cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), are involved in a number of biological processes and play crucial roles in biological systems. Thus, the detection of biothiols is highly important for early diagnosis of diseases and evaluation of disease progression. Herein, we developed a new turn-on fluorescent probe 1 based on 7-nitro-2,1,3-benzoxadiazole (NBD) with high selectivity and sensitivity for Cys/Hcy on account of nucleophilic substitution and Smiles rearrangement reaction. The probe could sense Cys/Hcy rapidly, the intensity of fluorescence increased immediately within 1min. Furthermore, the probe is low toxic and has been successfully applied to detect intracellular Cys/Hcy by cell fluorescence imaging in living normal and cancer cells. PMID- 29126009 TI - Characteristics and origin of agates from Ploczki Gorne (Lower Silesia, Poland): A combined microscopic, micro-Raman, and cathodoluminescence study. AB - Agates from Ploczki Gorne hosted by Permian basaltic rocks are predominantly made of length-fast chalcedony, and subordinately megaquartz and quartzine. Moganite occurs in traces mainly in transparent, outer, darker regions of white-grey coloured agates. Silica matrix of agates comprises a wide variety of solid inclusions represented by celadonite, plagioclases, hematite, goethite, barite, calcite, heulandite-clinoptyloite, nontronite-saponite, and Mn-dioxides (ramsdellite). Mineral phases are locally accompanied by black aggregations of carbonaceous matter, which gives a Raman signature of disordered carbon. These organic components were probably deposited from a hydrothermal fluids at low temperature conditions and originated from sedimentary rocks found in the surrounding area of Ploczki Gorne. The abundance of various SiO2 phases, mineral inclusions as well as various micro-textures (colloform, comb, feathery, and jigsaw-puzzle) in agates resulted from physicochemical fluctuations of SiO2 bearing mineralizing solutions at various stages of these gems formation. Agates from Ploczki Gorne formed during post-magmatic stage of basaltic host rocks evolution. Not only were the hydrothermal fluids enriched in silica, but also they contained other elements such as Na, Ca, Al, Mg, Mn, Fe, Ba, SO4, and CO2, which were mobilized from host rocks or surrounding area. PMID- 29126010 TI - A lysosome-targetable turn-on fluorescent probe for the detection of thiols in living cells based on a 1,8-naphthalimide derivative. AB - Biological thiols, like cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), play crucial roles in biological systems and in lysosomal processes. Highly selective probes for detecting biological thiols in lysomes of living cells are rare. In this work, a lysosome-targetable turn-on fluorescent probe for the detection of thiols in living cells was designed and synthesized based on a 1,8 naphthalimide derivative. The probe has a 4-(2-aminoethyl)morpholine unit as a lysosome-targetable group and an acrylate group as the thiol recognition unit as well as a fluorescence quencher. In the absence of biothiols, the probe displayed weak fluorescence due to the photoinduced electron transfer (PET) process. Upon the addition of biothiols, the probe exhibited an enhanced fluorescence emission centered at 550nm due to cleavage of the acrylate moiety. The probe had high selectivity toward biothiols. Moreover, the probe features fast response time, excitation in the visible region and ability of working in a wide pH range. The linear response range covers a concentration range of Cys from 1.5*10-7 to 1.0*10 5mol.L-1 and the detection limit is 6.9*10-8mol.L-1 for Cys. The probe has been successfully applied to the confocal imaging of biothiols in lysosomes of A549 cells with low cell toxicity. Furthermore, the method was successfully applied to the determination of thiols in a complex multicomponent mixture such as human serum, which suggests our proposed method has great potential for diagnostic purposes. All of such good properties prove it can be used to monitor biothiols in lysosomes of living cells and to be a good fluorescent probe for the selective detection of thiols. PMID- 29126011 TI - Multi-parameters monitoring during traditional Chinese medicine concentration process with near infrared spectroscopy and chemometrics. AB - As a powerful process analytical technology (PAT) tool, near infrared (NIR) spectroscopy has been widely used in real-time monitoring. In this study, NIR spectroscopy was applied to monitor multi-parameters of traditional Chinese medicine (TCM) Shenzhiling oral liquid during the concentration process to guarantee the quality of products. Five lab scale batches were employed to construct quantitative models to determine five chemical ingredients and physical change (samples density) during concentration process. The paeoniflorin, albiflorin, liquiritin and samples density were modeled by partial least square regression (PLSR), while the content of the glycyrrhizic acid and cinnamic acid were modeled by support vector machine regression (SVMR). Standard normal variate (SNV) and/or Savitzkye-Golay (SG) smoothing with derivative methods were adopted for spectra pretreatment. Variable selection methods including correlation coefficient (CC), competitive adaptive reweighted sampling (CARS) and interval partial least squares regression (iPLS) were performed for optimizing the models. The results indicated that NIR spectroscopy was an effective tool to successfully monitoring the concentration process of Shenzhiling oral liquid. PMID- 29126012 TI - A highly selective chemiluminescent probe for the detection of chromium(VI). AB - In present work, rhodamine B hydrazide and rhodamine 6G hydrazide were synthesized and the chemiluminescence performance has been investigated. Based on the chemiluminescence of rhodamine 6G hydrazide-chromium(VI), a selective and sensitive method for the direct detection of chromium(VI) was developed. The chemiluminescence intensity was linearly related to the concentration of chromium(VI) in the range of 2.60*10-8-8.00*10-6mol/L with a correlation coefficient of r=0.998 and a detection limit of 1.4*10-8mol/L (S/N=3). The results indicated rhodamine 6G hydrazide was an excellent chemiluminescent probe for chromium(VI) without reduction of chromium(VI) to chromium(III). A possible mechanism of CL emission was also suggested. PMID- 29126013 TI - 1,4-Bis(2-methylstyryl)benzene doped PMMA fibre for blue range fluorescent applications. AB - The fluorescent dyes allow new optical applications in polymer-based optical fibre technology. The article presents highly fluorescent 1,4-Bis(2 methylstyryl)benzene doped poly(methyl methacrylate) (PMMA) fibre. The multi-peak (422, 450, 488nm) fluorescence spectrum of the bulk specimen under 355nm excitation is presented. The polymerization and fibre drawing process is also shown. The fluorescent properties vs. fibre length at excitation 405nm are investigated. Significant spectrum shape changes and red shift phenomena of individual peaks are presented using one end excitation and fibre cutting method measurements for fibre length 2-90cm. Obtained attenuation level 0.69dB/m limits useful fibre length but obtained results can be useful in new polymeric fibers applications (e.g. sensors, light sources). PMID- 29126014 TI - Evaluation on the concentration change of paeoniflorin and glycyrrhizic acid in different formulations of Shaoyao-Gancao-Tang by the tri-level infrared macro fingerprint spectroscopy and the whole analysis method. AB - As a kind of common prescriptions, Shaoyao-Gancao-Tang (SGT) contains two Chinese herbs with four different proportions which have different clinical efficacy because of their various components. In order to investigate the herb-herb interaction mechanisms, we used the method of tri-level infrared macro fingerprint spectroscopy to evaluate the concentration change of active components of four SGTs in this research. Fourier transform infrared spectroscopy (FT-IR) and Second derivative infrared spectroscopy (SD-IR) can recognize the multiple prescriptions directly and simultaneously. 2D-IR spectra enhance the spectral resolution and obtain much new information for discriminating the similar complicated samples of SGT. Furthermore, the whole analysis method from the analysis of the main components to the specific components and the relative content of the components may evaluate the quality of TCM better. Then we concluded that paeoniflorin and glycyrrhizic acid were the highest proportion in active ingredients in SGT-12:1 and the lowest one in SGT-12:12, which matched the HPLC-DAD results. It is demonstrated that the method composed by the tri-level infrared macro-fingerprint spectroscopy and the whole analysis can be applicable for effective, visual and accurate analysis and identification of very complicated and similar mixture systems of traditional Chinese medicine. PMID- 29126015 TI - Single-cell transcriptomic analysis of oligodendrocyte lineage cells. AB - Oligodendrocytes (OLs) are glial cells in the central nervous system (CNS), which produce myelin, a lipid-rich membrane that insulates neuronal axons. The main function ascribed to OLs is to regulate the speed of electric pulse transmission, and as such OLs have been widely considered as a single and discrete population. Nevertheless, OLs and their precursor cells (OPCs) throughout the CNS have different morphologies and regional functional differences have been observed. Moreover, OLs have recently been involved in other functional processes such as metabolic coupling with axons. In this review, we focus on recent advances in single-cell transcriptomics suggesting that OLs are more heterogeneous than previously thought, with defined subpopulations and cell states that are associated with different stages of lineage progression and might also represent distinct functional states. PMID- 29126016 TI - Go and stop signals for glial regeneration. AB - The regenerative response of ensheating glia to central nervous system (CNS) injury involves proliferation and differentiation, axonal re-enwrapment and some recovery of behaviour. Understanding this limited response could enable the enhancement of it. In Drosophila, the glial progenitor state is maintained by Notch, an activator of cell division and Prospero (Pros), a repressor. Injury provokes the activation of NFkappaB and up-regulation of Kon-tiki (Kon), driving cell proliferation. Homeostatic switch-off comes about as two negative feedback loops involving Pros terminate the response. Importantly, the functions of the kon and pros homologues NG2 and prox1, respectively, are conserved in mammalian NG2 glia. Controlling these genes is key for therapeutic manipulation of progenitors and stem cells to promote regeneration of the damaged CNS. PMID- 29126017 TI - Epidermal growth factor receptor overexpression and outcomes in early breast cancer: A systematic review and a meta-analysis. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is a member of the ErbB family of membrane tyrosine-kinase receptors. Studies exploring the prognostic role of EGFR-overexpression in early breast cancer have shown variable results, and the true prognostic value of EGFR is unknown. METHODS: A systematic review of identified publications exploring the association between EGFR-overexpression (as defined from different techniques and cut-offs) and outcomes [disease-free (DFS) and, overall survival (OS)] in women with early breast cancer. The hazard ratios (HR) for DFS and OS were weighted and pooled in a meta-analysis using generic inverse variance and random effects modeling. RESULTS: Fifty-three studies comprising 21,418 women were included. EGFR-overexpression was found in 27% of the patients. Primary analysis included studies reporting HRs from multivariable analyses (10 studies including 4857 patients with HRs for OS and 17 studies comprising 8747 patients with HRs for DFS), EGFR-overexpression was associated with worse OS (HR 1.98, 95% CI: 1.59-2.47, p < .001) and DFS (HR 1.59, 95% CI 1.30-1.95, p < .001). The influence of EGFR overexpression on DFS was greater in women with triple negative tumors compared to women with non-triple negative tumors (HR 2.35 versus HR 1.45, respectively; p = .01). Analysis looking at odd ratios for both 5-year and 10-year for DFS and OS showed similar results. CONCLUSION: EGFR-overexpression appears to be associated with reduced OS and DFS in women with early breast cancer. Patients with triple negative and EGFR overexpression have poorer OS and DFS than those with triple negative tumors and normal EGFR expression. PMID- 29126018 TI - The epidemiological and clinical characteristics study on epilepsy in 8 ethnic groups of China. AB - : To survey the epidemiological characteristics and clinical features on epilepsy in eight ethnic groups in Yunnan province of China. METHODES: The investigation was based on the WHO questionnaire and ICBERG screening questionnaire. This study was performed through random cluster sampling and door-to-door survey. RESULTS: A total of 76,302 individuals from eight ethnic groups were surveyed. The crude prevalence of epilepsy ranged from 1.2/1000 to 6.5/1000 in the eight ethnic groups, and the age-adjusted prevalence of epilepsy was from 2.1/1000 to 7.3/1000. The prevalence of active epilepsy varied from 1.0/1000 to 5.2/1000 in the eight ethnic groups, and the age-adjusted prevalence of active epilepsy was from 1.8/1000 to 6.7/1000. The age peak for seizures was below twenty, the patients of 61.1%-95.0% suffered from generalized seizures and 5%-21.2% had partial seizures. More than 60% of the cases in five ethnic groups, and the frequency of seizures were more than 10 events per year. More than 50% in other three ethnic groups, and the seizures had occurred less than 10 events per year. The treatment gap for active epilepsy ranged from 43.7% to 100.0% among the eight ethnic groups, while the natural remission rate varied from 5.6% to 21.0%. CONCLUSION: There were both disparity and similarity in the epidemiological and clinical features of epilepsy in different ethnic group communities. PMID- 29126019 TI - A set of biogenetically interesting polyhalogenated acetogenins from Ptilonia magellanica. AB - Ptilonines A-F, pyranosylmagellanicus D-E and magellenediol are previously undescribed acetogenins isolated from the red alga Ptilonia magellanica. Their structures were determined from spectroscopic evidence. The absolute configuration of the known pyranosylmagellanicus A, was established by derivatization with (R)- and (S)-alpha-methoxy -alpha-phenylacetic acids (MPA). Ptilonines exhibit an unusual halogenation pattern, that may confer evolutionary advantages to Ptilonia magellanica, for which a biogenetic origin is proposed. The antimicrobial effect of some of these compounds was evaluated. PMID- 29126020 TI - Mechanistic insight in potential dual role of sinigrin against Helicoverpa armigera. AB - The adverse effect of glucosinolates on diverse phytophagous insects is well documented, but its impact on insect physiology has remained enigmatic. Here we report insights into detrimental effects of plant glucosinolate molecule, sinigrin, on Helicoverpa armigera growth and development. In-silico screening of multiple glucosinolates predicted sinigrin as one of the potential inhibitor of H. armigera cathepsin B and L. Insects fed on sinigrin containing diet showed significantly reduced growth (20-30%), delayed pupation (10-15%), decreased fecundity (50-80%) and developmental abnormalities. Further, sinigrin showed 50 60% inhibition of ex-vivo cathepsin like activity which might be a reason for growth and development related abnormalities. In-vitro and mass spectrometry studies highlighted the cytotoxicity caused due to the hydrolysis of sinigrin, into toxic isothiocyanates, in presence of H. armigera whole body extract. In conclusion, insect cathepsin inhibition and isothiocyanate mediated cytotoxicity lead to the dual adverse effect of sinigrin on H. armigera. PMID- 29126021 TI - Contributory fault and level of personal injury to drivers involved in head-on collisions: Application of copula-based bivariate ordinal models. AB - The main objective of this study is to simultaneously investigate the degree of injury severity sustained by drivers involved in head-on collisions with respect to fault status designation. This is complicated to answer due to many issues, one of which is the potential presence of correlation between injury outcomes of drivers involved in the same head-on collision. To address this concern, we present seemingly unrelated bivariate ordered response models by analyzing the joint injury severity probability distribution of at-fault and not-at-fault drivers. Moreover, the assumption of bivariate normality of residuals and the linear form of stochastic dependence implied by such models may be unduly restrictive. To test this, Archimedean copula structures and normal mixture marginals are integrated into the joint estimation framework, which can characterize complex forms of stochastic dependencies and non-normality in residual terms. The models are estimated using 2013 Virginia police reported two vehicle head-on collision data, where exactly one driver is at-fault. The results suggest that both at-fault and not-at-fault drivers sustained serious/fatal injuries in 8% of crashes, whereas, in 4% of the cases, the not-at-fault driver sustained a serious/fatal injury with no injury to the at-fault driver at all. Furthermore, if the at-fault driver is fatigued, apparently asleep, or has been drinking the not-at-fault driver is more likely to sustain a severe/fatal injury, controlling for other factors and potential correlations between the injury outcomes. While not-at-fault vehicle speed affects injury severity of at-fault driver, the effect is smaller than the effect of at-fault vehicle speed on at fault injury outcome. Contrarily, and importantly, the effect of at-fault vehicle speed on injury severity of not-at-fault driver is almost equal to the effect of not-at-fault vehicle speed on injury outcome of not-at-fault driver. Compared to traditional ordered probability models, the study provides evidence that copula based bivariate models can provide more reliable estimates and richer insights. Practical implications of the results are discussed. PMID- 29126022 TI - The impact of police presence on angry and aggressive driving. AB - An extensive body of research has found that angry and aggressive driving are both significantly related to crash involvement. There has also been a large body of research investigating the situational factors related to angry and aggressive driving, but one interesting question that has not yet been answered is whether the enforcement of traffic laws causes or reduces angry and aggressive driving. The independent region of Northern Kosovo represents a unique opportunity to investigate the impact of a lack of traffic enforcement on driving behaviour. Therefore, the present study set out to investigate whether the presence of traffic enforcement has a significant impact on the level of driver anger and aggressive driving. Registered owners of motor vehicles in Northern Kosovo and Serbia were both sent a questionnaire which contained the 28-item Dula Dangerous Driving Index (DDDI) and the 21-item UK Driving Anger Scale (UKDAS). This found that anger was higher in two of the four driving anger factors (direct hostility and progress impeded) and two of the three DDDI factors (risky driving & aggressive driving). Furthermore, the present study found that the lack of police enforcement was a significant predictor of both aggressive and risky driving, even after the driving anger and demographic variables had been partialled out. Therefore, it appears that introducing or increasing traffic enforcement may be one method of reducing aggressive and risky driving behaviour. PMID- 29126023 TI - Latitudinal patterns of leaf N, P stoichiometry and nutrient resorption of Metasequoia glyptostroboides along the eastern coastline of China. AB - Latitudinal patterns of leaf stoichiometry and nutrient resorption were not consistent among published studies, likely due to confounding effects from taxonomy (e.g., plant distribution and community composition), and environment, which is also influenced by altitude and longitude. Thus, the latitudinal patterns and environmental mechanism could be best revealed by testing a given species along a latitude gradient with similar altitude and longitude. We determined nitrogen (N) and phosphorus (P) concentrations of green (leaf) and senesced leaves (litter) from eight Metasequoia glyptostroboides forests along the eastern coastline of China, with similar altitude and longitude. Leaf N, P concentrations increased along latitude, mainly driven by mean annual temperature (MAT), mean annual precipitation (MAP), annual evaporation (AE), aridity index (AI), and annual total solar radiation (ATSR); While leaf N:P ratio was stable with no latitudinal pattern. Nitrogen resorption efficiency (NRE) increased along latitude, and was also mainly influenced by MAT, MAP, AE, and AI. Phosphorus resorption efficiency (PRE) first increased and then decreased with latitude, which was impacted by soil available P. These results indicated that only climate (such as heat, water, and light) controlled the shift in leaf stoichiometry and NRE, while soil nutrient was likely responsible for the shift in PRE along eastern China. Our findings also suggested that leaf N, P stoichiometry and NRE displayed similar latitudinal patterns at regional scale when studied for a given species (this study) or multi-species (previous studies). PMID- 29126024 TI - Nitrate attenuation in low-permeability sediments based on isotopic and microbial analyses. AB - This study investigated nitrate attenuation in low-permeability sediments (LPS) in a multi-layer aquifer by integrating hydrochemical, isotopic and microbiological molecular techniques in a field site. In the meantime, the overlying high-permeability sediment (HPS) was also examined on the nitrate attenuation for the sake of comparison. Additionally, laboratory flow-through experiments were conducted to assess the overall nitrate reduction rate in the two types of sediment. The delta15N-NO3- and delta34S-SO42- values were more enriched by approximately 370/00 and 150/00 in the LPS than the overlying HPS associated with substantial reductions of the NO3- and SO42- concentration, indicating the occurrence of strong bio-reductions in nitrate and sulfate. The microbial community diversity analyses showed a higher diversity of the denitrifiers encoding nirS- (Shannon Index SI=6.3) and nrf-type gene (SI=2.7), and the sulfate reduction bacteria (SRB) encoding the dsr gene (SI=6.4) in the LPS than in the HPS. The bacterial community structure was influenced by the groundwater hydrochemistry and the redox conditions. Due to the presence of anoxic groundwater with low levels of nutrients, the LPS featured higher abundances of nitrate reducers belonging to Alphaproteobacteria and SRB belonging to the strictly anaerobic class Clostridia relative to the HPS. Notably, chemolithotrophs were abundant in the LPS and likely coupled the reduction of nitrate with the oxidation of iron. Furthermore, the LPS was demonstrated to attenuate nitrate at a rate two times of the HPS in flow-through experiments, and denitrification accounted for approximately 93% of the nitrate reduction. The high nitrate reduction rate of the LPS was likely attributable to its high functional genes diversity. This study confirmed the occurrence of strong nitrate attenuation in the LPS. The LPS was found to play a significant role in protecting aquifers from anthropogenic contamination. PMID- 29126025 TI - Metallurgical residues reused as filler after 35years and their natural weathering implications in a mountain area. AB - The natural weathering of EAF (Electric Arc Furnace) and LF (Ladle Furnace) steel slag was evaluated through changes in the mineralogical and elemental composition. For that purpose, black steel slag and mixture of black and white steel slag were collected from two forest tracks, where they had been used as filler 19 and 35years ago respectively in a protected mountain area. Primary/original and secondary/degradation compounds were identified by spectroscopic techniques (Raman Spectroscopy, X-Ray Diffraction (XRD) and Scanning Electron Microscopy/Energy Dispersive X-Ray Spectroscopy (SEM/EDS)). Among secondary compounds, brucite (Mg(OH)2), portlandite (Ca(OH)2), thaumasite (Ca3Si(CO3)(SO4)(OH)6.12H2O) were identified. Secondary compounds indicated the reactivity of the slag with the surrounding environment (underground waters, atmosphere, lands and organisms), and volume change of the material. This effect could promote fractures in the road and thus, increase the possibility of leaching of hazardous elements (HE), present in the slags, to lands, rivers, etc. Besides, potentially toxic compounds such as hashemite (BaCrO4) and crocoite (PbCrO4) were identified as Cr(VI), which means a potential hazard to the surrounding environment and human life, since the sampling location is a mountain area with recreational activities. Cr(VI) can affect to the growth and development of plants, soil microbial communities, animals and cause allergy, asthma and respiratory tract cancer in humans. Moreover, Inductively Coupled Plasma Mass Spectrometry (ICP-MS) allowed us to observe similar ranges of elemental concentrations in slag samples of the two forest tracks, with the exception of Ca, Mg, Sr, Pb, Ni and As concentration values. They were higher in the forest track with mixture of black and white slag than in the track with only black slag, and therefore, more likely to be leached and to be an environmental risk over time. By contrast, Na, V, Cr and W values were higher in the track with only black steel slag. PMID- 29126026 TI - Legacy and novel brominated flame retardants in indoor dust from Beijing, China: Occurrence, human exposure assessment and evidence for PBDEs replacement. AB - Levels of legacy brominated flame retardants (BFRs), including tetrabromobisphenol A (TBBPA), hexabromocyclododecane isomers (HBCDs) and polybrominated diphenyl ethers (PBDEs), and six currently used novel BFRs were determined in house dust and office dust collected from a community in Beijing, China. This is the first study where the three kinds of legacy BFRs and novel BFRs were all measured in dust samples from China. HPLC-MS/MS was used for the detection of TBBPA and HBCDs, and the other BFRs were tested on a GC-NCI/MS. Decabromodiphenyl ethane (DBDPE), PBDEs, HBCD and TBBPA were found to be the main BFRs in the dust samples, with median levels of 709, 241, 199 and 26.7ng/g dust, respectively. Due to the high density of electronic equipment used in offices, levels of BFRs in office dust were found to be higher than those in house dust. DBDPE, as a replacement of PBDEs, was the predominant BFR, and the median level of DBDPE was not only several orders of magnitude higher than that of other novel BFRs but also 3 to 27 times higher than that of the three legacy BFRs, indicating that the consumption pattern of BFRs in the Chinese market has shifted from PBDEs to PBDE alternatives. Median estimated daily intakes (EDIs) of BFRs through dust ingestion for adults (>20years) and toddlers (<2years) were in the range of 2.8*10-5-0.201ng/kg body weight (bw)/day and 5.7*10-4-2.52ng/kg bw/day, respectively. The body burden of BFRs for toddlers was far higher than that for adults; however, a comparison between EDIs and threshold values suggested that daily intakes of BFRs for both adults and toddlers were unlikely to raise significant health concerns. PMID- 29126027 TI - Strong differences between two congeneric species in sensitivity to pesticides in a warming world. AB - To predict the impact of pesticides in a warming world we need to know how species differ in the interaction pathways between pesticides and warming. Trait based approaches have been successful in identifying the 'pace of life' and body size as predictors of sensitivity to pesticides among distantly related species. However, it remains to be tested whether these traits allow predicting differences in sensitivity to pesticides between closely related species, and in the strength of the interaction pathways between pesticides and warming. We tested the effects of multiple pulses of chlorpyrifos (allowing accumulation) under warming on key life history traits, heat tolerance (CTmax) and physiology of two congeneric damselfly species: the fast-paced (fast growth and development, high metabolic rate), small Ischnura pumilio and the slow-paced, large I. elegans. Chlorpyrifos reduced survival and growth, but contrary to current trait based predictions I. pumilio was 8* less sensitive than I. elegans. The lower sensitivity of I. pumilio could be explained by a higher fat content, and higher activities of acetylcholinesterase and of detoxifying and anti-oxidant enzymes. While for I. pumilio the effect of chlorpyrifos was small and did not depend on temperature, for I. elegans the impact was higher at 20 degrees C compared to 24 degrees C. This matches the higher pesticide accumulation in the water after multiple pulses at 20 degrees C than at 24 degrees C. The expected reduction in heat tolerance after pesticide exposure was present in I. elegans but not in I. pumilio. Our results demonstrate that closely related species can have very different sensitivities to a pesticide resulting in species-specific support for the "toxicant-induced climate change sensitivity" and the "climate-induced toxicant sensitivity" interaction pathways. Our results highlight that trait based approaches can be strengthened by integrating physiological traits. PMID- 29126028 TI - Organization environmental footprint applying a multi-regional input-output analysis: A case study of a wood parquet company in Spain. AB - Wood has been presented as a carbon-neutral material capable of significantly contribute to climate change mitigation and has become an appealing option for the building sector. This paper presents the quantification of the organization environmental footprint of a wood parquet company. The multi-regional input output (MRIO) database EXIOBASE was used with a further structural path analysis decomposition. The application of the proposed method quantifies 14 environmental impacts. Highly influential sectors and regions responsible for these impacts are assessed to propose efficient measures. For the parquet company studied, the highest impact category once normalized was ozone depletion and the dominant sector responsible for this impact was the chemical industry from Spain and China. The structural path decomposition related to ozone loss revealed that the indirect impacts embedded in the supply chain are higher than the direct impacts. It can be concluded that the assessment of the organizational environmental footprint can be carried out applying this well-structured and robust method. Its implementation will enable tracking of the environmental burdens through a company's supply chain at a global scale and provide information for the adoption of environmental strategies. PMID- 29126029 TI - Analysis of organochlorine pesticides in surface water of the Songhua River using magnetoliposomes as adsorbents coupled with GC-MS/MS detection. AB - A simple and effective method based on magnetic separation has been developed for the extraction of organochlorine pesticides (OCPs) from river water samples using magnetoliposomes as adsorbents. This method avoided the time-consuming column passing process of loading large volume samples in traditional SPE through the rapid isolation of magnetoliposomes with an adscititious magnet. Lipid bilayers formed on the surface of Fe3O4 showed great adsorptive tendency towards analytes through hydrophobic interactions, and zwitterions headgroups endowed the outer surface of magnetoliposomes with hydrophilicity to improve the dispersing property of adsorbents in the sample matrix. The target analytes were detected by gas chromatography-tandem mass spectrometry, and the limits of detection obtained are in the range of 0.04-0.35ngL-1. The relative standard deviations of intra- and inter-day are in the range of 2-5% and 4-7%, respectively. The proposed method was employed for analysis of six OCPs in the surface water samples from two cities along the Songhua River in different seasons. Compared with the traditional methods, the proposed method could reduce the consumption of the organic solvent and shorten the sample preparation time. PMID- 29126030 TI - Evaluating the effect of adding Fish oil to Fingolimod on TNF-alpha, IL1beta, IL6, and IFN-gamma in patients with relapsing-remitting multiple sclerosis: A double-blind randomized placebo-controlled trial. AB - OBJECTIVES: Fish oil is claimed to improve outcome in multiple sclerosis (MS) through anti-inflammatory and antioxidant effects by reducing cytokines including TNF-alpha, IFN-gamma, IL6, and IL-1beta. We aimed to evaluate the efficacy of adding fish oil to Fingolimod on these serum cytokines. PATIENTS AND METHODS: This double-blind randomized trial was conducted during April 2015 to September 2016 in Isfahan, Iran. Patients with diagnosis of relapsing remitting MS, aged 18 45years old and expanded disability status scale (EDSS) <=5 were enrolled in the study. The experimental group received 1g/day of fish oil. Serum levels of TNF alpha, IFN-gamma, IL6, and IL-1beta were measured before intervention, 6 months, and 12 months after intervention as the primary outcome. Also, EDSS was evaluated before and at the end of study. RESULTS: 50 patients were recruited initially and nine of them left the study. We found no difference between serum levels of TNF alpha, IFN-gamma, IL6, and IL-1beta at three time-points between two groups (P value >0.05). Also, there was no statistically significant difference in the mean EDSS between the experimental group and the control group after 12 months of intervention (P-value=0.08). CONCLUSIONS: Administration of fish oil did not lower the serum levels of TNF-alpha, IL1beta, IL6, and IFN-gamma compared to placebo. Similarly, it did not improve the disability in patients. PMID- 29126031 TI - NLRP3 inflammasome pathways in atherosclerosis. AB - Atherosclerosis is the major cause of death and disability. Atherosclerotic plaques are characterized by a chronic sterile inflammation in the large blood vessels, where lipid-derived and damage-associated molecular patterns play important roles in inciting immune responses. Following the initial demonstration that NLR family Pyrin domain containing 3 (NLRP3) was important for atherogenesis, a substantial number of studies have emerged addressing the basic mechanisms of inflammasome activation and their relevance to atherosclerosis. In this review, we introduce the basic cellular and molecular mechanisms of NLRP3 inflammasome activation, and discuss the current findings and therapeutic strategies that target NLRP3 inflammasome activation during the development and progression of atherosclerosis. PMID- 29126032 TI - Human myeloma IgG4 reveals relatively rigid asymmetric Y-like structure with different conformational stability of CH2 domains. AB - Human IgG4 (hIgG4) has weak pro-inflammatory activity. The structural basis for this is still unclear. Here a 3D model of myeloma hIgG4 was created at ~3nm resolution using electron microscopy (EM) with negative staining and single particle 3D reconstruction. The hIgG4 model reveals relatively rigid asymmetric Y like structure. The model shows that one Fab subunit is closer to the upper portion of the Fc subunit (CH2 domain) than the other Fab. This is in agreement with X-ray crystallography and X-ray/neutron scattering, recently published by others. The same hIgG4 sample was studied with differential scanning calorimetry (DSC) and fluorescence. The thermodynamics and fluorescence observations indicate that one CH2 domain displays less conformational stability than the other. This finding is consistent with the flipping of one CH2 domain, observed in pembrolizumab (recombinant hIgG4) by X-ray crystallography. The specific feature of hIgG4 CH2 domains together with relatively rigid asymmetric Y-like structure, in which one Fab subunit is closer to the upper portion of the Fc subunit (CH2 domain) than the other Fab, can explain the unique biological properties of hIgG4, such as its weak pro-inflammatory activity. PMID- 29126033 TI - Natural attenuation of chlorinated ethenes in hyporheic zones: A review of key biogeochemical processes and in-situ transformation potential. AB - Chlorinated ethenes (CEs) are legacy contaminants whose chemical footprint is expected to persist in aquifers around the world for many decades to come. These organohalides have been reported in river systems with concerning prevalence and are thought to be significant chemical stressors in urban water ecosystems. The aquifer-river interface (known as the hyporheic zone) is a critical pathway for CE discharge to surface water bodies in groundwater baseflow. This pore water system may represent a natural bioreactor where anoxic and oxic biotransformation process act in synergy to reduce or even eliminate contaminant fluxes to surface water. Here, we critically review current process understanding of anaerobic CE respiration in the competitive framework of hyporheic zone biogeochemical cycling fuelled by in-situ fermentation of natural organic matter. We conceptualise anoxic-oxic interface development for metabolic and co-metabolic mineralisation by a range of aerobic bacteria with a focus on vinyl chloride degradation pathways. The superimposition of microbial metabolic processes occurring in sediment biofilms and bulk solute transport delivering reactants produces a scale dependence in contaminant transformation rates. Process interpretation is often confounded by the natural geological heterogeneity typical of most riverbed environments. We discuss insights from recent field experience of CE plumes discharging to surface water and present a range of practical monitoring technologies which address this inherent complexity at different spatial scales. Future research must address key dynamics which link supply of limiting reactants, residence times and microbial ecophysiology to better understand the natural attenuation capacity of hyporheic systems. PMID- 29126034 TI - Electrolytic and electro-irradiated technologies for the removal of chloramphenicol in synthetic urine with diamond anodes. AB - Hospital effluents are a major source for the occurrence of pharmaceuticals in the environment. In this work, the treatment of synthetic urine polluted with chloramphenicol is studied by using three different conductive-diamond electrochemical oxidation technologies: electrolysis (single electrolysis), photoelectrolysis and high-frequency ultrasound sonoelectrolysis. These technologies were evaluated at 10 and 100 mA cm-2. Results shows that not only chloramphenicol but also other organics contained in urine are completely mineralized by electrolysis. Ammonium is the main inorganic nitrogen species formed and it can react with the electrogenerated hypochlorite, favouring the formation of chloramines. These species prevent the potential formation of perchlorate from chlorides contained in urine at low current densities (10 mA cm 2) and delay its occurrence at high current densities (100 mA cm-2). On the other hand, irradiation of ultraviolet (UV) light or high-frequency ultrasound (US) produce changes in the performance of the electrolytic treatment, but these changes are not as important as in other cases of study shown in the literature. Nonetheless, the effect of electroirradiated technologies seems to be higher and depends on the type of pollutant when working at low current densities (10 mA cm 2). It is positive in the case of the degradation of the antibiotic and the uric acid and negative in the case of urea where there is a clear antagonistic effect. Production of oxidants increases with the current density although in lower ratio than expected. These results are of great importance because clearly point out that electrolytic technologies can be applied to minimize the diffuse pollution associated to pharmaceuticals before discharge into municipal sewers. PMID- 29126035 TI - Histomorphological and biochemical properties of plantar soft tissue in diabetes. AB - BACKGROUND: Diabetes results in pathophysiological changes, leading to tissue that is unable to withstand and adapt to the same loads, resulting in breakdown. Certain locations are more susceptible to breakdown, yet differences between locations are largely not well understood. The authors performed a histological and biochemical analysis of isolated plantar adipose tissue at six relevant locations. METHODS: Tissue from six plantar locations (hallux, first, third and fifth metatarsal heads, lateral midfoot and calcaneus) was taken from fresh cadaveric feet of older diabetic and older non-diabetic intact donors. Histomorphological and biochemical analysis of isolated plantar tissue from both diabetic and non-diabetic feet at six relevant locations was performed. RESULTS: The main differences found between diabetic and non-diabetic tissue were in the thickness of the septal walls and the elastin content. Diabetic tissue had significantly thicker septal walls and an increased elastin concentration. When comparing the calcaneus to other locations, although there were no differences found in the thickness of the septal walls of diabetic tissue, elastin content was lower in the calcaneous tissue compared to the non-calcaneus sites. CONCLUSIONS: Modifications in the structural and biochemical properties could translate to changes in the mechanical properties. This information could lead to an understanding of how the structural and biochemical changes result in an increase in susceptibility of tissue to breakdown with load at the different locations of the foot. PMID- 29126036 TI - Bone cyst formation after ankle arthroplasty may be caused by stress shielding. A numerical simulation of the strain adaptive bone remodelling. AB - BACKGROUND: The history of total ankle arthroplasty (TAA) has different evolution steps to improve the outcome. The third generation implants show an overall 8 year survival rate up to 93%. The main reported reason for early failure of TAA is aseptic loosening, cyst formation is also frequently reported. The aim of the present study is to use the finite element (FE) method to analyze the adaptive bone remodeling processes, including cyst formation after TAA. METHODS: Bone characteristics applied to the model corresponded to information obtained from computed tomography. Finite element models for the tibia and the talus were developed and implant components were virtually implanted. RESULTS: The calculated total bone loss is 2% in the tibia and 17% in the talus. Cysts and areas of increased bone density were detectable dependent on prosthesis design in the tibia and talus. CONCLUSION: Our FE simulation provides a theoretical explanation for cyst formation and increasing bone density depending on implant design. However, cysts are not mono-causal, histo-chemical reactions should also be considered. Further clinical studies are necessary to evaluate the relevance of cyst formation and therapeutic strategies. PMID- 29126037 TI - Radiographic evaluation of first MTP joint arthrodesis for severe hallux valgus: Does the introduction of a lag screw improve union rates and correction of the intermetatarsal angle? AB - BACKGROUND: First metatarsophalangeal (MTP-1) joint fusion is a reliable method for the correction of various deformities including hallux valgus and hallux rigidus. Ideal constructs provide high rates of fusion in desired alignment. The present study examines the union rates, as well as the change in dorsiflexion angle during the follow up period in patients who underwent MTP-1 fusion with a dorsal locking plate and a lag screw, versus patients fused with a dorsal locking plate alone. METHODS: This is a retrospective review of 99 feet undergoing MTP-1 fusion. Joints were fused using either a dorsal locking plate alone or a lag screw plus a dorsal locking plate. Union was determined radiographically during the follow up period. Suspected nonunions were confirmed with CT. Dorsiflexion angles were radiographically measured at first post-operative visit and at final follow up. RESULTS: There were 36 patients in the lag screw plus dorsal plate group, and 63 in the dorsal plate group. Mean follow up was 12.9 months (Range: 12-33.5 months). The dorsal plate plus lag screw group had a significantly lower change in mean dorsiflexion angle (0.57 degrees +/-5.01 degrees ) during the post operative period compared to the dorsal plate group at final follow up versus the dorsal plate group (6.73 degrees +/-7.07 degrees ). CONCLUSION: The addition of a lag screw to a dorsal locking plate for MTP-1 arthrodesis may offer improved stability of the joint in the sagittal plane over time compared to a dorsal plate alone. LEVEL OF EVIDENCE: Retrospective level III evidence. PMID- 29126038 TI - Magnetic resonance imaging findings of chronic plantar fasciitis before and after extracorporeal shock wave therapy. AB - INTRODUCTION: The objective of this study is to examine the relationships between treatment outcome and changes in magnetic resonance (MR) imaging findings after extracorporeal shock wave therapy (ESWT) for chronic plantar fasciitis. METHODS: The subjects were 23 feet of 23 patients of refractory plantar fasciitis. The mean age was 53.7 years. The thickness of the plantar fascia (PF) and findings of a high-signal intensity area (HSIA) inside the PF, edema around the PF, and bone marrow edema (BME) of the calcaneus were investigated on MR images. The Japanese Society for Surgery of the Foot (JSSF) ankle-hindfoot scale and a visual analogue scale (VAS) were used. Correlations between an improvement in symptoms and one in the MRI findings were analyzed. RESULTS: The mean thickness of the PF was 4.4+/ 1.6mm before ESWT and 4.6+/-1.8mm six months after ESWT. After ESWT, there was a decrease in the numbers of feet showing HSIA inside the PF from 15 to 6, in edema around the PF from 16 to 2, and in BME of the calcaneus from 11 to 4. Clinical outcomes improved with ESWT from 70.3+/-5.5 to 88.6+/-9.1 points (JSSF), 74.1+/ 25.3 to 28.5+/-24.4 points (VAS), respectively. Improvements in symptoms according to the JSSF and VAS scores and improvement in edema around the PF on MR images showed a significant correlation. CONCLUSIONS: Edema around the PF improved significantly in association with an improvement in symptoms after ESWT. PMID- 29126039 TI - The resistance to failure of spring ligament reconstruction. AB - INTRODUCTION: The spring ligament (SL) is increasingly recognised as the major structure that fails in acquired adult flatfoot deformity (AAFD). This is the first study that demonstrates integrity of repair of the SL. PATIENTS AND METHODS: Six pairs of fresh frozen cadavers were setup in a standardised fashion with ankle in plantargrade (mean age 59 years, BMI 25). A 25N lateral force was applied to the medial metatarsal head using an algometer. Lateral displacement of the foot was measured with SL intact, sectioned, following FibreWire(r) repair, then Arthrex InternalBrace (IB) reconstruction, then with selective sectioning of each limb of the IB reconstruction. RESULTS: In 12 specimens, overall lateral translation with SL intact was 21mm+/-4.9. This increased to 39.2mm+/-10.9 (p<0.05) with SL sectioning, no significant improvement to 34.2mm+/-9.5 with repair (p=0.159), before significantly returning to baseline 16.55mm+/-5.1 (p<0.001) with the IB. Augmenting with FDL did not influence lateral translation (p=0.586). CONCLUSION: Restoration of SL integrity is fundamental to prevent flatfoot. This study shows traditional repair models fail to provide sufficient resistance to planovalgus. Using an augmented device such as the IB provides optimal resistance to lateral translation and hence planovalgus, particularly the plantar limb of the augmentation. PMID- 29126040 TI - 5-year results of the 1.5cm incision Achilles tendon repair. AB - BACKGROUND: To study a hypothesis that the cost-effective 1.5cm medial incision Achilles tendon repair technique will provide good functional outcomes which are maintained for over 5 years. METHOD: Prospective study of 12 consecutive cases with a minimal 5-year follow-up were recruited from April 2008 to November 2010. Cases whom were mentally incompetent or those which required concomitant procedures were excluded. Outcomes measures included the numeric pain rating scale, motor power strength, range of motion, functional scoring using the AOFAS hindfoot score and patient's self-assessment using the Foot and Ankle Outcome Score (FAOS). RESULT: No re-ruptures or sural nerve injured were identified after a minimal 5-year follow-up. Pain was minimal at 0.5/10, calf power was 5/5 and ankle range was good (plantarflexion: 38 degrees /dorsiflexion: 21 degrees ). The AOFAS hindfoot score was 97.4 and all 5 sub-categories of the Foot and Ankle Outcome Score (FAOS) were good. CONCLUSION: The 1.5cm medial incision repair of the Achilles tendon is an economically sound surgical technique, with minimal complications, which gives good medium length functional outcomes. LEVEL OF EVIDENCE: IV. PMID- 29126041 TI - The effect of eliminating leg length difference on plantar foot pressure distribution in patients wearing forefoot offloading shoe. AB - BACKGROUND AND PURPOSE: Elevated heel construction offloads the forefoot after surgery. However, side-to-side height difference alters limb kinetics, whereas leg-length equalizing-sole at non-operated side may have beneficial effects on foot loading. The purpose of this study was to characterize leg-length equalizing sole effect on bilateral plantar pressures when using heel-lift forefoot offloading shoe. MATERIALS AND METHODS: Twenty men were tested walking. Plantar peak pressures (PP) and pressure-time integrals (PTI) in the forefoot-offloading shoe and in contralateral running shoe were compared between two conditions: one with- and the other without leg-length equalizing sole elevation at the running shoe. RESULTS: Adding leg-length equalizing sole to the running shoe resulted in the following changes in the forefoot-offloading shoe: increased lateral midfoot PP (8.7%, p=0.03), increased lateral midfoot (11.3%, p=0.05) and lateral metatarsals PTI (10.3%, p=0.04), and decreased medial and lateral heel PTI (>5%, p=0.02). These changes were non-significant when applying a Bonferroni correction. Changes in the running shoe were: increased medial midfoot (20.5%, p=0.03) and decreased 2nd and lateral metatarsals PP (23%, p<0.01). PTI increased in medial and lateral heel (>25%, p<0.01), medial midfoot (63.2%, p<0.01) and lateral midfoot (9.2%, p=0.04) and decreased in 2nd and lateral metatarsals (>24.5%, p<0.01). CONCLUSION: Leg-length equalizing sole at contralateral running shoe in subjects wearing forefoot-offloading shoe results in lateral load shift alongside heel pressure attenuation within the forefoot-offloading shoe, which is beneficial during first month after medial forefoot surgery. Reciprocal medial load-shift in the elevated running shoe itself should yet be considered when bilateral medial forefoot pathology is present. PMID- 29126042 TI - Successful treatment of infected wound dehiscence after minimally invasive locking-plate osteosynthesis of tibial pilon and calcaneal fractures by plate preservation, surgical debridement and antibiotics. AB - OBJECTIVE: The aim is to present a case series that illustrates possible benefits from combining minimally invasive plate osteosynthesis (MIPO), plastic surgery and antibiotic therapy, in order to treat and eradicate infection in patients with tibial pilon or calcaneal fractures. METHODS: Eleven consecutive patients with dehiscence of the surgical wound in outcomes MIPO using a Locking Compression Plate (LCP) for tibial pilon, or calcaneus fractures. The patients had developed a documented infection of the surgical wound. All patients were treated and followed-up by the multidisciplinary team with the orthopedic surgeon, the plastic surgeon and the infectious disease physician. All patients were followed by the plastic surgeon to treat the wound dehiscence, as well as by the orthopedic surgeon until fracture consolidation. The duration of the antibiotic therapy was from 4 to 6 months. After 6 weeks, the intravenous treatment was replaced by oral administration. The follow-up intervals were 15 days, 40 days, and 3 months. RESULTS: The average time of wound closure was 109+/ 60 days. The antibiotics used were chosen according to the antibiogram. The antibiotic therapy had a duration of 4-6 months, and after 6 weeks, the therapy switched to oral administration. At the 3-month follow-up, all patients had excellent outcomes and had returned to their normal activity of daily living. CONCLUSION: The patients in this study responded positively to a combination of MIPO, plastic surgery and antibiotic therapy, confirming that multidisplinary treatment in association with titanium devices are able to eradicate infection in short time. PMID- 29126043 TI - Biphasic bioresorbable scaffold (TruFit Plug(r)) for the treatment of osteochondral lesions of talus: 6- to 8-year follow-up. AB - BACKGROUND: The ideal treatment of osteochondral lesions of the talus (OLT) is debatable. The TruFit plug has been investigated as a potential treatment method for osteochondral defects. This is a biphasic scaffold designed to stimulate cartilage and subchondral bone formation. The purpose of this retrospective study was to investigate the long-term functional and MRI outcomes of the TruFit Plug for the treatment of OLT. METHODS: Twelve consecutive patients treated from March 2007 to April 2009 for OLT were evaluated. Clinical examination included the American Orthopaedic Foot and Ankle Society (AOFAS) ankle score and the visual analog scale (VAS) for pain. MRI scans were optained pre-treatment and at last follow-up. The Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score was used to assess cartilage incorporation. RESULTS: Mean follow-up was 7.5 years (range, 6.5-8.7 years). The average age was of 38.6 years (range, 22-57 years). The sex ratio between males and females was 3:1 (9 males, 3 females). The mean AOFAS score improved from a preoperative score of 47.2+/-10.7 to 84.4+/-8 (p<0.05). According to the postoperative AOFAS scores 1 case obtained excellent results, 9 were classified as good, and 2 were fair. VAS score improved from a preoperative value of 6.9+/-1.4 points to 1.2+/-1.1 points at last follow-up (p<0.05). The MOCART score for cartilage repair tissue on postoperative MRI averaged 61.1 points (range, 25-85 points). CONCLUSIONS: The long-term results suggest that the technique of Trufit Plug for OLT is safe and demonstrates good post-operative scores including improvement of pain and function, with discordant MRI results. However, randomized controlled clinical trials comparing TruFit Plug with an established treatment method are needed to improve synthetic biphasic implants as therapy for osteochondral lesions. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 29126044 TI - Medial forefoot fillet flap for primary closure of transmetatarsal amputation: A series of four cases. AB - Amputation of the forefoot is a salvage procedure for several forefoot acute or chronic infection. A good, sensate and durable skin cover is important for quicker and better rehabilitation. The use of filleted flaps (or "spare parts technique") has been published in the past as a creative technique. The purpose of this article is to introduce a reproducible, pre-planned, technique that requires less creativity for the use of the "spare parts". The authors describe a case series of 4 patients with deep infection and osteomyelitis of the forefoot, without involvement of the medial skin that underwent two staged procedure for transmetatarsal amputation with medial forefoot fillet flap. The first procedure was amputation of the 4 lesser metatarsal and the wound was left open. After a few days the second operation was done with amputation of the first metatarsal bone and using the filleted medial skin and subcutaneous tissue for closure of the wound. In conclusion the medial fillet flap is an effective method of covering large wounds after partial, lateral forefoot amputation. This method shortens the healing time of the patient, and in hospital stay. The authors recommend using the staged method when dealing with diabetic patients with partial, central and lateral forefoot deep infection and/or necrosis. PMID- 29126045 TI - The effectiveness of conservative, non-pharmacological treatment, of plantar heel pain: A systematic review with meta-analysis. AB - Plantar heel pain is one of the most common causes of pain and musculoskeletal pathologies of the foot. The aim of this systematic review was to identify the most effective, conservative and non-pharmacological treatments regarding pain in patients with plantar heel pain. The authors searched 5 databases and included only randomized control trials which investigated the efficacy of a conservative non-pharmacological treatment compared to the placebo, for the outcome of pain. Study selection, data collection and risk of bias assessment were conducted independently by two authors, and consensus was reached with a third author. Results were quantitatively summarized in meta-analyses, by separating homogeneous subgroups of trials by type of intervention. A total of 20 studies that investigated the efficacy of 9 different types of interventions were included, with a total of 4 meta-analyses carried out. The interventions: shock waves, laser therapy, orthoses, pulsed radiofrequency, dry-needling, and calcaneal taping resulted in being effective treatments for the outcome pain in patients with plantar heel pain when compared to the placebo. However, considering that the improvements were very small, and the quality of evidence was mostly low or moderate for many of the interventions, it was not possible to give definitive conclusions for clinical practice. PMID- 29126046 TI - Study on the foot shape characteristics of the elderly in China. AB - BACKGROUND: With aging, the feet of the elderly above 60 years old in China present degenerative changes, deformities, and diseases, which significantly affect their daily activities. OBJECTIVES: The authors aimed to study the morphological characteristics of the feet and identify the foot type according to size (length and width) and defect characteristics of elderly feet in China. METHODS: A convenient sample of 1000 subjects above 60 years old was recruited mainly in the regions of Shanghai, Shaanxi, Henan, Hebei, and Sichuan in China. Foot images were collected, and 800 (male 398, female 402) valid questionnaires were recovered. A total of 800 elderly subjects as the test group were invited to measure their foot sizes by means of a Footprint Collector (Tong Yuan Tang Health Management Limited, Qingdao in Shandong province). The foot type of the elderly was compared with that of the general adult Chinese population as the control group using the t-test for independent samples. RESULTS: Hallux valgus (46.9%) and flat foot (50.0%) were the most common foot shape deformities. The most frequent foot diseases were foot scaling (91.2%) and calluses (96.3%). The medial width of the first metatarsal-toe joint of the elderly was significantly higher (elderly female, 44.95+/-4.86mm; elderly male, 48.55+/-4.94mm) than that of the general adult population (adult female, 40.18+/-3.43mm; adult male, 43.22+/ 3.20mm) (p<0.01). CONCLUSION: The foot length of the elderly was not significantly different from that of the general adult Chinese population. The width of the first metatarsal-toe joint in the forefoot of the elderly was significantly higher than that of the general adult Chinese population, which was consistent with the result that a high proportion of elderly subjects presented hallux valgus. PMID- 29126047 TI - Clinico-sonographical evaluation of idiopathic clubfoot and its correction by Ponseti method - A prospective study. AB - BACKGROUND: Objective evaluation of infant with clubfoot is required as conventional imaging modality is of limited usefulness. Ultrasound shows to be a promising technique for assessing deformity and monitoring of clubfoot correction. AIM: Study was done to evaluate the deformity sonographically; to assess the changes in these parameters after treatment by Ponseti method and to correlate these ultrasonographic variables with clinical Pirani score. MATERIALS AND METHODS: 82 feet in 54 children were observed. Clinical assessment was done using Pirani six point system and ultrasound machine with 7.5-12MHz linear transducer was used to measure several parameters and data obtained was assessed to derive correlation between sonographic parameters and clinical system. RESULTS: Medial malleolus navicular distance (MMN) measured on medial view, calcaneo-cuboid distance (CCD) and calcaneo-cuboid angle (CCA) measured on lateral view, talar length (TAL) measured on dorsal view and tibio-calcaneal distance (TCL) measured on posterior view showed statistical significance. Sonographic parameters correlated statistically with Pirani scoring system on measuring Pearson correlation coefficient. CONCLUSION: Ultrasound is a relatively simple, non invasive and widely available procedure that can improve pathomorphological documentation of nonossified clubfoot and its correction. LEVEL OF EVIDENCE: Level II prospective study, as per guidelines for authors. PMID- 29126048 TI - Lennox-Gastaut syndrome in adulthood: Long-term clinical follow-up of 38 patients and analysis of their recorded seizures. AB - Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy with childhood onset that usually continues through adolescence and into adulthood. In the long term, patients with this condition still have intractable seizures, intellectual disability, behavioral problems, and physical comorbidities. The aim of this study was to describe the clinical and EEG characteristics of a group of adults with Lennox-Gastaut syndrome. We identified 38 (22 females, 16 males) patients with LGS older than age 18years at their last evaluation, with mean age of 43.3+/ 10.6years. Median follow-up was 14.4years (range: 2-40). All of our patients had 3 or more seizure types during their clinical history. The most prevalent seizure types at follow-up were atypical absences (28/38), tonic (28/38), generalized tonic-clonic (17/38), focal (11/38), and myoclonic seizures (9/38). All patients had drug-resistant seizures. Besides epilepsy, intellectual disability and behavioral problems were prominent features. Surprisingly, paroxysmal nonepileptic seizures were reported in 3 patients. Our observations confirm the poor outcome of Lennox-Gastaut syndrome through adulthood, regardless of age at seizure onset, etiology, and history of previous West syndrome. PMID- 29126049 TI - Large-scale subject-specific cerebral arterial tree modeling using automated parametric mesh generation for blood flow simulation. AB - In this paper, we present a novel technique for automatic parametric mesh generation of subject-specific cerebral arterial trees. This technique generates high-quality and anatomically accurate computational meshes for fast blood flow simulations extending the scope of 3D vascular modeling to a large portion of cerebral arterial trees. For this purpose, a parametric meshing procedure was developed to automatically decompose the vascular skeleton, extract geometric features and generate hexahedral meshes using a body-fitted coordinate system that optimally follows the vascular network topology. To validate the anatomical accuracy of the reconstructed vasculature, we performed statistical analysis to quantify the alignment between parametric meshes and raw vascular images using receiver operating characteristic curve. Geometric accuracy evaluation showed an agreement with area under the curves value of 0.87 between the constructed mesh and raw MRA data sets. Parametric meshing yielded on-average, 36.6% and 21.7% orthogonal and equiangular skew quality improvement over the unstructured tetrahedral meshes. The parametric meshing and processing pipeline constitutes an automated technique to reconstruct and simulate blood flow throughout a large portion of the cerebral arterial tree down to the level of pial vessels. This study is the first step towards fast large-scale subject-specific hemodynamic analysis for clinical applications. PMID- 29126050 TI - Metagenomic analysis of the bacterial communities and their functional profiles in water and sediments of the Apies River, South Africa, as a function of land use. AB - Water quality is an important public health issue given that the presence of pathogenic organisms in such waters can adversely affect human and animal health. Despite the numerous studies conducted to assess the quality of environmental waters in many countries, limited efforts have been put on investigating the microbial quality of the sediments in developing countries and how this relates to different land uses. The present study evaluated the bacterial diversity in water and sediments in a highly used South African river to find out how the different land uses influenced the bacterial diversity, and to verify the human diseases functional classes of the bacterial populations. Samples were collected on river stretches influenced by an informal, a peri-urban and a rural settlement. Genomic DNA was extracted from water and sediment samples and sequenced on an Illumina(r) MiSeq platform targeting the 16S rRNA gene variable region V3-V4 from the genomic DNA. Metagenomic data analysis revealed that there was a great diversity in the microbial populations associated with the different land uses, with the informal settlement having the most considerable influence on the bacterial diversity in the water and sediments of the Apies River. The Proteobacteria (69.8%), Cyanobacteria (4.3%), Bacteroidetes (2.7%), and Actinobacteria (2.7%) were the most abundant phyla; the Alphaproteobacteria, Betaproteobacteria and Anaerolineae were the most recorded classes. Also, the sediments had a greater diversity and abundance in bacterial population than the water column. The functional profiles of the bacterial populations revealed an association with many human diseases including cancer pathways. Further studies that would isolate these potentially pathogenic organisms in the aquatic environment are therefore needed as this would help in protecting the lives of communities using such rivers, especially against emerging bacterial pathogens. PMID- 29126051 TI - Oxidation resistance of biochars as a function of feedstock and pyrolysis condition. AB - Assessing biochar's ability to resist oxidation is fundamental to understanding its potential to sequester carbon. Chemical oxidation exhibits good performance in estimating the oxidation resistance of biochar. Herein, oxidation resistance of 14 types of biochars produced from four feedstocks at different pyrolysis conditions (hydrothermal versus thermal carbonization) was investigated via hydrogen peroxide oxidation with varying concentrations. The oxidation resistance of organic carbon (C) of hydrochars was relatively higher than that of 250 degrees C pyrochars (P250) but was comparable to that of 450 degrees C pyrochars (P450). Both hydrochars and P450 from ash-rich feedstocks contained at least three different C pools (5.9-18.3% labile, 43.2-56.5% semi-labile and 26.9-45.9% stable C). Part (<33%) of aromatic C within 600 degrees C pyrochars (P600) was easily oxidizable, which consisted of amorphous C. The influence of pyrolysis temperature upon oxidation resistance of biochars depended on the feedstock. For ash-rich feedstock (rice straw, swine manure and poultry litter), the oxidation resistance of biochars was determined by both aromaticity and mineral components, and mineral protection was regulated by pyrolysis conditions. The amorphous silicon within hydrochars and P450 could interact with C, preventing C from being oxidized, to some extent. Nevertheless, this type of protection did not occur for P250 and P600. PMID- 29126052 TI - Field assessment of bacterial communities and total trihalomethanes: Implications for drinking water networks. AB - Operation and maintenance (O&M) of drinking water distribution networks (DWDNs) in tropical countries simultaneously face the control of acute and chronic risks due to the presence of microorganisms and disinfection by-products, respectively. In this study, results from a detailed field characterization of microbiological, chemical and infrastructural parameters of a tropical-climate DWDN are presented. Water physicochemical parameters and the characteristics of the network were assessed to evaluate the relationship between abiotic and microbiological factors and their association with the presence of total trihalomethanes (TTHMs). Illumina sequencing of the bacterial 16s rRNA gene revealed significant differences in the composition of biofilm and planktonic communities. The highly diverse biofilm communities showed the presence of methylotrophic bacteria, which suggest the presence of methyl radicals such as THMs within this habitat. Microbiological parameters correlated with water age, pH, temperature and free residual chlorine. The results from this study are necessary to increase the awareness of O&M practices in DWDNs required to reduce biofilm formation and maintain appropriate microbiological and chemical water quality, in relation to biofilm detachment and DBP formation. PMID- 29126053 TI - A new method and a new index for identifying socioeconomic drought events under climate change: A case study of the East River basin in China. AB - Drought is a complex natural hazard that may have destructive damages on societal properties and even lives. Generally, socioeconomic drought occurs when water resources systems cannot meet water demand, mainly due to a weather-related shortfall in water supply. This study aims to propose a new method, a heuristic method, and a new index, the socioeconomic drought index (SEDI), for identifying and evaluating socioeconomic drought events on different severity levels (i.e., slight, moderate, severe, and extreme) in the context of climate change. First, the minimum in-stream water requirement (MWR) is determined through synthetically evaluating the requirements of water quality, ecology, navigation, and water supply. Second, according to the monthly water deficit calculated as the monthly streamflow data minus the MWR, the drought month can be identified. Third, according to the cumulative water deficit calculated from the monthly water deficit, drought duration (i.e., the number of continuous drought months) and water shortage (i.e., the largest cumulative water deficit during the drought period) can be detected. Fourth, the SEDI value of each socioeconomic drought event can be calculated through integrating the impacts of water shortage and drought duration. To evaluate the applicability of the new method and new index, this study examines the drought events in the East River basin in South China, and the impact of a multi-year reservoir (i.e., the Xinfengjiang Reservoir) in this basin on drought analysis is also investigated. The historical and future streamflow of this basin is simulated using a hydrologic model, Variable Infiltration Capacity (VIC) model. For historical and future drought analysis, the proposed new method and index are feasible to identify socioeconomic drought events. The results show that a number of socioeconomic drought events (including some extreme ones) may occur in future, and the appropriate reservoir operation can significantly ease such situation. PMID- 29126054 TI - A study of genotoxicity and oxidative stress induced by mercuric chloride in the marine polychaete Perinereis aibuhitensis. AB - The marine polychaete worm Perinereis aibuhitensis was used to study the genotoxic effects of mercuric chloride by means of the comet assay and micronucleus (MN) test. P. aibuhitensis was subjected in vivo to two different concentrations of mercuric chloride (0.05mgL-1 and 0.5mgL-1) for 96h. The comet assay of coelomocytes demonstrated that TailDNA% values increased with extended exposure to or increased concentrations of HgCl2 (p<0.01). The frequency of MNs was the highest in the treatment with 96h of exposure at all concentrations (p<0.01). The genotoxic effect of HgCl2 was both dose- and time-dependent in exposed P. aibuhitensis. The activities of the antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidases (GPx) were also estimated. Significant variations in antioxidant enzyme activities depended on the sampling time and the concentrations of mercuric chloride. Compared with the control, the activities of the antioxidant enzymes (SOD and GPx) were elevated at the lower concentration of mercuric chloride (0.05mg L-1) (p<0.05) for shorter exposure periods (24h and 72h). At the higher concentration of mercury (0.5mgL-1), the activities of GPx and SOD were inhibited; no variation was observed. These results proved that the use of the comet assay and MN test in coelomocytes of P. aibuhitensis is appropriate for determining the levels of DNA damage and that P. aibuhitensis is a species that is sensitive to mercury pollutants. This species may be considered a suitable candidate for monitoring marine heavy metal pollution. PMID- 29126055 TI - Estrogen-responsive gene networks in the teleost liver: What are the key molecular indicators? AB - An overarching goal of environmental genomics is to leverage sensitive suites of markers that are robust and reliable to assess biological responses in a range of species inhabiting variable environments. The objective of this study was to identify core groups of transcripts and molecular signaling pathways that respond to 17alpha-ethylinestadiol (EE2), a ubiquitous estrogenic contaminant, using transcriptome datasets generated from six independent laboratories. We sought to determine which biomarkers and gene networks were those most robust and reliably detected in multiple laboratories. Six laboratories conducted microarray analysis in pieces of the same liver from male fathead minnows exposed to ~15ng/L EE2 for 96h. There were common transcriptional networks identified in every dataset. These included down-regulation of gene networks associated with blood clotting, complement activation, triglyceride storage, and xenobiotic metabolism. Noteworthy was that more than ~85% of the gene networks were suppressed by EE2. Leveraging both these data and those mined from the Comparative Toxicogenomics Database (CTD), we narrowed in on an EE2-responsive transcriptional network. All transcripts in this network responded ~+/-5-fold or more to EE2, increasing reliability of detection. This network included estrogen receptor alpha, transferrin, myeloid cell leukemia 1, insulin like growth factor 1, insulin like growth factor binding protein 2, and methionine adenosyltransferase 2A. This estrogen-responsive interactome has the advantage over single markers (e.g. vitellogenin) in that these entities are directly connected to each other based upon evidence of expression regulation and protein binding. Thus, it represents an interacting functional suite of estrogenic markers. Vitellogenin, the gold standard for estrogenic exposures, can show high individual variability in its response to estrogens, and the use of a multi-gene approach for estrogenic chemicals is expected to improve sensitivity. In our case, the coefficient of variation was significantly lowered by the gene network (~67%) compared to Vtg alone, supporting the use of this transcriptional network as a sensitive alternative for detecting estrogenic effluents and chemicals. We propose that screening chemicals for estrogenicity using interacting genes within a defined expression network will improve sensitivity, accuracy, and reduce the number of animals required for endocrine disruption assessments. PMID- 29126056 TI - Developing the role of Swedish advanced practice nurse (APN) through a blended learning master's program: Consequences of knowledge organisation. AB - This paper reports on a research study conducted with a group of nurses in Sweden enrolled in a newly developed blended learning master's programme to become advanced practice nurses (APNs). As background, the paper presents the regional needs the programme is intended to address and describes how the programme was designed. The aim was to understand how, from students' perspective, the nurse master's programme structured knowledge for their future position as APNs. The research question focuses on how the master's programme prepares students by meeting their diverse needs for knowledge. Empirical material was collected at two times during the students' first and second years of study through semi structured qualitative interviews. The findings highlight the process in which these master's students gained a more advanced identity of becoming APNs. This process demonstrates how students perceive their current position as nurses based on a discourse of knowledge in relation to the practical and theoretical knowledge they encounter in the master's programme. This article concludes by recommending that attention should be paid to developing APN role models in the current Swedish healthcare system. PMID- 29126057 TI - An investigation of nurse education service models in acute care metropolitan hospitals across Australia. AB - This paper outlines a study that was undertaken to investigate the different nurse education service models being utilised in acute care metropolitan hospitals across Australia with a view to make recommendations for future nurse education service delivery within healthcare organisations. This research study used a mixed methods approach comprising three phases. Phase one involved interviews and focus groups with nurse educators at one tertiary teaching hospital in Perth, Western Australia (WA). Phase two involved focus groups and interviews with nurse educators and coordinators of nurse education services in acute care metropolitan hospitals in W.A. Phase three of the study consisted of the development of a survey tool from the findings of the previous phases and a national survey of nurse educators in acute care metropolitan hospitals across Australia. The findings of this study demonstrate that a centralised nurse education service model undertakes more functions than, and delivers significant advantages over, the decentralised and combination models. PMID- 29126058 TI - Empowering clinical supervisors to flourish though critical companionship. AB - Education for professional nursing practice has undergone a significant shift over the last few decades impacting nursing practice and the relationship between nurses. Enhancing professional practice and acting as a conduit for empowering nurses to be active participants in their learning and development is Practice Development. This action research project with philosophical premises of critical companionship and human flourishing aimed to develop the knowledge and skills of registered nurses in their ability to provide clinical supervision of nursing students in practice. The overall project consisted of two action research cycles in two different health facilities. Participants in both projects identified similar issues and common learning needs including; how to better understand and develop skills in reflective practice; how to provide a positive learning and enabling environment; and how to provide effective solution focused feedback. Workshop facilitators witnessed the flourishing of participants as they were enabled to negotiate their learning requirements; grow and develop in their roles over the workshop series. Participants themselves identified personal growth in skills, knowledge and confidence in being a preceptor as a result of the workshops in the study. Overall, this study has resulted in the development and capacity building of the nursing workforce clinical placement capacity through the development of clinical supervisors. PMID- 29126059 TI - Enhancing early psychosis treatment using smartphone technology: A longitudinal feasibility and validity study. AB - Smartphone applications that promote symptom tracking and self-management may improve treatment of serious mental illness (SMI). Although feasibility has been established in chronic adult outpatient or inpatient SMI samples, no data exist regarding implementation of smartphone technology in adolescent and young adult populations as part of early psychosis (EP) outpatient care. We implemented a smartphone "app" plus clinician Dashboard as an add-on treatment tool in the University of California, Davis Early Psychosis Program. Participants completed daily and weekly surveys examining mood, symptoms, and treatment relevant factors via the app for up to 14 months. Clinicians discussed symptom ratings and surveys during regular treatment sessions using the Dashboard. We report methodological details of the study, feasibility metrics, and analyses of the validity of measuring symptoms via self-report using mobile health (mHealth) technology in comparison to gold-standard clinician-rated interviews based on a comprehensive longitudinal analysis of within-person data. Results demonstrate that integrating mHealth technology into EP care is feasible and self-report assessment of symptoms via smartphone provides symptom data comparable to that obtained via gold-standard clinician-rated assessments. PMID- 29126060 TI - Selenium treatment differentially affects sulfur metabolism in high and low glucosinolate producing cultivars of broccoli (Brassica oleracea L.). AB - The effect of selenium (Se) application on the sulfur (S)-rich glucosinolate (GSL)-containing plant, broccoli (Brassica oleracea L. var. italica) was examined with a view to producing germplasm with increased Se and GSL content for human health, and to understanding the influence of Se on the regulation of GSL production. Two cultivars differing in GSL content were compared. Increased Se application resulted in an increase in Se uptake in planta, but no significant change in total S or total GSL content in either cultivar. Also no significant change was observed in the activity of ATP sulfurylase (ATPS, EC 2.7.7.4) or O acetylserine(thiol) lyase (OASTL, EC 2.5.1.47) with increased Se application. However, in the first investigation of APS kinase (APSK, EC 2.7.1.25) expression in response to Se fertilisation, an increase in transcript abundance of one variant of APS kinase 1 (BoAPSK1A) was observed in both cultivars, and an increase in BoAPSK2 transcript abundance was observed in the low GSL producing cultivar. A mechanism by which increased APSK transcription may provide a means of controlling the content of S-containing compounds, including GSLs, following Se uptake is proposed. PMID- 29126061 TI - Carbon-bromine bond cleavage - A perspective from bromine and carbon kinetic isotope effects on model debromination reactions. AB - In this work, we explore the effect of solvent on 13C and 81Br kinetic isotope effects (KIEs) during elimination of bromine substituent from brominated organic compounds promoted by hydroxyl anion. In the present study, we investigate HBr elimination from 2-bromoethylbenzene in three different polar media (water, ethanol, and acetonitrile) as well as bromide ion elimination from 1,2 dibromoethane upon nucleophilic substitution by the hydroxyl ion in aqueous solution using carbon and bromine isotope analysis as mechanistic tools. We reconsider the hypothesis that the magnitude of leaving group halide KIE should visibly depend on the solvent and bond-breaking in a protic solvent should be accompanied by hydrogen bonding which would result in less zero-point energy loss than in an aprotic solvent. Modeling the elimination reaction using the available popular theoretical methods along with different approaches for including environment effects we demonstrate in the presented study no interpretable effect of the solvent on the transition state structure and hence on the theoretically predicted KIEs. The comparison of the magnitudes of carbon and bromine kinetic isotope effects for two different mechanistic pathways (elimination vs substitution) is also discussed. PMID- 29126062 TI - Habitat fragmentation caused by contaminants: Atrazine as a chemical barrier isolating fish populations. AB - Information on how atrazine can affect the spatial distribution of organisms is non-existent. As this effect has been observed for some other contaminants, we hypothesized that atrazine-containing leachates/discharges could trigger spatial avoidance by the fish Poecilia reticulata and form a chemical barrier isolating upstream and downstream populations. Firstly, guppies were exposed to an atrazine gradient in a non-forced exposure system, in which organisms moved freely among the concentrations, to assess their ability to avoid atrazine. Secondly, a chemical barrier formed by atrazine, separating two clean habitats (extremities of the non-forced system), was simulated to assess whether the presence of the contaminant could prevent guppies from migrating to the other side of the system. Fish were able to avoid atrazine contamination at environmentally relevant concentrations (0.02 MUg L-1), below those described to cause sub-lethal effects. The AC50 (atrazine concentration causing avoidance to 50% of the population) was 0.065 MUg L-1. The chemical barrier formed by atrazine at 150 MUg L-1 (concentration that should produce an avoidance around 82%) caused a reduction in the migratory potential of the fish by 47%; while the chemical barrier at 1058 MUg L-1 (concentration that produces torpidity) caused a reduction in the migratory potential of the fish by 91%. Contamination by atrazine, besides driving the spatial distribution of fish populations, has potential to act as a chemical barrier by isolating fish populations. This study includes a novel approach to be integrated in environmental risk assessment schemes to assess high tier contamination effects such as habitat fragmentation and population displacement and isolation. PMID- 29126063 TI - Estimation of chemical emissions from down-the-drain consumer products using consumer survey data at a country and wastewater treatment plant level. AB - Deriving reliable estimates of chemical emissions to the environment is a key challenge for impact and risk assessment methods and typically the associated uncertainty is not characterised. We have developed an approach to spatially quantify annual chemical emission loads to the aquatic environment together with their associated uncertainty using consumer survey data and publicly accessible and non-confidential data sources. The approach is applicable for chemicals widely used across a product sector. Product usage data from consumer survey studies in France, the Netherlands, South Korea and the USA were combined with information on typical product formulations, wastewater removal rates, and the spatial distribution of populations and wastewater treatment plants (WWTPs) in the four countries. Results are presented for three chemicals common to three types of personal care products (shampoo, conditioner, and bodywash) at WWTP and national levels. Uncertainty in WWTP-specific emission estimates was characterised with a 95% confidence interval and ranged up to a factor of 4.8 around the mean, mainly due to uncertainty associated with removal efficiency. Estimates of whole country product usage were comparable to total market estimates derived from sectorial market sales data with differences ranging from a factor 0.8 (for the Netherlands) to 5 (for the USA). The proposed approach is suitable where measured data on chemical emissions is missing and is applicable for use in risk assessments and chemical footprinting methods when applied to specific product categories. PMID- 29126064 TI - Effect of alkaline precipitation on Cr species of Cr(III)-bearing complexes typically used in the tannery industry. AB - Various organic compounds extensively used in the leather industry could influence the performance of alkaline precipitation with Cr(III). This study focused on two typical Cr(III)-bearing complexes (Cr(III)-collagen and Cr(III) citrate) ubiquitous in tannery effluent yet with distinct treatment efficiencies, as Cr(III) was much more difficult to remove in the Cr(III)-citrate solution. Comprehensive analytical methods were employed to explore the intrinsic mechanism. It was found that a lower removal efficiency towards Cr(III) was significantly associated with higher oligomers. The molecular size of the Cr(III) citrate complex continued to increase with rising pH, making it larger overall than Cr(III)-collagen species. The growing oligomer moiety of dissolved Cr(III) complex species could persist in the stronger basic pH range, leading to the large amount of residual Cr(III) in the Cr(III)-citrate system. Combining this result with potentiometric titration and X-ray photoelectron spectroscopy data, it was believed that the polymeric species other than monomers facilitated resisting the attack from hydroxide ions, and the postulated Cr(III)-citrate species towards higher oligomers were discovered. Beyond that, both charge neutralization and sweeping effects were presented among the gradually emerging flocs in the Cr(III)-collagen system together with the electric double layer compression effect derived from salinity, thus resulting in a larger floc size and higher Cr(III) removal efficiency in saline solutions. PMID- 29126065 TI - Bioconversion of alkaloids to high-value chemicals: Comparative analysis of newly isolated lupanine degrading strains. AB - This work explores the potential for development of a lupanine valorization process evaluating different isolated microorganisms for their capacity to metabolize the alkaloid. Ecotoxicological assessment demonstrated that lupanine is toxic for Vibrio fischeri and Daphnia magna exhibiting EC50 values of 89 mg L 1 and 47 mg L-1 respectively, while acting both as growth inhibitor for a monocotyledonous and as promoter for a dicotyledonous plant. Among the eight aerobic and anaerobic strains isolated and identified Rhodococcus rhodochrous LPK211 achieved 81% removal for 1.5 g L-1 lupanine, while no end-products were detected by NMR constituting a promising microorganism for lupanine biodegradation. Moreover, Rhodococcus ruber LPK111 and Rhodococcus sp. LPK311 exhibited 66% and 71% of removal respectively, including potential formation of lupanine N-oxide. Pseudomonas putida LPK411 reached 80% of lupanine removal and generated three fermentation products potentially comprising 17-oxolupanine and lupanine derivatives with open ring structures enabling the development of alkaloid valorization processes. PMID- 29126066 TI - Formaldehyde regulates vascular tensions through nitric oxide-cGMP signaling pathway and ion channels. AB - Formaldehyde (FA) has been linked to the detrimental cardiovascular effects. Here, we explored the effects and mechanisms of FA on rat aortas both in vivo and in vitro. The results presented that FA evidently lowered the blood pressures of rats. The expression levels of BKCa subunits alpha and beta1 and iNOS of the aortas were up-regulated by FA in vivo. However, FA markedly reduced the levels of Cav1.2 and Cav1.3, which are the subunits of L-Ca2+ channel. Furthermore, the contents of NO, cGMP and iNOS in the aortas were augmented by FA. To further confirm these findings, the mechanisms accredited to these effects were examined in vitro. The data showed that FA contracted the isolated aortic rings at low concentrations (<300 MUM), while it relaxed the rings at high concentrations (>500 MUM). The FA-induced vasoconstriction at low concentrations was blocked partly by an inhibitor of ACE. The relaxation caused by FA at high concentrations was attenuated by the inhibitors of NO-cGMP pathway, L-Ca2+ channel and BKCa channel, respectively. Similarly, the expression of iNOS was strongly enhanced by FA in vitro. The effects of FA on the aortic rings with endothelium were significantly greater than those on the rings without endothelium. Our results indicate that the vasoconstriction of FA at low concentrations might be partially pertinent to endothelin, and the FA-caused vasorelaxation at high concentrations is possibly associated with the NO-cGMP pathway, L-Ca2+ channel and BKCa channel. This study will improve our understanding of the pathogenic mechanisms for FA related cardiovascular diseases. PMID- 29126067 TI - N-doping effectively enhances the adsorption capacity of biochar for heavy metal ions from aqueous solution. AB - N-doping was successfully employed to improve the adsorption capacity of biochar (BC) for Cu2+ and Cd2+ by direct annealing of crop straws in NH3. The surface N content of BC increased more than 20 times by N-doping; meanwhile the content of oxidized-N was gradually diminished but graphitic-N was formed and increased with increasing annealing temperature and duration time. After N-doping, a high graphitic-N percentage (46.4%) and SBET (418.7 m2/g) can be achieved for BC. As a result, the N-doped BC exhibited an excellent adsorption capacity for Cu2+ (1.63 mmol g-1) and Cd2+ (1.76 mmol g-1), which was up to 4.0 times higher than that of the original BC. Furthermore, the adsorption performance of the N-doped BC remained stable even at acidic conditions. A positive correlation can be found between adsorption capacity with the graphitic N content on BC surface. The surface chemistry of N-doped BC before and after the heavy metal ions adsorption was carefully examined by XPS and FTIR techniques, which indicated that the adsorption mechanisms mainly included cation-pi bonding and complexation with graphitic-N and hydroxyl groups of carbon surfaces. PMID- 29126068 TI - Margined winner-take-all: New learning rule for pattern recognition. AB - The neocognitron is a deep (multi-layered) convolutional neural network that can be trained to recognize visual patterns robustly. In the intermediate layers of the neocognitron, local features are extracted from input patterns. In the deepest layer, based on the features extracted in the intermediate layers, input patterns are classified into classes. A method called IntVec (interpolating vector) is used for this purpose. This paper proposes a new learning rule called margined Winner-Take-All (mWTA) for training the deepest layer. Every time when a training pattern is presented during the learning, if the result of recognition by WTA (Winner-Take-All) is an error, a new cell is generated in the deepest layer. Here we put a certain amount of margin to the WTA. In other words, only during the learning, a certain amount of handicap is given to cells of classes other than that of the training vector, and the winner is chosen under this handicap. By introducing the margin to the WTA, we can generate a compact set of cells, with which a high recognition rate can be obtained with a small computational cost. The ability of this mWTA is demonstrated by computer simulation. PMID- 29126069 TI - Visualizing deep neural network by alternately image blurring and deblurring. AB - Visualization from trained deep neural networks has drawn massive public attention in recent. One of the visualization approaches is to train images maximizing the activation of specific neurons. However, directly maximizing the activation would lead to unrecognizable images, which cannot provide any meaningful information. In this paper, we introduce a simple but effective technique to constrain the optimization route of the visualization. By adding two totally inverse transformations, image blurring and deblurring, to the optimization procedure, recognizable images can be created. Our algorithm is good at extracting the details in the images, which are usually filtered by previous methods in the visualizations. Extensive experiments on AlexNet, VGGNet and GoogLeNet illustrate that we can better understand the neural networks utilizing the knowledge obtained by the visualization. PMID- 29126070 TI - Deep neural networks for texture classification-A theoretical analysis. AB - We investigate the use of Deep Neural Networks for the classification of image datasets where texture features are important for generating class-conditional discriminative representations. To this end, we first derive the size of the feature space for some standard textural features extracted from the input dataset and then use the theory of Vapnik-Chervonenkis dimension to show that hand-crafted feature extraction creates low-dimensional representations which help in reducing the overall excess error rate. As a corollary to this analysis, we derive for the first time upper bounds on the VC dimension of Convolutional Neural Network as well as Dropout and Dropconnect networks and the relation between excess error rate of Dropout and Dropconnect networks. The concept of intrinsic dimension is used to validate the intuition that texture-based datasets are inherently higher dimensional as compared to handwritten digits or other object recognition datasets and hence more difficult to be shattered by neural networks. We then derive the mean distance from the centroid to the nearest and farthest sampling points in an n-dimensional manifold and show that the Relative Contrast of the sample data vanishes as dimensionality of the underlying vector space tends to infinity. PMID- 29126072 TI - An unusual case of giant ileal diverticulum-A case report. AB - Small bowel diverticulosis is rare with an incidence of 1-2% in the general population. It is an uncommon cause of gastrointestinal bleeding that ranges from obscure to overt bleeding. Large ileal diverticula are extremely rare and bleeding complications can result in high overall mortality. A young gentleman presented with persistent per-rectal bleeding and drop in hemoglobin level. He was recently diagnosed with acute myeloid leukemia and was undergoing chemotherapy. A computed tomography scan of the abdomen and pelvis revealed a giant ileal diverticulum. In view of on-going bleeding, he underwent double balloon enteroscopy which revealed active bleeding from an ulcer within the giant ileal diverticulum and successful hemostasis was performed with hemostatic clips. Small bowel diverticulosis though uncommon has to be considered during workup for gastrointestinal bleeding. Endoscopic treatment is a modern approach towards small bowel diverticular bleeding that is effective and less invasive. PMID- 29126071 TI - alpha-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurofibrillary tangles (NFTs) composed of Tau protein. alpha Lipoic acid (LA) has been found to stabilize the cognitive function of AD patients, and animal study findings have confirmed its anti-amyloidogenic properties. However, the underlying mechanisms remain unclear, especially with respect to the ability of LA to control Tau pathology and neuronal damage. Here, we found that LA supplementation effectively inhibited the hyperphosphorylation of Tau at several AD-related sites, accompanied by reduced cognitive decline in P301S Tau transgenic mice. Furthermore, we found that LA not only inhibited the activity of calpain1, which has been associated with tauopathy development and neurodegeneration via modulating the activity of several kinases, but also significantly decreased the calcium content of brain tissue in LA-treated mice. Next, we screened for various modes of neural cell death in the brain tissue of LA-treated mice. We found that caspase-dependent apoptosis was potently inhibited, whereas autophagy did not show significant changes after LA supplementation. Interestingly, Tau-induced iron overload, lipid peroxidation, and inflammation, which are involved in ferroptosis, were significantly blocked by LA administration. These results provide compelling evidence that LA plays a role in inhibiting Tau hyperphosphorylation and neuronal loss, including ferroptosis, through several pathways, suggesting that LA may be a potential therapy for tauopathies. PMID- 29126073 TI - Facile synthesis of ultrafine cobalt oxides embedded into N-doped carbon with superior activity in hydrogenation of 4-nitrophenol. AB - Design and synthesis of low-cost catalysts with high activity and stability for hydrogenation reactions is an important research area of applied catalysis. In this work, we present a kind of ultrafine cobalt oxides encapsulated by N-doped carbon (donated as CoOx/CN) as efficient catalysts for hydrogenation of 4 nitrophenol (4-NP) process. The CoOx/CN was fabricated through a pyrolysis strategy using an N-containing metal-organic framework (Co-MOF) as precursor followed by a fine thermal-treatment. With an optimized pyrolysis temperature of 500 degrees C, the CoOx species present as ultrafine particles highly dispersed in the obtained catalyst (CoOx/CN-500). CoOx/CN-500 exhibits excellent activity and stability in hydrogenation of 4-NP at ambient conditions. The activity is much higher than that of not only bulk cobalt oxides, but also carbon supported CoOx catalysts. It could be used for more than 8 times without obvious fading in activity. In addition, the concrete role of Co-MOF precursor and pyrolysis condition in the catalyst design was investigated in detail. The interaction between organic ligands and Co ions and the confinement of the crystalline structure of Co-MOF could restrain the aggregation of Co ions during pyrolysis and lead to high dispersion of ultrafine CoOx species. Meanwhile, the N containing ligands could be transformed into doped N species (pyridinic and pyrrolic N), endowing the CoOx species with high electron density and promoting the formation of active sites for the hydrogenation reaction. PMID- 29126074 TI - Amphiphilic PA-induced three-dimensional graphene macrostructure with enhanced removal of heavy metal ions. AB - Phytic acid (PA) induced graphene macrostructures were synthesized and investigated for the sorption characteristics and mechanisms of mercury. The as synthesized graphene foam possessed large specific surface area and amphiphilicity. FTIR and XPS analysis revealed that the as-prepared graphene macrostructure retained oxygen-containing functional groups after hydrothermal reduction and also captured new phosphorus-containing groups because of the introduction of PA. Different experimental parameters, such as pH, PA fractions and contact time were applied to probe into the Hg(II) adsorption performance of as-synthesized macrostructure. Pseudo-second-order kinetic model and Langmuir isotherm model fitted well to the obtained sorption kinetic and isothermal data. The maximum adsorption capacity at pH = 7.2 for mercury was 361.01 mg/g. The dominant mechanisms for mercury removal were mainly ion exchange and surface complexation. Real application in river water and seawater exhibited very promising results, indicating its broad prospect in water purification. PMID- 29126075 TI - Spin diffusion and 1H spin-lattice relaxation in Cs2(HSO4)(H2PO4) containing a small amount of ammonium ions. AB - Inorganic solid acid salts with hydrogen bond networks frequently show very long spin-lattice relaxation times even for 1H because the hydrogen bonds suppress motions. In the present work, the 1H spin-lattice relaxation in Cs2(HSO4)(H2PO4) containing a small amount of ammonium ions were studied in detail by use of the effect of magic angle spinning (MAS) on the relaxation. The 1H spin-lattice relaxation times of the acid protons decrease with increase in the content of ammonium ions. Reorientation of the NH4 group fluctuates the dipole-dipole interaction and relaxes the ammonium protons as well as the acid protons. The 1H relaxation times of the acid protons are a little bit longer than those of the ammonium protons at the MAS rate of 8 kHz. The spinning at 50 kHz makes the relaxation times of the acid protons longer and those of the ammonium protons shorter. Spin diffusion between the acid and the ammonium protons averages partially the 1H relaxation of the acid and the ammonium protons at the MAS rate of 8 kHz. The spin diffusion is suppressed completely at the MAS rate of 50 kHz. Spin diffusion between the acid protons is not suppressed at the MAS rate of 50 kHz. The acid protons always show the same relaxation times. The intrinsic relaxation times not affected by spin diffusion are evaluated quantitatively for both the acid and the ammonium protons. Those values are independent of the ammonium content. Contribution of the spin diffusion between the acid and the ammonium protons to the relaxation is estimated quantitatively. Using those parameters, the effect of ammonium ions on the 1H spin-lattice relaxation can be predicted. The 1H spin-lattice relaxation is a sensitive tool to study the distribution of ammonium ions in solids. PMID- 29126076 TI - A rapid and sensitive chiral LC-MS/MS method for the determination of ketamine and norketamine in mouse plasma, brain and cerebrospinal fluid applicable to the stereoselective pharmacokinetic study of ketamine. AB - A novel method for the rapid and sensitive chiral determination of ketamine and norketamine in mouse plasma, brain and cerebrospinal fluid (CSF) was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This method reduces the required matrix volume, compared with a previously reported chiral assay method for ketamine and norketamine. The method involves the deproteinization of a small amount of biological matrix (corresponding to 5MUL of plasma, 10mg of brain, or 2.5MUL of CSF) using a water-miscible organic solvent containing 2H4-norketamine as an internal standard, the direct injection of the organic supernatant into an LC-MS/MS system, chiral separation on a CHIRALPAK AS 3R column (4.6mm i.d.*100mm, 3MUm particles), and detection by electrospray ionization-selected reaction monitoring with an analytical run time of 5min. The lower limits of quantification for ketamine and norketamine enantiomers were 1ng/mL (plasma), 0.5ng/g (brain) and 2ng/mL (CSF). A good linearity of the calibration curves was obtained within a range of 1000-fold. The newly developed method was successfully used to determine the concentrations of ketamine and norketamine in mouse samples (plasma, brain and CSF) in a stereoselective manner. Therefore, this method is expected to contribute to the elucidation of the roles of ketamine and its metabolites in the antidepressant actions of ketamine. PMID- 29126077 TI - The activation of transversus abdominis muscle during rapid limb movements depends on the anticipation of postural demand rather than on respiratory reflexes. PMID- 29126078 TI - The effect of a short course of moderate pressure sunflower oil massage on the weight gain velocity and length of NICU stay in preterm infants. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of five-day course of sunflower oil massage with moderate pressure on the weight gain and length of NICU stay in preterm infants. METHODS: Forty-four healthy preterm infants with a corrected gestational age of 30-36 weeks at the time of the study, were randomly assigned to the study group receiving body massage with sunflower oil and the control group receiving only routine NICU care. The massage was performed three times per day, each session including three consecutive five-minute stages, for five days. The primary outcome was to evaluate the efficacy of a short course of moderate pressure sunflower oil massage on the weight gain velocity. The secondary outcome was to compare the length of NICU stay between the two groups. RESULTS: During the study period, the increase in the average daily and fifth-day weight gain was significant in the intervention group. The length of NICU stay was shorter in the intervention group significantly. CONCLUSION: Our findings suggest that even a short course of body massage with sunflower oil for only five days increases preterm infants' weight gain and decreases their duration of NICU stay significantly. PMID- 29126079 TI - Self-control, parenting, and problem behavior in early childhood: A multi-method, multi-informant study. AB - BACKGROUND: Early childhood self-control and parenting are suggested to play key roles in the development of child problem behavior. The current study aims to 1) replicate earlier work by examining the unique and combined effects of child self control and parenting on child problem behavior and 2) extend earlier work by including both mother and father reports. METHODS: Data were used from 107 Dutch families: mothers, fathers, and their two-year old child. Child self-control was measured using both father's and mother's reports of effortful control and with an observed behavioral task (i.e., gift-in-bag task). Similarly, parenting (i.e., emotional availability and discipline) and child problem behavior (i.e., externalizing and internalizing problems) were measured by using both father's and mother's reports. RESULTS: Child self-control reported by fathers and mothers, but not observed self-control, was related to fewer externalizing and (mother-reported) internalizing problems. Paternal emotional availability showed a modest association with fewer child externalizing problems, maternal emotional availability was related to fewer internalizing problems. Finally, there was an interaction between father- (but not mother) reported self-control and paternal emotional availability in the prediction of child internalizing problems. No main or interaction effect was revealed for discipline. CONCLUSION: Findings confirm prior work on self-control, parenting, and child problem behavior. Most importantly however, the current study adds to the literature by highlighting the need for additional research including maternal as well as paternal data. Specifically, insight in the unique role of fathers may shed light on aspects of child adjustment not covered by mother reports alone. PMID- 29126080 TI - Impact of the disability trajectory on the mortality risk of older adults in China. AB - Using data from the Chinese Longitudinal Health Longevity Survey of 2005, 2008 and 2011, the authors compared the difference in the disability trajectory (DT) of survivor, decedent and dropped-out survey respondents and examined gender differences in DT using a group-based trajectory model, gender differences in the impact of DT on mortality risk (MR) among older adults, and mediating effects of resources and health status during late life through survival analysis. This analysis shows that the DTs of the survivors, decedents and dropped-out respondents differ remarkably. The trajectories of the decedents generally begin higher and increase more rapidly. Three types of DT exist for both genders: Type 1, the "independent type"; Type 2, the "low start, rapidly increasing in late life type"; and Type 3, the "high start, rapid development type". Women are more likely to experience a DT of functional impairment. Men who experience the Type 3 trajectory suffer the highest MR, followed by those of the Type 1 and Type 2 trajectories. Women who experience the Type 3 trajectory suffer the highest MR, followed by those of the Type 2 and Type 1 trajectories. In addition, economic status, medical treatment, daily care by the family and chronic diseases mediate the impact of DT on MR for both genders, while the mediating effect of emotional support from children was only observed for women. PMID- 29126081 TI - Multiple chronic condition profiles and survival among oldest-old male patients with hip fracture. AB - To improve understanding of survival among very elderly male patients with surgically repaired hip fractures, this study applied classification techniques to multiple chronic conditions (MCC) then modeled survival by latent class. Veterans Health Administration (VHA)'s electronic medical records on male inpatients age 85-100 years (n=896) with hip fracture diagnosis and repair were used. MCC defined by Charlson and Elixhauser disorders, medications, demographic covariates, and 5 years follow-up survival were included. Latent Class Analysis (LCA) identified three classes based on patterns of MCC, medications, and demographic covariates: Low-comorbidity (16%), High-longevity (55%), and High comorbidity (29%). Overall, survival censored at 5 years post-op averaged 717days. The Low-comorbidity group was more likely to be Hispanic, less disabled per VHA determination of eligibility for care, with less risk of postoperative emergency department (ED) visit, and taking no prescription medications. The High longevity group had longer survival. The High-comorbidity group had more MCC, more prescription medications and shorter survival than the other two groups. Accelerated failure time (AFT) modeled associations between MCC and 5-year survival by class. In AFT models, fewer days until first postoperative ED visit was significantly associated with survival across the three classes. About one in male hip fractured veteran patients over the age of 85 had high levels of MCC and ED use and experienced shorter survival. Hip fracture patients with MCC may merit enhanced post-discharge management. Close investigation targeted to MCC and hip fractures is needed to optimize clinical practices for oldest-old patients in community healthcare systems as well as VHA. PMID- 29126082 TI - Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control. AB - Accelerated stability studies of pharmaceutical products are commonly conducted at various combinations of temperature and relative humidity (RH). The RH of the sample environment can be controlled to set points using humidity-controlled stability chambers or via storage of the sample in a closed container in the presence of a saturated aqueous salt solution. Herein we report an unexpected N nitrosation reaction that occurs upon storage of carvedilol- or propranolol excipient blends in a stability chamber in the presence of saturated sodium nitrite (NaNO2) solution to control relative humidity (~60% RH). In both cases, the major products were identified as the corresponding N-nitroso derivatives of the secondary amine drugs based on mass spectrometry, UV-vis and retention time. These degradation products were not observed upon storage of the samples at the same temperature and humidity but in the presence of saturated potassium iodide (KI) solution (~60% RH) for humidity control. The levels of the N-nitrosamine derivatives varied with the pH of various NaNO2 batches. The presence of volatile NOx species in the headspace of a container containing saturated NaNO2 solution was confirmed via the Griess assay. The process for formation of the N nitrosamine derivatives is proposed to involve volatilization of nitric oxide (NO) from aqueous nitrite solution into the headspace of the container followed by diffusion into the solid drug-excipient blend and subsequent reaction of NOx with the secondary amine. PMID- 29126083 TI - HPLC/UV/MS method application for the separation of obeticholic acid and its related compounds in development process and quality control. AB - An HPLC method with UV and electrospray ionization - mass spectrometry (ESI-MS) detection was developed for the separation and determination of obeticholic acid (OBE) and its related compounds in development process and quality control. OBE and its related compounds were classified into three major group based on the mass spectra profiles: (A) those containing a hydroxyl group at position 3 and 7, (B) those containing a hydroxyl group and/or carbonyl group at position 3, hydrogen, ethyl or ethylidene group at position 6 and a hydroxyl group and/or carbonyl group at position 7, and (C) those containing carbonyl groups at position 3 and 7. ESI-MS ionization of OBE and its related compounds often produced intense adduct ions [M+H+98]+ and/or [M+H+196]+ that were identified as the adduct ions of phosphoric acid ([M+H+H3PO4]+ and [M+H+2H3PO4]+) originating from the mobile phase. The separation on HPLC system was accomplished using stationary phase based on XSelect CSH C18 (3.0*150mm*2.5MUm) and a linear gradient elution using acetonitrile and 0.05% of o-phosphoric acid. The condition of chromatographic system was set as follows: flow rate 0.7mL/min, temperature 45 degrees C and UV detection at 192nm. The separation of the 19 compounds was finished in less than 18min (including equilibration time). The HPLC/UV method was partially validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines in terms of repeatability, selectivity, linearity and limit of quantification and detection. PMID- 29126084 TI - A simple and highly selective molecular imprinting polymer-based methodology for propylparaben monitoring in personal care products and industrial waste waters. AB - In this work, a novel molecularly imprinted polymer (MIP) proposed as solid phase extraction sorbent was developed for the determination of propylparaben (PP) in diverse cosmetic samples. The use of parabens (PAs) is authorized by regulatory agencies as microbiological preservative; however, recently several studies claim that large-scale use of these preservatives can be a potential health risk and harmful to the environment. Diverse factors that influence on polymer synthesis were studied, including template, functional monomer, porogen and crosslinker used. Morphological characterization of the MIP was performed using SEM and BET analysis. Parameters affecting the molecularly imprinted solid phase extraction (MISPE) and elution efficiency of PP were evaluated. After sample clean-up, the analyte was analyzed by high performance liquid chromatography (HPLC). The whole procedure was validated, showing satisfactory analytical parameters. After applying the MISPE methodology, the extraction recoveries were always better than 86.15%; the obtained precision expressed as RSD% was always lower than 2.19 for the corrected peak areas. Good linear relationship was obtained within the range 8-500ngmL-1 of PP, r2=0.99985. Lower limits of detection and quantification after MISPE procedure of 2.4 and 8ngmL-1, respectively were reached, in comparison with previously reported methodologies. The development of MISPE-HPLC methodology provided a simple an economic way for accomplishing a clean-up/preconcentration step and the subsequent determination of PP in a complex matrix. The performance of the proposed method was compared against C-18 and silica solid phase extraction (SPE) cartridges. The recovery factors obtained after applying extraction methods were 96.6, 64.8 and 0.79 for MISPE, C18-SPE and silica-SPE procedures, respectively. The proposed methodology improves the retention capability of SPE material plus robustness and possibility of reutilization, enabling it to be used for PP routine monitoring in diverse personal care products (PCP) and environmental samples. PMID- 29126085 TI - Fatty acid-binding protein genes of the ancient, air-breathing, ray-finned fish, spotted gar (Lepisosteus oculatus). AB - With the advent of high-throughput DNA sequencing technology, the genomic sequence of many disparate species has led to the relatively new discipline of genomics, the study of genome structure, function and evolution. Much work has been focused on the role of whole genome duplications (WGD) in the architecture of extant vertebrate genomes, particularly those of teleost fishes which underwent a WGD early in the teleost radiation >230 million years ago (mya). Our past work has focused on the fate of duplicated copies of a multigene family coding for the intracellular lipid-binding protein (iLBP) genes in the teleost fishes. To define the evolutionary processes that determined the fate of duplicated genes and generated the structure of extant fish genomes, however, requires comparative genomic analysis with a fish lineage that diverged before the teleost WGD, such as the spotted gar (Lepisosteus oculatus), an ancient, air breathing, ray-finned fish. Here, we describe the genomic organization, chromosomal location and tissue-specific expression of a subfamily of the iLBP genes that code for fatty acid-binding proteins (Fabps) in spotted gar. Based on this work, we have defined the minimum suite of fabp genes prior to their duplication in the teleost lineages ~230-400 mya. Spotted gar, therefore, serves as an appropriate outgroup, or ancestral/ancient fish, that did not undergo the teleost-specific WGD. As such, analyses of the spatio-temporal regulation of spotted gar genes provides a foundation to determine whether the duplicated fabp genes have been retained in teleost genomes owing to either sub- or neofunctionalization. PMID- 29126086 TI - Genome-wide identification of 31 cytochrome P450 (CYP) genes in the freshwater rotifer Brachionus calyciflorus and analysis of their benzo[alpha]pyrene-induced expression patterns. AB - While marine invertebrate cytochrome P450 (CYP) genes and their roles in detoxification mechanisms have been studied, little information is available regarding freshwater rotifer CYPs and their functions. Here, we used genomic sequences and RNA-seq databases to identify 31 CYP genes in the freshwater rotifer Brachionus calyciflorus. The 31 Bc-CYP genes with a few tandem duplications were clustered into CYP 2, 3, 4, mitochondrial, and 46 clans with two marine rotifers Brachionus plicatilis and Brachionus koreanus. To understand the molecular responses of these 31 Bc-CYP genes, we also examined their expression patterns in response to benzo[alpha]pyrene (B[alpha]P). Three Bc-CYP genes (Bc-CYP3044B3, Bc-CYP3049B4, Bc-CYP3049B6) were significantly upregulated (P<0.05) in response to B[alpha]P, suggesting that these CYP genes can be involved in detoxification in response to B[alpha]P exposure. These genes might be useful as biomarkers of B[alpha]P exposure in B. calyciflorus. Overall, our findings expand the repertoire of known CYPs and shed light on their potential roles in xenobiotic detoxification in rotifers. PMID- 29126087 TI - Label-free based quantitative proteomic analysis identifies proteins involved in the testis maturation of Bactrocera dorsalis (Hendel). AB - Complex structural and biochemical processes take place in insect testis maturation, but the mechanisms by which functional proteins induce and regulate male fertility are unknown. Proteomics has been widely used to identify functional proteins involved in such complex physiological processes. In this study, we performed a label-free based quantitative proteomic analysis of developing testis of Bactrocera dorsalis with the aim of shedding light on spermatogenesis, sperm formation and also tissue development. A total of 1912 reliable proteins were identified, including 1589, 1705 and 1723 proteins in 1-, 5- and 9-d-old testis, respectively. Most of these proteins (76.68%) were identified by two to ten peptides, and the mean number of peptides was 7.46 with an average sequence coverage of 30.71%. Quantitative proteomic analysis showed that there were 141 and 111 proteins which were abundant in the 5- and 9-d-old testis, respectively. The Gene Ontology (GO) and Clusters of Orthologous Groups (COG) analyses showed that many of these proteins function in cellular and metabolic processes, including binding and catalytic activities in molecular function analysis, and energy production, cell division, and cell motility in COG analysis. Potential functional proteins, such as heat shock proteins, glutathione S-transferase, transferrin, metalloproteinase and energy metabolism-related proteins, were found to be abundant in the intermediate and sexual maturity stages of testis. The findings in this study help us to better understand the molecular mechanisms behind testis development and spermatogenesis, which is essential for manipulating male fertility for ecological regulation and potential control of this species. PMID- 29126088 TI - In the immuno-oncology era, is anti-PD-1 or anti-PD-L1 immunotherapy modifying the sensitivity to conventional cancer therapies? AB - INTRODUCTION: The advent of anti-programmed death receptor-1/ligand-1 antibodies (anti-PD(L)1) is profoundly changing the therapeutic strategy of oncology. As anti-PD(L)1 modulate tumour microenvironment, it might impact sensitivity to conventional cancer therapy (CCT). Therefore, we explored whether sensitivity to CCT was different before and after anti-PD(L)1 therapy. METHODS: Patients who started anti-PD(L)1 treatment at Gustave Roussy Cancer Centre between February 2012 and December 2015, and who received at least one line of CCT immediately before and immediately after anti-PD(L)1, were eligible. We analysed progression free survival (PFS) and overall response rate (ORR) of the CCT line immediately before (PFSpre/ORRpre) and after (PFSpost/ORRpost) anti-PD(L)1. PFS and ORR were compared using Wilcoxon signed rank and McNemar tests in a paired data subset for patients having received identical class of CCT pre and post anti-PD(L)1 therapy. RESULTS: Among 118 eligible patients, 65% received anti-PD1 and 35% anti-PD-L1 agents. Median PFSpre versus PFSpost was 4.7 versus 3.5 months (p = 0.011), respectively; it was 5.7 versus 6.8 months (NS) for patients who derived clinical benefit from immunotherapy and 3.9 versus 3.0 months (p = 0.012) for patients who were primary resistant to anti-PD(L)1 therapy. Subgroup analysis did not reveal any significant difference in PFS or ORR before versus after anti-PD(L)1 therapy according to CCT class or to its ability to induce immunogenic cell death. CONCLUSION: Patients who derive benefit from immune therapies tend to have better PFS on conventional therapies after having received the anti-PD(L)1 agent. Further studies on larger data sets are warranted to confirm these findings. PMID- 29126089 TI - Fertility outcomes after laparoscopic partial bladder resection for deep endometriosis: Retrospective analysis from two expert centres and review of the literature. AB - OBJECTIVE: To evaluate fertility outcomes after laparoscopic partial bladder resection in women with bladder endometriosis and to review the literature. STUDY DESIGN: A retrospective study conducted at two tertiary referral centres -Tenon University Hospital and Poissy University Hospital (Canadian Task Force Classification Level II-2)-from July 2006 to November 2015. Patients with bladder endometriosis who underwent either laparoscopic partial bladder resection (PBR) alone for those without posterior endometriotic lesions (PBR group) or both laparoscopic PBR and associated posterior deep infiltrating endometriosis (DIE) resection (PBR-PDIE group) were included. Pregnancy and live birth rates according to prior infertility, and associated posterior DIE resection were analysed. RESULTS: Thirty-four patients were included; 15 in the PBR group and 19 in the PBR-PDIE group. The median age (range) was 31 years (25-37), Seventeen patients (50%) had prior infertility. The median follow-up after bladder resection was 60.6 months (12-116). Overall, of the 25 (73.5%) patients who wished to conceive, 17 (68%) achieved pregnancies resulting in a live birth rate of 76.4%. Among the 17 patients with prior infertility, nine (52.9%) conceived. Overall, eight patients (53.3%) in the PBR group conceived and nine (47.3%) in the PBR-PDIE group (difference not significant). CONCLUSION: The present study demonstrates that laparoscopic PBR results in a high pregnancy rate in patients with prior infertility as well as in those with associated posterior DIE suggesting that surgery could be an acceptable alternative to first-line assisted reproductive technology. PMID- 29126090 TI - The "vanishing follicle" in women with low number of developing follicles during assisted reproduction. AB - OBJECTIVE: To investigate the occurrence of the "vanishing follicle" phenomenon in women with low number of developing follicles in assisted reproduction. STUDY DESIGN: Women with <= 6 follicles on the day of hCG administration with >= 14mm diameter were prospectively studied. Primary outcome measures were disappearance of >=14mm and all-diameter follicles on the day of oocyte pick-up compared to the day of hCG administration. RESULTS: Among the 120 women recruited, 95 were found eligible and completed the study. The "vanishing follicle" phenomenon occurred in 3.1% (95% confidence level: 0.7%-9.0%) and 18.9% (95% confidence level: 11.6% 28.3%) of cases affecting >=14mm and all-diameter follicles, respectively. In all cases, mid-late follicular serum LH and P levels remained within normal follicular phase range and trans-vaginal scan did not show signs of ovulation. Markedly, the main significant difference between the study and control groups in the >=14mm follicle group was serum E2 level on the day of hCG administration; median (Interquartile range), corresponding to 395 (382.0-405.5) versus 823.0 (544.5-1291.0) pg/mL, respectively (P=0.04). The same trend was encountered in all-diameter vanishing follicles group but it did not reach significance. Interestingly, in all-diameter vanishing group, chronic smoking and the P/E2 ratio on the hCG day were significantly higher than controls. Post hoc multiple logistic regression analysis of data in accordance with the Bologna criteria reveled that antral follicle count was found to significantly affect the development of the "vanishing follicle" phenomenon. CONCLUSIONS: The "vanishing follicle" phenomenon occasionally occurs in women with low number of developing follicles during assisted reproduction with no signs of ovulation. Our preliminary findings suggest that this phenomenon may be related to exhausted ovarian reserve however, an early-unrecognized LH elevation could not be ruled out. PMID- 29126091 TI - Older cancer patients in cancer clinical trials are underrepresented. Systematic literature review of almost 5000 meta- and pooled analyses of phase III randomized trials of survival from breast, prostate and lung cancer. AB - BACKGROUND: Older people represent increasing proportions of the population with cancer. To understand the representivity of cancer treatments in older people, we performed a systematic literature review using PRISMA guidelines of the age distribution of clinical trial participants for three leading cancer types, namely breast, prostate, and lung. METHODS: We used PubMed to identify articles detailing meta or pooled-analyses of phase III, randomised controlled trials (RCTs) of survival for breast, prostate and lung cancer, published <=5 years from 2016. We compared the age distribution of participants to that of these cancers for "More developed regions". RESULTS: 4993 potential papers were identified, but only three papers on breast cancer, three on lung cancer, and none on prostate cancer presented the age distribution of their participants. Except for one paper of breast cancer, participants >=70 years in all other papers were underrepresented. CONCLUSIONS: We recommend the age distribution of patients be clearly reported in all clinical trials, as per guidelines. Clinical trials ought to be more representative of the populations most affected by the disease for which treatments are being tested. This should lead to better knowledge of effectiveness of treatments and better translation of trial results to optimal care of older cancer patients. PMID- 29126092 TI - Environmental concentrations and toxicology of 2,4,6-tribromophenol (TBP). AB - 2,4,6-Tribromophenol is the most widely produced brominated phenol. In the present review, we summarize studies dealing with this substance from an environmental point of view. We cover concentrations in the abiotic and biotic environment including humans, toxicokinetics as well as toxicodynamics, and show gaps of the current knowledge about this chemical. 2,4,6-Tribomophenol occurs as an intermediate during the synthesis of brominated flame retardants and it similarly represents a degradation product of these substances. Moreover, it is used as a pesticide but also occurs as a natural product of some aquatic organisms. Due to its many sources, 2,4,6-tribromophenol is ubiquitously found in the environment. Nevertheless, not much is known about its toxicokinetics and toxicodynamics. It is also unclear which role the structural isomer 2,4,5 tribromophenol and several degradation products such as 2,4-dibromophenol play in the environment. Due to new flame retardants that enter the market and can degrade to 2,4,6-tribromophenol, this compound will remain relevant in future years - not only in aquatic matrices, but also in house dust and foodstuff, which are an important exposure route for humans. PMID- 29126093 TI - Temporal-spatial characteristics and source apportionment of PM2.5 as well as its associated chemical species in the Beijing-Tianjin-Hebei region of China. AB - PM2.5 and its major chemical compositions were sampled and analyzed in January, April, July and October of 2014 at Beijing (BJ), Tianjin (TJ), Langfang (LF) and Baoding (BD) in order to probe the temporal and spatial characteristics as well as source apportionment of PM2.5 in the Beijing-Tianjin-Hebei (BTH) region. The results showed that PM2.5 pollution was severe in the BTH region. The average annual concentrations of PM2.5 at four sampling sites were in the range of 126 180 MUg/m3, with more than 95% of sampling days exceeding 35 MUg/m3, the limit ceiling of average annual concentration of PM2.5 regulated in the Chinese National Ambient Air Quality Standards (GB3095-2012). Additionally, concentrations of PM2.5 and its major chemical species were seasonally dependent and demonstrated spatially similar variation characteristics in the BTH region. Concentration of toxic heavy metals, such as As, Cd, Cr, Cu, Mn, Ni, Pb, Sb, Se, and Zn, were higher in winter and autumn. Secondary inorganic ions (SO42-, NO3-, and NH4+) were the three-major water-soluble inorganic ions (WSIIs) of PM2.5 and their mass ratios to PM2.5 were higher in summer and autumn. The organic carbon (OC) and elemental carbon (EC) concentrations were lower in spring and summer than in autumn and winter. Five factors were selected in Positive Matrix Factorization (PMF) model analysis, and the results showed that PM2.5 pollution was dominated by vehicle emissions in Beijing, combustion emissions including coal burning and biomass combustion in Langfang and Baoding, and soil and construction dust emissions in Tianjin, respectively. The air mass that were derived from the south and southeast local areas around BTH regions reflected the features of short-distant and small-scale air transport. Shandong, Henan, and Hebei were identified the major potential sources-areas of secondary aerosol emissions to PM2.5. PMID- 29126094 TI - Evolutionarily adapted hormesis-inducing stressors can be a practical solution to mitigate harmful effects of chronic exposure to low dose chemical mixtures. AB - Although the toxicity of synthetic chemicals at high doses is well known, chronic exposure to low-dose chemical mixtures has only recently been linked to many age related diseases. However, it is nearly impossible to avoid the exposure to these low-dose chemical mixtures as humans are exposed to a myriad of synthetic chemicals as a part of their daily lives. Therefore, coping with possible harms due to low dose chemical mixtures is challenging. Interestingly, within the range of environmental exposure, disease risk does not increase linearly with increasing dose of chemicals, but often tends to plateau or even decrease with increasing dose. Hormesis, the over-compensation of various adaptive responses through cellular stresses, is one possible mechanism for this non-linearity. Although the hormetic effects of synthetic chemicals or radiation have long been debated in the field of toxicology, the hormesis concept has recently been generalized in the field of molecular biology; similar to responses to synthetic chemicals, mild to moderate intermittent stressors from any source can induce hormetic responses. Examples of stressors are exercise, calorie restriction, intermittent fasting, cognitive stimulation, and phytochemicals. Mitohormesis is hormesis induced by such stressors through mitochondrial retrograde signalling including the increased production of mild reactive oxygen species. Xenohormesis is phytochemical-induced hormesis, reflective of a mutualistic relationship between plant and animals. As humans had repeated exposure to all of these stressors during their evolution, the hormetic effects of these health behaviours may be considered to be evolutionarily adapted. Although hormesis induced by synthetic chemicals occurs in humans, such hormesis may not be recommended to the public due to unresolved issues on safety including the impossibility of control exposure. However, the use of personal health behaviors which enhance mitohormetic- or xenohormetic-stress can be readily incorporated into everyone's daily lives as a practical way to counteract harmful effects of unavoidable low dose chemical mixtures. PMID- 29126095 TI - Characterizing isotopic compositions of TC-C, NO3--N, and NH4+-N in PM2.5 in South Korea: Impact of China's winter heating. AB - The origin of PM2.5 has long been the subject of debate and stable isotopic tools have been applied to decipher. In this study, weekly PM2.5 samples were simultaneously collected at an urban (Seoul) and rural (Baengnyeong Island) site in Korea from January 2014 through February 2016. The seasonal variation of isotopic species showed significant seasonal differences with sinusoidal variation. The isotopic results implied that isotope species from Baengnyeong were mostly originated from coal combustion during China's winter heating seasons, whereas in summer, the isotopic patterns observed that were more likely to be from marine. In Seoul, coal combustion related isotopic patterns increased during China's winter heating period while vehicle related isotopic patterns were dominated whole seasons by default. Therefore, aerosol formation was originated from long-range transported coal combustion-related NOx by vehicle-related NH3 in Seoul. deltaN-NH4+ in Seoul showed highly enriched 15N compositions in all seasons, indicating that NH3 from vehicle emission is the important source of NH4+ in PM2.5 in Seoul. In addition, Baengnyeong should be consistently considered as a key region for observing the changes of isotopic features depend on the contribution of individual emissions to the atmospheric as a result of the reduction of coal consumption in China. PMID- 29126096 TI - Vitamin D status of children with Autism Spectrum Disorder: Case-control study from India. PMID- 29126097 TI - Cue-induced craving among inhalant users: Development and preliminary validation of a visual cue paradigm. AB - INTRODUCTION: Cue-induced craving is known to be associated with a higher risk of relapse, wherein drug-specific cues become conditioned stimuli, eliciting conditioned responses. Cue-reactivity paradigm are important tools to study psychological responses and functional neuroimaging changes. However, till date, there has been no specific study or a validated paradigm for inhalant cue-induced craving research. The study aimed to develop and validate visual cue stimulus for inhalant cue-associated craving. METHOD: The first step (picture selection) involved screening and careful selection of 30 cue- and 30 neutral-pictures based on their relevance for naturalistic settings. In the second step (time optimization), a random selection of ten cue-pictures each was presented for 4s, 6s, and 8s to seven adolescent male inhalant users, and pre-post craving response was compared using a Visual Analogue Scale(VAS) for each of the picture and time. In the third step (validation), craving response for each of 30 cue- and 30 neutral-pictures were analysed among 20 adolescent inhalant users. RESULTS: Findings revealed a significant difference in before and after craving response for the cue-pictures, but not neutral-pictures. Using ROC-curve, pictures were arranged in order of craving intensity. Finally, 20 best cue- and 20 neutral pictures were used for the development of a 480s visual cue paradigm. CONCLUSION: This is the first study to systematically develop an inhalant cue picture paradigm which can be used as a tool to examine cue induced craving in neurobiological studies. Further research, including its further validation in larger study and diverse samples, is required. PMID- 29126098 TI - Hair: A bio-marker for detection of drugs of abuse. PMID- 29126100 TI - Using Reports of Latent Tuberculosis Infection Among Young Children to Identify Tuberculosis Transmission in New York City, 2006-2012. AB - The presence of latent tuberculosis infection (LTBI) in young children indicates recent tuberculosis (TB) transmission. We reviewed surveillance reports of children with LTBI to assess whether more follow-up is needed to prevent TB in this high-risk population. Data on all children under 5 years of age who were reported by health-care providers or laboratories to the New York City Department of Health during 2006-2012 were abstracted from the TB surveillance and case management system, and those with LTBI were identified. Potential source cases, defined as any infectious TB case diagnosed in the 2 years before a child was reported and whose residence was within 0.5 miles (0.8 km) of the child's residence, were identified. Neighborhood risk factors for TB transmission were examined. Among 3,511 reports of children under age 5 years, 1,722 (49%) had LTBI. The children were aged 2.9 years, on average, and most (64%) had been born in the United States. A potential source case was identified for 92% of the children; 27 children lived in the same building as a TB patient. Children with potential source cases were more likely to reside in neighborhoods with high TB incidence, poverty, and population density. The high proportion of children born in the United States and the young average age of the cases imply that undetected TB transmission occurred. Monitoring reports could be used to identify places where transmission occurred, and additional investigation is needed to prevent TB disease. PMID- 29126099 TI - Clinical Utility of Select Neuropsychological Assessment Battery Tests in Predicting Functional Abilities in Dementia. AB - Objective: Neuropsychological test performance can provide insight into functional abilities in patients with dementia, particularly in the absence of an informant. The relationship between neuropsychological measures and instrumental activities of daily living (IADLs) is unclear due to hetereogeneity in cognitive domains assessed and neuropsychological tests administered. Practical and ecologically valid performance-based measures of IADLs are also limited. The Neuropsychological Assessment Battery (NAB) is uniquely positioned to provide a dual-purpose assessment of cognitive and IADL function, as it includes Daily Living tests that simulate real-world functional tasks. We examined the utility of select NAB tests in predicting informant-reported IADLs in mild cognitive impairment and dementia. Methods: The sample of 327 participants included 128 normal controls, 97 individuals with mild cognitive impairment, and 102 individuals with Alzheimer's disease dementia from the Boston University Alzheimer's Disease Center research registry. Informants completed the Lawton Brody Instrumental Activities of Daily Living Scale, and study participants were administered selected NAB tests that were complementary to the existing protocol. Results: ROC curves showed strongest prediction of IADL (AUC > 0.90) for memory measures (List Learning delayed recall and Daily Living Memory delayed recall) and Daily Living Driving Scenes. At a predetermined level of specificity (95%), List Learning delayed recall (71%) and Daily Living Memory delayed recall (88%) were the most sensitive. The Daily Living Memory and Driving Scenes tests strongly predicted IADL status, and the other Daily Living tests contributed unique variance. Conclusions: NAB memory measures and Daily Living Tests may have clinical utility in detecting informant-rated functional impairment in dementia. PMID- 29126101 TI - PREFMD: a web server for protein structure refinement via molecular dynamics simulations. AB - Summary: Refinement of protein structure models is a long-standing problem in structural bioinformatics. Molecular dynamics-based methods have emerged as an avenue to achieve consistent refinement. The PREFMD web server implements an optimized protocol based on the method successfully tested in CASP11. Validation with recent CASP refinement targets shows consistent and more significant improvement in global structure accuracy over other state-of-the-art servers. Availability and implementation: PREFMD is freely available as a web server at http://feiglab.org/prefmd. Scripts for running PREFMD as a stand-alone package are available at https://github.com/feiglab/prefmd.git. Contact: feig@msu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126103 TI - Salazosulphapyridine-related Stevens-Johnson Syndrome Caused by Sulphapyridine and Confirmed by Enzyme-linked Immunospot Assay. PMID- 29126102 TI - MiRNA-513a-5p inhibits progesterone receptor expression and constitutes a risk factor for breast cancer: the hOrmone and Diet in the ETiology of breast cancer prospective study. AB - MicroRNAs (miRNAs) might be considered both predictors and players of cancer development. The aim of the present report was to investigate whether many years before the diagnosis of breast cancer miRNA expression is already disregulated. In order to test this hypothesis, we compared miRNAs extracted from leukocytes in healthy women who later developed breast cancer and in women who remain healthy during the whole 15-year follow-up time. Accordantly, we used a case-control study design nested in the hOrmone and Diet in the ETiology of breast cancer (ORDET) prospective cohort study addressing the possibility that miRNAs can serve as both early biomarkers and components of the hormonal etiological pathways leading to breast cancer development in premenopausal women. We compared leukocyte miRNA profiles of 191 incident premenopausal breast cancer cases and profiles of 191 women who remained healthy over a follow-up period of 20 years. The analysis identified 20 differentially expressed miRNAs in women candidate to develop breast cancer versus control women. The upregulated miRNAs, miR-513-a-5p, miR-513b-5p and miR-513c-5p were among the most significantly deregulated miRNAs. In multivariate analysis, miR-513a-5p upregulation was directly and statistically significant associated with breast cancer risk (OR = 1.69; 95% CI 1.08-2.64; P = 0.0293). In addition, the upregulation of miR-513-a-5p displayed the strongest direct association with serum progesterone and testosterone levels. The experimental data corroborated the inhibitory function of miR-513a-5p on progesterone receptor expression confirming that progesterone receptor is a target of miR-513a-5p. The identification of upregulated miR-513a-5p with its oncogenic potential further validates the use of miRNAs as long-term biomarker of breast cancer risk. PMID- 29126104 TI - FIVE AUTHORS REPLY. PMID- 29126105 TI - Reply to Napp et al. PMID- 29126106 TI - AIRVF: a filtering toolbox for precise variant calling in Ion Torrent sequencing. AB - Summary: Ion Torrent sequencing is one of the most frequently used platforms in healthcare research and industry. Despite many advantages, platform-specific artifacts complicate efficient separation of true variants from errors, especially in variants with lower allele frequencies (<15%). Here, we developed a multi-step filtering toolbox AIRVF that works on flowgram, raw and mapped reads and called variants to reduce artifact-driven false variant calls. Tests on sequencing data of standard reference material showed up to ~98% reduction of false variants when combined to conventional public pipelines and ~48% to the in house commercial solution, with a minimal loss of sensitivity. Availability and implementation: The program with a detailed manual is available at https://sourceforge.net/projects/airvf/. Contact: swkim@yuhs.ac. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126107 TI - Predicting delirium: are we there yet? PMID- 29126108 TI - Laboratory-scale photobiotechnology-current trends and future perspectives. AB - Phototrophic bioprocesses are a promising puzzle piece in future bioeconomy concepts but yet mostly fail for economic reasons. Besides other aspects, this is mainly attributed to the omnipresent issue of optimal light supply impeding scale up and -down of phototrophic processes according to classic established concepts. This MiniReview examines two current trends in photobiotechnology, namely microscale cultivation and modeling and simulation. Microphotobioreactors are a valuable and promising trend with microfluidic chips and microtiter plates as predominant design concepts. Providing idealized conditions, chip systems are preferably to be used for acquiring physiological data of microalgae while microtiter plate systems are more appropriate for process parameter and medium screenings. However, these systems are far from series technology and significant improvements especially regarding flexible light supply remain crucial. Whereas microscale is less addressed by modeling and simulation so far, benchtop photobioreactor design and operation have successfully been studied using such tools. This particularly includes quantitative model-assisted understanding of mixing, mass transfer, light dispersion and particle tracing as well as their relevance for microalgal performance. The ultimate goal will be to combine physiological data from microphotobioreactors with hybrid models to integrate metabolism and reactor simulation in order to facilitate knowledge-based scale transfer of phototrophic bioprocesses. PMID- 29126109 TI - Do prospective payment systems (PPSs) lead to desirable providers' incentives and patients' outcomes? A systematic review of evidence from developing countries. AB - The reform of provider payment systems, from retrospective to prospective payment, has been heralded as the right move to contain costs in the light of rising health expenditures in many countries. However, there are concerns on quality trade-off. The heightened attention given to prospective payment system (PPS) reforms and the rise of empirical evidence regarding PPS interventions among developing countries suggest that a systematic review is necessary to understand the effects of PPS reforms in developing countries. A systematic search of 14 databases and a hand search of health policy journals and grey literature from October to November 2016 were carried out, guided by a set of inclusion and exclusion criteria. Data were extracted based on the Consolidated Health Economics Evaluation Reporting Standards checklist. Drummond's 10-item checklist for economic evaluation, Cochrane Collaboration's tool in assessing risk of bias for randomized trials, and Risk of Bias in Non-randomized Studies of Interventions were used to critically appraise the evidence. A total of 12 studies reported in China, Thailand and Vietnam were included in this review. Substantial heterogeneity was present in PPS policy design across different localities. PPS interventions were found to have reduced health expenditures on both the supply and demand side, as well as length of stay and readmission rates. In addition, PPS generally improved service quality outcomes by reducing the likelihood or percentage of physicians prescribing unnecessary drugs and diagnostic procedures. PPS is a promising policy tool for middle-income countries to achieve reasonable health policy objectives in terms of cost containment without necessarily compromising the quality of care. More evaluations of PPS will need to be conducted in the future in order to broaden the evidence base beyond middle-income countries. PMID- 29126110 TI - Risks of Infection and Mortality Among Patients Colonized With Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae: Validation of Scores and Proposal for Management. AB - Background: The management and indication of empiric treatment in Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp)-colonized patients should be improved. Methods: A prospective cohort of 94 patients colonized by KPC Kp was followed for 90 days to validate (i) the Giannella risk score (GRS) to predict the development of any type of KPC-Kp infection and (ii) the INCREMENT CPE score (ICS) to predict 30-day mortality in patients with infection. Both scores were combined to recommend appropriate empiric treatment. The predictive ability of the scores was measured by calculating the area under the receiver operating characteristic (AUROC) curve. Results: The GRS showed an AUROC curve for infection due to KPC-Kp of 0.92 (95% confidence interval [CI], .87-.98). The optimal cutoff point was fixed at <7 and >=7 (92.9% sensitivity, 84.8% specificity); infection developed in 6.3% patients in the 0-6 GRS group and in 84.8% patient in the >=7 GRS group. According to the ICS, the severity of the infection was also significantly higher in the >=7 GRS group. The ICS showed an AUROC of 0.78 (95% CI, .65-.91) for 30-day all-cause mortality among patients with infection. A classification and regression tree analysis confirmed the GRS cutoff point at 7, and selected >=12 points to predict a KPC-Kp infection with a high ICS. Conclusions: Our results validate the GRS and ICS for indicating empiric therapy in KPC-Kp-colonized patients. PMID- 29126111 TI - Second Radioiodine Treatment: Limited Benefit for Differentiated Thyroid Cancer With Locoregional Persistent Disease. AB - Objectives: Radioactive iodine (RAI) treatment is often indicated after total thyroidectomy in differentiated thyroid cancer (DTC). However, its role in biochemical or locoregional persistent DTC is unclear. We aimed to investigate the effect of a second RAI treatment in patients with incomplete response to initial treatment and no evidence of distant metastases. Methods: Patients who underwent at least two RAI treatments over a 20-year period at a tertiary hospital were identified. Thyroglobulin levels and neck imaging were compared before and 1 to 2 years after RAI retreatment and evaluated at the last visit. Results: The cohort included 164 patients (103 female; mean age, 46.6 +/- 17 years). Of 114 patients retreated without prior reoperation, 53 had structural disease. At 1 to 2 years after RAI retreatment, 10 of the 41 patients with sufficient data had structural progression, 5 resolution/shrinkage, and 26 stable disease. Stimulated thyroglobulin (stTg) measured 93.7.1 +/- 108 ng/mL before and 102.2 +/- 124 ng/mL after retreatment (P = NS). The other 61 patients had biochemical-only persistence. Their stTg levels decreased from 41.9 +/- 56 to 24.6 +/- 54 ng/mL (P = 0.003). The 50 patients who underwent neck reoperation before RAI retreatment showed no substantial change in stTg; 21 (42%) still had imaging findings 1 to 2 years later. At final follow-up, despite additional treatment in 63/164 patients (38.4%), only 56/164 (34.1%) had no evidence of disease. Conclusions: This comprehensive study showed limited benefit of second RAI treatment in DTC patients with biochemical or locoregional structural persistent disease. Prospective studies are needed to distinguish patients for whom repeated RAI may be indicated to avoid unnecessary exposure. PMID- 29126112 TI - Risk scoring to guide antiplatelet therapy post-percutaneous coronary intervention for acute coronary syndrome results in improved clinical outcomes. AB - Aims: To use the Global Registry of Acute Coronary Events (GRACE) and Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) scores to risk stratify antiplatelet treatment post-acute coronary syndrome (ACS). Methods and results: This was a prospective registry of 3374 patients undergoing percutaneous coronary intervention for ACS between 2013 and 2015 at a UK cardiac centre. Patients with either low GRACE or high CRUSADE risk scores were stratified either to clopidogrel therapy or ticagrelor was used. The primary endpoint was major adverse cardiac events (MACE) defined as death, non-fatal myocardial infarction, stroke, or target vessel revascularization with bleeding rates as a secondary outcome, assessed at a median follow-up of 1.8 years (interquartile range 0.8-3.4 years). A total of 1723 (51.1%) patients were risk stratified to either clopidogrel (n = 520) or ticagrelor treatment (n = 1203), with the remaining 1651 not risk scored and treated with clopidogrel therapy. Patients in the risk score stratified group were older than the control group otherwise the groups were similar. Over the follow-up period, a significant reduction in MACE rates between the patients' risk score stratified and control (clopidogrel therapy) (13.7% vs. 19.7%, P < 0.0001) was seen [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.31-0.86]. This persisted after adjusting for baseline variables (HR 0.65, 95% CI 0.37-0.89) and propensity matching (HR = 0.63, 95% CI 0.27-0.93; P = 0.0015) No significant differences in the rate of major bleeding were seen between the groups (5.3% vs. 5.1%, P = 0.86). In the risk-stratified group, no difference in outcome (ischaemic/bleeding) was seen between clopidogrel and ticagrelor. Conclusion: Our registry data suggest that using appropriate risk scoring to guide antiplatelet therapy after ACS is safe and can result in improved clinical outcomes. PMID- 29126113 TI - Bacteria associated with decomposing dead wood in a natural temperate forest. AB - Dead wood represents an important pool of organic matter in forests and is one of the sources of soil formation. It has been shown to harbour diverse communities of bacteria, but their roles in this habitat are still poorly understood. Here, we describe the bacterial communities in the dead wood of Abies alba, Picea abies and Fagus sylvatica in a temperate natural forest in Central Europe. An analysis of environmental factors showed that decomposing time along with pH and water content was the strongest drivers of community composition. Bacterial biomass positively correlated with N content and increased with decomposition along with the concurrent decrease in the fungal/bacterial biomass ratio. Rhizobiales and Acidobacteriales were abundant bacterial orders throughout the whole decay process, but many bacterial taxa were specific either for young (<15 years) or old dead wood. During early decomposition, bacterial genera able to fix N2 and to use simple C1 compounds (e.g. Yersinia and Methylomonas) were frequent, while wood in advanced decay was rich in taxa typical of forest soils (e.g. Bradyrhizobium and Rhodoplanes). Although the bacterial contribution to dead wood turnover remains unclear, the community composition appears to reflect the changing conditions of the substrate and suggests broad metabolic capacities of its members. PMID- 29126114 TI - CORRIGENDUM FOR "A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis". PMID- 29126115 TI - HOMINID: a framework for identifying associations between host genetic variation and microbiome composition. AB - Recent studies have uncovered a strong effect of host genetic variation on the composition of host-associated microbiota. Here, we present HOMINID, a computational approach based on Lasso linear regression, that given host genetic variation and microbiome taxonomic composition data, identifies host single nucleotide polymorphisms (SNPs) that are correlated with microbial taxa abundances. Using simulated data, we show that HOMINID has accuracy in identifying associated SNPs and performs better compared with existing methods. We also show that HOMINID can accurately identify the microbial taxa that are correlated with associated SNPs. Lastly, by using HOMINID on real data of human genetic variation and microbiome composition, we identified 13 human SNPs in which genetic variation is correlated with microbiome taxonomic composition across body sites. In conclusion, HOMINID is a powerful method to detect host genetic variants linked to microbiome composition and can facilitate discovery of mechanisms controlling host-microbiome interactions. PMID- 29126116 TI - C-621/15 - W and Others v Sanofi Pasteur: An Example of Judicial Distortion and Indifference to Science. AB - This case commentary examines the CJEU's recent decision in C-621/15 W and Others v Sanofi Pasteur MSD SNC [2017] ECR I. This commentary critically examines the decision through the lens of the cultural conflict between law and science. We argue that the CJEU's decision reflects both a distortion of scientific knowledge and an improper indifference to the legitimate methods by which scientific knowledge is generated in the context of vaccines. These judicial approaches may, the authors argue, inadvertently fuel the vaccine scepticism that is growing across the developed world, and in particular in Europe. PMID- 29126118 TI - Decentralized and reproducible geocoding and characterization of community and environmental exposures for multisite studies. AB - Objective: Geocoding and characterizing geographic, community, and environmental characteristics of study participants is frequently done in epidemiological studies. However, participant addresses are identifiable protected health information (PHI) and geocoding must be conducted in a Health Insurance Portability and Accountability Act-compliant manner. Our objective was to create a software application for this process that addresses limitations in current approaches. Materials and Methods: We used a containerization platform to create DeGAUSS (Decentralized Geomarker Assessment for Multi-Site Studies), a software application that facilitates reproducible geocoding and geomarker assessment while maintaining the confidentiality of PHI. To validate the software, 215 350 addresses in Hamilton County, Ohio, were geocoded using DeGAUSS, ArcGIS, Google, and SAS and compared to a gold-standard approach. We distributed the DeGAUSS software to sites in an ongoing multisite study (Electronic Medical Records and Genomics, or eMERGE), and individual sites independently geocoded and assigned median census tract-level income and distance to nearest major roadway to their participants' addresses, removed associated PHI, and returned deidentified data. Results: Within a multisite study, 52 244 study participants' addresses across 5 sites were geocoded with a median distance to roadway of 10 022m and a median census tract income of $57 266, demonstrating the feasibility of DeGAUSS within a multisite study. Compared to other commonly used geocoding platforms, DeGAUSS had similar geocoding and geomarker assessment accuracies. Conclusion: The open source DeGAUSS software overcomes multiple challenges in the use of address data in multisite studies and also serves as a more general reproducible research tool for geocoding and geomarker assessment. PMID- 29126117 TI - Dynamic reorganization of open chromatin underlies diverse transcriptomes during spermatogenesis. AB - During spermatogenesis, germ cells undergo massive cellular reconstruction and dynamic chromatin remodeling to facilitate highly diverse transcriptomes, which are required for the production of functional sperm. However, it remains unknown how germline chromatin is organized to promote the dynamic, complex transcriptomes of spermatogenesis. Here, using ATAC-seq, we establish the varied landscape of open chromatin during spermatogenesis. We identify the reorganization of accessible chromatin in intergenic and intronic regions during the mitosis-to-meiosis transition. During the transition, mitotic-type open chromatin is closed while the de novo formation of meiotic-type open chromatin takes place. Contrastingly, differentiation processes such as spermatogonial differentiation and the meiosis-to-postmeiosis transition involve chromatin closure without the de novo formation of accessible chromatin. In spermiogenesis, the germline-specific Polycomb protein SCML2 promotes the closure of open chromatin at autosomes for gene suppression. Paradoxically, we identify the massive de novo formation of accessible chromatin when the sex chromosomes undergo meiotic sex chromosome inactivation, and this is also mediated by SCML2. These results reveal meiotic sex chromosome inactivation as an active process for chromatin organization. Together, our results unravel the genome-wide, dynamic reorganization of open chromatin and reveal mechanisms that underlie diverse transcriptomes during spermatogenesis. PMID- 29126119 TI - Lower Trabecular Bone Score in Patients With Primary Aldosteronism: Human Skeletal Deterioration by Aldosterone Excess. AB - Context: Despite the potential detrimental effects of aldosterone excess on bone metabolism, discrepancies exist between fracture risk and bone mass in patients with and without primary aldosteronism (PA). Objective: To clarify the possibility that aldosterone excess might mainly affect bone properties not explained by the bone mineral density (BMD). Design, Setting, and Patients: Among 625 consecutive patients with newly diagnosed adrenal incidentaloma (AI), 72 with biochemically confirmed PA and 335 with nonfunctional AI were defined as cases and controls, respectively. Results: In women, although no statistically significant differences in lumbar spine BMD were found between groups, the lumbar spine trabecular bone score (TBS) was significantly lower in patients with PA than in controls after adjustment for confounders (P = 0.007). Consistently, the plasma aldosterone concentration (PAC) correlated inversely with the lumbar spine TBS (P = 0.028) but not with bone mass in women. Compared with women in the lowest PAC quartile, those in the highest PAC quartile had significantly lower lumbar spine TBSs (P = 0.004). Importantly, all these observations in women remained statistically significant after additional adjustment for the lumbar spine BMD in the multivariable model. However, BMD and TBS at the lumbar spine did not differ according to the presence of PA and the level of PAC in men. Conclusion: These findings provide clinical evidence that aldosterone excess in PA might contribute to deteriorated bone quality through weak microarchitecture, regardless of bone mass, especially in women. PMID- 29126120 TI - Cranial Chordoma: A New Preoperative Grading System. AB - BACKGROUND: Chordomas are rare but challenging neoplasms involving the skull base. A preoperative grading system will be useful to identify both areas for treatment and risk factors, and correlate to the degree of resection, complications, and recurrence. OBJECTIVE: To propose a new grading system for cranial chordomas designed by the senior author. Its purpose is to enable comparison of different tumors with a similar pathology to clivus chordoma, and statistically correlate with postoperative outcomes. METHODS: The numerical grading system included tumor size, site of the tumor, vascular encasement, intradural extension, brainstem invasion, and recurrence of the tumor either after surgery or radiotherapy with a range of 2 to 25 points; it was used in 42 patients with cranial chordoma. The grading system was correlated with number of operations for resection, degree of resection, number and type of complications, recurrence, and survival. RESULTS: We found 3 groups: low-risk 0 to 7 points, intermediate-risk 8 to 12 points, and high-risk >=13 points in the grading system. The 3 groups were correlated with the following: extent of resection (partial, subtotal, or complete; P < .002); number of operative stages to achieve removal (P < .014); tumor recurrence (P = .03); postoperative Karnofsky Performance Status (P < .001); and with successful outcome (P = .005). The grading system itself correlated with the outcome (P = .005). CONCLUSION: The proposed chordoma grading system can help surgeons to predict the difficulty of the case and know which areas of the skull base will need attention to plan further therapy. PMID- 29126121 TI - The Relationship Between Neighborhood Disorder and Barriers to Cessation in a Sample of Impoverished Inner-City Smokers in Baltimore, Maryland, United States. AB - Introduction: Economic disparities in rates of smoking have been well documented in many countries. These disparities exist on an individual and geographic or neighborhood level. This cross-sectional study examined the relationship between neighborhood physical and social disorder and barriers to smoking cessation among an impoverished urban sample. Methods: A sample of current smokers were recruited through street outreach, posted advertisements, and word of mouth from impoverished neighborhoods in Baltimore, Maryland, USA for a study of psychosocial factors and smoking behaviors. Neighborhood disorder was assessed with a 10-item scale from the Block Environmental Inventory and barriers to cessation with a 9-item scale. Results: In the multiple logistic regression model, perceived stress (aOR = 1.60, 95% CI = 1.32 to 1.95), neighborhood disorder (aOR= 1.34, 95% CI = 1.11 to 1.63), and level of nicotine dependence (aOR = 1.97), 95% CI = 1.62 to 2.40) were all strongly associated with barriers to cessation. Conclusion: The results of this study suggest that neighborhood disorder may lead to barriers to cessation among low-income populations. The findings also indicate that tobacco control interventions should examine and address social and physical aspects of impoverished neighborhoods. Implications: In many countries, tobacco control programs and policies have been less effective among low-income populations as compared to more affluent populations. Little is known about how neighborhood factors influence smoking cessation. This study examined the relationship between neighborhood disorder and barriers to cessation among a low-income population. We recruited a convenience sample of hard-to-reach cigarette smokers from low-income neighborhoods. Even after controlling for level of nicotine dependence and stress, neighborhood disorder was found to be associated with barriers to cessation. The findings suggest the important role of neighborhood disorder as a barrier to smoking cessation. PMID- 29126124 TI - Predicting Drug Safety and Communicating Risk: Benefits of a Bayesian Approach. AB - Drug toxicity is a major source of attrition in drug discovery and development. Pharmaceutical companies routinely use preclinical data to predict clinical outcomes and continue to invest in new assays to improve predictions. However, there are many open questions about how to make the best use of available data, combine diverse data, quantify risk, and communicate risk and uncertainty to enable good decisions. The costs of suboptimal decisions are clear: resources are wasted and patients may be put at risk. We argue that Bayesian methods provide answers to all of these problems and use hERG-mediated QT prolongation as a case study. Benefits of Bayesian machine learning models include intuitive probabilistic statements of risk that incorporate all sources of uncertainty, the option to include diverse data and external information, and visualizations that have a clear link between the output from a statistical model and what this means for risk. Furthermore, Bayesian methods are easy to use with modern software, making their adoption for safety screening straightforward. We include R and Python code to encourage the adoption of these methods. PMID- 29126122 TI - Mode and Rate of Evolution of Haemosporidian Mitochondrial Genomes: Timing the Radiation of Avian Parasites. AB - Haemosporidians are a diverse group of vector-borne parasitic protozoa that includes the agents of human malaria; however, most of the described species are found in birds and reptiles. Although our understanding of these parasites' diversity has expanded by analyses of their mitochondrial genes, there is limited information on these genes' evolutionary rates. Here, 114 mitochondrial genomes (mtDNA) were studied from species belonging to four genera: Leucocytozoon, Haemoproteus, Hepatocystis, and Plasmodium. Contrary to previous assertions, the mtDNA is phylogenetically informative. The inferred phylogeny showed that, like the genus Plasmodium, the Leucocytozoon and Haemoproteus genera are not monophyletic groups. Although sensitive to the assumptions of the molecular dating method used, the estimated times indicate that the diversification of the avian haemosporidian subgenera/genera took place after the Cretaceous-Paleogene boundary following the radiation of modern birds. Furthermore, parasite clade differences in mtDNA substitution rates and strength of negative selection were detected. These differences may affect the biological interpretation of mtDNA gene lineages used as a proxy to species in ecological and parasitological investigations. Given that the mitochondria are critically important in the parasite life cycle stages that take place in the vector and that the transmission of parasites belonging to particular clades has been linked to specific insect families/subfamilies, this study suggests that differences in vectors have affected the mode of evolution of haemosporidian mtDNA genes. The observed patterns also suggest that the radiation of haemosporidian parasites may be the result of community-level evolutionary processes between their vertebrate and invertebrate hosts. PMID- 29126123 TI - PedAM: a database for Pediatric Disease Annotation and Medicine. AB - There is a significant number of children around the world suffering from the consequence of the misdiagnosis and ineffective treatment for various diseases. To facilitate the precision medicine in pediatrics, a database namely the Pediatric Disease Annotations & Medicines (PedAM) has been built to standardize and classify pediatric diseases. The PedAM integrates both biomedical resources and clinical data from Electronic Medical Records to support the development of computational tools, by which enables robust data analysis and integration. It also uses disease-manifestation (D-M) integrated from existing biomedical ontologies as prior knowledge to automatically recognize text-mined, D-M-specific syntactic patterns from 774 514 full-text articles and 8 848 796 abstracts in MEDLINE. Additionally, disease connections based on phenotypes or genes can be visualized on the web page of PedAM. Currently, the PedAM contains standardized 8528 pediatric disease terms (4542 unique disease concepts and 3986 synonyms) with eight annotation fields for each disease, including definition synonyms, gene, symptom, cross-reference (Xref), human phenotypes and its corresponding phenotypes in the mouse. The database PedAM is freely accessible at http://www.unimd.org/pedam/. PMID- 29126125 TI - Highly specific determination of IDH status using edited in vivo magnetic resonance spectroscopy. AB - Background: Mutations in the isocitrate dehydrogenase (IDH) enzyme affect 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG) and to compare performance of these methods with DNA sequencing and tissue 2HG analysis. Methods: Twenty-four subjects with suspected diagnosis of low-grade glioma were included prospectively in the study. For all subjects, MRS data were acquired at 3T using 2 MRS methods, edited MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and a PRESS sequence optimized for 2HG detection, using a volume of interest larger than 6 mL. IDH mutational status was determined by a combination of automated immunohistochemical analysis and Sanger sequencing. Levels of 2HG in tissue samples measured by gas chromatography-mass spectrometry were compared with those estimated by MRS. Results: Edited MRS provided 100% specificity and 100% sensitivity in the detection of 2HG. The 2HG levels estimated by this technique were in line with those derived from tissue samples. Optimized PRESS provided lower performance, in agreement with previous findings. Conclusions: Our results suggest that edited MRS is one of the most reliable tools to predict IDH mutation noninvasively, showing high sensitivity and specificity for 2HG detection. Integrating edited MRS in clinical practice may be highly beneficial for noninvasive diagnosis of glioma, prognostic assessment, and treatment planning. PMID- 29126126 TI - Exposure to Point-of-Sale Marketing of Cigarettes and E-Cigarettes as Predictors of Smoking Cessation Behaviors. AB - Introduction: Cue-reactivity theory suggests smoking-related visual cues such as point-of-sale (POS) marketing (e.g., advertising, product displays) may undermine cessation attempts by causing an increase in nicotine cravings among users. This study examined the relationship between recall of exposure to POS marketing and subsequent cessation behaviors among young adult cigarette smokers. Methods: Participants included 813 18-29 year old (m=21.1, sd=2.70) current cigarette smokers attending 24 Texas colleges. Multivariable logistic regression models examined the impact of baseline self-reported exposure to cigarette and e cigarette advertising and product displays, on using e-cigarettes for cessation and successful cigarette cessation at 6-month follow-up. Two-way interactions between product-specific advertising and between product-specific displays were examined to determine if the marketing of one product strengthened the cue reactivity of the other. Baseline covariates included socio-demographic factors, past quit attempts, intentions to quit smoking, and nicotine dependence. Results: Exposure to e-cigarette displays was associated with lower odds of cigarette smoking cessation, controlling for covariates and conventional cigarette display exposure. E-cigarette advertising was positively associated with use of e cigarettes for cigarette cessation among participants exposed to low (i.e., at least one standard deviation below the mean) levels of cigarette advertising. Cigarette advertising was associated with use of e-cigarettes for cigarette cessation only among those exposed to low levels of e-cigarette advertising. Exposure to cigarette displays was not associated with either outcome. Conclusion: Smoking-related cues at POS may undermine successful cigarette cessation. Exposure to product displays decrease odds of cessation. Advertising exposure increased odds for using e-cigarettes for cessation attempts, but may have guided smokers towards an unproven cessation aid. Implications: By examining the interaction of conventional cigarette and e-cigarette marketing exposure, this study adds a unique insight into the impact of retail tobacco marketing on cigarette smoking cessation behavior among young adults. These findings suggest policies should be considered that balance encouraging cigarette smoking cessation while limiting marketing strategies, such as POS product displays, that may undermine successful cessation attempts. PMID- 29126127 TI - Conservatism and the neural circuitry of threat: economic conservatism predicts greater amygdala-BNST connectivity during periods of threat vs safety. AB - Political conservatism is associated with an increased negativity bias, including increased attention and reactivity toward negative and threatening stimuli. Although the human amygdala has been implicated in the response to threatening stimuli, no studies to date have investigated whether conservatism is associated with altered amygdala function toward threat. Furthermore, although an influential theory posits that connectivity between the amygdala and bed nucleus of the stria terminalis (BNST) is important in initiating the response to sustained or uncertain threat, whether individual differences in conservatism modulate this connectivity is unknown. To test whether conservatism is associated with increased reactivity in neural threat circuitry, we measured participants' self-reported social and economic conservatism and asked them to complete high resolution fMRI scans while under threat of an unpredictable shock and while safe. We found that economic conservatism predicted greater connectivity between the BNST and a cluster of voxels in the left amygdala during threat vs safety. These results suggest that increased amygdala-BNST connectivity during threat may be a key neural correlate of the enhanced negativity bias found in conservatism. PMID- 29126128 TI - Identification of the Optimal Protocol for Automated Office Blood Pressure Measurement Among Patients With Treated Hypertension. AB - BACKGROUND: Automated office blood pressure (AOBP) involving repeated, unobserved blood pressure (BP) readings during one clinic visit is recommended for in-office diagnosis and assessment of hypertension. However, the optimal AOBP protocol to determine BP control in the least amount of time with the fewest BP readings is yet to be determined and was the aim of this study. METHODS: One hundred and eighty-nine patients (mean age 62.8 +/- 12.1 years; 50.3% female) with treated hypertension referred to specialist clinics at 2 sites underwent AOBP in a quiet room alone. Eight BP measurements were taken starting immediately after sitting and then at 2-minute intervals (15 minutes total). The optimal AOBP protocol was defined by the smallest mean difference and highest intraclass correlation coefficient (ICC) compared with daytime ambulatory BP (ABP). The same BP device (Mobil-o-graph, IEM) was used for both AOBP and daytime ABP. RESULTS: Average 15 minute AOBP and daytime ABP were 134 +/- 22/82 +/- 13 and 137 +/- 17/83 +/- 11 mm Hg, respectively. The optimal AOBP protocol was derived within a total duration of 6 minutes from the average of 2 measures started after 2 and 4 minutes of seated rest (systolic BP: mean difference (95% confidence interval) 0.004(-2.21, 2.21) mm Hg, P = 1.0; ICC = 0.81; diastolic BP: mean difference 0.37(-0.90, 1.63) mm Hg, P = 0.57; ICC = 0.86). AOBP measures taken after 8 minutes tended to underestimate daytime ABP (whether as a single BP or the average of more than 1 BP reading). CONCLUSIONS: Only 2 AOBP readings taken over 6 minutes (excluding an initial reading immediately after sitting) may be needed to be comparable with daytime ABP. PMID- 29126129 TI - TUGging at heartstrings: control of aortic valve calcification by non-coding RNA. PMID- 29126130 TI - Physician Preferences to Communicate Neuropsychological Results: Comparison of Qualitative Descriptors and a Proposal to Reduce Communication Errors. AB - Objective: Errors in communication are a leading cause of medical errors. A potential source of error in communicating neuropsychological results is confusion in the qualitative descriptors used to describe standardized neuropsychological data. This study sought to evaluate the extent to which medical consumers of neuropsychological assessments believed that results/findings were not clearly communicated. In addition, preference data for a variety of qualitative descriptors commonly used to communicate normative neuropsychological test scores were obtained. Methods: Preference data were obtained for five qualitative descriptor systems as part of a larger 36-item internet-based survey of physician satisfaction with neuropsychological services. A new qualitative descriptor system termed the Simplified Qualitative Classification System (Q-Simple) was proposed to reduce the potential for communication errors using seven terms: very superior, superior, high average, average, low average, borderline, and abnormal/impaired. A non-random convenience sample of 605 clinicians identified from four United States academic medical centers from January 1, 2015 through January 7, 2016 were invited to participate. Results: A total of 182 surveys were completed. A minority of clinicians (12.5%) indicated that neuropsychological study results were not clearly communicated. When communicating neuropsychological standardized scores, the two most preferred qualitative descriptor systems were by Heaton and colleagues (26%) and a newly proposed Q-simple system (22%). Comprehensive norms for an extended Halstead Reitan battery: Demographic corrections, research findings, and clinical applications. Odessa, TX: Psychological Assessment Resources) (26%) and the newly proposed Q-Simple system (22%). Discussion: Initial findings highlight the need to improve and standardize communication of neuropsychological results. These data offer initial guidance for preferred terms to communicate test results and form a foundation for more standardized practice among neuropsychologists. PMID- 29126131 TI - Continuous Kisspeptin Restores Luteinizing Hormone Pulsatility Following Cessation by a Neurokinin B Antagonist in Female Sheep. AB - Pulsatile secretion of the gonadotropin-releasing hormone (GnRH) drives pulsatile secretion of the luteinizing hormone (LH), with evidence that this depends on kisspeptin (Kiss) input to GnRH neurons. Kiss administration causes acute GnRH/LH secretion, and electrophysiological data suggest that Kiss neurons may act in a phasic manner to drive GnRH secretion, but there is not definitive evidence for this. The product of the Kiss-1 gene is proteolytically cleaved to smaller products, and the 10 amino acid C-terminal product (Kiss-10) displays full bioactivity. We have shown previously that continuous delivery of Kiss-10 to anestrous ewes can cause a surge in GnRH secretion and ovulation and increases LH pulse frequency in humans. Here, we tested the hypothesis that continuous Kiss-10 delivery can support pulsatile GnRH/LH secretion in the sheep. Neurokinin B (NKB) provides positive drive to Kiss neurons, so we therefore infused an NKB antagonist (ANT-08) intracerebroventricularly to induce cessation of pulsatile GnRH/LH secretion, with or without concomitant continuous Kiss-10 infusion. ANT 08 suppressed GnRH/LH pulsatility, which was immediately restored with continuous Kiss-10 infusion. These data support the notion that Kiss-10 action is downstream of NKB signaling and that continuous Kiss-10 stimulation of GnRH neurons is sufficient to support a pulsatile pattern of GnRH/LH secretion. This offers further support to the theory that GnRH pulse generation is intrinsic to GnRH neurons and that pulsatile GnRH release can be affected with continuous stimulation by Kiss-10. PMID- 29126132 TI - Cost-effective and accurate method of measuring fetal fraction using SNP imputation. AB - Motivation: With the discovery of cell-free fetal DNA in maternal blood, the demand for non-invasive prenatal testing (NIPT) has been increasing. To obtain reliable NIPT results, it is important to accurately estimate the fetal fraction. In this study, we propose an accurate and cost-effective method for measuring fetal fractions using single-nucleotide polymorphisms (SNPs). Results: A total of 84 samples were sequenced via semiconductor sequencing using a 0.3* sequencing coverage. SNPs were genotyped to estimate the fetal fraction. Approximately 900 000 SNPs were genotyped, and 250 000 of these SNPs matched the semiconductor sequencing results. We performed SNP imputation (1000Genome phase3 and HRC v1.1 reference panel) to increase the number of SNPs. The correlation coefficients (R2) of the fetal fraction estimated using the ratio of non-maternal alleles when coverage was reduced to 0.01 following SNP imputation were 0.93 (HRC v1.1 reference panel) and 0.90 (1000GP3 reference panel). An R2 of 0.72 was found at 0.01* sequencing coverage with no imputation performed. We developed an accurate method to measure fetal fraction using SNP imputation, showing cost-effectiveness by using different commercially available SNP chips and lowering the coverage. We also showed that semiconductor sequencing, which is an inexpensive option, was useful for measuring fetal fraction. Availability and implementation: python source code and guidelines can be found at https://github.com/KMJ403/fetalfraction-SNPimpute. Contact: kangskim@ajou.ac.kr or sunshinkim3@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126134 TI - The Study of Local Adaptation: A Thriving Field of Research. PMID- 29126133 TI - Cohort Profile: The 2015 Pelotas (Brazil) Birth Cohort Study. PMID- 29126135 TI - Habitat Modification by the Leaf-Cutter Ant, Atta cephalotes, and Patterns of Leaf-Litter Arthropod Communities. AB - Ecosystem engineers are profoundly important in many biological communities. A Neotropical taxonomic group considered to have engineering effects is the Formicidae (ants). Leaf-cutter ants (LCAs), in particular, which form extensive colonies of millions of individuals, can be important ecosystem engineers in these environments. While the effects of LCAs on plant community structure and soil chemistry are well-studied, their effects on consumers are poorly understood. Therefore, we examined the indirect effects of the LCA Atta cephalotes L. on the leaf-litter arthropod community. We compared abundance and diversity patterns at ant nests to areas distant from nests, utilizing both a factorial design and gradient analysis for both nocturnal and diurnal arthropods. We found that arthropod abundance and diversity was significantly lower for multiple taxonomic groups and trophic levels near leaf-cutter nests, and this pattern was strongest at night. Exceptions to this pattern included two morphospecies of Collembola that were more abundant on nests, suggesting some specialization for these species. For the gradient analysis, abundance increased exponentially for most groups of arthropods. However, for the dominant arthropod species, the amphipod Cerrorchestia hyloraina Lindeman, a quadratic function was the best fit curvilinear model for abundance. It appeared that C. hyloraina had maximal abundance at the transition between nest site and less disturbed forest. These results indicate that LCA activity has a strong effect on the leaf-litter arthropod community, adding to spatial heterogeneity within neotropical forests. These effects may translate into changes in important ecological processes such as nutrient cycling and food web function. PMID- 29126136 TI - DrugBank 5.0: a major update to the DrugBank database for 2018. AB - DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education. PMID- 29126137 TI - Study of mesophilic Aeromonas salmonicida A527 strain sheds light on the species' lifestyles and taxonomic dilemma. AB - The Gram-negative bacterium Aeromonas salmonicida contains five subspecies: salmonicida, smithia, achromogenes, masoucida and pectinolytica. Pectinolytica is a mesophilic subspecies with the ability to thrive at a wide range of temperatures, including 37 degrees C, while the four other subspecies are psychrophilic, restricted to lower temperatures. The psychrophilic subspecies are known to infect a wide range of fishes. However, there is no evidence of pathogenicity for the mesophilic subspecies pectinolytica. Study of the differences between the mesophilic and psychrophilic subspecies is hampered by the lack of completely sequenced and closed genomes from the mesophilic subspecies. A previous study reported that insertion sequences, which can induce genomic rearrangements at temperatures around 25 degrees C, could be one of the determinants explaining the differences in lifestyle (mesophilic or psychrophilic) between the subspecies. In this study, the genome of mesophilic strain A527 of A. salmonicida was sequenced, closed and analyzed to investigate the mesophilic-psychrophilic discrepancy. This reference genome supports the hypothesis that insertion sequences are major determinants of the lifestyle differences between the A. salmonicida subspecies. Moreover, the phylogenetic analysis performed to position strain A527 within the taxonomy raises an issue regarding the intraspecies structure of A. salmonicida. PMID- 29126138 TI - "Those Conversations in My Experience Don't Go Well": A Qualitative Study of Primary Care Provider Experiences Tapering Long-term Opioid Medications. AB - Objective: Given the risks of long-term opioid therapy, patients may benefit from tapering these medications. There is little evidence to guide providers' approach to this process. We explored primary care providers' experiences discussing and implementing opioid tapering with patients on long-term opioid therapy. Design: Qualitative study using six semistructured, in-person focus groups. Subject: Primary care providers (N = 40). Setting: Six academically affiliated primary care clinics in university, urban safety net, and Veterans Health Administration medical centers in Colorado. Methods: Focus groups were audio-recorded, transcribed, and analyzed using a mixed inductive-deductive approach in ATLAS.ti. Emergent themes were identified through an iterative, multidisciplinary team based process. Results: We identified 1) strategies for identifying candidates for opioid tapering, 2) barriers to opioid tapering, and 3) facilitators of opioid tapering. Strategies for identifying candidates for opioid tapering included evidence of high-risk behavior, serious adverse events, opioid-related side effects, and patient preference. Barriers included the providers' emotional burden, inadequate resources, and a lack of trust between patient and provider. Facilitators of opioid tapering included empathizing with the patient's experience, preparing patients for opioid tapering, individualizing implementation of opioid tapering, and supportive guidelines and policies. Conclusions: While discussing and implementing opioid tapering present significant challenges, primary care providers described key facilitators. These findings suggest a need to develop and test the effectiveness of resources to support patient-centered opioid tapering and locally developed policies to support and standardize providers' approaches to opioid prescribing. PMID- 29126139 TI - Alendronate Use and the Risk of Nonvertebral Fracture During Glucocorticoid Therapy: A Retrospective Cohort Study. AB - Context: Glucocorticoids increase the risk of nonvertebral fracture, but no clinical trial has shown that nonvertebral fractures can be prevented by coadministration of an antiosteoporotic drug. Objective: To estimate the effect of alendronate on the risk of nonvertebral fracture in older adults taking oral glucocorticoids. Design: Retrospective cohort study using national Swedish registers. Setting: Hospitalized care and ambulatory specialist care. Patients: Among adults aged >=50 years (N = 3,347,959), we identified those who initiated oral glucocorticoid therapy from 2006 through 2011 (>=2.5 mg/d of prednisone or equivalent for >=91 days). The final analysis included 16,890 alendronate users and 16,890 nonusers, who were matched using time-dependent propensity scores. Main Outcome Measure: Nonvertebral fracture. This was not prespecified. Results: Over a median follow-up of 14.5 months, the incidence rate of nonvertebral fracture was 2.0 cases/100 person-years in alendronate users and 2.4 cases in nonusers. This difference corresponded to a 16% lower rate in users (hazard ratio 0.84; 95% confidence interval, 0.75 to 0.94). For hip fractures specifically, the rate was 34% lower in alendronate users relative to nonusers (hazard ratio 0.66; 95% confidence interval, 0.55 to 0.78). The association of alendronate use with a lower risk of nonvertebral fracture was strongest in patients who received high doses of glucocorticoid. Conclusion: Alendronate use was associated with a lower risk of nonvertebral fracture, including hip fracture. Similar, but not statistically significant, associations have been reported in meta-analyses of clinical trials. PMID- 29126141 TI - Gastric Carcinomas With Lymphoid Stroma: Categorization and Comparison With Solid Type Colonic Carcinomas. AB - Objectives: To determine whether histologic features could help identify gastric carcinomas with lymphoid stroma associated with microsatellite instability (MSI) (ie, "medullary carcinomas"), Epstein-Barr virus (EBV) infection (termed lymphoepithelioma-like carcinomas in other organ systems), or neither. Methods: We identified 17 solid-type gastric carcinomas with lymphoid stroma, assessed EBV and MSI status, and compared features across groups. We also compared them with 51 solid-type colorectal adenocarcinomas. Results: In the stomach, EBV-associated carcinomas (n = 8) contained intratumoral germinal centers (P = .024) and eosinophils (P = .030) and lacked necrosis (P = .019) compared with MSI associated carcinomas (n = 5) and non-EBV, non-MSI carcinomas (n = 4). In the colon, MSI-driven carcinomas (n = 40) more frequently contained intratumoral lymphocytes (P = .017) and neutrophils (P = .0050) and less often metastasized to distant sites (P = .0040) than poorly differentiated carcinomas lacking MSI (n = 11). Conclusions: Morphology may help classify gastric carcinomas with lymphoid stroma, although ancillary testing appears more reliable. Lymphoepithelioma-like carcinoma and medullary carcinoma should not be used interchangeably. PMID- 29126140 TI - Zona pellucida-binding protein 2 (ZPBP2) and several proteins containing BX7B motifs in human sperm may have hyaluronic acid binding or recognition properties. AB - STUDY QUESTION: Are there novel hyaladherins in human sperm? SUMMARY ANSWER: Zona pellucida-binding protein 2 (ZPBP2), containing a Link-like hyaluronic acid (HA) binding domain, and several other proteins containing BX7B motifs, such as ADAM32 and Midkine, may be novel hyaladherins with HA-binding properties. WHAT IS KNOWN ALREADY: HA-binding proteins (hyaladherins), which can bind HA surrounding the cumulus-oophorus complex, are distinct from hyases such as PH 20 (SPAM1) and are expressed by mature spermatozoa. Although HABP1 and CD44 are reasonably well characterized hyaladherins and the former has been implicated in sperm-oocyte interactions, the overall significance of sperm hyaladherins for male fertility is still poorly understood. STUDY DESIGN, SIZE, DURATION: This was a laboratory based investigation into human sperm hyaladherins undertaken as part of a three year PhD programme sponsored by the EU Marie Curie Training network, Reprotrain. PARTICIPANTS/MATERIALS, SETTING, METHODS: Protein homogenates of sperm obtained from young men of unknown fertility (N = 4) were partitioned into HA-binding and non-binding fractions by a protein affinity 'panning' method; their subsequent characterization was by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and partitioning behaviour was confirmed by western blotting. Sequences of proteins from both fractions were submitted to PDBsum to look for orthologous entries (PDB codes) and all returned codes were queried against the matching protein using SAS (Sequences Annotated by Structure) looking for structural similarities between them. A systematic search for other common features of hyaladherins was also undertaken. MAIN RESULTS AND THE ROLE OF CHANCE: The presence of BX7B sequence motifs found in several well-described hyaladherins including RHAMM was used to assess efficacy of potential hyaladherin partitioning by the HA substrate. The data showed that 50% (14/28) and 34.5% (28/81) of proteins in the bound and unbound fractions, respectively, contained these motifs (one-tailed Z-score = 1.45; P = 0.074), indicating weak discrimination by the substrate. Querying PDBsum with sequences for all bound proteins returned several PDB codes matching ZPBP2 with the HA-binding Link domain of the hyaladherin, CD44. Western blot analysis confirmed the affinity partitioning of proteins indicated by the LC-MS/MS results, with ADAM32 (containing two BX7B motifs) and ZPBP2 (containing a Link-like HA-binding domain) present only in the binding fraction. There remains the possibility that the putative hyaladherins uncovered by this study were coincidentally enriched by HA-binding. LARGE SCALE DATA: The full proteomics data set is available on request. LIMITATIONS REASONS FOR CAUTION: The protein extraction methods or the HA substrate used to pan them in this study were probably not ideal, as hyaladherins expected to be present in sperm homogenates (such as CD44 and RHAMM) were not detected. WIDER IMPLICATIONS OF THE FINDINGS: The results provide evidence that ZPBP2, found only in the bound fraction, may have hyaladherin-like properties, which could reflect the evolutionary background context of contemporary sperm-oocyte interaction mechanisms. STUDY FUNDING AND COMPETING INTEREST(S): An EU Marie Curie Sklodowska Initial Training Network Scholarship, supporting Ms Torabi, is gratefully acknowledged. This project was also supported and funded by the Efficacy and Mechanism Evaluation Programme, a UK MRC and NIHR partnership (Grant No 11/14/ 34). There is no conflict of interest in relation to this work. PMID- 29126142 TI - Stereotactic Radiosurgery in the Management of Limited (1-4) Brain Metasteses: Systematic Review and International Stereotactic Radiosurgery Society Practice Guideline. AB - BACKGROUND: Guidelines regarding stereotactic radiosurgery (SRS) for brain metastases are missing recently published evidence. OBJECTIVE: To conduct a systematic review and provide an objective summary of publications regarding SRS in managing patients with 1 to 4 brain metastases. METHODS: Using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using PubMed and Medline up to November 2016. A separate search was conducted for SRS for larger brain metastases. RESULTS: Twenty-seven prospective studies, critical reviews, meta-analyses, and published consensus guidelines were reviewed. Four key points came from these studies. First, there is no detriment to survival by withholding whole brain radiation (WBRT) in the upfront management of brain metastases with SRS. Second, while SRS on its own provides a high rate of local control (LC), WBRT may provide further increase in LC. Next, WBRT does provide distant brain control with less need for salvage therapy. Finally, the addition of WBRT does affect neurocognitive function and quality of life more than SRS alone. For larger brain metastases, surgical resection should be considered, especially when factoring lower LC with single-session radiosurgery. There is emerging data showing good LC and/or decreased toxicity with multisession radiosurgery. CONCLUSION: A number of well conducted prospective and meta-analyses studies demonstrate good LC, without compromising survival, using SRS alone for patients with a limited number of brain metastases. Some also demonstrated less impact on neurocognitive function with SRS alone. Practice guidelines were developed using these data with International Stereotactic Radiosurgery Society consensus. PMID- 29126143 TI - Understanding How Dogs Age: Longitudinal Analysis of Markers of Inflammation, Immune Function, and Oxidative Stress. AB - As in human populations, advances in nutrition and veterinary care have led to an increase in the lifespan of companion animals. Detrimental physiological changes occurring later in life must be understood before interventions can be made to slow or reduce them. One important aspect of human aging is upregulation of the inflammatory response and increase in oxidative damage resulting in pathologies linked to chronic inflammation. To determine whether similar processes occur in the aging dog, changes in markers of inflammation and oxidative stress were investigated in 80 Labrador retrievers from adulthood to the end of life. Serum levels of immunoglobulin M (p < .001) and 8-hydroxy-2-deoxyguanosine (p < .001) increased with age, whereas no effect of age was detected for immunoglobulin G or C-reactive protein unless the last year of life was included in the analysis (p = .002). Baseline levels of heat shock protein 70 decreased with age (p < .001) while those after exposure to heat stress were maintained (p = .018). However, when excluding final year of life data, a decline in the heat shock protein 70 response after heat stress was observed (p = .004). These findings indicate that aging dogs undergo changes similar to human inflammaging and offer the possibility of nutritional or pharmacological intervention to delay or reduce these effects. PMID- 29126144 TI - Multiscale Mathematical Model of Drug-Induced Proximal Tubule Injury: Linking Urinary Biomarkers to Epithelial Cell Injury and Renal Dysfunction. AB - Drug-induced nephrotoxicity is a major cause of acute kidney injury, and thus detecting the potential for nephrotoxicity early in the drug development process is critical. Various urinary biomarkers exhibit different patterns following drug induced injury, which may provide greater information than traditional biomarkers like serum creatinine. In this study, we developed a multiscale quantitative systems pharmacology model relating drug exposure to proximal tubule (PT) epithelial cell injury and subsequently to expression of multiple urinary biomarkers and organ-level functional changes. We utilized urinary kidney injury molecule-1 (Kim-1), alpha glutathione S-transferase, albumin (alphaGST), glucose, and urine volume time profiles as well as serum creatinine and histopathology data obtained from rats treated with the nephrotoxicant cisplatin to develop the model. Although the model was developed using single-dose response to cisplatin, the model predicted the serum creatinine response to multidose cisplatin regimens. Further, using only the urinary Kim-1 response to gentamicin (a nephrotoxicant with a distinctly different injury time course than cisplatin), the model detected and predicted mild to moderate PT injury, as confirmed with histopathology, even when serum creatinine was unchanged. Thus, the model is generalizable, and can be used to deconvolute the underlying degree and time course of drug-induced PT injury and renal dysfunction from a small number of urinary biomarkers, and may provide a tool to determine optimal dosing regimens that minimize renal injury. PMID- 29126145 TI - Screening of systemic arteriopathy in patients with spontaneous coronary artery dissection. PMID- 29126146 TI - Genomic and Proteomic Evidence for the Presence of a Peroxisome in the Apicomplexan Parasite Toxoplasma gondii and Other Coccidia. AB - Apicomplexans are successful parasites responsible for severe human diseases including malaria, toxoplasmosis, and cryptosporidiosis. For many years, it has been discussed whether these parasites are in possession of peroxisomes, highly variable eukaryotic organelles usually involved in fatty acid degradation and cellular detoxification. Conflicting experimental data has been published. With the age of genomics, ever more high quality apicomplexan genomes have become available, that now allow a new assessment of the dispute. Here, we provide bioinformatic evidence for the presence of peroxisomes in Toxoplasma gondii and other coccidians. For these organisms, we have identified a complete set of peroxins, probably responsible for peroxisome biogenesis, division, and protein import. Moreover, via a global screening for peroxisomal targeting signals, we were able to show that a complete set of fatty acid beta-oxidation enzymes is equipped with either PTS1 or PTS2 sequences, most likely mediating transport of these factors to putative peroxisomes in all investigated Coccidia. Our results further imply a life cycle stage-specific presence of peroxisomes in T. gondii and suggest several independent losses of peroxisomes during the evolution of apicomplexan parasites. PMID- 29126147 TI - Adrenocorticotropin Acutely Regulates Pregnenolone Sulfate Production by the Human Adrenal In Vivo and In Vitro. AB - Background: Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in human circulation, and adrenocorticotropic hormone (ACTH) is considered the major regulator of its synthesis. Pregnenolone sulfate (PregS) and 5 androstenediol-3-sulfate (AdiolS) have recently emerged as biomarkers of adrenal disorders. Objective: To define the relative human adrenal production of Delta5 steroid sulfates under basal and cosyntropin-stimulated conditions. Methods: Liquid chromatography-tandem mass spectrometry was used to quantify three unconjugated and four sulfated Delta5-steroids in (1) paired adrenal vein (AV) and mixed venous serum samples (21 patients) and (2) cultured human adrenal cells both before and after cosyntropin stimulation, (3) microdissected zona fasciculata (ZF) and zona reticularis (ZR) from five human adrenal glands, and (4) a reconstituted in vitro human 17alpha-hydroxylase/17,20-lyase/(P450 17A1) system. Results: Of the steroid sulfates, PregS had the greatest increase after cosyntropin stimulation in the AV (32-fold), whereas DHEAS responded modestly (1.8-fold). PregS attained concentrations comparable to those of DHEAS in the AV after cosyntropin stimulation (AV DHEAS/PregS, 24 and 1.3 before and after cosyntropin, respectively). In cultured adrenal cells, PregS demonstrated the sharpest response to cosyntropin, whereas DHEAS responded only modestly (21-fold vs 1.8-fold higher compared with unstimulated cells at 3 hours, respectively). Steroid analyses in isolated ZF and ZR showed similar amounts of PregS and 17alpha-hydroxypregnenolone in both zones, whereas DHEAS and AdiolS were higher in ZR (P < 0.05). Conclusion: Our studies demonstrated that unlike DHEAS, PregS displayed a prominent acute response to cosyntropin. PregS could be used to interrogate the acute adrenal response to ACTH stimulation and as a biomarker in various adrenal disorders. PMID- 29126149 TI - "They're thinking, well it's not as bad, I probably won't get addicted to that. But it's still got the nicotine in it, so...": Maturity, control and socialising: Negotiating identities in relation to smoking and vaping. A qualitative study of young adults in Scotland. AB - Objective: To explore the understandings of and engagement with e-cigarettes, of young adults from disadvantaged backgrounds, and how these may be impacting upon existing smoking identities. Methods: Twenty-two small group and 11 individual qualitative interviews conducted in Central Scotland with 72 16-24 year olds between September 2015 and April 2016. Participants were mostly smokers and ex smokers from socio-economically disadvantaged backgrounds. Results: While most participants had tried e-cigarettes, they generally held ambivalent views about e cigarettes and vaping. Two overarching themes were identified which helped understand this. Firstly, e-cigarettes were understood by the participants in relation to their existing smoking identities. Vaping was viewed as less controllable and more addictive than smoking, which did not fit with their self identity as controlled smokers. Secondly, they felt that vaping could not replace the social and cultural importance that smoking had in their lives. Conclusion: This study suggests that while young adults from disadvantaged areas are trying e cigarettes for various reasons, vaping is rarely sustained. Through their own experiences of vaping and their observations of others vaping, the participants perceive the behaviour as endangering an existing acceptable and controlled smoking identity. Additionally, e-cigarettes were considered to be a jarring presence in existing social situations were smoking was valued. This study therefore provides insights into how young adults may be rationalising their continued smoking in the face of potentially less harmful alternatives. Implications: As new and novel nicotine delivery devices, and due to their similarity to smoking, e-cigarettes have the potential to help smokers in their quit attempts. However, the findings from this study raise questions about whether e-cigarettes are regarded as having this potential by young adult smokers from disadvantaged socio-economic environments where smoking is more commonplace and acceptable. PMID- 29126148 TI - Consensus coding sequence (CCDS) database: a standardized set of human and mouse protein-coding regions supported by expert curation. AB - The Consensus Coding Sequence (CCDS) project provides a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assembly in genome annotations produced independently by NCBI and the Ensembl group at EMBL-EBI. This dataset is the product of an international collaboration that includes NCBI, Ensembl, HUGO Gene Nomenclature Committee, Mouse Genome Informatics and University of California, Santa Cruz. Identically annotated coding regions, which are generated using an automated pipeline and pass multiple quality assurance checks, are assigned a stable and tracked identifier (CCDS ID). Additionally, coordinated manual review by expert curators from the CCDS collaboration helps in maintaining the integrity and high quality of the dataset. The CCDS data are available through an interactive web page (https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi) and an FTP site (ftp://ftp.ncbi.nlm.nih.gov/pub/CCDS/). In this paper, we outline the ongoing work, growth and stability of the CCDS dataset and provide updates on new collaboration members and new features added to the CCDS user interface. We also present expert curation scenarios, with specific examples highlighting the importance of an accurate reference genome assembly and the crucial role played by input from the research community. PMID- 29126150 TI - THE AUTHORS REPLY. PMID- 29126151 TI - RE: "ACTIVE AND PASSIVE SMOKING AND RISK OF NASOPHARYNGEAL CARCINOMA: A POPULATION-BASED CASE-CONTROL STUDY IN SOUTHERN CHINA". PMID- 29126152 TI - Association between shift work and risk of prostate cancer: a systematic review and meta-analysis of observational studies. AB - Observational studies suggest that shift work may be associated with prostate cancer. However, the results are inconsistent. The objective of this study is to quantitatively assess the association between shift work and the risk of prostate cancer. Relevant studies were identified by a comprehensive search of the PubMed, Embase, Web of Science and China National Knowledge Infrastructure databases to September 2017. We also reviewed the reference lists from retrieved articles. Observational studies that reported relative risk (RR) with 95% confidence intervals (CIs) for the association between shift work and the risk of prostate cancer were included. Linear and non-linear dose-response meta-analyses were performed. Fifteen studies with 16 independent reports involving 2 546 822 individuals and 10 715 patients with prostate cancer were included. The pooled adjusted RR for the association between ever exposure to shift work and prostate cancer risk was 1.23 (95% CI, 1.08-1.41; P < 0.001). A non-linear association of prostate cancer risk with duration of shift work was identified (P for non linearity = 0.001). Subgroup analysis demonstrated a higher pooled RR of prostate cancer for studies among Asian populations (RR = 1.98, 95% CI, 1.34-2.93; P = 0.618). A positive association was observed in rotating shift groups (RR = 1.10, 95% CI, 1.00-1.26; P = 0.156), but not in other shift groups. Integrated evidence from this meta-analysis suggests that shift work is significantly associated with an increased risk of prostate cancer, and a non-linear association between duration of shift work and prostate cancer was found. PMID- 29126153 TI - An empirical Bayes test for allelic-imbalance detection in ChIP-seq. AB - Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) has enabled discovery of genomic regions enriched with biological signals such as transcription factor binding and histone modifications. Allelic-imbalance (ALI) detection is a complementary analysis of ChIP-seq data for associating biological signals with single nucleotide polymorphisms (SNPs). It has been successfully used in elucidating functional roles of non-coding SNPs. Commonly used statistical approaches for ALI detection are often based on binomial testing and mixture models, both of which rely on strong assumptions on the distribution of the unobserved allelic probability, and have significant practical shortcomings. We propose Non-Parametric Binomial (NPBin) test for ALI detection and for modeling Binomial data in general. NPBin models the density of the unobserved allelic probability non-parametrically, and estimates its empirical null distribution via curve fitting. We demonstrate the advantages of NPBin in terms of interpretability of the estimated density and the accuracy in ALI detection using simulations and analysis of several ChIP-seq data sets. We also illustrate the generality of our modeling framework beyond ALI detection by an application to a baseball batting average prediction problem. This article has supplementary material available at Biostatistics online. The code and the sample input data have been also deposited to github https://github.com/QiZhangStat/ALIdetection. PMID- 29126154 TI - A cost-minimization analysis of large overjet reduction with two removable functional appliances based on a randomized controlled trial. AB - Objective: The purpose of this study was to assess and relate the societal costs of reducing large overjet with a prefabricated functional appliance (PFA), or a slightly modified Andresen activator (AA), using a cost-minimization analysis (CMA). Design, settings, and participants: A multicentre, prospective, randomized clinical trial was conducted with patients from 12 general dental practices. Ninety-seven patients with an Angle Class II, division 1 malocclusion, and an overjet of >=6 mm were randomly allocated by lottery to treatment with either a PFA or an AA. The PFA and AA groups consisted of 57 and 40 subjects, respectively. Blinding was not performed. Duration of treatment, number of scheduled/unscheduled appointments, and retreatment were registered. Direct and indirect costs were analysed with reference to intention-to-treat (ITT), successful (S), and unsuccessful (US) outcomes. Societal costs were described as the total of direct and indirect costs, not including retreatments. Interventions: Treatment with a PFA or an AA. Results: The direct and societal costs were significantly lower for the PFA than for the AA group. The number of visits was lower in the PFA group, when ITT was considered, and for the US cases as well. No difference in retreatment rate could be seen between the groups. Limitations: Costs depend on local factors and thus should not be generalized to other settings. Harms: No harms were detected during the study. Conclusion: The success rate of the both appliances was low. However, the PFA was the preferred approach for reduction of a large overjet in mixed dentition, since it minimized costs and there were no difference in clinical outcomes between PFA and AA. Registration: This trial was registered at 'FoU i Sverige' (http://www.fou.nu/is/sverige), registration number: 97131. Protocol: The protocol was not published before trial commencement. PMID- 29126156 TI - Antithrombotic therapy after myocardial infarction in patients with atrial fibrillation undergoing percutaneous coronary intervention. AB - Aims: Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) in patients with myocardial infarction (MI) and atrial fibrillation is uncertain. In this study, we compared antithrombotic regimes with regard to a composite cardiovascular outcome of all-cause mortality, MI or ischaemic stroke, and major bleeds. Methods and results: Patients between October 2005 and December 2012 were identified in Swedish registries, n = 7116. Landmark 0-90 and 91-365 days of outcome were evaluated with Cox-regressions, with dual antiplatelet therapy as reference. At discharge, 16.2% received triple therapy (aspirin, clopidogrel, and warfarin), 1.9% aspirin plus warfarin, 7.3% clopidogrel plus warfarin, and 60.8% dual antiplatelets. For cardiovascular outcome, adjusted hazard ratio with 95% confidence interval (HR) for triple therapy was 0.86 (0.70 1.07) for 0-90 days and 0.78 (0.58-1.05) for 91-365 days. A HR of 2.16 (1.48 3.13) and 1.61 (0.98-2.66) during 0-90 and 91-365 days, respectively, was observed for major bleeds. For aspirin plus warfarin, HR 0.82 (0.54-1.26) and 0.62 (0.48-0.79) was observed for cardiovascular outcome and 1.30 (0.60-2.85) and 1.01 (0.63-1.62) for major bleeds during 0-90 and 91-365 days, respectively. For clopidogrel plus warfarin, HR of 0.90 (0.68-1.19) and 0.68 (0.49-0.95) was observed for cardiovascular outcome and 1.28 (0.71-2.32) and 1.08 (0.57-2.04) for major bleeds during 0-90 and 91-365 days, respectively. Conclusion: Compared to dual antiplatelets, aspirin or clopidogrel plus warfarin therapy was associated with similar 0-90 days and lower 91-365 days of risk of the cardiovascular outcome, without higher risk of major bleeds. Triple therapy was associated with non-significant lower risk of cardiovascular outcome and higher risk of major bleeds. PMID- 29126155 TI - Isl1 mediates mesenchymal expansion in the developing external genitalia via regulation of Bmp4, Fgf10 and Wnt5a. AB - Genital malformations are among the most common human birth defects, and both genetic and environmental factors can contribute to these malformations. Development of the external genitalia in mammals relies on complex signaling networks, and disruption of these signaling pathways can lead to genital defects. Islet-1 (ISL1), a member of the LIM/Homeobox family of transcription factors, has been identified as a major susceptibility gene for classic bladder exstrophy in humans, a common form of the bladder exstrophy-epispadias complex (BEEC), and is implicated in a role in urinary tract development. We report that deletion of Isl1 from the genital mesenchyme in mice led to hypoplasia of the genital tubercle and prepuce, with an ectopic urethral opening and epispadias-like phenotype. These mice also developed hydroureter and hydronephrosis. Identification of ISL1 transcriptional targets via ChIP-Seq and expression analyses revealed that Isl1 regulates several important signaling pathways during embryonic genital development, including the BMP, WNT, and FGF cascades. An essential function of Isl1 during development of the external genitalia is to induce Bmp4-mediated apoptosis in the genital mesenchyme. Together, these studies demonstrate that Isl1 plays a critical role during development of the external genitalia and forms the basis for a greater understanding of the molecular mechanisms underlying the pathogenesis of BEEC and urinary tract defects in humans. PMID- 29126157 TI - A Survey of the Species of Squash Bug (Hemiptera: Coreidae) Egg Parasitoids in Virginia and Their Distribution. AB - Squash bug, Anasa tristis DeGeer (Hemiptera: Coreidae), is a major pest of squash and pumpkins in the United States. In order to better understand the importance of natural egg parasitism of this species in Virginia, we conducted a 2-yr statewide survey. In total, 1,127 squash bug egg masses (~20,000 total eggs) were sampled from squash and pumpkins from 43 counties in Virginia from 2014 to 2015. Egg masses were brought back to the lab to record levels of squash bug nymphal emergence or adult parasitoid eclosion and identification. Over 50% of the total squash bug eggs collected statewide were parasitized. Gryon pennsylvanicum Ashmead (Hymenoptera: Scelionidae) was the predominant egg parasitoid accounting for over 98% of all parasitoid adults recovered. The only other species emerging from squash bug eggs was Anastatus reduvii Howard (Hymenoptera: Eupelmidae), which is a generalist parasitoid. G. pennsylvanicum was found in 75% of the counties surveyed with the highest levels of parasitism occurring in the Northern, Southwestern Mountain, and Western Piedmont regions of the state and the lowest levels of parasitism occurring in the Tidewater region in the southeastern portion of the state. Based on this 2-yr survey, G. pennsylvanicum was determined to be a major natural enemy of squash bug, significantly reducing the number of nymphs that emerge from deposited eggs. Conservation of this natural enemy should therefore be a priority for integrated pest management programs in cucurbits. PMID- 29126159 TI - RE: "THE RELATIONSHIP BETWEEN OCCUPATIONAL STANDING AND SITTING AND INCIDENT HEART DISEASE OVER A 12-YEAR PERIOD IN ONTARIO, CANADA". PMID- 29126158 TI - Full genome survey and dynamics of gene expression in the greater amberjack Seriola dumerili. AB - Background: Teleosts of the genus Seriola, commonly known as amberjacks, are of high commercial value in international markets due to their flesh quality and worldwide distribution. The Seriola species of interest to Mediterranean aquaculture is the greater amberjack (Seriola dumerili). This species holds great potential for the aquaculture industry, but in captivity, reproduction has proved to be challenging, and observed growth dysfunction hinders their domestication. Insights into molecular mechanisms may contribute to a better understanding of traits like growth and sex, but investigations to unravel the molecular background of amberjacks have begun only recently. Findings: Illumina HiSeq sequencing generated a high-coverage greater amberjack genome sequence comprising 45 909 scaffolds. Comparative mapping to the Japanese yellowtail (Seriola quinqueriadiata) and to the model species medaka (Oryzias latipes) allowed the generation of in silico groups. Additional gonad transcriptome sequencing identified sex-biased transcripts, including known sex-determining and differentiation genes. Investigation of the muscle transcriptome of slow-growing individuals showed that transcripts involved in oxygen and gas transport were differentially expressed compared with fast/normal-growing individuals. On the other hand, transcripts involved in muscle functions were found to be enriched in fast/normal-growing individuals. Conclusion: The present study provides the first insights into the molecular background of male and female amberjacks and of fast- and slow-growing fish. Therefore, valuable molecular resources have been generated in the form of a first draft genome and a reference transcriptome. Sex biased genes, which may also have roles in sex determination or differentiation, and genes that may be responsible for slow growth are suggested. PMID- 29126160 TI - PDBe: towards reusable data delivery infrastructure at protein data bank in Europe. AB - The Protein Data Bank in Europe (PDBe, pdbe.org) is actively engaged in the deposition, annotation, remediation, enrichment and dissemination of macromolecular structure data. This paper describes new developments and improvements at PDBe addressing three challenging areas: data enrichment, data dissemination and functional reusability. New features of the PDBe Web site are discussed, including a context dependent menu providing links to raw experimental data and improved presentation of structures solved by hybrid methods. The paper also summarizes the features of the LiteMol suite, which is a set of services enabling fast and interactive 3D visualization of structures, with associated experimental maps, annotations and quality assessment information. We introduce a library of Web components which can be easily reused to port data and functionality available at PDBe to other services. We also introduce updates to the SIFTS resource which maps PDB data to other bioinformatics resources, and the PDBe REST API. PMID- 29126161 TI - Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II. AB - Background: Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS)-II prevention and ductal carcinoma in situ (DCIS) trials, and its association with early symptoms. Patients and methods: In the prevention trial, 3864 postmenopausal women were randomized to placebo versus anastrozole. A total of 2980 postmenopausal women with DCIS were randomized to tamoxifen versus anastrozole. Adherence to trial medication was calculated using the Kaplan-Meier method and all P-values were two-sided. Results: In the prevention trial, adherence was 65.8% [anastrozole (65.7%) versus placebo (65.9%); HR = 0.97 (0.87 1.09), P = 0.6]. Adherence was lower for those reporting arthralgia in the placebo group (P = 0.02) or gynecological symptoms in the anastrozole group (P = 0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% [anastrozole (67.5%) versus tamoxifen (65.8%); HR = 1.06 (0.94-1.20), P = 0.4]. Hot flashes were associated with greater adherence in the anastrozole arm (P = 0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials. Conclusions: In the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy. PMID- 29126162 TI - High Circulating Free Thyroxine Levels May Increase the Risk of Frailty: The Rotterdam Study. AB - Context: Thyroid hormones affect metabolism in various tissues, organs, and systems. However, the overall impact of thyroid function on an individual's vulnerability to adverse outcomes remains unclear. Objective: To investigate the cross-sectional and prospective association of thyroid function with the frailty index, a well-established measure of overall health. Design and Setting: The Rotterdam Study, a population-based, prospective cohort study. Participants and Main Outcome Measurements: Participants with baseline measurements of thyroid function and the frailty index were eligible. The frailty index was measured at baseline and after a median follow-up time of 10.1 years (interquartile range, 5.7 to 10.8 years). A higher frailty index indicated a worse health state. We assessed the association of thyroid function with frailty at baseline, frailty at follow-up, and frailty changes over time, adjusting for age, sex, cohort, smoking, alcohol, and education. Results: We included 9640 participants (mean age, 64.9 years). There was a U-shaped association of thyrotropin (TSH; P < 0.0003) and free thyroxine (FT4; P < 0.0001) with frailty at baseline. There was no association of TSH, but a positive association of FT4 with frailty at follow up and frailty changes over time (beta, 1.22; confidence interval, 0.73 to 1.72 per 1 unit FT4). Conclusion: In this population-based study, participants with low and high thyroid function were more likely to be frail than participants with normal thyroid function. However, only those with higher FT4 levels had an increased risk of becoming more frail over time. The identification of FT4 as a potential marker of health deterioration could have future implications regarding the prediction and prevention of frailty. PMID- 29126164 TI - The Association Between Diabetes and Olfactory Function in Adults. AB - Diabetes is a significant chronic disease that in limited studies has been linked with olfactory dysfunction. We investigated the cross-sectional association between diabetes and olfactory dysfunction in 3151 adults aged >=40 years who participated in US National Health and Nutrition Examination Survey 2013-2014 with information on olfactory dysfunction and diabetes. Diabetes was defined from fasting serum glucose >=126 mg/dL, oral glucose tolerance test >=200 mg/dL, HbA1c levels >=6.5%, physician-diagnosed diabetes, or current use of oral hypoglycemic agents and/or insulin. Self-reported olfactory dysfunction was defined as a positive answer to any of the following questions: 1) "Have you had problem with smell in the past 12 months?"; 2) "Have you had a change in the ability to smell since age 25?", or 3) "Do you have phantom smells?". Participants were considered to have severe hyposmia or anosmia if they had <5 correct answers in the 8-item pocket smell test. Analyses were adjusted for the main confounders, including olfactory dysfunction risk factors. Compared to non-diabetics, diabetics under insulin treatment showed a higher prevalence of phantom odors [OR(95% CI): 2.42 (1.16; 5.06)] and a non-significant higher prevalence of severe hyposmia/anosmia [OR(95% CI): 1.57 (0.89; 2.78)]. Amongst diabetics, there was a significant trend to severe hyposmia/anosmia for those on more aggressive treatments [OR (95% CI) including oral and insulin treatment compared to those who reported no use of drug treatment, respectively: 1.33 (0.60; 2.96) and 2.86 (1.28; 6.40); P trend 0.01]. No association was observed between diabetes duration and prevalence of olfactory dysfunction. PMID- 29126163 TI - Identification of cancer biomarkers of prognostic value using specific gene regulatory networks (GRN): a novel role of RAD51AP1 for ovarian and lung cancers. AB - To date, microarray analyses have led to the discovery of numerous individual 'molecular signatures' associated with specific cancers. However, there are serious limitations for the adoption of these multi-gene signatures in the clinical environment for diagnostic or prognostic testing as studies with more power need to be carried out. This may involve larger richer cohorts and more advanced analyses. In this study, we conduct analyses-based on gene regulatory network-to reveal distinct and common biomarkers across cancer types. Using microarray data of triple-negative and medullary breast, ovarian and lung cancers applied to a combination of glasso and Bayesian networks (BNs), we derived a unique network-containing genes that are uniquely involved: small proline-rich protein 1A (SPRR1A), follistatin like 1 (FSTL1), collagen type XII alpha 1 (COL12A1) and RAD51 associated protein 1 (RAD51AP1). RAD51AP1 and FSTL1 are significantly overexpressed in ovarian cancer patients but only RAD51AP1 is upregulated in lung cancer patients compared with healthy controls. The upregulation of RAD51AP1 was mirrored in the bloods of both ovarian and lung cancer patients, and Kaplan-Meier (KM) plots predicted poorer overall survival (OS) in patients with high expression of RAD51AP1. Suppression of RAD51AP1 by RNA interference reduced cell proliferation in vitro in ovarian (SKOV3) and lung (A549) cancer cells. This effect appears to be modulated by a decrease in the expression of mTOR-related genes and pro-metastatic candidate genes. Our data describe how an initial in silico approach can generate novel biomarkers that could potentially support current clinical practice and improve long-term outcomes. PMID- 29126165 TI - Foramen Magnum Dural Arteriovenous Fistulas: Clinical Presentations and Treatment Outcomes, A Case-Series of 12 Patients. AB - BACKGROUND: Dural arteriovenous fistulas (DAVFs) are usually seen in relation to the venous sinuses, but in certain rare instances fistulas may not drain directly into the venous sinuses but rather drain into the cortical veins. This rare form of DAVF may present with either intracranial hemorrhage or myelopathy. The mode of clinical presentation is influenced by the venous outflow into either intracranial drainage or caudally intraspinal drainage. OBJECTIVE: To evaluate the clinical presentations, angioarchitectural characteristics, and treatment of 12 patients who presented with DAVF in the region of the foramen magnum. METHODS: In this case series we reviewed clinical charts, radiological images, and operative notes of 12 patients who were diagnosed of foramen magnum DAVF from December 1993 until April 2017. The angiographic studies were analyzed for feeding arteries, the location of the shunt, the venous drainage patterns, and the presence of venous side aneurysms. RESULTS: Twelve patients were angiographically confirmed with foramen magnum DAVFs. They included 11 males and 1 female (M:F = 11:1). Mean age of 55.6 yr ranging between 42 yr and 71 yr of age. Eight patients presented with progressive myelopathy, 3 patients with posterior fossa intracranial hemorrhage, and 1 patient presented with lower cranial nerve IX and XII palsies due to mass effect. CONCLUSION: A dural arteriovenous shunt, which may be located in the region of the foramen magnum, should be suspected in those cases of subarachnoid hemorrhage in the posterior fossa or progressive myelopathy mimicking spinal DAVF. PMID- 29126166 TI - Fabrication of circular assemblies with DNA tetrahedrons: from static structures to a dynamic rotary motor. AB - DNA tetrahedron as the simplest 3D DNA nanostructure has been applied widely in biomedicine and biosensing. Herein, we design and fabricate a series of circular assemblies of DNA tetrahedron with high purity and decent yields. These circular nanostructures are confirmed by endonuclease digestion, gel electrophoresis and atomic force microscopy. Inspired by rotary protein motor, we demonstrate these circular architectures can serve as a stator for a rotary DNA motor to achieve the circular rotation. The DNA motor can rotate on the stators for several cycles, and the locomotion of the motor is monitored by the real-time fluorescent measurements. PMID- 29126167 TI - Outcome of long-term complications after permanent metallic left bronchial stenting in children. AB - OBJECTIVES: We describe the way we treated 7 children with critical long-term complications after metallic balloon-expandable stenting in the left mainstem bronchus. METHODS: Endoscopic follow-up included a first bronchoscopy 3 weeks after stenting, then monthly for 3 months, every 4-6 months up to 1 year and at scheduled times to calibrate stent diameter up to final calibration. When major complications occurred, patients underwent chest computed tomographic angiography. RESULTS: In 1 of the 7 children (median age 2.8 years), metallic left bronchial stenting served as a bridge to surgery. After a median 4-year follow-up, all 7 children experienced recurrent stent ovalizations with stent breakage in 3 and erosion in 1. In 4 children, computed tomographic angiography showed abundant peribronchial fibrous tissue, in 2 left mediastinal rotation and in 1 displacement along the left bronchus after pulmonary re-expansion as the cause of stent-related complication. Of the 7 children, 6 underwent surgery (5 posterior aortopexy and 1 section of the ligamentum arteriosus) and 3 required nitinol stents placement within the metallic ones. One patient completed the follow-up, and 1 patient was lost to follow-up. All 5 remaining children still have permanent bronchial stents in place, patent and re-epithelialized after a median 10.5-year follow-up. There were no deaths. CONCLUSIONS: Satisfactory anatomical relationships when children have stents placed in the left mainstem bronchus alone do not guarantee the final success. Several mechanisms intervene to cause critical stent-related complications in children during growth. Permanent metallic stents should be used carefully, and only in selected patients. PMID- 29126169 TI - Dose-dependent effect of cotinine-verified tobacco smoking on serum immunoglobulin E levels in Korean adult males. AB - Background: Smoking is one of the risk factors to exacerbate allergic diseases, and it may affect serum immunoglobulin E (IgE) levels. However, few studies have relied on an objective biomarker to examine the effect of tobacco smoking on serum IgE levels. Method: A nationwide cross-sectional study was conducted to examine the relationship between urinary cotinine (Ucot) concentrations and IgE levels in 973 males using data from the 2010 Korean National Health and Nutrition Examination Survey (KNHANES). Ucot was classified into four groups based on concentration (ng/mL) as follows: nonsmoker group (Ucot <50 ng/mL) and three tertile groups in smokers (T1 [Ucot: 50.00-921.28 ng/mL]; T2 [Ucot: 921.29 1,869.36 ng/mL]; and T3 [Ucot >=1,869.37 ng/mL]). The dose-response relationships between Ucot concentrations and total serum IgE level were estimated using analysis of covariance (ANCOVA) and multiple linear regression analysis after adjusting for confounding variables. Results: We found a significant and positive dose-related effect of cigarette smoking as measured by Ucot concentrations on total serum IgE level. The multivariate adjusted means of total serum IgE levels (SE) were 321.0 (36.3), 404.4 (102.7), 499.2 (79.2), and 534.7 (82.7) IU/mL, after adjusting for age, body mass index, alcohol ingestion, physical exercise, job, and household income. The regression coefficient beta for total serum IgE was beta = 68.6 with increasing level of Ucot group after adjusting for the same co-variables (P = 0.009). Conclusion: These findings suggest that the amount of smoking may have a dose-dependent effect on total serum IgE levels. Implication: Smoking is one of the risk factors to exacerbate allergic diseases, and it may affect serum immunoglobulin E (IgE) levels, which is closely related to type 1 mediated allergic diseases. However, few studies have relied on an objective biomarker to examine the effect of tobacco smoking on serum IgE levels. We found that tobacco exposure, as measured by Ucot concentrations, increased the serum IgE levels in a dose-response manner in a representative sample of Korean adult males. PMID- 29126170 TI - Changes in social support over time in a faith-based physical activity intervention. AB - African-American women report higher levels of chronic conditions and church attendance relative to the overall US population. Therefore, efforts have increased over the past decade to design church-based health promotion programs. The present study compared changes in religiosity, religious social support and general social support across time within a church-based physical activity study. In a clustered randomized controlled trial, 31 churches and ~15 African-American women per church were recruited to participate. Churches were randomized to one of three 10-month programs to promote physical activity: faith-integrated (FI), non-faith integrated (NFI) or self-guided control program (C). Comparisons were made between baseline and 10-month time points to assess differences over time. A significant reduction in general social support was observed across all groups. Private religious practices and religious emotional support received increases in C and FI, respectively. Prior research findings and the current study highlight difficulty in demonstrating strong, unilateral changes in religiosity, social support and health. Additional research is needed to identify more accurate measures of these concepts. Findings from the current study have implications for the role of social support in future church-based health promotion studies. PMID- 29126168 TI - Endocrine Disruptors and Developmental Origins of Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic worldwide, particularly in countries that consume a Western diet, and can lead to life threatening conditions such as cirrhosis and hepatocellular carcinoma. With increasing prevalence of NAFLD in both children and adults, an understanding of the factors that promote NAFLD development and progression is crucial. Environmental agents, including endocrine-disrupting chemicals (EDCs), which have been linked to other diseases, may play a role in NAFLD development. Increasing evidence supports a developmental origin of liver disease, and early-life exposure to EDCs could represent one risk factor for the development of NAFLD later in life. Rodent studies provide the strongest evidence for this link, but further studies are needed to define whether there is a causal link between early life EDC exposure and NAFLD development in humans. Elucidating the molecular mechanisms underlying development of NAFLD in the context of developmental EDC exposures may identify biomarkers for people at risk, as well as potential intervention and/or therapeutic opportunities for the disease. PMID- 29126171 TI - Copy Number Variant in the Region of Adenosine Kinase (ADK) and Its Possible Contribution to Schizophrenia Susceptibility. AB - Background: Adenosine kinase (ADK) is supposed to be a schizophrenia susceptibility gene based on the findings that ADK is an enzyme that catalyzes transfer of the gamma-phosphate from ATP to adenosine, which interacts with dopamine and glutamate neurotransmitters. However, no reports of schizophrenia cases with loss of function variants in the ADK region have been published. In our previous study investigating copy number variants in schizophrenia, we detected a copy number variant in the ADK region in 1 of 1699 schizophrenia patients. Methods: We validated the ADK deletion by determining the breakpoint. Then, we compared the relative expression of ADK in 32 schizophrenia patients, including a schizophrenia patient with deletion of ADK, with 29 healthy controls using lymphoblastoid cell lines. Furthermore, we evaluated the clinical phenotypes of the schizophrenia with ADK deletion. Result: We validated the copy number variants with Sanger sequencing and predicted that this copy number variant results in loss of function of ADK. Furthermore, expression analysis of mRNA from peripheral blood in this schizophrenia patient with the ADK deletion showed an extremely low level of ADK. Here we describe a case report of a patient with ADK deletion with phenotypes (schizophrenia, parkinsonism, epilepsy) that are predicted when ADK function is disrupted. Conclusion: Considering that the patient had a low ADK mRNA level and showed a phenotype that may be related to ADK deficiency, the copy number variants in the region of ADK may be strongly related to the phenotypes described here, such as schizophrenia, Parkinsonism, and epilepsy. PMID- 29126172 TI - Native Honey Bees Outperform Adventive Honey Bees in Increasing Pyrus bretschneideri (Rosales: Rosaceae) Pollination. AB - The foraging behavior of different bee species is a key factor influencing the pollination efficiency of different crops. Most pear species exhibit full self incompatibility and thus depend entirely on cross-pollination. However, as little is known about the pear visitation preferences of native Apis cerana (Fabricius; Hymenoptera: Apidae) and adventive Apis mellifera (L.; Hymenoptera: Apidae) in China. A comparative analysis was performed to explore the pear-foraging differences of these species under the natural conditions of pear growing areas. The results show significant variability in the pollen-gathering tendency of these honey bees. Compared to A. mellifera, A. cerana begins foraging at an earlier time of day and gathers a larger amount of pollen in the morning. Based on pollen collection data, A. mellifera shows variable preferences: vigorously foraging on pear on the first day of observation but collecting pollen from non target floral resources on other experimental days. Conversely, A. cerana persists in pear pollen collection, without shifting preference to other competitive flowers. Therefore, A. cerana outperforms adventive A. mellifera with regard to pear pollen collection under natural conditions, which may lead to increased pear pollination. This study supports arguments in favor of further multiplication and maintenance of A. cerana for pear and other native crop pollination. Moreover, it is essential to develop alternative pollination management techniques to utilize A. mellifera for pear pollination. PMID- 29126173 TI - Immunogenicity of Different Routine Poliovirus Vaccination Schedules: A Randomized, Controlled Trial in Karachi, Pakistan. AB - Background: We assessed immunity against polioviruses induced with a new Pakistani poliovirus immunization schedule and compared it to alternative poliovirus immunization schedules. Methods: Newborns were randomized to undergo vaccination based on 1 of 5 vaccination schedules, with doses administered at birth and at 6, 10, and 14 weeks of age. Arm A received inactivated poliovirus vaccine (IPV) at all time points. Arm B received bivalent oral poliovirus vaccine (bOPV) at all time points. Arms C and D received bOPV at the first 3 time points and bOPV plus IPV at the final time point (the current schedule). Arm E received trivalent OPV (tOPV) at all time points. At 22 weeks of age, all children received 1 challenge dose of tOPV, and children in arm D received 1 additional IPV dose. Sera were analyzed for the presence of poliovirus neutralizing antibodies at birth and 14 and 22 weeks of age. Results: Seroconversion for poliovirus type 1 (PV1) at 22 weeks of age was observed in 80% of individuals in arm A, 97% in arm B, 94% in arm C, 96% in arm D, and 94% in arm E; for PV2, seroconversion frequencies were 84%, 19%, 53%, 49%, and 93%, respectively; and for PV3, seroconversion frequencies were 93%, 94%, 98%, 94%, and 85%, respectively. Conclusions: The current immunization schedule in Pakistan induced high seroconversion rates for PV1 and PV3; however, it induced PV2 seroconversion in only half of study subjects. There is a growing cohort of young children in Pakistan who are unprotected against PV2; and this creates an increasing risk of a large-scale outbreak of poliomyelitis caused by circulating vaccine-derived PV2. PMID- 29126175 TI - Conventional and pioneer modes of glucocorticoid receptor interaction with enhancer chromatin in vivo. AB - Glucocorticoid hormone plays a major role in metabolism and disease. The hormone bound glucocorticoid receptor (GR) binds to a specific set of enhancers in different cell types, resulting in unique patterns of gene expression. We have addressed the role of chromatin structure in GR binding by mapping nucleosome positions in mouse adenocarcinoma cells. Before hormone treatment, GR-enhancers exist in one of three chromatin states: (i) Nucleosome-depleted enhancers that are DNase I-hypersensitive, associated with the Brg1 chromatin remodeler and flanked by nucleosomes incorporating histone H2A.Z. (ii) Nucleosomal enhancers that are DNase I-hypersensitive, marked by H2A.Z and associated with Brg1. (iii) Nucleosomal enhancers that are inaccessible to DNase I, incorporate little or no H2A.Z and lack Brg1. Hormone-induced GR binding results in nucleosome shifts at all types of GR-enhancer, coinciding with increased recruitment of Brg1. We propose that nucleosome-depleted GR-enhancers are formed and maintained by other transcription factors which recruit Brg1 whereas, at nucleosomal enhancers, GR behaves like a pioneer factor, interacting with nucleosomal sites and recruiting Brg1 to remodel the chromatin. PMID- 29126174 TI - miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions. AB - MicroRNAs (miRNAs) are small non-coding RNAs of ~ 22 nucleotides that are involved in negative regulation of mRNA at the post-transcriptional level. Previously, we developed miRTarBase which provides information about experimentally validated miRNA-target interactions (MTIs). Here, we describe an updated database containing 422 517 curated MTIs from 4076 miRNAs and 23 054 target genes collected from over 8500 articles. The number of MTIs curated by strong evidence has increased ~1.4-fold since the last update in 2016. In this updated version, target sites validated by reporter assay that are available in the literature can be downloaded. The target site sequence can extract new features for analysis via a machine learning approach which can help to evaluate the performance of miRNA-target prediction tools. Furthermore, different ways of browsing enhance user browsing specific MTIs. With these improvements, miRTarBase serves as more comprehensively annotated, experimentally validated miRNA-target interactions databases in the field of miRNA related research. miRTarBase is available at http://miRTarBase.mbc.nctu.edu.tw/. PMID- 29126176 TI - Hand-arm vibration in orthopaedic surgery: a neglected risk. AB - Background: Hand-arm vibration syndrome is an occupational disease caused by exposure to hand-arm transmitted vibration. The Health and Safety Executive has set limits for vibration exposure, including an exposure action value (EAV), where steps should be taken to reduce exposure, and an exposure limit value (ELV), beyond which vibrating equipment must not be used for the rest of the working day. Aims: To measure hand-arm transmitted vibration among orthopaedic surgeons, who routinely use hand-operated saws. Methods: We undertook a cadaveric study measuring vibration associated with a tibial cut using battery-operated saws. Three surgeons undertook three tibial cuts each on cadaveric tibiae. Measurements were taken using a frequency-weighted root mean square acceleration, with the vibration total value calculated as the root of the sums squared in each of the three axes. Results: A mean (SD) vibration magnitude of 1 (0.2) m/s2 in the X-axis, 10.3 (1.9) m/s2 in the Y-axis and 4.2 (1.3) m/s2 in the Z-axis was observed. The weighted root mean squared magnitude of vibration was 11.3 (1.7) m/s2. These results suggest an EAV of 23 min and ELV of 1 h 33 min using this equipment. Conclusions: Our results demonstrate that use of a battery-operated sagittal saw can transmit levels of hand-arm vibration approaching the EAV or ELV through prolonged use. Further study is necessary to quantify this risk and establish whether surveillance is necessary for orthopaedic surgeons. PMID- 29126177 TI - CD30 Expression in Monomorphic Posttransplant Lymphoproliferative Disorder, Diffuse Large B-Cell Lymphoma Correlates With Greater Regulatory T-Cell Infiltration. AB - Objectives: CD30 is a protein thought to promote cell proliferation/survival and downregulate the immune response. Twenty percent to 40% of de novo diffuse large B-cell lymphomas (DLBCLs) express CD30, and some patients have been treated with the anti-CD30 agent brentuximab. In the solid organ transplant setting, allograft regulatory T cells (Tregs) have been shown to be modulated via CD30 signaling. Methods: Posttransplant lymphoproliferative disorders (PTLDs) constitute a heterogeneous group of lymphomas, and since CD30 expression has been rarely formally assessed in PTLDs, we analyzed a cohort of PTLDs. Results: We found that 26 (79%) of 33 PTLDs were CD30+. Of these, 17 (77%) of 22 DLBCL monomorphic PTLDs were CD30+ compared with 56 (38%) of 148 de novo DLBCLs (P = .009). The median FoxP3+ Treg count was higher in CD30+ than in CD30- PTLDs, 3.0 vs 0 (P = .012). Conclusions: These findings suggest a pathophysiologic link between CD30 activity and Tregs and may indicate differential expression of CD30 in B-cell lymphomas arising in the setting of immune dysregulation. PMID- 29126178 TI - The Impact of Intradialytic Pedaling Exercise on Arterial Stiffness: A Pilot Randomized Controlled Trial in a Hemodialysis Population. AB - OBJECTIVES: Regular exercise is known to reduce arterial stiffness (AS) in hemodialysis patients. However, the impact of a more realistic intradialytic form of exercise, such as pedaling, is unclear. We aimed to examine (i) the effect of intradialytic pedaling exercise on AS over 4 months and (ii) the longer term effect of pedaling on AS 4 months after exercise cessation. METHODS: Patients on stable in-center hemodialysis (3 x/week) were randomly assigned 1:1 to either intradialytic pedaling exercise (EX) or to a control group receiving usual hemodialysis (nonEX) for 4 months. At baseline and 4 months, peripheral and central blood pressure (BP) indices, heart rate (HR), augmentation index HR corrected (AIx75), and carotid-femoral pulse wave velocity (cfPWV) were assessed (applanation tonometry). Measurements were repeated in the EX group 4 months postexercise cessation. RESULTS: As per protocol analysis was completed in 10 EX group participants (58 +/- 17 years, body mass index 26 +/- 4 kg/m2) and 10 nonEX group participants (53 +/- 15 years, body mass index 27 +/- 6 kg/m2). Peripheral and central BP was unchanged in both groups. AIx75 was unchanged in the EX group, however, a significant median increase of 3.5% [interquartile range, IQR 1.0, 8.5] was noted in the nonEX group (P = 0.009). We noted a significantly greater absolute decrease in cfPWV in the EX group compared to controls: -1.00 [IQR 1.95, 0.05] vs. 0.20 [IQR -0.10, 0.90] (P = 0.033). Interestingly, the decrease in cfPWV observed in the EX group was partially reversed 4 months after exercise cessation. CONCLUSION: Intradialytic pedaling exercise has a beneficial impact on AS. This relationship warrants further investigation. CLINICAL TRIALS REGISTRATION: Trial Number #NCT03027778 (clinicaltrials.gov). PMID- 29126179 TI - Dimethyl sulfoxide and quercetin prolong the survival, motility, and fertility of cold-stored mouse sperm for 10 days. AB - Technology for preserving sperm is useful for disseminating valuable male genetic traits. Cold storage is suitable for easily transporting sperm as an alternative to the shipment of live animals. However, there is a technical limitation in that the fertility of cold-stored sperm declines within 3 days. To overcome this problem, we examined the protective effects of quercetin and dimethyl sulfoxide (DMSO). DMSO and quercetin maintained the fertility and motility of cold-stored sperm for 10 days. In addition, quercetin attenuated the reduction of mitochondrial membrane potential of cold-stored sperm during sperm preincubation, allowing the induction of capacitation, and it localized to the midpiece of sperm. Furthermore, DMSO and quercetin enhanced the level of tyrosine phosphorylation of cold-stored sperm. DMSO and quercetin have life-prolonging effects on sperm during cold storage. Cold storage using DMSO and quercetin will provide a robust system for internationally transporting valuable sperm samples. PMID- 29126180 TI - RepLong: de novo repeat identification using long read sequencing data. AB - Motivation: The identification of repetitive elements is important in genome assembly and phylogenetic analyses. The existing de novo repeat identification methods exploiting the use of short reads are impotent in identifying long repeats. Since long reads are more likely to cover repeat regions completely, using long reads is more favorable for recognizing long repeats. Results: In this study, we propose a novel de novo repeat elements identification method namely RepLong based on PacBio long reads. Given that the reads mapped to the repeat regions are highly overlapped with each other, the identification of repeat elements is equivalent to the discovery of consensus overlaps between reads, which can be further cast into a community detection problem in the network of read overlaps. In RepLong, we first construct a network of read overlaps based on pair-wise alignment of the reads, where each vertex indicates a read and an edge indicates a substantial overlap between the corresponding two reads. Secondly, the communities whose intra connectivity is greater than the inter connectivity are extracted based on network modularity optimization. Finally, representative reads in each community are extracted to form the repeat library. Comparison studies on Drosophila melanogaster and human long read sequencing data with genome-based and short-read-based methods demonstrate the efficiency of RepLong in identifying long repeats. RepLong can handle lower coverage data and serve as a complementary solution to the existing methods to promote the repeat identification performance on long-read sequencing data. Availability and implementation: The software of RepLong is freely available at https://github.com/ruiguo-bio/replong. Contact: ywsun@szu.edu.cn or zhuzx@szu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126182 TI - Robbins Basic Pathology. PMID- 29126181 TI - Childhood Music Training Induces Change in Micro and Macroscopic Brain Structure: Results from a Longitudinal Study. AB - Several studies comparing adult musicians and nonmusicians have shown that music training is associated with structural brain differences. It is not been established, however, whether such differences result from pre-existing biological traits, lengthy musical training, or an interaction of the two factors, or if comparable changes can be found in children undergoing music training. As part of an ongoing longitudinal study, we investigated the effects of music training on the developmental trajectory of children's brain structure, over two years, beginning at age 6. We compared these children with children of the same socio-economic background but either involved in sports training or not involved in any systematic after school training. We established at the onset that there were no pre-existing structural differences among the groups. Two years later we observed that children in the music group showed (1) a different rate of cortical thickness maturation between the right and left posterior superior temporal gyrus, and (2) higher fractional anisotropy in the corpus callosum, specifically in the crossing pathways connecting superior frontal, sensory, and motor segments. We conclude that music training induces macro and microstructural brain changes in school-age children, and that those changes are not attributable to pre-existing biological traits. PMID- 29126183 TI - Up in Smoke: Uncovering a Lack of Evidence for Proton Pump Inhibitors as a Source of Tetrahydrocannabinol Immunoassay False Positives. AB - Objective: It is recommended that positives in immunoassay drug screens be followed up with more specific confirmatory testing. The drug package insert for pantoprazole mentions reports of false-positive urine screening tests for tetrahydrocannabinol in patients receiving proton pump inhibitors, but no method details or data are given, referenced, or found in literature searches. Thus, we investigated this using our laboratory's assay. Methods: A spiked sample and samples from 32 patients taking a proton pump inhibitor were analyzed using the EMIT II Plus Cannabinoid assay with a 20 ng/mL cutoff. Additionally, we examined urine samples from 50 patients with false-positive or low-positive screens for evidence of a proton pump inhibitor. To determine whether O-desmethyl pantoprazole sulfate, the major metabolite, shares any structural or electrostatic similarity to suggest a basis for cross-reactivity in the immunoassay, we used computational techniques for analyses. Molecular electrostatic potential energy (MEP) maps were calculated for the global minimum conformers, and the maximum common substructure Tanimoto similarity was calculated for the modeled compounds. Results: Neither the spiked sample nor the patient samples were found to screen positive. None of the false-positive or low positive screens were found to contain a proton pump inhibitor. Computational studies showed very little similarity in shape or electrostatics between the two molecules. Conclusions: We find no supporting evidence of pantoprazole as the cause of false positives in the EMIT II Plus Cannabinoid assay and caution the use of proton pump inhibitors as an explanation for tetrahydrocannabinol immunoassay false positives. PMID- 29126184 TI - Bark and Ambrosia Beetle (Curculionidae: Scolytinae) Diversity Found in Agricultural and Fragmented Forests in Piracicaba-SP, Brazil. AB - Land use changes and forest fragmentation result in biodiversity loss and displacement, with insects among the most affected groups. Among these, bark beetles (Curculionidae: Scolytinae) occupy a prominent position due to their close ties to food resources, i.e., trees, and importance as primary decomposers in forest ecosystems. Therefore, our study aimed to document scolytine biodiversity associated with landscape components that vary based on their physical or botanical composition. Bark beetle diversity was sampled monthly for 12 mo in an Atlantic forest remnant and five adjacent vegetation plots (mixed Agroforestry System-AFS, of native trees and fruit species; AFS of rubber trees and coffee plants; coffee monoculture; rubber monoculture; and pasture). In total, 1,833 individuals were sampled from 38 species of which 24 (63%) were detected in very low abundance. The remaining 14 species were more abundant and widespread almost in all areas. Hypothenemus hampei (Westwood), Premnobius cavipennis (Eichhoff), Hypothenemus sp1., and Xyleborus volvulus (Fabricius) were the most abundant. The greatest abundance and richness of bark beetles were found in the dry and cold season. The varied microclimatic conditions of the vegetation plots greatly affected the diversity of the Scolytinae. Solar radiation presented a significant negative effect on abundance in almost all the studied areas. The greatest scolytine diversity was found in anthropic areas with tree canopy structure. Open areas (pasture and coffee monocrop) had a lower species diversity. Similarly, a lower abundance and species richness were found for the Atlantic forest remnant. PMID- 29126185 TI - Corticotropin-Releasing Hormone Suppresses Synapse Formation in the Hippocampus of Male Rats via Inhibition of CXCL5 Secretion by Glia. AB - Corticotropin-releasing hormone (CRH) is believed to play a critical role in stress-induced synaptic formation and modification. In the current study, we explored the mechanisms underlying CRH modulation of synaptic formation in the hippocampus by using various models in vitro. In cultured hippocampal slices, CRH treatment decreased synapsin I and postsynaptic density protein 95 (PSD95) levels via CRH receptor type 1 (CRHR1). In isolated hippocampal neurons, however, it increased synapsin I-labeled presynaptic terminals and PSD95-labeled postsynaptic terminals via CRHR1. Interestingly, the inhibitory effect of CRH on synapsin I labeled and PSD95-labeled terminals occurred in the model of neuron-glia cocultures. These effects were prevented by CRHR1 antagonist. Moreover, treatment of the neurons with the media of CRH-treated glia led to a decrease in synaptic terminal formation. The media collected from CRH-treated glial cells with CRHR1 knockdown did not show an inhibitory effect on synaptic terminals in hippocampal neurons. Unbiased cytokine array coupled with confirmatory enzyme-linked immunosorbent assay revealed that CRH suppressed C-X-C motif chemokine 5 (CXCL5) production in glia via CRHR1. Administration of CXCL5 reversed the inhibitory effects of CRH-treated glia culture media on synaptic formation. Our data suggest that CRH suppresses synapse formation through inhibition of CXCL5 secretion from glia in the hippocampus. Our study indicates that glia-neuron intercommunication is one of the mechanisms responsible for neuronal circuit remodeling during stress. PMID- 29126186 TI - The Importance of Human Immunodeficiency Virus Research for Transgender and Gender-Nonbinary Individuals. AB - Transgender and gender-nonbinary (trans/GNB) individuals are disproportionally affected by human immunodeficiency virus (HIV), yet they are not adequately represented in HIV research and often underserved in clinical care. By building on community strengths and addressing structural, psychological and biological challenges, we can improve the engagement of trans/GNB people in research and ultimately improve prevention, testing, and care for this population. Here, we review the current state of the science related to HIV for trans/GNB people and discuss next steps to expand research that aims to improve the lives and well being of trans/GNB persons. PMID- 29126188 TI - Insulin-Like Growth Factor-1 and Receptor Contribute Genetic Susceptibility to Hypertension in a Han Chinese Population. AB - BACKGROUND: Insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) have been suggested to mediate the pathophysiological response to elevated blood pressure. This study aims to evaluate the association of IGF-1 and IGF-1R with hypertension. METHODS: Overall, 2,012 hypertensive cases and 2,210 controls were included in a case-control study, and 10 tagging single nucleotide polymorphisms (tagSNPs) were selected. The association of these SNPs with hypertension was further evaluated in a follow-up analysis and in an adolescent population. RESULTS: A case-control study indicated that rs1815009 and rs2654981 in IGF-1R were significantly associated with hypertension, with odds ratios of 0.89 (P = 0.009) and 1.19 (P = 0.034), respectively, after adjusting for covariates. Stratification analyses revealed significant associations with hypertension (P < 0.05) for rs35767 in normal weight and obese populations; for rs2229765 in individuals <55 years of age and in overweight and nondrinking populations; and for rs2002880 in overweight and drinking populations. In a follow-up study, rs13379905 in IGF-1R was associated with hypertension incidence (hazard ratio, HR = 1.24, P = 0.042). This association was more significant in individuals with a hypertensive family history (HR = 2.10, P = 0.001). The association of rs13379905 with prehypertension and hypertension was further replicated in adolescent males (P = 0.005). Significant associations with hypertension incidence (P < 0.05) were observed for rs6219 in individuals <55 years of age and among those with obesity and a hypertensive family history as well as rs2002880 in obese individuals. CONCLUSIONS: Our findings suggest that IGF-1R may contribute to the genetic susceptibility to hypertension, with BMI, age, and family history of hypertension all potentially modulating the genetic effects of IGF-1 on hypertension. PMID- 29126187 TI - Med12 regulates ovarian steroidogenesis, uterine development and maternal effects in the mammalian egg. AB - The transcriptional factor MED12 is part of the essential mediator transcriptional complex that acts as a transcriptional coactivator in all eukaryotes. Missense gain-of-function mutations in human MED12 are associated with uterine leiomyomas, yet the role of MED12 deficiency in tumorigenesis and reproductive biology has not been fully explored. We generated a Med12 reproductive conditional knockout mouse model to evaluate its role in uterine mesenchyme, granulosa cells, and oocytes. Mice heterozygous for Med12 deficiency in granulosa cells and uterus (Med12fl/+ Amhr2-Cre) were subfertile, while mice homozygous for Med12 deficiency in granulosa cells and uterus (Med12fl/fl Amhr2 Cre) were infertile. Morphological and histological analysis of the Med12fl/fl Amhr2-Cre reproductive tract revealed atrophic uteri and hyperchromatic granulosa cells with disrupted expression of Lhcgr, Esr1, and Esr2. Med12fl/fl Amhr2-Cre mice estrous cycle was disrupted, and serum analysis showed blunted rise in estradiol in response to pregnant mare serum gonadotropin. Uterine atrophy was partially rescued by exogenous steroid supplementation with dysregulation of Notch1 and Smo expression in steroid supplemented Med12fl/fl Amhr2-Cre uteri, indicating intrinsic uterine defects. Oocyte-specific ablation of Med12 caused infertility without disrupting normal folliculogenesis and ovulation, consistent with maternal effects of Med12 in early embryo development. These results show the critical importance of Med12 in reproductive tract development and that Med12 loss of function does not cause tumorigenesis in reproductive tissues. PMID- 29126190 TI - Early life exposure to China's 1959-61 famine and midlife cognition. AB - Background: Existing studies of the 1944-45 Dutch famine found little evidence of the association between early life malnutrition and midlife cognition. Methods: Among 2446 rural participants born between 1958 and 1963 in the China Health and Retirement Longitudinal Study, we examined effects of exposure to China's 1959-61 Great Leap Forward famine during prenatal and early postnatal life, on four cognitive measures in 2011 (baseline) and changes in cognition between 2011 and 2013 (first follow-up). We obtained difference-in-differences (DID) estimates of the famine effects by exploiting temporal variation in the timing and duration of famine exposure across six birth cohorts born between 1958 and 1963, together with geographical variation in famine severity at the prefecture level. Results: After adjusting for gender, marital status and provincial fixed effects, we found that the 1961 cohort who experienced full-term prenatal and partial-term postnatal exposures to famine had lower scores on the Telephone Interview of Cognitive Status (TICS), a test of drawing pentagons, and general cognition at age 50 years compared with the unexposed 1963 cohort. Adjusting for education, the famine effects on drawing pentagons and general cognition were fully attenuated, but the effect on TICS persisted. We also found a robust negative famine effect on the longitudinal change in general cognition during the 2-year follow-up in the 1959 cohort. Conclusions: Severe nutritional deprivation during prenatal and postnatal periods has a lasting impact on cognitive performance in Chinese adults in their early 50s. PMID- 29126189 TI - Comparative Genome Analysis Reveals Adaptation to the Ectophytic Lifestyle of Sooty Blotch and Flyspeck Fungi. AB - Sooty blotch and flyspeck (SBFS) fungi are a distinctive group of plant pathogens which, although phylogenetically diverse, occupy an exclusively surface-dwelling niche. They cause economic losses by superficially blemishing the fruit of several tree crops, principally apple, in moist temperate regions worldwide. In this study, we performed genome-wide comparative analyses separately within three pairs of species of ascomycete pathogens; each pair contained an SBFS species as well as a closely related but plant-penetrating parasite (PPP) species. Our results showed that all three of the SBFS pathogens had significantly smaller genome sizes, gene numbers and repeat ratios than their counterpart PPPs. The pathogenicity-related genes encoding MFS transporters, secreted proteins (mainly effectors and peptidases), plant cell wall degrading enzymes, and secondary metabolism enzymes were also drastically reduced in the SBFS fungi compared with their PPP relatives. We hypothesize that the above differences in genome composition are due largely to different levels of acquisition, loss, expansion, and contraction of gene families and emergence of orphan genes. Furthermore, results suggested that horizontal gene transfer may have played a role, although limited, in the divergent evolutionary paths of SBFS pathogens and PPPs; repeat induced point mutation could have inhibited the propagation of transposable elements and expansion of gene families in the SBFS group, given that this mechanism is stronger in the SBFS fungi than in their PPP relatives. These results substantially broaden understanding of evolutionary mechanisms of adaptation of fungi to the epicuticular niche of plants. PMID- 29126192 TI - Effects of Exyra ridingsii (Lepidoptera: Noctuidae) on Sarracenia flava (Nepenthales: Sarraceniaceae). AB - Exyra ridingsii (Riley) (Lepidoptera: Noctuidae) is a moth whose obligate host is the pitcher plant Sarracenia flava (L.) (Nepenthales: Sarraceniaceae). The entire life cycle of the moth is completed in the trumpets of this fire-dependent plant that is found throughout the southeastern United States in bogs, long-leaf pine savannas, and pocosins. The purpose of this study was to determine the effects of E. ridingsii on S. flava, including the effect of herbivory on trumpet height in the year subsequent to feeding and whether moths select trumpets for oviposition based on height. Although most forms of herbivory by insects might be expected to have negative effects on plants by reducing photosynthetic abilities, it would be counterproductive for herbivory by E. ridingsii to negatively affect S. flava as this plant is the only possible habitat for E. ridingsii. At each site in selected quadrats, the number of trumpets, trumpet height, trumpet status, number of trumpets in a clump, and number of clumps were recorded. The relationship between height and herbivory was analyzed using a linear model, and a positive correlation was found between height and herbivory. E. ridingsii herbivory had no effect on the next year's growth of S. flava based on a Spearman's correlation. Therefore, we concluded that E. ridingsii has little effect on S. flava populations and has likely evolved to selectively avoid herbivory on more vulnerable, smaller plants. PMID- 29126191 TI - Evolution of exploitative interactions during diversification in Bacillus subtilis biofilms. AB - Microbial biofilms are tightly packed, heterogeneous structures that serve as arenas for social interactions. Studies on Gram negative models reveal that during evolution in structured environments like biofilms, isogenic populations commonly diversify into phenotypically and genetically distinct variants. These variants can settle in alternative biofilm niches and develop new types of interactions that greatly influence population productivity. Here, we explore the evolutionary diversification of pellicle biofilms of the Gram positive, spore forming bacterium Bacillus subtilis. We discovered that-similarly to other species-B. subtilis diversifies into distinct colony variants. These variants dramatically differ in biofilm formation abilities and expression of biofilm related genes. In addition, using a quantitative approach, we reveal striking differences in surface complexity and hydrophobicity of the evolved colony types. Interestingly, one of the morphotypes completely lost the ability of independent biofilm formation and evolved to hitchhike with other morphotypes with improved biofilm forming abilities. Genome comparison suggests that major phenotypic transformations between the morphotypes can be triggered by subtle genetic differences. Our work demonstrates how positive complementarity effects and exploitative interactions intertwine during evolutionary diversification in biofilms. PMID- 29126193 TI - Early Onset of Distress Disorders and High-School Dropout: Prospective Evidence From a National Cohort of Australian Adolescents. AB - Prior research examining whether depression and anxiety lead to high-school dropout has been limited by a reliance on retrospective reports, the assessment of mental health at a single point in time (often remote from the time of high school exit), and the omission of important measures of the social and familial environment. The present study addressed these limitations by analyzing 8 waves of longitudinal data from a cohort of Australian adolescents (n = 1,057) in the Household, Income and Labor Dynamics in Australia (HILDA) Survey (2001-2008). Respondents were followed from the age of 15 years through completion of or exit from high school. Discrete-time survival analysis was used to assess whether the early experience of a distress disorder (indicated by scores <50 on the 5-item Mental Health Inventory from the Short Form Health Survey) predicted subsequent high-school dropout, after controlling for household and parental socioeconomic characteristics and for tobacco smoking and alcohol consumption. Adolescents with a prior distress disorder had twice the odds of high-school dropout compared with those without (odds ratio = 1.99, 95% confidence interval: 1.24, 3.17). This association was somewhat attenuated but remained significant in models including tobacco and alcohol consumption (odds ratio = 1.74, 95% confidence interval: 1.74; 1.09, 2.78). These results suggest that improving the mental health of high school students may promote better educational outcomes. PMID- 29126194 TI - Central and peripheral slow-pressor mechanisms contributing to Angiotensin II salt hypertension in rats. AB - Aims: High salt intake markedly enhances hypertension induced by angiotensin II (Ang II). We explored central and peripheral slow-pressor mechanisms which may be activated by Ang II and salt. Methods and results: In protocol I, Wistar rats were infused subcutaneously with low-dose Ang II (150 ng/kg/min) and fed regular (0.4%) or high salt (2%) diet for 14 days. In protocol II, Ang II-high salt was combined with intracerebroventricular infusion of mineralocorticoid receptor (MR) blockers (eplerenone, spironolactone), epithelial sodium channel (ENaC) blocker (benzamil), angiotensin II type 1 receptor (AT1R) blocker (losartan) or vehicles. Ang II alone raised mean arterial pressure (MAP) ~10 mmHg, but Ang II-high salt increased MAP ~50 mmHg. Ang II-high salt elevated plasma corticosterone, aldosterone and endogenous ouabain but not Ang II alone. Both Ang II alone and Ang II-high salt increased mRNA and protein expression of CYP11B2 (aldosterone synthase gene) in the adrenal cortex but not of CYP11B1 (11-beta-hydroxylase gene). In the aorta, Ang II-high salt increased sodium-calcium exchanger-1 (NCX1) protein. The Ang II-high salt induced increase in MAP was largely prevented by central infusion of MR blockers, benzamil or losartan. Central blockades significantly lowered plasma aldosterone and endogenous ouabain and markedly decreased Ang II-high salt induced CYP11B2 mRNA expression in the adrenal cortex and NCX1 protein in the aorta. Conclusion: These results suggest that in Ang II high salt hypertension, MR-ENaC-AT1R signalling in the brain increases circulating aldosterone and endogenous ouabain, and arterial NCX1. These factors can amplify blood pressure responses to centrally-induced sympatho-excitation and thereby contribute to severe hypertension. PMID- 29126195 TI - Structural insights into simocyclinone as an antibiotic, effector ligand and substrate. AB - Simocyclinones are antibiotics produced by Streptomyces and Kitasatospora species that inhibit the validated drug target DNA gyrase in a unique way, and they are thus of therapeutic interest. Structural approaches have revealed their mode of action, the inducible-efflux mechanism in the producing organism, and given insight into one step in their biosynthesis. The crystal structures of simocyclinones bound to their target (gyrase), the transcriptional repressor SimR and the biosynthetic enzyme SimC7 reveal fascinating insight into how molecular recognition is achieved with these three unrelated proteins. PMID- 29126196 TI - Interface, information, interaction: a narrative review of design and functional requirements for clinical decision support. AB - Objective: Provider acceptance and associated patient outcomes are widely discussed in the evaluation of clinical decision support systems (CDSSs), but critical design criteria for tools have generally been overlooked. The objective of this work is to inform electronic health record alert optimization and clinical practice workflow by identifying, compiling, and reporting design recommendations for CDSS to support the efficient, effective, and timely delivery of high-quality care. Material and Methods: A narrative review was conducted from 2000 to 2016 in PubMed and The Journal of Human Factors and Ergonomics Society to identify papers that discussed/recommended design features of CDSSs that are associated with the success of these systems. Results: Fourteen papers were included as meeting the criteria and were found to have a total of 42 unique recommendations; 11 were classified as interface features, 10 as information features, and 21 as interaction features. Discussion: Features are defined and described, providing actionable guidance that can be applied to CDSS development and policy. To our knowledge, no reviews have been completed that discuss/recommend design features of CDSS at this scale, and thus we found that this was important for the body of literature. The recommendations identified in this narrative review will help to optimize design, organization, management, presentation, and utilization of information through presentation, content, and function. The designation of 3 categories (interface, information, and interaction) should be further evaluated to determine the critical importance of the categories. Future work will determine how to prioritize them with limited resources for designers and developers in order to maximize the clinical utility of CDSS. Conclusion: This review will expand the field of knowledge and provide a novel organization structure to identify key recommendations for CDSS. PMID- 29126197 TI - Impaired Insulin Action Is Associated With Increased Glucagon Concentrations in Nondiabetic Humans. AB - Context: Abnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of alpha-cell dysfunction in prediabetes are unclear. Objective: We sought to determine the relative contributions of insulin secretion and action to alpha-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance. Design: This was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance. Setting: An inpatient clinical research unit at an academic medical center. Participants: A total of 310 nondiabetic persons participated in this study. Interventions: Participants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control. Main Outcome Measure(s): We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants. Results: Fasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of beta-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations. Conclusions: In nondiabetic participants, glucagon secretion was altered by changes in insulin action. PMID- 29126198 TI - Thyroid Hormone Receptor alpha- and beta-Knockout Xenopus tropicalis Tadpoles Reveal Subtype-Specific Roles During Development. AB - Thyroid hormone (TH) binds TH receptor alpha (TRalpha) and beta (TRbeta) to induce amphibian metamorphosis. Whereas TH signaling has been well studied, functional differences between TRalpha and TRbeta during this process have not been characterized. To understand how each TR contributes to metamorphosis, we generated TRalpha- and TRbeta-knockout tadpoles of Xenopus tropicalis and examined developmental abnormalities, histology of the tail and intestine, and messenger RNA expression of genes encoding extracellular matrix-degrading enzymes. In TRbeta-knockout tadpoles, tail regression was delayed significantly and a healthy notochord was observed even 5 days after the initiation of tail shortening (stage 62), whereas in the tails of wild-type and TRalpha-knockout tadpoles, the notochord disappeared after ~1 day. The messenger RNA expression levels of genes encoding extracellular matrix-degrading enzymes (MMP2, MMP9TH, MMP13, MMP14, and FAPalpha) were obviously reduced in the tail tip of TRbeta knockout tadpoles, with the shortening tail. The reduction in olfactory nerve length and head narrowing by gill absorption were also affected. Hind limb growth and intestinal shortening were not compromised in TRbeta-knockout tadpoles, whereas tail regression and olfactory nerve shortening appeared to proceed normally in TRalpha-knockout tadpoles, except for the precocious development of hind limbs. Our results demonstrated the distinct roles of TRalpha and TRbeta in hind limb growth and tail regression, respectively. PMID- 29126200 TI - Response to Letter to the Editor: "Development and Risk Factors of Type 2 Diabetes in a Nationwide Population of Women With Polycystic Ovary Syndrome". PMID- 29126201 TI - Using Mahalanobis Distance to Evaluate Recovery in Acute Stroke. AB - Objective: In the weeks immediately following a stroke, impairments across multiple cognitive domains are pervasive yet there is little literature that explores cognitive recovery during this period. This paper evaluates the use of Mahalanobis distance as a means of statistically evaluating cognitive change at the individual level. Method: A small battery of standardized neuropsychological tests was administered on five or six occasions across a 2-week period to the participants recovering from a stroke and a non-stroke control group. Mahalanobis distance was used to evaluate the change profile of those who were recovering from a stroke relative to the non-stroke control. Results: The outcomes of three patients show that Mahalanobis distance could statistically differentiate recovery, no change, and deterioration from normal repetition effects. Discussion: In the acute phase of stroke using Mahalanobis distance it is possible to distinguish between recovery, normal learning, and gerneralized learning deficits thereby identifying likely candidates for further cognitive assessment and rehabilitation. PMID- 29126199 TI - Evolutionary Epigenomics of Retrotransposon-Mediated Methylation Spreading in Rice. AB - Plant genomes contain numerous transposable elements (TEs), and many hypotheses on the evolutionary drivers that restrict TE activity have been postulated. Few models, however, have focused on the evolutionary epigenomic interaction between the plant host and its TE. The host genome recruits epigenetic factors, such as methylation, to silence TEs but methylation can spread beyond the TE sequence and influence the expression of nearby host genes. In this study, we investigated this epigenetic trade-off between TE and proximal host gene silencing by studying the epigenomic regulation of repressing long terminal repeat (LTR) retrotransposons (RTs) in Oryza sativa. Results showed significant evidence of methylation spreading originating from the LTR-RT sequences, and the extent of spreading was dependent on five factors: 1) LTR-RT family, 2) time since the LTR RT insertion, 3) recombination rate of the LTR-RT region, 4) level of LTR-RT sequence methylation, and 5) chromosomal location. Methylation spreading had negative effects by reducing host gene expression, but only on host genes with LTR-RT inserted in its introns. Our results also suggested high levels of LTR-RT methylation might have a role in suppressing TE-mediated deleterious ectopic recombination. In the end, despite the methylation spreading, no strong epigenetic trade-off was detected and majority of LTR-RT may have only minor epigenetic effects on nearby host genes. PMID- 29126202 TI - ActiveDriverDB: human disease mutations and genome variation in post translational modification sites of proteins. AB - Interpretation of genetic variation is needed for deciphering genotype-phenotype associations, mechanisms of inherited disease, and cancer driver mutations. Millions of single nucleotide variants (SNVs) in human genomes are known and thousands are associated with disease. An estimated 21% of disease-associated amino acid substitutions corresponding to missense SNVs are located in protein sites of post-translational modifications (PTMs), chemical modifications of amino acids that extend protein function. ActiveDriverDB is a comprehensive human proteo-genomics database that annotates disease mutations and population variants through the lens of PTMs. We integrated >385,000 published PTM sites with ~3.6 million substitutions from The Cancer Genome Atlas (TCGA), the ClinVar database of disease genes, and human genome sequencing projects. The database includes site-specific interaction networks of proteins, upstream enzymes such as kinases, and drugs targeting these enzymes. We also predicted network-rewiring impact of mutations by analyzing gains and losses of kinase-bound sequence motifs. ActiveDriverDB provides detailed visualization, filtering, browsing and searching options for studying PTM-associated mutations. Users can upload mutation datasets interactively and use our application programming interface in pipelines. Integrative analysis of mutations and PTMs may help decipher molecular mechanisms of phenotypes and disease, as exemplified by case studies of TP53, BRCA2 and VHL. The open-source database is available at https://www.ActiveDriverDB.org. PMID- 29126203 TI - A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913. AB - Background: This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods: Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results: A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6 methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion: Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study. PMID- 29126204 TI - Proteomic analysis of germinal vesicles in the domestic cat model reveals candidate nuclear proteins involved in oocyte competence acquisition. AB - STUDY QUESTION: Do nuclear proteins in the germinal vesicle (GV) contribute to oocyte competence acquisition during folliculogenesis? SUMMARY ANSWER: Proteomic analysis of GVs identified candidate proteins for oocyte competence acquisition, including a key RNA processing protein-heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). WHAT IS KNOWN ALREADY: The domestic cat GV, which is physiologically similar to the human GV, gains the intrinsic ability to resume meiosis and support early embryo development during the pre-antral-to-antral follicle transition. However, little is known about nuclear proteins that contribute to this developmental process. STUDY DESIGN SIZE, DURATION: GVs were enriched from pre-antral (incompetent) and antral (competent) follicles from 802 cat ovaries. Protein lysates were subjected to quantitative proteomic analysis to identify differentially expressed proteins in GVs from the two follicular categories. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two biological replicates (from independent pools of ovaries) of pre-antral versus antral samples were labeled by tandem mass tags and then assessed by liquid chromatography-tandem mass spectrometry. Proteomic data were analyzed according to gene ontology and a protein-protein interaction network. Immunofluorescent staining and protein inhibition assays were used for validation. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 174 nuclear proteins was identified, with 54 being up-regulated and 22 down-regulated (>=1.5-fold) after antrum formation. Functional protein analysis through gene ontology over-representation tests revealed that changes in molecular network within the GVs during this transitional phase were related to chromatin reorganization, gene transcription, and maternal RNA processing and storage. Protein inhibition assays verified that hnRNPA2B1, a key nuclear protein identified, was required for oocyte meiotic maturation and subsequent blastocyst formation. LARGE SCALE DATA: Data are available via ProteomeXchange with identifier PXD007211. LIMITATIONS REASONS FOR CAUTION: Proteins identified by proteomic comparison may (i) be involved in processes other than competence acquisition during the pre-antral-to-antral transition or (ii) be co-expressed in other macrostructures besides the GV. Expressional and functional validations should be performed for candidate proteins before downstream application. WIDER IMPLICATIONS OF THE FINDINGS: Collective results generated a blueprint to better understand the molecular mechanisms involved in GV competence acquisition and identified potential nuclear competence markers for human fertility preservation. STUDY FUNDING AND COMPETING INTEREST(S): Funded by the National Center for Research Resources (R01 RR026064), a component of the National Institutes of Health (NIH) and currently by the Office of Research Infrastructure Programs/Office of the Director (R01 OD010948). The authors declare that there is no conflict of interest. PMID- 29126205 TI - Complex analyses of inverted repeats in mitochondrial genomes revealed their importance and variability. AB - Motivation: The NCBI database contains mitochondrial DNA (mtDNA) genomes from numerous species. We investigated the presence and locations of inverted repeat sequences (IRs) in these mtDNA sequences, which are known to be important for regulating nuclear genomes. Results: IRs were identified in mtDNA in all species. IR lengths and frequencies correlate with evolutionary age and the greatest variability was detected in subgroups of plants and fungi and the lowest variability in mammals. IR presence is non-random and evolutionary favoured. The frequency of IRs generally decreased with IR length, but not for IRs 24 or 30 bp long, which are 1.5 times more abundant. IRs are enriched in sequences from the replication origin, followed by D-loop, stem-loop and miscellaneous sequences, pointing to the importance of IRs in regulatory regions of mitochondrial DNA. Availability and implementation: Data were produced using Palindrome analyser, freely available on the web at http://bioinformatics.ibp.cz. Contact: vaclav@ibp.cz. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126206 TI - The incidence and origin of segmental aneuploidy in human oocytes and preimplantation embryos. AB - STUDY QUESTION: What is the incidence, origin and clinical significance of segmental aneuploidy in human oocytes and preimplantation embryos? SUMMARY ANSWER: Segmental aneuploidy occurs at a considerable frequency in preimplantation embryos with a majority being mitotic in origin. WHAT IS KNOWN ALREADY: In recent years, accurate techniques for the detection of aneuploidy in single cells have been developed. Research using such methods has confirmed that aneuploidy is a common feature of human oocytes and preimplantation embryos. However, thus far research has mainly focused on loss or gain of whole chromosomes. We utilized sensitive molecular methods to study another important form of cytogenetic abnormality at the earliest stages of human development, namely segmental aneuploidy. STUDY DESIGN, SIZE, DURATION: Chromosomal copy number data was obtained from oocytes and embryos of 635 IVF patients, who requested chromosome screening for various reasons, most commonly for advanced maternal age or previously unsuccessful IVF treatments. A total of 3541 samples comprising of 452 human oocytes, 1762 cleavage stage and 1327 blastocyst stage embryos were investigated in the present study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole genome amplification (Sureplex, Illumina) was performed on cells biopsied from oocytes and embryos of IVF patients who requested chromosome screening. The samples were subsequently processed and analyzed for their chromosome complement using microarray comparative genomic hybridization (aCGH), (Illumina, Cambridge, UK). MAIN RESULTS AND THE ROLE OF CHANCE: Segmental abnormalities, involving loss or gain of chromosomal fragments in excess of 15 Mb, were found to occur at a high frequency. The incidence of such abnormalities was 10.4% in oocytes, but this increased dramatically during the first 3 days of embryonic development (24.3%), before starting to decline as embryos reached the final (blastocyst) stage of preimplantation development (15.6%). While some segmental errors were clearly of meiotic origin, most appear to arise during the first few mitoses following fertilization. The reduction in frequency at the blastocyst stage suggests that many cells/embryos affected by segmental abnormalities are eliminated (e.g. via arrest of the affected embryos or apoptosis of abnormal cells). Interestingly, sites of chromosome breakage associated with segmental aneuploidy were not entirely random but tended to occur within distinct chromosomal regions. Some of the identified hotspots correspond to known fragile sites while others may be considered novel and may be specific to gametogenesis and/or embryogenesis. LIMITATIONS REASONS FOR CAUTION: The cytogenetic analysis was performed on biopsies of embryos, which might not be representative of the true incidence of mosaic segmental aneuploidy of the entire embryo. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study are valuable for understanding the origin of subchromosomal duplications and deletions, a clinically important class of abnormalities that are a common cause of congenital abnormalities and miscarriage. Furthermore, the results provide additional evidence that control of the cell cycle is more relaxed during the first few mitotic divisions following fertilization, permitting DNA double-strand breaks to occur and persist through cell division. The data are also of great relevance for preimplantation genetic testing, where the detection of segmental aneuploidy is currently considered problematic for embryo diagnosis and patient counseling. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by institutional funding (Reprogenetics UK). Additionally, DW is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme. DB was supported by the University of Oxford's Clarendon funding. No conflict of interests to declare. PMID- 29126208 TI - Influence of Range Position on Locally Adaptive Gene-Environment Associations in Populus Flowering Time Genes. AB - Local adaptation is pervasive in forest trees, which are characterized by large effective population sizes spanning broad climatic gradients. In addition to having relatively contiguous populations, many species also form isolated populations along the rear edge of their range. These rear-edge populations may contain unique adaptive diversity reflecting a history of selection in marginal environments. Thus, discovering genomic regions conferring local adaptation in rear edge populations is a key priority for landscape genomics to ensure conservation of genetic resources under climate change. Here, we report on adaptive gene-environment associations in single nucleotide polymorphisms (SNPs) from 27 genes in the Populus flowering time gene network, analyzed on a range wide collection of >1000 balsam poplar trees, including dense sampling of the southern range edge. We use a combined approach of local adaptation scans to identify candidate SNPs, followed by modeling the compositional turnover of adaptive SNPs along multivariate climate gradients using gradient forests (GF). Flowering time candidate genes contained extensive evidence of climate adaptation, namely outlier population structure and gene-environment associations, along with allele frequency divergence between the core and edge of the range. GF showed strong allele frequency turnover along gradients of elevation and diurnal and temperature variability, as well as threshold responses to summer temperature and precipitation, with turnover especially strong in edge populations that occur at high elevation but southerly latitudes. We discuss these results in light of how climate may disrupt locally adaptive gene environment relationships, and suggest that rear edge populations hold climate adaptive variants that should be targeted for conservation. PMID- 29126207 TI - Effects of 30% and 50% Cigarette Pack Graphic Warning Labels on Visual Attention, Negative Affect, Quit Intentions, and Smoking Susceptibility among Disadvantaged Populations in the United States. AB - Introduction: Though the WHO Framework Convention for Tobacco Control (FCTC) calls for the implementation of large graphic warning labels (GWLs) on cigarette boxes, the courts have blocked the implementation of 50% labels in the United States. We conducted an experiment to explore whether changing the size of GWLs is associated with changes in visual attention, negative affect, risk beliefs, and behavioral intentions. Method: We recruited adult smokers (N = 238) and middle-school youth (N = 237) throughout the state of New York in May 2016. We randomly assigned participants to one of three between-subject conditions (no GWL [control], 30% GWL, 50% GWL). Results: Adult and youth participants looked at the GWLs longer when the GWL covered 50% versus 30% of the pack's front. Increasing GWL size from 30% to 50% did not influence negative affect or risk beliefs, though both GWL sizes increased negative affect relative to the no-GWL control group. Exposure to 50% GWLs increased adult smokers' intentions to quit compared to no-GWL, but smokers exposed to 30% GWLs did not differ from control. There were no differences between 50% GWLs, 30% GWLs, and control on youth smoking susceptibility. Conclusions: Findings provide some evidence of the benefits of a 50% versus 30% GWL covering the front of the pack for adult smokers and at-risk youth from socioeconomically disadvantaged backgrounds-though not on all outcomes. Implications: This research shows that 30% GWLs on cigarette packages increase negative affect relative to packages without front-of-package GWLs. Larger GWLs on cigarette packages (50% vs. 30%) increase visual attention to the warning and its pictorial content among low-SES smokers and at-risk youth but do not further increase negative affect. A 50% GWL increased adults' quit intention compared to no GWL at all, but we were underpowered to detect modest differences in quit intentions between a 50% and 30% GWL. Future work should thus continue to explore the boundary conditions under which relatively larger GWLs influence cognitive, affective, and behavioral outcomes. PMID- 29126209 TI - Effect of Real-Time Monitoring and Notification of Smoking Episodes on Smoking Reduction: A Pilot Study of a Novel Smoking Cessation App. AB - Introduction: Smartphone applications (apps) for smoking cessation are becoming increasingly available, but their efficacy remains to be demonstrated. We conducted a pilot study of SmokeBeat, a novel app designed for use with smartwatches and wristbands. SmokeBeat is powered by a data analytics software platform that processes information from the sensors embedded in wearables. It relies on an original algorithm to identify in real time the hand-to-mouth gestures that characterize smoking a cigarette. We examined whether merely monitoring and notifying smokers on smoking episodes in real time via the SmokeBeat app would lead to reduction in smoking. Methods: Forty smokers (9 women and 31 men) who expressed a wish to reduce or quit smoking were randomly assigned to using the SmokeBeat app for 30 days or to a wait-list control group. All participants completed questionnaires at baseline and at the end of the study, including their level of smoking. Smokers in the experimental condition were notified whenever the SmokeBeat system detected a smoking episode and were asked to confirm or deny it. Results: The SmokeBeat algorithm correctly detected over 80% of the smoking episodes and produced very few false alarms. According to both self-report and detection of smoking episodes by the SmokeBeat system, smokers in the experimental condition showed a significant decline in smoking rate over the 30-day trial (p < .001). There was no change in the smoking rate of the control group. Conclusion: These preliminary results suggest that automatic monitoring of smoking episodes and alerting the smoker in real time may facilitate smoking reduction in motivated smokers. Implications: Raising the awareness of smokers to the act of smoking in real time, as the SmokeBeat app is able to do, can counter the automaticity of the smoking habit. Bringing smoking under conscious awareness may benefit smokers who are motivated to reduce or quit smoking to gain better control of their smoking behavior and reduce cigarette intake. PMID- 29126211 TI - The Reproducibility of Racial Differences in Ambulatory Blood Pressure Phenotypes and Measurements; Methodological Issues. PMID- 29126210 TI - The functional role of ventral anterior cingulate cortex in social evaluation: disentangling valence from subjectively rewarding opportunities. AB - Despite robust associations between the ventral anterior cingulate cortex (vACC) and social evaluation, the role of vACC in social evaluation remains poorly understood. Two hypotheses have emerged from existing research: detection of positive valence and detection of opportunities for subjective reward. It has been difficult to understand whether one or both hypotheses are supported because previous research conflated positive valence with subjective reward. Therefore, the current functional magnetic resonance imaging study drew on a social evaluation paradigm that disentangled positive valence and subjective reward. Participants evaluated in-group and out-group politicians in a social evaluation paradigm that crossed trait valence with opportunity for subjectively rewarding affirmation (i.e. a chance to affirm positive traits about in-group politicians and affirm negative traits about out-group politicians). Participants rated in group politicians more positively and out-group politicians more negatively. One subregion of vACC was modulated by positive valence and another relatively posterior region of vACC was modulated by opportunity for subjective reward (i.e. a politician * valence interaction). The current findings demonstrate the importance of incorporating vACC function into models of social cognition and provide new avenues for sharpening our understanding of the psychological significance of vACC function in social evaluation and related domains such as reward and affect. PMID- 29126213 TI - Comparison of respondent-reported and sensor-recorded latrine utilization measures in rural Bangladesh: a cross-sectional study. AB - Background: Health improvements realized through sanitation are likely achieved through high levels of facilities utilization by all household members. However, measurements of sanitation often rely on either the presence of latrines, which does not guarantee use, or respondent-reported utilization of sanitation facilities, which is prone to response bias. Overstatement of sanitation metrics limits the accuracy of program outcome measures, and has implications for the interpretation of related health impact data. Methods: We conducted a cross sectional study of 213 households in 14 village water, sanitation and hygiene committee clusters throughout rural Bangladesh and used a combined data- and relationship-scale approach to assess agreement between respondent-reported latrine utilization and sensor-recorded measurement. Results: Four-day household level respondent-reported defecation averaged 28 events (inter-quartile range [IQR] 20-40), while sensor-recorded defecation averaged 17 events (IQR 11-29). Comparative analyses suggest moderately high accuracy (bias correction factor=0.84), but imprecision in the data (broad scatter of data, Pearson's r=0.35) and thus only weak concordance between measures (rhoc=0.29 [95% BCa CI 0.15 to 0.43]). Conclusions: Respondent-reported latrine utilization data should be interpreted with caution, as evidence suggests use is exaggerated. Coupling reported utilization data with objective measures of use may aid in the estimation of latrine use. PMID- 29126214 TI - Diapause Induced by Temperature and Photoperiod Affects Fatty Acid Compositions and Cold Tolerance of Phthorimaea Operculella (Lepidoptera: Gelechiidae). AB - To find out the potential condition for diapause induction in the potato tuber moth Phthorimaea operculella (Zeller), combination of constant temperatures (15, 20, and 30 degrees C) and photoperiods (8, 9, 10, 11, 12, 14, and 16 h) were employed from egg to adult emergence. In addition, changes in the total phospholipid fatty acid content and cold tolerance of non-diapausing and diapausing pupae were examined. The critical daylength for diapause induction were 12.43 h at 20 degrees C and lower temperatures that can induce in 50% of population. Moreover, the composition of total phospholipid fatty acids in the pupae revealed seven major fatty acids in both non-diapausing and diapausing pupae: oleic (26-32%), palmitic (21-29%), linoleic (18-21%), palmitoleic (4-10%), stearic (9%), linolenic (7-8%), and pentadecanoic acids (3-5%) with an increase in proportion of unsaturated fatty acids in diapause state. In contrast to increase of oleic acid (C18:1) from 26 to 32% in non-diapausing to diapausing pupae, a decrement trend from 29 to 21% in palmitic acid (C16:0) was observed at the same state. Additionally, supercooling point was observed to be significantly lower in diapausing (-22.6 degrees C) than in non-diapausing pupae (-18.5 degrees C) and the fresh weight of diapausing pupae was found to be significantly higher than non-diapausing ones. The significance of these findings would allow us a better understanding of interrelationship between diapause and cold tolerance. PMID- 29126212 TI - Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. AB - Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7alpha hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27 hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683 1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27 hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia. PMID- 29126215 TI - Demonstration and Quantification of Restricted Mating Between Fall Armyworm Host Strains in Field Collections by SNP Comparisons. AB - Gene introgression between related pest populations is an important component in the assessment of how rapidly economically important traits, such as pesticide resistance, can spread within a region. An example of this is provided by the noctuid moth Spodoptera frugiperda (J.E. Smith), or fall armyworm, which is composed of two 'host strains' that differ in their host plant preferences. Resistance to a Bacillus thuringiensis toxin has been observed in some populations and there is concern about its spread throughout the Western Hemisphere. If this trait is easily transmitted between strains, it would expand the range of plants affected and make control efforts more difficult. A complicating factor is that the strains are morphologically indistinguishable and can only be identified by a small number of genetic markers. As a result, little is known about the frequency of interstrain hybridization in the wild. This study uses a novel strategy involving comparisons between two single-nucleotide polymorphisms (SNPs) to quantify the frequency of interstrain mating in field populations. The results demonstrate that hybridization between strains is 4- to 5-fold reduced compared to that within strains. In addition, it appears that directional interstrain mating biases observed in laboratory studies are probably not a major factor in determining the distribution of hybrid genotypes in field populations. The differential SNP technique is a significant improvement over current methods for identifying interstrain hybrids and should facilitate our understanding of fall armyworm strain and hybrid distributions in the field and the frequency of genetic exchanges between strains. PMID- 29126216 TI - PAGER 2.0: an update to the pathway, annotated-list and gene-signature electronic repository for Human Network Biology. AB - Integrative Gene-set, Network and Pathway Analysis (GNPA) is a powerful data analysis approach developed to help interpret high-throughput omics data. In PAGER 1.0, we demonstrated that researchers can gain unbiased and reproducible biological insights with the introduction of PAGs (Pathways, Annotated-lists and Gene-signatures) as the basic data representation elements. In PAGER 2.0, we improve the utility of integrative GNPA by significantly expanding the coverage of PAGs and PAG-to-PAG relationships in the database, defining a new metric to quantify PAG data qualities, and developing new software features to simplify online integrative GNPA. Specifically, we included 84 282 PAGs spanning 24 different data sources that cover human diseases, published gene-expression signatures, drug-gene, miRNA-gene interactions, pathways and tissue-specific gene expressions. We introduced a new normalized Cohesion Coefficient (nCoCo) score to assess the biological relevance of genes inside a PAG, and RP-score to rank genes and assign gene-specific weights inside a PAG. The companion web interface contains numerous features to help users query and navigate the database content. The database content can be freely downloaded and is compatible with third-party Gene Set Enrichment Analysis tools. We expect PAGER 2.0 to become a major resource in integrative GNPA. PAGER 2.0 is available at http://discovery.informatics.uab.edu/PAGER/. PMID- 29126217 TI - Change in Pneumococcus Serotypes but not Mortality or Morbidity in Pre- and Post 13-Valent Polysaccharide Conjugate Vaccine Era: Epidemiology in a Pediatric Intensive Care Unit over 10 Years. AB - Aim: Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally cause severe pneumococcal disease with high mortality and morbidity. We reviewed all pneumococcal serotypes and mortality/morbidity in a pediatric intensive care unit (PICU) following universal pneumococcal conjugate vaccine (PCV) immunization. Methods: A 13-valent PCV was introduced in the universal immunization program in late 2011 in Hong Kong. We retrospectively reviewed all pneumococcal serotypes in the pre-(2007-11) and post-(2012-16) 13-valent PCV era. Results: There were 29 (1.9%) PICU patients with pneumococcal isolation, of which 6 died (20% motality). Serogroups 6 and 19 predominated before and Serogroup 3 after 2012. In the post 13-valent PCV era, the prevalence of pneumococcus isolation in PICU was increased from 1 to 2% (p = 0.04); Serogroup 3 was the major serotype of morbidity, despite supposedly under vaccine coverage. The majority of pneumococcus were penicillin sensitive (94%) in the post 13-valent PCV era. All pneumococcus specimens were sensitive to cefotaxime and vancomycin. Binary logistic regression showed that there were reductions in Serogroup 6 (odds ratio [OR], 0.050; 95% confidence interval [CI], 0.004-0.574; p = 0.016) and Serogroup 19 (odds ratio [OR], 0.105; 95% confidence interval [CI], 0.014-0.786; p = 0.028) but not mortality or morbidity for patients admitted after 2012. Conclusions: SPD is associated with significant morbidity and mortality, despite treatment with systemic antibiotics and ICU support. The expanded coverage of 13-valent PCV results in the reduction of Serotypes 6 and 19 but not mortality/morbidity associated with SPD in the setting of a PICU. PMID- 29126218 TI - LIBRA-WA: a web application for ligand binding site detection and protein function recognition. AB - Summary: Recently, LIBRA, a tool for active/ligand binding site prediction, was described. LIBRA's effectiveness was comparable to similar state-of-the-art tools; however, its scoring scheme, output presentation, dependence on local resources and overall convenience were amenable to improvements. To solve these issues, LIBRA-WA, a web application based on an improved LIBRA engine, has been developed, featuring a novel scoring scheme consistently improving LIBRA's performance, and a refined algorithm that can identify binding sites hosted at the interface between different subunits. LIBRA-WA also sports additional functionalities like ligand clustering and a completely redesigned interface for an easier analysis of the output. Extensive tests on 373 apoprotein structures indicate that LIBRA-WA is able to identify the biologically relevant ligand/ligand binding site in 357 cases (~96%), with the correct prediction ranking first in 349 cases (~98% of the latter, ~94% of the total). The earlier stand-alone tool has also been updated and dubbed LIBRA+, by integrating LIBRA WA's improved engine for cross-compatibility purposes. Availability and implementation: LIBRA-WA and LIBRA+ are available at: http://www.computationalbiology.it/software.html. Contact: polticel@uniroma3.it. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126219 TI - The short- and long-term risks of venoarterial extracorporeal membrane oxygenation watershed. PMID- 29126220 TI - Catching RNAs on chromatin using hybridization capture methods. AB - The growing appreciation of the importance of long noncoding RNAs (lncRNAs), together with the awareness that some of these RNAs are associated with chromatin, has inspired the development of methods to detect their sites of interaction on a genome-wide scale at high resolution. Hybridization capture methods combine antisense oligonucleotide hybridization with enrichment of RNA from cross-linked chromatin extracts. These techniques have provided insight into lncRNA localization and the interactions of lncRNAs with protein to better understand biological roles of lncRNAs. Here, we review the core principles of hybridization capture methods, focusing on the three most commonly used protocols: capture hybridization analysis of RNA targets (CHART), chromatin isolation by RNA purification (ChIRP) and RNA affinity purification (RAP). We highlight the general principles of these techniques and discuss how differences in experimental procedures present distinct challenges to help researchers using these protocols or, more generally, interpreting the results of hybridization capture experiments. PMID- 29126221 TI - Identification and characterization of mcr mediated colistin resistance in extraintestinal Escherichia coli from poultry and livestock in China. AB - Antimicrobial resistance to colistin has emerged worldwide threatening the efficacy of one of the last-resort antimicrobials used for the treatment of multidrug-resistant Enterobacteriaceae infection in humans. In this study, we investigated the presence of colistin resistance genes (mcr-1, mcr-2, mcr-3) in Escherichia coli strains isolated from poultry and livestock collected between 2004 and 2012 in China. Furthermore, we studied the maintenance and transfer of the mcr-1 gene in E. coli after serial passages. Overall, 2.7% (17/624) of the E. coli isolates were positive for the mcr-1 gene while none were positive for the mcr-2 and mcr-3 genes. The prevalences of mcr-1 were similar in E. coli isolates from chickens (3.2%; 13/404), pigs (0.9%; 1/113) and ducks (6.8%; 3/44) but were absent in isolates from cattle (0/63). The mcr-1 gene was maintained in the E. coli after six passages (equivalent to 60 generations). In vitro transfer of mcr 1 was evident even without colistin selection. Our data indicate the presence of mcr-1 in extraintestinal E. coli from food-producing animals in China, and suggest that high numbers of the mcr-1-positive bacteria in poultry and livestock do not appear to be readily lost after withdrawal of colistin as a food additive. PMID- 29126222 TI - Lumbar Disc Herniation, the Association Between Quantitative Sensorial Test and Magnetic Resonance Imaging Findings. AB - Objective: Quantitative sensorial tests (QST) are used for evaluating specific sensorial nerve function. In this study, QST and magnetic resonance imaging (MRI) findings are compared in lumbar disc herniation patients, and the accuracy of QST data was investigated. Material and Methods: Sixty-four patients between 18 and 70 years of age suffering from radicular pain with positive Lasegue's test were included in this study. Specific criteria included complaints due to L5 discopathy. MRI findings were classified according to the Pfirmann grading system, and QST was applied to the L5 dermatoma of both symptomatic and nonsymptomatic legs of all patients. Vibration detection threshold, heat detection threshold, cold detection threshold, and heat pain detection threshold values were obtained, and MRI findings were classified according to the Pfirmann grading system. Results: When we compared the symptomatic and nonsymptomatic legs of participants, there were significant differences by means of all QST parameters (0 = 0.00). In a comparison of the QST and MRI Pfirmann grading systems, there is also a strong parallel statistical correlation between the Pfirmann grade and QST parameters (P < 0.05). Conclusions: According to the results of our study, QST has an additive effect to MRI for nerve root compression evaluation in the clinical basis, which might enable more sensitive diagnosis and treatment protocol. QST can also be an alternative method for evaluation of nerve root compression in patients who have contraindications for MRI. PMID- 29126223 TI - Atheroprone flow activates inflammation via endothelial ATP-dependent P2X7-p38 signalling. AB - Objective: Atherosclerosis is a focal disease occurring at arterial sites of disturbed blood flow that generates low oscillating shear stress. Endothelial inflammatory signalling is enhanced at sites of disturbed flow via mechanisms that are incompletely understood. The influence of disturbed flow on endothelial adenosine triphosphate (ATP) receptors and downstream signalling was assessed. Methods and results: Cultured human endothelial cells were exposed to atheroprotective (high uniform) or atheroprone (low oscillatory) shear stress for 72 h prior to assessment of ATP responses. Imaging of cells loaded with a calcium sensitive fluorescent dye revealed that atheroprone flow enhanced extracellular calcium influx in response to 300 uM 2'(3')-O-(4-Benzoylbenzoyl) adenosine-5' triphosphate. Pre-treatment with pharmacological inhibitors demonstrated that this process required purinergic P2X7 receptors. The mechanism involved altered expression of P2X7, which was induced by atheroprone flow conditions in cultured cells. Similarly, en face staining of the murine aorta revealed enriched P2X7 expression at an atheroprone site. Functional studies in cultured endothelial cells showed that atheroprone flow induced p38 phosphorylation and up-regulation of E-selectin and IL-8 secretion via a P2X7-dependent mechanism. Moreover, genetic deletion of P2X7 significantly reduced E-selectin at atheroprone regions of the murine aorta. Conclusions: These findings reveal that P2X7 is regulated by shear forces leading to its accumulation at atheroprone sites that are exposed to disturbed patterns of blood flow. P2X7 promotes endothelial inflammation at atheroprone sites by transducing ATP signals into p38 activation. Thus P2X7 integrates vascular mechanical responses with purinergic signalling to promote endothelial dysfunction and may provide an attractive potential therapeutic target to prevent or reduce atherosclerosis. PMID- 29126225 TI - Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. AB - Bedaquiline, a new antituberculosis drug, has already been used in >50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This article aims to review currently identified mechanisms of resistance and the emergence of bedaquiline resistance, and discuss strategies to delay the resistance acquisition. In vitro and clinical studies as well as reports from compassionate use have identified the threat of bedaquiline resistance and cross-resistance with clofazimine, emphasizing the crucial need for the systematic surveillance of resistance. Currently known mechanisms of resistance include mutations within the atpE, Rv0678, and pepQ genes. The development of standardized drug susceptibility testing (DST) for bedaquiline is urgently needed. Understanding any target and non-target-based mechanisms is essential to minimize resistance development and treatment failure and help to develop appropriate DST for bedaquiline and genetic-based resistance screening. PMID- 29126224 TI - DBTSS/DBKERO for integrated analysis of transcriptional regulation. AB - DBTSS (Database of Transcriptional Start Sites)/DBKERO (Database of Kashiwa Encyclopedia for human genome mutations in Regulatory regions and their Omics contexts) is the database originally initiated with the information of transcriptional start sites and their upstream transcriptional regulatory regions. In recent years, we updated the database to assist users to elucidate biological relevance of the human genome variations or somatic mutations in cancers which may affect the transcriptional regulation. In this update, we facilitate interpretations of disease associated genomic variation, using the Japanese population as a model case. We enriched the genomic variation dataset consisting of the 13,368 individuals collected for various genome-wide association studies and the reference epigenome information in the surrounding regions using a total of 455 epigenome datasets (four tissue types from 67 healthy individuals) collected for the International Human Epigenome Consortium (IHEC). The data directly obtained from the clinical samples was associated with that obtained from various model systems, such as the drug perturbation datasets using cultured cancer cells. Furthermore, we incorporated the results obtained using the newly developed analytical methods, Nanopore/10x Genomics long-read sequencing of the human genome and single cell analyses. The database is made publicly accessible at the URL (http://dbtss.hgc.jp/). PMID- 29126226 TI - Optimizing Tuberculosis Diagnosis in Human Immunodeficiency Virus-Infected Inpatients Meeting the Criteria of Seriously Ill in the World Health Organization Algorithm. AB - Background: The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill human immunodeficiency virus (HIV)-infected patients lacks a firm evidence base. We aimed to develop a clinical prediction rule for the diagnosis of tuberculosis and to determine the diagnostic utility of the Xpert MTB/RIF assay in seriously ill HIV-infected patients. Methods: We conducted a prospective study among HIV-infected inpatients with any cough duration and WHO-defined danger signs. Culture-positive tuberculosis from any site was the reference standard. A priori selected variables were assessed for univariate associations with tuberculosis. The most predictive variables were assessed in a multivariate logistic regression model and used to establish a clinical prediction rule for diagnosing tuberculosis. Results: We enrolled 484 participants. The median age was 36 years, 65.5% were female, the median CD4 count was 89 cells/uL, and 35.3% were on antiretroviral therapy. Tuberculosis was diagnosed in 52.7% of participants. The c-statistic of our clinical prediction rule (variables: cough >=14 days, unable to walk unaided, temperature >39 degrees C, chest radiograph assessment, hemoglobin, and white cell count) was 0.811 (95% confidence interval, .802-.819). The classic tuberculosis symptoms (fever, night sweats, weight loss) added no discriminatory value in diagnosing tuberculosis. Xpert MTB/RIF assay sensitivity was 86.3% and specificity was 96.1%. Conclusions: Our clinical prediction rule had good diagnostic utility for tuberculosis among seriously ill HIV-infected inpatients. Xpert MTB/RIF assay, incorporated into the updated 2016 WHO algorithm, had high sensitivity and specificity in this population. Our findings could facilitate improved diagnosis of tuberculosis among seriously ill HIV-infected inpatients in resource-constrained settings. PMID- 29126227 TI - Letter to the Editor: "Development and Risk Factors of Type 2 Diabetes in a Nationwide Population of Women With Polycystic Ovary Syndrome". PMID- 29126228 TI - Prospective, Randomized Blind Effect-on-Outcome Study of Conventional vs High Frequency Spinal Cord Stimulation in Patients with Pain and Disability Due to Failed Back Surgery Syndrome. AB - Objectives: Spinal cord stimulation (SCS) for patients with failed back surgery syndrome (FBSS) show variable results and limited to moderate evidence. In the last years the stimulation of high frequency (HF) has been considered as a better alternative in this pathology for its supposed benefits compared to the stimulation with conventional frequency (CF). To compare in one year follow-up, the efficacy of high-frequency SCS (HF) versus conventional frequency SCS (CF) on the patients with FBSS. Design: Prospective, Randomized blind trial. Setting: Academic University Pain Medicine Center. Subject: Seventy eight patients with FBSS diagnosis based on internationally recognized criteria, and refractory to conservative therapy for at least 6 months, have been initially recruited, and. Methods: Sixty subjects met the eligibility criteria and were randomized and scheduled for the trial phase.The patients were randomly assigned in either, one of the two groups: CF SCS or HF SCS. Within the study methods, special attention was paid to standardizing patient programming, so that these parameters would not impact the results.The trial period was considered successful if there was ?50% reduction in the NRS from baseline. Results: A total of 55 subjects successfully completed all assessments during one year follow-up. Change patterns in scores do not differ based on high versus conventional frequency, with significant global average reduction at 1 year similarly for both groups. Among all the items included in the Short Form-12 questionnaire (SF-12), only the variations in the social function score between the instants t1 and t2 are somewhat higher in the high frequency group. Conclusion: The evolutionary pattern of the different parameters studied in our patients with FBSS does not differ according to their treatment by spinal stimulation, with conventional or high frequency, in one year follow-up. PMID- 29126230 TI - A survey of software tools for microRNA discovery and characterization using RNA seq. AB - Since the small RNA-sequencing (sRNA-seq) technology became available, it allowed the discovery of thousands new microRNAs (miRNAs) in humans and many other species, providing new data on these small RNAs (sRNAs) of high biological and translational relevance. MiRNA discovery has not yet reached saturation, even in the most studied model organisms, and many researchers are using sRNA-seq in studies with different aims in biomedicine, fundamental research and in applied animal sciences. We review several miRNA discovery and characterization software tools that implement different strategies, providing a useful guide for researchers to select the programs best suiting their study objectives and data. After a brief introduction on miRNA biogenesis, function and characteristics, useful to understand the biological background considered by the algorithms, we survey the current state of miRNA discovery bioinformatics discussing 26 different sRNA-seq-based miRNA prediction software and toolkits released in the past 6 years, including 15 methods specific for miRNA prediction and 11 more general-purpose software suites for sRNA-seq data analysis. We highlight the main features of mature miRNAs and miRNA precursors considered by the methods categorizing them according to prediction strategy and implementation. In addition, we describe a typical miRNA prediction and analysis workflow by delineating the objectives, potentialities and main steps of sRNA-seq data analysis projects, from preparatory data processing to miRNA prediction, quantification and diverse downstream analyses. Finally, we outline the caveats affecting sRNA-seq-based prediction tools, and we indicate the possibilities offered by data set pooling and by integration with other types of high throughput sequencing data. PMID- 29126229 TI - Osteoblast AMP-Activated Protein Kinase Regulates Postnatal Skeletal Development in Male Mice. AB - Studies have shown that AMP-activated protein kinase (AMPK), a crucial regulator of energy homeostasis, plays important roles in osteoblast differentiation and mineralization. However, little is known about in vivo roles of osteoblastic AMPK in bone development. Thus, to investigate in vivo roles of osteoblast AMPK, we conditionally inactivated Ampk in osterix (Osx)-expressing cells by crossing Osx Cre mice with floxed AMPKalpha1 to generate mice lacking AMPKalpha1 in osteoblasts (Ampk-/- mice). Compared with wild-type and Ampk+/- mice, Ampk-/- mice displayed retardation of postnatal bone development, although bone deformity was not observed at birth. Microcomputed tomography showed significant reductions in trabecular bone volume, cortical bone length, and density, as well as increased cortical porosity in femur as well as development defects of skull in 8 week-old Ampk-/- mice. Surprisingly, histomorphometric analysis demonstrated that the number of osteoclasts was significantly increased, although bone formation rate was not altered. Loss of trabecular network connections and mass, as well as shortened growth plates and reduced thickness of cartilage adjacent to the growth plate, was observed in Ampk-/- mice. In primary cultured osteoblasts from calvaria, the expressions of alkaline phosphatase, type 1 collagen, osteocalcin, bone morphogenetic protein 2, Runx2, and osterix were significantly inhibited in Ampk-/- osteoblasts, whereas the expression of receptor activator of nuclear kappaB ligand (RANKL) and the RANKL/osteoprotegerin ratio were significantly increased. These findings indicate that osteoblastic AMPK plays important roles in bone development in vivo and that deletion of AMPK in osteoblasts decreases osteoblastic differentiation and enhances bone turnover by increasing RANKL expression. PMID- 29126232 TI - Corrigendum. PMID- 29126231 TI - Irrigation management and phosphorus addition alter the abundance of carbon dioxide-fixing autotrophs in phosphorus-limited paddy soil. AB - In this study, we assessed the interactive effects of phosphorus (P) application and irrigation methods on the abundances of marker genes (cbbL, cbbM, accA and aclB) of CO2-fixing autotrophs. We conducted rice-microcosm experiments using a P limited paddy soil, with and without the addition of P fertiliser (P-treated-pot (P) versus control pot (CK)), and using two irrigation methods, namely alternate wetting and drying (AWD) and continuous flooding (CF). The abundances of bacterial 16S rRNA, archaeal 16S rRNA, cbbL, cbbM, accA and aclB genes in the rhizosphere soil (RS) and bulk soil (BS) were quantified. The application of P significantly altered the soil properties and stimulated the abundances of Bacteria, Archaea and CO2-fixation genes under CF treatment, but negatively influenced the abundances of Bacteria and marker genes of CO2-fixing autotrophs in BS soils under AWD treatment. The response of CO2-fixing autotrophs to P fertiliser depended on the irrigation management method. The redundancy analysis revealed that 54% of the variation in the functional marker gene abundances could be explained by the irrigation method, P fertiliser and the Olsen-P content; however, the rhizosphere effect did not have any significant influence. P fertiliser application under CF was more beneficial in improving the abundance of CO2-fixing autotrophs compared to the AWD treatment; thus, it is an ideal irrigation management method to increase soil carbon fixation. PMID- 29126233 TI - Endothelin-1 promotes human germinal vesicle-stage oocyte maturation by downregulating connexin-26 expression in cumulus cells. AB - STUDY QUESTION: Does endothelin-1 (ET-1) promote human oocyte maturation and by what mechanism? SUMMARY ANSWER: Addition of ET-1 to the medium in which human germinal vesicle (GV)-stage immature oocytes are cultured enhances the GV breakdown (GVBD) rate; the resumption of meiosis may be initiated by ET-1 downregulating the expression of connexin-26 (Cx26) in cumulus cells via endothelin receptor type B (ETRB), leading to decreased cAMP levels in the oocyte. WHAT IS KNOWN ALREADY: The paracrine factor ET-1 is secreted by ovarian somatic cells in pre-ovulatory follicles and regulates oocyte maturation in mice. Connexins, or gap junction proteins, form intercellular membrane channels that play important roles in the resumption of meiosis. STUDY DESIGN, SIZE, DURATION: This laboratory study was conducted over a 1-year period. The effects of ET-1 on meiotic resumption were evaluated in human GV-stage cumulus-oocyte complexes (COCs; 70 oocytes/group). The transcriptome profiles of ET-1-treated or untreated cumulus cells were compared to explore the possible mechanisms by which ET-1 may regulate oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: The ET-1, ETRA and ETRB expression levels in human cumulus cells from oocytes at different stages of maturation were evaluated using real-time quantitative PCR. Human GV stage COCs collected from patients undergoing IVF at a university-affiliated infertility centre were cultured with or without ET-1, and cumulus cells were subsequently denuded using hyaluronidase and cultured in alpha-MEM. A GeneChip(r) Human Transcriptome Array was applied to explore differences in the whole-genome transcriptome profiles of cumulus cells treated with or without ET-1. Real-time quantitative PCR and Western blotting were used respectively to examine Cx26 mRNA and protein levels in cumulus cells. Changes in cAMP levels in both oocytes and cumulus cells after ET-1 treatment were measured using an enzyme-linked immunosorbent assay. MAIN RESULTS AND THE ROLE OF CHANCE: Cumulus cells from MII stage oocytes exhibited upregulated ET-1 expression, compared to those from GV stage oocytes. The addition of ET-1 to the culture medium enhanced the GVBD rate of cumulus cell-enclosed human oocytes. Whole-genome transcriptome microarray analyses revealed significantly downregulated Cx26 expression in cumulus cells after ET-1 treatment, and this action was blocked by an ETRB antagonist. The involvement of Cx26 was further supported by the finding that ET-1 treatment led to decreased cAMP levels in oocytes but increased cAMP levels in cumulus cells. LARGE SCALE DATA: Microarray data are published in the GEO database (GSE97684). LIMITATIONS, REASONS FOR CAUTION: The heterogeneity of human COCs collected from patients undergoing IVF might affect the maturation results in vitro. Although we focused on the effects of ET-1 on human oocyte maturation in the present study, mammalian oocyte maturation is a complicated process involving many endocrine and paracrine factors. WIDER IMPLICATIONS OF THE FINDINGS: Our present study suggests that in vitro, human GV-stage oocyte maturation could be enhanced by adding ET-1 to the culture medium. In the present study, we explored the molecular mechanisms by which ET-1 initiates the resumption of meiosis and demonstrated that ET-1 promotes oocyte maturation by downregulating the expression of the gap junction protein Cx26 in cumulus cells. These results expand our understanding of the molecular mechanisms underlying mammalian oocyte maturation and provide a basis for better in-vitro maturation strategies. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by grants from the China Natural Science Foundation (Grant Nos. 81170567 and 81370761). The authors declare that they have no conflicts of interest associated with this manuscript. PMID- 29126235 TI - Clinical Significance of Interferon-gamma Neutralizing Autoantibodies Against Disseminated Nontuberculous Mycobacterial Disease. AB - Background: Interferon-gamma neutralizing autoantibodies (nIFNgamma-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNgamma-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNgamma-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNgamma-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNgamma-autoAb titer (P < .0001, chi2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNgamma-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNgamma-autoAbs and 21% in those without. Conclusions: nIFNgamma-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNgamma-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection. PMID- 29126234 TI - Bardet-Biedl syndrome-8 (BBS8) protein is crucial for the development of outer segments in photoreceptor neurons. AB - Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by developmental abnormalities and vision loss. To date, mutations in 21 genes have been linked to BBS. The products of eight of these BBS genes form a stable octameric complex termed the BBSome. Mutations in BBS8, a component of the BBSome, cause early vision loss, but the role of BBS8 in supporting vision is not known. To understand the mechanisms by which BBS8 supports rod and cone photoreceptor function, we generated animal models lacking BBS8. The loss of BBS8 protein led to concomitant decrease in the levels of BBSome subunits, BBS2 and BBS5 and increase in the levels of the BBS1 and BBS4 subunits. BBS8 ablation was associated with severe reduction of rod and cone photoreceptor function and progressive degeneration of each photoreceptor subtype. We observed disorganized and shortened photoreceptor outer segments (OS) at post-natal day 10 as the OS elaborates. Interestingly, loss of BBS8 led to changes in the distribution of photoreceptor axonemal proteins and hyper-acetylation of ciliary microtubules. In contrast to properly localized phototransduction machinery, we observed OS accumulation of syntaxin3, a protein normally found in the cytoplasm and the synaptic termini. In conclusion, our studies demonstrate the requirement for BBS8 in early development and elaboration of ciliated photoreceptor OS, explaining the need for BBS8 in normal vision. The findings from our study also imply that early targeting of both rods and cones in BBS8 patients is crucial for successful restoration of vision. PMID- 29126237 TI - Corrigendum to: The use of Twitter to facilitate sharing of clinical expertise in urology. PMID- 29126236 TI - Identification and genomic characterization of a KPC-2-, NDM-1- and NDM-5 producing Klebsiella michiganensis isolate. PMID- 29126238 TI - Seizure Outcome After Surgical Resection of Insular Glioma. AB - BACKGROUND: A majority of patients with insular tumors present with seizures. Although a number of studies have shown that greater extent of resection improves overall patient survival, few studies have documented postoperative seizure control after insular tumor resection. OBJECTIVE: To (1) characterize seizure control rates in patients undergoing insular tumor resection, (2) identify predictors of seizure control, and (3) evaluate the association between seizure recurrence and tumor progression. METHODS: The study population included adults who had undergone resection of insular gliomas between 1997 and 2015 at our institution. Preoperative seizure characteristics, tumor characteristics, surgical factors, and postoperative seizure outcomes were reviewed. RESULTS: One hundred nine patients with sufficient clinical data were included in the study. At 1 yr after surgery, 74 patients (68%) were seizure free. At final follow-up, 42 patients (39%) were seizure free. Median time to seizure recurrence was 46 mo (95% confidence interval 31-65 mo). Multivariate Cox regression analysis revealed that greater extent of resection (hazard ratio = 0.2899 [0.1129, 0.7973], P = .0127) was a significant predictor of seizure freedom. Of patients who had seizure recurrence and tumor progression, seizure usually recurred within 3 mo prior to tumor progression. Repeat resection offered additional seizure control, as 8 of the 22 patients with recurrent seizures became seizure free after reoperation. CONCLUSION: Maximizing the extent of resection in insular gliomas portends greater seizure freedom after surgery. Seizure recurrence is associated with tumor progression, and repeat operation can provide additional seizure control. PMID- 29126239 TI - Morphometric Analysis of the Umbilicus According to Age. AB - Background: Morphometric and anatomical analyses of the shape and position of the umbilicus have been conducted in adults, but umbilicoplasty in children remains challenging because growth is still occurring. Objectives: The main objective of this study was to evaluate the difference in the position and shape of the umbilicus between childhood and adulthood. The secondary objective was to improve the surgical management of umbilicoplasty in children. Methods: This prospective single-center study focused on the morphometric analysis of the umbilicus in 200 adults and children. All data, including standardized measures and pictures, were determined by one single operator. Results: Despite a variation of approximately 2% in the xiphoid-pubis distance, the location of the umbilicus remains stable during the entire growth period. In a supine individual, the location is at one half to two thirds of the xiphoid-pubis distance (slightly lower in children), with a mean ratio of 0.57 for the xiphoid-umbilicus distance to the xiphoid-pubis distance. In the general population, the most common shapes are round and vertical oval. T-shaped umbilici were only observed in adults. Round and protruding shapes were twice as frequent in children under 18 as in adults. The horizontal oval shape was twice as frequent in adults. Conclusions: Abdominal growth and changes in the repartition of subcutaneous adipose tissues with age are responsible for the vertical orientation and deepening of the umbilicus as well as its horizontal orientation. To promote final cosmetic outcomes, secondary umbilicoplasty must place the umbilicus between one half and two thirds of the xiphoid-pubis distance. Level of Evidence 4: PMID- 29126240 TI - Sampling Plans for the Thrips Frankliniella schultzei (Thysanoptera: Thripidae) in Three Lettuce Varieties. AB - The common blossom thrips, Frankliniella schultzei Trybom (Thysanoptera: Thripidae), is an important lettuce pest worldwide. Conventional sampling plans are the first step in implementing decision-making systems into integrated pest management programs. However, this tool is not available for F. schultzei infesting lettuce crops. Thus, the objective of this work was to develop a conventional sampling plan for F. schultzei in lettuce crops. Two sampling techniques (direct counting and leaf beating on a white plastic tray) were compared in crisphead, looseleaf, and Boston lettuce varieties before and during head formation. The frequency distributions of F. schultzei densities in lettuce crops were assessed, and the number of samples required to compose the sampling plan was determined. Leaf beating on a white plastic tray was the best sampling technique. F. schultzei densities obtained with this technique were fitted to the negative binomial distribution with a common aggregation parameter (common K = 0.3143). The developed sampling plan is composed of 91 samples per field and presents low errors in its estimates (up to 20%), fast execution time (up to 47 min), and low cost (up to US $1.67 per sampling area). This sampling plan can be used as a tool for integrated pest management in lettuce crops, assisting with reliable decision making in different lettuce varieties before and during head formation. PMID- 29126241 TI - Lactobacillus backii and Pediococcus damnosus isolated from 170-year-old beer recovered from a shipwreck lack the metabolic activities required to grow in modern lager beer. AB - In 2010, bottles of beer containing viable bacteria of the common beer-spoilage species Lactobacillus backii and Pediococcus damnosus were recovered from a shipwreck near the Aland Islands, Finland. The 170-year quiescent state maintained by the shipwreck bacteria presented a unique opportunity to study lactic acid bacteria (LAB) evolution vis-a-vis growth and survival in the beer environment. Three shipwreck bacteria (one L. backii strain and two P. damnosus strains) and modern-day beer-spoilage isolates of the same two species were genome sequenced, characterized for hop iso-alpha-acid tolerance, and growth in degassed lager and wheat beer. In addition, plasmid variants of the modern-day P. damnosus strain were analyzed for the effect of plasmid-encoded genes on growth in lager beer. Coding content on two plasmids was identified as essential for LAB growth in modern lager beer. Three chromosomal regions containing genes related to sugar transport and cell wall polysaccharides were shared by pediococci able to grow in beer. Our results show that the three shipwreck bacteria lack the necessary plasmid-located genetic content to grow in modern lager beer, but carry additional genes related to acid tolerance and biofilm formation compared to their modern counterparts. PMID- 29126242 TI - Differential manipulation of leaf angle throughout the canopy: current status and prospects. AB - Leaf angle is defined as the inclination between the midrib of the leaf blade and the vertical stem of a plant. This trait has been identified as a key component in the development of high-yielding varieties of cereal species, particularly maize, rice, wheat, and sorghum. The effect of leaf angle on light interception efficiency, photosynthetic rate, and yield has been investigated since the 1960s, yet, significant knowledge gaps remain in understanding the genetic control of this complex trait. Recent advances in physiology and modeling have proposed a plant ideotype with varying leaf angles throughout the canopy. In this context, we present historical and recent evidence of: (i) the effect of leaf angle on photosynthetic efficiency and yield; (ii) the hormonal regulation of this trait; (iii) the current knowledge on its quantitative genetic control; and (iv) the opportunity to utilize high-throughput phenotyping methods to characterize leaf angle at multiple canopy levels. We focus on research conducted on grass species of economic importance, with similar plant architecture and growth patterns. Finally, we present the challenges and strategies plant breeders will need to embrace in order to manipulate leaf angle differentially throughout the canopy and develop superior crops for food, feed, and fuel production. PMID- 29126243 TI - Faster Evolving Primate Genes Are More Likely to Duplicate. AB - An attractive and long-standing hypothesis regarding the evolution of genes after duplication posits that the duplication event creates new evolutionary possibilities by releasing a copy of the gene from constraint. Apparent support was found in numerous analyses, particularly, the observation of higher rates of evolution in duplicated as compared with singleton genes. Could it, instead, be that more duplicable genes (owing to mutation, fixation, or retention biases) are intrinsically faster evolving? To uncouple the measurement of rates of evolution from the determination of duplicate or singleton status, we measure the rates of evolution in singleton genes in outgroup primate lineages but classify these genes as to whether they have duplicated or not in a crown group of great apes. We find that rates of evolution are higher in duplicable genes prior to the duplication event. In part this is owing to a negative correlation between coding sequence length and rate of evolution, coupled with a bias toward smaller genes being more duplicable. The effect is masked by difference in expression rate between duplicable genes and singletons. Additionally, in contradiction to the classical assumption, we find no convincing evidence for an increase in dN/dS after duplication, nor for rate asymmetry between duplicates. We conclude that high rates of evolution of duplicated genes are not solely a consequence of the duplication event, but are rather a predictor of duplicability. These results are consistent with a model in which successful gene duplication events in mammals are skewed toward events of minimal phenotypic impact. PMID- 29126244 TI - Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long term survivors of esophageal or junctional cancer: results from the randomized CROSS trial. AB - Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods: Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4 Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results: After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen's d -0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen's d -0.56 and 0.51, respectively, both P < 0.001). Conclusions: Although physical functioning and fatigue remain reduced after long-term follow up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number: Netherlands Trial Register NTR487. PMID- 29126245 TI - Eyelid Make-Up to Manage Transient Blepharoptosis After Botulinum Toxin Injection. PMID- 29126246 TI - Bringing numerous methods for expression and promoter analysis to a public cloud computing service. AB - Summary: Every year, a large number of novel algorithms are introduced to the scientific community for a myriad of applications, but using these across different research groups is often troublesome, due to suboptimal implementations and specific dependency requirements. This does not have to be the case, as public cloud computing services can easily house tractable implementations within self-contained dependency environments, making the methods easily accessible to a wider public. We have taken 14 popular methods, the majority related to expression data or promoter analysis, developed these up to a good implementation standard and housed the tools in isolated Docker containers which we integrated into the CyVerse Discovery Environment, making these easily usable for a wide community as part of the CyVerse UK project. Availability and implementation: The integrated apps can be found at http://www.cyverse.org/discovery-environment, while the raw code is available at https://github.com/cyversewarwick and the corresponding Docker images are housed at https://hub.docker.com/r/cyversewarwick/. Contact: info@cyverse.warwick.ac.uk or D.L.Wild@warwick.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126247 TI - The mycorrhizal type governs root exudation and nitrogen uptake of temperate tree species. AB - Even though the two dominant mycorrhizal associations of temperate tree species differentially couple carbon (C) and nitrogen (N) cycles in temperate forests, systematic differences between the biogeochemical cycles of arbuscular mycorrhizal (AM) and ectomycorrhizal (ECM) tree species remain poorly described. A classification according to the mycorrhizal type offers the chance, though, to develop a global frame concept for the prediction of temperate ecosystem responses to environmental change. Focusing on the influence of mycorrhizal types on two key plant processes of biogeochemical cycling (root exudation and N acquisition), we investigated four temperate deciduous tree species per mycorrhizal type in a drought experiment in large mesocosms. We hypothesized that (H1) C loss by root exudation is higher in ECM than in AM trees, (H2) drought leads to higher reductions in root exudation of drought-sensitive ECM trees and (H3) inorganic N uptake is higher in AM than in ECM trees. In contradiction to H2, we found no systematic difference in root exudation between the mycorrhizal types at ample soil moisture, but almost twofold higher exudation in ECM trees when exposed to soil drought. In addition, photosynthetic C cost of root exudation strongly increased by ~10-fold in drought-treated ECM trees, while it only doubled in AM trees, which confirms H1. With respect to H3, we corroborated that AM trees had higher absolute and relative inorganic N acquisition rates than ECM trees, while the organic N uptake did not differ between mycorrhizal types. We conclude that ECM trees are less efficient in inorganic N uptake than AM trees, but ECM trees increase root C release as an adaptive response to dry soil to maintain hydraulic conductivity and/or nutrient availability. These systematic differences in key biogeochemical processes support hints on the key role of the mycorrhizal types in coupling C and N cycles in temperate forests. PMID- 29126248 TI - Reply to Kuehl et al. PMID- 29126249 TI - The Encyclopedia of DNA elements (ENCODE): data portal update. AB - The Encyclopedia of DNA Elements (ENCODE) Data Coordinating Center has developed the ENCODE Portal database and website as the source for the data and metadata generated by the ENCODE Consortium. Two principles have motivated the design. First, experimental protocols, analytical procedures and the data themselves should be made publicly accessible through a coherent, web-based search and download interface. Second, the same interface should serve carefully curated metadata that record the provenance of the data and justify its interpretation in biological terms. Since its initial release in 2013 and in response to recommendations from consortium members and the wider community of scientists who use the Portal to access ENCODE data, the Portal has been regularly updated to better reflect these design principles. Here we report on these updates, including results from new experiments, uniformly-processed data from other projects, new visualization tools and more comprehensive metadata to describe experiments and analyses. Additionally, the Portal is now home to meta(data) from related projects including Genomics of Gene Regulation, Roadmap Epigenome Project, Model organism ENCODE (modENCODE) and modERN. The Portal now makes available over 13000 datasets and their accompanying metadata and can be accessed at: https://www.encodeproject.org/. PMID- 29126252 TI - Monoamines in glioblastoma: complex biology with therapeutic potential. AB - Glioblastoma (GBM) is characterized by extremely poor prognoses, despite the use of gross surgical resection, alkylating chemotherapeutic agents, and radiotherapy. Evidence increasingly highlights the role of the tumor microenvironment in enabling this aggressive phenotype. Despite this interest, the role of neurotransmitters, brain-specific messengers underlying synaptic transmission, remains murky. These signaling molecules influence a complex network of molecular pathways and cellular behaviors in many CNS-resident cells, including neural stem cells and progenitor cells, neurons, and glia cells. Critically, available data convincingly demonstrate that neurotransmitters can influence proliferation, quiescence, and differentiation status of these cells. This ability to affect progenitors and glia-GBM-initiating cells-and their availability in the CNS strongly support the notion that neurotransmitters participate in the onset and progression of GBM. This review will focus on dopamine and serotonin, as studies indicate they contribute to gliomagenesis. Particular attention will be paid to how these neurotransmitters and their receptors can be utilized as novel therapeutic targets. Overall, this review will analyze the complex biology governing the interaction of GBM with neurotransmitter signaling and highlight how this interplay shapes the aggressive nature of GBM. PMID- 29126251 TI - Evidence for a role of PDZ domain-containing proteins to mediate hypophosphatemia in calcium stone formers. AB - Background: Hypophosphatemia (HYP) is common among calcium stone formers (SFs) and in rare cases is associated with mutations in sodium-phosphate cotransporters or in Na+/H+ exchanger regulatory factor 1 (NHERF1), but the majority of cases are unexplained. We hypothesized that reduced sodium-phosphate cotransporter activity mediated via NHERF1 or a similar PDZ domain-containing protein, causes HYP. If so, other transport activities controlled by NHERF1, such as NHE3 and URAT1, might be reduced in HYP. Methods: To test this idea, we analyzed two large but separate sets of 24-h urine samples and paired serums of 2700 SFs from the University of Chicago and 11 073 SFs from Litholink, a national laboratory. Patients were divided into quintiles based on serum phosphate. Results: Males were more common in the lowest phosphate tiles in both datasets. Phosphate excretion did not vary across the quintiles, excluding diet as a cause of HYP. Tubule maximum (Tm) phosphate per unit glomerular filtration rate decreased and fractional excretion increased with decreasing phosphate quintiles, indicating reduced tubule phosphate reabsorption was responsible for HYP. Urine pH and serum chloride increased with decreasing serum phosphate, suggesting a coordinate change in NHE3 activity. Serum uric acid and Tm uric acid decreased significantly with decreasing serum phosphate, while uric acid excretion did not vary. Conclusion. HYP in SFs results from decreased tubule phosphate reabsorption and, being associated with related changes in other proximal tubule transporters, may arise from alterations in or signaling to PDZ-containing proteins. PMID- 29126253 TI - Enabling phenotypic big data with PheNorm. AB - Objective: Electronic health record (EHR)-based phenotyping infers whether a patient has a disease based on the information in his or her EHR. A human annotated training set with gold-standard disease status labels is usually required to build an algorithm for phenotyping based on a set of predictive features. The time intensiveness of annotation and feature curation severely limits the ability to achieve high-throughput phenotyping. While previous studies have successfully automated feature curation, annotation remains a major bottleneck. In this paper, we present PheNorm, a phenotyping algorithm that does not require expert-labeled samples for training. Methods: The most predictive features, such as the number of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes or mentions of the target phenotype, are normalized to resemble a normal mixture distribution with high area under the receiver operating curve (AUC) for prediction. The transformed features are then denoised and combined into a score for accurate disease classification. Results: We validated the accuracy of PheNorm with 4 phenotypes: coronary artery disease, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. The AUCs of the PheNorm score reached 0.90, 0.94, 0.95, and 0.94 for the 4 phenotypes, respectively, which were comparable to the accuracy of supervised algorithms trained with sample sizes of 100-300, with no statistically significant difference. Conclusion: The accuracy of the PheNorm algorithms is on par with algorithms trained with annotated samples. PheNorm fully automates the generation of accurate phenotyping algorithms and demonstrates the capacity for EHR-driven annotations to scale to the next level - phenotypic big data. PMID- 29126254 TI - Visual Disability in Ebola Survivors. PMID- 29126255 TI - Economic Evaluations of Mass Drug Administration: The Importance of Economies of Scale and Scope. AB - It is recognized that changing the current approaches for the control of the neglected tropical diseases will be needed to reach the World Health Organization's (WHO) 2020 goals. Consequently, it is important that economic evaluations of the alternative approaches are conducted. A vital component of such evaluations is the issue of how the intervention's costs should be incorporated. We discuss this issue-focusing on mass drug administration. We argue that the common approach of assuming an intervention's cost per treatment is constant, regardless of the number of individuals treated, is a misleading way to consider the delivery costs of mass drug administration due to the occurrence of economies/diseconomies of scale and scope. Greater care and consideration are required when the costs are incorporated into such analyses. Without this, these economic evaluations could potentially lead to incorrect policy recommendations. PMID- 29126256 TI - Digging Out the Evidence-How Strong Is the IDSA Recommendation Against Antibiotic Prophylaxis in Basilar Skull Fracture and Cerebrospinal Fluid Leakage? PMID- 29126257 TI - Experimental design for single-cell RNA sequencing. AB - Single-cell RNA sequencing (scRNA-seq) has opened new avenues for the characterization of heterogeneity in a large variety of cellular systems. As this is a relatively new technique, the field is fast evolving. Here, we discuss general considerations in experimental design and the two most popular approaches, plate-based Smart-Seq2 and microdroplet-based scRNA-seq at the example of 10x Chromium. We discuss advantages and disadvantages of both methods and point out major factors to consider in designing successful experiments. PMID- 29126258 TI - Treatment of intramural ventricular tachycardia in cardiac sarcoidosis with transcoronary ethanol ablation. PMID- 29126259 TI - An Open-Label Study of Sufentanil Sublingual Tablet 30 Mcg in Patients with Postoperative Pain. AB - Objective: To evaluate sufentanil sublingual tablet 30 mcg (SST 30 mcg) for postoperative pain in an older patient population with comorbidities. Design: Multicenter, open-label, single-arm study. Setting: Nine hospitals across the United States. Subjects: Adults aged >=40 years who had undergone a surgical procedure. Methods: Patients with a postoperative pain intensity score >=4 on an 11-point numeric rating scale (NRS) were allowed to enter the study and receive SST 30 mcg as requested for pain (minimum 60-minute redosing interval) over the 12-hour study period. Efficacy was assessed by patient reports of pain intensity on the NRS and a five-point pain relief scale. Safety was monitored throughout the study; plasma sufentanil concentrations were also measured. The primary efficacy endpoint was the time-weighted summed pain intensity difference (SPID) to baseline over 12 hours (SPID12). Results: Of the 140 patients enrolled, 69% were American Society of Anesthesiologists Physical Class II or III, 44% had a body mass index (BMI) >=30 mg/kg2, and 29% had hepatic and/or renal impairment. Average age was 54.7 years (SD = 9.9 years), and average baseline pain intensity was 6.2 (SD = 1.9). The most common surgeries were abdominal (59%) and orthopedic (20%). The mean SPID12 was 36.0 (standard error of the mean = 2.2); mean scores were similar, regardless of age, sex, race, and BMI. From baseline, mean pain intensity decreased significantly starting 30 minutes postdose, and mean pain relief increased significantly starting 15 minutes postdose, remaining relatively stable through 12 hours (P < 0.001 at each time point). Four (3%) patients discontinued due to inadequate analgesia, and 45 (32%) patients had one or more adverse events that were considered possibly or probably related to the study drug. Mean plasma sufentanil concentrations were generally similar regardless of age, sex, BMI, or organ impairment status. Conclusions: SST 30 mcg was effective and well tolerated for the management of moderate-to-severe acute postoperative pain. PMID- 29126260 TI - Association Between Risk-of-Bias Assessments and Results of Randomized Trials in Cochrane Reviews: The ROBES Meta-Epidemiologic Study. AB - Flaws in the design of randomized trials may bias intervention effect estimates and increase between-trial heterogeneity. Empirical evidence suggests that these problems are greatest for subjectively assessed outcomes. For the Risk of Bias in Evidence Synthesis (ROBES) Study, we extracted risk-of-bias judgements (for sequence generation, allocation concealment, blinding, and incomplete data) from a large collection of meta-analyses published in the Cochrane Library (issue 4; April 2011). We categorized outcome measures as mortality, other objective outcome, or subjective outcome, and we estimated associations of bias judgements with intervention effect estimates using Bayesian hierarchical models. Among 2,443 randomized trials in 228 meta-analyses, intervention effect estimates were, on average, exaggerated in trials with high or unclear (versus low) risk-of-bias judgements for sequence generation (ratio of odds ratios (ROR) = 0.91, 95% credible interval (CrI): 0.86, 0.98), allocation concealment (ROR = 0.92, 95% CrI: 0.86, 0.98), and blinding (ROR = 0.87, 95% CrI: 0.80, 0.93). In contrast to previous work, we did not observe consistently different bias for subjective outcomes compared with mortality. However, we found an increase in between-trial heterogeneity associated with lack of blinding in meta-analyses with subjective outcomes. Inconsistency in criteria for risk-of-bias judgements applied by individual reviewers is a likely limitation of routinely collected bias assessments. Inadequate randomization and lack of blinding may lead to exaggeration of intervention effect estimates in randomized trials. PMID- 29126262 TI - Relapsing polychondritis: a clinical review for rheumatologists. AB - Relapsing polychondritis (RPC) is a rare autoimmune rheumatic disorder that is traditionally classified as a systemic vasculitis. It is characterized by inflammation of cartilage, and typical presenting features include chondritis of the nasal bridge, auricular chondritis, ocular inflammation and involvement of the bronchial tree. Its rarity often leads to considerable delay in establishing a diagnosis and poses a significant management challenge to clinicians, as no conventional guidelines exist. This review summarizes the clinical features of RPC and provides guidance for rheumatologists on making the diagnosis and assessing organ involvement. The current state of RPC management is reviewed, with a focus on the use of the anti-TNF-alpha agents in patients with pulmonary involvement, the leading cause of mortality and morbidity in RPC. PMID- 29126261 TI - Heme promotes transcriptional and demethylase activities of Gis1, a member of the histone demethylase JMJD2/KDM4 family. AB - The yeast Gis1 protein is a transcriptional regulator belonging to the JMJD2/KDM4 subfamily of demethylases that contain a JmjC domain, which are highly conserved from yeast to humans. They have important functions in histone methylation, cellular signaling and tumorigenesis. Besides serving as a cofactor in many proteins, heme is known to directly regulate the activities of proteins ranging from transcriptional regulators to potassium channels. Here, we report a novel mechanism governing heme regulation of Gis1 transcriptional and histone demethylase activities. We found that two Gis1 modules, the JmjN + JmjC domain and the zinc finger (ZnF), can bind to heme specifically in vitro. In vivo functional analysis showed that the ZnF, not the JmjN + JmjC domain, promotes heme activation of transcriptional activity. Likewise, measurements of the demethylase activity of purified Gis1 proteins showed that full-length Gis1 and the JmjN + JmjC domain both possess demethylase activity. However, heme potentiates the demethylase activity of full-length Gis1, but not that of the JmjN + JmjC domain, which can confer heme activation of transcriptional activity in an unrelated protein. These results demonstrate that Gis1 represents a novel class of multi-functional heme sensing and signaling proteins, and that heme binding to the ZnF stimulates Gis1 demethylase and transcriptional activities. PMID- 29126264 TI - Pulmonary azygous lobe. PMID- 29126266 TI - Non-insulin antidiabetic pharmacotherapy in patients with established cardiovascular disease: a position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy. PMID- 29126265 TI - Stomatal and growth responses to hydraulic and chemical changes induced by progressive soil drying. AB - A better understanding of physiological responses of crops to drought stress is important for ensuring sustained crop productivity under climate change. Here, we studied the effect on 15-day-old maize (Zea mays L.) plants of a 6 d non-lethal period of soil drying [soil water potential (SWP) decreased from -0.20 MPa to 0.81 MPa]. Root growth was initially stimulated during drying (when SWP decreased from -0.31 MPa to -0.38 MPa, compared with -0.29 MPa in well-watered pots), followed by inhibition during Days 5-6 (SWP from -0.63 MPa to -0.81 MPa). Abscisic acid (ABA) in the root began to accumulate as the root water potential declined during Days 2-3. Leaf elongation was inhibited from Day 4 (SWP less than -0.51 MPa), just after leaf ABA content began to increase, but coinciding with a decline in leaf water potential. The stomatal conductance was restricted earlier in the younger leaf (fourth) (on Day 3) than in the older leaf (third). The ethylene content of leaves and roots decreased during drying, but after the respective increase in ABA contents. This work identified critical timing of hydraulic and chemical changes at the onset of soil drying, which can be important in initiating early stomatal and growth responses to drought. PMID- 29126268 TI - Duration of Antibiotic Use Among Adults With Uncomplicated Community-Acquired Pneumonia Requiring Hospitalization in the United States. AB - Background: Previous studies suggest that duration of antibiotic therapy for community-acquired pneumonia (CAP) often exceeds national recommendations and might represent an important opportunity to improve antibiotic stewardship nationally. Our objective was to determine the average length of antibiotic therapy (LOT) for patients treated for uncomplicated CAP in US hospitals and the proportion of patients with excessive durations. Methods: Records of retrospective cohorts of patients aged 18-64 years with private insurance and aged >=65 years with Medicare hospitalized for CAP in 2012-2013 were used. Inpatient LOT was estimated as a function of length of stay. Outpatient LOT was based on prescriptions filled post discharge based on data from outpatient pharmacy files. Excessive duration was defined as outpatient LOT >3 days. Results: Inclusion criteria were met for 22128 patients aged 18-64 years across 2100 hospitals and 130746 patients aged >=65 years across 3227 hospitals. Median total LOT was 9.5 days. LOT exceeded recommended duration for 74% of patients aged 18-64 years and 71% of patients aged >=65 years. Patients aged 18-64 years had a median (quartile 1-quartile 3) 6 (3-7) days outpatient LOT and those aged >=65 years had 5 (3-7) days. Conclusions: In this nationwide sample of patients hospitalized for CAP, median total LOT was just under 10 days, with more than 70% of patients having likely excessive treatment duration. Better adherence to recommended CAP therapy duration by improving prescribing at hospital discharge may be an important target for antibiotic stewardship programs. PMID- 29126267 TI - Identification of universal gut microbial biomarkers of common human intestinal diseases by meta-analysis. AB - Intestinal diseases, such as Crohn's disease (CD), ulcerative colitis (UC) and pseudomembranous colitis (CDI), are among the most common diseases in humans and may lead to more serious pathologies, e.g. colorectal cancer (CRC). Next generation sequencing has in recent years allowed the identification of correlations between intestinal bacteria and diseases, although the formulation of universal gut microbial biomarkers for such diseases is only in its infancy. In the current study, we selected and reanalyzed a total of 3048 public datasets obtained from 16S rRNA profiling of individuals affected by CD, UC, CDI and CRC. This meta-analysis revealed possible biases in the reconstruction of the gut microbiota composition due to the use of different primer pairs employed for PCR of 16S rRNA gene fragments. Notably, this approach also identified common features of individuals affected by gut diseases (DS), including lower biodiversity compared to control subjects. Moreover, potential universal intestinal disease microbial biomarkers were identified through cross-disease comparisons. In detail, CTRL showed high abundance of the genera Barnesiella, Ruminococcaceae UCG-005, Alistipes, Christensenellaceae R-7 group and unclassified member of Lachnospiraceae family, while DS exhibited high abundance of Lactobacillus, unclassified member of Erysipelotrichaceae family and Streptococcus genera. PMID- 29126263 TI - Notch Signaling Regulates Differentiation and Steroidogenesis in Female Mouse Ovarian Granulosa Cells. AB - The Notch pathway is a highly conserved juxtacrine signaling mechanism that is important for many cellular processes during development, including differentiation and proliferation. Although Notch is important during ovarian follicle formation and early development, its functions during the gonadotropin dependent stages of follicle development are largely unexplored. We observed positive regulation of Notch activity and expression of Notch ligands and receptors following activation of the luteinizing hormone-receptor in prepubertal mouse ovary. JAG1, the most abundantly expressed Notch ligand in mouse ovary, revealed a striking shift in localization from oocytes to somatic cells following hormone stimulation. Using primary cultures of granulosa cells, we investigated the functions of Jag1 using small interfering RNA knockdown. The loss of JAG1 led to suppression of granulosa cell differentiation as marked by reduced expression of enzymes and factors involved in steroid biosynthesis, and in steroid secretion. Jag1 knockdown also resulted in enhanced cell proliferation. These phenotypes were replicated, although less robustly, following knockdown of the obligate canonical Notch transcription factor RBPJ. Intracellular signaling analysis revealed increased activation of the mitogenic phosphatidylinositol 3 kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal regulated kinase pathways following Notch knockdown, with a mitogen-activated protein kinase kinase inhibitor blocking the enhanced proliferation observed in Jag1 knockdown granulosa cells. Activation of YB-1, a known regulator of granulosa cell differentiation genes, was suppressed by Jag1 knockdown. Overall, this study reveals a role of Notch signaling in promoting the differentiation of preovulatory granulosa cells, adding to the diverse functions of Notch in the mammalian ovary. PMID- 29126269 TI - Evaluation of the KPC K-SeT(r) immunochromatographic assay for the rapid detection of KPC carbapenemase producers from positive blood cultures. PMID- 29126270 TI - Neural Plasticity with Age: Unilateral Maximal Strength Training Augments Efferent Neural Drive to the Contralateral Limb in Older Adults. AB - Efferent neural drive during strong muscle contractions is attenuated with age, even after life-long strength training. However, it is unknown if this deterioration may impede contralateral neural plasticity, and limit the clinical value of unilateral strength training. We assessed muscle force-generating capacity, evoked potentials recordings (V-wave and H-reflex normalized to M-wave; V/M-ratio and H/M-ratio) and voluntary activation (VA) in the plantar flexors of the contralateral limb following unilateral maximal strength training (MST) with the dominant limb for 3 weeks (nine sessions). Twenty-three 73 +/- 4(SD) year old males were randomized to a MST group (N = 11), exercising with an intensity of ~90% of maximal strength, or a control group (CG, N = 12). MST improved contralateral maximal strength (107.6 +/- 27.0 to 119.1 +/- 34.8 Nm; 10%) and rate of force development (197.3 +/- 54.1 to 232.8 +/- 77.7 Nm s-1; 18%) (both p < .05). These strength gains were associated with (r = 0.465-0.608) an enhanced soleus V/M-ratio (0.12 +/- 0.09 to 0.21 +/- 0.17) and VA (79.5 +/- 5.1 to 83.3 +/ 5.2%) (all p < .05). H/M-ratio (10% maximal strength) remained unaltered after MST, and no changes were apparent in the CG. In conclusion, cross-limb effects in older adults are regulated by efferent neural drive enhancement, and advocate the clinical relevance of MST to improve neuromuscular function in individuals with conditions that results in unilateral strength reductions. PMID- 29126271 TI - Examining the Transitions Between Cigarette and Smokeless Tobacco Product Use in the United States Using the 2002-2003 and 2010-2011 Longitudinal Cohorts. AB - Introduction: Smokeless tobacco (SLT) use in the United States has remained constant or even increased slightly in recent years, whereas smoking has continuously decreased. Characterization of transitions between tobacco products is critical to understand the reasons behind the continuing use of smokeless tobacco. Methods: Two longitudinal cohorts of Tobacco Use Supplement of the Current Population Survey (TUS-CPS), 2002-2003 (n = 14996) and 2010-2011 (n = 18226), were used to examine transitions between cigarette and SLT use over 1 year periods. Weighted population percentages of four use categories (exclusive cigarette use, exclusive SLT use, dual use, and neither) were calculated for different demographic groups. Transition between use categories and quit rates by product were calculated for each cohort. Results: Relative to 2002-2003, smoking quit rates of male exclusive smokers significantly increased in 2010-2011 (11.6% vs. 24.4%, p < .0001), but the corresponding SLT use quit rates remained stable (41.3% vs. 40.0%, p = .87). Similar patterns were found in females with smoking quit rates increasing considerably (12.3% vs. 24.2%, p < .0001). Smoking quit rates increased in most sociodemographic groups analyzed. Male SLT use quit rates were significantly lower in SLT exclusive users than in dual users in the 2010 2011 cohort (40.0% vs. 62.2%; p = .04), but smoking quit rates in exclusive smokers and in dual users were roughly equivalent (24.4% vs. 29.5%, p = .68). Conclusions: Although smoking quit rates doubled overall and increased in most sociodemographic groups, SLT quit rates remained constant with little transition between products. Longer-term prospective data examining polytobacco use are needed to better understand transitions between tobacco products. Implications: This study uses two longitudinal surveys to investigate changes in switching behaviors between tobacco products. We found that quit rates of self-reported smoking doubled between 2002-2003 and 2010-2011 in most sociodemographic groups in the United States, whereas in contrast quit rates of self-reported Smokeless Tobacco (SLT) use remained roughly constant. This explains in part the opposing trends of tobacco use by product in the United States, with smoking continuing its decrease, whereas SLT use remains constant. Moreover, smokers were unlikely to switch to other forms of tobacco compared to SLT users. Lastly, smoking cessation for dual users was not significantly different from that of exclusive smokers. Understanding transitions between smoking and SLT use is critical to assess the potential long-term impact of SLT use, and potentially that of other alternative tobacco products, on tobacco-related health outcomes. PMID- 29126272 TI - Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model. AB - Antigen-specific regulatory T cells (Tregs) possess the potential to reduce excess immune responses in autoimmune diseases, allergy, rejection after organ transplantation and graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. Although in vitro-expanded antigen-specific induced Tregs (iTregs) have been considered to be a promising therapeutic agent against such excessive immune reactions, the instability of iTregs after transfer is a fundamental problem in their clinical application. In this study, we searched for the optimal way to generate stable iTregs for the prevention of the murine GVHD model, in which conventional iTregs are reported to be inefficient. Allo-antigen specific iTregs were generated by co-culturing naive T cells with allogenic dendritic cells in the presence of TGF-beta and retinoic acid. By examining various agents and genes, we found that vitamin C stabilized Foxp3 expression most effectively in adoptively transferred iTregs under a GVHD environment. Vitamin C treatment caused active DNA demethylation specifically on the conserved non-coding sequence 2 (CNS2) enhancer of the Foxp3 gene locus in allo-antigen specific iTregs and reduced iTreg conversion into pathogenic exFoxp3 cells. Vitamin C-treated iTregs suppressed GVHD symptoms more efficiently than untreated iTregs. Vitamin C also facilitated induction of a FOXP3high iTreg population from human naive T cells, which was very stable even in the presence of IL-6 in vitro. The treatment of vitamin C for iTreg promises innovative clinical application for adoptive Treg immunotherapy. PMID- 29126274 TI - RightCare: wrong answers. AB - Background: NHS RightCare is an NHS England programme describing itself as 'a proven approach that delivers better patient outcomes'. It identifies opportunities for savings and quality improvements, comparing each Clinical Commissioning Group (CCG) with the 'Best 5' of a fixed set of 'Similar 10' CCGs chosen using equally weighted demographic and deprivation indicators. This article tests whether these indicators are sufficient and equal weighting is appropriate, and evaluates significance. Methods: Robust public data on lung, colorectal, and breast cancer mortality is modelled using the indicators and incidence. Peers chosen using the preferred models are compared with the Similar 10. Confidence intervals are obtained for comparator group averages. RightCare significance is simulated. Results: Preferred models have unequally weighted covariates. Incidence is the strongest predictor of lung cancer mortality. The 'Similar 10' are inappropriate comparators. RightCare significance ignores variability of comparator outcomes, causing 12% Type I errors. Whilst RightCare shows 1842 annual avoidable lung cancer deaths in 80 CCGs, only 168 deaths in 8 CCGs appear exceptional using appropriate peers and CIs. Conclusion: CCGs cannot expect to match the average performance of the RightCare 'Best 5'. Until the methodology is examined with data of known quality, claims that RightCare is a 'proven approach' are unsubstantiated. PMID- 29126250 TI - Diabetic Microvascular Disease: An Endocrine Society Scientific Statement. AB - Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations. PMID- 29126273 TI - Genetics of membranous nephropathy. AB - An HLA-DR3 association with membranous nephropathy (MN) was described in 1979 and additional evidence for a genetic component to MN was suggested in 1984 in reports of familial MN. In 2009, a pathogenic autoantibody was identified against the phospholipase A2 receptor 1 (PLA2R1). Here we discuss the genetic studies that have proven the association of human leucocyte antigen class II and PLA2R1 variants and disease in MN. The common variants in PLA2R1 form a haplotype that is associated with disease incidence. The combination of the variants in both genes significantly increases the risk of disease by 78.5-fold. There are important genetic ethnic differences in MN. Disease outcome is difficult to predict and attempts to correlate the genetic association to outcome have so far not been helpful in a reproducible manner. The role of genetic variants may not only extend beyond the risk of disease development, but can also help us understand the underlying molecular biology of the PLA2R1 and its resultant pathogenicity. The genetic variants identified thus far have an association with disease and could therefore become useful biomarkers to stratify disease risk, as well as possibly identifying novel drug targets in the near future. PMID- 29126275 TI - Active antimicrobial efflux in Staphylococcus epidermidis: building up of resistance to fluoroquinolones and biocides in a major opportunistic pathogen. AB - Objectives: To analyse the efflux-mediated response of Staphylococcus epidermidis to ethidium bromide (EtBr), a substrate of multidrug efflux pumps (EPs). Methods: The susceptible reference strain S. epidermidis ATCC 12228 was exposed to a step wise adaptation to EtBr. The resulting EtBr-adapted strains were characterized regarding their antibiotic and biocide susceptibility by MIC determination and evaluation of efflux activity by re-determination of MICs in the presence of known efflux inhibitors and real-time fluorometry. Mutations in the QRDR of grlA and gyrA were screened by sequencing. The expression levels of S. epidermidis homologues of the main Staphylococcus aureus EP genes were quantified by RT-qPCR. Results: Exposure to EtBr led to a gradual increase in resistance to antimicrobials, with the final EtBr-adapted strain, ATCC 12228_EtBr, displaying phenotypic resistance to fluoroquinolones and reduced susceptibility to several antiseptics and disinfectants, although no mutations were detected in the QRDR of the grlA/gyrA genes. A reduction in the MICs of fluoroquinolones and selected biocides promoted by efflux inhibitors suggested an efflux-mediated response to EtBr exposure. Detailed analysis of the EtBr-adapted strains detected a gradual increase in efflux activity. Gene expression assays revealed a temporal activation of S. epidermidis EPs, with an early response involving norA, SE2010 and SE1103 followed by a late response mediated by norA, which coincided with the occurrence of the mutation -1A->T in the norA promoter region. Conclusions: This study demonstrated that S. epidermidis has the potential to develop a multiple resistance phenotype mediated by efflux when exposed to a non-antibiotic substrate of multidrug EPs. PMID- 29126276 TI - Erratum to: Evaluation of an electronic health record-supported obesity management protocol implemented in a community health center: a cautionary note. PMID- 29126277 TI - [18F]FDG positron emission tomography in patients presenting with suspicion of giant cell arteritis-lessons from a vasculitis clinic. AB - Aims: The usefulness of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) for diagnosing giant cell arteritis (GCA) has been previously reported. Yet, the interpretation of PET scans is not clear-cut. The present study aimed at determining the best method to analyse PET/CT in a large, real-life cohort of patients presenting with suspicion of GCA. Methods and results: One hundred and three patients with clinical suspicion of GCA undergoing PET/CT between 2006 and 2012 were included. Clinical data were retrieved from patients' charts. PET/CT was categorized by visual scoring of the uptake and by the artery/liver standardized uptake values (SUV) ratios. Diagnosis of GCA was confirmed in 68 patients and excluded in 35 patients, which served as the controls. GCA patients were older (median age 75 vs. 68 years), and presented more often with ischaemic symptoms. The best discrimination between GCA patients and controls was achieved for PET/CT findings within the supra-aortic arteries (sensitivity 0.71, specificity 0.91 for a SUV/LE cut-off value of 1.0). Specificity of PET/CT for the aorta and the iliofemoral arteries was lower (<0.34). Visual scoring correlated poorly to SUV measurements (Kendall Tau-b 0.13-0.55) and had a lower diagnostic accuracy (sensitivity 0.77, specificity 0.75). Prednisone treatment for >=10 days significantly reduced PET/CT sensitivity (P = 0.009). Conclusion: SUV based analysis of PET/CT enhances diagnostic accuracy with best discrimination in the supra-aortic region, particularly in steroid naive patients. For discrimination based on the aorta and the iliofemoral region, higher cut-off values have to be applied, resulting in lower sensitivities for diagnosing GCA. PMID- 29126279 TI - Comment on: Residual disease activity in psoriatic arthritis: discordance between the rheumatologist's opinion and minimal disease activity measurement. PMID- 29126278 TI - Occupational radiation exposure in the electrophysiology laboratory with a focus on personnel with reproductive potential and during pregnancy: A European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS). PMID- 29126281 TI - Retuning the Radio in Radiobiology. PMID- 29126280 TI - Composing a new song for trials: the Standardized Outcomes in Nephrology (SONG) initiative. PMID- 29126282 TI - Comment on: High levels of susceptibility to new and older antibiotics in Neisseria gonorrhoeae isolates from Saskatchewan (2003-15): time to consider point-of-care or molecular testing for precision treatment? PMID- 29126283 TI - Surgical Management of Penile Lesions Secondary to Foreign Body Reaction: A Case Report and Systematic Review. AB - Background: To improve the penile contour, some men choose to undergo implantation or injection of nonbiological materials. Foreign body reactions in penile tissue may produce scarring, deformity, ulceration, necrosis, and even gangrene. Consensus is lacking regarding the most effective surgical procedure for reconstruction of these penile lesions. Objectives: The authors describe one case study and the first systematic review focusing on reconstructive surgical management for penile lesions secondary to foreign body reaction. Methods: PubMed, Medline, and Cochrane databases were queried for publications written in English, French, Portuguese, and Spanish from 1951 to May 2017. Multiple search terms were applied. Results: Of the 3304 articles identified, 51 were included in the systematic review. All were retrospective studies, case series, or case reports. A total of 260 patients underwent surgical procedures, and the complication rate was 37.3%. The scrotal flap technique was performed most frequently (43.4%) and resulted in 65.6% of the total complications observed. One Brazilian case study was also described with an extensive and circumferential ulcer after six mineral oil bolls implant in the penile subcutaneous tissue. Conclusions: Restoration of the penile shape preserving the functionality and maintaining a good physician-patient relationship may be a challenge. The scrotal pouch may be advantageous for patch grafting of penile soft-tissue lesions, owing to its skin laxity and good blood supply. A less aggressive surgical approach has the benefits of shorter healing time and fewer early complications. Penile injuries are best treated by experienced surgeons on a case-by-case basis with care given to identify the most appropriate treatment. Level of Evidence 5: PMID- 29126285 TI - ReMap 2018: an updated atlas of regulatory regions from an integrative analysis of DNA-binding ChIP-seq experiments. AB - With this latest release of ReMap (http://remap.cisreg.eu), we present a unique collection of regulatory regions in human, as a result of a large-scale integrative analysis of ChIP-seq experiments for hundreds of transcriptional regulators (TRs) such as transcription factors, transcriptional co-activators and chromatin regulators. In 2015, we introduced the ReMap database to capture the genome regulatory space by integrating public ChIP-seq datasets, covering 237 TRs across 13 million (M) peaks. In this release, we have extended this catalog to constitute a unique collection of regulatory regions. Specifically, we have collected, analyzed and retained after quality control a total of 2829 ChIP-seq datasets available from public sources, covering a total of 485 TRs with a catalog of 80M peaks. Additionally, the updated database includes new search features for TR names as well as aliases, including cell line names and the ability to navigate the data directly within genome browsers via public track hubs. Finally, full access to this catalog is available online together with a TR binding enrichment analysis tool. ReMap 2018 provides a significant update of the ReMap database, providing an in depth view of the complexity of the regulatory landscape in human. PMID- 29126286 TI - Deep learning for tumor classification in imaging mass spectrometry. AB - Motivation: Tumor classification using imaging mass spectrometry (IMS) data has a high potential for future applications in pathology. Due to the complexity and size of the data, automated feature extraction and classification steps are required to fully process the data. Since mass spectra exhibit certain structural similarities to image data, deep learning may offer a promising strategy for classification of IMS data as it has been successfully applied to image classification. Results: Methodologically, we propose an adapted architecture based on deep convolutional networks to handle the characteristics of mass spectrometry data, as well as a strategy to interpret the learned model in the spectral domain based on a sensitivity analysis. The proposed methods are evaluated on two algorithmically challenging tumor classification tasks and compared to a baseline approach. Competitiveness of the proposed methods is shown on both tasks by studying the performance via cross-validation. Moreover, the learned models are analyzed by the proposed sensitivity analysis revealing biologically plausible effects as well as confounding factors of the considered tasks. Thus, this study may serve as a starting point for further development of deep learning approaches in IMS classification tasks. Availability and implementation: https://gitlab.informatik.uni bremen.de/digipath/Deep_Learning_for_Tumor_Classification_in_IMS. Contact: jbehrmann@uni-bremen.de or christianetmann@uni-bremen.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126284 TI - Genetic Drift and Indel Mutation in the Evolution of Yeast Mitochondrial Genome Size. AB - Mitochondrial genomes (mitogenomes) are remarkably diverse in genome size and organization, but the origins of dynamic mitogenome architectures are still poorly understood. For instance, the mutational burden hypothesis postulates that the drastic difference between large plant mitogenomes and streamlined animal mitogenomes can be driven by their different mutation rates. However, inconsistent trends between mitogenome sizes and mutation rates have been documented in several lineages. These conflicting results highlight the need of systematic and sophisticated investigations on the evolution and diversity of mitogenome architecture. This study took advantage of the strikingly variable mitogenome size among different yeast species and also among intraspecific strains, examined sequence dynamics of introns, GC-clusters, tandem repeats, mononucleotide repeats (homopolymers) and evaluated their contributions to genome size variation. The contributions of these sequence features to mitogenomic variation are dependent on the timescale, over which extant genomes evolved from their last common ancestor, perhaps due to a combination of different turnover rates of mobile sequences, variable insertion spaces, and functional constraints. We observed a positive correlation between mitogenome size and the level of genetic drift, suggesting that mitogenome expansion in yeast is likely driven by multiple types of sequence insertions in a primarily nonadaptive manner. Although these cannot be explained directly by the mutational burden hypothesis, our results support an important role of genetic drift in the evolution of yeast mitogenomes. PMID- 29126287 TI - For Better or Worse? Couples' Time Together in Encore Adulthood. AB - Objective: This study examined the amount of time married couples share together in a new "encore adult" life course stage around the 50s, 60s, and 70s. Also investigated was the relationship between shared time and experienced well-being for this age group. Method: Time diary and survey data were used from nationally representative 2003-2014 American Time Use Survey (ATUS) data for 26,303 adults aged 50-79 years. Analyses examined amount of total and exclusive shared couple time and experiences of happiness and stress when together using multivariate models. Results: Shared time was positively associated with couples living on their own, conjoint employment/nonemployment, and age. Encore women and men reported feeling happier and less stressed when with their spouses. Men seemed to find time with spouses more enjoyable if both partners or just their wives were working. Discussion: Encore adults are living longer as couples; results suggest couple relationships may occupy most of their days, with potentially positive implications for emotional well-being. Men and women are happier during time with a spouse when the woman works, with men reporting even higher levels of happiness than women. This is important as contemporary couples navigate increasingly complex work/retirement transitions in gendered ways. PMID- 29126289 TI - Erratum. PMID- 29126288 TI - Socioeconomic status and impact of the economic crisis on dietary habits in Italy: results from the INHES study. AB - Background: There is lack of evidence about the likely impact of the economic crisis on dietary habits in Western societies. We aimed to assess dietary modifications that possibly occurred during the recession and to investigate major socioeconomic factors associated with such modifications. Methods: Cross sectional analysis on 1829 subjects from the general population recruited in the larger INHES study (n = 9319) a telephone-based survey on nutrition and health conducted in Italy from 2010 to 2013. Association of socioeconomic (education, household income, occupation) with self-reported impact of the economic crisis on dietary habits was tested by multivariable logistic regression analysis. Results: Low-educated subjects (OR = 2.30; 95% CI: 1.39-3.80), those with poor income (OR = 5.71; 95% CI: 3.68-8.85), and unemployed (OR = 3.93; 95% CI: 1.62-9.56) had higher odds of reporting undesirable dietary changes due to recession. Adherence to the Mediterranean diet was lower in subjects reporting a negative impact of the crisis on diet as compared to those declaring no effect, whereas the quality of grocery items was higher in the latter. Conclusions: Undesirable dietary changes due to the economic crisis were mainly reported by lower socioeconomic groups. Subjects perceiving a negative impact of the recession on their diet also showed a lower adherence to Mediterranean diet and reduced quality of grocery products. PMID- 29126290 TI - Effects of Levothyroxine on Pregnant Women With Subclinical Hypothyroidism, Negative for Thyroid Peroxidase Antibodies. AB - Context: Currently, there is no consensus on universal thyroid screening and levothyroxine (LT4) treatment of pregnant women with subclinical hypothyroidism (SCH) who are negative for thyroid peroxidase antibody (TPOAb-). Objective: We aimed to evaluate the benefits of LT4 treatment on pregnancy outcomes in SCH TPOAb- women. Design: This study was conducted within the framework of the Tehran Thyroid and Pregnancy Study. A single-blind randomized clinical trial was undertaken in pregnant women who were SCH-TPOAb-. Setting: Prenatal care centers of the Shahid Beheshti University of Medical Sciences. Patients: Using the thyrotropin (TSH) cut point of 2.5 mIU/L, 366 SCH-TPOAb- and 1092 euthyroid TPOAb women were recruited. Intervention: SCH-TPOAb- women were randomly assigned to two groups: group A (n = 183) who were treated with LT4 and group B (n = 183) who received no treatment. A total of 1,028 euthyroid TPOAb- women served as the control group (group C). Main Outcome Measure: The primary outcome was the rate of preterm delivery. Results: Using the TSH cutoff of 2.5 mIU/L, no significant difference in preterm delivery was observed between groups A and B [relative risk (RR): 0.86; 95% confidence interval (CI): 0.47 to 1.55; P = 0.61]. However, log binomial model analysis based on a cut point of 4.0 mIU/L demonstrated a significantly lower rate of preterm delivery in LT4-treated women compared with those who received no treatment (RR: 0.38; 95% CI: 0.15 to 0.98; P = 0.04). Conclusions: Despite no beneficial effect of LT4 therapy in reducing preterm delivery in SCH-TPOAb- women with a TSH cut point of 2.5 to 4 mIU/L, LT4 could precisely decrease this complication using the newly recommended cutoff >=4.0 mIU/L. PMID- 29126291 TI - The dynamic development of germ cells during chicken embryogenesis. AB - Appropriate regulation of cell proliferation during embryogenesis is crucial for the maintenance of germness. An in-depth understanding of germ cell developmental processes may yield valuable information on germ cell biology and applied sciences. However, direct evidences about germ cell proliferation and cell cycling during avian embryonic development has not been well-studied. Thus, we explored chicken germ cell dynamics during embryonic development via flow cytometry employing a germ cell-specific anti-cVASA antibody (the chicken VASA homolog is termed CVH) and propidium iodide staining. The numbers of male germ cells increased significantly during early embryonic development, but proliferation was decreased significantly with accumulation at the G0/G1 phase after embryonic d 14 (E.14), indicating initiation of mitotic arrest in the testis. On the other hand, the number of female germ cells increased significantly throughout embryogenesis, and proliferating cells were continuously evident in the ovary to the time of hatching, although gradual accumulation of cells at the G2/M phase was also evident. 5-ethynyl-2?-deoxyuridine (EdU) incorporation analysis revealed that populations of mitotically active germ cells existed in both sexes during late embryogenesis, indicating either the maintenance of stem cell populations, or asynchronous meiosis. Collectively, these results indicate that chicken germ cells exhibited conserved developmental processes that were clearly sexually dimorphic. PMID- 29126293 TI - Commentary on: Effect of Use of Platelet-Rich Plasma (PRP) in Skin With Intrinsic Aging Process. PMID- 29126292 TI - Safety and Immunogenicity of Inactivated Varicella-Zoster Virus Vaccine in Adults With Autoimmune Disease: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Trial. AB - Background: Immunogenicity and safety of inactivated zoster vaccine (ZVIN) were evaluated in adults with autoimmune disease. Methods: Adults with autoimmune disease treated with immunosuppressive therapy (biologic or nonbiologic) were randomized to receive 4 doses of ZVIN, ZVIN containing a higher quantity of antigen, or placebo. To measure varicella-zoster virus (VZV)-specific immune responses using glycoprotein enzyme-linked immunosorbent assay (gpELISA) and interferon-gamma enzyme-linked immunospot (IFN-gamma ELISPOT), blood samples were collected at baseline, post-doses 2, 3, and 4. The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses, measured by gpELISA or ELISPOT, at approximately 28 days post-dose 4. Safety and tolerability was assessed through 28 days post-dose 4. Results: ZVIN elicited a statistically significant VZV-specific immune response approximately 28 days post-dose 4, measured by gpELISA (estimated geometric mean fold rise from baseline [GMFR] = 1.6 [95% confidence interval [CI], 1.4,1.7], P value < .0001) and IFN-gamma ELISPOT (estimated GMFR = 2.0 [95% CI, 1.6,2.6], P value < .0001); both results met the prespecified success criterion. Overall, 57% (164/289) of all ZVIN and 21% (13/62) of placebo recipients reported >=1 injection-site adverse events (AEs), and 52% (149/289) and 47% (29/62) reported >=1 systemic AEs, respectively. Eight ZVIN and 1 placebo recipients experienced serious AEs, including 2 events (ZVIN group) determined by the investigator to be vaccine related (keratitis; amnesia). Overall frequency of AEs decreased with subsequent doses of vaccine. Conclusions: In adults with autoimmune disease, ZVIN was well tolerated and elicited statistically significant VZV-specific immune responses approximately 28 days post-dose 4, measured by gpELISA and IFN-gamma ELISPOT. Clinical Trials Registration: NCT01527383. PMID- 29126295 TI - MoonProt 2.0: an expansion and update of the moonlighting proteins database. AB - MoonProt 2.0 (http://moonlightingproteins.org) is an updated, comprehensive and open-access database storing expert-curated annotations for moonlighting proteins. Moonlighting proteins contain two or more physiologically relevant distinct functions performed by a single polypeptide chain. Here, we describe developments in the MoonProt website and database since our previous report in the Database Issue of Nucleic Acids Research. For this V 2.0 release, we expanded the number of proteins annotated to 370 and modified several dozen protein annotations with additional or updated information, including more links to protein structures in the Protein Data Bank, compared with the previous release. The new entries include more examples from humans and several model organisms, more proteins involved in disease, and proteins with different combinations of functions. The updated web interface includes a search function using BLAST to enable users to search the database for proteins that share amino acid sequence similarity with a protein of interest. The updated website also includes additional background information about moonlighting proteins and an expanded list of links to published articles about moonlighting proteins. PMID- 29126296 TI - Reply to Steptoe et al. PMID- 29126294 TI - GnRH Neurons on LSD: A Year of Rejecting Hypotheses That May Have Made Karl Popper Proud. AB - Gonadotropin-releasing hormone (GnRH) neurons are critical to many aspects of fertility regulation, from producing episodic release critical to both sexes, to providing a central signal to induce the ovulatory cascade in females. This year saw progress through the rejection, and occasional support, of hypotheses in understanding how GnRH neurons contribute to these processes. This brief review provides one laboratory's view of new insights into possible roles for these cells in development, adult reproductive function, and what may go wrong with GnRH neurons in some cases of infertility. PMID- 29126297 TI - Tellurate enters Escherichia coli K-12 cells via the SulT-type sulfate transporter CysPUWA. AB - Soluble forms of tellurium are environmental contaminants that are toxic to microorganisms. While tellurite [Te(IV)] is a well-characterized antimicrobial agent, little is known about the interactions of tellurate [Te(VI)] with bacterial cells. In this study, we investigated the role of sulfate transporters in the uptake of tellurate in Escherichia coli K-12. Mutant strains carrying a deletion of the cysW gene in the CysPUWA sulfate transporter system accumulated less cellular tellurium and exhibited higher resistance to tellurate compared with the wild-type strain. Complementation of the mutation restored tellurate sensitivity and uptake. These results indicate that tellurate enters E. coli cells to cause toxic effects via the CysPUWA sulfate transporter. PMID- 29126298 TI - What Proportion of People Who Try One Cigarette Become Daily Smokers? A Meta Analysis of Representative Surveys. AB - Introduction: The "conversion rate" from initial experimentation to daily smoking is a potentially important metric of smoking behavior, but estimates of it based on current representative data are lacking. Methods: The Global Health Data Exchange was searched for representative surveys conducted in English speaking, developed countries after the year 2000 that included questions about ever trying a cigarette and ever smoking daily. The initial search identified 2776 surveys that were further screened for language, location, year, sample size, survey structure, and representativeness. Forty-four surveys that passed the screening process were accessed, and their codebooks were examined to see whether the two questions of interest were included. Eight datasets allowed extraction or estimation of relevant information. Survey quality was assessed with regards to response rates, sampling methods, and data collection procedures. PRISMA guidelines were followed, with explicit rules for approaching derived variables and skip patterns. Proportions were pooled using random effects meta-analysis. Results: The eight surveys used representative samples of the general adult population. Response rates varied from 45% to 88%. Survey methods were on par with the best practice in this field. Altogether, 216314 respondents were included of whom 60.3% (95% CI = 51.3 to 69.3) ever tried a cigarette. Among them, 68.9% (95% CI = 60.9 to 76.9%) progressed to daily smoking. Conclusions: Over two-thirds of people who try one cigarette become, at least temporarily, daily smokers. The finding provides strong support for the current efforts to reduce cigarette experimentation among adolescents. Implications: The transition from trying the first cigarette through occasional to daily smoking usually implies that a recreational activity is turning into a compulsive need that has to be satisfied virtually continuously. The "conversion rate" from initial experimentation to daily smoking is thus a potentially important metric of smoking behavior, but estimates of it based on representative data are lacking. The present meta-analysis addressed this gap. Currently, about two-thirds of nonsmokers experimenting with cigarettes progress to daily smoking. The finding supports strongly the current efforts to reduce cigarette experimentation among adolescents. PMID- 29126299 TI - CNS penetration of ART in HIV-infected children. AB - Background: Paediatric data on CNS penetration of antiretroviral drugs are scarce. Objectives: To evaluate CNS penetration of antiretroviral drugs in HIV infected children and explore associations with neurocognitive function. Patients and methods: Antiretroviral drug levels were measured in paired CSF and blood samples of clinically stable HIV-infected children between 8 and 18 years old on long-term combined ART. Plasma drug concentrations were corrected for protein binding. We evaluated CNS penetration using CSF/plasma ratios and compared CSF concentrations with the IC50 as a surrogate marker for effectiveness. Blood-brain barrier permeability was assessed for possible confounding. Associations with neurocognitive function were explored using linear regression analysis. Results: Median CSF/plasma ratios (IQR) were: lopinavir 0.059 (0.024-0.157, n = 7), efavirenz 0.681 (0.555-0.819, n = 12), tenofovir 0.021 (0.020-0.024, n = 4), lamivudine 0.464 (0.331-0.607, n = 17), emtricitabine 0.365 (0.343-0.435, n = 3), nevirapine 1.203 (n = 1), zidovudine 0.718 (0.711-1.227, n = 5) and abacavir 1.344 (0.670-2.450, n = 10). CSF concentrations were below the IC50 for tenofovir (100%), emtricitabine (100%), abacavir (50%) and zidovudine (17%). Lamivudine, lopinavir, efavirenz and nevirapine concentrations were all above the IC50. All participants were virologically suppressed in blood and CSF. CSF drug concentrations were not associated with blood-brain barrier permeability or neurocognitive function. Conclusions: We showed adequate CSF concentrations of lamivudine, lopinavir, efavirenz and nevirapine, and potential suboptimal CSF concentrations of tenofovir, abacavir and emtricitabine in long-term treated HIV infected children. None the less, the use of combined antiretroviral drugs led to adequate viral suppression. PMID- 29126300 TI - Deproteinization is Necessary for the Accurate Determination of Ammonia Levels by Glutamate Dehydrogenase Assay in Blood Plasma From Subjects With Liver Injury. AB - Objective: To determine the effect of presence of high concentrations of nicotinamide adenine dinucleotide (NADH)- and nicotinamide adenine dinucleotide phosphate (NADPH)-consuming enzymes on the accuracy of glutamate dehydrogenase (GLDH) assay for ammonia. Methods: We measured ammonia concentrations using GLDH and NADH or NADPH in blood-plasma specimens and specimens deproteinized by sulfosalicylic acid from CCl4-treated or control rats. The nonspecific oxidation of NADH and NADPH was measured in mixtures without GLDH. Results: We observed a gradual decrease (~0.5%) in absorbance in the plasma of controls after the addition of NADH but not after adding NADPH. The decrease in absorbance in plasma of CCl4-treated animals was 13.2% and 5.2% after the addition of NADH and NADPH, respectively. The decrease in absorbance was not detected in deproteinized specimens. The values of ammonia concentration were higher in the plasma specimens compared with the deproteinized ones. Conclusion: Deproteinization is necessary for accurate measurement of ammonia using GLDH assay in the blood plasma of subjects with liver injury. PMID- 29126301 TI - Coagulation Testing in the Core Laboratory. AB - Primary hemostasis begins with endothelial injury. VWF, produced by endothelial cells, binds to platelets and links them to subendothelial collagen. Platelet derived ADP and thromboxane activate non-adhered platelets via their GPIIb/IIIa receptors, allowing these platelets to participate in platelet aggregation. Secondary hemostasis is initiated with the binding of factor VII to extravascular tissue factor (TF). Factors II, VII, IX and X are vitamin K-dependent factors. The role of vitamin K is to assist in the addition of gamma carboxylate groups to glutamic acids in the "GLA" domains of these factors.In vitro the intrinsic pathway is initiated when fresh whole blood is placed in a glass tube. The negative charge of the glass initiates the "contact pathway" where FXII is activated and then FXIa cleaves FIX to FIXa. The extrinsic pathway is triggered when tissue factor, phospholipid and calcium are added to plasma anticoagulated with citrate. In vitro, FVII is activated to FVIIa, and TF-FVIIa preferentially converts FX to FXa activating the common pathway.The prothrombin time is commonly used to monitor warfarin anticoagulant therapy. To correct for differences in reagent and instrument, the international normalized ratio was developed to improve standardization of PT reporting globally. The activated partial thromboplastin time (aPTT) is used to evaluate the intrinsic and common pathways of coagulation. The aPTT is useful clinically as a screening test for inherited and acquired factor deficiencies as well as to monitor unfractionated heparin therapy although the anti-Xa assay is now the preferred measure of the effects of unfractionated heparin. The Clauss assay is the most commonly performed fibrinogen assay and uses diluted plasma where clotting is initiated with a high concentration of reagent thrombin.The mixing study assists in the assessment of an abnormally prolonged PT or aPTT. An equal volume of citrated patient plasma is mixed with normal pooled plasma and the PT or aPTT are repeated on the 1:1 mix. Factor activity assays are most commonly performed as a one-stage assay. The patient's citrated plasma is diluted and mixed 1-to-1 with a single factor deficient substrate plasma. A PT or aPTT is performed on the above mix, depending on the factor being tested.Factor inhibitors are antibodies that are most commonly diagnosed in male patients with severe hemophilia A (FVIII deficiency) where they are induced by factor replacement therapy.Factor inhibitors can also appear in the form of spontaneous autoantibodies in both male and female individuals who were previously well. This is an autoimmune condition called "acquired hemophilia."Most coagulation laboratories can measure the plasma concentration of VWF protein (VWF antigen) by an immunoturbidimetric technique. Testing the functional activity of VWF, utilizes the drug ristocetin.The state of multimerization of VWF is important and is assessed by electrophoresis on agarose gels. Type 2a and 2b VWD are associated with the lack of intermediate- and high molecular weight multimers.The antiphospholipid syndrome (APLS) is an acquired autoimmune phenomenon associated with an increased incidence of both venous and arterial thromboses, as well as fetal loss. Typically, there is a paradoxical prolongation of the aPTT in the absence of any clinical features of bleeding. This is the so-called "lupus anticoagulant (LA) effect." The laboratory definition of the APLS requires the presence of either a "lupus anticoagulant" or a persistent titer of antiphospholipid antibodies.There are now 2 broad classes of direct-acting oral anticoagulants (DOACs): [1] The oral direct thrombin inhibitors (DTIs) such as dabigatran; and [2] The oral direct factor Xa inhibitors such as rivaroxaban and apixaban. The PT and aPTT are variably affected by the DOACs and are generally unhelpful in monitoring their concentrations. Most importantly, a normal PT or aPTT does NOT exclude the presence of any of the DOACs. PMID- 29126302 TI - The Clinical Utility of Measuring IgG Subclass Immunoglobulins During Immunological Investigation for Suspected Primary Antibody Deficiencies. AB - Measurement of IgG subclass concentrations is a standard laboratory test run as part of a panel to investigate the suspicion of antibody deficiency. The assessment is clinically important when total IgG is within the normal age specific reference range. The measurement is useful for diagnosis of IgG subclass deficiency, to aid the diagnosis of specific antibody deficiency, as a supporting test for the diagnosis of common variable immunodeficiency, as well as for risk stratification of patients with low IgA. The measurement of IgG subclasses may also help determine a revaccination strategy for patients and support patient management. In certain circumstances, the measurement of IgG subclasses may be used to monitor a patient's humoral immune system. In this review, we discuss the utility of measuring IgG subclass concentrations. PMID- 29126304 TI - SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas. AB - Context: Germline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHx mutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB immunostaining has also been found in a subset of PGLs that lack SDHx mutations. Settings: Here, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations. Results: Integration of multiplatform data revealed somatic SDHC methylation and loss of the 1q23.3 region containing the SDHC gene. This correlated with decreased SDHC messenger RNA (mRNA) and protein levels. Furthermore, another genetic event found affected the VHL gene, which showed a decreased DNA copy number, associated with low VHL mRNA levels, and an absence of VHL protein detected by immunohistochemistry. In addition, the tumor displayed a pseudohypoxic phenotype consisting in overexpression of the hypoxia-inducible factor (HIF)-1alpha and miR-210, as well as downregulation of the iron-sulfur cluster assembly enzyme (ISCU) involved in SDHB maturation. This profile resembles that of SDHx- or VHL-mutated PGLs but not of PGLs with decreased VHL copy number, pointing to SDHC rather than VHL as the pathogenic driver. Conclusions: Collectively, these findings demonstrate the potential importance of both the SDHC epigenomic event and the activation of the HIF-1alpha/miR-210/ISCU axis in the pathogenesis of SDHx wild-type/SDHB-negative PGLs. To our knowledge, this is the first case of a sporadic parasympathetic PGL that carries silencing of SDHC, fulfilling the two-hit Knudson's model for tumorigenesis. PMID- 29126303 TI - Inhibition of the Mitochondrial Pyruvate Carrier by Tolylfluanid. AB - Several recent studies have suggested that compounds known as endocrine disrupting chemicals (EDCs) can promote obesity by serving as ligands for nuclear receptors, including the peroxisome proliferator-activated receptor gamma (PPARgamma) and the glucocorticoid receptor (GR). Thiazolidinedione insulin sensitizers, which act as ligands for PPARgamma, also interact with and regulate the activity of the mitochondrial pyruvate carrier (MPC). We evaluated whether several EDCs might also affect MPC activity. Most of the EDCs evaluated did not acutely affect pyruvate metabolism. However, the putative endocrine disruptors tributyltin (TBT) and tolylfluanid (TF) acutely and markedly suppressed pyruvate metabolism in isolated mitochondria. Using mitochondria isolated from brown adipose tissue in mice with adipocyte-specific deletion of the MPC2 protein, we determined that the effect of TF on pyruvate metabolism required MPC2, whereas TBT did not. We attempted to determine whether the obesogenic effects of TF might involve MPC2 in adipose tissue. However, we were unable to replicate the published effects of TF on weight gain and adipose tissue gene expression in wild type or fat-specific MPC2 knockout mice. Treatment with TF modestly enhanced adipogenic gene expression in vitro but had no effect on GR activation or phosphorylation in cultured cells. These data suggest that TF may affect mitochondrial pyruvate metabolism via the MPC complex but also call into question whether this compound affects GR activity and is obesogenic in mice. PMID- 29126305 TI - Membranome 2.0: database for proteome-wide profiling of bitopic proteins and their dimers. AB - Motivation: Structural studies of TM domains of single-spanning (bitopic) membrane proteins are impeded by their instability, flexibility and heterogeneity. The new computational method TMDOCK allows reliable modeling of homodimers of transmembrane (TM) alpha-helices on a proteomic scale. Results: 3D models of 2129 parallel homodimers formed by TM alpha-helices of bitopic proteins from six evolutionarily distant organisms were modeled by TMDOCK, verified through experimental data available for nearly 600 proteins, and included in the Membranome database (v.2.0) along with related information to facilitate structural and evolutionary analysis of bitopic proteins. Availability and implementation: http://membranome.org. Contact: almz@umich.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29126307 TI - Universal correction of enzymatic sequence bias reveals molecular signatures of protein/DNA interactions. AB - Coupling molecular biology to high-throughput sequencing has revolutionized the study of biology. Molecular genomics techniques are continually refined to provide higher resolution mapping of nucleic acid interactions and structure. Sequence preferences of enzymes can interfere with the accurate interpretation of these data. We developed seqOutBias to characterize enzymatic sequence bias from experimental data and scale individual sequence reads to correct intrinsic enzymatic sequence biases. SeqOutBias efficiently corrects DNase-seq, TACh-seq, ATAC-seq, MNase-seq and PRO-seq data. We show that seqOutBias correction facilitates identification of true molecular signatures resulting from transcription factors and RNA polymerase interacting with DNA. PMID- 29126308 TI - Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction. AB - Background: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central mediator of cellular responses to oxidative stress. We hypothesized that Nrf2 modulates progression from acute tubular damage to renal fibrosis. We asked whether Nrf2 deletion increases renal injury in mice following unilateral ureteral obstruction (UUO). Methods: We explored the time course of renal injury and Nrf2 expression in Nrf2+/+ mice following UUO. We compared Nrf2+/+ and Nrf2-/ mice following UUO in tubular damage, transdifferentiation [vimentin, proliferating cell nuclear antigen (PCNA)], fibrosis [fibronectin, alpha-smooth muscle actin (SMA)], antioxidative and inflammatory responses. We studied Nrf2 in renal biopsies of patients with acute, subacute and chronic tubulointerstitial nephritis (TIN). Results: In Nrf2+/+ mice, renal Nrf2 expression and Nrf2 regulated glutamate-cysteine ligase catalytic (Gclc) and heme oxygenase-1 (Ho-1) were elevated, and renal injury occurred between 2 and 14 days after UUO. On Day 2 following UUO, in Nrf2-/- mice compared with Nrf2+/+ mice, tubular damage, apoptotic cell numbers, cleaved caspase3 and cleaved-poly ADP-ribose polymerase were increased. On Day 5, protein levels of vimentin and PCNA and the co expressed cells of both proteins were increased. On Day 14, fibronectin and alpha SMA protein levels were increased. Nrf2 deletion decreased expression of antioxidative genes (Gclc and Ho-1) and increased expression of inflammatory response genes (Tgfbeta, Tnf, IL-6, IL-1beta and F4/80). Finally, Nrf2 expression was upregulated in renal biopsies of patients with TIN. Conclusions: Following UUO, Nrf2 deficiency increased tubular damage, transdifferentiation, fibrosis and inflammatory response while decreasing antioxidative responses. The renal protective role of Nrf2 in the development of tubulointerstitial fibrosis in UUO may be mediated by antioxidative and anti-inflammatory pathways. PMID- 29126309 TI - A CPAnet consensus statement on research priorities for chronic pulmonary aspergillosis: a neglected fungal infection that requires attention. AB - Chronic pulmonary aspergillosis (CPA) is a severe fungal infection with a high morbidity and mortality, and is usually seen in immunocompetent patients with respiratory disorders. Clinical presentation is nonspecific and often overlaps with the symptoms and the radiological pattern caused by the underlying disease. Clinical management of CPA is further hampered by limited information about the epidemiology, disease dynamics, sensitivity and specificity of different mycological tests, mechanisms of antifungal resistance, efficient treatment and management strategies. In order to contribute to a better understanding and to improve CPA patient management and outcome, we established the Chronic Pulmonary Aspergillosis Network (CPAnet), a self-organized multinational research collaboration. Key research priorities, defined by using a modified Delphi process, include the establishment of a multinational web-based registry, the validation of different diagnostic tests, the establishment of a culture collection from samples of patients with proven CPA and the establishment of a consensus on a treatment outcome definition. PMID- 29126310 TI - Current Epidemiology and Trends in Meningococcal Disease-United States, 1996 2015. AB - Background: In 2005, meningococcal conjugate vaccine (MenACWY) was recommended for routine use among adolescents aged 11-18 years. This report describes the epidemiologic features of meningococcal disease and trends in meningococcal disease incidence following MenACWY introduction in the United States. Methods: Incidence rates and case-fatality ratios by age group and serogroup during 2006 2015 were calculated using data from the National Notifiable Diseases Surveillance System (NNDSS); changes in incidence during this time were evaluated. Additionally, 20-year trends (1996-2015) in age- and race-standardized incidence were examined using data from Active Bacterial Core surveillance (ABCs). Results: During the years 2006-2015, 7924 cases of meningococcal disease were reported to NNDSS, resulting in an average annual incidence of 0.26 cases per 100000 population; 14.9% of cases were fatal. Among cases with serogroup information, 2290 (35.8%) were serogroup B, 1827 (28.5%) were serogroup Y, 1457 (22.8%) were serogroup C, 436 (6.8%) were serogroup W, and 392 (6.1%) were other serogroups. The incidence of serogroups A, C, W, and Y combined declined 76% among persons aged 11-20 years from 2006-2010 to 2011-2015 (P < .0001). From 1996 through 2015, the incidence of meningococcal disease declined among all age groups and predominant serogroups. Conclusions: Declines in meningococcal disease incidence in the United States have been observed among all age groups and predominant serogroups (B, C, and Y). Reductions in the incidence of meningococcal disease due to serogroups A, C, W, and Y among adolescents suggest an impact of the MenACWY vaccine program in this age group. PMID- 29126306 TI - The Future of Radiobiology. AB - Innovation and progress in radiation oncology depend on discovery and insights realized through research in radiation biology. Radiobiology research has led to fundamental scientific insights, from the discovery of stem/progenitor cells to the definition of signal transduction pathways activated by ionizing radiation that are now recognized as integral to the DNA damage response (DDR). Radiobiological discoveries are guiding clinical trials that test radiation therapy combined with inhibitors of the DDR kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and immune or cell cycle checkpoint inhibitors. To maintain scientific and clinical relevance, the field of radiation biology must overcome challenges in research workforce, training, and funding. The National Cancer Institute convened a workshop to discuss the role of radiobiology research and radiation biologists in the future scientific enterprise. Here, we review the discussions of current radiation oncology research approaches and areas of scientific focus considered important for rapid progress in radiation sciences and the continued contribution of radiobiology to radiation oncology and the broader biomedical research community. PMID- 29126313 TI - Comment on: Kidney disease in primary antiphospholipid antibody syndrome. PMID- 29126311 TI - Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort. AB - Background: Henoch-Schonlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods: This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results: We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1beta, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P < 0.005 for all comparisons). After follow-up (1 year), 22 patients showed a poor outcome. Among the tested markers, urine IgA at disease onset adequately reclassified the risk of poor outcome over conventional clinical factors, including estimated glomerular filtration rate, proteinuria and age (continuous net reclassification improvement = 0.72, P = 0.001; integrated discrimination improvement = 0.13, P = 0.009) in IgAV patients. Conclusions: Taken together, these results showed that serum Gd-IgA1 and urinary IgA, IgG, IgM, NGAL, IL 1beta, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were associated with nephritis in IgAV patients. Urinary IgA level may improve patient risk stratification for poor outcome. PMID- 29126312 TI - MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome. AB - Methyltranscriptome is an exciting new area that studies the mechanisms and functions of methylation in transcripts. A knowledge base with the systematic collection and curation of context specific transcriptome-wide methylations is critical for elucidating their biological functions as well as for developing bioinformatics tools. Since its inception in 2014, the Met-DB (Liu, H., Flores, M.A., Meng, J., Zhang, L., Zhao, X., Rao, M.K., Chen, Y. and Huang, Y. (2015) MeT DB: a database of transcriptome methylation in mammalian cells. Nucleic Acids Res., 43, D197-D203), has become an important resource for methyltranscriptome, especially in the N6-methyl-adenosine (m6A) research community. Here, we report Met-DB v2.0, the significantly improved second version of Met-DB, which is entirely redesigned to focus more on elucidating context-specific m6A functions. Met-DB v2.0 has a major increase in context-specific m6A peaks and single-base sites predicted from 185 samples for 7 species from 26 independent studies. Moreover, it is also integrated with a new database for targets of m6A readers, erasers and writers and expanded with more collections of functional data. The redesigned Met-DB v2.0 web interface and genome browser provide more friendly, powerful, and informative ways to query and visualize the data. More importantly, MeT-DB v2.0 offers for the first time a series of tools specifically designed for understanding m6A functions. Met-DB V2.0 will be a valuable resource for m6A methyltranscriptome research. The Met-DB V2.0 database is available at http://compgenomics.utsa.edu/MeTDB/ and http://www.xjtlu.edu.cn/metdb2. PMID- 29126314 TI - Cost-effectiveness Analysis of Nivolumab for Treatment of Platinum-Resistant Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. AB - Background: The CheckMate 141 trial found that nivolumab improved survival for patients with recurrent or metastatic head and neck cancer (HNC). Despite the improved survival, nivolumab is much more expensive than standard therapies. This study assesses the cost-effectiveness of nivolumab for the treatment of HNC. Methods: We constructed a Markov model to simulate treatment with nivolumab or standard single-agent therapy for patients with recurrent or metastatic platinum refractory HNC. Transition probabilities, including disease progression, survival, and probability of toxicity, were derived from clinical trial data, while costs (in 2017 US dollars) and health utilities were estimated from the literature. Incremental cost-effectiveness ratios (ICERs), expressed as dollar per quality-adjusted life-year (QALY), were calculated, with values of less than $100 000/QALY considered cost-effective from a health care payer perspective. We conducted one-way and probabilistic sensitivity analyses to assess model uncertainty. Results: Our base case model found that treatment with nivolumab increased overall cost by $117 800 and improved effectiveness by 0.400 QALYs compared with standard therapy, leading to an ICER of $294 400/QALY. The model was most sensitive to the cost of nivolumab, though nivolumab only became cost effective if the cost per cycle decreased from $13 432 to $3931. The model was not particularly sensitive to assumptions about survival. If one assumed that all patients alive at the end of the CheckMate 141 trial were cured of their disease, nivolumab was still not cost-effective (ICER $244 600/QALY). Conclusion: While nivolumab improves overall survival, at its current cost it would not be considered a cost-effective treatment option for patients with HNC. PMID- 29126315 TI - Packaging of Mycobacterium smegmatis bacteria into fecal pellets by the ciliate Tetrahymena pyriformis. AB - Mycobacteria are widespread microorganisms that live in various environments, including man-made water systems where they cohabit with protozoa. Environmental mycobacterial species give rise to many opportunistic human infections and can infect phagocytic protozoa. Protozoa such as amoebae and ciliates feeding on bacteria can sometimes get rid of non-digestible or pathogenic material by packaging it into secreted fecal pellets. Usually, packaged bacteria are still viable and are protected against chemical and physical stresses. We report here that mycobacteria can be packaged into pellets by ciliates. The model bacterium Mycobacterium smegmatis survived digestion in food vacuoles of the ciliate Tetrahymena pyriformis and was included in expelled fecal pellets. LIVE/DEAD(r) staining confirmed that packaged M. smegmatis cells preserved their viability through the process. Scanning and transmission electron microscopy revealed that bacteria are packaged in undefined filamentous and/or laminar substances and that just a thin layer of material seemed to keep the pellet contents in a spherical shape. These results imply that packaging of bacteria is more common than expected, and merits further study to understand its role in persistence and dissemination of pathogens in the environment. PMID- 29126316 TI - The Reciprocal Relationship Between Social Connectedness and Mental Health Among Older European Adults: A SHARE-Based Analysis. AB - Objectives: The current study aimed to understand the reciprocal relationship between social networks and mental health in old age. It explored the dynamic aspects of that relationship and assessed the influence of social networks on mental health, as well as a concurrent influence of mental health on change in social connectedness. Method: The data came from two measurement points in the Survey of Health, Aging and Retirement in Europe (SHARE). The analytic sample was composed of adults aged 65 years and above (N = 14,706). Analyses were conducted via latent change score models. Results: Analyses showed a reciprocal association between social networks and mental health; baseline social connectedness led to mental health improvements and a better initial mental state led to richer social networks. The results further indicated that the relative effect of mental health on change in social network connectedness was greater than the corresponding effect of social network connectedness on change in mental health. No gender differences were found regarding the reciprocal associations. Discussion: The results of this study demonstrate the dynamic inter-relationship of social networks and mental health. It highlights the need to take into account both directions of influence when studying the impact of social relationships on mental health. PMID- 29126317 TI - Inflammation: friend or foe for animal production? AB - Inflammation is an essential immune response that seeks to contain microbial infection and repair damaged tissue. Increased pro-inflammatory mediators have been associated with enhanced resistance to a range of important poultry and pig pathogens. However, inflammation may also have undesirable consequences, including potentially exacerbating tissue damage and diverting nutrients away from productive purposes. The negative effects of inflammation have led to the active pursuit of anti-inflammatory feed additives and/or strategies. These approaches may, however, impair the ability of an animal to respond appropriately and effectively to the array of pathogens that are likely to be encountered in commercial production, and specifically young animals who may be particularly reliant on innate immune responses. Thus, promoting an animal's capacity to mount a rapid, acute inflammatory response to control and contain the infection and the timely transition to anti-inflammatory, tissue repair processes, and a homeostatic state are suggested as the optimum scenario to maintain an animal's resistance to pathogens and minimize non-productive nutrient losses. Important future studies will help to unravel the trade-offs, and relevant metabolic pathways, between robust immune defense and optimum productive performance, and thus provide real insight into methods to appropriately influence this relationship. PMID- 29126319 TI - Effects of Vitamin D Supplementation on Semen Quality, Reproductive Hormones, and Live Birth Rate: A Randomized Clinical Trial. AB - Context: Results of animal models and cross-sectional cohort studies have suggested a beneficial role for vitamin D in male reproduction. Objective: Determine the effect of vitamin D and calcium supplementation on semen quality in infertile men with serum 25-hydroxyvitamin-D (25OHD) levels <=50 nmol/L. Design: A single-center, triple-blinded, randomized clinical trial. Participants: A total of 1427 infertile men were screened to include 330; 1002 men did not meet inclusion criteria and 95 did not wish to participate. Intervention: The active group received cholecalciferol 300,000 IU initially, then 1400 IU cholecalciferol and 500 mg of calcium daily for 150 days; the other group received placebo. Results: Serum concentrations of 25OHD and 1,25-dihydroxyvitamin D3 were significantly higher in men in the treatment group compared with the placebo group. Vitamin D supplementation was not associated with changes in semen parameters, although spontaneous pregnancies tended to be higher in couples in which the man was in the treatment group [7.3% vs 2.4%, Delta5.0% (-0.6%; 10.5%)]. Vitamin D treatment in a subgroup of oligozoospermic men increased the chance for a live birth compared with placebo [35.6% vs 18.3%, Delta17.3% (1.6%; 32.9%)]. Moreover, serum inhibin B levels were higher in men deficient in vitamin D who were randomly assigned to receive high-dose vitamin D [193 pg/mL vs 143 pg/mL, Delta49 pg/mL (8; 91 pg/mL)]; however, the increase in sperm concentration was not significantly higher than in the placebo group (P = 0.07). Conclusion: High-dose vitamin D supplementation did not improve semen quality in vitamin D insufficient infertile men. The positive impact of vitamin D supplementation on live birth rate and serum inhibin B in oligozoospermic and vitamin D-deficient men may be of clinical importance and warrant verification by others. PMID- 29126318 TI - RNase H sequence preferences influence antisense oligonucleotide efficiency. AB - RNase H cleaves RNA in RNA-DNA duplexes. It is present in all domains of life as well as in multiple viruses and is essential for mammalian development and for human immunodeficiency virus replication. Here, we developed a sequencing-based method to measure the cleavage of thousands of different RNA-DNA duplexes and thereby comprehensively characterized the sequence preferences of HIV-1, human and Escherichia coli RNase H enzymes. We find that the catalytic domains of E. coli and human RNase H have nearly identical sequence preferences, which correlate with the efficiency of RNase H-recruiting antisense oligonucleotides. The sequences preferred by HIV-1 RNase H are distributed in the HIV genome in a way suggesting selection for efficient RNA cleavage during replication. Our findings can be used to improve the design of RNase H-recruiting antisense oligonucleotides and show that sequence preferences of HIV-1 RNase H may have shaped evolution of the viral genome and contributed to the use of tRNA-Lys3 as primer during viral replication. PMID- 29126320 TI - Screening lactic acid bacteria to manufacture two-stage fermented feed and pelleting to investigate the feeding effect on broilers. AB - Bacillus subtilis var. natto N21 (BS) and different lactic acid bacteria were applied to produce two-stage fermented feeds. Broilers were fed these feeds to select the best fermented feed. The selected fermented feed was pelleted and investigated for its effects on growth performance, carcass traits, intestinal microflora, serum biochemical constituents, and apparent ileal nutrient digestibility. Trial 1 involved three hundred thirty-six 1-d-old broilers with equal numbers of each sex, randomly assigned into control, BS + Bacillus coagulans L12 (BBC), BS + Lactobacillus casei (BLC), BS + Lactobacillus acidophilus (BLA), BS + Lactobacillus acidophilus L15 (BLA15), BS + Lactobacillus delbruekckii (BLD), and BS + Lactobacillus reuteri P24 (BLR24) groups with 3 replicates per group. Trial 2 involved two hundred forty 1-d-old broilers with equal numbers of each sex, randomly assigned into control, BBC, and pelleted BS + Bacillus coagulans L12 fermented feed (PBBC) groups with 4 replicates per group. Trial 3 involved sixteen 21-d-old male broilers randomly assigned into control and PBBC groups with 4 replicates per group for a nutrient digestibility trial. The feed conversion ratio (FCR) in the BBC group was better than the control (P < 0.05), and the production efficiency factor (PEF) was the best. However, weight gain (WG), feed intake (FI), and PEF were the lowest in the BLD group (P < 0.05). The WG during 0 to 21 d and 0 to 35 d in the PBBC groups were higher than the control (P < 0.05). The relative weight of the proventriculus + gizzard in the BBC and PBBC groups were higher than the control (P < 0.05). The digestible amino acid content in the PBBC group increased significantly (P < 0.05). Bacillus coagulans L12 is the best lactic acid bacteria for second stage fermentation. PBBC improved broiler growth performance, which may be due to the higher digestible amino acid content, it has the potential to become a commercial feed. PMID- 29126321 TI - Reciprocal Nucleopeptides as the Ancestral Darwinian Self-Replicator. AB - Even the simplest organisms are too complex to have spontaneously arisen fully formed, yet precursors to first life must have emerged ab initio from their environment. A watershed event was the appearance of the first entity capable of evolution: the Initial Darwinian Ancestor. Here, we suggest that nucleopeptide reciprocal replicators could have carried out this important role and contend that this is the simplest way to explain extant replication systems in a mathematically consistent way. We propose short nucleic acid templates on which amino-acylated adapters assembled. Spatial localization drives peptide ligation from activated precursors to generate phosphodiester-bond-catalytic peptides. Comprising autocatalytic protein and nucleic acid sequences, this dynamical system links and unifies several previous hypotheses and provides a plausible model for the emergence of DNA and the operational code. PMID- 29126324 TI - A Moth and Its Flame: Mate Selection Found to Evolve from Response to Flower Odors. PMID- 29126323 TI - New Approach to Antibiotic Therapy is a Dead End for Pathogens. PMID- 29126322 TI - Characterization of Odorant Receptors from a Non-ditrysian Moth, Eriocrania semipurpurella Sheds Light on the Origin of Sex Pheromone Receptors in Lepidoptera. AB - Pheromone receptors (PRs) are essential in moths to detect sex pheromones for mate finding. However, it remains unknown from which ancestral proteins these specialized receptors arose. The oldest lineages of moths, so-called non ditrysian moths, use short-chain pheromone components, secondary alcohols, or ketones, so called Type 0 pheromones that are similar to many common plant volatiles. It is, therefore, possible that receptors for these ancestral pheromones evolved from receptors detecting plant volatiles. Hence, we identified the odorant receptors (ORs) from a non-ditrysian moth, Eriocrania semipurpurella (Eriocraniidae, Lepidoptera), and performed functional characterization of ORs using HEK293 cells. We report the first receptors that respond to Type 0 pheromone compounds; EsemOR3 displayed highest sensitivity toward (2S, 6Z)-6 nonen-2-ol, whereas EsemOR5 was most sensitive to the behavioral antagonist (Z)-6 nonen-2-one. These receptors also respond to plant volatiles of similar chemical structures, but with lower sensitivity. Phylogenetically, EsemOR3 and EsemOR5 group with a plant volatile-responding receptor from the tortricid moth Epiphyas postvittana (EposOR3), which together reside outside the previously defined lepidopteran PR clade that contains the PRs from more derived lepidopteran families. In addition, one receptor (EsemOR1) that falls at the base of the lepidopteran PR clade, responded specifically to beta-caryophyllene and not to any other additional plant or pheromone compounds. Our results suggest that PRs for Type 0 pheromones have evolved from ORs that detect structurally-related plant volatiles. They are unrelated to PRs detecting pheromones in more derived Lepidoptera, which, in turn, also independently may have evolved a novel function from ORs detecting plant volatiles. PMID- 29126325 TI - An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors. PMID- 29126326 TI - Cold Comfort: Fat-Rich Diets and Adaptation Among Indigenous Siberian Populations. PMID- 29126327 TI - Control versus cognition: the changing paradigm of adjuvant therapy for resected brain metastasis. PMID- 29126328 TI - Repeated Administration Effects on Psychomotor Vigilance Test Performance. AB - Study Objectives: The Psychomotor Vigilance Test (PVT) is reported to be free of practice effects that can otherwise confound the effects of sleep loss and circadian misalignment on performance. This differentiates the PVT from more complex cognitive tests. To the best of our knowledge, no study has systematically investigated practice effects on the PVT across multiple outcome domains, depending on administration interval, and in ecologically more valid settings. Methods: We administered a validated 3-minute PVT (PVT-B) 16 times in 45 participants (23 male, mean +/- SD age 32.6 +/- 7.3 years, range 25-54 years) with administration intervals of >=10 days, <=5 days, or 4 times per day. We investigated linear and logarithmic trends across repeated administrations in 10 PVT-B outcome variables. Results: The fastest 10% of response times (RT; plin = .0002), minimum RT (plog = .0010), and the slowest 10% of reciprocal RT (plog = .0124) increased while false starts (plog = 0.0050) decreased with repeated administration, collectively decreasing RT variability (plog = .0010) across administrations. However, the observed absolute changes were small (e.g., -0.03 false starts per administration, linear fit) and are probably irrelevant in practice. Test administration interval did not modify the effects of repeated administration on PVT-B performance (all p > .13 for interaction). Importantly, mean and median RT, response speed, and lapses, which are among the most frequently used PVT outcomes, did not change systematically with repeated administration. Conclusions: PVT-B showed stable performance across repeated administrations. Combined with its high sensitivity, this corroborates the status of the PVT as the de facto gold standard measure of the neurobehavioral effects of sleep loss and circadian misalignment. PMID- 29126329 TI - Effect of Benzo[a]Pyrene on Spindle Misorientation and Fidelity of Chromosome Segregation in Lung Epithelial BEAS-2B Cells. AB - Benzo[a]pyrene (B[a]P) is an environmental carcinogen found in tobacco smoke. It leads to high levels of DNA adducts in the lungs of cigarette smokers contributing to genomic instability. Alterations in the mitotic spindle apparatus play a major role in the generation of genomic instability through promoting chromosome mis-segregation and aneuploidy. To date, the effect of B[a]P exposure on altering the mitotic apparatus in normal lung epithelial cells remains unknown. In our study, BEAS-2B human bronchial epithelial cells were exposed to B[a]P and spindle dynamics were evaluated. Confocal imaging showed that B[a]P exposure significantly alters spindles misorientation, leading to chromosome mis segregations in the form of chromosome lags and bridges. In addition, centrosome duplication and premature centriole disengagement were induced leading to misaligned and multipolar spindle formation. Comparative genomic analysis of mitotic spindle associated genes, revealed downregulation of AurA-Plk1-AurB signaling cascade by B[a]P. In addition, we analyzed the status of p53 and its downstream p21 in B[a]P-treated cells and showed a suppression of p53-p21 axis. When the extent of DNA damage associated with induced mitotic abnormalities was investigated using gamma-H2AX, a significant increase and persistence in DNA damage was observed. Overall, our findings show that B[a]P potently induces mitotic abnormalities, DNA damage, and genetic instability. PMID- 29126330 TI - [Management of Complications of Pancreatic Anastomoses]. AB - BACKGROUND: The pancreatic anastomosis may be the Achilles heel in pancreatic surgery. When a postoperative pancreatic fistula develops, be it mild or severe, in some cases life-threatening, POPF-associated complications can occur. OBJECTIVES: Possibilities for the prophylaxis, diagnosis and therapy of POPF and POPF-associated complications in an interdisciplinary setting. RESULTS: Differentiated diagnostic and therapeutic management of POPF grade A - C is supported by recent studies to reduce morbidity and mortality. Depending on time and severity of POPF and POPF-associated complications, a conservative/interventional or surgical approach is indicated. CONCLUSION: With the precise classification of POPF and POPF-associated complications, interdisciplinary diagnostic and therapeutic management can reduce morbidity and mortality after pancreatic surgery. PMID- 29126331 TI - [A rare differential diagnosis of supraglottic oedema]. PMID- 29126332 TI - Correction: Do adjuvants add to the efficacy and tolerance of bowel preparations? A meta-analysis of randomized trials. PMID- 29126333 TI - Preliminary use of a double-flanged, fully covered, self-expandable, metal stent with cautery in endoscopic ultrasound-guided gastroenterostomy. PMID- 29126334 TI - Metastatic duodenal germ cell tumor diagnosed with endoscopic ultrasound. PMID- 29126335 TI - Line-assisted endoscopic complete closure of a large perforation during colonic endoscopic submucosal dissection. PMID- 29126336 TI - Sprint Interval Training Decreases Circulating MicroRNAs Important for Muscle Development. AB - Small non-coding RNAs, such as microRNAs (miRNAs), have emerged as powerful post transcriptional regulators of gene expression that play important roles in many developmental and biological processes. In this study, we assessed the abundance of circulating microRNAs important for skeletal muscle and heart adaptations to exercise (miR-1, miR-133a, miR-133b and miR-486), following acute exercise and short-term sprint interval training (SIT). Twenty-eight individuals completed four all-out efforts on a cycle ergometer, and donated blood before and 30 min after the cessation of exercise. A subset of 10 untrained men completed 4-6 efforts of SIT, three times a week for 6 weeks, and donated resting blood samples before and after the intervention. MiRNA TaqMan qPCR was performed and whilst no changes were observed after a single session of SIT (all p>0.05), the 6-wk SIT intervention significantly reduced the whole blood content of all four miRNAs (mean fold-changes: 0.37-0.48, all p<0.01). Our data suggests that circulating miRNAs are responsive to short-term SIT and could have roles in SIT-induced health and performance adaptations. Further work is required to establish whether circulating miRNAs could serve as biomarkers for predicting exercise training responses and monitoring exercise interventions. PMID- 29126337 TI - Factors Predicting Lower Leg Chronic Exertional Compartment Syndrome in a Large Population. AB - Knowledge about lower leg chronic exertional compartment syndrome (CECS) is largely obtained from highly selected populations. Patient characteristics may therefore not be appropriate for the general population. Our purpose was to describe a heterogeneous population of individuals suspected of lower leg CECS and to identify predictors of CECS. Charts of individuals who were analyzed for exercise-induced lower leg pain in a referral center between 2001 and 2013 were retrospectively studied. Patients were included if history and physical examination were suggestive of CECS and if they had undergone a dynamic intracompartmental pressure measurement. Six hundred ninety-eight of 1411 individuals were diagnosed with CECS in one or more of three lower leg muscle compartments (anterior tibial, deep flexor, lateral). Prevalence of CECS peaked around the age of 20-25 years and decreased thereafter, although a plateau around 50 years was found. Age, gender, bilateral symptoms, previous lower leg pathology, sports (running and skating) and tender muscle compartments were identified as independent predictors of lower leg CECS. The proposed predictive model has moderate discriminative ability (AUC 0.66) and good calibration over the complete range of predicted probabilities. The predictive model, displayed as a nomogram, may aid in selecting individuals requiring an invasive dynamic intracompartmental muscle pressure measurement. PMID- 29126338 TI - Effect of Neuromuscular Electrical Stimulation on Brain-derived Neurotrophic Factor. AB - Brain-derived neurotrophic factor (BDNF) has been considered an essential mediator responsible for the beneficial effects of physical activity in preventing cognitive impairment. This study aimed at examining the effects of a single bout of neuromuscular electrical stimulation (NMES) on levels of BDNF in the plasma and on cognitive performance in healthy adult men. Thirteen healthy adult men participated in three experimental sessions. The first session was 30 min of NMES to both legs, the second was 30 min of cycling exercise at the intensity of 60% peak oxygen uptake, and the third was 30 min of complete rest. Blood was examined for plasma BDNF levels and glucose concentrations, and cognitive performance tests were performed before and after each session. A single bout of NMES significantly increased plasma BDNF levels (p<0.05), which were equivalent to the amount of plasma BDNF released during the exercise session (p>0.05). However, there were no significant changes in cognitive performance between the sessions (p>0.05). The present study found that a single bout of NMES significantly increased plasma BDNF to levels normally present during moderate voluntary exercise. Therefore, NMES could serve as an alternative method of exercise, and might shed light on individuals for whom voluntary physical exercise is contraindicated. PMID- 29126339 TI - The Force-Velocity Relationship in Older People: Reliability and Validity of a Systematic Procedure. AB - This study compared the reliability and validity of different protocols evaluating the force-velocity (F-V) relationship and muscle power in older adults. Thirty-one older men and women (75.8+/-4.7 years) underwent two F-V tests by collecting the mean and peak force and velocity data exerted against increasing loads until one repetition maximum (1RM) was achieved in the leg press exercise. Two attempts per load were performed, with a third attempt when F-V points deviated from the linear F-V regression equation. Then, the subjects performed 2*3 repetitions at 60% 1RM to compare purely concentric and eccentric concentric repetitions. The Short Physical Performance Battery was conducted to assess the validity of the different protocols. Significant differences were found in maximal power (Pmax) between mean and peak values and between protocols differing in the number of attempts per load (p<0.01). Registering mean values, a third attempt, and multiple loads (>3), was significantly more reliable (Pmax: CV=2.6%; ICC=0.99) than the other alternatives. Mean values were also observed to be more associated with physical function than peak values (R2=0.34 and 0.15, respectively; p<0.05). No significant differences were observed between concentric and eccentric-concentric repetitions. Thus, collecting mean force and velocity values against multiple loads, while monitoring the linearity of the F-V relationship, seemed to be the more adequate procedure to assess the F-V profile and muscle power in older adults. PMID- 29126340 TI - [Treatment of Hallux Valgus: Current Diagnostic Testing and Surgical Treatment Performed by German Foot and Ankle Surgeons]. AB - BACKGROUND: Hallux valgus is one of the most prevalent foot deformities, and surgical treatment of Hallux valgus is one of the most common procedures in foot and ankle surgery. Diagnostic and treatment standards show large variation despite medical guidelines and national foot and ankle societies. The aim of this nationwide survey is a description of the current status of diagnostics and therapy of Hallux valgus in Germany. MATERIAL AND METHODS: A nationwide online questionnaire survey was sent to two German foot and ankle societies. The participants were asked to answer a questionnaire of 53 questions with four subgroups (general, diagnostics, operation, preoperative management). Surgical treatment for three clinical cases demonstrating a mild, moderate and severe Hallux valgus deformity was inquired. RESULTS: 427 foot and ankle surgeons answered the questionnaire. 388 participants were certified foot and ankle surgeons from one or both foot and ankle societies. Medical history (78%), preoperative radiographs (100%) and preoperative radiographic management (78%) are of high or very high importance for surgical decision pathway. Outcome scores are used by less than 20% regularly. Open surgery is still the gold standard, whereas minimally invasive surgery is performed by only 7%. CONCLUSION: Our survey showed that diagnostic standards are met regularly. There is a wide variation in the type of procedures used to treat Hallux valgus deformity. TMT I arthrodesis is preferred in severe Hallux valgus, but also used to treat moderate and mild deformities. Minimally invasive surgery is still used by a minority of surgeons. It remains to be seen, to what extent minimally invasive surgery will be performed in the future. PMID- 29126341 TI - [Acceptance of Online-based Therapy by Patients with Light to Moderate Depressive Disorders]. AB - OBJECTIVES: Over the past few years, there has been a considerable increase in online-based therapeutic services for people affected by depressive disorders. The efficacy and efficiency of these programmes is well documented by now. User acceptance is considered as a significant factor of success in establishing this new patient-centered care. Theory-based acceptance surveys can provide valuable scientific knowledge regarding long-term introduction. METHODS: A nationwide online survey was conducted to determine the attitude towards web-based psychotherapy services for depressive disorders, the current state of knowledge and the intention of 186 participants (124 female and 62 male participants; aged 21 and above) to use these services. The participants were recruited from support groups for depressive disorders. The determinants of the intention to use online therapy, which is included in the binary logistic regression, are based upon the Unified Theory of Acceptance and Use of Technology (UTAUT). RESULTS: Nearly two thirds of the respondents could conceive making use of online-based therapeutic services in the near future. The perceived performance and expected effort proved to be significantly influential predictors regarding the intention to use. Specifically, these included an evaluation of the use of E-Mental Health to assist disease management, and better assessment of the course of one's disease. CONCLUSION: The actual contribution of E-Mental Health is closely connected to technical and jurisprudential assessments. But also, it significantly depends on evidence-based issues as well as user orientation in research, development and implementation. The results offer an initial theory-based approach to an increased user-oriented technology research in health care, with further diversity criteria to be taken into account in the future. PMID- 29126342 TI - [Tuberculosis Among Refugees and Asylum Seekers: Tuberculosis Screening on Arrival and Case Management]. AB - The statement of the Federal Association of Physicians of Public Health Services provides recommendations concerning tuberculosis screening of refugees and asylum seekers on arrival specific to different groups of persons (adults, children, pregnant women, unaccompanied minors), taking into account the legal background and the current recommendations of the Robert Koch Institute as well as of the German Society for Pediatric Infectiology. In addition, recommendations are given to ensure treatment success in refugees and asylum seekers with tuberculosis, to carry out contact investigations and for preventive treatment of latent tuberculosis infection among refugees and asylum seekers. PMID- 29126343 TI - Oxidative stress-triggered interactions between the succinyl- and acetyl proteomes of rice leaves. AB - Protein lysine acylations, such as succinylation and acetylation, are important post-translational modification (PTM) mechanisms, with key roles in cellular regulation. Antibody-based affinity enrichment, high-resolution liquid chromatography mass spectrometry analysis, and integrated bioinformatics analysis were used to characterize the lysine succinylome (Ksuc ) and acetylome (Kace ) of rice leaves. In total, 2,593 succinylated and 1,024 acetylated proteins were identified, of which 723 were simultaneously acetylated and succinylated. Proteins involved in photosynthetic carbon metabolism such as the large and small subunits of RuBisCO, ribosomal functions, and other key processes were subject to both PTMs. Preliminary insights into oxidant-induced changes to the rice acetylome and succinylome were gained from treatments with hydrogen peroxide. Exposure to oxidative stress did not regulate global changes in the rice acetylome or succinylome but rather led to modifications on a specific subset of the identified sites. De-succinylation of recombinant catalase (CATA) and glutathione S-transferase (OsGSTU6) altered the activities of these enzymes showing that this PTM may have a regulatory function. These findings not only greatly extend the list of acetylated and/or succinylated proteins but they also demonstrate the close cooperation between these PTMs in leaf proteins with key metabolic functions. PMID- 29126345 TI - Integrating Item Accuracy and Reaction Time to Improve the Measurement of Inhibitory Control Abilities in Early Childhood. AB - Efforts to improve children's executive function are often hampered by the lack of measures that are optimized for use during the transition from preschool to elementary school. Whereas preschool-based measures often emphasize response accuracy, elementary school-based measures emphasize reaction time (RT) especially for measures inhibitory control (IC) tasks that typically have a speeded component. The primary objective of this study was to test in a preschool aged sample whether the joint use of item-level accuracy and RT data resulted in improved scoring for three IC tasks relative to scores derived from accuracy data alone. Generally, the joint use of item-level accuracy and RT data resulted in modest improvements in the measurement precision of IC abilities. Moreover, the joint use of item-level accuracy and RT helped eliminate floor and ceiling effects that occurred when accuracy data were considered alone. Results are discussed with respect to the importance of scoring IC tasks in ways that are maximally informative for program evaluation and longitudinal modeling. PMID- 29126346 TI - Paritaprevir/Ritonavir/Ombitasvir Plus Dasabuvir Therapy-Related Severe Anemia. PMID- 29126344 TI - Genetic and Epigenetic of Medullary Thyroid Cancer AB - Medullary thyroid carcinoma (MTC) is an infrequent, calcitonin producing neuroendocrine tumor and initiates from the parafollicular C cells of the thyroid gland. Several genetic and epigenetic alterations are collaterally responsible for medullary thyroid carcinogenesis. In this review article, we shed light on all the genetic and epigenetic hallmarks of MTC. From the genetic perspective, RET, HRAS, and KRAS are the most important genes that are characterized in MTC. From the epigenetic perspective, Ras-association domain family member 1A, telomerase reverse transcriptase promoter methylations, overexpression of histone methyltransferases, EZH2 and SMYD3, and wide ranging increase and decrease in non coding RNAs can be responsible for medullary thyroid carcinogenesis. PMID- 29126347 TI - Language profiles in young children with autism spectrum disorder: A community sample using multiple assessment instruments. AB - This study investigated language profiles in a community-based sample of 104 children aged 1-3 years who had been diagnosed with autism spectrum disorder using Diagnostic and Statistical Manual of Mental Disorders (5th ed.) diagnostic criteria. Language was assessed with the Mullen scales, Preschool Language Scale, fifth edition, and Vineland-II parent-report. The study aimed to determine whether the receptive-to-expressive language profile is independent from the assessment instrument used, and whether nonverbal cognition, early communicative behaviors, and autism spectrum disorder symptoms predict language scores. Receptive-to-expressive language profiles differed between assessment instruments and reporters, and Preschool Language Scale, fifth edition profiles were also dependent on developmental level. Nonverbal cognition and joint attention significantly predicted receptive language scores, and nonverbal cognition and frequency of vocalizations predicted expressive language scores. These findings support the administration of multiple direct assessment and parent-report instruments when evaluating language in young children with autism spectrum disorder, for both research and in clinical settings. Results also support that joint attention is a useful intervention target for improving receptive language skills in young children with autism spectrum disorder. Future research comparing language profiles of young children with autism spectrum disorder to children with non-autism spectrum disorder developmental delays and typical development will add to our knowledge of early language development in children with autism spectrum disorder. PMID- 29126348 TI - Validity of Self-Rated Memory Among Middle-Aged and Older Chinese Adults: Results From the China Health and Retirement Longitudinal Study (CHARLS). AB - Memory self-ratings are often used in primary care practice and social surveys due to its relative ease of administration. Yet their usefulness to accurately measure individuals' memory-related cognitive function is largely unknown. This article assesses the construct validity of self-rated memory for measuring memory related cognitive function among middle-aged and older adults (45+ years) in China using a national sample ( N = 13,690) from the China Health and Retirement Longitudinal Study. We first compare self-rated memory with a number of well established memory tests and then investigate the role of sociodemographic factors in determining self-reports conditional on memory test performance. We find that self-rated memory is only weakly correlated with memory test performance and yields low sensitivity and specificity in detecting individuals with relatively poor memory test performance. We also find evidence for substantial differential item functioning across sociodemographic groups. Our results, therefore, caution against the use of simple self-rated memory measures for memory assessments in primary care or survey research. PMID- 29126349 TI - Bone Marrow Aspirate Concentrate for Cartilage Defects of the Knee: From Bench to Bedside Evidence. AB - Objective To critically evaluate the current basic science, translational, and clinical data regarding bone marrow aspirate concentrate (BMAC) in the setting of focal cartilage defects of the knee and describe clinical indications and future research questions surrounding the clinical utility of BMAC for treatment of these lesions. Design A literature search was performed using the PubMed and Ovid MEDLINE databases for studies in English (1980-2017) using keywords, including ["bone marrow aspirate" and "cartilage"], ["mesenchymal stem cells" and "cartilage"], and ["bone marrow aspirate" and "mesenchymal stem cells" and "orthopedics"]. A total of 1832 articles were reviewed by 2 independent authors and additional literature found through scanning references of cited articles. Results BMAC has demonstrated promising results in the clinical application for repair of chondral defects as an adjuvant procedure or as an independent management technique. A subcomponent of BMAC, bone marrow derived-mesenchymal stem cells (MSCs) possess the ability to differentiate into cells important for osteogenesis and chondrogenesis. Modulation of paracrine signaling is perhaps the most important function of BM-MSCs in this setting. In an effort to increase the cellular yield, authors have shown the ability to expand BM-MSCs in culture while maintaining phenotype. Conclusions Translational studies have demonstrated good clinical efficacy of BMAC both concomitant with cartilage restoration procedures, at defined time points after surgery, and as isolated injections. Early clinical data suggests BMAC may help stimulate a more robust hyaline cartilage repair tissue response. Numerous questions remain regarding BMAC usage, including cell source, cell expansion, optimal pathology, and injection timing and quantity. PMID- 29126350 TI - Newly developed triaxial microcatheter for complicated interventions. AB - Recent advances have been made in the development of microcatheters, and have contributed to super-selective catheterization. One new tool is the triple co axial (triaxial) system, which consists of a small microcatheter, large microcatheter, and 4- or 5-Fr. catheter. This system may be applied to complex interventions. We herein introduce the technique for and advantages of the triaxial system. PMID- 29126351 TI - The factors associated with geriatric depression in rural China: stratified by household structure. AB - Depressive symptoms and empty nest phenomenon of rural elderly people are both important public health issues, which should not be ignored. We aimed to estimate the prevalence of depressive symptoms and related factors of the empty nest elderly in rural China. We recruited 3182 eligible subjects and gathered data by face-to-face interview. Multivariate logistic regression models were used to explore the related factors of depressive symptoms. The present study showed that the prevalence of depressive symptoms significantly differed between empty nest old adults and non-empty nesters (24.1% vs. 19.0%). The elderly living alone had highest OR of depressive symptoms. Depressive symptoms of empty nest elderly was associated with sleep quality, economic status, pain, social support and ADL. While it was associated with gender, economic status, pain and PSMS in non-empty nest group. Number of chronic disease showed significant associations with depressive symptoms in the elderly living alone. Subjective support, support utilization and pain were positively associated with depressive symptoms in the elderly living with spouse. Sleep quality, economic status and ADL were common factors. Depressive symptoms obviously prevail among empty nest elderly than non empty nesters. It reminded us that complementary social support from family and society is essential. PMID- 29126352 TI - Fatal myocarditis and rhabdomyolysis induced by nivolumab during the treatment of type B3 thymoma. AB - Immune checkpoint inhibitors including programmed death-1 inhibitors are promising agents for many types of malignancies; however, it is still an off label choice for type B3 thymoma. We reported for the first time a patient with type B3 thymoma developed fatal myocarditis and rhabdomyolysis after one dose of nivolumab administration. The results from myocardial and muscle biopsies revealed extensive myocyte damage, T-lymphocytic infiltration and strongly expression of PD-L1 which confirmed the nivolumab-related immune-related adverse events (irAEs). The blood tests showed elevated levels of serum AChR-binding antibody and inflammatory cytokines, in addition abnormal lymphocyte subsets were noted. Our report suggested that administration of nivolumab in type B3 thymoma could cause rare but fatal myocarditis and rhabdomyolysis, over-expressed AChR binding antibody and inflammatory cytokines may be potential biomarkers for irAEs. PMID- 29126353 TI - Potential for Bias and the American Orthopaedic Foot and Ankle Society Ankle Hindfoot Scoring System. AB - BACKGROUND: The American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scoring System (AOFAS-AH) has not been validated and has significant risk for researcher bias, given that 40 out of 100 points are assessed by study staff subjectively. The purpose of this study is to evaluate its recent use in the orthopaedic literature to determine the percentage of previously published studies for which study conclusions would be changed if the AOFAS-AH scores were artificially altered, representing the effect of a systematic researcher bias. MATERIALS AND METHODS: Articles from January 2012 and February 2015 in three orthopaedic journals were queried for use of the AOFAS-AH. Quantities of 4, 8, or 12 points were added to or subtracted from mean AOFAS-AH scores for each study while otherwise maintaining the reported standard deviation to simulate a researcher bias when scoring the subjective sections. Statistical analysis was performed with the adjusted AOFAS-AH mean scores in order to elucidate a potential "reversal" in statistical significance and conclusion. RESULTS: A 1582 original research articles were published during this time period. 128 articles utilized the AOFAS-AH score. 30 articles (23.4%) reported the required statistical data to permit manipulation of AOFAS-AH scores. Nine of the 30 articles (30%) had a reversal following a manipulation of 12 or fewer points. Seven (5.5%) reported the blinding status of the researchers. CONCLUSION: The potential for bias is high with the AOFAS-AH and its continued is questionable. Researchers utilizing the AOFAS-AH should at a minimum appropriately blind study staff and consider pre-study clarification of subjective terminology. LEVELS OF EVIDENCE: Level IV. PMID- 29126354 TI - Salivary glutamate is elevated in individuals with chronic migraine. AB - Background Glutamate has been implicated in migraine pathogenesis, and is elevated in the plasma, cerebrospinal fluid, and saliva in migraineurs. However, no comparison of glutamate levels among chronic migraine, episodic migraine and controls has been reported. The aim is to compare salivary glutamate levels of individuals with chronic migraine with those of individuals with episodic migraine and healthy controls. Methods We investigated salivary glutamate level of 46 women with chronic migraine, 50 women with episodic migraine, and 19 healthy controls via enzyme linked immunosorbent assay. Results The salivary glutamate level of the chronic migraine group (median and interquartile range, 20.47 [15.27-30.15] pmol/mg total protein) was significantly higher than those of the episodic migraine (16.17 [12.81-20.15] pmol/mg total protein, p = 0.008) and control (12.18 [9.40-16.24] pmol/mg total protein, p = 0.001) groups. The salivary glutamate level of the episodic migraine group was marginally elevated from that of the control group (post hoc p = 0.016). Thresholds of 16.58 and 17.94 pmol/mg total protein optimize the sensitivity and specificity to differentiate chronic migraine participants from healthy controls and episodic migraine participants, respectively. Conclusions Salivary glutamate level was elevated in chronic migraine participants. These data suggest that salivary glutamate level could be an indicator of CM. PMID- 29126355 TI - Elevated circulating endothelial-specific microRNAs in migraine patients: A pilot study. AB - Background Evidence of vascular dysfunction in migraine is increasing. MicroRNAs (miRs) have emerged as important regulators of vascular endothelial functions. This exploratory study investigated whether circulating levels of miRs associated with endothelial function are altered in migraine patients. Methods Thirty patients with migraine (20-50 years old) without overt vascular risk factors and 30 sex- and age-matched healthy controls participated. The levels of four miRs that regulate endothelial function (miR-155, miR-126, miR-21, and Let-7g) were quantified and expressed in terms of fold changes (2-DeltaDeltact) relative to mean levels in the control group. Associations of miRs levels with headache features and syncope comorbidity were explored. Results Compared to controls, migraine patients had upregulated expression of miR-155 (6.17-fold, p = 0.018), miR-126 (6.17-fold, p = 0.013), and let-7g (7.37-fold, p = 0.005). Levels of miR 155 (r = 0.375, p = 0.041) and miR-126 (r = 0.375, p = 0.041) were associated with syncope frequency in the past year in migraine patients. Migraine patients with aura have insignificant higher expression of miRs levels compared to those without. Conclusions In this pilot study, circulating levels of endothelial specific miRs appear to be elevated in migraine patients and may be associated with syncope comorbidity. PMID- 29126356 TI - Twelve tips for embedding human factors and ergonomics principles in healthcare education. AB - Safety and improvement efforts in healthcare education and practice are often limited by inadequate attention to human factors/ergonomics (HFE) principles and methods. Integration of HFE theory and approaches within undergraduate curricula, postgraduate training and healthcare improvement programs will enhance both the performance of care systems (productivity, safety, efficiency, quality) and the well-being (experiences, joy, satisfaction, health and safety) of all the people (patients, staff, visitors) interacting with these systems. Patient safety and quality improvement education/training are embedded to some extent in most curricula, providing a potential conduit to integrate HFE concepts. To support evolving curricula and professional development at all levels - and also challenge prevailing "human factors myths and misunderstandings" - we offer professional guidance as "tips" for educators on fundamental HFE systems and design approaches. The goal is to further enhance the effectiveness of safety and improvement work in frontline healthcare practice. PMID- 29126357 TI - Successful treatment of high-grade pancreatic neuroendocrine neoplasms with everolimus. PMID- 29126359 TI - What do parents of children with autism expect from participation in research? A community survey about early autism studies. AB - Engagement with stakeholders is an essential part of the research process. This is particularly the case for early autism research with infant cohorts and their families, where a range of ethical issues are pertinent. Here, we report on a large survey of parents who have a child on the autism spectrum (n = 1040) which specifically probed attitudes to early autism research. The large majority of parents showed positive attitudes overall, and these were associated with greater access to services, higher service quality ratings and higher rates of intellectual disability among their children. Parents valued the scientific goals of research, but half of parents also reported that an intervention component would be an essential prerequisite for them to participate in research. If enrolled in a study, parents were positive about most commonly used measures though less favourably disposed towards brain scans for children. They valued direct contact with the research team and openness in data sharing. We interpret our findings in terms of lessons for the early autism research community and for stakeholder engagement projects. PMID- 29126358 TI - Characterizing Anxiety Among Individuals Receiving Treatment for Alcohol and Substance Use Disorders. AB - BACKGROUND: Despite high prevalence of generalized anxiety disorder (GAD) substance use disorder (SUD) comorbidity, little is known regarding demographic characteristics associated with GAD in SUD treatment seekers. OBJECTIVE: To characterize demographic differences between inpatient SUD treatment seekers reporting varying levels of GAD symptomatology. DESIGN: General linear models, chi-square test, t test, and correlational analyses were utilized to assess group differences. Groups included those with no history of significant anxiety (No GAD; n = 256), subclinical anxiety (Subclinical; n = 85), and those meeting GAD diagnostic criteria (GAD; n = 61). RESULTS: The No GAD group differed substantially from Subclinical and GAD individuals. With the exception of polysubstance use, no differences were found regarding Subclinical and GAD groups. CONCLUSION: Individuals with subclinical GAD symptoms and those meeting diagnostic criteria were nearly identical regarding precursors to problematic substance use, severity of use, and key mental health indicators. Findings suggest subclinical levels of GAD should not be overlooked when assessing and treating SUDs. PMID- 29126360 TI - Endodontic treatment of canine teeth in a cynomolgus monkey ( Macaca fascicularis). AB - A case of bilateral superior canine tooth pulp necrosis in an 18-year-old male Macaca fascicularis is described . A skull computed tomography scan was performed to confirm the diagnostic suspicion. A successful bilateral endodontic treatment with coronotomy was performed using rotary nickel-titanium instruments. Post operative dental radiographs confirmed the correct positioning of the sealant. A rapid and excellent clinical recovery was obtained after each surgery. This innovative approach may contribute to improving the quality of root canal treatments provided to non-human primates. PMID- 29126361 TI - A survey of the current practice of intramuscular Botulinum toxin injections for hemiplegic shoulder pain in the UK. AB - PURPOSE: To describe the current UK practice for the use of intramuscular Botulinum Toxin type A injections to treat hemiplegic shoulder pain. METHOD: A UK based cross-sectional study using an online survey. Participants (n = 68) were medical and non-medical practitioners recruited via the membership of the British Society for Rehabilitation Medicine and the British Neurotoxin Network. Data was analysed using descriptive statistics and content analysis. RESULTS: The majority of respondents would consider Botulinum Toxin type A for hemiplegic shoulder pain (86.8%), though most of these respondents inject for this goal infrequently (83.1%). Pectoralis major was most commonly selected to achieve this goal. Barriers to this intervention included difficulties determining the cause of pain (29.4%), difficulty isolating muscles (27.9%), and a lack of evidence (25%). The doses reported regularly deviated from guidelines and a substantial range in the volumes suggested was observed. Clinicians were mostly reliant on unstandardised measures to assess outcomes. CONCLUSIONS: Current UK practice of Botulinum Toxin type A injections for hemiplegic shoulder pain associated with spasticity is highly variable. There are large gaps between current practice and available evidence with regards to muscle selection and doses used. A number of areas for further investigation have been identified to progress current understanding of this intervention. Implications for rehabilitation There are wide variations in practice for this complex intervention and clinicians should consider that their individual decision-making could be based on their own beliefs rather than available evidence. Pectoralis major is most commonly injected to treat hemiplegic shoulder pain, but further evaluation is required to address whether it is the most effective. Clinicians most often use a limitation of shoulder abduction and external rotation, flexor patterning of the upper limb, and pain on passive movement to identify when hemiplegic shoulder pain is due to spasticity over other causes. Further research is needed to identify which patients are most likely to benefit from this intervention and at what stage post-stroke its use is most optimal. PMID- 29126362 TI - Bioactive isoquinoline alkaloids from Cissampelos pareira. AB - The phytochemical and biological investigation of Cissampelos pareira leads to the isolation of one new isoquinoline alkaloid (7) along with six known isoquinoline alkaloids, namely, magnoflorine (1), magnocurarine (2), cissamine (3), curine (4), hayatinine (5) and cycleanine (6). Magnoflorine (1) and magnocurarine (2) were isolated for the first time from C. pareira. A new, rapid, simple and sensitive UPLC method was developed for simultaneous quantification of five pure compounds (1-5). Seasonal variation study revealed higher content of these compounds during the rainy season. The chloroform (CPCF) and n-butanol (CPBF) fractions showed cytotoxic efficacy against KB cells. Among pure compounds, hayatinine (5) was found to be most active against KB and A549, while, cycleanine (6) against KB cells. PMID- 29126363 TI - The intestinal absorption properties of flavonoids in Hippophae rhamnoides extracts by an in situ single-pass intestinal perfusion model. AB - The purpose of this study was to investigate the absorption properties of isorhamnetin (IS), quercetin (QU), and kaempferol (KA) in total flavones of Hippophae rhamnoides L. (TFH) by an in situ single-pass intestinal perfusion model. The results indicated that IS, QU, and KA in TFH were absorbed site dependently, and both enterohepatic circulation and intestinal flora could participate in their absorption processes. The absorption mechanisms of IS, QU, and KA in TFH were involved in both passive diffusion and active transport, and the mediation of efflux transporter multidrug resistance-associated proteins (MRPs) should not be neglected. PMID- 29126364 TI - Efficient Monte Carlo Estimation of the Expected Value of Sample Information Using Moment Matching. AB - BACKGROUND: The Expected Value of Sample Information (EVSI) is used to calculate the economic value of a new research strategy. Although this value would be important to both researchers and funders, there are very few practical applications of the EVSI. This is due to computational difficulties associated with calculating the EVSI in practical health economic models using nested simulations. METHODS: We present an approximation method for the EVSI that is framed in a Bayesian setting and is based on estimating the distribution of the posterior mean of the incremental net benefit across all possible future samples, known as the distribution of the preposterior mean. Specifically, this distribution is estimated using moment matching coupled with simulations that are available for probabilistic sensitivity analysis, which is typically mandatory in health economic evaluations. RESULTS: This novel approximation method is applied to a health economic model that has previously been used to assess the performance of other EVSI estimators and accurately estimates the EVSI. The computational time for this method is competitive with other methods. CONCLUSION: We have developed a new calculation method for the EVSI which is computationally efficient and accurate. LIMITATIONS: This novel method relies on some additional simulation so can be expensive in models with a large computational cost. PMID- 29126365 TI - Suicidal ideation, suicide attempts, and psychological distress among intoxicated adolescents in the pediatric emergency department. AB - BACKGROUND: Studies have emphasized screening for psychiatric disorders, especially suicide risk in emergency departments. Psychiatric disorders and experimentation with alcohol increase in adolescence and intoxications among patients challenge the staff in emergency departments. AIMS: This study examined the degree of suicidal ideation (SI) and suicidal behavior in adolescents, and the extent to which they differed from non-suicidal patients in terms of alcohol use, psychological distress, self-esteem, and perceived social support. METHODS: The study comprised 120 adolescents, a mean age of 14.2 years. Of them 60% were females. We collected data on the clinical characteristics and assessed the patient's psychiatric status using self-report scales and analyzed blood samples for alcohol. A consulting psychiatrist interviewed each patient before discharge to evaluate potential SI or suicide attempt (SA) using structured and semi structured scales. RESULTS: Of the 120 patients 20% had SI or had made a SA. High psychological distress in girls, low blood alcohol levels (BALs), as well as low scores on self-esteem, on social support and on familial support were associated with patients with SI/SA. Logistic regression showed that the most significant variables with suicidal patients included low BAL and low self-esteem and high alcohol consumption. Psychological distress had a direct and mediational role in the suicidal patients. CONCLUSIONS: Adolescents referred to the pediatric emergency department with intoxication displaying high psychological distress and low self-esteem represent a high-risk group of teens. In this group, careful assessment of mental health status, screening for suicidal ideation, and SAs seems warranted. PMID- 29126366 TI - Bioactive compounds and antioxidant potential for polyphenol-rich cocoa extract obtained by agroindustrial residue. AB - Processing of cocoa (Theobroma cacao L.) beans responsible for agricultural exports leads to large amounts of solid waste that were discarded, however, this one presents high contents of metabolites with biological activities. The major objective of this study was to valorise cocoa agroindustrial residue obtained by hydraulic pressing for extract rich in antioxidants. For it, the centesimal composition of residue was investigated, the green extraction was carried out from the residue after, the bioactive compounds, sugar contents and screaming by HPTLC were quantified for extract. The extract has a total polyphenol content of 229.64 mg/g and high antioxidant activity according to ABTS 225.0 MUM/g. HTPLC analysis confirmed the presence in the extract, residue of terpenes, sesquiterpenes, flavonoids and antioxidant activity. These results, as a whole, suggest that the extract from the cocoa residue has interesting characteristics to alternative crops with potential industrial uses. PMID- 29126367 TI - T2*-Mapping of Acetabular Cartilage in Patients With Femoroacetabular Impingement at 3 Tesla: Comparative Analysis with Arthroscopic Findings. AB - Objective To evaluate the diagnostic accuracy of T2*-mapping for detecting acetabular cartilage damage in patients with symptomatic femoroacetabular impingement (FAI). Design A total of 29 patients (17 females, 12 males, mean age 35.6 +/- 12.8 years, mean body mass index 25.1 +/- 4.1 kg/m2, 16 right hips) with symptomatic FAI underwent T2* MRI and subsequent hip arthroscopy. T2* values were obtained by region of interest analysis in seven radially reformatted planes around the femoral neck (anterior, anterior-superior, superior-anterior, superior, superior-posterior, posterior-superior, posterior). Intraoperatively, a modified Outerbridge classification was used for assessment of the cartilage status in each region. T2* values and intraoperative data were compared, and sensitivity, specificity, negative predictive values (NPV) and positive predictive values (PPV) as well as the correlation between T2*-mapping and intraoperative findings, were determined. The mean time interval between MRI and arthroscopy was 65.7 +/- 48.0 days. Results Significantly higher T2* values were noted in arthroscopically normal evaluated cartilage than in regions with cartilage degeneration (mean T2* 25.6 +/- 4.7 ms vs. 19.9 +/- 4.5 ms; P < 0.001). With the intraoperative findings as a reference, sensitivity, specificity, NPV and PPV were 83.5%, 67.7%, 78.4% and 74.4%, respectively. The correlation between T2*-mapping and intraoperative cartilage status was moderate (rho = -0.557; P < 0.001). Conclusions T2*-mapping enabled analysis of acetabular cartilage with appropriate correlation with intraoperative findings and promising results for sensitivity, specificity, PPV, and NPV in this cohort. Our results emphasize the value of T2*-mapping for the diagnosis of hip joint cartilage pathologies in symptomatic FAI. PMID- 29126368 TI - Associations between cooperation, reactive aggression and social impairments among boys with autism spectrum disorder. AB - Cooperation is a fundamental human ability that seems to be inversely related to aggressive behaviour in typical development. However, there is no knowledge whether similar association holds for children with autism spectrum disorder. A total of 27 boys with autism spectrum disorder and their gender, age and total score intelligence matched controls were studied in order to determine associations between cooperation, reactive aggression and autism spectrum disorder-related social impairments. The participants performed a modified version of the Prisoner's Dilemma task and the Pulkkinen Aggression Machine which measure dimensions of trust, trustworthiness and self-sacrifice in predisposition to cooperate, and inhibition of reactive aggression in the absence and presence of situational cues, respectively. Autism spectrum disorder severity-related Autism Diagnostic Interview-algorithm scores were ascertained by interviewing the parents of the participants with a semi-structured parental interview (Developmental, Dimensional and Diagnostic Interview). The results showed that albeit the boys with autism spectrum disorder were able to engage in reciprocation and cooperation regardless of their social impairments, their cooperativeness was positively associated with lower levels of reactive aggression and older age. Thus, strengthening inhibition mechanisms that regulate reactive aggression might make boys with autism spectrum disorder more likely to prefer mutual gain over self-interest in cooperation. PMID- 29126369 TI - Secondary metabolites from endemic species Iris adriatica Trinajstic ex Mitic (Iridaceae). AB - This manuscript describes the first detailed chemical investigation of endemic species Iris adriatica, including isolation and structure elucidation. Chemical analyses of the rhizome CH2Cl2/MeOH (2:1) extract revealed fourteen secondary metabolites, mainly isoflavonoids. Among isoflavonoids, two groups have been found: nigricin-type and tectorigenin-type. Dominant group of the isolated compounds has been nigricin-type isoflavones: nigricin, nigricin-4'-(1-O-beta-D glucopyranoside) and nigricin-4'-(1-O-beta-D-glucopyranosyl (1-6)-beta-D glucopyranoside) with 2.5, 10 and 1% of the total extract, respectively. Irisxanthone - xanthone C-glucoside, beta-sitosterol, benzophenone and one of its derivatives have also been found. Nigricin-type isoflavonoids and irisxanthone can be considered as possible chemotaxonomic markers for I. adriatica. 5,3',5' Trimethoxy-6,7-methylenedioxyisoflavone-4'-(1-O-beta-D-glucopyranoside) and benzophenone have been isolated from Iris species for the first time. PMID- 29126370 TI - Evaluation of final irrigation regimens with maleic acid for smear layer removal and wettability of root canal sealer. AB - OBJECTIVE: To evaluate the smear layer removal and wettability of AH Plus sealer on root canal dentin treated with MA (maleic acid), MA + CTR (cetrimide) and MA + CTR + CHX (chlorhexidine) as final irrigating regimens. MATERIAL AND METHODS: For smear layer removal, 40 teeth were instrumented to size F4 and divided into four groups: (1) 7% MA, (2) 7% MA + 0.2% CTR, (3) 7% MA + 0.2% CTR + 2% CHX, (4) distilled water (control). After irrigation, teeth were subjected to SEM analysis. For contact angle analysis, 20 teeth were split longitudinally and divided into four groups similar to smear layer analysis. AH plus sealer was placed on each specimen and contact angle was analysed. RESULTS: In both smear layer (p = .393) and contact angle analysis (p = .961), there was no significant difference between the groups MA and MA + CTR. However, MA + CTR + CHX removed smear layer less effectively (p = .023) and increased the contact angle of the sealer (p = .005). In smear layer analysis, specimens in negative control group were heavily smeared. In case of contact angle analysis, samples in the control group had least contact angle. CONCLUSION: MA alone or in combination with CTR removed smear layer effectively and increased the wettability of AH plus sealer to root canal dentin. PMID- 29126371 TI - Changes in spending and service use after a state autism insurance mandate. AB - Almost all states have insurance coverage mandates for childhood autism spectrum disorder treatment, yet little is known about how mandates affect spending and service use. We evaluated a 2011 Kansas law mandating comprehensive coverage of autism spectrum disorder treatments in the State Employee Health Plan. Data were extracted from the Kansas All-Payer Claims Database from 2009 to 2013 for enrollees of State Employee Health Plan and private health plans. The sample included children aged 0-18 years with >2 claims with an autism spectrum disorder diagnosis insured through State Employee Health Plan or a comparison group enrolled through private health plans. We estimated differences-in-differences regression models to compare trends among State Employee Health Plan to privately insured children. Average annual total spending on autism spectrum disorder services increased by US$912 (95% confidence interval: US$331-US$1492) and average annual out-of-pocket spending on autism spectrum disorder services increased by US$138 (95% confidence interval: US$53-US$223) among diagnosed children in the State Employee Health Plan relative to the comparison group following the mandate, representing 92% and 75% increases over baseline total and out-of-pocket autism spectrum disorder spending, respectively. Average annual quantity of outpatient autism spectrum disorder services increased by 15.0 services (95% confidence interval: 8.4-21.6) among children in the State Employee Health Plan, more than doubling the baseline average. Implementation of a comprehensive autism spectrum disorder mandate in the Kansas State Employee Health Plan was associated with substantial increases in service use and spending for autism spectrum disorder treatment among autism spectrum disorder-diagnosed children. PMID- 29126373 TI - Quality assessment in percutaneous coronary interventions: the QERMID Belgian PCI registry. AB - BACKGROUND: The recent increase in the number of interventional cathlabs that followed a moratorium of several years has resulted in an abrupt increase in the number of PCI and a dilution of the experience per centre and per operator. METHODS: Based on data extracted from the national "Quality Oriented Electronic Registration of Medical Implant Devices" (QERMID) database, we compared the characteristics and outcome of patients treated in 2015 in the 21 newly (<3 years) approved PCI centres with those of patients treated in the 28 historical PCI centres. RESULTS: The proportion of acute coronary syndromes was slightly higher in new than in historical centres (48% vs. 44%; p < 0.01) but few differences in co-morbidities were observed. Considering separately the patients treated for an acute coronary syndrome or for stable ischaemia, no significant difference in the overall in-hospital or 30-days mortality and in the proportion of same week bypass surgery was observed between newly approved and historical centres. In a substantial proportion (39%) of patients treated for stable angina or silent ischaemia, no test confirming the presence of ischaemia before PCI is reported, without significant difference between new and historical centres. CONCLUSIONS: Pending the limitations of the QERMID database, including a limited dataset and the absence of systematic on-site monitoring, no significant difference in the rate of major complications was identified between new and historical Belgian PCI centres. PMID- 29126374 TI - Encoding-Stage Adaptation Effects: Long-Term Memory. AB - Given adaptation changes perceptual experience, it probably shapes long-term memory (LTM). Across four experiments, participants were adapted to strongly gendered (male, female: Experiments 1 and 2) or aged faces (old, young: Experiments 3 and 4) before LTM encoding and later completed an LTM test in which the encoded faces were morphed with the opposite end of the relevant continuum. At retrieval, participants judged whether probe faces were more or less male or female or young or old than when presented during encoding. For male, female, and young faces, encoding-stage adaptation significantly shifted the point of subjective equality in the unadapted direction. Additionally, encoding-stage adaptation significantly enhanced recognition of faces during LTM retrieval. We conclude that encoding-related adaptation is reflected in LTM. PMID- 29126372 TI - Exercise improves recognition memory and synaptic plasticity in the prefrontal cortex for rats modelling vascular dementia. AB - OBJECTIVES: Functional electrical stimulation (FES) may induce involuntary exercise and make beneficial effects on vascular dementia (VD) by strengthening the BDNF-pCREB-mediated pathway and hippocampal plasticity. Whether FES improves recognition memory and synaptic plasticity in the prefrontal cortex (PFC) was investigated by establishing a VD model. METHODS: The VD rats were administered with two weeks of voluntary exercise, forced exercise, or involuntary exercise induced with FES. Sham-operated and control groups were also included. The behavioral changes were assessed with the novel object recognition test and novel object location test. The expression levels of key proteins related to synaptic plasticity in the PFC were also detected. RESULTS: All types of exercise improved the rats' novel object recognition index, but only voluntary exercise and involuntary exercise induced with FES improved the novel object location index. Any sort of exercise enhanced the expression of key proteins in the PFC. CONCLUSION: Involuntary exercise induced with FES can improve recognition memory in VD better than forced exercise. The mechanism is associated with increased synaptic plasticity in the PFC. FES may be a useful alternative tool for cognitive rehabilitation. PMID- 29126375 TI - A clinical survey about commercial games in lower limb prosthetic rehabilitation. AB - BACKGROUND: Despite the popularity of commercial games in lower limb prosthetic rehabilitation, data about their prevalence of use as well as therapists' perspectives about these games are still lacking. OBJECTIVES: To learn about the prevalence of use of commercial games in lower limb prosthetic rehabilitation and therapists' perspectives about these games. STUDY DESIGN: Cross-sectional. METHODS: An online survey was sent to physical and occupational therapists across prosthetic rehabilitation facilities in Canada. The survey had questions about the use of commercial games and therapists' perspectives. RESULTS: Data were collected from 82 therapists. Overall, 46.3% (38/82) reported that they use commercial games; of those, 94.7% (36/38) used the Nintendo Wii Fit. The most reported perceived benefits were the Wii Fit helping to improve weight shifting ( n = 76/82, 92.7%) and balance ( n = 75/82, 91.5%), and being motivating and complementing traditional therapy ( n = 75/82, 91.5%). The most reported perceived barriers/challenges were lack of time and familiarity with the games ( n = 58/82, 70.7%). CONCLUSION: Commercial games, particularly the Wii Fit, are commonly used in lower prosthetic rehabilitation in Canada. Most of the queried therapists view the Wii Fit positively. Knowledge translation activities and developing standard treatment protocols would be helpful in minimizing the barriers identified in this study. Clinical relevance The Wii Fit is prevalent in lower limb prosthetic rehabilitation in Canada and it is viewed positively by therapists as having the potential to improve balance and weight bearing, making rehabilitation more motivating, and complementing traditional therapy. Future studies should investigate the efficacy of the Wii Fit in prosthetic rehabilitation. PMID- 29126376 TI - Constructing the 32-item Fitness-to-Drive Screening Measure. AB - The Fitness-to-Drive Screening Measure(c) (FTDS) enables proxies to identify at risk older drivers via 54 driving-related items, but may be too lengthy for widespread uptake. We reduced the number of items in the FTDS and validated the shorter measure, using 200 caregiver responses. Exploratory factor analysis and classical test theory techniques were used to determine the most interpretable factor model and the minimum number of items to be used for predicting fitness to drive. The extent to which the shorter FTDS predicted the results of the 54-item FTDS was evaluated through correlational analysis. A three-factor model best represented the empirical data. Classical test theory techniques lead to the development of the 32-item FTDS. The 32-item FTDS was highly correlated ( r = .99, p = .05) with the FTDS. The 32-item FTDS may provide raters with a faster and more efficient way to identify at-risk older drivers. PMID- 29126377 TI - What's in a name? The orchestrated erosion of doctor-power in the NHS. PMID- 29126378 TI - Effects of evolving quality of landfill leachate on microbial fuel cell performance. AB - Microbial fuel cell (MFC) is a novel technology for landfill leachate treatment with simultaneous electric power generation. In recent years, more and more modern landfills are operating as bioreactors to shorten the time required for landfill stabilization and improve the leachate quality. For landfills to operate as biofilters, leachate is recirculated back to the landfill, during which time the organics of the leachate can be decomposed. Continuous recirculation typically results in evolving leachate quality, which chronologically corresponds to evolution stages such as hydrolysis, acidogenesis, acetogenesis, methanogenesis, and maturation. In this research, variable power generation (160 to 230 mW m-2) by MFC was observed when leachate of various evolutionary stages was used as the feed. The power density followed a Monod-type kinetic model with the chemical oxygen demand (COD) equivalent of the volatile fatty acids (VFAs) ( p < 0.001). The coulombic efficiency decreased from 20% to 14% as the leachate evolved towards maturation. The maximum power density linearly decreased with the increase of internal resistance, resulting from the change of the conductivity of the solution. The decreased conductivity boosted the internal resistance and consequently limited the power generation. COD removal as high as 90% could be achieved with leachate extracted from appropriate evolutionary stages, with a maximum energy yield of 0.9 kWh m-3 of leachate. This study demonstrated the importance of the evolving leachate quality in different evolutionary stages for the performance of leachate-fed MFCs. The leachate extracted from acidogenesis and acetogenesis were optimal for both COD reduction and energy production in MFCs. PMID- 29126379 TI - An audit of a novel electronic messaging treatment service for Chlamydia trachomatis at a community pharmacy. AB - In 2016, NHS Lothian regional sexual and reproductive health services introduced an electronic pharmacy treatment voucher that could be sent to the mobile phones of patients with Chlamydia trachomatis and their sexual contacts. A retrospective audit of the electronic treatment voucher database was conducted for vouchers issued between April and December 2016. Five hundred and forty-nine vouchers were issued and 56% were redeemed at a pharmacy within one week of issue. This suggests that electronic vouchers are a popular and effective means of providing expedited treatment for uncomplicated C. trachomatis at a community pharmacy. PMID- 29126380 TI - What makes for sound science? AB - The inclusive threshold policy for publication in BMC journals including BMC Plant Biology means that editorial decisions are largely based on the soundness of the research presented rather than the novelty or potential impact of the work. Here we discuss what is required to ensure that research meets the requirement of scientific soundness. BMC Plant Biology and the other BCM-series journals ( https://www.biomedcentral.com/p/the-bmc-series-journals ) differ in policy from many other journals as they aim to provide a home for all publishable research. The inclusive threshold policy for publication means that editorial decisions are largely based on the soundness of the research presented rather than the novelty or potential impact of the work. The emphasis on scientific soundness ( http://blogs.biomedcentral.com/bmcseriesblog/2016/12/05/vital importance-inclusive/ ) rather than novelty or impact is important because it means that manuscripts that may be judged to be of low impact due to the nature of the study as well as those reporting negative results or that largely replicate earlier studies, all of which can be difficult to publish elsewhere, are available to the research community. Here we discuss the importance of the soundness of research and provide some basic guidelines to assist authors to determine whether their research is appropriate for submission to BMC Plant Biology.Prior to a research article being sent out for review, the handling editor will first determine whether the research presented is scientifically valid. To be valid the research must address a question of biological significance using suitable methods and analyses, and must follow community agreed standards relevant to the research field. PMID- 29126381 TI - A genotype-phenotype study of hereditary multiple exostoses in forty-six Chinese patients. AB - BACKGROUND: Hereditary multiple exostoses (HME) is a rare autosomal dominant skeletal disorder that can cause a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of HME by using a scoring system and correlate the genotypes with different clinical phenotypes in Chinese patients. METHODS: Forty-six patients from different families were prospectively enrolled. The mutations were identified by direct sequencing of PCR-amplified genomic DNA or by multiplex ligation-dependent probe amplification (MLPA). Patients' demographic data, height, age of onset, number of anatomical sites, forearm deformity, and lower extremity alignment were analysed according to genotype and gender. A scoring system was used to assess the severity of the clinical phenotype. RESULTS: Thirty (60%) patients presented mutations in the EXT1 gene, and 16 (32%) presented mutations in the EXT2 gene. The mean age of onset was 2.96 years. The mean number of involved anatomic sites was 15.35. Male patients had more lesion sites than female patients (15.97 vs. 13.77, p = 0.046). The height evaluation illustrated that 67% of the patients (31 of 46) were below the 50th percentile, and the patients with EXT1 mutations were shorter than those with EXT2 mutations (p = 0.005). Forearm deformity showed a significant correlation with the number of involved anatomical sites (r = 0.382, p = 0.009). Moreover, a higher total score was found in patients with EXT1 mutations (p = 0.001). CONCLUSIONS: The clinical manifestations of 46 Chinese HME patients were similar to those in previous reports of Western populations. Patients with EXT1 mutations have a more severe clinical phenotype than patients with EXT2 mutations. PMID- 29126382 TI - Analysis of medical service use of knee osteoarthritis and knee meniscal and ligament injuries in Korea: a cross-sectional study of national patient sample data. AB - BACKGROUND: Osteoarthritis (OA) and meniscal and ligament injuries of the knee are the two most common knee disorders in Korea. The aim of this study was to analyze the demographic characteristics, medical service use and related costs for these disorders, and the results are expected to help inform practitioners, researchers, and policy-makers. METHODS: The present study aimed to evaluate incidence and patient characteristics, and to assess current medical service use, usual care, and medical expenses of knee disorders by analyzing 2014 national patient sample data from the Korean Health Insurance Review and Assessment Service. Data was extracted using 3% stratified sampling from all Korea national health insurance claims submitted in 2014, and analyzed. Usual care for M17 knee osteoarthritis and S83 knee meniscal and ligament injury codes of the International Classification of Diseases, 10th revision (ICD-10) were determined by investigating total number of patients, sociodemographic characteristics, days in care, number of visits, and expenses. RESULTS: Knee OA showed the highest incidence in females aged >=60 years, whereas meniscal and ligament injuries of the knee were most prevalent among patients aged <20 years and young adults. Total inpatient care expenses exceeded the cost of ambulatory care for both disorders. Ambulatory care was mainly provided at primary care clinics, with 90% of these visits made to orthopedic specialists. Medical expenses for knee OA and meniscal and ligament injuries were largely due to procedures/surgeries and injections, and procedures/surgeries and hospitalizations, respectively. Total replacement arthroplasty was the most commonly performed surgery for knee OA, while meniscectomy and cruciate ligament reconstruction were the most often performed surgeries for meniscal and ligament injuries. Intra-articular injection rates were 55% in knee OA patients and 3% in meniscal and ligament injury patients. Aceclofenac, diclofenac, and tramadol were the most frequently prescribed analgesics. CONCLUSIONS: The current findings may be used as basic data for establishing medical policies and can benefit researchers and clinicians in recognizing trends and patterns of treatment for knee disorders. PMID- 29126383 TI - Predictive performance of four frailty screening tools in community-dwelling elderly. AB - BACKGROUND: This study compares the performance of four frailty screening tools in predicting relevant adverse outcome (disability, institutionalization and mortality) in community-dwelling elderly. METHODS: Our study involved a secondary analysis of data from the FreLE cohort study. We focused on the following four frailty screening tools: the abbreviated Comprehensive Geriatric Assessment (aCGA), the Groningen Frailty Indicator (GFI), the Vulnerable Elders Survey-13 (VES-13) and the Fried scale. We used the Barberger-Gateau scale to assess disability. For comparison, we determined the capacity of these tools to predict the occurrence of disability, institutionalization or death using the receiver operating characteristic (ROC) curve. We also determined the threshold at which an optimal balance between sensitivity and specificity was reached. Odds ratios (ORs) were calculated to compare the risk of adverse outcome in the frail versus non-frail groups. RESULTS: In total, 1643 participants were included in the mortality analyses; 1224 participants were included in the analyses of the other outcomes (74.5% of the original sample). The mean age was 77.7 years, and 48.1% of the participants were women. The prevalence of frailty in this sample ranged from 15.0% (Fried) to 52.2% (VES-13). According to the Barberger-Gateau scale, 643 (52.5%) participants were fully independent; 392 (32.0%) were mildly disabled; 118 (9.6%) were moderately disabled; and 71 (5.8%) were severely disabled. The tool with the greatest sensitivity for predicting the occurrence of disability, mortality and institutionalization was VES-13, which showed sensitivities of 91.0%, 89.7% and 92.3%, respectively. The values for the area under the curve (AUC) of the four screening tools at the proposed cut-off points ranged from 0.63 to 0.75. The odds (univariate and multivariate analysis) of developing a disability were significantly greater among the elderly identified as being frail by all four tools. CONCLUSION: The multivariate analyses showed that the VES-13 may predict the occurrence of disability, mortality and institutionalization. However, the AUC analysis showed that even this tool did not have good discriminatory ability. These findings suggest that despite the high number of frailty screening tools described in the literature, there is still a need for a screening tool with high predictive performance. PMID- 29126384 TI - Population differentiation in allele frequencies of obesity-associated SNPs. AB - BACKGROUND: Obesity is emerging as a global health problem, with more than one third of the world's adult population being overweight or obese. In this study, we investigated worldwide population differentiation in allele frequencies of obesity-associated SNPs (single nucleotide polymorphisms). RESULTS: We collected a total of 225 obesity-associated SNPs from a public database. Their population level allele frequencies were derived based on the genotype data from 1000 Genomes Project (phase 3). We used hypergeometric model to assess whether the effect allele at a given SNP is significantly enriched or depleted in each of the 26 populations surveyed in the 1000 Genomes Project with respect to the overall pooled population. Our results indicate that 195 out of 225 SNPs (86.7%) possess effect alleles significantly enriched or depleted in at least one of the 26 populations. Populations within the same continental group exhibit similar allele enrichment/depletion patterns whereas inter-continental populations show distinct patterns. Among the 225 SNPs, 15 SNPs cluster in the first intron region of the FTO gene, which is a major gene associated with body-mass index (BMI) and fat mass. African populations exhibit much smaller blocks of LD (linkage disequilibrium) among these15 SNPs while European and Asian populations have larger blocks. To estimate the cumulative effect of all variants associated with obesity, we developed the personal composite genetic risk score for obesity. Our results indicate that the East Asian populations have the lowest averages of the composite risk scores, whereas three European populations have the highest averages. In addition, the population-level average of composite genetic risk scores is significantly correlated (R2 = 0.35, P = 0.0060) with obesity prevalence. CONCLUSIONS: We have detected substantial population differentiation in allele frequencies of obesity-associated SNPs. The results will help elucidate the genetic basis which may contribute to population disparities in obesity prevalence. PMID- 29126385 TI - Dilemma between health and environmental motives when purchasing animal food products: sociodemographic and nutritional characteristics of consumers. AB - BACKGROUND: Dietary guidelines in France give quantitative recommendations for intake of meat, fish and dairy products whereas consumers are increasingly concerned by the environmental impacts associated with the production of these foods. This potentially leads to consumer dilemmas when purchasing food products. The present study aimed at investigating the sociodemographic profiles of individuals reporting health and environmental dilemmas when purchasing meat, fish and dairy products, and comparing diet quality of individuals with and without dilemma. METHODS: A total of 22,936 adult participants in the NutriNet Sante cohort were included in this cross-sectional analysis. Participants completed a questionnaire assessing motives when purchasing meat, fish and dairy products, including health and environmental determinants. Environmental vs. health dilemmas were assessed using implicit and explicit methods. Sociodemographic data as well as dietary intake using repeated 24 h-records were collected. The association between sociodemographic characteristics and presence of dilemma was assessed using logistic regression models and between dilemma and intake of these products, adherence to food group guidelines, or overall dietary quality, using covariance analysis. RESULTS: Among participants, 13% were torn between buying meat for health reasons and to avoid buying it for environmental reasons, 12% in the case of fish and 5% in the case of dairy products. Older participants, women and low income individuals were more likely to report dilemmas. Participants reporting dilemmas for meat and dairy products consumed less of these foods (P < 0.05 and P < 0.0001, respectively) and had a better dietary quality overall (both P < 0.0001). In addition, participants with meat dilemma showed a better adherence to meat/fish/eggs guidelines (P < 0.001). CONCLUSIONS: Individuals reporting dilemmas concerning animal products had specific sociodemographic characteristics and showed higher diet quality overall compared with those having no dilemma. Our data suggest that having environmental concerns is not contradictory with adherence to nutritional guidelines. PMID- 29126386 TI - Venous thromboembolism and mortality in breast cancer: cohort study with systematic review and meta-analysis. AB - BACKGROUND: Breast cancer patients are at an increased risk of venous thromboembolism (VTE). However, current evidence as to whether VTE increases the risk of mortality in breast cancer patients is conflicting. We present data from a large cohort of patients from the UK and pool these with previous data from a systematic review. METHODS: Using the Clinical Practice Research Datalink (CPRD) dataset, we identified a cohort of 13,202 breast cancer patients, of whom 611 were diagnosed with VTE between 1997 and 2006 and 12,591 did not develop VTE. Hazard ratios (HR) were used to compare mortality between the two groups. These were then pooled with existing data on this topic identified via a search of the MEDLINE and EMBASE databases (until January 2015) using a random-effects meta analysis. RESULTS: Within the CPRD, VTE was associated with increased mortality when treated as a time-varying covariate (HR = 2.42; 95% CI, 2.13-2.75), however, when patients were permanently classed as having VTE based on presence of a VTE event within 6 months of cancer diagnosis, no increased risk was observed (HR = 1.22; 0.93-1.60). The pooled HR from seven studies using the second approach was 1.69 (1.12-2.55), with no effect seen when restricted to studies which adjusted for key covariates. CONCLUSION: A large HR for VTE in the time-varying covariate analysis reflects the known short-term mortality following a VTE. When breast cancer patients are fortunate to survive the initial VTE, the influence on longer term mortality is less certain. PMID- 29126387 TI - Thoracoscopic and hand assisted laparoscopic esophagectomy with radical lymph node dissection for esophageal squamous cell carcinoma in the left lateral decubitus position: a single center retrospective analysis of 654 patients. AB - BACKGROUND: The rates of thoracoscopic esophagectomy performed in the prone and left lateral decubitus positions are similar in Japan. We retrospectively reviewed short- and long-term outcomes of thoracoscopic esophagectomy for esophageal cancer performed in the left lateral decubitus position. METHODS: Between 1996 and 2015, 654 patients with esophageal cancer underwent thoracoscopic esophagectomy in the left lateral decubitus position. Patients were divided into early (1996-2008) and late groups (2009-2015, with standardization of the procedure and formalized training), and their clinical outcomes reviewed. RESULTS: The completion rate of thoracoscopic esophagectomy was 99.5%, and the procedure was converted to thoracotomy in three patients, due to hemorrhage. The mean intrathoracic operative time, intrathoracic blood loss, and number of dissected mediastinal lymph nodes were 205.0 min, 127.3 mL, and 24.7, respectively. Postoperative complications included pneumonia (8.5%), anastomotic leakage (7.5%), and recurrent nerve paralysis (3.5%). Postoperative (30d) mortality was 4/654 (0.61%) due to anastomotic leak and pneumonia. The five year overall survival rate was 70%. A comparison of the 289 early- and 365 late-study period cases revealed significant differences in mean intrathoracic blood loss (174.0 vs. 94.2 mL), number of mediastinal lymph nodes dissected (20.0 vs. 28.4), hospital length of stay (33.4 vs. 20.0 days, p < 0.001), and postoperative anastomotic leakage (14% vs. 1.6%, p < 0.0001). CONCLUSIONS: Standardization of the procedure for thoracoscopic esophagectomy in the left lateral decubitus position, with a standardized clinical pathway for perioperative care led to significant improvements in surgical outcomes. PMID- 29126388 TI - YRNA expression predicts survival in bladder cancer patients. AB - BACKGROUND: Non-coding RNAs play an important role in human carcinogenesis. YRNAs (Ro-associated Y), a novel class of non-coding RNAs, have been identified as biomarker in various malignancies, but remain to be studied in urinary bladder cancer (BCA) patients. METHODS: The expression of all four YRNAs (RNY1, RNY3, RNY4, RNY5) was determined in archival BCA (urothelial carcinoma, n = 88) and normal urothelial bladder (n = 30) tissues using quantitative real-time PCR. Associations with clinicopathological parameters and prognostic role for overall and cancer-specific survival were analysed. RESULTS: All YRNAs were significantly downregulated in BCA tissue. A low expression of RNY1, RNY3 and RNY4 was associated with muscle-invasive BCA, lymph node metastases and advanced grade. Furthermore, expression of RNY1 and RNY3 was predictive for BCA patients' overall (also RNY4) and cancer-specific survival as estimated using Kaplan-Meier and univariate (but not multivariate) Cox regression analyses. RNY1, RNY3 and RNY4 show good discriminative ability between tumor and normal tissue, as well as between muscle-invasive and non-muscle-invasive urothelial carcinoma. CONCLUSIONS: The expression of YRNAs is altered in BCA and associated with poor prognosis. Possible diagnostic role of YRNAs should be investigated in further studies. PMID- 29126389 TI - Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter "real life" study. AB - BACKGROUND: To evaluate the safety and efficacy of abiraterone acetate (AA) in the "real life" clinical practice for men with chemotherapy-naive metastatic castration-resistant prostate. METHODS: A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected. Demographics, clinical parameters, treatment outcomes and toxicity were recorded. The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated. Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic. RESULTS: We included 145 patients (mean age 76.5y). All patients were on androgen deprivation therapy. Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively. 57% of the patients had a Gleason score higher more than 7 at diagnosis. 62% were asymptomatic patients. The median serum total PSA at AA start was 17 ng/mL (range 0,4-2100). The median exposure to AA was 10 months (range 1-35). The proportion of patients achieving a PSA decline >=50% at 12 weeks was 49%. Distribution of patient satisfaction was 32% "greatly improved", 38% "improved", 24% "not changed", 5.5% "worsened". Grade 3 and 4 toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels). At the last follow-up, median progression free and overall survival were 17 and 26.5 months, respectively. Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline. CONCLUSIONS: The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a "real life" setting. The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline. TRIAL REGISTRATION: The study was retrospectively registered at ISRCTN as DOI: 10.1186/ISRCTN 52513758 in date April the 30th 2016. PMID- 29126390 TI - Reference-guided de novo assembly approach improves genome reconstruction for related species. AB - BACKGROUND: The development of next-generation sequencing has made it possible to sequence whole genomes at a relatively low cost. However, de novo genome assemblies remain challenging due to short read length, missing data, repetitive regions, polymorphisms and sequencing errors. As more and more genomes are sequenced, reference-guided assembly approaches can be used to assist the assembly process. However, previous methods mostly focused on the assembly of other genotypes within the same species. We adapted and extended a reference guided de novo assembly approach, which enables the usage of a related reference sequence to guide the genome assembly. In order to compare and evaluate de novo and our reference-guided de novo assembly approaches, we used a simulated data set of a repetitive and heterozygotic plant genome. RESULTS: The extended reference-guided de novo assembly approach almost always outperforms the corresponding de novo assembly program even when a reference of a different species is used. Similar improvements can be observed in high and low coverage situations. In addition, we show that a single evaluation metric, like the widely used N50 length, is not enough to properly rate assemblies as it not always points to the best assembly evaluated with other criteria. Therefore, we used the summed z-scores of 36 different statistics to evaluate the assemblies. CONCLUSIONS: The combination of reference mapping and de novo assembly provides a powerful tool to improve genome reconstruction by integrating information of a related genome. Our extension of the reference-guided de novo assembly approach enables the application of this strategy not only within but also between related species. Finally, the evaluation of genome assemblies is often not straight forward, as the truth is not known. Thus one should always use a combination of evaluation metrics, which not only try to assess the continuity but also the accuracy of an assembly. PMID- 29126391 TI - MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1. AB - BACKGROUND: Melanoma is the most lethal type of skin cancer. Since chemoresistance is a significant barrier, identification of regulators affecting chemosensitivity is necessary in order to create new forms of intervention. Prohibitin 1 (PHB1) can act as anti-apoptotic or tumor suppressor molecule, depending on its subcellular localization. Our recent data shown that accumulation of PHB1 protects melanoma cells from chemotherapy-induced cell death. Lacking of post-transcriptional regulation of PHB1 could explain this accumulation. Interestingly, most of melanoma patients have down-regulation of microRNA-195. Here, we investigate the role of miR-195, its impact on PHB1 expression, and on chemosensitivity in melanoma cells. METHODS: TCGA-RNAseq data obtained from 341 melanoma patient samples as well as a panel of melanoma cell lines were used in an expression correlation analysis between PHB1 and predicted miRNAs. miR-195 impact on PHB1 mRNA and protein levels and relevance of this regulation were investigated in UACC-62 and SK-MEL-5 melanoma lines by RT-qPCR and western blot, luciferase reporter and genetic rescue experiments. Cell proliferation, cell-cycle analysis and caspase 3/7 assay were performed to investigate the potential action of miR-195 as chemosensitizer in melanoma cells treated with cisplatin and temozolomide. RESULTS: Analysis of the TCGA-RNAseq revealed a significant negative correlation (Pearson) between miR-195 and PHB1 expression. Moreover, RT-qPCR data showed that miR-195 is down-regulated while PHB1 is up-regulated in a collection of melanoma cells. We demonstrated that miR 195 regulates PHB1 directly by RT-qPCR and western blot in melanoma cells and luciferase assays. To establish PHB1 as a relevant target of miR-195, we conducted rescue experiments in which we showed that PHB1 transgenic expression could antagonize the suppressive effect miR-195 on the proliferation of melanoma cells. Finally, transfection experiments combined with drug treatments performed in the UACC-62 and SK-MEL-5 melanoma cells corroborated miR-195 as potential anti proliferative agent, with potential impact in sensitization of melanoma cell death. CONCLUSIONS: This study support the role of miR-195 as anti-proliferative miRNA via targeting of PHB1 in melanoma cells. PMID- 29126392 TI - miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy. METHODS: We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model. RESULTS: The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR 17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = -0.28, P = 3.88 * 10-3). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient. CONCLUSIONS: Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC. PMID- 29126393 TI - Genomic characterisation of clinical and environmental Pseudomonas putida group strains and determination of their role in the transfer of antimicrobial resistance genes to Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas putida is a Gram-negative, non-fermenting bacterium frequently encountered in various environmental niches. P. putida rarely causes disease in humans, though serious infections and outbreaks have been reported from time to time. Some have suggested that P. putida functions as an exchange platform for antibiotic resistance genes (ARG), and thus represents a serious concern in the spread of ARGs to more pathogenic organisms within a hospital. Though poorly understood, the frequency of ARG exchange between P. putida and the more virulent Pseudomonas aeruginosa and its clinical relevance are particularly important for designing efficient infection control strategies, such as deciding whether high-risk patients colonized with a multidrug resistant but typically low pathogenic P. putida strain should be contact isolated or not. RESULTS: In this study, 21,373 screening samples (stool, rectal and throat swab) were examined to determine the presence of P. putida in a high-risk group of haemato-oncology patients during a 28-month period. A total of 89 P. putida group strains were isolated from 85 patients, with 41 of 89 (46.1%) strains harbouring the metallo beta-lactamase gene bla VIM. These 41 clinical isolates, plus 18 bla VIM positive environmental P. putida isolates, and 17 bla VIM positive P. aeruginosa isolates, were characterized by whole genome sequencing (WGS). We constructed a maximum likelihood tree to separate the 59 bla VIM positive P. putida group strains into eight distinct phylogenetic clusters. Bla VIM-1 was present in 6 clusters while bla VIM-2 was detected in 4 clusters. Five P. putida group strains contained both, bla VIM-1 and bla VIM-2 genes. In contrast, all P. aeruginosa strains belonged to a single genetic cluster and contained the same ARGs. Apart from bla VIM-2 and sul genes, no other ARGs were shared between P. aeruginosa and P. putida. Furthermore, the bla VIM-2 gene in P. aeruginosa was predicted to be only chromosomally located. CONCLUSION: These data provide evidence that no exchange of comprehensive ARG harbouring mobile genetic elements had occurred between P. aeruginosa and P. putida group strains during the study period, thus eliminating the need to implement enhanced infection control measures for high-risk patients colonized with a bla VIM positiv P. putida group strains in our clinical setting. PMID- 29126394 TI - Prospective study of autism phenomenology and the behavioural phenotype of Phelan McDermid syndrome: comparison to fragile X syndrome, Down syndrome and idiopathic autism spectrum disorder. AB - BACKGROUND: The limited behavioural phenotype literature on Phelan-McDermid syndrome (PMS) indicates atypically high levels of activity, impulsivity and autism spectrum disorder (ASD) behaviours. Divergent profiles of ASD in PMS are also reported, with some studies demonstrating similarities to idiopathic ASD and others indicating an uneven profile of social and communication impairments and repetitive behaviours. An evaluation of the behavioural phenotype of PMS and the prevalence and phenomenology of ASD is warranted, particularly given the causal involvement of the SHANK3 gene in the aetiology of PMS. METHODS: Carers of individuals with PMS (N = 30; mean age = 10.55, SD = 7.08) completed questionnaires relating to impulsivity, overactivity, mood, interest and pleasure, repetitive behaviour and ASD phenomenology. These data were compared to data from matched samples of individuals with fragile X and Down syndromes and idiopathic ASD. In order to evaluate the profile of ASD phenomenology in PMS, two comparisons were made: first, including the total sample with PMS, and second, including only those who met the threshold indicative of autism on an ASD screening measure. RESULTS: The results revealed lower mood in individuals with PMS, but no differences in impulsivity and overactivity. Compulsive and routine driven repetitive behaviours were less common in the total sample with PMS; however, motor-based stereotyped behaviours were more common. ASD phenomenology was highly prevalent, with 87% of the sample meeting the cutoff score for ASD and 57% meeting the cutoff for autism. The profile of ASD phenomenology in the total sample with PMS differed from those with idiopathic ASD across impairments in communication and social interaction and repetitive behaviour. However, the profile of those who met the threshold for autism was commensurate to those with idiopathic ASD. CONCLUSIONS: ASD phenomenology is common within PMS. Whilst the total sample may display an atypical profile of ASD behaviour, the profile in those who met the threshold for autism was very similar to those with idiopathic ASD. These results are discussed in relation to the wider behavioural phenotype and the emerging evidence of an autism endophenotype in PMS. PMID- 29126395 TI - Contrast-enhanced ultrasound of small cell carcinoma in urinary bladder: a case report and review of literature. AB - BACKGROUND: Small cell carcinoma of the urinary bladder (SCCB) is a relatively rare malignant bladder tumor, and few reports have investigated the microvasculature of SCCB imaged using contrast-enhanced ultrasound (CEUS). CASE PRESENTATION: A 63-year-old female was admitted to our hospital after experiencing painless gross hematuria for one week. The gray-scale ultrasound (US) demonstrated a 4.8 * 3.4 * 3.6-cm3 hypoechoic mass in the apex of the urinary bladder with a wide base and an irregular surface; the mass did not move with changes in body position. Color Doppler flow imaging (CDFI) showed rich blood flow in the mass. CEUS with low mechanical index (MI) of 0.06 confirmed a highly enhanced 5.0 * 3.3 * 3.8 cm3 mass within the bladder at the apex wall. The time-intensity curves (TICs) showed a wash-in time of 10 s, a time to peak (TTP) of 33 s, a signal intensity (SI) of 62.7% and a wash-out time > 60 s. Finally, the transurethral resection of the bladder tumor (TURBT) was performed, and the pathological examination proved the diagnosis of SCCB. CONCLUSION: CEUS can provide valuable information related to the rich microvasculature of SCCB, which may be helpful in its diagnosis. PMID- 29126396 TI - Feasibility of structured endurance training and Mediterranean diet in BRCA1 and BRCA2 mutation carriers - an interventional randomized controlled multicenter trial (LIBRE-1). AB - BACKGROUND: Women with pathogenic BRCA germline mutations have an increased risk for breast and ovarian cancer that seems to be modified by life-style factors. Though, randomized trials investigating the impact of lifestyle interventions on cancer prevention and prognosis in BRCA carriers are still missing. METHODS: We implemented a multicenter, prospective randomized controlled trial in BRCA1/2 patients, comparing a lifestyle intervention group (IG) with a control group (CG) with the primary aim to prove feasibility. Intervention comprised a structured, individualized endurance training alongside nutrition education based on the Mediterranean diet (MD) for 3 months, plus monthly group training and regular telephone contact during the subsequent 9 months. The CG attended one session on healthy nutrition and the benefits of physical activity. Primary endpoints were feasibility, acceptance and satisfaction over 12 months. Furthermore, effects on physical fitness, diet profile, body mass index (BMI), quality of life and perceived stress were investigated. RESULTS: Sixty-eight participants (mean age 41, mean BMI 23.2 kg/m2) were enrolled, of whom 55 (81%, 26 IG, 29 CG) completed 12 months. 73% (n = 26) participated in at least 70% of all intervention sessions. Predictors for drop-outs (19%; n = 13) or non-adherence (27%; n = 7) were not found. 73% rated the program highly and 80% would participate again. Severe adverse events did not occur. Positive effects in the IG compared to the CG were observed for secondary endpoints: BMI, MD eating pattern and stress levels. CONCLUSIONS: This lifestyle intervention was feasible, safe and well accepted. Positive results on eating habits, physical fitness and stress levels warrant a larger randomized trial. TRIAL REGISTRATION: The study has been retrospectively registered at ClinicalTrials.gov (reference: NCT02087592 ) on March 12, 2014. The first patient was included on February 24, 2014. PMID- 29126397 TI - No MERS-CoV but positive influenza viruses in returning Hajj pilgrims, China, 2013-2015. AB - BACKGROUND: There is global health concern that the mass movement of pilgrims to and from Mecca annually could contribute to the international spread of Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In China, about 11,000 Muslim pilgrims participate in the Hajj gathering in Mecca annually. This is the first report of MERS-CoV and respiratory virus molecular screening of returning pilgrims at points of entry in China from 2013 to 2015. METHODS AND RESULTS: A total of 847 returning Hajj pilgrims participated in this study. The test results indicated that of the travelers, 34 tested positive for influenza A virus, 14 for influenza B virus, 4 for metapneumo virus, 2 for respiratory syncytial virus, and 3 for human coronavirus. There was a significant difference in the rates of positive and negative influenza virus tests between Hajj pilgrims with symptoms and those without. The detection rates of influenza virus were not significantly different among the three years studied, at 5.3, 6.0 and 6.3% for 2013, 2014 and 2015, respectively. DISCUSSION AND CONCLUSION: The MERS-CoV and respiratory viruses detection results at points of entry in China from 2013 to 2015 indicated that there were no MERS-CoV infection but a 5.7% positive influenza viruses in returning Chinese pilgrims. PMID- 29126398 TI - Characteristics of allelic gene expression in human brain cells from single-cell RNA-seq data analysis. AB - BACKGROUND: Monoallelic expression of autosomal genes has been implicated in human psychiatric disorders. However, there is a paucity of allelic expression studies in human brain cells at the single cell and genome wide levels. RESULTS: In this report, we reanalyzed a previously published single-cell RNA-seq dataset from several postmortem human brains and observed pervasive monoallelic expression in individual cells, largely in a random manner. Examining single nucleotide variants with a predicted functional disruption, we found that the "damaged" alleles were overall expressed in fewer brain cells than their counterparts, and at a lower level in cells where their expression was detected. We also identified many brain cell type-specific monoallelically expressed genes. Interestingly, many of these cell type-specific monoallelically expressed genes were enriched for functions important for those brain cell types. In addition, function analysis showed that genes displaying monoallelic expression and correlated expression across neuronal cells from different individual brains were implicated in the regulation of synaptic function. CONCLUSIONS: Our findings suggest that monoallelic gene expression is prevalent in human brain cells, which may play a role in generating cellular identity and neuronal diversity and thus increasing the complexity and diversity of brain cell functions. PMID- 29126399 TI - Production and purification of chimeric HBc virus-like particles carrying influenza virus LAH domain as vaccine candidates. AB - BACKGROUND: The lack of a universal influenza vaccine is a global health problem. Interest is now focused on structurally conserved protein domains capable of eliciting protection against a broad range of influenza virus strains. The long alpha helix (LAH) is an attractive vaccine component since it is one of the most conserved influenza hemagglutinin (HA) stalk regions. For an improved immune response, the LAH domain from H3N2 strain has been incorporated into virus-like particles (VLPs) derived from hepatitis B virus core protein (HBc) using recently developed tandem core technology. RESULTS: Fermentation conditions for recombinant HBc-LAH were established in yeast Pichia pastoris and a rapid and efficient purification method for chimeric VLPs was developed to match the requirements for industrial scale-up. Purified VLPs induced strong antibody responses against both group 1 and group 2 HA proteins in mice. CONCLUSION: Our results indicate that the tandem core technology is a useful tool for incorporation of highly hydrophobic LAH domain into HBc VLPs. Chimeric VLPs can be successfully produced in bioreactor using yeast expression system. Immunologic data indicate that HBc VLPs carrying the LAH antigen represent a promising universal influenza vaccine component. PMID- 29126401 TI - Dyslipidaemia for patients with low-energy femoral neck fractures after the treatment of cancellous screws: a retrospective study with a 3-year minimum follow-up. AB - BACKGROUND: Avascular necrosis of the femoral head (AVNFH) occurs infrequently following femoral neck fracture. The association between AVNFH and dyslipidaemia remains controversial. Although major risk factors for AVNFH have been proposed, most of them remain under discussion. Our purpose herein was to evaluate the association between dyslipidaemia and AVNFH following low-energy femoral neck fractures treated with cancellous screws in elderly patients in our tertiary care centre. METHODS: Four hundred and seventy-two consecutive patients (472 hips) with low-energy femoral neck fractures were identified and treated with cancellous screws from July 2007 to April 2013. Patients underwent evaluations preoperatively and each subsequent postoperative visit (months 1, 6, 12, 18, 24, 30, and 36). Clinical and radiographic evaluations were documented at each visit. The risk factors of AVNFH were assessed by multivariate binary logistic analysis. RESULTS: Follow-up was available for 277 patients, which included 135 patients diagnosed with AVNFH (AVNFH group) and 142 patients without AVNFH (control group). The median follow-up for patients alive at the time of analysis was 40 months (range, 37 to 46 months). The mean total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo-B) values were considerably higher in the AVNFH group compared with those in the control group. The mean high density lipoprotein cholesterol (HDL-C) and apolipoprotein A1(Apo-A1) values were significantly lower in the AVNFH group compared with those in the control group. A multivariate logistic backward regression model showed that HDL-C and LDL-C were the only variables associated with the development of postoperative AVNFH in patients with a femoral neck fracture (Odds ratio[OR] 33.09, 95% Confidence Interval[CI]: 2.65-19.42, p < 0.001 and OR 45.94, 95% CI: 0.47-27.75, p < 0.001, respectively). CONCLUSION: Our results suggest that both low HDL-C and high LDL-C have a tendency to result in the occurrence of AVNFH in elderly patients with low-energy femoral neck fractures treated with cancellous screws. PMID- 29126402 TI - Using social media to support small group learning. AB - BACKGROUND: Medical curricula are increasingly using small group learning and less didactic lecture-based teaching. This creates new challenges and opportunities in how students are best supported with information technology. We explored how university-supported and external social media could support collaborative small group working on our new undergraduate medical curriculum. METHODS: We made available a curation platform (Scoop.it) and a wiki within our virtual learning environment as part of year 1 Case-Based Learning, and did not discourage the use of other tools such as Facebook. We undertook student surveys to capture perceptions of the tools and information on how they were used, and employed software user metrics to explore the extent to which they were used during the year. RESULTS: Student groups developed a preferred way of working early in the course. Most groups used Facebook to facilitate communication within the group, and to host documents and notes. There were more barriers to using the wiki and curation platform, although some groups did make extensive use of them. Staff engagement was variable, with some tutors reviewing the content posted on the wiki and curation platform in face-to-face sessions, but not outside these times. A small number of staff posted resources and reviewed student posts on the curation platform. CONCLUSIONS: Optimum use of these tools depends on sufficient training of both staff and students, and an opportunity to practice using them, with ongoing support. The platforms can all support collaborative learning, and may help develop digital literacy, critical appraisal skills, and awareness of wider health issues in society. PMID- 29126400 TI - The preoperative neutrophil to lymphocyte ratio is a superior indicator of prognosis compared with other inflammatory biomarkers in resectable colorectal cancer. AB - BACKGROUND: Growing evidence has indicated that some inflammatory markers, including lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), can be used as indicators in the prognosis of colorectal cancer (CRC). However, there is controversy concerning what is the best predictor of prognosis in CRC. METHODS: A cohort of 1744 CRC patients in our institution was analyzed retrospectively. Harrell's concordance index (c-index) and Bayesian information criterion (BIC) were used to determine the optimal cut-off values of inflammatory markers and compare their predictive capacity. The association of inflammatory markers with overall survival (OS) and cancer-specific survival (CSS) was analyzed using Kaplan-Meier methods with log-rank test, followed by multivariate Cox proportional hazards model. RESULTS: The multivariate analysis indicated that among these inflammatory markers, NLR (< 2.0 vs. >= 2.0) was the only independent prognostic factor for poor OS [hazard ratio (HR) = 0.758, 95% confidence intervals (CI) = 0.598-0.960, P = 0.021)] and CSS (HR = 0.738, 95% CI = 0.573 0.950, P = 0.018). Among these inflammatory markers, the c-index and BIC value for NLR were maximum and minimum for OS, respectively. In addition, the c-index was higher and the BIC value was smaller in TNM staging combined with NLR compared with the values obtained in TNM staging alone. CONCLUSION: NLR is a superior indicator of prognosis compared with LMR, PLR, and PNI in CRC patients, and NLR may serve as an additional indicator based on the current tumor staging system. PMID- 29126404 TI - Correction to: Flipping for success: evaluating the effectiveness of a novel teaching approach in a graduate level setting. AB - Following publication of the original article [1], author 2 pointed out that his name has since changed from Adiba Islam to Adiba Ashrafi. PMID- 29126403 TI - Optimization of physical conditions for the production of thermostable T1 lipase in Pichia guilliermondii strain SO using response surface methodology. AB - BACKGROUND: Pichia guilliermondii was found capable of expressing the recombinant thermostable lipase without methanol under the control of methanol dependent alcohol oxidase 1 promoter (AOXp 1). In this study, statistical approaches were employed for the screening and optimisation of physical conditions for T1 lipase production in P. guilliermondii. RESULT: The screening of six physical conditions by Plackett-Burman Design has identified pH, inoculum size and incubation time as exerting significant effects on lipase production. These three conditions were further optimised using, Box-Behnken Design of Response Surface Methodology, which predicted an optimum medium comprising pH 6, 24 h incubation time and 2% inoculum size. T1 lipase activity of 2.0 U/mL was produced with a biomass of OD600 23.0. CONCLUSION: The process of using RSM for optimisation yielded a 3 fold increase of T1 lipase over medium before optimisation. Therefore, this result has proven that T1 lipase can be produced at a higher yield in P. guilliermondii. PMID- 29126405 TI - Electronic portfolio use in pediatric residency and perceived efficacy as a tool for teaching lifelong learning. AB - BACKGROUND: Residency programs use electronic portfolios (efolios) to organize data, track resident performance, and sometimes teach and assess lifelong learning (LLL) skills. Published studies on efolios in graduate medical education are mostly descriptions of implementation at individual institutions. METHODS: An anonymous online survey was sent to 199 pediatric residency program directors across the United States. Efolio usage patterns were described and compared between program directors that perceived efolios effective at fostering LLL and those that did not. RESULTS: Surveys were completed by 82 of 199 program directors (41%), and 55% used efolios. The 20% (9 of 45) of program directors that believed efolios were effective at teaching LLL more often used self assessment (88% vs. 50%, p = 0.05) and goal-setting (75% vs. 40%, p = 0.03) functionalities. Common efolio challenges included limited usability and difficulty integrating data. Most non-users (65%) would like to invest in efolios. CONCLUSIONS: Respondents reported technical and convenience-related challenges to efolio use, which need to be addressed for efolios to meet their potential as valuable learning tools. The use of self-assessments and goal setting features was associated with program directors' perceptions that efolios were effective at fostering LLL. PMID- 29126406 TI - Perceptions of the 2011 ACGME duty hour requirements among residents in all core programs at a large academic medical center. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) implemented revisions to resident duty hour requirements (DHRs) in 2011 to improve patient safety and resident well-being. Perceptions of DHRs have been reported to vary by training stage and specialty among internal medicine and general surgery residents. The authors explored perceptions of DHRs among all residents at a large academic medical center. METHODS: The authors administered an anonymous cross-sectional survey about DHRs to residents enrolled in all ACGME accredited core residency programs at their institution. Residents were categorized as medical and pediatric, surgery, or other. RESULTS: In total, 736 residents representing 24 core specialty residency programs were surveyed. The authors received responses from 495 residents (67%). A majority reported satisfaction (78%) with DHRs and believed DHRs positively affect their training (73%). Residents in surgical specialties and in advanced stages of training were significantly less likely to view DHRs favorably. Most respondents believed fatigue contributes to errors (89%) and DHRs reduce both fatigue (80%) and performance of clinical duties while fatigued (74%). A minority of respondents (37%) believed that DHRs decrease medical errors. This finding may reflect beliefs that handovers contribute more to errors than fatigue (41%). Negative perceived effects included diminished patient familiarity and continuity of care (62%) and diminished clinical educational experiences for residents (41%). CONCLUSIONS: A majority of residents reported satisfaction with the 2011 DHRs, although satisfaction was significantly less among residents in surgical specialties and those in advanced stages of training. PMID- 29126407 TI - TP53 Arg72 as a favorable prognostic factor for Chinese diffuse large B-cell lymphoma patients treated with CHOP. AB - BACKGROUND: TP53 Arg72Pro (SNP rs1042522) is associated with risk of non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL. However, the relationship between this SNP and prognosis of DLBCL in Asians is unknown. METHODS: Genotyping of TP53 Arg72Pro was done in 425 Chinese DLBCL patients. Two hundred and eighty-nine patients were treated with R-CHOP, and 136 patients received CHOP or CHOP-like as frontline regimen. Three hundred and ninety-six patients were assessable for the efficacy. RESULTS: Patients with Arg/Arg and Arg/Pro at codon 72 of TP53 had a higher complete response rate (61% vs. 44%, P = 0.007) than those with Pro/Pro. In the subgroup treated with CHOP or CHOP-like therapy, patients with Arg/Arg and Arg/Pro showed a higher 5-year overall survival (OS) rate than those with Pro/Pro (68.8% vs. 23.2%, P = 0.001). Multivariate Cox regression analysis revealed TP53 Arg72 as a favorable prognostic factor in this group. However, the combination of rituximab with CHOP significantly increased the 5-year OS rate of patients with Pro/Pro to 63%. CONCLUSION: This study revealed TP53 Arg72 as a favorable prognostic factor for Chinese DLBCL patients treated with CHOP or CHOP-like as frontline therapy. PMID- 29126408 TI - Concomitant glenohumeral pathologies in high-grade acromioclavicular separation (type III - V). AB - BACKGROUND: Acromioclavicular joint (ACJ) dislocations are common injuries of the shoulder associated with physical activity. The diagnosis of concomitant injuries proves complicated due to the prominent clinical symptoms of acute ACJ dislocation. Because of increasing use of minimally invasive surgery techniques concomitant pathologies are diagnosed more often than with previous procedures. METHODS: The aim of this study was to identify the incidence of concomitant intraarticular injuries in patients with high-grade acromioclavicular separation (Rockwood type III - V) as well as to reveal potential risk constellations. The concomitant pathologies were compiled during routine arthroscopically assisted treatment in altogether 163 patients (147 male; 16 female; mean age 36.8 years) with high-grade acromioclavicular separation (Rockwood type III: n = 60; Rockwood type IV: n = 6; Rockwood type V: n = 97). RESULTS: Acromioclavicular separation occurred less often in women than men (1:9). In patients under 35, the most common cause for ACJ dislocation was sporting activity (37.4%). Rockwood type V was observed significantly more often than the other types with 57.5% (Rockwood type III = 36.8%, Rockwood type IV 3.7%). Concomitant pathologies were diagnosed in 39.3% of the patients with that number rising to as much as 57.3% in patients above 35 years. Most common associated injuries were rotator cuff injuries (32.3%), chondral defects (30.6%) and SLAP-lesions (22.6%). Of all patients, 8.6% needed additional reconstructive surgery. CONCLUSION: Glenohumeral injuries are a much more common epiphenomenon during acromioclavicular separation than previously ascertained. High risk group for accompanying injuries are patients above 35 years with preexisting degenerative disease. The increasing use of minimally invasive techniques allows for an easier diagnosis and simultaneous treatment of the additional pathologies. PMID- 29126410 TI - More than visual literacy: art and the enhancement of tolerance for ambiguity and empathy. AB - BACKGROUND: Comfort with ambiguity, mostly associated with the acceptance of multiple meanings, is a core characteristic of successful clinicians. Yet past studies indicate that medical students and junior physicians feel uncomfortable with ambiguity. Visual Thinking Strategies (VTS) is a pedagogic approach involving discussions of art works and deciphering the different possible meanings entailed in them. However, the contribution of art to the possible enhancement of the tolerance for ambiguity among medical students has not yet been adequately investigated. We aimed to offer a novel perspective on the effect of art, as it is experienced through VTS, on medical students' tolerance of ambiguity and its possible relation to empathy. METHODS: Quantitative method utilizing a short survey administered after an interactive VTS session conducted within mandatory medical humanities course for first-year medical students. The intervention consisted of a 90-min session in the form of a combined lecture and interactive discussions about art images. The VTS session and survey were filled by 67 students in two consecutive rounds of first-year students. RESULTS: 67% of the respondents thought that the intervention contributed to their acceptance of multiple possible meanings, 52% thought their visual observation ability was enhanced and 34% thought that their ability to feel the sufferings of other was being enhanced. Statistically significant moderate-to-high correlations were found between the contribution to ambiguity tolerance and contribution to empathy (0.528-0.744; p <= 0.01). CONCLUSIONS: Art may contribute especially to the development of medical students' tolerance of ambiguity, also related to the enhancement of empathy. The potential contribution of visual art works used in VTS to the enhancement of tolerance for ambiguity and empathy is explained based on relevant literature regarding the embeddedness of ambiguity within art works, coupled with reference to John Dewey's theory of learning. Given the situational nature of the tolerance for ambiguity in this context, VTS provides a path for enhancing ambiguity tolerance that is less conditioned by character traits. Moreover, the modest form of VTS we utilized, not requesting a significant alteration in the pre-clinical curricula, suggests that enhancing the tolerance of ambiguity and empathy among medical students may be particularly feasible. PMID- 29126409 TI - Genomic determinants of long-term cardiometabolic complications in childhood acute lymphoblastic leukemia survivors. AB - BACKGROUND: While cure rates for childhood acute lymphoblastic leukemia (cALL) now exceed 80%, over 60% of survivors will face treatment-related long-term sequelae, including cardiometabolic complications such as obesity, insulin resistance, dyslipidemia and hypertension. Although genetic susceptibility contributes to the development of these problems, there are very few studies that have so far addressed this issue in a cALL survivorship context. METHODS: In this study, we aimed at evaluating the associations between common and rare genetic variants and long-term cardiometabolic complications in survivors of cALL. We examined the cardiometabolic profile and performed whole-exome sequencing in 209 cALL survivors from the PETALE cohort. Variants associated with cardiometabolic outcomes were identified using PLINK (common) or SKAT (common and rare) and a logistic regression was used to evaluate their impact in multivariate models. RESULTS: Our results showed that rare and common variants in the BAD and FCRL3 genes were associated (p<0.05) with an extreme cardiometabolic phenotype (3 or more cardiometabolic risk factors). Common variants in OGFOD3 and APOB as well as rare and common BAD variants were significantly (p<0.05) associated with dyslipidemia. Common BAD and SERPINA6 variants were associated (p<0.05) with obesity and insulin resistance, respectively. CONCLUSIONS: In summary, we identified genetic susceptibility loci as contributing factors to the development of late treatment-related cardiometabolic complications in cALL survivors. These biomarkers could be used as early detection strategies to identify susceptible individuals and implement appropriate measures and follow-up to prevent the development of risk factors in this high-risk population. PMID- 29126411 TI - Thermal conditions during early life influence seasonal maternal strategies in the three-spined stickleback. AB - BACKGROUND: Conditions experienced by a female during early life may affect her reproductive strategies and maternal investment later in life. This effect of early environmental conditions is a potentially important mechanism by which animals can compensate for the negative impacts of climate change. In this study, we experimentally tested whether three-spined sticklebacks (Gasterosteus aculeatus) change their maternal strategy according to environmental temperatures experienced earlier in life. We studied maternal investment from a life-history perspective because females are expected to adjust their reproductive strategy in relation to their current and future reproductive returns as well as offspring fitness. RESULTS: F1 families were reared in control and elevated winter temperatures and their reproductive trajectories were studied when returned to common conditions. Females that had experienced the warm winter treatment (n = 141) had a lower fecundity and reduced breeding and total lifespan compared to the control individuals (n = 159). Whereas the control females tended to produce their heaviest and largest clutches in their first reproductive attempt, the warm acclimated females invested less in their first clutch, but then produced increasingly heavy clutches over the course of the breeding season. Egg mass increased with clutch number at a similar rate in the two groups. The warm acclimated females increased the investment of carotenoids in the first and last clutches of the season. Thus, any transgenerational effects of the maternal thermal environment on offspring phenotype may be mediated by the allocation of antioxidants into eggs but not by egg size. CONCLUSIONS: Our results indicate that conditions experienced by females during juvenile life have a profound effect on life-time maternal reproductive strategies. The temperature-induced changes in maternal strategy may be due to constraints imposed by the higher energetic costs of a warm environment, but it is possible that they allow the offspring to compensate for higher energetic costs and damage when they face the same thermal stress as did their mothers. PMID- 29126412 TI - Obstetric fistulae in southern Mozambique: incidence, obstetric characteristics and treatment. AB - BACKGROUND: Obstetric fistula is one of the most devastating consequences of unmet needs in obstetric services. Systematic reviews suggest that the pooled incidence of fistulae in community-based studies is 0.09 per 1000 recently pregnant women; however, as facility delivery is increasing, for the most part, in Africa, incidence of fistula should decrease. Few population-based studies on fistulae have been undertaken in Sub-Saharan Africa, including Mozambique. This study aimed to estimate the incidence of obstetric fistulae in recently delivered mothers, and to describe the clinical characteristics and care, as well as the outcome, after surgical repair. METHODS: We selected women who had delivered up to 12 months before the start of the study (June, 1st 2016). They were part of a cohort of women of reproductive age (12-49 years), recruited from selected clusters in rural areas of Maputo and Gaza provinces, Southern Mozambique, who were participating in an intervention trial (the Community Level Interventions for Pre-eclampsia trial or CLIP trial). Case identification was completed by self reported constant urine leakage and was confirmed by clinical assessment. Women who had confirmed obstetric fistulae were referred for surgical repair. Data were entered into a REDCap database and analysed using R software. RESULTS: Five women with obstetric fistulae were detected among 4358 interviewed, giving an incidence of 1.1 per 1000 recently pregnant women (95% CI 2.16-0.14). All but one had Caesarean section and all of the babies died. Four were stillborn, and one died very soon after birth. All of the patients identified and reached the primary health facility in reasonable time. Delays occurred in the care: in diagnosis of obstructed labour, and in the decision to refer to the secondary or third-level hospital. All but one of the women were referred to surgical repair and the fistulae successfully closed. CONCLUSION: This population-based study reports a high incidence of obstetric fistulae in an area with high numbers of facility births. Few first and second delays in reaching care, but many third delays in receiving care, were identified. This raises concerns for quality of care. PMID- 29126413 TI - Leaves from banana (Musa nana) and maize (Zea mays) have no phyto-prophylactic effects on the susceptibility of grass carp (Ctenopharyngodon idella) to Aeromonas hydrophila infection. AB - BACKGROUND: The ubiquitous and opportunistic bacterial pathogen Aeromonas hydrophila has been associated with ulcerative dermatitis in fish, especially under stressful conditions. It can cause severe losses in fresh water aquaculture and is particularly prevalent in tropical and subtropical regions. Fresh leaves from maize and bananas have been used as feed supplement by fish farmers in Vietnam and it has been reported that they may have phyto-prophylactic benefits. In the present study, a feeding trial was conducted to investigate the benefits of providing maize and banana leaves as feed supplement: to determine if they were taken up and digested by grass carp (Ctenopharyngodon idella), if this uptake resulted in improved growth performance, and if leaf supplementation protected fish when challenged with A. hydrophila by intramuscular injection. RESULTS: All fish were fed an identical ratio of commercial pelleted feed relative to biomass. However, in 12/18 tanks, this diet was supplemented with either fresh banana leaves or fresh maize leaves; offered ad libitum. Addition of leaves increased the overall feed conversion ratio (FCR) significantly. However, if only the pellet were taken into account, then no difference was found between treatments. Changes to the isotopic composition of the fish showed leaf nutrient uptake occurred. No prophylactic effects of feeding banana or maize leaves were detected against infection with A. hydrophila, and the diet did not induce changes in the fish haematocrit. However, addition of the maize leaves was associated with significantly reduced severity of the skin lesions, which could improve the market value of the fish. CONCLUSIONS: Addition of the leaf supplement did not result in significantly improved growth performance. Similarly, the effect of the supplement on the fish survival to infection was not significant. PMID- 29126414 TI - High-density lipoprotein cholesterol efflux capacity is inversely associated with cardiovascular risk: a systematic review and meta-analysis. AB - BACKGROUND: A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL C) is associated with cardiovascular risk. A key cardioprotective property of HDL is cholesterol efflux capacity (CEC), the ability of HDL to accept cholesterol from macrophages. In this study, we aimed to identify the predictive value of CEC for cardiovascular risk. METHODS: The relative risks (RRs) and 95% confidence intervals (CIs) were pooled to analyze the association between CEC and the incidence of cardiovascular events and all-cause mortality. The odds ratios (ORs) and 95% CIs were pooled to estimate the association of CEC and the prevalence of cardiovascular events. RESULTS: A total of 15 studies were included. Results showed that the highest CEC was significantly associated with a reduced risk of cardiovascular events incidents compared to the lowest CEC (RR, 0.56; 95% CI, 0.37 to 0.85; I 2, 89%); the pooled RR of cardiovascular risk for per unit SD increase was 0.87 (95% CI, 0.73 to 1.04; I 2, 67%). Dose-response curve indicated that cardiovascular risk decreased by 39% (RR, 0.61; 95% CI, 0.51 to 0.74) for per unit CEC increase. Similarly, an inverse association was observed between CEC and the prevalence of cardiovascular events (highest vs. lowest, OR, 0.30; 95% CI, 0.17 to 0.5; I 2 = 63%; per unit SD increase, OR, 0.94; 95% CI, 0.90 to 0.98; I 2 = 71%). However, based on the current data, CEC was not significantly associated with all-cause mortality. CONCLUSIONS: Findings from this meta analysis suggest that HDL-mediated CEC is inversely associated with cardiovascular risk, which appears to be independent of HDL concentration. The growing understanding of CEC and its role in cardiovascular risk decrease may improve the accuracy of cardiovascular risk prediction and also open important avenues to develop novel therapeutic targeting HDL metabolism. PMID- 29126415 TI - Cost of illness of atrial fibrillation: a nationwide study of societal impact. AB - BACKGROUND: The prevalence of atrial fibrillation is increasing rapidly; however, to date, population-based data are lacking on the attributable cost of illness of atrial fibrillation from a societal perspective, including both direct and indirect costs. METHODS: The study was an incidence-based cost-of-illness study based on national registries covering the entire population of Denmark. We identified all patients with a first-time hospital diagnosis of atrial fibrillation between 2001 and 2012. For every atrial fibrillation patient, we identified three age- and sex-matched controls from the general population. Both the total and the attributable costs of atrial fibrillation were estimated based on individual level information on hospital care (in- and out-patient contacts), primary sector care, use of prescription drugs and productivity loss. RESULTS: Average 3-year societal costs per patient attributable to atrial fibrillation were estimated to be ?20,403-26,544 during the study period. The costs were highest during the first year after diagnosis of atrial fibrillation. Admission costs constituted the largest cost component, whereas primary sector costs and medicine costs only constituted minor components. The attributable costs were more than two-fold higher among patients experiencing a stroke. The total 3-year cost attributable to atrial fibrillation in Denmark was estimated to be ?219-295 million. CONCLUSIONS: The societal costs attributable to atrial fibrillation are significant. Reducing the need for hospitalizations, in particular from stroke, is a key factor in controlling the costs. PMID- 29126416 TI - Adjunctive use of physostigmine salicylate (Anticholium(r)) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo controlled, monocentric trial (Anticholium(r) per Se). AB - BACKGROUND: Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor physostigmine (Anticholium(r)). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. METHODS: Anticholium(r) per Se is a randomized, double-blind, placebo controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with physostigmine salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. DISCUSSION: This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of physostigmine (Anticholium(r)) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. TRIAL REGISTRATION: EudraCT Number: 2012-001650 26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017). PMID- 29126417 TI - Sclerosing angiomatoid nodular transformation of the spleen in a patient with Maffucci syndrome: a case report and review of literature. AB - BACKGROUND: Maffucci syndrome is a congenital, non-hereditary mesodermal dysplasia characterized by multiple enchondromas and hemangiomas. The presence of visceral vascular lesions in this syndrome is exceedingly rare. CASE PRESENTATION: We report a 26-year-old female who was diagnosed with Maffucci syndrome along with sclerosing angiomatoid nodular transformation (SANT) of the spleen. The patient underwent a laparoscopic splenectomy. Immunostaining of the excised specimen revealed 3 distinct types of vessels in the angiomatoid nodules: CD34-/CD8-/CD31+ small veins, CD34-/CD8+/CD31+ sinusoids, and CD34+/CD8-/CD31+ capillaries, leading to the diagnosis of SANT of the spleen. CONCLUSIONS: This case reports the first patient in the literature exhibiting the features of Maffucci syndrome along with SANT of the spleen. The spleen is probably a predilection site of visceral vascular lesions in this syndrome with a proportion of 4 out of 14. An abdominal Computed Tomography (CT) scan is recommended for any cases of abdominal discomfort. Surgical excision is usually sufficient because of the relatively benign behavior of SANT, however, a more aggressive follow-up is proposed due to the high risk of malignant transformation of enchondromas and development of other neoplasms associated with this syndrome. Further studies are required to reveal its genetic basis for comprehensive prognosis evaluation and therapeutic guidance. PMID- 29126418 TI - An image cytometric technique is a concise method to detect adenoviruses and host cell proteins and to monitor the infection and cellular responses induced. AB - BACKGROUND: Genetically modified adenoviruses (Ad) with preferential replications in tumor cells have been examined for a possible clinical applicability as an anti-cancer agent. A simple method to detect viral and cellular proteins is valuable to monitor the viral infections and to predict the Ad-mediated cytotoxicity. METHODS: We used type 5 Ad in which the expression of E1A gene was activated by 5'-regulatory sequences of genes that were augmented in the expression in human tumors. The Ad were further modified to have the fiber-knob region replaced with that derived from type 35 Ad. We infected human mesothelioma cells with the fiber-replaced Ad, and sequentially examined cytotoxic processes together with an expression level of the viral E1A, hexon, and cellular cleaved caspase-3 with image cytometric and Western blot analyses. RESULTS: The replication-competent Ad produced cytotoxicity on mesothelioma cells. The infected cells expressed E1A and hexon 24 h after the infection and then showed cleavage of caspase-3, all of which were detected with image cytometry and Western blot analysis. Image cytometry furthermore demonstrated that increased Ad doses did not enhance an expression level of E1A and hexon in an individual cell and that caspase-3-cleaved cells were found more frequently in hexon-positive cells than in E1A-positive cells. Image cytometry thus detected these molecular changes in a sensitive manner and at a single cell level. We also showed that an image cytometric technique detected expression changes of other host cell proteins, cyclin-E and phosphorylated histone H3 at a single cell level. CONCLUSIONS: Image cytometry is a concise procedure to detect expression changes of Ad and host cell proteins at a single cell level, and is useful to analyze molecular events after the infection. PMID- 29126420 TI - Healthcare access for refugee women with limited literacy: layers of disadvantage. AB - BACKGROUND: Record numbers of people, across the world, are forced to be displaced because of conflict or other violations of their human rights, thus becoming refugees. Often, refugees not only have a higher burden of disease but also compromised access to healthcare, as they face many barriers, such as limited knowledge of the local language. However, there is very limited knowledge on the lived experiences of this population. Moreover, the strategies people might develop in their efforts to access healthcare have not been explored in depth, despite their value in establishing peer- support, community based programs. METHODS: In this article, we present the findings of a study aiming to explore the lived experiences of accessing healthcare in the greater Vancouver area for recently-arrived, government-assisted refugee women, who were non literate and non-English-speaking when they arrived in the country. We carried out sixteen semi-structured interviews with eight refugee women, guided by descriptive phenomenology. RESULTS: The findings highlight the intersection of limited knowledge of the local language with low literacy, gender, and refugee status and how it impacts women's access to healthcare, leading to added layers of disadvantage. We discuss three themes: (1) Dependence, often leading to compromised choice and lack of autonomy, (2) Isolation, manifesting as fear in navigating the healthcare system, rejection, or shame for a perceived inadequacy, and (3) Resourcefulness in finding ways to access healthcare. DISCUSSION: We propose that a greater understanding of the intersections of gender, low literacy, and refugee status can guide healthcare workers and policy makers in improving services for this population. Furthermore, It is important to enable seldom-heard, hard to reach populations and facilitate their participation in research in order to understand how vectors of disadvantage intersect. PMID- 29126419 TI - The adverse vascular effects of multi-walled carbon nanotubes (MWCNTs) to human vein endothelial cells (HUVECs) in vitro: role of length of MWCNTs. AB - BACKGROUND: Increasing evidences indicate that exposure to multi-walled carbon nanotubes (MWCNTs) could induce adverse vascular effects, but the role of length of MWCNTs in determining the toxic effects is less studied. This study investigated the adverse effects of two well-characterized MWCNTs to human umbilical vein endothelial cells (HUVECs). METHODS: The internalization and localization of MWCNTs in HUVECs were examined by using transmission electron microscopy (TEM). The cytotoxicity of MWCNTs to HUVECs was assessed by water soluble tetrazolium-8 (WST-8), lactate dehydrogenase (LDH) and neutral red uptake assays. Oxidative stress was indicated by the measurement of intracellular glutathione (GSH) and reactive oxygen species (ROS). ELISA was used to determine the release of inflammatory cytokines. THP-1 monocyte adhesion to HUVECs was also measured. To indicate the activation of endoplasmic reticulum (ER) stress, the expression of ddit3 and xbp-1s was measured by RT-PCR, and BiP protein level was measured by Western blot. RESULTS: Transmission electron microscopy observation indicates the internalization of MWCNTs into HUVECs, with a localization in nuclei and mitochondria. The longer MWCNTs induced a higher level of cytotoxicity to HUVECs compared with the shorter ones. Neither of MWCNTs significantly promoted intracellular ROS, but the longer MWCNTs caused a higher depletion of GSH. Exposure to both types of MWCNTs significantly promoted THP-1 adhesion to HUVECs, accompanying with a significant increase of release of interleukin-6 (IL 6) but not tumor necrosis factor alpha (TNFalpha), soluble ICAM-1 (sICAM-1) or soluble VCAM-1 (sVCAM-1). Moreover, THP-1 adhesion and release of IL-6 and sVCAM 1 induced by the longer MWCNTs were significantly higher compared with the responses induced by the shorter ones. The biomarker of ER stress, ddit3 expression, but not xbp-1s expression or BiP protein level, was significantly induced by the exposure of longer MWCNTs. CONCLUSIONS: Combined, these results indicated length dependent toxic effects of MWCNTs to HUVECs in vitro, which might be associated with oxidative stress and activation of ER stress. PMID- 29126421 TI - Peroneal artery perforator flap for the treatment of chronic lower extremity wounds. AB - BACKGROUND: Reconstruction of chronic lower extremity wounds remains challenging. These wounds are mainly associated with diabetes mellitus, infections, and osteomyelitis. Although several reconstructive techniques are available, the peroneal artery perforator flap has unique advantages. METHODS: In this study, we discuss our experiences with peroneal artery perforator flaps in 55 patients who had suffered from chronic lower limb wounds. The size of the defect, comorbidities, etiology, flap size, and complications were recorded and analyzed based on a retrospective chart review. RESULTS: All 55 flaps survived. In two cases, small superficial necrosis occurred, one of which healed with conservative treatment and the other was reconstructed with split thickness skin grafts. Partial necrosis was observed in nine cases, seven of which were covered with split thickness skin grafts and the remaining two sutured directly after adequate debridement. Vascular compromise was observed in one patient, which was salvaged successfully by performing an exploratory procedure and releasing a few sutures. No complications were seen in the remaining 44 cases. CONCLUSION: The peroneal artery perforator flap is a reliable option for reconstruction of chronic lower extremity wounds. PMID- 29126422 TI - Changes in total and differential leukocyte counts during the clinically silent liver phase in a controlled human malaria infection in malaria-naive Dutch volunteers. AB - BACKGROUND: Both in endemic countries and in imported malaria, changes in total and differential leukocyte count during Plasmodium falciparum infection have been described. To study the exact dynamics of differential leukocyte counts and their ratios, they were monitored in a group of healthy non-immune volunteers in two separate Controlled Human Malaria Infection (CHMI) studies. METHODS: In two CHMI trials, CHMI-a and CHMI-b, 15 and 24 healthy malaria-naive volunteers, respectively, were exposed to bites of infected mosquitoes, using the P. falciparum research strain NF54 and the novel clones NF135.C10 and NF166.C8. After mosquito bite exposure, twice-daily blood draws were taken to detect parasitaemia and to monitor the total and differential leukocyte counts. All subjects received a course of atovaquone-proguanil when meeting the treatment criteria. RESULTS: A total of 39 volunteers participated in the two trials. Thirty-five participants, all 15 participants in CHMI-a and 20 of the 24 volunteers in CHMI-b, developed parasitaemia. During liver stage development of the parasite, the median total leukocyte count increased from 5.5 to 6.1 * 109 leukocytes/L (p = 0.005), the median lymphocyte count from 1.9 to 2.2 (p = 0.001) and the monocyte count from 0.50 to 0.54 (p = 0.038). During the subsequent blood stage infection, significant changes in total and differential leukocyte counts lead to a leukocytopenia (nadir median 3.3 * 109 leukocytes/L, p = 0.0001), lymphocytopenia (nadir median 0.7 * 109 lymphocytes/L, p = 0.0001) and a borderline neutropenia (nadir median 1.5 * 109 neutrophils/L, p = 0.0001). The neutrophil to lymphocyte count ratio (NLCR) reached a maximum of 4.0. Significant correlations were found between parasite load and absolute lymphocyte count (p < 0.001, correlation coefficient - 0.46) and between parasite load and NLCR (p < 0.001, correlation coefficient 0.50). All parameters normalized after parasite clearance. CONCLUSIONS: During the clinically silent liver phase of malaria, an increase of peripheral total leukocyte count and differential lymphocytes and monocytes occurs. This finding has not been described previously. This increase is followed by the appearance of parasites in the peripheral blood after 2-3 days, accompanied by a marked decrease in total leukocyte count, lymphocyte count and the neutrophil count and a rise of the NLCR. PMID- 29126423 TI - The many meanings of evidence: a comparative analysis of the forms and roles of evidence within three health policy processes in Cambodia. AB - BACKGROUND: Discussions within the health community routinely emphasise the importance of evidence in informing policy formulation and implementation. Much of the support for the evidence-based policy movement draws from concern that policy decisions are often based on inadequate engagement with high-quality evidence. In many such discussions, evidence is treated as differing only in quality, and assumed to improve decisions if it can only be used more. In contrast, political science scholars have described this as an overly simplistic view of the policy-making process, noting that research 'use' can mean a variety of things and relies on nuanced aspects of political systems. An approach more in recognition of how policy-making systems operate in practice can be to consider how institutions and ideas influence which pieces of evidence appear to be relevant for, and are used within, different policy processes. METHODS: Drawing on in-depth interviews undertaken in 2015-2016 with key health sector stakeholders in Cambodia, we investigate the evidence perceived to be relevant to policy decisions for three contrasting health policy examples, namely tobacco control, HIV/AIDS and performance-based salary incentives. These cases allow us to examine the ways that policy-relevant evidence may differ given the framing of the issue and the broader institutional context in which evidence is considered. RESULTS: The three health issues show few similarities in how pieces of evidence were used in various aspects of policy-making, despite all being discussed within a broad policy environment in which evidence-based policy-making is rhetorically championed. Instead, we find that evidence use can be better understood by mapping how these health policy issues differ in terms of the issue characteristics, and also in terms of the stakeholders structurally established as having a dominant influence for each issue. Both of these have important implications for evidence use. Contrasting concerns of key stakeholders meant that evidence related to differing issues could be understood in terms of how it was relevant to policy. The stakeholders involved, however, could further be seen to possess differing logics about how to go about achieving their various outcomes - logics that could further help explain the differences seen in evidence utilisation. CONCLUSION: A comparative approach reiterates that evidence is not a uniform concept for which more is obviously better, but rather illustrates how different constructions and pieces of evidence become relevant in relation to the features of specific health policy decisions. An institutional approach that considers the structural position of stakeholders with differing core goals or objectives, as well as their logics related to evidence utilisation, can further help to understand some of the complexities of evidence use in health policy-making. PMID- 29126424 TI - Salivary pH, calcium, phosphorus and selected enzymes in healthy dogs: a pilot study. AB - BACKGROUND: Saliva in dogs, as in humans, is a complex fluid secreted by different salivary glands in the oral cavity to protect the oral mucosa and teeth. The use of saliva as a substitute for blood in diagnosing and prognosticating disease in humans is widely accepted. Salivary biochemistry has also been used as a marker for periodontal disease in humans. No studies have as yet investigated the relation between salivary biochemistry and periodontal disease in dogs, however; neither has the salivary composition of healthy dogs with no oral disease been assessed. The purpose of this study was to obtain an overview on pH distribution and a set of salivary biochemical analytes (calcium, phosphorus, lactate dehydrogenase, lysozyme and amylase) commonly related to oral health in humans in a subset population of healthy young dogs with no periodontal disease or previous oral disease. Data were analyzed to gather salivary reference ranges for pH and each parameter and to assess a possible correlation between salivary and serum analytes. RESULTS: Twenty-nine adult client-owned dogs were recruited for the study. Lactate dehydrogenase and lysozyme showed higher concentrations in saliva than in serum, whereas amylase showed the contrary. Salivary biochemistry values did not differ between males and females or between non-neutered and neutered individuals. No significant correlations between salivary and serum calcium, phosphorus, lactate dehydrogenase, amylase and lysozyme were identified in this study. Data allowed intervals for the salivary pH and other analytes investigated to be obtained from healthy dogs with healthy oral conditions. CONCLUSIONS: These preliminary data can contribute to enlarge our understanding of the functional role of saliva and its relation to oral health in dogs. PMID- 29126425 TI - Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation. AB - BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1-11 and SIRT1-7 in mammals) that deacetylate histones and non-histone proteins, in cancers are largely unknown. METHODS: Hdac7 +/-/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac7 gene in lung cancer. Kaplan-Meier survival analysis was performed to explore the relationship between HDAC7 expression and prognosis of human lung cancers. Recombinant lentivirus-mediated in vivo gene expression or knockdown, Western blotting, and pull-down assay were applied to investigate the underlying molecular mechanism by which Hdac7 promotes lung tumorigenesis. RESULTS: The number and burden of lung tumor were dramatically reduced in Hdac7 +/-/K-Ras mice compared to control K-Ras mice. Also, in Hdac7 +/ /K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Similarly, cell proliferation and anchorage independent growth of human lung cancer cell lines expressing shHDAC7 were also significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac7 mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat3 and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac7 mutant-mediated inhibitory effects on lung tumorigenesis in mice and cell proliferation/soft agar colony formation of human lung cancer cell lines were respectively reversed by expressing dnStat3. Finally, the high HDAC7 mRNA level was found to be correlated with poor prognosis of human lung cancer patients. CONCLUSION: Our study suggests that Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation via deacetylating Stat3 and may shed a light on the design of new therapeutic strategies for human lung cancer. PMID- 29126426 TI - The influence of immediately loaded implant treatment in the atrophic edentulous maxilla on oral health related quality of life of edentulous patients: 3-year results of a prospective study. AB - BACKGROUND: To evaluate oral health related quality of life (OHQoL) in edentulous patients treated with immediately loaded implants in the maxilla. METHODS: Fifty one edentulous patients in two centers received six maxillary implants each were loaded within 24 h with provisional restoration. Definitive restoration was delivered 20-24 weeks later. OHQoL was evaluated preoperatively with the Oral Health Impact Profile 49 questionnaire (OHIP-49) and on five subsequent occasions. OHIP-49 includes seven domains representing functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap. A reduction in OHIP scores indicated an improved OHQoL. RESULTS: Forty-five patients reached the three-year follow up. OHQoL improved after treatment. A plateau of OHQoL improvement was observed at 12 months after surgery. The seven domains improved at different pace, 12 weeks to 12 months after treatment. OHIP showed continuously low scores with no significant changes at consecutive visits 12 months to three years after treatment. Dental status with removable prosthesis in the mandible had a negative impact on OHQoL prior to and during treatment, but did not affect OHQoL after permanent restoration was placed. Patients age or gender did not affect OHQoL. CONCLUSIONS: Patients with edentulous maxilla who received prosthetic rehabilitation on immediately loaded implants experienced the highest improved OHQoL 12 months after implant installation. Quality of life related to oral health continued to be high after three years. Edentulous patients with atrophy of the maxilla experience an improved OHQoL after implant treatment with immediate loading protocol. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00711022 . PMID- 29126427 TI - A murine model for developmental dysplasia of the hip: ablation of CX3CR1 affects acetabular morphology and gait. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is a debilitating condition whose distinguishing signs include incomplete formation of the acetabulum leading to dislocation of the femur, accelerated wear of the articular cartilage and joint laxity resulting in osteoarthritis. It is a complex disorder having environmental and genetic causes. Existing techniques fail to detect milder forms of DDH in newborns leading to hip osteoarthritis in young adults. A sensitive, specific and cost effective test would allow identification of newborns that could be non-invasively corrected by the use of a Pavlik harness. Previously, we identified a 2.5 MB candidate region on human chromosome 3 by using linkage analysis of a 4 generation, 72 member family. Whole exome sequencing of the DNA of 4 severely affected members revealed a single nucleotide polymorphism variant, rs3732378 co-inherited by all 11 affected family members. This variant causes a threonine to methionine amino acid change in the coding sequence of the CX3CR1 chemokine receptor and is predicted to be harmful to the function of the protein To gain further insight into the function of this mutation we examined the effect of CX3CR1 ablation on the architecture of the mouse acetabulum and on the murine gait. METHODS: The hips of 5 and 8 weeks old wild type and CX3CR1 KO mice were analyzed using micro-CT to measure acetabular diameter and ten additional dimensional parameters. Eight week old mice were gait tested using an inclined treadmill with and without load and then underwent micro-CT analysis. RESULTS: (1) KO mice showed larger a 5-17% larger diameter left acetabula than WT mice at both ages. (2) At 8 weeks the normalized area of space (i.e. size discrepancy) between the femur head and acetabulum is significantly larger [38% (p = 0.001) 21% (p = 0.037)] in the KO mice. (3) At 8 weeks gait analysis of these same mice shows several metrics that are consistent with impairment in the KO but not the WT mice. These deficits are often seen in mice and humans who develop hip OA. CONCLUSION: The effect of CX3CR1 deletion on murine acetabular development provides suggestive evidence of a susceptibility inducing role of the CX3CR1 gene on DDH. PMID- 29126428 TI - Validity and reliability of the Spanish version of the Organizational Readiness for Knowledge Translation (OR4KT) questionnaire. AB - BACKGROUND: Organizational readiness to change healthcare practice is a major determinant of successful implementation of evidence-based interventions. However, we lack of comprehensive, valid, and reliable instruments to measure it. We assessed the validity and reliability of the Spanish version of the Organizational Readiness for Knowledge Translation (OR4KT) questionnaire in the context of the implementation of the Prescribe Vida Saludable III project, which seeks to strengthen health promotion and chronic disease prevention in primary healthcare organizations of the Osakidetza (Basque Health Service, Spain). METHODS: A cross-sectional study was conducted including 127 professionals from 20 primary care centers within Osakidetza. They filled in the OR4KT questionnaire twice in a 15- to 30-day period to test repeatability. In addition, we used the Survey of Organizational Attributes for Primary Care (SOAPC) and we documented the number of healthcare professionals who formally engaged in the Prescribe Vida Saludable III project within each participating center to assess concurrent validity. RESULTS: Cronbach's alpha for the overall OR4KT was .95, and the overall repeatability coefficient was 6.95%, both excellent results. Confirmatory factor analysis supported the underlying theoretical structure of 6 dimensions and 23 sub-dimensions. There were positive moderate-to-high internal correlations between these six dimensions, and there was evidence of good concurrent validity (correlation coefficient of .76 with SOAPC, and .80 with the proportion of professionals engaged by center). A score higher than 64 (out of 100) would be indicative of an organization with high level of readiness to implement the intervention (sensitivity = .75, specificity = 1). CONCLUSIONS: The Spanish version of the OR4KT exhibits very strong reliability and good validity, although it needs to be validated in a larger sample and in different implementation contexts. PMID- 29126429 TI - RNA-sequencing analysis of lung primary fibroblast response to eosinophil degranulation products predicts downstream effects on inflammation, tissue remodeling and lipid metabolism. AB - BACKGROUND: The association of eosinophils with inflammation and tissue remodeling is at least partially due to their release of toxic granule proteins and other mediators, including cytokines. Tissue remodeling and consequent functional defects are affected by activity of connective tissue fibroblasts. Exaggerated fibroblast activation, accumulation and change of phenotype may lead to fibrosis and loss of tissue function. So far, little information has been reported on how eosinophils affect inflammation and tissue remodeling via the activation of fibroblasts. We have recently shown that eosinophil activation with IL-3 led to a robust eosinophil degranulation on immunoglobin-G (IgG) coated plates. Thus, in the present study, we analyze the effects of IL-3-activated eosinophil degranulation products on primary human lung fibroblasts (HLF) using whole transcriptome sequencing. METHODS: Conditioned media was obtained from eosinophils that were pre-activated with IL-3 or IL-5 and subsequently cultured for 6 h on IgG to induce degranulation. This conditioned media was added on human lung fibroblasts (HLF) for 24 h and the cell lysates were then subjected to whole transcriptome sequencing to identify global changes in gene expression. Differentially expressed genes were analyzed using the Ingenuity Pathway Analysis (IPA), and validated by qPCR. RESULTS: In HLF, the expression level of 300 genes was changed by conditioned media from IL-3-activated eosinophils compared to control fibroblast cultures. Among these 300 genes, the expression level of 35 genes coding for known proteins was upregulated by IL-3- versus IL-5-pre activated eosinophils. Of the 35 upregulated genes, IPA identified C3, CH25H, CXCL1, CXCL8, CYP1A1, ICAM1, IL6 and UCN2 as having downstream functions on inflammation, tissue remodeling and lipid synthesis. This analysis combined with previous RNA sequencing analyses of eosinophils suggest IL-1beta, OSM and TNFSF12 as potential upstream regulators of fibroblasts. CONCLUSIONS: This study has identified several novel pro-inflammatory and pro-remodeling mediators produced by fibroblasts in response to activated eosinophils. These findings may have significant implications on the role of eosinophil/fibroblast interactions in eosinophilic disorders. PMID- 29126430 TI - Lack of chronic neuroinflammation in the absence of focal hemorrhage in a rat model of low-energy blast-induced TBI. AB - Blast-related traumatic brain injury (TBI) has been a common cause of injury in the recent conflicts in Iraq and Afghanistan. Blast waves can damage blood vessels, neurons, and glial cells within the brain. Acutely, depending on the blast energy, blast wave duration, and number of exposures, blast waves disrupt the blood-brain barrier, triggering microglial activation and neuroinflammation. Recently, there has been much interest in the role that ongoing neuroinflammation may play in the chronic effects of TBI. Here, we investigated whether chronic neuroinflammation is present in a rat model of repetitive low-energy blast exposure. Six weeks after three 74.5-kPa blast exposures, and in the absence of hemorrhage, no significant alteration in the level of microglia activation was found. At 6 weeks after blast exposure, plasma levels of fractalkine, interleukin 1beta, lipopolysaccharide-inducible CXC chemokine, macrophage inflammatory protein 1alpha, and vascular endothelial growth factor were decreased. However, no differences in cytokine levels were detected between blast-exposed and control rats at 40 weeks. In brain, isolated changes were seen in levels of selected cytokines at 6 weeks following blast exposure, but none of these changes was found in both hemispheres or at 40 weeks after blast exposure. Notably, one animal with a focal hemorrhagic tear showed chronic microglial activation around the lesion 16 weeks post-blast exposure. These findings suggest that focal hemorrhage can trigger chronic focal neuroinflammation following blast-induced TBI, but that in the absence of hemorrhage, chronic neuroinflammation is not a general feature of low-level blast injury. PMID- 29126431 TI - Successful long-term maintenance of Mansonella perstans in an in vitro culture system. AB - BACKGROUND: Approximately 114 million people are infected with Mansonella perstans in large proportions of Africa. In contrast to other filariae that infect humans, M. perstans-infected individuals show no distinct pathology or specific clinical picture, indicating a well-tuned adaptation to the host. In addition, since M. perstans adult worms reside in serous cavities which are difficult to access, research has been hindered and there is a paucity of knowledge about the biology of M. perstans, especially the development of the different life stages as well as M. perstans-driven immune responses. Thus in this study, an in vitro culture system was developed which allows an in-depth analysis of M. perstans. RESULTS: Culicoides species were caught in Ediki (Kumba), Southwest Region within Cameroon following a blood meal on a microfilaremic donor that had 1500 microfilariae/ml of peripheral blood and kept in captivity for 12 days at 23 degrees C. In a pilot experiment, 15 infective larvae were obtained from the midges and co-cultured with a confluent monolayer of monkey kidney epithelial cells (LLC-MK2) in DMEM medium supplemented with 10% FBS for up to 77 days. The resulting survival rates of 33% revealed that the cell conditioned medium was suitable for long-term maintenance of M. perstans worms. To confirm these preliminary observations, 249 infective larvae were cultured for 50 days and their development was monitored daily and microscopically graded for motility. In total, 170 (68.3%) filariae survived and 124 (49.8%) larvae moulted between days 21-30 to become L5 stage larvae which were motile and showed continuous vigorous movement. CONCLUSION: We have established an in vitro culture system for the generation and long-term maintenance of viable M. perstans worms. This technique will be an important tool to study parasite biology and development, the role in host immunity, and might be helpful to discover novel treatment strategies against this filariae. PMID- 29126432 TI - Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus. AB - BACKGROUND: The aim was to assess the attainability and outcome of the lupus low disease activity state (LLDAS) in the early stages of systemic lupus erythematosus (SLE). METHODS: LLDAS prevalence was evaluated at 6 (T1) and 18 (T2) months after diagnosis and treatment initiation (T0) in a monocentric cohort of 107 (median disease duration 9.7 months) prospectively followed Caucasian patients with SLE. Reasons for failure to achieve LLDAS were also investigated. Multivariate models were built to identify factors associated with lack of LLDAS achievement and to investigate the relationship between LLDAS and Systemic Lupus International Collaboration Clinics (SLICC)/Damage Index (SDI) accrual. RESULTS: There were 47 (43.9%) patients in LLDAS at T1 and 48 (44.9%) at T2. The most frequent unmet LLDAS criterion was prednisolone dose >7.5 mg/day (83% of patients with no LLDAS at T1). Disease manifestations with the lowest remission rate during follow up were increased anti-double-stranded DNA (persistently present in 85.7% and 67.5% of cases at T1 and T2, respectively), low serum complement fractions (73.2% and 66.3%) and renal abnormalities (46.4% and 28.6%). Renal involvement at T0 was significantly associated with failure to achieve LLDAS both at T1 (OR 7.8, 95% CI 1.4-43.4; p = 0.019) and T2 (OR 3.9, 95% CI 1.4-10.6; p = 0.008). Presence of any organ damage (SDI >=1) at T2 was significantly associated with lack of LLDAS at T1 (OR 5.0, 95% CI 1.5-16.6; p = 0.009) and older age at diagnosis (OR 1.05 per year, 95% CI 1.01-1.09; p = 0.020). CONCLUSION: LLDAS is a promising treatment target in the early stages of SLE, being attainable and negatively associated with damage accrual, but it fit poorly to patients with renal involvement. PMID- 29126433 TI - Mosquito larvicidal activity of Cassia tora seed extract and its key anthraquinones aurantio-obtusin and obtusin. AB - BACKGROUND: The edible and medicinal leguminous plant Cassia tora L. (Fabaceae) is known to possess insecticidal properties against a wide range of plant-feeding insects. However, the bioactivity of extracts of this plant and their constituents against vectors of medical importance has been largely unexplored. We investigated the mosquito larvicidal activity of the seed extract and its major anthraquinones against larvae of the African malaria vector Anopheles gambiae (s.s.). METHODS: Third-fourth instar larval mortality was observed after 24, 48, 72 and 96 h of exposure to varying doses of the extracts, and two anthraquinones isolates identified using liquid chromatography- quadrupole time of flight mass spectrometry (LC-QtoF-MS). The mosquito larval mortality was evaluated relative to the natural insecticide azadirachtin. RESULTS: Fractionation of the crude extract decreased mosquito larvicidal activity, however, larvicidal activity increased with increasing dose of the treatment and exposure time. The known anthraquinones aurantio-obtusin and obtusin were identified as key larvicidal compounds. Aurantio-obtusin and obtusin, exhibited similar toxicity to larvae of A. gambiae (s.s.) with LD50 values of 10 and 10.2 ppm, respectively. However, the two anthraquinones were four- and ~ six-fold less potent than that of the crude seed extract and azadirachtin, which had comparable LD50 values of 2.5 and 1.7 ppm, respectively. CONCLUSION: Both aurantio-obtusin and obtusin showed mosquito larvicidal activity which were comparable to their respective fractions although they were less potent relative to the crude extract and azadirachtin. Further studies need to be conducted on C. tora for its exploitation as a potential eco-friendly tool in mosquito larval source reduction. PMID- 29126435 TI - Human amnion cells reverse acute and chronic pulmonary damage in experimental neonatal lung injury. AB - BACKGROUND: Despite advances in neonatal care, bronchopulmonary dysplasia (BPD) remains a significant contributor to infant mortality and morbidity. While human amnion epithelial cells (hAECs) have shown promise in small and large animal models of BPD, there is scarce information on long-term benefit and clinically relevant questions surrounding administration strategy remain unanswered. In assessing the therapeutic potential of hAECs, we investigated the impact of cell dosage, administration routes and timing of treatment in a pre-clinical model of BPD. METHODS: Lipopolysaccharide was introduced intra-amniotically at day 16 of pregnancy prior to exposure to 65% oxygen (hyperoxia) at birth. hAECs were administered either 12 hours (early) or 4 days (late) after hyperoxia commenced. Collective lung tissues were subjected to histological analysis, multikine ELISA for inflammatory cytokines, FACS for immune cell populations and 3D lung stem cell culture at neonatal stage (postnatal day 7 and 14). Invasive lung function test and echocardiography were applied at 6 and 10 weeks of age. RESULTS: hAECs improved the tissue-to-airspace ratio and septal crest density in a dose dependent manner, regardless of administration route. Early administration of hAECs, coinciding with the commencement of postnatal hyperoxia, was associated with reduced macrophages, dendritic cells and natural killer cells. This was not the case if hAECs were administered when lung injury was established. Fittingly, early hAEC treatment was more efficacious in reducing interleukin-1beta, tumour necrosis factor alpha and monocyte chemoattractant protein-1 levels. Early hAEC treatment was also associated with reduced airway hyper-responsiveness and normalisation of pressure-volume loops. Pulmonary hypertension and right ventricle hypertrophy were also prevented in the early hAEC treatment group, and this persisted until 10 weeks of age. CONCLUSIONS: Early hAEC treatment appears to be advantageous over late treatment. There was no difference in efficacy between intravenous and intratracheal administration. The benefits of hAEC administration resulted in long-term improvements in cardiorespiratory function. PMID- 29126434 TI - Whole blood microRNA expression pattern differentiates patients with rheumatoid arthritis, their seropositive first-degree relatives, and healthy unrelated control subjects. AB - BACKGROUND: Epigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA). To better understand their role, we evaluated microRNA (miRNA, miR) expression profile in indigenous North American patients with RA who were positive for anticitrullinated protein antibodies; their autoantibody-positive, asymptomatic first-degree relatives (FDRs); and disease-free healthy control subjects (HCs). METHODS: Total RNA was isolated from whole blood samples obtained from HC (n = 12), patients with RA (n = 18), and FDRs (n = 12). Expression of 35 selected relevant miRNAs, as well as associated downstream messenger RNA (mRNA) targets of miR-103a-3p, was determined by qRT-PCR. RESULTS: Whole blood expression profiling identified significantly differential miRNA expression in patients with RA (13 miRNAs) and FDRs (10 miRNAs) compared with HCs. Among these, expression of miR-103a-3p, miR-155, miR-146a-5p, and miR-26b-3p was significantly upregulated, whereas miR-346 was significantly downregulated, in both study groups. Expression of miR-103a-3p was consistently elevated in FDRs at two time points 1 year apart. We also confirmed increased miR-103a-3p expression in peripheral blood mononuclear cells from patients with RA compared with HCs. Predicted target analyses of differentially expressed miRNAs in patients with RA and FDRs showed overlapping biological networks. Consistent with these curated networks, mRNA expression of DICER1, AGO1, CREB1, DAPK1, and TP53 was downregulated significantly with miR-103a-3p expression in FDRs. CONCLUSIONS: We highlight systematically altered circulating miRNA expression in at-risk FDRs prior to RA onset, a profile they shared with patients with RA. Prominently consistent miR-103a-3p expression indicates its utility as a prognostic biomarker for preclinical RA while highlighting biological pathways important for transition to clinically detectable disease. PMID- 29126437 TI - Framing the conversation: use of PRECIS-2 ratings to advance understanding of pragmatic trial design domains. AB - BACKGROUND: There continues to be debate about what constitutes a pragmatic trial and how it is distinguished from more traditional explanatory trials. The NIH Pragmatic Trials Collaborative Project, which includes five trials and a coordinating unit, has adopted the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) instrument. The purpose of the study was to collect PRECIS-2 ratings at two points in time to assess whether the tool was sensitive to change in trial design, and to explore with investigators the rationale for rating shifts. METHODS: A mixed-methods design included sequential collection and analysis of quantitative data (PRECIS-2 ratings) and qualitative data. Ratings were collected at two annual, in-person project meetings, and subsequent interviews conducted with investigators were recorded, transcribed, and coded using NVivo 11 Pro for Windows. Rating shifts were coded as either (1) actual change (reflects a change in procedure or protocol), (2) primarily a rating shift reflecting rater variability, or (3) themes that reflect important concepts about the tool and/or pragmatic trial design. RESULTS: Based on PRECIS-2 ratings, each trial was highly pragmatic at the planning phase and remained so 1 year later in the early phases of trial implementation. Over half of the 45 paired ratings for the nine PRECIS-2 domains indicated a rating change from Time 1 to Time 2 (N = 24, 53%). Of the 24 rating changes, only three represented a true change in the design of the trial. Analysis of rationales for rating shifts identified critical themes associated with the tool or pragmatic trial design more generally. Each trial contributed one or more relevant comments, with Eligibility, Flexibility of Adherence, and Follow-up each accounting for more than one. CONCLUSIONS: PRECIS-2 has proved useful for "framing the conversation" about trial design among members of the Pragmatic Trials Collaborative Project. Our findings suggest that design elements assessed by the PRECIS-2 tool may represent mostly stable decisions. Overall, there has been a positive response to using PRECIS-2 to guide conversations around trial design, and the project's focus on the use of the tool by this group of early adopters has provided valuable feedback to inform future trainings on the tool. PMID- 29126436 TI - New insights on the MMP-13 regulatory network in the pathogenesis of early osteoarthritis. AB - Osteoarthritis (OA) is the most common joint disorder and affects approximately half of the aged population. Current treatments for OA are largely palliative until the articular cartilage has been deeply damaged and irreversible morphological changes appear. Thus, effective methods are needed for diagnosing and monitoring the progression of OA during its early stages when therapeutic drugs or biological agents are most likely to be effective. Various proteinases involved in articular cartilage degeneration in pre-OA conditions, which may represent the earliest reversible measurable changes, are considered diagnostic and therapeutic targets for early OA. Of these proteinases, matrix metalloproteinase 13 (MMP-13) has received the most attention, because it is a central node in the cartilage degradation network. In this review, we highlight the main MMP-13-related changes in OA chondrocytes, including alterations in the activity and expression level of MMP-13 by upstream regulatory factors, DNA methylation, various non-coding RNAs (ncRNAs), and autophagy. Because MMP-13 and its regulatory networks are suitable targets for the development of effective early treatment strategies for OA, we discuss the specific targets of MMP-13, including upstream regulatory proteins, DNA methylation, non-coding RNAs, and autophagy-related proteins of MMP-13, and their therapeutic potential to inhibit the development of OA. Moreover, the various entities mentioned in this review might be useful as early biomarkers and for personalized approaches to disease prevention and treatment by improving the phenotyping of early OA patients. PMID- 29126438 TI - Therapeutic effects of bone marrow-derived mononuclear cells from healthy or silicotic donors on recipient silicosis mice. AB - BACKGROUND: Administration of bone marrow mononuclear cells (BMMCs) modulates lung inflammation and fibrosis in experimental silicosis. However, no studies have evaluated whether silicosis affects the efficacy of autologous BMMCs treatment. We hypothesized that BMMCs obtained from healthy or silicotic mice may improve lung function, but they might affect the inflammatory and fibrotic processes differently in experimental silicosis. METHODS: C57BL/6 mice were randomly divided into control (C) and silicosis (SIL) groups. Mice in the SIL group were instilled with silica particles intratracheally; the C animals received saline using the same protocol. On day 15, the animals were treated with saline (Sal) or BMMCs (2 * 106 cells) from healthy (BMMC-healthy) and silicotic (BMMC-sil) donors. Lung mechanics were measured, and lungs were collected for histology and molecular biology analysis. RESULTS: BMMCs obtained from healthy and silicotic donors presented similar percentages of cell populations. 99mTc BMMCs tracking revealed preferential migration of cells to the liver, and only a few GFP+ BMMCs were observed in lung tissue 24 h after treatment, regardless of donor type. Both the SIL-BMMC-healthy and SIL-BMMC-sil groups showed improvement in lung function, a reduction in the fractional area of granuloma, and a decrease in the number of mononuclear and apoptotic cells in lung parenchyma. In addition, the number of F4/80+ macrophages, the levels of interleukin-1 beta and transforming growth factor beta, and collagen fiber content in granuloma were reduced in SIL-BMMC-healthy mice, whereas mRNA expression of MMP-9 and procollagen I and III was reduced in the SIL-BMMC-sil group. CONCLUSIONS: Administration of BMMCs from healthy and silicotic donors reduced lung inflammation and fibrosis, thus improving lung function. In addition, BMMC healthy exhibited a greater improvement in lung morpho-functional changes in murine model of silicosis. PMID- 29126439 TI - Artificial neural networks to predict future bone mineral density and bone loss rate in Japanese postmenopausal women. AB - OBJECTIVE: Predictions of the future bone mineral density and bone loss rate are important to tailor medicine for women with osteoporosis, because of the possible presence of personal risk factors affecting the severity of osteoporosis in the future. We investigated whether it was possible to predict bone mineral density and bone loss rate in the future using artificial neural networks. RESULTS: A total of 135 women over 50 years old residing in T town of Wakayama Prefecture, Japan were analyzed to establish a statistical model. Artificial neural networks models were constructed using the two variables of bone mineral density and bone loss rate. The multiple correlation coefficients between the actual and measured values for lumbar and femoral bone mineral densities in 2003 showed R2 = 0.929 and R2 = 0.880, respectively, by linear regression analyses, while the values for bone loss rates in lumbar and femoral bone mineral densities were R2 = 0.694 and R2 = 0.609, respectively. Statistical models by artificial neural networks were superior to those by multiple regression analyses. The prediction of future bone mineral density values estimated by artificial neural networks was considered to be useful as a tool to tailor medicine for the early diagnosis of and intervention for women osteoporosis with women. PMID- 29126440 TI - Chromatin organization changes during the establishment and maintenance of the postmitotic state. AB - BACKGROUND: Genome organization changes during development as cells differentiate. Chromatin motion becomes increasingly constrained and heterochromatin clusters as cells become restricted in their developmental potential. These changes coincide with slowing of the cell cycle, which can also influence chromatin organization and dynamics. Terminal differentiation is often coupled with permanent exit from the cell cycle, and existing data suggest a close relationship between a repressive chromatin structure and silencing of the cell cycle in postmitotic cells. Heterochromatin clustering could also contribute to stable gene repression to maintain terminal differentiation or cell cycle exit, but whether clustering is initiated by differentiation, cell cycle changes, or both is unclear. Here we examine the relationship between chromatin organization, terminal differentiation and cell cycle exit. RESULTS: We focused our studies on the Drosophila wing, where epithelial cells transition from active proliferation to a postmitotic state in a temporally controlled manner. We find there are two stages of G0 in this tissue, a flexible G0 period where cells can be induced to reenter the cell cycle under specific genetic manipulations and a state we call "robust," where cells become strongly refractory to cell cycle reentry. Compromising the flexible G0 by driving ectopic expression of cell cycle activators causes a global disruption of the clustering of heterochromatin associated histone modifications such as H3K27 trimethylation and H3K9 trimethylation, as well as their associated repressors, Polycomb and heterochromatin protein 1 (HP1). However, this disruption is reversible. When cells enter a robust G0 state, even in the presence of ectopic cell cycle activity, clustering of heterochromatin-associated modifications is restored. If cell cycle exit is bypassed, cells in the wing continue to terminally differentiate, but heterochromatin clustering is severely disrupted. Heterochromatin-dependent gene silencing does not appear to be required for cell cycle exit, as compromising the H3K27 methyltransferase Enhancer of zeste, and/or HP1 cannot prevent the robust cell cycle exit, even in the face of normally oncogenic cell cycle activities. CONCLUSIONS: Heterochromatin clustering during terminal differentiation is a consequence of cell cycle exit, rather than differentiation. Compromising heterochromatin-dependent gene silencing does not disrupt cell cycle exit. PMID- 29126441 TI - TGFbeta3 recruits endogenous mesenchymal stem cells to initiate bone regeneration. AB - BACKGROUND: The recruitment of a sufficient number of endogenous mesenchymal stem cells (MSCs) is the first stage of in-situ tissue regeneration. Transforming growth factor beta-3 (TGFbeta3) could recruit stem or progenitor cells and endothelial cells to participate in tissue regeneration. However, the mechanism of TGFbeta3 recruiting MSCs toward bone regeneration has remained obscure. METHODS: We estimated the promigratory property of TGFbeta3 on human bone marrow MSCs (hBMSCs) cocultured with the vascular cells (human umbilical artery smooth muscle cells or human umbilical vein endothelial cells) or not by Transwell assay. After the addition of the inhibitor (SB431542) or Smad3 siRNA, the levels of MCP1 and SDF1 in coculture medium were tested by ELISA kit, and then the migratory signaling pathway of hBMSCs induced by TGFbeta3 was investigated by western blot analysis. In vivo, a 2-mm FVB/N mouse femur defect model was used to evaluate chemokine secretion, endogenous cell homing, and bone regeneration induced by scaffolds loading 1 MUg TGFbeta3 through qPCR, immunofluorescent staining, immunohistochemical analysis, and Micro-CT, compared to the vehicle group. RESULTS: TGFbeta3 (25 ng/ml) directly showed a nearly 40% increase in migrated hBMSCs via the TGFbeta signaling pathway, compared to the vehicle treatment. Then, in the coculture system of hBMSCs and vascular cells, TGFbeta3 further upregulated nearly 3-fold MCP1 secretion from vascular cells in a Smad3 dependent manner, to indirectly enhance nearly more than 50% of migrated hBMSCs. In vivo, TGFbeta3 delivery improved MCP1 expression by nearly 7.9-fold, recruited approximately 2.0-fold CD31+ vascular cells and 2.0-fold Sca-1+ PDGFR-alpha+ MSCs, and achieved 2.5-fold bone volume fraction (BV/TV) and 2.0-fold bone mineral density, relative to TGFbeta3-free delivery. CONCLUSIONS: TGFbeta3, as a MSC homing molecule, recruited MSCs to initiate bone formation in the direct dependent and indirect-dependent mechanisms. This may shed light on the improvement of MSC homing in bone regeneration. PMID- 29126442 TI - Effect of enriched housing on levels of natural (auto-)antibodies in pigs co infected with porcine reproductive and respiratory syndrome virus (PRRSV) and Actinobacillus pleuropneumoniae. AB - Housing of pigs in barren, stimulus-poor housing conditions may influence their immune status, including antibody responses to (auto-)antigens, and thus affect immune protection, which will influence the onset and outcome of infection. In the present study, we investigated the effects of environmental enrichment versus barren housing on the level of natural (auto-)antibodies (NA(A)b) and their isotypes (IgM and IgG) binding keyhole limpet hemocyanin (KLH), myelin basic protein (MBP), and phosphorycholine conjugated to bovine serum albumin (PC-BSA) in pigs co-infected with porcine reproductive and respiratory syndrome virus (PRRSV) and Actinobacillus pleuropneumoniae (A. pleuropneumoniae). Pigs (n = 56) were housed in either barren or enriched pens from birth to 54 days of age. They were infected with PRRSV on 44 days of age, and with A. pleuropneumoniae 8 days later. Blood samples were taken on 7 different sampling days. Housing significantly affected the overall serum levels of NA(A)b binding KLH, MBP and PC BSA, and before infection barren housed pigs had significantly higher levels of NA(A)b than enriched housed pigs, except for KLH-IgM and PC-BSA-IgG. Infection only affected the IgM, but not the IgG isotype. Moreover, changes in MBP-IgM and PC-BSA-IgM following infection were different for enriched and barren housed pigs. These results suggest that the effect of infection on NA(A)b is influenced by housing conditions and that NA(A)b, especially IgM may be affected by infection. PMID- 29126443 TI - Ubiquitin C-terminal hydrolase isozyme L1 is associated with shelterin complex at interstitial telomeric sites. AB - BACKGROUND: Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells and has been associated with various diseases, including many cancers. It is a multifunctional protein involved in deubiquitination, ubiquitination and ubiquitin homeostasis, but its specific roles are disputed and still generally undetermined. RESULTS: Herein, we demonstrate that UCHL1 is associated with genomic DNA in certain prostate cancer cell lines, including DU 145 cells derived from a brain metastatic site, and in HEK293T embryonic kidney cells with a neuronal lineage. Chromatin immunoprecipitation and sequencing revealed that UCHL1 localizes to TTAGGG repeats at telomeres and interstitial telomeric sequences, as do TRF1 and TRF2, components of the shelterin complex. A weak or transient interaction between UCHL1 and the shelterin complex was confirmed by immunoprecipitation and proximity ligation assays. UCHL1 and RAP1, also known as TERF2IP and a component of the shelterin complex, were bound to the nuclear scaffold. CONCLUSIONS: We demonstrated a novel feature of UCHL1 in binding telomeres and interstitial telomeric sites. PMID- 29126444 TI - Expectations towards participation in easily accessible pain management interventions: a qualitative study. AB - BACKGROUND: People with chronic pain use a range of healthcare services, but they also report a high degree of dissatisfaction with treatments. One reason for dissatisfaction might be participants' expectations towards treatments. The aim of this study was to explore expectations of people with chronic pain towards participation in easily accessible pain management interventions delivered in public primary care. METHODS: A qualitative study using semi-structured individual face-to-face interviews with 21 informants. The informants were recruited among participants enrolled in a randomised controlled trial on the effect of an easily accessible self-management course for people with chronic pain. The data were analysed thematically using Systematic Text Condensation. RESULTS: Having experienced pain for a long time, there was no specific expectation of a cure or a significant alleviation of the pain. The informants' expectations mainly concerned a hope that participation could lead to a better everyday life. The informants said that hope was important as it motivated them to keep going and continue self-care activities. The hope acted as a driving force towards trying new interventions and maintaining motivation to do activities they experienced as beneficial. Both concrete aspects of the current intervention and an understanding of what interventions in general could offer contributed to the informants hope. The expectations centred about the interventions being something new, as they had not previously tried this service, an opportunity to gain and reinforce skills, to help them continue to grow as a person, to meet others in similar situations, and to access professional support in an easy manner. Participating in interventions provided by healthcare services was seen by some as an act of self-care, where they did something active to manage their health. CONCLUSIONS: Expectations towards the interventions were related to a hope for participation leading to a better everyday life. The role of hope for peoples' motivation to self-care implies that service providers should be aware of and help to maintain hope for a better everyday life. The importance of social support as part of self-care should be acknowledged when developing interventions targeting chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02531282 . Registered on August 21 2015. PMID- 29126446 TI - Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy. AB - BACKGROUND: To determine the potential role of 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) in radiotherapy (RT) planning for prostate cancer (PCa). METHODS: One hundred twenty-nine patients (pts) with 68Ga PSMA PET/CT were retrospectively analysed. Potentially influencing factors (androgen deprivation therapy, amount of 68Ga-PSMA-HBED-CC, PSA doubling time <=/> 10 months, PSA before PET/CT, T-/N-category and Gleason score) were evaluated by logistic regression analysis. The detection rate of PSMA PET/CT was compared to contrast enhanced CT and its impact on RT management analysed. RESULTS: One hundred twenty-nine patients (pts) (20 at initial diagnosis, 49 with PSA relapse and 60 with PSA persistence after radical prostatectomy) received PSMA PET/CT prior to RT. The majority of pts. (71.3%) had PET-positive findings (55.1% of pts. with PSA recurrence, 75% of pts. with PSA persistence and 100% of newly diagnosed pts). Median PSA before PET/CT in pts. with pathological findings (n = 92) was 1.90 ng/ml and without (n = 37) 0.30 ng/ml. PSA level at time of PET/CT was the only factor associated with PET-positivity. In pts. with a PSA <= 0.2 ng/ml, the detection rate of any lesion was 33.3%, with a PSA of 0.21-0.5 ng/ml 41.2% and with a PSA of 0.51-1.0 ng/ml 69.2%, respectively. Regarding the anatomic distribution of lesions, 42.2% and 14.7% of pts. with relapse or persistence had pelvic lymph node and distant metastases. In pts. at initial diagnosis the detection rate of pelvic lymph nodes and distant metastases was 20% and 10%. 68Ga-PSMA PET/CT had a high detection rate of PCa recurrence outside the prostatic fossa in pts. being considered for salvage RT (22.4% PET-positive pelvic lymph nodes and 4.1% distant metastases). Compared to CT, PSMA PET/CT had a significantly higher sensitivity in diagnosing rates of local recurrence/primary tumour (10.1% vs. 38%), lymph nodes (15.5% vs. 38.8%) and distant metastases (5.4% vs. 14.0%). This resulted in a modification of RT treatment in 56.6% of pts. CONCLUSIONS: The detection of PCa is strongly associated with PSA level at time of 68Ga-PSMA PET/CT. PSMA PET/CT differentiates between local, regional and distant metastatic disease with implications for disease management. PSMA PET/CT allows for tumour detection in post-prostatectomy pts. with PSA <= 0.5 ng/ml considered for salvage RT. PMID- 29126445 TI - YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias. AB - BACKGROUND: YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. METHODS: In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease specific neuroinflammatory signatures. RESULTS: YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer's disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around beta-amyloid plaques, and surrounding vessels with beta amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL 40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson's disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. CONCLUSIONS: Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component. PMID- 29126447 TI - Hypoglycemic and hypolipidemic effects of different parts and formulations of bitter gourd (Momordica Charantia). AB - BACKGROUND: Cardiovascular diseases and diabetes are responsible for large number of deaths throughout the globe. Bitter gourd has the potential to become a component of the diet or a dietary supplement for diabetic and pre-diabetic patients owing to the presence of insulin like molecules. Recent investigations have suggested that bitter gourd extracts may ameliorate high fat diet induced obesity and hyperlipidemia in animal models. Moreover, its supplements in food result in lowering weight gain and visceral fat mass. METHODS: The current study was designed to investigate the nutraceutical potential of skin, flesh and whole fruit of bitter gourd cultivars against hyperglycemia and hyperlipidemia. For the purpose, various bitter gourd cultivars were procured from local market. Bio evaluation studies were carried out on biochemical parameters using rodent experiment model. RESULTS: From results, it was revealed that maximum reduction in blood glucose skin 1.06%, flesh 2.65%, whole fruit 4.29%, total cholesterol skin 6.60%, flesh 6.04%, whole fruit 6.70%, low density lipoprotein skin 5.55%, flesh 6.81%, whole fruit 6.60%, and triglycerides skin 0.04%, flesh 3.38%, whole fruit 2.02%, were observed. Moreover, insulin skin 2.14%, flesh 3.52%, whole fruit 2.73%, production was slightly enhanced with improved levels of high density lipoprotein in whole fruit of bitter gourd. CONCLUSION: Overwhelmingly, it may be inferred here that bitter gourd holds the potential to significantly improve diabetic conditions and associated late complications with no ill effects on body organs. PMID- 29126449 TI - Advancing 'real-world' trials that take account of social context and human volition. AB - BACKGROUND: The recent paper in Trials by Porter and colleagues highlights the utility of applying a critical realism approach in randomised trials, an approach central to the Medical Research Council's (MRC) Framework for the Development and Evaluation of Complex Healthcare Interventions. The MRC framework offers a pragmatic step towards a more open systems approach that bridges randomised evaluation with social context and human agency in an effort to improve the generalisability of trial outcomes. MAIN BODY: The MRC framework has contributed to the proliferation of a more open systems approach in health research; however, the broader acceptance of the realist approach to health research does not seem to be emulated by norms in research fund allocation, which largely prioritises laboratory-based research. CONCLUSION: This commentary is simply a plea, to those who make the strategic decisions regarding allocation of research funding, to support all phases of health intervention research in complex systems that contribute to the development of effective, translational and sustainable interventions in the promotion of health. PMID- 29126448 TI - The epidemiology of Norovirus in the Middle East and North Africa (MENA) region: a systematic review. AB - Norovirus (NoV) is considered the second leading cause of viral acute gastroenteritis (AGE). To our knowledge, there are no systematic reviews assessing the role of NoV in AGE in the Middle East and North Africa (MENA) region. Consequently, we conducted an extensive systematic literature review on articles studying NoV in the 24 countries of the MENA region during the past 15 years (2000-2015). The methods and reporting were set according to the 2015 PRISMA-P and based on the elements from the international prospective register of systematic reviews (PROSPERO). We retrieved 38 studies meeting our predefined inclusion criteria and were used to extract full data. Studies reporting on NoV were conducted in 15 out of the 24 countries of the region. The reported NoV infection rates in MENA countries ranged between 0.82% and 36.84%. The majority of studies were clinical observational studies assessing NoV rates mainly among children. Participants were recruited from in- and outpatient clinics. NoV infection was reported all year round with with peaks observed mainly during cold months. GII.4 was the predominant genotype detected in stool of participants as reported by 16 out of 25 studies (64%). Overall, there is an increasing recognition of NoV as an important causative agent of AGE across all age groups in the MENA region. Further studies are needed to assess the national and the regional burden of NoV among different age groups, its molecular diversity and seasonal variability. PMID- 29126450 TI - The macrophage C-type lectin receptor CLEC5A (MDL-1) expression is associated with early plaque progression and promotes macrophage survival. AB - BACKGROUND: Biomarkers of early plaque progression are still elusive. Myeloid DAP12-associating lectin-1 (MDL-1), also called CLEC5A, is a C-type lectin receptor implicated in the progression of multiple acute and chronic inflammatory diseases. However, the relationship between its level and atherosclerosis is unknown. In this study, we aimed to investigate the correlation between macrophage MDL-1 expression and early atherosclerosis progression. METHODS: Immunofluorescence staining, real-time PCR and western blot were performed to analyze MDL-1 expression in aorta or mice macrophages. The role of MDL-1 in macrophage survival was further investigated by adenovirus infection and TUNEL assay. RESULTS: Significant MDL-1 expression was found in advanced human and apoE /- mice atherosclerotic plaques, especially in lesional macrophages. In the model of atherosclerosis regression, we found MDL-1 expression was highly downregulated in lesional macrophages from ldlr-/- mouse regressive plaques, coincident with a reduction in lesional macrophage content and marker of M1 proinflammatory macrophages. Furthermore, we found MDL-1 was significantly expressed in inflammatory M1 subtype polarized bone marrow-derived macrophages. In vitro experiments, the level of MDL-1 was remarkably elevated in macrophages treated with pathophysiological drivers of plaque progression, such as oxidized low density lipoprotein (ox-LDL) and hypoxia. Mechanistically, we demonstrated that MDL-1 overexpression notably promoted macrophage survival and decreased cleaved caspase-3 expression under ox-LDL stimulation, which suggested that it could maintain lesional macrophage survival and cause its accumulation. CONCLUSIONS: This study firstly demonstrated that MDL-1 is mainly expressed in atherosclerotic lesional macrophages and increased macrophage MDL-1 expression is associated with early plaque progression and promotes macrophage survival. PMID- 29126451 TI - Acceleration sensors in abdominal wall position as a non-invasive approach to detect early breathing alterations induced by intolerance of increased airway resistance. AB - BACKGROUND: Early detection of respiratory overload is crucial to mechanically ventilated patients, especially during phases of spontaneous breathing. Although a diversity of methods and indices has been established, there is no highly specific approach to predict respiratory failure. This study aimed to evaluate acceleration sensors in abdominal and thoracic wall positions to detect alterations in breathing excursions in a setting of gradual increasing airway resistance. METHODS: Twenty-nine healthy volunteers were committed to a standardized protocol of a two-minutes step-down spontaneous breathing on a 5 mm, 4 mm and then 3 mm orally placed endotracheal tube. Accelerator sensors in thoracic and abdominal wall position monitored breathing excursions. 15 participants passed the breathing protocol ("completed" group), 14 individuals cancelled the protocol due to subjective intolerance to the increasing airway resistance ("abandoned" group). RESULTS: Gradual increased respiratory workload led to a significant decrease of acceleration in abdominal wall position in the "abandoned" group compared to the "completed" group (p < 0.001), while these gradual accelerating changes were not observed in thoracic wall position (p = 0.484). Thoracic acceleration sensors did not detect any time- and group-specific changes (p = 0.746). CONCLUSIONS: The abdominal wall position of the acceleration sensors may be a non-invasive, economical and practical approach to detect early breathing alterations prior to respiratory failure. TRIAL REGISTRATION: EK 309 15; by the Ethics Committee of the Faculty of Medicine, RWTH Aachen, Aachen, Germany. Retrospectively registered 28th of December 2015. PMID- 29126452 TI - High-performing trauma teams: frequency of behavioral markers of a shared mental model displayed by team leaders and quality of medical performance. AB - BACKGROUND: High quality team leadership is important for the outcome of medical emergencies. However, the behavioral marker of leadership are not well defined. The present study investigated frequency of behavioral markers of shared mental models (SMM) on quality of medical management. METHOD: Training video recordings of 27 trauma teams simulating emergencies were analyzed according to team leader's frequency of shared mental model behavioral markers. RESULTS: The results showed a positive correlation of quality of medical management with leaders sharing information without an explicit demand for the information ("push" of information) and with leaders communicating their situational awareness (SA) and demonstrating implicit supporting behavior. When separating the sample into higher versus lower performing teams, the higher performing teams had leaders who displayed a greater frequency of "push" of information and communication of SA and supportive behavior. No difference was found for the behavioral marker of team initiative, measured as bringing up suggestions to other teammembers. CONCLUSION: The results of this study emphasize the team leader's role in initiating and updating a team's shared mental model. Team leaders should also set expectations for acceptable interaction patterns (e.g., promoting information exchange) and create a team climate that encourages behaviors, such as mutual performance monitoring, backup behavior, and adaptability to enhance SMM. PMID- 29126453 TI - Public-on-private dual practice among physicians in public hospitals of Tigray National Regional State, North Ethiopia: perspectives of physicians, patients and managers. AB - BACKGROUND: Physicians who work in the private sector while also holding a salaried job in a public hospital, known as "dual practice," is one of the main retention strategies adopted by the government of Ethiopia. Dual practice was legally endorsed in Tigray National Regional State, Ethiopia in 2010. Therefore, the aim of this study was to explore the extent of dual practice, reasons why physicians engage in it, and its effects on public hospital services in this state in northern Ethiopia. METHODS: A cross-sectional study using mixed methods was conducted from February to March 2011 in six geographically representative public hospitals of Tigray National Regional State. A semi-structured, self administered questionnaire was distributed to all physicians working in the study hospitals, and an interviewer-administered, structured questionnaire was used to collect data from admitted patients. Focus group discussions were conducted with hospital governing boards. Quantitative and qualitative data were used in the analysis. RESULTS: Data were collected from 31 physicians and 449 patients in the six study hospitals. Six focus group discussions were conducted. Twenty-eight (90.3%) of the physicians were engaged in dual practice to some extent: 16 (51.6%) owned private clinics outside the public hospital, 5 (16.1%) worked part time in outside private clinics, and 7 (22.6%) worked in the private wing of public hospitals. Income supplementation was the primary reason for engaging in dual practice, as reported by 100% of the physicians. The positive effects of dual practice from both managers' and physicians' perspectives were physician retention in the public sector. Ninety-one patients (20.3%) had been referred from a private clinic immediately prior to their current admission-a circular diversion pattern. Eighteen (19.8%) of the diverted patients reported that health workers in the public hospitals diverted them. CONCLUSIONS: Circular diversion pattern of referral system is the key negative consequence of dual practice. Physicians and hospital managers agreed that health worker retention was the main positive consequence of dual practice upon the public sector, and banning dual practice would result in a major loss of senior physicians. The motive behind the circular diversion pattern described by patients should be studied further. PMID- 29126454 TI - An analysis on intersectional collaboration on non-communicable chronic disease prevention and control in China: a cross-sectional survey on main officials of community health service institutions. AB - BACKGROUND: Our study aimed to design a tool of evaluating intersectional collaboration on Non-communicable Chronic Disease (NCD) prevention and control, and further to understand the current status of intersectional collaboration in community health service institutions of China. METHODS: We surveyed 444 main officials of community health service institutions in Beijing, Tianjin, Hubei and Ningxia regions of China in 2014 by using a questionnaire. A model of collaboration measurement, including four relational dimensions of governance, shared goals and vision, formalization and internalization, was used to compare the scores of evaluation scale in NCD management procedures across community healthcare institutions and other ones. Reliability and validity of the evaluation tool on inter-organizational collaboration on NCD prevention and control were verified. RESULTS: The test on tool evaluating inter-organizational collaboration in community NCD management revealed a good reliability and validity (Cronbach's Alpha = 0.89,split-half reliability = 0.84, the variance contribution rate of an extracted principal component = 49.70%). The results of inter-organizational collaboration of different departments and management segments showed there were statistically significant differences in formalization dimension for physical examination (p = 0.01).There was statistically significant difference in governance dimension, formalization dimension and total score of the collaboration scale for health record sector (p = 0.01,0.00,0.00). Statistical differences were found in the formalization dimension for exercise and nutrition health education segment (p = 0.01). There were no statistically significant difference in formalization dimension of medication guidance for psychological consultation, medical referral service and rehabilitation guidance (all p > 0.05). CONCLUSION: The multi-department collaboration mechanism of NCD prevention and control has been rudimentarily established. Community management institutions and general hospitals are more active in participating in community NCD management with better collaboration score, whereas the CDC shows relatively poor collaboration in China. Xing-ming Li and Alon Rasooly have the same contribution to the paper. Xing-ming Li and Alon Rasooly listed as the same first author. PMID- 29126455 TI - Micrognathia with temporomandibular joint ankylosis and obstructive sleep apnea treated with mandibular distraction osteogenesis using skeletal anchorage: a case report. AB - BACKGROUND: We describe the case of a 16-year-old female patient with micrognathia, temporomandibular joint (TMJ) ankylosis, and obstructive sleep apnea, who was treated with mandibular distraction osteogenesis (DO) combined with sliding genioplasty, using skeletal anchorage. CASE PRESENTATION: We first performed interpositional arthroplasty, in which an interposition of fascia temporalis and surrounding fat tissue was inserted into the defect after bilateral condylectomy, increasing the maximum mouth opening from 5.0 to 32.0 mm. Subsequently, orthodontic treatment and advancement of the mandible were carried out by mandibular DO, using miniscrews and miniplates. Finally, sliding genioplasty was performed to bring the tip of the mandible forward. The total amount of mandibular advancement at the menton was 16.0 mm. An improved facial appearance and good occlusion were eventually achieved, and the apnea-hypopnea index decreased from 37.1 to 8.7. There was no obvious bone resorption or pain in the temporomandibular region, limited mouth opening (maximum mouth opening: 33.0 mm), myofascial pain or headache, downward rotation of the mandible, or lateral shift of mandibular position evident at 5 years and 6 months after mandibular DO. CONCLUSION: Mandibular DO using skeletal anchorage with intermaxillary elastics is useful for preventing extrusion of the upper and lower anterior teeth, thereby preventing rotation of the mandible. In addition, mandibular DO combined with sliding genioplasty is effective at improving both dentofacial deformities and impaired respiratory function. PMID- 29126456 TI - Virological response, HIV-1 drug resistance mutations and genetic diversity among patients on first-line antiretroviral therapy in N'Djamena, Chad: findings from a cross-sectional study. AB - BACKGROUND: The national antiretroviral therapy in the Republic of Chad provides free of charge antiretroviral regimens and therapeutic monitoring for patients receiving antiretroviral therapy nationwide. For a successful programmatic uptake, these efforts merit to be supported by thorough assessments of antiretroviral therapy response and HIV-1 drug resistance surveillance, especially with risks of cross-resistance due to the gradual stavudine phasing out in such national settings. We therefore evaluated the virological response to antiretroviral therapy, HIV-1 drug resistance emergence and circulating HIV-1 clades in a Chad context. A cross-sectional and prospective study was conducted among 116 patients (41 [delta +/- 6.87] years, 59% female) receiving first-line antiretroviral therapy for >= 6 months in Ndjamena, Chad, in 2011-2012, enrolled consecutively. To ensure accuracy, plasma viral load was concomitantly measured using Abbott Real-Time and Cobas AmpliPrep/TaqMan (v2.0), and virological failure defined as >= 1000 HIV-1 RNA copies/ml. Plasma from patients experiencing virological failure were processed for sequencing of HIV-1 protease-reverse transcriptase using the ANRS-AC.11 resistance testing protocol; drug resistant mutations were interpreted using the ANRS-AC11 algorithm; and phylogenetic analysis was performed using MEGA.v.6. RESULTS: Majority of patients was receiving zidovudine plus lamivudine plus nevirapine (46%), stavudine plus lamivudine plus nevirapine (41%) and tenofovir plus emtricitabine plus efavirenz (11%), for a median time-on-treatment of 5 [IQR 4-7] years. The rate of virological failure was 43% (50/116), with 86% (43/50) sequencing performance. Overall, 32% (37/116) patients presented >= one major drug resistant mutation(s), with 29% (34/116) to nucleos(t)ide reverse transcriptase inhibitors (67% [29/43] M184V/I, 30% [13/43] T215Y/F, 19% [8/43] V75A/F/I/L/M, 9% [4/43] K70P/R/W, 9% [4/43] K219E/N/Q and 5% [2/43] A62V); 86% (37/43) to non-nulceos(t)ide reverse transcriptase inhibitors (30% [13/43] K103N/S/E, 26% [11/43] Y181C/V/F/L, 2% [1/43] L100I, 2% [1/43] F227L, 2% [1/43] P225H); and 2% (1/43) to protease inhibitors (M46I, I54V, V82S). Six HIV-1 subtypes were found: 30% circulating recombinant form (CRF02_AG), 30% J, 16% G, 9% A, 9% D, 5% F. CONCLUSIONS: In Chad, almost half of patients are failing first-line antiretroviral therapy after 5 years, with considerable drug resistant mutations at failure. Absence of K65R supports the use of tenofovir-containing regimens as preferred first-line and as suitable drug for second-line combinations, in this setting with significant HIV 1 genetic diversity. PMID- 29126457 TI - Chest compression-related fatal internal mammary artery injuries manifesting after venoarterial extracorporeal membrane oxygenation: a case series. AB - BACKGROUND: Cardiopulmonary resuscitation-related bleeding, especially internal mammary artery injuries, can become life-threatening complications after initiating venoarterial extracorporeal membrane oxygenation owing to the frequent involvement of concomitant anticoagulant treatment, antiplatelet treatment, targeted temperature management, and bleeding coagulopathy. We report the cases of five patients who experienced this complication and discuss their management. CASE PRESENTATION: We retrospectively evaluated five patients with cardiopulmonary resuscitation-related internal mammary artery injuries who were treated between February 2011 and February 2016 at our institution. All five patients were Asian men, aged 56 to 68-years old, who had received concomitant intravenously administered unfractionated heparin (3000 units) with antiplatelet therapy. Four patients received targeted temperature management. The injuries and hematomas were detected using contrast-enhanced computed tomography in all cases. Three patients were treated using transcatheter arterial embolization within 6 hours following cardiopulmonary arrest, and two were resuscitated and received appropriate treatment following early recognition of their injuries. Two patients died of hemorrhagic shock with delayed intervention. Four of the five patients had excessively prolonged activated partial thromboplastin times before their interventions. CONCLUSIONS: Computed tomography should be performed as soon as possible after the return of spontaneous circulation to identify injuries and consider appropriate treatments for patients who have experienced cardiac arrest. Delayed bleeding may develop after treating hypovolemic shock and relieving arterial spasms; therefore, transcatheter arterial embolization should be performed aggressively to prevent delayed bleeding even in the absence of extravasation. This approach may be superior to thoracotomy because it is less invasive, causes less bleeding, and can selectively stop arterial bleeding sooner. A 3000-unit intravenous bolus of unfractionated heparin may be redundant; heparin-free extracorporeal cardiopulmonary resuscitation may be a more appropriate alternative. Unfractionated heparin treatment can commence after the bleeding has stopped. PMID- 29126458 TI - Epidemiology of hypertension in Fulani indigenous populations-age, gender and drivers. AB - BACKGROUND: Hypertension is a public health problem and the main contributor to cardiovascular mortality and morbidity. Little is known about hypertension among the minority, diverse and socially disadvantaged 23-24 million Fulani/Peul populations dispersed in West, Central and East Africa, undergoing a transition from traditional to transitional and modern lifestyle. This study describes age and gender variations in blood pressure and drivers of hypertension among rural Fulani population of Cameroon. METHODS: We analysed population-based cross sectional data collected in 2013 by standard methods from 1337 Fulani/Peul aged >= 20 years. Hypertension was defined as systolic blood pressure (SBP) >= 140 mmHg and/or diastolic blood pressure >= 90 mmHg or current use of anti hypertensive medication. We elucidated the occurrence and drivers of hypertension by chi-square test, Student's t test and univariate and multivariable logistic regression models. RESULTS: The prevalence of hypertension was 31.1% (men 36.5% and women 28.7%). Systolic and diastolic blood pressure increased with age. Older women suffered more from grades 1, 2 and 3 hypertension than older men. Old age, divorced/separated, never attended school, current/former smoker, family history (FH) of hypertension, diabetic, underweight and substantially increased risk from waist circumference were independently associated with hypertension. Insomnia and had 8-12 children were the only drivers of hypertension among men. CONCLUSION: Prevalence of hypertension was high. Awareness and control were low. Hypertension prevalence increased with age and was more prevalent among men than women. Older women experienced severe hypertension more than older men. Culturally embedded interventions are warranted to curb the high burden of hypertension among the Fulani. PMID- 29126459 TI - Emergency Department waiting times in a tertiary children's hospital in Israel: a retrospective cohort study. AB - BACKGROUND: The purpose of this study was to assess ethnic differences in Emergency Department (ED) waiting times between Jewish and Arab children in a tertiary childrens' hospital in Israel. METHODS: This was a retrospective cohort study of all children who were admitted to the pediatric ED of the largest hospital in northern Israel, between January 2011 and December 2015. Univariate and multivariate analyses were used to assess the strength of association between ethnicity category and waiting time. The following were tested as possible confounders: triage category, age, gender, time of arrival category. The effect of nurse-patient ethnic concordance was assessed. RESULTS: Full data were available in 82,883 patients, 55,497 (67.0%) Jews and 27,386 (33.0%) Arabs. Jews and Arabs had a similar median waiting time of 38 min (interquartile range [IQR] 22-63 and IQR 21-61, respectively). Ethnicity was not associated with a change in waiting time (p = 0.36). Factors that most influenced shorter waiting time were triage category 1 (change in waiting time: -25.5%; 95% confidence interval [CI]: 29.3 to -21.7), or triage category 2 (change in waiting-time: -21.8%; 95% CI: 23.7 to -20.05). Factors that most influenced longer waiting time were patient arrival during the morning shift period (change in waiting time: 5.45%; 95% CI: 4.59 to 6.31), or during the evening shift period (change in waiting time: 4.46%; 95% CI: 3.62 to 5.29). Ethnic discordance between triage nurses and patients did not yield longer waiting times. CONCLUSION: In this large pediatric cohort, ethnic differences in ED waiting time were not found. PMID- 29126460 TI - Dirofilaria repens transmission in southeastern Finland. AB - BACKGROUND: The spread of vector-borne diseases to new regions has become a global threat due to climate change, increasing traffic, and movement of people and animals. Dirofilaria repens, the canine subcutaneous filarioid nematode, has expanded its distribution range northward during the last decades. The northernmost European locations, where the parasite life-cycle has been confirmed, are Estonia and the Novgorod Region in Russia. RESULTS: Herein, we describe an autochthonous D. repens infection in a Finnish woman. We also present two cases of D. repens infection in imported dogs indicating the life-cycle in the Russian Vyborg and St Petersburg areas, close to the Finnish border. CONCLUSIONS: The most obvious limiting factor of the northern distribution of D. repens is the summer temperature, due to the temperature-dependent development of larvae in vectors. With continuing climate change, further spread of D. repens in Fennoscandia can be expected. PMID- 29126462 TI - Prediction of drowsiness events in night shift workers during morning driving. AB - The morning commute home is an especially vulnerable time for workers engaged in night shift work due to the heightened risk of experiencing drowsy driving. One strategy to manage this risk is to monitor the driver's state in real time using an in vehicle monitoring system and to alert drivers when they are becoming sleepy. The primary objective of this study is to build and evaluate predictive models for drowsiness events occurring in morning drives using a variety of physiological and performance data gathered under a real driving scenario. We used data collected from 16 night shift workers who drove an instrumented vehicle for approximately two hours on a test track on two occasions: after a night shift and after a night of rest. Drowsiness was defined by two outcome events: performance degradation (Lane-Crossing models) and electroencephalogram (EEG) characterized sleep episodes (Microsleep Models). For each outcome, we assessed the accuracy of sets of predictors, including or not including a driver factor, eyelid measures, and driving performance measures. We also compared the predictions using different time intervals relative to the events (e.g., 1-min prior to the event through 10-min prior). By examining the Area Under the receiver operating characteristic Curve (AUC), accuracy, sensitivity, and specificity of the predictive models, the results showed that the inclusion of an individual driver factor improved AUC and prediction accuracy for both outcomes. Eyelid measures improved the prediction for the Lane-Crossing models, but not for Microsleep models. Prediction performance was not changed by adding driving performance predictors or by increasing the time to the event for either outcome. The best models for both measures of drowsiness were those considering driver individual differences and eyelid measures, suggesting that these indicators should be strongly considered when predicting drowsiness events. The results of this paper can benefit the development of real-time drowsiness detection and help to manage drowsiness to avoid related motor-vehicle crashes and loss. PMID- 29126461 TI - Impact of a deferred recruitment model in a randomised controlled trial in primary care (CREAM study). AB - BACKGROUND: Recruitment of participants is particularly challenging in primary care, with less than a third of randomised controlled trials (RCT) achieving their target within the original time frame. Participant identification, consent, randomisation and data collection can all be time-consuming. Trials recruiting an incident, as opposed to a prevalent, population may be particularly affected. This paper describes the impact of a deferred recruitment model in a RCT of antibiotics for children with infected eczema in primary care, which required the recruitment of cases presenting acutely. METHODS: Eligible children were identified by participating general practitioners (GPs) and referred to a study research nurse, who then visited them at home. This allowed the consent and recruitment processes to take place outside the general practice setting. Information was recorded about patients who were referred and recruited, or if not, the reasons for non-recruitment. Data on recruitment challenges were collected through semi-structured interviews and questionnaires with a sample of participating GPs. Data were thematically analysed to identify key themes. RESULTS: Of the children referred to the study 34% (58/171) were not recruited - 48% (28/58) because of difficulties arranging a baseline visit within the defined time frame, 31% (18/58) did not meet the study inclusion criteria at the time of nurse assessment, and 21% (12/58) declined participation. GPs had positive views about the recruitment process, reporting that parents valued and benefitted from additional contact with a nurse. GPs felt that the deferred recruitment model did not negatively impact on the study. CONCLUSIONS: GPs and parents recognised the benefits of deferred recruitment, but these did not translate into enhanced recruitment of participants. The model resulted in the loss of a third of children who were identified by the GP as eligible, but not subsequently recruited to the study. If the potential for improving outcomes in primary care through complex studies is to be realised, new approaches to recruitment into primary care trials need to be developed and evaluated. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN96705420 . Registered on 27 June 2012. PMID- 29126463 TI - A cell surface specific two-photon fluorescent probe for monitoring intercellular transmission of hydrogen sulfide. AB - Hydrogen sulfide (H2S) is a new endogenously generated gasotransmitter and has implicated in many physiologies and pathologies closely related to its intracellular and intercellular signaling transduction. Although many fluorescent probes have been exploited to track and quantify H2S in living systems, none of them could be used for monitoring intercellular transmission of H2S. Herein, we developed a cell surface specific H2S probe, 4-azido-6-sulfo-N-hexadecyl-1,8 naphthalimide, sodium salt (ASNHN-N3), trying to investigate the behaviors of extracellular release of H2S. ASNHN-N3 is week fluorescent and could react with H2S at 37 degrees C in pH 7.4 buffer solutions to form product ASNHN-NH2 with strong fluorescence (Phi = 0.22). Using ASNHN-N3 as H2S probe, excellent linear correlation versus the concentration of NaHS was obtained ranging from 0 to 10 MUM and the detection limit was 0.75 MUM. With the lipid anchor and the hydrophilic sulfonic group introduced into the 1,8-naphthalimide (a skeleton of two-photon fluorescent probe), the amphiphilic probe is located at the surface of living cells which can record H2S efflux from the cell diffusing across the plasma membrane in living cells and deep-tissue by using two-photon microscopy. Thus we present a new strategy for further studying the mechanism of signaling molecules in cell communication and signal pathways. PMID- 29126464 TI - Direct Electrochemical DNA Sensor based on a new redox oligomer modified with ferrocene and carboxylic acid: Application to the detection of Mycobacterium tuberculosis mutant strain. AB - A new redox oligomer "oligo-methoxy-phenyl-acetonitrile" (Fc-acid-OMPA) modified with ferrocene groups and carboxylic acids as functional groups in side chains, has been synthesized. The redox indicator has been used for monitoring the electrochemical behavior. The functional groups give the flexibility for direct covalent attachment of biomolecules. The electrochemical properties of the redox oligomer film deposited on gold electrodes have been studied by cyclic voltammetry (CV), which showed a rate of electron transfer of 6.43 s-1. The oligomer has been studied as a transducer for electrochemical DNA sensing and for this purpose the acid functional group of Fc-acid-OMPA was attached with the DNA probe of hepatitis C bearing amino group in 5' position through amid link. The efficiency of DNA attachment on the oligomer film has been analyzed by X-Ray Photoelectron Spectrometry (XPS) and FT-IR spectroscopy. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) have been used to analyze the biosensor construction and DNA detection. A wide linear range of detection from 1 fM to 100 pM have been demonstrated with a limit of detection (LOD) of 0.2 fM. The biosensor has showed an appreciated sensitivity to PCR samples of genomic DNA from Mycobacterium tuberculosis, and has been able to detect a single mutation which confers resistance of M. tuberculosis to rifampicin drug. PMID- 29126465 TI - Facile synthesis of magnetic metal organic frameworks for highly efficient proteolytic digestion used in mass spectrometry-based proteomics. AB - Mass spectrometry (MS) based bottom-up strategy is now the first choice for proteomics analysis. In this process, highly efficient and complete enzymatic degradation of protein samples is extremely important to achieve in-depth protein coverage and high-throughput protein profiling. However, conventional in-solution digestion suffer from long digestion time and enzyme autolysis that limit the protein sample processing throughput and identification accuracy. Here, we developed a novel type of magnetic metal organic frameworks (MOFs)-based immobilized enzyme reactor, Fe3O4@DOTA-ZIF-90-trypsin. By introducing a stable chelator, 1,4,7,10-tetraazacyclododecane N,N',N",N'''-tetraacetic acid (DOTA), onto the magnetic cores, the hybrid supporting matrix of the immobilized enzyme reactor Fe3O4@DOTA-ZIF-90 has novel characteristics that include: i) favourable magnetic response (1.01 emu g-1) that makes the operation easy and convenient, ii) ultrahigh surface area (565.21 m2 g-11) and active sites that ensure high loading amounts and covalent linkage of enzyme, and iii) excellent structural and thermal stability that endows the immobilized enzyme reactor a prolonged lifespan. The performance of the magnetic MOFs-immobilized trypsin is first investigated using the standard protein, BSA, and the results showed that the immobilized enzyme reactor exhibits satisfactory digestion efficiency within only 1 min with the sequence coverage (80%) that is comparable or even better than that (70%) of the traditional 12 h-free trypsin digestion. To test the applicability of the magnetic MOFs-based immobilized enzyme reactor, protein samples extracted from 400 oocytes in mice were digested through the new immobilized enzyme reactor. In total, 8957 peptides corresponding to 1843 protein groups are identified, which are nearly of 40% and 67% increases in the number of identified proteins and peptides compared to using in-solution digestion with free proteases. Specifically, the identification of oocyte-specific proteins was critical in the discovery of and understanding the regulation mechanism of oocyte maturation. Thus, this synthetic procedure of Fe3O4@DOTA-ZIF-90 provides a universal method for fabrication of magnetic MOFs materials, and the successful application of Fe3O4@DOTA-ZIF-90-trypsin in efficient protein digestion for deeper proteome coverage will undoubtedly enlarge the uses for MOFs. PMID- 29126466 TI - Graphene grown on stainless steel mesh as a highly efficient sorbent for sorptive microextraction of polycyclic aromatic hydrocarbons from water samples. AB - In this study, graphene grown on stainless steel mesh efficiently incorporates the advanced properties of graphene in the form of an ultra-thin coating with the open geometry of the substrate, resulting in a highly sensitive and fast sorptive device capable of extracting target analytes directly from sample matrices. The synthesis of graphene on the stainless steel mesh was confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The advantages of the new microextraction device have been investigated for the determination of polycyclic aromatic hydrocarbons (PAHs) in environmental water samples in combination with gas chromatography-flame ionization detector (GC FID). The factors affecting the extraction efficiency such as stirring speed, extraction time, ionic strength and desorption conditions, were investigated and the optimal extraction conditions were established. Under the optimal extraction condition, linearity was in the range of 0.003-100 ng mL-1 with a correlation coefficient of 0.9923-0.9985. The limits of detection (LODs) of the developed method are obtained between 1 and 3 pg mL-1. The repeatability was assessed at two concentration levels (0.01 and 10 ng mL-1) and the relative standard deviations (RSDs) obtained were 4.9-8.7%. The preparation reproducibility of sorbent device, evaluated with the RSDs, was in the range of 7.3-10.2% (n = 5) in one batch, and 8.3-11.0% (n = 5) among different batches. Finally, the proposed method is applied for the determination of the target PAHs in the real water samples. PMID- 29126468 TI - Enhancing carbohydrate ion yield by controlling crystalline structures in matrix assisted laser desorption/ionization mass spectrometry. AB - Carbohydrate analysis is challenging due to lack of sensitive detection and efficient separation methods. Although matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is a sensitive tool, the low ionization efficiency of carbohydrates makes mass analyses inefficient. This work systematically examines the correlation between MALDI-MS sensitivity and carbohydrate sample morphology. Depending on the properties of the matrix used, the morphology changes through sample recrystallization after drying or imposition of hydrodynamic flows during droplet drying. Observation shows that amorphous solids and finer crystals offer higher carbohydrate sensitivity and spatial homogeneity than larger crystals. Clear evidences of an inverse correlation between sensitivity and crystal size are obtained when various kinds of carbohydrates are mixed with different matrixes. Similar experiments on proteins and peptides showed a negative or negligible effect. The result serves as a general guideline for improving efficiency in routine carbohydrate analysis. PMID- 29126467 TI - Rapid fingerprinting of lignin by ambient ionization high resolution mass spectrometry and simplified data mining. AB - Ambient ionization techniques are typically used to analyze samples in their native states with minimal or no sample pretreatment prior to mass spectrometric (MS) analysis. Desorption electrospray ionization (DESI) and direct analysis in real time (DART) were systematically investigated in this work for direct solid analysis of depolymerized lignin samples, with the goal of rapidly fingerprinting these samples, to efficiently characterize the subunits of this renewable energy source. High resolution MS was required for enhanced selectivity in this study due to the inherent structural complexity of lignin. DESI provided results across a broader mass range (up to m/z 700) than DART and also ionized saturated compounds of low oxygen-to-carbon (O/C) ratios and low double bond equivalents (DBE). While DART detected the same core lignin monomeric and dimeric compounds as seen with DESI and electrospray ionization (ESI), results were restricted to a narrower mass range to m/z 500, due to thermal degradation and losses of methoxy groups. In contrast to DESI and ESI, the DART spectra were nearly void of saturated components. On a structural level, the core lignin compounds were visually fingerprinted and ionization method performances critically assessed by employing simplified Kendrick-based data mining approaches. A novel simplified data visualization approach was developed in this work based on modified Kendrick mass defect (KMD) filtering for lignin subunits and plotting the mass defect values against the degree of unsaturation. Direct visualization of monomeric, dimeric and trimeric lignin species was simplified by the KMD separation plots, easily allowing the core lignin compounds to be visually identified and compared. Modified KMD bases, namely methoxy and phenol bases, which represent monomer specific lignin constituents, were successfully used to classify and group the complex mixture of lignin species. Further separation of methoxy-related lignin species was successfully achieved by employing the more specific phenolic KMD base. PMID- 29126469 TI - High reliable and robust ultrathin-layer gold coating porous silver substrate via galvanic-free deposition for solid phase microextraction coupled with surface enhanced Raman spectroscopy. AB - That intense demand for both high sensitivity and high reliability has been a key factor strengthening the surface enhanced Raman spectroscopy (SERS) in the analytical application, particular in the hyphenation with pre-concentration technique. Credible data acquisition and processing is very dependent on the stable and uniform performance of SERS-active substrate. Here, a reliable and uniform ultrathin-layer Au was proposed for protecting the porous Ag fiber (porous Ag@Au) and applied in the solid phase microextraction coupled with SERS. The Au layer was carefully deposited on porous Ag surface to form the uniform film by a galvanic-free displacement reaction. This coating endowed the substrate with high oxidation-resistance under heating and good durability in the atmosphere condition. The extraction and SERS performance of Nitrofurazone and Semicarbazide were investigated on this fiber, the bands at 1350 cm-1 and 1387 cm 1 were selected as the characteristic peaks for quantitative determination, respectively. This robust and sensitive substrate provide the high enhancement factor of 1.3 * 106 and low LOD of 5.1 ppb for the extraction and identification of Nitrofurazone compounds. Importantly, this work develops a versatile strategy for rapid detection of prohibited antibiotic and its marker residue in a complex matrix. PMID- 29126470 TI - Controlling the orientation of probe molecules on surface-enhanced Raman scattering substrates: A novel strategy to improve sensitivity. AB - Typically, the surface-enhanced Raman scattering (SERS) technique is employed in precious metallic substrates with spontaneously adsorbed probing molecules to acquire signals. Preferred chemical conditions including aggregate status, hydrophilic/hydrophobic surroundings, and smart linkers were created to enable the detection of targets in very low concentrations (lower than 1.0 * 10-7 M). Although the sensitivity of SERS is applicable to certain areas, it is not satisfied in several cases that require obtaining good resolved signals involving extremely few surface molecules. Thus, further improvements in the sensitivity based on existing SERS techniques pose a challenge and is desirable for all aspects of analytical chemistry. In this study, a novel strategy was employed by constructing a molecular template (MT) on the SERS substrates with spontaneously adsorbed probe molecules to improve the detection sensitivity of probe molecules. The proposed MT-assisted SERS technique differed from previous methods as it provides a completely new method for improving the limit of detection (LOD) of SERS by controlling molecular orientations. The surface selection rules of SERS spectra were first introduced as an effective strategy to improve the detection sensitivity, and this was extremely beneficial with respect to analytical applications. The use of the MT-assisted SERS technique indicated that the LOD of probe molecules of p-aminobenzenethiol (8.0 * 10-9 M) and 4-mercaptobenzoic (1.0 * 10-7 M) acids on noble metallic substrates exhibited nearly one order of magnitudes. Hence, the proposed method paves a way to detect the molecules under improved sensitivity at extreme low concentrations. The study corresponded to a proof-of-concept study of MT-assisted SERS for SERS-based applications in ultra sensitive analysis. PMID- 29126471 TI - A near-infrared fluorescent probe based on BODIPY derivative with high quantum yield for selective detection of exogenous and endogenous cysteine in biological samples. AB - Cysteine (Cys) is involved in cellular growth and Cys deficiency is related with many diseases. So far, a number of fluorescent probes have been constructed for the detection of Cys successfully. However, the probes are difficult to discriminate Cys from Hcy and the emission wavelength of the probes is in ultraviolet or visible range. Herein, a NIR fluorescent probe named NIR-BODIPY-Ac is synthesized and used to detect Cys. The emission wavelength of the probe is at 708 nm that belongs to near-infrared (NIR) region by attaching indolium to BODIPY core, which is suitable for bioimaging in vivo. Moreover, the probe exhibits high fluorescence quantum yield (Phi = 0.51) after the addition of Cys and high sensitivity toward Cys with 81-fold fluorescence enhancement. The linear range of the probe for Cys covers from 0.2 to 30 MUM with a detection limit of 0.05 MUM. Furthermore, the probe shows high selectivity towards Cys owing to the fact that there is more fast reaction rate between the probe and Cys than that of Hcy. In particular, the NIR fluorescent probe is applied for the detection of exogenous and endogenous Cys in biological samples such as cell, tissue and mouse with satisfactory results. PMID- 29126472 TI - A novel visible-light driven photoelectrochemical immunosensor based on multi amplification strategy for ultrasensitive detection of microcystin-LR. AB - An ultrasensitive photoelectrochemical (PEC) immunoassay based on multiple signal amplification strategy was fabricated for the detection of microcystin-LR (MC LR). The CdS/TiO2 nanorod arrays (CdS/TiO2 NRAs) modified FTO electrode, which can weaken the self-oxidation by photogenerated holes of CdS nanoparticles, and limit the recombination of electron-hole pairs and broaden optical absorption of TiO2 NRAs, was used as a visible-light driven material to immobilize antigens. Then, Fe3O4 nanoparticles/polydopamine (Fe3O4@PDA) was used as the carrier to load secondary antibody (Ab2) and horseradish peroxidase (HRP), where Fe3O4 nanoparticles and HRP can synergistically accelerate the oxidation of 4-chloro-1 naphthol (4-CN) by H2O2 to produce biocatalytic precipitation (BCP) on the surface of modified electrode. Due to the catalytic activity of Fe3O4 nanoparticles and HRP, the nonproductive absorption of HRP and the steric hindrance by BCP, the photocurrent change was amplified. The proposed PEC immunosensor can detect MC-LR in a range of 0.005-500 MUg/L with a detection limit of 0.001 MUg/L. Meanwhile, the PEC immunosensor exhibited high sensitivity, good stability, acceptable selectivity and reproducibility, indicating its potential application in environmental monitoring. PMID- 29126473 TI - A luminescent probe of mismatched DNA hybridization: Location and number of mismatches. AB - The human genome is susceptible to change; base mismatches can arise from damaged DNA, replication errors, and spontaneous mutation, and have the potential to cause apoptosis, carcinogenesis, and mutagenesis. Many techniques have been developed for DNA mismatch detection, but many of these methods have complex, time-consuming procedures and are limited to the detection of specific types of DNA mismatches. In this work, we present a general method for the simple and sensitive nucleobase-sensitized luminescent detection of mismatches in double stranded DNA (dsDNA) using terbium ions. Terbium ions luminesce differently depending on the site of coordination in DNA due to the proximity effect of the energy transfer process that occurs from excited, non-hydrogen bonded nucleobases in single-stranded DNA (ssDNA) regions to the terbium ions. We examined the effect of location and number of mismatches on the sensitivity and selectivity of this probe in both synthetic oligonucleotides containing mismatches and natural calf thymus DNA exposed to UV light to induce reduced base pairing due to damage. This method shows good sensitivity for the determination of DNA mismatches, with limit of detection and limit of quantification of 1 and 3 mismatches, respectively, per dsDNA sequence. PMID- 29126474 TI - Erratum. PMID- 29126475 TI - Development and application of mass spectrometric techniques for ultra-trace determination of 236U in environmental samples-A review. AB - Measurements of the long-lived radionuclide 236U are an important endeavor, not only in nuclear safeguards work, but also in terms of using this emerging nuclide as a tracer in chemical oceanography, hydrology, and actinide sourcing. Depending on the properties of a sample and its neutron irradiation history, 236U/238U ratios from different sources vary significantly. Therefore, this ratio can be treated as an important fingerprint for radioactive source identification, and in particular, affords a definitive means of discriminating between naturally occurring U and specific types of anthropogenic U. The development of mass spectrometric techniques makes it possible to determine ultra-trace levels of 236U in environmental samples. In this paper, we review the current status of mass spectrometric approaches for determination of 236U in environmental samples. Various sample preparation methods are summarized and compared. The mass spectrometric techniques emphasized herein are thermal ionization mass spectrometry (TIMS), inductively coupled plasma mass spectrometry (ICP-MS) and accelerator mass spectrometry (AMS). The strategies or principles used by each technique for the analysis of 236U are described. The performances of these techniques in terms of abundance sensitivity and detection limit are discussed in detail. To date, AMS exhibits the best capability for ultra-trace determinations of 236U. The levels and behaviors of 236U in various environmental media are summarized and discussed as well. Results suggest that 236U has an important, emerging role as a tracer for geochemical studies. PMID- 29126476 TI - High throughput human plasma N-glycan analysis using DNA analyzer and multivariate analysis for biomarker discovery. AB - Carbohydrates form the majority of organic compounds found in nature and their presence on proteins influences many important bioactivities. Therefore, glycan profiling shows potential in clinical applications. This work demonstrates the use of a high-throughput GlycanAssureTM sample preparation technology and multi capillary DNA analyzer for the analysis of the major N-linked glycans (N-glycans) found in human plasma. The application involves two biomarker studies: (1) in profiling patients with chronic kidney disease and (2) in differentiating heart disease patients with normal controls in response to an antiplatelet drug from hypo-responders. Due to complexity of the study data, bio-statistical methods were applied to data processing. 37 N-glycan peaks were observed from separation results, with confirmed structure for most glycans. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to build models to differentiate the patient groups. The percentages of correct classification of the models reached 95.45% for the chronic kidney disease dataset and 85.42% for the anti-platelet drug response dataset. Given that blood N-glycan profiles had been shown to reflect certain disease states, this high-throughput platform could potentially be used for the simultaneous screening of multiple glycan biomarkers, with as little as one drop of blood sample. PMID- 29126477 TI - Integration of capillary electrophoresis with gold nanoparticle-based colorimetry. AB - A method integrating capillary electrophoresis (CE) and gold nanoparticle aggregation-based colorimetry (AuNP-ABC) was described. By using a dual-sheath interface, the running buffer was isolated from the colorimetric reaction solution so that CE and AuNP-ABC would not interfere with each other. The proof of-concept was validated by assay of polyamidoamine (PAMAM) dendrimers that were fortified in human urine samples. The factors influencing the CE-AuNP-ABC performances were investigated and optimized. Under the optimal conditions, the dendrimers were separated within 8 min, with detection limits of 0.5, 1.2 and 2.6 MUg mL-1 for PAMAM G1.0, G2.0 and G3.0, respectively. The sensitivity of CE-AuNP ABC was comparable to or even better than those of liquid chromatography fluorimetry and liquid chromatography-mass spectrometry. The results suggested that the proposed strategy can be applied to facile and quick determination of analytes of similar properties in complex matrices. PMID- 29126478 TI - Optimization of GC/TOF MS analysis conditions for assessing host-gut microbiota metabolic interactions: Chinese rhubarb alters fecal aromatic amino acids and phenol metabolism. AB - In this paper, an optimized method based on gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) platform has been developed for the analysis of gut microbial-host related co-metabolites in fecal samples. The optimization was performed with proportion of chloroform (C), methanol (M) and water (W) for the extraction of specific metabolic pathways of interest. Loading Bi-plots from the PLS regression model revealed that high concentration of chloroform emphasized the extraction of short chain fatty acids and TCA intermediates, while the higher concentration of methanol emphasized indole and phenyl derivatives. Low level of organic solution emphasized some TCA intermediates but not for indole and phenyl species. The highest sum of the peak area and the distribution of metabolites corresponded to the extraction of methanol/chloroform/water of 225:75:300 (v/v/v), which was then selected for method validation and utilized in our application. Excellent linearity was obtained with 62 reference standards representing different classes of gut microbial-host related co-metabolites, with correlation coefficients (r2) higher than 0.99. Limit of detections (LODs) and limit of qualifications (LOQs) for these standards were below 0.9 nmol and 1.6 nmol, respectively. The reproducibility and repeatability of the majority of tested metabolites in fecal samples were observed with RSDs lower than 15%. Chinese rhubarb-treated rats had elevated indole and phenyl species, and decreased levels of polyamine such as putrescine, and several amino acids. Our optimized method has revealed host-microbe relationships of potential importance for intestinal microbial metabolite receptors such as pregnane X receptor (PXR) and aryl hydrocarbon receptor (AHR) activity, and for enzymes such as ornithine decarboxylase (ODC). PMID- 29126479 TI - Fast probing of glucose and fructose in plant tissues via plasmonic affinity sandwich assay with molecularly-imprinted extraction microprobes. AB - Determination of specific target compounds in agriculture food and natural plant products is essential for many purposes; however, it is often challenging due to the complexity of the sample matrices. Herein we present a new approach called plasmonic affinity sandwich assay for the facile and rapid probing of glucose and fructose in plant tissues. The approach mainly relies on molecularly imprinted plasmonic extraction microprobes, which were prepared on gold-coated acupuncture needles via boronate affinity controllable oriented surface imprinting with the target monosaccharide as the template molecules. An extraction microprobe was inserted into plant tissues under investigation, which allowed for the specific extraction of glucose or fructose from the tissues. The glucose or fructose molecules extracted on the microprobe were labeled with boronic acid functionalized Raman-active silver nanoparticles, and thus affinity sandwich complexes were formed on the microprobes. After excess Raman nanotags were washed away, the microprobe was subjected to Raman detection. Upon being irradiated with a laser beam, surface plasmon on the gold-coated microprobes was generated, which further produced plasmon-enhanced Raman scattering of the silver-based nanotags and thereby provided sensitive detection. Apple fruits, which contain abundant glucose and fructose, were used as a model of plant tissues. The approach exhibited high specificity, good sensitivity (limit of detection, 1 MUg mL-1), and fast speed (the whole procedure required only 20 min). The spatial distribution profiles of glucose and fructose within an apple were investigated by the developed approach. PMID- 29126480 TI - Photometric flow analysis system for biomedical investigations of iron/transferrin speciation in human serum. AB - The Multicommutated Flow Analysis (MCFA) system for the estimation of clinical iron parameters: Serum Iron (SI), Unsaturated Iron Binding Capacity (UIBC) and Total Iron Binding Capacity (TIBC) has been proposed. The developed MCFA system based on simple photometric detection of iron with chromogenic agent (ferrozine) enables a speciation of transferrin (determination of free and Fe-bound protein) in human serum. The construction of manifold was adapted to the requirements of measurements under changing conditions. In the course of studies, a different effect of proteins on SI and UIBC determination has been proven. That was in turn the reason to perform two kinds of calibration methods. For measurements in acidic medium for SI/holotransferrin determination, the calibration curve method was applied, characterized by limit of determination and limit of quantitation on the level of 3.4 MUmol L-1 and 9.1 MUmol L-1, respectively. The determination method for UIBC parameter (related to apotransferrin level) in physiological medium of pH 7.4 forced the use of standard addition method due to the strong influence of proteins on obtaining analytical signals. These two different methodologies, performed in the presented system, enabled the estimation of all three clinical iron/transferrin parameters in human serum samples. TIBC corresponding to total transferrin level was calculated as a sum of SI and UIBC. PMID- 29126481 TI - Quantum Chemical Fragment Precursor Tests: Accelerating de novo annotation of tandem mass spectra. AB - Tandem mass spectrometry is widely used to assign and distinguish chemical structures in proteomics, metabolomics, lipidomics, and many other areas. Spectral annotation remains a major bottleneck. Our "Quantum Chemical Fragment Precursor Tests" (QC-FPT) approach brings the accuracy and generality of modern quantum chemistry to combinatorial-search-based computer-aided spectral annotation. QC-FPT takes as input the dominant fragment peaks from a particular experiment, and one or more chemically reasonable hypotheses for the precursor ion's three-dimensional structure. The algorithm automatically generates possible precursor ion fragmentations matching the target experimental peaks, uses quantum chemistry calculations (geometry optimization with gas-phase semiempirical or density functional theory calculations) to predict each neutral or charged fragment's structure and energy, and reports the thermodynamically feasible predicted fragment assignments. Applications demonstrate that QC-FPT recovers known spectral annotations, can handle multiple ionization and fragmentation methods and adducts, and can capture some fragment rearrangements. We apply QC FPT to assign previously unassigned peaks in an experimental LC-ESI-MS2 spectrum of dimethylarsinothioyl glutathione (Yehiayan et al., Chem. Res. Toxicol. 2014, 27, 754-764), and to a hypothetical experiment distinguishing two isomeric candidates for an "unknown" pesticide's experimental LC-ESI-MS2 spectrum. Our results suggest QC-FPT is a practical tool to sharpen and refine the chemical intuition of experimentalists engaged in the laborious process of annotating tandem mass spectra. PMID- 29126482 TI - Identification of new tetrahydroxylated metabolites of Polycyclic Aromatic Hydrocarbons in hair as biomarkers of exposure and signature of DNA adduct levels. AB - The present study addresses the hypothesis that the concentration of tetrahydroxylated Polycylic Aromatic Hydrocarbons (tetra-OH-PAHs) in hair might be a useful biomarker of human exposure to PAHs, providing quantitative assessment of the internal dose, as well as information on the associated toxicity in relation to individual's specific metabolism. By means of animal models, this work aimed at identifying new tetra-OH-PAHs which can be released from the hydrolysis of DNA-adducts and can also be directly detected in biological matrices usually used in the field of biomonitoring such as hair and urine. Results obtained from a targeted gas chromatography coupled with tandem mass spectrometry (GC-MS/MS) approach, demonstrated the presence of 8 tetrahydroxylated metabolites in DNA and 23 in hairs of rats exposed to mixtures of PAHs, which had never been analyzed before. Ten tetra-OH-PAHs were clearly characterized by using their analytical standards, corresponding to 4 parent PAHs (phenanthrene, chrysene, benz[a]anthracene and benzo[a]pyrene) whereas 13 tetra OH-PAHs from 3 other parents (anthracene, fluoranthene and benz[k]fluoranthene) were detected but not yet characterized. No tetrahydroxylated metabolite has been clearly identified for naphthalene, fluorene, benzo[b]fluoranthene, benzo[g,h,i]perylene, or dibenzo[a,h]anthracene, which can all potentially form adducts. The relevance of tetra-OH-PAH analysis in hair as biomarkers of PAH exposure was evaluated in a dose-response study conducted on 64 rats (Long Evans females/n = 8 per groups) under repeated exposure (3 times per week) to a mixture of 16 PAHs at low doses (0.01-0.8 mg/kg) for 90 days. Most of the tetra-OH-PAHs targeted in the method were detected in the hairs of the rats, regardless of the dose of exposure. Significant linear relationships (R2 ranging from 0.558 to 0.964, p < 0.001) were observed between the administered dose and the tetra-OH PAH concentrations in the hairs for 20 out of the 23 metabolites. By widening the range of PAH metabolites used as biomarkers of exposure so as to include the analysis of PAH tetrahydroxylated forms (especially those exhibiting more than 5 aromatic rings), the present methodology will enable multi-exposure assessments which are more accurately representative of actual situations of exposure to PAHs. PMID- 29126483 TI - Multi-parametric polymer-based potentiometric analytical microsystem for future manned space missions. AB - The construction and evaluation of a Cyclic Olefin Copolymer (COC)-based continuous flow potentiometric microanalyzer to simultaneously monitor potassium, chloride and nitrate ions in samples from an on-board water recycling process expected to be installed in future manned space missions is presented. The main goals accomplished in this work address the specific required characteristics for a miniaturized on-line monitoring system to control water quality in such missions. To begin with, the integration of three ion-selective electrodes (ISEs) and a reference electrode in a compact microfluidic platform that incorporates a simple automatic autocalibration process allows obtaining information about the concentration of the three ions with optimal analytical response characteristics, but moreover with low reagents consumption and therefore with few waste generation, which is critical for this specific application. By a simple signal processing (signal removal) the chloride ion interference on the nitrate electrode response can be eliminated. Furthermore, all fluidics management is performed by computer-controlled microvalves and micropumps, so no manual intervention of the crew is necessary. The analytical features provided by the microsystem after the optimization process were a linear range from 6.3 to 630 mg L-1 and a detection limit of 0.51 mg L-1 for the potassium electrode, a linear range from 10 to 1000 mg L-1 and a detection limit of 1.58 mg L-1 for the chloride electrode and a linear range from 10 to 1000 mg L-1 and a detection limit of 3.37 mg L-1 for the nitrate electrode with a reproducibility (RSD) of 4%, 2% and 3% respectively. Sample throughput was 12 h-1 with a reagent consumptions lower than 2 mL per analysis. PMID- 29126484 TI - Performance of electrokinetic stacking enhanced paper-based analytical device with smartphone for fast detection of fluorescent whitening agent. AB - Quantification is a fundamental aspect of performance of an analytical system. Paper-based analytical device (PAD) as an on-site detection platform has drawn wide attention mainly due to its portability and cost effectiveness. In this work, a portable and low-cost PAD for online preconcentration and sensitive determination of fluorescent whitening agent (FWA) was demonstrated, which was consisted of ultra violet light-emitting diode (UV LED), macro-focusing lens, smartphone and miniaturized DC voltage source. Taking a widely used FWA component VBL as the analyte, the performance of the PAD enhanced with electrokinetic stacking (ES) and fluorescence imaging detection was systematically investigated. With ES, the sensitivity of the PAD system was 160-fold enhanced, and a limit of detection (LOD) of 0.06 MUg mL-1 was achieved. The dynamic range was 0.1-10.0 MUg mL-1 (linear in 0.1-0.7 MUg mL-1, R2 = 0.99). With manual operation, the relative standard deviation (RSD) of intra-day and inter-day were all below 15%. Eventually, VBL from different napkin samples and toilet paper was determined with average recovery rates in the range of 90%-95% (RSD = 8.0%-12.0%). This work shows that with ES, the sensitivity of PAD can be greatly improved, and a LOD close to a desktop fluorescent spectrophotometer can be achieved as demonstrated by the detection of FWA component. PMID- 29126485 TI - A highly sensitive fluorescent turn-on biosensor for glycoproteins based on boronic acid functional polymer capped Mn-doped ZnS quantum dots. AB - A simple fluorescence turn-on sensor has been designed for the highly sensitive detection of glycoproteins on the basis of boronic acid functional polymer capped Mn-doped ZnS quantum dots (QDs@MPS@AAPBA). In the absence of glycoproteins, the fluorescence emission intensity of the QDs@MPS@AAPBA was relatively weaker due to the effective electronic transfer from the QDs to the boron moieties on its surface. While the glycoproteins were introduced into the system, an obvious fluorescence enhancement was observed. It was attributed to the boron moieties covalent binding glycans of the glycoproteins resulting in the electronic transfer process being inhibited. Under the optimal conditions, this fluorescent probe not only could be applied in a wide pH range of 5.0-9.0, but also the binding constants and detection limits of the QDs@MPS@AAPBA for horseradish peroxidase (HRP) and transferrin (TRF) were up to 7.23 * 106 M-1, 1.53 * 107 M-1 and 1.44 * 10-10 M, 3.36 * 10-10 M, respectively. Finally, this proposed method has also been utilized for the TRF determination in serum without any complicated pretreatment and the recovery was in the range of 95.7%-103.0%. As a result, it is promising for application on the glycoproteins detection in complex biological samples. PMID- 29126486 TI - Functionalized carbon quantum dots with dopamine for tyrosinase activity analysis. AB - Tyrosinase (TYR) is a key enzyme in melanin biosynthesis and its activity is an important biomarker for dermatological disorders, such as vitiligo, melanoma and actinic damages. Sensitive assay for TYR activity is significant for basic and clinical research. In this work, a facile fluorescent assay for TYR activity based on dopamine functionalized carbon quantum dots (CQDs-Dopa) has been developed. Dopamine (Dopa) was covalently bond to CQDs through a simple one-pot hydrothermal method, and the prepared CQDs-Dopa exhibited a fluorescence emission at 499 nm under exciting wavelength at 310 nm with a quantum yield of approximately 2.1%. When TYR was mixed with CODs-Dopa, the dopamine moiety in CQDs-Dopa conjugate was oxidized to O-dopaquinone, and an intra-particle photo induced electron transfer (PET) process consequently occurred between CQDs and O dopaquinone to quench the fluorescence of CQDs-Dopa. TYR activity can be determined based on the fluorescence quenching degree of CQDs-Dopa. This assay covered two broad linear ranges: 44.4-711.1 U L-1 and 711.1-2925.4 U L-1, with detection limit of 17.7 U L-1. The proposed fluorescent assay was applied to TYR activity measurement in human serum samples. It showed promising potential for TYR activity assay in clinical applications. PMID- 29126487 TI - Evaluation and Management of Oral Potentially Malignant Disorders. AB - Oral potentially malignant disorders (OPMDs) refer to epithelial lesions and conditions with an increased risk for malignant transformation; oral leukoplakia is the most commonly encountered. Overall, OPMDs have a low risk for malignant transformation, yet the challenge is the difficulty to reliably identify and predict which patients with OPMDs are at the highest risk for malignant transformation. Future research is needed to elucidate the molecular aspects of OPMDs, to improve current diagnostic strategies, leading to personalized management. PMID- 29126488 TI - Human Papillomavirus and Oropharyngeal Cancer. AB - Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) comprises approximately 25% of all head and neck cancers (head and neck squamous cell carcinoma, HNSCC). Epidemiologic studies have shown a dramatic increase of HPV-OPSCC in the past 2 decades, whereas tobacco-related HNSCC rates are decreasing worldwide. The distinctions between HPV-OPSCC and oral cavity cancers are now reflected in the most recent editions of the World Health Organization Classification of Tumors of the Head and Neck and the American Joint Committee on Cancer Staging Manual, respectively. This review describes current understanding of the link between HPV infection and OPSCC. PMID- 29126489 TI - Dental Treatment Planning for the Patient with Oral Cancer. AB - Oral cancer therapy is associated with a multitude of head and neck sequelae that includes, but is not limited to, hyposalivation, increased risk for dental caries, osteoradionecrosis of the jaw, radiation fibrosis syndrome, mucositis, chemotherapy-induced neuropathy, dysgeusia, dysphagia, mucosal lesions, trismus, and infections. Preparing a comprehensive treatment plan for patients undergoing cancer therapy is essential to help minimize their risks for developing these oral and dental complications. In addition, dentists must take into account a patient's ongoing oncologic therapy for those patients who present to the dentist while concurrently receiving cancer treatment. PMID- 29126490 TI - Dental Management of Patients Who Have Undergone Oral Cancer Therapy. AB - Oral cancer therapies are associated with orofacial complications that could result in dose-limiting cancer treatment and consequent suboptimal tumor control. Oral cancer treatment complications include oral mucositis, salivary gland hypofunction, odontogenic infections, pain, dermatitis, neurotoxicity, soft tissue fibrosis, trismus, osteoradionecrosis, and potential cancer recurrence. These complications significantly affect cancer survivorship, quality of life, and psychosocial status. Effective dental management of patients with oral cancer involves the coordination of care among several health care professionals before, during, and after cancer therapy. The goal is to minimize complications, and establish optimal quality of life for survivors. PMID- 29126491 TI - Impact of Oral Cancer on Quality of Life. AB - The clinical manifestations of oral cancer and the effects of treatment can have a negative impact on a patient's quality of life. Physiologic functions, cosmetic appearance, and psychological well-being can become compromised during the diagnosis, treatment, and survivorship of patients with oral cancer. This article addresses the relationship of oral cancer and quality of life, as well as the different aspects affected by this condition. PMID- 29126492 TI - Oral Cancer: Genetics and the Role of Precision Medicine. AB - Oral squamous cell carcinoma (OSCC) is one of the leading cancers in the world. OSCC patients are managed with surgery and/or chemoradiation. Prognoses and survival rates are dismal, however, and have not improved for more than 20 years. Recently, the concept of precision medicine was introduced, and the introduction of targeted therapeutics demonstrated promising outcomes. This article reviews the current understanding of initiation, progression, and metastasis of OSCC from both genetic and epigenetic perspectives. In addition, the applications and integration of omics technologies in biomarker discovery and drug development for treating OSCC are reviewed. PMID- 29126493 TI - Evaluation and Staging of Oral Cancer. AB - Although the American Joint Committee on Cancer developed its first cancer specific staging system in 1959, the TNM classification, as it has become known, has undergone many revisions mainly due to the advancements in both diagnosis and management of cancer, Although the basic purpose of the cancer staging system has remained fundamentally unchanged, the ease with which the cancer can be staged has evolved with newer methods. This article reviews cancer evaluation for staging, as well as the introduction of a new staging method effective as of 2018. PMID- 29126494 TI - Adjunctive Diagnostic Techniques for Oral and Oropharyngeal Cancer Discovery. AB - The most important prognostic factor in predicting the outcome of oral and oropharyngeal cancer (OPC) is the stage at which it is diagnosed. Only 30% of patients are diagnosed with early-stage disease. The oral health care provider performs an important role in early diagnosis of oral cancer. The conventional oral examination consists of a visual and tactile assessment of accessible oral, and head and neck structures. Any suspicious or equivocal lesion should be reevaluated within 4 weeks. Evidence supporting the use of adjunctive devices to improve the ability to screen for and identify OPCs and oral premalignant lesions remains low. PMID- 29126495 TI - Surgical Management of Oral Cancer. AB - Today, most head and neck cancer subsites, such as the larynx, hypopharynx, nasopharynx, and oropharynx, are treated with radiation therapy with or without chemotherapy as a primary treatment modality. Surgery is reserved for the salvage of recurrent tumors that occur within the head and neck in the absence of distant (ie, lung, liver) metastasis. However, unlike all other head and neck subsites, oral cancer should ideally be managed with primary surgery with the possibility of adjuvant radiation therapy with or without chemotherapy depending on the presence of certain high-risk pathologic features. PMID- 29126496 TI - Chemotherapy for Oral Cancer. AB - The use of chemotherapy, including immunotherapy, in oral squamous cell carcinoma has expanded considerably in the past several years. Its use mirrors that in the treatment of squamous cell carcinoma affecting other structures in the head and neck. This article summarizes the current evidence that guides use of chemotherapy both in combination with radiation and as monotherapy for patients with advanced disease. It also addresses the expanding role of immunotherapy, particularly use of programmed cell death-ligand 1 inhibitors, in the treatment of advanced disease. PMID- 29126497 TI - Radiation Therapy for Oral Cavity and Oropharyngeal Cancers. AB - Radiotherapy is a key therapeutic modality used in the treatment of oral cavity and oropharyngeal cancers, whether as definitive treatment or postoperatively for those with high-risk factors after surgery. Although radiotherapy is a proven, effective treatment of cancer control, it can result in significant acute and late toxicities. Pretreatment patient education, supportive care, and posttreatment adherence to rehabilitative and preventive care can help mitigate toxicities. Advances in radiation delivery, such as through continued technological advances, or novel approaches to customizing radiation dose and volume, to maximize the therapeutic efficacy while minimizing side effects, are warranted. PMID- 29126498 TI - Oral Cancer. PMID- 29126499 TI - Economic Impact of Atopic Dermatitis in Adults: A Population-Based Study (IDEA Study). AB - OBJECTIVE: To determine resource usage and costs associated with atopic dermatitis in adults according to severity and comorbid conditions in daily clinical practice. PATIENTS AND METHODS: We performed an observational, retrospective study based on a review of registries of patients aged >=18 years who sought health care in 2013 and 2014 in an area of Catalonia, Spain, with a population of 215,634 persons. We established 3 classes of severity depending on the treatment prescribed. The variables evaluated were total comorbid conditions, concomitant/specific medication, and direct/indirect health care costs. The statistical analysis was based on multiple regression models. Statistical significance was set at P<.05. RESULTS: We included 6,186 patients with a diagnosis of atopic dermatitis (mean age, 47.1 years; women, 61.6%). We established 3 groups based on severity, as follows: mild (n=3,445 [55.7%]); moderate (n=2,361 [38.2%]); and severe (n=380 [6.1%]). Severe atopic dermatitis was associated with risk of presenting comorbid conditions (beta=0.192), namely, asthma (beta=0.138), depression (beta=0.099), cardiovascular events (beta=0.087), obesity (beta=0.085), and smoking (beta=0.025); P<.001. Costs reached ?9.3 million (health care costs, 75.5%; loss of productivity, 24.5%), with an average unit cost of ?1,504 per year. The corrected average unit cost (ANCOVA) was greater in severe atopic dermatitis compared with moderate and mild disease (?3,397 vs. ?2,111 vs. ?885; P<.001), respectively. CONCLUSIONS: Severe atopic dermatitis generates considerable usage of health care resources and high costs for the National Health System. These are in proportion with the severity of the disease. General comorbid conditions and asthma were the factors with the greatest impact on health care costs. PMID- 29126501 TI - Overview of paediatric IBD. AB - Inflammatory bowel disease (IBD) is a chronic complex disease of children and adults requiring a range of medications and surgical techniques to induce and maintain remission. In common with other immune-mediated inflammatory disorders, it has shown an ever-increasing rise in incidence worldwide over the last 50 years. The cause of IBD arises from interactions between the microbiome in the gut and the gastrointestinal and systemic immune system in genetically susceptible persons, and with environmental triggers to both develop IBD and have relapses of IBD. The burden of IBD in children and adolescents can be high, and treatment needs a multi-disciplinary approach aiming to abolish symptoms, promote growth and development, and support a restriction-free life. Achieving healing of the intestinal mucosa promotes long-term remission and helps to avoid disease complications. PMID- 29126500 TI - Preface. PMID- 29126502 TI - Clinical presentation of Crohn's, ulcerative colitis, and indeterminate colitis: Symptoms, extraintestinal manifestations, and disease phenotypes. AB - The incidence of inflammatory bowel disease (IBD) is rising with 25% of IBD diagnosed in children under 18 years of age. The clinical presentation of IBD in children is often vague leading to initial misdiagnosis as infectious colitis or irritable bowel syndrome. When IBD is identified, overlap in histologic and endoscopic features may lead to difficulty distinguishing Crohn's disease from ulcerative colitis, resulting in a higher frequency of the diagnosis indeterminate colitis or IBD unspecified. Recognizing the common and the atypical presentation of pediatric IBD and extraintestinal manifestations will aid in expeditious referral and early diagnosis. Activity severity scoring tools and more specific classification systems for pediatric IBD direct therapeutic algorithms and allow for improved longitudinal assessment since disease severity and location have been shown to be associated with outcome. PMID- 29126503 TI - Very early onset inflammatory bowel disease. AB - Very early onset inflammatory bowel disease (VEO-IBD) represents a unique and growing subset of patients with inflammatory bowel disease (IBD). Some VEO-IBD patients present with immunodeficiency and possess loss of function genetic mutations involving immune pathways that cause their IBD. A search for Mendelian causes of IBD is likely most beneficial when the presentation involves extra intestinal autoimmunity or involves intestinal histopathology that is atypical for IBD. While a subset of these young patients will have highly aggressive courses (and likely present with immunodeficiency), the majority of patients with VEO-IBD appear to have disease courses similar to that of their older counterparts. Most notably, many of these young children will require long courses of immunosuppression simply as a result of the profoundly early presentation-thus increasing their long-term risks of cancer and opportunistic infections. PMID- 29126504 TI - Medical management of pediatric inflammatory bowel disease. AB - Inflammatory bowel diseases (IBD) are chronic autoimmune conditions of the gut affecting both pediatric and adult patients. Medical therapy is often successful at inducing and maintaining remission and preventing disease complications. The mainstays of treatment are medications and other therapies that reduce inflammation and suppress the overactive immune system. Here we review current medical therapies for pediatric IBD, discuss future therapeutics, and present current treatment goals and approaches. PMID- 29126505 TI - Management of acute severe ulcerative colitis in children. AB - The incidence of pediatric-onset ulcerative colitis (UC) is rising. Children often present with a more severe disease phenotype as compared to adults with over a third requiring hospitalization for the management of acute severe ulcerative colitis (ASUC). Further, in pediatric patients presenting with inflammatory bowel disease (IBD) limited to the colon, a definitive diagnosis of UC vs. Crohn's disease is often unclear. Here, we review the unique aspects of pediatric ASUC including the epidemiology, diagnosis, medical, and surgical management of this disease. PMID- 29126506 TI - Surgical care of the pediatric Crohn's disease patient. AB - Despite the significant advances in the medical management of inflammatory bowel disease over the last decade, surgery continues to play a major role in the management of pediatric Crohn's disease (CD). While adult and pediatric Crohn's disease may share many clinical characteristics, pediatric Crohn's patients often have a more aggressive phenotype, and the operative care given by the pediatric surgeon to the newly diagnosed Crohn's patient is very different in nature to the surgical needs of adult patients after decades of disease progression. Children also have the unique surgical indication of growth failure to consider in the overall clinical decision making. While surgery is never curative in CD, it has the ability to transform the disease process in children, and appropriately timed operations may have tremendous impact on a child's physical and mental maturation. This monograph aims to address the surgical care of Crohn's disease in general, with a specific emphasis on the surgical treatment of small intestinal and ileocecal involvement. PMID- 29126507 TI - Surgical options in the treatment of ulcerative colitis. AB - Children and young adults with ulcerative colitis tend to present with more extensive colonic disease than an adult population. The need for surgical intervention in the pediatric population with ulcerative colitis occurs earlier after diagnosis and has a greater incidence than a comparably matched adult population with an estimated need for colectomy at 5 years following diagnosis of 14-20%. Perhaps, even more than the adult population, there is a desire to restore intestinal continuity for the pediatric patient to achieve as healthy and normal quality of life as possible. With surgery playing such a prominent role in the treatment of ulcerative colitis in this age group, an understanding of the surgical treatment options that are available is important. The surgeon's awareness of the complexities of the different operations associated with proctocolectomy and reestablishing intestinal continuity may help to avoid early complications and minimize the risk of less than ideal long-term outcomes. PMID- 29126508 TI - Complications in children with ulcerative colitis undergoing ileal pouch-anal anastomosis. AB - Total colectomy with ileal pouch-anal anastomosis (IPAA) is considered the standard procedure for the surgical management of ulcerative colitis. Despite the widespread utility of the procedure, as many as 75% of patients who undergo IPAA, experience at least 1 complication. This review highlights difficult intraoperative scenarios and complications of pouch surgery in children, including intraoperative, postoperative, and functional complications. Intraoperative scenarios include insufficient mesenteric length and positive leak tests. Postoperative complications include surgical site infection, anastomotic leak, stricture, fistula, pouchitis, small bowel obstruction, and pouch failure. Less common complications include afferent limb syndrome, pouch prolapse, and superior mesenteric artery syndrome. Functional complications include incontinence, impaired quality of life, infertility, and sexual dysfunction. Despite complications, most patients are satisfied with their outcomes and report an improvement in their lifestyle. PMID- 29126509 TI - Treatment of perianal Crohn's disease. AB - Perianal Crohn's is a common manifestation of Crohn's disease. Primary manifestations of perianal disease mirror common anorectal conditions, however treatment is less successful than in those patients without Crohn's related perianal disease. A multimodal approach to therapy including medical and surgical modalities is often necessary. The goal of treatment is to manage symptoms while maintaining continence. PMID- 29126511 TI - Endocrine-disrupting chemicals, a multifaceted danger. PMID- 29126510 TI - Long-term outcomes of pediatric inflammatory bowel disease. AB - The incidence and prevalence of childhood-onset inflammatory bowel diseases (IBD), including subtypes Crohn's disease and ulcerative colitis, have risen dramatically in recent years, and have emerged globally as important pediatric chronic diseases. Therefore, health care providers are more frequently encountering very young children with IBD, a chronic and incurable condition requiring life-long therapy. These children are living long lives with IBD and therefore knowledge of long-term outcomes is increasingly important to better counsel families and determine the best course of treatment. This review summarizes the current knowledge and literature surrounding long-term outcomes of pediatric IBD, with emphasis on the following areas: need for surgery due to complicated disease behavior, risk of disease remission and recurrence, mental health and psychosocial well-being, educational outcomes, linear growth impairment, cancer risk, and mortality. In addition, we review recent research about predicting negative long-term outcomes in children with IBD. PMID- 29126512 TI - What is an endocrine disruptor? AB - Endocrine disrupting chemicals (EDCs) and potential EDCs are mostly man-made found in various materials. By interfering with the body's endocrine system, endocrine disruptors produce adverse developmental, reproductive, neurological, and immune effects in humans, abnormal growth patterns and neurodevelopmental delays in children. Thus, diethylstilbestrol (DES) a non-steroidal estrogen, which is regarded as a proof of concept, induces clear cell carcinoma among young women. EDCS may be found in plastic bottles and metal food cans (BPA), medical devices (phthalates), detergents, flame retardants (polybrominated diphenyl ethers), food (BPA), toys (phthalates), cosmetics and drugs (parabens), and pesticides (alkyl phenols such as nonylphenol). The deleterious effects of endocrine disruptors constitute a real public health issue. However concerning the mechanisms of action of EDCs, many questions remain unanswered and need further investigations. PMID- 29126513 TI - Endocrine disruptors: Revisiting concepts and dogma in toxicology. AB - During the last decades, a large number of observations have shown that some exogenous substances could interfere with hormone levels or hormone action and could induce toxic effects. This has led to the identification of endocrine disruptors more than 25 years ago as a new class of toxic agents (Zoeller et al., 2014). Those widely used agents correspond to a variety of chemical classes, are not identified by their chemical structure or by a specific type of usage, but rather by their mechanisms of action; this is not unprecedented in toxicology since genotoxicants have also been identified by their mechanism of action, i.e. their ability to alter DNA structure and function. PMID- 29126514 TI - Structural and functional evidences for the interactions between nuclear hormone receptors and endocrine disruptors at low doses. AB - Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system mainly by interacting with nuclear hormone receptors (NRs). Humans are generally exposed to low doses of pollutants, and current researches aim at deciphering the mechanisms accounting for the health impact of EDCs at environmental concentrations. Our correlative analysis of structural, interaction and cell-based data has revealed a variety of, sometimes unexpected, binding modes, reflecting a wide range of EDC affinities and specificities. Here, we present a few representative examples to illustrate various means by which EDCs achieve high-affinity binding to NRs. These examples include the binding of the mycoestrogen alpha-zearalanol to estrogen receptors, the covalent interaction of organotins with the retinoid X- and peroxisome proliferator-activated receptors, and the cooperative binding of two chemicals to the pregnane X receptor. We also discuss some hypotheses that could further explain low-concentration effects of EDCs with weaker affinity towards NRs. PMID- 29126517 TI - Editorial: State of the Journal. PMID- 29126515 TI - Endocrine disruptors (EDs) and hormone-dependent cancers: Correlation or causal relationship? AB - The selective increase in the incidence of hormone-dependent cancers (breast, prostate, testicular) in industrialized countries is associated with the increasing number of endocrine disruptors (EDs) in the environment and raises questions about the role of EDs in mammary carcinogenesis. Answering these questions is difficult because the number of EDs is large and varies with time. Moreover hormonal carcinogenesis is multifactorial and progresses slowly and in stages. This discussion will be limited to breast cancer and three EDs: distilbene, bisphenol A (BPA), and dichlorodiphenyltrichloroethane (DDT). All these three EDs bind estrogen receptors, albeit with widely different affinities. Several complementary approaches have been used: French cancer records, epidemiological studies on cohorts followed over several decades, numerous in vitro experimental studies using cell cultures and in vivo animal studies. These approaches all converge to the same result, strongly suggesting a causal relationship between EDs and precancerous lesions. Except for distilbene, the mechanisms and molecular targets involved are still unclear, which makes it difficult to look for substitute products that are just as efficient, but less toxic. PMID- 29126518 TI - Drugged pleasures: Commentary. PMID- 29126519 TI - Materialising drugged pleasures: Practice, politics, care. PMID- 29126520 TI - Tuberculosis - A holocaust of the prime. PMID- 29126521 TI - For Michael, Who Waits. PMID- 29126522 TI - Sharp Points. PMID- 29126523 TI - Meta-analysis Does Not Establish Effectiveness of the Device. PMID- 29126524 TI - Response. PMID- 29126525 TI - Comparing Ramped Position vs Sniffing Position for Intubation: Study Design Is Crucial. PMID- 29126526 TI - Response. PMID- 29126527 TI - Only Oxygen for Acute Bronchiolitis. PMID- 29126529 TI - Correction to text in: Giants in Chest Medicine: Steven E. Weinberger, MD, FCCP. PMID- 29126528 TI - Response. PMID- 29126530 TI - Correction to Endorsement in: Symptomatic Treatment of Cough Among Adult Patients With Lung Cancer: CHEST Guideline and Expert Panel Report. PMID- 29126531 TI - CAP, HCAP, HAP, VAP: The Diachronic Linguistics of Pneumonia. PMID- 29126532 TI - Justifying Hyperbaric Oxygen Delivery for Carbon Monoxide Poisoning: Time to Respond to Pressure With a Large-Scale Randomized Controlled Trial. PMID- 29126533 TI - The St. George's Respiratory Questionnaire Appendix to the Food and Drug Administration Draft Guidance on COPD: Why a Small Step Forward Is So Important. PMID- 29126534 TI - Usefulness of Ultrasound to Help Solve Severe Sepsis. PMID- 29126535 TI - Diagnostic Value of Quantitative Chest CT Scan in a Case of Spontaneous Pneumothorax. AB - An 18-year-old woman with no previous medical history presented to an outside hospital facility with acute chest pain. She had mild shortness of breath, particularly with exertion, for the prior 2 months. PMID- 29126536 TI - A 53-Year-Old Man With a Bronchial Mass and Multiple Bone Lesions. AB - CASE PRESENTATION: A 53-year-old man was admitted with complaints of back pain of 3 months' duration along with numbness and weakness in his left upper and lower extremities. He denied any respiratory complaints or anorexia but did report an 11 kg weight loss over the last 3 months. He had no other significant medical history and denied any history of cigarette smoking or recreational drug use. Family history was significant for prostate cancer in his father. PMID- 29126537 TI - A 47-Year-Old Man With Recurrent Unilateral Pleural Effusion. AB - CASE PRESENTATION: A 47-year-old man with a medical history of hypertension, diabetes, hyperlipidemia, and OSA presented with a 7- to 10-day history of progressively worsening dyspnea on exertion, with a walking distance of 60 feet. He had bilateral lower-extremity swelling and was prescribed furosemide without clinical improvement. At baseline, he used three pillows for sleeping. The patient was noncompliant with his CPAP treatment. He had no smoking history and was retired from working in technology sales. On review of systems, he denied cough, chest pain, hemoptysis, fevers, chills, or weight loss. PMID- 29126539 TI - Sublingual dexamethasone may result in a small decrease in pain after impacted mandibular third-molar surgical extraction. PMID- 29126538 TI - Recurrent Pulmonary Aneurysms: Hughes-Stovin Syndrome on the Spectrum of Behcet Disease. AB - In this report, we describe a male patient who presented with recurrent life threatening hemoptysis due to the sequential formation of multiple pulmonary aneurysms. Both pulmonary artery coil embolization and right lower lobectomy were performed, with limited success. The patient experienced extensive bilateral femoral DVT extending into the inferior vena cava, with massive hemoptysis, fulfilling the diagnosis of Hughes-Stovin syndrome. A final diagnosis of Behcet disease was made following extensive investigation, and the patient responded well to prednisone 20 mg orally and azathioprine 100 mg orally. PMID- 29126540 TI - Insufficient evidence about which odontogenic infections should be treated with antibiotics owing to serious limitations in a systematic review. PMID- 29126541 TI - Osteotome sinus floor elevation without bone graft seems to result in high survival rates and small amount of bone loss after 10 years. PMID- 29126542 TI - Professional tooth cleaning and scaling and root planing with oral hygiene instructions may reduce volatile sulfur compounds in patients with periodontal disease. PMID- 29126543 TI - Platelet-rich fibrin added to graft may increase bone defect fill in intrabony defects 9 months after graft placement. PMID- 29126544 TI - Insufficient evidence about outcomes of immediately provisionalized compared with traditionally restored implants. PMID- 29126545 TI - MRI ankle and subtalar characteristics in haemochromatosis arthropathy: a case control study. AB - AIM: To examine the magnetic resonance imaging (MRI) features of the ankle and subtalar joints that might distinguish genetic haemochromatosis (GH). MATERIALS AND METHODS: The present study was a retrospective case-control study comparing 30 MRI studies of GH patients with ankle or subtalar arthropathy with 30 matched controls with ankle pain. Anonymised images were scored using a semi-quantative tool adapted from the MRI osteoarthritis knee score. Scores were generated for bone marrow lesions size, number, and distinguishing the proportion of each lesion consisting of subchondral cyst versus oedema. Articular cartilage loss and osteophytes were documented. The primary comparator was bone marrow lesion size. Paired Student's t-test and the chi-squared test were utilised to compare outcomes. RESULTS: Bone marrow lesion/cyst size and number, presence and extent of full-thickness cartilage loss, and osteophyte scores were significantly higher in ankle joints of GH cases (p<0.01). In the middle subtalar articulation, there were significantly higher scores for full-thickness cartilage loss and extent and osteophytes in GH cases (p<0.05). There were no significant differences in the posterior subtalar articulation. CONCLUSION: The finding of both numerous and large cysts on ankle MRI should raise suspicion of GH. Other MRI features of potential diagnostic value include large osteophytes and the presence of extensive full-thickness cartilage loss in the ankle joint and middle subtalar articulation. PMID- 29126546 TI - Changes in lingual-alveolar contact pressure during speech over six months in amyotrophic lateral sclerosis. AB - PURPOSE: This study compared lingual-alveolar contact pressures during consonant (LACP-Sp) production between adults with and without amyotrophic lateral sclerosis (ALS) over three visits within six months and assessed the relationship between LACP-Sp and speech intelligibility. METHODS: Ten people with ALS and nine without read sentences with lingual-alveolar consonants embedded as LACP-Sp was recorded. Recordings were done at study entry, then three and six months after entry. Six of ten with ALS had bulbar symptoms detected in clinical encounter at the time of study enrollment (ALS-B); the remaining four had only spinal symptoms (ALS-S). RESULTS: Main and interaction effects varied across experimental stimuli. However, the pattern of results from the ANOVAs indicated that the ALS-B had lower LACP-Sp values than the other groups. Time main effects were present indicating a reduction in LACP-Sp. However, there were interaction effects for fricatives and/l/, with the ALS-S group demonstrating greater reduction over time than the other groups. Word intelligibility had moderate to large correlations with LACP-Sp but confidence intervals were broad and only a few were statistically significant. CONCLUSION: LACP-Sp does decrease over time in people with ALS and may reflect a general weakening of the tongue. Confirmation of these group changes will require assessment with a larger sample size. PMID- 29126547 TI - Microvolt T-wave alternans monitoring in a patient with levofloxacin-induced Torsade de Pointes. AB - We present the case of a 62-year-old woman with levofloxacin-induced Torsade de Pointes, in whom microvolt T-wave alternans was measured during acute hospitalization and when QT interval was dynamically changing, illustrating a means for monitoring proarrhythmia. PMID- 29126548 TI - Chronic kidney disease, mineral bone disease and future risk of peripheral artery disease: Do associations rule? PMID- 29126549 TI - Predicting New-Onset Post-Coronary Artery Bypass Graft Atrial Fibrillation With Existing Risk Scores. AB - BACKGROUND: New-onset atrial fibrillation (AF) after coronary artery bypass graft (CABG) operation is associated with poorer survival. Blanket prophylaxis efforts have not appreciably decreased incidence, making targeted prevention for high risk patients desirable. We compared predictive abilities of existing scores developed/used to predict adverse CABG outcomes (Society of Thoracic Surgeons' [STS] risk of mortality) or AF not associated with cardiac operation (the Cohorts for Heart and Aging Research in Genomic Epidemiology [CHARGE]-AF score, the CHA2DS2-VASc score), and a risk model for predicting postoperative AF following cardiac operations (POAF score), with age (the most consistently identified post CABG AF risk factor). METHODS: Data submitted to the STS Adult Cardiac Surgery Database were used to assess new-onset AF in 8,976 consecutive patients without preoperative AF undergoing isolated CABG from 2004 to 2010 at five participating centers. Five logistic regression models (for CHA2DS2-VASc score, CHARGE-AF score, POAF score, STS risk score, and age, respectively, all modeled with restricted cubic splines) with a random effect for site were fitted to predict post-CABG AF. Estimates were used to compute and compare receiver operating characteristic (ROC) areas. RESULTS: New-onset AF occurred in 2,141 patients (23.9%). The ROC area was greatest for CHARGE-AF (0.68, 95% confidence interval [CI]: 0.67-0.69), followed by age (0.66, 95% CI: 0.65-0.68), POAF score (0.65, 95% CI: 0.64-0.66), CHA2DS2-VASc (0.59, 95% CI: 0.58 to 0.60), and STS risk of mortality (0.58, 95% CI: 0.56-0.59). CHARGE-AF was significantly more predictive than age (p < 0.0001); the other scores were significantly less predictive (p < 0.0001). CONCLUSIONS: Only CHARGE-AF performed better than age alone. Its performance was moderate and comparable with published risk models specifically targeted at new-onset post-isolated CABG AF. Future research should continue to focus on developing better predictive models. PMID- 29126550 TI - Trends in pediatric adjusted shock index predict morbidity and mortality in children with severe blunt injuries. AB - PURPOSE: The utility of measuring the pediatric adjusted shock index (SIPA) at admission for predicting severity of blunt injury in pediatric patients has been previously reported. However, the utility of following SIPA after admission is not well described. METHODS: The trauma registry from a level-one pediatric trauma center was queried from January 1, 2010 to December 31, 2015. Patients were included if they were between 4 and 16years old at the time of admission, sustained a blunt injury with an Injury Severity Score>=15, and were admitted less than 12h after their injury (n=286). Each patient's SIPA was then calculated at 0, 12, 24, 36, and 48h after admission and then categorized as elevated or normal at each time frame based upon previously reported values. Trends in outcome variables as a function of time from admission for patients with an abnormal SIPA to normalize as well as patients with a normal admission SIPA to abnormal were analyzed. RESULTS: In patients with a normal SIPA at arrival, 18.4% of patients who developed an elevated SIPA at 12h after admission died, whereas 2.4% of patients who maintained a normal SIPA throughout the first 48h of admission died (p<0.01). Among patients with an elevated SIPA at arrival, increased length of time to normalize SIPA correlated with increased length of stay (LOS) and intensive care unit (ICU) LOS. Similarly, elevation of SIPA after arrival in patients with a normal initial SIPA correlated to increased LOS and ICU LOS. CONCLUSIONS: Patients with a normal SIPA at time of arrival who then have an elevated SIPA in the first 24h of admission are at increased risk for morbidity and mortality compared to those whose SIPA remains normal throughout the first 48h of admission. Similarly, time to normalize an elevated admission SIPA appears to directly correlate with LOS, ICU LOS, and other markers of morbidity across a mixed blunt trauma population. Whether trending SIPA early in the hospital course serves only as a marker for injury severity or if it has utility as a resuscitation metric has not yet been determined. TYPE OF STUDY: Prognostic. LEVEL OF EVIDENCE: Level II. PMID- 29126551 TI - No gut syndrome: liver failure is the issue. PMID- 29126552 TI - Discussion. PMID- 29126553 TI - Discussion. PMID- 29126554 TI - Preoperative genetic testing in pheochromocytomas and paragangliomas influences the surgical approach and the extent of adrenal surgery. AB - BACKGROUND: Our knowledge of the susceptibility genes for pheochromocytomas/paragangliomas has increased; however, data on its impact on surgical decision-making has not been described. The aim of this study was to determine the effect of routine preoperative genetic testing on the operative intervention in patients with pheochromocytomas/paragangliomas. METHODS: One hundred-eight patients diagnosed with pheochromocytomas/paragangliomas who underwent 118 operations had preoperative genetic testing for 9 known pheochromocytoma/paraganglioma susceptibility genes. A retrospective analysis of a prospective database was performed to evaluate clinical factors associated with the surgical approach selected and the outcome of the surgical intervention. RESULTS: In 51 patients (47%), a germline mutation was detected and one-third had no family history of pheochromocytoma/paraganglioma. In 77 operations (65%), it was the first operative intervention for the disease site (60 laparoscopic, 17 open), and 41 (35%) were reoperative interventions (36 open, 5 laparoscopic). For initial operations, variables associated with whether an open or laparoscopic approach was used were tumor size (P = .009) and presence of germline mutation (P = .042). Sixty-eight adrenal operations were performed (54 total, 14 cortical sparing). Variables significantly associated with a cortical-sparing adrenalectomy being performed were the presence of germline mutation (P = .006) and tumor size (P = .013). CONCLUSION: Preoperative knowledge of the germline mutation status affects the surgical approach and extent of adrenalectomy. PMID- 29126555 TI - New terminology-noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) and its effect on the rate of malignancy at a single institution. AB - BACKGROUND: The cytologic qualities of noninvasive follicular neoplasm with papillary-like nuclear features mimic papillary thyroid carcinoma (PTC) on fine needle aspiration, leading to difficulty in distinguishing the 2 preoperatively. The aim of this study was to determine the impact of reclassification of noninvasive follicular neoplasm with papillary-like nuclear features at our practice. METHODS: We searched 1,046 patient charts for those cases with preoperative cytology and subsequent follicular-variant papillary thyroid carcinoma diagnosis on resection. Endocrine pathologists reviewed the cases to determine the reclassification of noninvasive follicular neoplasm with papillary like nuclear features. RESULTS: Sixty (6%) follicular-variant papillary thyroid carcinomas were identified, 4% (44) in the index nodule. Of the 44 patients, 84% (37) met the criteria for evaluation. Of these, 46% (17) were noninvasive follicular neoplasm with papillary-like nuclear features. After reclassification of noninvasive follicular-variant papillary thyroid carcinoma to noninvasive follicular neoplasm with papillary-like nuclear features, the overall cancer rate changed from 31% to 29%. Malignancy rates across Bethesda cytologic categories changed as follows: benign (n = 419) from 3.5% to 3.3%; atypia of undetermined significance/follicular lesion of undetermined significance (n = 240) from 17% to 15%; suspicious for follicular neoplasm (n = 104) from 23% to 21%; suspicious for malignancy (n = 85) from 68% to 60%, and malignant (n = 198) from 93% to 92%. CONCLUSION: Reclassification of noninvasive follicular neoplasm with papillary like nuclear features led to a small decrease in the overall malignancy rate. The most affected Bethesda category was suspicious for malignancy. Because the majority of noninvasive follicular neoplasm with papillary-like nuclear features will be indeterminate lesions by cytology/molecular testing, thyroidectomy will remain a common treatment modality. Noninvasive follicular neoplasm with papillary-like nuclear features classification will primarily affect decision making to avoid excessive treatment/monitoring. PMID- 29126556 TI - Vulvar intraepithelial neoplasia: Risk factors for recurrence. AB - OBJECTIVE: We studied a large population of women with high-grade vulvar intraepithelial neoplasia (VIN) in order to identify patient and treatment related risk factors for recurrence and progression to cancer. METHODS: For this retrospective cohort study of women with a histologic diagnosis of VIN within Southern California Permanente Medical Group between 1995 and 2007 medical records were reviewed; clinical, demographic and pathologic data were collected. Statistical analyses included Chi-squared and Student's t-tests, univariate and multivariate logistic regression, and cumulative incidence analysis. RESULTS: 914 patients with high-grade VIN were identified; 784 met inclusion criteria. We found 26.3% recurrences among treated women, with 2.2% progression to cancer (8.2% among those with recurrence). Risk factors for recurrence on multivariate analysis were: age >50years (OR, 1.44; 95%CI 1.01-2.07), immunosuppression (OR 2.08; 95%CI 1.42-3.06), metasynchronous VAIN or CIN (OR 1.76; 95%CI 1.08-2.88) in addition to margin status (OR 8.17; 95%CI 4.60-14.51) and adjacent LSA (OR 9.91; 95%CI 1.53-31.32) or HPV (OR 2.15; 95%CI 1.13-3.37) with excisional treatment. Recurrence rates did not differ significantly by smoking status and treatment modalities. Median time to recurrence was 16.9months; 25% had late recurrences (44-196months). Cumulative incidence analyses of time to recurrence shows a significantly higher risk among patients over age 50 (log-rank p=0.0031). CONCLUSION: We identified independent risk factors for recurrence including age >50years, immunosuppression, metasynchronous vaginal or intraepithelial neoplasia, positive excision margins, and adjacent lichen sclerosus or human papilloma-virus. Regardless of treatment modality, 25% of recurrences occurred late, highlighting the need for long-term surveillance in women treated for VIN. PMID- 29126557 TI - [Keratoacanthomas on recent tattoos: Two cases]. AB - BACKGROUND: Increasing numbers of reports of rapidly arising, isolated or eruptive keratoacanthomas (KA) and squamous cell carcinomas (CSC) on the red part of tattoos tend to suggest a non-fortuitous link with the procedure. We report herein two different presentations of KAs on tattoos: one patient with multiple eruptive KAs on sun-exposed areas of a recent red tattoo and another with a solitary lesion on a recent tattoo. We discuss the issues related to the distinction between KAs and CSCs in this particular context. PATIENTS AND METHODS: Case No. 1: A 55-year-old heavily tattooed man presented multiple round keratotic verrucous-like lesions restricted to a red tattoo. The tattoo had been performed by a professional tattooist in summer 2016, a week before the onset of the symptoms. The patient did not protect a part of his tattoo from sun-exposure during the healing phase and lesions developed only on the sun-exposed tattooed parts. In January 2017, he consulted with about ten lesions. The histologic study by shaving of a lesion militated in favor of a CSC, KA type. The physical examination was unremarkable. He had no previous history of skin cancer. Two weeks later, most of the lesions regressed spontaneously. Based on the clinical history and progression of the lesions, a diagnosis was made of eruptive KA on a red tattoo. Residual lesions were treated by cryotherapy or excision. Case No. 2: A 72-year-old woman developed a 1-cm painful dome-shaped nodule with a central crust three weeks after tattooing. Full excision confirmed the diagnosis of KA. DISCUSSION: To date, we have found 31 case reports and series (17 men, median age: 50.5 years) of KA and CSC on tattoos. Lesions usually develop rapidly after completion of the tattoo, after between one week and several months. Exceptional cases have been described in old tattoos. Red tattoo ink is most commonly the culprit. The main difficulty lies in distinguishing between KA and CSC. Nowadays pathologists agree that a KA should be considered as a variant of CSC. Eruptive forms of KA present a peculiar situation. They may sometimes be inherited, and KA on recent traumatized areas or drug-induced have been described. Like other authors, we believe that cases of CSC on red tattoos belong rather to the KA type. The physiopathogenesis of tattoo-associated eruptive KA and CSC is not clearly understood, but could be multifactorial, involving: the trauma induced by tattooing, local inflammatory reaction, a component of the red ink, external factors such UV exposure, and a possible genetic predisposition. Rapidly arising KA and eruptive KA on top of recent (red) tattoos are not fortuitous. The lesions should be excised and the patient monitored. Additional studies on tumor specimens are warranted to identify the possible causative agents in tattoo ink that may be responsible for such reactions. PMID- 29126558 TI - Raising Awareness for Sepsis, Sepsis Screening, Early Recognition, and Treatment in the Emergency Department. PMID- 29126559 TI - Outcomes of a Simplified Ultrasound-Guided Intravenous Training Course for Emergency Nurses. AB - INTRODUCTION: Various medical or anatomical conditions can lead to difficult intravenous access (DIVA) in the emergency department. It was hypothesized that developing an emergency nurse-training program could reduce IV attempts in the emergency department, improving throughput and patient care. METHODS: Emergency nurses completed a 4-hour ultrasound-guided intravenous (USGIV) access course and achieved competency after 10 successful supervised USGIV insertions on patients. Data were collected from a nurse-completed USGIV log and the electronic medical record. Experience levels, rates of completion, rates of success, and the effects on attempts of IV access were analyzed. RESULTS: Thirty-four emergency nurses enrolled in the study over 9 months, and 12 (35%) developed competency. Successful cannulation rates improved from 81% for procedure attempts 1 to 10, to 96% for attempts 21 to 30. Overall IV attempts by nurses and physicians (n = 24,471) decreased by 2%, P = 0.013. DIVA IV attempts (n = 1,366) decreased by 7%, P = 0.003. DISCUSSION: USGIV training programs can decrease total number of IV attempts. A simplified and economical USGIV training program for emergency nurses can be successful and may be dependent on emergency nurse experience levels and initiative. PMID- 29126560 TI - Assessment of fecal pollution in Lake Pontchartrain, Louisiana. AB - Water quality in Lake Pontchartrain was deteriorating and recreational activities along the beach were restricted by the end of the 20th Century. A microbial source tracking (MST) study was conducted to determine the fecal contamination sources at public beach of the lake, so that effective pollution control strategies can be developed. Water samples were collected over an eight-month period at ten locations along the lake in 2016 and 2017. E. coli and Enterococcus were detected in 90.6% (culture) and 97.5% (qPCR), 95.8% (culture) and 91.8% (qPCR) of water samples from all sampling sites, respectively. Significant positive relationship between E. coli and Enterococcus results was observed for both qPCR and culture methods. HF183 marker was detected in 94.3% water samples (149 of 158), with concentrations ranging from 29.0 to 6073.5GC/100ml and from 129.8 to 38,465.6GC/100ml in summer and winter, respectively. The results also indicate that significant rainfall events have the potential to supply considerable loads of fecal bacteria to lake waters. Further research is needed to determine the contribution of other animals to fecal contamination in the region. PMID- 29126562 TI - Posterior staphyloma in a hyperopic eye. PMID- 29126561 TI - Intravascular large B-cell lymphoma mimicking cerebral amyloid angiopathy-related inflammation. PMID- 29126563 TI - [Giant infantile hemangioma of the eyelid]. PMID- 29126564 TI - Information Theory Broadens the Spectrum of Molecular Ecology and Evolution. AB - Information or entropy analysis of diversity is used extensively in community ecology, and has recently been exploited for prediction and analysis in molecular ecology and evolution. Information measures belong to a spectrum (or q profile) of measures whose contrasting properties provide a rich summary of diversity, including allelic richness (q=0), Shannon information (q=1), and heterozygosity (q=2). We present the merits of information measures for describing and forecasting molecular variation within and among groups, comparing forecasts with data, and evaluating underlying processes such as dispersal. Importantly, information measures directly link causal processes and divergence outcomes, have straightforward relationship to allele frequency differences (including monotonicity that q=2 lacks), and show additivity across hierarchical layers such as ecology, behaviour, cellular processes, and nongenetic inheritance. PMID- 29126565 TI - Planetary Boundaries for Biodiversity: Implausible Science, Pernicious Policies. AB - The notion of a 'safe operating space for biodiversity' is vague and encourages harmful policies. Attempts to fix it strip it of all meaningful content. Ecology is rapidly gaining insights into the connections between biodiversity and ecosystem stability. We have no option but to understand ecological complexity and act accordingly. PMID- 29126566 TI - Venous thromboembolic events in lymphoma patients: Actual relationships between epidemiology, mechanisms, clinical profile and treatment. AB - Venous thromboembolic events (VTE) are an underestimated health problem in patients with lymphoma. Many factors contribute to the pathogenesis of thromboembolism and the interplay between various mechanisms that provoke VTE is still poorly understood. The identification of parameters that are associated with an increased risk of VTE in lymphoma patients led to the creation of several risk-assessment models. The models that evaluate potential VTE risk in lymphoma patients in particular are quite limited, and have to be validated in larger study populations. Furthermore, the VTE prophylaxis in lymphoma patients is largely underused, despite the incidence of VTE. The lack of adequate guidelines for the prophylaxis and treatment of VTE in lymphoma patients, together with a cautious approach due to an increased risk of bleeding, demands great efforts to ensure the implementation of current knowledge in order to reduce the incidence and complications of VTE in lymphoma patients. PMID- 29126567 TI - The role of different functional groups in a novel adsorption-complexation reduction multi-step kinetic model for hexavalent chromium retention by undissolved humic acid. AB - Undissolved humic acid (HA) has a great retention effect on the migration of hexavalent chromium [Cr(VI)] in soil, and HA functional groups play a predominant role in this process. However, the coupled mode between Cr(VI) retention and HA functional groups reaction is still unclear. In this study, it was found that a fair amount of Cr on HA existed in the forms of ion exchangeable and binding Cr(VI) during the reaction resulting from the ion exchange adsorption and complexation of Cr(VI). According to the results of two-dimensional correlation spectroscopic analysis (2DCOS), HA functional groups participated in the reaction with Cr(VI) in the order of carboxyl ~ chelated carboxyl > phenol > polysaccharide > methyl, and all the functional groups were more likely to be located at aromatic domains. Based on the results of XPS spectra, rather than to be oxidized by Cr(VI), carboxyl more tended to be complexed by chromium, which is regarded as the precondition for Cr(VI) reduction. Phenol, polysaccharide and methyl with distinct reaction activities successively acted as major electron donors for Cr(VI) reduction in different reaction stages. Consequently, it was determined that the retention of Cr(VI) by undissolved HA followed an adsorption complexation-reduction mechanism, and based on this, a multi-step kinetic model with multiple types of complexation/reduction sites was developed to simulate the retention processes resulting in a much better fitting effect (R2 > 0.99) compared with traditional first-order and second-order kinetic models (R2 < 0.95). This demonstrated that the multi-step kinetic model is of great potential in accurately simulating the migration and transformation of Cr(VI) in soil environment. PMID- 29126568 TI - Treatment options and predictive factors for recurrence and cancer-specific mortality in bladder cancer after renal transplantation: A multi-institutional analysis. AB - OBJECTIVES: Bladder cancer (BC) in the transplanted population can represent a challenge owing to the immunosuppressed state of patients and the higher rate of comorbidities. The objective was to analyze the treatment of BC after renal transplant (RT), focusing on the mode of presentation, diagnosis, treatment options and predictive factors for recurrence. MATERIAL AND METHODS: We conducted an observational prospective study with a retrospective analysis of 88 patients with BC after RT at 10 European centers. Clinical and oncologic data were collected, and indications and results of adjuvant treatment reviewed. The Kaplan Meier method and uni- and multivariate Cox regression analyses were performed. RESULTS: A total of 10,000 RTs were performed. Diagnosis of BC occurred at a median of 73 months after RT. Median follow-up was 126 months. Seventy-one patients (81.6%) had non-muscle invasive bladder cancer, of whom 29 (40.8%) received adjuvant treatment; of these, six (20.6%) received bacillus Calmette Guerin and 20 (68.9%) mitomycin C. At univariate analysis, patients who received bacillus Calmette-Guerin had a significantly lower recurrence rate (P=.043). At multivariate analysis, a switch from immunosuppression to mTOR inhibitors significantly reduced the risk of recurrence (HR 0.24, 95% CI: 0.053-0.997, P=.049) while presence of multiple tumors increased it (HR 6.31, 95% CI: 1.78 22.3, P=.004). Globally, 26 patients (29.88%) underwent cystectomy. No major complications were recorded. Overall mortality (OM) was 32.2% (28 patients); the cancer-specific mortality was 13.8%. CONCLUSIONS: Adjuvant bacillus Calmette Guerin significantly reduces the risk of recurrence, as does switch to mTOR inhibitors. Multiple tumors increase the risk. PMID- 29126569 TI - Screening for human immunodeficiency virus. PMID- 29126570 TI - Genomics-Driven Natural Product Discovery in Actinomycetes. AB - The prevalence of antimicrobial-resistant pathogens has highlighted the urgent need for new drugs. Actinomycetes have been the most prominent sources of natural products for drug discovery and development. Advances in genomics have inspired several emerging strategies to reinvigorate the field of natural product discovery, especially in actinomycete-derived natural products. PMID- 29126571 TI - Potential Applications of the Escherichia coli Heat Shock Response in Synthetic Biology. AB - The Escherichia coli heat shock response (HSR) is a complex mechanism triggered by heat shock and by a variety of other growth-impairing stresses. We explore here the potential use of the E. coli HSR mechanism in synthetic biology approaches. Several components of the regulatory mechanism (such as heat shock promoters, proteins, and RNA thermosensors) can be extremely valuable in the creation of a toolbox of well-characterized biological parts to construct biosensors or microbial cell factories with applications in the environment, industry, or healthcare. In the future, these systems can be used for instance to detect a pollutant in water, to regulate and optimize the production of a compound with industrial relevance, or to administer a therapeutic agent in vivo. PMID- 29126572 TI - Functionally-Relevant Morphological Profiling: A Tool to Assess Cellular Heterogeneity. AB - Heterogeneity in cell function has presented a significant hurdle to the successful clinical translation of many cellular therapies. Current techniques for assessing cell quality and the effects of microenvironmental cues and manufacturing processes on cell behavior often inadequately address heterogeneity due to issues such as population versus single-cell measurements and the therapeutic relevance and throughput/robustness of the assay. Due to the well established relationship between morphology and cellular function, morphological profiling has become increasingly utilized to better understand functional heterogeneity and its impact on therapeutic development. In this review, we introduce an emerging field we term functionally-relevant morphological profiling with great potential to improve our understanding of cellular heterogeneity through discovering novel quality attributes, optimizing manufacturing, and screening drugs/biomaterials. PMID- 29126573 TI - Lipoid pneumonia mimicking multifocal lung cancer in a patient with a remote laryngectomy and a recently diagnosed lung cancer: PET/CT findings. PMID- 29126574 TI - Incidental retroperitoneal malignant solitary fibrous tumor detected at lung cancer screening with low-dose thoracic CT. PMID- 29126575 TI - Validation of Prostate Imaging-Reporting and Data System Version 2: A Retrospective Analysis. AB - PURPOSE: Use of magnetic resonance imaging (MRI)/transrectal ultrasound fusion biopsies to determine the accuracy of multiparametric MRI (mpMRI), using Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2), for detecting clinically significant prostate cancer in the overall gland and specifically the peripheral zone (PZ) and transitional zone (TZ). METHODS: A retrospective analysis of patients who underwent fusion biopsy identified 137 men with 231 prostate lesions was approved by the Institutional Review Board. Subjects initially classified under PI-RADSv1 criteria were regraded using PI-RADSv2 by a radiologist blinded to PI-RADSv1 score and biopsy results. Spearman correlation, chi-squared, and logistic regression analysis were performed. RESULTS: There was positive correlation between PI-RADSv2 and Gleason scores (P < 0.001). In the PZ, mpMRI demonstrated 100% sensitivity, 100% negative predictive value, and 35.9% positive predictive value, compared to 100%, 100%, and 27.1%, respectively, for TZ lesions. When predicting clinically significant prostate cancer, the PI-RADSv2 area under the curve for TZ lesions was 0.844 (95% CI: 0.753-0.935, P < 0.001) and 0.769 (95% CI: 0.684-0.854, P < 0.001) for PZ lesions. Combining PI-RADSv2 with additional risk factors (body mass index, prostate-specific antigen density, digital rectal examination) improved the area under curve. CONCLUSIONS: PI-RADSv2 achieves excellent sensitivity and negative predictive value for both PZ and TZ lesions. PMID- 29126576 TI - Beginner's Guide to Medicare Access and CHIP Reauthorization Act's Quality Payment Program. PMID- 29126577 TI - The Efficacy of Postoperative Iron Therapy in Improving Clinical and Patient Centered Outcomes Following Surgery: A Systematic Review and Meta-Analysis. AB - Postoperative anemia is a common occurrence in surgical patients and leads to an increased risk for allogeneic blood transfusions. The efficacy of iron therapy in treating postoperative anemia has not been firmly established. The objective of this systematic review was to evaluate the efficacy of postoperative oral and intravenous (IV) iron therapy in increasing hemoglobin levels and improving patient outcomes following elective surgery. The databases Medline, EMBASE, CENTRAL, the Transfusion Evidence Library, and ClinicalTrials.gov were searched. Eligible studies were randomized controlled trials or prospective cohorts having a control group, where postoperative oral or IV iron was administered to elective surgery patients. Primary outcomes were hemoglobin levels and patient-centered outcomes of quality of life and functioning. Secondary outcomes were the safety of postoperative iron and blood transfusion requirement. Meta-analysis using a random-effects model was performed. Seventeen relevant studies were identified, of which 7 investigated IV iron, 7 investigated oral iron, and 3 compared IV with oral iron. Postoperative oral and IV iron therapies were ineffective in improving quality of life and functioning (the Grading of Recommendations Assessment, Development and Evaluation [GRADE]: moderate-low quality). Compared with control, IV iron increased mean hemoglobin levels by 3.40 g/L (95% confidence interval [CI]: 1.18-5.62) (GRADE: moderate quality); however, this increase is likely not clinically meaningful. Overall, oral iron was ineffective in increasing hemoglobin concentrations compared with control (mean difference=0.77, 95% CI: 1.48-3.01) (GRADE: moderate quality). Postoperative iron therapy did not significantly reduce the risk of blood transfusion (relative risk=0.75; 95% CI: 0.53-1.07) (GRADE: low quality). IV iron was not associated with a significantly increased risk of adverse events (relative risk=4.50, 95% CI: 0.64-31.56). There was insufficient information to determine the risk of adverse events for postoperative oral iron. This systematic review found no evidence to support the routine use of postoperative iron therapy in all elective surgery patient populations; however, results are based largely on studies with non-iron deficient patients preoperatively. Further research on the role of postoperative IV iron is warranted for certain high-risk groups, including patients with iron deficiency or anemia prior to surgery. This systematic review is registered in PROSPERO (CRD42017057837). PMID- 29126578 TI - The Earliest Blood Transfusions in 17th-Century in Italy (1667-1668). AB - Historical accounts of the earliest experiments in blood transfusion celebrate work done in France and England in 1667 to 1668. Less attention has been given to pioneering experiments conducted at the same period in Italy. We review records of the first blood transfusion experiments conducted in 17th century Italy. Using original source documents, we provide details of early experiments focusing on the identity of early researchers, their instruments, and techniques. Accounts of the period describe animal-to-animal, animal-to-human, and human-to-human transfusions. We highlight how transfusion was considered a new form of emergency surgery, carried out in order to save patients who could not be cured with traditional therapy of the time. PMID- 29126579 TI - Chest pain as a manifestation of hypokalemia in a pediatric patient. AB - Patients presenting to the emergency department with chest pain are common and a cause of significant concern to patients and families and physicians alike. The causes of chest pain are myriad. These causes span diverse categories including cardiovascular, respiratory, abdominal and gastrointestinal, musculoskeletal, psychiatric, hematologic and oncologic, and neurologic Thull-Freedman (2010) [1]. These diverse etiologies present a diagnostic and management challenge to the ER physician who is tasked to minimize unnecessary diagnostics while not missing any significant disease. Multiple reviews have discussed the various etiologies of chest pain in the pediatric patient presenting to the ER but none of these recent reviews has included hypokalemia as a cause of chest pain Talner and Carboni (2000), Cava and Sayger (2004), Ringstrom and Freedman (2006), Foy and Filippone (2015), Yeh and Yeh (2015) [2-6]. Additionally, no reviews of hypokalemia describe this condition presenting with chest pain (Mandal, 1997; Gennari, 2002; Medford-Davis and Rafique, 2014 [7-9]). This case report describes a pediatric patient who presents with chest pain that was attributed to hypokalemia. This report attempts to make practitioners aware that hypokalemia may present with chest pain and to encourage ER providers to include this in the differential diagnosis. PMID- 29126580 TI - Codebook-based electrooculography data analysis towards cognitive activity recognition. AB - With the advancement in mobile/wearable technology, people started to use a variety of sensing devices to track their daily activities as well as health and fitness conditions in order to improve the quality of life. This work addresses an idea of eye movement analysis, which due to the strong correlation with cognitive tasks can be successfully utilized in activity recognition. Eye movements are recorded using an electrooculographic (EOG) system built into the frames of glasses, which can be worn more unobtrusively and comfortably than other devices. Since the obtained information is low-level sensor data expressed as a sequence representing values in constant intervals (100 Hz), the cognitive activity recognition problem is formulated as sequence classification. However, it is unclear what kind of features are useful for accurate cognitive activity recognition. Thus, a machine learning algorithm like a codebook approach is applied, which instead of focusing on feature engineering is using a distribution of characteristic subsequences (codewords) to describe sequences of recorded EOG data, where the codewords are obtained by clustering a large number of subsequences. Further, statistical analysis of the codeword distribution results in discovering features which are characteristic to a certain activity class. Experimental results demonstrate good accuracy of the codebook-based cognitive activity recognition reflecting the effective usage of the codewords. PMID- 29126581 TI - Serum Potassium Levels During Admissions for Acute Decompensated Heart Failure: Identifying Possible Threats to Outcome. PMID- 29126582 TI - Effect of Body Mass Index on Exercise Capacity in Patients With Hypertrophic Cardiomyopathy. AB - The objective of this study was to evaluate the relation between body mass index (BMI), exercise capacity, and symptoms in patients with hypertrophic cardiomyopathy (HC) and to utilize results of cardiopulmonary exercise tests (CPX) and transthoracic echocardiograms to understand the mechanism(s) of reduced exercise capacity across body mass index groups. Over a 6-year period, 510 consecutive patients with HC seen at a tertiary referral center underwent (CPX) and a transthoracic echocardiogram. Increasing BMI was associated with decreased exercise capacity as assessed by peak VO2 (ml/kg/min). However, the prevalence of cardiac impairment did not vary by BMI group. In conclusion, these findings suggest that in some patients with hypertrophic cardiomyopathy, cardiac impairment is not the primary cause of exercise limitation and weight loss may result in improved exercise capacity. PMID- 29126583 TI - Effect of Changes in Physical Activity on Risk for Cardiac Death in Patients With Coronary Artery Disease. AB - Leisure-time physical activity (LTPA) is associated with longevity in patients with coronary artery disease (CAD). However, less is known about prognostic significance of longitudinally assessed LTPA in patients with stable CAD. The present study assessed the relationship between changes in LTPA and cardiac mortality in patients with CAD. Patients with angiographically documented CAD (n = 1,746) underwent clinical examination and echocardiography at the baseline. Lifestyle factors, including LTPA (inactive, irregularly active, active, highly active), were surveyed at baseline and after 2 years' follow-up. Thereafter, the patients entered the follow-up (median: 4.5 years; first to third quartile: 3.4 to 5.8 years) during which cardiac deaths were registered (n = 68, 3.9%). The patients who remained inactive (n = 114, 18 events, 16%) and became inactive (n = 228, 18 events, 8%) had 7.6- (95% confidence interval [CI] 4.2 to 13.6) and 3.7 fold (95% CI 2.1 to 6.7) univariate risk for cardiac death compared with those who remained at least irregularly active (n = 1,351, 30 events, 2%), respectively. After adjustment for age, gender, body mass index, diabetes, previous myocardial infarction, left ventricular ejection fraction, angina pectoris grading, cardiovascular event during initial 2-year follow-up, smoking and alcohol consumption, the patients who remained inactive and became inactive still had 4.9- (95% CI 2.4 to 9.8, p <0.001) and 2.4-fold (95% CI 1.3 to 4.5, p <0.01) risk for cardiac death, respectively, compared with patients remaining at least irregularly active. In conclusion, LTPA has important prognostic value for cardiac death in patients with stable CAD. Even minor changes in LTPA over 2 years were related to the subsequent risk for cardiac death. PMID- 29126584 TI - Comparison of 4 Cardiac Risk Calculators in Predicting Postoperative Cardiac Complications After Noncardiac Operations. AB - The 2014 American College of Cardiology/American Heart Association Perioperative Guidelines suggest using the Revised Cardiac Risk Index, myocardial infarction or cardiac arrest, or American College of Surgeons-National Surgical Quality Improvement Program calculators for combined patient-surgical risk assessment. There are no published data comparing their performance. This study compared these risk calculators and a reconstructed Revised Cardiac Risk Index in predicting postoperative cardiac complications, both during hospitalization and 30 days after operation, in a patient cohort who underwent select surgical procedures in various risk categories. Cardiac complications occurred in 14 of 663 patients (2.1%), of which 11 occurred during hospitalization. Only 3 of 663 patients (0.45%) had a myocardial infarction or cardiac arrest. Because these calculators used different risk factors, different outcomes, and different durations of observation, a true direct comparison is not possible. We found that all 4 risk calculators performed well in the setting they were originally studied but were less accurate when applied in a different manner. In conclusion, all calculators were useful in defining low-risk patients in whom further cardiac testing was unnecessary, and the myocardial infarction or cardiac arrest may be the most reliable in selecting higher risk patients. PMID- 29126585 TI - [Information booklet for related hematopoietic stem cell donors: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM TC)]. AB - Providing information to living donors is first and foremost a legal obligation as well as an ethical one, not to mention necessary to health care provision. It's been shown that quality of information concerning the procedure's practical aspects, scheduling of clinical tests and examinations, withdrawing stem cells for the donation, post-donation symptoms, and support provided by healthcare teams, directly impacts the donor's quality of experience. Taking this into consideration our group decided it was essential to create an informational support for donors in the form of a booklet to be provided in different hematopoietic stem cell transplant centers across France. In September 2016 in Lille, France, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allergenic hematopoietic stem cell transplantation clinical practices harmonization workshops. As part of these workshops, our group worked collectively to develop a basis of indispensable information to be included in the booklet and presented using clear and accessible language. PMID- 29126586 TI - [Analysis of uterus cervical cancer screening campaign results in Conakry, Guinea]. AB - OBJECTIVE: Reduce morbidity and death rates of women with cervical cancer in Guinea. METHODOLOGY: This was a five-day cross-sectional study carried out in two successive years (2012 and 2013) at the CERFFO-PCG in Conakry. The target population was women aged 25-49. Approximately 500 women for 2012 and 900 women were expected in these cervical screening campaigns by visual methods (IVA and IVL) with immediate treatment of precancerous lesions. After histologic confirmation of the cancer lesions, the management was carried out according to the protocols in force in the country. We performed a simple descriptive analysis and the results expressed as a percentage and on average. RESULTS: The target population represented 60.4% in 2012 and 76.2% in 2013, of the total number of women received. The incidence rate of high-grade intraepithelial lesions and cancers increased from 2.6% in 2012 to 0.9% in 2013. In 2012, the 57 precancerous lesions were treated with immediate treatment and 10 cases of cancers out of the 16 had a surgical treatment. Also in 2013, all precancerous lesions were treated immediately and 2 cancers out of the 4 benefited from surgery. CONCLUSION: Our research shows that, with creativity, flexibility, good organization and efficient use of resources, morbidity and death rates of women with cervical cancer in a very resources can be significantly reduced. PMID- 29126587 TI - Dispersive magnetic immunoaffinity extraction. Anatoxin-a determination. AB - Specific monoclonal antibodies were coupled with magnetic Sepharose-based beads and used, for the first time. The methodology was applied to preconcentrate anatoxin-a from water and the later determination by ion mobility spectrometry (IMS). Dispersive magnetic immunoaffinity (d-MagIA) extraction methodology provided a limit of detection of 0.02MUgL-1 and a satisfactory precision with a relative standard deviation lower than 15%. Recoveries were evaluated at 0.5, 1.0 and 5.0MUgL-1 anatoxin-a with quantitative values from 91 to 115%. Additionally, isobaric interferences with phenylalanine were completely avoided by the use of the developed d-MagIA extraction coupled to IMS determinations. PMID- 29126588 TI - Automated single-ion peak fitting as an efficient approach for analyzing complex chromatographic data. AB - Chromatography provides important detail on the composition of environmental samples and their chemical processing. However, the complexity of these samples and their tendency to contain many structurally and chemically similar compounds frequently results in convoluted or poorly resolved data. Data reduction from raw chromatograms of complex environmental data into integrated peak areas consequently often requires substantial operator interaction. This difficulty has led to a bottleneck in analysis that increases analysis time, decreases data quality, and will worsen as advances in field-based instrumentation multiply the quantity and informational density of data produced. In this work, we develop and validate an automated approach to fitting chromatographic data within a target retention time window with a combination of multiple idealized peaks (Gaussian peaks either with or without an exponential decay component). We compare this single-ion peak fitting approach to drawn baseline integration methods of more than 70,000 peaks collected by field-based chromatographs spanning across a wide range of volatilities and functionalities. Accuracy of peak fitting under real world conditions is found to be within 10%. The quantitative parameters describing the fit (e.g. coefficients, fit residuals, etc.) are found to provide valuable information to increase the efficiency of quality control and provide constraints to accurately integrate peaks that are significantly convoluted with neighboring peaks. Implementation of the peak fitting method is shown to yield accurate integration of peaks otherwise too poorly resolved to separate into individual compounds and improved quantitative metrics to determine the fidelity of the data reduction process, while substantially decreasing the time spent by operators on data reduction. PMID- 29126589 TI - Explicit role of ionic strength in retention behavior of polystyrene latex particles in sedimentation field-flow fractionation: Slip boundary model. AB - We investigate an explicit role of the ionic strength in the retention behaviors of polystyrene (PS) latex particles in sedimentation field-flow fractionation (SdFFF) by hinging upon the retention theory recently developed [1] asR=(Ro+vb*)/(1+vb*). Here R is an experimental retention ratio, and Ro is the analytical expression of the standard retention theory based on the parabolic flow velocity. The reduced boundary velocityvb* is expressed in terms of the ionic strength I of the carrier liquid as vb*=vb,o*/(1+epsilonI), where vb,o*=0.070and epsilon=60 mM-1 for all the PS latex systems under investigation. We then apply this to study the explicit ionic strength effect on the retention behaviors of PS beads of 200, 300, 400, and 500nm, respectively. As a primary result, the strong dependence of the retention ratio on the ionic strength can be quantitatively accounted for in an excellent accuracy: The slip effect at the channel surface is significant, particularly when I?0.5mM, without showing any distinguishable dependence on the specific additives to control I, such as FL-70, SDS, NaNO3, and NaN3. Based on the present study, we put forward an experimental means to estimate the ionic strength of an aqueous solution using an FFF technique. PMID- 29126590 TI - Pediatric Headache: A Case Study. PMID- 29126591 TI - Parental Refusal of Human Papillomavirus Vaccine: Multisite Study. AB - INTRODUCTION: The purpose of this study was to explore reasons why parents may refuse administration of the human papillomavirus vaccine to their children. The data from this multisite study will contribute to our understanding of why parents may refuse administration of the vaccine. METHODS: This mixed-methods study took place in several pediatric settings after a pilot study was completed. After a health visit in which the vaccine was refused, a survey was provided to the parent in a private room. The survey was kept confidential and anonymous. RESULTS: There were 72 surveys completed. Demographic data were reported. Data were analyzed for descriptive statistics, and themes were extracted. Overall, 58% of parents refused the vaccine because it was too new, and 50% believed the vaccine required more research. DISCUSSION: The data from this study correlated with the pilot study regarding parental perceptions of the vaccine; however, it appears that with new public campaigns and education, parents' perceptions are improving. Nurse practitioners are in an excellent position to clarify information about human papillomavirus vaccination. PMID- 29126592 TI - Pediatric Bipolar Disorder: A Case Presentation and Discussion. PMID- 29126593 TI - The impact of the repeal of Michigan's universal helmet law on traumatic brain injury: A statewide analysis. AB - BACKGROUND: In April of 2012, Michigan repealed its 35-year-old universal motorcycle helmet law in favor of a partial helmet law, which permits motorcyclists older than 21 years old with sufficient insurance and experience to drive un-helmeted. We evaluated the clinical impact of the repeal. METHODS: The Michigan Trauma Quality Improvement Program's trauma database was queried for motorcycle crash patients between 1/1/09-4/12/12 and between 4/13/12-12/31/14. RESULTS: There were 1970 patients in the pre-repeal analysis and 2673 patients in the post-repeal analysis. Following the repeal, patients were more likely to be un-helmeted (p < 0.001) and to have a traumatic brain injury (p < 0.001). Patients were also more likely to require neurosurgical interventions (relative risk 1.4, p = 0.011). CONCLUSION: Following the repeal of the universal helmet law, there has been a significant increase in traumatic brain injuries and neurosurgical interventions. This analysis highlights another detrimental impact of the repeal of the universal helmet law. PMID- 29126594 TI - Seeing the forest beyond the trees: Predicting survival in burn patients with machine learning. AB - BACKGROUND: This study aims to identify predictors of survival for burn patients at the patient and hospital level using machine learning techniques. METHODS: The HCUP SID for California, Florida and New York were used to identify patients admitted with a burn diagnosis and merged with hospital data from the AHA Annual Survey. Random forest and stochastic gradient boosting (SGB) were used to identify predictors of survival at the patient and hospital level from the top performing model. RESULTS: We analyzed 31,350 patients from 670 hospitals. SGB (AUC 0.93) and random forest (AUC 0.82) best identified patient factors such as age and absence of renal failure (p < 0.001) and hospital factors such as full time residents (p < 0.001) and nurses (p = 0.004) to be associated with increased survival. CONCLUSIONS: Patient and hospital factors are predictive of survival in burn patients. It is difficult to control patient factors, but hospital factors can inform decisions about where burn patients should be treated. PMID- 29126595 TI - Burn patients with infection-related ventilator associated complications have worse outcomes compared to those without ventilator associated events. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) replaced its definition for ventilator-associated pneumonia (VAP) in 2013. The aim of the current study is to compare the outcome of burn patients with ventilator associated events (VAEs). METHODS: Burn patients with at least two days of ventilator support were identified from the registry between 2013 and 2016. Kruskal-Wallis and Fisher's exact tests were utilized for continuous and categorical variables, respectively. A logistic regression was used for the association between VAE and in-hospital mortality. RESULTS: 243 patients were admitted to our burn center, of whom 208 had no VAE, 8 had a VAC, and 27 had an IVAC or PVAP. There was no difference in hospital length of stay, ICU length of stay and ventilator support days between those with no VAE and a VAC. Those with IVAC-plus had significantly worse outcomes compared to patients with no VAEs. CONCLUSIONS: Burn patients with IVAC-plus had significantly longer hospital and ICU lengths of stay, days on ventilator compared with patients with no VAEs. PMID- 29126596 TI - Underuse Versus Overuse of Neonatal Intensive Care: What Is the Right Amount? PMID- 29126597 TI - Role of autophagy in MHC class I-restricted antigen presentation. AB - Major histocompatibility complex (MHC) class I molecules present peptide antigens to MHC class I-restricted CD8+ T lymphocytes. The peptides loaded onto MHC class I molecules are typically derived from cytosolic antigens, which includes both self and foreign proteins. In addition to this classical MHC class I antigen presentation pathway, some cell types, especially dendritic cells can present antigens from exogenous sources to MHC class I-restricted CD8+ T cells, in a process called cross-presentation. A variety of cellular processes, including endocytosis, vesicle trafficking, and autophagy, play critical roles in these antigen presentation pathways. In this review article, we discuss the role of autophagy, an intracellular degradation system that delivers cytoplasmic constituents to lysosomes, in MHC class I-restricted antigen presentation. A mechanistic understanding of the role of autophagy-related proteins in MHC class I restricted antigen presentation may guide future efforts in manipulating autophagy to prevent or treat human disease. PMID- 29126599 TI - Department of Error. PMID- 29126598 TI - Tranexamic acid: is it about time? PMID- 29126601 TI - An international, cross-sectional survey of the management of Vancouver type B1 periprosthetic femoral fractures around total hip arthroplasties. AB - INTRODUCTION: The incidence of periprosthetic femoral fractures around total hip arthroplasties is increasing. Fractures around a stable implant stem (Vancouver type B1) are among the most common of these fractures. Various fixation strategies for Vancouver type B1 periprosthetic fractures have been reported in the literature; however, little high-level evidence exists. This study was designed to determine the current management strategies and opinions among orthopaedic surgeons treating Vancouver type B1 periprosthetic femoral fractures, and to evaluate the need for a large prospective randomized controlled trial for the management of these injuries. METHODS: Orthopaedic surgeon members of the Orthopaedic Trauma Association (OTA), the Canadian Orthopaedic Association (COA), and the Hip Society were invited to participate in a 51-item web-based survey surrounding the management of periprosthetic femoral fractures around total hip replacements, as well as the perceived need for future research in this area. Responses were summarized using proportions, and further stratified by practice type, case volume, surgeon age, and fellowship training. RESULTS: For Vancouver type B1 fractures, open reduction and internal fixation (ORIF) with locked plating was favoured slightly over ORIF with cable plating +/- cortical strut allograft (51.1% versus 45.5%). When compared to cable plating with cortical strut allograft, respondents believed that isolated locked plating resulted in lower nonunion and reoperation rates, but similar infection and malunion rates. Subgroup analyses revealed that practice type, surgeon age, case volume, and fellowship training influenced surgeons' management of periprosthetic femoral fractures and beliefs regarding complications. There is high demand for a large prospective randomized controlled trial for Vancouver type B1 fracture fixation. CONCLUSIONS: Consensus surrounding the management of Vancouver type B1 periprosthetic femoral fractures is lacking, and there is a perceived need among orthopaedic surgeons for a large prospective randomized controlled trial in order to define the optimal management of these injuries. PMID- 29126600 TI - Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients. AB - BACKGROUND: Antifibrinolytics reduce death from bleeding in trauma and post partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics. METHODS: We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155. FINDINGS: We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2-3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1.20, 95% CI 1.08-1.33; p=0.001), with no heterogeneity by site of bleeding (interaction p=0.7243). Treatment delay reduced the treatment benefit (p<0.0001). Immediate treatment improved survival by more than 70% (OR 1.72, 95% CI 1.42-2.10; p<0.0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0.5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events. INTERPRETATION: Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid. FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial). PMID- 29126602 TI - The potential of blended learning in education and training for advanced civilian and military trauma care. AB - INTRODUCTION: In the field of advanced care of the complex trauma patient, there is an emerging need for focused education and training. However, several hospitals do not support further education and training in this field, and the challenge of releasing time for physicians and nurses is well-known. Educational strategies using blended learning, which combines traditional classroom methods with modern computer-assisted methods and media, have not yet been widely used. This study analysed the educational challenges and areas for improvement, according to senior physicians and nurses, and investigated the potential use of blended learning. METHOD: The setting was an international course, Definitive Surgical Trauma Care (DSTC) - Military Version, part of a programme which prepares health professionals for work during extreme conditions. The sample consisted of senior physicians and nurses, participating in the course in September 2015. A survey was completed, interviews were performed and a post course survey was conducted 18 months later in March 2017. RESULTS: The most difficult aspect of learning how to manage the complex trauma patient, was the lack of real practice. Even though the respondents were knowledgeable in advanced trauma, they lacked personal experience in managing complex trauma cases. Cases presented during the course represented significantly greater complexity of injury compared to those usually seen in hospitals and during military deployment. The following educational challenges were identified from the study: (1) Lack of experience and knowledge of advanced trauma care. (2) Lack of the use of blended learning as support for education and training. (3) Limited time available for preparation and reflection in the education and training process. (4) Lack of support for such education and training from home hospitals. (5) The unfulfilled requirement for multidisciplinary team-training in the military medical environment. CONCLUSION: Educational strategies and methods, such as blended learning can support education and training, and the learning process by unlimited practice in reasoning and decision making in virtual patients. It can also provide flexibility and mobility for senior health professionals and their home hospitals, and contribute to an improved military pre-deployment training with less time strain on the civilian home hospitals. PMID- 29126603 TI - Effect of integration time on the morphometric, densitometric and mechanical properties of the mouse tibia. AB - Micro-Computed Tomography (microCT) images are used to measure morphometric and densitometric properties of bone, and to develop finite element (FE) models to estimate mechanical properties. However, there are concerns about the invasiveness of microCT imaging due to the X-rays ionising radiation induced by the repeated scans on the same animal. Therefore, the best compromise between radiation dose and image quality should be chosen for each preclinical application. In this study, we investigated the effect of integration time (time the bone is exposed to radiation at each rotation step during microCT imaging) on measurements performed on the mouse tibia. Four tibiae were scanned at 10.4 um voxel size using four different procedures, characterized by decreasing integration time (from 200 ms to 50 ms) and therefore decreasing nominal radiation dose (from 513 mGy to 128 mGy). From each image, trabecular and cortical morphometric parameters, spatial distribution of bone mineral content (BMC) in the whole tibia and FE-based estimations of stiffness and strength were obtained. A high-resolution scan (4.3 um voxel size) was used to quantify measurement errors. Integration time had the largest effect on trabecular morphometric parameters (7-28%). Lower effects were observed on cortical parameters (1-3%), BMC (1-10%) distribution, and FE-based estimations of mechanical properties (1-3%). In conclusion, the effect of integration time on image-based measurements has been quantified. This data should be considered when defining the in vivo microCT scanning protocols in order to find the best compromise between nominal radiation exposure and accuracy in the estimation of bone parameters. PMID- 29126604 TI - Zonal variation of MRI-measurable parameters classifies cartilage degradation. AB - Osteoarthritis (OA) is a degenerative joint disease resulting in the deterioration of articular cartilage, a tissue with minimal ability to self repair. Early diagnosis of OA with non-invasive imaging techniques such as magnetic resonance imaging (MRI) could provide an opportunity to intervene and slow or reverse this degeneration process. This study examines the classification of degradation states using MRI measurements. Enzymatic degradation was used to specifically target proteoglycans alone, collagen alone and both cartilage components sequentially. The resulting degradation was evaluated using MRI imaging techniques (T1, T2, diffusion tensor imaging, and gadolinium enhanced T1) and derived measures of water, glycosaminoglycan and collagen content. We compared the classification ability of full thickness averages of these parameters with zonal averages (superficial, medial, and deep). Finally, we determined minimum variables sets to identify the smallest number of variables that allowed for complete separation of all degradation groups and ranked them by impact on the separation. Zonal analysis was much more sensitive than full thickness averages and allowed perfect separation of all four groups. Superficial zone cartilage was more sensitive to enzymatic degradation than the medial or deep zone, or the full thickness average. Variable ranking consistently identified collagen content and organization as the most impactful variables in the classification algorithm. The aim of this study is to classify cartilage degradation using only non-invasive MRI parameters that could be applied to OA diagnosis. Our results highlight the importance of zonal variation in the diagnosis of cartilage degeneration. Our novel, non-invasive collagen content measurement was crucial for complete separation of degraded groups from control cartilage. These findings have significant implications for clinical cartilage MRI for disease diagnosis. PMID- 29126605 TI - A novel patterned magnetic micropillar array substrate for analysis of cellular mechanical responses. AB - Traction forces generated at cellular focal adhesions (FAs) play an essential role in regulating various cellular functions. These forces (1-100 nN) can be measured by observing the local displacement of a flexible substrate upon which cells have been plated. Approaches employing this method include using microfabricated arrays of poly(dimethylsiloxane) (PDMS) micropillars that bend by cellular traction forces. A tool capable of applying a force to FAs independently, by actively moving the micropillars, should become a powerful tool to delineate the cellular mechanotransduction mechanisms. Here, we developed a patterned magnetic micropillar array PDMS substrate that can be used for the mechanical stimulation of cellular FAs and the measurement of associated traction forces. The diameter, length, and center-to-center spacing of the micropillars were 3, 9, and 9 um, respectively. Iron particles were embedded into the micropillars, enabling the pillars to bend in response to an external magnetic field, which also controlled their location on the substrate. Applying a magnetic field of 0.3 T bent the pillars by ~4 um and allowed transfer of external forces to the actin cytoskeleton through FAs formed on the pillar top. Using this approach, we investigated the traction force changes in cultured aortic smooth muscle cells (SMCs) after local compressive stimuli to release cell pretension. The mechanical responses of SMCs were roughly classified into two types: almost a half of the cells showed a little decrease of traction force at each pillar following compressive stimulation, although cell area increased significantly; and the rest showed the opposite, with increased forces and a simultaneous decrease in area. The traction forces of SMCs fluctuated markedly during the local compression. The root mean square of traction forces significantly increased during the compression, and returned to the baseline level after its release. These results suggest that the fluctuation of forces may be caused by active reorganization of the actin cytoskeleton and/or its dynamic interaction with myosin molecules. Thus, our magnetic micropillar substrate would be useful in investigating the mechanotransduction mechanisms of cells. PMID- 29126606 TI - Balance study in asymptomatic subjects: Determination of significant variables and reference patterns to improve clinical application. AB - Postural control is essential when carrying out everyday activities and its possible disorders have a very significant impact on personal autonomy. To provide the means to accurately measure postural control in the clinical environment, this study checks and discusses the suitability of procedures for a new balance assessment system with a stabilometric platform (MoveHuman-Dyna (c) UZ-IDERGO), which meets the criteria of clinical stabilometric standardisation established by the International Society for Posture and Gait Research (ISPGR) at the Bologna meeting (2009). The study was applied to a sample of 30 healthy volunteers (12 women, 18 men) aged between 18 and 30 years. A total of six balance tests were performed: four variations of the Romberg test, one test for a study of the limits of stability (LoS) and one test for rhythmic weight shift (RWS). Analysis of the results confirms that the variables assessed yielded similar values to other studies, the consistency of values between tests was checked, and preliminary reference values were obtained for asymptomatic subjects. We propose the following variables as the most significant for balance diagnosis: CoP mean speed, RMS, Range of CoP displacement and area. As a result of the study, the system is considered of interest in the medical/legal and forensic settings to assess the balance control and degree of collaboration during the tests. PMID- 29126607 TI - Effect of pedicle screw diameter on screw fixation efficacy in human osteoporotic thoracic vertebrae. AB - The selection of an ideal screw size plays a crucial role in the success of spinal instrumentation as larger diameter screws are thought to provide better fixation strength but increase the risk of pedicle failure during insertion. On the other hand, smaller diameter screws are with lesser risk of pedicle breakage but are thought to compromise the stability of the instrumentation. By investigating the relationship between screw diameter and the pullout strength of pedicle screws after fatigue loading, this study seeks to find quantitative biomechanical data for surgeons in determining the most ideal diameter size screws when performing surgical implementations on osteoporotic vertebrae. Twenty seven osteoporotic (BMD ranged: 0.353-0.848 g/cm2) thoracic vertebrae (T3-T8) were harvested from 5 human cadavers. Two sizes of poly-axial screws (5.0 mm * 35 and 4.35 mm * 35) were implanted into each pedicles of the vertebrae by an experienced surgeon. Specimens were randomly distributed into control group, fatigue group of 5000 and 10,000 cycles with peak-to-peak loadings of 10-100 N at 1 Hz. Each specimen was then axial pullout tested at a constant rate of 5 mm/min. The ultimate pullout strength (N) & stiffness (N/mm) were obtained for analysis. The results showed that although the larger diameter screws achieved superior pullout strength immediately after the implantation, both sizes of screws exhibited comparable pullout strengths post fatigue loading. This indicates that the smaller diameter screws may be considered for surgical techniques performed on osteoporotic vertebrae for reduced risk of pedicle breakage without sacrificing fixation strength. PMID- 29126608 TI - Diagnostic scales for the post-thrombotic syndrome. AB - Post-thrombotic syndrome (PTS) is the most common long-term complication after deep vein thrombosis (DVT) developing in up to 70% of the patients. PTS is diagnosed on the basis of typical symptoms and signs of the lower limb with a previous DVT, but no objective diagnostic test exists. A number of diagnostic scales have been developed primarily for research purposes. An optimal diagnostic test for PTS should be reliable and easy to use, sensitive and specific, able to grade PTS severity, and to identify changes over time. We have identified reports on seven diagnostic scales that have been used for the diagnosis of PTS; the Widmer classification, the Clinical-Etiological-Anatomical-Pathological (CEAP) classification, the Venous Clinical Severity Score (VCSS), the Brandjes scale, the Ginsberg measure, the Villalta scale, and the Patient-reported Villalta scale. The aim of this paper was to review and present the existing diagnostic scales for PTS in adults and their utility in clinical studies. PMID- 29126609 TI - Meta-analysis of adult height and birth length in schizophrenia. AB - OBJECTIVE: As a group, people with schizophrenia have a number of subtle anatomical abnormalities as well as physiological abnormalities that precede antipsychotic treatment. Some studies have also found shorter birth length or shorter adult height in people with schizophrenia compared to control subjects. We performed a systematic review and meta-analysis of studies of birth length and adult height in schizophrenia, following PRISMA guidelines (Prospero Registration # CRD42016043718). DATA SOURCES: We searched the PsycInfo, Web of Science, and PubMed databases for articles published 1947-2016. STUDY SELECTION: Articles were included if they had data for patients diagnosed with schizophrenia and a matched control group of subjects without a psychotic disorder; both groups were measured for birth length and/or adult height (18years or older); and the paper was published in English. DATA EXTRACTION: One author extracted the data, which was verified by the other. RESULTS: For adult height, six studies with 1,122 patients and 250,200 control subjects were included in analyses. There were six birth length studies, which included 984 patients and 976,296 controls. The patients did not differ from comparison subjects in birth length (effect size estimate= 0.03; CI: -0.09, 0.03), but adults were slightly shorter than comparison subjects (-0.15; -0.24, -0.06). In meta-regression of adult studies, the variables of first episode versus clinical sample, and population registry versus non-registry were not significant. Matching for several important variables was usually lacking in these studies. CONCLUSIONS: While there appears to be no difference in birth length between people with schizophrenia and comparison subjects, the former may be slighter shorter in adult life. The cause of such a discrepancy, if confirmed, is not clear, and lack of matching on potentially confounding variables undermines confidence in any conclusion. PMID- 29126610 TI - Building evaluative culture in community services: Caring for evidence. AB - An organization with a strong evaluative culture engages in self-reflection, evidence-based learning and experimentation. It sees evidence as essential for managing well, but building such a culture is challenging. Community service organizations seek to provide effective services for their clients. To build an evaluative culture, they need to acquire basic monitoring and evaluation capabilities, be provided with opportunities for using these capabilities and be adequately motivated to care about evidence as a means to improve services to their clients. Leadership along with a phased in approach are key in bringing about these behaviour changes. PMID- 29126611 TI - Diaphragmatic thickness ratio (inspiratory/expiratory) as a diagnostic method of diaphragmatic palsy associated with interescalene block. AB - INTRODUCTION: Diaphragmatic paralysis is a side-effect associated with interscalene block. Thickness index of the diaphragm muscle (inspiratory thickness/expiratory thickness) obtained by ultrasound has recently been introduced in clinical practice for diagnosis of diaphragm muscle atrophy. Our objective was to evaluate this index for the diagnosis of acute phrenic paresis associated with interscalene block. PATIENTS AND METHODS: We designed an observational study in 22 patients scheduled for shoulder arthroscopy. Spirometry was performed (criteria of phrenic paresis was a decrease in FVC and FEV1 >=20%). Ultrasound apposition zone was assessed in anterior axillary line and diaphragmatic displacement was evaluated on inspiration and expiration (number of intercostal spaces; phrenic paresis considered a reduction >=25%) and thickness of the diaphragm muscle (a phrenic paresis was considered an index <1.2). These determinations were performed before and at 20min after interscalene block at C5 C6 with 20ml of 0.5% ropivacaine. RESULTS: Twenty-one patients (95%) presented phrenic nerve block according to one or more of the methods used. One patient did not show any symptoms or signs suggestive of phrenic paralysis and was excluded. All the patients presented phrenic paresis based on the diaphragmatic thickness index, with the pre-block index being 1.8+/-0.5 and post-block of 1.05+/-0.06 (P<0.001). Ninety percent of the patients (19) presented phrenic paresis according to spirometry and all the patients had a reduction in diaphragmatic movement after the block (from 1.9+/-0.5 intercostal spaces to 0.5+/-0.3; P<0.001). CONCLUSION: The index of inspiratory / expiratory diaphragmatic thickness at cut-off <1.2 seems to be useful in the diagnosis of phrenic paresis associated with interscalene block. This index does not require a baseline pre assessment. PMID- 29126612 TI - Desflurane versus propofol in post-operative quality of recovery of patients undergoing day laparoscopic cholecystectomy. Prospective, comparative, non inferiority study. AB - OBJECTIVE: Recently, the evaluation of postoperative results has focused on the opinion of the patient as of great relevance. Our objective was to evaluate the quality of recovery by questionnaire (QoR-15) in patients undergoing laparoscopic cholecystectomy, comparing desflurane versus a total intravenous technique with propofol (TIVA). A non-inferiority hypothesis was proposed between both techniques. MATERIAL AND METHODS: Prospective longitudinal cohort study in patients undergoing laparoscopic cholecystectomy in which multimodal management was applied including low pneumoperitoneum pressures, deep neuromuscular block and pain prevention strategy and PONV. Anaesthesia maintenance was performed with either desflurane or propofol at the discretion of the anaesthesiologist. QoR-15 was evaluated pre-and 24hours after surgery. RESULTS: Sixty-one patients were evaluated: 29 in the desflurane group and 32 in the TIVA group with no differences in demographic parameters, ASA grade, and preoperative QoR-15 questionnaire. The duration of the intervention was superior in TIVA group, 55 +/ 15 vs. 45 +/- 9min in desflurane group; p =.05. The desflurane group received more fentanyl than the TIVA group: 200 +/- 65 vs. 113 +/- 38MUg; p =.05. No differences in pain, PONV or time of stay between groups. QoR-15 at 24h decreased 7% relative to baseline, with no differences between groups. CONCLUSIONS: The quality of recovery evaluated by the patient was as favourable in the patients of the desflurane group as in those of the TIVA group in patients undergoing laparoscopic cholecystectomy as outpatients. PMID- 29126614 TI - Machine-learning phenotypic classification of bicuspid aortopathy: Did the mountain give birth to a mouse? PMID- 29126615 TI - What industry taught us about repeated time-related events. PMID- 29126617 TI - Apparently, size matters...in congenital heart disease and brain injury. PMID- 29126616 TI - Show me the money. PMID- 29126613 TI - Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study. AB - OBJECTIVE: To evaluate endometrial BCL6 expression as a prognostic biomarker for IVF outcome in women with unexplained infertility (UI) before ET. DESIGN: Prospective cohort study. SETTING: University-associated infertility clinic. PATIENT(S): Women with UI for >1 year. INTERVENTION(S): We studied women with UI who underwent testing for endometrial BCL6, in an LH-timed midluteal phase biopsy and completed an IVF cycle and ET. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR) and live birth rate per transfer was compared for women positive or negative for BCL6 expression. An abnormal BCL6 result was defined by an histologic score (>1.4). RESULT(S): Women with normal and abnormal BCL6 and those who conceived or not had similar characteristics. Women with low levels of BCL6 expression had a significantly higher clinical PR (11/17; 64.7%; 95% confidence interval [CI] 41.3-82.6) compared with women with abnormal (high) BCL6 expression (9/52; 17.3%; 95% CI 9.3-30.8). These results yield a relative risk of 0.267 (95% CI 0.13-0.53; P=.0004) for those with normal BCL6 expression, an absolute benefit of 47.4% (95% CI 22.5-72.0). Live birth rate was also significantly higher in women with low BCL6 expression (10/17; 58.8%; 95% CI 36.0-78.4) compared with women with abnormal BCL6 expression (6/52; 11.5%; 95% CI 5.4-23.0). The relative risk was 0.19 (95% CI 0.08-0.45; P=.0002), yielding an absolute benefit of 47.3% (95% CI 21.8-67.8). CONCLUSION(S): Aberrant BCL6 expression (histologic score, >1.4) was strongly associated with poor reproductive outcomes in IVF cycles in women with UI. PMID- 29126618 TI - Hiding from the good guys. PMID- 29126619 TI - The pathway toward the success of a new transcatheter aortic valve replacement device: A surgeon's adventure. PMID- 29126620 TI - Extracorporeal membrane oxygenation: A bleeding patient's best friend? PMID- 29126621 TI - If two are better than one, three are better than two. PMID- 29126622 TI - Pannus, thrombus, calcium-Bioprosthetic mitral replacement in young children has it all. PMID- 29126623 TI - Is the venoarterial extracorporeal membrane oxygenation circuit your frenemy? PMID- 29126624 TI - Mega-aortic surgery: The whole enchilada or divide and conquer. PMID- 29126625 TI - Accused and prosecutor: The importance of a trial. PMID- 29126626 TI - Rosacea and alcohol intake. PMID- 29126627 TI - [Clinical and mycological characteristics of onychomycosis due to Candida at Institut Pasteur of Cote d'Ivoire]. AB - OBJECTIVE: This study aims to study the clinical and mycological characteristics of onychomycosis due to Candida in mycology unit of Institut Pasteur of Cote d'Ivoire. PATIENTS AND METHODS: This is a retrospective study which was carried out on patients from 1990 to 2016 for mycological diagnosis of onychomycosis and which socio-demographic characteristics, direct examination and culture results were recorded. RESULTS: In this study, 1898 patient files were selected. The average age of the patients was 31.69 years (standard deviation=15.11) with a sex ratio of 0.87. The frequency of Candida onychomycosis from patients received was 61.7%. Finger nails (67.7%) were more affected by this condition, followed by those of the toes (25.3%). Ninety cases of double localization of the nails of the hands and toes have been found. Candida albicans was the most frequent species accounting for 79.1% of isolated yeasts. Among the non-albicans, C. parapsilosis and C. tropicalis were isolated at the level of the toenails with frequencies rate of 11.2 and 9.6%. CONCLUSION: Onychomycosis due to Candida are relatively common in Abidjan and are dominated by C. albicans. The mycological confirmation of the fungal etiology in onychopathy and a good hygiene of the nails will allow a better management. PMID- 29126628 TI - Effect of transportation on the sympatho-adrenal system responses in horses. AB - The objective of current study was to evaluate the effect of transportation stress on the circulating adrenaline (A), noradrenaline (NA) and dopamine (DA) responses of stallions, according to the different distances. Forty-two stallions were studied before and after road transportation of 100, 200 and 300km, for a period of 1-3h. An increase in plasma A after 100km (P<0.001) was observed. A similar result was seen in plasma NA after 100km (P<0.001), and 300km (P<0.001). Increases in plasma DA after 100 and 200km (P<0.0001) were observed, with a decrease after 300km (P<0.0001). Significant interactions among groups and times for A (P<0.0001), NA (P<0.0006) and DA (P<0.0001) changes were observed. These results indicate that the sympatho-adrenal system response of horses was greater after short (100km), than medium-longer period of transportation (200 and 300km). This may indicate an adaptation process during transport, considering A and NA as the primary candidate neurotransmitters for the maintenance of homeostatic process to alleviate the effects of the perceived transportation stress. PMID- 29126629 TI - Characterization of innate responses induced by in ovo administration of encapsulated and free forms of ligands of Toll-like receptor 4 and 21 in chicken embryos. AB - Toll-like receptors (TLRs) are a family of innate receptors that recognize pathogen-associated molecular patterns, including double-stranded RNA, CpG DNA and lipopolysaccharide (LPS). After interaction with their ligands, TLRs initiate innate responses that are manifested by activating cells and inducing expression of cytokines that help mediate adaptive immune responses. TLR ligands (TLR-Ls) have the potential to be used prophylactically (alone) or as vaccine adjuvants to promote host immunity. Encapsulating TLR-Ls in nanoparticles, such as Poly (d,l lactic-co-glycolic acid), may prolong responses through sustained release of the ligands. PLGA nanoparticles protect encapsulated TLR-Ls from degradation and extend the half-life of these ligands by reducing their rapid removal from the body. In this study, encapsulated and free forms of LPS and CpG ODN were administered to embryonation day 18 (ED18) chicken embryos. Spleen, lungs and bursa of Fabricius were collected at 6, 18 and 48hour post-stimulation (hps) and cytokine gene expressions were evaluated using quantitative real-time PCR. Results indicate that both the free and encapsulated forms of LPS and CpG ODN induced innate immune responses in ED18 chicken embryos. Innate responses induced in embryos seem similar to those reported in mature chickens. Significant upregulation of cytokine genes generally occurred by 48hps. Further studies are needed to evaluate long term immunomodulatory effects of encapsulated TLR-Ls and their ability to mediate protection against pathogens of young chicks. PMID- 29126630 TI - Ecological role of bluefin tuna (Thunnus thynnus) fish farms for associated wild fish assemblages in the Mediterranean Sea. AB - The ecological effects of tuna fish farms are largely undocumented. This study confirmed their high capacity to attract surrounding wild fish. The aggregation effect persisted year round, without detectable seasonal differences. Farm impact was restricted to close proximity of the sea cages, and was more prominent over the bottom than in the water column strata. Tuna fish farms proved to be high energy trophic resources, as indicated by the enhanced fitness status of two focal species, bogue and seabream. Under abundant food supply, seabream appear to allocate the majority of energy reserves to gonad development. Farm associated bogue had greater parasite loads, with no detrimental effect on fitness status. Overall, tuna fish farms can be regarded as population sources for aggregated wild fish, and under the no fishing conditions within the leasehold areas, can serve as functional marine protected areas. PMID- 29126632 TI - An estimate of the percentage of non-predatory dead variability in coastal zooplankton of the southern Humboldt Current System. AB - Non-predatory dead variability in zooplankton remains poorly quantified worldwide. Here, we make the first estimation of the percentage of dead organisms in coastal zooplankton communities in the Humboldt Current System (HCS) under in situ conditions. The study was conducted in four coastal sites of the southern HCS (between 36 and 37 degrees S) over a period of one year. Percentages of dead organisms were based on the classification as live or dead of 158,220 holoplankton and 17,591 meroplankton individuals using neutral red staining technique. The percentage of dead organisms in total-zooplankton was between 4.3% in Coronel Bay (summer) and 76.9% in Llico (autumn). The percentage of dead total holoplankton varied from 4.2% (Itata River Mouth; autumn) to 77.6% (Llico; autumn), while the percentage of dead total-meroplankton ranged from 1.5% to 56.8% in Coronel Bay and Coliumo Bay, respectively. The most abundant taxa analyzed were the copepods Acartia sp., Paracalanus sp., Calanoides sp., Cladocera, Polychaeta, and the eggs of anchoveta Engraulis ringens. Among these taxa, there was a high degree of interspecific variability in the estimation of the dead organisms. The Pearson correlation shows significant relationships between maximum temperature, and minimum salinity, with the percentage of dead individuals of Acartia sp. and Paracalanus sp. Environmental factors explaining those relationships were: the El Nino 2015-2016 event, and freshwater river runoff. The use of vital staining to estimate non-predatory death for total zooplankton and selected sentinel species is a promising tool to establish baselines to evaluate natural perturbations (e.g. ENSO), and anthropogenic alterations in coastal pelagic ecosystems. PMID- 29126631 TI - Antioxidant response to heat stress in seagrasses. A gene expression study. AB - Seawater warming associated to the ongoing climate change threatens functioning and survival of keystone coastal benthic species such as seagrasses. Under elevated temperatures, the production of reactive oxygen species (ROS) is increased and plants must activate their antioxidant defense mechanisms to protect themselves from oxidative damage. Here we explore from a molecular perspective the ability of Mediterranean seagrasses to activate heat stress response mechanisms, with particular focus on antioxidants. The level of expression of targeted genes was analyzed in shallow and deep plants of the species Posidonia oceanica and in shallow plants of Cymodocea nodosa along an acute heat exposure of several days and after recovery. The overall gene expression response of P. oceanica was more intense and complete than in C. nodosa and reflected a higher oxidative stress level during the experimental heat exposure. The strong activation of genes with chaperone activity (heat shock proteins and a luminal binding protein) just in P. oceanica plants, suggested the higher sensitivity of the species to increased temperatures. In spite of the interspecific differences, genes from the superoxide dismutase (SOD) family seem to play a pivotal role in the thermal stress response of Mediterranean seagrasses as previously reported for other marine plant species. Shallow and deep P. oceanica ecotypes showed a different timing of response to heat. Shallow plants early responded to heat and after a few days relaxed their response which suggests a successful early metabolic adjustment. The response of deep plants was delayed and their recovery incomplete evidencing a lower resilience to heat in respect to shallow ecotypes. Moreover, shallow ecotypes showed some degree of pre adaptation to heat as most analyzed genes showed higher constitutive expression levels than in deep ecotypes. The recurrent exposure of shallow plants to elevated summer temperatures has likely endowed them with a higher basal level of antioxidant defense and a faster responsiveness to warming than deep plants. Our findings match with previous physiological studies and supported the idea that warming will differently impact Mediterranean seagrass meadows depending on the species as well as on the depth (i.e. thermal regimen) at which the meadow grows. The increase in the incidence of summer heat waves could therefore produce a significant change in the distribution and composition of Mediterranean seagrass meadows with considerable consequences for the functioning of the whole ecosystem and for the socio-economic services that these ecosystems offer to the riverine populations. PMID- 29126633 TI - Mechanical behavior of endodontically restored canine teeth: Effects of ferrule, post material and shape. AB - OBJECTIVE: To assess the effect of a ferrule design with specific post material shape combinations on the mechanical behavior of post-restored canine teeth. METHODS: Micro-CT scan images of an intact canine were used to create a 3-D tessellated CAD model, from which the shapes of dentin, pulp and enamel were obtained and geometric models of post-endodontically restored teeth were created. Two types of 15mm post were evaluated: a quartz fiber post with conical-tapered shape, and a carbon (C) fiber post with conical-cylindrical shape. The abutment was created around the coronal portion of the posts and 0.1mm cement was added between prepared crown and abutment. Cement was also added between the post and root canal and a 0.25mm periodontal ligament was modeled around the root. Four models were analysed by Finite Element (FE) Analysis: with/without a ferrule for both types of post material and shape. A load of 50N was applied at 45 degrees to the longitudinal axis of the tooth, acting on the palatal surface of the crown. The maximum normal stress criterion was adopted as a measure of potential damage. RESULTS: Models without a ferrule showed greater stresses (16.3MPa) than those for models with a ferrule (9.2MPa). With a ferrule, stress was uniformly distributed along the abutment and the root, with no critical stress concentration. In all models, the highest stresses were in the palatal wall of the root. Models with the C-fiber post had higher stress than models with the quartz fiber posts. The most uniform stress distribution was with the combination of ferrule and quartz fiber post. SIGNIFICANCE: The FE analysis confirmed a beneficial ferrule effect with the combination of ferrule and quartz fiber post, with tapered shape, affording no critical stress concentrations within the restored system. PMID- 29126634 TI - [Antiepileptic drugs administration by nasogastric tube in comatose patients]. AB - AIM: To evaluate the modalities of administration of antiepileptic drugs (AED) with nasogastric tube (NGT) by nurses and to draw up recommendations. METHODS: Our study consisted on investigating the modalities of administration of AED's with NGT by nurses during four months. We prepared 10 questions including demographic information. Participation was voluntary and anonymous. The questionnaire was distributed in seven intensive care departments after authorization of each head of the department. Thus, 45 nurses were included. RESULTS: Nurses sex ratio was 1.5 and mean age was 31 years (25 to 37 years). Among the nurses, 60% mentioned that the NGT were silicone made and 4% that they were PVC made. The mean duration before replacing the NGT was thought to be 5+/-3 days. Among the nurses, 91% affirmed to clear the NGT after each use. All the nurses had agreed that the solid form is the most commonly used pharmaceutical form in the NGT. AED were associated with the enteral feeding solution in 56%. The AED should be crushed before administration for 98% of the nurses even in case of polymedication. Among them, 62% recommended to crush all of the associated drugs together. Before introducing the AED into the NGT, 93% of the nurses reported mixing with tap water. We have noticed that 62% of nurses felt the need to improve their knowledge AED administration with NGT. CONCLUSION: To optimize AED therapy, modalities of administration by NGT in epileptic comatose patients should be enhanced. PMID- 29126635 TI - On-road and laboratory emissions of NO, NO2, NH3, N2O and CH4 from late-model EU light utility vehicles: Comparison of diesel and CNG. AB - Exhaust emissions of eight Euro 6 light duty vehicles - two station wagons and six vans - half powered by diesel fuel and half by compressed natural gas (CNG) were examined using both chassis dynamometer and on-road testing. A portable on board FTIR analyzer was used to measure concentrations of reactive nitrogen compounds - NO, NO2 and ammonia, of CO, formaldehyde, acetaldehyde and greenhouse gases CO2, methane and N2O. Exhaust flow was inferred from engine control unit data. Total emissions per cycle were compared and found to be in good agreement with laboratory measurements of NOX, CO and CO2 during dynamometer tests. On diesel engines, mean NOX emissions were 136-1070mg/km in the laboratory and 537 615mg/km on the road, in many cases nearly an order of magnitude higher compared to the numerical value of the Euro 6 limit. Mean N2O emissions were 3-19mg/km and were equivalent to several g/km CO2. The measurements suggest that NOX and N2O emissions from late-model European light utility vehicles with diesel engines are non-negligible and should be continuously assessed and scrutinized. High variances in NOX emissions among the tested diesel vehicles suggest that large number of vehicles should be tested to offer at least some insights about distribution of fleet emissions among vehicles. CNG engines exhibited relatively low emissions of NOX (12-186mg/km) and NH3 (10-24mg/km), while mean emissions of methane were 18-45mg/km, under 1g/km CO2 equivalent, and N2O, CO, formaldehyde and acetaldehyde were negligible. The combination of a relatively clean-burning fuel, modern engine technology and a three-way catalyst has resulted in relatively low emissions under the wide variety of operating conditions encountered during the tests. The on-board FTIR has proven to be a useful instrument capable of covering, with the exception of total hydrocarbons, essentially all gaseous pollutants of interest. PMID- 29126636 TI - Sustainability of agro-livestock integration: Implications and results of Emergy evaluation. AB - This study aims to assess the sustainability of an agroforestry system: i.e. a system obtained by the union of two productions to get at least two by-products from the same productive space. In particular, this case study presents the integration of a goose raising system with an organic grape production, from an environmental point of view. This integration is mainly designed to have two simultaneous co-products (grape and goose meat) with: i) a less intensive use of machineries for weeding and ii) avoiding use of chemical fertilizers and weeding. The sustainability is assessed by means of emergy evaluation. Emergy is a thermodynamic based tool able to estimates the environmental cost of products and services in terms of the solar energy (directly and indirectly) required for its production. As Emergy is not a state function, its final value depends on the way the product is made. The set theory applied to the emergy evaluation enables the comparison between the integrated system and the originating isolated systems in a proper way. Results confirm that the integrated system enables a saving, in emergy terms, amounting to 33% compared to the two originating isolated production systems. Emergy evaluation is able to keep track of the lower amount of resources required from outside the agroforestry system due to the optimization of resources internally available. PMID- 29126637 TI - Association of high-level humidifier disinfectant exposure with lung injury in preschool children. AB - BACKGROUND: Children aged <=6years reportedly account for 52% of victims of humidifier disinfectant-associated lung injuries. OBJECTIVES: To evaluate the association of humidifier disinfectants with lung injury risk among children aged <=6years. METHODS: Patients with humidifier disinfectant-associated lung injuries (n=214) who were clinically evaluated to have a definite (n=108), probable (n=49), or possible (n=57) association with humidifier disinfectants as well as control patients (n=123) with lung injury deemed unlikely to be associated with humidifier disinfectant use were evaluated to determine factors associated with increased risk of humidifier disinfectant-associated lung injury using unconditional multiple logistic regression analysis. RESULTS: For estimated airborne humidifier disinfectant concentrations, risk of humidifier disinfectant associated lung injury increased >=two-fold in a dose-dependent manner in the highest quartile (Q4, 135-1443MUg/m3) compared with that in the lowest quartile (Q1, <=33MUg/m3). Registered patients using more than two humidifier disinfectant brands were at an increased risk of humidifier disinfectant-associated lung injury (adjusted OR, 2.2; 95% confidence interval, 1.3-3.8) compared with those using only one brand. With respect to the duration of humidifier disinfectant use, risk of humidifier disinfectant-associated lung injury increased >=two-fold in the lowest quartile (<=5months) compared with that in the highest quartile (>=14months; adjusted OR 0.3; 95% confidence interval, 0.2-0.6). CONCLUSIONS: Younger children are more vulnerable to HDLI when exposed to HD chemicals within short period in early life. PMID- 29126638 TI - Mental disease-related emergency admissions attributable to hot temperatures. AB - OBJECTIVE: The association between high temperature and mental disease has been the focus of several studies worldwide. However, no studies have focused on the mental disease burden attributable to hot temperature. Here, we aim to quantify the risk attributed to hot temperatures based on the exposure-lag-response relationship between temperature and mental diseases. METHOD: From data on daily temperature and emergency admissions (EA) for mental diseases collected from 6 major cities (Seoul, Incheon, Daejeon, Daegu, Busan, and Gwangju in South Korea) over a period of 11years (2003-2013), we estimated temperature-disease associations using a distributed lag non-linear model, and we pooled the data by city through multivariate meta-analysis. Cumulative relative risk and attributable risks were calculated for extreme hot temperatures, defined as the 99th percentile relative to the 50th percentile of temperatures. RESULTS: The strongest association between mental disease and high temperature was seen within a period of 0-4days of high temperature exposure. Our results reveal that 14.6% of EA for mental disease were due to extreme hot temperatures, and the elderly were more susceptible (19.1%). Specific mental diseases, including anxiety, dementia, schizophrenia, and depression, also showed significant risk attributed to hot temperatures. Of all EA for anxiety, 31.6% were attributed to extremely hot temperatures. CONCLUSIONS: High temperature was responsible for an attributable risk for mental disease, and the burden was higher in the elderly. This finding has important implications for designing appropriate public health policies to minimize the impact of high temperature on mental health. PMID- 29126639 TI - Sedimentary black carbon and organochlorines in Lesser Himalayan Region of Pakistan: Relationship along the altitude. AB - Black carbon (BC) and total organic carbon (TOC) along with their relationship with organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were assessed in Lesser Himalayan Region (LHR) in different altitudinal zones based on anthropogenic influence/source proximity under the scope of this study. Results revealed the concentrations of BC, TOC, OCPs and PCBs varied between 0.3 and 43.5mgg-1, 1.7-65.4mgg-1, 0.59-3.64ngg-1 and 0.01-1.31ngg-1, respectively. Spatial distribution trends have shown higher levels of OCPs and PCBs contamination near populated and urban areas along the altitude. It is implicated that upslope, short and long-range transport and local emission sources contribute to the contamination of different altitudinal zones of LHR. The relationship of BC and TOC with OCPs and PCBs was evaluated using principal component analysis (PCA) and Pearson correlation analysis that indicated higher sorptive influence of BC over TOC in distribution status of organochlorines in LHR. Further research is required to find relationship of BC and TOC in surface riverine sediments, particularly in aquatic systems along the altitude in mountain regions of the world. PMID- 29126640 TI - The response of tree growth to nitrogen and phosphorus additions in a tropical montane rainforest. AB - Rapid increase of global nitrogen (N) deposition has greatly altered carbon cycles and functioning of forest ecosystems. Previous studies have focused on changes in carbon dynamics of temperate and subtropical forests through N enrichment experiments; however, the effects of N deposition on tree growth remain inconsistent, especially in tropical forests. Here, we conducted a five year N addition experiment (0 and 50kgNha-1yr-1) in a tropical montane rain forest in Hainan Island, China, to explore the effects of enhanced N deposition on growth of trees. We also set phosphorus (P) treatment (50kgPha-1yr-1) and N+P treatment (50kgNha-1yr-1+50kgPha-1yr-1) to examine potential P limitation driven by N deposition. Our results showed that N addition has not significantly influenced tree growth, while P addition significantly increased the relative growth rate of small (diameter at breast height, DBH<=10cm) and medium (10=55 Gy. At a median follow-up of 6.8 years, the 5-year actuarial local relapse (LR) rate was 7% (95% CI: 4.4-10%). The median time to the first LR was 2.7 years (range: 0.6 11.2 years). The LR was most often located within the irradiated field (26/32; 81%), where the median total applied dose was 56 Gy (range, 40-60 Gy). The 5-year LR rates were 4%, and 15% in patients receiving <55 Gy, and in those who had >=55 Gy (p < 0.001), respectively. In the multivariate analysis, dose >=55 Gy (HR [hazard ratio]: 2.9; p = 0.02), certain histological subtypes (HR: 7.8; p < 0.001), and minimal surgical margins <1 mm (HR: 2.9; p = 0.02) were associated to higher LR rates. In the subgroup of patients with "positive" margins <1 mm (n = 102), these histological subtypes (HR: 4.4; p = 0.03), and inadequate initial surgery justifying re-excision (HR: 3; p = 0.048) predicted for an increased LR, whereas dose of irradiation did not (p = 0.2). Patients who had late complications (n = 64; 15%) received higher doses of irradiation as compared with other patients (median: 55 Gy vs. 50 Gy, respectively; p < 0.001). CONCLUSION: In this retrospective analysis of patients having enlarged surgery and RT, histological subtype is the strongest predictor of LR, whereas dose de-escalation did not lead to worse outcomes. A dose of 50 Gy may be recommended in case of planned enlarged surgery with R0 margins. PMID- 29126650 TI - Plasticity in the auditory system. AB - Over the last 30 years a wide range of manipulations of auditory input and experience have been shown to result in plasticity in auditory cortical and subcortical structures. The time course of plasticity ranges from very rapid stimulus-specific adaptation to longer-term changes associated with, for example, partial hearing loss or perceptual learning. Evidence for plasticity as a consequence of these and a range of other manipulations of auditory input and/or its significance is reviewed, with an emphasis on plasticity in adults and in the auditory cortex. The nature of the changes in auditory cortex associated with attention, memory and perceptual learning depend critically on task structure, reward contingencies, and learning strategy. Most forms of auditory system plasticity are adaptive, in that they serve to optimize auditory performance, prompting attempts to harness this plasticity for therapeutic purposes. However, plasticity associated with cochlear trauma and partial hearing loss appears to be maladaptive, and has been linked to tinnitus. Three important forms of human learning-related auditory system plasticity are those associated with language development, musical training, and improvement in performance with a cochlear implant. Almost all forms of plasticity involve changes in synaptic excitatory - inhibitory balance within existing patterns of connectivity. An attractive model applicable to a number of forms of learning-related plasticity is dynamic multiplexing by individual neurons, such that learning involving a particular stimulus attribute reflects a particular subset of the diverse inputs to a given neuron being gated by top-down influences. The plasticity evidence indicates that auditory cortex is a component of complex distributed networks that integrate the representation of auditory stimuli with attention, decision and reward processes. PMID- 29126652 TI - Reply to Francesco Massari, Vincenzo Di Nunno, and Andrea Ardizzoni's Letter to the Editor re: Robert J. Motzer, Alain Ravaud, Jean-Jacques Patard, et al. Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2017.09.008. PMID- 29126651 TI - Effects of noise exposure on young adults with normal audiograms II: Behavioral measures. AB - An estimate of lifetime noise exposure was used as the primary predictor of performance on a range of behavioral tasks: frequency and intensity difference limens, amplitude modulation detection, interaural phase discrimination, the digit triplet speech test, the co-ordinate response speech measure, an auditory localization task, a musical consonance task and a subjective report of hearing ability. One hundred and thirty-eight participants (81 females) aged 18-36 years were tested, with a wide range of self-reported noise exposure. All had normal pure-tone audiograms up to 8 kHz. It was predicted that increased lifetime noise exposure, which we assume to be concordant with noise-induced cochlear synaptopathy, would elevate behavioral thresholds, in particular for stimuli with high levels in a high spectral region. However, the results showed little effect of noise exposure on performance. There were a number of weak relations with noise exposure across the test battery, although many of these were in the opposite direction to the predictions, and none were statistically significant after correction for multiple comparisons. There were also no strong correlations between electrophysiological measures of synaptopathy published previously and the behavioral measures reported here. Consistent with our previous electrophysiological results, the present results provide no evidence that noise exposure is related to significant perceptual deficits in young listeners with normal audiometric hearing. It is possible that the effects of noise-induced cochlear synaptopathy are only measurable in humans with extreme noise exposures, and that these effects always co-occur with a loss of audiometric sensitivity. PMID- 29126653 TI - Perioperative levosimendan in cardiac surgery: A systematic review with meta analysis and trial sequential analysis. AB - BACKGROUND: Several studies suggested beneficial effects of perioperative levosimendan on postoperative outcome after cardiac surgery. However, three large randomized controlled trials (RCTs) have been recently published and presented neutral results. We performed a systematic review with meta-analysis and trial sequential analysis (TSA) to assess benefits and harms of perioperative levosimendan therapy in cardiac surgery. METHODS: Electronic databases were searched up to September 2017 for RCTs on preoperative levosimendan versus any type of control. The Cochrane methodology was employed. We calculated odds ratio (OR) or Risk Ratio (OR) and 95% confidence interval (CI) using fixed-effects meta analyses and we further performed TSA. RESULTS: We included data from 40 RCTs and 4246 patients. Pooled analysis of 5 low risk of bias trials (1910 patients) showed no association between levosimendan and mortality (OR 0.86 [95% CI, 0.62, 1.18], p=0.34, TSA inconclusive), acute kidney injury, need of renal replacement therapy, myocardial infarction, ventricular arrhythmias, and serious adverse events, but an association with higher incidence of supraventricular arrhythmias (RR 1.11 [95% CI, 1.00, 1.24], p=0.05, TSA inconclusive) and hypotension (RR 1.15 [95% CI, 1.01, 1.30], p=0.04, TSA inconclusive). Analysis including all 40 trials found that levosimendan was associated with lower postoperative mortality (OR 0.56 [95% CI, 0.44, 0.71], p<0.00001, TSA conclusive), acute kidney injury, and renal replacement therapy, and higher incidence of hypotension. CONCLUSIONS: There is not enough high-quality evidence to neither support nor discourage the systematic use of levosimendan in cardiac surgery. PMID- 29126654 TI - Myeloperoxidase: A promising therapeutic target in prevention of atherosclerosis. PMID- 29126655 TI - Incidence of infective endocarditis and its thromboembolic complications in a pediatric population over 30years. AB - BACKGROUND: Pediatric infective endocarditis (IE) has been associated with high morbidity and mortality, mostly related to thromboembolic complications (TEC). The objective of our study was to describe the experience in children with IE and to review the changes over a thirty-year period, regarding origin of IE, incidence of vegetations, TEC and their respective morbidity and mortality rates. METHODS: A retrospective chart review of children aged 0-18years with IE defined by the Duke Criteria and admitted to The Hospital for Sick Children, was conducted. Data were divided into three periods (P); P1 (1979-1988); P2 (1989 1998); and P3 (1999-2008). RESULTS: The study included 113 patients, median age 7yrs.; females: 46 (41%), congenital heart defects 95 (84%), comparable in all periods. Overall, cardiac vegetations were found in 68/113 patients (60%); large vegetations (>=1cm) in 32 patients (28%). Fourty-five (45/133 [40%]) TEC were documented, 22 patients (20%) developed cerebrovascular events (CVE) and 23 patients (20%) had non-CVE. Patients diagnosed during P3 were older, had more vegetations (p<0.05), and a higher incidence of community acquired-IE (p<0.05). Overall, mortality was 15%, comparable in all periods. Significant risk factors for mortality were vegetations (HR 6.44; 95% CI: 2.07-20.01, p=0.002) and heart failure (HR 28.39; 95% CI: 10.49-76.85, p<0.001). CONCLUSIONS: Over the study period, we report a growing incidence of community acquired pediatric IE in older children accompanied by an increasing rate of TEC. Heart failure and vegetations were associated with an increased mortality. These preliminary data need to be confirmed by prospective data. PMID- 29126656 TI - The effect of IkappaK-16 on lipopolysaccharide-induced impaired monocytes. AB - This study focuses on impaired monocyte function, which occurs in some patients after trauma, major elective surgery, or sepsis. This monocyte impairment increases the risk of secondary infection and death. We aimed to determine the influence IkappaK-16 had on monocytes using an ex-vivo model of human monocyte impairment. We included the effects of the well-studied comparators interferon gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on impaired monocytes. Primary human monocytes were stimulated with 10ng/mL of lipopolysaccharide (LPS) for 16h and then challenged with 100ng/mL LPS to assess the monocyte inflammatory response. Treatment regimens, consisting of either IkappaK-16, IFN-gamma, or GM-CSF, were administered to impaired monocytes near the time of initial LPS stimulation. Stimulation with 10ng/mL LPS initially promoted a pro-inflammatory response but subsequently impaired production of both tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) and decreased HLA-DR expression. IkappaK-16 treatment attenuated TNF-alpha production and programmed death-ligand 1 (PD-L1) expression and increased IL-10 and CD14 expression. IFN-gamma treatment increased TNF-alpha production as well as PD-L1 and HLA-DR expression. In conclusion, limiting early inflammation with IkappaK-16 suppresses TNF-alpha production and PD-L1 expression but enhances IL-10 production and preserves CD14 expression for potential future exposure to infective stimuli. PMID- 29126657 TI - Response to Letter to the Editor on "Risk Factors, Outcomes, and Timing of Manipulation Under Anesthesia After Total Knee Arthroplasty". PMID- 29126658 TI - [Food and nutrition in primary care in Brazil]. AB - OBJECTIVE: To describe food and nutrition actions in primary health care in Brazil. METHODS: Exploratory review of articles published between 2007 and 2016. Lilacs, PubMed, Scopus and Web of Science databases were consulted. RESULTS: 103 articles were included, mostly published between 2012 and 2016 and developed mainly in the Southeast region of Brazil. The most prevalent research topics were food behaviour or consumption, nutritional status and non-communicable diseases. Most research was led by universities and was focused on diagnosis. Few actions on health promotion, healthy eating, assistance, treatment, integral health care and prevention of diseases related to food and nutrition were found in the review. CONCLUSION: National interest in food and nutrition has increased, however academic production is still far from the actual needs for providing evidence that impacts health status. More research is needed to describe, propose and evaluate programmes and actions. Therefore, it is essential for closer relationships to be forged between universities, managers and health services in order to identify common interests and to develop research that meets the needs of the area and contribute to planning and improving programmes and actions. PMID- 29126659 TI - Phases of match-play in professional Australian Football: Descriptive analysis and reliability assessment. AB - OBJECTIVES: To examine the frequency and time spent in the phases of Australian Football (AF) match-play and to assess the intra-assessor reliability of coding these phases of match-play. DESIGN: Observational, intra-reliability assessment. METHODS: Video footage of 10 random quarters of AF match-play were coded by a single researcher. Phases of offence, defence, contested play, umpire stoppage, set shot and goal reset were coded using a set of operational definitions. Descriptive statistics were provided for all phases of match-play. Following a 6 month washout period, intra-coder reliability was assessed using typical error of measurement (TEM) and intra-class correlation coefficients (ICC). RESULTS: A quarter of AF match-play involved 128+/-20 different phases of match-play. The highest proportion of match-play involved contested play (25%), followed by offence (18%), defence (18%) and umpire stoppages (18%). The mean duration of offence, defence, contested play, umpire stoppage, set shot and goal reset were 14, 14, 10, 11, 28 and 47s, respectively. No differences were found between the two coding assessments (p>0.05). ICCs for coding the phases of play demonstrated very high reliability (r=0.902-0.992). TEM of the total time spent in each phase of play represented moderate to good reliability (TEM=1.8-9.3%). Coding of offence, defence and contested play tended to display slightly poorer TEMs than umpire stoppages, set shots and goal resets (TEM=8.1 vs 4.5%). CONCLUSIONS: Researchers can reliably code the phases of AF match-play which may permit the analysis of specific elements of competition. PMID- 29126660 TI - Evaluation of the efficacy of a posaconazole and anidulafungin combination in a murine model of pulmonary aspergillosis due to infection with Aspergillus fumigatus. AB - Posaconazole (PSC) in combination with anidulafungin (AFG) was evaluated in a murine model of pulmonary aspergillosis. Immunosuppressed animals were infected via the nasal cavity with 2 different A. fumigatus strains. The animals received PSC (oral, 20mg/kg per day) and/or AFG (i.p., 10mg/kg per day) for 7days. On Day 8, the mice were euthanized and fungal burdens were determined from the lungs. Survival curves were constructed for mortality analysis. Compared to untreated groups, groups singly treated with PSC or AFG showed a reduced fungal burden in the lungs (P=0.0001-0.006) and prevention of mortality (66.66-83.33% of survival). Combination treatment with PSC and AFG significantly reduced the fungal burden (or sterilized the lungs) compared to the findings in the untreated and monotherapy groups and improved the survival rate to 100%. The PSC and AFG combination therapy was highly effective and should be evaluated in larger-scale experiments. PMID- 29126662 TI - Levosimendan in patients with cardiogenic shock complicating myocardial infarction: A meta-analysis. AB - PURPOSE: Cardiac shock is the leading cause of death in patients with acute myocardial infarction. The objective of this systematic review and meta-analysis was to evaluate whether levosimendan, compared to any type of control, is associated with improved clinical outcomes in patients with cardiogenic shock complicating myocardial infarction. MATERIALS AND METHODS: The PubMed, EMBASE, Cochrane Central Register, and China National Knowledge Information databases were searched for pertinent studies published up until 1 May 2016. Randomized and non-randomized clinical trials comparing levosimendan to standard therapy or placebo, in adult patients with cardiogenic shock complicating myocardial infarction, and reporting at least one outcome of interest were included. The primary outcome was mortality, whereas secondary outcomes were length of ICU stay, SOFA score, cardiac index (CI), cardiac power index (CPI), ejection fraction (EF), end-systolic volume (ESV), mean blood pressure (MBP), pulmonary arterial pressure (PAP), mixed venous oxygen saturation (SvO2), pulmonary artery occlusion pressure (PAOP) and glomerular filtration rate (GFR). We pooled risk ratio (RR) and 95% confidence interval (CI) using fixed and random effects models. RESULTS: Thirteen studies comprising a total of 648 patients were included in the analysis. There was a nonsignificant reduction in mortality with levosimendan compared to the controls (RR=0.82 [0.65-1.01], P for effect=0.07, I2=0%). In the levosimendan group PAP and ESV were significantly reduced, while CI, CPI, EF, MBP and SvO2 were significantly increased. No differences in SOFA score, ICU days, PAOP or GFR were noted. CONCLUSIONS: Levosimendan can improve hemodynamic parameters and cardiac function when compared with a control group, with no evidence of benefit in terms of survival. PMID- 29126661 TI - A Supermarket Double-Dollar Incentive Program Increases Purchases of Fresh Fruits and Vegetables Among Low-Income Families With Children: The Healthy Double Study. AB - OBJECTIVE: To carry out a pilot study to determine whether a supermarket double dollar fruit and vegetable (F&V) incentive increases F&V purchases among low income families. DESIGN: Randomized controlled design. Purchases were tracked using a loyalty card that provided participants with a 5% discount on all purchases during a 3-month baseline period followed by the 4-month intervention. SETTING: A supermarket in a low-income rural Maine community. PARTICIPANTS: A total of 401 low-income and Supplemental Nutrition Assistance Program (SNAP) supermarket customers. INTERVENTION: Same-day coupon at checkout for half-off eligible fresh, frozen, or canned F&V over 4 months. MAIN OUTCOME MEASURE: Weekly spending in dollars on eligible F&V. ANALYSIS: A linear model with random intercepts accounted for repeated transactions by individuals to estimate change in F&V spending per week from baseline to intervention. Secondary analyses examined changes among SNAP-eligible participants. RESULTS: Coupons were redeemed among 53% of eligible baskets. Total weekly F&V spending increased in the intervention arm compared with control ($1.83; 95% confidence interval [CI], $0.29 to $3.88). The largest increase was for fresh F&V ($1.97; 95% CI, $0.49 to $3.44). Secondary analyses revealed greater increases in F&V spending among SNAP eligible participants who redeemed coupons ($5.14; 95% CI, $1.93 to $8.34) than among non-SNAP eligible participants who redeemed coupons ($3.88; 95% CI, $1.67 to $6.08). CONCLUSIONS AND IMPLICATIONS: A double-dollar pricing incentive increased F&V spending in a low-income community despite the moderate uptake of the coupon redemption. Customers who were eligible for SNAP saw the greatest F&V spending increases. Financial incentives for F&V are an effective strategy for food assistance programs to increase healthy purchases and improve dietary intake in low-income families. PMID- 29126663 TI - The "true clinicians" do not need formal tools to define the complexity of their patients. Is this statement always true? PMID- 29126664 TI - Fatal DRESS syndrome under tocilizumab treatment for seronegative polyarthritis. PMID- 29126665 TI - Risk factors for unintentional occupational injury among urban transit bus drivers: a cohort longitudinal study. AB - PURPOSE: Although many studies have focused on bus operators' occupational diseases, work-related injury and associated risk factor data are limited. The purpose of this longitudinal study was to investigate unintentional injury and exposures that may affect injury risk among metropolitan bus operators. METHODS: Demographic, work-related, and injury data obtained from a metropolitan transit company for a 5-year period, enabled estimates of rates per 100 full time equivalents (FTEs) and adjusted Hazard Ratios (HRs), with 95% confidence intervals (CIs), using Generalized Estimating Equations and Cox proportional hazards models, respectively. RESULTS: The 2095 bus operators, included in this study, had an unintentional injury rate (95% CI) of 17.8 (16.1-19.7) per 100 FTEs. Multivariable analysis identified increased risks for operators who were female, compared to male (HR = 2.4; 2.0-2.8); worked less than 7 versus 7 to less than 12 hours per day (HR = 4.6; 3.8-5.5); and drove less than 7 versus 7 to less than 12 hours per day (HR = 3.2; 2.7-3.8). Suggestive increased risks were identified for operators working split versus straight shifts (HR = 1.2; 1.0-1.4) and for driving limited versus regular bus routes (HR = 1.36; 1.0-1.8). CONCLUSIONS: Results serve as a basis for further studies and inform the development of targeted intervention strategies to reduce bus operators' occupational injuries. PMID- 29126666 TI - Preparation and immunological evaluation of inactivated avian influenza virus vaccine encapsulated in chitosan nanoparticles. AB - Efficacy maximization of inactivated avian influenza vaccine using safe adjuvants was investigated. Chitosan nanoparticles were prepared by ionic gelation method with average size of 150 nm and their Zeta potential was 11.5 mV. After encapsulation of avian influenza vaccine, the average size was 397 nm and Zeta potential was 4.29 mV. The highest HI antibody titer results were shown in chicken group vaccinated with inactivated avian influenza virus AIV-chitosan followed by the group vaccinated with inactivated AIV-chitosan nanoparticles then the group vaccinated with oil inactivated AIV vaccine, on using chicken antigen at 2 weeks post second vaccination. Upon using duck antigen, the highest HI antibody titers were shown in chicken group vaccinated with inactivated AIV oil emulsion vaccine followed by chicken group vaccinated with AIV-chitosan nanoparticles then the group vaccinated with AIV-chitosan. Chicken in the group vaccinated with AIV-chitosan nanoparticles induced the best results of lymphocyte proliferation assay. The results of phagocytic activity percentage and phagocytic index of AIV-chitosan nanoparticles and AIV-chitosan groups at 3 days post first vaccination were increased significantly in comparison with other groups, whereas at 14 days post first vaccination, group vaccinated with AIV-chitosan nanoparticles showed significant increase in phagocytic activity percentage and phagocytic index. PMID- 29126668 TI - Comparison of the in vitro effects of low-level laser therapy and low-intensity pulsed ultrasound therapy on bony cells and stem cells. AB - To compare the in vitro effectiveness of Low-Level Laser Therapy (LLLT) and Low Intensity Pulsed Ultrasound (LIPUS) on bony cells and related stem cells. In this study, we aim to systematically review the published scientific literature which explores the use of LLLT and LIPUS to biostimulate the activity or the proliferation of bony cells or stem cells in vitro. We searched the database PubMed for LLLT or LIPUS, with/without bone, osteoblast, osteocyte, stem cells, the human osteosarcoma cell line (MG63), bone-forming cells, and cell culture (or in vitro). These studies were subdivided into categories exploring the effect of LLLT or LIPUS on bony cells, stem cells, and other related cells. 75 articles were found between 1987 and 2016; these included: 50 full paper articles on LLLT and 25 full papers on LIPUS. These articles met the eligibility criteria and were included in our review. A detailed and concise description of the LLLT and the LIPUS protocols and their individual effects on bony cells or stem cells and their results are presented in five tables. Based on the main results and the conclusions of the reviewed articles in the current work, both, LLLT and LIPUS, apply a biostimulatory effect on osteoblasts, osteocytes, and enhance osteoblast proliferation and differentiation on different bony cell lines used in in vitro studies, and therefore, these may be useful tools for bone regeneration therapy. Moreover, in consideration of future cell therapy protocols, both, LLLT and LIPUS (especially LLLT), enhnce a significant increase in the initial number of SCs before differentiation, thus increasing the number of differentiated cells for tissue engineering, regenerative medicine, and healing. Further studies are necessary to determine the LLLT or the LIPUS parameters, which are optimal for biostimsulating bony cells and SCs for bone healing and regenerative medicine. PMID- 29126667 TI - Smartphone-based ecological momentary assessment (EMA) of alcohol and cannabis use in older adults with and without HIV infection. AB - INTRODUCTION: Ecological momentary assessment (EMA) has been used to characterize substance use among adult populations; however, little is known about the validity of EMA and the patterns and predictors of substance use among older adults with and without HIV infection. METHODS: Thirty-five (22 HIV-positive, 13 HIV-negative) older adults aged 50-74 were assessed for 14days and completed up to four smartphone-based surveys per day. RESULTS: Participants completed an average of 89.5% of possible EMA surveys. EMA self-reported alcohol and cannabis use were significantly positively correlated with laboratory-assessed, self reported days of alcohol (r=0.52, p=0.002) and cannabis (r=0.61, p<0.001) used and quantity of alcohol (r=0.42, p=0.013) and cannabis (r=0.41, p=0.016) used in the 30days prior to baseline assessment. In a subset of 15 alcohol or cannabis users, preliminary analyses of the effects of mood and pain on alcohol or cannabis use showed: 1) greater anxious mood predicted substance use at the next EMA survey (OR=1.737, p=0.023), 2) greater happiness predicted substance use later in the day (OR=1.383, p<0.001), and 3) higher pain level predicted substance use earlier in the day (OR=0.901, p=0.005). CONCLUSIONS: Findings demonstrate that EMA-measured alcohol and cannabis use has convergent validity among older adults with and without HIV infection. Preliminary results showing predictors of substance use highlight the importance of gathering EMA data to examine daily variability and time-dependent antecedents of substance use among this population. PMID- 29126669 TI - What can DTI tell about early cognitive impairment? - Differentiation between MCI subtypes and healthy controls by diffusion tensor imaging. AB - Mild cognitive impairment (MCI) gained a lot of interest recently, especially that the conversion rate to Alzheimer Disease (AD) in the amnestic subtype (aMCI) is higher than in the non-amnestic subtype (naMCI). We aimed to determine whether and how diffusion-weighted MRI (DWI) using the diffusion tensor model (DTI) can differentiate MCI subtypes from healthy subjects. High resolution 3D T1W and DWI images of patients (aMCI, n = 18; naMCI, n = 20; according to Petersen criteria) and controls (n = 27) were acquired at 3T and processed using ExploreDTI and SPM. Voxel-wise and region of interest (ROI) analyses of fractional anisotropy (FA) and mean diffusivity (MD) were performed with ANCOVA; MD was higher in aMCI compared to controls or naMCI in several grey and white matter (GM, WM) regions (especially in the temporal pole and the inferior temporal lobes), while FA was lower in WM ROI-s (e.g. left Cingulum). Moreover, significant correlations were identified between verbal fluency, visual and verbal memory performance and DTI metrics. Logistic regression showed that measuring FA of the crus of fornix along GM volumetry improves the discrimination of aMCI from naMCI. Additional information from DWI/DTI aids preclinical detection of AD and may help detecting early non-Alzheimer type dementia, too. PMID- 29126670 TI - A comparison of gamma-glutamyl transferase and alkaline phosphatase as prognostic markers in patients with coronary heart disease. AB - BACKGROUND AND AIMS: Whether gamma-glutamyl transferase (GGT) or alkaline phosphatase (ALP) is a better prognostic marker in patients with coronary heart disease (CHD) remains unknown. The aim of this study was to compare the prognostic value of GGT and ALP in patients with CHD. METHODS AND RESULTS: This study included 3768 patients with CHD. The main study outcome was 3-year all cause mortality. The median values of GGT and ALP were 36.2 U/L and 69.3 U/L. Patients were divided into subgroups according to GGT or ALP activity > or <=median. Overall, there were 304 deaths: 195 deaths occurred in patients with GGT >median (n = 1882) and 109 deaths occurred in patients with GGT <=median (n = 1886); Kaplan-Meier [KM] estimates of all-cause mortality were 11.9% and 6.4% (unadjusted hazard ratio [HR] = 1.85, 95% confidence interval [CI], 1.46 to 2.34]; P < 0.001). According to ALP activity, 186 deaths occurred in patients with ALP >median (n = 1883) and 118 deaths occurred in patients with ALP <=median (n = 1885); KM estimates of all-cause mortality were 11.4% and 7.1% (unadjusted HR = 1.64 [1.30-2.06]; P < 0.001). After adjustment, GGT (adjusted HR = 1.32 [1.11-1.58]; P = 0.002) but not ALP (adjusted HR = 1.20 [1.00-1.43]; P = 0.051, with both HR calculated per 1 unit increment in logarithmic GGT or ALP scale) remained significantly associated with the risk for mortality. The C statistic of the mortality model with GGT was greater than the C statistic of the model with ALP (0.831 [0.802-0.859] vs. 0.826 [0.793-0.855]; P < 0.001). CONCLUSIONS: In patients with CHD, GGT was a stronger correlate of all-cause mortality than ALP. PMID- 29126672 TI - Does portal vein embolization prior to liver resection influence the oncological outcomes - A propensity score matched comparison. AB - INTRODUCTION: There is an ongoing controversy surrounding portal vein embolization (PVE) regarding the short-term safety of PVE and long-term oncological benefit. This study aims to compare survival outcomes of patients subjected to major liver resection for colorectal liver metastases (CRLM) with or without PVE. METHODS: All consecutive patients who underwent major liver resection for CRLM in four high volume liver centres between January 2000 and December 2015 were included. Major liver resection was defined as resection of at least three Couinaud liver segments. To reduce selection bias, propensity score matching was performed for PVE and non-PVE patients with overall and disease-free survival as primary endpoints. For matching, all patients who underwent PVE followed by a major liver resection were selected. Patients were matched to patients who had undergone major liver resection without PVE. RESULTS: Of 745 patients undergoing major liver resection for CRLM, 53 patients (7%) underwent PVE before liver resection. In the overall cohorts, PVE patients had inferior DFS and a trend towards inferior OS. A total of 46 PVE patients were matched to 46 non-PVE patients to create comparable cohorts and between these two matched cohorts no differences in DFS (3-year DFS 16% vs 9%, p = 0.776) or OS (5-year OS 14% vs 14%, p = 0.866) were found. CONCLUSIONS: This retrospective, matched analysis does not suggest a negative impact of PVE on long-term outcomes after liver resection in patients with CRLM. PMID- 29126673 TI - Pulmonary Hypertension in Patients for Transcatheter and Surgical Aortic Valve Replacement: A Focus on Outcomes and Perioperative Management. PMID- 29126674 TI - Echocardiography as an Adjunct in Venovenous Extracorporeal Membrane Oxygenation. PMID- 29126675 TI - Combined Somatic and Cerebral Oximetry Monitoring in Liver Transplantation: A Novel Approach to Clinical Diagnosis. PMID- 29126676 TI - Deep Hypothermic Circulatory Arrest in a Patient With Severe G6PD Deficiency. PMID- 29126671 TI - Treatment challenges in and outside a specialist network setting: Pancreatic neuroendocrine tumours. AB - Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network. PMID- 29126677 TI - Comparing Factor Concentrates for Post-Bypass Coagulopathy: Is There One Best Option? PMID- 29126678 TI - The Increasing Importance of Percutaneous Mechanical Circulatory Support in High Risk Transcatheter Coronary Interventions: An Evidence-Based Analysis. PMID- 29126679 TI - The Evidence Base Surrounding Lung Isolation Often Is Wider Than Described. PMID- 29126680 TI - Anesthetic and Perioperative Considerations for Combined Heart-Kidney Transplantation. AB - OBJECTIVE: To describe detailed perioperative features of combined heart and kidney transplant (HKT). DESIGN: Retrospective study. SETTING: Tertiary care university hospital. PARTICIPANTS: All consecutive HKT recipients aged 18 years and older. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After approval of the Institutional Review Board, the authors studied all consecutive adult patients who underwent HKT between January 2013 and July 2016. Recipient and donor's demographic data, hemodynamic profile, and perioperative data were analyzed. Actuarial survival rate was 57% and 43% for in-hospital and after a mean follow-up of 135 (266) days, respectively. Among patients who required postoperative hemodialysis (n = 4), 75% (n = 3) died during hospital stay. In unadjusted analysis, patients who died had a lower postoperative cardiac index (5.4 [2.7] v 3.2 [1] L/min/m2; p = 0.034) and central venous pressure (11 [5] v 8.5 [3] mmHg; p = 0.032). All patients underwent a nonstaged surgery. When compared with preoperative hemodynamic variables, early postoperative values showed decreased systemic vascular resistance (1,333 [433] dyn/s/cm-5v 595 [176] dyn/s/cm-5; p = 0.028) and higher cardiac output (4.3 [1.4] L/min v 6.7 [3] L/min; p = 0.018). Median hospital stay was 63 (44) days. CONCLUSIONS: Anesthesiologists should be actively involved in perioperative strategies on how to manage these critical patients with severe cardiac and noncardiac comorbidities applying their expertise to HKT procedure. PMID- 29126681 TI - A Split From Conventional Blood Component Therapy? PMID- 29126682 TI - Oxygen, Cardiac Surgery, and Delirium. PMID- 29126683 TI - A Game of Twister: What 3D TEE Rendering Tells Us About the Mitral Annulus During OPCAB. PMID- 29126685 TI - Cerebral Hypoxia Caused by Flow Confliction During Minimally Invasive Cardiac Surgery With Retrograde Perfusion: A Word of Caution. PMID- 29126684 TI - A Tale of Three Surgeries: Management of a Massive Recurrent Mycotic Aortic Pseudoaneurysm. PMID- 29126686 TI - Transfusion Threshold of Hemoglobin 80 g/L Is Comparable to 100 g/L in Terms of Bleeding in Cardiac Surgery: A Prospective Randomized Study. AB - OBJECTIVE: Anemia is common after cardiac surgery and, according to some suggestive evidence, may be associated with increased bleeding, other morbidity, and mortality. However, transfusion of red blood cells (RBC) may cause adverse effects and increase cost. The authors hypothesized that the restrictive hemoglobin threshold (Hb of 80 g/L) may aggravate bleeding more than the higher Hb threshold (Hb 100 g/L). DESIGN: Prospective randomized trial. TYPE OF HOSPITAL: University Hospital of Helsinki, Finland. PARTICIPANTS: Eighty patients with written informed consent, scheduled for elective open-heart surgery were randomized in 2 groups. INTERVENTIONS: Two study groups had RBC transfusion threshold of either Hb 80 g/L or 100 g/L. These triggers were followed for a 24 hour period postoperatively. A medical follow-up was carried out for 7 days after surgery. MEASUREMENTS AND MAIN RESULTS: Rotational thromboelastometry (ROTEM) and conventional laboratory tests were performed to evaluate coagulation. There was no significant difference in bleeding or ROTEM parameters between the groups. Complication rate and Hb concentration after 7-day follow-up were not different between the groups, but Group 100 g/L had received twice the amount of RBC transfusions. CONCLUSION: Hb threshold of 80 g/L for RBC transfusion in cardiac surgery is comparable to 100 g/L in terms of bleeding and possibly short-term complications. PMID- 29126687 TI - A New Comer Steps to the Plate: Should Ultrasound Join the ICU Starting Lineup? PMID- 29126688 TI - Prediction of Postoperative Blood Loss Using Thromboelastometry in Adult Cardiac Surgery: Cohort Study and Systematic Review. AB - OBJECTIVE: The aim was to evaluate the predictive value of thromboelastometry for postoperative blood loss in adult cardiac surgery with cardiopulmonary bypass. DESIGN: Retrospective cohort study and systematic review of the literature. SETTING: A tertiary university hospital. PARTICIPANTS: 202 patients undergoing elective cardiac surgery. INTERVENTIONS: Thromboelastometry was performed before cardiopulmonary bypass and 3 minutes after protamine administration. MEASUREMENTS AND MAIN RESULTS: The cohort study showed that the preoperative and postoperative thromboelastometric positive predicting value was poor (0%-22%); however, the negative predicting value was high (89%-94%). The systematic review of the literature to evaluate the predictive value of thromboelastometry for major postoperative bleeding in cardiac surgery resulted in 1,311 articles, 11 of which were eligible (n = 1,765; PubMed and Embase, until June 2016). Two studies found a good predictive value, whereas the other 9 studies showed a poor predictability for major postoperative bleeding after cardiac surgery. The overall negative predicting value was high. CONCLUSIONS: Thromboelastometry does not predict which patients are at risk for major postoperative bleeding. PMID- 29126689 TI - The Feasibility and Impact of Routine Combined Limited Transthoracic Echocardiography and Lung Ultrasound on Diagnosis and Management of Patients Admitted to ICU: A Prospective Observational Study. AB - OBJECTIVES: Limited transthoracic echocardiography (TTE) and lung ultrasound increasingly is performed in the intensive care unit (ICU), though used in a goal directed rather than routine manner. DESIGN: Prospective observational study. SETTINGS: Tertiary ICU. PARTICIPANTS: Ninety-three critically ill participants within 24 hours of admission to ICU. METHODS: A treating intensivist documented a clinical diagnosis and management plan before and after combined limited TTE and lung ultrasound. Ultrasound was performed by an independent intensivist and checked for accuracy offline by a second reviewer. RESULTS: Ultrasound images were interpretable in 99%, with good interobserver agreement. The hemodynamic diagnosis was altered in 66% of participants, including new (14%) or altered (25%) abnormal states or exclusion of clinically diagnosed abnormal state (27%). Valve pathology of at least moderate severity was diagnosed for mitral regurgitation (7%), aortic stenosis (1%), aortic stenosis and mitral regurgitation (1%), tricuspid regurgitation (3%), and 1 case of mitral regurgitation was excluded. Lung pathology diagnosis was changed in 58% of participants including consolidation (13%), interstitial syndrome (4%), and pleural effusion (23%), and exclusion of clinically diagnosed consolidation (6%), interstitial syndrome (3%), and pleural effusion (9%). Management changed in 65% of participants including increased (12%) or decreased (23%) fluid therapy, initiation (10%), changing (6%) or cessation (9%) of inotropic, vasoactive or diuretic drugs, non-invasive ventilation (3%), and pleural drainage (2%). CONCLUSION: Routine screening of patients with combined limited TTE and lung ultrasound on admission to ICU is feasible and frequently alters diagnosis and management. PMID- 29126690 TI - Evaluation of peri-implant bone levels and soft tissue dimensions around zirconia implants-a three-year follow-up study. AB - The aim of this study was to measure bone levels around zirconia implants during follow-up of up to 3 years. Additionally, the effect of clinical contact point positions on the papilla deficit was evaluated. Eighty-one patients with 105 zirconia implants were examined at the 3-year follow-up. Bone levels were measured on the date of implant placement and at 3 months, 1year, and 3 years thereafter. Distances between the first bone-implant contact and the contact point of the crowns and between the bone level at the adjacent tooth and the contact point of the crowns were assessed. The effect of the clinical contact point position on the papilla deficit was also assessed. Significant reductions in the distances between the bone-implant contact and the implant shoulder, as well as the contact point of the crowns, and between the bone level at the adjacent tooth and the contact point of the crowns, were found. A significant association was found between the papilla deficit and the height of the contact point. Implant survival was 100% and implant success was 95.4%. While zirconia implants presented little bone loss up to 1year, significant bone apposition was observed up to 3years. Low contact points correlated with full papillae, whereas high contact points were associated with a papilla deficit. PMID- 29126691 TI - The effect of different dosage regimens of tranexamic acid on blood loss in bimaxillary osteotomy: a randomized, double-blind, placebo-controlled study. AB - The purpose of this study was to compare the effects of three dosage regimens of intravenous tranexamic acid and normal saline placebo on blood loss and the requirement for transfusion during bimaxillary osteotomy. A prospective, randomized, double-blind, placebo-controlled study was performed. Eighty patients scheduled for elective bimaxillary osteotomy were divided into four groups: a placebo group and three groups receiving a single dose of tranexamic acid 10, 15, or 20mg/kg body weight after the induction of anaesthesia. Demographic data, the anaesthetic time, the operative time, and the experience of the surgical team were similar in the four groups. Patients receiving placebo had increased blood loss compared to those receiving tranexamic acid. No significant difference in blood loss was found among those who received 10, 15, or 20mg/kg body weight of tranexamic acid. There was no significant difference in transfusion requirement, amount of 24-h postoperative vacuum drainage, length of hospital stay, or complications among the four groups. Prophylactic tranexamic acid decreased bleeding during bimaxillary osteotomy. Of the three dosages of tranexamic acid studied, the most efficacious and cost-effective dose to reduce bleeding was 10mg/kg body weight. PMID- 29126692 TI - Biomaterials in temporomandibular joint replacement: current status and future perspectives-a narrative review. AB - The alloplastic total temporomandibular joint (TMJ) prosthesis has a long history, with many different materials and designs used. While several of these materials have proven valuable over time, many others have not been suitable for implantation, resulting in failure and the need for explantation of the implant. Because of the failure of several of these systems, the use of alloplastic prostheses has reduced dramatically, despite their advantages over autogenous restoration. The aim of this narrative review is to discuss the criteria that must be met by a biomaterial in order for it to be considered suitable for implantation, as well as the common complications that can occur. Currently used materials are highlighted, as well as potential future materials that might prove better suitable for implantation. Several surface modification techniques are proposed as an alternative to the materials used in current TMJ prosthesis systems. PMID- 29126693 TI - Characterization of patients with autoimmune hepatitis at an university hospital in Medellin-Colombia: cohort study. AB - INTRODUCTION: Autoimmune hepatitis is a chronic liver disease that impacts on morbidity and mortality of patients. Few epidemiological data exist of this in Latin America and Colombia. OBJECTIVES: The aim of this study is to describe the demographic, clinical and laboratory characteristics of the patients; the treatment and the response to it, the evolution and course of the disease, requirement of liver transplantation and mortality. METHODS: Historical cohort study that include patients attended at an University Hospital in Medellin, Colombia between January 2010 and December 2016 with >=16 years age at the time of diagnosis of autoimmune hepatitis. Data collection was done from the review of medical records. Statistical analysis was performed using SPSS version 20. RESULTS: The study included 278 patients, 90% of the patients were women, the median age at diagnosis was 50 years. 37.8% were cirrhotic at the time of diagnosis. The biochemical remission was 85%. In patients who developed cirrhosis it was found a higher proportion of men (21.2 vs. 7.8%, p=.027), a greater frequency of overlap autoimmune-primary sclerosant cholangitis (6.0 vs. 0% p=.006) and a greater frequency of non-response to treatment (12.1 vs. 1.6%, p=.004). CONCLUSION: Autoimmune hepatitis is not a rare disease in Colombian population; it predominates in women but has a less favourable course in men. An important number of patients are cirrhotic at the time of diagnosis, the response to treatment and complications in our population are similar to those described worldwide. PMID- 29126694 TI - Decay data for the positron emission tomography imaging radionuclide 124I: A DDEP evaluation. AB - A new decay data evaluation for the positron emitting radionuclide 124I has been performed using the Decay Data Evaluation Project (DDEP) methodology. New recommended values for the half-life, gamma-ray emission probabilities, beta+ branching ratios, and other relevant nuclear and atomic data are provided. This paper provides a summary of the evaluation; the complete set of recommended data tables and detailed evaluator comments are available at the DDEP website. PMID- 29126695 TI - A new digital 4pigamma system with a NaI well-type detector at LMR-CNEA. AB - A 4pigamma integral counting system with a NaI(Tl) well-type detector and a digital interface to acquire measurement data was implemented at LMR-CNEA. The detection efficiency as a function of the energy was computed by Monte Carlo simulations and the total efficiencies for ampoules and point sources were calculated considering all the decay branches. A computer code was developed to analyse data. This program reads the files generated by the digitizer module, corrects for dead time and calculates source activities and their uncertainties. Ampoules with solutions of 113Sn, 192Ir and 131I were measured. PMID- 29126696 TI - Coordination of mitochondrial biogenesis by PGC-1alpha in human skeletal muscle: A re-evaluation. AB - The transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1alpha) is proposed to coordinate skeletal muscle mitochondrial biogenesis through the integrated induction of nuclear- and mitochondrial-encoded gene transcription. This paradigm is based largely on experiments demonstrating PGC-1alpha's ability to co-activate various nuclear transcription factors that increase the expression of mitochondrial genes, as well as PGC-1alpha's direct interaction with mitochondrial transcription factor A within mitochondria to increase the transcription of mitochondrial DNA. While this paradigm is supported by evidence from cellular and transgenic animal models, as well as acute exercise studies involving animals, the up-regulation of nuclear- and mitochondrial-encoded genes in response to exercise does not appear to occur in a coordinated fashion in human skeletal muscle. This review re evaluates our current understanding of this phenomenon by highlighting evidence from recent studies examining the exercise-induced expression of nuclear- and mitochondrial-encoded genes targeted by PGC-1alpha. We also highlight several possible theories that may explain the apparent inability of PGC-1alpha to coordinately up-regulate the expression of genes required for mitochondrial biogenesis in human skeletal muscle, and provide directions for future work exploring mitochondrial biogenic gene expression following exercise. PMID- 29126697 TI - Use of automated learning techniques for predicting mandibular morphology in skeletal class I, II and III. AB - BACKGROUND: The prediction of the mandibular bone morphology in facial reconstruction for forensic purposes is usually performed considering a straight profile corresponding to skeletal class I, with application of linear and parametric analysis which limit the search for relationships between mandibular and craniomaxillary variables. OBJECTIVE: To predict the mandibular morphology through craniomaxillary variables on lateral radiographs in patients with skeletal class I, II and III, using automated learning techniques, such as Artificial Neural Networks and Support Vector Regression. MATERIALS AND METHODS: 229 standardized lateral radiographs from Colombian patients of both sexes aged 18-25 years were collected. Coordinates of craniofacial landmarks were used to create mandibular and craniomaxillary variables. Mandibular measurements were selected to be predicted from 5 sets of craniomaxillary variables or input characteristics by using automated learning techniques, and they were evaluated through a correlation coefficient by a ridge regression between the real value and the predicted value. RESULTS: Coefficients from 0.84 until 0.99 were obtained with Artificial Neural Networks in the 17 mandibular measures, and two coefficients above 0.7 were obtained with the Support Vector Regression. CONCLUSION: The craniomaxillary variables used, showed a high predictability ability of the selected mandibular variables, this may be the key to facial reconstruction from specific craniomaxillary measures in the three skeletal classifications. PMID- 29126699 TI - Subcutaneous treprostinil in pediatric patients with failing single-ventricle physiology. PMID- 29126698 TI - Hybrid drug combination: Combination of ferulic acid and metformin as anti diabetic therapy. AB - BACKGROUND AND PURPOSE: Ferulic acid, an anti-oxidant phytochemical present in several dietary components, is known to produce wide range of pharmacological effects. It is approved for use in food industry as a preservative and in sports food. Previous reports from our lab have shown synergistic interaction of ferulic acid with metformin in cell lines and diabetic rats. The purpose of this review is to compile information about anti-diabetic activity of ferulic acid in in vitro and in vivo models with special emphasis on activity of ferulic acid when combined with metformin. The mechanism of synergistic interaction between ferulic acid and metformin is also proposed after carefully studying effects of these compounds on molecules involved in glucose metabolism. METHODS: Scientific literature for the purpose of this review was collected using online search engines and databases such as ScienceDirect, Scopus, PubMed and Google scholar. RESULTS: Ferulic acid forms resonance stabilized phenoxyl radical which scavenges free radicals and reduce oxidative stress. It improves glucose and lipid profile in diabetic rats by enhancing activities of antioxidant enzymes, superoxide dismutase and catalase in the pancreatic tissue. Combining ferulic acid with metformin improves both, in vitro glucose uptake activity and in vivo hypoglycemic activity of the latter. It is possible to reduce the dose of metformin by four folds (from 50 to 12.5 mg/kg body weight) by combining it with 10 mg of ferulic acid/kg body weight in diabetic rats. Ferulic acid improves glucose uptake through PI3-K pathway whereas metformin activates AMPK pathway to improve glucose uptake. CONCLUSION: The synergistic interaction of ferulic acid and metformin is due their action on parallel pathways which are involved in glucose uptake. Due to synergistic nature of their interaction, it is possible to reduce the dose of metformin (by combining with ferulic acid) required to achieve normoglycemia. Since the dose of metformin is reduced, the dose associated side effects of metformin therapy can be reduced. PMID- 29126700 TI - Structure and function of haemoglobins. AB - Haemoglobin (Hb) is widely known as the iron-containing protein in blood that is essential for O2 transport in mammals. Less widely recognised is that erythrocyte Hb belongs to a large family of Hb proteins with members distributed across all three domains of life-bacteria, archaea and eukaryotes. This review, aimed chiefly at researchers new to the field, attempts a broad overview of the diversity, and common features, in Hb structure and function. Topics include structural and functional classification of Hbs; principles of O2 binding affinity and selectivity between O2/NO/CO and other small ligands; hexacoordinate (containing bis-imidazole coordinated haem) Hbs; bacterial truncated Hbs; flavohaemoglobins; enzymatic reactions of Hbs with bioactive gases, particularly NO, and protection from nitrosative stress; and, sensor Hbs. A final section sketches the evolution of work on the structural basis for allosteric O2 binding by mammalian RBC Hb, including the development of newer kinetic models. Where possible, reference to historical works is included, in order to provide context for current advances in Hb research. PMID- 29126701 TI - The role of digital health in making progress toward Sustainable Development Goal (SDG) 3 in conflict-affected populations. AB - PURPOSE: The progress of the Millennium Development Goals (MDGs) shows that sustained global action can achieve success. Despite the unprecedented achievements in health and education, more than one billion people, many of them in conflict-affected areas, were unable to reap the benefits of the MDG gains. The recently developed Sustainable Development Goals (SDGs) are even more ambitious then their predecessor. SDG 3 prioritizes health and well-being for all ages in specific areas such as maternal mortality, communicable diseases, mental health, and healthcare workforce. However, without a shift in the approach used for conflict-affected areas, the world's most vulnerable people risk being left behind in global development yet again. We must engage in meaningful discussions about employing innovative strategies to address health challenges fragile, low resource, and often remote settings. In this paper, we will argue that to meet the ambitious health goals of SDG 3, digital health can help to bridge healthcare gaps in conflict-affected areas. METHODS: First, we describe the health needs of populations in conflict-affected environments, and how they overlap with the SDG 3 targets. Secondly, we discuss how digital health can address the unique needs of conflict-affected areas. Finally, we evaluate the various challenges in deploying digital technologies in fragile environments, and discuss potential policy solutions. DISCUSSION: Persons in conflict-affected areas may benefit from the diffusive nature of digital health tools. Innovations using cellular technology or cloud-based solutions overcome physical barriers. Additionally, many of the targets of SDG 3 could see significant progress if efficacious education and outreach efforts were supported, and digital health in the form of mHealth and telehealth offers a relatively low-resource platform for these initiatives. Lastly, lack of data collection, especially in conflict-affected or otherwise fragile states, was one of the primary limitations of the MDGs. Greater investment in data collection efforts, supported by digital health technologies, is necessary if SDG 3 targets are to be measured and progress assessed. Standardized EMR systems as well as context-specific data warehousing efforts will assist in collecting and managing accurate data. Stakeholders such as patients, providers, and NGOs, must be proactive and collaborative in their efforts for continuous progress toward SDG 3. Digital health can assist in these inter-organizational communication efforts. CONCLUSION: The SDGS are complex, ambitious, and comprehensive; even in the most stable environments, achieving full completion towards every goal will be difficult, and in conflict-affected environments, this challenge is much greater. By engaging in a collaborative framework and using the appropriate digital health tools, we can support humanitarian efforts to realize sustained progress in SDG 3 outcomes. PMID- 29126702 TI - Delay in pediatric epilepsy surgery: A caregiver's perspective. AB - The timing of epilepsy surgery is complex, and there is not a structured pathway to help families decide whether to continue medical management or pursue surgical treatment. We surveyed caregivers of pediatric epilepsy surgery patients. Fifty eight respondents answered the majority of questions. Thirty caregivers wished their child had undergone epilepsy surgery earlier compared with twenty who felt surgery was done at the appropriate time, and eight were unsure. In retrospect, caregivers who wished their child's surgery had been performed sooner had a significantly longer duration of epilepsy prior to the surgery [44.1+/-71.7 (months+/-standard deviation (SD), N=27)], compared with those who felt content with the timing of the surgery [12.8+/-14.1 (months+/-SD, N=20), p=0.0034]. Caregivers were willing to accept a lower likelihood of seizure freedom than their physician reported was likely. Most caregivers were willing to accept deficits in all domains surveyed; caregivers had high acceptance of motor deficits, cognitive deficits, behavioral change, and language loss. Future studies are needed to focus on how to improve the education of caregivers and neurologists about the benefits and risks of epilepsy surgery and accelerate the pipeline to epilepsy surgery to improve caregiver satisfaction. PMID- 29126703 TI - Epilepsy, stigma, and family. AB - Epilepsy is surrounded by prejudice and stigma. Little is known about the perception of stigma by cohabiting relatives (CR) of people with epilepsy (PWE). The study investigated whether the Stigma Scale of Epilepsy (SSE) scores of 90 CR and 148 adult PWE were related to the PWE's clinical aspects and QOLIE-31 at a significance level of p<0.05. The SSE scores of the CR were equivalent to those of PWE dyads (ICC=0.385, p=0.001). Cohabiting relatives of PWE with depressive disorder perceived more stigma (t-test: p=0.038). Higher perceived stigma by PWE was significantly related to exclusively generalized seizures (p=0.005), longer disease duration (p=0.002), and higher perception of stigma by CR in the linear regression model. Both PWE and CR have high perception of stigma, which is related to clinical aspects. Higher perceptions of stigma by PWE and CR are associated with worse QoL in PWE. PMID- 29126705 TI - Recipe for a Successful Hybrid Academic-Community Radiology Practice: Canadian Experience. PMID- 29126704 TI - Decreased neurite density within frontostriatal networks is associated with executive dysfunction in temporal lobe epilepsy. AB - OBJECTIVE: Executive dysfunction is observed in a sizable number of patients with refractory temporal lobe epilepsy (TLE). The frontostriatal network has been proposed to play a significant role in executive functioning, however, because of the complex architecture of these tracts, it is difficult to generate measures of fiber tract microstructure using standard diffusion tensor imaging. To examine the association between frontostriatal network compromise and executive dysfunction in TLE, we applied an advanced, multishell diffusion model, restriction spectrum imaging (RSI), that isolates measures of intraaxonal diffusion and may provide better estimates of fiber tract compromise in TLE. METHODS: Restriction spectrum imaging scans were obtained from 32 patients with TLE [16 right TLE (RTLE); 16 left TLE (LTLE)] and 24 healthy controls (HC). An RSI-derived measure of intraaxonal anisotropic diffusion (neurite density; ND) was calculated for the inferior frontostriatal tract (IFS) and superior frontostriatal tract (SFS) and compared between patients with TLE and HC. Spearman correlations were performed to evaluate the relationships between ND of each tract and verbal (i.e., D-KEFS Category Switching Accuracy and Color-Word Interference Inhibition/Switching) and visuomotor (Trail Making Test) set shifting performances in patients with TLE. RESULTS: Patients with TLE demonstrated reductions in ND of the left and right IFS, but not SFS, compared with HC. Reduction in ND of left and right IFS was associated with poorer performance on verbal set-shifting in TLE. Increases in extracellular diffusion (isotropic hindered; IH) were not associated with executive dysfunction in the patient group. SIGNIFICANCE: Restriction spectrum imaging-derived ND revealed microstructural changes within the IFS in patients with TLE, which was associated with poorer executive functioning. This suggests that axonal/myelin loss to fiber networks connecting the striatum to the inferior frontal cortex is likely contributing to executive dysfunction in TLE. PMID- 29126706 TI - [Clinical governance and patient safety culture in clinical laboratories in the Spanish National Health System]. AB - AIM: To conduct a situational analysis of patient safety culture in public laboratories in the Spanish National Health System and to determine the clinical governance variables that most strongly influence patient safety. METHOD: A descriptive cross-sectional study was carried out, in which a Survey of Patient Safety in Clinical Laboratories was addressed to workers in 26 participating laboratories. In this survey, which consisted of 45 items grouped into 6 areas, scores were assigned on a scale from 0 to 100 (where 0 is the lowest perception of patient safety). Laboratory managers were asked specific questions about quality management systems and technology. RESULTS: The mean scores for the 26 participating hospitals were evaluated, and the following results observed: in 4of the 6areas, the mean score was higher than 70 points. In the third area (equipment and resources) and the fourth area (working conditions), the scores were lower than 60 points. Every hospital had a digital medical record system. This 100% level of provision was followed by that of an electronic request management system, which was implemented in 82.6% of the hospitals. CONCLUSIONS: The results obtained show that the culture of security is homogeneous and of high quality in health service laboratories, probably due to the steady improvement observed. However, in terms of clinical governance, there is still some way to go, as shown by the presence of weaknesses in crucial dimensions of safety culture, together with variable levels of implementation of fail-safe technologies and quality management systems. PMID- 29126707 TI - Questioning the value of margin status in treated cervical precancer. PMID- 29126709 TI - Corrigendum to "Mapping the end-tidal CO2 response function in the resting-state BOLD fMRI signal: Spatial specificity, test-retest reliability and effect of fMRI sampling rate." PMID- 29126708 TI - Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis. AB - BACKGROUND: Incomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure. METHODS: We did a systematic review and meta analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta analysis of binomial data and analysed using random-effects models. FINDINGS: 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23.1% (95% CI 20.4-25.9) overall and varied by treatment procedure (ranging from 17.8% [12.9-23.2] for laser conisation to 25.9% [22.3-29.6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6.6% (95% CI 4.9-8.4) and was increased with positive compared with negative resection margins (relative risk 4.8, 95% CI 3.2-7.2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55.8% (95% CI 45.8-65.5) and 84.4% (79.5 88.4), respectively, for the margin status, and 91.0% (82.3-95.5) and 83.8% (77.7 88.7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0.8%, whereas this risk was 3.7% when margins were free. INTERPRETATION: The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than margin status. FUNDING: European Federation for Colposcopy and Institut national du Cancer (INCA). PMID- 29126710 TI - Immunologic, microbial, and epithelial interactions in atopic dermatitis. AB - OBJECTIVE: To provide an overview of studies contributing to the understanding of immunologic, microbial, and epithelial interactions in atopic dermatitis. DATA SOURCES: PubMed literature review (2000-2017) and meeting abstracts from recent international dermatology conferences. STUDY SELECTIONS: Articles discussing primarily human disease. RESULTS: Clinical studies showed that atopic dermatitis is a type 2 immune-centered disease with a systemic inflammatory component but with heterogeneous treatment responses. This suggests that other factors are likely involved in shaping the skin disease phenotype, including microbial dysbiosis and epidermal barrier dysfunction. CONCLUSION: Recent clinical investigation has significantly expanded our knowledge on disease pathogenesis in atopic dermatitis, and current and future clinical trials will most likely further help to elucidate this complex, heterogeneous skin disease. PMID- 29126711 TI - Home-based program of maintaining unresponsiveness in children with allergic reactions to larger amounts of peanuts. PMID- 29126712 TI - [First molecular characterization of two Algerian strains of Toxoplasma gondii isolated from two congenital toxoplasmosis case patients]. PMID- 29126713 TI - Turmeric (Curcuma longa): miRNAs and their regulating targets are involved in development and secondary metabolite pathways. AB - Turmeric has been used as a therapeutic herb over centuries in traditional medicinal systems due to the presence of several secondary metabolite compounds. microRNAs are known to regulate gene expression at the post-transcriptional level by transcriptional cleavage or translation repression. miRNAs have been demonstrated to play an active role in secondary metabolism regulation. The present work was focused on the identification of the miRNAs involved in the regulation of secondary metabolite and development process of turmeric. Eighteen miRNA families were identified for turmeric. Sixteen miRNA families were observed to regulate 238 target transcripts. LncRNAs targets of the putative miRNA candidates were also predicted. Our results indicated their role in binding, reproduction, stress, and other developmental processes. Gene annotation and pathway analysis illustrated the biological function of the targets regulated by the putative miRNAs. The miRNA-mediated gene regulatory network also revealed co regulated targets that were regulated by two or more miRNA families. miR156 and miR5015 were observed to be involved in rhizome development. miR5021 showed regulation for terpenoid backbone biosynthesis and isoquinoline alkaloid biosynthesis pathways. The flavonoid biosynthesis pathway was observed to be regulated by miR2919. The analysis revealed the probable involvement of three miRNAs (miR1168.2, miR156b and miR1858) in curcumin biosynthesis. Other miRNAs were found to be involved in the growth and developmental process of turmeric. Phylogenetic analysis of selective miRNAs was also performed. PMID- 29126715 TI - Reply, Letter to the Editor- Undergraduate nutrition education of health professionals in Greek medical, dentistry, pharmacy, nursing and midwifery departments. PMID- 29126714 TI - Testicular steroidogenic enzymes in the lizard Podarcis sicula during the spermatogenic cycle. AB - Steroidogenic Acute Regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-hydroxysteroid dehydrogenase (17beta-HSD), 5alpha-Reductase (5alpha-Red), P450 aromatase are key enzymes involved in steroidogenesis. Recently, we showed the expression and the localization of P450 aromatase in Podarcis sicula testis during the different phases of the reproductive cycle, showing its involvement in the control of steroidogenesis, particularly in 17beta estradiol synthesis. Now, we have investigated the presence and distribution of the other enzymes involved in steroidogenesis, i.e. StAR, 3beta-HSD, 17beta-HSD and 5alpha-Red, during three significant periods of the reproductive cycle: summer stasis (July-August), autumnal resumption (November) and reproductive period (May-June). We demonstrated for the first time that all these enzymes are always present in somatic cells (Leydig and Sertoli) and germ cells (spermatogonia, spermatocytes I and II, spermatids and spermatozoa) of Podarcis testis, mainly in spermatids and spermatozoa. The present results strongly suggest that in Podarcis testis both somatic and germ cells could be involved in local sex hormone synthesis and that 5alpha-Red and P450 could carry out a pivot role. PMID- 29126716 TI - Antitumor and antimetastatic effects of walnut oil in esophageal adenocarcinoma cells. AB - BACKGROUND: Walnuts contain many components including specific fatty acids, which could be active against cancer. Even though the anticarcinogenic effect of some of the individual fatty acids in walnut oil has been described, the effect of walnut oil itself on esophageal cancer cells hasn't yet been investigated. OBJECTIVE: We aimed to investigate whether walnut oil affects tumor growth and metastatic potential in esophageal cancer cells. METHODS: The human esophageal adenocarcinoma cell line, OE19, was treated with different doses of walnut oil and cell viability, apoptosis/necrosis and cell cycle analyses were performed using WST-1 assay and flow cytometry respectively. Adhesion, colony formation and wound healing assays were performed to assess the antimetastatic effects of walnut oil. NFkB expression was evaluated with western blot analysis. RESULTS: Walnut oil decreased the cell viability of esophageal cancer cells in a dose dependent manner. 20 mg/mL walnut oil reduced cell viability by ~50% when compared with control. The analysis revealed that necrosis and accumulation of cells in G0/G1 phase was induced in the cells treated with high doses of walnut oil. It also down-regulated the protein levels of NFkB. Walnut oil suppressed the adhesion, migration and colony formation of the cells. CONCLUSIONS: High-dose short-term administration of walnut oil reduces the cell viability and metastatic ability of esophageal cancer cells, while exhibiting anticarcinogenic effect by inducing necrosis and cell cycle arrest at the G0/G1 phase, probably through suppression of the NFkB pathway. These data indicate that walnut oil, and by extension walnut consumption, may have beneficial effects in esophageal cancer in humans. This should be tested by clinical trials in the future. PMID- 29126717 TI - 2013 ACR/EULAR systemic sclerosis classification criteria in patients with associated pulmonary arterial hypertension. AB - OBJECTIVE: To analyze the performance of the 1980 ACR and new 2013 ACR/EULAR criteria for systemic sclerosis (SSc) in cutaneous SSc (lcSSc) patients, especially those affected by lcSSc and pulmonary arterial hypertension (PAH). METHODS: All patients with a clinical lcSSc diagnosis from a prospective observational SSc cohort were included. Sociodemographic and disease-related variables were collected, and PAH confirmed by right heart catheterization (RHC). Performance of the 2013 and 1980 SSc criteria was analyzed in terms of clinical diagnosis. Descriptive and between-group analyses were performed as to the fulfillment of criterion sets, including comparison of survival. RESULTS: Overall, 321 patients were included, 63% of whom fulfilled the 1980 ACR and 93% the 2013 ACR/EULAR criteria. Agreement between both criteria sets proved poor (kappa = 0.23). LcSSC patients fulfilling both criterion sets were significantly younger at diagnosis, whilst presenting organ involvement, calcinosis, fingertip digital ulcers, and pitting scars more frequently than those who met the 2013 criteria only. Patients who fulfilled the 2013 but not the 1980 criteria presented a higher degree of ACA positivity and PAH. Nearly 12% of patients developed PAH. Patients who did not meet the 1980 criteria were affected by a milder disease from but demonstrated higher pulmonary vascular resistance and lower cardiac index than those fulfilling both criterion sets. Whereas patients with PAH met the 2013 criteria, only 47% fulfilled the 1980 criteria. Regardless of criterion set fulfillment, high mortality was observed in PAH patients, with no significant between-patient difference based on criterion set. CONCLUSION: The new 2013 ARC/EULAR criteria prove more accurate than the former 1980 ACR criteria in identifying and differentiating patients with lcSSc, especially those with associated PAH. Since PAH exhibits a better prognosis if treated early, all SSc patients should undergo PAH screening. PMID- 29126718 TI - Vitamin D and antiphospholipid syndrome: A retrospective cohort study and meta analysis. AB - OBJECTIVES: (a) To determine serum 25-OH vitamin D (vitD) levels in primary antiphospholipid syndrome (APS) and to compare them with patients with positive antiphospholipid serology who do not meet clinical criteria for APS, and with healthy controls. (b) To analyze the association of vitD levels with both the clinical manifestations and the immunological profile of patients with primary APS. (c) To perform a meta-analysis evaluating potential differences in serum vitD levels between APS and controls as well as the frequency of vitD deficiency in APS patients. METHODS: Retrospective study including 74 patients with primary APS, 54 with positive antiphospholipid (aPL) serology not meeting clinical criteria for APS, and 215 healthy controls. We considered 30 and 10ng/ml as the thresholds for vitD insufficiency and deficiency, respectively. Meta-analysis included four case-control studies (325 primary APS patients and 507 controls) and was conducted by fitting random effects models and checked for heterogeneity. RESULTS: Median serum vitD levels were similar in the three groups: 21ng/ml in primary APS, 25ng/ml in the aPL-positive group, and 21ng/ml in controls (p = 0.115). However, we found differences in the PTH levels, being 40.4 +/- 24.9pg/ml in APS, 34.1 +/- 18.2pg/ml in aPL serology, and 23.4 +/-12.6pg/ml in healthy controls (p < 0.001). Regarding vitD deficiency, we found significant differences across the groups: 16.2% in APS, 11.1% in patients with positive serology, and 3.7% in controls (p = 0.001). There was a trend for the presence of thrombotic events in patients with vitD deficiency (38.9% vs 19.1%, p = 0.071). The meta analysis confirmed that the combined mean difference in serum vitD levels between APS and controls was -3.605 (p < 0.001) and that APS patients had an increased frequency of vitD deficiency, with an OR = 3.06 (95% CI: 2.12-4.43, p < 0.001). CONCLUSIONS: APS patients show higher frequency of vitD deficiency than the healthy individuals. The meta-analysis study, including three cohorts and ours, suggests that APS patients have significantly lower serum vitD levels and higher frequency of vitD deficiency than controls. PMID- 29126719 TI - The effectiveness of school educating program for betel quid chewing: A pilot study in Papua New Guinea. AB - BACKGROUND: To investigate the effectiveness of educating program among primary and secondary school students in Papua New Guinea, where has the highest incidence of oral cancer all over the world. METHODS: A cross-sectional school based survey was arranged in primary and secondary school in Papua New Guinea in June, 2015. A self-administrated questionnaire was administered before and after education done by health experts from Taiwan. The subjects were chosen by random. The schools provided the students we educated and did the questionnaires on. RESULTS: Ninety five primary school students and 55 secondary school students in Papua New Guinea participated in the study. Before education, both groups lacked the knowledge that betel quid is harmful to health and had no motivation to quit betel quid consumption with the average score 4.580 out of the total score of 8 for primary school students, and the average score of 4.600 out of the total score of 8 for secondary school students. After education, improvements were noted in knowledge of betel quid among both groups, and reached the statistical significance for secondary school students (mean difference 0.700 +/- 0.277, 95% CI 0.164-1.248, p-value = 0.018). CONCLUSION: A great achievement was gained by a short time of education. To prevent the incidence and mortality of oral cancer in Papua New Guinea, education programs should be arranged aggressively and effectively. PMID- 29126720 TI - Stimulus, response and excitability - What is new? PMID- 29126721 TI - Synthesis, monoamine oxidase inhibition activity and molecular docking studies of novel 4-hydroxy-N'-[benzylidene or 1-phenylethylidene]-2-H/methyl/benzyl-1,2 benzothiazine-3-carbohydrazide 1,1-dioxides. AB - Three series of 4-hydroxy-N'-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl 1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9-11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4 hydroxy-N'-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1 dioxide (9i) with an IC50 value of 0.11 +/- 0.005 MUM, whereas, methyl 4-hydroxy 2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 +/- 0.01 MUM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability. PMID- 29126722 TI - Synthesis, beta-hematin inhibition studies and antimalarial evaluation of new dehydroxy isoquine derivatives against Plasmodium berghei: A promising antimalarial agent. AB - Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I and II clinical trials, respectively. Nevertheless, pharmacodynamic studies have demonstrated that isoquine is highly sensitive to form O-glucuronide metabolite, which may affect its accumulation in tissues. To avoid the O-glucuronide formation and its negative influence in the accumulation process, a series of novel five dehydroxy isoquine derivatives were designed and prepared herein as potential antimalarial agents. By a simple three-step procedure, five dehydroxy isoquines were prepared and subsequently examined on the inhibition of haemozoin formation, the main target of the 4-aminoquinolines. Four derivatives displayed significant inhibitory activities at low IC50 values from 1.66 to 1.86 MUM comparable to CQ. On the basis of the results, these four compounds were subsequently tested against Plasmodium berghei ANKA model in mice, showing to be as active as CQ with significant curative responses and parasitemia suppression in mice infected. On the other hand, these four compounds showed an acceptable non specific cytotoxicity on murine peritoneal macrophague and human erythrocyte cells. Thus, the presented data indicate that the dehydroxy isoquines 4b, 4c and 4e constitute promising cost-effective leads for the development of new antiplasmodial targeted at blood-stage malaria parasites. PMID- 29126723 TI - Design, synthesis, and evaluation of NDGA analogues as potential anti-ischemic stroke agents. AB - Exogenous supplementation of antioxidants with ROS scavenging activity would be a potential therapy to cerebral ischemia-reperfusion injury in stroke. In the present study, a series of NDGA analogues with attenuation oxidative stress by directly scavenging ROS and indirectly through keap1/Nrf2/ARE pathway activation were designed and synthesized. All analogues were found to effectively remove ROS directly by DPPH radical scavenging assay, and compound 3a conferred potent protection from the oxidative injury in PC12 cells via promoting Nrf2 to translocate into nucleus and increasing expression of heme oxygenase-1(HO-1), where strongly reduced intracellular ROS level indirectly. More importantly, 3a significantly reduced brain infarction after cerebral ischemia-reperfusion injury in rats subjected to transient middle cerebral artery occlusion (MCAO). Overall, our findings shown compound 3a could serve as a promising compound for the treatment of stroke. PMID- 29126724 TI - Dual or multi-targeting inhibitors: The next generation anticancer agents. AB - Dual-targeting/Multi-targeting of oncoproteins by a single drug molecule represents an efficient, logical and alternative approach to drug combinations. An increasing interest in this approach is indicated by a steady upsurge in the number of articles on targeting dual/multi proteins published in the last 5 years. Combining different inhibitors that destiny specific single target is the standard treatment for cancer. A new generation of dual or multi-targeting drugs is emerging, where a single chemical entity can act on multiple molecular targets. Dual/Multi-targeting agents are beneficial for solving limited efficiencies, poor safety and resistant profiles of an individual target. Designing dual/multi-target inhibitors with predefined biological profiles present a challenge. The latest advances in bioinformatic tools and the availability of detailed structural information of target proteins have shown a way of discovering multi-targeting molecules. This neoteric artifice that amalgamates the molecular docking of small molecules with protein-based common pharmacophore to design multi-targeting inhibitors is gaining great importance in anticancer drug discovery. Current review focus on the discoveries of dual targeting agents in cancer therapy using rational, computational, proteomic, bioinformatics and polypharmacological approach that enables the discovery and rational design of effective and safe multi-target anticancer agents. PMID- 29126725 TI - Conformationally rigid derivatives of WAY-267,464: Synthesis and pharmacology at the human oxytocin and vasopressin-1a receptors. AB - WAY-267,464 (1) and twelve conformationally rigid analogues (3a-f-4a-f) were synthesised, characterised and evaluated in cellular assays with the aim of systematically exploring interactions with the oxytocin receptor (OTR). Each analogue was evaluated in radioligand binding displacement assays at both human OTR and arginine vasopressin 1a receptors (V1aR). Physiological characterisation was determined by whole cell IP1 accumulation assays on stably transfected human embryonic kidney (HEK) cells. Incorporation of the rigid, optionally substituted benzene ring abolished OTR activity and diminished V1aR pharmacology when compared to 1. A general trend was observed in V1aR affinity for the propyl analogues (3d-3f) which identified the ortho-substituted analogue as the best in series (Ki = 251 nM) followed by a decrease in affinity through the meta and para derivatives (3e; Ki = 874 nM and 3f; Ki = 1756 nM respectively). This study confirms the importance of the central pharmacophoric motifs of WAY-267,464 and illuminates the differences in the binding pocket of the highly conserved OTR and V1aR. PMID- 29126726 TI - Exploration of 1,2,3-triazole-pyrimidine hybrids as potent reversal agents against ABCB1-mediated multidrug resistance. AB - ABCB1-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A series of pyrimidine-based hybrid molecules containing 1,2,3-triazole moiety were evaluated for their reversal activities against MDR. The majority of target compounds displayed moderate to great reversal potency. Among these compounds, compound 25 displayed the most potent reversal activity, about 7-fold more potent than Verapamil (VRP). Further mechanism studies revealed that compound 25 could obviously reverse paclitaxel (PTX) resistance in SW620/AD300 cells by increasing accumulation and extending maintenance of PTX. Our findings indicate that the 1,2,3-triazole-pyrimidine-based derivatives may serve as an interesting lead for the development of new potent and efficacious ABCB1-dependent MDR modulators. PMID- 29126727 TI - Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents. AB - New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19. PMID- 29126728 TI - Amphiphilic glycoconjugates as potential anti-cancer chemotherapeutics. AB - Amphiphilicity is one of the desirable features in the process of drug development which improves the biological as well as the pharmacokinetics profile of bioactive molecule. Carbohydrate moieties present in anti-cancer natural products and synthetic molecules influence the amphiphilicity and hence their bioactivity. This review focuses on natural and synthetic amphiphilic anti-cancer glycoconjugates. Different classes of molecules with varying degree of amphiphilicity are covered with discussions on their structure-activity relationship and mechanism of action. PMID- 29126729 TI - Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity. AB - A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing African sleeping sickness and malaria. The dicyanoindoles needed to synthesize the target diamidines were obtained through Stille coupling reactions while the bis-cyanobenzimidazoles intermediates were made via condensation/cyclization reactions of different aldehydes with 4-cyano-1,2 diaminobenzene. Different amidine synthesis methodologies namely, lithium bis trimethylsilylamide (LiN[Si(CH3)3]2) and Pinner methods were used to prepare the diamidines. Both types (indole and benzimidazole) derivatives of the new diamidines bind strongly with the DNA minor groove and generally show excellent in vitro antitrypanosomal activity. The diamidino-indole derivatives also showed excellent in vitro antimalarial activity while their benzimidazole counterparts were generally less active. Compound 7c was highly active in vivo and cured all mice infected with Trypanosoma brucei rhodesiense, a model that mimics the acute stage of African sleeping sickness, at a low dose of 4 * 5 mg/kg i.p. and hence 7c is more potent in vivo than pentamidine. PMID- 29126730 TI - Optimization of pharmacokinetic properties by modification of a carbazole-based cannabinoid receptor subtype 2 (CB2) ligand. AB - Recently, the development of the fluorinated PET tracer [18F]1a for imaging of CB2 receptors in the central nervous system was reported. [18F]1a showed high CB2 affinity and selectivity over the CB1 subtype, but rapid biotransformation in mice. In addition to the amide hydrolysis, oxidative N-dealkylation and carbazole oxidation were postulated as main metabolic pathways. Based on these results, novel carbazole derivatives with additional 6-substituents (23a, 24a), modified hydrogenation state (26a) and enlarged fluoroalkyl substituent (13a, 13b) were synthesized and pharmacologically evaluated. The key step in the synthesis of substituted carbazoles 23a, 24a and 26a was a Fischer indole synthesis. Nucleophilic substitution of tosylated lactate 5 by carbazole anion provided the fluoroisopropyl derivatives 13a and 13b. Partial hydrogenation of the aromatic carbazole system (26a) was not tolerated by the CB2 receptor. A methylsulfonyl moiety in 6-position (24a) led to considerably reduced CB2 affinity, whereas a 6 methoxy moiety (23a) was well tolerated. An additional methyl moiety in the fluoroethyl side chain of 1a resulted in fluoroisopropyl derivatives 13 with unchanged high CB2 affinity and CB2: CB1 selectivity. Compared with the fluoroethyl derivative 1a, the carbazole N-atom of the fluoroisopropyl derivative 13a (Ki(CB2) = 2.9 nM) is better shielded against the attack of CYP enzymes as formation of N-oxides was not observed and N-dealkylation took place to a less amount. PMID- 29126731 TI - Synthesis, antibacterial properties and 2D-QSAR studies of quinolone-triazole conjugates. AB - A set of 1,2,3-triazole incorporated quinolone antibiotic conjugates 10-15, 17-19 were synthesized via microwave assisted click chemistry technique. Some of the aryl-substituted conjugates 17-19 show promising antibacterial properties against the tested Gram-positive (S. aureus and S. pyogenes) and Gram-negative bacteria (S. typhi) with potency higher than that of the parent antibiotics 1-3. 2D-QSAR modeling supports the observed biological properties. PMID- 29126732 TI - 2-Arylbenzofurans from Artocarpus lakoocha and methyl ether analogs with potent cholinesterase inhibitory activity. AB - In vitro screening for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of the Artocarpus lakoocha root-bark extracts revealed interesting results. Bioassay-guided fractionation resulted in the isolation of two new (1 and 2) and six known 2-arylbenzofurans 3-8, along with one stilbenoid 9 and one flavonoid 10. The structures of the isolated compounds were elucidated by UV, IR, 1D- and 2D-NMR and MS spectroscopic data analysis. Compounds 4, 6 and 7 exhibited more potent AChE inhibitory activity (IC50 = 0.87 1.10 MUM) than the reference drug, galantamine. Compounds 4, 8 and 9 displayed greater BChE inhibition than the standard drug. The preferential inhibition of BChE over AChE indicated that 4 also showed a promising dual AChE and BChE inhibitor. The synthetic mono-methylated analogs 4a-c and 6a-b were found to be good BChE inhibitors with IC50 values ranging between 0.31 and 1.11 MUM. Based on the docking studies, compounds 4 and 6 are well-fitted in the catalytic triad of AChE. Compounds 4 and 6 showed different binding orientations on BChE, and the most potent BChE inhibitor 4 occupied dual binding to both CAS and PAS more efficiently. PMID- 29126734 TI - A chiral template-driven synthesis of a 3'-deoxy-3'-18F-fluorothymidine precursor. AB - An asymmetric synthesis of a 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) precursor has been developed wherein the deoxysugar moiety was synthesized using a novel Ga mediated allylation of (R)-2,3-cyclohexylideneglyceraldehyde as the key step. The synthesis deviates significantly from the previous syntheses of the 18F-FLT precursors wherein the expensive starting material, thymidine was used. PMID- 29126733 TI - Allicin-inspired pyridyl disulfides as antimicrobial agents for multidrug resistant Staphylococcus aureus. AB - A chemical library comprised of nineteen synthesized pyridyl disulfides that emulate the chemical reactivity of allicin (garlic) was evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus (VISA, VRSA) demonstrated the highest level of susceptibility toward analogs with S-alkyl chains of 7-9 carbons in length. Further biological studies revealed that the disulfides display synergy with vancomycin against VRSA, cause dispersal of S. aureus biofilms, exhibit low cytotoxicity, and decelerate S. aureus metabolism. In final analysis, pyridyl disulfides represent a novel class of mechanism-based antibacterial agents that have a potential application as antibiotic adjuvants in combination therapy of S. aureus infections with reduced vancomycin susceptibility. PMID- 29126735 TI - Design, synthesis and evaluation of amino-substituted 1H-phenalen-1-ones as anti leishmanial agents. AB - Screening of a designed collection of mono-substituted amino-1H-phenalen-1-ones against promastigote forms of L. donovani and L. amazonensis, identified seven compounds with anti-leishmanial activities comparable or better than the commonly prescribed anti-leishmanial drug, miltefosine. Structure-activity analysis revealed that appendages containing a basic tertiary nitrogen were favored, and that the position of the appendage also affected their potency. Like miltefosine, several of these active compounds significantly reduced the mitochondrial membrane potential in promastigotes. Further studies in amastigotes of L. amazonensis revealed that compounds 14, 15 and 33 were more active and more selective than miltefosine, with sub-micromolar potencies and selectivity indices >100. PMID- 29126736 TI - Synthesis and bioactivities study of new antibacterial peptide mimics: The dialkyl cationic amphiphiles. AB - The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 MUg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains. PMID- 29126737 TI - Synthesis and in vitro biological evaluation of three 4'-(4-methoxyphenyl) 2,2':6',2"-terpyridine iridium(III) complexes as new telomerase inhibitors. AB - There iridium(III) complexes, [Ir(3-MeO-Phtpy)Cl3] (1), [Ir(2-MeO-Phtpy)Cl3] (2) and [Ir(4-MeO-Phtpy)Cl3] (3) with 4'-(3-methoxyphenyl)-2,2':6',2"-terpyridine (3 MeO-Phtpy), 4'-(2-methoxyphenyl)-2,2':6',2"-terpyridine (2-MeO-Phtpy) and 4'-(4 methoxyphenyl)-2,2':6',2"-terpyridine (4-MeO-Phtpy) as ligands, respectively, were synthesized and evaluated for their antiproliferative activities. In these complexes, the iridium(III) center adopts a six-coordinate distorted octahedral geometry. Among them, complex 1 exhibited the most potent activity, with IC50 values of 3.19-27.77 MUM against four cancer cell lines (BEL-7404, Hep-G2, NCI H460 and MGC80-3 cells). Cellular mechanism studies suggested that complexes 1-3 directly targeted c-myc promoter elements and inhibited the telomerase activity. In addition, complexes 1-3 may trigger cell apoptosis via a mitochondrial dysfunction pathway. We postulated that the difference in the in vitro antitumor activities of complexes 1-3 is mainly dependent on the position of the methoxy group on the phenyl ring of the iridium ligand. PMID- 29126738 TI - Biphenylthiazole antibiotics with an oxadiazole linker: An approach to improve physicochemical properties and oral bioavailability. AB - A new series of oxadiazolylbiphenylthiazoles was prepared with the objective of improving the limited solubility of first-generation derivatives while maintaining antibacterial activity against drug-resistant Staphylococcus aureus. Studying the structure-activity relationship at the cationic part provided the piperazine-1-carboximidamide derivative 27 with a MIC (MRSA) value of 1.1 MUg/mL, bactericidal mode of action, and a 50-fold improvement in aqueous solubility. Additionally, 27 exhibited a wider safety margin against mammalian cells, and most importantly, a significant improvement in oral bioavailability. PMID- 29126739 TI - Discovery of simplified sampangine derivatives as novel fungal biofilm inhibitors. AB - Lack of novel antifungal agents and severe drug resistance have led to high incidence and associated mortality of invasive fungal infections. To tackle the challenges, novel antifungal agents with new chemotype, fungicidal activity and anti-resistant potency are highly desirable. On the basis of our previously identified simplified analogue of antifungal natural product sampangine, systemic structure-activity relationships were clarified and two novel derivatives showed promising features as novel antifungal lead compounds. Compounds 22b and 22c showed good fungicidal activity against both fluconazole-sensitive and fluconazole-resistant Candida albicans strains. Moreover, they were proven to be potent inhibitors of Candida albicans biofilm formation and yeast-to-hypha morphological transition by down-regulating biofilm-associated genes. In a rat vaginal Candida albicans infection model, compounds 22b and 22c showed excellent therapeutic effects with low toxicity. The results highlighted the potential of sampangine derivatives to overcome fluconazole-related and biofilm-related drug resistance. PMID- 29126740 TI - Platelet storage lesion in interim platelet unit concentrates: A comparison with buffy-coat and apheresis concentrates. AB - Platelet storage lesion is characterized by morphological changes and impaired platelet function. The collection method and storage medium may influence the magnitude of the storage lesion. The aim of this study was to compare the newly introduced interim platelet unit (IPU) platelet concentrates (PCs) (additive solution SSP+, 40% residual plasma content) with the more established buffy-coat PCs (SSP, 20% residual plasma content) and apheresis PCs (autologous plasma) in terms of platelet storage lesions. Thirty PCs (n=10 for each type) were assessed by measuring metabolic parameters (lactate, glucose, and pH), platelet activation markers, and in vitro platelet aggregability on days 1, 4, and 7 after donation. The expression of platelet activation markers CD62p (P-selectin), CD63 (LAMP-3), and phosphatidylserine was measured using flow cytometry and in vitro aggregability was measured with multiple electrode aggregometry. Higher platelet activation and lower in vitro aggregability was observed in IPU than in buffy coat PCs on day 1 after donation. In contrast, metabolic parameters, expression of platelet activation markers, and in vitro aggregability were better maintained in IPU than in buffy-coat PCs at the end of the storage period. Compared to apheresis PCs, IPU PCs had higher expression of activation markers and lower in vitro aggregability throughout storage. In conclusion, the results indicate that there are significant differences in platelet storage lesions between IPU, buffy coat, and apheresis PCs. The quality of IPU PCs appears to be at least comparable to buffy-coat preparations. Further studies are required to distinguish the effect of the preparation methods from storage conditions. PMID- 29126741 TI - Design, synthesis, and biological evaluation of hydantoin bridged analogues of combretastatin A-4 as potential anticancer agents. AB - A series of novel hydantoin-bridged analogues of combretastatin A-4 (CA-4) were designed, synthesized and evaluated for antiproliferative activities in vitro and in vivo. The most potent compound 8d, showed potent cytotoxicity against four human cancer cell lines with IC50 values of 0.186-0.279 MUM, and possessed the efficacy of inhibiting tubulin polymerization, disrupting in vitro vascularization, blocking cell cycle in G2/M phase and inducing cell apoptosis. In the nude mice xenograft model, 8d significantly inhibited the tumor growth and showed low toxicity. Further chiral separation proved (R)-(-)-8d to be the preferential enantiomer with IC50 values of 0.081-0.157 M. These results indicated that the hydantoin derivatives merit further investigation as potential anticancer agents that inhibit tubulin polymerization. PMID- 29126742 TI - Ionic liquid mediated stereoselective synthesis of alanine linked hybrid quinazoline-4(3H)-one derivatives perturbing the malarial reductase activity in folate pathway. AB - Grimmel's method was optimized as well as modified leading to the cyclization and incorporation of alanine linked sulphonamide in 4-quinazolin-(3H)-ones. Further, the generation of heterocyclic motif at position-3 of 4-quinazolinones was explored by synthesis of imines, which unfortunately led to an isomeric mixture of stereoisomers. The hurdle of diastereomers encountered on the path was eminently rectified by development of new rapid and reproducible methodology involving the use of imidazolium based ionic liquid as solvents as well as catalyst for cyclization as well as synthesis of imines in situ at position-3 leading to procurement of single E-isomer as the target hybrid heterocyclic molecules. The purity and presence of single isomer was also confirmed by HPLC and spectroscopic techniques. Further, the synthesized sulphonamide linked 4 quinazolin-(3H)-ones hybrids were screened for their antimalarial potency rendering potent entities (4b, 4c, 4 l, 4 t and 4u). The active hybrids were progressively screened for enzyme inhibitory efficacy against presumed receptor Pf-DHFR and h-DHFR computationally as well as in vitro, proving their potency as dihydrofolate reductase inhibitors. The ADME properties of these active molecules were also predicted to enhance the knowhow of the oral bioavailability, indicating good bioavailability of the active entities. PMID- 29126743 TI - Benign and malignant pathology of the uterus. AB - The diagnosis of a uterine myoma size and location can be very precise when a 3D sonograph and knowledge are available. The majority of fibroids are asymptomatic, and expectant management is recommended. In young patients, fibroids cause infertility and in middle-aged women, abnormal uterine bleedings. Laparoscopic myomectomy is the preferred way of surgery for IM and SS fibroids, versus hysteroscopy for SM fibroids. In both cases, the size, number of fibroids and the surgeon's experience determine the limitations of the MIGS. Medical treatments provide only temporary tumor reduction and symptom alleviation. Leiomyosarcoma risk is higher in older women usually carrying fibroids larger than 8 cm. There are no other pathognomonic parameters ruling out a sarcoma. In case of suspected fibroid malignancy, the best treatment option is laparotomy and total hysterectomy. Myomectomy complications can be reduced when MIGS is performed by a surgeon with proper training and experience. PMID- 29126744 TI - Regulation of Salmonella-host cell interactions via the ubiquitin system. AB - Salmonella infections cause acute intestinal inflammatory responses through the action of bacterial effector proteins secreted into the host cytosol. These proteins promote Salmonella survival, amongst others, by deregulating the host innate immune system and interfering with host cell ubiquitylation signaling. This review describes the recent findings of dynamic changes of the host ubiquitinome during pathogen infection, how bacterial effector proteins modulate the host ubiquitin system and how the host innate immune system counteracts Salmonella invasion by using these pathogens as signaling platforms to initiate immune responses. PMID- 29126745 TI - Xenophagic pathways and their bacterial subversion in cellular self-defense - pialphanutaualpha rhoepsiloniota - everything is in flux. AB - Autophagy is an evolutionarily ancient and highly conserved eukaryotic mechanism that targets cytoplasmic material for degradation. Autophagic flux involves the formation of autophagosomes and their degradation by lysosomes. The process plays a crucial role in maintaining cellular homeostasis and responds to various environmental conditions. While autophagy had previously been thought to be a non selective process, it is now clear that it can also selectively target cellular organelles, such as mitochondria (referred to as mitophagy) and/or invading pathogens (referred to as xenophagy). Selective autophagy is characterized by specific substrate recognition and requires distinct cellular adaptor proteins. Here we review xenophagic mechanisms involved in the recognition and autolysosomal or autophagolysosomal degradation of different intracellular bacteria. In this context, we also discuss a recently discovered cellular self defense pathway, termed mito-xenophagy, which occurs during bacterial infection of dendritic cells and depends on a TNF-alpha-mediated metabolic switch from oxidative phosphorylation to glycolysis. PMID- 29126746 TI - The efficacy of attentional distraction and sensory monitoring in chronic pain patients: A meta-analysis. AB - Attentional strategies, such as distraction and sensory monitoring, are often offered to reduce pain and pain-related distress. However, evidence for their efficacy in chronic pain patients is equivocal. We report a meta-analysis on the efficacy of distraction and sensory monitoring in chronic pain patients, and explore possible methodological and theoretical moderators. The scientific literature was searched for relevant articles, which were coded for methodological quality and several theoretical and methodological moderator variables. Only 10 articles fulfilled the search criteria. Eight studies allowed us to compare distraction with a control condition, two studies to compare sensory monitoring with a control condition, and four studies to compare the effect of distraction with the effect of sensory monitoring. Overall, results indicate that distraction did not differ from control in altering pain experience (k=8; Hedges' g=0.10, ns) and distress (k=2; Hedges' g=0.549). Sensory monitoring did also not alter pain experience (k=2; Hedges' g=-0.21, ns) and distress (k=1; Hedges' g=-0.191, ns). We found no evidence to support the superiority of distraction or sensory monitoring in altering pain compared to control conditions. We offer guidance for future theory-driven research to investigate distraction and sensory monitoring in this largely unexplored field, albeit one replete with methodological difficulties. PMID- 29126748 TI - [Erratum to the abstracts of the scientific communications presented at the 21st Congres de pneumologie de langue francaise. January 27-29, 2017, Marseille (France)]. PMID- 29126747 TI - Mindfulness-based interventions for psychiatric disorders: A systematic review and meta-analysis. AB - Despite widespread scientific and popular interest in mindfulness-based interventions, questions regarding the empirical status of these treatments remain. We sought to examine the efficacy of mindfulness-based interventions for clinical populations on disorder-specific symptoms. To address the question of relative efficacy, we coded the strength of the comparison group into five categories: no treatment, minimal treatment, non-specific active control, specific active control, and evidence-based treatment. A total of 142 non overlapping samples and 12,005 participants were included. At post-treatment, mindfulness-based interventions were superior to no treatment (d=0.55), minimal treatment (d=0.37), non-specific active controls (d=0.35), and specific active controls (d=0.23). Mindfulness conditions did not differ from evidence-based treatments (d=-0.004). At follow-up, mindfulness-based interventions were superior to no treatment conditions (d=0.50), non-specific active controls (d=0.52), and specific active controls (d=0.29). Mindfulness conditions did not differ from minimal treatment conditions (d=0.38) and evidence-based treatments (d=0.09). Effects on specific disorder subgroups showed the most consistent evidence in support of mindfulness for depression, pain conditions, smoking, and addictive disorders. Results support the notion that mindfulness-based interventions hold promise as evidence-based treatments. PMID- 29126749 TI - Corrigendum to "Efficacy of E2 glycoprotein fused to porcine CD154 as a novel chimeric subunit vaccine to prevent classical swine fever virus vertical transmission in pregnant sows". AB - Here we evaluated the effect of double vaccination with a novel subunit marker vaccine candidate based in the CSFV E2 glycoprotein fused to the porcine CD154 to prevent CSFV vertical transmission. A lentivirus-based gene delivery system was used to obtain a stable recombinant HEK 293 cell line for the expression of E2 fused to porcine CD154 molecule. Six pregnant sows were distributed in two groups and at 64days of gestation animals numbered 1-4 (group 1) were vaccinated via intramuscular inoculation with 50MUg of E2-CD154 subunit vaccine. Animals from group 2 (numbered 5 and 6, control animals) were injected with PBS. Seventeen days later sows from group 1 were boosted with the same vaccine dose. Twenty seven days after the first immunization, the sows were challenged with a virulent CSFV Margarita strain and clinical signs were registered. Samples were collected during the experiment and at necropsy to evaluate immune response and virological protection. Between 14 and 18days after challenge, the sows were euthanized, the foetuses were obtained and samples of sera and tissues were collected. E2-CD154 vaccinated animals remained clinically healthy until the end of the study; also, no adverse reaction was shown after vaccination. An effective boost effect in the neutralizing antibody response after the second immunization and viral challenge was observed and supports the virological protection detected in these animals after vaccination. Protection against CSFV vertical transmission was found in the 100% of serums samples from foetus of vaccinated sows. Only two out of 208 samples (0.96%) were positive with Ct value about 36 corresponding to one tonsil and one thymus, which may be non-infective viral particles. Besides, its DIVA potential and protection from vertical transmission, the novel CSFV E2 bound to CD154 subunit vaccine, is a promising alternative to the live-attenuated vaccine for developing countries. PMID- 29126750 TI - Hidden Secrets of Sigma54 Promoters Revealed. AB - Bacterial sigma54 (sigma54) promoters are the DNA-binding motif for sigma54 containing RNA polymerase (RNAP) holoenzymes. A recent study using a combination of synthetic oligonucleotide library screening, biochemical characterization, and bioinformatics has uncovered a new and unexpected role for sigma54 promoters, encoding a form of bacterial 'insulator sequence' to dampen unwanted translation. PMID- 29126751 TI - Shift to community-onset Clostridium difficile infection in the national Veterans Health Administration, 2003-2014. AB - BACKGROUND: Clostridium difficile infection (CDI) occurs frequently in inpatient settings; however, community-onset cases have been reported more frequently in recent years. This study evaluated hospital-onset and community-onset CDI in the national Veterans Health Administration (VHA) population over a 12-year period. METHODS: This was a retrospective cohort study of all adult VHA beneficiaries with CDI between October 1, 2002, and September 30, 2014. Data were obtained from the Veterans Affairs Informatics and Computing Infrastructure. CDI was categorized into community-associated CDI (CA-CDI); community-onset, health care facility-associated CDI; and health care facility-onset CDI (HCFO-CDI). Each type was described longitudinally and was assessed as an independent risk factor for health outcomes using multivariable logistic regression. RESULTS: Overall, 30,326 patients with a first CDI episode were included. HCFO-CDI was the predominant type (60.2%), followed by CO-HCFA-CDI (20.6%) and CA-CDI (19.2%). The proportion of patients with HCFO-CDI decreased from 73.5% during fiscal year 2003 to 53.2% during fiscal year 2014, whereas CA-CDI increased from 8.3% to 26.7%. HCFO-CDI was a positive predictor of severe CDI (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.59-1.84) and 30-day mortality (OR, 1.46; 95% CI, 1.32-1.61), but a negative predictor of 60-day recurrence (OR, 0.41; 95% CI, 0.37-0.46). CONCLUSIONS: HCFO-CDI was the predominant CDI type. The proportion of patients with CA-CDI increased and HCFO-CDI decreased in recent years. Patients with HCFO CDI experienced higher rates of severe CDI and mortality. PMID- 29126752 TI - Statement and Recommendations on Interventional Ultrasound as a Thyroid Diagnostic and Treatment Procedure. AB - The recently published guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) on interventional ultrasound (INVUS) guided procedures summarize the intended interdisciplinary and multiprofessional approach. Herewith, we report on recommendations for interventional procedures for diagnosis and treatment of the thyroid gland. PMID- 29126753 TI - Usefulness of Contrast-Enhanced Ultrasound in Differentiating Inflammatory Bowel Disease From Colon Cancer. AB - To evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in differential diagnosis of inflammatory bowel disease (IBD) and colon cancer, we enrolled 51 patients with thickened bowel walls (13 with IBD and 38 with colon cancer). Ultrasound and CEUS were performed and both qualitative and quantitative features were analyzed. The intestinal wall stratification was preserved in 63.6% of the IBD group but in only 2.6% of the colon cancer group (p <0.01). On CEUS, disordered enhancement and heterogeneous enhancement were shown in only 9.1% and 0%, respectively, of the IBD group while in 94.7% and 78.9%, respectively, of the colon cancer group (p <0.01). For quantitative analysis, compared to IBD, colon cancer showed later enhancement and slower wash-out with less speed to reach peak intensity (p <0.05). In conclusion, CEUS may prove useful for the differential diagnosis of IBD and colon cancer, but more studies are required. PMID- 29126754 TI - Effect of Pulsed Therapeutic Ultrasound and Diosmin on Skeletal Muscle Oxidative Parameters. AB - Cyclodextrins (CDs) have been widely used as a promising alternative in the formation of inclusion complexes with poorly soluble molecules. From this perspective, the present study aimed to study the inclusion complexes of diosmin in beta-cyclodextrin, chemically quantify the diosmin-in-gel preparation and analyze the stability of the gels. Furthermore, we evaluated the effect of therapeutic pulsed ultrasound (TPU) in association with the gel-diosmin complex on the parameters of muscle damage and oxidative stress in rats. Serum creatine kinase (CK) levels were used as an indicator of skeletal muscle injury. Lipid peroxidation (thiobarbituric acid-reactive substances [TBARS]) and superoxide dismutase and catalase activities were used as indicators of oxidative stress. The results obtained indicated that the inclusion complex obtained by co evaporation had the highest complexation efficiency and stability; there was no change in the features of diosmin on incorporation into the Carbopol gel. Additionally, a significant (p <0.05) decrease was observed in CK levels (TPU plus gel-diosmin: 178.4 +/- 85.3 U/L) relative to the untreated group (527.8 +/- 46.1 U/L). Levels of TBARS were lower in the TPU plus gel-diosmin group (0.008 +/ 0.0004 nmol malondialdehyde/mg protein, p <0.05) compared with the untreated group (0.081 +/- 0.011 nmol malondialdehyde/mg protein, p <0.05, n = 6). Catalase activity did not statistically significantly differ between the treatment groups, and superoxide dismutase activity was lower in the diosmin-treated group (0.320 +/- 0.11 U/mg protein) compared with the untreated group (0.983 +/- 0.40 U/mg protein). These results suggest that TPU in association with the diosmin-gel complex is effective in reducing muscle damage and oxidative stress after mechanical trauma. PMID- 29126755 TI - [Cannabis and lung. What we know and everything we don't know yet]. AB - Cannabis use increased sharply from 2010 to 2014 in France. Cannabis is often consumed with tobacco, although the use of marijuana is developing. Tobacco and cannabis smoke have many common characteristics in terms of irritants, carcinogens and carbon monoxide. They also differentiate by their dependence mechanisms, with nicotine and its receptors for tobacco and tetra-hydro cannabinol (THC) and its specific receptors for cannabis. Chronic inhalation (700,000 daily users in France) over a long period most likely increases the relative risk of bronchial cancer. But long-term cohort studies targeting this group of strong cannabis users, especially over time, are lacking. Inhalation of cannabis smoke, despite an acute bronchodilator effect, is associated with the risk of chronic bronchitis in the case of regular use. However, the risk of developing COPD in the exclusive marijuana smoker group with no associated tobacco is not yet clear, with studies yielding discordant results. There is also a lack of long-term follow-up studies of respiratory investigations in large cannabis users. Finally, cannabis smoke contains various cannabinoids, for example cannabidiol which also have anti-inflammatory and antifibrotic properties, with the unconfirmed hypothesis that these properties can partially modulate the deleterious action of cannabis smoke. PMID- 29126756 TI - [Vascular dysfunction in obstructive sleep apnoea: Implication of microparticules]. AB - Obstructive sleep apnea (OSA) is associated with increased cardiovascular diseases, including myocardial infarction and stroke and promotes cardiovascular risk factors including diabetes and hypertension. OSA has also been proposed to have a direct proatherogenic effects. Recent studies have investigated the role of microparticles (MPs) in the atherogenic process. MPs are small plasma membrane vesicles that can be released by a variety of vascular or blood cells and that contain membrane and cytosolic elements. Case-control studies have suggested that OSA is associated with an increase in circulating platelet-, endothelial- and leukocyte-derived MPs. MPs from OSA patients injected to mice have also been shown to induce vascular inflammation and endothelial dysfunction. In this article, we provide an overview of the main characteristics of MPs expressed in OSA and their potential role in the atherogenic process. PMID- 29126757 TI - Quantifying the Rate of Ellipsoid Zone Loss in Stargardt Disease. AB - PURPOSE: To determine a reliable method of using the ellipsoid zone (EZ) on optical coherence tomography (OCT) to track disease progression in Stardgardt disease (STGD). DESIGN: Retrospective reliability study. METHODS: STGD patients with genetically confirmed ABCA4 gene mutations seen at the Wilmer Eye Institute with follow-up visits separated by at least 12 months were identified. Spectral domain optical coherence tomography (SD-OCT) macula volume scans centered at the fovea and fundus autofluorescence (FAF) images were obtained. The area of EZ loss was calculated from the SD-OCT and the area of retinal pigment epithelium (RPE) loss from the FAF. Scans were reanalyzed by the primary grader to assess intragrader reliability, and reanalyzed by a second grader to assess intergrader reliability. RESULTS: Sixteen STGD patients (total of 31 eyes) were followed for a mean of 2 years (range 1-4.7 years). The mean rate of EZ loss, 0.31 +/- 0.31 mm2/year, was similar to the average rate of RPE loss, 0.33 +/- 0.38 mm2/year. The average area of EZ loss at the initial examination, 4.18 +/- 1.91 mm2, was larger than the initial area of RPE loss, 2.25 +/- 1.66 mm2 (P < .01). The absolute difference of the area of EZ loss on test-retest for the first grader was 0.12 +/- 0.10 mm2, and between graders 0.21 +/- 0.21 mm2. The intraclass correlation (ICC) of both intragrader and intergrader reliability for EZ loss was excellent at 0.99. CONCLUSIONS: Tracking the area of EZ loss on SD-OCT macular volume scans longitudinally is a reliable way of monitoring disease progression in STGD. This could be used as a sensitive anatomic outcome measure in clinical trials related to STGD. PMID- 29126758 TI - Maspin expression and subcellular localization in invasive ductal carcinoma of the breast: Prognostic significance and relation to microvessel density. AB - Maspin (Mammary serine protease inhibitor) is a tumor suppressor serine. Its clinical significance and role in breast carcinoma are contradictory and inconclusive. Researches demonstrated that the function of maspin differs according to its subcellular localization. This study was conducted to investigate the expression of maspin in invasive ductal carcinoma (IDC) of the breast with special emphasis on its subcellular localization and to evaluate its prognostic role in relation to clinicopathological parameters and microvessel density (MVD) of the tumor. The expression of maspin was evaluated immunohistochemically in 45 IDC cases. The positive rate of maspin expression was 73.3%. Maspin positivity was significantly related to higher tumor grade (p value = 0.041), nodal metastasis (p value = 0.044), perineural invasion (p value = 0.047), and high CD34+MVD (p value = 0.002). Nuclear maspin was detected in 36.6% whereas cytoplasmic maspin was detected in 63.4% of maspin positive cases. A significant inverse relationship was observed between nuclear maspin and high tumor grade (p value = 0.016), and nodal metastasis (p value = 0.047). These results suggest that maspin expression has a prognostic role in breast cancer. Maspin expression is related to increased angiogenesis. Subcellular localization of maspin can strongly affect cancer prognosis. Cytoplasmic maspin relates to poor prognostic parameters whereas nuclear maspin relates to good prognostic ones. PMID- 29126759 TI - Malnutrition Increases the Incidence of Death, Cardiovascular Events, and Infections in Patients with Stroke after Rehabilitation. AB - BACKGROUND: Although the impact of malnutrition in patients with acute stroke has been reported, its significance after rehabilitation is not well understood. The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional screening tool that predicts poor prognosis in elderly patients and in those with a high risk of cardiovascular events. We investigated the associations between GNRI and all-cause mortality, cardiovascular events, and infectious diseases in patients with stroke after rehabilitation. METHODS: This study included 138 patients aged 80 years or below who were discharged between 2010 and 2013 in a single center, and followed up for more than 1 year. Malnutrition was defined as a GNRI of 96 or lower. RESULTS: The mean age was 63.9 +/- 11.0 years, the mean GNRI at discharge was 98.8 +/- 6.5, and the mean total functional independence measure (FIM) score at discharge was 91.8 +/- 25.8. Among the patients, 37 (27%) had malnutrition. During the follow-up period, all-cause mortality, cardiovascular events, and infectious diseases were recorded in 11 (8%), 21 (15%), and 20 (15%) patients, respectively. Kaplan-Meier curves showed a significantly higher incidence of each outcome in patients with a GNRI of 96 or lower. In the Cox proportional analysis, GNRI was an independent determinant of all-cause mortality (hazard ratio [HR], .71; 95% confidence interval [CI], .61 .83), cardiovascular events (HR, .87; 95% CI, .80-.95), and infectious diseases (HR, .80; 95% CI, .74-.87) after adjusting for age, gender, and total FIM score. CONCLUSIONS: Malnutrition has a negative impact on prognosis in patients with stroke even after rehabilitation. PMID- 29126760 TI - Nuances in component nasal hump reduction. AB - IMPORTANCE: Nasal hump reduction is a frequent manoeuvre in rhinoplasty. Over the last years, composite hump reduction has been advocated in favour of component hump reduction. The latter allows a more controlled and stepwise approach in reducing the nasal dorsum by deprojecting the cartilaginous dorsum separately from the bony dorsum. This approach also preserves the upper lateral cartilages (ULCs) and their mucosa. OBJECTIVE: To analyse the intricacies of the anatomic transition zone between the ULCs, the rhinion and the nasal bones as they pertain to component hump reduction. METHOD: Anatomical dissections with five fresh cadaveric heads were performed in this study. The cephalic extension of the ULCs beneath the nasal bones was modified and measured after component hump reduction on both sides of the rhinion. RESULTS: Central detachment of the ULCs from the bony dorsum and their release from the medial undersurface of the nasal bones allows for complete preservation of the ULCs. This is achieved by inferior-medial rotation of the cephalic ends of the ULCs against the septum. If not released completely during hump reduction, a substantial loss of the ULCs may be the consequence. CONCLUSIONS: The described manoeuvre allows the preservation of the cephalic components of the ULCs underneath the bony dorsum during component hump reduction. The result is a smoother transition line at the keystone area and along the entire bony-cartilaginous dorsum with a straighter aesthetic dorsal profile and oblique view. The present findings allowed us to present an operative algorithm with implementation into clinical practice. PMID- 29126761 TI - MR planimetry in neurodegenerative parkinsonism yields high diagnostic accuracy for PSP. AB - INTRODUCTION: Several previous studies examined different brainstem-derived MR planimetric measures with regards to their diagnostic accuracy in separating patients with neurodegenerative parkinsonian disorders and reported conflicting results. The current study aimed to compare their performance in a well characterized sample of patients with neurodegenerative parkinsonian disorders. METHODS: MR planimetric measurements were assessed in a large retrospective cohort of 55 progressive supranuclear palsy (PSP), 194 Parkinson's disease (PD) and 63 multiple system atrophy (MSA) patients. This cohort served as a training set used to build C4.5 decision tree models to discriminate PSP, PD and MSA. The models were validated in two independent test sets. The first test set comprised 84 patients with early, clinically unclassifiable parkinsonism (CUP). A prospective cohort of patients with PSP (n = 23), PD (n = 40) and MSA (n = 22) was exploited as a second test-set. RESULTS: The pons-to-midbrain diameter ratio, the midbrain diameter, the middle cerebellar peduncle width and the pons area were identified as the most predictive parameters to separate PSP, MSA and PD in C4.5 decision tree models derived from the training set. Using these decision models, AUCs in discriminating PSP, MSA and PD were 0.90, 0.57 and 0.73 in the CUP-cohort and 0.95, 0.61 and 0.87 in the prospective cohort, respectively. CONCLUSION: We were able to demonstrate that brainstem-derived MR planimetric measures yield high diagnostic accuracy for the discrimination of PSP from related disorders when decision tree algorithms are applied, even at early, clinically uncertain stages. However, their diagnostic accuracy in discriminating PD and MSA was suboptimal. PMID- 29126762 TI - Association between abnormal nocturnal blood pressure profile and dementia in Parkinson's disease. AB - BACKGROUND: Circadian blood pressure alterations are frequently observed in Parkinson's disease, but the association between these changes and dementia in the condition remains unclear. Here, we assess the relationship between abnormal nocturnal blood pressure profiles and dementia in Parkinson's disease. METHODS: We enrolled 137 patients with Parkinson's disease, who underwent 24 h ambulatory blood pressure monitoring, following cognitive and clinical assessment. RESULTS: Twenty-seven patients (19.7%) were diagnosed with dementia in this cohort. We observed significant associations of dementia with age, male gender, Hoehn-Yahr (H-Y) stage, diabetes mellitus, history of stroke, presence of cerebrovascular lesions on MRI, and orthostatic hypotension. Univariate logistic regression analysis showed that among the patterns of nocturnal blood pressure profiles, the riser pattern was significantly associated with dementia (OR 11.6, 95%CI: 2.14 215.0, P < 0.01), and this trend was observed after adjusting for all confounding factors except orthostatic hypotension (OR 19.2, 95%CI: 1.12-1960.3, P = 0.04). However, coexistence of a riser pattern and orthostatic hypotension was related to a higher prevalence of dementia (45.2%) than was a riser pattern alone (9.5%). Furthermore, coexistence of a riser pattern and orthostatic hypotension was significantly more associated with dementia than was a riser pattern alone, even after adjusting for confounders (OR 1625.1, 95%CI: 21.9-1343909.5, P < 0.01). CONCLUSIONS: Our results suggest a relationship between a riser pattern coexisting with orthostatic hypotension and dementia in Parkinson's disease. Further prospective studies are warranted to investigate whether abnormal nocturnal blood pressure profiles predict dementia in Parkinson's disease. PMID- 29126763 TI - A novel compound heterozygous TH mutation in a Japanese case of dopa-responsive dystonia with mild clinical course. PMID- 29126764 TI - STAT5a and STAT6 gene expression levels in multiple sclerosis patients. AB - Multiple sclerosis (MS) is a complex inflammatory, autoimmune disease of the central nervous system (CNS). The disease pathogenesis is not well defined yet. Cytokines have an important role in inflammation as characteristic feature of the disease. Janus kinase/signal transducers and activators of transcriptions (JAK/STAT) family promote cytokine-mediated cell activation. Failure in the JAK/STAT signaling pathway is associated with the pathological outcome in MS. In this study, we compared the expression levels of STAT5a and STAT6 genes in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls by Taqman Quantitative Real-Time PCR in patients and healthy control group. We found that STAT5a expression was significantly down-regulated (p = .049), whereas STAT6 gene expression was significantly up-regulated (p = .046) in MS patients compared with controls. Moreover, there was significant correlation between the STAT6 gene expression and Kurtzke Expanded Disability Status Scale (EDSS) criterion. However, no significant correlation was demonstrated between the expression of STAT5a gene and clinical findings. Furthermore, there was not significant correlation between expression levels of STAT5a and STAT6 genes. Our findings suggest that STAT5a and STAT6 dysregulation may have a critical role in modification of immune responses leading to imbalance between Th2- and Th1 related cytokines. However, the mechanisms underlying it still remain to be elucidated. Future studies are needed to explore the role of STAT5a and STAT6 as prognostic biomarkers in research, design of experimental therapies or clinical settings of the MS. PMID- 29126766 TI - Raman spectroscopic analysis of oral cells in the high wavenumber region. AB - Raman spectroscopy can provide a molecular-level signature of the biochemical composition and structure of cells with submicrometer spatial resolution and could be useful to monitor changes in composition for early stage and non invasive cancer diagnosis, both ex-vivo and in vivo. In particular, the fingerprint spectral region (400-1800cm-1) has been shown to be very promising for optical biopsy purposes. However, limitations for discrimination of dysplastic and inflammatory processes based on the fingerprint region have been demonstrated. In addition, the Raman spectral signal of dysplastic cells is one important source of misdiagnosis of normal versus pathological tissues. The high wavenumber region (2800-3600cm-1) provides more specific information based on NH, OH and CH vibrations and can be used to identify the subtle changes which could be important for discrimination of samples. In this study, we demonstrate the potential of the high-wavenumber spectral region in this context by collecting Raman spectra of nucleolus, nucleus and cytoplasm from oral epithelial cancer (SCC-4) and dysplastic (DOK) cell lines and from normal oral epithelial primary cells, in vitro, in water immersion, which were then analyzed by principal components analysis as a method to discriminate the spectra. Analysis was performed before and after digital subtraction of the bulk water signal. In the normal cell line, the three subcellular regions are well differentiated before water subtraction, although the discrimination of the two nuclear regions is less well defined after water subtraction. Comparing the respective subcellular regions of the three cell lines, before water subtraction, the cell lines can be discriminated using sequential PCA and Feature Discriminant Analysis with up to ~100% sensitivity and 97% specificity for the cytoplasm, which is improved to 100% sensitivity and 99% specificity for the nucleus. The results are discussed in terms of discrimination comparing the CH vibrational modes of nucleic acids, proteins and lipids. The potential role of the OH vibrations, considering free water and confined water, in the discrimination of cell cultures and pathological processes are also discussed. PMID- 29126765 TI - New insights into the phenotype of FARS2 deficiency. AB - Mutations in FARS2 are known to cause dysfunction of mitochondrial translation due to deficient aminoacylation of the mitochondrial phenylalanine tRNA. Here, we report three novel mutations in FARS2 found in two patients in a compound heterozygous state. The missense mutation c.1082C>T (p.Pro361Leu) was detected in both patients. The mutations c.461C>T (p.Ala154Val) and c.521_523delTGG (p.Val174del) were each detected in one patient. We report abnormal in vitro aminoacylation assays as a functional validation of the molecular genetic findings. Based on the phenotypic data of previously reported subjects and the two subjects reported here, we conclude that FARS2 deficiency can be associated with two phenotypes: (i) an epileptic phenotype, and (ii) a spastic paraplegia phenotype. PMID- 29126767 TI - The quality of life analysis of knee prosthesis with complete microprocessor control in trans-femoral amputees. AB - OBJECTIVE: The aim of this study was to analyze the patient demographics, etiology of limb loss as well as reporting SF-36 scores for microprocessor prosthesis users in Turkish population. METHODS: We reviewed 72 patients (61 male and 11 female; mean age: 37.7 +/- 10.7) with uni-lateral, above knee amputation and a history of regular and microprocessor prosthesis use. All patients were called back for a last follow-up and they were asked to fill a self-administered general health status questionnaire (SF-36). RESULTS: According to the SF-36 results; physical component score (PCS) score was 46 +/- 7.3 and mental components summary (MCS) score was 46.5 +/- 9.1. These scores have statistical similarity with Turkish healthy controls, except SF (social functioning) sub dimension. PCS score for women microprocessor users were significantly lower than men (43.3 vs. 48.7, p = 0.03), but MCS scores were similar in between genders (46 vs. 48.2, p = 0.13). Conventional prostheses usage time was positively correlated with physical function (PF) scores (r = 0.322, p = 0.010). Microprocessor prosthesis usage time was negatively correlated with role limitations due to emotional problem (RE) scores (r = -0,313, p = 0.009). CONCLUSION: The quality of life surveys were showed that the loss of an extremity have higher physical and psychological impact on women's physical scores. Overall, SF-36 results were similar in microprocessor using amputee's and Turkish normal controls. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29126768 TI - Increased functional coupling of 5-HT1A autoreceptors to GIRK channels in Tph2-/- mice. AB - Firing activity of serotonergic neurons is under regulatory control by somatodendritic 5-HT1A autoreceptors (5-HT1AARs). Enhanced 5-HT1AAR functioning may cause decreased serotonergic signaling in brain and has thereby been implicated in the etiology of mood and anxiety disorders. Tryptophan hydroxylase 2 knockout (Tph2-/-) mice exhibit sensitization of 5-HT1A agonist-induced inhibition of serotonergic neuron firing and thus represents a unique animal model of enhanced 5-HT1AAR functioning. To elucidate the mechanisms underlying 5 HT1AAR supersensitivity in Tph2-/- mice, we characterized the activation of G protein-coupled inwardly-rectifying potassium (GIRK) conductance by the 5-HT1A receptor agonist 5-carboxamidotryptamine using whole-cell recordings from serotonergic neurons in dorsal raphe nucleus. Tph2-/- mice exhibited a mean twofold leftward shift of the agonist concentration-response curve (p < 0.001) whereas the maximal response, proportional to the 5-HT1AAR number, was not different (p = 0.42) compared to Tph2+/- and Tph2+/+ littermates. No differences were found in the basal inwardly-rectifying potassium conductance, determined in the absence of agonist, (p = 0.80) nor in total GIRK conductance activated by intracellular application of GTP-gamma-S (p = 0.69). These findings indicate increased functional coupling of 5-HT1AARs to GIRK channels in Tph2-/- mice without a concomitant increase in 5-HT1AARs and/or GIRK channel density. In addition, no changes were found in alpha1-adrenergic facilitation of firing (p = 0.72) indicating lack of adaptive changes Tph2-/- mice. 5-HT1AAR supersensitivity may represents a previously unrecognized cause of serotonergic system hypofunction and associated disorders and provides a possible explanation for conflicting results on the correlation between 5-HT1AAR density and depression in clinical imaging studies. PMID- 29126769 TI - Cardiovascular complications in head & neck microvascular flap reconstruction: A retrospective risk stratification and outcomes assessment. AB - BACKGROUND: To determine the incidence and predictors of cardiac complications (CC) in head & neck microvascular flap reconstruction. METHODS: A series of 216 microvascular flaps performed between 2012 and 2015 were analyzed using the Revised Cardiac Risk Index (CRCI) and the Charlson Comorbidity Index (CCI). Multivariate regression analysis was undertaken for predictive factors of outcomes. RESULTS: Twenty patients developed CC (9.7%) with transient cardiac arrhythmia (6.5%) and myocardial infarction (2.8%) occurring most frequently. Univariate analyses demonstrated significant differences between the two groups in terms of their age, smoking status, occurrence of peripheral vascular disease, CCI, RCRI, length of hospitalization and duration of anesthesia. Multivariate analyses showed that RCRI (p < 0.001) and amount of blood transfused (p = 0.02) were independent predictors of CC. CONCLUSIONS: Cardiac complications are uncommon in head and neck microvascular flap surgery. The RCRI is a useful screening tool for estimating cardiac complication risk and improving patient and flap outcomes. PMID- 29126770 TI - Effects of unilateral vertical mandibular distraction osteogenesis on airway anatomy in children with hemifacial microsomia. AB - PURPOSE: To assess the two- and three-dimensional airway changes following unilateral vertical mandibular distraction osteogenesis (vMDO) in patients with hemifacial microsomia (HFM). METHODS: A retrospective evaluation was performed for consecutive patients over an 18-month period with HFM and with Kaban Pruzansky Type-II mandibular deformities who underwent unilateral vMDO for correction of vertical mandibular asymmetry. Patients with complete records and a minimum of 12 months of clinical follow-up post-consolidation were included. Pre operative airway dimensions (diameters, cross-sectional areas, and volumes) were measured for the oropharynx and nasopharynx. Pre-operative airway dimensions were compared to post-distraction measurements taken from 3D-CT data obtained at a minimum of 3 months post-consolidation. RESULTS: Five patients met inclusion criteria. Median age was 12.6 years, 3 were female, and median distraction length was 21.3 mm. Median final follow-up CT was performed 5 months after completion of distraction. There were no major or minor complications. Median total airway volume change was +33.7%, corresponding to median volume changes of 80.5% and 10.5% for the oropharyngeal and nasopharyngeal airways, respectively. CONCLUSION: Unilateral vMDO expands the minimum diameter and volume of the oropharyngeal to a greater extent than the nasopharyngeal airway in HFM patients with Kaban Pruzansky Type-II mandibular deformities. PMID- 29126771 TI - BMP-2 plasmid DNA-loaded chitosan films - A new strategy for bone engineering. AB - OBJECTIVES: Bone defects are common in every area of medicine and remain a clinical challenge. Tissue engineering has led to promising new strategies in accelerating bone repair. Bone morphogenetic proteins (BMPs) play crucial roles in bone regeneration, but are required in supra-physiological doses, which are expensive and produce severe side effects. METHODS: To address these issues, we prepared BMP-2 plasmid DNA-loaded chitosan films, and examined their effects on mouse osteoblast-like MC3T3-E1 cell morphology, proliferation, and runt-related transcription factor 2 (RUNX2) expression. In vivo testing was performed using calvarial critical-sized defects and histomorphometry in 36 Sprague-Dawley rats. Unloaded chitosan films and empty defects served as controls. RESULTS: In contrast to the controls, cells grown on BMP-2 plasmid DNA-loaded chitosan films had well established filopodia and lamellipodia, significantly higher proliferation 2, 4, and 6 days post-seeding (P <= 0.05), and higher nuclear RUNX2 expression. In vivo, new bone growth was significantly greater in the BMP-2 group than in the control groups at 4, 8, and 12 weeks (P <= 0.01). CONCLUSIONS: Based on our study findings, BMP-2 plasmid DNA-loaded chitosan films provide an effective strategy for GBR, combining cellular compatibility with biocapability in vivo. PMID- 29126772 TI - Data-Driven Methods to Diversify Knowledge of Human Psychology. AB - Psychology aims to understand real human behavior. However, cultural biases in the scientific process can constrain knowledge. We describe here how data-driven methods can relax these constraints to reveal new insights that theories can overlook. To advance knowledge we advocate a symbiotic approach that better combines data-driven methods with theory. PMID- 29126773 TI - Clomipramine counteracts lipid raft disturbance due to short-term muscle disuse. AB - Disuse-induced skeletal muscle dysfunction is a serious consequence of long-term spaceflight, numerous diseases and conditions for which treatment possibilities are still strictly limited. We have previously shown that acute hindlimb suspension (HS)-mediated disuse disrupts membrane lipid rafts in the unloaded muscle. Here, we investigated whether pretreatment of rats with the inhibitor of acid sphingomyelinase, clomipramine (1.25mg/g/day, intramuscularly, for 5days before HS), is able to hinder the loss in lipid raft integrity in response to 12h of HS. Clomipramine pretreatment significantly counteracted the decrease in labeling of the plasma membranes with lipid raft markers (fluorescent cholera toxin B subunit and bodipy-GM1-ganglioside) specifically in the junctional regions of the suspended soleus muscle. This was associated with: a) enhancing raft disrupting potential of exogenous sphingomyelinase in the junctional membranes; b) prevention of both ceramide accumulation and cholesterol loss; c) prevention of decline in nicotinic acetylcholine receptor labeling in the unloaded muscle. Our data suggest that sphingomyelinase-mediated raft disturbance serves as one of the earlier events in HS effects. PMID- 29126774 TI - Fixating at far distance shortens reaction time to peripheral visual stimuli at specific locations. AB - The purpose of the present study was to examine whether the fixation distance in real three-dimensional space affects manual reaction time to peripheral visual stimuli. Light-emitting diodes were used for presenting a fixation point and four peripheral visual stimuli. The visual stimuli were located at a distance of 45cm and at 25 degrees in the left, right, upper, and lower directions from the sagittal axis including the fixation point. Near (30cm), Middle (45cm), Far (90cm), and Very Far (300cm) fixation distance conditions were used. When one of the four visual stimuli was randomly illuminated, the participants released a button as quickly as possible. Results showed that overall peripheral reaction time decreased as the fixation distance increased. The significant interaction between fixation distance and stimulus location indicated that the effect of fixation distance on reaction time was observed at the left, right, and upper locations but not at the lower location. These results suggest that fixating at far distance would contribute to faster reaction and that the effect is specific to locations in the peripheral visual field. The present findings are discussed in terms of viewer-centered representation, the focus of attention in depth, and visual field asymmetry related to neurological and psychological aspects. PMID- 29126775 TI - Lithium prevents scopolamine-induced memory impairment in zebrafish. AB - We examined whether lithium carbonate (Li2CO3, 100mg/L) is able to prevent memory impairment induced by scopolamine. Moreover, we evaluated the effects of lithium on anxiety-like behavior and acetylcholinesterase activity in adult zebrafish. We demonstrated that lithium prevents the memory impairment induced by scopolamine, decreases exploration and increases the activity of acetylcholinesterase in zebrafish. Collectively, this contributes to a better understanding of the pharmacology of lithium, its interaction with cholinergic neurotransmission, and its possible application to therapeutic treatments aimed at improving cognition. PMID- 29126777 TI - Graded photochemical spinal cord injury results in chronic hyperalgesia and depression-like behaviour but no anxiety exacerbation in female BALB/c mice. AB - Neuropathic pain (NP) is present in 40-to-50% of spinal cord injured patients. It tends to chronicity and correlates with lower quality-of-life. Moreover, the role of NP in the eventual exacerbation of anxiety- and depression-like behaviours during its development and chronification in genetically susceptible individuals remains unclear. Thus, although solely few animal models are available, new specific models are needed to complete the array of chances to assay new therapeutic strategies with the aim of treating chronic NT and its associated mood disorders. The present study was conceived to evaluate hyperalgesic responses and anxiety- and depression-like behaviours after graded photochemical spinal cord injury (SCI) up to chronic phase. BALB/c strain was used: it expresses a phenotype characterized by high innate anxiety levels, allowing to elucidate whether NP may exacerbate mood disorders at SCI chronic phase. After different photoinduction-times on exposed spinal cord, the mice developed a graded chronic hyperalgesia with minor to non-existent motor dysfunction. Behavioural data suggest that whilst hyperalgesia associated to SCI does not exacerbate BALB/c anxiety-like behaviours, it may result in depression-like behaviour at SCI chronic phase. Our study demonstrates that chronic central hyperalgesia may exacerbate despair-like behaviour at the SCI chronic phase in a mouse model of high anxiety-related behaviour. This implies that photochemical SCI may be a suitable model to study the comorbidity between chronic NP and mood disorders. PMID- 29126776 TI - Effects of acupuncture on the anxiety-like behavior induced by withdrawal from chronic morphine use. AB - OBJECTIVES: In the previous studies, it has been demonstrated that acupuncture treatment was effective on the suppression of withdrawal signs as well as self administration behavior induced by morphine. Based on, the present study has investigated whether acupuncture could attenuate the anxiety-like behavior induced by withdrawal from chronic morphine treatment. MATERIALS & METHODS: Male Sprague-Dawley rats weighing 270-300g were treated saline or morphine hydrochloride (10mg/kg, s.c.) for 2 weeks. Following abstinence of 5days in home cage, rats were subjected to the measurement of anxiety-like behavior in the elevated plus maze. Bicuculline (1mg/kg, i.p.) and SCH 50911 (2mg/kg, i.p.) were used to investigate the possible mechanism of acupuncture effects focusing on the GABA receptors system. RESULTS: Acupuncture at HT7 increased the time spent in open arms significantly. Also, these effects of acupuncture at HT7 were blocked by GABAA receptor antagonist. CONCLUSION: Results of the present study suggest that acupuncture at HT7 can attenuate anxiety-like behavior induced by withdrawal from chronic morphine treatment through the mediation of GABAA receptor system. PMID- 29126778 TI - Seeing in context: Comment on "Seeing mental states: An experimental strategy for measuring the observability of other minds" by Cristina Becchio et al. PMID- 29126779 TI - Squamous Cell Carcinoma Transformation from EGFR-mutated Lung Adenocarcinoma: A Case Report and Literature Review. PMID- 29126781 TI - Influence of abdominal obesity and habitual behaviors on incident atrial fibrillation in Japanese. AB - BACKGROUND: As atrial fibrillation (AF) increases with the aging of the population, it is urgently required to clarify modifiable factors to prevent AF. However, evidence regarding the independent influence of abdominal-obesity and habitual behaviors on incident AF is limited among Japanese. METHODS AND RESULTS: Those aged 40-79 years undergoing periodic health checkups during 2008-2014 were followed-up in 2015 (n=96,841) and the independent risk of incident AF was estimated using multivariate Cox proportional hazards regression models after adjustment for potential covariates. Participants were classified into four groups according to the baseline body mass index (BMI: kg/m2) (normal-BMI or overweight: < or >=25) and waist circumference (WC: cm) (normal-WC or abdominal obesity: < or >=85 for male, >=90 for female). Baseline habitual behaviors, smoking status, alcohol intake, and physical activity, were also included as modifiable factors. Among 65,984 eligible participants, 349 developed AF over mean follow-up of 5.5+/-1.6 years. Increase of both BMI and WC significantly elevated the risk of AF. Compared to the normal-BMI and normal-WC group, the normal-BMI but abdominal-obesity and the overweight and abdominal-obesity groups in males and the overweight and abdominal-obesity group in females had significantly elevated risk of AF. Among modifiable behavioral factors including abdominal-obesity, alcohol intake (>=40g/day) and abdominal-obesity significantly elevated the risk of AF in males, and abdominal-obesity was the strongest risk factor in both sexes, but smoking and physical activity were not significant. However, an aggregation of these four behavioral factors increased the risk of AF more than 2.5 times in both sexes. CONCLUSIONS: Abdominal-obesity could be a crucial risk factor in prediction of AF in Japanese, and an aggregation of four behavioral factors increased the risk of AF almost three times. To prevent incident AF, practicing healthy habitual behaviors is recommended. PMID- 29126782 TI - Feasibility and limitations of mitral valve repair, with or without left ventricular reconstruction in non-ischemic dilated cardiomyopathy. AB - BACKGROUND: Although non-transplant surgical interventions for non-ischemic dilated cardiomyopathy (NIDCM) are relatively effective, their feasibility and limitations have not been fully elucidated. The aim of this study was to define the feasibility and limitations of mitral valve repair, with or without surgical ventricular reconstruction for patients with NIDCM in terms of postoperative low cardiac output syndrome (LOS). METHODS: Twenty non-transplant candidates (aged 57+/-13 years) with NIDCM and significant mitral regurgitation had undergone mitral valve repair combined with submitral procedures. Using a 72-mL plastic ellipsoidal sizer, left ventricular reconstruction was performed concomitantly in 14/20 (70%) patients with extremely large ventricles. Total stroke volume, deceleration time of early trans-mitral flow wave, and the slope (Mw) in the preload recruitable stroke-work relationship were assessed using transthoracic echocardiography. LOS was defined as in-hospital death due to heart failure or a cardiac index less than 2.2L/min/m2 before discharge. RESULTS: There were three in-hospital deaths and four patients with postoperative cardiac index less than 2.2L/min/m2 [n=7 (35%), LOS group]. Preoperative total stroke volume, deceleration time, and the Mw were significantly lower in the LOS group compared to those in the non-LOS group; the predicted cut-off values for LOS were 84mL/beat (p=0.008), 133ms (p=0.015), and 45ergcm-3*103 (p=0.036), respectively. Preoperative left ventricular ejection fraction and ventricular size could not predict postoperative LOS. The one-year survival rate was 0% in the LOS group and 84% in the non-LOS group (p<0.001). CONCLUSIONS: Mitral valve repair, with or without left ventricular reconstruction, could be contraindicated for NIDCM patients with low total stroke volume, deceleration time, and Mw in terms of high postoperative incidence of LOS. For high-risk patients, other therapeutic strategies might be necessary. PMID- 29126780 TI - Identification of protein W, the elusive sixth subunit of the Rhodopseudomonas palustris reaction center-light harvesting 1 core complex. AB - The X-ray crystal structure of the Rhodopseudomonas (Rps.) palustris reaction center-light harvesting 1 (RC-LH1) core complex revealed the presence of a sixth protein component, variably referred to in the literature as helix W, subunit W or protein W. The position of this protein prevents closure of the LH1 ring, possibly to allow diffusion of ubiquinone/ubiquinol between the RC and the cytochrome bc1 complex in analogous fashion to the well-studied PufX protein from Rhodobacter sphaeroides. The identity and function of helix W have remained unknown for over 13years; here we use a combination of biochemistry, mass spectrometry, molecular genetics and electron microscopy to identify this protein as RPA4402 in Rps. palustris CGA009. Protein W shares key conserved sequence features with PufX homologs, and although a deletion mutant was able to grow under photosynthetic conditions with no discernible phenotype, we show that a tagged version of protein W pulls down the RC-LH1 complex. Protein W is not encoded in the photosynthesis gene cluster and our data indicate that only approximately 10% of wild-type Rps. palustris core complexes contain this non essential subunit; functional and evolutionary consequences of this observation are discussed. The ability to purify uniform RC-LH1 and RC-LH1-protein W preparations will also be beneficial for future structural studies of these bacterial core complexes. PMID- 29126783 TI - Two Case Reports: Using Simulated Reattachment to Treat Persistent Complex Bereavement Disorder and PTSD. AB - These case reports focus on a rapid treatment for persistent complex bereavement disorder and posttraumatic stress disorder (PTSD), which appears to activate the mirror neuron network. Simulated reattachment is a technique which has been found to repair phantom limb pain in just a few sessions. The same neuroplasticity that accomplishes phantom pain relief has been found to occur in the treatment of complicated grief and PTSD using similar methods. The simulated reattachment for the client in Case one was found to significantly reduce the symptoms of both complicated grief and obsessive-compulsive disorder (OCD) within one session. In Case two, symptoms of PTSD and depression were significantly reduced in a client with lupus after two sessions of simulated reattachment. In addition, inflammatory markers antinuclear autoantibodies (ANA) and C-reactive protein (CRP) declined from the beginning of treatment to the end. PMID- 29126784 TI - Steroids from Helleborus caucasicus reduce cancer cell viability inducing apoptosis and GRP78 down-regulation. AB - Helleborus caucasicus (Ranunculaceae) is an endemic plant of the Caucasian flora, widely distributed in West Georgia. Biological activities for the extracts of some Helleborus species including H. caucasicus have been reported. In this work we found that butanolic extract of the underground parts of H. caucasicus and isolated compounds decreased cell viability in vitro on cancer cell line of lung origin (Calu-1) in a concentration-dependent manner, compared to the normal cell line. In particular, we identified that furostanol derivative (25S)-22alpha,25 epoxyfurost-5-ene-3beta,11beta,26-triol 26-O-beta-d-glucopyranoside (5), 20 hydroxyecdysone (6), and 3beta,5beta,14beta-trihydroxy-19-oxo-bufa-20,22 dienolide 3-O-alpha-l-rhamnopyranoside, known as deglucohellebrin (7) exerted a strong cytotoxic effect on the same cells and on other cancer cell lines (HepG2 and Caco-2) reducing the S-phase entry (compound 6) and inducing cell apoptosis associated with activation of caspase-3 (compound 7). Moreover we demonstrated that 6 and 7 significantly decreased protein expression of GRP78, a general ER stress marker, suggesting pro-apoptotic functions. These findings indicated that selected compounds from H. caucasicus are potential interesting agents in anti cancer therapy. PMID- 29126785 TI - Glycated heamoglobin A1c as a tool for epidemiological studies to assess diabetes prevalence: How has it been used since its official recommendation for diabetes diagnosis? PMID- 29126786 TI - Development of an efficient conjugal DNA transfer system between Escherichia coli and a non-sporulating Streptomyces strain. AB - Bacterial conjugation is a powerful tool used for DNA transfer from Escherichia coli into various bacteria including streptomycetes. In this methodology, spores are usually employed as recipient cells of the genetic information. However, some industrially important Streptomyces do not produce spores making difficult their genetic manipulation. In these strains, the use of mechanically fragmented mycelia allows DNA transfer with low efficiency. Streptomyces peucetius var. caesius is a non-sporulating bacteria which produces the antitumor compound doxorubicin. The use of aerial mycelia of this microorganism, failed to get intergeneric conjugation with E. coli. In the present work, by using young aerial mycelia of this microorganism and an excess of E. coli cells (~7*108cellsmL-1) in soybean-mannitol medium (MS) supplemented with 20mMMgCl2 resulted in a high number of exconjugant colonies (5*10-4) when compared to other reports from this genus (1.1*10-5 to 2.5*10-8). The effectiveness of these conditions was confirmed by isolating null mutants of two different glucokinases from S. peucetius var. caesius. The novelty in using young aerial mycelia as receptor cells, allowed an efficient conjugative process and opened the way for genetic manipulation of additional non-spore forming actinobacteria exhibiting natural resistance to be genetically manipulated. PMID- 29126787 TI - Anxiety Disorders in Old Age: Psychiatric Comorbidities, Quality of Life, and Prevalence According to Age, Gender, and Country. PMID- 29126788 TI - Images in Aging. PMID- 29126789 TI - Molecular Control of Male Fertility for Crop Hybrid Breeding. AB - In many plant species, male-sterile female lines with cytoplasmic male sterility (CMS) or nuclear-controlled environment-sensitive genic male sterility (EGMS) have long been used to efficiently produce hybrids that harness hybrid vigor or heterosis. However, the underlying molecular mechanisms for these applications have only recently been uncovered in a few species. We provide here an update on the understanding of cytoplasmic-nuclear communication based on the discovery of mitochondrial CMS genes and their corresponding nuclear fertility determinants. Recent findings that uncover diverse mechanisms such as epigenetic, transcriptional, and post-transcriptional controls of EGMS by temperature and photoperiod signals are also reviewed. Furthermore, translational research that applies basic knowledge of plant male fertility control to hybrid seed production practice is highlighted. PMID- 29126790 TI - Translational Research: Exploring and Creating Genetic Diversity. AB - The crop selection process has created a genetic bottleneck ultimately restricting breeding output. Wild relatives of major crops as well as the so called 'neglected plant' species represent a reservoir of genetic diversity that remains underutilized. These species could be used as a tool to discover new alleles of agronomic interest or could be the target of breeding programs. Targeted induced local lesions in the genome (TILLING) can be used to translate in neglected crops what has been discovered in major crops and reciprocally. However, random mutagenesis, used in TILLING approaches, provides only a limited density of mutational events at a defined target locus. Alternatively, clustered regularly interspaced short palindromic repeats (CRISPR) associated 9 (Cas9) fused to a cytidine deaminase could serve as a localized mutagenic agent to produce high-density mutant populations. Artificial evolution is at hand. PMID- 29126791 TI - The cardioprotective effects of (-)-Epicatechin are mediated through arginase activity inhibition in a murine model of ischemia/reperfusion. AB - The production of nitric oxide (NO) by nitric oxide synthases (NOS) depends on the bioavailability of L-arginine as NOS competes with arginase for this common substrate. As arginase activity increases, less NO is produced and adverse cardiovascular consequences can emerge. (-)-Epicatechin (EPI), the most abundant flavonoid in cacao, has been reported to stimulate endothelial and neuronal NOS expression and function leading to enhanced vascular function and cardioprotective effects. However, little is known about the effects of EPI on myocardial arginase activity. The aim of the present study was to determine if EPI is able to interact and modulate myocardial arginase and NOS expression and activity. For this purpose, in silico modeling, in vitro activity assays and a rat model of ischemia/reperfusion injury were used. In silico and in vitro results demonstrate that EPI can interact with arginase and significantly decrease its activity. In vivo, 10 days of EPI pretreatment reduces ischemic myocardium arginase expression while increasing NOS expression and phosphorylation levels. Altogether, these results may partially account for the cardioprotective effects of EPI. PMID- 29126792 TI - In vivo cellular and molecular gastroprotective mechanisms of chrysin; Emphasis on oxidative stress, inflammation and angiogenesis. AB - Gastric ulcer is one of the major gastrointestinal disorders affecting people worldwide. Despite medical advances, management of gastric ulcer and its complications remains a challenge facing medicine nowadays. In addition, currently available medicines exhibit limited efficacy and several side effects. In the current study, the potential protective effects of chrysin -naturally occurring flavonoid - were tested against indomethacin-induced gastric ulcer model in rats. It was found that chrysin in both doses; 50 and 100mg/kg were effective in promoting mucus secretion and preventing the rise in ulcer and lesion indices, acid production and histologic changes induced by indomethacin. During investigation of the possible underlying mechanisms, chrysin significantly attenuated indomethacin-induced oxidative injury and inflammatory response. Also, chrysin activated peroxisome proliferator activated receptor-gamma (PPAR-gamma) leading to a phenotypic switch from pro-inflammatory M1 macrophages to the anti inflammatory M2 macrophages that evidenced by the upregulated mRNA expression levels of PPAR-gamma and M2 marker genes (Arg-1 and CD206) and down regulation of M1 marker genes (IL-6 and CCL3). Furthermore, chrysin promoted angiogenesis via increasing expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and cluster of differentiation-31 (CD31). Collectively, these findings indicate that chrysin possesses a potential protective effect against indomethacin-induced gastric ulcer. PMID- 29126793 TI - Inhibition of Notch1/Hes1 signaling pathway improves radiosensitivity of colorectal cancer cells. AB - Notch signaling pathway has been demonstrated to mediate radioresistance of several tumors. Our study aims to explore the function of Notch1/HES1 pathway in the radioresistance of colorectal cancer (CRC). The results demonstrated that expressions of Notch1 and Hes1 were up-regulated with the increasing irradiation dose. DAPT (N-[(3,5-difluorophenacetyl)acety1]-L-alanyl-2-phenyl]glycine-1,1 dimethylethyl ester) or si-Notch1 reduced expressions of Notch1 and Hes1, exacerbated irradiation-induced cell proliferation inhibition, and improved radiosensitivity of CRC cells. Moreover, DAPT or si-Notch1 increased radiation induced DNA damage and attenuated radiation-triggered DNA-PK activity. Furthermore, xenograft in nude mice demonstrated that co-treated with DAPT and irradiation could inhibited tumor growth additively in vivo. Taken together, inhibition of Notch1/Hes1 signaling pathway enhances radiosensitivity of CRC cells, providing a potential therapeutic target to improve the therapeutic effect of radiotherapy for CRC patients. PMID- 29126794 TI - Interventions for reducing fear of childbirth: A systematic review and meta analysis of clinical trials. AB - INTRODUCTION: Fear of childbirth is a problematic mental health issue during pregnancy. But, effective interventions to reduce this problem are not well understood. OBJECTIVES: To examine effective interventions for reducing fear of childbirth. MATERIAL AND METHODS: The Cochrane Central Register of Controlled Trials, PubMed, Embase and PsycINFO were searched since inception till September 2017 without any restriction. Randomised controlled trials and quasi-randomised controlled trials comparing interventions for treatment of fear of childbirth were included. The standardized mean differences were pooled using random and fixed effect models. The heterogeneity was determined using the Cochran's test and I2 index and was further explored in meta-regression model and subgroup analyses. RESULTS: Ten studies inclusive of 3984 participants were included in the meta-analysis (2 quasi-randomized and 8 randomized clinical trials). Eight studies investigated education and two studies investigated hypnosis-based intervention. The pooled standardized mean differences of fear for the education intervention and hypnosis group in comparison with control group were -0.46 (95% CI -0.73 to -0.19) and -0.22 (95% CI -0.34 to -0.10), respectively. CONCLUSIONS: Both types of interventions were effective in reducing fear of childbirth; however our pooled results revealed that educational interventions may reduce fear with double the effect of hypnosis. Further large scale randomized clinical trials and individual patient data meta-analysis are warranted for assessing the association. PMID- 29126795 TI - Providers' perspectives of barriers experienced in maternal health care among Marshallese women. AB - PROBLEM: Pacific Islanders are disproportionately burdened by poorer maternal health outcomes with higher rates of pre-term births, low birth weight babies, infant mortality, and inadequate or no prenatal care. PURPOSE: The purpose of this study was twofold: (1) to explore maternal health care providers' perceptions and experiences of barriers in providing care to Marshallese women, and (2) providers perceived barriers of access to care among Marshallese women. This is the first paper to explore perceived barriers to maternal health care among a Marshallese community from maternal health care providers' perspectives in the United States. METHODS: A phenomenological, qualitative design, using a focus group and in-depth interviews with 20 maternal health care providers residing in northwest Arkansas was chosen. FINDINGS: Several perceived barriers were noted, including transportation, lack of health insurance, communication and language, and socio-cultural barriers that described an incongruence between traditional and Western medical models of care. There was an overall discord between the collectivist cultural identity of Marshallese families and the individualistic maternal health care system that merits further research. DISCUSSION: Solutions to these barriers, such as increased cultural competency training for maternal health care providers and the incorporation of community health workers are discussed. PMID- 29126796 TI - Pregnancy nutrition knowledge and experiences of pregnant women and antenatal care clinicians: A mixed methods approach. AB - BACKGROUND: Dietary intake of pregnant women do not appear to meet the dietary recommendations. Nutrition knowledge and practices of pregnant women and their antenatal care clinicians are factors that may be influential on dietary intakes of pregnant women. AIM: To assess and compare pregnancy nutrition recommendation knowledge and to explore how nutrition knowledge impacts on food choices in pregnant women and nutrition education practices of antenatal care providers. METHODS: An explanatory sequential research mixed methods study design was applied. All participants were recruited from a metropolitan maternity hospital in Melbourne, Australia. The first phase assessed pregnancy nutrition knowledge and sources of nutrition information using a questionnaire (n=202) then followed semi-structured interviews with women and clinicians (n=31). FINDINGS: The clinicians obtained significantly higher nutrition scores than compared to women, however, nutrition knowledge gaps were highlighted for both women and clinicians. Women reported receiving limited nutrition advice, a reflection of the clinicians reporting they provided limited nutrition advice. CONCLUSION: A key challenge for women adhering to dietary recommendations was having inadequate knowledge of the dietary recommendations and receiving limited information from their care providers. Similarly, as well as time constraints, limited nutrition knowledge and a lack of nutrition training impacted on the capacity of clinicians to provide adequate nutrition education. PMID- 29126797 TI - The Cytokine TGF-beta Promotes the Development and Homeostasis of Alveolar Macrophages. AB - Alveolar macrophages (AMs) derive from fetal liver monocytes, which colonize the lung during embryonic development and give rise to fully mature AMs perinatally. AM differentiation requires granulocyte macrophage colony-stimulating factor (GM CSF), but whether additional factors are involved in AM regulation is not known. Here we report that AMs, in contrast to most other tissue macrophages, were also dependent on transforming growth factor-beta receptor (TGF-betaR) signaling. Conditional deletion of TGF-betaR in mice at different time points halted the development and differentiation of AMs. In adult mice, TGF-beta was also critical for AM homeostasis. The source of TGF-beta was AMs themselves, indicative of an autocrine loop that promotes AM self-maintenance. Mechanistically, TGF-betaR signaling resulted in upregulation of PPAR-gamma, a signature transcription factor essential for the development of AMs. These findings reveal an additional layer of complexity regarding the guidance cues, which govern the genesis, maturation, and survival of AMs. PMID- 29126798 TI - CD4+ T Cell Help Confers a Cytotoxic T Cell Effector Program Including Coinhibitory Receptor Downregulation and Increased Tissue Invasiveness. AB - CD4+ T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes in CTLs resulting from CD4+ T cell help after anti-cancer vaccination or virus infection. The gene expression signatures revealed that CD4+ T cell help during priming optimized CTLs in expression of cytotoxic effector molecules and many other functions that ensured efficacy of CTLs throughout their life cycle. Key features included downregulation of PD-1 and other coinhibitory receptors that impede CTL activity, and increased motility and migration capacities. "Helped" CTLs acquired chemokine receptors that helped them reach their tumor target tissue and metalloprotease activity that enabled them to invade into tumor tissue. A very large part of the "help" program was instilled in CD8+ T cells via CD27 costimulation. The help program thus enhances specific CTL effector functions in response to vaccination or a virus infection. PMID- 29126799 TI - Mitodepressive, antioxidant, antifungal and anti-inflammatory effects of wild growing Romanian native Arctium lappa L. (Asteraceae) and Veronica persica Poiret (Plantaginaceae). AB - The present study aims to evaluate the potential uses of hydroalcoholic extracts obtained from Romanian native wild-growing plants. The hydroalcoholic extracts were obtained from the burdock roots and respectively the aerial parts of birdeye speedwell. The extracts were characterised by HPLC (quantifying 13 compounds in the V. persica extract, 6 compounds in the A. lappa extract and confirming the presence of arctiin and arctigenin in the burdock extract). The antioxidant potential of the crude extracts was evaluated using two methods: the DPPH assay (79.91% for speedwell extract, 76.23% for burdock extract) and the phosphomolybdate method (296.5 mg/g ascorbic acid equivalents for burdock, 324.4 mg/g for speedwell). The crude extracts were found to be active against both fungal lines used (Aspergillus niger and Penicillium hirsutum), inhibition zones 17.1 mm and 13.1 mm against P. hirsutum, respectively ca. 22 mm for both extracts against A. niger. The cytogenetic effects (assessed using the Allium cepa assay) revealed a series of chromosomal aberrations and nuclear aberrations induced in the meristematic root cells. The anti-inflammatory effect, estimated in two inflammation experimental models, showed a significant effect, especially for the speedwell extract. The results recommend the evaluated extracts as promising sources of biologically-active compounds. PMID- 29126800 TI - Nanoencapsulated Illicium verum Hook.f. essential oil as an effective novel plant based preservative against aflatoxin B1 production and free radical generation. AB - The study reports efficacy of Illicium verum essential oil (IvEO) against food borne moudls and its nanoencapsulation for enhancing antifungal and antiaflatoxigenic potency. Chemical characterization of the IvEO showed anethole (89.12%) as major compound followed by estragole (4.859%). The IvEO showed broad fungitoxic spectrum against common food borne moulds. It's minimum inhibitory concentration (MIC) and minimum aflatoxin B1 inhibitory concentration (MAIC) against aflatoxigenic strain Aspergillus flavus LHP-PV-1 were 0.7, and 0.5 MUL/mL respectively. Morphological observations of treatment sets by SEM and TEM along with decrease in ergosterol content and enhanced leakage of Ca2+, K+ and Mg2+ ions denoted fungal cell membrane as site of action. The IvEO showed promising free radical scavenging activity and favourable safety profile with high LD50 value on mice. The IvEO also exhibited considerable protection of Pistacia vera from fungal contamination and complete protection from aflatoxin B1 contamination in storage containers. Nanoencapsulated IvEO in gel form and lyophilized form exhibited enhanced efficacy as fungal inhibitor and aflatoxin suppressor. The chemically characterised IvEO may be recommended as plant based preservative having favourable safety and its nanocapsules may be of industrial significance as shelf life enhancer of food items. This is the first report on in situ antiaflatoxigenic efficacy and nanoencapsulation of IvEO. PMID- 29126801 TI - Species differences between rat and human in vitro metabolite profile, in vivo predicted clearance, CYP450 inhibition and CYP450 isoforms that metabolize benzanthrone: Implications in risk assessment. AB - Benzanthrone (BNZ) is a polycyclic aromatic hydrocarbon found in industrial effluent causing skin, respiratory, gastrointestinal, genitourinary, nervous and hemopoietic toxicity. While its toxicity has been well studied, its metabolism in humans has not been investigated. The aim of this study was to characterize species differences in the in vitro metabolism of BNZ in rat and human liver microsomes and to identify the CYP isoforms involved in its metabolism. Upon incubation in liver microsomes, BNZ was found to be a direct substrate of phase I metabolism in both rat and human, undergoing oxidation and reduction. The Km in rat, 11.62 +/- 1.49 MUM, was two-fold higher than humans (5.97 +/- 0.83 MUM) suggesting higher affinity for human CYPs. Further, incubation with human rCYPs, BNZ was found to be substrate of multiple CYPs. The predicted in vivo hepatic clearance was 63.55 and 18.91 mL/min/kg in rat and human, respectively, indicating BNZ to be a high clearance compound. BNZ was found to be a moderate inhibitor of human CYP1A2. BNZ metabolism by multiple CYPs indicates that single enzyme genetic polymorphism is unlikely to have profound effect on the toxicokinetics of BNZ and default uncertainty factor of 3.16 might be sufficient to capture the intraspecies kinetic variability. PMID- 29126802 TI - Gamma-irradiated black ginseng extract inhibits mast cell degranulation and suppresses atopic dermatitis-like skin lesions in mice. AB - Gamma irradiation is able to affect various structural modification and an increase of the biological properties of biomaterials. This study was conducted to investigate the anti-allergenic effect of gamma-irradiated black ginseng extract (BGE) using in vitro and in vivo experiments. IgEantigen complex-induced degranulation was measured in RBL-2H3 mast cells. In addition, an anti-atopic dermatitis (AD) test was carried out by spreading gamma-irradiated BGE on the dorsal skin of 2,4-dinitrochlorobenzene (DNCB)-induced BALB/c mice. The content of arginylfructose (AF) of gamma-irradiated BGE was higher than that of BGE. In RBL-2H3 mast cells, gamma-irradiated BGE treatments significantly reduced the IgE antigen complex-induced release of beta-hexosaminidase, histamine, intracellular ROS, and Ca2+ influx. A western blot analysis showed that gamma-irradiated BGE had an inhibitory activity on the FcepsilonRI-mediated signaling in mast cells. In the DNCB-induced AD model, gamma-irradiated BGE significantly alleviated the ADlike skin symptoms and clinical signs. The suppression of AD by gamma irradiated BGE was accompanied by a decrease in the serum level of IgE and IL-4, as well as the number of leukocyte. Gamma-irradiated BGE also suppressed IL-4 and increased IFN-gamma in splenocytes. Our data suggests that gamma-irradiated BGE may be effective therapeutic agents for the treatment of AD. PMID- 29126803 TI - Sex differences in ochratoxin a toxicity in F344 rats after 7 and 21 days of daily oral administration. AB - Ochratoxin A (OTA) is a potent renal carcinogen in male rats but not in females. The mechanisms underlying these differences are unknown. The sex-dependent response of F344 rats after a repeated OTA oral administration for 7 (0.50 mg/kg bw) or 21 days (0.21 and 0.50 mg/kg bw) was evaluated. General toxicity, sex and thyroid hormones and histopathology were studied. OTA was quantified (HPLC-FLD) in plasma, kidney and liver and the expression of kidney transporters (RT-qPCR) was studied. After 7 days, kidney histopathology showed more pronounced signs of toxicity in males than in females. After 21 days, a higher toxicity was observed but sex differences disappeared. OTA concentration in plasma and tissues was similar in both sexes. Downregulation was the general OTA-induced effect. Oats' downregulation was slow in males and Oat3 did not change in females. Oatp1 was strongly downregulated in males after 21 days. An opposite effect was observed in Bcrp after 21 days: downregulation in males and upregulation in females. Females showed a dose- and time-dependent decrease of progesterone. Despite the sex differences, the final balance in OTA toxicokinetics at renal cell level does not seem to support a higher accumulation of OTA in male kidneys. PMID- 29126804 TI - Clinical significance of human cytomegalovirus viruria and the effect of antiviral therapy in hematopoietic stem cell transplant recipients. AB - BACKGROUND: Cytomegalovirus (CMV) causes life-threatening infections in immunocompromised host. The clinical significance of asymptomatic CMV viruria in patients receiving hematopoietic stem cell transplantation (HSCT) remains unclear. This study aims to clarify whether antiviral therapy is associated with a favorable clinical outcome. METHODS: HSCT recipients whose urine was culture positive for CMV were retrospectively reviewed and followed. Viruria episodes were divided according to whether or not antiviral therapy was used. Mortality and the estimated glomerular filtration rate (eGFR) in 2 years following CMV viruria were compared between patients with and without antiviral therapy. RESULTS: Sixty-two episodes of culture-proven asymptomatic CMV viruria were identified in 28 HSCT recipients. Antiviral therapy was used in 35 (56.5%) and spared in 27 (43.5%) viruric episodes. Compared with the baselines, there were no significant difference in the decrements of eGFR between the two groups at the end the 1st year (4.78 vs 5.02 mL/min/1.73 m2, p = 0.968) and the 2nd year (1.13 vs 7.66 mL/min/1.73 m2, p = 0.276). Antiviral therapy for asymptomatic CMV viruria was also not associated with a favorable survival (p = 0.288). On the other hand, presence of CMV viremia correlated with a poorer survival (2-year mortality rate 60% vs 13.33%, p < 0.001). CONCLUSION: Antiviral therapy for asymptomatic CMV viruria is not associated with a clear clinical benefit in HSCT recipients. Further studies may be needed to identify if specific patient populations may benefit from antiviral therapy in CMV viruria. PMID- 29126805 TI - Determinants of influenza vaccination among high-risk Black and White adults. AB - BACKGROUND: Adults with chronic conditions are at much greater risk of influenza related morbidity and mortality, yet flu vaccine uptake remains suboptimal. Research focused on the high-risk population has been limited, particularly related to racial disparities in vaccination. We explore a broad range of demographic, racial, and psychosocial factors to identify predictors of vaccination among high-risk adults, with a focus on identify differences between Black and White adults. METHODS: We conducted an online survey in March 2015, utilizing international research firm GfK's KnowledgePanel, for a nationally representative sample of Black and White adults (>=18, USA) and limited analysis adults with high-risk of influenza-related complications. Using two-way ANOVA, we assessed demographic, racial, and psychosocial predictors across vaccine uptake in the past five years and across racial group. RESULTS: 424 (52.2%) Black and 388 (47.8%) White respondents with high-risk complications completed the survey. 383 (47.3%) reported vaccination annually, 99 (12.2%) most years, 104 (12.9%) once/twice, and 223 (27.6%) never.ANOVA confirmed significant differences in vaccine behavior for most demographic predictors (except education), all racial factors (including racial fairness, experiences of discrimination, etc.), and most psychosocial factors (including vaccine attitudes, trust in the vaccine, etc.). ANOVA confirmed significant differences for most factors by race. We observed significant interaction effects between race and vaccine behavior for subjective social status, access to medical care, knowledge of vaccine recommendations, vaccine attitudes, perceived side effect risks, descriptive norms, subjective norms, flu vaccine hesitancy, and flu vaccine confidence, thus implying racial differences in the connection between vaccine uptake and key demographic, racial, and psychosocial factors. CONCLUSIONS: This study provides a novel examination of flu vaccine behavior among high-risk Blacks and Whites that identified factors influencing vaccine uptake.We found significant differences by race. Health care professionals can use this information to more effectively target high-risk adults during flu season. PMID- 29126806 TI - Modeling the consequences of regional heterogeneity in human papillomavirus (HPV) vaccination uptake on transmission in Switzerland. AB - BACKGROUND: Completed human papillomavirus (HPV) vaccination by age 16 years among women in Switzerland ranges from 17 to 75% across 26 cantons. The consequences of regional heterogeneity in vaccination coverage on transmission and prevalence of HPV-16 are unclear. METHODS: We developed a deterministic, population-based model that describes HPV-16 transmission among young adults within and between the 26 cantons of Switzerland. We parameterized the model using sexual behavior data from Switzerland and data from the Swiss National Vaccination Coverage Survey. First, we investigated the general consequences of heterogeneity in vaccination uptake between two sub-populations. We then compared the predicted prevalence of HPV-16 resulting from heterogeneous HPV vaccination uptake in all of Switzerland with homogeneous vaccination at an uptake that is identical to the national average (52%). RESULTS: In our baseline scenario, HPV 16 prevalence in women is 3.34% when vaccination is introduced and begins to diverge across cantons, ranging from 0.19 to 1.20% after 15 years of vaccination. After the same time period, overall prevalence of HPV-16 in Switzerland is only marginally higher (0.63%) with heterogeneous vaccination uptake than with homogeneous uptake (0.59%). Assuming inter-cantonal sexual mixing, cantons with low vaccination uptake benefit from a reduction in prevalence at the expense of cantons with high vaccination uptake. CONCLUSIONS: Regional variations in uptake diminish the overall effect of vaccination on HPV-16 prevalence in Switzerland, but the effect size is small. Cantonal efforts towards HPV-prevalence reduction by increasing vaccination uptake are impaired by cantons with low vaccination uptake. Although the expected impact on national prevalence would be relatively small, harmonization of cantonal vaccination programs would reduce inter-cantonal differences in HPV-16 prevalence. PMID- 29126808 TI - Innovative vaccine delivery strategies in response to a cholera outbreak in the challenging context of Lake Chilwa. A rapid qualitative assessment. AB - A reactive campaign using two doses of Shanchol Oral Cholera Vaccine (OCV) was implemented in 2016 in the Lake Chilwa Region (Malawi) targeting fish dependent communities. Three strategies for the second vaccine dose delivery (including delivery by a community leader and self-administration) were used to facilitate vaccine access. This assessment collected vaccine perceptions and opinions about the OCV campaign of 313 study participants, including: fishermen, fish traders, farmers, community leaders, and one health and one NGO officer. Socio-demographic surveys were conducted, In Depth Interviews and Focus Group Discussions were conducted before and during the campaign. Some fishermen perceived the traditional delivery strategy as reliable but less practical. Delivery by traditional leaders was acceptable for some participants while others worried about traditional leaders not being trained to deliver vaccines or beneficiaries taking doses on their own. A slight majority of beneficiaries considered the self administration strategy practical while some beneficiaries worried about storing vials outside of the cold chain or losing vials. During the campaign, a majority of participants preferred receiving oral vaccines instead of injections given ease of intake and lack of pain. OCV was perceived as efficacious and safe. However, a lack of information on how sero-protection may be delayed and the degree of sero-protection led to loss of trust in vaccine potency among some participants who witnessed cholera cases among vaccinated individuals. OCV campaign implementation requires accompanying communication on protective levels, less than 100% vaccine efficacy, delays in onset of sero-protection, and out of cold chain storage. PMID- 29126807 TI - Post-exposure immunization by capsid-modified AdC7 vector expressing Pseudomonas aeruginosa OprF clears P. aeruginosa respiratory infection. AB - Respiratory infections with Pseudomonas aeruginosa are major health problems, particularly in patients with cystic fibrosis (CF). No vaccine against P. aeruginosa is yet available. A vaccine that controls colonization of the respiratory tract with P. aeruginosa could be useful to prevent chronic infection and exacerbations. Replication-deficient adenoviral (Ad) vectors based on non human serotypes are attractive vaccine platforms as they can circumvent the problem of pre-existing anti-Ad immunity in humans. The primate-based AdC7 vector AdC7OprF.RGD that expresses the outer membrane protein F (OprF) of P. aeruginosa (AdC7OprF) and that displays an integrin-binding arginine-glycine-aspartic acid (RGD) sequence is a potent inducer of lung mucosal and protective immunity. Here, we investigated the efficacy of immunization with AdC7OprF.RGD to clear an already established P. aeruginosa respiratory infection in mice (wild-type and CF) and rats. Intratracheal administration of the clinical P. aeruginosa strain RP73 embedded in agar beads was used to establish persistent infection. Subsequent intranasal immunization with AdC7OprF.RGD induced robust P. aeruginosa specific systemic and mucosal, humoral and cellular immune responses. Importantly, the AdC7OprF.RGD immunized mice effectively cleared P. aeruginosa from the lungs. Likewise, immunization with AdC7OprF.RGD of CF mice and Sprague Dawley rats with established P. aeruginosa respiratory infection showed enhanced anti-Pseudomonas immune responses and increased clearance of P. aeruginosa from the lungs. These data suggest that AdC7OprF.RGD can be effective as a post exposure vaccine and may be useful in clinical settings in particular for patients with CF who frequently harbor the bacteria over prolonged periods. PMID- 29126809 TI - [Importance of maternal death autopsy]. PMID- 29126810 TI - Sensory trick splint as a multimodal therapy for oromandibular dystonia. AB - PURPOSE: Many patients with oromandibular dystonia, which is characterized by involuntary masticatory, lower facial, and/or tongue muscle contractions, experience relief of symptoms through sensory tricks such as eating chewing gum or candy. The aim of this study was to identify the factors influencing the effects of splints in patients with oromandibular dystonia. METHODS: Occlusal splints were inserted in 128 patients (89 women, 39 men) with oromandibular dystonia (102 with jaw closing dystonia, 20 with lingual dystonia, 5 with jaw deviation dystonia, 4 with jaw opening dystonia, 3 with lip dystonia, and 2 with jaw protrusion dystonia). Patients who showed improvement with the use of splints and continued to wear them for at least 3 months were defined as responders. In contrast, patients who showed little or no effect and/or were unable to insert splints were defined as non-responders. Differences in demographic and clinical data were statistically compared between responders and non-responders. RESULTS: Ninety-eight patients (76.6%) were responders (subjective improvement: 30.5%). Thirty patients (23.4%) were non-responders (subjective improvement: 7.2%). The responders were significantly older than the non-responders (53.8 years vs 47.0 years; p<0.05). Patients with jaw closing dystonia showed the most favorable results. The proportion of patients with sensory tricks was significantly higher in responders than in non-responders (66.3% vs 26.7%; p<0.05). CONCLUSIONS: The sensory trick splint is especially helpful for patients with jaw closing dystonia. It is useful, although partially effective, as an alternative therapy in patients for whom other therapies have been unsatisfactory. PMID- 29126811 TI - Properties of tonic episodes of masseter muscle activity during waking hours and sleep in subjects with and without history of orofacial pain. AB - PURPOSE: To provide a scientific data related to the tonic activity of masseter muscle in subjects with and without history of orofacial pain during their normal daily life. METHODS: Thirty-three subjects were divided into two groups, a pain history group (PHG) and a non-pain history group (non-PHG), based on their responses to the Research Diagnostic Criteria for Temporomandibular Disorders questionnaire. After excluding four subjects with incomplete recordings, full-day masseter muscle surface EMGs of 29 subjects (10 men, 19 women; mean age 24.1 years) were analyzed. Tonic episode (TE) was defined as continuous EMG activity with a duration at least 2s with intensities above twice the baseline noise level. TEs were classified into 6 strength categories (<7.5%, 7.5-10%, 10-15%, 15 25%, 25-40% and >40% of the maximum voluntary clenching (MVC)). The mean duration of activity observed in the non-PHG+2 SD was adopted as a cutoff for identifying sustained TE. RESULTS: During waking hours, the incidence of sustained TEs was significantly higher in the PHG than in the non-PHG (p<0.05). The incidence and total duration of sustained TEs were significantly higher in the PHG than in the non-PHG at intensities of 7.5-10% MVC, 10-15% MVC, and 15-25% MVC (p<0.05). No significant difference was observed during sleep. CONCLUSIONS: Within the limitations of this study, it would be concluded that sustained TEs may have a correlation with orofacial pain and the intensity range of 7.5-25% MVC would be an important range for future clenching studies. PMID- 29126812 TI - Infectious disease risks among refugees from North Korea. AB - OBJECTIVES: The characteristics of disease in North Korea, including severe malnutrition and infectious disease risks, have not been openly and widely analyzed. This study was performed to estimate the risks of infectious diseases among refugees from North Korea. METHODS: A literature review of clinical studies among North Korean defectors was conducted to statistically estimate the risks of infectious diseases among North Korean subjects. RESULTS: A total of six groups of data from five publications covering the years 2004 to 2014 were identified. Tuberculosis and viral hepatitis appeared to be the two most common infectious diseases, especially among adult refugees. When comparing the risks of infectious diseases between North Korean and Syrian refugees, it is critical to remember that Plasmodium vivax malaria has been endemic in North Korea, while cutaneous leishmaniasis has frequently been seen among Syrian migrants. CONCLUSIONS: Valuable datasets from health surveys of defectors were reviewed. In addition to tuberculosis and viral hepatitis, which were found to be the two most common infectious diseases, a special characteristic of North Korean defectors was Plasmodium vivax malaria. This needs to be added to the list of differential diagnoses for pyretic patients. PMID- 29126813 TI - Automated immunohistochemical method to analyze large areas of the human cortex. AB - BACKGROUND: There have been inconsistencies in the histological abnormalities found in the cerebral cortex from patients with schizophrenia, bipolar disorder and major depression. Discrepancies in previously published reports may arise from small sample sizes, inconsistent methodology and biased cell counting. METHODS: We applied automated quantification of neuron density, neuron size and cortical layer thickness in large regions of the cerebral cortex in psychiatric patients. This method accurately segments DAPI positive cells that are also stained with CUX2 and FEZF2. Cortical layer thickness, neuron density and neuron size were automatically computed for each cortical layer in numerous Brodmann areas. RESULTS: We did not find pronounced cytoarchitectural abnormalities in the anterior cingulate cortex or orbitofrontal cortex in patients with schizophrenia, bipolar disorder or major depressive disorder. There were no significant differences in layer thickness measured in immunohistochemically stained slides compared with traditional Nissl stained slides. Automated cell counts were correlated, reliable and consistent with manual counts, while being much less time-consuming. CONCLUSION: We demonstrate the validity of using a novel automated analysis approach to post-mortem brain tissue. We were able to analyze large cortical areas and quantify specific cell populations using immunohistochemical markers. Future analyses could benefit from efficient automated analysis. PMID- 29126814 TI - A daily topical decontamination regimen reduces catheter-related bloodstream infections in haematology patients. AB - OBJECTIVE: To assess impact of a topical decontamination regimen on rates of catheter-related bloodstream infections (CRBSI) in intensively-treated haematology patients. METHODS: A historically-controlled cohort study was used to evaluate the effect of applying chlorhexidine or Octenisan(r) body washes and nasal Prontoderm(r) ointment for 5 days around the time of Hickman line insertion on the incidence of CRBSI and infection-free catheter time. Lines inserted during a 24 month period prior to implementation of the decolonisation regimen were compared with those inserted during a 12 month period after the intervention was applied. RESULTS: During the post-intervention period, 163 lines were inserted in 147 patients, compared to 303 lines in 242 patients in the pre-intervention period. CRBSI rates in treated and untreated patients respectively were 6.8 and 35.0 cases per 10,000 line-days by 21 days (p = 0.009), and 14.4 and 26.0 cases respectively per 10,000 line-days by 180 days (p = 0.025). The incidence rate of Staphylococcus aureus CRBSI in treated and untreated patients were 0.0 and 4.6 cases per 10,000 line-days respectively (p = 0.012). Multivariable Cox regression estimated an 81% probability (95% confidence interval 74%-85%) that a treated line develops a CRBSI later than an untreated line by 21 days post-insertion. CONCLUSION: Implementation of this safe and effective topical decontamination regimen enhances routine CRBSI-prevention measures for haematology patients requiring central venous line insertion. PMID- 29126815 TI - Analysis of Suicide Risk in Patients with Penile Cancer and Review of the Literature. AB - The treatment for penile cancer has been shown to cause harmful psychiatric symptoms as well as have detrimental effects on well-being. In the past several years, alternatives to total or partial penectomy have emerged, such as chemotherapy, radiation, penile sparing, and laser ablation therapies. A more specific breakdown for penile cancer is in order as the therapy has the potential for life changing surgery. We examined the Surveillance, Epidemiology, and End Results (SEER) database (1973-2013), comprising 28% of the United States population. International Classification of Diseases, Tenth revision codes C60.8 C60.9 and the International Classification of Diseases-Oncology codes 8010/2, 8010/3, 8051/2, 8051/3, 8052/2, 8052/3, 8070/2, 8070/3-8072/3, 8074/3, 8076/3, and 8083/3-8084/3 were used. Age, race, marital status, and clinicopathologic variables were studied. We used contingency tables of suicide rates; mid-P exact test was used for analysis. There were 13 suicides noted in 6155 patients with squamous cell carcinoma of the penis. All patients that committed suicide had undergone a surgical intervention. Certainly, penile cancer after treatment has a powerful effect on quality of life as increased depression and sexual anxiety have been documented in postoperative patients. This is in contrast to the observed suicide rate. Despite the reported negative psychological effects in patients with penile cancer, suicide rates are among the lowest of all urologic malignancies. PMID- 29126816 TI - Effects of spermine and the passive avoidance learning (PAL) following cerebral ischemia in chicks: Association with neuroprotection of pyramidal cells. AB - The aim of this study is to investigate the effects of spermine and the passive avoidance learning on hippocampus following transient cerebral ischemia in the chicks. The study is composed of the pure control (CG), sham (SG) and experimental groups (n=20). Experimental groups (ischemia group, IG and ischemia spermine group, ISG) were exposed to ischemia for 20min whereas the SG was exposed to sham operation and CG group was not exposed to any operation. Passive avoidance learning (PAL) was applied to the half number of the subjects in each group. Both before and after 7days from the ischemia, operated animals were taken to PAL and then they were sacrificed. Total numbers of neurons in the hippocampus were stereologically estimated using Cresyl violet stained sections. We detected that number of neurons was increased following PAL and especially spermine treatment. According to our results, we suggested that spermine may reduce the deleterious effects of the ischemia by causing to increase in the neuronal number and so, it may be slightly supportive to the PAL. PMID- 29126817 TI - Serum anti-PLA2R antibody as a diagnostic biomarker of idiopathic membranous nephropathy: The optimal cut-off value for Chinese patients. AB - BACKGROUND: The M-type phospholipase A2 receptor (PLA2R) is a specific target autoantigen identified in idiopathic membranous nephropathy (IMN). The autoantibody against PLA2R (anti-PLA2R) may be used to diagnose IMN. However, the appropriate diagnosis cut-off value for Chinese patients with IMN has not been established. METHODS: In total, 119 patients who underwent renal biopsy (57 patients with IMN and 62 patients with non-IMN glomerulonephritis) and 22 healthy individuals were recruited for our observation study from Qianfoshan Hospital between September 2011 and March 2016. The serum concentration of anti-PLA2R was measured using a quantitative enzyme-linked immunosorbent assay (ELISA). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and receiver operating characteristic (ROC) curve of anti-PLA2R in diagnosing IMN were analysed based on the ELISA detection. RESULTS: The sensitivity, specificity, PPV, and NPV of anti-PLA2R in the diagnosis of IMN in the Chinese patients were 82.5, 75, 69.1, and 86.3% for the 2RU/ml cut-off value; 78.9, 91.7, 86.5, and 86.5% for the 2.6RU/ml cut-off value; 59.6, 95.2, 89.5, and 77.7% for the 14RU/ml cut-off value; 50.9, 96.4, 90.6, and 74.3% for the 20RU/ml cut-off value; and 47.4, 97.6, 93.1, and 73.2% for the 40RU/ml cut-off value, respectively. The area under the ROC curve was 0.879. CONCLUSIONS: The cut-off value of 2.6RU/ml is recommended for the use of anti-PLA2R for the diagnosis of IMN in Chinese patients based on the ELISA. PMID- 29126818 TI - Composite Y Grafts From the Left Internal Mammary Artery: Current Considerations. AB - The use of composite coronary artery bypass grafts from the left internal mammary artery (LIMA) has increased over the last 20 years. Total arterial revascularisation can be achieved with two arterial conduits and is associated with a reduced risk of stroke. However, the traditional coronary bypass graft configurations of the in situ LIMA and aorto-coronary saphenous vein grafts remain as the mainstay of coronary bypass surgery in most centres. Concerns regarding composite Y grafts relate to (1) the adequacy of a single inflow for all coronary bypass grafts; (2) the risk of compromising the LIMA flow to the left anterior descending coronary artery; (3) the effects of competitive flow on graft patency; and (4) the use of sequential coronary anastomoses. The evidence upon which these concerns are based will be discussed along with the evidence relating to the use of the various second conduit options. PMID- 29126820 TI - Blend design tools for Medium Combustion Plants (MCP) firing biomass wastes. AB - A feasible alternative for agricultural or forestry waste management is the operation of a distributed network of sustainable Medium Combustion Plants (MCPs). However, one of the main factors that hinder its development is the propensity to operational problems derived from corrosion, slagging and fouling characteristics of both bottom and fly ashes. Therefore, a cost-effective approach for these multi-product MCP could be based on predictive tools for an optimal formulation of a fuel blend. This work focuses on the assessment of the ability of these methods to provide guidance for preventing ash-related operational problems and to provide fuel-blending rules. The more widespread tools pertain to two types: compositional classification based on chemical analysis of laboratory ashes, and thermodynamic prediction of the most likely species and phases. Both criterion numbers and compositional maps are ranking methods based on the chemical analysis at a given ashing temperature. Thermodynamic equilibrium modeling is not constrained by any difference in the physical conditions of the MCP compared to those in the laboratory. Both kind of prediction tools have been validated in an MCP firing olive tree pruning residues as well as its typical blends in order to mimic a plausible pattern of fuels along a full year operating campaign. An intensive experimental campaign encompasses plant monitoring and off-line analysis of the ashes along the process line. Interpretation of compositional plots has revealed to be potentially sensitive to ashing temperature. Here are presented examples showing how this variable could lead to either insignificant differences or to a substantial disparity in the a priori fuel diagnosis. Some inconsistencies have been observed between the predictions based on criterion numbers, even for the same fuel and for ranking rules specifically formulated for biomasses. Moreover, it does not match consistently with the information obtained from phase diagrams. Therefore, their use should be limited to the case of a well-established selection of a fuel index for a well-defined fuel provided empirical evidence of an enough good description of the ash behavior, which is not the most frequent case. Thermodynamic equilibrium calculations allow a more precise prediction of the main species in the condensed phase, without the constraint of the ashing temperature. Elemental closure of main ash-forming elements with the chemical analysis of the process ashes presents small differences, and their proximity localization on the phase diagrams denote similar prediction between predicted and process ashes. PMID- 29126821 TI - Spatial and temporal characteristics of elevated temperatures in municipal solid waste landfills, Navid H. Jafari, Timothy D. Stark, and Todd Thalhamer, Waste Management, 2017, Vol. 59, p. 286-301. PMID- 29126822 TI - Blending based optimisation and pretreatment strategies to enhance anaerobic digestion of poultry manure. AB - Anaerobic digestion of poultry manure is limited by the excessive levels of nitrogen and the high concentration of dry matter. These limitations are usually overcome either by applying procedures to remove nitrogen or by employing pretreatments that allows to solubilise organic matter. In this work, the treatment of poultry manure was enhanced by co-digestion with pig manure through the methodological determination of optimal mixtures combined together with a thermochemical pretreatment coupled to ammonia stripping. The optimum poultry-pig mixture, resulting in a 24%:76% (volume basis) poultry-pig manure, was determined by applying a methodology based on linear programming which calculates the proportions of the blend which returns the maximum methane production while keeping a stable process. Pretreatment batch experiments, consisting of increasing both temperature and pH simultaneously with ammonia stripping process was optimised for a temperature of 90 degrees C and a pH of 10 resulting in a nitrogen removal efficiency of 72% and a 1.2-fold higher methane production in comparison to the unpretreated mixture. Continuous anaerobic co-digestion of pretreated optimum mixture enhanced the COD removal efficiency by 37% when compared with the treatment of unpretreated feedstock (37% vs 27%, respectively). This study indicates that combining blending optimisation of substrates, thermochemical pretreatments and ammonia stripping procedures prior to anaerobic co-digestion becomes a good strategy to overtake the limitations offered by solid and nitrogen-rich substrates, such as poultry manure. PMID- 29126819 TI - To Reduce the Global Burden of Human Schistosomiasis, Use 'Old Fashioned' Snail Control. AB - Control strategies to reduce human schistosomiasis have evolved from 'snail picking' campaigns, a century ago, to modern wide-scale human treatment campaigns, or preventive chemotherapy. Unfortunately, despite the rise in preventive chemotherapy campaigns, just as many people suffer from schistosomiasis today as they did 50 years ago. Snail control can complement preventive chemotherapy by reducing the risk of transmission from snails to humans. Here, we present ideas for modernizing and scaling up snail control, including spatiotemporal targeting, environmental diagnostics, better molluscicides, new technologies (e.g., gene drive), and 'outside the box' strategies such as natural enemies, traps, and repellants. We conclude that, to achieve the World Health Assembly's stated goal to eliminate schistosomiasis, it is time to give snail control another look. PMID- 29126823 TI - Pilot scale evaluation of a model to distinguish the rates of simultaneous anaerobic digestion, composting and methane oxidation in static waste beds. AB - The aim of this paper was to apply and validate a model for measuring the rate and extent of anaerobic digestion, composting and CH4 oxidation in laboratory scale beds. Degradation studies were performed in four reactors each packed with shredded unsorted municipal solid waste, with one bed covered with a 100 mm layer of soil. The rates of production of CH4, CO2, 13C-CO2 and the rate of consumption of O2 were measured and used as inputs to a mass balance expressions for these components to calculate the rates of anaerobic digestion, composting and CH4 oxidation. The results showed that anaerobic digestion, composting and CH4 oxidation occurred simultaneously in both the covered and uncovered beds. The analysis showed that 50 +/- 4% of the solids (COD basis) in the uncovered beds degraded anaerobically, with the generated CH4 subsequently oxidized, and that 32 +/- 4% of the solids degraded aerobically in the covered bed. PMID- 29126825 TI - Artificial Intelligence in Medical Practice: The Question to the Answer? AB - Computer science advances and ultra-fast computing speeds find artificial intelligence (AI) broadly benefitting modern society-forecasting weather, recognizing faces, detecting fraud, and deciphering genomics. AI's future role in medical practice remains an unanswered question. Machines (computers) learn to detect patterns not decipherable using biostatistics by processing massive datasets (big data) through layered mathematical models (algorithms). Correcting algorithm mistakes (training) adds to AI predictive model confidence. AI is being successfully applied for image analysis in radiology, pathology, and dermatology, with diagnostic speed exceeding, and accuracy paralleling, medical experts. While diagnostic confidence never reaches 100%, combining machines plus physicians reliably enhances system performance. Cognitive programs are impacting medical practice by applying natural language processing to read the rapidly expanding scientific literature and collate years of diverse electronic medical records. In this and other ways, AI may optimize the care trajectory of chronic disease patients, suggest precision therapies for complex illnesses, reduce medical errors, and improve subject enrollment into clinical trials. PMID- 29126826 TI - Autoimmune Neurologic Disorders. AB - The practice of autoimmune neurology focuses on the diagnosis and treatment of a wide spectrum of neurological conditions driven by abnormal immune responses directed against neural tissues. These include autoimmune, paraneoplastic, postinfectious, and iatrogenic conditions. Symptoms of autoimmune neurologic disorders can be diverse and often difficult to recognize in their early stages, complicating the diagnosis. This review discusses the classification and management of common autoimmune neurological conditions, placing an emphasis on the rapid identification of autoimmune etiology and mechanism of immune dysfunction to allow for the timely institution of appropriate treatment. PMID- 29126824 TI - Video Intervention to Increase Perceived Self-Efficacy for Condom Use in a Randomized Controlled Trial of Female Adolescents. AB - STUDY OBJECTIVE: To assess the effects of the Seventeen Days interactive video on young women's perceived self-efficacy for using condoms 6 months after being offered the intervention, relative to a control. DESIGN: Multisite randomized controlled trial. SETTING: Twenty participating health clinics and county health departments in Ohio, Pennsylvania, and West Virginia. PARTICIPANTS: Sexually active female adolescents ages 14 to 19 years. INTERVENTIONS: Seventeen Days (treatment intervention; sex education) vs Driving Skills for Life (control intervention; driving education). MAIN OUTCOME MEASURES: Perceived self-efficacy for condom use. RESULTS: Participants in the Seventeen Days group reported higher perceived condom acquisition self-efficacy after 6 months than those in the driving group. This finding held after controlling for baseline self-efficacy scores and other covariates. CONCLUSION: The Seventeen Days program shows promise to improve perceived self-efficacy to acquire condoms among sexually active female adolescents-an important precursor to behavior change. PMID- 29126827 TI - On the Palms of His Hands: ACTH-Induced Hyperpigmentation. PMID- 29126828 TI - Imported malaria in Bulgaria, status and prognosis after eradication in 1965. AB - BACKGROUND: This retrospective analysis assessed all recorded malaria cases in Bulgaria after 1965, when the country was certified as malaria-free by the World Health Organization (WHO), and evaluated the readiness of the public health system to interrupt an outbreak of local transmission in case of infection importation. METHODS: The cases were analyzed according to causative species; geographic origin of the imported case; and the citizenship, age, and gender of the infected individuals. RESULTS: In the 50-year study period (1966-2015), there were a total of 3011 cases of malaria imported to Bulgaria from different regions of the world. The majority of the cases originating in Africa were caused by Plasmodium falciparum (65.5%), while most of these originating in Asia were caused by P. vivax (80.9%). The potential season for malaria transmission in Bulgaria is from April to October, and 58.5% of the malaria cases were imported during that time of the year. CONCLUSIONS: The increasing movement of people to and from areas endemic for malaria requires the health authorities of countries with appropriate conditions for reintroduction to conduct enhanced measures for surveillance and control of this potentially deadly disease. PMID- 29126829 TI - Palliative Care in Diffuse Interstitial Lund Disease: Results of a Spanish Survey. AB - INTRODUCTION: Interstitial lung diseases (ILD) and, in particular, idiopathic pulmonary fibrosis, may have a significant impact on patient survival. Recent studies highlight the need for palliative care (PC) in the management of ILD patients. The aim of this study was to determine the current situation of PC in patients in Spain. METHODS: A 36-question survey addressing the main aspects of PC in ILD patients was designed. The survey was sent via email to all members of the Spanish Society of Pulmonology and Thoracic Surgery. Participation was voluntary. RESULTS: One hundred and sixty-four participants responded to the survey. Ninety-eight percent said they were interested in PC, 46% had received specific training, and 44% reported being responsible for PC in their ILD patients. Symptom control and end-of-life stage were the most frequent reasons for referral to PC teams. Regarding end-of-life, 78% reported consensual agreement with patients on the limitation of therapeutic efforts, 35% helped prepare an end-of-life advance directive, and 22% agreed on the place of death. CONCLUSION: Despite the well-known need for PC in patients with ILD and the notable interest of the survey participants in this subject, there are clear formative and organizational gaps that should be addressed to improve care in this area in ILD patients in Spain. PMID- 29126830 TI - Transcriptome studies of granulosa cells at different stages of ovarian follicular development in buffalo. AB - The normal maturation and ovulation from ovarian follicles is important in ensuring conception and improving fertility of buffalo. The molecular regulation mechanism of buffalo follicles growth, however, remains unknown. This study analyzed the gene expression profiles associated with buffalo ovarian follicle growth. According to the analysis of RNA sequencing, 17,700 unigenes and 13,672 differentially expressed genes (DEGs) were detected. A total of 30 common DEGs were identified during four stages of follicle growth, and the expression patterns are basically synchronized, suggesting the products as a result of expressions of these genes may cooperate to regulate follicular development. Furthermore, GO and KEGG enrichment analyses revealed that the majority of DEGs in early stage of follicular growth were enriched in ribosomal and oxidative phosphorylation signaling pathways, and the expression patterns of these DEGs are basically up-regulated at the beginning of follicular growth (<8mm, diameter), and then down-regulated (8-12mm) in the following stages of follicular development. The pathway of immune signaling, including allograft rejection, chemokine signaling pathway, natural killer cell mediated cytotoxicity, phagosome, and antigen processing and presentation, was significantly enriched in the last stage of follicular development (>12mm), which indicates that the immune system has an important role in the last stage of follicular maturation and ovulation. This study provided a gene expression profile of buffalo follicle growth, and provided an insight into biological processes associated with molecular regulation of ovarian follicle growth. PMID- 29126831 TI - Characterization of the ovarian preantral follicle populations and its correlation with age and nutritional status in Brazilian Northeastern donkeys (Equus assinus). AB - This study aimed to characterize the ovarian follicular population and to determine its correlations with the age and nutritional status of donkeys of the Northeastern Brazilian breed. A total of 10 females with a mean age of 5.1+/ 3.2years were submitted to ovariectomy by videolaparoscopy to obtain the ovaries. In the laboratory, the ovaries were sectioned into 6-12 fragments of approximately 7mm in diameter, which were fixed in Carnoy, dehydrated in increasing concentrations of alcohol (85%, 95% and absolute), clarified using xylol and embedded in blocks of histological paraffin. The blocks were cut in sections of 7MUm and each 120th section was mounted on a slide for observation using optical microscopy. The follicle counting and identification allowed the characterization of the population of the preantral follicles. A total of 21.135+/-10.821 preantral follicles was counted, of which, 91.3% were primordial, 8.3% were primary follicles and 0.4% were secondary follicles. There were no differences between the two ovaries of each animal regarding the follicular population (P>0.05). There was a rate of 9.77% degenerated follicles. Values of 0.99% follicles containing two oocytes were also identified and classified as multi-oocyte follicles, always of the primordial category. The thickness of the granulosa cell layer was 1.85MUm+/-1.39, 3.56MUm+/-2.08 and 21.85MUm+/-17.27, for primordial, primary and secondary follicles, respectively. There was a significant inverse correlation (r=-0.66; P<0.001) between the age of the animals and the population of ovarian follicles. A negative influence of the weight and body score on the ovarian follicular population was also observed, when donkeys had very little or a great amount of body condition. This is the first study to describe the morphometric characteristics and estimation of the population of preantral ovarian follicles in Northeastern Brazilian donkey, showing that number of preantral follicles decreased with increasing age of the animals and this finding may be affected by nutritional status of the animals. PMID- 29126832 TI - Corrigendum to "Relationship between time post-ovulation and progesterone on oocyte maturation and pregnancy in canine cloning" [Anim. Reprod. Sci. 185 (2017) 75-82]. PMID- 29126833 TI - BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers. AB - The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in 4 digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry on tissue microarrays. A total of 1546 samples of 4 types of cancer tissues, their matched adjacent nontumor tissues, and corresponding benign tissues were studied, respectively. Immunohistochemistry expression patterns of the 2 proteins and their correlation with patients' clinical parameters and overall survival were analyzed. The results showed that low expression of cytoplasmic BRCA1 and BRCA2 was commonly associated with advanced tumor-lymph node-metastasis stage, whereas high expression of nuclear BRCA1 was generally correlated with advanced tumor stages in these cancers. High expression of cytoplasmic BRCA1 and BRCA2 had significantly favorable overall survival in digestive system cancers; in contrast, BRCA1 nuclear expression usually predicted poor outcomes. We conclude that BRCA1 and BRCA2 could be used as clinicopathological biomarkers to evaluate the prognosis of digestive system cancers. PMID- 29126834 TI - Low expression of NKD2 is associated with enhanced cell proliferation and poor prognosis in human hepatocellular carcinoma. AB - NKD2 is a member of the Naked cuticle (Nkd) protein family and functions as a negative regulator of the Wnt signaling pathway. We investigated the prognostic value of NKD2 expression in hepatocellular carcinoma (HCC). Western blot and immunohistochemical analyses revealed that NKD2 was significantly downregulated in HCC specimens compared with adjacent nontumorous tissues. Next, we found that NKD2 expression correlated significantly with several clinicopathologic features, such as tumor grade, tumor size, and Ki-67 expression. Univariate and multivariate analyses demonstrated that NKD2 was an independent prognostic factor for the survival of HCC patients. In particular, Kaplan-Meier survival curves suggested that low NKD2 was statistically associated with poor overall survival. Furthermore, serum refeeding of cultured HCC cells led to impaired amounts of NKD2 and induced HepG2 and Huh7 cells to transition from the G1 to the S phase. Small interfering RNA-mediated depletion of NKD2 in LO2 hepatocytes caused accelerated cell growth. To further clarify the role of NKD2 in cell cycle progression, a Flag-tagged NKD2 construct was used to overexpress NKD2 exogenously in Huh7 cells. These results showed that overexpression of NKD2 induced G1-phase cell cycle arrest. Reduced expression of NKD2 correlated with hyperactivation of the Wnt/beta-catenin pathway and doxorubicin resistance in HCC cells. On the basis of these findings, we conclude that NKD2 may be a novel prognostic marker and therapeutic target in HCC. PMID- 29126835 TI - Tumor-infiltrating T lymphocytes and morphogenesis of follicular lymphoma-reply. PMID- 29126836 TI - New insights into the structural and functional involvement of the gate loop in AcrB export activity. AB - AcrB is a major multidrug exporter in Escherichia coli and other Gram-negative bacteria. Its gate loop, located between the proximal and the distal pockets, have been reported to play important role in the export of many antibiotics. This loop location, rigidity and interactions with substrates have led recent reports to suggest that AcrB export mechanism operates in a sequential manner. First the substrate binds the proximal pocket in the access monomer, then it moves to bind the distal pocket in the binding monomer and subsequently it is extruded in the extrusion monomer. Recently, we have demonstrated that the gate loop is not required for the binding of Erythromycin but the integrity of this loop is important for an efficient export of this substrate. However, here we show that the antibiotic susceptibilities of the same AcrB gate loop mutants for Doxorubicin were unaffected, suggesting that this loop is not required for its export, and we demonstrate that this substrate may use principally the tunnel-1, located between transmembranes 8 and 9, more often than previously reported. To further explain our findings, here we address the gate loop mutations effects on AcrB solution energetics (fold, stability, molecular dynamics) and on the in vivo efflux of Erythromycin and Doxorubicin. Finally, we discuss the efflux and the discrepancy between the structural and the functional experiments for Erythromycin in these gate loop mutants. PMID- 29126838 TI - Results of cytomegalovirus DNA viral loads expressed in copies per millilitre and international units per millilitre are equivalent. AB - Quantification of Cytomegalovirus (CMV) DNA is required for the initiation and monitoring of anti-viral treatment and the detection of viral resistance. However, due to the lack of standardisation of CMV DNA nucleic acid tests, it is difficult to set universal thresholds. In 2010, the 1st WHO International Standard for Human Cytomegalovirus for Nucleic Acid Amplification Techniques was released. Since then CMV DNA viral load assays have been calibrated using this standard. Three external quality assessment (EQA) providers sent the same five samples to their participants and analysed the results to determine the equivalence of reporting CMV DNA results in international units per millilitre (IU/mL), and compared the difference in results reported in IU/mL with those reported in copies per millilitre (c/mL), and to determine the rate of adoption of IU/mL. About 78% of participants continue to report results in c/mL even though six of the 12 commercial assays are calibrated against the standard. The range of the results reported in IU/mL was less than those reported in c/mL indicating that the adoption of the WHO standard successfully improved the reporting of the CMV viral load. The variation in individual sample results reported by different assays, irrespective of whether in IU/mL or c/mL, is still great and therefore more standardisation of the assays is needed to allow the setting of treatment and monitoring thresholds. This study can act as a bench mark to determine rate of future adoption if reporting CMV DNA viral load results in IU/mL. PMID- 29126837 TI - Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce Androgen Receptor Expression in Castration-Resistant Prostate Cancer Xenografts. AB - The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P < 0.05) and the AR splice variants 1 (threefold, P < 0.05) and 7 (threefold, P < 0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels. PMID- 29126839 TI - The epidemic typhus and trench fever are risk for public health due to increased migration in southeast of Turkey. AB - Pediculus humanus capitis is a small ectoparasitic insect that has lived and feds on human beings for thousands of years. Molecular techniques have been used for Pediculus species identification and evolutionary, phylogenic, and ecological studies. A total of 23 adults of P. h. capitis were collected in Gaziantep, located in southeast Turkey, and DNA was isolated from all P. h. capitis using DNA extraction kit. All DNA samples were screened for investigate of Ricettsia prowazekii, Bartonella quintana and Borrelia recurrentis with real-time polymerase chain reaction. In addition, we investigated genetic variation in DNA samples of Pediculus humanus capitis using the cytochrome oxidase I genetic DNA sequence. We found 4 (17.4%) Ricettsia prowazekii and 3 (13.1%) Bartonella quintana in DNA samples of Pediculus humanus capitis, while we did not find any Bartonella recurrentis in any of the DNA samples. We demonstrated 1.8% genetic variations in DNA samples of Pediculus humanus capitis with Bartonella quintana. The phylogenetic tree based on the cytochrome oxidase I gene revealed that P. h. capitis in southeast Turkey are classified into two clades (clade A, clade B) and Bartonella quintana was found in only clade B. However, we did not find any genetic variations in other DNA samples in this region. The genetic variations may be related to P. h.capitis vector of Bartonella quintana has found in this study. In addition, this study was shown that P. h. capitis do transmit Rickettsia prowazekii and Bartonella quintana to people, epidemic typhus and trench fever may emergence in Gaziantep southeast of Turkey in the future. PMID- 29126840 TI - Neuroprotective effect of cannabinoid receptor 1 antagonist in the MNU-induced retinal degeneration model. AB - Endocannabinoid system involves in neuroprotective effects on the central neural system. The cannabinoid receptor 1 (CB1R) is widely expressed in the mouse retina. However, the role of cannabinoid receptors in the retina remains unclear. In this work, we established a photoreceptor degeneration mouse model via N methyl-N-nitrosourea (MNU) administration to identify the neuroprotective effects of cannabinoid receptors. The MNU-induced retinal degeneration behaves similarly to that in the human retinitis pigmentosa (RP). Administration of the CB1R antagonist SR141716A distinctly recovered the photoreceptor loss, decreased glial reactivity and reduced abnormal vascular complexes in an MNU-induced mouse model. The BC dendrites were shrunk in the MNU-treated retina with eliminated ON-BCs responses and partially diminished OFF-BCs responses in patch-clamp recordings. In the MNU + SR1 group, both the function and structure of ON-BCs recovered. Taken together, our study showed that the inhibition of CB1R can effectively prevent MNU-induced retinal degeneration, suggesting a potential therapeutic effect of the CB1R antagonist SR1 in retinal degeneration diseases. PMID- 29126842 TI - Autoimmunity and COPD: Clinical Implications. AB - COPD is a leading cause of morbidity and mortality worldwide. Long-term cigarette smoking is the cause of > 90% of COPD cases in Westernized countries. However, only a fraction of chronic heavy smokers develop symptomatic COPD by age 80. COPD is characterized by an abnormal immune response in the lower airways, and its progression is associated with infiltration of the lung by innate and adaptive inflammatory immune cells that form lymphoid follicles. There is growing evidence that both cellular- and antibody-mediated autoimmunity has a fundamental role in the pathogenesis of stable COPD. In particular, carbonyl-modified proteins may help to drive autoimmunity in COPD and cause the characteristic small airways abnormalities and even contribute to the pathogenesis of pulmonary emphysema. Although direct, indirect, and circumstantial evidence of a role for autoimmunity in stable patients with COPD has been identified, no cause-and-effect relationship between autoimmunity and the mechanisms of COPD has been firmly established in man. As such, the potential contribution of an autoimmune response to the pathogenesis of COPD exacerbation is still being investigated and represents an area of active research. Many drugs targeting autoimmune responses are already available, and the results of controlled clinical trials are awaited with great interest. The potential for measuring specific serum autoantibodies as biomarkers to predict clinical phenotypes or progression of stable COPD is promising. PMID- 29126841 TI - [Exercise as a protective cardiovascular and metabolic factor in end stage renal disease patients]. AB - OBJECTIVE: The aim of the study was to test the effectiveness of Physical Activity (PA) during haemodialysis as a protective treatment against cardiovascular (CV) diseases. METHODS: Eighty volunteer patients were included in this multicentric prospective study and followed for two years: 40 patients in the Exercise group (EX), 40 patients in the Control group (Ctrl). CV risk factors: Total Cholesterol, HDL Cholesterol (HDL-c), LDL cholesterol (LDL-c), Triglycerides (TG) and Hemoglobin (Hb), and Prealbumin, Albumin, Parathormon, 25 OH Vitamin D, were checked at Month 0 (M0) and Month 24 (M24). The number of antihypertensive treatments and the Erythropoietin Stimulating Agent (ESA) required doses were collected. We noted for each group during the follow-up the number of hospitalizations for CV reasons. After two years, we compared 31 patients in EX and 35 in Ctrl. RESULTS: We observed a significant decrease of total cholesterol EX group: 1.86+/-0.49g/L at M0 versus 1.64+/-0.38g/L at M24 (P<0.05). HDLc and but LDL-c remained stable in both groups. TG decreased significantly in EX: 1.76+/-0.89g/L vs 1.44+/-0.69g/L (P<0.05). The number of antihypertensive drugs per patient decreased significantly (P<0.05) in the EX group between M0 and M24 (1.61+/-1.28 at M0 and 0.74+/-0.85 at M24). The EX patients were three times less frequently hospitalized for cardiovascular reasons. There were five hospital stays versus 14 for the Ctrl group. CONCLUSION: Our study demonstrates that an intradialytic aerobic cycling training program promotes beneficial effects on cardiovascular protection. Physical activity reduced the number of CV events in our population during two years follow-up. PMID- 29126844 TI - Prospective Outcome Analysis of the Safety and Efficacy of Partial and Complete Cryoablation in Organ-confined Prostate Cancer. AB - OBJECTIVE: To determine the rate of complications and change in International Prostate Symptom Score and Sexual Health Inventory for Men scores following cryotherapy treatment of low- and intermediate-risk prostate cancer. The secondary end points were the change in prostate-specific antigen post cryotherapy and biopsy-proven recurrence. MATERIALS AND METHODS: Enrollment occurred from 2007 to 2015 to assess long-term complications of cryotherapy. A prostate biopsy was performed at 1 year or in the event of biochemical failure. Subjects were staged and graded by standard 12- to 14-core transrectal ultrasound (TRUS) biopsy. A subset of subjects underwent additional 3-dimensional mapping biopsy if the cancer was suspected to be downgraded. Analyses of functional outcomes were stratified into focal and nonfocal treatments. RESULTS: The study consisted of 393 men with low- and intermediate-risk prostate cancer, aged 44-89 years. Patient IPSS scores improved significantly in the nonfocal treatment strata at all time points and after 1 year in the focal strata with a median drop at 1 year of 4 points (P <.001). No significant difference was detected for a change in preprocedural SHIM score in either treatment strata after 2 years (P >.7). Eighty-two patients (20.9%) had a rise in prostate-specific antigen resulting in biochemical failure. Seventy patients had detected recurrence for an overall recurrence rate of 20.4% in 343 patients. A total of 109 patients (27.7%) reported urinary retention and urgency post cryotherapy, with 15.3% requiring catheterization for up to 3 weeks. Thirty-seven patients (9.4%) experienced urethral meatal stricture, and 36 patients (9.2%) reported unresolved new-onset erectile dysfunction. CONCLUSION: Complication rates, most significantly erectile dysfunction, are decreased in this study compared with those previously reported in the literature for cryotherapy for prostate cancer. PMID- 29126843 TI - The role of platelet reactivity assessment in dual antiplatelet prophylaxis after transcatheter aortic valve implantation. AB - BACKGROUND: Dual antiplatelet therapy (DAPT) is recommended prophylaxis after transcatheter aortic valve implantation (TAVI). The usefulness of platelet reactivity (PLTR) tests in predicting the safety of periprocedural DAPT in the TAVI population is unknown. AIM: To analyze the value of aspirin/clopidogrel PLTR testing in predicting the risk of in-hospital TAVI-related bleeding. METHODS: PLTR, expressed as P2Y12/aspirin reaction units (PRU/ARU), was performed using optical aggregometry with the VerifyNow(r) device, in the 24h before and on the sixth day after TAVI. Follow-up was by telephone. Bleeding was defined according to VARC-2, and comprised in-hospital, major and life-threatening events. RESULTS: Overall, 100 patients undergoing TAVI were included; 30 (30%) had bleeding. Clopidogrel PLTR before TAVI (area under the curve [AUC] 0.686, 95% confidence interval [CI] 0.542-0.808; P=0.02) and after TAVI (AUC 0.970, 95% CI 0.904-0.995; P<0.001) correlated with bleeding, with PRU cut-off values of <=204 and <=124 as bleeding predictors, respectively. A significant periprocedural decrease in clopidogrel PLTR was noted, with a PRU drop of >78 as bleeding predictor (AUC 0.851, 95% CI 0.725-0.935; P<0.001). Only postprocedural aspirin PLTR was associated with bleeding (AUC 0.697, 95% CI 0.585-0.794; P=0.008). Follow-up (359+/-73 days after TAVI) included 85 patients (85%) (after exclusion for in hospital death [n=4] and lack of contact [n=11]). Major bleeding was noted in four patients (4.7%), all on combined prophylaxis. CONCLUSIONS: TAVI-related bleeding occurs mainly during the procedure or in the early postprocedural period. Testing of periprocedural clopidogrel PLTR, but not aspirin PLTR, seems useful because of its predictive value for TAVI-related bleeding. PLTR testing suggests that premedication with clopidogrel, enhanced response to clopidogrel early after TAVI and significant periprocedural drop in clopidogrel PLTR might increase the risk of TAVI-related bleeding. PMID- 29126845 TI - A Race to Imaging Revolution: Pioneers in Fiber Optics. PMID- 29126846 TI - Sexual Function and Quality of Life in Adult Male Individuals with Exstrophy Epispadias Complex-a Survey of the German CURE-Network. AB - OBJECTIVE: To investigate sexual function and quality of life (QoL) in adult male individuals with exstrophy-epispadias complex (EEC). Data from the German Network for Congenital Urorectal Malformations (CURE-Net) were used. PATIENTS AND METHODS: Fifty-one male participants (>=18 years) recruited by CURE-Net between 2009 and 2012 were re-contacted per mail and asked to fill out 4 questionnaires including International Index of Erectile Function (IIEF-5), Cologne Assessment of Erectile Dysfunction (KEED), the Short-Form 36 (SF-36), and one self-designed questionnaire about their medical history, current health status, and sexual experience. The SF-36 results were compared with general German population. RESULTS: Nineteen male participants (37%) completed all questionnaires (median age 26 years, 84% classical bladder exstrophy). The majority (68%) was reconstructed in a staged or single-staged approach; further 32% had a primary urinary diversion. Seventy-four percent of the participants reported a certain degree of urinary incontinence. Mean IIEF-15 results showed mild to moderate or moderate impairment in all domains. The SF-36 results revealed no difference in the German population. Subgroup analysis showed statistically significant lower results in certain SF-36 domains with regard to incontinence, dissatisfaction with genital appearance, and antihypertensive drug intake. CONCLUSION: Although there is no difference in overall QoL comparing male individuals with EEC to the general German population, incontinence, dissatisfaction with genital appearance, and taking antihypertensive medication seem to have a considerable impact on QoL. Furthermore, mild to moderate erectile dysfunction and moderate intercourse satisfaction were confirmed, suggesting the need for further improvement in care for adult male individuals with EEC. PMID- 29126847 TI - Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [11C]-D-deprenyl PET/CT. AB - BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [11C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [11C]-D deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [11C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naive subjects. The aim of this study was to investigate if [11C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience. METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [11C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury. RESULTS: Acute [11C] D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [11C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [11C]-D-deprenyl uptake in painful locations. CONCLUSIONS AND IMPLICATIONS: The data provide further support that [11C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management. PMID- 29126848 TI - Evaluation of external vibratory stimulation as a treatment for chronic scrotal pain in adult men: A single center open label pilot study. AB - BACKGROUND AND AIMS: Chronic scrotal pain is a common yet poorly understood urologic disease. Current treatment paradigms are sub-optimal and include anti inflammatory drugs and opioids as well as invasive surgical management such as microdenervation of the spermatic cord. In this study, the efficacy of external vibratory stimulation (EVS) was evaluated as an alternative treatment option for idiopathic scrotal pain. MATERIALS AND METHODS: Ten consecutive patients presenting to an academic urology clinic between December 2016 and April 2017 with scrotal pain were prospectively enrolled. After a comprehensive history and physical exam, patients were presented with and oriented to a spherical vibratory device that they were instructed to use topically each day for four weeks. Average and maximum pain severity, frequency, and bother scores were tracked at 2 week intervals using a visual analog scale (0-10) via survey. Descriptive statistics facilitated interpretation of individual changes in pain. RESULTS: Nine men, with a median age of 46 years, completed at least 2 weeks of the study intervention. 78% (7/9) of men achieved some improvement in daily scrotal pain levels. Overall, average pain decreased from 4.9 to 2.7 (p=0.009) while maximum pain severity decreased from 6.3 to 4.0 (p=0.013). The frequency of pain also decreased for 55.6% (5/9) of men. No severe side effects were noted by any of the participants though several patients reported mild paresthesia only during application of the device. The majority of men expressed interest in continuing treatment after conclusion of the study. CONCLUSION: External vibratory stimulation has been suggested as a promising non-invasive tool to alleviate chronic pain. As a proof-of-concept, we implemented EVS to treat men with idiopathic orchialgia. The majority of patients noted benefit in both severity and frequency of pain. Given its low risk profile, EVS deserves further evaluation and inclusion in treatment guidelines as a promising experimental therapy for a disease with few conservative treatment options available to providers. IMPLICATIONS: In this longitudinal study, external vibratory stimulation was found to decrease chronic scrotal pain without any adverse effects. The use of this non-invasive, non-pharmaceutical therapy to treat chronic scrotal pain has the potential to decrease physician and patient dependence on surgical procedures and opioid prescriptions. Future randomized, double blind clinical trials with a placebo arm are required to corroborate these findings and establish the true efficacy of EVS. PMID- 29126849 TI - Introduction of 2-O-benzyl abasic nucleosides to the 3'-overhang regions of siRNAs greatly improves nuclease resistance. AB - Chemically modified siRNAs containing 2-O-benzyl-1-deoxy-d-ribofuranose (RHOBn) in their 3'-overhang region were significantly more resistant towards serum nucleases than siRNAs possessing the natural nucleoside in this region. The knockdown efficacies and binding affinities of these modified siRNAs to the recombinant human Argonaute protein 2 (hAgo2) PAZ domain were comparable with that of siRNA with a thymidine dimer at the 3'-end. PMID- 29126850 TI - PSMA-targeted bispecific Fab conjugates that engage T cells. AB - Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an alphaCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an alphaPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of alphaPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines. Both bispecific formats demonstrated excellent potency and antigen selectivity. PMID- 29126851 TI - CCR6 signaling inhibits suppressor function of induced-Treg during gut inflammation. AB - CCR6 is a G protein-coupled receptor (GPCR) that binds to a specific chemokine, CCL20. The role of CCR6-CCL20 is very well studied in the migration of immune cells, but the non-chemotaxis functions of CCR6 signaling were not known. Here, we show that during gut inflammation, the frequency of Foxp3+CD4+ T cells (Tregs) reduced in the secondary lymphoid tissues and CCR6+ Tregs enhanced the expression of RORgammat. The peripheral blood mononuclear cells (PBMCs) of ulcerative colitis (UC) patients showed lower percentages of Foxp3+CD4+ T cells, as compared to healthy individuals, with CCR6+ Tregs showing higher RORgammat expression as compared to CCR6-Tregs. CCL20 inhibited the TGF-beta1-induced Treg (iTreg) differentiation and directed them towards the pathogenic Th17-lineage in a CCR6 dependent manner. The iTreg that differentiated in the presence of CCL20 showed lower surface expression of suppressor molecules such as CD39, CD73 and FasL, and had impaired suppressive function. Furthermore, CCR6 signaling induced phosphorylation of Akt, mTOR, and STAT3 molecules in T cells. In conclusion, we have identified a new role of CCR6 signaling in the differentiation of iTregs during inflammation and gut autoimmunity. PMID- 29126852 TI - A three-step health services research approach to improve prescribing. AB - Medications are often prescribed suboptimally; some effective medications are underused, some ineffective medications are overused, and some medications that should be received by a few are instead given to many. The underlying causes of suboptimal prescribing likely differ for each medication, and therefore must be understood anew, although previous studies can help generate hypotheses. This perspective sets forth a 3-step research agenda, which has worked well for us in several recently completed and ongoing projects. The three steps are to 1) demonstrate variation in suboptimal prescribing for the targeted medication; 2a) use mixed methods to understand the patient-, provider-, and system-level causes of suboptimal prescribing for this medication; 2b) develop a justification for improving the use of this medication, often involving a business case analysis; and 3) develop and implement interventions to improve prescribing of the targeted medication, informed by what has been learned in Steps 1 and 2 and relying on the principles of implementation science. Previous efforts have focused disproportionately on Step 1, or documenting gaps in practice, and Step 3, or deploying and evaluating efforts to improve practice. Our contention is that addressing all three steps sequentially, while effort-intensive, will maximize the chances of deploying a more effective intervention that will impact population health. We commend this three-step approach to health services researchers who wish to maximize impact by basing their research on a natural progression from documenting problems, to understanding their causes, to formulating and deploying a solution. PMID- 29126853 TI - Absorption, metabolism, distribution and excretion of (-)-epicatechin: A review of recent findings. AB - This paper reviews pioneering human studies, their limitations and recent investigations on the absorption, metabolism, distribution and excretion (aka bioavailability) of (-)-epicatechin. Progress has been made possible by improvements in mass spectrometric detection when coupled to high performance liquid chromatography and through the increasing availability of authentic reference compounds of in vivo metabolites of (-)-epicatechin. Studies have shown that [2-14C](-)-epicatechin is absorbed in the small intestine with the 12 structural-related (-)-epicatechin metabolites (SREMs), mainly in the form of (-) epicatechin-3'-O-glucuronide, 3'-O-methyl-(-)-epicatechin-5-sulfate and (-) epicatechin-3'-sulfate, attaining sub-MUmol/L peak plasma concentrations (Cmax) ~1 h after ingestion. SREMs were excreted in urine over a 24 h period in amounts corresponding to 20% of (-)-epicatechin intake. On reaching the colon the flavan 3-ol undergoes microbiota-mediated conversions yielding the 5C-ring fission metabolites (5C-RFMs) 5-(hydroxyphenyl)-gamma-valerolactones and 5 (hydroxyphenyl)-gamma-hydroxyvaleric acids which appear in plasma as phase II metabolites with a Cmax of 5.8 h after intake and are excreted in quantities equivalent to 42% of the ingested (-)-epicatechin. Other catabolites excreted in 0-24 h urine in amounts equivalent to 28% of intake included 3-(3' hydroxyphenyl)hydracrylic acid, hippuric acid and 3'-hydroxyhippuric acid. Overall (-)-epicatechin is highly bioavailable with urinary excretion indicating that 95% is absorbed and passes through the circulatory systems as a diversity of phase II metabolites. Rats produce a very different profile of SREMs than that of humans. These findings demonstrate that ex vivo studies investigating the mechanisms underlying the protective effects of (-)-epicatechin on human health should make use of physiological concentrations human of SREMs and 5C-RFMs, and not the parent (-)-epicatechin, with model systems derived from human cells. In epidemiological studies 5-(4'-hydroxyphenyl)-gamma-valerolactone-3'-sulfate and 5 (4'-hydroxyphenyl)-gamma-valerolactone-3'-O-glucuronide, the principal 5C-RFMs in both plasma and urine, could serve as key biomarkers of (-)-epicatechin intake. PMID- 29126854 TI - Biomedical applications of glyconanoparticles based on quantum dots. AB - BACKGROUND: Quantum dots (QDs) are outstanding nanomaterials of great interest to life sciences. Their conjugation versatility added to unique optical properties, highlight these nanocrystals as very promising fluorescent probes. Among uncountable new nanosystems, in the last years, QDs conjugated to glycans or lectins have aroused a growing attention and their application as a tool to study biological and functional properties has increased. SCOPE OF REVIEW: This review describes the strategies, reported in the literature, to conjugate QDs to lectins or carbohydrates, providing valuable information for the elaboration, improvement, and application of these nanoconjugates. It also presents the main applications of these nanosystems in glycobiology, such as their potential to study microorganisms, the development of diseases such as cancer, as well as to develop biosensors. MAJOR CONCLUSIONS: The development of glyconanoparticles based on QDs emerged in the last decade. Many works reporting the conjugation of QDs with carbohydrates and lectins have been published, using different strategies and reagents. These bioconjugates enabled studies that are very sensitive and specific, with potential to detect and elucidate the glycocode expressed in various normal or pathologic conditions. GENERAL SIGNIFICANCE: Produce a quick reference source over the main advances reached in the glyconanotechnology using QDs as fluorescent probes. PMID- 29126855 TI - N-Docosahexaenoylethanolamine (synaptamide): Carbon-14 radiolabeling and metabolic studies. AB - N-Docosahexaenoylethanolamine (synaptamide) is structurally similar to the endocannabinoid N-arachidonoylethanolamine (anandamide), but incorporates the omega-3 22:6 fatty acid docosahexaenoic acid (DHA) in place of the omega-6 20:4 fatty acid arachidonic acid (AA). Some brain membrane lipid effects may be mediated via synaptamide. In competition experiments with mouse brain homogenate in vitro, we found that synaptamide was an order-of-magnitude poorer inhibitor of radioactive anandamide hydrolysis than was anandamide itself. Also, enzyme mediated hydrolysis of synaptamide was observed to occur at a slower rate than for anandamide. We have synthesized synaptamide radiolabeled with carbon-14 in both the ethanolamine ([alpha,beta-14C2]synaptamide) and in the DHA ([1 14C]synaptamide) moieties. The brain penetration, distribution, and metabolism of radiolabeled synaptamide were studied in mice in vivo relative to anandamide, DHA, and AA. Brain uptake of labeled synaptamide was greater than for labeled DHA, consistent with previous studies of labeled anandamide and AA in our laboratory. After administering either isotopomer of radiolabeled synaptamide, radiolabeled phospholipids were found in mouse brain. Pretreatment of mice with PF3845, a potent, specific inhibitor of fatty acid amide hydrolase (FAAH), eliminated formation of labeled phospholipids measured after 15min, suggesting that synaptamide is hydrolyzed nearly exclusively by FAAH, though it is a poorer substrate for FAAH than anandamide. PMID- 29126856 TI - NLX-112, a highly selective 5-HT1A receptor agonist: Effects on body temperature and plasma corticosterone levels in rats. AB - NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT1A receptors. It possesses marked activity in a variety of animal models of depression, pain and L DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT1A receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT1A receptor agonists in humans. NLX-112 elicited dose-dependent hypothermia (minimal effective dose, MED: 0.31mg/kg p.o.) and also increased plasma corticosterone both by oral and intraperitoneal routes (MED: 0.63mg/kg in both cases). The increase in corticosterone induced by NLX-112 (0.63mg/kg p.o.) was abolished by co-administration of the selective 5-HT1A receptor antagonist, WAY100635. Additionally, NLX-112 also dose-dependently induced flat body posture, forepaw treading and lower lip retraction (MEDs 0.31-0.63mg/kg p.o.). The doses of NLX 112 which induce hypothermia or corticosterone release were similar to those inducing serotonergic behaviors but greater than those reported previously in models of therapeutic-like activity (range 0.04 to 0.16mg/kg). Overall, the present study provides information for clinical dose estimations of NLX-112 and suggests that therapeutic effects may occur at doses below those at which biomarker responses are observed. PMID- 29126857 TI - Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women. AB - BACKGROUND AND OBJECTIVE: Data from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine-seeking behavior. In a recent study, we found that cocaine-dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine-dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug-paired cue that was preceded by a stressor in cocaine-dependent women. METHODS: Cocaine-dependent women with low (<4ng/ml; n=16) and high (>=4ng/ml; n=9) plasma progesterone levels received either the alpha-2 adrenergic receptor antagonist yohimbine (21.6mg) or placebo before each of two cocaine-cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double-blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60min after the cue. RESULTS: The anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition*progesterone level interaction, F1,23=9.8, p=0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition*progesterone level interaction, F1,23=13.9, p=0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition. CONCLUSIONS: These preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug-cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women. PMID- 29126859 TI - The need for anaesthetic assessment in obstetric patients with airway abnormalities. PMID- 29126858 TI - Age, Sex, and Dose Effects of Nonbenzodiazepine Hypnotics on Hip Fracture in Nursing Home Residents. AB - OBJECTIVE: The Food and Drug Administration recommends a reduced dose of nonbenzodiazepine hypnotics in women, yet little is known about the age-, sex-, and dose-specific effects of these drugs on risk of hip fracture, especially among nursing home (NH) residents. We estimated the age-, sex-, and dose-specific effects of nonbenzodiazepine hypnotics on the rate of hip fracture among NH residents. DESIGN AND SETTING: Case-crossover study in US NHs. PARTICIPANTS: A total of 691 women and 179 men with hip fracture sampled from all US long-stay NH residents. MEASUREMENTS: Measures of patient characteristics were obtained from linked Medicare and the Minimum Data Set (2007-2008). The outcome was hospitalization for hip fracture with surgical repair. We estimated rate ratios (RRs) and 95% confidence intervals (CIs) from conditional logistic regression models for nonbenzodiazepine hypnotics (vs nonuse) comparing 0 to 29 days before hip fracture (hazard period) with 60 to 89 and 120 to 149 days before hip fracture (control periods). We stratified analyses by age, sex, and dose. RESULTS: The average RR of hip fracture was 1.7 (95% CI 1.5-1.9) for any use. The RR of hip fracture was higher for residents aged >=90 years vs <70 years (2.2 vs 1.3); however, the CIs overlapped. No differences in the effect of the hypnotic on risk of hip fracture were evident by sex. Point estimates for hip fracture were greater with high-dose versus low-dose hypnotics (RR 1.9 vs 1.6 for any use), but these differences were highly compatible with chance. CONCLUSIONS: The rate of hip fracture in NH residents due to use of nonbenzodiazepine hypnotics was greater among older patients than among younger patients and, possibly, with higher doses than with lower doses. When clinicians are prescribing a nonbenzodiazepine hypnotic to any NH resident, doses of these drugs should be kept as low as possible, especially among those with advanced age. PMID- 29126860 TI - It's not easy being green, or is it? Alkaline battery versus A/C power for programmed intermittent epidural bolus pumps. PMID- 29126861 TI - Is the grass on the other side greener? PMID- 29126862 TI - Cortical activity in fine-motor tasks in children with Developmental Coordination Disorder: A preliminary fNIRS study. AB - Developmental Coordination Disorder (DCD) is as a neurodevelopmental condition characterized by poor motor proficiency, which impacts academic performance and activities of daily living. Several studies have determined that children with DCD activate different regions of the brain when performing motor skills in comparison to typically developing (TD) children. However, none have used Functional Near-Infrared Spectroscopy (fNIRS) to explore cortical activation in this population. With that, the goal of this preliminary study was to investigate cortical activation using fNIRS in six children with DCD and six TD children between ages of 8 and 12 years. Three fine-motor tasks were performed: Finger Tapping (FT), Curve Tracing (CT), and Paragraph Writing (PW). Tasks were presented in counterbalanced order and had a baseline of 30s. Cortical activity elicited during performance of the FT, CT, and PW tasks was measured by fNIRS, and activation areas within each group were statistically compared. Results indicated that participant groups used different focal activation areas as well as different neural networks to perform the tasks. These distinct patterns were also task-specific, with differences in the right Pre-Motor Cortex (Pre-MC) and Supplementary Motor Area (SMA) for CT, and the right Dorsolateral Prefrontal Cortex (DLPFC) and the right Pre-MC for the PW task. These results add to the body of research exploring neurological alterations in children with DCD, and establish the feasibility of using fNIRS technology with this population. PMID- 29126863 TI - Utility of transient elastography (fibroscan) and impact of bariatric surgery on nonalcoholic fatty liver disease (NAFLD) in morbidly obese patients. AB - BACKGROUND: Controlled attenuation parameter (CAP) is a novel, noninvasive technique for assessing hepatic steatosis. However, its role in morbidly obese individuals is unclear. The effect of bariatric surgery on inflammation and fibrosis needs to be explored. OBJECTIVES: To assess the utility of CAP for assessment of hepatic steatosis in morbidly obese individuals and evaluate the effect of bariatric surgery on hepatic steatosis and fibrosis. SETTING: A tertiary care academic hospital. METHODS: Baseline details of anthropometric data, laboratory parameters, FibroScan (XL probe), and liver biopsy were collected. Follow-up liver biopsy was done at 1 year. RESULTS: Of the 124 patients screened, 76 patients were included; mean body mass index was 45.2 +/- 7.1 kg/m2. FibroScan success rate was 87.9%. The median liver stiffness measurement (LSM) and CAP were 7.0 (5.0-9.5) kPa and 326.5 (301-360.5) dB/m, respectively. On liver histopathology, severe steatosis and nonalcoholic steatohepatitis were present in 5.3% and 15.8%; significant fibrosis (>=stage 2) and cirrhosis in 39.5% and 2.6%, respectively. Area under receiver operator characteristic curve of LSM for prediction of significant fibrosis (F2-4 versus F0-1) and advanced fibrosis (F3-4 versus F0-2) was .65 (95% confidence interval [CI]: .52-.77) and .83 (95% CI: .72-.94), respectively. The area under receiver operator characteristic curve of CAP for differentiating moderate hepatic steatosis (S2-3 versus S0-1) and severe hepatic steatosis (S3 versus S0-2) was .74 (95% CI: .62-.86) and .82 (95% CI: .73-.91), respectively. At 1-year follow up, 32 patients underwent liver biopsy. In these patients, there was significant improvement in hepatic steatosis (P = .001), lobular inflammation (P = .033), ballooning (P<.001), and fibrosis (P = .003). Nonalcoholic steatohepatitis was resolved in 3 of 4 (75%) patients. LSM and CAP significantly declined. CONCLUSIONS: LSM and CAP are feasible and accurate at diagnosing advanced fibrosis and severe hepatic steatosis in morbidly obese individuals. Bariatric surgery is associated with significant improvement in LSM, CAP, steatohepatitis, and fibrosis. PMID- 29126864 TI - The impact of bariatric surgery on pulmonary function: a meta-analysis. AB - Morbid obesity may affect several body systems and cause ill effects to the cardiovascular, hepatobiliary, endocrine, and mental health systems. However, the impact on the pulmonary system and pulmonary function has been debated in the literature. A systematic review and meta-analysis for studies that have evaluated the impact of bariatric surgery on pulmonary function were pooled for this analysis. PubMed, Cochrane, and Embase databases were evaluated through September 31, 2016. They were used as the primary search engine for studies evaluating the impact pre- and post-bariatric surgery on pulmonary function. Pooled effect estimates were calculated using random-effects model. Twenty-three studies with 1013 participants were included in the final meta-analysis. Only 8 studies had intervention and control groups with different time points, but 15 studies had matched groups with different time points. Overall, pulmonary function score was significantly improved after bariatric surgery, with a pooled standardized mean difference of .59 (95% confidence interval: .46-.73). Heterogeneity test was performed by using Cochran's Q test (I2 = 46%; P heterogeneity = .10). Subgroup analysis and univariate meta-regression based on study quality, age, presurgery body mass index, postsurgery body mass index, study design, female patients only, study continent, asthmatic patients in the study, and the type of bariatric surgery confirmed no statistically significant difference among these groups (P value>.05 for all). A multivariate meta-regression model, which adjusted simultaneously for these same covariates, did not change the results (P value > .05 overall). Assessment of publication bias was done visually and by Begg's rank correlation test and indicated the absence of publication bias (asymmetric shape was observed and P = .34). This meta-analysis shows that bariatric surgery significantly improved overall pulmonary functions score for morbid obesity. PMID- 29126865 TI - Vitrification of dog spermatozoa: Effects of two cryoprotectants (sucrose or trehalose) and two warming procedures. AB - Sperm vitrification is a low cost and simple technique that does not require special equipment and may represent an attractive alternative to the costly and time consuming conventional dog spermatozoa cryopreservation techniques. The objective of this study was to evaluate different cryoprotectants and warming temperatures on the vitrification of dog spermatozoa. Pooled semen samples from 10 beagle dogs were vitrified with four extenders, based on Tris, citric acid and glucose, 20% egg yolk (TCG-20% EY) and different combinations of sucrose and/or trehalose: 250 mM sucrose; 250 mM trehalose; 125 mM sucrose + 125 mM trehalose; 250 mM sucrose + 250 mM trehalose. Samples were vitrified by dropping 50 MUL of sperm suspension directly into liquid nitrogen. After vitrification, warming was done either fast (at 65 degrees C for 2-5 s) or slow (at 37 degrees C for one minute). Motility was assayed using a computer-aided sperm analysis (CASA) system; membrane integrity and acrosomal status were analyzed by fluorescence microscopy. For comparison, samples were also conventionally frozen in liquid nitrogen vapor using a TCG-20% egg yolk extender plus 5% glycerol. Frozen straws were thawed in a water bath at 37 degrees C for 30 s. Poorer motility results (P < 0.05) but similar viability were obtained when vitrification was performed, compared to conventional freezing (P > 0.05). When vitrification was used, cryoprotectants containing either 250 mM sucrose or 250 mM trehalose and warmed at 37 degrees C returned the best sperm quality variables. PMID- 29126866 TI - Advances in Diagnosis and Management of Diffuse Large B-cell Lymphoma. AB - The management of diffuse large B-cell lymphoma (DLBCL) has been gradually evolving since the discovery of its 2 major forms, the germinal center B-like (GCB) and activated B-cell (ABC) types. Although the reference standard for the identification of these cell types is considered gene expression profiling (GEP), currently the only method commercially available is immunohistochemistry (IHC). The application of various IHC-based algorithms and their correlation with GEP and clinical outcome are discussed. Because of the adverse prognostic implications of the non-GCB type and its potential effects on treatment selection, the recently revised World Health Organization classification has included these biologic cell types. The management of double hit lymphomas, which almost exclusively fall under the GCB category, is discussed, together with the double expresser phenotype, which is usually grouped under the non-GCB type. The role of lenalidomide and ibrutinib in the management of the non-GCB type is examined. We also discuss the front-line management of primary mediastinal large cell lymphoma using the EPOCH (etoposide, prednisolone, Oncovin [vincristine], cyclophosphamide, hydroxydaunorubicin [doxorubicin]) regimen and examine new salvage data on immune checkpoint inhibitors for this clinical subtype. The prognosis, clinical features, and management of de novo CD5+ DLBCL are discussed, and newer and promising developments in the management of primary central nervous system lymphomas are presented in detail. The most popular salvage regimens and the application of high-dose chemotherapy with stem cell transplantation are assessed in detail. Finally, data on new treatment tactics such as CART (chimeric antigen receptor T-cell) cells and promising new drugs, including blinatumomab and venetoclax, are presented. PMID- 29126867 TI - Allogeneic Hematopoietic Cell Transplantation for Richter Syndrome: A Single Center Experience. AB - BACKGROUND: Recent studies have shown dismal outcomes when chronic lymphocytic leukemia progresses to Richter syndrome after patients receive ibrutinib, with a median overall survival ranging from 2.6 to 3.5 months. Published data on efficacy of allogeneic hematopoietic cell transplantation in Richter syndrome are limited to single-center case series and registry data. PATIENTS AND METHODS: We evaluated the efficacy of allogeneic transplantation in 10 patients, median age of 63 (range, 50-74) years, allografted at a median of 5 (range, 4-25) months from diagnosis of Richter syndrome. All showed an objective response to therapy before transplantation (first complete remission = 7 [70%], first partial response = 2 [20%], second partial response = 1 [10%]). Most received a myeloablative conditioning regimen (n = 7, 70%). Filgrastim-mobilized peripheral blood stem cells was the preferred cell source (n = 10, 100%). RESULTS: Median follow-up of surviving patients was 46 (range, 15-82) months. The 4-year overall survival was 50% (95% confidence interval [CI], 19%-81%). Nonrelapse mortality at 1 year and 4 years post-transplantation were 40% (95% CI, 19%-85%) for both time points. The 4-year incidence of relapse/progression was 10% (95% CI, 2%-64%). CONCLUSION: Allogeneic hematopoietic cell transplantation is an effective treatment for patients with Richter syndrome who show an objective response before allografting. Patients must be referred to transplant centers as soon as the diagnosis is confirmed to evaluate candidacy for the procedure and identify a suitable donor in a timely manner. PMID- 29126868 TI - Up-regulated miR-548k promotes esophageal squamous cell carcinoma progression via targeting long noncoding RNA-LET. AB - Dysregulated noncoding RNAs have been observed in diverse cancers. MIR458K is frequently amplified in esophageal squamous cell carcinoma (ESCC). However, the expression, clinical significances, and action mechanisms of miR-548k in ESCC are still unclear. In this study, we found that miR-548k is significantly up regulated in ESCC tissues and cell lines. Up-regulated miR-548k expression is significantly correlated with advanced invasion depth, lymph node metastasis, advanced TNM stage, and poor overall survival. Gain-of- and loss-of-function assays demonstrated that miR-548k promotes the proliferation and migration of ESCC cells in vitro and tumor growth in vivo. Mechanistically, we found that miR 548k directly targets and represses the expression of long noncoding RNA-LET (lncRNA-LET), and further down-regulates p53 and up-regulates NF90. In addition, we found that lncRNA-LET is down-regulated and inversely correlated with miR-548k in ESCC. Down-regulated lncRNA-LET also indicated poor overall survival of ESCC patients. Functional assays demonstrated that lncRNA-LET inhibits the proliferation and migration of ESCC cells, and the effects of miR-548k on ESCC are dependent on the negative regulation of lncRNA-LET. In summary, our data revealed the critical roles of miR-548k-lncRNA-LET regulation axis in ESCC and suggested that the miR-548k-lncRNA-LET regulation axis may be promising prognostic biomarkers and therapeutic targets for ESCC. PMID- 29126869 TI - An investigation of endocytosis of targeted nanoparticles in a shear flow by a statistical approach. AB - The receptor-ligand mediated endocytosis of nanoparticles by endothelium cells in a shear flow is investigated theoretically. A set of population balance equations is used to calculate the number of endocytosed nanoparticles of diameters about 100 nm for a given period of time. Hydrodynamic analysis reveals that whether a wash-out procedure is effective to remove incompletely endocytosed nanoparticles depends on the bond formation and rupture rates rather than the shear rate since the rupture rate of bonds linking nanoparticles and endothelium cells does not change with the shear rate appreciably. Furthermore, it is shown that critical bond formation and rupture rates, above which the elevation in ligand expression on cell surfaces stimulated by the shear flow will increase the number of endocytosed nanoparticles significantly, exist for typical average endocytosis durations. PMID- 29126870 TI - Susceptibility to unconscious influences is unaffected by a challenging inhibitory task or mental exhaustion. AB - Unconscious influences have been demonstrated in a variety of behavioural contexts, however, a key question remains - to what extent do such influences vary with our changing mental states? We examine whether a prior inhibitory challenge increases susceptibility to subliminal priming in a stem completion task employing neutral (Experiment 1) and reward salient terms (Experiment 2). Results show stem completions to be significantly influenced by unconscious priming, and the challenging inhibitory task (the Stroop) to be significantly more mentally exhausting than the control task. However, neither the degree of inhibitory challenge, trait self-control, nor task-related mental exhaustion significantly influenced unconscious priming. Bayesian analysis provides strong evidence that prior inhibitory challenge does not affect susceptibility to unconscious priming. The study supports the conclusion that unconscious processing can be independent of consciously experienced mental states and provides reassurance that inhibitory impairment, common to mood disorders, should not increase susceptibility to unconscious influences. PMID- 29126871 TI - Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR. AB - OBJECTIVE: Evaluation of the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease. METHODS: Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV1) <40 received lumacaftor 400 mg/ivacaftor 250mg every 12h (full dose) for 24weeks in an open-label, prospective study (NCT02390219). Dose modification to half dose for 1-2weeks (including at initiation) was permitted. Safety and tolerability were the primary outcome measures; clinical outcomes were also assessed. RESULTS: Of 46 patients (initiated on full dose: n=28; initiated on half dose: n=18), 35 (76%) completed 24weeks of treatment. The most common adverse events included infective pulmonary exacerbation, abnormal respiration, cough, and dyspnea. Compared with patients initiating on full dose, patients initiating at half dose had less frequent respiratory events (56% vs 71%) of shorter median duration (4 vs 9days). No dose modifications or discontinuations as a result of respiratory events occurred in patients initiating on half dose who were then increased to the full dose over 2weeks (versus three each for patients on full dose). Following an initial reduction, ppFEV1 was similar to baseline from week 4 throughout the remainder of the study (least squares mean [95% confidence interval] at week 24: -0.4 [-1.9, 1.1]; p=0.6249). Compared with the 24weeks prior to study, the annualized hospitalization rate was lower (rate ratio: 0.41; p=0.00026) and the duration of intravenous antibiotics was shorter (mean [standard deviation] difference: -8.52 [24.91] days; p=0.0369) through study week 24. CONCLUSIONS: Compared with patients with higher lung function, respiratory events were more common in patients with ppFEV1<40; aside from these events, the lumacaftor/ivacaftor safety profile was consistent with previous studies. Results suggest that patients with ppFEV1<40 may benefit from treatment initiation at a lower dose with augmented monitoring before increasing to the full dose. PMID- 29126872 TI - Phylogenetic analyses of DENV-3 isolated from field-caught mosquitoes in Thailand. AB - Dengue virus serotype 3 (DENV-3) can cause all forms of dengue diseases and is a predominant serotype in many countries. This serotype is classified into five genotypes: I-V. Genotypes I-III have widely spread throughout the world, whereas genotypes IV and V are rare. Despite the impact on the spread of dengue diseases, only a few studies have reported the characteristics of DENV present in mosquito vectors. Hence, this study aimed to identify DENV-3 genotypes and reveal genetic variation of this virus presented in field-caught mosquitoes collected from endemic areas in Thailand during 2011-2015. First, we examined the effectiveness of the E gene sequence on DENV-3 genotyping, with results supporting the use of this gene for genotype identification. Then, we sequenced this gene in ten DENV-3 strains isolated from mosquitoes. The results showed that eight and two samples were genotypes III and V, respectively, and that they are closely related to DENV 3 isolated from Southeast and East Asian samples. The translated E gene sequences showed 25 unique amino acid (AA) residues located at 23 positions. Eight out of 25 residues have different chemical properties compared to the conserved AAs that are distributed across the three domains functioning in virus-host interaction. Hence, our study reports the first DENV-3 genotype V in Thailand, with these viruses potentially influencing both the disease severity and epidemic potential of DENV-3. PMID- 29126873 TI - Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis. AB - OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). METHODS: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2-7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. RESULTS: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. CONCLUSIONS: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD. PMID- 29126874 TI - Decreased serum undercarboxylated osteocalcin is associated with cognitive impairment in male patients with type 2 diabetes. AB - BACKGROUND: Basic and clinical researches have suggested that type 2 diabetes (T2DM) is associated with cognitive impairment, and diabetes mellitus increases the risk of cognitive impairment and dementia. Recently, some reports found that undercarboxylated osteocalcin (ucOC) could affect brain functions, and decreased in patients with T2DM. We aimed to investigate the association of serum ucOC with cognitive impairment in T2DM patients. METHODS: A total of 196 male T2DM patients without medications known to affect bone metabolism or history of bone fracture, aged >=18years were recruited and divided into impaired cognition group and normal cognition group. We use the scores of Minimum Mental State Examination (MMSE) to evaluate the subjects' cognitive function. Detailed cognitive performance was also evaluated by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum ucOC was measured by Enzyme-Linked Immunosorbent Assay (ELISA) kit. RESULTS: Compared to male T2DM patients with normal cognition, the mean osteocalcin concentrations were significantly lower in male T2DM patients with impaired cognition (P<0.05). RBANS total and all indexes scores were also lower in patients with impaired cognition (all P<0.05). After adjusted effects of confounding factors, serum ucOC was positively correlated with a variety indexes of RBANS except visuospatial/constructional. CONCLUSIONS: The serum ucOC is positively correlated with RBANS scores in male T2DM patients. It suggests that serum ucOC may be involved in the development and progression of cognitive dysfunction in T2DM patients. PMID- 29126875 TI - Molecular mechanisms of astrocyte-neuron signaling. PMID- 29126876 TI - "Melanie's measles" is deadly and causes permanent neurologic impairment. PMID- 29126877 TI - Chidamide, a histone deacetylase inhibitor-based anticancer drug, effectively reactivates latent HIV-1 provirus. AB - Although combination antiretroviral therapy (cART) is highly effective in suppressing human immunodeficiency virus type 1 (HIV-1) replication, it fails to eradicate the virus from HIV-1-infected individuals because HIV-1 integrates into the resting CD4+ T cells, establishing latently infected reservoirs. Histone deacetylation is a key element in regulating HIV-1 latent infection. Chidamide, a new anticancer drug, is a novel type of selective histone deacetylase inhibitor. Here we showed that chidamide effectively reactivated HIV-1 latent provirus in different latently infected cell lines in a dose- and time-dependent manner. Chidamide had relatively low cytotoxicity to peripheral blood mononuclear cells (PBMCs) and other latent cell lines. We have demonstrated that chidamide reactivated HIV-1 latent provirus through the NF-kappaB signaling pathway. The replication of the newly reactivated HIV-1 could then be effectively inhibited by the anti-HIV-1 drugs Zidovudine, Nevirapine, and Indinavir. Therefore, chidamide might be used in combination with cART for functional HIV-1 cure. PMID- 29126878 TI - Dendritic cells in systemic sclerosis: Advances from human and mice studies. AB - Systemic sclerosis (SSc) is a complex heterogeneous fibrotic autoimmune disease with an unknown exact etiology, and characterized by three hallmarks: fibrosis, vasculopathy, and immune dysfunction. Dendritic cells (DCs) are specialized cells in pathogen sensing with high potency of antigen presentation and capable of releasing mediators to shape the immune response. Altered DCs distributions and their impaired functions may account for their role in breaking the immune tolerance and driving inflammation in SSc, and the direct contribution of DCs in promoting endothelial dysfunction and fibrotic process has only begun to be understood. Plasmacytoid dendritic cells in particular have been implicated due to their high production of type I interferon as well as other cytokines and chemokines, including the pro-inflammatory and anti-angiogenic CXCL4. Furthermore, a deeper understanding of human and mouse DC biology has clarified their identification and function in different tissues, and novel DC subsets have only recently been discovered. In this review, we highlight key findings and recent advances exploring DC role in the pathogenesis of SSc and other related autoimmune diseases, and consideration of their potential use as targeted therapy in SSc. PMID- 29126879 TI - Mechanical stretch increases L-type calcium channel stability in cardiomyocytes through a polycystin-1/AKT-dependent mechanism. AB - The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells. We recently reported that PC1 regulates LTCC stability in cardiomyocytes under stress; however, the mechanism underlying this effect remains unknown. Here, we use cultured neonatal rat ventricular myocytes and hypo-osmotic stress (HS) to model mechanical stretch. The model shows that the Cavbeta2 subunit is necessary for LTCC stabilization in cardiomyocytes during mechanical stretch, acting through an AKT-dependent mechanism. Our data also shows that AKT activation depends on the G protein-coupled receptor activity of PC1, specifically its G protein-binding domain, and the associated Gbetagamma subunit of a heterotrimeric Gi/o protein. In fact, over-expression of the human PC1 C-terminal mutant lacking the G protein binding domain blunted the AKT activation-induced increase in Cav1.2 protein in cardiomyocytes. These findings provide novel evidence that PC1 is involved in the regulation of cardiac LTCCs through a Gibetagamma-AKT-Cavbeta2 pathway, suggesting a new mechanism for regulation of cardiac function. PMID- 29126880 TI - A heart-enriched antisense long non-coding RNA regulates the balance between cardiac and skeletal muscle triadin. AB - : Non-coding RNAs play major roles in cardiac pathophysiology. Recent studies reported that long non-coding RNAs (lncRNAs) are dysregulated in the failing heart, but how they contribute to heart failure development is unclear. In this study, we aimed to identify heart-enriched lncRNAs and investigate their regulation and function in the failing heart. RESULTS: Analysis of a RNA-seq dataset of 15 Caucasian tissues allowed the identification of 415 heart-enriched lncRNAs. Fifty-three lncRNAs were located on the genome in close vicinity to protein-coding genes associated with cardiac function and disease. Analysis of a second RNA-seq dataset of 16 failing human hearts highlighted one lncRNA which we arbitrarily named TRDN-AS due to its localisation in the antisense position of the gene encoding triadin (TRDN). Expression of TRDN-AS and cardiac TRDN was up regulated in biopsies from failing human hearts compared to control hearts. In failing hearts, TRDN-AS was positively correlated with a cardiac isoform of TRDN and negatively correlated with a skeletal muscle isoform of TRDN. A murine homolog of human TRDN-AS was identified and found to be enriched in the heart and localised in the nuclear compartment of cardiomyocytes. Trdn-AS expression as well as the ratio between cardiac and skeletal muscle isoforms were down regulated after experimental myocardial infarction. In murine cardiomyocytes, activation of Trdn-AS transcription with the CRISPR/dCas9-VPR system enhanced the ratio between cardiac and skeletal isoforms of Trdn. CONCLUSION: The lncRNA TRDN AS regulates the balance between cardiac and skeletal isoforms of triadin. This finding may have implications for the treatment of heart failure. PMID- 29126881 TI - Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1/PD-L1 agents. AB - Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches. Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the TNBC microenvironment and, in response to several stimuli, undergo M1 (classical) or M2 (alternative) activation. In TNBC, TAMs promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of Tumor Infiltrating Lymphocytes (TILs) and the promotion of Regulatory T cell (Treg). Interestingly, TAMs have been shown to directly and indirectly modulate PD-1/PD L1 expression in tumor environment. On this scenario, several TAM-centered strategies have been proposed, such as the suppression of TAM recruitment, the depletion of their number, the switch of M2 TAMs into antitumor M1 phenotype and the inhibition of TAM-associated molecules. In this review, we will illustrate the activity of TAMs and associated molecules in TNBC, focusing on their role in modulating the expression of PD-1/PD-L1 and on the emerging TAM-tailored strategies for TNBC patients. PMID- 29126882 TI - The Role of Magnetic Resonance Imaging-Diffusion Tensor Imaging in Predicting Pain Related to Endometriosis: A Preliminary Study. AB - OBJECTIVES: To evaluate the sacral nerve root features by the means of magnetic resonance imaging-diffusion tensor imaging (MRI-DTI) tractography in women with endometriosis and/or adenomyosis, and to analyze the correlations among DTI abnormalities, pain symptoms, and endometriotic lesions found at surgery. DESIGN: A cross-sectional, observational study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Women (n = 76) with clinical suspicion of endometriosis. INTERVENTIONS: Before surgery, dysmenorrhea, deep dyspareunia, and noncyclic pelvic pain (NCPP) were assessed using a 10-point visual analog scale. MRI enabled a 3-dimensional reconstruction of S1, S2, and S3. Fractional anisotropy was calculated for each root. Laparoscopic treatment of endometriosis was performed in 56 patients. MEASUREMENTS AND MAIN RESULTS: Our findings revealed correlations among sacral root reconstruction by MRI-DTI, pain symptoms, and laparoscopic findings. DTI of sacral roots revealed a regular and homogeneous appearance in 17 patients (25.8%) and abnormalities in microstructure reconstruction, with fiber irregularities and disorganization and loss of the simple unidirectional course, in 44 patients (66.7%). At laparoscopy, ovarian endometriomas were found in 82.1% of the patients, and deeply infiltrating endometriosis (DIE) were found in 57.1%. Endometriosis was staged according to the revised American Society for Reproductive Medicine classification. Pathological DTI findings were significantly associated with the severity of dysmenorrhea and NCPP, pain duration, presence of tubo-ovarian and cul-de-sac adhesions, and DIE. CONCLUSION: The presence of pathological DTI findings of the sacral nerve roots correlates with the type of pain, adhesions, and DIE. At present, DTI can be useful for providing a better understanding of pain; however, DTI could become a useful tool in therapeutic planning for patients with endometriosis. PMID- 29126883 TI - Different Blocking Sequences Performed by Laparoscopy. AB - STUDY OBJECTIVE: To demonstrate the application of different knot blocking sequences in laparoscopic surgery. DESIGN: A step-by-step demonstration of different blocking sequences performed by laparoscopic surgery (Canadian Task Force classification III). SETTING: Private hospital in Curitiba, Parana, Brazil. INTERVENTION: The correct placement of one knot over the other is rarely taught in the surgical literature. Laparoscopic knot-tying techniques may be performed using one hand (monomanual technique) or alternating both hands (bimanual technique). Rotation of the needle holders around the thread (clockwise or counterclockwise rotation) is very important to have a symmetric or an asymmetric configuration of the knot, which affects the stability of the entire knot sequence. The monomanual knot-tying technique needs to alternate the rotation of the needle holder, and the bimanual technique does not when performing half knots (square or flat knots). The half hitch is an asymmetric knot that is obtained when the surgeon makes asymmetric traction on one thread (passive thread) and place the knot using the other thread (active thread). To block 2 half hitches, the surgeon needs to change the active and the passive threads. Beginners in laparoscopy commonly make mistakes tying knots, leading to an insecure knot sequence that may slip and/or open under minimal forces. In this video, we demonstrate different types of blocking sequences performed by laparoscopy applied in different surgical procedures. Ethics Committee approval was obtained for this video. CONCLUSION: Knot-tying is a basic surgical skill that must be mastered by all laparoscopists. PMID- 29126884 TI - Hyaluronan in experimental injured/inflamed cartilage: In vivo studies. AB - Joint disease is characterized by an imbalance between the synthesis and degradation of articular cartilage and subchondral bone accompanied by capsular fibrosis, osteophyte formation and varying degrees of inflammation of the synovial membrane. Many animal models have been developed to study arthritis and osteoarthritis that enable experimental conditions, diet and environmental risk factors to be carefully controlled. Animal-based studies have demonstrated the positive effects of exogenous HA on the preservation of joint cartilage in different models of arthritis and osteoarthritis. Although many promising effects of exogenous HA have been reported, there remains uncertainty as to its effectiveness in reversing cartilage injury and other manifestations of joint diseases because of difficulties in interpreting and unifying the results of these studies. A review of the literature of the last decade was conducted to report the results and to determine what we have learned from animal models in relation to joint inflammation induced by experimental models and HA treatment. PMID- 29126885 TI - Medial frontal cortex response to unexpected motivationally salient outcomes. AB - The medial frontal cortex (MFC) plays a central role allocating resources to process salient information, in part by responding to prediction errors. While there is some recent debate, the feedback-related negativity (FRN) is thought to index a reward prediction error by signaling outcomes that are worse than expected. A recent study utilizing electric shock provided data inconsistent with these accounts and reported that the omission of both appetitive (money) and aversive outcomes (electric shocks) elicited a medial frontal negativity. These data suggest that the ERPs within this time range support a salience prediction error that responds to unexpected events regardless of valence. To compare the reward and salience prediction error models, we employed a design that delivered both appetitive (monetary) and aversive (noise burst) outcomes. Participants completed a passive S1/S2 prediction design where S1 predicted S2 with 80% accuracy and S2 predicted the outcome with 100% accuracy. We compared both earlier and later ERP responses over the medial frontal cortex to compare the salience and reward prediction hypotheses. Considering both time windows, the ERP response to S2 in the early time window was most positive when S2 signaled that an outcome was unexpectedly delivered and in the later time window, was most negative when an outcome was unexpectedly withheld, regardless of outcome valence. Thus, these results are more consistent with a salience prediction error rather than a reward prediction error. PMID- 29126886 TI - Platinum, palladium, rhodium, molybdenum and strontium in blood of urban women in nine countries. AB - BACKGROUND: There is little reliable information on human exposure to the metals platinum (Pt), palladium (Pd) and rhodium (Rh), despite their use in enormous quantities in catalytic converters for automobile exhaust systems. OBJECTIVES: To evaluate blood concentrations of Pt (B-Pt), Pd (B-Pd) and Rh (B-Rh) in women from six European and three non-European countries, and to identify potentially influential factors. In addition, molybdenum (Mo) and strontium (Sr) were analysed. METHODS: Blood from 248 women aged 47-61 was analysed by high resolution inductively coupled plasma mass spectrometry under strict quality control. RESULTS: The medians were: B-Pt 0.8 (range <0.6-5.2), B-Pd <5 (<5-9.3), B-Rh <0.4 (<0.4-3.6)ng/L and B-Mo 2.0 (0.2-16) and B-Sr 16.6 (3.5-49) MUg/L. Two women with highly elevated B-Pt (242 and 60ng/L), previously cancer treated with cis-platinum, were not included in the data analysis. All elements varied geographically (2-3 times) (B-Pd P=0.05; all other elements P<0.001); variations within each area were generally 5-10 times. Traffic was not associated with increased concentrations. CONCLUSIONS: General population blood concentrations of Pt, Pd and Rh are within or below the single digit ng/L range, much lower than in most previous reports. This is probably due to improved analytical performance, allowing for more reliable information at ultra-trace levels. In general, Mo and Sr agreed with previously reported concentrations. All elements showed geographical and inter-individual variations, but no convincing relationships with self-reported traffic intensity were found. Pt from the antineoplastic drug cis-platinum is retained in the body for years. PMID- 29126887 TI - Combined administration of resolvin E1 and lipoxin A4 resolves inflammation in a murine model of Alzheimer's disease. AB - Dysfunction in the resolution of inflammation may play a key role in Alzheimer's disease (AD). In this study, we found that the levels of specialized pro resolving lipid mediators (SPMs) in the hippocampus of 5xFAD mice are significantly lower than in non-transgenic littermates. We, therefore, tested the hypothesis that treatment with resolvin E1 (RvE1) and lipoxin A4 (LXA4) alone or in combination will reverse the neuroinflammatory process and decrease Abeta pathology. 5xFAD mice were treated intraperitoneally starting at 1month of age with RvE1 or LXA4 alone or in combination at a dose of 1.5 MUg/kg, 3 times a week until 3months of age. We found that treatment with RvE1 or LXA4 alone or in combination increased the concentration of RvE1, LXA4, and RvD2 in the hippocampus as measured by ELISA. Combination treatment of RvE1 and LXA4 had a more potent effect on the activation of microglia and astrocytes than either treatment alone, measured by immunohistochemistry with Iba1 and GFAP antibodies, respectively. The concentrations of Abeta40 and Abeta42 were measured by ELISA and the percentage of Abeta plaques were analyzed by immunohistochemistry. All treatments single and in combination, decreased the measures of Abeta pathology and restored the homeostasis reversing the inflammatory process for inflammatory cytokines and chemokines (GM-CSF, IFN-gamma, IL-1beta, IL-6, IL-10, TNF-alpha, MCP-1, MIP-1alpha, MIP-1beta, and RANTES) as measured by multiplex immunoassay. Overall, the study showed that the levels of SPMs in the hippocampus of 5xFAD mice were significantly lower than in wild-type mice; that treatment with RvE1 and LXA4 restored the level of these compounds, reversed the inflammatory process, and decreased the neuroinflammation associated with Abeta pathology in 5xFAD mice. PMID- 29126889 TI - Impaired glutamatergic projection from the motor cortex to the subthalamic nucleus in 6-hydroxydopamine-lesioned hemi-parkinsonian rats. AB - The glutamatergic projection from the motor cortex to the subthalamic nucleus (STN) constitutes the cortico-basal ganglia circuit and plays a critical role in the control of movement. Emerging evidence shows that the cortico-STN pathway is susceptible to dopamine depletion. Specifically in Parkinson's disease (PD), abnormal electrophysiological activities were observed in the motor cortex and STN, while the STN serves as a key target of deep brain stimulation for PD therapy. However, direct morphological changes in the cortico-STN connectivity in response to PD progress are poorly understood at present. In the present study, we used a trans-synaptic anterograde tracing method with herpes simplex virus green fluorescent protein (HSV-GFP) to monitor the cortico-STN connectivity in a rat model of PD. We found that the connectivity from the primary motor cortex (M1) to the STN was impaired in parkinsonian rats as manifested by a marked decrease in trans-synaptic infection of HSV-GFP from M1 neurons to STN neurons in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. Ultrastructural analysis with electron microscopy revealed that excitatory synapses in the STN were also impaired in parkinsonian rats. Glutamatergic terminals identified by a specific marker (vesicular glutamate transporter 1) were reduced in the STN, while glutamatergic neurons showed an insignificant change in their total number in both the M1 and STN regions. These results indicate that the M1-STN glutamatergic connectivity is downregulated in parkinsonian rats. This downregulation is mediated probably via a mechanism involving the impairments of excitatory terminals and synapses in the STN. PMID- 29126890 TI - How to prevent, recognize and manage complications of AF ablation? AB - Ablation of atrial fibrillation (AF) is one of most complex procedures in electrophysiology. Many technical improvements have been incorporated lately in order to improve clinical results and reducing risks. Currently, cardiac tamponade, stroke, PV stenosis, phrenic palsy and atrial esophageal fistula are still recognized as the major risks of AF ablation, although their managements have been much better established. The aim of this article is to review recent data in how to avoid, to identify and to treat such complications. PMID- 29126888 TI - Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury. AB - There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il corpus callosum (CC: -30%) and external capsule (EC: -21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (-17%) and EC (-13%), corresponding to histopathological evidence of white matter loss (cl-CC: -68%; cl EC: -30%) associated with ongoing microgliosis and astrogliosis. These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration. PMID- 29126891 TI - Early, real-world experience with direct oral anticoagulants in the treatment of intermediate-high risk acute pulmonary embolism. AB - INTRODUCTION: Intermediate-high risk pulmonary embolism (IHR-PE) has a poor prognosis, but is under-represented in trials of direct oral anticoagulants (DOACs) in venous thromboembolic disease (VTE). We aimed to assess whether the administration of DOACs was equivalent to the conventional (CONV) treatment of low-molecular weight heparin bridged with warfarin for treating IHR-PE. METHODS: We conducted a retrospective cohort study including 59 consecutive patients admitted with IHR-PE and followed for up to three months after discharge. Two groups were created based on the anticoagulant strategy: CONV (n=35) and DOAC (n=24). The efficacy endpoints were death, recurrent PE, estimated pulmonary artery systolic pressure (PASP), right ventricular systolic function (RVSF) at discharge, and length of stay; the safety endpoint was major bleeding. RESULTS: The two groups were similar regarding demographics, PE etiology and markers of clinical severity. There were four in-hospital deaths in the CONV group and none in the DOAC group. No recurrent PE or major bleeding event was recorded in either group. At discharge, neither PASP nor RVSF was different between the groups. Patients in the DOAC group were discharged 1.7 days earlier on average than patients in the CONV group (4.7+/-2.4 vs. 3.0+/-1.5 days, p=0.002). CONCLUSIONS: The adoption of a DOAC treatment strategy in this real-world cohort of IHR-PE patients was associated with similar efficacy and safety to the CONV approach. The fact that monitoring of anticoagulation effect was unnecessary probably led to the significant reduction in length of stay. PMID- 29126892 TI - Atrial fibrillation ablation beyond pulmonary veins: The role of left atrial appendage. AB - The role of pulmonary vein isolation in patients with non-paroxysmal atrial fibrillation (AF) is only modest. Several studies have demonstrated the role of the left atrial appendage (LAA) in initiating and maintaining of this arrhythmia. We review in this article the incremental benefit in free-arrhythmia recurrence of LAA electrical isolation in patients undergoing procedures for persistent AF or long standing persistent AF either using radiofrequency ablation, cryoablation or Lariat device implantation. Likewise, acute complications, anticoagulation and the risk of ischemic stroke after LAA electrical isolation (LAAEI) are analyzed. LAAEI in addition to standard ablation appears to have a substantial incremental benefit to achieve freedom from all atrial arrhythmias in patients with persistent AF and long standing persistent atrial fibrillation (LSPAF) without increasing acute procedural complications and without raising the risk of ischemic stroke. PMID- 29126893 TI - Commemorating twenty years since the first catheter-based pulmonary vein isolation to treat atrial fibrillation by ablation. PMID- 29126894 TI - Developments in pre-hospital patient transport in ST-elevation myocardial infarction. AB - INTRODUCTION: ST-elevation myocardial infarction (STEMI) is a medical emergency that benefits from rapid access to specialized care. The objective of this study was to describe developments in patient transport via the pre-hospital emergency medical system (EMS) and its impact on clinical outcomes. METHODS: We retrospectively studied STEMI patients who underwent primary percutaneous coronary intervention between January 2008 and July 2015. Patients were divided according to type of admission. Total ischemic time (TIT), door-to-balloon time (DBT) and in-hospital and one-year clinical outcomes were assessed for each group. RESULTS: A total of 764 patients were included, of whom 33.5% were transported by the EMS and 45.8% by their own means, 13.7% were transferred from another institution and 6.9% were transported by non-EMS ambulance. There was a trend for more frequent recourse to the EMS over the eight-year period. There was a higher percentage of patients with prior myocardial infarction and Killip class III/IV in the EMS group compared to the non-EMS group. Significant differences were seen between groups in reperfusion times, EMS patients having the shortest TIT and DBT (195 vs. 286 min, p<0.001 and 61 vs. 90 min, p<0.001, respectively), but no significant difference in event rates was observed. Patients presenting to the hospital early had higher rates of effective reperfusion and lower in hospital mortality (6.9% vs. 33.9%, p<0.001). CONCLUSIONS: Recourse to the EMS significantly reduced ischemic times. Although this improvement was not directly associated with significant differences in event rates, it was associated with higher rates of effective reperfusion that were reflected in lower in-hospital mortality. PMID- 29126895 TI - Extracorporeal membrane oxygenation in circulatory and respiratory failure - A single-center experience. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) provides mechanical pulmonary and circulatory support for patients with shock refractory to conventional medical therapy. In this study we aim to describe the indications, clinical characteristics, complications and mortality associated with use of ECMO in a single tertiary hospital. METHODS: We conducted a retrospective observational cohort study of all patients supported with ECMO in two different intensive care units (general and cardiac), from the first patient cannulated in April 2011 up to October 2016. RESULTS: Overall, 48 patients underwent ECMO: 29 venoarterial ECMO (VA-ECMO) and 19 venovenous ECMO (VV-ECMO). In VA-ECMO, acute myocardial infarction was the main reason for placement. The most frequent complication was lower limb ischemia and the most common organ dysfunction was acute renal failure. In VV-ECMO, acute respiratory distress syndrome after viral infection was the leading reason for device placement. Access site bleeding and hematologic dysfunction were the most prevalent complication and organ dysfunction, respectively. Almost 70% of ECMO episodes were successfully weaned in each group. Survival to discharge was 37.9% for VA-ECMO and 63.2% for VV-ECMO. In VA-ECMO, the number of inotropic agents was a predictor of mortality. CONCLUSION: Patients with respiratory indications for ECMO experienced better survival than cardiac patients. The need for more inotropic drugs was a predictor of mortality in VA-ECMO. This is the first published record of the overall experience with ECMO in a Portuguese tertiary hospital. PMID- 29126896 TI - The continuous challenge of AF ablation: From foci to rotational activity. AB - Pulmonary vein isolation (PVI) is central to ablation approaches for atrial fibrillation (AF), yet many patients still have arrhythmia recurrence after one or more procedures despite the latest technology for PVI. Ablation of rotational or focal sources for AF, which lie outside the pulmonary veins in many patients, is a practical approach that has been shown to improve success by many groups. Localized sources lie in atrial regions shown mechanistically to sustain AF in optical mapping and clinical studies of human AF, as well as computational and animal studies. Because they arise in localized atrial regions, AF sources may explain central paradoxes in clinical practice - such as how limited ablation in patient specific sites can terminate persistent AF yet extensive anatomical ablation at stereotypical locations, which should extinguish disordered waves, does not improve success in clinical trials. Ongoing studies may help to resolve many controversies in the field of rotational sources for AF. Studies now verify rotational activation by multiple mapping approaches in the same patients, at sites where ablation terminates persistent AF. However, these studies also show that certain mapping methods are less effective for detecting AF sources than others. It is also recognized that the success of AF source ablation is technique dependent. This review article provides a mechanistic and clinical rationale to ablate localized sources (rotational and focal), and describes successful techniques for their ablation as well as pitfalls to avoid. We hope that this review will serve as a platform for future improvements in the patient-tailored ablation for complex arrhythmias. PMID- 29126897 TI - Self-efficacy and physical activity among adults with visual impairments. AB - BACKGROUND: According to empirical evidence, adults with visual impairments are generally less physically active than their sighted peers, however less is known about what specific motivational factors influence physical activity participation among this population. While research has identified self-efficacy as one important motivational factor for physical activity, no previous research has examined this association among individuals with visual impairments. OBJECTIVE: The primary purpose of the current study was to examine the association between self-efficacy and physical activity for adults with visual impairments. METHODS: A total of 147 participants (Mage = 44.5, 65.2% female) completed three online surveys (i.e., demographic questionnaire, International Physical Activity Questionnaire-Short Form [IPAQ-SF], and Self-Efficacy for Exercise Beliefs [SEEB] scale) and were included in the analysis. MET-min/wk and SE beliefs were analyzed descriptively and inferentially using correlation and multiple regression analyses. RESULTS: Participants reported an average of 2799.98 MET-min/wk. Body mass measures showed a mean BMI of 27.59, which was within the overweight range. A positive association (r = 0.29, p < 0.01) was found between self-efficacy and MET-min/wk. A significant amount of variance (10.2%) in MET-min/wk was explained by the overall model. CONCLUSIONS: A positive relationship was found between physical activity participation and self-efficacy beliefs, which is aligned with earlier research conducted among individuals without disabilities. This finding underscores the need for further exploration of motivational constructs associated with physical activity engagement among individuals with visual impairments in order to better understand what specific factors impact and can be leveraged to promote physical activity engagement of this population. PMID- 29126898 TI - Structural Basis for the Selective Inhibition of c-Jun N-Terminal Kinase 1 Determined by Rigid DARPin-DARPin Fusions. AB - To untangle the complex signaling of the c-Jun N-terminal kinase (JNK) isoforms, we need tools that can selectively detect and inhibit individual isoforms. Because of the high similarity between JNK1, JNK2 and JNK3, it is very difficult to generate small-molecule inhibitors with this discriminatory power. Thus, we have recently selected protein binders from the designed ankyrin repeat protein (DARPin) library which were indeed isoform-specific inhibitors of JNK1 with low nanomolar potency. Here we provide the structural basis for their isotype discrimination and their inhibitory action. All our previous attempts to generate crystal structures of complexes had failed. We have now made use of a technology we recently developed which consists of rigid fusion of an additional special DARPin, which acts as a crystallization enhancer. This can be rigidly fused with different geometries, thereby generating a range of alternative crystal packings. The structures reveal the molecular basis for isoform specificity of the DARPins and their ability to prevent JNK activation and may thus form the basis of further investigation of the JNK family as well as novel approaches to drug design. PMID- 29126899 TI - Merimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogens. AB - Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to abnormal pregnancies, fetal death, microcephaly, and Guillain-Barre syndrome in humans. Merimepodib (MMPD, VX-497), a potent inhibitor of inosine-5' monophosphate dehydrogenase (IMPDH), has shown antiviral activity against HCV and a variety of DNA and RNA viruses in vitro. In this report, we expand the antiviral spectrum of MMPD, and demonstrate that MMPD inhibits ZIKV RNA replication with an EC50 of 0.6 MUM. Furthermore, MMPD reduces the virus production of ZIKV as well as several other important emerging viral pathogens such as Ebola, Lassa, Chikungunya, and Junin viruses. The inhibition can be reversed by addition of exogenous guanosine to culture media, consistent with the mechanism of action of MMPD as an IMPDH inhibitor. We also provide evidence that MMPD can be used in combination with other antivirals such as ribavirin and T-705 (favipiravir) to enhance suppression of virus production. PMID- 29126900 TI - Activity of nucleic acid polymers in rodent models of HBV infection. AB - Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes. These compounds have been previously shown to have the unique ability to eliminate serum surface antigen in DHBV-infected Pekin ducks and achieve multilog reduction of HBsAg or HBsAg loss in patients with chronic HBV infection and HBV/HDV coinfection. In ducks and humans, the blockage of HBsAg release by NAPs occurs by the selective targeting of the assembly and/or secretion of subviral particles (SVPs). The clinically active NAP species REP 2055 and REP 2139 were investigated in other relevant animal models of HBV infection including woodchucks chronically infected with WHV, HBV transgenic mice and HBV infected SCID-Hu mice. The liver accumulation of REP 2139 in woodchucks following subcutaneous administration was examined and was found to be similar to that observed in mice and ducks. However, in woodchucks, NAP treatment was associated with only mild (36-79% relative to baseline) reductions in WHsAg (4/10 animals) after 3-5 weeks of treatment without changes in serum WHV DNA. In HBV infected SCID-Hu mice, REP 2055 treatment was not associated with any reduction of HBsAg, HBeAg or HBV DNA in the serum after 28 days of treatment. In HBV transgenic mice, no reductions in serum HBsAg were observed with REP 2139 with up to 12 weeks of treatment. In conclusion, the antiviral effects of NAPs in DHBV infected ducks and patients with chronic HBV infection were weak or absent in woodchuck and mouse models despite similar liver accumulation of NAPs in all these species, suggesting that the mechanisms of SVP assembly and or secretion present in rodent models differs from that in DHBV and chronic HBV infections. PMID- 29126901 TI - Omega-3 polyunsaturated fatty acids protect human hepatoma cells from developing steatosis through FFA4 (GPR120). AB - Protective effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on non alcoholic fatty liver disease has been demonstrated. FFA4 (also known as GPR120; a G protein-coupled receptor) has been suggested to be a target of n-3 PUFA. FFA4 expression in hepatocytes has also been reported from liver biopsies in child fatty liver patients. In order to assess the functional role of FFA4 in hepatic steatosis, we used an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis. FFA4 expression was confirmed in Hep3B and HepG2 human hepatoma cells. T0901317 (a specific LXR activator) induced lipid accumulation and docosahexaenoic acid (DHA; a representative n-3 PUFA) inhibited lipid accumulation. This DHA-induced inhibition was blunted by treatment of AH7614 (a FFA4 antagonist) and by transfection of FFA4 siRNA. SREBP-1c (a key transcription factor of lipogenesis) was induced by treatment with T0901317, and SREBP-1c induction was also inhibited by DHA at mRNA and protein levels. DHA-induced suppression of SREBP-1c expression was also blunted by FFA4-knockdown. Furthermore, DHA inhibited T0901317-induced lipid accumulation in primary hepatocytes from wild type mice, but not in those from FFA4 deficient mice. In addition, DHA-induced activations of Gq/11 proteins, CaMKK, and AMPK were found to be signaling components of the steatosis protective pathway. The results of this study suggest that n-3 PUFA protect hepatic steatosis by activating FFA4 in hepatocytes, and its signaling cascade sequentially involves FFA4, Gq/11 proteins, CaMKK, AMPK, and SREBP-1c suppression. PMID- 29126902 TI - Identification and characterization of the mitochondrial membrane sorting signals in phosphatidylserine decarboxylase 1 from Saccharomyces cerevisiae. AB - Phosphatidylserine decarboxylase 1 (Psd1p) catalyzes the formation of the majority of phosphatidylethanolamine (PE) in the yeast Saccharomyces cerevisiae. Psd1p is localized to mitochondria, anchored to the inner mitochondrial membrane (IMM) through membrane spanning domains and oriented towards the mitochondrial intermembrane space. We found that Psd1p harbors at least two inner membrane associated domains, which we named IM1 and IM2. IM1 is important for proper orientation of Psd1p within the IMM (Horvath et al., J. Biol. Chem. 287 (2012) 36744-55), whereas it remained unclear whether IM2 is important for membrane association of Psd1p. To discover the role of IM2 in Psd1p import, processing and assembly into the mitochondria, we constructed Psd1p variants with deletions in IM2. Removal of the complete IM2 led to an altered topology of the protein with the soluble domain exposed to the matrix and to decreased enzyme activity. Psd1p variants lacking portions of the N-terminal moiety of IM2 were inserted into IMM with an altered topology. Psd1p variants with deletions of C-terminal portions of IM2 accumulated at the outer mitochondrial membrane and lost their enzyme activity. In conclusion we showed that IM2 is essential for full enzymatic activity, maturation and correct integration of yeast Psd1p into the inner mitochondrial membrane. PMID- 29126903 TI - The influence of sleep on human hypothalamic-pituitary-adrenal (HPA) axis reactivity: A systematic review. AB - Inadequate sleep is highly prevalent and known to decline both physical- and mental health. Literature suggests that altered functioning of the hypothalamic pituitary-adrenal (HPA) axis might underlie this association. This assumption is mainly based on changes in basal neuroendocrine activity and it is of equal importance to elucidate whether sleep may also influence HPA stress responsiveness. The present review provides a complete outline of recent human studies that have investigated how different aspects of sleep influence cortisol reactivity to laboratory stress. From the available data it can be concluded that both objective and subjective decrements in sleep quality potentiate the stress reactivity of the HPA axis. On the contrary, normal variations in sleep duration do not seem to influence cortisol stress responsiveness whereas excessive daytime sleepiness is associated with a blunting of the cortisol response. Given its well established health consequences, sensitization of the HPA axis might well be a crucial component linking inadequate sleep to stress-related pathology. PMID- 29126904 TI - Enhancement of tioconazole ungual delivery: Combining nanocapsule formulation and nail poration approaches. AB - This work investigated the impact of formulation including in vitro release profile, repeated dosing, and nail poration on the ex vivo nail delivery performance of antifungal formulations. Chitosan coated and uncoated tioconazole loaded nanocapsules and a nano-based film-forming vehicle were assessed via in vitro release and in vitro permeation tests using an artificial membrane and human nail clippings, respectively. The later involved single and daily dosing experiments with intact and porated nails. Additional experiments with Nile Red loaded formulations evaluated the depth of penetration of the fluorescent marker into the nail by laser scanning confocal microscopy. The nanocapsule formulations prolonged release of tioconazole for longer than the control solutions and this ability was related to an enhanced nail penetration of the drug. Further, the new film-forming formulation delivered its drug payload more efficiently than a marketed product. Daily dosing of the formulations doubled the amount of drug recovered from the nails. Porating the nails enhanced tioconazole delivery in single dose experiments only. The depth of penetration of Nile Red into the nails clippings ranged between 90-160 MUm. This research suggests that ensuring prolonged release of a drug is fundamental to develop efficacious topical nail formulations. PMID- 29126905 TI - Failure of active targeting by a cholesterol-anchored ligand and improvement by altering the lipid composition to prevent ligand desorption. AB - Although anti-angiogenic therapy is predicted to be an effective therapy for treating cancer, selectively targeting tumor endothelial cells (TECs), and not normal endothelial cells, remains a major obstacle. Modifying a drug carrier with a targeting ligand is a popular strategy for developing an active-targeting type drug delivery system (DDS). We previously reported that a cyclo(Arg-Gly-Asp-D-Phe Lys) (cRGD)-equipped liposome that contains encapsulated siRNA (RGD-MEND) achieved an efficient therapeutic outcome in a murine cancer model. To develop a more efficient TEC-targeting DDS, we examined the effect of the length of the polyethylene glycol (PEG) that is used as a peptide-linker on the cholesterol scaffold, and liposomal composition on the efficiency of delivery of siRNA to cRGD receptor alphaVbeta3 integrin positive cells. An RGD-MEND modified with shorter linker/no-linker, PEG350 or no-PEG, showed a higher cellular uptake in vitro. However, a shorter or no-linker RGD-cholesterol-modified MEND showed no silencing effect despite its high, in vitro silencing efficiency. To examine the possibility that the cholesterol-scaffold ligand was removed from the surface of the RGD-MEND by interactions with serum proteins, the RGD-MEND was incubated in the presence of a 50% serum solution. The cellular uptake of the cholesterol scaffold ligand was drastically reduced by the incubation in serum. Increasing the cholesterol ratio in the lipid envelope and adding a helper lipid improved the in vivo knockdown efficiency, probably due to an enhanced ligand retention, even in in vivo conditions. The findings reported herein suggest that the lipid composition and the ligand scaffold of the MEND are major factors in successfully developing an efficient active-targeting DDS. PMID- 29126907 TI - Influence of cholesterol inclusion on the doxorubicin release characteristics of lysolipid-based thermosensitive liposomes. AB - Fast hyperthermia (i.e. 39-42 degrees C) triggered doxorubicin release from lysolipid-containing thermosensitive liposomes (LTSL) in the tumor vasculature has been demonstrated to result in considerable enhancement of bioavailable drug levels in heated tumor tissue in preclinical tumor models. However, there is also significant leakage of doxorubicin already at 37 degrees C in the bloodstream, making these LTSL less efficient and increasing the risk for systemic toxicity. In conventional liposomes, cholesterol is incorporated in the bilayer to increase the stability of the liposomes. Here, we investigate the effect of cholesterol inclusion on the doxorubicin release characteristics of LTSL at 37 degrees C and hyperthermic temperatures. For this purpose, three LTSL formulations with 0, 5 and 10 mol% cholesterol were prepared. Inclusion of cholesterol reduced the undesired doxorubicin leakage at 37 degrees C in Hepes-buffered saline (HBS) as well as in fetal bovine serum (FBS). The incorporation of cholesterol in the LTSL bilayers did not influence the hyperthermia-triggered release property of the LTSL. These results were supported by DSC measurements. Therefore, in conclusion, our data indicate that cholesterol inclusion in LTSL offers a simple solution to the problem of significant leakage of doxorubicin from LTSL already at 37 degrees C in the bloodstream. PMID- 29126906 TI - Development and characterization of an organic solvent free, proliposomal formulation of Busulfan using quality by design approach. AB - Parenteral administration of Busulfan (BU) conquers the bioavailability and biovariability related issues of oral BU by maintaining the plasma drug concentration in therapeutic range with minimal fluctuations thereby significantly reducing the side effects. Busulfex(r) is the only commercially available parenteral formulation of BU composed of organic solvents N, N dimethylacetamide and polyethylene glycol 400. Since, BU is highly susceptible to hydrolytic degradation; Busulfex(r) has poor physical and chemical stability in IV fluids. It is quintessential to develop organic solvent free formulation of BU using parenterally acceptable excipients to enhance its solubility and stability in IV fluids. The Proliposomal formulation of BU was prepared by adsorption sonicaton method using egg phosphotidylcholine, cholesterol, tween 80 and mannitol. Vesicle size and entrapment efficiency were optimized using 24 full factorial design and characterized by DSC, PXRD and TEM. Optimized formulation spontaneously forms 74.0 +/- 1.7 nm sized nanovesicles with 72.9 +/- 1.5 % entrapment efficiency. DSC and PXRD studies revealed that BU was present in phospholipid bilayer in amorphized form and TEM images confirmed the multi lamellar vesicular structure. Physicochemical stability of BU was significantly enhanced with proliposomal formulation. In-vivo studies in Sprague Dawley rats showed proliposomal formulation has comparable immunosuppression activity and 110.62 % relative bioavailability as compared to marketed Busulfan formulation i.e. Busulfex(r). PMID- 29126908 TI - A novel formulation of [6]-gingerol: Proliposomes with enhanced oral bioavailability and antitumor effect. AB - [6]-Gingerol, one of the components of the rhizome of Ginger, has a variety of biological activities such as anticoagulant, antioxidative, antitumor, anti inflammatory, antihypertensive, and so forth. However, as one of the homologous phenolic ketones, [6]-gingerol is insoluble in water which limits its applications. Herein, we prepared [6]-gingerol proliposomes through modified thin film dispersion method, which was spherical or oval, and physicochemically stable with narrow size distribution. Surprisingly, in vitro release of [6]-gingerol loaded proliposome compared with the free [6]-gingerol was significantly higher and its oral bioavailability increased 5-fold in vivo. Intriguingly, its antitumor effect was enhanced in the liposome formulation. Thus, our prepared [6] gingerol proliposome proved to be a novel formulation for [6]-gingerol, which significantly improved its antitumor effect. PMID- 29126909 TI - [Demographic analysis of a congenital heart disease clinic of the Mexican Institute of Social Security, with special interest in the adult]. AB - INTRODUCTION: Congenital heart disease (CHD) has an incidence of 8-10 cases per 1000 live births. In Mexico, there are 18,000-20,000 new cases per year. Most tertiary care centers for CHD attend only pediatric population; the Mexican Institute of Social Security (IMSS) has a clinic that attends pediatric and adult population. OBJECTIVE: To analyze the demographic aspects of the CHD clinic of IMSS. METHODS: From 2011 to 2016 a cross-sectional study of the CC clinic of a third level hospital of the IMSS, including all patients with confirmed structural heart disease of recent diagnosis was carried out. The sex, age, reference entity, antecedent of pregnancy and treatment were registered. The population was divided into age ranges (<2 years, 2.1-6 years, 6.1-10 years, 10.1 17 years and >17.1 years). Descriptive statistics and chi2 test were used in qualitative variables. RESULTS: 3,483 patients with CHD (male:female ratio, 0.8:1.2) were included. Increased pulmonary flow acyanogenic cardiopathies were the most frequent CHD group (47.2%), with atrial septal defect being the most frequent diagnosis overall; 25.6% were adults and 35% of women with a history of pregnancy. Chiapas was Federal entity with greater proportion of patients diagnosed in the adult stage (33.82%); 7% were not candidates for any treatment for complications of the disease. CONCLUSIONS: CHD is a late diagnosis; it is necessary to create a national register to promote new health policies and a rational distribution of resources for these patients. PMID- 29126910 TI - Impaired oligodendrogenesis and myelination by elevated S100B levels during neurodevelopment. AB - High levels of the inflammatory molecule S100B protein have been identified in sera from several perinatal inflammatory conditions involving myelin damage and associated with an adverse prognosis or the emergence of sequelea. S100B is essential for oligodendrocyte (OL) differentiation and maturation, but it remains to be established if excessive levels of released S100B upon early brain injury are deleterious in the neurodevelopmental period. Here, we investigated this possibility by evaluating how elevated S100B affects oligodendrogenesis during this period. First, using primary cultures of OL we observed that damage-induced micromolar levels of S100B impair OL differentiation process. S100B elevated concentrations reduced both transition from immature NG2+ oligodendrocyte precursor cells (OPC) to mature MBP+ OL, and morphological maturation of differentiated OL. Interestingly, these effects were abolished by the use of receptor for advanced glycation end-products (RAGE) antagonist FPS-ZM1, suggesting an involvement of the S100B-RAGE axis on oligodendrogenesis impairment. Next, we used organotypic cerebellar slice cultures to explore the role of S100B in a more complex multicellular environment. Also in this model excessive S100B levels impaired oligodendrogenesis resulting in a reduced myelination. Further, elevated S100B levels compromised neuronal and synaptic integrity, while inducing astrogliosis, nuclear factor (NF)-kB activation and inflammation. Again, the FPS-ZM1 co-treatment prevented S100B-induced damaging effects. Overall, our results indicate that persistently elevated S100B levels have deleterious effects during the neurodevelopmental period through RAGE dependent processes. Thus, targeting high S100B levels and/or S100B-RAGE interaction may constitute good therapeutic strategies to reduce brain injury, including deficits in neuronal architecture, synaptogenesis and myelination associated with perinatal inflammatory conditions. PMID- 29126911 TI - Why MDMA therapy for alcohol use disorder? And why now? AB - Alcohol use disorder represents a serious clinical, social and personal burden on its sufferers and a significant financial strain on society. Current treatments, both psychological and pharmacological are poor, with high rates of relapse after medical detoxification and dedicated treatment programs. The earliest historical roots of psychedelic drug-assisted psychotherapy in the 1950s were associated with Lysergic acid diethylamide (LSD)-assisted psychotherapy to treat what was then called, alcoholism. But results were varied and psychedelic therapy with LSD and other 'classical' psychedelics fell out of favour in the wake of socio political pressures and cultural changes. A current revisiting of psychedelic clinical research is now targeting substance use disorders - and particularly alcohol use disorder - again. 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has never been formally explored as a treatment for any form of substance use disorder. But in recent years MDMA has risen in prominence as an agent to treat posttraumatic stress disorder (PTSD). With its unique receptor profile and a relatively well-tolerated subjective experience of drug effects when used clinically, MDMA Therapy is ideally suited to allow a patient to explore and address painful memories without being overwhelmed by negative affect. Given that alcohol use disorder is so often associated with early traumatic experiences, the author is proposing in a current on-going UK-based study that patients with alcohol use disorder who have undergone a medical detoxification from alcohol might benefit from a course of MDMA-assisted psychotherapy. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29126912 TI - AGBL2 promotes cancer cell growth through IRGM-regulated autophagy and enhanced Aurora A activity in hepatocellular carcinoma. AB - AGBL2 has been reported to catalyze alpha-tubulin detyrosination, by which it promotes tumorigenesis and cancer progression. However, its potential role in the pathogenesis of hepatocellular carcinoma (HCC) has not been revealed yet. In the present study, AGBL2 was frequently found being overexpressed in HCC tissues and cell lines. In a large cohort of clinical HCC tissues, high expression of AGBL2 was positively associated with tumor size, tumor multiplicity and advanced clinical stage (p < 0.05), and it was an independent prognostic factor for HCC patients. In HCC cell lines, ectopic overexpression of AGBL2 substantially enhanced HCC cells survival and proliferation in vitro and promoted tumor growth in vivo. In addition, we demonstrated that overexpression of AGBL2 in HCC cells notably inhibited apoptosis by enhancing IRGM-regulated autophagy. Meanwhile, AGBL2 could up-regulate the expression of TPX2 and Aurora A activity to promote cell proliferation in HCC cells. In summary, our findings suggest that up regulation of AGBL2 plays a critical oncogenic role in the pathogenesis of HCC through modulation on autophagy and Aurora A activity, and it could be a candidate for prognostic marker and therapeutic target in HCC. PMID- 29126913 TI - IWR-1, a tankyrase inhibitor, attenuates Wnt/beta-catenin signaling in cancer stem-like cells and inhibits in vivo the growth of a subcutaneous human osteosarcoma xenograft. AB - Wnt/beta-catenin or canonical Wnt signaling pathway regulates the self-renewal of cancer stem-like cells (CSCs) and is involved in tumor progression and chemotherapy resistance. Previously, we reported that this pathway is activated in a subset of osteosarcoma CSCs and that doxorubicin induced stemness properties in differentiated cells through Wnt/beta-catenin activation. Here, we investigated whether pharmacological Wnt/beta-catenin inhibition, using a tankyrase inhibitor (IWR-1), might constitute a strategy to target CSCs and improve chemotherapy efficacy in osteosarcoma. IWR-1 was specifically cytotoxic for osteosarcoma CSCs. IWR-1 impaired spheres' self-renewal capacity by compromising landmark steps of the canonical Wnt signaling, namely translocation of beta-catenin to the nucleus and subsequent TCF/LEF activation and expression of Wnt/beta-catenin downstream targets. IWR-1 also hampered the activity and expression of key stemness-related markers. In vitro, IWR-1 induced apoptosis of osteosarcoma spheres and combined with doxorubicin elicited synergistic cytotoxicity, reversing spheres' resistance to this drug. In vivo, IWR-1 co administration with doxorubicin substantially decreased tumor progression, associated with specific down-regulation of TCF/LEF transcriptional activity, nuclear beta-catenin and expression of the putative CSC marker Sox2. We suggest that targeting the Wnt/beta-catenin pathway can eliminate CSCs populations in osteosarcoma. Combining conventional chemotherapy with Wnt/beta-catenin inhibition may ameliorate therapeutic outcomes, by eradicating the aggressive osteosarcoma CSCs and reducing drug resistance. PMID- 29126914 TI - Targeting immuno-metabolism to improve anti-cancer therapies. AB - The immunology community has made significant strides in recent years in using the immune system to target and eliminate cancer. Therapies such as hematopoietic stem cell transplantation (HSCT) are the standard of care treatment for several malignancies, while therapies incorporating chimeric antigen receptor (CAR) T cells or checkpoint molecule blockade have been revolutionary. However, these approaches are not optimal for all cancers and in some cases, have failed outright. The greatest obstacle to making these therapies more effective may be rooted in one of the most basic concepts of cell biology, metabolism. Research over the last decade has revealed that T cell proliferation and differentiation is intimately linked to robust changes in metabolic activity, delineation of which may provide ways to manipulate the immuno-oncologic responses to our advantage. Here, we provide a basic overview of T cell metabolism, discuss what is known about metabolic regulation of T cells during allogeneic HSCT, point to evidence on the importance of T cell metabolism during CAR T cell and solid tumor therapies, and speculate about the role for compounds that might have dual-action on both immune cells and tumor cells simultaneously. PMID- 29126915 TI - Steps, moderate-to-vigorous physical activity, and cardiometabolic profiles. AB - The relative benefits of meeting the current moderate-to-vigorous intensity physical activity (MVPA) and active step count recommendations are unknown. Using robust linear regressions, we compared cardiometabolic marker differences (blood pressure, lipid levels, Homeostatic Model Assessment of Insulin Resistance (HOMA IR), hemoglobin A1C, C-reactive protein (CRP), and body mass index (BMI)) across MVPA (150min/week) and step (10,000 steps/day) thresholds and between step categories (low active: 5000 to 7499, somewhat active: 7500 to 9999, and active: >=10,000 steps/day vs. inactive: <5000 steps/day) in approximately 6000 Canadian adults (41.5years, SD 14.9). Differences across MVPA and step thresholds were similar but additional benefits were observed for BMI and A1C for the MVPA target (i.e., above vs. below 150min/week MVPA: -1.02kg/m2 (95% Confidence Interval [CI] -1.25 to -0.80) and -0.04% (95% CI -0.06 to -0.02); above vs. below >=10,000 steps/day: -0.40kg/m2 (95% CI -0.63 to -0.16) and 0.01% (95% CI -0.01 to 0.03)). In terms of steps categories, the greatest incremental improvement was achieved at the somewhat active threshold (e.g., somewhat active vs. inactive: -0.90kg/m2, 95% CI -1.28 to -0.53; low active vs. inactive: -0.36kg/m2, 95% CI -0.73 to 0.02). Additional benefits beyond the 10,000 step/day threshold were limited (e.g., -0.93kg/m2, 95% CI -1.30 to -0.57). Given that most benefits to markers of cardiometabolic health were at the >=7500 step/day threshold and that there was some additional benefit across the 150min/week MVPA threshold compared to a 10,000 steps/day threshold, we suggest aiming for >=7500 steps/day and then advancing to a 150min/MVPA goal. PMID- 29126916 TI - How well are U.S. primary care providers assessing whether their male patients have male sex partners? AB - Identifying patients at-risk for HIV infection, such as men who have sex with men (MSM), is an important step in providing HIV testing and prevention interventions. It is unknown how primary care providers (PCPs) assess MSM status and related HIV-risk factors. We analyzed data from a panel-derived web-based survey for healthcare providers conducted in 2014 to describe how PCPs in the U.S. determined their patients' MSM status. We calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) to describe PCP characteristics associated with systematically determining MSM status (i.e., PCP used "a patient completed questionnaire" or "routine verbal review of sex history"). Among the 1008 PCPs, 56% determined MSM status by routine verbal review of sexual history; 41% by patient disclosure; 39% by questions driven by symptoms/history; 23% by using a patient-completed questionnaire, and 9% didn't determine MSM status. PCPs who systematically determined MSM status (n=665; 66%) were more likely to be female (aPR=1.16, CI=1.06-1.26), to be affiliated with a teaching hospital (aPR=1.15, CI=1.06-1.25), to routinely screen all patients aged 13-64 for HIV (aPR=1.29, CI=1.18-1.41), and to estimate that 6% or more of their male patients are MSM (aPR=1.14, CI=1.01-1.30). The majority of PCPs assessed MSM status and HIV risk factors through routine verbal reviews of sexual history. Implementing a systematic approach to identify MSM status and assess risk may allow PCPs to identify more patients needing frequent HIV testing and other preventive services, while mitigating socio-cultural barriers to obtaining such information. PMID- 29126917 TI - A method for the inclusion of physical activity-related health benefits in cost benefit analysis of built environment initiatives. AB - The built environment has a significant influence on population levels of physical activity (PA) and therefore health. However, PA-related health benefits are seldom considered in transport and urban planning (i.e. built environment interventions) cost-benefit analysis. Cost-benefit analysis implies that the benefits of any initiative are valued in monetary terms to make them commensurable with costs. This leads to the need for monetised values of the health benefits of PA. The aim of this study was to explore a method for the incorporation of monetised PA-related health benefits in cost-benefit analysis of built environment interventions. Firstly, we estimated the change in population level of PA attributable to a change in the built environment due to the intervention. Then, changes in population levels of PA were translated into monetary values. For the first step we used estimates from the literature for the association of built environment features with physical activity outcomes. For the second step we used the multi-cohort proportional multi-state life table model to predict changes in health-adjusted life years and health care costs as a function of changes in PA. Finally, we monetised health-adjusted life years using the value of a statistical life year. Future research could adapt these methods to assess the health and economic impacts of specific urban development scenarios by working in collaboration with urban planners. PMID- 29126918 TI - Community-wide physical activity intervention based on the Japanese physical activity guidelines for adults: A non-randomized controlled trial. AB - : Very few community intervention studies that promote physical activity (PA) using guidelines and its dissemination and implementation have been conducted. Consequently, we evaluated the effectiveness of a community-wide intervention (CWI) of PA with adults based on the Japanese guidelines for promoting PA. This was a non-randomized controlled trial, with four administrative districts in Fujisawa city assigned to the intervention group and nine to the control group. The CWI, conducted from 2013 to 2015, comprised information dissemination, education, and community support. The primary outcome was change in PA participation. Secondary outcomes were CWI awareness and PA guideline knowledge. Outcomes were assessed using questionnaires distributed to two independent, random samples of 3000 community-based adults (aged >=20years). Two separate samples-1230 adults at baseline and 1393 at the two-year follow-up-responded to the survey. The median time spent in PA did not differ between intervention and control groups after adjusting for potential confounders (adjusted difference between groups=-0.02min/day [95% confidence interval (CI): -0.11, 0.10]). However, intervention group participants were more aware of the CWI (33.8%) than were control group participants (25.2%) at the two-year follow-up (odds ratio=1.44 [95% CI: 1.06, 1.95]). A significant difference was also observed in participants' PA guideline knowledge (adjusted difference between groups=0.82% [95% CI: 0.33, 1.31]). Although significant differences in awareness and knowledge were observed between groups, this CWI did not change PA levels over two years. Future studies should investigate the long-term effects of CWIs beyond two years. TRIAL REGISTRATION NUMBER: UMIN-CTR UMIN000018389. PMID- 29126919 TI - School-based mental health services, suicide risk and substance use among at-risk adolescents in Oregon. AB - This study examined whether an increase in the availability of mental health services at school-based health centers (SBHCs) in Oregon public schools was associated with the likelihood of suicidal ideation, suicide attempts and substance use behaviors among adolescents who experienced a depressive episode in the past year. The study sample included 168 Oregon public middle and high schools and 9073 students who participated in the Oregon Healthy Teens Survey (OHT) in 2013 and 2015. Twenty-five schools had an SBHC, and 14 of those schools increased availability of mental health services from 2013 to 2015. The OHT included questions about having a depressive episode, suicidal ideation, attempting suicide in the past year, and substance use behaviors in the past 30days. Multi-level logistic regression analyses were conducted in 2017 to examine associations between increasing mental health services and the likelihood of these outcomes. Analysis results indicated that students at SBHC schools that increased mental health services were less likely to report any suicidal ideation [odds ratio (OR) (95% C.I.)=0.66 (0.55, 0.81)], suicide attempts [OR (95% C.I.)=0.71 (0.56, 0.89)] and cigarette smoking [OR (95% C.I.)=0.77 (0.63, 0.94)] from 2013 to 2015 compared to students in all other schools. Lower frequencies of cigarette, marijuana and unauthorized prescription drug use were also observed in SBHC schools that increased mental health services relative to other schools with SBHCs. This study suggests that mental health services provided by SBHCs may help reduce suicide risk and substance use behaviors among at-risk adolescents. PMID- 29126920 TI - The 'fentanyl epidemic' in Canada - Some cautionary observations focusing on opioid-related mortality. AB - In Canada, opioid-related overdose mortality has steeply increased in recent years; as a substantial number of opioid-related deaths are related to fentanyl products, this phenomenon has widely been described as the 'fentanyl epidemic', also implying that these deaths are largely caused by clandestinely produced illicit fentanyl products. We examined numbers and rates of opioid- and fentanyl related deaths in six pan-Canadian provinces with respective (coroner-based) data available from 2010 to 2016. While fentanyl-related deaths are clearly increasing from relatively low levels in all provinces, those increases are strongest in the two Western provinces (e.g., British Columbia, where fentanyl accounts for the majority of opioid deaths in 2016 and Alberta), and, to some extent, Ontario. However, fentanyl-related deaths remain a minority of deaths in Ontario (40%) and the remaining provinces (<25%). Furthermore, it is uncertain what proportion of fentanyl-related deaths is actually related to illicit fentanyl products. We conclude that fentanyl-related overdose deaths have risen - most strongly in the West - due to both a high availability of medical fentanyl products, as well as an influx of illegal fentanyl products. In most provinces, the majority of opioid deaths remain associated with other (non-fentanyl) products. Appropriate (prevention, treatment and policy) interventions need to be targeted at the full range of opioid deaths from different sources. Overall, a realistic framing of the social (e.g., media) discourse about the nature of the 'opioid overdose death crisis' is required, which is not exclusively an 'illicit fentanyl death crisis' even though this may be a socio-politically appealing image. PMID- 29126921 TI - The role of TRPV4 in fibrosis. AB - The transient receptor potential vanilloid 4 (TRPV4) is a highly Ca2+-permeable non-selective cation channel in TRPV family. Accumulating evidence hints that TRPV4 play a significant role in a wide diversity of pathologic changes. Fibrosis is a kind of chronic disease which was characterized by the formation of excessive accumulation of extracellular matrix (ECM) components in tissues and organs. In recent years, a growing body of studies showed that TRPV4 acted as a crucial regulator in the progression of fibrosis including myocardial fibrosis, cystic fibrosis, pulmonary fibrosis, hepatic fibrosis and pancreatic fibrosis, suggesting TRPV4 may be a potential therapeutic vehicle in fibrotic diseases. However, the mechanisms by which TRPV4 regulates fibrosis are still undefined. In this review, firstly, we intend to sum up the collective knowledge of TRPV4. Then we provided the latent mechanism between TRPV4 and fibrosis. We also elaborated the distinct signaling pathways focus on TRPV4 with fibrosis. Finally, we discussed its potential as a novel therapeutic target for fibrosis. PMID- 29126922 TI - The unrecognized role of tumor suppressor genes in atrial fibrillation. AB - Epidemiogical evidence has shown that the incidence of atrial fibrillation in tumor patients is higher than non-tumor patients and general population. The potential risk factors predisposing tumor patients to atrial fibrillation include advanced age, comorbidities, direct anatomic local occupying effect of tumors in the heart or adjacent organs, paraneoplastic manifestations of some tumors, tumor induced dys-regulation of metabolism, radio-, bio- and chemo-therapeutics, disturbance of autonomous nerve system because of physical pain and psychological sufferings, chronic inflammation typical of most tumors, and surgical interventions among others. However, whether tumor suppressor genes commonly mutated or dys-regulated in tumor play any roles in the pathogenesis of atrial fibrillation remain largely unexplored. Tumor suppressor genes or genes possessing tumor suppressing function have been reported to be constitutively expressed in quiescent heart, and mutations, small nucleotide polymorphisms, or disturbed expression of tumor suppressor genes has been implicated in the pathogenesis of atrial fibrillation. Here, we provide a state-of-the-art overview of the unrecognized roles of tumor suppressor genes in the pathogenesis of atrial fibrillation, focusing mainly on the two well-characterized tumor suppressor genes, zinc finger homeobox protein-3 and esophageal cancer related gene-4. PMID- 29126923 TI - CLOCK interacts with RANBP9 and is involved in alternative splicing in spermatogenesis. AB - The core circadian gene CLOCK plays an important role in regulating male reproduction. However, the underlying mechanism still remains unclear. In the present study, we executed yeast two-hybrid screening using cDNA fragment of CLOCK PAS A domain as bait, and identified RANBP9 as a novel protein interacting with CLOCK. The interaction between CLOCK and RANBP9 was further validated by in vivo and in vitro assays. Previous studies have confirmed that SF3B3 was a RANBP9 interacting protein. Subsequently, our study also found that CLOCK and SF3B3 can interact with each other by co-immunoprecipitation in mouse testis. In order to dissect the underlying mechanism of CLOCK in spermatogenesis, we also performed RNA-immunoprecipitation followed by high-throughput sequencing (RIP-Seq) in mouse testis. The result of sequence analyses and Gene Ontology enrichment analyses (biological processes) demonstrated that CLOCK can directly bind 186 key mRNA transcripts in mouse spermatogenesis. Taken together, our results firstly showed that CLOCK can interact with RANBP9 and bind with mRNAs, demonstrating that CLOCK is involved in alternative splicing in spermatogenesis. These results reveal a novel mechanism for CLOCK in spermatogenesis. PMID- 29126924 TI - Suppression of p53R2 gene expression with specific siRNA sensitizes HepG2 cells to doxorubicin. AB - INTRODUCTION: p53R2 is a p53-inducible protein that contributes to DNA repair by providing dNTPs in response to DNA damage. The roles of p53R2 in cancer cells and malignancies still remain controversial. Herein, we examined the effects of p53R2 silencing on HepG2 human hepatocellular carcinoma (HHC) cell line (wild-type p53) viability, apoptosis and cell cycle arrest in the presence and absence of doxorubicin. METHODS: Cell transfection was performed using a liposomal approach. Gene silencing was determined by quantitative real-time PCR and western blot analysis. To evaluate the cell growth rate after transfection, trypan blue dye exclusion assay was employed. The cytotoxicity of the doxorubicin and p53R2 siRNA as single agents or in combination against HepG2 cell was analyzed by MTT assay and the drug combination effects was evaluated by calculating the combination index. The effects of treatments on different stages of cell cycle were analyzed by flow cytometry using propidium iodide (PI) and induction of apoptosis was assessed using DNA-histone ELISA. RESULTS: We found that silencing of p53R2 alone had a strong effect on growth inhibition and spontaneous apoptosis in HepG2 cells. p53R2 siRNA synergistically enhanced the cytotoxic effect of doxorubicin. Furthermore, when used in combination with doxorubicin (0.4MUM), a significant increase in the rate of apoptosis was observed (P<0.05). Moreover, cell cycle at S and G2/M phases progressed at a lower rate after p53R2 combination treatment compared with doxorubicin mono-therapy. CONCLUSION: These findings suggest that siRNA-mediated silencing of p53R2 has great potential as a therapeutic tool and adjuvant in chemotherapy. PMID- 29126925 TI - Comparative transcriptomic characterization of a new mib mutant allele, mibnn2002, in zebrafish. AB - mibnn2002, identified from an allele screen, shows early segmentation defect and severe cell death phenotypes, which are different from those of other described mib mutant alleles. We have previously reported its defects in somitogenesis and identified its origin of mutation, a large deletion in LG2. The report here is a continuous study, where we applied the bioinformatics analysis to profile the genetic background of mibnn2002 mutants. By comparing the transcriptomic data of mibnn2002 mutants with those of AB wild-type, a total of 1945 differentially expressed genes were identified, including 685 up- and 1260 down-regulated genes. The Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis and Ingenuity Pathway Analysis (IPA) identified the enriched pathways and their related biological functions. Our data further demonstrated that the defects in the somitogenesis were related to the down-regulated segmentation genes, such as foxc1a, smyhc1, myod1 and mylpfa. PMID- 29126926 TI - AJUBA increases the cisplatin resistance through hippo pathway in cervical cancer. AB - Though LIM-domain protein AJUBA was identified as a putative oncogene, the function and underlying mechanisms of AJUBA in cervical cancer remain largely unknown. Firstly, AJUBA expression was detected via real-time quantitative PCR in patients' samples. Furthermore, Hela and Siha cells were transfected with AJUBA overexpressing plasmids, and then exposed to cisplatin, the apoptosis was measured by cytometry assay. In addition, the expression of YAP and TAZ was disclosed through western blot assay. Our results revealed that AJUBA expression was significantly higher in the cervical cancer patients resistant to cisplatin treatment compared with cervical cancer patients sensitive to cisplatin treatment. In addition, overall survival time was significantly shorter in the cervical cancer patients with high AJUBA expression compare with those with low AJUBA expression using kaplan-meier analysis. Hela and Siha cells transfected with AJUBA-expressing plasmids exposed to cisplatin treatment had higher survival rate compared with the cells transfected with empty vector control. Mechanistic studies revealed the AJUBA upregulated the downstream targets YAP and TAZ. These results suggest that high AJUBA level enhances cervical cancer cells drug resistance to cisplatin, also associates with decreased patient survival times. PMID- 29126927 TI - Mechanisms of macular edema: Beyond the surface. AB - Macular edema consists of intra- or subretinal fluid accumulation in the macular region. It occurs during the course of numerous retinal disorders and can cause severe impairment of central vision. Major causes of macular edema include diabetes, branch and central retinal vein occlusion, choroidal neovascularization, posterior uveitis, postoperative inflammation and central serous chorioretinopathy. The healthy retina is maintained in a relatively dehydrated, transparent state compatible with optimal light transmission by multiple active and passive systems. Fluid accumulation results from an imbalance between processes governing fluid entry and exit, and is driven by Starling equation when inner or outer blood-retinal barriers are disrupted. The multiple and intricate mechanisms involved in retinal hydro-ionic homeostasis, their molecular and cellular basis, and how their deregulation lead to retinal edema, are addressed in this review. Analyzing the distribution of junction proteins and water channels in the human macula, several hypotheses are raised to explain why edema forms specifically in the macular region. "Pure" clinical phenotypes of macular edema, that result presumably from a single causative mechanism, are detailed. Finally, diabetic macular edema is investigated, as a complex multifactorial pathogenic example. This comprehensive review on the current understanding of macular edema and its mechanisms opens perspectives to identify new preventive and therapeutic strategies for this sight-threatening condition. PMID- 29126928 TI - Predicting an HLA-DPB1 expression marker based on standard DPB1 genotyping: Linkage analysis of over 32,000 samples. AB - The risk of acute graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation is increased with donor-recipient HLA-DPB1 allele mismatching. The single-nucleotide polymorphism (SNP) rs9277534 within the 3' untranslated region (UTR) correlates with HLA-DPB1 allotype expression and serves as a marker for permissive HLA-DPB1 mismatches. Since rs9277534 is not routinely typed, we analyzed 32,681 samples of mostly European ancestry to investigate if the rs9277534 allele can be reliably imputed from standard DPB1 genotyping. We confirmed the previously-defined linkages between rs9277534 and 18 DPB1 alleles and established additional linkages for 46 DPB1 alleles. Based on these linkages, the rs9277534 allele could be predicted for 99.6% of the samples based on DPB1 genotypes (99.99% concordance). We demonstrate that 100% prediction accuracy could be achieved if the prediction utilized exon 3 sequence information. DPB1 genotyping based on exon 2 data alone allows no unambiguous rs9277534 allele prediction but was estimated to maintain 99% accuracy for samples of European descent. We conclude that DPB1 genotyping is sufficient to infer the DPB1 expression marker rs9277534 with high accuracy. This information could be used to select donors with permissive HLA-DPB1 mismatches without directly screening for rs9277534. PMID- 29126929 TI - Machiavellian tendencies increase following damage to the left dorsolateral prefrontal cortex. AB - Machiavellianism - a personality trait that is characterized by a tendency to distrust, deceive and exploit others - has been the focus of growing attention in psychological research. Neuroimaging studies of Machiavellianism highlight the influence of the dorsolateral prefrontal cortex (dlPFC) on Machiavellianism tendencies. However, knowledge regarding the causal role of the left and right dlPFC on Machiavellianism is still obscure. Here, we measured general Machiavellian tendencies, as well as two subscales (i.e., Machiavellian Views and Machiavellian Tactics) in a large sample of brain-injured patients (N = 129) and non-brain-injured control participants (N = 37) to determine whether Machiavellianism tendencies can be altered by brain damage. We analyzed Machiavellianism tendencies as a function of lesion location, with patients separated into four groups based on dlPFC damage: left dlPFC damage, right dlPFC damage, non-dlPFC damage, and healthy controls. We found that left dlPFC damage increased Machiavellianism in general, and Machiavellian perspective (views) in particular, but did not modulate behavior (tactics). Critically, left dlPFC damage predicted higher levels of Machiavellianism after controlling for general and emotional intelligence, linguistic abilities, empathy and psychopathology. These findings establish a causal role of the left dlPFC in modulating Machiavellian views, and indicate that one can hold Machiavellian views without necessarily endorsing Machiavellian tactics. PMID- 29126930 TI - White matter integrity mediates decline in age-related inhibitory control. AB - Previous DTI studies have reported associations between white matter integrity and performance on the Stroop interference task. The current study aimed to add to these studies of inhibitory control by investigating how the differences in age and in white matter integrity relate to Stroop performance, and to examine whether the effect of age on Stroop performance is mediated by white matter integrity. 179 healthy adults from 20 to 80 years old were recruited in the study. DTI data were processed through TRACULA and the mean fractional anisotropy (FA) of 18 major white matter tracts were extracted and used for statistical analysis. Correlation analysis showed a strong negative relationship between age and the Stroop interference score (IG). Higher IG indicated better inhibitory control. Simple linear regression analyses indicated that most of the tracts showed negative relationships with age, and positive relationships with IG. Moderation effect of age on the relationship between FA and IG was tested on tracts that significantly predicted IG after multiple comparison corrections, but none of these moderations were significant. Then we tested if these tracts mediated the effect of age on IG and found significant indirect effects of age on IG through the FA of the left corticospinal tract and through the right inferior longitudinal fasciculus. Our results highlight the role of a number of major white matter tracts in the processes supporting the Stroop inhibitory performance and further pinpointed the lower white matter integrity of specific tracts as contributors to the decrease in inhibitory control ability associated with the Stroop test in older age. PMID- 29126931 TI - Phytochemical allylguaiacol exerts a neuroprotective effect on hippocampal cells and ameliorates scopolamine-induced memory impairment in mice. AB - Allylguaiacol is a phytochemical occurring in various plants such as cloves, cinnamon, basil, and nutmeg. Pharmacological effects of allylguaiacol include antimicrobial, anti-inflammatory, anticancer, antioxidant, and neuroprotective activity. Although allylguaiacol is considered to have neuroprotective effects, there is no report on its regulatory mechanisms at the molecular level. In the present study, we investigated the mechanisms of allylguaiacol as an antioxidant and neuroprotective agent using hydrogen peroxide (H2O2)-treated HT22 hippocampal cells. Allylguaiacol increased the scavenging activities of free radicals 2,2' azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and 2,2-diphenyl-1 picrylhydrazyl (DPPH), and enhanced the expression of antioxidant enzymes manganese superoxide dismutase (MnSOD) and catalase. In addition, allylguaiacol inhibited H2O2-induced damage of HT22 with increasing production of brain-derived neurotrophic factor (BDNF), phosphorylation of phosphoinositide 3-kinase (PI3K), and cyclic AMP response element-binding protein (CREB). Furthermore, antibody microarray data revealed that phospho-regulation of nuclear factor kappa B (NF kappaB) p65 and death domain-associated protein (DAXX) is involved in protection against neuronal cell damage. In a mouse model of short-term memory impairment, allylguaiacol (2.5 or 5mg/kg) significantly ameliorated scopolamine-mediated cognitive impairment in a passive avoidance task. In addition, allylguaiacol significantly increased the expression of TrkA and B in the hippocampus from scopolamine-treated mice. Taken together, our findings suggest that allylguaiacol exerts a neuroprotective effect through the antioxidant activation and protein regulation of NF-kappaB p65 and DAXX-related signaling. The ameliorating effect of allylguaiacol may be useful for treatment of memory impairment in Alzheimer's and its related diseases. PMID- 29126933 TI - The RAPIDD Ebola forecasting challenge special issue: Preface. PMID- 29126932 TI - Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury. AB - Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide with 1.5 million people inflicted yearly. Several neurotherapeutic interventions have been proposed including drug administration as well as cellular therapy involving neural stem cells (NSCs). Among the proposed drugs is docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibiting neuroprotective properties. In this study, we utilized an innovative intervention of neonatal NSCs transplantation in combination with DHA injections in order to ameliorate brain damage and promote functional recovery in an experimental model of TBI. Thus, NSCs derived from the subventricular zone of neonatal pups were cultured into neurospheres and transplanted in the cortex of an experimentally controlled cortical impact mouse model of TBI. The effect of NSC transplantation was assessed alone and/or in combination with DHA administration. Motor deficits were evaluated using pole climbing and rotarod tests. Using immunohistochemistry, the effect of transplanted NSCs and DHA treatment was used to assess astrocytic (Glial fibrillary acidic protein, GFAP) and microglial (ionized calcium binding adaptor molecule-1, IBA-1) activity. In addition, we quantified neuroblasts (doublecortin; DCX) and dopaminergic neurons (tyrosine hydroxylase; TH) expression levels. Combined NSC transplantation and DHA injections significantly attenuated TBI-induced motor function deficits (pole climbing test), promoted neurogenesis, coupled with an increase in glial reactivity at the cortical site of injury. In addition, the number of tyrosine hydroxylase positive neurons was found to increase markedly in the ventral tegmental area and substantia nigra in the combination therapy group. Immunoblotting analysis indicated that DHA+NSCs treated animals showed decreased levels of 38kDa GFAP-BDP (breakdown product) and 145kDa alphaII-spectrin SBDP indicative of attenuated calpain/caspase activation. These data demonstrate that prior treatment with DHA may be a desirable strategy to improve the therapeutic efficacy of NSC transplantation in TBI. PMID- 29126934 TI - Neuropsychological functioning in military pesticide applicators from the Gulf War: Effects on information processing speed, attention and visual memory. AB - 1991 Gulf War (GW) veterans continue to experience debilitating cognitive and mood problems more than two decades following their return from deployment. Suspected causes for these cognitive complaints include additive and/or synergistic effects of the varying combinations of exposures to chemicals in theater, including pesticides and pyridostigmine bromide (PB) pills. This study was undertaken to address one of the key recommendations of the US Department of Defense Environmental Exposure Report on Pesticides, which was to conduct an epidemiological study to further evaluate the role of neurotoxicant exposures in the expression of central nervous system symptoms reported by GW veterans. This study evaluated the role of pesticides and/or PB in the development of chronic neuropsychological dysfunction in GW veterans. We examined the associations between self-reported measures of pesticide and PB exposures and performance on neuropsychological tests in a group of 159 GW-deployed preventative medicine personnel who had varying levels of pesticide exposures during their work as pesticide applicators or other preventative medicine roles. These veterans had a unique knowledge of pesticides and their usage during the war. It was hypothesized that pesticide applicator personnel with higher exposures would perform significantly worse on objective cognitive measures than lower-exposed personnel and that multiple chemical exposures (pesticide and PB) would further diminish cognitive functioning and increase mood complaints. Study results showed that the participants with both high pesticide and high PB exposure performed worse on specific measures than the groups with high single exposures or low exposures to both toxicants. High combined exposure was associated with significantly slower information processing reaction times, attentional errors, worse visual memory functioning, and increased mood complaints. In addition, stepwise regression analyses of individual pesticide exposures found that pest strip exposure was associated with slower reaction times and attentional errors, and that fly bait and delouser exposures predicted greater mood complaints. PMID- 29126935 TI - Age-dependent and region-specific alteration of parvalbumin neurons and perineuronal nets in the mouse cerebral cortex. AB - Cognitive function declines with age. Such function depends on gamma-oscillation in the frontal cortex. Pyramidal neurons, and the parvalbumin-expressing interneurons (PV neurons) that control them, are important for the generation of gamma-oscillation. The mechanism by which cognitive function declines is unclear. Perineuronal nets (PNNs) mainly surround the soma and proximal dendrites and axon segments of PV neurons in the cerebral cortex. Previous evidence indicates that PNNs inhibit neural plasticity. If this is true, an increase in the number of neurons surrounded by PNNs or in the thickness or density of the PNNs around neurons could decrease plasticity in the cortex. To determine if an aging-related change in cortical PNNs occurs, we examined the influence of aging on PV neurons and whether Wisteria floribunda agglutinin-positive PNNs differ depending on the cortical area. The results showed that the number of PV neurons/mm2 did not change in many areas of the cortex as mice aged. In contrast, the number of neurons in the sensory cortex surrounded by PNNs increased as mice aged. Thus, with age, PNN density increases in some cortical areas but not in others. In addition, the expression level of PV protein in PV neurons decreased with aging in the whole cortex. We suggest that decreased expression of PV protein impairs fast spiking in PV neurons. We propose that PNNs surround more neurons as age increases. This aging-related increase in PNNs decreases plasticity in the cerebral cortex and reduces cognitive function. The first step in investigating this proposal would be to determine if PNN density increases with age. PMID- 29126936 TI - Smoking Influences Fecal Volatile Organic Compounds Composition. PMID- 29126937 TI - Coccinia indica agglutinin, a 17kDa PP2 like phloem lectin: Affinity purification, primary structure and formation of self-assembled filaments. AB - Phloem protein-2 (PP2) is an abundant soluble protein in the sieve elements in plants. Its lectin property was reported in various species. The primary structure of a 17kDa PP2 from Coccinia indica (Coccinia indica agglutinin, CIA17), determined by mass spectrometry, shows extensive homology with PP2 super family phloem lectins. Analysis of mass spectrometric data indicated the presence of 16 potential allelic variants of CIA17 with insignificant divergence in the primary structure. The primary structure contains an intramolecular disulfide bridge between Cys-34 and Cys-51, which is conserved across various cucurbit species and hence likely to be important for carbohydrate binding. CD spectroscopic studies revealed that CIA17 is rich in antiparallel beta-sheets, similar to PP2 proteins from Cucurbita maxima and Arabidopsis thaliana. CD spectra recorded at various temperatures showed very little change in the spectral intensity and shape up to 90 degrees C, suggesting that CIA17 is a highly thermostable protein. Atomic force microscopic studies revealed that CIA17 forms filamentous structures at higher concentrations. In light of these results, we propose that CIA17 and other PP2 proteins play a role in the plant defense against pathogens by directly binding with the chitin cell wall, and also promote wound healing by forming self-assembled filaments. PMID- 29126938 TI - Yacon fructans (Smallanthus sonchifolius) extraction, characterization and activation of macrophages to phagocyte yeast cells. AB - Yacon (Smallanthus sonchifolius) originates from the Andean region and has spread across South America, Europe and Japan. In contrast with most roots, yacon stores its carbohydrates in fructooligosaccharides (FOS) and contains approximately 37% of FOS in its root dry matter. Aqueous extracts of yacon were characterized through TLC, methylation, NMR, and ESI-MS. FOS of yacon showed as linear fructooligosaccharides containing almost exclusively (2->1)-linked beta fructofuranosyl units, with terminal alpha-glucopyranosyl and beta fructofuranosyl units. ESI-MS analyses indicated a wide degree of polymerization (DP) ranging from 2 to 10. The effect of the isolated FOS on non-specific immune activity by THP-1 cells was evaluated through phagocytic activity against heat killed yeast (Saccharomices cerevisiae). The stimulant effect of yacon FOS was dose- and time-dependent, showing results more effective than branched FOS observed in previous studies. The results reinforce the use of linear yacon FOS as immunomodulators. PMID- 29126940 TI - Adsorption of mercury ions from wastewater aqueous solution by amide functionalized cellulose from sugarcane bagasse. AB - A novel effective cellulose-based adsorbent was prepared through two common reactions, which included the esterification of sugarcane bagasse cellulose with excess stearic acid and the reaction of grafting polyacrylamide brush by ultraviolet radiation initiation. The adsorbent can effectively adsorb Hg(II) ion from wastewater. The characterization of the adsorbents was conducted by optical microscope (OM), scanning electron microscopy (SEM-EDS) and infrared spectrometry (FTIR). Full kinetic and thermodynamic investigations as well as isotherm analysis were also undertaken. Due to the abundant amide groups, the cellulose based adsorbents exhibit excellent adsorption performance for the removal of Hg(II) ion from aqueous solution with a maximum adsorption capacity of 178mg/g. Furthermore, the cellulose-based adsorbents can be easily separated from the aqueous solution after adsorption and regenerated using 0.2M HCl solution, which exhibits high adsorption capacity after six adsorption-desorption cycles. In view of the easily-operated cost-effective preparation technique, substantial adsorption efficiency and excellent adsorption recyclability, therefore, the eco friendly cellulose-based adsorbents could be used for water purification effectively. More importantly, this work improves value of low-cost biomass resources. PMID- 29126939 TI - Synthesis and evaluation of anti-fungal activities of sodium alginate amphotericin B conjugates. AB - Sodium alginate (SA) was oxidized using periodate and amphotericin B (AmB) was conjugated via imine and amine linkages to the oxidized alginate. Oxidization drastically reduced the molecular weight (MW) of the alginate. The conjugates were highly water-soluble to the extent of 1000mg/mL making them useful for therapeutic applications. SA-AmB conjugates derived from 20 and 50% oxidized alginate were non-toxic to HEK 293T and RAW 264.7 cell line at 100MUg/mL and was also non-hemolytic to human blood at 100MUg/mL. In vitro release of AmB into phosphate buffer from the imine conjugates was negligible with less than 0.2% of the drug released in 48h. Capping of residual aldehyde handles using 2 ethanolamine or glycine resulted in increased release of the drug in vitro. Injectable gels of gelatin crosslinked with oxidized alginate incorporating the SA-AmB conjugates as well as AmB were also fabricated and drug release was examined. In vitro release from the gel discs showed that AmB was released to the extent of 15-20% in 2days. The SA-AmB conjugates showed potent anti-fungal activity against C. albicans, C. neoformans and C. parapsilosis. The injectable gels seem to have potential for prolonged release of AmB when implanted. PMID- 29126941 TI - Glycol chitosan functionalized asenapine nanostructured lipid carriers for targeted brain delivery: Pharmacokinetic and teratogenic assessment. AB - Blood brain barrier (BBB) is a complex, tight barrier between endothelial cells of cerebral blood vessels. It acts as a physical barrier and provides access to only those moieties which are necessary for proper brain functioning. However, this selective prudence also acts as a hindrance in therapeutic targeting of brain necessitating pharmaceutical intervention. Intranasal drug delivery is one such approach which we have exploited here for targeted brain delivery of asenapine by glycol chitosan coated nanostructured lipid carrier (GC-ANLC). The best formulation was characterized for particle size (184.2+/-5.59nm), zeta potential (18.83+/-1.18mV), entrapment efficiency (83.52+/-2.59%) and surface morphology (spherical and smooth). In-vitro drug-release study showed that Higuchi model (r2=0.9938, AIC=52.94) dictated asenapine release from GC-ANLC. Cell compatibility study suggested biocompatibility of GC-ANLC with A549 cell line as well as nasal epithelial cell membrane. After intranasal delivery, Charles-Foster rats demonstrated approximately 2.3 and 4 fold higher systemic and brain bioavailability of GC-ANLC compared to asenapine solution (ASM). Embryo fetal toxicity study was further conducted to investigate the teratogenic effect of GC-ANLC. In conclusion, prepared GC-ANLC could be used as a promising drug carrier for delivery of asenapine via intranasal route with better pharmacokinetic and safety profile. PMID- 29126942 TI - Design of an electrochemical DNA-based biosensor for selective determination of cadmium ions using a DNA hybridization indicator. AB - A simple electrochemical DNA- based biosensor was designed for determination of Cd2+ using ethyl green (EG) as a DNA hybridization indicator on the surface of carbon paste electrode (CPE). The interaction of Cd2+ with double strand DNA (dsDNA) led to the destabilizing of dsDNA and the increase in the reduction peak currents of EG. The difference in the values of electrochemical responses of EG before and after DNA helix destabilization in the presence of Cd2+ (DeltaI) was used for Cd2+ determination and was linearly related to the concentration of Cd2+ over the ranges of 1.0pM-1.0nM and 10.0nM-1.0MUM. Detection limit was achieved as low as 0.3pM using simple and low cost working electrode and without applying any materials for modification of electrode or DNA. The proposed biosensor was utilized successfully to real sample analysis of Cd2+. PMID- 29126943 TI - SugE belongs to the small multidrug resistance (SMR) protein family involved in tributyltin (TBT) biodegradation and bioremediation by alkaliphilic Stenotrophomonas chelatiphaga HS2. AB - Tributyltin (TBT) used in a variety of industrial processes, subsequent discharge into the environment, its fate, toxicity and human exposure are topics of current concern. TBT degradation by alkaliphilic bacteria may be a key factor in the remediation of TBT in high pH contaminated sites. In this study, Stenotrophomonas chelatiphaga HS2 were isolated and identified from TBT contaminated site in Mediterranean Sea. S. chelatiphaga HS2 has vigor capability to transform TBT into dibutyltin and monobutyltin (DBT and MBT) at pH 9 and 7% NaCl (w/v). A gene was amplified and characterized from strain HS2 as SugE protein belongs to SMR protein family, a reverse transcription polymerase chain reaction analysis confirmed that SugE protein involved in the TBT degradation by HS2 strain. TBT bioremediation was investigated in stimulated TBT contaminated sediment samples (pH 9) using S chelatiphaga HS2 in association with E. coli BL21 (DE3)-pET28a(+) sugE instead of S chelatiphaga HS2 alone reduced significantly the TBT half-life from 12d to 5d, although no TBT degradation appeared using E. coli BL21 (DE3) pET28a(+)-sugE alone. This finding indicated that SugE gene increased the rate and degraded amount of TBT and is necessary in enhancing TBT bioremediation. PMID- 29126944 TI - Physicochemical and microstructural properties of a novel edible film synthesized from Balangu seed mucilage. AB - This paper reports the synthesis of a novel edible film from Balangu seed mucilage (BSM) as a new carbohydrate source. Optimal formulation of the proposed edible film was found through fabricating several distinct films with different concentrations of BSM and glycerol. The effect of these formulation variables on the physical, mechanical, thermal, barrier, and microstructural properties of the manufactured films was then investigated. Optimal formulation of the BSM edible film was then determined based on the measured mechanical and barrier characteristics. These characteristics were found to deteriorate with an excessive use of glycerol which caused non-homogeneity of the films as observed through scanning electron micrographs. In-depth analysis of the optimal BSM film properties was performed through investigating its oxygen permeability, Fourier transform infrared spectroscopy, atomic force microscopy, X-ray diffraction, and water sorption isotherm. The superior mechanical and barrier characteristics of the obtained optimal BSM edible film make it a potential candidate for packaging that aim at an extended shelf-life. PMID- 29126945 TI - Simultaneous aerobic exercise and rTMS: Feasibility of combining therapeutic modalities to treat depression. PMID- 29126947 TI - Transradial versus Transfemoral access in patients undergoing peripheral artery angioplasty/stenting: A meta-analysis. AB - Transradial (TR) access has been extensively compared to transfemoral (TF) access in patients undergoing percutaneous coronary interventions, with TR method showing a clear benefit over the latter. However, comparative data concerning peripheral artery endovascular interventions has been limited in the literature. Therefore, a systematic review was conducted in order to compare main outcomes between TR and TF access in patients undergoing peripheral artery angioplasty and/or stenting. Main outcomes included technical success, major/minor bleeding risk, access site complications, hospital stay, death, myocardial infarction, neurological events and other procedural parameters. TR and TF access methods seem to be associated with similar early outcomes in patients undergoing non coronary endovascular angioplasty and/or stenting although paucity of data necessitates the conduction of better designed studies. PMID- 29126946 TI - Sensory percepts induced by microwire array and DBS microstimulation in human sensory thalamus. AB - BACKGROUND: Microstimulation in human sensory thalamus (ventrocaudal, VC) results in focal sensory percepts in the hand and arm which may provide an alternative target site (to somatosensory cortex) for the input of prosthetic sensory information. Sensory feedback to facilitate motor function may require simultaneous or timed responses across separate digits to recreate perceptions of slip as well as encoding of intensity variations in pressure or touch. OBJECTIVES: To determine the feasibility of evoking sensory percepts on separate digits with variable intensity through either a microwire array or deep brain stimulation (DBS) electrode, recreating "natural" and scalable percepts relating to the arm and hand. METHODS: We compared microstimulation within ventrocaudal sensory thalamus through either a 16-channel microwire array (~400 kOmega per channel) or a 4-channel DBS electrode (~1.2 kOmega per contact) for percept location, size, intensity, and quality sensation, during thalamic DBS electrode placement in patients with essential tremor. RESULTS: Percepts in small hand or finger regions were evoked by microstimulation through individual microwires and in 5/6 patients sensation on different digits could be perceived from stimulation through separate microwires. Microstimulation through DBS electrode contacts evoked sensations over larger areas in 5/5 patients, and the apparent intensity of the perceived response could be modulated with stimulation amplitude. The perceived naturalness of the sensation depended both on the pattern of stimulation as well as intensity of the stimulation. CONCLUSIONS: Producing consistent evoked perceptions across separate digits within sensory thalamus is a feasible concept and a compact alternative to somatosensory cortex microstimulation for prosthetic sensory feedback. This approach will require a multi-element low impedance electrode with a sufficient stimulation range to evoke variable intensities of perception and a predictable spread of contacts to engage separate digits. PMID- 29126948 TI - Polymerisation, antibacterial and bioactivity properties of experimental orthodontic adhesives containing triclosan-loaded halloysite nanotubes. AB - OBJECTIVE: To evaluate the immediate enamel bond strength, in situ degree of conversion and the polymerisation rate of three experimental orthodontic adhesives containing triclosan-loaded halloysite nanotubes. The antibacterial and bioactivity properties of such experimental materials were also assessed. MATERIALS AND METHODS: Three experimental orthodontic adhesives were formulated by incorporating triclosan-loaded halloysite nanotubes (TCN-HNT) at different concentrations (5wt%, 10wt% and 20wt%) into a resin blend (Control). The maximum polymerisation rate of the tested adhesives was evaluated trough FTIR, while Raman was used to analyse the in situ degree of conversion (DC) at the bracket/enamel interface. The shear bond strength (SBS) of the enamel-bonded specimens was assessed at 24h. The antibacterial properties of the experimental materials against S. Mutans were evaluate up to 72h, while, their bioactivity was evaluated after 14days of artificial saliva (AS) storage through SEM-EDS and Raman spectromicroscopy. RESULTS: Incorporation of TCN-HNT increased the polymerisation properties without interfering with the immediate bonding properties of the experimental adhesives. All experimental adhesives containing TCN-HNT inhibited bacterial growth at 24h, and induced mineral deposition after 14days of AS storage. At 72h, only the experimental system containing 20% TCN-HNT maintained such a capability. CONCLUSIONS: Adhesives doped with TCN-HNT present improved polymerisation properties and suitable bonding performance. However, only the adhesives containing TCN-HNT >10% might promote long-term antibacterial activity and reliable mineral deposition. CLINICAL SIGNIFICANCE: The use of adhesives containing triclosan-loaded halloysite represents a promising "smart" approach to bond orthodontic brackets and bands; these might prevent enamel demineralisation and induce enamel remineralisation during the treatment. PMID- 29126949 TI - A patient with an extensive coronary artery thrombus. PMID- 29126950 TI - Leadless pacing systems: A valuable alternative for patients with severe access problems. PMID- 29126951 TI - Circulating microRNAs as novel biomarkers for heart failure. AB - OBJECTIVE: We Sought to identify circulating miRNAs suitable for HF diagnosis. METHODS: In this study, a genome-wide plasma miRNA microarray was performed in 13 HF patients and 3 controls. The expression levels of selected differentially expressed, upregulated miRNAs (miR-3135b, miR-3908 and miR-5571-5p) were validated with quantitative real-time PCR (qRT-PCR) assays in an independent cohort of 33 HF patients and 20 controls. RESULTS: Of all the miRNAs analyzed, miR-3135b (P<0.001), miR-3908 (P<0.001), and miR-5571-5p (P<0.001) were found to have significantly different expression levels in HF compared to controls. The Receiver operating characteristic (ROC) curves for miR-3135b, miR-3908, and miR 5571-5p revealed area under the curve (AUC) values of 1.00, 0.86, and 0.94, respectively. More importantly, miR-3135b and miR-3908 were able to discriminate heart failure with reduced ejection fraction (HFrEF) from heart failure with preserved ejection fraction (HFpEF) (P<0.05). The miR-5571-5p plasma level was significantly associated with NYHA class (P<0.001). CONCLUSION: This study demonstrated for the first time that some specific microRNAs (miR-3135b, miR 3908, and miR-5571-5p) are useful biomarkers for HF and for differentiating HFrEF from HFpEF. PMID- 29126952 TI - Antibacterial activities of the phytochemicals-characterized extracts of Callistemon viminalis, Eucalyptus camaldulensis and Conyza dioscoridis against the growth of some phytopathogenic bacteria. AB - Three bacterial isolates were isolated from infected potato tubers showing soft and brown rots like symptoms as well as one isolate from infected peach tree showing crown gall symptom. The morphological, biochemical and molecular assays proved that bacterial isolates belonging to Pectobacterium carotovorum subsp. carotovorum, Ralstonia solanacearum, Dickeya spp. and Agrobacterium tumefaciens. The acetone (AcE) and n-butanol (ButE) extracts of Callistemon viminalis flowers and essential oil from aerial parts of Conyza dioscoridis as well as ButE of Eucalyptus camaldulensis bark are evaluated at different concentrations against the growth of the isolated bacteria. The diameter of inhibition zone (IZ) and the minimum inhibitory concentrations (MICs) are compared. Results indicated that the highest IZ values were 20.0 mm and 18.3 mm for E. camaldulensis bark ButE and C. viminalis flower ButE, respectively, against P. carotovorum; 16.3 mm and 16.0 mm for E. camaldulensis bark ButE and C. viminalis flower ButE, respectively, against R. solanacearum; 18.5 mm for C. viminalis flower AcE and C. dioscoridis aerial parts EO against Dickeya spp.; and 15.0 mm for C. viminalis flower AcE against A. tumefaciens. MICs ranged from <16 MUg/mL for D. solani to >4000 MUg/mL for A. tumefaciens. It was proved that C. viminalis flowers AcE contains mainly 5 hydroxymethylfurfural (20.6%), palmitic acid (18.5%), and pyrogallol (16.4%); while C. viminalis flower ButE contains palmitic acid (36.3%), 2-hydroxymyristic acid (9.4%), 5-hydroxymethylfurfural (7.2%), and shikimic acid (6.6%); whereas E. camaldulensis bark ButE contains 8-nonynoic acid methyl ester (45.6), camphor (30.9%), menthol (8.8%), and 1,8-cineole (eucalyptol) (8.2%), whilst the EO of C. dioscoridis aerial parts comprises Z-(13,14-epoxy)tetradec-11-en-1-ol acetate (11.6%), gamma-elemene (10.2%), tau.-muurolol (7.1%), and cadina-3,9-diene (4.7%). It can be concluded that phytochemical extracts of C. viminalis, E. camaldulensis and C. dioscoridis demonstrated strong to moderate antibacterial effects against the studied plant bacterial pathogens. PMID- 29126953 TI - Radiological risk factors for progression of ossification of posterior longitudinal ligament following laminoplasty. AB - BACKGROUND CONTEXT: Research shows the progression of ossification of the posterior longitudinal ligament (OPLL) following decompressive surgery for cervical myelopathy, particularly in cases presenting with continuous or mixed radiographic types. To date, no study has investigated OPLL progression within each motion segment. PURPOSE: To evaluate progression of cervical OPLL in each motion segment using a novel system of classification, and to identify risk factors for OPLL progression following laminoplasty. STUDY DESIGN/SETTING: Retrospective case series. PATIENT SAMPLE: This study included 34 patients (86 segments) with cervical myelopathy secondary to OPLL. OUTCOME MEASURES: Clinical and radiological data (plain radiographs and computed tomography [CT]) were obtained. METHODS: Clinical data from 34 patients (86 segments) with cervical myelopathy secondary to OPLL were evaluated retrospectively. All subjects had undergone laminoplasty at a single center. Sagittal reconstructive CT images were used to measure OPLL thickness in each segment. Ossified masses were classified into four types according to the degree of disc space involvement: type 1 (no involvement); type 2 (involving disc space but not crossing); type 3 (crossing disc space but not fused); and type 4 (complete bridging). Range of motion (ROM) for each segment was measured using dynamic radiographs. Statistical analyses were performed to determine the degree of OPLL progression according to the four disc space involvement types and ROM. RESULTS: Mean OPLL progression was significantly higher in types 2 (1.3 mm) and 3 (1.5 mm) than in type 1 (0.5 mm) (p<.001). Severe progression (change in thickness >2 mm) was more frequent in types 2 (8 of 29) and 3 (7 of 16) than in types 1 (1 of 35) or 4 (0 of 6) (p=.002). In types 2 or 3, ROM>5 degrees was correlated with severe OPLL progression (52% vs. 8%; p=.035). CONCLUSIONS: Type 2 or 3 disc involvement and segmental ROM>5 degrees were risk factors for OPLL progression. Classification of cervical OPLL according to disc involvement may help predict OPLL progression following laminoplasty. Close follow-up is warranted in cases of type 2 or 3 with greater segmental motion. PMID- 29126955 TI - White Matter Changes Correlates of Peripheral Neuroinflammation in Patients with Parkinson's Disease. AB - Neuroinflammatory pathology has long been identified to contribute to the pathology of Parkinson disease. Early microstructural changes in white matter tracts might give a clue for earlier detection of PD. We investigated through diffusion MRI connectometry the structural correlates of white matter tracts of 81 patients with PD with whole blood neutrophil-to-lymphocyte ratio (NLR), controlling for age and sex. Diffusion data were reconstructed in the MNI space using q-space diffeomorphic reconstruction to obtain the spin distribution function. The spin distribution function (SDF) values were used in DMRI connectometry analysis. The connectometry analyses identified white matter QA of the following fibers to be correlated with NLR score after adjustment for age and sex: bilateral cingulum, body and left crus of fornix, bilateral corticospinal tract (CST), and body and splenium of corpus callosum (CC) and superior cerebellar peduncle with decreased connectivity related to NLR (FDR = 0.04542). Keeping with emerging evidence on the role of neuroinflammation in PD pathology, these results with functional relevance to prodromal Parkinson disease, bring new insights to pivotal role of peripheral inflammation in CNS neurodegeneration. PMID- 29126954 TI - Quantitative Analysis of Kynurenine Aminotransferase II in the Adult Rat Brain Reveals High Expression in Proliferative Zones and Corpus Callosum. AB - Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, acts as an endogenous antagonist of alpha7 nicotinic and NMDA receptors and is implicated in a number of neurophysiological and neuropathological processes including cognition and neurodegenerative events. Therefore, kynurenine aminotransferase II (KAT II/AADAT), the enzyme responsible for the formation of the majority of neuroactive kynurenic acid in the brain, has prompted significant interest. Using immunohistochemistry, this enzyme was localized primarily in astrocytes throughout the adult rat brain, but detailed neuroanatomical studies are lacking. Here, we employed quantitative in situ hybridization to analyze the relative expression of KAT II mRNA in the brain of rats under normal conditions and 6 h after the administration of lipopolysaccharides (LPSs). Specific hybridization signals for KAT II were detected, with the highest expression in the subventricular zone (SVZ), the rostral migratory stream and the floor of the third ventricle followed by the corpus callosum and the hippocampus. This pattern of mRNA expression was paralleled by differential protein expression, determined by serial dilutions of antibodies (up to 1:1 million), and was confirmed to be primarily astrocytic in nature. The mRNA signal in the SVZ and the hippocampus was substantially increased by the LPS treatment without detectable changes elsewhere. These results demonstrate that KAT II is expressed in the rat brain in a region-specific manner and that gene expression is sensitive to inflammatory processes. This suggests an unrecognized role for kynurenic acid in the brain's germinal zones. PMID- 29126956 TI - Effect of graduated compression stockings on venous lower limb hemodynamics in healthy amateur runners. AB - OBJECTIVE: The objective of this study was to analyze the effect of graduated compression stockings (GCS) on venous lower limb hemodynamics in healthy amateur runners. METHODS: Ten runners were evaluated during rest and after a 10-km run without and with knee-high GCS of 20 to 30 mm Hg. Air plethysmography evaluated venous filling index (VFI), ejection fraction, and residual volume fraction (RVF) in both limbs. Capillary lactate level and heart rate were also measured. RESULTS: Right VFI was 1.38 mL/s during rest, 1.98 mL/s without compression, and 1.32 mL/s with compression (P = .006). Left VFI was 1.35 mL/s during rest, 1.64 mL/s without compression, and 1.21 mL/s with compression (P = .006). In both limbs, ejection fraction was not different in the three situations. Right RVF was 22.35% during rest, 19.40% without compression, and 10.50% with compression (P = .006). Left RVF was similar in all situations. Capillary lactate level increased in runners without compression (P = .004) but kept stable in those wearing compression. The difference between after-run and before-run capillary lactate levels was similar in runners with and without compression. Rest, peak, and after run heart rates were similar in runners with and without compression. CONCLUSIONS: Healthy amateur runners had associated hemodynamic improvements when wearing knee-high GCS of 20 to 30 mm Hg during a 10-km treadmill run. VFI dropped in both limbs and RVF dropped at least in the right limb. There was no positive effect on calf muscle pump; capillary lactate variation; or rest, peak, and after run heart rates. PMID- 29126957 TI - 3-Arylisoindolinone and sesquiterpene derivatives from the mangrove endophytic fungi Aspergillus versicolor SYSU-SKS025. AB - A pair of 3-arylisoindolinone enantiomers: (+)-asperglactam A (1), (-) asperglactam A (1) and a pair of nor-bisabolane enantiomers: (+)-1 hydroxyboivinianic acid (2), (-)-1-hydroxyboivinianic acid (2), along with seven known compounds (3-8) were obtained from the mangrove endophytic fungus Aspergillus versicolor SYSU-SKS025. Their structures were determined on the basis of HRESIMS and NMR spectroscopic data, and X-ray diffraction. (+)-Asperglactam A (1) and (-)-asperglactam A (1) are the first optically pure examples in the 3 arylisoindolinone family, which are rarely found in natural sources. All isolated compounds were evaluated for alpha-glucosidase inhibitory activity. The enantiomers of 1-3 showed moderate inhibitory activity against alpha-glucosidase with IC50 values ranging from 50 to 190MUM. Compound 7 exhibited significant inhibitory activity against alpha-glucosidase with IC50 value of 7.5MUM. In addition, compound 7 was found to inhibit nitric oxide production in RAW 264.7 macrophages with IC50 value of 12.5MUM. PMID- 29126958 TI - Effects of LED-Based photodynamic therapy using red and blue lights, with natural hydrophobic photosensitizers on human glioma cell line. AB - Photodynamic therapy (PDT) has received high attention in cancer treatment due to its minimal side effects, specific cancer-targeting, non-invasion and low cost. It utilizes a specific group of anti-cancer drugs called photosensitizers (PS), which can be only activated under a certain wavelength light illumination and kills cancer cells. To screen the potential of PS and setup of PDT treatment protocol, it is essential to assess the PDT efficacy in vitro. In this study, a light-emitting diode- (LED-) based illumination system at two wavelengths (red & blue) with homogeneous and stable irradiation, and constant temperature conditions in 96-well plates was provided. The photodynamic effect of curcumin (CUR) and methyl ester of 5-aminolevulinic acid (MAL) using LED light on human glioma cell line was investigated. The obtained results indicate that this homemade LED-based illumination system is a favorable light source for in vitro PDT in 96-well plates. The PDT using CUR and MAL was efficient at final concentrations of 25MUM and 2mM, and light doses of 60J/cm2 and 40J/cm2 respectively. The blue PDT efficiency was dependent on the light and PS doses. MAL-PDT and CUR-PDT using blue LED significantly decreased cell viability in the treatment groups compared with control groups. Furthermore, MAL-PDT using blue LEDs was more effective in comparison with conventional red LEDs on the human glioma cell line. PMID- 29126960 TI - PC-FACS. AB - PC-FACS(FastArticleCriticalSummaries for Clinicians inPalliativeCare) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PC-FACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at pc facs@aahpm.org. PMID- 29126959 TI - Nanocarriers as phototherapeutic drug delivery system: Appraisal of three different nanosystems in an in vivo and in vitro exploratory study. AB - The use of nanosystems as diagnosing and therapy systems is increasing each year. There are several nanosystems available and the most prominent ones are: mesoporous silica, nanoemulsion and polymeric nanoparticles. With characteristics like low toxicology, and easy-producing process they have advantages when compared with the traditional system used, as they show specific targeting, controlled release, and higher penetration. In this study we tested three different nanocarriers (polymeric nanoparticles, nanoemulsion and mesoporous silica) containing phthalocyanineas possible PDT drugs (nanodrugs). They were tested in vitro and in vivo: cells and healthy mice, respectively, in order to understand the biological behavior and reach the initial conclusions. The results in cells showed that a dose response was observed with different concentrations of the three nanocarriers. The results in animal showed that all nanosystems have potential for application in PDT, since they were able to produce a visible effect in healthy animals. PMID- 29126961 TI - PC-FACS. AB - PC-FACS(FastArticleCriticalSummaries for Clinicians inPalliativeCare) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PC-FACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at pc facs@aahpm.org. PMID- 29126962 TI - Your attention makes me smile: Direct gaze elicits affiliative facial expressions. AB - Facial electromyographic responses and skin conductance responses were measured to investigate whether, in a neutral laboratory environment, another individual's direct gaze elicits a positive or negative affective reaction in the observer. The results showed that greater zygomatic responses associated with positive affect were elicited by seeing another person with direct as compared to averted gaze. The zygomatic responses were greater in response to another person's direct gaze both when the participant's own gaze was directed towards the other and when the participant was not looking directly towards the other. Compatible with the zygomatic responses, the corrugator activity (associated with negative affect) was decreased below baseline more in response to another person's direct than averted gaze. Replicating previous research, the skin conductance responses were greater to another person's direct than averted gaze. The results provide evidence that, in a neutral context, another individual's direct gaze is an affiliative, positive signal. PMID- 29126963 TI - On the implicit influence of pain cues on cognitive effort: Evidence from cardiovascular reactivity. AB - To extend previous findings on the impact of implicit affect on behavior, two experiments investigated the influence of priming pain cues on cognitive effort. Effort was assessed as cardiovascular reactivity (PEP, SBP, DBP, and HR) during an easy or difficult cognitive task integrating briefly presented and masked pain related words. The control condition included neutral words (Experiment 1) or anger-related words (Experiment 2). The pain primes were expected to increase the perceived difficulty of the task and to result in stronger effort during the easy task, compared to the control condition, and to lower effort during the difficult task, due to disengagement. Overall, cardiovascular reactivity of both experiments supported the predictions. Moreover, pain primes increased self reported subjective difficulty. Finally, most participants could not report the content of the primes. Findings are discussed regarding the influence of implicit processes in pain experience and regarding the self-regulatory consequences of the influence of pain on effort mobilization. PMID- 29126964 TI - Simple and robust two-step ex vivo whole blood stimulation assay suitable for investigating IL-17 pathway in a clinical laboratory setting. AB - We describe a simple and robust tube-based ex vivo whole blood stimulation procedure suitable for use in clinical laboratories by multiple operators on repeated occasions to study cytokine production in phase 1 human trials of investigational medicines, developed by the authors specifically to study IL-17A expression in man. The stimulation procedure is further proposed as a useful tool for biomarker assay development and validation, for example to prepare quality control samples without reliance on recombinant materials for spiking. PMID- 29126966 TI - Host plant associated enhancement of immunity and survival in virus infected caterpillars. AB - Understanding the interaction between host plant chemistry, the immune response, and insect pathogens can shed light on host plant use by insect herbivores. In this study, we focused on how interactions between the insect immune response and plant secondary metabolites affect the response to a viral pathogen. Based upon prior research, we asked whether the buckeye caterpillar, Junonia coenia (Nymphalidae), which specializes on plants containing iridoid glycosides (IGs), is less able to resist the pathogenic effects of a densovirus infection when feeding on plants with high concentrations of IGs. In a fully factorial design, individuals were randomly assigned to three treatments, each of which had two levels: (1) exposed to the densovirus versus control, (2) placed on a plant species with high concentrations of IGs (Plantago lanceolata, Plantaginaceae) versus low concentrations of IGs (P. major), and (3) control versus surface sterilized to exclude surface microbes that may contribute to viral resistance. We measured phenoloxidase (PO) activity, hemocyte counts, and gut bacterial diversity (16S ribosomal RNA) during the fourth larval instar, as well as development time, pupal weight, and survival to adult. Individuals infected with the virus were immune-suppressed (as measured by PO response and hemocyte count) and developed significantly faster than virus-free individuals. Contrary to our predictions,mortality was significantly less for virus challengedindividuals reared on the high IG plant compared to the low IG plant.This suggests that plant secondary metabolites can influence survival from viral infection and may be associated with activation of PO. Removing egg microbes did not affect the immune response or survival of the larvae. In summary, these results suggest that plant secondary metabolites are important for survival against a viral pathogen. Even though the PO response was better on the high IG plant, the extent to which this result contributes to survival against the virus needs further investigation. PMID- 29126967 TI - Effects of temperature and salinity on prevalence and intensity of infection of blue crabs, Callinectes sapidus, by Vibrio cholerae, V. parahaemolyticus, and V. vulnificus in Louisiana. AB - Coastal marine and estuarine environments are experiencing higher average temperatures, greater frequency of extreme temperature events, and altered salinities. These changes are expected to stress organisms and increase their susceptibility to infectious diseases. However, beyond these generalities, little is known about how environmental factors influence host-pathogen relationships in the marine realm. We investigated the prevalence and intensity of infections by Vibrio cholerae, V. parahaemolyticus, and V. vulnificus in blue crabs, Callinectes sapidus, from Louisiana saltmarshes in relation to temperature and salinity. We evaluated relationships for single measurements taken at the time of collection and for more complex measurements representing accumulated exposure to physiologically-stressful environmental conditions for up to 31 days prior to collection. We found that: (1) prevalence of infection varied across the Louisiana coast, (2) prevalence of all three Vibrio species was influenced by temperature and salinity, and (3) measurements that represent accumulated exposure to extreme conditions are useful predictors of infection prevalence and can provide insights into underlying biological mechanisms. PMID- 29126969 TI - SNHG16/miR-216-5p/ZEB1 signal pathway contributes to the tumorigenesis of cervical cancer cells. AB - Long non-coding RNAs (lncRNAs) have been confirmed as crucial regulators in tumorgenesis. Small nucleolar RNA host gene 16 (SNHG16) has been recently uncovered to be a potential oncogene in several types of cancers. However, its expression level and potential role in cervical cancer remain uncertain. In our research, we assessed the expression level of SNHG16 in clinical cervical cancer tissues and cells. We made use of functional assays to determine the biological effects of SNHG16 on cell proliferation and migration of cervical cancer. By employing the bioinformatics analysis tools, we revealed that miR-216-5p could interact with SNHG16 and there existed a negative correlation between the expression levels of miR-216-5p and SNHG16 in cervical cancer specimens. Furthermore, RIP assay, RNA pulldown system and dual luciferase reporter assays confirmed that SNHG16 directly targeted miR-216-5p by harboring the binding sites of microRNA in the SNHG16 sequence. Additionally, bioinformatics analysis provided an evidence that ZEB1 was a potential target of miR-216-5p. Collectively, it was suggested that SNHG16 could serve as an oncogene that promoted tumor progression by acting as an endogenous 'sponge' to regulate miR 216A-5p/ZEB1. PMID- 29126965 TI - Brain state expression and transitions are related to complex executive cognition in normative neurodevelopment. AB - Adolescence is marked by rapid development of executive function. Mounting evidence suggests that executive function in adults may be driven by dynamic control of neurophysiological processes. Yet, how these dynamics evolve over adolescence and contribute to cognitive development is unknown. In a sample of 780 youth aged 8-22 yr (42.7% male) from the Philadelphia Neurodevelopment Cohort, we use a dynamic graph approach to extract activation states in BOLD fMRI data from 264 brain regions. We construct a graph in which each observation in time is a node and the similarity in brain states at two different times is an edge. Using this graphical approach, we identify two primary brain states reminiscent of intrinsic and task-evoked systems. We show that time spent in these two states is higher in older adolescents, as is the flexibility with which the brain switches between them. Increasing time spent in primary states and flexibility among states relates to increases in a complex executive accuracy factor score over adolescence. Flexibility is more positively associated with accuracy toward early adulthood. These findings suggest that brain state dynamics are associated with complex executive function across a critical period of adolescence. PMID- 29126968 TI - JNK signaling pathway regulates sorbitol-induced Tau proteolysis and apoptosis in SH-SY5Y cells by targeting caspase-3. AB - Growing evidence suggests that Diabetes Mellitus increases the risk of developing Alzheimer's disease. It is well known that hyperglycemia, a key feature of Diabetes Mellitus, may induce plasma osmolarity disturbances. Both hyperglycemia and hyperosmolarity promote the altered post-translational regulation of microtubule-associated protein Tau. Interestingly, abnormal hyperphosphorylation and cleavage of Tau have been proven to lead to the genesis of filamentous structures referred to as neurofibrillary tangles, the main pathological hallmark of Alzheimer's disease. We have previously described that hyperosmotic stress induced by sorbitol promotes Tau proteolysis and apoptosis in SH-SY5Y cells via caspase-3 activation. In order to gain insights into the regulatory mechanisms of such processes, in this work we explored the intracellular signaling pathways that regulate these events. We found that sorbitol treatment significantly enhanced the activation of conventional families of MAPK in SH-SY5Y cells. Tau proteolysis was completely prevented by JNK inhibition but not affected by either ERK1/2 or p38 MAPK blockade. Moreover, inhibition of JNK, but not ERK1/2 or p38 MAPK, efficiently prevented sorbitol-induced apoptosis and caspase-3 activation. In summary, we provide evidence that JNK signaling pathway is an upstream regulator of hyperosmotic stress-induced Tau cleavage and apoptosis in SH-SY5Y through the control of caspase-3 activation. PMID- 29126970 TI - Malignant melanoma presenting as amelanotic caruncular lesion in a child. AB - Conjunctival melanoma is a rare malignant neoplasm that can present in childhood in any part of the conjunctiva. The infrequency with which conjunctival melanoma is encountered in childhood caruncular lesions makes it a formidable but important aspect of the differential diagnosis. We report the case of a 10-year old boy who presented with a left caruncular lesion. On histopathologic analysis, the lesion was determined to be BRAF-negative invasive melanoma arising in association with melanocytic nevus. The melanoma was excised using no-touch technique and double freeze thaw cryotherapy. A full systemic work-up revealed no metastasis or abnormality. PMID- 29126971 TI - Prevalence and Postdischarge Incidence of Malignancies in Patients With Acute Coronary Syndrome. AB - INTRODUCTION AND OBJECTIVES: Malignancies are the second cause of death in developed countries after cardiovascular disease and both share common risk factors. METHODS: This prospective study assessed the prevalence and postdischarge incidence of malignancies in all consecutive patients admitted for an acute coronary syndrome. RESULTS: A total of 1819 patients were included. On admission, the prevalence of malignancies was 3.4%, and 41.9% of the patients were considered disease-free; of the 1731 discharged patients, the incidence was 3.1% (53 cases) and the most common locations were the colon, lung, bladder, and pancreas. Patients with prevalent malignancies were older and had more comorbidities and complications. There were no differences in the revascularization rate, but implantation of drug-eluting stents was less frequent in patients with prevalent malignancies. During follow-up, the median time to diagnosis of incident malignancies was 25 months. On multivariate analysis, independent risk factors were age and current or former smoking. All-cause mortality was much higher in patients with incident (64.2%) or prevalent (40.0%) malignancies. Multivariate analysis showed that prevalent and incident malignancies increased the risk of all-cause mortality by 4-fold. CONCLUSIONS: Among patients admitted for an acute coronary syndrome, 3.8% had a history of malignancy, with less than 50% considered cured. The incidence of new malignancies was 3.4% and both types of malignancies substantially impaired the long-term prognosis. PMID- 29126973 TI - Percutaneous Left Atrial Appendage Occlusion: Multimodality Imaging Step-by-step. PMID- 29126972 TI - Initial Experience in the Iberian Peninsula With the Transfemoral ACURATE-neo TF Transcatheter Aortic Prosthesis: Procedure and Outcomes. PMID- 29126974 TI - An Unusual "Black" Transcatheter Aortic Valve Implantation. PMID- 29126975 TI - Aortic Stent Implantation Using Live 3-dimensional Image Fusion Guidance. PMID- 29126976 TI - Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer's like pathology. AB - The present study was conducted to correlate the cellular and molecular alterations in Alzheimer's pathology employing streptozotocin (STZ) induced experimental rat model. The STZ was administered in rat brain bilaterally by intracerebroventricular route using stereotaxic surgery followed by donepezil dosing. The Alzheimer's related pathological marker like acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation were observed after STZ administration. STZ treatment showed decreased glucose and glucose transporters (GLUT) level along with augmented level of calcium in both cortical and hippocampal regions of rat brain. Increased calcium level may correlate with endoplasmic reticulum (ER) stress and significantly increased expression of ER stress markers like GRP78, GADD and caspase-12 were observed in STZ treated rat brain. Cellular communication was also affected by STZ administration as observed by increased expression connexin 43. With this view the activation of astrocytes and microglia was also assessed and observed by augmented GFAP and cd11b expression which were partially inhibited with donepezil treatment. The significantly increased level of degenerating neurons, caspase-3 and DNA fragmentation was also observed in rat brain regions which were not inhibited with donepezil treatment and validating the clinical observations. In conclusion, study indicated the STZ induced occurrence of Alzheimer's pathology. Further, STZ administration also caused depleted glucose level, inhibited mitochondrial activity, augmented calcium levels, ER stress, altered cellular communication and neuronal death which were partially attenuated with donepezil treatment. PMID- 29126978 TI - Toxoplasma gondii seroprevalence in goats, cats and humans in Russia. AB - Toxoplasmosis, a most common zoonosis, is caused by the protozoan parasite Toxoplasma gondii. However, there is little epidemiological information on T. gondii infections in humans and livestock animals in Russia. Therefore, in this study, the seroprevalence of T. gondii in goats in Russia was investigated. A total of 216 goats from 32 farms were investigated and 95 of them were seropositive for T. gondii. The difference in seroprevalence between the examined regions was not statistically significant. We next collected serum samples from 99 cats and 181 humans in Kazan city, the state capital of the Republic of Tatarstan, Russia, and examined their T. gondii seroprevalences. Thirty-nine of the 99 cat samples and 56 of the 181 human samples showed seropositivity. Logistical regression analysis revealed that the cat breeding history of the human subjects, but not their sex or age is a significant risk factor for T. gondii seropositivity. These findings suggest that the natural environment in Russia may be widely polluted with T. gondii oocysts shed by cats, and ingestion of these oocysts provides a major route for human infection with this parasite. PMID- 29126977 TI - Enhancement of inosine-mediated A2AR signaling through positive allosteric modulation. AB - Inosine is an endogenous nucleoside that is produced by metabolic deamination of adenosine. Inosine is metabolically more stable (half-life 15h) than adenosine (half-life <10s). Inosine exerts anti-inflammatory and immunomodulatory effects similar to those observed with adenosine. These effects are mediated in part through the adenosine A2A receptor (A2AR). Relative to adenosine inosine exhibits a lower affinity towards the A2AR. Therefore, it is generally believed that inosine is incapable of activating the A2AR through direct engagement, but indirectly activates the A2AR upon metabolic conversion to higher affinity adenosine. A handful of studies, however, have provided evidence for direct inosine engagement at the A2AR leading to activation of downstream signaling events and inhibition of cytokine production. Here, we demonstrate that under conditions devoid of adenosine, inosine as well as an analog of inosine 6-S-[(4 Nitrophenyl)methyl]-6-thioinosine selectively and dose-dependently activated A2AR mediated cAMP production and ERK1/2 phosphorylation in CHO cells stably expressing the human A2AR. Inosine also inhibited LPS-stimulated TNF-alpha, CCL3 and CCL4 production by splenic monocytes in an A2AR-dependent manner. In addition, we demonstrate that a positive allosteric modulator (PAM) of the A2AR enhanced inosine-mediated cAMP production, ERK1/2 phosphorylation and inhibition of pro-inflammatory cytokine and chemokine production. The cumulative effects of allosteric enhancement of adenosine-mediated and inosine-mediated A2AR activation may be the basis for the sustained anti-inflammatory and immunomodulatory effects observed in vivo and thereby provide insights into potential therapeutic interventions for inflammation- and immune-mediated diseases. PMID- 29126979 TI - Ropivacaine and Bupivacaine prevent increased pain sensitivity without altering neuroimmune activation following repeated social defeat stress. AB - OBJECTIVE: Mounting evidence indicates that stress influences the experience of pain. Exposure to psychosocial stress disrupts bi-directional communication pathways between the central nervous system and peripheral immune system, and can exacerbate the frequency and severity of pain experienced by stressed subjects. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates the immune and behavioral responses to stress observed in humans, including activation of stress-reactive neurocircuitry and increased pro inflammatory cytokine production. It is unclear, however, how these stress induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD. Here we used a technique of regional analgesia with local anesthetics in mice to block the development of mechanical allodynia during RSD. We next investigated the degree to which pain blockade altered stress-induced neuroimmune activation and depressive-like behavior. METHODS: Following development of a mouse model of regional analgesia with discrete sensory blockade over the dorsal-caudal aspect of the spine, C57BL/6 mice were divided into experimental groups and treated with Ropivacaine (0.08%), Liposomal Bupivacaine (0.08%), or Vehicle (0.9% NaCl) prior to exposure to stress. This specific region was selected for analgesia because it is the most frequent location for aggression-associated pain due to biting during RSD. Mechanical allodynia was assessed 12 h after the first, third, and sixth day of RSD after resolution of the sensory blockade. In a separate experiment, social avoidance behavior was determined after the sixth day of RSD. Blood, bone marrow, brain, and spinal cord were collected for immunological analyses after the last day of RSD in both experiments following behavioral assessments. RESULTS: RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Mice treated with either Ropivacaine or Liposomal Bupivacaine did not develop mechanical allodynia following exposure to stress, but did develop social avoidance behavior. Neither drug affected stress induced activation of monocytes in the bone marrow, blood, or brain. Neuroinflammatory responses developed in all treatment groups, as evidenced by elevated IL-1beta mRNA levels in the brain and spinal cord after RSD. CONCLUSIONS: In this study, psychosocial stress was associated with increased pain sensitivity in mice. Development of mechanical allodynia with RSD was blocked by regional analgesia with local anesthetics, Ropivacaine or Liposomal Bupivacaine. Despite blocking mechanical allodynia, these anesthetic interventions did not prevent neuroimmune activation or social avoidance associated with RSD. These data suggest that stress-induced neuroinflammatory changes are not associated with increased sensitivity to pain following RSD. Thus, blocking peripheral nociception was effective in inhibiting enhanced pain signaling without altering stress-induced immune or behavioral responses. PMID- 29126980 TI - Brain-derived neurotrophic factor in adjuvant-induced arthritis in rats. Relationship with inflammation and endothelial dysfunction. AB - OBJECTIVES: Both peripheral and central brain-derived neurotrophic factor (BDNF) levels are decreased in depression and normalized by efficient anti-depressive therapies. While depression symptoms are frequent in rheumatoid arthritis, BDNF has been poorly investigated in this pathology. Therefore, the present study explored cerebral and peripheral BDNF in arthritis rats as well as the link between brain BDNF and the two factors recently involved in the pathogenesis of depression and present in rheumatoid arthritis namely inflammation and endothelial dysfunction. METHODS: The brain (hippocampus and frontal cortex) and blood (serum) were collected in rats subjected to adjuvant-induced arthritis (AIA) when inflammatory symptoms and endothelial dysfunction are fully developed. Anhedonia as a core symptom of depression symptom was assessed from preference for a saccharin drinking solution. Inflammation was assessed from the arthritis score and serum levels of TNFalpha and IL-1beta. Treatment with the arginase inhibitor N(w)-hydroxy-nor-l-arginine (nor-NOHA) was used as a strategy to prevent endothelial dysfunction without improving inflammatory symptoms. RESULTS: As compared to controls, AIA rats displayed decreased brain BDNF levels that coexisted with anhedonia but contrasted with increased BDNF levels in serum. Brain BDNF deficiency correlated neither with arthritis score nor with pro inflammatory cytokines levels, while it was mitigated by nor-NOHA treatment. A positive correlation was observed between serum BDNF and TNFalpha levels. CONCLUSIONS: Our study reveals that arthritis decreases BDNF levels in the brain and that endothelial dysfunction rather than inflammation contributes to the decrease. It also identifies a disconnection between serum and brain BDNF levels in arthritis. PMID- 29126981 TI - Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: A double-blind, randomized clinical trial. AB - BACKGROUND: Schizophrenia is one of the most disabling psychiatric syndromes with the prevalence of 1% in the general population. Despite availability of various antipsychotics, negative symptoms and cognitive impairment are difficult to treat. In addition antipsychotic monotherapy is not effective in most of these patients. Current evidence indicates the roles of glutamatergic system in this disorder. N-acetyl cysteine (NAC) also increases extracellular glutamate. This study was conducted to evaluate the clinical effects of oral NAC as an add-on to maintenance medication for the treatment of chronic schizophrenia. MATERIALS AND METHODS: This 12-week, double-blind, randomized, placebo-controlled, clinical trial was performed to determine the effectiveness of 1200mg N-acetyl cysteine as an adjunctive treatment with conventional antipsychotic medications in 84 patients with chronic schizophrenia. The subjects were evaluated with the Positive and Negative Syndrome Scale (PANSS), Mini-Mental State Examination (MMSE), and a standard neuropsychological screening test. Data were analyzed with SPSS-16 software. RESULTS: NAC-treated patients showed significantly improvement in the positive (F=5.47, P=0.02) and negative (F=0.20, df=1) PANSS subscale. Also the general and total PANSS score of NAC group declined over times whilst it was increased for placebo group. Regarding cognitive functions, improvement was observed in some explored areas, such as attention, short-term and working memory, executive functioning and speed of processing. There was no significant difference between the 2 groups in the frequency of adverse effects. CONCLUSION: The present study detected improvement in positive, negative, general and total psychopathology symptoms as well as cognitive performance with NAC treatment. It is also well-tolerated, safe and easy-to-use agent as an effective therapeutic strategy to improve outcome in schizophrenia treatment. PMID- 29126982 TI - Effects of chronic social defeat on social behaviors in adult female mandarin voles (Microtus mandarinus): Involvement of the oxytocin system in the nucleus accumbens. AB - Chronic social defeat affects many aspects of behavior. Most previous studies have focused on effects on males and defeat during adolescence. The extents to which chronic social defeat can impact female social behavior in adulthood and the neural mechanisms of such effects are poorly understood. Using highly social and aggressive female mandarin voles (Microtus mandarinus), the present study found that chronic social defeat reduced social preference in adult females, and that the defeated voles exhibited a high level of freeze, self-grooming and defensive behavior, as well as reduced exploration, intimacy and aggression during social interactions. Furthermore, chronic social defeat reduced levels of oxytocin (OT) and OT receptors (OTR) in the shell region of the nucleus accumbens (NACC). Intra-NACC shell OT microinjections reversed alterations in social behavior induced by chronic social defeat, whereas injections of an OTR antagonist (OTR-A) blocked the effects of OT. Taken together, our data demonstrate that chronic social defeat suppresses measures of sociability, and that these effects are mediated by the action of OT on the OTR in the NACC. NACC OT may be a promising target to treat socio-emotional disorders induced by chronic social stress. PMID- 29126983 TI - Yeast-like microorganisms in the scale insect Kermes quercus (Insecta, Hemiptera, Coccomorpha: Kermesidae). Newly acquired symbionts? AB - Scale insects, like other plant sap-consumers, are host to symbiotic microorganisms which provide them with the substances missing from their diet. In contrast to most scale insects, Kermes quercus (Linnaeus) was regarded as asymbiotic. Our histological and ultrastructural observations show that in the body of the feeding stages of K. quercus collected in two locations (Warsaw and Cracow), numerous yeast-like microorganisms occur. These microorganisms were localized in the cytoplasm of fat body cells. The yeast-like microorganisms were observed neither in other organs of the host insect nor in the eggs. These microorganisms did not cause any damage to the structure of the ovaries and the course of oogenesis of the host insect. The females infected by them produced about 1300 larvae. The lack of these microorganisms in the cytoplasm of eggs indicates that they are not transmitted transovarially from mother to offspring. Molecular analyses indicated that the microorganisms which reside in the body of K. quercus are closely related to the entomopathogenic fungi Cordyceps and Ophiocordyceps, which belong to the Sordariomycetes class within the Ascomycota. The role of yeast-like microorganisms to their host insects remains unknown; however, it has been suggested that they may represent newly acquired symbionts. PMID- 29126984 TI - Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone. AB - Seven proprotein convertases cleave the basic amino acid consensus sequence K/R Xn-K/R? (where n=0, 2, 4 or 6 variable amino acids) to activate precursor proteins. Despite similarities in substrate specificity, basic amino acid specific proprotein convertases have a distinct tissue distribution allowing for enzymatic actions on tissue-resident substrates. Proprotein convertase 5/6 (PC5/6) has two splice variants - soluble PC5/6A and membrane-bound PC5/6B - and is expressed during mouse development in many tissues including bone and tooth, but little is known about the substrates for PC5/6 therein. Osteopontin (OPN) is an abundant bone extracellular matrix protein with roles in mineralization, cell adhesion and cell migration, and it has putative consensus sequence sites for cleavage by PC5/6, which may modify its function in bone. Since PC5/6-knockout mouse embryos show developmental abnormalities, and reduced overall mineralization, we designed this study to determine whether OPN is a substrate of PC5/6. In silico analysis of OPN protein sequences identified four potential PC5/6 consensus cleavage sites in human OPN, and three sites - including a noncanonical sequence - in mouse OPN. Ex vivo co-transfections with human OPN revealed complete OPN cleavage reducing full-length OPN (~70kDa) to an N-terminal fragment migrating at ~50kDa and two C-terminal fragments at ~18kDa and ~16kDa. Direct cleavage of OPN by PC5/6A - the predominant isoform expressed in human osteoblast cells - was confirmed by cell-free enzyme-substrate assays and by mass spectrometry. The latter was also used to investigate potential cleavage sites. Co-transfections of PC5/6 and mouse OPN showed partial cleavage of OPN into a C terminal OPN fragment migrating at ~30kDa and an N-terminal fragment migrating at ~29kDa. Micro-computed tomography of PC5/6-knockout embryos at E18.5 confirmed a reduction in mineralized bone, and in situ hybridization performed on cryo sections of normal mouse bone using Pcsk5 and Opn anti-sense and control-sense cRNA probes indicated the co-localization of the expression of these genes in bone cells. This mRNA expression profile was supported by semi-quantitative RT PCR using osteoblast primary cultures, and cultured MC3T3-E1 osteoblast and MLO Y4 osteocyte cell lines. Immunoblotting for OPN from mouse bone extracts showed altered OPN processing in PC5/6-knockout mice compared to wildtype mice. OPN fragments migrated at ~25kDa and ~16kDa in wildtype bone and were not present in PC5/6-deficient bone. In conclusion, this study demonstrates that Pcsk5 is expressed in bone-forming cells, and that OPN is a novel substrate for PC5/6. Cleavage of OPN by PC5/6 may modify the function of OPN in bone and/or modulate other enzymatic cleavages of OPN, leading to alterations in the bone phenotype. PMID- 29126985 TI - Spatiotemporal expression pattern of Connexin 43 during early chick embryogenesis. AB - During embryogenesis, a single cell develops into new tissues and organs that are made up of a number of different cell types. The assembly of the trigeminal ganglion (cranial nerve V), an important component of the peripheral nervous system, typifies this process. The trigeminal ganglia perform key sensory functions, including sensing pain and touch in the face, and arise from cells of two different progenitor populations, the neural crest and the cranial placodes. One question that remains poorly understood is how these two populations of cells interact with each other during development to form a functional ganglion. Gap junctions are intercellular channels that allow for the passage of small solutes between connected cells and could serve as one potential mechanism by which neural crest and placode cells communicate to create the trigeminal ganglia. To this end, we have generated a comprehensive spatiotemporal expression profile for the gap junction protein Connexin 43, a highly expressed member of the Connexin protein family during development. Our results reveal that Connexin 43 is expressed in the neural folds during neural fold fusion and in premigratory neural crest cells prior to the epithelial-to-mesenchymal transition (EMT), during EMT, and in migratory neural crest cells. During trigeminal gangliogenesis, Connexin 43 is expressed in cranial neural crest cells and the mesenchyme but is strikingly absent in the placode-derived neurons. These data underscore the complexity of bringing two distinct cell populations together to form a new tissue during development and suggest that Connexin 43 may play a key role within neural crest cells during EMT, migration, and trigeminal gangliogenesis. PMID- 29126986 TI - Functional redundancy of glucose acquisition mechanisms in the hindgut of Pacific hagfish (Eptatretus stoutii). AB - This study examined the mechanisms of glucose acquisition in the hindgut of Pacific hagfish (Eptatretus stoutii) using in vitro gut sac techniques. The intestine was determined to have the capacity to digest maltose into glucose along the entirety of the tract, including the foregut. Glucose uptake was biphasic and consisted of a high-affinity, low-capacity concentration-dependent component conforming to Michaelis-Menten kinetics (Km 0.37mM, Jmax 8.48nmol/cm2/h) as well as a diffusive component. There was no observed difference in glucose flux rate along the length of the intestine, similar to other nutrients investigated in the hagfish intestine. A reduced sodium (<1mM) environment did not result in a change in glucose uptake rates, likely due to a functional redundancy of glucose transporters. There was no observed effect of phloretin, yet the sodium glucose-linked transporter (SGLT)-specific inhibitor phlorizin significantly reduced glucose uptake at all concentrations tested (0.0001-1mM). Additionally, the glucose transporter (GLUT) inhibitor cytochalasin b significantly reduced glucose transport rates. The effects of these pharmacological inhibition experiments suggest the presence of multiple types of glucose transport proteins. This study clarifies the uptake strategies used by hagfish to acquire glucose at the intestine and provides insight into the evolution of such transport systems in early-diverging vertebrates. PMID- 29126987 TI - Endothelial and kidney function in women with a history of preeclampsia and healthy parous controls: A case control study. AB - INTRODUCTION: Preeclampsia (PE) is a pregnancy related endothelial disease characterized by hypertension and albuminuria. Postpartum endothelial dysfunction often persists in these women. We postulate that in women with a history of PE reduced endothelial dependent vasodilation coincides with attenuated kidney function, as both reflect endothelial dysfunction. METHODS: We assessed endothelial and kidney function in women with a history of PE (n=79) and uncomplicated pregnancies (n=49) at least 4years postpartum. Women with hypertension, diabetes or kidney disease prior to pregnancy were excluded. Brachial artery flow mediated dilatation (FMD) was measured and analysed by a custom designed edge-detection and wall-tracking software. We measured albumin and creatinine levels in a 24-h urine sample and calculated glomerular filtration rate (GFR) by CKD-EPI. RESULTS: Women with a history of PE had lower FMD but comparable GFR and albumin creatinine ratio (ACR) compared with controls. Independent of obstetric history, in both controls and women with a history of PE respectively, GFR (r=0.19, p=0.17 and r=0.12, p=0.29) and albumin creatinine ratio (r=0.07, p=0.62 and r=0.06 p=0.57) did not correlate with FMD. CONCLUSION: At least 4years after pregnancy, women with a history of PE demonstrated decreased flow mediated dilatation when compared to healthy parous controls. In this study, decreased flow mediated dilation however did not coincide with decreased kidney function. PMID- 29126988 TI - Morinda officinalis How. - A comprehensive review of traditional uses, phytochemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal plant Morinda officinalisHow. (MO) and its root have long been used in traditional medicines in China and northeast Asia as tonics for nourishing the kidney, strengthening the bone and enhancing immunofunction in the treatment of impotence, osteoporosis, depression and inflammatory diseases such as rheumatoid arthritis and dermatitis. AIM OF THE REVIEW: This review aims to sum up updated and comprehensive information about traditional usage, phytochemistry, pharmacology and toxicology of MO and provide insights into potential opportunities for future research and development of this plant. METHODS: A bibliographic investigation was performed by analyzing the information available on MO in the internationally accepted scientific databases including Pubmed, Scopus and Web of Science, SciFinder, Google Scholar, Yahoo, Ph.D. and M.Sc. dissertations in Chinese. Information was also obtained from some local and foreign books on ethnobotany and ethnomedicines. RESULTS: The literature supported the ethnomedicinal uses of MO as recorded in China for various purposes. The ethnomedical uses of MO have been recorded in many regions of China. More than 100 chemical compounds have been isolated from this plant, and the major constituents have been found to be polysaccharides, oligosaccharides, anthraquinones and iridoid glycosides. Crude extracts and pure compounds of this plant are used as effective agents in the treatment of depression, osteoporosis, fatigue, rheumatoid arthritis, and infertility due to their anti-depressant, anti-osteoporosis, pro-fertility, anti-radiation, anti Alzheimer disease, anti-rheumatoid, anti-fatigue, anti-aging, cardiovascularprotective, anti-oxidation, immune-regulatory, and anti inflammatory activities. Pharmacokinetic studies have demonstrated that the main components of MO including monotropein and deacetyl asperulosidic acid are distributed in various organs and tissues. The investigation on acute toxicity and genotoxicity indicated that MO is nontoxic. There have no reports on significant adverse effect at a normal dose in clinical application, but MO at dose of more than 1000mg/kg may cause irritability, insomnia and unpleasant sensations in individual cases. CONCLUSION: MO has emerged as a good source of traditional medicines. Some uses of this plant in traditional medicines have been validated by pharmacological investigations. However, the molecular mechanism, structure-activity relationship, and potential synergistic and antagonistic effects of its multi-components such as polysaccharides, oligosaccharides, anthraquinones and iridoid glycosides need to be further elucidated, and the structural feature of polysaccharides also need to be further clarified. Sophisticated analytical technologies should be developed to comprehensively evaluate the quality of MO based on HPLC-fingerprint and content determination of the active constituents, knowing that these investigations will help further utilize this plant. PMID- 29126989 TI - Anti-thrombotic and pro-angiogenic effects of Rubia cordifolia extract in zebrafish. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rubia cordifolia is a common traditional Chinese medicine that promotes blood circulation and eliminates blood stasis, and has been used to cure diseases related to blood stasis syndrome (BSS) clinically for many years. It has been previously demonstrated that anti-thrombosis and pro angiogenesis can improve BSS. However, the anti-thrombotic and pro-angiogenic activities of Rubia cordifolia have not been well investigated. AIM OF STUDY: To determine the potential anti-thrombotic and pro-angiogenic activities of Rubia cordifolia and to elucidate the underlying mechanisms. In addition, the major chemical constituents of Rubia cordifolia extract (QC) were qualitatively analysed by UPLC-Q-TOF/MS to explore the association between pharmacological activity and chemical constituents. MATERIAL AND METHODS: The QC samples were composed of a 95% ethanol extract and an aqueous extract following extraction using 95% ethanol. UPLC-Q-TOF/MS was used to analyse the major chemical constituents of QC. For the anti-thrombotic experiment of QC, a phenylhydrazine (PHZ)-induced AB strain zebrafish thrombosis model was used. The zebrafish larvae were stained using O-dianisidine, and the heart and caudal vein of the zebrafish were observed and imaged with a fluorescence microscope. The staining intensity of erythrocytes in the heart (SI) of each group and the morphology of thrombus in the caudal vein were used to assess the anti-thrombotic effect of QC. For the pro angiogenic assay of QC, the intersegmental blood vessel (ISV) insufficiency model of Tg(fli-1: EGFP)y1 transgenic zebrafish (Flik zebrafish), which was induced by the VEGF receptor tyrosine kinase inhibitor II (VRI), was used. The morphology of the intact ISVs and defective ISVs was observed to evaluate the pro-angiogenic activity of QC. The mechanism involved in promoting angiogenesis was studied with real-time PCR. RESULTS: A total of 12 components in QC were identified based on standard compounds and references, including nine anthraquinones and three naphthoquinones. After treatment with QC, the PHZ-induced thrombosis in AB strain zebrafish larvae decreased to a certain degree, which we believe was related to its dosages, and the therapeutic effect within the 50-200 ug/mL QC treatment groups was especially prominent (P < 0.01, P < 0.001) compared to that in the PHZ model group. Similarly, QC also recovered the loss of the ISVs, which was induced by VRI in Flik zebrafish larvae, which have a certain dose-effect relationship. The pro-angiogenic activity of QC was also conspicuous (P < 0.01, P < 0.001) compared to that of the VRI model group. The following real-time PCR assay proved that QC significantly restored the VRI-induced downregulation of vWF, VEGF-A, kdrl, and flt-1 in Flik zebrafish (P < 0.05, P < 0.01, P < 0.001). CONCLUSIONS: A total of 12 compounds from QC were analysed by UPLC-Q-TOF/MS. The data of the pharmacological experiments demonstrated that QC presented anti-thrombotic and pro-angiogenic activities in zebrafish, and the principal active components were likely anthraquinones and naphthoquinones. Thus, the current study provided a theoretical basis for the clinical use of Rubia cordifolia as a traditional Chinese medicine in promoting blood circulation and eliminating stasis. PMID- 29126990 TI - A proanthocyanidin-rich extract from Cassia abbreviata exhibits antioxidant and hepatoprotective activities in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cassia abbreviata is a small to medium sized branched umbrella-shaped deciduous tree. It is widely spread in the tropics, especially in Africa, having a long history in traditional medicine for the treatment of numerous conditions such as headaches, diarrhea, constipation, some skin diseases, malaria, syphilis, pneumonia, stomach troubles, uterine pains, and against gonorrhea. AIM OF THE STUDY: We investigated the phytochemical constituents of a root extract from Cassia abbreviata using HPLC-PDA-ESI-MS/MS. We also determined the antioxidant activities in vitro and in vivo using the nematode Caenorhabditis elegans as a model organism. The hepatoprotective activities in case of D-galactosamine (D-GaIN)-induced hepatotoxicity were studied in a rat model. MATERIALS AND METHODS: HPLC-PDA-ESI-MS/MS analysis allowed the identification of the secondary metabolites of the methanol extract. DPPH and FRAP assays were used to determine the antioxidant activities in vitro. Using the C. elegans model, survival rates under juglone induced oxidative stress, intracellular ROS content, quantification of Phsp-16.2: GFP expression and subcellular DAF-16: GFP localization were investigated to determine the antioxidant activities in vivo. The in vivo hepatoprotective potential of the root extract was evaluated for D-galactosamine (D-GaIN)-induced hepatotoxicity in rats. The activity of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT), in addition to liver peroxidation product malondialdehyde (MDA) and glutathione content (GSH), as well as albumin and total bilirubin concentration, were determined. A histopathological study was also performed. RESULTS AND CONCLUSIONS: C. abbreviata root extract is rich in polyphenolics, particularly proanthocyanidins. HPLC-PDA-ESI-MS/MS analysis resulted in the identification of 57 compounds on the bases of their mass spectra. (epi)-Catechin, (epi)-afzelechin, (epi) guibourtinidol, and (ent)-cassiaflavan monomers as well as their dimers, trimers, and their diastereomers are the main components of the extract. The total phenolic content amounted for 474mg/g root extract expressed as gallic acid equivalent using the Folin-Ciocalteu method. The extract exhibited powerful antioxidant activity with EC50 of 6.3MUg/mL in DPPH and 19.15mM FeSO4 equivalent/mg sample in FRAP assay. In C. elegans model, the extract (200MUg/mL) was able to increase the survival rate by 44.56% and reduced the ROS level to 61.73%, compared to control group. Pretreatment of rats with 100mg extract/kg (b. wt.) reduced MDA by 47.36% and elevated GSH by 59.1%. The extract caused a significant reduction of ALT, AST and GGT activities by 11%, 35.7% and 65%, respectively. The findings of this study suggest that the proanthocyanidin-rich extract from C. abbreviata may be an interesting candidate for hepatoprotective activity in case of hepatocellular injury. PMID- 29126992 TI - Selection of carbapenem-resistant Pseudomonas aeruginosa in a haematology unit? PMID- 29126991 TI - Rainbow trout (Oncorhynchus mykiss) adipose tissue undergoes major changes in immune gene expression following bacterial infection or stimulation with pro inflammatory molecules. AB - In mammals, visceral adipose is increasingly seen as playing an important role in immune function with numerous pro-inflammatory, anti-inflammatory and immune modulating proteins and peptides being identified in adipocytes. Adipose is also now known as a tissue that has an important role in the regulation of peritoneal immune responses. Despite this, only lately has consideration been given to visceral adipose as an important immune tissue in fish, especially in the context of intraperitoneal vaccination. The present study demonstrates that fish visceral adipose is capable of expressing a large range of immune molecules in response to stimulation with a live bacterium (A. salmonicida), a bacterial PAMP (Y. ruckeri flagellin), and the pro-inflammatory cytokines IL-1beta, TNF-alpha3 and IFN gamma. Following infection and stimulation with flagellin and IL-1beta a large upregulation of pro-inflammatory and antimicrobial molecules was seen, with a high degree of overlap. TNF-alpha treatment affected relatively few genes and the effects were more modest. IFN-gamma had the smallest impact on adipose but IFN gamma inducible genes showed some of the largest effects. Overall, it is clear that adipose tissue should be considered an active immune site in fish, capable of participating in and influencing immune responses. PMID- 29126993 TI - Trophic effect of PACAP on human corneal endothelium. AB - Cornea's posterior surface includes endothelium maintaining stromal hydration and clarity. Due to their limited proliferative capability, the loss of endothelial cells can outcome in permanent opacity. In the last years, different studies have demonstrated the protective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) in different ocular diseases. However, its role on human corneal endothelial cells (HCECs) has not been investigated, yet. Here, we have developed a culture protocol to differentiate HCECs from donor's cornea. PACAP treatment prevented damage induced by growth factors deprivation of cells grown on transwell supports as revealed by TERR measurements. Moreover, this peptide significantly increased tight junction proteins expression by conferring resistance to endothelial barrier. This effect is also related to promotion of cell viability as demonstrated by MTT assay. Furthermore, PACAP stimulated repairing of corneal endothelium lesion as shown by wound healing analysis. In conclusion, our data suggest that this peptide could represent an important trophic factor in maintaining functionality of human corneal endothelium. PMID- 29126995 TI - FVD: The fish-associated virus database. AB - With the expanding of marine and freshwater aquaculture, the outbreaks of aquatic animal diseases have increasingly become the major threats to the healthy development of aquaculture industries. Notably, viral infections lead to massive fish deaths and result in great economic loss every year across the world. Hence, it is meaningful to clarify the biodiversity, geographical distribution and host specificity of fish-associated viruses. In this study, viral sequences detected in fish samples were manually collected from public resources, along with the related metadata, such as sampling time, location, specimen type and fish species. Moreover, the information regarding the host fish, including aliases, diet type and geographic distribution were also integrated into a database (FVD). To date, FVD covers the information of 4860 fish-associated viruses belonging to 15 viral families, which were detected from 306 fish species in 57 countries. Meanwhile, sequence alignment, live data statistics and download function are available. Through the user-friendly interface, FVD provides a practical platform that would not only benefit virologists who want to disclose the spread of fish associated viruses, but also zoologists who focus on the health of domestic and wild animals. Furthermore, it may facilitate the surveillance and prevention of fish viral diseases. Database URL: http://bioinfo.ihb.ac.cn/fvd. PMID- 29126994 TI - A Dual-Promoter Gene Orchestrates the Sucrose-Coordinated Synthesis of Starch and Fructan in Barley. AB - Sequential carbohydrate synthesis is important for plant survival because it guarantees energy supplies for growth and development during plant ontogeny and reproduction. Starch and fructan are two important carbohydrates in many flowering plants and in human diets. Understanding this coordinated starch and fructan synthesis and unraveling how plants allocate photosynthates and prioritize different carbohydrate synthesis for survival could lead to improvements to cereals in agriculture for the purposes of greater food security and production quality. Here, we report a system from a single gene in barley employing two alternative promoters, one intronic/exonic, to generate two sequence-overlapping but functionally opposing transcription factors, in sensing sucrose, potentially via sucrose/glucose/fructose/trehalose 6-phosphate signaling. The system employs an autoregulatory mechanism in perceiving a sucrose controlled trans activity on one promoter and orchestrating the coordinated starch and fructan synthesis by competitive transcription factor binding on the other promoter. As a case in point for the physiological roles of the system, we have demonstrated that this multitasking system can be exploited in breeding barley with tailored amounts of fructan to produce healthy food ingredients. The identification of an intron/exon-spanning promoter in a hosting gene, resulting in proteins with distinct functions, adds to the complexity of plant genomes. PMID- 29126996 TI - Blastocystis genetic diversity among children of low-income daycare center in Southeastern Brazil. AB - Blastocystis, an unicellular anaerobic eukaryote, is known to be a very common intestinal parasite found in humans and animals fecal samples worldwide. Currently, there is an increasing interest to yield insights into its prevalence and diversity in human populations living in poor and deprived areas. In this study, we describe the prevalence and genetic variability of Blastocystis isolates obtained from daycare center attendees aged 0 to 6years and staff, as well as some children family members and their dogs in a low-income community in Sao Paulo State, Brazil. A total of 181 stool samples (123 from daycare children, 14 from workers, 44 from household members and 20 from dogs) were submitted to DNA extraction, tested by polymerase chain reaction (PCR) targeting the SSUrDNA gene and the amplicons retrieved were sequenced. The prevalence of Blastocystis was 40.7% (50/123) in children, 28.6% (4/14) in workers and 50% (22/44) in household members. No dog was found positive. Of the 76 PCR products generated, 57 were successfully sequenced. Four subtypes were identified and the most common were ST1 (54.4%) and ST3 (33.3%), followed by ST2 (7.0%) and ST7 (5.3%). The intra-subtype analysis revealed a total of 10 different alleles previously reported. No statistically significant correlation was observed between subtypes and sociodemographic variables analyzed. Here, the following findings must be highlighted: (1) predominance of subtypes 1 and 3, a pattern that has been observed in many populations worldwide; (2) absence of ST4, a common subtype in Europe but rarely detected in South America's human populations and, (3) human infection with ST7, a subtype primarily found in birds but occasionally seen in human infections, raising the possibility of zoonotic transmission. PMID- 29126997 TI - Changes in the time of day of conditioning with respect to the pre-exposure interfere with the latent inhibition of conditioned taste aversion in rats. AB - In rats, the reduction of the magnitude of a conditioned taste aversion (CTA) that occurs after taste pre-exposures (that is, the latent inhibition of CTA) can be attenuated by contextual changes of the external cues in the conditioning stage. Similarly, circadian internal cues such as those induced by the time of day may also modulate the magnitude of the taste aversion. Under a long period of temporal-contextual habituation, the latent inhibition of CTA is reduced if the pre-exposure and conditioning stages occur at different times of day. However, it is unknown if this effect is consistent when different changes in the time of day of conditioning with respect to the pre-exposure are compared. In this study, the effect of two different changes in the time of day of conditioning (one from morning to evening, and one from evening to morning) on the latent inhibition of CTA was compared with the response of a typical latent inhibition group without temporal change between stages, and with control groups without pre-exposures. The results indicate that the latent inhibition of CTA of both groups with temporal change between pre-exposure and conditioning is significantly reduced when compared with the latent inhibition of the group without temporal change. These findings suggest that the temporal context may be a critical cue for the latent inhibition of CTA, and they show that different changes in the time of day of conditioning interfere similarly with this learning. PMID- 29126998 TI - High-runner mice have reduced incentive salience for a sweet-taste reward when housed with wheel access. AB - To explore reward substitution in the context of voluntary exercise, female mice from four replicate high-runner (HR) lines (bred for wheel running) and four non selected control (C) lines were given simultaneous access to wheels and palatable solutions as competing rewards (two doses of saccharin [0.1, 0.2% w/v]; two doses of common artificial sweetener blends containing saccharin [Sweet 'N Low(r): 0.1, 0.2% w/v], aspartame [Equal(r): 0.04, 0.08% w/v], or sucralose [Splenda(r): 0.08, 0.16% w/v]; or two doses of sucrose [3.5, 10.5% w/v]). Wheel running and fluid consumption were measured daily, with each dose (including plain water) lasting two days and two "washout" days between solutions. In a separate set of mice, the experiment was repeated without wheel access. The artificial sweeteners had no statistical effect on wheel running. However, based on proportional responses, both doses of sucrose significantly elevated wheel running in C but not HR mice. In contrast, the high dose of sucrose suppressed home-cage activity for both linetypes. Both sucrose and the artificial blends generally increased fluid consumption in a dose-dependent manner. When they had access to wheels, HR had a significantly smaller increase in consumption of artificial sweetener blends when compared with C mice, but not when housed without wheels. Overall, these results provide further evidence that the reward system of HR mice has evolved, and specifically suggest that HR mice have a reduced incentive salience for some artificial sweetener blends, likely attributable to the stronger competing reward of wheel running that has evolved in these lines. PMID- 29126999 TI - On the use of liposome controls in studies investigating the clinical potential of extracellular vesicle-based drug delivery systems - A commentary. AB - The field of extracellular vesicle (EV)-based drug delivery systems has evolved significantly through the recent years, and numerous studies suggest that these endogenous nanoparticles can function as efficient drug delivery vehicles in a variety of diseases. Many characteristics of these EV-based drug delivery vehicles suggest them to be superior at residing in the systemic circulation and possibly at mediating therapeutic effects compared to synthetic drug delivery vehicles, e.g. liposomes. In this Commentary, we discuss how some currently published head-to-head comparisons of EVs versus liposomes are weakened by the inadequate choice of liposomal formulation, and encourage researchers to implement better controls to show any potential superiority of EVs over other synthetic nanoparticles. PMID- 29127000 TI - Drug delivery systems functionalized with bone mineral seeking agents for bone targeted therapeutics. PMID- 29127002 TI - Post-acquisition hippocampal blockade of the NMDA receptor subunit GluN2A but not GluN2B sustains spatial reference memory retention. AB - While it has been shown that the blockade of N-methyl-d-aspartate type glutamate receptors (NMDARs) impairs memory acquisition, recent studies have reported that the post-acquisition administration of NMDAR antagonists suppresses spatial memory decay. These findings suggest that NMDARs are important not only for the acquisition of new memories but also for the decay of previously acquired memories. The present study investigated the contributions of specific NMDAR subunits to spatial memory decay using NVP-AAM077 (NVP), an NMDAR antagonist that preferentially binds to GluN2A subunits, and the selective GluN2B blocker Ro 25 6981 (Ro). Following Morris water maze training (four trials/day for four days), NVP and/or Ro were subchronically infused into the rat hippocampus for five days. Seven days after training, NVP-treated rats and NVP/Ro-treated rats explored the target area significantly more than the control and Ro-treated rats. These results demonstrate that post-acquisition treatment with NVP, but not Ro, suppresses the forgetting of previously acquired spatial memories. The NVP treated rats more persistently explored the target area in the second test, which was conducted one day after the first, while the NVP/Ro-treated rats did not, which suggest that Ro treatment downregulates memory retention. In conclusion, the present results indicate that the NMDAR GluN2A and GluN2B subunits contribute to spatial memory deterioration and maintenance, respectively. PMID- 29127001 TI - Long-term intraocular pressure reduction with intracameral polycaprolactone glaucoma devices that deliver a novel anti-glaucoma agent. AB - Long-term treatment of glaucoma, a major leading cause of blindness, is challenging due to poor patient compliance. Therefore, a drug delivery device that can achieve drug release over several months can be highly beneficial for glaucoma management. Here, we evaluate the long-term pharmacokinetics and therapeutic efficacy of polycaprolactone intracameral drug delivery devices in rabbit eyes. Our study showed that a single drug delivery device loaded with a proprietary hypotensive agent, DE-117, reduced intraocular pressure in normotensive rabbits significantly for 23weeks. In addition, we demonstrated that concentration of DE-117 and its hydrolyzed active form (hDE-117) was maintained in the aqueous humor and the target tissue (iris-ciliary body) up to 24weeks. Our proof-of-concept glaucoma implant shows potential as a long-term treatment that circumvents patient compliance barriers compared to current treatment via eye drops. PMID- 29127003 TI - Recombinant alpha-fetoprotein receptor-binding domain co-expression with polyglutamate tags facilitates in vivo folding in E. coli. AB - A wide range of methods are known to increase the prokaryotic intracellular recombinant proteins solubility, for instance, growth at low temperature, supplementation of culture media with "chemical chaperones" (proline, glycine betaine, and trehalose), co-expression with chaperones or highly soluble fusion partners. As an alternative, we have introduced the polyglutamate tag, which, as it has been shown, increased the protein solubility and facilitated folding. In this study we evaluated the minimal quantity of high density negatively charged EEEEVE amino acid repeats (pGlu) necessary to switch the recombinant receptor binding domain of human alpha-fetoprotein (rbdAFP) expression almost entirely from the inclusion bodies to the soluble cytoplasmic fraction in E. coli. For this purpose, genetic constructs based on pET vectors coding rbdAFP and containing from 1 to 4 additional EEEEVE repeats at the C-terminus have been prepared. It was found that 3 pGlu repeats is the minimal number, that leads to a complete shift of the expression to the soluble cytoplasmic fraction in E. coli SHuffle Express T7 while 4 repeats were required for that in E. coli BL21(DE3). The rbdAFP contained 4 pGlu repeats was purified making use of ion-exchange chromatography and characterized by circular dichroism and ability to bind and accumulate in AFP receptor positive cancer cells in order to check for the structural and specific activity alterations related to the additional polyanionic sequence introduction. PMID- 29127004 TI - Molecular cloning and characterization of the SIFamide precursor and receptor in a hymenopteran insect, Bombus terrestris. AB - SIFamides (SIFa) are a family of neuropeptides that are highly conserved among arthropods. In insects, this peptide is mainly expressed in four medial interneurons in the pars intercerebralis and affects sexual behavior, sleep regulation and pupal mortality. Furthermore, an influence on the hatching rate has been observed. The first SIFa receptor (SIFR) was pharmacologically characterized in Drosophila melanogaster and is homologous to the vertebrate gonadotropin-inhibitory hormone (GnIH) receptor (NPFFR). In this study, we pharmacologically characterized the SIFR of the buff-tailed bumblebee Bombus terrestris. We demonstrated an intracellular increase in calcium ions and cyclic AMP (cAMP) upon ligand binding with an EC50 value in the picomolar and nanomolar range, respectively. In addition, we studied the agonistic properties of a range of related and modified peptides. By means of quantitative real time PCR (qPCR), we examined the relative transcript levels of Bomte-SIFa and Bomte-SIFR in a variety of tissues. PMID- 29127006 TI - sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer's disease model. AB - The main causes of Alzheimer's disease (AD) have not determined and effective treatment has not been developed yet, even though extensive researches and several clinical trials have been conducted.. Fortunately, stem cell transplantation is emerging as a potential therapeutic candidate for AD, but the success of stem cell based therapy depends on the survival of transplanted cells. Here, we generated sRAGE secreting mesenchymal stem cells (sRAGE-MSCs) and then injected these MSCs or control MSCs with amyloid beta 1-42 (Abeta1-42) into the entorhinal cortices of male Sprague Dawley rats. The survival of transplanted cell, the number of T lymphocytes and microglia, expression of RAGE and its ligands and neuronal cell death were determined, 4 weeks after sRAGE-MSC transplantation. Transplanted sRAGE-MSCs survived longer than control MSCs and sRAGE-MSCs showed reduced level of CD4 and CD3d positive T lymphocyte. Furthermore, the number of M1 microglia in MSCs was more than that of sRAGE-MSCs as well. On the other hand, the number of M2 microglia in sRAGE-MSCs was increased compared with that of MSCs. In addition, sRAGE-MSCs decreased RAGE and RAGE ligand expressions and their interactions more effectively than those of MSCs. Finally, sRAGE-MSC transplantation protected from apoptosis and prevented decreasing numbers of neuron in Abeta1-42 treated rat brains. These observations suggest continuous sRAGE secretion from sRAGE-MSCs might appreciably improve the effectiveness of cell therapy in Abeta1-42 injected rat brains. PMID- 29127005 TI - The Pleckstrin homology like domain family member, TDAG51, is temporally regulated during skeletal muscle regeneration. AB - The capacity for skeletal muscle to repair from daily insults as well as larger injuries is a vital component to maintaining muscle health over our lifetime. Given the importance of skeletal muscle for our physical and metabolic well being, identifying novel factors mediating the growth and repair of skeletal muscle will thus build our foundational knowledge and help lead to potential therapeutic avenues for muscle wasting disorders. To that end, we investigated the expression of T-cell death associated gene 51 (TDAG51) during skeletal muscle repair and studied the response of TDAG51 deficient (TDAG51-/-) mice to chemically-induced muscle damage. TDAG51 mRNA and protein expression within uninjured skeletal muscle is almost undetectable but, in response to chemically induced muscle damage, protein levels increase by 5 days post-injury and remain elevated for up to 10 days of regeneration. To determine the impact of TDAG51 deletion on skeletal muscle form and function, we compared adult male TDAG51-/- mice with age-matched wild-type (WT) mice. Body and muscle mass were not different between the two groups, however, in situ muscle testing demonstrated a significant reduction in force production both before and after fatiguing contractions in TDAG51-/- mice. During the early phases of the regenerative process (5 days post-injury), TDAG51-/- muscles display a significantly larger area of degenerating muscle tissue concomitant with significantly less regenerating area compared to WT (as demonstrated by embryonic myosin heavy chain expression). Despite these early deficits in regeneration, TDAG51-/- muscles displayed no morphological deficits by 10 days post injury compared to WT mice. Taken together, the data presented herein demonstrate TDAG51 expression to be upregulated in damaged skeletal muscle and its absence attenuates the early phases of muscle regeneration. PMID- 29127007 TI - miR-3065-5p regulates mouse odontoblastic differentiation partially through bone morphogenetic protein receptor type II. AB - Illumination of the molecular mechanisms regulating odontoblastic differentiation of dental papilla cells is of great significance for proper dentinogenesis and dental pulp regeneration. In this study, we discovered that microRNA (miR)-3065 5p is up-regulated during odontoblastic differentiation. Overexpression of miR 3065-5p promoted odontoblastic differentiation in vitro. Dual luciferase report assay verified that miR-3065-5p could bind to the 3'UTR of bone morphogenetic protein receptor type II (BMPR2), which dramatically increased in the beginning of odontoblastic differentiation but decreased in the terminal differentiation stage. Inhibition of Bmpr2 in the early stage retarded odontoblastic differentiation while knockdown of Bmpr2 in the terminal stage enhanced odontoblastic differentiation, resembling the effect of miR-3065-5p. Taken together, our present study suggests that miR-3065-5p positively regulates odontoblastic differentiation by directly binding to Bmpr2 in the terminal differentiation stage. PMID- 29127008 TI - Direct regulation of IL-2 by curcumin. AB - Interleukin-2 (IL-2) is a crucial growth factor for both regulatory and effector T cells. Thus, IL-2 plays a critical role in the stimulation and suppression of immune responses. Recently, anti-IL-2 antibodies (Abs) have been shown to possess strong IL-2 modulatory activities by affecting the interaction between IL-2 and IL-2 receptors. In this study, we screened an herbal library to identify a compound that regulates IL-2, which resulted in the identification of curcumin as a direct binder and inhibitor of IL-2. Curcumin is a phytochemical with well known anti-cancer properties. In this study, curcumin mimicked or altered the binding pattern of anti-IL-2 Abs against IL-2 and remarkably inhibited the interaction of recombinant IL-2 with the IL-2 receptor alpha, CD25. Interestingly, curcumin neutralized the biological activities of IL-2 both in vitro and in vivo. In this report, we elucidated the unsolved mechanism of the anti-cancer effect of curcumin by identifying IL-2 as a direct molecular target. Curcumin, as a small molecule IL-2 modulator, has the potential to be used to treat IL-2 related pathologic conditions. PMID- 29127009 TI - Nicorandil alleviates myocardial injury and post-infarction cardiac remodeling by inhibiting Mst1. AB - BACKGROUND: Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI. METHODS: A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury. RESULTS: Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis. CONCLUSIONS: Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition. PMID- 29127010 TI - Cyclosporine A exhibits gender-specific nephrotoxicity in rats: Effect on renal tissue inflammation. AB - Cyclosporine A (CSA) is a widely used immunosuppressant drug known to commonly cause cardio and nephrotoxicity. A study looking at the sex specificity of the cardiotoxicity of CSA revealed that sexual dimorphism existed when looking at the electrocardiographs and left ventricles of CSA-treated rats. We hypothesized that cyclosporine A exhibited gender-specific nephrotoxicity by testing various parameters of kidney function in male and female rats treated for 21 days with 15 mg/kg CSA versus control male and female rats that received a vehicle consisting of 18% kolliphore and 2% ethanol in sterile saline. It was found that male rats treated with CSA had significantly higher levels of serum creatinine and lower creatinine clearance than control males. However, serum creatinine and creatinine clearance were not affected by CSA treatment in females. Histopathological examination of kidney cross-sections revealed a heavy aggregation of inflammatory cells and significant vascular congestion in males treated with CSA, which was less prominent in female rats receiving CSA. In addition CSA treated male rats had higher levels of serum cholesterol compared with control while, CSA did not affect serum cholesterol in female rats. Kidney tumor necrosis factor alpha (TNF alpha) levels were found to drop in female rats following CSA treatment, whereas no change was observed in male rats before and after treatment. These results suggest that CSA exhibits gender-related nephrotoxicity in rats that might be mediated by differences in the inflammatory response between males and females. PMID- 29127011 TI - Rational design of small molecules that modulate the transcriptional function of the response regulator PhoP. AB - The response regulator PhoP, which is part of the PhoP/PhoQ two-component system, regulates the expression of multiple genes involved in controlling virulence in Salmonella enterica serovar Typhimurium and other species of Gram-negative bacteria. Modulating the phosphorylation-mediated dimerization in the receiver domain may interfere with the transcriptional function of PhoP. In this study, we analyzed the therapeutic potential of the PhoP receiver domain by exploring it as a potential target for drug design. The structural information was then applied to identify the first hit compounds from commercial chemical libraries by combining pharmacophore modelling and docking methods with a GFP (Green Fluorescent Protein)-based promoter-fusion bioassay. In total, one hundred and forty compounds were selected, purchased, and tested for biological activity. Several novel scaffolds showed acceptable potency to modulate the transcriptional function of PhoP, either by enhancing or inhibiting the expression of PhoP dependent genes. These compounds may be used as the starting point for developing modulators that target the protein-protein interface of the PhoP protein as an alternative strategy against antibiotic resistance. PMID- 29127012 TI - Dystonia-4 (DYT4)-associated TUBB4A mutants exhibit disorganized microtubule networks and inhibit neuronal process growth. AB - Dystonia-1 (DYT1) is an autosomal dominant early-onset torsion form of dystonia, a neurological disease affecting movement. DYT1 is the prototypic hereditary dystonia and is caused by the mutation of the tor1a gene. The gene product has chaperone functions important for the control of protein folding and stability. Dystonia-4 (DYT4) is another autosomal dominant dystonia that is characterized by onset in the second to third decade of progressive laryngeal dysphonia. DYT4 is associated with the mutation of the tubb4a gene, although it remains to be understood how disease-associated mutation affects biochemical as well as cell biological properties of the gene product as the microtubule component (a tubulin beta subunit). Herein we demonstrate that DYT4-associated TUBB4A missense mutants (Arg2-to-Gly or Ala271-to-Thr) form disorganized tubulin networks in cells. Transfected mutants are indeed expressed in cytoplasmic regions, as observed in wild-type transfectants. However, mutant proteins do not exhibit typical radial tubulin networks. Rather, they have diminished ability to interact with tubulin alpha subunits. Processes do not form in sufficient amounts in cells of the N1E 115 neuronal cell line expressing each of these mutants as compared to parental cells. Together, DYT4-associated TUBB4A mutants themselves form aberrant tubulin networks and inhibit neuronal process growth, possibly explaining progress through the pathological states at cellular levels. PMID- 29127013 TI - Lycorine possesses notable anticancer potentials in on-small cell lung carcinoma cells via blocking Wnt/beta-catenin signaling and epithelial-mesenchymal transition (EMT). AB - Lycorine, an natural isoquinoline alkaloid has reportedly that possesses multi anticancer activity. However, to date, the anticancer feature of lycorine in non small cell lung carcinoma (NSCLC) has still not fully been spelled out. The present study mainly focused on the molecular mechanism of lycorine against NSCLC in vitro and vivo. The results showed that lycorine evidently inhibited proliferation of A549 and H460 with IC50 values were 10.83 +/- 1.14 MUM and 12.35 +/- 1.13 MUM, while caused slight cytotoxicity in normal pulmonary epithelial Beas-2B cells, and arrested cell cycle in G0/G1 phase. Hoechst DNA-binding staining showed that typical characteristics of nuclear morphology apoptosis, AnnexinV-FITC/PI staining revealed the early-period apoptosis and the dissipation of mitochondrial membrane potential (Deltapsim) were also captured after lycorine treatment. Moreover, lycorine effectively repressed the Wnt/beta-catenin signaling and reversed epithelial-mesenchymal transition (EMT). In addition, lycorine also intervened the caspase-mediated mitochondrial apoptosis pathway. Furthermore, A549/Luc tumor xenograft model was also corroborated that lycorine significantly suppressed the growth and metastasis of the lung tumor. These data highlight the significance of lycorine as potential anti-neoplastic agents to combat NSCLC. PMID- 29127014 TI - Structural insights and binding of a natural ligand, succinic acid with serine and cysteine proteases. AB - In the age of growing infectious diseases, there is a great demand for new inhibitors which can exhibit minimum side effects. Owing to the importance of proteases in life cycle and invasion, they have been projected as attractive targets for structure based drug designing against microbes including viruses. Here we report the inhibitory activity of a well known natural compound succinic acid against both serine and cysteine proteases. The ligand is found co crystallized with Bovine pancreatic trypsin in one of our crystallization trials and the diffraction data up to1.9 A reveal its interactions with the catalytic triad residues Histidine 57 and Serine 195. Binding of the ligand with these proteases have been validated using caseinolysis inhibition. With trypsin, ITC analysis showed tight binding of the ligand, resulting in change in Gibb's free energy (DeltaG) by -20.31 kJ/mol. To understand the existence of succinic acid at the active site, molecular docking was performed and it revealed binding of it with trypsin and papain at corresponding active sites. This dual inhibitory activity of natural ligand, succinic acid can be accounted for the recent reports on anti-viral property of plant extracts where dicarboxilic fatty acids are normally abundant. PMID- 29127015 TI - Oxotremorine-M potentiates NMDA receptors by muscarinic receptor dependent and independent mechanisms. AB - Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease. In this study we developed a simple system in which muscarinic modulation of NMDA receptors can be studied in vitro. Human M1 receptors and NR1/2B NMDA receptors were co-expressed in Xenopus oocytes and various muscarinic agonists were assessed for their modulatory effects on NMDA receptor-mediated responses. As expected, NMDA receptor-mediated responses were potentiated by oxotremorine-M, oxotremorine or xanomeline when the drugs were applied between subsequent NMDA responses, an effect which was fully blocked by the muscarinic receptor antagonist atropine. However, in oocytes expressing NR1/2B NMDA receptors but not muscarinic M1 receptors, oxotremorine-M co-applied with NMDA also resulted in a potentiation of NMDA currents and this effect was not blocked by atropine, demonstrating that oxotremorine-M is able to directly potentiate NMDA receptors. Oxotremorine, which is a close analogue of oxotremorine-M, and xanomeline, a chemically distinct muscarinic agonist, did not potentiate NMDA receptors by this direct mechanism. Comparing the chemical structures of the three different muscarinic agonists used in this study suggests that the tri-methyl ammonium moiety present in oxotremorine-M is important for the compound's interaction with NMDA receptors. PMID- 29127016 TI - Enhanced activation of circulating plasmacytoid dendritic cells in patients with Chronic Obstructive Pulmonary Disease and experimental smoking-induced emphysema. AB - Plasmacytoid dendritic cells (pDCs) are key cells bridging the innate with adaptive immunity. However, the phenotypic characteristics of circulating pDCs and its role in smoking related-Chronic Obstructive Pulmonary Disease (COPD) remain largely unknown. The aim of this study was analyzed the phenotype of circulating pDCs and the expression of IFN-gamma producing CD8+T cells and IL-17 producing CD8+T cells in patients with COPD by using multi-colour flow cytometry. The cytokine profiles in peripheral blood from all subjects were measured by ELISA. The influence of cigarette smoke on pDCs was evaluated in an experimental mouse model of emphysema. Circulating pDCs in patients with COPD and in mice exposed to cigarette smoke expressed high levels of co-stimulatory molecules CD40 or CD86 accompanied by exaggerated IFN-gamma producing CD8+T cells and IL-17 producing CD8+T cells. In vitro, cigarette smoke directly promoted pDCs maturation and release of IFN-alpha, IL-6 and IL-12, subsequently inducing differentiation of IFN-gamma producing CD8+T cells and IL-17-producing CD8+T cells from mouse naive CD8+T cells. These data suggested that circulating pDCs display an enhanced activation phenotype in patients with COPD and in experimental smoking mouse model of emphysema, which might contribute to exaggerated IFN-gamma producing CD8+T and IL-17-producing CD8+T cell-mediated immune responses. PMID- 29127017 TI - The Educational Opportunities Provided by a Pediatric Orthopedic Urgent Case Review Conference: Keep Score to Provide a Better Experience. AB - OBJECTIVE: To evaluate the distribution of conditions presented at a case conference to assess resident educational exposure to acute pediatric orthopedic conditions. DESIGN: Retrospective review of emergency department and inpatient consultations presented at a daily pediatric orthopedic case conference over a 3 year period. Consultations were divided into 3-month resident rotation blocks for analysis. SETTING: Tertiary children's hospital in the southern United States which host residents from 2 orthopedic surgery residency programs. PARTICIPANTS: The case conference is attended by pediatric orthopedic surgeons, 1 pediatric orthopedic fellow, and 4 PGY III/IV residents. RESULTS: A total of 1762 consultations were presented at the conference. The consultations were obtained for traumatic injuries, 86.5% (1524/1762); infections, 7.7% (136/1762); and congenital/other problems, 5.8% (102/1762). The 3 most common consultations per rotation were fractures: both-bone forearm (mean, 46.1; range: 24-64), supracondylar humerus (mean, 23.8; range: 17-31), and distal radius (mean, 13.8; range: 7-33). Less common consultations per rotation were septic arthritis (mean, 1.6; range: 0-5), child abuse (mean, 1.3; range: 0-5), Monteggia fracture (mean, 0.3; range: 0-1), compartment syndrome (mean, 0.2; range: 0-1) and patella sleeve fracture (mean, 0.1; range: 0-1). CONCLUSIONS: There was a large disparity between conditions in the number of times presented and reviewed within a 3-month rotation at the daily case conference, with some important conditions not being discussed at all in each rotation. This finding documents a disadvantage of case conferences based on limiting discussion to current patients, and highlights an opportunity for educational improvement. PMID- 29127018 TI - Curriculum Using the In-Situ Operating Room Setting. AB - OBJECTIVE: The American College of Surgeons/Association of Program Directors in Surgery is a comprehensive, simulation-based curriculum for General Surgery residents which exists in 3 phases. While phases 1 and 2 deal with core skills and advanced procedures respectively, phase 3 targets team-based skills. To date, the 3rd phase of this curriculum has not seen wide scale implementation. This is a pilot study to verify the feasibility of implementing the phase 3 curriculum in the in-situ setting. DESIGN: In our initial attempt to implement Phase 3 at our institution, we chose to perform the training in an in-situ setting within an operating room (OR) at our main hospital, despite our having a separate simulation center. By choosing the in-situ OR environment for this training we were able to minimize concerns regarding resident and faculty availability and able to successfully complete 8 separate sessions during the academic year. During 7 sessions, 2 separate scenarios were performed while a single scenario was performed in 1 session. This single session was excluded from analysis, leaving a total of 14 scenarios to evaluate. The unique scenarios included laparoscopic crisis, postoperative myocardial infarction, anaphylaxis, and postoperative hypotension. All sessions were audiovisually recorded. In order to evaluate the effect of the training, the videos were viewed by 3 independent reviewers and all surgery, anesthesia and nursing participants were rated using the NOTECHs II scale. Degree of inter-rater agreement was established. The difference between the first and second simulations on the same day was then assessed. In addition, participant opinions of the simulations were assessed through electronic surveys following the training. SETTING: Tertiary Care University Hospital. PARTICIPANTS: We performed a total of 8 sessions, for a total of 15 scenarios. Eight surgery residents at the postgraduate year 1 (PGY1) PGY3 level, 16 anesthesia residents at the PGY3-PGY4 level, 16 nurses and 13 ancillary staff participated. RESULTS: From the first to the second scenario, the total team NOTECHs II score increased from 69.4 +/- 1.4 to 77.3 +/- 0.5 (p = 0.007). The NOTECHs II scores for each subteam also improved, from 24.2 +/- 0.6 to 26.4 +/- 0.5 (p = 0.007) for surgery residents, 23.7 +/- 0.9 to 26.7 +/- 0.4 (p = 0.03) for anesthesia, and 21.6 +/- 0.3 to 24.3 +/- 0.5 (p = 0.01) for nursing. The inter-rater reliability as measured by Kendall's coefficient of concordance was modest for the whole team score. Most of the participant responses were either favorable or strongly favorable. CONCLUSION: The in-situ OR environment is both a unique and effective setting to perform team-based training. Furthermore, training in the in-situ setting minimizes or removes many of the logistic issues involved in designing and implementing team-based training curricula for general surgery residency programs. However, we found that administrative and departmental (surgery, anesthesia, and nursing) "buy in" as well as protected faculty time for education were all necessary for in-situ training to be successful. NOTECHs II is an established scale for the evaluation of teams in this simulation setting and appears to be a valid tool based on the results of this study. However, further assessment of inter-rater reliability as well as improved training of evaluators are necessary to determine if inter-rater reliability can improve. PMID- 29127019 TI - A Survey on Recent Medical School Graduate Comfort With the Level 1 Milestones. AB - OBJECTIVE: The Next Accreditation System implemented 5 levels of milestones for orthopedic surgery residents in 2013. The Level 1 milestones were noted as those "expected of an incoming resident." While the milestones were intended for assessing resident progression and readiness for independent practice, this designation can also be used to assess how well prepared graduating medical students are for beginning an orthopedic surgery residency. The primary objective of this paper is to measure recent medical school graduate comfort with the Level 1 milestones. DESIGN, SETTING, AND PARTICIPANTS: In June 2015, the program directors for the Midwest Orthopaedic Surgical Skills (MOSS) Consortium affiliated residency programs were sent an online survey for distribution to the recent medical school graduates who matched at their respective programs. The survey was about recent graduate comfort with the Level 1 milestone handles associated with 16 orthopedic milestones spanning multiple subspecialties. Responses were grouped based on comfort with individual milestone handles with orthopedic conditions (e.g., carpal tunnel) or with broader categories spanning orthopedic milestones (e.g., imaging). RESULTS: In all, 66 of 112 graduates (58.9%) responded. Of 60 milestone handles surveyed, respondents were "Comfortable" with an average of 31.6 +/- 14.2 handles with some conditions performing much better than others. The median "Comfortable" response rate was 31 handles. The 8 broader categories had "Comfortable" response rates between 35% and 70%. All 8 orthopedic conditions had significantly higher "Comfortable" response rates for "Evaluation & Knowledge" handles than for "Decision Making & Treatment" handles. CONCLUSIONS: Most recent medical student graduates who matched into an orthopedic surgery residencies are only comfortable with about half of the Level 1 milestone handles even though they are expected to meet the Level 1 milestones upon beginning residency. This finding suggests the development of an assessment based on the Level 1 milestones would be appropriate to better inform both graduate and undergraduate medical education in orthopedic surgery. PMID- 29127020 TI - Does the use of antifungal agents in agriculture and food foster polyene resistance development? A reason for concern. AB - Environmental fungicides are used in agriculture to reduce fungal spoilage of crops to a minimum, and the polyene macrolide natamycin is used as a food preservative. The use of natamycin in yoghurt has recently been authorised in the USA and some other countries. However, resistance development is a serious risk associated with the use of antimicrobials as food additives and environmental fungicides. Cross-resistance between agricultural and medical azoles and between azoles and amphotericin B (AMB) not being used in agriculture has been demonstrated in clinical and environmental isolates. Polyene resistance can be elicited in vitro by the use of subinhibitory polyene concentrations and a large number of transfers. This condition may mirror the exposure of faecal Candida spp. to natamycin following consumption of natamycin-containing food. A large number of environmental and clinical isolates are resistant to AMB, and strong evidence linking farm antibiotic use and multidrug resistance, including AMB resistance, in human infections has been provided. In contrast to the acquisition of resistant environmental strains, consumption of natamycin-containing food may expose the gastrointestinal fungal flora directly to resistance selective pressure. So far, whether natamycin itself may cause the emergence of polyene resistance in gastrointestinal fungal flora and/or may act as an AMB resistance selector is probable but speculative. Use of any anti-infective agent as a food preservative should be limited to an absolute minimum as the clinical efficacy of anti-infectives used to treat serious life-threatening infections has to be preserved. PMID- 29127021 TI - Severe delayed haemolytic anaemia associated with artemether-lumefantrine treatment of malaria in a Japanese traveller. AB - Delayed haemolytic anaemia has been reported in association with intravenous artesunate treatment in patients with severe Plasmodium falciparum malaria, and furthermore, oral artemisinin-based combination therapies including artemether lumefantrine (AL) have also been incriminated. However, definite cases of delayed haemolytic anaemia associated with AL appear to be scarce, as reported cases were often treated concomitantly with other anti-malarials. In this study, we report a severe case of delayed haemolytic anaemia following AL alone in a Japanese traveller with severe parasitaemia caused by numerous P. falciparum parasites and a few P. vivax parasites. We also stress the need by further studies to differentiate between delayed haemolytic anaemia and blackwater fever, the latter being another malaria-related haemolytic condition, more clearly than they are now. PMID- 29127022 TI - Genetic and Immune Profiles of Solid Predominant Lung Adenocarcinoma Reveal Potential Immunotherapeutic Strategies. AB - INTRODUCTION: Subtype classification of lung adenocarcinoma (LUAD) divides different survivals and therapeutic vulnerabilities; however, little is known about the disease's underlying molecular mechanism. This study sought to determine the genetic and immune profiles of histologic subtypes and identify the evidence for adjuvant immunotherapy. METHODS: We performed an integrated analysis of multidimensional data from a discovery set consisting of cohorts of The Cancer Genome Atlas and the Broad Institute data set from the LUAD public database and a validation set from the Guangdong Lung Cancer Institute. Immunohistochemical staining was carried out to determine the expression of the proteins programmed cell death 1 ligand (PD-L1) and CD8. RESULTS: Patients with solid predominant LUAD showed poor disease-free survival and a high frequency of relapse/metastasis compared with those with the nonsolid subtype of LUAD. The solid subtype tended to occur more frequently in those with a history of smoking. Solid predominant LUAD exclusively showed increased expression of PD-L1 and a high proportion of dual positive PD-L1- and tumor-infiltrating lymphocytes. Meanwhile, a notable increase in the tumor mutation burden and higher frequency of GC>TA transversions were specifically identified in tumors of the solid subtype. Furthermore, the solid subtype of tumor displayed an active cytotoxic immune signature and increased incidence of genetic mutations related to immunogenicity. CONCLUSION: Solid predominant LUAD was identified as a subtype with adaptive immune resistance, higher cytotoxic activity, and enhanced immunogenicity. These findings suggest that patients with solid predominant LUAD may represent a potential selective group that will benefit from adjuvant programmed cell death 1 blockade immunotherapy. PMID- 29127024 TI - The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives. AB - The immunomodulatory drug fingolimod (FTY720, GilenyaR) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P1 subtype by induction of receptor downregulation. Since S1P1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases. PMID- 29127025 TI - Effect of yolk corticosterone on begging in the yellow-legged gull. AB - Behavioral lateralization is widespread across vertebrates. The development of lateralization is affected by both genetic and environmental factors. In birds, maternal substances in the egg can affect offspring lateralization via activational and/or organizational effects. Corticosterone affects the development of brain asymmetry, suggesting that variation in yolk corticosterone concentration may also influence post-natal behavioral lateralization, a hypothesis that has never been tested so far. In the yellow-legged gull (Larus michahellis), we increased yolk corticosterone concentration within physiological limits and analyzed the direction of lateralization of hatchlings in reverting from supine to prone position ('RTP' response) and in pecking at dummy parental bills to solicit food provisioning ('begging' response). We found that corticosterone treatment negatively affected the frequency of begging and it may cause a slight leftward lateralization. However, the direction of lateralization of the RTP response was not affected by corticosterone administration. Thus, our study shows a maternal effect mediated by corticosterone on a behavioral trait involved in parent-offspring communication during food provisioning events. The findings on lateralization are not conclusive due to the weak effect size but provide information for further ecological and evolutionary studies, investigating mechanisms underlying the development of lateralization. PMID- 29127023 TI - Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung. AB - Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen kappa statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (kappa score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status. PMID- 29127026 TI - Resource forecasting: Differential effects of glucose taste and ingestion on delay discounting and self-control. AB - We tested a novel hypothesis that glucose taste acts as a signal for resource acquisition, motivating preference for immediate rewards while actual glucose ingestion prompts resource conservation, promoting future-orientated self regulation. In Study 1, participants were engaged in a delay-discounting task and a grip-control task before and after a beverage intervention (glucose drink, water drink, or glucose mouth-rinse). Glucose ingestion decreased delay discounting, making larger-and-later rewards more attractive. In contrast, glucose rinse increased delay discounting. Water ingestion had none of the effects. In the grip-control task, only glucose ingestion improved the performance. Study 2 using fMRI revealed that glucose rinse and glucose ingestion resulted in distinct brain activational patterns. Compared to glucose rinse, glucose ingestion deactivated a few brain regions (e.g., the anterior cingulate gyrus and inferior frontal gyrus) that are previously shown to be more active when making more difficult intertemporal choices, suggesting that glucose ingestion eases the process of making intertemporal choice. In sum, our behavioral and neuroimaging findings together suggest a dual signaling role of glucose sensation and ingestion in regulating delay discounting and self-control. PMID- 29127027 TI - A mitochondrial manganese superoxide dismutase involved in innate immunity is essential for the survival of Chlamys farreri. AB - Superoxide dismutase (SOD) ubiquitously found in both prokaryotes and eukaryotes functions as the first and essential enzyme in the antioxidant system. In the present study, a manganese SOD (designated as CfmtMnSOD) was cloned from Zhikong scallop Chlamys farreri. The complete cDNA sequence of CfmtMnSOD contained a 681 bp open reading frame (ORF), encoding a peptide of 226 amino acids. A SOD_Fe_N domain and a SOD_Fe_C domain were found in the deduced amino acid sequence of CfmtMnSOD. The mRNA transcripts of CfmtMnSOD were constitutively expressed in all the tested tissues, including gill, gonad, hepatopancreas, hemocytes, mantle and muscle, with the highest expression level in hemocytes. After the stimulation of Vibrio splendidus, Staphylococcus aureus and Yarrowia lipolytica, the mRNA transcripts of CfmtMnSOD in hemocytes all significantly increased. The purified rCfmtMnSOD protein exhibited Mn2+ dependent specific and low stable enzymatic activities. After Vibrio challenge, the cumulative mortality of CfmtMnSOD suppressed scallops was significantly higher than those of control groups and the semi-lethal time for CfmtMnSOD-suppressed scallops was rather shorter than those of control groups either. Moreover, the final mortality rate of CfmtMnSOD suppressed group was significant higher than those of control groups, even without Vibrio challenge. All these results indicated that CfmtMnSOD was efficient antioxidant enzyme involved in the innate immunity, and also essential for the survival of C. farreri. PMID- 29127028 TI - Effects of dietary Panax notoginseng extract on growth performance, fish composition, immune responses, intestinal histology and immune related genes expression of hybrid grouper (Epinephelus lanceolatus ? * Epinephelus fuscoguttatus ?) fed high lipid diets. AB - Growth, plasma biochemical parameters, fish composition, immune parameters, intestinal histology, and expressions of immune-related genes were examined in hybrid grouper (Epinephelus lanceolatus ? * Epinephelus fuscoguttatus ?) that fed respectively six diets containing Panax notoginseng extract (PNE) at 0, 0.5, 1, 2, 4, and 10 g kg-1 after 8 weeks. Results indicated that dietary PNE significantly improved growth, feed efficiency ratio, protein efficiency ratio, and protein deposit rate, and significantly increased crude protein and crude lipid levels of whole body and crude protein level of muscle. Dietary PNE significantly increased plasma total protein, alkaline phosphatase, immunoglobulin, complement 3 and complement 4 contents, but significantly decreased cholesterol, triglyceride, glucose, and low density lipoprotein cholesterol contents. Furthermore, dietary PNE increased villus length and muscle thickness in foregut, midgut, and hindgut, activities of hepatic superoxide dismutase and total antioxidant capacity, and increased the expression levels of immune related genes (IL-10, TGF-beta1, TOR, MHC2 and TLR3) in the head kidney and the expression levels of antioxidant genes (CAT and GR) in fish that fed PNE at 0.5-4 g kg-1. In conclusion, grouper fed high lipid diets supplemented with PNE at 0.5-10 g kg-1 improved growth, feed utilization, blood immune parameters, hepatic antioxidant status, intestine morphology and expression levels of immune related genes in the head kidney. PMID- 29127029 TI - Extract from the fermented soybean product Natto inhibits Vibrio biofilm formation and reduces shrimp mortality from Vibrio harveyi infection. AB - Many bacteria, including Vibrio pathogens of shrimp, need to colonize and/or form biofilms in hosts or the environment to cause disease. Thus, one possible control strategy for shrimp Vibriosis is biofilm inhibition. With this objective, an extract from the Japanese fermented soybean product, Natto was tested with the luminescent shrimp pathogen Vibrio harveyi (VH) for its ability to inhibit or degrade biofilm and to interfere with cell growth in broth. Natto is a traditional fermentation product of Bacillus subtilis var Natto (BSN1). Using 96 well microtiter plates coated with 0.4% chitosan, we found that biofilm formation by VH was inhibited, while growth in parallel broth cultures was not. When an extract from Natto prepared using BSN1 was mixed with feed for the whiteleg shrimp Penaeus vannamei before immersion challenge with V. harveyi at 106 cfu/ml, survival was significantly higher (p<=0.05) than for control shrimp given feed without these additives. Further work done to test whether d-amino acids were involved in biofilm formation as previously reported for B. subtilis, Staphylococus aureus and Pseudomonas aeruginosa gave negative results. In conclusion, we discovered that Natto extract can inhibit Vibrio biofilm formation and that it or BSN1 alone added to shrimp feed can significantly reduce shrimp mortality in immersion challenges with pathogenic VH. This shows some promise for possible application against Vibriosis in shrimp since Natto is generally regarded as safe (GRAS) for human consumption. PMID- 29127030 TI - Hybridization improved bacteria resistance in abalone: Evidence from physiological and molecular responses. AB - Hybridization is an effective way of improving germplasm in abalone, as it often generates benign traits in the hybrids. The hybrids of Haliotis discus hannai and H. gigantea have shown heterosis in terms of disease resistance than one or both parental species. In the present study, to elucidate the physiological and molecular mechanism of this heterosis, we analyzed the dynamic changes of several immune indexes including survival rate, total circulating haemocyte count (THC), phagocytic activity, reactive oxygen species level (ROS) and phenoloxidase activity (PO) in two parental species, H. discus hannai (DD) and H. gigantea (GG), and their reciprocal hybrids H. discus hannai ? * H. gigantea ? (DG), H. gigantea ? * H. discus hannai ? (GD) challenged with a mixture of Vibrio harveyi, V. alginolyticus and V. parahaemolyticus (which have been demonstrated to be pathogenic to abalone). Besides, we cloned and analyzed three important immune genes: heat shock protein 70 (hsp70), ferritin and cold shock domain protein (csdp) in H. discus hannai and H. gigantea, then further investigated their mRNA level changes in the four abalone genotypes after bacterial challenge. Results showed that these physiological and molecular parameters were significantly induced by bacterial exposure, and their changing patterns were obviously different between the four genotypes: (1) Survival rates of the two hybrids were higher than both parental species after bacterial exposure; (2) DG had higher THC than the other three genotypes; (3) Phagocytosis responded slower in the hybrids than in the parental species; (4) DD's ROS level was lower than the other three genotypes at 48 h post infection; (5) Phenoloxidase activity was lower in DD during the infection compared to the other genotypes; (6) mRNA levels of hsp70 and csdp, were always lower in at least one parental species (DD) than in the hybrids after the bacterial exposure. Results from this study indicate that the hybrids are more active or efficient in immune system function, hence they could effectively defense against a bacterial invasion, leading to higher survival rates after challenge. This study provides physiological and molecular evidences for interpreting the disease resistant heterosis in this abalone hybrid system, which could help us in a better understanding and utilization of heterosis in abalone aquaculture. PMID- 29127032 TI - Efficacy of the antinicotinic compound MB327 against soman poisoning - Importance of experimental end point. AB - Medical countermeasures for acute poisoning by organophosphorus nerve agents are generally assessed over 24h following poisoning and a single administration of treatment. At 24h, the antinicotinic bispyridinium compound MB327 (1,10-(propane 1,3-diyl)bis(4-tert-butylpyridinium)) dimethanesulfonate is as effective as the oxime HI-6 against poisoning by soman, when used as part of a treatment containing atropine and avizafone. In this study, we hypothesised that an earlier endpoint, at 6h, would be more appropriate for the pharmacokinetics and mechanism of action of MB327 and would therefore result in improved protection. MB327 diiodide (33.8mg/kg) or the oxime HI-6 DMS (30mg/kg), in combination with atropine and avizafone (each at 3mg/kg) was administered intramuscularly to guinea pigs 1min following subcutaneous soman and the LD50 of the nerve agent was determined at 6h after poisoning for each treatment. The treatment containing HI 6 gave a similar level of protection at 6h as previously determined at 24h (protection ratios 3.9 and 2.9, respectively). In contrast, the protection achieved by treatment containing MB327 showed a striking increase at 6h (protection ratio >15.4) compared to the 24h end point (protection ratio 2.8). The treatment gave full protection for at least 5h against doses of soman up to 525MUg/kg; in contrast, mortality began in animals treated with HI-6 after 1h. This study demonstrates the importance of using an appropriate end point and has shown that treatment including MB327 was far superior to oxime-based treatment for poisoning by soman, when assessed over a pharmacologically-relevant duration. The improved outcome was seen following a single dose of treatment: it is possible that additional doses to maintain therapeutic plasma concentrations would further increase survival time. Antinicotinic compounds therefore offer a promising addition to treatment, particularly for rapidly aging or oxime insensitive nerve agents. PMID- 29127031 TI - Sulfur mustard induced mast cell degranulation in mouse skin is inhibited by a novel anti-inflammatory and anticholinergic bifunctional prodrug. AB - Sulfur mustard (SM, bis(2-chloroethyl sulfide) is a potent vesicating agent known to cause skin inflammation, necrosis and blistering. Evidence suggests that inflammatory cells and mediators that they generate are important in the pathogenic responses to SM. In the present studies we investigated the role of mast cells in SM-induced skin injury using a murine vapor cup exposure model. Mast cells, identified by toluidine blue staining, were localized in the dermis, adjacent to dermal appendages and at the dermal/epidermal junction. In control mice, 48-61% of mast cells were degranulated. SM exposure (1.4g/m3 in air for 6min) resulted in increased numbers of degranulated mast cells 1-14days post exposure. Treatment of mice topically with an indomethacin choline bioisostere containing prodrug linked by an aromatic ester-carbonate that targets cyclooxygenases (COX) enzymes and acetylcholinesterase (1% in an ointment) 1 14days after SM reduced skin inflammation and injury and enhanced tissue repair. This was associated with a decrease in mast cell degranulation from 90% to 49% 1 3days post SM, and from 84% to 44% 7-14days post SM. These data suggest that reduced inflammation and injury in response to the bifunctional indomethacin prodrug may be due, at least in part, to abrogating mast cell degranulation. The use of inhibitors of mast cell degranulation may be an effective strategy for mitigating skin injury induced by SM. PMID- 29127033 TI - The role of TGFbeta receptor 1-smad3 signaling in regulating the osteoclastic mode affected by fluoride. AB - Studies that have focused on the role TGFbeta signaling plays in osteoclast activity are gradually increasing; however, literature is rare in terms of fluorosis. The aim of this study is to observe the role the TbetaR1/Smad3 pathway plays in fluoride regulating cellsosteoclast-like cells that are under the treatment of TGFbeta receptor 1 kinase. The RANKL-mediated osteoclast-like cells from RAW264.7 cells were used as osteoclast precursor model. The profile of miRNA expression in fluoride-treated osteoclast-like cells exhibited 303 upregulated miRNAs, 61 downregulated miRNAs, and further drew 37 signaling pathway maps by KEGG and Biocarta pathway enrichment analysis. TGFbeta and its downstream effectors were included among them. Osteoclast viability, formation and function were detected via MTT method, bone resorption pit and tartrate-resistant acid phosphatase (TRACP) staining, respectively. Results demonstrated that different doses of fluoride exhibited a biphasic effect on osteoclast cell viability, differentiation, formation and function. It indicated that a low dose of fluoride treatment stimulated them, but high dose inhibited them. SB431542 acted as TbetaR1 kinase inhibitor and blocked viability, formation and function of osteoclast-like cells regulated by fluoride. The expression of the osteoclast marker, RANK, and TbetaR1/Smad3 at gene and protein level was analyzed under fluoride with and without SB431542 treatment. Fluoride treatment indicated little effect on the RANK protein expression; however it significantly influenced TRACP expression in osteoclast-like cells. The stimulation of fluoride on the expression of Smad3 gene and phosphorylated Smad3 protein exhibited dose dependent manner. SB431542 significantly impeded phosphorylation of Smad3 protein and TRACP expression in osteoclast-like cells that were exposed to fluoride. Our work demonstrated that TGFbeta signaling played a key role in fluoride regulating osteoclast differentiation, formation and function. It elucidated that TbetaR1/Smad3 pathway participated in the mechanism of biphasic modulation of osteoclast mode regulated by fluoride. PMID- 29127034 TI - Balancing nanotoxicity and returns in health applications: The Prisoner's Dilemma. AB - Over the past 30 years, there have been significant advancements in the field of nanomaterials. The possibility to use them in applications such as cancer treatment is extremely promising; however, the toxicity of many nanomaterials as well as the high costs associated with their use is still a concern. This paper aims to study the connection between nanomaterial toxicity and cost. This synergy may be interpreted as a different version of the classic "Prisoner's Dilemma" game, which in this case attempts to explain the possible outcomes of cooperation versus conflict between science advocating for the use of high-risk, possibly toxic materials due to their high returns, and society that might be dubious about the use of high-risk materials. In an effort to create diverse evaluation methodologies, this work uses a forecast horizon to evaluate the current status and expected future of the nanomaterials market. The historical progress of each market, toxicity information, and possible returns stemming from their use is taken into account to analyze the predictions. Our results suggest various trends for the associated costs and nanotoxicity of the studied materials. PMID- 29127036 TI - Amphiphilic poly(alpha)glutamate polymeric micelles for systemic administration of siRNA to tumors. AB - RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target "undruggable" oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(alpha)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides. APA polymers complexed with siRNA to form round-shaped, homogenous and reproducible nano-sized polyplexes bearing ~50 nm size and slightly negative charge. In addition, APA:siRNA polyplexes were shown to be potent gene regulators in vitro. In light of these preferred physico-chemical characteristics, their performance as systemically administered siRNA nanocarriers was investigated. Intravenously-injected APA:siRNA polyplexes accumulated selectively in tumors and did not accumulate in the lungs, heart, liver or spleen. Nevertheless, the polyplexes failed to induce specific mRNA degradation, hence neither reduction in tumor volume nor prolonged mice survival was seen. PMID- 29127037 TI - Exosome function in aerodigestive mucosa. AB - Exosomes are 30-150 nm membrane-bound vesicles which are secreted by virtually all cell types. Exosomes have been studied in a wide range of both normal and pathologic human tissues, most notably cancer. The role of exosomes in immune surveillance and in non-invasive biomarker sampling, and their potential to act as therapeutic carriers lend particular importance to mucosal barrier derived exosomes. This review focuses specifically on current knowledge regarding exosomes derived from aerodigestive membranes. Specific topics covered include: isolation and characterization techniques, physiological function, protein expression, function as biomarkers of disease, and potential therapeutic uses. PMID- 29127035 TI - The high-production volume fungicide pyraclostrobin induces triglyceride accumulation associated with mitochondrial dysfunction, and promotes adipocyte differentiation independent of PPARgamma activation, in 3T3-L1 cells. AB - Pyraclostrobin is one of the most heavily used fungicides, and has been detected on a variety of produce, suggesting human exposure occurs regularly. Recently, pyraclostrobin exposure has been linked to a variety of toxic effects, including neurodegeneration and triglyceride (TG) accumulation. As pyraclostrobin inhibits electron transport chain complex III, and as mitochondrial dysfunction is associated with metabolic syndrome (cardiovascular disease, type II diabetes, obesity), we designed experiments to test the hypothesis that mitochondrial dysfunction underlies its adipogenic activity. 3T3-L1 cells were differentiated according to standard protocols in the presence of pyraclostrobin, resulting in TG accumulation. However, TG accumulation occurred without activation of the peroxisome proliferator activated nuclear receptor gamma (PPARgamma), the canonical pathway mediating adipogenesis. Furthermore, cells failed to express many markers of adipogenesis (PPARgamma, lpl, CEBPalpha), while co-exposure to pyraclostrobin and two different PPARgamma antagonists (GW9662, T0070907) failed to mitigate TG accumulation, suggesting TG accumulation occurred through a PPARgamma-independent mechanism. Instead, pyraclostrobin reduced steady-state ATP, mitochondrial membrane potential, basal mitochondrial respiration, ATP linked respiration, and spare respiratory capacity, demonstrating mitochondrial dysfunction, while reduced expression of genes involved in glucose transport (Glut-4), glycolysis (Pkm, Pfkl, Pfkm), fatty acid oxidation (Cpt-1b), and lipogenesis (Fasn, Acacalpha, Acacbeta) further suggested a disruption of metabolism. Finally, inhibition of cAMP responsive element binding protein (CREB), a PPARgamma coactivator, partially mitigated pyraclostrobin-induced TG accumulation, suggesting TG accumulation is occurring through a CREB-driven mechanism. In contrast, rosiglitazone, a known PPARgamma agonist, induced TG accumulation in a PPARgamma-dependent manner and enhanced mitochondrial function. Collectively, these results suggest pyraclostrobin-induced mitochondrial dysfunction inhibits lipid homeostasis, resulting in TG accumulation. Exposures that disrupt mitochondrial function may have the potential to contribute to the rising incidence of metabolic syndrome, and thus more research is needed to understand the human health impact of pyraclostrobin exposure. PMID- 29127038 TI - Lysine-containing cationic liposomes activate the NLRP3 inflammasome: Effect of a spacer between the head group and the hydrophobic moieties of the lipids. AB - Cationic lipids containing lysine head groups and ditetradecyl, dihexadecyl or dioctadecyl glutamate hydrophobic moieties with/without propyl, pentyl or heptyl spacers were applied for the preparation of cationic liposomes using a simple bath type-sonicator. The size distribution, zeta potential, cellular internalization, and cytotoxicity of the liposomes were characterized, and the innate immune stimulation, e.g., the NLRP3 inflammasome activation of human macrophages and THP-1 cells, was evaluated by the detection of IL-1beta release. Comparatively, L3C14 and L5C14 liposomes, made from the lipids bearing lysine head groups, ditetradecyl hydrophobic chains and propyl or pentyl spacers, respectively, were the most potent to activate the NLRP3 inflammasome. The possible mechanism includes endocytosis of the cationic liposomes and subsequent lysosome rupture without significant inducement of reactive oxygen species production. In summary, we first disclosed the structural effect of cationic liposomes on the NLRP3 inflammasome activation, which gives an insight into the application of nanoparticles for improved immune response. PMID- 29127040 TI - Improved pharmacokinetic profile of lipophilic anti-cancer drugs using alphanubeta3-targeted polyurethane-polyurea nanoparticles. AB - Glutathione degradable polyurethane-polyurea nanoparticles (PUUa NP) with a disulfide-rich multiwalled structure and a cyclic RGD peptide as a targeting moiety were synthesized, incorporating a very lipophilic chemotherapeutic drug named Plitidepsin. In vitro studies indicated that encapsulated drug maintained and even improved its cytotoxic activity while in vivo toxicity studies revealed that the maximum tolerated dose (MTD) of Plitidepsin could be increased three fold after encapsulation. We also found that pharmacokinetic parameters such as maximum concentration (Cmax), area under the curve (AUC) and plasma half-life were significantly improved for Plitidepsin loaded in PUUa NP. Moreover, biodistribution assays in mice showed that RGD-decorated PUUa NP accumulate less in spleen and liver than non-targeted conjugates, suggesting that RGD-decorated nanoparticles avoid sequestration by macrophages from the reticuloendothelial system. Overall, our results indicate that polyurethane-polyurea nanoparticles represent a very valuable nanoplatform for the delivery of lipophilic drugs by improving their toxicological, pharmacokinetic and whole-body biodistribution profiles. PMID- 29127039 TI - Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. AB - Therapeutic cancer vaccines require adjuvants leading to robust type I interferon and proinflammatory cytokine responses in the tumor microenvironment to induce an anti-tumor response. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. However, their efficacy may be limited to micromolar concentrations due to the cytosolic residence of STING in the ER membrane. Here we utilized biodegradable, poly(beta amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro. The leading CDN PBAE nanoparticle formulation induced a log-fold improvement in potency in treating established B16 melanoma tumors in vivo when combined with PD-1 blocking antibody in comparison to free CDN without nanoparticles. This nanoparticle-mediated cytosolic delivery method for STING agonists synergizes with checkpoint inhibitors and has strong potential for enhanced cancer immunotherapy. PMID- 29127041 TI - Logical comparison over RDF resources in bio-informatics. AB - Comparison of resources is a frequent task in different bio-informatics applications, including drug-target interaction, drug repositioning and mechanism of action understanding, among others. This paper proposes a general method for the logical comparison of resources modeled in Resource Description Framework and shows its distinguishing features with reference to the comparison of drugs. In particular, the method returns a description of the commonalities between resources, rather than a numerical value estimating their similarity and/or relatedness. The approach is domain-independent and may be flexibly adapted to heterogeneous use cases, according to a process for setting parameters which is completely explicit. The paper also presents an experiment using the dataset Bioportal as knowledge source; the experiment is fully reproducible, thanks to the elicitation of criteria and values for parameter customization. PMID- 29127042 TI - Does endometrial scratching really improve intrauterine insemination outcome? Injury timing can make a huge difference. PMID- 29127043 TI - Fourier phase based depth-resolved nanoscale nuclear architecture mapping for cancer detection. AB - Quantitative phase imaging (QPI) modality has been widely adopted in a variety of applications ranging from identifying photomask defects in lithography to characterizing cell structure and tissue morphology in cancer. Traditional QPI utilizes the electromagnetic phase of transmitted light to measure, with nanometer scale sensitivity, alterations in the optical thickness of a sample of interest. In our work, the QPI paradigm is generalized to study depth-resolved properties of phase objects with slowly varying refractive index without a strong interface by utilizing the Fourier phase associated with Fourier-domain optical coherence tomography (FD-OCT). Specifically, based on computing the Fourier phase of light back-scattered by cell nuclei, we have developed nanoscale nuclear architecture mapping (nanoNAM) method that quantifies, with nanoscale sensitivity, (a) the depth-resolved alterations in mean nuclear optical density, and (b) depth-resolved localized heterogeneity in optical density of the cell nuclei. We have used nanoNAM to detect malignant transformation in colon carcinogenesis, even in tissue that appears histologically normal according to pathologists, thereby showing its potential as a pathology aid in cases where pathology examination remains inconclusive, and for screening patient populations at risk of developing cancer. In this paper, we integrate all aspects of nanoNAM, from principle through instrumentation and analysis, to show that nanoNAM is a promising, low-cost, and label-free method for identifying pathologically indeterminate pre-cancerous and cancerous cells. Importantly, it can seamlessly integrate into the clinical pipeline by utilizing clinically prepared formalin fixed, paraffin-embedded tissue sections. PMID- 29127044 TI - Modeling the sub-diffraction focusing phenomenon of light propagation through scattering medium. AB - Optical techniques are assuming greater importance in biomedical applications, however, due to extreme complexity involved in light propagation through scattering medium, it is very challenging to analyze experimentally. Here we report a two-stage simulation technique to simulate phase-conjugated light propagation through scattering medium with macroscopic dimensions. The reported simulation yields accurate information with flexibility to access research parameters. The proposed simulation method is suitable for finite-difference time domain (FDTD) technique, pseudospectral time-domain (PSTD) technique, and other simulation techniques based upon numerical solutions of Maxwell's equations. We demonstrate modeling phase-conjugated light propagation through a scattering medium. The reported simulation technique is applicable to model the propagation of continuous-wave (CW) light with specific amplitude and phase through a scattering medium of macroscopic dimensions. More importantly, the flexibility of simulation enables analysis of research factors that are challenging to access experimentally. PMID- 29127046 TI - Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis. AB - Discovery of the myogenic regulatory factor family of transcription factors MYF5, MYOD, Myogenin and MRF4 was a seminal step in understanding specification of the skeletal muscle lineage and control of myogenic differentiation during development. These factors are also involved in specification of the muscle satellite cell lineage, which becomes the resident stem cell compartment inadult skeletal muscle. While MYF5, MYOD, Myogenin and MRF4 have subtle roles in mature muscle, they again play a crucial role in directing satellite cell function to regenerate skeletal muscle: linking the genetic control of developmental and regenerative myogenesis. Here, I review the role of the myogenic regulatory factors in developing and mature skeletal muscle, satellite cell specification and muscle regeneration. PMID- 29127047 TI - Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections. AB - Heteroresistance is common in a variety of microbes, however carbapenem heteroresistance among invasive Pseudomonas aeruginosa infections has not been thoroughly characterised to date. The objective of this study was to investigate the mechanisms, molecular epidemiology and risk factors for invasive carbapenem heteroresistant P. aeruginosa (CHPA) infections between 2011 and 2015 in Chongqing, China. A significant increase in the rates of heteroresistance to imipenem and meropenem was observed during the study period. Mechanistic analysis revealed that efflux system overexpression and decreased OprD could have contributed to carbapenem heteroresistance in P. aeruginosa. It was also observed that all of the subpopulations produced enhanced levels of biofilm compared with their native strains. Moreover, previous carbapenem exposure was identified as a common independent risk factor for imipenem-heteroresistant (IPM-HR) and meropenem-heteroresistant (MEM-HR) isolates, but patients infected with MEM-HR isolates were at higher risk of poor outcomes than those with IPM-HR isolates. Most importantly, there was a remarkable increase in the prescription of carbapenems during the study period, which was demonstrated to correlate significantly with the quarterly increasing prevalence of IPM-HR and MEM-HR isolates, respectively. These findings show the necessity of routine detection of carbapenem-heteroresistant strains and that strict control of carbapenem use is critical to reduce CHPA infections in hospitalised patients. PMID- 29127048 TI - Spread of mcr-1.5 in the community: an emerging threat. PMID- 29127045 TI - The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration. AB - The Myogenic Regulatory Factors (MRFs) Myf5, MyoD, myogenin and MRF4 are members of the basic helix-loop-helix family of transcription factors that control the determination and differentiation of skeletal muscle cells during embryogenesis and postnatal myogenesis. The dynamics of their temporal and spatial expression as well as their biochemical properties have allowed the identification of a precise and hierarchical relationship between the four MRFs. This relationship establishes the myogenic lineage as well as the maintenance of the terminal myogenic phenotype. The application of genome-wide technologies has provided important new information as to how the MRFs function to activate muscle gene expression. Application of combined functional genomics technologies along with single cell lineage tracing strategies will allow a deeper understanding of the mechanisms mediating myogenic determination, cell differentiation and muscle regeneration. PMID- 29127049 TI - Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli. AB - Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time-kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time-kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection. PMID- 29127050 TI - Do antibacterial and antifungal combinations have better activity against clinically relevant fusarium species? in vitro synergism. AB - The aim of this study was to evaluate the susceptibility of 20 clinical isolates of Fusarium spp. to classic antifungals [amphotericin B (AmB), itraconazole (ITR), voriconazole (VRC) and caspofungin (CAS)] and to non-antifungal agents [amiodarone (AMD), doxycycline (DOX) and moxifloxacin (MFX)] by the broth microdilution method. Combinations between these antifungal and non-antifungal agents were also evaluated to determine the fractional inhibitory concentration indices using the chequerboard technique. Synergistic interactions were observed for the following combinations (% synergism): AMD + VRC, 80%; MFX + AmB, 75%; AMD + AmB, 65%; DOX + VRC, 60%; MFX + VRC, 55%; DOX + AmB, 50%; and AMD + CAS, 30%. Synergism was not observed for associations with ITR. Antagonism was not seen in any combination. These findings suggest that the combinations of AMD, DOX or MFX with AmB or VRC to have potential for future in vivo investigations. PMID- 29127052 TI - A new Editor for JAAD. PMID- 29127051 TI - Genomic analysis of in vivo acquired resistance to colistin and rifampicin in Acinetobacter baumannii. AB - Acinetobacter baumannii is an opportunistic pathogen in healthcare facilities responsible for nosocomial infections mostly in immunocompromised patients. Colistin resistance is increasingly reported worldwide in A. baumannii. Here we describe the in vivo selection of colistin and rifampicin resistance in carbapenem-resistant A. baumannii. Antimicrobial susceptibility testing, plasmid analysis and whole-genome sequencing (WGS) were performed to fully characterise the resistome of two clinical isolates (AbS1 and AbS2) selected during treatment. Clinical isolate AbS1 remained susceptible to colistin, rifampicin and tigecycline, whilst AbS2 was susceptible only to tigecycline. PCR analysis revealed the presence of a blaOXA-23-like carbapenemase gene. Kieser extraction revealed an ca. 74 kb plasmid harbouring blaOXA-23. WGS revealed genomes of 3.8 Mbp in size with a G + C content of 38.9%, and both belonged to ST281 according to the Oxford MLST scheme and ST641 according to the Institut Pasteur scheme. The resistome was also composed of naturally occurring beta-lactamases, i.e. ADC-25 cephalosporinase and OXA-82 oxacillinase, aminoglycoside resistance genes [aac(3) Ia, aadA1 and aph(3')-VIa (aphA6)], and mutations in DNA gyrases explaining fluoroquinolone resistance. Single nucleotide polymorphism analysis revealed that both isolates were identical except for a 30-nucleotide duplication within the pmrB gene and a point mutation in the rpoB gene resulting in colistin and rifampicin resistance, respectively. This study highlights the genomic plasticity of A. baumannii under antibiotic pressure. The 10-amino acid duplication in PmrB affects colistin susceptibility by regulating lipopolysaccharide modification through the PmrAB two-component system. These findings provide further information on the molecular mechanisms leading to colistin resistance in A. baumannii. PMID- 29127054 TI - Ask the Authors. PMID- 29127053 TI - Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne. AB - Scientific advances are continually improving the knowledge of acne and contributing to the refinement of treatment options; it is important for clinicians to regularly update their practice patterns to reflect current standards. The Global Alliance to Improve Outcomes in Acne is an international group of dermatologists with an interest in acne research and education that has been meeting regularly since 2001. As a group, we have continuously evaluated the literature on acne. This supplement focuses on providing relevant clinical guidance to health care practitioners managing patients with acne, with an emphasis on areas where the evidence base may be sparse or need interpretation for daily practice. PMID- 29127055 TI - Fractionation separation of human plasma proteins using HPLC with a homemade iron porphyrin based monolithic column. AB - In this work a polymer monolithic column was fabricated within the confines of a stainless steel column (50*4.6mm i.d.) via radical polymerization by using iron porphyrin and butyl methacrylate as co-monomers, ethylene glycol dimethacrylate as crosslinking agent, ethylene glycol, isopropyl alcohol and N, N dimethylformamide as tri-porogens, benzoyl peroxide and N,N-dimethylaniline as initiators. The resulting monolithic column was characterized by elemental analysis, scanning electron microscopy, nitrogen adsorption BET surface area, and mercury intrusion porosimetry, respectively. Results showed that the homemade monolith occupied relatively uniform pore structure, low back pressure, and enhanced selectivity for proteins in complex bio-samples. The present work described a simple and efficient method for "fractionation separation" of human plasma proteins, and it is a promising separation method for complex bio-samples in proteomic research. PMID- 29127056 TI - Metabolites identificaion of two bioactive constituents in Trollius ledebourii in rats using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - Orientin and vitexin, 4'-hydroxyl-2-phenylchromen-4-one, are both major flavones derivatives found in Trollius ledebourii possessing definite pharmacological activities. In this study, in vitro metabolisms investigated on rat liver microsomes (RLMs) and in vivo metabolisms explored on Male Sprague Dawley rats of orientin and vitexin were tested, respectively. A systematic method based on ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was developed to characterize metabolites by means of electrospray ionization (ESI) mass spectrometry in positive ion mode. An on-line data acquisition method multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS) was developed to observe probable relevant metabolites. By comparison of chromatographic behaviors with reference substances, exact protonated ions, MS/MS fragment ions and relevant literature, a total of 12 metabolites of orientin and 23 metabolites of vitexin were detected, respectively, which suggested that orientin is more metabolically stable than vitexin. Oxidation, methylation, acetylation, reduction, loss of C6H10O5 and glucuronide conjugation were the major biotransformation routes of both of them in rats. More significant, glutamine conjugation, loss of CO and loss of CH2O were the unique metabolic pathways of vitexin compared with that of orientin for the first time. Besides, most metabolites were observed in rat urine and feces, implying that urine and feces were the active metabolic places for flavones. This is the first study on metabolisms of orientin and vitexin in vitro and in vivo simultaneously and the proposed metabolic pathways of them might provide further understanding of their pharmacological mechanisms and later study on their excretion. PMID- 29127057 TI - Quantitative analysis of clonidine and ephedrine by a microfluidic system: On chip electromembrane extraction followed by high performance liquid chromatography. AB - In this work, a microfluidic device was developed for on-chip electromembrane extraction of trace amounts of ephedrine (EPH) and clonidine (CLO) in human urine and plasma samples followed by HPLC-UV analysis. Two polymethylmethacrylate plates were used as substrates and a microchannel was carved in each plate. The microchannel channel on the underneath plate provided the flow pass of the sample solution and the one on the upper plate dedicated to a compartment for the stagnant acceptor phase. A piece of polypropylene sheet was impregnated by an organic solvent and mounted between the two parts of the chip device. An electrical field, across the porous sheet, was created by two embedded platinum electrodes placed in the bottom of the channels which were connected to a power supply. The analytes were converted to their ionized form, passed through the supported liquid membrane, and then extracted into the acceptor phase by the applied voltage. All the effective parameters including the type of the SLM, the SLM composition, pH of donor and acceptor phases, and the quantity of the applied voltage were evaluated and optimized. Several organic solvents were evaluated as the SLM to assess the effect of SLM composition. Other parameters were optimized by a central composite design. Under the optimal conditions of voltage of 74V, flow rate of 28MULmin-1, 100 and 20mM HCl as acceptor and donor phase composition, respectively, the calibration curves were plotted for both analytes. The limits of detection were less than 7.0 and 11MUgL-1 in urine and plasma, respectively. The linear dynamic ranges were within the range of 10-450 and 25 500MUgL-1 (r2?0.9969) for CLO, and within the range of 20-450 and 30-500MUgL-1 (r2?0.9907) for EPH in urine and plasma, respectively. To examine the capability of the method, real biological samples were analyzed. The results represented a high accuracy in the quantitative analysis of the analytes with relative recoveries within the range of 94.6-105.2% and acceptable repeatability with relative standard deviations lower than 5.1%. PMID- 29127058 TI - Trace anti-inflammatory beta-carboline alkaloid identified in Arenaria kansuensis by two-dimensional chromatography coupled with UniElut C18AEX based solid-phase extraction re-enrichment technology. AB - Traditional Chinese medicine is important for discovery of drug precursors. However, information about trace chemical composition of them is very limited due to the lack of appropriate enrichment and chromatographic purification methods In our work, A. kansuensis was taken as an example, a novel two-dimensional reversed phase/hydrophilic interaction liquid chromatography coupled with UniElut C18AEX solid-phase extraction re-enrichment method based on anti-inflammatory bioactivity-guided assay was developed for gathering and purifying trace beta carboline alkaloids with high purity from the ethyl acetate extract of A. kansuensis. Extraction with ethyl acetate as the first enrichment method, then, a UniElut C18AEX column was employed to re-enrich trace fraction which was hardly detected by diode array detector during high performance liquid chromatography analysis, eighteen grams of UniElut C18AEX was used as sorbent material to pack a 60mL pipette tip for the extraction of beta-carboline alkaloids from 100mL of ethyl acetate sample. The whole extraction process was finished in 10min, and the volume of eluent used was only 120mL. The enriching fraction (100mg) was used for the following two-dimensional purification. First-dimensional preparation was carried on a RP-Megress-C18 prep column, and four anti-inflammatory fractions were obtained from the 100mg re-enriching sample with a recovery of 66.9%. A HILIC-XAmide prep column was selected for the second dimensional preparation. Finally, two pair of analogue beta-carboline alkaloids and one other beta carboline alkaloid were purified from A. kansuensis. The purity of the isolated compounds was ?>98%, which indicated that the method was efficient to re-enrich and manufacture single trace beta-carboline alkaloids with high purity from A. kansuensis. Additionally, this method showed great potential to serve as a good example for the purification and enrichment of analogue structure anti inflammation carboline alkaloids from other plant materials. PMID- 29127059 TI - Hypertension and cardiovascular risk: General aspects. AB - Hypertension is the strongest or one of the strongest risk factors for almost all different cardiovascular diseases acquired during life, including coronary disease, left ventricular hypertrophy and valvular heart diseases, cardiac arrhythmias including atrial fibrillation, cerebral stroke and renal failure. The continuous relationship between blood pressure and cardiovascular and renal events makes the distinction between high normal blood pressure and hypertension based on arbitrary cut-off values for blood pressures. Overall the prevalence of hypertension in different European countries appears to be around 30-45% of the general population, with a steep increase with ageing. The prevention of cardiovascular disease and treatment recommendations should be related to quantification of total cardiovascular risk which could be estimated from several different models. However the impact of age on risk is so strong that young adults (particularly women) are unlikely to reach high-risk levels even when they have more than one major risk factor and a clear increase in relative risk. Therefore age-adjusted models, models assessing relative risks compared to others of same age and models including thorough assessments of target organ damage and ambulatory 24h blood pressure are needed together with national models because of the large variations between countries. PMID- 29127062 TI - Haemopoietic stem cell therapy in cirrhosis: the end of the story? PMID- 29127060 TI - Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial. AB - BACKGROUND: Results of small-scale studies have suggested that stem-cell therapy is safe and effective in patients with liver cirrhosis, but no adequately powered randomised controlled trials have been done. We assessed the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) and haemopoietic stem-cell infusions in patients with liver cirrhosis. METHODS: This multicentre, open label, randomised, controlled phase 2 trial was done in three UK hospitals and recruited patients with compensated liver cirrhosis and MELD scores of 11.0-15.5. Patients were randomly assigned (1:1:1) to receive standard care (control), treatment with subcutaneous G-CSF (lenograstim) 15 MUg/kg for 5 days, or treatment with G-CSF for 5 days followed by leukapheresis and intravenous infusion of three doses of CD133-positive haemopoietic stem cells (0.2 * 106 cells per kg per infusion). Randomisation was done by Cancer Research UK Clinical Trials Unit staff with a minimisation algorithm that stratified by trial site and cause of liver disease. The coprimary outcomes were improvement in severity of liver disease (change in MELD) at 3 months and the trend of change in MELD score over time. Analyses were done in the modified intention-to-treat population, which included all patients who received at least one day of treatment. Safety was assessed on the basis of the treatment received. This trial was registered at Current Controlled Trials on Nov 18, 2009; ISRCTN, number 91288089; and the European Clinical Trials Database, number 2009-010335-41. FINDINGS: Between May 18, 2010, and Feb 26, 2015, 27 patients were randomly assigned to the standard care, 26 to the G-CSF group, and 28 to the G-CSF plus stem-cell infusion group. Median change in MELD from day 0 to 90 was -0.5 (IQR -1.5 to 1.1) in the standard care group, -0.5 (-1.7 to 0.5) in the G-CSF group, and -0.5 (-1.3 to 1.0) in the G-CSF plus stem-cell infusion group. We found no evidence of differences between the treatment groups and control group in the trends of MELD change over time (p=0.55 for the G-CSF group vs standard care and p=0.75 for the G-CSF plus stem cell infusion group vs standard care). Serious adverse events were more frequent the in G-CSF and stem-cell infusion group (12 [43%] patients) than in the G-CSF (three [11%] patients) and standard care (three [12%] patients) groups. The most common serious adverse events were ascites (two patients in the G-CSF group and two patients in the G-CSF plus stem-cell infusion group, one of whom was admitted to hospital with ascites twice), sepsis (four patients in the G-CSF plus stem cell infusion group), and encephalopathy (three patients in the G-CSF plus stem cell infusion group, one of whom was admitted to hospital with encephalopathy twice). Three patients died, including one in the standard care group (variceal bleed) and two in the G-CSF and stem-cell infusion group (one myocardial infarction and one progressive liver disease). INTERPRETATION: G-CSF with or without haemopoietic stem-cell infusion did not improve liver dysfunction or fibrosis and might be associated with increased frequency of adverse events compared with standard care. FUNDING: National Institute of Health Research, The Sir Jules Thorn Charitable Trust. PMID- 29127063 TI - Regulation of tRNA synthesis by posttranslational modifications of RNA polymerase III subunits. AB - RNA polymerase III (RNAPIII) transcribes tRNA genes, 5S RNA as well as a number of other non-coding RNAs. Because transcription by RNAPIII is an energy-demanding process, its activity is tightly linked to the stress levels and nutrient status of the cell. Multiple signaling pathways control RNAPIII activity in response to environmental cues, but exactly how these pathways regulate RNAPIII is still poorly understood. One major target of these pathways is the transcriptional repressor Maf1, which inhibits RNAPIII activity under conditions that are detrimental to cell growth. However, recent studies have found that the cell can also directly regulate the RNAPIII machinery through phosphorylation and sumoylation of RNAPIII subunits. In this review we summarize post-translational modifications of RNAPIII subunits that mainly have been identified in large-scale proteomics studies, and we highlight several examples to discuss their relevance for regulation of RNAPIII. PMID- 29127064 TI - Multifunctional pH sensitive 3D scaffolds for treatment and prevention of bone infection. AB - : Multifunctional-therapeutic three-dimensional (3D) scaffolds have been prepared. These biomaterials are able to destroy the S. aureus bacterial biofilm and to allow bone regeneration at the same time. The present study is focused on the design of pH sensitive 3D hierarchical meso-macroporous 3D scaffolds based on MGHA nanocomposite formed by a mesostructured glassy network with embedded hydroxyapatite nanoparticles, whose mesopores have been loaded with levofloxacin (Levo) as antibacterial agent. These 3D platforms exhibit controlled and pH dependent Levo release, sustained over time at physiological pH (7.4) and notably increased at infection pH (6.7 and 5.5), which is due to the different interaction rate between diverse Levo species and the silica matrix. These 3D systems are able to inhibit the S. aureus growth and to destroy the bacterial biofilm without cytotoxic effects on human osteoblasts and allowing an adequate colonization and differentiation of preosteoblastic cells on their surface. These findings suggest promising applications of these hierarchical MGHA nanocomposite 3D scaffolds for the treatment and prevention of bone infection. STATEMENT OF SIGNIFICANCE: Multifunctional 3D nanocomposite scaffolds with the ability for loading and sustained delivery of an antimicrobial agent, to eliminate and prevent bone infection and at the same time to contribute to bone regeneration process without cytotoxic effects on the surrounding tissue has been proposed. These 3D scaffolds exhibit a sustained levofloxacin delivery at physiological pH (pH 7.4), which increasing notably when pH decreases to characteristic values of bone infection process (pH 6.7 and pH 5.5). In vitro competitive assays between preosteoblastic and bacteria onto the 3D scaffold surface demonstrated an adequate osteoblast colonization in entire scaffold surface together with the ability to eliminate bacteria contamination. PMID- 29127065 TI - Fatigue performance of additively manufactured meta-biomaterials: The effects of topology and material type. AB - : Additive manufacturing (AM) techniques enable fabrication of bone-mimicking meta-biomaterials with unprecedented combinations of topological, mechanical, and mass transport properties. The mechanical performance of AM meta-biomaterials is a direct function of their topological design. It is, however, not clear to what extent the material type is important in determining the fatigue behavior of such biomaterials. We therefore aimed to determine the isolated and modulated effects of topological design and material type on the fatigue response of metallic meta biomaterials fabricated with selective laser melting. Towards that end, we designed and additively manufactured Co-Cr meta-biomaterials with three types of repeating unit cells and three to four porosities per type of repeating unit cell. The AM meta-biomaterials were then mechanically tested to obtain their normalized S-N curves. The obtained S-N curves of Co-Cr meta-biomaterials were compared to those of meta-biomaterials with same topological designs but made from other materials, i.e. Ti-6Al-4V, tantalum, and pure titanium, available from our previous studies. We found the material type to be far more important than the topological design in determining the normalized fatigue strength of our AM metallic meta-biomaterials. This is the opposite of what we have found for the quasi-static mechanical properties of the same meta-biomaterials. The effects of material type, manufacturing imperfections, and topological design were different in the high and low cycle fatigue regions. That is likely because the cyclic response of meta-biomaterials depends not only on the static and fatigue strengths of the bulk material but also on other factors that may include strut roughness, distribution of the micro-pores created inside the struts during the AM process, and plasticity. STATEMENT OF SIGNIFICANCE: Meta-biomaterials are a special class of metamaterials with unusual or unprecedented combinations of mechanical, physical (e.g. mass transport), and biological properties. Topologically complex and additively manufactured meta-biomaterials have been shown to improve bone regeneration and osseointegration. The mechanical properties of such biomaterials are directly related to their topological design and material type. However, previous studies of such biomaterials have largely neglected the effects of material type, instead focusing on topological design. We show here that neglecting the effects of material type is unjustified. We studied the isolated and combined effects of topological design and material type on the normalized S-N curves of metallic bone-mimicking biomaterials and found them to be more strongly dependent on the material type than topological design. PMID- 29127066 TI - Surface modifications and oxidative degradation in MPC-grafted highly cross linked polyethylene liners retrieved from short-term total hip arthroplasty. AB - : Highly cross-linked polyethylene (HXLPE) hip liners grafted with 2 methacryloyloxyethyl phosphorylcholine (MPC) on their bearing surfaces have recently been commercialized as components of a new generation of artificial hip joints, while improvements in wear resistance and biocompatibility were reported based on in vitro studies. The present study aimed at evaluating the surface modification and oxidative degradation in short-term retrieved MPC-grafted liners by X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared spectroscopy (FT-IR) with attenuated total reflection (ATR) equipment and Raman spectroscopy. In none of 3 samples of retrieved MPC-grafted liners, detectable MPC graft remained on the bearing surfaces although 2 samples yet contained remains of MPC polymer in their rim zone. These results revealed that the MPC polymer might have quickly disappeared from the bearing surface under in vivo loading, which is more severe than the in vitro one. Furthermore, a detectable oxidation index (OI) value (>0.1) was not only observed in any zone of any sample investigated, but also in the rim zones of Samples 1 and 2, which surprisingly experienced the most remarkable increase in OI value detected in this study. We thus confirmed that: (i) annealing of HXLPE cannot completely remove free radicals; (ii) the MPC graft has no beneficial effect in protecting HXLPE against oxidation and wear; and, (iii) lipid absorption occurred even in the rim zone where the MPC layer remained. Based on these evidences we consider that the declaimed advanced MPC technology is not a suitable one to elongate the in vivo lifetime of hip joints. STATEMENT OF SIGNIFICANCE: Several studies reported that highly crosslinked polyethylene (HXLPE) have resulted in reduced wear in total hip arthroplasty. Beyond those studies, HXLPE hip liners grafted with 2 methacryloyloxyethyl phosphorylcholine (MPC) on their bearing surface were extensively studied in vitro and then commercialized as a new generation of artificial hip joints. The present study reports for the first time results about the evaluation of surface modification and oxidative degradation in retrieved the MPC grafted liners. The findings of this investigation clearly show that the MPC layer has been peeled off on the bearing surface of the liner main wear zone although the MPC layer remained on the surface of the rim zones. Furthermore, we assessed the microstructural modifications and the oxidation drifts that occurred in vivo in the hip joints despite the presence of the MPC layer. PMID- 29127067 TI - Understanding the structural drivers governing glass-water interactions in borosilicate based model bioactive glasses. AB - : The past decade has witnessed a significant upsurge in the development of borate and borosilicate based resorbable bioactive glasses owing to their faster degradation rate in comparison to their silicate counterparts. However, due to our lack of understanding about the fundamental science governing the aqueous corrosion of these glasses, most of the borate/borosilicate based bioactive glasses reported in the literature have been designed by "trial-and-error" approach. With an ever-increasing demand for their application in treating a broad spectrum of non-skeletal health problems, it is becoming increasingly difficult to design advanced glass formulations using the same conventional approach. Therefore, a paradigm shift from the "trial-and-error" approach to "materials-by-design" approach is required to develop new-generations of bioactive glasses with controlled release of functional ions tailored for specific patients and disease states, whereby material functions and properties can be predicted from first principles. Realizing this goal, however, requires a thorough understanding of the complex sequence of reactions that control the dissolution kinetics of bioactive glasses and the structural drivers that govern them. While there is a considerable amount of literature published on chemical dissolution behavior and apatite-forming ability of potentially bioactive glasses, the majority of this literature has been produced on silicate glass chemistries using different experimental and measurement protocols. It follows that inter-comparison of different datasets reveals inconsistencies between experimental groups. There are also some major experimental challenges or choices that need to be carefully navigated to unearth the mechanisms governing the chemical degradation behavior and kinetics of boron-containing bioactive glasses, and to accurately determine the composition-structure-property relationships. In order to address these challenges, a simplified borosilicate based model melt quenched bioactive glass system has been studied to depict the impact of thermal history on its molecular structure and dissolution behavior in water. It has been shown that the methodology of quenching of the glass melt impacts the dissolution rate of the studied glasses by 1.5*-3* depending on the changes induced in their molecular structure due to variation in thermal history. Further, a recommendation has been made to study dissolution behavior of bioactive glasses using surface area of the sample - to - volume of solution (SA/V) approach instead of the currently followed mass of sample - to - volume of solution approach. The structural and chemical dissolution data obtained from bioactive glasses following the approach presented in this paper can be used to develop the structural descriptors and potential energy functions over a broad range of bioactive glass compositions. STATEMENT OF SIGNIFICANCE: Realizing the goal of designing third generation bioactive glasses requires a thorough understanding of the complex sequence of reactions that control their rate of degradation (in physiological fluids) and the structural drivers that control them. In this article, we have highlighted some major experimental challenges and choices that need to be carefully navigated in order to unearth the mechanisms governing the chemical dissolution behavior of borosilicate based bioactive glasses. The proposed experimental approach allows us to gain a new level of conceptual understanding about the composition-structure-property relationships in these glass systems, which can be applied to attain a significant leap in designing borosilicate based bioactive glasses with controlled dissolution rates tailored for specific patient and disease states. PMID- 29127068 TI - Mono vs multilayer fibronectin coatings on polar/hydrophobic/ionic polyurethanes: Altering surface interactions with human monocytes. AB - : Monocyte interactions with materials that are biofunctionalized with fibronectin (Fn) are of interest because of the documented literature which associates this protein with white blood cell function at implant sites. A degradable-polar hydrophobic ionic polyurethane (D-PHI), has been reported to promote an anti-inflammatory response from human monocytes. The aim of the current work was to study the influence of intrinsic D-PHI material chemistry on Fn adsorption (mono and multi-layer structures), and to investigate the influence of such chemistry on the structural state of the Fn, as well as the latter's influence on the activity of human monocytes on the protein coated substrates. Significant differences in Fn adsorption, surface hydrophobicity and the availability of defined peptide sequences (N terminal, C terminal or Cell Binding Domain) for the Fn in mono vs multilayer structures were observed as a function of the changes in intrinsic material chemistry. A D-PHI-formulated polyurethane substrate with subtle changes in anionic and hydrophobic domain content relative to the polar non-ionic urethane/carbonate groups within the polymer matrix promoted the lowest activation of monocytes, in the presence of multi-layer Fn constructs. These results highlight the importance of chemical heterogeneity as a design parameter for biomaterial surfaces, and establishes a desired strategy for controlling human monocyte activity at the surface of devices, when these are coated with multi-layer Fn structures. The latter is an important step towards functionalizing the materials with multi-layer protein drug carriers as interventional therapeutic agents. STATEMENT OF SIGNIFICANCE: The control of the behavior of monocytes, especially migration and activation, is of crucial interest to modulate the inflammatory response at the site of implanted biomaterial. Several studies report the influence of adsorbed serum proteins on the behavior of monocytes on biomaterials. However, few studies show the influence of surface chemical group distribution on the controlled adsorption and the subsequent induced conformation- of mono versus multi-layer assembled structures generated from specific proteins implicated in wound repair. The current research considered the role of Fn adsorption and conformation in thin films while interacting with the intrinsic chemistry of segmented block polyurethanes; and the influence of the former on modulation and activation of human monocytes. PMID- 29127069 TI - Lectin-conjugated pH-responsive mesoporous silica nanoparticles for targeted bone cancer treatment. AB - : A novel multifunctional nanodevice based in doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs) as nanoplatforms for the assembly of different building blocks has been developed for bone cancer treatment. These building blocks consists of: i) a polyacrylic acid (PAA) capping layer grafted to MSNs via an acid-cleavable acetal linker, to minimize premature cargo release and provide the nanosystem of pH-responsive drug delivery ability; and ii) a targeting ligand, the plant lectin concanavalin A (ConA), able to selectively recognize, bind and internalize owing to certain cell-surface glycans, such as sialic acids (SA), overexpressed in given tumor cells. This multifunctional nanosystem exhibits a noticeable higher internalization degree into human osteosarcoma cells (HOS), overexpressing SA, compared to healthy preosteoblast cells (MC3T3-E1). Moreover, the results indicate that small DOX loading (2.5 ug mL-1) leads to almost 100% of osteosarcoma cell death in comparison with healthy bone cells, which significantly preserve their viability. Besides, this nanodevice has a cytotoxicity on tumor cells 8-fold higher than that caused by the free drug. These findings demonstrate that the synergistic combination of different building blocks into a unique nanoplatform increases antitumor effectiveness and decreases toxicity towards normal cells. This line of attack opens up new insights in targeted bone cancer therapy. STATEMENT OF SIGNIFICANCE: The development of highly selective and efficient tumor-targeted smart drug delivery nanodevices remains a great challenge in nanomedicine. This work reports the design and optimization of a multifunctional nanosystem based on mesoporous silica nanoparticles (MSNs) featuring selectivity towards human osteosarcoma cells and pH-responsive antitumor drug delivery capability. The novelty and originality of this manuscript relies on proving that the synergistic assembly of different building blocks into a unique nanoplatform increases antitumor effectiveness and decreases toxicity towards healthy cells, which constitutes a new paradigm in targeted bone cancer therapy. PMID- 29127070 TI - An early experience of mild adversity involving temporary denial of maternal contact affects the serotonergic system of adult male rats and leads to a depressive-like phenotype and inability to adapt to a chronic social stress. AB - Adverse early life experiences can affect adaptability to chronic stressors and lead to depressive-like behaviors in animal models. We employed an early experience model in which rat pups during postnatal days 10-13 are exposed to a T maze in which they learn the location of their mother motivated by the rewarding stimulus of maternal contact; one group of rats receives the expected reward, by being allowed contact with the mother upon finding her, while the other group is temporarily denied this contact (Denied Expected Reward, DER), thus experiencing mild adversity. The results presented herein show that the DER early life experience results in a depressive-like phenotype in adulthood, as indicated by the absence of sucrose preference -anhedonia- exhibited by these animals, in adulthood. Following exposure to a chronic social stress (CSS), DER male rats were unable to adapt, evident by reduced general locomotion and time spent in the centre of an open field which indicate anxiety and/or decreased motivation for exploration. They also exhibited increased immobility time in the forced swimming test, suggesting a passive coping strategy. The depressive-like and anxious phenotype of the DER males was accompanied by changes in the serotonergic system, such as lower serotonin levels, higher serotonin turnover and higher levels of the type 1 serotonin receptor in the hippocampus. Our results corroborate findings showing that early life adversity disturbs behavioral regulation in adulthood. They also suggest that even mild adversity, if it involves intervention in mother-offspring interactions, can be sufficient to compromise adaptability. PMID- 29127072 TI - No effect of a pulsed magnetic field on induced ischemic muscle pain. A double blind, randomized, placebo-controlled trial. AB - Empirical evidence supporting the effectiveness of pulsed (electro)magnetic field (PEMF) therapy on chronic and acute pain is equivocal. In the current randomized, double-blind, placebo-controlled experiment, impact of a commercially available whole-body PEMF mat on acute ischemic muscle pain induced in the forearm was studied with the participation of 70 healthy volunteers. The device emitted a pulsed magnetic field with a repetition frequency of 2.05Hz and a maximum flux density of 25.3MUT (rms). The highest dB/dt was 48mT/s. No differences between the groups receiving actual and sham PEMF were found in terms of pain threshold, pain tolerance, heart rate, and perceived decrease of pain. However, participants' expectation concerning the effectiveness of the intervention improved pain tolerance and affected perceived change of pain. In conclusion, the used PEMF device had no specific effect on acute ischemic muscle pain, while the contribution of the placebo effect was considerable. PMID- 29127073 TI - Estrogen receptor beta maintains expression of KLF15 to prevent cardiac myocyte hypertrophy in female rodents. AB - Maintaining a healthy, anti-hypertrophic state in the heart prevents progression to cardiac failure. In humans, angiotensin II (AngII) indirectly and directly stimulates hypertrophy and progression, while estrogens acting through estrogen receptor beta (ERbeta) inhibit these AngII actions. The KLF15 transcription factor has been purported to provide anti-hypertrophic action. In cultured neonatal rat cardiomyocytes, we found AngII inhibited KLF1 expression and nuclear localization, substantially prevented by estradiol (E2) or beta-LGND2 (beta LGND2), an ERbeta agonist. AngII stimulation of transforming growth factor beta expression in the myocytes activated p38alpha kinase via TAK1 kinase, inhibiting KLF15 expression. All was comparably reduced by E2 or beta-LGND2. Knockdown of KLF15 in the myocytes induced myocyte hypertrophy and limited the anti hypertrophic actions of E2 and beta-LGND2. Key aspects were confirmed in an in vivo model of cardiac hypertrophy. Our findings define additional anti hypertrophic effects of ERbeta supporting testing specific receptor agonists in humans to prevent progression of cardiac disease. PMID- 29127074 TI - Sensing and responding to energetic stress: Evolution of the AMPK network. AB - AMP-activated protein kinase is an enzyme that mediates communication between cellular energy status and diverse effector proteins, particularly those that play roles in determining the metabolic phenotype. By phosphorylating metabolic enzymes, transcriptional regulators and proteins involved in cellular structure, it can modify energy metabolism in both the short term and long term. Its basic features are highly conserved, with homologues in all eukaryotes. Gene and/or genome duplications endowed early vertebrates with paralogs of AMPK subunits, though the nature of their subfunctionalization remains uncertain, even in mammals. While most research focuses on the role of the enzyme in human health, a great deal can be learned from comparative studies targeting non-traditional model animals. Fish, in particular, are interesting models because of the diversity in the metabolic properties and complex relationships between metabolism and environmental challenges. In this review, we examine what is known about AMPK structure and function though the lens of comparative physiology, looking for opportunities to better understand how this vital energy sensor has evolved in animals. PMID- 29127071 TI - Sickness-induced changes in physiology do not affect fecundity or same-sex behavior. AB - Previous work in our lab has shown that early-life infection affects female reproductive physiology and function (i.e., smaller ovaries, abnormal estrous cycles) and alters investigation and aggression towards male conspecifics in a reproductive context. Although many studies have investigated the effects of postnatal immune challenge on physiological and behavioral development, fewer studies have examined whether these changes have ultimate effects on reproduction. In the current study, we paired Siberian hamsters (Phodopus sungorus) and simulated a bacterial infection in early life by administering lipopolysaccharide (LPS) to male and female pups on pnd3 and pnd5. In adulthood, hamsters were paired with novel individuals of the same sex, and we scored an array of social behaviors (e.g., investigation, aggression). We then paired animals with individuals of the opposite sex for 5 consecutive nights, providing them with the opportunity to mate. We found that females exhibited impaired reproductive physiology and function in adulthood (i.e., smaller ovaries and abnormal estrous cycles), similar to our previous work. However, both LPS-treated males and females exhibited similar same-sex social behavior when compared with saline-treated controls, they successfully mated, and there were no significant changes in fecundity. These data suggest that the physiological changes in response to neonatal immune challenge may not have long-term effects on reproductive success in a controlled environment. Collectively, the results of this study are particularly important when investigating the relationships between physiology and behavior within an ultimate context. Animals exposed to early-life stress may in fact be capable of compensating for changes in physiology in order to survive and reproduce in some contexts. PMID- 29127075 TI - Evidence of high transport and phosphorylation capacity for both glucose and fructose in the ruby-throated hummingbird (Archilochus colubris). AB - Hummingbirds are able to fuel hovering flight entirely with recently ingested glucose or fructose. Among vertebrates, several steps of sugar flux from circulation to skeletal muscle are potentially rate-limiting, including transport into muscle and subsequent phosphorylation. While capacities for glucose flux are substantial, capacities for fructose flux are comparatively low. The mechanisms underlying apparent high rates of glucose and fructose oxidation in hummingbird flight muscle remain unclear. We examined relative expression of facilitative sugar transporters (GLUTs) and enzymes of fructolysis in ruby-throated hummingbird (Archilochus colubris) tissues involved in energy homeostasis and flight, via qPCR and measured hexokinase activity in pectoralis in vitro. We hypothesized that expression of these genes was upregulated in hummingbird flight muscle compared to other vertebrates. We found that hummingbird pectoralis had high relative transcript abundance of GLUT1 and GLUT5 compared to expression profiles of other vertebrates. In particular, GLUT5 expression in pectoralis was similar to that of intestine. We demonstrated minimal relative densities of fructolytic enzymes in pectoralis, suggesting that the ketohexokinase pathway does not rapidly metabolize fructose in these muscles. Instead, we found that the capacity for phosphorylation of either glucose or fructose by hexokinase is very high in pectoralis in vitro. The contributions of individual hexokinase isoforms remain to be determined. Our results further characterize the strategies by which hummingbirds, and perhaps other nectarivores, accomplish rapid sugar flux. High transport and sugar phosphorylation capacities appear to exist in flight muscle, though the enzymatic pathways that catalyze the phosphorylation of sugar in muscle remain uncertain. PMID- 29127077 TI - Is Connected Health Contributing to a Healthier Population? AB - Connected health tools, including mobile phones, incorporate various functions that capture events, direct actions, and make informed decisions based on complex sources of data. Connected health, a term recently proposed by some academics and industry, refers to the development, testing, and integration of smart technology tools into health care. Through these means, connected health creates interconnectivity across various environments, profoundly changing the way we learn, self-regulate, and communicate with one another. In health care, mobile phones enable more precise diagnostics, personalized health recommendations that enhance patient experiences and outcomes while containing health care costs. However, for connected health to achieve its full potential, issues must be addressed pertaining to active engagement in use, privacy, security, and quality, as well as the development of evidence-based guidelines. This commentary discusses these key challenges and explores the promise of connected health, specifically eHealth and mHealth. Anchored within the context of cancer, the authors' area of expertise, the ideas put forward can readily be applied to other health-related disciplines. PMID- 29127078 TI - Voters back Obamacare in local and state elections. PMID- 29127076 TI - Tailored Web-Based Interventions for Pain: Systematic Review and Meta-Analysis. AB - BACKGROUND: Efforts have multiplied in the past decade to underline the importance of pain management. For both acute and chronic pain management, various barriers generate considerable treatment accessibility issues, thereby providing an opportunity for alternative intervention formats to be implemented. Several systematic reviews on Web-based interventions with a large emphasis on chronic pain and cognitive behavioral therapy have been recently conducted to explore the influence of these interventions on pain management However, to our knowledge, the specific contribution of tailored Web-based interventions for pain management has not been described and their effect on pain has not been evaluated. OBJECTIVE: The primary aim of this systematic review was to answer the following research question: What is the effect of tailored Web-based pain management interventions for adults on pain intensity compared with usual care, face-to-face interventions, and standardized Web-based interventions? A secondary aim was to examine the effects of these interventions on physical and psychological functions. METHODS: We conducted a systematic review of articles published from January 2000 to December 2015. We used the DerSimonian-Laird random effects models with 95% confidence intervals to calculate effect estimates for all analyses. We calculated standardized mean differences from extracted means and standard deviations, as outcome variables were measured on different continuous scales. We evaluated 5 different outcomes: pain intensity (primary outcome), pain-related disability, anxiety, depression, and pain catastrophizing. We assessed effects according to 3 time intervals: short term (<1 month), medium term (1-6 months), and long term (6-12 months). RESULTS: After full-text review, we excluded 31 articles, resulting in 17 eligible studies. Only 1 study concerned acute pain and was removed from the meta-analysis, resulting in 16 studies available for quantitative assessment. Compared with standard care or a waiting list, tailored Web-based intervention showed benefits immediately after, with small effect sizes (<0.40) for pain intensity (10 randomized controlled trials [RCTs], n=1310, P=.003) and pain-related disability (6 RCTs, n=953, P<.001). No other improvements were observed at follow-up in the medium and long terms. Compared with the active control group, no improvements were found for the primary outcome (pain intensity) or any of the outcomes except for a small effect size on pain catastrophizing (2 RCTs, n=333, P<.001) immediately after the intervention. CONCLUSIONS: Tailored Web-based interventions did not prove to be more efficacious than standardized Web-based interventions in terms of pain intensity, pain-related disability, anxiety, and depression. An interesting finding was that some efficacy was shown on pain catastrophizing compared with active control interventions. Considering the diversity of approaches used in tailored Web-based interventions for chronic pain management, their efficacy is yet to be explored. Moreover, their contribution to acute pain management is embryonic. TRIAL REGISTRATION: International prospective register of systematic reviews (PROSPERO): CRD42015027669; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42015027669 (Archived by WebCite at http://www. webcitation.org/6uneWAuyR). PMID- 29127079 TI - Retraction: Effect of acupuncture and Chinese herbal medicine on subacute stroke outcomes: a single center randomized controlled trial. PMID- 29127081 TI - Should cost effectiveness analyses for NICE always consider future unrelated medical costs? PMID- 29127082 TI - Better value primary care is needed now more than ever. PMID- 29127080 TI - A Naturalistic, Randomized Pilot Trial of E-Cigarettes: Uptake, Exposure, and Behavioral Effects. AB - Background: Most studies of electronic nicotine delivery systems (ENDS) compare self-selected users versus nonusers. The few randomized studies to date generally support a positive impact on reducing smoking behavior, but these studies are focused on guided ENDS use. This study presents a randomized, naturalistic trial of ENDS with prospective outcomes of uptake and behavioral changes in smoking.Methods: Adult smokers with minimal ENDS history were randomized in a 2:1 ratio to receive product for 3 weeks (n = 46), or not (n = 22). Changes in nicotine delivery (16 vs. 24 mg), midway through the study allowed a compelling opportunity to examine two ENDS products compared with the control group. Primary outcomes, assessed via daily diaries during sampling period and in-person laboratory visits over 4 months, included uptake and usage of ENDS, cessation related outcomes, and exposure to smoke constituents.Results: All ENDS participants tried product at least once, with 48% of 24 mg and 30% of 16 mg using their assigned product for the entire sampling period. Within the 24 mg ENDs group, 57% made an independent purchase of ENDS, versus 28% of 16 mg, and 14% of control participants (P = 0.01). Smokers in both ENDS groups significantly reduced their smoking, whereas control participants did not (P = 0.03). Cessation behaviors (quit attempts, biologically verified abstinence) numerically but not statistically favored ENDS participants.Conclusions: Results suggest that cigarette smokers are willing to use ENDS with trends toward reduced cigarette smoking and positive changes in cessation-related behaviors.Impact: Randomized, naturalistic trials such as presented herein are needed to understand the population impact of e-cigarettes. Cancer Epidemiol Biomarkers Prev; 26(12); 1795 803. (c)2017 AACR. PMID- 29127086 TI - Acalabrutinib Approved for MCL. AB - The FDA granted accelerated approval to the second-generation BTK inhibitor acalabrutinib, which, because of its increased selectivity, seems to cause fewer side effects than ibrutinib, previously the only BTK inhibitor on the market. PMID- 29127089 TI - Researchers and WHO clash over global threat of drug resistant malaria. PMID- 29127090 TI - NHS needs L4bn boost in budget to protect care, think tanks warn. PMID- 29127091 TI - GP leader urges government to step up investment. PMID- 29127092 TI - Low-dose CT detects more progression of bone formation in comparison to conventional radiography in patients with ankylosing spondylitis: results from the SIAS cohort. AB - OBJECTIVES: To compare the CT Syndesmophyte Score (CTSS) for low-dose CT (ldCT) with the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) for conventional radiographs (CR) in patients with ankylosing spondylitis (AS). METHODS: Patients with AS in the Sensitive Imaging in Ankylosing Spondylitis cohort had lateral cervical and lumbar spine CR and whole spine ldCT at baseline and 2 years. CR and ldCT images were scored by two readers, paired by patient, blinded to time order, per imaging modality. For the total score analysis, we used average scores of readers per corner on CR or quadrant on ldCT. For the syndesmophyte analysis we used individual reader and consensus scores, regarding new or growing syndesmophyte at the same corner/quadrant. RESULTS: 50 patients were included in the syndesmophyte analysis and 37 in the total score analysis. Mean (SD) status scores for mSASSS (range 0-72) and CTSS (range 0-552) at baseline were 17.9 (13.8) and 161.6 (126.6), and mean progression was 2.4 (3.8) and 17.9 (22.1). Three times as many patients showed new or growing syndesmophytes at >=3 quadrants on ldCT compared with >=3 corners on CR for individual readers; for consensus this increased to five times. In 50 patients, 36 new or growing syndesmophytes are seen on CR compared with 151 on ldCT, most being found in the thoracic spine. CONCLUSIONS: ldCT, covering the whole spine, detects more progression in the form of new and growing syndesmophytes in patients with AS compared with CR, which is limited to the cervical and lumbar spine. Most progression occurred in the thoracic spine. PMID- 29127093 TI - Development of the CT Syndesmophyte Score (CTSS) in patients with ankylosing spondylitis: data from the SIAS cohort. AB - OBJECTIVES: To develop the CT Syndesmophyte Score (CTSS) for low-dose CT (ldCT) to assess structural damage in the spine of patients with ankylosing spondylitis (AS) and test its reliability. METHODS: Patientswith AS in the SIAS cohort had whole spine ldCT at baseline and 2 years. Syndesmophytes were scored in coronal and sagittal planes in eight quadrants per vertebral unit (VU) as absent=0, <50% of the intervertebral disc space (IDS)=1, >=50%=2 or bridging the IDS=3 (range 0 552). Images were scored by two readers, paired by patient, blinded to time order. Whole spine and spinal segment status and change scores were calculated. Inter-reader reliability was assessed by intraclass correlation coefficient (ICC), smallest detectable change (SDC) and frequency of scores per VU. RESULTS: 49 patients (mean age 50 years (SD 9.8), 84% men, 88% human leucocyte antigen B27 positive) were included. Mean (SD) scores of reader 1 were: whole spine baseline status score 163 (126) and change score 16 (21), spinal segment baseline status scores 30 (41), 97 (77) and 36 (36) and change scores 2 (7), 12 (18) and 3 (4) for the cervical, thoracic and lumbar spine, respectively. Scores of reader 2 were similar. Whole spine status score ICC was 0.99 and 0.97-0.98 for spinal segments. Whole spine change score ICC was 0.77 and 0.32-0.75 for spinal segments. Whole-spine SDC was 14.4. Score distribution pattern per VU was similar between readers. CONCLUSIONS: Using the CTSS, new bone formation in the spine of patients with AS can be assessed reliably. Most progression was seen in the thoracic spine. PMID- 29127094 TI - Use of urate-lowering therapies is not associated with an increased risk of incident dementia in older adults. PMID- 29127095 TI - Stop rollout of online consultations until there is evidence of benefit to patients, say LMCs. PMID- 29127097 TI - Differentiating between "baby blues," severe depression, and psychosis. PMID- 29127096 TI - Retention of Interstitial Genes between TMPRSS2 and ERG Is Associated with Low Risk Prostate Cancer. AB - TMPRSS2-ERG gene fusions occur in over 50% of prostate cancers, but their impact on clinical outcomes is not well understood. Retention of interstitial genes between TMPRSS2 and ERG has been reported to influence tumor progression in an animal model. In this study, we analyzed the status of TMPRSS2-ERG fusion genes and interstitial genes in tumors from a large cohort of men treated surgically for prostate cancer, associating alterations with biochemical progression. Through whole-genome mate pair sequencing, we mapped and classified rearrangements driving ETS family gene fusions in 133 cases of very low-, low-, intermediate-, and high-risk prostate cancer from radical prostatectomy specimens. TMPRSS2-ERG gene fusions were observed in 44% of cases, and over 90% of these fusions occurred in ERG exons 3 or 4. ERG fusions retaining interstitial sequences occurred more frequently in very low-risk tumors. These tumors also frequently displayed ERG gene fusions involving alternative 5'-partners to TMPRSS2, specifically SLC45A3 and NDRG1 and other ETS family genes, which retained interstitial TMPRSS2/ERG sequences. Lastly, tumors displaying TMPRSS2 ERG fusions that retained interstitial genes were less likely to be associated with biochemical recurrence (P = 0.028). Our results point to more favorable clinical outcomes in patients with ETS family fusion-positive prostate cancers, which retain potential tumor-suppressor genes in the interstitial regions between TMPRSS2 and ERG Identifying these patients at biopsy might improve patient management, particularly with regard to active surveillance. Cancer Res; 77(22); 6157-67. (c)2017 AACR. PMID- 29127098 TI - Long-term follow-up after bilateral percutaneous epiphysiodesis around the knee to reduce excessive predicted final height. PMID- 29127100 TI - How does pollution damage children's health? PMID- 29127099 TI - Individualised advance care planning in children with life-limiting conditions. AB - INTRODUCTION: In 2013, the Pediatric Association of the Netherlands launched an evidence-based guideline 'Palliative care for children'. To promote implementation in daily practice and hereby improve quality of paediatric palliative care, we aimed to develop a functional individualised paediatric palliative care plan (IPPCP) that covers physical, psychological, spiritual and social functioning, with great emphasis on the guideline's recommendations, advance care planning and patients' and parents' preferences and desires. METHODS: A Dutch working group (28 individuals) with a strong multidisciplinary character developed a draft IPPCP, which was piloted retrospectively and prospectively. In the pilots we completed, the IPPCPs for patients who were recently diagnosed with a life-threatening or life-limiting condition and evaluated completeness, usability and user-friendliness. RESULTS: The final IPPCP comprised five domains: (1) IPPCP data, (2) basics, (3) social, (4) psychosocial and spiritual and (5) physical care. Each domain covered various components. In both pilots, the IPPCP was considered a comprehensive document that covered all areas of paediatric palliative care and was experienced as an improvement to the present situation. However, the current form was regarded to lack user friendliness. CONCLUSION: We propose a set of essential components of a comprehensive IPPCP for paediatric palliative care with extra attention for advance care planning and anticipatory action. Patients' and parents' preferences and desires are included next to the recommendations of the evidence-based guideline 'Palliative care for children'. PMID- 29127101 TI - Fighting vessel dysmorphia to improve glioma chemotherapy. PMID- 29127103 TI - Old adversaries in new places. PMID- 29127102 TI - Algorithms to guide ambulance clinicians in the management of emergencies in patients with implanted rotary left ventricular assist devices. AB - Advances in left ventricular assist device (LVAD) therapy have resulted in increasing numbers of adult LVAD recipients in the community. However, device failure, stroke, bleeding, LVAD thrombosis and systemic infection can be life threatening emergencies. Currently, four LVAD systems are implanted in six UK transplant centres, each of which provides device-specific information to local emergency services. This has resulted in inconsistent availability and content of information with the risks of delayed or inappropriate decision-making. In order to improve patient safety, a consortium of UK healthcare professionals with expertise in LVADs developed universally applicable prehospital emergency algorithms. Guidance was framed as closely as possible on the standard ABCDE approach to the assessment of critically ill patients. PMID- 29127104 TI - Chemical suppressors of mlo-mediated powdery mildew resistance. AB - Loss-of-function of barley mildew locus o (Mlo) confers durable broad-spectrum penetration resistance to the barley powdery mildew pathogen, Blumeria graminis f. sp. hordei (Bgh). Given the importance of mlo mutants in agriculture, surprisingly few molecular components have been identified to be required for this type of resistance in barley. With the aim to identify novel cellular factors contributing to mlo-based resistance, we devised a pharmacological inhibitor screen. Of the 41 rationally chosen compounds tested, five caused a partial suppression of mlo resistance in barley, indicated by increased levels of Bgh host cell entry. These chemicals comprise brefeldin A (BFA), 2',3' dideoxyadenosine (DDA), 2-deoxy-d-glucose, spermidine, and 1-aminobenzotriazole. Further inhibitor analysis corroborated a key role for both anterograde and retrograde endomembrane trafficking in mlo resistance. In addition, all four ribonucleosides, some ribonucleoside derivatives, two of the five nucleobases (guanine and uracil), some guanine derivatives as well as various polyamines partially suppress mlo resistance in barley via yet unknown mechanisms. Most of the chemicals identified to be effective in partially relieving mlo resistance in barley also to some extent compromised powdery mildew resistance in an Arabidopsis mlo2 mlo6 double mutant. In summary, our study identified novel suppressors of mlo resistance that may serve as valuable probes to unravel further the molecular processes underlying this unusual type of disease resistance. PMID- 29127105 TI - EPOR2/betacR2-independendent effects of low-dose epoetin-alpha in porcine liver transplantation. AB - Ischemia-reperfusion injury (IRI) remains a key component of graft damage during transplantation. Erythropoietin (EPO) induces anti-inflammatory and anti apoptotic effects via the EPOR2/betacR2 complex, with a potential risk of thrombosis. Previous work indicates that EPO has EPOR2/betacR2-independent protective effects via direct effects on the endothelium. As the EPOR2/betacR2 receptor has a very low affinity for EPO, we aimed to test the hypothesis that EPO doses below the level that stimulate this receptor elicit cytoprotective effects via endothelial stimulation in a porcine liver transplantation model. Landrace pigs underwent allogenic liver transplantation (follow-up: 6 h) with a portojugular shunt. Animals were divided into two groups: donor and recipient treatment with low-dose EPO (65 IU/kg) or vehicle, administered 6 h before cold perfusion and 30 min after warm reperfusion. Fourteen of 17 animals (82.4%) fulfilled the inclusion criteria. No differences were noted in operative values between the groups including hemoglobin, cold or warm ischemic time. EPO-treated animals showed a significantly lower histopathology score, reduced apoptosis, oxidative stress, and most important a significant up-regulation of endothelial nitric oxide (NO) synthase (eNOS). Donor and recipient treatment with low-dose EPO reduces the hepatic IRI via EPOR2/betacR2-independent cytoprotective mechanisms and represents a clinically applicable way to reduce IRI. PMID- 29127106 TI - A melanin-mediated cancer immunotherapy patch. AB - Melanin is capable of transforming 99.9% of the absorbed sunlight energy into heat, reducing the risk of skin cancer. We here develop a melanin-mediated cancer immunotherapy strategy through a transdermal microneedle patch. B16F10 whole tumor lysate containing melanin is loaded into polymeric microneedles that allow sustained release of the lysate upon insertion into the skin. In combination with the near-infrared light irradiation, melanin in the patch mediates the generation of heat, which further promotes tumor-antigen uptake by dendritic cells, and leads to enhanced antitumor vaccination. We found that the spatiotemporal photoresponsive immunotherapy increases infiltration of polarized T cells and local cytokine release. These immunological effects increase the survival of mice after tumor challenge and elicited antitumor effects toward established primary tumor and distant tumor. Collectively, melanin generates local heat, boosts T cell activities by transdermal vaccines, and promotes antitumor immune responses. PMID- 29127107 TI - Heating up cancer vaccines. AB - A microneedle patch containing melanin promotes systemic antitumor response upon photothermal irradiation. PMID- 29127108 TI - Egg Case Silk Gene Sequences from Argiope Spiders: Evidence for Multiple Loci and a Loss of Function Between Paralogs. AB - Spiders swath their eggs with silk to protect developing embryos and hatchlings. Egg case silks, like other fibrous spider silks, are primarily composed of proteins called spidroins (spidroin = spider-fibroin). Silks, and thus spidroins, are important throughout the lives of spiders, yet the evolution of spidroin genes has been relatively understudied. Spidroin genes are notoriously difficult to sequence because they are typically very long (>= 10 kb of coding sequence) and highly repetitive. Here, we investigate the evolution of spider silk genes through long-read sequencing of Bacterial Artificial Chromosome (BAC) clones. We demonstrate that the silver garden spider Argiope argentata has multiple egg case spidroin loci with a loss of function at one locus. We also use degenerate PCR primers to search the genomic DNA of congeneric species and find evidence for multiple egg case spidroin loci in other Argiope spiders. Comparative analyses show that these multiple loci are more similar at the nucleotide level within a species than between species. This pattern is consistent with concerted evolution homogenizing gene copies within a genome. More complicated explanations include convergent evolution or recent independent gene duplications within each species. PMID- 29127109 TI - INCB040093 Is a Novel PI3Kdelta Inhibitor for the Treatment of B Cell Lymphoid Malignancies. AB - Phosphatidylinositol 3-kinase delta (PI3Kdelta) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kdelta small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kdelta kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kdelta-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein 1beta (MIP-1beta) and tumor necrosis factor-beta (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies. PMID- 29127113 TI - Validation of an ICD-9-CM and ICD-10-CM map to AIS 2005 Update 2008. AB - Although the Abbreviated Injury Scale (AIS) is the most widely used severity scoring system for traumatic injuries, hospitals are required to document and bill based on the International Classification of Diseases (ICD). An expert panel recently developed a map between ICD-9-CM and ICD-10-CM to AIS 2005 Update 2008. This study aimed to validate the recently developed map using a large trauma registry. The map demonstrated moderate to substantial agreement for maximum AIS (MAIS) scores per body region based on expert chart review versus map-derived values (range: 44%-86%). Injury Severity Scores (ISSs) calculated from expert coders versus map-derived values were also compared and demonstrated moderate agreement (ICD-9-CM: 48%, ICD-10-CM: 54%). Although not a perfect conversion tool, the new ICD-AIS map provides a systematic method to assign injury severity for datasets with only ICD-9-CM and ICD-10-CM codes available and can be used for future injury-related research and data analysis. PMID- 29127110 TI - Pathways of cellular proteostasis in aging and disease. AB - Ensuring cellular protein homeostasis, or proteostasis, requires precise control of protein synthesis, folding, conformational maintenance, and degradation. A complex and adaptive proteostasis network coordinates these processes with molecular chaperones of different classes and their regulators functioning as major players. This network serves to ensure that cells have the proteins they need while minimizing misfolding or aggregation events that are hallmarks of age associated proteinopathies, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. It is now clear that the capacity of cells to maintain proteostasis undergoes a decline during aging, rendering the organism susceptible to these pathologies. Here we discuss the major proteostasis pathways in light of recent research suggesting that their age-dependent failure can both contribute to and result from disease. We consider different strategies to modulate proteostasis capacity, which may help develop urgently needed therapies for neurodegeneration and other age-dependent pathologies. PMID- 29127114 TI - Compared with what? Estimating the effects of injury prevention policies using the synthetic control method. AB - INTRODUCTION: This paper discusses the application of the synthetic control method to injury-related interventions using aggregate data from public information systems. The method selects and determines the optimal control unit in the data by minimising the difference between the pre-intervention outcomes in one treated unit (eg, a state) and a weighted combination of potential control units. METHOD: I demonstrate the synthetic control method by an application to Florida's post-2010 policy and law enforcement initiatives aimed at bringing down opioid overdose deaths. Using opioid-related mortality data for a panel of 46 states observed from 1999 to 2015, the analysis suggests that a weighted combination of Maine (46.1%), Pennsylvania (34.4%), Nevada (5.4%), Washington (5.3%), West Virginia (4.3%) and Oklahoma (3.4%) best predicts the preintervention trajectory of opioid-related deaths in Florida between 1999 and 2009. Model specification and placebo tests, as well as an iterative leave-k-out sensitivity analysis are used as falsification tests. RESULTS: The results indicate that the policies have decreased the incidence of opioid-related deaths in Florida by roughly 40% (or -6.19 deaths per 100.000 person-years) by 2015 compared with the evolution projected by the synthetic control unit. Sensitivity analyses yield an average estimate of -4.55 deaths per 100.000 person-years (2.5th percentile: -1.24, 97.5th percentile: -7.92). The estimated cumulative effect in terms of deaths prevented in the postperiod is 3705 (2.5th percentile: 1302, 97.5th percentile: 6412). DISCUSSION: Recommendations for practice, future research and potential pitfalls, especially concerning low-count data, are discussed. Replication codes for Stata are provided. PMID- 29127112 TI - Reduced Expression of Glutathione S-Transferase alpha 4 Promotes Vascular Neointimal Hyperplasia in CKD. AB - Neointima formation is the leading cause of arteriovenous fistula (AVF) failure. We have shown that CKD accelerates this process by transforming the vascular smooth muscle cells (SMCs) lining the AVF from a contractile to the synthetic phenotype. However, the underlying mechanisms affecting this transformation are not clear. Previous studies have shown that the alpha-class glutathione transferase isozymes have an important role in regulating 4-hydroxynonenal (4 HNE)-mediated proliferative signaling of cells. Here, using both the loss- and gain-of-function approaches, we investigated the role of glutathione S transferase alpha4 (GSTA4) in modulating cellular 4-HNE levels for the transformation and proliferation of SMCs. Compared with non-CKD controls, mice with CKD had downregulated expression of GSTA4 at the mRNA and protein levels, with concomitant increase in 4-HNE in arteries and veins. This effect was associated with upregulated phosphorylation of MAPK signaling pathway proteins in proliferating SMCs. Overexpressing GSTA4 blocked 4-HNE-induced SMC proliferation. Additionally, inhibitors of MAPK signaling inhibited the 4-HNE-induced responses. Compared with wild-type mice, mice lacking GSTA4 exhibited increased CKD-induced neointima formation in AVF. Transient expression of an activated form of GSTA4, achieved using a combined Tet-On/Cre induction system in mice, lowered levels of 4-HNE and reduced the proliferation of SMCs. Together, these results demonstrate the critical role of GSTA4 in blocking CKD-induced neointima formation and AVF failure. PMID- 29127115 TI - Effective dietary recommendations could help to prevent age-related cognitive decline. PMID- 29127117 TI - Very Early Subclinical Valve Thrombosis After Transcatheter Aortic Valve Replacement. PMID- 29127118 TI - The ACRA Anatomy Study (Assessment of Disability After Coronary Procedures Using Radial Access): A Comprehensive Anatomic and Functional Assessment of the Vasculature of the Hand and Relation to Outcome After Transradial Catheterization. AB - BACKGROUND: The palmar arches serve as the most important conduits for digital blood supply, and incompleteness may lead to digital ischemia when the radial artery becomes obstructed after cardiac catheterization. The rate of palmar arch incompleteness and the clinical consequences after transradial access are currently unknown. METHODS AND RESULTS: The vascular anatomy of the hand was documented by angiography in 234 patients undergoing transradial cardiac catheterization. In all patients, a preprocedural modified Allen test and Barbeau test were performed. Upper-extremity function was assessed at baseline and 2-year follow-up by the QuickDASH. Incompleteness of the superficial palmar arch (SPA) was present in 46%, the deep palmar arch was complete in all patients. Modified Allen test and Barbeau test results were associated with incompleteness of the SPA (P=0.001 and P=0.001). The modified Allen test had a 33% sensitivity and 86% specificity for SPA incompleteness with a cutoff value of >10 seconds and a 59% sensitivity and 60% specificity with a cutoff value of >5 seconds. The Barbeau test had a 7% sensitivity and 98% specificity for type D and a 21% sensitivity and 93% specificity for types C and D combined. Upper-extremity dysfunction was not associated with SPA incompleteness (P=0.77). CONCLUSIONS: Although incompleteness of the SPA is common, digital blood supply is always preserved by a complete deep palmar arch. Preprocedural patency tests have thus no added benefit to prevent ischemic complications of the hand. Finally, incompleteness of the SPA is not associated with a loss of upper-extremity function after transradial catheterization. PMID- 29127119 TI - RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non-Small Cell Lung Carcinomas Sensitive to MEK Inhibition. AB - Purpose: Ras-GTPase-activating proteins (RasGAP), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of non-small cell lung carcinoma (NSCLC) with RASA1 mutations in comparison with NF1-mutated cases.Experimental Design: Large genomic datasets of NSCLC [MSK-IMPACT dataset at MSKCC (n = 2,004), TCGA combined lung cancer dataset (n = 1,144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBEC) and NSCLC lines with truncating mutations in RASA1, NF1, or both.Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (P = 0.02) and KRAS (P = 0.02) mutations. Unexpectedly, RASA1-truncating mutations had a strong tendency to co occur with NF1-truncating mutations (P < 0.001). Furthermore, all patients (16/16) with concurrent RASA1/NF1-truncating mutations lacked other known lung cancer drivers. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RASA1 mutated cells reduced MAPK and PI3K signaling. Although growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040 MUmol/L trametinib). Finally, simultaneous genetic silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition.Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss-of-function mutations as a strong mitogenic driver in NSCLC, which may sensitize to trametinib. Clin Cancer Res; 24(6); 1436 47. (c)2017 AACRSee related commentary by Kitajima and Barbie, p. 1243. PMID- 29127116 TI - Predicting Mortality After Transcatheter Aortic Valve Replacement: External Validation of the Transcatheter Valve Therapy Registry Model. AB - BACKGROUND: The Transcatheter Valve Therapy (TVT) registry model was recently developed to predict the risk of in-hospital mortality in patients undergoing transcatheter aortic valve replacement. We sought to externally validate the model in an independent data set of consecutively enrolled patients in the Swiss Transcatheter Aortic Valve Implantation registry. METHODS AND RESULTS: The original prediction model was retrospectively applied to 3491 consecutive patients undergoing transcatheter aortic valve replacement in Switzerland between February 2011 and February 2016. We examined model performance in terms of discrimination (Harrel C index) and calibration (Hosmer-Lemeshow goodness-of-fit test) for prediction of in-hospital and 30-day mortality and compared its predictive accuracy with the Society of Thoracic Surgeons Predicted Risk of Mortality score. Rates of in-hospital and 30-day mortality in the external validation cohort were 2.9% and 3.8%, respectively. The TVT registry model was found to have moderate discrimination (C index, 0.66; 95% confidence interval, 0.60-0.72 and C index, 0.67; 95% confidence interval, 0.62-0.72 for in-hospital and 30-day mortality, respectively) and good calibration. Compared with the Society of Thoracic Surgeons Predicted Risk of Mortality score, the TVT registry model demonstrated improved calibration for in-hospital (slope, 0.83; P=0.23 versus slope, 0.24; P<0.001, respectively) and 30-day (slope, 1.11; P=0.40 versus slope, 0.41; P<0.001, respectively) mortality. CONCLUSIONS: In a large, multicenter, non-US cohort of patients with transcatheter aortic valve replacement, the validation of the TVT registry model demonstrated moderate discrimination and good calibration for the prediction of in-hospital and 30-day mortality. As a result, the TVT registry model should be considered an alternative to the Society of Thoracic Surgeons Predicted Risk of Mortality score for decision making and assessment of early outcome in patients eligible for transcatheter aortic valve replacement. PMID- 29127120 TI - Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma. AB - Immune checkpoint inhibitors have revolutionized the treatment of patients with advanced-stage metastatic melanoma, as well as patients with many other solid cancers, yielding long-lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed "acquired resistance"), whereas others do not respond at all (termed "primary resistance"). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma, and the known mechanisms underlying each involves various components of the cancer immune cycle, and interactions between multiple signaling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma and detail potential therapeutic strategies to prevent and overcome them. Clin Cancer Res; 24(6); 1260-70. (c)2017 AACR. PMID- 29127122 TI - Enhancing the residency interview process with the inclusion of standardised questions. PMID- 29127123 TI - Dermoscopy of pseudoxanthoma elasticum. PMID- 29127124 TI - Selective aplasia of global fibres of all extraocular muscles in congenital fibrosis of extraocular muscles (CFEOM): a rare presentation. PMID- 29127125 TI - Vancomycin-resistant Enterococcus faecium bacteraemia as a complication of Kayexalate (sodium polystyrene sulfonate, SPS) in sorbitol-induced ischaemic colitis. AB - We present the case report of an 80-year-old woman with chronic kidney disease stage G5 admitted to the hospital with fluid overload and hyperkalaemia. Sodium polystyrene sulfonate (SPS, Kayexalate) in sorbitol suspension was given orally to treat her hyperkalaemia, which precipitated an episode of SPS in sorbitol induced ischaemic colitis with the subsequent complication of vancomycin resistant Enterococcus (VRE) bacteraemia. SPS (Kayexalate) in sorbitol suspension has been implicated in the development of intestinal necrosis. Sorbitol, which is added as a cathartic agent to decrease the chance of faecal impaction, may be primarily responsible through several proposed mechanisms. The gold standard of diagnosis is the presence of SPS crystals in the colon biopsy. On a MEDLINE search, no previous reports of a VRE bacteraemia as a complication of biopsy confirmed SPS in sorbitol ischaemic colitis were found. To the best of our knowledge, ours would be the first such case ever reported. PMID- 29127121 TI - Protein Kinase C Epsilon Is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia. AB - Purpose: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown.Experimental Design: Utilizing several chemical and genetically encoded redox sensing probes across multiple human and mouse models of AML, we evaluated the role of the serine/threonine kinase PKC-epsilon (PKCepsilon) in intracellular redox biology, cell survival and disease progression.Results: We show that RNA interference-mediated inhibition of PKCepsilon significantly reduces patient-derived AML cell survival as well as disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. We also show that PKCepsilon inhibition induces multiple reactive oxygen species (ROS) and that neutralization of mitochondrial ROS with chemical antioxidants or co expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigates the anti-leukemia effects of PKCepsilon inhibition. Moreover, direct inhibition of SOD2 increases mitochondrial ROS and significantly impedes AML progression in vivo Furthermore, we report that PKCepsilon over-expression protects AML cells from otherwise-lethal doses of mitochondrial ROS-inducing agents. Proteomic analysis reveals that PKCepsilon may control mitochondrial ROS by controlling the expression of regulatory proteins of redox homeostasis, electron transport chain flux, as well as outer mitochondrial membrane potential and transport.Conclusions: This study uncovers a previously unrecognized role for PKCepsilon in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML. Clin Cancer Res; 24(3); 608-18. (c)2017 AACR. PMID- 29127126 TI - Atraumatic bilateral humeral head fracture secondary to single seizure. PMID- 29127127 TI - Abrikossoff's tumour on the upper limb: a rare presentation. AB - Abrikossoff's tumour or granular cell tumour is a rare entity. Most common locations are the head and neck, with only a few cases reported on the upper limbs. A 55-year-old man with a nodular lesion on the left arm resorted to surgery consultation. Nodule was firm, mobile, painless and non-ulcerated. Total excision using a Limberg flap procedure was performed. Following 3 months of follow-up, the patient is fine. Abrikossoff's tumour is frequently presented in the second to sixth decade of life as an ulcerated nodule with progressive growth. Malignant form is rare, with metastases occurring in up to 3% of patients. Excision must be accomplished with free margins. Recurrence is rare. Abrikossoff's tumour on the upper limbs is rare. Although benignity is the rule, doctors must be aware of the possibility of harbouring a cancer. Surgery is the treatment of choice. PMID- 29127129 TI - Heart failure in dilated cardiomyopathy mimicking asthma triggered by pneumonia. AB - Heart failure is a rare cause of wheezing and may develop into a critical condition in children. Few cases report patients with heart failure, secondary to dilated cardiomyopathy, with high fever. A 23-month-old girl visited the emergency department with high fever, cough, first wheezing episode, chest retraction and tachycardia. The chest X-ray revealed consolidation on the left lower lung field; the cardiothoracic ratio was 60%. She was diagnosed with bronchial asthma triggered by pneumonia, which remained unchanged during four visits. Subsequently, she was diagnosed with heart failure in idiopathic dilated cardiomyopathy and discharged without sequelae. During the first wheezing episode in children with abnormal vital signs, heart failure should be considered in the differential diagnosis, and a chest X-ray should be performed. Additionally, when the cardiothoracic ratio is greater than 50%, 12-lead ECG and echocardiography should be performed. Moreover, cognitive bias should be considered in all emergency care unit situations. PMID- 29127128 TI - All sorts of tests, only one question: an unexpected cause of hypertension. AB - A 48-year-old woman presented to the Accident and Emergency department with a 4 month history of headaches, nausea and dizziness. She was found to have severe hypertension and hypokalaemia. Extensive investigations did not find any secondary cause for hypertension. The patient was discharged with oral doxazosin therapy which controlled the blood pressure. Before the follow-up appointment at the hypertension clinic, the patient and her husband identified that her headaches coincided with liquorice tea consumption of up to three cups per day. This information was not obtained in the clinical assessment. The patient is now headache and medication free after cessation of liquorice tea. Liquorice ingestion is often a forgotten reversible cause of hypertension. A good history is key to this diagnosis. PMID- 29127130 TI - Eosinophilic oesophagitis and coeliac disease: is there an association? AB - A 25-year-old man was seen in outpatient clinic for progressive solid food dysphagia. He was already medicated with a proton pump inhibitor with no improvement. His blood tests showed a slight microcytic anaemia and peripheral eosinophilia. The oesophago-gastro-duodenoscopy showed longitudinal furrows in the distal two-thirds of the oesophagus and a concentric distal stenosis. The biopsies taken showed eosinophilic infiltrates consistent with eosinophilic oesophagitis. There was no improvement with topical fluticasone, so the patient was started on a systemic corticosteroid with resolution of dysphagia and of the oesophageal stenosis. He was kept on topical steroids for symptomatic control. On repeat endoscopy, the duodenal mucosa showed multiple papules that were biopsied. Histology showed features consistent with coeliacdisease. The patient was asymptomatic but there was evidence of iron deficiency anaemia, and so a gluten free diet was started. Despite only a partial adherence to the diet, the iron deficiency anaemia resolved. PMID- 29127131 TI - Giant atrium, giant clot: need for anticoagulation. PMID- 29127132 TI - Pleomorphic sarcoma of the breast. PMID- 29127133 TI - Nephrotic syndrome and acute kidney injury induced by malathion toxicity. AB - We treated a case of acute kidney injury and nephrotic syndrome after malathion inhalation. A 69-year-old Japanese man presented with oedema 15 days after inhalation of malathion, a widely used pesticide. Serum albumin was 2.4 g/dL, urinary protein 8.6 g/gCr and serum creatinine 2.5 mg/dL. Kidney biopsy revealed tubular cell damage, epithelial cell damage in glomeruli and diffuse foot process effacement in electron microscopy. Acute kidney injury progressed to treatment with dialysis. Renal function recovered after corticosteroid administration from the 43rd day after admission. Malathion inhalation should be ruled out as a differential diagnosis in individuals who develop acute kidney injury and nephrotic syndrome, especially in rural-dwelling patients. PMID- 29127134 TI - Radiation retinopathy treated successfully with aflibercept. AB - Aflibercept (aflibercept) is a novel anti-vascular endothelial growth factor drug indicated for wet age-related macular degeneration and macular oedema secondary to retinal vein occlusion and diabetic macular oedema. While only newly introduced on the market, it is growing in popularity and over 5.5 million doses have been prescribed worldwide. Due to its versatile mechanism, it is indicated for numerous eye pathologies, and in particular, has been adapted to treat various types of retinopathy. To our knowledge, this is the first case report of solely using aflibercept to treat cystoid macular oedema in radiation retinopathy. PMID- 29127135 TI - Traditional Chinese medicine-facilitated treatments may relieve anxiety symptoms during drug switching from methadone to buprenorphine/naloxone for treating opioid dependence. AB - This study investigated a 51-year-old married man with a history of heroin dependence who underwent methadone maintenance treatment for 7 years. He received traditional Chinese medicine (TCM)-facilitated treatments and switched from methadone to buprenorphine/naloxone. Strong anxiety symptoms were observed during the initial stage; therefore, we prescribed a combination of Chaihu-Shugan-San, Zhi Bai Di Huang and Chin-Gin-Kuan-Ming decoction as the major herbal synergic regimen to relieve the symptoms of opioid withdrawal, anxiety and insomnia. During the treatment course, no precipitating withdrawal syndromes were noted, and the subject was gradually relieved of his anxiety symptoms through continual TCM treatments. In conclusion, TCM is effective in facilitating the switch from methadone to buprenorphine/naloxone and relieving anxiety symptoms. Therefore, focus on TCM-facilitated treatments for heroin dependence should be increased. PMID- 29127136 TI - Tuberculosis epididymitis complicated by a cutaneous fistula. AB - A 63-year-old man developed scrotal swelling that became bilateral over 2 months. His symptoms persisted after treatment for epididymitis, and he developed a scrotal fistula with drainage. Mycobacterium tuberculosis grew from the urine and fistula. His symptoms resolved and fistula closed with medical therapy. His case highlights the importance of early recognition, diagnosis and treatment of this form of extrapulmonary tuberculosis. PMID- 29127137 TI - Ethics of treatment interruption trials in HIV cure research: addressing the conundrum of risk/benefit assessment. AB - Though antiretroviral therapy is the standard of care for people living with HIV, its treatment limitations, burdens, stigma and costs lead to continued interest in HIV cure research. Early-phase cure trials, particularly those that include analytic treatment interruption (ATI), involve uncertain and potentially high risk, with minimal chance of clinical benefit. Some question whether such trials should be offered, given the risk/benefit imbalance, and whether those who choose to participate are acting rationally. We address these questions through a longitudinal decision-making study nested in a Thai acute HIV research cohort.In depth interviews revealed central themes about decisions to join. Participants felt they possessed an important identity as members of the acute cohort, viewing their bodies as uniquely suited to both testing and potentially benefiting from HIV cure approaches. While acknowledging risks of ATI, most perceived they were given an opportunity to interrupt treatment, to test their own bodies and increase normalcy in a safe, highly monitored circumstance. They were motivated by potential benefits to themselves, the investigators and larger acute cohort, and others with HIV. They believed their own trial experiences and being able to give back to the community were sufficient to offset participation risks.These decisions were driven by the specific circumstances experienced by our participants. Judging risk/benefit ratios without appreciating these lived experiences can lead to false determinations of irrational decision- making. While this does not minimise vital oversight considerations about risk reduction and protection from harm, it argues for inclusion of a more participant-centered approach. PMID- 29127138 TI - delta-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy. AB - OBJECTIVE: To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE). METHODS: We performed exome sequencing for 3 patients of our FCMTE family. Next, we performed knock-down (shRNA) and rescue experiments by overexpressing wild-type and mutant human delta catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain. RESULTS: We identified a missense mutation, p.Glu1044Lys, in the CTNND2 gene that cosegregated with the FCMTE phenotype. The knock-down of Ctnnd2 in cultured cortical mouse neurons revealed increased neurite outgrowth that was rescued by overexpression of wild type, but not mutant, CTNND2 and was reminiscent of the morphologic abnormalities observed in cerebellar Purkinje cells from patients with FCMTE. CONCLUSIONS: We propose CTNND2 as the causal gene in FCMTE3. Functional testing of the mutant protein revealed abnormal neuronal sprouting, consistent with the abnormal cerebellar Purkinje cell morphology in patients with FCMTE. PMID- 29127139 TI - Conference presentation in palliative medicine: predictors of subsequent publication. AB - OBJECTIVES: Concerns have been raised about poor-quality palliative care research and low publication rate from conference abstracts. The study objectives: to estimate the publication rate for European Association for Palliative Care research conference abstracts (2008) and explore associated characteristics and to understand reasons for non-publication. METHODS: Full published papers were searched to March 2015 (Medline; Pubmed; Google Scholar) and data extracted: country of origin, study design/population/topic. Multivariate logistic regression was used to identify predictors of publication.Members of two different palliative care associations were surveyed to understand reasons for non-publication. chi2 statistic was used to explore associations with publication. RESULTS: Overall publication rate of the 445 proffered abstracts was 57%. In the final model, publication was more likely for oral presentations (OR 2.13; 95% CI 1.28 to 3.55; P=0.003), those from Europe (3.24; 1.09 to 9.56; P=0.033) and much less likely for non-cancer topics (0.21; 0.07 to 0.64; P=0.006). Funding status, academic unit or study design were not associated with publication. SURVEY: 407/1546 (26.3%) physicians responded of whom 254 (62%) had submitted a conference abstract. Full publication was associated with: oral presentation (P<0.001), international conference abstracts (P=0.01) and academic clinicians versus clinicians (P<0.001). Reasons for non-publication included: low priority for workload (53%) and time constraints (43%). CONCLUSIONS: The publication rate was similar to 2005 clinical conference. Probable quality markers were associated with publication: oral presentations selected by conference committee, international conference abstracts and abstracts from those with an academic appointment. Publication was given a low priority among clinical time pressures. PMID- 29127140 TI - Cancer genes mutation profiling in calcifying epithelial odontogenic tumour. AB - AIMS: To identify calcifying epithelial odontogenic tumour (CEOT) mutations in oncogenes and tumour suppressor genes. METHODS: A panel of 50 genes commonly mutated in cancer was sequenced in CEOT by next-generation sequencing. Sanger sequencing was used to cover the region of the frameshift deletion identified in one sample. RESULTS: Missense single nucleotide variants (SNVs) with minor allele frequency (MAF) <1% were detected in PTEN, MET and JAK3. A frameshift deletion in CDKN2A occurred in association with a missense mutation in the same gene region, suggesting a second hit in the inactivation of this gene. APC, KDR, KIT, PIK3CA and TP53 missense SNVs were identified; however, these are common SNVs, showing MAF >1%. CONCLUSION: CEOT harbours mutations in the tumour suppressor PTEN and CDKN2A and in the oncogenes JAK3 and MET. As these mutations occurred in only one case each, they are probably not driver mutations for these tumours. PMID- 29127141 TI - Copper deposition in focal nodular hyperplasia and inflammatory hepatocellular adenoma. AB - AIMS: To examine copper deposition in focal nodular hyperplasia (FNH) and inflammatory hepatocellular adenoma (IHA) and to determine if it can play a role in their differentiation. METHODS: 28 FNHs and 19 IHAs from surgical resections showing typical morphological and immunohistochemical features were stained with rhodanine to evaluate for copper deposition. Histological features such as nodularity, fibrous bands, ductular proliferation, steatosis, ballooned hepatocytes and lymphocytic inflammation were also scored. RESULTS: Copper deposition was detected in 96% (27/28) of FNHs and 37% (7/19) of IHAs, P<0.001. In all cases, copper was seen within the hepatocytes only around the pseudo portal tracts or areas of fibrosis. Copper deposition in IHA was significantly associated with presence of lymphocytic inflammation (P=0.04) but not associated with features like nodularity, fibrous bands, ductular proliferation, ballooned hepatocytes and steatosis (P>0.05, for all). In FNH, the presence and degree of copper deposition was not significantly associated with any histological features (P>0.05, for all). CONCLUSIONS: Copper deposition occurs more frequently in FNH (96%) than IHA (37%), P<0.001. However, the presence of copper alone cannot be used as a feature to differentiate between FNH and IHA. PMID- 29127142 TI - Can reference images improve interobserver agreement in reporting liver fibrosis? AB - Staging of fibrosis in medical liver biopsies has inherent interobserver variability. There are a number of disease-specific scoring systems available. While recognising the importance of these scoring systems, there is scope to consider how concordance amongst histopathologists could be improved using a generic fibrosis staging system.Using virtual slides, we approached both specialist liver histopathologists and general histopathologists from the UK to assess the degree of fibrosis against a proposed four-tiered reporting system. Example reference images were then produced and distributed to the same responders who were asked to rate a second set of slides to assess if the use of reference images improved concordance between pathologists.The use of reference images eliminated spread across three categories (from 15% to 0%). Overall, agreement was already good; our study showed an improved agreement amongst all participants for percentage agreement (67.79% to 70.08%) and interobserver agreement improved (Fleiss' Kappa 0.55 to 0.59). PMID- 29127143 TI - SATB1 Conditional Knockout Results in Sjogren's Syndrome in Mice. AB - Sjogren's syndrome (SS) is an autoimmune disease in which exocrine tissues are affected by cellular and humoral immunity. As a result, the salivary and lacrimal glands of patients with SS are damaged, leading to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Because experimental approaches to investigate SS pathogenesis in human patients are limited, development of a mouse model is indispensable for understanding the disease. In this study, we show that special AT-rich sequence binding protein-1 conditional knockout (SATB1cKO) mice, in which the SATB1 gene is specifically deleted from hematopoietic cells, develop SS by 4 wk of age, soon after weaning. Female mice presented an earlier onset of the disease than males, suggesting that female SATB1cKO mice are more susceptible to SS. T cell-dominant immune cell infiltration was observed in the salivary glands of 4 wk old SATB1cKO mice, and the frequency of B cells gradually increased as the mice aged. Consistently, levels of anti-SSA and anti-SSB Abs were increased around 8 wk of age, after salivary production reached its lowest level in SATB1cKO mice. These results suggest that SATB1cKO mice can be a novel SS model, in which the progression and characteristics of the disease resemble those of human SS. PMID- 29127144 TI - Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B. AB - Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott-Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency. Here, we describe two brothers with hematopoietic and immunologic symptoms reminiscent of Wiskott Aldrich syndrome (WAS). However, these patients lacked mutations in any of the genes previously associated with WAS. Whole-exome sequencing revealed a homozygous 2 bp deletion, n.c.G623DEL-TC (p.V208VfsX20), in Arp2/3 complex component ARPC1B that causes a frame shift resulting in premature termination. Modeling of the disease in zebrafish revealed that ARPC1B plays a critical role in supporting T cell and thrombocyte development. Moreover, the defects in development caused by ARPC1B loss could be rescued by the intact human ARPC1B ortholog, but not by the p.V208VfsX20 variant identified in the patients. Moreover, we found that the expression of ARPC1B is restricted to hematopoietic cells, potentially explaining why a mutation in ARPC1B has now been observed as a cause of WAS, whereas mutations in other, more widely expressed, components of the Arp2/3 complex have not been observed. PMID- 29127145 TI - TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen Specific CD8 T Cells by Activating mTORC1. AB - T cell expression of TIM-3 following Ag encounter has been associated with a continuum of functional states ranging from effector memory T cells to exhaustion. We have designed an in vitro culture system to specifically address the impact of anti-TIM-3/TIM-3 engagement on human Ag-specific CD8 T cells during a normal response to Ag and found that anti-TIM-3 treatment enhances T cell function. In our in vitro T cell culture system, MART1-specific CD8 T cells were expanded from healthy donors using artificial APCs. To ensure that the T cells were the only source of TIM-3, cells were rechallenged with peptide-loaded artificial APCs in the presence of anti-TIM-3 Ab. In these conditions, anti-TIM-3 treatment promotes generation of effector T cells as shown by acquisition of an activated phenotype, increased cytokine production, enhanced proliferation, and a transcription program associated with T cell differentiation. Activation of mTORC1 has been previously demonstrated to enhance CD8 T cell effector function and differentiation. Anti-TIM-3 drives CD8 T cell differentiation through activation of the mTORC1 as evidenced by increased levels of phosphorylated S6 protein and rhebl1 transcript. Altogether these findings suggest that anti-TIM-3, together with Ag, drives differentiation in favor of effector T cells via the activation of mTOR pathway. To our knowledge, this is the first report demonstrating that TIM-3 engagement during Ag stimulation directly influences T cell differentiation through mTORC1. PMID- 29127146 TI - Cutting Edge: Processing of Oxidized Peptides in Macrophages Regulates T Cell Activation and Development of Autoimmune Arthritis. AB - APCs are known to produce NADPH oxidase (NOX) 2-derived reactive oxygen species; however, whether and how NOX2-mediated oxidation affects redox-sensitive immunogenic peptides remains elusive. In this study, we investigated a major immunogenic peptide in glucose-6-phosphate isomerase (G6PI), a potential autoantigen in rheumatoid arthritis, which can form internal disulfide bonds. Ag presentation assays showed that presentation of this G6PI peptide was more efficient in NOX2-deficient (Ncf1m1J/m1J mutant) mice, compared with wild-type controls. IFN-gamma-inducible lysosomal thiol reductase (GILT), which facilitates disulfide bond-containing Ag processing, was found to be upregulated in macrophages from Ncf1 mutant mice. Ncf1 mutant mice exhibited more severe G6PI peptide-induced arthritis, which was accompanied by the increased GILT expression in macrophages and enhanced Ag-specific T cell responses. Our results show that NOX2-dependent processing of the redox-sensitive autoantigens by APCs modify T cell activity and development of autoimmune arthritis. PMID- 29127148 TI - Ubc9 Binds to ADAP and Is Required for Rap1 Membrane Recruitment, Rac1 Activation, and Integrin-Mediated T Cell Adhesion. AB - Although the immune adaptor adhesion and degranulation-promoting adaptor protein (ADAP) acts as a key mediator of integrin inside-out signaling leading to T cell adhesion, the regulation of this adaptor during integrin activation and clustering remains unclear. We now identify Ubc9, the sole small ubiquitin related modifier E2 conjugase, as an essential regulator of ADAP where it is required for TCR-induced membrane recruitment of the small GTPase Rap1 and its effector protein RapL and for activation of the small GTPase Rac1 in T cell adhesion. We show that Ubc9 interacted directly with ADAP in vitro and in vivo, and the association was increased in response to anti-CD3 stimulation. The Ubc9 binding domain on ADAP was mapped to a nuclear localization sequence (aa 674-700) within ADAP. Knockdown of Ubc9 by short hairpin RNA or expression of the Ubc9 binding-deficient ADAP mutant significantly decreased TCR-induced integrin adhesion to ICAM-1 and fibronectin, as well as LFA-1 clustering, although it had little effect on the TCR proximal signaling responses and TCR-induced IL-2 transcription. Furthermore, downregulation of Ubc9 impaired TCR-mediated Rac1 activation and attenuated the membrane targeting of Rap1 and RapL, but not Rap1 interacting adaptor molecule. Taken together, our data demonstrate for the first time, to our knowledge, that Ubc9 acts as a functional binding partner of ADAP and plays a selective role in integrin-mediated T cell adhesion via modulation of Rap1-RapL membrane recruitment and Rac1 activation. PMID- 29127147 TI - IgG1 Is Required for Optimal Protection after Immunization with the Purified Porin OmpD from Salmonella Typhimurium. AB - In mice, the IgG subclass induced after Ag encounter can reflect the nature of the Ag. Th2 Ags such as alum-precipitated proteins and helminths induce IgG1, whereas Th1 Ags, such as Salmonella Typhimurium, predominantly induce IgG2a. The contribution of different IgG isotypes to protection against bacteria such as S. Typhimurium is unclear, although as IgG2a is induced by natural infection, it is assumed this isotype is important. Previously, we have shown that purified S. Typhimurium porins including outer membrane protein OmpD, which induce both IgG1 and IgG2a in mice, provide protection to S. Typhimurium infection via Ab. In this study we report the unexpected finding that mice lacking IgG1, but not IgG2a, are substantially less protected after porin immunization than wild-type controls. IgG1-deficient mice produce more porin-specific IgG2a, resulting in total IgG levels that are similar to wild-type mice. The decreased protection in IgG1 deficient mice correlates with less efficient bacterial opsonization and uptake by macrophages, and this reflects the low binding of outer membrane protein OmpD specific IgG2a to the bacterial surface. Thus, the Th2-associated isotype IgG1 can play a role in protection against Th1-associated organisms such as S. Typhimurium. Therefore, individual IgG subclasses to a single Ag can provide different levels of protection and the IgG isotype induced may need to be a consideration when designing vaccines and immunization strategies. PMID- 29127150 TI - Cutting Edge: c-Maf Is Required for Regulatory T Cells To Adopt RORgammat+ and Follicular Phenotypes. AB - Regulatory T cells (Tregs) adopt specialized phenotypes defined by coexpression of lineage-defining transcription factors, such as RORgammat, Bcl-6, or PPARgamma, alongside Foxp3. These Treg subsets have unique tissue distributions and diverse roles in maintaining organismal homeostasis. However, despite extensive functional characterization, the factors driving Treg specialization are largely unknown. In this article, we show that c-Maf is a critical transcription factor regulating this process in mice, essential for generation of both RORgammat+ Tregs and T follicular regulatory cells, but not for adipose resident Tregs. c-Maf appears to function primarily in Treg specialization, because IL-10 production, expression of other effector molecules, and general immune homeostasis are not c-Maf dependent. As in other T cells, c-Maf is induced in Tregs by IL-6 and TGF-beta, suggesting that a combination of inflammatory and tolerogenic signals promote c-Maf expression. Therefore, c-Maf is a novel regulator of Treg specialization, which may integrate disparate signals to facilitate environmental adaptation. PMID- 29127149 TI - Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis. AB - Regnase-1 and Roquin are RNA binding proteins that are essential for degradation of inflammatory mRNAs and maintenance of immune homeostasis. Although deficiency of either of the proteins leads to enhanced T cell activation, their functional relationship in T cells has yet to be clarified because of lethality upon mutation of both Regnase-1 and Roquin. By using a Regnase-1 conditional allele, we show that mutations of both Regnase-1 and Roquin in T cells leads to massive lymphocyte activation. In contrast, mutation of either Regnase-1 or Roquin affected T cell activation to a lesser extent than the double mutation, indicating that Regnase-1 and Roquin function nonredundantly in T cells. Interestingly, Regnase-1 and Roquin double-mutant mice suffered from severe inflammation and early formation of fibrosis, especially in the heart, along with the increased expression of Ifng, but not Il4 or Il17a Consistently, mutation of both Regnase-1 and Roquin leads to a huge increase in the Th1, but not the Th2 or Th17, population in spleens compared with T cells with a single Regnase-1 or Roquin deficiency. Regnase-1 and Roquin are capable of repressing the expression of a group of mRNAs encoding factors involved in Th1 differentiation, such as Furin and Il12rb1, via their 3' untranslated regions. Moreover, Regnase-1 is capable of repressing Roquin mRNA. This cross-regulation may contribute to the synergistic control of T cell activation/polarization. Collectively, our results demonstrate that Regnase-1 and Roquin maintain T cell immune homeostasis and regulate Th1 polarization synergistically. PMID- 29127152 TI - Objective cardiovascular assessment in the neonatal intensive care unit. AB - Traditionally, cardiovascular well-being was essentially based on whether the mean blood pressure was above or below a certain value. However, this singular crude method of assessment provides limited insight into overall cardiovascular well-being. Echocardiography has become increasingly used and incorporated into clinical care. New objective modality assessments of cardiovascular status continue to evolve and are being evaluated and incorporated into clinical care. In this review article, we will discuss some of the recent advances in objective assessment of cardiovascular well-being, including the concept of multimodal monitoring. Sophisticated haemodynamic monitoring systems are being developed, including mechanisms of data acquisition and analysis. Their incorporation into clinical care represents an exciting next stage in the management of the infant with cardiovascular compromise. PMID- 29127151 TI - Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells. AB - Copper has previously been implicated in the regulation of immune responses, but the impact of this metal on mast cells is poorly understood. In this article, we address this issue and show that copper starvation of mast cells causes increased granule maturation, as indicated by higher proteoglycan content, stronger metachromatic staining, and altered ultrastructure in comparison with nontreated cells, whereas copper overload has the opposite effects. In contrast, copper status did not impact storage of histamine in mast cells, nor did alterations in copper levels affect the ability of mast cells to degranulate in response to IgER cross-linking. A striking finding was decreased tryptase content in mast cells with copper overload, whereas copper starvation increased tryptase content. These effects were associated with corresponding shifts in tryptase mRNA levels, suggesting that copper affects tryptase gene regulation. Mechanistically, we found that alterations in copper status affected the expression of microphthalmia associated transcription factor, a transcription factor critical for driving tryptase expression. We also found evidence supporting the concept that the effects on microphthalmia-associated transcription factor are dependent on copper mediated modulation of MAPK signaling. Finally, we show that, in MEDNIK syndrome, a condition associated with low copper levels and a hyperallergenic skin phenotype, including pruritis and dermatitis, the number of tryptase-positive mast cells is increased. Taken together, our findings reveal a hitherto unrecognized role for copper in the regulation of mast cell gene expression and maturation. PMID- 29127153 TI - Analysis of unsuccessful intubations in neonates using videolaryngoscopy recordings. AB - OBJECTIVES: Neonatal intubation is a difficult skill to learn and teach. If an attempt is unsuccessful, the intubator and instructor often cannot explain why. This study aims to review videolaryngoscopy recordings of unsuccessful intubations and explain the reasons why attempts were not successful. STUDY DESIGN: This is a descriptive study examining videolaryngoscopy recordings obtained from a randomised controlled trial that evaluated if neonatal intubation success rates of inexperienced trainees were superior if they used a videolaryngoscope compared with a laryngoscope. All recorded unsuccessful intubations were included and reviewed independently by two reviewers blinded to study group. Their assessment was correlated with the intubator's perception as reported in a postintubation questionnaire. The Cormack-Lehane classification system was used for objective assessment of laryngeal view. RESULTS: Recordings and questionnaires from 45 unsuccessful intubations were included (15 intervention and 30 control). The most common reasons for an unsuccessful attempt were oesophageal intubation and failure to recognise the anatomy. In 36 (80%) of intubations, an intubatable view was achieved but was then either lost, not recognised or there was an apparent inability to correctly direct the endotracheal tube. Suctioning was commonly performed but rarely improved the view. CONCLUSIONS: Lack of intubation success was most commonly due to failure to recognise midline anatomical structures. Trainees need to be taught to recognise the uvula and epiglottis and use these landmarks to guide intubation. Excessive secretions are rarely a factor in elective and premedicated intubations, and routine suctioning should be discouraged. Better blade design may make it easier to direct the tube through the vocal cords. PMID- 29127154 TI - Stability of general cognition in children born extremely preterm as they grow older: good or bad news? PMID- 29127155 TI - Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. AB - The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients-including Tsc2-thereby preventing their ubiquitination and proteasomal degradation. PMID- 29127158 TI - No evidence for homeopathy, says RCVS. PMID- 29127157 TI - Introducing Vet Record' s new look. PMID- 29127161 TI - Putting vets on shortage occupation list is an 'immediate priority', say vet leaders. PMID- 29127156 TI - MYC and tumor metabolism: chicken and egg. AB - Transcription factors of the MYC family are deregulated in the majority of all human cancers. Oncogenic levels of MYC reprogram cellular metabolism, a hallmark of cancer development, to sustain the high rate of proliferation of cancer cells. Conversely, cells need to modulate MYC function according to the availability of nutrients, in order to avoid a metabolic collapse. Here, we review recent evidence that the multiple interactions of MYC with cell metabolism are mutual and review mechanisms that control MYC levels and function in response to metabolic stress situations. The main hypothesis we put forward is that regulation of MYC levels is an integral part of the adaptation of cells to nutrient deprivation. Since such mechanisms would be particularly relevant in tumor cells, we propose that-in contrast to growth factor-dependent controls-they are not disrupted during tumorigenesis and that maintaining flexibility of expression is integral to MYC's oncogenic function. PMID- 29127164 TI - 'You are in a position to make a real difference'. AB - Georgina Mills outlines the key messages from next week's antibiotic awareness campaign that aims to ensure antibiotics are preserved for our future. PMID- 29127172 TI - Botulism outbreak causes high mortality in Scottish cattle. AB - SAc C VS disease Surveillance report for july 2017 Botulism in finishing cattleSeasonal dermatitis in Cheviot ewesStreptococcus suis type 2 meningitis and septicaemia in pigletsRodenticide toxicity in chickens. PMID- 29127173 TI - Antimicrobial resistance in animal agriculture: understanding user attitudes and behaviours. PMID- 29127175 TI - Confirmation of squirrelpox in Welsh red squirrels. PMID- 29127176 TI - Benchmarking antimicrobial use. PMID- 29127177 TI - What is the connection between human and animal abuse? PMID- 29127178 TI - Rabbit haemorrhagic disease in the UK. PMID- 29127179 TI - What is your client thinking and why should you care? AB - Zoe Belshaw is coordinating our new series that gives an insight into what clients' experiences are and how you can help them. Here, she outlines how the series came into being. PMID- 29127181 TI - A true moderniser of equine practice. AB - Peter Rossdale recently celebrated his 90th birthday. Tim Greet describes the career of this pioneering equine vet. PMID- 29127180 TI - Labour and love for Mr Pink. AB - Louise Locock describes the challenges and rewards of caring for her cat with chronic kidney disease. PMID- 29127184 TI - Cardiac troponin: the next tool for cardiovascular disease prevention in ambulatory patients? PMID- 29127183 TI - Genome-wide association study of PR interval in Hispanics/Latinos identifies novel locus at ID2. AB - OBJECTIVE: PR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies. METHODS: Study-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry, study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results. RESULTS: We identified a novel genome-wide association (P<5*10-8) with PR at ID2 (rs6730558), which replicated in Asian and European populations (P<0.017). Additionally, we generalised 10 previously identified PR loci to Hispanics/Latinos. Bioinformatics annotation provided evidence for regulatory function in cardiac tissue. Further, for six loci that generalised, the Hispanic/Latino index SNP was genome-wide significant and identical to (or in high linkage disequilibrium with) the previously identified GWAS lead SNP. CONCLUSIONS: Our results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations. PMID- 29127185 TI - Advances in computational modelling for personalised medicine after myocardial infarction. AB - Myocardial infarction (MI) is a leading cause of premature morbidity and mortality worldwide. Determining which patients will experience heart failure and sudden cardiac death after an acute MI is notoriously difficult for clinicians. The extent of heart damage after an acute MI is informed by cardiac imaging, typically using echocardiography or sometimes, cardiac magnetic resonance (CMR). These scans provide complex data sets that are only partially exploited by clinicians in daily practice, implying potential for improved risk assessment. Computational modelling of left ventricular (LV) function can bridge the gap towards personalised medicine using cardiac imaging in patients with post-MI. Several novel biomechanical parameters have theoretical prognostic value and may be useful to reflect the biomechanical effects of novel preventive therapy for adverse remodelling post-MI. These parameters include myocardial contractility (regional and global), stiffness and stress. Further, the parameters can be delineated spatially to correspond with infarct pathology and the remote zone. While these parameters hold promise, there are challenges for translating MI modelling into clinical practice, including model uncertainty, validation and verification, as well as time-efficient processing. More research is needed to (1) simplify imaging with CMR in patients with post-MI, while preserving diagnostic accuracy and patient tolerance (2) to assess and validate novel biomechanical parameters against established prognostic biomarkers, such as LV ejection fraction and infarct size. Accessible software packages with minimal user interaction are also needed. Translating benefits to patients will be achieved through a multidisciplinary approach including clinicians, mathematicians, statisticians and industry partners. PMID- 29127186 TI - Formyl peptide receptor 2 is regulated by RNA mimics and viruses through an IFN beta-STAT3-dependent pathway. AB - The regulation of host factors is a key strategy employed by viruses to suppress host defense systems and enhance their propagation; however, the mechanisms that underlie this regulation is still unclear. Formyl peptide receptor 2 (FPR2) recognizes numerous proinflammatory and anti-inflammatory stimuli, and emerging reports indicate elevated levels of FPR2 in several disease conditions. Although studies have implicated FPR2 in a myriad of inflammatory conditions, how viruses exploit this cell-surface receptor to facilitate disease progression remains unknown. In this study, we show that the activation of TLR3 and TLR7 induces the up-regulation of FPR2. We provide evidence that signal transducer and activator of transcription 3 (STAT3) phosphorylation is critical for the induction of FPR2 by double-stranded RNA, but not single-stranded RNA viral mimetics. Use of bone marrow-derived macrophages (BMDMs) from IFN-alphabeta receptor-deficient mice revealed that signaling via the type I IFN-STAT3 pathway is essential for FPR2 induction. We demonstrate that virus infection with enterovirus 71 and H1N1 PR8 influenza virus results in increased FPR2 expression. Inhibition of STAT3 phosphorylation in virus-infected cells repressed the induction of FPR2, which led to a reduction in viral loads. Finally, the absence of FPR2 in murine BMDMs resulted in lower viral loads, which suggests that FPR2 may be important for virus replication. Altogether, our study provides novel insights into how RNA viruses may hijack the immune system to facilitate their replication and survival. Identification of these regulatory elements may be useful in designing therapeutics for inflammatory disease conditions that are associated with elevated levels of FPR2.-Ampomah, P. B., Moraes, L. A., Lukman, H. M., Lim, L. H. K. Formyl peptide receptor 2 is regulated by RNA mimics and viruses through an IFN-beta-STAT3-dependent pathway. PMID- 29127187 TI - Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle. AB - Apobec2 is a member of the activation-induced deaminase/apolipoprotein B mRNA editing enzyme catalytic polypeptide cytidine deaminase family expressed in differentiated skeletal and cardiac muscle. We previously reported that Apobec2 deficiency in mice leads to a shift in muscle fiber type, myopathy, and diminished muscle mass. However, the mechanisms of myopathy caused by Apobec2 deficiency and its physiologic functions are unclear. Here we show that, although Apobec2 localizes to the sarcomeric Z-lines in mouse tissue and cultured myotubes, the sarcomeric structure is not affected in Apobec2-deficient muscle. In contrast, electron microscopy reveals enlarged mitochondria and mitochondria engulfed by autophagic vacuoles, suggesting that Apobec2 deficiency causes mitochondrial defects leading to increased mitophagy in skeletal muscle. Indeed, Apobec2 deficiency results in increased reactive oxygen species generation and depolarized mitochondria, leading to mitophagy as a defensive response. Furthermore, the exercise capacity of Apobec2-/- mice is impaired, implying Apobec2 deficiency results in ongoing muscle dysfunction. The presence of rimmed vacuoles in myofibers from 10-mo-old mice suggests that the chronic muscle damage impairs normal autophagy. We conclude that Apobec2 deficiency causes mitochondrial defects that increase muscle mitophagy, leading to myopathy and atrophy. Our findings demonstrate that Apobec2 is required for mitochondrial homeostasis to maintain normal skeletal muscle function.-Sato, Y., Ohtsubo, H., Nihei, N., Kaneko, T., Sato, Y., Adachi, S.-I., Kondo, S., Nakamura, M., Mizunoya, W., Iida, H., Tatsumi, R., Rada, C., Yoshizawa, F. Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle. PMID- 29127188 TI - Epigenetically mediated inhibition of S-adenosylhomocysteine hydrolase and the associated dysregulation of 1-carbon metabolism in nonalcoholic steatohepatitis and hepatocellular carcinoma. AB - The substantial rise in the prevalence of nonalcoholic steatohepatitis (NASH), an advanced form of nonalcoholic fatty liver disease, and the strong association between NASH and the development of hepatocellular carcinoma indicate the urgent need for a better understanding of the underlying mechanisms. In the present study, by using the Stelic animal model of NASH and NASH-derived liver carcinogenesis, we investigated the role of the folate-dependent 1-carbon metabolism in the pathogenesis of NASH. We demonstrated that advanced NASH and NASH-related liver carcinogenesis are characterized by a significant dysregulation of 1-carbon homeostasis, with diminished expression of key 1-carbon metabolism genes, especially a marked inhibition of the S-adenosylhomocysteine hydrolase ( Ahcy) gene and an increased level of S-adenosyl-l-homocysteine (SAH). The reduction in Ahcy expression was associated with gene-specific cytosine DNA hypermethylation and enrichment of the gene promoter by trimethylated histone H3 lysine 27 and deacetylated histone H4 lysine 16, 2 main transcription-inhibiting markers. These results indicate that epigenetically mediated inhibition of Ahcy expression may be a driving force in causing SAH elevation and subsequent downstream disturbances in transsulfuration and transmethylation pathways during the development and progression of NASH.-Pogribny, I. P., Dreval, K., Kindrat, I., Melnyk, S., Jimenez, L., de Conti, A., Tryndyak, V., Pogribna, M., Ortega, J. F., James, S. J., Rusyn, I., Beland, F. A. Epigenetically mediated inhibition of S-adenosylhomocysteine hydrolase and the associated dysregulation of 1-carbon metabolism in nonalcoholic steatohepatitis and hepatocellular carcinoma. PMID- 29127190 TI - Vesicle-mediated secretion of misfolded prion protein molecules from cyclosporin A-treated cells. AB - Loss of protein homeostasis is a hazardous situation that jeopardizes cellular functionality and viability. Cells have developed mechanisms that supervise protein integrity and direct misfolded molecules for degradation. Nevertheless, subsets of aggregation-prone proteins escape degradation and form aggregates that can underlie the development of neurodegenerative disorders. In some cases, cells deposit hazardous protein aggregates in designated sites, like aggresomes, or secrete them with vesicles. The prion protein (PrP) is an aggregation-prone, membrane-anchored glycoprotein, whose aggregation causes familial and sporadic, fatal, neurodegenerative diseases. The proper maturation of PrP is assisted by cyclophilin B, an endoplasmic reticulum-resident foldase. Accordingly, the inhibition of cyclophilins by the drug cyclosporin A (CsA) leads to the accumulation of aggregated PrP and to its deposition in aggresomes. In this study, we asked whether secretion is an alternative strategy that cells adopt to get rid of misfolded PrP molecules and found that, upon treatment with CsA, cells secrete PrP by exosomes, a subtype of secretion vesicles, and by additional types of vesicles. CsA-induced, PrP-containing exosomes originate from the endoplasmic reticulum in a Golgi-independent manner. These findings divulge a new cellular response that is activated upon CsA treatment to secrete misfolded PrP species from the cell and may underlie the spreading of toxic prions among cells and across tissues.-Pan, I., Roitenberg, N., Cohen, E. Vesicle-mediated secretion of misfolded prion protein molecules from cyclosporin A-treated cells. PMID- 29127189 TI - Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer. AB - Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor alpha (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER+ breast cancer cells. PI3K inhibition with GDC 0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor-induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3-only proapoptotic proteins Bim and PUMA. Treatment with GDC-0941, CQ, or the combination, significantly suppressed the growth of ER+ breast cancer xenografts in mice. In an antiestrogen-resistant xenograft model, GDC-0941 synergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER+ breast cancer.-Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer. PMID- 29127191 TI - Dysfunction of different cellular degradation pathways contributes to specific beta-amyloid42-induced pathologies. AB - The endosomal-lysosomal system (ELS), autophagy, and ubiquitin-proteasome system (UPS) are cellular degradation pathways that each play a critical role in the removal of misfolded proteins and the prevention of the accumulation of abnormal proteins. Recent studies on Alzheimer's disease (AD) pathogenesis have suggested that accumulation of aggregated beta-amyloid (Abeta) peptides in the AD brain results from a dysfunction in these cellular clearance systems. However, the specific roles of these pathways in the removal of Abeta peptides and the pathogenesis underlying AD are unclear. Our in vitro and in vivo genetic approaches revealed that ELS mainly removed monomeric beta-amyloid42 (Abeta42), while autophagy and UPS clear oligomeric Abeta42. Although overproduction of phosphatidylinositol 4-phosphate-5 increased Abeta42 clearance, it reduced the life span of Abeta42 transgenic flies. Our behavioral studies further demonstrated impaired autophagy and UPS-enhanced Abeta42-induced learning and memory deficits, but there was no effect on Abeta42-induced reduction in life span. Results from genetic fluorescence imaging showed that these pathways were damaged in the following order: UPS, autophagy, and finally ELS. The results of our study demonstrate that different degradation pathways play distinct roles in the removal of Abeta42 aggregates and in disease progression. These findings also suggest that pharmacologic treatments that are designed to stimulate cellular degradation pathways in patients with AD should be used with caution.-Ji, X.-R., Cheng, K.-C., Chen, Y.-R., Lin, T.-Y., Cheung, C. H. A., Wu, C.-L., Chiang, H.-C. Dysfunction of different cellular degradation pathways contributes to specific beta-amyloid42-induced pathologies. PMID- 29127193 TI - Maintained exercise-enhanced brain executive function related to cerebral lactate metabolism in men. AB - High-intensity interval exercise (HIIE) improves cerebral executive function (EF), but the improvement in EF is attenuated after repeated HIIE, perhaps because of lower lactate availability for the brain. This investigation examined whether improved EF after exercise relates to brain lactate uptake. Fourteen healthy, male subjects performed 2 HIIE protocols separated by 60 min of rest. Blood samples were obtained from the right internal jugular venous bulb and from the brachial artery to determine arterial-venous differences across the brain for lactate (a-v difflactate), glucose (a-v diffglucose), oxygen (a-v diffoxygen), and brain-derived neurotrophic factor (BDNF; a-v diffBDNF). EF was evaluated by the color-word Stroop task. The first HIIE improved EF for 40 min, whereas the second HIIE improved EF only immediately after exercise. The a-v diffglucose was unchanged, whereas the a-v diffBDNF increased similarly after both HIIEs, and the a-v difflactate increased, but the increase was attenuated after the second HIIE, compared with the first HIIE ( P < 0.05). The EF after HIIE correlated with the a v difflactate ( r2 = 0.62; P < 0.01). We propose that attenuated improvement in EF after repeated HIIE relates to reduced cerebral lactate metabolism and is, thereby, linked to systemic metabolism as an example of the lactate shuttle mechanism.-Hashimoto, T., Tsukamoto, H., Takenaka, S., Olesen, N. D., Petersen, L. G., Sorensen, H., Nielsen, H. B., Secher, N. H., Ogoh, S. Maintained exercise enhanced brain executive function related to cerebral lactate metabolism in men. PMID- 29127192 TI - Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes. AB - Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and are synthesized by distinct enzymes, ceramide synthase (CerS)1-CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5-derived ceramides but also in very long chain (VLC) ceramides derived from CerS2. Overexpression of CerS2 elevated VLC ceramides caused insulin resistance, oxidative stress, mitochondrial dysfunction, and mitophagy. Palmitate induced CerS2 and oxidative stress, mitophagy, and apoptosis, which were prevented by depletion of CerS2. Neither overexpression nor knockdown of CerS5 had any function in these processes, suggesting a chain-length dependent impact of ceramides on mitochondrial function. This concept was also supported by the observation that synthetic mitochondria-targeted ceramides led to mitophagy in a manner proportional to N-acyl chain length. Finally, blocking mitophagy exacerbated cell death. Taken together, our results support a model by which CerS2 and VLC ceramides have a distinct role in lipotoxicity, leading to mitochondrial damage, which results in subsequent adaptive mitophagy. Our data reveal a novel lipotoxic pathway through CerS2.-Law, B. A., Liao, X., Moore, K. S., Southard, A., Roddy, P., Ji, R., Szulc, Z., Bielawska, A., Schulze, P. C., Cowart, L. A. Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes. PMID- 29127194 TI - Dump the pump: manual aspiration thrombectomy (MAT) with a syringe is technically effective, expeditious, and cost-efficient. AB - INTRODUCTION: Syringe aspiration for manual aspiration thrombectomy (MAT) is a cost- and time-efficient alternative to an aspiration pump with likely similar efficacy. It is counterintuitive to expect the pump to perform better than direct vacuum with a syringe, as the pump must deliver vacuum additionally through a canister and meters of tubing. OBJECTIVE: To present in vitro and clinical results of MAT with a syringe. METHODS: An in vitro analysis was performed comparing vacuum pressures generated by syringe aspiration and with pump aspiration. This was then complemented with prospective clinical data providing details of angiographic and clinical outcomes for syringe MAT. RESULTS: The in vitro analysis demonstrated that equal to slightly greater vacuum pressures were generated by a 60 cc syringe as compared with the pump in both static and partial flow conditions. In our clinical series, 106/113 acute stroke thrombectomies over a 6-month period were performed with syringe MAT on the first pass. Syringe usage instead of pump tubing and a canister led to a total savings of $58 300. The rate of Thrombolysis in Cerebral Infarction 2b/3 recanalization was 93%. Adjunctive stentriever usage was performed in 23% of cases. Median puncture to reperfusion time was 25 min; mean change in National Institute of Health Stroke Scale score at 24 hours was an improvement of 5.1 (median 6). The in-hospital mortality rate was 10%. Seventy percent of patients were discharged to home (modified Rankin Scale (mRS) score 0-2) or a rehabilitation facility (mRS score 2-4). CONCLUSION: MAT using a syringe is a safe, fast, and more cost-effective approach than using an aspiration pump. PMID- 29127195 TI - Microcatheter contrast injection in stent retriever neurothrombectomy is safe and useful: insights from SWIFT PRIME. AB - : Microcatheter contrast injection (MCI) prior to stent retriever deployment for the treatment of acute ischemic stroke may be useful for evaluation of distal anatomy and flow patterns beyond the occlusion. However, prior data from intra arterialthrombolysis suggested that MCI increases the risk of intracranial hemorrhage (ICH). The safety and utility of MCI has not been investigated in the setting of thrombectomy. METHODS: We analyzed the Solitaire With the Intention For Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) trial to correlate pre-intervention MCI flow with collateral flow, and to investigate its impact on ICH and clinical outcome after thrombectomy with the Solitaire device. RESULTS: MCI was noted in 52% (n=51) of patients with a prevalence for the M2 location of 71% (n=36). Dichotomized correlation demonstrated a strong inverse relationship for partial collaterals with good MCI flow (p=0.004; OR 8.25). None of the MCI variables (presence, number, or grades) correlated with ICH and clinical outcome. The most significant predictors of non-disabled outcome were higher Alberta Stroke Program early CT Score (ASPECTS) (OR 1.61; p=0.0361) and younger age (OR 0.922; p = 0.0109). Higher ASPECTS was also a strong predictor of lower ICH risk (OR 0.501, p=0.0078). CONCLUSIONS: Collateral flow inversely correlated with MCI flow in the endovascular arm of the SWIFT PRIME trial. This finding warrants further validation in larger cohorts as MCI may be influenced by individual operator's technique and choice of syringe size. Evaluation of flow and distal anatomy with MCI prior to stent retriever deployment is safe with no evidence of an impact on ICH or clinical outcome. CLINICAL TRIAL REGISTRATION: NCT01657461: Post- results. PMID- 29127196 TI - Mechanical thrombectomy for acute ischemic stroke with occlusion of the M2 segment of the middle cerebral artery: a meta-analysis. AB - BACKGROUND: Endovascular thrombectomy has demonstrated benefit for patients with acute ischemic stroke from proximal large vessel occlusion. However, limited evidence is available from recent randomized trials on the role of thrombectomy for M2 segment occlusions of the middle cerebral artery (MCA). METHODS: We conducted a systematic review and meta-analysis to investigate clinical and radiographic outcomes, rates of hemorrhagic complications, and mortality after M2 occlusion thrombectomy using modern devices, and compared these outcomes against patients with M1 occlusions. Recanalization was defined as Thrombolysis in Cerebral Infarction (TICI) 2b/3 or modified TICI 2b/3. RESULTS: A total of 12 studies with 1080 patients with M2 thrombectomy were included in our analysis. Functional independence (modified Rankin Scale 0-2) rate was 59% (95% CI 54% to 64%). Mortality and symptomatic intracranial hemorrhage rates were 16% (95% CI 11% to 23%) and 10% (95% CI 6% to 16%), respectively. Recanalization rates were 81% (95% CI 79% to 84%), and were equally comparable for stent-retriever versus aspiration (OR 1.05; 95% CI 0.91 to 1.21). Successful M2 recanalization was associated with greater rates of favorable outcome (OR 4.22; 95% CI 1.96 to 9.1) compared with poor M2 recanalization (TICI 0-2a). There was no significant difference in recanalization rates for M2 versus M1 thrombectomy (OR 1.05; 95% CI 0.77 to 1.42). CONCLUSIONS: This meta-analysis suggests that mechanical thrombectomy for M2 occlusions that can be safely accessed is associated with high functional independence and recanalization rates, but may be associated with an increased risk of hemorrhage. PMID- 29127197 TI - Communicating malapposition of flow diverters assessed with optical coherence tomography correlates with delayed aneurysm occlusion. AB - BACKGROUND: Optical coherence tomography (OCT) is a high resolution intravascular imaging method that allows visualization of flow diverter struts and the vessel wall. In this study, malapposition of the flow diverter that continues into the neck of the aneurysm, named communicating malapposition (CM), was investigated as a potential factor for delayed aneurysm healing. METHODS: 40 New Zealand White rabbits underwent elastase induced aneurysm creation, and were subsequently assigned to one of four treatment groups based on flow diverter type and administration of antiplatelet therapy. All animals underwent post device deployment balloon angioplasty and subsequent OCT to assess device/vessel apposition. The incidence of CM seen on OCT was assessed with a binary scoring system: 0-CM present; 1-CM absent. At 30 days, DSA was acquired to assess aneurysm healing. Aneurysm healing on terminal DSA was measured using a previously developed 5 point scale, with a score of 3 or 4 considered a positive outcome. RESULTS: All animals were grouped into a single cohort for analysis as no difference in the rate of CM or healing was seen in the four treatment groups. Significant interaction between the absence of CM and a positive outcome was confirmed by Fisher exact test (P=0.0034). Angioplasty was shown to treat 33% of the cases of CM seen at implant, and these treated cases overwhelmingly had a positive outcome (P<0.001). CONCLUSION: The use of OCT to assess CM of flow diverters has been shown to be predictive of the 30 day healing rate of an animal model of aneurysms. PMID- 29127198 TI - Probing the metastable state of influenza hemagglutinin. AB - Viral entry into host cells is mediated by membrane proteins in a metastable state that transition to a more stable state upon a stimulus. For example, in the influenza envelope protein hemagglutinin (HA), the low pH in the endosome triggers a transition from the metastable prefusion conformation to the stable fusion conformation. To identify probes that interfere with HA function, here we screened a library of H7 HA peptides for inhibition of H7 HA-mediated entry. We discovered a peptide, PEP87 (WSYNAELLVAMENQHTI), that inhibited H7 and H5 HA mediated entry. PEP87 corresponds to a highly conserved helical region of the HA2 subunit of HA that self-interacts in the neutral pH conformation. Mutagenesis experiments indicated that PEP87 binds to its native region in the HA trimer. We also found that PEP87 is unstructured in isolation but tends to form a helix as evidenced by CD and NMR studies. Fluorescence, chemical cross-linking, and saturation transfer difference NMR data suggested that PEP87 binds to the neutral pH conformation of HA and disrupts the HA structure without affecting its oligomerization state. Together, this work provides support for a model in which PEP87 disrupts HA function by displacing native interactions of the neutral pH conformation. Moreover, our observations indicate that the HA prefusion structure (and perhaps the metastable states of other viral entry proteins) is more dynamic with transient motions being larger than generally appreciated. These findings also suggest that the ensemble of prefusion structures presents many potential sites for targeting in therapeutic interventions. PMID- 29127199 TI - The full-length interleukin-33 (FLIL33)-importin-5 interaction does not regulate nuclear localization of FLIL33 but controls its intracellular degradation. AB - Human mature IL-33 is a member of the IL-1 family and a potent regulator of immunity through its pro-T helper cell 2 activity. Its precursor form, full length interleukin-33 (FLIL33), is an intranuclear protein in many cell types, including fibroblasts, and its intracellular levels can change in response to stimuli. However, the mechanisms controlling the nuclear localization of FLIL33 or its stability in cells are not understood. Here, we identified importin-5 (IPO5), a member of the importin family of nuclear transport proteins, as an intracellular binding partner of FLIL33. By overexpressing various FLIL33 protein segments and variants in primary human lung fibroblasts and HEK293T cells, we show that FLIL33, but not mature interleukin-33, physically interacts with IPO5 and that this interaction localizes to a cluster of charged amino acids (positions 46-56) but not to an adjacent segment (positions 61-67) in the FLIL33 N-terminal region. siRNA-mediated IPO5 knockdown in cell culture did not affect nuclear localization of FLIL33. However, the IPO5 knockdown significantly decreased the intracellular levels of overexpressed FLIL33, reversed by treatment with the 20S proteasome inhibitor bortezomib. Furthermore, FLIL33 variants deficient in IPO5 binding remained intranuclear and exhibited decreased levels, which were also restored by the bortezomib treatment. These results indicate that the interaction between FLIL33 and IPO5 is localized to a specific segment of the FLIL33 protein, is not required for nuclear localization of FLIL33, and protects FLIL33 from proteasome-dependent degradation. PMID- 29127200 TI - Steroid receptor coactivator-2 (SRC-2) coordinates cardiomyocyte paracrine signaling to promote pressure overload-induced angiogenesis. AB - Pressure overload-induced cardiac stress induces left ventricular hypertrophy driven by increased cardiomyocyte mass. The increased energetic demand and cardiomyocyte size during hypertrophy necessitate increased fuel and oxygen delivery and stimulate angiogenesis in the left ventricular wall. We have previously shown that the transcriptional regulator steroid receptor coactivator 2 (SRC-2) controls activation of several key cardiac transcription factors and that SRC-2 loss results in extensive cardiac transcriptional remodeling. Pressure overload in mice lacking SRC-2 induces an abrogated hypertrophic response and decreases sustained cardiac function, but the cardiomyocyte-specific effects of SRC-2 in these changes are unknown. Here, we report that cardiomyocyte-specific loss of SRC-2 (SRC-2 CKO) results in a blunted hypertrophy accompanied by a rapid, progressive decrease in cardiac function. We found that SRC-2 CKO mice exhibit markedly decreased left ventricular vasculature in response to transverse aortic constriction, corresponding to decreased expression of the angiogenic factor VEGF. Of note, SRC-2 knockdown in cardiomyocytes decreased VEGF expression and secretion to levels sufficient to blunt in vitro tube formation and proliferation of endothelial cells. During pressure overload, both hypertrophic and hypoxic signals can stimulate angiogenesis, both of which stimulated SRC-2 expression in vitro Furthermore, SRC-2 coactivated the transcription factors GATA binding protein 4 (GATA-4) and hypoxia-inducible factor (HIF)-1alpha and -2alpha in response to angiotensin II and hypoxia, respectively, which drive VEGF expression. These results suggest that SRC-2 coordinates cardiomyocyte secretion of VEGF downstream of the two major angiogenic stimuli occurring during pressure overload bridging both hypertrophic and hypoxia-stimulated paracrine signaling. PMID- 29127201 TI - Loss of the mucosal barrier alters the progenitor cell niche via Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. AB - The mucous barrier of our digestive tract is the first line of defense against pathogens and damage. Disruptions in this barrier are associated with diseases such as Crohn's disease, colitis, and colon cancer, but mechanistic insights into these processes and diseases are limited. We have previously shown that loss of a conserved O-glycosyltransferase (PGANT4) in Drosophila results in aberrant secretion of components of the peritrophic/mucous membrane in the larval digestive tract. Here, we show that loss of PGANT4 disrupts the mucosal barrier, resulting in epithelial expression of the IL-6-like cytokine Upd3, leading to activation of JAK/STAT signaling, differentiation of cells that form the progenitor cell niche, and abnormal proliferation of progenitor cells. This niche disruption could be recapitulated by overexpressing upd3 and rescued by deleting upd3, highlighting a crucial role for this cytokine. Moreover, niche integrity and cell proliferation in pgant4-deficient animals could be rescued by overexpression of the conserved cargo receptor Tango1 and partially rescued by supplementation with exogenous mucins or treatment with antibiotics. Our findings help elucidate the paracrine signaling events activated by a compromised mucosal barrier and provide a novel in vivo screening platform for mucin mimetics and other strategies to treat diseases of the oral mucosa and digestive tract. PMID- 29127202 TI - Drosophila and human FHOD family formin proteins nucleate actin filaments. AB - Formins are a conserved group of proteins that nucleate and processively elongate actin filaments. Among them, the formin homology domain-containing protein (FHOD) family of formins contributes to contractility of striated muscle and cell motility in several contexts. However, the mechanisms by which they carry out these functions remain poorly understood. Mammalian FHOD proteins were reported not to accelerate actin assembly in vitro; instead, they were proposed to act as barbed end cappers or filament bundlers. Here, we show that purified Drosophila Fhod and human FHOD1 both accelerate actin assembly by nucleation. The nucleation activity of FHOD1 is restricted to cytoplasmic actin, whereas Drosophila Fhod potently nucleates both cytoplasmic and sarcomeric actin isoforms. Drosophila Fhod binds tightly to barbed ends, where it slows elongation in the absence of profilin and allows, but does not accelerate, elongation in the presence of profilin. Fhod antagonizes capping protein but dissociates from barbed ends relatively quickly. Finally, we determined that Fhod binds the sides of and bundles actin filaments. This work establishes that Fhod shares the capacity of other formins to nucleate and bundle actin filaments but is notably less effective at processively elongating barbed ends than most well studied formins. PMID- 29127203 TI - Receptor for advanced glycation end products mediates sepsis-triggered amyloid beta accumulation, Tau phosphorylation, and cognitive impairment. AB - Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-beta peptide (Abeta) and Ser-202-phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFalpha, IL-1beta, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nepsilon [carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Abeta and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Abeta and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation. PMID- 29127206 TI - Structure and functional analysis of LptC, a conserved membrane protein involved in the lipopolysaccharide export pathway in Escherichia coli. PMID- 29127205 TI - Orchestrating phospholipid biosynthesis: Phosphatidic acid conducts and Opi1p performs. AB - Phosphatidic acid (PA) and the conserved integral ER membrane protein Scs2p regulate localization of the transcriptional repressor Opi1p, which controls expression of phospholipid biosynthesis genes, but the mechanisms conducting Opi1p localization are not fully understood. A new study suggests the existence of a distinct pool of PA in the ER that is required for regulation of Opi1p localization and thus phospholipid metabolism in yeast. PMID- 29127207 TI - Perinatal Outcomes After Treatment With ADHD Medication During Pregnancy. AB - OBJECTIVES: To analyze perinatal outcomes after maternal use of attention deficit/hyperactivity disorder (ADHD) medication during pregnancy. METHODS: The study included singletons born between 2006 and 2014 in Sweden. Data on prescription drug use, pregnancies, deliveries, and the newborn infants' health were obtained from the Swedish Medical Birth Register, the Prescribed Drug Register, and the Swedish Neonatal Quality Register. We compared infants exposed to ADHD medication during pregnancy with infants whose mothers never used these drugs and infants whose mothers used ADHD medication before or after pregnancy. Analyses were performed with logistic regression. RESULTS: Among 964 734 infants, 1591 (0.2%) were exposed to ADHD medication during pregnancy and 9475 (1.0%) had mothers treated before or after pregnancy. Exposure during pregnancy increased the risk for admission to a NICU compared with both no use and use before or after pregnancy (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.3-1.7; and aOR, 1.2; 95% CI, 1.1-1.4, respectively). Infants exposed during pregnancy had more often central nervous system-related disorders (aOR, 1.9; 95% CI, 1.1-3.1) and were more often moderately preterm (aOR, 1.3; 95% CI, 1.1-1.6) than nonexposed infants. There was no increased risk for congenital malformations or perinatal death. CONCLUSIONS: Treatment with ADHD medication during pregnancy was associated with a higher risk for neonatal morbidity, especially central nervous system-related disorders such as seizures. Because of large differences in background characteristics between treated women and controls, it is uncertain to what extent this can be explained by the ADHD medication per se. PMID- 29127204 TI - Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. AB - The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy. PMID- 29127208 TI - Effectiveness of a Kindergarten-Based Intervention for Preventing Childhood Obesity. AB - BACKGROUND AND OBJECTIVES: Interventions to prevent childhood obesity targeting school age children have mostly reported limited effectiveness, suggesting such prevention programs may need to start at an earlier age, but evidence has been scarce. We reported a pilot study aiming to demonstrate the feasibility of a multifaceted intervention for preschool children and to provide a preliminary assessment of the effectiveness. METHODS: This nonrandomized controlled trial recruited children aged 3 to 6 years from 6 kindergartens in Guangzhou, China. Based on the preference of the School and Parents Committees, 4 kindergartens (648 children) received a 3-component intervention (training of kindergarten staff, initiating healthy curriculum for children, and close collaboration between families and kindergartens) over 12 months, while the other 2 kindergartens (336 children), serving as controls, received routine health care provision. Outcome measures were the changes in BMI z score between baseline and the end of 12 months, and the prevalence of postintervention children who were overweight or obese. RESULTS: By 12 months, children within the intervention group had a smaller BMI z score increase (0.24) compared to the control (0.41), with a difference of -0.31 (95% CI -0.47 to -0.15). The prevalence of overweight or obesity was also lower among the intervention group at the end of the study (OR: 0.43, 95% CI 0.19 to 0.96), adjusted for baseline status. CONCLUSIONS: Our results indicated a multicomponent health behavior intervention might be effective in reducing the prevalence of obesity, but the longer term effects will need confirmation from randomized controlled trials. PMID- 29127209 TI - Counseling on Sun Protection and Indoor Tanning. AB - BACKGROUND: The US Preventive Services Task Force recommends clinical counseling for individuals ages 10 to 24 years to decrease skin cancer risk. METHODS: A national, random sample of US American Academy of Pediatrics members practicing primary care in 2002 (response rate 55%) and 2015 (response rate 43%). Surveys explored attitudes and experiences regarding sun protection counseling; indoor tanning questions were added in 2015. chi2 tests compared demographics and counseling responses across years, and multivariable logistic regression models examined counseling predictors. RESULTS: More pediatricians in 2015 (34%) than in 2002 (23%) reported discussing sun protection during recent summer months with >=75% of patients. This pattern held across all patient age groups (each P <.001). Female and suburban pediatricians counseled more; those in the South and West counseled less. More pediatricians in 2015 than in 2002 named time as a barrier. Sun protection ranked lowest among preventive topics in both years. In 2015, approximately one-third of pediatricians reported discussing indoor tanning at least once with 10 to 13 year-old patients; approximately half discussed this with older adolescents. Most (70%) did not know if their states had laws on minors' indoor tanning access; those stating they knew whether a law existed counseled more. CONCLUSIONS: Although improved, sun protection counseling rates remain low. Indoor tanning counseling can be improved. Because early-life exposure to UV radiation increases risk and clinician counseling can positively impact prevention behaviors, pediatricians have an important role in skin cancer prevention; counseling may save lives. Time constraints remain a barrier. PMID- 29127211 TI - Mechanistic implications of enhanced editing by a HyperTRIBE RNA-binding protein. AB - We previously developed TRIBE, a method for the identification of cell-specific RNA-binding protein targets. TRIBE expresses an RBP of interest fused to the catalytic domain (cd) of the RNA-editing enzyme ADAR and performs adenosine-to inosine editing on RNA targets of the RBP. However, target identification is limited by the low editing efficiency of the ADARcd. Here we describe HyperTRIBE, which carries a previously characterized hyperactive mutation (E488Q) of the ADARcd. HyperTRIBE identifies dramatically more editing sites, many of which are also edited by TRIBE but at a much lower editing frequency. HyperTRIBE therefore more faithfully recapitulates the known binding specificity of its RBP than TRIBE. In addition, separating RNA binding from the enhanced editing activity of the HyperTRIBE ADAR catalytic domain sheds light on the mechanism of ADARcd editing as well as the enhanced activity of the HyperADARcd. PMID- 29127212 TI - Cephalexin plus trimethoprim-sulfamethoxazole was not superior to cephalexin alone for the treatment of outpatient non-purulent cellulitis. PMID- 29127210 TI - HIV-1 NC-induced stress granule assembly and translation arrest are inhibited by the dsRNA binding protein Staufen1. AB - The nucleocapsid (NC) is an N-terminal protein derived from the HIV-1 Gag precursor polyprotein, pr55Gag NC possesses key functions at several pivotal stages of viral replication. For example, an interaction between NC and the host double-stranded RNA-binding protein Staufen1 was shown to regulate several steps in the viral replication cycle, such as Gag multimerization and genomic RNA encapsidation. In this work, we observed that the overexpression of NC leads to the induction of stress granule (SG) assembly. NC-mediated SG assembly was unique as it was resistant to the SG blockade imposed by the HIV-1 capsid (CA), as shown in earlier work. NC also reduced host cell mRNA translation, as judged by a puromycylation assay of de novo synthesized proteins, and this was recapitulated in polysome profile analyses. Virus production was also found to be significantly reduced. Finally, Staufen1 expression completely rescued the blockade to NC mediated SG assembly, global mRNA translation as well as virus production. NC expression also resulted in the phosphorylation of protein kinase R (PKR) and eIF2alpha, and this was inhibited with Staufen1 coexpression. This work sheds light on an unexpected function of NC in host cell translation. A comprehensive understanding of the molecular mechanisms by which a fine balance of the HIV-1 structural proteins NC and CA act in concert with host proteins such as Staufen1 to modulate the host stress response will aid in the development of new antiviral therapeutics. PMID- 29127213 TI - Minimal difference in survival between radical prostatectomy and observation in men with modest life expectancy. PMID- 29127214 TI - SOFA criteria predict infection-related in-hospital mortality in ICU patients better than SIRS criteria and the qSOFA score. PMID- 29127215 TI - In patients with localised prostate cancer, active surveillance is associated with better sexual function, urinary symptoms and bowel symptoms. PMID- 29127216 TI - Emerging candidate treatment strategies for Hutchinson-Gilford progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare premature aging disorder affecting children, with a disease incidence of ~1 in 18 million individuals. HGPS is usually caused by a de novo point mutation in exon 11 of the LMNA gene (c.1824C>T, p.G608G), resulting in the increased usage of a cryptic splice site and production of a truncated unprocessed lamin A protein named progerin. Since the genetic cause for HGPS was published in 2003, numerous potential treatment options have rapidly emerged. Strategies to interfere with the post-translational processing of lamin A, to enhance progerin clearance, or directly target the HGPS mutation to reduce the progerin-producing alternative splicing of the LMNA gene have been developed. Here, we give an up-to-date resume of the contributions made by our and other research groups to the growing list of different candidate treatment strategies that have been tested, both in vitro, in vivo in mouse models for HGPS and in clinical trials in HGPS patients. PMID- 29127218 TI - Reply to Benkman: Hispaniolan crossbills formerly resided in the Bahamas. PMID- 29127217 TI - Adding landscape genetics and individual traits to the ecosystem function paradigm reveals the importance of species functional breadth. AB - Animal pollination mediates both reproduction and gene flow for the majority of plant species across the globe. However, past functional studies have focused largely on seed production; although useful, this focus on seed set does not provide information regarding species-specific contributions to pollen-mediated gene flow. Here we quantify pollen dispersal for individual pollinator species across more than 690 ha of tropical forest. Specifically, we examine visitation, seed production, and pollen-dispersal ability for the entire pollinator community of a common tropical tree using a series of individual-based pollinator-exclusion experiments followed by molecular-based fractional paternity analyses. We investigate the effects of pollinator body size, plant size (as a proxy of floral display), local plant density, and local plant kinship on seed production and pollen-dispersal distance. Our results show that while large-bodied pollinators set more seeds per visit, small-bodied bees visited flowers more frequently and were responsible for more than 49% of all long-distance (beyond 1 km) pollen dispersal events. Thus, despite their size, small-bodied bees play a critical role in facilitating long-distance pollen-mediated gene flow. We also found that both plant size and local plant kinship negatively impact pollen dispersal and seed production. By incorporating genetic and trait-based data into the quantification of pollination services, we highlight the diversity in ecological function mediated by pollinators, the influential role that plant and population attributes play in driving service provision, and the unexpected importance of small-bodied pollinators in the recruitment of plant genetic diversity. PMID- 29127219 TI - Crossbills were unlikely resident in the Bahamas; thus, there was no population to be extirpated. PMID- 29127221 TI - Genetics of metabolic syndrome: potential clues from wild-derived inbred mouse strains. AB - The metabolic syndrome (MetS) is a complex constellation of metabolic abnormalities including obesity, abnormal glucose metabolism, dyslipidemia, and elevated blood pressure that together substantially increase risk for cardiovascular disease and Type 2 diabetes. Both genetic and environmental factors contribute to the development of MetS, but this process is still far from understood. Human studies have revealed only part of the underlying basis. Studies in mice offer many strengths that can complement human studies to help elucidate the etiology and pathophysiology of MetS. Here we review the ways mice can contribute to MetS research. In particular, we focus on the information that can be obtained from studies of the inbred strains, with specific focus on the phenotypes of the wild-derived inbred strains. These are newly derived inbred strains that were created from wild-caught mice. They contain substantial genetic variation that is not present in the classical inbred strains, have phenotypes of relevance for MetS, and various mouse strain resources have been created to facilitate the mining of this new genetic variation. Thus studies using wild derived inbred strains hold great promise for increasing our understanding of MetS. PMID- 29127220 TI - Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. AB - Chronic kidney disease (CKD), defined as reduced glomerular filtration rate, is increasingly becoming a major public health issue. At the histological level, renal fibrosis is the final common pathway leading to end-stage renal disease, irrespective of the initial injury. According to this view, antifibrotic agents should slow or halt the progression of CKD. However, due to multiple overlapping pathways stimulating fibrosis, it has been difficult to develop antifibrotic drugs that delay or reverse the progression of CKD. MicroRNAs (miRNAs) are small noncoding RNA molecules, 18-22 nucleotides in length, that control many developmental and cellular processes as posttranscriptional regulators of gene expression. Emerging evidence suggests that miRNAs targeted against genes involved in renal fibrosis might be potential candidates for the development of antifibrotic therapies for CKD. This review will discuss some of the miRNAs, such as Let-7, miR-21,-29, -192, -200,-324, -132, -212, -30, -126, -433, -214, and 199a, that are implicated in renal fibrosis and the potential to exploit these molecular targets for the treatment of CKD. PMID- 29127222 TI - MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation. AB - Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders. PMID- 29127224 TI - Clinical prediction rule for neurological sequelae due to acute encephalopathy: a medical community-based validation study in Harima, Japan. AB - OBJECTIVES: This study aimed to verify the screening performance of our clinical prediction rule for neurological sequelae due to acute encephalopathy (NSAE-CPR), which previously identified the following three variables as predictive of poor outcomes: (1) refractory status epilepticus; (2) consciousness disturbance and/or hemiplegia at 6 hours from onset and (3) aspartate aminotransferase >90 IU/L within 6 hours of onset. DESIGN: Medical community-based multicentre retrospective cohort study. SETTING: Six regional hospitals in Harima and one tertiary centre in Kobe, Japan, from 2008 to 2012. PARTICIPANTS: We enrolled a total of 1612 patients aged <16 years who met the diagnostic criteria for an initial diagnosis of complex febrile seizure. Patients with a history of neurological disease and those included in the derivation cohort were excluded. PRIMARY OUTCOME MEASURES: Univariate and multivariate analyses were performed to determine the association between each of the three predictor variables and poor AE outcome (Pediatric Cerebral Performance Category score >=2). Receiver operating characteristic curve (ROC) analysis was also performed to assess the screening performance of the NSAE-CPR. RESULTS: The ROC analysis identified at least one of the three predictive variables as an optimal cut-off point, with an area under the curve of 0.915 (95% CI 0.825 to 1.000). The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios and Matthews correlation coefficient were 0.867, 0.954, 0.149, 0.999, 18.704, 0.140 and 0.349, respectively. CONCLUSIONS: Our findings indicate that the NSAE-CPR can be used for the screening and identification of patients with poor outcomes due to acute encephalopathy within 6 hours of onset. PMID- 29127223 TI - Systems genetic analysis of brown adipose tissue function. AB - Brown adipose tissue (BAT) has been suggested to play an important role in lipid and glucose metabolism in rodents and possibly also in humans. In the current study, we used genetic and correlation analyses in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), to identify genetic determinants of BAT function. Linkage analyses revealed a quantitative trait locus (QTL) associated with interscapular BAT mass on chromosome 4 and two closely linked QTLs associated with glucose oxidation and glucose incorporation into BAT lipids on chromosome 2. Using weighted gene coexpression network analysis (WGCNA) we identified 1,147 gene coexpression modules in the BAT from BXH/HXB rats and mapped their module eigengene QTLs. Through an unsupervised analysis, we identified modules related to BAT relative mass and function. The Coral4.1 coexpression module is associated with BAT relative mass (includes Cd36 highly connected gene), and the Darkseagreen coexpression module is associated with glucose incorporation into BAT lipids (includes Hiat1, Fmo5, and Sort1 highly connected transcripts). Because multiple statistical criteria were used to identify candidate modules, significance thresholds for individual tests were not adjusted for multiple comparisons across modules. In summary, a systems genetic analysis using genomic and quantitative transcriptomic and physiological information has produced confirmation of several known genetic factors and significant insight into novel genetic components functioning in BAT and possibly contributing to traits characteristic of the metabolic syndrome. PMID- 29127225 TI - Exploring the characteristics of the high-cost population from the family perspective: a cross-sectional study in Jiangsu Province, China. AB - BACKGROUND: Across a range of healthcare settings, 5% of the population accounts for half of healthcare spending: these patients are identified as a 'high-cost population'. Characterising high-cost users is essential for predicting potential high-cost patients and the development of appropriate interventions to improve the management and financing of these patients. OBJECTIVE: This cross-sectional study aimed to explore the characteristics of this high-cost population from a family perspective in China and provide suggestions for social health insurance policy development. METHODS: This study used data from the Fifth Health Service Investigation of Jiangsu Province (2013), and 12 600 families were enrolled for analysis. Households whose medical expenditures were among the top 5% were identified to be high-cost families. A t-test, a Chi2 test, and a binary logistic regression were used. RESULTS: High-cost families (n=631, 5%) accounted for 44.9% of the total medical expenditure of sampled families. High-cost families had 3.2 members and 1.2 chronic disease patients per household, which is significantly more than the 2.9 members and 0.7 people in the remaining families, respectively (p<0.05). Bi-weekly emergency department visits and annual hospitalisations preceding the household investigation of high-cost families were 1.19 and 0.98 per household, which is significantly more than the 0.68 and 0.17 of the remaining families, respectively (p<0.05). A binary logistic regression indicated that the number of family members (OR 1.152), the number of chronic disease patients (OR 1.508), bi-weekly emergency department visits (OR 1.218), and annual hospitalisations (OR 4.577) were associated with high costs. CONCLUSION: The 5% high-cost families in Jiangsu Province accounted for approximately half of medical expenditures. The effectiveness of Chinese Social Health Insurance in lowering high-cost families' risk of catastrophic health expenditure was modest. Policymakers need to ascertain the priority of lowering the burden of high-cost families' out-of-pocket expenses through improving the reimbursement proportion and reducing avoidable medical services. PMID- 29127226 TI - Risk of sudden cardiac death in relation to season-specific cold spells: a case crossover study in Finland. AB - OBJECTIVE: To test a priori hypothesis of an association between season-specific cold spells and sudden cardiac death (SCD). METHODS: We conducted a case crossover study of 3614 autopsy-verified cases of SCD in the Province of Oulu, Finland (1998-2011). Cold spell was statistically defined by applying an individual frequency distribution of daily temperatures at the home address during the hazard period (7 days preceding death) and 50 reference periods (same calendar days of other years) for each case using the home coordinates. Conditional logistic regression was applied to estimate ORs for the association between the occurrence of cold spells and the risk of SCD after controlling for temporal trends. RESULTS: The risk of SCD was associated with a preceding cold spell (OR 1.33; 95% CI 1.00, 1.78). A greater number of cold days preceding death increased the risk of SCD approximately 19% per day (OR 1.19; 95% CI 1.07 to 1.32). The association was strongest during autumn (OR 2.51; 95% CI 1.27 to 4.96) and winter (OR 1.70; 95% CI 1.13 to 2.55) and lowest during summer (OR 0.42; 95% CI 0.15 to 1.18) and spring (OR 0.89; 95% CI 0.45 to 1.79). The association was stronger for ischaemic (OR 1.55; 95% CI 1.12 to 2.13) than for non-ischaemic SCD (OR 0.68; 95% CI 0.32 to 1.45) verified by medicolegal autopsy. CONCLUSIONS: Our results indicate that there is an association between cold spells and SCD, that this association is strongest during autumn, when the weather event is prolonged, and with cases suffering ischaemic SCD. These findings are subsumed with potential prevention via weather forecasting, medical advice and protective behaviour. PMID- 29127227 TI - Protocol for hospital based-surveillance of cerebral palsy (CP) in Hanoi using the Paediatric Active Enhanced Disease Surveillance mechanism (PAEDS-Vietnam): a study towards developing hospital-based disease surveillance in Vietnam. AB - INTRODUCTION: The epidemiology, pathogenesis, management and outcomes of cerebral palsy (CP) in low-income and middle-income countries including Vietnam are unknown because of the lack of mechanisms for standardised collection of data. In this paper, we outline the protocol for developing a hospital-based surveillance system modelled on the Paediatric Active Enhanced Disease Surveillance (PAEDS) system in Australia. Using PAEDS-Vietnam we will define the aetiology, motor function and its severity, associated impairments, and nutritional and rehabilitation status of children with CP in Hanoi, Vietnam. These essential baseline data will inform future health service planning, health professional education and training, and family support. METHODS AND ANALYSIS: This is a hospital-based prospective surveillance of children with CP presenting to the rehabilitation, neurology and general paediatric services at the National Children's Hospital and St Paul Hospital in Hanoi. We will use active, prospective daily case-finding for all children with CP aged <18 years who are hospitalised or present to outpatient departments. Following parental consent, data will be collected using a modified version of the Australian Cerebral Palsy Register questionnaire. The data collection form has been developed in consultation with local and international experts and translated into Vietnamese. Information collected will include demographics, maternal health and birth history, type and severity of CP, known risk factors for CP, and nutrition, immunisation, education and rehabilitation status. ETHICS AND DISSEMINATION: This study was approved by the Hanoi Medical University Institutional Review Board (decision no 1722) and The University of Sydney Human Research Ethics Committee (approval no 2016/456). Establishment of PAEDS-Vietnam will enable hospital-based surveillance of CP for the first time in Vietnam. It will identify preventable causes of CP, patient needs and service gaps, and facilitate early diagnosis and intervention. Study findings will be disseminated through local and international conferences and peer-reviewed publications. PMID- 29127228 TI - Association between body mass index and outcomes after percutaneous coronary intervention in multiethnic South East Asian population: a retrospective analysis of the Malaysian National Cardiovascular Disease Database-Percutaneous Coronary Intervention (NCVD-PCI) registry. AB - OBJECTIVE: To examine the relationship between body mass index (BMI) and outcomes after percutaneous coronary intervention (PCI) in a multiethnic South East Asian population. SETTING: Fifteen participating cardiology centres contributed to the Malaysian National Cardiovascular Disease Database-Percutaneous Coronary Intervention (NCVD-PCI) registry. PARTICIPANTS: 28 742 patients from the NCVD-PCI registry who had their first PCI between January 2007 and December 2014 were included. Those without their BMI recorded or BMI <11 kg/m2 or >70 kg/m2 were excluded. MAIN OUTCOME MEASURES: In-hospital death, major adverse cardiovascular events (MACEs), vascular complications between different BMI groups were examined. Multivariable-adjusted HRs for 1-year mortality after PCI among the BMI groups were also calculated. RESULTS: The patients were divided into four groups; underweight (BMI <18.5 kg/m2), normal BMI (BMI 18.5 to <23 kg/m2), overweight (BMI 23 to <27.5 kg/m2) and obese (BMI >=27.5 kg/m2). Comparison of their baseline characteristics showed that the obese group was younger, had lower prevalence of smoking but higher prevalence of diabetes, hypertension and dyslipidemia. There was no difference found in terms of in-hospital death, MACE and vascular complications after PCI. Multivariable Cox proportional hazard regression analysis showed that compared with normal BMI group the underweight group had a non-significant difference (HR 1.02, p=0.952), while the overweight group had significantly lower risk of 1-year mortality (HR 0.71, p=0.005). The obese group also showed lower HR but this was non-significant (HR 0.78, p=0.056). CONCLUSIONS: Using Asian-specific BMI cut-off points, the overweight group in our study population was independently associated with lower risk of 1-year mortality after PCI compared with the normal BMI group. PMID- 29127229 TI - Relationship between hormone replacement therapy and spinal osteoarthritis: a nationwide health survey analysis of the elderly Korean population. AB - OBJECTIVES: To identify the effects of hormone replacement therapy (HRT) on spinal osteoarthritis (OA). METHODS AND DESIGN: A cross-sectional study of a nationwide survey was performed. SETTING: This study collected data from the fifth Korean National Health and Nutrition Examination Survey (2010-2012). PARTICIPANTS: After excluding ineligible respondents, the total number of participants in this study was 4265 females. Participants were asked to report symptoms and disabilities related to spinal OA. In addition, plain radiographs of the spine were taken of all patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographic and lifestyle variables were compared between the HRT and non-HRT groups. In addition, radiographic examination and symptom assessment were performed to determine the existence of spinal OA. RESULTS: Marital status, education, income and HRT were correlated with spinal OA. A risk analysis of related factors showed that HRT and age had effects on spinal OA (ORs 0.717 and 1.257). Nevertheless, in the HRT group, smokers had a increased risk of spinal OA. In addition, the HRT group demonstrated a lower prevalence of spinal OA. The calculated risk for compromised morbidity with HRT compared with the prevalence of spinal OA was 0.717 (OR). The duration of HRT was also related to the risk for spinal OA. The group that had been taking HRT for more than 1 year showed decreased risk (OR 0.686) compared with patients with <1 year of HRT (OR 0.744; P<0.05). CONCLUSION: Women receiving HRT showed a lower prevalence of spinal OA. HRT also correlated with a decrease in spinal OA morbidity. PMID- 29127230 TI - Primary care management of headaches and how direct-access MRI fits: a qualitative study of UK general practitioners' views. AB - OBJECTIVES: To develop a better understanding of general practitioners' (GPs) views and experiences of the management of patients with headaches and use of direct-access MRI scans, and observe outcomes of an educational session offered by a GP with a special interest (GPwSI) to GPs. DESIGN: A qualitative study using semistructured interviews, analysed using thematic analysis. A GPwSI in headaches visited practices delivering a talk on headache medication, diagnosis and management. SETTING: Sixteen (16) primary care family practices in South London, UK. PARTICIPANTS: Twenty (20) GPs. RESULTS: Not all GPs were aware of the availability of direct-access MRI, but all acknowledged having used referral or direct scans to manage patients' concern about their headaches. A normal scan result helped resolve uncertainty for patient and GP and helped management towards discussion of preventative treatment. However, patients with psychological and/or severe headache symptoms could not necessarily be reassured. GPs reported difficulty interpreting radiology reports, particularly incidental abnormalities. Those who received the educational talk gained knowledge in diagnosis and medication, improving their confidence in management. CONCLUSIONS: Increased access to imaging, training in headache management, addressing physical and psychological symptoms and standardised reporting of scans may improve GPs' use of direct-access MRI in the future. PMID- 29127231 TI - Evaluation of psychometric properties of the German Hospital Survey on Patient Safety Culture and its potential for cross-cultural comparisons: a cross sectional study. AB - OBJECTIVE: To study the psychometric characteristics of German version of the Hospital Survey on Patient Safety Culture and to compare its dimensionality to other language versions in order to understand the instrument's potential for cross-national studies. DESIGN: Cross-sectional multicentre study to establish psychometric properties of German version of the survey instrument. SETTING: 73 units from 37 departments of two German university hospitals. PARTICIPANTS: Clinical personnel (n=995 responses, response rate 39.6%). PRIMARY AND SECONDARY OUTCOME MEASURES: Psychometric properties (eg, model fit, internal consistency, construct validity) of the instrument and comparison of dimensionality across different language translations. RESULTS: The instrument demonstrated acceptable to good internal consistency (Cronbach's alpha 0.64-0.88). Confirmatory factor analysis of the original 12-factor model resulted in marginally satisfactory model fit (root mean square error of approximation (RMSEA)=0.05; standardised root mean residual (SRMR)=0.05; comparative fit index (CFI)=0.90; goodness of fit index (GFI)=0.88; Tucker-Lewis Index (TLI)=0.88). Exploratory factor analysis resulted in an alternative eight-factor model with good model fit (RMSEA=0.05; SRMR=0.05; CFI=0.95; GFI=0.91; TLI=0.94) and good internal consistency (Cronbach's alpha 0.73-0.87) and construct validity. Analysis of the dimensionality compared with models from 10 other language versions revealed eight dimensions with relatively stable composition and appearance across different versions and four dimensions requiring further improvement. CONCLUSIONS: The German version of Hospital Survey on Patient Safety Culture demonstrated satisfactory psychometric properties for use in German hospitals. However, our comparison of instrument dimensionality across different language versions indicates limitations concerning cross-national studies. Results of this study can be considered in interpreting findings across national contexts, in further refinement of the instrument for cross-national studies and in better understanding the various facets and dimensions of patient safety culture. PMID- 29127233 TI - Vascular endothelial function masks increased sympathetic vasopressor activity in rats with metabolic syndrome. AB - Sympathetic hyperactivation, a common feature of obesity and metabolic syndrome, is a key trigger of hypertension. However, some obese subjects with autonomic imbalance present a dissociation between sympathetic activity-mediated vasoconstriction and increased blood pressure. Here, we aimed to determine in a rat model of metabolic syndrome whether the endothelium endothelial nitric oxide (NO) synthase (eNOS)-NO pathway contributes to counteract the vasopressor effect of the sympathetic system. Rats were fed a high-fat and high-sucrose (HFS) diet for 15 wk. Sympathovagal balance was evaluated by spectral analysis of heart rate variability and plasmatic catecholamine measurements. Blood pressure was measured in the presence or absence of N-nitro-l-arginine methyl ester (l-NAME) to inhibit the contribution of eNOS. Vascular reactivity was assessed on isolated aortic rings in response to alpha1-adrenergic agonist. The HFS diet increased sympathetic tone, which is characterized by a higher low on the high-frequency spectral power ratio and a higher plasmatic concentration of epinephrine. Despite this, no change in blood pressure was observed. Interestingly, HFS rats exhibited vascular hyporeactivity (-23.6%) to alpha1-adrenergic receptor stimulation that was abolished by endothelial removal or eNOS inhibition (l-NAME). In addition, eNOS phosphorylation (Ser1177) was increased in response to phenylephrine in HFS rats only. Accordingly, eNOS inhibition in vivo revealed higher blood pressure in HFS rats compared with control rats (147 vs. 126 mmHg for mean blood pressure, respectively). Restrain of adrenergic vasopressor action by endothelium eNOS is increased in HFS rats and contributes to maintained blood pressure in the physiological range. NEW & NOTEWORTHY Despite the fact that prohypertensive sympathetic nervous system activity is markedly increased in rats with early metabolic syndrome, they present with normal blood pressure. These observations appear to be explained by increased endothelial nitric oxide synthase response to adrenergic stimulation, which results in vascular hyporeactivity to alpha adrenergic stimulation, and therefore blood pressure is preserved in the physiological range. Listen to this article's corresponding podcast at http://www.physiology.org/doi/10.1152/ajpheart.00217.2017 . PMID- 29127232 TI - Epidemiology of hypertension in Northern Tanzania: a community-based mixed methods study. AB - INTRODUCTION: Sub-Saharan Africa is particularly vulnerable to the growing global burden of hypertension, but epidemiological studies are limited and barriers to optimal management are poorly understood. Therefore, we undertook a community based mixed-methods study in Tanzania to investigate the epidemiology of hypertension and barriers to care. METHODS: In Northern Tanzania, between December 2013 and June 2015, we conducted a mixed-methods study, including a cross-sectional household epidemiological survey and qualitative sessions of focus groups and in-depth interviews. For the survey, we assessed for hypertension, defined as a single blood pressure >=160/100 mm Hg, a two-time average of >=140/90 mm Hg or current use of antihypertensive medications. To investigate relationships with potential risk factors, we used adjusted generalised linear models. Uncontrolled hypertension was defined as a two-time average measurement of >=160/100 mm Hg irrespective of treatment status. Hypertension awareness was defined as a self-reported disease history in a participant with confirmed hypertension. To explore barriers to care, we identified emerging themes using an inductive approach within the framework method. RESULTS: We enrolled 481 adults (median age 45 years) from 346 households, including 123 men (25.6%) and 358 women (74.4%). Overall, the prevalence of hypertension was 28.0% (95% CI 19.4% to 38.7%), which was independently associated with age >60 years (prevalence risk ratio (PRR) 4.68; 95% CI 2.25 to 9.74) and alcohol use (PRR 1.72; 95% CI 1.15 to 2.58). Traditional medicine use was inversely associated with hypertension (PRR 0.37; 95% CI 0.26 to 0.54). Nearly half (48.3%) of the participants were aware of their disease, but almost all (95.3%) had uncontrolled hypertension. In the qualitative sessions, we identified barriers to optimal care, including poor point-of-care communication, poor understanding of hypertension and structural barriers such as long wait times and undertrained providers. CONCLUSIONS: In Northern Tanzania, the burden of hypertensive disease is substantial, and optimal hypertension control is rare. Transdisciplinary strategies sensitive to local practices should be explored to facilitate early diagnosis and sustained care delivery. PMID- 29127234 TI - PPAR-alpha agonists acutely inhibit Ca2+-independent PLA2 to reduce H2O2-induced contractions in aortae of spontaneously hypertensive rats. AB - Hypertension is associated with endothelial dysfunction, which favors the release of endothelium-derived contracting factors, including vasoconstrictor prostanoids and reactive oxygen species. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists, clinically used as lipid-lowering drugs, possess antioxidant properties and exert beneficial effects in the vascular system. The present study aimed to identify the mechanism(s) underlying the acute effects of the PPAR-alpha agonists Wy14643 and fenofibate on endothelium-dependent contractions, in particular those related to oxidative stress, in the aorta of the spontaneously hypertensive rat (SHR). Aortic rings with and without endothelium of male SHRs and normotensive Wistar-Kyoto rats were suspended in organ chambers for isometric tension measurements and homogenized for enzyme activity assays. Contractions to acetylcholine in quiescent SHR aortae with endothelium were reduced by tiron (superoxide anion scavenger), diethyldithiocarbamic acid (superoxide dismutase inhibitor), and acute treatment with either Wy14643 or fenofibrate. Similarly to contractions evoked by acetylcholine, H2O2-induced increases in tension in SHR aortae involved, in succession, phospholipase A2 (PLA2), cyclooxygenase, and thromboxane-prostanoid receptors. Wy14643 or fenofibrate, by decreasing the activity of endothelial Ca2+ independent PLA2, attenuated the contractions to H2O2. In conclusion, the increased oxidative stress in the SHR aorta (mainly increased production of H2O2 and its partially reduced product, hydroxyl radical) contributed to acetylcholine induced, endothelium-dependent contractions; PPAR-alpha agonists likely inhibit the H2O2-mediated contractions by inhibiting endothelial Ca2+-independent PLA2. The present study highlights the prospective therapeutic effects of PPAR-alpha agonists in improving endothelial function in hypertension and other vascular implications due to oxidative stress. NEW & NOTEWORTHY Peroxisome proliferator activated receptor-alpha agonists, which are used clinically as lipid-lowering drugs, acutely reduce H2O2-induced contractions in aortae of hypertensive rats by inhibiting the activity of endothelial Ca2+-independent phospholipase A2. These vascular effects of peroxisome proliferator-activated receptor-alpha agonists suggest that they may help to prevent vascular complications under pathological conditions associated with oxidative stress. PMID- 29127235 TI - Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart. AB - The left ventricular working, crystalloid-perfused heart is used extensively to evaluate basic cardiac function, pathophysiology, and pharmacology. Crystalloid perfused hearts may be limited by oxygen delivery, as adding oxygen carriers increases myoglobin oxygenation and improves myocardial function. However, whether decreased myoglobin oxygen saturation impacts oxidative phosphorylation (OxPhos) is unresolved, since myoglobin has a much lower affinity for oxygen than cytochrome c oxidase (COX). In the present study, a laboratory-based synthesis of an affordable perfluorocarbon (PFC) emulsion was developed to increase perfusate oxygen carrying capacity without impeding optical absorbance assessments. In left ventricular working hearts, along with conventional measurements of cardiac function and metabolic rate, myoglobin oxygenation and cytochrome redox state were monitored using a novel transmural illumination approach. Hearts were perfused with Krebs-Henseleit (KH) or KH supplemented with PFC, increasing perfusate oxygen carrying capacity by 3.6-fold. In KH-perfused hearts, myoglobin was deoxygenated, consistent with cytoplasmic hypoxia, and the mitochondrial cytochromes, including COX, exhibited a high reduction state, consistent with OxPhos hypoxia. PFC perfusate increased aortic output from 76 +/- 6 to 142 +/- 4 ml/min and increased oxygen consumption while also increasing myoglobin oxygenation and oxidizing the mitochondrial cytochromes. These results are consistent with limited delivery of oxygen to OxPhos resulting in an adapted lower cardiac performance with KH. Consistent with this, PFCs increased myocardial oxygenation, and cardiac work was higher over a wider range of perfusate Po2. In summary, heart mitochondria are limited by oxygen delivery with KH; supplementation of KH with PFC reverses mitochondrial hypoxia and improves cardiac performance, creating a more physiological tissue oxygen delivery. NEW & NOTEWORTHY Optical absorbance spectroscopy of intrinsic chromophores reveals that the commonly used crystalloid-perfused working heart is oxygen limited for oxidative phosphorylation and associated cardiac work. Oxygen-carrying perfluorocarbons increase myocardial oxygen delivery and improve cardiac function, providing a more physiological mitochondrial redox state and emphasizing cardiac work is modulated by myocardial oxygen delivery. PMID- 29127236 TI - Structural and functional changes of the pulmonary vasculature after hypoxia exposure in the neonatal period: a new swine model of pulmonary vascular disease. AB - Pulmonary vascular disease (PVD) represents an underestimated and increasing clinical burden not only in the neonatal period but also later in life, when exercise tolerance is decreased. Animal models performing long-term followup after a perinatal insult are lacking. This study aimed to develop and characterize a neonatal swine model with hypoxia-induced PVD during long-term followup after reexposure to normoxia and to investigate the exercise response in this model. Piglets were exposed to a normoxic ( n = 10) or hypoxic environment ( n = 9) for 4 wk. Neonatal hypoxia exposure resulted in pulmonary hypertension. Mean pulmonary artery pressure was elevated 1 day after reexposure to normoxia (30.2 +/- 3.3 vs. 14.3 +/- 0.9 mmHg) and remained significantly higher in the second week (32.8 +/- 3.8 vs. 21.4 +/- 1.2 mmHg), accompanied by decreased exercise tolerance. Exercise resulted in a trend toward an exaggerated increase of pulmonary artery pressure in hypoxia-exposed animals ( week 6, P = 0.086). Although pulmonary hypertension was transient, thickening of pulmonary arterioles was found at the end of followup. Furthermore, right ventricular dilation, lower right ventricular fractional area change ( week 8, 40.0 +/- 2.7% vs. 29.5 +/- 4.7%), and tricuspid annular plane systolic excursion ( week 8, 27.0 +/- 2.5 vs. 22.9 +/- 2.1 mm) persisted during followup. Male animals showed more severe PVD than female animals. In conclusion, we developed a neonatal swine model that allows examination of the long-term sequelae of damage to the developing neonatal lung, the course of the disease and the effect of therapy on long-term outcome. NEW & NOTEWORTHY The swine model of neonatal pulmonary vascular disease developed in the present study is the first that allows exercise testing and examination of long-term sequelae of a perinatal hypoxic insult, the course of the disease, and the effect of therapy on long-term outcome. PMID- 29127237 TI - Metaboreflex-mediated hemodynamic abnormalities in individuals with coronary artery disease without overt signs or symptoms of heart failure. AB - This study was devised to investigate the effect of coronary artery disease (CAD) without overt signs of heart failure on the cardiovascular responses to muscle metaboreflex activation. We hypothesized that any CAD-induced preclinical systolic and/or diastolic dysfunction could impair hemodynamic response to the metaboreflex test. Twelve men diagnosed with CAD without any sign or symptoms of heart failure and 11 age-matched healthy control (CTL) subjects participated in the study. Subjects performed a postexercise muscle ischemia (PEMI) test to activate the metaboreflex. They also performed a control exercise recovery test to compare data from the PEMI test. The main results were that the CAD group reached a similar mean arterial blood pressure response as the CTL group during PEMI. However, the mechanism by which this response was achieved was different between groups. In particular, CAD achieved the target mean arterial blood pressure by increasing systemic vascular resistance (+383.8 +/- 256.6 vs. +91.2 +/- 293.5 dyn.s-1.cm-5 for the CAD and CTL groups, respectively), the CTL group by increasing cardiac preload (-0.92 +/- 8.53 vs. 5.34 +/- 4.29 ml in end diastolic volume for the CAD and CTL groups, respectively), which led to an enhanced stroke volume and cardiac output. Furthermore, the ventricular filling rate response was higher in the CTL group than in the CAD group during PEMI ( P < 0.05 for all comparisons). This study confirms that diastolic function is pivotal for normal hemodynamics during the metaboreflex. Moreover, it provides evidence that early signs of diastolic impairment attributable to CAD can be detected by the metaboreflex test. NEW & NOTEWORTHY Individuals suffering from coronary artery disease without overt signs of heart failure may show early signs of diastolic dysfunction, which can be detected by the metaboreflex test. During the metaboreflex, these subjects show impaired preload and stroke volume responses and exaggerated vasoconstriction compared with controls. PMID- 29127238 TI - Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes. AB - Clinical studies have suggested that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction. Ferroptosis has recently been reported as a mechanism of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well understood. Mechanistic target of rapamycin (mTOR) protects the heart against pathological stimuli such as ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated cell death, we examined cardiomyocyte (CM) cell viability under excess iron and ferroptosis conditions. Adult mouse CMs were isolated from cardiac-specific mTOR transgenic mice, cardiac-specific mTOR knockout mice, or control mice. CMs were treated with ferric iron [Fe(III)]-citrate, erastin, a class 1 ferroptosis inducer, or Ras-selective lethal 3 (RSL3), a class 2 ferroptosis inducer. Live/dead cell viability assays revealed that Fe(III)-citrate, erastin, and RSL3 induced cell death. Cotreatment with ferrostatin-1, a ferroptosis inhibitor, inhibited cell death in all conditions. mTOR overexpression suppressed Fe(III) citrate, erastin, and RSL3-induced cell death, whereas mTOR deletion exaggerated cell death in these conditions. 2',7'-Dichlorodihydrofluorescein diacetate measurement of reactive oxygen species (ROS) production showed that erastin induced ROS production was significantly lower in mTOR transgenic versus control CMs. These findings suggest that ferroptosis is a significant type of cell death in CMs and that mTOR plays an important role in protecting CMs against excess iron and ferroptosis, at least in part, by regulating ROS production. Understanding the effects of mTOR in preventing iron-mediated cell death will provide a new therapy for patients with myocardial infarction. NEW & NOTEWORTHY Ferroptosis has recently been reported as a new form of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well characterized. Using cultured adult mouse cardiomyocytes, we demonstrated that the mechanistic target of rapamycin plays an important role in protecting cardiomyocytes against excess iron and ferroptosis. PMID- 29127239 TI - A novel method for quantitative myocardial contrast echocardiography in mice. AB - The small size of the mouse heart frequently imparts technical challenges when applying conventional in vivo imaging methods for assessing heart function. Here, we describe the use of high-frequency ultrasound imaging in conjunction with a size-tuned blood pool contrast agent for quantitatively assessing myocardial perfusion in living mice. A perflurocarbon microbubble formulation exhibiting a narrow size distribution was developed, and echogenicity was assessed at 18 MHz in vitro. Adult mice were subjected to permanent ligation of the left anterior descending artery. Ultrasound imaging was performed on day 7, and a cohort of intact mice was used as a control. Parasternal long-axis cine clips were acquired at 18 MHz before and after contrast administration. Reduced ejection fraction and increased end-systolic volume were observed in infarcted compared with control mice. In control animals, washin of the contrast agent was visible in all myocardial segments. Reduced contrast enhancement was observed in apical posterolateral regions of all infarcted mice. A novel method for reslicing of the imaging data through the time domain provided a two-dimensional presentation of regional contrast agent washin, enabling convenient identification of locations exhibiting altered perfusion. Myocardial segments exhibiting diminished contractility were observed to have correspondingly low relative myocardial perfusion. The contrast agent formulation and methods demonstrated here provide the basis for simplifying routine in vivo estimation of infarct size in mice and may be particularly useful in longitudinal evaluation of revascularization interventions and assessment of peri-infarct ischemia. NEW & NOTEWORTHY Murine myocardial contrast echocardiography frequently suffers from poor sensitivity to contrast. Here, we formulated a novel size-tuned microbubble contrast agent and validated it for use with ultra-high-frequency ultrasound. A novel data method for evaluating myocardial perfusion based on reslicing the imaging data through the time domain is presented. PMID- 29127241 TI - Monocyte DPP4 Expression in Human Atherosclerosis Is Associated With Obesity and Dyslipidemia. PMID- 29127242 TI - Gamma camera based method for 131I capsule counting: an alternate method to Uptake probe method. AB - The main objective of this study was to check the validity of using gamma camera as an alternate method to thyroid uptake probe, for counting 25uCi (0.925 MBq) and 50uCi (1.85 MBq) 131I capsules before administration to thyroid patients. Methods: - 10 sets each of 25uCi (0.925 MBq) and 50uCi (1.85 MBq) 131I capsules received from Board Of Radiation and Isotope Technology, Department Of Atomic Energy, India (BRIT, DAE) have been counted individually using thyroid uptake probe for 10 seconds following institutional protocol and also by keeping individual capsule of a set with 8cm gap between each of them .These capsules were also scanned by Scintillation gamma camera for 100 seconds. Capsules having counts within the range of mean +/-2 Standard Deviation (SD) were accepted for patient administration. After analysing both the data, correlation coefficient between these two methods has been evaluated. Results: Scanned images were analysed by drawing Identical ROI around each set of 25uCi (0.925 MBq) and 50uCi (1.85 MBq) 131I capsules. Capsules with counts within 2 Standard Deviation from mean were accepted for patient administration. Good correlation coefficient (r >0.95) was observed between these two counts set. Conclusion: Gamma camera based 131I -capsule counting method is an easy and time saving method compared to probe based capsule counting method as we can scan a set of capsules in a single acquisition. It can provide uniformity information for a batch of 131I -capsules and avoid the time consuming method of individual capsule counting with the thyroid uptake probe. PMID- 29127240 TI - The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes. AB - OBJECTIVE: There is suggestive evidence linking hypoglycemia with cardiovascular disease, but few data have been collected in a community-based setting. Information is lacking on individual cardiovascular outcomes and cause-specific mortality. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort analysis of 1,209 participants with diagnosed diabetes from the Atherosclerosis Risk in Communities (ARIC) study (analytic baseline, 1996-1998). Severe hypoglycemic episodes were identified using first position ICD-9 codes from hospitalizations, emergency department visits, and ambulance calls through 2013. Cardiovascular events and deaths were captured through 2013. We used adjusted Cox regression models with hypoglycemia as a time-varying exposure. RESULTS: There were 195 participants with at least one severe hypoglycemic episode during a median fellow-up of 15.3 years. After severe hypoglycemia, the 3-year cumulative incidence of coronary heart disease was 10.8% and of mortality was 28.3%. After adjustment, severe hypoglycemia was associated with coronary heart disease (hazard ratio [HR] 2.02, 95% CI 1.27-3.20), all-cause mortality (HR 1.73, 95% CI 1.38-2.17), cardiovascular mortality (HR 1.64, 95% CI 1.15-2.34), and cancer mortality (HR 2.49, 95% CI 1.46-4.24). Hypoglycemia was not associated with stroke, heart failure, atrial fibrillation, or noncardiovascular and noncancer death. Results were robust within subgroups defined by age, sex, race, diabetes duration, and baseline cardiovascular risk. CONCLUSIONS: Severe hypoglycemia is clearly indicative of declining health and is a potent marker of high absolute risk of cardiovascular events and mortality. PMID- 29127243 TI - Pelvic Meckel's Diverticulum Mimicking Bladder on Meckel Scan; The Impact of Quality Control and Technical Issues. AB - Quality control and technical issues are essential for high-quality imaging. An important technical parameter of image acquisition is selecting zoom factor according to camera field-of-view dimensions and patient's body size. Here, we present a case of atypically located Meckel's diverticulum mimicking bladder on Meckel scan. PMID- 29127244 TI - Imaging of the thyroid and parathyroid using a cardiac cadmium zinc telluride camera: Phantom studies. AB - Purpose: Cadmium zinc telluride (CZT) detectors have recently been introduced to the field of clinical nuclear cardiology. However, the feasibility of using them for organs other than the heart remains unclear. The aim of this study was to evaluate the potential of a cardiac CZT camera to acquire thyroid and parathyroid images. We used custom-made phantoms and the currently available standard protocols for CZT, instead of a sodium-iodine scintillation (NaI) camera. Materials and Methods: Thyroid phantoms with or without parathyroid adenomas were made from agar using radiopharmaceuticals (99mTc or 123I) and imaged using CZT and NaI cameras. Using the CZT camera data, we prepared maximum intensity projection (MIP) images and planar equivalent (PE) images. Image counts were compared to those from the NaI camera, and the radioactivity of the phantoms was measured. For parathyroid imaging, three different protocols with the NaI camera were tested using MIP images. Results: For thyroid imaging, MIP could provide images as clear as those obtained from the NaI camera. The radioactivity and image counts correlated better for the PE images than the MIP images, especially for 123I images. We succeeded in obtaining clear parathyroid adenoma images from MIP images using all three protocols. Conclusion: A cardiac CZT camera can effectively perform qualitative and quantitative assessments of the thyroid and parathyroid organs. PMID- 29127245 TI - Hypertrophic Osteoarthropathy on Bone Scintigraphy. AB - We present the case report of a patient with a history of lung cancer in whom the typical pattern of hypertrophic osteoarthropathy was seen on bone scintigraphy. We discuss the etiologies, pathophysiology, and management of this entity. PMID- 29127246 TI - Non-oncologic Applications of PET/CT and PET/MR in Musculoskeletal, Orthopedic, and Rheumatologic Imaging: General Considerations, Techniques, and Radiopharmaceuticals. AB - Positron Emission Tomography (PET) is often underutilized in the field of musculoskeletal imaging, with key reasons including the excellent performance of conventional musculoskeletal MRI, the limited spatial resolution of PET, and the lack of reimbursement for PET for non-oncologic musculoskeletal indications. However, with improvements in PET/CT and PET/MR imaging over the last decade as well as an increased understanding of the pathophysiology of musculoskeletal diseases, there is an emerging potential for PET as a primary or complementary modality in the management of rheumatologic and orthopedic patients. Specific advantages of PET include the convenience of whole body imaging in a single session, the relative resilience of the modality in the imaging of metallic implants compared to CT and MRI, the ability to evaluate deep joints not amenable to palpation, and the potential for improved specificity of diagnosis with novel radiopharmaceuticals. In this review, we discuss multiple radiopharmaceuticals and technical consideration of PET/CT and PET/MRI that can be employed in imaging of non-tumoral bone and soft tissue disorders. Both PET/CT and PET/MR hold significant promise in the field of musculoskeletal imaging, and with further radiopharmaceutical development and clinical research, these hybrid modalities can potentially transform the current management of patients with orthopedic and rheumatologic disease. PMID- 29127247 TI - Novel Method to Detect and Characterize 18F-FDG Infiltration at the Injection Site: A Single-Institution Experience. AB - A novel quality control and quality assurance device provides time-activity curves that can identify and characterize PET/CT radiotracer infiltration at the injection site during the uptake phase. The purpose of this study was to compare rates of infiltration detected by the device with rates detected by physicians. We also assessed the value of using the device to improve injection results in our center. Methods: 109 subjects consented to the study. All had passive device sensors applied to their skin near the injection site and mirrored on the contralateral arm during the entire uptake period. Nuclear medicine physicians reviewed standard images for the presence of dose infiltration. Sensor-generated time-activity curves were independently examined and then compared with the physician reports. Injection data captured by the software were analyzed, and the results were provided to the technologists. Improvement measures were implemented, and rates were remeasured. Results: Physician review of the initial 40 head-to-toe field-of-view images identified 15 cases (38%) of dose infiltration (9 minor, 5 moderate, and 1 significant). Sensor time-activity curves on these 40 cases independently identified 22 cases (55%) of dose infiltration (16 minor, 5 moderate, and 1 significant). After the time-activity curve results and the contributing factor analysis were shared with technologists, injection techniques were modified and an additional 69 cases were studied. Of these, physician review identified 17 cases (25%) of infiltration (13 minor, 3 moderate, and 1 significant), a 34% decline. Sensor time-activity curves identified 4 cases (6%) of infiltration (2 minor and 2 moderate), an 89% decline. Conclusion: The device provides valuable quality control information for each subject. Time-activity curves can further characterize visible infiltration. Even when the injection site was out of the field of view, the time-activity curves could still detect and characterize infiltration. Our initial experience showed that the quality assurance information obtained from the device helped reduce the rate and severity of infiltration. The device revealed site-specific contributing factors that helped nuclear medicine physicians and technologists customize their quality improvement efforts to these site-specific issues. Reducing infiltration can improve image quality and SUV quantification, as well as the ability to minimize variability in a site's PET/CT results. PMID- 29127248 TI - Utility of 111In-Cl3 scintigraphy for differentiating bone marrow reconversion. AB - Indium chloride (111In-Cl3) scintigraphy has been used to evaluate various hematological diseases for many years. However, there have been few reports on patients with bone marrow reconversion showing high uptake in 111In-Cl3 scintigraphy. Herein, we report a case of a 68-year-old man with esophageal cancer who underwent 18F-FDG PET/CT for staging of the disease. 18F-FDG PET/CT demonstrated high uptake in the first lumbar vertebral body, which was difficult to distinguish bone metastasis and bone marrow reconversion. 111In-Cl3 scintigraphy demonstrated specific findings with high uptake in the lesion, indicating bone marrow hyperplasia or reconversion. PMID- 29127249 TI - 18F-FDG PET/CT for Monitoring Response to Therapy of Choroidal Metastasis. AB - A 38-year-old woman with metastatic breast carcinoma reported seeing "halos and flashes" in her left eye. Funduscopic exam revealed an elevated mass in the choroid of the left globe consistent with metastasis. Subsequent 18F-FDG PET/CT revealed focal uptake in the nasal aspect of the left choroid of the eye corresponding to the mass seen on the funduscopic exam. Through correlation with the PET/CT, the lesion was retrospectively identified on the MRI. 18F-FDG PET/CT post-radiotherapy showed complete response and thus supports that this imaging modality can be used for diagnosis and monitoring response. History of breast cancer and visual symptoms should trigger the nuclear medicine physician to take extra care in reading the initial slices of the PET/CT scan through the orbits in order to make this challenging imaging diagnosis. PMID- 29127250 TI - Malignant peripheral nerve sheath tumours of the pericardium in a patient with Neurofibromatosis type 1: The diagnostic value of 18F-FDG PET-CT and I-123 MIBG SPECT-CT. AB - A 25 year old female with known neurofibromatosis type 1 with a large anterior mediastinal mass was investigated. F18-FDG PET-CT revealed a radiotracer avid anterior mediastinal mass with SUVmax of 4.3 and demonstrating a hypoactive center. The Iodine-123 MIBG SPECT-CT study performed subsequently did not demonstrate any uptake, thereby excluding for the most part the diagnoses of paraganglioma or neuroblastoma. At final pathology, a malignant peripheral nerve sheath tumour (MPNST) of the pericardium with areas of chondrosarcomatous and angiosarcomatous differentiation was diagnosed. PMID- 29127251 TI - Looking beyond the indication: Bone scan for trauma providing unsuspected initial diagnosis of acute critical lower limb arterial compromise. AB - We report a case of rare incidental initial detection of unsuspected arterial supply compromise to the right lower extremity on a bone scan done to rule out fracture in a patient with right hip pain following a fall. Follow up CT angiogram confirmed near complete occlusion of right lower extremity arteries for which patient underwent above knee amputation. PMID- 29127252 TI - Validation of an ergonomic method to withdraw [99mTc] radiopharmaceuticals. AB - The main objective of the present work was to ensure quality of radiopharmaceuticals syringes withdrawn with a "Spinal needle/obturator In Stopper" system. Methods: Visual examinations and physicochemical tests are performed at T0 and T+4h for [99mTc]albumin nanocolloid and T+7h for [99mTc]eluate, [99mTc] HydroxyMethylene DiPhosphonate and [99mTc]Human Serum Albumin. Microbiological validation was performed according to European pharmacopoeia. Fingertip radiation exposure was evaluated to confirm the safety of the system. Results: Results show stable visual and physicochemical properties. The integrity of the connector was not affected after 30 punctures (no cores). No microbiological contamination was found on tested syringes. Conclusion: The system could be used 30 times. The stability of syringes drawing with this method is guaranteed up to 4 hours for [99mTc]albumin nanocolloid and 7 hours for [99mTc]eluate, [99mTc]HydroxyMethylene DisPhosphonate and [99mTc]Human serum albumin. PMID- 29127253 TI - First biochemical and crystallographic characterization of a fast-performing ferritin from a marine invertebrate. AB - Ferritin, a multimeric cage-like enzyme, is integral to iron metabolism across all phyla through the sequestration and storage of iron through efficient ferroxidase activity. While ferritin sequences from ~900 species have been identified, crystal structures from only 50 species have been reported, the majority from bacterial origin. We recently isolated a secreted ferritin from the marine invertebrate Chaetopterus sp. (parchment tube worm), which resides in muddy coastal seafloors. Here, we present the first ferritin from a marine invertebrate to be crystallized and its biochemical characterization. The initial ferroxidase reaction rate of recombinant Chaetopterus ferritin (ChF) is 8-fold faster than that of recombinant human heavy-chain ferritin (HuHF). To our knowledge, this protein exhibits the fastest catalytic performance ever described for a ferritin variant. In addition to the high-velocity ferroxidase activity, ChF is unique in that it is secreted by Chaetopterus in a bioluminescent mucus. Previous work has linked the availability of Fe2+ to this long-lived bioluminescence, suggesting a potential function for the secreted ferritin. Comparative biochemical analyses indicated that both ChF and HuHF showed similar behavior toward changes in pH, temperature, and salt concentration. Comparison of their crystal structures shows no significant differences in the catalytic sites. Notable differences were found in the residues that line both 3-fold and 4-fold pores, potentially leading to increased flexibility, reduced steric hindrance, or a more efficient pathway for Fe2+ transportation to the ferroxidase site. These suggested residues could contribute to the understanding of iron translocation through the ferritin shell to the ferroxidase site. PMID- 29127254 TI - Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male. AB - The translocator protein (TSPO) has been proposed to act as a key component in a complex important for mitochondrial cholesterol importation, which is the rate limiting step in steroid hormone synthesis. However, TSPO function in steroidogenesis has recently been challenged by the development of TSPO knockout (TSPO-KO) mice, as they exhibit normal baseline gonadal testosterone and adrenal corticosteroid production. Here, we demonstrate that despite normal androgen levels in young male TSPO-KO mice, TSPO deficiency alters steroidogenic flux and results in reduced total steroidogenic output. Specific reductions in the levels of progesterone and corticosterone as well as age-dependent androgen deficiency were observed in both young and aged male TSPO-KO mice. Collectively, these findings indicate that while TSPO is not critical for achieving baseline testicular and adrenal steroidogenesis, either indirect effects of TSPO on steroidogenic processes, or compensatory mechanisms and functional redundancy, lead to subtle steroidogenic abnormalities which become exacerbated with aging. PMID- 29127257 TI - Disclosure of genetic information to relatives: balancing confidentiality and relatives' interests. PMID- 29127255 TI - Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. AB - There is compelling evidence for the role of the leucine-rich repeat kinase 2 (LRRK2) and in particular its kinase function in Parkinson's disease. Orally bioavailable, brain penetrant and potent LRRK2 kinase inhibitors are in the later stages of clinical development. Here, we describe a facile and robust assay to quantify LRRK2 kinase pathway activity by measuring LRRK2-mediated phosphorylation of Rab10 in human peripheral blood neutrophils. We use the selective MJFF-pRab10 monoclonal antibody recognising the Rab10 Thr73 phospho epitope that is phosphorylated by LRRK2. We highlight the feasibility and practicability of using our assay in the clinical setting by studying a few patients with G2019S LRRK2 associated and sporadic Parkinson's as well as healthy controls. We suggest that peripheral blood neutrophils are a valuable resource for LRRK2 research and should be considered for inclusion in Parkinson's bio repository collections as they are abundant, homogenous and express relatively high levels of LRRK2 as well as Rab10. In contrast, the widely used peripheral blood mononuclear cells are heterogeneous and only a minority of cells (monocytes and contaminating neutrophils) express LRRK2. While our LRRK2 kinase pathway assay could assist in patient stratification based on LRRK2 kinase activity, we envision that it may find greater utility in pharmacodynamic and target engagement studies in future LRRK2 inhibitor trials. PMID- 29127256 TI - Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson's disease kinase. AB - Mutations that activate the LRRK2 (leucine-rich repeat protein kinase 2) protein kinase predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector-binding switch-II motif. In the present study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho specific antibodies raised against nine different LRRK2-phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43). We identify rabbit monoclonal phospho-specific antibodies (MJFF-pRAB10) that are exquisitely selective for LRRK2-phosphorylated Rab10, detecting endogenous phosphorylated Rab10 in all analysed cell lines and tissues, including human brain cingulate cortex. We demonstrate that the MJFF pRAB10 antibodies can be deployed to assess enhanced Rab10 phosphorylation resulting from pathogenic (R1441C/G or G2019S) LRRK2 knock-in mutations as well as the impact of LRRK2 inhibitor treatment. We also identify rabbit monoclonal antibodies displaying broad specificity (MJFF-pRAB8) that can be utilised to assess LRRK2-controlled phosphorylation of a range of endogenous Rab proteins, including Rab8A, Rab10 and Rab35. The antibodies described in the present study will help with the assessment of LRRK2 activity and examination of which Rab proteins are phosphorylated in vivo These antibodies could also be used to assess the impact of LRRK2 inhibitors in future clinical trials. PMID- 29127258 TI - Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly. AB - BACKGROUND: Bardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype. METHODS: SNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity. RESULTS: Patients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating CEP19 c.194_195insA (p.Tyr65*) mutation. We also found glioma-associated oncogene homolog 1(GLI1) c.820G>C (p.Gly274Arg) in the homozygous state in most patients. In silico modelling strongly suggests that it is damaging. Also, different combinations of four possible modifier alleles in BBS-related genes were detected. Two are known modifier alleles for BBS, splicing variant CCDC28B c.330C>T and missense MKKS/BBS6 p.Ile339Val, and the others are C8ORF37/BBS21 p.Ala178Val and TMEM67/BBS14 modifier p.Asp799Asp. Some patients carry all those five known/possible modifier alleles. Such variants are highly significantly more abundant in our patients than in a control group. CONCLUSION: CEP19 encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in GLI1, encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state. PMID- 29127259 TI - Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome. AB - BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS: In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome. PMID- 29127260 TI - An Improved Brome mosaic virus Silencing Vector: Greater Insert Stability and More Extensive VIGS. AB - Virus-induced gene silencing (VIGS) is used extensively for gene function studies in plants. VIGS is inexpensive and rapid compared with silencing conducted through stable transformation, but many virus-silencing vectors, especially in grasses, induce only transient silencing phenotypes. A major reason for transient phenotypes is the instability of the foreign gene fragment (insert) in the vector during VIGS. Here, we report the development of a Brome mosaic virus (BMV)-based vector that better maintains inserts through modification of the original BMV vector RNA sequence. Modification of the BMV RNA3 sequence yielded a vector, BMVCP5, that better maintained phytoene desaturase and heat shock protein70-1 (HSP70-1) inserts in Nicotiana benthamiana and maize (Zea mays). Longer maintenance of inserts was correlated with greater target gene silencing and more extensive visible silencing phenotypes displaying greater tissue penetration and involving more leaves. The modified vector accumulated similarly to the original vector in N. benthamiana after agroinfiltration, thus maintaining a high titer of virus in this intermediate host used to produce virus inoculum for grass hosts. For HSP70, silencing one family member led to a large increase in the expression of another family member, an increase likely related to the target gene knockdown and not a general effect of virus infection. The cause of the increased insert stability in the modified vector is discussed in relationship to its recombination and accumulation potential. The modified vector will improve functional genomic studies in grasses, and the conceptual methods used to improve the vector may be applied to other VIGS vectors. PMID- 29127261 TI - SHORTROOT-Mediated Increase in Stomatal Density Has No Impact on Photosynthetic Efficiency. AB - The coordinated positioning of veins, mesophyll cells, and stomata across a leaf is crucial for efficient gas exchange and transpiration and, therefore, for overall function. In monocot leaves, stomatal cell files are positioned at the flanks of underlying longitudinal leaf veins, rather than directly above or below. This pattern suggests either that stomatal formation is inhibited in epidermal cells directly in contact with the vein or that specification is induced in cell files beyond the vein. The SHORTROOT pathway specifies distinct cell types around the vasculature in subepidermal layers of both root and shoots, with cell type identity determined by distance from the vein. To test whether the pathway has the potential to similarly pattern epidermal cell types, we expanded the expression domain of the rice (Oryza sativa ssp japonica) OsSHR2 gene, which we show is restricted to developing leaf veins, to include bundle sheath cells encircling the vein. In transgenic lines, which were generated using the orthologous ZmSHR1 gene to avoid potential silencing of OsSHR2, stomatal cell files were observed both in the normal position and in more distant positions from the vein. Contrary to theoretical predictions, and to phenotypes observed in eudicot leaves, the increase in stomatal density did not enhance photosynthetic capacity or increase mesophyll cell density. Collectively, these results suggest that the SHORTROOT pathway may coordinate the positioning of veins and stomata in monocot leaves and that distinct mechanisms may operate in monocot and eudicot leaves to coordinate stomatal patterning with the development of underlying mesophyll cells. PMID- 29127262 TI - Evidence for Selection-by-Environment but Not Genotype-by-Environment Interactions for Fitness-Related Traits in a Wild Mammal Population. AB - How do environmental conditions influence selection and genetic variation in wild populations? There is widespread evidence for selection-by-environment interactions (S*E), but we reviewed studies of natural populations estimating the extent of genotype-by-environment interactions (G*E) in response to natural variation in environmental conditions and found that evidence for G*E appears to be rare within single populations in the wild. Studies estimating the simultaneous impact of environmental variation on both selection and genetic variation are especially scarce. Here, we used 24 years of data collected from a wild Soay sheep population to quantify how an important environmental variable, population density, impacts upon (1) selection through annual contribution to fitness and (2) expression of genetic variation, in six morphological and life history traits: body weight, hind leg length, parasite burden, horn length, horn growth, and testicular circumference. Our results supported the existence of S*E: selection was stronger in years of higher population density for all traits apart from horn growth, with directional selection being stronger under more adverse conditions. Quantitative genetic models revealed significant additive genetic variance for body weight, leg length, parasite burden, horn length, and testes size, but not for horn growth or our measure of annual fitness. However, random regression models found variation between individuals in their responses to the environment in only three traits, and did not support the presence of G*E for any trait. Our analyses of St Kilda Soay sheep data thus concurs with our cross-study review that, while natural environmental variation within a population can profoundly alter the strength of selection on phenotypic traits, there is less evidence for its effect on the expression of genetic variance in the wild. PMID- 29127263 TI - Coalescent Processes with Skewed Offspring Distributions and Nonequilibrium Demography. AB - Nonequilibrium demography impacts coalescent genealogies leaving detectable, well studied signatures of variation. However, similar genomic footprints are also expected under models of large reproductive skew, posing a serious problem when trying to make inference. Furthermore, current approaches consider only one of the two processes at a time, neglecting any genomic signal that could arise from their simultaneous effects, preventing the possibility of jointly inferring parameters relating to both offspring distribution and population history. Here, we develop an extended Moran model with exponential population growth, and demonstrate that the underlying ancestral process converges to a time inhomogeneous psi-coalescent. However, by applying a nonlinear change of time scale-analogous to the Kingman coalescent-we find that the ancestral process can be rescaled to its time-homogeneous analog, allowing the process to be simulated quickly and efficiently. Furthermore, we derive analytical expressions for the expected site-frequency spectrum under the time-inhomogeneous psi-coalescent, and develop an approximate-likelihood framework for the joint estimation of the coalescent and growth parameters. By means of extensive simulation, we demonstrate that both can be estimated accurately from whole-genome data. In addition, not accounting for demography can lead to serious biases in the inferred coalescent model, with broad implications for genomic studies ranging from ecology to conservation biology. Finally, we use our method to analyze sequence data from Japanese sardine populations, and find evidence of high variation in individual reproductive success, but few signs of a recent demographic expansion. PMID- 29127265 TI - Mortality and health-related habits in 900 Finnish former elite athletes and their brothers. AB - BACKGROUND: There is conflicting evidence on the associations between participation in vigorous sports, health habits, familial factors and subsequent mortality. We investigated all-cause mortality and health-related behaviour among former elite athletes and their brothers. METHODS: The mortality of Finnish male former elite athletes, who had represented Finland between 1920 and 1965 (n=900) and their age-matched brothers (n=900), was followed from the time when athlete started an elite athlete career until 31 December 2015. The age-adjusted HRs were calculated by a paired Cox proportional hazards model. In 2001, surviving participants (n=199 athletes and n=199 age-matched brothers) reported their self rated health (SRH), physical activity, alcohol consumption and smoking habits in the questionnaire. RESULTS: During the total follow-up period, 1296 deaths (72% of the cohort) occurred. The age-adjusted HRs for all-cause mortality in former athletes was 0.75 (95% CI 0.65 to 0.87, P<0.001) compared with their age-matched brothers. Median age at death was 79.9 years for endurance, 75.9 years for mixed sports and 72.2 years for power sports athletes, and 77.5, 73.7 and 72.2 years for their age-matched brothers, respectively. In 2001, compared with their brothers, former athletes smoked less (P<0.001), were more physically active (P<0.05) and rated their health more often as very good (P<0.05). CONCLUSIONS: Former elite athletes are more physically active, smoke less, have better self rated health and live longer than their brothers. Genetic differences between athletes and brothers, aerobic training for endurance elite sports and a healthier lifestyle may all contribute to reduced mortality. PMID- 29127266 TI - Injuries in female and male elite taekwondo athletes: a 10-year prospective, epidemiological study of 1466 injuries sustained during 250 000 training hours. AB - OBJECTIVES: We aimed to determine the injury patterns associated with training activities in elite South Korean taekwondo athletes training for the Olympic Games. METHODS: We collected data prospectively from 2007 to 2016 at the Korea National Training Center in Seoul, South Korea. A sports injury was defined as acute or chronic musculoskeletal signs and symptoms due to taekwondo activities during training sessions. Athletes were assessed by an on-site sports medicine specialist. The elite taekwondo athletes were stratified according to sex, weight class (flyweight, featherweight, welterweight and heavyweight), injury location (body region and site) and injury severity (mild or level I, requiring treatment for 1-3 days; moderate or level II, requiring treatment for 4-7 days; or severe or level III, requiring treatment for >=8 days). RESULTS: Athlete exposure was 56 160 training sessions that took 249 600 hours. 1466 injuries were recorded in 283 athletes, with an average of 4.6 injuries per athlete annually. Of these, more than half (56%) were mild injuries, with most injuries occurring in the lower extremities (65.5%), followed by injuries to the trunk (16%), upper extremities (14%) and head and neck area (4%). Among these athletes, women had higher injury rates in the featherweight and welterweight categories (P<=0.0001), but there were no sex differences in other weight categories. In general, female athletes and male athletes experienced a comparable risk of injury (relative ratio: 1.55; 95% CI 0.89 to 2.68). CONCLUSION: In elite South Korean taekwondo athletes, most injuries occur in the lower extremities and were graded as minor. Injury severity depended on weight class. PMID- 29127264 TI - Protein Moonlighting Revealed by Noncatalytic Phenotypes of Yeast Enzymes. AB - A single gene can partake in several biological processes, and therefore gene deletions can lead to different-sometimes unexpected-phenotypes. However, it is not always clear whether such pleiotropy reflects the loss of a unique molecular activity involved in different processes or the loss of a multifunctional protein. Here, using Saccharomyces cerevisiae metabolism as a model, we systematically test the null hypothesis that enzyme phenotypes depend on a single annotated molecular function, namely their catalysis. We screened a set of carefully selected genes by quantifying the contribution of catalysis to gene deletion phenotypes under different environmental conditions. While most phenotypes were explained by loss of catalysis, slow growth was readily rescued by a catalytically inactive protein in about one-third of the enzymes tested. Such noncatalytic phenotypes were frequent in the Alt1 and Bat2 transaminases and in the isoleucine/valine biosynthetic enzymes Ilv1 and Ilv2, suggesting novel "moonlighting" activities in these proteins. Furthermore, differential genetic interaction profiles of gene deletion and catalytic mutants indicated that ILV1 is functionally associated with regulatory processes, specifically to chromatin modification. Our systematic study shows that gene loss phenotypes and their genetic interactions are frequently not driven by the loss of an annotated catalytic function, underscoring the moonlighting nature of cellular metabolism. PMID- 29127267 TI - Cervicovestibular rehabilitation following sport-related concussion. PMID- 29127269 TI - Intracerebral Hemorrhage and Outcome After Thrombolysis in Stroke Patients Using Selective Serotonin-Reuptake Inhibitors. AB - BACKGROUND AND PURPOSE: Selective serotonin-reuptake inhibitors (SSRIs) impair platelet function and have been linked to a higher risk of spontaneous intracerebral hemorrhage-an association that may be augmented by oral anticoagulants (OAC). We aimed to assess whether preadmission treatment with SSRIs in patients with acute ischemic stroke is associated with post-thrombolysis symptomatic intracerebral hemorrhage (sICH) and functional outcome. METHODS: A multicenter retrospective analysis was conducted in prospective registries of patients treated by thrombolysis within 4.5 hours of stroke onset. The association between preadmission treatment with SSRIs and sICH (ECASS II definition [European Cooperative Acute Stroke Study]) or unfavorable 3-month outcome (modified Rankin Scale >2) was assessed by logistic regression, taking into account potential interaction with concomitant use of antithrombotics. RESULTS: Six thousand two hundred forty-two patients were included (mean age, 70.1+/-14.0 years; median National Institutes of Health Stroke Scale, 9 [5-16]). Preadmission treatment with SSRIs was present in 4.3% (n=266) of patients. Overall, SICH rate was 3.9% (95% confidence interval [CI], 3.5%-4.4%; n=244), and SSRI use was not significantly associated with sICH in unadjusted (odds ratio [OR], 1.28; 95% CI, 0.72-2.27) or adjusted (OR, 1.30; 95% CI, 0.71-2.40) analysis. However, there was a significant interaction of concomitant use of OACs (international normalized ratio <1.7) and SSRI for occurrence of sICH (P=0.01). SICH was significantly more frequent in patients taking both OAC and SSRI (23.1%; 95% CI, 8.2%-50.3%) than in patients taking OAC but not SSRI (adjusted OR, 9.04; 95% CI, 1.95-41.89). Preadmission use of SSRI was associated with unfavorable 3 month outcome (unadjusted OR, 1.90; 95% CI, 1.48-2.46; adjusted OR, 1.59; 95% CI, 1.15-2.19). CONCLUSIONS: Preadmission treatment with SSRIs was not significantly associated with an increased risk of post-thrombolysis sICH in this cohort study. However, subgroup analysis suggested an increased risk of sICH in patients taking both SSRI and OAC. Preadmission treatment with SSRIs was associated with unfavorable outcome, which may reflect the prognostic significance of prestroke depression. PMID- 29127270 TI - Low-Dose Tirofiban Improves Functional Outcome in Acute Ischemic Stroke Patients Treated With Endovascular Thrombectomy. AB - BACKGROUND AND PURPOSE: Chinese patients largely experience acute ischemic stroke (AIS) because of large artery atherosclerosis rather than cardioembolism, and whether tirofiban is safe and effective in these patients treated with endovascular thrombectomy (ET) is unknown. This study evaluated the safety and efficacy of tirofiban in Chinese patients with AIS treated with ET. METHODS: This observational study is based on a single-center prospective registry study. Patients with AIS undergoing ET with second-generation stent retrievers from January 2013 to February 2017 were treated with ET alone or ET plus low dose of tirofiban. The primary outcome was symptomatic intracerebral hemorrhage (sICH). The secondary outcomes included rate of early reocclusion, any ICH, fatal ICH, and 3-month and long-term functional outcomes. RESULTS: One hundred eighty AIS subjects were included in the analysis, including 90 subjects treated with tirofiban and 90 subjects without tirofiban. Sixty-three subjects (35%) had any ICH, 19 of them (11%) were sICH, and 9 of them (5%) were fatal ICH. Ten subjects (11%) treated with tirofiban experienced sICH and 9 subjects (10%) not given tirofiban experienced sICH, not a significant difference (P=0.808). Early reocclusion happened in 4 of 90 subjects (4.4%) treated with tirofiban and 8 of 90 subjects (8.9%) not treated with tirofiban (P=0.370). One hundred sixty-one subjects (89%) completed long-term follow-up, subjects treated tirofiban were associated with lower odds of death (23% versus 44%, P=0.005) when compared with those who were not treated. Additionally, tirofiban was associated with better odds of long-term functional independence (adjusted odds ratio, 4.37; 95% confidence interval, 1.13-16.97; P=0.033). CONCLUSIONS: In patients with AIS undergoing ET, tirofiban is not associated with higher sICH, it seems to lead to lower odds of deaths and better odds of long-term functional independence. Further investigations are needed to determine the efficacy of tirofiban in preventing early reocclusion, the underlying mechanisms, and its optimal treatment protocol. PMID- 29127268 TI - Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment. AB - BACKGROUND AND PURPOSE: The effects of lytic stroke therapy in patients with sickle cell anemia are unknown, although a recent study suggested that coexistent sickle cell anemia does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, and then in patients. There is also a need for additional predictive markers of sickle cell anemia-associated vasculopathy. METHODS: We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive mild hypoxia-ischemia- and transient hypoxia-ischemia-induced stroke at 3 or 6 months of age, respectively. We also examined the effects of tPA (tissue-type plasminogen activator) treatment in transient hypoxia-ischemia-injured sickle mice. RESULTS: Three-month-old sickle cell (SS) mice showed elevated resistive index in the carotid artery and higher sensitivity to repetitive mild hypoxia-ischemia-induced cerebral infarct. Six-month-old SS mice showed greater resistive index and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of PAI-1 (plasminogen activator inhibitor-1) and P-selectin, suggesting a proadhesive and prothrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortality after transient hypoxia-ischemia. Yet, post-transient hypoxia-ischemia treatment with tPA reduced thrombosis and mortality in SS mice. CONCLUSIONS: Sickle mice are sensitive to hypoxia/ischemia-induced cerebral infarct but benefit from thrombolytic treatment. An increased resistive index in carotid arteries may be an early marker of sickle cell vasculopathy. PMID- 29127271 TI - Whole Grain Consumption and Risk of Ischemic Stroke: Results From 2 Prospective Cohort Studies. AB - BACKGROUND AND PURPOSE: Higher intake of whole grains may exert cardiometabolic benefits, although findings on stroke risk are inconclusive. The potentially differential effects of individual whole grain foods on ischemic stroke have not been examined. METHODS: We analyzed whole grain consumption in relation to ischemic stroke among 71 750 women from the Nurses' Health Study and 42 823 men from the Health Professionals Follow-up Study who were free of cardiovascular disease, diabetes mellitus, and cancer at baseline (1984 and 1986, respectively) through 2010 using a Cox proportional hazards model. Validated semiquantitative food frequency questionnaires were used to assess consumption of whole grain intake, including whole grain cold breakfast cereal, dark bread, oatmeal, brown rice, popcorn, bran, and germ. Self-reported incident cases of ischemic stroke were confirmed through medical record review. RESULTS: During 2 820 128 person years of follow-up in the 2 cohorts, 2458 cases of ischemic stroke were identified and confirmed. Intake of total whole grains was not associated with risk of ischemic stroke after adjustment for covariates: the pooled hazard ratio (95% confidence interval) comparing extreme intake levels was 1.04 (0.91-1.19). However, intake of whole grain cold breakfast cereal and total bran was inversely associated with ischemic stroke after multivariate adjustment: the pooled hazard ratios (95% confidence intervals) were 0.88 (0.80-0.96; Ptrend=0.008) and 0.89 (0.79-1.00; Ptrend=0.004), respectively. Other whole grain foods were not associated with a lower risk of ischemic stroke. CONCLUSIONS: Although overall consumption of whole grains was not associated with lower risk of ischemic stroke, greater consumption of whole grain cold breakfast cereal and bran was significantly associated with a lower risk of ischemic stroke. More studies are needed to replicate these associations between individual whole grain foods and risk of ischemic stroke among other populations. PMID- 29127273 TI - Correction: Quality standards in upper gastrointestinal endoscopy: a position statement of the British Society of Gastroenterology (BSG) and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS). PMID- 29127272 TI - Structural Integrity of Normal Appearing White Matter and Sex-Specific Outcomes After Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Women have worse poststroke outcomes than men. We evaluated sex-specific clinical and neuroimaging characteristics of white matter in association with functional recovery after acute ischemic stroke. METHODS: We performed a retrospective analysis of acute ischemic stroke patients with admission brain MRI and 3- to 6-month modified Rankin Scale score. White matter hyperintensity and acute infarct volume were quantified on fluid-attenuated inversion recovery and diffusion tensor imaging MRI, respectively. Diffusivity anisotropy metrics were calculated in normal appearing white matter contralateral to the acute ischemia. RESULTS: Among 319 patients with acute ischemic stroke, women were older (68.0 versus 62.7 years; P=0.004), had increased incidence of atrial fibrillation (21.4% versus 12.2%; P=0.04), and lower rate of tobacco use (21.1% versus 35.9%; P=0.03). There was no sex-specific difference in white matter hyperintensity volume, acute infarct volume, National Institutes of Health Stroke Scale, prestroke modified Rankin Scale score, or normal appearing white matter diffusivity anisotropy metrics. However, women were less likely to have an excellent outcome (modified Rankin Scale score <2: 49.6% versus 67.0%; P=0.005). In logistic regression analysis, female sex and the interaction of sex with fractional anisotropy, radial diffusivity, and axial diffusivity were independent predictors of functional outcome. CONCLUSIONS: Female sex is associated with decreased likelihood of excellent outcome after acute ischemic stroke. The correlation between markers of white matter integrity and functional outcomes in women, but not men, suggests a potential sex-specific mechanism. PMID- 29127274 TI - Effect of Hydrogen-Rich Saline on Postoperative Intra-Abdominal Adhesion Bands Formation in Mice. AB - BACKGROUND Postsurgical peritoneal adhesions (PPAs) are pathologic fibrous bands within the peritoneal cavity. The aim of this study was to investigate the protective effect of hydrogen-rich saline (HRS) on PPAs formation in mice. MATERIAL AND METHODS Adhesions were induced in mice using the cecum rubbing model. The mice were allocated into 4 groups: control sham group without cecum rubbing; PPA group with saline applied intraperitoneally (i.p.) daily after cecum rubbing; PPA+HRS (5) group with 5 ml/kg of HRS applied i.p. daily after cecum rubbing; and PPA+HRS (10) group with 10 ml/kg of HRS applied i.p. daily after cecum rubbing. On the 1st, 3rd, and 7th days after the operation, mice were killed and pathological adhesion bands were quantified to detect the effect of HRS on PPAs formation. RESULTS HRS did not affect PPAs formation on the 1st day, but did make a significant reduction on the 3rd and 7th days. A significant increase of t-PA and decrease of TGF-b1 and PAI-1 in the peritoneal fluids were observed in the HRS-treated groups. The levels of MDA and MPO in the HRS-treated groups were significantly lower than those in the PPA group. TNF-alpha and IL-6 levels in HRS-treated groups significantly decreased compared with those in the PPA group on postoperative day 3 and 7. Moreover, HRS decreased the mRNA levels of pro-inflammatory cytokines and TGF-beta1 expression in the postsurgical adhesion bands. CONCLUSIONS These results showed that HRS had therapeutic potential for preventing PPAs formation, possibly through balancing the expression of TGF-beta1, t-PA, and PAI-1, and inhibiting oxidative stress and inflammation. PMID- 29127275 TI - Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next generation HSCT-mediated therapies for solid organ tolerance, cure of non malignant hematological disease, and HIV reservoir clearance. PMID- 29127276 TI - Multicolor lineage tracing reveals clonal architecture and dynamics in colon cancer. AB - Colon cancers are composed of phenotypically heterogeneous tumor cell subpopulations with variable expression of putative stem cell and differentiation antigens. While in normal colonic mucosa, clonal repopulation occurs along differentiation gradients from crypt base toward crypt apex, the clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. Using a multicolor lineage tracing approach in colon cancer xenografts that reflect primary colon cancer architecture, we here demonstrate that clonal outgrowth is mainly driven by tumor cells located at the leading tumor edge with clonal axis formation toward the tumor center. While our findings are compatible with lineage outgrowth in a cancer stem cell model, they suggest that in colorectal cancer tumor cell position may be more important for clonal outgrowth than tumor cell phenotype. PMID- 29127277 TI - Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology. AB - Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine refractory cancer cell lines when used in combination with gemcitabine. Here we report a reverse proteomic approach that identifies the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors, such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target. PMID- 29127278 TI - The North American bullfrog draft genome provides insight into hormonal regulation of long noncoding RNA. AB - Frogs play important ecological roles, and several species are important model organisms for scientific research. The globally distributed Ranidae (true frogs) are the largest frog family, and have substantial evolutionary distance from the model laboratory Xenopus frog species. Unfortunately, there are currently no genomic resources for the former, important group of amphibians. More widely applicable amphibian genomic data is urgently needed as more than two-thirds of known species are currently threatened or are undergoing population declines. We report a 5.8 Gbp (NG50 = 69 kbp) genome assembly of a representative North American bullfrog (Rana [Lithobates] catesbeiana). The genome contains over 22,000 predicted protein-coding genes and 6,223 candidate long noncoding RNAs (lncRNAs). RNA-Seq experiments show thyroid hormone causes widespread transcriptional change among protein-coding and putative lncRNA genes. This initial bullfrog draft genome will serve as a key resource with broad utility including amphibian research, developmental biology, and environmental research. PMID- 29127280 TI - Electrostrictive microelectromechanical fibres and textiles. AB - Microelectromechanical systems (MEMS) enable many modern-day technologies, including actuators, motion sensors, drug delivery systems, projection displays, etc. Currently, MEMS fabrication techniques are primarily based on silicon micromachining processes, resulting in rigid and low aspect ratio structures. In this study, we report on the discovery of MEMS functionality in fibres, thereby opening a path towards flexible, high-aspect ratio, and textile MEMS. The method used for generating these MEMS fibres leverages a preform-to-fibre thermal drawing process, in which the MEMS architecture and materials are embedded into a preform and drawn into kilometers of microstructured multimaterial fibre devices. The fibre MEMS functionality is enabled by an electrostrictive P(VDF-TrFE-CFE) ferrorelaxor terpolymer layer running the entire length of the fibre. Several modes of operation are investigated, including thickness-mode actuation with over 8% strain at 25 MV m-1, bending-mode actuation due to asymmetric positioning of the electrostrictive layer, and resonant fibre vibration modes tunable under AC driving conditions. PMID- 29127279 TI - The emergence of piRNAs against transposon invasion to preserve mammalian genome integrity. AB - Transposable elements (TEs) contribute to the large amount of repetitive sequences in mammalian genomes and have been linked to species-specific genome innovations by rewiring regulatory circuitries. However, organisms need to restrict TE activity to ensure genome integrity, especially in germline cells to protect the transmission of genetic information to the next generation. This review features our current understandings of mammalian PIWI-interacting RNAs (piRNAs) and their role in TE regulation in spermatogenesis. Here we discuss functional implication and explore additional molecular mechanisms that inhibit transposon activity and altogether illustrate the paradoxical arms race between genome evolution and stability. PMID- 29127282 TI - Nanoscale design of polarization in ultrathin ferroelectric heterostructures. AB - The success of oxide electronics depends on the ability to design functional properties such as ferroelectricity with atomic accuracy. However, despite tremendous advances in ferroelectric heterostructures, the development towards multilevel architectures with precise layer-by-layer command over the polarization is impeded by the lack of continuous control over the balance of electrostatics, strain, chemistry and film thickness during growth. Moreover, the polarization in the deeper layers becomes inaccessible when these are buried by the ongoing deposition. Taking ferroelectric BaTiO3 and multiferroic BiFeO3 as model systems, we observe and engineer the emergence, orientation and interaction of ferroelectric polarization in ultrathin heterostructures with monolayer accuracy. We achieve this by optical second harmonic generation which tracks the evolution of spontaneous polarization in real time throughout the deposition process. Such direct and in situ access to the polarization during growth leads us to heterostructures with user-defined polarization sequences-towards a new class of functional ferroic materials. PMID- 29127281 TI - Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease. AB - Elevated sphingosine 1-phosphate (S1P) is detrimental in Sickle Cell Disease (SCD), but the mechanistic basis remains obscure. Here, we report that increased erythrocyte S1P binds to deoxygenated sickle Hb (deoxyHbS), facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increases deoxyHbS polymerization, sickling, hemolysis and disease progression. Functional studies revealed that S1P and 2,3-BPG work synergistically to decrease both HbA and HbS oxygen binding affinity. The crystal structure at 1.9 A resolution deciphered that S1P binds to the surface of 2,3-BPG-deoxyHbA and causes additional conformation changes to the T-state Hb. Phosphate moiety of the surface bound S1P engages in a highly positive region close to alpha1-heme while its aliphatic chain snakes along a shallow cavity making hydrophobic interactions in the "switch region", as well as with alpha2-heme like a molecular "sticky tape" with the last 3-4 carbon atoms sticking out into bulk solvent. Altogether, our findings provide functional and structural bases underlying S1P-mediated pathogenic metabolic reprogramming in SCD and novel therapeutic avenues. PMID- 29127283 TI - Environmental sensing by mature B cells is controlled by the transcription factors PU.1 and SpiB. AB - Humoral immunity requires B cells to respond to multiple stimuli, including antigen, membrane and soluble ligands, and microbial products. Ets family transcription factors regulate many aspects of haematopoiesis, although their functions in humoral immunity are difficult to decipher as a result of redundancy between the family members. Here we show that mice lacking both PU.1 and SpiB in mature B cells do not generate germinal centers and high-affinity antibody after protein immunization. PU.1 and SpiB double-deficient B cells have a survival defect after engagement of CD40 or Toll-like receptors (TLR), despite paradoxically enhanced plasma cell differentiation. PU.1 and SpiB regulate the expression of many components of the B cell receptor signaling pathway and the receptors for CD40L, BAFF and TLR ligands. Thus, PU.1 and SpiB enable B cells to appropriately respond to environmental cues. PMID- 29127285 TI - Real-space and real-time dynamics of CRISPR-Cas9 visualized by high-speed atomic force microscopy. AB - The CRISPR-associated endonuclease Cas9 binds to a guide RNA and cleaves double stranded DNA with a sequence complementary to the RNA guide. The Cas9-RNA system has been harnessed for numerous applications, such as genome editing. Here we use high-speed atomic force microscopy (HS-AFM) to visualize the real-space and real time dynamics of CRISPR-Cas9 in action. HS-AFM movies indicate that, whereas apo Cas9 adopts unexpected flexible conformations, Cas9-RNA forms a stable bilobed structure and interrogates target sites on the DNA by three-dimensional diffusion. These movies also provide real-time visualization of the Cas9-mediated DNA cleavage process. Notably, the Cas9 HNH nuclease domain fluctuates upon DNA binding, and subsequently adopts an active conformation, where the HNH active site is docked at the cleavage site in the target DNA. Collectively, our HS-AFM data extend our understanding of the action mechanism of CRISPR-Cas9. PMID- 29127286 TI - Correspondence: Reply to 'Revisiting the theoretical cell membrane thermal capacitance response'. PMID- 29127284 TI - A thermostable Cas9 with increased lifetime in human plasma. AB - CRISPR-Cas9 is a powerful technology that has enabled genome editing in a wide range of species. However, the currently developed Cas9 homologs all originate from mesophilic bacteria, making them susceptible to degradation and unsuitable for applications requiring cleavage at elevated temperatures. Here, we show that the Cas9 protein from the thermophilic bacterium Geobacillus stearothermophilus (GeoCas9) catalyzes RNA-guided DNA cleavage at elevated temperatures. GeoCas9 is active at temperatures up to 70 degrees C, compared to 45 degrees C for Streptococcus pyogenes Cas9 (SpyCas9), which expands the temperature range for CRISPR-Cas9 applications. We also found that GeoCas9 is an effective tool for editing mammalian genomes when delivered as a ribonucleoprotein (RNP) complex. Together with an increased lifetime in human plasma, the thermostable GeoCas9 provides the foundation for improved RNP delivery in vivo and expands the temperature range of CRISPR-Cas9. PMID- 29127287 TI - Molecular speciation and transformation of soil legacy phosphorus with and without long-term phosphorus fertilization: Insights from bulk and microprobe spectroscopy. AB - Soil legacy phosphorus (P) represents a substantial secondary P resource to postpone the global P crisis. To fully utilize this P reserve, the transformation of legacy P speciation in a black soil with and without P fertilization for 27 years was investigated by chemical fractionation, molecular-level bulk (P K-edge X-ray absorption near-edge, XANES; solution 31P nuclear magnetic resonance) and microprobe (u-X-ray fluorescence and u-XANES) spectroscopy. Results from both fractionation and P bulk-XANES concordantly indicated that Ca2-P [Ca(H2PO4)2] acts as a reserve of labile P in response to soils with or without P fertilization. Cropping for 27 years depleted hydroxyapatite while enriched iron bound P in soils irrespective of P application. Similar accumulation of soil organic P (Po), probably due to root residue inputs, occurred in both soils with and without P fertilization; the accumulated Po was present as orthophosphate diesters in soils with P fertilization more than in soils without P fertilization, suggesting that the release of labile Po was triggered by soil P deficits. These results provide vital information for agronomically and environmentally sustainable P management by demonstrating the potential crop availability of legacy soil P, which could reduce future P fertilization. PMID- 29127289 TI - Probing dopant segregation in distinct cation sites at perovskite oxide polycrystal interfaces. AB - Although theoretical studies and experimental investigations have demonstrated the presence of space-charge-induced dopant segregation, most work has been confined largely to the crystal-free surface and some special grain boundaries, and to the best of our knowledge there has been no systematic comparison to understand how the segregation varies at different types of interfaces in polycrystals. Here, through atomic-column resolved scanning transmission electron microscopy in real polycrystalline samples, we directly elucidate the space charge segregation features at five distinct types of interfaces in an ABO3 perovskite oxide doped with A- and B-site donors. A series of observations reveals that both the interfacial atomic structure and the subsequent segregation behaviour are invariant regardless of the interface type. The findings in this study thus suggest that the electrostatic potential variation by the interface excess charge and compensating space charge provides a crucial contribution to determining not only the distribution of dopants but also the interfacial structure in oxides. PMID- 29127288 TI - Novel genetically encoded fluorescent probes enable real-time detection of potassium in vitro and in vivo. AB - Changes in intra- and extracellular potassium ion (K+) concentrations control many important cellular processes and related biological functions. However, our current understanding of the spatiotemporal patterns of physiological and pathological K+ changes is severely limited by the lack of practicable detection methods. We developed K+-sensitive genetically encoded, Forster resonance energy transfer-(FRET) based probes, called GEPIIs, which enable quantitative real-time imaging of K+ dynamics. GEPIIs as purified biosensors are suitable to directly and precisely quantify K+ levels in different body fluids and cell growth media. GEPIIs expressed in cells enable time-lapse and real-time recordings of global and local intracellular K+ signals. Hitherto unknown Ca2+-triggered, organelle specific K+ changes were detected in pancreatic beta cells. Recombinant GEPIIs also enabled visualization of extracellular K+ fluctuations in vivo with 2-photon microscopy. Therefore, GEPIIs are relevant for diverse K+ assays and open new avenues for live-cell K+ imaging. PMID- 29127290 TI - KSRP specifies monocytic and granulocytic differentiation through regulating miR 129 biogenesis and RUNX1 expression. AB - RNA-binding proteins (RBPs) integrate the processing of RNAs into post transcriptional gene regulation, but the direct contribution of them to myeloid cell specification is poorly understood. Here, we report the first global RBP transcriptomic analysis of myeloid differentiation by combining RNA-seq analysis with myeloid induction in CD34+ hematopoietic progenitor cells. The downregulated expression of the KH-Type Splicing Regulatory Protein (KSRP) during monocytopoiesis and up-regulated expression during granulopoiesis suggests that KSRP has divergent roles during monocytic and granulocytic differentiation. A further comparative analysis of miRNA transcripts reveals that KSRP promotes the biogenesis of miR-129, and the expression patterns and roles of miR-129 in myeloid differentiation are equivalent to those of KSRP. Finally, miR-129 directly blocks the expression of Runt Related Transcription Factor 1 (RUNX1), which evokes transcriptional modulation by RUNX1. Based on our findings, KSRP, miR-129, and RUNX1 participate in a regulatory axis to control the outcome of myeloid differentiation. PMID- 29127291 TI - Structural basis of arrestin-3 activation and signaling. AB - A unique aspect of arrestin-3 is its ability to support both receptor-dependent and receptor-independent signaling. Here, we show that inositol hexakisphosphate (IP6) is a non-receptor activator of arrestin-3 and report the structure of IP6 activated arrestin-3 at 2.4-A resolution. IP6-activated arrestin-3 exhibits an inter-domain twist and a displaced C-tail, hallmarks of active arrestin. IP6 binds to the arrestin phosphate sensor, and is stabilized by trimerization. Analysis of the trimerization surface, which is also the receptor-binding surface, suggests a feature called the finger loop as a key region of the activation sensor. We show that finger loop helicity and flexibility may underlie coupling to hundreds of diverse receptors and also promote arrestin-3 activation by IP6. Importantly, we show that effector-binding sites on arrestins have distinct conformations in the basal and activated states, acting as switch regions. These switch regions may work with the inter-domain twist to initiate and direct arrestin-mediated signaling. PMID- 29127292 TI - Thermostability improvement of a Talaromyces leycettanus xylanase by rational protein engineering. AB - Thermophilic xylanases with high catalytic efficiency are of great interest in the biofuel, food and feed industries. This study identified a GH11 xylanase gene, Tlxyn11B, in Talaromyces leycettanus JCM12802. Recombinant TlXyn11B produced in Pichia pastoris is distinguished by high specific activity (8259 +/- 32 U/mg with beechwood xylan as substrate) and excellent pH stability (from 1.0 to 10.5). The beechwood xylan hydrolysates consisted mainly of xylobiose, xylotriose and xylotetraose, thus TlXyn11B could be used for the production of prebiotic xylooligosaccharide. By using the structure-based rational approach, the N-terminal sequence of TlXyn11B was modified for thermostability improvement. Mutants S3F and S3F/D35V/I/Q/M had elevated T m values of 60.01 to 67.84 degrees C, with S3F/D35I the greatest. Homology modeling and molecular dynamics (MD) simulation analysis revealed that the substituted F3 and I35 formed a sandwich structure with S45 and T47, which may enhance the overall structure rigidity with lowered RMSD values. This study verifies the efficiency of rational approach in thermostability improvement and provides a xylanase candidate of GH11 with great commercialization potential. PMID- 29127293 TI - Three dimensional printed polylactic acid-hydroxyapatite composite scaffolds for prefabricating vascularized tissue engineered bone: An in vivo bioreactor model. AB - The repair of large bone defects with complex geometries remains a major clinical challenge. Here, we explored the feasibility of fabricating polylactic acid hydroxyapatite (PLA-HA) composite scaffolds. These scaffolds were constructed from vascularized tissue engineered bone using an in vivo bioreactor (IVB) strategy with three-dimensional printing technology. Specifically, a rabbit model was established to prefabricate vascularized tissue engineered bone in two groups. An experimental group (EG) was designed using a tibial periosteum capsule filled with 3D printed (3DP) PLA-HA composite scaffolds seeded with bone marrow stromal cells (BMSCs) and crossed with a vascular bundle. 3DP PLA-HA scaffolds were also combined with autologous BMSCs and transplanted to tibial periosteum without blood vessel as a control group (CG). After four and eight weeks, neovascularisation and bone tissues were analysed by studying related genes, micro-computed tomography (Micro-CT) and histological examinations between groups. The results showed that our method capably generated vascularized tissue engineered bone in vivo. Furthermore, we observed significant differences in neovascular and new viable bone formation in the two groups. In this study, we demonstrated the feasibility of generating large vascularized bone tissues in vivo with 3DP PLA-HA composite scaffolds. PMID- 29127294 TI - Preventing shivering with adjuvant low dose intrathecal meperidine: A meta analysis of randomized controlled trials with trial sequential analysis. AB - The aim of this systematic review and meta-analysis is to evaluate the pros and cons of adjuvant low dose intrathecal meperidine for spinal anaesthesia. We searched electronic databases for randomized controlled trials using trial sequential analysis (TSA) to evaluate the incidence of reduced rescue analgesics, shivering, pruritus, nausea and vomiting when applying adjuvant intrathecal meperidine. Twenty-eight trials with 2216 patients were included. Adjuvant intrathecal meperidine, 0.05-0.5 mg kg-1, significantly reduced incidence of shivering (relative risk, RR, 0.31, 95% confidence interval, CI, 0.24 to 0.40; TSA-adjusted RR, 0.32, 95% CI, 0.25 to 0.41). Intrathecal meperidine also effectively reduced need for intraoperative rescue analgesics (RR, 0.27, 95% CI, 0.12 to 0.64; TSA-adjusted RR, 0.27, 95% CI, 0.08 to 0.91) and the incidence of pruritus was unaffected (RR, 2.31, 95% CI, 0.94 to 5.70; TSA-adjusted RR, 1.42, 95% CI, 0.87 to 2.34). However, nausea and vomiting increased (RR, 1.84, 95% CI, 1.29 to 2.64; TSA-adjusted RR, 1.72, 95% CI, 1.33 to 2.23; RR, 2.23, 95% CI, 1.23 to 4.02; TSA-adjusted RR,1.96, 95% CI, 1.20 to 3.21). Under TSA, these results provided a sufficient level of evidence. In conclusion, adjuvant low dose intrathecal meperidine effectively attenuates spinal anaesthesia-associated shivering and reduces rescue analgesics with residual concerns for the nausea and vomiting. PMID- 29127296 TI - An electrically reconfigurable logic gate intrinsically enabled by spin-orbit materials. AB - The spin degree of freedom in magnetic devices has been discussed widely for computing, since it could significantly reduce energy dissipation, might enable beyond Von Neumann computing, and could have applications in quantum computing. For spin-based computing to become widespread, however, energy efficient logic gates comprising as few devices as possible are required. Considerable recent progress has been reported in this area. However, proposals for spin-based logic either require ancillary charge-based devices and circuits in each individual gate or adopt principals underlying charge-based computing by employing ancillary spin-based devices, which largely negates possible advantages. Here, we show that spin-orbit materials possess an intrinsic basis for the execution of logic operations. We present a spin-orbit logic gate that performs a universal logic operation utilizing the minimum possible number of devices, that is, the essential devices required for representing the logic operands. Also, whereas the previous proposals for spin-based logic require extra devices in each individual gate to provide reconfigurability, the proposed gate is 'electrically' reconfigurable at run-time simply by setting the amplitude of the clock pulse applied to the gate. We demonstrate, analytically and numerically with experimentally benchmarked models, that the gate performs logic operations and simultaneously stores the result, realizing the 'stateful' spin-based logic scalable to ultralow energy dissipation. PMID- 29127295 TI - Clinical Potential of an Enzyme-based Novel Therapy for Cocaine Overdose. AB - It is a grand challenge to develop a truly effective medication for treatment of cocaine overdose. The current available, practical emergence treatment for cocaine overdose includes administration of a benzodiazepine anticonvulsant agent (e.g. diazepam) and/or physical cooling with an aim to relieve the symptoms. The inherent difficulties of antagonizing physiological effects of drugs in the central nervous system have led to exploring protein-based pharmacokinetic approaches using biologics like vaccines, monoclonal antibodies, and enzymes. However, none of the pharmacokinetic agents has demonstrated convincing preclinical evidence of clinical potential for drug overdose treatment without a question mark on the timing used in the animal models. Here we report the use of animal models, including locomotor activity, protection, and rescue experiments in rats, of drug toxicity treatment with clinically relevant timing for the first time. It has been demonstrated that an efficient cocaine-metabolizing enzyme developed in our previous studies can rapidly reverse the cocaine toxicity whenever the enzyme is given to a living rat, demonstrating promising clinical potential of an enzyme-based novel therapy for cocaine overdose as a successful example in comparison with the commonly used diazepam. PMID- 29127297 TI - Rab5 is critical for SNAP23 regulated granule-granule fusion during compound exocytosis. AB - Compound exocytosis is considered the most massive mode of exocytosis, during which the membranes of secretory granules (SGs) fuse with each other to form a channel through which the entire contents of their granules is released. The underlying mechanisms of compound exocytosis remain largely unresolved. Here we show that the small GTPase Rab5, a known regulator of endocytosis, is pivotal for compound exocytosis in mast cells. Silencing of Rab5 shifts receptor-triggered secretion from a compound to a full exocytosis mode, in which SGs individually fuse with the plasma membrane. Moreover, we show that Rab5 is essential for FcepsilonRI-triggered association of the SNARE protein SNAP23 with the SGs. Direct evidence is provided for SNAP23 involvement in homotypic SG fusion that occurs in the activated cells. Finally, we show that this fusion event is prevented by inhibition of the IKKbeta2 kinase, however, neither a phosphorylation-deficient nor a phosphomimetic mutant of SNAP23 can mediate homotypic SG fusion in triggered cells. Taken together our findings identify Rab5 as a heretofore-unrecognized regulator of compound exocytosis that is essential for SNAP23-mediated granule-granule fusion. Our results also implicate phosphorylation cycles in controlling SNAP23 SNARE function in homotypic SG fusion. PMID- 29127298 TI - Sub genome anchored physical frameworks of the allotetraploid Upland cotton (Gossypium hirsutum L.) genome, and an approach toward reference-grade assemblies of polyploids. AB - Like those of many agricultural crops, the cultivated cotton is an allotetraploid and has a large genome (~2.5 gigabase pairs). The two sub genomes, A and D, are highly similar but unequally sized and repeat-rich, which pose significant challenges for accurate genome reconstruction using standard approaches. Here we report the development of BAC libraries, sub genome specific physical maps, and a new-generation sequencing approach that will lead to a reference-grade genome assembly for Upland cotton. Three BAC libraries were constructed, fingerprinted, and integrated with BAC-end sequences (BES) to produce a de novo whole-genome physical map. The BAC map was partitioned by sub genomes through alignment to the diploid progenitor D-genome reference sequence with densely spaced BES anchor points and computational filtering. The physical maps were validated with FISH and genetic mapping of SNP markers derived from BES. Two pairs of homeologous chromosomes, A11/D11 and A12/D12, were used to assess multiplex sequencing approaches for completeness and scalability. The results represent the first sub genome anchored physical maps of Upland cotton, and a new-generation approach to the whole-genome sequencing, which will lead to the reference-grade assembly of allopolyploid cotton and serve as a general strategy for sequencing other polyploid species. PMID- 29127299 TI - Origin of the omnipotence of eukaryotic release factor 1. AB - Termination of protein synthesis on the ribosome requires that mRNA stop codons are recognized with high fidelity. This is achieved by specific release factor proteins that are very different in bacteria and eukaryotes. Hence, while there are two release factors with overlapping specificity in bacteria, the single omnipotent eRF1 release factor in eukaryotes is able to read all three stop codons. This is particularly remarkable as it is able to select three out of four combinations of purine bases in the last two codon positions. With recently determined 3D structures of eukaryotic termination complexes, it has become possible to explore the origin of eRF1 specificity by computer simulations. Here, we report molecular dynamics free energy calculations on these termination complexes, where relative eRF1 binding free energies to different cognate and near-cognate codons are evaluated. The simulations show a high and uniform discrimination against the near-cognate codons, that differ from the cognate ones by a single nucleotide, and reveal the structural mechanisms behind the precise decoding by eRF1. PMID- 29127300 TI - Publisher Correction: Membrane association of the bacterial riboregulator Hfq and functional perspectives. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29127301 TI - Femtosecond time-resolved observation of butterfly vibration in electronically excited o-fluorophenol. AB - The butterfly vibration during the hydrogen tunneling process in electronically excited o-fluorophenol has been visualized in real time by femtosecond time resolved ion yield spectroscopy coupled with time-resolved photoelectron imaging technique. A coherent superposition of out-of-plane C-F butterfly motions is prepared in the first excited electronic state (S1). As the C-F bond vibrates with respect to the aromatic ring, the nuclear geometry varies periodically, leading to the corresponding variation in the photoionization channel. By virtue of the more favorable ionization probability from the nonplanar minimum via resonance with the Rydberg states, the evolution of the vibrational wave packet is manifested as a superimposed beat in the parent-ion transient. Moreover, time resolved photoelectron spectra offer a direct mapping of the oscillating butterfly vibration between the planar geometry and nonplanar minimum. The beats for the photoelectron peaks originating from the planar geometry are out of phase with those from the nonplanar minimum. Our results provide a physically intuitive and complete picture of the oscillatory flow of energy responsible for the coherent vibrational motion on the excited state surface. PMID- 29127302 TI - Ferroelectric thin film acoustic devices with electrical multiband switching ability. AB - Design principles of a new class of microwave thin film bulk acoustic resonators with multiband resonance frequency switching ability are presented. The theory of the excitation of acoustic eigenmodes in multilayer ferroelectric structures is considered, and the principle of selectivity for resonator with an arbitrary number of ferroelectric layers is formulated. A so called "criterion function" is suggested that allows to determine the conditions for effective excitation at one selected resonance mode with suppression of other modes. The proposed theoretical approach is verifiedusing thepreexisting experimental data published elsewhere. Finally, the possible application of the two ferroelectric layers structures for switchable microwave overtone resonators, binary and quadrature phase-shift keying modulators are discussed. These devices could play a pivotal role in the miniaturization of microwave front-end antenna circuits. PMID- 29127304 TI - On Economic Complexity and the Fitness of Nations. AB - Complex economic systems can often be described by a network, with nodes representing economic entities and edges their interdependencies, while network centrality is often a good indicator of importance. Recent publications have implemented a nonlinear iterative Fitness-Complexity (FC) algorithm to measure centrality in a bipartite trade network, which aims to represent the 'Fitness' of national economies as well as the 'Complexity' of the products being traded. In this paper, we discuss this methodological approach and conclude that further work is needed to identify stable and reliable measures of fitness and complexity. We provide theoretical and numerical evidence for the intrinsic instability in the nonlinear definition of the FC algorithm. We perform an in depth evaluation of the algorithm's rankings in two real world networks at the country level: the global trade network, and the patent network in different technological domains. In both networks, we find evidence of the instabilities predicted theoretically, and show that 'complex' products or patents tend often to be those that countries rarely produce, rather than those that are intrinsically more difficult to produce. PMID- 29127303 TI - Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance. AB - Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs). PTEN, DCDC1 and CUL3 were first reported as SMGs in ESCC. Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC. Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2. Moreover, database annotation suggested that two significantly differential CNA genes (PIK3CA and FBXW7) between subtype3 and subtype2 may serve as therapeutic drug targets. This study has extended our knowledge of the genetic basis of ESCC and shed some light into the clinical relevance, which would help improve the therapy and prognosis of ESCC patients. PMID- 29127305 TI - Cis-SNPs Set Testing and PrediXcan Analysis for Gene Expression Data using Linear Mixed Models. AB - Understanding the functional mechanism of SNPs identified in GWAS on complex diseases is currently a challenging task. The studies of expression quantitative trait loci (eQTL) have shown that regulatory variants play a crucial role in the function of associated SNPs. Detecting significant genes (called eGenes) in eQTL studies and analyzing the effect sizes of cis-SNPs can offer important implications on the genetic architecture of associated SNPs and interpretations of the molecular basis of diseases. We applied linear mixed models (LMM) to the gene expression level and constructed likelihood ratio tests (LRT) to test for eGene in the Geuvadis data. We identified about 11% genes as eGenes in the Geuvadis data and found some eGenes were enriched in approximately independent linkage disequilibrium (LD) blocks (e.g. MHC). We further performed PrediXcan analysis for seven diseases in the WTCCC data with weights estimated using LMM and identified 64, 5, 21 and 1 significant genes (p < 0.05 after Bonferroni correction) associated with T1D, CD, RA and T2D. We found most of the significant genes of T1D and RA were also located within the MHC region. Our results provide strong evidence that gene expression plays an intermediate role for the associated variants in GWAS. PMID- 29127306 TI - Upregulation of microRNA-4417 and Its Target Genes Contribute to Nickel Chloride promoted Lung Epithelial Cell Fibrogenesis and Tumorigenesis. AB - Nickel compounds have been classified as carcinogens and shown to be associated with induction of epithelial-mesenchymal transition (EMT) in fibrogenesis and tumorigenesis, as well as the crucial role of microRNAs (miRNAs) and their related genes in controlling EMT and cancer metastasis. Thus, the mechanisms involved in the regulation of EMT in nickel-treated cells are of potential interest in understanding lung fibrosis and tumor progression. We investigated the miRNA-dependent mechanisms involved in nickel-induced EMT in lung epithelial cells. Nickel increased miR-4417 expression and decreased its target gene TAB2 expression. Treatment of cells with TGF-beta inhibitor SB525334 significantly blocked NiCl2 and TGF-beta-induced EMT. The expression of miR-4417 was abolished by SB525334 in TGF-beta-treated cells, but not in nickel-treated cells. Both overexpression of miR-4417 and silencing of TAB2 induced fibronectin expression, but did not reduce E-cadherin expression. Moreover, oral administration of nickel promoted lung tumor growth in nude mice that had received BEAS-2B transformed cells by intravenous injection. The induction of EMT by nickel is mediated through multiple pathways. Induction of abundant miR-4417 and reduction of TAB2 expression following nickel exposure and may be involved in nickel-induced fibronectin. These findings provide novel insight into the roles of nickel in fibrogenesis and tumor progression. PMID- 29127307 TI - Climate induced human demographic and cultural change in northern Europe during the mid-Holocene. AB - The transition from hunter-gatherer-fisher groups to agrarian societies is arguably the most significant change in human prehistory. In the European plain there is evidence for fully developed agrarian societies by 7,500 cal. yr BP, yet a well-established agrarian society does not appear in the north until 6,000 cal. yr BP for unknown reasons. Here we show a sudden increase in summer temperature at 6,000 cal. yr BP in northern Europe using a well-dated, high resolution record of sea surface temperature (SST) from the Baltic Sea. This temperature rise resulted in hypoxic conditions across the entire Baltic sea as revealed by multiple sedimentary records and supported by marine ecosystem modeling. Comparison with summed probability distributions of radiocarbon dates from archaeological sites indicate that this temperature rise coincided with both the introduction of farming, and a dramatic population increase. The evidence supports the hypothesis that the boundary of farming rapidly extended north at 6,000 cal. yr BP because terrestrial conditions in a previously marginal region improved. PMID- 29127308 TI - A viscous quantum hydrodynamics model based on dynamic density functional theory. AB - Dynamic density functional theory (DDFT) is emerging as a useful theoretical technique for modeling the dynamics of correlated systems. We extend DDFT to quantum systems for application to dense plasmas through a quantum hydrodynamics (QHD) approach. The DDFT-based QHD approach includes correlations in the the equation of state self-consistently, satisfies sum rules and includes irreversibility arising from collisions. While QHD can be used generally to model non-equilibrium, heterogeneous plasmas, we employ the DDFT-QHD framework to generate a model for the electronic dynamic structure factor, which offers an avenue for measuring hydrodynamic properties, such as transport coefficients via x-ray Thomson scattering. PMID- 29127309 TI - Efficient multiparty quantum key agreement with collective detection. AB - As a burgeoning branch of quantum cryptography, quantum key agreement is a kind of key establishing processes where the security and fairness of the established common key should be guaranteed simultaneously. However, the difficulty on designing a qualified quantum key agreement protocol increases significantly with the increase of the number of the involved participants. Thus far, only few of the existing multiparty quantum key agreement (MQKA) protocols can really achieve security and fairness. Nevertheless, these qualified MQKA protocols are either too inefficient or too impractical. In this paper, an MQKA protocol is proposed with single photons in travelling mode. Since only one eavesdropping detection is needed in the proposed protocol, the qubit efficiency and measurement efficiency of it are higher than those of the existing ones in theory. Compared with the protocols which make use of the entangled states or multi-particle measurements, the proposed protocol is more feasible with the current technologies. Security and fairness analysis shows that the proposed protocol is not only immune to the attacks from external eavesdroppers, but also free from the attacks from internal betrayers. PMID- 29127310 TI - Wavefront aberrations and retinal image quality in different lenticular opacity types and densities. AB - To investigate wavefront aberrations in the entire eye and in the internal optics (lens) and retinal image qualities according to different lenticular opacity types and densities. Forty-one eyes with nuclear cataract, 33 eyes with cortical cataract, and 29 eyes with posterior subcapsular cataract were examined. In each group, wavefront aberrations in the entire eye and in the internal optics and retinal image quality were measured using a raytracing aberrometer. Eyes with cortical cataracts showed significantly higher coma-like aberrations compared to the other two groups in both entire eye and internal optic aberrations (P = 0.012 and P = 0.007, respectively). Eyes with nuclear cataract had lower spherical-like aberrations than the other two groups in both entire eye and internal optics aberrations (P < 0.001 and P < 0.001, respectively). In the nuclear cataract group, nuclear lens density was negatively correlated with internal spherical aberrations (r = -0.527, P = 0.005). Wavefront technology is useful for objective and quantitative analysis of retinal image quality deterioration in eyes with different early lenticular opacity types and densities. Understanding the wavefront optical properties of different crystalline lens opacities may help ophthalmic surgeons determine the optimal time to perform cataract surgery. PMID- 29127311 TI - Lensless Photoluminescence Hyperspectral Camera Employing Random Speckle Patterns. AB - We propose and demonstrate a spectrally-resolved photoluminescence imaging setup based on the so-called single pixel camera - a technique of compressive sensing, which enables imaging by using a single-pixel photodetector. The method relies on encoding an image by a series of random patterns. In our approach, the image encoding was maintained via laser speckle patterns generated by an excitation laser beam scattered on a diffusor. By using a spectrometer as the single-pixel detector we attained a realization of a spectrally-resolved photoluminescence camera with unmatched simplicity. We present reconstructed hyperspectral images of several model scenes. We also discuss parameters affecting the imaging quality, such as the correlation degree of speckle patterns, pattern fineness, and number of datapoints. Finally, we compare the presented technique to hyperspectral imaging using sample scanning. The presented method enables photoluminescence imaging for a broad range of coherent excitation sources and detection spectral areas. PMID- 29127312 TI - Progesterone attenuates temporomandibular joint inflammation through inhibition of NF-kappaB pathway in ovariectomized rats. AB - Sex hormones may contribute to the symptomatology of female-predominant temporomandibular disorders (TMDs) inflammatory pain. Pregnant women show less symptoms of TMDs than that of non-pregnant women. Whether progesterone (P4), one of the dominant sex hormones that regulates multiple biological functions, is involved in symptoms of TMDs remains to be explored. Freund's complete adjuvant were used to induce joint inflammation. We evaluated the behavior-related and histologic effects of P4 and the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 in the synovial membrane. Primary TMJ synoviocytes were treated with TNF-alpha or IL-1beta with the combination of P4. Progesterone receptor antagonist RU-486 were further applied. We found that P4 replacement attenuated TMJ inflammation and the nociceptive responses in a dose dependent manner in the ovariectomized rats. Correspondingly, P4 diminished the DNA-binding activity of NF-kappaB and the transcription of its target genes in a dose-dependent manner in the synovial membrane of TMJ. Furthermore, P4 treatment showed decreased mRNA expression of proinflammatory cytokines, and partially reversed TNF-alpha and IL-1beta induced transcription of proinflammatory cytokines in the primary synoviocytes. Moreover, progesterone receptor antagonist RU-486 partially reversed the effects of P4 on NF-kappaB pathway. In conclusion, progesterone ameliorated TMJ inflammation through inhibition of NF-kappaB pathway. PMID- 29127313 TI - Current source density mapping of antennal sensory selectivity reveals conserved olfactory systems between tephritids and Drosophila. AB - Ecological specialization of insects involves the functional and morphological reshaping of olfactory systems. Little is known about the degree to which insect sensitivity to odorant compounds is conserved between genera, tribes, or families. Here we compared the olfactory systems of six tephritid fruit fly species spanning two tribes and the distantly related Drosophila melanogaster at molecular, functional, and morphological levels. Olfaction in these flies is mediated by a set of olfactory receptors (ORs) expressed in different functional classes of neurons located in distinct antennal regions. We performed a phylogenetic analysis that revealed both family-specific OR genes and putative orthologous OR genes between tephritids and Drosophila. With respect to function, we then used a current source density (CSD) analysis to map activity across antennae. Functional maps mirrored the intrinsic structure of antennae observed with scanning electron microscopy. Together, the results revealed partial conservation of the olfactory systems between tephritids and Drosophila. We also demonstrate that the mapping of olfactory responses is necessary to decipher antennal sensory selectivity to olfactory compounds. CSD analysis can be easily applied to map antennae of other species and therefore enables the rapid deriving of olfactory maps and the reconstructing of the target organisms' history of evolution. PMID- 29127314 TI - Modulation of transcriptional mineralocorticoid receptor activity by casein kinase 2. AB - The pathogenesis of cardiovascular diseases is a multifunctional process in which the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, is involved as proven by numerous clinical studies. The development of pathophysiological MR actions depends on the existence of additional factors e.g. inflammatory cytokines and seems to involve posttranslational MR modifications e.g. phosphorylation. Casein kinase 2 (CK2) is a ubiquitously expressed multifunctional serine/threonine kinase that can be activated under inflammatory conditions as the MR. Sequence analysis and inhibitor experiments revealed that CK2 acts as a positive modulator of MR activity by facilitating MR-DNA interaction with subsequent rapid MR degradation. Peptide microarrays and site directed mutagenesis experiments identified the highly conserved S459 as a functionally relevant CK2 phosphorylation site of the MR. Moreover, MR-CK2 protein-protein interaction mediated by HSP90 was shown by co immunoprecipitation. During inflammation, cytokine stimulation led to a CK2 dependent increased expression of proinflammatory genes. The additional MR activation by aldosterone during cytokine stimulation augmented CK2-dependent NFkappaB signaling which enhanced the expression of proinflammatory genes further. Overall, in an inflammatory environment the bidirectional CK2-MR interaction aggravate the existing pathophysiological cellular situation. PMID- 29127315 TI - Human Gingiva-Derived Mesenchymal Stem Cells Ameliorate Streptozoticin-induced T1DM in mice via Suppression of T effector cells and Up-regulating Treg Subsets. AB - There is yet no cure for type 1 diabetes (T1DM) so far. A significant body of evidence has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) showed great potential in controlling T1DM. But there exists much difficulty in using BMSCs as a clinical therapy. We here test whether a new population of mesenchymal stem cells from human gingiva (GMSCs), which has many advantages over BMSCs, can delay or prevent progress of T1DM. GMSCs were adoptively transferred to multiple low-dose streptozotocin (STZ)-induced T1DM. Blood glucose levels and disease severities were analyzed. T cells subsets in blood, spleen and lymph nodes were detected dynamically by flow cytometry. GMSC distribution was dynamically analyzed. We found that infusion of GMSCs but not fibroblast cells significantly controlled blood glucose levels, delayed diabetes onset, ameliorated pathology scores in pancreas, and down-regulated production of IL-17 and IFN-gamma in CD4+ and CD8+ T cells in spleens, pancreatic lymph nodes (pLN) and other lymph nodes. GMSCs also up-regulated the levels of CD4+ Treg induced in the periphery. Mechanismly, GMSCs could migrate to pancreas and local lymph node and function through CD39/CD73 pathway to regulate effector T cells. Thus, GMSCs show a potential promise in treating T1DM in the clinic. PMID- 29127317 TI - Carbon Nanotube Array Based Binary Gabor Zone Plate Lenses. AB - Diffractive zone plates have a wide range of applications from focusing x-ray to extreme UV radiation. The Gabor zone plate, which suppresses the higher-order foci to a pair of conjugate foci, is an attractive alternative to the conventional Fresnel zone plate. In this work, we developed a novel type of Beynon Gabor zone plate based on perfectly absorbing carbon nanotube forest. Lensing performances of 0, 8 and 20 sector Gabor zone plates were experimentally analyzed. Numerical investigations of Beynon Gabor zone plate configurations were in agreement with the experimental results. A high-contrast focal spot having 487 times higher intensity than the average background was obtained. PMID- 29127316 TI - Exercise - induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects. AB - Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) have similar profiles of pain, fatigue, cognitive dysfunction and exertional exhaustion. Post exertional malaise suggests exercise alters central nervous system functions. Lumbar punctures were performed in GWI, CFS and control subjects after (i) overnight rest (nonexercise) or (ii) submaximal bicycle exercise. Exercise induced postural tachycardia in one third of GWI subjects (Stress Test Activated Reversible Tachycardia, START). The remainder were Stress Test Originated Phantom Perception (STOPP) subjects. MicroRNAs (miRNA) in cerebrospinal fluid were amplified by quantitative PCR. Levels were equivalent between nonexercise GWI (n = 22), CFS (n = 43) and control (n = 22) groups. After exercise, START (n = 22) had significantly lower miR-22-3p than control (n = 15) and STOPP (n = 42), but higher miR-9-3p than STOPP. All post-exercise groups had significantly reduced miR-328 and miR-608 compared to nonexercise groups; these may be markers of exercise effects on the brain. Six miRNAs were significantly elevated and 12 diminished in post-exercise START, STOPP and control compared to nonexercise groups. CFS had 12 diminished miRNAs after exercise. Despite symptom overlap of CFS, GWI and other illnesses in their differential diagnosis, exercise-induced miRNA patterns in cerebrospinal fluid indicated distinct mechanisms for post exertional malaise in CFS and START and STOPP phenotypes of GWI. PMID- 29127318 TI - Minimally Invasive Hemostatic Materials: Tackling a Dilemma of Fluidity and Adhesion by Photopolymerization in situ. AB - Hemostasis in vivo is a key to success in minimally invasive surgery (MIS). However, solid hemostatic materials cannot pass through the sheath tube of the MIS apparatus, while liquid ones are restricted by their low adhesion, which leads to them peeling off of tissue. To tackle the dilemma of fluidity and adhesion, a formulation containing a multifunctional sucrose allyl ether (SAE) monomer and an alpha-hydroxyketone liquid photoinitiator (HMPP) was applied as a lead hemostatic material for MIS. Real-time infrared results showed that SAE initiated by HMPP can rapidly polymerize into a transparent crosslinking membrane. Quantum chemistry showed that this occurs via a free radical addition reaction mechanism. Thermodynamic properties, such as reaction driving force and enthalpy change, were similar to those for a corresponding small molecular analogue, allyl methyl ether (AME), but the addition rate was lower than that for AME. The CC50 values of SAE and HMPP were also obtained by cell experiments. A hemostasis experiment in vivo was performed by comparing the formulation with chitosan and a traditional Chinese medicine (Yunnan Baiyao powder). The result showed that the formulation had a competitive advantage for use in MIS. PMID- 29127320 TI - Crystalline Soda Can Metamaterial exhibiting Graphene-like Dispersion at subwavelength scale. AB - Graphene, a honeycomb lattice of carbon atoms ruled by tight-binding interaction, exhibits extraordinary electronic properties due to the presence of Dirac cones within its band structure. These intriguing singularities have naturally motivated the discovery of their classical analogues. In this work, we present a general and direct procedure to reproduce the peculiar physics of graphene within a very simple acoustic metamaterial: a double lattice of soda cans resonating at two different frequencies. The first triangular sub-lattice generates a bandgap at low frequency, which induces a tight-binding coupling between the resonant defects of the second honeycomb one, hence allowing us to obtain a graphene-like band structure. We prove the relevance of this approach by showing that both numerical and experimental dispersion relations exhibit the requested Dirac cone. We also demonstrate the straightforward monitoring of the coupling strength within the crystal of resonant defects. This work shows that crystalline metamaterials are very promising candidates to investigate tantalizing solid state physics phenomena with classical waves. PMID- 29127319 TI - Mitochondrial gene polymorphism is associated with gut microbial communities in mice. AB - Gut microbial communities are key mediators of health and disease and have the capacity to drive the pathogenesis of diverse complex diseases including metabolic and chronic inflammatory diseases as well as aging. Host genetics is also a major determinant of disease phenotypes, whereby two different genomes play a role, the nuclear (nDNA)- and mitochondrial genome (mtDNA). We investigated the impact of mutations in mtDNA on the gut microbiota using conplastic mouse strains exhibiting distinct mutations in their mtDNA on an identical nDNA. Each of three strain tested harbors a distinct gut microbiota, ranging from differences at the phylum- to operational taxonomic units level. The C57BL/6J-mt FVB/NJ strain, carrying a mutation in the mitochondrial ATP8 synthase gene, exhibits higher Firmicutes abundance than Bacteroidetes, indicating a possible indicative for metabolic dysfunctions. In line with this, the C57BL/6J mt FVB/NJ displays a variety of different phenotypes, including increased susceptibility to metabolic-related and inflammatory disorders. Furthermore, we discuss the cross-talk between mitochondrial genome/mitochondria and commensal microbiota in relation to clinical phenotypes. In summary, we demonstrate that mutations in mtDNA lead to significant differences in the composition of gut microbial communities in mice. Such differences may facilitate the emergence of metabolic disease and therefore constitute potential therapeutic targets. PMID- 29127321 TI - Metabolic Profiling of healthy and cancerous tissues in 2D and 3D. AB - Metabolism is a compartmentalized process, and it is apparent in studying cancer that tumors, like normal tissues, demonstrate metabolic cooperation between different cell types. Metabolic profiling of cells in 2D culture systems often fails to reflect the metabolism occurring within tissues in vivo due to lack of other cell types and 3D interaction. We designed a tooling and methodology to metabolically profile and compare 2D cultures with cancer cell spheroids, and microtissue slices from tumors, and normal organs. We observed differences in the basal metabolism of 2D and 3D cell cultures in response to metabolic inhibitors, and chemotherapeutics. The metabolic profiles of microtissues derived from normal organs (heart, kidney) were relatively consistent when comparing microtissues derived from the same organ. Treatment of heart and kidney microtissues with cardio- or nephro-toxins had early and marked effects on tissue metabolism. In contrast, microtissues derived from different regions of the same tumors exhibited significant metabolic heterogeneity, which correlated to histology. Hence, metabolic profiling of complex microtissues is necessary to understand the effects of metabolic co-operation and how this interaction, not only can be targeted for treatment, but this method can be used as a reproducible, early and sensitive measure of drug toxicity. PMID- 29127323 TI - Mechanisms of the decrease in low-temperature electrochemical performance of Li4Ti5O12-based anode materials. AB - The electrochemical performances of Li4Ti5O12 (LTO) and Li4Ti5O12-rutile TiO2 (LTO-RTO) composite electrodes at low temperatures were evaluated. The electrochemical performance of both electrodes decreased at low temperatures; regardless, the LTO-RTO electrode performed better than the LTO electrode. First, high viscosity and low ion conductivity of liquid electrolytes at low temperatures significantly reduce electrochemical performance. Second, cycling at low temperatures changes the crystal structure of LTO-based electrodes, impeding lithium ion diffusion and even causing the diffusion path to change from easy to difficult. However, changes in the crystal structure of the LTO-RTO electrode were not sufficient to change this path; thus, diffusion continued along the 8a 16c-8a pathway. Finally, from the perspective of dynamics, aggravation of a side reaction, increase in charge transfer resistance and polarization, and decrease in lithium ion diffusion at low temperatures reduce the electrochemical performance of LTO-based anode materials. However, the activation energy based on lithium ion diffusion is lower in the LTO-RTO electrode than the LTO electrode. The results confirmed that the electrochemical performance of the LTO-RTO electrode was better than that of the LTO electrode at low temperatures. PMID- 29127322 TI - Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. AB - The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection. 1280 FDA/EMA-approved drugs were screened to identify compounds that reduce uptake of taurocholic acid and lower Myrcludex B-binding in U2OS cells stably expressing human NTCP. HBV/HDV viral entry inhibition was studied in HepaRG cells. The four most potent inhibitors of human NTCP were rosiglitazone (IC50 5.1 uM), zafirlukast (IC50 6.5 uM), TRIAC (IC50 6.9 uM), and sulfasalazine (IC50 9.6 uM). Chicago sky blue 6B (IC50 7.1 uM) inhibited both NTCP and ASBT, a distinct though related bile acid transporter. Rosiglitazone, zafirlukast, TRIAC, sulfasalazine, and chicago sky blue 6B reduced HBV/HDV infection in HepaRG cells in a dose dependent manner. Five out of 1280 clinically approved drugs were identified that inhibit NTCP-mediated bile acid uptake and HBV/HDV infection in vitro. PMID- 29127324 TI - Stress-induced long-range ordering in spider silk. AB - The emergence of order from disorder is a topic of vital interest. We here propose that long-range order can arise from a randomly arranged two-phase material under mechanical load. Using Small-Angle Neutron Scattering (SANS) experiments and Molecular Dynamics based finite element (FE) models we show evidence for stress-induced ordering in spider dragline silk. Both methods show striking quantitative agreement of the position, shift and intensity increase of the long period upon stretching. We demonstrate that mesoscopic ordering does not originate from silk-specific processes such as strain-induced crystallization on the atomistic scale or the alignment of tilted crystallites. It instead is a general phenomenon arising from a non-affine deformation that enhances density fluctuations of the stiff and soft phases along the direction of stress. Our results suggest long-range ordering, analogously to the coalescence of defects in materials, as a wide-spread phenomenon to be exploited for tuning the mechanical properties of many hybrid stiff and soft materials. PMID- 29127325 TI - Acinar injury and early cytokine response in human acute biliary pancreatitis. AB - Clinical acute pancreatitis (AP) is marked by an early phase of systemic inflammatory response syndrome (SIRS) with multiorgan dysfunction (MODS), and a late phase characterized by sepsis with MODS. However, the mechanisms of acinar injury in human AP and the associated systemic inflammation are not clearly understood. This study, for the first time, evaluated the early interactions of bile acid induced human pancreatic acinar injury and the resulting cytokine response. We exposed freshly procured resected human pancreata to taurolithocolic acid (TLCS) and evaluated for acinar injury, cytokine release and interaction with peripheral blood mononuclear cells (PBMCs). We observed autophagy in acinar cells in response to TLCS exposure. There was also time-dependent release of IL 6, IL-8 and TNF-alpha from the injured acini that resulted in activation of PBMCs. We also observed that cytokines secreted by activated PBMCs resulted in acinar cell apoptosis and further cytokine release from them. Our data suggests that the earliest immune response in human AP originates within the acinar cell itself, which subsequently activates circulating PBMCs leading to SIRS. These findings need further detailed evaluation so that specific therapeutic targets to curb SIRS and resulting early adverse outcomes could be identified and tested. PMID- 29127327 TI - Publisher Correction: Atomic-scale engineering of ferroelectric-ferromagnetic interfaces of epitaxial perovskite films for functional properties. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29127326 TI - Proteolytic cleavage of transmembrane cell adhesion molecule L1 by extracellular matrix molecule Reelin is important for mouse brain development. AB - The cell adhesion molecule L1 and the extracellular matrix protein Reelin play crucial roles in the developing nervous system. Reelin is known to activate signalling cascades regulating neuronal migration by binding to lipoprotein receptors. However, the interaction of Reelin with adhesion molecules, such as L1, has remained poorly explored. Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically cleave L1 to generate an L1 fragment with a molecular mass of 80 kDa (L1-80). Expression of N-R6 and generation of L1 80 coincide in time at early developmental stages of the cerebral cortex. Reelin mediated generation of L1-80 is involved in neurite outgrowth and in stimulation of migration of cultured cortical and cerebellar neurons. Morphological abnormalities in layer formation of the cerebral cortex of L1-deficient mice partially overlap with those of Reelin-deficient reeler mice. In utero electroporation of L1-80 into reeler embryos normalised the migration of cortical neurons in reeler embryos. The combined results indicate that the direct interaction between L1 and Reelin as well as the Reelin-mediated generation of L1 80 contribute to brain development at early developmental stages. PMID- 29127329 TI - Urban Seismology: on the origin of earth vibrations within a city. AB - Urban seismology has become an active research field in the recent years, both with seismological objectives, as obtaining better microzonation maps in highly populated areas, and with engineering objectives, as the monitoring of traffic or the surveying of historical buildings. We analyze here the seismic records obtained by a broad-band seismic station installed in the ICTJA-CSIC institute, located near the center of Barcelona city. Although this station was installed to introduce visitors to earth science during science fairs and other dissemination events, the analysis of the data has allowed to infer results of interest for the scientific community. The main results include the evidence that urban seismometers can be used as a easy-to-use, robust monitoring tool for road traffic and subway activity inside the city. Seismic signals generated by different cultural activities, including rock concerts, fireworks or football games, can be detected and discriminated from its seismic properties. Beside the interest to understand the propagation of seismic waves generated by those rather particular sources, those earth shaking records provide a powerful tool to gain visibility in the mass media and hence have the opportunity to present earth sciences to a wider audience. PMID- 29127328 TI - OsMTP11 is localised at the Golgi and contributes to Mn tolerance. AB - Membrane transporters play a key role in obtaining sufficient quantities of manganese (Mn) but also in protecting against Mn toxicity. We have characterized OsMTP11, a member of the Cation Diffusion Facilitator/Metal Tolerance Protein (CDF/MTP) family of metal cation transporters in Oryza sativa. We demonstrate that OsMTP11 functions in alleviating Mn toxicity as its expression can rescue the Mn-sensitive phenotype of the Arabidopsis mtp11-3 knockout mutant. When expressed stably in Arabidopsis and transiently in rice and tobacco, it localises to the Golgi. OsMTP11 partially rescues the Mn-hypersensitivity of the pmr1 yeast mutant but only slightly alleviates the Zn sensitivity of the zrc1 cot1 yeast mutant. Overall, these results suggest that OsMTP11 predominantly functions as a Mn-transporting CDF with lower affinity for Zn. Site-directed mutagenesis studies revealed four substitutions in OsMTP11 that appear to alter its transport activity. OsMTP11 harbouring a substitution of leucine 150 to a serine fully rescued pmr1 Mn-sensitivity at all concentrations tested. The other substitutions, including those at conserved DxxxD domains, reduced complementation of pmr1 to different levels. This indicates their importance for OsMTP11 function and is a starting point for refining transporter activity/specificity. PMID- 29127330 TI - Giant thermal expansion and alpha-precipitation pathways in Ti-alloys. AB - Ti-alloys represent the principal structural materials in both aerospace development and metallic biomaterials. Key to optimizing their mechanical and functional behaviour is in-depth know-how of their phases and the complex interplay of diffusive vs. displacive phase transformations to permit the tailoring of intricate microstructures across a wide spectrum of configurations. Here, we report on structural changes and phase transformations of Ti-Nb alloys during heating by in situ synchrotron diffraction. These materials exhibit anisotropic thermal expansion yielding some of the largest linear expansion coefficients (+ 163.9*10-6 to -95.1*10-6 degrees C-1) ever reported. Moreover, we describe two pathways leading to the precipitation of the alpha-phase mediated by diffusion-based orthorhombic structures, alpha"lean and alpha"iso. Via coupling the lattice parameters to composition both phases evolve into alpha through rejection of Nb. These findings have the potential to promote new microstructural design approaches for Ti-Nb alloys and beta-stabilized Ti-alloys in general. PMID- 29127331 TI - Divergent effects of Wnt/beta-catenin signaling modifiers on the preservation of human limbal epithelial progenitors according to culture condition. AB - Wnt signaling plays an important role in the regulation of self-renewal in stem cells. Here we investigated the effect of CHIR99021, the primary transducer of the Wnt signaling canonical pathway, and IWP2, a wide action Wnt signal blocker, on the growth and differentiation of the limbal epithelial progenitor cells when these cells are cultured in two different, common culture approaches, outgrowth from limbal biopsy explants and isolated cell seeded in low calcium medium. Consistent with their expected effects, irrespective of the culture system, IWP2 decreased total beta-catenin while CHIR99021 increased it in nuclear localization. However, IWP2 increased stem/progenitor cell marker (p63alpha and ABCG2) content and clonogenic capacity in the explants but had opposite effects on isolated cells. CHIR99021 reduced the growth rate, stem/progenitor cell marker content and clonogenic capacity in the explants but also had the opposite effect on the isolated cells. These results show that the outcome of Wnt/beta-catenin signaling modification is dependent on the culture systems. Transplantation of limbal epithelial sheets from explant cultures is one of the standard treatments of limbal stem cell deficiency. Our study shows that Wnt-associated activity has a strong negative impact on stem/progenitor cell preservation in limbal explant cultures. PMID- 29127333 TI - A Light-Activated Antimicrobial Surface Is Active Against Bacterial, Viral and Fungal Organisms. AB - Evidence has shown that environmental surfaces play an important role in the transmission of nosocomial pathogens. Deploying antimicrobial surfaces in hospital wards could reduce the role environmental surfaces play as reservoirs for pathogens. Herein we show a significant reduction in viable counts of Staphylococcus epidermidis, Saccharomyces cerevisiae, and MS2 Bacteriophage after light treatment of a medical grade silicone incorporating crystal violet, methylene blue and 2 nm gold nanoparticles. Furthermore, a migration assay demonstrated that in the presence of light, growth of the fungus-like organism Pythium ultimum and the filamentous fungus Botrytis cinerea was inhibited. Atomic Force Microscopy showed significant alterations to the surface of S. epidermidis, and electron microscopy showed cellular aggregates connected by discrete surface linkages. We have therefore demonstrated that the embedded surface has a broad antimicrobial activity under white light and that the surface treatment causes bacterial envelope damage and cell aggregation. PMID- 29127332 TI - Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. AB - Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions. PMID- 29127335 TI - Early diverging lineages within Cryptomycota and Chytridiomycota dominate the fungal communities in ice-covered lakes of the McMurdo Dry Valleys, Antarctica. AB - Antarctic ice-covered lakes are exceptional sites for studying the ecology of aquatic fungi under conditions of minimal human disturbance. In this study, we explored the diversity and community composition of fungi in five permanently covered lake basins located in the Taylor and Miers Valleys of Antarctica. Based on analysis of the 18S rRNA sequences, we showed that fungal taxa represented between 0.93% and 60.32% of the eukaryotic sequences. Cryptomycota and Chytridiomycota dominated the fungal communities in all lakes; however, members of Ascomycota, Basidiomycota, Zygomycota, and Blastocladiomycota were also present. Of the 1313 fungal OTUs identified, the two most abundant, belonging to LKM11 and Chytridiaceae, comprised 74% of the sequences. Significant differences in the community structure were determined among lakes, water depths, habitat features (i.e., brackish vs. freshwaters), and nucleic acids (DNA vs. RNA), suggesting niche differentiation. Network analysis suggested the existence of strong relationships among specific fungal phylotypes as well as between fungi and other eukaryotes. This study sheds light on the biology and ecology of basal fungi in aquatic systems. To our knowledge, this is the first report showing the predominance of early diverging lineages of fungi in pristine limnetic ecosystems, particularly of the enigmatic phylum Cryptomycota. PMID- 29127334 TI - Biological assessments of multifunctional hydrogel-decorated implantable neural cuff electrode for clinical neurology application. AB - The implantable cuff electrode is an effective neuroprosthetic device in current nerve tissue engineering. However, biocompatibility and stability are still a serious dispute in terms of in vivo function and continuous monitoring. In this regard, assessing the host's biological response to biomaterials is one of the key factors of chronic implantation. In this article, we analyzed the peripheral nerve specific-biological responses to the application of multi-functional hydrogel-coated electrodes. The surface of the cuff electrode was modified using a multifunctional hydrogel composed of PEG hydrogel, cyclosporin A(CsA) microsphere(MS) and electrodeposited PEDOT:PSS. Through our approach, we have found that the multifunctional hydrogel coatings improve the neural electrode function, such as peak-to-peak amplitude increase. Additionally, the multifunctional hydrogel coated electrodes exhibited improved biocompatibility, such as reduced apoptotic properties and increased axonal myelination. Furthermore, 12 genes (BDNF, Gfra1, IL-6, Sox 10, S100B, P75 NTR , GAP43, MBP, MPZ, NrCAM, NE-FL, CB1) were upregulated at 5 weeks post-implant. Finally, double immunofluorescence revealed the effect of endocannabinoid system on neuroprotective properties and tissue remodeling of peripheral nerves during cuff electrode implantation. These results clearly confirmed that multifunctional hydrogel coatings could improve electrode function and biocompatibility by enhancing neuroprotective properties, which may provide a valuable paradigm for clinical neurology application. PMID- 29127337 TI - Electroluminescence properties of InGaN/GaN multiple quantum well-based LEDs with different indium contents and different well widths. AB - Two InGaN/GaN multiple quantum well (MQW)-based blue light emitting diodes (LEDs) emitting photons at approximately the same wavelength, with different indium contents and well widths, are prepared, and the temperature-dependences of their electroluminescence (EL) spectra at different fixed injection currents are investigated. The results show that, compared with sample B with its lower indium content and larger well width, sample A with its higher indium content and smaller well width, has a stronger carrier localization effect and higher external quantum efficiency (EQE) at the lower fixed currents; however, upon increasing the injection current, both the localization effect and EQE for sample A decrease at a faster rate. The former is mainly attributed to the deeper potential levels due to the larger indium fluctuations originating from the higher indium content, and to the smaller well width-induced stronger carrier quantum-confine effect (QCE); the latter is mainly attributed to the more significant growing in the electron leakage and/or electron overflow originating from the smaller well width and larger lattice mismatch-induced stronger piezoelectric field, and to the more significant reduction in carrier localization effect originating from the smaller well width-induced smaller density of high-energy localized states. PMID- 29127336 TI - Intermediate Levels of Network Heterogeneity Provide the Best Evolutionary Outcomes. AB - Complex networks impact the diffusion of ideas and innovations, the formation of opinions, and the evolution of cooperative behavior. In this context, heterogeneous structures have been shown to generate a coordination-like dynamics that drives a population towards a monomorphic state. In contrast, homogeneous networks tend to result in a stable co-existence of multiple traits in the population. These conclusions have been reached through the analysis of networks with either very high or very low levels of degree heterogeneity. In this paper, we use methods from Evolutionary Game Theory to explore how different levels of degree heterogeneity impact the fate of cooperation in structured populations whose individuals face the Prisoner's Dilemma. Our results suggest that in large networks a minimum level of heterogeneity is necessary for a society to become evolutionary viable. Moreover, there is an optimal range of heterogeneity levels that maximize the resilience of the society facing an increasing number of social dilemmas. Finally, as the level of degree heterogeneity increases, the evolutionary dominance of either cooperators or defectors in a society increasingly depends on the initial state of a few influential individuals. Our findings imply that neither very unequal nor very equal societies offer the best evolutionary outcome. PMID- 29127338 TI - Identification and in vitro characterization of two new PCSK9 Gain of Function variants found in patients with Familial Hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by pathogenic variants in genes encoding for LDL receptor (LDLR), Apolipoprotein B and Proprotein convertase subtilisin/kexin type 9 (PCSK9). Among PCSK9 variants, only Gain-of- Function (GOF) variants lead to FH. Greater attention should be paid to the classification of variants as pathogenic. Two hundred sixty nine patients with a clinical suspect of FH were screened for variants in LDLR and the patients without pathogenic variants were screened for variants in PCSK9 and APOB. Functional characterization of PCSK9 variants was performed by assessment of protein secretion, of LDLR activity in presence of PCSK9 variant proteins as well as of the LDLR affinity of the PCSK9 variants. Among 81 patients without pathogenic variants in LDLR, 7 PCSK9 heterozygotes were found, 4 of whom were carriers of variants whose role in FH pathogenesis is still unknown. Functional characterization revealed that two variants (p.(Ser636Arg) and p.(Arg357Cys)) were GOF variants. In Conclusions, we demonstrated a GOF effect of 2 PCSK9 variants that can be considered as FH-causative variants. The study highlights the important role played by functional characterization in integrating diagnostic procedures when the pathogenicity of new variants has not been previously demonstrated. PMID- 29127339 TI - Ectoine protects DNA from damage by ionizing radiation. AB - Ectoine plays an important role in protecting biomolecules and entire cells against environmental stressors such as salinity, freezing, drying and high temperatures. Recent studies revealed that ectoine also provides effective protection for human skin cells from damage caused by UV-A radiation. These protective properties make ectoine a valuable compound and it is applied as an active ingredient in numerous pharmaceutical devices and cosmetics. Interestingly, the underlying mechanism resulting in protecting cells from radiation is not yet fully understood. Here we present a study on ectoine and its protective influence on DNA during electron irradiation. Applying gel electrophoresis and atomic force microscopy, we demonstrate for the first time that ectoine prevents DNA strand breaks caused by ionizing electron radiation. The results presented here point to future applications of ectoine for instance in cancer radiation therapy. PMID- 29127341 TI - Classification Rule for 5-year Cardiovascular Diseases Risk using decision tree in Primary Care Chinese Patients with Type 2 Diabetes Mellitus. AB - Cardiovascular disease(CVD) is the leading cause of mortality among patients with type 2 diabetes mellitus(T2DM), and a risk classification model for CVD among primary care diabetic patients is pivotal for risk-based interventions and patient information. This study developed a simple tool for a 5-year CVD risk prediction for primary care Chinese patients with T2DM. A retrospective cohort study was conducted on 137,935 primary care Chinese T2DM patients aged 18-79 years without history of CVD between 1 January 2010 and 31 December 2010. New events of CVD of the cohort over a median follow up of 5 years were extracted from the medical records. A classification rule of 5-year CVD risk was obtained from the derivation cohort and validated in the validation cohort. Significant risk factors included in decision tree were age, gender, smoking status, diagnosis duration, obesity, unsatisfactory control on haemoglobin A1c and cholesterol, albuminuria and stage of chronic kidney disease, which categorized patients into five 5-year CVD risk groups(<5%; 5-9%; 10-14%; 15-19% and >=20%). Taking the group with the lowest CVD risk, the hazard ratios varied from 1.92(1.77,2.08) to 8.46(7.75,9.24). The present prediction model performed comparable discrimination and better calibration from the plot compared to other current existing models. PMID- 29127342 TI - Chemical Analysis of Morphological Changes in Lysophosphatidic Acid-Treated Ovarian Cancer Cells. AB - Ovarian cancer (OvCa) cells are reported to undergo biochemical changes at the cell surface in response to treatment with lysophosphatidic acid (LPA). Here we use scanning electron microscopy (SEM) and multiplex coherent anti-Stokes Raman scattering (CARS) imaging via supercontinuum excitation to probe morphological changes that result from LPA treatment. SEM images show distinct shedding of microvilli-like features upon treatment with LPA. Analysis of multiplex CARS images can distinguish between molecular components, such as lipids and proteins. Our results indicate that OvCa429 and SKOV3ip epithelial ovarian cancer cells undergo similar morphological and chemical responses to treatment with LPA. The microvilli-like structures on the surface of multicellular aggregates (MCAs) are removed by treatment with LPA. The CARS analysis shows a distinct decrease in protein and increase in lipid composition on the surface of LPA-treated cells. Importantly, the CARS signals from cellular sheddings from MCAs with LPA treatment are consistent with cleavage of proteins originally present. Mass spectrometry on the cellular sheddings show that a large number of proteins, both membrane and intracellular, are present. An increased number of peptides are detected for the mesenchymal cell line relative to the epithelial cell indicating a differential response to LPA treatment with cancer progression. PMID- 29127343 TI - Global phylogenetic analysis of Escherichia coli and plasmids carrying the mcr-1 gene indicates bacterial diversity but plasmid restriction. AB - To understand the dynamics behind the worldwide spread of the mcr-1 gene, we determined the population structure of Escherichia coli and of mobile genetic elements (MGEs) carrying the mcr-1 gene. After a systematic review of the literature we included 65 E. coli whole genome sequences (WGS), adding 6 recently sequenced travel related isolates, and 312 MLST profiles. We included 219 MGEs described in 7 Enterobacteriaceae species isolated from human, animal and environmental samples. Despite a high overall diversity, 2 lineages were observed in the E. coli population that may function as reservoirs of the mcr-1 gene, the largest of which was linked to ST10, a sequence type known for its ubiquity in human faecal samples and in food samples. No genotypic clustering by geographical origin or isolation source was observed. Amongst a total of 13 plasmid incompatibility types, the IncI2, IncX4 and IncHI2 plasmids accounted for more than 90% of MGEs carrying the mcr-1 gene. We observed significant geographical clustering with regional spread of IncHI2 plasmids in Europe and IncI2 in Asia. These findings point towards promiscuous spread of the mcr-1 gene by efficient horizontal gene transfer dominated by a limited number of plasmid incompatibility types. PMID- 29127344 TI - Catabolic Effects of Human PTH (1-34) on Bone: Requirement of Monocyte Chemoattractant Protein-1 in Murine Model of Hyperparathyroidism. AB - The bone catabolic actions of parathyroid hormone (PTH) are seen in patients with hyperparathyroidism, or with infusion of PTH in rodents. We have previously shown that the chemokine, monocyte chemoattractant protein-1 (MCP-1), is a mediator of PTH's anabolic effects on bone. To determine its role in PTH's catabolic effects, we continuously infused female wild-type (WT) and MCP-1-/- mice with hPTH or vehicle. Microcomputed tomography (uCT) analysis of cortical bone showed that hPTH-infusion induced significant bone loss in WT mice. Further, MUCT analysis of trabecular bone revealed that, compared with the vehicle-treated group, the PTH treated WT mice had reduced trabecular thickness and trabecular number. Notably, MCP-1-/- mice were protected against PTH-induced cortical and trabecular bone loss as well as from increases in serum CTX (C-terminal crosslinking telopeptide of type I collagen) and TRACP-5b (tartrate-resistant acid phosphatase 5b). In vitro, bone marrow macrophages (BMMs) from MCP-1-/- and WT mice were cultured with M-CSF, RANKL and/or MCP-1. BMMs from MCP-1-/- mice showed decreased multinucleated osteoclast formation compared with WT mice. Taken together, our work demonstrates that MCP-1 has a role in PTH's catabolic effects on bone including monocyte and macrophage recruitment, osteoclast formation, bone resorption, and cortical and trabecular bone loss. PMID- 29127345 TI - The synthetic neuroactive steroid SGE-516 reduces seizure burden and improves survival in a Dravet syndrome mouse model. AB - Dravet syndrome is an infant-onset epileptic encephalopathy with multiple seizure types that are often refractory to conventional therapies. Treatment with standard benzodiazepines like clobazam, in combination with valproate and stiripentol, provides only modest seizure control. While benzodiazepines are a first-line therapy for Dravet syndrome, they are limited by their ability to only modulate synaptic receptors. Unlike benzodiazepines, neuroactive steroids potentiate a wider-range of GABAA receptors. The synthetic neuroactive steroid SGE-516 is a potent positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors. Prior work demonstrated anticonvulsant activity of SGE-516 in acute seizure assays in rodents. In this study, we evaluated activity of SGE-516 on epilepsy phenotypes in the Scn1a +/- mouse model that recapitulates many features of Dravet syndrome, including spontaneous seizures, premature death and seizures triggered by hyperthermia. To evaluate SGE-516 in Scn1a +/- mice, we determined the effect of treatment on hyperthermia-induced seizures, spontaneous seizure frequency and survival. SGE-516 treatment protected against hyperthermia induced seizures, reduced spontaneous seizure frequency and prolonged survival in the Scn1a +/- mice. This provides the first evidence of SGE-516 activity in a mouse model of Dravet syndrome, and supports further investigation of neuroactive steroids as potential anticonvulsant compounds for refractory epilepsies. PMID- 29127340 TI - Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes. AB - Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables. PMID- 29127346 TI - Microelectrode implantation in motor cortex causes fine motor deficit: Implications on potential considerations to Brain Computer Interfacing and Human Augmentation. AB - Intracortical microelectrodes have shown great success in enabling locked-in patients to interact with computers, robotic limbs, and their own electrically driven limbs. The recent advances have inspired world-wide enthusiasm resulting in billions of dollars invested in federal and industrial sponsorships to understanding the brain for rehabilitative applications. Additionally, private philanthropists have also demonstrated excitement in the field by investing in the use of brain interfacing technologies as a means to human augmentation. While the promise of incredible technologies is real, caution must be taken as implications regarding optimal performance and unforeseen side effects following device implantation into the brain are not fully characterized. The current study is aimed to quantify any motor deficit caused by microelectrode implantation in the motor cortex of healthy rats compared to non-implanted controls. Following electrode insertion, rats were tested on an open-field grid test to study gross motor function and a ladder test to study fine motor function. It was discovered that rats with chronically indwelling intracortical microelectrodes exhibited up to an incredible 527% increase in time to complete the fine motor task. This initial study defines the need for further and more robust behavioral testing of potential unintentional harm caused by microelectrode implantation. PMID- 29127347 TI - Unique architecture of thermophilic archaeal virus APBV1 and its genome packaging. AB - Archaeal viruses have evolved to infect hosts often thriving in extreme conditions such as high temperatures. However, there is a paucity of information on archaeal virion structures, genome packaging, and determinants of temperature resistance. The rod-shaped virus APBV1 (Aeropyrum pernix bacilliform virus 1) is among the most thermostable viruses known; it infects a hyperthermophile Aeropyrum pernix, which grows optimally at 90 degrees C. Here we report the structure of APBV1, determined by cryo-electron microscopy at near-atomic resolution. Tight packing of the major virion glycoprotein (VP1) is ensured by extended hydrophobic interfaces, and likely contributes to the extreme thermostability of the helical capsid. The double-stranded DNA is tightly packed in the capsid as a left-handed superhelix and held in place by the interactions with positively charged residues of VP1. The assembly is closed by specific capping structures at either end, which we propose to play a role in DNA packing and delivery. PMID- 29127348 TI - Large area few-layer graphene with scalable preparation from waste biomass for high-performance supercapacitor. AB - Carbonaceous materials with high surface area and a sheet-like structure promote fast ion-transport kinetics, making them an ideal choice to be used in supercapacitors. Few-layer graphene (FLG)-like nanosheets with abundance of micro as well as mesopores are achieved via mechanical exfoliation method from an agricultural waste biomass: peanut shell (PS). A well-known elementary method of probe-sonication, for the achievement of FLG sheets from renewable sources, is introduced in this study for the very first time. The Peanut shell-derived FLG (PS-FLG) possesses remarkably high specific surface area (2070 m2 g-1) with a sufficiently large pore volume of 1.33 cm3 g-1. For the fabrication of a binder free supercapacitor, the PS-FLG-based electrodes exhibited a high specific capacity of 186 F g-1 without the use of any binder in 1 M H2SO4 as supporting electrolyte. The highest energy density of 58.125 W h Kg-1 and highest power density of 37.5 W Kg-1 was achieved by the material. Surprisingly, the working potential increased to 2.5 V in an organic electrolyte leading to an obvious increase in the energy density to 68 W h Kg-1. Solid-state-supercapacitor was fabricated with this material for the possible use of low-cost, high energy promising energy storage device. PMID- 29127349 TI - Hydrogen adsorption on doped MoS2 nanostructures. AB - Electrochemical devices for efficient production of hydrogen as energy carrier rely still largely on rare platinum group metal catalysts. Chemically and structurally modified metal dichalcogenide MoS2 is a promising substitute for these critical raw materials at the cathode side where the hydrogen evolution reaction takes place. For precise understanding of structure and hydrogen adsorption characteristics in chemically modified MoS2 nanostructures, we perform comprehensive density functional theory calculations on transition metal (Fe, Co, Ni, Cu) doping at the experimentally relevant MoS2 surfaces at substitutional Mo sites. Clear benefits of doping the basal plane are found, whereas at the Mo- and S-edges complex modifications at the whole edge are observed. New insight into doping-enhanced activity is obtained and guidance is given for further experiments. We study a machine learning model to facilitate the screening of suitable structures and find a promising level of prediction accuracy with minimal structural input. PMID- 29127350 TI - Memory Regulatory T cells Increase Only In Inflammatory Phase of Chronic Hepatitis B Infection and Related to Galectin-9/Tim-3 interaction. AB - CD4+Foxp3+ regulatory T cells (Tregs) are the main immune suppressors with subpopulation of inflamed-tissue related memory Tregs (mTregs) and non-related resting Treg (rTregs). Previously, Treg was proposed to be the cause of chronicity of hepatitis B virus (HBV) infection but with controversies. We then investigated the role of mTregs in distinct immune phases of chronic HBV infection, especially the non-inflammatory versus inflammatory phases. It was found mTregs but not rTregs increased only in the inflammatory phase and correlated with serum alanine aminotransferase (ALT) level. These mTregs accumulated in the inflamed liver, expressed significantly higher Tim-3, CCR4, CCR5 and fewer CCR7, and possessed potent suppressive function. These mTregs mainly originated from natural Tregs because of high Helios expression. Hierarchical clustering analysis showed higher frequency of mTreg was concordant with higher serum ALT and galectin-9 levels. Furthermore, galectin-9 could expand mTregs through galectin-9/Tim-3 interaction. In conclusion, increased mTregs are found only in inflammatory phase of chronic HBV infection. Galectin-9, associated with liver inflammation, contributes to the expansion of mTregs through galectin 9/Tim-3 interaction. Therefore, this expansion of mTregs only reflects as an immune regulatory mechanism to limit the on-going liver damages rather than the cause of chronicity of HBV infection. PMID- 29127351 TI - PDGF Family Expression in Glioblastoma Multiforme: Data Compilation from Ivy Glioblastoma Atlas Project Database. AB - Glioblastoma Multiforme (GBM) is the most frequent and lethal primary brain cancer. Due to its therapeutic resistance and aggressiveness, its clinical management is challenging. Platelet-derived Growth Factor (PDGF) genes have been enrolled as drivers of this tumour progression as well as potential therapeutic targets. As detailed understanding of the expression pattern of PDGF system in the context of GBM intra- and intertumoral heterogeneity is lacking in the literature, this study aims at characterising PDGF expression in different histologically-defined GBM regions as well as investigating correlation of these genes expression with parameters related to poor prognosis. Z-score normalised expression values of PDGF subunits from multiple slices of 36 GBMs, alongside with clinical and genomic data on those GBMs patients, were compiled from Ivy Glioblastoma Atlas Project - Allen Institute for Brain Science data sets. PDGF subunits show differential expression over distinct regions of GBM and PDGF family is heterogeneously expressed among different brain lobes affected by GBM. Further, PDGF family expression correlates with bad prognosis factors: age at GBM diagnosis, Phosphatase and Tensin Homolog deletion and Isocitrate Dehydrogenase 1 mutation. These findings may aid on clinical management of GBM and development of targeted curative therapies against this devastating tumour. PMID- 29127352 TI - Margination of Stiffened Red Blood Cells Regulated By Vessel Geometry. AB - Margination of stiffened red blood cells has been implicated in many vascular diseases. Here, we report the margination of stiffened RBCs in vivo, and reveal the crucial role of the vessel geometry in the margination by calculations when the blood is seen as viscoelastic fluid. The vessel-geometry-regulated margination is then confirmed by in vitro experiments in microfluidic devices, and it establishes new insights to cell sorting technology and artificial blood vessel fabrication. PMID- 29127353 TI - Clinicopathological and prognostic significance of PKM2 protein expression in cirrhotic hepatocellular carcinoma and non-cirrhotic hepatocellular carcinoma. AB - Pyruvate kinase M2 (PKM2), a key protein in glucose and lipid metabolism, has been reported to be related to carcinogenesis in various malignancies. However, its roles in hepatocellular carcinoma with cirrhotic liver (CL) and hepatocellular carcinoma with non-cirrhoticliver (NCL) haves not been investigated. In our study western bloting, qRT-PCR and immunohistochemistry were performed to evaluate the clinical significance of PKM2 protein expression in CL and NCL. The results revealed that PKM2 protein expression was significantly higher in HCC tissues than in their adjacent non-tumour tissues. The high expression rates of PKM2 were more frequently noted in CL (45. 6%) than in NCL (31. 9%) tissues. High PKM2 expression in CL and NCL tissues was significantly associated with vascular invasion (P = 0.002 and P = 0.004, respectively) and intrahepatic metastasis (P < 0.001 and P = 0.019, respectively). Importantly, Kaplan-Meier survival analysis showed that the disease-specific survival (DSS) and recurrence-free survival (RFS) were lower in CL with high PKM2 expression than in NCL with high PKM2 expression (P = 0.003 and P = 0.003, respectively). Overall, high PKM2 expression was more frequently found in CL than in NCL, and PKM2 overexpression was associated with poor survival rates in patients with CL and NCL. PMID- 29127354 TI - Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy. AB - Point mutations in the peripheral myelin protein 22 (PMP22) gene have been identified to cause demyelinating Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsy (HNPP). To investigate the mutation spectrum of PMP22 in Han-Chinese population residing in Taiwan, 53 patients with molecularly unassigned demyelinating CMT and 52 patients with HNPP like neuropathy of unknown genetic causes were screened for PMP22 mutations by Sanger sequencing. Three point mutations were identified in four patients with demyelinating CMT, including c.256 C > T (p.Q86X) in two, and c.310delA (p.I104FfsX7) and c.319 + 1G > A in one each. One PMP22 missense mutation, c.124 T > C (p.C42R), was identified in a patient with HNPP-like neuropathy. The clinical presentations of these mutations vary from mild HNPP-like syndrome to severe infantile-onset demyelinating CMT. In vitro analyses revealed that both PMP22 p.Q86X and p.I104FfsX7 mutations result in truncated PMP22 proteins that are almost totally retained within cytosol, whereas the p.C42R mutation partially impairs cell membrane localization of PMP22 protein. In conclusion, PMP22 point mutations account for 7.5% and 1.9% of demyelinating CMT and HNPP patients with unknown genetic causes, respectively. This study delineates the clinical and molecular features of PMP22 point mutations in Taiwan, and emphasizes their roles in demyelinating CMT or HNPP-like neuropathy. PMID- 29127355 TI - The Habitats Humans Provide: Factors affecting the diversity and composition of arthropods in houses. AB - The indoor biome is a novel habitat which recent studies have shown exhibit not only high microbial diversity, but also high arthropod diversity. Here, we analyze findings from a survey of 50 houses (southeastern USA) within the context of additional survey data concerning house and room features, along with resident behavior, to explore how arthropod diversity and community composition are influenced by physical aspects of rooms and their usage, as well as the lifestyles of human residents. We found that indoor arthropod diversity is strongly influenced by access to the outdoors and carpeted rooms hosted more types of arthropods than non-carpeted rooms. Arthropod communities were similar across most room types, but basements exhibited more unique community compositions. Resident behavior such as house tidiness, pesticide usage, and pet ownership showed no significant influence on arthropod community composition. Arthropod communities across all rooms in houses exhibit trophic structure-with both generalized predators and scavengers included in the most frequently found groups. These findings suggest that indoor arthropods serve as a connection to the outdoors, and that there is still much yet to be discovered about their impact on indoor health and the unique ecological dynamics within our homes. PMID- 29127356 TI - A transcriptomic study of myogenic differentiation under the overexpression of PPARgamma by RNA-Seq. AB - To study the cellular and molecular function of peroxisome proliferator-activated receptor gamma (PPARgamma) in skeletal muscle differentiation, we have generated inducible gain-of-function to overexpress PPARgamma in C2C12 myoblasts. In order to identify PPARgamma targets, RNA sequencing (RNA-seq) was used to evaluate and quantify the transcriptomes and expression patterns during myogenic differentiation under the overexpression of PPARgamma. The formation of myotubes and the expression of muscle-specific myogenic genes such as MyoD and MyoG may be inhibited by PPARgamma overexpression. Multiple genes and pathways were significantly involved in this process, including 11 genes such as Fndc9 and Slc14a1 with fundamental change of regulation modes, 9 genes of which were validated by the data of qRT-PCR. Our studies demonstrate that PPARgamma would play critical roles on myoblasts differentiation, mediating crosstalk among several pathways and transcription factors. Our data is available in the Gene Expression Omnibus (GEO) database with the accession number as GSE99399. PMID- 29127357 TI - Critical switching current density induced by spin Hall effect in magnetic structures with first- and second-order perpendicular magnetic anisotropy. AB - In this study, we derive analytical expressions for the critical switching current density induced by spin Hall effect in magnetic structures with the first and second-order perpendicular magnetic anisotropy. We confirm the validity of the expressions by comparing the analytical results with those obtained from a macrospin simulation. Moreover, we find that for a particular thermal stability parameter, the switching current density can be minimized for a slightly positive second-order perpendicular magnetic anisotropy and the minimum switching current density can further be tuned using an external magnetic field. The analytical expressions are of considerable value in designing high-density magnetic random access memory and cryogenic memory. PMID- 29127358 TI - Effects of elevated CO2 on fine root biomass are reduced by aridity but enhanced by soil nitrogen: A global assessment. AB - Plant roots play a crucial role in regulating key ecosystem processes such as carbon (C) sequestration and nutrient solubilisation. Elevated (e)CO2 is expected to alter the biomass of fine, coarse and total roots to meet increased demand for other resources such as water and nitrogen (N), however, the magnitude and direction of observed changes vary considerably between ecosystems. Here, we assessed how climate and soil properties mediate root responses to eCO2 by comparing 24 field-based CO2 experiments across the globe including a wide range of ecosystem types. We calculated response ratios (i.e. effect size) and used structural equation modelling (SEM) to achieve a system-level understanding of how aridity, mean annual temperature and total soil nitrogen simultaneously drive the response of total, coarse and fine root biomass to eCO2. Models indicated that increasing aridity limits the positive response of fine and total root biomass to eCO2, and that fine (but not coarse or total) root responses to eCO2 are positively related to soil total N. Our results provide evidence that consideration of factors such as aridity and soil N status is crucial for predicting plant and ecosystem-scale responses to future changes in atmospheric CO2 concentrations, and thus feedbacks to climate change. PMID- 29127359 TI - Stable Isotopes Reveal Rapid Enamel Elongation (Amelogenesis) Rates for the Early Cretaceous Iguanodontian Dinosaur Lanzhousaurus magnidens. AB - Lanzhousaurus magnidens, a large non-hadrosauriform iguanodontian dinosaur from the Lower Cretaceous Hekou Group of Gansu Province, China has the largest known herbivorous dinosaur teeth. Unlike its hadrosauriform relatives possessing tooth batteries of many small teeth, Lanzhousaurus utilized a small number (14) of very large teeth (~10 cm long) to create a large, continuous surface for mastication. Here we investigate the significance of Lanzhousaurus in the evolutionary history of iguanodontian-hadrosauriform transition by using a combination of stable isotope analysis and CT imagery. We infer that Lanzhousaurus had a rapid rate of tooth enamel elongation or amelogenesis at 0.24 mm/day with dental tissues common to other Iguanodontian dinosaurs. Among ornithopods, high rates of amelogenesis have been previously observed in hadrosaurids, where they have been associated with a sophisticated masticatory apparatus. These data suggest rapid amelogenesis evolved among non-hadrosauriform iguanodontians such as Lanzhousaurus, representing a crucial step that was exapted for the evolution of the hadrosaurian feeding mechanism. PMID- 29127360 TI - A Mouse Model of Autoimmune Cholangitis via Syngeneic Bile Duct Protein Immunization. AB - Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular biliary ductules, which progressively leads to cholestasis, hepatic fibrosis, cirrhosis, and eventually liver failure. Several mouse models have been used to clarify the pathogenesis of PBC and are generally considered reflective of an autoimmune cholangitis. Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals. None have focused on the classic models of breaking tolerance, namely immunization with self-tissue. Here, we report a novel mouse model of autoimmune cholangitis via immunization with syngeneic bile duct protein (BDP). Our results demonstrate that syngeneic bile duct antigens efficiently break immune tolerance of recipient mice, capturing several key features of PBC, including liver-specific inflammation focused on portal tract areas, increased number and activation state of CD4 and CD8 T cells in the liver and spleen. Furthermore, the germinal center (GC) responses in the spleen were more enhanced in our mouse model. Finally, these mice were 100% positive for anti-mitochondrial antibodies (AMAs). In conclusion, we developed a novel mouse model of PBC that may help to elucidate the detailed mechanism of this complex disease. PMID- 29127361 TI - Reentry via high-frequency pacing in a mathematical model for human-ventricular cardiac tissue with a localized fibrotic region. AB - Localized heterogeneities, caused by the regional proliferation of fibroblasts, occur in mammalian hearts because of diseases like myocardial infarction. Such fibroblast clumps can become sources of pathological reentrant activities, e.g., spiral or scroll waves of electrical activation in cardiac tissue. The occurrence of reentry in cardiac tissue with heterogeneities, such as fibroblast clumps, can depend on the frequency at which the medium is paced. Therefore, it is important to study the reentry-initiating potential of such fibroblast clumps at different frequencies of pacing. We investigate the arrhythmogenic effects of fibroblast clumps at high- and low-frequency pacing. We find that reentrant waves are induced in the medium more prominently at high-frequency pacing than with low frequency pacing. We also study the other factors that affect the potential of fibroblast clumps to induce reentry in cardiac tissue. In particular, we show that the ability of a fibroblast clump to induce reentry depends on the size of the clump, the distribution and percentage of fibroblasts in the clump, and the excitability of the medium. We study the process of reentry in two-dimensional and a three-dimensional mathematical models for cardiac tissue. PMID- 29127362 TI - Functional Analysis of VDR Gene Mutation R343H in A Child with Vitamin D Resistant Rickets with Alopecia. AB - The functional study of different mutations on vitamin D receptor (VDR) gene causing hereditary vitamin D-resistant rickets (HVDRR) remains limited. This study was to determine the VDR mutation and the mechanisms of this mutation causing phenotype in a family with HVDRR and alopecia. Phenotype was analyzed, and in vitro functional studies were performed. The proband and his affected sister exhibited typical HVDRR with alopecia, and their biochemical and radiographic abnormalities but not alopecia responded to supraphysiological doses of active vitamin D3. A novel homozygous missense R343H mutation in the exon 9 of VDR residing in the retinoid X receptor (RXR)-binding domain was identified. The expression level and C-terminal conformation of R343H mutant are not different from the wild-type VDR. This mutant had no effect on the nuclear localization of VDR, VDR-RXR heterodimerization, but it impaired CYP24A1 promoter activity in the presence of 1,25 (OH)2 vitamin D3, at least in part, mediated through specific nuclear receptor coactivator. Simulation models revealed the vanished interaction between guanidinium group of R343 and carboxyl group of E269. Without affecting the expression, conformation, nuclear location of VDR or heteridimerization with RXR, VDR-R343H impairs the transactivation activity of VDR on downstream transcription, accounting for HVDRR features with alopecia. PMID- 29127363 TI - Scalable symmetry detector and its applications by using beam splitters and weak nonlinearities. AB - We describe a method to detect twin-beam multiphoton entanglement based on a beam splitter and weak nonlinearities. For the twin-beam four-photon entanglement, we explore a symmetry detector. It works not only for collecting two-pair entangled states directly from the spontaneous parametric down-conversion process, but also for generating them by cascading these symmetry detectors. Surprisingly, by calculating the iterative coefficient and the success probability we show that with a few iterations the desired two-pair can be obtained from a class of four photon entangled states. We then generalize the symmetry detector to n-pair emissions and show that it is capable of determining the number of the pairs emitted indistinguishably from the spontaneous parametric down-conversion source, which may contribute to explore multipair entanglement with a large number of photons. PMID- 29127364 TI - Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein. AB - Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7-15 ug/L), AOA2 (15-65 ug/L) and AT (>65 ug/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing. PMID- 29127365 TI - The primary cilium is necessary for the differentiation and the maintenance of human adipose progenitors into myofibroblasts. AB - The primary cilium is an organelle, present at the cell surface, with various biological functions. We, and others, have shown that it plays a role in the differentiation of adipose progenitors (APs) into adipocytes. APs can also differentiate into myofibroblasts when treated with TGF-beta1. Several components of the TGF-beta1 pathway are located within the cilium suggesting a function for this organelle in AP myofibrogenesis. We studied differentiation of APs into myofibroblasts in two human models: APs of the adipose tissue (aAPs) and APs resident in the skeletal muscles (mAPs). We showed that, in vivo, myofibroblasts within muscles of patients with Duchenne Muscular Dystrophy were ciliated. In vitro, myofibroblasts derived from APs maintained a functional primary cilium. Using HPI4, a small molecule that inhibits ciliogenesis, and siRNA against Kif 3A, we provide evidence that the primary cilium is necessary both for the differentiation of APs into myofibroblasts and the maintenance of the phenotype. Disruption of the primary cilium inhibited TGF-beta1-signalisation providing a molecular mechanism by which the cilium controls myofibroblast differentiation. These data suggest that myofibroblasts from various origins are controlled differently by their primary cilium. PMID- 29127366 TI - Objective quantification of nanoscale protein distributions. AB - Nanoscale distribution of molecules within small subcellular compartments of neurons critically influences their functional roles. Although, numerous ways of analyzing the spatial arrangement of proteins have been described, a thorough comparison of their effectiveness is missing. Here we present an open source software, GoldExt, with a plethora of measures for quantification of the nanoscale distribution of proteins in subcellular compartments (e.g. synapses) of nerve cells. First, we compared the ability of five different measures to distinguish artificial uniform and clustered patterns from random point patterns. Then, the performance of a set of clustering algorithms was evaluated on simulated datasets with predefined number of clusters. Finally, we applied the best performing methods to experimental data, and analyzed the nanoscale distribution of different pre- and postsynaptic proteins, revealing random, uniform and clustered sub-synaptic distribution patterns. Our results reveal that application of a single measure is sufficient to distinguish between different distributions. PMID- 29127367 TI - Spontaneous attention-capture by auditory distractors as predictor of distractibility: a study of domestic horses (Equus caballus). AB - Distractibility (i.e. individual distraction from his ongoing activity) is thoughts to affect daily life. The present study develops an easy way to assess inter-individual variations of distractibility of an animal model, the domestic horse. We developed the 'distractibility test' (DT), based on auditory stimuli, a major source of distraction in daily life. We hypothesized that the broadcast of unusual sounds would provide a reliable source of distraction and that the responses to these unusual sounds would yield a good estimation of a horse's level of distractibility. Validity of the DT was assessed by comparing the subjects' interest towards the sound in this test to their attentional state in experimental visual attention tasks and in a working task. Our results showed inter-individual differences in response to the stimuli, with consistency over time. The subjects' responses to this DT were negatively correlated to their attentional skills in separate experimental tests and in a working task. This is to our knowledge the first 'real-world' estimate of an animal's distractibility in its home environment that could potentially be adapted for humans. PMID- 29127368 TI - Diagnostic value of blood-derived microRNAs for schizophrenia: results of a meta analysis and validation. AB - There is an increasing interest in searching biomarkers for schizophrenia (SZ) diagnosis, which overcomes the drawbacks inherent with the subjective diagnostic methods. MicroRNA (miRNA) fingerprints have been explored for disease diagnosis. We performed a meta-analysis to examine miRNA diagnostic value for SZ and further validated the meta-analysis results. Using following terms: schizophrenia/SZ, microRNA/miRNA, diagnosis, sensitivity and specificity, we searched databases restricted to English language and reviewed all articles published from January 1990 to October 2016. All extracted data were statistically analyzed and the results were further validated with peripheral blood mononuclear cells (PBMNCs) isolated from patients and healthy controls using RT-qPCR and receiver operating characteristic (ROC) analysis. A total of 6 studies involving 330 patients and 202 healthy controls were included for meta-analysis. The pooled sensitivity, specificity and diagnostic odds ratio were 0.81 (95% CI: 0.75-0.86), 0.81 (95% CI: 0.72-0.88) and 18 (95% CI: 9-34), respectively; the positive and negative likelihood ratio was 4.3 and 0.24 respectively; the area under the curve in summary ROC was 0.87 (95% CI: 0.84-0.90). Validation revealed that miR-181b-5p, miR-21-5p, miR-195-5p, miR-137, miR-346 and miR-34a-5p in PBMNCs had high diagnostic sensitivity and specificity in the context of schizophrenia. In conclusion, blood-derived miRNAs might be promising biomarkers for SZ diagnosis. PMID- 29127370 TI - Exosomal miR-126 as a circulating biomarker in non-small-cell lung cancer regulating cancer progression. AB - Lung cancer is one of the leading causes of cancer-related deaths. It is diagnosed mostly at the locally advanced or metastatic stage. Recently, micro RNAs (miRs) and their distribution in circulation have been implicated in physiological and pathological processes. In this study, miR-126 was evaluated in serum, exosome and exosome-free serum fractions in non-small cell lung cancer (NSCLC) patients at early and advanced stages, and compared with healthy controls. Down-regulation of miR-126 was found in serum of advanced stage NSCLC patients. In healthy controls, circulating miR-126 was equally distributed between exosomes and exosome-free serum fractions. Conversely, in both early and advanced stage NSCLC patients, miR-126 was mainly present in exosomes. Different fractions of miR-126 in circulation may reflect different conditions during tumour formation. Incubation of exosomes from early and advanced NSCLC patients induced blood vessel formation and malignant transformation in human bronchial epithelial cells. On the other hand, exosome-enriched miR-126 from normal endothelial cells inhibited cell growth and induces loss of malignancy of NSCLC cells. These findings suggest a role of exo-miRs in the modulation of the NSCLC microenvironmental niche. Exosome-delivered miRs thus hold a substantial promise as a diagnostics biomarker as well as a personalized therapeutic modality. PMID- 29127371 TI - Spatially Resolved Thermometry of Resistive Memory Devices. AB - The operation of resistive and phase-change memory (RRAM and PCM) is controlled by highly localized self-heating effects, yet detailed studies of their temperature are rare due to challenges of nanoscale thermometry. Here we show that the combination of Raman thermometry and scanning thermal microscopy (SThM) can enable such measurements with high spatial resolution. We report temperature dependent Raman spectra of HfO2, TiO2 and Ge2Sb2Te5 (GST) films, and demonstrate direct measurements of temperature profiles in lateral PCM devices. Our measurements reveal that electrical and thermal interfaces dominate the operation of such devices, uncovering a thermal boundary resistance of 28 +/- 8 m2K/GW at GST-SiO2 interfaces and an effective thermopower 350 +/- 50 uV/K at GST-Pt interfaces. We also discuss possible pathways to apply Raman thermometry and SThM techniques to nanoscale and vertical resistive memory devices. PMID- 29127369 TI - Suppression of Th17-polarized airway inflammation by rapamycin. AB - Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17 dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation. PMID- 29127372 TI - Quasi-static and dynamic experimental studies on the tensile strength and failure pattern of concrete and mortar discs. AB - As concrete and mortar materials widely used in structural engineering may suffer dynamic loadings, studies on their mechanical properties under different strain rates are of great importance. In this paper, based on splitting tests of Brazilian discs, the tensile strength and failure pattern of concrete and mortar were investigated under quasi-static and dynamic loadings with a strain rate of 1 200 s-1. It is shown that the quasi-static tensile strength of mortar is higher than that of concrete since coarse aggregates weaken the interface bonding strength of the latter. Numerical results confirmed that the plane stress hypothesis lead to a lower value tensile strength for the cylindrical specimens. With the increase of strain rates, dynamic tensile strengths of concrete and mortar significantly increase, and their failure patterns change form a single crack to multiple cracks and even fragment. Furthermore, a relationship between the dynamic increase factor and strain rate was established by using a linear fitting algorithm, which can be conveniently used to calculate the dynamic increase factor of concrete-like materials in engineering applications. PMID- 29127373 TI - High-accuracy wavefront sensing by phase diversity technique with bisymmetric defocuses diversity phase. AB - We investigate a specific diversity phase for phase diversity (PD) phase retrieval, which possesses higher accuracy than common PD, especially for large scale and high-frequency wavefront sensing. The commonly used PD algorithm employs the image intensities of the focused plane and one defocused plane to build the error metric. Unlike the commonly used PD, we explore a bisymmetric defocuses diversity phase, which employs the image intensities of two symmetrical defocused planes to build the error metric. This kind of diversity phase, named PD-BD (bisymmetric defocuses phase diversity), is analysed with the Cramer-Rao lower bound (CRLB). Statistically, PD-BD shows smaller CRLBs than the commonly used PD, which indicates stronger capacity of phase retrieval. Numerical simulations also verify that PD-BD has higher accuracy of phase retrieval than the commonly used PD when dealing with large-scale and high-frequency wavefront aberrations. To further affirm that PD-BD possesses higher accuracy of wavefront sensing than PD, we also perform a simple verification experiment. PMID- 29127374 TI - Prediction of human prenatal exposure to bisphenol A and bisphenol A glucuronide from an ovine semi-physiological toxicokinetic model. AB - Bisphenol A (BPA) risk assessment is hampered by the difficulty of determining the extent of internal exposure in the human fetus and uncertainties regarding BPA toxicokinetics (TK) in the maternal-fetal unit. A feto-maternal TK model describing BPA and BPA glucuronide (BPAG) disposition in sheep was humanized, using human TK data obtained after d6-BPA administration on a cookie, to predict BPA and BPAG kinetics in the human mother-fetus unit. Validation of the model predictions included the assessed dose proportionality of BPA and BPAG disposition and the similarity between the simulated and measured time courses of BPA and BPAG in fetal rhesus monkeys after BPA maternal dosing. The model predicted fluctuations in fetal BPA concentrations associated with typical maternal exposure to BPA through the diet, with similar trough (0.011 ng/L vs 0.014 ng/L) and lower peak BPA concentrations (0.023 ng/L vs 0.14 ng/L) in fetal than in maternal plasma. BPAG concentrations in fetal plasma were predicted to increase over time to reach a steady value (29 ng/L) reflecting the cumulative BPA dose received by the fetus. Model-predicted BPAG concentrations in fetal plasma are consistent with reported levels in human cord blood that may be considered as relevant markers of the BPA dose entering blood throughout fetal life. PMID- 29127375 TI - DNA damage-induced histone H1 ubiquitylation is mediated by HUWE1 and stimulates the RNF8-RNF168 pathway. AB - The DNA damage response (DDR), comprising distinct repair and signalling pathways, safeguards genomic integrity. Protein ubiquitylation is an important regulatory mechanism of the DDR. To study its role in the UV-induced DDR, we characterized changes in protein ubiquitylation following DNA damage using quantitative di-Gly proteomics. Interestingly, we identified multiple sites of histone H1 that are ubiquitylated upon UV-damage. We show that UV-dependent histone H1 ubiquitylation at multiple lysines is mediated by the E3-ligase HUWE1. Recently, it was shown that poly-ubiquitylated histone H1 is an important signalling intermediate in the double strand break response. This poly ubiquitylation is dependent on RNF8 and Ubc13 which extend pre-existing ubiquitin modifications to K63-linked chains. Here we demonstrate that HUWE1 depleted cells showed reduced recruitment of RNF168 and 53BP1 to sites of DNA damage, two factors downstream of RNF8 mediated histone H1 poly-ubiquitylation, while recruitment of MDC1, which act upstream of histone H1 ubiquitylation, was not affected. Our data show that histone H1 is a prominent target for ubiquitylation after UV-induced DNA damage. Our data are in line with a model in which HUWE1 primes histone H1 with ubiquitin to allow ubiquitin chain elongation by RNF8, thereby stimulating the RNF8-RNF168 mediated DDR. PMID- 29127376 TI - Genuine Multipartite Entanglement in the 3-Photon Decay of Positronium. AB - The electron-positron annihilation into two photons is a standard technology in medicine to observe e.g. metabolic processes in human bodies. A new tomograph will provide the possibility to observe not only direct e + e - annihilations but also the 3 photons from the decay of ortho-positronium atoms formed in the body. We show in this contribution that the three-photon state with respect to polarisation degrees of freedom depends on the angles between the photons and exhibits various specific entanglement features. In particular genuine multipartite entanglement, a type of entanglement involving all degrees of freedom, is subsistent if the positronium was in a definite spin eigenstate. Remarkably, when all spin eigenstates are mixed equally, entanglement -and even stronger genuine multipartite entanglement- survives. Due to a "symmetrization" process, however, Dicke-type or W-type entanglement remains whereas GHZ-type entanglement vanishes. The survival of particular entanglement properties in the mixing scenario may make it possible to extract quantum information in the form of distinct entanglement features, e.g., from metabolic processes in human bodies. PMID- 29127377 TI - Bayesian Networks Analysis of Malocclusion Data. AB - In this paper we use Bayesian networks to determine and visualise the interactions among various Class III malocclusion maxillofacial features during growth and treatment. We start from a sample of 143 patients characterised through a series of a maximum of 21 different craniofacial features. We estimate a network model from these data and we test its consistency by verifying some commonly accepted hypotheses on the evolution of these disharmonies by means of Bayesian statistics. We show that untreated subjects develop different Class III craniofacial growth patterns as compared to patients submitted to orthodontic treatment with rapid maxillary expansion and facemask therapy. Among treated patients the CoA segment (the maxillary length) and the ANB angle (the antero posterior relation of the maxilla to the mandible) seem to be the skeletal subspaces that receive the main effect of the treatment. PMID- 29127378 TI - First insights into the pleiotropic role of vrf (yedF), a newly characterized gene of Salmonella Typhimurium. AB - Salmonella possesses virulence determinants that allow replication under extreme conditions and invasion of host cells, causing disease. Here, we examined four putative genes predicted to encode membrane proteins (ydiY, ybdJ, STM1441 and ynaJ) and a putative transcriptional factor (yedF). These genes were identified in a previous study of a S. Typhimurium clinical isolate and its multidrug resistant counterpart. For STM1441 and yedF a reduced ability to interact with HeLa cells was observed in the knock-out mutants, but an increase in this ability was absent when these genes were overexpressed, except for yedF which phenotype was rescued when yedF was restored. In the absence of yedF, decreased expression was seen for: i) virulence-related genes involved in motility, chemotaxis, attachment and survival inside the host cell; ii) global regulators of the invasion process (hilA, hilC and hilD); and iii) factors involved in LPS biosynthesis. In contrast, an increased expression was observed for anaerobic metabolism genes. We propose yedF is involved in the regulation of Salmonella pathogenesis and contributes to the activation of the virulence machinery. Moreover, we propose that, when oxygen is available, yedF contributes sustained repression of the anaerobic pathway. Therefore, we recommend this gene be named vrf, for virulence-related factor. PMID- 29127379 TI - RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations. AB - Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, beta-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers. PMID- 29127380 TI - Limited evidence of declining growth among moisture-limited black and white spruce in interior Alaska. AB - Boreal forests play critical roles in global carbon, water and energy cycles. Recent studies suggest drought is causing a decline in boreal spruce growth, leading to predictions of widespread mortality and a shift in dominant vegetation type in interior Alaska. We took advantage of a large set of tree cores collected from random locations across a vast area of interior Alaska to examine long-term trends in carbon isotope discrimination and growth of black and white spruce. Our results confirm that growth of both species is sensitive to moisture availability, yet show limited evidence of declining growth in recent decades. These findings contrast with many earlier tree-ring studies, but agree with dynamic global vegetation model projections. We hypothesize that rising atmospheric [CO2] and/or changes in biomass allocation may have compensated for increasing evaporative demand, leaving recent radial growth near the long-term mean. Our results highlight the need for more detailed studies of tree physiological and growth responses to changing climate and atmospheric [CO2] in the boreal forest. PMID- 29127381 TI - Probing the mechanical stability of bridged DNA-H-NS protein complexes by single molecule AFM pulling. AB - Atomic force microscopy (AFM) has proven to be a powerful tool for the study of DNA-protein interactions due to its ability to image single molecules at the nanoscale. However, the use of AFM in force spectroscopy to study DNA-protein interactions has been limited. Here we developed a high throughput, AFM based, pulling assay to measure the strength and kinetics of protein bridging of DNA molecules. As a model system, we investigated the interactions between DNA and the Histone-like Nucleoid-Structuring protein (H-NS). We confirmed that H-NS both changes DNA rigidity and forms bridges between DNA molecules. This straightforward methodology provides a high-throughput approach with single molecule resolution which is widely applicable to study cross-substrate interactions such as DNA-bridging proteins. PMID- 29127382 TI - Birth of clones of the world's first cloned dog. AB - Animal cloning has gained popularity as a method to produce genetically identical animals or superior animals for research or industrial uses. However, the long standing question of whether a cloned animal undergoes an accelerated aging process is yet to be answered. As a step towards answering this question, we compared longevity and health of Snuppy, the world's first cloned dog, and its somatic cell donor, Tai, a male Afghan hound. Briefly, both Snuppy and Tai were generally healthy until both developed cancer to which they succumbed at the ages of 10 and 12 years, respectively. The longevity of both the donor and the cloned dog was close to the median lifespan of Afghan hounds which is reported to be 11.9 years. Here, we report creation of 4 clones using adipose-derived mesenchymal stem cells from Snuppy as donor cells. Clinical and molecular follow up of these reclones over their lives will provide us with a unique opportunity to study the health and longevity of cloned animals compared with their cell donors. PMID- 29127383 TI - Tunable Mid IR focusing in InAs based semiconductor Hyperbolic Metamaterial. AB - Noble Metals such as Gold and Silver demonstrated for mid IR metamaterials have suffered many obstacles such as: high losses and lack of tunability. The application of doped semiconductors has allowed overcoming the tunability restriction, besides, possessing lower losses as compared to metals. In addition, doped semiconductors have small magnitude of negative real permittivity which is required to realize mid IR Hyperbolic Metamaterials (HMMs). We theoretically demonstrate super focusing based on an all Semiconductor planar HMM using InAs heterostructure. By applying a single slit integrated with doped InAs/InAs HMM, incident light can be coupled to high propagation wave vectors of the HMM modes leading to sub diffraction focusing within the mid IR wave length range. Our proposed structure shows a wide controllable/ tunable operation by changing the doping concentration of InAs. As a consequence, focusing resolution can be tuned over the mid IR ranging from 4.64 MUm to 19.57 MUm with the maximum achieved resolution is up to 0.045lambda at an operating wavelength of 19.57 MUm. In addition, we show the effect of substrate refractive index on tuning and enhancing the focusing resolution. Our proposed HMM is an all single based material in which it will not suffer lattice mismatch restrictions during fabrication. PMID- 29127385 TI - Characterization of the Optical Properties of Turbid Media by Supervised Learning of Scattering Patterns. AB - Fabricated tissue phantoms are instrumental in optical in-vitro investigations concerning cancer diagnosis, therapeutic applications, and drug efficacy tests. We present a simple non-invasive computational technique that, when coupled with experiments, has the potential for characterization of a wide range of biological tissues. The fundamental idea of our approach is to find a supervised learner that links the scattering pattern of a turbid sample to its thickness and scattering parameters. Once found, this supervised learner is employed in an inverse optimization problem for estimating the scattering parameters of a sample given its thickness and scattering pattern. Multi-response Gaussian processes are used for the supervised learning task and a simple setup is introduced to obtain the scattering pattern of a tissue sample. To increase the predictive power of the supervised learner, the scattering patterns are filtered, enriched by a regressor, and finally characterized with two parameters, namely, transmitted power and scaled Gaussian width. We computationally illustrate that our approach achieves errors of roughly 5% in predicting the scattering properties of many biological tissues. Our method has the potential to facilitate the characterization of tissues and fabrication of phantoms used for diagnostic and therapeutic purposes over a wide range of optical spectrum. PMID- 29127384 TI - Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death. AB - Dasatinib and radotinib are oral BCR-ABL tyrosine kinase inhibitors that were developed as drugs for the treatment of chronic myeloid leukemia. We report here that the c-KIT (CD117) targeting with dasatinib and radotinib promotes acute myeloid leukemia (AML) cell death, and c-KIT endocytosis is essential for triggering c-KIT-positive AML cell death by dasatinib and radotinib during the early stages. In addition, dasatinib and radotinib reduce heat shock protein 90beta (HSP90beta) expression and release Apaf-1 in c-KIT-positive AML cells. Finally, this activates a caspase-dependent apoptotic pathway in c-KIT-positive AML cells. Moreover, the inhibition of c-KIT endocytosis by dynamin inhibitor (DY) reversed cell viability and c-KIT expression by dasatinib and radotinib. HSP90beta expression was recovered by DY in c-KIT-positive AML cells as well. Furthermore, the effect of radotinib on c-KIT and HSP90beta showed the same pattern in a xenograft animal model using HEL92.1.7 cells. Therefore, dasatinib and radotinib promote AML cell death by targeting c-KIT. Taken together, these results indicate that dasatinib and radotinib treatment have a potential role in anti-leukemic therapy on c-KIT-positive AML cells. PMID- 29127386 TI - SnO2 hollow nanotubes: a novel and efficient support matrix for enzyme immobilization. AB - A major challenge in the industrial use of enzymes is maintaining their stability at elevated temperatures and in harsh organic solvents. In order to address this issue, we investigated the use of nanotubes as a support material for the immobilization and stabilization of enzymes in this work. SnO2 hollow nanotubes with a high surface area were synthesized by electrospinning the SnCl2 precursor and polyvinylpyrrolidone (dissolved in dimethyl formamide and ethanol). The electrospun product was used for the covalent immobilization of enzymes such as lipase, horseradish peroxidase, and glucose oxidase. The use of SnO2 hollow nanotubes as a support was promising for all immobilized enzymes, with lipase having the highest protein loading value of 217 mg/g, immobilization yield of 93%, and immobilization efficiency of 89%. The immobilized enzymes were fully characterized by various analytical methods. The covalently bonded lipase showed a half-life value of 4.5 h at 70 degrees C and retained ~91% of its original activity even after 10 repetitive cycles of use. Thus, the SnO2 hollow nanotubes with their high surface area are promising as a support material for the immobilization of enzymes, leading to improved thermal stability and a higher residual activity of the immobilized enzyme under harsh solvent conditions, as compared to the free enzyme. PMID- 29127387 TI - Controlling the Bidirectional Circular Polarization States Using Ultrathin Back to-Back Quarter-Wave Plates Cavity. AB - Efficiently manipulating the polarization states of electromagnetic waves is of great importance for communication, imaging, and sensing. In this paper, we aim to control the circular polarization states, e.g., left-hand, or right-hand, for the bidirectional radiated waves utilizing a pair of back-to-back quarter-wave plates, which are integrated within an ultrathin cavity. As an example, a bidirectional circularly polarized wave with the same helicity in forward and backward is generated based on numerical analyses, and proved by experiments in microwave region. The proposed ultrathin back-to-back quarter-wave plates cavity can be adopted to higher frequencies, e.g., terahertz and mid-infrared ranges, with lower metallic conductivity. The proposed method exhibits the advantages of compact dimension and low-cost implementation in engineering the bidirectional polarization states of electromagnetic waves. PMID- 29127389 TI - High-brightness laser imaging with tunable speckle reduction enabled by electroactive micro-optic diffusers. AB - High coherence of lasers is desirable in high-speed, high-resolution, and wide field imaging. However, it also causes unavoidable background speckle noise thus degrades the image quality in traditional microscopy and more significantly in interferometric quantitative phase imaging (QPI). QPI utilizes optical interference for high-precision measurement of the optical properties where the speckle can severely distort the information. To overcome this, we demonstrated a light source system having a wide tunability in the spatial coherence over 43% by controlling the illumination angle, scatterer's size, and the rotational speed of an electroactive-polymer rotational micro-optic diffuser. Spatially random phase modulation was implemented for the lower speckle imaging with over a 50% speckle reduction without a significant degradation in the temporal coherence. Our coherence control technique will provide a unique solution for a low-speckle, full-field, and coherent imaging in optically scattering media in the fields of healthcare sciences, material sciences and high-precision engineering. PMID- 29127388 TI - Brief targeted memory reactivation during the awake state enhances memory stability and benefits the weakest memories. AB - Reactivation of representations corresponding to recent experience is thought to be a critical mechanism supporting long-term memory stabilization. Targeted memory reactivation, or the re-exposure of recently learned cues, seeks to induce reactivation and has been shown to benefit later memory when it takes place during sleep. However, despite recent evidence for endogenous reactivation during post-encoding awake periods, less work has addressed whether awake targeted memory reactivation modulates memory. Here, we found that brief (50 ms) visual stimulus re-exposure during a repetitive foil task enhanced the stability of cued versus uncued associations in memory. The extent of external or task-oriented attention prior to re-exposure was inversely related to cueing benefits, suggesting that an internally-orientated state may be most permissible to reactivation. Critically, cueing-related memory benefits were greatest in participants without explicit recognition of cued items and remained reliable when only considering associations not recognized as cued, suggesting that explicit cue-triggered retrieval processes did not drive cueing benefits. Cueing benefits were strongest for associations and participants with the poorest initial learning. These findings expand our knowledge of the conditions under which targeted memory reactivation can benefit memory, and in doing so, support the notion that reactivation during awake time periods improves memory stabilization. PMID- 29127390 TI - Indoor PM2.5 exposure affects skin aging manifestation in a Chinese population. AB - Traffic-related air pollution is known to be associated with skin aging manifestations. We previously found that the use of fossil fuels was associated with skin aging, but no direct link between indoor air pollutants and skin aging manifestations has ever been shown. Here we directly measured the indoor PM2.5 exposure in 30 households in Taizhou, China. Based on the directly measured PM2.5 exposure and questionnaire data of indoor pollution sources, we built a regression model to predict the PM2.5 exposure in larger datasets including an initial examination group (N = 874) and a second examination group (N = 1003). We then estimated the association between the PM2.5 exposure and skin aging manifestations by linear regression. In the initial examination group, we showed that the indoor PM2.5 exposure levels were positively associated with skin aging manifestation, including score of pigment spots on forehead (12.5% more spots per increase of IQR, P-value 0.0371), and wrinkle on upper lip (7.7% more wrinkle on upper lip per increase of IQR, P-value 0.0218). The results were replicated in the second examination group as well as in the pooled dataset. Our study provided evidence that the indoor PM2.5 exposure is associated with skin aging manifestation in a Chinese population. PMID- 29127391 TI - Cooperative polariton dynamics in feedback-coupled cavities. AB - The emerging field of cavity spintronics utilizes the cavity magnon polariton (CMP) induced by magnon Rabi oscillations. In contrast to a single-spin quantum system, such a cooperative spin dynamics in the linear regime is governed by the classical physics of harmonic oscillators. It makes the magnon Rabi frequency independent of the photon Fock state occupation, and thereby restricts the quantum application of CMP. Here we show that a feedback cavity architecture breaks the harmonic-oscillator restriction. By increasing the feedback photon number, we observe an increase in the Rabi frequency, accompanied with the evolution of CMP to a cavity magnon triplet and a cavity magnon quintuplet. We present a theory that explains these features. Our results reveal the physics of cooperative polariton dynamics in feedback-coupled cavities, and open up new avenues for exploiting the light-matter interactions. PMID- 29127392 TI - SaccharomycesIDentifier, SID: strain-level analysis of Saccharomyces cerevisiae populations by using microsatellite meta-patterns. AB - Saccharomyces cerevisiae is a common yeast with several applications, among which the most ancient is winemaking. Because individuals belonging to this species show a wide genetic and phenotypic variability, the possibility to identify the strains driving fermentation is pivotal when aiming at stable and palatable products. Metagenomic sequencing is increasingly used to decipher the fungal populations present in complex samples such as musts. However, it does not provide information at the strain level. Microsatellites are commonly used to describe the genotype of single strains. Here we developed a population-level microsatellite profiling approach, SID (Saccharomyces cerevisiae IDentifier), to identify the strains present in complex environmental samples. We optimized and assessed the performances of the analytical procedure on patterns generated in silico by computationally pooling Saccharomyces cerevisiae microsatellite profiles, and on samples obtained by pooling DNA of different strains, proving its ability to characterize real samples of grape wine fermentations. SID showed clear differences among S. cerevisiae populations in grape fermentation samples, identifying strains that are likely composing the populations and highlighting the impact of the inoculation of selected exogenous strains on natural strains. This tool can be successfully exploited to identify S. cerevisiae strains in any kind of complex samples. PMID- 29127394 TI - Systematic population spike delays across cortical layers within and between primary sensory areas. AB - The coordinated propagation of activity across cortical layers enables simultaneous local computation and inter-areal interactions. A pattern of upward propagation from deeper to more superficial layers, which has been repeatedly demonstrated in spontaneous activity, would allow these functions to occur in parallel. But it remains unclear whether upward propagation also occurs for stimulus evoked activity, and how it relates to activity in other cortical areas. Here we used a new method to analyze relative delays between spikes obtained from simultaneous laminar recordings in primary sensory cortex (S1) of both hemispheres. The results identified systematic spike delays across cortical layers that showed a general upward propagation of activity in evoked and spontaneous activity. Systematic spike delays were also observed between hemispheres. After spikes in one S1 the delays in the other S1 were shortest at infragranular layers and increased in the upward direction. Model comparisons furthermore showed that upward propagation was better explained as a step-wise progression over cortical layers than as a traveling wave. The results are in line with the notion that upward propagation functionally integrates activity into local processing at superficial layers, while efficiently allowing for simultaneous inter-areal interactions. PMID- 29127395 TI - Extra-territorial movements differ between territory holders and subordinates in a large, monogamous rodent. AB - Territorial animals carry out extra-territorial movements (forays) to obtain pre dispersal information or to increase reproductive success via extra-pair copulation. However, little is known about other purposes and spatial movement patterns of forays. In this study, we GPS-tagged 54 Eurasian beavers (Castor fiber), a year-round territorial, monogamous mammal, during the non-mating season. We investigated forays in territory-holding breeders (dominants) and non breeding (subordinate) family members. Twenty of 46 dominant individuals (44%), and 6 of 10 subordinates (60%) conducted forays. Generally, beavers spent between 0 and 11% of their active time on forays, travelled faster and spend more time in water when on forays compared to intra-territorial movements, suggesting that forays are energetically costly. Further, beavers in smaller territories conducted more forays. Possibly, smaller territories might not have sufficient resources and thus dominant individuals might conduct forays to assess possibilities for territory expansion, and potentially for foraging. Generally, besides territory advertisement (e.g. via scent-marking), forays might serve as an additional mechanism for territory owners to assess neighbours. Subordinates spent more time on forays, moved greater distances and intruded into more territories than dominant individuals did, suggesting that they prospected to gain information on the population density and available mates before dispersal. PMID- 29127393 TI - Large-scale identification of lysine acetylated proteins in vegetative hyphae of the rice blast fungus. AB - Lysine acetylation is a major post-translational modification that plays important regulatory roles in diverse biological processes to perform various cellular functions in both eukaryotes and prokaryotes. However, roles of lysine acetylation in plant fungal pathogens were less studied. Here, we provided the first lysine acetylome of vegetative hyphae of the rice blast fungus Magnaporthe oryzae through a combination of highly sensitive immune-affinity purification and high-resolution LC-MS/MS. This lysine acetylome had 2,720 acetylation sites in 1,269 proteins. The lysine acetylated proteins were involved indiverse cellular functions, and located in 820 nodes and 7,709 edges among the protein-protein interaction network. Several amino acid residues nearby the lysine acetylation sites were conserved, including KacR, KacK, and KacH. Importantly, dozens of lysine acetylated proteins are found to be important to vegetative hyphal growth and fungal pathogenicity. Taken together, our results provided the first comprehensive view of lysine acetylome of M.oryzae and suggested protein lysine acetylation played important roles to fungal development and pathogenicity. PMID- 29127396 TI - Infrared single photon detector based on optical up-converter at 1550 nm. AB - High performance single photon detector at the wavelength of 1550 nm has drawn wide attention and achieved vast improvement due to its significant application in quantum information, quantum key distribution, as well as cosmology. A novel infrared up-conversion single photon detector (USPD) at 1550 nm was proposed to work in free-running regime based on the InGaAs/ InP photodetector (PD)- GaAs/AlGaAs LED up-converter and Si single photon avalanche diode (SPAD). In contrast to conventional In0.53Ga0.47As SPAD, the USPD can suppress dark count rate and afterpulsing efficiently without sacrificing the photon detection efficiency (PDE). A high PDE of ~45% can be achieved by optical adhesive coupling between up-converter and Si SPAD. Using a developed analytical model we gave a noise equivalent power of 1.39 * 10-18 WHz1/2 at 200 K for the USPD, which is better than that of InGaAs SPAD. This work provides a new single photon detection scheme for telecom band. PMID- 29127397 TI - sPAGM: inferring subpathway activity by integrating gene and miRNA expression robust functional signature identification for melanoma prognoses. AB - MicroRNAs (miRNAs) regulate biological pathways by inhibiting gene expression. However, most current analytical methods fail to consider miRNAs, when inferring functional or pathway activities. In this study, we developed a model called sPAGM to infer subpathway activities by integrating gene and miRNA expressions. In this model, we reconstructed subpathway graphs by embedding miRNA components, and characterized subpathway activity (sPA) scores by simultaneously considering the expression levels of miRNAs and genes. The results showed that the sPA scores could distinguish different samples across tumor types, as well as samples between tumor and normal conditions. Moreover, the sPAGM model displayed more specificities than the entire pathway-based analyses. This model was applied to melanoma tumors to perform a prognosis analysis, which identified a robust 55 subpathway signature. By using The Cancer Genome Atlas and independently verified data sets, the subpathway-based signature significantly predicted the patients' prognoses, which were independent of clinical variables. In the prognostic performance comparison, the sPAGM model was superior to the gene-only and miRNA only methods. Finally, we dissected the functional roles and interactions of components within the subpathway signature. Taken together, the sPAGM model provided a framework for inferring subpathway activities and identifying functional signatures for clinical applications. PMID- 29127398 TI - Overexpression of DYRK1A, a Down Syndrome Candidate gene, Impairs Primordial Germ Cells Maintenance and Migration in zebrafish. AB - DYRK1A, located on chromosome 21, is a major candidate gene of Down syndrome (DS, trisomy21), and its overexpression is associated with abnormal phenotype of Down syndrome patients. The defects of gonads and germ cells in Down Syndrome suggest that overexpression of DYRK1A has potential effect on primordial germ cells (PGCs) development. Human and zebrafish DYRK1A protein sequence possess 75.6% similarity and same function domains, suggesting the evolutional conservation. Here, we used zebrafish model to detect the definite role of excessive expression of DYRK1A in PGCs development during embryogenesis. We injected DYRK1A mRNA into embryos and detected the PGCs marker gene vasa and nanos1. Results showed depletion in numbers and disordering migration of PGCs in human or zebrafish DYRK1A overexpressed zebrafish embryos. Quantitative proteome analysis indicated that embryonic proteins were significantly altered in DYRK1A overexpressed embryos. Of note, ca15b and piwil1, two identified critical factors for PGCs development, showed ectopic expression induced by overexpressed DYRK1A. In brief, we demonstrate that overexpression of DYRK1A, a candidate gene of Down's syndrome, impairs PGCs development during early embryogenesis by altering key factors in embryos. Importantly, our work may provide a conceivable mechanism for the gonads and germ cells defects of Down syndrome patients. PMID- 29127400 TI - Folded fabric tunes rock deformation and failure mode in the upper crust. AB - The micro-mechanisms of brittle failure affect the bulk mechanical behaviour and permeability of crustal rocks. In low-porosity crystalline rocks, these mechanisms are related to mineralogy and fabric anisotropy, while confining pressure, temperature and strain rates regulate the transition from brittle to ductile behaviour. However, the effects of folded anisotropic fabrics, widespread in orogenic settings, on the mechanical behaviour of crustal rocks are largely unknown. Here we explore the deformation and failure behaviour of a representative folded gneiss, by combining the results of triaxial deformation experiments carried out while monitoring microseismicity with microstructural and damage proxies analyses. We show that folded crystalline rocks in upper crustal conditions exhibit dramatic strength heterogeneity and contrasting failure modes at identical confining pressure and room temperature, depending on the geometrical relationships between stress and two different anisotropies associated to the folded rock fabric. These anisotropies modulate the competition among quartz- and mica-dominated microscopic damage processes, resulting in transitional brittle to semi-brittle modes under P and T much lower than expected. This has significant implications on scales relevant to seismicity, energy resources, engineering applications and geohazards. PMID- 29127401 TI - Publisher Correction: Electron momentum densities near Dirac cones: Anisotropic Umklapp scattering and momentum broadening. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29127399 TI - Radial Extracorporeal Shock Wave Therapy Enhances the Proliferation and Differentiation of Neural Stem Cells by Notch, PI3K/AKT, and Wnt/beta-catenin Signaling. AB - Neural stem cell (NSC) proliferation and differentiation play a pivotal role in the repair of brain function in central nervous system (CNS) diseases. Radial extracorporeal shock wave therapy (rESWT) is a non-invasive and innovative treatment for many conditions, yet little is known about the effects of this treatment on NSCs. Mouse NSCs (NE-4C) were exposed to rESWT with 1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 bar (500 impulses, and 2 Hz) in vitro. Cell viability test results indicated that rESWT, at a dose of 2.5 bar, 500 impulses, and 2 Hz, increased NE-4C viability within 72 h, and that the PI3K/AKT pathway was involved in its mechanisms. Exposure to rESWT also affected proliferation and differentiation of NE-4C after 8 weeks, which may be associated with Wnt/beta catenin and Notch pathways. This assessment is corroborated by the ability of inhibitors of Wnt/beta-catenin [Dickkopf-1 (Dkk-1)] and the Notch pathway (DAPT) to weaken proliferation and differentiation of NSCs. In summary, a proper dose of rESWT enhanced NSCs augment via the PI3K/AKT pathway initially. Also, Wnt/beta catenin and the Notch pathway play important roles in regulation of the long-term efficacy of rESWT. This study reveals a novel approach to culture NSCs in vitro and support neurogenesis. PMID- 29127402 TI - The nature of ancient Egyptian copper-containing carbon inks is revealed by synchrotron radiation based X-ray microscopy. AB - For the first time it is shown that carbon black inks on ancient Egyptian papyri from different time periods and geographical regions contain copper. The inks have been investigated using synchrotron-based micro X-ray fluorescence (XRF) and micro X-ray absorption near-edge structure spectroscopy (XANES) at the European Synchrotron Radiation Facility (ESRF). The composition of the copper-containing carbon inks showed no significant differences that could be related to time periods or the geographical locations. This renders it probable that the same technology for ink production was used throughout Egypt for a period spanning at least 300 years. It is argued that the black pigment material (soot) for these inks was obtained as by-products of technical metallurgy. The copper (Cu) can be correlated with the following three main components: cuprite (Cu2O), azurite (Cu3[CO3]2[OH]2) and malachite (Cu2CO3[OH]2). PMID- 29127403 TI - Superconducting Properties in Arrays of Nanostructured beta-Gallium. AB - Samples of nanostructured beta-Ga wires were synthesized by a novel method of metallic-flux nanonucleation. Several superconducting properties were observed, revealing the stabilization of a weak-coupling type-II-like superconductor ([Formula: see text] [Formula: see text] 6.2 K) with a Ginzburg-Landau parameter [Formula: see text] = 1.18. This contrasts the type-I superconductivity observed for the majority of Ga phases, including small spheres of beta-Ga with diameters near 15 MUm. Remarkably, our magnetization curves reveal a crossover field [Formula: see text], where we propose that the Abrikosov vortices are exactly touching their neighbors inside the Ga nanowires. A phenomenological model is proposed to explain this result by assuming that only a single row of vortices is allowed inside a nanowire under perpendicular applied field, with an appreciable depletion of Cooper pair density at the nanowire edges. These results are expected to shed light on the growing area of superconductivity in nanostructured materials. PMID- 29127405 TI - Atomistic Structure of Mineral Nano-aggregates from Simulated Compaction and Dewatering. AB - The porosity of clay aggregates is an important property governing chemical reactions and fluid flow in low-permeability geologic formations and clay-based engineered barrier systems. Pore spaces in clays include interlayer and interparticle pores. Under compaction and dewatering, the size and geometry of such pore spaces may vary significantly (sub-nanometer to microns) depending on ambient physical and chemical conditions. Here we report a molecular dynamics simulation method to construct a complex and realistic clay-like nanoparticle aggregate with interparticle pores and grain boundaries. The model structure is then used to investigate the effect of dewatering and water content on micro porosity of the aggregates. The results suggest that slow dewatering would create more compact aggregates compared to fast dewatering. Furthermore, the amount of water present in the aggregates strongly affects the particle-particle interactions and hence the aggregate structure. Detailed analyses of particle particle and water-particle interactions provide a molecular-scale view of porosity and texture development of the aggregates. The simulation method developed here may also aid in modeling the synthesis of nanostructured materials through self-assembly of nanoparticles. PMID- 29127404 TI - Investigation of novel metabolites potentially involved in the pathogenesis of coronary heart disease using a UHPLC-QTOF/MS-based metabolomics approach. AB - Coronary heart disease (CHD) is associated with complex metabolic disorders, but its molecular aetiology remains unclear. Using a novel nontargeted metabolomics approach, we explored the global metabolic perturbation profile for CHD. Blood samples from 150 patients with severe obstructive CHD and 150 angiographically normal controls were collected. Metabolic fingerprinting was performed by ultra high performance liquid chromatography coupled to quadruple time-of-flight mass spectrometry (UHPLC-QTOF/MS) technique. After adjusting for CHD traditional risk factors and metabolic batch, a comprehensive list of 105 metabolites was found to be significantly altered in CHD patients. Among the metabolites identified, six metabolites were discovered to have the strongest correlation with CHD after adjusting for multiple testing: palmitic acid (beta = 0.205; p < 0.0001), linoleic acid (beta = 0.133; p < 0.0001), 4-pyridoxic acid (beta = 0.142; p < 0.0001), phosphatidylglycerol (20:3/2:0) (beta = 0.287; p < 0.0001), carnitine (14:1) (beta = 0.332; p < 0.0001) and lithocholic acid (beta = 0.224; p < 0.0001); of these, 4-pyridoxic acid, lithocholic acid and phosphatidylglycerol (20:3/2:0) were, to the best of our knowledge, first reported in this study. A logistic regression model further quantified their positive independent correlations with CHD. In conclusion, this study surveyed a broad panel of nontargeted metabolites in Chinese CHD populations and identified novel metabolites that are potentially involved in CHD pathogenesis. PMID- 29127406 TI - Technospheric Mining of Rare Earth Elements from Bauxite Residue (Red Mud): Process Optimization, Kinetic Investigation, and Microwave Pretreatment. AB - Some rare earth elements (REEs) are classified under critical materials, i.e., essential in use and subject to supply risk, due to their increasing demand, monopolistic supply, and environmentally unsustainable and expensive mining practices. To tackle the REE supply challenge, new initiatives have been started focusing on their extraction from alternative secondary resources. This study puts the emphasis on technospheric mining of REEs from bauxite residue (red mud) produced by the aluminum industry. Characterization results showed the bauxite residue sample contains about 0.03 wt% REEs. Systematic leaching experiments showed that concentrated HNO3 is the most effective lixiviant. However, because of the process complexities, H2SO4 was selected as the lixiviant. To further enhance the leaching efficiency, a novel process based on microwave pretreatment was employed. Results indicated that microwave pretreatment creates cracks and pores in the particles, enabling the lixiviant to diffuse further into the particles, bringing more REEs into solution, yielding of 64.2% and 78.7% for Sc and Nd, respectively, which are higher than the maximum obtained when HNO3 was used. This novel process of "H2SO4 leaching-coupled with-microwave pretreatment" proves to be a promising technique that can help realize the technological potential of REE recovery from secondary resources, particularly bauxite residue. PMID- 29127407 TI - Crystal Structure of Borrelia turicatae protein, BTA121, a differentially regulated gene in the tick-mammalian transmission cycle of relapsing fever spirochetes. AB - Tick-borne relapsing fever (RF) borreliosis is a neglected disease that is often misdiagnosed. RF species circulating in the United States include Borrelia turicatae, which is transmitted by argasid ticks. Environmental adaptation by RF Borrelia is poorly understood, however our previous studies indicated differential regulation of B. turicatae genes localized on the 150 kb linear megaplasmid during the tick-mammalian transmission cycle, including bta121. This gene is up-regulated by B. turicatae in the tick versus the mammal, and the encoded protein (BTA121) is predicted to be surface localized. The structure of BTA121 was solved by single-wavelength anomalous dispersion (SAD) using selenomethionine-derivative protein. The topology of BTA121 is unique with four helical domains organized into two helical bundles. Due to the sequence similarity of several genes on the megaplasmid, BTA121 can serve as a model for their tertiary structures. BTA121 has large interconnected tunnels and cavities that can accommodate ligands, notably long parallel helices, which have a large hydrophobic central pocket. Preliminary in-vitro studies suggest that BTA121 binds lipids, notably palmitate with a similar order of binding affinity as tablysin-15, a known palmitate-binding protein. The reported data will guide mechanistic studies to determine the role of BTA121 in the tick-mammalian transmission cycle of B. turicatae. PMID- 29127408 TI - Statistical Analysis for Collision-free Boson Sampling. AB - Boson sampling is strongly believed to be intractable for classical computers but solvable with photons in linear optics, which raises widespread concern as a rapid way to demonstrate the quantum supremacy. However, due to its solution is mathematically unverifiable, how to certify the experimental results becomes a major difficulty in the boson sampling experiment. Here, we develop a statistical analysis scheme to experimentally certify the collision-free boson sampling. Numerical simulations are performed to show the feasibility and practicability of our scheme, and the effects of realistic experimental conditions are also considered, demonstrating that our proposed scheme is experimentally friendly. Moreover, our broad approach is expected to be generally applied to investigate multi-particle coherent dynamics beyond the boson sampling. PMID- 29127409 TI - Frequency of Human CD45+ Target Cells is a Key Determinant of Intravaginal HIV-1 Infection in Humanized Mice. AB - Approximately 40% of HIV-1 infections occur in the female genital tract (FGT), primarily through heterosexual transmission. FGT factors determining outcome of HIV-1 exposure are incompletely understood, limiting prevention strategies. Here, humanized NOD-Rag1-/- gammac-/- mice differentially reconstituted with human CD34+ -enriched hematopoietic stem cells (Hu-mice), were used to assess target cell frequency and viral inoculation dose as determinants of HIV-1 infection following intravaginal (IVAG) challenge. Results revealed a significant correlation between HIV-1 susceptibility and hCD45+ target cells in the blood, which correlated with presence of target cells in the FGT, in the absence of local inflammation. HIV-1 plasma load was associated with viral dose at inoculation and frequency of target cells. Events following IVAG HIV-1 infection; viral dissemination and CD4 depletion, were not affected by these parameters. Following IVAG inoculation, HIV-1 titres peaked, then declined in vaginal lavage while plasma showed a reciprocal pattern. The greatest frequency of HIV-1 infected (p24+) cells were found one week post-infection in the FGT versus blood and spleen, suggesting local viral amplification. Five weeks post-infection, HIV 1 disseminated into systemic tissues, in a dose-dependent manner, followed by depletion of hCD45+ CD3+ CD4+ cells. Results indicate target cell frequency in the Hu-mouse FGT is a key determinant of HIV-1 infection, which might provide a useful target for prophylaxis in women. PMID- 29127410 TI - Ultrafiltration combined with size exclusion chromatography efficiently isolates extracellular vesicles from cell culture media for compositional and functional studies. AB - Appropriate isolation methods are essential for unravelling the relative contribution of extracellular vesicles (EVs) and the EV-free secretome to homeostasis and disease. We hypothesized that ultrafiltration followed by size exclusion chromatography (UF-SEC) provides well-matched concentrates of EVs and free secreted molecules for proteomic and functional studies. Conditioned media of BEAS-2B bronchial epithelial cells were concentrated on 10 kDa centrifuge filters, followed by separation of EVs and free protein using sepharose CL-4B SEC. Alternatively, EVs were isolated by ultracentrifugation. EV recovery was estimated by bead-coupled flow cytometry and tuneable resistive pulse sensing. The proteomic composition of EV isolates and SEC protein fractions was characterized by nano LC-MS/MS. UF-SEC EVs tended to have a higher yield and EV to-protein rate of purity than ultracentrifugation EVs. UF-SEC EVs and ultracentrifugation EVs showed similar fold-enrichments for biological pathways that were distinct from those of UF-SEC protein. Treatment of BEAS-2B cells with UF-SEC protein, but not with either type of EV isolate increased the IL-8 concentration in the media whereas EVs, but not protein induced monocyte adhesion to endothelial cells. Thus, UF-SEC is a useful alternative for ultracentrifugation and allows comparing the proteomic composition and functional effects of EVs and free secreted molecules. PMID- 29127411 TI - Performance of Solid-state Hybrid Energy-storage Device using Reduced Graphene oxide Anchored Sol-gel Derived Ni/NiO Nanocomposite. AB - The influence of (nickel nitrate/citric acid) mole ratio on the formation of sol gel end products was examined. The formed Ni/NiO nanoparticle was anchored on to reduced graphene-oxide (rGO) by means of probe sonication. It was found that the sample obtained from the (1:1) nickel ion: citric acid (Ni2+: CA) mole ratio resulted in a high specific capacity of 158 C/g among all (Ni2+: CA) ratios examined. By anchoring Ni/NiO on to the rGO resulted in enhanced specific capacity of as high as 335 C/g along with improved cycling stability, high rate capability and Coulombic efficiency. The high conductivity and increased surface area seemed responsible for enhanced electrochemical performances of the Ni/NiO@rGO nanocomposite. A solid-state hybrid energy-storage device consisting of the Ni/NiO@rGO (NR2) as a positive electrode and the rGO as negative electrode exhibited enhanced energy and power densities. Lighting of LED was demonstrated by using three proto-type (NR2(+)|| rGO(-)) hybrid devices connected in series. PMID- 29127412 TI - Rapid and selective surface functionalization of the membrane for high efficiency oil-water separation via an atmospheric pressure plasma process. AB - Oil-water separation is a worldwide challenge because of the increasing production of industrial oily wastewater and frequent oil spills. The growing environmental and economic demands emphasize the need to develop effective solutions to separate oil and water. Recently, oil-water separation methods were developed by tuning the wettability of membranes via surface functionalization. However, the industrialization of such methods remains challenging due to the easy-fouling, high cost and complex fabrication. Herein, a simple and rapid pathway to separate oil from oil-water mixtures is reported using plasma surface functionalization in an open-air environment. The fine tuning and study of the plasma process parameters enables the selective functionalization of each side of the membranes which led respectively to a superhydrophobic-superoleophilic and superhydrophobic-oleophobic sides. The successful separation, without any external force, of a 50 mL oil-water solution in 6 minutes was achieved. This work paves the way for an efficient, low cost and easily upscalable method for oil-water separation due to the high versatility of the atmospheric pressure plasma processes. PMID- 29127414 TI - Orthogonal navigation of multiple visible-light-driven artificial microswimmers. AB - Nano/microswimmers represent the persistent endeavors of generations of scientists towards the ultimate tiny machinery for device manufacturing, targeted drug delivery, and noninvasive surgery. In many of these envisioned applications, multiple microswimmers need to be controlled independently and work cooperatively to perform a complex task. However, this multiple channel actuation remains a challenge as the controlling signal, usually a magnetic or electric field, is applied globally over all microswimmers, which makes it difficult to decouple the responses of multiple microswimmers. Here, we demonstrate that a photoelectrochemically driven nanotree microswimmer can be easily coded with a distinct spectral response by loading it with dyes. By using different dyes, an individual microswimmer can be controlled and navigated independently of other microswimmers in a group. This development demonstrates the excellent flexibility of the light navigation method and paves the way for the development of more functional nanobots for applications that require high-level controllability. PMID- 29127413 TI - Thermodynamics of lipid multi-lamellar vesicles in presence of sterols at high hydrostatic pressure. AB - We compared the effect of cholesterol at different concentration on the phase behaviour of DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) multilamellar vesicles. We used pressure perturbation differential scanning calorimetry (PPC) that studies a system on the whole by giving access to relevant thermodynamic quantities, and elastic incoherent neutron scattering (EINS) that probes local motions of a system at the atomic level by allowing extraction of dynamical parameters. PPC revealed that the volume expansion coefficient of DMPC and DMPC/Cholesterol samples with 13 and 25 mol% cholesterol is a linear function of the heat capacity measured by differential scanning calorimetry. Neutron backscattering spectroscopy showed that the mean square displacements of H atoms do exhibit an increase with temperature and a decrease under increasing pressure. Cholesterol added at concentrations of 25 and 50 mol% led to suppression of the main phase transition. Taking advantage of these results, the present study aims (i) to show that calorimetry and EINS using the Bicout and Zaccai model equally permit to get access to thermodynamic quantities characterizing pure DMPC and DMPC/cholesterol mixtures, thus directly confirming the theoretical method, and (ii) to validate our approach as function of temperature and of pressure, as both are equally important and complementary thermodynamic variables. PMID- 29127416 TI - Author Correction: Visuotactile integration modulates motor performance in a perceptual decision-making task. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.a. PMID- 29127415 TI - Sequencing and characterization of the complete mitochondrial genome of Japanese Swellshark (Cephalloscyllium umbratile). AB - To further comprehend the genome features of Cephalloscyllium umbratile (Carcharhiniformes), an endangered species, the complete mitochondrial DNA (mtDNA) was firstly sequenced and annotated. The full-length mtDNA of C. umbratile was 16,697 bp and contained ribosomal RNA (rRNA) genes, 13 protein coding genes (PCGs), 23 transfer RNA (tRNA) genes, and a major non-coding control region. Each PCG was initiated by an authoritative ATN codon, except for COX1 initiated by a GTG codon. Seven of 13 PCGs had a typical TAA termination codon, while others terminated with a single T or TA. Moreover, the relative synonymous codon usage of the 13 PCGs was consistent with that of other published Carcharhiniformes. All tRNA genes had typical clover-leaf secondary structures, except for tRNA-Ser (GCT), which lacked the dihydrouridine 'DHU' arm. Furthermore, the analysis of the average Ka/Ks in the 13 PCGs of three Carcharhiniformes species indicated a strong purifying selection within this group. In addition, phylogenetic analysis revealed that C. umbratile was closely related to Glyphis glyphis and Glyphis garricki. Our data supply a useful resource for further studies on genetic diversity and population structure of C. umbratile. PMID- 29127417 TI - The positive effects of Xueshuan Xinmai tablets on brain functional connectivity in acute ischemic stroke: a placebo controlled randomized trial. AB - Through a placebo controlled randomized study, the purpose of this report was to investigate the effects of Xueshuan Xinmai tablets (XXMT) on neurologic deficits, quality of life and brain functional connectivity in acute ischemic stroke patients and to explore the mechanism of action of XXMT. In total, 44 acute ischemic stroke patients were randomly divided to the XXMT treatment group (n = 22) or the placebo group (n = 22) in a 2-week trial. Before and after the treatment, the neurological assessment and functional magnetic resonance imaging examinations were carried out. Compared to the placebo group, the scores of the National Institutes of Health Stroke Scale (NIHSS) and Stroke-Specific Quality of Life Scale (SSQOL) significantly improved in the treatment group. In addition, XXMT-treated patients demonstrated significantly enhanced functional connectivity within the default mode, frontal-parietal, and motor control networks. Furthermore, the changed connectivity in the left precuneus was positively correlated to the improvement of NIHSS and SSQOL scores. The present study indicated that XXMT treatment significantly improved the neurologic deficit and quality of life of acute ischemic stroke patients and that the therapeutic effect may be based on the modulation of XXMT on the functional connectivity of brain networks. PMID- 29127418 TI - Exploration and recency as the main proximate causes of probability matching: a reinforcement learning analysis. AB - Research has not yet reached a consensus on why humans match probabilities instead of maximise in a probability learning task. The most influential explanation is that they search for patterns in the random sequence of outcomes. Other explanations, such as expectation matching, are plausible, but do not consider how reinforcement learning shapes people's choices. We aimed to quantify how human performance in a probability learning task is affected by pattern search and reinforcement learning. We collected behavioural data from 84 young adult participants who performed a probability learning task wherein the majority outcome was rewarded with 0.7 probability, and analysed the data using a reinforcement learning model that searches for patterns. Model simulations indicated that pattern search, exploration, recency (discounting early experiences), and forgetting may impair performance. Our analysis estimated that 85% (95% HDI [76, 94]) of participants searched for patterns and believed that each trial outcome depended on one or two previous ones. The estimated impact of pattern search on performance was, however, only 6%, while those of exploration and recency were 19% and 13% respectively. This suggests that probability matching is caused by uncertainty about how outcomes are generated, which leads to pattern search, exploration, and recency. PMID- 29127419 TI - Bacteremic and non-bacteremic pneumonia caused by Acinetobacter baumannii in ICUs of South China: A Clinical and Microbiological Study. AB - Acinetobacter baumannii has been a dreadful problem for ICU physicians for a long time. Bacteremic pneumonia (BP) caused by this organism has a higher mortality compared to other organisms. Between 2012 and 2015, 86 BP and 89 non-bacteremic pneumonia (NBP) patients from five ICUs were enrolled into the study. The 7-day and 14-day mortality rates were higher in BP patients than in NBP patients (P < 0.001). Procalcitonin elevation, high APACHEII score and recent surgery, were independently associated with BP episodes. Acute respiratory distress syndrome, coma, high APACHEII score and procalcitonin elevation, were independently associated with mortality in the BP group. Extensively drug-resistant isolates were detected in 34.9% of BP and 25.8% of NBP isolates. PFGE identified 12 and 9 genotypes in the BP and NBP isolates, respectively, with 6 genotypes shared by both groups. ST195 was the most prevalent type (40%), followed by ST457 (18.9%). The pandemic clonal complex 92 was predominant, accounting for 94.3% of the strains. For all studied periods, mortality remained higher in the BP than the NBP group. Disease severity was the main risk factor for high mortality in the BP group, and other factors related to mortality were infection, and not treatment or microbiology-related. PMID- 29127420 TI - Genome-wide analyses of long noncoding RNA expression profiles in lung adenocarcinoma. AB - LncRNAs have emerged as a novel class of critical regulators of cancer. We aimed to construct a landscape of lncRNAs and their potential target genes in lung adenocarcinoma. Genome-wide expression of lncRNAs and mRNAs was determined using microarray. qRT-PCR was performed to validate the expression of the selected lncRNAs in a cohort of 42 tumor tissues and adjacent normal tissues. R and Bioconductor were used for data analysis. A total of 3045 lncRNAs were differentially expressed between the paired tumor and normal tissues (1048 up and 1997 down). Meanwhile, our data showed that the expression NONHSAT077036 was associated with N classification and clinical stage. Further, we analyzed the potential co-regulatory relationship between the lncRNAs and their potential target genes using the 'cis' and 'trans' models. In the 25 related transcription factors (TFs), our analysis of The Cancer Genome Atlas database (TCGA) found that patients with lower expression of POU2F2 and higher expression of TRIM28 had a shorter overall survival time. The POU2F2 and TRIM28 co-expressed lncRNA landscape characterized here may shed light into normal biology and lung adenocarcinoma pathogenesis, and be valuable for discovery of biomarkers. PMID- 29127421 TI - Captive bottlenose dolphins and killer whales harbor a species-specific skin microbiota that varies among individuals. AB - Marine animals surfaces host diverse microbial communities, which play major roles for host's health. Most inventories of marine animal surface microbiota have focused on corals and fishes, while cetaceans remain overlooked. The few studies focused on wild cetaceans, making difficult to distinguish intrinsic inter- and/or intraspecific variability in skin microbiota from environmental effects. We used high-throughput sequencing to assess the skin microbiota from 4 body zones of 8 bottlenose dolphins (Tursiops truncatus) and killer whales (Orcinus orca), housed in captivity (Marineland park, France). Overall, cetacean skin microbiota is more diverse than planktonic communities and is dominated by different phylogenetic lineages and functions. In addition, the two cetacean species host different skin microbiotas. Within each species, variability was higher between individuals than between body parts, suggesting a high individuality of cetacean skin microbiota. Overall, the skin microbiota of the assessed cetaceans related more to the humpback whale and fishes' than to microbiotas of terrestrial mammals. PMID- 29127422 TI - Correspondence: Revisiting the theoretical cell membrane thermal capacitance response. PMID- 29127423 TI - Tumor suppressor NPRL2 induces ROS production and DNA damage response. AB - The SEA/GATOR complex is an essential regulator of the mTORC1 pathway. In mammals the GATOR1 complex is composed of the proteins DEPDC5, NPRL2 and NPRL3. GATOR1 serves as an mTORC1 inhibitor and activates the mTORC1-modulating RagA GTPase. However, several GATOR members have mTORC1 independent functions. Here we characterize mammalian cells overexpressing the GATOR1 component NPRL2. We demonstrate that, in the cells with active p53, ectopic expression of NPRL2 induces NOX2-dependent production of reactive oxygen species and DNA damage. Overexpressed NPRL2 accumulates in the nucleus, together with apoptosis-inducing factor (AIF). These events are accompanied by phosphorylation of p53, activation of a DNA-damage response and cell cycle arrest in G1 phase, followed by apoptosis. In the cells negative for active p53, NPRL2 ectopic expression leads to activation of CHK1 or CHK2 kinases and cell cycle arrest in S or G2/M phases. Combined, these results demonstrate a new role for the NPRL2, distinct from its function in mTORC1 regulation. PMID- 29127424 TI - Involvement of galanin and galanin receptor 1 in nociceptive modulation in the central nucleus of amygdala in normal and neuropathic rats. AB - The present study was performed to explore the role of galanin and galanin receptor 1 (GalR 1) in nociceptive modulation in the central nucleus of amygdala (CeA) in normal rats and rats with neuropathy, and the involvement of GalR 1 and PKC was also investigated. The hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulations were increased in a dose-dependent manner after intra-CeA injection of galanin in both normal rats and rats with neuropathy. The increased HWLs were significantly attenuated by intra-CeA injection of galanin receptor antagonist M40, indicating an involvement of galanin receptor in nociceptive modulation in CeA. Furthermore, intra-CeA administration of the GalR 1 agonist M 617 induced increases in HWLs in normal rats, suggesting that GalR 1 may be involved in galanin-induce antinociception in CeA. Additionally, intra-CeA injection of the PKC inhibitor inhibited galanin-induced antinociception, showing an involvement of PKC in galanin-induced antinociception in CeA of normal rats. Moreover, there was a significant increase in GalR1 content in CeA in rats with neuropathy than that in normal rats. These results illustrated that galanin induced antinociception in CeA in normal rats and rats with neuropathy, and there is an up-regulation of GalR1 expression in rats with neuropathy. PMID- 29127425 TI - The effects of vitamin E or lipoic acid supplementation on oxyphytosterols in subjects with elevated oxidative stress: a randomized trial. AB - Despite increased serum plant sterol concentrations after consumption of plant sterol enriched margarines, plasma oxyphytosterol concentrations were not increased in healthy subjects. Here, we assessed plasma oxyphytosterol concentrations and whether they are affected by antioxidants in subjects with elevated oxidative stress. Twenty subjects with impaired glucose tolerance (IGT) or type 2 diabetes (DM2) consumed for 4 weeks placebo, vitamin E (804 mg/d) or lipoic acid capsules (600 mg/d). Plasma and blood cell oxyphytosterol and oxycholesterol concentrations were determined in butylated hydroxytoluene enriched EDTA plasma via GC-MS. Also, markers reflecting oxidative stress and antioxidant capacity were measured. Plasma oxycampesterol and oxysitosterol concentrations were 122% and 83% higher in IGT or DM2 subjects than in healthy subjects, as determined in an earlier study. Vitamin E or lipoic acid supplementation did not reduce plasma oxyphytosterol and oxycholesterol concentrations, or other markers reflecting oxidative stress or antioxidative capacity. Concentrations of different oxyphytosterols correlated within plasma, and within red blood cells and platelets. However, plasma and blood cell oxyphytosterol levels did not correlate. Although plasma oxyphytosterol concentrations are higher in IGT or DM2 subjects than in healthy subjects, 4 weeks vitamin E or lipoic acid supplementation does not lower plasma oxycholesterol or oxyphytosterol concentrations. PMID- 29127426 TI - Hearing with exceptionally thin tympana: Ear morphology and tympanal membrane vibrations in eneopterine crickets. AB - The receiver sensory system plays a crucial role in the evolution of new communication signals in insects. Among acoustic communicating crickets, the tribe Lebinthini (Eneopterinae) has evolved a unique communication system in that males produce exceptionally high-frequency calls and females respond with vibratory signals to guide males towards them. In this study, we describe nine species of Eneopterinae in which the sound receiving structures have undergone considerable morphological changes. We revealed that the anterior tympanal membrane (ATM) of the ear was extremely thin, as little as 0.35 um thick, and to the best of our knowledge, this is the thinnest tympanal membrane found in crickets thus far. Measurements of tympanum vibrations obtained from Lebinthus bitaeniatus demonstrated a strong sensitivity towards higher frequencies. The finding also coincides with the neuronal tuning of ascending neurons and the behavioural response of the Lebinthini. The morphologically specialized ATM and its mechanical sensitivity for high frequencies, therefore, may have driven the sensory exploitation of an anti-predator behaviour that led to the evolution of a new communication system known for this group of crickets. The hypothetical phylogenetic origin of the investigated tympanal ears is discussed. PMID- 29127427 TI - Amniotic membrane promotes focal adhesion remodeling to stimulate cell migration. AB - During wound healing, the migration of keratinocytes onto newly restored extracellular matrix aims to reestablish continuity of the epidermis. The application of amniotic membrane (AM) to chronic, deep traumatic, non-healing wounds has proven successful at stimulating re-epithelialization. When applied on epithelial cell cultures, AM activates extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal kinases 1/2 (JNK1/2), with the overexpression and phosphorylation of c-Jun along the wound edge. The effect of AM on the migration of cells was investigated by studying critical proteins involved in the focal adhesions turn-over: Focal Adhesion Kinase (FAK), Paxillin and Vinculin. In Mv1Lu and HaCaT cells, validated models for cell migration and wound healing, AM affected the expression and activation of Paxillin, but did not affect Vinculin expression, both factors which integrate into focal adhesions. Moreover, AM regulation also affected FAK activity through phosphorylation. Finally, we have determined that AM regulation of focal adhesions involves both JNK and MEK MAP kinase signaling pathways. This data provides a molecular background to understand how AM regulates critical cell and molecular aspects of cell migration, organizing and directing the movement of cells by the continuous formation, maturation, and turnover of focal adhesion structures at the migration leading edge. PMID- 29127428 TI - QED cascade with 10 PW-class lasers. AB - The intensities of the order of 1023-24 W/cm2 are required to efficiently generate electron-positron pairs in laser-matter interaction when multiple laser beam collision is employed. To achieve such intense laser fields with the upcoming generation of 10 PW laser beams, focusing to sub-micron spot size is required. In this paper, the possibility of pair production cascade development is studied for the case of a standing wave created by two tightly focused colliding laser pulses. Even though the stronger ponderomotive force expels the seed particles from the interaction volume when a tightly focused laser beam is used, tight focusing allows to achieve cascade pair production due to the higher intensity in the focal spot. Optimizing the target density can compensate the expulsion by the ponderomotive force and lower the threshold power required for cascade pair production. This will in principle allow to produce pairs with 10 PW class laser facilities which are now under construction and will become accessible soon. PMID- 29127430 TI - Harassment, a field study. PMID- 29127429 TI - A high-density consensus linkage map of white lupin highlights synteny with narrow-leafed lupin and provides markers tagging key agronomic traits. AB - White lupin (Lupinus albus L.) is a valuable source of seed protein, carbohydrates and oil, but requires genetic improvement to attain its agronomic potential. This study aimed to (i) develop a new high-density consensus linkage map based on new, transcriptome-anchored markers; (ii) map four important agronomic traits, namely, vernalization requirement, seed alkaloid content, and resistance to anthracnose and Phomopsis stem blight; and, (iii) define regions of synteny between the L. albus and narrow-leafed lupin (L. angustifolius L.) genomes. Mapping of white lupin quantitative trait loci (QTLs) revealed polygenic control of vernalization responsiveness and anthracnose resistance, as well as a single locus regulating seed alkaloid content. We found high sequence collinearity between white and narrow-leafed lupin genomes. Interestingly, the white lupin QTLs did not correspond to previously mapped narrow-leafed lupin loci conferring vernalization independence, anthracnose resistance, low alkaloids and Phomopsis stem blight resistance, highlighting different genetic control of these traits. Our suite of allele-sequenced and PCR validated markers tagging these QTLs is immediately applicable for marker-assisted selection in white lupin breeding. The consensus map constitutes a platform for synteny-based gene cloning approaches and can support the forthcoming white lupin genome sequencing efforts. PMID- 29127431 TI - Effect of Cornea Preservation Time on Success of Descemet Stripping Automated Endothelial Keratoplasty: A Randomized Clinical Trial. AB - Importance: Demonstrating that success of Descemet stripping automated endothelial keratoplasty is similar across donor cornea preservation times (PTs) could increase the donor pool. Objective: To determine whether the 3-year rate of graft success using corneal donor tissue preserved 8 to 14 days is noninferior to that of donor tissue preserved 7 days or less. Design, Setting, and Participants: A multicenter, double-masked, randomized noninferiority clinical trial was conducted from April 16, 2012, to June 5, 2017, at 40 clinical sites (70 surgeons) in the United States, with donor corneas provided by 23 US eye banks. A total of 1090 individuals (1330 study eyes) underwent Descemet stripping automated endothelial keratoplasty (1255 eyes [94.4%] for Fuchs endothelial corneal dystrophy). Interventions: Descemet stripping automated endothelial keratoplasty with random assignment of a donor cornea with a PT of 7 days or less (0-7d PT) or 8 to 14 days (8-14d PT). Main Outcomes and Measures: Graft success at 3 years. Results: Of the 1090 participants (1330 study eyes; 60.2% women and 39.8% men; median age at enrollment, 70 years [range, 42-90 years]), the 3-year cumulative probability of graft success was 95.3% (95% CI, 93.6%-96.9%) in the 0 7d PT group and 92.1% (95% CI, 89.9%-94.2%) in the 8-14d PT group (difference, 3.2%). The upper limit of the 1-sided 95% CI on the difference was 5.4%, exceeding the prespecified noninferiority limit of 4%. The difference was mostly owing to more primary donor failures in the 8-14d PT group, with the conditional probability of failure after the first month being 2.4% in the 0-7d PT group and 3.1% in the 8-14d PT group. In preplanned secondary analyses, longer PT was associated with a lower rate of graft success (unadjusted hazard ratio for graft failure per additional day of PT, 1.10; 95% CI, 1.03-1.18; P = .008 [PT analyzed as days]), with success rates of 96.5% (95% CI, 92.3%-98.4%) for PT of 4 days or less, 94.9% (95% CI, 92.5%-96.6%) for PT of 5 to 7 days, 93.8% (95% CI, 91.0% 95.8%) for PT of 8 to 11 days, and 89.3% (95% CI, 84.4%-92.7%) for PT of 12 to 14 days (P = .01 [PT analyzed as categorical variable]). Conclusions and Relevance: The 3-year success rate in eyes undergoing Descemet stripping automated endothelial keratoplasty was high irrespective of PT. However, the study was unable to conclude that the success rate with donor corneas preserved 8 to 14 days was similar to that of corneas preserved 7 days or less with respect to the prespecified noninferiority limit. Although longer PT was associated with a lower success rate, the difference in rates was small when PT was less than 12 days. PMID- 29127432 TI - Corneal Endothelial Cell Loss 3 Years After Successful Descemet Stripping Automated Endothelial Keratoplasty in the Cornea Preservation Time Study: A Randomized Clinical Trial. AB - Importance: Demonstrating that endothelial cell loss following Descemet stripping automated endothelial keratoplasty (DSAEK) is independent of donor cornea preservation time (PT) could increase the pool of corneal tissue available for keratoplasty. Objective: To determine whether endothelial cell loss 3 years after successful DSAEK is related to PT. Design, Setting, and Participants: A multicenter, double-masked, randomized clinical trial included 40 clinical sites (70 surgeons) in the United States, with donor corneas provided by 23 US eye banks. A total of 945 eyes of 769 participants were included in the Cornea Preservation Time Study that had not experienced graft failure 3 years after DSAEK, performed primarily for Fuchs endothelial corneal dystrophy (96% of the cohort). The study was conducted from April 16, 2012, to June 5, 2017. Interventions: DSAEK with random assignment of a donor cornea with PT of 0 to 7 days (0-7d PT) or 8 to 14 days (8-14d PT). Main Outcomes and Measures: Endothelial cell density (ECD) at 3 years determined by a central image analysis reading center from clinical specular or confocal central endothelial images. Results: Nine hundred forty-five eyes of 769 participants (median age, 70 years [range, 42-90 years], 60.8% women, 93.0% white) in the Cornea Preservation Time Study that had not experienced graft failure 3 years after DSAEK were included. At the initial eye bank tissue screening, mean (SD) central ECD was 2746 (297) cells/mm2 in the 0-7d PT group (n = 485) and 2723 (284) cells/mm2 in the 8-14d PT group (n = 460). At 3 years, the mean (SD) ECD decreased from baseline by 37% (21%) in the 0-7d PT group and 40% (22%) in the 8-14d PT group to 1722 (626) cells/mm2 and 1642 (631) cells/mm2, respectively (mean difference, 73 cells/mm2; 95% CI, 8-138 cells/mm2; P = .03). When analyzed as a continuous variable (days), longer PT was associated with lower ECD (mean difference by days, 15 cells/mm2; 95% CI, 4-26 cells/mm2; P = .006). Endothelial cell loss (ECL) was comparable from 4 to 13 days' PT (n = 878; 36%-43% when tabulated by day). Available extension study ECD results at 4 years mirrored those at 3 years in the 203 eyes in the 0-7d PT group (mean [SD] ECD, 1620 [673] cells/mm2 and mean [SD] ECL, 41% [23%]) and 209 eyes in the 8-14d PT group (mean [SD] ECD, 1537 [683] cells/mm2 and mean [SD] ECL, 44% [23%]) (mean difference, 112 cells/mm2; 95% CI, 5-219 cells/mm2; P = .04). Conclusions and Relevance: Although ECL 3 years after Descemet stripping automated endothelial keratoplasty is greater with longer PT, the effect of PT on ECL is comparable from 4 to 13 days' PT. PMID- 29127433 TI - Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor. AB - Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1beta (HRG1beta) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1beta-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1beta-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy. PMID- 29127436 TI - ? PMID- 29127434 TI - BRD7 regulates the insulin-signaling pathway by increasing phosphorylation of GSK3beta. AB - Reduced hepatic expression levels of bromodomain-containing protein 7 (BRD7) have been suggested to play a role in the development of glucose intolerance in obesity. However, the molecular mechanism by which BRD7 regulates glucose metabolism has remained unclear. Here, we show that BRD7 increases phosphorylation of glycogen synthase kinase 3beta (GSK3beta) in response to activation of the insulin receptor-signaling pathway shortly after insulin stimulation and the nutrient-sensing pathway after feeding. BRD7 mediates phosphorylation of GSK3beta at the Serine 9 residue and this effect on GSK3beta occurs even in the absence of AKT activity. Using both in vitro and in vivo models, we further demonstrate that BRD7 mediates phosphorylation of ribosomal protein S6 kinase (S6K) and leads to increased phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and, therefore, relieves its inhibition of the eukaryotic translation initiation factor 4E (eIF4E). However, the increase in phosphorylation of 4E-BP1 with BRD7 overexpression is blunted in the absence of AKT activity. In addition, using liver-specific BRD7 knockout (LBKO) mice, we show that BRD7 is required for mTORC1 activity on its downstream molecules. These findings show a novel basis for understanding the molecular dynamics of glucose metabolism and suggest the unique function of BRD7 in the regulation of glucose homeostasis. PMID- 29127435 TI - Intensified preoperative chemoradiation by adding oxaliplatin in locally advanced, primary operable (cT3NxM0) rectal cancer : Impact on long-term outcome. Results of the phase II TAKO 05/ABCSG R-02 trial. AB - PURPOSE: The major goals of preoperative treatment for locally advanced rectal cancers (LARCs) are improvement of local tumor control, tumor downsizing, and downstaging. Modifications with respect to standardized chemoradiation protocol, e. g., integrating oxaliplatin, are realized with the aim of improving primary tumor response and patient outcome. PATIENTS AND METHODS: In this phase II multicenter study, patients with LARC of the mid- or lower rectum, cT3cNxcM0 as staged by MRI, were included and treated preoperatively with a combination of capecitabine and oxaliplatin following a standardized protocol during radiation. The focus of this long-term analysis was overall (OS) and disease-free survival (DFS). RESULTS: A total of 60 patients (19 women, 41 men, median age 60.5 years) were initially enrolled, 1 patient was excluded (violation of study protocol), and 1 was patient lost of follow-up, leading to a total of 58 patients for long term analysis. The 3-year OS was 85.5%; 3-year DFS 71.2%. Over time, 15 patients (25.9%) developed tumor recurrence (1 locoregional, 6.7%; 11 distant, 73.3%; 3 locoregional+distant, 20%). Recurrence-specific therapy was planned in the majority of patients, in 9 of 15 patients (60%) with a radical surgical approach. Of these, 4 patients (44.4%) are again tumor-free at the end of investigation. While tumor downsizing (T level) or pathologically complete response did not influence patient survival, lymph node negativity (LNneg) after preoperative chemoradiation showed significant influence. CONCLUSION: LNneg after preoperative treatment for LARC significantly influences patient survival. A radical surgical approach for recurrent LARC (locoregional, distant) should be contemplated when possible as we were able to clearly demonstrate its importance and efficacy. PMID- 29127439 TI - Trauma patients centralization for the mechanism of trauma: old questions without answers. AB - INTRODUCTION: Centralization of trauma patients has become the standard of care. Unfortunately, overtriage can overcome the capability of Trauma Centres. This study aims to analyse the association of different mechanisms of injury with severe or major trauma defined as Injury Severity Score (ISS) greater than 15 and an estimation of overtriage upon our Trauma Centre. METHODS: A retrospective review of our prospective database was undertaken from March 2014 to August 2016. Univariate and multivariable logistic regression models were used to estimate the association between covariates (gender, age, and mechanisms of injury) and the risk of major trauma. RESULTS: The trauma team (TT) treated 1575 patients: among the 1359 (86%) were triaged only because of dynamics or mechanism of trauma. Overtriage according to an ISS < 15, was 74.6% on all trauma team activation (TTA) and 83.2% among the TTA prompted by the mechanism of injury. Patients aged 56-70 years had an 87% higher risk of having a major trauma than younger patients (OR 1.87, 95% CI 1.29-2.71) while for patients aged more than 71 years OR was 3.45, 95% CI 2.31-5.15. Car head-on collision (OR 2.50, 95% CI 1.27-4.92), intentional falls (OR 5.61, 95% CI 2.43-12.97), motorbike crash (OR 1.67, 95% CI 1.06-2.65) and pedestrian impact (OR 2.68, 95% CI 1.51-4.74) were significantly associated with a higher risk of major trauma in a multivariate analysis. CONCLUSIONS: Significant association with major trauma was demonstrated in the multivariate analysis of different mechanisms of trauma in patients triaged only for dynamics. A revision of our field triage protocol with a prospective validation is needed to improve overtriage that is above the suggested limits. PMID- 29127438 TI - [Bony Bankart lesions and glenoid defects : From refixation techniques to bony augmentation]. AB - Rim defects of the anterior glenoid cavity are a main reason for residual shoulder instability after traumatic dislocation of the shoulder. These defects can be the result of a glenoid rim fracture or chronic glenoid erosion after repeated shoulder dislocations. Treatment concepts for these entities are entirely different. While in the acute fracture situation glenoid rim fractures can be treated operatively or non-operatively, augmentation of the anterior glenoid for stabilization of the shoulder should be considered if the defect exceeds 15-25% of the anterior glenoid. The purpose of this article is to summarize the diagnostics and indications for treatment of glenoid rim fractures. Radiological assessment and options for augmentation are reviewed for both acute fractures as well as chronic instability following an anterior glenoid rim defect. PMID- 29127437 TI - [Morbidity and mortality due to meningioma after cranial radiotherapy]. PMID- 29127440 TI - Is a stepdown unit safe for patients with mild traumatic intracranial hemorrhages? AB - PURPOSE: Traumatic brain injuries (TBIs) are a major source of disability in the United States. The ideal unit in the hospital for patients with mild traumatic intracranial hemorrhages (ICHs) has not been elucidated. We sought to investigate whether patients treated in the surgical stepdown area had worse outcomes than those treated in the surgical ICU. METHODS: We compared patients with ICHs and a Glasgow Coma Scale (GCS) upon admission of 14 or 15 who went to the ICU to those who went to the stepdown area from April 2014 to November 2016. We compared age, gender, Injury Severity Score (ISS), admission GCS (14 or 15), operative intervention, discharge destination, hospital length of stay (HLOS), mortality, and cost between these two groups. RESULTS: Patients admitted to the ICU had a significantly longer HLOS. Admission costs for patients admitted to ICU were also significantly higher than their stepdown area counterparts. This was true for both total charges (p = 0.0001) and for net revenue (p = 0.002) (Table 2). There was no statistically significant difference in mortality, operative intervention, or discharge destination. CONCLUSION: A surgical stepdown unit can be a safe disposition for patients with mild traumatic ICHs and represents an effective use of hospital resources. PMID- 29127441 TI - Verification of a genetic locus for methamphetamine intake and the impact of morphine. AB - A quantitative trait locus (QTL) on proximal chromosome (Chr) 10 accounts for > 50% of the genetic variance in methamphetamine (MA) intake in mice selectively bred for high (MAHDR) and low (MALDR) voluntary MA drinking. The u-opioid receptor (MOP-r) gene, Oprm1, resides at the proximal end of Chr 10, and buprenorphine reduces MA intake in MAHDR mice. However, this drug has only partial agonist effects at MOP-r. We investigated the impact of a full MOP-r agonist, morphine, on MA intake and saccharin intake, measured MOP-r density and affinity in several brain regions of the MA drinking lines and their C57BL/6J (B6) and DBA/2J (D2) progenitor strains, and measured MA intake in two congenic strains of mice to verify the QTL and reduce the QTL interval. Morphine reduced MA intake in the MAHDR line, but also reduced saccharin and total fluid intake. MOP-r density was lower in the medial prefrontal cortex of MAHDR, compared to MALDR, mice, but not in the nucleus accumbens or ventral midbrain; there were no MOP-r affinity differences. No significant differences in MOP-r density or affinity were found between the progenitor strains. Finally, Chr 10 congenic results were consistent with previous data suggesting that Oprm1 is not a quantitative trait gene, but is impacted by the gene network underlying MA intake. Stimulation of opioid pathways by a full agonist can reduce MA intake, but may also non-specifically affect consummatory behavior; thus, a partial agonist may be a better pharmacotherapeutic. PMID- 29127442 TI - Increased frequencies of circulating CXCL10-, CXCL8- and CCL4-producing monocytes and Siglec-3-expressing myeloid dendritic cells in systemic sclerosis patients. AB - OBJECTIVE: To investigate the ex vivo pro-inflammatory properties of classical and non-classical monocytes as well as myeloid dendritic cells (mDCs) in systemic sclerosis (SSc) patients. METHODS: Spontaneous production of CXCL10, CCL4, CXCL8 and IL-6 was intracellularly evaluated in classical, non-classical monocytes and Siglec-3-expressing mDCs from peripheral blood of SSc patients and healthy controls (HC) through flow cytometry. In addition, production of these cytokines was determined upon toll-like receptor (TLR) 4 plus Interferon-gamma (IFN-gamma) stimulation. RESULTS: The frequency of non-classical monocytes spontaneously producing CXCL10 was increased in both limited (lcSSc) and diffuse cutaneous (dcSSC) subsets of SSc patients and CCL4 was augmented in dcSSc patients. The proportion of CCL4-producing mDCs was also elevated in dcSSc patients and the percentage of mDCS producing CXCL10 only in lcSSc patients. Upon stimulation, the frequency of non-classical monocytes expressing CXCL8 was increased in both patient groups and mDCs expressing CXCL8 only in lcSSc. Moreover, these parameters in unsupervised clustering analysis identify a subset of patients which are characterized by lung fibrosis and reduced pulmonary function. CONCLUSIONS: These data point towards a role of activated non-classical monocytes and mDCs producing enhanced levels of proinflammatory cytokines in SSc, potentially contributing to lung fibrosis. PMID- 29127444 TI - Altered mTORC1 signalling may contribute to macrophage dysregulation in hidradenitis suppurativa. PMID- 29127443 TI - Astragaloside IV attenuates orbital inflammation in Graves' orbitopathy through suppression of autophagy. AB - INTRODUCTION: Graves' orbitopathy (GO) is an autoimmune inflammatory disorder affecting the orbit around the eye. Astragaloside IV (AS-VI) is the main active ingredient of the Chinese herbal medicine Huangqi (Radix Astragali Mongolici). AS IV exhibits antioxidant and anti-inflammatory properties, and shows therapeutic potential in a number of ischemic and inflammatory diseases; however, its pharmaceutical activities in GO remain undefined. MATERIALS AND METHODS: In this study, we investigated the effects of AS-IV on interleukin (IL)-1beta-induced orbital fibroblast inflammation in vitro and GO orbital inflammation and ocular histopathological changes in vivo, as well as the underlying mechanisms responsible for these effects. RESULTS AND CONCLUSION: The results show that IL 1beta increased mRNA expression of the inflammatory cytokines IL-6, IL-8, TNF alpha, and MCP-1 in cultured orbital fibroblasts. This IL-1beta-induced inflammation was accompanied by increased autophagic activity as reflected in increased Beclin-1 and Agt-5 expression, as well as LC3-I to LC3-II conversion. Pretreatment with the autophagy inhibitors 3-MA and bafilomycin A1, or silencing of autophagy-related proteins Beclin-1 and Atg-5, prevented IL-1beta-induced orbital fibroblast inflammation, while pretreatment with the autophagy activator rapamycin had the opposite effects. These data suggested that autophagy was involved in GO orbital inflammation. AS-IV treatment significantly decreased IL 1beta-induced inflammatory cytokine production in orbital fibroblasts in vitro and attenuated GO orbital inflammation, fat accumulation, collagen deposition, and macrophage infiltration in vivo. These in vitro and in vivo protective effects of AS-IV against GO were accompanied by decreased autophagic activities in orbital fibroblasts and GO orbital tissues, respectively. Collectively, our findings suggested that AS-IV protects against GO through suppression of autophagy. Thus, AS-IV may have preventive benefits for GO. PMID- 29127446 TI - [Reduced visual field due to a benign tumor of the upper eyelid]. PMID- 29127445 TI - Negative Epistasis in Experimental RNA Fitness Landscapes. AB - Mutations and their effects on fitness are a fundamental component of evolution. The effects of some mutations change in the presence of other mutations, and this is referred to as epistasis. Epistasis can occur between mutations in different genes or within the same gene. A systematic study of epistasis requires the analysis of numerous mutations and their combinations, which has recently become feasible with advancements in DNA synthesis and sequencing. Here we review the mutational effects and epistatic interactions within RNA molecules revealed by several recent high-throughput mutational studies involving two ribozymes studied in vitro, as well as a tRNA and a snoRNA studied in yeast. The data allow an analysis of the distribution of fitness effects of individual mutations as well as combinations of two or more mutations. Two different approaches to measuring epistasis in the data both reveal a predominance of negative epistasis, such that higher combinations of two or more mutations are typically lower in fitness than expected from the effect of each individual mutation. These data are in contrast to past studies of epistasis that used computationally predicted secondary structures of RNA that revealed a predominance of positive epistasis. The RNA data reviewed here are more similar to that found from mutational experiments on individual protein enzymes, suggesting that a common thermodynamic framework may explain negative epistasis between mutations within macromolecules. PMID- 29127447 TI - [When a name becomes a unit: Rolf Maximilian Sievert]. PMID- 29127448 TI - Personalized health in a public health perspective. PMID- 29127449 TI - Determining a threshold sub-acute dose leading to minimal physiological alterations following prolonged exposure to the nerve agent VX in rats. AB - VX, a potent inhibitor of cholinesterase (ChE), is considered as one of the most toxic, persistent and least volatile nerve agents. VX is absorbed in various environmental surfaces and is gradually released long after its initial dispersal. Its toxicity is mainly caused by disrupting central and peripheral cholinergic nervous system activity, leading to potential long-term detrimental effects on health. The primary objective of the present study was to assess the threshold VX dose leading to minimal physiological alterations following prolonged VX exposure. Characterization of such a threshold is crucial for dealing with unresolved operative dilemmas such as when it is safe enough to resettle a population that has been evacuated from a VX-contaminated area. Rats, continuously exposed to various doses of VX (0.225-45 ug/kg/day) for 4 weeks via implanted mini-osmotic pumps, showed a dose-dependent and continuous decrease in ChE activity in whole blood, brain and muscles, ranging between 20 and 100%. Exposure to 13.5 ug/kg/day led to a stable low ChE activity level (~ 20%), accompanied by transient and negligible electrocorticogram spectral power transformations, especially in the theta and alpha brain wave frequencies, and a significant decrease in total brain M2 receptor density. These changes were neither accompanied by observable signs of intoxication nor by changes in motor function, circadian rhythm or TSPO level (a reliable marker of brain damage). Following exposure to lower doses of 2.25 and 0.225 ug/kg/day, the only change measured was a reduction in ChE activity of 60 and 20%, respectively. Based on these results, we delineate ChE inhibition as the physiological measure most susceptible to alterations following prolonged VX exposure, and determine for the first time the threshold sub-acute VX dose for minimal physiological effects (up to 20% reduction in ChE activity) in the rat as 0.225 ug/kg/day. PMID- 29127450 TI - Standardisation of defined approaches for skin sensitisation testing to support regulatory use and international adoption: position of the International Cooperation on Alternative Test Methods. AB - Skin sensitisation is the regulatory endpoint that has been at the centre of concerted efforts to replace animal testing in recent years, as demonstrated by the Organisation for Economic Co-operation and Development (OECD) adoption of five non-animal methods addressing mechanisms under the first three key events of the skin sensitisation adverse outcome pathway. Nevertheless, the currently adopted methods, when used in isolation, are not sufficient to fulfil regulatory requirements on the skin sensitisation potential and potency of chemicals comparable to that provided by the regulatory animal tests. For this reason, a number of defined approaches integrating data from these methods with other relevant information have been proposed and documented by the OECD. With the aim to further enhance regulatory consideration and adoption of defined approaches, the European Union Reference Laboratory for Alternatives to Animal testing in collaboration with the International Cooperation on Alternative Test Methods hosted, on 4-5 October 2016, a workshop on the international regulatory applicability and acceptance of alternative non-animal approaches, i.e., defined approaches, to skin sensitisation assessment of chemicals used in a variety of sectors. The workshop convened representatives from more than 20 regulatory authorities from the European Union, United States, Canada, Japan, South Korea, Brazil and China. There was a general consensus among the workshop participants that to maximise global regulatory acceptance of data generated with defined approaches, international harmonisation and standardisation are needed. Potential assessment criteria were defined for a systematic evaluation of existing defined approaches that would facilitate their translation into international standards, e.g., into a performance-based Test Guideline. Informed by the discussions at the workshop, the ICATM members propose practical ways to further promote the regulatory use and facilitate adoption of defined approaches for skin sensitisation assessments. PMID- 29127451 TI - Development and validation of 3D printed virtual models for robot-assisted radical prostatectomy and partial nephrectomy: urologists' and patients' perception. AB - PURPOSE: To test the face and content validity of 3D virtual-rendered printed models used before robot-assisted prostate cancer and nephron-sparing surgery. METHODS: Patients who underwent live surgery during an international urological meeting organized in January 2017 were enrolled. Those with organ-confined prostate cancer underwent robot-assisted radical prostatectomy. Patients with a single renal tumor underwent minimally invasive nephron-sparing surgery. High resolution (HR) imaging was obtained for all patients. Those with kidney tumors received contrast-enhanced CT scan with angiography; those with prostate cancer underwent mp-MRI. Images in DICOM format were processed by dedicated software. The first step was the rendering of a 3D virtual model. The models were then printed. They were presented during the live surgery of the urological meeting. All the participants and the operated patients were asked to fill a questionnaire about their opinion expressed in Likert scale (1-10) about the use and application of the 3D printed models. RESULTS: 18 patients were enrolled, including 8 undergoing robot-assisted radical prostatectomy and 10 undergoing minimally invasive partial nephrectomy. For each patient, a virtual 3D printed model was created. The attendants rated the utility of printed models in surgical planning, anatomical representation and the role of technology in surgical training as 8/10, 10/10 and 9/10, respectively. All patients reported favorable feedbacks (from 9 to 10/10) about the use of the technology during the case discussion with the surgeon. CONCLUSIONS: In our experience, 3D printing technology has been perceived as a useful tool for the purpose of surgical planning, physician education/training and patient counseling. Further researches are expected to increase the level of evidence. PMID- 29127452 TI - Accuracy and prognostic value of variant histology and lymphovascular invasion at transurethral resection of bladder. AB - OBJECTIVES: To evaluate the concordance rate of lymphovascular invasion (LVI) and variant histology (VH) of transurethral resection (TUR) with radical cystectomy (RC) specimens. Furthermore, to evaluate the value of LVI and VH at TUR for predicting non-organ confined (NOC) disease, lymph node metastasis, and survival outcomes. PATIENTS AND METHODS: Two hundred and sixty-eight patients who underwent TUR and subsequent RC were reviewed. Logistic regression analyses were performed to evaluate the association of LVI and VH with NOC and lymph node metastasis at RC. Cox regression analyses were used to estimate recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: LVI and VH were detected in 13.8 and 11.2% of TUR specimens, and in 30.2 and 25.4% of RC specimens, respectively. The concordance rate between LVI and VH at TUR and subsequent RC was 69.8 and 83.6%, respectively. They were both associated with adverse pathological features such as lymph node metastasis and advanced stage. TUR LVI and VH were both independently associated with lymph node metastasis and TUR VH was independently associated with NOC. On univariable Cox regression analyses, TUR LVI was associated with RFS and CSS while TUR VH was only associated with RFS. Only TUR LVI was independently associated with RFS. CONCLUSION: Detection of LVI is missed in a third of TUR specimens while VH seems more accurately identified. TUR LVI and VH are associated with more advanced disease and LVI predicts disease recurrence. Assessment and reporting of LVI and VH on TUR specimen are important for risk stratification and decision-making. PMID- 29127454 TI - The Distal Gut Bacterial Community of Some Primates and Carnivora. AB - Huge numbers of bacteria reside in the digestive tract of host and these microorganisms play a vital role in the host health, especially in the digestion of food and the development of immune system. Host phylogeny and diet, especially long-term diet, both have great influence on the gut bacterial community. Other aspects of host, such as gender, age, and the geography and weather they lived, are also correlated to their gut bacterial community. Feces are usually used for gut bacteria study and fecal bacteria can represent the distal gut bacteria. In order to determine the influence of the host phylogeny and diet on the composition of distal gut bacterial community and to interpret bacterial population and diversity in the intestinal of animals, the distal gut bacterial community of four kinds of primates and five kinds of carnivora (including herbivorous, omnivorous, and carnivorous) were investigated using high-throughput sequencing and the isolation of the Actinobacteria from fresh feces of several primates was processed. The results showed the host phylogeny had a greater influence on the distal gut bacterial community of the primates and carnivora than the host diet. A total of 44 bacteria phyla and two archaea phyla were detected, which indicated that the distal gut bacteria of these animals were abundant. The distal gut bacteria were relatively stable and wildly shared in primates and carnivora. The difference in distal gut bacteria of the two animal orders is mainly determined by relative abundance of most distal gut bacteria rather than by the taxa of these bacteria. PMID- 29127455 TI - The Functional Mechanisms and Application of Electron Shuttles in Extracellular Electron Transfer. AB - Electron shuttles extensively exist in various environments. Some kinds of organic substances can be applied by microorganisms to produce electrons, and then the electrons can be transferred to other substances or microorganisms through electron shuttles, resulting in coexistence and interaction of diverse species of microbes. In this review, the functional mechanisms of extracellular electron transfer mediated by different electron shuttles are described. And different subtypes as well as the application of electron shuttles in microbial degradation of pollutants, microbial electricity, and the promotion of energy generation are also discussed. Summary results show that extracellular electron transfer is based on the electrogenesis microorganism with the structure of cytochromes or pili. Materials were usually used in long-distance electron transfer because of their widespread presence and abundance. Therefore, the review is beneficial to perceive the pathways of extracellular electron transfer mediated by electron shuttles and explore the contribution of different electron shuttles in extracellular electron transfer. PMID- 29127456 TI - Catalytic Activity Profile of Polyphosphate Kinase 1 from Myxococcus xanthus. AB - Polyphosphate kinase 1 (Ppk1) catalyzes reverse transfer of the terminal phosphate from ATP to form polyphosphate (polyP) and from polyP to form ATP, and is responsible for the synthesis of most of cellular polyPs. When Ppk1 from Myxococcus xanthus was incubated with 0.2 mM polyP60-70 and 1 mM ATP or ADP, the rate of ATP synthesis was approximately 1.5-fold higher than that of polyP synthesis. If in the same reaction the proportion of ADP in the ATP/ADP mixture exceeded one-third, the equilibrium shifted to ATP synthesis, suggesting that M. xanthus Ppk1 preferentially catalyzed ATP formation. At the same time, GTP and GDP were not recognized as substrates by Ppk1. In the absence of polyP, Ppk1 generated ATP and AMP from ADP, and ADP from ATP and AMP, suggesting that the enzyme catalyzed the transfer of a phosphate group between ADP molecules yielding ATP and AMP, thus exhibiting adenylate kinase activity. PMID- 29127457 TI - The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer. AB - This review considers the "promise" of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary folates. The recognition that PCFT was highly expressed in many tumors stimulated substantial interest in using PCFT for cytotoxic drug targeting, taking advantage of its high level transport activity under the acidic pH conditions that characterize many tumors. For pemetrexed, among the best PCFT substrates, transport by PCFT establishes its importance as a clinically important transporter in malignant pleural mesothelioma and non-small cell lung cancer. In recent years, the notion of PCFT targeting has been extended to a new generation of tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine compounds that are structurally and functionally distinct from pemetrexed, and that exhibit near exclusive transport by PCFT and potent inhibition of de novo purine nucleotide biosynthesis. Based on compelling preclinical evidence in a wide range of human tumor models, it is now time to advance the most optimized PCFT-targeted agents with the best balance of PCFT transport specificity and potent antitumor efficacy to the clinic to validate this novel paradigm of highly selective tumor targeting. PMID- 29127458 TI - Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an antagonistic anti-CD40 antibody in healthy subjects: a potential novel treatment for autoimmune diseases. AB - PURPOSE: The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial. METHODS: Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0.2 120 mg) or subcutaneous (SC; 40-120 mg) doses of BI 655064 or placebo. Safety, plasma exposure, CD40 receptor occupancy and CD40L-induced CD54 upregulation were assessed over 12 weeks. RESULTS: Adverse events (AEs) were reported in 43% of subjects (n = 31). Frequency and intensity of AEs were generally similar between BI 655064 and placebo and showed no dose relationship. The most frequent AEs were headache and nasopharyngitis. One mild rash and one local reaction occurred with SC BI 655064; two serious AEs were reported, both judged unrelated to BI 655064. Pharmacokinetic evaluation demonstrated a more than proportional increase in plasma exposure relative to BI 655064 dose, with a terminal half-life between 4 h and 4 days IV and approximately 5 days SC; doses >= 20 mg IV and 120 mg SC showed > 90% CD40 receptor occupancy and inhibition of CD54 upregulation, which lasted 7 days in the 120 mg IV and SC groups. CONCLUSIONS: Single doses up to 120 mg BI 655064 IV and SC were well tolerated and showed a high potential to block the CD40-CD40L pathway, supporting further clinical development of BI 655064 in patients with autoimmune disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01510782. PMID- 29127460 TI - Hepatic metabolism of licochalcone A, a potential chemopreventive chalcone from licorice (Glycyrrhiza inflata), determined using liquid chromatography-tandem mass spectrometry. AB - The metabolism of the chemoprevention agent licochalcone A, which is a chemopreventive chalcone found in abundance in the licorice species Glycyrrhiza inflata, was investigated using human liver microsomes and human hepatocytes combined with analysis using high performance liquid chromatography-mass spectrometry (LC-MS). Five oxygenated phase I metabolites of licochalcone A were formed by human liver microsomes, including a catechol on the A-ring, two intramolecular cyclization products following epoxidation of the exocyclic alkene at position 5 of the B-ring, and two dioxygenated products. Nine phase II monoglucuronides of licochalcone A and its oxygenated phase I metabolites were formed during incubation with human hepatocytes. These included (E)-licochalcone A-4-glucuronide, (E)-licochalcone A-4'-glucuronide, (Z)-licochalcone A-4 glucuronide, glucuronic acid conjugates of all of the monooxygenated phase I metabolites, and glucuronides of the licochalcone catechol after methylation by catechol-O-methyl transferase. In addition, human hepatocytes formed one sulfate conjugate and one glutathione conjugate of licochalcone A. The structures of all major metabolites were determined using a combination of accurate mass measurement, LC-tandem mass spectrometry, LC-UV, nuclear magnetic resonance, and comparison with standards. The cytochrome P450 enzymes and UDP glucuronosyltransferases responsible for the formation of the major metabolites were identified. Based on in vitro hepatic clearance calculations, licochalcone A is predicted to be metabolized primarily by phase II conjugation reactions. Graphical abstract Phase I and II metabolism of licochalcone A from the licorice species Glycyrrhiza inflata by human liver microsomes and hepatocytes determined using LC-MS/MS, LC-UV and NMR. PMID- 29127461 TI - Bioinspired recognition elements for mycotoxin sensors. AB - Mycotoxins are low molecular weight molecules produced as secondary metabolites by filamentous fungi that can be found as natural contaminants in many foods and feeds. These toxins have been shown to have adverse effects on both human and animal health, and are the cause of significant economic losses worldwide. Sensors for mycotoxin analysis have traditionally applied elements of biological origin for the selective recognition purposes. However, since the 1970s there has been an exponential growth in the use of genetically engineered or synthetic biomimetic recognition elements that allow some of the limitations associated with the use of natural receptors for the analyses of these toxins to be circumvented. This review provides an overview of recent advances in the application of bioinspired recognition elements, including recombinant antibodies, peptides, aptamers, and molecularly imprinted polymers, to the development of sensors for mycotoxins based on different transduction elements. Graphical abstract Novel analytical methods based on bioinspired recognition elements, such as recombinant antibodies, peptides, aptamers, and molecularly imprinted polymers, can improve the detection of mycotoxins and provide better tools than their natural counterparts to ensure food safety. PMID- 29127459 TI - The use of an electronic clinical rule to discontinue chronically used benzodiazepines and related Z drugs. AB - PURPOSE: The chronic use of benzodiazepines and benzodiazepine-related drugs (BZ/Z) in older people is common and not without risks. The objective of this study was to evaluate whether the implementation of a clinical rule promotes the discontinuation of chronically used BZ/Z for insomnia. METHODS: A clinical rule, generating an alert in case of chronic BZ/Z use, was created and applied to the nursing home (NH) setting. The clinical rule was a one-off intervention, and alerts did not occur over time. Reports of the generated alerts were digitally sent to NH physicians with the advice to phase out and eventually stop the BZ/Z. In cases where the advice was adopted, a follow-up period of 4 months on the use of BZ/Z was taken into account in order to determine whether the clinical rule alert led to a successful discontinuation of BZ/Z. RESULTS: In all, 808 NH patients were screened. In 161 (19.1%) of the patients, BZ/Z use resulted in a clinical rule alert. From these, the advice to phase out and stop the BZ/Z was adopted for 27 patients (16.8%). Reasons for not following the advice consisted of an unsuccessful attempt in the past (38 patients), patients family and/or patient resistance (37 patients), the non-continuous use of BZ/Z (32 patients) and indication still present (27 patients). Of the 12 NH physicians, seven adopted the advice. CONCLUSIONS: The success rate of a clinical rule for discontinuation of chronically used BZ/Z for insomnia was low, as reported in the present study. Actions should be taken to help caregivers, patients and family members understand the importance of limiting BZ/Z use to achieve higher discontinuation rates. PMID- 29127462 TI - Ionic liquid capillary columns for analysis of multi-component volatiles by gas chromatography-mass spectrometry: performance, selectivity, activity and retention indices. AB - This study investigates applications and performance evaluation of SLB-IL60, SLB IL76 and SLB-IL111 columns, in relation to a DB-Wax column, for the analysis of coffee volatile compounds. Both standards and an authentic coffee sample were analysed, with solid-phase microextraction (SPME) sampling of the latter. A cryofocusing method was applied to improve resolution of the earliest eluting peaks using splitless injection SPME sample analysis. The Grob test was used to verify the inertness and efficiency of the columns, helping to understand the interactions between analytes and stationary phases, particularly toward more polar coffee analytes. A DB-5 column was used only in analysis of n-alkanes and Grob test mixtures as an apolar reference. The evaluated ionic liquid columns showed a moderate acid-base character and low inertness for compounds with hydrogen bond capabilities, especially for the hydroxylated analytes, 2,3 butanediol in the Grob test, and furanones and acids in the coffee standards. The columns exhibiting the best resolution and efficiency were DB-Wax and SLB-IL60, both for samples and standards. Although the DB-Wax column is preferred for analysis of coffee volatiles, due to better inertness, the evaluated ionic liquid columns allowed identification of compounds that were not observed in separations with the Wax-phase column in this work. Among these compounds is 3,4-dimethyl-2,5 furandione, seldom reported in the literature of coffee. Proposed improvement by the manufacturer in the inertness of the columns evaluated in this study may lead to better results; so future versions of IL phases may be better applied in the separation of target analytes, especially those with basic character. Graphical abstract Illustrative representation of the sample (coffee) and the chemical structures of the stationary phases of the ionic liquid capillary columns used as object of study in the present work. PMID- 29127463 TI - Correction to: International Scholarship Programs of the American College of Surgeons: Expansion of the Global Surgical Network. AB - In the original article, the top of Fig. 1 was inadvertently cut off. The original article has been corrected. The publisher regrets the error. PMID- 29127464 TI - Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Did We Trade Six for a Half a Dozen? PMID- 29127465 TI - Radical Surgery Improves Survival in Patients with Stage 4 Neuroblastoma. AB - BACKGROUND: Neuroblastoma (NBL) is the most common extracranial solid tumor in children. Despite a good overall prognosis in NBL patients, the outcome of children with stage 4 disease, even with multimodal intensive therapy, remains poor. The role of extended surgical resection of the primary tumor is in numerous studies controversial. The aim of this study was to retrospectively analyze the impact of radical surgical resection on the overall- and event-free survival of stage 4 NBL patients. METHODS: We retrospectively analyzed patient charts of 40 patients with stage 4 NBL treated in our institution between January 1990 and May 2012. All clinical and pathological findings of stage 4 NBL patients were included. Extent of surgery was assessed from the operation records and was classified as non-radical (tumor biopsy, partial 50-90% resection) or radical (near-complete >90% resection, complete resection). Overall- (OS) and event-free (EFS) survival was assessed using the Kaplan-Meier analysis and log-rank test. A multivariate Cox regression analysis was used to demonstrate independency. RESULTS: In total, 29/40 patients were operated radically (>90% resection), whereas 11 patients received subtotal resection or biopsy only. OS and EFS were significantly increased in patients with radical operation compared with non radical resection (p = 0.0003 for OS, p = 0.004 for EFS; log-rank test). A multivariate Cox regression analysis revealed radical operation as a significant and independent parameter for OS and EFS. CONCLUSIONS: Our data indicate that radical (over 90% resection) surgery improves OS and EFS in stage 4 NBL patients. PMID- 29127466 TI - An Evolving Understanding of the Clinical Implications of NIFTP. PMID- 29127467 TI - Recent advances in microbial production of aromatic natural products and their derivatives. AB - Aromatic natural products represent a diverse class of chemicals with great industrial significance. Usually, they serve as the building blocks for production of various polymers, esters, fibers, nutraceuticals, and pharmaceuticals. However, industrial synthesis of aromatic natural products still relies heavily on petroleum-based chemical processes, which are not sustainable and eco-friendly. In the past decades, construction of microbial cell factories that are able to efficiently convert renewable carbon sources into value-added products has made significant progress. This review highlights the recent advances in metabolic engineering efforts for biological production of aromatic natural products and their derivatives. Many novel pathways, enzymes, and products were reported in the literatures but have not yet detailed and informative viewed so far. Our goals are to provide a landscape of current works and present guidelines to address future challenges in biosynthesis of aromatic natural products and their derivatives using engineered microorganisms. PMID- 29127468 TI - Production of D-arabitol from D-xylose by the oleaginous yeast Rhodosporidium toruloides IFO0880. AB - The sugar alcohol D-arabitol is one of the Department of Energy's top twelve bio based building block chemicals. In this study, we found that the oleaginous yeast Rhodosporidium toruloides IFO0880 produces D-arabitol during growth on xylose in nitrogen-rich medium. Efficient xylose utilization was a prerequisite for extracellular D-arabitol production. During growth in complex media, R. toruloides produced 22 +/- 2, 32 +/- 2, and 49 +/- 2 g/L D-arabitol from 70, 105, and 150 g/L xylose, respectively. In addition, we found that R. toruloides could potentially be used for the co-production of lipids and D-arabitol from xylose. These results demonstrate that R. toruloides can be used to produce multiple value-added chemicals from xylose. PMID- 29127469 TI - The right intercostobronchial trunk: anatomical study in respect of posterior intercostal artery origin and its clinical application. AB - PURPOSE: The right bronchial artery usually arises from the descending thoracic aorta as a common trunk with the right intercostal artery and forms the right intercostobronchial trunk. Both, the third right posterior intercostal artery and the right intercostobronchial trunk, are described as the most constant vessels. The focus of the study was to determine the characteristics of the right intercostobronchial trunk regarding the origins of the posterior intercostal arteries from the thoracic aorta. METHODS: Posterior intercostal arteries and the right bronchial arteries were dissected in 43 human cadavers, preserved after Thiel's embalming method with intraarterial infusion of red colored latex. RESULTS: Postmortem examination gave valued information on the right intercostobronchial trunk present in 58% of cases. The right intercostobronchial trunk was mapped and new classification regarding the origin of the posterior intercostal arteries from the thoracic aorta suggested type A, B and C, the latter ones into subtypes 1 and 2. Type A was proportional to the origin level of the PIA and its corresponding intercostal space. Size of outer diameter at the origin did not indicate the right bronchial artery branch. In subtype 2 of type B the proximal posterior intercostal artery diameter that gave off right bronchial artery was thicker than distal one. CONCLUSIONS: The right bronchial artery originates from the second to the fifth posterior intercostal artery forming the right intercostobronchial trunk. Various origin and types of origin, diameter and course of the right intercostobronchial trunk described and analyzed in the study offer valuable information on the procedures involving the right intercostobronchial trunk. PMID- 29127470 TI - Rectus abdominis muscle innervation: an anatomical study with surgical implications in diep flap harvesting. AB - PURPOSE: To improve the current knowledge of rectus abdominis innervation, so as to identify a safe area where the vascular pedicle should be dissected to reduce the risk of nerve damage during deep inferior epigastric perforator (DIEP) flap harvesting. METHODS: Ten abdominal wall dissections were performed. Perforating arteries were identified and classified into nerve-related perforators and non nerve-related perforators depending on the presence of nerve branches crossing vessels. The width of rectus abdominis and the distance between perforators and lateral edge of rectus abdominis muscle were measured. In contralateral hemi abdomen, full-thickness specimens were sampled for microscopical analysis. RESULTS: Nerves enter the rectus sheath piercing the lateral edge (60% of cases) or the posterolateral surface of the sheath (40% of cases). They enter the rectus abdominis muscle at a mean distance of 4.3 cm from the lateral margin of the sheath. Within rectus abdominis, nerves have a mean thickness of 200.3 um and split into 2-4 sensitive and 2-4 muscular branches. Close relationship between muscular branches and deep inferior epigastric artery perforators were shown. The mean distance between nerve-related perforators and the lateral edge of the rectus abdominis was of 3.26 +/- 0.88 cm. The mean distance between non-nerve related perforators and the lateral edge of the rectus abdominis was of 6.26 +/- 0.90 cm. CONCLUSIONS: To spare nerves and reduce donor-site complications, a perforator located beyond an imaginary line of 3.26 +/- 0.88 cm far from the lateral edge of rectus abdominis muscle should be included in the DIEP flap. PMID- 29127471 TI - An anatomic study on the attachment of the joint capsule to the tibia in the lateral side of the knee. AB - PURPOSE: The purpose of the current study was to examine the width, area, and histological characteristics of the capsular attachment to the tibia in the lateral side of the knee. METHODS: A total of 27 knees were used in this study. The joint capsule of the knee was peeled away from the tibia and the width of the capsular attachment to the tibia was measured by two independent observers using a caliper. Interclass correlation coefficients for each value were calculated to evaluate the validity of the measurement. The capsular attachment to the tibia of the seven knees was histologically analyzed using Masson's trichrome staining. RESULTS: At the posterior border of Gerdy's tubercle, the capsular attachment was wide; the average width was 8.6 mm (SD 3.0). Toward the posterolateral aspect of the knee, the capsular attachment gradually tapered. Finally, the capsular attachment was linear at the apex of the head of the fibula. Histological analysis at the posterior border of Gerdy's tubercle revealed developed uncalcified fibrocartilage on the capsular attachment. In contrast, at the apex of the head of the fibula, the joint capsule was adhered to the capsule of the proximal tibiofibular joint. Fibrous connective tissue was directly attached to the calcified fibrocartilage. CONCLUSIONS: The attachment width of the knee joint capsule at the lateral side varied according to location. We consider that this finding on the capsular attachment will facilitate an understanding of the pathology or mechanism of diseases on the lateral side of the knee joint. PMID- 29127473 TI - Colorectal cancer and thrombosis. AB - SIGNIFICANCE: Colorectal cancer (CRC), results in a hypercoagulable state which manifests clinically as venous thromboembolism (VTE), often presenting as a deep vein thrombosis (DVT) or pulmonary embolism (PE). The consequences of VTE in CRC can be devastating, resulting in long-term morbidity and are a frequent cause of death, even amongst those who would have otherwise had a favourable cancer prognosis. The incidence of VTE in all cancers is increasing, whilst the exact incidence of VTE in CRC is likely to be underestimated. All cancer treatments increase the risk of VTE in an already at risk population. CRITICAL ISSUES: CRC associated VTE is a challenging entity to manage with recurrences occurring more frequently in cancer patients, despite anticoagulation. Anticoagulation, whether treatment or prophylactic, increases the risk of bleeding, especially in patients with cancer. Although strong evidence underpins the initial management of cancer associated VTE, there is uncertainty with regard optimum treatment duration. For VTE prevention, extended (28 days), pharmacological thromboprophylaxis post CRC surgery is internationally recommended. Pharmacological thromboprophylaxis is not routinely recommended for nonhospitalised patients receiving chemotherapy. FUTURE DIRECTIONS: There is growing evidence of a symbiotic relationship between cancer biology and the clotting system. Tissue factor (TF), the initiator of the clotting pathway, promotes cancer via clotting dependent and independent mechanisms. Clotting pathway factors, including TF, may have utility as biomarkers in CRC, for assessment of VTE risk in addition to cancer prognosis. The clotting system may also be a target for potential anti-cancer therapies, either via existing anticoagulants or experimental direct TF inhibitors. PMID- 29127474 TI - A traditional dietary pattern is associated with lower odds of overweight and obesity among preschool children in Lebanon: a cross-sectional study. AB - PURPOSE: The high burden of preschool overweight in the Middle East and North Africa highlights the need for rigorous investigations of its determinants. This study aims at identifying dietary patterns amongst preschoolers in Lebanon and assessing their association with overweight and obesity. METHODS: A national cross-sectional survey was conducted amongst 2-5-year-old children (n = 525). Socio-demographic, dietary, lifestyle and anthropometric variables were collected. Dietary patterns were derived by factor analysis. Overweight/obesity was defined based on the World Health Organization 2006 criteria (BMI-for-age z score > + 2). RESULTS: Two patterns, "Fast Food and Sweets" and "Traditional Lebanese", were identified. The "Fast Food and Sweets" pattern was characterized by higher consumption of sweetened beverages, fast foods, salty snacks and sweets. The "Traditional Lebanese" was driven by higher intakes of cereals, dairy products, fruits and vegetables. Children belonging to the 3rd tertile of the Traditional pattern scores had significantly lower odds of overweight/obesity compared to the 1st tertile (OR 0.33; 95% CI 0.11, 0.97). Higher maternal education and higher frequency of eating with family predicted adherence to the traditional pattern, while the presence of a household helper was a negative determinant. Adherence to the Fast Food and Sweets pattern was positively associated with the child's age, and negatively associated with female gender and maternal education. CONCLUSIONS: The "Traditional Lebanese" pattern was associated with decreased risk of preschool overweight. Policies aiming at re anchoring this traditional dietary pattern in contemporary lifestyles may be developed as potential preventive strategies against overweight in this age group. PMID- 29127472 TI - Prognostic impact of atrial fibrillation in cardiogenic shock complicating acute myocardial infarction: a substudy of the IABP-SHOCK II trial. AB - BACKGROUND: Aim of the current study was to analyse the impact of atrial fibrillation (AF) on prognosis in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI), which has never been investigated yet. METHODS: The current analysis is a substudy of the IABP-SHOCK II trial. Patients were grouped according to the presence or absence of AF. The primary endpoint was all-cause mortality at 30-day follow-up. Secondary endpoints included all-cause mortality, recurrent myocardial infarction, repeat revascularisation, and stroke at 12 months. RESULTS: AF was documented in 28.2% (n = 169) of all 600 patients initially enrolled in the IABP-SHOCK II trial. There were no significant differences with respect to mortality at 30 days and 12 months between patients with and without AF (p = 0.81, p = 0.74). Similarly, the rates of recurrent myocardial infarction, repeat revascularisation, and stroke did not differ between groups (all p > 0.05). There was no interaction of intraaortic balloon counterpulsation (IABP) and no IABP in patients with or without AF with respect to clinical outcome at 30 days and 12 months (p > 0.05). CONCLUSION: AF is not associated with clinical outcome at 30 days and 12 months in CS complicating AMI. PMID- 29127475 TI - Associations between the adherence to the Mediterranean diet and cardiorespiratory fitness with total and central obesity in preschool children: the PREFIT project. AB - PURPOSE: Early recognition of risk factors associated with overweight/obesity is an important step towards preventing long-term health consequences. The aim of the current study was to examine the associations of the adherence to the Mediterranean dietary pattern (MDP) and cardiorespiratory fitness (CRF) with adiposity in preschool children from the north of Spain. METHODS: The adherence to the MDP (KIDMED), CRF (20-m shuttle run test), total (BMI) and central (waist circumference) adiposity and socio-demographic factors were assessed in 619 children (48.6% girls) who were on average 4.7 years old. RESULTS: Higher MDP index (P < 0.05) and CRF levels (P < 0.01) were significantly related to lower waist circumference. CRF was inversely associated with BMI (P <= 0.001), yet no significant association was observed between MDP and BMI. Children not having high CRF levels and high MDP (i.e., non-upper sex-specific tertile of CRF or MDP, respectively) had the highest waist circumference. CONCLUSIONS: Our findings support that higher adherence to the MDP and higher CRF are associated with lower waist circumference in preschool children, pointing them as relevant modifiable factors to be targeted by educational strategies aiming to prevent central obesity and later obesity-related comorbidities. PMID- 29127476 TI - Co-supplementation of isomalto-oligosaccharides potentiates metabolic health benefits of polyphenol-rich cranberry extract in high fat diet-fed mice via enhanced gut butyrate production. AB - PURPOSE: Cranberries are a rich source of polyphenolic antioxidants. Purified sugars or artificial sweeteners are being added to cranberry-based food products to mask tartness. Refined sugar and artificial sweeteners intake modulate gut microbiota and result in metabolic complications. We evaluated effects of isomalto-oligosaccharides (IMOs; sweet tasting non-digestible oligosaccharides) with cranberry extract (CRX) on high fat diet (HFD)-induced metabolic alterations in mice. METHODS: Male Swiss albino mice were fed normal chow or HFD (58% fat kcal), and were administered either CRX (200 mg/kg) alone or in combination with IMOs (1 g/kg). Cecal short-chain fatty acids, abundances of selected (1) butyrate producing, (2) metabolically beneficial, and (3) selective lipopolysaccharides producing gram negative gut bacteria were studied. Further, gut-related histological, biochemical, genomic changes along with circulating pro-/anti inflammatory markers and systemic obesity-associated metabolic changes were studied. RESULTS: Co-supplementation of CRX and IMOs significantly improved cecal SCFAs, especially butyrate levels, selected butyrate-producing bacteria (clostridial cluster XIVa bacteria) and butyrate kinase expression in HFD-fed mice. The combination also significantly improved gut beneficial bacterial abundance, gut histology and related changes (colon mucin production, gut permeability) as compared to individual agents. It also prevented HFD-induced systemic and tissue inflammation, glucose intolerance and systemic obesity associated metabolic changes in adipose tissue and liver. The combination of CRX and IMOs appeared more effective in the prevention of HFD-induced gut derangements. CONCLUSION: Combination of CRX and IMOs could be advantageous for normalization of metabolic alterations seen in diet-induced obesity via beneficial modulation of gastrointestinal health. PMID- 29127477 TI - Maternal adipose tissue becomes a source of fatty acids for the fetus in fasted pregnant rats given diets with different fatty acid compositions. AB - PURPOSE: The utilization of long-chain polyunsaturated fatty acids (LCPUFA) by the fetus may exceed its capacity to synthesize them from essential fatty acids, so they have to come from the mother. Since adipose tissue lipolytic activity is greatly accelerated under fasting conditions during late pregnancy, the aim was to determine how 24 h fasting in late pregnant rats given diets with different fatty acid compositions affects maternal and fetal tissue fatty acid profiles. METHODS: Pregnant Sprague-Dawley rats were given isoenergetic diets containing 10% palm-, sunflower-, olive- or fish-oil. Half the rats were fasted from day 19 of pregnancy and all were studied on day 20. Triacylglycerols (TAG), glycerol and non-esterified fatty acids (NEFA) were analyzed by enzymatic methods and fatty acid profiles were analyzed by gas chromatography. RESULTS: Fasting caused increments in maternal plasma NEFA, glycerol and TAG, indicating increased adipose tissue lipolytic activity. Maternal adipose fatty acid profiles paralleled the respective diets and, with the exception of animals on the olive oil diet, maternal fasting increased the plasma concentration of most fatty acids. This maintains the availability of LCPUFA to the fetus during brain development. CONCLUSIONS: The results show the major role played by maternal adipose tissue in the storage of dietary fatty acids during pregnancy, thus ensuring adequate availability of LCPUFA to the fetus during late pregnancy, even when food supply is restricted. PMID- 29127478 TI - Risk factors for episodic neck pain in workers: a 5-year prospective study of a general working population. AB - PURPOSE: Development of neck pain (NP) in workers has a multifactorial etiology and depends on both individual and workplace factors. The aim of this study was to investigate risk factors for episodic NP in a large diverse sample of active workers. METHODS: A prospective study based on the surveillance program implemented by the French Public Health Agency in the Loire Valley region. Between 2002 and 2005, 3710 workers were included. Between 2007 and 2010, 2332 workers responded to a follow-up questionnaire which assessed: (1) musculoskeletal symptoms (Nordic questionnaire) and (2) individual and work related risk factors. Associations between episodic NP in 2007 (i.e., free subjects at baseline and who suffered at least 8 days during the preceding 12 months) and individual and work-related risk factors at baseline were studied using logistic regression modeling, stratified by sex. RESULTS: Among the 1510 workers (914 men, 596 women) still active at follow-up, 10.4% (8.4-12.4) of men and 14.6% (11.8-17.4) of women declared episodic NP. Among men, work pace dependence of guests or permanent hierarchical controls were risk factors of NP [OR = 1.8 (1.1-2.8) and OR = 2.1 (1.3-3.3), respectively]. Among women, the combination of sustained/repeated arm abduction with high physical perceived exertion was the strongest risk factor for NP [OR = 3.5 (1.7-7.2)]; age and paced work were also predictors for NP in women. CONCLUSIONS: NP results from complex relationships between individual and work-related variables. High physical workload, awkward postures, and poor organizational environment together with age differently predicted episodic NP according to the sex. PMID- 29127479 TI - Tall young females get ahead: size-specific fecundity in wild kangaroos suggests a steep trade-off with growth. AB - When resources are limited, organisms face allocation conflicts. Indeterminate growth creates a persistent conflict with reproduction, as growth may enhance future reproduction, but diverts resources from current reproduction. Little is known about allocation trade-offs in mammals with indeterminate growth. We studied growth and reproduction in adult female eastern grey kangaroos (Macropus giganteus), an iteroparous mammal with indeterminate growth. Allocation trajectories varied with age and size: for 4-year-old females, fecundity increased from 30 to 82% from shortest to average-sized individuals. Older females had high fecundity regardless of size. The smallest females grew 30% more annually than average-sized females, but females that reached average size at an older age had lower growth rates. Environmental conditions affected allocation to size and reproduction. Rainy springs increased fecundity from 61 to 84% for females that had previously reproduced, but rainy winters reduced leg growth. Females in better relative condition grew 40% more than average, whereas most young of females below average relative condition failed to survive to 10 months of age. These results highlight an age-specific trade-off between growth and reproduction. Tall young females benefit from a smaller trade-off between somatic growth and early fecundity than shorter females of the same age, but older females appear to favor reproduction over growth regardless of size. Our study highlights how individual heterogeneity determines trade-offs between life history components. We speculate that cohort effects affect age-specific reproductive success in this long-lived mammal. PMID- 29127480 TI - Quality assessment of atopic dermatitis clinical practice guidelines in <= 18 years. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects the patients' quality of life greatly often from a very young age. Its worldwide incidence in children and adults varies, but it is usually among the first ten causes of dermatological consultation worldwide. There is a wide variety of treatment options for this condition including topical and systemic regimes. The decision to choose a treatment option in dermatological diseases is greatly influenced by the personal experience of each specialist, which increases variability in the selection of available therapies. Clinical practice guidelines (CPGs) not only offer recommendations supported on the available scientific evidence, but also are intended to assist in making appropriate decisions in clinical scenarios. To standardize the way in which CPGs should be developed, an instrument called AGREE II (Appraisal of Guidelines for Research and Evaluation) is used. In this study, ten clinical practice guidelines in <= 18 years were evaluated. Six domains (scope and purpose, stakeholder involvement, rigor of development, clarity and presentation, applicability, and editorial independence) were assessed for each guideline, by three reviewers. Most of the domains obtained high scores except in the applicability domain. It is suggested that future atopic dermatitis CPGs should emphasize in the facilitating factors and barriers that may influence the application of guideline recommendations. PMID- 29127481 TI - Expression of Janus Kinase 1 in vitiligo & psoriasis before and after narrow band UVB: a case-control study. AB - Janus kinases (JAKs) are non-receptor protein tyrosine kinases that are expressed in many tissues. Once the JAKs are activated, a cascade of further signaling events is triggered involving phosphorylation of selected receptor chain tyrosines, binding of signal transducer and activator of transcription (STAT) proteins and phosphorylation of these STATs. Due to their ability to selectively modulate immune function, targeted JAK inhibitors are promising candidates for some skin diseases such as psoriasis and atopic dermatitis. The aim of this study was to assess the level of JAK1 in both vitiligo and psoriasis patients before and after treatment with NB-UVB which is considered a gold standard therapy for both diseases. This study was conducted on 10 patients with psoriasis, 10 patients with vitiligo and 10 controls. JAK1 levels before and after treatment with NB-UVB 311 nm (36 sessions) were measured using Western blot assay. The level of JAK1 was significantly higher in vitiligo and psoriasis patients than controls. There was a decline in the level of JAK1 after treatment, which was statistically significant. VASI and PASI scores of patients decreased after treatment with NB-UVB. In psoriatic patients, the JAK1 level positively correlated with the female participants, disease duration and PASI change. It was concluded that JAK1 plays a role in the pathogenesis of both vitiligo and psoriasis based on its upregulated level before treatment and downregulated level after treatment. This raises the possibility of using the JAK1 inhibitors as targeted immunotherapy for vitiligo and psoriasis. PMID- 29127482 TI - A single low dose of Fe ions can cause long-term biological responses in NL20 human bronchial epithelial cells. AB - Space radiation cancer risk may be a potential obstacle for long-duration spaceflight. Among all types of cancer space radiation may induce, lung cancer has been estimated to be the largest potential risk. Although previous animal study has shown that Fe ions, the most important contributor to the total dose equivalent of space radiation, induced a higher incidence of lung tumorigenesis per dose than X-rays, the underlying mechanisms at cellular level remained unclear. Therefore, in the present study, we investigated long-term biological changes in NL20 human bronchial epithelial cells after exposure to Fe ion or X ray irradiation. We found that compared with sham control, the progeny of NL20 cells irradiated with 0.1 Gy of Fe ions showed slightly increased micronucleus formation, significantly decreased cell proliferation, disturbed cell cycle distribution, and obviously elevated intracellular ROS levels accompanied by reduced SOD1 and SOD2 expression, but the progeny of NL20 cells irradiated with 0.9 Gy of X-rays did not show any significant changes. More importantly, Fe ion exposure caused much greater soft-agar colony formation than X-rays did in the progeny of irradiated NL20 cells, clearly suggesting higher cell transformation potential of Fe ions compared with X-rays. These data may shed the light on the potential lung tumorigenesis risk from Fe ion exposure. In addition, ATM inhibition by Ku55933 reversed some of the changes in the progeny of Fe ion irradiated cells but not others such as soft-agar colony formation, suggesting complex processes from DNA damage to carcinogenesis. These data indicate that even a single low dose of Fe ions can induce long-term biological responses such as cell transformation, etc., suggesting unignorable health risk from space radiation to astronauts. PMID- 29127483 TI - High-definition transcranial direct current stimulation of the dorsolateral prefrontal cortex for tinnitus modulation: a preliminary trial. AB - Tinnitus is the perception of sound in the absence of its external source. Non invasive neuromodulation techniques have been used in the past decade to investigate the impact of stimulation on tinnitus perception. The objective is to invest the impact of high-definition transcranial direct current stimulation (HD tDCS) of dorsolateral prefrontal cortex (DLPFC) stimulation on tinnitus loudness and annoyance. Thirteen participants underwent two sessions of HD-tDCS (real and sham) in a double blind, sham controlled, randomized trial. The washout period between the real and sham stimulation session was 1 week. Tinnitus loudness and annoyance was measured using a ten-point tinnitus loudness/annoyance numeric rating scale at the baseline, after 5, 10, 15 and 20 min of stimulation. There was a significant reduction in the tinnitus loudness after the HD-tDCS of DLPFC. A comparison of the different time points (5, 10, 15 and 20 min) with the baseline measurement for tinnitus loudness showed a statistically significant reduction after 15 min (t = 1.82, p = 0.047) and 20 min (t = 1.82, p = 0.047) of stimulation using the real HD-tDCS; this effect was not observed for tinnitus annoyance. HD-tDCS of DLPFC is a safe technique for tinnitus modulation. The most common transient sensations experienced during HD-tDCS were tingling, sleepiness and scalp pain. HD-tDCS of DLPFC resulted in transient tinnitus loudness suppression after 15 min of stimulation. We propose the optimum stimulation duration for HD-tDCS of DLPFC for tinnitus suppression to be 15 min instead of 20 min. PMID- 29127485 TI - OCT-based deep learning algorithm for the evaluation of treatment indication with anti-vascular endothelial growth factor medications. AB - PURPOSE: Intravitreal injections with anti-vascular endothelial growth factor (anti-VEGF) medications have become the standard of care for their respective indications. Optical coherence tomography (OCT) scans of the central retina provide detailed anatomical data and are widely used by clinicians in the decision-making process of anti-VEGF indication. In recent years, significant progress has been made in artificial intelligence and computer vision research. We trained a deep convolutional artificial neural network to predict treatment indication based on central retinal OCT scans without human intervention. METHOD: A total of 183,402 retinal OCT B-scans acquired between 2008 and 2016 were exported from the institutional image archive of a university hospital. OCT images were cross-referenced with the electronic institutional intravitreal injection records. OCT images with a following intravitreal injection during the first 21 days after image acquisition were assigned into the 'injection' group, while the same amount of random OCT images without intravitreal injections was labeled as 'no injection'. After image preprocessing, OCT images were split in a 9:1 ratio to training and test datasets. We trained a GoogLeNet inception deep convolutional neural network and assessed its performance on the validation dataset. We calculated prediction accuracy, sensitivity, specificity, and receiver operating characteristics. RESULTS: The deep convolutional neural network was successfully trained on the extracted clinical data. The trained neural network classifier reached a prediction accuracy of 95.5% on the images in the validation dataset. For single retinal B-scans in the validation dataset, a sensitivity of 90.1% and a specificity of 96.2% were achieved. The area under the receiver operating characteristic curve was 0.968 on a per B-scan image basis, and 0.988 by averaging over six B-scans per examination on the validation dataset. CONCLUSION: Deep artificial neural networks show impressive performance on classification of retinal OCT scans. After training on historical clinical data, machine learning methods can offer the clinician support in the decision making process. Care should be taken not to mistake neural network output as treatment recommendation and to ensure a final thorough evaluation by the treating physician. PMID- 29127484 TI - Progress in developing transgenic monkey model for Huntington's disease. AB - Huntington's disease (HD) is a complex neurodegenerative disorder that has no cure. Although treatments can often be given to relieve symptoms, the neuropathology associated with HD cannot be stopped or reversed. HD is characterized by degeneration of the striatum and associated pathways that leads to impairment in motor and cognitive functions as well as psychiatric disturbances. Although cell and rodent models for HD exist, longitudinal study in a transgenic HD nonhuman primate (i.e., rhesus macaque; HD monkeys) shows high similarity in its progression with human patients. Progressive brain atrophy and changes in white matter integrity examined by magnetic resonance imaging are coherent with the decline in cognitive behaviors related to corticostriatal functions and neuropathology. HD monkeys also express higher anxiety and irritability/aggression similar to human HD patients that other model systems have not yet replicated. While a comparative model approach is critical for advancing our understanding of HD pathogenesis, HD monkeys could provide a unique platform for preclinical studies and long-term assessment of translatable outcome measures. This review summarizes the progress in the development of the transgenic HD monkey model and the opportunities for advancing HD preclinical research. PMID- 29127486 TI - Crosstalk of Nanosystems Induced Extracellular Vesicles as Promising Tools in Biomedical Applications. AB - Hybrid vesicles are considered as a bridge between natural nanosystems (NNSs) and artificial nanosystems (ANSs). NNSs are extracellular vesicles (EVs), membranous, bio-formed endogenously, which act as endogenous cargoes, and reflecting cellular dynamics. EVs have cellular tropism, permeate tight junctions, and are non immunogenic. EVs are used as tools in the development of diagnostic and therapeutic agents. ANSs can induce biogenesis of hybrid vesicles as promising smart diagnostic agents, and innovative drug cargoes. EVs can encapsulate small molecules, macromolecules, and ANSs. The manipulation of EVs during biogenesis was suggested for engineering hybrid EVs. This review article highlights the role of ANSs in the biogenesis of NNSs, and introduces hybrid nanosystems research. PMID- 29127488 TI - The Influence of Synthesis Parameters on Vertically Aligned CNT Sheets: Empirical Modeling and Process Optimization Using Response Surface Methodology. AB - In the present work, vertically aligned carbon nanotube (VA-CNT) sheets were synthesized via pyrolysis of polybenzimidazole (PBI)-Kapton inside the pores of anodized aluminum oxide (AAO). The synthesized VA-CNT sheets were then evaluated for the desalination of salty water. The results indicated that the VA-CNT sheets were effective for application as an adsorbent for desalination of salty water due to their high adsorption capacity, with no loss of CNTs in the treated water. This study explored the impact of operating time and temperature on liquid adsorption performance through optimization and modeling methods. An empirical model was developed through the evolution of a full factorial design process which considered two significant factors for enhanced antibacterial efficiency and adsorption uptake. The highest antibacterial efficiency was achieved with carbon precursors synthesized at a higher temperature. However, optimal values were obtained for both antibacterial efficiency and adsorption uptake (NaCl) with a combination of CNT membranes. The best conditions for such a membrane were 800 degrees C and 18 min. Under these conditions, antibacterial efficiency, contact angle, carbon content, adsorption uptake (NaCl = 10,000) and adsorption uptake (NaCl = 20,000) were 90.079, 1.69256, 75.213, 76.2352 and 0.997, respectively. PMID- 29127489 TI - Genetic characterization of the complete genome of a mutant canine parvovirus isolated in China. AB - A field canine parvovirus (CPV) strain, CPV-SH14, was previously isolated from an outbreak of severe gastroenteritis in Shanghai in 2014. The complete genome of CPV-SH14 was determined by using PCR with modified primers. When compared to other CPV-2 strains, several insertions, deletions, and point mutations were identified in the 5' and 3' UTR, with key amino acid (aa) mutations (K19R, E572K in NS1 and F267Y, Y324I and T440A in VP2) also being observed in the coding regions of CPV-SH14. These results indicated that significant and unique genetic variations have occurred at key sites or residues in the genome of CPV-SH14, suggesting the presence of a novel genetic variant of new CPV-2a. Phylogenetic analysis of the VP2 gene revealed that CPV-SH14 may have the potential to spread worldwide. In conclusion, CPV-SH14 may be a novel genetic variant of new CPV-2a, potentially with a selective advantage over other strains. PMID- 29127490 TI - Fetuin-A levels and risk of type 2 diabetes mellitus: a systematic review and meta-analysis. AB - AIMS: Fetuin-A has been linked to insulin resistance and obesity. Its role in the pathogenesis of type 2 diabetes (T2DM) has also been discussed. We aimed to investigate the prospective association of fetuin-A and the risk of T2DM in a systematic review and meta-analysis. METHODS: A systematic search of studies from the MEDLINE, EMBASE, Pubmed and Web of Science using fetuin-A, diabetes and various synonyms was conducted up to June 5, 2017. Relevant studies were extracted by two reviewers independently. The quality of studies was assessed using Newcastle-Ottawa scales. Overall estimates were pooled using fixed effect with inverse variance meta-analysis. Subgroup analyses by gender, study population, techniques of assessing fetuin-A, diabetes ascertainment methods, follow-up duration and measures of association were conducted. RESULTS: Seven studies comprising a total of 11,497 individuals and 2176 cases of T2DM were included in the systematic review and meta-analysis. Overall, one SD increment of fetuin-A level was associated with a 23% greater risk of incident T2DM (RR: 1.23, 95% CI 1.16-1.31). No significant heterogeneity or publication bias was found. The association was relatively stable across different subgroups. However, the association seemed only evident in women, but not in men. CONCLUSIONS: Higher circulating fetuin-A levels were associated with increased risk of T2DM. However, the causality deserved further analysis. PMID- 29127487 TI - Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology. AB - Lithium has literally been everywhere forever, since it is one of the three elements created in the Big Bang. Lithium concentration in rocks, soil, and fresh water is highly variable from place to place, and has varied widely in specific regions over evolutionary and geologic time. The biological effects of lithium are many and varied. Based on experiments in which animals are deprived of lithium, lithium is an essential nutrient. At the other extreme, at lithium ingestion sufficient to raise blood concentration significantly over 1 mM/, lithium is acutely toxic. There is no consensus regarding optimum levels of lithium intake for populations or individuals-with the single exception that lithium is a generally accepted first-line therapy for bipolar disorder, and specific dosage guidelines for sufferers of that condition are generally agreed on. Epidemiological evidence correlating various markers of social dysfunction and disease vs. lithium level in drinking water suggest benefits of moderately elevated lithium compared to average levels of lithium intake. In contrast to other biologically significant ions, lithium is unusual in not having its concentration in fluids of multicellular animals closely regulated. For hydrogen ions, sodium ions, potassium ions, calcium ions, chloride ions, and magnesium ions, blood and extracellular fluid concentrations are closely and necessarily regulated by systems of highly selective channels, and primary and secondary active transporters. Lithium, while having strong biological activity, is tolerated over body fluid concentrations ranging over many orders of magnitude. The lack of biological regulation of lithium appears due to lack of lithium specific binding sites and selectivity filters. Rather lithium exerts its myriad physiological and biochemical effects by competing for macromolecular sites that are relatively specific for other cations, most especially for sodium and magnesium. This review will consider what is known about the nature of this competition and suggest using and extending this knowledge towards the goal of a unified understanding of lithium in biology and the application of that understanding in medicine and nutrition. PMID- 29127491 TI - Pink1 attenuates propofol-induced apoptosis and oxidative stress in developing neurons. AB - BACKGROUND: The underlying mechanisms of propofol-induced neurotoxicity in developing neurons are still not completely understood. We examined the role of PTEN-induced kinase 1 (Pink1), an antioxidant protein, in propofol-induced apoptosis in developing neurons. MATERIALS AND METHODS: Primary hippocampal neurons isolated from neonatal Sprague-Dawley rats were exposed to propofol 20 MUM for 2, 4, 6 and 12 h. Subsequently, neurons underwent overexpression and knockdown of Pink1, followed by propofol exposure (20 MUM, 6 h). Neuron apoptosis was detected by terminal transferase deoxyuridine triphosphate-biotin nick-end labeling (TUNEL). Reactive oxygen species (ROS) production in neurons was detected by using a 2,7-dichlorodihydro-fluorescein diacetate probe and target protein or mRNA levels were analyzed by Western blotting or real-time polymerase chain reaction. RESULTS: Propofol treatment time-dependently increased the number of TUNEL-positive neurons and the expression levels of cleaved caspase-3 and B cell lymphoma 2 (BcL-2) associated X protein, but decreased expression levels of BcL-2. Furthermore, propofol treatment time-dependently reduced the expression levels of Pink1 mRNA and protein. ROS production and the markers of oxidative stress, 2,4-dinitrophenol and 4-hydroxynonenal, were increased by propofol treatment. However, these propofol-induced changes were significantly restored by Pink1 overexpression. CONCLUSIONS: Pink1 plays an important role in neuronal apoptosis induced by propofol. Our results may provide some new insights in propofol-induced neurotoxicity in developing neurons. PMID- 29127492 TI - Effect of dexmedetomidine for attenuation of propofol injection pain in electroconvulsive therapy: a randomized controlled study. AB - PURPOSE: Current analgesic strategies for propofol injection pain may cause adverse reactions during electroconvulsive therapy (ECT), such as shortening seizure duration. This study investigated whether dexmedetomidine could attenuate propofol injection pain in ECT. METHODS: Participants were randomly allocated to receive 0.2 MUg/kg dexmedetomidine (Dex-0.2 group), 0.5 MUg/kg dexmedetomidine (Dex-0.5 group) or saline (control group) prior to ECT. The composite pain scale and objective Surgical Pleth Index (SPI) were used to measure the intensity of injection pain, and the percentage of patients with pain score > 2 was the primary outcome. RESULTS: Of 137 patients recruited, 46 were assigned to each of the Dex-0.2 or Dex-0.5 groups, while 45 were in the control group. The percentage of pain score > 2 was reduced from 68.9% (31/45) in the control group to 34.8% (16/46) in the Dex-0.2 group (P < 0.001) and 15.2% (7/46) in the Dex-0.5 group (P < 0.001). The pain score and SPI at 5 s after propofol injection were greater in the control group than in the Dex-0.2 [pain scores 3 (2-4) vs. 1 (1-3), P < 0.001, SPI 76.6 +/- 10.0 vs. 58.0 +/- 11.0, P < 0.001] and Dex-0.5 groups [pain scores 3 (2-4) vs. 1 (0-1), P < 0.001, SPI 76.6 +/- 10.0 vs. 51.2 +/- 12.3, P < 0.001]. There were no significant differences in seizure duration between the three groups. No patients developed bradycardia and hypotension. CONCLUSIONS: Pretreatment with dexmedetomidine was able to reduce the propofol injection pain in ECT without interfering with the seizure duration and causing adverse effects such as bradycardia and hypotension. In addition, close monitoring of hemodynamic variables and preparation of a treatment plan and drugs for bradycardia are essential. PMID- 29127493 TI - Late sodium current associated cardiac electrophysiological and mechanical dysfunction. AB - Late sodium current (INaL) is a small sustained inward current observed during the cardiac action potential plateau phase following decay of the early peak INa. The endogenous INaL is relatively small in normal hearts but exerts functionally significant effects on cardiomyocyte repolarization with potentially pro arrhythmic effects in hearts with reduced repolarization reserve. Enhanced INa,L occurs in long QT syndrome 3 (LQTS 3) patients, and under a number of pathological and pharmacological cardiovascular conditions, including bradycardia, myocardial ischemia, reperfusion injury, and heart failure. It may there play important roles in arrhythmogenesis and mechanical dysfunction. Experimental and clinical research suggests that INaL inhibition may prevent and treat cardiac arrhythmias and improve ventricular pump function. Selective INa,L inhibitors, exemplified by ranolazine, GS-967 and GS-458967 have little or no effect on peak sodium current and/or IKr, and carry no or minimal pro-arrhythmic risk compared to those associated with administration of classical class I or III antiarrhythmic drugs, particularly in patients with ischemic heart disease. This increased understanding of INaL may be encouraging to clinicians in use of INaL inhibitors to treat cardiac arrhythmias and mechanical dysfunction directly associated with enhanced INaL such as LQTS type 3, and myocardial ischemia. This review discusses the roles of endogenous and enhanced INaL in arrhythmogenesis and mechanical dysfunction, and the basic and clinical research of INaL inhibitors. PMID- 29127494 TI - Knockdown of LncRNA ANRIL suppresses cell proliferation, metastasis, and invasion via regulating miR-122-5p expression in hepatocellular carcinoma. AB - OBJECTIVE: Previous studies reported that lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) was upregulated in hepatocellular carcinoma (HCC) tissues and decreased expression of ANRIL could suppress cell proliferation, metastasis, and invasion and induce apoptosis of HCC cells. However, the molecular mechanism of ANRIL involved in HCC tumorigenesis is still unknown. METHODS: The expressions of ANRIL and miR-122-5p in HCC tissues and cells were quantified by qRT-PCR. MTT assay, colony formation assay, wound healing assay, and transwell invasion assay were performed to evaluate cell growth, metastasis, and invasion, respectively. RNA immunoprecipitation (RIP) assay and luciferase reporter assay were performed to determine whether ANRIL could directly bind to miR-122-5p in HCC cells. Xenograft tumor experiment was conducted to confirm the biological role and underlying mechanism of ANRIL in vivo. RESULTS: The results showed that ANRIL was upregulated and miR-122-5p was downregulated in HCC tissues and cells. ANRIL was negatively correlated with miR-122-5p expression in HCC tissues. Knockdown of ANRIL or miR-122-5p overexpression suppressed HCC cell viability, colony formation ability, metastasis, and invasion. ANRIL was demonstrated to directly bind to miR-122-5p and inhibit its expression. Forced expression of ANRIL abolished the inhibitory effect of miR-122-5p overexpression on HCC progression. In vivo experiment demonstrated that ANRIL knockdown impeded tumor growth in vivo and increased miR-122-5p expression. CONCLUSION: Our finding suggested that knockdown of ANRIL suppressed cell proliferation, metastasis and invasion via regulating miR-122-5p expression in HCC, illustrating the underlying mechanism of the oncogenic role of ANRIL in HCC. PMID- 29127495 TI - Size and heterologous elements predict metastases in malignant phyllodes tumours of the breast. AB - Phyllodes tumours (PTs) of the breast are uncommon fibroepithelial neoplasms comprising 0.3-1.0% of all primary breast tumours. The majority of PTs are benign and generally well managed with surgery. However, malignant PTs, and occasionally borderline PTs, can behave in a clinically aggressive manner by metastasizing to distant organs. Although distant metastasis is rare, the prognosis of patients with metastasis is dismal as many are unresponsive to standard chemotherapy and the risk of death is high. In this study, we correlated clinicopathological parameters to survival outcomes in a cohort of patients diagnosed with malignant PTs in our institution. The study cohort comprised 83 cases of malignant PTs diagnosed at the Department of Anatomical Pathology, Singapore General Hospital from 1994 to 2015. Clinicopathological features and follow-up were obtained from hospital records. Metastasis-free survival (MFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared between groups using the log rank test. Cox regression was carried out to identify factors predictive for metastasis. Mean and median age of patients was 48 years (range 21-71 years). Tumour size measured from 30 to 220 mm (mean 90 mm, median 77 mm). Follow-up data was available for 68 patients. Mean and median follow-up was 90 and 57 months, respectively, with a maximum of 291 months. Distant metastasis occurred in 16 out of 68 patients (23.5%). The most common site of metastasis was the lung. Malignant heterologous elements were observed in 16 (19.3%) cases. Individual clinicopathological parameters had no impact on outcome. On Kaplan-Meier analysis, women with large tumours and presence of malignant heterologous elements showed trends for poorer MFS (p = 0.217 and p = 0.566, respectively). However, the combination of large tumours (>= 90 mm) containing malignant heterologous elements disclosed significantly worse MFS (p = 0.043) and a trend for poorer OS (p = 0.238). On multivariate analysis, large tumours harbouring malignant heterologous elements independently predicted metastasis (95% CI 1.041 12.517, HR 2.434, p = 0.049). Our study demonstrates that tumour size and presence of malignant heterologous elements predicted metastasis in malignant PTs. Further work needs to be done in determining if protein biomarkers and genomic aberrations are able to additionally refine metastatic risk and define therapeutic targets. PMID- 29127496 TI - Classification of eosinophilic disorders of the small and large intestine. AB - Eosinophilic gastrointestinal diseases (EGIDs), including eosinophilic gastroenteritis and eosinophilic colitis, have been increasing in prevalence in Western countries in recent years. Eosinophils are normally scanty in the gastrointestinal tract, and increased numbers of eosinophils can denote pathology. Normal values for tissue eosinophils vary widely between different segments of the colon, thus location of the biopsy is critically important for the interpretation of findings. However, no standard diagnostic criteria have been proposed for the diagnosis of eosinophilic gastroenteritis or eosinophilic colitis. Gut eosinophilia encompasses entitites that are predominantly immunoglobulin E (IgE)-mediated, the primary EGIDs and those that are secondary and not IgE-mediated. A final diagnosis of eosinophilic gastrointestinal diseases requires careful pathological assessment, clinical correlation and exclusion of several differential diagnoses. PMID- 29127498 TI - Dynamics in prevalence of Down syndrome in children with congenital heart disease. AB - : We assessed the dynamics in the prevalence of children with congenital heart disease (CHD) and Down syndrome in Germany with regard to phenotype, severity, and gender. Data from patients with CHD and Down syndrome born between 1980 and 2014 were analyzed, who are registered with the German National Register for Congenital Heart Defects. One thousand six hundred eighteen CHD patients with Down syndrome were identified. The prevalence of children born with both Down syndrome and CHD was constant from 2005 to 2009 but increased from 2010 to 2014. Regarding CHD groups, complex and simple lesions have become more equal since 2005. The number of simple lesions with shunt has a peak prevalence in the period of 2010-2014. Atrioventricular septal defect was the most common CHD phenotype, but temporal changes were found within the group of CHD phenotypes over the observation period. CONCLUSION: Our findings suggest a growing number of CHD and Down syndrome, which may be the result of improved medical management and progress in educational, social, and financial support. This development is noteworthy as it adds new aspects to present discussions in the media and political settings. What is known: * Congenital heart disease is regarded to be the most important clinical phenomenon in children with Down syndrome, due to its significant impact on morbidity and mortality. * New developments in prenatal diagnostic and therapy management of congenital heart disease continue to influence the number of patients diagnosed with congenital heart disease and Down syndrome. What is New: * This study provides essential data giving the first overview of the dynamics in the prevalence of congenital heart disease and Down syndrome over an extended length of time up to 2015 in a large patient cohort, taking recent developments into account. * Our data suggest a growing prevalence of congenital heart disease and Down syndrome, which may be the result of improved medical management for Down syndrome patients and progress in educational, social, and financial support for their families; this development is noteworthy as it adds new aspects to the present discussion in the media and political settings. PMID- 29127499 TI - Dynamic modeling of nitrogen removal for a three-stage integrated fixed-film activated sludge process treating municipal wastewater. AB - The integrated fixed-film activated sludge (IFAS) process is being increasingly used to enhance nitrogen removal for former activated sludge systems. The aim of this work is to evaluate a numerical model of a new nitrifying/denitrifying IFAS configuration. It consists of two carrier-free reactors (anoxic and aerobic) and one IFAS reactor with a filling ratio of 43% of carriers, followed by a clarifier. Simulations were carried out with GPS-X involving the nitrification reaction combined with a 1D heterogeneous biofilm model, including attachment/detachment processes. An original iterative calibration protocol was created comprising four steps and nine actions. Experimental campaigns were carried out to collect data on the pilot in operation, specifically for modelling purpose. The model used was able to predict properly the variations of the activated sludge (bulk) and the biofilm masses, the nitrification rates of both the activated sludge and the biofilm, and the nitrogen concentration in the effluent for short (4-10 days) and long (300 days) simulation runs. A calibrated parameter set is proposed (biokinetics, detachment, diffusion) related to the activated sludge, the biofilm and the effluent variables to enhance the model prediction on hourly and daily data sets. PMID- 29127500 TI - Distinct Communities of Poplar Endophytes on an Unpolluted and a Risk Element Polluted Site and Their Plant Growth-Promoting Potential In Vitro. AB - Numerous studies demonstrated that endophytic microbes can promote plant growth and increase plant stress resistance. We aimed at isolating poplar endophytes able to increase their hosts' fitness both in nutrient-limited and polluted environments. To achieve this goal, endophytic bacteria and fungi were isolated from roots and leaves of hybrid poplars (Populus nigra * P. maximowiczii clone Max-4) on an unpolluted and a risk element-polluted site in the Czech Republic and subsequently screened by a number of in vitro tests. Bacterial communities at the unpolluted site were dominated by Gammaproteobacteria with Pseudomonas sp. as the prominent member of the class, followed by Bacilli with prevailing Bacillus sp., whereas Alphaproteobacteria, mostly Rhizobium sp., prevailed at the polluted site. The fungal endophytic community was dominated by Ascomycetes and highly distinct on both sites. Dothideomycetes, mostly Cladosporium, prevailed at the non-polluted site while unclassified Sordariomycetous fungi dominated at the polluted site. Species diversity of endophytes was higher at the unpolluted site. Many tested endophytic strains solubilized phosphate and produced siderophores, phytohormones, and antioxidants. Some strains also exhibited ACC-deaminase activity. Selected bacteria showed high tolerance and the ability to accumulate risk elements, making them promising candidates for use in inocula promoting biomass production and phytoremediation. Graphical Abstract ?. PMID- 29127501 TI - Characterization of a novel yeast species Metschnikowia persimmonesis KCTC 12991BP (KIOM G15050 type strain) isolated from a medicinal plant, Korean persimmon calyx (Diospyros kaki Thumb). AB - The yeast strain Metschnikowia persimmonesis Kang and Choi et al., sp. nov. [type strain KIOM_G15050 = Korean Collection for Type Cultures (KCTC) 12991BP] was isolated from the stalk of native persimmon cultivars (Diospyros kaki Thumb) obtained from different regions of South Korea and was characterized phenotypically, genetically, and physiologically. The isolate grew between 4 and 40 degrees C (optimum temperature: 24-28 degrees C), pH 3-8 (pH optimum = 6.0), and in 0-4% NaCl solution (with optimal growth in absence of NaCl). It also exhibited strong antibiotic and antimicrobial activities. Morphologically, cells were characterized by the presence of long, needle-shaped ascospores. Based on 18S ribosomal DNA gene sequence analysis, the new species was found to belong to the genus Metschnikowia as a sister clade of Metschnikowia fructicola. We therefore conclude that this yeast isolate from D. kaki is a new member of the genus Metschnikowia and propose the name M. persimmonesis sp. nov. This strain has been deposited in the KCTC for future reference. This discovery provides a basis for future research on M. persimmonesis sp. nov., including its possible contribution to the medicinal properties of the host persimmon plant. PMID- 29127502 TI - Piperacillin-tazobactam as alternative to carbapenems for ICU patients. AB - Several studies suggest that alternatives to carbapenems, and particulary beta lactam/beta-lactamase inhibitor combinations, can be used for therapy of extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE)-related infections in non-ICU patients. Little is known concerning ICU patients in whom achieving the desired plasmatic pharmacokinetic/pharmacodynamic (PK/PD) target may be difficult. Also, in vitro susceptibility to beta-lactamase inhibitors might not translate into clinical efficacy. We reviewed the recent clinical studies examining the use of BL/BLI as alternatives to carbapenems for therapy of bloodstream infection, PK/PD data and discuss potential ecological benefit from avoiding the use of carbapenems. With the lack of prospective randomized studies, treating ICU patients with ESBL-PE-related infections using piperacillin tazobactam should be done with caution. Current data suggest that BL/BLI empirical use should be avoided for therapy of ESBL-PE-related infection. Also, definitive therapy should be reserved to patients in clinical stable condition, after microbial documentation and results of susceptibility tests. Optimization of administration and higher dosage should be used in order to reach pharmacological targets. PMID- 29127505 TI - High-resolution ultrasonography of the normal extratemporal facial nerve. AB - The technical advances in sonography of the past decade have supported the rapid improvement of high-resolution imaging, which enables the quick visualization of peripheral nerves at relatively limited costs. Recently, the possibility of visualizing the extratemporal facial nerve (FN) has been considered. This manuscript describes the first systematic evaluation in cadavers, of a novel ultrasonographic approach with this specific aim. Eight cadaveric hemifaces were evaluated by means of high-frequency ultrasound with two linear (13 and 22 MHz) and a convex transducer (6.6 MHz), to detect the extratemporal course of the FN starting from its exit at the stylomastoid foramen: the main trunk, the parotid plexus between the two parts of the parotid gland, the distal branches terminating into the orbicularis oculi and the zygomatic major muscle. Ultrasound guided color injections and FN dissection were performed to confirm the results. The main trunk of the FN, as it exits the stylomastoid foramen, was correctly stained in 6/8 cases, the parotid plexus in 8/8 cases. The branches innervating the orbicularis oculi muscle were stained in 7/7 and the branches innervating the zygomatic major muscle in 6/7 hemifaces, after 1 was withdrawn due to insufficient image quality. Through our novel approach of high-resolution ultrasonography we could identify the various portions of the extratemporal FN, including its main trunk leaving the stylomastoid foramen, in an accurate and reproducible way. Further in vivo animal and clinical studies have been planned to confirm these initial results from cadavers. PMID- 29127504 TI - Glycocalyx in Atherosclerosis-Relevant Endothelium Function and as a Therapeutic Target. AB - PURPOSE OF REVIEW: The cell surface-attached extracellular glycocalyx (GCX) layer is a major contributor to endothelial cell (EC) function and EC-dependent vascular health and is a first line of defense against vascular diseases including atherosclerosis. Here, we highlight our findings regarding three GCX dependent EC functions, which are altered when GCX is shed and in atherosclerosis. We discuss why the GCX is a viable option for the prevention and treatment of atherosclerosis. RECENT FINDINGS: GCX regulated EC activities such as barrier and filtration function, active cell-to-cell communication, and vascular tone mediation contribute to function of the entire vascular wall. Atheroprone vessel regions, including bifurcation sites, exhibit breakdown in GCX. This GCX degradation allows increased lipid flux and thereby promotes lipid deposition in the vessel walls, a hallmark of atherosclerosis. GCX degradation also alters EC-to-EC communication while increasing EC-to-inflammatory cell interactions that enable inflammatory cells to migrate into the vessel wall. Inflammatory macrophages and foam cells, to be specific, appear in early stages of atherosclerosis. Furthermore, GCX degradation deregulates vascular tone, by causing ECs to reduce their expression of endothelial nitric oxide synthase (eNOS) which produces the vasodilator, nitric oxide. Loss of vasodilation supports vasoconstriction, which promotes the progression of atherosclerosis. Common medicinal atherosclerosis therapies include lipid lowering and anti platelet therapies. None of these treatments specifically target the endothelial GCX, although the GCX is at the front-line in atherosclerosis combat. This review demonstrates the viability of targeting the GCX therapeutically, to support proper EC functionality and prevent and/or treat atherosclerosis. PMID- 29127506 TI - Perhaps consider transmeatal approach for microscopic myringoplasty. PMID- 29127503 TI - Relationships between low-grade peripheral inflammation and psychotropic drugs in schizophrenia: results from the national FACE-SZ cohort. AB - Low-grade inflammation has repeatedly been associated with schizophrenia (SZ) and in particular with cognitive impairment. Female gender, overweight and tobacco smoking have been suggested as risk factors to increase inflammation while preclinical inconsistent findings have been found regarding the association with psychotropic drugs. The aim of this study was to explore if psychotropic drugs were associated with inflammation in SZ and to determine which psychotropic drug was associated with inflammation in stable SZ subjects while considering clinical confounding factors. Participants were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia and received a thorough clinical assessment, including recording of current treatment. High-sensitivity CRP (hs CRP) was measured for each participant as a proxy to define peripheral low-grade inflammation. The zero-inflated Poisson regression model estimated the relationship between low-grade inflammation and psychotropic drug. Four hundred and five stabilized, community-dwelling SZ subjects (mean age = 32.6 years, 74% male gender) have been included. In total, 148 participants (36.5%) were found with undetectable blood hs-CRP level. The probability of having an undetectable CRP was associated with a lower body mass index (p < 0.0001) and no cyamemazine add-on antipsychotic therapy (p = 0.001). The other 257 participants (63.5%) were found to have low-grade inflammation (hs-CRP > 0 mg/L). Low-grade inflammation was significantly associated with female gender (p = 0.004), higher body mass index (p < 0.0001), current tobacco smoking (p < 0.0001), clomipramine (p = 0.04), quetiapine (p < 0.0001) and hypnotic (p = 0.0006) consumption while decreased hs-CRP blood levels was associated with aripiprazole (p = 0.004) and valproate/valpromide (p = 0.03) consumption. The present study suggests that some psychotropic drugs (quetiapine, cyamemazine, clomipramine) may be associated with increased peripheral low-grade inflammation in SZ patients while others (aripiprazole, valproate) may be associated with decreased peripheral low-grade inflammation. These results should be replicated in SZ and non-SZ populations and the biological underpinnings should be further explored. PMID- 29127507 TI - Influence of coupler size on revision rate and timing of revision after free flap tissue transfer in the head and neck. AB - OBJECTIVE: Microvascular coupler devices have been proven an effective alternative to standard hand-sutured anastomoses in reconstructive surgery. Until now, the influence of the coupler size on the revision rate after free flap tissue transfer in head and neck surgery has not been investigated. Neither has its influence on the timing of venous revisions. MATERIALS AND METHODS: A retrospective mono-center cohort study was performed in order to analyze the influence of coupler size on timing and revision rate of microvascular procedures. RESULTS: 437 patients who had undergone surgery between 2009 and 2015 were included. The statistical analysis of coupler size and revision rate due to venous complications showed a significant reduction of more than 40% in the revision rate for each additional mm in the coupler size. We observed revisions due to venous congestion until the fourth day postoperatively within our cohort. However, when the coupler size used was >= 3 mm, no venous congestion occurred later than 12 h after surgery. CONCLUSION: The quantitative effects of coupler size on the revision rate in head and neck reconstruction were demonstrated for the first time. We recommend spending extra time and effort on dissecting the largest possible vein in order to be able to choose the largest possible coupler size for the venous anastomosis. As a consequence of our findings, we limit our postoperative monitoring for patients with a coupler >= 3 mm to 24 h, as later venous congestions are very unlikely. PMID- 29127508 TI - Active and passive recovery influence responses of luteinizing hormone and testosterone to a fatiguing strength loading. AB - The purpose of this study was to examine the acute hormonal and muscular responses to a strenuous strength loading [bilateral leg press (LP) 10 * 10 1RM] followed by loading-specific active (AR, n = 7, LP 10 * 10 * 30% 1RM) or passive (PR, n = 11, seated) recovery. The subjects were men age: 26 +/- 4 years, height: 174 +/- 8 cm, body mass: 75 +/- 13 kg. After control measurements, experimental measurements were conducted at pre- and post-loading as well as post-recovery and next morning. A significantly higher absolute concentration (p < 0.05) of serum luteinizing hormone (LH) was observed in AR than PR at next morning while no differences were observed in serum testosterone (T), cortisol (C) or sex hormone binding globulin (SHBG). Significant differences in relative hormonal responses to the loading were observed at next morning with greater responses observed in AR than in PR in terms of LH, and T (p < 0.05). Maximal bilateral isometric force (MVC) and countermovement jump height (CMJ) decreased significantly (p < 0.001) from the control measurements in both AR and PR but returned to control levels by next morning. No between-group differences were observed in mean absolute or relative changes in MVC or CMJ. From a hormonal perspective, the present AR method appears to have had some favorable effects following the strenuous strength loading; however, acute decreases in muscular force production did not significantly differ between groups. These results provide insight into the development of training programs that may help to support the performance of individuals involved in strenuous tasks. PMID- 29127509 TI - Heart rate variability and plasma nephrines in the evaluation of heat acclimatisation status. AB - PURPOSE: Heat adaptation (HA) is critical to performance and health in a hot environment. Transition from short-term heat acclimatisation (STHA) to long-term heat acclimatisation (LTHA) is characterised by decreased autonomic disturbance and increased protection from thermal injury. A standard heat tolerance test (HTT) is recommended for validating exercise performance status, but any role in distinguishing STHA from LTHA is unreported. The aims of this study were to (1) define performance status by serial HTT during structured natural HA, (2) evaluate surrogate markers of autonomic activation, including heart rate variability (HRV), in relation to HA status. METHODS: Participants (n = 13) were assessed by HTT (60-min block-stepping, 50% VO2peak) during STHA (Day 2, 6 and 9) and LTHA (Day 23). Core temperature (Tc) and heart rate (HR) were measured every 5 min. Sampling for HRV indices (RMSSD, LF:HF) and sympathoadrenal blood measures (cortisol, nephrines) was undertaken before and after (POST) each HTT. RESULTS: Significant (P < 0.05) interactions existed for Tc, logLF:HF, cortisol and nephrines (two-way ANOVA; HTT by Day). Relative to LTHA, POST results differed significantly for Tc (Day 2, 6 and 9), HR (Day 2), logRMSSD (Day 2 and Day 6), logLF:HF (Day 2 and Day 6), cortisol (Day 2) and nephrines (Day 2 and Day 9). POST differences in HRV (Day 6 vs. 23) were + 9.9% (logRMSSD) and - 18.6% (logLF:HF). CONCLUSIONS: Early reductions in HR and cortisol characterised STHA, whereas LTHA showed diminished excitability by Tc, HRV and nephrine measures. Measurement of HRV may have potential to aid real-time assessment of readiness for activity in the heat. PMID- 29127510 TI - Recovery following a marathon: a comparison of cold water immersion, whole body cryotherapy and a placebo control. AB - PURPOSE: Cryotherapy is an increasingly popular recovery strategy used in an attempt to attenuate the negative impact of strenuous physical activity on subsequent exercise. Therefore, this study aimed to assess the effects of whole body cryotherapy (WBC) and cold water immersion (CWI) on markers of recovery following a marathon. METHODS: Thirty-one endurance trained males completed a marathon. Participants were randomly assigned to a CWI, WBC or placebo group. Perceptions of muscle soreness, training stress and markers of muscle function were recorded before the marathon and at 24 and 48 h post exercise. Blood samples were taken at baseline, post intervention and 24 and 48 h post intervention to assess inflammation and muscle damage. RESULTS: WBC had a harmful effect on muscle function compared to CWI post marathon. WBC positively influenced perceptions of training stress compared to CWI. With the exception of C-reactive protein (CRP) at 24 and 48 h, neither cryotherapy intervention positively influenced blood borne markers of inflammation or structural damage compared to placebo. CONCLUSION: The findings show WBC has a negative impact on muscle function, perceptions of soreness and a number of blood parameters compared to CWI, contradicting the suggestion that WBC may be a superior recovery strategy. Further, cryotherapy is no more effective than a placebo intervention at improving functional recovery or perceptions of training stress following a marathon. These findings lend further evidence to suggest that treatment belief and the placebo effect may be largely responsible for the beneficial effects of cryotherapy on recovery following a marathon. PMID- 29127511 TI - Adjacent segment degeneration after intervertebral fusion surgery by means of cervical block vertebrae. AB - BACKGROUND: The prevalence of cervical block vertebrae is unknown. Furthermore, there is no consensus on the cause of adjacent segment degeneration (ASD) after cervical fusion. QUESTIONS/PURPOSES: (1) What is the incidence of cervical block vertebrae? Is there a gender difference? (2) Among cervical block vertebrae cases, is ASD related to age and segment? And what is the specific relationship? (3) What are the imaging findings and characteristics of this disease? PATIENTS AND METHODS: We retrospectively diagnosed cervical block vertebrae cases with bony fusions in any segments of the cervical spine without intervertebral fusion surgery of 33,762 patients reported from 2006 to 2011 in north China. Then the X ray of the obtained cases were observed and counted. The primary outcome was incidence of ASD according to age and segment. The secondary outcome measures were C2-7 angle in fusion (single segment fusion of lower cervical vertebra) and control groups (randomly selected cases of non-fusion), Cobb's angle of fusion segments, and curvature of each lower cervical segment in the control group. RESULTS: A total of 218 cervical block vertebrae cases were found, with a incidence of 0.65%, and C2-3 represented the highest number of fusion segment cases. There were no significant differences in the incidence by sex. Varying degrees of degeneration in the adjacent segment was present in 112 cases (51.4%). The incidence of ASD increased with age, with the ASD growth rate reaching its peak at the age of 51-60 years (55.08%). Cervical curvature shows no significant difference between patients with cervical block vertebrae and normal individuals. The segmental curvature was lower in the fusion group than in the control group, with statistical significance achieved in fusion segments located in C4-5, C5-6, and C6-7, but not C3-4. CONCLUSIONS: Fusion segments located in C4-5, C5-6, and C6-7 are more prone to ASD than C3-4. The incidence of ASD in patients with vertebral fusion increases with age. LEVEL OF EVIDENCE: III. PMID- 29127512 TI - Surgical management of spinal solitary fibrous tumor/hemangiopericytoma: a case series of 20 patients. AB - PURPOSE: Spinal solitary fibrous tumor/hemangiopericytoma (SFT/HPC), a rare mesenchymal tumor that arises from pericytes of Zimmerman, comprises only 0.08% of all primary bone tumors and 0.1% of primary malignant bone tumor and rarely occurs in the spine. We attempt to correlate the clinical factors and different treatment options with the recurrence rate and overall survival of SFT/HPC over time. METHODS: A retrospective study of 20 patients with spinal osseous SFT/HPCs who were surgically treated in our center between 2003 and 2015 was performed. Kaplan-Meier curves and log-rank tests were used to compare the survival probability or recurrence-free probability between groups, and P values < 0.05 were considered statistically significant. RESULTS: Three surgical management strategies, including subtotal resection, piecemeal total resection, and total en bloc spondylectomy (TES) were applied. Postoperative radiotherapy was carried out in 14 cases. The mean follow-up period was 38.3 (median 35, range 7-93) months, and 6 patients passed away with the mean follow-up time of 47.7 (median 41, range 24-77) months. Relapse was detected in 9 patients (45%) with the mean time from surgery to recurrence being 36.6 (median 28, range 12-73) months. Our results indicate that grade III is an adverse prognostic factor for both recurrence and over survival (OS) for spinal osseous SFT/HPC, while total resection, especially TES, is a positive prognostic factor. CONCLUSIONS: Spinal osseous SFT/HPC is a challenging clinical entity given its high local recurrence rate. Surgical management plays a crucial role in the whole treatment of spinal SFT/HPCs and total excision, especially TES, should be strived for whenever possible. Postoperative radiotherapy is recommended to lower the recurrent rate. This study also confirms that pathology grade III is an adverse prognostic factor for spinal osseous SFT/HPCs. PMID- 29127514 TI - Does tranexamic acid increase the risk of thromboembolism after bilateral simultaneous total knee arthroplasties in Asian Population? AB - PURPOSE: To ascertain whether tranexamic acid reduces the blood loss and transfusion rate and volumes; increase the prevalence of deep vein thrombosis (DVT); and investigate factors associated with DVT in patients undergoing primary bilateral total knee arthroplasties (TKAs) without use of chemical thromboprophylaxis. METHODS: There were 874 patients (1748 knees) in the control group who did not receive tranexamic acid and 871 patients (1742 knees) in the study group who received tranexamic acid. Mechanical compression device was applied without any chemical thromboprophylaxis. Transfusion rates and volumes were recorded. DVT was diagnosed using both sonogram and venogram at 7 or 8 day post-operatively. RESULTS: Intra- and post-operative blood loss and transfusion volumes were significantly lower in the tranexamic acid group. The prevalence of DVT was 14% (245 of 1748 knees) in the control group and 18% (314 of 1742 knees) in the tranexamic acid group. Pre- and post-operative perfusion lung scans revealed no evidence of PE in any patients in either group. Coagulation or thrombophilic data or molecular genetic testing was not significantly different between the two groups. CONCLUSION: The use of tranexamic acid reduces the volume of blood transfusion and does not increase the prevalence of DVT or PE in the patients who did not receive routine chemical thromboprophylaxis after primary bilateral simultaneous sequential TKAs in Asian patients. PMID- 29127515 TI - Correction to: Insertion of the Ascension PyroCarbon PIP total joint in 152 human cadaver fingers: analysis of implant positions and malpositions. AB - In the experimental study the distal component of the Ascension PyroCarbon proximal interphalangeal total joint prosthesis was implanted 180 degrees rotated. Figures 2-5 show the implant malpositions. The methods, results, and conclusion of the study were not affected by this. PMID- 29127513 TI - Pentosidine concentration is associated with degenerative lumbar scoliosis in older women: preliminary results. AB - PURPOSE: Advanced glycation end products (AGEs) have been implicated in the pathogenesis of sarcopenia. The objective of the study was to investigate the prevalence of sarcopenia in degenerative lumbar scoliosis (DLS), and the relationship between biochemical markers including major AGEs, pentosidine, and DLS in older women. METHODS: Our study participants were 20 elderly women with idiopathic DLS (mean age 76.4 years, range 56-88). Nineteen age- and sex-matched volunteers (mean age 74.0 years, range 62-86) served as controls. Spinal and femoral BMD of all participants was measured using dual-energy X-ray absorptiometry. We used a bioelectrical impedance analyzer to analyze body composition, including appendicular skeletal muscle mass index [SMI; appendicular lean mass (kg)/(height (m)]2. SMI < 5.75 was considered diagnostic for sarcopenia. Coronal and sagittal spinal alignments were measured. The following biochemical markers were measured: serum and urinary pentosidine, serum homocysteine, 1,25(OA)2D, and 25(OH)D. The level of each variable was compared between DLS and controls. The relationship between biochemical markers including pentosidine and DLS was examined. RESULTS: Sarcopenia was observed at a high prevalence in participants with DLS: 50% compared with 15.8% of healthy controls. Height, weight, femoral BMI, appendicular lean mass, total lean mass, and SMI all had significantly lower values in the DLS group. Serum pentosidine was significantly higher for the DLS group compared with controls. Correlations with serum pentosidine revealed a significant positive correlation between lumbar scoliosis, pelvic tilt, and pelvic incidence-lumbar lordosis mismatch, and a significantly negative correlation between thoracic kyphosis (P < 0.05). CONCLUSIONS: We found that sarcopenia was involved in DLS, and high serum pentosidine levels are associated with severity of coronal and sagittal malalignment in older women, suggesting that high levels of AGEs are a potential biomarker for the progression of lumbar scoliosis and kyphotic deformity. Further studies are needed to clarify the pathogenesis of DLS. PMID- 29127517 TI - Correction to : Coordinate expression of pan-neuronal and functional signature genes in sympathetic neurons. AB - The published online version contains mistake. We apologize for errors in the lettering of Fig. 3d and also would like to correct the legend of Fig. 2b. PMID- 29127516 TI - Vision and Visual History in Elite/Near-Elite-Level Cricketers and Rugby-League Players. AB - BACKGROUND: The importance of optimal and/or superior vision for participation in high-level sports remains the subject of considerable clinical research interest. Here, we examine the vision and visual history of elite/near-elite cricketers and rugby-league players. METHODS: Stereoacuity (TNO), colour vision, and distance (with/without pinhole) and near visual acuity (VA) were measured in two cricket squads (elite/international-level, female, n = 16; near-elite, male, n = 23) and one professional rugby-league squad (male, n = 20). Refractive error was determined, and details of any correction worn and visual history were recorded. RESULTS: Overall, 63% had their last eye examination within 2 years. However, some had not had an eye examination for 5 years or had never had one (near-elite cricketers 30%; rugby-league players 15%; elite cricketers 6%). Comparing our results for all participants to published data for young, optimally corrected, non-sporting adults, distance VA was ~ 1 line of letters worse than expected. Adopting alpha = 0.01, the deficit in distance VA was significant, but only for elite cricketers (p < 0.001) (near-elite cricketers, p = 0.02; rugby-league players, p = 0.03). Near VA did not differ between subgroups or relative to published norms for young adults (p > 0.02 for all comparisons). On average, near stereoacuity was better than in young adults, but only in elite cricketers (p < 0.001; p = 0.03, near-elite cricketers; p = 0.47, rugby-league players). On-field visual issues were present in 27% of participants and mostly (in 75% of cases) comprised uncorrected ametropia. Some cricketers (near-elite 17.4%; elite 38%) wore refractive correction during play, but no rugby-league player did. Some individuals with prescribed correction choose not to wear it when playing. CONCLUSIONS: Aside from near stereoacuity in elite cricketers, the basic visual abilities we measured were not better than equivalent, published data for optimally corrected adults; 20-25% exhibited sub-optimal vision, suggesting that the clearest possible vision might not be critical for participation at the highest levels in the sports of cricket or rugby league. Although vision could be improved in a sizeable proportion of our sample, the impact of correcting these, mostly subtle, refractive anomalies on playing performance is unknown. PMID- 29127519 TI - Neutrophil biology within hepatic environment. AB - Neutrophils are the most abundant leukocyte in the human circulation. These short lived cells are constantly produced from hematopoietic stem cells (HSC) within the bone marrow from which they daily reach the blood and perform major roles in innate immunity. Neutrophils are the first cells to reach inflamed tissues and are armed with a plethora of enzymes that help both with their trafficking within tissues and the killing of pathogens. Damaged or infected organs are rapidly invaded by neutrophils. Their erroneous activation within parenchyma or the vasculature is involved in the pathogenesis of several inflammatory diseases including arthritis, colitis, sepsis, acute lung injury and liver failure. Despite the proposal of a canonical pathway that governs neutrophil migration into tissues, the liver has been extensively described as a unique environment for leukocyte recruitment. Since the control of inflammatory responses is considered one of the most promising avenues for novel therapeutics, the expansion of our understanding of the mechanisms behind neutrophil accumulation within injured liver might add to the development of specific and more efficacious treatments. In this review, we discuss the basic concepts of neutrophil ontogeny and biology, with a focus on the particularities and the molecular steps involved in neutrophil recruitment to the liver. PMID- 29127518 TI - Identifying molecular mediators of environmentally enhanced neurogenesis. AB - Adult hippocampal neurogenesis occurs throughout life and supports healthy brain functions. The production of new neurons decreases with age, and deficiencies in adult neurogenesis are associated with neurodevelopmental and degenerative disease. The rate of neurogenesis is dynamically sensitive to an individual's environmental conditions and experiences, and certain stimuli are known robustly to enhance neurogenesis in rodent models, including voluntary exercise, enriched environment, and electroconvulsive shock. In these models, information about an organism's environment and physiological state are relayed to neurogenic cell types within the hippocampus through a series of tissue and cellular interfaces, ultimately eliciting a neurogenic response from neural stem cells and newborn neurons. Therefore, an understanding of the way that novel genes and proteins act in specific cell types within this circuit-level context is of scientific and therapeutic value. Several well-studied neurotrophic factors have been implicated in environmentally enhanced neurogenesis. This review highlights recently discovered, novel molecular mediators of neurogenesis in response to environmental cues and summarizes the contribution of advanced, large-scale gene expression and function assessment technology to past, present, and future efforts aimed at elucidating cell-type-specific molecular mediators of environmentally enhanced neurogenesis. PMID- 29127521 TI - Comment to: Desarda's technique versus Lichtenstein technique for the treatment of primary inguinal hernia: a systematic review and meta-analysis of randomized controlled trials. Emile SH, Elfeki H. PMID- 29127520 TI - Association between miR-146a rs2910164 polymorphism and specific cancer susceptibility: an updated meta-analysis. AB - The rapidly increasing of cancer risk nationwide and worldwide has threatened human health and caused the changes of disease and death spectrum. MicroRNA (MiRNA) as cancer biomarker on susceptibility has enjoyed a high level of concern. This article will discuss the association between miR-146 rs2910164 polymorphism and cancer susceptibility in 38 independent case-control studies from 34905 individuals. The 38 case-control studies which were searched from PubMed were used for conducting a meta-analysis. There were 14670 cases and 20235 controls. ORs and 95% CIs were used for reflecting the strength of association between miR-146a rs2910164 polymorphism and cancer susceptibility. Subgroup analysis based on the cancer type, ethnicity and study designs. All analysis were performed by using the Stata 11.0 software. MiR-146a rs2910164 polymorphism and overall cancer susceptibility were significantly uncorrelated in all genetic models. In the subgroup analysis for cancer types, miR-146a rs2910164 polymorphism was associated with the susceptibility of lung cancer (CC vs. GG: OR 1.275, 95% CI 1.117-1.455 (P = 0.000); CC + CG vs. GG: OR 1.166, 95% CI 1.052 1.293 (P = 0.003); CC vs. CG + GG: OR 1.239, 95% CI 1.116-1.375 (P = 0.000); C vs. G OR 1.151, 95% CI 1.080-1.227 (P = 0.000)) and nasopharyngeal carcinoma (CC vs. GG: OR 1.713, 95% CI 1.183-2.479 (P = 0.004); CC vs. CG + GG: OR 1.672, 95% CI 1.330-2.103 (P = 0.000); C vs. G: OR 1.400, 95% CI 1.181-1.659 (P = 0.000)), but it was not associated with hepatocellular carcinoma and gastric cancer. However, in the other subgroup analysis by ethnicity and study designs, no significant associations were found. MiR-146a rs2910164 polymorphism might be associated with the susceptibility to lung cancer and nasopharyngeal carcinoma. PMID- 29127522 TI - Common genetic variation within miR-146a predicts disease onset and relapse in multiple sclerosis. AB - Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course. PMID- 29127523 TI - Identification of Quantitative Trait Loci for Resistance to RSIVD in Red Sea Bream (Pagrus major). AB - Red sea bream iridoviral disease (RSIVD) is a major viral disease in red sea bream farming in Japan. Previously, we identified one candidate male individual of red sea bream that was significantly associated with convalescent individuals after RSIVD. The purpose of this study is to identify the quantitative trait loci (QTL) linked to the RSIVD-resistant trait for future marker-assisted selection (MAS). Two test families were developed using the candidate male in 2014 (Fam 2014) and 2015 (Fam-2015). These test families were challenged with RSIV, and phenotypes were evaluated. Then, de novo genome sequences of red sea bream were obtained through next-generation sequencing, and microsatellite markers were searched and selected for linkage map construction. One immune-related gene, MHC class IIbeta, was also used for linkage map construction. Of the microsatellite markers searched, 148 and 197 were mapped on 23 and 27 linkage groups in the female and male linkage maps, respectively, covering approximately 65% of genomes in both sexes. One QTL linked to an RSIVD-resistant trait was found in linkage group 2 of the candidate male in Fam-2014, and the phenotypic variance of the QTL was 31.1%. The QTL was closely linked to MHC class IIbeta. Moreover, the QTL observed in Fam-2014 was also significantly linked to an RSIVD-resistant trait in the candidate male of Fam-2015. Our results suggest that the RSIVD-resistant trait in the candidate male was controlled by one major QTL closely linked to the MHC class IIbeta gene and could be useful for MAS of red sea bream. PMID- 29127525 TI - Cellular mechanisms of action and resistance of Plasmodium falciparum to artemisinin. AB - The recent reports of high failure rates and decline in in vitro sensitivity of Plasmodium falciparum to artemisinin-based combination therapies (ACTs) suggest the possibility of clinical artemisinin resistance along the Thai-Cambodian and Thai-Myanmar borders. The study investigated cellular mechanisms of action and resistance of P. falciparum to artesunate (stage specific activity, interaction with hemozoin, and anti-oxidant levels) in the two paired P. falciparum isolates (MSF046 and MSF060) collected before treatment with a 3-day artesunate-mefloquine and at the time of recrudescence. In addition, the link of these cellular mechanisms to the polymorphisms of the candidate artemisinin-resistant genes (pfatp6, pfcrt, pfmdr1, pfmrp1, and K13 propeller) was also investigated. Morphological change was observed in both pairs of the primary and recrudesced P. falciparum isolates during 12-48 h of exposure to artesunate (at IC90). A marked decrease in parasite viability was found in the recrudesced isolates of both MSF046 and MSD060. The extent of the reduction (% change of baseline) in total glutathione concentrations was significantly lower in recrudesced (32.1 and 1.7%) compared with primary (45.5 and 53.7%) isolates of both MSF046 and MSF060. The extent of reduction of hemozoin content in MSF046 was significantly higher in the recrudesced (76.8%) isolate compared with the primary isolate (99.5%). For MSF060 on the other hand, increase in hemozoin content was found in the recrudesced isolate and the extent of such increase was significantly higher in recrudesced (93.1%) than the primary isolate (87.5%). Polymorphism of K13 (N458Y) together with pfmdr1 copy number correlated well with sensitivity of both isolates to artesunate. Results of this preliminary study suggests possible role of glutathione-dependent detoxification system as well as heme degradation as cellular mechanisms of action and resistance of artemisinins. PMID- 29127526 TI - Phlebotomine sandflies and factors associated with their abundance in the leishmaniasis endemic area of Attiki, Greece. AB - Leishmaniasis is a parasitic disease of animals and humans caused by several Leishmania species and transmitted by phlebotomine sandflies. The aim of the present study was to identify the species of field collected phlebotomine sandflies in the endemic area of the Attiki during 4 consecutive years, to isolate the Leishmania parasites from the infected sandflies, and identify possible factors associated with sandfly abundance in the area. A total of 542 trappings were made in 46 collection sites, in purely urban areas, periurban areas, and purely rural areas in Attiki. Out of the 3254 sandflies trapped, 1448 (44.43%) were female and 241 (16.64%) of the females were blood fed while Leishmania infantum DNA was detected in the 0.41% of them. Regarding sandfly species, the most prevalent was Phlebotomus tobbi (41.52%) followed by Sergentomyia minuta (27.44%), P. neglectus (14.83%), P. simici (11.08%), P. papatasi (3.68%), P. similis (0.89%), and P. alexandri (0.56%). Periurban areas were found to have the highest density of sandfly populations. PMID- 29127527 TI - Molecular detection of Giardia duodenalis and Cryptosporidium spp. in canine faecal samples contaminating public areas in Northern Italy. AB - Giardia duodenalis and Cryptosporidium spp. are common intestinal pathogens of humans and animals. Dogs may be infected by zoonotic isolates of G. duodenalis and Cryptosporidium spp. that, consequently, have high interest under public health perspective. This study estimated the occurrence of these protozoa in canine faeces polluting public areas of Padua municipality (Northern Italy), towards a potential evaluation of health risks for dogs and humans. A total of 705 canine stools was collected in green (n = 270) and urban (n = 435) areas and processed by duplex real-time PCR and real-time PCR SYBR(r) Green I for the detection of both protozoa. Positive samples were submitted to specific nested PCRs (i.e. beta-giardin/SSU-rRNA genes for Giardia; SSU-rRNA gene for Cryptosporidium) to obtain detailed information on the isolates retrieved.Giardia and Cryptosporidium prevalence were 28.9% and 1.7%, respectively. Twenty-one Giardia-positive samples were successfully identified as dog-specific assemblages C and D, and 1 as the human-specific assemblage B. One isolate was identified as Cryptosporidium canis, while the other 11 were confirmed to belong to the Cryptosporidium parvum species complex. Contrariwise to the Cryptosporidium low prevalence, the wide distribution of Giardia suggests a high risk of infection for dogs attending public areas. Although data indicate a limited risk for human health, it is necessary to improve general education to reduce canine faecal pollution towards a widespread awareness of health risks. PMID- 29127528 TI - Changes in volume and incidence of lymphedema during and after treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) in patients with breast cancer. AB - PURPOSES: The purposes of this study were to investigate the incidence of lymphedema in patients with breast cancer during and after adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC), to identify predictors for development of lymphedema, and to describe consequences in daily life in relation to lymphedema. METHODS: This is a prospective study with measurements before chemotherapy (T0), during chemotherapy before cycle 2 (T1), cycle 4 (T2), and 1 month after completion of treatment (T3). Volume change was monitored using tape measurements. Lymphedema was defined as >= 10% volume difference. Linear mixed-effect models were estimated to analyze differences in arm volume and consequences in daily life (total score and domain scores of the Lymph International Classification of Functioning (ICF) questionnaire) over time and to identify treatment and patient characteristics as predictors for changes in volume. RESULTS: Forty-eight patients completed all measurements. Volume did not change during TAC treatment. One month after treatment, volume was significantly increased compared to T0-T2, and 12 patients (25%) had developed lymphedema. Axillary lymph node dissection was associated with lymphedema (ES 2.9, 95% CI 0.02-5.7; p < 0.05). In patients with and without lymphedema, 1 month after completion (T3), the Lymph-ICF questionnaire showed significant limitations in physical function compared to T0-T2. In patients with lymphedema at T3, a significant association between volume and total score on the Lymph-ICF questionnaire on physical function and mobility activities was observed. CONCLUSIONS: One month after treatment in 12 patients (25%), volume difference increased over 10%. Axillary lymph node dissection was predictive for development of lymphedema. All patients, but more patients with lymphedema, perceived difficulties in activities in daily life after treatment. PMID- 29127530 TI - EEG Frequency-Tagging and Input-Output Comparison in Rhythm Perception. AB - The combination of frequency-tagging with electroencephalography (EEG) has recently proved fruitful for understanding the perception of beat and meter in musical rhythm, a common behavior shared by humans of all cultures. EEG frequency tagging allows the objective measurement of input-output transforms to investigate beat perception, its modulation by exogenous and endogenous factors, development, and neural basis. Recent doubt has been raised about the validity of comparing frequency-domain representations of auditory rhythmic stimuli and corresponding EEG responses, assuming that it implies a one-to-one mapping between the envelope of the rhythmic input and the neural output, and that it neglects the sensitivity of frequency-domain representations to acoustic features making up the rhythms. Here we argue that these elements actually reinforce the strengths of the approach. The obvious fact that acoustic features influence the frequency spectrum of the sound envelope precisely justifies taking into consideration the sounds used to generate a beat percept for interpreting neural responses to auditory rhythms. Most importantly, the many-to-one relationship between rhythmic input and perceived beat actually validates an approach that objectively measures the input-output transforms underlying the perceptual categorization of rhythmic inputs. Hence, provided that a number of potential pitfalls and fallacies are avoided, EEG frequency-tagging to study input-output relationships appears valuable for understanding rhythm perception. PMID- 29127532 TI - Correction to: Women's Experience of Orgasm During Intercourse: Question Semantics Affect Women's Reports and Men's Estimates of Orgasm Occurrence. AB - The name of coauthor Kaytlin J. Renfro has been corrected since this article was originally published. PMID- 29127529 TI - The impact of prostate cancer diagnosis and treatment decision-making on health related quality of life before treatment onset. AB - OBJECTIVE: The objective of this study is to test if patients' health-related quality of life (HRQoL) declines after prostate biopsy to detect Pca, and after subsequent treatment decision-making in case Pca is confirmed, and to test whether personality state and traits are associated with these potential changes in HRQoL. METHODS: Patients who were scheduled for prostate biopsy to detect Pca (N = 377) filled out a baseline questionnaire about HRQoL (EORTC QLQ-C30 and PR25), "big five" personality traits (BFI-10), optimism (LOT-r), and self efficacy (Decision Self-efficacy Scale) (t0). Patients with confirmed Pca (N = 126) filled out a follow-up questionnaire on HRQoL within 2 weeks after treatment was chosen but had not yet started (t1). RESULTS: HRQoL declined between t0 and t1, reflected in impaired role and cognitive functioning, and elevated fatigue, constipation, and prostate-specific symptoms. Sexual activity and functioning improved. Baseline HRQoL scores were unrelated to the selection of a particular treatment, but for patients who chose a curative treatment, post-decision HRQoL showed a greater decline compared to patients who chose active surveillance. Optimism was associated with HRQoL at baseline; decisional self-efficacy was positively associated with HRQoL at follow-up. No associations between HRQoL and the "big five" personality traits were found. CONCLUSION: Patients who have undergone prostate biopsy and treatment decision-making for Pca experience a decline in HRQoL. Choosing treatment with a curative intent was associated with greater decline in HRQoL. Interventions aimed at optimism and decision self efficacy could be helpful to reduce HRQoL impairment around the time of prostate biopsy and treatment decision-making. PMID- 29127531 TI - Impact of a robotic surgical system on treatment choice for men with clinically organ-confined prostate cancer. AB - BACKGROUND: Introducing a new surgical technology may affect behaviors and attitudes of patients and surgeons about clinical practice. Robot-assisted laparoscopic radical prostatectomy (RALP) was approved in 2012 in Japan. We investigated whether the introduction of this system affected the treatment of organ-confined prostate cancer (PCa) and the use of radical prostatectomy (RP). METHODS: We conducted a retrospective multicenter study on 718 patients with clinically determined organ-confined PCa treated at one of three Japanese academic institutions in 2011 (n = 338) or 2013 (n = 380). Two patient groups formed according to the treatment year were compared regarding the clinical characteristics of PCa, whether referred or screened at our hospital, comorbidities and surgical risk, and choice of primary treatment. RESULTS: Distribution of PCa risk was not changed by the introduction of RALP. Use of RP increased by 70% (from 127 to 221 cases, p < 0.0001), whereas the number of those undergoing radiotherapy or androgen deprivation therapy decreased irrespective of the disease risk of PCa. Increased use of RP (from 34 to 100 cases) for intermediate- or high-risk PCa patients with mild perioperative risk (American Society of Anesthesiologists score 2) accounted for 70% of the total RP increase, whereas the number of low- or very low-risk PCa patients with high comorbidity scores (Charlson Index >= 4) increased from 8 to 25 cases, accounting for 18%. Use of expectant management (active surveillance, watchful waiting) in very low risk PCa patients was 15% in 2011 and 12% in 2013 (p = 0.791). CONCLUSIONS: Introduction of a robotic surgical system had little effect on the risk distribution of PCa. Use of RP increased, apparently due to increased indications in patients who are candidates for RP but have mild perioperative risk. Although small, there was an increase in the number of RPs performed on patients with severe comorbidities but with low-risk or very low-risk PCa. PMID- 29127533 TI - A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma. AB - Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24 week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression. Results Seventy six patients received at least 1 dose of ontuxizumab (40 received 2 mg/kg, 36 received 4 mg/kg). The primary endpoint, 24-week PFS value, was 11.4% (95% Confidence Interval [CI]: 5.3%-19.9%) for all patients (13.5% for 2 mg/kg and 8.9% for 4 mg/kg). The median PFS for all patients was 8.3 weeks (95% CI: 8.1 12.3 weeks). One patient receiving 4 mg/kg had a partial response, as measured by Response Evaluation Criteria in Solid Tumors v1.1. Twenty-seven of 66 response evaluable patients (40.9%) had stable disease. The median overall survival was 31.0 weeks (95% CI: 28.3-44.0 weeks). The most common adverse events overall were headache (55.3%), fatigue (48.7%), chills (42.1%), and nausea (36.8%), mostly grade 1 or 2. Conclusions Ontuxizumab at both doses was well tolerated. The 24 week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4 mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low. PMID- 29127535 TI - Predictors of HIV Testing and Their Influence on PrEP Acceptance in Men Who Have Sex with Men: A Cross-Sectional Study. AB - HIV testing is the gateway to biomedical means of prevention and treatment. Identifying predictors of HIV testing is important to inform future preventive interventions. Of 444 men who have sex with men without known HIV infection enrolled in a study in Hong Kong, 64% had ever been HIV-tested. Testers were generally older, better educated, had a higher monthly income, and more likely self-identified as gay. Testers often used Internet and frequented saunas for sex networking, compared with non-testers attending bars, massage centres and public toilets. HIV testing habit also varied with the profile of body image type and preferred type in sex networking. Higher acceptance of pre-exposure prophylaxis (PrEP) was observed among testers. Overall, socioeconomic status played an important role in both HIV testing and access to PrEP. Interventions targeting sex networking venues and alternative means of testing provision are needed to increase coverage of HIV testing. PMID- 29127534 TI - 'Test and Treat' Among Women at High Risk for HIV-infection in Kampala, Uganda: Antiretroviral Therapy Initiation and Associated Factors. AB - Data on implementation of 'Test and Treat' among key populations in sub-Saharan Africa are still limited. We examined factors associated with prompt antiretroviral therapy/ART (within 1 month of HIV-positive diagnosis or 1 week if pregnant) among 343 women at high risk for HIV infection in Kampala-Uganda, of whom 28% initiated prompt ART. Most (95%) reported paid sex within 3 months prior to enrolment. Multivariable logistic regression was used to determine baseline characteristics associated with prompt ART. Sex work as main job, younger age and being widowed/separated were associated with lower odds of prompt ART; being enrolled after 12 months of implementing the intervention was associated with higher odds of prompt ART. Younger women, widowed/separated and those reporting sex work as their main job need targeted interventions to start ART promptly after testing. Staff supervision and mentoring may need strengthening during the first year of implementing 'test and treat' interventions. PMID- 29127537 TI - Open Versus Minimally Invasive Resection of Gastric GIST: A Multi-Institutional Analysis of Short- and Long-Term Outcomes: A Reply. PMID- 29127536 TI - Correlation between microcirculation and contrast-enhanced ultrasonography after crush injury of limbs. AB - PURPOSE: To explore the microcirculation formation mechanism of contrast-enhanced (CE) ultrasonography imaging performance in rabbits with limb muscle crush injury. METHODS: Seventy-two New Zealand white rabbits were randomly divided into two groups. A limb muscle crush injury model was created by airing a balloon cuff device with a force of 40 kpa. CE ultrasonography parameters were detected in the first group. In vivo microcirculation parameters were detected in the second group. Fine blood vessel diameter and blood flow velocity were calculated before extrusion and 0.5, 2, 6, 24 h, and 3 days after decompression. RESULTS: Compared with the uninjured muscle, reperfusion of the injured muscles showed early and high enhancement in CE ultrasonography images. The time-intensity curve showed a trend of rapid elevation and gradual drop. Compared with the control group, fine artery and vein diameters in the experimental group were wider and the blood flow velocity was slower, especially in the fine veins. CONCLUSION: In vivo microcirculation detection can reflect changes in muscle microvascular diameter and blood flow velocity, which have a correlation with quantitative ultrasound imaging parameters. PMID- 29127538 TI - The Shifting Paradigm for Breast Cancer Surgery in Patients Undergoing Neoadjuvant Chemotherapy. AB - INTRODUCTION: Surgical therapy for newly diagnosed breast cancer has changed over the past decade, but these trends have not been well documented in patients undergoing neoadjuvant therapy (NAC). METHODS: In a retrospective cohort study of the National Cancer Database (NCDB), we selected 285,514 women with clinical stage I-III breast cancer who underwent NAC or adjuvant therapy (AC) from 2006 to 2014. Breast-conserving surgery (BCS), unilateral mastectomy (UM), and bilateral mastectomy (BM) rates were compared between patients undergoing NAC and AC. RESULTS: Of 285,514 women, 68,850 (24.1%) underwent NAC. Of NAC patients, 18,158 (26.4%) underwent BM and 27,349 (39.7%) BCS compared with 31,886 (14.7%) and 120,626 (55.7%) AC patients, respectively. From 2006 to 2014, BM increased from 16.1 to 28.8% (p < 0.001) for NAC and from 7.4 to 17.5% (p < 0.001) for AC. After adjusting for patient, tumor, and facility factors, NAC patients were 1.50 times [odds ratio (OR) 1.50, confidence interval (CI) 1.42-1.51] more likely to undergo BM then AC patients. The difference in BM rates between patients receiving NAC versus AC varied significantly by cT classification. This difference was the greatest among cT1 tumors between NAC and AC (31.7 vs. 13.0%, p < 0.001), followed by cT2 tumors (24.1 vs. 16.6%, p < 0.001) and cT3 tumors (24.3 vs. 22.3%). CONCLUSIONS AND RELEVANCE: More NAC patients are undergoing BM while fewer are undergoing BCS compared with patients undergoing AC. This trend is particularly striking for those patients with smaller tumors who would otherwise be candidates for BCS. PMID- 29127539 TI - Biotreatment of effluent from 'Adire' textile factories in Ibadan, Nigeria. AB - In this present study, bacteria were isolated from wastewater and polluted soil collected from two cottage textile factories in Ibadan. These bacteria isolates were used for the biotreatment of textile mill effluent. The physicochemical parameters of the textile mill effluent before treatment were carried out and percentage decolourisation of the effluent was analysed using ultraviolet-visible spectroscopy (UV-vis technique). The degradation products of the textile mill effluent characterised by Fourier transform infrared spectroscopy (FTIR). The pH values of the effluent were within the permissible limit of Federal Environmental Protection Agency (FEPA) and National Environmental Standards and Regulations Enforcement Agency (NESREA), while temperature and electric conductivity of the effluents were below the permissible limit of FEPA and NESREA. The BOD, COD, TSS, TDS and chloride of the textile mill effluent from the two cottage textile factories were above the permissible limits of FEPA and NESREA. Twelve bacteria isolates were screened, effective in decolourising commercial dyes and used to decolourise the textile mill effluent. The bacteria isolates were characterised and identified as Bacillus sp., Micrococcus sp., Erwinia sp., Acinetobacter sp. and Nocardia sp. The decolourisation of textile effluent was observed through the changes of spectra of UV-visible spectrophotometer. The following bacteria revealed different percentage proportion of decolouration profile:- Bacillus sp., had the highest percentage decolourisation of 57.7%, whereas Micrococcus sp. and Acinetobacter sp. had percentage decolourisation of 32.8 and 26.3%, respectively. The degradation profile of textile effluent was revealed through FTIR spectral analysis. The changes in the position of major peaks revealed from the textile effluent through FTIR spectral analysis, appearances of new peaks and the disappearances of existing peaks signify the degradation of the wastewater. Thus, some native microorganisms from the textile effluent could be enhanced to effectively degrade effluent from such environments. PMID- 29127540 TI - Evaluation of Lighting Systems, Carbon Sources, and Bacteria Cultures on Photofermentative Hydrogen Production. AB - Fluorescent and incandescent lighting systems were applied for batch photofermentative hydrogen production by four purple non-sulfur photosynthetic bacteria (PNSB). The hydrogen production efficiency of Rhodopseudomonas palustris, Rhodobacter sphaeroides, Rhodobacter capsulatus, and Rhodospirillum rubrum was evaluated using different carbon sources (acetate, butyrate, lactate, and malate). Incandescent light was found to be more effective for bacteria cell growth and hydrogen production. It was observed that PNSB followed substrate selection criteria for hydrogen production. Only R. palustris was able to produce hydrogen using most carbon sources. Cell density was almost constant, but cell growth rate and hydrogen production were significantly varied under the different lighting systems. The kinetics study suggested that initial substrate concentration had a positive correlation with lag phase duration. Among the PNSB, R. palustris grew faster and had higher hydrogen yields of 1.58, 4.92, and 2.57 mol H2/mol using acetate, butyrate, and lactate, respectively. In the integrative approach with dark fermentation effluents rich in organic acids, R. palustris should be enriched in the phototrophic microbial consortium of the continuous hydrogen production system. PMID- 29127541 TI - The bargaining of professionalism in emergency care practice: NHS paramedics and higher education. AB - Over the past 2 decades, as part of reforms to the National Health Service and with it organizational changes to ambulance work in the UK, paramedic education has undergone a process of academisation and a shift from in-house, apprenticeship weeks-long occupational training, to university-based undergraduate programs. While the professional regulation and standardization of Allied Health Professionals' education in high-income countries has captured scholarly attention, the study of paramedic practice is still in its infancy and there is a need to explore its evolvement in relation to the fluid societal political circumstances affecting its provision and demand. Based on interviews with front-line paramedics, paramedic educators and paramedic science students in the South of England, this article examines how the reforms to paramedic education have impacted the professionalization of paramedics and their discourse of professionalism. Framed within to the 'new' sociology of professions, the case of British paramedics demonstrates the complex nature of the relationship between the university and professional practice. It appears that universities, the providers of paramedic education, are caught between two opposing discourses of professionalism: on the one hand, that of providing a platform for students' socialization and engagement with professionalism 'from within' practice which is based on students' common goals and mutual experiences, and, on the other hand, serving as a conduit for managerial/organizational strategies of professionalism which appear to undermine the role of university socialization. PMID- 29127542 TI - Left atrial function after epicardial pulmonary vein isolation in patients with atrial fibrillation. AB - PURPOSE: Epicardial pulmonary vein isolation has become an increasingly used therapy for medically resistant atrial fibrillation. The purpose of the present study was therefore to evaluate if epicardial pulmonary vein isolation combined with ganglionated plexi ablation affects the size and mechanical function of the left atrium, and whether the effects are dependent on the extensiveness of the ablation applications. METHODS: A total of 42 patients underwent an echocardiographic examination prior to and 6 months after a minimal invasive epicardial pulmonary vein isolation procedure for the assessment of the effects on left atrial size and function. In 27 patients, who had sinus rhythm both at baseline and follow-up, was a comparison of atrial size and function possible at these time intervals. Fractional area changes were obtained from the left atrial end-systolic and end-diastolic areas in the apical four-chamber view. Pulsed Doppler was used to assess the transmitral flow velocities to evaluate mechanical function. RESULTS: Left atrial size and function at 6-month follow-up had not changed significantly from those at baseline as indicated by left atrial maximal area (17.1 +/- 4.6 vs. 18.7 +/- 5.3, p = 0.118), minimal area (12.5 +/- 3.8 vs. 13.4 +/- 4.7, p = 0.248), fractional area change (27.4 +/- 8.2 vs. 28.7 +/- 10.6, p = 0.670), and E/A ratio (1.49 +/- 0.47 vs. 1.54 +/- 0.67, p = 0.855). CONCLUSIONS: Radiofrequency ablation for epicardial pulmonary vein isolation combined with ganglionated plexi ablation has no major effects on atrial function or size. A preserved atrial function for those maintaining sinus rhythm may have important implications for thromboembolic risk after surgery, but warrants confirmation in larger trials. PMID- 29127543 TI - Self-efficacy, pain, and quadriceps capacity at baseline predict changes in mobility performance over 2 years in women with knee osteoarthritis. AB - This study examined the extent to which baseline measures of quadriceps strength, quadriceps power, knee pain and self-efficacy for functional tasks, and their interactions, predicted 2-year changes in mobility performance (walking, stair ascent, stair descent) in women with knee osteoarthritis. We hypothesized that lesser strength, power and self-efficacy, and higher pain at baseline would each be independently associated with reduced mobility over 2 years, and each of pain and self-efficacy would interact with strength and power in predicting 2-year change in stair-climbing performance. This was a longitudinal, observational study of women with clinical knee osteoarthritis. At baseline and follow-up, mobility was assessed with the Six-Minute Walk Test, and stair ascent and descent tasks. Quadriceps strength and power, knee pain, and self-efficacy for functional tasks were also collected at baseline. Multiple linear regression examined the extent to which 2-year changes in mobility performances were predicted by baseline strength, power, pain, and self-efficacy, after adjusting for covariates. Data were analyzed for 37 women with knee osteoarthritis over 2 years. Lower baseline self-efficacy predicted decreased walking (beta = 1.783; p = 0.030) and stair ascent (beta = -0.054; p < 0.001) performances over 2 years. Higher baseline pain intensity/frequency predicted decreased walking performance (beta = 1.526; p = 0.002). Lower quadriceps strength (beta = 0.051; p = 0.015) and power (beta = 0.022; p = 0.022) interacted with lesser self-efficacy to predict worsening stair ascent performance. Strategies to sustain or improve mobility in women with knee osteoarthritis must focus on controlling pain and boosting self-efficacy. In those with worse self-efficacy, developing knee muscle capacity is an important target. PMID- 29127545 TI - Future Directions in Employment, Occupational Rehabilitation, and Disability: Introduction to the Special Section. AB - Purpose From an array of disciplinary perspectives, the articles in this special section examine opportunities and challenges in the economic, social, and civic participation of individuals across the spectrum of disabilities. Methods At multiple levels of analysis, the contributors consider employment law and policy frameworks, occupational and vocational rehabilitation strategies, and corporate practices in support of the full and equal inclusion of people with disabilities in society. Results and Conclusions The implications for policymakers, public and private sector stakeholders, and occupational rehabilitation professional are presented to help inform future policies, practices, and strategies to improve employment outcomes for people with disabilities. PMID- 29127544 TI - A Brazilian family with inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia linked to the VCP pGly97Glu mutation. AB - The objective of this study is to report a Brazilian patient and his family with inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). A systematic review of the literature on the valosin-containing protein (VCP) mutation was also performed. The proband (patient) was initially treated as a case of possible refractory polymyositis with Paget's disease and later as an inclusion body myopathy. However, after admission to our service, and considering his personal and familial antecedents, whole exome sequencing was performed revealing valosin-containing protein (VCP) c.290G>A (p.Gly97Glu) mutation in the patient and his nine family members. The clinical presentation of the patient and his family was characterized by different degrees and evaluations of IBMPFD. According to the literature, only one family (Chinese) has this same VCP mutation concomitantly with different IBMPFD phenotype manifestations. The present study shows that IBMPFD should be considered as a differential diagnosis in patients with inflammatory myopathies associated to bone disease and/or cognitive impairment. Moreover, the study expands the genotypic spectrum of missense mutations of VCP gene in a Brazilian family with variable phenotypes. PMID- 29127546 TI - Split Probabilities and Species Tree Inference Under the Multispecies Coalescent Model. AB - Using topological summaries of gene trees as a basis for species tree inference is a promising approach to obtain acceptable speed on genomic-scale datasets, and to avoid some undesirable modeling assumptions. Here we study the probabilities of splits on gene trees under the multispecies coalescent model, and how their features might inform species tree inference. After investigating the behavior of split consensus methods, we investigate split invariants-that is, polynomial relationships between split probabilities. These invariants are then used to show that, even though a split is an unrooted notion, split probabilities retain enough information to identify the rooted species tree topology for trees of 5 or more taxa, with one possible 6-taxon exception. PMID- 29127547 TI - The Effects of Magnesium and Zinc Co-Supplementation on Biomarkers of Inflammation and Oxidative Stress, and Gene Expression Related to Inflammation in Polycystic Ovary Syndrome: a Randomized Controlled Clinical Trial. AB - : Magnesium and zinc are known to exert multiple beneficial effects including anti-inflammatory and antioxidant actions. To our knowledge, data on the effects of magnesium and zinc co-supplementation on biomarkers of inflammation and oxidative stress and gene expression related to inflammation in subjects of polycystic ovary syndrome (PCOS) are scarce. This study was conducted to evaluate the effects of magnesium and zinc co-supplementation on biomarkers of inflammation and oxidative stress and gene expression related to inflammation in subjects with PCOS. This randomized double-blind, placebo-controlled trial was conducted among 60 subjects with PCOS diagnosed according to the Rotterdam criteria, aged 18-40 years old. Participants were randomly assigned into two groups to take either 250 mg of magnesium oxide plus 220 mg of zinc sulfate (containing 50 mg zinc) supplements (n = 30) or placebo (n = 30) twice a day for 12 weeks. Biomarkers of inflammation and oxidative stress were assessed at baseline and at end of treatment. Gene expression related to inflammatory cytokines was assessed in peripheral blood mononuclear cells (PBMCs) of PCOS women with RT-PCR method. After the 12-week intervention, compared with the placebo, magnesium and zinc co-supplementation significantly decreased serum high sensitivity C-reactive protein (hs-CRP) (- 1.6 +/- 2.4 vs. + 0.1 +/- 0.7 mg/L, P = 0.001) and protein carbonyl (PCO) (- 0.14 +/- 0.28 vs. + 0.02 +/- 0.07 mmol/mg protein, P = 0.002) and significantly increased plasma total antioxidant capacity (TAC) levels (+ 60.7 +/- 69.4 vs. - 1.5 +/- 141.5 mmol/L, P = 0.03). Results of RT-PCR demonstrated that compared with the placebo, magnesium and zinc co supplementation downregulated gene expression of interleukin-1 (IL-1) (P = 0.007) and tumor necrosis factor alpha (TNF-alpha) (P = 0.03) in PBMCs of subjects with PCOS. Overall, magnesium and zinc co-supplementation, compared with the placebo, for 12 weeks among PCOS women had beneficial effects on serum hs-CRP, plasma PCO, TAC, and gene expression of IL-1 and TNF-alpha. CLINICAL TRIAL REGISTRATION NUMBER: http://www.irct.ir : IRCT201706075623N121. PMID- 29127548 TI - Protective Effect of Agaricus blazei Polysaccharide Against Cadmium-Induced Damage on the Testis of Chicken. AB - Cadmium (Cd) exposure can cause reproductive toxicity through oxidative stress and inflammatory response. A polysaccharide extract of the edible mushroom Agaricus blazei Murill has been isolated and exhibits antioxidant activity and immunoregulatory effect. The aim of this study was to investigate the protective role of Agaricus blazei polysaccharide (ABP) against Cd-induced damage in chicken testis through enhancing antioxidant activity and alleviating inflammatory response. One hundred twenty healthy 7-day-old Hy-Line male chickens (Harbin, China) were randomly divided into four groups, and each group consisted of 30 chickens: Normal control was fed daily with full feed and 0.2 mL distilled water per day via oral gavage; Cd-treated group was fed daily with full feed that contained 140 mg/kg CdCl2 and 0.2 mL distilled water per day by gavage; Polysaccharide-treated group was fed daily with full feed with 0.2 mL ABP(30 mg/ml) solution per day via oral gavage; Cd/polysaccharide-treated group was fed daily with full feed containing 140 mg/kg CdCl2 and 0.2 mL ABP(30 mg/ml) solution per day by gavage. On the 20, 40, and 60 days, the testis was immediately removed. The contents of Cd in the testis, activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), malondialdehyde (MDA) production, messenger RNA (m RNA) levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin-6 (IL-6), protein expressions of heat shock proteins (HSPs) (HSP60, HSP70, and HSP90), and the histopathological changes of the testis were determined. The results indicated that ABP improved Cd caused testicular tissue damage by increasing the SOD and GSH-Px activities: decreasing the Cd accumulation and MDA content, mRNA levels of TNF-alpha, IL 1beta, and IL-6, and protein expressions of HSP60, HSP70, and HSP90. Results suggest that ABP for the mitigation of damage induced by cadmium in chicken testis through enhancing antioxidant activity and alleviating Inflammatory response. PMID- 29127549 TI - Preservation of the celiac branch of the vagal nerve for pylorus-preserving gastrectomy: is it meaningful? AB - BACKGROUND: Preserving the hepatic and pyloric branches of the vagal nerve in laparoscopic pylorus-preserving gastrectomy (LPPG) is considered necessary to maintain the function of the pyloric cuff. However, the clinical benefits of preservation of the celiac branch of the vagal nerve (CBVN) remain unclear. METHODS: Of 391 patients who underwent LPPG for early gastric cancer, 116 patients in whom the CBVN was preserved (CBP group) and 58 patients in whom it was not preserved (non-CBP group) were selected through the propensity score matching method. To evaluate the surgical and oncological safety of preserving the CBVN, postoperative morbidity and mortality were analyzed between these matched groups. Postoperative nutritional status, body weight changes, endoscopic findings, and the incidence of gallstones were compared to evaluate any functional advantages. RESULTS: The short-term surgical outcomes in the CBP group were similar to those in the non-CBP group. The number of dissected lymph nodes did not differ (34 vs. 33.5, P = 0.457), and the 5-year recurrence-free survival rates were also similar between both groups (99.1% vs. 97.1%, P = 0.844). There were no significant differences in postoperative nutritional status, body weight changes, or the incidence of gallstones. By endoscopy, 1 year after surgery residual food was frequently observed in both groups; however, there were no significant differences in the frequency of remnant gastritis and esophageal and bile reflux. CONCLUSIONS: Preserving CBVN in LPPG for early gastric cancer is a feasible procedure. However, no clinical benefits of the preservation of the CBVN after LPPG are identified. PMID- 29127550 TI - A Proposal of the Ur-proteome. AB - Herein we outline a plausible proteome, encoded by assuming a primeval RNY genetic code. We unveil the primeval phenotype by using only the RNA genotype; it means that we recovered the most ancestral proteome, mostly made of the 8 amino acids encoded by RNY triplets. By looking at those fragments, it is noticeable that they are positioned, not at catalytic sites, but in the cofactor binding sites. It implies that the stabilization of a molecule appeared long before its catalytic activity, and therefore the Ur-proteome comprised a set of proteins modules that corresponded to Cofactor Stabilizing Binding Sites (CSBSs), which we call the primitive bindome. With our method, we reconstructed the structures of the "first protein modules" that Sobolevsky and Trifonov (2006) found by using only RMSD. We also examine the probable cofactors that bound to them. We discuss the notion of CSBSs as the first proteins modules in progenotes in the context of several proposals about the primitive forms of life. PMID- 29127552 TI - MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding. AB - PURPOSE: Recent evidence suggests that the tau radiotracer [18F]THK-5351 displays high affinity for the monoamine oxidase type B (MAO-B) enzyme. Utilizing another tau-tracer, flortaucipir ([18F]AV-1451), we previously reported that non-demented Parkinson's disease patients show off-target binding in subcortical structures, but no appreciable cortical uptake. However, 59 % of these patients were receiving MAO-B inhibitors at the time of their scan. Here, we retrospectively investigated if MAO-B inhibitors in clinical doses affect flortaucipir binding. PROCEDURES: We compared the standard uptake values of flortaucipir at regional and voxel levels in Parkinson's disease patients who received MAO-B inhibitors with those who did not. RESULTS: Sixteen of 27 Parkinson's disease patients received MAO-B inhibitors at the time of scan. We found no significant flortaucipir uptake differences between the groups at voxel or regional levels. CONCLUSION: Use of MAO-B inhibitors at pharmaceutical levels did not significantly affect flortaucipir binding. Thus, MAO-B does not appear to be a significant binding target of flortaucipir. PMID- 29127551 TI - Endoscopic Evaluation/Management of Bariatric Surgery Complications. AB - OPINION STATEMENT: Purpose of Review Bariatric surgery has become increasingly common given the increasing prevalence of obesity and its associated co morbidities. As a result, patients who have surgically altered anatomy will be seen with increasing frequency by gastroenterologists. Recent Findings Complications that arise in this patient population are unique and require specific knowledge for appropriate treatment. Summary A basic understanding of surgical anatomy, possible complications, and endoscopic techniques for management is crucial. This review focus on major complications that arise in the setting of bariatric surgery and commonly seen by endoscopists. PMID- 29127553 TI - Identification of Histidine 303 as the Catalytic Base of Lysyl Oxidase via Site Directed Mutagenesis. AB - Lysyl oxidase (LOX) is a copper-dependent amine oxidase enzyme that catalyzes the formation of crosslinkages of collagen and elastin in connective tissues by oxidative deamination of lysine. Using site-directed mutagenesis, Histidine 303 has been shown to be a key residue that acts as the necessary catalytic base for this enzyme to function properly. Histidine 303 was mutated to isoleucine to remove catalytic activity and to aspartate and glutamate, respectively, in order to provide alternate residues that could act as a general base that could maintain catalytic activity. Overexpression of the H303I mutant yielded 3.9 mg of enzyme per liter of media, the H303D mutant yielded 3.3 mg of enzyme per liter of media, and the H303E mutant yielded 3.0 mg/L of media. Overexpression of wildtype LOX yielded 4.5 mg/L of media, which is a slight improvement from previous yields. Total copper incorporation for H303I was calculated to be 68% and no copper was detected for the H303D and H303E mutants. As LOX requires the self processed cofactor lysyl tyrosyl quinone (LTQ) for activity, total LTQ content was obtained by reacting the enzyme with phenylhydrazine and using the previously reported extinction coefficient of 15.4 mM/cm. LTQ content for the wildtype enzyme was determined to be 92%, for H303I the total LTQ content was determined to be 36%, and no LTQ was detected for the H303D and H303E mutants. No catalytic activity was detected for any mutants when compared to the wildtype which has a previously reported activity of 0.11 U/mg. Comparison of excitation-emission matrices (EEM) of each of the mutants as compared to the wildtype indicate that all the mutations cause a change in the internal environment of the enzyme, albeit to varying degrees, as evidenced by the observed shifts. PMID- 29127555 TI - Continuous monitoring of blood pressure by analyzing the blood flow sound of arteriovenous fistula in hemodialysis patients. AB - BACKGROUND: Patients with end-stage renal disease undergoing hemodialysis (HD) have an elevated risk of cardiovascular disease-related morbidity and mortality. To prevent from such a life-threatening event, the continuous blood pressure (BP) monitoring system may contribute to detect BP decline in early stages and may help to do appropriate disposal. Our research team has introduced an electronic stethoscope (Asahi Kasei Co, Ltd., Tokyo, Japan), which translates sound intensity of Arteriovenous Fistula (AVF) to BP data using the technique of Fourier transformation that can predict continuous BP non-invasively. This study, we investigated whether electronic stethoscope-guided estimated BP (e-BP) would actually reflect systolic BP measured by sphygmomanometer (s-BP), and whether e BP could predict fall of BP during HD. METHODS: Twenty-six patients who underwent HD treatment in our hospital were evaluated prospectively. We obtained sound intensity data from the electronic stethoscope which was equipped with the return line of HD. Then, the data were translated into e-BP data to be compared with s BP. Correlation of total of 315 data sets obtained from each method was examined. An accuracy of diagnosis of intra-dialytic hypotension (IDH) was evaluated. RESULTS: Total of 315 data sets were obtained. A close correlation was observed between e-BP and s-BP (r = 0.887, p < 0.0001). Sensitivity and positive predictive value of predicted-BP for detection of IDH was 90 and 81.3%, respectively. CONCLUSIONS: Electronic stethoscope-guided BP measurement would be helpful for real-time diagnosis of BP fall in HD patients. Further investigations are needed. PMID- 29127554 TI - Is there any role for minimally invasive surgery in NET? AB - Neuroendocrine tumors (NET) represent the variability of almost benign lesions either secreting hormones occurring as a single lesion up to malignant lesions with metastatic potential. Treatment of NET is usually performed by surgical resection. Due to the rarity of NET, surgical treatment is mainly based on the experience and recommendations of experts and less on the basis of prospective randomized studies. In addition, the development and establishment of new surgical procedures is made more difficult by their rarity. The development of laparoscopic-assisted surgery has significantly improved the treatment of many diseases. Due to the well-known advantages of laparoscopic surgery, this method has also been increasingly used to treat NET. However, due to limited comparative data, the assumed superiority of laparoscopic surgery in the area NET remains often unclear or not yet proven. This review focuses on the present usage of laparoscopic techniques in the area of NET. Relating to the current literature, this review presents the evidence of various laparoscopic procedures for treatment of adrenal, pancreatic and intestine NET as well as extraadrenal pheochromocytoma and neuroendocrine liver metastases. Further, this review focuses on recent new developments of minimally invasive surgery in the area of NET. Here, robotic-assisted surgery and single-port surgery are promising approaches. PMID- 29127557 TI - DAI-1 Receptor Expression in Placenta in Earlyand Late-Onset Preeclampsia. AB - DAI-1 receptor (DNA-dependent activator of IFN-regulatory factors; DLM-1/ZBP-1) is an innate immunity cytoplasmic receptor of the DNA-recognition receptor class of antiviral immunity. DAI-1 expression reflects the severity of the inflammatory response that plays the key role in the pathogenesis of pregnancy complications. We studied DAI-1 receptor expression in the placental villi in early- and late onset preeclampsia. In case of early-onset preeclampsia DAI-1 staining intensity was lower (p=0.01), and in case of late preeclampsia - significantly higher (p<0.005) than in the reference groups at the corresponding gestational age. There was revealed a correlation between the decrease in DAI-1 receptor expression and the severity of disease progression. PMID- 29127556 TI - Nationwide multicenter kidney biopsy study of Japanese patients with hypertensive nephrosclerosis. AB - BACKGROUND: Nephrosclerosis is an increasingly reason for dialysis in Japan. However, kidney biopsy specimens for hypertensive nephrosclerosis are very limited; thus, the pathologic evaluation of hypertensive nephrosclerosis currently remains unclear. METHODS: Clinical and pathologic data of a total of 184 biopsy-confirmed hypertensive nephrosclerosis patients were collected from 13 centers throughout Japan. Seven pathological findings were assessed in this study. The outcomes of interest for this study were dialysis, composite kidney events, cardiovascular events, and all-cause mortality. RESULTS: The Green and Yellow (G&Y), Orange, and Red groups of the chronic kidney diseases (CKD) heat map contained 36, 57, and 91 cases, respectively. The mean observation period was 7.3 +/- 5.2 (median, IQR; 6.1, 2.6-9.7) years. Global glomerulosclerosis (GScle), interstitial fibrosis and tubular atrophy (IFTA), arteriolar hyalinosis in Red exhibited higher scores than those in G&Y and Orange. The incidence rates of the composite kidney end points in 100 person-years for the G&Y, Orange, and Red groups were 1.42, 2.16, and 3.98, respectively. In the univariate Cox analysis for the composite kidney end points, GScle, IFTA and interstitial cell infiltration exhibited statistically significant high hazard ratios (1.18, 1.84, 1.69, respectively). However, after adjustment for clinical and medication data, the Red group in the CKD heat map category was risk factor for the composite kidney end points (HR 9.51). CONCLUSIONS: In summary, although pathologic findings had minor impacts on the prediction of composite outcomes in this study, the clinical stage of the CKD heat map is a good predictor of composite kidney events. PMID- 29127558 TI - Effect of dexamethasone dose and route on the duration of interscalene brachial plexus block for outpatient arthroscopic shoulder surgery: a randomized controlled trial. AB - PURPOSE: Dexamethasone prolongs the duration of interscalene block, but the benefits of higher doses and perineural vs intravenous administration remain unclear. METHODS: This factorial design, double-blinded trial randomized 280 adult patients undergoing ambulatory arthroscopic shoulder surgery at a single centre in a 1:1:1:1 ratio. Patients received ultrasound-guided interscalene block with 30 mL 0.5% bupivacaine and 4 mg or 8 mg dexamethasone by either the perineural or intravenous route. The primary outcome (block duration measured as the time of first pain at the surgical site) and secondary outcomes (adverse effects, postoperative neurologic symptoms) were assessed by telephone. In this superiority trial, the predetermined minimum clinically important difference for comparisons between doses and routes was 3.0 hr. RESULTS: The perineural route significantly prolonged the mean block duration by 2.0 hr (95% confidence interval [CI], 0.4 to 3.5 hr; P = 0.01), but 8 mg of dexamethasone did not significantly prolong the mean block duration compared with 4 mg (1.3 hr; 95% CI, -0.3 to 2.9 hr, P = 0.10), and there was no significant statistical interaction (P = 0.51). The mean (95% CI) block durations, in hours, were 24.0 (22.9 to 25.1), 24.8 (23.2 to 26.3), 25.4 (23.8 to 27.0), and 27.2 (25.2 to 29.3) for intravenous doses of 4 and 8 mg and perineural doses of 4 and 8 mg, respectively. There were no marked differences in side effects between groups. At 14 postoperative days, 57 (20.4%) patients reported neurologic symptoms, including dyspnea and hoarseness. At six months postoperatively, only six (2.1%) patients had residual symptoms, with four (1.4%) patients' symptoms unlikely related to interscalene block. CONCLUSION: Compared with the intravenous route, perineural dexamethasone prolongs the mean interscalene block duration by a small amount that may or may not be clinically significant, regardless of dose. However, the difference in mean block durations between 8 mg and 4 mg of dexamethasone is highly unlikely to be clinically important, regardless of the administration route. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02426736). Registered 14 April 2015. PMID- 29127559 TI - A 13C-detected 15N double-quantum NMR experiment to probe arginine side-chain guanidinium 15Neta chemical shifts. AB - Arginine side-chains are often key for enzyme catalysis, protein-ligand and protein-protein interactions. The importance of arginine stems from the ability of the terminal guanidinium group to form many key interactions, such as hydrogen bonds and salt bridges, as well as its perpetual positive charge. We present here an arginine 13Czeta-detected NMR experiment in which a double-quantum coherence involving the two 15Neta nuclei is evolved during the indirect chemical shift evolution period. As the precession frequency of the double-quantum coherence is insensitive to exchange of the two 15Neta; this new approach is shown to eliminate the previously deleterious line broadenings of 15Neta resonances caused by the partially restricted rotation about the Czeta-Nepsilon bond. Consequently, sharp and well-resolved 15Neta resonances can be observed. The utility of the presented method is demonstrated on the L99A mutant of the 19 kDa protein T4 lysozyme, where the measurement of small chemical shift perturbations, such as one-bond deuterium isotope shifts, of the arginine amine 15Neta nuclei becomes possible using the double-quantum experiment. PMID- 29127561 TI - The Role of Public Health in the Development of a Collaborative Agreement with Rural and Semi-urban Partners in Cases of Severe Domestic Squalor and Hoarding. AB - When confronted with complex situations of hoarding and severe domestic squalor, small municipal communities and their partners frequently feel overwhelmed due to limited resources at their disposal. Stakeholders often report these situations to Public Health Service and seek their support. In order to facilitate more effective and coordinated actions, the main stakeholders involved (municipal, fire, police, public health and the regional health center) must agree on the most appropriate intervention strategies. An agreement providing services for the management of severe cases of domestic squalor in rural and semi-urban areas located in Quebec, Canada was produced by the Laurentians regional public health, and signed with fourteen local municipalities. PMID- 29127560 TI - Characteristics of Medicaid Recipients Receiving Persistent Antipsychotic Polypharmacy. AB - Antipsychotic polypharmacy (APP) is a common strategy despite guidelines advising against this practice. This article seeks to quantify the prevalence and correlates of APP using Medicaid Analytic eXtract files from 2003 to 2004. Nineteen percent of Medicaid recipients who received an antipsychotic were treated with APP. Individuals who received APP were more likely to be white, male, disabled, between the ages of 18-29, diagnosed with a psychotic disorder, and diagnosed with a higher number of psychiatric conditions. Geographic variation in APP rates was also observed. Quality improvement initiatives may help reduce APP for medically vulnerable patients. PMID- 29127562 TI - Impact of a Pilot Videogame-Based Physical Activity Program on Walking Speed in Adults with Schizophrenia. AB - The purpose of this report is to describe the impact of a videogame-based physical activity program using the Kinect for Xbox 360 game system (Microsoft, Redmond, WA) on walking speed in adults with schizophrenia. In this randomized controlled trial, 28 participants played either an active videogame for 30 min (intervention group) or played a sedentary videogame for 30 min (control group), once a week for 6 weeks. Walking speed was measured objectively with the Short Physical Performance Battery at enrollment and at the end of the 6-week program. The intervention group (n = 13) showed an average improvement in walking speed of 0.08 m/s and the control group (n = 15) showed an average improvement in walking speed of 0.03 m/s. Although the change in walking speed was not statistically significant, the intervention group had between a small and substantial clinically meaningful change. The results suggest a videogame based physical activity program provides clinically meaningful improvement in walking speed, an important indicator of health status. PMID- 29127563 TI - Reasons for Nonadherence to Psychiatric Medication and Cardiovascular Risk Factors Treatment Among Latino Bipolar Disorder Patients Living in Puerto Rico: A Qualitative Study. AB - Latinos with bipolar disorder (BD) have a high rate of nonadherence to psychiatric medication and treatment for other medical conditions such as cardiovascular disease (CVD) risk factors than non-Latinos with BD. The aim of this study is to identify patients' perspectives on the reasons for nonadherence to psychiatric medication and for CVD risk factors conditions in outpatients with BD. Three focus group sessions were held for a total of 22 adults ranging from 23 to 60 years old. Participants had BD, Type I/II and CVD risk factors. Audio recordings of focus groups were transcribed and a content analysis was performed. Reasons identified as barriers to adherence were somewhat different for BD medications in comparison to CVD risk factors suggesting the need for integrated interventions targeting these barriers to adherence for both BD and CVD risk factors. PMID- 29127565 TI - Families in Assertive Community Treatment (ACT) Teams in Norway: A Cross Sectional Study on Relatives' Experiences of Involvement and Alienation. AB - International research shows that relatives of people with mental illness are rarely involved by mental health services. Assertive Community Treatment (ACT) has been recently implemented in Norway. The experience of relatives of ACT users is largely unknown. The aim of this study was to explore relatives' experience with ACT-teams in Norway. Data were collected using the family involvement and alienation questionnaire, consisting of experiences of approach, and alienation from the provision of professional care. 38 Relatives participated in this study. A majority experienced a positive approach (openness, confirmation, and cooperation) from the ACT teams, which also was considered better compared to previous services. They considered openness and cooperation as essential aspects from the professionals. Almost half did not feel alienated (powerlessness and social isolation). Higher level of being approached positively was significantly associated with lower level of feeling alienated. The knowledge of what constituted relatives' positive experiences with the ACT teams should be transferred into practice regarding how to form a positive alliance with relatives. PMID- 29127564 TI - The Association Between Social Network Factors with Depression and Anxiety at Different Life Stages. AB - This study examines whether social network factors influence individual's depression and anxiety outcomes at different life stages. Data was drawn from the Household, Income and Labour Dynamics in Australia survey. Hierarchical regression modelling was applied to examine the effects within and across different life stages. The depression and anxiety measures were taken from the Kessler Psychological Distress Scale (K10) and the social network factors were taken from the self-completion questionnaire. With the exception of social trust in seniors, the social network factors were significant predictors of depression and anxiety. This has practical implications for the design of social policy initiatives. PMID- 29127566 TI - Monitoring and Treating Metabolic Abnormalities in Patients with Early Psychosis Initiated on Antipsychotic Medications. AB - Antipsychotic medications carry an established lifetime risk of metabolic syndrome. This retrospective chart review evaluated feasibility of a metabolic monitoring clinical decision support tool (CDST) for weight, lipid, blood glucose, and blood pressure management of 163 clients in an early psychosis outpatient clinic over 2 years. Each parameter had at least 98 (60.1%) clients with a recorded value, the most being documented for weight with 112 (68.7%) clients. CDST adherence ranged from at least 54.3-100% for non-pharmacologic interventions (e.g. clinic counseling, referral to health program or primary care) and at least 33.3-100% for pharmacologic interventions (e.g. metformin). Though no baseline cardiometabolic abnormalities were identified, dyslipidemia and obesity were later found in 37 (22.7%) and 35 (21.5%) clients, respectively. Only 14 (8.6%) clients were prescribed medications for cardiometabolic abnormalities by psychiatrists in the clinic. Increasing focus on physical health is needed to better this population's long-term prognosis. PMID- 29127567 TI - The root of Actinidia chinensis inhibits hepatocellular carcinomas cells through LAMB3. AB - The root of Actinidia chinensis, as traditional Chinese medicine, has been shown to inhibit cell proliferation in numerous cancer cells. However, the mechanisms underlying its inhibitory activity remain unclear. Death rates of hepatocellular carcinoma (HCC) are increasing, but therapies for advanced HCC are not well developed. We choose the extract from root of Actinidia chinensis (ERAC) to treat the HCC cell lines in vitro, displaying distinct effects on cell proliferation, S phase cell cycle arrest, and apoptosis. LAMB3, the gene encoding laminin subunit beta-3, plays a key role in the proliferation suppression and S-phase cell cycle arrest of HepG2 cells treated with ERAC. The downstream genes ITGA3, CCND2, and TP53 in LAMB3 pathway show the same response to ERAC as LAMB3. Thus, LAMB3 pathways, along with extracellular matrix-receptor interaction, pathways in cancer, and focal adhesion, are involved in the ERAC-induced suppressive response in HepG2. PMID- 29127570 TI - Behavior Genetics Association 47th Annual Meeting Abstracts. PMID- 29127569 TI - Cooperative Formation of Icosahedral Proline Clusters from Dimers. AB - Ion mobility spectrometry-mass spectrometry and Fourier transform infrared spectroscopy (FTIR) techniques were combined with quantum chemical calculations to examine the origin of icosahedral clusters of the amino acid proline. When enantiopure proline solutions are electrosprayed (using nanospray) from 100 mM ammonium acetate, only three peaks are observed in the mass spectrum across a concentration range of five orders of magnitude: a monomer [Pro+H]+ species, favored from 0.001 to 0.01 mM proline concentrations; a dimer [2Pro+H]+ species, the most abundant species for proline concentrations above 0.01 mM; and, the dimer and dodecamer [12Pro+2H]2+ for 1.0 mM and more concentrated proline solutions. Electrospraying racemic D/L-proline solutions from 100 mM ammonium acetate leads to a monomer at low proline concentrations (0.001 to 0.1 mM), and a dimer at higher concentrations (>0.09 mM), as well as a very small population of 8 to 15 Pro clusters that comprise <0.1% of the total ion signals even at the highest proline concentration. Solution FTIR studies show unique features that increase in intensity in the enantiopure proline solutions, consistent with clustering, presumably from the icosahedral geometry in bulk solution. When normalized for the total proline, these results are indicative of a cooperative formation of the enantiopure 12Pro species from 2Pro. Graphical Abstract. PMID- 29127571 TI - The Promise and Perils of Population Research on Same-Sex Families. AB - As a follow-up to our 2016 study, this article presents new findings examining the relationship between same-sex family structure and child health using the 2008-2015 National Health Interview Survey (NHIS). After discussing NIHS data problems, we examine the relationship between family structure and a broad range of child well-being outcomes, including school days lost, behavior, parent-rated health, emotional difficulties, and activity limitations. We find both similarities (school days lost, behavior, parent-rated health) and differences (emotional difficulties and activity limitations) across our two studies using different survey years, but our overall conclusions are robust. We further discuss the implications of our findings for future research on this topic, including how to account for biological relatedness in a study on child health in same-sex families. PMID- 29127572 TI - Strong Surface Enhanced Florescence of Carbon Dot Labeled Bacteria Cells Observed with High Contrast on Gold Film. AB - Strong surface (metal) enhanced fluorescence (SEF or MEF) is observed from clusters and single E coli bacteria cells labeled with Carbon nanodots (CDs), which were synthesized from date pits. The enhancement factor (EF) for SEF of the cell clusters were close to 50 for both 533 and 633 nm laser excitation wavelength. Those EFs are ratios of emission peak areas from CD labeled cell clusters on gold film to the peak areas of the same batch cell clusters on glass substrate. SEF with 633 nm excitation performed better than SEF with 532 nm excitation, achieving higher fluorescence intensity and much higher contrast. The contrast as high as 66 for cell clusters on gold film is a ratio of fluorescent emission peak area measured at the CD labeled cell clusters to the fluorescent peak area measured at unlabeled cell clusters (autofluorescence) on the same substrate. The contrast with the background (S/N) or the ratio of fluorescent peak area measured at bacteria cells to area measured at bare substrate was as high as 200. This report may pave a way for the broader application of surface enhanced fluorescence and especially metal enhanced fluorescence imaging of CD labeled cells and other biological objects. Graphical abstract Carbon dots, synthesized from dates, are used for direct staining of E coli cells. Emission fluorescent spectroscopy of those CD labelled cells on gold film and glass, demonstrated enhancement factor about 50 for emission on gold as compared to glass, Excitation at 633 nm appears far superior to excitation at 532 nm in terms of contrast (up to 67) with unlabeled cells /control due to decrease in auto fluorescence of cells. Maximum Signal to noise ratio is 200. PMID- 29127573 TI - Eosinophilic granulomatosis with polyangiitis complicated by subarachnoid hemorrhage and coronary vasculitis: a case report and review of the literature. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by necrotizing vasculitis of small-sized vessels with extravascular granulomas and eosinophilic infiltration. The case of a 48-year-old Japanese woman with EGPA, who presented concurrently with subarachnoid hemorrhage (SAH) and coronary vasculitis, is reported. She initially presented with bronchial asthma, and then 8 months later she developed various symptoms caused by systemic eosinophilic vasculitis and was admitted to our hospital. Three days after admission, she started oral corticosteroid therapy, and her 2009 Five-Factor Score (FFS) was 0. However, she developed an SAH, followed by coronary vasculitis 1 day later. With extensive treatment with a combination of betamethasone, cyclophosphamide, intravenous immunoglobulin, and rituximab, her systemic vasculitis improved dramatically. This seems to be the first case of EGPA with SAH and coronary vasculitis. In previous reports of EGPA with SAH, 4 of 11 cases developed SAH as an exacerbation of systemic vasculitis during remission induction therapy. The present patient also had SAH during remission induction therapy. However, the period between bronchial asthma and SAH was only 8 months. This is the shortest among case reports of EGPA with SAH. In addition, the present patient rapidly developed coronary vasculitis. These findings suggest that EGPA causes SAH and coronary vasculitis as early complications of systemic vasculitis. In EGPA, it is necessary to pay careful attention to rapid changes of disease activity, even when the FFS indicates a good prognosis. PMID- 29127574 TI - Biologic treatment for chronic recurrent multifocal osteomyelitis: report of four cases and review of the literature. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is a rare non-infectious inflammatory disorder with unpredictable clinical course, characterized by acute exacerbations and spontaneous remissions. There are no randomized-controlled trials about treatment options. Non-steroidal anti-inflammatory drugs (NSAID) are the first-line treatment option; glucocorticoids seem to be effective; positive outcomes have been obtained with bisphosphonates. In the last few years successful use of biologic agents like anti-TNF agents has been reported. We report the cases of 3 children suffering from CRMO who were treated with NSAID, steroid, bisphosphonates and eventually received etanercept and 1 case without vertebral involvement treated with etanercept after NSAID and steroid; all cases showed clinical improvement. The mean ages at symptoms onset and diagnosis were 8 and 10 years and 10 months, respectively. Two patients presented with back pain and three had vertebral lesions. Mean interval from diagnosis to the onset of anti-TNF treatment was 14 months. According to our small experience, we suggest considering therapy with etanercept for the treatment of severe cases with persistently active disease despite multiple treatments. PMID- 29127575 TI - Bright light therapy improves cancer-related fatigue in cancer survivors: a randomized controlled trial. AB - PURPOSE: Cancer-related fatigue (CRF) is a common and distressing symptom that can persist after cancer treatment has concluded. Bright light therapy has shown preliminary efficacy in reducing CRF, but its impact on other psychosocial factors is unclear. The purpose was to examine the impact of a 1-month light therapy intervention on fatigue, mood, and quality of life in cancer survivors with fatigue. METHODS: This 4-week blinded randomized controlled trial recruited cancer survivors who met diagnostic criteria for CRF. Participants were randomly assigned to receive a light therapy device that produced either bright white light (BWL; intervention) or dim red light (DRL; active control). Participants were instructed to use the device daily for 30 min upon waking for 28 days. The primary outcome, fatigue, was assessed weekly. Secondary outcomes assessed pre- and post-intervention included mood, depressive symptoms, and quality of life. RESULTS: A total of 81 participants were randomly assigned to receive BWL (n = 42) or DRL (n = 39). Analyses revealed a group-by-time interaction for fatigue (p = .034), wherein the BWL condition reported a 17% greater reduction in fatigue than those in the DRL condition (between group d = .30). There were also significant improvements over time for both groups on measures of mood, depressive symptoms, and quality of life (p's < .01). CONCLUSIONS: BWL was associated with greater improvements in fatigue and both groups displayed improvements on secondary psychosocial outcomes. IMPLICATIONS FOR CANCER SURVIVORS: These findings, along with previous reports of light therapy for CRF, support the use of this intervention to improve fatigue in cancer survivors. PMID- 29127576 TI - Skipping of Chinese characters does not rely on word-based processing. AB - Previous eye-movement studies have indicated that people tend to skip extremely high-frequency words in sentence reading, such as "the" in English and "/de" in Chinese. Two alternative hypotheses have been proposed to explain how this frequent skipping happens in Chinese reading: one assumes that skipping happens when the preview has been fully identified at the word level (word-based skipping); the other assumes that skipping happens whenever the preview character is easy to identify regardless of whether lexical processing has been completed or not (character-based skipping). Using the gaze-contingent display change paradigm, we examined the two hypotheses by substituting the preview of the third character of a four-character Chinese word with the high-frequency Chinese character "/de", which should disrupt the ongoing word-level processing. The character-based skipping hypothesis predicts that this manipulation will enhance the skipping probability of the target character (i.e., the third character of the target word), because the character "/de" has much higher character frequency than the original character. The word-based skipping hypothesis instead predicts a reduction of the skipping probability of the target character because the presence of the character "/de" is lexically infelicitous at word level. The results supported the character-based skipping hypothesis, indicating that in Chinese reading the decision of skipping a character can be made before integrating it into a word. PMID- 29127577 TI - Predictors of Success in Bariatric Surgery: the Role of BMI and Pre-operative Comorbidities. AB - BACKGROUND: This is a retrospective review of 204 patients who underwent bariatric surgery. The impact of weight regain (WR), pre-operative comorbidities and BMI values on the recurrence of comorbidities was evaluated, and an equation was elaborated to estimate BMI at 5 years of bariatric surgery. METHODS: Pre operative data, after 1 year and after 5 years, was collected from the medical records. Descriptive analyses and bivariate hypothesis tests were performed first, and then, a generalised linear regression model with Tweedie distribution was adjusted. The hit rate and the Kendall coefficient of concordance (Kendall's W) of the equation were calculated. At the end, the Mann-Whitney test was performed between the BMI, WR and the presence of comorbidities, after a post operative period of 5 years. RESULTS: The adjustment of the model resulted in an equation that estimates the mean value of BMI 5 years after surgery. The hit rate was 82.35% and the value of Kendall's W was 0.85 for the equation. It was found that patients with comorbidities presented a higher median WR (10.13%) and a higher mean BMI (30.09 kg/m2) 5 years after the surgery. CONCLUSIONS: It is concluded that the equation is useful for estimating the mean BMI at 5 years of surgery and that patients with low pre-operative HDL and folic acid levels, with depression and/or anxiety and a higher BMI, have a higher BMI at 5 years of surgery and higher incidence of comorbid return and dissatisfaction with post operative results. PMID- 29127579 TI - Correction to: The Impact of Religiosity on Substance Abuse and Obesity in African Americans. AB - The original version of this article unfortunately contained a mistake in the author names. The co-author names should be David Meetze and Ronald Whicker Jr. instead of David Meetz and Ronald Wicker. The original article has been corrected. PMID- 29127578 TI - Comparative Outcomes of Bariatric Surgery in Patients With and Without Human Immunodeficiency Virus. AB - BACKGROUND: Paradoxically, advances in anti-retroviral therapy that has increased survival for patients with human immunodeficiency virus (HIV) have resulted in greater numbers of HIV+ patients developing other chronic diseases, including obesity. Little comparative literature exists detailing perioperative or metabolic outcomes of bariatric surgery in the HIV+ population compared to HIV negative (HIV-) controls. METHODS: This is a retrospective case-control study with both HIV+ (case) and HIV- control patients. Individuals undergoing sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) between January 1, 2006 and December 31, 2015 were included. HIV+ status was defined as any individual with documented history of HIV. RESULTS: Eleven HIV+ patients underwent RYGB or SG during the study period. After matching (1:5 HIV+: HIV-) both cohorts had similar mean age (42 years), gender distribution (63% female), and preoperative BMI (48 kg/m2), as well as comorbidities. There were no differences in postoperative length of stay, or all cause 30-day morbidity. There were 63.7% HIV+ and 76.4% with 1-year follow-up available. Both percent excess weight loss (56% HIV+ vs. 60% HIV-) and BMI (32 HIV+ vs. 34 kg/m2 HIV-) were similar in both groups. There were minimal changes to CD4 count or HIV viral load in the patients during the follow-up period. CONCLUSION: Bariatric surgery is safe and feasible in HIV infected population well controlled on anti-retroviral medication. The short-term surgical and metabolic outcomes are similar to HIV- controls with minimal effect on the CD4 count and viral load in HIV+ cohort for long-term follow-up. PMID- 29127580 TI - Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition but Protect Against Pathological Oxidative Stress. AB - The sigma1 receptor (sigma1R) is a chaperone protein residing at mitochondria associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca2+ exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IP3Rs). The sigma1R is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer's disease (AD) models in vitro and in vivo. sigma1R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of sigma1R ligands in mouse mitochondria preparations on reactive oxygen species (ROS) production, mitochondrial respiration, and complex activities, in physiological condition and after direct application of amyloid Abeta1-42 peptide. sigma1R agonists (2-(4 morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (PRE-084), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (ANAVEX1-41, AN1-41), (S) 1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one (ANAVEX3-71, AN3-71), dehydroepiandrosterone-3 sulfate (DHEA), donepezil) increased mitochondrial ROS in a sigma1R antagonist-sensitive manner but decreased Abeta1-42-induced increase in ROS. sigma1R ligands (agonists or antagonists) did not impact respiration but attenuated Abeta1-42-induced alteration. sigma1R agonists (PRE-084, AN1-41, tetrahydro-N,N-dimethyl-2,2 diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, AN2-73), AN3-71) increased complex I activity, in a Ca2+-dependent and sigma1R antagonist-sensitive manner. sigma1R ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the sigma1R-induced increase in ROS since ligands failed to affect other sources of ROS accumulation in mitochondria and homogenates, namely NADPH oxidase (NOX) and superoxide dismutase (SOD) activities. Furthermore, Abeta1-42 significantly decreased the activity of complexes I and IV and sigma1R agonists attenuated the Abeta1-42-induced complex I and IV dysfunctions. sigma1R activity in mitochondria therefore results in a Ying-Yang effect, by triggering moderate ROS increase acting as a physiological signal and promoting a marked anti-oxidant effect in pathological (Abeta) conditions. PMID- 29127582 TI - Lessons learned from participating in D3R 2016 Grand Challenge 2: compounds targeting the farnesoid X receptor. AB - D3R 2016 Grand Challenge 2 focused on predictions of binding modes and affinities for 102 compounds against the farnesoid X receptor (FXR). In this challenge, two distinct methods, a docking-based method and a template-based method, were employed by our team for the binding mode prediction. For the new template-based method, 3D ligand similarities were calculated for each query compound against the ligands in the co-crystal structures of FXR available in Protein Data Bank. The binding mode was predicted based on the co-crystal protein structure containing the ligand with the best ligand similarity score against the query compound. For the FXR dataset, the template-based method achieved a better performance than the docking-based method on the binding mode prediction. For the binding affinity prediction, an in-house knowledge-based scoring function ITScore2 and MM/PBSA approach were employed. Good performance was achieved for MM/PBSA, whereas the performance of ITScore2 was sensitive to ligand composition, e.g. the percentage of carbon atoms in the compounds. The sensitivity to ligand composition could be a clue for the further improvement of our knowledge-based scoring function. PMID- 29127581 TI - Lessons learned in induced fit docking and metadynamics in the Drug Design Data Resource Grand Challenge 2. AB - Two of the major ongoing challenges in computational drug discovery are predicting the binding pose and affinity of a compound to a protein. The Drug Design Data Resource Grand Challenge 2 was developed to address these problems and to drive development of new methods. The challenge provided the 2D structures of compounds for which the organizers help blinded data in the form of 35 X-ray crystal structures and 102 binding affinity measurements and challenged participants to predict the binding pose and affinity of the compounds. We tested a number of pose prediction methods as part of the challenge; we found that docking methods that incorporate protein flexibility (Induced Fit Docking) outperformed methods that treated the protein as rigid. We also found that using binding pose metadynamics, a molecular dynamics based method, to score docked poses provided the best predictions of our methods with an average RMSD of 2.01 A. We tested both structure-based (e.g. docking) and ligand-based methods (e.g. QSAR) in the affinity prediction portion of the competition. We found that our structure-based methods based on docking with Smina (Spearman rho = 0.614), performed slightly better than our ligand-based methods (rho = 0.543), and had equivalent performance with the other top methods in the competition. Despite the overall good performance of our methods in comparison to other participants in the challenge, there exists significant room for improvement especially in cases such as these where protein flexibility plays such a large role. PMID- 29127584 TI - 'If You Choose to Abort, You Have Acted As an Instrument of Satan': Zimbabwean Health Service Providers' Negative Constructions of Women Presenting for Post Abortion Care. AB - PURPOSE: Health service providers play a crucial role in providing post abortion care in countries where abortion legislation is restrictive and abortion is stigmatised. Research in countries where these factors apply has shown that health service providers can be barriers to women accessing post abortion services. Much of this research draws from attitude theory. In this paper, we utilise positioning theory to show how the ways in which Zimbabwean health service providers' position women and themselves are rooted in cultural and social power relations. In light of recent efforts by the Zimbabwean Ministry of Health and foreign organisations to improve post abortion care, we explore the implications that these positionings have for post abortion care. METHOD: As part of a larger study on abortion decision-making, the data featured in this article were collected using in-depth semi-structured interviews with six health service providers working in different facilities in Harare, Zimbabwe. Discursive and positioning thematic analysis was used to analyse the data. RESULTS: Our analysis points to women who have abortions being positioned in negative terms, as transgressors of acceptable norms; irresponsible and manipulative; and ignorant. The health service providers drew from cultural, religious, gender and trauma discourses that portray abortion as evil and socially unacceptable. Reflexive positions taken up by the health service providers include positions as being experts, helpers and protectors of culture/religion, sympathisers and professional positions as health care providers. CONCLUSION: The continued strengthening of post abortion services should be conducted in conjunction with dialogical interventions that challenge health service providers to reflect on the power relations within which women who terminate pregnancies are located, that contest their negative positionings of these women and that present alternative narratives and subject positionings for both the women who have abortions and the health service providers. PMID- 29127583 TI - Effective prediction of bacterial type IV secreted effectors by combined features of both C-termini and N-termini. AB - Various bacterial pathogens can deliver their secreted substrates also called as effectors through type IV secretion systems (T4SSs) into host cells and cause diseases. Since T4SS secreted effectors (T4SEs) play important roles in pathogen host interactions, identifying them is crucial to our understanding of the pathogenic mechanisms of T4SSs. A few computational methods using machine learning algorithms for T4SEs prediction have been developed by using features of C-terminal residues. However, recent studies have shown that targeting information can also be encoded in the N-terminal region of at least some T4SEs. In this study, we present an effective method for T4SEs prediction by novelly integrating both N-terminal and C-terminal sequence information. First, we collected a comprehensive dataset across multiple bacterial species of known T4SEs and non-T4SEs from literatures. Then, three types of distinctive features, namely amino acid composition, composition, transition and distribution and position-specific scoring matrices were calculated for 50 N-terminal and 100 C terminal residues. After that, we employed information gain represent to rank the importance score of the 150 different position residues for T4SE secretion signaling. At last, 125 distinctive position residues were singled out for the prediction model to classify T4SEs and non-T4SEs. The support vector machine model yields a high receiver operating curve of 0.916 in the fivefold cross validation and an accuracy of 85.29% for the independent test set. PMID- 29127585 TI - The regulation effect of AMPK in immune related diseases. AB - AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation. Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy. PMID- 29127587 TI - Copanlisib: First Global Approval. AB - Bayer are developing copanlisib (AliqopaTM)-a pan-class I phosphoinositide 3 kinase (PI3K) inhibitor-as a treatment for various haematological and solid malignancies. The US FDA has granted copanlisib accelerated approval for the treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies based on the results of a phase II trial. Phase III trials are underway evaluating copanlisib as treatment for relapsed/refractory diffuse large B-cell lymphoma and in combination with rituximab or rituximab based chemotherapy or standard immunochemotherapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma. Phase I/II studies are underway in relapsed or refractory peripheral T-cell or NK/T-cell lymphoma, advanced cholangiocarcinoma, hormone receptor-positive HER2-negative stage I-IV breast cancer, HER2-positive breast cancer and recurrent and/or metastatic head and neck squamous cell carcinomas harbouring a PI3KCA mutation/amplification and/or a PTEN loss. This article summarizes the milestones in the development of copanlisib leading to this first approval for relapsed follicular lymphoma. PMID- 29127589 TI - Correction to: Exercise following breast cancer: exploratory survival analyses of two randomised, controlled trials. AB - In the original publication of the article, under the heading Discussion, 1st paragraph, the sentence that reads as, "Nonetheless, our observed improvements of over 50% for OS and over 30% for DFS (HRs: 0.45 and 0.66, respectively) are consistent with results from other available studies" should read as "Nonetheless, our observed improvements of over 50% for OS and DFS (HRs: 0.45 and 0.66, respectively) are consistent with results from other available studies." Under the heading Discussion, 3rd paragraph, the sentence that reads as "We cannot discount the possibility ...such as education, income and access to care [1, 7]" should read as "We cannot discount the possibility...such as education, income and access to care, which ultimately have on survival outcomes [1, 7]." PMID- 29127588 TI - Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. AB - Intravenous daratumumab (DARZALEX(r)) is a first-in-class human IgG1kappa monoclonal antibody against CD38 available for use in patients with relapsed and/or refractory multiple myeloma. In phase I/II and II trials and a pooled analysis of these studies, daratumumab monotherapy induced an overall response (partial response or better) in approximately one-third of patients; responses were rapid, deep and durable. An overall survival (OS) benefit was seen with daratumumab monotherapy, including in patients with a minimal response or stable disease. In phase III trials, daratumumab in combination with either bortezomib plus dexamethasone or lenalidomide plus dexamethasone significantly prolonged progression-free survival and induced deep and durable responses compared with bortezomib plus dexamethasone or lenalidomide plus dexamethasone. An OS benefit with daratumumab triple combination therapy is yet to be demonstrated (as the OS data were not mature at the time of the last analysis). Daratumumab was generally well tolerated when used as monotherapy and had a generally manageable tolerability profile when used in combination therapy. Infusion-related reactions (IRRs) were the most common adverse events; these were predominantly grade 1 or 2 and mostly occurred during the first infusion. The most common grade 3-4 adverse events associated with daratumumab triple combination therapy were thrombocytopenia, neutropenia and anaemia. Although final OS data are awaited, current evidence indicates that daratumumab is a valuable addition to the treatment options currently available for patients with relapsed or refractory multiple myeloma. PMID- 29127590 TI - Body mass index, diet, and exercise: testing possible linkages to breast cancer risk via DNA methylation. AB - PURPOSE: To examine DNA methylation as a mechanism linking diet, physical activity, weight status, and breast cancer risk. METHODS: Insufficiently active women of varying weight status, without a history of cancer, completed a maximal exercise test, clinical measurement of height and weight, and a dietary intake measure. They also provided blood samples, which were analyzed to ascertain average methylation of candidate genes related to breast cancer (BRCA1, RUNX3, GALNT9, and PAX6) and inflammation (TLR4 and TLR6). RESULTS: Elevated weight status (r = - .18, p < .05) and poorer aerobic fitness (r = .24, p < .01) were each associated with decreased methylation of inflammation genes. Methylation of inflammation genes statistically mediated the relationship between weight status and cancer gene methylation (standardized indirect effect = .12, p < .05) as well as between cardiorespiratory fitness and cancer gene methylation (standardized indirect effect = - .172, p < .01). However, recent dietary behavior was not associated with methylation of either inflammation or cancer genes. CONCLUSIONS: Both weight status and cardiovascular fitness are associated with methylation of genes associated with both inflammation and cancer. Methylation of inflammatory genes might serve as a mechanistic link between lifestyle factors and methylation changes in genes that increase risk for breast cancer. PMID- 29127592 TI - Disease of mRNA Regulation: Relevance for Ischemic Brain Injury. AB - In this mini-review we give an overview of the role of mRNA-binding proteins and their associated messenger ribonucleoprotein complexes (mRNPs) in several disease states, and bring this information to bear on the pathophysiology of brain ischemia. One conclusion reached is that mRNPs may play a causal role in proteotoxicity instead of being merely passive targets. Ischemia therapies targeting mRNPs have advantages over targeting single pathways, but the behavior of mRNPs needs to be considered in the design of therapies. PMID- 29127593 TI - SEOM clinical guideline for treatment of cancer pain (2017). AB - Pain is a highly prevalent symptom in patients with cancer. Despite therapeutic advances and well-accepted treatment guidelines, a percentage of patients with pain are under-treated. Currently, it has been recognized that several barriers in pain management still exist and, in addition, there are new challenges surrounding complex subtypes of pain, such as breakthrough and neuropathic pain, requiring further reviews and recommendations. This is an update of the guide our society previously published and represents the continued commitment of SEOM to move forward and improve supportive care of cancer patients. PMID- 29127594 TI - Morphine: double-faced roles in the regulation of tumor development. AB - Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects. PMID- 29127595 TI - Neurological manifestations of congenital Zika virus infection. AB - INTRODUCTION: In 2015, it was observed a rise in the number of microcephalic newborns associated with a history of non-specific febrile sickness and rash during pregnancy in Brazil. Since then, microcephaly has emerged as a public health concern. A few months after, the causal relation between congenital microcephaly and the Zika virus was discovered. Zika virus, an arbovirus, is a new TORCH member that leads to congenital infection through vertical transmission and harms the developing brain, disrupting synaptogenesis, and causing other central nervous system lesions. OBJECTIVE: The purpose of this article is to report the congenital Zika syndrome (CZS) and to emphasize the need for follow-up of the affected children to better know the evolutionary history of this new agent and to optimize the provision of healthcare and improve the quality of life of these patients. METHODS: We review the most relevant literature about clinical manifestations and neuroimaging findings related to neurotropism of Zika virus to characterize the congenital Zika syndrome and suggest the systematization of some exams and procedures to evaluate children exposed to ZIKV with or without microcephaly, according to the author's own experience. CONCLUSIONS: Vertical ZIKV infection can cause a wide spectrum of neurological manifestations that go beyond microcephaly, and even the non-microcephalic child should be followed during the first years of life, because infection may be asymptomatic or lead to neuropsicomotor delay, epilepsy, and visual abnormalities. The appropriate prospective multidisciplinary follow-up of these patients aims to understand the natural history of this new agent and to provide a better development and quality of life for them and their families. PMID- 29127596 TI - International development of four EORTC disease-specific quality of life questionnaires for patients with Hodgkin lymphoma, high- and low-grade non Hodgkin lymphoma and chronic lymphocytic leukaemia. AB - PURPOSE: This paper describes the international, cross-cultural development of four disease-specific EORTC QoL questionnaires, to supplement the EORTC QLQ-C30, for patients with Hodgkin lymphoma (HL), high- or low-grade non-Hodgkin lymphoma (HG/LG-NHL), and CLL. METHODS: Questionnaire development was conducted according to guidelines from the EORTC Quality of Life Group. Phase I comprised generation of QoL issues relevant to patients. Phase II included operationalization and assessment of item relevance. In phase III, items were pretested in a cross cultural sample. RESULTS: In Phase I, 75 issues were identified through focus groups and systematic literature searches. Interviews with 80 health-care professionals and 245 patients resulted in a provisional module of 38 items (phase II) representing items relevant for all or at least one of the four malignancies. In Phase III, this was tested in 337 patients from five European countries and resulted in a questionnaire with 27 items for HL (EORTC QLQ-HL27), 29 items for HG-NHL (EORTC QLQ-NHL-HG29), 20 items for LG-NHL (EORTC QLQ-NHL LG20) and 17 items for CLL (EORTC QLQ-CLL17). CONCLUSIONS: This study provides four new EORTC modules for use in clinical research and routine practice in conjunction with the EORTC QLQ-C30 for assessing QoL in patients with lymphoma and CLL. PMID- 29127597 TI - Development of a practical outcome measure to account for individual differences in quality-of-life appraisal: the Brief Appraisal Inventory. AB - BACKGROUND: The present study evaluated the distributional and structural characteristics and explanatory power of the 23-item Brief Appraisal Inventory (BAI), a more practical appraisal measure for use in clinical research and practice. METHODS: A heterogeneous, online cohort of chronic disease patients and caregivers completed the BAI, along with demographics, comorbidities, PROMIS-10, and the Brief NEO Personality Inventory. Principal components, bivariate, and linear and logistic regression analyses addressed BAI item distributions, structure, and construct validity. RESULTS: The study sample (n = 592) had a mean age of 43.8 (SD = 18.5), and was 79% female. The BAI items exhibited good distributions, and principal component analysis yielded five composite scores: (1) Health Worries; (2) Interpersonal and Independence concerns; (3) Accomplishing Goals and Problem-Solving; (4) Calm, Peaceful, and Active; (5) Spiritual Growth and Altruism. The construct validity of appraisal factors is supported by their zero-order correlations with demographic, health, personality, and health-related QOL measures. Comparisons of appraisal-correlates among comorbidity-burden subgroups shed light on the mediating role that appraisal may play in adapting to chronic illness. Appraisal moderated the influence of comorbidities on emotional but not physical functioning. The performance of the BAI in explaining unique variance in physical and emotional functioning is comparable to results obtained with earlier measures. CONCLUSIONS: The BAI provides a practical, short tool for evaluating appraisal in a wide range of assessment situations. Future research might utilize the BAI in longitudinal research aimed at detecting response-shift effects over time, and in clinical settings to improve patient-provider communication about concerns related to health, health care, or QOL. PMID- 29127599 TI - CB1 Receptors Mediated Inhibition of ATP-Induced [Ca2+]i Increase in Cultured Rat Spinal Dorsal Horn Neurons. AB - Spinal cannabinoid receptor 1 (CB1R) and purinergic P2X receptors (P2XR) play a critical role in the process of pathological pain. Both CB1R and P2XR are expressed in spinal dorsal horn (DH) neurons. It is not clear whether CB1 receptor activation modulates the function of P2X receptor channels within dorsal horn. For this reason, we observed the effect of CP55940 (cannabinoid receptor agonist) on ATP-induced Ca2+ mobilization in cultured rat DH neurons. The changes of intracellular calcium concentration ([Ca2+]i) were detected with confocal laser scanning microscopy using fluo-4/AM as a calcium fluorescent indicator. 100 MUM ATP caused [Ca2+]i increase in cultured DH neurons. ATP-evoked [Ca2+]i increase in DH neurons was blocked by chelating extracellular Ca2+ and P2 purinoceptor antagonist PPADS. At the same time, ATP-gamma-S (a non-hydrolyzable ATP analogue) mimicked the ATP action, while P2Y receptor agonist ADP failed to evoke [Ca2+]i increase in cultured DH neurons. These data suggest that ATP induced [Ca2+]i elevation in cultured DH neurons is mediated by P2X receptor. Subsequently, we noticed that, in cultured rat DH neurons, ATP-induced Ca2+ mobilization was inhibited after pretreated with CP55940 with a concentration dependent manner, which implies that the opening of P2X receptor channels are down-regulated by activation of cannabinoid receptor. The inhibitory effect of CP55940 on ATP-induced Ca2+ response was mimicked by ACEA (CB1R agonist), but was not influenced by AM1241 (CB2R agonist). Moreover, the inhibitory effect of CP55940 on ATP-induced Ca2+ mobilization was blocked by AM251 (CB1 receptor antagonist), but was not influenced by AM630 (CB2 receptor antagonist). In addition, we also observed that forskolin (an activator of adenylate cyclase) and 8-Br-cAMP (a cell-permeable cAMP analog) reversed the inhibitory effect of CP55940, respectively. In a summary, our observations raise a possibility that CB1R rather than CB2R can downregulate the opening of P2X receptor channels in DH neurons. The reduction of cAMP/PKA signaling is a key element in the inhibitory effect of CB1R on P2X-channel-induced Ca2+ mobilization. PMID- 29127598 TI - GABA Uptake Inhibition Reduces In Vivo Extraction Fraction in the Ventral Tegmental Area of Long Evans Rats Measured by Quantitative Microdialysis Under Transient Conditions. AB - Inhibitory signaling in the ventral tegmental area (VTA) is involved in the mechanism of action for many drugs of abuse. Although drugs of abuse have been shown to alter extracellular gamma-aminobutyric acid (GABA) concentration in the VTA, knowledge on how uptake mechanisms are regulated in vivo is limited. Quantitative (no-net-flux) microdialysis is commonly used to examine the extracellular concentration and clearance of monoamine neurotransmitters, however it is unclear whether this method is sensitive to changes in clearance for amino acid neurotransmitters such as GABA. The purpose of this study was to determine whether changes in GABA uptake are reflected by in vivo extraction fraction within the VTA. Using quantitative (no-net-flux) microdialysis adapted for transient conditions, we examined the effects of local perfusion with the GABA uptake inhibitor, nipecotic acid, in the VTA of Long Evans rats. Basal extracellular GABA concentration and in vivo extraction fraction were 44.4 +/- 1.9 nM (x-intercepts from 4 baseline regressions using a total of 24 rats) and 0.19 +/- 0.01 (slopes from 4 baseline regressions using a total of 24 rats), respectively. Nipecotic acid (50 MUM) significantly increased extracellular GABA concentration to 170 +/- 4 nM and reduced in vivo extraction fraction to 0.112 +/ 0.003. Extraction fraction returned to baseline following removal of nipecotic acid from the perfusate. Conventional microdialysis substantially underestimated the increase of extracellular GABA concentration due to nipecotic acid perfusion compared with that obtained from the quantitative analysis. Together, these results show that inhibiting GABA uptake mechanisms within the VTA alters in vivo extraction fraction measured using microdialysis and that in vivo extraction fraction may be an indirect measure of GABA clearance. PMID- 29127600 TI - A Review of Current and Emerging Approaches to Pain Management in the Emergency Department. AB - INTRODUCTION: Pain is the most common symptom prompting an emergency department visit and emergency physicians are responsible for managing both acute pain and acute exacerbations of chronic pain resulting from a broad range of illnesses and injuries. The responsibility to treat must be balanced by the duty to limit harm resulting from analgesics. In recent years, opioid-related adverse effects, including overdose and deaths, have increased dramatically in the USA. In response to the US opioid crisis, emergency physicians have broadened their analgesic armamentarium to include a variety of non-opioid approaches. For some of these therapies, sparse evidence exists to support their efficacy for emergency department use. The purpose of this paper is to review historical trends and emerging approaches to emergency department analgesia, with a particular focus on the USA and Canada. METHODS: We conducted a qualitative review of past and current descriptive studies of emergency department pain practice, as well as clinical trials of emerging pain treatment modalities. The review considers the increasing use of non-opioid and multimodal analgesic therapies, including migraine therapies, regional anesthesia, subdissociative dose ketamine, nitrous oxide, intravenous lidocaine and gabapentinoids, as well as broad programmatic initiatives promoting the use of non-opioid analgesics and nonpharmacologic interventions. RESULTS: While migraine therapies, regional anesthesia, nitrous oxide and subdissociative-dose ketamine are supported by a relatively robust evidence base, data supporting the emergency department use of intravenous lidocaine, gabapentinoids and various non-pharmacologic analgesic interventions remain sparse. CONCLUSION: Additional research on the relative safety and efficacy of non-opioid approaches to emergency department analgesia is needed. Despite a limited research base, it is likely that non-opioid analgesic modalities will be employed with increasing frequency. A new generation of emergency physicians is seeking additional training in pain medicine and increasing dialogue between emergency medicine and pain medicine researchers, educators and clinicians could contribute to better management of emergency department pain. PMID- 29127601 TI - Interpreting Adaptation to Concurrent Compared with Single-Mode Exercise Training: Some Methodological Considerations. AB - Incorporating both endurance and resistance training into an exercise regime is termed concurrent training. While there is evidence that concurrent training can attenuate resistance training-induced improvements in maximal strength and muscle hypertrophy, research findings are often equivocal, with some suggesting short term concurrent training may instead further enhance muscle hypertrophy versus resistance training alone. These observations have questioned the validity of the purported 'interference effect' on muscle hypertrophy with concurrent versus single-mode resistance training. This article aims to highlight some methodological considerations when interpreting the concurrent training literature, and, in particular, the degree of changes in strength and muscle hypertrophy observed with concurrent versus single-mode resistance training. Individual training status clearly influences the relative magnitude and specificity of both training adaptation and post-exercise molecular responses in skeletal muscle. The training status of participants is therefore likely a key modulator of the degree of adaptation and interference seen with concurrent training interventions. The divergent magnitudes of strength gain versus muscle hypertrophy induced by resistance training also suggests most concurrent training studies are likely to observe more substantial changes in (and in turn, any potential interference to) strength compared with muscle hypertrophy. Both the specificity and sensitivity of measures used to assess training-induced changes in strength and muscle hypertrophy also likely influence the interpretation of concurrent training outcomes. Finally, the relative importance of any modulation of hypertrophic versus strength adaptation with concurrent training should be considered in context with the relevance of training-induced changes in these variables for enhancing athletic performance and/or functional capacity. Taken together, these observations suggest that aside from various training-related factors, additional non-training-related variables, including participant training status and the measures used to assess changes in strength and muscle hypertrophy, are important considerations when interpreting the outcomes of concurrent training interventions. PMID- 29127603 TI - Attempting a Laparoscopic Approach in Patients Undergoing Left-Sided Colorectal Surgery Who Have Had a Previous Laparotomy: Is it Feasible? AB - BACKGROUND: The feasibility of a laparoscopic approach in patients who have had a prior laparotomy (PL) remains controversial. We hypothesized that laparoscopic colorectal resection was safe and feasible in patients with previous open abdominal surgery. METHODS: A retrospective review (2007-2015) of all patients undergoing laparoscopic resection for sigmoid and rectal adenocarcinoma with or without prior midline laparotomy (NPL) was performed. Primary endpoints included conversion and perioperative morbidity. Secondary endpoints included length of stay and perioperative outcomes. Demographics, surgical history, oncologic staging, and short-term outcomes were reviewed. RESULTS: We identified 211 patients, of whom 33 (15.6%) had a prior laparotomy. Significantly more patients in the PL group were female (76.2 vs. 52.8%, p = 0.004). Patients with PL were of similar age to NPL patients (69.3 vs. 62.5, p = 0.09), and comorbidities, tumor staging, and neoadjuvant therapy were comparable between groups (all p > 0.05). Additional trocar placement was significantly higher in PL group (33.3 vs. 17.4%, p = 0.03), while conversion rate did not reach statistical significance (24.2 vs. 12.9%, p = 0.08). The postoperative complication rate was comparable between PL and NPL patients (33.3 vs. 25.3%, respectively, p = 0.2). CONCLUSIONS: Prior laparotomy should not be a contraindication to patients undergoing laparoscopic colorectal surgery, though surgeons should anticipate a higher likelihood of conversion to open. PMID- 29127602 TI - Effect of High-Intensity Interval Training on Total, Abdominal and Visceral Fat Mass: A Meta-Analysis. AB - BACKGROUND: High-intensity interval training (HIIT) is promoted as a time efficient strategy to improve body composition. OBJECTIVE: The aim of this meta analysis was to assess the efficacy of HIIT in reducing total, abdominal, and visceral fat mass in normal-weight and overweight/obese adults. METHODS: Electronic databases were searched to identify all related articles on HIIT and fat mass. Stratified analysis was performed using the nature of HIIT (cycling versus running, target intensity), sex and/or body weight, and the methods of measuring body composition. Heterogeneity was also determined RESULTS: A total of 39 studies involving 617 subjects were included (mean age 38.8 years +/- 14.4, 52% females). HIIT significantly reduced total (p = 0.003), abdominal (p = 0.007), and visceral (p = 0.018) fat mass, with no differences between the sexes. A comparison showed that running was more effective than cycling in reducing total and visceral fat mass. High-intensity (above 90% peak heart rate) training was more successful in reducing whole body adiposity, while lower intensities had a greater effect on changes in abdominal and visceral fat mass. Our analysis also indicated that only computed tomography scan or magnetic resonance imaging showed significant abdominal and/or visceral fat-mass loss after HIIT interventions. CONCLUSION: HIIT is a time-efficient strategy to decrease fat-mass deposits, including those of abdominal and visceral fat mass. There was some evidence of the greater effectiveness of HIIT running versus cycling, but owing to the wide variety of protocols used and the lack of full details about cycling training, further comparisons need to be made. Large, multicenter, prospective studies are required to establish the best HIIT protocols for reducing fat mass according to subject characteristics. PMID- 29127604 TI - Association of Adjuvant Therapy with Improved Survival in Ampullary Cancer: A National Cohort Study. AB - BACKGROUND: There are limited data on the efficacy of adjuvant therapy in ampullary cancer. The aim of this study was to determine whether adjuvant therapy was associated with improved survival for patients with ampullary cancer. METHODS: From the National Cancer Database, we identified ampullary cancer patients who underwent resection between 2004 and 2013. We performed 1:1 propensity score matching, comparing patients who had postoperative observation to patients who received adjuvant chemotherapy (ACT) or adjuvant chemoradiotherapy (ACRT). RESULTS: We identified 4190 patients who fit our inclusion criteria; 63% had postoperative observation, 21% received ACT, and 16% underwent ACRT. In the matched cohorts, the use of ACT was associated with improved overall survival (HR = 0.82, 95% CI = 0.71 to 0.95). The median overall survival was 47.2 months for the ACT group and 35.5 months for the observation group. In a separate matched analysis, ACRT was also associated with improved survival (HR = 0.84, 95% CI = 0.72 to 0.98) as compared to observation. The median overall survival was 38.1 months for the ACRT group and 31.0 months for the observation group. The benefit was more pronounced in high-risk patients, such as ones with higher T and N categories. CONCLUSIONS: In this retrospective study, the use of adjuvant therapy in ampullary cancer was associated with significantly improved overall survival. The benefit of adjuvant therapy for this disease should be confirmed in a more rigorous fashion via randomized controlled trials. PMID- 29127605 TI - Er:YAG laser, piezosurgery, and surgical drill for bone decortication during orthodontic mini-implant insertion: primary stability analysis-an animal study. AB - It is important to identify factors that affect primary stability of orthodontic mini-implants because it determines the success of treatment. We assessed mini implant primary stability (initial mechanical engagement with the bone) placed in pig jaws. We also assessed mini-implant insertion failure rate (mini-implant fracture, mini-implants to root contact). A total of 80 taper-shaped mini implants (Absoanchor(r) Model SH1312-6; Dentos Inc., Daegu, Korea) 6 mm long with a diameter of 1.1 mm were used. Bone decortication was made before mini-implant insertion by means of three different methods: Group G1: Er:YAG laser (LiteTouch(r), Light Instruments, Yokneam, Israel) at energy of 300 mJ, frequency 25 Hz, fluence 38.2 J/cm2, cooling 14 ml/min, tip 1.0 * 17 mm, distance 1 mm, time of irradiation 6 s; Group G2: drill (Hager & Meisinger GmbH, Hansemannstr, Germany); Group G3: piezosurgery (Piezotom Solo, Acteon, NJ, USA). In G4 group (control), mini-implants were driven by a self-drilling method. The primary stability of mini-implants was assessed by measuring damping characteristics between the implant and the tapping head of Periotest device (Gulden Medizinteknik, Eschenweg, Modautal, Germany). The results in range between - 8 to + 9 allowed immediate loading. Significantly lower Periotest value was found in the control group (mean 0.59 +/- 1.57, 95% CI 0.7, 2.4) as compared with Er:YAG laser (mean 4.44 +/- 1.64, 95% CI 3.6, 5.3), piezosurgery (mean 17.92 +/- 2.73, 95% CI 16.5, 19.3), and a drill (mean 5.91 +/- 1.52, 95% CI 5.2, 6.6) (p < 0.05). The highest failure rate (33.3%) during mini-implant insertion was noted for self drilling method (G4) as compared with G1, G2, and G3 groups (p < 0.05). The small diameter decortication by Er:YAG laser appeared to provide better primary stability as compared to drill and piezosurgery. Decortication of the cortical bone before mini-implant insertion resulted in reduced risk of implant fracture or injury of adjacent teeth. The high initial stability with a smaller diameter of the mini-implant resulted in increased risk of fracture, especially for a self drilling method. PMID- 29127607 TI - Lax Prophylaxis: Vaccinating the Inflammatory Bowel Disease Patient. PMID- 29127606 TI - Wls Expression Correlates with Tumor Differentiation and TNM Stage in Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. Effective biomarkers are necessary to predict the clinical course and outcome of patients with HCC. Wntless (Wls) is a key modulator of Wnt protein secretion and is overexpressed in various human cancers. However, the mechanism and alteration of Wls expression in HCC have not been clarified. AIMS: The aim of this study was to evaluate expression level of Wls in HCC and its clinical significance. METHODS: The levels of Wls expression were investigated in 84 HCC tissues using immunohistochemistry. RESULTS: Wls was negatively expressed in normal liver tissue and was negatively or weakly (score 0) expressed in liver cirrhosis. Twenty-eight out of 84 samples (33.3%) were negative or weakly (score 0) expressed Wls, 38 out of 84 (45.2%) moderately (1+) expressed Wls, and 18 out of 84 (21.4%) strongly (2+) expressed Wls. Wls expression was positively associated with tumor size (P = 0.005, r = 0.302), tumor TNM stage (P = 0.017, r = 0.261), AFP (P = 0.051), and HBV infection (P = 0.009, r = 0.283), and was negatively associated with differentiation (P < 0.001, r = - 0.552). No significant relationship between Wls expression and liver cirrhosis, ALT, GGT, age, sex, or tumor focality was found. CONCLUSIONS: Our data showed that Wls was differentially expressed in HCC. Statistical analysis results suggest that Wls expression might increase as HCC progresses. PMID- 29127608 TI - Cut and Paste: Endoscopic Management of a Perforating Biliary Stent Utilizing Scissors and Clips. PMID- 29127610 TI - PVP VA64 as a novel release-modifier for sustained-release mini-matrices prepared via hot melt extrusion. AB - The purpose of this study was to explore poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) as a novel release-modifier to tailor the drug release from ethylcellulose (EC)-based mini-matrices prepared via hot melt extrusion (HME). Quetiapine fumarate (QF) was selected as model drug. QF/EC/PVP VA64 mini-matrices were extruded with 30% drug loading. The physical state of QF in extruded mini matrices was characterized using differential scanning calorimetry, X-ray powder diffraction, and confocal Raman microscopy. The release-controlled ability of PVP VA64 was investigated and compared with that of xanthan gum, crospovidone, and low-substituted hydroxypropylcellulose. The influences of PVP VA64 content and processing temperature on QF release behavior and mechanism were also studied. The results indicated QF dispersed as the crystalline state in all mini-matrices. The release of QF from EC was very slow as only 4% QF was released in 24 h. PVP VA64 exhibited the best ability to enhance the drug release as compared with other three release-modifiers. The drug release increased to 50-100% in 24 h with the addition of 20-40% PVP VA64. Increasing processing temperature slightly slowed down the drug release by decreasing free volume and pore size. The release kinetics showed good fit with the Ritger-Peppas model. The values of release exponent (n) increased as PVP VA64 is added (0.14 for pure EC, 0.41 for 20% PVP VA64, and 0.61 for 40% PVP VA64), revealing that the addition of PVP VA64 enhanced the erosion mechanism. This work presented a new polymer blend system of EC with PVP VA64 for sustained-release prepared via HME. PMID- 29127609 TI - Gender-Based Differences in a Population-Based Cohort with Celiac Disease: More Alike than Unalike. AB - BACKGROUND: There is a gap in research focused on gender-based differences in non referral populations with celiac disease. AIMS: The aim of this study was to estimate those differences in a unique population-based cohort of patients with celiac disease with respect to (1) presenting symptoms, (2) associated autoimmune disorders, and (3) survival. METHODS: Clinical data were systematically abstracted from the electronic medical record of a population-based incident cohort of patients with celiac disease. Logistic regression was used to assess the strength of the association of presenting symptoms and gender. Survival differences between genders were evaluated with Cox regression. RESULTS: We included 282 patients (females 65%, median age 39 years) diagnosed between 1990 and 2015. The female to male ratio was 1.85:1. Men and women presented similarly. Women were more likely to present with constipation (OR 2.33; 95% CI 1.06-5.12; p = 0.035). Anemia and abdominal distention or bloating were more frequently seen in women, but not on a statistically significant level. Overall autoimmune diseases were equally prevalent (31.6%) in males (30.2%) and females (32.2%) (p = 0.74). Hypothyroidism predominated in women. Age-adjusted survival was lower among men than women (HR 3.00; 95% CI 1.26-7.21, p = 0.014), but not more so than in the general population. Cancer was the most common cause of death, and there were two possible celiac disease-related deaths. CONCLUSIONS: This study showed that men and women are more alike than unalike when it comes to celiac disease presentation and prevalence of concurrent autoimmune disease. PMID- 29127612 TI - Corporal Punishment in Children and its Implications on Mental Health. PMID- 29127611 TI - Tacrolimus as an adjunct to autologous minced muscle grafts for the repair of a volumetric muscle loss injury. AB - BACKGROUND: Volumetric muscle loss (VML) following extremity orthopaedic trauma or surgery results in chronic functional deficits and disability. A current translational approach to address the devastating functional limitations due to VML injury is the use of an autologous minced muscle graft (~1 mm3 pieces of muscle tissue) replacement into the injured defect area, although limitations related to donor site morbidity are still unaddressed. This study was designed to explore adjunct pharmacological immunomodulation to enhance graft efficacy and promote muscle function following VML injury, and thereby reduce the amount of donor tissue required. FINDINGS: Using a validated VML porcine injury model in which 20% of the muscle volume was surgically removed, this study examined muscle function over 3 months post-VML injury. In vivo isometric torque of the peroneus teritus (PT) muscle was not different before surgery among sham, non-repaired, non-repaired with tacrolimus, graft-repaired, and graft-repaired with tacrolimus VML groups. Bi-weekly torque analysis of the VML injured musculature presented a significant strength deficit of ~26% compared to pre-injury in the non-repaired, non-repaired with tacrolimus, and graft-repaired groups. Comparatively, the strength deficit in the graft-repair with systemic tacrolimus was marginally improved (~19%; p = 0.056). Both of the minced graft repaired groups presented a greater proportion of muscle tissue in full-thickness histology specimen. CONCLUSIONS: We demonstrate that adjunctive use of tacrolimus with an ~50% minced muscle graft replacement resulted in modest improvements in muscle function 3 months after injury and repair, but the magnitude of improvement is not expected to elicit clinically meaningful functional improvements. PMID- 29127613 TI - Nosocomial Cytomegalovirus Infection Resulting in Worsening of Retinopathy of Prematurity. PMID- 29127614 TI - Dental Caries: A Disease Which Needs Attention - Correspondence. PMID- 29127615 TI - Fungal and Parasitic CNS Infections. AB - Central nervous system fungal infections can be broadly divided into those that infect a healthy host such as Cryptococcus, Coccidioides, Histoplasma, Blastomyces, Sporothrix spp., and those that cause opportunistic infections in an immunocompromised host such as Candida, Aspergillus, Zygomycetes, Trichosporon spp. The clinical manifestations of central nervous system fungal infections commonly seen in children in clinical practice include a chronic meningitis or meningoencephalitis syndrome, brain abscess, rhino-cerebral syndrome and rarely, a fungal ventriculitis. Fungal central nervous system infections should be suspected in any child with subacute to chronic febrile encephalopathy or meningitis with or without raised intracranial pressure, seizures, orbital pain and/or sero-sanguinous nasal discharge. Diagnosis is corroborated by cerebrospinal fluid analysis, culture and PCR, special stains, serological tests and neuroimaging. Management of fungal central nervous system infections include specific antifungal therapy and supportive measures for associated problems, management of underlying predisposing condition and surgical intervention in cases with localized disease, abscess or presence of simultaneous foreign body such as intracranial shunts. In addition to the fungi, several parasitic infections can cause central nervous system infections in children. Of these, authors briefly discuss cerebral malaria, and amebic meningo-encephalitis. PMID- 29127616 TI - Worm Infestation: Diagnosis, Treatment and Prevention. AB - Worm infections continue to be among the most common diseases affecting children from low and middle income countries. Major worm infections of public health importance include Ascariasis, Trichuriasis, Hookworm, and Enterobiasis, which are transmitted through contaminated soil. In India, combined prevalence rates of worm infestation as per pooled data of 127 surveys is over 20%. Although most helminthic infections are mild and are often asymptomatic, but moderate to heavy worm infestations are generally associated with growth faltering, nutritional compromise, anemia and suboptimal academic performance among children from endemic regions. Migration of larval or adult worms also underpins pulmonary and gastrointestinal morbidity in affected children. Some of the distinctive life cycle and clinical features of various worms are discussed in the review. The gold standard diagnostic technique for evaluation of worm infestation includes stool microscopy for direct egg detection and species identification. Most of the community based surveys for detecting soil transmitted helminths (STH) use Kato Katz technique. The drug armamentarium against worm infestation has evolved tremendously in last three to four decades with the availability of more efficacious and broad spectrum anthelminthics. The key strategies of a multi component integrated management of worm infestation include individualized treatment, community management (mass drug administration) as well as preventive measures. Finally, barriers to diagnosis, treatment and prevention of worm infestations need to be identified and aggressively managed at individual, family and societal levels so that WHO's 75% coverage target can be achieved to eliminate soil transmitted helminthiasis in children by 2020. PMID- 29127617 TI - Effects of Growth Hormone Treatment on Lipid Profiles. AB - OBJECTIVES: To assess the effects of growth hormone (GH) on lipid profiles in children and whether the effect is pharmacological. METHODS: The authors determined serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and low-density lipoprotein cholesterol (LDL-C) every year during 3-y GH treatment in 48 GH deficient (GHD) short children and 22 children with short stature born small for gestational age (SGA). RESULTS: The abnormally high levels of TC, non HDL-C, and LDL-C showed a high frequency in GHD short children compared with epidemiological studies in Japan. The high prevalence of high level of TC was also shown in SGA short children. Three-year GH treatment decreased serum TC, non HDL-C, and LDL-C levels in both patient groups. CONCLUSIONS: GH treatment is clearly a pharmacological therapy in SGA short children and so may also be in GHD short children at the Japanese standard therapeutic dose. Taken together, GH improves lipid profiles, and its effect has the possibility of medical properties. PMID- 29127618 TI - Asthma, GERD and Obesity: Triangle of Inflammation. AB - There is increasing prevalence of both asthma and obesity in children globally in recent years. Various epidemiological studies link obesity as a risk factor for asthma and suggest a possible causal association. Obesity asthma phenotype is considered as distinct in view of greater severity and poor asthma control. Various mechanisms underlying this phenotype have been suggested including mechanical effects of obesity and systemic inflammation, but still the exact mechanism is unclear. Also, the comorbidities like gastroesophageal reflux disease (GERD) and sleep disordered breathing (SDB) lead to inflammation in airways and contribute to asthma obesity association. A better understanding of mechanisms by which obesity and GERD lead to inflammation in airways and increase the risk of asthma may provide insight towards targeted treatment approach of these patients. PMID- 29127619 TI - Changes in the lung bacteriome in relation to antipseudomonal therapy in children with cystic fibrosis. AB - The lung in cystic fibrosis (CF) is home to numerous pathogens that shorten the lives of patients. The aim of the present study was to assess changes in the lung bacteriome following antibiotic therapy targeting Pseudomonas aeruginosa in children with CF. The study included nine children (9-18 years) with CF who were treated for their chronic or intermittent positivity for Pseudomonas aeruginosa. The bacteriomes were determined in 16 pairs of sputa collected at the beginning and at the end of a course of intravenous antibiotic therapy via deep sequencing of the variable region 4 of the 16S rRNA gene, and the total bacterial load and selected specific pathogens were assessed using quantitative real-time PCR. The effect of antipseudomonal antibiotics was observable as a profound decrease in the total 16S rDNA load (p = 0.001) as well as in a broad range of individual taxa including Staphylococcus aureus (p = 0.03) and several members of the Streptococcus mitis group (S. oralis, S. mitis, and S. infantis) (p = 0.003). Improvements in forced expiratory volume (FEV1) were associated with an increase in Granulicatella sp. (p = 0.004), whereas a negative association was noted between the total bacterial load and white blood cell count (p = 0.007). In conclusion, the data show how microbial communities differ in reaction to antipseudomonal treatment, suggesting that certain rare species may be associated with clinical parameters. Our work also demonstrates the utility of absolute quantification of bacterial load in addition to the 16S rDNA profiling. PMID- 29127621 TI - How Well is the Medical Home Working for Latino and Black Children? AB - Objective To examine the benefits of having a medical home among Latino and Black school-aged children, both with and without special health care needs (CSHCN). Methods Data from the 2011-2012 National Survey of Children's Health (NSCH) were analyzed to examine the associations of preventive dental and medical care, unmet dental or medical care, or missed school days with having a medical home among Latino and Black children compared to White children. Multivariate logistic regression with survey weights was used to adjust for child, parent, home, and geographic characteristics and an interaction term to estimate differences in outcomes among Black or Latino children receiving care in a medical home compared to White children with a medical home. Results Approximately 35% of Latino CSHCN and Latino non-CSHCN ages 6-17 years of age had a medical home. In the adjusted model comparing the effectiveness of the medical home by race and ethnicity, Latino non-CSHCN compared to White non-CSHCN were associated with lower odds of having one or more preventive dental visit in the last 12 months (OR 0.66; 95% CI 0.46-0.95) and no other associations between having a medical home and outcomes were found among Latinos compared to Whites regardless of non-CSHCN or CHSCN status. Meanwhile, having a medical home among Black non-CHSCN and CHSCN, compared to their White counterparts, showed potential benefits in regards to unmet medical care needs after adjusting for covariates, (OR 0.15; 95% CI 0.06 0.35; OR 0.16; 95% CI 0.05-0.55). Conclusions Medical homes may not be effective in delivering health services to the majority of Latino children but provide some benefit to Black children with and without CSHCN. Alternatively, the medical home may function differently for Latinos due to the specific medical home components measured by NSCH. PMID- 29127620 TI - Potential of the strain Raoultella sp. KDF8 for removal of analgesics. AB - The bacterial strain KDF8 capable of growth in the presence of diclofenac and codeine analgesics was obtained after chemical mutagenesis of nature isolates from polluted soils. The strain KDF8 was identified as Raoultella sp. based on its morphology, biochemical properties, and 16S rRNA gene sequence. It was deposited in the Czech Collection of Microorganisms under the number CCM 8678. A growing culture efficiently removed diclofenac (92% removal) and partially also codeine (about 30% degradation) from culture supernatants within 72 h at 28 degrees C. The degradation of six analgesics by the whole cell catalyst was investigated in detail. The maximum degradation of diclofenac (91%) by the catalyst was achieved at pHINI of 7 (1 g/L diclofenac). The specific removal rate at high concentrations of diclofenac and codeine increased up to 16.5 mg/gCDW per h and 5.1 mg/gCDW per h, respectively. HPLC analysis identified 4' hydroxydiclofenac as a major metabolite of diclofenac transformation and 14 hydroxycodeinone as codeine transformation product. The analgesics ibuprofen and ketoprofen were also removed, albeit to a lower extent of 3.2 and 2.0 mg/gCDW per h, respectively. Naproxen and mefenamic acid were not degraded. PMID- 29127622 TI - The Joint Effects of Antenatal Steroids and Gestational Age on Improved Outcomes in Neonates. AB - OBJECTIVES: Antenatal corticosteroids are standard of care for women at risk of a preterm birth and demonstrated to be protective against poor outcomes in neonates including respiratory disorders, mortality and intraventricular hemorrhage (IVH). Its benefits may vary by gestational age, and accurate estimation is needed in a single-center population to account for practice variation. METHODS: A retrospective cohort of infants admitted to the hospital's neonatal intensive care unit, 1997-2015. Using Poisson regression, we separately modeled the incidence rate ratio of death, grade III or IV intraventricular hemorrhage (IVH), and moderate to severe bronchopulmonary dysplasia (BPD) testing the moderating effects of gestation on antenatal steroids, controlling for potential confounding. RESULTS: Among 5314 infants admitted, death occurred in 298 (6%), severe IVH in 244 (5%), and BPD in 527 (10%). Antenatal steroids were protective of death and BPD in the adjusted analysis, and there was multiplicative interaction where each week increase in gestational age combined with steroid therapy resulted in 13% reduced incidence for each outcome. CONCLUSIONS FOR PRACTICE: Antenatal steroids are protective against severe IVH and moderate to severe BPD, and when combined with gestational age, steroids are associated with greater protective benefits in older neonates. There is likely an ideal window to maximize the benefits of antenatal steroids, and future etiologic research should consider the joint effects with gestational age. PMID- 29127623 TI - Differences in bacterial composition between men's and women's restrooms and other common areas within a public building. AB - Humans distribute a wide range of microorganisms around building interiors, and some of these are potentially pathogenic. Recent research established that humans are the main drivers of the indoor microbiome and up to now significant literature has been produced about this topic. Here we analyzed differences in bacterial composition between men's and women's restrooms and other common areas within the same public building. Bacterial DNA samples were collected from restrooms and halls of a three-floor building from the Federal University of Pampa, RS, Brazil. The bacterial community was characterized by amplification of the V4 region of the 16S rRNA gene and sequencing. Throughout all samples, the most abundant phylum was Proteobacteria, followed by Actinobacteria, Bacteroidetes and Firmicutes. Beta diversity metrics showed that the structure of the bacterial communities were different among the areas and floors tested, however, only 6-9% of the variation in bacterial communities was explained by the area and floors sampled. A few microorganisms showed significantly differential abundance between men's and women's restrooms, but in general, the bacterial communities from both places were very similar. Finally, significant differences among the microbial community profile from different floors were reported, suggesting that the type of use and occupant demographic within the building may directly influence bacterial dispersion and establishment. PMID- 29127624 TI - Evidence from the gut microbiota of swarming alates of a vertical transmission of the bacterial symbionts in Nasutitermes arborum (Termitidae, Nasutitermitinae). AB - Studies on termite symbiosis have revealed that significant symbiont lineages are maintained across generations. However, most studies have focused only on the worker caste. Little is known about the gut microbiota of reproductives, the most probable vectors for transmitting these lineages to offspring. Using 16S rRNA gene-based Illumina MiSeq sequencing, we compared the gut microbiota of swarming alates of the higher termite Nasutitermes arborum with those of their nestmates from the parental colony. The OTU-based alpha diversity indices showed that the gut microbiota of the alates was at least as diverse as those of non-reproductive adults. It was largely dominated by Spirochaetes mostly of the Treponema I cluster (63.1% of reads), the same dominant taxa found in soldiers and workers of this species and in workers of closely related Nasutitermes species. The termite specific lineages also included other representative taxa such as several clusters of Bacteroidetes and Fibrobacteres-TG3 group. The microbiota of alates was dominated by a core set of host-specific lineages (87% of reads, 77.6% of OTUs), which were always present across all castes/stages. This first comprehensive survey of the microbiota of the founding reproductives of these xylophagous higher termites shows that the bulk of the host endogenous symbionts, mostly taxa that cannot thrive outside the gut, are brought from the parent colony. The royal pair therefore seems to be a key player in the transmission of symbionts across generations and thereby in host-symbiont codiversification. The high proportion of fiber-degrading lineages in their gut suggests a wood-rich diet unlike the larval stages. PMID- 29127625 TI - Gene Therapy for Hemophilia: Progress to Date. AB - Hemophilia is a congenital bleeding disorder that affects nearly half a million individuals worldwide. Joint bleeding and other co-morbidities are a significant source of debilitation for this population. Current therapies are effective but must be given lifelong at regular intervals, are costly, and are available to only about 25% of the hemophilia population living in resource-rich countries. Gene therapy for hemophilia has been in development for three decades and is now entering pivotal-stage clinical trials. While many different technology platforms exist for gene therapy, all current clinical trials for hemophilia employ adeno associated vector (AAV)-based cell transduction. This small viral particle is capable of packaging modified F8 or F9 transgenes, can be generated robustly from cell lines, and transduces several relatively end-differentiated target tissues such as the liver with high efficiency. While pre-existing neutralizing antibodies to the AAV capsid are recognized to limit current therapy, other challenges have been identified in human studies that were not seen in preclinical studies. Both liver transaminase elevations and immune-mediated loss of transgene expression have been observed in clinical trials. Toll-like receptors, cytotoxic T cells, and other components of the immune response have been implicated in the loss of factor expression, but a full understanding of the immune response awaits clarification. Despite these challenges, many patients enrolled in gene therapy trials have attained long-term expression of factors VIII and IX. This emerging technology now represents a cure for the severe bleeding and joint damage associated with hemophilia. PMID- 29127626 TI - Impact of Infliximab and Etanercept Biosimilars on Biological Disease-Modifying Antirheumatic Drugs Utilisation and NHS Budget in the UK. AB - OBJECTIVE: Biological disease-modifying antirheumatic drugs (bDMARDs) are effective but expensive options for treating rheumatoid arthritis. The introduction of infliximab and etanercept biosimilars presents a significant potential cost saving in a financially constrained health system such as the National Health Service (NHS) in the UK. This study examines the impact of the introduction of infliximab and etanercept biosimilars on the utilisation of bDMARDs and subsequent budget impact. METHODS: We conducted an interrupted time series analysis of secondary care utilisation data in rheumatology specialities from the DEFINE database, between March 2014 and February 2017. RESULTS: The cumulative cost savings from the introduction of infliximab and etanercept biosimilars was L38.8 million over 2 years. There was a statistically significant increase in average monthly utilisation of bDMARDs for adalimumab (0.48%), certolizumab pegol (1.90%), golimumab (3.06%), abatacept (2.97%) and tocilizumab (2.24%), but not for etanercept. In contrast, the overall utilisation of infliximab decreased slightly by an average of 0.03% per month. The introduction of infliximab biosimilars negatively affected the monthly utilisation of branded infliximab significantly. Similarly, the introduction of an etanercept biosimilar negatively affected the monthly utilisation of branded etanercept significantly. CONCLUSIONS: The introduction of bDMARDs biosimilars has resulted in considerable cost savings to the NHS, with the branded products reducing their prices in response to the availability of less expensive biosimilars and competition between the biosimilars themselves. Our results also suggest that when a biosimilar is available for a directly comparable branded molecule, price is the key influencing factor in the prescribing of a specific product. PMID- 29127627 TI - Trichohepatoenteric Syndrome Presenting with Severe Infection and Later Onset Diarrhoea. PMID- 29127628 TI - Immunohistochemistry with Anti-BRAF V600E (VE1) Mouse Monoclonal Antibody is a Sensitive Method for Detection of the BRAF V600E Mutation in Colon Cancer: Evaluation of 120 Cases with and without KRAS Mutation and Literature Review. AB - The major aim of this study was to evaluate the performance of anti-BRAF V600E (VE1) antibody in colorectal tumors with and without KRAS mutation. KRAS and BRAF are two major oncogenic drivers of colorectal cancer (CRC) that have been frequently described as mutually exclusive, thus the BRAF V600E mutation is not expected to be present in the cases with KRAS mutation. In addition, a review of 25 studies comparing immunohistochemistry (IHC) using the anti-BRAF V600E (VE1) antibody with BRAF V600E molecular testing in 4041 patient samples was included. One-hundred and twenty cases with/without KRAS or BRAF mutations were acquired. The tissue were immunostained with anti-BRAF V600E (VE1) antibody with OptiView DAB IHC detection kit. The KRAS mutated cases with equivocal immunostaining were further evaluated by Sanger sequencing for BRAF V600E mutation. Thirty cases with BRAF V600E mutation showed unequivocal, diffuse, uniform, positive cytoplasmic staining and 30 cases with wild-type KRAS and BRAF showed negative staining with anti-BRAF V600E (VE1) antibody. Out of 60 cases with KRAS mutation, 56 cases (93.3%) were negative for BRAF V600E mutation by IHC. Four cases showed weak, equivocal, heterogeneous, cytoplasmic staining along with nuclear staining in 25 90% of tumor cells. These cases were confirmed to be negative for BRAF V600E mutation by Sanger sequencing. Overall, IHC with anti-BRAF V600E (VE1) antibody using recommended protocol with OptiView detection is optimal for detection of BRAF V600E mutation in CRC. Our data are consistent with previous reports indicating that KRAS and BRAF V600E mutation are mutually exclusive. PMID- 29127629 TI - Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals. AB - We have developed a virtual screening procedure to identify potential ligands to the aryl hydrocarbon receptor (AhR) among a set of industrial chemicals. AhR is a key target for dioxin-like compounds, which is related to these compounds' potential to induce cancer and a wide range of endocrine and immune system related effects. The virtual screening procedure included an initial filtration aiming at identifying chemicals with structural similarities to 66 known AhR binders, followed by 3 enrichment methods run in parallel. These include two ligand-based methods (structural fingerprints and nearest neighbor analysis) and one structure-based method using an AhR homology model. A set of 6445 commonly used industrial chemicals was processed, and each step identified unique potential ligands. Seven compounds were identified by all three enrichment methods, and these compounds included known activators and suppressors of AhR. Only approximately 0.7% (41 compounds) of the studied industrial compounds was identified as potential AhR ligands and among these, 28 compounds have to our knowledge not been tested for AhR-mediated effects or have been screened with low purity. We suggest assessment of AhR-related activities of these compounds and in particular 2-chlorotrityl chloride, 3-p-hydroxyanilino-carbazole, and 3-(2-chloro 4-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one. PMID- 29127630 TI - Analysis of various effects of abamectin on erythrocyte morphology in Japanese quails (Coturnix japonica). AB - Although previous studies have already confirmed the toxicological potential of abamectin (ABA) in different experimental models (from invertebrates to vertebrates), almost nothing is known about the impacts the exposure to this pesticide can cause on birds. Thus, the aim of our study is to investigate the cytotoxic effects on the erythrocytes of female Japanese quails (Coturnix japonica) exposed to low abamectin concentrations. In order to do so, three experimental groups were proposed: "control," composed of quails exposed to abamectin-free drinking water; "ABA 1% median lethal dose (LD50)," comprising birds exposed to water containing 15.5 mg a.i./L of abamectin (via commercial formulation Kraft(r) 36EC), and "ABA 10% LD50," composed by birds exposed to water containing 155.0 mg a.i./L of abamectin. The micronucleus test and the tests applied to other nuclear abnormalities in the peripheral blood of birds were conducted 40 days after exposure. Our study revealed significant physical abnormalities in nuclear shapes (erythrocytes with asymmetric constriction nuclei, notched nuclei, indented and moved nucleus) of those birds exposed to higher abamectin levels. When all nuclear abnormalities were tallied, a significant dose-dependent trend was noted. Therefore, our study presents initial imprints on determination of abamectin-mediated cellular toxicity in avifauna which can be instrumental in checking polluted ecosystems. PMID- 29127631 TI - The impact of urbanization on CO2 emissions in China: an empirical study using 1980-2014 provincial data. AB - Towns and cities are not only the focus of attention for their consumption of energy and resources; they are also scrutinized closely for their emissions of greenhouse gases. China's urbanization level now exceeds 50%, but there is still much disparity compared with the level of urbanization in developed countries. This study selects China's urban population and carbon emissions data for the years 1980-2014 and discusses the timing and cause effect of urbanization and the corresponding carbon emissions using the Granger causality test and an error correction model (ECM) then uses STIRPAT models to extract six indicators to measure the quality of urbanization, namely, the level of urbanization, area of built-up regions, added value of tertiary industries, disposable income per capita, green areas per capita, and energy intensity. These six indicators represent population agglomeration, the expansion of urban areas, industrial agglomeration, quality of life improvements, ecological conservation, and technological improvements, respectively. The study divides 29 provinces in China into three groups based on the quality of urbanization and analyzes the impacts of the six indicators of urbanization quality on carbon emissions. The findings show that the impacts of different factors on carbon emissions vary substantially among the provinces. Finally, the study uses the findings to give suggestions on how to develop low-carbon urbanization. PMID- 29127632 TI - Oxidative removal of metronidazole from aqueous solution by thermally activated persulfate process: kinetics and mechanisms. AB - Metronidazole (MNZ) is widely used in clinical applications and animal feed as an antibiotic agent and additive, respectively. Widespread occurrence of MNZ in wastewater treatment and hospital effluents has been reported. In this study, the mechanism of MNZ degradation in aqueous solutions via thermally activated persulfate (TAP) process was established under different conditions. The kinetic model was derived for MNZ degradation and followed pseudo-first-order reaction kinetics and was consistent with the model fitted by experimental data (R 2 > 98.8%). The rate constant increased with the initial dosage of persulfate, as well as the temperature, and the yielding apparent activation energy was 23.9 kcal mol-1. The pH of the solutions did not have significant effect on MNZ degradation. The degradation efficiency of MNZ reached 96.6% within 180 min for an initial MNZ concentration of 100 mg L-1 under the optional condition of [PS]0 = 20 mM, T = 60 degrees C, and unadjusted pH. [Formula: see text] and HO . were confirmed using electron paramagnetic resonance (EPR) spectra during TAP process. Radical quenching study revealed that [Formula: see text] was mainly responsible for MNZ degradation at an unadjusted pH. MNZ mineralization evaluation showed that the removal efficiency of total organic carbon (TOC) reached more than 97.2%. PMID- 29127633 TI - Natural and anthropogenic particulate-bound aliphatic and polycyclic aromatic hydrocarbons in surface waters of the Gulf of Gabes (Tunisia, southern Mediterranean Sea). AB - Particulate-bound aliphatic and polycyclic aromatic hydrocarbons (AHs and PAHs) were investigated in the surface waters of the Gulf of Gabes (Tunisia, southern Mediterranean Sea). Samples were collected off the Sfax and Gabes-Ghannouch coasts. Concentrations in total resolved n-alkanes ranged from 0.03 to 3.2 MUg L 1, and concentrations in total parents + alkylated PAHs ranged from bdl to 108.6 ng L-1. The highest concentrations were recorded in the southern Sfax. AHs were mainly of biogenic origin with odd n-alkane predominance, although an anthropogenic contribution was also detected. The PAH molecular patterns revealed a mixed origin with the presence of low molecular weight and alkylated compounds, characteristic of uncombusted oil-derived products, and the presence of high molecular weight compounds, typical of combustion residues. Rainfall events induced an increase in PAH concentrations by a factor 1.5-23.5. The particle water partition coefficients (Koc) suggest that the partitioning of PAHs between the particulate and dissolved phases is driven by hydrophobicity and organic matter composition. PMID- 29127634 TI - Changes of chromium speciation and organic matter during low-temperature pyrolysis of tannery sludge. AB - The application or disposal of char derived from tannery sludge is directly influenced by the mobility and bioavailability of Cr during pyrolysis process. This study focused on the changes of Cr speciation and organic matter in tannery sludge during low-temperature pyrolysis (100-400 degrees C) to evaluate the toxicity of char in terms of the leaching possibility of Cr. The results showed that (1) lower char yield and more porous structure were observed after pyrolysis. (2) Higher pyrolysis temperature increased Cr content in the char; however, Cr in this case was converted into the residual fraction which minimized its bioavailability therefore lowers its potential risk to the environment. (3) Organic matters in the acid and alkali leachates were mainly humic acid-like substance, and condensed organic matter might appear at 200 degrees C and then destruct. (4) Despite the comparatively high content of Cr in the char, the leaching toxicity of char was within the security range according to the national standard of China. The Cr content in the acid and alkali leachates decreased to the range of 16.5-35.3 and 0.2-6.8 mg/L, respectively. It was suggested that the potential toxicity of tannery sludge from Cr could be reduced before utilization or disposal by pyrolysis, especially under 400 degrees C. PMID- 29127635 TI - Immobilisation of metals in a contaminated soil with biochar-compost mixtures and inorganic additives: 2-year greenhouse and field experiments. AB - Besides carbon sequestration and improvement of soil properties, biochar (BC) has increasingly been studied as an amendment to immobilise heavy metals in contaminated soils. In a 2-year experiment, we analysed the effects of poplar BC (P-BC, mixed with compost) and gravel sludge with siderite-bearing material (GSFe) on a Cd-, Pb- and Zn-contaminated soil and on metal concentration in Miscanthus * giganteus shoots under greenhouse and field conditions. In the greenhouse, 1% (m/m) P-BC addition reduced NH4NO3-extractable Cd, Pb and Zn concentrations by 75, 86 and 92%, respectively, at the end of the study. In the leachates, P-BC (1%) could significantly reduce Cd and Zn in both years. In the field, P-BC (3%) induced a reduction of extractable Cd by 87% whereas a combination of P-BC + GSFe reduced Pb by 82% and Zn by 98% in the first year and by 83 and 96% in the second year. In contrast, the metal immobilisation in the soil was hardly reflected in the shoots of Miscanthus * giganteus which generally showed metal concentrations close to control. While Cd was not influenced in both years, Pb and Zn were slightly reduced. Our study confirmed that Miscanthus is an efficient metal excluder, corroborating its suitability for the production of renewable biomass on metal-contaminated soils. PMID- 29127636 TI - Release of nutrients and heavy metals from biochar-amended soil under environmentally relevant conditions. AB - Biochar is a potential amendment for improving soil fertility due to its richness of nutrients, P, K, Ca, and Mg. However, soil amended with metal-rich biochars may pose a risk of heavy metal release to the environment. Biochars derived from pig manure and sewage sludge (PM-biochar and SS-biochar) were investigated for their nutrient and heavy metal release in two soils (acidic and alkaline soil) under simulated landfill and acid rain conditions. Results showed that under both environmental conditions, adding PM-biochar into the soil increased K, P, and Mg release significantly by about 40-50 times, while only 2-4 times increase of the nutrients was observed in the SS-biochar-amended soil. The Ca release was higher in the SS-biochar-amended soil than in the PM-biochar-amended soil. Higher P, Ca, and Mg nutrient release was observed in alkaline soil than in acidic soil under the two environmental conditions though K release was not significant in both soils. A kinetic study in solution illustrated that the release of nutrients from biochar was initially via desorption and diffusion under environmental conditions and then through slow dissolution of insoluble species. More release of nutrients and heavy metals was observed in the biochar-amended soil under the landfill condition than under the acid rain condition. Although this release was limited under the acid rain condition, leaching of Fe and Mn exceeded the limitations of the groundwater standard value of China. Overall, biochar could be utilized as a prospective soil fertilizer by supplying nutrients such as P, K, Ca, and Mg, while the release of Fe and Mn should be paid more attention due to the risk of these metals impacting groundwater. PMID- 29127637 TI - Insights into doxycycline adsorption onto graphene nanosheet: a combined quantum mechanics, thermodynamics, and kinetic study. AB - Recently, pharmaceutically active compounds including antibiotics have been detected in drinking water at very low levels, mostly nanogram/liter concentrations, proposing that these materials were unaffected by water treatment processes. Adsorption processes were suggested to play a significant role in the removal of antibiotics. In this study, the adsorption behavior of doxycycline (DC) in aqueous solution was evaluated. The four factors influencing the adsorption of DC onto graphene nanosheet (GNS) were studied. The results showed that initial pH ~ 6 to 7 and contact time ~ 200 min are optimum. The monolayer adsorption capacity was reduced with the increasing temperature from 25 to 45 degrees C. Nonlinear regressions were carried out to define the best fit model for every system. Among various models, the Hill isotherm model represented the equilibrium adsorption data of antibiotics while the kinetic data were well fitted by the Elovich kinetic model. The maximum adsorption capacity (q max) was 110 mg.g-1, obtained from the Hill equation. Semiempirical molecular orbital theory was used to investigate the molecular interaction of the adsorption system. The experiments and semiempirical computation have systematically demonstrated that DC could be adsorbed onto GNS by pi- pi and electrostatic interactions. It was shown that there is a good compromise with the experimental results. Graphical abstract Insights into doxycycline adsorption onto graphene nanosheet: quantum mechanics, thermodynamics, and kinetic study. PMID- 29127638 TI - Technical-financial evaluation of rainwater harvesting systems in commercial buildings-case ase studies from Sonae Sierra in Portugal and Brazil. AB - Water is an essential and increasingly scarce resource that should be preserved. The evolution of the human population and communities has contributed to the global decrease of potable water availability and the reduction of its consumption is now compulsory. Rainwater harvesting systems (RWHS) are emerging as a viable alternative source for water consumption in non-potable uses. The present study aims to contribute to the promotion of water efficiency, focusing on the application of rainwater harvesting systems in commercial buildings, and comprises four stages: (i) development of a technical evaluation tool to aid the design of RWHS and support their financial evaluation; (ii) validation of the tool using operational data from an existing RWHS installed at Colombo Shopping Center, in Lisbon, Portugal; (iii) assessment of the sensibility of the technical evaluation tool results to the variation of the inputs, namely the precipitation and consumption, through a parametric analysis for the Colombo Shopping Center; and (iv) comparison of the performance and financial feasibility of hypothetical RWHS in two existing commercial buildings. The technical tool was applied to two Sonae Sierra's shopping centers, one in Portugal and one in Brazil. The installation of a 200-m3 tank is advised for the first case study, allowing non potable water savings of 60% but a payback period of about 19 years. In the Brazilian shopping, the implementation of a tank with a capacity ranging from 100 to 400 m3 leads to non-potable savings between 20 and 50%, but with smaller payback period, under 2 years, due to the relatively lower investment costs and higher water fees. PMID- 29127639 TI - Reactivation and reuse of TiO2-SnS2 composite catalyst for solar-driven water treatment. AB - One of the most important features of photocatalytic materials intended to be used for water treatment is their long-term stability. The study is focused on the application of thermal and chemical treatments for the reactivation of TiO2 SnS2 composite photocatalyst, prepared by hydrothermal synthesis and immobilized on the glass support using titania/silica binder. Such a catalytic system was applied in solar-driven treatment, solar/TiO2-SnS2/H2O2, for the purification of water contaminated with diclofenac (DCF). The effectiveness of studied reactivation methods for retaining TiO2-SnS2 activity in consecutive cycles was evaluated on basis of DCF removal and conversion, and TOC removal and mineralization of organic content. Besides these water quality parameters, biodegradability changes in DCF aqueous solution treated by solar/TiO2-SnS2/H2O2 process using simply reused (air-dried) and thermally and chemically reactivated composite photocatalyst through six consecutive cycles were monitored. It was established that both thermal and chemical reactivation retain TiO2-SnS2 activity in the second cycle of its reuse. However, both treatments caused the alteration in the TiO2-SnS2 morphology due to the partial transformation of visible-active SnS2 into non-active SnO2. Such alteration, repeated through consecutive reactivation and reuse, was reflected through gradual activity loss of TiO2-SnS2 composite in applied solar-driven water treatment. PMID- 29127640 TI - Single and combined metal contamination in coastal environments in China: current status and potential ecological risk evaluation. AB - With the development of industrialization and urbanization, metal and metalloid pollution is one of the most serious environmental problems in China. Current contamination status of metals and metalloid and their potential ecological risks along China's coasts were reviewed in the present paper by a comprehensive study on metal contents in marine waters and sediments in the past few decades. The priority metals/metalloid cadmium (Cd), mercury (Hg), chromium (Cr), lead (Pb), and arsenic (As), which were the target elements of the designated project "Comprehensive Prevention and Control of Heavy Metal Pollution" issued by the Chinese government in 2011, were selected considering their high toxicity, persistence, and prevalent existence in coastal environment. Commonly used environmental quality evaluation methods for single and combined metals were compared, and we accordingly suggest the comprehensive approach of joint utilization of the Enrichment Factor and Effect Range Median combined with Pollution Load Index and Mean Effect Range Median Quotient (EEPME); this battery of guidelines may provide consistent, internationally comparable, and accurate understanding of the environment pollution status of combined metals/metalloid and their potential ecological risk. PMID- 29127641 TI - Technical, hygiene, economic, and life cycle assessment of full-scale moving bed biofilm reactors for wastewater treatment in India. AB - Moving bed biofilm reactor (MBBR) is a highly effective biological treatment process applied to treat both urban and industrial wastewaters in developing countries. The present study investigated the technical performance of ten full scale MBBR systems located across India. The biochemical oxygen demand, chemical oxygen demand, total suspended solid, pathogens, and nutrient removal efficiencies were low as compared to the values claimed in literature. Plant 1 was considered for evaluation of environmental impacts using life cycle assessment approach. CML 2 baseline 2000 methodology was adopted, in which 11 impact categories were considered. The life cycle impact assessment results revealed that the main environmental hot spot of this system was energy consumption. Additionally, two scenarios were compared: scenario 1 (direct discharge of treated effluent, i.e., no reuse) and scenario 2 (effluent reuse and tap water replacement). The results showed that scenario 2 significantly reduce the environmental impact in all the categories ultimately decreasing the environmental burden. Moreover, significant economic and environmental benefits can be obtained in scenario 2 by replacing the freshwater demand for non-potable uses. To enhance the performance of wastewater treatment plant (WWTP), there is a need to optimize energy consumption and increase wastewater collection efficiency to maximize the operating capacity of plant and minimize overall environmental footprint. It was concluded that MBBR can be a good alternative for upgrading and optimizing existing municipal wastewater treatment plants with appropriate tertiary treatment. Graphical abstract ?. PMID- 29127642 TI - Predictors of Mental Health in Chinese Parents of Children with Autism Spectrum Disorder (ASD). AB - The aim of this study was to explore the influence of parental intolerance of Uncertainty (IU), sensory sensitivity (SS) and Broader Autism Phenotype (BAP), as well as the severity of their children's autism symptoms and co-morbid symptoms, on the mental health of Chinese parents of children with autism spectrum disorder (ASD). One hundred and twenty-two parents (86.9% mothers; M age = 35.64 years, SD = 4.21) of children with ASD took part. Regression and mediation analyses showed that children's internalizing difficulties, parental BAP and IU had a direct effect, and SS had an indirect effect through IU, on parental mental health. We did not find a significant relationship between parental mental health and children's ASD severity. Our findings emphasise the need to focus on parental traits when considering their well-being and mental health, and have implications for the design of evidence-based services to support the needs of parents. PMID- 29127643 TI - Characterization of a novel asparaginase from soil metagenomic libraries generated from forest soil. AB - OBJECTIVES: To screen soil metagenomic libraries for novel enzymes with enhanced activities. RESULTS: To screen soil metagenomic libraries for novel enzymes with enhanced activities. A novel L-asparaginase was identified from forest soil metagenome and its characteristics were studied. The purified protein had a specific activity of 696 IU mg-1 and optimum activity at pH 7 and 35 degrees C. Enhanced enzyme activities were observed in the presence of Mg2+, Ca2+ and K+. The Km value, 2 mM, and enzyme specificity constant 7.7 mM-1s-1 indicated that the recombinant enzyme has good substrate affinity to L-asparagine compared with commercially-available Escherichia coli asparaginase. The IC50 value of 0.78 ug ml-1 (0.47 IU ml-1) was observed with HL60 cell line and 0.39 ug ml-1(0.23 IU ml 1) with MOLT-3 and MOLT-4 cell lines, which is better than that of commercially available drugs. CONCLUSION: The soil metagenome derived L-asparaginase with enhanced activities could be a potential candidate to develop as a drug in Acute Lymphoblastic Leukemia (ALL) therapy. PMID- 29127644 TI - Erasmus Mundus Master of Bioethics: a case for an effective model for international bioethics education. AB - Designing bioethics curriculum for international postgraduate students is a challenging task. There are at least two main questions, which have to be resolved in advance: (1) what is a purpose of a particular teaching program and (2) how to respectfully arrange a classroom for students coming from different cultural and professional backgrounds. In our paper we analyze the case of the Erasmus Mundus Master of Bioethics program and provide recommendations for international bioethics education. In our opinion teaching bioethics to postgraduate international students goes beyond curriculum. It means that such a program requires not only well-defined goals, including equipping students with necessary skills and knowledge, but also it should first and foremost facilitate positive group dynamics among students and enables them to engage in dialogue to learn from one another. PMID- 29127645 TI - Remote monitoring of pulmonary artery pressures with CardioMEMS in patients with chronic heart failure and NYHA class III: first experiences in the Netherlands. AB - We report the first patient experiences with the CardioMEMS device in the Erasmus MC Thorax Center in the Netherlands. In line with clinical trial evidence, the device is applicable in patients with chronic heart failure in functional New York Heart Association class III with at least 1 admission for heart failure in the past 12 months. CardioMEMS has been shown to be safe and reliable, and effective in reducing the number of hospitalisations for heart failure by guided therapy based on pulmonary artery pressures. PMID- 29127646 TI - Can we spice up our Christmas dinner? : Busting the myth of the 'Chinese restaurant syndrome'. AB - BACKGROUND: Monosodium glutamate (MSG), also referred to as Vetsin or E621, is a flavour enhancer frequently used in Asian cuisine and abundantly present in the famous Chinese dish Peking duck. MSG is notorious for triggering the onset of the so-called 'Chinese restaurant syndrome' (CRS), a complex of unpleasant symptoms, which might include flushing, sweating and the onset of atrial fibrillation (AF). This study aims to determine the effects of MSG on the occurrence of AF. METHODS: We conducted a placebo self-controlled single-arm study in the Academic Medical Centre in Amsterdam. We included paroxysmal AF patients who reported a consistent onset of AF upon MSG intake. During three admissions, participants were subsequently administered: placebo, 1.5 g and 3 g MSG. If AF was recorded after the dose of 1.5 g MSG, patients were given another placebo instead of 3 g MSG. The primary outcome was the onset of AF registered by 24-hour Holter monitoring. The secondary outcomes were any other arrhythmia and the onset of CRS defined as two or more symptoms of CRS after MSG intake. RESULTS: Six men participated in the study. Both 1.5 g and 3 g MSG were unrelated to CRS, arrhythmias or AF occurrence. CONCLUSION: Peking duck can be put on the Christmas menu without risking guests to be admitted to the emergency department with new episodes of AF. PMID- 29127647 TI - O-GlcNAcylation in women's cancers: breast, endometrial and ovarian. AB - O-GlcNAcylation is emerging as a critical regulatory post-translational modification, impacting proteins that regulate cell division, apoptosis, metabolism, cell signaling, and transcription. O-GlcNAc also affects biological homeostasis by integrating information coming from the environment, such as nutrient conditions and extracellular stimuli, with cellular response. Aberrant O GlcNAc modulation has been linked to metabolic and neurodegenerative diseases, as well as cancers. While many studies have highlighted the significance of O-GlcNAc in cancer, a specific function for O-GlcNAc during tumorigenesis remains unclear and seems to differ according to cancer type. Herein, we review the impact of altered O-GlcNAcylation in breast, ovarian and uterine cancers. PMID- 29127649 TI - [Results after surgical management of ileal perforation due to typhoid fever, about 29 cases in Ouahigouya (Burkina Faso)]. AB - The aim of this study was to determine the results of management of typhoid perforations. This was a descriptive cross-sectional study carried out from January 1, 2016 to December 31, 2016 in the General Surgery Department of the Regional Teaching Hospital Center of Ouahigouya (Burkina Faso). It involved 29 operated patients, in whom the diagnosis of typhoid perforation was confirmed at laparotomy: age, sex, admission time, clinical, therapeutic and prognostic aspects were analyzed. Typhoid perforations accounted for 20% of acute generalized peritonitis and 38.1% of digestive perforations. Twenty-three patients were males and six were females (sex-ratio: 3.8). The average age of patients was 19 years. The mean diagnostic time was 9.8 days. The excision-suture of the perforation was the most used technique with 62% of the cases. The treatment lead to complications in 10 cases with a morbidity of 34.5%. Four deaths were recorded, representing an overall mortality of 13.8%. Prognostic factors were diagnostic delay, age, number of perforations and resection anastomosis. PMID- 29127650 TI - [Plasmodium ovale wallikeri and Plasmodium ovale curtisi Malaria in Senegal in 2016]. AB - Recently in Senegal, a case of Plasmodium ovale malaria had led to a diagnostic difficulty due to the ignorance of this parasite and the neglect of it. The objective of this study was to actively investigate cases of P. ovale malaria that would be misdiagnosed in the health centre structures of Senegal. The study was conducted in three areas that reflect different epidemiological strata of malaria. Microscopy was performed by microscopy experts on suspected malaria patients. The results were validated by Rougemont real-time PCR. Positive P. ovale cases were genotyped by nested PCR targeting the potra gene. A total of 406 samples were taken. Microscopy of Giemsa stained thick and thin smears recorded 228 cases of Plasmodium falciparum (97%), 3 cases of Plasmodium malariae (1.3%), and 4 cases of P. ovale (1.7%). The cases of P. ovale observed at microscopy were confirmed by real-time PCR. Genotyping of P. ovale revealed 3 cases of P. ovale wallikeri and 1 case of P. ovale curtisi. The prevalence of P. ovale malaria remains low in Senegal. However, malaria microscopists should be trained to recognize non-falciparum species in order to avoid the diagnostic delays and unnecessary investigations. National malaria control program should consider those species for the better management of malaria control in the country. Simplified molecular methods like, loop-mediated isothermal amplification (LAMP) may be useful to better characterize the epidemiology of non-falciparum malaria. PMID- 29127651 TI - Unexpected delayed bleeding after native renal biopsy: a case report. AB - Percutaneous native renal biopsy is recognized as a safe procedure. The majority of bleeding events occur within 24 h after the procedure, and reports of delayed major complications are very limited. We report a patient presenting with sudden flank pain 7 days after renal biopsy, in whom abdominal computed tomography showed increased hematoma size with extravasation and who was treated with radiological intervention. Careful attention should be paid to diagnose and treat delayed major complications in patients undergoing native renal biopsy. PMID- 29127648 TI - Serum apolipoprotein B is inversely associated with eccentric left ventricular hypertrophy in peritoneal dialysis patients. AB - OBJECTIVES: The study aimed to examine the relationship of serum apolipoprotein B level with left ventricular (LV) structural and functional characteristics, in particular, LV remodeling parameters in peritoneal dialysis (PD) patients. METHODS: A total of 182 patients with end-stage renal disease (ESRD) receiving PD were identified. Conventional echocardiography was performed for each patient, and echocardiographic characteristics were analyzed according to apo B quartile groups. Multivariate linear regression models were used to determine the associations between serum apo B and LV remodeling indices. RESULTS: A high serum apo B level was significantly related to the reduction in left atrium dimension (r = - 0.20, P = 0.011), LV dimensions (end-diastolic: r = - 0.27, P = 0.001; end systolic: r = - 0.24, P = 0.003), peak velocities of early filling divided by peak velocities of atrial filling (r = - 0.38, P < 0.001), and LV volumetric dimension (end-diastolic: r = - 0.27, P < 0.001; end-systolic: r = - 0.28, P < 0.001). After adjustment for clinical confounding factors, the effect of serum apo B on LV eccentric remodeling modestly weakened but remained statistically significant (P = 0.038), while other associations were not significant. In multivariate linear regression analysis, conventional lipid profiles were not significantly associated with LV eccentric remodeling, whereas serum apo B was an independent determinant of LV dilatation (beta: - 42.10, 95% CI - 74.82 to - 9.38, P = 0.012). CONCLUSIONS: Serum apo B was significantly and inversely associated with LV dilatation, independently of conventional lipids and other CV risk factors in our ESRD patients undergoing PD. It suggested that low serum apo B level could be a powerful risk marker for eccentric left ventricular geometry remodeling and could be potentially used to risk-stratify PD patients. PMID- 29127652 TI - Dapagliflozin as a cause of acute tubular necrosis with heavy consequences: a case report. AB - A 50-year-old man with type II diabetes, hypertension and dyslipidemia, presented with non-oliguric acute kidney injury (AKI) and anemia. Renal biopsy showed acute tubular necrosis (ATN) with extensive cytoplasmic vacuolization and areas of tubulitis. These findings were ultimately attributed to dapagliflozin, which he started 3 months earlier due to poor glycemic control. ATN with similar microscopic findings has been described with larger doses of dapagliflozin in non clinical trials. Our patient was started on dialysis and remained dialysis dependent for 4 weeks while his renal function improved gradually thereafter. Sixteen months after initial presentation he is being followed as an outpatient with chronic kidney disease (CKD) stage 3a. Dapagliflozin belongs to a novel class of antidiabetic drugs for which clinical trials show great beneficial effects on cardiovascular outcomes and glycemic control and as with many new drugs, their safety profile is being constantly revised. We report the first biopsy-proven ATN caused by dapagliflozin. Great caution together with continuous monitoring of renal function is advised when implementing SGLT-2 inhibitors in clinical practice. PMID- 29127653 TI - Development of a 3D workspace shoulder assessment tool incorporating electromyography and an inertial measurement unit-a preliminary study. AB - Traditional shoulder range of movement (ROM) measurement tools suffer from inaccuracy or from long experimental setup times. Recently, it has been demonstrated that relatively low-cost wearable inertial measurement unit (IMU) sensors can overcome many of the limitations of traditional motion tracking systems. The aim of this study is to develop and evaluate a single IMU combined with an electromyography (EMG) sensor to monitor the 3D reachable workspace with simultaneous measurement of deltoid muscle activity across the shoulder ROM. Six volunteer subjects with healthy shoulders and one participant with a 'frozen' shoulder were recruited to the study. Arm movement in 3D space was plotted in spherical coordinates while the relative EMG intensity of any arm position is presented graphically. The results showed that there was an average ROM surface area of 27291 +/- 538 deg2 among all six healthy individuals and a ROM surface area of 13571 +/- 308 deg2 for the subject with frozen shoulder. All three sections of the deltoid show greater EMG activity at higher elevation angles. Using such tools enables individuals, surgeons and physiotherapists to measure the maximum envelope of motion in conjunction with muscle activity in order to provide an objective assessment of shoulder performance in the voluntary 3D workspace. Graphical abstract The aim of this study is to develop and evaluate a single IMU combined with an electromyography (EMG) sensor to monitor the 3D reachable workspace with simultaneous measurement of deltoid muscle activity across the shoulder ROM. The assessment tool consists of an IMU sensor, an EMG sensor, a microcontroller and a Bluetooth module. The assessment tool was attached to subjects arm. Individuals were instructed to move their arms with the elbow fully extended. They were then asked to provide the maximal voluntary elevation envelope of the arm in 3D space in multiple attempts starting from a small movement envelope going to the biggest possible in four consecutive circuits. The results showed that there was an average ROM surface area of 27291 +/- 538 deg2 among all six healthy individuals and a ROM surface area of 13571 +/ 308 deg2 for the subject with frozen shoulder. All three sections of the deltoid show greater EMG activity at higher elevation angles. Using such tools enables individuals, surgeons and physiotherapists to measure the maximum envelope of motion in conjunction with muscle activity in order to provide an objective assessment of shoulder performance in the voluntary 3D workspace. PMID- 29127654 TI - The endoscope-assisted contralateral paramedian approach to large falcine meningiomas. AB - BACKGROUND: Resection of large falcine meningiomas can be challenging as overlaying cortical brain is endangered during the surgical approach. METHOD: We describe the endoscope-assisted contralateral paramedian approach to large left falcine meningiomas to avoid retraction of the ipsilateral thin layer of eloquent brain cortex. CONCLUSIONS: The contralateral paramedian approach enables complete tumor resection with endoscopic-assisted removal of tumor remnants in the superior aspect of the resection cavity, sparing any manipulation of ipsilateral brain tissue. PMID- 29127655 TI - The endoscopic endonasal approach is not superior to the microscopic transcranial approach for anterior skull base meningiomas-a meta-analysis. AB - OBJECT: In the past decade, the endonasal transsphenoidal approach (eTSA) has become an alternative to the microsurgical transcranial approach (mTCA) for tuberculum sellae meningiomas (TSMs) and olfactory groove meningiomas (OGMs). The aim of this meta-analysis was to evaluate which approach offered the best surgical outcomes. METHODS: A systematic review of the literature from 2004 and meta-analysis were conducted in accordance with the PRISMA guidelines. Pooled incidence was calculated for gross total resection (GTR), visual improvement, cerebrospinal fluid (CSF) leak, intraoperative arterial injury, and mortality, comparing eTSA and mTCA, with p-interaction values. RESULTS: Of 1684 studies, 64 case series were included in the meta-analysis. Using the fixed-effects model, the GTR rate was significantly higher among mTCA patients for OGM (eTSA: 70.9% vs. mTCA: 88.5%, p-interaction < 0.01), but not significantly higher for TSM (eTSA: 83.0% vs. mTCA: 85.8%, p-interaction = 0.34). Despite considerable heterogeneity, visual improvement was higher for eTSA than mTCA for TSM (p interaction < 0.01), but not for OGM (p-interaction = 0.33). CSF leak was significantly higher among eTSA patients for both OGM (eTSA: 25.1% vs. mTCA: 10.5%, p-interaction < 0.01) and TSM (eTSA: 19.3%, vs. mTCA: 5.81%, p-interaction < 0.01). Intraoperative arterial injury was higher among eTSA (4.89%) than mTCA patients (1.86%) for TSM (p-interaction = 0.03), but not for OGM resection (p interaction = 0.10). Mortality was not significantly different between eTSA and mTCA patients for both TSM (p-interaction = 0.14) and OGM resection (p interaction = 0.88). Random-effect models yielded similar results. CONCLUSION: In this meta-analysis, eTSA was not shown to be superior to mTCA for resection of both OGMs and TSMs. PMID- 29127657 TI - Real-World Cost Savings Demonstrated by Switching Patients with Refractory Diabetic Macular Edema to Intravitreal Fluocinolone Acetonide (Iluvien): A Retrospective Cost Analysis Study. AB - INTRODUCTION: It is hypothesized that using fluocinolone acetonide (FAc) implants such as Iluvien for the treatment of diabetic macular edema (DME) may reduce the total number of intravitreal injections and clinic visits, resulting in an overall treatment cost reduction. The primary aim of this study is to identify the real-world cost savings achievable in a tertiary National Health Service (NHS) hospital. METHODS: A retrospective cost analysis study was conducted. The inclusion criteria were patients with refractory DME who were switched to Iluvien. The average yearly costs were calculated both before and after the switch to Iluvien. All costs including medicines, investigations, clinics, and management of raised intraocular pressure (IOP) were calculated. The cost differences over the 3 years' worth of Iluvien treatment were calculated and analyzed. To ensure non-inferiority of this treatment intervention, the best corrected visual acuity (BCVA) and central retinal thickness (CRT) were also analyzed. Statistical analysis was conducted with a Student t test where appropriate and statistical significance is identified where p < 0.05. RESULTS: Fourteen eyes of 13 patients met the inclusion criteria. Switching patients to Iluvien achieved on average a saving of L2606.17 per patient (p = 0.33) over the 3 years. However, seven cases (50%) had a rise in IOP after Iluvien that warranted medical treatment and two cases (14.3%) required glaucoma surgery. Incorporating the costs of glaucoma management reduced the overall savings over 3 years to L1064.66 per patient. The BCVA and CRT analysis showed a non-inferiority relationship between Iluvien and any previous treatment. CONCLUSIONS: The use of Iluvien in refractory DME patients represents a cost- and time-saving procedure, while showing non-inferiority in terms of efficacy. PMID- 29127656 TI - Altered oscillatory brain dynamics of emotional processing in young binge drinkers. AB - Heavy episodic drinking, also termed binge drinking, is commonly practiced by young adults. It is accompanied by a range of cognitive, affective, and social problems, but the neural dynamics underlying changes in emotional functions is poorly understood. To investigate the behavioral and brain indices of affective processing as a function of binge drinking, young, healthy participants (23.3 +/- 3.3 years) were assigned to two groups (n = 32 each) based on their drinking habits. Binge drinking (BD) participants reported drinking heavily with at least five binge episodes in the last 6 months, whereas light drinkers (LD) reported no more than one binge episode in the last 6 months. Participants provided subjective ratings of emotionally evocative images with negative, positive, erotic, and neutral themes mostly selected from the International Affective Picture System (IAPS). Electroencephalography (EEG) signal was recorded with a 64 channel system and analyzed in theta frequency band (4-7 Hz) with Morlet wavelets. Subjective ratings of the IAPS pictures were equivalent across both groups. However, affective modulation of event-related theta power both during early appraisal and later integrative processing stages was attenuated in BD, particularly those engaging in high-intensity drinking. These findings suggest that binge drinking is associated with altered neurophysiological indices of affective functions that are reflected in lower theta responsivity to emotions. The blunted long-range cortico-cortical and corticolimbic integration is consistent with compromised affective functions in alcohol use disorder. These findings may have implications for diagnostic and intervention strategies in heavy alcohol users. PMID- 29127658 TI - Significant increase in cyanide degradation by Bacillus sp. M01 PTCC 1908 with response surface methodology optimization. AB - Cyanide is used in many industries despite its toxicity. Cyanide biodegradation is affordable and eco-friendly. Sampling from cyanide-contaminated areas from the Muteh gold mine and isolation of 24 bacteria were performed successfully. The selected bacteria-'Bacillus sp. M01'-showed maximum tolerance (15 mM) to cyanide and deposited in Persian Type Culture Collection by PTCC No.: 1908. In the primary experiments, effective factors were identified through the Plackett Burman design. In order to attain the maximum degradation by Bacillus sp. M01 PTCC 1908, culture conditions were optimized by using response surface methodology. By optimizing the effective factor values and considering the interaction between them, the culture conditions were optimized. The degradation percentage was calculated using one-way ANOVA vs t test, and was found to have increased 2.35 times compared to pre-optimization. In all of the experiments, R2 was as high as 91%. The results of this study are strongly significant for cyanide biodegradation. This method enables the bacteria to degrade 86% of 10 mM cyanide in 48 h. This process has been patented in Iranian Intellectual Property Centre under Licence No: 90533. PMID- 29127659 TI - Characterization of LhSorTGA2, a novel TGA2-like protein that interacts with LhSorNPR1 in oriental hybrid lily Sorbonne. AB - BACKGROUND: Non-expressor of pathogenesis-related genes 1 (NPR1) regulates expression of pathogenesis-related (PR) genes by interacting with TGA family proteins during systemic acquired resistance (SAR). However, no TGA-like proteins or their interacting partners have been characterized in lily. RESULTS: In the present study, LhSorTGA2, a novel TGA-like protein, was identified as an interacting partner of LhSorNPR1 (an NPR-like protein) by bimolecular fluorescence complementation (BIFC) and yeast two-hybrid assay (Y2H). Subcellular localization of GFP-tagged proteins targeted LhSorTGA2 to the nucleus, whereas GFP-labeled LhSorNPR1 was observed both in the nucleus and at the cytomembrane. Sequence alignment revealed that LhSorTGA2 was featured with a basic leucine zipper (bZIP) domain and two glutamine rich acid domains (QI and QII). Further phylogenetic analysis showed that TGA family proteins can be grouped into three subclades, within which LhSorTGA2 was clustered into subclade I, together with AtTGA2/5/6. Expression of LhSorTGA2 was investigated in different tissues by qPCR, and the highest expression level was observed in stem. Besides, when treated with phytohormones (SA, MeJA, ETH and ABA) or fungal pathogen Botrytis elliptica, LhSorTGA2 expression was also induced at different time points post treatments. CONCLUSIONS: Collectively, these results suggested that LhSorTGA2 was an interacting partner of LhSorNPR1, which might function in regulating expression of PR genes in lily during SAR. PMID- 29127660 TI - Exposure to a sublethal concentration of imidacloprid and the side effects on target and nontarget organs of Apis mellifera (Hymenoptera, Apidae). AB - The use of insecticides has become increasingly frequent, and studies indicate that these compounds are involved in the intoxication of bees. Imidacloprid is a widely used neonicotinoid; thus, we have highlighted the importance of assessing its oral toxicity to Africanized bees and used transmission electron microscopy to investigate the sublethal effects in the brain, the target organ, and the midgut, responsible for the digestion/absorption of food. In addition, the distribution of proteins involved in important biological processes in the brain were evaluated on the 1st day of exposure by MALDI-imaging analysis. Bioassays were performed to determine the Median Lethal Concentration (LC50) of imidacloprid to bees, and the value obtained was 1.4651 ng imidacloprid/MUL diet. Based on this result, the sublethal concentration to be administered at 1, 4 and 8 days was established as a hundredth (1/100) of the LC50. The results obtained from the ultrastructural analysis showed alterations in the midgut cells of bees as nuclear and mitochondrial damage and an increase of vacuoles. The insecticide caused spacing among the Kenyon cells in the mushroom bodies, chromatin condensation and loss of mitochondrial cristae. The MALDI-imaging analysis showed an increase in the expression of such proteins as vascular endothelial growth factor receptor, amyloid protein precursor and protein kinase C, which are related to oxygen supply, neuronal degeneration and memory/learning, and a decrease in the expression of the nicotinic acetylcholine receptor alpha 1, which is fundamental to the synapses. These alterations demonstrated that imidacloprid could compromise the viability of the midgut epithelium, as well as inhibiting important cognitive processes in individuals, and may be reflected in losses of the colony. PMID- 29127661 TI - Investigations to extend viability of a rainbow trout primary gill cell culture. AB - The primary culture of fish gill cells can provide functional, cell diverse, model in vitro platforms able to tolerate an aqueous exposure analogous to in vivo tissues. The utility of such models could be extended to a variety of longer term exposure scenarios if a method could be established to extend culture viability when exposed to water for longer periods. Here we report findings of a series of experiments to establish increased longevity, as monitored by culture transepithelial electrical resistance (TEER) and concurrent histological developments. Experimental cultures improved TEER during apical freshwater exposure for a mean of twelve days, compared to previous viabilities of up to 3 days. Cultures with larger surface areas and the use of trout serum rather than foetal bovine serum (FBS) contributed to the improvement, while perfusion of the intact gill prior to cell harvest resulted in a significantly faster preparation. Detailed scanning electron microscopy analysis of cultures revealed diverse surface structures that changed with culture age. Cultures grown on membranes with an increased porosity, collagen coating or 3D structure were of no benefit compared to standard membranes. Increased culture longevity, achieved in this study and reported for the first time, is a significant breakthrough and opens up a variety of future experimentation that has previously not been possible. The extended viability facilitates exploration of in vitro chronic or pulse-exposure test paradigms, longer term physiological and environmental monitoring studies and the potential for interactive co-culture with other organoid micro-tissues. PMID- 29127662 TI - JNJ7777120 Ameliorates Inflammatory and Oxidative Manifestations in a Murine Model of Contact Hypersensitivity via Modulation of TLR and Nrf2 Signaling. AB - JNJ7777120, a histamine H4 receptor antagonist, was shown to be effective in different experimental settings of allergic inflammation, including contact hypersensitivity. Toll-like receptors (TLRs) are thought to function as a link between innate and adaptive immune responses to various haptens. Here, we studied the suppression of TLR signaling as a possible mechanism by which JNJ7777120 exerts its anti-inflammatory effects against the chemical hapten, fluorescein isothiocyanate (FITC). The potential anti-oxidant effect of JNJ7777120 in this model was also examined. Mice subjected to FITC sensitization and challenge showed significantly elevated plasma immunoglobulin E (IgE) level, ear interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-alpha), and thiobarbituric acid reactive substance (TBARS) contents as well as increased myeloid differentiation factor 88 (MyD88) gene expression, nuclear factor-kappa B p65 (NF kappaB p65), and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) protein expression. This was accompanied by enhanced ear myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activities as well as diminished glutathione (GSH) content and superoxide dismutase (SOD) activity. JNJ7777120 treatment perceivably reversed these effects, denoting profound anti-inflammatory and anti oxidant character of JNJ7777120 which was confirmed by its mitigation of FITC induced pathological changes in mouse ear. JNJ7777120 additionally enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), providing a novel mechanism by which JNJ7777120 functions as an anti-oxidant in this model. To conclude, JNJ7777120 afforded a remarkable amendment of FITC skin insult by virtue of its anti-inflammatory and anti-oxidant effects; the mechanistic basis of these effects may include modulation of TLR and Nrf2 pathways. PMID- 29127663 TI - Poly(I:C) Priming Exacerbates Cecal Ligation and Puncture-Induced Polymicrobial Sepsis in Mice. AB - Sepsis continues to be a major healthcare issue with one of the highest mortality rates in intensive care units. Toll-like receptors are pattern recognition receptors that are intricately involved in the pathogenesis of sepsis. TLR3 is a major receptor for double-stranded RNA and is largely associated with immunity to viral infection. In this study, we examined the role of TLR3 priming in the immunopathology of sepsis using cecal-ligation and puncture (CLP) model of sepsis in mice. Mice injected with vehicle or poly(I:C) were subjected to sham or CLP surgery and various parameters of sepsis, including mortality, inflammation, and bacterial clearance were assessed. Poly(I:C) pre-treatment significantly enhanced mortality in mice subjected to CLP. Consistent with this, inflammatory cytokines including TNFalpha, IL-12p40, IFNgamma, and MCP-1 were enhanced both systemically and locally in the poly(I:C)-treated group compared to the vehicle control. In addition, bacterial load was significantly higher in the poly(I:C)-treated septic mice. These changes were associated with reduced macrophage activation (but not neutrophils) in the peritoneal cavity of poly(I:C) pre-treated mice compared to vehicle pre-treatment. Together our results demonstrate that poly(I:C) priming in sepsis is likely to be detrimental to the host due to effects on systemic inflammatory cytokines and bacterial clearance. PMID- 29127665 TI - Hepatocellular Carcinoma Surveillance-Experience from Croatian Referral Centre for Chronic Liver Diseases. AB - PURPOSE: For patients at high-risk of developing hepatocellular carcinoma (HCC), biannual ultrasound surveillance has long been recommended, in order to detect the tumor in the early, potentially curative stages. However, globally reported HCC surveillance rates vary greatly, ranging from as low as 1.7 to as high as 80%. Our aim was to assess the utilization of surveillance with biannual ultrasound in high-risk Croatian patients and to identify the factors that impact the implementation of the recommended protocol. METHODS: This retrospective study included 145 newly diagnosed HCC patients in the period from January 2010 to September 2015. We identified low-risk and high-risk patients. The latter were further subdivided into the regular biannual ultrasound surveillance group and the non-surveillance group. The groups were compared according to demographic characteristics and BCLC stage at the time of HCC diagnosis. RESULTS: Among 145 patients, 80 patients were classified as high-risk according to EASL criteria. During the relevant period, 28.7% underwent regular surveillance, while 71.25% did not. Younger patients were more likely to undergo surveillance (OR 0.935 CI 0.874-0.999; p = 0.05). The patients who underwent regular surveillance had a higher chance of being diagnosed at a curative stage (BCLC 0 or A) (OR 3.701 CI 1.279-10.710; p < 0.05).Gender was not a predictor of participation in the regular surveillance protocol. Among the high-risk patients who did not undergo regular surveillance, 56.1% were not aware of the chronic liver disease prior to the HCC diagnosis. CONCLUSION: HCC surveillance is still underutilized in high risk Croatian patients despite its obvious benefits possibly due to the untimely diagnosis of the chronic liver disease. PMID- 29127664 TI - larvalign: Aligning Gene Expression Patterns from the Larval Brain of Drosophila melanogaster. AB - The larval brain of the fruit fly Drosophila melanogaster is a small, tractable model system for neuroscience. Genes for fluorescent marker proteins can be expressed in defined, spatially restricted neuron populations. Here, we introduce the methods for 1) generating a standard template of the larval central nervous system (CNS), 2) spatial mapping of expression patterns from different larvae into a reference space defined by the standard template. We provide a manually annotated gold standard that serves for evaluation of the registration framework involved in template generation and mapping. A method for registration quality assessment enables the automatic detection of registration errors, and a semi automatic registration method allows one to correct registrations, which is a prerequisite for a high-quality, curated database of expression patterns. All computational methods are available within the larvalign software package: https://github.com/larvalign/larvalign/releases/tag/v1.0. PMID- 29127666 TI - Care for Mental Health of Caribbean Medical Students. PMID- 29127667 TI - "The Rack of His Imagination": Literature and the Psychotic Experience. PMID- 29127668 TI - Coordination through databases can improve prescribed burning as a conservation tool to promote forest biodiversity. AB - Prescribed fires are a common nature conservation practice. They are executed by several parties with limited coordination among them, and little consideration for wildfire occurrences and habitat requirements of fire-dependent species. Here, we gathered data on prescribed fires and wildfires in Sweden during 2011 2015 to (i) evaluate the importance and spatial extent of prescribed fires compared to wildfires and (ii) illustrate how a database can be used as a management tool for prescribed fires. We found that on average only 0.006% (prescribed 65%, wildfires 35%) of the Swedish forest burns per year, with 58% of the prescribed fires occurring on clearcuts. Also, both wildfires and prescribed fires seem to be important for the survival of fire-dependent species. A national fire database would simplify coordination and make planning and evaluation of prescribed fires more efficient. We propose an adaptive management strategy to improve the outcome of prescribed fires. PMID- 29127669 TI - Conserving connectivity: Human influence on subsidy transfer and relevant restoration efforts. AB - Conservation efforts tend to focus on the direct impacts humans have on their surrounding environment; however there are also many ways in which people indirectly affect ecosystems. Recent research on ecological subsidies-the transfer of energy and nutrients from one ecosystem to another-has highlighted the importance of nutrient exchange for maintaining productivity and diversity at a landscape scale, while also pointing toward the fragility of ecotones and vulnerability of subsidies to human activities. We review the recent literature on landscape connectivity and ecosystem subsidies from aquatic systems to terrestrial systems. Based on this review, we propose a conceptual model of how human activities may alter or eliminate the flow of energy and nutrients between ecosystems by influencing the delivery of subsidies along the pathway of transfer. To demonstrate the utility of this conceptual model, we discuss it in the context of case studies of subsidies derived from salmon, marine mammals, sea turtles, sea birds, and shoreline debris. Subsidy restoration may require a different set of actions from simply reversing the pathway of degradation. We suggest that effective restoration and conservation efforts will require a multifaceted approach, targeting many steps along the subsidy transfer pathway, to address these issues. PMID- 29127670 TI - Identifying women's attitudes and barriers to participating in a proposed community-based conservation group in western Belize. AB - With mounting research showing the many benefits of having women involved in community-based conservation (CBC) efforts, we wanted to identify and measure the attitudes and barriers to women participating in a CBC program in western Belize. We surveyed 500 women in communities surrounding the Vaca Forest Reserve to measure their interest in, attitudes toward, and possible barriers to participating in a CBC program. We assessed women's intent to participate in CBC activities using the Theory of Planned Behavior to identify the attitudinal, normative, and behavioral control constructs that best predict their intentions to participate. Women indicated positive attitudes toward participating in a CBC program, while perceived behavioral controls had the largest influence on their intent to participate. Understanding the importance of and influence of these constructs on women's participation will help us and other conservation scientists work with women to collaboratively design effective conservation programs. PMID- 29127671 TI - The Frequency of Reporting Ethical Issues in Human Subject Articles Published in Iranian Medical Journals: 2009-2013. AB - Researchers should strictly consider the participants' rights. They are required to document such protections as an ethical approval of the study proposal, the obtaining "informed consent", the authors' "conflict of interests", and the source of "financial support" in the published articles. The purpose of this study was to assess the frequency of reporting ethical issues in human subject articles published in Iranian medical journals during 2009-2013. In this cross sectional study, we randomly reviewed 1460 human subject articles published in Iranian medical journals during 2009-2013 in two Persian and English language groups. Data collection was carried out by assessing articles, focusing on the documentation "ethics committee approval", patients' "informed consent", "financial support", "confidentiality", and "conflict of interest". Of 1460 evaluated articles, 443 (30.3%) reported "ethics committee approval", 686 (47.0%) reported "informed consent", 594 (40.7%) reported "financial support", and 341 (23.4%) reported "conflict of interest". 13% of the articles referred to patients' confidentiality in their text. There was a significant association between these ethical documentations and the year of publication. Articles published in English language journals reported "ethics committee approval", "financial support", and "conflict of interest" significantly more than Persian language journals, but the frequency of "informed consent" was similar. Ethical documentation rate in Iranian medical journals is not up to the expected standards of reputable journals which might be related to a lack of awareness and the education of the authors and the journal's editors. Precise reporting of ethical considerations in medical articles by authors are recommended. It is suggested journals and policymakers pay more attention to reporting this issue while providing standard guidelines in this regard. PMID- 29127672 TI - Responsible Conduct of Human Subjects Research in Islamic Communities. AB - In order to increase understanding of the ethical implications of biomedical, behavioral and clinical research, the Fogarty International Center, part of the United States National Institutes of Health, established an International Research Ethics Education and Curriculum Development Award (R25) to support programs in low- and middle-income countries. To develop research ethics expertise in Jordan, the University of California San Diego fellowship program in collaboration with Jordan University of Science and Technology provides courses that enable participants to develop skills in varied research ethics topics, including research with human subjects. The program provides a master's level curriculum, including practicum experiences. In this article we describe a practicum project to modify an existing introduction to human subjects research for a US audience to be linguistically and culturally appropriate to Arabic speaking-Islamic communities. We also highlight key differences that guided the conversion of an English version to one that is in Arabic. And finally, as Institutional Review Boards follow the ethical principles of the Belmont Report in evaluating and approving biomedical and behavioral human subjects research proposals, we provide observations on the conformity of the three ethical principles of the Belmont Report with Islam. PMID- 29127673 TI - Technology Development as a Normative Practice: A Meaning-Based Approach to Learning About Values in Engineering-Damming as a Case Study. AB - Engineering, as a complex and multidimensional practice of technology development, has long been a source of ethical concerns. These concerns have been approached from various perspectives. There are ongoing debates in the literature of the philosophy of engineering/technology about how to organize an optimized view of the values entailed in technology development processes. However, these debates deliver little in the way of a concrete rationale or framework that could comprehensively describe different types of engineering values and their multi aspect interrelations in real engineering practices. Approaching engineering values from a meaning-based perspective, as in this paper, can be a reliable method of tackling such a controversial problem. This paper therefore proposes that technology development be considered a systemic normative practice and attempts to provide a comprehensive view of various built-in values, their different origins and features, and a way of prioritizing them in real engineering processes. Studying two cases of the Zayandeh Rood Dam and the Abbasi Dam will lead to practical insights into how to understand norms in technology development and incorporate them into engineering practice. PMID- 29127675 TI - Clinical Features of beta-Thalassemia and Sickle Cell Disease. AB - Sickle cell disease (SCD) and beta-thalassemia are among the most common inherited diseases, affecting millions of persons globally. It is estimated that 5-7% of the world's population is a carrier of a significant hemoglobin variant. Without early diagnosis followed by initiation of preventative and therapeutic care, both SCD and beta-thalassemia result in significant morbidity and early mortality. Despite great strides in the understanding of the molecular basis and pathophysiology of these conditions, the burden of disease remains high, particularly in limited resource settings. Current therapy relies heavily upon the availability and safety of erythrocyte transfusions to treat acute and chronic complications of these conditions, but frequent transfusions results in significant iron overload, as well as challenges from acquired infections and alloimmunization. Hydroxyurea is a highly effective treatment for SCD but less so for beta-thalassemia, and does not represent curative therapy. As technology and use of cellular and gene therapies expand, SCD and thalassemia should be among the highest disease priorities. PMID- 29127674 TI - Pharmacotherapeutic Management of Pediatric Lymphoma. AB - Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) comprise approximately 15% of all childhood malignancies. Cure rates for both lymphoma entities have evolved tremendously during the last couple of decades, raising the 5-year survival rates to almost 100% for HL and to 85% for NHL. The mainstay therapy for both malignancies is still chemotherapy-with different regimens recommended for different types of disease. In HL, combined modality treatment, i.e., chemotherapy followed by radiotherapy, has long been the standard regimen. In order to reduce long-term side effects, such as second malignancies, most major pediatric HL consortia have studied response-based radiotherapy reduction strategies over the last 3 decades. For recurrent disease, high-dose chemotherapy followed by an autologous or an allogeneic hematopoietic stem-cell transplant is an option. No targeted agents have yet gained regulatory approval for use in pediatric patients with lymphoma. For adult lymphoma patients, the CD20 antibody rituximab and the CD30 antibody-drug conjugate brentuximab vedotin are targeted agents used regularly in first- and second-line treatment regimens. More recently, immune checkpoint inhibitors, phosphatidyl-inositol-3-kinase inhibitors, and Bruton's tyrosine kinase inhibitors appear to be very promising new treatment options in adult lymphoma. Here, we discuss the current experience with these types of agents in pediatric lymphoma patients. PMID- 29127676 TI - Genetic Basis and Genetic Modifiers of beta-Thalassemia and Sickle Cell Disease. AB - beta-thalassemia and sickle cell disease (SCD) are prototypical Mendelian single gene disorders, both caused by mutations affecting the adult beta-globin gene. Despite the apparent genetic simplicity, both disorders display a remarkable spectrum of phenotypic severity and share two major genetic modifiers-alpha globin genotype and innate ability to produce fetal hemoglobin (HbF, alpha2gamma2).This article provides an overview of the genetic basis for SCD and beta-thalassemia, and genetic modifiers identified through phenotype correlation studies. Identification of the genetic variants modifying HbF production in combination with alpha-globin genotype provide some prediction of disease severity for beta-thalassemia and SCD but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered.Nonetheless, genetic studies have been successful in characterizing some of the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation. PMID- 29127678 TI - Allogeneic/Matched Related Transplantation for beta-Thalassemia and Sickle Cell Anemia. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) can cure single gene disorders such as thalassemia and sickle cell anemia (SCA). These non-malignant diseases have in common severe hemolytic anemia and high proliferative bone marrow, requiring frequent transfusions. The risk of rejection is high and graft vs-host disease is not desirable. Important progress has been made in the management of these diseases, including leukocyte depletion of blood products, and chelation therapy, for both diseases, and erythrocytapheresis and hydroxycarbamide for SCA. However, morbidity and quality of life are still of concern. Results have also significantly improved for HSCT, with the reduction of rejection by using anti-thymocyte globulin (ATG), which also decreases the risk of chronic graft-vs-host disease. Current data show a more than 90% chance of cure with myeloablative conditioning in children with hemoglobinopathy and a geno identical donor. Results are similar whether the cell source is cord blood or bone marrow. Because of the risk of conditioning-related infertility, ovarian and/or testis cryopreservation should be discussed. Non-myeloablative conditioning regimens have also been successfully developed in adults with SCA and organ dysfunction, making cure possible. These encouraging results should incite to perform HLA typing early in families with hemoglobinopathies, and to systematically propose sibling cord blood cryopreservation for those without geno identical donor. PMID- 29127677 TI - Current Standards of Care and Long Term Outcomes for Thalassemia and Sickle Cell Disease. AB - Thalassemia and sickle cell disease (SCD) are disorders of hemoglobin that affect millions of people worldwide. The carrier states for these diseases arose as common, balanced polymorphisms during human history because they afforded protection against severe forms of malaria. These complex, multisystem diseases are reviewed here with a focus on current standards of clinical management and recent research findings. The importance of a comprehensive, multidisciplinary and lifelong system of care is also emphasized. PMID- 29127679 TI - Alternative Donor/Unrelated Donor Transplants for the beta-Thalassemia and Sickle Cell Disease. AB - Considerable progress with respect to donor source has been achieved in allogeneic stem cell transplant for patients with hemoglobin disorders, with matched sibling donors in the 1980s, matched unrelated donors and cord blood sources in the 1990s, and haploidentical donors in the 2000s. Many studies have solidified hematopoietic progenitors from matched sibling marrow, cord blood, or mobilized peripheral blood as the best source-with the lowest graft rejection and graft versus host disease (GvHD), and highest disease-free survival rates. For patients without HLA-matched sibling donors, but who are otherwise eligible for transplant, fully allelic matched unrelated donor (8/8 HLA-A, B, C, DRB1) appears to be the next best option, though an ongoing study in patients with sickle cell disease will provide data that are currently lacking. There are high GvHD rates and low engraftment rates in some of the unrelated cord transplant studies. Haploidentical donors have emerged in the last decade to have less GvHD; however, improvements are needed to increase the engraftment rate. Thus the decision to use unrelated cord blood units or haploidentical donors may depend on the institutional expertise; there is no clear preferred choice over the other. Active research is ongoing in expanding cord blood progenitor cells to overcome the limitation of cell dose, including the options of small molecule inhibitor compounds added to ex vivo culture or co-culture with supportive cell lines. There are inconsistent data from using 7/8 or lower matched unrelated donors. Before routine use of these less matched donor sources, work is needed to improve patient selection, conditioning regimen, GvHD prophylaxis, and/or other strategies. PMID- 29127681 TI - Reactivation of Fetal Hemoglobin for Treating beta-Thalassemia and Sickle Cell Disease. AB - Reactivation of fetal hemoglobin (HbF) in adult hematopoietic cells has the potential for great clinical benefit in patients bearing deleterious mutations in the beta-globin gene, such as beta-thalassemia and sickle cell disease (SCD), since increasing the production of HbF can compensate for underproduction of beta globin chains (in beta-thalassemia) and it can also disrupt sickle hemoglobin polymerization (in SCD). Thus for the past few decades, concerted efforts have been made to identify an effective way to induce the synthesis of HbF in adult erythroid cells for potential therapeutic relief from the effects of these beta globinopathies. Chemical inducers of HbF as well as a number of transcription factors that are able to reactivate HbF synthesis in vitro and in vivo in adult erythroid cells have been identified. However, there has been only limited success in attempts to manipulate either the drugs or regulatory proteins, and in only a fraction of patients, and there is wide variation in individual response to these drugs or transcription factors. These studies highlight the importance for understanding the molecular mechanisms underlying hemoglobin switching so that future studies can be designed to treat these disorders. PMID- 29127682 TI - Genome Editing for the beta-Hemoglobinopathies. AB - The beta-hemoglobinopathies are diverse set of disorders caused by mutations in the beta-globin (HBB) gene. Because HBB protein is a critical component (along with alpha-globin, heme, and iron) of hemoglobin, the molecule essential for oxygen delivery to tissues, mutations in HBB can result in lethal diseases or diseases with multi-organ dysfunction. HBB mutations can be roughly divided into two categories: those that cause a dysfunctional protein (such as sickle cell disease but also including varied diseases caused by high-affinity hemoglobins, low-affinity hemoglobins, and methemoglobinemia) and those that cause the insufficient production of HBB protein (beta-thalassemia). Sickle cell disease and beta-thalassemia are both the most prevalent and the most devastating of the beta-hemoglobinopathies. PMID- 29127680 TI - Gene Addition Strategies for beta-Thalassemia and Sickle Cell Anemia. AB - Beta-thalassemia and sickle cell anemia are two of the most common diseases related to the hemoglobin protein. In these diseases, the beta-globin gene is mutated, causing severe anemia and ineffective erythropoiesis. Patients can additionally present with a number of life-threatening co-morbidities, such as stroke or spontaneous fractures. Current treatment involves transfusion and iron chelation; allogeneic bone marrow transplant is the only curative option, but is limited by the availability of matching donors and graft-versus-host disease. As these two diseases are monogenic diseases, they make an attractive setting for gene therapy. Gene therapy aims to correct the mutated beta-globin gene or add back a functional copy of beta- or gamma-globin. Initial gene therapy work was done with oncoretroviral vectors, but has since shifted to lentiviral vectors. Currently, there are a few clinical trials underway to test the curative potential of some of these lentiviral vectors. This review will highlight the work done thus far, and present the challenges still facing gene therapy, such as genome toxicity concerns and achieving sufficient transgene expression to cure those with the most severe forms of thalassemia. PMID- 29127683 TI - Gene and Cell Therapy for beta-Thalassemia and Sickle Cell Disease with Induced Pluripotent Stem Cells (iPSCs): The Next Frontier. AB - In recent years, breakthroughs in human pluripotent stem cell (hPSC) research, namely cellular reprogramming and the emergence of sophisticated genetic engineering technologies, have opened new frontiers for cell and gene therapy. The prospect of using hPSCs, either autologous or histocompatible, as targets of genetic modification and their differentiated progeny as cell products for transplantation, presents a new paradigm of regenerative medicine of potential tremendous value for the treatment of blood disorders, including beta-thalassemia (BT) and sickle cell disease (SCD). Despite advances at a remarkable pace and great promise, many roadblocks remain before clinical translation can be realistically considered. Here we discuss the theoretical advantages of cell therapies utilizing hPSC derivatives, recent proof-of-principle studies and the main challenges towards realizing the potential of hPSC therapies in the clinic. PMID- 29127684 TI - Identification of ceruloplasmin as a biomarker of chronic kidney disease in urine of sickle cell disease patients by proteomic analysis. PMID- 29127686 TI - The challenge of modeling protein assemblies: the CASP12-CAPRI experiment. AB - We present the quality assessment of 5613 models submitted by predictor groups from both CAPRI and CASP for the total of 15 most tractable targets from the second joint CASP-CAPRI protein assembly prediction experiment. These targets comprised 12 homo-oligomers and 3 hetero-complexes. The bulk of the analysis focuses on 10 targets (of CAPRI Round 37), which included all 3 hetero-complexes, and whose protein chains or the full assembly could be readily modeled from structural templates in the PDB. On average, 28 CAPRI groups and 10 CASP groups (including automatic servers), submitted models for each of these 10 targets. Additionally, about 16 groups participated in the CAPRI scoring experiments. A range of acceptable to high quality models were obtained for 6 of the 10 Round 37 targets, for which templates were available for the full assembly. Poorer results were achieved for the remaining targets due to the lower quality of the templates available for the full complex or the individual protein chains, highlighting the unmet challenge of modeling the structural adjustments of the protein components that occur upon binding or which must be accounted for in template-based modeling. On the other hand, our analysis indicated that residues in binding interfaces were correctly predicted in a sizable fraction of otherwise poorly modeled assemblies and this with higher accuracy than published methods that do not use information on the binding partner. Lastly, the strengths and weaknesses of the assessment methods are evaluated and improvements suggested. PMID- 29127685 TI - The first case of ischemia-free organ transplantation in humans: A proof of concept. AB - Ischemia and reperfusion injury (IRI) is an inevitable event in conventional organ transplant procedure and is associated with significant mortality and morbidity post-transplantation. We hypothesize that IRI is avoidable if the blood supply for the organ is not stopped, thus resulting in optimal transplant outcomes. Here we described the first case of a novel procedure called ischemia free organ transplantation (IFOT) for patients with end-stage liver disease. The liver graft with severe macrovesicular steatosis was donated from a 25-year-old man. The recipient was a 51-year-old man with decompensated liver cirrhosis and hepatocellular carcinoma. The graft was procured, preserved, and implanted under continuous normothermic machine perfusion. The recipient did not suffer post reperfusion syndrome or vasoplegia after revascularization of the allograft. The liver function test and histological study revealed minimal hepatocyte, biliary epithelium and vascular endothelium injury during preservation and post transplantation. The inflammatory cytokine levels were much lower in IFOT than those in conventional procedure. Key pathways involved in IRI were not activated after allograft revascularization. No rejection, or vascular or biliary complications occurred. The patient was discharged on day 18 post transplantation. This marks the first case of IFOT in humans, offering opportunities to optimize transplant outcomes and maximize donor organ utilization. PMID- 29127687 TI - Nuclear inverse polarity papillary lesions lacking myoepithelial cells: A report of two cases. AB - Here, cases of a 68- (Case 1) and a 44-year-old (Case 2) female are presented. They had an abnormality in the breast, and came to our hospital for further examination and treatment. Radiologically, malignancy could not completely excluded so breast excision was performed. Histologically, both cases revealed papillary neoplastic lesions lined by fibrovascular core and nuclear inverse polarity without atypia. Loss of myoepithelial cells was observed by HE, p63, and calponin. Previous report indicate CK5/6, ER, p63 and MUC3 are important for distinguishing between papillary lesions according to the differential index (based on Allred score) of ([ER total score] + [MUC3 total score])/([CK5/6 total score] + [p63 total score] + 1). Based on this analysis, our two cases had benign lesions. However, based on immunopositivity for cell-cycle marker Cyclin-D1, Case 1 was negative, and Case 2 was about 70% positive. Additionally, the Ki-67 index was <1% in both cases, and no evidence of disease was observed after a maximum 62 months of follow-up in both cases, despite lack of additional treatment. Thus, we propose that lack of myoepithelial cells in papillary lesions do not necessarily indicate malignancy and are thought to be, at the most, uncertain malignant potential. PMID- 29127688 TI - Response to the letter of Dr Kizilarslanoglu, "Sarcopenia based on the Asian Working Group for Sarcopenia criteria and all-cause mortality risk in older Japanese adults". PMID- 29127689 TI - Comment on: Sarcopenia based on the Asian Working Group for Sarcopenia criteria and all-cause mortality risk in older Japanese adults. PMID- 29127690 TI - Response to the letter of Dr Ayubi, "Sarcopenia based on the Asian working Group for Sarcopenia criteria and all-cause mortality risk in older Japanese adults: Methodological issues". PMID- 29127691 TI - Sarcopenia based on the Asian working Group for Sarcopenia criteria and all-cause mortality risk in older Japanese adults: Methodological issues. PMID- 29127692 TI - Coagulation measurement from whole blood using vibrating optical fiber in a disposable cartridge. AB - In clinics, blood coagulation time measurements are performed using mechanical measurements with blood plasma. Such measurements are challenging to do in a lab on-a-chip (LoC) system using a small volume of whole blood. Existing LoC systems use indirect measurement principles employing optical or electrochemical methods. We developed an LoC system using mechanical measurements with a small volume of whole blood without requiring sample preparation. The measurement is performed in a microfluidic channel where two fibers are placed inline with a small gap in between. The first fiber operates near its mechanical resonance using remote magnetic actuation and immersed in the sample. The second fiber is a pick-up fiber acting as an optical sensor. The microfluidic channel is engineered innovatively such that the blood does not block the gap between the vibrating fiber and the pick-up fiber, resulting in high signal-to-noise ratio optical output. The control plasma test results matched well with the plasma manufacturer's datasheet. Activated-partial-thromboplastin-time tests were successfully performed also with human whole blood samples, and the method is proven to be effective. Simplicity of the cartridge design and cost of readily available materials enable a low-cost point-of-care device for blood coagulation measurements. PMID- 29127693 TI - X-ray luminescence computed tomography using a focused x-ray beam. AB - Due to the low x-ray photon utilization efficiency and low measurement sensitivity of the electron multiplying charge coupled device camera setup, the collimator-based narrow beam x-ray luminescence computed tomography (XLCT) usually requires a long measurement time. We, for the first time, report a focused x-ray beam-based XLCT imaging system with measurements by a single optical fiber bundle and a photomultiplier tube (PMT). An x-ray tube with a polycapillary lens was used to generate a focused x-ray beam whose x-ray photon density is 1200 times larger than a collimated x-ray beam. An optical fiber bundle was employed to collect and deliver the emitted photons on the phantom surface to the PMT. The total measurement time was reduced to 12.5 min. For numerical simulations of both single and six fiber bundle cases, we were able to reconstruct six targets successfully. For the phantom experiment, two targets with an edge-to-edge distance of 0.4 mm and a center-to-center distance of 0.8 mm were successfully reconstructed by the measurement setup with a single fiber bundle and a PMT. PMID- 29127694 TI - NUT Co Reactivity - ACquiring Knowledge for Elimination Recommendations (NUT CRACKER) study. AB - BACKGROUND: Ambiguities exist regarding the diagnosis of tree-nut allergy, necessitating either their elimination or the performance of oral food challenges (OFCs). OBJECTIVE: To examine the coincidences of allergies among tree-nuts and improve diagnostic testing to minimize the need for OFC. METHODS: Eighty-three patients prospectively evaluated for walnut, pecan, cashew, pistachio, hazelnut, and almond allergy. A history of previous reactions was obtained, and standardized skin prick tests (SPTs) using finely ground tree-nut solution and basophil activation tests (BAT) were performed. Patients underwent OFC for each tree-nut they eliminated and to which a reaction in the previous 2 years was not documented. RESULTS: While most patients were sensitized to 5-6 tree-nuts, over 50% were allergic to only 1-2 tree-nuts. The highest rate of allergy in sensitized patients was observed for walnut (74.6%) and cashew (65.6%). The rate of co-allergy for most tree-nuts was <30%. Two-thirds of walnut- and cashew allergic patients were also allergic to pecan and pistachio, respectively, while all pecan- and pistachio-allergic patients were allergic to walnut and cashew, respectively. Receiver-operating characteristic analysis for SPT and BAT was tree nut dependent and yielded area under the curve (AUC) values ranging from 0.75 to 0.94. Knowledge of coincident allergies in these pairs along with the combination of SPT and BAT correctly distinguished allergic from tolerant patients for walnut (87%), pecan (66%), cashew (71%), and pistachio (79%). CONCLUSION: The data presented here should assist in differentiating between allergic and tolerant patients, decrease the need for OFC, and allow for appropriate elimination recommendations. PMID- 29127695 TI - Management of the "Other" retroperitoneal sarcomas. AB - The focus of this review is on the management of the less common sarcomas occurring in the retroperitoneal space, including solitary fibrous tumor (SFT), malignant peripheral nerve sheath tumor (MPNST), perivascular epithelioid cell tumor (PEComa), and undifferentiated pleomorphic sarcoma (UPS) of the psoas muscle. As for other retroperitoneal sarcomas, surgical resection is the mainstay of curative therapy, and multidisciplinary preoperative assessment, including percutaneous needle biopsy for histologic confirmation, is the basis for personalized management, as the surgical management, and the integration of systemic therapy and radiation therapy is unique to each histologic subtype. PMID- 29127696 TI - Inspiring hope-A physician's responsibility, translating the science into clinical practice. AB - Giving hope to patients is our responsibility. It is the essence of a meaningful practice in medicine. Science now allows us to understand this complex and multidimensional human dynamic, and translate it into clinical practice. Quantitative research has shown hope is strong even in terminal illness. Through qualitative methodology hope fostering strategies and hope hindering behaviors have been identified. This exciting new knowledge facilitates the challenging task of disclosure of bad news while enabling hope. PMID- 29127697 TI - Retroperitoneal sarcomas: Big tumors that involve more than just "Getting it Out". PMID- 29127698 TI - Coincident proximal and distal retrograde left atrial activation: One or two accessory pathways? PMID- 29127699 TI - The maximum standardized uptake value of preoperative positron emission tomography/computed tomography in lung adenocarcinoma with a ground-glass opacity component of less than 30 mm. AB - BACKGROUND AND OBJECTIVES: This study evaluated the relationship between the maximum standardized uptake value (SUVmax) of preoperative positron emission tomography/computed tomography (PET/CT) and the characteristics of lung adenocarcinoma featuring ground-glass opacity nodules (GGN). METHODS: The association of the SUVmax of preoperative PET/CT with ground-glass opacity (GGO) proportion on CT, subtypes of adenocarcinoma (minimally invasive adenocarcinoma, invasive adenocarcinoma), predominant types of invasive adenocarcinoma, and size of the total and invasive components of pathology were evaluated in 190 patients who underwent resection for lung adenocarcinoma featuring GGN. RESULTS: The mean SUVmax of non-solid GGN and partly solid GGN were 0.53 and 1.32, respectively (P = 0.029). The mean SUVmax of the main masses in 38 patients with MIA and 152 with invasive adenocarcinoma were 0.86 and 1.36, respectively (P = 0.029). The mean SUVmax of acinar, lepidic, papillary, and solid tumors were 1.61, 0.87, 0.98, and 1.60, respectively. The mean SUVmax of invasive components measuring <=10 mm, 11 20 mm, and >20 mm were 0.84, 1.66, and 2.09, respectively (P < 0.001). CONCLUSIONS: The SUVmax of lung adenocarcinoma featuring GGN can vary depending on the GGO proportion. A higher SUVmax can be expected in invasive adenocarcinoma than in MIA, and solid and acinar-predominant invasive adenocarcinoma showed a higher SUVmax. PMID- 29127700 TI - Historical perspectives and future directions in the surgical management of retroperitoneal sarcoma. AB - Retroperitoneal sarcomas (RPS) have fascinated and intrigued physicians both past and present. Operative mortality rates were historically very high and complete resection was not possible for the majority of patients until only the last 2 decades. More recently, changes to the surgical approach and clinical decision making in RPS have improved patient outcomes. With select integration of nonsurgical therapies, continued RPS-specific research, and ongoing collaborative efforts among major referral centers, the future appears promising. PMID- 29127701 TI - Release kinetics of somatostatin from self-assembled nanostructured hydrogels. AB - Somatostatin-14 is a native neuropeptide with widespread functions in the body. Self-assembly of somatostatin-14 into amyloid-like nanofibrils has been previously demonstrated in aqueous media. We here hypothesize that the somatostatin nanofibrils can form a stable depot that release monomers in a controlled manner. This study aims to investigate if somatostatin monomers are released from physical hydrogels formed in water and in the presence of electrolytes. The release kinetics of the somatostatin monomers is investigated for the first time. This is correlated with the rheological properties of the hydrogels formed. We demonstrate that at the concentrations tested, there is release of somatostatin monomers from the hydrogels following a novel hybrid model of zero-order and first-order release. In the presence of electrolytes, somatostatin hydrogels demonstrated higher elastic moduli (G') which correlates to the narrower and higher density of nanofibrils observed with TEM. The presence of electrolytes resulted in a slower release of the somatostatin monomers and in a lower cumulative percentage released over 48 hrs. It is questionable that the concentrations released will be therapeutically effective. However, self assembled somatostatin hydrogels have the potential to act as a depot for ocular drug delivery. PMID- 29127703 TI - Comparison of Two Highly Automated ECG Algorithms for Detection of Drug-Induced Cardiac Ion Channel Block. AB - US Food and Drug Administration (FDA) investigators recently demonstrated in a crossover study that early (J-Tpeak c) and late (Tpeak -Tend ) repolarization duration can differentiate selective potassium block with a high arrhythmia risk from multichannel block with lower risk in subjects receiving dofetilide, verapamil, quinidine, or ranolazine. The purpose of this study was to determine if the findings by the FDA using their published software algorithm could be corroborated using an alternative software algorithm for the same metrics and to determine if methodological differences resulted in clinically meaningful differences in interpretation. Exposure-response relationships computed with linear mixed effects models and mean maximal effects on ECG intervals measured by the two algorithms were similar, corroborating the FDA findings, but with some differences in the modeled slopes and magnitude of changes. The alternative software resulted in an average 25% reduction in the 95% confidence intervals of the mixed effects models with generally lower Akaike Information Criterion values. PMID- 29127702 TI - Towards functional selectivity for alpha6beta3gamma2 GABAA receptors: a series of novel pyrazoloquinolinones. AB - BACKGROUND AND PURPOSE: The GABAA receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular alpha+/beta- interfaces, using a systematically varied series of pyrazoloquinolinones. EXPERIMENTAL APPROACH: Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA-elicited currents by the newly synthesized and reference compounds were investigated by the two-electrode voltage clamp method. KEY RESULTS: We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at alpha6beta3gamma2 GABAA receptors with nearly no residual activity at the other alphaxbeta3gamma2 (x = 1-5) subtypes. This modulation was independent of affinity for alpha+/gamma- interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular alpha+/beta- interfaces. CONCLUSION AND IMPLICATIONS: These results constitute a major step towards a potential selective positive modulation of certain alpha6-containing GABAA receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABAA receptor isoforms. PMID- 29127704 TI - Does neoadjuvant/perioperative chemotherapy improve overall survival for T2N0 gastric adenocarcinoma? AB - BACKGROUND: The purpose of this study was to determine whether neoadjuvant and/or perioperative chemotherapy (NAC) has an overall survival (OS) benefit for patients with T2N0 gastric adenocarcinoma. STUDY DESIGN: We performed retrospective analyses using the National Cancer Data Base, 2004-2013. Patients with T2N0 gastric adenocarcinoma were divided into two treatment groups: (1) NAC plus surgery (NA + S) and (2) surgery alone (S). RESULTS: Of 1,704 patients included, 277 (16.3%) received NAC, and 1,427 (83.7%) were treated with surgery alone. Patients in the NA + S group were more likely to be younger, have fewer comorbidities, and have larger tumors located in the proximal stomach. Although in an unadjusted analysis of OS, the NA + S group had improved survival compared to the S group (HR = 0.81, 95% CI 0.67-0.99, P < 0.0001), this was not maintained in a propensity adjusted analysis (HR = 0.89, 95% CI 0.68-1.18, P = 0.42). Similarly, propensity adjusted analyses accounting for potential bias from clinical misstaging or treatment effect from NAC did not show any OS benefit from NAC. CONCLUSION: Based on the largest cohort of clinically staged T2N0 gastric adenocarcinoma, there was no OS benefit derived from NAC compared to surgery alone. For select patients with reliable preoperative staging, NAC may be omitted. PMID- 29127705 TI - In reply: Management of thin melanoma. PMID- 29127706 TI - Peptide strand length controls the energetics of self-assembly and morphology of beta-sheet fibrils. AB - Self-assembling peptides can be used as versatile, natural, and multifunctional building blocks to produce a variety of well-defined nanostructures, materials and devices for applications in medicine and nanotechnology. Here, we concentrate on the 1D self-assembly of de novo designed Px-2 peptide beta-strands into anti parallel beta-sheet tapes and higher order aggregates. We study six members of the Px-2 family, ranging from 3 amino acids (aa) to 13 aa in length, using a range of complementary experimental techniques, computer simulation and theoretical statistical mechanics. The critical concentration for self-assembly (c*) is found to increase systematically with decreasing peptide length. The shortest peptide found to self-assemble into soluble beta-tapes in water is a 5 amino acid residue peptide. These investigations help decipher the role of the peptide length in controlling self-assembly, aggregate morphology, and material properties. By extracting free energies from these data using a statistical mechanical analysis and combining the results with computer simulations at the atomistic level, we can extract the entropy of association for individual beta strands. PMID- 29127707 TI - Acoustic Characterization and Enhanced Ultrasound Imaging of Long-Circulating Lipid-Coated Microbubbles. AB - OBJECTIVES: A long-circulating lipid-coated ultrasound (US) contrast agent was fabricated to achieve a longer wash-out time and gain more resistance against higher-mechanical index sonication. Systemic physical, acoustic, and in vivo imaging experiments were performed to better understand the underlying mechanism enabling the improvement of contrast agent performance by adjusting the physical and acoustic properties of contrast agent microbubbles. METHODS: By simply altering the gas core, a kind of US contrast agent microbubble was synthesized with a similar lipid-coating shell as SonoVue microbubbles (Bracco SpA, Milan, Italy) to achieve a longer wash-out time and higher inertial cavitation threshold. To bridge the structure-performance relationship of the synthesized microbubbles, the imaging performance of the microbubbles was assessed in vivo with SonoVue as a control group. The size distribution and inertial cavitation threshold of the synthesized microbubbles were characterized, and the shell parameters of the microbubbles were determined by acoustic attenuation measurements. All of the measurements were compared with SonoVue microbubbles. RESULTS: The synthesized microbubbles had a spherical shape, a smooth, consistent membrane, and a uniform distribution, with an average diameter of 1.484 MUm. According to the measured attenuation curve, the synthesized microbubbles resonated at around 2.8 MHz. Although the bubble's shell elasticity (0.2 +/- 0.09 N/m) was comparable with SonoVue, it had relatively greater viscosity and inertial cavitation because of the different gas core. Imaging studies showed that the synthesized microbubbles had a longer circulation time and a better chance of fighting against rapid collapse than SonoVue. CONCLUSIONS: Nano/micrometer long-circulating lipid-coated microbubbles could be fabricated by simply altering the core composition of SonoVue microbubbles with a higher molecular weight gas. The smaller diameter and higher inertial cavitation threshold of the synthesized microbubbles might make it easier to access deep seated organs and give prolonged imaging enhancement in the liver. PMID- 29127709 TI - Pulmonary damage following right ventricular outflow tachycardia ablation in a child: When electroanatomical mapping isn't good enough. AB - A 14-year-old female was referred for severe pulmonary valve insufficiency after undergoing radiofrequency ablation for a right ventricular outflow tract tachycardia that originated in the proximal pulmonary artery at 10 years of age. Clinical records indicated that ablation was guided solely by electrograms and electroanatomical mapping. Due to myocardial tissue extensions, mapping failed to identify the level of the pulmonary valve annulus, which resulted in delivery of energy on the valve proper and into the pulmonary artery. She developed severe pulmonary valve insufficiency and moderate proximal pulmonary artery stenosis necessitating intravascular stent placement 4 years later with an associated transcatheter valve. Although the nonfluoroscopic approach during ablation has gained wide acceptance for use in children, this report highlights the benefits of adjunctive imaging to identify the precise location of the pulmonary valve when ablation therapy is contemplated in the right ventricle outflow tract. PMID- 29127708 TI - Calcimimetic and calcilytic therapies for inherited disorders of the calcium sensing receptor signalling pathway. AB - : The calcium-sensing receptor (CaS receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss-of-function and gain-of function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS receptor signal transduction in the parathyroid glands is probably regulated by G-protein subunit alpha11 (Galpha11 ) and adaptor-related protein complex-2 sigma-subunit (AP2sigma), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS receptor, Galpha11 or AP2sigma proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient-based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS receptor signalling pathway. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc. PMID- 29127710 TI - Buthionine sulfoximine is a multitarget inhibitor of trypanothione synthesis in Trypanosoma cruzi. AB - Buthionine sulfoximine (BSO) induces decreased glutathione (GSH) and trypanothione [T(SH)2 ] pools in trypanosomatids, presumably because only gamma glutamylcysteine synthetase (gammaECS) is blocked. However, some BSO effects cannot be explained by exclusive gammaECS inhibition; therefore, its effect on the T(SH)2 metabolism pathway in Trypanosoma cruzi was re-examined. Parasites exposed to BSO did not synthesize T(SH)2 even when supplemented with cysteine or GSH, suggesting trypanothione synthetase (TryS) inhibition by BSO. Indeed, recombinant gammaECS and TryS, but not GSH synthetase, were inhibited by BSO and kinetics and docking analyses on a TcTryS 3D model suggested BSO binding at the GSH site. Furthermore, parasites overexpressing gammaECS and TryS showed ~ 50% decreased activities after BSO treatment. These results indicated that BSO is also an inhibitor of TryS. PMID- 29127711 TI - Can I serve this dish half-baked? Approaches to publishing some less than perfect research. PMID- 29127712 TI - Connectivity of cone photoreceptor telodendria in the zebrafish retina. AB - The connectivity amongst photoreceptors is critical to their function, as it underpins lateral inhibition and effective translation of stimuli into neural signals. Despite much work characterizing second-order interneurons in the outer retina, the synapses directly connecting photoreceptors have often been overlooked. Telodendria are fine processes that connect photoreceptor pedicles. They have been observed in diverse vertebrate groups, yet their roles in vision remain speculative. Here, we visualize telodendria via fluorescent protein expression in photoreceptor subtypes. We characterized short wavelength cone telodendria in adult and larval zebrafish retina. Additionally, in the larval retina, we investigated rod telodendria and UV cone telodendria in mutant and transgenic retinas with altered complements of cone types. In the adult retina, telodendria are twice as abundant and branch almost twice as often on blue cones compared to UV cones. Pedicles of neighboring UV and blue cones typically converge into contiguous pairs, despite the regular spacing of their cell bodies. In contrast to adults, larval UV cone telodendria are more numerous (1.3 times) than blue cone telodendria. UV cone telodendria are not detectably affected by ablation of blue cones, and are reduced twofold in mutant larval retina with few UV cones. We thus saw no evidence that telodendria increase in number in the absence of their typical cellular neighbors. We also found that larval rod telodendria are less abundant than short wavelength cone telodendria. In summary, we describe the development and morphology of zebrafish photoreceptor synaptic connectivity toward appreciating the function of telodendria in visual signal processing. PMID- 29127713 TI - Prevalence of key care indicators of pressure injuries, incontinence, malnutrition, and falls among older adults living in nursing homes in New Zealand. AB - Pressure injuries, incontinence, malnutrition, and falls are important indicators of the quality of care in healthcare settings, particularly among older people, but there is limited information on their prevalence in New Zealand (NZ). The aim of this study was to establish the prevalence of these four problems among older people in nursing home facilities. The cross-sectional study was an analysis of data collected on a single day for the 2016 National Care Indicators Programme New Zealand (NCIP-NZ). The sample included 276 people ages 65 and older who were residents in 13 nursing home facilities in a geographically diverse area of central NZ. Data were analyzed with descriptive statistics. Prevalence rates in these nursing home settings was pressure injuries 8%; urinary incontinence 57%; fecal incontinence 26%; malnutrition 20%, and falls 13%, of which half resulted in injuries. As people age, complex health issues can lead to increasing care dependency and more debilitating and costly health problems. Measuring the prevalence of basic care problems in NZ healthcare organizations and contributing to a NZ database can enable monitoring of the effectiveness of national and international guidelines. PMID- 29127714 TI - A rule of unity for human intestinal absorption 3: Application to pharmaceuticals. AB - The rule of unity is based on a simple absorption parameter, Pi, that can accurately predict whether or not an orally administered drug will be well absorbed or poorly absorbed. The intrinsic aqueous solubility and octanol-water partition coefficient, along with the drug dose are used to calculate Pi. We show that a single delineator value for Pi exist that can distinguish whether a drug is likely to be well absorbed (FA >= 0.5) or poorly absorbed (FA < 0.5) at any specified dose. The model is shown to give 82.5% correct predictions for over 938 pharmaceuticals. The maximum well-absorbed dose (i.e. the maximum dose that will be more than 50% absorbed) calculated using this model can be utilized as a guideline for drug design and synthesis. PMID- 29127716 TI - Conformational properties, membrane interaction, and antibacterial activity of the peptaibiotic chalciporin A: Multitechnique spectroscopic and biophysical investigations on the natural compound and labeled analogs. AB - In this work, an extensive set of spectroscopic and biophysical techniques (including FT-IR absorption, CD, 2D-NMR, fluorescence, and CW/PELDOR EPR) was used to study the conformational preferences, membrane interaction, and bioactivity properties of the naturally occurring synthetic 14-mer peptaibiotic chalciporin A, characterized by a relatively low (~20%), uncommon proportion of the strongly helicogenic Aib residue. In addition to the unlabeled peptide, we gained in-depth information from the study of two labeled analogs, characterized by one or two residues of the helicogenic, nitroxyl radical-containing TOAC. All three compounds were prepared using the SPPS methodology, which was carefully modified in the course of the syntheses of TOAC-labeled analogs in view of the poorly reactive alpha-amino function of this very bulky residue and the specific requirements of its free-radical side chain. Despite its potentially high flexibility, our results point to a predominant, partly amphiphilic, alpha helical conformation for this peptaibiotic. Therefore, not surprisingly, we found an effective membrane affinity and a remarkable penetration propensity. However, chalciporin A exhibits a selectivity in its antibacterial activity not in agreement with that typical of the other members of this peptide class. PMID- 29127717 TI - Salivary uric acid and C-reactive protein associations with hypertension in Midwestern Latino preadolescents and their parents. AB - Latino families face increased risk for hypertension. Serum-based uric acid and C reactive protein have been linked to hypertension. However, a paucity of salivary biomarker data exists in this area for Latino families. Using salivary biomarkers enables less invasive options for biomedical and biosocial research, which is especially important among vulnerable populations facing increased health disparities. This study examined the associations between salivary uric (sUA) acid, salivary C-reactive protein (sCRP), and hypertension among 151 participants (57 children, 57 mothers, 37 fathers) from 57 Midwestern Latino families. Participants self-administered the salivary samples, and blood pressure was measured by researchers. Results showed sUA was associated across family members, and child hypertension was related to parents' hypertension. sCRP was only related to sUA in fathers. Findings highlight the family-level health connections, along with the importance for further investigations using salivary biomarkers with Latinos, and the need for a robust sUA cut-off for hyperuricemia. PMID- 29127718 TI - Frontal eye field in prosimian galagos: Intracortical microstimulation and tracing studies. AB - The frontal eye field (FEF) in prosimian primates was identified as a small cortical region, above and anterior to the anterior frontal sulcus, from which saccadic eye movements were evoked with electrical stimulation. Tracer injections revealed FEF connections with cortical and subcortical structures participating in higher order visual processing. Ipsilateral cortical connections were the densest with adjoining parts of the dorsal premotor and prefrontal cortex (PFC). Label in a region corresponding to supplementary eye field (SEF) of other primates, suggests the existence of SEF in galagos. Other connections were with ventral premotor cortex (PMV), the caudal half of posterior parietal cortex, cingulate cortex, visual areas within the superior temporal sulcus, and inferotemporal cortex. Callosal connections were mostly with the region of the FEF of another hemisphere, SEF, PFC, and PMV. Most subcortical connections were ipsilateral, but some were bilateral. Dense bilateral connections were to caudate nuclei. Densest reciprocal ipsilateral connections were with the paralamellar portion of mediodorsal nucleus, intralaminar nuclei and magnocellular portion of ventral anterior nucleus. Other FEF connections were with the claustrum, reticular nucleus, zona incerta, lateral posterior and medial pulvinar nuclei, nucleus limitans, pretectal area, nucleus of Darkschewitsch, mesencephalic and pontine reticular formation and pontine nuclei. Surprisingly, the superior colliculus (SC) contained only sparse anterograde label. Although most FEF connections in galagos are similar to those in monkeys, the FEF-SC connections appear to be much less. This suggests that a major contribution of the FEF to visuomotor functions of SC emerged with the evolution of anthropoid primates. PMID- 29127715 TI - Relationship between preoperative breast MRI and surgical treatment of non metastatic breast cancer. AB - BACKGROUND AND OBJECTIVES: More extensive surgical treatments for early stage breast cancer are increasing. The patterns of preoperative MRI overall and by stage for this trend has not been well established. METHODS: Using Breast Cancer Surveillance Consortium registry data from 2010 through 2014, we identified women with an incident non-metastatic breast cancer and determined use of preoperative MRI and initial surgical treatment (mastectomy, with or without contralateral prophylactic mastectomy (CPM), reconstruction, and breast conserving surgery +/- radiation). Clinical and sociodemographic covariates were included in multivariable logistic regression models to estimate adjusted odds ratios and 95% confidence intervals. RESULTS: Of the 13 097 women, 2217 (16.9%) had a preoperative MRI. Among the women with MRI, results indicated 32% higher odds of unilateral mastectomy compared to breast conserving surgery and of mastectomy with CPM compared to unilateral mastectomy. Women with preoperative MRI also had 56% higher odds of reconstruction. CONCLUSION: Preoperative MRI in women with DCIS and early stage invasive breast cancer is associated with more frequent mastectomy, CPM, and reconstruction surgical treatment. Use of more extensive surgical treatment and reconstruction among women with DCIS and early stage invasive cancer whom undergo MRI warrants further investigation. PMID- 29127719 TI - Critical evaluation of the American Joint Commission on Cancer (AJCC) 8th edition staging system for patients with Hepatocellular Carcinoma (HCC): A Surveillance, Epidemiology, End Results (SEER) analysis. AB - BACKGROUND: Recently, the American Joint Committee on Cancer (AJCC) released its 8th edition changes to the staging system for hepatocellular cancer (HCC). We sought to validate the 8th edition staging system and compare the performance to the 7th edition using a population-based data set. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database (1998-2013), patients undergoing resection or transplant for non-metastatic HCC were identified. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Concordance indices (c-indices) were calculated from Cox proportional hazards models to evaluate discriminatory power. RESULTS: The study included 8918 patients resected (63%) or transplanted (37%) for HCC. Nodal staging was performed in 19%, of whom 5% had positive nodes. The c-index for the AJCC 8th edition staging system was 0.60, similar to that for the 7th edition (0.59). Survival was better for solitary tumors >2 cm with vascular invasion than for multifocal tumors <5 cm (median not reached vs 57 months, P < 0.0001), although the staging system groups these tumors together as T2. For multifocal tumors <=5 cm, those with vascular invasion had worse survival than those without (median 42 vs 50 months, P < 0.001), although the staging system draws no such distinction. CONCLUSION: The AJCC 8th edition staging system for HCC performs similarly to the 7th edition. Future revisions should consider substratification of early HCC, specifically by distinguishing solitary tumors >2 cm from multifocal tumors <=5 cm, and by considering the prognostic impact of vascular invasion in multifocal tumors <=5 cm. Future studies should aim to validate these findings. PMID- 29127720 TI - Breaking the polar-nonpolar division in solvation free energy prediction. AB - Implicit solvent models divide solvation free energies into polar and nonpolar additive contributions, whereas polar and nonpolar interactions are inseparable and nonadditive. We present a feature functional theory (FFT) framework to break this ad hoc division. The essential ideas of FFT are as follows: (i) representability assumption: there exists a microscopic feature vector that can uniquely characterize and distinguish one molecule from another; (ii) feature function relationship assumption: the macroscopic features, including solvation free energy, of a molecule is a functional of microscopic feature vectors; and (iii) similarity assumption: molecules with similar microscopic features have similar macroscopic properties, such as solvation free energies. Based on these assumptions, solvation free energy prediction is carried out in the following protocol. First, we construct a molecular microscopic feature vector that is efficient in characterizing the solvation process using quantum mechanics and Poisson-Boltzmann theory. Microscopic feature vectors are combined with macroscopic features, that is, physical observable, to form extended feature vectors. Additionally, we partition a solvation dataset into queries according to molecular compositions. Moreover, for each target molecule, we adopt a machine learning algorithm for its nearest neighbor search, based on the selected microscopic feature vectors. Finally, from the extended feature vectors of obtained nearest neighbors, we construct a functional of solvation free energy, which is employed to predict the solvation free energy of the target molecule. The proposed FFT model has been extensively validated via a large dataset of 668 molecules. The leave-one-out test gives an optimal root-mean-square error (RMSE) of 1.05 kcal/mol. FFT predictions of SAMPL0, SAMPL1, SAMPL2, SAMPL3, and SAMPL4 challenge sets deliver the RMSEs of 0.61, 1.86, 1.64, 0.86, and 1.14 kcal/mol, respectively. Using a test set of 94 molecules and its associated training set, the present approach was carefully compared with a classic solvation model based on weighted solvent accessible surface area. (c) 2017 Wiley Periodicals, Inc. PMID- 29127721 TI - The impact of preoperative magnetic resonance imaging and lumpectomy cavity shavings on re-excision rate in pure ductal carcinoma in situ-A single institution's experience. AB - BACKGROUND AND OBJECTIVES: The impact of preoperative magnetic resonance imaging (pMRI) and cavity shave margins (CSM) on re-excision rate (RR) in DCIS is unclear. We investigated whether either modality was associated with RR in DCIS. METHODS: This is a single-institution retrospective study of 295 women undergoing breast conservation surgery for pure DCIS (2010-2013). CSM were the systematic resection of 4-6 margins during lumpectomy whereas selective shave margins (SSM) were the selective resection of 1-3 margins. Patient demographics and clinical characteristics were abstracted. RR was analyzed according to the use of pMRI, SSM, or CSM with respect to three high-volume breast surgeons at our institution. RESULTS: RR was not associated with the use of pMRI (P = 0.87). Any shave margins (P = 0.05), DCIS size (P < 0.001), and DCIS grade (P = 0.14) associated with a lower RR. Of our high-volume surgeons, RR was lower for Surgeon A (P = 0.02). Multivariate analyses showed larger DCIS (OR 1.35, P = 0.005) and practices specific to surgeons B (OR 3.23, P = 0.04) and C (OR 3.57, P = 0.04) increased re excision odds. CONCLUSIONS: SSM/CSM and pMRI use varied among surgeons. Our results suggested the routine use of CSM, not pMRI, could lower re-excision rate, which highlighted a quality improvement opportunity at our institution. PMID- 29127722 TI - Two members of the velvet family, VmVeA and VmVelB, affect conidiation, virulence and pectinase expression in Valsa mali. AB - Velvet protein family members are important fungal-specific regulators which are involved in conidial development, secondary metabolism and virulence. To gain a broader insight into the physiological functions of the velvet protein family of Valsa mali, which causes a highly destructive canker disease on apple, we conducted a functional analysis of two velvet protein family members (VmVeA and VmVelB) via a gene replacement strategy. Deletion mutants of VmVeA and VmVelB showed increased melanin production, conidiation and sensitivity to abiotic stresses, but exhibited reduced virulence on detached apple leaves and twigs. Further studies demonstrated that the regulation of conidiation by VmVeA and VmVelB was positively correlated with the melanin synthesis transcription factor VmCmr1. More importantly, transcript levels of pectinase genes were shown to be decreased in deletion mutants compared with those of the wild-type during infection. However, the expression of other cell wall-degrading enzyme genes, including cellulase, hemi-cellulase and ligninase genes, was not affected in the deletion mutants. Furthermore, the determination of pectinase activity and immunogold labelling of pectin demonstrated that the capacity for pectin degradation was attenuated as a result of deletions of VmVeA and VmVelB. Finally, the interaction of VmVeA with VmVelB was identified through co immunoprecipitation assays. VmVeA and VmVelB play critical roles in conidiation and virulence, probably via the regulation of the melanin synthesis transcription factor VmCmr1 and their effect on pectinase gene expression in V. mali, respectively. PMID- 29127723 TI - Molecular Magnesium Hydrides. AB - Solid magnesium hydride [MgH2 ]infinity has been pursued as a potential hydrogen storage material. Organic chemists were rather interested in soluble magnesium hydride reagents from mid-20th century. It was only in the last two decades that molecular magnesium hydride chemistry received a major boost from organometallic chemists with a series of structurally well-characterized examples that continues to build a whole new class of compounds. More than 40 such species have been isolated, ranging from mononuclear terminal hydrides to large hydride clusters with more than 10 magnesium atoms. They provide not only insights into the structure and bonding of Mg-H motifs, but also serve as models for hydrogen storage materials. Some of them are also recognized to participate in catalytic transformations, such as hydroelementation. Herein, an overview of these molecular magnesium hydrides is given, focusing on their synthesis and structural characterization. PMID- 29127724 TI - Safety Aspects of the Use of Quercetin as a Dietary Supplement. AB - The flavonoid quercetin is frequently found in low amounts as a secondary plant metabolite in fruits and vegetables. Isolated quercetin is also marketed as a dietary supplement, mostly as the free quercetin aglycone, and frequently in daily doses of up to 1000 mg d-1 exceeding usual dietary intake levels. The present review is dedicated to safety aspects of isolated quercetin used as single compound in dietary supplements. Among the numerous published human intervention studies, adverse effects following supplemental quercetin intake have been rarely reported and any such effects were mild in nature. Published adequate scientific data for safety assessment in regard to the long-term use (>12 weeks) of high supplemental quercetin doses (>=1000 mg) are currently not available. Based on animal studies involving oral quercetin application some possible critical safety aspects could be identified such as the potential of quercetin to enhance nephrotoxic effects in the predamaged kidney or to promote tumor development especially in estrogen-dependent cancer. Furthermore, animal and human studies with single time or short-term supplemental quercetin application revealed interactions between quercetin and certain drugs leading to altered drug bioavailability. Based on these results, some potential risk groups are discussed in the present review. PMID- 29127725 TI - A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function. AB - We report on a homozygous frameshift deletion in DDX59 (c.185del: p.Phe62fs*13) in a family presenting with orofaciodigital syndrome phenotype associated with a broad neurological involvement characterized by microcephaly, intellectual disability, epilepsy, and white matter signal abnormalities associated with cortical and subcortical ischemic events. DDX59 encodes a DEAD-box RNA helicase and its role in brain function and neurological diseases is unclear. We showed a reduction of mutant cDNA and perturbation of SHH signaling from patient-derived cell lines; furthermore, analysis of human brain gene expression provides evidence that DDX59 is enriched in oligodendrocytes and might act within pathways of leukoencephalopathies-associated genes. We also characterized the neuronal phenotype of the Drosophila model using mutant mahe, the homolog of human DDX59, and showed that mahe loss-of-function mutant embryos exhibit impaired development of peripheral and central nervous system. Taken together, our results support a conserved role of this DEAD-box RNA helicase in neurological function. PMID- 29127727 TI - Diversity in peptide recognition by the SH2 domain of SH2B1. AB - SH2B1 is a multidomain protein that serves as a key adaptor to regulate numerous cellular events, such as insulin, leptin, and growth hormone signaling pathways. Many of these protein-protein interactions are mediated by the SH2 domain of SH2B1, which recognizes ligands containing a phosphorylated tyrosine (pY), including peptides derived from janus kinase 2, insulin receptor, and insulin receptor substrate-1 and -2. Specificity for the SH2 domain of SH2B1 is conferred in these ligands either by a hydrophobic or an acidic side chain at the +3 position C-terminal to the pY. This specificity for chemically disparate species suggests that SH2B1 relies on distinct thermodynamic or structural mechanisms to bind to peptides. Using binding and structural strategies, we have identified unique thermodynamic signatures for each peptide binding mode, and several SH2B1 residues, including K575 and R578, that play distinct roles in peptide binding. The high-resolution structure of the SH2 domain of SH2B1 further reveals conformationally plastic protein loops that may contribute to the ability of the protein to recognize dissimilar ligands. Together, numerous hydrophobic and electrostatic interactions, in addition to backbone conformational flexibility, permit the recognition of diverse peptides by SH2B1. An understanding of this expanded peptide recognition will allow for the identification of novel physiologically relevant SH2B1/peptide interactions, which can contribute to the design of obesity and diabetes pharmaceuticals to target the ligand-binding interface of SH2B1 with high specificity. PMID- 29127728 TI - Supramolecular Radical Anions Triggered by Bacteria In Situ for Selective Photothermal Therapy. AB - A supramolecular complex that can be selectively reduced to radical anions in situ by facultative anaerobic bacteria is reported. To this end, a water-soluble bifunctional monomer bearing perylene diimide was synthesized, and its supramolecular complex with cucurbit[7]uril was fabricated on the basis of host guest complexation, which could be reduced to forming radical anions in the presence of E. coli. It was found that this supramolecular complex could display different ability of generating radical anions by facultative anaerobic and aerobic bacteria in terms of their various reductive abilities. The selective antibacterial activity of the supramolecular complex could be realized by the photothermal performance of the radical anions under near-infrared irradiation. It is anticipated that this method may lead to a novel bacteria-responsive photothermal therapy to regulate balance of bacterial flora. PMID- 29127726 TI - Self-reported marijuana use over 25 years and abdominal adiposity: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - AIMS: We investigated the association between cumulative lifetime and current marijuana use with total abdominal adipose tissue (AT), visceral AT, subcutaneous AT, intermuscular AT, and mean liver attenuation (LA) at mid-life. DESIGN: Longitudinal and cross-sectional secondary data analysis of participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. SETTING: CARDIA field centers in Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA, USA. PARTICIPANTS: CARDIA participants, aged 18-30 years in 1985-1986, who were present at the clinic examination in 2010-2011 (n = 2902). MEASUREMENTS: Marijuana use was assessed from responses to self-administered questionnaires at 8 CARDIA examinations over 25 years, determined as cumulative marijuana-years and current use status. Non-contrast computed tomography imaging of the abdomen was obtained in 2010-2011. FINDINGS: In 2010-2011, 84% of participants reported a history of marijuana use with 11% reporting use within the past 30 days. Before adjustment, we observed greater cumulative marijuana use was associated with lower total abdominal and subcutaneous AT volume and lower LA and current marijuana use was associated with lower subcutaneous AT. However, after adjustment for age, sex, race, field center, cigarette pack-years and current use, regular alcohol consumption, cumulative drink-years, and physical activity, neither cumulative marijuana use nor current use showed an association with any abdominal adipose depot. Our estimates did not differ by age, sex, or race nor after accounting for cohort attrition. CONCLUSION: Neither cumulative marijuana use nor current marijuana use is associated with total abdominal, visceral, subcutaneous, or intermuscular adipose tissue, or liver attenuation in mid-life. PMID- 29127729 TI - Tips for endoscopic stone extraction using new short-type double balloon endoscope for common bile duct stones in patients with surgically altered gastrointestinal anatomy. PMID- 29127732 TI - Current Resources for Evidence-Based Practice, November/December 2017. PMID- 29127731 TI - Endoscopic submucosal dissection of early gastric neoplasms in the fornix using the newly developed scissor-type SB knife GX. PMID- 29127730 TI - Comprehensive study of three novel cases of TFEB-amplified renal cell carcinoma and review of the literature: Evidence for a specific entity with poor outcome. AB - The first case of TFEB-amplified renal cell carcinoma was published in 2014. Since then, 29 additional cases have been described. The prognostic and therapeutic implications of this rare entity remain to be determined. We describe here the clinical, histological, and genetic features of three novel cases, and the first complete literature review. Four tumors were examined from three patients selected from the large collection of genetically characterized renal tumors in our institution. The pathological and immunohistochemical features were centrally reviewed by a uropathologist. Quantitative and structural genomic abnormalities were analyzed using comparative genomic hybridization, fluorescence in situ hybridization, and next generation sequencing. The three cases showed high-level amplification but no translocation of TFEB. Histologically, two tumors showed a papillary or pseudopapillary architecture. They did not show similarities with renal cell carcinoma harboring translocation of TFEB. The tumors were locally advanced high-grade lesions. They exhibited a metastatic course, which was rapidly leading to death in one patient. A second patient developed metastatic disease that did not respond to four lines of targeted treatments. The third patient had a protracted history of pulmonary and cardiac metastases. Complete clinical and biological data were examined and compared to those of the reported cases. Within the classification of renal tumors, TFEB amplified renal cell carcinoma may constitute a novel entity characterized histologically by high-grade, papillary or pseudopapillary architecture, and necrotic remodeling and clinically by a poor outcome. Its pathogenesis has to be further characterized to develop appropriate targeted therapy. PMID- 29127733 TI - 99 Tc NMR determination of the oxygen isotope content in 18 O-enriched water. AB - 99 Tc NMR has been suggested as an original method of evaluating the content of oxygen isotopes in oxygen-18-enriched water, a precursor for the production of radioisotope fluorine-18 used in positron emission tomography. To this end, solutions of NH4 TcO4 or NaTcO4 (up to 0.28 mol/L) with natural abundance of oxygen isotopes in virgin or recycled 18 O-enriched water have been studied by 99 Tc NMR. The method is based on 16 O/17 O/18 O intrinsic isotope effects in the 99 Tc NMR chemical shifts, and the statistical distribution of oxygen isotopes in the coordination sphere of TcO4- and makes it possible to quantify the composition of enriched water by measuring the relative intensities of the 99 Tc NMR signals of the Tc16 O4-n18 On- isotopologues. Because the oxygen exchange between TcO4- and enriched water in neutral and alkaline solutions is characterized by slow kinetics, gaseous HCl was bubbled through a solution for a few seconds to achieve the equilibrium distribution of oxygen isotopes in the Tc coordination sphere without distortion of the oxygen composition of the water. Pertechnetate ion was selected as a probe due to its high stability in solutions and the significant 99 Tc NMR shift induced by a single 16 O->18 O substitution ( 0.43 +/- 0.01 ppm) in TcO4- and spin coupling constant 1 J(99 Tc-17 O) (131.46 Hz) favourable for the observation of individual signals of Tc16 O4-n18 On- isotopologues. PMID- 29127734 TI - Population representation among anatomical donors and the implication for medical student education. AB - Dissection provides a unique opportunity to integrate anatomical and clinical education. Commonly, cadavers are randomly assigned to courses, which may result in skewed representation of patient populations. The primary aim of this study was to determine if the anatomical donors studied by students at the University of Massachusetts Medical School (UMMS) accurately represent the disease burden of the local patient population. This cross-sectional study compared the University of Massachusetts Memorial Medical Center patient claims data and body donation data from the UMMS Anatomical Gift Program (AGP). This study examined age, race, sex, and morbidities within a 10-year timeframe in 401,258 patients and 859 anatomical donors who met inclusion criteria. An independent t test was conducted to compare the mean ages of the two populations. Chi square analysis was conducted on race, sex, and 10 morbidity categories. A Fischer's exact test was conducted for two morbidity categories with n < 10. Demographic analysis showed a significant difference in age, and racial representation between the populations. No statistical difference was found regarding sex. Morbidities were separated into 22 ICD-10 categories. Twelve categories were excluded and 10 were analyzed for population comparison. Two categories were over represented and seven were under-represented in the AGP population. One category showed no significant difference between populations. Targeted selection of cadavers in anatomy courses would improve morbidity variability in the anatomy lab. In addition, AGP acceptance guidelines should be evaluated to increase disease variation among the donor population. Clin. Anat. 31:250-258, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29127735 TI - Profiles of women in science: Prof. Ingrid Olson of Temple University. PMID- 29127736 TI - Liver X receptor activation inhibits SGLT2-mediated glucose transport in human renal proximal tubular cells. AB - NEW FINDINGS: What is the central question of this study? The liver X receptor (LXR) has been reported to regulate several membrane transporters. It is imperative to investigate whether LXR activation regulates SGLT2-mediated glucose transport in human renal proximal tubular cells. What is the main finding and its importance? Liver X receptor activation inhibits SGLT2 transport function in normal and high-glucose conditions via reduction of SGLT2 protein expression. Liver X receptors (LXRs) are members of a nuclear receptor family consisting of two isoforms, LXRalpha and LXRbeta. They play a major role in energy metabolism, including lipid and glucose metabolism. Recent studies reported that LXRs regulate plasma glucose, although the mechanism is still uncertain. The present study investigated whether LXR activation regulates sodium glucose cotransporter2 (SGLT2) in human renal proximal tubular cells. LXR agonists, T0901317 and GW3965, inhibited SGLT2-mediated glucose uptake in a concentration-dependent manner. The effect of T0901317 and GW3965 was attenuated by a LXR antagonist, fenofibrate. Activation of the retinoid X receptor (RXR) agonist, bexarotene, potentiates the inhibitory effect of these ligands. Thus, the inhibitory effect of LXR agonists on SGLT2 was mediated and facilitated by LXR and RXR activation, respectively. In addition, the inhibitory effect of LXR agonists was not mediated by cytotoxicity. Exposing HK-2 cells, a renal proximal tubular cell line, to LXR agonists significantly reduced the maximal transport rate of SGLT2 without any effect on transporter affinity. Western blot analysis revealed that LXR activation significantly decreased protein expression of SGLT2 with no change in mRNA level. In addition, LXR activation inhibited canagliflozin-sensitive short-circuit current, which represents SGLT2-mediated glucose transport in a polarized human renal proximal tubular cell monolayer. Furthermore, LXR activation inhibited the transport function of SGLT2 in hyperglycaemic conditions. As such, this study represents evidence for the inhibitory effect of LXR activation on glucose transport in human renal proximal tubular cells. PMID- 29127737 TI - Genomic data from arthropods reveal high conservation but divergent evolutionary pattern of Polycomb/Trithorax group genes in arthropods. AB - Epigenetic gene control is maintained by chromatin-associated Polycomb group (PcG) and Trithorax group (TrxG) genes, which act antagonistically via the interplay between PcG and TrxG regulation to generate silenced or permissive transcriptional states. In this study, we searched for PcG/TrxG genes in 180 arthropod genomes, covering all the sequenced arthropod genomes at the time of conducting this study, to perform a global investigation of PcG/TrxG genes in a phylogenetic frame. Results of ancestral state reconstruction analysis revealed that the ancestor of arthropod species has an almost complete repertoire of PcG/TrxG genes, and most of these genes were seldom lost above order level. The domain diversity analysis indicated that the PcG/TrxG genes show variable extent of domain structure changes; some of these changes could be associated with lineage-specific events. The likelihood ratio tests for selection pressure detected a number of PcG/TrxG genes which underwent episodic positive selection on the branch leading to the insects with holometabolous development. These results suggest that, despite their high conservation across arthropod species, different members of PcG/TrxG genes showed considerable differences in domain structure and sequence divergence in arthropod evolution. Our cross species comparisons using large-scale genomic data provide insights into divergent evolutionary pattern on highly conserved genes in arthropods. PMID- 29127738 TI - Concerted millisecond timescale dynamics in the intrinsically disordered carboxyl terminus of gamma-tubulin induced by mutation of a conserved tyrosine residue. AB - Tubulins are an ancient family of eukaryotic proteins characterized by an amino terminal globular domain and disordered carboxyl terminus. These carboxyl termini play important roles in modulating the behavior of microtubules in living cells. However, the atomic-level basis of their function is not well understood. These regions contain multiple acidic residues and their overall charges are modulated in vivo by post-translational modifications, for example, phosphorylation. In this study, we describe an application of NMR and computer Monte Carlo simulations to investigate how the modification of local charge alters the conformational sampling of the gamma-tubulin carboxyl terminus. We compared the dynamics of two 39-residue polypeptides corresponding to the carboxyl-terminus of yeast gamma-tubulin. One polypeptide comprised the wild-type amino acid sequence while the second contained a Y > D mutation at Y11 in the polypeptide (Y445 in the full protein). This mutation introduces additional negative charge at a site that is phosphorylated in vivo and produces a phenotype with perturbed microtubule function. NMR relaxation measurements show that the Y11D mutation produces dramatic changes in the millisecond-timescale motions of the entire polypeptide. This observation is supported by Monte Carlo simulations that similar to NMR-predict the WT gamma-CT is largely unstructured and that the substitution of Tyr 11 with Asp causes the sampling of extended conformations that are unique to the Y11D polypeptide. PMID- 29127739 TI - Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass. AB - Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts. PMID- 29127740 TI - Molecular mobility in several imidazolium-based ionic liquids according to data of 1 H and 13 C NMR relaxation. AB - Temperature dependences are compared for 1 H and 13 C NMR 1/T1 curves relaxation rates in three imidazolium-based ionic liquids (ILs), namely, in [bmim]PF6 , [bmim]BF4 , and [emim]CH3 COO. 13 C curves show alike behavior for all three ILs and follow a well-known Bloembergen-Pound-Purcell (BPP) equation. On the contrary, an essential part of 1 H curves differ strongly from corresponding 13 C ones and also have different shapes for different ILs. For the first time, we have detected the specific, two-maximum shape of 1 H relaxation curve for hydrogen atom of C(2)H group of the [emim]CH3 COO. Assuming that this maximum reflects the correlated rotation of several adjoining ion pairs, we have tried to destroy this rotation by addition of glycerol to the [emim]CH3 COO. The second, high-temperature maximum has disappeared in the [emim]CH3 COO-glycerol mixture, and this fact confirms our assumption. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29127741 TI - PlpA, a PilZ-like protein, regulates directed motility of the bacterium Myxococcus xanthus. AB - The rod-shaped bacterium Myxococcus xanthus moves on surfaces along its long cell axis and reverses its moving direction regularly. Current models propose that the asymmetric localization of a Ras-like GTPase, MglA, to leading cell poles determines the moving direction of cells. However, cells are still motile in the mutants where MglA localizes symmetrically, suggesting the existence of additional regulators that control moving direction. In this study, we identified PlpA, a PilZ-like protein that regulates the direction of motility. PlpA and MglA localize into opposite asymmetric patterns. Deletion of the plpA gene abolishes the asymmetry of MglA localization, increases the frequency of cellular reversals and leads to severe defects in cell motility. By tracking the movements of single motor particles, we demonstrated that PlpA and MglA co-regulated the direction of gliding motility through direct interactions with the gliding motor. PlpA inhibits the reversal of individual gliding motors while MglA promotes motor reversal. By counteracting MglA near lagging cell poles, PlpA reinforces the polarity axis of MglA and thus stabilizes the direction of motility. PMID- 29127743 TI - Three-Dimensional Graphene Networks with Abundant Sharp Edge Sites for Efficient Electrocatalytic Hydrogen Evolution. AB - To achieve sustainable production of hydrogen (H2 ) through water splitting, establishing efficient and earth-abundant electrocatalysts is of great necessity. Morphology engineering of graphene is now shown to modulate the electronic structure of carbon skeleton and in turn endow it with excellent ability of proton reduction. Three-dimensional (3D) graphene networks with a high density of sharp edge sites are synthesized. Electrocatalytic measurements indicate that the obtained 3D graphene networks can electrocatalyze H2 evolution with an extremely low onset potential of about 18 mV in 0.5 m H2 SO4 solution, together with good stability. A combination of control experiments and density functional theory (DFT) investigations indicates that the exceptional H2 evolution performance is attributed to the abundant sharp edge sites of the advanced frameworks, which are responsible for promoting the adsorption and reduction of protons. PMID- 29127744 TI - [Endocrine orbitopathy: the present view of a clinical endocrinologist]. AB - Graves orbitopathy (GO) occurs in 25-50 % cases of Graves disease. Only in 5 % of patients the eye threatening GO is present. About 5-10 % and 10 % cases are present in euthyroid and hypothyroid patients respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Basic preconditions of the treatment are maintenance of euthyroidism, an effort to stop smoking, and referring of patients with moderate to severe and sight threatening GO to specialized thyroid eye centers. The first line treatment includes maintenance of wet eye (lubricants), supplementation of selenium deficiency, intravenous glucocorticoids, radiotherapy and surgery. Cases with moderate to severe GO should be treated with intravenous glucocorticoids in thyroid eye centers, however, the risk/benefit ratio in all cases should be considered. Cases with sight threatening GO should be immediately referred to thyroid eye centers, high-dose intravenous glucocorticoids are administered, and when the clinical response is absent within 2 weeks, surgical orbital decompression is recommended. Other immunosuppressive drugs (cyclosporine, mycophenolate mofetil) or biological therapy (teprotumumab) are not routinely recommended because of lack of evidence obtained by randomized controlled trials.Key words: clinical activity score - dysthyroid optic neuropathy - Graves orbitopathy - intravenous glucocorticoids - mycophenolate mofetil. PMID- 29127746 TI - [Surgical treatment of aortic root aneurysm: comparison of Bentall procedure and David reimplantation of aortic valve]. AB - INTRODUCTION: The aortic root aneurysm is associated with a more frequent occurrence of aortic dissection and development of aortic regurgitation. The aim of this study was to compare outcomes of composite graft replacement and valve sparing root replacement in treating aortic root aneurysms. METHODS: From January 2006 to December 2015 a total of 137 patients (mean age 46.3 +/- 14.5, range 16 65) underwent elective surgery for aortic root aneurysm without valvular structural defects. Replacement by mechanical composite graft (Bentall procedure) has been performed in 46 patients while 91 patients underwent valve sparing root replacement (David procedure). The mean length of follow-up has been 77 months. RESULTS: There was no operative death. Overall 9 patients died during follow-up. Five patients were after Bentall procedure and 4 were after reimplantation of aortic valve. Thromboembolic and bleeding complications were observed in 7 patients, 5 of them were after Bentall surgery and 2 after reimplantation of the aortic valve. Five patients after reimplantation of aortic valve underwent reoperation. Four of these patients had aortic valve replacement and in 1 case aortic homograft was implanted. CONCLUSION: Bentall procedure used to be the standard treatment for patients with aortic root aneurysms. During the past two decades, aortic valve sparing procedure has gained widespread use to reduce thromboembolic and bleeding complications.Key words: aortic root aneurysm - composite graft replacement - valve-sparing root replacement. PMID- 29127745 TI - [Medication adherence to non-vitamin K antagonist oral anticoagulants at non valvular atrial fibrillation - the literature review]. AB - Medication adherence is a complex problem reflecting variations in terms of medication taking behavior. It is essential in maximizing of the effect and risk minimization of the therapy and health care costs reduction, even in the case of oral anticoagulants (non-vitamin K antagonist oral anticoagulants - NOACs). The aim of this paper was to review the published literature and to discuss results in the field of medication adherence to NOACs in patients with non-valvular atrial fibrillation (NVAF). Based on the searching in databases Embase and PubMed 25 studies were identified, of which conclusions were summarized in this paper. Patients treated with dabigatran reported poorer medication adherence than patients with rivaroxaban. However, medication adherence is influenced by many circumstances as well as included studies were not sufficiently uniform, therefore, a prerequisite for further investigation of this issue is expected.Key words: apixaban - atrial fibrillation - dabigatran - medication adherence - patient compliance - rivaroxaban. PMID- 29127742 TI - Literature review of the epidemiology of influenza B disease in 15 countries in the Asia-Pacific region. AB - Influenza control strategies focus on the use of trivalent influenza vaccines containing two influenza A virus subtypes and one of the two circulating influenza type B lineages (Yamagata or Victoria). Mismatches between the vaccine B lineage and the circulating lineage have been regularly documented in many countries, including those in the Asia-Pacific region. We conducted a literature review with the aim of understanding the relative circulation of influenza B viruses in Asia-Pacific countries. PubMed and Western Pacific Region Index Medicus were searched for relevant articles on influenza type B published since 1990 in English language for 15 Asia-Pacific countries. Gray literature was also accessed. From 4834 articles identified, 121 full-text articles were analyzed. Influenza was reported as an important cause of morbidity in the Asia-Pacific region, affecting all age groups. In all 15 countries, influenza B was identified and associated with between 0% and 92% of laboratory-confirmed influenza cases in any one season/year. Influenza type B appeared to cause more illness in children aged between 1 and 10 years than in other age groups. Epidemiological data for the two circulating influenza type B lineages remain limited in several countries in the Asia-Pacific, although the co-circulation of both lineages was seen in countries where strain surveillance data were available. Mismatches between circulating B lineages and vaccine strains were observed in all countries with available data. The data suggest that a shift from trivalent to quadrivalent seasonal influenza vaccines could provide additional benefits by providing broader protection. PMID- 29127747 TI - [Treatment strategy of type 2 diabetes used in Czech Republic after metformin therapy failure]. AB - INTRODUCTION: Type 2 diabetes is an enormous medical problem caused by increasing prevalence of the disease and increasing prevalence of severe chronic complications of diabetes. New ADA/EASD guidelines and also Czech diabetes society guidelines enable effective individual approach to the patient. Goal of the therapy is optimal compensation of diabetes and prevention of acute and chronic complications of diabetes and decrease of mortality. Diabetes therapy is started by education in diet a regime combined with metformin. According to the progressive character of the disease it is usually necessary to intensify the therapy by adding antidiabetics from other groups. AIM: This study was proposed to analyse the use of therapy algorithm in Czech Republic in patients with insufficient metformin therapy. Secondary objectives were to describe level of compensation of diabetes in time and level of components of the metabolic syndrome in different treatment combinations.Methodic and results: In the sample of 1 516 patients, frequency of use of antidiabetic medication after metformin it was gliflozins 33% and gliptins 28% in the first phase of the study and the number increased later during the study. Median of HbA1c in the beginning of the study was 65 mmol/mol, greatest decrease was found in patents using combination of incretine analogs with metformin - 89 % of them had the HbA1c level < 60 mmol/mol. CONCLUSION: The study showed also that antidiabetic drugs used after metformin in Czech Republic are very effective in reducing weight, and improving blood pressure and lipid profile. Therapy using combination of metformin with gliflozins, gliptins or incretin analogs is most effective when metformin is not effective enough.Key words: diabetes type 2 - gliflozins - gliptins - incretine analogs - metformin therapy failure. PMID- 29127748 TI - [Issues related to secondary osteoporosis associated with growth hormone deficiency in adulthood]. AB - Growth hormone (GH) increases linear bone growth through complex hormonal reactions, mainly mediated by insulin like growth factor 1 (IGF1) that is produced mostly by hepatocytes under influence of GH and stimulates differentiation of epiphyseal prechondrocytes. IGF1 and GH play a key role in the linear bone growth after birth and regulation of bone remodelation during the entire lifespan. It is known that adult GH deficient (GHD) patients have decreased BMD and increased risk of low-impact fractures. Most data gathered thus far on the effect of GH replacement on bone status comprise the measurement of quantitative changes of bone mass. Some animal studies with GHD showed that the bone microarchitecture, measured using computed tomography methods, is significantly compromised and improve after GH replacement. However, human studies did not show significantly decreased bone microarchitecture, but limited methodological quality does not allow firm conclusions on this subject.Key words: bone mass - bone quality - fracture - growth hormone - IGF1. PMID- 29127749 TI - [Is it possible to improve long-term compliance of patients to statin therapy?] AB - Statins are key drugs for patients in secondary prevention of cardiovascular disease, as well as for primary prevention patients at high or very high risk of fatal cardiovascular events. However, long-term compliance of patients to statin therapy is relatively low, decreasing with the time of statin use; moreover a significant proportion of patients stop statins medication over the course of several years. To the early termination of statin treatment often contributes apprehension of the occurence of statin's side effects (i.g. increased creatine kinase in the blood and muscle problems), although these symptoms are usually not causally related to statin therapy. To the low compliance may also contribute administration of statins in the evening hours, as well as the fear of developing diabetes or drug interactions. The above issues are discussed in the text of this article.Key words: compliance - creatinkinase - diabetes mellitus -LDL cholesterol - statins. PMID- 29127750 TI - [COSYREL - an efficient fixed combination for treatment of hypertension, stable ISHD and heart failure]. AB - Fixed combinations of two or three drugs are being frequently used in cardiovascular diseases. This approach markedly increases adherence of the patients to prolonged therapy and thus leads to better control of the diseases. Fixed combinations are often used in hypertension and coronary artery disease (CAD). Cosyrel is the first fixed combination of betablocker (bisoprolol fumarat) and ACE inhibitor (perindopril arginin) available in czech market. The advantage is availability in several concentrations (10 mg/10 mg, 10 mg/5 mg a 5 mg/10 mg a 5 mg/5 mg) , when first indicates bisoprolol dose and the second perindopril. This combination is indicated in arterial hypertension and/or in stable CAD (in patients after myocardial infarction or revascularisation) and/or in dosages 5 mg/5 mg and 5 mg/10 mg in patients with chronic heart failure with systolic dysfunction. This article aimed to evaluate briefly clinical characteristics of this fixed combination. Bisoprol and perindopril arginin have a lot of data indication their positive impact on CV risk and prognosis.Key words: bisoprolol - coronary artery disease - heart failure - hypertension - perindopril. PMID- 29127751 TI - [The benefit of new angiogenesis (bevacizumab and aflibercept) inhibitors for multiple angiomatosis therapy: a case report]. AB - Angiomatosis is a term for multiple, gradually proliferating hemangiomas (angiodysplasia), affecting multiple organs or tissues at the same time. We describe a 12-year course of treatment of a patient with multiple hemangiomas located in the abdomen, retroperitoneum, oesophagus, mediastinum and also in vertebrae. The diagnosis was made in 2005 within probatory laparotomy, at the age of 28 years. The treatment was commenced right after making the diagnosis with interferon alpha. Due to its adverse effects (fatigue, anorexia), the use of interferon alpha was limited to the first year, after which the interferon dose was gradually being reduced until it was discontinued completely. From 2006 to 2011 the treatment was based on thalidomide and temporarily also on lenalidomide. By the end of the year 2011 the patient was stabilized through the effect of these drugs, without a need of repeated blood transfusions. In 2012 his condition got worse again, which required several transfusions in one month. We tested metronomic administration of cyclophosphamide and further administration of propranolol, however neither of them improved the patients situation. Injections of octreotide (Sandostatin 0.1 mg twice a day) helped reduce losses during bleeding into the alimentary tract. Still the patient continued to depend on blood transfusions. Therefore, in 2013, bevacizumab was added to the therapy (7.5 mg/kg in 3-week intervals). This treatment stabilized the patient, it reduced the use of transfusions for a period of 2 years, however after 2 years of a successful therapy with bevacizumab there was disease progression shown on CT imaging and hemorrhagic pleural effusion was also detected. After the treatment of hemorrhagic effusion, early in 2015 we transferred to the administration of aflibercept, at first at the dose of 4 mg/kg in 14-day intervals. Arising of massive proteinuria led to the dose reduction to 2 mg/kg while maintaining 14-day intervals. While receiving this dose, the patient tolerates aflibercept thera-py without significant adverse effects. At the time of publication, the patient has been treated with aflibercept for 24 months already, of that for the last ten months he has been fully independent of transfusions. Just before commencement of treatment with aflibercept his conditions required several transfusions in a week. This description demonstrates that the efficiency of individual medications for multiple angiomatosis is always time-limited and newly developed and more efficient drugs are needed to manage the disease. Bevacizumab and aflibercept are beneficial for patients with serious forms of multiple angiomatosis.Key words: aflibercept - angiomatosis - angiodysplasia - bevacizumab - hemangiomas. PMID- 29127752 TI - [Faster Insulin Aspart - a new prandial insulin analogue]. AB - Preventing postprandial blood glucose excursions is one of the most challenging aspects of achieving adequate control, especially in patients with better long term compensation of diabetes. Contemporary prandial insulin analogues that have more favorable properties than human insulin in terms of accelerated absorption, earlier onset of action and shorter duration of action are still significantly slower than endogenous insulin in healthy individuals. Fast-acting insulin aspart (FIAsp - faster aspart) is insulin aspart enriched with two excipients, of which niacinamide is responsible for accelerating absorption after subcutaneous administration. The responsible mechanism is to accelerate the formation of monomers and to accelerate the transfer through capillary endothelial cells into the bloodstream. The article summarizes the most important outcomes of preclinical and clinical evaluation of new insulin and its relevance to practice.Key words: faster apart - FIAsp - Onset trial - pharmacodynamics - pharmacokinetics - postprandial glycaemia. PMID- 29127753 TI - [Intestinal adaptation following gut resection]. AB - Gut resection is followed by wide changes in the gastrointestinal tract. The goal is to increase nutrient, water and mineral absorption in the remnant intestine. These changes are going on for several months. They affect gut mucosa structure, intestine peristaltic activity and enterocytes function. The crucial role is ileum preserving. Ileum has higher adaptation ability comparing to jejunum and inhibits peristaltic function of proximal parts of GIT. A lot of factors involved in intestinal adaptation were identified, hormones, growth factors, regulating peptides, intracellular signalizing cascades, cytokines and tissue factors. The most important seems to be GLP2 (glucagon like peptide 2) which has positive trophic influence on gut mucosa. Early enteral nutrition after gut resection enhances its adaptation. Recombinant analogueGLP2 teduglutide was introduced to be used in the short bowel syndrome treatment. It inhibits stomach evacuation and hypersecretion, increases intestine perfusion and enhances intestinal adaptation. Its long-term application accelerates the parenteral nutrition weaning.Key words: enteral nutrition - enterocytes - GLP2 - gut resection - intestinal adaptation. PMID- 29127754 TI - [Osteoarthritis as part of metabolic syndrome?] AB - Osteoarthritis (OA) is the most frequent joint disease, whereas etiopathogenesis of OA is not entirely clarified. It is a heterogeneous disorder and genetic as well as biomechanical, endocrine and inflammatory effects may be involved in its origin. The author examines the problems concerning relationships between the metabolic syndrome and OA, and states that the prevalence of metabolic syndrome in patients with OA is higher than in those without OA (59 % vs 23 %). It remains problematic that one of the main components of metabolic syndrome is obesity which in itself is a risk factor for arthrosis development in the weight-bearing joints, not for OA in the hands. After adjustment for BMI the relationships between the metabolic syndrome and OA are less expressed. Over the last decade evidence has been gained about adipose tissue being the source of numerous cytokines and adipokines which may cause inflammation of low-activity synovial tissue, sometimes also called "meta-inflammation." The most data was gathered on leptin, resistin, adiponectin and visfatin. Mostly there were serum levels of these adiponectins assessed and the results were sometimes inconsistent. Two studies have been published this year presenting a histological and immunohistochemical evaluation of the fat stored in 2 tissues right in the joints of patients with metabolic syndrome and OA, and the fat on an experimental OA model, concluding that the secretion activity of the potentially pro-inflammatory adipokines through adipocytes may differ in the synovial membrane, infrapatellar fat body and in abdominal fat. It is evident that the components of metabolic syndrome and OA can share a common pathological process which is an "adipose tissue associated inflammation." The changed secretion profile of pro inflammatory adipokines is present in obese individuals, an older population and postmenopausal women, the populations at high risk for both metabolic syndrome and OA. Significant mechanical loads may stimulate OA of the knee joints in obese patients, however not of the hands, and further differences between arthrosis of the knee joints and the hands. The adipose tissue induced inflammation is the common pathological mechanism for both metabolic syndrome and OA and it may account for some of the variations.Key words: adiponectins - metabolic syndrome - osteoarthritis. PMID- 29127755 TI - [Metabolic syndrome and the role of the polypill in the prevention of its complications]. AB - The first mention concerning occurrence of cardiometabolic risk factors together appeared 100 years ago. Metabolic syndrome brings 5times higher risk for type 2 diabetes development and 2-3times higher cardiovascular (CV) risk in comparison to the subjects without that syndrome. Healthy life habits and rational pharmacotherapy of hypertension, dyslipidemia and hyperglycemia represent an effective way for high cardiometabolic risk reduction. The problem are patient's low adherence and persistence to the recommendation and pharmacotherapy. Right now polypill (fixed combination of antihypertensives and lipid modifying drugs) are solving in the CV disease prevention. However sufficient evidence exist in the secondary CV prevention, some gap of knowledge is persisting in the primary CV prevention. Right combination of drugs in the polypill might be a suitable solving of CV disease and diabetes prevention for the patients with metabolic syndrome.Key words: cardiometabolic risk - cardiovascular disease prevention - metabolic syndrome - polypill. PMID- 29127756 TI - [Diabetes mellitus and cognitive disorders from the diabetologists perspective]. AB - Diabetes mellitus is associated with cognitive impairment which may convert to vascular or neurodegenerative dementia. Impairment of cognitive functions affects patients with type 1 and especially type 2 diabetes, with a number of vascular, metabolic and psychosocial factors involved in its development. As hyperglycemia and hypoglycemia also play an important role, important is the correct strategy of diabetes therapy which utilizes a combination of metformin with modern safe antidiabetics (incretin drugs, gliflozins, insulin analogues). It seems that some antidiabetic drugs (metformin, incretin drugs) and nasal form of application of insulin could improve cognition in diabetics.Key words: antidiabetic drugs - diabetes mellitus - hyperglycemia - hypoglycemia - cognition. PMID- 29127757 TI - [Gliflozins slow down the progression of diabetic kidney disease]. AB - Until recently progression of diabetic kidney disease could have been slowed down only by the inhibition of the renin-angiotensin system. Inhibitors of SGLT2 (sodium-glucose transporter 2) in the proximal tubulus of the kidney induce natriuresis and by the activation of the tubuloglomerular feedback increase the tone of the afferent arteriole and decrease the glomerular pressure. Empagliflozin in the study EMPA-REG Outcome significantly decreased the risk of progression of diabetic kidney disease and further analyses also demonstrated its potent antiproteinuric effect. Taking into consideration the concomitant cardioprotective and renoprotective effect of empagliflozin and high mortality, cardiovascular morbidity and risk of progression into end-stage renal disease of diabetic kidney disease treatment with gliflozins should be considered in all patients with diabetic nephropathy. Exact place of gliflozins in the treatment of patients with diabetic kidney disease will be established by the further ongoing studies with other gliflozins with primary renal endpoints.Key words: diabetic kidney disease - empagliflozin - glomerular hypertension - progression. PMID- 29127758 TI - [Physical activity - the Holy Grail of modern medicine?] AB - Movement is the basic attribute of life. It is not surprising that the return to regular physical activity is a very effective and cheap means of preventing and treating most non-cummunicable diseases. Therefore, every physician should be able to prescribe a suitable physical activity. The minimum amount of physical activity with proven effects in primary prevention of chronic diseases is relatively low: 150 minutes of moderate physical activity or 75 minutes of high intensity exercise per week or a combination of the two. The simplest and safe way of physical activity is walking (at least 10 000 steps/day or 6 000 steps/day on top of daily activities). The FITT model is a more sophisticated way of prescribing physical activity that already requires a stress test. Patients at risk of atherosclerosis or with any manifestation of atherosclerosis (patients with coronary artery disease, post-stroke, peripheral artery disease) benefit from exercise as well as patients with chronic heart failure. Physical activity also helps patients with lung disease (COPD, asthma), metabolic diseases (diabetes mellitus, obesity, osteoporosis) and also rheumatologic diseases. Regular exercise improves cognitive function, reduces depression and anxiety, and helps addicted people. Recently, it has been shown that exercise also changes the gut microbiome. One of the mechanisms that contribute to the beneficial effect of exercise is so-called "exercise factors" - myokines. Physical activity, when properly prescribed, is an inexpensive and universal medication with minimal side effects. It is our "home pharmacy" we always have with us.Key words: cancer - cardiovascular diseases - neuropsychiatric diseases - physical activity - type 2 diabetes. PMID- 29127759 TI - Is irisin the new player in exercise-induced adaptations or not? A 2017 update. AB - Irisin is produced by a proteolytic cleavage of fibronectin type III domain containing protein 5 (FNDC5) and has emerged as a potential mediator of exercise induced energy metabolism. The purpose of this study was to review the results of studies that investigated irisin responses to acute and chronic exercise and provide an update. A comprehensive search in the databases of MEDLINE was performed (74 exercise studies). The focus of the analysis was on data concerning FNDC5 mRNA expression in skeletal muscle and circulating irisin concentration relatively to exercise mode, intensity, frequency and duration and the characteristics of the sample used. Circulating irisin levels may either not relate to FNDC5 transcription or expression of the later precedes irisin rise in the blood. Acute speed/strength and endurance exercise protocols represent potent stimuli for irisin release if they are characterized by adequate intensity and/or duration. There are no reports regarding irisin responses to field sport activities. Although animal studies suggest that irisin may also respond to systematic exercise training, the majority of human studies has produced contradictory results. Certain methodological issues need to be considered here such as the analytical assays used to measure irisin concentration in the circulation. Results may also be affected by subjects' age, conditioning status and exercise intensity. The role of irisin as a moderator of energy metabolism during exercise remains to be seen. PMID- 29127760 TI - Preoperative breast MRI-examination for all patients with histologically proven breast cancer? A concept for a prospective multicenter trial. AB - Background A published retrospective data of our study group demonstrated that premenopausal women, patients with lobular invasive breast cancer or patients with high breast density [American College of Radiology (ACR) classification 3+4] significantly benefit from magnetic resonance imaging (MRI) leading to additional detection of malignant foci of 20.2% in the index and 2.5% in the contralateral breast, which would otherwise not be detected by routine imaging. Critics of preoperative MRI focus on higher false-positive rates leading to unnecessary surgical procedures and mastectomies. Therefore, MRI in preoperative imaging remains controversial. Methods To validate our retrospective data we initiate a prospective one-armed multicenter trial for patients with histologically confirmed breast cancer performing routine imaging by ultrasound and mammography followed by MRI imaging based on menopause status, histologic subtype, ACR and Breast Imaging Reporting and Data System (BIRADS)-classification. Primary endpoint is the rate of additional findings and change of treatment strategy, secondary endpoints are local recurrence-free, distant recurrence-free and overall survival. Additional MRI findings are calculated to be above 10% with a number of 100 patients recruited and a power of 80%. Conclusion MRI is detecting more tumor foci than conventional imaging but remains controversial in primary breast cancer for preoperative imaging because of the fear of over-diagnosis and the increased morbidity of additional potentially unnecessary surgical procedures. This planned one-armed prospective multicenter trial is designed to confirm our retrospectively revealed data defining subgroups with significant benefit of preoperative MRI to come to a consensus avoiding over-diagnosis and false-positive results leading to clinically beneficial and cost-effective use of preoperative MRI. PMID- 29127762 TI - Anti-invasive and antiproliferative effects of Pleurotus ostreatus extract on acute leukemia cell lines. AB - BACKGROUND: Currently, mushrooms have been used in traditional and folk medicines for their therapeutic activities, such as antibiotic, antitumor, anti inflammatory, anticancer, antileukemic and immunomodulatory actions. This investigation evaluates the anti-invasive, antiproliferative and cytotoxic effects of Pleurotus ostreatus (Pleurotaceae) on leukemia cell lines. METHODS: The proliferation of KG-1 cells was measured by using 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay after treatment with gradient dilutions of P. ostreatus extract. Then, the minimum inhibitory concentration (MIC) of the extract was determined. Moreover, the proliferation of Jurkat cells and bone marrow mesenchymal stem cells (BMSCs), a cancerous cell line and normal body cells, respectively, was considered. The apoptotic morphology of treated KG-1 cells was evaluated with Giemsa staining. The invasion and migration of cells were evaluated using transwell invasion assay. Thereafter, the rates of apoptosis and necrosis were measured by using flow cytometry, and BAX and MMP-9 gene expression were evaluated using quantitative reverse transcription-polymerase chain reaction as apoptotic and metastatic genes, respectively. RESULTS: The MIC of the extract was determined to be 1 mg/mL after 48 h. According to the results, the extract decreased the proliferation of leukemia cell lines (KG-1 and Jurkat cells) but had no antiproliferative effects on BMSCs. Moreover, KG-1 cell migration and MMP-9 gene expression decreased after the treatment, and the rate of apoptosis and BAX gene expression increased significantly. CONCLUSIONS: According to the efficient therapeutic properties of P. ostreatus on leukemia cell lines, this mushroom could be introduced as a natural medicine to cure leukemic patients who suffer from the harmful side effects and enormous costs of chemotherapy. PMID- 29127761 TI - Seizure vulnerability and anxiety responses following chronic co-administration and acute withdrawal of caffeine and ethanol in a rat model. AB - BACKGROUND: Caffeine antagonizes the intoxicating effects of alcohol. Consequently, there has been a dramatic global increase in the consumption of caffeinated drinks together with alcohol, especially among young adults. We assessed the seizure vulnerability and anxiety responses following the chronic co administration of, and withdrawal from, caffeine and ethanol in male rats. METHODS: The rats were randomly assigned to six groups consisting of 10 animals each: 10 mg/kg of caffeine, 20 mg/kg of caffeine, 4 g/kg of 20% ethanol, combined caffeine (20 mg/kg) and ethanol (4 g/kg of 20%), 4 mL/kg distilled water, and an untreated control group. The test substances were administered intragastrically twice daily for 29 days. On day 29, the rats were tested on the elevated plus maze to assess anxiety-related responses. On day 30, pentylenetetrazol (PTZ), a chemoconvulsant, was administered intraperitoneally at a dose of 40 mg/kg to the animals. Seizure responses and mortality up to 72 h were recorded. RESULTS: Compared with the control group, the rats that received chronic treatment with low-dose caffeine, ethanol alone, and combined caffeine and ethanol exhibited significant anxiogenic-like effects, unlike with high-dose caffeine. Both low- and high-dose caffeine significantly increased PTZ seizure latency. Ethanol alone and combined caffeine and ethanol both lowered PTZ seizure latency. No significant difference occurred between the controls and the untreated group for either anxiety or seizure expression. Combined caffeine and ethanol increased the seizure-induced mortality from withdrawal effects at 72 h. CONCLUSIONS: These findings suggest that the chronic co-administration of caffeine and ethanol and the acute withdrawal from these drugs lead to anxiogenic effects and increased seizure vulnerability. PMID- 29127763 TI - Thyroid evaluation of children and adolescents with Williams syndrome in Zhejiang Province. AB - BACKGROUND: The objective of the study was to describe the prevalence of abnormal thyroid function and volume in children and adolescents with Williams syndrome (WS) in Zhejiang Province, China. METHODS: Thyroid function, including thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in 83 patients with WS, aged 0.2-16.5 years. Twenty-three patients were followed for an average of 1.7 years (0.4-4.1), and multiple TSH determinations were considered. Thyroid ultrasonography was performed on 49 patients. RESULTS: One patient was diagnosed with overt hypothyroidism, and 23 patients (27%) had subclinical hypothyroidism (SH). Thyroid antibodies were absent in all patients. In five age groups (0-1 years, 1-3 years, 3-6 years, 6-9 years, 9-18 years), the prevalence of patients with subclinical hypothyroidism was 25%, 28.5%, 44.4%, 16.7% and 4.7%, respectively. Through ultrasound examination, 21 patients (42%) were observed to have thyroid hypoplasia (TH), and there were no cases of thyroid haemiagenesis. The incidence rate of TH increased with age, rising from 20% in the youngest group to 66% in the oldest. CONCLUSIONS: SH and TH is common in children and adolescents with WS. Yearly evaluation of thyroid must be performed in all patients in this population, regardless of the result of the neonatal screening. Age under 6 years and existing thyroid abnormalities are risk factors for developing SH, and a shorter follow-up interval is needed for screening in these individuals, SH is often self-limiting, and clinicians should be alert to overt hypothyroidism. PMID- 29127764 TI - Could a combination of heterozygous ABCC8 and KCNJ11 mutations cause congenital hyperinsulinism? AB - BACKGROUND: Congenital hyperinsulinism (CHI) is frequently caused by mutations in one of the KATP channel subunits encoded by the genes ABCC8 and KCNJ11. The effect of simultaneous mutations in both of these genes on the pancreatic beta cell function is not known and patients with CHI carrying both ABCC8 and KCNJ11 mutations have not yet been reported. We questioned if a combination of heterozygous mutations in the ABCC8 and KCNJ11 genes could also lead to beta-cell dysfunction presenting as CHI. METHODS: As a model, we used a patient with transient CHI that paternally inherited novel heterozygous mutations in ABCC8 (p.Tyr1293Asp) and KCNJ11 (p.Arg50Trp) genes. The pathogenic effects on the pancreatic beta-cells function were examined in an in vitro functional study using radioactive rubidium efflux assay. RESULTS: We showed that the activation of the mutated KATP channels by diazoxide was decreased by 60.9% in the channels with the heterozygous combination of both mutations compared to the wild type channels. This could indicate the pathogenic effect on the pancreatic beta-cell function leading to CHI although conclusive evidence is needed to be added. CONCLUSIONS: Our findings may widen the spectrum of genetic causes of CHI and suggest a novel pathogenic mechanism of CHI that must however, be further investigated. PMID- 29127765 TI - High aldosterone and cortisol levels in salt wasting congenital adrenal hyperplasia: a clinical conundrum. AB - BACKGROUND: Salt wasting syndrome (hyponatremia, hyperkalemia, dehydration, metabolic acidosis) in early infancy could be caused by either mineralocorticoid deficiency as in congenital adrenal hyperplasia (CAH) and adrenal insufficiency or mineralocorticoid resistance as in pseudohypoaldosteronism (PHA). In salt wasting CAH, serum aldosterone and cortisol levels are expected to be low. Cross reactivity between high levels of adrenal steroid precursors and aldosterone has recently been reported resulting in elevated aldosterone levels in CAH, leading to difficulty in differentiating between CAH and PHA. CASE PRESENTATION: We report four such cases of salt wasting CAH, where high aldosterone levels and high normal cortisol levels led to initial diagnostic confusion with PHA. Diagnosis of CAH was later established on the basis of significantly elevated adrenocorticotropic hormone (ACTH) stimulated 17-hydroxyprogesterone (17-OHP) values. CONCLUSIONS: By reporting these cases we draw attention to the possibility that high levels of adrenal steroid precursors can cross react with aldosterone and cortisol, and underscore the significance of ACTH stimulated 17 OHP values in differentiating CAH and PHA. PMID- 29127766 TI - Etiologies of short stature in a pediatric endocrine clinic in Southern Thailand. AB - BACKGROUND: Short stature is one of the common disorders referred for investigation of an endocrine disorder. The etiologies of short stature vary and are commonly grouped into pathological and non-pathological disorders. The objective of the study was to determine the etiologies and describe the characteristics of short stature patients who attended the Pediatric Endocrinology Clinic and to compare factors between normal variant short stature (NVSS) and growth hormone deficiency (GHD). METHODS: This was a retrospective review of 572 patients referred for evaluation of short stature between January 2004 and December 2015. Short stature was defined as height below -2 standard deviation score (SDS) by gender and age based on population data of Thai children. RESULTS: In total, 521 patients were identified as having short stature. NVSS was the most common etiology (44.9%) and pathological short stature was found in 35.3% of the cases, of which 21.2% had GHD. The median age at presentation of NVSS patients was 8.6 years while that of pathological short stature patients was 2.1 years (p<0.001). Patients with NVSS had significantly higher median height SDS (HSDS) than patients with pathological diseases. The common etiologies in severe short patients, defined by HSDS <=-3, were syndromic short stature (16.2%) and GHD (14.1%). In the moderate short stature group (HSDS between -2 and -3), constitutional delay of growth and puberty (CDGP) was the most common etiology (34.1%). CONCLUSIONS: NVSS was the most common etiology of short stature, followed by syndromic short stature and GHD. Physical examination is crucial to identify GHD from syndromic short patients. PMID- 29127767 TI - Marine-Lenhart syndrome in two adolescents, including one with thyroid cancer: a case series and review of the literature. AB - BACKGROUND: The coexistence of functional thyroid nodules and Graves' disease (GD) is a rare condition known as Marine-Lenhart syndrome. Thyroid cancer has been described in several adults, but never in children, with Marine-Lenhart syndrome. This paper discusses the challenges in diagnosis and the unique management of this condition in children, in the context of extant literature. CONTENT: In this case report, two adolescent female patients with Marine-Lenhart syndrome, aged 15 and 16 years, exhibited biochemical evidence of hyperthyroidism, and were found to have unilateral hyperfunctioning thyroid nodules via thyroid scintigraphy. Additionally, both patients showed elevated thyroid-stimulating immunoglobulins (TSI) and increased glandular activity, confirming background GD. Notably, one patient was also diagnosed with intranodular thyroid cancer upon preoperative examination. Both patients were treated via surgical resection. Summary and outlook: Diagnosis of Marine-Lenhart syndrome can be made in patients with functional thyroid nodules and increased glandular activity on thyroid scintigraphy. Standard doses of radioiodine ablation are not effective in the majority of patients and should be avoided due to the increased risk for thyroid cancer, making thyroidectomy the preferred treatment. PMID- 29127768 TI - Diabetic ketoacidosis, hyperuricemia and encephalopathy intractable to regular dose insulin. AB - BACKGROUND: Diabetic ketoacidosis (DKA) in children less than 1 year of age is a rare occurrence. Typical presentation includes a prodrome of weight loss and polyuria with subsequent presentation to medical care when acidosis becomes symptomatic. CASE PRESENTATION: We describe an unusual case of a previously healthy infant with a 3 days' history of constipation, presenting acutely with abdominal pain, lethargy, and dehydration. On initial evaluation, our patient had profound encephalopathy, with marked tachypnea and work of breathing. Arterial blood gas revealed a pH of 6.9, pCO2 of 20 and a bicarbonate level of <5. There was profound leukocytosis (WBC 77 K/MUL), hyperuricemia (uric acid 15.9 mg/dL), and evidence of pre-renal azotemia [blood urea nitrogen (BUN) 54, Cr 0.82]. Blood glucose was >700 mg/dL. Despite fluid resuscitation and insulin infusion of 0.1 unit/kg/h, which are the mainstays of therapy for DKA, her severe metabolic acidosis and altered mental status did not improve. Differential diagnosis for her metabolic derangements included inborn errors of metabolism, insulin receptor defects, toxic ingestions, and septic shock secondary to an underlying oncologic or intra-abdominal process. The patient was treated with broad spectrum antibiotics and rasburicase. She continued to have significant shock for the first 30 h of her hospital stay, requiring moderate vasoactive support. Due to her refractory acidosis and persistent hyperglycemia, insulin infusion was increased to 0.15 units/kg/h. A hemoglobin A1C obtained on the second hospital day revealed a level of 7.4 and helped to solidify the diagnosis. CONCLUSIONS: Metabolic acidosis in an infant requires a broad differential. Rasburicase should be considered in hyperuricemia and DKA. PMID- 29127769 TI - Relation between circulating oxidized-LDL and metabolic syndrome in children with obesity: the role of hypertriglyceridemic waist phenotype. AB - BACKGROUND: The association between oxidative stress (OS) and metabolic syndrome (MetS) has been reported in adults. We analyzed the relation between circulating oxidized low-density lipoproteins (Ox-LDL) and MetS in pediatric ages in order to define whether plasma Ox-LDL levels are correlated to obesity and whether oxidative damage, using serum Ox-LDL levels as a proxy, are associated with MetS. METHODS: We enrolled 178 children (11.8+/-2.6 years). On the basis of a body mass index (BMI) threshold, the subjects were classified as: normal weight BMI <75th percentile; overweight BMI 75-97th percentile; obese BMI >97th percentile. Patients were classified as having MetS if they met three or more of the following criteria for age and sex: BMI >97th percentile, triglyceride levels >95th percentile, high-density lipoprotein (HDL) cholesterol level <5th percentile, systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) >95th percentile and impaired glucose tolerance. RESULTS: Obese children showed increased MetS prevalence (p=0.001) and higher Ox-LDL levels compared to normal- and overweight subjects (p<0.05), with a limited relation between Ox-LDL and MetS (p=0.06). Waist-to-height ratio (W/HtR) (p=0.02), triglycerides (TG) (p=0.001) and LDL-cholesterol (p<0.001) resulted independent predictors of increased plasma Ox-LDL levels. CONCLUSIONS: Oxidative damage was correlated with a hypertriglyceridemic waist phenotype and can be a precocious marker of MetS and cardiometabolic risk in obese children. PMID- 29127770 TI - The burden of firearm violence in the United States: stricter laws result in safer states. AB - BACKGROUND: Increasing firearm violence has resulted in a strong drive for stricter firearm legislations. Aim of this study was to determine the relationship between firearm legislations and firearm-related injuries across states in the United States. METHODS: We performed a retrospective analysis of all patients with trauma related hospitalization using the 2011 Nationwide Inpatient Sample database. Patients with firearm-related injury were identified using E-codes. States were dichotomized into strict firearm laws [SFL] or non strict firearm laws [Non-SFL] states based on Brady Center score. Outcome measures were the rate of firearm injury and firearm mortality. Linear Regression and correlation analysis were used to assess outcomes among states. RESULTS: 1,277,250 patients with trauma related hospitalization across 44 states were included of which, 2,583 patients had firearm-related injuries. Ten states were categorized as SFL and 34 states as Non-SFL. Mean rate of firearm related injury per 1000 trauma patients was lower in SFL states (1.3+/-0.5 vs. 2.1+/-1.4; p=0.006) and negatively correlated with Brady score (R2 linear=-0.07; p=0.04). SFL states had a 28% lower incidence of firearm related injuries compared to Non SFL states (Beta coefficient, -0.28; 95% CI, -1.7- -0.06; p=0.04). Firearm related mortalities resulted in overall 9,722 potential life years lost and more so in the non-SFL states (p=0.001). CONCLUSIONS: States without SFL have higher firearm related injury rates, higher firearm related mortality rate, and significant potential years of life lost compared to SFL states. Further analysis of differences in the legislation between SFL and non-SFL states may help reduce firearm related injury rate. PMID- 29127771 TI - Comparison of the Anteroposterior and Posterior Approaches for Percutaneous Catheter Drainage of Tuberculous Psoas Abscess. AB - BACKGROUND Tuberculous infection of the lumbar spine may be associated with psoas abscess. The aim of this clinical study was to compare the outcome of posterior lumbar debridement and spinal fusion, combined with either a one-stage anteroposterior (AP) or posterior (P) approach to percutaneous catheter drainage (PCD) for the treatment of lumbar tuberculosis with psoas abscess. MATERIAL AND METHODS From January 2008 to June 2012, 74 patients were diagnosed at our hospital with lumbar tuberculosis with unilateral or bilateral psoas abscess. Forty-three patients underwent P-PCD (group A), and 31 patients underwent AP-PCD (group B). Operative duration, blood loss, the length of hospital stay, spinal correction, clinical cure rate, and other clinical outcomes in the two groups were compared. RESULTS Comparison of the outcome for the P-PCD and AP-PCD patients showed that there was no significant difference in outcome for spinal bone fusion, correction of spinal deformity, or cure rate from tuberculosis infection (P>0.05). Blood loss, operative time, and the length of hospital stay for patients in group A, the P-PCD group, were significantly less than for group B, the AP-PCD group (P<0.05). Also, group B, the AP-PCD group, had an increased incidence of complications than group A, the P-PCD group, leading to increased hospital stay (OR 3.04, CI 0.52-17.75). CONCLUSIONS For the treatment of tuberculous psoas abscess using PCD, the posterior approach may achieve the same clinical efficacy as the anteroposterior approach, but is associated with reduced length of hospital stay, and lower risk of complications. PMID- 29127773 TI - The Sentinel Bleed. PMID- 29127774 TI - Characteristics of Supernumerary Teeth in Nonsyndromic Population in an Urban Dental School Setting. AB - PURPOSE: The purpose of this study was to analyze the clinical records of all patients evaluated for supernumerary teeth at the University of Illinois-Chicago Department of Oral and Maxillofacial Surgery postgraduate clinic from January 1, 2010 to October 31, 2015 to determine the demographics of impacted supernumerary teeth among different ethnicities in the city of Chicago. MATERIALS AND METHODS: A retrospective case series was completed on patients eligible for inclusion in the study who had a diagnosis of at least 1 full bony impacted supernumerary tooth (D7240). Other variables evaluated included date of surgical intervention, age at time of treatment, gender, ethnicity, location and number of supernumerary teeth present, and family history of supernumerary teeth. RESULTS: There were 459 male and 308 female patients (male-to-female ratio, 1.5:1). Patient ages ranged from 4 to 51 years (average, 13.1) at the time of surgery. Five hundred seventy three patients (74.7%) were of Hispanic descent. Supernumerary teeth were found most frequently in the maxilla (69.9%), specifically in the central incisor region (526 teeth; 51.2%). Of the responding patient sample (258 patients), 53 patients (20.5%) reported a family history of supernumerary dentition. Of these 53 patients who reported a family history of supernumerary dentition, 37 (69.8%) were of Hispanic descent. Most of these Hispanic patients (83.8%) originated from Mexico. CONCLUSIONS: The incidence of supernumerary teeth is higher in male patients (male-to-female ratio, 1.5:1), and these teeth are most frequently found in the maxilla (69.9%), specifically the central incisor region (51.2%). A large percentage of patients (20.5%) also had first-degree relatives with a supernumerary dentition, and this fact might warrant further investigation into the possible genetics responsible for the formation of supernumerary teeth. PMID- 29127772 TI - Interventions for treating collagenous colitis. AB - BACKGROUND: Collagenous colitis is a cause of chronic diarrhea. This updated review was performed to identify therapies for collagenous colitis that have been assessed in randomized controlled trials (RCTs). OBJECTIVES: The primary objective was to assess the benefits and harms of treatments for collagenous colitis. SEARCH METHODS: We searched CENTRAL, the Cochrane IBD Group Specialized Register, MEDLINE and EMBASE from inception to 7 November 2016. SELECTION CRITERIA: We included RCTs comparing a therapy with placebo or active comparator for the treatment of active or quiescent collagenous colitis. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two authors. The primary outcome was clinical response or maintenance of response as defined by the included studies. Secondary outcome measures included histological response, quality of life and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The Cochrane risk of bias tool was used to assess bias. The overall quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Twelve RCTs (476 participants) were included. These studies assessed bismuth subsalicylate, Boswellia serrata extract, mesalamine, cholestyramine, probiotics, prednisolone and budesonide therapy. Four studies were low risk of bias. One study assessing mesalamine and cholestyramine was judged to be high risk of bias due to no blinding. The other studies had an unclear risk of bias for random sequence generation (five studies) allocation concealment (six studies), blinding (one study), incomplete outcome data (one study) and selective outcome reporting (one study). Clinical response occurred in 100% (4/4) of patients who received bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks) compared to 0% (0/5) of patients who received placebo (1 study; 9 participants; RR 10.80, 95% CI 0.75 to 155.93; GRADE = very low). Clinical response occurred in 44% (7/16) of patients who received Boswellia serrata extract (three 400 mg/day capsules for 8 weeks) compared to 27% (4/15) of patients who received placebo (1 study; 31 participants; RR 1.64, 95% CI 0.60 to 4.49; GRADE = low). Clinical response occurred in 80% (24/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study; 55 participants; RR 1.82, 95% CI 1.13 to 2.93; GRADE = low). Histological response was observed in 87% (26/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study, 55 participants; RR 1.97, 95% CI 1.24 to 3.13; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 0.69, 95% CI 0.43 to 1.10; GRADE = low), withdrawals due to adverse events (RR 0.09, 95% CI 0.01 to 1.65; GRADE = low) and serious adverse events (RR 0.12, 95% CI 0.01 to 2.21; GRADE = low). Clinical response occurred in 44% (11/25) of mesalamine patients (3 g/day) compared to 59% (22/37) of placebo patients (1 study; 62 participants; RR 0.74, 95% CI 0.44 to 1.24; GRADE = low). Histological response was observed in 44% (11/25) and 51% (19/37) of patients receiving mesalamine and placebo, respectively (1 study; 62 participants; RR 0.86, 95% CI 0.50 to 1.47; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 1.26, 95% CI 0.84 to 1.88; GRADE = low), withdrawals due to adverse events (RR 5.92, 95% CI 0.70 to 49.90; GRADE = low) and serious adverse events (RR 4.44, 95% CI 0.49 to 40.29; GRADE = low). Clinical response occurred in 63% (5/8) of prednisolone (50 mg/day for 2 weeks) patients compared to 0% (0/3) of placebo patients (1 study, 11 participants; RR 4.89, 95% CI 0.35 to 68.83; GRADE = very low). Clinical response occurred in 29% (6/21) of patients who received probiotics (2 capsules containing 0.5 x 1010 CFU each of L. acidophilus LA-5 and B. animalis subsp. lactis strain BB-12 twice daily for 12 weeks) compared to 13% (1/8) of placebo patients (1 study, 29 participants, RR 2.29, 95% CI 0.32 to 16.13; GRADE = very low). Clinical response occurred in 73% (8/11) of patients who received mesalamine (800 mg three times daily) compared to 100% (12/12) of patients who received mesalamine + cholestyramine (4 g daily) (1 study, 23 participants; RR 0.74, 95% CI 0.50 to 1.08; GRADE = very low). Clinical response occurred in 81% (38/47) of patients who received budesonide (9 mg daily in a tapering schedule for 6 to 8 weeks) compared to 17% (8/47) of placebo patients (3 studies; 94 participants; RR 4.56, 95% CI 2.43 to 8.55; GRADE = low). Histological response was higher in budesonide participants (72%, 34/47) compared to placebo (17%, 8/47) (RR 4.15, 95% CI 2.25 to 7.66; GRADE = low). Clinical response was maintained in 68% (57/84) of budesonide patients compared to 20% (18/88) of placebo patients (3 studies, 172 participants, RR 3.30 95% CI 2.13 to 5.09; GRADE = low). Histological response was maintained in 48% (19/40) of budesonide patients compared to 15% (6/40) of placebo patients (2 studies; 80 participants; RR 3.17, 95% CI 1.44 to 6.95; GRADE = very low). No difference was found between budesonide and placebo for adverse events (5 studies; 290 participants; RR 1.18, o95% CI 0.92 to 1.51; GRADE = low), withdrawals due to adverse events (5 studies, 290 participants; RR 0.97, 95% CI 0.43 to 2.17; GRADE = very low) or serious adverse events (4 studies, 175 participants; RR 1.11, 95% CI 0.15 to 8.01; GRADE = very low). Adverse effects reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, excessive sweating and headache. Adverse effects reported in the mesalamine studies included nausea and skin rash. Adverse effects in the prednisolone study included abdominal pain, headache, sleep disturbance, mood change and weight gain. AUTHORS' CONCLUSIONS: Low quality evidence suggests that budesonide may be effective for inducing and maintaining clinical and histological response in patients with collagenous colitis. We are uncertain about the benefits and harms of therapy with bismuth subsalicylate, Boswellia serrata extract, mesalamine with or without cholestramine, prednisolone and probiotics. These agents and other therapies require further study. PMID- 29127775 TI - Four-Dimensional Computed Tomography Evaluation of Condylar Movement in a Patient With Temporomandibular Joint Osteoarthritis. AB - Temporomandibular joint (TMJ) osteoarthritis (OA) is a disease of the bone, cartilage, and supporting tissues of the joint. Patients with advanced TMJ-OA often have symptoms such as pain, swelling, and joint dysfunction, and they sometimes require surgical intervention when conservative treatment is not effective. The etiology of TMJ-OA remains elusive. The usefulness of 4 dimensional (4D) computed tomography (CT) in motion analysis of various joints has recently been reported. This article introduces a novel imaging technique of 4D CT that aims to identify kinematic features that may be associated with the etiology of TMJ-OA. In a 69-year-old female patient with severe TMJ-OA, 4D CT evaluation of condylar movement was performed. During the scan, she was instructed to masticate a cookie normally and her natural condylar movement during mastication was evaluated. The coronal 4D CT motion images showed that the synovial cavity was narrower on the affected side than on the unaffected side. Repeated friction between the articular surface of the condyle and the caudal surface of the articular eminence was observed during natural mastication. Although friction between the condyle and articular eminence has been considered a factor in the initiation and progression of TMJ-OA in previous experimental studies using animals, this is the first study to directly visualize the friction between the atrophic and flattened condylar surface and the articular eminence. Four-dimensional CT is a novel imaging technique with the potential to assess kinematic features that cannot be visualized with other imaging modalities in patients with TMJ disease. PMID- 29127779 TI - Editorial Comment. PMID- 29127776 TI - Working memory capacity and intra-individual variability of proactive control. AB - Two datasets of 110 young adults were examined to investigate the relationship between individual differences in working memory capacity (WMC) and dynamic cognitive control. The results delve into the specific differences between high- and low-WMC individuals' ability to enact and maintain cognitive control using the AX version of the continuous performance test (AX-CPT). Compared to high-WMC individuals, low-WMC individuals: (a) made more errors, specifically to AX targets; (b) exhibited a partial shift to proactive control with more time-on task; (c) had more exaggerated slower AX target responses in the tail of the response time distribution; and (d) were equally likely to adjust control after conflict. These results fit with the dual mechanisms of cognitive control theory and goal-maintenance account, and further clarify how individual differences in WMC manifests as intra-individual variability in cognitive control. PMID- 29127778 TI - Editorial Comment. PMID- 29127777 TI - Editorial Comment. PMID- 29127780 TI - Editorial Comment. PMID- 29127781 TI - Editorial Comment. PMID- 29127782 TI - Editorial Comment. PMID- 29127783 TI - Reply by Authors. PMID- 29127785 TI - Tobacco and alcohol use disorders: Evaluating multimorbidity. AB - There is growing interest in applying the multimorbidity model for mental health disorders - i.e. the interactive effects of co-occurring diagnoses. Alcohol use disorder (AUD) and tobacco use disorder (TUD) often occur together, but distinctive correlates of their co-occurrence have not been studied. Veterans treated by the Veterans Health Administration (VHA) nationally in FY 2012 with diagnoses of both AUD and TUD were compared to those with only AUD or only TUD on socio-environmental factors, medical and psychiatric diagnoses, and service use. Multimorbid effects were defined as those in which patients with both AUD and TUD had more serious problems greater likelihood of specific co-occurring conditions than those with either AUD alone or TUD alone. Veterans with concurrent AUD and TUD (N=153,397), as compared to those with AUD only (N=191,900) or with TUD only (N=643,377), had significantly higher rates of homelessness [odd ratios (ORs)=1.24, 1.68], hepatic disease (ORs=1.11, 2.18), substance use disorders (ORs=1.42, 3.14), receipt of a VA disability pension (ORs=1.26, 1.30) and use of substance and mental health outpatient services (ORs=1.04, 1.12). Veterans with AUD and TUD appear to have more severe problems in some, but not all, socio environmental, medical, psychiatric, and service use domains than veterans with either of these diagnoses alone. The combination of AUD and TUD yield generally more adverse effects in diverse areas and thus reflect an emergent phenomenon that may a require a distinctive treatment approach. PMID- 29127784 TI - Social media e-cigarette exposure and e-cigarette expectancies and use among young adults. AB - A vast majority of U.S. young adults use social media such as Facebook and Instagram daily. Research suggests that young adults are commonly exposed to e cigarette-related marketing or user-generated content on the social media they use. Currently, however, there is limited empirical evidence as to how social media e-cigarette exposure is associated with e-cigarette use beliefs and behavior. In particular, limited evidence exists to support the proposition that social media e-cigarette exposure is uniquely associated with e-cigarette use, even after adjusting for the effects of e-cigarette use in young adults' in person or 'offline' social networks. This study was conducted to test the hypotheses that 1) social media e-cigarette exposure is associated with e cigarette use outcome expectancies and current e-cigarette use; and 2) the association between social media and e-cigarette use is linked via outcome expectancies. We collected cross-sectional data from a sample of 470 young adult college students in Hawaii. Hypotheses were tested by fitting a structural equation model to the data. The model accounted for the associations of demographic variables, cigarette smoking history, as well as e-cigarette use in individuals' actual social networks with expectancies and behavior. Results indicated that social media e-cigarette exposure was associated with current e cigarette use indirectly through two of the four positive outcome expectancies examined, namely, positive "smoking" experience and positive sensory experience. We discuss the implications of the findings in the context of tobacco control efforts. PMID- 29127786 TI - Development and initial testing of the brief adolescent smoking curiosity scale (ASCOS). AB - BACKGROUND: Although the reasons behind tobacco smoking at young age are complex, research has identified curiosity as a potent driver of smoking among adolescents. OBJECTIVE: The objective of the current study is to develop and provide initial evidence of reliability and validity of a short scale assessing smoking curiosity among adolescents (first measure of its kind). In particular, we developed and tested the adolescent smoking curiosity scale (ASCOS). METHODS: After scale development, 101 adolescents completed a survey on smoking-related measures, including ASCOS (June to August 2014). We conducted exploratory factor analysis and Cronbach's alpha calculation to inspect factor-structure and reliability. We conducted multiple linear regression models to examine the scale's capacity to predict antecedents of smoking initiation. RESULTS: Factor analysis supported a single-factor structure of smoking curiosity. ASCOS was internally reliable (Cronbach's alpha=0.83). Controlling for demographics, the measure correlated significantly with temptation to try smoking (beta=0.41, p<0.01), number of friends who smoke (beta=0.27, p<0.01), agreeing with the pros of smoking (beta=0.41, p<0.001), sensation seeking (beta=0.21, p<0.05), and depression (beta=0.23, p<0.01). When controlling for a single-item measure for smoking curiosity, ASCOS significantly predicted susceptibility to smoke cigarettes (OR=3.40, p<0.05) and cigars (OR=6.66, p<0.01). CONCLUSIONS: ASCOS presented good psychometric properties and passed initial validity-testing through associations with antecedents of smoking. ASCOS was a better predictor of susceptibility to smoke than did a traditional single-item measure used by previous research. As an implication, ASCOS can be crucial to the development of tailored interventions for smoking prevention that can reduce smoking curiosity. PMID- 29127787 TI - E-cigarette marketing exposure and combustible tobacco use among adolescents in the United States. AB - E-cigarette advertising has been shown to be associated with use of e-cigarettes, but its association with tobacco use has not been studied. Therefore, we examined the association between e-cigarettes advertisement and tobacco use. Data from nationally representative 22,007 middle and high school students (grades 6-12) were used to conduct the analysis. Logistic regression models estimated the adjusted odds ratios (AOR) of ever and current use of cigarette, hookah, cigar, and polytobacco use. Odds ratios were weighted and adjusted for study design, non response rates, school level, gender, race/ethnicity, e-cigarette use, and smoking at home. E-cigarette marketing exposure was significantly associated with ever use of cigarettes (AOR: 1.3, 95% CI: 1.1-1.5), hookah (AOR: 1.4, 95% CI: 1.2 1.7), cigars (AOR: 1.5, 95% CI: 1.4-1.6), and polytobacco (AOR: 1.7, 95% CI: 1.5 1.8). Likewise, E-cigarette marketing exposure was significantly associated with current use of cigarettes (AOR: 1.3, 95% CI: 1.1-1.6), hookah (AOR: 1.3, 95% CI: 1.03-1.7), cigars (AOR: 1.3, 95% CI: 1.1-1.6), and polytobacco use (AOR: 1.8, 95% CI: 1.5-2.1). The results suggest that e-cigarette advertisement is associated with use of cigarettes, hookah, cigars, and polytobacco products. These results add to the evidence about the risks of e-cigarette marketing and highlight the need for stricter regulation of e-cigarette advertisements. PMID- 29127788 TI - Rapid prediction of total petroleum hydrocarbons concentration in contaminated soil using vis-NIR spectroscopy and regression techniques. AB - Visible and near infrared spectrometry (vis-NIRS) coupled with data mining techniques can offer fast and cost-effective quantitative measurement of total petroleum hydrocarbons (TPH) in contaminated soils. Literature showed however significant differences in the performance on the vis-NIRS between linear and non linear calibration methods. This study compared the performance of linear partial least squares regression (PLSR) with a nonlinear random forest (RF) regression for the calibration of vis-NIRS when analysing TPH in soils. 88 soil samples (3 uncontaminated and 85 contaminated) collected from three sites located in the Niger Delta were scanned using an analytical spectral device (ASD) spectrophotometer (350-2500nm) in diffuse reflectance mode. Sequential ultrasonic solvent extraction-gas chromatography (SUSE-GC) was used as reference quantification method for TPH which equal to the sum of aliphatic and aromatic fractions ranging between C10 and C35. Prior to model development, spectra were subjected to pre-processing including noise cut, maximum normalization, first derivative and smoothing. Then 65 samples were selected as calibration set and the remaining 20 samples as validation set. Both vis-NIR spectrometry and gas chromatography profiles of the 85 soil samples were subjected to RF and PLSR with leave-one-out cross-validation (LOOCV) for the calibration models. Results showed that RF calibration model with a coefficient of determination (R2) of 0.85, a root means square error of prediction (RMSEP) 68.43mgkg-1, and a residual prediction deviation (RPD) of 2.61 outperformed PLSR (R2=0.63, RMSEP=107.54mgkg-1 and RDP=2.55) in cross-validation. These results indicate that RF modelling approach is accounting for the nonlinearity of the soil spectral responses hence, providing significantly higher prediction accuracy compared to the linear PLSR. It is recommended to adopt the vis-NIRS coupled with RF modelling approach as a portable and cost effective method for the rapid quantification of TPH in soils. PMID- 29127789 TI - Configuration of multiple human stressors and their impacts on fish assemblages in Alpine river basins of Austria. AB - This work addresses multiple human stressors and their impacts on fish assemblages of the Drava and Mura rivers in southern Austria. The impacts of single and multiple human stressors on riverine fish assemblages in these basins were disentangled, based on an extensive dataset. Stressor configuration, i.e. various metrics of multiple stressors belonging to stressor groups hydrology, morphology, connectivity and water quality were investigated for the first time at river basin scale in Austria. As biological response variables, the Fish Index Austria (FIA) and its related single as well as the WFD biological- and total state were investigated. Stressor-response analysis shows divergent results, but a general trend of decreasing ecological integrity with increasing number of stressors and maximum stressor is observed. Fish metrics based on age structure, fish region index and biological status responded best to single stressors and/or their combinations. The knowledge gained in this work provides a basis for advanced investigations in Alpine river basins and beyond, supports WFD implementation and helps prioritizing further actions towards multi-stressor restoration- and management. PMID- 29127790 TI - Oil and gas development footprint in the Piceance Basin, western Colorado. AB - Understanding long-term implications of energy development on ecosystem function requires establishing regional datasets to quantify past development and determine relationships to predict future development. The Piceance Basin in western Colorado has a history of energy production and development is expected to continue into the foreseeable future due to abundant natural gas resources. To facilitate analyses of regional energy development we digitized all well pads in the Colorado portion of the basin, determined the previous land cover of areas converted to well pads over three time periods (2002-2006, 2007-2011, and 2012 2016), and explored the relationship between number of wells per pad and pad area to model future development. We also calculated the area of pads constructed prior to 2002. Over 21million m2 has been converted to well pads with approximately 13million m2 converted since 2002. The largest land conversion since 2002 occurred in shrub/scrub (7.9million m2), evergreen (2.1million m2), and deciduous (1.3million m2) forest environments based on National Land Cover Database classifications. Operational practices have transitioned from single well pads to multi-well pads, increasing the average number of wells per pad from 2.5 prior to 2002, to 9.1 between 2012 and 2016. During the same time period the pad area per well has increased from 2030 m2 to 3504 m2. Kernel density estimation was used to model the relationship between the number of wells per pad and pad area, with these curves exhibiting a lognormal distribution. Therefore, either kernel density estimation or lognormal probability distributions may potentially be used to model land use requirements for future development. Digitized well pad locations in the Piceance Basin contribute to a growing body of spatial data on energy infrastructure and, coupled with study results, will facilitate future regional and national studies assessing the spatial and temporal effects of energy development on ecosystem function. PMID- 29127791 TI - Land use changes and socio-economic development strongly deteriorate river ecosystem health in one of the largest basins in China. AB - It is important to assess river ecosystem health in large-scale basins when considering the complex influence of anthropogenic activities on these ecosystems. This study investigated the river ecosystem health in the Haihe River Basin (HRB) by sampling 148 river sites during the pre- and post-rainy seasons in 2013. A model was established to assess the river ecosystem health based on water physicochemical, nutrient, and macroinvertebrate indices, and the health level was divided into "very poor," "poor," "fair," "good," and "excellent" according to the health score calculated from the assessment model. The assessment results demonstrated that the river ecosystem health of the HRB was "poor" overall, and no catchments were labeled "excellent." The percentages of catchments deemed to have "very poor," "poor," "fair," or "good" river ecosystem health were 12.88%, 40.91%, 40.15%, and 6.06%, respectively. From the pre- to the post-rainy season, the macroinvertebrate health levels improved from "poor" to "fair." The results of a redundancy analysis (RDA), path analysis of the structural equation model (SEM), and X-Y plots indicated that the land use types of forest land and grassland had positive relationships with river ecosystem health, whereas arable land, urban land, gross domestic product (GDP) per capita, and population density had negative relationships with river ecosystem health. The variance partitioning (VP) results showed that anthropogenic activities (including land use and socio economy) together explained 30.9% of the variations in river ecosystem health in the pre-rainy season, and this value increased to 35.9% in the post-rainy season. Land use intensity was the first driver of river ecosystem health, and socio economic activities was the second driver. Land use variables explained 20.5% and 25.7% of the variations in river ecosystem health in the pre- and post-rainy season samples, respectively, and socio-economic variables explained 12.3% and 17.2% of the variations, respectively. The SEM results revealed that urban land had the strongest impact on water quality health and that forest land had the strongest impact on macroinvertebrate health. This study has implications for the selection of appropriate indicators to assess river ecosystem health and generated data to examine the effects of anthropogenic activities on river ecosystem health in a fast-growing region. PMID- 29127792 TI - Direct evidence for the enhanced acquisition of phosphorus in the rhizosphere of aquatic plants: A case study on Vallisneria natans. AB - There are few studies about the processes and mechanisms for aquatic plants to take up phosphorus (P) in wetland soils and sediments. Direct observation of P mobilization in rhizosphere is lacking. In this study, high-resolution dialysis (HR-Peeper) and diffusive gradients in thin films (DGT) techniques were used to capture the small-scale changes of soluble reactive P (SRP) and soluble Fe, and labile P in the rhizosphere of Vallisneria natans (V. natans), respectively. The results showed 5.92- and 3.12-fold enrichments of P and Fe in the Fe plaques formed on the root surfaces, respectively, in comparison with the P and Fe concentrations in the non-rhizosphere sediments. Moreover, simultaneous releases of P and Fe appeared in rhizosphere and the SRP concentration showed up to 114 fold increases compared to the non-rhizosphere sediments. Five kinds of low molecular weight organic acids (LMWOAs) were detected in the root exudates; oxalic acid accounted for 87.5% of the total. Extraction of Fe and P in the Fe plaques was greatly enhanced by root exudates compared to deionized water, and oxalic acid contributed to 67% and 75% of the total extracted Fe and P, respectively. The coupling processes of Fe plaque enrichment of P and oxalic acid complexation of Fe(III) led to significantly enhanced P acquisition in the rhizosphere of V. natans. PMID- 29127793 TI - Pest management under climate change: The importance of understanding tritrophic relations. AB - Plants and insects depend on climatic factors (temperature, solar radiation, precipitations, relative humidity and CO2) for their development. Current knowledge suggests that climate change can alter plants and insects development and affect their interactions. Shifts in tritrophic relations are of particular concern for Integrated Pest Management (IPM), because responses at the highest trophic level (natural enemies) are highly sensitive to warmer temperature. It is expected that natural enemies could benefit from better conditions for their development in northern latitudes and IPM could be facilitated by a longer period of overlap. This may not be the case in southern latitudes, where climate could become too warm. Adapting IPM to future climatic conditions requires therefore understanding of changes that occur at the various levels and their linkages. The aim of this review is to assess the current state of knowledge and highlights the gaps in the existing literature concerning how climate change can affect tritrophic relations. Because of the economic importance of wine production, the interactions between grapevine, Vitis vinifera (1st), Lobesia botrana (2nd) and Trichogramma spp., (3rd), an egg parasitoid of Lobesia botrana, are considered as a case study for addressing specific issues. In addition, we discuss models that could be applied in order quantify alterations in the synchrony or asynchrony patterns but also the shifts in the timing and spatial distribution of hosts, pests and their natural enemies. PMID- 29127794 TI - Novel biochar-concrete composites: Manufacturing, characterization and evaluation of the mechanical properties. AB - In this study, biochar, a carbonaceous solid material produced from three different waste sources (poultry litter, rice husk and pulp and paper mill sludge) was utilized to replace cement content up to 1% of total volume and the effect of individual biochar mixed with cement on the mechanical properties of concrete was investigated through different characterization techniques. A total of 168 samples were prepared for mechanical testing of biochar added concrete composites. The results showed that pulp and paper mill sludge biochar at 0.1% replacement of total volume resulted in compressive strength close to the control specimen than the rest of the biochar added composites. However, rice husk biochar at 0.1% slightly improved the splitting tensile strength with pulp and papermill sludge biochar produced comparable values. Biochar significantly improved the flexural strength of concrete in which poultry litter and rice husk biochar at 0.1% produced optimum results with 20% increment than control specimens. Based on the findings, we conclude that biochar has the potential to improve the concrete properties while replacing the cement in minor fractions in conventional concrete applications. PMID- 29127796 TI - Effects of warming on N2O fluxes in a boreal peatland of Permafrost region, Northeast China. AB - Climate warming is expected to increasingly influence boreal peatlands and alter their greenhouse gases emissions. However, the effects of warming on N2O fluxes and the N2O budgets were ignored in boreal peatlands. Therefore, in a boreal peatland of permafrost zone in Northeast China, a simulated warming experiment was conducted to investigate the effects of warming on N2O fluxes in Betula. Fruticosa community (B. Fruticosa) and Ledum. palustre community (L. palustre) during the growing seasons from 2013 to 2015. Results showed that warming treatment increased air temperature at 1.5m aboveground and soil temperature at 5cm depth by 0.6 degrees C and 2 degrees C, respectively. The average seasonal N2O fluxes ranged from 6.62 to 9.34MUgm-2h-1 in the warming plot and ranged from 0.41 to 4.55MUgm-2h-1 in the control plots. Warming treatment increased N2O fluxes by 147% and transformed the boreal peatlands from a N2O sink to a source. The primary driving factors for N2O fluxes were soil temperature and active layer depth, whereas soil moisture showed a weak correlation with N2O fluxes. The results indicated that warming promoted N2O fluxes by increasing soil temperature and active layer depth in a boreal peatland of permafrost zone in Northeast China. Moreover, elevated N2O fluxes persisted in this region will potentially drive a noncarbon feedback to ongoing climate change. PMID- 29127795 TI - An investigation of the leaf retention capacity, efficiency and mechanism for atmospheric particulate matter of five greening tree species in Beijing, China. AB - Urban trees have the potential to reduce air pollution, but the retention capacity and efficiency of different tree species for atmospheric particulate matter (PM) accumulation and the underlying mechanism hasn't been well understood. To select tree species with high air purification abilities, the supplementing ultrasonic cleaning (UC) procedure was first introduced into the conventional leaf cleaning methods [single water cleaning (WC) or plus brush cleaning (BC)] for eluting the leaf-retained PM. Further updates to the methodology were applied to investigate the retention capacity, efficiency, and mechanism for PM of five typical greening tree species in Beijing, China. Meanwhile, the particle size distribution of PM on the leaves, the PM retention efficiencies of easily removable (ERP), difficult-to-remove (DRP) and totally removable (TRP) particles on the leaf (AEleaf), and the individual tree scales were estimated. The experimental leaf samples were collected from trees with similar sizes 4 (SDR) and 14days (LDR) after rainfall. When the leaves were cleaned by WC+BC, there was, on average, 29%-46% of the PM remaining on the leaves of different species, which could be removed almost completely if UC was supplemented. From SDR to LDR, the mass of the leaf-retained PM increased greatly, and the particle size distribution changed markedly for all species except for Sophorajaponica. Pinus tabuliformis retains particles with the largest average diameter (34.2MUm), followed by Ginkgo biloba (20.5MUm), Sabina chinensis (16.4MUm), Salix babylonica (16.0MUm), and S. japonica (13.1MUm). S. japonica and S. chinensis had the highest AEleaf to retain the TRP and ERP of both PM1 and PM1 2.5, respectively. Conversely, S. babylonica and P. tabuliformis could retain both TRP and ERP of PM2.5-5 and PM5-10, and PM>10 and TSP with the highest AEleaf, respectively. In conclusion, our results could be useful in selecting greening tree species with high air purification abilities. PMID- 29127797 TI - The environmental consequences of permafrost degradation in a changing climate. PMID- 29127798 TI - Characterization and sources of colored dissolved organic matter in a coral reef ecosystem subject to ultramafic erosion pressure (New Caledonia, Southwest Pacific). AB - The eastern lagoon of New Caledonia (NC, Southwest Pacific), listed as a UNESCO World Heritage site, hosts the world's second longest double-barrier coral reef. This lagoon receives river inputs, oceanic water arrivals, and erosion pressure from ultramafic rocks, enriched in nickel (Ni) and cobalt (Co). The aim of this study was to characterize colored dissolved organic matter (CDOM), as well as to determine its main sources and its possible relationships (through the use of Pearson correlation coefficients, r) with biogeochemical parameters, plankton communities and trace metals in the NC eastern lagoon. Water samples were collected in March 2016 along a series of river/lagoon/open-ocean transects. The absorption coefficient at 350nm (a350) revealed the influence of river inputs on the CDOM distribution. The high values of spectral slope (S275-295, >0.03m-1) and the low values of specific ultraviolet absorbance (SUVA254, <4Lmg-C-1m-1) highlighted the photodegradation of CDOM in surface waters. The application of parallel factor analysis (PARAFAC) on excitation-emission matrices (EEMs) allowed the identification of four CDOM components: (1) one humic- and one tyrosine-like fluorophores. They had terrestrial origin, exported through rivers and undergoing photo- and bio-degradation in the lagoon. These two fluorophores were linked to manganese (Mn) in southern rivers (r=0.46-0.50, n=21, p<0.05). (2) A tryptophan like fluorophore, which exhibited higher levels offshore. It would be potentially released from the coral reef. (3) A second tyrosine-like ("tyrosine 2-like") fluorophore. Linked to Prochlorococcus cyanobacteria (r=0.39, n=47, p<0.05), this fluorophore would have an oceanic origin and enter in the lagoon through its southern and northern extremities. It also displayed relationships with Ni and Co content (r=0.53-0.54, n=21, p<0.05). This work underlines the diversity of CDOM sources in the NC eastern lagoon. PMID- 29127799 TI - Persistence of antibiotic resistance genes and bacterial community changes in drinking water treatment system: From drinking water source to tap water. AB - As emerging contaminants, antibiotic resistance genes (ARGs) have become a public concern. This study aimed to investigate the occurrence and diversity of ARGs, and variation in the composition of bacterial communities in source water, drinking water treatment plants, and tap water in the Pearl River Delta region, South China. Various ARGs were present in the different types of water. Among the 27 target ARGs, floR and sul1 dominated in source water from three large rivers in the region. Pearson correlation analysis suggested that sul1, sul2, floR, and cmlA could be potential indicators for ARGs in water samples. The total abundance of the detected ARGs in tap water was much lower than that in source water. Sand filtration and sedimentation in drinking water treatment plants could effectively remove ARGs; in contrast, granular activated carbon filtration increased the abundance of ARGs. It was found that Pseudomonas may be involved in the proliferation and dissemination of ARGs in the studied drinking water treatment system. Bacteria and ARGs were still present in tap water after treatment, though they were significantly reduced. More research is needed to optimize the water treatment process for ARG removal. PMID- 29127800 TI - Regulation of chemicals in children's products: How U.S. and EU regulation impacts small markets. AB - Toys and children's products may contain trace metals and organic compounds that are potentially harmful to the health and development of infants and young children. Intergovernmental organizations and individual countries regulate chemicals in consumer products, but a coordinated international approach is lacking. This paper examines the implications of chemical regulation in children's products in large markets for a smaller market, namely Israel. We compared chemical regulations in children's products in the U.S., EU and Israel, and conducted in-depth interviews with diverse stakeholders in the Israeli product standardization process. Israel adopted EU chemical standards for certain chemicals (e.g., trace metals, phthalates) but not others (e.g., bisphenol A, flame retardants, trace metals in children's jewelry). Israeli regulation of chemicals in consumer products relies on regulations in large markets such as the U.S. and EU, which therefore have impacts beyond their territories. However, Israel adopts only product-specific standards and has regulatory gaps due to the lack of an overarching regulatory approach that exists in the U.S. and the EU. Furthermore, Israeli policy is to adopt parallel standards from large markets in order to remove trade barriers, despite their different approaches to chemical regulation, an approach which prioritizes trade considerations over health considerations. We conclude with policy recommendations for Israel, which have relevance for other small markets. PMID- 29127801 TI - The potential of chironomid larvae-based metrics in the bioassessment of non wadeable rivers. AB - The chironomid community in non-wadeable lotic systems was tested as a source of information in the construction of biological metrics which could be used into the bioassessment protocols of large rivers. In order to achieve this, we simultaneously patterned the chironomid community structure and environmental factors along the catchment of the Danube and Sava River. The Self organizing map (SOM) recognized and visualized three different structural types of chironomid community for different environmental properties, described by means of 7 significant abiotic factors (a multi-stressor gradient). Indicator species analysis revealed that the chironomid taxa most responsible for structural changes significantly varied in their abundance and frequency along the established environmental gradients. Out of 40 biological metrics based on the chironomid community, the multilayer perceptron (MLP), an supervised type of artificial neural network, derived 5 models in which the abundance of Paratrichocladius rufiventis, Orthocladiinae, Cricotopus spp., Cricotopus triannulatus agg. and Cricotopus/Orthocladius ratio achieved a significant relationship (the r Pearson's linear correlation coefficient>0.7) with the multi stressor environment. The sensitivity analysis "partial derivatives" (PaD) method showed that all 5 biological metrics within the multi-stressor gradient were mostly influenced by dissolved organic carbon (DOC). Despite short and monotonous environmental gradients and the absence of reference conditions, the chironomid community structure and biological metrics predictably changed along the multistress range, showing a great potential for the bioassessment of large rivers. PMID- 29127802 TI - Resistance mechanisms and their difference between the root and leaf of Microsorum pteropus - A novel potential aquatic cadmium hyperaccumulator. AB - Microsorum pteropus (M. pteropus), an aquatic Polypodiaceae fern, was identified as a novel potential cadmium (Cd) hyperaccumulator in our previous study. This study reveals the Cd-resistance mechanisms and their difference between the root and leaf of M. pteropus based on analyses of photosynthesis, antioxidant systems and gene expression. A high level of Cd at 500MUM was used to treat the samples to test the effects of this compound. Superoxide dismutase (SOD), peroxidase (POD), malondialdehyde (MDA) and flavonoids were used as indicators for antioxidant system changes. Five chlorophyll fluorescent parameters including the maximal photochemical efficiency of photosystem II (Fv/Fm), effective quantum yield of photosystem II (Y(II)), photochemical quenching (qP), nonphotochemical quenching (qN) and electron transport rate (ETR) were measured to determine the photosynthetic changes. RNA-sequencing analysis was used to study the changes in gene expression. The results showed that after exposure to high levels of Cd, the concentrations of enzymatic oxidants (SOD and POD) were significantly increased, while the MDA levels were significantly decreased. There were no significant changes for the chlorophyll fluorescent parameters during Cd stress, which indicates that M. pteropus is highly effective at protecting itself. Certain functional genes, including photosystem genes and secondary metabolites, had significantly altered levels of expression. Different Cd-resistance mechanisms were found between the root and leaf tissues of M. pteropus. The root tissues of M. pteropus resist Cd damage using antioxidants, while its leaf tissues mainly protect themselves using photosystem self-protection. PMID- 29127803 TI - Development of thresholds of excess toxicity for environmental species and their application to identification of modes of acute toxic action. AB - The acute toxicity of organic pollutants to fish, Daphnia magna, Tetrahymena pyriformis, and Vibrio fischeri was investigated. The results indicated that the Toxicity Ratio (TR) threshold of log TR =1, which has been based on the distribution of toxicity data to fish, can also be used to discriminate reactive or specifically acting compounds from baseline narcotics for Daphnia magna and Vibrio fischeri. A log TR=0.84 is proposed for Tetrahymena pyriformis following investigation of the relationships between the species sensitivity and the absolute averaged residuals (AAR) between the predicted baseline toxicity and the experimental toxicity. Less inert compounds exhibit relatively higher toxicity to the lower species (Tetrahymena pyriformis and Vibrio fischeri) than the higher species (fish and Daphnia magna). A greater number of less inert compounds with log TR greater than the thresholds was observed for Tetrahymena pyriformis and Vibrio fischeri. This may be attributed to the hydrophilic compounds which may pass more easily through cell membranes than the skin or exoskeleton of organisms and have higher bioconcentration factors in the lower species, leading to higher toxicity. Most of classes of chemical associated with excess toxicity to one species also exhibited excess toxicity to other species, however, a few classes with excess toxicity to one species exhibiting narcotic toxicity to other species and thus may have different MOAs between species. Some ionizable compounds have log TR much lower than one because of the over-estimated log KOW. The factors that influence the toxicity ratio calculated from baseline level are discussed in this paper. PMID- 29127804 TI - Impact of rainfall patterns and frequency on the export of pesticides and heavy metals from agricultural soils. AB - The combined influence of soil characteristics, pollutant aging and rainfall patterns on the export of pollutants from topsoils is poorly understood. We used laboratory experiments and parsimonious modeling to evaluate the impact of rainfall characteristics on the ponding and the leaching of a pollutant mixture from topsoils. The mixture included the fungicide metalaxyl, the herbicide S metolachlor, as well as copper (Cu) and zinc (Zn). Four rainfall patterns, which differed in their durations and intensities, were applied twice successively with a 7days interval on each soil type. To evaluate the influence of soil type and aging, experiments included crop and vineyard soils and two stages of pollutant aging (0 and 10days). The global export of pollutants was significantly controlled by the rainfall duration and frequency (P<0.01). During the first rainfall event, the longest and most intense rainfall pattern yielded the largest export of metalaxyl (44.5+/-21.5% of the initial mass spiked in the soils), S metolachlor (8.1+/-3.1%) and Cu (3.1+/-0.3%). Soil compaction caused by the first rainfall reduced in the second rainfall the leaching of remaining metalaxyl, S metolachlor, Cu and Zn by 2.4-, 2.9-, 30- and 50-fold, respectively. In contrast, soil characteristics and aging had less influence on pollutant mass export. The soil type significantly influenced the leaching of Zn, while short-term aging impacted Cu leaching. Our results suggest that rainfall characteristics predominantly control export patterns of metalaxyl and S-metolachlor, in particular when the aging period is short. We anticipate our study to be a starting point for more systematic evaluation of the dissolved pollutant ponding/leaching partitioning and the export of pollutant mixtures from different soil types in relation to rainfall patterns. PMID- 29127805 TI - Prenatal contribution of 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) to total body burden in young children. AB - Many scientists made estimates of the body burden of PBDEs from breastmilk and house dust. Interestingly, they have not included the prenatal contribution to the body burden in young children after birth. In order to address how the prenatal contribution is important in the risk assessment of PBDEs in infants up to five years old, we used the median measurements of BDE-47 as a model chemical in 108 neonates in Korea, and made simulations of its disposition out of body from birth to five years. During the simulation periods, the environmental exposure was considered for house dust, babyfood, breastmilk consumption, etc., with assumption of typical exposure scenario applicable to general infants in Korea. About 22% of the total amounts of BDE-47 in newborn remained up to 5years after birth. The relative amounts of BDE-47 from the prenatal source were 20%, 14%, 10%, 8%, 6%, and 4% of the total body burden for 1-, 2-, 3-, 4- and 5-year after birth, respectively. The contribution from breastfeeding was 95.2% and 92.2% of the total postnatal exposure amounts at 6-month and 1-year after birth, respectively. After cease of breastfeeding at 1-yr, house dust and food were the important sources of exposure up to 5-yr; however, their contributions to the bodyburden were negligible with consideration of the remaining amounts of the analytes from the breastmilk and prenatal exposure. Suggestively, the innate amounts and pharmacokinetics should be counted in estimating bodyburden of BDE 47. PMID- 29127806 TI - Blood DNA methylation as a potential biomarker of dementia: A systematic review. AB - Dementia is a major public health issue with rising prevalence rates, but many individuals remain undiagnosed. Accurate and timely diagnosis is key for the optimal targeting of interventions. A noninvasive, easily measurable peripheral biomarker would have greatest utility in population-wide diagnostic screening. Epigenetics, including DNA methylation, is implicated in dementia; however, it is unclear whether epigenetic changes can be detected in peripheral tissue. This study aimed to systematically review the evidence for an association between dementia and peripheral DNA methylation. Forty-eight studies that measured DNA methylation in peripheral blood were identified, and 67% reported significant associations with dementia. However, most studies were underpowered and limited by their case-control design. We emphasize the need for future longitudinal studies on large well-characterized populations, measuring epigenetic patterns in asymptomatic individuals. A biomarker detectable in the preclinical stages of the disease would have the greatest utility in future intervention and treatment trials. PMID- 29127807 TI - Electrochemical activation of persulfates at BDD anode: Radical or nonradical oxidation? AB - The combination of persulfates (peroxydisulfate (PDS) and peroxymonosulfate (PMS)) and electrolysis using boron-doped diamond (BDD) anode is a promising green advanced oxidation process. In comparison with electrolysis alone, electrochemical activation of persulfates at BDD anode considerably enhanced the degradation of carbamazepine (CBZ). The experimental results indicate that the surface-adsorbed hydroxyl radical (HO) played the dominant role. The generally proposed nonradical oxidation mechanism ignored hydroxyl radical (HO) oxidation because low concentration of radical scavenger (<10 M methanol or 5 M tertbutanol) could not effectively scavenge the surface-adsorbed HO. The quasi steady-state concentration of HO was estimated to be about 5.0-9.1 * 10-12 M for electrolysis with BDD anode, and it was increased to 1.1-1.6 * 10-11 M and 3.2 5.0 * 10-11 M for addition of 5 mM PDS and PMS, respectively. The results of cyclic voltammetry (CV) and chronoamperometry as well as evolution of dissolved oxygen (DO) reveal that the electrochemically activated persulfates molecule (PDS*/PMS*) promoted the production of HO via water dissociation at BDD anode and enhanced the direct electron transfer (DET) reaction, which otherwise inhibited the oxygen evolution side reaction. Therefore, higher current efficiency was achieved in electrochemical activation of persulfates process compared with electrolysis process. Additionally, the transformation products of CBZ were also investigated and their formation pathways were proposed. PMID- 29127808 TI - Improving autocoding performance of rare categories in injury classification: Is more training data or filtering the solution? AB - INTRODUCTION: Classical Machine Learning (ML) models have been found to assign the external-cause-of-injury codes (E-codes) based on injury narratives with good overall accuracy but often struggle with rare categories, primarily due to lack of enough training cases and heavily skewed nature of injurdata. In this paper, we have: a) studied the effect of increasing the size of training data on the prediction performance of three classical ML models: Multinomial Naive Bayes (MNB), Support Vector Machine (SVM) and Logistic Regression (LR), and b) studied the effect of filtering based on prediction strength of LR model when the model is trained on very-small (10,000 cases) and very-large (450,000 cases) training sets. METHOD: Data from Queensland Injury Surveillance Unit from years 2002-2012, which was categorized into 20 broad E-codes was used for this study. Eleven randomly chosen training sets of size ranging from 10,000 to 450,000 cases were used to train the ML models, and the prediction performance was analyzed on a prediction set of 50,150 cases. Filtering approach was tested on LR models trained on smallest and largest training datasets. Sensitivity was used as the performance measure for individual categories. Weighted average sensitivity (WAvg) and Unweighted average sensitivity (UAvg) were used as the measures of overall performance. Filtering approach was also tested for estimating category counts and was compared with approaches of summing prediction probabilities and counting direct predictions by ML model. RESULTS: The overall performance of all three ML models improved with increase in the size of training data. The overall sensitivities with maximum training size for LR and SVM models were similar (~82%), and higher than MNB (76%). For all the ML models, the sensitivities of rare categories improved with increasing training data but they were considerably less than sensitivities of larger categories. With increasing training data size, LR and SVM exhibited diminishing improvement in UAvg whereas the improvement was relatively steady in case of MNB. Filtering based on prediction strength of LR model (and manual review of filtered cases) helped in improving the sensitivities of rare categories. A sizeable portion of cases still needed to be filtered even when the LR model was trained on very large training set. For estimating category counts, filtering approach provided best estimates for most E-codes and summing prediction probabilities approach provided better estimates for rare categories. CONCLUSIONS: Increasing the size of training data alone cannot solve the problem of poor classification performance on rare categories by ML models. Filtering could be an effective strategy to improve classification performance of rare categories when large training data is not available. PMID- 29127809 TI - Optimisation of the antifungal potency of the amidated peptide H-Orn-Orn-Trp-Trp NH2 against food contaminants. AB - The design of novel efficient antimicrobial peptides (AMPs) faces several issues, such as cost of synthesis, proteolytic stability or cytotoxicity. The identification of key determinants involved in the activity of AMPs, such as cationicity and amphipathicity, allowed the synthesis of short peptides with optimized properties. An ultrashort peptide made of the sequence H-Orn-Orn-Trp Trp-NH2 (O3TR) showed antifungal activity against several contaminants from food products. This peptide inhibited the growth of the filamentous fungi Fusarium culmorum, Penicillium expansum and Aspergillus niger within a range of concentration of 12.5-50MUg/ml. In addition, O3TR inhibited the growth of the yeast Saccharomyces cerevisiae, Zygosaccharomyces bailii, Zygosaccharomyces rouxii, Debaryomyces hansenii and Kluyveromyces lactis within the range 12.5 50MUg/ml. A derivative peptide, called C12O3TR, made by the addition of lauric acid at the N-terminus of O3TR was 2- to 8-fold more active than O3TR against every species. In addition to the inhibition of conidial germination, O3TR and C12O3TR killed F. culmorum hyphae at 100 and 50MUg/ml respectively. The MIC of the two peptides against F. culmorum and Z. bailii after heat treatment at 100 degrees C for 60 min and within the pH range 3-10, were not changed. However, the activity of O3TR against F.culmorum and Z. bailii was strongly reduced in salt solutions, whereas the lauric acid peptide kept its antifungal activity and resistance to proteolytic digestion. The conjugation with lauric acid reduced the random coiled structure and increased the alpha-helical content of O3TR. After conjugation with the dye tetramethylrhodamine (TMR), both peptides entered F. culmorum spores. They also both induced permeabilization of F. culmorum hyphae but only C12O3TR permeabilized Z. bailii membrane. In contrast to the lipopeptide, O3TR did not show haemolytic or cytotoxic activity when applied at the concentrations that exhibited antifungal potency. The two peptides were challenged against a yeast cocktail of S. cerevisiae and Z. bailii, and A. niger in different commercial beverages. After 7 days, O3TR was able to inhibit the yeast cocktail in a commercial lager and carbonated drink. Due to its antifungal potency, high stability and low cytotoxicity, the tetrapeptide could represent a promising starting point of a novel food preservative. PMID- 29127810 TI - Antimicrobial activities of gaseous essential oils against Listeria monocytogenes on a laboratory medium and radish sprouts. AB - The aim of this study was to evaluate the antimicrobial activities of gaseous essential oils (EO gases) against Listeria monocytogenes on the surfaces of a laboratory medium and radish sprouts. We determined the minimal inhibitory concentration (MIC) and minimal lethal concentration (MLC) values of EO gases from eight EOs extracted from basil leaves, carrot seed, cinnamon bark, cinnamon leaves, clove flower buds, oregano leaves, thyme flowers (linalool), and thyme leaves (thymol) against L. monocytogenes on a nutrient agar supplemented with 1% glucose and 0.025% bromocresol purple (NGBA). Oregano, thyme thymol, and cinnamon bark EO gases showed the strongest antilisterial activities (MIC and MLC, 78.1MUL/L). We also investigated the inhibitory and lethal activities of these gases against L. monocytogenes on the surface of radish sprouts. The number of L. monocytogenes after exposure to EO gases at >=156MUL/L was significantly (P<=0.05) lower than that of untreated L. monocytogenes. For example, the initial number of L. monocytogenes on the surface of radish sprouts (ca. 6.3logCFU/g) decreased by 1.4logCFU/g within 24h at 30 degrees C and 43% relative humidity (RH) without EO gas treatment, whereas the number of L. monocytogenes after exposure to oregano, thyme thymol, and cinnamon bark EO gases at 156MUL/L decreased by 2.1, 2.1, and 1.8logCFU/g, respectively, after 24h. Although EO gases exerted greater lethal activities at higher concentrations (312 and 625MUL/L), L. monocytogenes on the surface of radish sprouts was not completely inactivated. The number of L. monocytogenes on sprouts treated with oregano, thyme thymol, and cinnamon bark EO gases at 625MUL/L decreased by 2.7-3.0logCFU/g after 24h at 30 degrees C and 43% RH. Results indicate that EO gases that showed antilisterial activities on a laboratory medium also exhibited reduced lethal activity on the surface of radish sprouts. These findings will be useful when developing strategies to inactivate L. monocytogenes and possibly other foodborne pathogens on sprouts and perhaps other foods using EO gases. PMID- 29127811 TI - Distribution and incidence of atoxigenic Aspergillus flavus VCG in tree crop orchards in California: A strategy for identifying potential antagonists, the example of almonds. AB - To identify predominant isolates for potential use as biocontrol agents, Aspergillus flavus isolates collected from soils of almond, pistachio and fig orchard in the Central Valley of California were tested for their membership to 16 atoxigenic vegetative compatibility groups (VCGs), including YV36, the VCG to which AF36, an atoxigenic isolate commercialized in the United States as biopesticide, belongs. A surprisingly large proportion of isolates belonged to YV36 (13.3%, 7.2% and 6.6% of the total almond, pistachio and fig populations, respectively), while the percentage of isolates belonging to the other 15 VCGs ranged from 0% to 2.3%. In order to gain a better insight into the structure and diversity of atoxigenic A. flavus populations and to further identify predominant isolates, seventeen SSR markers were then used to genetically characterize AF36, the 15 type-isolates of the VCGs and 342 atoxigenic isolates of the almond population. There was considerable genetic diversity among isolates with a lack of differentiation among micro-geographical regions or years. Since isolates sharing identical SSR profiles from distinct orchards were rare, we separated them into groups of at least 3 closely-related isolates from distinct orchards that shared identical alleles for at least 15 out of the 17 loci. This led to the identification of 15 groups comprising up to 24 closely-related isolates. The group which contained the largest number of isolates were members of YV36 while five groups were also found to be members of our studied atoxigenic VCGs. These results suggest that these 15 groups, and AF36 in particular, are well adapted to various environmental conditions in California and to tree crops and, as such, are good candidates for use as biocontrol agents. PMID- 29127813 TI - The effectiveness of Culturally Sensitive Collaborative Treatment of depressed Chinese in family medicine clinics: A randomized controlled trial. AB - OBJECTIVE: To investigate whether the Culturally Sensitive Collaborative Treatment (CSCT) would improve outcomes for patients with major depression who were managed in family medicine clinics in Taiwan. METHOD: A single-blinded randomized trial was conducted in 26 family medicine clinics. Patients with major depressive disorder were consecutively randomized to either CSCT or treatment as usual (TAU). The primary outcome was the severity of depression. Secondary outcomes included treatment response, treatment remission, quality of life, and medication adherence. Outcomes were compared using hierarchical linear models (mixed-effects models) from baseline to 26-week follow-up assessments. RESULTS: Of the 280 patients, 141 were randomized to TAU and 139 to CSCT. Hierarchical linear modeling revealed that the CSCT group displayed significantly greater improvement in depressive symptoms over the study period when compared to the TAU group (B=-2.60, P<0.001). The odds of achieving the response, remission, and medication adherence were significantly greater for the CSCT group compared to the TAU group (odds ratio=4.65, 4.12, and 2.06, respectively; all Ps<0.05). However, both groups did not differ significantly in quality of life. CONCLUSION: CSCT is effective in improving treatment outcomes for major depression in family medicine clinics in Taiwan. PMID- 29127812 TI - Optimism as predictor of patient-reported outcomes in patients with an implantable cardioverter defibrillator (data from the WEBCARE study). AB - OBJECTIVE: The implantable cardioverter defibrillator (ICD) is the treatment of choice for prevention of sudden cardiac death. However, a subgroup of ICD patients experiences psychological adjustment problems post implant. To date, positive psychological constructs (e.g. optimism) have been understudied in this population. Hence, we examined the association between optimism and anxiety, depression, and health status at 12-months post implant. METHODS: Patients (N=171) enrolled in the WEB-based distress management study for ICD patients were included in the analyses. Optimism and pessimism (LOT), and Type D personality (DS14) were administered at baseline, while anxiety (GAD-7), depression (PHQ-9), and health status (SF-12) were assessed at 12-months. RESULTS: The mean age was 59.6+/-10.06 with 81% being male. After controlling for demographic, personality, and clinical variables, baseline optimism was associated with lower anxiety (beta=-0.210; p=0.011) and depression (beta=-0.222; p=0.005), and better physical (beta=0.227; p=0.004) and mental health status (beta=0.350; p=0.000) at follow up. Optimism was also associated with change in mental health status (beta=0.195; p=0.007) but not with change in anxiety, depression, and physical health status at follow-up. CONCLUSIONS: Our findings indicate that optimism is associated with less distress and possibly helps safeguard mental health in ICD patients. Increase optimism might be the way forward to reduce long-term distress and impaired health status. TRIAL REGISTRATION: http://www.ClinicalTrials.gov. Identifier: NCT00895700. PMID- 29127814 TI - Alexithymia, not fibromyalgia, predicts the attribution of pain to anger-related facial expressions. AB - BACKGROUND: Fibromyalgia (FM) is a syndrome characterized by chronic, widespread musculoskeletal pain, occurring predominantly in women. Previous studies have shown that patients with FM display a pattern of selective processing or cognitive bias which fosters the encoding of pain-related information. The present study tested the hypothesis of an increased attribution of pain to facial expressions of emotions (FEE), in patients with FM. As previous studies have shown that alexithymia influences the processing of facial expressions, independent of specific clinical conditions, we also investigated whether alexithymia, rather than FM per se, influenced attribution of pain to FEE. METHODS: One hundred and twenty-three women (41 with FM, 82 healthy controls, HC) were enrolled in this cross-sectional case-control study. We adopted two pain attribution tasks, the Emotional Pain Estimation and the Emotional Pain Ascription, both using a modified version of the Ekman 60 Faces Test. Psychological distress was assessed using the Hospital Anxiety and Depression Scale, and alexithymia was assessed using the Toronto Alexithymia Scale. RESULTS: Patients with FM did not report increased attribution of pain to FEE. Alexithymic individuals demonstrated no specific problem in the recognition of basic emotions, but attributed significantly more pain to angry facial expression. LIMITATIONS: Our study involved a relatively small sample size. The use of self reported instruments might have led to underestimation of the presence of frank alexithymia in individuals having borderline cut-off scores. CONCLUSIONS: Alexithymia, rather than FM per se, plays a key role in explaining the observed differences in pain attribution to anger-related facial expressions. PMID- 29127815 TI - Distribution of metal and metalloid elements in human scalp hair in Taiyuan, China. AB - This study investigated the levels of metal and metalloid elements (As, Ca, Cd, Cr, Cu, Fe, Hg, Mg, Ni, Pb, and Zn) in scalp hair samples collected from 161 people of different age and gender groups living in the six districts of Taiyuan, an industrial city with rich coal reserve in Shanxi province in China. Levels of most elements in the hair were high in the 26-40 age groups and increased with the length of residence. Calcium, Cr, Mg, Ni and Zn levels in the females' hair were significantly higher than those in the males' (p < 0.05). Element levels in the hair didn't have significantly differences between industrial and non industrial districts because most of industry factories are in the upper wind position in Taiyuan, and contamination is prone to spread to non-industrial districts. The principal component analysis indicates that the main sources of these elements are mining activities, the neighboring stainless steel industry, and coal combustion. These results indicate that the industrial activities primarily contribute to the metal and metalloid pollution in Taiyuan, whereas numerous factors caused the metals accumulation in hair. PMID- 29127816 TI - Comparative study on the effects of putrescine and spermidine pre-treatment on cadmium stress in wheat. AB - In several cases a correlation was found between polyamines and abiotic stress tolerance. However, the individual polyamines may have different effects, which also vary depending on the type of treatment. When applied as seed soaking or added hydroponically 0.5mM putrescine and spermidine, different changes were induced during 50uM cadmium stress in wheat plants. Seed-soaked plants were exposed to cadmium immediately after germination for 5 days, while plants pre treated with polyamines hydroponically were stressed at age of 14 days for 7 days. Putrescine pre-treatment was beneficial both as seed soaking and applied hydroponically, while spermidine only had a protective effect in the case of seed soaking, enhancing the Cd-induced oxidative stress when were pre-treated hydroponically. The differences observed were related to the polyamine metabolism. The accumulation of endogenous putrescine beyond a certain amount may be in relation with the negative effect of hydroponic spermidine pre-treatment during Cd stress. The increased putrescine content was also correlated with the highest accumulation of Cd, salicylic acid and proline contents in plants treated with a combination of spermidine and Cd. However, the expression level of the gene encoding phytochelatin synthase was only influenced by hydroponically applied spermidine, which decreased it under cadmium stress. Changes in the activities of antioxidant enzymes, diamine and polyamine oxidases were also discussed. PMID- 29127817 TI - Heavy metals detection using biosensor cells of a novel marine luminescent bacterium Vibrio sp. MM1 isolated from the Caspian Sea. AB - Monitoring and assessing toxic materials which are being released into the environment along with wastewater is a growing concern in many industries. The current research describes a highly sensitive and rapid method for the detection of toxic concentrations of heavy metals in aquatic environments. Water samples were collected from southern coasts of the Caspian Sea followed by screening of luminescent bacteria. Phylogenetic analysis, including gene sequence of 16S rRNA, and biochemical tests were performed for identification of the isolate. Luminescence activity was tested and measured after treatment of the isolate with different concentrations of heavy metals and reported as EC50 value for each metal. A luminous, gram negative bacterium with the shape of a curved rod was isolated from the Caspian Sea. Biochemical tests and 16S rRNA gene sequence analysis indicated that the isolate MM1 had more than 99% similarity to Vibrio campbellii. The novel isolate is able to emit high levels of light. Bioluminescence inhibitory assay showed that the Vibrio sp. MM1 had the highest sensitivity to zinc and the lowest sensitivity to cadmium; EC50 values were 0.97mgl-1 and 14.54mgl-1, respectively. The current research shows that even low concentrations of heavy metals can cause a detectable decline in luminescence activity of the novel bacterium Vibrio sp. MM1; hence, it makes a good choice for commercial kits for the purpose of monitoring toxic materials. PMID- 29127818 TI - Cytokinesis-block micronucleus cytome assay parameters in peripheral blood lymphocytes of the general population: Contribution of age, sex, seasonal variations and lifestyle factors. AB - The cytokinesis-block micronucleus cytome (CBMN Cyt) assay was used to evaluate the baseline frequency of cytogenetic damage in peripheral blood lymphocytes of the general population (average age, 38.28 +/- 12.83 years) in relation to age, sex, body mass index, seasonal variations (season of sampling, period of sampling and different meteorological parameters) and lifestyle factors (smoking habit, alcohol consumption, exposure to medications and diagnostic radiation, physical activity, and family history of cancer). The background frequency of micronuclei (MNi) for the 200 subjects assayed was 5.06 +/- 3.11 per 1000 binucleated cells, while the mean frequency of nucleoplasmic bridges (NPBs) was 1.21 +/- 1.46 and of nuclear buds (NBUDs) 3.48 +/- 2.14. The background frequency of apoptosis and necrosis was 1.58 +/- 1.50 and 1.39 +/- 1.56, respectively, while the mean nuclear division index (NDI) was 1.99 +/- 0.14. The cut-off value, which corresponds to the 95th percentile of the distribution of 200 individual values, was 11 MNi, 4 NPBs and 7 NBUDs. The study also confirmed an association of the above mentioned parameters with age, sex and several lifestyle factors. Moreover, significant confounders based on our results are also sampling season, sampling period and different meteorological parameters that were dependent on the CBMN Cyt assay parameters. In line with the above mentioned, several factors should be taken into account when it comes to the monitoring of exposed populations using cytogenetic biomarkers. Moreover, the normal and cut-off values obtained in this study present background data for the general population, and can later serve as baseline values for further biomonitoring studies. PMID- 29127819 TI - Morphological response of a cactus to cement dust pollution. AB - Cement dust from cement plants around the world has multiple negative effects on organisms and their environment. Cement's effects come from its strongly alkaline nature and high content of heavy metals. Previous studies on plants have documented that cement dust deposition can influence plant vegetative growth, the lipid and ionic composition of tissues, and foliar temperature. Here we evaluate the effects of cement dust coming from a plant in western Argentina on the morphology of the cactus Tephrocactus aoracanthus. In sites located at 0.15km, 2km and 6km from the cement plant, we recorded five morphological attributes of the cactus: length and number of spines, cladode (stem) diameter, and fresh and dry weight. We also transplanted plants in situ to evaluate the effect of distance from the cement plant. In addition, we set an experiment spreading cement dust weekly on the aerial and ground parts of the cactus. Results of our field observational and experimental studies indicate that cement dust deposition on aerial parts of the plant leads to increased spine length, number of spines, and wet and dry weights of cladodes. PMID- 29127820 TI - Waterborne Zn influenced Zn uptake and lipid metabolism in two intestinal regions of juvenile goby Synechogobius hasta. AB - The present study explored the influence of Zn addition in the water on Zn transport and lipid metabolism of two intestinal regions in goby Synechogobius hasta. Zn contents in water were 0.004 (control), 0.181 and 0.361mg Zn L-1, respectively. The experiment lasted for 28 days. TG and Zn contents, mRNA contents of genes of Zn transport and lipid metabolism, and enzyme activity from anterior and mid-intestine tissues were analyzed. In anterior intestine, Zn addition in the water increased Zn contents, and mRNA concentrations of ZIP4, ZIP5, ATGL, PPARalpha, ZNF202 and KLF7, decreased TG contents, 6PGD and G6PD activities, and mRNA contents of 6PGD, G6PD, FAS, PPARgamma, ICDH and KLF4. In mid-intestine tissue, the highest Zn and TG contents were observed for 0.18mg Zn/l group, in parallel with the highest expressions of ZnT1, ZIP4, ZIP5, 6PGD, FAS, ICDH, PPARgamma, PPARalpha, ZNF202, KLF4 and KLF7, and with the highest FAS, 6PGD and G6PD activities. Thus, in the anterior intestine, Zn addition increased lipolysis and decreased lipogenesis, and accordingly reduced TG content. However, the highest mid-intestinal TG content in 0.18mg Zn/l group was due to the up regulated lipogenesis. Although lipolysis was also increased, the incremental lipid synthesis was enough to compensate for lipid degradation, which led TG accumulation. Our results, for the first time, show an anterior/mid functional regionalization of the intestine in lipid metabolism and Zn transport of S. hasta following Zn exposure. PMID- 29127821 TI - Study on adsorption of rhodamine B onto Beta zeolites by tuning SiO2/Al2O3 ratio. AB - The exploration of the relationship between zeolite composition and adsorption performance favored to facilitate its better application in removal of the hazardous substances from water. The adsorption capacity of rhodamine B (RB) onto Beta zeolite from aqueous solution was reported. The relationship between SiO2/Al2O3 ratio and adsorption capacity of Beta zeolite for RB was explored. The structure and physical properties of Beta zeolites with various SiO2/Al2O3 ratios were determined by XRD, FTIR, TEM, BET, UV-vis and so on characterizations. The adsorption behavior of rhodamine B onto Beta zeolite matched to Langmuir adsorption isotherm and more suitable description for the adsorption kinetics was a pseudo-second-order reaction model. The maximum adsorption capacity of the as prepared Beta zeolite with SiO2/Al2O3 = 18.4 was up to 27.97mg/g. PMID- 29127822 TI - A review of the empirical literature on the use of limpets Patella spp. (Mollusca: Gastropoda) as bioindicators of environmental quality. AB - The need to carry out monitoring programs for environmental pollution of coastal ecosystems makes it necessary to increase the number of indicator species in order to have a wide range of suitable organisms for most of the possible toxic substances and ways of exposure. With the purpose of analyzing the suitability of limpets (Patella spp.) for their use in biomonitoring programs, a literature review was performed on 88 cases found in the Web of Science online platform. The capacity of limpets to accumulate metals and hydrocarbons has been examined in several field studies. In most cases there is a clear relationship between body content of a pollutant in soft tissues of limpets and the corresponding environmental level. Likewise, different responses to pollutants have been reported in limpets, including induction of DNA damage, induction of metallothioneins, oxidative stress, decrease of Neutral Red retention or variations in heart rate. Regarding the study of changes in community structure, an uneven response to disturbances (e.g. oil spills, wastewater discharge) by species of the genus Patella has been documented. Moreover, generally limpets respond to pollutants similarly to, or even more effectively than, mussels; therefore, their inclusion as sentinel organisms in regional monitoring plans seems appropriate. PMID- 29127823 TI - Removal of anionic dyes (Reactive Black 5 and Congo Red) from aqueous solutions using Banana Peel Powder as an adsorbent. AB - The adsorption characteristics of Reactive Black 5 (RB5) and Cong Red (CR) onto Banana Peel Powder (BPP) from aqueous solution were investigated as a function of pH, contact time, initial dye concentration and temperature. The BPP was characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM) analysis. FTIR results revealed that hydroxyl (-OH), amine (-NH) and carboxyl (-C?O) functional groups present on the surface of BPP. The SEM results show that BPP has an irregular and porous surface morphology which is adequate for dye adsorption. The equilibrium data were analyzed using Langmuir and Freundlich isotherm models. Experimental results were best represented by the Langmuir isotherm model. The adjustments of models were confirmed by the Chi-square (chi2) test and the correlation coefficients (R2). The maximum monolayer adsorption capacities of RB5 and CR on BPP calculated from Langmuir isotherm model were 49.2 and 164.6mg/g at pH 3.0 and 298K. Experimental data were also tested in terms of adsorption kinetics using pseudo-first-order and pseudo-second-order kinetic models. The results showed that the adsorption processes of both RB5 and CR followed well pseudo-second-order kinetic models. The calculated thermodynamic parameters DeltaG degrees , DeltaH degrees and DeltaS degrees showed that the adsorption of RB5 and CR onto BPP was feasible, spontaneous and endothermic in the temperature range 298-318K. The RB5 and CR were desorbed from BPP using 0.1M NaOH. The recovery for both anionic dyes was found to be higher than 90%. Based on these it can be concluded that BPP can be used as an effective, low cost, and eco-friendly adsorbent for CR removal than RB5 from aqueous solution. PMID- 29127824 TI - Effects of subphase pH, temperature and ionic strength on the aggregation behavior of PnBA-b-PAA at the air/water interface. AB - Aggregation behavior of an amphiphilic diblock polyelectrolyte poly(n butylacrylate)-b-poly(acrylic acid) (PnBA-b-PAA) at the air/water interface and morphologies of its LB films were characterized by the Langmuir monolayer technique and atomic force microscopy (AFM), respectively. Effects of subphase pH, temperature and ionic strength on the isotherms and hysteresis curves of the PnBA-b-PAA monolayers and the morphologies of its LB films were systematically studied. With the increase of subphase pH, the isotherms shift negatively and the quasi-plateaus disappear under neutral and alkaline conditions. Hysteresis phenomena of the PnBA-b-PAA monolayers on acidic and neutral subphases are quite obvious and similar, while the compression and expansion isotherms under alkaline condition are almost overlapped. The LB films of PnBA-b-PAA transferred from acidic subphase exhibit isolated circular micelles with large size, while those from alkaline subphase exhibit condensed ones with small size. With the rise in subphase temperature, PnBA blocks on the water surface are more likely to aggregate into large cores due to the higher molecular mobility. Furthermore, the totally ringlike nanostructures prepared from alkaline subphase with medium ionic strength are observed for the first time in LB films of block copolymers. PMID- 29127825 TI - Surfactant structural effects on mediated electrocatalytic dechlorination: Links between the micellar enhancement of dechlorination reactions and micellar properties. AB - Electrocatalytic dechlorination mediated by micelle-solubilized electrocatalysts has attracted considerable current interest for pollutant degradation. Aggregation in micellar assemblies and their interactions with the additives in solution are affected by the surfactant structure. By choosing appropriate surfactant molecules, the system properties may be altered to achieve enhanced dechlorination efficiency. Cetyltrimethylammonium bromide-based surfactants with different hydrocarbon lengths and headgroup structures were studied for their structural effects on [Co(I)(bipyridine)3]+-mediated dechlorination reactions. A widely used pollutants allyl chloride derivatives were studied as the substrates. The performance of the surfactants towards various dechlorination reactions was evaluated by cyclic voltammetry (CV) based on the catalytic efficiency. Key micellar parameters were determined by CV and rotating disc electrode using [Co(II)(bipyridine)3]2+ as the micelle-solubilized redox probe. The surfactants affected the dechlorination reaction to different extents, correlating well with their structure. The catalytic efficiency was explained by the interactions of the Co(II)/Co(I) with the surfactant hydrophobic tail and headgroup. This is the first report quantitatively linking the performance of the surfactants in dechlorination reactions with their molecular structure, showing that is possible to use variant surfactant structures to tune the micellar properties for their application towards the enhanced dechlorination of organic pollutants. Substrate structure-susceptibility to reduction relationships were also discussed. PMID- 29127826 TI - Behavioral and neurophysiological mechanisms underlying motor skill learning in patients with post-stroke hemiparesis. AB - OBJECTIVE: Given the presence of execution deficits after stroke, it is difficult to determine if patients with stroke have deficits in motor skill learning with the paretic arm. Here, we controlled for execution deficits while testing practice effects of the paretic arm on motor skill learning, long-term retention, and corticospinal excitability. METHODS: Ten patients with unilateral stroke and ten age-matched controls practiced a kinematic arm skill for two days and returned for retention testing one-day and one-month post-practice. Motor skill learning was quantified as a change in speed-accuracy tradeoff from baseline to retention tests. Transcranial magnetic stimulation (TMS) was used to generate an input-output curve of the ipsilesional motor cortex (M1), and measure transcallosal inhibition from contralesional to ipsilesional M1. RESULTS: While the control group had greater overall accuracy than the stroke group, both groups showed comparable immediate and long-term improvements with practice. Skill improvements were accompanied by greater excitability of the ipsilesional corticospinal system and reduced transcallosal inhibition from contralesional to ipsilesional M1. CONCLUSIONS: When execution deficits are accounted for, patients with stroke demonstrate relatively intact motor skill learning with the paretic arm. Paretic arm learning is accompanied by modulations in corticospinal and transcallosal mechanisms. SIGNIFICANCE: Functional recovery after stroke relies on ability for skill learning and the underlying mechanisms. PMID- 29127827 TI - Spectrophotometric and spectrofluorimetric methods for determination of certain biologically active phenolic drugs in their bulk powders and different pharmaceutical formulations. AB - Two simple and sensitive spectrophotometric and spectrofluorimetric methods for the determination of terbutaline sulfate, fenoterol hydrobromide, etilefrine hydrochloride, isoxsuprine hydrochloride, ethamsylate, doxycycline hyclate have been developed. Both methods were based on the oxidation of the cited drugs with cerium (IV) in acid medium. The spectrophotometric method was based on measurement of the absorbance difference (DeltaA), which represents the excess cerium (IV), at 317nm for each drug. On the other hand, the spectrofluorimetric method was based on measurement of the fluorescent of the produced cerium (III) at emission wavelength 354nm (lambdaexcitation=255nm) for the concentrations studied for each drug. For both methods, the variables affecting the reactions were carefully investigated and the conditions were optimized. Linear relationships were found between either DeltaA or the fluorescent of the produced cerium (III) values and the concentration of the studied drugs in a general concentration range of 2.0-24.0MUgmL-1, 20.0-24.0ngmL-1 with good correlation coefficients in the following range 0.9990-0.9999, 0.9990-0.9993 for spectrophotometric and spectrofluorimetric methods respectively. The limits of detection and quantitation of spectrophotometric method were found in general concentration range 0.190-0.787 and 0.634-2.624MUgmL-1respectively. For spectrofluorimetric method, the limits of detection and quantitation were found in general concentration range 4.77-9.52 and 15.91-31.74ngmL-1 respectively. The stoichiometry of the reaction was determined, and the reactions pathways were postulated. The analytical performance of the methods, in terms of accuracy and precision, were statistically validated and the results obtained were satisfactory. The methods have been successfully applied to the determination of the cited drugs in their commercial pharmaceutical formulations. Statistical comparison of the results with the reference methods showed excellent agreement and proved that no significant difference in the accuracy and precision. PMID- 29127828 TI - Development of online automatic detector of hydrocarbons and suspended organic matter by simultaneously acquisition of fluorescence and scattering. AB - Permanent online monitoring of water supply pollution by hydrocarbons is needed for various industrial plants, to serve as an alert when thresholds are exceeded. Fluorescence spectroscopy is a suitable technique for this purpose due to its sensitivity and moderate cost. However, fluorescence measurements can be disturbed by the presence of suspended organic matter, which induces beam scattering and absorption, leading to an underestimation of hydrocarbon content. To overcome this problem, we propose an original technique of fluorescence spectra correction, based on a measure of the excitation beam scattering caused by suspended organic matter on the left side of the Rayleigh scattering spectral line. This correction allowed us to obtain a statistically validated estimate of the naphthalene content (used as representative of the polyaromatic hydrocarbon contamination), regardless of the amount of suspended organic matter in the sample. Moreover, it thus becomes possible, based on this correction, to estimate the amount of suspended organic matter. By this approach, the online warning system remains operational even when suspended organic matter is present in the water supply. PMID- 29127829 TI - Bioaugmentation of rapid sand filters by microbiome priming with a nitrifying consortium will optimize production of drinking water from groundwater. AB - Ammonium oxidation to nitrite and then to nitrate (nitrification) is a key process in many waterworks treating groundwater to make it potable. In rapid sand filters, nitrifying microbial communities may evolve naturally from groundwater bacteria entering the filters. However, in new filters this may take several months, and in some cases the nitrification process is never sufficiently rapid to be efficient or is only performed partially, with nitrite as an undesired end product. The present study reports the first successful priming of nitrification in a rapid sand filter treating groundwater. It is shown that nitrifying communities could be enriched by microbiomes from well-functioning rapid sand filters in waterworks and that the enriched nitrifying consortium could be used to inoculate fresh filters, significantly shortening the time taken for the nitrification process to start. The key nitrifiers in the enrichment were different from those in the well-functioning filter, but similar to those that initiated the nitrification process in fresh filters without inoculation. Whether or not the nitrification was primed with the enriched nitrifying consortium, the bacteria performing the nitrification process during start-up appeared to be slowly outcompeted by Nitrospira, the dominant nitrifying bacterium in well functioning rapid sand filters. PMID- 29127830 TI - Development and modelling of a steel slag filter effluent neutralization process with CO2-enriched air from an upstream bioprocess. AB - The main objective of this project was to develop a steel slag filter effluent neutralization process by acidification with CO2-enriched air coming from a bioprocess. Sub-objectives were to evaluate the neutralization capacity of different configurations of neutralization units in lab-scale conditions and to propose a design model of steel slag effluent neutralization. Two lab-scale column neutralization units fed with two different types of influent were operated at hydraulic retention time of 10 h. Tested variables were mode of flow (saturated or percolating), type of media (none, gravel, Bionest and AnoxKaldnes K3), type of air (ambient or CO2-enriched) and airflow rate. One neutralization field test (saturated and no media, 2000-5000 ppm CO2, sequential feeding, hydraulic retention time of 7.8 h) was conducted for 7 days. Lab-scale and field scale tests resulted in effluent pH of 7.5-9.5 when the aeration rate was sufficiently high. A model was implemented in the PHREEQC software and was based on the carbonate system, CO2 transfer and calcite precipitation; and was calibrated on ambient air lab tests. The model was validated with CO2-enriched air lab and field tests, providing satisfactory validation results over a wide range of CO2 concentrations. The flow mode had a major impact on CO2 transfer and hydraulic efficiency, while the type of media had little influence. The flow mode also had a major impact on the calcite surface concentration in the reactor: it was constant in saturated mode and was increasing in percolating mode. Predictions could be made for different steel slag effluent pH and different operation conditions (hydraulic retention time, CO2 concentration, media and mode of flow). The pH of the steel slag filter effluent and the CO2 concentration of the enriched air were factors that influenced most the effluent pH of the neutralization process. An increased concentration in CO2 in the enriched air reduced calcite precipitation and clogging risks. Stoichiometric calculations showed that a typical domestic septic tank effluent with 300 mg/L of biodegradable COD provides enough biological CO2 for neutralization of a steel slag effluent with pH of 10.5-11.5. A saturated neutralization reactor with no media operated at hydraulic retention time of 10 h and a concentration of 2000 ppm in CO2 enriched air is recommended for full-scale applications. PMID- 29127831 TI - Modeling the transport of sodium dodecyl benzene sulfonate in riverine sediment in the presence of multi-walled carbon nanotubes. AB - The environmental risks of carbon nanotubes have received considerable attention. In this work, the effects of multi-walled carbon nanotubes (MWCNTs) on the adsorption of sodium dodecyl benzene sulfonate (SDBS) by riverine sediment and the transport of SDBS in sediment were studied. MWCNTs could significantly increase the adsorption capacity of the sediment for SDBS, thus affecting the transport of SDBS in sediment. Maximum adsorption capacity of the sediment for SDBS increases from 2.29 to 2.99 mg/g with the increasing content of MWCNTs from 0% to 1.5%. Breakthrough curves (BTCs) of SDBS obtained from the column experiments were described by the convection-dispersion equation, Thomas model, and Yan model. The estimated retardation factor R increases with the incorporation of MWCNTs, either in water or sediment. Additionally, the value of R is well correlated to the content of MWCNTs in sediment. Compared with Thomas model, Yan model is more suitable for fitting the BTCs with all the values of R2 >= 0.951, but it tends to overestimate the maximum adsorption capacity when the content of MWCNTs in sediment is relatively higher. The results of SDBS retention in sediment indicate that MWCNTs can increase the accumulation of SDBS in the top sediment layer, while they can impede the transport of SDBS into deeper sediment layer when incorporated into the sediment. These effects should be taken into consideration for risk assessment of CNTs in the aquatic environment. PMID- 29127832 TI - Uranium in groundwater - A synopsis based on a large hydrogeochemical data set. AB - Most of the knowledge on the occurrence of Uranium (U) in groundwater comes from in-situ manipulation experiments in the field, computational modelling studies or from laboratory analyses where individual processes of U mobilization were studied in isolation. Because of Uranium's vital redox chemistry it interacts, often simultaneously, with many other element cycles (e.g., sulfur, carbon, iron, and manganese) making it difficult to predict U concentrations in natural environments. For the present study a large data set was analyzed to predict the occurrence of U in groundwater from basic hydrochemistry. The data set consists of more than 8000 chemical groundwater analyses (including Uranium concentrations) from more than 2000 sampling locations. A strong relation between U concentrations and electric conductivity as well as alkalinity was observed, suggesting that weathering of geogenic source material and desorption from mineral surfaces is the principle mechanism of U release. Except for aquifers with strongly reducing conditions this process leads to a slow but continuous accumulation of U in groundwater in most cases. Importantly, the occurrence of U is modulated by the prevailing redox conditions in an aquifer. Uranium concentrations were moderate under oxic conditions and highest under manganese and nitrate-reducing conditions (heterotrophic as wells as autotrophic nitrate reduction). Only in iron- and sulfate-reducing groundwater the probability of U concentrations above 1 MUg l-1 was virtually zero, as these ground waters act as U sinks. The combination of mineral weathering (especially carbonates) with mobilization of U under manganese and nitrate reducing conditions results in the highest risk of detecting U. In contrast, a low risk is associated with low pH (<7) and low mineralization of groundwater, which is the case in granitic catchments, for example. Our results further provide evidence, that agricultural practices such as liming, use of fertilizers and irrigation influence the occurrence of U in groundwater in multiple ways. Accurate management of aquifers underlying farmland will therefore become more and more important in the future. In summary, we find that the vulnerability of an aquifer to elevated U concentrations cannot be explained by a single factor. This complicates efforts to target elevated U concentrations in groundwaters that are abstracted for drinking water production. PMID- 29127833 TI - Carboxylic acid reductase enzymes (CARs). AB - Carboxylate reductases (CARs) are emerging as valuable catalysts for the selective one-step reduction of carboxylic acids to their corresponding aldehydes. The substrate scope of CARs is exceptionally broad and offers potential for their application in diverse synthetic processes. Two major fields of application are the preparation of aldehydes as end products for the flavor and fragrance sector and the integration of CARs in cascade reactions with aldehydes as the key intermediates. The latest applications of CARs are dominated by in vivo cascades and chemo-enzymatic reaction sequences. The challenge to fully exploit product selectivity is discussed. Recent developments in the characterization of CARs are summarized, with a focus on aspects related to the domain architecture and protein sequences of CAR enzymes. PMID- 29127834 TI - Comparison of chlordecone and NDL-PCB decontamination dynamics in growing male kids after cessation of oral exposure: Is there a potential to decrease the body levels of these pollutants by dietary supplementation of activated carbon or paraffin oil? AB - Sixteen weaned male Alpine kids (Capra hircus) were subjected to a 21-day oral daily exposure of 0.05 mg kg-1 BW. d-1 of chlordecone (CLD) and 0.30 MUg kg-1 BW. d-1 of each non-dioxin-like polychlorinated biphenyls (NDL-PCBs, congeners 28, 52, 101, 138, 153 and 180). Four kids, identified as the CONTA group, were slaughtered at the end of the exposure, while the remaining animals (n = 12) were fed with specific diets for an additional 21-day decontamination period before slaughtering. Kids from the DECONTA (n = 4) group were fed a control diet, while those from the AC10% and PO8% group received pellets supplemented with 10% activated carbon (AC) and 8% paraffin oil (PO), respectively. CLD and NDL-PCB levels in blood, liver, peri-renal fat and muscles from different groups were analysed to compare the decontamination dynamics of the pollutants and to determine the efficiency of AC and PO to decrease the body levels of pollutants. After the decontamination period, the CLD levels considerably decreased (more than 60%) in blood, liver, muscles and fat. Concerning NDL-PCBs, the decontamination process was much lower. Overall, CLD appeared to be less retained in kids' organism compared with NDL-PCBs, and the decontamination dynamics of these pollutants appeared to be different because of their specific physicochemical properties and lipophilicity. Furthermore, the dietary supplementation with AC or PO did not significantly affect the decontamination dynamics. PMID- 29127835 TI - Spatial variations, source apportionment and potential ecological risks of polycyclic aromatic hydrocarbons and synthetic musks in river sediments in Shanghai, China. AB - The aims of this study were to investigate the levels, possible sources and potential ecological risks of 26 polycyclic aromatic hydrocarbons (PAHs) including highly carcinogenic dibenzopyrene (DBP) isomers and 4 synthetic musks (SMs) in river sediments from Shanghai. 74 sediment samples were collected from the Huangpu River and its main tributaries. The total concentrations ranged from 52.0 to 11400 ng g-1 for Sigma26PAHs, 25.1-9910 ng g-1 for 16 USEPA priority PAHs (Sigma16PAHs), 0.769-384 ng g-1 for Sigma4DBPs, and 0.080-63.3 ng g-1 for Sigma4SMs, respectively. Seven sources of PAHs in river sediments were identified by positive matrix factorization (PMF) model. Coal combustion, vehicle and creosote were the major emission sources for PAHs. SMs came mainly from domestic and industrial wastewaters. The toxic equivalent quantities of the benzo[a]pyrene (TEQBaP) ranged from 7.64 to 3920 ng g-1 for Sigma24PAHs, 2.07-1150 ng g-1 for Sigma16PAHs, and 5.53-3150 ng g-1 for Sigma4DBPs. The TEQBaP of Sigma4DBPs made up 73.9% of Sigma24PAHs, which indicated that DBPs were the major carcinogenic contributors to total PAHs in sediments. According to sediment quality guidelines (SQGs) and mean PEL-Q values, the risks posed by PAHs in sediments were at medium level at most sampling sites, and SMs posed a low ecological risk to sediment dwelling organisms in Shanghai. PMID- 29127836 TI - Combined use of microbial consortia isolated from different agricultural soils and cyclodextrin as a bioremediation technique for herbicide contaminated soils. AB - The phenylurea herbicide diuron is persistent in soil, water and groundwater and is considered to be a highly toxic molecule. The principal product of its biodegradation, 3,4-dichloroaniline, exhibits greater toxicity than diuron and is persistent in the environment. Five diuron degrading microbial consortia (C1C5), isolated from different agricultural soils, were investigated for diuron mineralization activity. The C2 consortium was able to mineralize 81.6% of the diuron in solution, while consortium C3 was only able to mineralize 22.9%. Isolated consortia were also tested in soil slurries and in all cases, except consortium C4, DT50 (the time required for the diuron concentration to decline to half of its initial value) was drastically reduced, from 700 days (non-inoculated control) to 546, 351, and 171 days for the consortia C5, C2, and C1, respectively. In order to test the effectiveness of the isolated consortium C1 in a more realistic scenario, soil diuron mineralization assays were performed under static conditions (40% of the soil water-holding capacity). A significant enhancement of diuron mineralization was observed after C1 inoculation, with 23.2% of the herbicide being mineralized in comparison to 13.1% for the control experiment. Hydroxypropyl-beta-cyclodextrin, a biodegradable organic enhancer of pollutant bioavailability, used in combination with C1 bioaugmentation in static conditions, resulted in a significant decrease in the DT50 (214 days; 881 days, control experiment). To the best of our knowledge, this is the first report of the use of soil-isolated microbial consortia in combination with cyclodextrins proposed as a bioremediation technique for pesticide contaminated soils. PMID- 29127837 TI - Usage Proposal of a common urban decorative tree (Salix alba L.) to monitor the dispersion of gaseous mercury: A case study from Turda (Romania). AB - Closure of chloralkali plants poses a risk of abandonment of important sources of gaseous mercury. In this work, an assessment has been made of the potential for pollution from one of these plants in the proximity of a densely populated town in central Romania. The work involved a comparison between two major types of monitoring survey: biomonitoring using leaves of a tree common in urban environments; and LUMEX-based gaseous mercury analysis. For biomonitoring, 21 samples from Salix alba L. trees were taken in Turda area. Atmospheric monitoring included two mobile surveys and one at a fixed location. The results from both monitoring systems show similarities in gaseous mercury dispersion patterns, with high mercury contents clearly related to the presence of the chloralkali plant. Particularly high levels were measured in the following situations: (i) in a 'smog' area related with thermal inversion and (ii) during dusk. Direct monitoring suffered from limitations in acquiring information, especially in a medium-long time range, but biomonitoring provided these data and is capable of covering studies on temporary trends or comparative assessments between European cities with contrasting gaseous mercury sources. The thermal speciation of mercury contents indicates that the whole fraction of mercury in leaves corresponds to organic mercury. This finding implies a non-reversible uptake process, which in turn ensures the applicability of this technique to biomonitor long-term exposure. As a conclusion, the assessment of gaseous mercury pollution based on biomonitoring using S. alba has proven to be a useful, reliable and cost effective methodology. PMID- 29127838 TI - Potential chromosome damage, cell-cycle kinetics/and apoptosis induced by epoxiconazole in bovine peripheral lymphocytes in vitro. AB - The epoxiconazole was tested in vitro for its potential on induction of chromosome damage and/or cell cycle kinetics in cultured bovine peripheral lymphocytes. Cytogenetic endpoints such as: Chromosome Aberrations (CA); Sister Chromatid Exchanges (SCE); Micronuclei (MN); Mitotic Index (MI); Proliferation Index (PI); and Cytokinesis Block Proliferation Index (CBPI) were investigated for 24 h and 48 h of incubation. The cultured lymphocytes were exposed to the epoxiconazole at concentrations of 2.5, 5, 10, 25, 50 and 100 MUg mL-1. From our results is evident that treatment of bovine peripheral lymphocytes with the epoxiconazole was not related to DNA damage; no genotoxic effect and/or clastogenic/aneugenic effects were recorded. However, epoxiconazole has ability to significantly affect cell cycle kinetics/and induce apoptosis. A decrease of proliferation in the MI, CBPI and identically in the PI were observed; hence, cytostatic/cytotoxic effects of epoxiconazole have been recorded. The prolonged time of exposure at the highest concentration caused an inhibition of the replication. Electrophoretic analysis confirmed the epoxiconazole potential to induce ladder-like patterns of DNA fragments that are a hallmark of apoptosis. PMID- 29127840 TI - Calculation of corrected flow time: Wodey's formula vs. Bazett's formula. PMID- 29127839 TI - Hydrophobic networked PbO2 electrode for electrochemical oxidation of paracetamol drug and degradation mechanism kinetics. AB - A hydrophobic networked PbO2 electrode was deposited on mesh titanium substrate and utilized for the electrochemical elimination towards paracetamol drug. Three dimensional growth mechanism of PbO2 layer provided more loading capacity of active materials and network structure greatly reduced the mass transfer for the electrochemical degradation. The active electrochemical surface area based on voltammetric charge quantity of networked PbO2 electrode is about 2.1 times for traditional PbO2 electrode while lower charge transfer resistance (6.78 Omega cm2) could be achieved on networked PbO2 electrode. The electrochemical incineration kinetics of paracetamol drug followed a pseudo first-order behavior and the corresponding rate constant were 0.354, 0.658 and 0.880 h-1 for traditional, networked PbO2 and boron doped diamond electrode. Higher electrochemical elimination kinetics could be achieved on networked PbO2 electrode and the performance can be equal to boron doped diamond electrode in result. Based on the quantification of reactive oxidants (hydroxyl radicals), the utilization rate of hydroxyl radicals could reach as high as 90% on networked PbO2 electrode. The enhancement of excellent electrochemical oxidation capacity towards paracetamol drug was related to the properties of higher loading capacity, enhanced mass transfer and hydrophobic surface. The possible degradation mechanism and pathway of paracetamol on networked PbO2 electrode were proposed in details accordingly based on the intermediate products. PMID- 29127841 TI - Comparison of the performance of SOFA, qSOFA and SIRS for predicting mortality and organ failure among sepsis patients admitted to the intensive care unit in a middle-income country. AB - INTRODUCTION: The Sepsis-3 definition provides a change of two or more scores from zero or a known baseline of the Sequential Organ Failure Assessment (SOFA) as criteria of sepsis. The aim of this study was to compare the SOFA score and the quick SOFA (qSOFA) to Systemic Inflammatory Response Syndrome (SIRS) criteria in predictive ability of mortality and organ failure. METHODS: A-10year retrospective cohort study was conducted in a teaching hospital in Thailand. RESULTS: A total of 2350 of mixed sepsis patients by Sepsis-2 definition were included. The all-cause hospital mortality rate was 44.5%. Of the total sample, 95.6% (n=2247) of patients met criteria for sepsis under the Sepsis-3 definition. The SOFA score presented the best discrimination with an area under the receiver operating characteristic curve (AUC) of 0.839. The AUC of SOFA score for hospital mortality was significantly higher than qSOFA (AUC 0.814, P=0.003) and SIRS (AUC 0.587, P<0.0001). Also, the SOFA score had superior performance than other scores for predicting intensive care unit (ICU) mortality and organ failure. CONCLUSIONS: The SOFA is a superior prognostic tool for predicting mortality and organ failure than qSOFA and SIRS criteria among sepsis patients admitted to the ICU. PMID- 29127842 TI - Budesonide facilitates weaning from mechanical ventilation in difficult-to-wean very severe COPD patients: Association with inflammatory mediators and cells. AB - INTRODUCTION: Mechanical ventilatory support is life-saving therapy for patients with respiratory failure in intensive care units (ICU) but is linked to ventilator-associated pneumonia and other nosocomial infections. Interventions that improve the efficiency of weaning from mechanical ventilation may improve patient outcomes. OBJECTIVE: To determine whether inhaled budesonide decreases time-to-weaning in COPD stage 4 difficult-to-wean patients and reduces the release of pro-inflammatory cytokines in ICU patients. MATERIALS AND METHODS: We recruited 55 difficult-to-wean COPD patients (Stage 4) within the ICU of the Masih Daneshvari Hospital. Subjects were randomly assigned to receive inhaled budesonide (0.5mg/day) or placebo (normal saline). Dynamic compliance and BAL cytokines were measured. RESULTS: Budesonide significantly reduced the number of days on MV (days-to-weaning=4.6+/-1.6days) compared to that seen in the control group (7.2+/-2.7days, p=0.014). Dynamic compliance was significantly improved in the budesonide group on days 3 (p=0.018) and 5 (p=0.011) The levels of CXCL-8 and IL-6 diminished on days 3-5 after start of budesonide (p<0.05). CONCLUSION: In COPD patients on MV, nebulized budesonide was associated with reduced BAL CXCL8 and IL-6 levels and neutrophil numbers as well as an improvement in ventilatory mechanics and facilitated weaning. PMID- 29127843 TI - IFN-beta regulates Th17 differentiation partly through the inhibition of osteopontin in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) and the corresponding animal model, experimental autoimmune encephalomyelitis (EAE), are chronic neuroinflammatory autoimmune diseases. Increased activation of CD4+T cells, especially the Th1 and Th17 subsets, is thought to play a causal role in this disease. IFN-beta is widely used in the treatment of MS and is found to decrease IL-17 and OPN production in MS patients and EAE mice. However, a definitive molecular mechanism has not yet been fully elucidated. In this study, we investigated the immunomodulatory effect of IFN-beta on the EAE model. We observed disease progression and determined the percentage of Th1/Th17 cells in the peripheral immune organs, brain, and spinal cord of mice. Furthermore, the levels of related cytokines and transcription factors were measured in splenocytes, and the effects of IFN-beta on Th17 differentiation were assessed in vitro. Compared to the control group, IFN-beta treatment significantly reduced the incidence of EAE and the associated pathological damage. Th1 and Th17 cells in IFN-beta-treated mice were significantly reduced, and the levels of cytokines, such as IFN-gamma, IL-17, and OPN, were significantly decreased in splenocyte supernatants as well as the levels of corresponding transcription factors. IFN-beta inhibited downstream inflammatory cytokines through the inhibition of PI3K/AKT/NF-kappaB axis and p38, JNK-MAPK, as well as the regulation of mTOR complexes. Moreover, IFN-beta inhibited Th17 differentiation and neutralizing OPN antibodies offset the inhibitory effect of IFN-beta on Th17 cells. Meanwhile, IFN-beta influenced the acetylation of the Il17a and Opn gene promoters. The findings described herein provide novel evidence for the role of IFN-beta in Th17 differentiation partly through the inhibition of OPN. PMID- 29127844 TI - The role of A-to-I RNA editing in cancer development. AB - Adenosine-to-inosine (A-to-I) RNA editing is the most common type of post transcriptional nucleotide modification in humans, which is catalyzed in ADAR enzymes. Recent genomic studies have revealed thousands of altered RNA editing events in various cancer tissues, leading to diverse functional consequences. A critical role of individual A-to-I RNA editing events in cancer has been reported. Here, we review the current state of our knowledge on key A-to-I RNA editing events in coding and non-coding regions for their roles in cancer development and discuss their potential clinical utility. A better understanding of A-to-I RNA editing and its oncogenic mechanisms may facilitate the development of novel cancer therapeutic strategies. PMID- 29127846 TI - Supramolecular glycorhodamine-polymer dot ensembles for the homogeneous, fluorogenic analysis of lectins. AB - We have developed a new series of glycoprobe-polymer dot ensembles for the fluorogenic, homogeneous detection of lectins. Electrostatic self-assembly between positively charged rhodamine-based glycosides and negatively charged poly(3-hexylthiophene-2,5-diyl)/poly(styrene-co-maleic anhydride) polymer dots produces the ensembles with a quenched fluorescence. Fluorescence spectroscopy showed that the ensembles exhibited a concentration-dependent fluorescence enhancement with selective lectins over a range of unselective lectins and proteins. This research provides insight into the development of simple fluorogenic probes for homogeneous lectin analyses based on the supramolecular assembly between polymeric nanoparticles and fluorescent glycoprobes. PMID- 29127845 TI - Highly sensitive determination of alendronate in human plasma and dialysate using metal-free HPLC-MS/MS. AB - A highly sensitive method was developed for the analysis of alendronate in human plasma and dialysate using MonoSpinTM SAX(r) extraction and metal-free high performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) following methylation with trimethylsilyldiazomethane. The chromatographic separation of the derivatives for alendronate and alendronate-d6 was achieved on an L-column2 ODS metal-free column (50 mm * 2 mm i.d., particle size 3 um) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.3 ml/min. Quantification was performed by multiple reaction monitoring (MRM) with positive-ion electrospray ionization (ESI). Distinct peaks were observed for alendronate and for the internal standard on each channel within 1 min. The regression equations showed good linearity within the ranges of 2.0-100 ng/0.5 ml for the plasma and 1.0-100 ng/0.5 ml for the dialysate, with the limits of detection at 1.0 ng/0.5 ml for the plasma and 0.5 ng/0.5 ml for the dialysate. Extraction efficiencies for alendronate for the plasma and dialysate were 41.1-51.2% and 63.6-73.4%, respectively. The coefficient of variation (CV) was <=8.5%. The method was successfully applied to the analyses of real plasma and dialysate samples derived after intravenous administration of alendronate. PMID- 29127847 TI - Effect of sucralose on the enzyme kinetics of invertase using real-time NMR spectroscopy and progress curve analysis. AB - Sucralose, a derivative of sucrose, is widely used in noncaloric artificial sweeteners (NAS). Contrary to the belief that sucralose is physiologically inert and a healthy alternative sweetener to natural sugar, emerging studies indicate that sucralose alters the host metabolism as well as the composition of the microbiome. In this manuscript, we use real-time nuclear magnetic resonance (NMR) spectroscopy to demonstrate that sucralose alters the enzymatic conversion of sucrose to glucose and fructose. The real-time NMR progress curve analysis suggests that sucralose has the characteristic of a competitive inhibitor on the kinetics of the enzymatic process. This affects the rate of glucose production, and thus indirectly affecting the mutarotation process of alpha-D-glucose to beta D-glucose conversion. At a 1:2 M ratio of sucrose to sucralose, the results show that the catalytic efficiency of the enzyme is reduced by more than 50% in comparison to the measurements without sucralose. Altogether, as sucralose alters the rate of glucose production, sucralose cannot be considered inert to the metabolism as several downstream events in both prokaryotic and eukaryotic systems strongly depend on the rate of glucose metabolism. PMID- 29127848 TI - Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials. AB - OBJECTIVE: To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). METHODS: Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2-week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule. RESULTS: 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had >=1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD. CONCLUSIONS: Initiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation. PMID- 29127849 TI - Quasi-experimental evidence on tobacco tax regressivity. AB - Tobacco taxes are known to reduce tobacco consumption and to be regressive, such that tobacco control policy may have the perverse effect of further harming the poor. However, if tobacco consumption falls faster amongst the poor than the rich, tobacco control policy can actually be progressive. We take advantage of persistent and committed tobacco control activities in South Africa to examine the household tobacco expenditure burden. For the analysis, we make use of two South African Income and Expenditure Surveys (2005/06 and 2010/11) that span a series of such tax increases and have been matched across the years, yielding 7806 matched pairs of tobacco consuming households and 4909 matched pairs of cigarette consuming households. By matching households across the surveys, we are able to examine both the regressivity of the household tobacco burden, and any change in that regressivity, and since tobacco taxes have been a consistent component of tobacco prices, our results also relate to the regressivity of tobacco taxes. Like previous research into cigarette and tobacco expenditures, we find that the tobacco burden is regressive; thus, so are tobacco taxes. However, we find that over the five-year period considered, the tobacco burden has decreased, and, most importantly, falls less heavily on the poor. Thus, the tobacco burden and the tobacco tax is less regressive in 2010/11 than in 2005/06. Thus, increased tobacco taxes can, in at least some circumstances, reduce the financial burden that tobacco places on households. PMID- 29127850 TI - "It's gym, like g-y-m not J-i-m": Exploring the role of place in the gendering of physical activity. AB - Physical activity is a highly gendered health behaviour, with women less likely than men to meet internationally accepted physical activity guidelines. In this article, we take up recent arguments on the potential of indoor spaces to illuminate processes shaping health, together with social theories of gender, to conceptualize the place of the gym as a window into understanding and intervening in wider gender disparities in physical activity. Using a triangulated strategy of qualitative methods, including semi-structured interviews, drawing, and journaling with men and women in a mid-sized Canadian city, we examine how gender influences exercise practices and mobilities in gym environments. Results of our thematic analysis reveal three socio-spatial processes implicated in the gendering of physical activity: 1) embodying gender ideals, 2) policing gender performance, and 3) spatializing gender relations. A fourth theme illustrates the situated agency some individuals enact to disrupt gendered divisions. Although women were unduly disadvantaged, both women and men experienced significant limitations on their gym participation due to the presiding gendered social context of the gym. Gender-transformative interventions that go beyond engaging women to comprehensively contend with the place-based gender relations that sustain gender hegemony are needed. While gyms are potentially sites for health promotion, they are also places where gendered inequities in health opportunities emerge. PMID- 29127851 TI - Autonomy to health care professionals as a vehicle for value-based health care? Results of a quasi-experiment in hospital governance. AB - Health care systems increasingly aim to create value for money by simultaneous incentivizing of quality along with classical goals such as activity increase and cost containment. It has recently been suggested that letting health care professionals choose the performance metrics on which they are evaluated may improve value of care by facilitating greater employee initiative, especially in the quality domain. There is a risk that this strategy leads to loss of performance as measured by the classical goals, if these goals are not prioritized by health care professionals. In this study we investigate the performance of eight hospital departments in the second largest region of Denmark that were delegated the authority to choose their own performance focus during a three-year test period from 2013 to 2016. The usual activity-based remuneration was suspended and departments were instructed to keep their global budgets and maintain activity levels, while managing according to their newly chosen performance focuses. Our analysis is based on monthly observations from two years before to three years after delegation. We collected data for 32 new performance indicators chosen by hospital department managements; 11 new performance indicators chosen by a centre management under which 5 of the departments were organised; and 3 classical indicators of priority to the central administration (activity, productivity, and cost containment). Interrupted time series analysis is used to estimate the effect of delegation on these indicators. We find no evidence that this particular proposal for giving health care professionals greater autonomy leads to consistent quality improvements but, on the other hand, also no consistent evidence of harm to the classical goals. Future studies could consider alternative possibilities to create greater autonomy for hospital departments. PMID- 29127852 TI - Social interaction and pain: An arctic expedition. AB - Complex human behaviour can only be understood within its social environment. However, disentangling the causal links between individual outcomes and social network position is empirically challenging. We present a research design in a closed real-world setting with high-resolution temporal data to understand this interplay within a fundamental human experience - physical pain. Study participants completed an isolated 3-week hiking expedition in the Arctic Circle during which they were subject to the same variation in environmental conditions and only interacted amongst themselves. Adolescents provided daily ratings of pain and social interaction partners. Using longitudinal network models, we analyze the interplay between social network position and the experience of pain. Specifically, we test whether experiencing pain is linked to decreasing popularity (increasing isolation), whether adolescents prefer to interact with others experiencing similar pain (homophily), and whether participants are increasingly likely to report similar pain as their interaction partners (contagion). We find that reporting pain is associated with decreasing popularity - interestingly, this effect holds for males only. Further exploratory analyses suggest this is at least partly driven by males withdrawing from contact with females when in pain, enhancing our understanding of pain and masculinity. Contrary to recent experimental and clinical studies, we found no evidence of pain homophily or contagion in the expedition group. PMID- 29127853 TI - Metal chelating ability and antioxidant properties of Curcumin-metal complexes - A DFT approach. AB - Curcumin, a well-documented phytochemical compound used to treat various diseases because of its more tolerability in the human body and has no side effects. The present study describes the metal chelating ability of Curcumin for Mn2+, Fe2+ and Zn2+ metal ions and their antioxidant properties using density functional theory in both gas and DMSO solvent phases. Results reveal that the carbonyl group at diketo moiety is destabilized due to the metal ion coordination. The interaction energies reveal that CurEN-Zn2+ are the most stable rather than the CurEN-Mn2+ and CurEN-Fe2+ complexes. The AIM analysis confirms that the interaction between the metal ions and Curcumin are to be electrostatic dominant. The HOMO-LUMO orbital analysis shows that the charge transfer interaction is dominant for CurEN-Mn2+ and CurEN-Fe2+ complexes. The DMSO solvent interactions decrease the stability of the CurEN-M2+ cation complexes. The antioxidant mechanism is more reactive for metal complexes than the isolated Curcumin. Since Curcumin possess both metal chelating and antioxidant properties, it can be used in chelation therapy for the cure of Alzheimer's disease. PMID- 29127854 TI - Comparative modeling and molecular docking analysis of white, brown and soft rot fungal laccases using lignin model compounds for understanding the structural and functional properties of laccases. AB - Extrinsic catalytic properties of laccase enable it to oxidize a wide range of aromatic (phenolic and non-phenolic) compounds which makes it commercially an important enzyme. In this study, we have extensively compared and analyzed the physico-chemical, structural and functional properties of white, brown and soft rot fungal laccases using standard protein analysis software. We have computationally predicted the three-dimensional comparative models of these laccases and later performed the molecular docking studies using the lignin model compounds. We also report a customizable rapid and reliable protein modelling and docking pipeline for developing structurally and functionally stable protein structures. We have observed that soft rot fungal laccases exhibited comparatively higher structural variation (higher random coil) when compared to brown and white rot fungal laccases. White and brown rot fungal laccase sequences exhibited higher similarity for conserved domains of Trametes versicolor laccase, whereas soft rot fungal laccases shared higher similarity towards conserved domains of Melanocarpus albomyces laccase. Results obtained from molecular docking studies showed that aminoacids PRO, PHE, LEU, LYS and GLN were commonly found to interact with the ligands. We have also observed that white and brown rot fungal laccases showed similar docking patterns (topologically monomer, dimer and trimer bind at same pocket location and tetramer binds at another pocket location) when compared to soft rot fungal laccases. Finally, the binding efficiencies of white and brown rot fungal laccases with lignin model compounds were higher compared to the soft rot fungi. These findings can be further applied in developing genetically efficient laccases which can be applied in growing biofuel and bioremediation industries. PMID- 29127855 TI - Dispersion corrected density functional study of CO oxidation on pristine/functionalized/doped graphene surfaces in aqueous phase. AB - The catalytic oxidation of CO by molecular oxygen (O2) over graphene, epoxy functionalized graphene and sulphur doped graphene surface is investigated theoretically by employing dispersion corrected Density Functional Theory. The adsorption of O2 and CO molecules over the pristine, functionalized and doped graphene surface has been compared. The channel for oxidation of CO to CO2 is elucidated in detail in the presence of aqueous solvent. Computations suggest that catalytic cycle of CO oxidation is initiated through the ER-mechanism, with the formation of a carbonate intermediate, the second pre-adsorbed CO reacts with the carbonate intermediate through LH-mechanism whereby, two CO2 molecules are released and adsorption surface becomes available for the subsequent reaction. The activation barrier for CO oxidation is considerably lowered in the case of oxidation over functionalized 12.45kcal/mol and doped 14.52kcal/mol graphene surface in comparison to the observed barrier of 23.98kcal/mol for the pristine graphene. PMID- 29127856 TI - Acute and long-term effects of fingolimod on heart rhythm and heart rate variability in patients with multiple sclerosis. AB - BACKGROUND: Fingolimod can lead to increased risk of cardiac events such as bradycardia or atrioventricular (AV) block. OBJECTIVE: Evaluate acute and long term effects of fingolimod on heart rhythm (HR), heart rate variability (HRV) and development of AV-blocks. METHODS: In 64 patients with relapsing-remitting multiple sclerosis Holter ECG monitoring (HEM) and HRV analysis were performed 24h before, six h during and 72h after initiation of fingolimod. We additionally analyzed a 24h HEM after a follow up of >= three months. RESULTS: Heart rate (HR) decreased significantly (p < 0.001) under fingolimod treatment with nadir at five hours after starting and maintained decreased for 72h. Five (7.8%) patients suffered from new-onset AV-block requiring cessation of treatment. In four of five patients (80%), the AV-block could only be documented in the 72h-HEM with a median time of occurrence at 14h. The mean heart rate was still significant lower after a mean follow up time of 14.1 +/- 9.6 months (85.0 +/- 9.8 vs. 75.3 +/- 16.2 bpm; p = 0.002) in comparison to baseline. CONCLUSION: The treatment with fingolimod leads to an increase of vagal activation which persists even after 14 months of treatment. These changes did not return to baseline levels on treatment with fingolimod. Based on our data an additional at least 24h hour-HEM after the initiation of fingolimod therapy should be considered. PMID- 29127857 TI - The updated network meta-analysis of neoadjuvant therapy for HER2-positive breast cancer. AB - BACKGROUND: We previously described a systematic assessment of the neoadjuvant therapies for human epidermal growth factor receptor-2 (HER2) positive breast cancer, using network meta-analysis. Accumulation of new clinical data has compelled us to update the analysis. METHODS: Randomized trials comparing different anti-HER2 regimens in the neoadjuvant setting were included, and odds ratio for pathologic complete response (pCR) in seven treatment arms were assessed by pooling effect sizes. Direct and indirect comparisons using a Bayesian statistical model were performed. All statistical tests were two-sided. RESULTS: A database search identified 993 articles with 13 studies meeting the eligibility criteria, including three new studies with lapatinib (lpnb). In an indirect comparison, dual anti-HER2 agents with CT achieved a better pCR rate than other arms. The credibility intervals of CT + tzmb + lpnb arm were largely reduced compared to our former report, which we added sufficient clinical evidence by this update. Values of surface under the cumulative ranking (SUCRA) suggested that CT + tzmb + pzmb had the highest probability of being the best treatment arm for pCR, widening the difference between the top two dual-HER2 blockade arms compared to our former report. The overall consistency with our first report enhanced the credibility of the results. CONCLUSION: Network meta analysis using new clinical data firmly establish that combining two anti-HER2 agents with CT is most effective against HER2-positive breast cancer in the neoadjuvant setting. New pzmb related trials are required to fully determine the best neoadjuvant dual-HER2 blockade regimen. PMID- 29127859 TI - The risk of subsequent epilepsy in children with febrile seizure after 5 years of age. AB - PURPOSE: Despite their age-dependent definition, febrile seizures (FS) may be observed in people of almost any age. The risk of developing unprovoked seizures after an FS is well defined. However, there are limited data about FS starting or persisting after 5 years of age. In the present study, we evaluated patients who developed FS after 5 years of age. METHOD: Between 2010 and 2014, we prospectively enrolled all patients with FS. We collected demographic and clinical features, radiologic images, electroencephalograms (EEGs), and results of psychomotor development tests and treatment data of the patients. The patients were grouped into two groups. Group 1 consisted of patients who had the first FS after 5 years of age, and group 2 consisted of patients in whom FS persisted after 5 years of age. Fisher's exact test and Pearson's chi-square test were used to analyse the study data and derive conclusions. RESULTS: Sixty-four patients were enrolled, and afebrile seizure was observed in 12 (18.8%) of them. Nine (14%) patients were diagnosed to have epilepsy in their follow-up examination. Subsequent epilepsy occurrence was independent of gender, mean age, medical history of the patient, family history of epilepsy, presence of afebrile seizure, type of seizure, type of FS, duration of seizure, semiology of seizure, peak fever and EEG and magnetic resonance imaging (MRI) findings in our total cohort. There were no statistical differences between the groups with regard to the occurrence of subsequent afebrile seizure or epilepsy (p>0.5). CONCLUSION: Close follow-up is important in patients with FS after the age of 5 years. These seizures are generally benign, but tend to recur and increase the risk of development of epilepsy in the patient. Further studies with a larger cohort are warranted to clarify risk factors and incidence of epilepsy in these patients. PMID- 29127858 TI - Telephonic review for outpatients with epilepsy-A prospective randomized, parallel group study. AB - PURPOSE: Our objective was to assess how telephonic review of outpatients with stable epilepsy compared with conventional face-to-face clinic management. METHODS: We constructed a randomized parallel group study of suitable patients attending our Epilepsy Clinic and compared telephonic review with conventional clinic visit based management. Primary outcomes were the percentage of patients with breakthrough seizures and total number of breakthrough seizures. We also compared cost, patient satisfaction and numbers defaulting. RESULTS: A total of 465 patients were randomized and 429 were included in the final analysis. There was no significant difference in breakthrough seizures between the two groups. Mean time spent in the consultation was 10min in the telephone group (FT) and 22h in the face-to-face group (FC) and cost was INR 865 more expensive on an average in the FC group. Satisfaction was over 90% in the FT group. Significantly more people in the FC group were lost to follow-up. CONCLUSION: This study provides Class I evidence that the number of stable epilepsy patients who have breakthrough seizures and the total number of breakthrough seizures remain the same irrespective of whether patients are reviewed telephonically or face-to-face in the clinic. Clinicians managing epilepsy patients should consider using telephonic review for selected patients. Telephonic reviews have the potential of effectively reducing the secondary treatment gap in millions of patients who do not have easy access to doctors. PMID- 29127861 TI - Altered EZH2 splicing and expression is associated with impaired histone H3 lysine 27 tri-Methylation in myelodysplastic syndrome. AB - BACKGROUND: EZH2 (enhancer of zeste homolog 2) is a histone H3K27 methyltransferase involved in the pathogenesis of various hematological malignancies. In myelodysplastic syndromes (MDS), loss of function of EZH2 is known to contribute to pathogenesis, however the pattern of EZH2 mRNA and protein expression in MDS has not been extensively characterized. MATERIAL AND METHODS: A total of 26 patients diagnosed with MDS were analyzed in this study. The relationship between EZH2 expression in patient bone marrow samples, evaluated by RT-PCR and immunoblotting, and patient characteristics were analyzed. The function of truncated EZH2 proteins was examined in vitro. RESULTS: EZH2 expression levels and transcript sizes varied considerably between patients, but there was no relationship with the percentage blast component of patient samples. Cloning and sequencing of amplified RT-PCR fragments demonstrated that patients expressed multiple EZH2 transcripts containing insertions or deletions, with or without frameshift, mainly induced by altered splicing. All identified frameshift mutations were found to be 5' to the functional SET domain, and resulted in truncated protein translation. Altered patterns of EZH2 expression was observed in patients with or without alterations in genes involved with RNA splicing, SRSF2, U2AF1 and SF3B1. Functional analysis in vitro revealed that C-terminally truncated EZH2, lacking the SET domain, may impair the methyltransferase function of wild-type EZH2 in a dominant negative fashion. CONCLUSION: Our findings suggest that the loss of function of EZH2 induced by aberrant splicing, and/or EZH2 mutations resulting in the production of C-terminally truncated proteins, may be involved in MDS pathogenesis. PMID- 29127860 TI - Human embryonic stem cell-derived cardiovascular progenitor cells efficiently colonize in bFGF-tethered natural matrix to construct contracting humanized rat hearts. AB - Bioengineering of whole hearts using human embryonic stem cells (hESCs)-derived cardiovascular progenitor cells (CPCs) and natural matrices is a promising approach to overcome organ donor shortage threatening millions of patients awaiting for heart transplantation. Here, we developed a novel strategy for generation of heart constructs by repopulating engineered decellularized rat hearts using hESCs-derived CPCs. Careful expansion of CPCs in a scalable stirred suspension bioreactor combined with step-wise seeding (60 million cells in 3 steps of 20 million per 1.5 h) onto decellularized hearts containing immobilized basic fibroblast growth factor (bFGF) resulted in improved retention of CPCs and differentiation to cardiomyocytes, smooth muscle cells and endothelial cells as evaluated by immunohistochemistry and qRT-PCR. We observed spontaneous and synchronous contractions of humanized hearts after 12 days of perfusion as well as advanced alignment of myofilaments. Our study provides a robust platform for generation of artificial human hearts and resolves major bottlenecks hindering further development of this technology. PMID- 29127862 TI - Frondoside A potentiates the effects of conventional therapeutic agents in acute leukemia. AB - Acute leukemia is the major cause of mortality in hematological malignancies. Despite improvement of survival with current chemotherapies, patients die from the disease or side-effects of treatment. Thus, new therapeutic agents are needed. Frondoside A is a triterpenoid glycoside originally isolated from the sea cucumber, Cucumaria frondosa that has potent antitumor effects in various cancers. The current study investigated the effects of frondoside A in acute leukemia cell lines alone and in combination with drugs used for this malignancy. This study is the first comparing the efficacy of frondoside A to available conventional drugs. The acute leukemia cell lines used were CCRF-CEM, HL-60 and THP-1. Cells were cultured and treated with different concentrations of vincristine sulphate, asparaginase and prednisolone alone and in combination with frondoside A. The inhibitory concentration 50 (IC50) for each compound was determined for the cell lines. CCRF-CEM cells were very sensitive to frondoside A treatment while HL-60 and THP1 were less sensitive. Frondoside A markedly enhanced the anticancer effects of all of the conventional drugs. Synergistic effects were seen with most of the combinations. Frondoside A may be valuable in the treatment of acute leukemia, particularly when used in combination with current therapeutic drugs. PMID- 29127863 TI - Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: The PDER PAN study. AB - BACKGROUND AND AIMS: Patients on parenteral nutrition for short bowel syndrome (SBS) have a high risk of thrombotic complications and are often treated with parenteral anticoagulation. Direct oral anticoagulants are absorbed proximally in the digestive tract and may represent alternative regimens in selected SBS patients. In our pilot study, we provided pharmacokinetics parameters of dabigatran etexilate and rivaroxaban in this setting and compared peak (Cmax), trough (Ctrough) concentrations, and areas-under-the-concentration-time-curve (AUC0-t) to reference values retrieved from phase I-III studies. METHODS: We enrolled 6 adults with a remaining small bowel length<=200cm, normal renal/hepatic function, and intact stomach. In our crossover study, patients were exposed to twice-daily dabigatran etexilate 150mg and once-daily rivaroxaban 20mg. RESULTS: After 5days of dabigatran dosing, Ctrough and Cmax geometric means were 39MUg/L (90% CI: 23-66) and 88MUg/L (90% CI: 56-137), respectively; AUC0-12h was 958MUg*h/L (90% CI: 635-1445). After 5days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9MUg/L (90% CI: 1-71) and 167MUg/L (90% CI: 102-276), respectively; AUC0-24h was 1720MUg*h/L (90% CI: 899-3300). Absorption was negligible in one patient with ultra-short (~15cm) bowel. For dabigatran, Cmax ratio was 0.57 (SD 0.33) and Ctrough ratio was 0.35 (SD 0.44). For rivaroxaban, the mean observed-to-reference ratios AUC0-24h and Cmax ratios were 0.73 (SD 0.32) and 0.76 (SD 0.34), respectively. CONCLUSIONS: While in SBS patients there is some absorption of the oral anticoagulants dabigatran etexilate and rivaroxaban, it appears to be lower than reference values. Plasma drug levels showed significant inter-individual variability. PMID- 29127864 TI - Assessment of the quality of anticoagulation management in patients with pulmonary arterial hypertension. AB - BACKGROUND: Studies assessing the quality of anticoagulation therapy in patients with pulmonary arterial hypertension (PAH) have not been conducted. OBJECTIVE: To assess the quality of anticoagulation management, the rate of anticoagulation related complications in patients with PAH, and to identify risk factors for poor anticoagulation. METHODS: This observational, retrospective cohort study included patients with confirmed PAH taking a regimen of oral anticoagulants from two centers: Brigham and Women's Hospital in Boston, and Hospital Universitario La Paz in Madrid from January 2009 to August 2015. Efficacy of anticoagulation management and time spent within therapeutic range of study participants were assessed. RESULTS: There were a total of 121 patients with PAH taking oral anticoagulants. Time spent within range (TTR) of those taking vitamin K antagonists (VKAs) was 57.0%. Forty-seven patients (38.8%) had a total of 105 anticoagulation-related events. The odds ratio of having an event in patients with a TTR<60% was 2.43 (CI 95%, 1.01-5.83; p=0.046). Possible factors that affected the quality of the anticoagulation were the age, sex, functional capacity, atrial fibrillation and certain pulmonary arterial hypertension specific medications. CONCLUSION: The quality of targeted anticoagulation in patients with PAH was low. Patients with low TTR were at a higher risk of experiencing anticoagulation-related complications. Specialized anticoagulation centers showed better management of oral anticoagulants. PMID- 29127865 TI - Which information on women's issues in epilepsy does a community pharmacist need to know? A Delphi consensus study. AB - OBJECTIVE: The aim of this study was to develop and achieve consensus on a core list of important knowledge items that community pharmacists should know on women's issues in epilepsy. METHODS: This was a consensual study using a modified Delphi technique. Knowledge items were collected from the literature and from nine key contacts who were interviewed on their views on what information community pharmacists should have on women's issues in epilepsy. More knowledge items were suggested by five researchers with interest in women's issues who were contacted to rate and comment on the knowledge items collected. Two iterative Delphi rounds were conducted among a panel of pharmacists (n=30) to achieve consensus on the knowledge items to be included in the core list. Ten panelists ranked the knowledge items by their importance using the Analytical Hierarchy Process (AHP). RESULTS: Consensus was achieved to include 68 knowledge under 13 categories in the final core list. Items ranked by their importance were related to the following: teratogenicity (10.3%), effect of pregnancy on epilepsy (7.4%), preconception counseling (10.3%), bone health (5.9%), catamenial epilepsy (7.4%), menopause and hormonal replacement therapy (2.9%), contraception (14.7%), menstrual disorders and infertility (8.8%), eclampsia (2.9%), breastfeeding (4.4%), folic acid and vitamin K (5.9%), counseling on general issues (14.7%), and sexuality (4.4%). CONCLUSION: Using consensual knowledge lists might promote congruence in educating and/or training community pharmacists on women's issues in epilepsy. Future studies are needed to investigate if such lists can improve health services provided to women with epilepsy (WWE). PMID- 29127866 TI - Placental hypoxia inducible factor -1alpha & CHOP immuno-histochemical expression relative to maternal circulatory syncytiotrophoblast micro-vesicles in preeclamptic and normotensive pregnancies. AB - OBJECTIVES: Preeclampsia (PE) occurs as a result placental hypoxia-induced oxidative and endoplasmic reticulum stress, and is associated with the activation of hypoxia inducible factor-1alpha (HIF-1alpha) and apoptotic CHOP pathways with the consequential shedding of syncytiotrophoblast microvesicles which may be central in mediating the maternal systemic immune response. The aim of this study was to immune-localise and morphometrically analyse CHOP and HIF-1alpha within the placenta of normotensive and pre-eclamptic pregnancies and concomitantly quantify syncytiotrophoblast released microvesicles in maternal circulation. STUDY DESIGN: Placental tissue and plasma were obtained from normotensive and pre eclamptic pregnant women. The expression of CHOP and HIF-1alpha was analysed using immunohistochemistry. Isolation and size distribution of the circulating maternal microvesicles was determined using nanoparticle tracking analysis. The concentration of syncytiotrophoblast microvesicles was determined using the placental alkaline phosphatase ELISA. RESULTS: This study demonstrates a significant increase in immunohistochemical expression of HIF-1 alpha and CHOP in preeclampsia compared to the normotensive women (p<0.05). In keeping with this, a significant increase in the mean syncytiotrophoblast microvesicles concentration was observed in PE, compared to normotensives (p<0.05). A positive correlation between placental expression of CHOP and HIF-1alpha and STBMs was obtained. CONCLUSION: This study demonstrates increased placental expression of HIF-1alpha and CHOP in preeclampsia compared to normotensive pregnancies which correlate to their increased syncytiotrophoblast microvesicles concentration in maternal circulation. These findings indicate that placental hypoxia and ER stress are interrelated contributory factors to the pathogenesis of PE and the consequential release of placental derived debris into the maternal circulation. PMID- 29127867 TI - Effects of ashes from a Brazilian savanna wildfire on water, soil and biota: An ecotoxicological approach. AB - Wildfire is very common in Brazilian savannas, and its effects on water, soil and aquatic/soil organisms are poorly understood. In this study, we observed the effects of fire, especially of ashes, on surface soil and subsurface water in a typical Brazilian savanna (Cerrado sensu strictu) for one year. Soil analyses (pH, organic matter content, potential acidity, K, Ca, Mg and P) and subsurface water analyses (NO3-, PO43- Mg2+, Ca2+ and K+) were assessed. We evaluated the ecotoxicological effects of ashes on three different endpoints and species, in fish Danio rerio (embryonic development), aquatic snail Biomphalaria glabrata (reproduction) and a soil species Enchytraeus sp. (reproduction). We found a higher amount of exchangeable cations and organic matter content in short-term fire effects on soil, but the higher availability of nutrients did not affect the soil pH in field plots. The effects of ashes on soil and subsurface water did not persist for one-year post-fire, except for organic matter content in burned areas. No toxic effects were observed on hatching success and incidences of developmental abnormalities in D. rerio embryos. However, ash input had adverse effects on reproduction in snails and enchytraeids. We reported a statistically significant decrease in snail eggs exposed to the 50g.L-1 and 100g.L-1 of ashes after four weeks (p<0.05, Dunnett's test and Tukey test). Enchytraeus sp. reproduction was negatively influenced by the natural soil, which presents high acidity, and also when exposed directly to the ashes from burned area, suggesting that pH and other ash compounds may limit the growth of enchytraeids. More studies in burned areas are strongly encouraged, addressing the potential important routes of exposure to ashes in order to understand the impact of intense fires on soil and aquatic biota in tropical savannas. PMID- 29127868 TI - Reduced irrigation increases the water use efficiency and productivity of winter wheat-summer maize rotation on the North China Plain. AB - The groundwater table has fallen sharply over the last 30years on the North China Plain, resulting in a shortage of water for winter wheat irrigation. Reducing irrigation may be an important strategy to maintain agricultural sustainability in the region; however, few studies have evaluated the transition from conventional irrigation management practices to reduced irrigation management practices in the winter wheat-summer maize rotation system. Here, we compare the yield, water consumption, and water use efficiency of winter wheat-summer maize rotation under conventional irrigation and reduced irrigation on the North China Plain from 2012 to 2015. Reducing irrigation decreased the yield but increased the water use efficiency and significantly advanced the harvest date of winter wheat. As a result, the summer maize sowing date advanced significantly, and the flowering date subsequently advanced 2-8days, thus extending the summer maize grain-filling stage. Therefore, the yield and water use efficiency of summer maize were higher under reduced irrigation than conventional irrigation, which compensated for the winter wheat yield loss under reduced irrigation. In addition, under reduced irrigation from 2012 to 2015, the yield and water use efficiency advantage of the winter wheat-summer maize rotation ranged from 0.0 to 9.7% and from 4.1 to 14.7%, respectively, and water consumption and irrigated water decreased by 20-61mm and 150mm, respectively, compared to conventional irrigation. Overall, the reduced irrigation management practice involving no irrigation after sowing winter wheat, and sowing summer maize on June 7 produced the most favorable grain yield with superb water use efficiency in the winter wheat-summer maize rotation. This study indicates that reducing irrigation could be an efficient means to cope with water resource shortages while maintaining crop production sustainability on the North China Plain. PMID- 29127869 TI - Trans-boundary air pollution in a city under various atmospheric conditions. AB - Trans-boundary air pollution (TAP) is a crucial factor affecting air quality, and its contribution may vary over time and differ under various atmospheric conditions. This study firstly applies an integrated statistical scheme to estimate the contributions of TAP and local sources to air pollutants in a city, and then investigate the influences of tropical cyclones (TC) on TAP. Hong Kong is chosen as an example because of its significant and special TAP characteristics. This study focuses on four major air pollutants, namely, respirable and fine suspended particulates (RSP/PM10 and FSP/PM2.5), sulfur dioxide (SO2), and nitrogen dioxide (NO2), from 2002 to 2013. Our results show that, on average, TAP is the major contributor of the annual RSP, FSP, SO2, and NO2 in Hong Kong. We estimate that when a TC is approaching, the increase in pollutant concentration in Hong Kong is mainly due to the increase in TAP contribution by the strengthened northerly wind at higher level of atmosphere (>=900hPa). These changes are accompanied by decreases in precipitation and increases in northerly/north-easterly wind, which may prolong the lifetime of pollutants, enhancing pollutant transport from mainland China to Hong Kong. PMID- 29127870 TI - Concentrations of several phthalates contaminants in Egyptian bottled water: Effects of storage conditions and estimate of human exposure. AB - The occurrence and concentrations of six common phthalates were investigated for the first time in bottled water locally produced in the Egyptian market. The compounds investigated were dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), n-butyl benzyl phthalate (BBP), diethyl hexyl phthalate (DEHP), and Di-n-octyl phthalate (D-n-OP). A set of 108 bottled water samples from six different commercial brands of water bottled in transparent polyethylene terephthalate (PET) plastic bottles with high density polyethylene (HDPE) plastic caps were investigated. Water samples were analyzed immediately after purchasing (~2weeks after production), after being stored at room temperature (25+/-5 degrees C), in a refrigerator (4+/-1 degrees C) and outdoor under sun exposure (daylight temperature of 40+/-5 degrees C). Samples were stored up to six months depending on the tested condition. Among the target compounds, only DEHP and DBP were detected in the samples analyzed immediately after purchasing with a detection frequency of 50 and 58% and mean concentrations of 0.104 and 0.082MUgl 1 respectively. Significant positive correlation was obtained between the storage time, temperature and the concentration of phthalate compounds detected in the bottled water, indicating possible migration from the PET plastic material as the source. The estimated contribution of bottled water consumption to the tolerable daily intake (TDI) levels of the two most abundant phthalates observed here for adults and toddlers did not exceed 0.16 and 0.72% for DBP while these values were 0.04 and 0.16% for DEHP respectively. These estimated daily intake values from PET bottled water consumption were far below their respective TDI values and therefore should constitute no adverse health effects. PMID- 29127871 TI - Marine radioecology after the Fukushima Dai-ichi nuclear accident: Are we better positioned to understand the impact of radionuclides in marine ecosystems? AB - This paper focuses on how a community of researchers under the COMET (CO ordination and iMplementation of a pan European projecT for radioecology) project has improved the capacity of marine radioecology to understand at the process level the behaviour of radionuclides in the marine environment, uptake by organisms and the resulting doses after the Fukushima Dai-ichi nuclear accident occurred in 2011. We present new radioecological understanding of the processes involved, such as the interaction of waterborne radionuclides with suspended particles and sediments or the biological uptake and turnover of radionuclides, which have been better quantified and mathematically described. We demonstrate that biokinetic models can better represent radionuclide transfer to biota in non equilibrium situations, bringing more realism to predictions, especially when combining physical, chemical and biological interactions that occur in such an open and dynamic environment as the ocean. As a result, we are readier now than we were before the FDNPP accident in terms of having models that can be applied to dynamic situations. The paper concludes with our vision for marine radioecology as a fundamental research discipline and we present a strategy for our discipline at the European and international levels. The lessons learned are presented along with their possible applicability to assess/reduce the environmental consequences of future accidents to the marine environment and guidance for future research, as well as to assure the sustainability of marine radioecology. This guidance necessarily reflects on why and where further research funding is needed, signalling the way for future investigations. PMID- 29127872 TI - Biomonitoring levels and trends of PAHs and synthetic musks associated with land use in urban environments. AB - Polycyclic aromatic hydrocarbons (PAHs) are some of the most studied organic compounds in urban environments, due to their known adverse effects on human health and persistence in environmental matrices. During the last decade, new groups of organic compounds with an intensive use worldwide such as synthetic musks have been raising the interest of the scientific community given their toxicity and health effects. However, literature is still scarce in studies dealing with their concentration in the environment, especially in developing countries, where they are even more rare or non-existing at all. We employed leaves of Ligustrum lucidum to assess the concentrations of PAHs and synthetic musks in different land use areas in Cordoba city, therefore contributing with environmental information in Argentina. We found higher levels of PAHs in urban and industrial areas than in the peri-urban sampling sites, naphthalene being one of the dominant PAHs in all sampling areas. Regarding synthetic musk fragrances, polycyclic musks were the most contributing compounds and the highest levels found in industrial areas as well. A high environmental risk could be expected due to the frequent occurrence of galaxolide in addition to the high hazardous potential of phantolide, which was present in 50% of the samples. The results of the present study indicate that leaves of an urban ubiquitous tree can be used to assess the spatial behavior of both "classic" and "emerging" organic pollutants, allowing an assessment of urban air quality in areas where common air sampling devices are unavailable. PMID- 29127873 TI - Local angiotensin II promotes adipogenic differentiation of human adipose tissue mesenchymal stem cells through type 2 angiotensin receptor. AB - Obesity is often associated with high systemic and local activity of renin angiotensin system (RAS). Mesenchymal stem cells of adipose tissue are the main source of adipocytes. The aim of this study was to clarify how local RAS could control adipose differentiation of human adipose tissue derived mesenchymal stem cells (ADSCs). We examined the distribution of angiotensin receptor expressing cells in human adipose tissue and found that type 1 and type 2 receptors are co expressed in its stromal compartment, which is known to contain mesenchymal stem cells. To study the expression of receptors specifically in ADSCs we have isolated them from adipose tissue. Up to 99% of cultured ADSCs expressed angiotensin II (AngII) receptor type 1 (AT1). Using the analysis of Ca2+ mobilization in single cells we found that only 5.2+/-2.7% of ADSCs specifically respond to serial Ang II applications via AT1 receptor and expressed this receptor constantly. This AT1const ADSCs subpopulation exhibited increased adipose competency, which was triggered by endogenous AngII. Inhibitory and expression analyses showed that AT1const ADSCs highly co-express AngII type 2 receptor (AT2), which was responsible for increased adipose competency of this ADSC subpopulation. PMID- 29127874 TI - Generation of induced pluripotent stem cells from a patient with Parkinson's disease carrying LRRK2 p.I2012T mutation. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by interactions between genetic and environmental factors. Leucine rich repeat kinase (LRRK2) is the most prevalent mutation in autosomal-dominant inheritance of PD. Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a female patient with p.I2012T mutation in LRRK2 gene by using the Sendai-virus delivery system. The resulting iPSCs had a normal karyotype. The iPSCs also showed pluripotency confirmed by immunofluorescent staining and differentiated into the 3 germ layers in vivo. This cellular model will provide a useful platform for further pathophysiological studies of PD. PMID- 29127875 TI - Derivation of the Duchenne muscular dystrophy patient-derived induced pluripotent stem cell line lacking DMD exons 49 and 50 (CCMi001DMD-A-3, ?49, ?50). AB - Duchenne muscular dystrophy (DMD) is caused by abnormalities in the dystrophin gene and is clinically characterised by childhood muscle degeneration and cardiomyopathy. We produced an induced pluripotent stem cell line from a DMD patient's dermal fibroblasts by electroporation with episomal vectors containing: hL-MYC, hLIN28, hSOX2, hKLF4, hOCT3/4. The resultant DMD iPSC line (CCMi001DMD-A 3) displayed iPSC morphology, expressed pluripotency markers, possessed trilineage differentiation potential and was karyotypically normal. MLPA analyses performed on DNA extracted from CCMi001DMD-A-3 showed a deletion of exons 49 and 50 (CCMi001DMD-A-3, ?49, ?50). PMID- 29127876 TI - Differentiating biliary cystadenomas from benign hepatic cysts: Preliminary analysis of new predictive imaging features. AB - OBJECTIVE: To identify performance of imaging features in differentiating hepatic cysts from biliary cystadenomas of the liver. METHODS: 25 pathologically confirmed hepatic cystic lesions (hepatic cysts or biliary cystadenomas) were evaluated retrospectively and predetermined imaging features assessed for performance in differentiation. RESULTS: Any septation which arose from a cyst wall without external indentation had a very high association with biliary cystadenoma, while the presence of a thick septation had only a moderate association. CONCLUSIONS: The relationship between septations and the wall of the cystic lesion performed better than previously reported features including thick septations. PMID- 29127877 TI - Breast Arterial Calcification on screening mammography can predict significant Coronary Artery Disease in women. AB - INTRODUCTION: Breast Arterial Calcification (BAC) on digital mammography has been associated with an increased risk of Coronary Artery Disease (CAD). We aimed to investigate the association of BAC with findings on Coronary Computed Tomography Angiography (CCTA) within a cohort of women from the national breast screening program. METHODS: Symptomatic women (chest pain) aged between 50 and 65 who underwent a CCTA and who also had a screening mammography between 2014 and 2015 were recorded. BAC and CAD-RADSTM: Coronary Artery Disease-Reporting and Data System were scored by separate blinded specialist radiologists. Cardiac risk factors were recorded. Patients' cardiac follow up (with Exercise Stress Test, Percutaneous Coronary Intervention or echocardiography) and cardio-protective medications were also documented. RESULTS: 219 eligible women underwent a CCTA. Of these, 104 patients also underwent digital mammography. Using standard linear regression BAC was identified as a significant predictor of CAD-RADs >=3 disease. Using binomial logistic regression, BAC remained associated with CAD-RADs >=3 (p=0.023). A significantly higher proportion of patients with BAC >1 were on cardio-protective medications (p=0.041) and had medications initiated or changed, or had further cardiac investigation (p=0.037 and p=0.019, respectively) than those with no BAC, after a mean follow-up of 20.6 (range 15-27) months. CONCLUSION: BAC diagnosed on 2 yearly screening mammography predicts CAD-RADs >=3 disease in symptomatic patients. PMID- 29127879 TI - Role of the right inferior parietal cortex in auditory selective attention: An rTMS study. AB - Selective attention is the process of directing limited capacity resources to behaviourally relevant stimuli while ignoring competing stimuli that are currently irrelevant. Studies in healthy human participants and in individuals with focal brain lesions have suggested that the right parietal cortex is crucial for resolving competition for attention. Following right-hemisphere damage, for example, patients may have difficulty reporting a brief, left-sided stimulus if it occurs with a competitor on the right, even though the same left stimulus is reported normally when it occurs alone. Such "extinction" of contralesional stimuli has been documented for all the major sense modalities, but it remains unclear whether its occurrence reflects involvement of one or more specific subregions of the temporo-parietal cortex. Here we employed repetitive transcranial magnetic stimulation (rTMS) over the right hemisphere to examine the effect of disruption of two candidate regions - the supramarginal gyrus (SMG) and the superior temporal gyrus (STG) - on auditory selective attention. Eighteen neurologically normal, right-handed participants performed an auditory task, in which they had to detect target digits presented within simultaneous dichotic streams of spoken distractor letters in the left and right channels, both before and after 20 min of 1 Hz rTMS over the SMG, STG or a somatosensory control site (S1). Across blocks, participants were asked to report on auditory streams in the left, right, or both channels, which yielded focused and divided attention conditions. Performance was unchanged for the two focused attention conditions, regardless of stimulation site, but was selectively impaired for contralateral left-sided targets in the divided attention condition following stimulation of the right SMG, but not the STG or S1. Our findings suggest a causal role for the right inferior parietal cortex in auditory selective attention. PMID- 29127878 TI - Absence of the subclavius muscle with contralateral subclavius posticus muscle: first imaging report. AB - We present a case of a 56-year-old man with pain in in his right anterior shoulder, arm, and hand. MRI studies demonstrated absence of the subclavius muscle with contralateral subclavius posticus muscle. To our knowledge, imaging of the total absence of subclavius muscle has not been previously described. Understanding and recognition of subclavius posticus muscle are important for its potential role in thoracic outlet syndrome. PMID- 29127880 TI - Effects of flavonoids on MicroRNA 145 regulation through Klf4 and myocardin in neointimal formation in vitro and in vivo. AB - MicroRNA 145 (miR-145) is a critical modulator of vascular smooth muscle cell (VSMC) phenotyping and proliferation. Flavonoids have been studied extensively due to their diverse pharmacological properties, including anti-inflammatory effects. The aims of this study is designed to evaluate the atheroprotective effects on angiotensin II (Ang II)-induced miR-145 and Klf4/myocardin expression in vitro and in vivo of flavonoids, including (-)-epigallocatechin gallate (EGCG), chrysin, wogonin, silibinin, and ferulic acid. Ang II significantly reduced the miR-145 compared with the control VSMC groups; all the tested flavonoids increased miR-145 in the 100 nM concentration. Among the test compounds, EGCG showed the strongest augmenting effect on miR-145 and myocardin, however, it also abolished Ang II-induced Klf4. A [3H]-thymidine incorporation proliferation assay demonstrated that EGCG inhibited Ang II-induced VSMC proliferation, and Klf4 siRNA presented with the similar results. Immunohistochemical analysis and confocal microscopy demonstrated increased Klf4 expression and the arterial lumen was narrowed after balloon injury 14 days. With the addition of EGCG (50 mg/kg) and Klf4 siRNA, neointimal formation was reduced by 40.7% and 50.5% compared with balloon injury 14 days; Klf4 expression also was attenuated. This study demonstrated EGCG increased miR-145 and attenuated Klf4, and ameliorated neointimal formation in vitro and in vivo. The novel suppressive effect was mediated through the miR-145 and Klf4/myocardin pathways. PMID- 29127881 TI - Grapevine immune signaling network in response to drought stress as revealed by transcriptomic analysis. AB - Drought is a ubiquitous abiotic factor that severely impedes growth and development of horticulture crops. The challenge postured by global climate change is the evolution of drought-tolerant cultivars that could cope with concurrent stress. Hence, in this study, biochemical, physiological and transcriptome analysis were investigated in drought-treated grapevine leaves. The results revealed that photosynthetic activity and reducing sugars were significantly diminished which were positively correlated with low stomatal conductance and CO2 exchange in drought-stressed leaves. Further, the activities of superoxide dismutase, peroxidase, and catalase were significantly actuated in the drought-responsive grapevine leaves. Similarly, the levels of abscisic acid and jasmonic acid were also significantly increased in the drought-stressed leaves. In transcriptome analysis, 12,451 differentially-expressed genes (DEGs) were annotated, out of which 8021 DEGs were up-regulated and 4430 DEGs were down regulated in response to drought stress. In addition, the genes encoding pathogen associated molecular pattern (PAMP) triggered immunity (PTI), including calcium signals, protein phosphatase 2C, calcineurin B-like proteins, MAPKs, and phosphorylation (FLS2 and MEKK1) cascades were up-regulated in response to drought stress. Several genes related to plant-pathogen interaction pathway (RPM1, PBS1, RPS5, RIN4, MIN7, PR1, and WRKYs) were also found up-regulated in response to drought stress. Overall the results of present study showed the dynamic interaction of DEG in grapevine physiology which provides the premise for selection of defense-related genes against drought stress for subsequent grapevine breeding programs. PMID- 29127882 TI - Anxiety sensitivity and sleep disturbance: Investigating associations among patients with co-occurring anxiety and substance use disorders. AB - Sleep disturbance is a common problem among individuals with anxiety and substance use disorders (SUD). Anxiety sensitivity (AS) is elevated in patients with anxiety disorders and SUD and has been linked to sleep-related problems, including insomnia and somnolence (i.e., daytime sleepiness). We examined the unique roles of AS cognitive, physical, and social concerns in sleep disturbance among a sample of 99 residential SUD patients with anxiety disorders. Clinical levels of insomnia or somnolence were evidenced by 53.5% of the sample. Consistent with predictions, AS physical concerns was significantly associated with insomnia, and AS cognitive concerns was significantly related to insomnia and somnolence. Hierarchical linear regression models were conducted to test the association of AS cognitive and physical concerns with insomnia and somnolence symptoms while controlling for relevant factors. AS cognitive concerns accounted for unique variance, above and beyond withdrawal symptoms, anxiety, and depressive symptoms, in the model examining insomnia symptoms (B=0.30, SE=0.13, p=0.023). Results suggest that AS cognitive concerns may represent an important transdiagnostic mechanism underlying sleep disturbance among individuals with dual diagnosis. PMID- 29127883 TI - Metabolic engineering of yeast for lignocellulosic biofuel production. AB - Production of biofuels from lignocellulosic biomass remains an unsolved challenge in industrial biotechnology. Efforts to use yeast for conversion face the question of which host organism to use, counterbalancing the ease of genetic manipulation with the promise of robust industrial phenotypes. Saccharomyces cerevisiae remains the premier host for metabolic engineering of biofuel pathways, due to its many genetic, systems and synthetic biology tools. Numerous engineering strategies for expanding substrate ranges and diversifying products of S. cerevisiae have been developed. Other yeasts generally lack these tools, yet harbor superior phenotypes that could be exploited in the harsh processes required for lignocellulosic biofuel production. These include thermotolerance, resistance to toxic compounds generated during plant biomass deconstruction, and wider carbon consumption capabilities. Although promising, these yeasts have yet to be widely exploited. By contrast, oleaginous yeasts such as Yarrowia lipolytica capable of producing high titers of lipids are rapidly advancing in terms of the tools available for their metabolic manipulation. PMID- 29127884 TI - Regional dysregulation of taurine and related amino acids in the fetal rat brain following gestational alcohol exposure. AB - The fetal brain exhibits exquisite alcohol-induced regional neuronal vulnerability. A candidate mechanism for alcohol-mediated brain deficits is disruption of amino acid (AA) bioavailability. AAs are vitally important for proper neurodevelopment, as they comprise the most abundant neurotransmitters in the brain and act as neurotransmitter precursors, nitric oxide donors, antioxidants, and neurotrophic factors, which induce synaptogenesis, neuronal proliferation, and migration. We hypothesized that gestational alcohol alters brain AA concentrations, disrupts AAs associated with neuropathogenesis, and that alterations are region-specific. We assigned pregnant Sprague-Dawley rats to either a pair-fed control or a binge alcohol treatment group on gestational day (GD) 4. Alcohol animals were acclimatized via a once-daily orogastric gavage of a 4.5 g/kg alcohol dose from GD 5-10, and progressed to a 6 g/kg alcohol dose from GD 11-20. Pair-fed animals received isocaloric maltose dextrin (once daily; GD 5 20). Fetal cerebral cortex, cerebellum, and hippocampus were collected on GD 21. Following collection, Fluorometric High Performance Liquid Chromatography (HPLC) involving pre-column derivatization with o-phthaldialdehyde quantified regional content of 22 AAs. Chronic binge alcohol administration to pregnant dams regionally altered AA concentrations in all three structures, with the cerebral cortex exhibiting the least vulnerability and the hippocampus exhibiting maximal vulnerability. We conjecture that the AA imbalances observed in this study are critically implicated in pathological and compensatory processes occurring in the brain in response to gestational alcohol exposure. PMID- 29127886 TI - Stealing behavior and impulsivity in individuals with kleptomania who have been arrested for shoplifting. AB - OBJECTIVES: Kleptomania is characterized by strong urges to steal and is one of only a few psychiatric disorders defined by illegal behaviors, but the clinical characteristics of individuals with kleptomania who have faced legal consequences due to their behavior are poorly understood. METHOD: From 2001 to 2012, we recruited 107 adult participants with DSM-IV kleptomania. Participants with a history of shoplifting-related arrest (N=82) were compared with those who had no such history (N=25) on demographics, clinical features, and a self-report measure of impulsivity. RESULTS: Participants whose shoplifting had resulted in arrest had higher self-rated impulsivity on a weak trend level (Eysenck Impulsiveness Questionnaire), with large to very large effect size (Cohen's d=1.12). Group comparisons showed no significant differences in terms of overall functioning (d=0.60), time spent stealing (d=0.73), frequency of stealing behavior (d=0.33), psychiatric comorbidity, or severity of kleptomania symptoms. CONCLUSIONS: Legal problems in kleptomania may be associated with generalized deficits in inhibitory control independent of kleptomania symptom severity. These findings emphasize the need for treatment to improve functional status in individuals with kleptomania and reduce the social and economic costs associated with reoffending. PMID- 29127887 TI - Pullout strength of cement-augmented and wide-suture transosseous fixation in the greater tuberosity. AB - BACKGROUND: Obtaining strong fixation in low-density bone is increasingly critical in surgical repair of rotator cuff tears because of the aging population. To evaluate two new methods of improving pullout strength of transosseous rotator cuff repair in low-density bone, we analyzed the effects of 1) using 2-mm suture tape instead of no. 2 suture and 2) augmenting the lateral tunnel with cement. METHODS: Eleven pairs of osteopenic or osteoporotic cadaveric humeri were identified by dual-energy x-ray absorptiometry. One bone tunnel and one suture were placed in the heads of 22 specimens. Five randomly selected pairs were repaired with no. 2 suture; the other six pairs were repaired with 2-mm suture tape. One side of each pair received lateral tunnel cement augmentation. Specimens were tested to suture pullout. Data were fitted to multivariate models that accounted for bone mineral density and other specimen characteristics. FINDINGS: Two specimens were excluded because of knot-slipping during testing. Use of suture tape versus no. 2 suture conferred a 75-N increase (95% CI: 37, 113) in pullout strength (P<0.001). Cement augmentation conferred a 42-N improvement (95% CI: 10, 75; P=0.011). Other significant predictors of pullout strength were age, sex, and bone mineral density. INTERPRETATION: We show two methods of improving the fixation strength of transosseous rotator cuff repairs in low-density bone: using 2-mm suture tape instead of no. 2 suture and augmenting the lateral tunnel with cement. These methods may improve the feasibility of transosseous repairs in an aging patient population. PMID- 29127885 TI - Summary of the 2016 Alcohol and Immunology Research Interest Group (AIRIG) meeting. AB - On November 18, 2016 the 21st annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at the Center for Translational Research and Education at Loyola University Chicago's Health Sciences Campus in Maywood, IL. The 2016 meeting focused broadly on alcohol and inflammation, epigenetics, and the microbiome. The four plenary sessions of the meeting were Alcohol, Inflammation, and Immunity; Alcohol and Epigenetics; Alcohol, Transcriptional Regulation, and Epigenetics; and Alcohol, Intestinal Mucosa, and the Gut Microbiome. Presentations in all sessions of the meeting explored putative underlying causes for chronic diseases and mortality associated with alcohol consumption, shedding light on future work and potential therapeutic targets to alleviate the negative effects of alcohol misuse. PMID- 29127888 TI - Histamine stimulates secretion of extracellular vesicles with nucleotidase activity in rat submandibular gland. AB - BACKGROUND: Extracellular vesicles released by different cells have been isolated from diverse fluids including saliva. We previously reported that rat submandibular glands secrete nanovesicles that catalyze hydrolysis of ATP, ADP and AMP, which are actors of the purinergic signaling system along with adenosine. Extracellular nucleotides like ATP and adenosine are involved in the regulation of inflammatory processes and apoptosis. Histamine, a widely distributed biogenic amine, is involved in inflammatory response. OBJECTIVE: To test if activation of histamine receptors in rat submandibular gland promotes changes in the release of vesicles with nucleotidase activity that could modulate purinergic signaling. METHODS: Rat submandibular glands were incubated in the absence or presence of histamine and JNJ7777120, an antagonist for H4 receptors. Extracellular vesicles were isolated from incubation media by differential centrifugation. Vesicular nucleotidase activity was measured following Pi release by 3mM MgATP, MgADP or MgAMP. RESULTS: Histamine increased the release of vesicles with nucleotidase activity in a concentration dependent manner. JNJ7777120 significantly reduced this effect. Vesicular nucleotidases obtained in the absence or presence of histamine promoted Pi production from ATP, ADP and AMP. CONCLUSION: The results show a relationship between histamine and the regulation of purinergic signaling, which could be important in the modulation of inflammatory processes. PMID- 29127889 TI - Nitric oxide and arginase levels in peri-implant tissues after delayed loading. AB - OBJECTIVE: Nitric oxide (NO) is synthesized from the conversion of L-arginine to L-citrulline by NO synthase (NOS). Arginase can compete with NOS for the common substrate L-arginine, and thus inhibit NO production. NO levels and arginase ezyme might affect the bone remodeling cycle around implants. The aim of this studywas to investigate NO and arginase levels in gingival crevicular fluid (GCF), peri-implant sulcular fluid (PISF), and saliva. MATERIALS AND METHODS: Twenty patients with one or more implants (Straumann(r); Institute Straumann AG, Basel, Switzerland) restored with fixed crown prostheses were included in the study. Plaque index (PI), gingival index (GI), probing depth (PD), and bleeding on probing (BOP) were recorded from six sites of each tooth and implant at baseline and at months 1, 3, and 6 after loading. The saliva, GCF, and PISF were collected at baseline and at months 1, 3, and 6 after loading. NO level and arginase enzyme were evaluated in GCF, PISF, and saliva. RESULTS: Arginase and NO levels in saliva did not change significantly from baseline to months 1, 3, and 6. However, both PISF NO and arginase levels showed an increased pattern from baseline to month 6. NO levels were significantly higher at months 3 and 6, compared to baseline, while PISF arginase levels increased significantly from baseline to months 3 and 6. CONCLUSION: NO and arginase enzyme measurements in saliva, GCF, and PISF may be beneficial in the determination of current peri implant tissues. In particular, PISF might provide more information than saliva. PMID- 29127890 TI - The role of ethyl glucuronide in supporting medico-legal investigations: Analysis of this biomarker in different postmortem specimens from 21 selected autopsy cases. AB - Ethanol determination in postmortem blood is one of the most frequently requested analyses in legal medicine and forensic toxicology. Ethyl glucuronide is a non oxidative ethanol metabolite. It is also a useful marker of ante-mortem alcohol ingestion when ethanol itself has been completely eliminated from the body and could be considered in autopsy cases to obtain more reliable indications. The aim of the present study was to investigate the ethyl glucuronide distribution in postmortem specimens from autopsy cases found to be positive for ethanol. We presented 21 autopsy cases in which central blood, peripheral blood and liver samples were available. Specimens were analyzed for ethyl glucuronide by liquid chromatography tandem mass spectrometry; we also recorded postmortem interval, case history, cause of death, use of drugs, metabolic disorders if present, putrefaction if present, history of ethanol abuse and information about ethanol intake before death. Our aim was to evaluate and to compare the ethyl glucuronide levels in different matrices taken from the same subject in order to provide a better understanding of the interpretation of postmortem ethyl glucuronide concentrations. PMID- 29127891 TI - Elevated maternal anxiety in the NICU predicts worse fine motor outcome in VLBW infants. AB - AIM: The literature is sparse with respect to the impact of elevated maternal psychological distress in the neonatal intensive care unit (NICU) on later neurodevelopmental outcome in VLBW infants. The objective of this study is to examine the impact of elevated maternal distress, defined as elevated depression, anxiety and perinatal-specific post-traumatic stress, during the NICU hospitalization on VLBW infant ND outcome at 20months corrected age (CA). METHODS: This was a prospective study of 69 mothers and their VLBW infants recruited in 2011-2012. Elevated maternal distress was collected by maternal questionnaire in the NICU. Elevated depression was quantified with the Center for Epidemiological Studies-Depression Scale, anxiety with the Spielberger State Trait Anxiety Inventory and perinatal-specific post-traumatic stress with the Modified Perinatal Posttraumatic Stress Disorder Questionnaire. VLBW infant ND outcome was assessed using the Bayley Scales of Infant & Toddler Development-III at 20months CA. Regression analyses determined the impact of elevated distress on ND outcome after adjusting for infant medical and maternal sociodemographic variables. RESULTS: After controlling for infant and maternal covariates, elevated maternal anxiety in the NICU predicted lower fine motor scores at 20months CA. CONCLUSION: Elevated maternal anxiety in the NICU is associated with adverse ND outcome in VLBW infants in the 2nd year of life. NICU-based support services may help mothers' quality of life and VLBW infant outcome. PMID- 29127892 TI - Estimation of the late postmortem interval using FTIR spectroscopy and chemometrics in human skeletal remains. AB - Due to a lack of reliable and accurate methods, determining the postmortem interval (PMI) of human skeletal remains is one of the most important and challenging tasks in forensic medicine. In this paper, we studied the changes to bone chemistry with increasing PMI in two different experimental conditions using Fourier transform infrared (FTIR) spectroscopy in conjunction with chemometrics methods Paired bone samples collected from 56 human corpses were buried (placed in soil) and unburied (exposed to the air) for intervals between 76 and 552 days. The results of principle component analysis (PCA) showed the chemical differences of these two cases had a significant influence on the rate of decomposition of the remains. Meanwhile, satisfactory predictions were performed by the genetic algorithm combined with partial least-squares (GA-PLS) with the root mean square errors of prediction (RMSEP) of 50.93days for buried bones and 71.03days for unburied bones. Moreover, the amide I region of proteins and the area around 1390cm-1, which is associated with fatty acids, were identified with regular changes by GA-PLS and played an important role in estimating PMI. This study illustrates the feasibility of utilizing FTIR spectroscopy and chemometrics as an attractive alternative for estimating PMI of human remains and the great potential of these techniques in real forensic cases with natural conditions. PMID- 29127894 TI - Detection and localization of copy-paste forgeries in digital videos. AB - Amidst the continual march of technology, we find ourselves relying on digital videos to proffer visual evidence in several highly sensitive areas such as journalism, politics, civil and criminal litigation, and military and intelligence operations. However, despite being an indispensable source of information with high evidentiary value, digital videos are also extremely vulnerable to conscious manipulations. Therefore, in a situation where dependence on video evidence is unavoidable, it becomes crucial to authenticate the contents of this evidence before accepting them as an accurate depiction of reality. Digital videos can suffer from several kinds of manipulations, but perhaps, one of the most consequential forgeries is copy-paste forgery, which involves insertion/removal of objects into/from video frames. Copy-paste forgeries alter the information presented by the video scene, which has a direct effect on our basic understanding of what that scene represents, and so, from a forensic standpoint, the challenge of detecting such forgeries is especially significant. In this paper, we propose a sensor pattern noise based copy-paste detection scheme, which is an improved and forensically stronger version of an existing noise-residue based technique. We also study a demosaicing artifact based image forensic scheme to estimate the extent of its viability in the domain of video forensics. Furthermore, we suggest a simplistic clustering technique for the detection of copy-paste forgeries, and determine if it possess the capabilities desired of a viable and efficacious video forensic scheme. Finally, we validate these schemes on a set of realistically tampered MJPEG, MPEG-2, MPEG-4, and H.264/AVC encoded videos in a diverse experimental set-up by varying the strength of post-production re-compressions and transcodings, bitrates, and sizes of the tampered regions. Such an experimental set-up is representative of a neutral testing platform and simulates a real-world forgery scenario where the forensic investigator has no control over any of the variable parameters of the tampering process. When tested in such an experimental set-up, the four forensic schemes achieved varying levels of detection accuracies and exhibited different scopes of applicabilities. For videos compressed using QFs in the range 70-100, the existing noise residue based technique generated average detection accuracy in the range 64.5%-82.0%, while the proposed sensor pattern noise based scheme generated average accuracy in the range 89.9%-98.7%. For the aforementioned range of QFs, average accuracy rates achieved by the suggested clustering technique and the demosaicing artifact based approach were in the range 79.1%-90.1% and 83.2% 93.3%, respectively. PMID- 29127893 TI - Traumatic fatal aortic rupture in motorcycle drivers. AB - Traumatic fatal aortic rupture (FAR) is a common finding in victims of motor vehicle crashes (MVC), but its aetiology and mechanisms of production remain an issue of major concern, above all in motorcyclists. This study reports a series of cases obtained from a retrospective analysis of traumatic FARs occurring in motorcycle drivers, with the aim of defining the injury patterns and correlating them with the mechanisms of FAR production. Circumstantial, autopsy and histology data were collected through a retrospective analysis of post mortem examinations performed at the Institute of Legal Medicine of the University of Padova between 2014 and 2016. Among 151 traffic related victims, 8 were motorcycle drivers and displayed traumatic FAR and were thus included in the study. In 7 cases, the presence of abdominal/thoracic injuries suggested that the external compression due to the accident was at least a concurrent cause of FAR, being the predominant mechanism of aortic injury in 4 cases, through the "osseous pinch" or the "waterhammer effect" mechanisms. Our study highlights the well-known role of "preventative forensic pathology", which has become routinary in traffic medicine since many years, also for defining the points of impact and the injury patterns of motorcyclists sustaining traumatic FAR, thereby facilitating the development of new prevention strategies and devices. Further studies, however, are needed in order to widen the investigated population and to estimate the real number of victims for which traumatic FAR might hypothetically be prevented with specific countermeasures. PMID- 29127895 TI - Moving nurse educators towards transcendence in simulation comfort. AB - Expensive simulation equipment continues to sit idle in nursing learning and teaching environments. To identify factors that influence nursing educator comfort in the use of simulation at an Australian university an explorative qualitative research project was undertaken using an interpretative constructivist methodology. The Goodwin et al. (2007) adapted Comfort Theory for nursing education has been used. The aim of the study was to identify factors that influence nurse educator's comfort in the use of simulation. Research question asked was: What are the barriers and enhancers to using simulation as a learning and teaching modality. Thematic analysis of data from focus groups on four different campus sites was undertaken. Four themes identified that affected participants' comfort in this study were: 1) Personal barriers; 2) Human resource barriers; 3) Structural barriers and 4) Suggestions to address barriers. Further understanding of the themes and how they relate to educator comfort with simulation are shared with the reader. The paper also outlines emerging recommendations to improve educator comfort. PMID- 29127896 TI - Student and preceptor perceptions of primary health care clinical placements during pre-service education: Qualitative results from a quasi-experimental study. AB - As a practice discipline, nursing education has a mandate to collaborate with all clinical settings, including primary health care (PHC), to prepare nursing students to function effectively in different settings upon deployment. Prior to 2011, nursing and midwifery students received minimal exposure to PHC settings in Lesotho. In 2010, the Maternal and Child Health Integrated Program began working with nurses' training institutions to support PHC clinical placements. Between April 2013 and June 2014, a multi-methods study was conducted to describe the effect of PHC placements on students and preceptors. The study employed qualitative methods, namely seven focus group discussions (FGDs), held with 69 students and preceptors. Data analysis followed the principles of grounded theory. Students, nurse educators and preceptors perceived PHC clinical placements as appropriate settings for acquisition of a variety of country relevant clinical experiences for nurses and midwives in Lesotho. Students expressed their likelihood to accept deployment at PHC settings post-graduation. Preceptors indicated that PHC clinical placements re-enforced the importance of continuing education for practicing clinicians. The placements supported an increase in competence and confidence of nursing and midwifery students, which will likely aid their transition into the workforce and perhaps increase the likelihood for the young professionals to accept deployment to these areas post graduation. Given the disease burden in Lesotho and that majority of Basotho people access healthcare at the PHC level, every effort should be taken to ensure that nursing and midwifery students get adequate exposure to health care provision at these facilities. PMID- 29127897 TI - Highly efficient charge transfer in Co/Co2P Schottky junctions embedded in nitrogen-doped porous carbon for enhancing bioelectricity generation. AB - Exploration of noble-metal free catalysts with high oxygen reduction reaction (ORR) activity and durability as alternatives for platinum/carbon (Pt/C) in microbial fuel cells (MFCs) remains a great challenge. This study reports the preparation of nitrogen-doped cobalt/cobalt phosphide/carbon (Co/Co2P/NC) catalysts via an in situ simultaneous doping/reduction method by using residual cornstalks as carbon source. Effects of carbonization temperature on structural characteristics and catalytic activity of Co/Co2P/NC catalysts are investigated. Co/Co2P/NC-850 with regular network structure obtains the maximum power density of 972 +/- 5mWm-2, which is higher than that of Pt/C (808 +/- 5mWm-2). The highest Coulombic efficiency (23.1%) and the lowest charge transfer resistance (0.93Omega) are also obtained by Co/Co2P/NC (850 degrees C). ORR catalyzed by Co/Co2P/NC-850 is mainly via 4e- reduction pathway. The better durability of Co/Co2P/NC (850 degrees C) is detected from long-term operation of MFCs. The promising catalytic activity for ORR is attributed to the introduction of Co/Co2P nanoparticles/Schottky junctions and N species in porous carbon skeleton, which are served as active sites to trap and consume electrons. Biomass-derived carbon with good electrical conductivity can provide large specific surface area and abundant interconnected holes, which contribute to efficient permeation and transport of O2. The synergistic effects between porous structure and sufficient active sites can energetically boost catalytic activity to improve ORR efficiency. These Co/Co2P/NC catalysts with durable power outputs are expected to have more extensive applications in MFCs. PMID- 29127898 TI - Capacitive aptasensor based on interdigitated electrode for breast cancer detection in undiluted human serum. AB - We report the development of a simple and powerful capacitive aptasensor for the detection and estimation of human epidermal growth factor receptor 2 (HER2), a biomarker for breast cancer, in undiluted serum. The study involves the incorporation of interdigitated gold electrodes, which were used to prepare the electrochemical platform. A thiol terminated DNA aptamer with affinity for HER2 was used to prepare the bio-recognition layer via self-assembly on interdigitated gold surfaces. Non-specific binding was prevented by blocking free spaces on surface via starting block phosphate buffer saline-tween20 blocker. The sensor was characterized using cyclic voltammetry, electrochemical impedance spectroscopy (EIS), atomic force microscopy and contact angle studies. Non Faradic EIS measurements were utilized to investigate the sensor performance via monitoring of the changes in capacitance. The aptasensor exhibited logarithmically detection of HER2 from 1pM to 100nM in both buffer and undiluted serum with limits of detection lower than 1pM. The results pave the way to develop other aptamer-based biosensors for protein biomarkers detection in undiluted serum. PMID- 29127899 TI - Robust immunosensing system based on biotin-streptavidin coupling for spatially localized femtogram mL-1 level detection of interleukin-6. AB - Detection of a very low amount of cytokines such as interleukin-6 (IL-6) in clinical fluids is important in biomedical research and clinical applications. Here, we demonstrate spatially-localized ultrasensitive (femtogram mL-1) level detection of IL-6 in serum and in cell culture media. Our approach is based on a sandwich immunosensor fabricated on the surface of an optical fibre. Firstly, the biotinylated IL-6 capture antibody was immobilized on the fibre surface by biotin streptavidin coupling. Then the fabricated fibre was used for capturing IL-6 followed by exposure to detection antibody which was labeled with the fluorescent magnetic nanoparticles to report the signal. A linear relationship between IL-6 concentration and the fluorescence signal was obtained in the range from 0.4pgmL 1 to 400pgmL-1 of IL-6, with the limit of detection down to 0.1pgmL-1. In addition, this optical fibre sensor was successfully applied for the localized detection of IL-6 with the spatial resolution of 200um and a sample volume of 1uL. Finally, the performance of the fibre sensor was demonstrated by detection of IL-6 secreted by BV-2 cells with comparable performance of the conventional enzyme-linked immunosorbent assay (ELISA). PMID- 29127900 TI - A reusable ratiometric electrochemical biosensor on the basis of the binding of methylene blue to DNA with alternating AT base sequence for sensitive detection of adenosine. AB - We develop a reusable ratiometric electrochemical biosensor on the basis of the binding of methylene blue (MB) to DNA with alternating AT base sequence for sensitive detection of adenosine. We design a strand 1 with MB-modified thymine (T) base in the proximal 3' termini as the capture probe for its immobilization on the gold electrode and a 3' termini ferrocene (Fc)-modified aptamer for the recognition of adenosine. The hybridization of strand 1 with the aptamer leads to the formation of a double-stranded DNA (dsDNA) and consequently the away of MB from the electrode surface and the close of Fc to the electrode surface, generating a small value of IMB/IFc (IMB and IFc are the peak currents of MB and Fc, respectively). In the presence of adenosine, its binding with the aptamer induces the release of Fc from the electrode surface and the close of MB to the electrode surface, generating a large value of IMB/IFc. As a result, adenosine may be accurately quantified by the measurement of ratiometric signal (IMB/IFc). This ratiometric electrochemical biosensor can be simply fabricated and exhibits high sensitivity with a limit of detection of as low as 90.8pM and a large dynamic range from 0.1nM to 100MUM. Moreover, this biosensor demonstrates good performance with excellent selectivity, regeneration capability, high reliability and good reproducibility, and may become a universal platform for the detection of various biomolecules which can be recognized by aptamers, holding great potential for further applications in biomedical research and clinical diagnosis. PMID- 29127901 TI - Cerium dioxide-doped carboxyl fullerene as novel nanoprobe and catalyst in electrochemical biosensor for amperometric detection of the CYP2C19*2 allele in human serum. AB - The disposition dose of clopidogrel is different in CYP2C19*2 gene carriers and non-carriers. High-dose clopidogrel has been recommended to overcome a low responsiveness to clopidogrel in patients with the CYP2C19*2 gene. To guide the choice of clopidogrel dosage and catalyse a development in the field of personalized therapy, we developed an ultrasensitive electrochemical biosensor to detect CYP2C19*2 gene. We constructed a novel assay based on cerium dioxide (CeO2)-functionalized carboxyl fullerene (c-C60) supported by Pt nanoparticles (c C60/CeO2/PtNPs) for signal amplification. Au nanoparticles @ Fe-MIL-88NH2 (AuNPs@Fe-MOFs) were synthesized by one-step method as the support platform to enhance the conductivity and immobilize more biotin-modified capture probe (bio CP) through the superior affinity and specificity between streptavidin and biotin. c-C60/CeO2/PtNPs were labeled with signal probe to form the signal label. After the sandwich reaction of CYP2C19*2 gene between capture probe and the signal label, a distinguishing electrochemical signal from the catalysis of H2O2 by signal label would be observed. Amperometry was applied to record electrochemical signals. Under optimized conditions, the approach showed a good linear dependence between current and the logarithm of CYP2C19*2 gene concentrations in the range of 1 fM to 50nM with a low detection limit of 0.33fM (S/N = 3). The proposed method showed good specificity to target DNA compared with possible interfering substances. More importantly, the fabricated biosensor achieved accurate quantitative detection of CYP2C19*2 gene in human serum samples demonstrated by excellent correlations with standard DNA sequencing and provided a promising strategy for electrochemical biosensor detection of other gene mutations. PMID- 29127902 TI - A survey of machine learning applications in HIV clinical research and care. AB - A wealth of genetic, demographic, clinical and biomarker data is collected from routine clinical care of HIV patients and exists in the form of medical records available among the medical care and research communities. Machine learning (ML) methods have the ability to identify and discover patterns in complex datasets and predict future outcomes of HIV treatment. We survey published studies that make use of ML techniques in HIV clinical research and care. An advanced search relevant to the use of ML in HIV research was conducted in the PubMed biomedical database. The survey outcomes of interest include data sources, ML techniques, ML tasks and ML application paradigms. A growing trend in application of ML in HIV research was observed. The application paradigm has diversified to include practical clinical application, but statistical analysis remains the most dominant application. There is an increase in the use of genomic sources of data and high performance non-parametric ML methods with a focus on combating resistance to antiretroviral therapy (ART). There is need for improvement in collection of health records data and increased training in ML so as to translate ML research into clinical application in HIV management. PMID- 29127903 TI - Causes of EHR projects stalling or failing: A study of EHR projects in Saudi Arabia. AB - BACKGROUND: Electronic Medical Records (EMRs) are designed to automatically collect, store, and retrieve patients' information from healthcare providers within an organization. They assist clinicians in deciding the future course of treatment. The primary objective of this study is to investigate the practices of Electronic Health Record (EHR) project managers regarding the causes of EHR projects getting stalled or failing in Saudi Arabia. METHODS: Three focus groups were identified across three main cities of Saudi Arabia, namely Riyadh, Jeddah, and Dammam during the years 2013 and 2014. Each group consisted of 10-15 experienced EHR project managers. Qualitative analysis consisted of immersion and crystallization to develop a coding scheme that included both preconceived and emergent themes. RESULTS AND CONCLUSION: The findings of this study highlight the difficulties, which ensue between EHR and project management practice as well as the issues that can arise from the common use of these terms. It highlights how the aims of an EHR project and its management are transformed, and how the reputation of the project management is to achieve the exact and short-term objectives associated with the comprehensive aims of an EHR project. PMID- 29127904 TI - Pharmacokinetics and brain uptake study of novel AMPA receptor antagonist perampanel in SD rats using a validated UHPLC-QTOF-MS method. AB - Perampanel (PER) is a novel AMPA receptor antagonist for antiepileptic therapy and is prospective for the treatment of other neurological disorders. A highly sensitive and rapid UHPLC-QTOF-MS method was developed for the quantification of PER in plasma/brain homogenate of SD rat with alogliptin as an internal standard (IS). Chromatographic separation was carried out on an Acquity UPLC HSS Cyano column (100mm*2.1mm, 1.8MUm) using gradient mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0. 4mL/min. Sample preparation was carried out by a simple protein precipitation method. The mass spectrometric analysis of target ions at [M+H]+m/z 350.1288 for PER and m/z 340.1779 for IS was monitored with extracted ion chromatography. The developed analytical method meets the US-FDA and EMA bioanalytical guidelines and was found to be precise, accurate, selective and rugged. It exhibited good sensitivity (0.4ng/mL) and linearity over a range of 0.4-400ng/mL in both the bio-matrices. The method was successfully applied to pharmacokinetics and brain uptake study of PER after oral administration to SD rats. The study results showed PER has penetrated the blood brain barrier, brain to plasma ratio (Kp) was found to be 0.62+/-0.05 and its rapidly eliminated from the brain. PMID- 29127905 TI - Dissolution studies of metamizole sodium and pseudoephedrine sulphate dosage forms - comparison and correlation of electronic tongue results with reference studies. AB - This work reports a critical evaluation of the results of the release of active substances (APIs) from novel pharmaceutical formulations provided by an electronic tongue system (ET). Detailed dissolution studies of modified-release granules used in pharmacotherapy containing metamizole sodium and pseudoephedrine sulphate were carried out. The impact of the dissolution-modifying excipients (carmellose sodium and hypromellose) on the dissolution process as well as on the outcomes of the sensor array of ion-selective electrodes was investigated. The obtained dissolution profiles were compared and correlated with those registered during the reference studies performed according to the pharmacopoeial method. It was pointed out that the proper evaluation of the efficiency of the release modification requires the examination of dosage forms as well as physical mixtures of API and excipient. Moreover, the results obtained using potentiometric ET were complementary to the classical methodology. Their partial inconsistency, remarked during several experiments, should be interpreted with caution owing to simultaneous sensing of APIs and excipients by the sensors and their various performances (i.e. selectivity and sensitivity) towards these components. PMID- 29127906 TI - Exploring the intermolecular interactions acting in solvent-modified MEKC by Molecular Dynamics and NMR: The effect of n-butanol on the separation of diclofenac and its impurities. AB - An integrated approach involving CE experiments, Molecular Dynamics (MD) simulations and two-dimensional NOE spectroscopy (2D-NOESY) experiments was employed to elucidate the intermolecular interactions and the separation mechanisms involved in a solvent-modified MEKC method for the simultaneous determination of diclofenac sodium and its impurities. The CE findings indicated that the addition of n-butanol (nBuOH) to the SDS micellar solution played a primary role for controlling the partitioning into the mixed micelles and the migration of the analytes and that the presence of nBuOH as cosurfactant was compulsory for achieving the complete separation of the compounds. The different capacity factors of the analytes were calculated and a change in solute association with the mixed micelle when changing the SDS/nBuOH molar ratio was highlighted. The optimal SDS/nBuOH molar ratio for the electrophoretic separation was 1:8. On the other hand, both MD simulations and NMR experiments indicated that the most favorable molar ratio for the formation of mixed SDS/nBuOH micelles was 1:2. These results suggested that probably there is an excess of nBuOH in the background electrolyte, both as free molecules and in form of aggregates, which is able to interact with the analytes, and thus may compete with mixed micelles for the considered compounds. The calculated values of gain in potential energy of the analytes when included in mixed micelles were in agreement with the observed migration order of the compounds. The role of methyl-beta-cyclodextrin (MbetaCyD) in the background electrolyte was also investigated, since the addition of this CyD to the solvent-modified MEKC system was found to be useful to reduce the analysis time. MD simulations and 2D-NOESY spectra highlighted the formation of inclusion complexes with MbetaCyD not only with the analytes, but also with SDS. MbetaCyD may lower the availability of both SDS and nBuOH for forming micelles and mostly may compete with the mixed micelle as a second pseudostationary phase. PMID- 29127907 TI - Synthesis of carbon quantum dots-doped dummy molecularly imprinted polymer monolithic column for selective enrichment and analysis of aflatoxin B1 in peanut. AB - In this study, a novel method was proposed to sensitively determine aflatoxin B1 (AFB1) in peanut sample by using a carbon quantum dots-coated dummy molecularly imprinted polymer (CDs-DMIP) monolithic column for pretreatment coupled with high performance liquid chromatography-fluorescence detection (HPLC-FLD). The CDs-DMIP monolithic column was prepared by in-situ polymerization in a water bath using 5,7-dimethoxycoumarin as dummy template molecule. The CDs-DMIP monolithic column was applied to determine AFB1 by HPLC-FLD. Satisfactory linearity was obtained over 0.5-2000ngmL-1, with a high correlation coefficient of 0.9999. The recoveries of AFB1 in peanut sample ranged from 79.5% to 91.2%, and the intraday and interday relative standard deviation ranged from 1.2% to 4.9%. Limit of detection (S/N=3) and limit of quantitation (S/N=10) were 0.118ngmL-1 and 0.393ngmL-1, respectively. Under the optimized conditions, the enrichment factor was over 71-fold. AFB1 in peanut sample and even some other samples could be sensitively determined by CDs-DMIP-HPLC-FLD method. PMID- 29127908 TI - Development and validation of a stability-indicating HPLC-UV method for the determination of triamcinolone acetonide and its degradation products in an ointment formulation. AB - A stability indicating high performance liquid chromatography method has been developed for the determination of triamcinolone acetonide (TCA) and its main degradation products in ointment formulations. The method, based on extensive stress testing using metal salts, azobisisobutyronitrile, acid, base and peroxide, showed that TCA undergoes oxidative degradation. All degradation products were identified using HPLC mass spectrometry. Separation and quantification was achieved using an Altima C18 RP18 HP column (250*4.6mm2, with 5MUm particles) using a mobile phase consisting of acetonitrile and water buffered at pH 7 using 10mM phosphate buffer. A gradient mode was operated at a flow rate of 1.5ml/min and detection was at 241nm. The method showed linearity for TCA and Impurity C in 0.02-125% of the workload, both square roots of the correlation coefficients were larger than 0.9999. Repeatability and intermediate precision were performed by six consecutive injections of both 1.25% and 125% of the work load for both TCA and Impurity C divided equally over two days. RSD were 0.6% and 0.7% for TCA and 0.5% and 0.1% for Impurity C respectively. Accuracy was determined as well, the average recoveries were 99.5% (+/-0.1%, n=3) for TCA and 96.9% (+/-1.3%, n=3) for impurity C respectively from spiked ointment samples. The robustness was also evaluated by variations of column (old vs new), mobile phase pH and filter retention. The applicability of the method was evaluated by analysis of a commercial ointment formulation. Interestingly, the extensive stress tests were able to predict all degradation products of TCA in a long term stability ointment sample. PMID- 29127909 TI - What is in a name?: The development of cross-cultural differences in referential intuitions. AB - Past work has shown systematic differences between Easterners' and Westerners' intuitions about the reference of proper names. Understanding when these differences emerge in development will help us understand their origins. In the present study, we investigate the referential intuitions of English- and Chinese speaking children and adults in the U.S. and China. Using a truth-value judgment task modeled on Kripke's classic Godel case, we find that the cross-cultural differences are already in place at age seven. Thus, these differences cannot be attributed to later education or enculturation. Instead, they must stem from differences that are present in early childhood. We consider alternate theories of reference that are compatible with these findings and discuss the possibility that the cross-cultural differences reflect differences in perspective-taking strategies. PMID- 29127910 TI - Evaluation of the efficacy and safety of beta-d-mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized, placebo-controlled, phase I/II clinical trial. AB - OBJECTIVE: To evaluate the efficacy, safety and tolerability of beta-d-mannuronic acid (M2000) in the treatment of ankylosing spondylitis (AS). METHODS: The study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, beta-d-mannuronic acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. RESULTS: Of the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 beta-d-mannuronic acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving beta-d-mannuronic acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P>0.05) and 19% of the patients in the placebo group (P=0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving beta-d-mannuronic acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, beta-d-mannuronic acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on beta-d-mannuronic acid and placebo. CONCLUSION: The present study demonstrated similar efficacy, but with a more favorable safety profile for beta-d-mannuronic acid than naproxen and, therefore, suggest that beta-d mannuronic acid is suitable for the management of AS. TRIAL REGISTRATION: Iranian registry of clinical trials; www.irct.ir; IRCT2013062213739N1. PMID- 29127912 TI - Pesticides contaminated dust exposure, risk diagnosis and exposure markers in occupational and residential settings of Lahore, Pakistan. AB - There are few studies documenting the dust loaded with pesticides as a potential non-dietary exposure source for occupational worker and populations living near agricultural farms and pesticides formulation plants. In present study we have evaluated the pesticide concentration in dust from potential sites and relevant health risk from dust ingestion. Furthermore, the effect of currently used pesticides was investigated on blood and urine parameters of subjects: farmer, factory worker, urban resident and rural resident and controlled subjects with presumably different levels of exposure. The urinary metabolites (TCPY and IMPY) were quantified as biomarkers of exposure to chlorpyrifos and diazinon in relation with biomarkers of effect including BuChE, LH, FSH, testosterone and oxidative stress. Results showed that chlorpyrifos and diazinon were present in higher concentration in dust and posed a high health risk to exposed subjects. The mean SOD value was high among the farmer (3048U/g Hb) followed by factory worker (1677.6U/g Hb). The urinary biomarkers - TCPY and IMPY- were found higher in exposed subjects as compared to control. Furthermore, testosterone was found in higher concentration in factory worker than control (12.63ng/ml vs 4.61ng/ml respectively). A decreased BuChE activity was noticed in occupational group and significant differences were observed in control verses exposed subjects. The PCA analysis evidenced the impact of pesticides on exposure biomarkers and male reproductive hormones. The study suggests that dust contaminated with pesticides engenders significant health risk particularly related to the nervous and endocrine system, not only for occupational workers exposed to direct ingestion but also for nearby residential community. Succinctly putting: Pesticides loaded dust in the city of Lahore, being a high priority concern for the government of Pakistan, demands to be addressed. PMID- 29127913 TI - The role of career adaptability and courage on life satisfaction in adolescence. AB - The present study aimed to extend understanding about the relationship between career adaptability, courage, and life satisfaction in a sample of Italian adolescents. It was hypothesized that courage partially mediated the relationship between career adaptability and life satisfaction. Specifically, 1202 Italian high school students with an age from 14 to 20 years (M = 16.87; SD = 1.47), of which 600 (49.9%) boys and 602 (50.1%) girls, were involved. Using a multigroup approach across gender, it was found that courage partially mediated the relationship between career adaptability and life satisfaction in boys and girls. Results suggested the relevance of career interventions to promote career adaptability and courage for strengthening life satisfaction in adolescence. PMID- 29127911 TI - Healthy minds from 0-100 years: Optimising the use of European brain imaging cohorts ("Lifebrain"). AB - The main objective of "Lifebrain" is to identify the determinants of brain, cognitive and mental (BCM) health at different stages of life. By integrating, harmonising and enriching major European neuroimaging studies across the life span, we will merge fine-grained BCM health measures of more than 5,000 individuals. Longitudinal brain imaging, genetic and health data are available for a major part, as well as cognitive and mental health measures for the broader cohorts, exceeding 27,000 examinations in total. By linking these data to other databases and biobanks, including birth registries, national and regional archives, and by enriching them with a new online data collection and novel measures, we will address the risk factors and protective factors of BCM health. We will identify pathways through which risk and protective factors work and their moderators. Exploiting existing European infrastructures and initiatives, we hope to make major conceptual, methodological and analytical contributions towards large integrative cohorts and their efficient exploitation. We will thus provide novel information on BCM health maintenance, as well as the onset and course of BCM disorders. This will lay a foundation for earlier diagnosis of brain disorders, aberrant development and decline of BCM health, and translate into future preventive and therapeutic strategies. Aiming to improve clinical practice and public health we will work with stakeholders and health authorities, and thus provide the evidence base for prevention and intervention. PMID- 29127914 TI - The differential influence of absent and harsh fathers on juvenile delinquency. AB - Researchers have identified father absence as a contributor to juvenile delinquency. Consequently, politicians and community leaders are making efforts to re-engage fathers. However, it is possible that the presence of fathers is not, in itself, a substantial protective factor and, in some cases, can even be more detrimental than father absence. Employing a diverse sample of male juvenile offenders in the U.S. (ages 13-17), the present study examined the differential effects of absent fathers and harsh fathers on delinquency. Results indicated that youth in the harsh-father group engaged in more offending behaviors and used more substances than youth in the absent-father group. This difference remained even after controlling for the mother-child relationship. Implications of these findings for future research and delinquency prevention programs are discussed. PMID- 29127915 TI - Sigmoid perforation caused by dentures-A rare case report. AB - Rare case of an elderly male presenting to the emergency department with an acute abdomen few days post accidental ingestion of his dentures. A detailed history along with a CT abdomen showed perforation in the sigmoid colon adjacent to the site of the swallowed denture. PMID- 29127916 TI - Laparoscopic management of a small bowel obstruction secondary to Elipse intragastric balloon migration: A case report. AB - INTRODUCTION: The ElipseTM intragastric balloon (IGB) for weight loss is a swallowable capsule that is filled with 550mL of fluid and resides in the stomach for four months before being excreted from the gastrointestinal tract. Although initial data showed that use of this device is safe and free from serious complications, we report for the first time the successful management of an ElipseTM IGB-related adverse event. PRESENTATION OF CASE: A 41-year-old woman presented to our emergency department following two days of abdominal pain, vomiting, and constipation. Her medical history included four caesarean sections and insertion of the ElipseTM IGB 16 weeks prior to presentation. The patient was vitally stable at presentation and abdominal examination revealed a mildly distended abdomen. Plain X-ray revealed a small bowel obstruction (SBO), and a double contrast computed tomography scan showed a dilated small bowel with mild free fluid proximal to a transition zone at the distal jejunum. Laparoscopic enterotomy was performed just proximal to the obstruction site, and the balloon was visualized and extracted after it had been incised and emptied. The enterotomy incision was closed with an intracorporeal continuous absorbable suture. The patient's recovery was uneventful and she was discharged on postoperative day 4. DISCUSSION: We discuss the possible etiologies of SBO following ElipseTM IGB insertion, and present a brief literature review regarding surgical and nonsurgical management options for such cases. CONCLUSION: Although initial data showed the ElipseTM IGB to be safe, complications can occur and be managed successfully. PMID- 29127917 TI - A giant mediastinal liposarcoma weighing 3500g resected with clam shell approach, a case report with review of literature. AB - INTRODUCTION: Liposarcoma is rare in the mediastinum and is less than 1% of all mediastinal tumors. In the present report, we demonstrated our case and summarized the principal treatment of the mediastinal liposarcoma with literature review. PRESENTATION OF CASE: A 50-year-old man presented at our hospital with complain of dyspnea. Chest radiography showed remarkable cardiomegaly. Computed tomography revealed an anterior mediastinal tumor from the level of the cephalic vein to the diaphragm of bilateral thoracic cavity with fat component. Using clam shell approach, complete en bloc resection of the tumor was performed. The weight of the tumor was 3500g. The pathological findings were 0that size of adipocyte and lipoblast were different, and the nuclei of atypical stromal cell were misshapen. Immune-histologic examination was negative for MDM2 and cyclin dependent kinase 4. The diagnosis was liposarcoma, well-differentiated type. He could discharge 10days after surgery. Without adjuvant therapy, disease free survival for three years has passed. DISCUSSION: From 1990-2016 in Japan, 60 cases of the mediastinal liposarcoma were reported. In analysis of the 61 cases including the present case, adjuvant therapy was performed in 14 cases, subsequently, and recurrence was recognized in 5 cases. Adjuvant therapy did not significantly suppress the recurrence. CONCLUSION: Mediastinal liposarcoma weighing 3500g could be resected using calm shell approach, and no recurrence interval for 3 years has been achieved without adjuvant therapy. Complete resection is the only means to achieve the favorable outcome in mediastinal liposarcoma. PMID- 29127918 TI - Management of type IIB and IIIB olecranon fractures. Case series. AB - OBJECTIVES: to report and evaluate the functional outcome of plate fixation in comminuted olecranon fractures (Mayo types IIB and IIIB). METHOD: 23 consecutive patients with comminuted fractures of the olecranon presenting to our unit Between Feb 2011 and Jan 2015, at a mean follow-up of thirty-six months. Main outcome measurements include radiographic healing, post-operative range of motion, complications, outcome score and patient satisfaction. RESULTS: Our study included thirteen females and ten males with a mean age of 55(18-97). Fourteen were Mayo type IIB and nine were Mayo type IIIB. Eighteen patients had no complications post-operatively with good outcome with mean oxford score of 45, full rotational ROM and mean flexion arc of 20-130 degrees . Five patients had range of motion between 40-90 degrees with full rotational ROM and mean oxford score of 24. Two patients out of five required metal work removal. No non-unions were noted in our series. CONCLUSION: Plate fixation of complex olecranon fracture is an effective, reliable method of treatment with low risk of non union. Restoration of a functional flexion arc of movement can be expected with application of correct technique. PMID- 29127919 TI - A case report of a de Garengeot hernia in a nonagenarian veteran. AB - INTRODUCTION: A hernia containing the vermiform appendix [de Garengeot hernia (DGH)] is an exceedingly rare event. Appendicitis occurring in this setting if further unusual. Most cases of DGH are made during inguinal exploration. In the present report, we discuss a patient who underwent an operation which revealed a DGH with appendicitis. PRESENTATION OF A CASE: A 94-year-old man with a past medical history significant for hypertension and Parkinson's disease was admitted to the hospital for the management of an event of CHF exacerbation. He developed acute onset of a painful right inguinal bulge. He had no prior hernia history. On physical exam, he had a 3-cm, tender, non-reducible right inguinal bulge without skin changes. Laboratory analyses were normal without leukocytosis. An acute abdominal series was obtained and demonstrated no obstruction. A groin exploration was performed under local anesthetic. An abscess was found associated with a femoral hernia containing the vermiform appendix. An appendectomy was performed through the hernia sac. The hernia was repaired via a McVay technique. At thirty days after his procedure, he had no complications and no signs of recurrence. CONCLUSION: Most cases of DGH are diagnosed intraoperatively. Limited work up might be sufficient for adequate management. Several surgical strategies are acceptable. Groin exploration, plus and minus an appendectomy, and tissue repair versus mesh placement are acceptable surgical strategies. Laparoscopic approach for the management of DGH has been reported. PMID- 29127920 TI - Uptake and phytotoxic effect of benzalkonium chlorides in Lepidium sativum and Lactuca sativa. AB - Cationic surfactants such as benzalkonium chlorides (BACs) are used extensively as biocides in hospitals, food processing industries, and personal care products. BACs have the potential to reach the rooting zone of crop plants and BACs might thereby enter the food chain. The two most commonly used BACs, benzyl dimethyl dodecyl ammonium chloride (BDDA) and benzyl dimethyl tetradecyl ammonium chloride (BDTA), were tested in a hydroponic system to assess the uptake by and phytotoxicity to lettuce (Lactuca sativa L.) and garden cress (Lepidium sativum L.). Individually and in mixture, BACs at concentrations up to 100 mg L-1 did not affect germination; however, emergent seedlings were sensitive at 1 mg L-1 for lettuce and 5 mg L-1 for garden cress. After 12 d exposure to 0.25 mg L-1 BACs, plant dry weight was reduced by 68% for lettuce and 75% for garden cress, and symptoms of toxicity (necrosis, chlorosis, wilting, etc.) were visible. High performance liquid chromatography-mass spectroscopy analysis showed the presence of BACs in the roots and shoots of both plant species. Although no conclusive relationship was established between the concentrations of six macro- or six micro-nutrients, growth inhibition or BAC uptake, N and Mg concentrations in BAC treated lettuce were 50% lower than that of control, indicating that BACs might induce nutrient deficiency. Although bioavailability of a compound in hydroponics is significantly higher than that in soil, these results confirm the potential of BACs to harm vascular plants. PMID- 29127922 TI - Photo- and chemocatalytic oxidation of dyes in water. AB - Three commonly used dyes, Acid Red-114 (AR-114), Reactive Black-5 (RB-5), and Disperse Black EX-SF (DB-EX-SF), were treated in a pH-neutral liquid with ultraviolet (UV) light by two reactive methods: photocatalysis with titanium dioxide (TiO2), and/or chemocatalysis with hydrogen peroxide (H2O2) as the oxidant and various ferrous-based electron mediators as catalysts. Important factors for dye oxidation were determined through bifactorial experiments. The optimum combinations and doses of the three key reagents, namely TiO2, H2O2, and EDTA-Fe, were also determined. The degradation kinetics of the studied dyes at their optimum doses reveal that the oxidation reactions are pseudo-first-order in nature, and that certain dyes are selectively degraded more by one method than the other. The overall results suggest that co-treatment using more than one oxidative method is beneficial for the treatment of wastewater from dyeing processes. PMID- 29127921 TI - Greywater characterization and generation rates in a peri urban municipality of a developing country. AB - The quantity and quality of combined greywater from houses with in-house water supply and houses that rely on external sources of a peri-urban area in a developing country were determined. Data for quantity of greywater was collected from 36 households while 180 samples of greywater were collected from 60 households between December 2016 and February 2017. The results indicate that, average water consumption from households with in-house access was 82.51 +/- 12.21 Lc-1d-1 while households which rely on external sources was 36.64 +/- 4.31 Lc-1d-1 with return factors of 74.16% and 88.57% respectively. Quality analysis also showed significant differences between greywater from the two sources with most of the quality parameters exceeding the regulatory limit. The ratio between biochemical oxygen demand (BOD5) and chemical oxygen demand (COD) ranged between 0.22 and 0.59 for greywater from in-house sources and 0.23-0.62 for external sources indicating low biodegradability of the greywater. The nutrients recorded exceeded the trigger levels for eutrophication while significant levels of microorganisms such as E. Coli and Salmonella spp. were also detected in both streams. Direct reuse of greywater for irrigation was found to be unsuitable based on the salinity and sodium hazard analysis. Principal component analysis of the data indicated that the characteristics of the combined greywater in the study area is influenced by cooking and cleaning practices, personal hygiene, biodegradability, frequency of water use before disposal and sanitary practices in the bathroom. The greywater discharged is detrimental to the environment and poses a health risk to humans and livestock. There is therefore the need for authorities involved to prioritize greywater management and treatment in peri urban areas of developing countries. PMID- 29127923 TI - In-situ capture and conversion of atmospheric CO2 into nano-CaCO3 using a novel pathway based on deep eutectic choline chloride-calcium chloride. AB - This study presents a newfangled method and provides a new approach toward capturing-entrapping the toxic and harmful greenhouse gas CO2 and subsequently employing it as a useful precursor for the production of value-added calcite (CaCO3) nanoparticles. All the processes are done in a single system (one-pot and in-situ processing) based on deep eutectic choline chloride-calcium chloride (Calcoline) at mild temperature of 50 degrees C in direct contact with air. The Calcoline eutectic mixture shows the calcite production yield of 6.2 mg/ml that is reduced up to 22.6% upon recycling. The eutectic mixture provides an interesting all-in-one system acting as carbon dioxide trapper/adsorbent, solvent to solubilize CO2, and reagent to convert solubilized CO2 into pure calcite nanoparticles with average particle size of 30 nm. The featured properties of the developed method including simplicity, recyclability, mobility, affordability, and sustainability make it feasible for large scale applications by which the simultaneous elimination of CO2 from the environment and conversion of it into value added nano-products will be practicable. PMID- 29127924 TI - Application of peroxymonosulfate-ozone advanced oxidation process for simultaneous waste-activated sludge stabilization and dewatering purposes: A comparative study. AB - In this study, the efficiency of the Peroxymonosulfate-ozone (PMS+O3) advanced oxidation process in lab scale by the aim of stabilization and dewatering the biological excess sludge was investigated and the results were compared with persulfate-ozone (PS+O3), hydrogen peroxide-ozone (H2O2+O3) and ozonation (O3) processes. The results show that the PMS+O3 is more effective than other mentioned procedures. Therefore, under optimized conditions (pH = 11, PMS/O3 = 0.06 and Dose O3 = 12.5 mmol), VS (Volatile solids) and fecal coliforms reduced respectively 42% and 89% after 60 min and the stabilized sludge in term of pathogen reduction requirements was class B. Furthermore, time to filter (TTF) of sludge decreased 70% relative to the raw sludge. In order to demonstrate the dewatering conditions' improvement, the variations of particle size distribution, extracellular polymeric substances (EPS) and zeta potential were evaluated. Overall, the results show that the PMS+O3 has the capability of stabilizing and dewatering the sludge simultaneously. PMID- 29127925 TI - Relationship between maturity and microbial communities during pig manure composting by phospholipid fatty acid (PLFA) and correlation analysis. AB - The dynamic of microbial community plays vital role during composting. We therefore conducted a combined study on the maturity of compost (by pig manure composting with covering matured compost) and the successions of microbial communities (via phospholipid fatty acid (PLFA)). Our results showed that pH, electrical conductivity (EC), NH4-N, and germination index (GI) were suitable indicators for compost maturity evalument. In addition, there was a closer correlation between maturity indexes (NH4-N and GI) and the microbial compositions (as evaluated by microbial PLFA). The regression predicting model for NH4-N used bacteria PLFA 15:0 and fungi PLFA 18:1omega9t (R2 = 0.98, P < 0.01) and for GI used fungi PLFA 18:1omega9t and 18:1omega9, 12 (R2 = 0.94, P < 0.01) as the evidences of good predictive ability. It also indicated that PLFA 18:1omega9t has a good relationship with the changes of NH4-N and GI during the composting. Our results revealed the potential of using microbial PLFA for evaluating the maturity during pig manure composting. PMID- 29127926 TI - Optimizing source-separated feces degradation and fertility using nitrifying microorganisms. AB - Resource-oriented sanitation (ROS) systems play an important role in handling source-separated human sanitary wastes intended to be used for other purposes. Usually, the purpose of employing such systems is to render the source-separated human feces suitable as fertilizer or soil conditioner. However, the high volume, low degradation rate, and lack of fertility management pose challenges to such enterprises. Accordingly, treatment by applying controlled amounts of nitrifying microorganisms could be useful. The effect of adding different amounts of Nitrosomonas Europaea bio-seed, along with a certain amount of Nitrobacter Winogradskyi bio-seed, to source-separated human feces was investigated. The results show that adding 7000-8000 or more N. Europaea cells, along with 10,000 N. Winogradskyi cells, to 1 g feces, resulted in up to 90% degradation of the organic matter by enhancing the growth of heterotrophic microorganisms. Moreover, the nitrogen composition and pH of the degraded feces were optimized to meet the criteria for standard fertilizer. The results can be useful for managing source separated feces in ROS systems in accordance with the specific aims of such systems, i.e., reducing feces volume by bio-degradation and increasing the fertility to meet the standard criteria for fertilizer. PMID- 29127927 TI - Hitching a ride: Seed accrual rates on different types of vehicles. AB - Human activities, from resource extraction to recreation, are increasing global connectivity, especially to less-disturbed and previously inaccessible places. Such activities necessitate road networks and vehicles. Vehicles can transport reproductive plant propagules long distances, thereby increasing the risk of invasive plant species transport and dispersal. Subsequent invasions by less desirable species have significant implications for the future of threatened species and habitats. The goal of this study was to understand vehicle seed accrual by different vehicle types and under different driving conditions, and to evaluate different mitigation strategies. Using studies and experiments at four sites in the western USA we addressed three questions: How many seeds and species accumulate and are transported on vehicles? Does this differ with vehicle type, driving surface, surface conditions, and season? What is our ability to mitigate seed dispersal risk by cleaning vehicles? Our results demonstrated that vehicles accrue plant propagules, and driving surface, surface conditions, and season affect the rate of accrual: on- and off-trail summer seed accrual on all-terrain vehicles was 13 and 3508 seeds km-1, respectively, and was higher in the fall than in the summer. Early season seed accrual on 4-wheel drive vehicles averaged 7 and 36 seeds km-1 on paved and unpaved roads respectively, under dry conditions. Furthermore, seed accrual on unpaved roads differed by vehicle type, with tracked vehicles accruing more than small and large 4-wheel drives; and small 4-wheel drives more than large. Rates were dramatically increased under wet surface conditions. Vehicles indiscriminately accrue a wide diversity of seeds (different life histories, forms and seed lengths); total richness, richness of annuals, biennials, forbs and shrubs, and seed length didn't differ among vehicle types, or additional seed bank samples. Our evaluation of portable vehicle wash units showed that approximately 80% of soil and seed was removed from dirty vehicles. This suggests that interception programs to reduce vehicular seed transportation risk are feasible and should be developed for areas of high conservation value, or where the spread of invasive species is of special concern. PMID- 29127928 TI - Native hypersaline sulphate reducing bacteria contributes to iron nanoparticle formation in saltpan sediment: A concern for aquaculture. AB - A hypersaline dissimilatory sulphate reducing bacterium, strain LS4, isolated from the sediments of Ribander saltpan, Goa, India was found to produce (Fe2O3) maghemite nanoparticles. The presence of maghemite nanoparticles was also detected in the same sediment. Strain LS4 was isolated anaerobically on modified Hatchikian's media at 300 psu, growing optimally at 30 degrees C, 150 psu salinity and pH 7.8. Based on biochemical characteristics and 16S rRNA sequence analysis, the strain LS4 belongs to genus Desulfovibrio. This isolate synthesized iron oxide nanoparticles in vitro when challenged with FeCl3 & FeSO4 in the growth medium. The biological nanoparticles were characterized to be Fe2O3 nanoparticle of 19 nm size by X-ray diffraction, transmission electron microscopy, fourier transform infrared spectroscopy, scanning electron microscopy and energy-dispersive x-ray spectroscopy. Maghemite nanoparticles (5.63 mg g-1) were isolated from the saltpan sediment by magnetic separation which showed similar characteristic features to the Fe2O3 nanoparticle produced by strain LS4 with an average size of 18 nm. Traditionally Goan saltpans were used for aquaculture during the non-salt making season, thus effects of these nanoparticles on Zebra fish embryo development were checked, which resulted in developmental abnormalities and DNA damage in a dose dependent manner. With the increasing nanoparticle concentration (0.1 mg.L-1 to100 mg.L-1), the mortality rate increased with a decrease in the hatching rate (93.05 +/- 2.4 to 25 +/- 4.16%) and heart rate (150-120 beats per minute). The nanoparticle exposed embryos developed malformed larvae with a characteristic of pericardial edema, curved body, curved notochord, curved tail and curved tail tip. These results suggest that strain LS4 might be playing a role as a contributor in the formation of iron oxide nanoparticle in the Ribander saltpan sediment, however; its high concentration will have a negative impact on aquaculture in these saltpans. PMID- 29127929 TI - Effective degradation of primary color direct azo dyes using Fe0 aggregates activated persulfate process. AB - The present study examined the oxidation power of a Fe0 aggregates/persulfate (PS/Fe0) system for the degradation of the wastewater containing mixed primary direct dyes (i.e., Sirius(r) Gelb S-2G, Sirius(r) Red F3B, and Sirius(r) Turkis GL01). Results indicated that decolorization efficiency was determined by operating parameters of the PS/Fe0 system and the structural complexity of dye molecules. System efficiency increased with increasing persulfate and Fe0 dosages. Faster decolorization was observed in experiments conducted at pH < 10. The process obeyed a first-order kinetics. Slow heterogeneous reactions were observed at high initial pH (>10.5) and low PS concentration (<2 * 10-3 M). Inhibitory effect occurred in systems containing salts Na2SO4, NaCl, Na2CO3, and Na2HPO4 at 1 * 10-2 M. The effect was suppressed when reaction temperature was raised to 55 degrees C. Heat enhanced not only decolorization efficiency, but also COD removal. Complete decolorization of a mixed dye containing ADMI (the American Dye Manufacture Institute) 15105 was achieved within10 min in the PS/Fe0/55 degrees C system with an initial pH of 6.0 and dosages of 5 * 10-3 M Na2S2O8 and 0.5 g/L Fe0. Low molecular weight intermediates including organic acids were identified. Due to a relatively low activation energy (4.68 kcaL/mol), the PS/Fe0 system exhibited higher efficiency at higher temperature. This study demonstrated that Fe0-activated PS is a promising process for the treatment of textile wastewaters containing mixed azo direct dyes. PMID- 29127930 TI - Indoor air quality of environments used for physical exercise and sports practice: Systematic review. AB - BACKGROUND: Systematic reviews have the potential to contribute substantially to environmental health and risk assessment. OBJECTIVE: This study aimed to investigate indoor air quality of environments used for physical exercise and sports practice through a systematic review. METHODS: The systematic review followed the PRISMA guidelines and was recorded in the PROSPERO registry (CRD42016036057). The search was performed using the SciELO, Science Direct, Scopus, LILACS, MEDLINE via PubMed, and SPORTDiscus databases, from their inception through April 2017. The search terms used in the databases were {air pollution" OR "air pollutants" OR "air quality"} AND {"physical exercise" OR "physical activity" OR "sport"}. The results of selected studies were divided into 5 categories for analysis: monitoring of air quality in the environment according to international guidelines, indoor-to-outdoor ratio (I/O), air quality during physical exercise, impact of air quality on health, and interventions to improve indoor air quality. RESULTS: Among 1281 studies screened, 34 satisfied the inclusion criteria. The monitoring of pollutants was conducted in 20 studies. CO and NO2 were the most investigated pollutants, and guidelines were discussed in most studies. The I/O ratio was investigated in 12 studies, of which 9 showed a higher concentration of some pollutants in indoor rather than outdoor environments. Among the 34 studies selected, only 7 investigated the impact of indoor air pollution on human health. The population in most of these studies consisted of hockey players. CONCLUSION: Most studies conducted monitoring of pollutants in indoor environments used for physical exercise and sports practice. The earliest studies were conducted in ice skating rinks and the most recent evaluated gymnasiums, fitness centers, and sports centers. The CO, particulate matter, and NO2 concentrations were the most investigated and have the longest history of investigation. These pollutants were within the limits established by guidelines in most studies. Studies that examined the association between air quality documented the adverse effects of pollution. There is a need for more studies focused on the relationship between pollution and health. PMID- 29127931 TI - Efficacy and tolerability of different doses of three new antidepressants for treating major depressive disorder: A PRISMA-compliant meta-analysis. AB - In last decade, the US FDA has approved three new antidepressants: vortioxetine, levomilnacipran, and vilazodone. Many studies have researched the effects of these antidepressants on major depressive disorder (MDD), but they have not determined the optimum dosage. This meta-analysis investigated the efficacies of these three drugs at different dosages in the treatment of MDD. The PubMed, Embase, Cochrane Library, psycINFO, and ClinicalTrials.gov databases were searched to identify relevant literature. The primary outcomes were efficacy [quantified as the change from baseline in total score on the Montgomery-Asberg Depression Rating Scale (MADRS)] and tolerability (discontinuations due to adverse events). The effect size was quantified as the weighted mean difference for continuous data and the risk ratio (RR) for dichotomous data. Overall 22 studies were included. The changes in the MADRS total score were significantly higher for vortioxetine at 5, 10, 20, and 10-20 mg/day than for placebo. The tolerability was significantly worse for 20 mg/day vortioxetine than for placebo (RR = 1.84, 95% confidence interval = 1.13 to 3.02). In addition, increasing the dosage improved the efficacy of vortioxetine but worsened the tolerability. Levomilnacipran and vilazodone at any dosage produced a significantly higher mean change from baseline in the MADRS total score and a worse tolerability than for placebo. In conclusion, considering both efficacy and tolerability, 10 mg/day vortioxetine might be optimal for the treatment of MDD. The long-term efficacy and safety of vortioxetine needed to be investigated, and more studies of levomilnacipran and vilazodone are needed to define their optimal dosages. PMID- 29127932 TI - The effects of different types of crop straw on the transformation of pentachlorophenol in flooded paddy soil. AB - The incorporation of various types of crop straw to agricultural soils has long been practiced to improve soil fertility. However, the effects of crop straw on the fate of organo-chlorine pesticides in flooded paddy soils are not well understood. The dechlorination of pentachlorophenol (PCP) in four vertical profiles (0-10, 10-20, 20-30, 30-50 mm depth) of two flooded paddy soils, a Plinthudult (Soil 1) and a Tropudult (Soil 2) was investigated following the application of four crop straws (rice, wheat, rape and Chinese milk vetch) to them. In all treatments, PCP dechlorination decreased with increasing soil depth. In the crop straw treatments, PCP was almost completely dechlorinated within 60 days, and rapidly transformed to 2,3,4,5-tetrachlorophenol, and further to 3,4,5 trichlorophenol. Further dechlorination of 3,4,5-trichlorophenol also occurred in all treatments except for the rape straw. It is possible that the NH4+ and NO3- derived from the straw are responsible for the inhibition of the 3,4,5 trichlorophenol dechlorination. The reduction of Fe (III) and SO42- increased following application of the crop straws. The RDA analysis indicated that the Fe (III) reducing bacteria might be involved in the ortho-dechlorination, while SO42 reducing bacteria were involved in para- and meta-dechlorination of PCP. The complete detoxification of PCP depended upon both the crop straw type and soil properties. PMID- 29127933 TI - Analysis of the relationships between environmental noise and urban morphology. AB - Understanding the effects of urban morphology on urban environmental noise (UEN) at a regional scale is crucial for creating a pleasant urban acoustic environment. This study seeks to investigate how the urban morphology influences the UEN in the Shenzhen metropolitan region of China, by employing remote sensing and geographic information data. The UEN in this study consists of not only regional environmental noise (RN), but also traffic noise (TN). The experimental results reveal the following findings: 1) RN is positively correlated with the nighttime light intensity (NTL) and land surface temperature (LST) (p < 0.05). More interestingly, landscape composition and configuration can also significantly affect RN. For instance, urban vegetation can mitigate the RN (r = 0.411, p < 0.01). There is a reduced RN effect when fewer buildings exist in an urban landscape, in terms of the positive relationship between building density and RN (r = 0.188, p < 0.01). Given the same percentage of building area, buildings are more effective at reducing noise when they are distributed across the urban scenes, rather than being spatially concentrated (r = -0.205, p < 0.01). 2) TN positively relates to large (r = 0.520, p < 0.01) and small-medium (r = 0.508, p < 0.01) vehicle flow. In addition, vegetation along or near roads can alleviate the TN effect (r = -0.342, p < 0.01). TN can also become more severe in urban landscapes where there is higher road density (r = 0.307, p < 0.01). 3) Concerning the urban functional zones, traffic land is the greatest contributor to urban RN, followed by mixed residential and commercial land. The findings revealed by this research will indicate how to mitigate UEN. PMID- 29127934 TI - Experimental manipulation of dietary arsenic levels in great tit nestlings: Accumulation pattern and effects on growth, survival and plasma biochemistry. AB - Arsenic (As) is a ubiquitous metalloid classified as one of the most hazardous substances, but information about its exposure and effects in free-living passerines is lacking. The aim of this study is to elucidate the effect of an As manipulation experiment on survival, growth and physiology of great tits (Parus major). Wild P. major nestlings inhabiting an unpolluted area were dosed with water, 0.2 or 1 MUg g-1 d-1 of sodium arsenite (Control, Low and High As groups), whereas those living in a metal-polluted area were dosed with water (Smelter group). Birds accumulated As in tissues (liver, bone and feathers) in a dose dependent way. Nestlings exposed to 1 MUg g-1 d-1 of sodium arsenite showed reduced number of fledglings per successful nest, and those exposed to 0.2 MUg g 1 d-1 had reduced wing growth, which could have post-fledging consequences such as increased predation risk. These results suggest that the LOAEL for effects on nestling survival and development in great tits is likely equal to or below 1 MUg g-1 d-1. However, limited effects on the biochemical parameters evaluated were found. It has been shown that As may produce oxidative stress and tissue damage, so further research exploring this issue will be carried out in a future study. PMID- 29127935 TI - Determinants of prenatal exposure to polybrominated diphenyl ethers (PBDEs) among urban, minority infants born between 1998 and 2006. AB - Polybrominated diphenyl ethers (PBDEs) are environmentally persistent chemicals that structurally resemble legacy pollutants, such as polychlorinated biphenyls (PCBs). PBDEs were added to consumer products for over 30 years, before being phased out due to evidence of toxicity. We examined temporal changes in prenatal exposure to PBDEs, as well as other sources of variation. We measured PBDEs in umbilical cord plasma from 327 minority infants born in New York City between 1998 and 2006. We used linear regression to examine changes in concentrations over time and in relation to lifestyle characteristics collected during pregnancy. We detected BDE-47 in 80% of samples with a geometric mean concentration of 14.1 ng/g lipid. Ethnicity was the major determinant of PBDE exposure; African American infants had 58% higher geometric mean cord plasma concentrations of BDE-47 (p < 0.01) compared to Dominican infants. Notably, African American mothers were more likely to be born in the United States, which itself was associated with 40% (p < 0.01) higher concentrations. We observed small decreases in PBDE concentrations by date of birth and no difference before and after their phase-out in 2004. Final multivariable models explained 8-12% of variability in PBDE concentrations depending on the congener. Our finding that prenatal exposure to PBDEs decreased only modestly between 1998 and 2006 is consistent with the persistent properties of PBDEs and their ongoing release from existing consumer products. PMID- 29127936 TI - Synthesis of N-(3-(4-[11C]methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a new potential PET agent for imaging of IRAK4 enzyme in neuroinflammation. AB - The reference standard N-(3-(4-methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (9) and its demethylated precursor N-(1-(5-methylpyridin-2-yl)-3-(piperazin-1-yl)-1H-pyrazol-5 yl)pyrazolo[1,5-alpha]pyrimidine-3-carboxamide (8) were synthesized from pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ethyl 2-cyanoacetate with overall chemical yield 13% in nine steps and 14% in eight steps, respectively. The target tracer N-(3-(4-[11C]methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5 yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ([11C]9) was prepared from its precursor with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 50-60% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/MUmol. PMID- 29127937 TI - Reduction-sensitive mixed micelles assembled from amphiphilic prodrugs for self codelivery of DOX and DTX with synergistic cancer therapy. AB - Clinically, codelivery of chemotherapeutics has been limited by poor water solubility and severe systemic toxicity. In this work, we developed a new reduction-sensitive mixed micellar system for self-codelivery of doxorubicin (DOX) and docetaxel (DTX). Biodegradable methoxy poly(ethylene glycol) poly(epsilon-caprolactone) (mPEG-PCL) was coupled with DOX and DTX by a reduction sensitive disulfide bond, resulting in mPEG-PCL-SS-DOX and mPEG-PCL-SS-DTX, respectively. mPEG-PCL-SS-DOX was mixed with mPEG-PCL-SS-DTX at a mole ratio of 1:1 in water, forming a mixed micellar system. The mixed micelles had a diameter of 223.7nm and a low critical micelle concentration. Reductive-triggered drug release revealed a "smart" characteristic of the mixed micelles. A cellular uptake and cytotoxicity assay in vitro showed that the mixed micelles could efficiently accumulate in MCF-7 cells and suppress the growth of tumour cells. The proposed reduction-sensitive mixed micelles assembled from amphiphilic prodrugs can be used as a promising drug codelivery system for cancer therapy. PMID- 29127939 TI - Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle. AB - The crude extract and some Chinese patented medicines of Leonurus japonicus Houtt. have been proven to affect the uterine smooth muscle. L. japonicus injection is widely used in obstetric departments in China for treating postpartum hemorrhage caused by uterine inertia. Bioassay-guided isolation of the 95% EtOH extract of L. japonicus yielded four cyclopeptides, nine alkaloids, and three flavonoid glycosides, including two previously undescribed cyclopeptides, namely, cycloleonuripeptide G and cycloleonuripeptide H. The structures of the cyclopeptides were elucidated to be cyclo-(L-Phe-L-Phe-Gly-L-Pro-Gly-L-Pro) and cyclo-(L-Phe-L-Ala-L-Pro-L-Ile-L-His-Gly-L-Ala-L-Pro), respectively, via spectroscopic and chemical methods. Cyclopeptides (cycloleonuripeptides C and D) and alkaloids (imperialine-3beta-D-glucoside and leonurine) promoted contraction of uterine smooth muscle strips isolated from normal rats. However, it was observed that flavonoid glycosides (spinosin, linarin, and apigenin-7-O-beta-D glucopyranoside) significantly inhibited contraction of the uterine smooth muscle strips. PMID- 29127938 TI - Caregiver feeding practices and weight status among African American adolescents: The Jackson Heart KIDS Pilot Study. AB - Adolescence is a stage in the life course during which youth become more autonomous in their health behaviors. Overweight and obesity during this developmental period are associated with short- and long-term physical and emotional morbidity, and African American youth are at pronounced risk for these health outcomes. The style of parenting employed by caregivers influences health behaviors in children, though the persistence of this influence into adolescence is not clear. This study examined associations among caregiver feeding practices, body mass index z-score (zBMI), and waist circumference (WC) in a cohort of 212 African American adolescents (50.5% girls; Mage=15.16years). Participants were children and grandchildren of individuals enrolled in the Jackson Heart Study, a prospective epidemiologic evaluation of cardiovascular disease among African Americans based in Jackson, Mississippi. Youth zBMI and WC were primary outcomes, and caregivers completed the Child Feeding Questionnaire, an assessment of attitudes, beliefs, and practices related to obesity proneness. Regression analyses revealed that while controlling caregiver feeding practices were associated with zBMI and WC, perceived responsibility for the type and amount of food provided to adolescents was not related to weight status. Among younger adolescents, more oversight of their eating practices was related to higher zBMI. Similarly, boys whose intake of unhealthy foods was restricted were more likely to have higher zBMI and WC. Results suggest that caregiver feeding practices continue to be associated with weight status during adolescence, and underscore the importance of culturally and developmentally appropriate prevention and intervention efforts targeting overweight and obesity. PMID- 29127940 TI - Deciphering the chemical origin of the semen-like floral scents in three angiosperm plants. AB - The chemical origin and biological role of distinct semen-like odor occasionally found in some flowers are very curious but remain scarcely studied. Here, we used direct ambient corona discharge ionization mass spectrometry (MS) to study the volatile chemical composition behind the semen-like odor emitted by the fresh flowers of Photinia serrulata, Castanopsis sclerophylla and Stemona japonica without any chemical pretreatment. Chemical identification was performed using high-resolution MS analysis in combination with tandem MS analysis and whenever possible was confirmed by the analysis of standard reference compounds. A total of 19 compounds, mostly belonging to nitrogenous volatiles, were identified in P. serrulata, C. sclerophylla, and S. japonica flowers, 1-pyrroline, 1-piperideine, 2-pyrrolidone, and phenethylamine being common in all the three studied species. Several lines of evidence indicate that the major component responsible for the semen-like odor is most likely 1-pyrroline. 1-Pyrroline is most probably formed via the oxidative deamination of putrescine, as indicated by the observation of signal from 4-amino-butanal intermediate. Flower visitation observations suggest that the released volatiles serve to attract dipterans, including Syrphidae, Calliphoridae, and Muscidae. On the analytical side, the comparison of our results to earlier studies also indicate that compared to the traditional GC-MS approach the direct corona discharge ionization mass spectrometry provides more sensitive detection of VOCs with high proton affinity, in particular volatile amines, and therefore can be used to complement traditional GC-MS approach for the highest chemical coverage of VOC analysis. PMID- 29127941 TI - Improving anti-adhesion performance of electrosurgical electrode assisted with ultrasonic vibration. AB - The electrosurgical electrode currently stands out as one of the most commonly used tools in minimally invasive surgery. In order to facilitate tissue cutting and accelerate wound healing, tissue adhesion to the electrosurgical electrode is considered as an extremely urgent problem to be solved. In this paper, a novel ultrasonic vibration assisted (UV-A) electrosurgical electrode is firstly proposed to overcome the problem of tissue sticking. The anti-adhesion effects were evaluated by measuring the adhesion force and the weight of tissue adhesion using the electrosurgical electrode with and without UV-A comparatively. Experimental results show that the average adhesion force and the tissue adhesion mass with UV-A were decreased by approximately 60% and 70% respectively, accompanied by smaller thermal injury area compared with that without UV-A. Moreover, the underlying mechanism of anti-adhesion effect with UV-A was revealed by investigating the influence of ultrasonic vibration on electric current, tissue removal and spark discharge. This research suggests that UV-A is a promising and practical method for improving the anti-adhesion performance of electrosurgical electrode. PMID- 29127942 TI - Attenuation measurements with ultrasonic diffraction grating show dependence upon particle size of slurry and viscosity of base liquid. AB - How can using an ultrasonic diffraction grating lead to slurry characterization? The diffraction grating, which is formed by machining triangular grooves on the flat surface of an aluminum unit, has send and receive transducers fastened to the unit at an angle of 30 degrees . The ultrasonic beam strikes the back of the grating, in contact with the slurry, and reflects a beam to the receive transducer; m = 0 and m = 1 beams are transmitted into the slurry. The angle of the m = 1 beam changes with frequency and, at the critical frequency fCR, it reaches 90 degrees . When f < fCR, the m = 1 beam disappears, its energy is shared with all other beams, producing a peak in the receive transducer. The change in peak height with slurry concentration determines the attenuation; the frequency at the peak yields the velocity of sound. The attenuation has been measured for polystyrene spheres, ranging in size from 98 um to 463 um, and slurry concentrations up to 20 wt%. When the spheres are immersed in water, sugar water, or mineral oil, the attenuation measurements show the effect of particle diameter and the viscosity of the base fluid. PMID- 29127943 TI - Quantum dot-Cramoll lectin as novel conjugates to glycobiology. AB - The optical properties of quantum dots (QDs) make them useful tools for biology, especially when combined with biomolecules such as lectins. QDs conjugated to lectins can be used as nanoprobes for carbohydrate expression analysis, which can provide valuable information about glycosylation changes related to cancer and pathogenicity of microorganisms, for example. In this study, we evaluated the best strategy to conjugate Cramoll lectin to QDs and used the fluorescent labeling of Candida albicans cells as a proof-of-concept. Cramoll is a mannose/glucose-binding lectin with unique biological properties such as immunomodulatory, antiparasitic, and antitumor activities. We probed covalent coupling and adsorption as conjugation strategies at different pH values. QDs conjugated to Cramoll at pH7.0 showed the best labeling efficiency in the fluorescence microscopy analysis. Moreover, QD-Cramoll conjugates remained brightly fluorescent and preserved identical biological activity according to hemagglutination assays. Flow cytometry revealed that approximately 17% of C. albicans cells were labeled after incubation with covalent conjugates, while approximately 92% of cells were labeled by adsorption conjugates (both at pH7.0). Inhibition assays confirmed QD-Cramoll specificity, which reduced the labeling to at most 3%. Therefore, the conjugates obtained by adsorption (pH7.0) proved to be promising and versatile fluorescent tools for glycobiology. PMID- 29127944 TI - An experimental validation of a Bayesian model for quantification in NMR spectroscopy. AB - The traditional peak integration method for quantitative analysis in nuclear magnetic resonance (NMR) spectroscopy is inherently limited by its ability to resolve overlapping peaks and is susceptible to noise. The alternative model based approaches not only extend quantification capabilities to these challenging examples but also provide a means for automation of the entire process of NMR data analysis. In this paper, we present a general model for an NMR signal that, in a principled way, takes into account the effects of chemical shifts, relaxation, lineshape imperfections, phasing, and baseline distortions. We test the model using both simulations and experiments, concentrating on simple spectra with well-resolved peaks where we expect conventional analysis to be effective. Our results of quantifying mixture compositions compare favorably with the established methods. At high SNR (>40dB), all approaches usually achieve for these test systems an absolute accuracy of at least 0.01mol/mol for the concentrations of all species. Our model-based approach is successful even for SNR<20dB; it achieves 0.05-0.1mol/mol accuracy in cases where precise phasing is practically impossible due to high levels of noise in the data. PMID- 29127945 TI - Attention and interpretation bias modification treatment for social anxiety disorder: A randomized clinical trial of efficacy and synergy. AB - BACKGROUND AND OBJECTIVES: Attention bias modification treatment (ABMT) and cognitive bias modification of interpretation (CBM-I) both have demonstrated efficacy in alleviating social anxiety, but how they compare with each other, their combination, and with a combined control condition has not been studied. We examined their relative and combined efficacy compared to control conditions in a randomized controlled trial (RCT). METHODS: Ninety-five adults diagnosed with social anxiety disorder (SAD), were randomly allocated to 4 groups: ABMT + CBM-I control (hereafter ABMT; n = 23), CBM-I + ABMT control (hereafter CBM-I; n = 24), combined ABMT + CBM-I (n = 23), and combined control (n = 25). Treatment included eight sessions over four weeks. Clinician-rated and self-reported measures of social anxiety symptoms, functional impairment, and threat-related attention and interpretive biases were evaluated at baseline, post-treatment, and 3-month follow-up. RESULTS: ABMT yielded greater symptom reduction as measured by both clinician-ratings (Cohen's ds = 0.57-0.70) and self-reports (ds = 0.70-0.85) compared with the CBM-I, the combined ABMT + CBM-I, and the combined control conditions. Neither of the other conditions demonstrated superior symptom change compared to the control condition. No group differences were found for functioning or cognitive biases measures. LIMITATIONS: Limitations mainly include the mix of active and control treatments applied across the different groups. Therefore, the net effect of each of the treatments by itself could not be clearly tested. CONCLUSIONS: Results suggest superiority of ABMT compared to CBM I and their combination in terms of symptom reduction. Possible interpretations and methodological issues underlying the observed findings are discussed. PMID- 29127946 TI - Seasonal trends of diagnosis of childhood malignant diseases and viral prevalence in South Korea. AB - BACKGROUND: Several studies have reported a seasonal trend in the diagnosis of childhood cancer suggesting seasonal factors such as infection. The present study aimed to analyze the diagnosis pattern of childhood malignant diseases using public health data, and to compare this pattern with seasonal viral infection trends. METHOD: Using the open data source of the Health Insurance Review and Assessment Service, we extracted data regarding all patients under 21 years of age and who had any cancer, aplastic anemia or myelodysplastic syndrome between September 2009 and December 2013. The positive detection rates of 11 viruses was collected from the surveillance data of Korea Centers for Disease Control and Prevention, and seasonality analysis were conducted with both data. RESULTS: In total, 9085 patients were diagnosed with malignant disease during the study period; there were about 175 new cases per month on average. Monthly stacked time series by year showed an apparent seasonal variation with the highest monthly average in January as 236, and the lowest in September as 120. In winter, significantly more patients were diagnosed with acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and Hodgkin's lymphoma than in other seasons. There was a temporal correlation with the diagnostic trends of several diseases and the prevalence of recent human parainfluenza virus. CONCLUSION: This study tentatively suggests that the diagnosis of childhood malignancy follows a seasonal trend in Korea, and has a possible correlation with viral prevalence in several diseases. Further long-term analysis of epidemiological data is needed to explore possible causality. PMID- 29127947 TI - The first external quality assessment of isolation and identification of influenza viruses in cell culture in the Asia Pacific region, 2016. AB - BACKGROUND: The isolation and propagation of influenza viruses from clinical specimens are essential tools for comprehensive virologic surveillance. Influenza viruses must be amplified in cell culture for detailed antigenic analysis and for phenotypic assays assessing susceptibility to antiviral drugs or for other assays. OBJECTIVES: To conduct an external quality assessment (EQA) of proficiency for isolation and identification of influenza viruses using cell culture techniques among National Influenza Centres (NICs) in the World Health Organisation (WHO) South East Asia and Western Pacific Regions. STUDY DESIGN: Twenty-one NICs performed routine influenza virus isolation and identification techniques on a proficiency testing panel comprising 16 samples, containing influenza A or B viruses and negative control samples. One sample was used exclusively to determine their capacity to measure hemagglutination titer and the other 15 samples were used for virus isolation and identification. RESULTS: All NICs performed influenza virus isolation using Madin Darby canine kidney (MDCK) or MDCK-SIAT-1 cells. If virus growth was detected, the type, subtype and/or lineage of virus present in isolates was determined using immunofluorescence, RT PCR and/or hemagglutination inhibition (HI) assays. Most participating laboratories could detect influenza virus growth and could identify virus amplified from EQA samples. However, some laboratories failed to isolate and identify viruses from EQA samples that contained lower titres of virus, highlighting issues regarding the sensitivity of influenza virus isolation methods between laboratories. CONCLUSION: This first round of EQA was successfully conducted by NICs in the Asia Pacific Region, revealing good proficiency in influenza virus isolation and identification. PMID- 29127949 TI - Effect of Adding Dexamethasone to Continued Ranibizumab Treatment in Patients With Persistent Diabetic Macular Edema: A DRCR Network Phase 2 Randomized Clinical Trial. AB - Importance: Some eyes have persistent diabetic macular edema (DME) following anti vascular endothelial growth factor (anti-VEGF) therapy for DME. Subsequently adding intravitreous corticosteroids to the treatment regimen might result in better outcomes than continued anti-VEGF therapy alone. Objective: To compare continued intravitreous ranibizumab alone with ranibizumab plus intravitreous dexamethasone implant in eyes with persistent DME. Design, Setting, and Participants: Phase 2 multicenter randomized clinical trial conducted at 40 US sites in 129 eyes from 116 adults with diabetes between February 2014 and December 2016. Eyes had persistent DME, with visual acuity of 20/32 to 20/320 after at least 3 anti-VEGF injections before a run-in phase, which included an additional 3 monthly 0.3-mg ranibizumab injections. Data analysis was according to intent to treat. Interventions: Following the run-in phase, study eyes that had persistent DME and were otherwise eligible were randomly assigned to receive 700 MUg of dexamethasone (combination group, 65 eyes) or sham treatment (ranibizumab group, 64 eyes) in addition to continued 0.3-mg ranibizumab in both treatment arms as often as every 4 weeks based on a structured re-treatment protocol. Main Outcomes and Measures: The primary outcome was change in mean visual acuity letter score at 24 weeks as measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS). The principal secondary outcome was change in mean central subfield thickness as measured with the use of optical coherence tomography. Results: Of the 116 randomized patients, median age was 65 years (interquartile range [IQR], 58-71 years); 50.9% were female and 60.3% were white. Mean (SD) improvement in visual acuity from randomization was 2.7 (9.8) letters in the combination group and 3.0 (7.1) letters in the ranibizumab group, with the adjusted treatment group difference (combination minus ranibizumab) of 0.5 letters (95% CI, -3.6 to 2.5; 2-sided P = .73). Mean (SD) change in central subfield thickness in the combination group was -110 (86) MUm compared with -62 (97) MUm for the ranibizumab group (adjusted difference, -52; 95% CI, -82 to -22; 2-sided P < .001). Nineteen eyes (29%) in the combination group experienced increased intraocular pressure or initiated treatment with antihypertensive eyedrops compared with 0 in the ranibizumab group (2-sided P < .001). Conclusions and Relevance: Although its use is more likely to reduce retinal thickness and increase intraocular pressure, the addition of intravitreous dexamethasone to continued ranibizumab therapy does not improve visual acuity at 24 weeks more than continued ranibizumab therapy alone among eyes with persistent DME following anti-VEGF therapy. Trial Registration: clinicaltrials.gov Identifier: NCT01945866. PMID- 29127950 TI - Retracted: siRNA Mediated Silencing of NIN1/RPN12 Binding Protein 1 Homolog Inhibits Proliferation and Growth of Breast Cancer Cells AB - Retraction:Retracted: siRNA mediated silencing of NIN1/RPN12 binding protein 1 homolog inhibits proliferation and growth of breast cancer cellsAsian Pacific Journal of Cancer Prevention has retracted the article titled "siRNA mediated silencing of NIN1/RPN12 binding protein 1 homolog inhibits proliferation and growth of breast cancer cells"(1) for reason of similarity with a series of articles identified by Byrne and Labbe (2).1. Huang WY1, Chen DH, Ning L, Wang LW. siRNA mediated silencing of NIN1/RPN12 binding protein 1 homolog inhibits proliferation and growth of breast cancer cells. Asian Pac J Cancer Prev. 2012;13(5):1823-7.2. J. A. Byrne and C. Labbe, "Striking similarities between publications from China describing single gene knockdown experiments in human cancer cell lines," Scientometrics, vol. 110, no. 3, pp. 1471-1493, 2017.Authors did not respond to request for comment. PMID- 29127948 TI - Association of High-Sensitivity Cardiac Troponin I Concentration With Cardiac Outcomes in Patients With Suspected Acute Coronary Syndrome. AB - Importance: High-sensitivity cardiac troponin I testing is widely used to evaluate patients with suspected acute coronary syndrome. A cardiac troponin concentration of less than 5 ng/L identifies patients at presentation as low risk, but the optimal threshold is uncertain. Objective: To evaluate the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome. Data Sources: Systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases from January 1, 2006, to March 18, 2017. Study Selection: Prospective studies measuring high-sensitivity cardiac troponin I concentrations in patients with suspected acute coronary syndrome in which the diagnosis was adjudicated according to the universal definition of myocardial infarction. Data Extraction and Synthesis: The systematic review identified 19 cohorts. Individual patient level data were obtained from the corresponding authors of 17 cohorts, with aggregate data from 2 cohorts. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random-effects model. Main Outcomes and Measures: The primary outcome was myocardial infarction or cardiac death at 30 days. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data. Results: Of 11 845 articles identified, 104 underwent full-text review, and 19 cohorts from 9 countries were included. Among 22 457 patients included in the meta-analysis (mean age, 62 [SD, 15.5] years; n = 9329 women [41.5%]), the primary outcome occurred in 2786 (12.4%). Cardiac troponin I concentrations were less than 5 ng/L at presentation in 11 012 patients (49%), in whom there were 60 missed index or 30-day events (59 index myocardial infarctions, 1 myocardial infarction at 30 days, and no cardiac deaths at 30 days). This resulted in a negative predictive value of 99.5% (95% CI, 99.3%-99.6%) for the primary outcome. There were no cardiac deaths at 30 days and 7 (0.1%) at 1 year, with a negative predictive value of 99.9% (95% CI, 99.7%-99.9%) for cardiac death. Conclusions and Relevance: Among patients with suspected acute coronary syndrome, a high sensitivity cardiac troponin I concentration of less than 5 ng/L identified those at low risk of myocardial infarction or cardiac death within 30 days. Further research is needed to understand the clinical utility and cost-effectiveness of this approach to risk stratification. PMID- 29127953 TI - Bridging existing governance gaps: five evidence-based actions that boards can take to pursue high quality care. AB - Objective To explore the impact of the organisational quality systems on quality of care in Victorian health services.Methods During 2015 a total of 55 focus groups were conducted with more than 350 managers, clinical staff and board members in eight Victorian health services to explore the effectiveness of health service quality systems. A review of the quality and safety goals and strategies outlined in the strategic and operating plans of the participating health services was also undertaken.Results This paper focuses on the data related to the leadership role of health service boards in ensuring safe, high-quality care. The findings suggest that health service boards are not fully meeting their governance accountability to ensure consistently high-quality care. The data uncovered major clinical governance gaps between stated board and executive aspirations for quality and safety and the implementation of these expectations at point of care. These gaps were further compounded by quality system confusion, over-reliance on compliance, and inadequate staff engagement.Conclusion Based on the existing evidence we propose five specific actions boards can take to close the gaps, thereby supporting improved care for all consumers.What is known about this topic? Effective governance is essential for high-quality healthcare delivery. Boards are required to play an active role in their organisation's pursuit of high quality care.What does this paper add? Recent government reports suggest that Australian health service boards are not fully meeting their governance requirements for high quality, safe care delivery, and our research pinpoints key governance gaps.What are the implications for practitioners? Based on our research findings we outline five evidence-based actions for boards to improve their governance of quality care delivery. These actions focus on an organisational strategy for high-quality care, with the chief executive officer held accountable for successful implementation, which is actively guided and monitored by the board. PMID- 29127951 TI - Sox12 Is a Cancer Stem-Like Cell Marker in Hepatocellular Carcinoma. AB - Recent studies on molecular carcinogenesis suggest that the chemo-resistance of some cancers is largely due to presence of cancer stem cells (CSCs), which affect the chemotherapy outcome for hepatocellular carcinoma (HCC). However, currently no consensus on a CSC phenotype in HCC has been obtained. Here, we examined Sox12 as a novel CSC marker in HCC. Sox12+ versus Sox12- cells were purified from HCC cell lines. The Sox12+ cells were compared with Sox12- HCC cells for tumor sphere formation, chemo-resistance, tumor formation after serial adoptive transplantations in nude mice, and the frequency of developing distal metastasis. We found that compared to Sox12- HCC cells, Sox12+ HCC cells generated significantly more tumor spheres in culture, were more chemo-resistant to cisplatin, were detected in circulation more frequently, and formed distal tumor more frequently. Moreover, Sox12 appeared to functionally contribute to the stemness of HCC cells. Thus, we conclude that Sox12 may be a novel marker for enriching CSCs in HCC. PMID- 29127952 TI - Diabetes mellitus in a patient with glycogen storage disease type Ia: a case report. AB - BACKGROUND: Glycogen storage disease type Ia is a genetic disorder that is associated with persistent fasting hypoglycemia and the inability to produce endogenous glucose. The development of diabetes with glycogen storage disease is exceedingly rare. The underlying pathogenesis for developing diabetes in these patients is unclear, and there are no guidelines for treatment. CASE PRESENTATION: We describe a case of a 34-year-old woman of South Asian descent with glycogen storage disease type Ia, who developed uncontrolled diabetes mellitus as a young adult. Hyperglycemia was noted after childbirth, and worsened years later. Treatment for diabetes was difficult due to risks of hypoglycemia from her underlying glycogen storage disease. With minimal hypoglycemic events, the patient's blood glucose improved with exercise in combination with a sodium glucose co-transporter 2 inhibitor and an alpha glucosidase inhibitor. CONCLUSION: We report a rare case of diabetes in the setting of glycogen storage disease-Ia. Based on the literature, there appears to be a relationship between glycogen storage disease and metabolic syndrome, which likely plays a role in the pathogenesis. The management of glycemic control remains a clinical challenge, requiring management of both fasting hypoglycemia from glycogen storage disease, as well as post-prandial hyperglycemia from diabetes mellitus. PMID- 29127954 TI - Human dimension of health service management. AB - This article identifies three relevant and valid constructs that are associated with personal and organisational performance that can be used in the training of current and future health service managers: personal engagement at work, emotional intelligence and conflict resolution. A review was undertaken of the literature in human resources management to identify key concepts that bind and strengthen the management of organisations. A curriculum content analysis was then performed of postgraduate health management courses in Australia to assess the extent of inclusion in these areas. Three concepts and practices of relevance to the human dimension of health management, namely personal engagement at work, emotional intelligence and conflict resolution, were found to: (1) have concept validity; (2) be associated with personal and organisational performance; and (3) be capable of being imparted by training. The analysis indicated that none of the competencies and/or skills identified has been given emphasis in postgraduate health management courses in Australia. Competence in the management of human relationships in health services has been given low priority in university postgraduate training in health management in Australia. The current situation poses challenges to all stakeholders of health services. PMID- 29127955 TI - Examining the high users of hospital resources: implications of a profile developed from Australian health insurance claims data. AB - Objective To develop and examine a profile of the demographic, hospital admission and clinical characteristics of high users of hospital resources within a cohort of privately insured Australians.Methods Hospital admissions claims data from a group of private health insurance funds were analysed. The top 1% of hospital users were selected based on three measures of resource utilisation: number of admissions, total bed days and total insurance benefits paid. The demographic, hospital admission and clinical characteristics data were compared for these three measures of resource utilisation.Results Compared with the general insured population, the three high-use cohorts are older, have more public hospital admissions and have more same-day admissions. The three high-use cohorts have the same top five principal diagnosis categories. These five categories account for more than two-thirds of admissions. The top 1% of users is responsible for a large proportion of total resource utilisation, accounting for 13% of total costs and 21% of total bed days.Conclusions The highest users of hospital resources have a distinct profile, accounting for a large proportion of total resource utilisation for a narrow range of health conditions. The age and hospital admission profile of this group suggest both policy and service considerations for the targeting of interventions to support this high-needs group.What is known about this topic? Statistics are regularly published on the uptake and use of private health insurance in Australia but there is little detailed information on resource utilisation in specific subgroups, particularly those with the highest levels of hospitalisation.What does this paper add? This paper provides a profile of high resource utilisation among a privately insured cohort, describing demographic, hospital admission and clinical characteristics across three measures of resource utilisation. Patterns of use are detailed in this profile, for example the top 1% of users have a higher proportion of public hospital admissions as a private patient. The clinical profile of admissions was similar for the three measures of resource utilisation and there was considerable overlap in the individuals categorised in each high-use group.What are the implications for practitioners? The narrow demographic and clinical profile of the high resource utilisation groups shows a chronic disease burden that is different to the focus of current chronic disease policy measures. The high-use conditions identified in this study are less amenable to preventive measures and new strategies may be required to target this high-needs group. PMID- 29127956 TI - Minimally Invasive Fetal Surgery. AB - Fetal surgery corrects severe congenital anomalies in utero to prevent their severe consequences on fetal development. The significant risk of open fetal operations to the pregnant mother has driven innovation toward minimally invasive procedures that decrease the risks inherent to hysterotomy. In this article, we discuss the basic principles of minimally invasive fetal surgery, the general history of its development, specific conditions and procedures used to treat them, and the future of the field. PMID- 29127957 TI - Esophageal Atresia and Upper Airway Pathology. AB - Esophageal atresia is an anomaly with frequently occurring sequelae requiring lifelong management and follow-up. Because of the complex issues that can be encountered, patients with esophageal atresia preferably should be managed in centers of expertise that have the ability to deal with all types of anomalies and sequelae and can perform rigorous lifelong follow-up. Tracheomalacia is an often-occurring concurrent anomaly that may cause acute life-threatening events and may warrant immediate management. In the past, major thoracotomies were necessary to carry out the aortopexy. Nowadays, aortopexy and posterior tracheopexy can both be performed thoracoscopically with quick recovery. PMID- 29127959 TI - Congenital Diaphragmatic Hernia and Diaphragmatic Eventration. AB - Congenital diaphragmatic hernia can be approached successfully using minimally invasive techniques. Although there are may be a suggestion of higher recurrence rates with thoracoscopic repair, this may be due to the learning curve. However, open repair is associated with additional morbidity, most notably an increased rate of small bowel obstruction. Appropriate patients who have congenital diaphragmatic hernia should be offered the benefits of minimally invasive repair. PMID- 29127958 TI - Minimally Invasive Patent Ductus Arteriosus Ligation. AB - A patent ductus arteriosus is a common condition, particularly in premature infants. Many spontaneously resolve but those that lead to clinical instability require closure. Conservative measures can be highly successful in selected groups. Surgical repair is effective and both open and minimally invasive approaches can be used. The minimally invasive approach may result in less long term morbidity from a thoracotomy and may prove advantageous for these fragile infants, including less pain, shorter time on the ventilator, and shorter hospital stays. PMID- 29127960 TI - Thoracoscopic Lobectomy for Congenital Lung Lesions. AB - Congenital lung lesions (CLLs) comprise a heterogeneous group of developmental and histologic entities often diagnosed on screening prenatal ultrasound. Most fetuses with CLL are asymptomatic at birth; however, the risk of malignancy and infection drives the decision to prophylactically resect these lesions. The authors describe their approach to minimally invasive lobectomy in children with CLLs, postoperative care, and management of procedure-specific complications. PMID- 29127962 TI - Minimally Invasive Hepatobiliary Surgery. AB - Comparative studies and large-scale case series that confirm the advantages of laparoscopy in children with hepatobiliary diseases are scarce, and the use of laparoscopy remains a matter of debate. This article reviews the current literature on the role of laparoscopic and robotic surgery in pediatric patients with choledochal cyst, biliary atresia, gallbladder diseases, and hepatobiliary malignancies. Studies were identified through a search of the MEDLINE database. Laparoscopy may be beneficial for resection of choledochal cyst and cholecystectomy. However, more data are required before recommendations on the use of minimally invasive techniques for other hepatobiliary conditions can be published. PMID- 29127961 TI - Fundoplication. AB - Gastroesophageal reflux disease (GERD) is a common condition in infants. Symptoms from pathologic GERD include regurgitation, irritability when feeding, failure to thrive, and respiratory problems. Treatment typically starts with dietary modifications and postural changes. Antireflux medications may then be added. Indications for operative management in neonates and infants include poor weight gain, failure to thrive, acute life-threatening events, and continued respiratory symptoms. Laparoscopic Nissen fundoplication has become the standard of care for surgical treatment of children with GERD. In this procedure, the fundus of the stomach is wrapped 360 degrees posteriorly around the lower esophagus. PMID- 29127963 TI - Minimally Invasive Surgery in the Management of Anorectal Malformations. AB - Imperforate anus, a variant of anorectal malformation (ARM), is a common congenital anomaly requiring surgical attention in the newborn period. It may present with a variety of anatomic configurations, largely dependent on the presence and location of a fistula. The location (or characteristics) of a fistula, which usually lies between the gastrointestinal tract and the genitourinary tract or perineum, is often used in determining the type and timing of operative management. This article discusses the work-up and management, modes of treatment and their postoperative outcomes, and continued controversy regarding the use of minimally invasive surgical approaches to ARM. PMID- 29127965 TI - Minimally Invasive Neonatal Surgery: Hirschsprung Disease. AB - Transanal pull-through (TAPT) is the procedure of choice for treating Hirschsprung disease and should be performed with laparoscopic assistance using the anorectal line (ARL) to ensure optimum postoperative bowel function (POBF). The dentate line (DL) has traditionally been used as the landmark for commencing dissection during TAPT, but we prefer the ARL because the DL is too subjective and can be associated with risk for injury to delicate sensory innervation required for normal defecation in the anal transition zone. An intact anal transition zone and total excision of the posterior rectal cuff are crucial for normal defecation. Objective assessment of POBF is essential for thorough follow up and early detection of potential late complications that may arise. PMID- 29127964 TI - Minimally Invasive Management for Vesicoureteral Reflux in Infants and Young Children. AB - Minimally invasive ureteral reimplantation is an attractive and useful tool in the armamentarium for the management of complicated vesicoureteral reflux (VUR). Subureteric dextranomer/hyaluronic acid injection, laparoscopic extravesical ureteric reimplantation and pneumovesicoscopic intravesical ureteral reimplantation with or without robotic assistance are established minimally invasive approaches to management of VUR. The high cost and the limited availability of robotics have restricted accessibility to these approaches. Laparoscopic and/or robotic ureteral reimplantation continues to evolve and will have a significant bearing on the management of complicated VUR in infants and young children. PMID- 29127966 TI - Inguinal Hernia. AB - Laparoscopy is a safe and effective technique in the repair of inguinal hernias. This article describes the different laparoscopic herniorrhaphy technique, as well as controversial topics, such as premature infants, contralateral repair, and incarcerated hernias. PMID- 29127967 TI - Erratum. PMID- 29127968 TI - Minimally Invasive Neonatal Surgery. PMID- 29127969 TI - Minimally Invasive Surgery: Is It the Carpenter or the Tools? PMID- 29127970 TI - ? PMID- 29127971 TI - ? PMID- 29127972 TI - [Applications and connected objects, new perspectives]. AB - Applications and connected objects appear promising in the world of wellbeing and health. Often cheap, they offer numerous perspectives for health promotion, in targeted fields or to fulfil 'niche' needs. This growth, extremely fast over the last five years, has also given rise to potential defiance on the part of users. PMID- 29127973 TI - ["Health professionals will become experts in the world of connected health"]. AB - The French national medical council (CNOM), in its white paper Connected health: From e-health to connected health, incites doctors to support the deployment of the digital world in the health sector and to integrate its useful and beneficial aspects into their own practices. Doctor Jacques Lucas, vice-president of the CNOM and general delegate for IT systems in health, highlights the challenges of this emerging world and evokes the impact on the nurse-patient relationship. PMID- 29127974 TI - [E-health applications and their users]. AB - France Assos Sante brings together 72 accredited user associations across France. It represents the views of users on health issues, notably in the field of technological innovation and connected health where the challenges are considerable. PMID- 29127975 TI - [Tools for assisting diagnosis]. AB - Connected objects are revolutionising practices, fulfil patients' needs for autonomy and the need to deploy healthcare provision beyond healthcare facilities. This article illustrates how these tools can be used in the case of epilepsy. PMID- 29127976 TI - [Connected tablets, tracking care and sharing patient records]. AB - A hospital at home team shares its experience of the use of connected tablets to enable caregivers to track the care provided and have shared access to the patient's records. An effective and modern solution which forms part of the extension of the computerisation of the hospital's medication pathway. PMID- 29127978 TI - [Virtual doctors and e-health]. AB - One of the challenges of e-health will be to give concrete form to personalised therapeutic solutions using connected objects, information and decision-making systems, and patient management behavioural programmes. Developed to improve the empathetic relationship with patients, virtual companions are the subject of research programmes. PMID- 29127977 TI - [Diabetes and connected objects, appropriation or rejection?] AB - There are numerous connected objects aimed at the 3.5 million people with diabetes in France. What do patients think of them and what use do they actually get out of them? Diabete LAB, the living lab of the French Federation of Diabetics, questions patients with diabetes about their experiences, their uses of the technical devices and health services, as well as their needs. PMID- 29127979 TI - [The 'City of the Kidney', a platform for co-constructing a therapeutic pathway]. AB - Innovative in terms of assisting shared medical decision making, the internet platform 'the City of the Kidney' aims to provide reliable and independent information to patients with kidney disease requiring dialysis or transplant as well as to their relatives. A tool which health professionals can recommend to their patients as a source of detailed information. PMID- 29127980 TI - [Private practice nurse and palliative care in the home]. AB - The development of palliative care in the home, requested by patients and recommended in the 2015-2018 national plan, requires the home to be considered as a specific place of care. Private practice nurses have an important role to play with the patient and their relatives, in the assessment of needs, coordination, relational care as well as in providing the care required for maintaining and continuing life, an increasingly technical process. PMID- 29127981 TI - [Managing the cold chain in healthcare facilities]. AB - The storage of temperature-sensitive healthcare products requires control of the cold chain. Healthcare facilities must have the appropriate equipment at their disposal and ensure the traceability and monitoring of temperatures. PMID- 29127982 TI - [Nursing role and TPE in patients with lymphoedema of the limbs]. AB - Lymphoedema, primary and secondary after cancer treatment, is a chronic condition which has a significant impact on patients' quality of life. Therapeutic education plays an important role in the initial care and in the follow-up of these conditions. PMID- 29127983 TI - ? PMID- 29127984 TI - Coping with a Patient Developing Hallucinations. AB - In Casualty, Pierre takes into care a young adult with abdominal pain who later confides in him that he is hearing strange voices. PMID- 29127985 TI - ? PMID- 29127986 TI - ? PMID- 29127987 TI - ? PMID- 29127988 TI - Mycoplasma ovis infection in goat farms from northeastern Brazil. AB - Although Mycoplasma ovis (formerly Eperythrozoon ovis) has been described in small ruminants worldwide, data on M. ovis in goats remain scarce. Accordingly, the aims of the present study were to i) determine the prevalence of hemoplasmas in goats, ii) identify the tick species parasitizing the animals, and iii) determine factors associated with infection in five dairy and three beef goat farms from the Paraiba State, northeastern Brazil. Blood samples were obtained from 402 goats. Samples were screened for hemoplasmas using a pan-hemoplasma PCR. The positive samples were confirmed by sequencing. An epidemiological questionnaire was given to each farm owner addressing age, gender, and presence of ticks. A total of 158/402 (39.3%) goats were positive for M. ovis by PCR. Sequencing of PCR positive samples has shown >=99% identity with multiple M. ovis 16S rDNA sequences deposited in GenBank, including M. ovis isolates from humans. Dairy (OR=2.15; 95% CI: 1.40-3.32%; P=0.0004) and anemic goats (OR=2.33; 95% CI: 1.51-3.71%; P=0.0001) were more likely to be infected than beef and non-anemic animals, respectively. Amblyomma parvum (49/52, 94.23%) and Rhipicephalus microplus (3/52, 5.77%) were the tick species found parasitizing the animals, with no significant association between the presence of ticks and infection by M. ovis (P=0.1164). This is the first reportedly molecular detection of M. ovis infection in goats from South America. In conclusion, M. ovis is highly prevalent in goats from northeastern Brazil, mainly in dairy animals. PMID- 29127989 TI - Antimicrobial resistant Escherichia coli in the reproductive tract microbiota of cows and sows. AB - Escherichia coli is a natural colonizer of the urogenital mucosa of healthy females; however it is one of the pathogens associated to reproductive failures in cows and sows. A better knowledge about the characteristics of native E. coli will allow us to differentiate them from pathogenic strains. Ninety autochthonous isolates from the reproductive tract of sows and cows were characterized to determine the phylogenetic profile, antibiotic resistance and virulence factors; also, comparisons between different breeding systems were performed. Vaginal colonization of E. coli was statistically higher in cows (57.5%) than sows (23.8%), and most isolates belonged to the phylogenetic group A: 79.69 and 80.77%, respectively; moreover phylo-groups B1 (12.5 and 11.54%) and D (7.81 and 7.69%) were significantly lower; however, none was classified as B2. Positive associations between virulence factors and group D were found. Isolates with antimicrobial susceptibility were associated with group A and the MDR (Multiple Drug Resistance) was related to the porcine source. These results contribute to the knowledge of extra-intestinal E. coli populations; which could affect the reproductive performance of females. PMID- 29127990 TI - Bartonella, bats and bugs: A review. AB - Ecological, immunological, and epidemiological factors enable bats to transmit an increasingly recognized spectrum of zoonotic agents, and bartonellae are among those emerging pathogens identified in bats and their arthropod ectoparasites. Current data reveal a multifaceted disease ecology where diverse host species distributed around the world interact with a number of Bartonella spp. and several potential vectors. This review summarizes the methods and findings of studies conducted since 2005 to illustrate that Bartonella bacteremia varies by bat species, location, and other potential variables, such as diet with a very high prevalence in hematophagous bats. Among bat families, Bartonella prevalence ranged from 7.3% among Nycteridae to 54.4% in Miniopteridae. Further research can build on these current data to better determine risk factors associated with Bartonella infection in bat populations and the role of their ectoparasites in transmission. PMID- 29127991 TI - Arthropod-borne agents in wild Orinoco geese (Neochen jubata) in Brazil. AB - Although Orinoco goose (Neochen jubata) is an anatid species widely distributed in South America, scarce are the reports on the occurrence of arthropod-borne pathogens in this avian species. The present work aimed to verify, by serological and molecular methods, the occurrence of haemosporida piroplasmids and Anaplasmataceae agents in wild Orinoco geese captured in Brazil. Between 2010 and 2014, 62 blood samples were collected from free-living geese captured in the Araguaia River, Goias State, Brazil. Six geese (10%) were seropositive for Anaplasma phagocytophilum, showing titers ranging from 40 and 80. Twenty out of 62 blood samples (32.25%) were positive in nested PCR for hemosporidia (cytochrome b gene). Fifteen and five sequences shared identity with Haemoproteus and Plasmodium, respectively. Six out of 62 blood samples (9.68%) were positive in nested PCR for Babesia spp. (18S rRNA gene); one sequence showed to be closely related to Babesia vogeli. Thirty (48.38%) out of 62 Orinoco geese blood samples were positive in nested cPCR assays for Anaplasmataceae agents (16S rRNA gene): three for Anaplasma spp. and 27 for Ehrlichia. Six geese were simultaneously positive to Haemoproteus and Ehrlichia; three animals were co-positive to different Ehrlichia species/genotypes; and one goose sample was positive for both Anaplasma and Ehrlichia. The present work showed the occurrence of Ehrlichia, Anaplasma, Babesia, Plasmodium, and Haemoproteus species in free-living N. jubata in Brazil. The threat of these arthropod-borne pathogens in Orinoco goose's fitness, especially during the breading season, should be assessed in the future. PMID- 29127992 TI - Leishmania infantum exerts immunomodulation in canine Kupffer cells reverted by meglumine antimoniate. AB - Kupffer cells (KC) are the liver macrophage population that resides in the hepatic sinusoids and efficiently phagocyte pathogens by establishing an intimate contact with circulating blood. KC constitute the liver host cells in Leishmania infection, nevertheless little is described about their role, apart from their notable contribution in granulomatous inflammation. The present study aims to investigate how canine KC sense and react to the presence of Leishmania infantum promastigotes and amastigotes by evaluating the gene expression of specific innate immune cell receptors and cytokines, as well as the induction of nitric oxide and urea production. Complementarily, the impact of a leishmanicidal drug - meglumine antimoniate (MgA) - in infected KC was also explored. KC revealed to be susceptible to both parasite forms and no major differences were found in the immune response generated. L. infantum parasites seem to interact with KC innate immune receptors and induce an anergic state, promoting immune tolerance and parasite survival. The addition of MgA to infected KC breaks the parasite imposed silence and increased gene expression of Toll-like receptors (TLR) 2 and TLR4, possibly activating downstream pathways. Understanding how KC sense and react to parasite presence could bring new insights into the control or even elimination of canine leishmaniasis. PMID- 29127993 TI - Molecular prevalence, risk factors assessment and haemato-biochemical alterations in hepatozoonosis in dogs from Punjab, India. AB - Hepatozoonosis caused by Hepatozoon canis is an important tick-borne disease of dogs in tropical and sub-tropical regions throughout the world. In the present study evaluation of blood samples collected from 225 dogs presented at Small Animal Clinics, GADVASU, Ludhiana, Punjab (India) was done for the presence of H. canis by PCR based assay targeting a portion of 18S rRNA gene. Of the total samples subjected to PCR, an amplicon of 666bp was detected in 13.78% samples whereas, routine blood smear examination revealed gamonts in 5.78% samples. Furthermore, prevalence of H. canis infection was found to be significantly associated with season, being highest in summer and lowest in winter while other risk factors e.g. age, sex and breed showed non-significant association. In terms of various clinico-pathological parameters, significant drop in haemoglobin, total red blood cell count, packed cell volume and lymphocytes were recorded in positive cases whereas the total white blood cell count was non-significantly increased. The haematological alterations in the positive cases were lymphopenia, anaemia, thrombocytopenia, relative neutrophilia, neutrophilic leucocytosis, eosinophilia, monocytosis and lymphocytosis while the biochemical profile revealed hypoproteinemia and increased levels of blood urea nitrogen and creatinine (in positive cases) pointing towards renal failure. PMID- 29127995 TI - Preface. PMID- 29127994 TI - Maedi-visna virus persistence: Antigenic variation and latency. AB - Maedi-visna virus (MVV), a lentivirus of sheep, shares with other lentiviruses the ability to establish a lifelong infection. In this study five sheep were infected intravenously with MVV and housed together with a number of uninfected sheep for natural transmission. All virus isolates from ten sheep that had been infected naturally had multiple mutations in the principal neutralization domain in Env and were antigenic variants, while three of four isolates from the carrier sheep had identical sequences to the infecting strain and were not antigenic variants. There was evidence of positive selection in the gene, particularly in amino acids comprising the neutralization epitope and some adjacent glycosylation sites. Together these results suggest that virus persistence is acquired by a reservoir of latent viruses, and that there is selection for antigenic variants of virus that is transmitted naturally. PMID- 29127996 TI - Highlights in immune response, microbiome and precision medicine in allergic disease and asthma. AB - Several recent key findings in immunology of allergic diseases that have led to a need of reassessment of our current thinking are reviewed in this issue of the journal. Recently developed strong evidence on the role of hygiene hypothesis in protection from allergic disease and its immune mechanisms is reviewed by Ober et al. The authors pointed out immunologic mechanisms of lower prevalence of asthma and allergic sensitization observed among Amish children living on traditional farms with higher endotoxin levels as compared to Hutterite children living on industrialized farms. Barcik et al. reviewed that biologically active histamine in humans is produced by certain bacteria in the gut in addition to several cells, and has broad immunoregulatory functions. Turcanu et al. reviewed immune mechanisms of a revolutionary change to protect from food allergy. The immunologic window of opportunity in the infants can be used to enable oral tolerance in severe allergy predisposed children. Accordingly, van de Veen et al. reviewed general mechanisms of allergen tolerance highlighting recent findings. Extensive usage of precision medicine due to emerging biologics is knocking the doors of allergic diseases and asthma. Boyd et al. reviewed the existing and future "immune monitoring" approaches in the multiple omics perspective with the hope of identifying better correlates of disease status, predictors of therapeutic outcomes, and potential side-effects of treatment. Paul et al. reviewed newly uncovered innate and adaptive immunologic mechanisms that contribute to the pathogenesis of eosinophilic esophagitis. Further highlighting newly developing disease subgroups and precision medicine, Guttman-Yassky & Kruger reviewed clinical subtypes of atopic dermatitis and psoriasis, which may potentially benefit from newly developing highly efficient biologicals. Complementing this paper, Kabashima & Nomura reviewed similarities and distinctions in mouse models of atopic dermatitis and psoriasis. PMID- 29127997 TI - Editorial overview: Offence is the best defense: host-pathogen interactions driving evolution of human immunity and the germs we live with. PMID- 29127998 TI - Spectral Computed Tomography: Technique and Applications for Head and Neck Cancer. AB - Spectral computed tomography (CT) or dual-energy CT (DECT) is an advanced form of CT with increasing applications in head and neck radiology. This article provides an overview of the DECT technique and reviews current applications for the evaluation of neck pathology, focusing on oncologic applications. Included are an overview of the basic underlying principles and approaches for DECT scan acquisition and material characterization; a discussion of various DECT reconstructions and a brief overview of practical issues pertaining to DECT implementation, including those related to workflow impact of DECT; and a discussion of various applications of DECT for the evaluation of the neck, especially in oncology. PMID- 29127999 TI - High-Resolution Isotropic Three-Dimensional MR Imaging of the Extraforaminal Segments of the Cranial Nerves. AB - High-resolution isotropic 3-dimensional (D) MR imaging with and without contrast is now routinely used for imaging evaluation of cranial nerve anatomy and pathologic conditions. The anatomic details of the extraforaminal segments are well-visualized on these techniques. A wide range of pathologic entities may cause enhancement or displacement of the nerve, which is now visible to an extent not available on standard 2D imaging. This article highlights the anatomy of extraforaminal segments of the cranial nerves and uses select cases to illustrate the utility and power of these sequences, with a focus on constructive interference in steady-state. PMID- 29128000 TI - Diffusion-Weighted Imaging in Head and Neck Cancer: Technique, Limitations, and Applications. AB - Diffusion-weighted imaging (DWI) of the head and neck represents a distinct method of MR imaging with far-ranging applications. Research continues to hone the capabilities of DWI in characterization, prediction, monitoring, assessing response to treatment, and detecting posttreatment changes and recurrent tumors. Pretreatment apparent diffusion coefficient (ADC) values can suggest the likelihood of response to treatment. DWI-obtained ADC values are able to look beyond the anatomy in posttreatment tumor beds and metastatic lymph nodes to evaluate for tumor recurrence. Further research should include large-scale, multiinstitutional studies to provide standardized ADC cutoff values for more widespread use. PMID- 29128001 TI - Dynamic Contrast-Enhanced MR Imaging in Head and Neck Cancer. AB - Dynamic contrast-enhanced (DCE) MR imaging uses rapid sequential MR image acquisition before, during, and after intravenous contrast administration to elucidate information on the microvascular biologic function of tissues. The derived pharmacokinetic parameters provide useful information on tissue perfusion and permeability that may help to evaluate entities that otherwise appear similar by conventional imaging. When specifically applied to the evaluation of head and neck cancer, DCE-MR imaging may provide valuable information to help predict treatment response, discriminate between posttreatment changes and residual tumor, and discriminate between various head and neck neoplasms. PMID- 29128002 TI - Update in Parathyroid Imaging. AB - Primary hyperparathyroidism (PHPT) is characterized by excessive, dysregulated production of parathyroid hormone (PTH) by 1 or more abnormal parathyroid glands. Minimally invasive surgical techniques have created a need for more precise localization of the parathyroid lesion by imaging. A variety of imaging protocols and techniques have been used for this purpose, but no one modality is clearly superior. Nuclear medicine scintigraphy and ultrasound imaging are established modalities, although multiphase or 4-dimensional computed tomography is an emerging modality with several advantages. This review provides a background regarding PHPT and key anatomy, and discusses these alternative parathyroid imaging modalities with updates. PMID- 29128003 TI - PET/MR Imaging in Head and Neck Cancer: Current Applications and Future Directions. AB - Clinical PET/MR imaging is being implemented at institutions worldwide as part of the standard-of-care imaging for select oncology patients. This article focuses on oncologic applications of PET/MR imaging in cancers of the head and neck. Although current published literature is relatively sparse, the potential benefits of a hybrid modality of PET/MR imaging are discussed along with several possible areas of research. With the increasing number of PET/MR imaging scanners in clinical use and ongoing research, the role of PET/MR imaging in the management of head and neck cancer is likely to become more evident in the near future. PMID- 29128004 TI - Perfusion and Permeability Imaging for Head and Neck Cancer: Theory, Acquisition, Postprocessing, and Relevance to Clinical Imaging. AB - Perfusion and permeability computed tomography and MR imaging applied to head and neck cancer provide powerful diagnostic and prognostic tools for clinicians. Understanding the basics of these techniques allows the radiologist to make informed decisions regarding the use of modeling algorithms, acquisition parameters, and postprocessing techniques. This helps to ensure that studies are acquired, analyzed, and reported appropriately and erroneous results are avoided. These techniques are highly automated, widely available, and can be easily and safely incorporated into daily imaging workflow. PMID- 29128005 TI - PET-Computed Tomography in Head and Neck Cancer: Current Evidence and Future Directions. AB - Head and neck cancers are among the most common cancers worldwide. More than 90% to 95% are squamous cell carcinomas (SCCs). Accurate staging at diagnosis optimizes treatment planning with improved outcomes. Recently, 18F fluorodeoxyglucose (FDG) PET-computed tomography (CT) has shown tremendous value at diagnosis for accurate staging, treatment planning, and prognostication; and after definitive therapy for assessing response and long-term surveillance. Novel non-FDG PET tracers are under investigation, which have great potential for improving patient care in this era of personalized medicine. PMID- 29128006 TI - Neck Imaging Reporting and Data System. AB - The Neck Imaging Reporting and Data System (NI-RADS) is a practical and clinically useful imaging surveillance template designed to guide appropriate imaging follow-up and next-management steps. This article is a practical guide for using NI-RADS to reduce report-generation time for radiologists and create useful reports for referring clinicians and patients. A review of the report template and legend is followed by a case-based and pictorial review of the proper assignment of NI-RADS categories. PMID- 29128007 TI - Computed Tomography Versus Magnetic Resonance in Head and Neck Cancer: When to Use What and Image Optimization Strategies. AB - This article provides a practical overview of head and neck cancers, outlining an approach to evaluating these lesions and optimizing imaging strategies. Recognition of key anatomic landmarks as suggested by American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) criteria is emphasized. Further, the recently updated eighth edition of the AJCC staging manual has introduced some modifications that influence the TNM staging. These modifications are discussed throughout the article to provide an updated review on head and neck cancer. PMID- 29128009 TI - Foreword. PMID- 29128008 TI - Practical Tips for MR Imaging of Perineural Tumor Spread. AB - Perineural tumor spread (PNS) substantially alters a patient's prognosis and treatment plan. Therefore, it is critical that the radiologists are familiar with the course of cranial nerves commonly affected by PNS and the neuronal connections to appropriately map the extent of PNS. Limited involvement of a nerve by PNS might be resectable, whereas advanced PNS may require radiation therapy. PMID- 29128010 TI - Advanced Imaging in Head and Neck Tumors. PMID- 29128011 TI - Overview of Hematopoietic Cell Transplantation for the Treatment of Hematologic Malignancies. AB - Allogeneic hematopoietic cell transplantation offers the best chance for cure in many hematologic malignancies. Key decisions include patient selection, donor and graft source, conditioning regimen, and graft-versus-host disease (GVHD) prophylaxis. Transplant is risky; only one-third survive long term. Complications include relapse, GVHD, infection, and end-organ dysfunction. Expanding indications for transplantation, advancing upper age limits, and improvements in patient care have resulted in increasing numbers of transplant survivors. These patients may suffer substantial long-term health consequences and require intensive follow-up. Future directions include graft engineering and cellular therapy, optimizing donor selection, sensitive disease assessments and/or maintenance therapies, and improvements in care. PMID- 29128012 TI - Noninfectious Acute Lung Injury Syndromes Early After Hematopoietic Stem Cell Transplantation. AB - Noninfectious acute lung injury syndromes are major causes of respiratory failure and early mortality after hematopoietic stem cell transplantation (HSCT). Pulmonary edema and transfusion-related acute lung injuries are important respiratory complications seen after HSCT and in the nontransplant setting. Early transplant-specific causes of lung injury, such as idiopathic pneumonia syndrome, are reviewed. Several complications, such as drug-induced pneumonitis and cryptogenic organizing pneumonia, that occur in both the early and later time periods after HSCT are also briefly discussed. The important role of pretransplant pulmonary function testing measurements in predicting posttransplant respiratory failure is highlighted. PMID- 29128013 TI - Bronchiolitis Obliterans Syndrome and Other Late Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation. AB - As more individuals survive their hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT), there is growing appreciation of the late organ complications of this curative procedure for malignant and nonmalignant hematologic disorders. Late noninfectious pulmonary complications encompass all aspects of the bronchopulmonary anatomy. There have been recent advances in the diagnostic recognition and management of bronchiolitis obliterans syndrome, which is recognized as a pulmonary manifestation of chronic graft versus-host disease. Organizing pneumonia and other interstitial lung diseases are increasingly recognized. This article provides an update on these entities as well as pleural and pulmonary vascular disease after allogeneic HSCT. PMID- 29128014 TI - Overview of Lung Transplantation, Heart-Lung Transplantation, Liver-Lung Transplantation, and Combined Hematopoietic Stem Cell Transplantation and Lung Transplantation. AB - Lung transplantation (LTx) has evolved to represent the therapy of choice for many patients with end-stage lung diseases. Appropriate candidate selection for LTx is an important determinant of a positive outcome from transplantation. Posttransplantation survival has steadily improved, but long-term survival continues to be a challenge with a median survival of 5.8 years. Similarly, combined heart-lung transplantation and simultaneous liver-lung transplantation has been performed successfully in select patients who are not expected to survive either organ transplant alone. Moreover, LTx has been performed in patients who develop end-stage pulmonary complications following hematopoietic stem cell transplantation. PMID- 29128016 TI - Extracorporeal Life Support in Lung Transplantation. AB - Extracorporeal life support in lung transplantation has been associated with poor posttransplant outcomes. However, recent advances have resulted in more favorable posttransplant outcomes. The increased use of this technology must be weighed against the risks inherent in its use, especially when complications arising in extracorporeal membrane oxygenation (ECMO)-dependent patients result in loss of transplant candidacy, leaving them with no viable alternative for long-term support. Existing and emerging data support the judicious use of this technology in carefully selected patients at high-volume transplant and ECMO centers that prioritize minimization of sedation, avoidance of endotracheal intubation, and early mobilization. PMID- 29128015 TI - Primary Graft Dysfunction After Lung Transplantation. AB - Primary graft dysfunction is a form of acute injury after lung transplantation that is associated with significant short- and long-term morbidity and mortality. Multiple mechanisms contribute to the pathogenesis of primary graft dysfunction, including ischemia reperfusion injury, epithelial cell death, endothelial cell dysfunction, innate immune activation, oxidative stress, and release of inflammatory cytokines and chemokines. This article reviews the epidemiology, pathogenesis, risk factors, prevention, and treatment of primary graft dysfunction. PMID- 29128017 TI - Acute Rejection and Antibody-Mediated Rejection in Lung Transplantation. AB - Despite advances in immunosuppression over the past 25 years, acute cellular rejection remains a common complication early after lung transplantation. Although acute cellular rejection has often not resulted in clinical signs or symptoms of allograft dysfunction, it has been widely recognized as a strong independent risk factor for the development of chronic rejection, emphasizing its clinical significance. In recent years, the role of humoral immunity in lung rejection has been increasingly appreciated, and antibody-mediated rejection is now recognized as a form of rejection that may result in allograft failure. PMID- 29128019 TI - Airway Complications After Lung Transplantation. AB - Airway complications remain a significant source of morbidity and mortality after lung transplantation. The incidence of complications is wide-ranging depending on the definition of the event, and there is still no universally accepted grading system for airway findings after transplantation. Additionally, although surgical technique and organ preservation have improved, other modifiable risk factors remain unclear. The management is as wide-ranging as the definitions. A multimodality approach is often needed with airway stenting reserved for refractory cases and stent management by a transplant team with expertise in placement and management of long-term complications." PMID- 29128018 TI - Update in Chronic Lung Allograft Dysfunction. AB - Chronic lung allograft dysfunction (CLAD) is the major limitation to posttransplant survival. This review highlights the evolving definition of CLAD, risk factors, treatment, and expected outcomes after the development of CLAD. PMID- 29128020 TI - Respiratory Viral Infections in Solid Organ and Hematopoietic Stem Cell Transplantation. AB - Respiratory viruses are common in solid organ and hematopoietic stem cell transplant recipients and a recognized cause of significant morbidity and mortality. Epidemiology, risk factors, and attributable mortality in both populations are reviewed. In addition, virus-specific prevention and treatment options, including emerging investigational therapies, are discussed for respiratory syncytial virus, influenza, adenovirus, parainfluenza, and other respiratory viruses. PMID- 29128021 TI - Respiratory Fungal Infections in Solid Organ and Hematopoietic Stem Cell Transplantation. AB - Respiratory fungal infections are associated with high morbidity and mortality in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients, and are caused primarily by molds. Aspergillus is the most common pathogen. The net state of immunosuppression plays a major role in the risk of respiratory fungal infections after transplantation. Clinical presentation can be atypical and diagnosis can be delayed due to low sensitivity of diagnostic methods or inability to obtain adequate specimens. Fungal infections in HSCT and SOT carry a higher risk of dissemination. New prophylaxis strategies have changed the epidemiology of fungal infections in this patient population. PMID- 29128022 TI - Noninfectious Pulmonary Complications of Liver, Heart, and Kidney Transplantation: An Update. AB - Despite significant advances in surgical techniques, perioperative care, and immunosuppressive therapy, solid organ transplantation still carries considerable risk of complications. Pulmonary complications, in particular, are a major cause of morbidity and mortality. Although infectious complications prevail, the lungs are also vulnerable to a variety of noninfectious complications related to the transplant surgery and adverse effects of the immunosuppressive regimen. This article focuses on noninfectious pulmonary complications associated with the 3 most commonly performed solid organ transplant procedures: liver, kidney, and heart. PMID- 29128024 TI - Mycobacterial Infections in Solid Organ and Hematopoietic Stem Cell Transplantation. AB - Mycobacterial infections are uncommon in solid organ and hematopoietic stem cell transplant recipients but carry significant morbidity and mortality. Donor screening strategies for tuberculosis should be emphasized in high-risk populations. Both tuberculosis and nontuberculous mycobacterial infections can have pulmonary and extrapulmonary manifestations of infections. Recommended treatment regimens typically involve multiple drugs with significant adverse effects and drug interactions. PMID- 29128023 TI - Evaluation and Management of the Potential Lung Donor. AB - The expansion of the donor lung pool has involved an evidence-driven redefinition of acceptable donors. Proceeding with transplantation with an acceptable rather than ideal donor depends on specific patient-related and organ-related risk factors as well as the severity of recipient illness. Although the physiologic optimization of brain-dead donors has not changed significantly in recent years, the use of donor management protocols has improved procurement rates. Ex vivo lung perfusion is an increasingly viable strategy to recondition lungs that would otherwise fall below the acceptable threshold for transplant. Ex vivo perfusion trials for preservation of standard donor lungs are ongoing. PMID- 29128025 TI - Posttransplant Lymphoproliferative Disorder in Solid Organ and Hematopoietic Stem Cell Transplantation. AB - Posttransplant lymphoproliferative disorders (PTLD) represent an immunosuppression-related lymphoid or plasmacytic proliferation that occur in the setting of solid organ transplant or allogeneic hematopoietic stem cell transplantation (HSCT). PTLD is a devastating consequence of HSCT and solid organ transplantation with a high morbidity and mortality. Most commonly, PTLD is related to Epstein-Barr virus (EBV) infection, but an increasing number of non EBV-related cases are occurring. Initial therapy involves withdrawal of immunosuppression with or without antibody or cytotoxic chemotherapy. Novel therapeutic approaches including EBV-specific cytotoxic T lymphocytes are currently being studied. PMID- 29128026 TI - Hepatopulmonary Syndrome and Portopulmonary Hypertension: Implications for Liver Transplantation. AB - Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) represent serious pulmonary complications of advanced liver diseases. Orthotopic liver transplantation (OLT) is capable of completely resolving the underlying abnormalities associated with HPS. On the other hand, post-OLT response in patients with PoPH is less predictable, although heavily influenced by pre-OLT mean pulmonary arterial pressure. It remains the case that the opportunity to reverse 2 potentially fatal organ dysfunctions in the liver and the lung make HPS and PoPH more than worthy for further clinical investigations. PMID- 29128027 TI - Pulmonary Considerations in Solid Organ and Hematopoietic Stem Cell Transplantation. PMID- 29128028 TI - From the Editor. PMID- 29128029 TI - 2018 Annual Conference. PMID- 29128030 TI - Understanding Similarities and Differences Among Cultures. PMID- 29128031 TI - Development of a Menu Board Literacy and Self-efficacy Scale for Children. AB - OBJECTIVE: An instrument to measure menu board literacy (MBL) was developed to capture children's understanding of menu board nutrition information, including abbreviations, serving sizes and calorie ranges, and self-efficacy for using this information. METHODS: A list of 55 potential items (47 MBL and 8 self-efficacy) was generated. Content validity was established by 29 registered dietitians. Cognitive interviews were conducted with 24 black and Hispanic fourth- and fifth grade students to assess comprehension and readability. The researchers assessed reliability in 2 fourth- and fifth-grade convenience samples (n = 32 and 141, respectively) of similarly representative students. RESULTS: The final instrument included 20 MBL and 7 self-efficacy items. Internal consistency estimates at both pretest and posttest for the first sample were 0.88 for the MBL scale and 0.80 for the self-efficacy scale. Results for the larger sample were similar. CONCLUSIONS AND IMPLICATIONS: This instrument could be used for assessing MBL and self-efficacy among fourth- and fifth-grade children. The MBL scale provides researchers and practitioners with a tool to measure the role of nutrition literacy and numeracy in point-of-purchase dietary decisions of children, with the potential for use with low-literacy adults as well. PMID- 29128032 TI - Acute effects of ambient air pollution on lower respiratory infections in Hanoi children: An eight-year time series study. AB - BACKGROUND: Lower respiratory diseases are the most frequent causes of hospital admission in children worldwide, particularly in developing countries. Daily levels of air pollution are associated with lower respiratory diseases, as documented in many time-series studies. However, investigations in low-and-middle income countries, such as Vietnam, remain sparse. OBJECTIVE: This study investigated the short-term association of ambient air pollution with daily counts of hospital admissions due to pneumonia, bronchitis and asthma among children aged 0-17 in Hanoi, Vietnam. We explored the impact of age, gender and season on these associations. METHODS: Daily ambient air pollution concentrations and hospital admission counts were extracted from electronic databases received from authorities in Hanoi for the years 2007-2014. The associations between outdoor air pollution levels and hospital admissions were estimated for time lags of zero up to seven days using Quasi-Poisson regression models, adjusted for seasonal variations, meteorological variables, holidays, influenza epidemics and day of week. RESULTS: All ambient air pollutants were positively associated with pneumonia hospitalizations. Significant associations were found for most pollutants except for ozone and sulfur dioxide in children aged 0-17. Increments of an interquartile range (21.9MUg/m3) in the 7-day-average level of NO2 were associated with a 6.1% (95%CI 2.5% to 9.8%) increase in pneumonia hospitalizations. These associations remained stable in two-pollutant models. All pollutants other than CO were positively associated with hospitalizations for bronchitis and asthma. Associations were stronger in infants than in children aged 1-5. CONCLUSION: Strong associations between hospital admissions for lower respiratory infections and daily levels of air pollution confirm the need to adopt sustainable clean air policies in Vietnam to protect children's health. PMID- 29128033 TI - Association of the Emergency Medical Services-Related Time Interval with Survival Outcomes of Out-of-Hospital Cardiac Arrest Cases in Four Asian Metropolitan Cities Using the Scoop-and-Run Emergency Medical Services Model. AB - BACKGROUND: Response time interval (RTI) and scene time interval (STI) are key time variables in the out-of-hospital cardiac arrest (OHCA) cases treated and transported via emergency medical services (EMS). OBJECTIVE: We evaluated distribution and interactive association of RTI and STI with survival outcomes of OHCA in four Asian metropolitan cities. METHODS: An OHCA cohort from Pan-Asian Resuscitation Outcome Study (PAROS) conducted between January 2009 and December 2011 was analyzed. Adult EMS-treated cardiac arrests with presumed cardiac origin were included. A multivariable logistic regression model with an interaction term was used to evaluate the effect of STI according to different RTI categories on survival outcomes. Risk-adjusted predicted rates of survival outcomes were calculated and compared with observed rate. RESULTS: A total of 16,974 OHCA cases were analyzed after serial exclusion. Median RTI was 6.0 min (interquartile range [IQR] 5.0-8.0 min) and median STI was 12.0 min (IQR 8.0-16.1). The prolonged STI in the longest RTI group was associated with a lower rate of survival to discharge or of survival 30 days after arrest (adjusted odds ratio [aOR] 0.59; 95% confidence interval [CI] 0.42-0.81), as well as a poorer neurologic outcome (aOR 0.63; 95% CI 0.41-0.97) without an increasing chance of prehospital return of spontaneous circulation (aOR 1.12; 95% CI 0.88-1.45). CONCLUSIONS: Prolonged STI in OHCA with a delayed response time had a negative association with survival outcomes in four Asian metropolitan cities using the scoop-and-run EMS model. Establishing an optimal STI based on the response time could be considered. PMID- 29128034 TI - Use of Extracorporeal Membrane Oxygenation and Surgical Embolectomy for Massive Pulmonary Embolism in the Emergency Department. AB - BACKGROUND: Massive pulmonary embolism (PE) carries significant morbidity and mortality with current standard of care modalities. CASE REPORT: We present the case of a 63-year-old male status post abdominal surgery 2 weeks before presenting to the emergency department with a massive pulmonary embolism and subsequent acute cardiopulmonary failure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Here we describe a case of extracorporeal membrane oxygenation (ECMO) deployed in the emergency department as a bridge to embolectomy to successfully treat massive pulmonary embolism. This provided the opportunity to establish a "Code ECMO" protocol and algorithm for PE with cardiopulmonary instability so that patients can be rapidly triaged to the appropriate treatment modality. PMID- 29128035 TI - Bedside Identification of Massive Pulmonary Embolism with Point-of-Care Transesophageal Echocardiography. AB - BACKGROUND: Pulmonary embolism can be difficult to diagnose, particularly in those who are hemodynamically unstable and cannot be imaged to confirm the diagnosis. Echocardiography can allow for rapid assessment of patients in shock, but requires adequate transthoracic windows to obtain clinically useful information. Emergency physician-performed transesophageal echocardiography (TEE) may be a useful tool when transthoracic echocardiography fails. CASE REPORT: An 86-year-old woman presented to the emergency department after a fall at home. She rapidly decompensated in the emergency department and sustained a pulseless electrical activity cardiac arrest. Attempts made during the resuscitation to obtain transthoracic echocardiographic views to elicit the cause of the patient's cardiac arrest were unsuccessful. An emergency physician, with previous focused training in TEE, performed emergent TEE. The TEE examination rapidly revealed a dilated right ventricle and an empty, hyperdynamic left ventricle, suggestive of an unsuspected massive acute pulmonary embolism. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: With continued growth and utility of point-of-care ultrasound in emergency medicine, TEE provides an attractive means to assess critically ill patients that may not otherwise be assessable. PMID- 29128036 TI - An Inexpensive Esophageal Balloon Tamponade Trainer. AB - BACKGROUND: Emergency medicine practitioners must be able to perform rare, life saving procedures. One such example is esophageal balloon tamponade, which is complex, fraught with complications, and difficult to demonstrate and practice. DISCUSSION: We constructed a simple, inexpensive model esophagus and stomach that we attached to a mannequin, allowing emergency medicine residents to visualize and practice esophageal balloon tamponade device placement. CONCLUSION: Our esophageal balloon tamponade model was easy to construct and allowed demonstration, conceptual visualization, and simulated performance of the procedure. PMID- 29128037 TI - Ultrasonographic Characteristics of Baker's Cysts: The Sonographic Foucher's Sign. PMID- 29128038 TI - Emergency Physicians Who Produce Higher Relative Value Units Per Hour Spend Similar Amounts of Time at Patient Bedsides as Their Colleagues. AB - BACKGROUND: Emergency physicians (EPs) are expected to deliver quality care while maintaining high levels of efficiency and productivity as measured by the relative value unit (RVU). OBJECTIVES: We sought to determine whether academic EPs with higher RVUs spend less time at the bedside than their colleagues. METHODS: This was a prospective, observational, cohort study. A 13-item task list was generated, pilot-tested, and placed onto a computerized tablet. RESULTS: There was no difference among EPs in terms of time spent at bedside, 26.7% of total time, 17.31 min (95% confidence interval [CI] 14.43-20.19), p = 0.052; resident interaction 13.1%, 8.46 min (95% CI 4.68-12.25), p = 0.959; charting, 11.1%, 7.17 min (95% CI .746-5.65), p = 0.055; information search, 10.5%, 6.80 min (95% CI 0.84-8.52), p = 0.320; walking, 9.0%, 5.86 min (95% CI 5.17-6.54), p = 0.112; consultant interaction, 8.2%, 5.28 min (95% CI 3.18-7.40), p = 0.404; writing orders, 6.5%, 4.19 min (95% CI 3.22-5.15), p = 0.109; nursing interaction, 5.6%, 3.65 min (95% CI 2.54-4.76), p = 0.260; other, 5.2%, 3.65 min (95% CI 1.76-5.02), p = 0.785; medical student interaction, 4.2%, 2.75 min (95% CI 0.53-4.97), p = 0.102; physician assistant interaction, 2.8%, 1.79 min (95% CI 1.08-2.50), p = 0.959; clerical interaction, 1.7%, 1.13 min (95% CI .69-1.57), p = 0.335; and electrocardiogram interpretation, 0.7%, 0.45 min (95% CI .32-.58), p = 0.793. CONCLUSIONS: Despite differences in RVU-based productivity data, academic EPs spend similar amounts of time involved in the daily tasks of taking care of patients, underscoring that direct physician-patient interaction is one practice parameter that is not compromised among these EPs. PMID- 29128039 TI - Healing the Hopeless, or Hopelessly Healing? PMID- 29128040 TI - Christmas Candies as Foreign Bodies. PMID- 29128041 TI - Intraperitoneal Urinary Bladder Perforation with Pneumoperitoneum in Association with Indwelling Foley Catheter Diagnosed in Emergency Department. AB - BACKGROUND: Indwelling Foley catheter is a rare cause of urinary bladder perforation, a serious injury with high mortality that demands accurate and prompt diagnosis. While the gold standard for diagnosis of bladder injury is computed tomography (CT) cystography, few bladder ruptures associated with Foley catheter have been reported to be diagnosed in the emergency department (ED). CASE REPORT: An 83-year-old man with indwelling Foley catheter presented to the ED for hematuria and altered mental status. He was diagnosed to have intraperitoneal rupture of the urinary bladder in the ED using abdominal and pelvic CT without contrast, which demonstrated bladder wall discontinuity, intraperitoneal free fluid, and pneumoperitoneum. The patient was treated successfully with medical management and bladder drainage. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: To our knowledge, this is the first report of intraperitoneal urinary bladder perforation associated with Foley catheter diagnosed in the ED by CT without contrast. Pneumoperitoneum found in this case was a clue to the diagnosis and is a benign finding that does not necessitate urgent surgical intervention. The early and accurate diagnosis in this case allowed for effective management with good clinical outcome. The use of indwelling Foley catheter has a high prevalence, especially in long-term care facility residents, who are frequent visitors in the ED. Therefore, emergency physicians and radiologists should be familiar with the presentation and imaging findings of this potential injury associated with Foley catheters. PMID- 29128043 TI - Transcriptome Alterations in Posttraumatic Stress Disorder. AB - Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder with a lifetime prevalence of nearly 8% in the general population. While the underlying molecular and cellular mechanisms of PTSD remain unknown, recent studies indicate that PTSD is associated with aberrant gene expression in brain as well as peripheral blood cells. The advent of next-generation sequencing technologies will allow us to elucidate the gene expression changes occurring in both brain and blood of patients with PTSD. RNA sequencing allows for analysis of the amount of transcript being made as well as alternative splicing, novel transcript identification, microRNA, and noncoding RNA quantification. Here we provide an overview of the different types of transcriptomic technologies as well as the gene expression studies performed in human peripheral blood and animal models of PTSD, and review the human PTSD postmortem brain gene profiling studies performed to date. PMID- 29128042 TI - Complex coacervation in charge complementary biopolymers: Electrostatic versus surface patch binding. AB - In this review, a number of systems are described to demonstrate the effect of polyelectrolyte chain stiffness (persistence length) on the coacervation phenomena, after we briefly review the field. We consider two specific types of complexation/coacervation: in the first type, DNA is used as a fixed substrate binding to flexible polyions such as gelatin A, bovine serum albumin and chitosan (large persistence length polyelectrolyte binding to low persistence length biopolymer), and in the second case, different substrates such as gelatin A, bovine serum albumin, and chitosan were made to bind to a polyion gelatin B (low persistence length substrate binding to comparable persistence length polyion). Polyelectrolyte chain flexibility was found to have remarkable effect on the polyelectrolyte-protein complex coacervation. The competitive interplay of electrostatic versus surface patch binding (SPB) leading to associative interaction followed by complex coacervation between these biopolymers is elucidated. We modelled the SPB interaction in terms of linear combination of attractive and repulsive Coulombic forces with respect to the solution ionic strength. The aforesaid interactions were established via a universal phase diagram, considering the persistence length of polyion as the sole independent variable. PMID- 29128044 TI - Incidence of Left Ventricular Thrombus in Patients With Acute ST-Segment Elevation Myocardial Infarction Treated with Percutaneous Coronary Intervention. AB - Previous studies using 2-dimensional non-contrast echocardiography have reported a post-ST segment elevation myocardial infarction (STEMI) left ventricular (LV) thrombus incidence of 3% to 24%. However, these studies were not performed with ultrasound contrast agents (UCAs), which improve accuracy in the diagnosis of LV thrombus. We aimed to determine the early incidence and clinical correlates of LV thrombus in a large consecutive cohort of patients with STEMI. This study included consecutive patients admitted to Saint Luke's Mid America Heart Institute with STEMI who also underwent early percutaneous coronary intervention (PCI) and an echocardiogram. A total of 1,698 patients (1,205 men, mean age 61 +/ 13 years) comprised the study group. Echocardiography was performed on hospital day 2, and a UCA was used in 1,292 patients (76%). LV thrombus was identified in 28 (1.6%) patients. A multivariable logistic regression model showed that left anterior descending intervention was independently associated with LV thrombus (odds ratio = 7.58, 95% confidence interval [CI] 2.20 to 26.19, p = 0.001), thrombolysis in myocardial infarction III flow was marginally associated with less LV thrombus (odds ratio = 0.41, 95% CI 0.16 to 1.04, p = 0.060), and higher LVEF was associated with less LV thrombus (odds ratio = 0.96, 95% CI 0.91 to 0.97, p <0.001). In conclusion, LV thrombus was identified in only 1.6% of patients in a large STEMI cohort, significantly lower than previous studies. A UCA was used in most echocardiograms, and it improves accuracy in the detection and exclusion of LV thrombus. PMID- 29128045 TI - Recombinant prohibitin protein of Leishmania infantum acts as a vaccine candidate and diagnostic marker against visceral leishmaniasis. AB - Visceral leishmaniasis (VL) represents a serious public health problem, as Leishmania infantum is one of main disease causative agents in the Americas. In a previous immunoproteomic study, the prohibitin (PHB) protein was identified in L. infantum promastigote and amastigote extracts by antibodies in asymptomatic and symptomatic VL dog sera. This protein was found to be highly conserved between different Leishmania spp., but it presented a low identity with amino acid sequences of other organisms. The aim of the present study was to evaluate the cellular response induced by the recombinant PHB (rPHB) protein in BALB/c mice, as well as in PBMCs purified from untreated and treated VL patients, as well as to evaluate its protective efficacy against an infection by L. infantum promastigotes. Our data showed that there was a Th1 cellular response to rPHB, based on high levels of IFN-gamma, IL-12, and GM-CSF in the immunized animals, as well as a proliferative response specific to the protein and higher IFN-gamma levels induced in PBMCs from individuals who had recovered from the disease. The protection was represented by significant reductions in the parasite load in the animals' spleen, liver, bone marrow, and draining lymph nodes, as compared to results found in the control groups. In addition, an anti-rPHB serology, using a canine and human serological panel, showed a high performance of this protein when diagnosing VL based on high sensitivity and specificity values, as compared to results found for the rA2 antigen and the soluble Leishmania antigenic extract. Our data suggest that PHB has a potential application for the diagnosis of canine and human VL through antibody detection, as well as an application as a vaccine candidate to protect against disease. PMID- 29128046 TI - Preoperative Anemia in Cardiac Operation: Does Hemoglobin Tell the Whole Story? AB - BACKGROUND: Preoperative anemia, defined by hemoglobin level, is associated with elevated risk after cardiac operation. Better understanding of anemia requires characterization beyond this. This investigation focuses on red cell size and its association with patient characteristics and outcomes after cardiac operation. METHODS: From January 2010 to January 2014, 10,589 patients underwent elective cardiac operations at Cleveland Clinic. Anemia was characterized as normocytic, microcytic, or macrocytic based on mean corpuscular volume (MCV). Models for hospital complications were developed using multivariable logistic regression. Other outcomes were postoperative transfusion and intensive care unit (ICU) and postoperative hospital lengths of stay. RESULTS: A total of 2,715 patients (26%) were anemic. Of these, 2,365 (87%) had normocytic, 219 (8.1%) microcytic, and 131 (4.8%) macrocytic anemia. Non-anemic patients (n = 2,041, 26%) received transfusions compared with 1,553 (66%) normocytic, 148 (68%) microcytic, and 97 (74%) macrocytic anemia patients. Patients with normocytic or macrocytic anemia had more renal failure (normocytic: odds ratio (OR) 1.9, macrocytic: OR 3.5), other complications (normocytic: OR 1.3, macrocytic: OR 2.2) and death (normocytic: OR 2.0, macrocytic: OR 6.2) than non-anemic patients; patients with microcytic anemia had fewer reoperations (OR 0.35) and less postoperative atrial fibrillation (OR 0.50). Anemic patients experienced longer ICU (27 versus 48 hours, p < 0.001) and postoperative hospital (6.1 versus 7.4 days, p < 0.001) length of stay than non-anemic patients. CONCLUSIONS: Cardiac surgical patients are often anemic. Demographic characteristics, comorbidities, and outcomes are dissimilar according to red cell size. Patients with microcytic anemia had the lowest hemoglobin levels, yet the best clinical outcomes among anemic patients. MCV from the standard complete blood count adds additional information beyond hemoglobin for targeted intervention. PMID- 29128047 TI - Use of Lung Allografts From Donation After Cardiac Death Donors: A Single-Center Experience. AB - BACKGROUND: Lung transplantation remains the only treatment for end-stage lung disease. Availability of suitable lungs does not parallel this growing trend. Centers using donation after cardiac death (DCD) donor lungs report comparable outcomes with those from brain-dead donors. Donor assessment protocols and consistent surgical teams have been advocated when considering using the use of DCD donors. We present our experience using lungs from Maastricht category III DCD donors. METHODS: Starting 2007 to July 2016, 73 DCD donors were assessed, 44 provided suitable lungs that resulted in 46 transplants. A 2012 to October 2016 comparative cohort of 379 brain-dead donors were assessed. Recipient and donor characteristics and primary graft dysfunction (PGD) and survival were monitored. RESULTS: Seventy-three DCD (40% dry run rate) donors assessed yielded 46 transplants (23 double, 6 right, and 17 left). Comparative cohort of 379 brain dead donors yielded 237 transplants (112 double, 43 right, and 82 left). One- and 3-year recipient survival was 91% and 78% for recipients of DCD lungs and 91% and 75% for recipients of lungs from brain-dead donors, respectively. PGD 2 and 3 in DCD recipients at 72 hours was 4 of 46 (9%) and 6 of 46 (13%), respectively. Comparatively, brain-dead donor recipient cohort at 72 hours with PGD 2 and 3 was 23 of 237 (10%) and 41 of 237 (17%), respectively. CONCLUSIONS: Our experience reaffirms the use of lungs from DCD donors as a viable source with favorable outcomes. Recipients from DCD donors showed equivalent PGD rate at 72 hours and survival compared with recipients from brain-dead donors. PMID- 29128049 TI - Clinical and Economic Burden of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with an increasing global prevalence associated with tremendous clinical, economic, and health-related quality-of-life burden. Clinically, NAFLD is considered the liver manifestation of metabolic syndrome. However, diagnosing NAFLD presents significant challenges due to the limited noninvasive and accurate diagnostic tools available to not only accurately diagnose nonalcoholic steatohepatitis but also to stage hepatic fibrosis, the major predictor of long-term outcomes, including mortality. PMID- 29128050 TI - The Use of Liver Biopsy in Nonalcoholic Fatty Liver Disease: When to Biopsy and in Whom. AB - Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder that can be divided into benign steatosis or nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Elastography and scoring systems based on clinical features and routine biochemical testing can be used to assess fibrosis in patients with NAFLD. Patients with fibrosis are thought to have NASH. However, only a liver biopsy can reliably diagnose NAFLD and differentiate NAFL from NASH. Because medical therapy for NASH is not available, it is not necessary to perform a liver biopsy in all patients. Patients suspected of having NASH should undergo liver biopsy. PMID- 29128051 TI - The Natural History of Nonalcoholic Fatty Liver Disease-An Evolving View. AB - Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease worldwide, and its clinical and economic burden will continue to grow with parallel increases in rates of obesity, diabetes, and the metabolic syndrome. Evolving understanding of the natural history of NAFLD suggests that these patients are at risk for disease progression to steatohepatitis, fibrosis, and cirrhosis. Recent studies also suggest that these patients are at elevated risk for cardiovascular-, malignancy-, and liver-related morbidity and mortality, although their risk for progression, decompensation, and hepatocellular carcinoma may be less than that of patients with alternative causes of chronic liver disease. PMID- 29128053 TI - Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. AB - Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) are highly prevalent, affecting approximately one-third of the US population. The relationship between NAFLD and MS is complex and may be bidirectionally associated. NAFLD is strongly associated with MS, the components of which include abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. NAFLD associated with certain genetic factors such as the PNPLA3 G allele variant is not accompanied by insulin resistance and MS. Lifestyle modification, including diet and physical activity targeting visceral adiposity, remains the standard of care for patients with NAFLD and MS. PMID- 29128052 TI - The Intestinal Microbiome in Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease is the most common cause of chronic liver disease in North America and is growing as a cause of chronic liver disease in many other parts of the world as well. It has 2 principal clinical-pathologic phenotypes: (1) nonalcoholic fatty liver and (2) nonalcoholic steatohepatitis. The development of both phenotypes is tightly linked to excess body weight and insulin resistance. This review discusses the emerging tools for the analysis of the microbiome, their limitations, and the existing literature with respect to the intestinal microbiome and their role in nonalcoholic fatty liver. PMID- 29128054 TI - The Role of Nonalcoholic Fatty Liver Disease on Cardiovascular Manifestations and Outcomes. AB - Cardiovascular disease has been postulated as the leading cause of mortality among patients with nonalcoholic fatty liver disease (NAFLD), rather than from sequalae of liver disease specifically. While there is ample evidence validating the association between NAFLD and increased cardiovascular comorbidities, events, and mortality, current data presents a challenge in attributing this effect solely due to NAFLD given the rampant presence of insulin resistance and type 2 diabetes mellitus (T2DM). Endpoints of increased cardiovascular risk remains tightly linked to the concomitant presence of insulin resistance and T2DM. Prospective studies accentuating early detection of NAFLD are imperative to institute early intervention and prevent future cardiovascular events. PMID- 29128055 TI - Current Treatment of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. AB - Treatment of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is focused on patients with NASH because they are at highest risk for progressive liver disease. Current first-line treatment consists of lifestyle modifications. Patients should lose at least 7% to 10% of body weight via a combination of physical exercise and calorie restriction dieting. Surgical or endoscopic surgery for weight loss can be considered in obese patients, depending on degree of excess body weight and comorbidities. There is no currently approved pharmacotherapy for NASH. Vitamin E and pioglitazone have the most evidence of therapeutic efficacy but have limitations. The treatment modality chosen should be individualized. PMID- 29128056 TI - Emerging Treatments for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. AB - This review discusses completed phase II randomized clinical trials with high quality published results for compounds that demonstrate effects on nonalcoholic steatohepatitis histology (obeticholic acid, elafibranor, and liraglutide). The authors also review the available preliminary data on cenicriviroc and selonsertib, with or without simtuzumab's phase II studies. Finally, the authors briefly discuss compounds that have been tested but did not achieve the primary end point of histologic improvement and appeared in high-quality published articles (cysteamine bitartrate and long-chain polyunsaturated fatty acids). PMID- 29128057 TI - Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma. AB - Although hepatocellular carcinoma (HCC) is more common in the setting of cirrhosis, there is increasing evidence that it can develop in the setting of noncirrhotic nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and that steatosis alone can promote carcinogenesis. In addition, obesity, diabetes, and metabolic syndrome are recognized risks for the development of HCC. A better understanding of the mechanisms involved in the development of NAFLD/NASH-related HCC will allow the discovery of new targets for therapeutic and preventive intervention. The surveillance for HCC in the setting of noncirrhotic NAFLD/NASH, obesity, diabetes, and metabolic syndrome remains an area of uncertainty. PMID- 29128058 TI - Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis in Liver Transplantation. AB - The number of transplants caused by nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) has been progressively increasing and this is expected to become the most common indication for liver transplant in the United States. Patients with NASH show many features of the metabolic syndrome and, as a result, are at higher risk for postoperative cardiovascular morbidity and mortality. Despite this, patients with NASH have long-term graft and patient survival rates comparable with other causes of chronic liver disease. Posttransplant metabolic syndrome is a common occurrence that increases the risk of steatosis in the graft liver. PMID- 29128059 TI - Pathophysiology of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH) and ultimately may lead to cirrhosis. Hepatic steatosis or fatty liver is defined as increased accumulation of lipids in hepatocytes and results from increased production or reduced clearance of hepatic triglycerides or fatty acids. Fatty liver can progress to NASH in a significant proportion of subjects. NASH is a necroinflammatory liver disease governed by multiple pathways that are not completely elucidated. This review describes the main mechanisms that have been reported to contribute to the pathophysiology of NAFLD and NASH. PMID- 29128060 TI - Risk Factors for the Development of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Including Genetics. AB - Nonalcoholic fatty liver disease is emerging as the most common cause of chronic liver disease worldwide. This trend is, in part, secondary, to the growing incidence of obesity, type 2 diabetes, and metabolic syndrome. Other risk factors include age, gender, race/ethnicity, genetic predisposition, and polycystic ovarian disease. With the introduction of genome-wide association studies, genetic mutations contributing to inherited susceptibility to steatosis have been identified, which hold keys to future improvement in diagnosis and management. This article expands on the aforementioned risk factors and summarizes the current available data on genetic and environmental factors associated with this common entity. PMID- 29128061 TI - The Genetics of Pediatric Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Severe fibrosis and cirrhosis are potential consequences of pediatric NAFLD and can occur within a few years of diagnosis. Observations suggest that genetics may be a strong modifying factor in the presentation, severity, and natural history of the disease. There is increasing interest in determining at-risk populations based on genetics in the hope of finding genotypes that correlate to NAFLD phenotype. Ultimately, the hope is to be able to tailor therapeutics to genetic predispositions and decrease disease morbidity in children with NAFLD. PMID- 29128062 TI - Diagnosis and Evaluation of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Including Noninvasive Biomarkers and Transient Elastography. AB - The incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) are increasing and identification of people at risk of disease progression is extremely important. The current gold standard for diagnosing NAFLD/nonalcoholic steatohepatitis (NASH) is by liver biopsy, but it has several limitations. Noninvasive tests via biomarkers and transient elastography to assess NAFLD/NASH are being used in clinical practice. The most validated diagnostic panels include the NAFLD fibrosis score, FIB-4 (Fibrosis-4), and FibroMeter. Transient elastography is very useful in evaluating advanced fibrosis and cirrhosis. PMID- 29128063 TI - Radiologic Imaging in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. AB - The article reviews the multimodality (ultrasound, computed tomography, and magnetic resonance [MR]) imaging appearance of nonalcoholic fatty liver disease (NAFLD) and discusses the radiologic diagnostic criteria as well as the sensitivity and specificity of these imaging methods. The authors review the role of both ultrasound and MR elastography for the diagnosis of fibrosis and for the longitudinal evaluation of patients following therapeutic intervention. Lastly, the authors briefly discuss the screening and diagnosis of hepatocellular carcinoma in patients with NAFLD, as there are special considerations in this population. PMID- 29128064 TI - Nonalcoholic Fatty Liver Disease: An Expanding Health Care Epidemic. PMID- 29128065 TI - Flow Cytometry of B-Cell Neoplasms. AB - Flow cytometric evaluation is considered a standard ancillary study for the diagnosis of most B-cell lymphoproliferative disorders. Establishing a neoplastic B-cell population depends on identification of light chain restriction or lack of light chain expression in mature neoplasms and demonstration of aberrant antigen expression in both immature and mature neoplasms, as compared with normal counterparts. The immunophenotypes of the most common B-cell neoplasms are herein described, with an emphasis on their immunophenotypic differential diagnosis and prognostic and therapeutic implications. PMID- 29128066 TI - Flow Cytometry of T cells and T-cell Neoplasms. AB - Flow cytometry is ideally suited for the immunophenotypic analysis of T-cell neoplasia. This article covers the spectrum of flow cytometric findings associated with frequently encountered benign and neoplastic T-cell populations and details the most common immunophenotypic features associated with specific neoplasms of both immature and mature T cells. PMID- 29128067 TI - Acute Myeloid Leukemia Immunophenotyping by Flow Cytometric Analysis. AB - Flow cytometry plays an indispensible role in the diagnosis and subclassification of acute myeloid leukemia (AML). Using a multiparametric approach, flow cytometry immunophenotyping has the advantage of efficiency with high sensitivity. This article reviews the general gating strategy, antibody panels for routine analysis, and additional markers for lineage assignment in the subclassification of AML. Also discussed are diagnostic immunophenotypic features of hard-to classify entities considered within the differential diagnosis of AML. Finally, briefly presented are the principles underlying the use of flow cytometry for minimal residual disease detection. PMID- 29128068 TI - B Lymphoblastic Leukemia Minimal Residual Disease Assessment by Flow Cytometric Analysis. AB - Among the most thoroughly evaluated modalities for assessment of minimal residual disease (MRD) in B acute lymphoblastic leukemia is multiparameter flow cytometry. Flow cytometric evaluation of MRD for B-ALL requires complete understanding of the immunophenotype of hematogones, the normal counterpart of leukemic B lymphoblasts. Assessment of multiple flow cytometry markers, in concert with each other in multidimensional histograms, is necessary to distinguish hematogones from malignant blasts. Emerging therapies targeting CD19 and other B-cell markers can disrupt the most frequently MRD assessment, requiring a revised approach as use of targeted therapies becomes widespread. PMID- 29128069 TI - How Do We Use Multicolor Flow Cytometry to Detect Minimal Residual Disease in Acute Myeloid Leukemia? AB - Multicolor flow cytometry (MFC), combined with molecular and cytogenetic studies, is the most common method for detecting minimal residual disease (MRD) in acute myeloid leukemia (AML). Studies have shown that a positive MFC MRD study after induction and/or consolidation, or before allogeneic hematopoietic stem cell transplantation, correlates with risk of relapse and inferior survival. However, there is little information on technical and analytical details. This article shares the authors' experience using MFC for AML MRD detection, including antibody panel design, data analysis, and interpretation. It summarizes diagnostic pearls and pitfalls, and provides practical information for pathologists or hematologists. PMID- 29128070 TI - Flow Cytometric Assessment of Chronic Myeloid Neoplasms. AB - Flow cytometry immunophenotyping of the hematopoietic cells from the bone marrow can help with diagnosis, prognosis, and therapy of chronic myeloid neoplasms. Unlike with B-cell neoplasms, there is no simple phenotypic test to substitute for clonality. Therefore, antigen panels to evaluate myeloid neoplasms are larger, and the gating strategies more complex than for lymphoid neoplasms. The number of phenotypic abnormalities in hematopoietic cells correlates with disease severity and cytogenetic complexity, and can be integrated into a scoring system for diagnostic and prognostic purposes. However, flow cytometry remains only an adjunct diagnostic modality. PMID- 29128072 TI - Paroxysmal Nocturnal Hemoglobinuria Assessment by Flow Cytometric Analysis. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon but frequently debilitating disease that, if untreated, may lead to death in up to 35% of patients within 5 years. Assessment of PNH clone size by flow cytometric analysis has increased in importance with the availability of therapeutic treatments, which prevent the hemolysis of red blood cells and, hence, the myriad symptoms that accompany the disease. This article addresses flow cytometric methodologies and highlights areas of importance in implementing testing, not only for classic PNH but also for other related bone marrow failure disorders, such as aplastic anemia and low-grade myelodysplastic syndrome. PMID- 29128073 TI - Mast Cell Disease Assessment by Flow Cytometric Analysis. AB - Mast cells are present at a low frequency in bone marrow, rendering high sensitivity multiparametric flow cytometric analysis an ideal method to assess antigen expression on mast cells. This article discusses the normal antigen expression profile of mast cells, established criteria to identify neoplastic mast cells, and new immunophenotypic markers and approaches to identify the presence of neoplastic mast cells in cases of mastocytosis. PMID- 29128074 TI - Flow Cytometry in Pediatric Hematopoietic Malignancies. AB - Utility of flow cytometry in the evaluation of pediatric hematopoietic neoplasms and the differences from adult hematopoietic neoplasms are discussed in this review. Distinction of hematogones from B-lymphoblasts, detection of residual/relapsed disease after novel targeted therapies, and evaluation of pediatric myeloid neoplasms are discussed. PMID- 29128075 TI - Flow Cytometric Evaluation of Primary Immunodeficiencies. AB - Primary immunodeficiency diseases are genetic disorders that mostly cause susceptibility to infections and are sometimes associated with autoimmune and malignant diseases. For early detection and management of these diseases, flow cytometric procedures allow an encompassing assessment of cellular phenotypes and cellular functions. State-of-the art cytometry is based today on 8- to 10-color staining and includes an assessment of lineage maturation and functional markers. PMID- 29128071 TI - Diagnosis of Plasma Cell Dyscrasias and Monitoring of Minimal Residual Disease by Multiparametric Flow Cytometry. AB - Plasma cell dyscrasia (PCD) is a heterogeneous disease that has seen a tremendous change in outcomes due to improved therapies. Over the past few decades, multiparametric flow cytometry has played an important role in the detection and monitoring of PCDs. Flow cytometry is a high-sensitivity assay for early detection of minimal residual disease (MRD) that correlates well with progression free survival and overall survival. Before flow cytometry can be effectively implemented in the clinical setting, sample preparation, panel configuration, analysis, and gating strategies must be optimized to ensure accurate results. Current consensus methods and reporting guidelines for MRD testing are discussed. PMID- 29128076 TI - Cost-Effective Flow Cytometry Testing Strategies. AB - Cost-effective flow cytometry (FC) requires development of FC panels focused to common diagnoses and strategies to identify cases where limited FC testing is sufficient. Focused panels include sufficient antibodies and to identify common diseases and appropriate analysis strategies to identify rare diseases that need additional FC testing. Strategies to limit FC testing include the use of algorithms to predict disease probability, with limited FC performed if disease is unlikely. Successful algorithms use easily available parameters, have well defined rules for use, and are periodically reviewed and updated to maximize efficiency while containing costs. PMID- 29128077 TI - Automated Analysis of Clinical Flow Cytometry Data: A Chronic Lymphocytic Leukemia Illustration. AB - Flow cytometry is used in cell-based diagnostic evaluation for blood-borne malignancies including leukemia and lymphoma. The current practice for cytometry data analysis relies on manual gating to identify cell subsets in complex mixtures, which is subjective, labor-intensive, and poorly reproducible. This article reviews recent efforts to develop, validate, and disseminate automated computational methods and pipelines for cytometry data analysis that could help overcome the limitations of manual analysis and provide for efficient and data driven diagnostic applications. It demonstrates the performance of an optimized computational pipeline in a pilot study of chronic lymphocytic leukemia data from the authors' clinical diagnostic laboratory. PMID- 29128078 TI - Applications of Mass Cytometry in Clinical Medicine: The Promise and Perils of Clinical CyTOF. AB - Mass cytometry is a novel technology similar to flow cytometry in which antibodies are tagged with heavy metal molecules rather than fluorophores and then detected with time-of-flight mass spectrometry. This enables measurement of up to 50 simultaneous parameters with no autofluorescent background and little or no spillover or required compensation. Mass cytometry has tremendous potential for the analysis of highly complex clinical samples for the diagnosis and monitoring of malignant and autoimmune disorders. The technology also presents several unique challenges for clinical use and will require new approaches to analyze the large amounts of data generated. PMID- 29128079 TI - Clinical Flow Cytometry: State-of-the-Art and New Approaches. PMID- 29128080 TI - [Crossed perceptions about malnutrition in patients and their doctors in oncology]. AB - Malnutrition is common in oncology. However, it is often detected too late and nutritional support is sub-optimal. The patient's opinion, although often sought in therapeutic decisions in oncology, does not appear to be frequently taken into account in dietetic management. In NutriCancer2012 study, we interviewed patients, relatives and doctors about their perceptions of the impact of malnutrition and its quality of care. Of the 2209 patients questioned, majority said they were concerned about nutrition with 75% considering it essential to take appropriate nutritional care but only 19% self-reported link between malnutrition and fatigue. Physicians underestimated impact of malnutrition on patient's "quality of life". Doctors referred to the lack of human resources and knowledge in nutrition, and more than 80% wished the creation of nutrition teams. Sensitization of the general public and patients (and relatives) as soon as the cancer diagnosis could lead to better malnutrition's screening. Better nutrition training for physicians and creation of nutrition team could optimize management and improve efficacy during cancer treatments. PMID- 29128081 TI - [Why and how to promote decision-making autonomy of cancer patients?] AB - Involvement of patients in decision-making about their health has been promoted nationally and internationally since several years. Despite this, patient (and their relatives) participation remains insufficient and one of the objectives of the current French national cancer policy (Plan cancer 2014-2019) is to give everyone the possibility to play an active role in the management of their care. This overview focuses on decision-making autonomy of cancer patients through two main questions: why and how to promote it? After a brief review of the decision making models described in the literature in the past decades insisting on the major role of the decisional context and the dynamic character of this context, this article presents a selection of published works which aimed to respond to those 2 questions. PMID- 29128082 TI - [National care logbook for patients undergoing autologous hematopoietic cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. AB - In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its seventh annual workshop series in September 2016 in Lille. This event brought together practitioners from across the country. Our workshop discusses the creation of a patient care logbook for patients undergoing autologous hematopoietic cell transplantation. PMID- 29128083 TI - Evolution of hepatocellular carcinoma epidemiology in Cote d'Ivoire. AB - INTRODUCTION: Hepatocellular carcinoma is a major concern for Public health in West Africa. In Cote d'Ivoire, the bulk of our knowledge stems from studies conducted decades ago. Our aim was, thus, to assess whether the epidemiological features of this tumor changed recently. METHODS: Records from 863 patients diagnosed between 2007 and 2014 were analyzed. RESULTS: We observed major drifts concerning hepatocellular carcinoma with regards to the 1970-1980 period. Age at presentation is substantially delayed (49.4+/-14.1 years) whereas sex ratio decreased substantially (M:F=2.6). Patients seropositive for hepatitis B surface antigen and anti-hepatitis C virus represented 65% and 25% of cases whereas alcohol intake was reported in 36%. AFP level was above 400ng/mL in 36% of cases and tumors were already multinodular and/or metastatic at diagnosis in 77% and 26% of patients. Geographical and anthropological variations were observed with excesses of female cases affecting regions (Lagunes) or linguisitic groups (Kru). North-Mande speakers were more often identified as nonBnonC than others. DISCUSSION: Ivorian epidemiology of hepatocellular carcinoma was reshaped during the last decades. These changes, most likely due to the spread of hepatitis C virus, resulted in an older and feminized population of patients. We fear that the current and future prevalence of anti-HCV cases might thwart the expected benefits of anti-hepatitis B immunization. Appropriate measures should be taken to prevent further transmission of hepatitis C in the country. PMID- 29128084 TI - [Chimerism analysis after hematopoietic cell transplantation: Guidelines from the Francophone Society of bone marrow transplantation and cellular therapy (SFGM TC)]. AB - Chimerism analysis is an important step for the patient follow-up after hematopoietic stem cell transplantation. It is used to quantify the donor and the recipient part of a cell population issued from blood or bone marrow sample. In addition to hemogram, this technique is necessary to appreciate the quality of engraftment. The aim of this article is to propose some recommendation about methods, result analysis and therapeutic decision in hematopoietic stem cell transplantation for malignant or non-malignant diseases. PMID- 29128085 TI - [HLA coding in ProMISe: Guidelines from the Francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. AB - As part of the 7th Annual francophone workshop series on the harmonization of clinical practices in allogeneic stem cell transplantation held in Lille in September 2016, our workgroup discussed how transplant centers might follow a collective approach to coding data. This was done mainly by analyzing the study results found in the literature that do not provide clear answers. In addition, we discuss practical ways of coding for both donor and recipient HLA typing in the European bone marrow transplantation database called ProMISe which is managed by the European Society for Blood and Marrow Transplantation (EBMT). PMID- 29128086 TI - Delayed presentation and diagnosis of breast cancer in African women: a systematic review. AB - PURPOSE: Africa has low breast cancer incidence rates but high mortality rates from this disease due to poor survival. Delays in presentation and diagnosis are major determinants of breast cancer survival, but these have not been comprehensively investigated in Africa. METHODS: MEDLINE, Embase, and Global Health were searched to identify studies reporting on delays in presentation and/or diagnosis of breast cancer published between January 1, 2000 and May 31, 2016. Data were synthesized in narrative, tabular, and graphical forms. Meta analyses were not possible due to between-study differences in the way delays were reported. RESULTS: Twenty-one studies were included in the review. Study specific average times between symptom recognition and presentation to a health care provider ranged from less than 1 to 4 months in North Africa and from less than 3 to greater than 6 months in sub-Saharan Africa. Study-specific average times from presentation to diagnosis were less than 1 month in North Africa but ranged from less than 3 to greater than 6 months in sub-Saharan Africa. Reported reasons for these delays included patient-mediated (e.g., socioeconomic factors) and health system-mediated factors (e.g., referral pathways). CONCLUSIONS: This systematic review revealed marked delays in presentation and diagnosis of breast cancer in Africa. Identification of their drivers is crucial to the development of appropriate control strategies in the continent. PMID- 29128087 TI - [Platelet-rich plasma (PRP) and disc lesions: A review of the literature]. AB - The spine has been the subject of extensive clinical research since it is the source of many painful complaints. However, there is little scientific evidence concerning the therapeutic proposals. During the course of life, the intervertebral disc degenerates, which over time diminishes its damping capacity and facilitates the expulsion of the nucleus pulposus through the annulus fibrosus. The degeneration of the intervertebral disc (DDI) is the origin of some back pain and various specific treatments have been developed. These include the infiltration at the center of the intervertebral disc of plasma rich platelet (PRP), composed of multiple growth factors which act on the disc degeneration. This treatment is recent and less invasive than surgery. Preliminary results seem promising. However, many gray areas and several parameters remained to be clarified. In an attempt to do this, a literature review was conducted based on bibliographic databases Pubmed, Medline and Scopus(r) using the following Mesh terms : PRP, platelet-rich plasma, intradiscal disc degeneration, disc, intradiscal, discogenic. This analysis reveals that at the present time, no reported study has a sufficient perspective to judge the effectiveness of the infiltration of PRP. Early harvest results will be used to set the limits of this treatment. Accordingly, it is therefore currently recommended to introduce PRP injection as a complementary solution to comprehensive care of the spine. Future research will need to generate randomized controlled studies including comparing the results with conservative treatment and measure the cost-benefit relationship. PMID- 29128088 TI - Emergency Contraception. PMID- 29128089 TI - Confidentiality in Adolescent Health Care. PMID- 29128090 TI - Crocus sativus L. aqueous extract reduces atherogenesis, increases atherosclerotic plaque stability and improves glucose control in diabetic atherosclerotic animals. AB - BACKGROUND AND AIMS: We aimed to evaluate a possible atheroprotective effect of saffron aqueous extract (SFE), and its potential anti-inflammatory mechanisms, in apoE knockout (ApoE-/-) mice. METHODS: Fifty male, ApoE-/- mice, fed a high-fat diet (HFD) for 12 weeks, were randomized into 5 groups: (1) baseline group, euthanatized, without intervention, (2) three saffron groups, receiving HFD and 30,60,90 mg/kg/day of SFE, respectively, for four weeks, per os through gavage, after reconstitution in water for injection (WFI), (3) control group (COG), receiving daily HFD and the same volume of WFI (four weeks). After blood sampling and euthanasia, aortic roots were excised and analyzed for gene expression and/or percentage of aortic stenosis, relative content of macrophages, smooth muscle cells (SMCs), connective tissue, tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases-2,-3,-9 (MMP-2,-3,-9) and their inhibitor (TIMP-2) and IL-6. SFE doses were determined by a pilot serum pharmacokinetic study in C57BL/6J wild-type mice. RESULTS: SFE did not affect body weight and total cholesterol levels (p > 0.05), while high SFE dose significantly ameliorated glucose and triglycerides profiles compared to other groups (p < 0.05). SFE considerably decreased aortic stenosis in a dose dependent manner (p < 0.05). Furthermore, increasing SFE doses proportionally reduced macrophages content and increased within plaques content of collagen, elastin, and SMCs, promoting more stable plaque phenotype compared to COG (p < 0.05). Those effects seemed to be associated with a considerable reduction (>30%) in IL-6, TNF-alpha, MCP-1, MMP-2,-3,-9 (p < 0.05) and MMP-2/TIMP-2 ratio. CONCLUSIONS: SFE exerted dose-dependent anti-atherosclerotic and plaque stabilizing effects in Apo-E-/- mice, probably mediated by a favorable modification of inflammatory mechanisms, which requires further investigation. PMID- 29128091 TI - Non-protease native allergens partially purified from bodies of eight domestic mites using p-aminobenzamidine ligand. AB - BACKGROUND: Optimised purification steps for concentrating trace target native antigens are needed. Combining the p-aminobenzamidine ligand with protease inactivation enables partial purification of mite non-protease allergens lacking proteases. OBJECTIVE: We sought to analyse in detail proteins obtained using this method from eight species of synanthropic acaridid mites and tested IgE reactivity using pooled human sera. MATERIALS AND METHODS: Proteins affinity bound to p-aminobenzamidine as a ligand were identified by MALDI TOF/TOF. After electroblotting, the proteins were visualised using the fluorescent SYPRO-Ruby protein blot stain, and IgE reactivity was further analysed using pooled human sera collected from patients allergic to house dust mites. RESULTS: MS/MS identification confirmed previous results that no proteases were purified. Protein patterns corresponding to the allergens Der f 7, Der f 30 and actins indicated that these proteins are purified using p-aminobenzamidine and are present across a wide spectrum of acaridid mites. When using Dermatophagoides farinae, apolipophorins (Der f 14), chitinase-like Der f 15 and 18, 70-kDa heat shock protein, and a Der f Alt a10 allergen homolog (gi|37958173) were also detected. The target antigens tropomyosins and paramyosins showed similar IgE binding among the mite species tested. IgE reactivity with miscellaneous D. farinae antigen was also observed. CONCLUSIONS: Partial purification of mite non protease antigens using a strategy combining p-aminobenzamidine with protease inactivation was verified by 1D-E and 2D-E analyses. IgE binding to p aminobenzamidine-purified native non-protease mite antigens was tested using pooled sera. This preliminary study allows for further work on individual serum samples, allowing confirmation of immunoreactivity. PMID- 29128092 TI - Quality requirements for allergen extracts and allergoids for allergen immunotherapy. AB - All allergen products for allergen immunotherapy currently marketed in the European Union are pharmaceutical preparations derived from allergen-containing source materials like pollens, mites and moulds. Especially this natural origin results in particular demands for the regulatory requirements governing allergen products. Furthermore, the development of regulatory requirements is complicated by the so far missing universal link between certain quality parameters, in particular biological potency, on the one hand and clinical efficacy on the other hand. As a consequence, each allergen product for specific immunotherapy has to be assessed individually for its quality, safety and efficacy. At the same time, biological potency of allergen products is most commonly determined using IgE inhibition assays based on human sera relative to product-specific in house references, ruling out full comparability of products from different manufacturers. This review article aims to summarize the current quality requirements for allergen products including the special requirements implemented for control of chemically modified allergen extracts (allergoids). PMID- 29128093 TI - Miniaturized matrix solid-phase dispersion followed by liquid chromatography tandem mass spectrometry for the quantification of synthetic dyes in cosmetics and foodstuffs used or consumed by children. AB - Miniaturized matrix solid-phase dispersion (MSPD) followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) has been proposed for the simultaneous analysis of different classes of synthetic dyes in confectionery and cosmetics intended for or mostly consumed by children. Selected compounds include most of the permitted dyes as food additives as well as some of the most frequently used to color cosmetic products in accordance with the respective European directives. MSPD procedure was optimized by means of experimental design, allowing an effective, rapid and simple extraction of dyes with low sample and reagents consumption (0.1g of sample and 2mL of elution solvent). LC MS/MS was optimized for good resolution, selectivity and sensitivity using a low ionic strength mobile phase (3mM NH4Ac-methanol). Method performance was demonstrated in real samples showing good linearity (R>=0.9928) and intra- and inter-day precision (%RSD<=15%). Method LODs were <=0.952MUgg-1 and <=0.476MUgg-1 for confectionery and cosmetic samples, respectively. Recoveries of compounds from nine different matrices were quantitative. The validated method was successfully applied to 24 commercial samples (14 cosmetics and 10 foods) in which 9 of the selected dyes were found at concentrations up to 989MUgg-1, exceeding in some cases the regulated maximum permitted limits. A non-permitted dye, Acid Orange 7, was found in one candy. PMID- 29128094 TI - Gas chromatographic sulphur speciation in heavy crude oil using a modified standard D5623 method and microfluidic Deans switching. AB - A modification to American Society for Testing and Materials (ASTM) method D5623 is proposed to enable successful and repeatable analysis of heavy crude oil samples. A two-dimensional gas chromatography configuration was implemented, with separation of sulphur compounds occurring on two columns. A Deans switch is used to enable heart-cutting of volatile sulphur compounds onto a DB-Sulfur stationary phase, and separation occurs concurrently with the backflushing of the primary column. The use of a sulphur-selective detector increases selectivity, and 22 volatile sulphur species are quantified in less than 15min, which is almost half the time of the original ASTM method. Samples ranging from light distillation cuts to whole crudes (boiling from 100 degrees C to >750 degrees C) were analyzed with minimal sample preparation. The calculated limit of detection was 0.7mg/kg, repeatability was 3% relative standard deviation (RSD), and a linear range of 1 250mg/kg was obtained, with an R2 value of 0.994 or better, depending on the compound. PMID- 29128095 TI - Olive oil polyphenols extracts inhibit inflammatory markers in J774A.1 murine macrophages and scavenge free radicals. AB - Here we evaluate the olive oil antiradical and anti-inflammatory potential through its polyphenols extracts and examine the influence of olive maturity on olive oil quality properties, polyphenols composition and biological potentials. Samples have been obtained from minor Tunisian olive cultivars (Chemchali, Fouji and Zarrazi) at different maturity indices. Principal quality properties were evaluated and polyphenols analysis was carried out by Folin Ciocalteu reagent and HPLC-UV-MS. Antiradical activity was examined by DPPH and FRAP scavenging assays while J774A.1 murine macrophages were used to evaluate anti-inflammatory potential by analyzing NO production with Griess reagent method and iNOS and COX 2 expression by cytofluorimetric analysis. Our results revealed that quality characteristics, total phenol content, as well as phenolic compound concentrations were significantly affected by the olive maturity levels. On the other hand, the polyphenols extracts showed an interesting radical scavenging capacity and a potential ability to inhibit inflammatory markers at 90% for NO release and 75% for iNOS expression. Thus, our study establishes that olive oil through its polyphenols extracts has a substantial antiradical and anti inflammatory potential. Likewise a lot of attention should be attributed to olive ripening level in order to decide the optimum harvesting time. PMID- 29128097 TI - ? PMID- 29128096 TI - ? PMID- 29128098 TI - Physical Activity and Age-related Macular Degeneration: A Systematic Literature Review and Meta-analysis. PMID- 29128100 TI - Improving the feasibility and utility of OpTrust-A tool assessing intraoperative entrustment. AB - BACKGROUND: Changes in the surgical training landscape have sparked an interest in developing new educational models anchored on entrustment assessment. We sought to optimize the validated OpTrust entrustment assessment tool by comparing ratings from short-course video reviews to previously validated intraoperative assessments. METHODS: Entrustment assessment scores for video-based and 1-h (short-course) observations were compared to previously validated intraoperative assessment scores. Faculty and residents were surveyed for their perceptions related to operative observation. RESULTS: There was a strong association between entrustment scores when comparing in-person to video-based observations (R2 = 0.76-0.84, p < 0.01) as well as short-course to full-duration observations (R2 = 0.65-0.76, p < 0.01). The majority of faculty and residents (>97%) felt observation did not negatively impact operative experience. CONCLUSIONS: Assessment of entrustment behaviors using short-course video review provides a feasible approach to intraoperative assessment. This latest application of OpTrust allows for the tool to be incorporated into surgical training programs across a variety of environments. PMID- 29128099 TI - Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury. AB - Alcoholic liver disease remains a major cause of liver-related morbidity and mortality, which ranges from alcoholic steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma, and the related mechanisms are understood poorly. In this study, we aimed to investigate the role of miR-34a in alcohol-induced cellular senescence and liver fibrosis. We found that hepatic miR-34a expression was upregulated in ethanol-fed mice and heavy drinkers with steatohepatitis compared with respective controls. Mice treated with miR-34a Vivo-Morpholino developed less severe liver fibrosis than wild-type mice after 5 weeks of ethanol feeding. Further mechanism exploration showed that inhibition of miR-34a increased cellular senescence of hepatic stellate cells (HSCs) in ethanol-fed mice, although it decreased senescence in total liver and hepatocytes, which was verified by the changes of senescence-associated beta-galactosidase and gene expression. Furthermore, enhanced cellular senescence was observed in liver tissues from steatohepatitis patients compared with healthy controls. In addition, the expression of transforming growth factor-beta1, drosophila mothers against decapentaplegic protein 2 (Smad2), and Smad3 was decreased after inhibition of miR-34a in ethanol-fed mice. Our in vitro experiments showed that silencing of miR-34a partially blocked activation of HSCs by lipopolysaccharide and enhanced senescence of HSCs. Furthermore, inhibition of miR-34a decreased lipopolysaccharide-induced fibrotic gene expression in cultured hepatocytes. In conclusion, our data suggest that miR-34a functions as a profibrotic factor that promotes alcohol-induced liver fibrosis by reducing HSC senescence and increasing the senescence of hepatocytes. PMID- 29128101 TI - Effect of protected research time on ABSITE scores during general surgery residency. AB - BACKGROUND: Objective - To determine whether residents with one or more years of dedicated research time (Research Residents, RR) improved their ABSITE scores compared to those without (Non-Research Residents, N-RR). METHODS: A retrospective review of general surgery residents' ABSITE scores from 1995 to 2016 was performed. RR were compared to N-RR. Additional analysis of At Risk (AR) v Not At Risk residents (NAR) (35th percentile as PGY1-2) was also performed. RESULTS: Cohort - 147 residents (34 RR and 113 N-RR). There were no differences in initial ABSITE scores (p = 0.47). By definition, the AR group had lower scores than NAR. Overall, post-research RR v PGY-4 N-RR scores did not differ (p = 0.84). Only the AR residents improved their scores (p = 0.0009 v NAR p = 0.42), regardless of research group (p = 0.70). CONCLUSION: Protected research time did not improve residents' ABSITE scores, regardless of initial scores. At Risk residents improved regardless of research group status. PMID- 29128102 TI - Emergent cholecystectomy is superior to percutaneous cholecystostomy tube placement in critically ill patients with emergent calculous cholecystitis. AB - BACKGROUND: The role of percutaneous cholecystostomy (PC) is undefined in patients with multiple comorbidities presenting with emergent calculous cholecystitis (CC). This study compared outcomes between PC, laparoscopic (LC), and open cholecystectomy (OC). METHODS: The Vizient UHC database was queried for high-risk patients with CC who underwent PC, LC, OC, or laparoscopic converted to open cholecystectomy (CONV). Demographics, outcomes, mortality, length of stay (LOS), and direct cost were compared between the groups. RESULTS: LC was the most common approach with the lowest risk of death, complications, LOS, and cost. Complication risk was highest in OC. Nearly 20% of patients underwent PC. Complication rate, LOS, infection, aspiration pneumonia, and mortality were higher in PC. Direct cost was lowest in LC, followed by CONV, PC, and OC. CONCLUSIONS: Emergent cholecystectomy for CC in high-risk patients is safer and more cost effective than PC and this study supports the use of cholecystectomy as the primary treatment approach in these patients. PMID- 29128103 TI - The benefits of a low dose complex carbohydrate/citrulline electrolyte solution for preoperative carbohydrate loading: Focus on glycemic variability. AB - BACKGROUND: Perioperative insulin resistance is associated with significant hyperglycemia-related morbidity in patients undergoing major surgery. We sought to assess the effect of preoperative loading with a low-dose maltodextrin/citrulline solution compared to a commercially available sports drink on glycemic levels in an established colorectal enhanced recovery program. METHODS: Retrospective analysis was undertaken of elective non-diabetic colectomies and enterectomies from January 2016-March 2017. Cohorts included simple (SIM) and complex carbohydrate (COM) groups. Statistical analysis was performed with linear and logarithmic regression. RESULTS: 83 patients were included (42 SIM, 41 COM). SIM group was older (61.7 vs 52.7 p = 0.012) Glycemic variability was less in the COM group (7.6% vs 21.4% P = 0.034). The frequency of hyperglycemia, postoperative complications, and length of stay trended higher in the SIM group. CONCLUSIONS: This retrospective analysis identifies significant improvement in the perioperative glycemic variability with preoperative low dose complex carbohydrate loading compared to simple carbohydrate loading in colorectal surgery patients. PMID- 29128104 TI - Effects of intermedin on autophagy in cerebral ischemia/reperfusion injury. AB - OBJECTIVE: This study aimed to evaluate the effects of intermedin (IMD) on autophagy in cerebral ischemia/reperfusion (I/R) injury (CIRI). METHODS: Sixty rats were randomly averaged into four groups: sham, ischemia/reperfusion (I/R), IMD, and 3-methyladenine (3-MA). In the sham group, the right common carotid artery, external carotid artery, and internal carotid artery were detached, and no monofilament was inserted. In the other groups, two hours after cerebral ischemia, the rats were injected through the lateral ventricle with normal saline for I/R group, IMD for the IMD group, and 3-MA for the 3-MA group for 24h. The cerebral injury was assessed by evaluation of neurological function, hematoxylin and eosin (H&E) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The expressions of autophagy associated proteins, such as microtubule-associated protein 1 light chain 3 (LC3), Beclin1, and sequestosome 1 (P62) were analyzed using immunohistochemistry staining and western blot. Meanwhile, transmission electron microscopy was used to investigate the ultrastructure of the brains. RESULTS: IMD could reduce neuron cell damage and infarction formation and has a protective effect against CIRI as 3-MA. The levels of LC3II/LC3I and Beclin1 were significantly decreased and the P62 level was significantly higher in the IMD group compared with I/R group, which is similar to the effect of 3-MA on CIRI. CONCLUSIONS: IMD has a similar effect as 3 MA, can reduce pathological neuronal injury and protect the brain against CIRI in rats by attenuating the effects of autophagy. Our findings provide evidence for IMD's protective effects in relation to ischemic cerebrovascular diseases. PMID- 29128105 TI - Factors associated with delivery of neoadjuvant chemotherapy in women with advanced stage ovarian cancer. AB - PURPOSE: To identify clinical and non-clinical factors associated with utilization of primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy (NACT) in women with advanced stage epithelial ovarian cancer (EOC). METHODS: Using the National Cancer Database, we identified women with stage IIIC and IV EOC diagnosed from 2012 to 2014. The primary outcome was receipt of NACT, defined in the primary analysis as utilization of chemotherapy as the first cancer directed therapy, irrespective of whether interval surgery was performed. Univariable and multivariable associations between clinical and non-clinical factors and receipt of NACT were investigated using mixed-effect logistic regression models. A secondary analysis excluded women who received primary chemotherapy but did not receive interval cytoreductive surgery. RESULTS: Among 17,302 eligible women, 10,948 (63.3%) underwent PCS and 6354 (36.7%) received NACT. Older age, stage IV disease, high-grade, and serous histology were associated with receipt of NACT in univariate (p<0.001) and multivariable analyses (p<0.001). Analysis of non-clinical factors revealed that residency in the Northeast region and receipt of treatment closer to home were associated with NACT in univariate (p<0.05) but not multivariable analysis (p>0.05). In multivariable analysis, African-American race/ethnicity (p=0.04), low-income level (p=0.02), treatment in high-volume centers (p<0.01), and insurance by Medicare or other government insurance (p<0.001) were associated with receipt of NACT. When women who received no surgery were excluded, all factors that were independent predictors of NACT in the main analysis remained significant, except for race/ethnicity. CONCLUSIONS: Non-clinical factors were associated with the use of NACT at a magnitude similar to that of clinically relevant factors. PMID- 29128106 TI - Who are the long-term survivors of high grade serous ovarian cancer? AB - Although the median survival for epithelial ovarian cancer (EOC) is <5years, approximately 15% of patients will survive for >10years. A better understanding of these exceptional responders could reveal opportunities to improve the dismal prognosis of most EOC patients. In this review, we examine the clinical and genomic features that have been associated with long-term survival, which is generally defined as survival of >7-10years after initial diagnosis. Clinical features influencing long-term survival have been best reported in large retrospective population-based studies. These studies find that long-term survival is associated with previously validated prognostic factors, including younger age at diagnosis, earlier clinicopathologic stage, lower grade, non serous histology, absence of ascites, primary debulking surgery, and optimal cytoreduction at primary surgery. Duration of survival after a recurrence also contributes to long-term survival and depends both on recurrence location and response to subsequent chemotherapy or surgery. Germline BRCA mutations, although associated with short-term chemosensitivity, do not appear to improve long-term survival. Unfortunately, the relative lack of recurrent somatic mutations in EOC has made the identification of genomic signatures associated with long-term survival difficult. Although six independent gene expression analyses of long term survivors (LTS) have identified signatures associated with prolonged survival, different gene sets are identified in each study. Genes differentially expressed in tumors of LTS are broadly involved in cell proliferation, tumor stromal interactions, the cytoskeleton, metabolism of nutrients, and immune/stress response. We anticipate that consistent selection of control and LTS groups, combined with the use of emerging transcriptomic, epigenomic, and proteomic platforms, is likely to identify conserved features associated with long-term survival. Further elucidating the factors contributing to long-term survival has the potential to contribute to our understanding of the biology of ovarian cancer, with the goal of improving the survival of all EOC patients. PMID- 29128107 TI - A Systematic Look at Environmental Modulation and Its Impact in Brain Development. AB - Several experimental procedures are currently used to investigate the impact of the environment on brain plasticity under physiological and pathological conditions. The available methodologies are aimed at obtaining global or specific reductions or intensifications of the stimuli, with initial standardization in animal models being paralleled by translational applications to humans. More procedures can be combined together or applied in series to obtain powerful experimental paradigms, and the choice of a given setting should take into account the specific genetic background, age, and phenotypic vulnerabilities of the target subjects. Sophisticated use of environmental manipulations can increase our knowledge of the mechanisms underlying experience-dependent plasticity, opening the way for new therapies for neurodevelopmental disorders, dysfunctions of plasticity, and brain aging. PMID- 29128109 TI - Out with the new and in with the old: Extracorporeal membrane oxygenation for massive hemorrhage after pulmonary endarterectomy. PMID- 29128108 TI - Rebalancing the Addicted Brain: Oxytocin Interference with the Neural Substrates of Addiction. AB - Drugs that act on the brain oxytocin (OXT) system may provide a much-needed treatment breakthrough for substance-use disorders. Targeting the brain OXT system has the potential to treat addiction to all major classes of addictive substance and to intervene across all stages of the addiction cycle. Emerging evidence suggests that OXT is able to interfere with such a wide range of addictive behaviours for such a wide range of addictive substances by rebalancing core neural systems that become dysregulated over the course of addiction. By improving our understanding of these interactions between OXT and the neural substrates of addiction, we will not only improve our understanding of addiction, but also our ability to effectively treat these devastating disorders. PMID- 29128110 TI - Stage IB: To give (chemo), or not to give? That is the question. PMID- 29128111 TI - Nocturnal phantom shock cessation with zolpidem. AB - A 77 year old man with a biventricular ICD-pacemaker complained of painful, electric jolts disturbing him nightly from sleep. Extensive work-up including device interrogation revealed no defibrillations or arrhythmia, and he was subsequently diagnosed with phantom shocks (PS). His nightly PS symptoms terminated after starting zolpidem 10 mg each night. To date, literature review reveals fifteen articles reporting 163 phantom shock (PS) cases. PS affects 5-9% of ICD recipients. Risk factors include psychiatric disease, atrial fibrillation, NYHA functional status III or greater, prior shock storm, and intraoperative awareness during ICD placement, with defibrillation threshold testing. This report describes a successful PS intervention, and reviews the current knowledge available in the pathophysiology and treatment of PS. PMID- 29128112 TI - Predicting pathological fracture in femoral metastases using a clinical CT scan based algorithm: A case-control study. AB - BACKGROUND: We assessed whether there was a difference in attenuation measurements (in Hounsfield units - HU) and geometric distribution of HU between femora with metastatic lesions that fracture, and metastatic lesions that did not fracture nor underwent prophylactic fixation. METHODS: Nine patients with femoral metastases who underwent CT and developed a pathological fracture were matched to controls. All femora were delineated in axial CT slices using a region of interest (ROI) tool; the HU within these ROIs were used to calculate: (1) the cumulative HU of the affected over the nonaffected side per slice and presented as a percentage, and (2) the cumulative HU accounting for geometric distribution (polar moment of HU). We repeated the analyses including cortical bone only (HU of 600 and above). RESULTS: CT-based calculations did not differ between patients with a lesion that fractured and those that did not fracture nor underwent prophylactic fixation when analyzing all tissue. However, when including cortical bone only, the pathological fracture group had a lower cumulative HU value compared to the no fracture and no fixation group for the weakest cross-sectional CT image (pathological fracture group, mean: 71, SD: 23 and no fracture and no prophylactic fixation group, mean: 85, SD: 18, p = 0.042) and the complete lesion analysis (pathological fracture group, mean: 78, SD: 21 and no fracture and no prophylactic fixation group, mean: 92, SD: 15, p = 0.032). CONCLUSION: The demonstrated CT-based algorithms can be useful for predicting pathological fractures in metastatic lesions. PMID- 29128114 TI - Saturated or unsaturated fat supplemented maternal diets influence omental adipose tissue proteome of suckling goat-kids. AB - The aim of the present study was to investigate how maternal diet can influence the adipose tissue of goat kids. Omental adipose tissue proteomes of goat-kids from mothers fed with diet enriched with stearic acid (ST-kids), fish oil (FO kids) and standard diets (CTRL) were determined by quantitative iTRAQ 2D-LC-MS/MS analysis. Twenty proteins were found to be differentially expressed in suckling kids' omental adipose tissue. Stearic acid induces changes in a higher number of proteins when compared to fish oil. Eleven proteins, namely AARS, ECl1, PMSC2, CP, HSPA8, GPD1, RPL7, OGDH, RPL24, FGA and RPL5 were decreased in ST-kids only. Four proteins, namely DLST, EEF1G, BCAP31 and RALA were decreased in FO-kids only, and one, NUCKS1, was increased. Four proteins, namely PMSC1, PPIB, TUB5*2 and EIF5A1, were be less abundant in both ST- and FO- kids. Most of the protein whose abundance was decreased in ST kids (10 out of 15) are involved in protein metabolism and catabolism pathways. Qualitative gene expression analysis confirmed that all the proteins identified by mass spectrometry, with the exception of FGA, were produced by adipose tissue. Quantitative gene expression analysis demonstrated that two proteins, namely CP, a minor acute phase protein, and ECl1, involved in fatty acid beta oxidation, were downregulated at mRNA level as well. ECl1 gene expression was downregulated in ST-kids AT as compared to Ctrl kids and CP was downregulated in both ST- and FO-kids. The present results demonstrate that it is possible to influence adipose goat-kid proteome by modifying the maternal diet. PMID- 29128113 TI - Measurement equivalence of the BDSx scale with young and older adults with bipolar disorder. AB - Instruments developed for mental health research are commonly devised and validated with young adults only. However, the measurement properties of these scales may differ over the lifespan. For this study, we set out to demonstrate the psychometric equivalence of the BDSx scale with an international sample of young and older adults with bipolar disorder (BD). We independently replicated the 4-factor model of BDSx responses with young and older participants (M = 45.63, range 19-87 years of age); we then compared the psychometric properties between models. This allowed us to compare responses to each BDSx item between groups, and the strength of association among depression and hypo/mania factors (cognitive depressive symptoms, somatic depressive symptoms, affrontive symptoms of hypo/mania, elation/loss of insight). Young and older adults responded to 19 of 20 BDSx items in similar ways. Only responses to the 'talkative' item were significantly higher for younger adults. Correlations between depression and mania factors are statistically indistinguishable between age groups. This suggests that symptoms cluster and present similarly for young and older adults with BD. The BDSx is currently being used for ecological momentary sampling of mood by the BADAS (Bipolar Affective Disorder and older Adults) Study app for iPhone. PMID- 29128115 TI - Chronic use of proton pump inhibitors, adverse events and potential biological mechanisms: A translational analysis. AB - Proton pump inhibitors (PPIs) are among the most frequently prescribed drugs. Even if PPI are usually considered as safe, there is a growing concern for a range of adverse effects of chronic PPI therapy often in the absence of appropriate indications. We propose, after a summary of renal, cardiovascular and neurological complications (dementia, chronic kidney disease, myocardial infarction and stroke), an integrative overview of the potential biological mechanisms involved. Eleven positive pharmacoepidemiological studies, mainly based on health insurance database linkage to hospital database, reported an increased risk of complications associated to PPI use and often a graded association suggesting also a possible dose-response relationship. Several mechanisms have been suggested through in vitro studies (endothelial dysfunction, endothelial senescence, hypomagnesemia, increase of chromogranin A levels, decrease of nitric oxide in endothelial cells) leading to the impairment of vascular homesostasis, paving the way to these complications. Evidence that PPIs may have off-targets and pleiotropic effects are mounting and may impose a cautious attitude in the prescription of PPI's, especially in elderly and/or in the context of chronic use. PMID- 29128116 TI - Design and synthesis of small molecule agonists of EphA2 receptor. AB - Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure-activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor. PMID- 29128117 TI - Cardiac Rhabdomyomas in Tuberous Sclerosis Complex. PMID- 29128119 TI - Sensitivity of Water-Energy Nexus to dam operation: A Water-Energy Productivity concept. AB - Understanding and modelling the complex nature of interlinkages between water and energy are essential for efficient use of the two resources. Hydropower storage dams represent an interesting example of the water-energy interdependencies since they are often multipurpose. The concept of Water-Energy Productivity (WEP), defined as the amount of energy produced per unit of water lost in the process, is introduced in this study to illustrate the relationship between energy generation and water losses by examining the sensitivity of the Water-Energy Nexus (WEN) to changing dam operation policy. This concept is demonstrated by developing a water allocation model of the White Nile in Sudan, including Jebel Aulia Dam (JAD), using a general river and reservoir simulation software called RiverWare. A number of 77 operation scenarios of JAD are examined for 30 hydrologic years (1980-2009), considering reducing the Full Supply Level (FSL) gradually from its current value to the minimum possible value, increasing the Minimum Operating Level (MOL) gradually to the maximum possible level, and operating the dam at a Constant Operating Level (COL). The results show that raising the operating level does not necessarily increase the WEP. In comparison to the current policy, the analysis shows that a maximum WEP of 32.6GWh/BCM (GWh/Billion Cubic Meters) would be reached by raising the MOL to 375masl (meters above sea level), resulting in an increase in average annual energy generation to 164.6GWh (+18.1%) at the expense of an annual water loss of 5.05BCM (+12.7%). Even though this operation policy results in a more efficient water use compared to the original operation policy, a basin-wide assessment that includes all hydropower storage dams in the Nile basin should be conducted to decide on where and how much energy should be generated. The present analysis and future examination of the multi-dimensions of the WEN in the context of dam operation are imperative to improve the decision making in the quest for efficient resource use and management. PMID- 29128118 TI - Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy. AB - BACKGROUND: Cancer-related cognitive impairment (CRCI) is often related to chemotherapy. Increased chronic inflammation is believed to play a key role in the development of CRCI related to chemotherapy but studies assessing this hypothesis specifically in patients receiving chemotherapy are rare. METHODS: We assessed several cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in twenty-two breast cancer patients currently receiving chemotherapy. We also measured inflammatory cytokine and receptor (MCP 1, TNF-alpha, sTNFRI, sTNFRII) concentrations in patient sera using Luminex assays. These concentrations were log-transformed to obtain a normal distribution. Associations between log-transformed cytokines and cognition were evaluated using Pearson correlations and linear regression, taking into account relevant covariates. RESULTS: Increased concentrations of sTNFRI and sTNFRII were associated with poorer performance on the CANTAB Delayed Matching to Sample (DMS, tests visual memory). Increasing sTNFRI levels were negatively correlated with DMS percent correct (r=-0.47, p=0.029) and DMS percent correct after a 12 second (s) delay (r=-0.65, p=0.001). Increasing levels of sTNFRII negatively correlated with DMS percent correct after 12s delay (r=-0.57, p=0.006). After controlling for relevant demographic (i.e. age, education) and clinical variables (i.e. disease stage, regimen type), we found that increased sTNFRI remained significantly related to decline on the DMS at the 12s delay (p=0.018). CONCLUSION: This preliminary study shows a significant association between higher sTNFRI and lower scores on the short-term visual memory delayed match to sample test in breast cancer patients receiving chemotherapy, supporting the hypothesis that sTNFRI is involved in CRCI. PMID- 29128120 TI - Effects of agricultural land use on dissolved organic carbon and nitrogen in surface runoff and subsurface drainage. AB - Dissolved organic carbon (DOC) load in discharges from cultivated soils may have negative impacts on surface waters. The magnitude of the load may vary according to soil properties or agricultural management practices. This study quantifies the DOC load of cultivated mineral soils and investigates whether the load is affected by agricultural practices. Discharge volumes and concentrations of DOC and dissolved organic nitrogen (DON) were continually measured at three sites from surface runoff and artificial subsurface drainage or from combined total discharge over a two-year period (2012-2014). Two experimental sites in South West Finland had clayey soils (with soil carbon contents of 2.7-5.9% in the topmost soil layer), and the third site in West-Central Finland had sandy soil (soil carbon contents of 4.3-6.2%). Permanent grassland, organic manure application, mineral fertilization, and conventional ploughing or no-till activities were studied. Furthermore, the biodegradable DOC pool of surface runoff and subsurface drainage water from no-till and ploughed fields was estimated in a 2-month incubation experiment with natural bacterial communities collected from the Baltic Sea seawater. The annual DOC and DON loads were affected by discharge volume and seasonal weather conditions. The loads varied between 25-52kgha-1 and 0.8-3.2kgha-1, respectively, and were comparable to those from boreal forests with similar soil types. The DOC load increased with increasing topsoil carbon content at all sites. There were slightly higher DOC concentrations and DOC load from permanent grassland, but otherwise we could not distinguish any clear management-induced differences in the total DOC loads. While only 6-17% of the DOC in discharge water was biologically degraded during the 2-month incubation, the proportion of biodegradable (labile) DOC in surface runoff appeared to increase when soil was ploughed compared to no-till. PMID- 29128121 TI - Occurrence of greenhouse gases in the aquifers of the Walloon Region (Belgium). AB - This work aims to (1) identify the most conductive conditions for the generation of greenhouses gases (GHGs) in groundwater (e.g., hydrogeological contexts and geochemical processes) and (2) evaluate the indirect emissions of GHGs from groundwater at a regional scale in Wallonia (Belgium). To this end, nitrous oxide (N2O), methane (CH4) and carbon dioxide (CO2) concentrations and the stable isotopes of nitrate (NO3-) and sulphate were monitored in 12 aquifers of the Walloon Region (Belgium). The concentrations of GHGs range from 0.05MUg/L to 1631.2MUg/L for N2O, 0MUg/L to 17.1MUg/L for CH4, and 1769 to 100,514ppm for the partial pressure of CO2 (pCO2). The highest average concentrations of N2O and pCO2 are found in a chalky aquifer. The coupled use of statistical techniques and stable isotopes is a useful approach to identify the geochemical conditions that control the occurrence of GHGs in the aquifers of the Walloon Region. The accumulation of N2O is most likely due to nitrification (high concentrations of dissolved oxygen and NO3- and null concentrations of ammonium) and, to a lesser extent, initial denitrification in a few sampling locations (medium concentrations of dissolved oxygen and NO3-). The oxic character found in groundwater is not prone to the accumulation of CH4 in Walloon aquifers. Nevertheless, groundwater is oversaturated with GHGs with respect to atmospheric equilibrium (especially for N2O and pCO2); the fluxes of N2O (0.32kgN2O-NHa-1y-1) and CO2 (27kgCO2Ha-1y-1) from groundwater are much lower than the direct emissions of N2O from agricultural soils and fossil-fuel-related CO2 emissions. Thus, indirect GHG emissions from the aquifers of the Walloon Region are likely to be a minor contributor to atmospheric GHG emissions, but their quantification would help to better constrain the nitrogen and carbon budgets. PMID- 29128122 TI - Resilience of carbon and nitrogen removal due to aeration interruption in aerated treatment wetlands. AB - Treatment wetlands have long been used for domestic and industrial wastewater treatment. In recent decades, treatment wetland technology has evolved and now includes intensified designs such as aerated treatment wetlands. Aerated treatment wetlands are particularly dependent on aeration, which requires reliable air pumps and, in most cases, electricity. Whether aerated treatment wetlands are resilient to disturbances such as an aeration interruption is currently not well known. In order to investigate this knowledge gap, we carried out a pilot-scale experiment on one aerated horizontal flow wetland and one aerated vertical flow wetland under warm (Twater>17 degrees C) and cold (Twater<10 degrees C) weather conditions. Both wetlands were monitored before, during and after an aeration interruption of 6d by taking grab samples of the influent and effluent, as well as pore water. The resilience of organic carbon and nitrogen removal processes in the aerated treatment wetlands depended on system design (horizontal or vertical flow) and water temperature. Organic carbon and nitrogen removal for both systems severely deteriorated after 4-5d of aeration interruption, resulting in effluent water quality similar to that expected from a conventional horizontal sub-surface flow treatment wetland. Both experimental aerated treatment wetlands recovered their initial treatment performance within 3-4d at Twater>17 degrees C (warm weather) and within 6-8d (horizontal flow system) and 4-5d (vertical flow system) at Twater<10 degrees C (cold weather). In the vertical flow system, DOC, DN and NH4-N removal were less affected by low water temperatures, however, the decrease of DN removal in the vertical flow aerated wetland at Twater>17 degrees C was twice as high as in the horizontal flow aerated wetland. The quick recovery of treatment performance highlights the benefits of aerated treatment wetlands as resilient wastewater treatment technologies. PMID- 29128123 TI - Biotechnology: a highly efficient tool for the current environmental challenges. PMID- 29128124 TI - A combination of ferric nitrate/EDDS-enhanced washing and sludge-derived biochar stabilization of metal-contaminated soils. AB - In this study, soil washing and stabilization as a two-step soil remediation strategy was performed to remediate Pb- and Cu-contaminated soils from shooting range and railway sites. Ferric nitrate (Fe(NO3)3) and [S,S]-ethylenediamine disuccinate (EDDS) were used as washing agents, whereas three types of sludge derived biochars and phosphogypsum were employed as soil stabilizers. While Fe(NO3)3 extracted larger amounts of metals compared to EDDS (84% Pb and 64% Cu from shooting range soil; 30% Pb and 40% Cu from railway site soil), it caused severe soil acidification. Both Fe(NO3)3 and EDDS washing enhanced the mobility of residual metals in the two soils, which in most cases could be mitigated by subsequent 2-month stabilization by sludge-derived biochars or phosphogypsum. By contrast, the metal bioaccessibility could only be reduced by soil washing. Nutrient-rich sludge-derived biochar replenished available P and K in both soils, whereas Fe(NO3)3 washing provided available nitrogen (N). Soil amendment enhanced acid phosphatase activity but marginally improved soil dehydrogenase and urease activity in the treated soils, possibly due to the influence of residual metals. This study supported the integration of soil washing (by Fe(NO3)3 or EDDS) with soil stabilization (by sludge-derived biochars or phosphogypsum) for accomplishing the reduction of metal mobility and bioaccessibility, while restoring the environmental quality of the treated soils. PMID- 29128125 TI - [Diagnostic issues of lymphogranuloma venereum: A case series of 5 patients]. AB - INTRODUCTION: Lymphogranuloma venereum (LG) is a sexually transmitted infection (STI) caused by Chlamydia trachomatis L serovar. METHODS: These five consecutive cases aim to highlight the risk of LG misdiagnosis, in case of initial presentation with isolated inguinal adenitis. RESULTS: Five men (mean age: 30+/-7 years) were seen in an internal medicine department, for inguinal adenopathy. One patient had clinical signs of urethritis. None presented an associated rectitis. Three patients had a history of STI, and two had a discovery of related HIV disease. Urinary polymerase chain reaction (PCR) was positive for the symptomatic patient and negative for the others. Lymph node PCR was positive in all patients within a L2b serotype (searched in 4 out of 5 cases). CONCLUSION: LG should be evoked in any patient with inguinal adenomegaly, particularly in case of STI history or risk factors. Negativity of urinary PCR should lead to further investigations, essentially a lymph node cytopuncture to evidence C. trachomatis. PMID- 29128126 TI - Inhaled cyanide poisoning as a vital sign in a room fire victim. AB - The corpse of a 71-year-old woman was found on the floor of her smoke-filled room. The source of the fire was the mattress of a double bed on which newspapers had apparently been set aflame. The woman's history in conjunction with the finding situation suggested an act of suicide. No signs of soot inhalation or soot swallowing were found at autopsy. Other vital signs were absent. Severe cardiac disease was the most notable pre-existing medical condition. Although the concentration of COHb in heart blood was low (3%), the concentration of cyanide was found to be 4.3mg/l in heart blood and 1.9mg/l in lung tissue. Cyanide was not found in the stomach contents. The BAC (blood alcohol concentration) was zero. Several prescribed drugs could also be demonstrated. The cause of death was deemed to be cyanide poisoning, possibly in conjunction with the pre-existing cardiac disease. The reported case illustrates that a lethal amount of cyanide can be inhaled during a fire even if there is no inhalation or swallowing of soot and no significant increase in the COHb level. In such cases, the demonstration of cyanide assumes significance as a vital sign indicating that the victim was alive when the fire started. PMID- 29128127 TI - A crossbow suicide. AB - The crossbow is an ancient ranged weapon originally conceived for war and hunting. Although nowadays its use in warfare has been surpassed by firearms, it continues to be used in hunting, sports and recreation. The authors present the case of a 40-year-old man who suffered from severe depression. When his condition further deteriorated, doctors ordered a forced hospitalization but, just a few hours before the measure became effective, the man committed suicide using a crossbow. The autopsy and police investigation showed possession of the crossbow darts which the man used to shoot himself in the head. The forensic pathologist found the dart stuck in the skull: the entry wound was in the suprahyoid region while the arrow tip emerged in the left parietal region meaning the arrow crossed the tongue, the middle fossa, the brain and the cranial wall. All the wounds presented a three-pointed star shape consistent with the three sharp blades of the dart. An extensive blood infiltration affected the subdural and subarachnoid space, particularly where the dart had passed. The severe brain injury, extensive subdural and subarachnoid bleeding and brain swelling following the trauma caused the death. Even though the use of the crossbow is only permitted in sporting/hunting contexts, the reported case highlights the sharp contrast between its potential for harm and the easy access to this kind of weapon, even for those affected by mental illness. PMID- 29128128 TI - CAD-FE modeling and analysis of class II restorations incorporating resin composite, glass ionomer and glass ceramic materials. AB - OBJECTIVES: To investigate the influence of specific resin-composite, glass ceramic and glass ionomer cement (GIC) material combinations in a "multi-layer" technique to replace enamel and dentin in class II mesio-occlusal-distal (MOD) dental restorations using 3D-Finite Element Analysis (FEA). METHODS: Four 3D-FE models (A-D) of teeth, adhesively restored with different filling materials, were created and analyzed in comparison with a 3D model (E) of a sound lower molar. Models A, B & C had "multilayer" constructions, consisting of three layers: adhesive, dentin replacement and enamel replacement. Model A: had a low modulus (8GPa) composite replacing dentin and a higher modulus (12GPa) composite replacing enamel. Model B: had a GI cement replacing dentin and a higher modulus (12GPa) composite replacing enamel. Model C: had a low modulus (8GPa) composite replacing dentin and a very high modulus (70GPa) inlay replacing enamel. Model D: had a lithium disilicate inlay replacing both dentin and enamel with a luting cement base-layer. Polymerization shrinkage effects were simulated and a load of 600N was applied. All the materials were assumed to behave elastically throughout the entire deformation. RESULTS: Model A showed the highest stress distribution along all the adhesive interfaces of the shrinking resin-based materials with a critical condition and failure risk marginally and internally. Model D, by contrast, showed a more favorable performance than either of the multilayer groups (A-C). Stress and displacement plots showed an elastic response similar to that obtained for the sound tooth model. Model B and Model C performed according to their bilayer material properties. The use of a non-shrink dentin component simulating a GIC clearly affected the shrinkage stress at the basis of the Model B; while the bulk resin composite having a 12GPa Young's modulus and linear polymerization shrinkage of 1% strongly influenced the biomechanical response in the bucco-lingual direction. SIGNIFICANCE: Direct resin-based composite materials applied in multilayer techniques to large class II cavities, with or without shrinking dentin layers, produced adverse FEA stress distributions and displacements. An indirect lithium disilicate inlay used to replace lost dentin and enamel in posterior restored teeth generated lower stress levels, within the limits of the elastic FEA model. PMID- 29128131 TI - The clinical and biological roles of transforming growth factor beta in colon cancer stem cells: A systematic review. AB - BACKGROUND: Transforming growth factor beta (TGF-beta) is a multipurpose cytokine, which plays a role in many cellular functions such as proliferation, differentiation, migration, apoptosis, cell adhesion and regulation of epithelial to mesenchymal transition. Despite many studies having observed the effect that TGF-beta plays in colorectal cancer, its role in the colorectal stem cell population has not been widely observed. METHOD: This systematic review will analyse the role of TGF-beta in the stem cell population of colorectal cancer. RESULTS: The effects on the stem cell phenotype are through the downstream proteins involved in activation of the TGF-beta pathway. Its involvement in the initiation of the epithelial to mesenchymal transition (EMT), the effect of colorectal invasion and metastasis regulated through the Smad protein involvement in the EMT, initiation of angiogenesis, promotion of metastasis of colorectal cancer to the liver and its ability to cross-talk with other pathways. CONCLUSION: TGF-beta is a key player in angiogenesis, tumour growth and metastasis in colon cancer. PMID- 29128130 TI - Spanish Guidelines on the Evaluation and Diagnosis of Bronchiectasis in Adults. AB - In 2008, the Spanish Society of Pulmonology (SEPAR) published the first guidelines in the world on the diagnosis and treatment of bronchiectasis. Almost 10 years later, considerable scientific advances have been made in both the treatment and the evaluation and diagnosis of this disease, and the original guidelines have been updated to include the latest scientific knowledge on bronchiectasis. These new recommendations have been drafted following a strict methodological process designed to ensure the quality of content, and are linked to a large amount of online information that includes a wealth of references. These guidelines cover aspects ranging from a consensual definition of bronchiectasis to an evaluation of the natural course and prognosis of the disease. The topics of greatest interest and some new areas are addressed, including epidemiology and economic costs of bronchiectasis, pathophysiological aspects, the causes (placing particular emphasis on the relationship with other airway diseases such as chronic obstructive pulmonary disease and asthma), clinical and functional aspects, measurement of quality of life, radiological diagnosis and assessment, diagnostic algorithms, microbiological aspects (including the definition of key concepts, such as bacterial eradication or chronic bronchial infection), and the evaluation of severity and disease prognosis using recently published multidimensional tools. PMID- 29128129 TI - Spanish Guidelines on Treatment of Bronchiectasis in Adults. AB - In 2008, the Spanish Society of Pulmonology (SEPAR) published the first guidelines in the world on the diagnosis and treatment of bronchiectasis. Almost 10 years later, considerable scientific advances have been made in both the treatment and the evaluation and diagnosis of this disease, and the original guidelines have been updated to include the latest therapies available for bronchiectasis. These new recommendations have been drafted following a strict methodological process designed to ensure quality of content, and are linked to a large amount of online information that includes a wealth of references. The guidelines are focused on the treatment of bronchiectasis from both a multidisciplinary perspective, including specialty areas and the different healthcare levels involved, and a multidimensional perspective, including a comprehensive overview of the specific aspects of the disease. A series of recommendations have been drawn up, based on an in-depth review of the evidence for treatment of the underlying etiology, the bronchial infection in its different forms of presentation using existing therapies, bronchial inflammation, and airflow obstruction. Nutritional aspects, management of secretions, muscle training, management of complications and comorbidities, infection prophylaxis, patient education, home care, surgery, exacerbations, and patient follow-up are addressed. PMID- 29128132 TI - Application of ensemble surrogates and adaptive sequential sampling to optimal groundwater remediation design at DNAPLs-contaminated sites. AB - In this study, we aimed to develop an optimal groundwater remediation design for sites contaminated by dense non-aqueous phase liquids by using an ensemble of surrogates and adaptive sequential sampling. Compared with previous approaches, our proposed method has the following advantages: (1) a surrogate surfactant enhanced aquifer remediation simulation model is constructed using a Gaussian process; (2) the accuracy of the surrogate model is improved by constructing ensemble surrogates using five different surrogate modelling techniques, i.e., polynomial response surface, radial basis function, Kriging, support vector regression, and Gaussian process; (3) we conducted comparisons and analyses based on 31 surrogate models derived from different combinations of the five surrogate modelling techniques; and (4) the reliability of the optimal solution was improved by implementing adaptive sequential sampling. The two proposed methods were applied to a hypothetical perchloroethylene-contaminated site in order to demonstrate their performance. The results showed that the best surrogate model integrated all five of the surrogate modelling methods, with an R2 value of 0.9913 and a root mean squared error of 0.0159, thereby demonstrating the advantage of using ensemble surrogates. In addition, the reliability of the optimization model solution was improved by adaptive sequential sampling, which avoided false solutions. PMID- 29128134 TI - Corrigendum to "Searching for anomalous methane in shallow groundwater near shale gas wells" [J. Contam. Hydrol. (195) (December 2016) 23-30]. PMID- 29128133 TI - Response and recovery of a pristine groundwater ecosystem impacted by toluene contamination - A meso-scale indoor aquifer experiment. AB - Microbial communities are the driving force behind the degradation of contaminants like aromatic hydrocarbons in groundwater ecosystems. However, little is known about the response of native microbial communities to contamination in pristine environments as well as their potential to recover from a contamination event. Here, we used an indoor aquifer mesocosm filled with sandy quaternary calciferous sediment that was continuously fed with pristine groundwater to study the response, resistance and resilience of microbial communities to toluene contamination over a period of almost two years, comprising 132days of toluene exposure followed by nearly 600days of recovery. We observed an unexpectedly high intrinsic potential for toluene degradation, starting within the first two weeks after the first exposure. The contamination led to a shift from oxic to anoxic, primarily nitrate-reducing conditions as well as marked cell growth inside the contaminant plume. Depth-resolved community fingerprinting revealed a low resistance of the native microbial community to the perturbation induced by the exposure to toluene. Distinct populations that were dominated by a small number of operational taxonomic units (OTUs) rapidly emerged inside the plume and at the plume fringes, partially replacing the original community. During the recovery period physico-chemical conditions were restored to the pristine state within about 35days, whereas the recovery of the biological parameters was much slower and the community composition inside the former plume area had not recovered to the original state by the end of the experiment. These results demonstrate the low resilience of sediment-associated groundwater microbial communities to organic pollution and underline that recovery of groundwater ecosystems cannot be assessed solely by physico-chemical parameters. PMID- 29128135 TI - [Post-traumatic iris cyst]. PMID- 29128136 TI - [Spontaneously reattached rhegmatogenous retinal detachment]. PMID- 29128137 TI - A rare variant of intracardiac total anomalous pulmonary venous connection. AB - Total anomalous pulmonary venous connection (TAPVC) with direct connection of the pulmonary veins to the morphologically right atrium is exceedingly rare other than in the setting of isomerism of the right atrial appendages. We present an interesting case of TAPVC in a patient with situs solitus that connected to the right atrium via a broad-mouthed common chamber. PMID- 29128138 TI - How to map persistent atrial fribillation and increase efficacy of ablation therapy. PMID- 29128139 TI - Different patterns of in-stent coverage in drug-eluting stents. PMID- 29128140 TI - Comparative Assessment of Serum Adipokines Zinc-alpha2-glycoprotein and Adipose Triglyceride Lipase, and Cardiovascular Risk Factors Between Normal Weight and Obese Patients with Hemodialysis. AB - BACKGROUND: Little is known about the potential relationship of obesity, adipose tissue and novel adipokines with cardiometabolic risk factors in end-stage renal disease. Zinc-alpha2-glycoprotein (ZAG) and adipose triglyceride lipase (ATGL) are novel adipokines with proposed desirable effects on inflammation, and lipid and glucose metabolism. The aim of this study was to investigate serum concentrations of ZAG and ATGL, and the relationship of these adipokines with cardiovascular risk factors in normal weight (NW) and obese (OB) patients undergoing hemodialysis. METHODS: Patients with regular hemodialysis including 44 normal weight (18.5=30 kg/m2) were enrolled. Serum lipid profile, high-sensitivity C-reactive protein (hsCRP) and nitric oxide metabolites along with ZAG and ATGL concentrations were assessed. RESULTS: ZAG concentrations were significantly lower in OB compared to NW group (100 +/- 34 vs. 106 +/- 31 ng/ml; p = 0.007). No significant difference was observed in ATGL between the two groups. A significant inverse correlation between ZAG and HDL (r = -0.236, p = 0.048) and a marginal inverse correlation between ATGL and HDL (r = -0.211, p = 0.078) were observed in all patients. ZAG had positive correlations with triglyceride/HDL (r = 0.279, p = 0.019), cholesterol/HDL (r = 0.319, p = 0.007), and LDL/HDL (r = 0.26, p = 0.029) ratios. Among cardiovascular risk factors, only LDL/HDL ratio and hsCRP were significantly higher in OB patients (p = 0.009 and p = 0.038, respectively). CONCLUSIONS: Serum concentrations of ZAG, but not ATGL, were significantly lower in the OB group. It appears that obesity overrides the role of hemodialysis in determining ZAG concentration. In contrast, uremic condition might overshadow the role of obesity in determining levels of traditional cardiovascular risk factors. PMID- 29128141 TI - Intranasal fentanyl improves time to analgesic delivery in sickle cell pain crises. PMID- 29128142 TI - Longitudinal effects of cognitive behavioral therapy for depression on the neural correlates of emotion regulation. AB - Cognitive behavioral therapy (CBT) is effective for a substantial minority of patients suffering from major depressive disorder (MDD), but its mechanism of action at the neural level is not known. As core techniques of CBT seek to enhance emotion regulation, we scanned 31 MDD participants prior to 14 sessions of CBT using functional magnetic resonance imaging (fMRI) and a task in which participants engaged in a voluntary emotion regulation strategy while recalling negative autobiographical memories. Eighteen healthy controls were also scanned. Twenty-three MDD participants completed post-treatment fMRI scanning, and 12 healthy volunteers completed repeat scanning without intervention. Better treatment outcome was associated with longitudinal enhancement of the emotion regulation-dependent BOLD contrast within subgenual anterior cingulate, medial prefrontal cortex, and lingual gyrus. Baseline emotion regulation-dependent BOLD contrast did not predict treatment outcome or differ between MDD and control groups. CBT response may be mediated by enhanced downregulation of neural activity during emotion regulation; brain regions identified overlap with those found using a similar task in a normative sample, and include regions related to self-referential and emotion processing. Future studies should seek to determine specificity of this downregulation to CBT, and evaluate it as a treatment target in MDD. PMID- 29128143 TI - Influence of type of sport on cardiac repolarization assessed by electrocardiographic T-wave morphology combination score. AB - INTRODUCTION: Interpreting repolarization changes in the electrocardiograms of athletes present a clinical challenge. AIM: Assessment of cardiac repolarization by T-wave morphology using the Morphology Combination Score (MCS), and evaluate how this quantitative description of T-wave morphology was influenced by the sport performed. MATERIALS AND METHODS: Digital electrocardiograms of 469 young elite athletes were analyzed for T-wave asymmetry, flatness and notching, and combined in the MCS. Athletes >22years were compared to a sex-and age matched control group from the general population (N=198). RESULTS: MCS increased with increasing endurance component of the sport performed ranging from 0.79+/-0.15 (low) to 0.92+/-0.21 (high) (p<0.0001). All subcomponents of MCS were increased compared to controls. MCS was unrelated to age, sex and ECG findings of the athlete's heart. CONCLUSION: This study suggests that sport induces repolarization changes detected by T-wave morphology, and a greater level of changes is seen in athletes from high endurance sports. PMID- 29128144 TI - The antipsychotic drug brexpiprazole reverses phencyclidine-induced disruptions of thalamocortical networks. AB - Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5-HT1A and D2 receptors and antagonist at alpha1B- and alpha2C-adrenergic and 5-HT2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; <4 Hz). These effects are reversed by antipsychotics. Here we assessed the ability of BREX to reverse PCP-induced hyperactivity of thalamocortical circuits, and the involvement of 5-HT1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2mg/kg), perhaps due to antagonism at alpha1B-adrenoceptors, abundantly expressed in the thalamus. Conversely, a cumulative 0.5 mg/kg dose reversed a PCP-induced LFO decrease in mPFC but not in CM/MD. BREX reduced LFO in both areas, yet with a different dose-response, and moderately excited mPFC neurons. The latter effect was reversed by the 5-HT1A receptor antagonist WAY-100635. Thus, BREX partly antagonizes PCP-induced thalamocortical hyperactivity, differentially in mPFC versus CM/MD. This regional selectivity may be related to the differential expression of alpha1B-, alpha2C-adrenergic and 5-HT2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT1A receptor-mediated increase in mPFC pyramidal neuron activity. Overall, the present data provide new insight on the brain elements involved in BREX's therapeutic actions. PMID- 29128145 TI - 2017 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary. AB - The International Liaison Committee on Resuscitation has initiated a near continuous review of cardiopulmonary resuscitation science that replaces the previous 5-year cyclic batch-and-queue approach process. This is the first of an annual series of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations summary articles that will include the cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation in the previous year. The review this year includes 5 basic life support and 1 paediatric Consensuses on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Each of these includes a summary of the science and its quality based on Grading of Recommendations, Assessment, Development, and Evaluation criteria and treatment recommendations. Insights into the deliberations of the International Liaison Committee on Resuscitation task force members are provided in Values and Preferences sections. Finally, the task force members have prioritised and listed the top 3 knowledge gaps for each population, intervention, comparator, and outcome question. PMID- 29128146 TI - Exposure therapy augmentation: A review and extension of techniques informed by an inhibitory learning approach. AB - Although exposure therapy is often considered a gold standard behavioral intervention for pathological anxiety, questions remain surrounding the mechanisms underlying exposure interventions, and some individuals are characterized by suboptimal treatment outcomes. Recently, a formulation known as the inhibitory learning theory, which is grounded in basic science principles of extinction learning and memory, has been proposed to provide a more parsimonious mechanistic explanation for the effects of exposure than previous, habituation based models [Craske, M.G., Kircanski, K., Zelikowsky, M., Mystkowski, J., Chowdhury, N., & Baker, A. 2008. Optimizing inhibitory learning during exposure therapy. Behaviour Research and Therapy, 46, 5-27; Craske, M.G., Treanor, M., Conway, C.C., Zbozinek, T., & Vervliet, B. 2014. Maximizing exposure therapy: An inhibitory learning approach. Behaviour Research and Therapy, 58, 10-23]. Strategies informed by this theory are proposed to maximize extinction learning by fostering the development of new, non-threat associations between stimuli in memory and enhancing the accessibility and retrieval of these safety-based associations. This comprehensive review serves as a critical examination of the empirical literature regarding major tenets of inhibitory learning theory and the potential for such techniques to augment exposure therapy for anxiety disorders. Limitations of the extant research, as well as potential future directions, are explored. PMID- 29128148 TI - Assessment of alcohol intake: Retrospective measures versus a smartphone application. AB - INTRODUCTION: Research investigating problem drinking often relies on retrospective measures to assess alcohol consumption behaviour. Limitations associated with such instruments can, however, distort actual consumption levels and patterns. We developed the smartphone application (app), CNLab-A, to assess alcohol intake behaviour in real-time. METHODS: Healthy individuals (N=671, M age 23.12) completed demographic questions plus the Alcohol Use Questionnaire and a 21-day Timeline Followback before using CNLab-A for 21days. The app asked participants to record alcohol consumption details in real time. We compared data reported via retrospective measures with that captured using CNLab-A. RESULTS: On average, participants submitted data on 20.27days using CNLab-A. Compared to Timeline Followback, a significantly greater percentage of drinking days (24.79% vs. 26.44%) and significantly higher total intake (20.30 vs. 24.26 standard drinks) was recorded via the app. CNLab-A captured a substantially greater number of high intake occasions at all levels from 8 or more drinks than Timeline Followback. Additionally, relative to the Alcohol Use Questionnaire, a significantly faster rate of consumption was recorded via the app. CONCLUSIONS: CNLab-A provided more nuanced information regarding quantity and pattern of alcohol intake than the retrospective measures. In particular, it revealed higher levels of drinking than retrospective reporting. This will have implications for how particular at-risk alcohol consumption patterns are identified in future and might enable a more sophisticated exploration of the causes and consequences of drinking behaviour. PMID- 29128147 TI - Using Indocyanine Green Extraction to Predict Liver Function After Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma. AB - PURPOSE: To test the hypothesis that mid-treatment measures of the retention of indocyanine green after 15 minutes (ICGR15) would improve the prediction of posttreatment liver function in the setting of hepatocellular carcinoma. METHODS AND MATERIALS: Between 2006 and 2015, 144 patients with hepatocellular carcinoma received 175 courses of stereotactic body radiation therapy (SBRT). Patient data, such as age, sex, portal vein thrombosis, cirrhosis, Child-Pugh (CP) score, prior liver-directed therapies, and liver function tests, including albumin-bilirubin (ALBI) and ICG clearance, and dosimetric data, such as tumor volume and radiation dose, were collected. Toxicity was evaluated as a 2-point increase in CP score or a change in ALBI score at 3 months from start of SBRT. Logistic or linear regression was used to build toxicity prediction models based on patient and tumor characteristics and ICG clearance variables. Performance of the models for the binary CP outcome was summarized using area under the curve and receive operating characteristic curves. Likelihood ratio tests were used to evaluate whether the model fit improved after incorporating the ICG variable information. RESULTS: In multivariable analysis age, baseline ICGR15, and change in ICGR15 were associated with toxicity defined by increased CP score. For the continuous ALBI outcome, being female, having cirrhosis, and increasing radiation dose were associated with increased toxicity. When incorporating ICGR15 into these models, an increase in ICGR15 from baseline to mid-treatment was most consistently significantly associated with an increase in toxicity. CONCLUSIONS: Incorporation of ICGR15 variables significantly improves the prediction of post-SBRT liver function. The use of ICGR15 can facilitate the delivery of the maximum safe dose of radiation for patients with hepatocellular carcinoma and has the potential to improve uncomplicated tumor control and survival. PMID- 29128149 TI - Vape pen product placement in popular music videos. PMID- 29128150 TI - Structural and ultrastructural analyses of bone regeneration in rabbit cranial osteotomy: Piezosurgery versus traditional osteotomes. AB - Clinical advantages of piezosurgery have been already proved. However, few investigations have focused on the dynamics of bone healing. The aim of this study was to evaluate, in adult rabbits, bone regeneration after cranial linear osteotomies with two piezoelectrical devices (Piezosurgery(r) Medical - PM and Piezosurgery(r) Plus - PP), comparing them with conventional rotary osteotomes (RO). PP was characterized by an output power three times higher than PM. Fifteen days after surgery, histomorphometric analyses showed that the osteotomy gap produced with PM and PP was about half the size of that produced by RO, and in a more advanced stage of recovery. Values of regenerated bone area with respect to the total osteotomy area were about double in PM and PP samples compared with RO ones, while the number of TRAP-positive (tartrate-resistant acid phosphatase positive) osteoclasts per linear surface showed a significant increase, suggesting greater bone remodelling. Under scanning electron microscopy, regenerated bone displayed higher cell density and less mineralized matrix compared with pre-existent bone for all devices used. Nanoindentation tests showed no changes in elastic modulus. In conclusion, PM/PP osteotomies can be considered equivalent to each other, and result in more rapid healing compared with those using RO. PMID- 29128151 TI - Is the Choosing Wisely(r) campaign model applicable to the management of multiple sclerosis in France? A GRESEP pilot study. AB - BACKGROUND: Launched in the US in 2012, Choosing Wisely(r) is a campaign promoted by the American Board of Internal Medicine (ABIM) Foundation with the goal of improving healthcare effectiveness by avoiding wasteful or unnecessary medical tests, treatments and procedures. It uses concise recommendations produced by national medical societies to start discussions between physicians and patients on the relevance of these services as part of a shared decision-making process. The Multiple Sclerosis Focus Group (Groupe de Reflexion Autour de la Sclerose en Plaques; GRESEP) undertook a pilot study to assess the relevance and feasibility of this approach in the management of multiple sclerosis (MS) in France. METHODS: Recommendations were developed using the formal consensus method from the guidelines of the French National Health Authority (HAS). A steering committee selected the themes and drafted concise evidence reviews. An independent rating group then assessed these recommendations for clarity, relevance and feasibility. RESULTS: Seven recommendations were accepted: (1) avoid systematic ordering of multimodal evoked potential studies for diagnosing MS; (2) do not treat MS relapses with low-dose oral corticosteroids; (3) when treating MS relapse with high-dose corticosteroids, the systematic use of the intravenous route is unnecessary if the oral route can be used; (4) systematic hospitalization is not necessary for treating MS relapse with high-dose corticosteroid therapy, particularly if the oral route is used, except for the first treated relapse and the presence of exclusion or non-eligibility criteria; (5) in the absence of clinical signs or symptoms of urinary infection, avoid systematic screening with urine microscopy and culture before the administration of corticosteroid therapy for MS relapse in patients using intermittent self-catheterization; (6) avoid antibiotic treatment of clinically asymptomatic MS patients using intermittent self-catheterization, even if urine microscopy and culture reveal the presence of microorganisms; and (7) avoid introducing symptomatic drug treatment for MS related fatigue. CONCLUSION: This pilot study, the first of its kind in France, has demonstrated the relevance and feasibility of adapting the Choosing Wisely(r) model to MS by practitioners specializing in the disorder. However, the acceptability of these recommendations by other practitioners in other specialist fields as well as their impact on everyday clinical practices now need to be studied. PMID- 29128152 TI - Intravenous thrombolytic therapy for acute anterior ischemic stroke: Experience at the French Military Teaching Hospital in Toulon from 2003 to 2014. AB - INTRODUCTION: Intravenous thrombolysis with rt-PA is the key treatment for acute ischemic stroke (IS), and has largely been developed at the Military Teaching Hospital in Toulon since 2003. This report is of the results of our practices compared with those in the literature, as well as our attempts to identify factors predictive of a favorable outcome after thrombolysis. METHODS: All patients treated with rt-PA for IS in the carotid territory between 2003 and 2014 were prospectively included. Disability was assessed at 3 months by modified Rankin Scale (m-RS) scores; outcome was considered unfavorable if the m-RS score was >2. Multivariate analyses were also performed to identify parameters correlating with poor and favorable outcomes. RESULTS: Of the 289 patients prospectively enrolled in the study [mean initial National Institutes of Health Stroke Scale (NIHSS) score: 14.3], 52.5% had an m-RS score >2 at 3 months of follow-up. Three independent predictive factors for poor functional outcomes at the 3-month follow-up were identified: NIHSS score>12 on admission (P=0.048); NIHSS score>8 at discharge (P<0.001); and early neurological worsening within the first 24h (P=0.015). Early neurological improvement within 24h of rt-PA infusion was significantly associated with recanalization of the stroke-related occluded cerebral artery (P<0.001, r=0.37). CONCLUSION: After 12 years of practice, our stroke unit has produced results similar to those of the major clinical studies in terms of safety and efficacy. High NIHSS scores on admission and a lack of neurological improvement during the first 24h of thrombolysis due to failure of early recanalization were identified as independent predictive factors of poor functional outcomes. PMID- 29128153 TI - Should we broaden indications for anti-JCV antibody tests in multiple sclerosis patients? Comments. Anti-JCV antibody index in multiple sclerosis care. PMID- 29128154 TI - A fatal encephalitic case of post-cutaneous leishmaniasis. PMID- 29128155 TI - Motor neuron disease in inherited neurometabolic disorders. AB - Inherited neurometabolic disorders represent a growing group of inborn errors of metabolism that present with major neurological symptoms or a complex spectrum of symptoms dominated by central or peripheral nervous system dysfunction. Many neurological presentations may arise from the same metabolic defect, especially in autosomal-recessive inherited disorders. Motor neuron disease (MND), mainly represented by amyotrophic lateral sclerosis, may also result from various inborn errors of metabolism, some of which may represent potentially treatable conditions, thereby emphasizing the importance of recognizing such diseases. The present review discusses the most important neurometabolic disorders presenting with motor neuron (lower and/or upper) dysfunction as the key clinical and neuropathological feature. PMID- 29128156 TI - Utility of a Power Aspiration-Based Extraction Technique as an Initial and Secondary Approach in the Treatment of Peripheral Arterial Thromboembolism: Results of the Multicenter PRISM Trial. AB - PURPOSE: To investigate the safety and initial efficacy of XTRACT, a power aspiration-based extraction technique for treatment of peripheral arterial thromboembolism with the use of the Penumbra/Indigo system. MATERIALS AND METHODS: A total of 79 patients were enrolled: 39 (49.4%) underwent XTRACT as the initial therapy and 40 (50.6%) underwent XTRACT after failed catheter-directed thrombolysis or other mechanical intervention or for removal of distal emboli that occurred during an intervention. Occlusion locations were as follows: 36.7% (n = 29) in the profunda, common, or superficial femoral artery; 35.4% (n = 28) in the popliteal artery; 15.2% (n = 12) in the tibial artery; 7.6% (n = 6) in the peroneal artery; and the remainder in the common iliac (n = 1), external iliac (n = 1), sciatic (n = 1), and brachial (n = 1) arteries. RESULTS: Complete or near complete revascularization (Thrombolysis In Myocardial Infarction [TIMI] grade 2/3 flow) was achieved in 87.2% of patients (68 of 78) immediately after the XTRACT procedure and before any other intervention. Successful revascularization was achieved in 79.5% of patients (31 of 39) as an initial treatment and in 92.5% (37 of 40) as salvage or secondary therapy. After additional adjunctive endovascular interventions, TIMI grade 2/3 flow was achieved in 96.2% of patients (76 of 79). Complete thrombus removal and restoration of normal flow (TIMI grade 3) was achieved in 77.2% of patients (61 of 79) after all endovascular treatment was completed. No patients required surgical revascularization. No device-related adverse events occurred. CONCLUSIONS: XTRACT was safe and effective for revascularization of acute or subacute peripheral arterial occlusions as a primary therapy or as a secondary therapy after other endovascular techniques had failed. PMID- 29128157 TI - Prophylactic Internal Iliac Artery Occlusion Balloon Placement to Reduce Operative Blood Loss in Patients with Invasive Placenta. AB - PURPOSE: To evaluate efficacy and safety of prophylactic internal iliac occlusion balloon placement before cesarean hysterectomy for invasive placenta. MATERIAL AND METHODS: A retrospective analysis was performed of patients with invasive placenta treated with and without occlusion balloon placement. Preoperative occlusion balloons were placed in 90 patients; 61 patients were treated without balloon placement (control group). Baseline demographics, including patient age, gestational age at delivery, gravidity, parity, and number of previous cesarean sections, were not significantly different (P > .05). Of the balloon placement group, 56% had placenta percreta compared with 25% in the control group (P < .001), and 83% had placenta previa compared with 66% in the control group (P = .012). RESULTS: Median blood loss was 2 L (range, 1.5-2.5 L) in the balloon placement group versus 2.5 L (range, 2-4 L) in the control group (P = .002). Patients with occlusion balloons were transfused a median of 2 U (range, 0-5 U) of packed red blood cells versus 5 U (range, 2-8 U) in patients in the control group (P = .002). In the balloon placement group, 34% had large volume blood loss > 2,500 mL versus 61% in the control group (P = .001), and 21% required blood transfusion > 6 U versus 44% in the control group (P = .002). Eight complications (9%) were attributed to occlusion balloon placement. CONCLUSIONS: Prophylactic internal iliac artery occlusion balloon placement reduces operative blood loss and transfusion requirements in patients undergoing hysterectomy for invasive placenta. PMID- 29128158 TI - Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. AB - The mitogen-activated protein kinases (MAPKs) participate in a multitude of processes that control hepatic metabolism. The liver regulates glucose and lipid metabolism, and under pathophysiological conditions such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) these processes become dysfunctional. Stress responses activate the hepatic MAPKs, and this is thought to impair insulin action and lipid metabolism. The MAPKs also activate the MAPK phosphatases (MKPs) which oppose their actions. How the MAPK/MKP balance is controlled in liver metabolism and how perturbations in these activities contribute to metabolic disease remains unclear. Discussion of recent insights into the MAPK/MKP signaling role in hepatic metabolic function and disease will be the focus of this review. PMID- 29128161 TI - Linear IgA bullous dermatosis: A rare manifestation of vancomycin hypersensitivity. PMID- 29128160 TI - Prone sleeping position in infancy: Implications for cardiovascular and cerebrovascular function. AB - Advances in neonatal care have improved the survival rates of preterm infants, however, the likelihood of brain injury and neurodevelopmental disability remains a significant problem. Whilst the etiology of preterm brain injury is complex, impairments in the cardio- and cerebro-vascular function have been implicated. During infancy, sleep is vital for brain development. However, instabilities in cardio- and cerebro-vascular function are most marked during sleep. Sleeping position is an important part of a safe sleeping environment. Prone sleeping increases the risk of sudden infant death syndrome and is associated with reduced blood pressure, cerebral oxygenation and impaired autonomic cardiovascular control in infants born at term. Importantly, these effects are amplified by preterm birth. Hospitalized preterm infants are often slept in the prone position to improve respiratory function. However, there is little consensus regarding the sustained benefits of prone sleeping in this population. In light of the impaired cardio- and cerebro-vascular function during prone sleeping in term and preterm infants after hospital discharge, the likely adverse effects of prone sleeping in hospitalized preterm infants are concerning. This review examines the cardiovascular and cerebrovascular effects of prone sleeping in infants born at term, those born preterm after term equivalent age and whilst hospitalized. PMID- 29128159 TI - Development of the head, pinnae, and acoustical cues to sound location in a precocial species, the guinea pig (Cavia porcellus). AB - The morphology of the head and pinna shape the spatial and frequency dependence of sound propagation that give rise to the acoustic cues to sound source location. During early development, the physical dimensions of the head and pinna increase rapidly. Thus, the binaural (interaural time and level differences, ITD and ILD) and monaural (spectral shape) cues are also hypothesized to change rapidly. Complex interactions between the size and shape of the head and pinna limit the accuracy of simple acoustical models (e.g. spherical) and necessitate empirical measurements. Here, we measured the cues to location in the developing guinea pig, a precocial species commonly used for studies of the auditory system. We measured directional transfer functions (DTFs) and the dimensions of the head and pinna in guinea pigs from birth (P0) through adulthood. Dimensions of the head and pinna increased by 87% and 48%, respectively, reaching adult values by ~8 weeks (P56). The monaural acoustic gain produced by the head and pinna increased with frequency and age, with maximum gains at higher frequencies (>8 kHz) reaching values of 10-21 dB for all ages. The center frequency of monaural spectral notches also decreased with age, from higher frequencies (~17 kHz) at P0 to lower frequencies (~12 kHz) in adults. In all animals, ILDs and ITDs were dependent on both frequency and spatial location. Over development, the maximum ILD magnitude increased from ~15 dB at P0 to ~30 dB in adults (at frequencies >8 kHz), while the maximum low frequency ITDs increased from ~185 MUs at P0 to ~300 MUs in adults. These results demonstrate that the changes in the acoustical cues are directly related to changes in head and pinna morphology. PMID- 29128162 TI - Three-dimensionally printed personalized guide plate for percutaneous radiofrequency thermal coagulation in idiopathic trigeminal neuralgia. AB - Radiofrequency thermocoagulation (RFT) is used widely for the treatment of idiopathic trigeminal neuralgia (TN). Precise puncture and placement of the electrode needle tip are crucial for successful RFT. This technical note introduces a novel method for performing RFT using a customized, three dimensionally (3D)-printed guide plate. Eleven patients with idiopathic TN were treated using this method between February and July 2016. Three had V2 branch TN and eight had V3 branch TN. Punctures in eight patients were successful at the first attempt; slight adjustments were required subsequently in the other three patients. The puncture time in all cases was less than 1min. The patients reported pain relief immediately after RFT, and no complications were observed in any patient. Thus, the customized 3D-printed guide plate offers the advantages of precise placement of the puncture needle and minimal complications. PMID- 29128164 TI - Grey matter volume loss is associated with specific clinical motor signs in Huntington's disease. AB - BACKGROUND: Motor disturbances are clinical hallmarks of Huntington's disease (HD) and involve chorea, dystonia, hypokinesia and visuomotor dysfunction. Investigating the association between specific motor signs and different regional volumes is important to understand the heterogeneity of HD. OBJECTIVE: To investigate the motor phenotype of HD and associations with subcortical and cortical grey matter volume loss. METHODS: Structural T1-weighted MRI scans of 79 HD patients and 30 healthy controls were used to calculate volumes of seven subcortical structures including the nucleus accumbens, hippocampus, thalamus, caudate nucleus, putamen, pallidum and amygdala. Multiple linear regression analyses, corrected for age, gender, CAG, MRI scan protocol and normalized brain volume, were performed to assess the relationship between subcortical volumes and different motor subdomains (i.e. eye movements, chorea, dystonia, hypokinesia/rigidity and gait/balance). Voxel-based morphometry analysis was used to investigate the relationship between cortical volume changes and motor signs. RESULTS: Subcortical volume loss of the accumbens nucleus, caudate nucleus, putamen, and pallidum were associated with higher chorea scores. No other subcortical region was significantly associated with motor symptoms after correction for multiple comparisons. Voxel-based cortical grey matter volume reductions in occipital regions were related with an increase in eye movement scores. CONCLUSION: In HD, chorea is mainly associated with subcortical volume loss, while eye movements are more related to cortical volume loss. Both subcortical and cortical degeneration has an impact on motor impairment in HD. This implies that there is a widespread contribution of different brain regions resulting in the clinical motor presentation seen in HD patients. PMID- 29128165 TI - In reply to: Salman MM, Goetze N, Badrinath M, Shah M. The videolaryngoscope as a first-line intubation device in women with hypertensive disease of pregnancy. International Journal of Obstetric Anesthesia 2017;33. doi: http://dx.doi.org/10.1016/j.ijoa.2017.07.005. PMID- 29128163 TI - Depsidone and xanthones from Garcinia xanthochymus with hypoglycemic activity and the mechanism of promoting glucose uptake in L6 myotubes. AB - Garcinia xanthochymus is a widely used folk medicine in southwestern China. Previous studies indicated it possesses potential anti-diabetic activities both in vitro (Fu et al., 2014; Nguyen et al., 2017) and in vivo (Shivanand et al., 2017). To discover bioactive ingredients from it and unveil their mechanism of action against diabetes, the present study was designed to isolate constituents from extract of G. xanthochymus, determine their structures, screen their activities and investigate mechanism of action of the active substances. Twenty compounds including a new depsidone named garciniadepsidone A (20) and 19 known xanthones were obtained. All of them were screened to discover the active compounds with anti-diabetic activities. Finally, three xanthones including 12b hydroxy-des-d-garcigerrin (5), 1,2,5,6-tretrahydroxy-4-(1,1-dimethyl-2-propenyl) 7-(3-methyl-2-butenyl) xanthone (13) and 1,5,6-trihydroxy-7,8-di(3-methyl-2 butenyl)-6',6'-dimethylpyrano (2',3':3,4) xanthone (18) were found to be able to significantly stimulate the glucose uptake in the skeleton muscle cells. The effects of the three compounds were comparable to those of insulin and metformin. Based on molecular mechanistic study, it was found that both of compound 5 and 13 promoted glucose uptake by activating phosphatidylinositol-3 kinase (PI3K)/the serine/threonine kinase protein kinase B (PKB/Akt) signaling pathway and AMP activated protein kinase (AMPK) signaling pathway, resulting in the translocation of GLUT4 in L6 myotubes without affecting the expression of GLUT4. Compound 5 and 13 have great potential to be developed as promising leads to target diabetes. PMID- 29128166 TI - Right ventricular dysfunction and Pre Implantation Vasopressors in Refractory ARDS Supported by VV-ECMO. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) has been shown to be frequently associated with haemodynamic instability requiring the use of vasopressors. To date, there is still some uncertainty in the use of veno-venous Extracorporeal Membrane Oxygenation (VV-ECMO) in haemodynamically unstable ARDS patients. METHODS: We therefore assessed whether patients receiving pre ECMO vasopressors had a worse prognosis and, furthermore, we reviewed the factors associated with the use of pre ECMO vasopressors in 92 consecutive patients with refractory ARDS treated with VV-ECMO. All patients were submitted to an echocardiogram before implantation. RESULTS: In our series, 55 patients (59.7%) were given a vasopressor. Septic shock is the main cause of vasopressor requirement (45.5%). When compared with patients without vasopressors, the subgroup under vasopressors showed a significantly higher sequential organ failure assessment (SOFA) score (p=0.040), a lower pH (p=0.013), lower pO2 values (p=0.030) and higher lactate levels (p=0.024). A higher incidence of right ventricular (RV) dysfunction and of biventricular dysfunction were observed in patients under vasopressors (p=0.018 and p=0.036, respectively). The intensive care unit (ICU) mortality rate was 43.4% (40/92) with no difference between the two subgroups. CONCLUSIONS: In refractory ARDS requiring VV-ECMO, infusion of vasopressors is needed in a high proportion of patients, who did not exhibit a worse prognosis when compared to haemodynamically stable patients. Pre ECMO echocardiography helps in characterising these patients since they showed a higher incidence of RV (and biventricular) dysfunction. According to our data, in ARDS patients refractory to conventional treatment, haemodynamic instability should not be considered a contraindication to VV-ECMO support. PMID- 29128167 TI - A prospective evaluation of hippocampal radiation dose volume effects and memory deficits following cranial irradiation. AB - BACKGROUND AND PURPOSE: To prospectively evaluate hippocampal radiation dose volume effects and memory decline following cranial irradiation. MATERIAL AND METHODS: Effects of hippocampal radiation over a wide range of doses were investigated by combining data from three prospective studies. In one, adults with small cell lung cancer received hippocampal-avoidance prophylactic cranial irradiation. In the other two, adults with glioblastoma multiforme received neural progenitor cell sparing radiation or no sparing with extra dose delivered to subventricular zone. Memory was measured by the Hopkins Verbal Learning Test Revised Delayed Recall (HVLT-R DR) at 6 months after radiation. Dose-volume histograms were generated and dose-response data were fitted to a nonlinear model. RESULTS: Of 60 patients enrolled, 30 were analyzable based on HVLT-R DR testing completion status, baseline HVLT-R DR and intracranial metastasis/recurrence or prior hippocampal resection status. We observed a dose response of radiation to the hippocampus with regard to decline in HVLT-R DR. D50% of the bilateral hippocampi of 22.1 Gy is associated with 20% risk of decline. CONCLUSIONS: This prospective study demonstrates an association between hippocampal dose volume effects and memory decline measured by HVLT-R DR over a wide dose range. These data support a potential benefit of hippocampal sparing and encourage continued trial enrollment. PMID- 29128168 TI - Fifteen years of adrenalectomies: impact of specialty training and operative volume. AB - BACKGROUND: Previous associations between surgeon volume with adrenalectomy outcomes examined only a sample of procedures. We performed an analysis of all adrenalectomies performed in New York state to assess the effect of surgeon volume and specialty on clinical outcomes. METHODS: Adrenalectomies performed in adults were identified from the New York Statewide Planning and Research Cooperative System from 2000-2014. Surgeon specialty, volume, and patient demographics were assessed. High volume was defined using a significance threshold at >=4 adrenalectomies per year. Outcome variables included in-hospital mortality, duration of stay, and in-hospital complications. RESULTS: A total of 6,054 adrenalectomies were included. Median patient age was 56 years; 41.9% were men and 68.3% were white. Urologists (n = 462) performed 46.8% of adrenalectomies, general surgeons (n = 599) performed 35.0%, and endocrine surgeons (n = 23) performed 18.1%. Significantly more endocrine surgeons were high-volume compared with urologists and general surgeons (65.2% vs 10.2% and 6.7%, respectively, P < .001). High-volume surgeons had significantly lower mortality compared with low-volume surgeons (0.56% vs 1.25%, P = .004) and a lower rate of complications (10.2% vs 16.4%, P = < .001). Endocrine surgeons were more likely to perform laparoscopic procedures (34.8% vs 22.4% general surgeons and 27.7% US, P < .001) and had the lowest median hospital duration of stay (2 days vs 4 days general surgeons and 3 days urologists, P < .001). After risk adjustment, low surgeon volume was an independent predictor of inpatient complications (odds ratio = 0.96, P = .002). CONCLUSION: Patients with adrenal disease should be referred to surgeons based on adrenalectomy volume regardless of specialty, but most endocrine surgeons that perform adrenalectomy are high volume for the procedure. PMID- 29128169 TI - Estrogen receptor subtype expression and regulation is altered in papillary thyroid cancer after menopause. AB - BACKGROUND: Estrogen receptors can regulate growth in papillary thyroid cancer and may affect prognosis after menopause. This study examines changes of estrogen receptor subtype ratio expression in papillary thyroid cancer cell lines derived from pre- and postmenopausal women. METHODS: Cells were harvested from papillary thyroid cancer and non-papillary thyroid cancer thyroid tissue (control) from pre (n = 9) and postmenopausal women (n = 11). Protein expression of estrogen receptor alpha, estrogen receptor beta, and phosphorylated extracellular signal regulated kinase and protein kinase B were analyzed. Matrix metalloproteinase-2 activity was determined as a measure of tumor invasiveness. Mitochondrial retrograde signaling was altered with ethidium bromide to determine its effect on estrogen receptor alpha protein expression. RESULTS: Estrogen receptor alpha expression was increased in postmenopausal papillary thyroid cancer cells compared with controls but was unchanged in premenopausal papillary thyroid cancer. Estrogen receptor beta expression did not change in either group. Increased matrix metalloproteinase-2 activity was observed only in postmenopausal papillary thyroid cancer. Premenopausal papillary thyroid cancer cells demonstrated increased extracellular signal-regulated kinase and unchanged protein kinase B activation. Conversely, postmenopausal papillary thyroid cancer cells had decreased extracellular signal-regulated kinase and increased protein kinase B activation. Ethidium bromide treatment resulted in increased estrogen receptor alpha protein expression only in premenopausal papillary thyroid cancer cells. CONCLUSION: Increased estrogen receptor alpha expression may be involved in papillary thyroid cancer aggressiveness after menopause. This process may be regulated by differential activation of intracellular pathways and differing sensitivities to mitochondrial signaling regulation. PMID- 29128170 TI - Discussion. PMID- 29128171 TI - Discussion. PMID- 29128172 TI - Discussion. PMID- 29128173 TI - Discussion. PMID- 29128174 TI - Health-related quality of life in MEN1 patients compared with other chronic conditions and the United States general population. AB - BACKGROUND: Health-related quality of life (HRQOL) in multiple endocrine neoplasia type-1 (MEN-1) is poorly described. HRQOL in MEN-1 was compared with other chronic conditions and the US general population. METHODS: Adults aged >=18 years recruited from an MEN-1 support group (n=153) completed the Patient Reported Outcomes Measurement Information System (PROMIS) 29-item profile. MEN-1 scores were compared with PROMIS scores reported in peer-reviewed literature from back pain (n=218), cancer (n=310), congestive heart failure (CHF; n=60), chronic obstructive pulmonary disease (COPD; n=79), major depressive disorder (n=196), rheumatoid arthritis (RA; n=521), neuroendocrine tumors (NET; n=619), and primary hyperparathyroidism (PHPT; n=45) cohorts. RESULTS: Patients with MEN-1 reported worse anxiety (mean=61.7), depression (57.9), fatigue (62.2), pain interference (55.4), sleep disturbance (58.0), physical functioning (44.4), and social functioning (44.7) compared to normative data (50, P < .05) and greater anxiety, depression, and fatigue than patients with back pain, cancer, COPD, RA, NETs, and PHPT (P < .001). MEN-1 respondents had greater pain interference (55.4) than those with cancer (51.9), NETs (52.3), and PHPT (38.4, P < .05). Physical functioning was higher in individuals with MEN-1 (44.4) than in those with back pain (37.5), CHF (34.8), COPD (38.0), and RA (40.7, P < .01). CONCLUSION: This is the first study to describe HRQOL in a large sample of adults with MEN-1. MEN 1respondents reported worse HRQOL across PROMIS 29-item profile measure domains compared with the US general population and higher levels of anxiety, depression, and fatigue compared with many other chronic conditions. PMID- 29128175 TI - Discussion. PMID- 29128177 TI - Discussion. PMID- 29128176 TI - Back so soon? Is early recurrence of papillary thyroid cancer really just persistent disease? AB - BACKGROUND: Papillary thyroid carcinoma has excellent survival, yet recurrence remains a challenge. We sought to determine the proportion of reoperations performed for persistent, rather than truly recurrent, disease. METHODS: We conducted a retrospective review of a prospectively maintained database. Patients with papillary thyroid carcinoma who underwent reoperation for disease from 2000 2016 were included. We defined recurrence as disease that developed after a patient had an undetectable thyroglobulin and a negative ultrasonography within 1 year of operation. RESULTS: A total of 69 patients underwent 92 reoperations. On initial pathology, mean tumor size was 2.6 cm, 51% were multifocal, and 42% had extrathyroidal extension. Half (46%) of the patients underwent a central/lateral neck dissection at the initial operation, and 77% were treated with postoperative radioactive iodine. The median time to first reoperation was 21 months (range, 1 292), and 42% occurred within 1 year. Only 3 operations met criteria for true "recurrence," while 71 operations were categorized as persistent disease. CONCLUSION: Many reoperations for papillary thyroid carcinoma are for management of persistent disease. More than half of the patients required reoperation within the first 2 years, which suggests strongly that improvements in the preoperative assessment and adequacy of initial operative therapy need to be made to improve the care of patients with thyroid cancer. PMID- 29128179 TI - Discussion. PMID- 29128178 TI - Cost-effectiveness of lobectomy versus genetic testing (Afirma(r)) for indeterminate thyroid nodules: Considering the costs of surveillance. AB - BACKGROUND: We evaluated whether diagnostic thyroidectomy for indeterminate thyroid nodules would be more cost-effective than genetic testing after including the costs of long-term surveillance. METHODS: We used a Markov decision model to estimate the cost-effectiveness of thyroid lobectomy versus genetic testing (Afirma(r)) for evaluation of indeterminate (Bethesda 3-4) thyroid nodules. The base case was a 40-year-old woman with a 1-cm indeterminate nodule. Probabilities and estimates of utilities were obtained from the literature. Cost estimates were based on Medicare reimbursements with a 3% discount rate for costs and quality adjusted life-years. RESULTS: During a 5-year period after the diagnosis of indeterminate thyroid nodules, lobectomy was less costly and more effective than Afirma(r) (lobectomy: $6,100; 4.50 quality-adjusted life- years vs Afirma(r): $9,400; 4.47 quality-adjusted life-years). Only in 253 of 10,000 simulations (2.5%) did Afirma(r) show a net benefit at a cost-effectiveness threshold of $100,000 per quality- adjusted life-years. There was only a 0.3% probability of Afirma(r) being cost saving and a 14.9% probability of improving quality-adjusted life-years. CONCLUSIONS: Our base case estimate suggests that diagnostic lobectomy dominates genetic testing as a strategy for ruling out malignancy of indeterminate thyroid nodules. These results, however, were highly sensitive to estimates of utilities after lobectomy and living under surveillance after Afirma(r). PMID- 29128180 TI - Notch3 as a novel therapeutic target in metastatic medullary thyroid cancer. AB - BACKGROUND: Medullary thyroid cancer portends poor survival once liver metastasis occurs. We hypothesize that Notch3 overexpression in medullary thyroid cancer liver metastasis will decrease proliferation and growth of the tumor. METHODS: TT cells were modified genetically to overexpress Notch3 in the presence of doxycycline, creating the TT-Notch3 cell line. Mice were injected intrasplenically with either TT-Notch3 or control vector TT-TRE cells. Each cell line had 3 treatment groups: control with 12 weeks of standard chow, early DOX with doxycycline chow at day 0 and for 70 days thereafter, and late DOX with doxycycline chow at 8 weeks. Each animal underwent micro-computed tomography to evaluate for tumor formation and tumor quantification was performed. Animals were killed at 12 weeks, and the harvested liver was stained with Ki-67, hematoxylin and eosin, and Notch3. RESULTS: Induction of Notch3 did not prevent formation of medullary thyroid cancer liver metastases as all mice in the early DOX group developed tumors. However, induction of Notch after medullary thyroid cancer liver tumor formation decreased tumor size, as seen on micro-computed tomography scans (late DOX group). This translated to a 37-fold decrease in tumor volume (P = .001). Notch3 overexpression also resulted in decreased Ki-67 index (P = .038). Moreover, Notch3 induction led to increased areas of neutrophil infiltration and necrosis on hematoxylin and eosin staining of the tumors CONCLUSION: Notch3 overexpression demonstrates an antiproliferative effect on established metastatic medullary thyroid cancer liver tumors and is a potential therapeutic target in treatment. PMID- 29128182 TI - Discussion. PMID- 29128181 TI - Predictive relevance of programmed cell death protein 1 and tumor-infiltrating lymphocyte expression in papillary thyroid cancer. AB - BACKGROUND: Co-signaling molecule programmed cell death 1 ligand 1 has been shown to induce potent inhibition of T cell-mediated antitumoral immunity. Our study aimed to investigate the prognostic value of programmed cell death 1 ligand 1 expression and tumor-infiltrating lymphocyte density as biomarkers in specimens from patients with papillary thyroid cancer. METHODS: We retrospectively analyzed the data and tissue samples of 75 patients with papillary thyroid cancer. Stained cells were counted manually and analyzed for clinical and histopathologic correlations and disease-free survival. RESULTS: Programmed cell death 1 ligand 1 expression was significantly correlated with increased incidence of lymphovascular invasion (P = .038), extrathyroidal extension (P = .026), and concurrent lymphocytic thyroiditis (P = .003). Patients with low CD8+ and CD3+ expression presented with a significantly higher incidence of lymph node metastasis (P = .042) and extrathyroidal extension (P = .015). The subgroup of cases with positive programmed cell death 1 ligand 1 expression and low CD8+ T cell infiltration demonstrated a significantly increased incidence of lymph node metastasis (P = .031). Univariate and multivariate analysis confirmed that a high CD8+ T cell density was significantly associated with favorable disease-free survival (P = .017). Subanalysis revealed that the shortest disease-free survival was evident in the programmed cell death 1 ligand 1+/CD8low group (P = .004). CONCLUSION: Our findings indicate that CD8+ tumor-infiltrating lymphocyte density and programmed cell death 1 ligand 1 expression may serve as valuable predictive biomarkers in patients with papillary thyroid cancer. PMID- 29128183 TI - Does intraoperative neuromonitoring of recurrent nerves have an impact on the postoperative palsy rate? Results of a prospective multicenter study. AB - BACKGROUND: The impact of intraoperative neuromonitoring on recurrent laryngeal nerve palsy remains debated. Our aim was to evaluate the potential protective effect of intraoperative neuromonitoring on recurrent laryngeal nerve during total thyroidectomy. METHODS: This was a prospective, multicenter French national study. The use of intraoperative neuromonitoring was left at the surgeons' choice. Postoperative laryngoscopy was performed systematically at day 1 to 2 after operation and at 6 months in case of postoperative recurrent laryngeal nerve palsy. Univariate and multivariate analyses and propensity score (sensitivity analysis) were performed to compare recurrent laryngeal nerve palsy rates between patients operated with or without intraoperative neuromonitoring. RESULTS: Among 1,328 patients included (females 79.9%, median age 51.2 years, median body mass index 25.6 kg/m2), 807 (60.8%) underwent intraoperative neuromonitoring. Postoperative abnormal vocal cord mobility was diagnosed in 131 patients (9.92%), including 69 (8.6%) and 62 (12.1%) in the intraoperative neuromonitoring and nonintraoperative neuromonitoring groups, respectively. Intraoperative neuromonitoring was associated with a lesser rate of recurrent laryngeal nerve palsy in univariate analysis (odds ratio = 0.68, 95% confidence interval, 0.47; 0.98, P = .04) but not in multivariate analysis (oddsratio = 0.74, 95% confidence interval, 0.47; 1.17, P = .19), or when using a propensity score (odds ratio = 0.76, 95% confidence interval, 0.53; 1.07, P = .11). There was no difference in the rates of definitive recurrent laryngeal nerve palsy (0.8% and 1.3% in intraoperative neuromonitoring and non-intraoperative neuromonitoring groups respectively, P = .39). The sensitivity, specificity, and positive and negative predictive values of intraoperative neuromonitoring for detecting abnormal postoperative vocal cord mobility were 29%, 98%, 61%, and 94%, respectively. CONCLUSION: The use of intraoperative neuromonitoring does not decrease postoperative recurrent laryngeal nerve palsy rate. Due to its high specificity, however, intraoperative neuromonitoring is useful to predict normal vocal cord mobility. From the CHU de Nantes,a Clinique de Chirurgie Digestive et Endocrinienne, Nantes, France; CHU Lille, Universite de Lille,b Chirurgie Generale et Endocrinienne, Lille, France; CHU Nancy-Hopital de Brabois,c Service de Chirurgie Digestive, Hepato-Biliaire, et Endocrinienne, Nancy, France; CHU Angers,d Chirurgie Digestive et Endocrinienne, Angers, France; CHU de Toulouse Hopital Larrey,e Chirurgie Thoracique, Pole Voies Respiratoires, Toulouse; CHU Saint-Etienne-Hopital Nord,f ORL et Chirurgie Cervico-Faciale et Plastique, Saint Etienne, France; CHU de Limoges-Hopital Dupuytren,g Chirurgie Digestive, Generale et Endocrinienne, Limoges, France; CHU de Besancon-Hopital Jean Minjoz,h Chirurgie Digestive, Besancon, France; Centre Hospitalier du Mans,i Service ORL et Chirurgie Cervico-Faciale, Le Mans, France; Centre Hospitalier Lyon-Sud,j Chirurgie Generale, Endocrinienne, Digestive et Thoracique, Pierre Benite, France; AP-HM-Hopital de La Conception,k Chirurgie Generale, Marseille, France; CHU de Rennes-Hopital Pontchaillou,l Service ORL et Chirurgie Maxillo-Faciale, Rennes, France; CHU de Caen,m ORL et Chirurgie Cervico-Faciale, Caen, France; CHU d'Angers,n ORL et Chirurgie Cervico-Faciale, Angers, France; CHU de Nantes,o Service ORL, Nantes, France; AP HP URCEco ile-de-France,p hopital de l'Hotel Dieu, Paris, France; DRCI, departement Promotion,q Nantes, France. PMID- 29128184 TI - Importance of surgeon-performed ultrasound in the preoperative nodal assessment of patients with potential thyroid malignancy. AB - INTRODUCTION: A comprehensive cervical ultrasound evaluation is essential in the operative planning of patients with thyroid disease. Reliance on radiographic reports alone may result in incomplete operative management as pathologic lymph nodes are often not palpable and evaluation of the lateral neck is not routine. This study examined the role of surgeon-performed ultrasound in the evaluation of patients who underwent lateral neck dissection for thyroid cancer. METHODS: We conducted a retrospective review of a prospectively maintained database of patients who underwent therapeutic lymph node dissection for thyroid cancer between 2001 and 2016 at our tertiary referral center. All patients had surgeon performed ultrasound preoperatively by 1 of 7 endocrine surgeons. These findings were compared with prereferral imaging studies to determine the value of surgeon performed ultrasound to their overall treatment. RESULTS: Of 92 patients who underwent thyroidectomy with lateral neck dissection, 97% had prereferral imaging of the neck (ultrasonography, computed tomography, positron emission tomography). Of these patients, nodal disease was suggested by computed tomography scanning in 70.8% and by ultrasonography in 54%. Of all patients, 45% had positive lateral neck nodes detected only on surgeon-performed ultrasound despite prior neck imaging. Nodal disease was identified in 50% of patients with only 1 study and 50% of patients with greater than 1 study before surgeon-performed ultrasound. Of patients with nodes detected by surgeon-performed ultrasound, only 67% had a prereferral diagnosis of thyroid cancer. CONCLUSIONS: Our data demonstrate that reliance on standard preoperative imaging alone would have led to an incorrect initial operation in 45% of our patients. Awareness of the limitations of prereferral imaging is important for surgeons treating patients with thyroid and parathyroid disease. Surgeon-performed ultrasound is a useful tool in the diagnosis and accurate staging of patients. PMID- 29128185 TI - Correct extent of thyroidectomy is poorly predicted preoperatively by the guidelines of the American Thyroid Association for low and intermediate risk thyroid cancers. AB - BACKGROUND: Recent guidelines from the American Thyroid Association recommend thyroid lobectomy for intrathyroidal differentiated thyroid cancers <4 cm. Our aim was to examine histology from patients with cytologic results that were positive or suspicious for malignancy to assess the extent of initial thyroidectomy based on criteria from the 2015 American Thyroid Association guidelines. METHODS: We studied consecutive patients who had either a positive or suspicious for malignancy cytologic diagnosis and under prior American Thyroid Association guidelines underwent initial total thyroidectomy +/- lymphadenectomy. RESULTS: Among 447 patients, high-risk features necessitating total thyroidectomy were present in 19% (72/380) of positive and 15% (10/67) of suspicious for malignancy patients (P = .5). Intermediate-risk features on histology were identified postoperatively in 46% (175/380) with positive and 15% (18/67) with suspicious for malignancy fine-needle aspiration results. In multivariable analysis, preoperative factors associated with intermediate-risk disease included age >=45 years, women, larger tumor size, positive fine-needle aspiration cytology, and BRAF V600E or RET/PTC positivity. CONCLUSION: When patients are considered for lobectomy under the 2015 American Thyroid Association guidelines, ~ 60% with positive and 30% with suspicious for malignancy cytology would need completion thyroidectomy based on intermediate-risk disease. The cost and risk implications of the new American Thyroid Association strategy were substantial and better tools are needed to improve preoperative risk stratification. PMID- 29128186 TI - Discussion. PMID- 29128187 TI - Discussion. PMID- 29128188 TI - Influence of concurrent chronic kidney disease on intraoperative parathyroid hormone monitoring during parathyroidectomy for primary hyperparathyroidism. AB - BACKGROUND: The influence of chronic kidney disease on intraoperative parathyroid hormone monitoring during parathyroidectomy for primary hyperparathyroidism has not been well-established. We hypothesize that chronic kidney disease influences intraoperative parathyroid hormone degradation kinetics during parathyroidectomy. METHODS: This is a single institution retrospective cohort study of consecutive patients with primary hyperparathyroidism underdoing parathyroidectomy. Patients were stratified according to normal kidney function (glomerular filtration rates >=60 mL/min/1.73 m2 or presence of chronic kidney disease (glomerular filtration rates 15 - 60 mL/min/1.73 m2). Demographics, laboratory data, operative findings, and intraoperative parathyroid hormone data were compared between groups. RESULTS: Of the 964 study patients, 235 had chronic kidney disease (24.4%), while 729 (75.6%) had normal kidney function. The chronic kidney disease population had a greater median preoperative serum parathyroid hormone (PTH) (125 vs 114 pg/mL; P < .001), but similar median intraoperative parathyroid hormone levels (chronic kidney disease versus normal): baseline (190 vs 189; P=.232), 5 minutes (51 vs 47; P = .667), 10 minutes (37 vs 35; P=.626), and at 15 minutes postexcision (28 vs 27; P=.539). There was no significant difference in the kinetics of the intraoperative parathyroid hormone degradation slope from the baseline to the 15 minute postexcision levels comparing chronic kidney disease with normal kidney function (-21.02 vs -20.83; P=.957). Patients with chronic kidney disease had 15 minute postexcision intraoperative parathyroid hormone levels within the normal range (12 - 65 pg/mL) as frequently as patients with normal kidney function (81% vs 82%; P=.906) and had similar rates of persistent disease (3.4% vs 3.4%; P=.985). CONCLUSION: Patients with chronic kidney disease undergoing parathyroidectomy for primary hyperparathyroidism have similar intraoperative parathyroid hormone degradation kinetics, and the intraoperative parathyroid hormone criteria used to predict cure should be similar to those with normal kidney function. PMID- 29128189 TI - Discussion. PMID- 29128190 TI - Development of the ThyCAT: A clinically useful computerized adaptive test to assess quality of life in thyroid cancer survivors. AB - BACKGROUND: Current quality of life assessment tools for thyroid cancer survivors are not clinically useful due to the length of available questionnaires. Computerized adaptive tests are easily administered electronically and can achieve highly accurate and efficient results in minimal time. We aimed to develop a quality of life computerized adaptive tests (ThyCAT) for thyroid cancer survivors. METHODS: A bifactor item response theory model was fit to questionnaire responses from 1,078 North American Thyroid Cancer Survivorship Study participants-a longitudinal cohort study of quality of life in thyroid cancer survivors. Tuning parameters were selected to maintain a correlation of r > 0.9 with the total item bank quality of life score obtained from the original North American Thyroid Cancer Survivorship Study questions, using a minimal number of adaptively administered ThyCAT items. RESULTS: The ThyCAT assesses quality of life with strong correlation (r = 0.96) with the original 75 North American Thyroid Cancer Survivorship Study questions using an average of 9.94 questions (SD +/- 3.03) administered in <2 minutes. There was no statistically significant difference in the number of ThyCAT questions required based on demographic or tumor characteristics. CONCLUSION: The ThyCAT can be administered on a smartphone app in <10 questions, and <2 minutes, allowing efficient and accurate in or out of clinic identification of patients struggling with quality of life issues after thyroid cancer treatment. PMID- 29128191 TI - Discussion. PMID- 29128192 TI - Efficacy and safety of benralizumab in Japanese patients with severe, uncontrolled eosinophilic asthma. AB - BACKGROUND: In the Phase III CALIMA trial, benralizumab significantly reduced asthma exacerbations, increased lung function, and alleviated symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate the efficacy and safety of benralizumab for Japanese patients in the CALIMA trial. METHODS: CALIMA was a randomised, controlled trial of 1306 patients (aged 12-75 years; registered at ClinicalTrials.gov: NCT01914757) with severe asthma uncontrolled by medium- to high-dosage inhaled corticosteroids and long-acting beta2-agonists (ICS/LABA). Patients received 56 weeks' benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), or placebo Q4W. The primary analysis population was patients receiving high-dosage ICS/LABA with blood eosinophils >=300 cells/MUL. This subgroup analysis covered Japanese patients from this group. RESULTS: Of 83 patients randomised in Japan, 46 were receiving high-dosage ICS/LABA and had blood eosinophils >=300 cells/MUL. Compared with placebo, benralizumab reduced the annual rate of asthma exacerbations by 66% (Q4W; rate ratio 0.34, 95% CI, 0.11-0.99) and 83% (Q8W; rate ratio 0.17, 95% CI, 0.05-0.60); increased prebronchodilator FEV1 by 0.334 L (Q4W; 95% CI, 0.020-0.647) and 0.198 L (Q8W; 95% CI, -0.118 to 0.514); and decreased total asthma symptom score by 0.17 (Q4W; 95% CI, -0.82 to 0.48) and 0.24 (Q8W; 95% CI, -0.87 to 0.40). Percentages of adverse events were consistent with the overall CALIMA group. CONCLUSIONS: Benralizumab reduced annual asthma exacerbations and symptoms, increased lung function, and was well-tolerated by Japanese patients with severe, uncontrolled eosinophilic asthma. PMID- 29128193 TI - Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27. AB - BACKGROUND: Approximately half of women taking aromatase inhibitor (AI) therapy develop AI-induced arthralgia (AIA), and many might discontinue AI therapy because of the pain. Using plasma samples from the MA.27 study, we assessed several factors potentially associated with AIA. PATIENTS AND METHODS: MA.27 is a phase III adjuvant trial comparing 2 AIs, exemestane versus anastrozole. Within an 893-participant nested case-control AIA genome-wide association study, we nested a 72 AIA case-144 control assessment of vitamin D plasma concentrations, corrected for seasonal and geographic variation. We also examined 9 baseline inflammatory cytokines: interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha, interferon (IFN)gamma, IL-10, IL-12p70, IL-17, IL-23, and chemokine ligand (CCL)-20. Finally, we analyzed the multivariate effects of baseline factors: vitamin D level, previously identified musculoskeletal single nucleotide polymorphisms, age, body mass index, and vitamin D receptor (VDR) Fok-I variant genotype on AIA development. RESULTS: Changes in vitamin D from baseline to 6 months were not significantly different between cases and controls. Elevated inflammatory cytokine levels were not associated with development of AIA. The multivariate model included no clinical factors associated with AIA. However, women with the VDR Fok-I variant genotype were more likely to have a lower IL 1beta level (P = .0091) and less likely to develop AIA after 6 months of AI compared with those with the wild type VDR (P < .0001). CONCLUSION: In this nested case-control correlative study, vitamin D levels were not significantly associated with development of AIA; however, patients with the Fok-I VDR variant genotype were more likely to have a significant reduction in IL-1beta level, and less likely to develop AIA. PMID- 29128194 TI - Treatment of electrical status epilepticus in sleep: Clinical and EEG characteristics and response to 147 treatments in 47 patients. AB - OBJECTIVE: Electrical status epilepticus in sleep (ESES) syndrome is characterized by near-continuous sleep-induced epileptiform activity and acquired cognitive deficits. Treatment is assumed mandatory to improve cognitive outcome. We aimed to compare EEG characteristics, subjective evaluation and objective neuropsychological assessment as measures to evaluate treatment efficacy, and to analyze possible predictors. METHODS: We retrospectively included patients with ESES syndrome treated in our center. Treatment effect was analyzed on sleep EEG spike wave index (SWI) and cognitive functioning. RESULTS: 47 patients had 147 (43 steroid and 104 non-steroid) treatments. Cognitive improvement was reported after 36% of treatments at first follow-up and 45% of treatments at last follow up. The median SWI change for treatments resulting in subjective cognitive improvement was -44%, and 0% for those not resulting in subjective cognitive improvement at first follow-up (p = 0.008) and -50% vs. +5% at last follow-up (p = 0.002). No clear association between subjective cognitive improvement and IQ change, and between SWI and IQ change was found. By means of logistic regression we found that steroid treatment, as compared to non-steroid treatment, was associated with cognitive improvement at first follow-up (multivariate OR after multiple imputation 2.5, 95% CI 1.1-5.7), while at last follow-up, higher age at diagnosis was related to cognitive improvement only in univariate analysis (OR 1.02, 95% CI 1.01-1.04). CONCLUSIONS: We found that in children with ESES, cognitive improvement after treatment was strongly associated with SWI decrease, while it was not reflected by a significant IQ increase. Steroid treatment was most successful in improving cognitive performance. PMID- 29128195 TI - [What support of young presenting a first psychotic episode, when schooling is being challenged?] AB - Psychiatric disorders (more specifically mood disorders and psychosis) represent the 1st cause of disability among young people. Unemployment rate between 75 to 95% for the person with schizophrenia. It is correlated to poor social integration and bad economic status, worse symptomatology loss of autonomy as well as global bad functioning. It is responsible of more than half of the overall cost of psychosis. The onset of most of psychiatric disorders occur between the age of 25 and 35 years old, a critical time in young adult life when they should build their professional as well as social future. Without appropriate care, young adult are unable to build satisfactory emotional relationships, continue their studies, live independently or fit into life. They are frequently dependent on their environment. They also have an increased suicide rate and frequent comorbid substance abuse. Despite this context, their care pathway is often marked by a delay or premature stop of care, drug treatments not always suitable and a lack of specific relay post-hospitalization regarding continuity of professional training or studies. All factors impacting future employability of adolescents. Furthermore they spend most of their time in school and school plays a key part in an individual's development including peer relationships, social interactions, academic attainment, cognitive progress, emotional control, behavioral expectations and physical and moral development. These areas are also reciprocally affected by mental illness. The initial phases of FEP are characterized by impaired academic performance, change in social behaviors and increasing absences from school, reflecting the prodrome of the illness that leads to disengagement from education. Functional decline often precedes onset of clinical symptoms and many adolescents and young adults are therefore isolated from school before their illness is recognized. School support staff may fail to recognize those who are functionally impaired because of evolving FEP although school is a key setting for promoting positive mental health, fostering resilience, detecting and responding to emerging mental ill health. So, people with psychotic illness have low levels of secondary school completion. School dropout has been defined as leaving education without obtaining a minimal credential, most often a higher secondary education diploma. In France, the school is compulsory up to the age of 16. Consequences are significant: among young people without a degree out of initial training for one to four years and present on the labour market, 47% are unemployed. School dropout depends on a number of factors, including grades, family and social environment and the relationship with the school, but also the emergence of psychiatric disorders. For first episode psychotic patients, age of onset, lack of family support, longer duration of psychosis, levels of premorbid global functioning and education, negative and cognitive symptoms, addictions, depressive comorbidities and stigma plays an important role in school dropout. However, young adults have historically received less treatment than expected considering prevalence of mental illness at that age. In the last few decades, early intervention programs for psychosis have been developed all around the world in order to promote rehabilitation and prevent long-term disabilities. Early intervention programs focus on the special needs of young people and their families and engage in some form of assertive community treatment, which attempts to treat patients in the community rather than using inpatient services. For early intervention in psychosis programs, the goal is to keep patients engaged with treatment, prevent them from further psychotic episodes and hospitalizations and promote rehabilitation. The additional services of an early intervention program include staff specialized in psychosis treatment, family/group/individual counseling sessions, assertive case management, and low-dose second generation anti-psychotics. In these programs, psychiatric rehabilitation practitioners already use individual counseling and supported education programs (SEd) to improve postsecondary educational outcomes. The goals of SEd are for individuals with serious mental illness to successfully be able to set and achieve an educational goal (e.g., training certificate or degree), to improve educational competencies (literacy, study skills, time management), to navigate the educational environment (e.g., applications, financial assistance), and to improve motivation toward completing educational goals. These approaches are often combined with efforts to support transitions to sustainable employment. Current evidence of these interventions are weak with limited information on specific difficulties experienced by young adults with FEP in educational tasks. Adaptive strategies are needed by young adults with FEP to succeed in educational settings but most studies do not explore it with rigorous methodology. However, common SEd components emerge: specialized and dedicated staffing, one-on-one and group skill-building activities, assistance with navigating the academic setting and coordinating different services, and linkages with mental health counseling. Continued specification, and testing of SEd core components are still needed. It is important that occupational therapy researchers and practitioners develop, and evaluate effective interventions to improve education outcomes for young adults with FEP. The objective of this work is to define school dropout, assess causes and consequences of FEP. How to help young people to maintain education? We will detail measures to support the academic re-insertion in France. PMID- 29128196 TI - What Is So Different About Psychotic Patients Who Have Extremely Long Institutional Stays? PMID- 29128198 TI - ? PMID- 29128199 TI - Local injection of carrageenan accelerates orthodontic tooth movement: A preliminary experimental animal study. AB - BACKGROUND: Orthodontic tooth movement (OTM) can be accelerated by increasing bone turnover. Carrageenan is a common food additive, which can induce inflammation. Hence, it might accelerate OTM. However, it has not been investigated to date. METHODS: This 2-phase preliminary animal experimental study was conducted on 28 Wistar rats. A pilot study on 5 mice was done to estimate the experimental dose of carrageenan. The first phase evaluated the effect of a 40MUL carrageenan 1% injection on inflammation status in 7 rats versus 7 control rats, 6hours after the injection. The second phase examined the effect of the same dose of carrageenan on OTM speed during 21 days of incisor retraction in rat, in two groups: control (normal saline) and carrageenan (n=7*2). This sample size was pre determined based on a priori power calculations. In phase II, osteoclastic activity was also evaluated, 21 days after the injection. The groups were compared statistically (alpha=0.05). RESULTS: Six hours after carrageenan injection, 1, 3, and 3 rats had inflammation scores of 3 to 1, respectively. Six hours after saline injection, 1 rat had a score of 1 and the remainder had no inflammation (P=0.0023, Mann-Whitney). Twenty-one days after saline and carrageenan injection, OTMs were 0.7+/-0.3 and 1.1+/-0.4mm, respectively, (P=0.053, Mann-Whitney). Twenty-one days after saline and carrageenan injection, mean osteoclast counts were, respectively, 4.87+/-1.849 and 7.143+/-1.727 per field (P=0.025, Mann-Whitney). CONCLUSION: Local injection of carrageenan can induce inflammation after 6hours. It can increase approximately 1.6-fold the speed of OTM, and increase the osteoclast count 1.5-fold after 21 days of space closure. PMID- 29128197 TI - Reirradiation of gliomas under stereotactic conditions: Prognostic factors for survival without relapse or side effects, a retrospective study at Tours regional university hospital (France). AB - PURPOSE: To search for factors correlated with relapse-free survival following stereotactic reirradiation in patients with recurrent glioma following radiochemotherapy and evaluate tolerance to this treatment. PATIENTS AND METHODS: Initial radiotherapy was given according to the protocol of Stupp and al. Reirradiation was performed using the CyberKnife(r) system. Patients could have had surgical resection initially and at the time of recurrence. We analysed 13 patients treated between July 2010 and September 2014. The median age was 55 years. The doses delivered ranged from 20 to 36Gy, in one to ten fractions. RESULTS: Median survival after stereotactic radiotherapy was 14 months. Survival without relapse was 3.7 months. Factors significantly influencing duration of relapse-free survival were: age (P=0.04), total dose (P=0.02), dose per fraction (P=0.04) and number of fractions (P=0.01). We found no correlation between gross tumour volume, clinical target volume, grade of tumour or prescription isodose and relapse-free survival following radiochemotherapy. Three patients developed radionecrosis. CONCLUSION: Reirradiation under stereotactic conditions is well tolerated. A dose of more than 30Gy delivered in 5 or more fractions seems to prolong relapse-free survival. PMID- 29128200 TI - Exploring sociodemographic and economic factors that promote adverse drug reactions reporting by patients. AB - BACKGROUND: Adverse drug reactions (ADRs) are recognized as a leading cause of morbidity and mortality, and an important cost factor to health systems. Patient reporting of ADRs has emerged as an important topic in recent years but reporting rates are still low in many countries. OBJECTIVE: To explore different countries' sociodemographic and economic features as explanatory factors for population ADRs reporting, including the propensity of patients' reporting to pharmacovigilance authorities. METHODS: Cross-sectional observational design. A data set of 42 global sociodemographic and economic factors for 44 countries were retrieved, as to analyse statistical associations between these factors and the patient reporting rate of ADRs. Multivariate logistic regression models were designed to identify the predictive covariables. RESULTS: Health investment indicators, such as per capita public health expenditure, hospital bed density and under five mortality rate were the relevant factors responsible to discriminate between countries that have higher patient reporting rates. CONCLUSIONS: This study shows that healthcare investment-related factors help explain the propensity of patients to report suspected ADRs, while pharmacovigilance features were not directly associated with higher patient participation in drug safety mechanisms. Although general, these results point a direction in further policy making to improve resources allocation concerning the promotion of patients' participation. PMID- 29128201 TI - [Report of the ordinary general assembly of the Morphologists' Association - 10th March 2017]. PMID- 29128202 TI - Multi-hazard risk assessment of coastal vulnerability from tropical cyclones - A GIS based approach for the Odisha coast. AB - The coastal region bordering the East coast of India is a thickly populated belt exposed to high risk and vulnerability from natural hazards such as tropical cyclones. Tropical cyclone frequencies that develop over the Bay of Bengal (average of 5-6 per year) region are much higher as compared to the Arabian Sea thereby posing a high risk factor associated with storm surge, inland inundation, wind gust, intense rainfall, etc. The Odisha State in the East coast of India experiences the highest number of cyclone strikes as compared to West Bengal, Andhra Pradesh, and Tamil Nadu. To express the destructive potential resulting from tropical cyclones the Power Dissipation Index (PDI) is a widely used metric globally. A recent study indicates that PDI for cyclones in the present decade have increased about six times as compared to the past. Hence there is a need to precisely ascertain the coastal vulnerability and risk factors associated with high intense cyclones expected in a changing climate. As such there are no comprehensive studies attempted so far on the determination of Coastal Vulnerability Index (CVI) for Odisha coast that is highly prone to cyclone strikes. With this motivation, the present study makes an attempt to investigate the physical, environmental, social, and economic impacts on coastal vulnerability associated with tropical cyclones for the Odisha coast. The study also investigates the futuristic projection of coastal vulnerability over this region expected in a changing climate scenario. Eight fair weather parameters along with storm surge height and onshore inundation were used to estimate the Physical Vulnerability Index (PVI). Thereafter, the PVI along with social, economic, and environmental vulnerability was used to determine the overall CVI using the GIS based approach. The authors believe that the comprehensive nature of this study is expected to benefit coastal zone management authorities. PMID- 29128203 TI - Study of correlation between genetic variants in three microRNA genes (hsa-miR 146a, hsa-miR-502 binding site, hsa-miR-27a) and breast cancer risk. AB - BACKGROUND AND AIM: MicroRNAs (miRNAs) represent noncoding RNAs that play a role in the gene regulation of oncogenes and tumor suppressors. Single nucleotide polymorphisms (SNPs) in miRNA genes are associated with risk of cancer. Some of these SNPs are more common including rs2910164 in the miR-146a, rs895819 in the miR-27a, and rs2910164 in the miR-502 binding site of the SET8. Our aim was to investigate the association between these polymorphisms and the risk of breast cancer in an Iranian population. MATERIALS AND METHODS: In this case-control study, 240 breast cancer patients and 231 healthy people, matched by age and geographical region, were studied. After sample taking and total genomic extraction, genotyping was conducted by using PCR-RFLP and the results confirmed by direct sequencing. Then, allele and genotype frequencies and the association between the SNPs and breast cancer were investigated by the data analysis conducted in the SPSS version 20. RESULTS: C allele in the variant rs895819 is associated with decreased risk of breast cancer. Such association was also obtained in dominant (OR=0.516) and overdominant (OR=0.527) models. The rs2910164 and rs16917496 SNPs were significantly associated with breast cancer (P=0.03 and 0.003, respectively). CONCLUSION: This study determined that genetic changes in miR-146a and the miR-502 binding site of the SET8 can be effective on the increased risk of breast cancer. Such variation in miR-27a can have protective effects against breast cancer. PMID- 29128204 TI - Uterine artery embolization: A review of current concepts. AB - Uterine artery embolization (UAE) has gained traction as a safe and effective treatment modality for symptomatic uterine leiomyomata since its introduction nearly two decades ago. This review includes an overview of current concepts with regard to patient selection, technique, and outcomes following UAE. Specific topics also include the impact of this procedure on fertility and pregnancy, the emerging role of UAE in the treatment of adenomyosis, and how UAE compares with surgical intervention for the treatment of symptomatic leiomyomata. PMID- 29128205 TI - Endometrial ablation. AB - Endometrial ablation (EA) includes a spectrum of procedures performed with or without hysteroscopic direction, designed to destroy the endometrium for the treatment of the symptom of heavy menstrual bleeding (HMB) secondary to a spectrum of causes, but most commonly those that are endometrial in origin (AUB E) or ovulatory disorders (AUB-O). Resectoscopic endometrial ablation (REA) is often mistakenly referred to as the "first generation" technique, while proprietary devices that do not use the resectoscope (nonresectoscopic EA or NREA) are often misperceived as "second generation" devices. Indeed, the origins of NREA date back to the late 19th century with the use of steam, and the early and mid 20th century, when radiofrequency and cryotherapy based NREA techniques were published - long before the resectoscope was used and reported. The NREA devices have also been mislabeled as "global", a misleading term borrowed from the marketing departments of device manufacturers - there is no device that predictably treats the entire endometrium. Consequently, none can be construed as being "global". Instead, EA is a procedure designed for women as an alternative to hysterectomy, or, perhaps, medical therapy, when future fertility is no longer desired. Women who select EA should anticipate a relatively low risk procedure that will likely reduce their HMB to normal levels or less. This paper will review the spectrum of EA techniques and devices, their clinical outcomes and adverse events, and explore their value compared to hysterectomy and selected medical therapies. PMID- 29128206 TI - Assembling the Puzzle of Advanced Prostate Cancer: Lessons from GETUG-AFU 15. PMID- 29128207 TI - Safeguarding the Future of Urological Research and Delivery of Clinical Excellence by Harnessing the Power of Youth to Spearhead Urological Research. AB - Trainee-led collaboratives offer exciting new perspectives and approaches to urological research. They provide a central network of expertise in methodology, mentoring, and knowledge of research processes that allows the conduct of large multicentre studies that can recruit quickly. This provides the consultant workforce of tomorrow with the skills required to deliver practice-changing clinical studies in urology. PMID- 29128208 TI - Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer. AB - BACKGROUND: Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT). OBJECTIVE: To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM). DESIGN, SETTING, AND PARTICIPANTS: A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) >=7 treated between 1987 and 2013. Median follow-up was 51 mo. INTERVENTIONS: WPRT and/or ADT in addition to PBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression. RESULTS AND LIMITATION: Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, p<0.001) and no ADT versus ADT (HR 1.70, p<0.001). WPRT was associated with a 5 yr FFBF of 62% versus 49% (p<0.001) for PBRT. ADT use was associated with improved 5-yr FFBF (55% vs 50%, p=0.012). No significant differences in DM cumulative incidence were found. CONCLUSIONS: For patients with GS >=7 receiving SRT, clinicians should weigh FFBF benefits of WPRT and ADT against toxicities. Future studies should explore the impact of WPRT on quality of life, clinical progression, and overall survival. PATIENT SUMMARY: We evaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning). PMID- 29128209 TI - Abiraterone or Docetaxel Plus Androgen Deprivation in Hormone-Sensitive Prostate Cancer: More Questions Than Answers. PMID- 29128210 TI - Short communication: The effects of morning compared with evening feed delivery in lactating dairy cows during the summer. AB - Delivering fresh feed in the evening is a management strategy sometimes used during periods of heat stress, but previous experiments have observed that night feeding increased feed intake during the 2 h after feeding and did not change intake during the overnight period. The objective of this study was to determine the effect of night feeding on daily rhythms of the dairy cow during the summer season. Twelve Holstein cows were used in a crossover design with 14-d periods. An automated system recorded the timing of feed intake over the last 7 d of each period. Treatments were ad libitum feeding with fresh feed delivery 1*/d at 0830 h or 2030 h. Milk yield and composition were not changed by treatment, but night feeding decreased the concentration of preformed fatty acids in milk fat. Night feeding decreased feed intake 1.7 kg/d, and decreased total-tract dry matter and neutral detergent fiber (NDF) digestibility by 0.7 and 0.8 percentage units, respectively. The amount of feed consumed in the first 2 h after feeding was 64% greater with night feeding, but intake did not differ between treatments during the night or early afternoon. A treatment by time of day interaction was observed for fecal NDF and indigestible NDF concentration and plasma glucose, insulin, and urea concentrations. Night feeding resulted in an increase in plasma insulin after feeding, which decreased plasma glucose. The daily rhythm of core body temperature was entrained by treatment, with the phase shifted and the amplitude decreased by night feeding indicating alteration of the central clock. In conclusion, feeding cows once per day in the evening during the summer caused a similar increase in feed intake and plasma insulin after feeding as previously observed during non-heat stress seasons. Night feeding also decreased intake and total-tract digestibility. The daily pattern of feed intake and other behaviors should be considered before initiation of night feeding. PMID- 29128212 TI - Liver proteomic analysis of postpartum Holstein cows exposed to heat stress or cooling conditions during the dry period. AB - Heat stress negatively affects cow performance, compromises immune function, and increases susceptibility to metabolic disorders, particularly during the dry period and as cows transition from gestation to lactation. Metabolic adaptations of the liver are critical for successful transition, yet it is unclear how heat stress affects metabolic pathways within the liver at the proteomic level. The objective of this study was to investigate the liver proteome of postpartum cows that were cooled or heat stressed during the dry period to gain insight into how protein expression is altered by prior heat stress and may contribute to performance and disease outcomes. During the dry period, cows were either housed in shaded barns with fans and water soakers [cooled group (CL); n = 5] or in shaded barns lacking these cooling devices [heat-stressed group (HT); n = 5]. Liver biopsies were collected at 2 d postpartum, and protein content was analyzed by label-free quantitative shotgun proteomics (nanoscale liquid chromatography coupled to tandem mass spectrometry). In the most comprehensive bovine liver proteomics analysis completed to date, we identified 3,270 proteins, 75 of which were differentially expressed between HT and CL cows (fold change +/-1.2). The top pathways differing between HT and CL cows were oxidative phosphorylation, mitochondrial dysfunction, farnesoid X receptor/retinoid X receptor (FXR/RXR) activation, and the methylmalonyl pathway. Cooling cows during the dry period likely improves ATP production, reduces oxidative stress, and prevents excessive accumulation of hepatic triglycerides and cholesterol, which may contribute to greater milk yield and lower susceptibility to transition-related diseases. PMID- 29128211 TI - Genome-wide association studies to identify quantitative trait loci affecting milk production traits in water buffalo. AB - Water buffalo is the second largest resource of milk supply around the world, and it is well known for its distinctive milk quality in terms of fat, protein, lactose, vitamin, and mineral contents. Understanding the genetic architecture of milk production traits is important for future improvement by the buffalo breeding industry. The advance of genome-wide association studies (GWAS) provides an opportunity to identify potential genetic variants affecting important economical traits. In the present study, GWAS was performed for 489 buffaloes with 1,424 lactation records using the 90K Affymetrix Buffalo SNP Array (Affymetrix/Thermo Fisher Scientific, Santa Clara, CA). Collectively, 4 candidate single nucleotide polymorphisms (SNP) in 2 genomic regions were found to associate with buffalo milk production traits. One region affecting milk fat and protein percentage was located on the equivalent of Bos taurus autosome (BTA)3, spanning 43.3 to 43.8 Mb, which harbored the most likely candidate genes MFSD14A, SLC35A3, and PALMD. The other region on the equivalent of BTA14 at 66.5 to 67.0 Mb contained candidate genes RGS22 and VPS13B and influenced buffalo total milk yield, fat yield, and protein yield. Interestingly, both of the regions were reported to have quantitative trait loci affecting milk performance in dairy cattle. Furthermore, we suggest that buffaloes with the C allele at AX-85148558 and AX-85073877 loci and the G allele at AX-85106096 locus can be selected to improve milk fat yield in this buffalo-breeding program. Meanwhile, the G allele at AX-85063131 locus can be used as the favorable allele for improving milk protein percentage. Genomic prediction showed that the reliability of genomic estimated breeding values (GEBV) of 6 milk production traits ranged from 0.06 to 0.22, and the correlation between estimated breeding values and GEBV ranged from 0.23 to 0.35. These findings provide useful information to understand the genetic basis of buffalo milk properties and may play a role in accelerating buffalo breeding programs using genomic approaches. PMID- 29128213 TI - The effects of feeding a partial mixed ration plus a top-dress before feeding on milk production and the daily rhythm of feed intake and plasma hormones and metabolites in dairy cows. AB - Total mixed rations (TMR) are commonly fed to dairy cows with a goal of reducing ruminal acidosis, but the daily pattern of feed intake has major implication for rumen fermentation and postabsorptive physiology. Generally there is low feed intake during the overnight period and high intake after feeding and during the afternoon. The objective of this study was to determine if feeding a partial mixed ration (PMR) plus a high starch top-dress before feeding of the PMR would improve production and modify key daily rhythms. The top-dress was fed before feeding as ruminal starch is at a nadir and amylolytic capacity is expected to be low. Ten Holstein cows were used in a crossover design with 14-d periods. Cows were housed in tie stalls with feed tubs and feed weight was recorded every 10 s for observation of feeding behavior. Treatments were a control TMR fed once per day at 0900 h or a partial mixed ration plus a top-dress (PMR+TD). The top-dress was fed at 9.5% of DMI offered at 0800 h and contained steamflaked corn, canola meal, and nonprotein nitrogen. No interaction was observed between treatment and milking time. Milk yield tended to be decreased 1.1 kg and milk fat yield was decreased 70 g/d by PMR+TD. Milk fat preformed fatty acids were decreased and no effect was observed of treatment on trans-10 C18:1 or other indicators of biohydrogenation-induced milk fat depression. No effect was observed of treatment on meal parameters including meal size and number. The PMR+TD increased total tract neutral detergent fiber (NDF) digestibility by 1.2 percentage points. Treatment changed the daily pattern of fecal NDF and indigestible NDF, indicating changes in rumen function over the day. No effect was observed on plasma glucose, but the amplitude of the daily rhythm of insulin was increased by PMR+TD. The PMR+TD also increased plasma nonesterified fatty acids and decreased blood urea nitrogen across the day. Core body temperature is entrained by the central biological clock and its phase was advanced 42 min and its amplitude slightly increased by PMR+TD. In conclusion, the top-dress appears to have modified the central circadian rhythm and plasma insulin and blood urea nitrogen. This demonstrates that timing of feeding can be used to manage daily rhythms of the dairy cow, although the optimal timing requires further investigation. PMID- 29128215 TI - Meta-analysis to predict the effects of metabolizable amino acids on dairy cattle performance. AB - Meta-analytic methods were used to determine statistical relationships between metabolizable AA supplies and milk protein yield, milk protein percentage, and milk yield in lactating dairy cows. Sixty-three research publications (258 treatment means) were identified through a search of published literature using 3 search engines and met the criteria for inclusion in this meta-analysis. The Cornell Net Carbohydrate and Protein System (CNCPS) version 6.5 was used to determine dietary nutrient parameters including metabolizable AA. Two approaches were used to analyze the data. First, mixed models were fitted to determine whether explanatory variables predicted responses. Each mixed model contained a global intercept, a random intercept for each experiment, and data were weighted by the inverse of the SEM squared. The second analysis approach used classical effect size meta-analytical evaluation of responses to treatment weighted by the inverse of the treatment variance and with a random effect of treatment nested within experiment. Regardless of the analytical approach, CNCPS-predicted metabolizable Met (g/d) was associated with milk protein percentage and yield. Milk yield was positively associated with CNCPS-predicted metabolizable His, Leu, Trp, Thr, and nonessential AA (g/d). Milk true protein yield was also associated with CNCPS-predicted metabolizable Leu (g/d). Predicted metabolizable Lysine (g/d) did not increase responses in production outcomes. However, mean metabolizable Lys supply was less than typically recommended and the change with treatment was minimal (157 vs. 162 g; 6.36 vs. 6.38% metabolizable protein). Experiments based solely on Lys or Met interventions were excluded from the study database. It is possible that the inclusion of these experiments may have provided additional insight into the effect of these AA on responses. This meta analysis supports other research indicating a positive effect of Met and His as co-limiting AA in dairy cows and suggests Leu, Trp, and Thr be given greater consideration in future research. PMID- 29128214 TI - Application of whey protein isolate in bone regeneration: Effects on growth and osteogenic differentiation of bone-forming cells. AB - Recently, milk-derived proteins have attracted attention for applications in the biomedical field such as tissue regeneration. Whey protein isolate (WPI), especially its main component beta-lactoglobulin, can modulate immunity and acts as an antioxidant, antitumor, antiviral, and antibacterial agent. There are very few reports of the application of WPI in tissue engineering, especially in bone tissue engineering. In this study, we tested the influence of different concentrations of WPI on behavior of human osteoblast-like Saos-2 cells, human adipose tissue-derived stem cells (ASC), and human neonatal dermal fibroblasts (FIB). The positive effect on growth was apparent for Saos-2 cells and FIB but not for ASC. However, the expression of markers characteristic for early osteogenic cell differentiation [type-I collagen (COL1) and alkaline phosphatase (ALP)] as well as ALP activity, increased dose-dependently in ASC. Importantly, Saos-2 cells were able to deposit calcium in the presence of WPI, even in a proliferation medium without other supplements that support osteogenic cell differentiation. The results indicate that, depending on the cell type, WPI can act as an enhancer of cell proliferation and osteogenic differentiation. Therefore, enrichment of biomaterials for bone regeneration with WPI seems a promising approach, especially due to the low cost of WPI. PMID- 29128216 TI - Strain hardening and anisotropy in tensile fracture properties of sheared model Mozzarella cheeses. AB - We studied the tensile fracture properties of model Mozzarella cheeses with varying amounts of shear work input (3.3-73.7 kJ/kg). After manufacture, cheeses were elongated by manual rolling at 65 degrees C followed by tensile testing at 21 degrees C on dumbbell-shaped samples cut both parallel and perpendicular to the rolling direction. Strain hardening parameters were estimated from stress strain curves using 3 different methods. Fracture stress and strain for longitudinal samples did not vary significantly with shear work input up to 26.3 kJ/kg and then decreased dramatically at 58.2 kJ/kg. Longitudinal samples with shear work input <30 kJ/kg demonstrated significant strain hardening by all 3 estimation methods. At shear work inputs <30 kJ/kg, strong anisotropy was observed in both fracture stress and strain. After a shear work input of 58.2 kJ/kg, anisotropy and strain hardening were absent. Perpendicular samples did not show strain hardening at any level of shear work input. Although the distortion of the fat drops in the cheese structure associated with the elongation could account for some of the anisotropy observed, the presence of anisotropy in the elongated nonfat samples reflected that shear work and rolling also aligned the protein structure. PMID- 29128217 TI - Altering the ratio of dietary palmitic, stearic, and oleic acids in diets with or without whole cottonseed affects nutrient digestibility, energy partitioning, and production responses of dairy cows. AB - The objective of this study was to evaluate the effects of varying the ratio of dietary palmitic (C16:0), stearic (C18:0), and oleic (cis-9 C18:1) acids in basal diets containing soyhulls or whole cottonseed on nutrient digestibility, energy partitioning, and production response of lactating dairy cows. Twenty-four mid lactation multiparous Holstein cows were used in a split-plot Latin square design. Cows were allocated to a main plot receiving either a basal diet with soyhulls (SH, n = 12) or a basal diet with whole cottonseed (CS, n = 12) that was fed throughout the experiment. Within each plot a 4 * 4 Latin square arrangement of treatments was used in 4 consecutive 21-d periods. Treatments were (1) control (CON; no supplemental fat), (2) high C16:0 supplement [PA; fatty acid (FA) supplement blend provided ~80% C16:0], (3) C16:0 and C18:0 supplement (PA+SA; FA supplement blend provided ~40% C16:0 + ~40% C18:0), and (4) C16:0 and cis-9 C18:1 supplement (PA+OA; FA supplement blend provided ~45% C16:0 + ~35% cis-9 C18:1). Interactions between basal diets and FA treatments were observed for dry matter intake (DMI) and milk yield. Among the SH diets, PA and PA+SA increased DMI compared with CON and PA+OA treatments, whereas in the CS diets PA+OA decreased DMI compared with CON. The PA, PA+SA, and PA+OA treatments increased milk yield compared with CON in the SH diets. The CS diets increased milk fat yield compared with the SH diets due to the greater yield of de novo and preformed milk FA. The PA treatment increased milk fat yield compared with CON, PA+SA, and PA+OA due to the greater yield of mixed-source (16-carbon) milk FA. The PA treatment increased 3.5% fat-corrected milk compared with CON and tended to increase it compared with PA+SA and PA+OA. The CS diets increased body weight (BW) change compared with the SH diets. Additionally, PA+OA tended to increase BW change compared with CON and PA and increased it in comparison with PA+SA. The PA and PA+OA treatments increased dry matter and neutral detergent fiber digestibility compared with PA+SA and tended to increase them compared with CON. The PA+SA treatment reduced 16-carbon, 18-carbon, and total FA digestibility compared with the other treatments. The CS diets increased energy partitioning toward body reserves compared with the SH diets. The PA treatment increased energy partitioning toward milk compared with CON and PA+OA and tended to increase it compared with PA+SA. In contrast, PA+OA increased energy partitioned to body reserves compared with PA and PA+SA and tended to increase it compared with CON. In conclusion, milk yield responses to different combinations of FA were affected by the addition of whole cottonseed in the diet. Among the combinations of C16:0, C18:0, and cis-9 C18:1 evaluated, fat supplements with more C16:0 increased energy output in milk, whereas fat supplements with more cis-9 C18:1 increased energy storage in BW. The combination of C16:0 and C18:0 reduced nutrient digestibility, which most likely explains the lower performance observed compared with other treatments. PMID- 29128218 TI - Exposure to light-emitting diodes may be more damaging to the sensory properties of fat-free milk than exposure to fluorescent light. AB - Light exposure can damage the sensory properties of milk, leading to adverse consumer responses. This is presumed to be through the action of photosensitive compounds such as riboflavin, present in milk and capable of releasing energy when irradiated, leading to damage of proteins and fats in the milk. Light emitting diode (LED) lighting is assumed to be less damaging to milk due to lower inherent power consumption. In this study, fat-free milk was exposed to LED and fluorescent light at 2,000 lx to compare the sensory thresholds of exposure, the flavor profile of milk produced by these exposures, and resultant consumer acceptance of the samples. Additionally, the effectiveness of light-protective packaging and supplementation with antioxidants was evaluated. The sensory threshold from LED exposure was no longer than from fluorescence, whereas with antioxidants (tocopherols and ascorbic acid), the majority of the panelists failed to discriminate milk exposed to LED light even at 48 h of exposure. Trained panelists described light-exposed milk as significantly higher in cardboard, old oil, and plastic, with LED exposure resulting in a marginally more plastic aroma, and fluorescent marginally more cardboard. Consumers reported higher liking for fluorescent-exposed samples versus those exposed to LED. The antioxidant-supplemented samples, and those exposed to LED light engineered to eliminate wavelengths below 480 nm (thus most of riboflavin's absorption peaks), resulted in significantly higher old oil aroma; however, the former received higher liking scores than LED-exposed samples. Light-protective packaging offered near-complete protection from LED exposure, with a similar flavor profile as unexposed milk, and the best liking scores of any treatment. Nevertheless, consumers disliked its appearance, due to unfamiliarity, suggesting some consumer education may be needed if this were to be an efficient protective strategy. PMID- 29128219 TI - Predicting milk protein responses and the requirement of metabolizable protein by lactating dairy cows. AB - The objective of this study was to develop a modeling framework to predict milk protein yield responses to varying metabolizable protein (MP) supplies and to determine the requirement of MP by lactating dairy cows. The logistic curve was used to model milk protein yield while accounting for a variable efficiency of MP utilization and between-study variability. Models were developed with databases from 2 recently published meta-analyses and based on either total MP supply or MP supply available for milk production. All models provided reasonable fit to data, with root mean square prediction error ranging from 18 to 20% of the average milk protein yield. The estimated horizontal asymptotes were 1.17 (posterior SD = 0.02) and 1.55 (posterior SD = 0.06) in the 2 databases, suggesting that the limiting milk protein yield, as MP supply increases, converges to 1.17 or 1.55 kg/d in the environments determined by the 2 databases. The observed efficiencies ranged from 0.75 to 0.18 when total MP supply was used as the denominator and above 1 to 0.24 when the MP supply available for milk production was used as the denominator. The predicted efficiencies were in good agreement with the data, decreasing nonlinearly with the MP supply. The MP requirement was calculated with a function constructed with the inverse of the logistic model and modified at regions of maximum marginal efficiency and minimum second derivative. This strategy assumes that the MP solution, or the MP needed to predict a given protein yield in the fitted logistic curve, determines the MP requirement for maintenance and lactation. Requirements calculated with the independent variable as total MP supply refer to the total requirement of maintenance plus lactation, whereas the requirement from models based on MP supply available for milk production are referent to the MP required only for lactation. The requirements were, on average, slightly smaller than the ones predicted by the current Northern American feeding system for dairy cows at lower protein yields and greater than currently recommended at high yields. PMID- 29128220 TI - Identification of potential embryokines in the bovine reproductive tract. AB - Knowledge of the molecules used by the maternal reproductive tract to regulate development of the preimplantation embryo is largely incomplete. The goal of the present experiment was to identify candidates for this function. The approach was to assess expression patterns in the endometrium and oviduct of 93 genes encoding for hormones, growth factors, chemokines, cytokines, and WNT-related molecules. Results show that all of the genes were expressed in the reproductive tract. Expression in oviduct was affected by day of the estrous cycle for 21 genes with 11 genes having highest expression at estrus (CCL21, CTGF, CXCL10, CXCL16, DKK3, FGF10, IL18, IL33, IL34, PGF, and SFRP2), 1 gene at d 3 (WNT4), 8 at d 5 (BMP7, HGF, IL6, SFRP1, TGFB1, WIF1, WNT2, and WNT5A), and 1 at d 7 (IK). For endometrium, expression of 34 genes was affected by day of the estrous cycle with 11 having highest expression at d 0 (BMP7, CCL14, CCL21, CCL26, CTGF, CXCL12, IGF2, IL16, IL33, SFRP2, and WIF1), 2 at d 3 (HDGF, IL15), 14 at d 5 (CSF2, CX3CL1, CXCL3, FGF1, FGF2, GRO1, HGF, IGF1, IL1B, IL8, SFRP1, SFRP4, WNT5A, and WNT16), and 7 at d 7 (CXCL16, FGF13, HDGFRP2, TDGF1, VEGFB, WNT7A, and WNT11). Results are consistent with a set of genes regulated by estradiol early in the estrous cycle and another set regulated by progesterone later in the cycle. The cell-signaling genes identified here as being expressed in the oviduct and endometrium could serve to regulate early embryonic development in a stage-of pregnancy-specific manner. PMID- 29128221 TI - Short communication: Genetic association of variations in the osteopontin gene (SPP1) with lactation persistency in dairy cattle. AB - Improving lactation persistency (LP) in dairy cattle has a beneficial effect on animal health and fertility and herd productivity. A complex trait, LP not only reflects the cow's ability to maintain milk secretion activity after the lactation peak but is also a function of the postcalving development of the mammary gland and, later on, of tissue remodeling as lactation declines. This decline is a consequence of an imbalance between cell proliferation and cell removal. In a previous study, single nucleotide polymorphisms were identified in the osteopontin (OPN) gene, SPP1. Osteopontin is a multifaceted protein that plays an important role in immune regulation and tissue remodeling. Because OPN is involved in involution, it might also have an effect on LP. The objective of the present study was to evaluate whether LP could be influenced by genetic variations in the SPP1 gene. This association with LP was analyzed in the population of 578 bulls characterized in a previous study. The population mean of estimated breeding value (EBV) for LP was 100.95 +/- 5.06 units. Allele and genotype association analyses were performed by comparing the frequencies of the different genotypes and alleles with EBV for LP for the respective lactation using logistic regression. The EBV for LP at the first lactation (LP1), second lactation (LP2), and third lactation (LP3) and for overall lactation (OLP) are reported for the genotypes SPP1c.-1301G>A, SPP1c.-1251C>T, SPP1c.-430G>A, and SPP1c.*40A>C. The first single nucleotide polymorphism, SPP1c.-1301G>A, affected LP1, LP2, LP3, and OLP. Analysis of the estimated average allele substitution effects also confirmed that G is a favorable allele for LP, given the gain observed over LP1, LP2, LP3, and OLP. Differences in EBV for LP were observed between animals with different haplotypes at LP1, LP2, LP3, and OLP. Contrast analysis for OLP revealed that mean EBV is greater for block H1 (101.34 +/- 0.30) than for animals that do not have H1 (98.20 +/- 0.77). The gain with block H1 (GCGA) suggests the presence of the favorable allele G (first position in the block: SPP1c.-1301G). The pleiotropic roles of OPN position it at the crossroads of immune regulation, tissue remodeling, and involution. From a genetic perspective, data from the present study suggest OPN as a candidate gene associated with LP for dairy cows. PMID- 29128222 TI - Phenotypic and genetic relationships between age at first calving, its component traits, and survival of heifers up to second calving. AB - The aim of this study was to answer the question whether models for genetic evaluations of longevity should include a correction for age at first calving (AFC). For this purpose, phenotypic and genetic relationships between AFC, its component traits age at first insemination (AFI) and interval from first to last insemination (FLI), and survival of different periods of the first lactation (S1: 0 to 49 d, S2: 50 to 249 d, S3: 250 d to second calving) were investigated. Data of 721,919 German Holstein heifers, being inseminated for the first time during the years from 2003 to 2012, were used for the analyses. Phenotypic correlations of AFI, FLI, and AFC to S1 to S3 were negative. Mean estimated heritabilities were 0.239 (AFI), 0.007 (FLI), and 0.103 (AFC) and 0.023 (S1), 0.016 (S2), and 0.028 (S3) on the observed scale. The genetic correlation between AFI and FLI was close to zero. Genetic correlations between AFI and the survival traits were 0.08 (S1), -0.02 (S2), and -0.10 (S3); those between FLI and the survival traits were -0.14 (S1), -0.20 (S2), and -0.44 (S3); and those between AFC and the survival traits were -0.09 (S1), -0.06 (S2), and -0.20 (S3). Some of these genetic correlations were different from zero, which suggests that correcting for AFC in genetic evaluations for longevity in dairy cows might remove functional genetic variance and should be reconsidered. PMID- 29128223 TI - Lowering rumen-degradable and rumen-undegradable protein improved amino acid metabolism and energy utilization in lactating dairy cows exposed to heat stress. AB - The objective of this study was to evaluate the effects of reducing dietary rumen degradable protein (RDP) and rumen-undegradable protein (RUP) on protein and energy metabolism in heat-stressed dairy cows. Eighteen primiparous and 30 multiparous mid-lactation Holstein cows were used in a completely randomized design arranged in a 2 * 2 factorial (n = 12/treatment). Cows were randomly assigned to 1 of 4 dietary treatments that included 2 levels of RDP (10 and 8%; D) and 2 levels of RUP (8 and 6%; U) of dry matter for 21 d as (1) 10D:8U, (2) 8D:8U, (3) 10D:6U, and (4) 8D:6U. Diets were isoenergetic and contained 50% forage and 50% concentrate (dry matter basis). Cows were housed in a freestall barn. Three weeks before start of treatments, all animals were fed the 10D:8U diet and received supplemental cooling to prevent heat stress. During the treatment period, cows experienced a daily increment in temperature-humidity index from 74 to 82 for 1000 to 2000 h. Blood samples were collected on d -1 and 21 of the treatment period to determine plasma concentrations of AA, glucose, insulin, fatty acids, and beta-hydroxybutyrate. For primiparous cows, reducing from 10 to 8% RDP decreased insulin concentrations. For multiparous cows, we found significant RDP by RUP interactions for insulin, beta-hydroxybutyrate, fatty acids, total essential AA, and 3-methylhistidine concentrations. Reducing from 10 to 8% RDP decreased insulin concentrations at 6% RUP, but concentrations did not change when reducing RDP at 8% RUP. Reducing from 10 to 8% RDP decreased beta-hydroxybutyrate concentrations at 8% RUP, but concentrations did not change when reducing RDP at 6% RUP. Reducing from 10 to 8% RDP increased nonesterified fatty acid and total essential AA concentrations at 8% RUP, but concentrations did not change when reducing RDP at 6% RUP. Reducing from 8 to 6% RUP decreased 3 methylhistidine concentration at 8% RDP, but not at 10% RDP. Reducing from 8 to 6% RUP increased milk protein yield efficiency in primiparous and multiparous cows. These results indicate that reducing RDP and RUP lowers circulating insulin, which was associated with mobilization and utilization of fatty acids. Reduced RDP and RUP increases the use of AA to maintain milk protein synthesis and limit AA catabolism in cows exposed to warm climates. PMID- 29128224 TI - Effect of 2-hydroxy-4-(methylthio)butanoate (HMTBa) on risk of biohydrogenation induced milk fat depression. AB - Diet-induced milk fat depression (MFD) is a multifactorial condition resulting from the interaction of numerous risk factors, including diet fermentability and unsaturated fatty acids concentration, feed additives, and individual cow effects. 2-Hydroxy-4-(methylthio)butanoate (HMTBa) is a methionine analog that has been observed to increase milk fat in some cases, and interactions with MFD risk factors may exist. The objective was to evaluate the effect of HMTBa supplementation on milk fat synthesis in cows with different levels of milk production and fed diets with increasing risk of biohydrogenation-induced MFD. Sixteen high-producing cows (44.1 +/- 4.5 kg of milk/d; mean +/- SD) and 14 low producing (31.4 +/- 4.3 kg of milk/d) were used in a randomized block design. Treatments were unsupplemented control and HMTBa fed at 0.1% of diet dry matter (25 g/d at 25 kg of dry matter intake). The experiment was 70 d and included a 14 d covariate period followed by 3 phases whereby diets were fed with increasing risk of MFD to determine the interaction of treatment and diet-induced MFD. During the low-risk phase, the base diet was balanced to 33.5% neutral detergent fiber (NDF) and had no exogenous oil (28 d); during the moderate-risk phase, the diet was balanced to 31% NDF and contained 0.75% soybean oil (14 d); and, during the high-risk phase, the diet was balanced to 28.5% NDF and contained 1.5% soybean oil (14 d). An interaction of treatment, production-level, and dietary phase was observed. Low producing cows neither experienced substantial biohydrogenation-induced MFD nor a response in milk fat to HMTBa supplementation. In high-producing cows, HMTBa maintained higher milk fat concentration during the moderate- (2.94 vs. 3.49%) and high-risk (2.38 vs. 3.11%) phases. High-producing cows receiving HMTBa also had greater milk fat yield (0.94 vs. 1.16 kg/d) and lower trans-10 C18:1 (6.11 vs. 1.50) during the high-risk phase. In conclusion, HMTBa increased milk fat in situations with a high risk of biohydrogenation induced MFD by decreasing absorption of alternate biohydrogenation intermediates. PMID- 29128225 TI - A longitudinal study of gastrointestinal parasites in English dairy farms. Practices and factors associated with first lactation heifer exposure to Ostertagia ostertagi on pasture. AB - The gastrointestinal nematode Ostertagia ostertagi is an important cause of lost production, health, and welfare in cattle. Detailed records were obtained over a 5-yr period (2010-2015) by questionnaires and qualitative interviews to investigate the practices adopted by dairy farmers to control cattle helminth infections and the factors associated with heifer exposure to O. ostertagi on pasture. In total, 1,454 heifers' individual milk samples were collected over a 1 yr period (2014-2015) in 43 dairy farms in England and tested for O. ostertagi antibody by ELISA. Multilevel linear regression models were used to investigate the association between individual milk optical density ratio (ODR) against O. ostertagi and heifer management from birth to time of sampling. Farm and heifer median ODR against O. ostertagi were 0.98 (interquartile range = 0.76-1.02) and 0.64 (interquartile range = 0.42-0.84), respectively. The majority of heifers (88%) received an anthelmintic treatment before sampling in this study. After controlling for the effect of anthelmintic treatments, heifer individual milk ODR against O. ostertagi significantly increased with high stocking rate at first grazing and co-grazing with adult cows before calving. Conversely, heifer individual milk ODR against O. ostertagi significantly decreased when heifers had co-grazed with sheep and pasture grass had frequently been mowed. Overall, these results provide evidence to support targeting grazing management toward limiting the use of anthelmintics in dairy young stock to enable sustainable control of cattle helminth infections in England. However, to be accepted and adopted by farmers, these best practices would need to take into account farmers' perspectives and contextual challenges. PMID- 29128226 TI - Camel milk protein hydrolysates with improved technofunctional properties and enhanced antioxidant potential in in vitro and in food model systems. AB - Camel milk protein hydrolysates (CMPH) were generated using proteolytic enzymes, such as alcalase, bromelain, and papain, to explore the effect on the technofunctional properties and antioxidant potential under in vitro and in real food model systems. Characterization of the CMPH via degree of hydrolysis, sodium dodecyl sulfate-PAGE, and HPLC revealed that different proteins in camel milk underwent degradation at different degrees after enzymatic hydrolysis using 3 different enzymes for 2, 4, and 6 h, with papain displaying the highest degradation. Technofunctional properties, such as emulsifying activity index, surface hydrophobicity, and protein solubility, were higher in CMPH than unhydrolyzed camel milk proteins. However, the water and fat absorption capacity were lower in CMPH compared with unhydrolyzed camel milk proteins. Antioxidant properties as assessed by 2,2-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl radical scavenging activities and metal-chelating activity were enhanced after hydrolysis, in contrast to ferric-reducing antioxidant power which showed a decrease after hydrolysis. The CMPH were also tested in real food model systems for their potential to inhibit lipid peroxidation in fish mince and grape seed oil-in-water emulsion, and we found that papain-produced hydrolysate displayed higher inhibition than alcalase- and bromelain-produced hydrolysates. Therefore, the CMPH demonstrated effective antioxidant potential in vitro as well as in real food systems and showed enhanced functional properties, which guarantees their potential applications in functional foods. The present study is one of few reports available on CMPH being explored in vitro as well as in real food model systems. PMID- 29128227 TI - Genome-wide association study for ketosis in US Jerseys using producer-recorded data. AB - Ketosis is one of the most frequently reported metabolic health events in dairy herds. Several genetic analyses of ketosis in dairy cattle have been conducted; however, few have focused specifically on Jersey cattle. The objectives of this research included estimating variance components for susceptibility to ketosis and identification of genomic regions associated with ketosis in Jersey cattle. Voluntary producer-recorded health event data related to ketosis were available from Dairy Records Management Systems (Raleigh, NC). Standardization was implemented to account for the various acronyms used by producers to designate an incidence of ketosis. Events were restricted to the first reported incidence within 60 d after calving in first through fifth parities. After editing, there were a total of 42,233 records from 23,865 cows. A total of 1,750 genotyped animals were used for genomic analyses using 60,671 markers. Because of the binary nature of the trait, a threshold animal model was fitted using THRGIBBS1F90 (version 2.110) using only pedigree information, and genomic information was incorporated using a single-step genomic BLUP approach. Individual single nucleotide polymorphism (SNP) effects and the proportion of variance explained by 10-SNP windows were calculated using postGSf90 (version 1.38). Heritability of susceptibility to ketosis was 0.083 [standard deviation (SD) = 0.021] and 0.078 (SD = 0.018) in pedigree-based and genomic analyses, respectively. The marker with the largest associated effect was located on chromosome 10 at 66.3 Mbp. The 10-SNP window explaining the largest proportion of variance (0.70%) was located on chromosome 6 beginning at 56.1 Mbp. Gene Ontology (GO) and Medical Subject Heading (MeSH) enrichment analyses identified several overrepresented processes and terms related to immune function. Our results indicate that there is a genetic component related to ketosis susceptibility in Jersey cattle and, as such, genetic selection for improved resistance to ketosis is feasible. PMID- 29128228 TI - Clinical Course of Preseptal and Orbital Cellulitis in 50 Immunocompromised Patients with Cancer. PMID- 29128229 TI - Proton Beam Therapy for Iris Melanomas in 107 Patients. AB - PURPOSE: To report on the clinical characteristics and outcomes for patients with iris melanoma using proton therapy. DESIGN: Retrospective study. PARTICIPANTS: One hundred seven patients with iris melanoma from 3 regional ophthalmologic centers. METHODS: A retrospective study was conducted for iris melanoma patients from 3 regional ophthalmologic centers referred to and treated at a single proton therapy facility between 1996 and 2015. MAIN OUTCOME MEASURES: At each follow-up visit, examinations included measurement of best-corrected VA, slit-lamp, examination, indirect ophthalmoscopy, and ultrasound biomicroscopy. RESULTS: With a median follow-up of 49.5 months, 5 of 107 patients experienced a local relapse within a median of 36.3 months. The cumulative incidence of relapse was 7.5% at 5 years. All 5 patients showed involvement of the iridocorneal angle (P = 0.056). Diffuse iris melanoma showed a higher risk of relapse (P = 0.044). Four patients showed out-of-field relapse and 1 showed angular relapse. Three patients were retreated with proton therapy, whereas 2 other patients, one with T1b disease and another with diffuse T3 disease, underwent secondary enucleation. None of the patients experienced metastases nor died of iris melanoma. Vision improved in 59.4% of patients (n = 60/101). However, cataracts occurred in 57.4% of the 54 patients (n = 31) without cataract or implant at diagnosis. Secondary glaucoma was reported in 7.6% of the patients (n = 8), uveitis in 4.7% (n = 5), and hyphema in 3.7% (n = 4). All but 5 cases of complications were mild, transient, and not sight limiting after treatment. Five cases of glaucoma, including 1 with uveitis, were severe and associated with visual deterioration. CONCLUSIONS: Proton therapy showed efficacy and limited morbidity in iris melanomas. PMID- 29128231 TI - Erratum. PMID- 29128230 TI - Clinical outcomes using image-guided interstitial brachytherapy for definitive cervical cancer patients with high-risk clinical target volumes greater than 30 cc. AB - PURPOSE: Given the limited data using an interstitial approach with 3D-based planning for definitive cervical cancer utilizing the GEC-ESTRO defined high-risk clinical target volume (HR-CTV), we reviewed our institutional experience of cervical cancer patients with HR-CTVs >= 30 cc to determine whether our clinical and toxicity outcomes are acceptable. METHODS: A retrospective review of 37 cervical cancer patients with high-risk clinical target volumes (HR-CTVs) >=30 cc treated with interstitial image-guided brachytherapy (IS IGBT) was performed. All patients received external beam radiotherapy to a median dose of 45 Gy, followed by IS IGBT delivered in a single implant to a median dose of 6 Gy * 5 fractions. Median HR-CTV was 59 cc. A median HR-CTV D90 of 87.44 Gy was achieved. Kaplan Meier method was used to evaluate local control (LC), distant control, and overall survival (OS), with stratification by overall treatment time (OTT) <= 7 or >7 weeks. RESULTS: Median followup was 17 months. The estimated 2-year LC, distant control, and OS were 77.6% (confidence interval [CI]: 63.8-94.5%), 56.8% (CI: 41.3-78.1%), and 54.4% (CI: 39.4-75%), respectively. The 2-year LC for OTT <=7 weeks and >7 weeks were 100% and 58.3%, respectively (p = 0.026). The 2-year OS for OTT <=7 weeks and >7 weeks were 77.8% and 38%, respectively (p = 0.021). DISCUSSIONS: IS IGBT can achieve a high D90 to the HR-CTV even in the setting of large-volume disease and results in a favorable LC and toxicity profile. OTT > 7 weeks is associated with significant decrease in LC and OS. CONCLUSIONS: Efforts should be made to complete whole treatment within 7 weeks as this is associated with improved clinical outcomes. PMID- 29128232 TI - Liposome-based immunity-inducing systems for cancer immunotherapy. AB - Cancer immunotherapy has gained much attention for next-generation cancer treatment. To conduct cancer immunotherapy, efficient antigen delivery systems must be able to deliver an antigen selectively to antigen-presenting cells, release it at suitable sites for induction of cross-presentation, and simultaneously induce activation of immunocompetent cells. Liposomes are a candidate for use as such multifunctional antigen delivery carriers because of their capability for easy functionalization. This review describes the rational design of liposome-based antigen delivery systems. Surface modification of liposomes by pH-responsive or fusogenic materials can achieve cytoplasmic delivery of antigen, leading to cross-presentation of exogenous antigen via a "cytosolic pathway." In contrast, targeting surface receptors on antigen presenting cells or the selective release of antigen in early endosome induced "vacuolar pathway"-mediated cross-presentation. Introduction of adjuvant molecules such as Toll like receptor agonists, synthetic cationic lipids or bioactive polysaccharides to liposomes improved their immunity-inducing ability. Combination with cancelling systems of immunosuppression in tumor microenvironment enhanced antitumor immunity of antigen delivery systems. Further understanding of immunity-inducing mechanism and molecular basis of tumor immunosuppressive environments and purposeful design of liposome-based antigen delivery systems can provide effective immunity-inducing systems for cancer immunotherapy. PMID- 29128234 TI - Skilled Nursing Facility Partnerships May Decrease 90-Day Costs in a Total Joint Arthroplasty Episode Under the Bundled Payments for Care Improvement Initiative. AB - BACKGROUND: The Bundled Payments for Care Improvement initiative was developed to reduce costs associated with total joint arthroplasty through a single payment for all patient care from index admission through a 90-day post-discharge period, including care at skilled nursing facilities (SNFs). The aim of this study is to investigate whether forming partnerships between hospitals and SNFs could lower the post-discharge costs. We hypothesize that institutionally aligned SNFs have lower post-discharge costs than non-aligned SNFs. METHODS: A cohort of 615 elective, primary total hip and knee arthroplasty subjects discharged to an SNF under the Bundled Payments for Care Improvement from 2014 to 2016 were included in our analysis. Patients were grouped into one of the 3 categories of SNF alignment: group 1: non-partners; group 2: agreement-based partners; group 3: institution-owned partners. Demographics, comorbidities, length of stay (LOS) at SNF, and associated costs during the 90-day post-operative period were compared between the 3 groups. RESULTS: Mean index hospital LOS was statistically shortest in group 3 (mean 2.7 days vs 3.5 for groups 1 and 2, P = .001). SNF LOS was also shortest in group 3 (mean 11 days vs 19 and 21 days in groups 2 and 1 respectively, P < .001). Total SNF costs and total 90-day costs were both significantly lower in group 3 compared with groups 1 and 2 (P < .001 for all), even after controlling for medical comorbidities. CONCLUSION: Institution-owned partner SNFs demonstrated the shortest patient LOS, and the lowest SNF and total 90-day costs, without increased risk of readmissions, compared with other SNFs. PMID- 29128233 TI - Cementless Total Knee Arthroplasty in Knee Osteonecrosis Demonstrated Excellent Survivorship and Outcomes at Three-Year Minimum Follow-Up. AB - BACKGROUND: Lack of consensus exists on the use of cementless total knee arthroplasty (TKA) in patients with knee osteonecrosis. Therefore, this study was conducted to evaluate (1) implant survivorship; (2) clinical outcomes and complications; and (3) radiographic outcomes of primary cementless TKA in knee osteonecrosis. METHODS: This study included 46 patients (49 knees) who had knee osteonecrosis and underwent primary cementless TKA and had a mean follow-up of 44 months (range 36-96). Kaplan-Meier analysis was used to evaluate implant survivorship. Follow-up was performed post-operatively at 6 weeks, 3 months, and annually thereafter. Clinical outcomes including the Knee Society Scores (KSS) for pain and function, changes in range-of-motion, complications, and radiographic outcomes were analyzed. RESULTS: Aseptic implant survivorship was 97.9% (95% confidence interval 1.01-0.93) and all-cause implant survivorship was 95.9% (95% confidence interval 1.01-0.9), with 1 septic and 1 aseptic failures. The mean KSS for pain was 93 points (range 85-100) and the mean KSS for function was 84 points (range 70-90). Additionally, 1 patient had superficial wound necrosis and was treated with local wound care with no further sequela. Otherwise, no evidence of loosening, subsidence, or progressive radiolucencies were noted on radiological evaluation. CONCLUSION: Excellent implant survivorship, clinical, and radiographic outcomes of primary cementless TKA in the setting of knee osteonecrosis was demonstrated. Although further long-term study is needed to validate survivorship, new generation cementless TKA implants provide promising results in this subset of patients. PMID- 29128235 TI - Characterization of Post-Operative Opioid Use Following Total Joint Arthroplasty. AB - BACKGROUND: The purpose of our study is to examine post-operative opioid use in total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients and describe factors associated with the need for refill prescriptions. METHODS: Using online prescription information, we calculated the number of filled prescriptions, total morphine equivalent dose (MED) and quantity of pills, and date of last opioid prescription (days) for 197 TKA and 186 THA patients. Patients were classified based on refill status. Opioid data were compared between TKA and THA patients. Relationships between comorbidities and refill status were examined. RESULTS: Number of prescriptions (P < .001), total quantity (P < .001) and MED (P < .001), and days on opioids (P < .001) were greater for TKA patients. TKA patients required more refills (P < .001) for a greater quantity of pills (P = .007). The presence of a comorbidity (P = .003) or anxiety/depression (P = .004) were correlated with refills for TKA patients only. A comorbidity increased the risk of refills by 3.1 times, while anxiety/depression had a 2.5 times greater risk of refills. CONCLUSION: Compared to THA patients, TKA patients were twice as likely to require refill opioid prescriptions and were prescribed a greater total MED for a longer period of time post-operatively. Patients undergoing TKA who present with a comorbidity or are currently being treated for anxiety or depression are more likely to require a refill. PMID- 29128236 TI - Introduction to the special issue on acutely ill patients. PMID- 29128237 TI - Medication management in Minnesota schools: The need for school nurse-pharmacist partnerships. AB - BACKGROUND: Pharmacist participation in school medication management (MM) is minimal. School nurses are responsible for increasingly complex medication administration and management in schools. OBJECTIVES: The purpose of this study was to 1) assess the MM needs of school nurses in Minnesota, and 2) determine if and how interprofessional partnerships between nurses and pharmacists might optimize MM for students. METHODS: Researchers from the University of Minnesota College of Pharmacy, School Nurse Organization of Minnesota, and Minnesota Department of Health conducted a 32-item online survey of school nurses. RESULTS: Nurses administered the majority of medications at their school (69.9%) compared with unlicensed assistive personnel (29%). Stimulants (37.7%), asthma medications (25.7%), over-the-counter analgesics (17.8%), and insulin (6.6%) were the most commonly administered drug therapies. A clear majority of school nurses were interested in partnering with pharmacists: 90.3% thought that a pharmacist could assist with MM, 80% would consult with a pharmacist, and 12.3% reported that they already have informal access to a pharmacist. Topics that nurses would discuss with a pharmacist included new medications (71.6%), drug-drug interactions (67.1%), proper administration (52%), and storage (39.4%). The top MM concerns included 1) availability of students' medications and required documentation, 2) health literacy, 3) pharmacist consultations, 4) lack of time available for nurses to follow up with and evaluate students, 5) family-centered care, 6) delegation, 7) communication, and 8) professional development. CONCLUSION: Although the majority of school nurses surveyed indicated that partnerships with pharmacists would improve school MM, few had a formal relationship. Interprofessional partnerships focused on MM and education are high on the list of services that school nurses would request of a consultant pharmacist. Study results suggest that there are opportunities for pharmacists to collaborate with school nurses; further study is necessary to advance high-quality MM for students in Minnesota schools. PMID- 29128238 TI - [Current findings on drug-induced skin reactions]. PMID- 29128239 TI - [Contribution of reflectance confocal microscopy in the diagnosis of conjunctival primary acquired melanosis without atypia]. PMID- 29128240 TI - [Cutaneous hyperpigmentation in a patient treated with minocycline for rheumatoid arthritis]. PMID- 29128241 TI - [Diagnosis and treatment of scabies by general practitioners: A survey of practices in France]. AB - BACKGROUND: Although there is evidence suggesting an epidemiologic increase of scabies in France, few studies have assessed medical practice in terms of diagnosis and treatment. OBJECTIVES: To describe the management of scabies by general practitioners (GPs). PATIENTS AND METHODS: A questionnaire was addressed to the 524 GPs of the Doubs department in France regarding the management of cases of scabies diagnosed between January and June 2015. RESULTS: The response rate was 57 % (n=299). At least one case of scabies was observed by 89 % of GPs in the previous six months and more than three cases were diagnosed by 59 % of GPs. The main clinical criterion for diagnosis was the specific localization of pruritus (82 %). No diagnostic test was used by 94 % of GPs other than except direct parasitological examination, which was used by 6 %. A systematic examination by a dermatologist was prescribed by 3 % of GPs, by 78 % of them in the case of diagnostic doubt, and not at all by 19 %, even though 66 % of GPs' offices were located under 10 kilometers from a dermatologist's office. Ivermectin (IVM) alone was prescribed by 38 % of GPs, either as a single dose (22 %) or as two repeated doses (16 %). Topical treatment alone was prescribed by 2 % of GPs and the association of IVM and topical treatment was used by 26 %, either as a single dose (19 %) or as two repeated doses (7 %). All household members and any sexual contacts were systematically treated by 77 % of GPs, but 9 % did not prescribe any treatment. Decontamination advice was given by 100 % of GPs. Recurrence of scabies was observed by 25 % of GPs despite systematic treatment (93 %) of patients' close contacts. DISCUSSION: Our study confirms the frequency of scabies in general medicine and the interest of GPs in this evaluation of practice. Our data also demonstrate the heterogeneity of management by GPs and the limitations of/poor compliance with national recommendations on scabies proposed by the Haut conseil de sante publique (Public Health Council) in 2012. CONCLUSION: Our study emphasizes the critical role of GPs in the management of scabies and the need for specific recommendations concerning their practices. PMID- 29128242 TI - Early changes of blood lipid levels during psychotropic drug treatment as predictors of long-term lipid changes and of new onset dyslipidemia. AB - BACKGROUND: Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels. OBJECTIVE: This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development. METHODS: Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment. RESULTS: Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (>=5%) for TC, LDL C, TG, and non-HDL-C and decrease (>=5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (>=30% TC, >=40% LDL-C, >=45% TG, >=55% non-HDL-C increase, and >=20% HDL-C decrease; sensitivity 70%-100%, specificity 53%-72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort (P <= .03) as well as in a replication cohort (n = 79; P <= .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others (P <= .01). CONCLUSION: Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia. PMID- 29128243 TI - An empirical model to predict road dust emissions based on pavement and traffic characteristics. AB - The relative impact of non-exhaust sources (i.e. road dust, tire wear, road wear and brake wear particles) on urban air quality is increasing. Among them, road dust resuspension has generally the highest impact on PM concentrations but its spatio-temporal variability has been rarely studied and modeled. Some recent studies attempted to observe and describe the time-variability but, as it is driven by traffic and meteorology, uncertainty remains on the seasonality of emissions. The knowledge gap on spatial variability is much wider, as several factors have been pointed out as responsible for road dust build-up: pavement characteristics, traffic intensity and speed, fleet composition, proximity to traffic lights, but also the presence of external sources. However, no parameterization is available as a function of these variables. We investigated mobile road dust smaller than 10 MUm (MF10) in two cities with different climatic and traffic conditions (Barcelona and Turin), to explore MF10 seasonal variability and the relationship between MF10 and site characteristics (pavement macrotexture, traffic intensity and proximity to braking zone). Moreover, we provide the first estimates of emission factors in the Po Valley both in summer and winter conditions. Our results showed a good inverse relationship between MF10 and macro-texture, traffic intensity and distance from the nearest braking zone. We also found a clear seasonal effect of road dust emissions, with higher emission in summer, likely due to the lower pavement moisture. These results allowed building a simple empirical mode, predicting maximal dust loadings and, consequently, emission potential, based on the aforementioned data. This model will need to be scaled for meteorological effect, using methods accounting for weather and pavement moisture. This can significantly improve bottom-up emission inventory for spatial allocation of emissions and air quality management, to select those roads with higher emissions for mitigation measures. PMID- 29128245 TI - The reproductive responses of earthworms (Eisenia fetida) exposed to nanoscale zero-valent iron (nZVI) in the presence of decabromodiphenyl ether (BDE209). AB - Reproductive toxicity of nanoscale zero-valent iron (nZVI) along with coexisting decabromodiphenyl ether (BDE209) to earthworm Eisenia fetida (E. fetida) remains unknown. In the present study, the reproductive responses of E. fetida exposed to 100, 500 and 1000 mg kg-1 of nZVI showed a significant (P < 0.05) decline up to 35.6%, 60.0% and 93.3%, respectively, compared to the controls. Expression levels of annetocin (ANN) gene indicated a remarkable (P < 0.05) down-regulation (59.2%, 58.2% and 95.0%, correspondingly), and it was positively correlated with reproductive rates (R = 0.94). Iron contents in E. fetida were also relevant to reproductive behavior (R = 0.84) and ANN expression (R = 0.75). Additionally, seminal vesicles displayed a progressive degeneration with increasing nZVI levels. The addition of BDE209 to low level of nZVI-polluted group (100 mg kg-1 dw) barely caused clear changes on reproduction, histopathology and ANN, while the coexistence resulted in significant impacts in comparison with high level of single nZVI exposure (1000 mg kg-1 dw). These observations would provide some significant information concerning joint toxicity of the two chemicals in a soil system. PMID- 29128244 TI - Source apportionment of secondary organic aerosol in China using a regional source-oriented chemical transport model and two emission inventories. AB - A Community Multiscale Air Quality (CMAQ) model with source-oriented lumped SAPRC 11 (S11L) photochemical mechanism and secondary organic aerosol (SOA) module was applied to determine the contributions of anthropogenic and biogenic sources to SOA concentrations in China. A one-year simulation of 2013 using the Multi resolution Emission Inventory for China (MEIC) shows that summer SOA are generally higher (10-15 MUg m-3) due to large contributions of biogenic (country average 60%) and industrial sources (17%). In winter, SOA formation was mostly due to anthropogenic emissions from industries (40%) and residential sources (38%). Emissions from other countries in southeast China account for approximately 14% of the SOA in both summer and winter, and 46% in spring due to elevated open biomass burning in southeast Asia. The Regional Emission inventory in ASia v2.1 (REAS2) was applied in this study for January and August 2013. Two sets of simulations with the REAS2 inventory were conducted using two different methods to speciate total non-methane carbon into model species. One approach uses total non-methane hydrocarbon (NMHC) emissions and representative speciation profiles from the SPECIATE database. The other approach retains the REAS2 speciated species that can be directly mapped to S11L model species and uses source specific splitting factors to map other REAS2 lumped NMHC species. Biogenic emissions are still the most significant contributor in summer based on these two sets of simulations. However, contributions from the transportation sector to SOA in January are predicted to be much more important based on the two REAS2 emission inventories (~30-40% vs. ~5% by MEIC), and contributions from residential sources according to REAS2 was much lower (~21-24% vs. ~42%). These discrepancies in source contributions to SOA need to be further investigated as the country seeks for optimal emission control strategies to fight severe air pollution. PMID- 29128246 TI - Long-term exposure to ambient PM2.5 associated with fall-related injury in six low- and middle-income countries. AB - Exposure to ambient air pollution has been linked with adverse health outcomes of the circulatory and nervous systems. Given that falls are closely related to circulatory and nervous health, we hypothesize that air pollution may adversely affect fall-related injury. We employed Wave 1 data from 36,662 participants aged >=50 years in WHO's Study on Global AGEing and Adult Health in six low- and middle-income countries. Ambient annual concentration of PM2.5 was estimated using satellite data. A three-level logistic regression model was applied to examine the long-term association between ambient PM2.5 and the prevalence of fall-related injury, and associated disease burden, as well as the potential effect modification of consumption of fruit and vegetables. Ambient PM2.5 was found to be significantly associated with the risk of fall-related injury. Each 10 MUg/m3 increase corresponded to 18% (OR = 1.18, 95% CI: 1.09, 1.28) increase in fall-related injury after adjusting for various covariates. The association was relatively stronger among participants with lower consumption of fruit (OR = 1.22, 95% CI: 1.12, 1.33) than higher consumption (OR = 1.06, 95% CI: 0.92, 1.23), and among those with lower vegetable consumption (OR = 1.18, 95% CI: 1.08, 1.28) than higher consumption (OR = 1.08, 95% CI: 0.91, 1.27). Our study suggests that ambient PM2.5 may be one risk factor for fall-related injury and that higher consumption of fruit and vegetables could alleviate this effect. PMID- 29128248 TI - Adsorption of 1,2,3-Trichloropropane (TCP) to meet a MCL of 5 ppt. AB - 1,2,3-Trichloropropane (TCP) is a groundwater contaminant in the drinking water aquifers in Hawaii and some other states. Granular activated carbon (GAC) has been used for 30 years to treat approximately 60 million gallons per day of TCP contaminated groundwater in Hawaii. The State of Hawaii's current maximum contaminant level (MCL) for TCP is 600 ng/L (ppt), and consideration is being given to lower the MCL to 5 ppt. There is no EPA MCL for TCP. A study was conducted to determine if any GAC could meet a 5 ppt MCL for TCP, and if so, how many bedvolumes (BVs) could be treated prior to breakthrough. Constant Diffusivity-Rapid Small-Scale Column Tests (CD-RSSCTs) were performed to evaluate GAC adsorption of TCP. Three different groundwaters and six different GACs were utilized. The RSSCTs with the currently-utilized GAC were predictive of the performance of the GAC contactors (50,000 BVs to breakthrough). Any of the six GACs could meet a MCL of 5 ppt and some could do so for 150,000 or more BVs. No single GAC was optimal for all three well sites, indicating effects of subtle undefined differences in the water matrix and/or GAC physiochemical properties. The coal-based direct-activated carbon currently being used is the least optimal for all three well sites with respect to meeting a potential new TCP MCL of 5 ppt. The most effective GACs for Kunia were the Calgon coal-based GAC and the Siemens enhanced coconut shell GAC, while the most effective for Waipahu were the Siemens regular and enhanced coconut shell GACs, and the most effective for Mililani was the Calgon coal-based GAC. Choosing just one GAC for use at all three well sites (rather than the optimal for each site) would result in a reduction of treatment run time of 1 year at one well site (63% reduction). PMID- 29128247 TI - Diagnosis of complex mixture toxicity in sediments: Application of toxicity identification evaluation (TIE) and effect-directed analysis (EDA). AB - Determining causality of sediment toxicity is of great importance in aquatic risk assessment, but there are tremendous challenges due to joint toxicity of trace pollutants in complex sediment matrices. Two approaches, namely toxicity identification evaluation (TIE) and effect-directed analysis (EDA) have been developed. Conventional sediment TIEs take the advantage of environmental relevance by using whole organism bioassays; however, they suffer from lack of effective methods for specifically identifying major contributors as it typically only evaluates contaminant class rather than specific contaminants. Alternatively, EDA is a powerful tool in identifying causes of sediment toxicity with sophisticated fractionation and chemical analysis of targeted and non targeted non-polar organic toxicants, but it is not always environmentally relevant due to the use of in-vitro bioassays and exhaustive solvent extraction. An integrated TIE and EDA method would provide an environmentally relevant and toxicant specific approach to effectively determine causality of sediment toxicity by combining the merits of the two methods. Bioavailability-based extraction and dosing techniques are recommended to be incorporated into the integrated method to improve the accuracy of toxicity diagnosis. Besides considering bioavailability in the integrated TIE and EDA approach, the premise of adverse outcome pathways should also be considered. Generally speaking, both TIE and EDA have focused on adverse effects at cellular and organism levels. The addition of trait-based approaches in screening multiple toxicological endpoints helps to extend effects on cellular and organism levels to population level, and provides a better understanding of potential impacts to the community and ecosystem. The outcome pathway underlies the critical role of determining causality in interpreting impacts of complex mixtures to benthic community and aquatic ecosystem. PMID- 29128249 TI - Nationwide ground-level ozone measurements in China suggest serious risks to forests. AB - We processed hourly ozone (O3) concentrations collected in 2015 and in 2016 by a network of 1497 stations across China, with the main aim of assessing the risk that present ambient O3 exposure is posing to Chinese forests. Our results indicate that the values of the metrics AOT40 (the accumulated hourly O3 concentrations above 40 ppb during daylight hours) recommended as European Union standard, and W126 (the sum of weighted hourly concentrations from 8:00 to 20:00) recommended as USA standard for forest protection, exceeded the critical levels (5 ppm h across 6 months for AOT40 and 7-21 ppm h over 3 months for W126) on average by 5.1 and 1.2 times, respectively. N100 showed on average 65 annual exceedances of 100 ppb as hourly value. The 12-h and 24-h averages showed a small difference, suggesting high concentrations also at night. Risk was higher for the northern temperate climate than for the southern tropical and sub-tropical climates, and overall for the northern regions than for the southern regions. Higher risk occurred in the non-urban areas than in the urban areas in northern, south-west and north-west China, whereas risk was higher at urban areas in eastern and southern China. The overall results of this first nationwide assessment suggest a significant risk for forests over the entire China and warrant for urgent measures for controlling O3 precursor emissions and establishing standards of protection. PMID- 29128250 TI - Sex-specific hypothalamic-pituitary-gonadal axis sensitivity in migrating songbirds. AB - In seasonally migratory species, the overlap between the migratory and breeding life history stages is a balance between the physiological and behavioral requirements of each stage. Previous studies investigating the degree to which songbirds prepare for breeding during spring migration have focused on either circulating hormone levels or direct measures of gonadal recrudescence. In this study, we evaluated the phenology of breeding preparation in a long-distance migratory songbird, the Swainson's Thrush (Catharus ustulatus), by assessing hypothalamic-pituitary-gonadal (HPG) axis sensitivity with gonadotropin-releasing hormone (GnRH) bioassays throughout the migratory period. During spring migration both males and females had a significant response to GnRH injections as reflected in elevated testosterone levels. The magnitude of response to GnRH injections, Rpotential, in females stayed consistent throughout spring migration; however, Rpotential in males increased as the migratory season progressed. It is clear that at least some degree of endocrinological breeding development occurs either before or during spring migration in both sexes, however the phenology appears to be sex specific. In males this breeding development continues at a relatively steady pace throughout the migratory period while in females, relatively little endocrine breeding development occurs during migration. These sex-specific differences in the phenology of the endocrine breeding development warrant future investigations for both male and female songbirds. Moreover, research focused on how physiological breeding development is balanced with the expression of migratory traits in long-distance songbird migrants is needed. PMID- 29128251 TI - Effects of temperature and particle size on the biochemical methane potential of municipal solid waste components. AB - The effects of temperature and substrate size on the biochemical methane potential (BMP) assay were tested using eight municipal solid waste components. Two sample sizes were tested; size-reduced particles (x < 2 mm) which are typically used for BMP assays and unground samples (x > 20-100 mm) more similar to an as-disposed condition. Two incubation temperatures (35 and 55 degrees C) were tested for each component. BMPs for office paper, newspaper, paperboard, and coated paper displayed little difference with regards to temperature or particle size. Mesophilic corrugated cardboard BMPs were significantly greater than their thermophilic counterparts. Hardwood, softwood, and cotton BMPs varied with particle size and temperature. Particle size reduction may increase the bioavailable carbon compounds for wood, but this step was not necessary to achieve similar methane yields for paper products. Extrapolating BMP results to predict landfill methane generation may have greater uncertainty for wood wastes and cotton textiles than paper products. PMID- 29128252 TI - Vaccination to reduce antimicrobial resistance. PMID- 29128253 TI - Correction to Lancet Glob Health 2017; 5: e1113-22. PMID- 29128254 TI - Anemia in Heart Failure: Still Relevant? AB - One-third of all patients with heart failure have anemia, and its presence is associated with more symptoms, increased rates of hospitalization, and increased mortality. The etiology of anemia is multifactorial, complex, and varies between patients. The most important factors leading to anemia in heart failure are inadequate erythropoietin production resulting from renal failure, intrinsic bone marrow defects, medication use, and nutritional deficiencies such as iron deficiency. Erythropoiesis-stimulating agents (ESAs) have been proven to successfully correct hemoglobin levels, albeit without significant improvement in clinical outcome. On the contrary, the use of ESAs has led to increased rates of thromboembolic events and ischemic stroke. This use of ESAs for the treatment of anemia in heart failure, therefore, cannot be recommended. In addition, these results question whether anemia is a therapeutic target or merely a marker of disease severity. Other therapies are being studied and include agents targeting the erythropoietin receptor, hepcidin pathway, or iron availability. This review focuses on the pathophysiology of anemia in heart failure, explains why investigated therapies might not have led to the desired results, and discusses promising future therapies. PMID- 29128255 TI - Patients' experience of the monitoring of free flaps after reconstruction for oral cancer. AB - Regular monitoring of free flaps is essential after microvascular free tissue transfer, but the frequency and duration of the observations vary between units and there is no consensus nationally. Best practice can be informed by the feedback of patients, but as we know of no such studies, we did a cross-sectional survey of a consecutive group of patients after free tissue transfer to find out what they thought about monitoring. We designed a study-specific questionnaire after consultation with the patient and carer forum, and sent it to 150 patients who had had free tissue transfer in the maxillofacial department at Aintree University Hospital during 2015 and 2016. A total of 106 (71%) responded, and a quarter (30/106, 28%) would have liked more information about monitoring. Generally, patients were worried little by the observations (91/106, 86%), but one-third (34/106, 32%) reported disturbed sleep. Just over half (n=55/104, 53%) were relieved when the monitoring changed from hourly to four-hourly, and almost all (99/101, 98%) were not worried by this. Nearly half (47/105, 45%) would have preferred fewer observations when asleep. In conclusion, our findings could help to inform a leaflet for patients about monitoring. Consideration could be given to reducing its frequency, for example, the checks at 1, 3, and 5am could be omitted during the second night, which could make a substantial difference to the patient. However, its impact on salvage needs to be audited. PMID- 29128256 TI - MEGF10 related myopathies: A new case with adult onset disease with prominent respiratory failure and review of reported phenotypes. AB - Recessive mutations in MEGF10 (multiple epidermal growth factor 10) have been reported in a severe early onset disorder named Early Myopathy, Areflexia, Respiratory Distress and Dysphagia, and a milder form with cores in the muscle biopsy; and a possible genotype-phenotype correlation determining the clinical presentation has been suggested. We undertook exome sequencing in a 66 year old male with a 20 year history of progressive proximal and distal weakness of upper and lower limbs, facial weakness and dysphagia, who developed respiratory failure requiring ventilation while still ambulant in his 50s. Muscle biopsy demonstrated myopathic changes with aggregation of myofibrillar proteins. Mutations in MEGF10 were identified: a novel essential splice site (c.1426+1G>T) and a novel missense variant (c.352T>C, p.(Cys118Arg)). We performed a detailed review of all reported MEGF10 cases (n = 20), and confirmed the presence of a genotype-phenotype correlation, namely that with >=1 null mutation onset of respiratory dysfunction occurs in the first year of life, whereas with 2 missense mutations, respiratory dysfunction occurs at 10 years old or much later, as in the patient reported here. Our findings expand the phenotype of MEGF10 mutations to include onset in the 5th decade, and discuss the spectrum of MEGF10 related disease. PMID- 29128257 TI - The role of clock genes in the etiology of Major Depressive Disorder: Special Section on "Translational and Neuroscience Studies in Affective Disorders". Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders. AB - BACKGROUND: Circadian rhythms are largely dysregulated in Major Depressive Disorder (MDD). The present review provides a summary of the findings about the role of clock genes in the etiology of MDD. METHODS: A careful search of articles on Pubmed, PsycINFO, Isi Web of Knowledge was performed in order to obtain a comprehensive review about the topic. RESULTS: The studies reported contrasting results about the association of different single nucleotide polymorphisms (SNPs) in clock genes and MDD. The most consistent result reported the association between SNP rs2287161 of CRY1 and MDD development. LIMITATIONS: Most of the published papers on the topic show bias as a prevalence of Asian ethnicity or not blinded conditions of laboratory experiments with respect to subjects' conditions (healthy controls or MDD). CONCLUSION: Further epigenetic and genome-wide studies are necessary to have a more clear idea about the role of clock genes in the etiology of MDD. PMID- 29128258 TI - Assessment of human exposure to pesticides by hair analysis: The case of vegetable-producing areas in Burkina Faso. AB - The present work assesses human exposure to pesticides in vegetable-producing areas in Burkina Faso, using hair as an indicator. The study design includes a comparison between operators who are occupationally exposed while working in the fields and a reference population (i.e. not occupationally exposed) to evaluate both occupational and indirect exposures. Hair samples from volunteers (n=101) were positive for 17 pesticides (38 analyzed). Acetamiprid, desethylatrazine, carbofuran, and deltamethrin were detected for the first time in field samples. With a maximum of 9 residues per sample, pesticide exposure was ubiquitous in both populations. Contamination by acetamiprid, cypermethrin, and lambda cyhalothrin (used in vegetable production) prevailed in operator samples. For other pesticides, such as imidacloprid and deltamethrin, no significant difference was found. This indicates a potentially large environmental exposure (dietary intake or atmospheric contamination) or the prevalence of other contamination sources. The present findings are concerning, as detected levels are globally higher than those previously reported, and indicate exposure to endocrine disrupting chemicals and probable carcinogens. Hair was found to be a suitable matrix for biomonitoring human exposure to pesticides and assessing dominant factors (i.e. sex, age, and protective equipment) in subgroups, as well as identifying geographical contamination patterns. PMID- 29128260 TI - Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology. AB - The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease. PMID- 29128259 TI - Role of Dysregulated Cytokine Signaling and Bacterial Triggers in the Pathogenesis of Cutaneous T-Cell Lymphoma. AB - Cutaneous T-cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic, and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome showed a highly heterogeneous landscape of genetic perturbations, and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway previously implicated in cutaneous T-cell lymphoma pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of cutaneous T-cell lymphoma. Using this mouse model, we show that T-cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota. PMID- 29128261 TI - Multi-parametric rigid and flexible, low-cost, disposable sensing platforms for biomedical applications. AB - The measurement of Na+, K+ and H+ is essential in medicine and plays an important role in the assessment of tissue ischemia. Microfabrication, inkjet- and screen printing can be used for solid contact ion selective electrodes (ISE) realization; these, however, can be non-standardized, costly and time consuming processes. We present the realization of ISEs on post-processed electrodes fabricated via standardized printed circuit board (PCB) manufacturing techniques. In vitro results are presented from two rigid platforms (32 ISEs) for liquid sample dip-stick measurements and two flexible platforms (6 and 32 ISEs) for post surgical intestinal tissue monitoring, each with a common reference electrode (RE). These are combined with optimized tetrapolar bioimpedance sensors for tissue ischemia detection. Both electroless and hard gold PCB finishes are examined. Apart from the electroless rigid platform, the rest demonstrated comparable and superior performance, with the pH sensors demonstrating the greatest deviation; the flexible hard gold platform achieved a sensitivity 4.6mV/pH and 49.2mV/pH greater than the electroless flexible and rigid platforms, respectively. The best overall performance was achieved with the hard gold flexible platform with sensitivities as large as 73.4mV/pH, 56.3mV/log [Na+], and 57.4mV/log [K+] vs. custom REs on the same substrate. Simultaneous measurement of target analytes is demonstrated with test solutions and saliva samples. The results demonstrate superior performance to other PCB-based pH sensors and Na+ and K+ PCB-based sensors with comparable performance to potentiometric sensors fabricated with other techniques, paving the way towards mass-produced, low-cost, disposable, multi-parametric chemical sensing diagnostic platforms. PMID- 29128262 TI - Intraoperative imaging during minimally invasive transoral robotic surgery using near-infrared light. AB - PURPOSE: The purpose of this study was to determine if the use of the FIREFLY imaging system could be an asset in transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). The system uses indocyanine green dye (ICG), which fluoresces when illuminated by near-infrared light from the Da Vinci robot. The system may improve visualization of tumor margins, highlight important vascular structures, and help identify the location of tumors and unknown primary head and neck cancers. METHODS: Six patients with OPSCC were enrolled in the study. Two of these cases were unknown primaries, one was base of tongue, and three were palatine tonsils. Each patient was given two 3ml doses of ICG, one at the beginning of the surgical case and one during resection of the tumor. The oropharynx was then visualized using the near-infrared light of the Da Vinci robot for a minute after injection. RESULTS: The FIREFLY system was unable to detect gross tumors, positive margins, unknown primaries, or vascular structures in any of the six subjects in the study. In addition, there were no adverse events or side effects in any of the subjects. CONCLUSION: The use of the FIREFLY system with indocyanine green fluorescence did not identify tumor boundaries, unknown primary head and neck cancers, or vascular structures in the oropharynx. PMID- 29128263 TI - Golden anniversary issue editorial. PMID- 29128264 TI - Coupling astogenic aging in the colonial tunicate Botryllus schlosseri with the stress protein mortalin. AB - Botryllus schlosseri, a colonial marine invertebrate, exhibits three generations of short-lived astogenic modules that continuously grow and die throughout the colony's entire lifespan, within week-long repeating budding cycles (blastogenesis), each consisting of four stages (A-D). At stage D, aging is followed by the complete absorption of adult modules (zooids) via a massive apoptotic process. Here we studied in Botryllus the protein mortalin (HSP70s member), a molecule largely known for its association with aging and proliferation. In-situ hybridization and qPCR assays reveal that mortalin follows the cyclic pattern of blastogenesis. Colonies at blastogenic stage D display the highest mortalin levels, and young modules exhibit elevated mortalin levels compared to old modules. Manipulations of mortalin with the specific allosteric inhibitor MKT-077 has led to a decrease in the modules' growth rate and the development of abnormal somatic/germinal morphologies (primarily in vasculature and in organs such as the endostyle, the stomach and gonads). We therefore propose that mortalin plays a significant role in the astogeny and aging of colonial modules in B. schlosseri, by direct involvement in the regulation of blastogenesis. PMID- 29128265 TI - Atrial Appendage Thrombosis Risk Is Lower for Atrial Flutter Compared with Atrial Fibrillation. AB - BACKGROUND: The risk of stroke and thromboembolism in atrial fibrillation is established. However, the evidence surrounding the risk of thromboembolism in patients with atrial flutter is not as clear. We hypothesized that atrial flutter would have indicators of less risk for thromboembolism compared with atrial fibrillation on transesophageal echocardiography, thereby possibly leading to a lower stroke risk. METHODS: A retrospective review of 2225 patients undergoing transesophageal echocardiography was performed. Those with atrial fibrillation or atrial flutter were screened. Exclusion criteria were patients being treated with chronic anticoagulation, the presence of a prosthetic valve, moderate to severe mitral regurgitation or stenosis, congenital heart disease, or a history of heart transplantation. A total of 114 patients with atrial fibrillation and 55 patients with atrial flutter met the criteria and were included in the analysis. RESULTS: Twelve patients (11%) in the atrial fibrillation group had left atrial appendage thrombus versus zero patients in the atrial flutter group (P < .05). The prevalence of spontaneous echocardiography contrast was significantly higher and left atrial appendage emptying velocity was significantly lower in the atrial fibrillation group compared with the atrial flutter group (P < .001). No spontaneous contrast was seen when the left atrial appendage emptying velocity was >60 cm/sec. CONCLUSIONS: Patients with atrial flutter have a lower incidence of left atrial appendage thrombi, higher left atrial appendage emptying velocity, and less left atrial spontaneous contrast compared with patients with atrial fibrillation, suggesting a lower risk for potential arterial thromboembolism. PMID- 29128267 TI - Clinical Relevance of Alternative Endpoints in Colorectal Cancer First-Line Therapy With Bevacizumab: A Retrospective Study. AB - BACKGROUND: We studied the relationship between intermediate criteria and overall survival (OS) in metastatic colorectal cancer (mCRC) patients who received first line chemotherapy with bevacizumab. PATIENTS AND METHODS: We assessed OS, progression-free survival (PFS), duration of disease control (DDC), the sum of the periods in which the disease did not progress, and the time to failure of strategy (TFS), which was defined as the entire period before the introduction of a second-line treatment. Linear correlation and regression models were used, and Prentice criteria were investigated. RESULTS: With a median follow-up of 57.6 months for 216 patients, the median OS was 24.5 months (95% confidence interval [CI], 21.3-29.7). The median PFS, DDC, and TFS were 8.9 (95% CI, 8.4-9.7), 11.0 (95% CI, 9.8-12.4), and 11.1 (95% CI, 10.0-13.0) months, respectively. The correlations between OS and DDC (Pearson coefficient, 0.79 [95% CI, 0.73-0.83], determination coefficient, 0.62) and OS and TFS (Pearson coefficient, 0.79 [95% CI, 0.73-0.84], determination coefficient, 0.63) were satisfactory. Linear regression analysis showed a significant association between OS and DDC, and between OS and TFS. Prentice criteria were verified for TFS as well as DDC. CONCLUSION: DDC and TFS correlated with OS and are relevant as intermediate criteria in the setting of patients with mCRC treated with a first-line bevacizumab-based regimen. PMID- 29128266 TI - Molecular Profiling of Patients With Advanced Colorectal Cancer: Princess Margaret Cancer Centre Experience. AB - BACKGROUND: Molecular aberrations in KRAS, NRAS, BRAF, and PIK3CA have been well described in advanced colorectal cancer. The incidences of other mutations are less known. We report results of molecular profiling of advanced colorectal cancer in an academic cancer center. PATIENTS AND METHODS: Patients with advanced colorectal were enrolled in an institution-wide molecular profiling program. Profiling was performed on formalin-fixed paraffin embedded archival tissues using a customized MassArray panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Cancer Panel (48 genes, 212 amplicons, >= 500* coverage) in a Clinical Laboratory Improvement Amendments-certified laboratory. PTEN was determined by immunohistochemistry. RESULTS: From March 2012 to April 2014, 245 patients were enrolled. At least one mutation was found in 54% (97/178) and 91% (61/67) of patients using MassArray or MiSeq platforms, respectively (P < .01). Of all patients, KRAS G12/13 mutation was identified in 39%, and non-G12/13 KRAS, BRAF, or NRAS mutations were present in 9%, 6%, and 4%, respectively. Other common mutations included TP53 (68.7%), APC (41.8%), and PIK3CA (13.5%). Co mutation with KRAS, NRAS, or BRAF was found in 75% of patients with PIK3CA mutation. Of 106 patients with known PTEN immunohistochemistry status, 16% were negative. A higher average number of mutations were observed in right versus left colorectal cancer (P < .01), with 13 of 14 BRAF mutations located in right colon cancer. CONCLUSION: Mutations are common in advanced colorectal cancer. Right colon cancers harbor more genetic aberrations than left colon or rectal cancers. These aberrations may contribute to differential outcomes to anti-epidermal growth factor receptor therapy among patients with right colon, left colon, or rectal cancers. PMID- 29128268 TI - Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency. AB - INTRODUCTION: Testosterone (T) deficiency (TD; hypogonadism) has deleterious effects on men's health; negatively affects glycometabolic and cardiometabolic functions, body composition, and bone mineral density; contributes to anemia and sexual dysfunction; and lowers quality of life. T therapy (TTh) has been used for the past 8 decades to treat TD, with positive effects on signs and symptoms of TD. AIM: To summarize the health benefits of TTh in men with TD. METHODS: A comprehensive literature search was carried out using PubMed, articles relevant to TTh were accessed and evaluated, and a comprehensive summary was synthesized. MAIN OUTCOME MEASURES: Improvements in signs and symptoms of TD reported in observational studies, registries, clinical trials, and meta-analyses were reviewed and summarized. RESULTS: A large body of evidence provides significant valuable information pertaining to the therapeutic value of TTh in men with TD. TTh in men with TD provides real health benefits for bone mineral density, anemia, sexual function, glycometabolic and cardiometabolic function, and improvements in body composition, anthropometric parameters, and quality of life. CONCLUSION: TTh in the physiologic range for men with TD is a safe and effective therapeutic modality and imparts great benefits on men's health and quality of life. Traish AM. Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency. Sex Med Rev 2018;6:86-105. PMID- 29128269 TI - Post-Orgasmic Illness Syndrome: A Review. AB - INTRODUCTION: Post-orgasmic illness syndrome (POIS) is a rare but debilitating cluster of postejaculatory symptoms affecting men. It is a chronic disorder manifesting as a constellation of flulike and allergic symptoms within seconds, minutes, or hours after ejaculation. POIS can be followed by mental sequelae such as diminished concentration and irritability. POIS negatively affects the life of patients by limiting sexual encounters, dampening romantic prospects, creating internal struggles to avoid eroticism, and affecting patients' schedules. First described in 2002, the prevalence and incidence of POIS are still unknown owing to a paucity of studies but is likely under-reported. There are approximately 50 cases of POIS in the literature. Despite the debilitating effects of POIS, the pathophysiology of POIS is still not well elucidated. AIM: To provide an update on the current literature on POIS, provide updated information on the pathophysiology of POIS, and discuss potential management options. METHODS: Comprehensive review of literature pertaining to POIS. MAIN OUTCOME MEASURES: The symptoms, classification, pathophysiology, diagnostic considerations, and management of POIS were reviewed. RESULTS: There are 5 preliminary diagnostic criteria for diagnosing this condition. POIS is categorized as primary or secondary. The autoimmune-allergy hypothesis is the most accepted hypothesis explaining the pathogenesis of POIS. A competing hypothesis involves a disorder involving endogenous MU-opioid receptors. Another hypothesis invokes impairment of the cytokine and neuroendocrine responses. There are no known treatment modalities for POIS; patients have been symptomatically treated with antihistamines, selective serotonin reuptake inhibitors, and benzodiazepines. A trial of hyposensitization therapy with autologous semen was successful. A trial of non-steroidal anti-inflammatory medication helped 1 patient described in a single case report, but failed to successfully treat other patients. CONCLUSIONS: POIS is a rare condition that is underdiagnosed and under-reported. Further studies are warranted to investigate the prevalence, pathophysiology, and treatment of this debilitating condition. Nguyen HMT, Bala A, Gabrielson AT, Hellstrom WJG. Post-Orgasmic Illness Syndrome: A Review. Sex Med Rev 2018;6:11 15. PMID- 29128270 TI - Low Serum Testosterone in Outpatient Psychiatry Clinics: Addressing Challenges to the Screening and Treatment of Hypogonadism. AB - INTRODUCTION: The symptoms of low testosterone frequently overlap with psychiatric complaints including depression and fatigue. Testosterone repletion has been shown to improve mood symptoms in men with low testosterone, although this finding has not been consistent across all studies. Despite the potential importance of low testosterone for psychiatry, the prevalence of low testosterone in men who present to psychiatric clinics with mental health complaints is unknown. AIM: To provide an overview of the current state of knowledge of the psychiatric complications of male hypogonadism, the challenges of screening for hypogonadism in a psychiatric population, and the potential mental health treatment implications of hypogonadism. METHODS: A literature review was conducted using PubMed. MAIN OUTCOME MEASURES: Publications pertaining to the epidemiology, psychiatric symptomatology, and impact of treatment of male hypogonadism on psychiatric outcomes. RESULTS: A review of the literature suggests a lack of information on the prevalence of low testosterone in patients presenting with psychiatric complaints despite an overlap in clinical symptoms. The identification of low testosterone could have a significant impact on treatment through urologic referral for testosterone repletion or the use of treatments that spare the gonadal axis. CONCLUSION: We hope our results will help those who care for patients in psychiatric settings to better assess for the presence of hypogonadism and its potential contribution to depressive illness. Smith JB, Rosen J, Colbert A. Low Serum Testosterone in Outpatient Psychiatry Clinics: Addressing Challenges to the Screening and Treatment of Hypogonadism. Sex Med Rev 2018;6:69-76. PMID- 29128271 TI - Predictors of Patient and Partner Satisfaction Following Radical Prostatectomy. AB - INTRODUCTION: The diagnosis and treatment of prostate cancer adversely affects the physical and emotional well-being of patients and partners and has been associated with sexual dysfunction in patients and their intimate partners. AIM: To identify predictors of sexual satisfaction in prostate cancer survivors and their partners based on a review of the current literature. METHODS: We performed a comprehensive review of the PubMed database from January 2000 to May 2017 focused on the (i) prevalence of patient and partner sexual dysfunction related to radical prostatectomy, (ii) differences in patient and partner perspectives of sexual function and dysfunction, and (iii) predictors of patient and partner sexual satisfaction after radical prostatectomy. MAIN OUTCOME MEASURES: Patient- and partner-reported sexual satisfaction. RESULTS: There is a paucity of published data examining sexual satisfaction in prostate cancer survivors and their partners. Patients and partners can have different expectations of sexual outcomes after radical prostatectomy and different attitudes toward the relative importance of recovery of sexual function after surgery. Available data suggest that patients' and partners' mental and physical health and the quality of communication between them are important contributors to their sexual satisfaction. Patient-perceived partner support also is associated with better patient-reported erectile function and greater relationship satisfaction. CONCLUSION: Mental health, physical health, quality of interpersonal communication, and patient-perceived partner support appear to be the most important predictors of sexual satisfaction for patients and partners in the post prostatectomy period. There is a definite need for further research on this topic to develop interventions to improve sexual function and quality of life for prostate cancer survivors and their intimate partners. Guercio C, Mehta A. Predictors of Patient and Partner Satisfaction Following Radical Prostatectomy. Sex Med Rev 2018;6:295-301. PMID- 29128272 TI - Cytoprotection of lipoic acid against toxicity induced by saxitoxin in hippocampal cell line HT-22 through in silico modeling and in vitro assays. AB - Saxitoxins (STXs) are potent neurotoxins that block voltage-gated channels in neurons and induce cytotoxicity. These toxins not only can generate reactive oxygen species but also can alter antioxidant levels, promoting oxidative stress. Under this pro-oxidant situation, the use of the antioxidant lipoic acid (LA) can represent a chemoprotective alternative to minimize the deleterious effects induced by neurotoxins as STXs. P-glycoprotein (P-gp) is a well-known ATP-binding cassette (ABC) transporter that plays a crucial role in the extrusion of toxic substances, decreasing their accumulation and potential intracellular effects in virtue of its broad substrate specificity, its expression in many excretory tissues and its large efflux capacity. The interaction of STXs with LA was evaluated by ab initio simulation, molecular docking and bioassays using the cell line HT-22. The interaction of STXs with LA occurs by physisorption. Molecular docking indicated that STXs can be a substrate of P-gp and, estimating the Free Energy of Binding (FEB), LA has lower amino acids residues binding sites, similar to verapamil, while STX and STX+LA_1 have similar amino acids residues and binding sites with similar FEB between this ligands.Cells were exposed to STXs and LA for 30min and 24h. LA treatment minimizes STX cytotoxicity, evaluated by trypan blue and MTT assay and both STX and STX-LA treatments were efficient to induce P-gp activity measured by rhodamine 123 dye extrusion. LA and STX+LA treatments induced low reactive oxygen species levels and low oxygen consumption. Based on our results, it can be concluded that LA was able to induce cytoprotection, including induction of cellular glutathione levels, and that STX+LA interaction reduced toxicity effects induced by STX. Overall, the in vitro results corroborated the semi-empirical evidences found using density functional theory ab initio simulation and molecular docking. PMID- 29128273 TI - Epidemiological and clinical characteristics of humans with avian influenza A (H7N9) infection in Guangdong, China, 2013-2017. AB - OBJECTIVE: To describe the demographics and clinical characteristics of patients with A (H7N9) infection, to test the differences in the distribution of demographics and clinical characteristics by clinical severity, and to explore potential factors associated with clinical severity. METHODS: This retrospective study was conducted to collect epidemiological and clinical information regarding the confirmed cases in Guangdong through field investigation and review of medical records. RESULTS: Of the 256 cases, 100 (39.0%) patients died, and 168 (65.6%) patients were admitted to ICUs. The male-to-female ratio was approximately 2.0:1, and the median age was 56 years (range, 1 to 88). Among the 215 patients accepting oseltamivir treatment, the median time from the onset of illness to oseltamivir treatment was 5days (range, 0 to 16); 35 patients received zanamivir treatment after a median of 8days (range, 0 to 23). The univariable logistic regression models demonstrated that time from the onset of illness to oseltamivir treatment (OR=1.10, 95% CI=1.01-1.10) and zanamivir treatment (OR=1.05, 95% CI=1.02-1.07) were associated with the death of patients. CONCLUSIONS: Preventive measures should focus on high-risk populations, such as the elderly and the groups with high frequency exposure to live poultry. Earlier oseltamivir and zanamivir treatment were recommended. PMID- 29128274 TI - [Should we consume less salt?] PMID- 29128275 TI - A Longitudinal Study of Motivations Before and Psychosexual Outcomes After Genital Gender-Confirming Surgery in Transmen. AB - BACKGROUND: Genital dissatisfaction is an important reason for transmen to undergo genital gender-confirming surgery (GCS; phalloplasty or metoidioplasty). However, little is known about motives for choosing specific techniques, how transmen benefit postoperatively, and whether psychosexual outcomes improve. AIM: To evaluate motivations for and psychosexual outcomes after GCS. METHODS: A longitudinal study of 21 transmen at least 1 year after GCS was conducted. Participants were recruited through their surgeon. Data were collected when they applied for surgery and at least 1 year after surgery. OUTCOMES: Data collection included semistructured questionnaires on motivations for surgery, postoperative experiences, and standardized measures of psychological symptoms, body image, self-esteem, sexuality, and quality of life (pre- and postoperative). Information on surgical complications and corrections was retrieved from medical records. RESULTS: Most participants underwent phalloplasty with urethral lengthening using a radial forearm flap. Although problematic voiding symptoms were prevalent, many participants were satisfied with their penile function. The strongest motivations to pursue penile surgery were confirmation of one's identity (100%), enabling sexual intercourse (78%), and voiding while standing (74%). No significant differences between postoperative and reference values were observed for standardized measures. After surgery, transmen were more sexually active (masturbation and with a partner) and used their genitals more frequently during sex compared with before surgery (31-78%). CLINICAL IMPLICATIONS: The present study provides input for preoperative decision making: (i) main motives for surgery include identity confirmation, voiding, and sexuality, (ii) surgery can result in more sexual activity and genital involvement during sex, although some distress can remain, but (iii) complications and voiding symptoms are prevalent. STRENGTH AND LIMITATIONS: Study strengths include its longitudinal design and the novelty of the studied outcomes. The main limitations include the sample size and the nature of the assessment. CONCLUSION: Counseling and decision making for GCS in transmen should be a highly personalized and interdisciplinary practice. van de Grift TC, Pigot GLS, Boudhan S, et al. A Longitudinal Study of Motivations Before and Psychosexual Outcomes After Genital Gender-Confirming Surgery in Transmen. J Sex Med 2017;14:1621-1628. PMID- 29128276 TI - Simultaneous determination of saikosaponin a, paeonol, and imperatorin, components of DA-9805, in rat plasma by LC-MS/MS and application to a pharmacokinetic study. AB - DA-9805 is a new botanical antiparkinson drug candidate formulated using an ethanolic extract of the root of Bupleurum falcatum, the root cortex of Paeonia suffruticosa, and the root of Angelica dahurica. In this study, a sensitive and rapid LC-MS/MS method was developed to simultaneously determine, saikosaponin a, paeonol, and imperatorin, three active/representative ingredients of DA-9805, in rat plasma. Plasma was extracted by mixture of ethyl acetate and methyl tertiary butyl ether. Chromatographic separation was carried out using a C18 column and a gradient elution of mobile phases consisting of 5mM formic acid in water and acetonitrile. Total chromatographic run time was 10.5min. Multiple reaction monitoring mode was used for mass spectrometry; the transitions were m/z 779.5 >617.2 for saikosaponin a in negative-ion mode, m/z 167->149 for paeonol and m/z 271.1->203 for imperatorin in positive-ion mode. Calibration curves were constructed in the range of 0.5-1000ng/mL for saikosaponin a, 20-10000ng/mL for paeonol, and 0.2-1000ng/mL for imperatorin. All the validation data, including the selectivity, linearity, precision, accuracy, recovery, matrix effect, and stability satisfied the acceptance requirements. The method was successfully applied in a pharmacokinetic study of saikosaponin a, paeonol, and imperatorin following oral administration of DA-9805. PMID- 29128278 TI - A validated UPLC-MS/MS method for biomonitoring the exposure to the fragrance 7 hydroxycitronellal. AB - 7-Hydroxycitronellal is a synthetic fragrance (CAS No. 107-75-5) which is used commonly in cosmetics, washing- and cleaning agents and as flavoring in foods. Due to its broad application in various fields, 7-hydroxycitronellal was selected for the development of a biomonitoring method for the quantitative exposure assessment within the frame of the cooperation project of the German Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) and the German Chemical Industry Association (VCI). For this purpose, an ultra performance liquid chromatography combined with tandem mass spectrometry (UPLC-MS/MS) based method was developed for the determination of potential biomarkers of 7-hydroxycitronellal (7-HC) in human urine samples. 7 Hydroxycitronellylic acid (7-HCA) turned out to be the quantitatively most important metabolite of 7-HC in human urine, occurring in 1000 times higher amounts than 7-hydroxycitronellol (7-HCO) or other potential metabolites. Therefore, an analytical method for 7-HCA was developed using stable isotope labeled 7-HCA as internal standard (IS). The method includes a cleavage step of possible metabolite conjugates with an enzyme mix of beta-glucuronidase and arylsulfatase. Subsequent sample cleanup was performed by liquid-liquid extraction (LLE) with dichloromethane. The method was calibrated by calculating the linear regression between the analyte/IS ratio and the nominal 7-HCA concentrations in water. The method was validated according to approved standard guidelines and proved to be robust, reliable and sensitive for the human biomonitoring of 7-HC. The method was applied to urine samples of 40 adult volunteers from the general population. 7-HCA was quantifiable in urine of all subjects. Thus the developed method proved to be suitable for assessing the background exposure to 7-HC in the general population. PMID- 29128277 TI - A fast, sensitive, and high throughput method for the determination of esomeprazole in dog plasma by UHPLC-MS/MS: Application to formulation development of the compound preparation of esomeprazole. AB - To investigate deeply into the preclinical pharmacokinetics and prescription design of esomeprazole, a sensitive, high throughput and robust UHPLC-MS/MS method had been developed and fully validated for the analysis of esomeprazole in dog plasma. Esomeprazole and diazepam (IS) were fast extracted from plasma by alkalified organic solvent, and separated on MP-C18 column with methanol and 0.1% formic acid. The quantification of esomeprazole and IS had been achieved using fragmentation transitions of m/z 346.1->198.1 and m/z 285.0->193.2 in MRM detection under positive ESI mode. The concentration of esomeprazole in dog plasma was linear with the range of 3.75-500ng/mL. The precisions of intra- and inter-day were no more than 11.6%, while the accuracies were all within +/-9.7% of the nominal values. The recovery was no more than 77.06%, and the matrix effect, stability, dilution integrity tests were all satisfied the currently criterion. Then the method was successfully performed to evaluating pharmacokinetics of esomeprazole and optimizing the prescription of modified esomeprazole with varied addition of sodium bicarbonate. Consequently, a pharmacokinetic study of three doses esomeprazole with the optimized addition of sodium bicarbonate in dogs has been successfully researched for the first time. It could be a promising approach to improve the stabilization of acid-labile esomeprazole and would provide a useful reference for the formulation design of esomeprazole. PMID- 29128279 TI - Comparison and characterization of volatile compounds as markers of oils stability during frying by HS-SPME-GC/MS and Chemometric analysis. AB - The formation and emission of volatile compounds, including the aldehydes and some toxic compounds of oil samples, ROPO pure (100%) and the blended ROPO/RCO (80-20%), were carried out during deep frying at 180 degrees C. The volatile profile of both oil samples was evaluated by an optimized HS-SPME-GC/MS method, before and after 20, 40 and 60 successive sessions of deep-frying. Actually, from 100 detected compounds, aldehydes were found to be the main group formed. In addition, the oil degradation under thermal treatment regarding the volatile compounds were evaluated and compared. Consequently, the blended ROPO/RCO revealed fewer formations of unsaturated aldehydes, including toxic ones, such as acrolein, and showed a greater stability against oxidative thermal degradation compared to ROPO pure. PMID- 29128280 TI - Geriatric nursing and resilience in the midst of tropical storm Harvey. PMID- 29128281 TI - Psychiatry residents' confidence in integrated care skills on a collaborative care rotation at a safety net health care system. AB - OBJECTIVE: This letter to the editor describes how psychiatry residents' confidence in delivering population based care improved after working within a collaborative care system. METHODS: An anonymous online survey was delivered to 24 psychiatry residents who matriculated through Cambridge Health Alliance residency from 2012 to 2014 and participated in the collaborative care rotation. During the rotation, residents provided direct and indirect consultations, used measurement-based care (MBC) and took a population approach to patient management. Items were asked about residents' level of confidence. RESULTS: Twenty of 24 residents responded to the survey (83% response rate) with no questions skipped. Among respondents, 80% were confident in the stepped care model, 65% were confident using MBC, 95% were confident communicating and coordinating with primary care teams, 65% felt they were likely to initiate lab checks (such as metabolic monitoring), and 95% had confidence the rotation helped clarify their role as a consultant to primary care teams. Only 30% were confident in providing indirect consultations to primary care teams. CONCLUSION: After a 6month rotation in a collaborative care model, psychiatry residents have gained confidence in multiple domains of integrated care. However, additional curriculum development and training is required to help residents improve confidence in indirect consultations. PMID- 29128282 TI - Daydreams incorporate recent waking life concerns but do not show delayed ('dream lag') incorporations. AB - This study investigates the time course of incorporation of waking life experiences into daydreams. Thirty-one participants kept a diary for 10 days, reporting major daily activities (MDAs), personally significant events (PSEs) and major concerns (MCs). They were then cued for daydream, Rapid Eye Movement (REM) and N2 dream reports in the sleep laboratory. There was a higher incorporation into daydreams of MCs from the previous two days (day-residue effect), but no day residue effect for MDAs or PSEs, supporting a function for daydreams of processing current concerns. A day-residue effect for PSEs and the delayed incorporation of PSEs from 5 to 7 days before the dream (the dream-lag effect) have previously been found for REM dreams. Delayed incorporation was not found in this study for daydreams. Daydreams might thus differ in function from REM sleep dreams. However, the REM dream-lag effect was not replicated here, possibly due to design differences from previous studies. PMID- 29128283 TI - Emotional prediction: An ALE meta-analysis and MACM analysis. AB - The prediction of emotion has been explored in a variety of functional brain imaging and neurophysiological studies. However, an overall picture of the areas involved this process remains unexploited. Here, we quantitatively summarized the published literature on emotional prediction using activation likelihood estimation (ALE) in functional magnetic resonance imaging (fMRI). Furthermore, the current study employed a meta-analytic connectivity modeling (MACM) to map the meta-analytic coactivation maps of regions of interest (ROIs). Our ALE analysis revealed significant convergent activations in some vital brain areas involved in emotional prediction, including the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), orbitofrontal cortex (OFC) and medial prefrontal cortex (MPFC). For the MACM analysis, we identified that the DLPFC, VLPFC and OFC were the core areas in the coactivation network of emotional prediction. Overall, the results of ALE and MACM indicated that prefrontal brain areas play critical roles in emotional prediction. PMID- 29128284 TI - [Brain injury knowledge in family members of neurosurgical patients]. AB - BACKGROUND AND OBJECTIVES: Several studies have shown misconceptions about brain injury in different populations. The aim of this study was to assess the knowledge and perceptions about brain injury of family members of neurosurgical patients in our hospital. MATERIAL AND METHODS: The participants (n=81) were relatives of patients admitted to the neurosurgery department between February and August 2016. They voluntarily completed a 19-item true-false format survey about brain injury based on a translation of other questionnaires used in previous studies from other countries (USA, Canada, UK, Ireland and New Zealand). Also, some sociodemographic data were collected (age, sex, education level and the patient's pathology). Data analysis was developed through graphical modelling with a regularisation parameter plotted on a network representing the association of the items of the questionnaire from the response pattern of participants. RESULTS: Data analysis showed two conceptual areas with a high rate of wrong answers: behaviour and management of patients, and expectations about acquired brain injury recovery. CONCLUSIONS: The results obtained in this study would enable us to objectify misconceptions about acquired brain injury in patients' relatives attended in the neurosurgery department. This lack of knowledge could be a great obstacle in patients' recovery process. Therefore, we suggest placing the emphasis on the provision of information on brain injury to patients' families, especially with regard to its symptoms and course of development. PMID- 29128285 TI - Prolonged and localized sweat stimulation by iontophoretic delivery of the slowly metabolized cholinergic agent carbachol. AB - BACKGROUND: Continuous non-invasive sampling and sensing of multiple classes of analytes could revolutionize medical diagnostics and wearable technologies, but also remains highly elusive because of the many confounding factors for candidate biofluids such as interstitial fluid, tears, saliva, and sweat. Eccrine sweat biosensing has seen a recent surge in demonstrations of wearable sampling and sensing devices. However, for subjects at rest, access to eccrine sweat is highly limited and unpredictable compared to saliva and tears. OBJECTIVE: Reported here is a prolonged and localized sweat stimulation by iontophoretic delivery of the slowly-metabolized nicotinic cholinergic agonist carbachol. METHODS: Presented here are detailed measurements of natural baseline sweat rates across multiple days, confirming a clear need for localized sweat stimulation. Iontophoresis was performed with either carbachol or pilocarpine in order to stimulate sweat in subjects at rest. Furthermore, improved methods of quantifying sweat generation rates (nL/min/gland) are demonstrated. RESULTS: In-vivo testing reveals that carbachol stimulation can surpass a major goal of 24-h sweat access, in some cases providing more than an order of magnitude longer duration than stimulation with commonly-used pilocarpine. Also demonstrated is reduction of the traditional iontophoretic dosage for sweat stimulation (<5.25-42mC/cm2). This increases the viability of repeated dosing as demonstrated herein, and for carbachol is as much as 100-1000X less than used for other applications. CONCLUSION: This work is not only significant for wearable sweat biosensing technology, but could also have broader impact for those studying topical skin products, antiperspirants, textiles and medical adhesives, nerve disorders, the effects of perspiration on skin-health, skin related diseases such as idiopathic pure sudomotor failure and hyperhidrosis, and other skin- and perspiration-related applications. PMID- 29128286 TI - TRPA1 channel participates in tacrolimus-induced pruritus in a chronic contact hypersensitivity murine model. PMID- 29128288 TI - Hypoglycaemic episodes and risk of diabetic peripheral neuropathy in patients with type 2 diabetes. PMID- 29128287 TI - Functional evaluation of swallowing in patients with tongue cancer before and after surgery using high-speed continuous magnetic resonance imaging based on T2 weighted sequences. AB - OBJECTIVES: The aim of this study was to determine the usefulness of evaluating the function of swallowing before and after surgery in patients with tongue cancer by using T2-weighted sequences of high-speed continuous magnetic resonance imaging (HSCMRI). STUDY DESIGN: The imaging findings and related parameters on HSCMRI along with those on routine MRI examinations before and after surgery were examined in 19 patients with tongue cancer. In addition, changes in various parameters during 1 year after surgery were evaluated in 10 patients. RESULTS: In most patients examined, the direction of flow to the esophagus could be seen on HSCMRI before and after surgery. Significant correlations were observed among 4 parameters and in the responses to a dysphagia questionnaire. CONCLUSIONS: The results of the present study suggest that the dynamics of swallowing can be directly visualized on HSCMRI by using 4 parameters that permit the evaluation of changes before and after surgery, and this enables objective evaluation of patients' swallowing complaints. PMID- 29128289 TI - Predictors of the response of HbA1c and body weight after SGLT2 inhibition. PMID- 29128290 TI - Antibody drug quantitation in coexistence with anti-drug antibodies on nSMOL bioanalysis. AB - Therapeutic monoclonal antibodies (mAbs) are developed for treatment of diverse cancers and autoimmune diseases. For expansion of mAbs approval against unapproved diseases and pharmaceutical development, pharmacokinetics study is very important. Bioanalysis provides one of the most essential index against pharmacokinetics information. So far, we developed useful method for bioanalysis of mAbs in plasma or serum, nSMOL: nano-surface and molecular-orientation limited proteolysis. This method can provide accurate and reproducible value of mAbs content in plasma. Quantification of mAbs using ELISA is strongly influenced by endogenous ligand or anti-drug antibodies. In this report, we exhibited the role of nSMOL proteolysis coupled to LC-MS/MS analysis against quantification of mAbs bound to some binding molecules. The ligands against mAbs do not affect quantification of mAbs concentration in plasma using nSMOL proteolysis. On the other hands, some anti-drug antibodies (ADA), such as idiotypic antibodies, inhibit quantification of mAbs using nSMOL proteolysis. Acid dissociation has some efficacy in accurate value of quantitation of ADA binding mAbs using nSMOL proteolysis coupled to LC-MS/MS analysis. Accordingly, we consider that nSMOL method will contribute to understanding of mAb PK data and therapeutic reference combining with ADA measurements. PMID- 29128291 TI - Detection of SNPs of T2DM susceptibility genes by a ligase detection reaction fluorescent nanosphere technique. AB - OBJECTIVE: To establish a high throughput, low cost, and simple nanotechnology based method for the detection of single nucleotide polymorphism (SNP) loci in type 2 diabetes mellitus (T2DM). METHODS: Multiplex ligase detection reaction (LDR) amplification was performed using fluorescently labeled magnetic nanosphere bound upstream LDR probes and downstream probes labeled with a unique fluorescent group for each SNP locus. The amplified LDR products were separated by magnetic nanospheres and then scanned by fluorescence spectroscopy. Four SNP loci associated with T2DM were detected, including the rs13866634 locus in SLC30A8, rs10811661in CDKN2A/2B, rs1111875 in the HHEX gene, and rs7903146 in the TCF7L2 gene. The SNP genotype was also determined by DNA sequencing as a control. RESULTS: The SNP genotypes of the four gene loci determined by the nanosphere based multiplex LDR method were consistent with the DNA sequencing results. The accuracy rate was 100%. CONCLUSION: A method based on multiplex PCR and LDR was established for simultaneous detection of four SNP loci of T2DM susceptibility genes. PMID- 29128292 TI - Profiling 5-tolyltriazole biodegrading sludge communities using next-generation sequencing and denaturing gradient gel electrophoresis. AB - Efficient biodegradation of 5-tolyltriazole (5-TTri) in wastewater treatment would minimize its potential detrimental effects on aquatic systems. Therefore, in order to profile 5-TTri biodegrading activated sludge communities (ASC) by DGGE and NGS, acclimation experiments with (i) easily degradable substrates, and (ii) various complex substrates mimicking wastewater conditions were performed. DGGE revealed four genera: Aminobacter (family Phyllobacteriaceae), Flavobacterium (family Flavobacteriaceae), Pseudomonas (family Pseudomonaceae), and Hydrogenophaga (family Comamonadaceae). Metagenomics (DNA) revealed the dominant families Alcaligenaceae, Pseudomonadaceae and Comamonadaceae that also represented the most active families at the RNA level (metatranscriptomics), which might indicate their importance for 5-TTri biodegradation. ASC acclimation and the composition of the substrate significantly affected 5-TTri biodegradation and the development of biodegrading communities. Using acetate only, a moderate 5 TTri degrading community was detected with a very low biodiversity and Pseudomonas spp. as dominant organisms. In contrast, setups fed 'sludge supernatant' (a complex substrate) efficiently biodegraded 5-TTri and formed a more diverse microbial community but with Hydrogenophaga spp. as the dominant group. Finally, a hypothetical 5-TTri biodegradation pathway was constructed based exclusively on the detected, biodegradation-related, Hydrogenophaga spp. genes. PMID- 29128293 TI - Test-retest reliability of sit-to-stand and stand-to-sit analysis in people with and without chronic non-specific low back pain. AB - BACKGROUND: Sit-to-stand (STD) and stand-to-sit (SIT) analysis can provide information on functional independence in daily activities in patients with low back pain (LBP). However, in order for measurements to be clinically useful, data on psychometric properties should be available. OBJECTIVES: The main purpose was to investigate intra-rater reliability of STD and SIT tasks in participants with and without chronic non-specific LBP (CNLBP). The second purpose was to detect any differences in lumbar spine and hips sagittal plane kinematics and coordination between asymptomatic individuals and CNLBP patients during STD and SIT. DESIGN: Cross-sectional study. METHOD: Twenty-three CNLBP patients and 23 demographically-matched controls were recruited. Ten markers were placed on specific anatomical landmarks. Participants were asked to perform STD and SIT at a preferred speed. Peak flexion angles, mean angular velocities, lumbar to hip movement ratios, and relative phase angles were measured. The procedure was repeated after 2 h and 6-8 days. Differences between two groups were analyzed using independent t-test. Intraclass correlation coefficient (ICC 3,k), standard error of measurement (SEM), and limits of agreement (LOAs) were also estimated. RESULTS: The ICC values showed moderate to excellent intra-rater reliability, with relatively low SEM values (<=10.17 degrees ). The 95% LOAs demonstrated that there were no differences between the measured parameters. Furthermore, CNLBP patients had limited sagittal plane angles, smaller angular velocities, and lumbar-hip dis-coordination compared to asymptomatic participants. CONCLUSIONS: The results indicated moderate to excellent test-retest reliability of STD and SIT analysis. Moreover, CNLBP patients had altered kinematics during STD and its reverse. PMID- 29128294 TI - Behavioral depression is associated with increased vagally mediated heart rate variability in adult female cynomolgus monkeys (Macaca fascicularis). AB - INTRODUCTION: Depressive symptoms (DS) in humans are associated with decreased resting state vagal activity, but sex seems to moderate this association. Recently, in human females DS have been associated with greater or similar cardiac vagal activity compared to men in both, clinical and non-clinical samples. A previously validated animal model of behavioral depression was used in the present study to investigate the association of DS and cardiac vagal activity in non-human primates. METHODS: The root mean square of successive differences between adjacent heart beats (RMSSD) was used as an indicator of vagally-mediated heart rate variability in 24h heart rate recordings collected via telemetry in 42 adult female cynomolgus monkeys (Macaca fascicularis). Hierarchical regression models were used to estimate differences in RMSSD comparing monkeys with and without DS. To capture circadian variation patterns of RMSSD, additional quadratic, cubic and quartic terms of hour were added. RESULTS: Monkeys showing behavioral DS had higher overall 24-h RMSSD. The interaction term of daytime with DS and polynomials of hour contributed significantly to the variance across models. CONCLUSIONS: This is the first study investigating the association of DS and 24h cardiac vagal control in female non-human primates. Results replicate existing human studies showing higher cardiac vagal control in behavioral depressed vs. non-depressed female monkeys. PMID- 29128295 TI - The impact of peer mentor communication with older adults on depressive symptoms and working alliance: A pilot study. AB - OBJECTIVE: The objective of this pilot study was to describe peer communication in meetings with depressed elders, associate their relationship with working alliance and depression and assess congruence of communication with training. METHODS: Three peers with a history of depression, in recovery, received 20h of training in peer mentoring for depression as part of an 8-week pilot program for 23 depressed older adults. Each peer-client meeting was recorded; a sample of 69 recorded meetings were chosen across the program period and coded with the Roter Interaction Analysis System, a validated medical interaction analysis system. Generalized linear mixed models were used to examine peer talk during meetings in relation to working alliance and client depression. RESULTS: Peers used a variety of skills congruent with their training including client-centered talk, positive rapport building and emotional responsiveness that remained consistent or increased over time. Client-centered communication and positive rapport were associated with increased working alliance and decreased depressive symptoms (all p<0.001). CONCLUSION: Trained peer mentors can use communication behaviors useful to older adults with depression. Specifically, client-centered talk may be important to include in peer training. PRACTICE IMPLICATIONS: Peer mentors can be a valuable resource in providing depression counseling to older adults. PMID- 29128296 TI - Sexual and Reproductive Health Care Receipt Among Young Males Aged 15-24. AB - PURPOSE: This study aimed to describe young men's sexual and reproductive health care (SRHC) receipt by sexual behavior and factors associated with greater SRHC receipt. METHODS: There were 427 male patients aged 15-24 who were recruited from 3 primary care and 2 sexually transmitted disease (STD) clinics in 1 urban city. Immediately after the visit, the survey assessed receipt of 18 recommended SRHC services across four domains: screening history (sexual health, STD/HIV test, family planning); laboratories (STDs/HIV); condom products (condoms/lubrication); and counseling (STD/HIV risk reduction, family planning, condoms); in addition, demographic, sexual behavior, and visit characteristics were examined. Multivariable Poisson regressions examined factors associated with each SRHC subdomain adjusting for participant clustering within clinics. RESULTS: Of the participants, 90% were non-Hispanic black, 61% were aged 20-24, 90% were sexually active, 71% had female partners (FPs), and 20% had male or male and female partners (M/MFPs). Among sexually active males, 1 in 10 received all services. Half or more were asked about sexual health and STD/HIV tests, tested for STDs/HIV, and were counseled on STD/HIV risk reduction and correct condom use. Fewer were asked about family planning (23%), were provided condom products (32%), and were counseled about family planning (35%). Overall and for each subdomain, never sexually active males reported fewer services than sexually active males. Factors consistently associated with greater SRHC receipt across subdomains included having M/MFPs versus FPs, routine versus non-STD-acute visit, time alone with provider without parent, and seen at STD versus primary care clinic. Males having FPs versus M/MFPs reported greater family planning counseling. CONCLUSIONS: Findings have implications for improving young men's SRHC delivery beyond the narrow scope of STD/HIV care. PMID- 29128297 TI - Role of Geriatric Oncologists in Optimizing Care of Urological Oncology Patients. AB - CONTEXT: Urological cancers are common. Since the median age of diagnosis is 60 70 yr, many patients require geriatric as well as urological evaluation if treatment is to be tailored to individual health status including comorbidities and frailty. OBJECTIVE: To review the most important features of geriatric assessment and its expected benefits. We also consider ways in which collaboration between urologists and geriatricians and geriatric teams can benefit patient well-being. EVIDENCE ACQUISITION: Members of a multidisciplinary International Society of Geriatric Oncology task force reviewed articles published in 2010-2017 using search terms relevant to urological cancers, the elderly, and geriatric evaluation. The final manuscript reflects their expert consensus. EVIDENCE SYNTHESIS: Elderly patients should be managed according to their individual health status and not according to age. As a first step, screening for cognitive impairment is mandatory to establish patient competence in making decisions. Initial evaluation of health status should use a validated screening tool, the G8 screening tool being generally preferred. Abnormal scores on the G8 should lead to a geriatric assessment that evaluates comorbid conditions and functional, nutritional, mental, and medicosocial status. When patients are frail or disabled or have severe comorbidities, comprehensive geriatric assessment is required. Diagnosis of health status impairment shows the need for geriatric interventions. This overall approach is realistic in the setting of a department of urological oncology and given the involvement of a multidisciplinary team including trained nurses and other professionals and collaboration with geriatricians. Mutual education and support of all those involved in managing elderly urological cancer patients is the key to effective care. CONCLUSIONS: Advances in geriatric evaluation and cancer treatment are contributing to more appropriate management of elderly patients with urological cancers. Better understanding of the role of all participants and professional collaboration are vital to the individualization of care. PATIENT SUMMARY: Many patients with urological cancers are elderly. In those physically fit, treatment should generally be the same as that in younger patients. Some elderly cancer patients are frail and have other medical problems. Treatment in individual patients should be based on health status and patient preference. PMID- 29128298 TI - Cellobiose dehydrogenase hosted in lipidic cubic phase to improve catalytic activity and stability. AB - Lipidic cubic phase systems (LCPs) are excellent carriers for immobilized enzymes due to their biocompatibility and well-defined nanoporous structure. Lipidic cubic phases act as a convenient matrix to incorporate enzymes and hold them in the vicinity of electrode surfaces in their fully active forms. Corynascus thermophilus cellobiose dehydrogenase (CtCDH) was trapped in a monoolein cubic phase, which increased not only its stability, but also its catalytic performance with both enhanced mediated and direct electron transfer with electrodes. For studies of mediated electron transfer, three mediators with different formal potentials (E degrees ') were employed: horse-heart cytochrome c (cyt c), electron acceptor active with the cytochrome domain of CtCDH, and 2,6 dichlorophenolindophenol (DCPIP) as well as hexaammineruthenium(II) chloride [Ru(NH3)Cl2] both electron acceptors with the dehydrogenase domain. Ru(NH3)Cl2, having the most negative E degrees ' of -0.138V vs. Ag|AgCl at pH7.5, gave a catalytic current for lactose oxidation of 32.10MUAcm-2 in MOPS buffer at pH7.5. The process carried out in the same solution but under direct electron conditions transfer resulted in a catalytic current of 9.22MUAcm-2. Electrodes covered with CtCDH in a LCP film retained their catalytic activity after 28days showing a slightly increased current density after 6days. PMID- 29128299 TI - Nutrition in the ICU: sometimes route does matter. PMID- 29128302 TI - Corrigendum to "Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes" [Int. J. Parasitol. Drugs and Drug Resist. 7 (2017) 174-180]. PMID- 29128301 TI - Portal vein reconstruction using primary anastomosis or venous interposition allograft in pancreatic surgery. AB - OBJECTIVE: Superior mesenteric vein/portal vein (SMV/PV) resection and reconstruction during pancreatic surgery are increasingly common. Several reconstruction techniques exist. The aim of this study was to evaluate characteristics of patients and clinical outcomes for SMV/PV reconstruction using interposed cold-stored cadaveric venous allograft (AG+) or primary end-to-end anastomosis (AG-) after segmental vein resections during pancreatic surgery. METHODS: All patients undergoing pancreatic surgery with SMV/PV resection and reconstruction from 2006 to 2015 were identified. Clinical and histopathologic outcomes as well as preoperative and postoperative radiologic findings were assessed. RESULTS: A total of 171 patients were identified. The study included 42 and 71 patients reconstructed with AG+ and AG-, respectively. Patients in the AG+ group had longer mean operative time (506 minutes [standard deviation, 83 minutes] for AG+ vs 420 minutes [standard deviation, 91 minutes] for AG-; P < .01) and more intraoperative bleeding (median, 1000 mL [interquartile range (IQR), 650-2200 mL] for AG+ vs 600 mL [IQR, 300-1000 mL] for AG-; P < .01). Neoadjuvant therapy was administered more frequently for patients in the AG+ group (23.8% vs 8.5%; P = .02). Patients with AG+ had a longer length of tumor vein involvement (median, 2.4 cm [IQR, 1.6-3.0 cm] for AG+ vs 1.8 cm [IQR, 1.2 2.4 cm] for AG-; P = .01), and a higher number of patients had a tumor-vein interface >180 degrees (35.7% for AG+ vs 21.1% for AG-; P = .02). There was no difference in number of patients with major complications (42.9% for AG+ vs 36.6% for AG-; P = .51) or early failure at the reconstruction site (9.5% for AG+ vs 8.5% for AG-; P = 1). A subgroup analysis of 10 patients in the AG+ group revealed the presence of donor-specific antibodies in all patients. CONCLUSIONS: The short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts is comparable to that of reconstruction with primary end-to-end anastomosis. Graft rejection could be a contributing factor to severe stenosis in patients reconstructed with allograft. PMID- 29128303 TI - The Mountain of Health: The Perceptions and Perceived Expectations of Youth Living With Type 2 Diabetes in Winnipeg, Manitoba, Canada, Through a Grounded Theory Study. AB - OBJECTIVE: The objective of this study was to explore youth's perceptions of diabetes management. METHODS: The study included 8 Manitoban youth with type 2 diabetes (n=7 girls). Each youth participated in a semistructured interview in person, via Skype or over the phone. The constructivist grounded theory methodologic approach guided the analysis of the data. RESULTS: Discussions about diabetes and health and its management revealed 2 viewpoints: 1) youth's perceptions and 2) youth's perceptions of health-care providers' expectations. The Mountain of Health was used to conceptualize the complex nature of diabetes management. Youth perceived that health-care providers prioritized physical health-behaviour changes in order to achieve successful diabetes management. Conflictingly, many youth described their mental and emotional health as taking precedence over their physical health. CONCLUSION: Future interventionists should be aware of the vast incongruence in patients' perceptions of health in type 2 diabetes and their perceptions of health-care providers' expectations during the development of interventions. PMID- 29128300 TI - Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA 2). AB - BACKGROUND: Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition. METHODS: In this randomised, controlled, multicentre, open label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01802099. FINDINGS: After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2.0%; [95% CI -1.9 to 5.8]; p=0.33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0.89 [95% CI 0.72-1.09]; p=0.25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1.89 [1.62-2.20]; p<0.0001), diarrhoea (432 [36%] vs 393 [33%]; 1.20 [1.05-1.37]; p=0.009), bowel ischaemia (19 [2%] vs five [<1%]; 3.84 [1.43-10.3]; p=0.007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3.7 [1.03-13.2; p=0.04). INTERPRETATION: In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition. FUNDING: La Roche-sur-Yon Departmental Hospital and French Ministry of Health. PMID- 29128304 TI - Symptoms of Mental Illness and Their Impact on Managing Type 2 Diabetes in Adults. AB - OBJECTIVES: People with mental illnesses are more likely to experience diabetes related complications that can reduce life expectancy by 10 to 15 years. Diabetes management and outcomes can be improved when lifestyle interventions addressing healthful eating habits and physical activity use content tailored to the learning needs of individuals or groups. Understanding the challenges that prevent adherence to diabetes recommendations can start to inform the design of tailored diabetes education care. The purpose of this pilot study was to explore the perspectives of clients with mental illnesses and type 2 diabetes with regard to challenges faced when engaging in diabetes self-care behaviours. METHODS: Focus groups were held with 17 people who had type 2 diabetes and mental illnesses, including depressive disorder, bipolar disorder, anxiety disorder, schizophrenia and schizoaffective disorder. In the groups, participants were asked to share their experiences with diabetes self-care and access to diabetes education services. Data were transcribed verbatim, assessed for quality and saturation and coded to identify relationships and meanings among identified themes. RESULTS: Participants identified many challenges and unmet needs that created multidimensional and interrelated barriers to care, ultimately resulting in poor diabetes self-care behaviours. Some challenges were psychological in nature and related to emotional states, lifestyles and food habits, perceptions of affordability, health literacy and value of health information. Other challenges included the physical states of health and social environments. CONCLUSIONS: Multidimensional diabetes education programs that consider psychological, physical and social challenges are needed to address the needs of people with mental illnesses. PMID- 29128305 TI - Methamphetamine-induced impulsivity during chronic methamphetamine treatment in rats: Effects of the TAAR 1 agonist RO5263397. AB - Impulsivity is an important personality trait associated with several clinical syndromes including drug abuse. While repeated drug exposure is known to increase certain behavioral responses, such as locomotion, to subsequent drug exposure, few studies have examined whether such sensitization develops for impulsive behavior. In the current study we tested the effects of methamphetamine acutely, during the course of, and upon discontinuation of chronic methamphetamine treatment on impulsive behavior in two models, the 5-choice serial reaction time task (5-CSRTT) and the delay-discounting task which measure impulsive action and impulsive choice, respectively. We also examined whether the trace amine associated receptor 1 (TAAR1) agonist RO5263397 attenuated methamphetamine induced effects in parallel tests. Acute methamphetamine dose-dependently increased premature responses in the 5-CSRTT and shifted the delay function upward in delay discounting. Up to 40 days of methamphetamine treatment did not significantly alter the dose-effect curve of methamphetamine-induced premature responses, but produced a significant effect in the delay-discounting task. RO5263397 attenuated acute methamphetamine-induced premature responses, but this effect became non-significant over the course of chronic treatment. RO5263397 did not significantly alter the delay-discounting performance. Discontinuation of methamphetamine treatment increased premature responses, which was attenuated by RO5263397, but did not significantly alter the delay discounting function. These results suggest that acute discontinuation from prolonged methamphetamine treatment increases impulsivity, which can be reduced by a TAAR1 agonist. PMID- 29128306 TI - Norman Bowery's discoveries about extrasynaptic and asynaptic GABA systems and their significance. AB - Before discovering the GABA-B receptor, Norman Bowery completed a series of studies on an extrasynaptic or asynaptic "GABA system" in the rat superior cervical sympathetic ganglion. First, he discovered an uptake system for GABA in neuroglial cells in the ganglia and in peripheral nerves, with a different substrate specificity than that in neurons. Second, he showed that accumulated GABA in sympathetic glial cells was metabolized to succinate by a transaminase enzyme. Third, he provided detailed structure-activity information about compounds activating an extrasynaptic GABA-A receptor on neurons in the rat sympathetic ganglion. Fourth, he showed that some amino acid substrates for the neuroglial transporter could indirectly stimulate neurons by releasing GABA from adjacent glial cells, and that GABA could also be released from neuroglial cells by membrane depolarization. In this review, these discoveries are briefly described and updated and some of their implications assessed. This article is part of the "Special Issue Dedicated to Norman G. Bowery". PMID- 29128309 TI - Whatever Happened to Kindness? PMID- 29128307 TI - Rescue of glutamate transport in the lateral habenula alleviates depression- and anxiety-like behaviors in ethanol-withdrawn rats. AB - Alcoholism and psychiatric disorders like depression and anxiety are often comorbid. Although the mechanisms underlying this comorbidity are unclear, emerging evidence suggests that maladaptation of the glial glutamate transporter GLT-1 may play a role. Findings from animal and human studies have linked aversive states, including those related to drugs of abuse and depression, to aberrant activity in the lateral habenula (LHb). The relationship between GLT-1 maladaptation, LHb activity, and abnormal behaviors related to alcohol withdrawal, however, remains unknown. Here we show that dihydrokainic acid (DHK), a GLT-1 blocker, potentiated glutamatergic transmission to LHb neurons in slices from ethanol naive rats; this potentiation, though, was not observed in slices from rats withdrawn from repeated in vivo ethanol administration, suggesting reduced GLT-1 function. Furthermore, GLT-1 protein expression was reduced in the LHb of withdrawn rats. This reduction was restored by systemic administration of ceftriaxone, a beta-lactam antibiotic known to increase GLT-1 expression. Systemic ceftriaxone treatment also normalized the hyperactivity of LHb neurons in slices from withdrawn rats, which was reversed by bath-applied DHK. Finally, systemic administration of ceftriaxone alleviated depression- and anxiety-like behaviors, which was fully blocked by intra-LHb administrations of DHK, suggesting that GLT-1's function in the LHb is critical. These findings highlight the significant role of LHb astrocytic GLT-1 in the hyperactivity of LHb neurons, and in depressive- and anxiety-like behaviors during ethanol withdrawal. Thus, GLT-1 in the LHb could serve as a therapeutic target for psychiatric disorders comorbid with ethanol withdrawal. PMID- 29128308 TI - Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. AB - The past two decades have witnessed remarkable advances in oxidative stress research, particularly in the context of ischemic brain injury. Oxidative stress in ischemic tissues compromises the integrity of the genome, resulting in DNA lesions, cell death in neurons, glial cells, and vascular cells, and impairments in neurological recovery after stroke. As DNA is particularly vulnerable to oxidative attack, cells have evolved the ability to induce multiple DNA repair mechanisms, including base excision repair (BER), nucleotide excision repair (NER) and non-homogenous endpoint jointing (NHEJ). Defective DNA repair is tightly correlated with worse neurological outcomes after stroke, whereas upregulation of DNA repair enzymes, such as APE1, OGG1, and XRCC1, improves long term functional recovery following stroke. Indeed, DNA damage and repair are now known to play critical roles in fundamental aspects of stroke recovery, such as neurogenesis, white matter recovery, and neurovascular unit remodeling. Several DNA repair enzymes are essential for comprehensive neural repair mechanisms after stroke, including Polbeta and NEIL3 for neurogenesis, APE1 for white matter repair, Gadd45b for axonal regeneration, and DNA-PKs for neurovascular remodeling. This review discusses the emerging role of DNA damage and repair in functional recovery after stroke and highlights the contribution of DNA repair to regenerative elements after stroke. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 29128311 TI - Motions of the SecA protein motor bound to signal peptide: Insights from molecular dynamics simulations. AB - SecA is an essential part of the Sec pathway for protein secretion in bacteria. In this pathway, SecA interacts with the N-terminal fragment of the secretory protein - the signal peptide, and couples binding and hydrolysis of adenosine triphosphate with movement of the secretory protein across the SecY protein translocon. How interactions with the signal peptide alter the conformational dynamics and long-distance conformational couplings of SecA is a key open question that we address here with molecular dynamics techniques. Analyses of protein motions indicate that the signal peptide alters SecA dynamics not only at the site where this peptide binds, but also at a nucleotide-binding domain. Hydrogen bond clusters contribute to the long-distance propagation of changes in SecA dynamics. PMID- 29128310 TI - Position-Specific contribution of interface tryptophans on membrane protein energetics. AB - Interface tryptophans are key residues that facilitate the folding and stability of membrane proteins. Escherichia coli OmpX possesses two unique interface tryptophans, namely Trp76, which is present at the interface and is solvent exposed, and Trp140, which is relatively more lipid solvated than Trp76 in symmetric lipid membranes. Here, we address the requirement for tryptophan and the consequences of aromatic amino acid substitutions on the folding and stability of OmpX. Using spectroscopic measurements of OmpX-Trp/Tyr/Phe mutants, we show that the specific mutation W76->Y allows barrel assembly >1.5-fold faster than native OmpX, and increases stability by ~0.4kcalmol-1. In contrast, mutating W140->F/Y lowers OmpX thermodynamic stability by ~0.4kcalmol-1, without affecting the folding kinetics. We conclude that the stabilizing effect of tryptophan at the membrane interface can be position-and local environment-specific. We propose that the thermodynamic contributions for interface residues be interpreted with caution. PMID- 29128314 TI - Early changes in M2 muscarinic acetylcholine receptors (mAChRs) induced by sarin intoxication may be linked to long lasting neurological effects. AB - The effect of sarin on the binding parameters (KD & Bmax) of M2 muscarinic acetylcholine receptor (mAChR) was studied 24h and 1 week post exposure. Male & female Sprague-Daweley rats were poisoned with 1XLD50 sarin (80MUg/kg, im) followed by treatment of trimedoxime bromide and atropine (7.5:5mg/kg, im) 1min later. Brains were removed and analyzed for M2 mAChR binding, using [3H]AFDX384, an M2 selective antagonist. A significant increase in KD of M2 mAChR was found in the cortex 24h post poisoning, displaying elevation from 4.65+/-1.16 to 8.45+/ 1.06nM and 5.24+/-0.93 to 9.29+/-1.56nM in male and female rats, respectively. A rise in KD was also noted 1 week following exposure from 5.04+/-1.20 to 11.75+/ 2.78 and from 5.37+/-1.02 to 11.66+/-1.73nM, presenting an added increase of 51 and 40% (compared to 24h) in males and females, respectively. Analysis of M2 receptor density (Bmax) revealed a significant reduction of 68% in males and insignificant reduction of 22% in females, 24h after sarin exposure which was followed by 37% recovery in males and 100% recovery in females, 1 week later. These results indicate that sarin induces a long-term decreased affinity in M2 mAChR (elevated KDs) and a transient effect on the number of this receptor subtype (Bmax). We hypothesize that the reduced affinity of the M2 receptors (negative auto-regulatory receptors) may cause long-term brain deficits by impairing the normal regulation release of ACh into the synaptic cleft. PMID- 29128313 TI - Reducing occupational lead exposures: Strengthened standards for a healthy workforce. AB - Outdated federal and state occupational lead standards leave workers and their families vulnerable to the adverse effects of lead. Standards should be updated to reflect the best available scientific and medical evidence, which documents harm to multiple organ systems even at low levels of exposure. This commentary will review the inadequacies of existing policies, highlight susceptible populations, and briefly summarize state revision efforts to date. Federal policies must be strengthened to protect all workers and their families from this well-documented hazard. PMID- 29128312 TI - Parosteal lipoma as a rare cause of peripheral neuropathy and local irritation: A report of 12 cases. AB - OBJECTIVE: The aim of this study was to evaluate the clinical features and functional results of patients with parosteal lipomas. METHODS: A total of 12 patients (8 females and 4 males; mean age: 45 (10-62) years) with parosteal lipomas who were treated between April 1986 and April 2014, were included into the study. The medical records of the patients were reviewed to analyze the clinical features and functional results of the patients. RESULTS: Of the 12 lipomas, 5 were localized in the proximal arm, 4 in the forearm, 1 in the distal arm, 1 in the distal thigh and 1 in the distal tibia. All patients presented with a progressive, slow-growing mass that was associated with thumb extension weakness in 1 case, and brachialgia-like symptoms in 1 case. Plain radiographs showed a juxtacortical mass in all cases and irregular ossification in 3 cases. In all cases, marginal excision was performed and no clinical recurrence was observed after a mean follow-up of 16 months. CONCLUSION: Parosteal lipomas are uncommon tumors that can be diagnosed with their characteristic radiological features. Parosteal lipomas occurring in the proximal radius may easily cause paralysis of the posterior interosseous nerve or muscle weakness. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 29128315 TI - Parathyroid hormone, calcidiol, calcitriol and adverse events in the acute coronary syndrome. AB - OBJECTIVE: To know the clinical profile as well as the prognostic significance of elevated levels of parathyroid hormone (PTH) in patients admitted for acute coronary syndrome (ACS). DESIGN AND SETTING: Observational and prospective study of patients admitted for ACS in a single Spanish center during a period of six months. INTERVENTION AND VARIABLES OF INTEREST: The circulating concentrations of PTH, calcidiol, calcitriol, NT-proBNP, C-reactive protein, cystatinC and fibrinogen were determined within the first 48h at admission. We performed adjusted models to predict death or re-entry for ACS after hospital discharge. RESULTS: A total of 161 patients were recruited (age 67+/-14 years, 75.2% were men). Forty-one (25.5%) patients had elevated PTH values. During follow-up for a period of 275 person-years, 50 adverse events were recorded. Patients with elevated PTH levels were proportionally more women (21.2 vs. 39.0%) and older (63.3 vs. 77.8 years, both P<.05). Likewise, they presented significantly more cardiovascular risk and a worse prognosis during follow-up (incidence rate ratio 2.64 CI 95%: 1.5-4.6). However, in an adjusted model by the GRACE score, PTH levels were not shown to be an independent risk factor (hazard ratio=1.1; 95% CI: 0.6-2.2), neither other components of the panel. CONCLUSIONS: The proportion of patients with elevated levels of PTH admitted for ACS was high. The presence of high PTH levels was associated with an unfavorable clinical profile and a worse outcome during the follow-up, although it was not an independent predictor of poor prognosis. PMID- 29128316 TI - Fecal calprotectin concentrations in young children with cystic fibrosis: Authors response. PMID- 29128317 TI - Lack of efficacy of Lactobacillus GG in reducing pulmonary exacerbations and hospital admissions in children with cystic fibrosis: A randomised placebo controlled trial. AB - BACKGROUND: Intestinal dysbiosis has been described in Cystic Fibrosis (CF) and probiotics have been proposed to restore microbial composition. Aim of the study was to investigate the effects of Lactobacillus rhamnosus GG (LGG) on clinical outcomes in children with cystic fibrosis (CF). METHODS: A multicentre, randomised double-blind, clinical trial was conducted in children with CF. After 6months of baseline assessment, enrolled children (2 to 16years of age) received Lactobacillus GG (6*109CFU/day) or placebo for 12months. Primary outcomes were proportion of subjects with at least one pulmonary exacerbation and hospitalisation over 12months. Secondary endpoints were total number of exacerbations and hospitalisations, pulmonary function, and nutritional status. RESULTS: Ninety-five patients were enrolled (51/95 female; median age of 103+/ 50months). In a multivariate GEE logistic analysis, the odds of experiencing at least one exacerbation was not significantly different between the two groups, also after adjusting for the presence of different microbial organisms and for the number of pulmonary exacerbations within 6months before randomisation (OR 0.83; 95% CI 0.38 to 1.82, p=0.643). Similarly, LGG supplementation did not significantly affect the odds of hospitalisations (OR 1.67; 95% CI 0.75 to 3.72, p=0.211). No significant difference was found for body mass index and FEV1. CONCLUSIONS: LGG supplementation had no effect on respiratory and nutritional outcomes in this large study population of children with CF under stringent randomised clinical trial conditions. Whether earlier interventions, larger doses, or different strains of probiotics may be effective is unknown. PMID- 29128318 TI - The 75th Diamond Anniversary of Gastroenterology: 1943-2018. PMID- 29128319 TI - A proteomic investigation into mechanisms underpinning corticosteroid effects on neural stem cells. AB - Corticosteroids (CSs) are widely used clinically, for example in pediatric respiratory distress syndrome, and immunosuppression to prevent rejection of stem cell transplant populations in neural cell therapy. However, such treatment can be associated with adverse effects such as impaired neurogenesis and myelination, and increased risk of cerebral palsy. There is increasing evidence that CSs can adversely influence key biological properties of neural stem cells (NSCs) but the molecular mechanisms underpinning such effects are largely unknown. This is an important issue to address given the key roles NSCs play during brain development and as transplant cells for regenerative neurology. Here, we describe the use of label-free quantitative proteomics in conjunction with histological analyses to study CS effects on NSCs at the cellular and molecular levels, following treatment with methylprednisolone (MPRED). Immunocytochemical staining showed that both parent NSCs and newly generated daughter cells expressed the glucocorticoid receptor, with nuclear localisation of the receptor induced by MPRED treatment. MPRED markedly decreased NSC proliferation and neuronal differentiation while accelerating the maturation of oligodendrocytes, without concomitant effects on cell viability and apoptosis. Parallel proteomic analysis revealed that MPRED induced downregulation of growth associated protein 43 and matrix metallopeptidase 16 with upregulation of the cytochrome P450 family 51 subfamily A member 1. Our findings support the hypothesis that some neurological deficits associated with CS use may be mediated via effects on NSCs, and highlight putative target mechanisms underpinning such effects. PMID- 29128320 TI - Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer's disease. AB - We investigated the effect of treadmill exercise training on the levels of Alzheimer's disease (AD)-related protein molecules in the DG and CA1 areas of a rat model of AD, i.c.v. infusion of Abeta1-42 peptide, 2weeks (250pmol/day). Abeta infusion markedly increased protein levels of amyloid precursor protein (APP), the secretase beta-site APP cleaving enzyme-1 (BACE-1) and Abeta in the CA1 and DG areas. The results also revealed that 4weeks of treadmill exercise prevented the increase in the levels of APP, BACE-1 and Abeta proteins in both hippocampal areas. Exercise, however, did not affect the levels of these proteins in normal rats. We suggest that exercise might be changing the equilibrium of APP processing pathway towards the nonpathogenic pathway most probably via increasing BDNF levels in the brain of AD model. PMID- 29128321 TI - PhotoVoice: Engaging School Communities in Wellness Efforts. PMID- 29128323 TI - Who needs antipsychotic maintenance treatment and who does not? Our need to profile and personalize the treatment of first episode psychosis. PMID- 29128322 TI - Role of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) in beta-lactoglobulin aggregation. AB - Protein aggregation is a prevalent phenomenon. It is important to study protein aggregation under different solution conditions. In this study, using 1 anilinonaphthalene-8-sulfonic acid (ANS) fluorescence spectra, we investigated the critical micelle concentration (CMC) of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). We also studied the effects of DOTAP on amyloid aggregation of beta-lactoglobulin using intrinsic fluorescence spectra, circular dichroism spectra, thioflavin T fluorescence, a Congo red binding assay and transmission electron microscopy. We observed that DOTAP had a dual role on beta-lactoglobulin amyloid aggregation. DOTAP inhibited the amyloid aggregation below the CMC, while it had the opposite effect above the CMC. Moreover, the results of transmission electron microscopy showed that spherical aggregates were formed above the CMC. These results led us to conclude that cationic lipids could be used as modulators of protein self-assembly. PMID- 29128324 TI - Overlooked fatal infectious diseases after long-term antipsychotic use in patients with psychiatric illness. PMID- 29128325 TI - Aripiprazole-induced tardive dyskinesia in patients with schizophrenia: A case report of twins. PMID- 29128326 TI - Cognitive remediation can improve negative symptoms and social functioning in first-episode schizophrenia: A randomized controlled trial. AB - BACKGROUND: Meta-analyses have reported that the effects of cognitive remediation might go beyond improvement in cognition to include unexpected benefits for schizophrenia patients such as negative symptom reduction and improvements in functioning. In addition, some evidence indicated that these potentially beneficial effects are also present in the initial course of schizophrenia, but work in this area is still developing. METHOD: A RCT compared Cognitive Remediation (CR) to Healthy Behaviors Training (HBT) in 80 patients (78% male) with a mean age of 21.9years and mean education of 12.3years who had a first psychotic episode within two years of study entry. Participants were trained using CR programs or received HBT involving 50 sessions over 6months and then booster sessions over the next 6months. The SANS and BPRS were used to assess symptoms. The UCLA Social Attainment Survey assessed social functioning. RESULTS: Using GLMM, improvements over 12months were found favoring CR for SANS Expressive Symptoms (p<0.01), which was composed of Affective Flattening (p<0.01) and Alogia (p=0.04), and for SANS Experiential Symptoms, composed of Avolition/Apathy (p=0.04) and Anhedonia/Asociality (p<0.01). CR was associated with improvements in social functioning (p=0.05) as compared to HBT. CONCLUSIONS: We confirmed that the beneficial effects of CR appear to extend beyond cognition to improvements in negative symptoms and social functioning in early course schizophrenia patients. These results suggest that cognitive remediation might have an impact when the reduction of risk factors for chronicity is most critical for promoting recovery. PMID- 29128327 TI - Clinical Predictors of Stroke Mimics in Patients Treated with Recombinant Tissue Plasminogen Activator according to a Normal Multimodal Computed Tomography Imaging. AB - BACKGROUND: Multimodal computed tomography imaging (MCTI) is increasingly used for rapid assessment of acute stroke. We investigated characteristics and final diagnoses of patients treated with recombinant tissue plasminogen activator (rt PA) while admission imaging was unremarkable. METHODS: From our prospectively collected stroke database (2013-2016), we identified consecutive patients treated with rt-PA on the basis of an unremarkable brain MCTI and assessed with a 24-hour follow-up brain magnetic resonance imaging (MRI). Demographic data, medical history, score on the 15-item National Institute of Health Stroke Scale, and final diagnosis were considered. Absence of MRI infarction and alternate diagnosis defined stroke mimics (SMs). Univariable and multivariable logistic regression analyses identified factors predictive of SMs. RESULTS: Sixty-eight (47.9%) SMs, 63 (44.4%) strokes, and 11 (7.7%) aborted strokes were found. SMs had more often aphasia (P = .003) and hemianopia (P = .0008), whereas upper limb weakness (ULW) (P = .03) and limb ataxia (P = .002) were more prevalent in strokes. Headache (adjusted odds ratio [Adj. OR], 3.89 [95% confidence interval {CI} 1.44-10.47]), relevant history of epilepsy, migraine, dementia or depression (Adj. OR 3.66 [95% CI 1.31-10.18]), unilateral sensory loss (Adj. OR 2.60 [95% CI 1.05-6.45]), and hemianopia (Adj. OR 4.94 [95% CI 1.46-16.77]) were independent predictors of SMs whereas ULW (Adj. OR 3.16 [95% CI 1.28-7.82]) and ataxia (Adj. OR 3.81 [95% CI 1.43-10.13]) predicted stroke. Sensitivity of hemianopia or aphasia for SMs was 52.9%, with specificity of 84.1%, positive predictive value of 78.3%, and negative predictive value of 62.4%. CONCLUSIONS: Hemianopia and/or aphasia with normal MCTI suggest SMs. Diffusion-weighted MRI might be discussed before rt-PA administration in patients with such a clinical pattern. PMID- 29128328 TI - Circulating MicroRNAs as Biomarkers for Acute Ischemic Stroke: A Systematic Review. AB - BACKGROUND: Acute ischemic stroke is a leading cause of death and disability worldwide. Unlike myocardial infarction, there is no current blood test to diagnose acute ischemic stroke. MicroRNAs (miRNAs) are very stable in the blood and have been suggested as potential diagnostic markers. MATERIALS AND METHODS: This review aimed to systematically assess case-control studies investigating the association of circulating miRNAs with acute ischemic stroke. Medline, CINAHL, Cochrane Library, Web of Science, Scopus, and PubMed were searched for studies that examined the association of circulating miRNAs in patients with acute ischemic stroke. Studies meeting specific inclusion and exclusion criteria (such as blood samples obtained within 24 hours of an acute ischemic stroke) were selected for data extraction. Two authors extracted data from the included studies relevant to the study design, the patient characteristics, and the relative miRNA expression. RESULTS: Eight studies were included involving 572 cases and 431 healthy controls. Twenty-two miRNAs (12 upregulated and 10 downregulated) were reported as differentially expressed. Only 1 miRNA, miR-106b, was reported as differentially expressed in at least 2 studies. Significant heterogeneity in the design and methods of the included studies was noted. CONCLUSIONS: Differential expression of a large number of miRNAs has been reported early following acute ischemic stroke. More research is required in larger patient populations to further evaluate the diagnostic potential of the reported miRNAs. PMID- 29128329 TI - Geographic Variation in Morbidity and Mortality of Cerebrovascular Diseases in Korea during 2011-2015. AB - BACKGROUND: Little is known about within-country variation in morbidity and mortality of cerebrovascular diseases (CVDs). Geographic differences in CVD morbidity and mortality have yet to be properly examined. This study examined geographic variation in morbidity and mortality of CVD, neighborhood factors for CVD morbidity and mortality, and the association between CVD morbidity and mortality across the 245 local districts in Korea during 2011-2015. METHODS: District-level health care utilization and mortality data were obtained to estimate age-standardized CVD morbidity and mortality. The bivariate Pearson correlation was used to examine the linear relationship between district-level CVD morbidity and mortality Z-scores. Simple linear regression and multivariate analyses were conducted to investigate the associations of area characteristics with CVD morbidity, mortality, and discrepancies between morbidity and mortality. RESULTS: Substantial variation was found in CVD morbidity and mortality across the country, with 1074.9 excess CVD inpatients and 73.8 excess CVD deaths per 100,000 between the districts with the lowest and highest CVD morbidity and mortality, respectively. Higher rates of CVD admissions and deaths were clustered in the noncapital regions. A moderate geographic correlation between CVD morbidity and mortality was found (Pearson correlation coefficient = .62 for both genders). Neighborhood level indicators for socioeconomic disadvantages, undersupply of health care resources, and unhealthy behaviors were positively associated with CVD morbidity and mortality and the relative standing of CVD mortality vis-a-vis morbidity. CONCLUSIONS: Policy actions targeting life-course socioeconomic conditions, equitable distribution of health care resources, and behavioral risk factors may help reduce geographic differences in CVD morbidity and mortality in Korea. PMID- 29128330 TI - Decreased Serum Brain-Derived Neurotrophic Factor May Indicate the Development of Poststroke Depression in Patients with Acute Ischemic Stroke: A Meta-Analysis. AB - BACKGROUND: Depression is a common complication after stroke and has been associated with poor outcome. Thus, it is of great importance to identify potential biomarkers that can aid in predicting and detecting patients with stroke at high risk of poststroke depression (PSD) development. Previous studies showed that brain-derived neurotrophic factor (BDNF) had potential use as a biomarker for discriminating patients with stroke at high risk of PSD. However, the results were inconsistent. METHODS: A meta-analysis was performed to evaluate the correlation between the peripheral BDNF levels and the development of PSD in the acute stage of stroke. RESULTS: Data were obtained from 4 studies including 499 patients with stroke. Among them, 171 patients were diagnosed with PSD at follow-ups. Our results showed that patients with stroke who were predisposed to developing PSD had significantly lower serum BDNF concentrations at the early stage of stroke. CONCLUSIONS: This study suggests a potential association between circulating BDNF concentrations at admission and subsequent PSD development, and provides additional support for the involvement of BDNF in the PSD development. PMID- 29128332 TI - Research digest: hypoglycaemia and glucose variability. PMID- 29128331 TI - Risk Factors for Epilepsy Recurrence after Revascularization in Pediatric Patients with Moyamoya Disease. AB - OBJECTIVE: We aimed to explore the risk factors of seizure recurrence and the optimal surgical procedure for epileptic pediatric patients with moyamoya disease (MMD). METHODS: We reviewed 696 consecutive patients with MMD admitted to our hospital from 2009 to 2015. Pediatric patients with MMD who had seizures before revascularization were identified. We summarized the characteristics of seizures in pediatric patients with MMD and analyzed the predictive factors of recurrent seizure events. RESULTS: We identified 28 pediatric patients with MMD who had seizures before revascularization. During follow-up (median 42 months), 7 patients (25.0%) experienced recurrent seizures. In the multivariate analysis, the duration of epilepsy was an independent predictor for postoperative seizure recurrences (odds ratio 3.84, 95% confidence interval 1.54-24.34; P = .035). The 2 common surgical modalities of MMD (direct and indirect bypass) had no significant difference in future seizure prevention in pediatric patients with MMD with epilepsy. CONCLUSIONS: We identified the duration of epilepsy as an independent risk factor for recurrent seizure after revascularization in pediatric patients with MMD. PMID- 29128333 TI - NF-kappaB Dynamics Discriminate between TNF Doses in Single Cells. AB - Although cytokine-dependent dynamics of nuclear factor kappaB (NF-kappaB) are known to encode information that regulates cell fate decisions, it is unclear whether single-cell responses are switch-like or encode more information about cytokine dose. Here, we measure the dynamic subcellular localization of NF-kappaB in response to a range of tumor necrosis factor (TNF) stimulation conditions to determine the prevailing mechanism of single-cell dose discrimination. Using an information theory formalism that accounts for signaling dynamics and non responsive cell subpopulations, we find that the information transmission capacity of single cells exceeds that predicted from a switch-like response. Instead, we observe that NF-kappaB dynamics within single cells contain sufficient information to encode multiple, TNF-dependent cellular states, and have an activation threshold that varies across the population. By comparing single-cell responses to an internal, experimentally observed reference, we demonstrate that cells can grade responses to TNF across several orders of magnitude in concentration. This suggests that cells contain additional control points to fine-tune their cytokine responses beyond the decision to activate. PMID- 29128334 TI - A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-kappaB Signaling. AB - Mitochondrial protein (MP) dysfunction has been linked to neurodegenerative disorders (NDs); however, the discovery of the molecular mechanisms underlying NDs has been impeded by the limited characterization of interactions governing MP function. Here, using mass spectrometry (MS)-based analysis of 210 affinity purified mitochondrial (mt) fractions isolated from 27 epitope-tagged human ND linked MPs in HEK293 cells, we report a high-confidence MP network including 1,964 interactions among 772 proteins (>90% previously unreported). Nearly three fourths of these interactions were confirmed in mouse brain and multiple human differentiated neuronal cell lines by primary antibody immunoprecipitation and MS, with many linked to NDs and autism. We show that the SOD1-PRDX5 interaction, critical for mt redox homeostasis, can be perturbed by amyotrophic lateral sclerosis-linked SOD1 allelic variants and establish a functional role for ND linked factors coupled with IkappaBE in NF-kappaB activation. Our results identify mechanisms for ND-linked MPs and expand the human mt interaction landscape. PMID- 29128335 TI - Hereditary Angioedema with Normal C1 Inhibitor and F12 Mutations in 42 Brazilian Families. AB - BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent. OBJECTIVES: Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations. METHODS: We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives. RESULTS: Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms. CONCLUSIONS: Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH. PMID- 29128336 TI - The Value of Fractional Exhaled Nitric Oxide and Forced Mid-Expiratory Flow as Predictive Markers of Bronchial Hyperresponsiveness in Adults with Chronic Cough. AB - BACKGROUND: Bronchial provocation tests are standard for diagnosing the etiology of chronic cough, but they are time consuming and can induce severe bronchospasm. A safer and faster clinical examination to predict bronchial hyperresponsiveness (BHR) is needed. OBJECTIVE: The objective of this study was to investigate whether small-airway function tests can predict BHR in adult patients with chronic cough. METHODS: A retrospective, cross-sectional study of diagnoses made using spirometry and bronchial provocation test results was performed in 290 patients with chronic nonproductive cough. BHR-predictive values were analyzed via the area under receiver operating characteristic curves (AUCs). Optimal cutoff values were determined by maximizing the sum of sensitivity and specificity. RESULTS: Patients with chronic cough with BHR showed lower forced expiratory flow between 25% and 75% (FEF25%-75%), higher fractional exhaled nitric oxide (FENO), and a higher percentage of eosinophils in blood than patients without BHR (P < .0001 for all). The AUCs of FENO and FEF25%-75% for a BHR diagnosis were 0.788 (95% CI, 0.725-0.851) and 0.702 (95% CI, 0.641-0.763), respectively. Optimal cutoff values were 43 ppb for FENO and 78.5% for FEF25% 75%, with negative predictive values of 85.38% and 81.34%, respectively. The combined use of FENO and FEF25%-75% increased the AUC to 0.843 (95% CI, 0.794 0.892), significantly higher than either FENO (P = .012) or FEF25%-75% (P < .0001) alone. CONCLUSIONS: Small-airway dysfunction is present in patients with chronic cough and BHR. FEF25%-75% has value as a negative predictive parameter for BHR, especially when combined with FENO. FENO > 43 ppb and FEF25%-75% < 78.5% strongly predicted a positive bronchial provocation test. PMID- 29128337 TI - The Urticaria Activity Score-Validity, Reliability, and Responsiveness. AB - BACKGROUND: Chronic spontaneous urticaria is characterized by fluctuating symptoms. Its activity is assessed with the urticaria activity score (UAS). Two versions of the urticaria activity score used for 7 consecutive days (UAS7) are available: (1) The guideline-recommended UAS7, with once-daily documentation, and (2) the UAS7TD, with twice-daily documentation. OBJECTIVE: To better characterize both UAS7 versions with regard to their validity, reliability, sensitivity to change, minimal important difference (MID), and smallest detectable change (SDC). METHODS: One hundred thirty adult patients with chronic spontaneous urticaria completed both UAS7 versions, the Patients Global Assessment (PatGA) of disease activity, the Urticaria Control Test (UCT), the Chronic Urticaria Quality of Life Questionnaire, and the Dermatology Life Quality Index before and after the initiation of omalizumab therapy. Physicians completed a Physician Global Assessment of disease activity. RESULTS: The UAS7 and the UAS7TD showed high correlation with the activity anchor PatGA (r = 0.568, P < .001 and r = 0.605, P < .001) and the UCT (r = -0.580, P < .001 and r = -0.585, P < .001). The wheal and pruritus scores of the UAS7 and the UAS7TD exhibited respectable internal consistency and, in each UAS7 version, correlated well with each other (Cronbach alpha = 0.78, r = 0.640, P < .001, and Cronbach alpha = 0.77, r = 0.626, P < .001). Changes in the UAS7 and UAS7TD correlated well with PatGA changes (r = 639, P < .001, and r = .763, P < .001) and with UCT changes (r = -0.642, P < .001, and r = -0.703, P < .001). The MID was 11 for the UAS7 (SDC = 12) and 12 for the UAS7TD (SDC = 11). CONCLUSIONS: The UAS7 and UAS7TD show good and comparable clinimetric properties, including good sensitivity to change, and similar MIDs. PMID- 29128338 TI - Association between defective spleen function and primary eosinophilic gastrointestinal disorders. PMID- 29128339 TI - rs6923761 gene variant in glucagon-like peptide 1 receptor: Allelic frequencies and influence on cardiovascular risk factors in a multicenter study of Castilla Leon. AB - BACKGROUND: Some GLP-1 receptor studies have identified polymorphisms in the GLP 1 receptor gene that might be related to different cardiovascular risk factors. OBJECTIVE: Our aim was to investigate the allelic distribution of rs6923761 GLP-1 receptor polymorphism in a geographic area of Spain (Community of Castilla y Leon) and to evaluate the influence of this polymorphism on obesity anthropometric parameters and cardiovascular risk factors in the fasted state in obese patients. DESIGN: A sample of 341 obese subjects (body mass index >= 30 kg/m2) was analyzed. Fasting blood glucose, C-reactive protein (CRP), plasma insulin, insulin resistance (HOMA-IR), and lipid profile were determined. Anthropometric parameters, dietary intake and blood pressure were recorded. RESULTS: One hundred and forty three patients (42.0%) had the genotype GG (wild type group) and one hundred and ninety eight (58.0%) patients were A carriers: GA (164 patients, 48.1%) or AA (34 patients, 9.9%) (mutant-type group). Valladolid and Segovia health areas had the lowest percentage of wild type genotype and G allelic (than other Health Areas). Burgos Health Area had a higher percentage of wild-type genotype. In wild-type group (GG genotype), BMI (0.9 +/- 1.3 kg/m2; p < 0.05), weight (3.3 +/- 1.1 kg; p < 0.05), fat mass (2.5 +/- 1.1 kg; p < 0.05), waist to hip ratio (0.02 +/- 0.005 cm; p < 0.05), waist circumference (2.8 +/- 1.1 cm; p < 0.05), triglycerides (14.4 +/- 3.3 mg/dl; p < 0.05) insulin (3.1 +/- 1.0 mg/dl; p < 0.05) and HOMA-IR (1.2 +/- 0.9 mg/dl; p < 0.05) were higher than A allele carriers. In non A allele carriers, lower HDL cholesterol levels than A allele carriers (6.4 +/- 2.3 mg/dl; p < 0.05) were found. CONCLUSION: Data from our study revealed different allelic distribution in this geographic area, with better parameters (Body mass index, weight, fat mass, waist circumference, triglycerides, insulin, HOMA-IR and HDL cholesterol) in A allele carriers than in non A allele carriers. PMID- 29128340 TI - The interaction between a HSP-70 gene variant with dietary calories in determining serum markers of inflammation and cardiovascular risk. AB - BACKGROUND: The high prevalence of cardiovascular disease (CVD) globally is attributable to an interaction between environmental and genetic factors. Gene * diet interaction studies aim to explore how a modifiable factor interacts with genetic predispositions. Here we have explored the interaction of a heat shock protein (HSP70) gene polymorphism (+1267A > G) with dietary intake and their possible association with serum C-reactive protein (CRP), an inflammatory marker, that is a major component of CVD risk. METHODS: HSP70 genotype was determined using a TaqMan real time PCR based method.Dietary intake was assessed using a dietary questionnaire. Serum high sensitivity (Hs) CRP and other cardiovascular risk factors were assessed by routine methods. This included coronary angioplasty to determine the presence of coronary artery stenosis. RESULTS: There were significant differences between serum lipid profile and Hs-CRP across the genotypes for Hsp70. The carriers of G allele had higher serum hs-CRP concentrations, compared with the AA homozygotes, with the wild genotype. Interaction analysis showed the association was modulated by total energy intake; the interaction of high energy intake with GG genotype: RERI = 0.77, AP = 0.26, S = 1.6. CONCLUSION: We have found a significant association between the +1267A > G variant of the HSP70 gene with cardiovascular risk factors and serum hs-CRP concentrations. It is possible that a low energy diet could ameliorate the unfavorable effects of G allele of HSP70. PMID- 29128341 TI - Vitamin D and health care costs: Results from two independent population-based cohort studies. AB - BACKGROUND & AIMS: Vitamin D deficiency is associated with higher morbidity. However, there is few data regarding the effect of vitamin D deficiency on health care costs. This study examined the cross-sectional and longitudinal associations between the serum 25-hydroxy vitamin D concentration (25OHD) and direct health care costs and hospitalization in two independent samples of the general population in North-Eastern Germany. METHODS: We studied 7217 healthy individuals from the 'Study of Health in Pomerania' (SHIP n = 3203) and the 'Study of Health in Pomerania-Trend' (SHIP-Trend n = 4014) who had valid 25OHD measurements and provided data on annual total costs, outpatient costs, hospital stays, and inpatient costs. The associations between 25OHD concentrations (modelled continuously using factional polynomials) and health care costs were examined using a generalized linear model with gamma distribution and a log link. Poisson regression models were used to estimate relative risks of hospitalization. RESULTS: In cross-sectional analysis of SHIP-Trend, non-linear associations between the 25OHD concentration and inpatient costs and hospitalization were detected: participants with 25OHD concentrations of 5, 10 and 15 ng/ml had 226.1%, 51.5% and 14.1%, respectively, higher inpatient costs than those with 25OHD concentrations of 20 ng/ml (overall p-value = 0.001) in multivariable models. CONCLUSIONS: We found a relation between lower 25OHD concentrations and increased inpatient health care costs and hospitalization. Our results thus indicate an influence of vitamin D deficiency on health care costs in the general population. PMID- 29128342 TI - Readers of DNA methylation, the MBD family as potential therapeutic targets. AB - DNA methylation represents a fundamental epigenetic modification that regulates chromatin architecture and gene transcription. Many diseases, including cancer, show aberrant methylation patterns that contribute to the disease phenotype. DNA methylation inhibitors have been used to block methylation dependent gene silencing to treat hematopoietic neoplasms and to restore expression of developmentally silenced genes. However, these inhibitors disrupt methylation globally and show significant off-target toxicities. As an alternative approach, we have been studying readers of DNA methylation, the 5-methylcytosine binding domain family of proteins, as potential therapeutic targets to restore expression of aberrantly and developmentally methylated and silenced genes. In this review, we discuss the role of DNA methylation in gene regulation and cancer development, the structure and function of the 5-methylcytosine binding domain family of proteins, and the possibility of targeting the complexes these proteins form to treat human disease. PMID- 29128343 TI - Post-stroke depression: Mechanisms and pharmacological treatment. AB - Depression, the most frequent psychiatric disorder following ischaemic stroke, negatively affects survivals' functional outcome, response to rehabilitation and quality of life. Approximately, one-third of them are affected by post-stroke depression (PSD), making it a serious social and public health problem and anti depressant preventive and curative therapies worth investigating. However, a two way association between depression and stroke has been also established: stroke increases the risk of PSD, but depression is an independent risk factor for stroke. The pathophysiology of PSD is presumably multifactorial, involving a combination of various ischaemia-induced neurobiological dysfunctions in the context of psychosocial distress. The damage of frontal-basal ganglia brainstem pathway suggested alterations of monoaminergic neurotransmitter systems. Several lines of evidence point to a relationship between neuroinflammatory response to acute ischaemic stroke, stress activation of the hypothalamic-pituitary-adrenal (HPA) axis and the impairment of adaptive response (neurogenesis) within a background of altered energy metabolism (i.e. mitochondrial dysfunction). The complexity of PSD mechanisms makes its biologically-based prevention and treatment a difficult task. So far, especially the selective serotonin (5 hydroxytriptamine, 5-HT) reuptake inhibitors (SSRIs) have mainly proved to be clinically active in preventing and treating PSD, although their effects have not been demonstrated unequivocally and they may cause bleeding and intracerebral haemorrhage. Besides the primary pharmacological activity of SSRIs (i.e. the inhibition of neuronal 5-HT reuptake) there is evidence supporting their pleiotropic mechanisms of action: anti-inflammatory and enhanced neurogenesis through the up-regulation of neurotrophins, conceivably supported by the stimulation of mitochondrial energy metabolism. In the future, novel developments might point at anti-cytokine modulators which can improve symptoms of depression, especially in subjects affected by inflammation processes. This review will address the various areas of epidemiology, pathophysiology, preventive and therapeutic strategies for PSD. The activity of SSRIs in clinical trials, as well as their pharmacology, pharmacokinetics, safety and mechanisms of action, will be examined in detail. A final section will deal with the effect of depression as risk factor for stroke. The literature on PubMed from 1990 to 2017 was reviewed. PMID- 29128344 TI - Validity of Combining History Elements and Physical Examination Tests to Diagnose Patellofemoral Pain. AB - OBJECTIVE: To assess the validity of diagnostic clusters combining history elements and physical examination tests to diagnose or exclude patellofemoral pain (PFP). DESIGN: Prospective diagnostic study. SETTINGS: Orthopedic outpatient clinics, family medicine clinics, and community-dwelling. PARTICIPANTS: Consecutive patients (N=279) consulting one of the participating orthopedic surgeons (n=3) or sport medicine physicians (n=2) for any knee complaint. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: History elements and physical examination tests were obtained by a trained physiotherapist blinded to the reference standard: a composite diagnosis including both physical examination tests and imaging results interpretation performed by an expert physician. Penalized logistic regression (least absolute shrinkage and selection operator) was used to identify history elements and physical examination tests associated with the diagnosis of PFP, and recursive partitioning was used to develop diagnostic clusters. Diagnostic accuracy measures including sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios with associated 95% confidence intervals (CIs) were calculated. RESULTS: Two hundred seventy-nine participants were evaluated, and 75 had a diagnosis of PFP (26.9%). Different combinations of history elements and physical examination tests including the age of participants, knee pain location, difficulty descending stairs, patellar facet palpation, and passive knee extension range of motion were associated with a diagnosis of PFP and used in clusters to accurately discriminate between individuals with PFP and individuals without PFP. Two diagnostic clusters developed to confirm the presence of PFP yielded a positive likelihood ratio of 8.7 (95% CI, 5.2-14.6) and 3 clusters to exclude PFP yielded a negative likelihood ratio of .12 (95% CI, .06-.27). CONCLUSIONS: Diagnostic clusters combining common history elements and physical examination tests that can accurately diagnose or exclude PFP compared to various knee disorders were developed. External validation is required before clinical use. PMID- 29128345 TI - Infectious gastroenteritis and the need for strict contact precaution procedures in adults presenting to the emergency department: a Danish register-based study. AB - BACKGROUND: Acute infectious gastroenteritis requires contact precautions to prevent spread. On acute admission, the cause of diarrhoea is unknown, so the decision regarding which patients to isolate has to be made on clinical information with a risk of inexpedient use of contact precautions. AIM: To investigate how often gastroenteritis occurs (and therefore how often the need for isolation has to be assessed) in Danish emergency departments, and how often patients have to remain on contact precautions according to the results of faecal samples. METHODS: This Danish register-based retrospective cohort study on adults in Danish emergency departments used three data sources: discharge diagnoses from the Danish National Patient Register; microbiological results from faecal samples provided in the emergency department; and the causes of hospital admission based on the chief complaint. FINDINGS: Among 66,885 acute admissions, 4.3% of patients had at least one feature of gastroenteritis: admission with diarrhoea as the chief complaint (1.6%); microbiological examination of faecal sample (2.8%); and discharged with a diagnosis of gastroenteritis (1.7%). Nineteen percent of those who had a faecal sample tested were found to have norovirus or Clostridium difficile, and needed to remain on strict contact precautions. CONCLUSION: The initiation of contact precautions has to be assessed for 4.3% of all emergency department patients; 19% of the patients who had a faecal sample tested had highly contagious gastroenteritis and required strict contact precautions. Further studies are needed to develop tools to determine which patients to isolate. PMID- 29128347 TI - Routine use of PICO dressings may reduce overall groin wound complication rates following peripheral vascular surgery. AB - BACKGROUND: Approximately 19% of morbidity in peripheral vascular surgery is attributable to wound complications, which can result in delayed healing, and also arterial or graft infection leading to limb loss and even mortality in extreme cases. AIM: To determine whether groin wound complications were reduced following the routine introduction of PICO negative pressure wound therapy dressings in patients who underwent peripheral vascular surgery. METHODS: Patients who underwent peripheral vascular surgery from 2011 to 2016 were identified and divided into PICO and non-PICO groups. Patient, procedure and wound characteristics were tabulated and analysed. Patients were followed-up for at least six weeks postoperatively. Wound complication rates, infection confirmed by microbiology, and requirement for re-admission due to wound complications were noted. Basic cost analysis was performed. FINDINGS: In total, 151 patients were analysed (N = 73 PICO, N = 78 non-PICO). No difference in age (P = 0.862), body mass index (P = 0.673), diabetes (P = 0.339), pre-operative albumin (P = 0.196), use of drain (P = 0.343) and history of meticillin-resistant Staphylococcus aureus (P = 0.281) was observed between groups. The PICO group contained more smokers than the non-PICO group (45% vs 29%, P = 0.034). Wound complications were seen in 8% (N = 6) of the PICO group and 19% (N = 15) of the non-PICO group (P = 0.042). No significant difference in infection was found between the two groups (3% vs 6%, P = 0.249), but fewer seromas were observed when PICO dressings were used (1.4% vs 7.7%, P = 0.069). Haematoma (2.7% vs 3.8%, P = 0.531) and dehiscence rates (1.4% vs 1.3%, P = 0.735) were similar between the two groups. CONCLUSIONS: Routine use of PICO dressings is associated with a reduction in wound complication rates following peripheral vascular surgery, and is cost effective. PMID- 29128346 TI - Mortality risk factors among non-ICU patients with nosocomial vascular catheter related bloodstream infections: a prospective cohort study. AB - BACKGROUND: Vascular catheter-related bloodstream infections (CRBSIs) are highly preventable hospital-acquired infections and a major threat to patient safety. While there is significant information regarding CRBSI outcome among intensive care unit (ICU) patients, data regarding non-ICU patients are scarce. AIM: To determine the risk factors associated with 30-day mortality among non-ICU patients with nosocomial CRBSIs. METHODS: Prospective cohort study of non-ICU patients with nosocomial CRBSIs in a tertiary care centre between January 2004 and December 2014. The primary outcome was 30-day mortality, defined as death from any cause within 30 days of CRBSI. Follow-up was performed 30 days after CRBSI onset. Time until death was the dependent variable in Cox regression analysis. FINDINGS: In total, 546 cases of CRBSI were identified. The mean age of patients was 64.5 years [interquartile range (IQR) 55-75 years], 66% were male, and the mean Charlson score was 3.59 (IQR 2-5). Of the 546 cases, 58.4% resulted from central venous catheters and 41.6% from peripheral venous catheters. The causative agents were Gram-positive cocci (70.1% of cases), Gram-negative bacilli (31.1%) and Candida spp. (1%). Mortality within 30 days was 13.9%, with no significant changes over the study period. Independent risk factors for 30-day mortality were Charlson score >=4 [hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.19-2.73], Staphylococcus aureus infection (HR 2.67, 95% CI 1.61 4.43) and Candida spp. infection (HR 6.1, 95% CI 2.08-18.04). Age; area of admission; type, use and site of vascular catheter; and administration of appropriate empirical antibiotic treatment were not independent risk factors for 30-day mortality. CONCLUSION: Nosocomial CRBSIs outside ICUs are associated with high risk of mortality, particularly among patients with a higher Charlson score and bloodstream infections caused by Staphylococcus aureus and Candida spp. PMID- 29128348 TI - Pattern of Gram-negative bloodstream infections and their antibiotic susceptibility profiles in a neonatal intensive care unit. PMID- 29128349 TI - A strategic plan to identify key neurophysiological mechanisms and brain circuits in autism. AB - Autism and Autism Spectrum Disorder (ASD) cover a large variety of clinical profiles which share two main dimensions: social and communication impairment and repetitive behaviors or restricted interests, which are present during childhood. There is now no doubt that genetic factors are a major component in the etiology of autism but precise physiopathological pathways are still being investigated. Furthermore, developmental trajectories combined with compensatory mechanisms will lead to various clinical and neurophysiological profiles which together constitute this Autism Spectrum Disorder. To better understand the pathophysiology of autism, comprehension of key neurophysiological mechanisms and brain circuits underlying the different bioclinical profiles is thus crucial. To achieve this goal we propose a strategy which investigates different levels of information processing from sensory perception to complex cognitive processing, taking into account the complexity of the stimulus and whether it is social or non-social in nature. In order to identify different developmental trajectories and to take into account compensatory mechanisms, we further propose that such protocols should be carried out in individuals from childhood to adulthood representing a wide variety of clinical forms. PMID- 29128350 TI - Biomechanical behavior of adhesive cement layer and periodontal tissues on the restored teeth with zirconia RBFDPs using three-kinds of framework design: 3D FEA study. AB - PURPOSE: To investigate stress and strain concentrations on resin-bonded fixed dental prostheses (RBFDPs) frameworks of different design using finite element analysis. METHODS: A human dry skull was scanned and models were produced using three-dimensional printer. After abutment preparation, three frameworks, including a three-unit RBFDP, and two-unit cantilevered RBFDPs using #21 and #23 for the abutment tooth, were fabricated. Scanned data were subtracted to define boundary of each structure. Occlusal force (200N) was loaded at 45 degrees to long axis of the pontic. The distributions of shear stress and principal strain in the RBFDP models were measured to evaluate the risk for framework-debonding from the abutment teeth and the impact on periodontal tissue. RESULTS: The percentage voxels with shear stress >11MPa in adhesive cement layer of three-unit RBFDP using #21 and #23 were 4.16% and 2.25%, respectively; in two-unit cantilevered RBFDPs, it was 19.25% using #21, and 23.4% using #23. The maximum principal strain on periodontal ligaments in two-unit cantilevered RBFDPs using #21 was the largest, and smallest in the three-unit RBFDP. The maximum principal strain in framework was largest in the two-unit cantilevered RBFDP using #23, and smallest in the three-unit RBFDP. CONCLUSIONS: The risk for framework-debonding in three-unit RBFDPs was substantially lower than that in two-unit RBFDPs. In difficult cases with indication for three-unit RBFDPs, two-unit cantilever design using the canine would be more advantageous for preservation of periodontal tissue, while for risk of framework-debonding, the design using the central incisor would be more advantageous. PMID- 29128351 TI - Drosophila models of FOP provide mechanistic insight. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare bone disease characterized by episodic events of heterotopic ossification (HO). All cases of FOP have been attributed to mutations in the ACVR1 gene that render the encoded BMP type I ALK2 receptor hypersensitive, resulting in the activation of BMP signaling, at inappropriate times in inappropriate locations. The episodic or sporadic nature of HO associated with FOP rests with the occurrence of specific 'triggers' that push the hypersensitive ALK2-FOP receptor into full signaling mode. Identification of these triggers and their mechanism of action is critical for preventing HO and its devastating consequences in FOP patients. Models of FOP, generated in Drosophila, are shown to activate the highly conserved BMP signaling pathway in both Drosophila cell culture and in developing tissues in vivo. The most common FOP mutation, R206H, in ALK2 and its synonymous mutation, K262H, in the orthologous Drosophila receptor Sax, abolish the ability of wild type receptors to inhibit BMP ligand-induced signaling and lead to ubiquitous pathway activation in both cases but with important differences. When expressed in Drosophila, human ALK2R206H exhibits constitutive signaling. SaxK262H on the other hand can elicit excessive signaling similar to that observed for ALK2R206H in mammalian systems in vivo. For example, hyperactive signaling mediated by SaxK262H is triggered by an increase in ligand or in type II receptors. Interestingly, while the constitutive nature of ALK2R2026H in Drosophila requires activation by the type II receptor, it does not require its ligand binding domain. The differences exhibited by the two Drosophila FOP models enable a valuable comparative analysis poised to reveal critical regulatory mechanisms governing signaling output from these mutated receptors. Modifier screens using these Drosophila FOP models will be extremely valuable in identifying genes or compounds that reduce or prevent the hyperactive BMP signaling that initiates HO associated with FOP. PMID- 29128352 TI - Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion. AB - Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers. Nevertheless, no studies have so far investigated the relationship between SR-B1 and NB. Elucidation of receptors that promote NB may pave the way for discovery of new therapeutic targets. Here we show that inhibition of SR-B1 reduced cell survival, migration and invasion, and cholesterol content in NB cell lines. Additionally analysis of SR-B1 levels in NB patient biopsies using the R2: Genomics Analysis and Visualization Platform showed that high SR-B1 expression correlated with decreased overall and event-free survival. PMID- 29128353 TI - Pyruvate dehydrogenase kinase 4 mediates lipogenesis and contributes to the pathogenesis of nonalcoholic steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is a progressive disease and poses a high risk of severe liver damage. However, the pathogenesis of NASH is still unclear. Accumulation of lipid droplets and insulin resistance is the hallmark of NASH. Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) plays key role in glucose metabolism via regulating the activity of pyruvate dehydrogenase complex (PDC). Here, we demonstrated a novel of PDK4 in NASH by regulating hepatic steatosis and insulin signaling pathway in methionine and choline deficient (MCD) diet induced NASH model. Hepatic PDK4 levels were highly induced in human patients with NASH and MCD diet fed mice, as well as in hepatocytes treated with oleic acid. The glucose and lipid metabolism were impaired in Pdk4-/- mice. Pdk4 deficiency ameliorated the hepatic steatosis significantly in NASH mice. Pdk4-/--MCD mice had reduced liver weights and triglyceride (TG) levels. And Pdk4 deficiency dramatically reduced the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis. In addition, elevated phosphorylated AMPK (p AMPK), p-SAPK/JNK and diminished p-ERK, p-P38, p-Akt and p-mTOR/p-4EBP1 proteins were observed. In conclusion, our data indicated that PDK4 potentially contributes to the hepatic steatosis in NASH via regulating several signaling pathway and PDK4 may be a new therapeutic strategy against NAFLD. PMID- 29128354 TI - Angiotensin-converting enzyme 2 regulates mitochondrial function in pancreatic beta-cells. AB - Mitochondrial metabolism plays an essential role in the regulation of insulin release and glucose homeostasis. Evidence demonstrated that the angiotensin converting enzyme 2 (ACE2) participates in the regulation of glucose metabolism, however, its role in mitochondrial metabolism remains unclear. The purpose of our study was to determine if ACE2 can regulate mitochondrial function in pancreatic beta-cells. We found that ACE2 over-expression restored glucose-stimulated insulin secretion (GSIS) and mitochondrial membrane potential (MMP) in the presence of H2O2 in INS-1 cells. PCR array demonstrated that ACE2 over-expression up-regulated 67 mitochondria-related genes in INS-1 cells. In pancreatic islets, ACE2 ablation attenuated intracellular calcium influx with a decrease in GSIS. Ace2-/y mice islets exhibited impaired mitochondrial respiration and lower production of ATP, along with decreased expression of genes involved in mitochondrial oxidation. In islets from db/db mice, ACE2 over-expression increased intracellular calcium influx and restored impaired mitochondrial oxidation, potentially causing an increase in GSIS. These results shed light on the potential roles of ACE2 in mitochondrial metabolism, moreover, may improve our understanding of diabetes. PMID- 29128355 TI - Upregulation of eIF6 inhibits cardiac hypertrophy induced by phenylephrine. AB - Cardiac hypertrophy is determined by an increase of cell size in cardiomyocytes (CMCs). Among the cellular processes regulating the growth of cell size, the increase of protein synthesis rate represents a critical event. Most of translational factors promoting protein synthesis stimulate cardiac hypertrophy. In contrast, activity of translational repressor factors, in cardiac hypertrophy, is not fully determined yet. Here we report the effect of a translational modulator, eIF6/p27BBP in the hypertrophy of neonatal rat CMCs. The increase of eIF6 levels surprisingly prevent the growth of cell size induced by phenylephrine, through a block of protein synthesis without affecting skeletal rearrangement and ANF mRNA expression. Thus, this work uncovers a new translational cardiac regulator independent by other well-known factors such as mTOR signalling or eIF2beta. PMID- 29128356 TI - Secreted glycoprotein BmApoD1 plays a critical role in anti-oxidation and anti apoptosis in Bombyx mori. AB - Recent studies highlighted that apolipoprotein D (ApoD) and its homologs exert neuroprotective and antioxidant functions in mammals and Drosophila. Unlike mammals and Drosophila, lepidopteran insects possess three distinct ApoD homologs. However, few information on their functions in lepidopteran insects are available. In this study, we investigated the protective potential of a novel ApoD homolog, BmApoD1, in Bombyx mori. Quantitative PCR analyses demonstrated that BmApoD1 is extensively expressed at low levels during the larval stage but abundantly expressed in the testis during the pupal and adult stages. Tryptophan fluorescence titration demonstrated that recombinant BmApoD1 protein can bind retinoic acid and ergosterol. In addition, we provided evidence that N-linked glycans of BmApoD1 are essential to BmApoD1 secretion, and three residues, namely, Asp69, Asp104, and Asp196, are the glycosylation sites of BmApoD1. Furthermore, we showed that BmApoD1 is significantly up-regulated in the larvae after oxidant or starvation treatment. The recombinant BmApoD1 protein can protect cells from oxidative stress induced by H2O2 and reduce actinomycin D induced cell apoptosis. These observations, together with the transcriptional up regulation of BmApoD1 in several tissues upon oxidative insult, identify BmApoD1 as a potent antioxidant. Our results demonstrate that BmApoD1 is critical for metabolic adaptation of B. mori to environmental challenges. PMID- 29128357 TI - OsPRX2 contributes to stomatal closure and improves potassium deficiency tolerance in rice. AB - Peroxiredoxins (Prxs) which are thiol-based peroxidases have been implicated in the toxic reduction and intracellular concentration regulation of hydrogen peroxide. In Arabidopsis thaliana At2-CysPrxB (At5g06290) has been demonstrated to be essential in maintaining the water-water cycle for proper H2O2 scavenging. Although the mechanisms of 2-Cys Prxs have been extensively studied in Arabidopsis thaliana, the function of 2-Cys Prxs in rice is unclear. In this study, a rice homologue gene of At2-CysPrxB, OsPRX2 was investigated aiming to characterize the effect of 2-Cys Prxs on the K+-deficiency tolerance in rice. We found that OsPRX2 was localized in the chloroplast. Overexpressed OsPRX2 causes the stomatal closing and K+-deficiency tolerance increasing, while knockout of OsPRX2 lead to serious defects in leaves phenotype and the stomatal opening under the K+-deficiency tolerance. Detection of K+ accumulation, antioxidant activity of transgenic plants under the starvation of potassium, further confirmed that OsPRX2 is a potential target for engineering plants with improved potassium deficiency tolerance. PMID- 29128358 TI - Plant salt-tolerance mechanism: A review. AB - Almost all crops that are important to humans are sensitive to high salt concentration in the soil. The presence of salt in soil is one of the most significant abiotic stresses in farming. Therefore, improving plant salt tolerance and increasing the yield and quality of crops in salty land is vital. Transgenic technology is a fast and effective method to obtain salt-tolerant varieties. At present, many scholars have studied salt damage to plant and plant salt-tolerance mechanism. These scholars have cloned a number of salt-related genes and achieved high salt tolerance for transgenic plants, thereby showing attractive prospects. In this paper, the salt-tolerance mechanism of plants is described from four aspects: plant osmotic stress, ion toxicity, oxidative stress, and salt tolerance genes. This review may help in studies to reveal the mechanism of plant salt tolerance, screen high efficiency and quality salt tolerance crops. PMID- 29128359 TI - Ubiquitin C-terminal hydrolase-L1 plays a key role in angiogenesis by regulating hydrogen peroxide generated by NADPH oxidase 4. AB - Ubiquitin C-terminal hydrolase-L1 (UCH-L1), which catalyzes the hydrolysis of ubiquitin esters and amides, is highly expressed in brain. Recently, UCH-L1 has been found to increase cancer cell migration and invasion by modulating hydrogen peroxide generated by NADPH oxidase 4 (NOX4). Because angiogenesis is also mediated by hydrogen peroxide, we explored the role of UCH-L1 in angiogenesis in human umbilical vein endothelial cells (HUVECs). Silencing UCH-L1 suppressed tubule formation in HUVECs, indicating that UCH-L1 promotes angiogenesis in vitro. This was confirmed using in vivo Matrigel plug studies of HUVECs, after overexpressing or silencing UCH-L1. Silencing UCH-L1 significantly suppressed VEGF-induced ROS levels as well as activation of VEGFR, both of which are required for angiogenesis. This study also showed that UCH-L1 promotes angiogenesis of HUVECs, as well as invasion in cancer cells, by up-regulating ROS by deubiquitination of NOX4, suggesting that UCH-L1 plays a key role in angiogenesis of HUVECS by regulating ROS levels by deubiquitination of NOX4. PMID- 29128360 TI - GOLGA2 loss causes fibrosis with autophagy in the mouse lung and liver. AB - Autophagy is a biological recycling process via the self-digestion of organelles, proteins, and lipids for energy-consuming differentiation and homeostasis. The Golgi serves as a donor of the double-membraned phagophore for autophagosome assembly. In addition, recent studies have demonstrated that pulmonary and hepatic fibrosis is accompanied by autophagy. However, the relationships among Golgi function, autophagy, and fibrosis are unclear. Here, we show that the deletion of GOLGA2, encoding a cis-Golgi protein, induces autophagy with Golgi disruption. The induction of autophagy leads to fibrosis along with the reduction of subcellular lipid storage (lipid droplets and lamellar bodies) by autophagy in the lung and liver. GOLGA2 knockout mice clearly demonstrated fibrosis features such as autophagy-activated cells, densely packed hepatocytes, increase of alveolar macrophages, and decrease of alveolar surfactant lipids (dipalmitoylphosphatidylcholine). Therefore, we confirmed the associations among Golgi function, fibrosis, and autophagy. Moreover, GOLGA2 knockout mice may be a potentially valuable animal model for studying autophagy-induced fibrosis. PMID- 29128361 TI - Involvement of mitochondrial fission in calcium sensing receptor-mediated vascular smooth muscle cells proliferation during hypertension. AB - Hyperproliferation of vascular smooth muscle cells (VSMC) is a major risk factor for cardiovascular diseases. Proper mitochondrial fission and fusion is involved with VSMC function. However, the role and mechanism of mitochondrial morphological changes in VSMC proliferation are not well understood. Here, we found that calcium sensing receptor (CaSR) was increased in the aortas from spontaneous hypertensive rats (SHRs) compared with age-matched Wistar Kyoto (WKY) rats. There was also an increase in mitochondrial fission and VSMC proliferation, which was attenuated by Calhex231. In primary rat VMSC, angiotensin II (Ang II) stimulation induced cytosolic [Ca2+]i increase, mitochondrial shortening and proliferation, all of which could be attenuated by pretreatment with mitochondrial division inhibitor-1 (Mdivi-1) and Calhex231. Our data indicate that CaSR-mediated mitochondrial fission could be a therapeutic target for hyperproliferative disorders. PMID- 29128362 TI - SENP1 attenuates the liver fibrosis through down-regulating the expression of SMAD2. AB - To investigate whether SENP1 could play a regulating role in the liver fibrosis process, the Sprague-Dawley (SD) rats were used to establish the liver fibrosis rat models by intraperitoneally injecting with 1 ml/kg of 10% CCl4, while the control normal rats were injected with olive oil. Then confirmation experiments to verify the successful establishment of these models were conducted by detecting the cellular and lobular architecture, and liver function indexes using hematoxylin-eosin staining, Masson's trichrome staining and microplate method, respectively. In addition, the expression levels of fibrosis markers including collagen I, collagen III, alpha-SMA and TGF-beta1 were inspected using quantitative real-time PCR (qRT-PCR), as well as SMAD2. Subsequently, the relative mRNA and protein level of SENP1 was also determined via qRT-PCR and western blot analysis. Next, the HSC-T6 cells of SENP1 knock-down were constructed and used to test the relative protein expression levels of alpha-SMA and SMAD2 in these cells. The results of hematoxylin-eosin staining, Masson's trichrome staining and microplate method turned out that the rat liver fibrosis models were constructed successfully, which was further confirmed by the increased expression of collagen I, collagen III, alpha-SMA and TGF-beta1 in mRNA and protein level, as well as SMAD2. Then the expression of SENP1 was overexpressed in the rat liver fibrosis models induced by CCl4 and the TGF-beta1 treatment could increase the protein expression level of collagen I, collagen III and alpha-SMA. Lastly, the SENP1 knockdown HSC-T6 cells were successfully constructed, while the silence of SENP1 down-regulated the protein expression of alpha-SMA and SMAD2. In conclusion, this study provided a new regulation mechanism about the liver fibrosis process. PMID- 29128363 TI - GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis. AB - Guanylate binding proteins (GBPs) are interferon-inducible large GTPases and play a crucial role in cell-autonomous immunity. However, the biology function of GBPs in cancer remains elusive. GBP3 is specifically expressed in adult brain. Here we show that GBP3 is highly elevated in human glioma tumors and glioma cell lines. Overexpression of GBP3 dramatically increased glioma cell proliferation whereas silencing GBP3 by RNA interference produced opposite effects. We further showed that GBP3 expression was able to induce sequestosome-1(SQSTM1, also named p62) expression and activate extracellular signal-regulated kinase (ERK1/2). The SQSTM1-ERK1/2 signaling cascade was essential for GBP3-promoted cell growth because depletion of SQSTM1 markedly reduced the phosphorylated ERK1/2 levels and GBP3-mediated cell growth, and inhibition of mitogen-activated protein kinase/ERK kinase abolished GBP3-induced glioma cell proliferation. Consistently, GBP3 overexpression significantly promoted glioma tumor growth in vivo and its expression was inversely correlated with the survival rate of glioma patients. Taken together, these results for the first time suggest that GBP3 contributes to the proliferation of glioma cells via regulating SQSTM1-ERK1/2 pathway, and GBP3 might represent as a new potential therapeutic target against glioma. PMID- 29128365 TI - Antiplatelet Strategies in Patients Undergoing Transcatheter Aortic Valve Implantation-Data Sharing Is Caring. PMID- 29128364 TI - One Versus 2-stent Strategy for the Treatment of Bifurcation Lesions in the Context of a Coronary Chronic Total Occlusion. A Multicenter Registry. AB - INTRODUCTION AND OBJECTIVES: There is little evidence on the optimal strategy for bifurcation lesions in the context of a coronary chronic total occlusion (CTO). This study compared the procedural and mid-term outcomes of patients with bifurcation lesions in CTO treated with provisional stenting vs 2-stent techniques in a multicenter registry. METHODS: Between January 2012 and June 2016, 922 CTO were recanalized at the 4 participating centers. Of these, 238 (25.8%) with a bifurcation lesion (side branch >= 2mm located proximally, distally, or within the occluded segment) were treated by a simple approach (n=201) or complex strategy (n=37). Propensity score matching was performed to account for selection bias between the 2 groups. Major adverse cardiac events (MACE) consisted of a composite of cardiac death, myocardial infarction, and clinically-driven target lesion revascularization. RESULTS: Angiographic and procedural success were similar in the simple and complex groups (94.5% vs 97.3%; P=.48 and 85.6% vs 81.1%; P=.49). However, contrast volume, radiation dose, and fluoroscopy time were lower with the simple approach. At follow-up (25 months), the MACE rate was 8% in the simple and 10.8% in the complex group (P=.58). There was a trend toward a lower MACE-free survival in the complex group (80.1% vs 69.8%; P=.08). After propensity analysis, there were no differences between the groups regarding immediate and follow-up results. CONCLUSIONS: Bifurcation lesions in CTO can be approached similarly to regular bifurcation lesions, for which provisional stenting is considered the technique of choice. After propensity score matching, there were no differences in procedural or mid-term clinical outcomes between the simple and complex strategies. PMID- 29128366 TI - Vaccarin protects human microvascular endothelial cells from apoptosis via attenuation of HDAC1 and oxidative stress. AB - Vaccarin (VAC), an active flavonoid glycoside from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protective effects. Histone deacetylase1 (HDAC1) is an epigenetic regulator in cellular apoptosis. In this study, we evaluated the protective effects of VAC on high glucose (HG)-induced cell apoptosis in human microvascular endothelial cells (HMEC-1). The levels of reactive oxygen species, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were measured. Expressions of HDAC1, Bax, Bcl-2, caspase-3 and cleaved caspase-3 were detected with western blot. Flow cytometry was used to determine cell apoptosis and cell cycle. We found that HG treatment decreased cell vitality, upregulated HDAC1 protein level, promoted reactive oxygen species production, induced cell cycle arrest and cell apoptosis in HMEC-1 cells, which were all rectified by VAC. Both scavenging reactive oxygen species and inhibition of HDAC1 alleviated the apoptosis of HMEC-1 cells in response to HG. Pretreatment with VAC prevented HG stimulated reactive oxygen species generation and HDAC1 expression in HMEC-1 cells. Taken together, these data suggested that VAC protected against HG-induced endothelial cell apoptosis via inhibition of reactive oxygen species accumulation and HDAC1 expression. VAC may be a potential therapeutic agent for treatment of diabetes mellitus (DM)-related endothelial dysfunction. PMID- 29128367 TI - NEMO Links Nuclear Factor-kappaB to Human Diseases. AB - The nuclear factor (NF)-kappaB essential modulator (NEMO) is a key regulator in NF-kappaB-mediated signaling. By transmitting extracellular or intracellular signals, NEMO can control NF-kappaB-regulated genes. NEMO dysfunction is associated with inherited diseases such as incontinentia pigmenti (IP), ectodermal dysplasia, anhidrotic, with immunodeficiency (EDA-ID), and some cancers. We focus on molecular studies, human case reports, and mouse models emphasizing the significance of NEMO molecular interactions and modifications in health and diseases. This knowledge opens new opportunities to engineer suitable drugs that may putatively target precise NEMO functions attributable to various diseases, while leaving other functions intact, and eliminating cytotoxicity. Indeed, with the advent of novel gene editing tools such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9, treating some inherited diseases may in the long run, become a reality. PMID- 29128368 TI - A look into centrosome abnormalities in colon cancer cells, how they arise and how they might be targeted therapeutically. AB - Cancer cells have long been noted for alterations in centrosome structure, number, and function. Colorectal cancers are interesting in this regard since two frequently mutated genes, APC and CTNNB1 (beta-catenin), encode proteins that directly interact with the centrosome and affect its ability to direct microtubule growth and establish cell polarity. Colorectal cancers also frequently display centrosome over-duplication and clustering. Efforts have been directed toward understanding how supernumerary centrosomes cluster and whether disrupting this clustering may be a way to induce aberrant/lethal mitoses of cancer cells. Given the important role of the centrosome in establishing spindle polarity and regulating some apoptotic signaling pathways, other approaches to centrosome targeting may be fruitful as well. Basic information on the nature and extent of centrosome defects in colorectal cancer, including why they over duplicate and whether this over-duplication compensates for their functional defects, could provide a framework for the development of novel approaches for the therapeutic targeting of colorectal cancer. PMID- 29128369 TI - Inhibition of poly(ADP-ribose) polymerase-1 alters expression of mitochondria related genes in PC12 cells: relevance to mitochondrial homeostasis in neurodegenerative disorders. AB - Alzheimer's disease (AD) is characterized by the release of amyloid beta peptides (Abeta) in the form of monomers/oligomers which may lead to oxidative stress, mitochondria dysfunction, synaptic loss, neuroinflammation and, in consequence, to overactivation of poly(ADP-ribose) polymerase-1 (PARP-1). However, Abeta peptides are also released in the brain ischemia, traumatic injury and in inflammatory response. PARP-1 is suggested to be a promising target in therapy of neurodegenerative disorders. We investigated the impact of PARP-1 inhibition on transcription of mitochondria-related genes in PC12 cells. Moreover, the effect of PARP-1 inhibitor (PJ34) on cells subjected to Abeta oligomers (AbetaO) - evoked stress was analyzed. Our data demonstrated that inhibition of PARP-1 in PC12 cells enhanced the transcription of genes for antioxidative enzymes (Sod1, Gpx1, Gpx4), activated genes regulating mitochondrial fission/fusion (Mfn1, Mfn2, Dnm1l, Opa1, Fis1), subunits of ETC complexes (mt-Nd1, Sdha, mt-Cytb) and modulated expression of several TFs, enhanced Foxo1 and decreased Nrf1, Stat6, Nfkb1. AbetaO elevated free radicals concentration, decreased mitochondria membrane potential (MMP) and cell viability after 24h. Gene transcription was not affected by AbetaO after 24h, but was significantly downregulated after 96h. In AbetaO stress, PJ34 exerted stimulatory effect on expression of several genes (Gpx1, Gpx4, Opa1, Mfn2, Fis1 and Sdha), decreased transcription of numerous TFs (Nrf1, Tfam, Stat3, Stat6, Trp53, Nfkb1) and prevented oxidative stress. Our results indicated that PARP-1 inhibition significantly enhanced transcription of genes involved in antioxidative defense and in regulation of mitochondria function, but was not able to ameliorate cells viability affected by Abeta. PMID- 29128370 TI - The inhibition of sphingomyelin synthase 1 activity induces collecting duct cells to lose their epithelial phenotype. AB - Epithelial tissue requires that cells attach to each other and to the extracellular matrix by the assembly of adherens junctions (AJ) and focal adhesions (FA) respectively. We have previously shown that, in renal papillary collecting duct (CD) cells, both AJ and FA are located in sphingomyelin (SM) enriched plasma membrane microdomains. In the present work, we investigated the involvement of SM metabolism in the preservation of the epithelial cell phenotype and tissue organization. To this end, primary cultures of renal papillary CD cells were performed. Cultured cells preserved the fully differentiated epithelial phenotype as reflected by the presence of primary cilia. Cells were then incubated for 24h with increasing concentrations of D609, a SM synthase (SMS) inhibitor. Knock-down experiments silencing SMS 1 and 2 were also performed. By combining biochemical and immunofluorescence studies, we found experimental evidences suggesting that, in CD cells, SMS 1 activity is essential for the preservation of cell-cell adhesion structures and therefore for the maintenance of CD tissue/tubular organization. The inhibition of SMS 1 activity induced CD cells to lose their epithelial phenotype and to undergo an epithelial mesenchymal transition (EMT) process. PMID- 29128371 TI - Assessments of neurocognitive and behavioral function in the mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders in which accumulation of glycosaminoglycans (GAGs) leads to progressive tissue and organ dysfunction. In addition to a variety of somatic signs and symptoms, patients with rapidly progressing MPS I (Hurler), II, III, and VII can present with significant neurological manifestations, including impaired cognitive abilities, difficulties in language and speech, behavioral abnormalities, sleep problems, and/or seizures. Neurological symptoms have a substantial impact on the quality of life of MPS patients and their families. Due to the progressive nature of cognitive impairment in these MPS patients, neurocognitive function is a sensitive indicator of disease progression, and a relevant outcome when testing efficacy of therapies for these disorders. In order to effectively manage and develop therapies that address neurological manifestations of MPS, it is important to use appropriate neurocognitive assessment tools that are sensitive to changes in neurocognitive function in MPS patients. This review discusses expert opinions on key issues and considerations for effective neurocognitive testing in MPS patients. In addition, it describes the neurocognitive assessment tools that have been used in clinical practice for these patients. The content of this review is based on existing literature and information from a meeting of international experts with extensive experience in managing and treating MPS disorders. PMID- 29128372 TI - Six-week retention after postplacental copper intrauterine device placement. AB - OBJECTIVES: We sought to evaluate the 6-week clinical outcomes (intrauterine device [IUD] retention, recognized expulsions, ability to visualize or palpate strings, and need for ultrasound evaluation) in women who received a TCu380A postplacental IUD (PPIUD) after vaginal (VD) or cesarean delivery (CD). STUDY DESIGN: We conducted a retrospective cohort study to examine the 6-week retention of TCu380A IUDs placed within 10 min of placental delivery in VD (n=137) and CD (n=73). We used Student's t test and Wilcoxon rank sum tests for continuous data and Pearson chi2 test and Fisher's Exact Test for categorical data. RESULTS: Of the 169 women who had follow-up, 151 (89.3%) retained their IUD at 6 weeks (95% CI 84.7%-93.9%). All women who underwent CD retained their IUD at 6 weeks postpartum (56/56), whereas 95/113 (84% [95% CI 76.0%-90.3%]) who underwent VD retained their original IUD (p<.01). Strings were detected more frequently in women who had a VD (93.1% [95% CI 85.6-97.4]) compared to those who delivered by CD (44.2% [95% CI 30.5-58.7]; p<.01). Women who underwent CD had an ultrasound to evaluate IUD location more frequently (42.9% [95% CI 29.7-56.8]) compared to women who underwent VD (13.7% [95% CI 7.5-22.3]; p<.01). CONCLUSION: Women are more likely to retain a PPIUD after CD compared to a VD (p<.01); however, women who have a PPIUD placed after CD are more likely to have nonvisible strings with a pelvic exam (p<.01) and undergo pelvic ultrasound evaluation (p<.01) compared to a PPIUD placed at the time of a VD. PMID- 29128373 TI - Regulation of the AcrAB-TolC efflux pump in Enterobacteriaceae. AB - Bacterial multidrug efflux systems are a major mechanism of antimicrobial resistance and are fundamental to the physiology of Gram-negative bacteria. The resistance-nodulation-division (RND) family of efflux pumps is the most clinically significant, as it is associated with multidrug resistance. Expression of efflux systems is subject to multiple levels of regulation, involving local and global transcriptional regulation as well as post-transcriptional and post translational regulation. The best-characterised RND system is AcrAB-TolC, which is present in Enterobacteriaceae. This review describes the current knowledge and new data about the regulation of the acrAB and tolC genes in Escherichia coli and Salmonella enterica. PMID- 29128374 TI - Agreement between patient-based and clinician-based assessment of the shoulder. AB - BACKGROUND: Patient home-based self-assessments after shoulder surgery have the potential to aid clinicians in reducing clinic time and decreasing follow-up requirements. The purpose of this systematic review was to determine the correlation between patient-based and physician-assessed outcome measures for range of motion (ROM), strength, and shoulder function. METHODS: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. MEDLINE, Embase, CINAHL, and Cochrane Central Register of Controlled Trials databases were searched. All studies comparing patient-reported and clinician-based assessments of shoulder ROM, strength, and function were eligible for inclusion. Studies that included patient or clinician assessment only, description of shoulder diseases or treatments only, and animal- or cadaveric-based studies were excluded. More than 250 abstracts were searched, and 4 studies were found eligible. RESULTS: Patients assessed their shoulder ROM, strength, and function with moderate-to-high accuracy compared with clinical assessment. There was less agreement between patients and clinicians regarding the symptomatic shoulder compared with the contralateral shoulder. There was less agreement between patients and clinicians on rotation than forward elevation. Patients who were less satisfied with their shoulder had less agreement with clinicians. CONCLUSION: There is moderate-to-high agreement between patients and clinicians in the assessment of the shoulder after surgery. Methods of assessment of rotation could be reviewed to create a more exact self-assessment tool. PMID- 29128376 TI - Radial head replacement with a bipolar system: an average 10-year follow-up. AB - BACKGROUND: We report the long-term results of a cohort of patients after radial head replacement with a bipolar design and a smooth cementless stem at a mean follow-up of 10.4 years. METHODS: Of 17 possible patients from a previous minimum 2-year follow-up study, 16 were available for review. Patients were assessed using clinical and radiographic examination and with standardized outcome measures. Range of motion, stability, and radiographic evaluation of implant loosening and joint degeneration were assessed. Comparisons were performed using the Wilcoxon signed rank test for unequal groups. RESULTS: The average follow-up was 10.5 years (range, 8.5-12 years). The median visual analog scale was 1 (range, 0-5), Minnesota Elbow Performance Index was 93 (range, 70-100), and the Disabilities of the Arm, Shoulder and Hand was 7.5 (range, 0-53). Range of motion was decreased on the operative side compared with the nonoperative side for flexion/extension (P = .005) and pronation/supination (P = .015). Grip strength was decreased on the affected side (P = .045). No patients had elbow instability. Significant arthritic changes developed in 2 patients at the ulnohumeral joint. The median cantilever quotient was 0.4 (range, 0.30-0.50). Osteolysis in zones 1 to 7 was found in all but 2 patients. The median stem radiolucency was 0.5 mm (range, 0.2-0.9 mm). No reoperations occurred since our previous report. Implant survival in this cohort was 97%. CONCLUSION: Bipolar radial head prosthesis with a smooth cementless stem effectively restores elbow stability and function after comminuted radial head fractures with or without concomitant elbow instability. Our study demonstrates excellent long-term implant survival. PMID- 29128375 TI - Is the pectoralis major tendon a reliable reference for restoration of humeral length with fracture hemiarthroplasty? AB - BACKGROUND: The primary objective was to calculate and to apply the numeric value of the distance from the pectoralis major tendon insertion to the superior aspect of the humeral head (PMTD) without any radiation exposure or equipment through basic data such as age, sex, height, and weight of Asian populations. METHODS: We analyzed shoulder magnetic resonance images of 260 patients (107 men and 153 women; average age, 59.8 years). The superior border of the pectoralis major was identified on the transverse section and cross-referenced with the coronal section. Measurements were made inferiorly from the corresponding transverse section to the top of the humeral head superiorly in coronal view. Correlation analysis was performed between variables including the patient's age, sex, height, weight, and body mass index and the PMTD by multiple linear regression analysis. RESULTS: The mean PMTD was 52 mm, with an average of 55 mm for men and 49 mm for women. Sex and height were significantly correlated with PMTD. The PMTD increased to a consistent level proportionally to height, and the difference in PMTD between men and women was 3.45 mm. An equation to estimate PMTD using these findings is as follows: PMTD (in mm) = 23 + (height [cm] * 0.17) + 3.45 (the last number is added for men). This equation had a prediction error of 0.3 mm. CONCLUSION: Our study demonstrated that PMTD is a useful and reliable reference for optimal humeral height during hemiarthroplasty for proximal humerus fractures in Asian populations. PMID- 29128377 TI - Viral hemorrhagic fever in the tropics: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. AB - Viral hemorrhagic fevers (VHFs) are a group of illnesses caused by four families of viruses namely Arenaviruses, Filoviruses, Bunyaviruses, and Flaviviruses. Humans are not the natural reservoir for any of these organisms and acquire the disease through vectors from animal reservoirs. In some conditions human to human transmission is possible increasing the risk to healthy individuals in the vicinity, more so to Health Care Workers (HCW). The pathogenesis of VHF, though poorly understood, varies according to the viruses involved. The resultant microvascular damage leads to increased vascular permeability, organ dysfunction and even death. The management is generally supportive but antiviral agents are of benefit in certain circumstances. PMID- 29128378 TI - Ebola virus disease: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. AB - Ebola virus is a filovirus that can cause fatal hemorrhagic fever (HF) and five distinct species exist that vary in terms of geographical distribution and virulence. Once the more virulent forms enter the human population, transmission occurs primarily through direct contact with infected body fluids and may result in significant outbreaks. The devastating has been the recent West African outbreak. Clinically, signs and symptoms are similar to those of the other VHFs [4]. The incubation period is 2-21days, followed by fever, headache, myalgia, diarrhoea, vomiting and dehydration; thereafter, there may be recovery or deterioration with collapse, neurological manifestations and bleeding, that can lead to a fatal outcome. Elevated hepatic transaminases is common and severe hepatitis is more common in fatal cases and frequently there is associated fluid depletion. Real time reverse transcription-PCR (RT-PCR) techniques on blood specimens are the gold standard for diagnosis [6]. Management is discussed and is essentially supportive with strict attention to infection control and prevention. None of the pharmacological interventions have shown conclusive benefit and future management of epidemics should centre around prevention and containment, specifically isolation, hygiene, and vaccination. PMID- 29128379 TI - Active SMS-based influenza vaccine safety surveillance in Australian children. AB - INTRODUCTION: Australia's novel, active surveillance system, AusVaxSafety, monitors the post-market safety of vaccines in near real time. We analysed cumulative surveillance data for children aged 6 months to 4 years who received seasonal influenza vaccine in 2015 and/or 2016 to determine: adverse event following immunisation (AEFI) rates by vaccine brand, age and concomitant vaccine administration. METHODS: Parent/carer reports of AEFI occurring within 3 days of their child receiving an influenza vaccine in sentinel immunisation clinics were solicited by Short Message Service (SMS) and/or email-based survey. Retrospective data from 2 years were combined to examine specific AEFI rates, particularly fever and medical attendance as a proxy for serious adverse events (SAE), with and without concomitant vaccine administration. As trivalent influenza vaccines (TIV) were funded in Australia's National Immunisation Program (NIP) in 2015 and quadrivalent (QIV) in 2016, respectively, we compared their safety profiles. RESULTS: 7402 children were included. Data were reported weekly through each vaccination season; no safety signals or excess of adverse events were detected. More children who received a concomitant vaccine had fever (7.5% versus 2.8%; p < .001). Meningococcal B vaccine was associated with the highest increase in AEFI rates among children receiving a specified concomitant vaccine: 30.3% reported an AEFI compared with 7.3% who received an influenza vaccine alone (p < .001). Reported fever was strongly associated with medical attendance (OR: 42.6; 95% Confidence Interval (CI): 25.6-71.0). TIV and QIV safety profiles included low and expected AEFI rates (fever: 4.3% for TIV compared with 3.2% for QIV (p = .015); injection site reaction: 1.9% for TIV compared with 3.0% for QIV (p < .001)). There was no difference in safety profile between brands. DISCUSSION: Active participant-reported data provided timely vaccine brand-specific safety information. Our surveillance system has particular utility in monitoring the safety of influenza vaccines, given that they may vary in composition annually. PMID- 29128380 TI - Low influenza vaccine effectiveness and the effect of previous vaccination in preventing admission with A(H1N1)pdm09 or B/Victoria-Lineage in patients 60 years old or older during the 2015/2016 influenza season. AB - BACKGROUND: The 2015/2016 influenza season was characterized in Europe by the circulation of A(H1N1)pdm09 clade 6B.1 and B/Victoria-lineage influenza viruses. The components of the vaccines used in the current and past two seasons in the Valencia region were similar but not well matched to the 2015/2016 dominant influenza-circulating strains. We estimate influenza vaccine effectiveness (IVE) and interference of previous vaccination in preventing admission with A(H1N1)pdm09 or B/Victoria-lineage in this particular season. METHODS: The Valencia Hospital Network for the Study of Influenza runs an active surveillance hospital-based study to collect clinical and virological data from consecutive admissions possibly related to influenza. Combined nasopharyngeal and pharyngeal swabs are analyzed by reverse transcription polymerase chain reaction, and the hemagglutinin is sequenced in a sample of positive influenza specimens. Vaccination is ascertained consulting a population vaccine information system. We estimate IVE using a test-negative approach. RESULTS: During the 2015-2016 season, we recruited 1049 eligible admissions of patients 60 years or older, and 187 tested positive for influenza. The adjusted IVE in preventing admission with A(H1N1)pdm09 was 20.2%; 95% confidence interval (CI) -21.3-47.5% and -33.2%; 95% CI, -140.1-26.1% in preventing admission with B/Victoria-lineage. The majority of A(H1N1)pdm09 sequenced viruses belonged to the emerging 6B.1 subclade, defined by S162N and I216T mutations in the hemagglutinin protein. When we restricted our analysis to those not vaccinated in the previous year, unadjusted IVE was 84.9% (95% CI 9.9-100.0) overall, 77.9% (-32.7-100.0%) in preventing A(H1N1)pdm09 and 48.8% (-219.5-100.0%) in preventing B/Yamagata-lineage admission. CONCLUSIONS: Our findings indicate that IVE was low in preventing A(H1N1)pdm09 and strongly correlated with vaccination in the previous season. No effect in preventing admission with B/Victoria-lineage was observed. For the 2015/2016 season, IVE was low due to a mismatch and lack of concordance between the circulating and vaccine viruses. PMID- 29128381 TI - Early impact of rotavirus vaccination in children less than five years of age in Mozambique. AB - BACKGROUND: Mozambique introduced rotavirus vaccine (Rotarix, GSK Biologicals) in the National Immunization Program in September 2015 with the objective of reducing the burden of total diarrheal disease and specifically severe rotavirus disease. This study aimed to evaluate the early impact of rotavirus vaccine in reducing all-cause diarrhea and rotavirus-specific hospitalizations. METHODS: We analysed stool specimens collected from children under five years old, between January 2014 and June 2017 within the National Surveillance for Acute Diarrhea. We compared annual changes in rotavirus positivity, median age of children hospitalized for rotavirus and the number of all-cause for diarrheal hospitalizations. Rotavirus detection was performed using enzyme immunoassay. RESULTS: During this period, 1296 samples were collected and analyzed. Rotavirus positivity before vaccine introduction was 40.2% (39/97) in 2014 and 38.3% (225/588) in 2015, then after vaccine introduction reduced to 12.2% and 13.5% in 2016 and 2017, respectively. The median age of children hospitalized for rotavirus was 9 and 11 months in 2014 and 2015 and 10 months in 2016 and 2017. Rotavirus hospitalizations exhibited a seasonal peak prior to vaccine introduction, between June and September in 2014 and 2015, coinciding with winter period in Mozambique. After vaccine introduction, the peak was delayed until August to December in 2016 and was substantially diminished. There was a reduction in all-cause acute diarrhea hospitalizations in children aged 0-11 months after vaccine introduction. CONCLUSION: We observed a reduction in rotavirus positivity and in the number of all-cause diarrhea hospitalizations after vaccine introduction. The data suggest rotavirus vaccine is having a positive impact on the control of rotavirus diarrheal disease in Mozambique. PMID- 29128382 TI - Bad news: The influence of news coverage and Google searches on Gardasil adverse event reporting. AB - BACKGROUND: Human papilloma virus vaccines are a safe and effective tool for reducing HPV infections that can cause cervical cancer. However, uptake of these vaccines has been suboptimal, with many people holding negative beliefs and misconceptions. Such beliefs have been linked with the experience of unpleasant side effects following medical treatment, and media coverage may heighten such concerns. METHODS: The present study sought to assess the influence of news coverage (number of news articles per month) on adverse event reporting in response to Gardasil vaccination in New Zealand over a 7.5-year period, and whether the influence of news coverage was mediated by internet search activity (Google search volumes). Multiple linear regression analyses and simple mediation analyses were used, controlling for year and number of vaccinations delivered. RESULTS: News coverage in the previous month, and Google search volumes in the same month, were significant predictors of adverse event reporting, after accounting for vaccination rates and year. Concurrent Google search volumes partially mediated the effect of prior news coverage. CONCLUSION: The results suggest that some of the adverse events reported were not related to the vaccination itself, but to news coverage and internet search volumes, which may have contributed to public concerns about potentially unpleasant or harmful outcomes. These findings have implications for the importance of psychological and social factors in adverse event reporting, and the role of the news media in disseminating health information. PMID- 29128383 TI - Influenza vaccination in preventing outbreaks in schools: A long-term ecological overview. AB - Influenza vaccination is the most effective way to reduce the incidence of influenza infections. However, the role of influenza vaccination, such as school based influenza vaccination, in preventing the influenza outbreaks in schools remains unclear now. In this study, a total of 286 school febrile outbreaks involving 6863 cases in the Beijing area from September 1, 2006 to March 31, 2017 were analyzed. We also tested 294 circulating strains isolated in Beijing during the same period and compared with that of vaccine strains identified every influenza season. The virological match/mismatch between vaccine strains and circulating strains, and the coverage of vaccination in schools were analyzed against outbreaks during the 11 years. It showed that over 80% school febrile outbreaks were caused by influenza A/B virus, the most frequent being A(H3N2) virus (53.25%), followed by A(H1N1)pdm09 virus (25.11%) and B virus (21.64%). More importantly, low vaccine coverage (in 2006-2007 influenza season) and vaccine mismatch (in 2014-2015 and 2015-2016 influenza season) were associated with an increased number of influenza school outbreaks. High vaccination coverage with a matched vaccine can significantly reduce influenza outbreaks in schools (OR: 0.111, p < .001). We have shown the effectiveness of school-based influenza vaccination in preventing outbreaks using trivalent inactivated influenza vaccine in schools. Thus the school-based vaccine policy should be paid more attention in China and other countries worldwide. PMID- 29128384 TI - Adverse effects of single-component measles vaccine in school children. AB - Measles is a highly contagious viral infection potentially with serious complications and the principal method of protection from the disease is vaccination. Measles vaccination resulted in a 79% drop in measles deaths between 2000 and 2015 worldwide. There has long been a debate about the necessity and benefit-loss ratio of routine MMR vaccination due to possible AE of MMR vaccine. Especially in developed countries which are thought to be free of measles there is an increasing tendency towards hesitation for vaccination though there have been continued outbreaks of measles in countries in which measles is considered to be eliminated. Considering those facts, we decided to publish our data about measles vaccination and adverse effects (AE) during national catch-up measles vaccination programme which took place December 8-26, 2003. A total of 152.648 children aged between seven and fourteen were vaccinated by a live attenuated measles vaccine of which 148.064 (97%) had received measles vaccine by age nine or twelve months. During one month follow-up the AE were recorded. Totally 30.302 AE were reported in 24.209 children, of which 52% of them were local and pain and swelling at injection side were the most common AE. Fever and headache were the most commonly observed systemic side effects. All AE were mild and transient except in four children in whom encephalitis was diagnosed during the one month observation period. Further investigation of the etiology of those cases revealed that they were not related to measles or measles vaccine. In conclusion, single component measles vaccine was found to be safe in previously MMR vaccinated children in short term and long term effects may be need to be clarified by further studies. PMID- 29128385 TI - The effectiveness of shingles vaccine among Albertans aged 50 years or older: A retrospective cohort study. AB - PURPOSE: We assessed the effectiveness of shingles vaccine in preventing incident shingles among Alberta residents aged 50 years or older over the period 2009 - 2015, using administrative health data. METHODS: The cohort comprised of Albertans from the Alberta Health Care Insurance Plan Registry (AHCIP) as of June 30, 2009 and aged 50 years or older. Those who received shingles vaccine were identified from the provincial pharmaceutical information network. The occurrence of incident shingles was identified through both inpatient and outpatients/community care data. Incident shingles was defined as the earliest dated record of ICD 9-CM 053 or ICD-10-CA B02. Starting on November 1, 2009, individuals with no history of shingles or shingles vaccination were followed until Nov 1, 2015 (6 years), or until shingles incidence, death, or AHCIP cancellation (including leaving Alberta). Vaccine effectiveness (VE) was estimated as the inverse of the relative risk of developing incident shingles in each year following vaccination compared to time at risk without vaccination, while adjusting for age, sex, income quintile, and immune compromising conditions (identified from physician claims, inpatient, and cancer registry data). RESULTS: There were 1,094,236 individuals in the cohort, with 85,439 (7.80%) vaccinated individuals. The shingles incidence rate was 9.03 [95% CI: 8.95, 9.11] cases per 1,000 person years (49,243 cases). Adjusted VE in the first year following immunization was 50.02% [95% CI: 44.71%, 54.83%] against incident shingles, decreasing to no effect by the fifth year (VE = 14.00% [95% CI: -20.99%, 38.88%]). CONCLUSIONS: Our findings are consistent with observations from other population based studies and provide population level data for policy-makers to review when making decisions related to public funding of shingles vaccine. PMID- 29128387 TI - Zen and the Art of a New England Surgeon. PMID- 29128386 TI - A pilot study of endoscopically inserted biodegradable biliary stents in the treatment of benign biliary strictures and cystic duct leaks. AB - BACKGROUND AND AIMS: Self-expanding biodegradable biliary stents (BDBSs) have recently become available for use in endoscopic retrograde cholangiography (ERC). The aim was to evaluate the effectiveness and safety of novel BDBSs in iatrogenic cystic duct leaks and benign biliary strictures (BBSs). METHODS: Patients providing informed consent were recruited for the prospective study. Braided self expanding poly-dioxanone BDBSs were inserted using ERC during from 2014 to 2016. Repeated liver function tests and magnetic resonance imaging were performed during follow-up. The main outcomes were treatment success and adverse events. RESULTS: Thirteen patients, 5 women, median age 67 years (range, 43-79) underwent BDBS insertion for iatrogenic cystic duct leak (n = 7) or BBS (n = 6). Stent insertion using ERC was successful in all cases. All bile leaks were treated uneventfully with BDBSs. In BBSs, the clinical success rate of BDBS therapy was 83% in a median of 21 months of follow-up (range, 14-25). Early ERC-related adverse events included 1 cholangitis (8%) and 1 pancreatitis (8%), both in the stricture group. During the first 90 days, 23% of patients were readmitted for mild cholangitis. CONCLUSIONS: The short- and long-term safety of endoscopically inserted poly-dioxanone BDBSs was satisfactory. The management of cystic duct leaks and benign distal common bile duct strictures was highly successful. Episodes of mild cholangitis during stent indwelling seemed to be typical of BDBSs. The advantage of BDBSs is the avoidance of repeated endoscopy for stent removal. (Clinical trial registration number: NCT02353286.). PMID- 29128388 TI - Intrahepatic Glissonean Pedicle Approach to Segment 7 from the Dorsal Side During Laparoscopic Anatomic Hepatectomy of the Cranial Part of the Right Liver. PMID- 29128389 TI - The impact of initial antibiotic treatment failure: Real-world insights in patients with complicated urinary tract infection. AB - OBJECTIVES: RECOMMEND (NCT02364284; D4280R00005) assessed treatment patterns and outcomes associated with initial antibiotic therapy (IAT; antibiotics received <48 h post-initiation of antibiotic therapy) in healthcare-associated infections across five countries. METHODS: Data from medical records of hospitalized patients aged >=18 years with healthcare-associated complicated urinary tract infections (cUTI) are presented. Univariate and multivariate logistic regression analyses identified potential risk factors associated with IAT failure. RESULTS: Mean (SD) age was 68.7 (17.4) years (n = 408). In patients with microbiological documentation (357/408), Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were most common (47.1%, 21.6% and 11.8%, respectively); 46.1% of patients had a multidrug resistant (MDR) pathogen isolated. Most patients received monotherapy IAT (72.5%). Mean IAT duration was 7.8 days. IAT failure, in hospital mortality, and mortality 30-day post-discharge were 54.4%, 35.0% and 37.3%, respectively. IAT failure was associated with age, Deyo-Charlson comorbidity score, country, MDR status and ICU admission in the univariate analysis; and country and age in the multivariate analysis. CONCLUSIONS: This study provides real-world insights into the high rates of IAT failure and morbidity observed in patients with cUTI. Further study is imperative to understand the epidemiology of cUTI, support appropriate IAT selection and management, and reduce the burden of this disease. PMID- 29128390 TI - Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein. AB - The multi-domain non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. Nsp3 is an essential component of the replication/transcription complex. It comprises various domains, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro), the Nsp3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003 as well as Middle-East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. In this review, the structures and functions of these domains of Nsp3 are discussed in depth. PMID- 29128391 TI - Preclinical models of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) can manifest as non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). NASH is often associated with progressive fibrosis which can lead to cirrhosis and hepatocellular carcinoma (HCC). NASH is increasing as an aetiology for end-stage liver disease as well as HCC. There are currently no approved therapies for NASH. A major barrier to development of therapeutics for NASH is the lack of preclinical models of disease that are appropriately validated to represent the biology and outcomes of human disease. Many in vitro and animal models have been developed. In vitro models do not fully capture the hepatic and extrahepatic milieu of human NASH and large animal models are expensive and logistically difficult to use. Therefore, there is considerable interest in the development and validation of mouse models for NAFLD, including NASH. Several models based on varying genetic or dietary manipulations have been developed. However, the majority do not recreate steatohepatitis, strictly defined as the presence of hepatocellular ballooning with or without Mallory-Denk bodies, accompanied by inflammation in the presence of macrovesicular steatosis. Others lack validation against human disease. Herein, we describe the best practices in development of mouse models of NASH. We further review existing models and the literature supporting their use as a surrogate for human disease. Finally, data on models to evaluate protective genes are discussed. It is hoped that this review will provide guidance for the interpretation of data derived from mouse models and also for the development and validation of newer models. PMID- 29128392 TI - Adrenergic manipulation inhibits pavlovian conditioned approach behaviors. AB - Environmental rewards and Pavlovian reward cues can acquire incentive salience, thereby eliciting incentive motivational states and instigate reward-seeking. In rats, the incentive salience of food cues can be measured during a Pavlovian conditioned approach paradigm, in which rats engage in cue-directed approach ("sign-tracking") or approach the food delivery location ("goal-tracking"). While it has been shown that dopamine signaling is necessary for sign-tracking, some studies have suggested that norepinephrine is involved in learning to sign-track as well. Thus, in order to investigate the influence of norepinephrine in Pavlovian conditioned approach, we administered three adrenergic drugs while rats learned that a food cue (an illuminated, retractable lever) preceded the delivery of banana-flavored food pellets into a food-cup. We found that pre-session injections of disulfiram (a dopamine-beta-hydroxylase inhibitor) inhibited the development of sign-tracking, but goal-tracking was only affected at the high dose. In one experiment, post-session injections of disulfiram blocked the development of sign-tracking, although this effect was not replicated in a separate set of rats. Post-session injections of prazosin (an alpha1-adrenergic receptor antagonist) and propranolol (a beta-adrenergic receptor antagonist) also blocked the development of sign-tracking but not goal-tracking. Taken together, these results suggest that adrenergic transmission mediates the acquisition of sign-tracking but not goal-tracking, and thus plays a selective role in the attribution of incentive salience food cues. PMID- 29128393 TI - REM sleep deprivation and dopaminergic D2 receptors modulation increase recognition memory in an animal model of Parkinson's disease. AB - Cognitive impairment is an important non-motor symptom of Parkinson's disease (PD). The neuronal death in nigrostriatal pathway is the main factor for motor symptoms and recent studies indicate a possible influence in non-motor symptoms as well. The pedunculopontine tegmental nucleus (PPT) and basal ganglia are closely related anatomically and functionally and, since they are affected by neurodegeneration in PD, they might be involved in recognition memory. To investigate this, we promoted an ibotenic acid lesion within the PPT or a rotenone lesion within substantia nigra pars compacta (SNpc) of Wistar rats, followed by 24h of REM sleep deprivation (REMSD). Then, we administered a dopaminergic D2 receptor agonist (piribedil, 3MUg/MUl), antagonist (raclopride, 10MUg/MUl) or vehicle (dimethylsulfoxide) directly in the striatum and the animals were submitted to the object recognition test (ORT). We observed that raclopride administration impaired object recognition memory as well as rotenone and ibotenic acid lesion. Interestingly, REMSD reversed the deleterious effects induced by these drugs. Also, raclopride administration after rotenone lesion allowed the animal to explore the new object for a longer time compared to the familiar object, suggesting that raclopride has a dual effect, dependent of the treatments. These findings suggest a role for PPT, SNpc and striatum in recognition memory and points the D2 receptors modulation and REMSD as possible targets for cognitive deficits in Parkinson's disease. PMID- 29128394 TI - T-cell depletion effects of low-dose antithymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. PMID- 29128395 TI - Structure analysis of capsid protein of Porcine circovirus type 2 from pigs with systemic disease. AB - Economic losses with high mortality rate associated with Porcine circovirus type 2 (PCV2) is reported worldwide. PCV2 commercial vaccine was introduced in 2006 in U.S. and in 2008 in Brazil. Although PCV2 vaccines have been widely used, cases of PCV2 systemic disease have been reported in the last years. Eleven nursery or fattening pigs suffering from PCV2 systemic disease were selected from eight PCV2 vaccinated farms with historical records of PCV2 systemic disease in Southern Brazil. PCV2 genomes were amplified and sequenced from lymph node samples of selected pigs. The comparison among the ORF2 amino acid sequences of PCV2 isolates revealed three amino acid substitutions in the positions F57I, N178S and A190T, respectively. Using molecular modeling, a structural model for the capsid protein of PCV2 was built. Afterwards, the mutated residues positions were identified in the model. The structural analysis of the mutated residues showed that the external residue 190 is close to an important predicted region for antibodies recognition. Therefore, changes in the viral protein conformation might lead to an inefficient antibody binding and this could be a relevant mechanism underlying the recent vaccine failures observed in swine farms in Brazil. PMID- 29128396 TI - Family meals then and now: A qualitative investigation of intergenerational transmission of family meal practices in a racially/ethnically diverse and immigrant population. AB - Having frequent family meals has consistently been associated with better health outcomes in children/adolescents. It is important to identify how intergenerational transmission of family meal practices occurs to help families benefit from the protective nature of family meals. Limited studies exist that explore the intergenerational transmission of family meal practices, particularly among racially/ethnically diverse and immigrant populations. This study explores how parents describe differences and similarities between meals "then" and "now", lessons they learned as children about family meals, lessons they passed onto their children, the challenges of carrying out family meals, and how families handle the barriers/challenges to intergenerational transmission of family meal practices. The study was conducted with a sample of African American, Native American, Latino, Hmong, Somali, and White families (25/category). Qualitative themes were explored with the overall sample, by race/ethnicity, immigrant status, and by time in the United States (US) as an immigrant. Parents overwhelmingly reported learning as children that family meals were important and conveying this message to their own children. Differences existed among racial/ethnic groups and time in the US as an immigrant. For example, Somali parents frequently endorsed having no challenges with intergenerational transmission of family meal practices. Immigrant parents in the US for a longer period of time were more likely to endorse learning/teaching about family meal importance, that the food eaten now is different than growing up, that a chaotic environment is a challenge to having family meals, and that they accommodate family member's schedules when planning family meals. Results demonstrate that exploring a parent's early family meal experiences may be important when intervening with parents from diverse racial/ethnic and immigrant populations when trying to improve or increase family meal practices. PMID- 29128398 TI - A sense oligonucleotide to inducible nitric oxide synthase mRNA increases the survival rate of rats in septic shock. AB - Natural antisense transcripts (asRNAs) that do not encode proteins are transcribed from rat, mouse, and human genes, encoding inducible nitric oxide synthase (iNOS), which catalyzes the production of the inflammatory mediator nitric oxide (NO). In septic shock, NO is excessively produced in hepatocytes and macrophages. The iNOS asRNA interacts with and stabilizes iNOS mRNA. We found that single-stranded 'sense' oligonucleotides corresponding to the iNOS mRNA sequence reduced iNOS mRNA levels by interfering with the mRNA-asRNA interactions in rat hepatocytes. The iNOS sense oligonucleotides that were substituted with phosphorothioate bonds and locked nucleic acids efficiently decreased the levels of iNOS mRNA and iNOS protein. In this study, the gene expression patterns in the livers of two endotoxemia model rats with acute liver failure were compared. Next, we optimized the sequence and modification of the iNOS sense oligonucleotides in interleukin 1beta-treated rat hepatocytes. When a sense oligonucleotide was simultaneously administered with d-galactosamine and bacterial lipopolysaccharide (LPS) to rats, their survival rate significantly increased compared to the rats administered d-galactosamine and LPS alone. In the livers of the sense oligonucleotide-administered rats, apoptosis in the hepatocytes markedly decreased. These results suggest that natural antisense transcript-targeted regulation technology using iNOS sense oligonucleotides may be used to treat human inflammatory diseases, such as sepsis and septic shock. PMID- 29128397 TI - Identification and characterization of molluscan caveolin-1 ortholog from Haliotis discus discus: Possible involvement in embryogenesis and host defense mechanism against pathogenic stress. AB - Caveolins are principal membrane proteins of caveolae that play a central role in signal transduction, substrate transport, and membrane trafficking in various cell types. Numerous studies have reported the crucial role of caveolin-1 (CAV1) in response to invading microbes; yet, very little is known about molluscan CAV1. In this study, we identified and characterized CAV1 ortholog from the disk abalone, Haliotis discus discus (HdCAV1). The cDNA sequence of HdCAV1 is 826 bp long and encodes a 127-amino acid polypeptide. Characteristic caveolin superfamily domain (Glu3 - Lys126) and two possible transmembrane domains (Cys48 Tyr67 and Ile103 - Phe120) were identified in the HdCAV1 protein. Homology analysis revealed that HdCAV1 shared higher identity (>47%) with molluscans, but lower identity with other species. Phylogenetic tree constructed by the neighbor joining (NJ) method revealed a distinct evolutionary pathway for molluscans. Transcriptional analysis by SYBR Green qPCR showed the highest expression of HdCAV1 mRNA in late veliger stage, as compared to that in other embryonic developmental stages of disk abalone. In adult animals, gill tissue showed highest HdCAV1 transcript levels under normal physiological condition. Stimulations with two bacteria (Vibrio parahaemolyticus and Listeria monocytogenes), viral hemorrhagic septicemia virus, and two pathogen-associated molecular patterns (LPS and poly I:C) significantly modulated the expression of HdCAV1 transcripts. Collectively, these data suggest that CAV1 plays an important role in embryogenesis and host immune defense in disk abalone. PMID- 29128400 TI - Strong modulation of nitrite reductase activity of cytoglobin by disulfide bond oxidation: Implications for nitric oxide homeostasis. AB - Globin-mediated nitric oxide (NO) dioxygenase and nitrite reductase activities have been proposed to serve protective functions within the cell by scavenging or generating NO respectively. Cytoglobin has rapid NO dioxygenase activity, similar to other globins, however, the apparent rates of nitrite reductase activity have been reported as slow or negligible. Here we report that the activity of cytoglobin nitrite reductase activity is strongly dependent on the oxidation state of the two surface-exposed cysteine residues. The formation of an intramolecular disulfide bond between cysteines C38 and C83 enhances the nitrite reductase activity by 50-fold over that of the monomer with free sulfhydryl or 140-fold over that of the dimer with intermolecular disulfide bonds. The NO dioxygenase reactivity of cytoglobin is very rapid with or without disulfide bond, however, binding of the distal histidine following dissociation of the nitrate are affected by the presence or absence of the disulfide bond. The nitrite reductase activity reported here for the monomer with intramolecular disulfide is much higher than of those previously reported for other mammalian globins, suggesting a plausible role for this biochemistry in controlling NO homeostasis the cell under oxidative and ischemic conditions. PMID- 29128399 TI - Nitric oxide production by glomerular podocytes. AB - Nitric Oxide (NO), a potent vasodilator and vital signaling molecule, has been shown to contribute to the regulation of glomerular ultrafiltration. However, whether changes in NO occur in podocytes during the pathogenesis of salt sensitive hypertension has not yet been thoroughly examined. We showed here that podocytes produce NO, and further hypothesized that hypertensive animals would exhibit reduced NO production in these cells in response to various paracrine factors, which might contribute to the damage of glomeruli filtration barrier and development of proteinuria. To test this, we isolated glomeruli from the kidneys of Dahl salt-sensitive (SS) rats fed a low salt (LS; 0.4% NaCl) or high salt (HS; 4% NaCl, 3 weeks) diets and loaded podocytes with either a combination of NO and Ca2+ fluorophores (DAF-FM and Fura Red, respectively) or DAF-FM alone. Changes in fluorescence were observed with confocal microscopy in response to adenosine triphosphate (ATP), angiotensin II (Ang II), and hydrogen peroxide (H2O2). Application of Ang II resulted in activation of both NO and intracellular calcium ([Ca2+]i) transients. In contrast, ATP promoted [Ca2+]i transients, but did not have any effects on NO production. SS rats fed a HS diet for 3 weeks demonstrated impaired NO production: the response to Ang II or H2O2 in podocytes of glomeruli isolated from SS rats fed a HS diet was significantly reduced compared to rats fed a LS diet. Therefore, glomerular podocytes from hypertensive rats showed a diminished NO release in response to Ang II or oxidative stress, suggesting that podocytic NO signaling is dysfunctional in this condition and likely contributes to the development of kidney injury. PMID- 29128401 TI - H2S protects lipopolysaccharide-induced inflammation by blocking NFkappaB transactivation in endothelial cells. AB - Hydrogen sulfide (H2S) is a novel gasotransmitter and acts as a multifunctional regulator in various cellular functions. Past studies have demonstrated a significant role of H2S and its generating enzyme cystathionine gamma-lyase (CSE) in the cardiovascular system. Lipopolysaccharide (LPS), a major pathogenic factor, is known to initiate the inflammatory immune response. The cross talk between LPS-induced inflammation and the CSE/H2S system in vascular cells has not yet been elucidated in detail. Here we showed that LPS decreased CSE mRNA and protein expression in human endothelial cells and blocked H2S production in mouse aorta tissues. Transfection of the cells with TLR4-specific siRNA knockdown TLR4 mRNA expression and abolished the inhibitory role of LPS on CSE expression. Higher dose of LPS (100MUg/ml) decreased cell viability, which was reversed by exogenously applied H2S at physiologically relevant concentration (30MUM). Lower dose of LPS (10MUg/ml) had no effect on cell viability, but significantly induced inflammation gene expressions and cytokines secretion and stimulated cell hyper permeability. H2S treatment prevented LPS-induced inflammation and hyper permeability. Lower VE-cadherin expression in LPS-incubated cells would contribute to cell hyper-permeability, which was reversed by H2S co-incubation. In addition, H2S treatment blocked LPS-induced NFkappaB transactivation. We further validated that LPS-induced hyper-permeability was reversed by CSE overexpression but further deteriorated by CRISPR/Cas9-mediated knockout of CSE. In vivo, deficiency of CSE sensitized the mice to LPS-induced inflammation in vascular tissues. Take together, these data suggest that CSE/H2S system protects LPS-induced inflammation and cell hyper-permeability by blocking NFkappaB transactivation. PMID- 29128402 TI - An anti-inflammatory chalcone derivative prevents heart and kidney from hyperlipidemia-induced injuries by attenuating inflammation. AB - Obesity is a growing pandemic in both developed and developing countries. Lipid overload in obesity generates a chronic, low-grade inflammation state. Increased inflammation in heart and renal tissues has been shown to promote the progression of heart and renal damage in obesity. Previously, we found that a novel chalcone derivative, L6H21, inhibited lipopolysaccharide-induced inflammatory response. In the present study, we investigated the effects of L6H21 on inflammatory responses in culture and in animal models of lipid overload. We utilized palmitic acid (PA) challenging in mouse peritoneal macrophages and apolipoprotein E knockout (ApoE-/ ) mice fed a high fat diet (HFD) to study whether L6H21 mitigates the inflammatory response. Our studies show that L6H21 significantly reduced PA induced expression of inflammatory cytokines in macrophages by inhibiting mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NFkappaB) signaling pathways. L6H21 also reduced fibrosis in the kidney and heart tissues, and indices of inflammatory response in the ApoE-/- mice fed a HFD. These effects in vivo were also associated with inhibition of MAPK and NFkappaB signaling by L6H21. These findings strongly suggest that L6H21 may be a potential agent for high fat diet-induced injuries in heart and kidney. PMID- 29128403 TI - Cln5 is secreted and functions as a glycoside hydrolase in Dictyostelium. AB - Ceroid lipofuscinosis neuronal 5 (CLN5) is a member of a family of proteins that are linked to neuronal ceroid lipofuscinosis (NCL). This devastating neurological disorder, known commonly as Batten disease, affects all ages and ethnicities and is currently incurable. The precise function of CLN5, like many of the NCL proteins, remains to be elucidated. In this study, we report the localization, molecular function, and interactome of Cln5, the CLN5 homolog in the social amoeba Dictyostelium discoideum. Residues that are glycosylated in human CLN5 are conserved in the Dictyostelium homolog as are residues that are mutated in patients with CLN5 disease. Dictyostelium Cln5 contains a putative signal peptide for secretion and we show that the protein is secreted during growth and starvation. We also reveal that both Dictyostelium Cln5 and human CLN5 are glycoside hydrolases, providing the first evidence in any system linking a molecular function to CLN5. Finally, immunoprecipitation coupled with mass spectrometry identified 61 proteins that interact with Cln5 in Dictyostelium. Of the 61 proteins, 67% localize to the extracellular space, 28% to intracellular vesicles, and 20% to lysosomes. A GO term enrichment analysis revealed that a majority of the interacting proteins are involved in metabolism, catabolism, proteolysis, and hydrolysis, and include other NCL-like proteins (e.g., Tpp1/Cln2, cathepsin D/Cln10, cathepsin F/Cln13) as well as proteins linked to Cln3 function in Dictyostelium (e.g., AprA, CfaD, CadA). In total, this work reveals a CLN5 homolog in Dictyostelium and further establishes this organism as a complementary model system for studying the functions of proteins linked to NCL in humans. PMID- 29128405 TI - Systems cues governing IL6 signaling in leishmaniasis. AB - IL-6 has been proposed to favor the development of Th2 responses and play an important role in the communication between cells of multicellular organisms. They are involved in the regulation of complex cellular processes such as proliferation, differentiation and act as key player during inflammation and immune response. Th2 cytokines play an immunoregulatory role in early infection. Literature says in mice infected with L. major, IL-6 may promote the development of both Th1 and Th2 responses. IL-4 is also considered to be the signature cytokine of Th-2 response. IL-10 was initially characterized as a Th2 cytokine but later on it was proved to be a pleiotropic cytokine, secreted from different cell types including the macrophages. A major challenge is to understand how these complex non-linear processes are connected and regulated. Systems biology approaches may be used to tackle this challenge in an iterative process of quantitative mathematical analysis. In this study, we created an in silico model of IL6 mediated macrophage activation which suffers from an excessive impact of the negative feedback loop involving SOCS3. The strategy adopted in this framework may help to reduce the complexity of the leishmanial IL6 model analysis and also laydown various physiological or pathological conditions of IL6 signaling in future. PMID- 29128404 TI - Milk from transgenic goat expressing human lysozyme for recovery and treatment of gastrointestinal pathogens. AB - Lysozyme is an important non-specific immune protein in human milk, modulating the immune response against bacterial infections. The aim of this study was to characterize the milk of a transgenic goat expressing a recombinant human lysozyme (rhLZ) in the milk, also testing the in vitro antibacterial activity of the rhLZ milk against pathogens of the gastrointestinal tract. Milk samples collected from Tg and non-transgenic goats (nTg) from the 3rd to the 11th week of lactation were submitted to physicochemical analyses, rhLZ semi-quantification, and to rhLZ antimicrobial activity against Micrococcus luteus, Shiguella sonnei and Enterococcus faecalis. Viability and cell migration were studied in ileum epithelial cells (IEC-18) in absence or presence of E. faecalis, Staphylococcus aureus, Escherichia coli (EPEC) and S. sonnei. The expression of ZO-1 and IL-6 genes was evaluated in IEC-18 to evaluate the effect of rhLZ milk on intestinal barrier function and intestinal inflammation. Physicochemical parameters between goat Tg and nTg milk were similar and within normal values for human consumption, with hLZ concentrations being similar between Tg (224MUg/mL) and human (226MUg/mL) milk. The Tg milk had bactericidal activity against M. luteus, no bactericidal effect on S. sonnei, and relative to discrete sensitivity against E. feacalis than controls. Better migrating parameters were observed in cells in culture with nTg and Tg than controls. In the presence of pathogens, the Tg milk promoted improved migrating parameters than controls, except for S. sonnei, with lower cell numbers in the presence of nTg samples and E. faecalis and S. sonnei. No differences in ZO-1 relative expression patterns were observed in cultured cells, with increased expression in IL-6 in cells exposed to nTg milk than controls, with the Tg group being similar to all groups. In conclusion, goat milk containing rhLZ demonstrated valid evidence for its potential use as a nutraceutical for improvement of health and nutrition quality in humans. PMID- 29128406 TI - Recognition of Candida albicans by gingival fibroblasts: The role of TLR2, TLR4/CD14, and MyD88. AB - Recent evidence indicates that nonprofessional immune cells such as epithelial cells, endothelial cells, and fibroblasts also contribute to innate immunity via secretion of cytokines. Fibroblasts are the principal type of cell found in the periodontal connective tissues and they are involved in the immune response during periodontal disease. The role of fibroblasts in the recognition of pathogens via Toll-like receptors (TLRs) has been established; however, few studies have been conducted concerning the involvement of innate immune receptors in the recognition of Candida albicans by gingival fibroblast. In the current study, we investigate the functional activity of TLR2, cluster of differentiation 14 (CD14), and myeloid differentiation primary response gene 88 (MyD88) molecules in the recognition of C. albicans by gingival fibroblast. First, we identified that gingival fibroblasts expressed TLR2, TLR3, and TLR4. Our results showed that TLR agonists had no effect on these receptors' expression by TLR2, MyD88, and CD14-deficient cells. Notably, C. albicans and a synthetic triacylated lipoprotein (Pam3CSK4) induced a remarkable increase of TLR3 expression on MyD88 deficient gingival fibroblasts. TLR4 expression levels were lower than TLR2 and TLR3 levels and remained unchanged after TLR agonist stimulation. Gingival fibroblasts presented morphological similarities; however, TLR2 deficiency on these cells leads to a lower proliferative response, whereas the deficiency on CD14 expression resulted in lower levels of type I collagen by these cells. In addition, the recognition of C. albicans by gingival fibroblasts had an effect on the secretion of cytokines and it was dependent on a specific recognition molecule. Specifically, tumor necrosis factor-alpha (TNF-alpha) production after the recognition of C. albicans was dependent on MyD88, CD14, and TLR2 molecules, whereas the production of interleukin-1beta (IL-1beta) and IL-13 was dependent on TLR2. These findings are the first to describe a role of gingival fibroblast in the recognition of C. albicans and the pathways involved in this process. An understanding of these pathways may lead to alternative treatments for patients with periodontal disease. PMID- 29128407 TI - A low proportion of systematic reviews in physical therapy are registered: a survey of 150 published systematic reviews. AB - BACKGROUND: Systematic reviews provide the best evidence about the effectiveness of healthcare interventions. Although systematic reviews are conducted with explicit and transparent methods, discrepancies might occur between the protocol and the publication. OBJECTIVES: To estimate the proportion of systematic reviews of physical therapy interventions that are registered, the methodological quality of (un)registered systematic reviews and the prevalence of outcome reporting bias in registered systematic reviews. METHODS: A random sample of 150 systematic reviews published in 2015 indexed on the PEDro database. We included systematic reviews written in English, Italian, Portuguese and Spanish. A checklist for assessing the methodological quality of systematic reviews tool was used. Relative risk was calculated to explore the association between meta-analysis results and the changes in the outcomes. RESULTS: Twenty-nine (19%) systematic reviews were registered. Funding and publication in a journal with an impact factor higher than 5.0 were associated with registration. Registered systematic reviews demonstrated significantly higher methodological quality (median=8) than unregistered systematic reviews (median=5). Nine (31%) registered systematic reviews demonstrated discrepancies between protocol and publication with no evidence that such discrepancies were applied to favor the statistical significance of the intervention (RR=1.16; 95% CI: 0.63-2.12). CONCLUSION: A low proportion of systematic reviews in the physical therapy field are registered. The registered systematic reviews showed high methodological quality without evidence of outcome reporting bias. Further strategies should be implemented to encourage registration. PMID- 29128409 TI - Breast cancer related perceptions and practices of health professionals working in Brazil's network of primary care units. AB - In 2004 the Brazilian National Cancer Institute (INCA) established breast cancer screening guidelines for women in Brazil: annual clinical breast exam for women age 40-49 and biennial mammogram for women age 50-69. Healthcare provider's adherence to these guidelines is currently unknown. The objective of this study is to describe the perceptions and practices related to breast cancer screening among physicians, nurses, and health unit coordinators working in the network of primary healthcare units (HCUs) in Brazil. In 2011, 1600 primary HCUs were randomly sampled from all regions in Brazil. At each HCU the coordinator and one health professional were asked to participate in a telephone survey to gathered information on their knowledge, attitudes, and practices related to breast cancer screening. Participation rates for coordinators, physicians, and nurses were 78%, 34%, and 65% respectively. Health unit coordinators identified numerous barriers that prevent patients from receiving appropriate screening, many (44%) were unaware of INCA cancer screening guidelines. Despite a high perceived impact of INCA guidelines, a majority of physicians and nurses did not follow them. Most physicians and nurses recommended mammograms on an annual basis (~75%) and 50.9% of nurses and 25.1% of physicians initiated routine breast cancer screening in women under age 40. Physicians and nurses in Brazil screen at younger ages and more frequently than recommended by INCA guidelines. Given that primary HCUs are the source of health care for many women, interventions that educate healthcare providers on the appropriate ages and intervals for breast cancer screening may prove useful. PMID- 29128408 TI - Adding folic acid to corn Masa flour: Partnering to improve pregnancy outcomes and reduce health disparities. AB - Although strides have been made in preventing neural tube defects (NTDs), Hispanic women remain more likely to have a baby born with an NTD and less likely to know the benefits of, or consume, folic acid than women of other race/ethnic groups. In 1998, the U.S. Food and Drug Administration (FDA) mandated that all enriched cereal grain products be fortified with folic acid; however, corn masa flour (CMF), used to make many corn products that are a diet staple of many Hispanic groups, was not included under this regulation. In 2006, a Working Group began a collaboration to address this disparity by pursuing a petition to FDA to allow folic acid to be added voluntarily to CMF. The petition process was a monumental effort that required collaboration and commitment by partners representing the affected population, manufacturers, scientists, and others. The petition was approved in 2016 and folic acid is now added to CMF products, with expected results of more women achieving the recommended daily folic acid intake, more infants born per year without an NTD, and millions of dollars in direct medical expenditures averted. This 10-year public-private partnership brought together diverse groups that traditionally have different goals. The Working Group continues to work toward ensuring that fortified CMF products are available to the consumer, with the end goal of achieving a reduction in NTD-affected pregnancies. PMID- 29128410 TI - Temporal trends in dancing among adults between 1994 and 2012: The Health Survey for England. AB - The benefits of physical activity are established, however, increasing population physical activity levels remains a challenge. Participating in activities that are enjoyable and multidimensional, such as dancing, are associated with better adherence. However, the extent to which the general population participates in dancing and its temporal trends has not been well studied. The aim of this study was to investigate temporal trends and patterns and correlates of dance participation in England from 1994 to 2012 using a series of large nationally representative surveys. We used data from the Health Survey for England 1994, 1997, 1998, 1999, 2003, 2004, 2006, 2008 and 2012 to examine dance temporal trends. Temporal trends data were age-standardized and correlates of dance participation were examined for males and females over each study year. Changes in population prevalence of dance participation were determined using multiple logistical regression with 1997 as the reference year. Of all survey participants (n=98,178) 7.8% (95%CI: 7.63-7.96) reported dance participation. There was a marked steady decrease over time, with the steepest decline from 2003 onwards. The multivariable-adjusted odds ratios for dance participation were 0.51 for males (95%CI 0.408-0.630, p<0.001) and 0.69 for females (95%CI: 0.598-0.973, p<0.001) in 2012 compared to 1997. Dance participation in adults in England has decreased markedly over time. This study suggests that dance is not being adequately utilized as a health enhancing physical activity, and therefore further research and resources should be dedicated to supporting dance in the community. PMID- 29128411 TI - Psychometric Properties of the Kidney Disease Quality of Life 36-Item Short-Form Survey (KDQOL-36) in the United States. AB - BACKGROUND: The Centers for Medicare & Medicaid Services require that dialysis patients' health-related quality of life be assessed annually. The primary instrument used for this purpose is the Kidney Disease Quality of Life 36-Item Short-Form Survey (KDQOL-36), which includes the SF-12 as its generic core and 3 kidney disease-targeted scales: Burden of Kidney Disease, Symptoms and Problems of Kidney Disease, and Effects of Kidney Disease. Despite its broad use, there has been limited evaluation of KDQOL-36's psychometric properties. STUDY DESIGN: Secondary analyses of data collected by the Medical Education Institute to evaluate the reliability and factor structure of the KDQOL-36 scales. SETTINGS & PARTICIPANTS: KDQOL-36 responses from 70,786 dialysis patients in 1,381 US dialysis facilities that permitted data analysis were collected from June 1, 2015, through May 31, 2016, as part of routine clinical assessment. MEASUREMENTS & OUTCOMES: We assessed the KDQOL-36 scales' internal consistency reliability and dialysis facility-level reliability using coefficient alpha and 1-way analysis of variance. We evaluated the KDQOL-36's factor structure using item-to-total scale correlations and confirmatory factor analysis. Construct validity was examined using correlations between SF-12 and KDQOL-36 scales and "known groups" analyses. RESULTS: Each of the KDQOL-36's kidney disease-targeted scales had acceptable internal consistency reliability (alpha=0.83-0.85) and facility-level reliability (r=0.75-0.83). Item-scale correlations and a confirmatory factor analysis model evidenced the KDQOL-36's original factor structure. Construct validity was supported by large correlations between the SF-12 Physical Component Summary and Mental Component Summary (r=0.40-0.52) and the KDQOL-36 scale scores, as well as significant differences on the scale scores between patients receiving different types of dialysis, diabetic and nondiabetic patients, and patients who were employed full-time versus not. LIMITATIONS: Use of secondary data from a clinical registry. CONCLUSIONS: The study provides support for the reliability and construct validity of the KDQOL-36 scales for assessment of health-related quality of life among dialysis patients. PMID- 29128412 TI - Association Between Gestational Diabetes and Incident Maternal CKD: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with increased risk for diabetes mellitus, metabolic syndrome, and cardiovascular disease. We evaluated whether GDM is associated with incident chronic kidney disease (CKD), controlling for prepregnancy risk factors for both conditions. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Of 2,747 women (aged 18-30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study in 1985 to 86, we studied 820 who were nulliparous at enrollment, delivered at least 1 pregnancy longer than 20 weeks' gestation, and had kidney function measurements during 25 years of follow-up. PREDICTOR: GDM was self-reported by women for each pregnancy. OUTCOMES: CKD was defined as the development of estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 or urine albumin creatinine ratio >= 25mg/g at any one CARDIA examination in years 10, 15, 20, or 25. MEASUREMENTS: HRs for developing CKD were estimated for women who developed GDM versus women without GDM using complementary log-log models, adjusting for prepregnancy age, systolic blood pressure, dyslipidemia, body mass index, smoking, education, eGFR, fasting glucose concentration, physical activity level (all measured at the CARDIA examination before the first pregnancy), race, and family history of diabetes. We explored for an interaction between race and GDM. RESULTS: During a mean follow-up of 20.8 years, 105 of 820 (12.8%) women developed CKD, predominantly increased urine albumin excretion (98 albuminuria only, 4 decreased eGFR only, and 3 both). There was evidence of a GDM-race interaction on CKD risk (P=0.06). Among black women, the adjusted HR for CKD was 1.96 (95% CI, 1.04-3.67) in GDM compared with those without GDM. Among white women, the HR was 0.65 (95% CI, 0.23-1.83). LIMITATIONS: Albuminuria was assessed by single untimed measurements of urine albumin and creatinine. CONCLUSIONS: GDM is associated with the subsequent development of albuminuria among black women in CARDIA. PMID- 29128413 TI - Association of Citizenship Status With Kidney Transplantation in Medicaid Patients. AB - BACKGROUND: Although individuals classified as nonresident aliens, including undocumented immigrants, are entitled to receive emergency dialysis in the United States regardless of their ability to pay, most states do not provide them with subsidized care for maintenance dialysis or kidney transplantation. We explored whether nonresident aliens have similar outcomes to US citizens after receiving kidney transplants covered by Medicaid, a joint federal and state health insurance program. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: All adult Medicaid patients in the US Renal Data System who received their first kidney transplant from 1990 to 2011. PREDICTOR: Citizenship status, categorized as US citizen, nonresident alien, or permanent resident. OUTCOME: All-cause transplant loss. MEASUREMENTS: HRs and 95% CIs estimated by applying Cox proportional hazards frailty models with transplantation center as a random effect. RESULTS: Of 10,495 patients, 8,660 (82%) were US citizens, 1,489 (14%) were permanent residents, and 346 (3%) were nonresident aliens, whom we assumed were undocumented immigrants. Nonresident aliens were younger, healthier, receiving dialysis longer, and more likely to have had a living donor. 71% underwent transplantation in California, and 61% underwent transplantation after 2005. Nonresident aliens had a lower unadjusted risk for transplant loss compared with US citizens (HR, 0.48; 95% CI, 0.35-0.65). Results were attenuated but still significant when adjusted for demographics, comorbid conditions, dialysis, and transplant-related factors (HR, 0.67; 95% CI, 0.46-0.94). LIMITATIONS: Citizenship status was self-reported, possible residual confounding. CONCLUSIONS: Our study suggests that the select group of insured nonresident aliens who undergo transplantation with Medicaid do just as well as US citizens with Medicaid. Policymakers should consider expanding coverage for kidney transplantation in nonresident aliens, including undocumented immigrants, given the associated high-quality outcomes in these patients. PMID- 29128414 TI - Mapping of the prenatal and postnatal methamphetamine effects on D1-like dopamine, M1 and M2 muscarinic receptors in rat central nervous system. AB - Methamphetamine (MA) is worldwide known drug with high potential for addiction that causes dopamine, noradrenaline and serotonin release. MA is also able to increase acetylcholine levels in adult rodents. The aim of this study was to map changes in D1-like dopamine receptors (DR), M1 and M2 muscarinic receptors (MR), and the total number of MR (M1-M5 MR) in the CNS of rats exposed to MA prenatally and in adulthood. Rat mothers were exposed to MA (5mg/kg s.c.) or saline during the entire gestation period and their male offspring were administered in adulthood with single MA (1mg/kg) or saline injection. Thus, the animals were divided into 4 groups: prenatally MA-exposed rats treated with saline (MA/S) or MA (MA/MA) in adulthood and prenatally saline-exposed rats treated with saline (S/S) or MA (S/MA) in adulthood. One hour after the acute treatment animals were sacrificed and their brains were removed. The numbers of M1, M2, total MR, and D1 DR were measured by autoradiography. The main effect was detected in the hippocampus with the most affected M1 MR. D1-DR were decreased in motor cortex and substantia nigra. M1MR were decreased in caudate-putamen, dorsal hippocampus, CA1, CA3 and dentate gyrus (DG). M2MR were decreased in DG only. Total number of MR was moreover decreased in dorsal hippocampus, CA1, CA3 and DG. Our results have shown different patterns of changes in DR and MR, suggesting a pilot role of M1 MR in the CNS changes induced by prenatal and adult MA exposure. PMID- 29128415 TI - The p38 mitogen activated protein kinase regulates beta-amyloid protein internalization through the alpha7 nicotinic acetylcholine receptor in mouse brain. AB - Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular beta-amyloid protein (Abeta) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The alpha7 nicotinic acetylcholine receptor (alpha7nAChR) has been suggested to play an important role in Abeta caused cognition. It has high affinity with Abeta and could mediate Abeta internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the alpha7nAChR mediated Abeta internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that Abeta is internalized by cholinergic and GABAergic neurons. The internalized Abeta were found deposits in lysosomes/endosomes and mitochondria. Abeta could form Abeta-alpha7nAChR complex with alpha7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of alpha7nAChR could in return mediate Abeta internalization in the cortex and hippocampus. In addition, by using the alpha7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with Abeta-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the alpha7nAChR-mediated internalization of Abeta. The activation of alpha7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD. PMID- 29128416 TI - Efficacy and safety of the topical application of tranexamic acid in primary cementless hip arthroplasty: prospective, randomised, double-blind and controlled study. AB - OBJECTIVE: To evaluate the efficacy of topical tranexamic acid topical in cementless total hip arthroplasty from the point of view of bleeding, transfusion requirements and length of stay, and describe the complications of use compared to a control group. MATERIAL AND METHODS: A prospective, randomised, double blinded and controlled study including all patients undergoing cementless total hip arthroplasty in our centre between June 2014 and July 2015. Blood loss was estimated using the formula described by Nadler and Good. RESULTS: The final analysis included 119 patients. The decrease in haemoglobin after surgery was lower in the tranexamic acid group (3.28+/-1.13g/dL) than in the controls (4.03+/ 1.27g/dL, P=.001) and estimated blood loss (1,216.75+/-410.46mL vs. 1,542.12+/ 498.97mL, P<.001), the percentage of transfused patients (35.9% vs. 19.3%, P<.05) and the number of transfused red blood cell units per patient (0.37+/-0.77 vs. 0.98+/-1.77; P<.05). There were no differences between groups in the occurrence of complications or length of stay. CONCLUSIONS: The use of topical tranexamic acid in cementless total hip arthroplasty results in a decrease in bleeding and transfusion requirements without increasing the incidence of complications. PMID- 29128417 TI - Exercise more or sit less? A randomized trial assessing the feasibility of two advice-based interventions in obese inactive adults. AB - OBJECTIVES: The risk of metabolic and cardiovascular disease may be reduced by a healthy pattern of daily physical activity. We investigated the feasibility and preliminary effectiveness of advice-based interventions aiming at either increasing moderate-to-vigorous intensity physical activity (MVPA) or reducing sedentary time (ST) in obese volunteers. DESIGN: Randomized non-blinded two-armed trial. METHOD: Inactive, obese adults were randomly assigned to reduce sedentary behavior (SitLess) (n=30) or increase MVPA (ExMore) (n=29) for 4 weeks. Participants wore ActivPAL (AP) and ActiGraph (AG) devices for 7 consecutive days at baseline and during the final week of the intervention period. Cardiometabolic risk factors (waist circumference, BMI, percent body fat, blood pressure, VO2max and blood markers) were measured at baseline and at follow-up. Trial was set in Midtjylland Denmark from 2012 to 2014. RESULTS: The interventions were completed by 77% (SitLess) and 69% (ExMore) of the participants. The SitLess group reduced sedentary time by 53min/day (95% CI 10; 96; P<0.05) while ExMore increased MVPA by 16min/day (95% CI 5; 27; P<0.05). SitLess and ExMore both improved VO2max by 8% and 11%, respectively (P<0.05). None of the other measured cardiometabolic risk factors changed over the 4 weeks of intervention. CONCLUSIONS: This trial showed that completion of 4-week, advice-based interventions led to reduced ST or increased MVPA in obese adults. Furthermore, both interventions led to small significant increases in VO2max. Studies of longer duration are needed to determine if these behavioral changes can be maintained, and to quantify possible longterm effects of reduced ST or increased MVPA on cardiometabolic risk factors. PMID- 29128418 TI - Accelerometer-measured sedentary time and physical activity-A 15 year follow-up of mortality in a Swedish population-based cohort. AB - OBJECTIVES: To investigate the associations of objectively assessed sedentary time, light intensity physical activity (PA), moderate to vigorous intensity PA (MVPA), and total PA with all-cause mortality and mortality from cardiovascular disease (CVD) or cancer in a Swedish population-based cohort with 15 years follow up time. DESIGN: Longitudinal prospective cohort study. METHODS: Data from 851 persons (56% women) >=35 years at baseline were included. Primary exposure variables were time (min/day) spent sedentary, in light intensity PA and in MVPA, and total counts from an Actigraph 7164 accelerometer. Data on all-cause mortality and mortality from CVD or cancer were obtained from Swedish registers. Cox proportional hazards models estimated hazard ratios (HR) of mortality with 95% confidence intervals (CI). RESULTS: Compared with the least sedentary participants, those in the most sedentary tertile had an increased risk of all cause mortality, HR: 2.7 (1.4, 5.3), CVD mortality, HR: 5.5 (1.4, 21.2) and cancer mortality, HR: 4.3 (1.2, 16.0). For all-cause mortality, those in the highest light intensity PA tertile had a HR 0.34 (0.17, 0.67) compared with the lowest tertile. A similar pattern was found for CVD and cancer mortality. More time spent in MVPA was associated with the largest risk reduction for CVD mortality, with an almost 90% lower risk in the tertile with the most time in MVPA. CONCLUSIONS: This study confirms a strong inverse relationship between MVPA and mortality, and adds new insight for the understanding of the associations between sedentary time and light intensity PA and mortality. PMID- 29128419 TI - Tramadol effects on physical performance and sustained attention during a 20-min indoor cycling time-trial: A randomised controlled trial. AB - OBJECTIVES: To investigate the effect of tramadol on performance during a 20-min cycling time-trial (Experiment 1), and to test whether sustained attention would be impaired during cycling after tramadol intake (Experiment 2). DESIGN: Randomized, double-blind, placebo controlled trial. METHODS: In Experiment 1, participants completed a cycling time-trial, 120-min after they ingested either tramadol or placebo. In Experiment 2, participants performed a visual oddball task during the time-trial. Electroencephalography measures (EEG) were recorded throughout the session. RESULTS: In Experiment 1, average time-trial power output was higher in the tramadol vs. placebo condition (tramadol: 220W vs. placebo: 209W; p<0.01). In Experiment 2, no differences between conditions were observed in the average power output (tramadol: 234W vs. placebo: 230W; p>0.05). No behavioural differences were found between conditions in the oddball task. Crucially, the time frequency analysis in Experiment 2 revealed an overall lower target-locked power in the beta-band (p<0.01), and higher alpha suppression (p<0.01) in the tramadol vs. placebo condition. At baseline, EEG power spectrum was higher under tramadol than under placebo in Experiment 1 while the reverse was true for Experiment 2. CONCLUSIONS: Tramadol improved cycling power output in Experiment 1, but not in Experiment 2, which may be due to the simultaneous performance of a cognitive task. Interestingly enough, the EEG data in Experiment 2 pointed to an impact of tramadol on stimulus processing related to sustained attention. TRIAL REGISTRATION: EudraCT number: 2015-005056-96. PMID- 29128420 TI - Neoadjuvant treatment for muscle-invasive bladder cancer: The past, the present, and the future. AB - BACKGROUND: Approximately half of patients who undergo radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) will succumb to metastatic disease. We summarize the evidence for neoadjuvant radiation (NAR), chemo (NAC), and immunotherapy (checkpoint inhibition) prior to RC for MIBC. MATERIALS AND METHODS: Data were obtained by a search of PubMed, ClinicalTrials.gov, and Cochrane databases for English language articles published from 1925 up to 2017. RESULTS: NAC usage has increased over the last decade, while NAR is rarely administered. Although NAR results in downstaging, its impact on survival is inconclusive. Based on level I evidence, cisplatin-based NAC (CB-NAC) is considered standard of care in cT2-4aN0M0 MIBC. NAC results in a 6% absolute 10 year overall survival (OS) benefit. In-depth analyses of key randomized controlled trials showed that failure to correct for uniform staging, surgical variation, and patient selection compromises the ability to identify factors predictive of response to NAC. The benefit appears to be restricted to patients downstaged to ypT1N0 or less. In these patients, 5-year OS is 80% to 90%. Regarding a number needed to treat of 17, most patients with cT2-4aN0M0 MIBC will be exposed to toxicity without benefit. Possible approaches to reduce overtreatment are suggested in this article and include patient selection, the chosen NAC regimen, and emerging molecular data to predict responsiveness to NAC. Neoadjuvant immunotherapy with checkpoint inhibitors is a promising future perspective currently under investigation. CONCLUSIONS: Past studies on NAR show inconclusive results and NAR is rarely administered. Instead, CB-NAC is advised in eligible patients with cT2-4aN0M0 MIBC prior to RC. In the near future, predictive biomarkers will be the key to tailor the use of CB-NAC and reduce harm to nonresponders. PMID- 29128421 TI - Trends in usage of cytoreductive partial nephrectomy and effect on overall survival in patients with metastatic renal cell carcinoma. AB - PURPOSE: Cytoreductive radical nephrectomy (cRN) improves survival in select patients with metastatic renal cell carcinoma (mRCC). It is unclear, however, whether cytoreductive partial nephrectomy (cPN) compromises oncologic efficacy. We evaluated trends in utilization of cPN and compared overall survival (OS) in patients who underwent cRN or cPN for mRCC. MATERIALS AND METHODS: We queried the National Cancer Database from 2006 to 2013 and identified patients who underwent cPN and cRN for mRCC. We analyzed rates of cPN over time. Logistic regression identified predictors of cPN. We matched patients based on propensity score for treatment. We used matched Kaplan-Meier survival analyses to compare OS, stratified by tumor size. We used multivariable Cox proportional hazards models to determine the effect of cPN and cRN on OS. RESULTS: A total of 10,144 patients met inclusion criteria, with 9,764 (96.2%) undergoing cRN and 381 (3.8%) undergoing cPN. Rates of cPN increased over time from 1.8% to 4.3% over the study period. Treatment at an academic/research facility, papillary and chromophobe histology, and more recent year of treatment were associated with increased odds of cPN. In a matched survival analysis, cPN was associated with improved OS compared with cRN (log rank, P = 0.001). This effect was limited to primary tumors<4cm. In a propensity-score adjusted multivariable Cox model, cPN was associated with improved OS (hazard ratio = 0.81; 95% CI: 0.71-0.93; P = 0.002). CONCLUSIONS: The use of cPN in patients with mRCC is increasing. cPN is associated with improved OS in patients with mRCC, although this effect is limited to patients with primary tumors<4cm. PMID- 29128422 TI - Ampholytic starch excipients for high loaded drug formulations: Mechanistic insights. AB - Ampholytic starch derivatives are proposed as a new class of excipients carrying simultaneously anionic carboxymethyl (CM) and cationic aminoethyl (AE) groups on starch (St) polymeric chains. Three different types of derivatives were obtained by using the same reagents and varying only the order of their addition in the reaction medium: in one step method (OS) the two reactants were added simultaneously, whereas in two steps method (TS) either CMSt or AESt were prepared separately in the first step, followed by subsequent addition of the second reactant. It was found that all ampholytic derivatives were able to generate monolithic tablets by direct compression and allowed 60% loading of acidic (Acetylsalicylic acid), basic (Metformin), zwitterion (Mesalamine) or neutral (Acetaminophen) as drug models. The in vitro dissolution tests followed for 2 h in SGF and then in SIF, showed that the mentioned starch derivatives were stabilized by self-assembling and generated matrices able to control the release of drugs for about 24 h. The addition order of reagents has an impact on ampholytic starch properties offering thus a high versatility of this new class of starch excipients that can be tailored for challenging formulations with high dosages of several drugs. PMID- 29128423 TI - Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery - An update. AB - Poor water-solubility remains a typical property of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate, and bioavailability of these active ingredients belonging to biopharmaceutical classification system (BCS) II and IV classifications. Since the early 2000s, nanocrystal delivery and amorphous solid dispersions are more established techniques to overcome the limitations of poorly water soluble drugs in FDA available products. This article provides an updated review of nanocrystal and amorphous solid dispersion techniques primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercially relevant scientific literature. PMID- 29128424 TI - The use of synthetic peptides for detection of anti-citrullinated protein antibodies in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. A characteristic feature of RA is the presence of anti-citrullinated protein antibodies (ACPA). Since ACPAs are highly specific for RA and are often present before the onset of RA symptoms, they have become valuable diagnostic and prognostic. As a result, several assays for detection of ACPAs exist, which vary in sensitivity and specificity. In this study, we analyzed the reactivity of RA sera to selected peptides by solid-phase immunoassays in order to develop an ACPA assay with improved sensitivity and specificity. ACPA levels were determined with respect to sensitivity and specificity in 332 serum samples using the newly developed peptide panel, which was compared to the commercial assays CCPlus (Eurodiagnostica) and CCP3.1 (Inova Diagnostics). A primary panel (peptides 814, 33062 and 33156) was identified, which obtained a sensitivity of 71%, while the complete peptide panel reacted with 79% of RA sera screened. Total specificities of 89% and 80% were obtained for the primary peptide panel and the complete peptide panel. Sensitivities for the commercial assays ranged between 71% and 76% and specificities between 88% and 90%. These findings indicate that the generated peptide panel is optimal for ACPA detection and able to compete with commercial available assays. Collectively, this study may contribute to characterize autoimmunity towards citrullinated proteins and to the development of new and improved diagnostic assays for detection of ACPA and determination of RA. PMID- 29128426 TI - Detection of early changes in the coronary artery microstructure after heart transplantation: A prospective optical coherence tomography study. AB - BACKGROUND: Optical coherence tomography (OCT) enables in-vivo cardiac allograft vasculopathy (CAV) microstructure characterization. Early coronary artery microstructure changes after heart transplantation (HTx) may provide valuable mechanistic information regarding CAV development. Our in this study was to describe and characterize changes in the coronary artery microstructure during the first year after HTx using serial OCT scans. METHODS: Twenty-six patients were enrolled at routine baseline coronary angiography 3 months after HTx. Coronary OCT scans were performed on all 3 major vessels at baseline and were repeated 12 months after HTx. We contoured the vessel layers for absolute and relative measurements. Lipid plaques, calcified plaques, layered fibrotic plaques (LFPs) and bright spots were analyzed by delineating circumferential borders and measuring angulation of total circumference. RESULTS: A total of 8,789 frames from 71 vessels were analyzed after 3 and 12 months (vessel length 79 +/- 24 mm vs 82 +/- 23 mm, respectively, p = 0.39). Mean intima area increased by 20% from 3 months to 12 months (1.6 [1.2 to 2.7] mm2 vs 1.9 [1.3 to 3.2] mm2, p < 0.0001). Mean lumen area decreased by 2% (9.1 [7.5 to 11.6] mm2 vs 8.9 [6.9 to 10.9] mm2, p < 0.01). LFPs showed an almost 5-fold increase at follow-up (1.0% [0% to 6.5%] vs 4.8% [0% to 24.5%], p < 0.0001). Bright spots were also detected more frequently at 12 months (0% [0% to 2.8%] vs 0.8% [0% to 6.8%], p < 0.001). We found no significant difference in extent of lipid plaque (p = 0.78) or calcified plaque (p = 0.37) during follow-up. The intima area change and LFP progression during follow-up correlated strongly (r2 = 0.51, p < 0.0001). CONCLUSIONS: Early CAV formation during the first year after HTx is characterized by a pronounced intima layer thickening strongly associated with LFP progression. In contrast, the extent of lipid plaque and calcifications remained stable. LFP formation may be a key mechanism in CAV. PMID- 29128425 TI - Using sweat to measure cytokines in older adults compared to younger adults: A pilot study. AB - BACKGROUND/OBJECTIVES: Current measures of cytokines involve urine, blood or saliva which have drawbacks including circadian rhythm variations and complicated collection methods. Sweat has been used to measure cytokines in young and middle aged adults, but not older adults. We sought to determine the feasibility of using sweat to measure cytokines in older adults compared to younger adults. DESIGN: Two visit cross-sectional pilot study stratified by age group. SETTING: Independent living facility and Johns Hopkins University both in Maryland. PARTICIPANTS: 23 community-dwelling adults aged 65 and older and 26 adults aged 18-40 were included. Those with active cancer treatment or with a known terminal illness diagnosis were excluded. MEASUREMENTS: Sweat interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) were collected using a non-invasive sweat patch worn for 72h by each participant. Samples were measured with a single molecule array (SIMOA) technology for ultrasensitive, multiplexed detection of proteins. RESULTS: 23 older adults and 26 younger adults with mean ages of 77+/-8.0years and 28+/-5.5years, respectively, completed the study. Both groups had high rates of compliance with patch wearing and removal. Higher concentrations of TNF-alpha, IL-6 and IL-10 were observed in older adults compared to younger adults, which remained significant after controlling for race, sex, body mass index, and chronic disease count (0.110+/-0.030 vs. 0.054+/-0.020pg/mL, 0.089+/-0.012 vs. 0.048+/ 0.018pg/mL, and 0.124+/-0.029 vs. 0.067+/-0.025pg/mL, respectively). CONCLUSION: These results suggest that sweat patches are a feasible method to collect cytokine data from older adults. Preliminary group differences in cytokine measurement between older and younger groups correspond with current literature that cytokines increase with age, suggesting that sweat measurement using the sweat patch provides a new method of exploring the impact of inflammation on aging. Further research using sweat and the sweat patch is recommended. PMID- 29128427 TI - Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR-Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib. PMID- 29128428 TI - Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer. AB - Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized. Unlike ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry (IHC), although fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage, potentially higher chemosensitivity (in particular, to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multitarget inhibitors with anti-rearranged during transfection proto-oncogene (RET) activity in patients with RET-rearranged lung cancer. In the clinical setting, the benefit in terms of response (16%-47%) and progression-free survival (2-7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multikinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn on account of discordant data coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET oncogene-addicted NSCLC underscores the clear need for development of more selective and potent RET inhibitors and for better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in patients with lung cancer. PMID- 29128429 TI - Practice Report / Bericht aus der Praxis: An exploration of peer tutor roles and recruitment at German medical schools. AB - BACKGROUND: Almost all medical faculties in Germany actively employ peer tutors. However, little is known about the roles these tutors play from a faculty point of view. Also, there are only few descriptions of the tutor recruitment and selection processes. METHODS: 32 of the medical faculties in Germany, where tutors are used in the training of medical students, were asked to provide information on the role and recruitment of tutors by means of a partially standardized questionnaire. RESULTS: At the surveyed faculties (return rate 28%), tutors are mostly employed for the purpose of teaching staff support. Even though desired in individual cases, tutors rarely play an active role in curriculum- or faculty development. The way tutor recruitment is handled strongly depends on the capabilities of the individual faculties and the way tutors are utilized. In many cases this process is structured, consisting of written and oral application phases, in other cases recruitment takes place without formal application procedures. The selection criteria, however, were found to be very similar at most faculties. CONCLUSION: The role of tutors from the faculties' point of view depends strongly on the respective nature of the tutorials, which are just as diverse as the approaches to tutor recruitment. PMID- 29128431 TI - Practice Report / Bericht aus der Praxis: Peer teaching: From method to philosophy. AB - Peer teaching or peer-assisted learning is a popular topic in the medical education literature. While not one method of education, a categorization is possible according to (a) the developmental distance between learner and peer teacher, (b) the scale or group size of learners in peer teaching arrangements and (c) the extent of formality or structure of the arrangement. That yields many different forms of peer teaching. Viewing peer teaching as a multifaceted method shows several benefits. On a deeper level however peer teaching may be viewed as a philosophy of medical education that has historical roots but aligns well with current thinking of teaching and learning across the continuum of medical education. PMID- 29128430 TI - [A reporting tool for practice guidelines in health care: the RIGHT statement]. AB - The quality of reporting practice guidelines is often poor, and there is no widely accepted guidance or standards for such reporting in health care. The international RIGHT (Reporting Items for practice Guidelines in HealThcare) Working Group was established to address this gap. The group followed an existing framework for developing guidelines for health research reporting and the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network approach. A checklist and an explanation and elaboration statement were developed. The RIGHT checklist includes 22 items that are considered essential for good reporting of practice guidelines: basic information (items 1 to 4), background (items 5 to 9), evidence (items 10 to 12), recommendations (items 13 to 15), review and quality assurance (items 16 and 17), funding and declaration and management of interests (items 18 and 19), and other information (items 20 to 22). The RIGHT checklist can assist developers in reporting guidelines, support journal editors and peer reviewers when considering guideline reports, and help health care practitioners understand and implement a guideline. PMID- 29128432 TI - Czech Version of the Patient Dignity Inventory: Translation and Validation in Incurable Patients. AB - CONTEXT: The Patient Dignity Inventory (PDI) is a valid, reliable screening tool to assess a range of issues that have been reported to affect the sense of dignity in patients with life-limiting conditions. OBJECTIVES: We investigated the item characteristics, factor structure, and reliability of the Czech version of the PDI (PDI-CZ) among cancer and noncancer patients. METHODS: The PDI was translated into the Czech language following state-of-the-art criteria (a five stage proceeding method for the translation). Two hundred thirty-nine participants completed the study (136 cancer and 103 noncancer patients). Internal consistency, test-retest reliability, and factor analysis were used for validation of the PDI-CZ. RESULTS: A Czech version of the PDI was obtained. The Cronbach's alpha for PDI-CZ was 0.92. Item 22 (not feeling supported by my health care providers) did not correlate with any other items, and it was skipped for factor analysis processing for this reason. Factor analysis resulted in a four factor solution, accounting for 56.34% of the overall variance (factor loadings range, 0.37-0.92). The factor labels were as follows: loss of purpose of life; loss of autonomy; loss of confidence; and loss of social support (internal consistencies range, Cronbach's alpha 0.58-0.90). Test-retest reliability was assessed with 25 patients after two weeks. The resulting range of the Gwet's coefficient, AC1, was between 0.58 and 1.00. CONCLUSION: The results from the study support the reliability of the PDI-CZ and its future use in patients with incurable cancer and noncancer patients. PMID- 29128433 TI - Shared Decision Making in Home Hospice Nursing Visits: A Qualitative Study. AB - CONTEXT: Shared decisions between health care providers and patients and families are replacing the traditional physician-driven plans of care. Hospice philosophy recognizes the patient and family as a unit of care and embraces their role in decision making. OBJECTIVE: The goal of this study was to evaluate the shared decisions between hospice nurses and patients and family members. METHODS: A secondary analysis of audio recordings of 65 home hospice nurse visits from 65 home hospice nurse visits in 11 different U.S. hospice programs. RESULTS: To varying degrees, hospice nurses used all the recommended elements of shared decision making during home visits with patients and families; however, not all elements were used in every visit. The most commonly used element was defining a problem, and the least used element was the assessment of patient and family understanding. CONCLUSIONS: Hospice staff can benefit from a more purposeful shared decision-making process and a greater focus on assessment of patient and family understanding and ability to implement plans of care. PMID- 29128434 TI - The Korean Version of the Voice Symptom Scale for Patients with Thyroid Operation, and Its Use in a Validation and Reliability Study. AB - OBJECTIVES: The Voice Symptom Scale (VoiSS) questionnaire is a self-reported measure of voice function. Compared with previous voice-rating tools, the VoiSS focuses more on communication difficulties, pharyngeal symptoms, and psychosocial distress. This study aimed to translate the VoiSS into the Korean language, validate it, and assess its reliability. STUDY DESIGN: This is a prospective patient study utilizing questionnaires and acoustic analysis. METHODS: A recognized methodology was used to translate the questionnaires. The final Korean version was used in 31 patients scheduled for thyroidectomy between November 2013 and February 2015 for preoperative voice assessment, and at 2 weeks, 3 months, and 6 months postoperatively. The participants included had no specific vocal disorders before surgery and no vocal cord paralysis after surgery, and completed the Korean versions of the VoiSS and Voice Handicap Index (VHI), and acoustic analysis. RESULTS: The Korean version of the VoiSS demonstrated high internal consistency (alpha = 0.97) and test-retest reliability of its subscales. There was a significant correlation between the VoiSS and VHI scores in the total thyroidectomy group at each time-point. With regard to subjective symptoms, the VoiSS appeared to be more accurate than the VHI in terms of physical and functional subscales. CONCLUSIONS: The Korean version of the VoiSS is ready for use for the assessment of voice dysfunction in Korean patients. It is an applicable and useful supplementary tool for evaluating patients' perceptions of voice dysfunction after thyroidectomy, for identifying multiple factors affecting patients' voices, and for measuring treatment efficacy before and after therapeutic intervention. PMID- 29128435 TI - Association between obesity and self-reported sleep duration variability, sleep timing, and age in the Japanese population. AB - OBJECTIVE: The objective of this study was to investigate the association between obesity and sleep habits, including bedtime, wake-up time, and sleep duration variability over a week. METHODS: We analyzed 9289 participants in this study. Following a health examination, each participant self-reported their sleep habits using a standardized 19-item questionnaire. High sleep duration variability was defined as sleep varying >=3h of the difference between the longest and shortest sleep durations reported over a week-long period. Late bedtime and early wake-up time were defined as 24:00h or later, and before 6:00h, respectively. Obesity was defined as a body mass index (BMI) of >=25kg/m2. Subgroup analysis included age (younger group defined as age <65 years vs. elderly group defined as age >=65 years). RESULTS: After adjusting for confounding factors and sleep duration, high sleep duration variability [odds ratio (OR), 1.20; p<0.005] was significantly associated with a high OR of obesity. Late bedtime (OR, 1.18; p<0.01) was significantly associated with a high OR of obesity, whereas early wake-up was not. In the subgroup analysis, high sleep duration variability had a significant association with the younger group (OR, 1.25; p<0.001), whereas late bedtime had a significant association with the elderly group (OR, 1.36; p<0.005). CONCLUSIONS: Inappropriate sleep habits, particularly high sleep duration variability in young individuals and late bedtime in the elderly, are associated with a high prevalence of obesity, independently of sleep duration. PMID- 29128436 TI - Comparison of antipseudomonal beta-lactams for febrile neutropenia empiric therapy. PMID- 29128437 TI - Participatory action research opens doors: Mentoring Indigenous researchers to improve midwifery in urban Australia. AB - PROBLEM: There is increasing demand for capacity building among the Aboriginal and Torres Strait Islander (Indigenous) maternal and infant health workforce to improve health outcomes for mothers and babies; yet few studies describe the steps taken to mentor novice Indigenous researchers to contribute to creating a quality evidence-base in this space. BACKGROUND: The Indigenous Birthing in an Urban Setting study is a partnership project aimed at improving maternity services for Indigenous families in South East Queensland. AIM: To describe our experience setting up a Participatory Action Research team to mentor two young Indigenous women as research assistants on the Indigenous Birthing in an Urban Setting study. METHODS: Case study reflecting on the first six months. FINDINGS: Participatory Action Research was a very effective method to actively mentor and engage all team members in reflective, collaborative research practice, resulting in positive changes for the maternity care service. The research assistants describe learning to conduct interviews and infant assessments, as well as gaining confidence to build rapport with families in the study. Reflecting on the stories shared by the women participating in the study has opened up a whole new world and interest in studying midwifery and child health after learning the difficulties and strengths of families during pregnancy and beyond. DISCUSSION: We encourage others to use Participatory Action Research to enable capacity building in the Aboriginal and Torres Strait Islander midwifery workforce and in health research more broadly. PMID- 29128438 TI - Renin-Angiotensin System Blockers and Statins Are Associated With Lower In Hospital Mortality in Very Elderly Hypertensives. AB - OBJECTIVES: Cardiovascular diseases are mainly related to hypertension and dyslipidemia and increase with aging because of the larger time span for these risk factors to damage arterial blood vessels. The impact of cardiovascular drug therapy on outcomes in the very elderly hospitalized is still not well established. The aim of our study was to evaluate the associations between cardiovascular therapy and in-hospital mortality in very elderly hypertensives. DESIGN: Prospective observational study. SETTING: Hospital assessment. PARTICIPANTS: 310 very elderly hypertensive patients admitted to our Internal Medicine and Geriatrics Department for medical conditions. MEASUREMENTS: Main comorbidities, laboratory parameters, and cardiovascular drug therapy taken before admission were considered for the analyses. RESULTS: The mean age was 88.1 +/- 5.1 years, with female prevalence of 57.4%. Among cardiovascular drugs taken before admission, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and statins were those associated with lower in-hospital mortality, even after adjusting for covariates (age, hemoglobin, albumin, acute kidney injury, ADL Hierarchy Scale, NT-proBNP levels) [odds ratio (OR) = 0.46, P = .045, and OR = 0.21, P = .008, respectively]. No difference regarding in hospital mortality was found between ACE inhibitors and angiotensin receptor blockers (P = .414). CONCLUSION: ACE inhibitors/angiotensin receptor blockers and statins, through their beneficial effects on the cardiovascular system, have a positive impact on survival in very elderly hospitalized patients. Our data confirm the important role of such drugs even in this particular population with a mean age higher than 88 years, where scientific evidence is still scanty. PMID- 29128439 TI - Robotic Splenectomy for Isolated Splenic Recurrence of Endometrial Adenocarcinoma. AB - STUDY OBJECTIVE: To demonstrate management of a rare case of an isolated intraparenchymal splenic metastasis of endometrial cancer with robotic-assisted surgery. DESIGN: Case report (Canadian Task Force Classification III). SETTING: A 55-year-old patient with a history of endometrial cancer was found to have a splenic lesion on a follow-up examination. She underwent surgical staging, involving total hysterectomy, bilateral salpingo-oopherectomy, pelvic lymphadenectomy, and peritoneal washing, in 2014, and the final pathological findings showed an endometrioid endometrial adenocarcinoma, International Federation of Gynecology and Obstetrics stage IB G2. Multidisciplinary counseling was provided, and the patient opted for strict medical surveillance. At 20 months after the primary treatment, the patient experienced a vaginal cuff recurrence and refused radiation therapy. She instead underwent robotic surgery, followed by 6 cycles of carboplatin 6 AUC and paclitaxel 175 mg/m2. Seventeen months later, a positron emission tomography/computed tomography scan revealed a 3-cm intraparenchymal lesion of the spleen, and robotic splenectomy was scheduled. The Institutional Review Board approved this study. INTERVENTION: The operative time was 90 minutes, and blood loss was <50 mL. The operation was performed successfully, with no intraoperative and postoperative complications. Histopathological analysis showed a 3-cm intraparenchymal splenic lesion. The patient was discharged on day +2, and 46 days later started adjuvant chemotherapy based on carboplatin 6 AUC and doxorubicin (Caelyx) 30 mg/m2. At a 2-month follow up, the patient was disease-free and in good general condition. CONCLUSION: This case demonstrates the successful robotic management of recurrent endometrial cancer. PMID- 29128440 TI - McCall Culdoplasty during Total Laparoscopic Hysterectomy: A Pilot Randomized Controlled Trial. AB - STUDY OBJECTIVE: To assess the feasibility and safety of a McCall culdoplasty at the time of total laparoscopic hysterectomy and to evaluate the differences in the total vaginal length, vaginal apex during Valsalva, and sexual function 12 months after McCall culdoplasty compared with standard cuff closure. DESIGN: A pilot randomized controlled, single-masked trial (Canadian Task Force classification I). SETTING: An academic tertiary care hospital. PATIENTS: Women undergoing total laparoscopic hysterectomy for benign indications from June 2013 to December 2013. INTERVENTIONS: Women were randomized (1:1) to McCall culdoplasty followed by standard cuff closure versus standard cuff closure. Patients underwent Pelvic Organ Prolapse Quantification examination and completed the Female Sexual Function Index immediately before surgery and at 6 months and 12 months postoperatively. The primary outcome was the operative time. Secondary outcomes included estimated blood loss, complications, total vaginal length, vaginal apex during Valsalva, and sexual function. MEASUREMENTS AND MAIN RESULTS: This study included 50 patients. The groups were similar in terms of preoperative and surgical characteristics. The operative time did not differ between the groups. The estimated blood loss and complications were also similar. The loss to follow-up was similar in both groups. Changes in the total vaginal length, vaginal apex during Valsalva, sexual function, and pain with intercourse did not differ between the groups. CONCLUSION: In this pilot study, the addition of McCall culdoplasty to standard cuff closure during total laparoscopic hysterectomy was not associated with an increase in operative time, estimated blood loss, or surgical complications. No differences in the total vaginal length or vaginal apex during Valsalva were observed at the 12-month follow-up. There were no differences in sexual dysfunction or dyspareunia. Given the well established risk reduction for the development of apical prolapse with McCall culdoplasty during vaginal hysterectomy, this procedure may be a feasible and safe addition to total laparoscopic hysterectomy. PMID- 29128441 TI - Toxocariasis in Africa: A One Health perspective. PMID- 29128442 TI - Urinary Excretion of Aluminium and Silicon in Secondary Progressive Multiple Sclerosis. AB - BACKGROUND: Progressive multiple sclerosis is a chronic autoimmune condition of unknown aetiology and few therapeutic options. Human exposure to aluminium has been linked with multiple sclerosis and affected individuals are known to excrete unusually high amounts of aluminium in their urine. Silicon-rich mineral waters facilitate the removal of aluminium from the body in urine and herein we have tested their efficacy in affecting urinary excretion of aluminium in individuals diagnosed with secondary progressive multiple sclerosis (SPMS). METHODS: Urinary excretion of aluminium and silicon, measured using transversely-heated graphite furnace atomic absorption spectrometry, was determined in 15 individuals diagnosed with SPMS over 24weeks, a 12week baseline period (control) followed by a 12week treatment period, during which individuals consumed up to 1.5L of a silicon-rich mineral water every day. FINDINGS: Individuals with SPMS excreted high amounts of aluminium during the baseline period (135.2nmol/mmol Crt (70.3 222.2, n=180) and females excreted significantly more aluminium than males. Regular drinking of a silicon-rich mineral water increased the urinary excretion of aluminium significantly (349.0nmol/mmol Crt (231.7-524.7, n=180; three-way ANOVA, F1,13=59.17, p-value=0.000003) relative to the baseline period. The majority of individuals, 14 out of 15, excreted more aluminium (MUmol/24h) following drinking of a silicon-rich mineral water (independent-test, p<0.05). Silicon-rich mineral waters may be an effective and non-invasive therapy for the removal of aluminium from the body of individuals with SPMS. PMID- 29128443 TI - Can Thyroid Hormone Analogues Be Used to Overcome Hypomyelination and Demyelination of the Central Nervous System? PMID- 29128445 TI - The promise of induced pluripotent stem cells for neurodevelopmental disorders. AB - A major challenge in clinical genetics and medicine is represented by genetically and phenotypically highly diverse neurodevelopmental disorders, like for example intellectual disability and autism. Intellectual disability is characterized by substantial limitations in cognitive function and adaptive behaviour. At the cellular level, this is reflected by deficits in synaptic structure and plasticity and therefore has been coined as a synaptic disorder or "synaptopathy". In this review, we summarize the findings from recent studies in which iPSCs have been used to model specific neurodevelopmental syndromes, including Fragile X syndrome, Rett syndrome, Williams-Beuren syndrome and Phelan McDermid syndrome. We discuss what we have learned from these studies and what key issues need to be addressed to move the field forward. PMID- 29128444 TI - Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients. AB - Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3-4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range-68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40-68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p=0.00009) and plasma 2-oxoglutarate concentrations (+12%, p=0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction. PMID- 29128447 TI - Developmental perspectives on methamphetamine abuse: Exploring adolescent vulnerabilities on brain and behavior. AB - Most people that experience illicit drugs do so for the first time during adolescence, and methamphetamine (meth) is no exception. Therefore, research into the effects of meth should highlight the adolescent period. Despite this, the vast majority of current literature has mainly focused on meth exposure during adulthood. In this review, we first describe existing literature that compares the behavioral effects of meth where exposure occurs in adolescence compared to adulthood. Given that there are actually very few such studies, we also look at what is known about neural effects of meth in the adult brain, and relate these to normal neural development occurring during the adolescent period to establish how meth may target maturing regions and related neurochemistry. What emerges overall is that adolescents appear to be more vulnerable to the rewarding and reinforcing effects of meth, and that meth indeed has effects on areas that are in flux during adolescence. However, there is some evidence for a paradoxical resistance to the neurotoxic effects during this period. We highlight the need for further age-related research to better understand, treat, and prevent meth use disorders and addiction in general. PMID- 29128446 TI - Disrupted focal white matter integrity in autism spectrum disorder: A voxel-based meta-analysis of diffusion tensor imaging studies. AB - BACKGROUND: Autism spectrum disorder (ASD) is a mental disorder that has long been considered to result from brain underconnectivity. However, volumetric analysis of structural MRI data has failed to find consistent white matter alterations in patients with ASD. The present study aims to examine whether there are consistent focal white matter alterations as measured by diffusion tensor imaging (DTI) in individuals with ASD compared with typically developing (TD) individuals. METHOD: Coordinate-based meta-analysis was performed on 14 studies that reported fractional anisotropy (FA) alterations between individuals with ASD and TD individuals. These studies have in total 297 subjects with ASD and 302 TD subjects. RESULTS: Activation likelihood estimation (ALE) analysis identified two clusters of white matter regions that showed consistent reduction of FA in individuals with ASD compared with TD individuals: the left splenium of corpus callosum and the right cerebral peduncle. CONCLUSIONS: Consistent focal white matter reductions in ASD could be identified by using FA, highlighting the cerebral peduncle which is usually overlooked in studies focusing on major white matter tracts. These focal reductions in the splenium and the cerebral peduncle may be associated with sensorimotor impairments seen in individuals with ASD. PMID- 29128449 TI - Writing a better research paper: Advice for young authors. PMID- 29128448 TI - Study design and statistical analysis. PMID- 29128450 TI - Presentation of data. PMID- 29128451 TI - Common reasons why manuscripts are rejected: Advice for young investigators. PMID- 29128452 TI - Correcting the literature. AB - We make important therapeutic decisions based on the best available evidence and it is important to correct the literature when results are in question. Appropriate actions may include publication of a correction, links to previously cited data to avoid double counting of outcomes, expressions of concern about study methods or integrity, and retraction of a published article. Corrections should be published as soon as possible, appear in a prominent position on a numbered page in the journal that originally published the article, and include the complete original citation to help ensure that an appropriate reference to the published erratum will be added to the MEDLINE citation. A retracted work should still be searchable, but should bear a clear indication that it was retracted and a statement regarding why the retraction occurred. As others may have acted upon the published data, it is important that corrections are appropriately visible and that the work doesn't simply disappear from literature searches. PMID- 29128453 TI - Getting the most out of on-line literature searches Tips for advanced searches. AB - Thorough and efficient literature searches are important to authors and practicing physicians alike, and modern search engines have many tools to expedite the process. In databases such as PubMed, new logic, or natural language, is set up to answer questions by simply typing them in. PMID- 29128454 TI - Duplicate publication. PMID- 29128455 TI - Responding to reviewers: Advice to young (and some older) authors. PMID- 29128456 TI - Sample size. PMID- 29128457 TI - Getting the most out of on-line literature searches - More on Boolean logic. PMID- 29128458 TI - An extemporaneous approach for optimizing acitretin dosing in pediatric patients. PMID- 29128459 TI - Successful treatment of moderate-to-severe alopecia areata improves health related quality of life. PMID- 29128460 TI - Misclassification of study designs in the dermatology literature. AB - BACKGROUND: The appropriate classification of study designs is important for review and assessment of the relevant scientific literature as a basis for decision making; however, little is known about whether study designs have been appropriately reported in the dermatology literature. OBJECTIVE: We aimed to validate the study designs in the dermatology literature and investigate discrepancies between author-reported and actual study designs. METHODS: We reviewed all issues of 3 major dermatology journals from January to December 2016. A total of 295 original articles investigating associations between exposures and health outcomes were included for analysis. We used a validated algorithm to classify the study designs. RESULTS: Among the 295 articles, 174 (59.0%) clearly mentioned the study design in the text. All interventional studies were correctly classified on the basis of study design (n = 42); however, 35 of 132 observational studies (26.5%) showed discrepancies between the author reported and actual study design. When the author-reported design was a prospective cohort, retrospective cohort, or case-control study (n = 61), approximately half of the studies were misclassified by the authors (n = 30). LIMITATIONS: We analyzed only 3 journals in the dermatology field. CONCLUSIONS: Our findings revealed substantial discrepancies between author-reported and actual study designs in the dermatologic literature, particularly among observational studies. PMID- 29128461 TI - Advice for reviewers (and authors and readers). PMID- 29128462 TI - Ethics and fairness during the review and publication process. PMID- 29128464 TI - Authorship. PMID- 29128463 TI - Objective outcome measures: Collecting meaningful data on alopecia areata. AB - BACKGROUND: Although alopecia areata is a common disorder, it has no US Food and Drug Administration-approved treatment and evidence-based therapeutic data are lacking. OBJECTIVE: To develop guidelines for the diagnosis, evaluation, assessment, response criteria, and end points for alopecia areata. METHODS: Literature review and expert opinion of a group of dermatologists specializing in hair disorders. RESULTS: Standardized methods of assessing and tracking hair loss and growth, including new scoring techniques, response criteria, and end points in alopecia areata are presented. LIMITATIONS: The additional time to perform the assessments is the primary limitation to use of the methodology in clinical practice. CONCLUSION: Use of these measures will facilitate collection of standardized outcome data on therapeutic agents used in alopecia areata both in clinical practice and in clinical trials. PMID- 29128466 TI - Planning better research projects: Advice for young researchers. PMID- 29128465 TI - Psoriasis and the risk of diabetes: A prospective population-based cohort study. AB - BACKGROUND: Data evaluating the impact of objectively measured psoriasis severity on type 2 diabetes mellitus (T2DM) risk are lacking. OBJECTIVE: To determine the risk for T2DM in patients with psoriasis compared with that in adults without psoriasis, stratified by categories of directly assessed body surface area (BSA) affected by psoriasis. METHODS: A prospective, population-based, cohort study from the United Kingdom in which 8124 adults with psoriasis and 76,599 adults without psoriasis were followed prospectively for approximately 4 years. RESULTS: There were 280 incident cases of diabetes in the psoriasis group (3.44%) and 1867 incident cases of diabetes in those without psoriasis (2.44%). After adjustment for age, sex and body mass index, the hazard ratios for development of incident diabetes were 1.21 (95% confidence interval [CI], 1.01-1.44), 1.01 (95% CI, 0.81 1.26), and 1.64 (95% CI, 1.23-2.18) in the groups with 2% or less of their BSA affected, 3% to 10% of their BSA affected, and 10% or more of their BSA affected compared with in the groups without psoriasis, respectively (P = .004 for trend). Worldwide, we estimate an additional 125,650 new diagnoses of T2DM per year in patients with psoriasis as compared with in those without psoriasis. LIMITATIONS: Relatively short-term follow-up and exclusion of prevalence cases, which may have masked associations in patients with less extensive psoriasis. CONCLUSION: Clinicians may measure BSA affected by psoriasis to target diabetes prevention efforts for patients with psoriasis. PMID- 29128467 TI - Volumetric response of the adult brain to seizures depends on the developmental stage when systemic inflammation was induced. AB - Inflammation has detrimental influences on the developing brain including triggering the epileptogenesis. On the other hand, seizure episodes may induce inflammatory processes and further increase of brain excitability. The present study focuses on the problem whether transitory systemic inflammation during developmental period may have critical importance to functional and/or structural features of the adult brain. An inflammatory status was induced with lipopolysaccharide (LPS) in 6- or 30-day-old rats. Two-month-old rats which experienced the inflammation and untreated controls received injections of pilocarpine, and the intensity of their seizure behavior was rated during a 6 hour period. Three days thereafter, the animals were perfused; their brains were postfixed and subjected to magnetic resonance imaging (MRI) scans. Then, volumes of the brain and of its main regions were assessed. LPS injections alone performed at different developmental stages led to different changes in the volume of adult brain and also to different susceptibility to seizures induced in adulthood. Moreover, the LPS pretreatments modified different volumetric responses of the brain and of its regions to seizures. The responses showed strong inverse correlations with the intensity of seizures but exclusively in rats treated with LPS on postnatal day 30. It could be concluded that generalized inflammation elicited at developmental stages may have strong age-dependent effects on the adult brain regarding not only its susceptibility to action of a seizuregenic agent but also its volumetric reactivity to seizures. PMID- 29128468 TI - The psychiatric risks of temporal epilepsy surgery. What should patients be told? PMID- 29128469 TI - The different patterns of seizure-induced aphasia in temporal lobe epilepsies. AB - OBJECTIVES: Ictal language disturbances may occur in dominant hemisphere temporal lobe epilepsy (TLE), but little is known about the precise anatomoelectroclinical correlations. This study investigated the different facets of ictal aphasia in intracerebrally recorded TLE. METHODS: Video-stereoelectroencephalography (SEEG) recordings of 37 seizures in 17 right-handed patients with drug-resistant TLE were analyzed; SEEG electroclinical correlations between language disturbance and involvement of temporal lobe structures were assessed. In the clinical analysis, we separated speech disturbance from loss of consciousness. RESULTS: According to the region involved, different patterns of ictal aphasia in TLE were identified. Impaired speech comprehension was associated with posterior lateral involvement, anomia and reduced verbal fluency with anterior mediobasal structures, and jargonaphasia with basal temporal involvement. The language production deficits, such as anomia and low fluency, cannot be simply explained by an involvement of Broca's area, since this region was not affected by seizure discharge. SIGNIFICANCE: Assessment of language function in the early ictal state can be successfully performed and provides valuable information on seizure localization within the temporal lobe as well as potentially useful information for guiding surgery. PMID- 29128470 TI - Is it worth it, or possible, to measure what matters to patients with epilepsy and their caregivers? AB - OBJECTIVE: The objective of this study was to collect perspectives, ideas, and values of people affected by epilepsy and their carer to include them in new research in this area. DESIGN: This is a semiquantitative study analyzing needs, emotions, and medical issues emerging from focus groups with patients and carers divided in three severity levels of disease. PARTICIPANTS: The participants were 25 patients and 36 carers attending outpatients' service of tertiary epilepsy center in Umbria, Italy. RESULTS: Assistance was the need expressed by more than 40% of the participants followed by experience-sharing, knowledge, control, clarity, and security. The only significant effect in logistic regression analysis after adjusting for severity was the patients' expressed need for "experience-sharing" more than their carers (OR 7.29, 95%CI: 1.76-30.18). Hope was the emotion expressed by more than 50% of the participants, followed by anger, fear, and resignation. After adjusting for severity, carers were more likely to express anger, in comparison with patients (OR 17.23, 95%CI: 3.55 83.74; P<0.001). The patients were 6.88 times more likely (95%CI 1.84-25.75; P=0.004) to express "resignation" than their carers. The most frequent medical issues were related to: "medications", "frequency of crises", "work impact", "quality of life", "psychomedical integration of care", and "development of new drugs". After adjusting for severity in a logistic regression analysis, patients were more likely to express concerns for the frequency of crises than carers (OR 3.57, 95%CI: 1.16-11.04; P=0.027). CONCLUSIONS: Patients' and carers' priorities, based on intense personal insight, represent a starting point to work for shared outcome measures in clinical trials and shared agenda in research, including research of strong evidence in complex intervention as service models for people with epilepsy. PMID- 29128471 TI - Development of verbal short-term memory and working memory in children with epilepsy: Developmental delay and impact of time-related variables. A cross sectional study. AB - While short-term memory (STM) and working memory (WM) are understood as being crucial for learning, and children with epilepsy often experience learning difficulties, little is known about the age-related development of memory span tasks in children with epilepsy. Short-term memory and WM, operationalized as digit span forwards (DSF) or digit span backwards (DSB), respectively, were studied. Participants were 314 children with epilepsy and 327 typically developing children in ages between 5 and 15years and full scale intelligence quotient (FS-IQ)>=75. Cross-sectional analyses of the data were done with analyses of variance and analyses of covariance ((M)ANCOVAs) and generalized linear analyses. The analyses revealed that STM problems in epilepsy were mediated by age-related gains in WM as well as by differences in IQ. Working memory developed at a quick pace in the younger children, the pace slowed down to some extent in the later primary school years and resumed again later on. Working memory problems prevailed in epilepsy, independent of IQ and development of STM. Timing of the epilepsy in terms of age at onset and duration determined memory development. The youngest children with epilepsy showed age-appropriate development in STM but were the most vulnerable in terms of WM development. Later in the course of the epilepsy, the WM problems of the young children attenuated. In later onset epilepsy, WM problems were smaller but persisted over time. PMID- 29128472 TI - Neutrophil-lymphocyte ratios in the prognostication of primary non-metastatic nasopharyngeal carcinoma. AB - INTRODUCTION: Nasopharyngeal carcinoma is a geographically and racially variable disease which has a high incidence in Malaysia. Based on current concepts in tumour related inflammation the inflammatory marker, neutrophil-lymphocyte ratio was tested to find its relationship with prognosis in nasopharyngeal carcinoma. OBJECTIVE: To investigate the effect of the neutrophil-lymphocyte ratio on prognosis in non-metastatic primary nasopharyngeal carcinoma patients and to further refine the cut off between high and low neutrophil-lymphocyte ratio values. METHODS: The medical charts of patients with histologically confirmed nasopharyngeal carcinoma from 1st January 2005 until 31st December 2009 were reviewed retrospectively and theneutrophil-lymphocyte ratio was calculated to see if there was any association between their higher values with higher failure rates. RESULTS: Records of 98 patients (n=98) were retrieved and reviewed. Only neutrophil-lymphocyte ratio (p=0.004) and tumor node metastasis staging (p=0.002) were significantly different between recurrent and non-recurrent groups, with the neutrophil-lymphocyte ratio being independent of tumor node metastasis staging (p=0.007). Treatment failure was significantly higher in the high neutrophil lymphocyte ratio group (p=0.001). Disease free survival was also significantly higher in this group (p=0.000077). CONCLUSION: High neutrophil-lymphocyte ratio values are associated with higher rates of recurrence and worse disease free survival in non-metastatic nasopharyngeal carcinoma patients undergoing primary curative treatment. PMID- 29128475 TI - Budesonide in Autoimmune Hepatitis: The Right Drug at the Right Time for the Right Patient. PMID- 29128474 TI - Clinical implications of guiding catheter extubation during fractional flow reserve measurements. AB - BACKGROUND: Fractional flow reserve (FFR) is defined by the maximal coronary flow ratio with and without stenosis. AIMS: We hypothesized that guiding catheter intubation in coronary ostia during FFR measurements may underestimate FFR value by limiting the increase of coronary flow during maximal hyperaemia. METHODS: Between June 2013 and January 2014, we prospectively included all patients with i.v. adenosine FFR measurements. FFR was measured with the guiding catheter intubated in the coronary ostia (FFRint) and extubated in the aorta (FFRext). We calculated the ratio between coronary ostium assessed by quantitative coronary angiography and guiding catheter surfaces, defined as the free ostial lumen ratio. RESULTS: In total, 151 lesions in 104 patients were included; 121 lesions and 88 patients were eligible for analysis. Mean+/-SD FFRext was significantly lower compared with FFRint; 0.82+/-0.08 and 0.84+/-0.08, respectively (P<0.001). Revascularization indication changed in 14 patients (16%). The difference induced by guiding extubation correlated significantly with the free ostial lumen ratio (R2=0.06, P=0.008). CONCLUSION: FFR value is significantly lower when the guiding catheter is extubated. The smaller the coronary ostium, the greater the difference observed between FFRext and FFRint. Guiding extubation during FFR measurements changed the revascularization indication in 16% of cases. PMID- 29128473 TI - Transfemoral aortic valve implantation is more successful with the Edwards Sapien 3 compared with the Edwards XT for the treatment of symptomatic severe aortic stenosis. AB - BACKGROUND: Residual aortic regurgitation (AR) after transfemoral aortic valve implantation (TAVI) is associated with increased mortality. The new Edwards Sapien 3 valve (ES3) is designed to reduce paravalvular AR. AIM: To compare a new generation and a late-generation balloon-expandable transcatheter heart valve. METHODS: In this study, 100 consecutive patients treated with the ES3 for symptomatic native severe aortic stenosis were compared with 100 consecutive patients treated with the Edwards Sapien XT valve (EXT); all valves were implanted via transfemoral access. We compared residual AR, rate of permanent pacemaker implantation, device success according to the second Valve Academic Research Consortium (VARC-2) criteria and 30-day follow-up. RESULTS: With the ES3, the risk of moderate/severe AR was lower (0% vs 3%), the risk of mild AR was lower (31% vs 40%) and the final result with no AR was higher (P=0.07). The mean aortic gradient was significantly higher with the ES3 (12.2+/-4.6 vs 9.4+/ 3.9mmHg; P<0.01). Device success according to the VARC-2 criteria was high with the ES3 and the EXT (97% vs 95%; P=0.48). Pacemaker implantation because of higher-grade atrioventricular block was similar: 9.3% after ES3 implantation and 6.9% after EXT implantation (P=0.56). There was significantly less major or life threatening bleeding with the ES3: 5% vs 14% (P=0.03) and 0% vs 8% (P<0.01), respectively. After 30 days, the VARC-2 early-safety endpoint was significantly lower with the ES3 (P<0.01). CONCLUSIONS: In conclusion, TAVI with the ES3 in patients with symptomatic severe aortic stenosis was associated with no moderate/severe AR, a trend towards a lower rate of mild AR, a significantly lower rate of major or life-threatening bleeding and early safety according to VARC-2 criteria within 30 days compared with the EXT. PMID- 29128476 TI - Increased Systemic Antibiotic Use and Clostridium difficile Infection Among Outpatients With Irritable Bowel Syndrome. PMID- 29128477 TI - Congenital Infiltrating Lipomatosis of the Face: Case Report With Presentation of a New Multistep Surgical Approach. AB - PURPOSE: This report describes the first case of congenital infiltrating lipomatosis of the face (CIL-F) that was successfully managed with 2-jaw orthognathic surgery. MATERIALS AND METHODS: The patient was followed from 4 to 18 years of age. The multistep approach used consisted of a facelift-type procedure at 12 years to improve the soft tissue profile. At 13 years, the transverse maxillary deficiency was treated with transpalatal distraction. At 14 years, the patient underwent bimaxillary orthognathic surgery with a genioplasty. RESULTS: The patient's satisfaction level was very high and remained constant during the 4-year follow up. Extraoral clinical examination showed nearly complete harmonization at the soft and hard tissue levels. There was no recurrence of hypertrophy of the bones or facial soft tissues during the 4-year follow-up. CONCLUSION: The results of this study indicate that a surgical approach for CIL-F at the soft and bony levels is possible if indicated. Orthognathic surgery can be performed and good esthetic and functional results can be achieved. To minimize the risk of recurrence, it is important to perform the treatment after the onset of puberty. This harmonization at the osseous level can greatly benefit the psychological well-being of the patient. PMID- 29128478 TI - Protein overexpression and gene amplification of cellular mesenchymal-epithelial transition factor is associated with poor prognosis in micropapillary-predominant subtype pulmonary adenocarcinoma. AB - Micropapillary-predominant subtype pulmonary adenocarcinoma (MPPAC) is a subtype of lung cancer with poor prognosis. Cellular mesenchymal-epithelial transition factor (c-MET) is a promising pharmaceutic target found to be associated with the survival of patients with pulmonary adenocarcinoma. In this study, we aimed to analyze c-MET protein overexpression and gene amplification in MPPAC samples and to elucidate their relationship with the clinicopathological characteristics of the patients. c-MET protein expression was examined by immunohistochemical analyses, and gene amplification was detected by fluorescence in situ hybridization. A total of 86 MPPAC cases were included in this study. The prevalence of c-MET protein overexpression and gene amplification were 62.8% and 10.5%, respectively. C-MET protein overexpression was significantly associated with smoking status, lymphatic and venous invasion, and tumor-node-metastasis stage (P = .014, P = .040, and P = .004, respectively), but c-MET gene amplification showed no relation with any of these characteristics. Univariate analysis revealed that pleural invasion, lymph node metastasis, lymphatic and venous invasion, tumor-node-metastasis stage, c-MET protein overexpression, and c MET gene amplification were associated with poor prognosis (P = .041, P < .001, P = .001, P < .001, P = .001 and P = .001, respectively), but only c-MET gene amplification was an independent prognostic marker (P = .04). These results indicated that c-MET is an important biomarker. Also, c-MET protein overexpression and gene amplification are highly related to poor prognosis in patients with MPPAC. PMID- 29128479 TI - Adipocyte size variability in benign and malignant lipomatous tumors and morphologic mimics: a quantitative definition using digital pathology. AB - Among well-differentiated lipomatous lesions, variability in adipocyte size has been proposed as a morphologic feature of malignancy. Specifically, normal adipose tissue and benign lipomas tend to contain adipocytes of uniform size, whereas atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) is described as containing adipocytes with a conspicuous variation in cell size. However, this proposed variance has never been objectively, quantitatively correlated with diagnosis. Using whole-slide scanning combined with semiautomated digital image analysis, we aimed to quantitatively test the hypothesis that variance in adipocyte size is a feature of malignancy in well-differentiated lipomatous tumors. Whole-slide scanning was performed on representative hematoxylin and eosin-stained slides selected from 130 cases representing benign (lipoma, spindle cell lipoma) and malignant lipomatous neoplasms (ALT/WDL) and morphologic mimics (normal adipose tissue, fat necrosis, fat atrophy). A previously validated, open source software package (Fiji-based Adiposoft) was used in semiautomated analysis of adipocyte size from a representative 1-cm2 portion of each slide. Median, range, and variance of cell sizes were compared across all diagnoses. Fat atrophy demonstrated smaller adipocyte cell size compared with other diagnoses. Among the remaining diagnostic groups, no significant differences were identified in adipocyte size or variance by objective quantitative morphologic analysis. However, the maximum range of adipocyte size was significantly higher in ALT/WDL than conventional lipoma and spindle cell lipoma. These data quantitate the morphology of ALT/WDL and its mimics and more specifically define the somewhat subjective "variability" of cell size as maximum range, rather than variance, of adipocyte size. PMID- 29128480 TI - Rapid detection of Haemophilus parasuis using cross-priming amplification and vertical flow visualization. AB - Haemophilus parasuis infection is of considerable economic importance in the swine industry due to high morbidity and mortality in naive swine populations. Accurate detection and identification of the causative agent are difficult, yet necessary, for disease control. In this study, a simple and rapid method of cross priming amplification (CPA) with a vertical flow (VF) visualization strip was established to detect H. parasuis. The reaction can specifically identify 15 serovar reference strains and 57 clinically isolated strains of H. parasuis, with a detection limit of 14CFU. The performance of the CPA-VF assay was evaluated and compared with that of species-specific PCR by testing 62 clinical culture positive specimens of H. parasuis. The entire process, from specimen processing to analysis of the results, can be completed in 2h without a complicated apparatus. The convenience and speed of the CPA-VF assay in this study make it a suitable choice for epidemiological investigation and point-of-care testing (POCT) for H. parasuis infection. PMID- 29128481 TI - A Novel Approach to Managing Trans-Subclavian Transcatheter Aortic Valve Replacement With Regional Anesthesia. PMID- 29128482 TI - Aortic Valve Cusp Coaptation Surface Area Using 3-Dimensional Transesophageal Echocardiography Correlates with Severity of Aortic Valve Insufficiency. AB - OBJECTIVE: The aim of this study was to test both in humans and using finite element (FE) aortic valve (AV) models whether the coaptation surface area (CoapSA) correlates with aortic insufficiency (AI) severity due to dilated aortic roots to determine the validity and utility of 3-dimensional transesophageal echocardiographic-measured CoapSA. DESIGN: Two-pronged, clinical and computational approach. SETTING: Single university hospital. PARTICIPANTS: The study comprised 10 patients with known AI and 98 FE simulations of increasingly dilated human aortic roots. INTERVENTIONS: The CoapSA was calculated using intraoperative 3-dimensional transesophageal echocardiography data of patients with isolated AI and compared with established quantifiers of AI. In addition, the CoapSA and effective regurgitant orifice area (EROA) were determined using FE simulations. MEASUREMENTS AND MAIN RESULTS: In the 10 AI patients, regurgitant fraction (RF) increased with EROA (R2 = 0.77, p = 0.0008); CoapSA decreased with RF (R2 = 0.72, p = 0.0020); CoapSA decreased with EROA (R2 = 0.71, p = 0.0021); and normalized CoapSA (CoapSA / [Ventriculo-Aortic Junction * Sinotubular Junction]) decreased with EROA (R2 = 0.60, p = 0.0088). In the 98 FE simulations, normalized CoapSA decreased with EROA (R2 = 0.50, p = 0.0001). CONCLUSIONS: In both human and FE AV models, CoapSA was observed to be inversely correlated with AI severity, EROA, and RF, thereby supporting the validity and utility of 3D TEE measured CoapSA. A clinical implication is the expectation that high values of CoapSA, measured intraoperatively after AV repairs, would correlate with better long-term outcomes of those repairs. PMID- 29128483 TI - Subcutaneous Implantable Cardioverter-Defibrillator Therapy for Secondary Prevention After Heart Transplantation: Is it Practical for All Patients? PMID- 29128484 TI - Transdiaphragmatic Echocardiography as a Rescue in Liver Transplantation. PMID- 29128485 TI - Neutrophil, Lymphocyte, and Platelet Counts and Acute Kidney Injury After Cardiovascular Surgery. AB - OBJECTIVE: Postoperative low platelet count and perioperative high neutrophil/lymphocyte (N/L) ratio are associated with acute kidney injury (AKI) and mortality after cardiac surgery. The authors investigated whether (1) their combination neutrophil/lymphocyte * platelet (N/LP) ratio is an independent predictor of AKI and postoperative mortality and (2) whether the N/LP ratio increases predictive ability compared with the N/L ratio or platelet nadir. DESIGN: This was a retrospective and observational study. SETTING: Single large university hospital. PARTICIPANTS: The study comprised 1,099 adult patients who underwent cardiovascular surgeries with cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Baseline clinical parameters including platelet counts, the N/L ratio, and the N/LP ratio measured before surgery, immediately after surgery, and on postoperative days 1 and 2 were obtained. Multivariable analysis revealed that the maximal N/LP ratio was an independent predictor of AKI and 5-year mortality. Propensity score matching was performed between the high and low preoperative N/LP ratio groups. Significant differences in the mortality rate and incidence of AKI also were found in the matched cohort. The area under the receiver operating characteristic curve (AUC) of the maximal N/LP ratio as a continuous variable was significantly higher than the AUC of the maximal N/L ratio or nadir platelet as continuous variables (maximal N/LP ratio: 0.62 v N/L ratio: 0.59; p = 0.026 v platelet nadir: 0.57; p = 0.003). The AUC of multivariable risk prediction with the maximal N/LP ratio (0.77) was significantly higher than the AUC without the N/LP ratio (0.70; p < 0.0001). CONCLUSIONS: High N/LP ratios were associated with postoperative AKI and 5-year mortality. The N/LP ratio may assist with the the prediction of AKI and mortality in high-risk cardiovascular surgery. PMID- 29128486 TI - Lower Dose of Sufentanil Does Not Enhance Fast Track Significantly-A Randomized Study. AB - OBJECTIVE: Adjustment in the doses of opioids has been a focus of interest for achieving better fast-track conditions in cardiac anesthesia, but relatively sparse information exists on the potential effect of psychologic and behavioral factors, such as stress, anxiety, and type of personality, on anesthesia requirements and patient turnover in the cardiac recovery unit (CRU); to the authors' knowledge, this particular focus has not been systematically investigated. In this randomized study, the authors tested the hypothesis that low-dose sufentanil, compared with a standard dose, can improve fast-track parameters and the overall quality of recovery. Opioid requirements related to personality type, pain sensitivity, and preoperative stress and anxiety also were assessed. DESIGN: A randomized, prospective study. PARTICIPANTS: The study comprised 60 patients scheduled for elective coronary artery bypass grafting with or without aortic valve replacement. SETTING: A university hospital. INTERVENTIONS: Patients were randomly assigned to receive either a standard dose (bolus 0.5 ug/kg) or low dose (bolus 0.25 ug/kg) of sufentanil combined with propofol. MEASUREMENTS AND MAIN RESULTS: The primary outcome variables were ventilation time and eligible time to discharge from the CRU. The secondary objective was to evaluate the relationship between opioid requirements and personality type, pain sensitivity, and preoperative stress and anxiety. The groups were comparable in selected demographics and perioperative parameters. There was no difference between groups in ventilation time (low dose: 191 [163 257] v standard dose: 205 [139-279] min; p = 0.405); eligible CRU discharge time (10.3 +/- 5.0 v 10.3 +/- 4.2 h; p = 0.978); or administration of postoperative morphine (25 [11-34) v 27 [10-39] g; p = 0.790). There was no difference between groups in total sufentanil administration and various preoperative psychologic and behavioral test levels nor in the time to reach bispectral index <50 during induction, except that personality type A demonstrated a longer induction time of 10 (8-12) minutes versus 6 (4-8) minutes in low-score patients. CONCLUSION: A lower dose of sufentanil, compared with a standard dose, does not enhance fast track conditions significantly. PMID- 29128487 TI - Elevated Pulse Pressure, Intraoperative Hemodynamic Perturbations, and Acute Kidney Injury After Coronary Artery Bypass Grafting Surgery. AB - OBJECTIVE: To explore whether baseline pulse pressure (PP) confers an increased risk for acute kidney injury (AKI) independent of intraoperative hypotension or hypertension in patients who undergo coronary artery bypass grafting (CABG) surgery. DESIGN: Retrospective study. SETTING: Single academic center. PARTICIPANTS: 5,808 patients who underwent CABG surgery. MEASUREMENTS AND MAIN RESULTS: Baseline arterial blood pressure was defined as the mean of the first 5 measurements recorded by the automated record keeping system before anesthesia was induced. Weighted duration of intraoperative hypotension and hypertension were defined as the area (min * mmHg) below a mean arterial pressure of 55 mmHg and above a mean arterial pressure of 100 mmHg. Multivariable logistic and proportional odds regression analyses were performed to determine whether baseline PP and weighted duration of intraoperative hypotension and hypertension were independently associated with postoperative AKI. Of the 5,808 patients, PP was <40 mmHg in 90 (1.6%), 40-to-80 mmHg in 2,463 (42.4 %), and >80 mmHg in 3,255 (56%) patients. The incidence of AKI was 57.7%, which included 7.4% (249 patients) and 2.8% (93 patients) who experienced stages 2 and 3 AKI, respectively. In the risk-adjusted analyses, baseline PP was associated with higher odds for postoperative AKI (odds ratio for every 20 mmHg increase in PP, 1.15; 95% confidence interval 1.10-1.21; p < 0.0001) and a higher severity of postoperative AKI (proportional odds ratio, 1.13; 95% confidence interval 1.03 1.24; p = 0.0098). There was no evidence that weighted duration of intraoperative hypotension or hypertension was associated with postoperative AKI or that either interacted with the association of baseline PP with AKI. CONCLUSIONS: Baseline PP was significantly associated with postoperative AKI after CABG surgery, independent of weighted duration of intraoperative hypotension or hypertension. PMID- 29128488 TI - Evidence Base Surrounding Bronchial Blocker Use Continues to Evolve. PMID- 29128489 TI - Prognostic Impacts of Increases in Amino Transaminases Following Coronary Artery Bypass Grafting on Mortality. AB - OBJECTIVE: To evaluate the prognostic impacts of postoperative increases in serum amino transaminases on 1-year mortality in patients who underwent coronary artery bypass graft. DESIGN: A retrospective analysis. SETTING: A tertiary care university hospital. PARTICIPANTS: A total of 1,950 patients who underwent coronary artery bypass graft. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Aspartate amino transaminase and alanine amino transaminase ratios were calculated as the ratio between the peak aspartate amino transaminase and alanine amino transaminase within the first 5 post-operative days and their respective upper limit of normal values. A ratio of 2.0 was seen to be the minimum for which a difference in 1-year mortality could be detected in univariate analysis, when considering simultaneously both aspartate amino transaminase and alanine amino transaminase ratios. Multivariable analysis showed an association between an aspartate amino transaminase ratio > 2.0 and increased 1-year mortality (hazard ratio [HR] 2.68, 95% confidence interval [CI] 1.42-5.05, P = 0.002), and also between both an aspartate amino transaminase and alanine amino transaminase ratio > 2.0 and increased 1-year mortality (HR 3.90, 95% CI 1.87-8.14, P < 0.001). However, increases in alanine amino transaminase only above the upper limit of normal were not associated with increased 1-year mortality. CONCLUSIONS: Postoperative increases in aspartate amino transaminase only and increases in both aspartate amino transaminase and alanine amino transaminase greater than twice the upper limit of normal were associated with increased 1-year mortality in patients undergoing coronary artery bypass graft. PMID- 29128490 TI - Responders to rTMS for depression show increased fronto-midline theta and theta connectivity compared to non-responders. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, but only some individuals respond. Predicting response could reduce patient and clinical burden. Neural activity related to working memory (WM) has been related to mood improvements, so may represent a biomarker for response prediction. PRIMARY HYPOTHESES: We expected higher theta and alpha activity in responders compared to non-responders to rTMS. METHODS: Fifty patients with treatment resistant depression and twenty controls performed a WM task while electroencephalography (EEG) was recorded. Patients underwent 5-8 weeks of rTMS treatment, repeating the EEG at week 1 (W1). Of the 39 participants with valid WM-related EEG data from baseline and W1, 10 were responders. Comparisons between responders and non-responders were made at baseline and W1 for measures of theta (4-8 Hz), upper alpha (10-12.5 Hz), and gamma (30-45 Hz) power, connectivity, and theta-gamma coupling. The control group's measures were compared to the depression group's baseline measures separately. RESULTS: Responders showed higher levels of WM-related fronto-midline theta power and theta connectivity compared to non-responders at baseline and W1. Responder's fronto-midline theta power and connectivity was similar to controls. Responders also showed an increase in gamma connectivity from baseline to W1, with a concurrent improvement in mood and WM reaction times. An unbiased combination of all measures provided mean sensitivity of 0.90 at predicting responders and specificity of 0.92 in a predictive machine learning algorithm. CONCLUSION: Baseline and W1 fronto-midline theta power and theta connectivity show good potential for predicting response to rTMS treatment for depression. PMID- 29128491 TI - Screening for fetal chromosomal and subchromosomal disorders. AB - Screening for fetal chromosomal disorders has evolved greatly over the last four decades. Initially, only maternal age-related risks of aneuploidy were provided to patients. This was followed by screening with maternal serum analytes and ultrasound markers, followed by the introduction and rapid uptake of maternal plasma cell-free DNA-based screening. Studies continue to demonstrate that cfDNA screening for common aneuploidies has impressive detection rates with low false positive rates. The technology continues to push the boundaries of prenatal screening as it is now possible to screen for less common aneuploidies and subchromosomal disorders. The optimal method for incorporating cfDNA screening into existing programs continues to be debated. It is important that obstetricians understand the biological foundations and limitations of this technology and provide patients with up-to-date information regarding cfDNA screening. PMID- 29128493 TI - Molecular characterization of a CC motif chemokine 19-like gene in ayu (Plecoglossus altivelis) and its role in leukocyte trafficking. AB - The CC motif chemokine 19 (CCL19) functions in acute inflammation by recruiting lymphocytes and other cells. However, CCL19 has only been investigated in few fish species. In this study, we characterized a CCL19-like molecule (PaCCL19l) in ayu (Plecoglossus altivelis), a teleost fish. Sequence analysis revealed that PaCCL19l was most closely related to Atlantic salmon (Salmon salar) CCL19l1, which belonged to the fish CCL19a.1 subcluster. PaCCL19l was constitutively expressed in the tested ayu tissues and peripheral blood mononuclear cells (PBMCs), with the highest transcript level in PBMCs. Upon infection with Vibrio anguillarum, the expressions of PaCCL19l in the head kidney, liver, spleen, PBMCs, and monocytes/macrophages (MO/MPhi) were dramatically up-regulated. Recombinant PaCCL19l (rPaCCL19l) exhibited a significant effect on the chemotaxis of lymphocytes and MO/MPhi in vitro and in vivo. Meanwhile, rPaCCL19l exerted a high chemotaxic activity for lipopolysaccharide (LPS)-stimulated MO/MPhi (M1 type), but not for cyclic adenosine monophosphate (cAMP)-stimulated MO/MPhi (M2 type). When ayu MO/MPhi was treated with rPaCCL19l along with Vibrio anguillarum infection, the mRNA expression of proinflammatory cytokines (IL-1beta, TNFalpha, IL-6, IL-12b, and IFN-gamma) was up-regulated, while that of anti-inflammatory cytokines (IL-10, TGFbeta, and IL-22) was down-regulated. Ayu MO/MPhi treated with anti-PaCCL19l IgG gave the opposite result. These results implicated that PaCCL19l is involved in the selective chemotaxis of ayu immune cells and promotes the host at a pro-inflammatory state. PMID- 29128492 TI - Expression of potassium-dependent sodium-calcium exchanger in the murine lens. AB - Loss of intracellular calcium homeostasis may contribute to the opacification of lens tissue during cortical cataract formation. In healthy lenses, the concentration of intracellular calcium is maintained at levels far below electrochemical equilibrium but the identity of the calcium extrusion mechanism in lens fiber cells has remained elusive. Previous studies focused on the role of plasma membrane calcium ATPases and sodium-calcium exchangers. Here, we examined the expression of mRNA transcripts encoding potassium-dependent sodium-calcium exchangers (Nckx's, encoded by the Slc24 gene family) in the mouse lens. The most abundant of the five Slc24 family members was Slc24a4 (Nckx4). Notably, Slc24a4 was the only family member with increased expression in fiber cells. Using an antibody raised against recombinant mouse Nckx4, we showed that the protein is expressed strongly in the outer cortical fibers, consistent with results of in situ hybridization experiments and earlier mass spectrometry analysis. To test the role of Nckx4 directly, we generated mice in which Slc24a4 was deleted conditionally in lens tissue. In conditional knockout animals, the level of Nckx4 protein was reduced to background levels without a discernible effect on lens growth or transparency. Thus, despite its relative abundance in the lens, Nckx4 does not appear to have an indispensable role in the maintenance of lens clarity. PMID- 29128494 TI - The shrimp hormone receptor acts as an anti-apoptosis and anti-inflammatory factor in innate immunity. AB - Previously, we found that the expression of several genes, including HR, varied in Drosophila melanogaster after white spot syndrome virus (WSSV) infection. In this present study, we further investigated the role of HR in Kuruma shrimp, Marsupenaeus japonicus and determined its anti-apoptosis and anti-inflammation role in the innate immune system. We successfully identified a partial sequence (866 bp in length) of the M. japonicus hormone receptor ligand binding domain (mjHR_LBD/mjHR). The 5' end of mjHR was successfully obtained; the open reading frame (ORF) ran from 33 to 701 bp, and encoded a protein containing 222 amino acids. mjHR belonged to the ligand binding domain of hormone receptors, was most likely part of a nuclear hormone receptor, and shared a close evolutionary relationship with other arthropods, such as insects. mjHR was expressed predominantly in immunity tissues such as gills, hemolymph and the hepatopancreas. WSSV infection could cause the down-regulation of mjHR, while infection with Vibrio alginolyticus could cause significant up-regulation of mjHR. The expression of mjHR was knocked down by dsRNA expressed by an engineered LITMUS 38i-HR plasmid. Virus and bacteria challenge experiment showed that the mortality of WSSV-infected shrimps was elevated in the absence of HR while the mortality of shrimps infected with V. alginolyticus was slightly reduced. Phenoloxidase (PO) activity, phagocytosis and apoptosis were promoted, while superoxide dismutase (SOD) activity was impaired, indicating that mjHR functions in an anti-apoptosis and anti-inflammation manner to prevent shrimp death caused by an over-load of immunity responses. Differences between mjHR expression and mortality change after WSSV or V. alginolyticus infection indicated that there was a different strategy for viruses or bacteria when confronted with the innate immune system. PMID- 29128495 TI - The interaction of Schiff Base complexes of nickel(II) and zinc(II) with duplex and G-quadruplex DNA. PMID- 29128497 TI - Replacement of oxidizable residues predicted by QM-MM simulation of a fungal laccase generates variants with higher operational stability. AB - In this work, we sought to obtain a more stable laccase with higher operational stability for the oxidation of phenols. During this reaction, phenoxy free radicals are produced that gradually inactivate the enzyme; the inactivation rate depends on the phenol chemical nature. In order to predict residues prone to oxidize within the active site, we simulated activated states of the catalytic region of a fungal laccase using QM-MM tools (Quantum Mechanics-Molecular Mechanics). After simulating the electron distribution in both the basal and activated state (plus or minus one electron) of several conformations of Coriolopsis gallica laccase, residues that could be susceptible to oxidation were identified, according to the values of spin density obtained from calculations. Three targets were selected (F357, F413, and F475) to be replaced by site directed mutagenesis with less oxidizable residues such as leucine, alanine, and isoleucine. The resulting variants displayed a higher specific activity (from 1.5 to 4-fold) than the parental enzyme. Catalyst depletion during phenol oxidation was 2.5-fold lower for the variants, reflecting a higher operational stability. PMID- 29128498 TI - Women in Radiology: Creating a Global Mentorship Network Through Social Media. PMID- 29128499 TI - Women in Radiology: A Retrospective Twin Study. PMID- 29128496 TI - Nickel (II) pyrrocorphin: Enhanced binding ability in a highly reduced porphyrin complex. AB - Pyrrocorphin is an air-sensitive porphyrinoid with a highly reduced hexahydroporphyrin core. In contrast, pyrrolidine-fused pyrrocorphin (Pyr) obtained by successive 1,3-dipolar cycloaddition reactions of azomethine ylide to 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin is less air-sensitive. In order to reveal the effect of highly reduced porphyrin rings on the physicochemical properties of their metal complexes, we have prepared diamagnetic (S=0) Ni(II) complex Ni(II)(Pyr). The addition of excess pyridine (Py) to the toluene solution of Ni(II)(Pyr) yielded five-coordinate Ni(II)(Pyr)(Py), which was then completely converted to six-coordinate paramagnetic (S=1) Ni(II)(Pyr)(Py)2. The latter was characterized by UV-Vis, 1H NMR, CV, SQUID, and X-ray crystallography as well as DFT calculations. As compared with analogous complexes of porphyrin (Por), chlorin (Chl), and isobacteriochlorin (Iso) reported by Herges and co-workers (R. Herges et al., Inorg. Chem. 2015), Ni(II)(Pyr)(Py)2 has longer equatorial NiN and shorter axial NiN bonds. The CV study has shown a large decrease in HOMO-LUMO gap as the reduction of porphyrin ring proceeds, which has further been confirmed by UV-Vis and DFT calculation. Titration studies using 1H NMR and UV-Vis have shown that the first binding constant of pyridine toward Ni(II)(Pyr) is ca. 4 times as large as that of Ni(II)(Iso) and ca 230 times as large as that of Ni(II)(Por). Thus, we have concluded that the binding constant of pyridine to Ni(II) porphyrinoid increases by the following order: Por= 3, compared to conventional shoes. CONCLUSION: Unloading shoes conferred additional symptomatic benefits over conventional shoes in people with moderate to severe knee OA. There was some evidence effects may be mediated by a reduction in peak KAM. However, we were underpowered for subgroup analyses. These patients may represent a subgroup to which biomechanical interventions designed to reduce the KAM may be more effectively targeted. PMID- 29128508 TI - Relative and absolute test-retest reliabilities of biomechanical risk factors for knee osteoarthritis progression: benchmarks for meaningful change. AB - OBJECTIVE: Biomechanical factors are important treatment targets in knee osteoarthritis. The knee adduction (KAM) and flexion (KFM) moments, quadriceps strength and power, load frequency, and body mass index (BMI) all have the potential to affect knee articular cartilage integrity by modulating forces across the joint. To identify clinically meaningful change, however, these measurements must be reliable and sensitive to change. This study estimated relative and absolute test-retest reliabilities over long periods of biomechanical risk factors for knee osteoarthritis progression. METHOD: Data from a longitudinal, observational study were analyzed for knee osteoarthritis patients with data at baseline, 6-month and 24-month follow-ups. Gait kinematics and kinetics, quadriceps strength and power, daily load frequency and BMI were collected. Relative and absolute test-retest reliabilities of these measures were estimated using intraclass correlation coefficients (ICCs) and standard errors of measurement (SEMs), respectively. Minimal detectable change at the 95% confidence level (MDC95) was also calculated. RESULTS: Data from 46 participants [36 women; age 61.0 (6.6) years] were included. Good-to-excellent relative reliabilities (ICC >= 0.80) indicated that KAM peak and impulse, quadriceps strength and power, and BMI had a strong ability to discriminate amongst participants. Absolute reliabilities were high for quadriceps strength and BMI, which demonstrated reasonable within-participant variability (SEMs <= 11% of the mean). The MDC95 values supported use of clinical interventions effective in reducing BMI and KAM, and increasing quadriceps strength. CONCLUSION: These data are useful in interpreting findings from interventional or longitudinal investigations by determining whether observed changes are beyond measurement error and interpretable as true change. PMID- 29128509 TI - Monocyte activation is elevated in women with knee-osteoarthritis and associated with inflammation, BMI and pain. AB - OBJECTIVE: Monocytes contribute to synovitis and disease pathogenesis in osteoarthritis (OA). Low-grade inflammation occurs in OA and correlates with disease severity and progression. Since monocyte development and function is altered by systemic inflammation, we analyzed monocyte numbers and function between individuals with knee OA and healthy age- and sex-matched controls. DESIGN: We analyzed markers of soluble and cellular inflammation in peripheral blood of women with knee OA and compared them to healthy age- and sex-matched controls. Soluble inflammatory mediators (TNF, IL-6, IL-10 and CRP) in the serum were measured by high-sensitivity ELISA. Leukocyte numbers, surface expression of monocyte activation markers, and monocyte production of pro-inflammatory mediators (TNF and IL-1beta) following stimulation were measured by flow cytometry. RESULTS: Women with knee OA (n = 15) had elevated levels of serum c reactive protein (CRP) and a lower proportion of circulating monocytes. Monocytes from OA participants had elevated expression of the activation markers CD16, CCR2, and HLA-DR and induced greater production of tumor necrosis factor (TNF) and IL-1beta compared to healthy controls. Higher serum TNF and BMI were correlated with increased monocyte expression of CCR2. Additionally monocyte CCR2 expression and serum TNF were correlated with worse pain on a validated questionnaire. CONCLUSIONS: Our findings suggest monocytes are activated prior to their entry into the synovium. Modulating systemic inflammation and monocyte recruitment to the synovium could be of therapeutic benefit. PMID- 29128510 TI - Enzymes involved in tumor-driven angiogenesis: A valuable target for anticancer therapy. AB - Angiogenesis plays a pivotal role in cancer progression and is required for tissue invasion and metastasis. Starting with Folkman's initial observations in 1971, basic research continued to shed new molecular insight into this multifaceted process, leading to the development of several anti-angiogenic drugs. To date, anti-vascular endothelial growth factor monoclonal antibodies, such as bevacizumab and ramucirumab, and receptor tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, regorafenib and axitinib) have had a profound impact on the way we treat patients with advanced cancer, providing in some cases unprecedented clinical benefit. The molecular mechanisms underlying tumor-driven angiogenesis have been explored extensively and have unveiled a number of potential clinically relevant targets, including several novel enzymes. In this review, we summarized the current strategies to target tumor-driven angiogenesis through the inhibition of relevant and selected classes of enzymes involved in this process. PMID- 29128511 TI - Inducing circular vection with tactile stimulation encircling the waist. AB - In general, moving sensory stimuli (visual and auditory) can induce illusory sensations of self-motion (i.e. vection) in the direction opposite of the sensory stimulation. The aim of the current study was to examine whether tactile stimulation encircling the waist could induce circular vection (around the body's yaw axis) and to examine whether this type of stimulation would influence participants' walking trajectory and balance. We assessed the strength and direction of perceived self-motion while vision was blocked and while either receiving tactile stimulation encircling the waist clockwise or counterclockwise or no tactile stimulation. Additionally, we assessed participants' walking trajectory and balance while receiving these different stimulations. Tactile stimulation encircling the waist was found to lead to self-reported circular vection in a subset of participants. In this subset of participants, circular vection was on average experienced in the same direction as the tactile stimulation. Additionally, perceived rotatory self-motion in participants that reported circular vection correlated with balance (i.e., sway velocity and the standard error of the mean in the medio-lateral dimension). The fact that, in this subset of participants, subjective reports of vection correlated with objective outcome measures indicates that tactile stimulation encircling the waist might indeed be able to induced circular vection. PMID- 29128514 TI - Corrections. PMID- 29128513 TI - Dihydroartemisinin induced caspase-dependent apoptosis through inhibiting the specificity protein 1 pathway in hepatocellular carcinoma SK-Hep-1 cells. AB - AIMS: Dihydroartemisinin (DHA) is a semi-synthetic derivative of artemisinin, well known for a safe and effective first-line antimalarial agent. This study investigated whether and how DHA induces apoptosis focusing on the specificity protein 1 (Sp1) pathway in hepatocellular carcinoma (HCC) SK-Hep-1 cells. MAIN METHODS: The cell viability was evaluated by MTT assay. Cell cycle analysis was performed after PI staining by flow cytometry system. Apoptosis was confirmed by DAPI staining and by detecting cytoplasmic histone-associated-DNA-fragments using a cell death detection ELISAPLUS kit. The expression of proteins involved in apoptosis was evaluated by Western blot. The nuclear localization of Sp1 was evaluated by immunofluorescence assay. KEY FINDINGS: DHA exerted potent cytotoxicity against HCC SK-Hep-1 cells compared with normal hepatocyte AML12 cells. The sub-G1 DNA content and apoptosis index were increased by DHA, which was accompanied by nuclei condensation and fragmentation. DHA activated caspase 3, caspase 8, and caspase 9 and cleaved poly (ADP-ribose) polymerase (PARP). DHA induced apoptotic cell death, activation of caspases and cleavage of PARP were dramatically inhibited by pan caspase inhibitor Z-VAD-FMK. DHA down-regulated protein expression and nuclear localization of Sp1, which in turn decreased Sp1 downstream target protein, X-linked inhibitor of apoptosis. Decreased Sp1 protein expression by DHA was restored by proteasome inhibitor MG132. DHA led to a down regulation of phospho-ERK, -p38 and -JNK without affecting their total forms. SIGNIFICANCE: These results demonstrate that DHA induces caspase-dependent apoptosis in HCC SK-Hep-1 cells by proteasome-dependent degradation of Sp1, which is involved in mitogen-activate protein kinase pathway. PMID- 29128515 TI - Injectable network biomaterials via molecular or colloidal self-assembly. AB - Self-assembly is a powerful tool to create functional materials. A specific application for which self-assembled materials are ideally suited is in creating injectable biomaterials. Contrasting with traditional biomaterials that are implanted through surgical means, injecting biomaterials through the skin offers numerous advantages, expanding the scope and impact for biomaterials in medicine. In particular, self-assembled biomaterials prepared from molecular or colloidal interactions have been frequently explored. The strategies to create these materials are varied, taking advantage of engineered oligopeptides, proteins, and nanoparticles as well as affinity-mediated crosslinking of synthetic precursors. Self-assembled materials typically facilitate injectability through two different mechanisms: i) in situ self-assembly, whereby materials would be administered in a monomeric or oligomeric form and self-assemble in response to some physiologic stimulus, or ii) self-assembled materials that, by virtue of their dynamic, non covalent interactions, shear-thin to facilitate flow within a syringe and subsequently self-heal into its reassembled material form at the injection site. Indeed, many classes of materials are capable of being injected using a combination of these two mechanisms. Particular utility has been noted for self assembled biomaterials in the context of tissue engineering, regenerative medicine, drug delivery, and immunoengineering. Given the controlled and multifunctional nature of many self-assembled materials demonstrated to date, we project a future where injectable self-assembled biomaterials afford improved practice in advancing healthcare. PMID- 29128512 TI - The role of betaII spectrin in cardiac health and disease. AB - Spectrins are large, flexible proteins comprised of alpha-beta dimers that are connected head-to-head to form the canonical heterotetrameric spectrin structure. Spectrins were initially believed to be exclusively found in human erythrocytic membrane and are highly conserved among different species. betaII spectrin, the most common isoform of non-erythrocytic spectrin, is found in all nucleated cells and forms larger macromolecular complexes with ankyrins and actins. Not only is betaII spectrin a central cytoskeletal scaffolding protein involved in preserving cell structure but it has also emerged as a critical protein required for distinct physiologic functions such as posttranslational localization of crucial membrane proteins and signal transduction. In the heart, betaII spectrin plays a vital role in maintaining normal cardiac membrane excitability and proper cardiac development during embryogenesis. Mutations in betaII spectrin genes have been strongly linked with the development of serious cardiac disorders such as congenital arrhythmias, heart failure, and possibly sudden cardiac death. This review focuses on our current knowledge of the role betaII spectrin plays in the cardiovascular system in health and disease and the potential future clinical implications. PMID- 29128516 TI - West Nile virus, Anopheles flavivirus, a novel flavivirus as well as Merida-like rhabdovirus Turkey in field-collected mosquitoes from Thrace and Anatolia. AB - Mosquitoes are involved in the transmission and maintenance of several viral diseases with significant health impact. Biosurveillance efforts have also revealed insect-specific viruses, observed to cocirculate with pathogenic strains. This report describes the findings of flavivirus and rhabdovirus screening, performed in eastern Thrace and Aegean region of Anatolia during 2016, including and expanding on locations with previously-documented virus activity. A mosquito cohort of 1545 individuals comprising 14 species were collected and screened in 108 pools via generic and specific amplification and direct metagenomics by next generation sequencing. Seven mosquito pools (6.4%) were positive in the flavivirus screening. West Nile virus lineage 1 clade 1a sequences were characterized in a pool Culex pipiens sensu lato specimens, providing the initial virus detection in Aegean region following 2010 outbreak. In an Anopheles maculipennis sensu lato pool, sequences closely-related to Anopheles flaviviruses were obtained, with similarities to several African and Australian strains of this new insect-specific flavivirus clade. In pools comprising Uranotaenia unguiculata (n=3), Cx. pipiens s.l. (n=1) and Aedes caspius (n=1) mosquitoes, sequences of a novel flavivirus, distantly-related to Flavivirus AV2011, identified previously in Spain and Turkey, were characterized. Moreover, DNA forms of the novel flavivirus were detected in two Ur. unguiculata pools. These sequences were highly-similar to the sequences amplified from viral RNA, with undisrupted reading frames, suggest the occurrence of viral DNA forms in natural conditions within mosquito hosts. Rhabdovirus screening revealed sequences of a recently-described novel virus, named the Merida-like virus Turkey (MERDLVT) in 5 Cx. pipiens s.l. pools (4.6%). Partial L and N gene sequences of MERDLVT were well-conserved among strains, with evidence for geographical clustering in phylogenetic analyses. Metagenomics provided the near-full genomic sequence in a specimen, revealing an identical genome organization and limited divergence from the prototype MERDLVT isolate. PMID- 29128517 TI - Molecular characterization of different equine-like G3 rotavirus strains from Germany. AB - The genetic heterogeneity of rotaviruses constitutes a substantial burden to human and animal health. Occasional interspecies transmissions can generate novel virus strains in the human population. We detected equine-like G3P[8] strains in feces sampled from three children in Germany in 2015 and 2016, respectively. Thereof two showed a DS-1-like backbone. In one strain the NSP2 gene segment was of distinct genotype (G3-P[8]-I2-R2-C2-M2-A2-N1-T2-E2-H2). Phylogenetic analyses of the German strains showed a relation to other equine-like G3 rotaviruses circulating in different countries. The reconstruction of reassortment events in the evolution of novel equine-like G3 rotaviruses suggests an independent introduction of the three strains into the local human rotavirus population. PMID- 29128518 TI - Verification of genetic loci responsible for the resistance/susceptibility to the Sendai virus infection using congenic mice. AB - Sendai virus (SeV) is one of the most important pathogens in the specific pathogen free rodents. It is known that there are some inbred mouse strains susceptible or resistant to SeV infection. The C57BL/6 (B6) and DBA/2 (D2) mice are representative of the resistant and susceptible strains, respectively. Previous study with the quantitative trait locus (QTL) analysis identified three QTLs responsible for resistance or susceptibility to SeV infection on different chromosomes and indicated that resistance or susceptibility to SeV infection was almost predicted by genotypes of these three QTLs. In this paper, to verify the above hypothesis, congenic lines were generated as follows; B6-congenic lines carrying one of the D2 alleles of three QTLs and combination of these three QTLs, and D2-congenic lines carrying single or combination of B6 alleles of three QTLs. All these congenic lines were then challenged with SeV infection. D2 congenic lines introgressed single or combination of B6 alleles of QTLs changed to resistance to SeV infection. Especially, a D2 triple-congenic line became resistant as similar level to B6-parental strain. However, B6-congenic lines introgressed single or combination of D2 alleles of QTLs all remained to be resistant to SeV infection. Both IL-6 and TNF-alpha in broncho-alveolar lavage fluid of D2 triple-congenic line were decreased to the similar level of B6 mice, suggesting that this is a part of factors that D2 triple-congenic line became resistant to the similar level of B6 mice. Data obtained from these congenic mice verified that three QTLs identified previously were indeed responsible for the resistance/susceptibility to SeV infection in B6 and D2 mice. PMID- 29128519 TI - Genetic structure of two erythrocyte binding antigens of Plasmodium falciparum reveals a contrasting pattern of selection. AB - Erythrocyte binding antigens 175 (EBA-175) and 140 (EBA-140) play key roles in erythrocyte invasion by binding to glycophorin A (GPA) and C (GPC) respectively in human malaria. Since antigenic variation in malaria endemic region is a major barrier to development of effective vaccine, we explore the nature and pattern of sequence diversity of these two vaccine candidates in Kolkata, India. Population genetic parameters based on parasite sequences representing region II of Pfeba 175 and Pfeba-140 genes were estimated using DnaSP V.5.10 and MEGA version 6.0. A novel molecular docking approach was implemented to assess the binding affinities of Kolkata Pfeba-175 variants with GPA. P. falciparum Kolkata isolates experienced a recent population expansion as documented by negative Tajima's D, Fu & Li's statistics, unimodal mismatch distribution and star-like median-joining network for both loci. Positive selection seemed to play a major role in shaping the diversity of Pfeba-175 (dN/dS=2.45, and McDonald-Kreitman P-value=0.04) with successive accumulation of Q584K/E, E592A and R664S deriving high frequency haplotypes designated here as F2KH3 and F2KH1. In silico molecular docking demonstrated that polypeptides encoded by F2KH1 and F2KH3 were capable of engaging the parasite ligand into energetically favorable interaction with GPA. Our data demonstrated emergence of Pfeba-175 sequences harboring selectively advantageous nonsynonymous substitutions on Pf3D7 sequence background in the Kolkata parasite isolates. A contrasting pattern of Pf3D7-centric expansion of parasite sequences was noted for Pfeba-140. Together, this study provides a firm genetic and biological support favoring a dominant role of EBA-175 in erythrocyte invasion. PMID- 29128520 TI - Mechanical ventilation: we have come a long way but still have a long road ahead. PMID- 29128521 TI - Prenatal chromosomal microarray analysis in fetuses with congenital heart disease: a prospective cohort study. AB - BACKGROUND: Currently, chromosomal microarray analysis is considered the first tier test in pediatric care and prenatal diagnosis. However, the diagnostic yield of chromosomal microarray analysis for prenatal diagnosis of congenital heart disease has not been evaluated based on a large cohort. OBJECTIVE: Our aim was to evaluate the clinical utility of chromosomal microarray as the first-tier test for chromosomal abnormalities in fetuses with congenital heart disease. STUDY DESIGN: In this prospective study, 602 prenatal cases of congenital heart disease were investigated using single nucleotide polymorphism array over a 5-year period. RESULTS: Overall, pathogenic chromosomal abnormalities were identified in 125 (20.8%) of 602 prenatal cases of congenital heart disease, with 52.0% of them being numerical chromosomal abnormalities. The detection rates of likely pathogenic copy number variations and variants of uncertain significance were 1.3% and 6.0%, respectively. The detection rate of pathogenic chromosomal abnormalities in congenital heart disease plus additional structural anomalies (48.9% vs 14.3%, P < .0001) or intrauterine growth retardation group (50.0% vs 14.3%, P = .044) was significantly higher than that in isolated congenital heart disease group. Additionally, the detection rate in congenital heart disease with additional structural anomalies group was significantly higher than that in congenital heart disease with soft markers group (48.9% vs 19.8%, P < .0001). No significant difference was observed in the detection rates between congenital heart disease with additional structural anomalies and congenital heart disease with intrauterine growth retardation groups (48.9% vs 50.0%), congenital heart disease with soft markers and congenital heart disease with intrauterine growth retardation groups (19.8% vs 50.0%), or congenital heart disease with soft markers and isolated congenital heart disease groups (19.8% vs 14.3%). The detection rate in fetuses with congenital heart disease plus mild ventriculomegaly was significantly higher than in those with other types of soft markers (50.0% vs 15.6%, P < .05). CONCLUSION: Our study suggests chromosomal microarray analysis is a reliable and high-resolution technology and should be used as the first-tier test for prenatal diagnosis of congenital heart disease in clinical practice. PMID- 29128522 TI - Neurobiological evidence for attention bias to food, emotional dysregulation, disinhibition and deficient somatosensory awareness in obesity with binge eating disorder. AB - OBJECTIVES: To refine the biobehavioral markers of binge eating disorder (BED). METHODS: We conducted fMRI brain scans using images of high energy processed food (HEPF), low energy unprocessed food (LEUF), or non-foods (NF) in 42 adults (obese with BED [obese -BED; n=13] and obese with no BED [obese non-BED; n=29]) selected via ads. Two blood oxygenated level dependent (BOLD) signal contrast maps were examined: food versus nonfood, and HEPF versus LEUF. In addition, score differences on the disinhibition scale were correlated with BOLD signals. RESULTS: food versus nonfood showed greater BOLD activity for BED in emotional, motivational and somatosensory brain areas: insula, anterior cingulate cortex (ACC), Brodmann areas (BA) 19 & 32, inferior parietal lobule (IPL), posterior cingulate cortex (PCC), and lingual, postcentral, middle temporal and cuneate gyri (p<=0.005; k>=88). HEPF versus LEUF showed greater BOLD activity for BED in inhibitory brain regions: BA 6, middle and superior frontal gyri (p<0.01; k>=119). The groups also differed in the relationships between disinhibition and BOLD activity in the postcentral gyrus (PCG; p=0.04) and ACC-BA 32 (p=0.02). For all participants jointly, PCG BOLD amplitude predicted greater disinhibition (p=0.04). DISCUSSION: Food images elicited neural activity indicating attention bias (cuneate & PCG), emotion dysregulation (BA 19 & 32), and disinhibition (MFG, BA6 & SFG) in obese with BED. These may help tailor a treatment for the obesity with BED phenotype. PMID- 29128523 TI - Acute effect of smoking and smoking abstinence on energy intake and appetite related hormones blood concentrations. AB - The effect of smoking on energy balance and the underlying mechanisms are not fully understood. The aim of the present study is to examine the acute effect of smoking and its abstinence on energy intake, subjective feelings of appetite and related hormones. Fourteen healthy smokers participated in a randomized, crossover study consisting of two trials: the Cigarette trial (participants smoked two cigarettes of their brand within 15min) and the Sham trial (they were asked to hold the cigarette as smoking, but without lighting it). After 45min the participants were offered an ad libitum variety of snacks, and their intake was recorded. Blood samples were taken at fasting, before the ad libitum meal and 1h after and were analyzed for obestatin, ghrelin, glucagon-like peptide-1, cholecystokinin and insulin levels. Subjective feelings of hunger, satiety and desired to eat, as well as smoking craving were evaluated by visual analog scales. Mean energy intake at the ad libitum meal was 825+/-310kcal in the Sham trial and 673+/-245kcal in the Cigarette trial (p=0.010). No significant intervention effects were observed for the reported appetite feelings or the appetite-related hormones levels. In conclusion, smoking was found to have an acute effect on dietary intake; this was not explained by changes in the hormonal levels that were evaluated. More research is needed to confirm these results in more prolonged periods of abstinence and explore other pathways through which smoking and its abstinence affect energy balance. PMID- 29128524 TI - Numerical study of the airflow structures in an idealized mouth-throat under light and heavy breathing intensities using large eddy simulation. AB - An excellent understanding of the airflow structures is critical to enhance the efficiency of drug delivery via the human oral airway. The present paper investigates the characteristics of both steady and unsteady airflow structures in an idealized mouth-throat using large eddy simulation (LES). Representative inhalation flow rates of 15L/min at rest and 60L/min in exercise are considered. The study shows that there are more secondary vortices in the pharynx and the laryngeal jet is much longer and more concave in the steady flow field at 15L/min compared to the higher inspiration rate, which decreases the possibility of drug impinging on the wall. In contrast, the laryngeal jet is much more unsteady at heavy breathing and its strong interaction with the recirculation zone in the trachea leads to a enlarged mixing zone, increasing the possibility for carrying the particles from the laryngeal jet into the recirculation zone, which will lead to a longer residence time of the particles in the trachea and this increases the possibility of drug deposition in this area. In addition, the recirculation zone size is larger, the separation region is far away from glottis, and the reversed flow is slower at light compared to heavy breathing. In conclusion, these airflow structures show distinct properties at light and heavy breathing conditions, particularly in the unsteady flow field. The study provides evidence about the physical processes leading to both enlarged mixing zones and recirculation zones. It is known that stronger secondary vortices, a stronger laryngeal jet and enlarged recirculation zones definitely increase the particle deposition in the upper airway. The present paper aims to uncover the physical properties of the airflow for different breathing conditions, and their detailed effect on particle deposition will be studied in future. PMID- 29128525 TI - Respiratory rehabilitation in multiple sclerosis: A narrative review of rehabilitation techniques. AB - BACKGROUND: Respiratory disorders in multiple sclerosis (MS) are an important issue. They can occur early during the course of the disease, are associated with the neurological impairment, and can lead to pneumonia and respiratory failure, which are the main causes of death in advanced MS. Prevailing impaired expiratory muscles and cough abilities has been demonstrated in this population and might constitute a specific target for rehabilitation interventions. However, international guidelines lack recommendations regarding respiratory rehabilitation in MS. Here we performed a systematic review of the published literature related to respiratory rehabilitation in MS. METHODS: We searched the databases MEDLINE via PubMed, PEDro and Cochrane Library for English or French reports of clinical trials and well-designed cohorts published up to December 2016 with no restriction on start date by using the search terms "multiple sclerosis", "respiratory rehabilitation", "respiratory muscle training", "lung volume recruitment", "cough assistance", and "mechanical in-exsufflation". Literature reviews, case reports and physiological studies were excluded. The Maastricht criteria were used to assess the quality of clinical trials. We followed the Oxford Centre for Evidence-Based Medicine guidelines to determine level of evidence and grade of recommendations. RESULTS: Among the 21 reports of studies initially selected, 11 were retained for review. Seven studies were randomized controlled trials (RCTs), 2 were non-RCTs, and 2 were observational studies. Respiratory muscle training (inspiratory and/or expiratory) by use of a portable resistive mouthpiece was the most frequently evaluated technique, with 2 level-1 RCTs. Another level-1 RCT evaluated deep-breathing exercises. All reviewed studies evaluated home-based rehabilitation programs and focused on spirometric outcomes. The disparities in outcome measures among published studies did not allow for a meta-analysis and cough assistance devices were not evaluated in this population. CONCLUSION: Although respiratory muscle training can improve maximal respiratory pressure in MS and lung volume recruitment can slow the decline in vital capacity, evidence is lacking to recommend specific respiratory rehabilitation programs adapted to the level of disability induced by the disease. PMID- 29128526 TI - Functional analysis of Cullin 3 E3 ligases in tumorigenesis. AB - Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis. PMID- 29128527 TI - Endogenously generated DNA nucleobase modifications source, and significance as possible biomarkers of malignant transformation risk, and role in anticancer therapy. AB - The DNA of all living cells undergoes continuous structural and chemical alteration, which may be derived from exogenous sources, or endogenous, metabolic pathways, such as cellular respiration, replication and DNA demethylation. It has been estimated that approximately 70,000 DNA lesions may be generated per day in a single cell, and this has been linked to a wide variety of diseases, including cancer. However, it is puzzling why potentially mutagenic DNA modifications, occurring at a similar level in different organs/tissue, may lead to organ/tissue specific cancers, or indeed non-malignant disease - what is the basis for this differential response? We suggest that it is perhaps the precise location of damage, within the genome, that is a key factor. Finally, we draw attention to the requirement for reliable methods for identification and quantification of DNA adducts/modifications, and stress the need for these assays to be fully validated. Once these prerequisites are satisfied, measurement of DNA modifications may be helpful as a clinical parameter for treatment monitoring, risk group identification and development of prevention strategies. PMID- 29128528 TI - Amblyospora khaliulini (Microsporidia: Amblyosporidae): Investigations on its life cycle and ecology in Aedes communis (Diptera: Culicidae) and Acanthocyclops vernalis (Copepoda: Cyclopidae) with redescription of the species. AB - A multi-year study was conducted to examine the natural ecology of the microsporidium Amblyospora khaliulini and more fully characterize parasite development and histopathology in all stages of its primary mosquito host, Aedes communis and intermediate copepod host, Acanthocyclops vernalis with redescription of the species. A. khaliulini exhibits polymorphic development, produces three morphologically and functionally distinct spores, and is both horizontally and vertically transmitted. Development in A. vernalis is restricted to females, occurs within the ovaries and results in death of the host. Development is haplophasic with division by binary and multiple fission producing rosette-shaped sporogonial plasmodia and conical uninucleate spores that are orally infectious to Ae. communis larvae. Both sexes are equally susceptible and infections are confined to testes in males and ovaries in females. Initial stages of development include uninucleate schizonts that undergo karyokinesis forming diplokaryotic meronts that divide repeatedly by binary fission. Sporogony occurs in both host sexes, but sporogenesis does not progress normally in adult males and elliptical, thin walled binucleate spores that function in vertical transmission of the microsporidium via infection of the ovaries and eggs are formed in adult females only. Development of vertically acquired infections in larval Ae. communis hosts occurs within fat body tissue, leads to the production of meiospores in male hosts only and results in death during the 4th larval stadium. Initial development is characterized by merogonial multiplication of diplokarya by synchronous binary division producing additional diplokarya. The cessation of merogony and the onset of sporogony are characterized by the simultaneous secretion of a sporophorous vesicle and meiotic division of diplokarya resulting in the formation of octonucleate sporonts that undergo cytokinesis and sporogenesis to form eight uninucleate, broadly ovoid meiospores enclosed within a sporophorous vesicle. The natural prevalence of patent vertically acquired fat body infections in field populations of Ae. communis ranged from 1.6% to 3.6%. Yearly infection rates in A. vernalis copepods ranged from 57.1% to 15.0%. Prevalence rates of horizontally acquired infections in emerging adult Ae. communis ranged from 69.0% to 11.9% in males and 50.0% to 16.4% in females. PMID- 29128529 TI - Laser processed calcium phosphate reinforced CoCrMo for load-bearing applications: Processing and wear induced damage evaluation. AB - : To mitigate shortcomings in current biomedical CoCrMo alloy, composites of CoCrMo with calcium phosphate (CaP) were envisioned. CoCrMo alloy was reinforced with CaP to enhance the wear resistance of the alloy. A powder based direct energy additive manufacturing technique of Laser Engineered Net Shaping (LENSTM) was used for processing of CoCrMo alloy with 1% and 3% (by weight) of CaP in the form of hydroxyapaptite. Addition of CaP was found to stabilize the epsilon (hcp) phase along with the more common gamma (fcc) phase of the CoCrMo alloy, and the microstructure showed discontinuous chromium carbide phase. The resultant composite showed hardness similar to the base material, however, there was significant increase in the wear resistance of the alloy due to the addition of CaP. During wear testing, a tribo-layer or a tribofilm was found to develop on the surface. This led to the reduction in the leaching of Co and Cr ions during wear testing. The tribofilm was found to be dependent on the wear distance, and made the CoCrMo-CaP composites an in situ self-protecting system. The overall coefficient of friction of the CoCrMo-CaP composite was found to increase but was more stable with the wear distance as compared to the CoCrMo alloy with no CaP addition. STATEMENT OF SIGNIFICANCE: Co-based alloys, an ideal choice for biomedical load-bearing implants, show low wear rates along with low coefficient of friction (COF) and good resistance to corrosive media. However, significant material loss can occur in vivo due to wear and/or corrosion of CoCrMo over long periods of time. Release of metal ions in the human body over time leads to medical complications such as metallosis, which can often require a revision surgery that can adversely affect the quality of life for the patient. We hypothesize that metal ion release from CoCrMo alloys can be reduced during articulation using an in situ formed inorganic tribofilm, and our results validate our hypothesis in calcium phosphate reinforced CoCrMo composites. PMID- 29128530 TI - Cell-instructive pectin hydrogels crosslinked via thiol-norbornene photo-click chemistry for skin tissue engineering. AB - : Cell-instructive hydrogels are attractive for skin repair and regeneration, serving as interactive matrices to promote cell adhesion, cell-driven remodeling and de novo deposition of extracellular matrix components. This paper describes the synthesis and photocrosslinking of cell-instructive pectin hydrogels using cell-degradable peptide crosslinkers and integrin-specific adhesive ligands. Protease-degradable hydrogels obtained by photoinitiated thiol-norbornene click chemistry are rapidly formed in the presence of dermal fibroblasts, exhibit tunable properties and are capable of modulating the behavior of embedded cells, including the cell spreading, hydrogel contraction and secretion of matrix metalloproteases. Keratinocytes seeded on top of fibroblast-loaded hydrogels are able to adhere and form a compact and dense layer of epidermis, mimicking the architecture of the native skin. Thiol-ene photocrosslinkable pectin hydrogels support the in vitro formation of full-thickness skin and are thus a highly promising platform for skin tissue engineering applications, including wound healing and in vitro testing models. STATEMENT OF SIGNIFICANCE: Photopolymerizable hydrogels are attractive for skin applications due to their unique spatiotemporal control over the hydrogel formation. This study reports the design of a promising photo-clickable pectin hydrogel which biophysical and biochemical properties can be independently tailored to control cell behavior. A fast method for the norbornene-functionalization of pectin was developed and hydrogels fabricated through UV photoinitiated thiol-norbornene chemistry. This one-pot click reaction was performed in the presence of cells using cell-adhesive and matrix metalloproteinase-sensitive peptides, yielding hydrogels that support extensive cell spreading. Keratinocytes seeded on top of the fibroblast-loaded hydrogel formed a compact epidermis with morphological resemblance to human skin. This work presents a new protease-degradable hydrogel that supports in vitro skin formation with potential for skin tissue engineering. PMID- 29128532 TI - Laponite nanoparticle-associated silated hydroxypropylmethyl cellulose as an injectable reinforced interpenetrating network hydrogel for cartilage tissue engineering. AB - : Articular cartilage is a connective tissue which does not spontaneously heal. To address this issue, biomaterial-assisted cell therapy has been researched with promising advances. The lack of strong mechanical properties is still a concern despite significant progress in three-dimensional scaffolds. This article's objective was to develop a composite hydrogel using a small amount of nano reinforcement clay known as laponites. These laponites were capable of self setting within the gel structure of the silated hydroxypropylmethyl cellulose (Si HPMC) hydrogel. Laponites (XLG) were mixed with Si-HPMC to prepare composite hydrogels leading to the development of a hybrid interpenetrating network. This interpenetrating network increases the mechanical properties of the hydrogel. The in vitro investigations showed no side effects from the XLG regarding cytocompatibility or oxygen diffusion within the composite after cross-linking. The ability of the hybrid scaffold containing the composite hydrogel and chondrogenic cells to form a cartilaginous tissue in vivo was investigated during a 6-week implantation in subcutaneous pockets of nude mice. Histological analysis of the composite constructs revealed the formation of a cartilage-like tissue with an extracellular matrix containing glycosaminoglycans and collagens. Overall, this new hybrid construct demonstrates an interpenetrating network which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, oxygen diffusion, or the ability of chondrogenic cells to self organize in the cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects in a large animal model of articular cartilage defects. STATEMENT OF SIGNIFICANCE: Articular cartilage is a tissue that fails to heal spontaneously. To address this clinically relevant issue, biomaterial-assisted cell therapy is considered promising but often lacks adequate mechanical properties. Our objective was to develop a composite hydrogel using a small amount of nano reinforcement (laponite) capable of gelling within polysaccharide based self-crosslinking hydrogel. This new hybrid construct demonstrates an interpenetrating network (IPN) which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, O2 diffusion and the ability of chondrogenic cells to self organize in cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects and will now be considered in a large animal model of articular cartilage defects. PMID- 29128531 TI - The hierarchical response of human corneal collagen to load. AB - : Fibrillar collagen in the human cornea is integral to its function as a transparent lens of precise curvature, and its arrangement is now well characterised in the literature. While there has been considerable effort to incorporate fibrillar architecture into mechanical models of the cornea, the mechanical response of corneal collagen to small applied loads is not well understood. In this study the fibrillar and molecular response to tensile load was quantified using small and wide angle X-ray scattering (SAXS/WAXS), and digital image correlation (DIC) photography was used to calculate the local strain field that gave rise to the hierarchical changes. A molecular scattering model was used to calculate the tropocollagen tilt relative to the fibril axis and changes associated with applied strain. Changes were measured in the D period, molecular tilt and the orientation and spacing of the fibrillar and molecular networks. These measurements were summarised into hierarchical deformation mechanisms, which were found to contribute at varying strains. The change in molecular tilt is indicative of a sub-fibrillar "spring-like" deformation mechanism, which was found to account for most of the applied strain under physiological and near-physiological loads. This deformation mechanism may play an important functional role in tissues rich in fibrils of high helical tilt, such as skin and cartilage. STATEMENT OF SIGNIFICANCE: Collagen is the primary mediator of soft tissue biomechanics, and variations in its hierarchical structure convey the varying amounts of structural support necessary for organs to function normally. Here we have examined the structural response of corneal collagen to tensile load using X-rays to probe hierarchies ranging from molecular to fibrillar. We found a previously unreported deformation mechanism whereby molecules, which are helically arranged relative to the axis of their fibril, change in tilt akin to the manner in which a spring stretches. This "spring-like" mechanism accounts for a significant portion of the applied deformation at low strains (<3%). These findings will inform the future design of collagen-based artificial corneas being developed to address world-wide shortages of corneal donor tissue. PMID- 29128534 TI - Development of gelatin/ascorbic acid cryogels for potential use in corneal stromal tissue engineering. AB - : To offer an ideal hospitable environment for corneal keratocyte growth, the carrier materials can be functionalized with incorporation of signaling molecules to regulate cell biological events. This study reports, for the first time, the development of gelatin/ascorbic acid (AA) cryogels for keratocyte carriers in vitro and in vivo. The cryogel samples were fabricated by blending of gelatin with varying amounts of AA (0-300 mg) and carbodiimide cross-linking via cryogelation technique. Hydrophilic AA content in the carriers was found to significantly affect cross-linking degree and pore dimension of cryogels, thereby dictating their mechanical and biological stability and AA release profile. The cryogel carriers with low-to-moderate AA loadings were well tolerated by rabbit keratocyte cultures and anterior segment eye tissues, demonstrating good ocular biocompatibility. Although higher incorporated AA level contributed to enhanced metabolic activity and biosynthetic capacity of keratocytes grown on cryogel matrices, the presence of excessive amounts of AA molecules could lead to toxic effect and limit cell proliferation and matrix production. The cytoprotective activity against oxidative stress was shown to be strongly dependent on AA release, which further determined cell culture performance and tissue reconstruction efficiency. With the optimum AA content in carrier materials, intrastromally implanted cell/cryogel constructs exhibited better capability to enhance tissue matrix regeneration and transparency maintenance as well as to mitigate corneal damage in an alkali burn-induced animal model. It is concluded that understanding of antioxidant molecule-mediated structure-property-function interrelationships in gelatin/AA cryogels is critical to designing carrier materials for potential use in corneal stromal tissue engineering. STATEMENT OF SIGNIFICANCE: Multifunctional cryogel material can offer an ideal hospitable environment for cell-mediated tissue reconstruction. To our knowledge, this is the first report describing the use of gelatin/ascorbic acid (AA) cryogels as keratocyte carriers for corneal stromal tissue engineering. The AA loading during cryogel fabrication is found to have a significant effect on cross-linking degree and pore dimension, mechanical and biological stability, ocular biocompatibility, cell culture performance, and cytoprotective activity, giving comprehensive insight into fine-tuning the structure-property-function interrelationships of keratocyte carrier material. Using an alkali burn-induced animal model, we present evidence that with the optimum AA loading into cryogel materials, intrastromally implanted cell/carrier constructs exhibited better capability to enhance tissue matrix regeneration and transparency maintenance as well as to mitigate corneal damage. PMID- 29128533 TI - Fabrication of dense anisotropic collagen scaffolds using biaxial compression. AB - : We developed a new method to manufacture dense, aligned, and porous collagen scaffolds using biaxial plastic compression of type I collagen gels. Using a novel compression apparatus that constricts like an iris diaphragm, low density collagen gels were compressed to yield a permanently densified, highly aligned collagen material. Micro-porosity scaffolds were created using hydrophilic elastomer porogens that can be selectively removed following biaxial compression, with porosity modulated by using different porogen concentrations. The resulting scaffolds exhibit collagen densities that are similar to native connective tissues (~10% collagen by weight), pronounced collagen alignment across multiple length scales, and an interconnected network of pores, making them highly relevant for use in tissue culture, the study of physiologically relevant cell matrix interactions, and tissue engineering applications. The scaffolds exhibited highly anisotropic material behavior, with the modulus of the scaffolds in the fiber direction over 100 times greater than the modulus in the transverse direction. Adipose-derived mesenchymal stem cells were seeded onto the biaxially compressed scaffolds with minimal cell death over seven days of culture, along with cell proliferation and migration into the pore spaces. This fabrication method provides new capabilities to manufacture structurally and mechanically relevant cytocompatible scaffolds that will enable more physiologically relevant cell culture studies. Further improvement of manufacturing techniques has the potential to produce engineered scaffolds for direct replacement of dense connective tissues such as meniscus and annulus fibrosus. STATEMENT OF SIGNIFICANCE: In vitro studies of cell-matrix interactions and the engineering of replacement materials for collagenous connective tissues require biocompatible scaffolds that replicate the high collagen density (15-25%/wt), aligned fibrillar organization, and anisotropic mechanical properties of native tissues. However, methods for creating scaffolds with these characteristics are currently lacking. We developed a new apparatus and method to create high density, aligned, and porous collagen scaffolds using a biaxial compression with porogens technique. These scaffolds have a highly directional structure and mechanical properties, with the tensile strength and modulus up to 100 times greater in the direction of alignment. We also demonstrated that the scaffolds are a suitable material for cell culture, promoting cell adhesion, viability, and an aligned cell morphology comparable to the cell morphology observed in native aligned tissues. PMID- 29128536 TI - A model for hydrolytic degradation and erosion of biodegradable polymers. AB - : For aliphatic polyesters such as PLAs and PGAs, there is a strong interplay between the hydrolytic degradation and erosion - degradation leads to a critically low molecular weight at which erosion starts. This paper considers the underlying physical and chemical processes of hydrolytic degradation and erosion. Several kinetic mechanisms are incorporated into a mathematical model in an attempt to explain different behaviours of mass loss observed in experiments. In the combined model, autocatalytic hydrolysis, oligomer production and their diffusion are considered together with surface and interior erosion using a set of differential equations and Monte Carlo technique. Oligomer and drug diffusion are modelled using Fick's law with the diffusion coefficients dependent on porosity. The porosity is due to the formation of cavities which are a result of polymer erosion. The model can follow mass loss and drug release up to 100%, which cannot be explained using a simple reaction-diffusion. The model is applied to two case studies from the literature to demonstrate its validity. The case studies show that a critical molecular weight for the onset of polymer erosion and an incubation period for the polymer dissolution are two critical factors that need to be considered when predicting mass loss and drug release. STATEMENT OF SIGNIFICANCE: In order to design bioresorbable implants, it is important to have a mathematical model to predict polymer degradation and corresponding drug release. However, very different behaviours of polymer degradation have been observed and there is no single model that can capture all these behaviours. For the first time, the model presented in this paper is capable of capture all these observed behaviours by switching on and off different underlying mechanisms. Unlike the existing reaction-diffusion models, the model presented here can follow the degradation and drug release all the way to the full disappearance of an implant. PMID- 29128535 TI - Branched peptides integrate into self-assembled nanostructures and enhance biomechanics of peptidic hydrogels. AB - : Self-assembling peptides (SAP) have drawn an increasing interest in the tissue engineering community. They display unquestionable biomimetic properties, tailorability and promising biocompatibility. However their use has been hampered by poor mechanical properties making them fragile soft scaffolds. To increase SAP hydrogel stiffness we introduced a novel strategy based on multiple ramifications of (LDLK)3, a well-known linear SAP, connected with one or multiple "lysine knots". Differently branched SAPs were tested by increasing the number of (LDLK)3 like branches and by adding the neuro-regenerative functional motif BMHP1 as a single branch. While pure branched peptides did not have appealing self assembling propensity, when mixed with the corresponding linear SAP they increased the stiffness of the overall hydrogel of multiple times. Notably, optimal results (or peak) were obtained 1) at similar molar ratio (between linear and branched peptides) for all tested sequences and 2) for the branched SAPs featuring the highest number of branches made of (LDLK)3. The functional motif BMHP1, as expected, seemed not to contribute to the increase of the storage modulus as efficiently as (LDLK)3. Interestingly, branched SAPs improved the beta sheet self-arrangement of (LDLK)3 and allowed for the formation of assembled nanofibers. Indeed in coarse-grained molecular dynamics we showed they readily integrate in the assembled aggregates providing "molecular connections" among otherwise weakly paired beta-structures. Lastly, branched SAPs did not affect the usual response of human neural stem cells cultured on (LDLK)3-like scaffolds in vitro. Hence, branched SAPs may be a valuable new tool to enhance mechanical properties of self-assembling peptide biomaterials harmlessly; as neither chemical nor enzymatic cross-linking reactions are involved. As a consequence, branched SAPs may enlarge the field of application of SAPs in tissue engineering and beyond. STATEMENT OF SIGNIFICANCE: Self-assembling peptides stand at the forefront of regenerative medicine because they feature biomimetic nano architectures that mimic the complexity of natural peptide-based extracellular matrices of living tissues. Their superior biocompatibility and ease of scale-up production are hampered by weak mechanical properties due to transient non covalent interactions among and within the self-assembled peptide chains, thus limiting their potential applications. We introduced new branched self-assembling peptides to be used as "molecular connectors" among self-assembled nanostructures made of linear SAPs. Branched SAPs could be mixed with linear SAPs before self assembling in order to have them intermingled with different beta-sheets of linear SAPs after gelation. This strategy caused a manifold increase of the stiffness of the assembled hydrogels (proportional to the number of self assembling branches), did not affect SAP propensity to form beta-sheet but, instead, further stimulated their secondary structure rearrangements. It is now possible to modularly improve SAP scaffold mechanical properties without using harmful chemical reactions. Therefore, branched SAPs represent an additional tool to be adopted for efficient and harmless SAP scaffold customization in tissue engineering. PMID- 29128537 TI - Biomaterials for articular cartilage tissue engineering: Learning from biology. AB - : Articular cartilage is commonly described as a tissue that is made of up to 80% water, is devoid of blood vessels, nerves, and lymphatics, and is populated by only one cell type, the chondrocyte. At first glance, an easy tissue for clinicians to repair and for scientists to reproduce in a laboratory. Yet, chondral and osteochondral defects currently remain an open challenge in orthopedics and tissue engineering of the musculoskeletal system, without considering osteoarthritis. Why do we fail in repairing and regenerating articular cartilage? Behind its simple and homogenous appearance, articular cartilage hides a heterogeneous composition, a high level of organisation and specific biomechanical properties that, taken together, make articular cartilage a unique material that we are not yet able to repair or reproduce with high fidelity. This review highlights the available therapies for cartilage repair and retraces the research on different biomaterials developed for tissue engineering strategies. Their potential to recreate the structure, including composition and organisation, as well as the function of articular cartilage, intended as cell microenvironment and mechanically competent replacement, is described. A perspective of the limitations of the current research is given in the light of the emerging technologies supporting tissue engineering of articular cartilage. STATEMENT OF SIGNIFICANCE: The mechanical properties of articular tissue reflect its functionally organised composition and the recreation of its structure challenges the success of in vitro and in vivo reproduction of the native cartilage. Tissue engineering and biomaterials science have revolutionised the way scientists approach the challenge of articular cartilage repair and regeneration by introducing the concept of the interdisciplinary approach. The clinical translation of the current approaches are not yet fully successful, but promising results are expected from the emerging and developing new generation technologies. PMID- 29128538 TI - Hyaluronan size alters chondrogenesis of adipose-derived stem cells via the CD44/ERK/SOX-9 pathway. AB - : Hyaluronan (HA) is a natural linear polymer that is one of the main types of extracellular matrix during the early stage of chondrogenesis. We found that the chondrogenesis of adipose-derived stem cells (ADSCs) can be initiated and promoted by the application of HA to mimic the chondrogenic niche. The aim of this study is to investigate the optimal HA molecular weight (Mw) for chondrogenesis of ADSCs and the detailed mechanism. In this study, we investigated the relationships among HA Mw, CD44 clustering, and the extracellular signal-regulated kinase (ERK)/SOX-9 pathway during chondrogenesis of ADSCs. Human ADSCs (hADSCs) and rabbit ADSCs (rADSCs) were isolated and expanded. Chondrogenesis was induced in rADSCs by culturing cells in HA-coated wells (HA Mw: 80 kDa, 600 kDa and 2000 kDa) and evaluated by examining cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and sulfated glycosaminoglycan (sGAG) deposition in vitro. Cartilaginous tissue formation in vivo was confirmed by implanting HA/rADSCs into joint cavities. CD44 clustering, ERK phosphorylation, SOX-9 expression and SOX-9 phosphorylation in cultured hADSCs were further evaluated. Isolated and expanded rADSCs showed multilineage potential and anchorage-independent growth properties. Cell aggregation, chondrogenic gene expression, and sGAG deposition increased with increasing HA Mw in rADSCs. The 2000 kDa HA had the most pronounced chondrogenic effect on rADSCs in vitro, and implanted 2000 kDa HA/rADSCs exhibited marked cartilaginous tissue formation in vivo. CD44 clustering and cell aggregation of hADSCs were enhanced by an increase in HA Mw. In addition, higher HA Mws further enhanced CD44 clustering, ERK phosphorylation, and SOX-9 expression and phosphorylation in hADSCs. Inhibiting CD44 clustering in hADSCs reduced HA induced chondrogenic gene expression. Inhibiting ERK phosphorylation also simultaneously attenuated HA-induced SOX-9 expression and phosphorylation and chondrogenic gene expression in hADSCs. Our results indicate that HA initiates ADSC chondrogenesis and that higher Mw HAs exhibit stronger effects, with 2000 kDa HA having the strongest effect. These effects may be mediated through increased CD44 clustering and the ERK/SOX-9 signaling pathway. STATEMENT OF SIGNIFICANCE: HA-based biomaterials have been studied in stem cell-based articular cartilage tissue engineering. However, little is known about the optimal HA size for stem cell chondrogenesis and the mechanism of how HA size modulates stem cell chondrogenesis. Accordingly, we used HAs with various Mws (80 2000 kDa) as culture substrates and tested their chondrogenic effect on ADSCs. Our results demonstrated that HAs with a Mw of 2000 kDa showed the optimal effect for chondrogenesis of ADSCs. Moreover, we found that HA size can regulate ADSC chondrogenesis via the CD44/ERK/SOX-9 pathway. This finding provides new information regarding the biochemical control of chondrogenesis by HA substrates that may add value to the development of HA-based biomaterials for articular cartilage regeneration. PMID- 29128539 TI - Injectable nanocomposite cryogels for versatile protein drug delivery. AB - : Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems. STATEMENT OF SIGNIFICANCE: Here we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein's activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications. PMID- 29128540 TI - Electrospun thermosensitive hydrogel scaffold for enhanced chondrogenesis of human mesenchymal stem cells. AB - : Hydrogels have shown great potential for cartilage tissue engineering applications due to their capability to encapsulate cells within biomimetic, 3 dimensional (3D) microenvironments. However, the multi-step fabrication process that is necessary to produce cell/scaffold constructs with defined dimensions, limits their off-the-shelf translational usage. In this study, we have developed a hybrid scaffolding system which combines a thermosensitive hydrogel, poly(ethylene glycol)-poly(N-isopropylacrylamide) (PEG-PNIPAAm), with a biodegradable polymer, poly(epsilon-caprolactone) (PCL), into a composite, electrospun microfibrous structure. A judicious optimization of material composition and electrospinning process produced a structurally self-supporting hybrid scaffold. The reverse thermosensitivity of PEG-PNIPAAm allowed its dissolution/hydration upon cell seeding within a network of PCL microfibers while maintaining the overall scaffold shape at room temperature. A subsequent temperature elevation to 37 degrees C induced the hydrogel's phase transition to a gel state, effectively encapsulating cells in a 3D hydrogel without the use of a mold. We demonstrated that the hybrid scaffold enhanced chondrogenic differentiation of human mesenchymal stem cells (hMSCs) based on chondrocytic gene and protein expression, which resulted in superior viscoelastic properties of the cell/scaffold constructs. The hybrid scaffold enables a facile, single step cell seeding process to inoculate cells within a 3D hydrogel with the potential for cartilage tissue engineering. STATEMENT OF SIGNIFICANCE: Hydrogels have demonstrated the excellent ability to enhance chondrogenesis of stem cells due to their hydrated fibrous nanostructure providing a cellular environment similar to native cartilage. However, the necessity for multi-step processes, including mixing of hydrogel precursor with cells and subsequent gelation in a mold to form a defined shape, limits their off-the-shelf usage. In this study, we developed a hybrid scaffold by combining a thermosensitive hydrogel with a mechanically stable polymer, which provides a facile means to inoculate cells in a 3D hydrogel with a mold-less, single step cell seeding process. We further showed that the hybrid scaffold enhanced chondrogenesis of mesenchymal stem cells, demonstrating its potential for cartilage tissue engineering. PMID- 29128541 TI - A PEGylated platelet free plasma hydrogel based composite scaffold enables stable vascularization and targeted cell delivery for volumetric muscle loss. AB - : Extracellular matrix (ECM) scaffolds are being used for the clinical repair of soft tissue injuries. Although improved functional outcomes have been reported, ECM scaffolds show limited tissue specific remodeling response with concomitant deposition of fibrotic tissue. One plausible explanation is the regression of blood vessels which may be limiting the diffusion of oxygen and nutrients across the scaffold. Herein we develop a composite scaffold as a vasculo-inductive platform by integrating PEGylated platelet free plasma (PFP) hydrogel with a muscle derived ECM scaffold (m-ECM). In vitro, adipose derived stem cells (ASCs) seeded onto the composite scaffold differentiated into two distinct morphologies, a tubular network in the hydrogel, and elongated structures along the m-ECM scaffold. The composite scaffold showed a high expression of ITGA5, ITGB1, and FN and a synergistic up-regulation of ang1 and tie-2 transcripts. The in vitro ability of the composite scaffold to provide extracellular milieu for cell adhesion and molecular cues to support vessel formation was investigated in a rodent volumetric muscle loss (VML) model. The composite scaffold delivered with ASCs supported robust and stable vascularization. Additionally, the composite scaffold supported increased localization of ASCs in the defect demonstrating its ability for localized cell delivery. Interestingly, ASCs were observed homing in the injured muscle and around the perivascular space possibly to stabilize the host vasculature. In conclusion, the composite scaffold delivered with ASCs presents a promising approach for scaffold vascularization. The versatile nature of the composite scaffold also makes it easily adaptable for the repair of soft tissue injuries. STATEMENT OF SIGNIFICANCE: Decellularized extracellular matrix (ECM) scaffolds when used for soft tissue repair is often accompanied by deposition of fibrotic tissue possibly due to limited scaffold vascularization, which limits the diffusion of oxygen and nutrients across the scaffold. Although a variety of scaffold vascularization strategies has been investigated, their limitations preclude rapid clinical translation. In this study we have developed a composite scaffold by integrating bi-functional polyethylene glycol modified platelet free plasma (PEGylated PFP) with adipose derived stem cells (ASCs) along with a muscle derived ECM scaffold (m-ECM). The composite scaffold provides a vasculo-inductive and an effective cell delivery platform for volumetric muscle loss. PMID- 29128542 TI - Truncated RAP-MUSIC (TRAP-MUSIC) for MEG and EEG source localization. AB - Electrically active brain regions can be located applying MUltiple SIgnal Classification (MUSIC) on magneto- or electroencephalographic (MEG; EEG) data. We introduce a new MUSIC method, called truncated recursively-applied-and-projected MUSIC (TRAP-MUSIC). It corrects a hidden deficiency of the conventional RAP-MUSIC algorithm, which prevents estimation of the true number of brain-signal sources accurately. The correction is done by applying a sequential dimension reduction to the signal-subspace projection. We show that TRAP-MUSIC significantly improves the performance of MUSIC-type localization; in particular, it successfully and robustly locates active brain regions and estimates their number. We compare TRAP MUSIC and RAP-MUSIC in simulations with varying key parameters, e.g., signal-to noise ratio, correlation between source time-courses, and initial estimate for the dimension of the signal space. In addition, we validate TRAP-MUSIC with measured MEG data. We suggest that with the proposed TRAP-MUSIC method, MUSIC type localization could become more reliable and suitable for various online and offline MEG and EEG applications. PMID- 29128543 TI - High frequency neurons determine effective connectivity in neuronal networks. AB - The emergence of flexible information channels in brain networks is a fundamental question in neuroscience. Understanding the mechanisms of dynamic routing of information would have far-reaching implications in a number of disciplines ranging from biology and medicine to information technologies and engineering. In this work, we show that the presence of a node firing at a higher frequency in a network with local connections, leads to reliable transmission of signals and establishes a preferential direction of information flow. Thus, by raising the firing rate a low degree node can behave as a functional hub, spreading its activity patterns polysynaptically in the network. Therefore, in an otherwise homogeneous and undirected network, firing rate is a tunable parameter that introduces directionality and enhances the reliability of signal transmission. The intrinsic firing rate across neuronal populations may thus determine preferred routes for signal transmission that can be easily controlled by changing the firing rate in specific nodes. We show that the results are generic and the same mechanism works in the networks with more complex topology. PMID- 29128544 TI - Experimental poisoning by Vernonia rubricaulis in sheep. AB - In order to evaluate the susceptibility of sheep to V. rubricaulis and to establish the clinical signs, serum biochemistry, and pathological findings, eight sheep were fed varying doses of V. rubricaulis. The onset of clinical signs occurred 6-48 h after the ingestion of V. rubricaulis. Clinical courses lasted 6 56 h after the ingestion of the plant. Serum activities of aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase were highly elevated and glucose blood levels were low in affected sheep. Clinical signs consisted of apathy, anorexia, dry muzzle, respiratory distress, abdominal pain, and mushy feces with streaks of blood and mucus. Two sheep had neurological signs including muscle fasciculation, nystagmus, paddling movements, and blindness. Liver necrosis could be detected antemortem through liver biopsy. Five sheep died and three recovered. The liver was affected in all necropsied sheep; it increased in volume and had marked accentuation of the lobular pattern with red, depressed areas intercalated with a pale yellow network. Ascites and hydropericardium were consistent findings. Microscopically, centrilobular to massive coagulative necrosis was observed. Coagulative necrosis was also observed in a few proximal renal tubules. Microscopic lesions were not found in any other organs. The severity of liver lesions was proportional to the dose. Chemical analysis to detect carboxyatractyloside in V. rubricaulis plant material was negative. It is concluded that V. rubricaulis poisoning in sheep is clinically, biochemically, and pathologically characteristic of an acute hepatoxicosis. PMID- 29128545 TI - Massive parallel sequencing of mitochondrial DNA genomes from mother-child pairs using the ion torrent personal genome machine (PGM). AB - Mitochondrial genome analysis is a potent tool in forensic practice and in the understanding of human phylogeny in the maternal lineage. With the development of molecular biology and bioinformatics techniques, high-throughput sequencing has enabled mtDNA analysis during whole genome sequencing, which provides more comprehensive information and raises the power of discrimination. In this study, peripheral blood samples were taken from 194 mother-offspring pairs and sequenced by Ion Torrent Personal Genome Machine and obtained high-coverage mitochondrial sequencing data, demonstrating the mutation levels at each position in the mitochondrial DNA (mtDNA) between maternally related pairs. A total of 14,332 variants were observed at 891 nucleotide positions from 388 individuals, and the result shows that all maternally related pairs shared the same detailed homoplasmic SNPs and haplotypes. With appropriate criteria for avoiding false positives due to sequencing errors and contamination by nuclear mitochondrial pseudogenes, we identified 33 heteroplasmies at a frequency of >=10% at 32 sites in 30 pairs. The maternally related pairs had the same heteroplasmic sites but with different allele frequencies. The dataset is available through EMPOP under accession number EMP00684 and will serve as an mtDNA reference database in forensic casework in Eastern China. PMID- 29128547 TI - Associations between asymmetric dimethylarginine (ADMA), nitrite-dependent renal carbonic anhydrase activity, and plasma testosterone levels in hypogonadal men. AB - BACKGROUND: Circulating inorganic nitrite (NO2-) is an abundant nitric oxide (NO) reservoir. Renal carbonic anhydrase (CA) mediates the absorption of urinary nitrite. The urinary nitrate-to-nitrite molar ratio UNOxR is a measure of nitrite dependent renal CA activity. The CA family is also involved in the bioactivation of nitrite to S-nitrosothiols and NO. Thus, CA isoforms may combat atherosclerosis. METHODS: In the plasma and urine of 10 hypogonadal men, we measured the major NO metabolites nitrite and nitrate and the endogenous inhibitor of NO synthase (NOS), i.e., asymmetric dimethylarginine (ADMA), before and after a 24-week testosterone treatment to normalize plasma testosterone levels. We tested potential correlations between plasma testosterone, ADMA, and UNOxR. RESULTS: Baseline UNOxR levels were low, indicating impaired nitrite dependent renal CA activity. Baseline plasma testosterone levels were inversely correlated with creatinine-corrected urinary nitrite excretion (r = -0.74, P = 0.036) and positively with UNOxR (r = 0.72, P = 0.044). Plasma testosterone level normalization deteriorated these correlations. At baseline, UNOxR correlated inversely with urinary excretion of ADMA (r = -0.75, P = 0.013). Plasma testosterone levels normalization did not affect UNOxR. Men with secondary and primary hypogonadal hypogonadism differed with respect to baseline biomarker levels and the testosterone effects. CONCLUSIONS: Impaired testosterone synthesis in hypogonadal men favors inflammatory processes, elevates inducible NOS-mediated NO formation, and impairs CA-dependent nitrite reabsorption. Normalization of plasma testosterone reverses these processes. Pharmacological testosterone may combat atherosclerosis in hypogonadal hypogonadism. PMID- 29128546 TI - A 1204-single nucleotide polymorphism and insertion-deletion polymorphism panel for massively parallel sequencing analysis of DNA mixtures. AB - Massively parallel sequencing (MPS) technology enables the simultaneous analysis of a huge number of single nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms (indels). MPS also enables the detection of the alleles of minor contributors in a highly unbalanced DNA mixture. In this study, we established a 1204-marker panel optimized for MPS consisting of 987 autosomal markers (964 SNPs and 23 indels), 27 X-chromosome SNPs, 61 Y-chromosome markers (56 SNPs and 5 indels), and 129 mitochondrial SNPs. The DNA samples of six unrelated individuals (two men and four women), 26 nondegraded DNA mixtures (with minor to major ratios of 1:29, 1:39, 1:79, and 1:99), and eight highly artificially degraded DNA mixtures (with minor to major ratios of 1:29, 1:39, 1:79, and 1:99) were analyzed through MPS by using the panel. A scoring system was developed to determine the minor contributors in DNA mixtures based on the genotypes identified using MPS. The genotypes of the 1204 markers were successfully profiled through MPS by using the custom-designed panel. The efficiency of MPS for analyzing these highly degraded samples was lower than that for analyzing nondegraded samples. All minor contributors in the 26 nondegraded and 8 degraded DNA mixtures were accurately assigned using this scoring system based on 964 autosomal SNPs. An association between the observed reads ratio and theoretical ratio of the minor component was noted for nondegraded mixtures. In conclusion, we established a 1204-marker individual identification panel for MPS that successfully analyzed autosomal, X chromosome, Y-chromosome, and mitochondrial SNPs and indels simultaneously. In combination with the newly developed scoring system, the panel can accurately identify minor contributors in nondegraded and highly degraded DNA mixtures. PMID- 29128548 TI - Eligibility for treatment with PCSK9 inhibitors among patients with stable coronary artery disease presumed to be on maximum hypolipidaemic therapy. PMID- 29128549 TI - Personality traits and appearance-ideal internalization: Differential associations with body dissatisfaction and compulsive exercise. AB - Thin-ideal internalization is a robust risk factor for body dissatisfaction and eating pathology. Conversely, athletic-ideal internalization is often unrelated to body dissatisfaction, but predicts compulsive exercise (i.e., rigid, rule driven exercise that is continued despite adverse consequences). Distinct personality traits could relate to internalization of different appearance ideals, which may be associated with divergent eating disorder outcomes. Past research has shown that neuroticism is related to body dissatisfaction, whereas extraversion and conscientiousness have been associated with regular and problematic exercise. The current study examined associations among personality traits (i.e., neuroticism, extraversion, conscientiousness), appearance-ideal internalization (i.e., thin- and athletic-ideal), and eating disorder cognitions/behaviors (i.e., body dissatisfaction, compulsive exercise) among 531 college men and women. Moreover, we tested whether appearance-ideal internalization mediated the relationships between personality traits with body dissatisfaction and compulsive exercise. As expected, body dissatisfaction was positively related to neuroticism, and compulsive exercise was positively associated with extraversion. Thin-ideal internalization positively correlated with neuroticism, athletic-ideal internalization positively correlated with conscientiousness, and both thin- and athletic-ideal internalization were positively related to extraversion. After controlling for gender, body mass index, the other appearance-ideal internalization, and the remaining personality traits, the indirect effects of both neuroticism and extraversion on body dissatisfaction through thin-ideal internalization were significant. Extraversion and conscientiousness were indirectly related to compulsive exercise through athletic-ideal internalization, whereas the indirect effect of neuroticism was dependent on covariates. As such, personality traits may be related to distinct eating disorder cognitions/behaviors through internalization of specific appearance ideals. PMID- 29128550 TI - Neural correlates of quantity processing of Chinese numeral classifiers. AB - Linguistic analysis suggests that numeral classifiers carry quantity information. However, previous neuroimaging studies have shown that classifiers did not elicit higher activation in the intraparietal sulcus (IPS), associated with representation of numerical magnitude, than tool nouns did. This study aimed to control the semantic attributes of classifiers and reexamine the underlying neural correlates. Participants performed a semantic distance comparison task in which they judged which one of the two items was semantically closer to the target. Processing classifiers elicited higher activation than tool nouns in the bilateral inferior parietal lobules (IPL), middle frontal gyri (MFG), right superior frontal gyrus (SFG), and left lingual gyrus. Conjunction analysis showed that the IPS was commonly activated for classifiers, numbers, dots, and number words. The results support that classifiers activate quantity representations, implicating that the system of classifiers is part of magnitude cognition. Furthermore, the results suggest that the IPS represents magnitude independent of notations. PMID- 29128551 TI - Transplant Decisions in Patients with Myelofibrosis: Should Mutations Be the Judge? AB - The prognosis of myeloproliferative neoplasms, including primary myelofibrosis (PMF), polycythemia vera, and essential thrombocythemia varies considerably, between these disorders as well as within each diagnosis. Molecular studies have identified "driver mutations" in JAK2, MPL1, and CALR and additional somatic DNA mutations, including ASXL1, EZH2, IDH1/2, and SRSF2, that affect prognosis differentially. Patients with mutations in CALR (type1) have a better outlook than patients with mutations in JAK2 or MPL, whereas patients without any of the driver mutations (triple negative) have the shortest life expectancy. Mutations in ASXL1, EZH2, and SRSF2 may be associated with shortened survival, and IDH mutations carry a higher risk of leukemic transformation. The combination and number of mutations are more important than a given single mutation. Mutations also appear to impact the outcome of hematopoietic cell transplantation (HCT), currently the only treatment with curative potential. Based on available data, the best post-HCT outcome is observed with CALR mutations. Triple negativity has a negative impact. The data on JAK2 are controversial. Mutations in ASXL1 or IDH1/2 reduce the probability of progression-free survival after HCT, although the impact of ASXL1 differs between patients with primary and secondary myelofibrosis. Although it is not clear to what extent HCT can overcome the risks associated with a given mutational pattern, at present, early HCT should be considered in triple-negative patients and patients with PMF who harbor mutations in ASXL1. Mutations in EZH2, SRSF2, or IDH, particularly if combined with other mutations, should also lead to consideration of HCT. Further studies are needed to validate the present observations and determine the impact of additional mutations that have been identified. PMID- 29128552 TI - Venous Thromboembolism in Pediatric Hematopoietic Cell Transplant: A Multicenter Cohort Study. AB - Hematopoietic cell transplant (HCT) is associated with a proinflammatory, procoagulant environment that places recipients at increased risk of venous thromboembolism (VTE). Although the incidence of VTE in adult HCT recipients has been extensively studied, similar data for children are lacking. We conducted a multicenter retrospective study to analyze the prevalence of VTE and associated risk factors in a large cohort of patients who underwent HCT at tertiary care US children's hospitals. The Pediatric Health Information System database, a large administrative database that contains clinical and resource utilization data from 49 freestanding children's hospitals in the United States, was used to extract data. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify HCT recipients, VTE events, post-HCT complications, and associated risk factors up to 1 year post-transplant. Data on patients who received HCT from January 2010 through September 2014 were collected. A total of 4158 unique patients mean +/- standard deviation age at transplant admit, 8.8 +/- 6.5 years; range, birth to 33.4 years) were identified. After HCT 290 subjects (6.9%) developed VTE. VTE prevalence was greater in patients aged >= 13 versus <13 years (8.54% versus 6.33%; P = .01) and in recipients of allogeneic versus autologous grafts (7.7% versus 5%; P <= .01). VTE was associated with prolonged median duration of hospitalization (81 versus 54 days; P <=.01) and increased 1-year mortality (13.9% versus 5.9%; P <= .01). Infections and presence of any graft-versus-host disease (GVHD) were significantly associated with VTE occurrence in recipients of allogenic grafts. Prevalence of VTE in patients who underwent HCT at pediatric tertiary care hospitals is about 7%. Age >= 13 years and allogeneic grafts were significant pre HCT VTE risk factors, with GVHD and infections seen more frequently in patients with VTE. PMID- 29128554 TI - Immunomodulatory Effects of Tyrosine Kinase Inhibitor In Vitro and In Vivo Study. AB - Pathogenesis of chronic graft-versus-host disease (cGVHD) is incompletely defined, involving donor-derived CD4 and CD8-positive T lymphocytes as well as B cells. Standard treatment is lacking for steroid-dependent/refractory cases; therefore, the potential usefulness of tyrosine kinase inhibitors (TKIs) has been suggested, based on their potent antifibrotic effect. However, TKIs seem to have pleiotropic activity. We sought to evaluate the in vitro and in vivo impact of different TKIs on lymphocyte phenotype and function. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured in the presence of increasing concentrations of nilotinib, imatinib, dasatinib, and ponatinib; in parallel, 44 PBMC samples from 15 patients with steroid-dependent/refractory cGVHD treated with nilotinib in the setting of a phase I/II trial were analyzed at baseline, after 90, and after 180 days of therapy. Flow cytometry was performed after labeling lymphocytes with a panel of monoclonal antibodies (CD3, CD4, CD16, CD56, CD25, CD19, CD45RA, FoxP3, CD127, and 7-amino actinomycin D). Cytokine production was assessed in supernatants of purified CD3+ T cells and in plasma samples from nilotinib-treated patients. Main T lymphocyte subpopulations were not significantly affected by therapeutic concentrations of TKIs in vitro, whereas proinflammatory cytokine (in particular, IL-2, IFN-gamma, tumor necrosis factor alpha, and IL-10) and IL-17 production showed a sharp decline. Frequency of T regulatory, B, and natural killer (NK) cells decreased progressively in presence of therapeutic concentrations of all TKIs tested in vitro, except for nilotinib, which showed little effect on these subsets. Of note, naive T regulatory cell (Treg) subset accumulated after exposure to TKIs. Results obtained in vivo on nilotinib-treated patients were largely comparable, both on lymphocyte subset kinetics and on cytokine production by CD3-positive cells. This study underlines the anti-inflammatory and immunomodulatory effects of TKIs and supports their potential usefulness as treatment for patients with steroid-dependent/refractory cGVHD. In addition, both in vitro and in vivo data point out that compared with other TKIs, nilotinib could better preserve the integrity of some important regulatory subsets, such as Treg and NK cells. PMID- 29128553 TI - Pediatric Hematopoietic Cell Transplant Patients Who Survive Critical Illness Frequently Have Significant but Recoverable Decline in Functional Status. AB - The number of pediatric hematopoietic cell transplant (HCT) patients who survive pediatric intensive care unit (PICU) admission is increasing, yet little is known about their functional morbidity after PICU discharge. We hypothesized that relative to control subjects, pediatric HCT patients who survive PICU admission would have greater rates of new functional morbidity at the time of PICU discharge and only some of these patients would return to their functional baseline by the end of the hospitalization. We performed a retrospective cohort study with secondary data analysis of the Trichotomous Outcomes in Pediatric Critical Care dataset. The pediatric HCT cohort was identified by querying International Classification of Diseases, 9th edition, diagnostic codes. A control group consisted of previously healthy patients matched 4:1 on age, sex, and illness severity, as estimated by the Pediatric Risk of Mortality (PRISM) score. We benchmarked our findings by comparing with a previously healthy group of children with lower respiratory tract infections. Functional impairment was measured by the Functional Status Scale, wherein new morbidity was defined as an increase of >=3 points relative to the prehospital baseline. Relative to matched control subjects, HCT patients had similar admission PRISM scores (P = .516) but greater PICU mortality (12.9% [11/85] versus 6.2% [21/340], P = .035). However, among those who survived to PICU discharge, HCT patients had similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 17.2% [55/319], P = .622) and similar rates of resolution of new morbidity by hospital discharge (54.5% [6/11] versus 60.0% [33/55], P = .737). Relative to the comparison group with lower respiratory tract infections, HCT patients had both greater admission PRISM scores (P < .001) and greater PICU mortality (12.9% [11/85] versus 1.6% [5/308], P < .001). However, among those who survived to PICU discharge, HCT patients again displayed similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 22.1% [67/303], P = .168) as well as resolution of new morbidity by hospital discharge (54.5% [6/11] versus 71.6% [48/67], P = .299). For pediatric HCT patients PICU survival with new functional morbidity is as prevalent an outcome as PICU mortality. Although pediatric HCT patients have greater PICU mortality than age-, sex-, and PRISM-matched control subjects, they have similar rates of new functional morbidity at PICU discharge and similar resolution of new functional morbidity at hospital discharge. Future interventions focused on improving functional status in pediatric HCT survivors of critical illness are warranted. PMID- 29128555 TI - Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia. AB - Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and >=3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results. PMID- 29128556 TI - PRO 140 Monoclonal Antibody to CCR5 Prevents Acute Xenogeneic Graft-versus-Host Disease in NOD-scid IL-2Rynull Mice. AB - Graft-versus-host disease (GVHD) is a prevalent and potentially lethal complication of hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic GVHD are important tools used to study the human immune response in vivo. Here we used NOD-scid IL-2Rynull mice (NSG) transplanted with human bone marrow stem cells to evaluate the role of immune cell engraftment in the production of acute GVHD. PRO 140, a humanized monoclonal antibody targeting the chemokine receptor, CCR5, was used to evaluate its influence on bone marrow cell engraftment and modulation of acute GVHD. We evaluated the kinetics of engraftment by determining the percentage and absolute numbers of human CD45+ cells and CD3+ T cells from peripheral blood, spleen, and bone marrow in treated and control mice. With a dosing schedule of 2 mg of test or control antibody administered i.p. twice weekly, PRO 140-treated mice showed no signs of GVHD throughout the 70-day study period and gained weight until they were killed at 70 days for flow cytometry analysis. Control mice started losing weight after 25 days, showed classic signs of GVHD (ruffled fur, lethargy, severe hunching), and all were killed by day 54. The percentage and absolute numbers of human CD45+ cells in peripheral blood increased in both groups of mice throughout the 50-day comparison period and was lower in the PRO 140-treated mice at day 50. There was no difference in human CD45+ cells detected in bone marrow from control and PRO 140-treated killed mice. At this time point 76.1% and 68.2% of the hematopoietic cells from peripheral blood and from bone marrow, respectively, were of human lineage and 14.9% and 28%, respectively, were of mouse origin. With a schedule using 10-fold less dose of antibody (.2 mg i.p. twice weekly), PRO 140 still significantly modulated acute GVHD in terms of both weight loss and survival times, but no mice from either control or test group survived. By targeting the CCR5 chemokine receptor, PRO 140 modulated acute GVHD in a dose-response fashion in this xenogeneic mouse model without significantly altering engraftment. PMID- 29128557 TI - The effect of diet, adiposity, and weight loss on the secretion of incretin hormones in cats. AB - Degree of adiposity and dietary macronutrient composition affect incretin hormone secretion in humans and mice, but little is known about their effect in cats. In this study, 7 overweight cats were fed a maintenance diet (MD) for at least 2 wk followed by a reduced calorie diet (RCD), which was lower in fat and higher in carbohydrates and fiber. Cats were fed ad libitum initially, and then, food was restricted to achieve 1%-2% loss of body weight weekly (11 wk). When lean, cats were fed MD for 2 wk. A standardized meal test (SMT) using a third diet was performed after at least 7 d on each diet, before and after weight loss (four SMT's total). Glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucose dependent insulinotropic peptide (GIP) concentrations were measured immediately before and over 6 h after feeding the SMT. Area under the curve (AUC) was compared for GLP-1, GIP, and insulin concentrations using 2-way analysis of variance. Leaner cats had increased GIPAUC compared to obese cats (P = 0.025). There was a trend toward increased GIPAUC on RCD compared to the MD (P = 0.085). There was a moderate negative correlation between body fat percentage and GLP 1AUC (r = -0.45; P = 0.05). There was no effect of diet on GLP-1AUC. In conclusion, degree of adiposity and dietary macronutrient content could be important in determining GIP responses not only acutely but also on a long-term basis. Further investigation of GIP responses in cats should take both diet and degree of adiposity into account. PMID- 29128558 TI - Effects of 35% carbon dioxide (CO2) inhalation in patients with post-traumatic stress disorder (PTSD): A double-blind, randomized, placebo-controlled, cross over trial. AB - BACKGROUND: In patients with post-traumatic stress disorder (PTSD) two open pilot studies about the effects of 35% carbon dioxide (CO2) exist. One shows an augmented panicogenic and anxiogenic response (Muhtz et al., 2011), the other does not (Talesnik et al. 2007). We further characterized the CO2 reactivity in PTSD using for the first time placebo-controlled and double-blind conditions. METHODS: In 20 patients with PTSD we assessed panic, anxiety, dissociative and PTSD symptoms after a single vital capacity inhalation of 35% CO2 compared to a placebo gas condition in a within-participant cross-over, placebo-controlled, double-blind and randomized design. RESULTS: Inhalation of 35% CO2 versus placebo provoked significantly increased panic, anxiety, dissociative and PTSD symptoms. The reaction to placebo gas was minimal. Order of inhalation, patients' sex or age did not influence the results. The panic and anxiety response under CO2 was considerably higher in the PTSD patients than in healthy controls from our previous open study. CONCLUSIONS: The results corroborate that our preceding findings of an increased CO2 reactivity in patients with PTSD are not false positive due to the open design or the lack of placebo control. Replication in a larger number of PTSD patients and matched control subjects is needed. The potential role of childhood traumatisation, psychiatric comorbidity, psychotropic medication and trait dissociation in prior contradictory reports should be clarified. PMID- 29128559 TI - Preliminary ecotoxicity hazard evaluation of DOPO-HQ as a potential alternative to halogenated flame retardants. AB - Recent regulatory and environmental pressures have led to increasing demands for environmentally friendly flame retardants as alternatives to halogenated flame retardants (HFRs). A new flame retardant alternative, 10-(2, 5-dihydroxyl phenyl) 9, 10-dihydro-9-oxa-10- phosphaphenanthrene-10-oxide (DOPO-HQ), was applied due to its high thermal stability and glass transition temperature. However, there is little information available for its ecotoxicology. For this purpose, the preliminary ecotoxicity of DOPO-HQ was investigated and evaluated, using aquatic, terrestrial and microorganism toxicity according to Organization for Economic Co operation and Development (OECD) guidelines under the framework of the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation. No effect was observed on Pseudokirchneriella subcapitata, Daphnia magna and Gobiocypris rarus at the saturation water solubility. For active sludge, Eisenia foetida and seedling emergence, no effect was observed at the limited highest concentration of 1000 mg/L or 1000 mg kg-1 dw. However, moderate effect on the shoot weight is observed with the maximum inhibition rate of 46.3% when exposed to 1000 mg kg-1 dw. Comparing the ecotoxicity of DOPO-HQ with that of HFRs and their typical alternatives, the toxicity of DOPO-HQ is markedly lower than those of triphenyl phosphate (TPP) and HFRs such as tris(2-chloro-1 methylethyl) phosphate (TCPP), tris(1,3-dichloro-2-propyl) phosphate (TDCCP), tris(2-chloroethyl) phosphate (TCEP) and tetrabromobisphenol A (TBBPA). Similar low effect levels were observed for resorcinol bis (biphenyl) phosphate (RDP), bisphenol A bis (biphenyl) phosphate (BDP) and its parent chemical 9, 10-dihydro 9-oxa-10-phosphaphenanthrene -10-oxide (DOPO). DOPO-HQ could be a potential alternative to HFRs from an environmental perspective. PMID- 29128560 TI - Renal toxicity of nanoparticles of cadmium sulphide in rat. AB - During present investigations, renal toxicity of CdSNPs (cadmium sulphide nanoparticles) (ranged 5-9 nm) was estimated in rat employing specific parameters. Treatment on each alternate day for 45 days with CdSNPs (10 mg/kg b.w.) yielded significant increase in Cd-MT (cadmium metallothionein), lipid peroxidation and H2O2 generation in the kidney of rat in comparison to bulk cadmium. Concentration of creatinine also increased in urine of CdSNPs treated rats. Histopathological observations revealed extensive damage in proximal tubules. Ultrastructural studies showed mitochondrial, nuclear and ER (endoplasmic reticulum) changes. Finally, renal toxicity of CdSNPs was confirmed by loss of alkaline phosphatase from the brush border of proximal convoluted tubules. These observations conclude that CdSNPs manifest greater toxicity in kidney than cadmium sulphide bulk particles. These effects have been attributed to their specific physicochemical properties, greater potential to generate ROS and induction of oxidative stress and impairment of renal structure and function. Present observations suggest that commercial/industrial use of CdSNPs may pose serious renal health problems in man. PMID- 29128561 TI - Infraciliature of Opisthotrichum janus, Epidinium ecaudatum, and Ophryoscolex purkynjei (Ciliophora, Entodiniomorphida). AB - We described the infraciliature of Opisthotrichum janus, Epidinium ecaudatum, and Ophryoscolex purkynjei, belonging to the family Ophryoscolecidae, from pyridinated silver carbonate impregnated specimens. The adoral polybrachykinety is C-shaped in Opi. janus, whereas it is spiral-shaped in Epi. ecaudatum and Oph. purkynjei. The vestibular polybrachykinety is slender and short in Opi. janus, whereas slender and long in Epi. ecaudatum and Oph. purkynjei. The paralabial kineties are composed of several short kineties along the adoral polybrachykinety. The dorsal polybrachykinety is displaced posteriorly. This study provides information on the diagnostic features of the subfamily Ophryoscolecinae to which Opi. janus, Epi. ecaudatum, and Oph. purkynjei belong. A C-shaped or spiral-shaped adoral polybrachykinety and slender vestibular polybrachykinety are the diagnostic features of the subfamily Ophryoscolecinae in addition to their general features of a cylindrical body, tubular vestibulum, dorsal ciliary zone considerably displaced posteriorly, well developed skeletal plates, and macronucleus beneath the right body surface. Opi. janus, Epi. ecaudatum, and Oph. purkynjei show the basic form of morphogenesis of the ciliature, similar to that in the subfamily Diplodiniinae, with four primordia developing into the oral and dorsal ciliature. PMID- 29128562 TI - Ciliates as restoration indicators in peatbogs - 10 years of study. AB - There is almost no information on how restoration of Sphagnum-dominated peatbogs, and in particular removal of reeds, affects the functioning of ciliate communities. Changes in vegetation patterns caused by restoration procedures may take years to be observed, while microbial processes already display effects after short-term exposure to changes in environmental conditions due to restoration. Based on the results of a long-term study, we assumed that mowing down of reeds causes changes in the physicochemical properties of peatbog water and sought to answer the question of how ciliate communities react to these changes and whether these microorganisms can play a significant role as bioindicators in evaluating the restoration process. Removal of reeds clearly modified the taxonomic composition and abundance of ciliates. This was reflected in an increase in the abundance and diversity of these protozoa and in a significant increase in the proportion of sphagnophilous species. Our results suggest an indicator species approach based on functional groups may be appropriate for biomonitoring peatbog restoration. A better understanding of what regulates microbial populations and activity in peatbogs and unravelling of these fundamental mechanisms are particularly critical in order to more accurately predict how peatbogs will respond to anthropogenic disturbances. PMID- 29128563 TI - Matrin 3 Is a Component of Neuronal Cytoplasmic Inclusions of Motor Neurons in Sporadic Amyotrophic Lateral Sclerosis. AB - Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA-binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43-negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43-positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43-positive NCIs. PMID- 29128564 TI - Epigenetic Mechanisms of ATM Activation after Helicobacter pylori Infection. AB - Gastric cancer (GC) is the second leading cause of cancer-related mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes. Among other risk factors, Helicobacter pylori infection is considered the main driving factor of GC development. H. pylori infection increases DNA damage levels and leads to epigenetic dysregulation, which may favor gastric carcinogenesis. An early step in double-strand break repair is the recruitment of ataxia-telangiectasia mutated serine/threonine kinase (ATM) to the damaged site, where it plays a key role in advancing the DNA damage checkpoint process. H. pylori infection has been associated with the introduction of double strand breaks in epithelial cells, triggering damage signaling and repair response involving ATM. Thus, the current study analyzed the effect of H. pylori infection on the DNA damage response sensor, ATM, in gastric epithelial cells and in biopsy specimens from patients with GC. In this study, we identified that H. pylori infection stimulated DNA damage, and therefore induced ATM in a virulence factor-dependent manner. In addition, we found that H. pylori might activate ATM through histone H3 and H4 hyperacetylation and DNA promoter hypomethylation. Our findings show a mechanism associating ATM signaling induction with H. pylori infection. PMID- 29128566 TI - Restoration of polr1c in Early Embryogenesis Rescues the Type 3 Treacher Collins Syndrome Facial Malformation Phenotype in Zebrafish. AB - Treacher Collins syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects. Recently, the authors' group unfolded the pathogenesis of polr1c Type 3 TCS by using the zebrafish model. Facial development depends on the neural crest cells, in which polr1c plays a role in regulating their expression. In this study, the authors aimed to identify the functional time window of polr1c in TCS by the use of photo morpholino to restore the polr1c expression at different time points. Results suggested that the restoration of polr1c at 8 hours after fertilization could rescue the TCS facial malformation phenotype by correcting the neural crest cell expression, reducing the cell death, and normalizing the p53 mRNA expression level in the rescued morphants. However, such recovery could not be reproduced if the polr1c is restored after 30 hours after fertilization. PMID- 29128565 TI - Obesity and Triple-Negative Breast Cancer: Disparities, Controversies, and Biology. AB - Once considered a problem of Western nations, obesity (body mass index >=30 kg/m2) has rapidly increased since the 1970s to become a major threat to world health. Since 1970, the face of obesity has changed from a disease of affluence and abundance to a disease of poverty. During the last 10 years, studies have mechanistically linked obesity and an obese tumor microenvironment with signaling pathways that predict aggressive breast cancer biology. For example, in the United States, African American women are more likely than non-Hispanic European American women to be obese and to be diagnosed with triple-negative breast cancer (TNBC). In 2008, the Carolina Breast Study found that obesity (increased waist/hip ratio) was linked to an increased incidence of TNBC in premenopausal and postmenopausal African American women. Subsequently, several groups have investigated the potential link between obesity and TNBC in African American women. To date, the data are complex and sometimes contradictory. We review epidemiologic studies that investigated the potential association among obesity, metabolic syndrome, and TNBC in African American women and mechanistic studies that link insulin signaling to the obese breast microenvironment, tissue inflammation, and aggressive TNBC biology. PMID- 29128567 TI - Haploinsufficiency of hnRNP U Changes Activity Pattern and Metabolic Rhythms. AB - The neuropeptides arginine vasopressin (Avp) and vasoactive intestinal polypeptide (Vip) are critical for the communication and coupling of suprachiasmatic nucleus neurons, which organize daily rhythms of physiology and behavior in mammals. However, how these peptides are regulated remains uncharacterized. We found that heterogeneous nuclear ribonucleoprotein U (hnRNP U) is essential for the expression of Avp and Vip. Loss of one copy of the Hnrnpu gene resulted in fragmented locomotor activities and disrupted metabolic rhythms. Hnrnpu+/- mice were more active than wild-type mice in the daytime but more inactive at night. These phenotypes were partially rescued by microinfusion of Avp and Vip into free-moving animals. In addition, hnRNP U modulated Avp and Vip via directly binding to their promoters together with brain and muscle Arnt-like protein-1/circadian locomotor output cycles kaput heterodimers. Our work identifies hnRNP U as a novel regulator of the circadian pacemaker and provides new insights into the mechanism of rhythm output. PMID- 29128568 TI - Colorectal Cancer Disparity in African Americans: Risk Factors and Carcinogenic Mechanisms. AB - African Americans have the highest incidence and mortality rates of colorectal cancer (CRC) of any ethnic group in the United States. Although some of these disparities can be explained by differences in access to care, cancer screening, and other socioeconomic factors, disparities remain after adjustment for these factors. Consequently, an examination of recent advances in the understanding of ethnicity-specific factors, including genetic and environmental factors relating to risk of CRC, the biology of CRC progression, and the changes in screening and mortality, is important for evaluating our progress toward eliminating the disparities. An overarching limitation in this field is the number and sample size of studies performed to characterize the etiological bases of CRC incidence and mortality in African Americans. Despite this limitation, significant differences in etiology are manifest in many studies. These differences need validation, and their impacts on disparities need more detailed investigation. Perhaps most heartening, improvements in CRC screening can be attributed to the smallest difference in CRC incidence between African Americans and whites since the late 1980s. Cancer mortality, however, remains a persistent difference. PMID- 29128570 TI - Outcomes in Degenerative Mitral Regurgitation: Current State-of-the Art and Future Directions. AB - Mitral regurgitation (MR) is the one of the most frequent valvular heart diseases in the developed world, often requiring surgical correction. Degenerative MR is the most common type of non-ischemic, organic MR in the western world. Since no medical treatment has been shown to be effective in preventing the consequences of volume overload in asymptomatic degenerative MR, risk stratification is essential. Currently, this is achieved using clinical and precisely quantified echocardiographic parameters, with newer technologies like cardiac magnetic resonance gaining increasing prominence. While surgical mitral repair, often performed using minimally invasive/robotic techniques, is the current gold standard for definitive therapeutic management, there is rapid emergence of percutaneous techniques for mitral valve repair/replacement in cases of degenerative MR. This state-of-the-art-review will discuss the latest knowledge in the natural history, imaging, surgical and percutaneous therapies in patients with degenerative MR. PMID- 29128569 TI - Lysophosphatidic Acid Receptor 1 Is Important for Intestinal Epithelial Barrier Function and Susceptibility to Colitis. AB - Intestinal epithelial cells form a barrier that is critical in protecting the host from the hostile luminal environment. Previously, we showed that lysophosphatidic acid (LPA) receptor 1 regulates proliferation of intestinal epithelial cells, such that the absence of LPA1 mitigates the epithelial wound healing process. This study provides evidence that LPA1 is important for the maintenance of epithelial barrier integrity. The epithelial permeability, determined by fluorescently labeled dextran flux and transepithelial resistance, is increased in the intestine of mice with global deletion of Lpar1, Lpar1-/- (Lpa1-/-). Serum liposaccharide level and bacteria loads in the intestinal mucosa and peripheral organs were elevated in Lpa1-/- mice. Decreased claudin-4, caudin 7, and E-cadherin expression in Lpa1-/- mice further suggested defective apical junction integrity in these mice. Regulation of LPA1 expression in Caco-2 cells modulated epithelial permeability and the expression levels of junctional proteins. The increased epithelial permeability in Lpa1-/- mice correlated with increased susceptibility to an experimental model of colitis. This resulted in more severe inflammation and increased mortality compared with control mice. Treatment of Caco-2 cells with tumor necrosis factor-alpha and interferon-gamma significantly increased paracellular permeability, which was blocked by cotreatment with LPA, but not LPA1 knockdown cells. Similarly, orally given LPA blocked tumor necrosis factor-mediated intestinal barrier defect in mice. LPA1 plays a significant role in maintenance of epithelial barrier in the intestine via regulation of apical junction integrity. PMID- 29128572 TI - Mitral valve repair: Robotic and other minimally invasive approaches. AB - Robotic and minimally invasive mitral valve (MV) procedures have been performed with increasing frequency over time. These alternatives offer similar efficacy to that achieved via standard median sternotomy, particularly in large volume centers, along with low perioperative morbidity and mortality rates. Moreover, patient acceptance is oftentimes increased due to less postoperative pain and shorter recovery times, as well as superior cosmetic results. However, these techniques are technically complex and associated with a significant learning curve. The following review offers an overview of the most relevant aspects related to minimally invasive and robotic MV repair. Although these techniques are well established in referral centers, future innovations should concentrate on decreasing complexity and improving reproducibility of these procedures. PMID- 29128571 TI - Exercise Testing in Mitral Regurgitation. AB - Mitral regurgitation (MR) is the second most common valvular heart disease referred for corrective surgery. Diagnostic and management dilemmas are not uncommon when dealing with MR patients. Exercise testing plays an important role in sorting out some of these clinical challenges. In primary asymptomatic MR, exercise testing allows symptom assessment, confident link of symptoms to valve disease severity, safe deferral of surgery for the next 1-year in patients with preserved exercise capacity, insights into the mechanism of exercise-induced dyspnea and helps in individual risk stratification. Moreover, exercise testing in the form of exercise stress echocardiography is also useful in the evaluation of patients with secondary ischemic MR for risk stratification as well as for the detection of patients with moderate ischemic MR in whom mitral valve repair at the time of surgical revascularization may add benefit. PMID- 29128573 TI - Oral chronic toxicity study of geniposide in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Geniposide, the major active constituent of Fructus Gardeniae (FG), has been widely used to treat various diseases in China. AIM OF THE STUDY: This chronic toxicity study was conducted to investigate the safety of geniposide. MATERIALS AND METHODS: Geniposide was administered to Sprague-Dawley (SD) rats of both sexes by oral gavage at dosages of 25, 50, or 100mg/kg in a volume of 10mL/kg once daily for 26 weeks. Endpoints included clinical observations, food consumption, body weights, blood biochemistry, haematology, and histomorphological observations. RESULTS: The administration of geniposide did not influence animal mortality, the general conditions of the animals, body weights or food consumption. After 4 weeks of administration, significant toxicity was not observed. However, in the 13th week of the toxicity study, a few haematological parameters and some relative organ weights of male rats in the 50 and 100mg/kg geniposide groups were significantly increased. The percentage of reticulocytes (Retic %) was significantly increased in male and female rats administered 100mg/kg geniposide. In addition, two female rats in the 100mg/kg geniposide group showed slight pathological changes in hepatic and renal tissues. Furthermore, in a chronic (26 weeks) toxicity study, differences were detected in alanine aminotransferase (ALT), aspartate aminotransferase (AST), sodium (Na+), potassium (K+), white blood cell (WBC), red blood cell (RBC), and haemoglobin (HGB) levels and the relative weights of the liver and spleen in male rats administered 100mg/kg geniposide. In addition, differences were detected in Retic % and the relative weights of the liver, thymus, and kidneys in female rats administered 100mg/kg geniposide. Urinalysis results from male and female rats in the 100mg/kg geniposide group revealed noticeable changes. The histopathological structures of hepatic and renal tissues in the high-dose geniposide group exhibited serious abnormalities and pigment deposition. CONCLUSION: Geniposide affected serum biochemistry, urinalysis, and haematological parameters as well as relative organ weights. The treatment also caused noticeable pathological abnormalities in liver and kidney tissues. Therefore, administration of a high dose of geniposide (100mg/kg) for 26 weeks could induced obvious liver and kidney damage. PMID- 29128574 TI - Conjunctivochalasis: a systematic review. AB - Conjunctivochalasis (CCH) is a conjunctival condition characterized by loose, redundant conjunctival folds, most typically in the inferior bulbar conjunctiva of both eyes. Although CCH is a common cause of ocular irritation and discomfort, especially in the elderly, it is often overlooked in clinical practice. CCH may be associated with various ocular and nonocular conditions; however, the most important risk factor is aging. Although often asymptomatic, CCH may cause symptoms related to tear film instability and/or delayed tear clearance. Pathogenesis of CCH remains largely unknown but may involve different elements such as aged conjunctiva, unstable tear film, mechanical friction, ocular surface inflammation, and delayed tear clearance. Contradictory results have been reported on histopathologic changes in CCH, with some studies showing a normal microscopic structure. For symptomatic CCH, medical treatment may include lubrication and anti-inflammatory medications. For symptomatic patients who fail to respond to medical treatment, a surgical procedure may be considered. Although various surgical procedures have been used for CCH, more often, it consists of conjunctival cauterization or excision of the redundant conjunctiva, with or without amniotic membrane transplantation. PMID- 29128575 TI - Strain specificities in age-related changes in mechanisms promoting and controlling rat spinal cord damage in experimental autoimmune encephalomyelitis. AB - The study investigated strain specificities in age-related differences in CD8+ T cell- and microglial cell-mediated mechanisms implicated in induction/perpetuation and/or control of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in Albino Oxford (AO) and Dark Agouti (DA) rats exhibiting age-related changes in the susceptibility to EAE in the opposite direction (increase in relatively resistant AO rats vs decrease in DA rats). In the inductive phase of EAE, the greater number of fully differentiated effector CD8+ T lymphocytes was found in draining lymph nodes (dLNs) from aged rats of both strains than in strain-matched young rats, but this was particularly prominent in AO rats, which exhibited milder EAE of prolonged duration compared with their DA counterparts. Consistently, dLN IFN-gamma+ and IL-17+ CD8+ T cell counts were greater in aged AO than in DA rats. Additionally, the magnitudes of myelin basic protein (MBP)-induced rise in the frequency of IFN-gamma+ and IL-17+ CD8+ T cells (providing important help to neuroantigen-specific CD4+ T cells in EAE models characterized by clinically mild disease) were greater in dLN cell cultures from aged AO rats. Consistently, the magnitudes of MBP-induced rise in the frequency of both IFN-gamma+ and IL-17+ CD8+ T cells were greater in spinal cord mononuclear cell cultures from aged AO rats compared with their DA counterparts. Besides, with aging CD4+CD25+Foxp3+/CD8+CD25+Foxp3+ regulatory T cell ratio changed in spinal cord in the opposite direction. Consequently, in aged AO rats it was shifted towards CD8+CD25+Foxp3+ regulatory T cells (exhibiting lower suppressive capacity) when compared with DA rats. Moreover, the frequency of CX3CR1+ cells among microglia changed with aging and the disease development. In aged rats, in the effector phase of EAE it was lower in AO than in DA rats. This was accompanied by higher frequency of cells expressing IL-1beta (whose down-regulation is central for CX3CR1-mediated neuroprotection), but lower that of phagocyting cells among microglia from aged AO compared their DA counterparts. The study indicates the control points linked with strain differences in age-related changes in EAE pathogenesis. PMID- 29128576 TI - Evaluation of Tumor Pseudocapsule Status and its Prognostic Significance in Renal Cell Carcinoma. AB - PURPOSE: We determined whether tumor pseudocapsule status, including the extent of invasion by cancer and lack of a pseudocapsule, has prognostic value in renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the records of 1,577 patients with different stages of renal cell carcinoma who underwent nephrectomy at our institution, of whom 1,307 (82.9%) were eligible for analysis. Presented pseudocapsules were classified as grade 0-completely intact, grade 1 merely involved and grade 2-penetrated. We studied overall and progression-free survival using the Kaplan-Meier method and a Cox regression model. RESULTS: Of the 1,307 patients 1,244 (95.2%) presented with a pseudocapsule, including 350 (28.1%), 643 (51.7%) and 251 (20.2%) with a grade 0, 1 and 2 pseudocapsule invasion extent, respectively. Kaplan-Meier curves revealed great losses in overall and progression-free survival for an increased extent of invasion and pseudocapsule absence. On multivariate analyses we identified significant overall and progression-free survival harms for grade 2 pseudocapsules (HR 2.12 and 2.66, each p <0.0001) and lack of a pseudocapsule (HR 1.95, p = 0.0248 and HR 2.54, p = 0.0007, respectively) compared to grade 0 pseudocapsules. A change in statistical risk from grade 1 to 0 was only detected for progression-free survival. The prognostic value of pseudocapsule status was shown by a higher HR on multivariable analyses in individuals with localized renal cell carcinoma. CONCLUSIONS: Our findings suggest that pseudocapsule status has good prognostic implications in renal cell carcinoma. Lack of a pseudocapsule certainly had a remarkably adverse impact on the patient outcome. Accessibility in use and cost makes pseudocapsule status a potential cost-effective parameter in clinical practice. PMID- 29128577 TI - Pathological and 3 Tesla Volumetric Magnetic Resonance Imaging Predictors of Biochemical Recurrence after Robotic Assisted Radical Prostatectomy: Correlation with Whole Mount Histopathology. AB - PURPOSE: We sought to identify the clinical and magnetic resonance imaging variables predictive of biochemical recurrence after robotic assisted radical prostatectomy in patients who underwent multiparametric 3 Tesla prostate magnetic resonance imaging. MATERIALS AND METHODS: We performed an institutional review board approved, HIPAA (Health Insurance Portability and Accountability Act) compliant, single arm observational study of 3 Tesla multiparametric magnetic resonance imaging prior to robotic assisted radical prostatectomy from December 2009 to March 2016. Clinical, magnetic resonance imaging and pathological information, and clinical outcomes were compiled. Biochemical recurrence was defined as prostate specific antigen 0.2 ng/cc or greater. Univariate and multivariate regression analysis was performed. RESULTS: Biochemical recurrence had developed in 62 of the 255 men (24.3%) included in the study at a median followup of 23.5 months. Compared to the subcohort without biochemical recurrence the subcohort with biochemical recurrence had a greater proportion of patients with a high grade biopsy Gleason score, higher preoperative prostate specific antigen (7.4 vs 5.6 ng/ml), intermediate and high D'Amico classifications, larger tumor volume on magnetic resonance imaging (0.66 vs 0.30 ml), higher PI-RADS(r) (Prostate Imaging-Reporting and Data System) version 2 category lesions, a greater proportion of intermediate and high grade radical prostatectomy Gleason score lesions, higher pathological T3 stage (all p <0.01) and a higher positive surgical margin rate (19.3% vs 7.8%, p = 0.016). On multivariable analysis only tumor volume on magnetic resonance imaging (adjusted OR 1.57, p = 0.016), pathological T stage (adjusted OR 2.26, p = 0.02), positive surgical margin (adjusted OR 5.0, p = 0.004) and radical prostatectomy Gleason score (adjusted OR 2.29, p = 0.004) predicted biochemical recurrence. CONCLUSIONS: In this cohort tumor volume on magnetic resonance imaging and pathological variables, including Gleason score, staging and positive surgical margins, significantly predicted biochemical recurrence. This suggests an important new imaging biomarker. PMID- 29128578 TI - Electrical brain stimulation (tES) improves learning more than performance: A meta-analysis. AB - Researchers have recently started evaluating whether stimulating the brain noninvasively with a weak and painless electrical current (transcranial Electrical Stimulation, tES) enhances physiological and cognitive processes. Some studies found that tES has weak but positive effects on brain physiology, cognition, or assessment performance, which has attracted massive public interest. We present the first meta-analytic test of the hypothesis that tES in a learning phase is more effective than tES in an assessment phase. The meta analysis included 246 effect sizes from studies on language or mathematical competence. The effect of tES was stronger when stimulation was administered during a learning phase (d=0.712) as compared to stimulation administered during test performance (d=0.207). The overall effect was stimulation-dosage specific and, as found in a previous meta-analysis, significant only for anodal stimulation and not for cathodal. The results provide evidence for the modulation of long-term synaptic plasticity by tES in the context of practically relevant learning tasks and highlight the need for more systematic evaluations of tES in educational settings. PMID- 29128579 TI - Revisiting the validity of the mouse forced swim test: Systematic review and meta analysis of the effects of prototypic antidepressants. AB - One problem area regarding animal models for affective disorders is unclear reproducibility, including external validity or generalizability. One way to evaluate external validity is with systematic reviews and meta-analyses. The current study presents a meta-analysis of the effects of prototypic antidepressants in the mouse forced swim test (FST). We identified studies that examined effects of antidepressants in the FST in mice and used standard protocol, male mice and acute drug administration. We calculated Effect sizes using Cohen's d, homogeneity using Q statistic and correlations using Pearson's correlation. Results indicate that all drugs reduce immobility in the FST. However, effect sizes for most drugs are heterogeneous and do not show a consistent dose/response relationship across variability factors. Reducing variability by examining only one strain or data from individual laboratories partially increases dose response relationship. These findings suggest that whereas the FST is a valid tool to qualitatively screen antidepressant effects its validity in the context of hierarchical comparison between doses or compounds might be relevant only to single experiments. PMID- 29128580 TI - Reduction of protein phosphatase 2A Calpha promotes in vivo bone formation and adipocyte differentiation. AB - Serine/threonine protein phosphatase 2A (PP2A) regulates diverse physiological processes such as cell cycle, growth, apoptosis, and signal transduction. Previously, we demonstrated that silencing of the alpha-isoform of PP2A catalytic subunit (PP2A Calpha) in osteoblasts accelerated osteoblast differentiation, whereas its overexpression suppressed differentiation. In this study, we examined the role of PP2A Calpha in in vivo bone formation by generating transgenic mice (PP2A-Tg), in which the dominant negative form of PP2A Calpha was specifically expressed in osteoblasts. PP2A-Tg mice exhibited an increase in body weight, cortical bone mineral density, and cortical bone thickness. Interestingly, they also displayed higher amounts of adipose tissue in the bone marrow of tibiae. The co-culture study showed that PP2A Calpha-knockdown osteoblasts stimulated adipocyte differentiation from undifferentiated mesenchymal cells via upregulation of the adipocyte marker genes, such as peroxisome proliferator activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha). These results indicated that the reduction of PP2A Calpha levels in osteoblasts promoted bone formation in vivo. Additionally, PP2A Calpha in osteoblasts was also potentially involved in controlling adipocyte differentiation through a paracrine mechanism. PMID- 29128581 TI - Trends in resource utilization and rate of cervical disc arthroplasty and anterior cervical discectomy and fusion throughout the United States from 2006 to 2013. AB - BACKGROUND CONTEXT: The typically accepted surgical procedure for cervical disc pathology has been the anterior cervical discectomy and fusion (ACDF), although recent trials have demonstrated equivalent or improved outcomes with cervical disc arthroplasty (CDA). Trends for these two procedures regarding utilization, revision procedures, and other demographic information have not been sufficiently explored. PURPOSE: The present study aims to provide data regarding ACDF and CDA from 2006 to 2013 in the United States. DESIGN: The present study is a retrospective national database analysis. PATIENT SAMPLE: The present study included 20% sample of discharges from US hospitals, which is weighted to provide national estimates. OUTCOME MEASURES: Functional measures such as national incidence, hospital costs, length of stay (LOS), routine discharge, revision burden, and patient characteristics were used in the present study. METHODS: Patients from the National Inpatient Sample (NIS) database who underwent primary ACDF, revision ACDF, primary CDA, and revision CDA from 2006 to 2013 were included. Demographic and economic data for the procedures' respective International Classification of Diseases, Ninth Revision, Clinical Modification codes were collected. RESULTS: A total of 1,059,403 ACDF and 13,099 CDA surgeries were performed in the United States from 2006 to 2013. The annual number of ACDF increased by 5.7% nonlinearly from 120,617 in 2006 to 127,500 in 2013 (mean per year 132,425; range 120,617-147,966); CDA increased by 190% nonlinearly from 540 in 2006 to 1,565 in 2013 (mean per year 1,637; range 540-2,381). Cervical disc arthroplasty patients were younger and had more private or "other" insurance, including worker's compensation (p<.0001). Mean LOS was longer for ACDF (ACDF 2.3 days vs. CDA 1.5; p<.0001). Routine discharge was higher in the CDA group (CDA 96% vs. ACDF 89%; p-value<.0001). The mean hospital-related cost was more expensive for ACDF (ACDF $16,178 vs. CDA $13,197; p-value=.0007). Cervical disc arthroplasty mean revision burden, defined as the ratio of revision procedures to the sum of primary and revision procedures, was greater (CDA 5.9% vs. ACDF 2.3%, p-value=.01). CONCLUSIONS: Nationally approximately 132,000 ACDFs are done each year compared with only 1,600 CDAs. The number of ACDF surgeries performed far outpaces CDA by a ratio of 81:1 in the United States without a clear direction in the trend for utilization given recent fluctuations. Cervical disc arthroplasty revision burden was more than double compared with the ACDF revision burden (5.9% vs. 2.3%), which was not accounted for by patient baseline demographics. The etiologies of these findings are likely multifactorial and require further research. PMID- 29128582 TI - Budget impact analysis of gene expression tests to aid therapy decisions for breast cancer patients in Germany. AB - OBJECTIVES: Many women with early-stage, hormone receptor-positive breast cancer may not benefit from adjuvant chemotherapy. Gene expression tests can reduce chemotherapy over- and undertreatment by providing prognostic information on the likelihood of recurrence and, with Oncotype DX, predictive information on chemotherapy benefit. These tests are currently not reimbursed by German healthcare payers. An analysis was conducted to evaluate the budget impact of gene expression tests in Germany. MATERIALS AND METHODS: Costs of gene expression tests and medical and non-medical costs associated with treatment were assessed from healthcare payer and societal perspectives. Costs were estimated from data collected at a university hospital and were combined with decision impact data for Oncotype DX, MammaPrint, Prosigna and EndoPredict (EPclin). Changes in chemotherapy use and budget impact were evaluated over 1 year for 20,000 women. RESULTS: Chemotherapy was associated with substantial annual costs of EUR 19,003 and EUR 84,412 per therapy from the healthcare payer and societal perspective, respectively. Compared with standard care, only Oncotype DX was associated with cost savings to healthcare payers and society (EUR 5.9 million and EUR 253 million, respectively). Scenario analysis showed that both women at high clinical but low genomic risk and low clinical but high genomic risk were important contributors to costs. CONCLUSIONS: Oncotype DX was the only gene expression test that was estimated to reduce costs versus standard care in Germany. The reimbursement of Oncotype DX testing in standard clinical practice in Germany should be considered. PMID- 29128583 TI - Patients' experiences with decisions on timing of chemotherapy for breast cancer. AB - INTRODUCTION: Despite potential advantages, application of chemotherapy in the neo-adjuvant (NAC) instead of adjuvant (AC) setting for breast cancer (BC) patients varies among hospitals. The aim of this study was to gain insight in patients' experiences with decisions on the timing of chemotherapy for stage II and III BC. MATERIALS AND METHODS: A 35-item online questionnaire was distributed among female patients (age>18) treated with either NAC or AC for clinical stage II/III invasive BC in 2013-2014 in the Netherlands. Outcome measures were the experienced exchange of information on the possible choice between both options and patients' involvement in the final decision on chemotherapy timing. Chemotherapy treatment experience was measured with the Cancer Therapy Satisfaction Questionnaire (CTSQ). RESULTS: Of 805 invited patients, 49% responded (179 NAC, 215 AC). NAC-treated patients were younger and more often treated in teaching/academic hospitals and high-volume hospitals. Information on the possibility of NAC was given to a minority of AC-treated patients (AC, stage II:14%, stage III: 31%). Information on pros and cons of both NAC and AC was rated sufficient in about three fourth of respondents. Respondents not always felt having a choice in the timing of chemotherapy (stage II: 54% NAC vs 36% AC; stage III: 26% NAC, 54% AC). CONCLUSION: The need to make a treatment decision on NAC was found to be made explicit in only a small number of adjuvant treated patients, in particular in BC stage II. Less than half of the respondents felt they had a real choice. PMID- 29128584 TI - The influence of maternal modeling on body image concerns and eating disturbances in preadolescent girls. AB - Research suggests that mothers may influence the development of body image concerns and eating disturbances in their daughters by modeling negative body image beliefs and unhealthy eating behaviors. However, the causal nature of that mode of influence is yet to be established. This study implemented an experimental design to examine the impact of mothers' modeling of negative comments about their own appearance and diet on their daughters' body image concerns and eating behaviors. Participants were 8-12 year old girls and their mothers (N = 50). While viewing thin-ideal magazine advertisements with their daughter, mothers were instructed to make either negative comments about their own weight, shape, and diet or to make no appearance or diet related comments. Daughters' levels of body esteem, body satisfaction, and eating attitudes were assessed pre- and post-manipulation, and their actual eating habits were measured post-manipulation. Girls whose mothers had made self-critical comments about their own appearance and diet reported lower body esteem, lower body satisfaction, more problematic eating attitudes, and ate significantly fewer sweets than girls whose mothers had not made self-critical comments. These results have implications for disordered eating prevention programs, suggesting that greater emphasis be placed on discouraging negative modeling behaviors among mothers. PMID- 29128585 TI - A return to the psychiatric dark ages with a two-system framework for fear. AB - The past several decades has seen considerable progress in our understanding of the neurobiology of fear and anxiety. These advancements were spurred on by envisioning fear as emerging from the coordinated activation of brain and behavioral systems that evolved for the purpose of defense from environmental dangers. Recently, Joseph LeDoux, a previous proponent of this view, published a series of papers in which he challenges the value of this approach. As an alternative, he and colleagues propose that a 'two-system' framework for the study of responses to threat will expedite the advancement of medical treatments for fear disorders. This view suggests one system for autonomic and behavioral responses and a second for the subjective feeling of fear. They argue that these two systems operate orthogonally and thus inferences concerning the emotion of fear cannot be gleaned from physiological and behavioral measures; confounding these systems has impeded the mechanistic understanding and treatment of fear disorders. Counter to the claim that this view will advance scientific progress, it carries the frightening implication that we ought to reduce the study of fear to subjective report. Here, we outline why we believe that fear is best considered an integrated autonomic, behavioral, and cognitive-emotional response to danger emerging from a central fear generator whose evolutionarily conserved function is that of defense. Furthermore, we argue that although components of the fear response can be independently modulated and studied, common upstream brain regions dictate their genesis, and therefore inferences about a central fear state can be garnered from measures of each. PMID- 29128587 TI - Selection in mixtures of food particles during oral processing in man. AB - OBJECTIVES: Two processes underlie food comminution during chewing: (1) selection, i.e. every particle has a chance of being placed between the teeth and being subjected to (2) breakage. Selection decreases with particle number by saturation of breakage sites, and it depends on competition between smaller and larger particles for breakage sites. Theoretical models were tested which describe competition between various sizes X. In the one-way model, small particles cannot compete with larger ones because of their smaller height. In the two-way model, small particles may compete when piled between antagonistic teeth. DESIGN: Five subjects participated in one-chew experiments on cubes made of Optosil(r). The critical particle number (nc(X)) at which saturation starts, and the number of breakage sites (nb(X)) were determined by varying particle numbers (nX) for single-sized cubes of 1.7-6.8mm. Using nc(X) and nb(X), the models predicted relationships between number of selected particles (ns(X)) and nX in one-chew experiments using simple mixtures with only two sizes. A fixed number (mean 6 or 26) of larger cubes (X=6.8 or 3.4mm) was mixed with various numbers (16-1024) of smaller cubes (X=4.8, 2.4 or 1.7mm), thus varying the factors X, nX, and possible particle piling (for X<4mm). RESULTS: The one-way model was largely followed with small numbers of smaller particles and the two-way model with large numbers. CONCLUSIONS: The two-way model applies to chewing a food which yields a loose aggregation of different-sized particles following an initial phase, whereas other circumstances may be favourable for the one-way model. As conditions of a food bolus can be approached by embedding hard Optosil particles in a soft medium, the models will, apart from dentistry, be of interest for controlling flavour release in food engineering. PMID- 29128586 TI - Contraception, pregnancy, and peripartum experiences among women with epilepsy in Bhutan. AB - INTRODUCTION: Reports on the reproductive health of women with epilepsy (WWE) in low- and middle-income countries (LMICs) are limited. Bhutan is a lower income country with a high estimated prevalence of epilepsy and no out-of-pocket payment requirements for health visits or medications. METHODS: We developed a 10 category survey to interview WWE ages 20-59 years in the Kingdom of Bhutan to understand their contraceptive use and peripartum experiences. WWE were recruited from 2016-2017 from an existing epilepsy cohort and their reproductive health data were merged with epilepsy and socioeconomic data obtained from initial clinical evaluations performed between 2014 and 2016. RESULTS: Of the 134 WWE eligible for the study, 94 were reachable and there was 1 refusal to participate (response rate 99% among reachable WWE; 69% of all WWE in the cohort). Of the 93 WWE (median age 27 years, range 20-52), 50 (54%) reported prior pregnancies. Of the entire cohort, 55 women responded on contraception: 26 (47%) WWE had never used contraception in their lifetime. Of the 29 WWE who had ever used contraception, the most commonly reported form was male condoms (14/29, 48%), followed by depot medroxyprogesterone acetate injections (13/29, 45%), and intrauterine devices (5/29, 17%). Sixty-three percent of WWE recalled receiving information on family planning (31 of 49). Of the 50 WWE with prior pregnancies, 37 of 46 (80%) used folic acid; 6 WWE reported commencing it in the first trimester while 29 WWE began supplementation in the second trimester. Primary school education or higher was associated with folic acid supplementation during pregnancy (26/29 vs. 11/17, p=0.040). Epilepsy affected at least one of the pregnancies in 38 of the cases (76%) with an average of 2.3 pregnancies per woman). There was a total of 86 pregnancies and an average inter-pregnancy interval of 3.5 years. Ninety-five percent of women attended prenatal care (36/38), 22% had at least one miscarriage (8/37), 14% had at least one pre-term delivery (5/36), and 21% had Caesarean sections (8/38). Seventeen of 38 (45%) of WWE had seizures during pregnancy. A majority of WWE (97%, 37 of 38) with a prior pregnancy reported breastfeeding their infant. CONCLUSIONS: Nearly half of Bhutanese WWE did not use contraception; among those who used it, male condoms were most common but 11% were at risk of potential drug-drug interactions between oral contraception and enzyme-inducing antiepileptic drugs. Bhutanese WWE had a high rate of prenatal visits. Folic acid was prescribed in most pregnant WWE but the majority began supplementation in the second trimester. The number of pregnancies in WWE in Bhutan (2.3 per woman) was comparable to the number of children per women in Bhutan (2.3). Breastfeeding was practiced almost universally. Points of intervention may include pre-conception initiation of folic acid, optimization of dosing of AEDs with contraceptives, guidelines for peripartum seizure treatment, and establishment of a prospective registry for WWE and their offspring. PMID- 29128588 TI - Curcumin loaded chitin-glucan quercetin conjugate: Synthesis, characterization, antioxidant, in vitro release study, and anticancer activity. AB - In this study, we have synthesized chitin-glucan quercetin conjugate (ChGCQ) by an easy and facile free radical grafting reaction. The structure of ChGCQ was confirmed by proton nuclear magnetic resonance (1H NMR) and Fourier transforms infrared spectroscopy (FT-IR). Curcumin was loaded into ChGCQ to study its anti cancer efficiency. The biocompatibility of ChGCQ and curcumin loaded ChGCQ (Cu ChGCQ) were analysed by different assays in Peripheral blood mononuclear cells (PBMCs) and cytotoxicity test was performed in a macrophage cancer cell line (J774). The result shows tremendous biocompatibility of ChGCQ and Cu-ChGCQ in peripheral blood mononuclear cells and excellent cytotoxity in macrophage cancer cell line (J774). Chitin-glucan complex (ChGC), ChGCQ and Cu-ChGCQ showed 51%, 66% and 74% of DPPH radical-scavenging activity at 1mg/ml respectively, which are much higher than that of ChGC and in ABTS*+ assay 58%, 71% and 83% show radical scavenging activity at 1mg/ml. Antioxidant assay of Cu-ChGCQ conjugate expressed much higher antioxidant activity than ChGCQ and ChGC. In vitro drug release study of Cu-ChGCQ conjuagate showed faster drug release in acidic medium in comparison to PBS of physiological pH and anticancer activity in vitro assay showed more anticancer activity of Cu-ChGCQ in comparison to ChGCQ conjugate. PMID- 29128589 TI - Formulation and statistical optimization of gastric floating alginate/oil/chitosan capsules loading procyanidins: in vitro and in vivo evaluations. AB - The aim of the present work was to develop gastric floating capsules containing oil-entrapped beads loading procyanidins. The floating beads were prepared by ionotropic gelation method using sodium alginate, CaCl2 and chitosan. The effect of three independent parameters (concentration of sodium alginate, CaCl2 and chitosan) on entrapment efficiency were analyzed by Box-Behnken design. The floating beads were evaluated for surface morphology, particle size, density, entrapment efficiency, buoyancy, release behavior in vitro and floating ability in vivo. The prepared beads were grossly spherical in shape and the mean size was approximately 1.54+/-0.17mm. The density was 0.97g/cm3. And the optimal conditions were as follows: concentration of sodium alginate, CaCl2 and chitosan were 33.75mg/mL, 9.84mg/mL and 9.05mg/mL, respectively. The optimized formulation showed entrapment efficiency of 88.84+/-1.04% within small error-value (0.65). The release mechanism of floating capsules followed Korsmeyer-Peppas model (r2=0.9902) with non-Fickian release. The gastric floating capsules exhibited 100% floating percentage in vitro and they could float on the top of gastric juice for 5h in vivo. Therefore, the floating capsules are able to prolong the gastroretentive delivery of procyanidins. PMID- 29128590 TI - Synthesis and characterization of a new soluble soybean polysaccharide-iron(III) complex using ion exchange column. AB - A new ion exchange column method was investigated to synthesize the soluble soybean polysaccharide-iron(III) complex (SSPS-FeIII1) using soluble soybean polysaccharides (SSPS). The feasibility of ion exchange column reaction was explored firstly. Results indicated the D730 anion macroporous adsorption resin could effectively absorb SSPS and the static adsorption saturation time was 20h. The iron content of the complex reached up to 15.07% when trisodium citrate concentration was 2mg/mL. The structure of SSPS-FeIII complex synthesized by this method (SSPS-FeIII12) was compared with that prepared by trisodium citrate - ferric chloride method (SSPS-FeIII23). UV-vis absorption spectra, FI-IR spectra and XRD patterns confirmed that both hydroxyl groups and carboxyl groups in SSPS were involved in the coordination reaction and the iron core of SSPS-FeIII1 was a polymerized beta- FeOOH structure. Those results indicated that the ion exchange column method could effectively prepare the SSPS-FeIII complex. PMID- 29128591 TI - Hemicellulose isolated from waste liquor of viscose fiber mill for preparation of polyacrylamide-hemicellulose hybrid films. AB - Huge amount of waste hemicellulose liquor annually produced in China was burned or discharged into surrounding environment without further sufficient utilization, causing severely environmental issues. In order to solve this problem, this study aimed to find a way to effectively use aqueous waste hemicellulose solution from viscose fiber mills for bio-based materials development. Hereby, polyacrylamide-hemicellulose hybrid films were synthesized through the copolymerization of acrylamide (AM) monomers and hemicellulose initiated by potassium persulfate/N,N,N',N'-tetramethylethylenediamine (KPS/TMEDA) redox initiator system with cross-linker N,N-Methylene bis(acrylamide) (MBA). The as-prepared films had been further characterized by Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), gel permeation chromatography (GPC), mechanical test, light transmittance determination and oxygen transmission rate measurement. The results showed that the hybrid films possessed many advantages, such as ambient-temperature water solubility, good recyclability, high stretchable properties and low oxygen permeability. These properties implied their application potentials in several areas, such as packaging electronics products, food and pesticide. Moreover, the utilization of aqueous waste hemicellulose solution from viscose fiber mills will have huge market potential and economic benefits. PMID- 29128592 TI - Thermal properties and free radicals generation in starch isolated from pumpkin fruits. AB - The selected thermal and rheological properties of pumpkin starches were compared with values evaluated for corn and potato starch. The pumpkin starches had lower pasting temperatures (by near 3 degrees C and 24 degrees C than potato or corn starch respectively), the peak viscosity (nearly 2300mPas lower than potato starch) and higher final viscosities (by 80-120mPas than those for potato starch and by 1700mPas in relation to corn starch). The thermal profile of pumpkin starches examined by the DSC method were quite similar to those of potato starch but lower than those of corn. The retrogradation degree of pumpkin starch was lower by 5-26% than that for corn or potato starches. The thermal treatment of starches led to the formation of radicals. Pumpkin starches were less susceptible to the formation of radicals than potato starch and had less about 0.3 1.3*1015radicals/g than potato starch. PMID- 29128593 TI - Nanochitosan enriched poly epsilon-caprolactone electrospun wound dressing membranes: A fine tuning of physicochemical properties, hemocompatibility and curcumin release profile. AB - Nanochitosan (NC) enriched Poly (epsilon-caprolactone) (PCL) nanofibrous membranes were fabricated for controlled curcumin delivery and wound dressing. A significant increase in hydrophilicity, PBS sorption, and vapour transmission were observed by incorporation of NC in PCL. Hemolysis assay, blood clot kinetics and platelet adhesion studies on PCL/NC membranes confirmed the hemocompatibility of the scaffold. NC also imparts appropriate antibacterial activity and biocompatibility promising for a wound dressing material. 15% NC (PCL/15NC) loaded membrane exhibits excellent bioavailability and sustained release behaviour of curcumin at different pH of 7.4, 5.8 and 1.2 with pH sensitive nature. Thus, it can be concluded that PCL/15NC nanofibrous membrane is a promising material for wound dressings and transdermal patches with tunable drug releasing properties with pH stimulus. PMID- 29128595 TI - Ultrafast Protein Folding in Membrane-Mimetic Environments. AB - Proteins fold on timescales from hours to microseconds. In addition to protein size, sequence, and topology, the environment represents an equally important factor in determining folding speed. This is particularly relevant for proteins that require a lipid membrane or a membrane mimic to fold. However, only little is known about how properties of such a hydrophilic/hydrophobic interface modulate the folding landscape of membrane-interacting proteins. Here, we studied the influence of different membrane-mimetic micellar environments on the folding and unfolding kinetics of the helical-bundle protein Mistic. Devising a single molecule fluorescence spectroscopy approach, we extracted folding and unfolding rates under equilibrium conditions and dissected the contributions from different detergent moieties to the free-energy landscape. While both polar and nonpolar moieties contribute to stability, they exert differential effects on the free energy barrier: Hydrophobic burial stabilizes the folded state but not the transition state in reference to a purely aqueous environment; by contrast, zwitterionic headgroup moieties stabilize the folded state and, additionally, lower the free-energy barrier to accelerate the folding of Mistic to achieve ultrafast folding times down to 35MUs. PMID- 29128594 TI - Soft Interactions with Model Crowders and Non-canonical Interactions with Cellular Proteins Stabilize RNA Folding. AB - Living cells contain diverse biopolymers, creating a heterogeneous crowding environment, the impact of which on RNA folding is poorly understood. Here, we have used single-molecule fluorescence resonance energy transfer to monitor tertiary structure formation of the hairpin ribozyme as a model to probe the effects of polyethylene glycol and yeast cell extract as crowding agents. As expected, polyethylene glycol stabilizes the docked, catalytically active state of the ribozyme, in part through excluded volume effects; unexpectedly, we found evidence that it additionally displays soft, non-specific interactions with the ribozyme. Yeast extract has a profound effect on folding at protein concentrations 1000-fold lower than found intracellularly, suggesting the dominance of specific interactions over volume exclusion. Gel shift assays and affinity pull-down followed by mass spectrometry identified numerous non canonical RNA-binding proteins that stabilize ribozyme folding; the apparent chaperoning activity of these ubiquitous proteins significantly compensates for the low-counterion environment of the cell. PMID- 29128596 TI - Comparison of the histologic risk assessment model between lower lip and oral squamous cell carcinoma. AB - INTRODUCTION: The histologic risk assessment (HRA) grading system was proposed as a practical measure to predict clinical outcome and its effectiveness has been shown in several studies. It has been suggested that the HRA model might exhibit differences among various oral subsites. The aim of the present study was to compare this system between squamous cell carcinomas (SCCs) of the lower lip (LL) and oral cavity. MATERIALS AND METHODS: All primary SCCs located in the LL and oral cavity were retrieved and graded using the HRA model. Data regarding risk score (RS), perineural invasion (PNI), lymphocytic infiltration (LI) and worst pattern of invasion (WPOI) were compared between LL and oral SCCs using chi2 analysis (P<0.05). RESULTS: There were a total of 33 LLSCCs, of which 15, 8 and 10 were categorized as low-risk (RS=0), intermediate-risk (RS=1-2) and high-risk (RS>=3) tumors, respectively. Corresponding values in the 48 oral SCCs were 7, 15 and 26 cases. Significant differences in RS (P=0.00), LI (P=0.01) and WPOI (P=0.01) were observed between LL and oral tumors. CONCLUSIONS: The HRA model could be included among the various factors suggested to be different between lip and oral SCCs. Low-risk tumors were more prevalent in the lip which corroborates the less aggressive nature of these cancers. Considering the significantly higher LI in LL SCCs, inflammation may be regarded as an important factor in regulating the invasive behavior of these tumors. PMID- 29128597 TI - Autophagy and oral cancers: A short review. AB - Autophagy is a catabolic process, which involves recycling of cellular elements and it seems to play a major role in etiopathogenesis of cancers. Autophagy is thought to buffer metabolic stress, thereby aiding in cell survival. Also, it is found that inhibiting autophagy under deficient nutrition can restore cell death to apoptosis. Therefore, autophagy plays a dual role in cancer therapeutics. Globally oral cancer is a major concern of numerous deaths, so comprehensive work needs to be undertaken in the field of its progression and to determine positive treatment modalities. There exists a serious dearth of knowledge to understand and comprehend the process of autophagy, and it is beyond doubt that further research in this field would bring forth several new methods of cancer prevention and treatment. PMID- 29128598 TI - Histological and radiological evaluation of subcutaneous implants in mouse of a 3D-printable material (Fulcure 720) and experimental application in mandibular reconstruction. AB - INTRODUCTION: The aim of this study was to evaluate the bioactivity of Fullcure compared to porous polyethylene implants (Medpor) in rats prior to custom-made scaffold support manufacturing for mandible segmental defects (MSD) reconstruction in sheep. METHODS: Twelve Fullcure and Medpor laminaes were implanted in the left and right dorsum respectively of six wistar rats. Toxicity was assessed by skin, kidney and liver histopathology three months post implantation. Computed Tomography (CT) was carried out in order to assess radiological differences between implants. Fullcure containers were subsequently manufactured by CAD/CAM to hold scaffold cylinders for MSD reconstruction in sheep. RESULTS: No statistical differences were observed in tissue response between implants. Fullcure radiodensity was higher than Medpor (P<0.05). Fullcure manufactured support was successfully used for mandible repair in sheep. Nevertheless, the manufactured container did not accomplish the goal of guiding new bone formation according to the mandible shape. CONCLUSIONS: Fullcure showed similar biocompatibility and stronger radiodensity than Medpor. Despite its cheaper price and endless 3D-printing possibilities as scaffold holder for mandible reconstruction, further animal studies are needed to ensure Fullcure biocompatibility as implantable biomaterial. PMID- 29128599 TI - Cutaneous metastasis of renal cell carcinoma masquerading as an infected sebaceous cyst. AB - Renal cell carcinoma (RCC) is the third most common genitourinary malignancy with an estimated one third of cases with metastatic disease at the time of diagnosis. Though rare, cutaneous metastasis from RCC is more frequent than any other genitourinary malignancy. Metastasis of RCC to skin carries poor prognosis as coexistent visceral spread is the norm. A 38-year-old man presented one year after radical nephrectomy for clear cell carcinoma of the left kidney with a submental lesion that proved to be metastatic. Clinical appearance of cutaneous RCC metastasis is varied and can closely mimic other skin lesions. It is incumbent on general practitioners, dermatologists and urologists to exercise diligence in clinical diagnosis of skin lesions in the background of previous oncological diagnosis. PMID- 29128600 TI - Monoterpenoid indole alkaloids from Gardneria multiflora. AB - Six new monoterpenoid indole alkaloids, 19(E)-9-demethoxy-16 dehydroxylchitosenine-17-O- beta-d-glucopyranoside (1), 19(E)-9,10-didemethoxy-16 dehydroxylchitosenine-17-O-beta-d-gluco-pyranoside (2), 19(E)-9,10-didemethoxy-16 dehydroxyl-11-methoxychitosenine (3), 19(E)-9,10-didemethoxy-16-dehydroxyl-11 methoxychitosenine-17-O-beta-d-glucopyranoside (4), 19(Z)-18-carboxylgardneramine (5), and 19(E)-18-demethoxygardneramine-N (4)-oxide (6), along with four known alkaloids, were isolated from Gardneria multiflora, and their structures were elucidated by spectroscopic analysis. Compounds 1, 2 and 4 are the first example of Gardneria alkaloids whose glucose units were attached to C-17. None of the compounds were cytotoxic to any of five human cancer cell lines. PMID- 29128601 TI - Isolation, modification and cytotoxic evaluation of stilbenoids from Acanthopanax leucorrhizus. AB - Twenty natural stilbenoids (1-20), including seven new stilbenoids (2, 4-7, 19, 20) and thirteen known stilbenoids (1, 3, 8-18), were isolated from the stem barks of Acanthopanax leucorrhizus, and six modified stilbenoid derivatives (1a, 2a, 4a, 4b, 7a and 17a) were obtained via methylation, demethylation and isopentenylation of the corresponding isolates (1, 2, 4, 7 and 17). These stilbenoids were structurally characterized by comprehensive analysis of their spectroscopic data and comparison with literature information, and evaluated for their cytotoxic activities against three human tumor cell lines (leukemia HL-60, hepatoma SMMC-7721 and breast carcinoma MCF-7) in vitro by MTT assay. The results showed that compounds 1a, 4a and 4b showed potent selective cytotoxicity against SMMC-7721 (IC50=10.16+/-1.95MUM and 9.76+/-1.32MUM) and MCF-7 (IC50=10.72+/ 2.78MUM) cell lines. The cytotoxic evaluation of these structurally modified stilbenoid derivatives have led to the establishment of a structure-activity relationship. PMID- 29128602 TI - Developmental effects of the protein kinase inhibitor kenpaullone on the sea urchin embryo. AB - The selection and validation of bioactive compounds require multiple approaches, including in-depth analyses of their biological activity in a whole-animal context. We exploited the sea urchin embryo in a rapid, medium-scale range screening to test the effects of the small synthetic kinase inhibitor kenpaullone. We show that sea urchin embryos specifically respond to this molecule depending on both dose and timing of administration. Phenotypic effects of kenpaullone are not immediately visible, since this molecule affects neither the fertilization nor the spatial arrangement of blastomeres at early developmental stages. Nevertheless, kenpaullone exposure from the beginning of embryogenesis profoundly perturbs specification, detachment from the epithelium, and migration of the primary mesenchyme cells, thus affecting the whole embryonic epithelial mesenchymal transition process. Our results reaffirm the sea urchin embryo as an excellent and sensitive in vivo system, which provides straightforward and rapid response to external stimuli. PMID- 29128603 TI - Optimal blood pressure control after coronary events: the challenge remains. AB - We identified sociodemographic, medical, and psychosocial factors associated with unfavorable blood pressure (BP) control in 1012 patients, hospitalized with myocardial infarction and/or a coronary revascularization procedure. This cross sectional study collected data from hospital records, a comprehensive self-report questionnaire, clinical examination, and blood samples after 2-36 (mean 17) months follow-up. Forty-six percent had unfavorable BP control (>=140/90 [80 in diabetics] mm Hg) at follow-up. Low socioeconomic status and psychosocial factors did not predict unfavorable BP control. Patients with unfavorable BP used on average 1.9 (standard deviation 1.1) BP-lowering drugs at hospital discharge, and the proportion of patients treated with angiotensin inhibitors and beta-blockers decreased significantly (P < .001) from discharge to follow-up. Diabetes (odds ratio [OR] 2.4), higher body mass index (OR 1.05 per 1.0 kg/m2), and older age (OR 1.04 per year) were significantly associated with unfavorable BP control in adjusted analyses. Only age (standardized beta [beta] 0.24) and body mass index (beta 0.07) were associated with systolic BP in linear analyses. We conclude that BP control was insufficient after coronary events and associated with obesity and diabetes. Prescription of BP-lowering drugs in hypertensive patients seems suboptimal. Overweight and intensified drug treatment thus emerge as the major factors to target to improve BP control. PMID- 29128605 TI - Erythrocytes as a biological model for screening of xenobiotics toxicity. AB - Erythrocytes are the main cells in circulation. They are devoid of internal membrane structures and easy to be isolated and handled providing a good model for different assays. Red blood cells (RBCs) plasma membrane is a multi-component structure that keeps the cell morphology, elasticity, flexibility and deformability. Alteration of membrane structure upon exposure to xenobiotics could induce various cellular abnormalities and releasing of intracellular components. Therefore the morphological changes and extracellular release of haemoglobin [hemolysis] and increased content of extracellular adenosine triphosphate (ATP) [as signs of membrane stability] could be used to evaluate the cytotoxic effects of various molecules. The nucleated RBCs from birds, fish and amphibians can be used to evaluate genotoxicity of different xenobiotics using comet, DNA fragmentation and micronucleus assays. The RBCs could undergo programmed cell death (eryptosis) in response to injury providing a useful model to analyze some mechanisms of toxicity that could be implicated in apoptosis of nucleated cells. Erythrocytes are vulnerable to peroxidation making it a good biological membrane model for analyzing the oxidative stress and lipid peroxidation of various xenobiotics. The RBCs contain a large number of enzymatic and non-enzymatic antioxidants. The changes of the RBCs antioxidant capacity could reflect the capability of xenobiotics to generate reactive oxygen species (ROS) resulting in oxidative damage of tissue. These criteria make RBCs a valuable in vitro model to evaluate the cytotoxicity of different natural or synthetic and organic or inorganic molecules by cellular damage measures. PMID- 29128606 TI - Salvianic acid A sodium protects HUVEC cells against tert-butyl hydroperoxide induced oxidative injury via mitochondria-dependent pathway. AB - Salvianic acid A (Danshensu) is a major water-soluble component extracted from Salvia miltiorrhiza (Danshen), which has been widely used in clinic in China for treatment of cardiovascular diseases (CVDs). This study aimed to investigate the protective effects of salvianic acid A sodium (SAAS) against tert-butyl hydroperoxide (t-BHP) induced human umbilical vein endothelial cell (HUVEC) oxidative injury and the underlying molecular mechanisms. In the antioxidant activity-assessing model, SAAS pretreatment significantly ameliorated the cell growth inhibition and apoptosis induced by t-BHP. An ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) based metabolic profiling was developed to investigate the metabolic changes of HUVEC cells in response to t-BHP and SAAS. The results revealed that t-BHP injury upregulated 13 metabolites mainly involved in tryptophan metabolism and phenylalanine metabolism which were highly correlated with mitochondrial function and oxidative stress, and 50 MUM SAAS pretreatment effectively reversed these metabolic changes. Further biomedical research indicated that SAAS pretreatment reduced the t-BHP induced increase of lactate dehydrogenase (LDH), intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and mitochondrial membrane potential (MMP), and the decrease of key antioxidant enzymes through mitochondria antioxidative pathways via JAK2/STAT3 and PI3K/Akt/GSK-3beta signalings. Taken together, our results suggested that SAAS may protect HUVEC cells against t-BHP induced oxidative injury via mitochondrial antioxidative defense system. PMID- 29128604 TI - Influence of maternal age on the effects of seleno-l-methionine in the model organism Daphnia pulex under standard and heat stress conditions. AB - Selenium deficiency and toxicity increase the risk of adverse developmental and reproductive outcomes; however, few multi-stressor studies have evaluated the influence of maternal age on organic selenium dose-response and additional stressors over the life course. While multi-stressor research in mammalian models is time-consuming and expensive, use of alternative models can efficiently produce screening data for prioritizing research in mammalian systems. As a well known eco-toxicological model, Daphnia pulex, may offer advantages in screening for impacts of multi-stressor exposures. We evaluated the influence of maternal age on the effects of seleno-methionine (SeMet) for lifespan, reproduction, and heat-stress resistance in D. pulex. Our results show effects of SeMet-treatment and maternal age, where the highest SeMet-treatment had reduced lifespan and absence of reproduction, and where Daphnia from late life broods had increased resistance to heat-induced stress. Further analysis suggests an additional interactive effect between maternal age and SeMet treatment on time to first reproduction. PMID- 29128607 TI - Effects of a new antiprotozoal drug, N,N'-diphenyl-4-methoxy-benzamidine, on energy-linked functions of rat liver mitochondria. AB - Amidines are chemically characterized by the presence of two nitrogen atoms that bind to the same carbon atom in its structure. Several biological activities have been ascribed to these compounds. Pentamidine, an aromatic diamidine, is effective in the treatment against Pneumocystis carinii and leishmaniasis, but it can also have severe side effects. New amidine derivatives have been synthesized, among them N,N'-diphenyl-4-methoxy-benzamidine (methoxyamidine), which is effective against Leishmania amazonensis (LD50 = 20 MUM) and Trypanosoma cruzi (LD50 = 59 nM). In the present study, methoxyamidine toxicity was evaluated in isolated rat liver mitochondria at the same range of concentrations that exert antiprotozoal activity. In these organelles, actively oxidizing glutamate + malate inhibited state 3 respiration (25 nmol mg-1 of protein) by ~15%. The sites of inhibition in the respiratory chain were complex I and the segment between ubiquinone and complex III. Methoxyamidine also stimulated state 4 respiration by ~32% and ~43% at 50 and 65 nmol mg-1 of protein, respectively. Its uncoupling effect was confirmed by a dose-dependent increase in oxygen consumption in state 4 respiration that was induced by oligomycin, reaching up to ~69% (65 nmol mg-1 of protein) and an increase in ATPase activity in intact mitochondria by ~27% and ~83% at 50 and 65 nmol mg-1 protein, respectively. Swelling that was supported by the oxidation of glutamate + malate in the presence of sodium acetate was reduced by methoxyamidine by ~16% and 32% at 50 and 65 nmol mg-1 protein, respectively. Mitochondrial swelling in the absence of substrate and in the presence of K+ and valinomycin was inhibited by ~20% at the same concentrations, suggesting that methoxyamidine affects mitochondrial membrane permeability and fluidity. Our data show that methoxyamidine has slight effects on the energy-linked functions of isolated mitochondria at concentrations that correspond to the LD50 against Leishmania amazonensis and Trypanosoma cruzi. These findings may prompt further studies that evaluate methoxyamidine toxicity in vivo. PMID- 29128608 TI - A retrospective comparison of survivors and non-survivors of massive pulmonary embolism receiving veno-arterial extracorporeal membrane oxygenation support. AB - INTRODUCTION: While the optimal care of patients with massive pulmonary embolism (PE) is unclear, the general goal of therapy is to rapidly correct the physiologic derangements propagated by obstructive clot. Extracorporeal membrane oxygenation (ECMO) in this setting is promising, however the paucity of data limits its routine use. Our institution expanded the role of ECMO as an advanced therapy option in the initial management of massive PE. The purpose of this project was to evaluate ECMO-treated patients with massive PE at an academic medical center and report shortterm mortality outcomes. METHODS: Thirty-two patients placed on ECMO for confirmed, massive PE from January 2012 to December 2015 were retrospectively analyzed. All patients had PE confirmed by computerized tomography and/or invasive pulmonary angiography. RESULTS: In our population of patients managed with ECMO, 21 (65.6%) patients survived to decannulation and 17 (53.1%) survived index hospitalization. Baseline characteristics and clinical variables showed no difference in age, gender, right ventricular-to-left ventricular ratios, or peak troponin-T between survivors and non-survivors. Non survivors tended to have a previous history of malignancy. Cardiac arrest prior to ECMO cannulation was associated with worse outcomes. All 5 patients who received concomitant systemic thrombolysis died, while 11 of 15 patients who received catheter-directed thrombolysis survived. A lactic acid level <=6mmol/L had an 82.4% sensitivity and 84.6% specificity for predicting survival to discharge. CONCLUSION: The practical approach of utilizing ECMO for massive PE is to reserve it for those who would receive the greatest benefit. Patients with poor perfusion, for example from cardiac arrest, may gain less benefit from ECMO. Our findings indicate that a serum lactate >6mmol/L may be an indicator of worse prognosis. Finally, in our patient population, catheter-directed thrombolytics was effectively combined with ECMO. PMID- 29128609 TI - Tracking changes in spatial frequency sensitivity during natural image processing in school age: an event-related potential study. AB - Several studies have shown that behavioral and electrophysiological correlates of processing visual images containing low or high spatial frequency (LSF or HSF) information undergo development after early childhood. However, the maturation of spatial frequency sensitivity during school age has been investigated using abstract stimuli only. The aim of the current study was to assess how LSF and HSF features affect the processing of everyday photographs at the behavioral and electrophysiological levels in children aged 7-15 years and adults. We presented grayscale images containing either animals or vehicles and their luminance matched modified versions filtered at low or high spatial frequencies. Modulations of classification accuracy, reaction time, and visual event-related potentials (posterior P1 and N1 components) were compared across five developmental groups and three image types. We found disproportionately worse response accuracies for LSF stimuli relative to HSF images in children aged 7 or 8 years, an effect that was accompanied by smaller LSF-evoked P1 amplitudes during this age period. At 7 or 8 years of age, P1 and N1 amplitudes were modulated by HSF and LSF stimuli (P1: HSF > LSF; N1: LSF > HSF), with a gradual shift toward the opposite pattern (P1: LSF > HSF; N1: HSF > LSF) with increasing age. Our results indicate that early cortical processing of both spatial frequency ranges undergo substantial development during school age, with a relative delay of LSF analysis, and underline the utility of our paradigm in tracking the maturation of LSF versus HSF sensitivity in this age group. PMID- 29128610 TI - Changes in redox regulation during transition from C3 to single cell C4 photosynthesis in Bienertia sinuspersici. AB - Bienertia sinuspersici performs single cell C4 photosynthesis without Kranz anatomy. Peripheral and central cytoplasmic compartments in a single chlorenchyma cell act as mesophyll cells and bundle sheath cells. Development of this specialized mechanism is gradual during plant development. Young leaves perform C3 photosynthesis, while mature leaves have complete C4 cycle. The aim of this work was to investigate changes in redox regulation and antioxidant defence during transition from C3 to single cell C4 photosynthesis in B. sinuspersici leaves. First, we confirmed gradual development of C4 with protein blot and qRT PCR analysis of C4 enzymes. After this activities and isoenzymes of superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), ascorbate peroxidase (APX), glutathione reductase (GR), dehydroascorbate reductase (DHAR) and H2O2 and TBARS and glutathione pool and redox status (GSH/GSSG) were determined in young, developing and mature leaves during transition from C3 to single cell C4 photosynthesis. Activities of SOD, APX and POX decrease, while GR and DHAR were increased. However, most striking results were the changes in isoenzyme patterns of SOD, CAT and GR which were gradual through transition to C4 photosynthesis. PMID- 29128611 TI - Intrathecal administration of antisense oligonucleotide against p38alpha but not p38beta MAP kinase isoform reduces neuropathic and postoperative pain and TLR4 induced pain in male mice. AB - p38 mitogen-activated protein kinase (MAPK) consists of two major isoforms: p38alpha and p38beta; however, it remains unclear which isoform is more important for chronic pain development. Recently, we developed potent, long-lasting, and p38 MAPK subtype-specific antisense oligonucleotides (ASOs). We examined the therapeutic effects of isoform-specific ASOs in several chronic pain models following single intrathecal injection (300 MUg/10 MUl) in CD1 mice. In the chronic constriction injury (CCI) model, p38alpha MAPK ASO, given on post operative day 5, reduced CCI-induced mechanical allodynia in male but not female mice. In contrast, mechanical allodynia after CCI in both sexes was not affected by p38beta MAPK ASO. Intrathecal injection of p38alpha or p38beta ASO resulted in a partial reduction (~ 50%) of spinal p38alpha or p38beta mRNA level, respectively, in both sexes at two weeks. In contrast, intrathecal injection of the ASOs did not affect p38alpha and p38beta MAPK mRNA levels in dorsal root ganglia. Intrathecal p38alpha ASO also reduced postoperative pain (mechanical and cold allodynia) in male mice after tibia fracture. However, intrathecal p38alpha ASO had no effect on mechanical allodynia in male mice after paclitaxel treatment. Intrathecal p38alpha MAPK ASO pre-treatment also prevented TLR4 mediated mechanical allodynia and downregulated levels of p38alpha MAPK and phosphorylated p38 MAPK following intrathecal treatment of lipopolysaccharide. In summary, our findings suggest that p38alpha MAPK is the major p38 MAPK isoform in the spinal cord and regulates chronic pain in a sex and model-dependent manner. Intrathecal p38alpha MAPK ASO may offer a new treatment for some chronic pain conditions. PMID- 29128612 TI - RIFM fragrance ingredient safety assessment, oxacyclohexadecane-2,13-dione, CAS Registry Number 38223-29-9. PMID- 29128613 TI - Submicromolar bisphenol A induces proliferation and DNA damage in human hepatocyte cell lines in vitro and in juvenile rats in vivo. AB - An association between bisphenol A (BPA) exposure and hepatic tumors was suggested, but the employment of high-dose levels raises questions about its relevance to human health. Here, we demonstrate that submicromolar concentrations of BPA induce the proliferation and DNA damage in human hepatocyte cell lines. In HepG2 and NKNT-3, undifferentiated and differentiated hepatocyte cell lines, respectively, submicromolar BPA concentrations promoted the cell proliferation, as indicated by enhanced DNA synthesis and elevated expression of cell-cycle proteins. At concentrations higher than 10 MUM, these effects disappeared, reflecting a non-monotonic dose-response relationship. Notably, histone H2AX was activated following exposure to BPA, which is a sensitive marker of DNA damage. Importantly, proliferative foci and DNA damage were also observed in liver tissue of rats orally exposed to BPA at 0.5 mg/kg for 90 days, from juvenile age (postnatal day 9) through adulthood. Reactive oxygen species appeared to play a role in the BPA-induced proliferation and DNA damage, as evidenced by a partial reversal of both processes upon pretreatment with an antioxidant, N acetylcysteine. Collectively, these results demonstrate that submicromolar BPA concentrations induce the DNA damage and promote the cell proliferation in the liver, which may support its role as a risk factor for hepatocarcinogenicity. PMID- 29128614 TI - Gene expression profiling in colon of mice exposed to food additive titanium dioxide (E171). AB - Dietary factors that may influence the risks of colorectal cancer, including specific supplements, are under investigation. Previous studies showed the capacity of food additive titanium dioxide (E171) to induce DNA damage in vitro and facilitate growth of colorectal tumours in vivo. This study aimed to investigate the molecular mechanisms behind these effects after E171 exposure. BALB/c mice were exposed by gavage to 5 mg/kgbw/day of E171 for 2, 7, 14, and 21 days. Transcriptome changes were studied by whole genome mRNA microarray analysis on the mice's distal colons. In addition, histopathological changes as well as a proliferation marker were analysed. The results showed significant gene expression changes in the olfactory/GPCR receptor family, oxidative stress, the immune system and of cancer related genes. Transcriptome analysis also identified genes that thus far have not been included in known biological pathways and can induce functional changes by interacting with other genes involved in different biological pathways. Histopathological analysis showed alteration and disruption in the normal structure of crypts inducing a hyperplastic epithelium. At cell proliferation level, no consistent increase over time was observed. These results may offer a mechanistic framework for the enhanced tumour growth after ingestion of E171 in BALB/c mice. PMID- 29128615 TI - RIFM fragrance ingredient safety assessment, Ethyl 2,3,6-trimethylcyclohexyl carbonate, CAS Registry Number 93981-50-1. PMID- 29128616 TI - Di-N-octylphthalate acts as a proliferative agent in murine cell hepatocytes by regulating the levels of TGF-beta and pro-apoptotic proteins. AB - Di-n-octylphthalate (DNOP) is a phthalate used in the manufacturing of a wide variety of polyvinyl chloride-containing medical and consumer products. A study on chronic exposure to DNOP in rodents showed the development of pre-neoplastic hepatic lesions following exposure to a tumor initiator. The objective of this study was to identify the mechanisms by which DNOP leads to pre-neoplastic hepatic lesions. Mouse hepatocyte AML-12 and FL83B cells were treated with DNOP. The rate of cell proliferation was increased in treated cells in a concentration dependent manner. DNOP increased the expression of transforming growth factor beta (tgf-beta) in both cell lines, and primary culture mouse hepatocytes. The TGF-beta receptor inhibitor LY2109761 impaired the effect of DNOP. The presence of pro-apoptotic proteins decreased in the presence of DNOP. Our observation indicates that DNOP, through an increase in the expression of tgf-beta and a decrease in the levels of pro-apoptotic proteins, acts as a proliferative agent in normal mouse hepatocytes. We also studied the morphological and functional changes of the mouse liver upon a short-term treatment of DNOP. Mice exposed to DNOP displayed an epithelial-to-mesenchymal transition and cholestasis, which was reflected in an increase in hepatic bile acids and glutathione levels. PMID- 29128617 TI - Benign preparation of aqueous core poly lactic-co-glycolic acid (PLGA) microcapsules. AB - Poly lactic-co-glycolic acid (PLGA) has attracted considerable attention as a polymer for drug delivery carriers. However, the hydrophobic property of PLGA often leads to the use of harmful organic solvents and poor encapsulation efficiency of hydrophilic materials. To our knowledge, a preparation method of aqueous core PLGA microcapsules without using harmful organic solvents has not been proposed. In this study, we attempted to establish an encapsulation technique of hydrophilic materials in aqueous core biodegradable and biocompatible PLGA microcapsules using vegetable oil as a continuous phase. As a result, the temperature of the oil/water mixture was required to be above the glass transition temperature. In this condition, two different types of morphology were prepared. When the water volume was below the solubility limit, PLGA microcapsules with a smooth shell were formed. In contrast, when the water volume was above the solubility limit, colloidosome-like microcapsules with PLGA nanoparticles assembled at the interface were formed. The obtained microcapsules were then heated at the glass transition temperature. The result is that aqueous core PLGA microcapsules with a smooth shell were prepared using plant oil as a continuous phase. Rhodamine B used as a hydrophilic model encapsulant, was successfully encapsulated in the PLGA microcapsules. PMID- 29128618 TI - Gold nanoparticles functionalized by rhodamine B isothiocyanate: A new tool to control plasmonic effects. AB - Gold nanoparticles with an average diameter of 10 nm, functionalized by the dye molecule rhodamine B isothiocyanate, have been synthesized. The resulting material has been extensively characterized both chemically, to investigate the bonding between the dye molecules and the nanoparticles, and physically, to understand the details of the aggregation induced by interaction between dye molecules on different nanoparticles. The plasmonic response of the system has been further characterized by measurement and theoretical simulation of the static UV-Vis extinction spectra of the aggregates produced following different synthesis procedures. The model parameters used in the simulation gave further useful information on the aggregation and its relationship to the plasmonic response. Finally, we investigated the time dependence of the plasmonic effects of the nanoparticles and fluorescence of the dye molecule using an ultrafast pump probe optical method. By modulating the quantity of dye molecules on the surface of the nanoparticles it was possible to exert fine control over the plasmonic response of nanoparticles. PMID- 29128619 TI - Preparation of porous carbon spheres from 2-keto-l-gulonic acid mother liquor by oxidation and activation for electric double-layer capacitor application. AB - A novel strategy is proposed for the increase of specific surface area (SSA) of porous carbon sphere (PCS) by oxidation and activation. 2-keto-l-gulonic acid mother liquor (GAML) as a high-pollution waste has a relatively high value of reutilization. For its high value-added utilization, GAML is used as the precursor for preparation of PCS as carbon-based electrode materials for electric double-layer capacitor. PCS is prepared by hydrothermal carbonization, carbonization and KOH activation, and Fe(NO3)3 9H2O is used as an oxidizing agent during carbonization. The as-prepared PCS has excellent porosity and high SSA of 2478 m2 g-1. Meanwhile, the pore structure of PCS can be controlled by the adjustment of carbonization parameters (carbonization temperature and the loading of Fe(NO3)3 9H2O). Besides, the SSA and specific capacitance of PCS can be increased remarkably when Fe(NO3)3 9H2O is added in carbonization. The specific capacitance of PCS can reach 303.7 F g-1 at 40 mA g-1. PCSs as electrode material have superior electrochemical stability. After 8000 cycles, the capacitance retention is 98.3% at 2 A g-1. The electric double-layer capacitance of PCS is improved when CS is carbonized with Fe(NO3)3 9H2O, and the economic and environmental benefits are achieved by the effective recycle of GAML. PMID- 29128620 TI - Patients with schizophrenia have a higher risk of psoriasis: A systematic review and meta-analysis. AB - Recent studies have suggested an increased risk of psoriasis among patients with schizophrenia although the results are still inconclusive. This systematic review and meta-analysis of cohort and case-control studies that compared the risk psoriasis among patients with schizophrenia versus subjects without schizophrenia was conducted to better characterize the risk. Pooled relative risks and 95% confidence intervals from the included studies were calculated using a random effect, generic inverse variance method of DerSimonian and Laird. After a comprehensive literature review, 2 retrospective cohort studies and 4 case control studies with approximately 6.1 million participants were identified. The meta-analysis found that the risk of psoriasis among patients with schizophrenia was significantly higher than non-schizophrenia subjects. Subgroup analysis by study design revealed a significantly higher risk in both cohort study and case control study subgroup. PMID- 29128621 TI - Empirical extension of the interpersonal theory of suicide: Investigating the role of interpersonal hopelessness. AB - The Interpersonal Theory of Suicide posits that hopelessness about thwarted belongingness and perceived burdensomeness is an important risk factor for the desire for suicide and suicide risk. Past research has indicated that general feelings of hopelessness interact with the constructs of thwarted belongingness and perceived burdensomeness to predict suicide ideation. However, no research has explicitly tested whether hopelessness specific to the interpersonal constructs of thwarted belongingness and perceived burdensomeness predicts suicide ideation and suicide risk. Participants in the current study (N = 173) were undergraduate students oversampled for history of suicide ideation, planning for suicide, and suicide attempt(s). Participants completed study measures online, including a new measure of hopelessness about thwarted belongingness and perceived burdensomeness. Results indicated that a three-way interaction of thwarted belongingness, perceived burdensomeness, and hopelessness about these interpersonal constructs, but not general hopelessness, predicted unique variance of suicide ideation and suicide risk. Results suggest that hopelessness about thwarted belongingness and perceived burdensomeness may be an important target for reducing suicidal desire. PMID- 29128622 TI - Efficacy and tolerability of pharmacological interventions for pulmonary arterial hypertension: A network meta-analysis. AB - PURPOSE: This network meta-analysis (NMA) is designed to compare the efficacy and tolerability of various therapies and combinations for pulmonary arterial hypertension (PAH). METHOD: We conducted a systematic search in databases PubMed, Embase, and Cochrane Library. Treatment efficacy and tolerability were compared by synthesizing direct and indirect evidence. The surface under the curve ranking area was utilized to rank multiple interventions. RESULT: A total of 43 randomized clinical trials were included in our NMA. With regard to efficacy outcomes, including 6 min walking distance (6MWD), functional class amelioration (FCA), death, clinical worsening (CW), pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), and mean right atrial pressure (mRAP), endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitor (PDE-5Is), ERA combined with PDE-5Is (EAP), and prostacyclin analogs (PGI) combined with ERA (PAE) performed better than others. Meanwhile PAP and PGE demonstrated better than others in tolerability. Overall, EAP and PAE showed good efficacy and were well-tolerated among all therapies. CONCLUSION: Overall, we recommend EAP as the optimal choice for patients with PAH in clinical practice and PAE as suboptimal in view of their desirable performance in efficacy. Most of the combination therapies performed better than monotherapies. PMID- 29128623 TI - Shape and form in plant development. PMID- 29128624 TI - Wernicke-Korsakoff syndrome complicated by subacute beriberi neuropathy in an alcoholic patient. AB - Thiamine (vitamin B1) deficiency is a common condition in alcohol abusers, which can lead to damage of both the peripheral and the central nervous systems. Here we describe the case of an alcoholic patient who presented with acute onset of ataxia, severe weakness of the four limbs, and hypoesthesia and dysesthesia of the distal portion of the upper and lower extremities. The clinical picture also included mental confusion and amnesia. A diagnosis of Wernicke-Korsakoff syndrome was made based on clinical symptoms and brain RMI findings. Electromyography and electroneurography revealed signs of subacute axonal sensory-motor polyneuropathy that were compatible with a rare acute presentation of beriberi. Patient immediately received parenteral thiamine administration, which resulted in rapid clinical amelioration of ataxia and confusion and also in a significant improvement of motor and sensory deficits. The association between Wernicke Korsakoff syndrome and acute axonal polyneuropathy is a very rare condition that could make less recognizable the clinical picture of a thiamine deficiency. However, the diagnosis of thiamine deficiency should be suspected in every alcoholic patient presenting with acute onset symptoms of central and/or peripheral nervous system involvement. This because the immediate replacement treatment can be life-saving and reverse the clinical symptoms. PMID- 29128625 TI - LXR activation increases the expression of GnRH AND alphaMSH in the rat hypothalamus in vivo. AB - Liver X receptors (LXR) are important transcription factors involved in the regulation of carbohydrate and lipid metabolism. Recently, we described LXR receptors expression in the hypothalamus but their function in this brain area remains unknown. Here, we evaluated the function of LXR on the expression of factors produced in the hypothalamus in vitro and in vivo by Western blotting and immunocytochemistry. More precisely we studied the expression of GnRH and GHRH, alphaMSH and NPY in male Sprague-Dawley rats. The effects of two synthetic LXR agonists, T0901317 and GW3965, were first tested in vitro. Hypothalamic explants were treated with either T0901317 or GW3965 (10MUM) for 2, 4, 6 and 8h. As a positive control the cholesterol ABCA1 and glucose GLUT2 transporters were used. No changes were observed in the expression of the factors evaluated in vitro. The effects of the LXR agonists were then tested in vivo. Rats were injected ICV into the third ventricle with either T0901317 or GW3965 (2.5MUg/5MUL ICV) and after 3.5h or 24h the hypothalami were dissected out and rapidly frozen for analysis. alphaMSH and GnRH expression was significantly increased after 3.5h of T0901317 treatment. Anterior/posterior hypothalamic ratio increases for alphaMSH expression and decreases for GnRH expression after 24h of LXR activation. Altogether these results show that LXR activation affects the expression of GnRH and alphaMSH, suggesting that LXR in the hypothalamus is capable of modulating hypothalamic responses related to appetite, sexual behavior and reproductive functions. PMID- 29128626 TI - Neuroprotective and neurotrophic effects of Lanthionine Ketimine Ester. AB - Lanthionine ketimine ethyl ester (LKE) is a synthetic derivative of the naturally occurring amino acid lanthionine ketimine. We previously showed that LKE reduced clinical signs in a mouse model of multiple sclerosis (MS) associated with reductions in axonal damage; however, whether LKE has direct beneficial actions on mammalian neuronal cells was not examined. In the current study, we tested the effects of LKE in SH-SY5Y human neuronal cells and in primary mouse cerebellar granule neurons. In both cell types, LKE dose-dependently reduced the cell death that occurred spontaneously followed a change in media. LKE also reduced cell death due to glutamate excitoxicity, accompanied by a reduction in production of reactive oxygen species. LKE induced neuritogenesis in both undifferentiated SH SY5Y cells and in primary neuron, increasing process numbers and lengths. These results demonstrate that direct neuroprotective and neurotrophic effects of LKE likely contribute to its beneficial actions in vivo. PMID- 29128627 TI - Inhibition of JAK1 by microRNA-708 promotes SH-SY5Y neuronal cell survival after oxygen and glucose deprivation and reoxygenation. AB - MicroRNAs mediates gene expression in various diseases. Studies have shown that aberrant expression of miRNAs affected cerebral protection. In this study, we have investigated the effects of microRNA-708 (miR-708) on cell survival of oxygen and glucose-deprived reoxygenation (OGD/R) human neuroblastoma cells (SH SY5Y) and explored whether miR-708 inhibited neuronal death by targeting JAK1. In vitro model of ischemia was used to investigate the neuroprotective functions of miR-708. MiR-708 mimics/siJAK1 transfected SH-SY5Y cells were treated with OGD. After 48h of reoxygenation, cell viability and cell survival were determined by EdU and FITC/PI double staining flow cytometry, respectively. Luciferase activity assay was performed to validate the role of JAK1 as a direct target of miR-708. qRT-PCR and Immunofluorescence assays were used to determine the expression of JAK1, MAP2 and NEUN in miR-708 mimics transfected SH-SY5Y cells. To explore the mechanisms involved in cell growth promotion by JAK1, morphological changes in cells were detected upon knockdown of JAK1, and the expression levels of JAK1, Bax, Bcl-2, cleaved-caspase-3, STAT3 and Mcl-1 were determined by Western blotting. The expression of miR-708 significantly decreased in cells treated with OGD/R. MiR-708 directly targeted JAK1 3'UTR to down-regulate JAK1 mRNA expression, whereas the expression of MAP2 and NEUN was upregulated. Previous studies have demonstrated that the suppression of JAK1 inhibited apoptosis phenocopied function of the miR-708 overexpression in OGD/R SH-SY5Y cells. miR 708 decreased the rate of apoptosis of OGD/R SH-SY5Y cells by suppressing the expression of JAK1. PMID- 29128629 TI - Influence of emotional stimuli on lower limb cutaneous reflexes during human gait. AB - Previous research has shown that cutaneous reflexes are modulated when walking with a threat to stability. It is unclear if this reflex modulation is purely related to the context of the imposed threat or if emotional changes associated with the threat exert an independent influence on reflex excitability. This study investigated the influence of emotional stimuli on lower limb cutaneous reflexes during treadmill walking. Twenty-eight healthy young adults walked at a self selected pace while viewing pictures that manipulated emotional arousal and valence (confirmed with electrodermal and self-report measures). Throughout each trial, cutaneous reflexes were evoked by electrically stimulating the sural nerve at heel contact, mid-stance, or toe off. Surface electromyography of the ipsilateral soleus (SOL), medial gastrocnemius (MG), tibialis anterior (TA), biceps femoris (BF), and vastus lateralis (VL) was recorded to assess reflexes. Highly arousing pictures, independent of valence, significantly facilitated TA, and trended toward facilitating SOL and BF reflexes during mid-stance. Unpleasant pictures, independent of arousal, significantly reduced reflex amplitudes in BF during mid-stance and TA during toe off. While changes in background muscle activity and step cadence were observed, they did not correlate with reflex changes. This study provides the first evidence that emotional stimuli exert an independent influence on cutaneous reflex excitability during gait. As cutaneous reflexes contribute to stability during gait, these findings support the notion that emotional state influences important sensorimotor processes underlying balance control. PMID- 29128628 TI - Optogenetic noise-photostimulation on the brain increases somatosensory spike firing responses. AB - We examined whether the optogenetic noise-photostimulation (ONP) of the barrel cortex (BC) of anesthetized Thy1-ChR2-YFP transgenic mice increases the neuronal multiunit-activity response evoked by whisker mechanical stimulation (whisker evoked MUA). In all transgenic mice, we found that the signal-to-noise ratio (SNR) of such whisker-evoked MUA signals exhibited an inverted U-like shape as a function of the ONP level. Numerical simulations of a ChR2-expressing neuron model qualitatively support our experimental data. These results show that the application of an intermediate intensity of ONP in the brain can increase cortical somatosensory spike responses to whisker protraction. These findings suggest that ONP of the mice-BC could produce improvements in somatosensory perception to whisker stimulation. PMID- 29128630 TI - Association analysis of SNP rs11868035 in SREBF1 with sporadic Parkinson's disease, sporadic amyotrophic lateral sclerosis and multiple system atrophy in a Chinese population. AB - BACKGROUND: The etiology of neurodegenerative disease remains unclear. Recently, SNP rs11868035, located in an intron of the sterol regulatory element binding factor (SREBF1) gene, was found to be associated with Parkinson's disease (PD) in a large European population in a genome-wide association study. To examine the possible genetic association of rs11868035 with sporadic PD, sporadic amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA) in a Chinese population, we conducted this large case-control study. METHODS: A total of 3115 subjects, which included 1150 sporadic PD, 833 sporadic ALS, 318 MSA patients, and 814 controls, were recruited in the study. All of the subjects were genotyped for rs11868035 using the Sequenom iPLEX Assay. RESULTS: Significant differences in the genotype distributions and minor allele frequency (MAF) of rs11868035 were observed between early onset ALS (EOALS) and matched controls (P=0.001 and P=0.002, respectively) and between female ALS patients and matched controls (P=0.016 and P=0.010, respectively). The minor allele "G"of rs11868035 is associated with a reduced risk for EOALS (OR=0.55[0.38-0.80]) and ALS in women (OR=0.74[0.59-0.93]). No significant differences in the genotype distributions and MAF of rs11868035 were observed between PD or controls, and between MSA and controls. CONCLUSION: Our results suggested that rs11868035 is likely to be associated with ALS in early-onset or female patients but not with PD or MSA in the Chinese population. PMID- 29128631 TI - Association between stimulus-evoked somatosensory inhibition and movement-related sensorimotor oscillation: A magnetoencephalographic study. AB - The interaction between the somatosensory and motor cortices is understood; however, their functional relationship remains elusive. To elucidate the association between somatosensory and sensorimotor functions, this study investigated the correlation between somatosensory activities in response to paired-pulse stimulation and sensorimotor oscillations during self-paced finger movement in 18 healthy male subjects by using a magnetoencephalographic recording. The main finding was that stimulus-evoked somatosensory gating activities were significantly correlated with movement-related sensorimotor oscillatory responses. Specifically, the gating ratios of somatosensory N20m were related to the power changes of sensorimotor beta event-related desynchronization (ERD) (p=0.003) and event-related synchronization (ERS) (p=0.05). In conclusion, we confirmed that the inhibition of stimulus-evoked somatosensory responses is associated with the oscillatory characteristics of movement-related sensorimotor activities. PMID- 29128632 TI - Genome-wide mapping of estrogen receptor alpha binding sites by ChIP-seq to identify genes related to sexual maturity in hens. AB - In ovarian follicle development, estrogen acts as a regulatory molecule to mediate proliferation and differentiation of follicular cells. ERalpha (estrogen receptor alpha) exerts regulatory function classically by binding directly to the estrogen response element, recruiting co-factors and activating or repressing transcription in response to E2. In this study, we used ChIP-seq to map ERalpha binding sites in ovaries of Hy-line Brown commercial hens at 45d, 90d and 160d. In total, 24,886, 21,680 and 23,348 binding sites were identified in the ovaries of hens at 45d, 90d and 160d, which are linked to 86, 83 and 74 genes, respectively. The PPI network contains 47 protein nodes and 164 interaction edges, among which, AKT1 (V-Akt Murine Thymoma Viral Oncogene Homolog 1) and ACTN2 (Actinin Alpha 2) with the highest weight in the network, followed by CREB1 (CAMP Responsive Element Binding Protein 1), and EPHA5 (EPH Receptor A5) were identified. These genes are likely related to sexual maturity in hens. This study also provides insight into the regulation of the ERalpha target gene networks and a reference for understanding ERalpha-regulated transcription. PMID- 29128633 TI - PHGDH is an independent prognosis marker and contributes cell proliferation, migration and invasion in human pancreatic cancer. AB - PURPOSE: To investigate the expression, clinical significance, biological function, and the potential mechanism of PHGDH in pancreatic cancer. METHODS: The expression of PHGDH in human pancreatic cancer tissues and corresponding adjacent normal tissues were analyzed through immunohistochemistry staining. Simultaneously, the association between the PHGDH expression and the clinicopathological parameters and OS and DFS was evaluated. Human pancreatic cancer cell line BxPC-3 and SW1990 were selected to investigate the effect of PHGDH knockdown on cell proliferation, migration, and invasion. In addition, we performed western blot to assess the expression of cyclin B1, and cyclin D1, MMP 2, and MMP-9 protein. RESULTS: Our results suggested that the expression of PHGDH is increased in pancreatic cancer compared with adjacent normal tissues and the increased expression of PHGDH is associated with tumor size, lymph node metastasis, and TNM state of pancreatic cancer patients. Moreover, the expression of PHGDH is an independent prognostic indicator for pancreatic cancer patients. In addition, we found that knockdown of PHGDH in pancreatic cancer cells inhibits the cell proliferation, migration, and invasion abilities by down-regulating the expression of cyclin B1, and cyclin D1, MMP-2, and MMP-9. CONCLUSIONS: Our data indicated that the expression of PHGDH is increased in pancreatic cancer and is an independent molecular prognostic factor for pancreatic cancer patients. In addition, PHGDH controls cell proliferation, migration and invasion abilities. Therefore, PHGDH could serve as an important prognostic indicator and therapeutic target for pancreatic cancer. PMID- 29128634 TI - Vitamin D receptor (VDR) polymorphisms are associated to spontaneous preterm birth and maternal aspects. AB - Preterm birth (PTB) is featured by less than 37weeks of gestational age or fewer than 259days since the first day from the last menstrual period. Complications of PTB are the major cause of neonatal deaths, several factors are linked to PTB increased risk including immunological and genetics. Vitamin D plays an important role in immune response modulation and its action occurs through the vitamin D receptor (VDR), which recently has been described as overexpressed in human placenta during the pregnancy. Herein we assessed two single nucleotide polymorphisms (SNPs) FokI (rs2228570 A>G) and Cdx-2 (rs11568820 T>C), within VDR, using TaqMan fluorogenic probes, and differential susceptibility to SPTB. We assessed 104 pregnant women with SPTB and 85 women with normal birth in a Northeastern Brazilian population. Statistically significant differences for both SNPs where found when comparing allele and genotype frequencies in both groups: the T allele for rs2228570 and A allele for rs11568820 were significantly more frequent in SPTB group than in normal birth group (p=0.000013 and p=0.00466, respectively). The rs11568820 A/A genotype was associated to clinical/demographic variables such as: premature birth (p=0.007), neonate weight (p=0.039), presence of infection during pregnancy (p=0.011) and premature birth among multiparous (p=0.015). The rs2228570 T/T genotype associated with gestational diabetes mellitus (p=0.044) and chorioamnionitis during pregnancy (p=0.043). In conclusion our findings indicate an association between polymorphisms FokI and Cdx-2 within VDR gene and SPTB, suggesting their involvement in the triggering of these syndromes. PMID- 29128635 TI - MicroRNA-374b reduces the proliferation and invasion of colon cancer cells by regulation of LRH-1/Wnt signaling. AB - Deregulation of microRNA (miRNA) has been suggested as a critical event in colon cancer development and progression. Recent studies have suggested that miR-374b is a novel cancer-related miRNA involved in several cancer types. Thus far, very little is known about the role of miR-374b in colon cancer; therefore, the goal of this study was to investigate the potential role of miR-374b in colon cancer. Here, we showed that miR-374b expression was significantly downregulated in colon cancer tissues and cell lines. Overexpression of miR-374b inhibited the proliferation and invasion of colon cancer cells, while miR-374b suppression promoted colon cancer cell proliferation and invasion. Liver receptor homolog-1 (LRH-1) was identified as a target of miR-374b in colon cancer cells. Both the mRNA and protein expression of LRH-1 were regulated by miR-374b. In addition, an inverse correlation between LRH-1 mRNA and miR-374b expression was evidenced in colon cancer specimens. Notably, overexpression of miR-374b also downregulated the Wnt signaling in colon cancer cells. Furthermore, restoration of LRH-1 expression significantly abolished the antitumor effect of miR-374b in colon cancer cells. These findings suggest that miR-374b inhibits colon cancer cell proliferation and invasion through downregulation of LRH-1 expression. Inhibiting LRH-1 by miR-374b may represent a novel therapeutic strategy for the treatment of colon cancer. PMID- 29128636 TI - Identification of key microRNAs associated with diffuse large B-cell lymphoma by analyzing serum microRNA expressions. AB - PURPOSE: This study aimed to investigate the molecular mechanism underlying diffuse large B-cell lymphoma (DLBCL). METHODS: Serum miRNA expression analysis for the serum samples of patients with DLBCL and those of controls was performed using the Illumina sequencing technology. Differentially expressed miRNAs (DEMs) were identified on the basis of the sequencing data. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and protein-protein interaction (PPI) network construction for the target genes of DEMs were also conducted. Moreover, the selected DEMs were verified using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Fifty-one DEMs were identified between DLBCL disease and control groups, of which two were upregulated and 49 were downregulated. In total, 3631 target genes of DEMs were obtained, and hsa-miR-34a-5p had the most target genes. Among the 51 DEMs, 19 were significantly enriched in 41 KEGG pathways. hsa-miR-34a-5p was enriched in 15 pathways such as the p53 signaling pathway. hsa-miR-323b-3p was enriched in four pathways such as pathways in cancer. The PPI network revealed that hsa-miR 34a-5p had the most target genes such as tumor protein p53 (TP53), and hsa-miR 431-5p regulated tyrosine protein kinase Fyn (FYN). Furthermore, qRT-PCR results showed that hsa-miR-34a-5p was upregulated, whereas hsa-miR-323b-3p and hsa-miR 431-5p were downregulated. CONCLUSION: hsa-miR-34a-5p may be directly regulated by TP53 and may be involved in DLBCL development via the p53 signaling pathway. Furthermore, hsa-miR-323b-3p may be related to DLBCL by participating in pathways in cancer. hsa-miR-431-5p may also play a role in DLBCL by regulating FYN. PMID- 29128637 TI - A MADS-box transcription factor of 'Kuerlexiangli'(Pyrus sinkiangensis Yu) PsJOINTLESS gene functions in floral organ abscission. AB - MADS-box proteins have been implicated in many biological processes. However, plant MADS-box proteins functioning in floral organ abscission and the underlying physiological mechanisms remain poorly understood. Here, we report the identification and functional characterization of PsJOINTLESS isolated from 'Kuerlexiangli'. PsJOINTLESS had a complete open reading frame of 672bp, encoding a 224 amino acid peptide, and shared high sequence identities with MADS-box from other plants. PsJOINTLESS was subcellularly targeted to the nucleus, supporting its role as a transcription factor. Expression levels of PsJOINTLESS in the calyx tube were strongly induced by calyx abscission treatment at 6d after full bloom. Overexpression of PsJOINTLESS in tomato enhanced the rate of pedicel abscission rate. Of special note, the transgenic plants increased the abscission zone cell layer compared with wild type. Furthermore, the tomato transgenic lines showed thinner flower pedicels, more cell number and small pedicel cell size. The cellulase activity in pedicel abscission zone of transgenic plants was higher than that of wild type. In addition, steady-state mRNA levels of five cell wall hydrolase genes coding for either functional or regulatory proteins were induced to higher levels in the transgenic lines. These results clearly demonstrate that PsJOINTLESS may affect pedicel abscission zone development. PMID- 29128639 TI - Degradation of pesticides with RSDL(r) (reactive skin decontamination lotion kit) lotion: LC-MS investigation. AB - This study examined the degradation of organophosphate (OP) and carbamate pesticides using RSDL(r) (Reactive Skin Decontamination Lotion Kit) lotion. Degradation occurs from a nucleophilic substitution (SN) reaction between an ingredient in the RSDL lotion, potassium 2,3-butanedione monoximate (KBDO), with susceptible sites in the pesticides. Evaluation at several molar ratios of KBDO:test articles using liquid chromatography-mass spectrometry (LC-MS) techniques was performed. The OP test articles, parathion, paraoxon, parathion methyl, paraoxon-methyl and chlorpyrifos were effectively degraded at molar ratios of four and above in less than 6min contact time. Malathion and malaoxon were similarly converted to inactive by-products at molar ratios as low as two in less than 4min. A minimum molar ratio of nine was found to be effective against the carbamate pesticide carbofuran. In the case of aldicarb, complete destruction was achieved at a molar ratio of fifteen and a reaction time of one hour. It is important to note that these studies are based on a direct liquid phase RSDL lotion reaction with the toxic chemicals without the added physical removal decontamination efficacy component provided by the sponge component of the RSDL kit. The RSDL kit is intended to be used to remove or neutralize chemical warfare agents (CWA) and T-2 toxin from the skin. In actual use, the majority of the CWA decontamination occurs through the combined action of the sponge in both removing the chemical from the skin, and in rapidly mixing the chemicals at a high molar ratio of KBDO:CWA within the pores of the sponge to enhance rapid neutralization of the chemical. PMID- 29128638 TI - ULK1-regulated autophagy: A mechanism in cellular protection for ALDH2 against hyperglycemia. AB - Mitochondrial aldehyde dehydrogenase 2 (ALDH2), an important enzyme in the elimination of toxic aldehydes, is involved in cardioprotection against diabetes mellitus. This study was designed to examine the mechanism behind ALDH2-offered protection against high glucose exposure with a focus on autophagy. H9C2 cells were cultured with normal or high glucose medium in the presence or absence of the ALDH2 agonist Alda-1. GFP-LC3 puncta and immunofluorescence were employed to assess autophagosome formation. Western blotting was applied to evaluate autophagy protein markers Atg5, LC3, p62, ULK1 phosphorylation and ALDH2. JC-1 staining was used to monitor mitochondrial membrane potential and mitochondrial injury. CCK-8 and TUNEL assays were employed for apoptosis and cell viability. Our results indicated that high glucose promoted cell death and decreased cell viability. Levels of autophagy protein marker Atg5, and LC3B were decreased and level of p62 was elevated in hyperglycemic condition, the effects of which were reversed by ALHD2. High glucose lowered mitochondrial membrane potential, the effect of which was accentuated by ULK1 knock-down. All these high glucose induced responses were negated by Alda-1 along with upregulated autophagy. The autophagy inhibitor 3-MA and lysosomal inhibitor bafilomycin A1 cancelled off whereas autophagy inducer rapamycin mimicked the Alda-1-offered protection against high glucose. High glucose suppressed phosphorylation of ULK1, the effect of which was mitigated by Alda-1. Knock-down of ULK1 using siRNA negated Alda-1 induced upregulation of autophagosome accumulation and LC3 expression. High glucose-dampened autophagy was also confirmed using GFP-LC3 puncta, and immunofluorescence. Taken together, these data suggested that ULK1 played a crucial role in ALDH2-offered protective effect against high glucose exposure induced cardiomyocyte injury through regulation of autophagy. PMID- 29128640 TI - Binding interactions of halogenated bisphenol A with mouse PPARalpha: In vitro investigation and molecular dynamics simulation. AB - The binding of bisphenol A (BPA) and its halogenated derivatives (halogenated BPAs) to mouse peroxisome proliferator-activated receptor alpha ligand binding domain (mPPARalpha-LBD) was examined by a combination of in vitro investigation and in silico simulation. Fluorescence polarization (FP) assay showed that halogenated BPAs could bind to mPPARalpha-LBD* as the affinity ligands. The calculated electrostatic potential (ESP) illustrated the different charge distributions of halogenated BPAs with altered halogenation patterns. As electron attracting substituents, halogens decrease the positive electrostatic potential and thereby have a significant influence on the electrostatic interactions of halogenated BPAs with mPPARalpha-LBD*. The docking results elucidated that hydrophobic and hydrogen-bonding interactions may also contribute to stabilize the binding of the halogenated BPAs to their receptor molecule. Comparison of the calculated binding energies with the experimentally determined affinities yielded a good correlation (R2=0.6659) that could provide a rational basis for designing environmentally benign chemicals with reduced toxicities. This work can potentially be used for preliminary screening of halogenated BPAs. PMID- 29128641 TI - Cell loss by apoptosis is involved in the intestinal degeneration that occurs during aestivation in the sea cucumber Apostichopus japonicus. AB - The sea cucumber Apostichopus japonicus (Selenka) commonly undergoes aestivation in response to high water temperatures. This process is accompanied by tissue regression and body mass reduction. Previous studies have suggested that apoptosis may play a role in the tissue remodeling that occurs during aestivation, although this has not definitively been shown. To investigate this hypothesis, the present study used A. japonicus as a model organism to examine cell loss through apoptosis in intestinal degeneration during aestivation. Apostichopus japonicus individuals were collected from Yellow Sea (N 36 degrees 05' 44.87", E 120 degrees 31' 58.51"), China in April 2016 and split into two groups. Aestivation was induced in the experimental group by incubation at 25 degrees C. This resulted in a significant decrease in body mass and increased evidence of intestinal degeneration in hematoxylin and eosin, Hoechst 33342, and in situ TUNEL analyses of tissue sections. Along with further Hoechst 33342 analysis using intestinal cell smears, these results showed that A. japonicus intestinal cell apoptosis occurred soon after the initial temperature increase, with most apoptotic events completing within 20days. Transcriptional quantification of the Ajcaspase-8 (CASP8) and Ajcaspase-3 (CASP3) apoptotic genes demonstrated that their expression was significantly elevated at the beginning of the experiment but was decreased at later stages of aestivation. The results of this study strongly suggest that apoptosis is involved in the intestinal regression of A. japonicus during aestivation, and play important role in understanding fundamental cellular events in tissue regression under environmental stress. PMID- 29128642 TI - The evolution of metabolic regulation in animals. AB - Energy metabolism is determined by a suite of regulatory mechanism, and their increasing complexity over evolutionary time provides the key to understanding the emergence of different metabolic phenotypes. Energy metabolism is at the core of biological processes because all organisms must maintain energy balance against thermodynamic gradients. Energy metabolism is regulated by a bewildering array of interacting molecular mechanisms, and much of what is known about metabolic regulation comes from the medical literature. However, ecology and evolutionary research would gain considerably by incorporating regulatory mechanisms more explicitly in research on topics such as the evolution of endothermy, metabolic plasticity, and energy balance. The purpose of this brief review is to summarise the main regulatory pathways of energy metabolism in animals and their evolutionary origins to make these complex interactions more accessible to researchers from a broad range of backgrounds. Some of the principal regulators of energy balance, such as the AMP-stimulated protein kinase, have an ancient prokaryotic origin. Most regulatory pathways (e.g. thyroid hormone, insulin, adipokines), however, are eukaryotic in origin and diversified substantially in metazoans and vertebrates. Diversification in vertebrates is at least partly due to genome duplications early in this lineage. The interaction between regulatory mechanisms permitted an increasingly sophisticated fine-tuning of energy balance and metabolism. Hence, regulatory complexity increased over evolutionary time, and taxa differ in their potential range of metabolic phenotypes. Choice of model organism therefore becomes important, and bacteria or even invertebrates are not good models for more derived vertebrates. Different metabolic phenotypes and their evolution, such as endothermy and metabolic plasticity, should be interpreted against this regulatory background. PMID- 29128643 TI - Transcriptional profiles of plasticity for desiccation stress in Drosophila. AB - We examined the transcriptional responses of desiccation resistance candidate genes in populations of Drosophila melanogaster divergent for desiccation resistance and in capacity to improve resistance via phenotypic plasticity. Adult females from temperate and tropical eastern Australian populations were exposed to a rapid desiccation hardening (RDH) treatment, and groups without RDH to acute desiccation stress, and the transcript expression of 12 candidate desiccation genes were temporally profiled during, and in recovery from stress. We found that desiccation exposure resulted in largely transitory, stress-specific transcriptional changes in all but one gene. However linking the expression profiles to the population-level phenotypic divergence was difficult given subtle, and time-point specific population expression variation. Nonetheless, rapid desiccation hardening had the largest effect on gene expression, resulting in distinct molecular profiles. We report a hitherto uncharacterised desiccation molecular hardening response where prior exposure essentially 'primes' genes to respond to subsequent stress without discernible transcript changes prior to stress. This, taken together with some population gene expression variation of several bona fide desiccation candidates associated with different water balance strategies speaks of the complexity of natural desiccation resistance and plasticity and provides new avenues for understanding the molecular basis of a trait of ecological significance. PMID- 29128644 TI - Mass drug administration and the sustainable control of schistosomiasis: Community health workers are vital for global elimination efforts. AB - OBJECTIVES: Schistosomiasis control is centred on preventive chemotherapy through mass drug administration (MDA). However, endemic countries continue to struggle to attain target coverage rates and patient compliance. In the Philippines, barangay health workers (BHWs) play a vital role in the coordination of MDA, acting as advocates, implementers, and educators. The aim of this study was to determine whether BHW knowledge and attitudes towards schistosomiasis and MDA is sufficient and correlated with resident knowledge and drug compliance. METHODS: A cross-sectional survey was conducted in 2015 among 2186 residents and 224 BHWs in the province of Northern Samar, the Philippines using a structured survey questionnaire. RESULTS: BHWs showed good familiarity on how schistosomiasis is acquired and diagnosed. Nevertheless, both BHWs and residents had poor awareness of the signs and symptoms of schistosomiasis, disease prevention, and treatment options. There was no correlation between the knowledge scores of the BHWs and the residents (r=0.080, p=0.722). Kruskal-Wallis analysis revealed significant differences in BHW knowledge scores between the low (3.29, 95% confidence interval 3.16-3.36), moderate (3.61, 95% confidence interval 3.49-3.69), and high (4.05, 95% confidence interval 3.77-4.13) compliance village groups (p=0.002), with the high compliance areas having the highest mean knowledge scores. CONCLUSIONS: This study highlights the importance of community health workers in obtaining the World Health Organization drug coverage rate of 75% and improving compliance with MDA in the community. Investing in the education of community health workers with appropriate disease-specific training is crucial if disease elimination is ultimately to be achieved. PMID- 29128645 TI - Kunitz-type protease inhibitor as a vaccine candidate against schistosomiasis mansoni. AB - OBJECTIVE: The aim of this study was to develop a vaccine against schistosomiasis, which is a major challenge due to the complex lifecycle of the causative schistosome parasite. METHODS: SmKI-1 is a 16-kDa Kunitz-type protease inhibitor present in the excretory-secretory products and tegument of adult worms and eggs of Schistosoma mansoni. Two independent vaccine trials were performed in mice to determine the efficacy of rSmKI-1 in developing protective immunity. RESULTS: The results obtained showed reductions of 23-33% in adult worms, 28-31% in intestinal eggs, 33-39% in faecal eggs, and 20-43% in liver eggs. Furthermore, rSmKI-1 significantly increased the production of interferon gamma, interleukin (IL)-10, and IL-6 in vaccinated mice, maintaining a Th1/Th2-type balanced protective response. CONCLUSIONS: rSmKI-1 generated partial protection against schistosomiasis mansoni in the murine model of infection and could be developed as part of a combination vaccine with other vaccine candidates to provide an even more solid level of protection. PMID- 29128646 TI - HIV drug resistance following a decade of the free antiretroviral therapy programme in India: A review. AB - OBJECTIVE: The objective of this review was to assess the burden of HIV drug resistance mutations (DRM) in Indian adults exposed to first-line antiretroviral therapy (ART) as per national guidelines. METHODS: An advanced search of the published literature on HIV drug resistance in India was performed in the PubMed and Scopus databases. Data pertaining to age, sex, CD4 count, viral load, and prevalence of nucleoside reverse transcriptase inhibitor (NRTI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) DRM were extracted from each publication. Year-wise Indian HIV-1 reverse transcriptase (RT) sequences were retrieved from the Los Alamos HIV database and mutation analyses were performed. A time trend analysis of the proportion of sequences showing NRTI resistance mutations among individuals exposed to first-line ART was conducted. RESULTS: Overall, 23 studies (1046 unique RT sequences) were identified indicating a prevalence of drug resistance to NRTI and NNRTI. The proportion of RT sequences with any DRM, any NRTI DRM, and any NNRTI DRM was 78.39%, 68.83%, and 73.13%, respectively. The temporal trend analysis of individual DRM from sequences retrieved during 2004 2014 indicated a rising trend in K65R mutations (p=0.013). CONCLUSIONS: Although the overall burden of resistance against first-line ART agents remained steady over the study decade, periodic monitoring is essential. There is the need to develop an HIV-1 subtype C-specific resistance database in India. PMID- 29128647 TI - A mathematical model to guide genetic engineering of photosynthetic metabolism. AB - The optimization of algae biomass productivity in industrial cultivation systems requires genetic improvement of wild type strains isolated from nature. One of the main factors affecting algae productivity is their efficiency in converting light into chemical energy and this has been a major target of recent genetic efforts. However, photosynthetic productivity in algae cultures depends on many environmental parameters, making the identification of advantageous genotypes complex and the achievement of concrete improvements slow. In this work, we developed a mathematical model to describe the key factors influencing algae photosynthetic productivity in a photobioreactor, using experimental measurements for the WT strain of Nannochloropsis gaditana. The model was then exploited to predict the effect of potential genetic modifications on algae performances in an industrial context, showing the ability to predict the productivity of mutants with specific photosynthetic phenotypes. These results show that a quantitative model can be exploited to identify the genetic modifications with the highest impact on productivity taking into full account the complex influence of environmental conditions, efficiently guiding engineering efforts. PMID- 29128648 TI - A hypertension emergency department intervention aimed at decreasing disparities: Design of a randomized clinical trial. AB - Effective interventions to identify and treat uncontrolled hypertension (HTN), particularly in underrepresented populations that use the emergency department (ED) for primary care, are critically needed. Uncontrolled HTN contributes significantly to cardiovascular morbidity and mortality and is more frequently encountered among patients presenting to the ED as compared to the primary care setting. EDs serve as the point of entry into the health care system for high risk patient populations, including minority and low-income patients. Previous studies have demonstrated that the prevalence of uncontrolled/undiagnosed HTN in patients presenting to the ED is alarmingly high. Thus ED engagement and early risk assessment/stratification is a feasible innovation to help close health disparity gaps in HTN. A Hypertension Emergency Department Intervention Aimed at Decreasing Disparities (AHEAD2) trial, funded by the National Heart, Lung, and Blood Institute (NHLBI) is a three-arm single site randomized clinical pilot trial of adults presenting to the ED with Stage 2 hypertension (blood pressure [BP]>160/100) comparing (1) an ED-initiated Screening, Brief Intervention, and Referral for Treatment (SBIRT) focused on HTN, (2) the same ED-initiated SBIRT coupled with a Post-Acute Care Hypertension Transition Consultation by ED Clinical Pharmacists, and (3) usual care. The primary outcome is mean BP differences between study arms. Secondary outcomes are proportion of participants with BP control (BP<140/90mmHg), and improvements in HTN knowledge and medication adherence scores between study arms. The objective of this report is to describe the development of the AHEAD2 trial, including the methods, research infrastructure, and other features of the randomized clinical trial design. PMID- 29128649 TI - Design of a randomized controlled trial examining the efficacy and biological mechanisms of web-prolonged exposure and present-centered therapy for PTSD among active-duty military personnel and veterans. AB - Improved accessibility of effective and efficient evidence-based treatments (EBTs) for military personnel suffering with posttraumatic stress disorder (PTSD) is an urgent need to meet the growing demand for timely care. In addition, a better understanding of the mechanism of action of behavioral therapy can inform the delivery of care to meet accessibility demands. Effective EBTs for PTSD are available, but logistical and stigma-related barriers to accessing behavioral healthcare can deter military personnel from receiving these treatments. Web based treatments represent an innovative way to overcome these barriers. The efficacy of previously developed web-based treatments for PTSD appears promising; however, they were not developed based on treatment protocols with strong empirical support for their efficacy. No study to date has examined web-based treatment of PTSD using a well-established evidence-based treatment, nor delineated the biological mechanisms through which a web-based treatment exerts its effects. This paper describes the rationale and methods of a randomized controlled trial comparing the efficacy and potential biological mediators of 10 sessions of a web-version of Prolonged Exposure (PE), "Web-PE," delivered over 8weeks compared to 10 sessions of in-person Present-Centered Therapy (PCT) delivered over 8weeks by a therapist in 120 active duty military personnel and veterans with PTSD. PMID- 29128650 TI - Parent and child care provider partnerships: Protocol for the Healthy Me, Healthy We (HMHW) cluster randomized control trial. AB - BACKGROUND: Formation of diet and physical activity habits begins during early childhood. However, many preschool-aged children in the United States do not achieve recommendations for a nutritious diet or active lifestyle. Two important spheres of influence, home and child care, could ensure that children receive consistent health messages. Innovative approaches that engage both parents and child care providers in a substantial way are needed. Social marketing, a promising approach for health promotion targeting children, uses principles that recognize the need to engage multiple stakeholders and to emphasize benefits and overcome barriers associated with behavior change. Yet, application of social marketing principles in interventions for preschool-age children is limited. METHODS: Healthy Me, Healthy We (HMHW) is 2-arm, cluster randomized controlled trial to evaluate the effect of a 8-month social marketing campaign on the diet and physical activity behaviors of preschool children (3-4years old), their parents, and child care providers. The campaign is delivered by the child care center and includes branded classroom and at-home activities and materials. Primary outcomes are children's diet quality (assessed with Healthy Eating Index scores) and minutes of non-sedentary activity (measured via accelerometers). Secondary outcomes assess children's body mass index, nutrition and physical activity practices at the child care center and at home, and health behaviors of child care providers and parents. CONCLUSION: HMHW is an innovative approach to promoting healthy eating and physical activity in preschool children. The campaign targets children during a key developmental period and leverages a partnership between providers and parents to affect behavior change. PMID- 29128651 TI - Design and rationale of the medical students learning weight management counseling skills (MSWeight) group randomized controlled trial. AB - Physicians have an important role addressing the obesity epidemic. Lack of adequate teaching to provide weight management counseling (WMC) is cited as a reason for limited treatment. National guidelines have not been translated into an evidence-supported, competency-based curriculum in medical schools. Weight Management Counseling in Medical Schools: A Randomized Controlled Trial (MSWeight) is designed to determine if a multi-modal theoretically-guided WMC educational intervention improves observed counseling skills and secondarily improve perceived skills and self-efficacy among medical students compared to traditional education (TE). Eight U.S. medical schools were pair-matched and randomized in a group randomized controlled trial to evaluate whether a multi modal education (MME) intervention compared to traditional education (TE) improves observed WMC skills. The MME intervention includes innovative components in years 1-3: a structured web-course; a role play exercise, WebPatientEncounter, and an enhanced outpatient internal medicine or family medicine clerkship. This evidence-supported curriculum uses the 5As framework to guide treatment and incorporates patient-centered counseling to engage the patient. The primary outcome is a comparison of scores on an Objective Structured Clinical Examination (OSCE) WMC case among third year medical students. The secondary outcome compares changes in scores of medical students from their first to third year on an assessment of perceived WMC skills and self-efficacy. MSWeight is the first RCT in medical schools to evaluate whether interventions integrated into the curriculum improve medical students' WMC skills. If this educational approach for teaching WMC is effective, feasible and acceptable it can affect how medical schools integrate WMC teaching into their curriculum. PMID- 29128652 TI - Differences in combinations and concentrations of drugs of abuse in fatal intoxication and driving under the influence cases. AB - BACKGROUND: In toxicology, international classification systems focus on single intoxicants as the cause of death. It is, however, well known that very few drug related deaths are caused by a single substance and that information concerning the drug concentrations as well as the combinations of drugs are essential in order to ascertain the cause of death. The aim of the study was to assess whether those prone to fatal intoxications differ significantly from chronic drug users - in terms of demographics and drug exposure patterns. MATERIAL AND METHODS: Fatal psychoactive drug intoxications in Norway during 2012, where a forensic autopsy including toxicological analysis were performed, were included. Analytical findings in blood were compared with concentrations in blood from apprehended drivers under the influence of drugs and ethanol (DUID) during the same time period. The opioid and benzodiazepine concentrations were assessed as morphine and diazepam equivalents, respectively, in order to compare concentrations across the different groups. RESULTS: A total of 194 autopsy cases and 4811 DUID cases were included. Opioids were detected in around 90% of the drug intoxication cases, but in only 16% of the DUID cases. The number of substances detected in fatal intoxications was 4.9 compared to 2.6 in the DUID cases. The total opioid concentrations were significantly higher in the fatal intoxication cases compared to DUID cases (229ng/mL versus 56.9ng/mL morphine equivalents, respectively). Benzodiazepines were detected in 90% of the fatal cases. Only one fatal opioid mono-intoxication was found; a case with a very high methadone concentration (1238ng/mL). DISCUSSION: Mono-intoxication with heroin was not seen in any of the fatal intoxications in Norway, and single drug intoxications were rare (1.5%). Fatal intoxications were caused by a combination of drugs with significantly more substances as well as higher total drug concentrations among the fatal cases compared to the DUID cases. The combination of opioids and benzodiazepines seemed to represent an increased risk of death. CONCLUSION: The total load of drugs influence the degree of intoxication and the total concentration level must be considered, including the total number of substances. Our findings imply that international statistics regarding an opioid being the main intoxicant should have a shift in focus towards combinations of drugs (especially opioids and benzodiazepines) as a major risk factor for fatal drug overdoses. PMID- 29128653 TI - Acoustic environment identification by Kullback-Leibler divergence. AB - This paper presents a forensic methodology that determines, from among a set of recording places, the probable place where allegedly a disputed digital audio recording was made. The methodology considers that digital audio recordings are noisy signals that have two involved noise components. One component is the multiplicative noise, which is an internal feature on the audio recording that is related to the recording device. The other component is the additive noise, which is an external feature on the audio recording that can be related to the recording place. Therefore, the proposed methodology estimates a likelihood rate that helps to decide which recording place is more plausible to be associated with a disputed audio recording. This likelihood rate is defined as the probability of a finding, supposing that a specific proposition is true, divided by the probability of a finding if an alternative proposition is true. Such probabilities are calculated by performing a statistical comparison through the Kullback-Leibler divergence [1], between the probability distribution function of the additive noise associated to the disputed recording and the probability distribution function of the additive noises associated to a set of audio recordings made on the possible recording places. Then, in order to determine the recording place, the analyst requires a list of possible places where the recording could have been carried out; in these places some reference recordings will be made. In this work, the additive noise is estimated by the Geometric Approach to Spectral Subtraction (GA-SS) filter [2], applied to the noisy audio recording. PMID- 29128654 TI - Kastle-Meyer blood test reagents are deleterious to DNA. AB - The Kastle-Meyer (KM) test is a quick and easy chemical test for blood used in forensic analyses. Two practical variations of this test are the KM-rub (indirect) test and the more sensitive KM-direct test, the latter of which is performed by applying reagents directly to a suspected blood stain. This study found that sodium hydroxide present in the KM reagents eliminated the potential to generate a DNA profile when applied directly to small quantities of blood. A modified approach to the KM-rub test that increases its sensitivity is presented as a method to replace destructive KM-direct testing. PMID- 29128655 TI - Nonlinear approximation method of vehicle velocity Vt and statistical population of experimental cases. AB - In car crash analysis three calculations methods can be distinguished: analytical (Campbell, McHenry, Strother, Prasad, Crash3 etc.), comparative and graphical (Lindquist et al., 2003; Prasad, 1990; Sharma et al., 2007; Wach and Unarski, 2006; Zuchowski, 2015) [15,23,25,29,33]. The number and reliability of these methods, in reference to modern vehicles and their structure, may lead to unclear conclusions. This issue proves to be significant, especially due to slight modifications of both input parameters and input data for the analysis of the method. This may give substantially different answers to the questions asked in court. After a thorough analysis of this problem, a new analytical method was devised, based on a new input database - NHTSA, which shows great improvement in the accuracy of obtained results. The aim of this paper is to prove that the nonlinear method is a very effective tool for processing experimental data in a large enough number of cases. PMID- 29128656 TI - Molecular and functional characterization of two malic enzymes from Leishmania parasites. AB - Leishmania parasites cause a broad spectrum of clinical manifestations in humans and the available clinical treatments are far from satisfactory. Since these pathogens require large amounts of NADPH to maintain intracellular redox homeostasis, oxidoreductases that catalyze the production of NADPH are considered as potential drug targets against these diseases. In the sequenced genomes of most Leishmania spp. two putative malic enzymes (MEs) with an identity of about 55% have been identified. In this work, the ME from L. major (LmjF24.0770, Lmj_ME 70) and its less similar homolog from L. mexicana (LmxM.24.0761, Lmex_ME-61) were cloned and functionally characterized. Both MEs specifically catalyzed NADPH production, but only Lmex_ME-61 was activated by l-aspartate. Unlike the allosterically activated human ME, Lmex_ME-61 exhibited typical hyperbolic curves without any sign of cooperativity in the absence of l-aspartate. Moreover, Lmex_ME-61 and Lmj_ME-70 differ from higher eukaryotic homologs in that they display dimeric instead of tetrameric molecular organization. Homology modeling analysis showed that Lmex_ME-61 and Lmj_ME-70 notably differ in their surface charge distribution; this feature encompasses the coenzyme binding pockets as well. However, in both isozymes, the residues directly involved in the coenzyme binding exhibited a good degree of conservation. Besides, only Lmex_ME-61 and its closest homologs were immunodetected in cell-free extracts from L. mexicana, L. amazonensis and L. braziliensis promastigotes. Our findings provide a first glimpse into the biochemical properties of leishmanial MEs and suggest that MEs could be potentially related to the metabolic differences among the species of Leishmania parasites. PMID- 29128657 TI - GIS based optimal impervious surface map generation using various spatial data for urban nonpoint source management. AB - Impervious surfaces are mainly artificial structures such as rooftops, roads, and parking lots that are covered by impenetrable materials. These surfaces are becoming the major causes of nonpoint source (NPS) pollution in urban areas. The rapid progress of urban development is increasing the total amount of impervious surfaces and NPS pollution. Therefore, many cities worldwide have adopted a stormwater utility fee (SUF) that generates funds needed to manage NPS pollution. The amount of SUF is estimated based on the impervious ratio, which is calculated by dividing the total impervious surface area by the net area of an individual land parcel. Hence, in order to identify the exact impervious ratio, large-scale impervious surface maps (ISMs) are necessary. This study proposes and assesses various methods for generating large-scale ISMs for urban areas by using existing GIS data. Bupyeong-gu, a district in the city of Incheon, South Korea, was selected as the study area. Spatial data that were freely offered by national/local governments in S. Korea were collected. First, three types of ISMs were generated by using the land-cover map, digital topographic map, and orthophotographs, to validate three methods that had been proposed conceptually by Korea Environment Corporation. Then, to generate an ISM of higher accuracy, an integration method using all data was proposed. Error matrices were made and Kappa statistics were calculated to evaluate the accuracy. Overlay analyses were performed to examine the distribution of misclassified areas. From the results, the integration method delivered the highest accuracy (Kappa statistic of 0.99) compared to the three methods that use a single type of spatial data. However, a longer production time and higher cost were limiting factors. Among the three methods using a single type of data, the land-cover map showed the highest accuracy with a Kappa statistic of 0.91. Thus, it was judged that the mapping method using the land-cover map is more appropriate than the others. In conclusion, it is desirable to apply the integration method when generating the ISM with the highest accuracy. However, if time and cost are constrained, it would be effective to primarily use the land-cover map. PMID- 29128658 TI - Mesoporous silica nanoparticles: a smart nanosystem for management of breast cancer. AB - Breast cancer is the second-leading cause of death in women worldwide owing to aggressive metastasis, lack of early diagnosis and poor access to treatment amenities. During the past decade, mesoporous silica nanoparticles (MSNs) have gained ground for the delivery of a wide variety of chemotherapeutic and bioimaging agents owing to their unique characteristics and straightforward fabrication methods. Present research studies based on MSNs have provided various potential insights in their applicability in breast cancer treatment by improving solubility and stability and decreasing the adverse effects of current treatment regimens. This review focuses on the applicability of this novel modality in the management of breast cancer. PMID- 29128659 TI - On-line confidence monitoring during decision making. AB - Humans can readily assess their degree of confidence in their decisions. Two models of confidence computation have been proposed: post hoc computation using post-decision variables and heuristics, versus online computation using continuous assessment of evidence throughout the decision-making process. Here, we arbitrate between these theories by continuously monitoring finger movements during a manual sequential decision-making task. Analysis of finger kinematics indicated that subjects kept separate online records of evidence and confidence: finger deviation continuously reflected the ongoing accumulation of evidence, whereas finger speed continuously reflected the momentary degree of confidence. Furthermore, end-of-trial finger speed predicted the post-decisional subjective confidence rating. These data indicate that confidence is computed on-line, throughout the decision process. Speed-confidence correlations were previously interpreted as a post-decision heuristics, whereby slow decisions decrease subjective confidence, but our results suggest an adaptive mechanism that involves the opposite causality: by slowing down when unconfident, participants gain time to improve their decisions. PMID- 29128660 TI - Antioxidant responses and oxidative stress in sheepshead minnow larvae exposed to Corexit 9500(r) or its component surfactant, DOSS. AB - Large-scale use of dispersants to remediate oil spills has raised concerns about their toxicity to marine organisms. Of particular concern is oxidative stress and resulting membrane damage due to exposure to surfactants in dispersant mixtures. We investigated the potential of the dispersant Corexit 9500(r) and one of its major components, the anionic surfactant dioctyl sodium sulfosuccinate (DOSS), to induce oxidative stress in larval sheepshead minnows after 24 and 96h exposures, at two sublethal concentrations, the lesser being environmentally realistic for each compound. Corexit exposures elicited only minimal antioxidant responses for most antioxidant components tested, with increased glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities observed only after 96h and at the higher exposure concentration. In contrast, DOSS induced statistically significant increases in the levels of reactive oxygen species (ROS), GPx, and lipid peroxidation, as well as depleted reduced glutathione (GSH) levels at both time points and concentrations. These data indicate that short-term and environmentally realistic exposures to DOSS can impact antioxidant response capabilities, raising concern about its use in oil dispersants and other high volume use products where environmental releases are likely. PMID- 29128661 TI - A self-assembly nanodrug delivery system based on amphiphilic low generations of PAMAM dendrimers-ursolic acid conjugate modified by lactobionic acid for HCC targeting therapy. AB - Ursolic acid (UA), a natural triterpene acid, is a promising anti-cancer drug due to its inhibitory effect on tumor growth and metastasis. However, clinical translation of UA is limited by its poor water solubility and low bioavailability. To overcome these problems, herein an amphiphilic self-assembly nanodrug composed of UA, lactobionic acid (LA) and low-polyamidoamine (low-PAMAM) dendrimers is developed. This near-spherical nanodrug with a uniform size (~180 nm) demonstrated to have an enhanced cytotoxicity against liver cancer SMMC7721 cells, and could attenuate the migration and adhesion of SMMC7721 cells at non toxic concentrations by suppressing metastasis-related protein MMP-9 expression. Furthermore, in vivo study indicates that the nanodrug exhibited prolonged circulation time in blood as well as increased AUC, MRT and Cmax, and could effectively inhibit the tumor growth in H22 mice model. Overall, the UA-based nanodrug delivery system reported in the present work represents a novel strategy for targeted tumor therapy. PMID- 29128662 TI - Activation of innate immunity in primary human cells using a plant virus derived nanoparticle TLR7/8 agonist. AB - Rod-shaped virus-like nanoparticles (VLNP) made of papaya mosaic virus (PapMV) coat proteins (CP) self-assembled around a single stranded RNA (ssRNA) were showed to be a TLR7 agonist. Their utilization as an immune modulator in cancer immunotherapy was shown to be promising. To establish a clinical relevance in human for PapMV VLNP, we showed that stimulation of human peripheral blood mononuclear cells (PBMC) with VLNP induces the secretion of interferon alpha (IFNalpha) and other pro-inflammatory cytokines and chemokines. Plasmacytoid dendritic cells (pDCs) were activated and secreted IFN-alpha upon VLNP exposure. Monocyte-derived dendritic cells upregulate maturation markers and produce IL-6 in response to PapMV VLNP stimulation, which suggests the activation of TLR8. Finally, when co-cultured with NK cells, PapMV induced pDCs promoted the NK cytolytic activity against cancer cells. These data obtained with primary human immune cells further strengthen the clinical relevance of PapMV VLNPs as a cancer immunotherapy agent. PMID- 29128663 TI - Chirality-dependent cell adhesion and enrichment in Janus nanocomposite hydrogels. AB - To assess chirality-dependent cell adhesion and cell enrichment in an extracellular matrix (ECM)-like model, in this study we created 3D nanocomposite (NC) hydrogels composed of periodic mesoporous organosilica (PMO) functionalized with chiral molecules [NC "homo-hydrogels" (NC hydrogels with one kind of functionalized PMO)]. Additionally, we prepared Janus NC hydrogel by connecting two enantiomorphous NC hydrogels, producing an advanced material that can be used to investigate the effect of opposite enantiomers on the behaviors of healthy and cancer cells in a single biomaterial at the same time and under the same reaction conditions. We found that the surface chirality of the functionalized PMO particles strongly influenced cell affinity to the NC hydrogels, especially in serum-containing media. Additionally, chirality was also successfully used to enrich healthy cells within the Janus NC hydrogel from a mixture of healthy cells and cancer cells. PMID- 29128664 TI - Intravenous anti-MRSA phosphatiosomes mediate enhanced affinity to pulmonary surfactants for effective treatment of infectious pneumonia. AB - The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application. PMID- 29128665 TI - The application of ion-mobility mass spectrometry for structure/function investigation of protein complexes. AB - Ion-mobility mass spectrometry (IM-MS) is an approach that can provide information on the stoichiometry, composition, protein contacts and topology of protein complexes. The power of this approach lies not only in its sensitivity and speed of analysis, but also in the fact that it is a technique that can capture the repertoire of conformational states adopted by protein assemblies. Here, we describe the array of available IM-MS based tools, and demonstrate their application to the structural characterization of various protein complexes, including challenging systems as amyloid aggregates and membrane proteins. We also discuss recent studies in which IM-MS was applied towards investigations of conformational transitions and stabilization effects induced by protein interactions. PMID- 29128666 TI - Comparison of plantar pressure distribution in CAD-CAM and prefabricated foot orthoses in patients with flexible flatfeet. AB - BACKGROUNDS: The effect of foot orthoses on plantar pressure distribution has been proven by researchers but there are some controversies about advantages of custom-made foot orthoses to less expensive prefabricated foot orthoses. METHODS: Nineteen flatfeet adults between 18 and 45 participated in this study. CAD-CAM foot orthoses were made for these patients according to their foot scan. Prefabricated foot orthoses were prepared according to their foot size. Plantar pressure, force and contact area were measured using pedar(r)-x in-shoe system wearing shoe alone, wearing CAD-CAM foot orthoses and wearing prefabricated foot orthoses. Repeated measures ANOVA model with post-hoc, Bonferroni comparison were used to test differences. RESULTS: CAD-CAM and prefabricated foot orthoses both decreased pressure and force under 2nd, 3-5 metatarsal and heel regions comparing to shoe alone condition. CAD-CAM foot orthosis increased pressure under lateral toe region in comparison to shoe alone and prefabricated foot orthosis. Both foot orthoses increased pressure and contact area in medial midfoot region comparing to shoe alone condition. Increased forces were seen at hallux and lateral toes by prefabricated foot orthoses in comparison with CAD-CAM foot orthoses and control condition, respectively. CONCLUSION: According to the results, both foot orthoses could decrease the pressure under heel and metatarsal area. It seems that the special design of CAD-CAM foot orthoses could not make great differences in plantar pressure distribution in this sample. Further research is required to determine whether these results are associated with different scan systems or design software. PMID- 29128667 TI - Bombyx mori ABC transporter C2 structures responsible for the receptor function of Bacillus thuringiensis Cry1Aa toxin. AB - Because Bombyx mori ABC transporter C2 (BmABCC2) has 1000-fold higher potential than B. mori cadherin-like protein as a receptor for Bacillus thuringiensis Cry1Aa toxin (Tanaka et al., 2013), the gate-opening ability of the latent pore under six extracellular loops (ECLs) of BmABCC2 was expected to be the reason for its higher potential (Heckel, 2012). In this study, cell swelling assays in Sf9 cells showed that BmABCC2 mutants lacking substrate-excreting activity retained receptor activity, indicating that the gate-opening activity of BmABCC2 is not responsible for Cry1Aa toxicity. The analysis of 29 BmABCC2 mutants demonstrated that 770DYWL773 of ECL 4 comprise a putative binding site to Cry1Aa. This suggests that specific toxicity of Cry1Aa toxin to a restricted range of lepidopteran insects is dependent on conservation and variation in the amino acid residues around 770DYWL773 of ECL 4 in the ABCC2. PMID- 29128668 TI - Inhibition of the complement system by saliva of Anopheles (Nyssorhynchus) aquasalis. AB - Anopheline mosquitoes are vectors of malaria parasites. Their saliva contains anti-hemostatic and immune-modulator molecules that favor blood feeding and parasite transmission. In this study, we describe the inhibition of the alternative pathway of the complement system (AP) by Anopheles aquasalis salivary gland extracts (SGE). According to our results, the inhibitor present in SGE acts on the initial step of the AP blocking deposition of C3b on the activation surfaces. Properdin, which is a positive regulatory molecule of the AP, binds to SGE. When SGE was treated with an excess of properdin, it was unable to inhibit the AP. Through SDS-PAGE analysis, A. aquasalis presented a salivary protein with the same molecular weight as recombinant complement inhibitors belonging to the SG7 family described in the saliva of other anopheline species. At least some SG7 proteins bind to properdin and are AP inhibitors. Searching for SG7 proteins in the A. aquasalis genome, we retrieved a salivary protein that shared an 85% identity with albicin, which is the salivary alternative pathway inhibitor from A. albimanus. This A. aquasalis sequence was also very similar (81% ID) to the SG7 protein from A. darlingi, which is also an AP inhibitor. Our results suggest that the salivary complement inhibitor from A. aquasalis is an SG7 protein that can inhibit the AP by binding to properdin and abrogating its stabilizing activity. Albicin, which is the SG7 from A. albimanus, can directly inhibit AP convertase. Given the high similarity of SG7 proteins, the SG7 from A. aquasalis may also directly inhibit AP convertase in the absence of properdin. PMID- 29128669 TI - Wip1 regulates blood-brain barrier function and neuro-inflammation induced by lipopolysaccharide via the sonic hedgehog signaling signaling pathway. AB - The blood brain barrier (BBB) is a diffusion barrier that maintains the brain environment. Wip1 is a nuclear phosphatase induced by many factors and involved in various stresses, tumorigenesis, organismal aging, and neurogenesis. Wip1's role in BBB integrity has not been thoroughly investigated. The purpose of the present study was to investigate the effect and mechanism of Wip1 on lipopolysaccharide (LPS)-induced BBB dysfunction and inflammation in an in vitro BBB model. The in vitro BBB model was established by co-culturing human brain microvascular endothelial cells and human astrocytes and then exposing them to 1MUg/ml LPS for 6, 12, 18, 24, and 48h. Wip1 expression was significantly elevated by LPS treatment. Knockdown of Wip1 aggravated the increased permeability and decreased transepithelial electrical resistance, protein expression of ZO-1, and occludin induced by LPS. Wip1 silencing augmented the elevated inflammatory cytokines TNF-alpha, IL-1beta, IL-12, and IL-6 of the BBB induced by LPS, whereas overexpression of Wip1 showed a contrary effect. Sonic hedgehog signaling (SHH) was activated by Wip1 overexpression and inhibited by Wip1 silencing. Additionally, activating or inhibiting the SHH pathway by purmorphamine or cyclopamine, respectively, abolished the Wip1-induced changes in transepithelial electrical resistance and permeability and inflammatory responses in the LPS-injured BBB model. Our results demonstrate that Wip1 may protect the BBB against LPS-induced integrity disruption and inflammatory response through the SHH signaling pathway. PMID- 29128670 TI - Synchronous immune alterations mirror clinical response during allergen immunotherapy. AB - BACKGROUND: Three years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS) trial demonstrated that 2 years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1 year after discontinuation. OBJECTIVE: We sought to examine in the GRASS trial the time course of immunologic changes during 2 years of sublingual and subcutaneous immunotherapy and for 1 year after treatment discontinuation. METHODS: We performed multimodal immunomonitoring to assess allergen-specific CD4 T-cell properties in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-facilitated allergen binding). RESULTS: All 3 of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years of allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunologic effect. Although frequencies of antigen-specific TH2 cells in peripheral blood determined by using HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE antibody-dependent functional assays remained inhibited in part 1 year after discontinuation. CONCLUSION: Two years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific TH2 cells most closely paralleled the transient clinical outcome, and it is likely that recurrence of the T-cell drivers of allergic immunity abrogated the potential for durable tolerance. On the other hand, the persistence of IgE blocking antibody 1 year after discontinuation might be an early indicator of a protolerogenic mechanism. PMID- 29128671 TI - Identification of dominant anti-glycan IgE responses in school children by glycan microarray. PMID- 29128672 TI - Long-term immune reconstitution after matched unrelated hematopoietic stem cell transplantation for immunodeficiency. PMID- 29128674 TI - Staged development of long-lived T-cell receptor alphabeta TH17 resident memory T cell population to Candida albicans after skin infection. AB - BACKGROUND: Candida albicans is a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (TRM) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and have been shown recently to have an immune system resembling that of neonatal human subjects. OBJECTIVE: We studied the evolution of the adaptive cutaneous immune response to Candida species. METHODS: We examined both human skin T cells and the de novo and memory immune responses in a mouse model of C albicans skin infection. RESULTS: In mice the initial IL-17-producing cells after C albicans infection were dermal gammadelta T cells, but by day 7, alphabeta TH17 effector T cells were predominant. By day 30, the majority of C albicans-reactive IL-17 producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days after infection. Between 30 and 90 days after infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. TRM cells rapidly clear an infectious challenge with C albicans more effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17-producing CD4+ TRM cells that responded to C albicans in an MHC class II-restricted fashion could be identified readily. CONCLUSIONS: These studies demonstrate that C albicans infection of skin preferentially generates CD4+ IL-17 producing TRM cells, which mediate durable protective immunity. PMID- 29128675 TI - Regionally variant collagen alignment correlates with viscoelastic properties of the disc of the human temporomandibular joint. AB - OBJECTIVE: To determine the regionally variant quality of collagen alignment in human TMJ discs and its statistical correlation with viscoelastic properties. DESIGN: For quantitative analysis of the quality of collagen alignment, horizontal sections of human TMJ discs with Pricrosirius Red staining were imaged under circularly polarized microscopy. Mean angle and angular deviation of collagen fibers in each region were analyzed using a well-established automated image-processing for angular gradient. Instantaneous and relaxation moduli of each disc region were measured under stress-relaxation test both in tensile and compression. Then Spearman correlation analysis was performed between the angular deviation and the moduli. To understand the effect of glycosaminoglycans on the correlation, TMJ disc samples were treated by chondroitinase ABC (C-ABC). RESULTS: Our imaging processing analysis showed the region-variant direction of collagen alignment, consistently with previous findings. Interestingly, the quality of collagen alignment, not only the directions, was significantly different in between the regions. The angular deviation of fiber alignment in the anterior and intermediate regions were significantly smaller than the posterior region. Medial and lateral regions showed significantly bigger angular deviation than all the other regions. The regionally variant angular deviation values showed statistically significant correlation with the tensile instantaneous modulus and the relaxation modulus, partially dependent on C-ABC treatment. CONCLUSION: Our findings suggest the region-variant degree of collagen fiber alignment is likely attributed to the heterogeneous viscoelastic properties of TMJ disc that may have significant implications in development of regenerative therapy for TMJ disc. PMID- 29128676 TI - How nature tunes isoenzyme activity in the multifunctional catalytic globin dehaloperoxidase from Amphitrite ornata. AB - The coelomic hemoglobin of Amphitrite ornata, termed dehaloperoxidase (DHP), is the first known multifunctional catalytic globin to possess biologically-relevant peroxidase and peroxygenase activities. Although the two isoenzymes of DHP, A and B, differ in sequence by only 5 amino acids out of 137 residues, DHP B consistently exhibits a greater activity than isoenzyme A. To delineate the contributions of each amino acid substitution to the activity of either isoenzyme, the substitutions of the five amino acids were systematically investigated, individually and in combination, using 22 mutants. Biochemical assays and mechanistic studies demonstrated that the mutants that only contained the I9L substitution showed increased i) kcat values (peroxidase activity), ii) 5 Br-indole conversion and binding affinity (peroxygenase activity), and iii) rate of Compound ES formation (enzyme activation). Whereas the X-ray structures of the oxyferrous forms of DHP B (L9I) (1.96A), DHP A (I9L) (1.20A), and WT DHP B (1.81A) showed no significant differences, UV-visible spectroscopy (ASoret/A380 ratio) revealed that the I9L substitution increased the 5-coordinate high-spin heme population characterized by the "open" conformation (i.e., distal histidine swung out of the pocket), which likely favors substrate binding. The positioning of the distal histidine closer to the heme cofactor in the solution state also appears to facilitate activation of DHP via the Compound ES intermediate. Taken together, the studies undertaken here shed light on the structure-function relationship in dehaloperoxidase, but also help to establish the foundation for understanding how enzymatic activity can be tuned in isoenzymes of a multifunctional catalytic globin. PMID- 29128677 TI - Macroeconomic conditions and opioid abuse. AB - We examine how deaths and emergency department (ED) visits related to use of opioid analgesics (opioids) and other drugs vary with macroeconomic conditions. As the county unemployment rate increases by one percentage point, the opioid death rate per 100,000 rises by 0.19 (3.6%) and the opioid overdose ED visit rate per 100,000 increases by 0.95 (7.0%). Macroeconomic shocks also increase the overall drug death rate, but this increase is driven by rising opioid deaths. Our findings hold when performing a state-level analysis, rather than county-level; are primarily driven by adverse events among whites; and are stable across time periods. PMID- 29128678 TI - Efficient operator splitting algorithm for joint sparsity-regularized SPIRiT based parallel MR imaging reconstruction. AB - Self-consistent parallel imaging (SPIRiT) is an auto-calibrating model for the reconstruction of parallel magnetic resonance imaging, which can be formulated as a regularized SPIRiT problem. The Projection Over Convex Sets (POCS) method was used to solve the formulated regularized SPIRiT problem. However, the quality of the reconstructed image still needs to be improved. Though methods such as NonLinear Conjugate Gradients (NLCG) can achieve higher spatial resolution, these methods always demand very complex computation and converge slowly. In this paper, we propose a new algorithm to solve the formulated Cartesian SPIRiT problem with the JTV and JL1 regularization terms. The proposed algorithm uses the operator splitting (OS) technique to decompose the problem into a gradient problem and a denoising problem with two regularization terms, which is solved by our proposed split Bregman based denoising algorithm, and adopts the Barzilai and Borwein method to update step size. Simulation experiments on two in vivo data sets demonstrate that the proposed algorithm is 1.3 times faster than ADMM for datasets with 8 channels. Especially, our proposal is 2 times faster than ADMM for the dataset with 32 channels. PMID- 29128673 TI - Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation. AB - BACKGROUND: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. OBJECTIVE: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. METHODS: Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. RESULTS: Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. CONCLUSIONS: This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation. PMID- 29128679 TI - Early-onset epileptic encephalopathy with de novo SCN8A mutation. AB - Early-onset epileptic encephalopathies (EOEEs) are clinically and genetically heterogeneous disorders characterized by intractable seizures and unremitting interictal paroxysmal epileptiform activity. Consequently, these syndromes impair neurodevelopment during the first year of life. Currently, the etiology of these disorders is largely unknown. In this study, Childhood-Onset Epilepsy Gene Panel Testing (containing 511 epilepsy-related genes) was performed in a parent offspring trio. In this family, the son had refractory seizures, intellectual disability, and motor abnormalities, and he was diagnosed with EOEE. The boy later died from a sudden unexpected death in epilepsy (SUDEP) at the age of 26 months. In this case, we identified a de novo mutation (c.4423G > A; glycine [Gly]1475 arginine [Arg]) classified as heterozygous missense located in the inactivation gate section of the SCN8A (voltage-gated sodium-channel type VIII alpha subunit) gene. This result strengthens the association between the SCN8A gene and EOEE, and more attention should be given to its high rate of SUDEP. Further studies to determine the pathogenic mechanisms of SCN8A mutations should be warranted at the inactivation gate section of this sodium channel in both neurons and cardiac muscles. PMID- 29128680 TI - Effects of roughness and permeability on solute transfer at the sediment water interface. AB - Understanding the mechanisms of solute transfer across the sediment-water interface plays a crucial role in water quality prediction and management. In this study, different arranged particles are used to form typical rough and permeable beds. Large Eddy Simulation (LES) is used to model the solute transfer from the overlying water to sediment beds. Three rough wall turbulence regimes, i.e., smooth, transitional and rough regime, are separately considered and the effects of bed roughness on solute transfer are quantitatively analyzed. Results show that the classic laws related to Schmidt numbers can well reflect the solute transfer under the smooth regime with small roughness Reynolds numbers. Under the transitional regime, the solute transfer coefficient (KL+) is enhanced and the effect of Schmidt number is weakened by increasing roughness Reynolds number. Under the rough regime, the solute transfer is suppressed by the transition layer (Brinkman layer) and controlled by the bed permeability. Moreover, it is found that water depth, friction velocity and bed permeability can be used to estimate the solute transfer velocity (KL) under the completely rough regime. PMID- 29128682 TI - Randomized double-masked trial of eyelid cleansing treatments for blepharitis. AB - PURPOSE: To compare the efficacy of a dedicated eyelid cleanser and diluted baby shampoo in the management of blepharitis. METHODS: Forty-three participants with clinical blepharitis signs were enrolled in a prospective, randomized, double masked, paired-eye trial. A dedicated eyelid cleanser (TheraTears(r) SteriLid(r)) was applied to the eyelids of one eye (randomized) and diluted baby shampoo (Johnson's(r) No More Tears(r)) to the fellow eye, twice daily for 4 weeks. Tear film parameters, ocular surface characteristics, symptomology and cytology markers were assessed at baseline and day 28. RESULTS: Baseline measurements did not differ between treatments (all p > 0.05). The eyelid cleanser was preferred over baby shampoo by the majority of participants (p < 0.001). Improvements in the tear lipid layer, inferior lid wiper epitheliopathy (LWE), cylindrical collarettes, and MMP-9 expression were limited to the dedicated eyelid cleanser (all p < 0.05), and a greater decrease in SANDE symptoms score was also observed (p = 0.04). Meibomian gland capping and MUC5AC expression worsened with baby shampoo treatment (both p < 0.05). SPEED symptoms score, superior LWE, seborrhoeic lash crusting, and trichiasis decreased significantly following application of both treatments (all p < 0.05), but did not differ between treatments (all p > 0.05). CONCLUSION: Clinical improvements in blepharitis occurred with both treatments. However, only the dedicated eyelid cleanser proved effective in reducing ocular surface inflammation, and was the preferred therapy. Long term impact of decreased goblet cell function secondary to baby shampoo treatment requires further exploration. PMID- 29128681 TI - Physicochemical transformation of Fe/Ni bimetallic nanoparticles during aging in simulated groundwater and the consequent effect on contaminant removal. AB - To assess the fate and long-term reactivity of bimetallic nanoparticles used in groundwater remediation, it is important to trace the physicochemical transformation of nanoparticles during aging in water. This study investigated the short-term (within 5 d) and long-term (up to 90 d) aging process of Fe/Ni bimetallic nanoparticles (Fe/Ni BNPs) in simulated groundwater and the consequent effect on the particle reactivity. Results indicate that the morphological, compositional and structural transformation of Fe/Ni BNPs happened during the aging. In the 5-d short-term aging, Fe0 corrosion occurred rapidly and was transformed to ferrous ions which were adsorbed onto the surface of Fe/Ni BNPs, accompanied by the elevation of solution pH and the negative redox potential. In the long-term aging, scanning electron microscopy (SEM) images show that the particles transformed from spherical to rod-like and further to sheet-like and needle-like. X-ray diffraction (XRD) analysis reveals that the main aging product was magnetite (Fe3O4) and/or maghemite (gamma-Fe2O3) after aging for 60-90 d. Energy dispersive spectrometer (EDS) analysis demonstrates that the mass ratio of Fe/Ni increased with aging, revealing that Ni were possibly gradually entrapped and covered by the iron oxides. Besides, the release of Ni into solution was also detected during the aging. The reactivity of the aged Fe/Ni BNPs was examined by studying its performance in tetracycline (TC) removal. The aged Fe/Ni BNPs within 2 d kept similar removal efficiency of TC as the fresh particles. However, the removal efficiency of TC by Fe/Ni BNPs aged for 5-15 d dropped by 20-50% due to aggregation and oxidation of particles, and the removal efficiency further decreased slowly with the prolongation of aging time up to 90 d. This reveals that Fe/Ni BNPs were vulnerable to passivation in water environments. PMID- 29128683 TI - DIY: "Do Imaging Yourself" - Conventional microscopes as powerful tools for in vivo investigation. AB - Intravital imaging has been increasingly employed in cell biology studies and it is becoming one of the most powerful tools for in vivo investigation. Although some protocols can be extremely complex, most intravital imaging procedures can be performed using basic surgery and animal maintenance techniques. More importantly, regular confocal microscopes - the same that are used for imaging immunofluorescence slides - can also acquire high quality intravital images and movies after minor adaptations. Here we propose minimal adaptations in stock microscopes that allow major improvements in different fields of scientific investigation. PMID- 29128684 TI - MAPK p38 regulates inflammatory gene expression via tristetraprolin: Doing good by stealth. AB - Tristetraprolin (TTP) is an RNA-destabilizing protein that exerts profound anti inflammatory effects by inhibiting the expression of tumour necrosis factor and many other inflammatory mediators. The mitogen-activated protein kinase (MAPK) p38 signaling pathway controls the strength and duration of inflammatory responses by regulating both the expression and function of TTP. The kinase MK2 (MAPK activated kinase 2) is activated by MAPK p38, and in turn phosphorylates TTP at two critical serine residues. One consequence of these phosphorylations is the protection of TTP from proteasome-mediated degradation. Another consequence is the loss of mRNA destabilizing activity. The control of TTP expression and function by the MAPK p38 pathway provides an elegant mechanism for coupling the on and off phases of inflammatory responses, and dictating the precise kinetics of expression of individual inflammatory mediators. PMID- 29128685 TI - Unravelling positive aspects of caregiving in dementia: An integrative review of research literature. AB - BACKGROUND: Family caregiving is the crucial informal care resource to lessen the burdens associated with dementia. Research in this field has focused on reducing the caregiver's burden, but little attention has been given to promoting the positive aspects of caregiving. OBJECTIVES: To conduct a systematic critical review of research on the nature of positive aspects of caregiving, and the factors predicting this phenomenon among family caregivers of dementia patients, with the ultimate purpose of gaining insights to explain how and why it emerges. REVIEW METHODS: A systematic search of the literature was undertaken in the databases OvidMedline, CINAHL, PsycINFO, Web of Science and Scopus, using the keywords 'care* AND Alzheimer OR dementia AND 'positive aspect' OR 'positive experience' OR 'positive perceptions' OR reward OR gain OR 'satisfaction with care*' OR 'care* satisfaction' OR benefit OR uplift OR meaning OR enjoyment OR pleasure OR growth OR hope OR gratification. The Critical Appraisal Skills Programme checklists for qualitative and cohort studies were used to evaluate data quality. Narrative data synthesis was undertaken using the five-stage Whittermore and Knafl method. RESULTS: A total of 3862 articles were identified, of which 41 were included in this review. The key findings are that positive aspects of caregiving among family caregivers of dementia patients form a multi dimensional construct which covers four key domains: a sense of personal accomplishment and gratification, feelings of mutuality in a dyadic relationship, an increase of family cohesion and functionality, and a sense of personal growth and purpose in life. By integrating the findings about the nature and conditions predicting positive aspects of caregiving, the presence of three conditions was identified as promoting the emergence of such qualities i) personal and social affirmation of role fulfilment, ii) effective cognitive emotional regulation and iii) contexts which favour finding meaning in the caregiving process. CONCLUSION: The findings of this review provide insight into catalysing the paradigm shift from 'reducing stress' to 'optimising positive experience' in developing caregiving support services for dementia, and may guide future empirical study to explain this unique dimension of caregiving experience. PMID- 29128686 TI - When is audit and feedback effective in dementia care? A systematic review. AB - BACKGROUND: Evidence-based care for people with dementia is a priority for patients, carers and clinicians and a policy priority. There is evidence that people with dementia do not always receive such care. Audit and feedback, also known as clinical audit, is an extensively-used intervention to improve care. However, there is uncertainty about the best way to use it. OBJECTIVES: To investigate whether audit and feedback is effective for improving health professionals' care of people with dementia. To investigate whether the content and delivery of audit and feedback affects its effectiveness in the context of health professionals' care for people with dementia. DESIGN: Systematic review DATA SOURCES: The Cochrane Central Register of Controlled Trials, Prospero, Medline (1946-December week 1 2016), PsycInfo (1967-January 2017), Cinahl (1982 January 2017), HMIC (1979-January 2017), Embase (1974-2017 week 1) databases and the Science Citation Index and Social Science Citation Index were searched combining terms for audit and feedback, health personnel, and dementia. REVIEW METHODS: Following screening, the data were extracted using the Template for Intervention Description and Replication (TIDieR), and synthesised graphically using harvest plots and narratively. RESULTS: Thirteen studies met the inclusion criteria. Published studies of audit and feedback in dementia rarely described more than one cycle. None of the included studies had a comparison group: 12 were before and after designs and one was an interrupted time series without a comparison group. The median absolute improvement was greater than in studies beyond dementia which have used stronger designs with fewer risks of bias. Included studies demonstrated large variation in the effectiveness of audit and feedback. CONCLUSIONS: Whilst methodological and reporting limitations in the included studies hinder the ability to draw strong conclusions on the effectiveness of audit and feedback in dementia care, the large interquartile range indicates further work is needed to understand the factors which affect the effectiveness of this much-used intervention. PMID- 29128687 TI - Translational Mobilisation Theory: A new paradigm for understanding the organisational elements of nursing work. AB - Translational Mobilisation Theory (TMT) is a generic sociological theory that explains how emergent projects of collective action are progressed in complex organisational contexts. Grounded in a substantial programme of research on healthcare work, it has value for understanding the organisational component of the nursing role for educational, practice and research purposes. This paper introduces Translational Mobilisation Theory, outlines its core components, and considers its application to nursing using ethnographic research on the organising work of nurses as an empirical reference. Organising work is a neglected element of the nursing function and lacks theoretical foundations. As the complexity and intensity of healthcare continues to accelerate this is an important gap in existing frameworks of understanding. PMID- 29128688 TI - Classification and analysis of the natural corner curving motion of humans based on gait motion. AB - The curving motion of the human body is more complex than gait motion for straight walking. In particular, when human can freely curve corners, the gait motion varies among and even within individuals. However, is it not possible to classify natural curving motion using a statistical method? This study investigates the natural curving motion, encompassing various walking paths selected by subjects, as opposed to previous studies that focused on specific stepping strategies or curving motion under precisely controlled conditions. As a result, the natural curving motions are statistically classified into five distinct groups based on certain motion indices. Each group represents a curving strategy and is mainly characterized by the inner inclination of the pelvis, outer rotation of hip joints at the time of heel contact of the inner leg, and inner and/or outer rotation of hip joints at the time of heel contact of the outer leg. Such strategies are speculated as typical motions within the large variation in natural curving motion. Another finding is that, unlike the joint pattern of lower limb joints in the sagittal plane, hip rotation and the abduction/adduction angle drastically change when curving. In particular, the large inner rotation and abduction angles of the hip joint of both legs, which reached approximately 30 degrees and 10 degrees , respectively, become important when considering the curving gait of a physical assistant robot. Our analysis and findings help specify the joint motion required for physical assistant robots. PMID- 29128689 TI - Simulating the mesoscale transport of krypton-85. AB - Due to its half-life, chemical inertness and low solubility in water, radioactive 85Kr is a valuable tracer for testing the performance of atmospheric dispersion models in simulating long-range transport of pollutants. This paper evaluates the capability of simulating the dispersion of radiokrypton emitted by a nuclear fuel reprocessing plant in north-west France. Three time periods during which elevated activity concentrations of 85Kr in ground level air were detected in south-west Germany are chosen. Simulations have been performed using the HYSPLIT code and the European Centre for Median-Range Weather Forecasts (ECMWF) data base. Although their results show a slight trend of underestimating the measured 85Kr concentrations, there is a significant correlation and moderate scatter between observations and simulations with about 50% of the results being within a factor of two of the measured concentrations. The simulated travel time distributions provided a valuable tool for providing additional insight into the dispersion of the tracer radionuclides and for identifying potential causes of deviations between measured and calculated concentrations. PMID- 29128690 TI - Transcriptome-based biological dosimetry of gamma radiation in Arabidopsis using DNA damage response genes. AB - Plants are used as representative reference biota for the biological assessment of environmental risks such as ionizing radiation due to their immobility. This study proposed a faster, more economical, and more effective method than conventional cytogenetic methods for the biological dosimetry of ionizing radiation in plants (phytodosimetry). We compared various dose-response curves for the radiation-induced DNA damage response (DDR) in Arabidopsis thaliana after relatively "low-dose" gamma irradiation (3, 6, 12, 24, and 48 Gy) below tens of Gy using comet (or single-cell gel electrophoresis), gamma-H2AX, and transcriptomic assays of seven DDR genes (AGO2, BRCA1, GRG, PARP1, RAD17, RAD51, and RPA1E) using quantitative real time PCR. The DDR signal from the comet assay was saturated at 6 Gy, while the gamma-H2AX signal increased up to 48 Gy, following a linear-quadratic dose-response model. The transcriptional changes in the seven DDR genes were fitted to linear or supra-linear quadratic equations with significant dose-dependency. The dose-dependent transcriptional changes were maintained similarly until 24 h after irradiation. The integrated transcriptional dose-response model of AGO2, BRCA1, GRG, and PARP1 was very similar to that of gamma-H2AX, while the transcriptional changes in the BRCA1, GRG, and PARP1 DDR genes revealed significant dependency on the dose-rate, ecotype, and radiation dose. These results suggest that the transcriptome-based dose-response model fitted to a quadratic equation could be used practically for phytodosimetry instead of conventional cytogenetic models, such as the comet and gamma-H2AX assays. The effects of dose-rate and ecotype on the transcriptional changes of DDR genes should also be considered to improve the transcriptome-based phytodosimetry model. PMID- 29128691 TI - Type I interferon-mediated autoinflammation and autoimmunity. AB - The monogenic type I interferonopathies comprise a heterogenous group of disorders of the innate immune system associated with constitutive activation of antiviral type I interferon (IFN). Despite a remarkable phenotypic diversity, type I interferonopathies are commonly characterized by autoinflammation and varying degrees of autoimmunity or immunodeficiency. The elucidation of the underlying genetic causes has revealed novel cell-intrinsic mechanisms that protect the organism against inappropriate immune recognition of self nucleic acids by cytosolic sensors such as cGAS or MDA5 through metabolizing or processing of intracellular DNA or RNA. What emerges from these findings is a more integrated picture of the different modes by which unabated type I IFN causes autoinflammation or drives autoimmunity. PMID- 29128693 TI - Effect of adding support structures for overhanging part on fatigue strength in selective laser melting. AB - Selective laser melting (SLM) technology was recently introduced to fabricate dental prostheses. However, the fatigue strength of clasps in removable partial dentures prepared by SLM still requires improvement. In this study, we attempted to improve the fatigue strength of clasps by adding support structures for overhanging parts, which can generally be manufactured at an angle to be self supporting. The results show that the fatigue strength of the supported specimens was more than twice that of unsupported specimens. Electron back-scattered diffraction analysis revealed that the supported specimens exhibited lower kernel average misorientation values than the unsupported specimens, which suggested that the support structure reduced the residual strain during the SLM process and helped to prevent micro-cracks led by thermal distortion. In addition, the supported specimens cooled more rapidly, thereby forming a finer grain size compared to that of the unsupported specimens, which contributed to improving the fatigue strength. The results of this study suggest that the fatigue strength of overhanging parts can be improved by intentionally adding support structures. PMID- 29128692 TI - COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss. AB - BACKGROUND: Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. METHODS: A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. RESULTS: Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. CONCLUSIONS: Aspirin did not protect from cisplatin related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here. PMID- 29128694 TI - Poly(L-lactide) nanocomposites containing poly(D-lactide) grafted nanohydroxyapatite with improved interfacial adhesion via stereocomplexation. AB - Biodegradable organic-inorganic composites composed of polylactide (PLA) and hydroxyapatite (HA) are important bone repairing materials, while the dispersibility of nanoscaled HA in PLA and the interfacial adhesion between HA and PLA remained unsatisfactory. In this study, poly(D-lactide) (PDLA) oligomers with different molecular weights were grafted onto HA nanorods (HA-PDLA), and the HA-PDLA hybrids were mixed with poly(L-lactide) (PLLA). Dispersibility of HA-PDLA hybrids in PLLA matrix was investigated, and the formation of PDLA/PLLA stereocomplex at the interface of HA-PDLA and PLLA was studied by characterizations including crystallization, mechanical and thermal properties, taking PLLA grafted HA (HA-PLLA) and unmodified HA as comparisons. Surface grafting of PLLA or PDLA oligomers both significantly improved the dispersibility of HA nanorods in PLLA matrix. Benefiting from PDLA/PLLA stereocomplexation, HA PDLA could increase the tensile strength and the elongation of resulting PLLA/HA nanocomposites more significantly than HA-PLLA. The interfacial interaction between HA-PDLA and PLLA matrix could be further strengthened by increasing the molecular weights of those grafted PDLA chains on HA, which was verified by changes in crystallization and glass transition behaviors. To sum up, the concept of using PDLA/PLLA stereocomplexation was feasible and effective in preparing PLA based organic-inorganic nanocomposites targeting bone repairing. PMID- 29128696 TI - Concise synthesis of 2,7-anhydrosialic acid derivatives and its application. AB - In N-acetylneuraminic acid, apart from O9 and O8, a possible glycosylation site is the O4 position. For example, gangliosides HLG-2 and HPG-7 are considered to be potential lead compounds for carbohydrate-based drug development to treat neural disorders. However, the construction of their alpha(1 -> 4) fucosyl sialic acid and alpha(2 -> 4) linkages between sialic acids is difficult because of the regioselectivity problem. Herein, N-acetyl-2,7-anhydroneuraminic acid was synthesized in three steps from Neu5Ac methyl ester through per-O trimethylsilylation, heating-assisted intramolecular anomeric protection (iMAP) and desilylation. The iMAP simultaneously circumvents both the 2- and 7-OH protection. Upon protecting the 8- and 9-OH groups as a benzylidene acetal, only 4-OH is free for glycosylation. These 2,7-anhydro-8,9-O-benzylidenesialic acid derivatives were examined as acceptor for an alpha-selective fucosylation to construct the glycosidic linkage of fucosyl alpha(1 -> 4) 2,7-anhydroneuraminic acid. PMID- 29128695 TI - Insights from structures of cancer-relevant pre-mRNA splicing factors. AB - Pre-mRNA splicing factors recognize consensus signals within preliminary transcripts, and as cogs of the spliceosome machine, orchestrate the excision and rejoining of pre-mRNA regions for gene expression. Large-scale sequencing has demonstrated that mutations in key genes encoding pre-mRNA splicing factors are common among myeloid neoplasms and also occur in a variety of other cancers. This revelation offers new therapeutic opportunities to target pre-mRNA splicing vulnerabilities in hematologic and other malignancies. The mutated residues typically alter 3' splice site choice for a subset of transcripts. In this review, we highlight mechanistic insights from recent 3D structures that reveal the affected residues poised for pre-mRNA recognition. PMID- 29128697 TI - Comparison of pregnancy outcomes using either an Ovsynch or a Cosynch protocol for the first timed AI with liquid or frozen semen in lactating dairy cows. AB - The objective of this study was to evaluate fertility to the first timed AI (TAI) using either liquid semen or frozen semen after an Ovsynch or a Cosynch protocol in lactating dairy cows. The hypothesis was that there is an increase in fertility to the first TAI when cows are inseminated with liquid semen compared to that when frozen semen is used in a Cosynch protocol. Lactating dairy cows (n = 1724; 540 primiparous, 1184 multiparous) from 9 commercial dairy farms were enrolled on a weekly basis to facilitate first timed AI. Two experiments were conducted. In experiment 1, all cows received GnRH, 7 d later PGF2alpha, and then received one of the following treatments: 1) GnRH + TAI with liquid semen 56 h after PGF2alpha; 2) GnRH + TAI with frozen semen 56 h after PGF2alpha; 3) GnRH 56 h after PGF2alpha + TAI with liquid semen 12-16 h after the second GnRH; 4) GnRH 56 h after PGF2alpha + TAI with frozen semen 12-16 h after the second GnRH. In experiment 2, all cows received GnRH, 7 d later PGF2alpha, and then received treatments 3 or 4 as described for experiment 1. Number of sperm per straw was 20 * 106 sperm/straw and 10 * 106 sperm/straw for frozen and liquid semen, respectively. Pregnancy diagnosis was performed by ultrasound scanning at 39 d after TAI. In experiment 1 (n = 1263), there was an interaction of semen preservation method by TAI protocol. Cows inseminated with liquid semen concurrently with the second GnRH (Cosynch-56) achieved greater pregnancy per AI (P/AI) than cows inseminated with frozen semen using the same synchronization protocol (20.0% vs. 27.5%; P = 0.032). There was no effect of semen preservation method (liquid semen 32.3% vs. frozen semen 28.6%; P = 0.330) when cows were inseminated approximately 16 h after the second GnRH injection (Ovsynch-56). Parity affected P/AI with primiparous having a greater P/AI than multiparous cows (34.8% vs. 20.2%; P = 0.001). In experiment 2 (n = 377), there was no effect of semen preservation method (liquid semen 26.5% vs. frozen semen 25.5%; P = 0.846) when cows were inseminated approximately 16 h after the second GnRH injection (Ovsynch-56). Parity affected P/AI with primiparous having a greater P/AI than multiparous cows (37.0% vs. 17.3%; P = 0.001). The results of this study provide evidence that liquid semen achieved greater P/AI in a TAI protocol with a long time interval between insemination and ovulation (Cosynch-56) compared with frozen semen indicating that liquid semen might have a longer viability in the reproductive tract. PMID- 29128698 TI - Seminal plasma antioxidants are directly involved in boar sperm cryotolerance. AB - Boar ejaculates are ejected in fractions with a specific composition in terms of sperm numbers and seminal plasma (SP), which is reflected in the varying sperm cryotolerance observed among different fractions. As boar sperm are particularly sensitive to oxidative stress, this study evaluated the role of SP antioxidants in the observed differences in sperm cryotolerance among ejaculate fractions. Ten ejaculates from five boars were manually collected in fractions: the first 10 mL of the sperm-rich fraction (SRF), the rest of the SRF and the post-SRF. Semen samples comprising the entire ejaculate (EE) were created by proportionally mixing the three fractions described above. Each of the 40 resulting semen samples was split into two aliquots: one was used for sperm cryopreservation following a standard protocol utilizing 0.5-mL straws, and the other was used to collect SP for antioxidant assessment. Frozen-thawed (FT) sperm from the SRF (the first 10 mL of the SRF and the rest of the SRF) and those from post-SRF were of the highest and worst quality, respectively, which was measured in terms of total and objective progressive motility and viability (P < 0.01). Viable FT sperm from the post-SRF generated more reactive oxygen species and experienced more lipid peroxidation than those from the SRF (both the first 10 mL and the rest of the SRF) (P < 0.01). The percentage of FT sperm exhibiting fragmented nuclear DNA did not differ among ejaculate fractions and the EE. Catalase, glutathione peroxidase and glutathione peroxidase 5 (GPx-5) were lowest in SP from the first 10 mL of the SRF (P < 0.001), whereas superoxide dismutase (SOD) and paraoxonase 1 (PON-1) were highest in SP of the SRF (both the first 10 mL and the rest of the SRF) (P < 0.01). Trolox-equivalent antioxidant capacity (TEAC) and the ferric-reducing ability of plasma (FRAP) were highest in SP from the first 10 mL of the SRF and lowest in the post-SRF (P < 0.001), whereas cupric-reducing antioxidant capacity was lowest (P < 0.05) in SP from the first 10 mL of the SRF. Regression analyses indicated that certain SP antioxidants had good predictive value for post-thaw recovery rates of total motility (R2 = 54.8%, P < 0.001; including SOD, TEAC and FRAP) and viability (R2 = 56.1%, P < 0.001; including SOD, PON-1, GPx-5 and TEAC). These results demonstrated that certain SP antioxidants are positively involved in boar sperm cryotolerance, minimizing the oxidative stress imposed by cryogenic handling. PMID- 29128699 TI - Feasibility of semen collection in red-winged tinamou (Rhynchotus rufescens) by manual stimulation and sazonality implications. AB - This study aimed to report in detail, the technique and challenges of cloacal massage, to collect and evaluate semen from red-winged tinamou (Rhynchotus rufescens) keep in captivity, performed by only one technician. Sixty-four semen collection attempts, from 16 adult males, during breeding season and 16 attempts form these same 16 males in non-breeding season, were performed. Prior to collection, all animals were conditioned to cloacal massage for 6 weeks and the ejaculates were succeed with viable spermatozoa and then, evaluated for feces, urine and mucus contamination, volume, concentration, sperm vigor, motility, morphological defects and acrosome integrity. Semen collection success rate was 63% in breeding season and 2 (5%) samples were discarded by grade 5 contamination. Only 3 ejaculates from 16 tinamou were obtained in non-breeding season. Sperm concentration and acrosome integrity was higher (p = 0.00) in breeding season, and the percentage of total sperm morphological defects, were high in both in breeding and out breeding season. Overall, we concluded that the red-winged tinamou breeding season, is linked to photoperiod (spring and summer), and at this period time, semen can be obtained by cloacal massage collection satisfactorily, allowing its use in reproduction biotechnologies and sperm cryopreservation. PMID- 29128700 TI - Long term maintenance of frozen mouse spermatozoa at -80 degrees C. AB - Maintaining mouse stocks as frozen materials offers both ethical and economical advantages over live animal breeding if the lines are not actively used. The European Mouse Mutant Archive (EMMA) promotes the archiving and distribution of important mouse models for biomedical research through the cryopreservation of their embryos and gametes. Embryo freezing in liquid nitrogen (LN2) at -196 degrees C has traditionally been the method of choice for archiving mouse lines. However, sperm freezing is emerging as a more convenient alternative due to the application of innovative cryopreservation and recovery protocols. In addition, frozen spermatozoa are less sensitive to post-freezing temperature fluctuations. We have previously reported that spermatozoa frozen using standard laboratory protocols can be safely stored in a -80 degrees C freezer or in dry ice (-79 degrees C) for at least seven days. We now report the extension of this period of maintenance at -80 degrees C up to two 2 years both for wild type and mutant strains, indicating that once frozen, mouse spermatozoa are quite resistant and can be transported, shared and stored at -80 degrees C for a long time without a significant loss of viability. The importance of this finding will be especially relevant for small laboratories with no constant access to liquid nitrogen and for labs generating many mouse mutant lines by CRISPR/Cas9 who do not want to saturate the limited space of a LN2 tank, using a more accessible -80 degrees C freezer. PMID- 29128701 TI - Quality evaluation of sperm from livebearing fishes: Standardized assessment of sperm bundles (spermatozeugmata) from Xenotoca eiseni (Goodeidae). AB - Standardized evaluation of sperm quality is essential for research, commercial scale cryopreservation, and induced spawning. However, standardized methods for evaluation of sperm bundles (spermatozeugmata or spermatophores) have not been established. The purpose of the present study was to use Redtail Splitfin (Xenotoca eiseni) as a model for freshwater livebearing fishes to establish initial standardized methods to collect sperm bundles, and quantitatively and qualitatively evaluate quality-related attributes. No sperm or sperm bundles were able to be collected by stripping. Testes were removed, rinsed, weighed, placed in 50 MUL of buffer solution on a glass slide, and crushed gently 3-5 times with angled spade-tip forceps. Sperm bundles were released into the buffer solution and collected with a pipette into 1.5-mL centrifuge tubes. To quantify size and shape, images of bundles were captured with a CCD camera connected to a microscope, and measured with computer software. There was no significant correlation between body wet weight and major bundle axis length (P = 0.6759), minor axis length (P = 0.5658), average axis length (P = 0.5869), aspect ratio (P = 0.7839), and observed area (P = 0.5727). The concentrations of sperm bundles, estimated with the three methods (Makler(r) counting chamber, a hemocytometer, and direct counting) were significantly different (P < 0.0001). Hemocytometers were suitable for estimation of bundles from X. eiseni. To evaluate activation of sperm, bundles were viewed with a microscope, and classified into one of five phases by evaluating morphology of the bundles and motion of sperm within the bundles as Phase 0 through Phase 4 that represented early through late activation stages. The frequencies and duration of each activation phase were used to evaluate dissociation of sperm bundles and motility capability of sperm within the bundles. Within 180 min of activation, all five phases were observed. Overall, this study for the first time established standardized methods to collect and evaluate quality-related attributes of sperm bundles. These standardized evaluations provide a basis for further modification, standardization, and generalization, which are useful in research on livebearing fishes involving male gametes, such as studies on cryopreservation, artificial insemination, and in development of germplasm repositories for imperiled species including goodeids. PMID- 29128702 TI - Effects of preovulatory follicle size on estradiol concentrations, corpus luteum diameter, progesterone concentrations and subsequent pregnancy rate in buffalo cows (Bubalus bubalis). AB - The present study was undertaken to investigate the effects of preovulatory follicle (POF) size on estradiol concentrations, luteal profile (CL diameter and progesterone concentration) and subsequent pregnancy rate in Murrah buffalo cows. The buffalo cows (n = 49) were synchronized for estrus by two doses of PGF2alpha given 11 days apart. The buffalo cows were inseminated during standing estrus and again after 24 h. Ovaries were scanned at estrus and 24 h intervals until ovulation, thereafter on days 5, 12 and 16 post-ovulation to examine the POF and CL diameter. Size of POF at estrus was divided into three categories; I: 10 to <=12; II: >12.0 to <=14.0; III: >14.0-16.0 mm. Blood samples were collected for estradiol (on day of estrus) and progesterone concentration (on days 5, 12 and 16). The estradiol concentrations were greater (P < 0.05) in category II than category I with the greatest (P < 0.05) concentrations estimated in category III. A positive correlation (P < 0.05) between POF and progesterone concentration, CL diameter and progesterone concentration was observed on all sampling day. Pregnant buffalo cows exhibited greater (P < 0.05) plasma progesterone as compared with their non-pregnant counterpart. Greater pregnancy rates were observed with an increased size of POF (chi2 = 2.9, P > 0.05). It was concluded that the POFs having diameters between 12 and 16 mm are mature enough to be transformed into CL of such optimum diameter and can secrete optimum progesterone concentrations that can sustain the pregnancy in Murrah buffalo cows. PMID- 29128703 TI - New results on global exponential dissipativity analysis of memristive inertial neural networks with distributed time-varying delays. AB - This paper is concerned with the global exponential dissipativity of memristive inertial neural networks with discrete and distributed time-varying delays. By constructing appropriate Lyapunov-Krasovskii functionals, some new sufficient conditions ensuring global exponential dissipativity of memristive inertial neural networks are derived. Moreover, the globally exponential attractive sets and positive invariant sets are also presented here. In addition, the new proposed results here complement and extend the earlier publications on conventional or memristive neural network dynamical systems. Finally, numerical simulations are given to illustrate the effectiveness of obtained results. PMID- 29128704 TI - Tandem mass spectrometry of fucoidan-derived fragments, labeled with heavy oxygen. AB - A procedure for the partial depolymerization of sulfated fucans and selective labeling with 18O was developed. A tandem electrospray ionization mass spectrometry (ESI MS/MS) was applied for the direct analysis of mixtures of structurally-different oligosaccharides, derived from the fucoidans of known structure. The presence of label allowed unambiguous distinguishing between the fragment ions of 0,2X0-type at m/z 287 and 2,4A-type at m/z 285, since 18O at the reducing end gave +2 mass shifting. Thus, ESI MS/MS was able to detect (1,2)-type of linkage in disaccharides from the fucoidan of brown alga S. cichorioides for the first time. It was also discovered that 2,4A-type fragments in 4-linked disaccharides that were incorrectly assigned to 0,2X-type previously, suggested, probably, substitution at C-4 in mono- and disaccharide fragments, derived from the fucoidan of the brown alga F. evanescens. PMID- 29128705 TI - 1,3-Di-n-butylimidazolium tribromide [BBim]Br3: An efficient recyclable catalyst mediated synthesis of N-substituted azepines and their biological evaluation interaction study with human serum albumin. AB - A majority of previously reported methods suffer from insufficient yields as well as more complicated experimental procedures, a smaller amount of isolated yields involving time-consuming and tiresome work-up with the use of metal catalyst and restricted scope of substrates. To overcome these issues, an environmentally benign, ionic liquid endorsed multi-component protocol to N-substituted azepines has been exploited by means of coupling aromatic amines, dimethyl/diethyl acetylene dicarboxylate, 2,5-dimethoxytetrahydrofuran using 1,3-Di-n butylimidazolium tribromide [BBim]Br3. The catalyst can be recycled and reused for subsequent reactions. The reactivated ionic liquid could be further reused twice as an accelerator All the synthesized compounds were further screened for their antimicrobial properties against three gram positive, four gram negative, and five fungal strains with chloromycin, norflaxacin, and fluconazole as reference drugs. Most of the tested compounds presented significant potency, especially, compound 4e displayed significant antibacterial activity (MIC=1 16MUg/mL) whereas compound 4k showed momentous antifungal efficacy (MIC=2 32MUg/mL). In addition binding behavior of compound 4e was investigated by binding study between calf thymus DNA and compound 4e by UV-Visible absorption spectroscopy and further research about HSA interactions were carried out. The observed wavelength showed a constancy thus revealing the occurrence of non covalent pi-pi stacking interactions of compound 4e and HSA. PMID- 29128706 TI - Consumption of ellagic acid and dihydromyricetin synergistically protects against UV-B induced photoaging, possibly by activating both TGF-beta1 and wnt signaling pathways. AB - Ellagic acid (EGA) and dihydromyricetin (DHM) are both found in fruits and vegetables are used for anti-aging treatment for the skin. The anti-photoaging efficacy of EGA and DHM was investigated in UV-B irradiated skin in vivo and the involvement of transforming growth factor (TGF)-beta1 and wnt signaling pathways were examined in vitro. HaCaT cells were treated with either 50MUM EGA, 50MUM DHM or 25MUM EGA+25MUM DHM before 100mJ/cm2 UV-B exposure, and then oxidative stress and inflammation was measured. The involvement of TGF-beta1 and wnt signaling was measured using their inhibitors, respectively, in HaCaT cells. Mice were fed a high fat diet with either 0.7% cellulose, 0.7% EGA, 0.7% DHM or 0.35% EGA+0.35% DHM for 3weeks and the dorsal skin of the mice had UV-B irradiation. 3% cellulose, 3% EGA, 3% DHM or 1.5% EGA+1.5% DHM in 1,3-buthylene glycol was applied onto the dorsal skin at 30min before 1 MED UV-B exposure. In 100mJ/cm2 UVB irradiation, EGA and DHM mainly decreased oxidative stress and inflammation, respectively in HaCaT cells. Their activities were blocked by the TGF-beta1 inhibitor, indicating their actions were mediated by TGF-beta1 signaling (TGF beta1?pSmad3?Smad7). DHM enhanced wnt signaling by increasing beta-catenin and decreasing Dickkopf-related protein-1. In mice, 1 MED UV-B exposure induced sunburn, redness, and blistering. EGA, DHM and especially EGA+DHM lessened their severity. UV-B increased epidermal thickness and damaged epidermal nucleus and cell structures. DHM and especially EGA+DHM prevented damage to the nucleus and cell structures. Expressions of circulating and dorsal skin IL-1beta and TNF alpha mRNA were lower in descending order of: control, EGA, DHM, EGA+DHM and normal-control. In conclusion, the consumption of EGA+DHM had a synergistically protective action against UV-B damage in the skin tissues of mice and HaCaT cells, and it may be associated with activating of both TGF-beta1 and wnt signaling. PMID- 29128707 TI - Nitric oxide inhibitors with a spiro diterpenoid skeleton from Scutellaria formosana: Structures, NO inhibitory effects, and interactions with iNOS. AB - A phytochemical investigation to obtain new NO inhibitors resulted in the isolation of five new spiro diterpenoids (1 -5) from the aerial parts of Scutellaria formosana. The structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of these compounds were established via comparison of experimental and calculated electronic circular dichroism (ECD) spectra. The nitric oxide (NO) inhibitory effects were evaluated and all of the compounds showed inhibitory effects on lipopolysaccharide-induced NO production in murine microglial BV-2 cells. The possible mechanism of NO inhibition of bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the iNOS protein. PMID- 29128708 TI - Childhood brain tumours, early infections and immune stimulation: A pooled analysis of the ESCALE and ESTELLE case-control studies (SFCE, France). AB - BACKGROUND: Few studies have investigated whether early infections and factors potentially related to early immune stimulation might be involved in the aetiology of childhood brain tumours (CBT). In this study, we investigated the associations between CBT with early day-care attendance, history of early common infections, atopic conditions (asthma/wheezing, eczema, allergic rhinitis), early farm residence/visits and contact with animals. METHODS: We pooled data from two nationwide French case-control studies, the ESCALE and ESTELLE studies. Children with a CBT diagnosed between 1 and 14 years of age were identified directly from the French National Registry of Childhood Cancers, while population controls were recruited from telephone subscribers. Odds-ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression adjusted for potential confounders. RESULTS: The analyses included 469 cases and 2719 controls. We found no association between attending a day-care centre (OR: 0.9, 95%CI: 0.7-1.2) or having had repeated common infections (OR: 0.9, 95%CI: 0.7-1.2) in the first year of life and the risk of CBT. There was also no association with a history of asthma/wheezing (OR: 0.8, 95%CI: 0.56-1.1). Farm visits (OR: 0.6, 95%CI: 0.5-0.8) as well as contact with pets (OR: 0.8, 95%CI: 0.6-1.0) in the first year of life were inversely associated with CBT. CONCLUSIONS: Our findings suggest a protective effect of early farm visits and contact with pets, but not with other markers of early immune stimulation. This might be related to immune stimulation but needs further investigation. PMID- 29128709 TI - Integrating experiment, theory and simulation to determine the structure and dynamics of mammalian chromosomes. AB - Eukaryotic chromosomes are complex polymers, which largely exceed in size most biomolecules that are usually modelled in computational studies and whose molecular interactions are to a large extent unknown. Since the folding of the chromatin fiber in the cell nucleus is tightly linked to biological function and gene expression in particular, characterizing the conformational and dynamical properties of chromosomes has become crucial in order to better understand how genes are regulated. In parallel with the development of experimental techniques allowing to measure physical contacts within chromosomes inside the cell nucleus, a large variety of physical models to study the structure and mechanisms of chromosome folding have recently emerged. Such models can be roughly divided into two classes, based on whether they adopt specific hypotheses on the interaction mechanism within chromosomes, or learn those interactions on the available experimental data using the principle of maximum entropy. All of them have played a key role in interpreting experimental data and advancing our understanding the folding principles of the chromatin fiber. PMID- 29128710 TI - Prevalence and motives for drugged driving among emerging adults presenting to an emergency department. AB - OBJECTIVES: Drugged driving [DD] is a public health concern, particularly among emerging adults who have the highest rates of drug use. Understanding involvement with DD could inform prevention efforts for this population. We evaluated the prevalence of, motives for, and correlates of past-year DD among emerging adults from an urban, under-resourced community. METHODS: Emerging adults (N=586) ages 18-25years (54% male, 56% African American, 34% European American) seeking care in an urban emergency department completed past-year surveys of demographics, frequency of DD within 4h of substance use, reasons for DD, and substance use. RESULTS: DD was reported by 24% of participants (with 25% of those engaging in high frequency DD). DD after cannabis use was most common (96%), followed by prescription opioids, sedatives, and stimulants (9%-19%). Common reasons for DD were: needing to go home (67%), not thinking drugs affected driving ability (44%), not having to drive far (33%), and not feeling high (32%). Demographics were not associated with DD, but, as expected, those with DD had riskier substance use. CONCLUSIONS: In this clinical sample, using a conservative measure, DD, particularly following cannabis use, was relatively common among emerging adults. Based on these data, clinical interventions for cannabis and other drug use should include content on prevention of DD, with particular attention to motives such as planning ahead for alternatives to get home safely and weighing benefits and risks of DD. PMID- 29128711 TI - Polysubstance use profiles among electronic dance music party attendees in New York City and their relation to use of new psychoactive substances. AB - BACKGROUND: Electronic Dance Music (EDM) party attendees are often polysubstance users and are at high risk for use of new psychoactive substances (NPS). We sought to identify patterns of use of common illegal drugs among EDM party attendees, sociodemographic correlates, and use of NPS as a function of patterns of use of more common drugs to inform prevention and harm reduction. METHOD: Using time-space-sampling, 1045 individuals aged 18-40 were surveyed entering EDM parties in New York City. We queried past-year use of common illegal drugs and 98 NPS. We conducted latent class analysis to identify polysubstance use profiles of use of eight common drugs (i.e., ecstasy, ketamine, LSD, mushrooms, powder cocaine, marijuana, amphetamine, benzodiazepines). Relationships between drug classification membership and sociodemographics and use of drugs within six NPS categories were examined. RESULTS: We identified four profiles of use of common drugs: non-polysubstance use (61.1%), extensive polysubstance use (19.2%), moderate polysubstance use/stimulants (12.8%), and moderate polysubstance use/psychedelics (6.7%). Those in the moderate/psychedelic group were at higher odds of using NPS with psychedelic-type effects (2C, tryptamines, and other "new" psychedelics; Ps<0.05). Extensive polysubstance users were at increased odds of reporting use of 2C drugs, synthetic cathinones ("bath salts"), tryptamines, other new (non-phenethylamine) psychedelics, new dissociatives, and synthetic cannabinoids (Ps<0.05). CONCLUSION: NPS preference is linked to the profile of use of common drugs among individuals in the EDM scene. Most participants were identified as non-polysubstance users, but findings may help inform preventive and harm reduction interventions among those at risk in this scene. PMID- 29128712 TI - The impact of a brief cessation induction intervention for waterpipe tobacco smoking: A pilot randomized clinical trial. AB - BACKGROUND: Waterpipe (WP) tobacco smoking delivers many of the same harmful toxicants as cigarette smoking and is on the rise in the US. This study evaluated the feasibility and efficacy of a brief personalized feedback intervention in affecting changes in WP smoking among current WP smokers. METHODS: Participants (N=109) were recruited as they entered WP lounges and completed a questionnaire and exhaled carbon monoxide (eCO) testing before entering the WP lounge. Participants were cluster-randomized to assessment-only control (AOC) or intervention conditions. The intervention condition received health risk information and personalized feedback on pre- and post-WP session eCO levels. Participants completed a survey at the end of the WP session and at 3-month follow-up. RESULTS: Compared to control, the intervention was effective in increasing knowledge of WP-related harms, correcting risk perceptions, increasing importance of quitting WP smoking, and increasing confidence in ability to quit WP smoking at post-WP session (p<0.05). Differences were maintained for knowledge of WP-related harms, risk perceptions, and commitment to quitting WP at 3-month follow-up; however, no significant difference (p>0.05) was observed in WP smoking (i.e., days smoked and number of WPs smoked) at 3-month follow-up between the intervention (M=3.97days, SD=9.83; M=6.45 bowls, SD=19.60) and control conditions (M=3.32days, SD=5.24; M=3.49 bowls, SD=5.10). CONCLUSIONS: The current research supports the use of personalized feedback as a useful intervention method to increase commitment to quit WP, but suggests more intensive interventions may be necessary to achieve WP cessation. PMID- 29128713 TI - Non-enzymatic electrochemical detection of glucose with a disposable paper-based sensor using a cobalt phthalocyanine-ionic liquid-graphene composite. AB - We introduce for the first time a paper-based analytical device (PAD) for the non enzymatic detection of glucose by modifying a screen-printed carbon electrode with cobalt phthalocyanine, graphene and an ionic liquid (CoPc/G/IL/SPCE). The modifying composite was characterized by UV-visible spectroscopy, energy dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The disposable devices show excellent conductivity and fast electron transfer kinetics. The results demonstrated that the modified electrode on PADs had excellent electrocatalytic activity towards the oxidation of glucose with NaOH as supporting electrolyte (0.1M). The oxidation potential of glucose was negatively shifted to 0.64V vs. the screen printed carbon pseudo-reference electrode. The paper-based sensor comprised a wide linear concentration range for glucose, from 0.01 to 1.3mM and 1.3-5.0mM for low and high concentration of glucose assay, respectively, with a detection limit of 0.67uM (S/N = 3). Additionally, the PADs were applied to quantify glucose in honey, white wine and human serum. The disposable, efficient, sensitive and low cost non-enzymatic PAD has great potential for the development of point-of-care testing (POCT) devices that can be applied in healthcare monitoring. PMID- 29128714 TI - Multiplex immunoassays using virus-tethered gold microspheres by DC impedance based flow cytometry. AB - Bead-based multiplex immunoassays for common use require enhanced sensitivity and effective prevention of non-specific adsorption, as well as miniaturization of the detection device. In this work, we have implemented virus-tethered gold microspheres for multiplex immunoassay applications, employing a DC impedance based flow cytometer as a detection element. The advantages of virus-tethered gold microspheres, including excellent prevention of non-specific adsorption, are extended to signal enhancement arising from the large quantity of antibody loading on each virion, and to flexible movement of filamentous virus. Individual virus-tethered beads generate their own DC impedance and fluorescence signals, which are simultaneously detected by a chip-based microfluidic flow cytometer. This system successfully realized multiplex immunoassays involving four biomarkers: cardiac troponin I (cTnI), prostate specific antigen (PSA), creatine kinase MB (CK-MB), and myoglobin in undiluted human sera, elevating sensitivity by up to 5.7-fold compared to the beads without virus. Constructive integration between filamentous virus-tethered Au-layered microspheres and use of a microfluidic cytometer suggests a promising strategy for competitive multiplex immunoassay development based on suspension arrays. PMID- 29128715 TI - Fabrication of ordered metallic glass nanotube arrays for label-free biosensing with diffractive reflectance. AB - In this study, a photoresist template with well-defined contact hole array was fabricated, to which radio frequency magnetron sputtering process was then applied to deposit an alloyed Zr55Cu30Al10Ni5 target, and finally resulted in ordered metallic glass nanotube (MGNT) arrays after removal of the photoresist template. The thickness of the MGNT walls increased from 98 to 126nm upon increasing the deposition time from 225 to 675s. The wall thickness of the MGNT arrays also increased while the dimensions of MGNT reduced under the same deposition condition. The MGNT could be filled with biomacromolecules to change the effective refractive index. The air fraction of the medium layer were evaluated through static water contact angle measurements and, thereby, the effective refractive indices the transverse magnetic (TM) and transverse electric (TE) polarized modes were calculated. A standard biotin-streptavidin affinity model was tested using the MGNT arrays and the fundamental response of the system was investigated. Results show that filling the MGNT with streptavidin altered the effective refractive index of the layer, the angle of reflectance and color changes identified by an L*a*b* color space and color circle on an a*b* chromaticity diagram. The limit of detection (LOD) of the MGNT arrays for detection of streptavidin was estimated as 25nM, with a detection time of 10min. Thus, the MGNT arrays may be used as a versatile platform for high-sensitive label-free optical biosensing. PMID- 29128716 TI - Smartphone based bioanalytical and diagnosis applications: A review. AB - A smartphone is a facile, handy-analytical device that makes our lives comfortable and stress-free in terms of health care diagnostic assessments. Due to recent advancements in the technology and the introduction of user friendly operating systems and applications, the smartphones have replaced laptops and desktop computers. Taking this fact into account, researchers have designed sensing systems which are more compatible with smartphones. Consequently, these devices are attracting the attention of researchers from fields such as telemedicine, biotechnology, chemical sciences and environmental sciences. In this review, our focus is on recent advances on smartphone based sensing and diagnosis applications. PMID- 29128717 TI - In vivo bioelectronic nose using transgenic mice for specific odor detection. AB - The olfactory system is a natural biosensor since its peripheral olfactory sensory neurons (OSNs) respond to the external stimuli and transmit the signals to the olfactory bulb (OB) where they are integrated and processed. The axonal connections from the OSNs expressing about 1000 different types of odorant receptors are precisely organized and sorted out onto 1800 glomeruli in the OB, from which the olfactory information is delivered to and perceived by the central nervous system. This process is carried out with particularly high sensitivity, specificity and rapidity, which can be used for explosive detection. Biomimetic olfactory biosensors use various biological components from the olfactory system as sensing elements, possessing great commercial prospects. In this study, we utilized the genetically labeled murine M72 olfactory sensory neurons with the green fluorescent protein (GFP) as sensing components and obtained long-term in vivo electrophysiological recordings from the M72 OSNs by implanting the microelectrode arrays (MEAs) into the behaving mouse's OB. The electrophysiological responses showed high reliability, reproducibility and specificity for odor detection, and particularly, the high sensitivity for the detection of odorants that contain benzene rings. Furthermore, our results indicated that it can detect trinitrotoluene (TNT) in liquid at a concentration as low as 10-5M and can distinguish TNT from other chemicals with a similar structure. Thus our study demonstrated that the in vivo biomimetic olfactory system could provide novel approaches to enhancing the specificity and increasing working lifespan of olfactory biosensors capable of detecting explosives. PMID- 29128718 TI - Claw hand mask ventilation in adults: An alternative and effective technique. PMID- 29128719 TI - Bring out your dead!: A study of income inequality and life expectancy in the United States, 2000-2010. AB - We test whether income inequality undermines female and male life expectancy in the United States. We employ data for all 50 states and the District of Columbia and two-way fixed effects to model state-level average life expectancy as a function of multiple income inequality measures and time-varying characteristics. We find that state-level income inequality is inversely associated with female and male life expectancy. We observe this general pattern across four measures of income inequality and under the rigorous conditions of state-specific and year specific fixed effects. If income inequality undermines life expectancy, redistribution policies could actually improve the health of states. PMID- 29128720 TI - Shared mechanisms among probiotic taxa: implications for general probiotic claims. AB - Strain-specificity of probiotic effects has been a cornerstone principle of probiotic science for decades. Certainly, some important mechanisms are present in only a few probiotic strains. But scientific advances now reveal commonalities among members of certain taxonomic groups of probiotic microbes. Some clinical benefits likely derive from these shared mechanisms, suggesting that sub-species specific, species-specific or genus-specific probiotic effects exist. Human trials are necessary to confirm specific health benefits. However, a strain that has not been tested in human efficacy trials may meet the minimum definition of the term 'probiotic' if it is a member of a well-studied probiotic species expressing underlying core mechanisms and it is delivered at an effective dose. PMID- 29128721 TI - Preparation of MgAl-EDTA-LDH based electrospun nanofiber membrane and its adsorption properties of copper(II) from wastewater. AB - Adsorption is recognized as one of the most promising technologies applied to remove heavy metals from contaminated water. However, the adsorption efficiency often decreases because of the aggregation and loss of adsorbents. Herein, a novel adsorbent was synthesized by intercalation ethylenediaminetetraacetic acid (EDTA) into layered double hydroxides (LDH) and subsequent encapsulated into PAN polymer matrix using electrospinning. The synthesized electrospun nanofiber membrane (MgAl-EDTA-LDH@PAN) was found to combine the advantages of LDH@PAN nanofiber membrane (high surface area, easy to separate, free from aggregation and loss) and EDTA (powerful chelating agent). The adsorption performance of the MgAl-EDTA-LDH@PAN was evaluated using Cu(II) as target metals by varying experimental conditions such as pH, contact time, initial adsorbent dosage, and temperature. The maximum adsorption capacity of MgAl-EDTA-LDH@PAN was 120.77mg/g with the initial Cu(II) concentrations ranging from 0.6 to 40mg/L. MgAl-EDTA LDH@PAN was also used in real industrial contaminated water treatment, and the final effluent was approximate to class-I criteria of the National Wastewater Discharge Standard of China. (GB 8978-1996). In addition, Cu K-edge XAS and XPS analyses were applied for unraveling the adsorptive performance of MgAl-EDTA LDH@PAN by revealing the molecular-level mechanism of Cu(II) uptake. PMID- 29128722 TI - Photocatalytic degradation of H2S aqueous media using sulfide nanostructured solid-solution solar-energy-materials to produce hydrogen fuel. AB - H2S is a corrosive, flammable and noxious gas, which can be neutralized by dissolving in alkaline media and employed as H2-source by utilizing inside semiconductor-assisted/photochemical reactors. Herein, through a facile hydrothermal route, a ternary nanostructured solid-solution of iron, zinc and sulfur was synthesized in the absence and presence of Ag-dopant, and applied as efficient photocatalyst of hydrogen fuel production from H2S media. The effect of pH on the photocatalyst performance was scrutinized and the maximum activity was attained at pH=11, where HS- concentration is high. BET, diffuse reflectance and photoluminescence studies indicated that the ternary solid-solution photocatalyst, in comparison to its solid-solvent (ZnS), has a greater surface area, stronger photon absorption and less charge recombination, which justify its superiority. Moreover, the effect of silver-dopant on the photocatalyst performance was examined. The investigations revealed that although silver could boost the absorption of photons and increase the surface area, it could not appreciably enhance the photocatalyst performance due to its weak influence on retarding the charge-recombination process. Finally, the phenomenon was discussed in detail from mechanistic viewpoint. PMID- 29128723 TI - Copper-mediated reductive dechlorination by green rust intercalated with dodecanoate. AB - A layered FeII-FeIII hydroxide (green rust, GR) was intercalated with dodecanoate (known as GRC12) and then amended with CuII (GRC12(Cu)) before reaction with chloroform (CF), carbon tetrachloride (CT), trichloroethylene (TCE) or tetrachloroethylene (PCE). Reduction of CT by GRC12(Cu) was 37 times faster than with GRC12 alone before the active Cu species was consumed. The Cu mediated reaction followed the dichloroelimination pathway as observed for GRC12 alone, with carbon monoxide (82.5%) and formate (26.6%) as main degradation products. Also, CF was reduced by GRC12(Cu), which is not seen with GRC12. Neither GRC12(Cu) nor GRC12 reacted with PCE or TCE. The chlorinated solvents can partition into dodecanoate interlayer but only small CS molecules (CF, CT) can transport through the dodecanoate interlayer. Copper(II) added to GRC12 was reduced to CuI by FeII in GR, but CuI was not regenerated during the dechlorination. High resolution TEM showed that Cu was evenly distributed in the GR without formation of Cu nanoparticles on edges of GR. The active CuI sites are most likely located between the iron hydroxide layer and the hydrated negatively charged carboxylate groups in the interlayer of GR. This work shines new light on the Cu accelerated dechlorination by GR. PMID- 29128725 TI - Flame deflagration in side-on vented detonation tubes: A large scale study. AB - : Venting is often used in process industries to reduce the possibility of dangerous rises in pressure levels and the severity of explosions. To date, the effectiveness of side-on venting on methane flame deflagration in large scale operations has not been clearly addressed. This work explicitly investigates the influences of side-on venting on varied methane flame deflagration concentrations in a 30m long Detonation Tube (DT). RESULTS: corresponding to this study prove the existence of a significant correlation between the fire and explosion driving parameters such as pressure rise and flame propagation velocity with the vent location. It observed venting the explosion at distance between 6.5m and 20.5m from the ignition source resulted in reducing the explosion total pressure by about 33% to 56%. For methane concentration of 7.5% the dynamic and static pressures reduced by about 66% and 33%, respectively. The reduced pressure observed to decelerate the flame velocity by about 70%. Significant pressure rise and flame deflagration velocity reductions were observed in both upstream and downstream of the DT corresponding to the location of the vent. For high methane concentrations vacuum effect observed to drawback the flame into the vent and trigger the secondary pressure rise. PMID- 29128724 TI - Fabrication and characterization of novel iodine doped hollow and mesoporous hematite (Fe2O3) particles derived from sol-gel method and their photocatalytic performances. AB - In this work, iodine (I) doped hollow and mesoporous Fe2O3 photocatalyst particles were fabricated for the first time through sol-gel method. Phase structure, surface morphology, particle size, specific surface area and optical band gap of the synthesized Fe2O3 photocatalysts were analyzed by X-ray diffraction (XRD), field emission scanning electron microscope (FESEM), X-ray photoelectron spectroscopy (XPS), BET surface analysis, particle size analyzer and UV-vis diffuse reflectance spectrum (UV-vis DRS), respectively. Also, electrochemical properties and photoluminescence spectra of Fe2O3 particles were measured. The results illustrated that high crystalline, hollow and mesoporous Fe2O3 particles were formed. The optical band gap values of the Fe2O3 photocatalysts changed between 2.104 and 1.93eV. Photocatalytic efficiency of Fe2O3 photocatalysts were assessed via MB solution. The photocatalytic activity results exhibited that I doping enhanced the photocatalytic efficiency. 1% mole iodine doped (I-2) Fe2O3 photocatalyst had 97.723% photodegradation rate and 8.638*10-2min-1 kinetic constant which showed the highest photocatalytic activity within 45min. Moreover, stability and reusability experiments of Fe2O3 photocatalysts were carried out. The Fe2O3 photocatalysts showed outstanding stability after four sequence tests. As a result, I doped Fe2O3 is a good candidate for photocatalysts. PMID- 29128726 TI - Joint release rate estimation and measurement-by-measurement model correction for atmospheric radionuclide emission in nuclear accidents: An application to wind tunnel experiments. AB - The release rate of atmospheric radionuclide emissions is a critical factor in the emergency response to nuclear accidents. However, there are unavoidable biases in radionuclide transport models, leading to inaccurate estimates. In this study, a method that simultaneously corrects these biases and estimates the release rate is developed. Our approach provides a more complete measurement-by measurement correction of the biases with a coefficient matrix that considers both deterministic and stochastic deviations. This matrix and the release rate are jointly solved by the alternating minimization algorithm. The proposed method is generic because it does not rely on specific features of transport models or scenarios. It is validated against wind tunnel experiments that simulate accidental releases in a heterogonous and densely built nuclear power plant site. The sensitivities to the position, number, and quality of measurements and extendibility of the method are also investigated. The results demonstrate that this method effectively corrects the model biases, and therefore outperforms Tikhonov's method in both release rate estimation and model prediction. The proposed approach is robust to uncertainties and extendible with various center estimators, thus providing a flexible framework for robust source inversion in real accidents, even if large uncertainties exist in multiple factors. PMID- 29128727 TI - Carbon nano tubes functionalized with novel functional group- amido-amine for sorption of actinides. AB - The manuscript presents the results on the sorption of U(VI), Am(III) & Eu(III) from pH medium by a novel amido-amine functionalized multiwalled carbon nanotube (MWCNT). The novel functional group was introduced in the MWCNT by two step processes and characterized by various instrumental techniques like Scanning Electron Microscopy (SEM), Raman and X-ray Photoelectron Spectroscopy (XPS). The sorption process was found to be highly dependent on the pH of the solution with maximum sorption for both 233U, 241Am & 152+154Eu at pH 7.0. Kinetics of sorption was found to be fast with equilibrium reached in ~15min and the sorption was found to be following pseudo 2nd order kinetics for the radionuclides. The sorption for both 233U and 152+154Eu followed Langmuir sorption model with maximum sorption capacity of 20.66mg/g and 16.1mg/g respectively. This has been explained by DFT calculations which shows that more negative solvation energy of U(VI) compared to Am(III) and Eu(III) and stronger U-MWCNT-AA complex is responsible for higher sorption capacity of U(VI) compared to Am(III) and Eu(III).The synthesized amido-amine functionalized MWCNT is a very promising candidate for removal of actinides and lanthanides from waste water solution with high efficiency. PMID- 29128728 TI - Novel synthesis of cyano-functionalized mesoporous silica nanospheres (MSN) from coal fly ash for removal of toxic metals from wastewater. AB - Trace amounts of toxic metals are usually difficult to be purified by conventional chemical precipitation or physical adsorption in wastewater. In this study, in order to realize high-value utilization of coal fly ash for wastewater purification, a novel method was applied to prepare high-performance mesoporous silica materials from coal fly ash. In comparison with a commonly used method, characterizations revealed that the new method obtained mesoporous silica nanospheres with uniformly distributed cyano groups (denoted by MSN), while the common method only obtained irregular sponge-like microstructure (denoted by ISM). Besides, MSN showed better hydrothermal stability, higher specific surface area (693m2/g) and more ordered mesopores from the comparison. Moreover, the sorption experiments of simulated wastewater suggested that MSN was better in removing toxic metals (Ni2+ and Cd2+) than ISM. For the practical wastewater from a battery plant, 2g/L dosage of MSN showed excellent performance for purification of trace amounts of various toxic metals (Ni, Cd, Mn, Zn, Hg and Pb), the concentration of which reduced to ppb level after MSN treated. The results suggested that MSN can be an effective and low-cost sorbent for removing various toxic metals from wastewater. PMID- 29128729 TI - Recent advances in inflammasome biology. AB - The inflammasome is a complex of proteins that through the activity of caspase-1 and the downstream substrates gasdermin D, IL-1beta, and IL-18 execute an inflammatory form of cell death termed pyroptosis. Activation of this complex often involves the adaptor protein ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. Here we discuss new regulatory mechanisms that have been identified for the canonical inflammasomes, the most recently identified NLRP9b inflammasome, and the new gasdermin family of proteins that mediate pyroptosis and other forms of regulated cell death. PMID- 29128731 TI - Prevalence of psychiatric disorder-related consequences in male prisoners: a cross-sectional study. PMID- 29128730 TI - Socio-economic inequalities in the incidence of four common cancers: a population based registry study. AB - OBJECTIVES: To investigate the relationship between socio-economic circumstances and cancer incidence in Scotland in recent years. STUDY DESIGN: Population-based study using cancer registry data. METHODS: Data on incident cases of colorectal, lung, female breast, and prostate cancer diagnosed between 2001 and 2012 were obtained from a population-based cancer registry covering a population of approximately 2.5 million people in the West of Scotland. Socio-economic circumstances were assessed based on postcode of residence at diagnosis, using the Scottish Index of Multiple Deprivation (SIMD). For each cancer, crude and age standardised incidence rates were calculated by quintile of SIMD score, and the number of excess cases associated with socio-economic deprivation was estimated. RESULTS: 93,866 cases met inclusion criteria, comprising 21,114 colorectal, 31,761 lung, 23,757 female breast, and 15,314 prostate cancers. Between 2001 and 2006, there was no consistent association between socio-economic circumstances and colorectal cancer incidence, but 2006-2012 saw an emerging deprivation gradient in both sexes. The incidence rate ratio (IRR) for colorectal cancer between most deprived and least deprived increased from 1.03 (95% confidence interval [CI] 0.91-1.16) to 1.24 (95% CI 1.11-1.39) during the study period. The incidence of lung cancer showed the strongest relationship with socio-economic circumstances, with inequalities widening across the study period among women from IRR 2.66 (95% CI 2.33-3.05) to 2.91 (95% CI 2.54-3.33) in 2001-03 and 2010 12, respectively. Breast and prostate cancer showed an inverse relationship with socio-economic circumstances, with lower incidence among people living in more deprived areas. CONCLUSION: Significant socio-economic inequalities remain in cancer incidence in the West of Scotland, and in some cases are increasing. In particular, this study has identified an emerging, previously unreported, socio economic gradient in colorectal cancer incidence among women as well as men. Actions to prevent, mitigate, and undo health inequalities should be a public health priority. PMID- 29128732 TI - Time-trend analysis and developing a forecasting model for the prevalence of multiple sclerosis in Kohgiluyeh and Boyer-Ahmad Province, southwest of Iran. AB - OBJECTIVE: This study was designed and implemented to assess the current situation and to estimate the time trend of multiple sclerosis (MS), as well as to explain potential factors associated with such a trend. METHODS: This longitudinal study was carried out based on analysis of the data from the monitoring and treatment surveillance system for 421 patients with MS in Kohgiluyeh and Boyer-Ahmad Province, Iran, from 1990 to 2015. To this end, curve estimation approach was used to investigate the changes in prevalence and incidence of the disease, and univariate time series model analysis was applied in order to estimate the disease incidence in the next 10 years. RESULTS: The mean and standard deviation of age were 29.78 and 8.5 years at the time of diagnosis, and the mean and 95% confidence interval of age were 29.18 (28.86 30.77) and 29.68 (28.06-31.30) at the time of diagnosis for women and men, respectively. The sex ratio (males to females) was estimated as 3.3, and the prevalence of the disease was estimated as 60.14 in 100,000 people. The diagram of the 35-year trend of the disease indicated three distinct patterns with a tendency to increase in recent years. CONCLUSION: The prevalence and incidence trend of the disease in the study population is consistent with regional and global changes. Climatic and environmental factors such as extreme weather changes, dust particles, expansion of the application of new industrial materials, and regional wars with potential use of banned weapons are among the issues that may, in part, be able to justify the global and regional changes of the disease. Predictive models indicate a growing trend of the disease, highlighting the need for more regular monitoring of the disease trend in upcoming years. PMID- 29128733 TI - Prevalence of curli genes among Cronobacter species and their roles in biofilm formation and cell-cell aggregation. AB - Cronobacter species are food-borne opportunistic pathogens that cause sepsis, meningitis, and necrotizing enterocolitis in neonates. Bacterial pathogens such as pathogenic Escherichia coli and Salmonella species express extracellular curli fimbriae that are involved in rugosity, biofilm formation, and host cell adherence. csgBAC operon encodes the major curli structural subunit CsgA and the nucleator protein CsgB. csgDEFG operon encodes the regulatory protein CsgD and putative assembly factors. In this study, the curli operons were analyzed in the sequences of 13 Cronobacter strains and other enteric bacterial pathogens. Isogenic mutants of csgA and csgB were generated in C. turicensis LMG23827 (z3032). csgA and csgB mutants did not express curli fimbriae as indicated by a lack of Congo red binding and absence of curli by electron microscopic evaluation. Compared to the wild type strain, biofilm formation and cell-cell aggregation of csgA and csgB mutants were remarkably decreased. The prevalence of curli operons were investigated in 231 Cronobacter strains isolated from different sources using polymerase chain reaction (PCR) assay. The results of the PCR analysis showed that csgA and csgG were present in 30% clinical isolates, 8% food, and 11% environmental isolates. These genes were present in C. dublinensis, C. malonaticus, C. turicensis, and C. universalis, but not in C. muytjensii and C. sakazakii. Our data indicate that csgBAC and csgDEFG operons were present about three fold higher in clinical isolates than in isolates from other sources. The csgA and csgB genes were shown to be involved in the early stages of biofilm development and cell-cell aggregation in Cronobacter. PMID- 29128734 TI - Promoting resilience among nursing students in clinical education. AB - Resilience is the ability to overcome adversity and grow stronger from the experience. Increased resilience has been shown to positively impact nurses in practice. With this knowledge, recommendations to incorporate resilience training into nursing education have been made. Research, integrative reviews and a theoretical model of resilience in nursing students are explored in this paper. The authors posit that facilitating resilience is important in the setting of clinical education. Through incorporating resilience training in the clinical setting, educators can better prepare students for challenges in their educational environment and ultimately for nursing practice. Specific strategies for clinical educators to incorporate resilience training are suggested. Strategies are organized into three categories, support, education and reflection. The position of facilitating resilience in clinical education may open a discussion for future educational practices. PMID- 29128735 TI - Nursing and midwifery students' experiences with the course of infertility and assisted reproductive techniques: A focus group study from Turkey. AB - Nurses and midwifes without sufficient knowledge of infertilitare not likely to provide counseling and support for people suffering from infertility. This study aimed to evaluate nursing and midwifery students' experiences with the Course on Infertility and Assisted Reproductive Techniques. Our study had a qualitative descriptive design. Total number of the participants was 75. The analysis revealed five primary themes and twenty-one sub-themes. The themes were (1) action, (2) learner centered method, (3) interaction, (4) nursing competencies, and (5) evaluation. The active learning techniques enabled the students to retrieve the knowledge that they obtained for a long time, contributed to social and cultural development and improved skills required for selfevaluation, communication and leadership, enhanced critical thinking, skills increased motivation and satisfaction and helped with knowledge integration. Infertility is a biopsychosocial condition, and it may be difficult for students to understand what infertile individuals experience. The study revealed that active learning techniques enabled the students to acquire not only theoretical knowledge but also an emotional and psychosocial viewpoint and attitude regarding infertility. The content of an infertility course should be created in accordance with changes in the needs of a given society and educational techniques. PMID- 29128736 TI - OPTIMAL practice conditions enhance the benefits of gradually increasing error opportunities on retention of a stepping sequence task. AB - INTRODUCTION: Physical therapists should implement practice conditions that promote motor skill learning after neurological injury. Errorful and errorless practice conditions are effective for different populations and tasks. Errorful learning provides opportunities for learners to make task-relevant choices. Enhancing learner autonomy through choice opportunities is a key component of the Optimizing Performance through Intrinsic Motivation and Attention for Learning (OPTIMAL) theory of motor learning. The objective of this study was to evaluate the interaction between error opportunity frequency and OPTIMAL (autonomy supportive) practice conditions during stepping sequence acquisition in a virtual environment. METHODS: Forty healthy young adults were randomized to autonomy supportive or autonomy-controlling practice conditions, which differed in instructional language, focus of attention (external vs internal) and positive versus negative nature of verbal and visual feedback. All participants practiced 40 trials of 4, six-step stepping sequences in a random order. Each of the 4 sequences offered different amounts of choice opportunities about the next step via visual cue presentation (4 choices; 1 choice; gradually increasing [1-2-3-4] choices, and gradually decreasing [4-3-2-1] choices). Motivation and engagement were measured by the Intrinsic Motivation Inventory (IMI) and the User Engagement Scale (UES). Participants returned 1-3 days later for retention tests, where learning was measured by time to complete each sequence. No choice cues were offered on retention. RESULTS: Participants in the autonomy-supportive group outperformed the autonomy-controlling group at retention on all sequences (mean difference 2.88s, p < .005, t[6835] = 3.42). Participants in both groups had the most difficulty acquiring the decreasing choice (4-3-2-1) sequence (p < .001, t[6835] = -4.26) and performed most poorly on the errorful (4 choice) sequence (p < .034, t[6835] = 2.65) at retention. Participants in the autonomy-supportive group performed best at retention on the increasing choice (1-2-3-4) sequence (p < .033, t[6835] = -2.7). Participants in both groups who reported greater attention to the task on the UES Average Focused Attention subscale during acquisition had poorer retention performance, particularly for the decreasing choice (4-3-2-1) sequence (p < .005, t(6835) = 3.39). Participants in the autonomy-supportive group reported significantly higher overall motivation (p = .007, t(38) = 0.728, d = 0.248) on the IMI as compared to the autonomy controlling group. CONCLUSION: Individual benefits of errorless learning and autonomy-supportive practice conditions, with an interaction effect for practice that begins errorless but adds increasing error opportunities over time, suggest that participants relied on implicit learning strategies for this full body task and that feedback about successes minimized errors and reduced their potential information-processing benefits. Subsequent work will continue to examine how assigning a positive versus a negative quality to error provision influences the benefits of errorful learning in a variety of tasks. PMID- 29128737 TI - A 8-year retrospective cohort study comparing Interferon-beta formulations for relapsing-remitting multiple sclerosis. AB - BACKGROUND: Interferon-beta has been approved for the treatment of relapsing remitting (RR) multiple sclerosis (MS), whereas its efficacy in preventing long term disability and conversion to secondary progressive (SP) MS is still debated. We aim to compare long-term clinical evolution of newly-diagnosed RRMS patients treated with different Interferon-beta formulations. METHODS: 507 patients were included in the analysis and followed-up for 8.5 +/- 3.9 years. 37.6% were treated with subcutaneous Interferon-beta1a 44mcg, 33.4% with intramuscular Interferon-beta1a 30mcg, and 29.0% with subcutaneous Interferon-beta1b 250mcg. Relapse occurrence, 1-point EDSS progression, reaching of EDSS 4.0 and conversion to SP were recorded as outcome measures. To reduce the selection bias, we calculated the propensity score of receiving the specific treatment considering age (32.7 +/- 8.3 years), gender (female 63.1%), disease duration (2.7 +/- 2.8 years), and baseline EDSS (1.5, range 1.0-3.5). Propensity score and covariates (age, gender, disease duration and EDSS) were included in the statistical models. RESULTS: At Cox regression models, the reaching of EDSS 4.0 was not-significantly higher for Interferon-beta1b 250mcg (HR = 1.207; p = 0.063) and for Interferon beta1a 30mcg (HR = 1.363; p = 0.095), when compared with Interferon-beta1a 44mcg. The rate of SP conversion was higher for Interferon-beta1b 250mcg (HR = 2.054; p = 0.042), and not-significantly higher for Interferon-beta1a 30mcg (HR = 1.884; p = 0.081), when compared with Interferon-beta1a 44mcg. CONCLUSIONS: Patients treated with Interferon-beta1a 44mcg presented with a marginally reduced risk of disability accrual in the long-term, when compared with Interferon-beta1b 250mcg and, at least in part, with Interferon-beta1a 30mcg. Formulation, frequency of administration and dose of Interferon-beta might affect the long-term clinical evolution of RRMS. PMID- 29128738 TI - Simulation of a Love wave device with ZnO nanorods for high mass sensitivity. AB - The paper presents 3D finite element simulation and analysis of Love wave resonator with different guiding layer materials and investigation of the coupled resonance effect with ZnO nanorods on the device surface. Analytical estimation of phase velocity and mass sensitivity of Love wave device with SiO2, ZnO, gold, SU-8, and parylene-C as guiding layer materials is performed for comparative analysis. Simulations are carried out to study the variation in electromechanical coupling coefficient, displacement profile and frequency response of the Love wave resonator. SU-8 offers high mass sensitivity of 1044 m2/kg while gold layer provides maximum K2 of 8.6%. In comparison to SiO2 and ZnO, polymers exhibit sharp rise and fall in K2 within a narrow range of normalized layer thickness (0.03-0.1). ZnO nanorods of varying height and surface nanorod density are designed over the Love wave resonator with SiO2 as the waveguiding layer. In the presence of coupled resonance, the nanorods and substrate vibrate in unison causing an increase in average stress and mass sensitivity but leads to decrease in the electromechanical coupling coefficient of the device. Surface nanorod packing density of 25 MUm-2 offers high mass sensitivity of 1304 m2/kg that is 20 times greater in comparison to the mass sensitivity of a plain Love wave device. PMID- 29128739 TI - Childbirth and parenting preparation in antenatal classes. AB - OBJECTIVES: to describe topics (1) presented by midwives' during antenatal classes and the amount of time spent on these topics and (2) raised and discussed by first-time parents and the amount of time spent on these topics. DESIGN: qualitative; data were gathered using video or tape recordings and analysed using a three-pronged content analysis approach, i.e., conventional, summative, and directed analyses. SETTING AND PARTICIPANTS: 3 antenatal courses in 2 antenatal units in a large Swedish city; 3 midwives; and 34 course participants. FINDINGS: class content focused on childbirth preparation (67% of the entire antenatal course) and on parenting preparation (33%). Childbirth preparation facilitated parents' understanding of the childbirth process, birthing milieu, the partner's role, what could go wrong during delivery, and pain relief advantages and disadvantages. Parenting preparation enabled parents to (i) plan for those first moments with the newborn; (ii) care for/physically handle the infant; (iii) manage breastfeeding; (iv) manage the period at home immediately after childbirth; and (v) maintain their relationship. During the classes, parents expressed concerns about what could happened to newborns. Parents' questions to midwives and discussion topics among parents were evenly distributed between childbirth preparation (52%) and parenting preparation (48%). KEY CONCLUSIONS: childbirth preparation and pain relief consumed 67% of course time. Parents particularly reflected on child issues, relationship, sex, and anxiety. Female and male participants actively listened to the midwives, appeared receptive to complex issues, and needed more time to ask questions. Parents appreciated the classes yet needed to more information for managing various post-childbirth situations. IMPLICATIONS FOR PRACTICE: while midwifery services vary among hospitals, regions, and countries, midwives might equalise content focus, offer classes in the second trimester, provide more time for parents to talk to each other, allow time in the course plan for parents to bring up new topics, and investigate: (i) ways in which antenatal course development and planning can improve; (ii) measures for evaluating courses; (iii) facilitator training; and (iv) parent satisfaction surveys. PMID- 29128740 TI - Motivational capacities after prolonged interpersonal childhood trauma in institutional settings in a sample of Austrian adult survivors. AB - A considerable amount of research has been conducted on the aversive impact of prolonged interpersonal childhood trauma, but data on possible associations with motivational concepts (self-efficacy, self-esteem and locus of control) in adult survivors is scarce. The purpose of this study is to investigate specific coherences between childhood abuse and adult life events with (a) motivational concepts (MC), (b) the emotion regulation strategy "goal-directed behavior" and (c) the possible mediation of emotion regulation (ER) on motivational concepts. We use data from a cross-sectional survey in Vienna (VIA-S) obtained from 220 adult survivors of prolonged interpersonal childhood trauma. In addition, we assess the Childhood Trauma Questionnaire, the Life Events Checklist for DSM-5, the subscale "Goals" (Difficulties in Emotion Regulation Questionnaire), the Short Scale for Measuring General Self-Efficacy Beliefs, the Multidimensional Self-Esteem Scale, and an extended version of the Internal-External Control Beliefs-4 Scale. An estimated multi-group path-model, divided by gender, was also conducted with the measures indicated above. Our results show that prolonged interpersonal childhood trauma directly relates to reduced self-efficacy, self esteem, and difficulties in ER. Concurrently, ER serves as a mediator for all MC. No gender differences were observed. Associations with adult life events were only found regarding self-efficacy. This study supports the notion that prolonged interpersonal childhood trauma in institutional settings impacts ER, which further mediates MC. Despite several study limitations (e.g. lack of a control group) the presented findings underline the importance of broadening the perception of trauma sequelae as well as integrating inhibited ER strategies and MC. PMID- 29128741 TI - Reliability of the knee muscle co-contraction index during gait in young adults with and without knee injury history. AB - Despite the frequent use of the electromyography-based muscle co-contraction index (CCI) to examine muscular control of the knee joint in young adults with and without knee injury history, the reliability of the CCI in this population is unknown. The purpose of this study was to quantify within-day and between-day reliability of the knee muscle CCI during gait in young adults with and without knee injury history. Twenty young adults (10 males, 10 females) with and without history of intra-articular knee injury performed repeated gait analyses on two different days. Surface electromyography of periarticular knee muscles was performed to determine CCIs for medial and lateral knee extensor - flexor pairs. Absolute (Bland-Altman ratio limits of agreement) and relative (ICCs) reliability were determined between two sessions on the same day as well as on different days. Within-day reliability was good to excellent for most analyzed co contraction outcomes (ICCs > 0.9) and was deemed acceptable in the context of clinically relevant changes in co-contraction in response to interventions. Between two separate days, the CCI showed poor reliability with measurement errors of up to 300% and was consequently not recommended as a tool to monitor long-term changes or group differences in knee muscular control. PMID- 29128742 TI - Corrigendum to "Harmony as a convergence attractor that minimizes the energy expenditure and variability in physiological gait and the loss of harmony in cerebellar ataxia."[Clin. Biomech. 48 (2017) 15-23]. PMID- 29128743 TI - The suppression of premature termination codons and the repair of splicing mutations in CFTR. AB - Premature termination codons (PTC) originate from nucleotide substitution introducing an in-frame PTC. They induce truncated, usually non-functional, proteins, degradation of the PTC containing transcripts by the nonsense-mediated decay (NMD) pathway and abnormal exon skipping. Readthrough compounds facilitate near cognate amino-acyl-tRNA incorporation, leading potentially to restoration of a functional full-length protein. Splicing mutations can lead to aberrantly spliced transcripts by creating a cryptic splice site or destroying a normal site. Most mutations result in disruption of the open reading frame and activation of NMD. Antisense oligonucleotides are single stranded short synthetic RNA-like molecules chemically modified to improve their stability and ability to recognize their target RNAs and modify the splice site. This review focuses on recent developments in therapies aiming to improve the health of CF patients carrying nonsense or splicing mutations. PMID- 29128744 TI - Comparison of two zoonotic viruses from the order Bunyavirales. AB - A comparison of two geographicallly distinct viruses in the order Bunyavirales that are zoonotic and known to cause congenital abnormalities in ruminant livestock was performed. One of these viruses, Cache Valley fever virus, is found in the Americas and is primarily associated with disease in sheep. The other, Rift Valley fever virus, is found in Sub-Saharan Africa and is associated with disease in camels, cattle, goats and sheep. Neither virus has been associated with teratogenicity in humans to date. These two viruses are briefly reviewed and potential for genetic changes especially if introduced into new ecology that could affect pathogenicity are discussed. PMID- 29128745 TI - A new method for determination of cocamidopropyl betaine synthesized from coconut oil through spectral shift of Eriochrome Black T. AB - Cocamidopropyl betaine (CAPB) is a zwitterionic surfactant that is synthesized using coconut oil and usually supplied in form of an aqueous solution with 25-37% w/w. In this study, a novel method based on UV-visible spectroscopy is developed for an accurate determination of CAPB synthesized from coconut oil. Eriochrome Black T (EBT) as a specific color indicator was added to CAPB and a red shift and color change were observed. This shift leads in increasing wavelength selectivity of the method. The change in the color intensity depends on the concentration of CAPB. By measuring the absorbance of a solution containing CAPB, its concentration was measured. After optimizing all the effective parameters, CAPB was detected in commercial real samples. Using the proposed approach, limit of quantification (LOQ) and relative standard deviation (RSD) were obtained about 4.30*10-5M and 4.8% respectively. None of unreacted materials or by-products, which were produced in the synthesis of CAPB, showed any interference in the determination of CAPB. This shows that the proposed method is specific and accurate, and can potentially be used for quantitative determination of CAPB in commercial samples with satisfactory results. PMID- 29128746 TI - Human serum albumin binding of certain antimalarials. AB - Interactions between eight in-house synthesized aminoquinolines, along with well known chloroquine, and human serum albumin (HSA) have been studied by fluorescence spectroscopy. The synthesized aminoquinolines, despite being structurally diverse, were found to be very potent antimalarials. Fluorescence measurements indicate that three compounds having additional thiophene or benzothiophene substructure bind more strongly to HSA than other studied compounds. Competitive binding experiments indicate that these three compounds bind significantly stronger to warfarin compared to diazepam binding site. Fluorescence quenching at three temperatures (20, 25, and 37 degrees C) was analyzed using classical Stern-Volmer equation, and a static quenching mechanism was proposed. The enthalpy and entropy changes upon sulphur-containing compound HSA interactions were calculated using Van't Hoff equation. Positive values of enthalpy and entropy changes indicate that non-specific, hydrophobic interactions are the main contributors to HSA-compound interaction. Molecular docking and calculated lipophilicity descriptors indicate the same, pointing out that the increased lipophilicity of sulphur-containing compounds might be a reason for their better binding to HSA. Obtained results might contribute to design of novel derivatives with improved pharmacokinetic properties and drug efficacy. PMID- 29128747 TI - Spectroscopy and energy transfer in lead borate glasses doubly doped with Tm3+ and Dy3+ ions. AB - Lead borate glasses singly and doubly doped with Tm3+ and Dy3+ were prepared by traditional melt-quenching technique. The emission spectra of rare earths in studied glass systems were registered under different excitation wavelengths. The observed emission bands are located in the visible spectral region. They correspond to 1D2->3F4 (blue) and 1G4->3H6 (blue) transitions of Tm3+ as well as 4F9/2->6H15/2 (blue), 4F9/2->6H13/2 (yellow) and 4F9/2->6H11/2 (red) transitions of Dy3+. Moreover, the energy transfer process from Tm3+ to Dy3+ was observed. The luminescence bands originating to characteristic transitions of thulium and dysprosium ions are present on emission spectra under direct excitation of Tm3+. Luminescence lifetimes for the excited states of Tm3+ and Dy3+ ions in lead borate glass were also determined based on decay measurements. The luminescence intensities and lifetimes depend significantly on the relative concentrations of the optically active dopants. PMID- 29128748 TI - Supramolecular interactions of oxidative stress biomarker glutathione with fluorone black. AB - Oxidative stress biomarkers, including glutathione (GSH) and related compounds, are involved in a variety of interactions enabling redox potential maintenance in living cells and protection against radicals. Since the oxidative stress is promoting and, in many cases, inducing serious illnesses, monitoring of GSH levels can aid in diagnostics and disease prevention. Herein, we report on the discovery of the formation of a supramolecular ensemble of GSH with fluorone black (9-phenyl fluorone, FB) which is optically active and enables sensitive determination of GSH by resonance elastic light scattering (RELS). We have found that supramolecular interactions of GSH with FB can be probed with spectroscopic, RELS, and electrochemical methods. Our investigations show that RELS intensity for FB solutions increases with GSH concentration while fluorescence emission of FB is not affected, as quenching begins only above 0.8mM GSH. The UV-Vis difference spectra show a positive peak at 383nm and a negative peak at 458nm, indicating a higher-energy absorbing complex in comparison to the non-bonded FB host. Supramolecular interactions of FB with GSH have also been corroborated by electrochemical measurements involving two configurations of FB-GSH ensembles on electrodes: (i) an inverted orientation on Au-coated quartz crystal piezoelectrode (Au@SG-FB), with strong thiolate bonding to gold, and (ii) a non inverted orientation on glassy carbon electrode (GCE@FB-GS), with weak pi-pi stacking attachment and efficient charge mediation through the ensemble. The formation of a supramolecular ensemble with hydrogen bonding has also been confirmed by quantum mechanical calculations. The discovery of supramolecular FB GSH ensemble formation enables elucidating the mechanisms of strong RELS responses, changes in UV-Vis absorption spectra, and the electrochemical reactivity. Also, it provides new insights to the understanding of the efficient charge-transfer in redox potential homeostasis which is likely based on an intermediate formation of a similar type of supramolecular ensembles. PMID- 29128749 TI - A chemiluminescence biosensor for the detection of thrombin based on the aptamer composites. AB - An efficient, rapid, simple and ultrasensitive chemiluminescence (CL) approach was proposed for thrombin detection based on the aptamer-thrombin recognition. The aptamer composites were synthesized in this work using graphene oxide (GO) as the backing material. The thrombin was adsorbed on the aptamer composites based on the aptamer-thrombin recognition. Thus, thrombin could be quantified by the difference value of the CL intensity between supernate of the sample and the mixture which composed of thrombin and coexisted substances. The CL intensity exhibits a stable response to thrombin over a concentration range from 2.5*10-10 to 1*10-9mol.L-1 with a detection limit as low as 8.3*10-11mol.L-1, the relative standard deviation (RSD) was found to be 4.9% for 11 determinations of 1.25*10 9mol.L-1 thrombin. Finally, the applicability of the method was verified by applying to serum samples. The recoveries were in the range of 90.3-101.0% with RSD of 2.6-3.2%. PMID- 29128750 TI - Reduction of interferences in the analysis of Children's Dimetapp using ultraviolet spectroscopy data and target factor analysis. AB - A calibration matrix has been developed and successfully applied to quantify actives in Children's Dimetapp(r), a cough mixture whose active components suffer from heavy spectral interference. High-performance liquid chromatography/photodiode array instrument was used to identify the actives and any other UV-detectable excipients that might contribute to interferences. The instrument was also used to obtain reference data on the actives, instead of relying on the manufacturer's claims. Principal component analysis was used during the developmental stages of the calibration matrix to highlight any mismatch between the calibration and sample spectra, making certain that "apples" were not compared with "oranges". The prediction model was finally calculated using target factor analysis and partial least squares regression. In addition to the actives in Children's Dimetapp(r) (brompheniramine maleate, phenylephrine hydrogen chloride, and dextromethorphan hydrogen bromide), sodium benzoate was identified as the major and FD&C Blue #1, FD&C Red #40, and methyl anthranilate as minor spectral interferences. Model predictions were compared before and after the interferences were included into the calibration matrix. Before including interferences, the following results were obtained: brompheniramine maleate=481.3mgL-1+/-134% RE; phenylephrine hydrogen chloride=1041mgL-1+/-107% RE; dextromethorphan hydrogen bromide=1571mgL-1+/-107% RE, where % RE=percent relative error based on the reference HPLC data. After including interferences, the results were as follows: brompheniramine maleate=196.3mgL-1+/-4.4% RE; phenylephrine hydrogen chloride=501.3mgL-1+/-0.10% RE; dextromethorphan hydrogen bromide=998.7mgL-1+/-1.6% RE as detailed in Table 6. PMID- 29128751 TI - A new silver metaniobate semiconductor of Ag0.5La0.5Nb2O6 with defect-perovskite structure. AB - Silver-containing lanthanum metaniobate Ag0.5La0.5Nb2O6 nanoparticles were synthesized by sol-gel polymerized complex method. A typical defect-perovskite structure was confirmed by XRD Rietveld refinements. The surface characteristics of the sample were tested by SEM, TEM and EDS measurements. SEM and TEM show that the sample presents ball-like particles with the diameters of 100nm to 400nm. The sample shows both self-activated luminescence and photocatalytic activities. Ag0.5La0.5Nb2O6 has a direct transition with band energy of 2.85eV. The Ag4d-O2p hybridization in the valence band contributes to the narrowed band gap. The luminescence properties of Ag0.5La0.5Nb2O6 have been investigated for the first time. The luminescence is characterized by two emission centers with maximum wavelength near 460 and 530nm. The emission and excitation spectra, decay curves and the thermal quenching mechanism were discussed. Ag0.5La0.5Nb2O6 shows the efficient photocatalytic activities and the photodegradation rate for methylene blue dye (MB) can reach about 95% under visible light (>420nm) irradiation in 5h. The trapped experiments for the active species were tested and discussed, which verified that OH radicals could be the major active species in photocatalysis. PMID- 29128752 TI - The roles of five conserved lentiviral RNA structures in HIV-1 replication. AB - The HIV-1 RNA genome contains complex structures with many structural elements playing regulatory roles during viral replication. A recent study has identified multiple RNA structures with unknown functions that are conserved among HIV-1 and two simian immunodeficiency viruses. To explore the roles of these conserved RNA structures, we introduced synonymous mutations into the HIV-1 genome to disrupt each structure. These mutants exhibited similar particle production, viral infectivity, and replication kinetics relative to the parent NL4-3 virus. However, when replicating in direct competition with the wild-type NL4-3 virus, mutations of RNA structures at inter-protein domain junctions can cause fitness defects. These findings reveal the ability of HIV-1 to tolerate changes in its sequences, even in apparently highly conserved structures, which permits high genetic diversity in HIV-1 population. Our results also suggest that some conserved RNA structures may function to fine-tune viral replication. PMID- 29128753 TI - Rab1A is required for assembly of classical swine fever virus particle. AB - Rab1A belongs to the small Rab GTPase family and is involved in the lifecycle of numerous viruses. Here, knockdown of Rab1A inhibited CSFV growth. Further study revealed that Rab1A depletion decreased intracellular and extracellular CSFV titers, but did not affect intracellular virus genome copies and E2 protein expression within a virus lifecycle, which suggested that Rab1A is required for CSFV particle assembly rather than for genome replication or virion release. This was proofed by blocking the spread of virus using neutralizing antibodies, through which the negative effects of Rab1A knockdown on multi-cycle replication of CSFV were eliminated. Moreover, co-immunoprecipitation and confocal microscopy assays showed that Rab1A bound to CSFV NS5A protein, indicating that Rab1A and viral NS5A proteins may work cooperatively during CSFV particle assembly. In conclusion, this study demonstrated for the first time that Rab1A is required for CSFV particle assembly and binds to viral particle assembly-related NS5A protein. PMID- 29128755 TI - Wheat streak mosaic virus coat protein is a determinant for vector transmission by the wheat curl mite. AB - Wheat streak mosaic virus (WSMV; genus Tritimovirus; family Potyviridae), is transmitted by the wheat curl mite (Aceria tosichella Keifer). The requirement of coat protein (CP) for WSMV transmission by the wheat curl mite was examined using a series of viable deletion and point mutations. Mite transmission of WSMV was completely abolished with deletions comprising CP amino acids 58-100. In contrast, the amino-proximal (amino acids 6-27 and 36-57) and carboxy-terminal (14 amino acids) regions of CP were expendable for mite transmission. Mutation of aspartic acid residues at amino acid positions 289 or 326 (D289A or D326A) at the carboxy-proximal region of CP significantly reduced mite transmission. Remarkably, every wheat plant infected by mutants D289A or D326A through mite transmission but not with in vitro transcripts contained a second-site mutation of R131C and N275H, respectively. Collectively, these data demonstrate for the first time that CP is a determinant for an eriophyid-transmitted plant virus. PMID- 29128754 TI - Development and characterization of a human monoclonal antibody targeting the N terminal region of hepatitis C virus envelope glycoprotein E1. AB - Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230-239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine. PMID- 29128756 TI - Integrase C-terminal residues determine the efficiency of feline foamy viral DNA integration. AB - Integrase (IN) is an essential enzyme in retroviral life cycle. It mediates viral cDNA integration into host cellular DNA. Feline foamy virus (FFV) is a member of the Spumavirus subfamily of Retroviridae. Recently, its life cycle has been proposed to be different from other retroviruses. Despite this important finding, FFV IN is not understood clearly. Here, we constructed point mutations in FFV IN C-terminal domain (CTD) to obtain a clear understanding of its integration mechanism. Mutation of the amino acid residues in FFV IN CTD interacting with target DNA reduced both IN enzymatic activities in vitro and viral productions in infected cells. Especially, the mutants, R307 and K340, made viral DNA integration less efficient and allowed accumulation of more unintegrated viral DNA, thereby suppressing viral replication. Therefore, we suggest that the CTD residues interacting with the target DNA play a significant role in viral DNA integration and replication. PMID- 29128757 TI - Lethal murine infection model for human respiratory disease-associated Pteropine orthoreovirus. AB - Pteropine orthoreovirus (PRV) is an emerging bat-borne human pathogen causing severe respiratory illness. To date, however, the evaluation of PRV virulence has largely depended on the limited numbers of clinical cases owing to the lack of animal models. To develop an in vivo model of PRV infection, an inbred C3H mouse strain was infected intranasally with pathogenic PRV strain Miyazaki-Bali/2007. C3H mice suffered severe lung infection with significant body weight reduction and died within 7 days after intranasal infection. Infectious viruses were isolated mainly from the lungs and trachea. Histopathological examination revealed interstitial pneumonia with monocytes infiltration. Following repeated intranasal infection, mice developed antibodies to particular structural and non structural proteins of PRV. The results of these immunological assays will help to develop laboratory protocols for sero-epidemiological studies. Our small rodent model of lethal respiratory infection will further allow investigation of the molecular mechanisms underlying the high pathogenicity of PRV. PMID- 29128759 TI - A conduction velocity adapted eikonal model for electrophysiology problems with re-excitability evaluation. AB - Computational models of heart electrophysiology achieved a considerable interest in the medical community as they represent a novel framework for the study of the mechanisms underpinning heart pathologies. The high demand of computational resources and the long computational time required to evaluate the model solution hamper the use of detailed computational models in clinical applications. In this paper, we present a multi-front eikonal algorithm that adapts the conduction velocity (CV) to the activation frequency of the tissue substrate. We then couple the eikonal new algorithm with the Mitchell-Schaeffer (MS) ionic model to determine the tissue electrical state. Compared to the standard eikonal model, this model introduces three novelties: first, it evaluates the local value of the transmembrane potential and of the ionic variable solving an ionic model; second, it computes the action potential duration (APD) and the diastolic interval (DI) from the solution of the MS model and uses them to determine if the tissue is locally re-excitable; third, it adapts the CV to the underpinning electrophysiological state through an analytical expression of the CV restitution and the computed local DI. We conduct series of simulations on a 3D tissue slab and on a realistic heart geometry and compare the solutions with those obtained solving the monodomain equation. Our results show that the new model is significantly more accurate than the standard eikonal model. The proposed model enables the numerical simulation of the heart electrophysiology on a clinical time scale and thus constitutes a viable model candidate for computer-guided radio-frequency ablation. PMID- 29128758 TI - Discovery of novel anelloviruses in small mammals expands the host range and diversity of the Anelloviridae. AB - The Anelloviridae comprises single-stranded DNA viruses currently grouped in sixty-eight species classified in twelve genera. They have been found in many vertebrate hosts including primates. In this study, we describe the application of the high-throughput sequencing to examine the frequency and diversity of anelloviruses in rodents, bats and opossums captured in Sao Paulo State, Brazil. We report a total of twenty-six anelloviruses with sixteen nearly complete genomes and ten partial genomes, which include eleven potential novel species identified in rodents (Cricetidae), bats (Molossidae and Phyllostomidae), and opossums (Didelphidae). We also propose the inclusion of two potential new genera within the Anelloviridae family, provisionally named Omegatorquevirus and Sigmatorquevirus, including six and three novel species of anelloviruses, respectively. In summary, this study expands the diversity and the host range of the known anelloviruses. PMID- 29128760 TI - Vitamin D deficiency in children with recurrent respiratory infections, with or without immunoglobulin deficiency. AB - PURPOSE: The objective of this study was to evaluate thevitamin D concentration in patients with recurrent respiratory infections with or without immunoglobulin G, A or M (IgG, IgA, IgM) deficiency, and to find a correlation between the vitamin D concentration and the response to hepatitis B vaccination. MATERIALS AND METHOD: The study involved 730 patients with recurrent respiratory infections. The concentration of 25-hydroxyvitamin D (25(OH)D), immunoglobulins G, A and M, anti-HBs was determined. RESULTS: The tests showed that 11% of patients presented IgG levels below the age related reference values. Children with reduced IgG concentration were also found to have significantly lower vitamin D concentrations in comparison to children with normal IgG. Vitamin D deficiency was observed in schoolchildren between 7 and 18 years of age. No correlation was found between 25(OH)D concentration and Hbs antibody levels. CONCLUSIONS: An investigation of a large group of patients who have recurrent infection found patients with IgG deficiency to whom special proceeding have to be performed: 1. Significantly lower vitamin D concentration observed in the group of children with IgG deficiency implicated in long-lasting monitoring of vitamin D level require adding to the practice guidelines for Central Europe 2013. 2. Intervention treatment with suitable doses of vitamin D to clarified metabolism of vitamin D has to be plan for children with IgG deficiency and significant lower vitamin D concentration. PMID- 29128762 TI - Stable isotope evidences for identifying crop water uptake in a typical winter wheat-summer maize rotation field in the North China Plain. AB - Better managing agricultural water resources, which are increasingly stressed by climate change and anthropogenic activities, is difficult, particularly because of variations in water uptake patterns associated with crop type and growth stage. Thus, the stable isotopes delta18O and delta2H were employed to investigate the water uptake patterns of a summer maize (Zea mays L.) and winter wheat (Triticum aestivum L.) rotation system in the North China Plain. Based on the soil water content, soil layers were divided into four groups (0-20cm, 20 40cm, 40-120cm, and 120-200cm) using a hierarchical cluster analysis. The main soil layer of water uptake for summer maize was from 0-20cm at the trefoil (77.8%) and jointing (48.6%) stages to 20-40cm at the booting (33.6%) and heading (32.6%) stages, became 40-120cm at the silking (32.0%) and milking (36.7%) stages, and then returned to 0-20cm at the mature (35.0%) and harvest (52.4%) stages. Winter wheat most absorbed water from the 0-20cm soil water at the wintering (86.6%), seedling (83.7%), jointing (45.2%), booting (51.4%), heading (28.8%), and mature (67.8%) stages, but it was 20-40cm at the flowering (34.8%) and milking (25.2%) stages. The dry root weight density was positively correlated with the contributions of the water uptake for winter wheat. However, no similar correlation was found in summer maize. Regression analysis indicated that the soil volumetric water content (SVWC) was negatively correlated with the contribution of the water uptake (CWU) for summer maize (CWU=-0.91*SVWC+57.75) and winter wheat (CWU=-2.03*SVWC+92.73). These different responses to water uptake contributions suggested that a traditional irrigation event should be postponed from the booting to flowering stage of winter wheat. This study provides insights into crop water uptake and agricultural water management. PMID- 29128763 TI - Improving the hydrocarbon production via co-pyrolysis of bagasse with bio-plastic and dual-catalysts layout. AB - Catalytic fast pyrolysis (CFP) of bagasse and bio-plastic (chicken feather keratin) and their mixtures were conducted to produce aromatic hydrocarbons over a HZSM-5, USY, and dual-catalysts layout. The effects of temperature, co-feeding ratios, feed-to-catalyst ratios and dual catalysts on hydrocarbon yields and selectivities were investigated. The results show a general improvement in the aromatic hydrocarbons yields in all cases compared to non-catalytic and pure biomass pyrolysis. The aromatic hydrocarbons increased by 10 fold with the increase of temperature from 400 degrees C to 700 degrees C. The aromatic yields increased 1.5 times at co-feeding, 2.0 greater at feed/HZSM-5 ratio of 1:6, 1.2 times at feed/USY ratio of 1:16, and 2.66 times at USY/HZSM-5 scenario. The selectivities towards benzene increased, at higher co-feeding ratios, while that of toluene shows an opposite trend. Xylenes selectivities were less sensitive to the changes of co-feeding ratios. In contrast, the USY catalyst only produced little amount of toluene and xylenes. The dual catalyst design (USY/HZSM-5) resulted in the highest aromatic yields, than other catalyst design scenarios. The pyrolysis temperature is a significant parameter for hydrocarbon production. Co-feeding bagasse and bio-plastic enhanced biomass conversion to aromatic compounds. For any type of zeolite catalyst, there was an optimum feed-to catalyst ratio that generated maximum hydrocarbons. Dual catalyst layout shows a new opportunity for efficient conversion of biomass materials into hydrocarbons. PMID- 29128761 TI - Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals. AB - It has been estimated that there are at least 1.5 million fungal species, mostly present in the environment, but only a few of these fungi cause human disease. Most fungal diseases are self-healing and benign, but some are chronic or life threatening. Acquired and inherited defects of immunity, including breaches of mucocutaneous barriers and circulating leukocyte deficiencies, account for most severe modern-day mycoses. Other types of infection typically accompany these fungal infections. More rarely, severe fungal diseases can strike otherwise healthy individuals. Historical reports of fungi causing chronic peripheral infections (e.g. affecting the nails, skin, hair), and invasive diseases (e.g. brain, lungs, liver), in otherwise healthy patients, can be traced back to the mid-20th century. These fungi typically cause endemic, but not epidemic diseases, are more likely to underlie sporadic than familial cases, and only threaten a small proportion of infected individuals. The basis of this 'idiosyncratic' susceptibility has long remained unexplained, but it has recently become apparent that 'idiopathic' fungal diseases, in children, teenagers, and even adults, may be caused by single-gene inborn errors of immunity. The study of these unusual primary immunodeficiencies (PIDs) has led to the identification of molecules and cells playing a crucial role in human host defenses against certain fungi at particular anatomic sites. A picture is emerging of inborn errors of IL-17 immunity selectively underlying chronic mucocutaneous candidiasis, with little inter-individual variability, and of inborn errors of CARD9 immunity underlying various life-threatening invasive fungal diseases, differing between patients. PMID- 29128764 TI - Synthetic and non-synthetic anthropogenic fibers in a river under the impact of Paris Megacity: Sampling methodological aspects and flux estimations. AB - Processed fibers are highly present in our daily life and can be either natural, artificial (regenerated cellulose) and synthetic (made with petrochemicals). Their widespread use lead inevitably to a high contamination of environment. Previous studies focus on plastic particles regardless of their type or shape as long as they are comprised between 330MUm and 5mm. On the contrary, this study focuses exclusively on fibers using a smaller mesh size net (80MUm) to sample freshwater. Moreover, all processed organic fibers are considered, irrespective to their nature. First, the short term temporal variability of the fibers in the environment was assessed. While exposing the sampling net during 1min a coefficient of variation of approx. 45% (with n=6) was determined. It was of only 26% (n=6) when the exposure was of 3min. The assessment of the distribution through the section showed a possible difference in concentrations between the middle of the water surface and the river banks which could be attributed to the intense river traffic within the Paris Megacity. The vertical variability seems negligible as turbulence and current conditions homogenize the distribution of the fibers. A monthly monitoring showed concentrations of 100.6+/-99.9fibers.m-3 in the Marne River and of: 48.5+/-98.5, 27.9+/-26.3, 27.9+/-40.3 and 22.1+/ 25.3fibers.m-3 from the upstream to downstream points in the Seine River. Once these concentrations are converted into fluxes, it seems that the impact generated by the Paris Megacity cannot be distinguished. Investigations on the role of sedimentation and deposition on the banks are required. This study helped fill some major knowledge gaps regarding the fibers in rivers, their sampling, occurrence, spatial-temporal distribution and fluxes. It is encouraged that future studies include both synthetic and none synthetic fibers. PMID- 29128765 TI - Exploring the links between groundwater quality and bacterial communities near oil and gas extraction activities. AB - Bacterial communities in groundwater are very important as they maintain a balanced biogeochemical environment. When subjected to stressful environments, for example, due to anthropogenic contamination, bacterial communities and their dynamics change. Studying the responses of the groundwater microbiome in the face of environmental changes can add to our growing knowledge of microbial ecology, which can be utilized for the development of novel bioremediation strategies. High-throughput and simpler techniques that allow the real-time study of different microbiomes and their dynamics are necessary, especially when examining larger data sets. Matrix-assisted laser desorption-ionization (MALDI) time-of flight mass spectrometry (TOF-MS) is a workhorse for the high-throughput identification of bacteria. In this work, groundwater samples were collected from a rural area in southern Texas, where agricultural activities and unconventional oil and gas development are the most prevalent anthropogenic activities. Bacterial communities were assessed using MALDI-TOF MS, with bacterial diversity and abundance being analyzed with the contexts of numerous organic and inorganic groundwater constituents. Mainly denitrifying and heterotrophic bacteria from the Phylum Proteobacteria were isolated. These microorganisms are able to either transform nitrate into gaseous forms of nitrogen or degrade organic compounds such as hydrocarbons. Overall, the bacterial communities varied significantly with respect to the compositional differences that were observed from the collected groundwater samples. Collectively, these data provide a baseline measurement of bacterial diversity in groundwater located near anthropogenic surface and subsurface activities. PMID- 29128766 TI - Low biodegradability of dissolved organic matter and trace metals from subarctic waters. AB - The heterotrophic mineralization of dissolved organic matter (DOM) controls the CO2 flux from the inland waters to the atmosphere, especially in the boreal waters, although the mechanisms of this process and the fate of trace metals associated with DOM remain poorly understood. We studied the interaction of culturable aquatic (Pseudomonas saponiphila) and soil (Pseudomonas aureofaciens) Gammaproteobacteria with seven different organic substrates collected in subarctic settings. These included peat leachate, pine crown throughfall, fen, humic lake, stream, river, and oligotrophic lake with variable dissolved organic carbon (DOC) concentrations (from 4 to 60mgL-1). The highest removal of DOC over 4days of reaction was observed in the presence of P. aureofaciens (33+/-5%, 43+/ 3% and 53+/-7% of the initial amount in fen water, humic lake and stream, respectively). P. saponiphila degraded only 5% of DOC in fen water but did not affect all other substrates. Trace elements (TE) were essentially controlled by short-term (0-1h) adsorption on the surface of cells. Regardless of the nature of organic substrate and the identity of bacteria, the degree of adsorption ranged from 20 to 60% for iron (Fe3+), 15 to 55% for aluminum (Al), 10 to 60% for manganese (Mn), 10 to 70% for nickel (Ni), 20 to 70% for copper (Cu), 10 to 60% for yttrium (Y), 30 to 80% for rare earth elements (REE), and 15 to 50% for uranium (UVI). Rapid adsorption of organic and organo-mineral colloids on bacterial cell surfaces is novel and potentially important process, which deserves special investigation. The long-term removal of dissolved Fe and Al was generally consistent with solution supersaturation degree with respect to Fe and Al hydroxides, calculated by visual Minteq model. Overall, the biomass-normalized biodegradability of various allochthonous substrates by culturable bacteria is much lower than that of boreal DOM by natural microbial consortia. PMID- 29128767 TI - Biochar alleviates phytotoxicity in Ficus elastica grown in Zn-contaminated soil. AB - Zinc (Zn) immobilization by two distinct biochars in soil, together with concomitant alleviation of phytotoxic responses in Ficus elastica Roxb. ex Hornem., were examined. Rooted cuttings of F. elastica were grown in 880mgkg-1 Zn spiked sandy soil amended with grain husk (GH) or cattle manure (CM) biochar at 0, 10, 30 and 50gkg-1 soil for a period of 6months. Addition of both GH and CM biochars had significant positive impacts on physiological parameters such as plant growth, leaf relative water content, photosynthetic pigments and leaf gas exchange characteristics. The responses to addition of CM biochar were significantly better than to GH biochar. Lipid peroxidation declined in leaves of plants grown in Zn-contaminated, biochar-amended soil. This was confirmed by luminescence and Fourier transform infrared analysis of the leaf material. Biochar significantly reduced the availability of soil Zn, as evidenced by lower concentrations of Zn in leaves and leachates of biochar treated plants relative to control plants. These findings show that biochar can effectively immobilize soil Zn, and as a result, alleviate Zn phytotoxicity by reducing its uptake and accumulation in the plant. Adding biochar to soils contaminated with metals thus holds promise as a means of restoring blighted lands. PMID- 29128768 TI - Contaminated land in Colombia: A critical review of current status and future approach for the management of contaminated sites. AB - Environmental contaminants can have negative effects on human health and land, air and water resources. Consequently, there have been significant advances in regulation for protecting the environment in developed countries including the development of remediation frameworks and guidelines. On the other hand, fewer studies have been reported on the risks and health effects of contaminants in developing regions and there is scarce information regarding contaminated land assessment and environmental remediation. Colombia is an important emerging economy and has started to take the first steps towards the development of a framework for the management of contaminated sites and there are opportunities for the country to learn from countries with well-established frameworks such as the United States (US) and the United Kingdom (UK) and for international collaboration with organisations such as CRC for Contamination Assessment and Remediation of the Environment (CARE). We review main pollution issues, current status of contaminated land management in Colombia to identify the gaps in policy and regulation. We also review the UK and US contaminated land policies and regulations to identify the elements of those experiences that could support progress in the country. Finally, we propose recommendations (e.g. risk based approach, soil screening criteria, clean-up funding, liability) for Colombia that could support further development and implementation of a more effective contaminated land management framework. PMID- 29128769 TI - Erosion-induced losses of carbon, nitrogen, phosphorus and heavy metals from agricultural soils of contrasting organic matter management. AB - Water erosion on agricultural land preferentially carries away fine particles. Due to the generally high specific density of sorption sites of these particles, their displacement can be associated with substantial particle-bound transfer also of nutrients and pollutants with low solubility. Organic matter amendments can reduce soil erosion, but to what extent they affect the erosion-induced element losses has not been studied much. Here, we carried out field rainfall experiments on three pairs of soil plots (1.5*0.75m) after incorporating a mixture of wheat straw and grass (2.12gC per kg soil) as organic amendment into the topsoil (0-5cm depth) of one plot in each pair (OI treatment). The other plot was prepared in the same way but without incorporation of the amendment (NI treatment). Artificial rainfall (49.1mmh-1) was simultaneously applied on each pair of plots for approximately 2h, and sediment samples were collected at designated time steps for the analyses of C, N, P, Cu, Zn and stable carbon isotope ratios. The organic amendment substantially reduced element losses, but to a lesser extent than soil loss, as the element concentrations were higher in the exported sediments in the OI than in the NI treatment. With and without organic amendment, the concentrations of the studied elements were consistently higher in the exported sediments than in the bulk soil. They were always maximal at the onset of discharge and then continuously decreased towards the values of the bulk soil. The delta13C values revealed that the eroded C was preferentially derived from the fresh organic residue added to the soil. Pairwise correlations between elements and sediment size indicate that the export of N, Cu and Zn was primarily associated with soil organic matter loss, whereas P export was more associated with mineral fractions. PMID- 29128770 TI - Ivermectin residues disrupt dung beetle diversity, soil properties and ecosystem functioning: An interdisciplinary field study. AB - Ivermectin is the most common endectocide used to control parasites affecting livestock. Short-term physiological and behavioural effects of ivermectin on dung beetles may have long-term consequences for beetle populations and ecosystem functioning. Long-term effects of the use of ivermectin can be estimated by comparing dung assemblages and ecosystem functions in areas with conventional ivermectin-treated livestock and environmentally similar areas in which livestock are not treated with veterinary medical products (organic farming). In this study, we investigated both short-term and long-term effects of the administration of ivermectin on the characteristics of dung beetle assemblages and the services they provided in a protected area (Donana National Park, SW Spain). We examined short-term dung colonization, dwelling, relocation, and disaggregation rates and the associations between these processes and the key assemblage parameters of species richness, abundance, biomass and functional diversity. Furthermore, we analysed changes in soil physical-chemical properties and processes. Short-term differences were observed in the total amount of dung relocated by dung beetles at different colonization vs. emigration stages, suggesting that dung beetles in this area were affected by the recent treatments of livestock with ivermectin. Moreover, short-term effects could also be responsible for the significant differences in dung spreading rates between sites. Conventional use of ivermectin disrupted ecosystem functioning by affecting species richness, abundance and biomass. The decrease in diversity parameters was related to a reduction in the functional efficiency, which resulted in the long-term accumulation of dung on the ground and considerable changes in soil functionality. PMID- 29128771 TI - The acute thermal respiratory response is unique among species in a guild of larval anuran amphibians-Implications for energy economy in a warmer future. AB - Climate change is bringing about increased temperatures of amphibian habitats throughout the world, where ectothermic larvae will experience elevated respiratory (metabolic) energy demands. We compared the acute, thermal respiratory response ("TRR") of four species of sympatric larval amphibians (Lithobates sphenocephalus, L. catesbeianus, Scaphiopus holbrookii, and Hyla chrysoscelis) to determine species-specific differences in the rate at which metabolic energy requirements increase with temperature. The TRR, the slope of the relationship between respiration rate and temperature within critical thermal limits, varied significantly among species such that the absolute, per capita change in metabolic energy requirement as temperature increased was greater for L. sphenocephalus and L. catesbeianus than for H. chrysoscelis and S. holbrookii. This was also reflected in the temperature coefficients (Q10,18.5-25.5), which ranged from 1.77 (S. holbrookii) to 2.70 (L. sphenocephalus) for per capita respiration rates. Our results suggest that L. sphenocephalus and L. catesbeianus will experience a more rapid increase in energetic requirements as temperature increases relative to the other species, possibly magnifying their influences on the resource pool. There is a critical paucity of information on the metabolic responses of most larval amphibians across a range of temperatures, despite that this relationship dictates the magnitude of the priority investment of assimilated energy in respiration, thus shaping the energetic economy of the individual. A broader knowledge of species-specific TRRs, combined with research to determine thermal acclimatory or adaptive potentials over chronic time scales, will provide a framework for evaluating whether asymmetric, climate-mediated differences in energetic demands among species could ultimately influence larval amphibian ecology in a warmer future. PMID- 29128772 TI - Intrinsic and extrinsic factors which influence metal adsorption to road dust. AB - The adsorption behaviour of metals deposited on road surfaces is a complex process and influenced by a range of factors common to the urban environment. However, all factors do not have the same level of importance. It is therefore important to identify the most crucial factors for accurate stormwater quality predictions and to implement effective stormwater pollution mitigation measures. Accordingly, this study investigated the extrinsic and intrinsic factors in terms of their degree of influence on the adsorption of individual metal cations to particulates. The variability associated with the adsorption of Zn, Cu, Pb, Cd, Cr and Ni to road dust was found to be influenced by changes to the antecedent dry days and land use characteristics. The initial dry days after a storm event exerts a significant influence on adsorption compared to the later dry days in all land uses. In terms of the intrinsic physico-chemical properties of road dust, the parameters that influence the adsorption process differ in terms of the type of metal cation and particle size fractions of solids. Based on the influential parameters identified, the bioavailability characteristics of Zn, Cd, Pb and Ni in <150MUm size fraction of road dust and potential stormwater quality impacts can be highlighted. PMID- 29128773 TI - Evaluation of potassium thiosulfate as a nitrification inhibitor to reduce nitrous oxide emissions. AB - Potassium thiosulfate (KTS, K2S2O3) has been shown to function as a nitrification inhibitor, thus has the potential to reduce nitrous oxide (N2O) emissions and play an important role in effective N management. The objective of this research was to determine the potential effects of KTS on N2O emissions and N transformation processes in comparison with commercial N transformation inhibitors (stabilizers). A laboratory incubation experiment was conducted using urea and ammonium nitrate (UAN) applied at 150mgNkg-1 in a Hanford sandy loam soil (coarse-loamy, mixed, superactive, nonacid, thermic Typic Xerorthents). Treatments included three rates of KTS (26, 51, and 102mgS2O32--Skg-1), a urease and nitrification inhibitor (Agrotain(r) Plus), a nitrification inhibitor (N Serve(r) 24), and an untreated control. Nitrous oxide emission, soil pH, and mineral N species were monitored for 35days. Total N2O emissions were reduced significantly by all KTS treatments as a function of KTS rate. At 102mgS2O32--Skg 1, KTS reduced N2O emissions by 48% (0.18% of total inorganic N), which was statistically similar to the N-Serve(r) 24 treatment (60% reduction) although lower than Agrotain(r) Plus (78% reduction). The KTS resulted in significantly less unaccounted (total N) loss compared to the commercial inhibitors. If the N2O emissions reductions observed in this laboratory study are validated in the field, using KTS for this purpose can also provide a fertility benefit and may reduce total chemical inputs into agronomic systems. Future research needs to determine the effectiveness of thiosulfate for improving overall nutrient management while reducing N2O emissions under field conditions. PMID- 29128775 TI - Lentic small water bodies: Variability of pesticide transport and transformation patterns. AB - Lentic small water bodies have a high ecological potential as they fulfill several ecosystem services such as the retention of water and pollutants. They serve as a hot spot of biodiversity. Due to their location in or adjacent to agricultural fields, they can be influenced by inputs of pesticides and their transformation products. Since small water bodies have rarely been part of monitorings/campaigns up to now, their current exposure and processes guiding the pesticide input are not understood, yet. This study presents results of a sampling campaign of 10 lentic small water bodies from 2015 to 2016. They were sampled once after the spring application for a pesticide target screening, before autumn application and three times after rainfall events following the application. The autumn sampling focused on the herbicides metazachlor, flufenacet and their transformation products - oxalic acid and - sulfonic acid as representatives for common pesticides in the study region. The concentrations were associated with rainfall before and after application, characteristics of the site and the water bodies, physicochemical parameters and the applied amount of pesticides. The key results of the pesticide screening in spring indicate positive detections of pesticides which have not been applied for years to the single fields. The autumn sampling showed frequent occurrences of the transformation products, which are formed in soil, from 39% to 94% of all samples (n=71). Discharge patterns were observed for metazachlor with highest concentrations in the first sample after application and then decreasing, but not for flufenacet. The concentrations of the transformation products increased over time and revealed highest values mainly in the last sample. Besides rainfall patterns right after application, the spatial and temporal dissemination of the pesticides to the water bodies seems to play a major role to understand the exposure of lentic small water bodies. PMID- 29128774 TI - The effect of hydraulic retention time in onsite wastewater treatment and removal of pharmaceuticals, hormones and phenolic utility substances. AB - Micropollutants such as pharmaceuticals, hormones and phenolic utility chemicals in sewage water are considered to be an emerging problem because of increased use and observed adverse effects in the environment. The study provides knowledge on the removal efficiency of micropollutants with a range of physical and chemical properties in three commercially available onsite wastewater treatment facilities (OWTFs), tested on influent wastewater collected from 2500 person equivalents in Bildchen, Germany. A longer hydraulic retention time would in theory be expected to have a positive effect, and this study presents results for three different OWTFs in full-scale comparable tests under natural conditions. A range of 24 different pharmaceuticals, five phenols and three hormones were analyzed. Flow proportional consecutive sampling was performed in order to determine the removal efficiency. Twenty-eight substances were detected in the effluent wastewater out of 32 substances included. Average effluent concentrations of Simvastatin, Estrone, Estradiol and Ethinylestradiol were above the indicative critical-effect concentration of pharmacological effect on fish in all facilities. Average effluent concentrations of both Diclofenac and Estradiol were higher than the Environmental Quality Standards applied in Sweden (190-240 times and 9-35 times respectively). The removal efficiency of micropollutants was high for substances with high logKow, which enhance the adsorption and removal with sludge. Low removal was observed for substances with low logKow and acidic characteristics, and for substances with stabilizing elements of the chemical structure. Facilities that use activated sludge processes removed hormones more efficiently than facilities using trickling filter treatment technique. Moreover, longer hydraulic retention time increased the removal of pharmaceuticals, hormones, turbidity and total nitrogen. Removal of Caffeine, Ibuprofen, Estrone, Naproxen and Estradiol, was strongly correlated to the sludge and particles removal. Thus, the efficiency of the tested OWTFs could be improved by adjusting the technical methods and increasing the hydraulic retention time. PMID- 29128776 TI - Facilitation of amphibious habit by physiological integration in the clonal, perennial, climbing herb Ipomoea aquatica. AB - Physiological integration of connected ramets of clonal plants can increase clonal performance when ramets grow in contrasting microenvironments within a habitat. In amphibious clonal species, integration of ramets in different habitats, terrestrial and aquatic, is possible. This may increase performance of amphibious clones, especially under eutrophic conditions. To test this, clonal fragments consisting of two ramets of the amphibious, perennial, climbing herb Ipomoea aquatica connected by a stem were placed such that the proximal ramet was rooted in a simulated riparian community of four other species, while the distal ramet extended into a simulated aquatic habitat with open water and sediment. The connection between ramets was either left intact or severed, and 0, 5, or 25mg N L-1 was added to the aquatic habitat to simulate different degrees of eutrophication. Without added N, fragments in which the original ramets were left connected accumulated two times more total mass than fragments in which the ramets were disconnected from one another. The positive effect of connection increased two-fold with increasing N. These results were consistent with the hypotheses that physiological integration between connected terrestrial and aquatic ramets can increase clonal performance in plants and that this effect can be greater when the aquatic ramet is richer in nutrients. Connection reduced root to shoot ratio in terrestrial ramets, but increased it in aquatic ones, suggesting that physiological integration induced a division of labor in which terrestrial ramets specialized for light acquisition and aquatic ramets specialized for acquisition of nutrients. This provides the first report of increase in clonal performance and induction of division of labor due to physiological integration between ramets in different habitats. PMID- 29128777 TI - A systematic review of heart failure dyadic self-care interventions focusing on intervention components, contexts, and outcomes. AB - BACKGROUND: Having support from an informal carer is important for heart failure patients. Carers have the potential to improve patient self-care. At the same time, it should be acknowledged that caregiving could affect the carer negatively and cause emotional reactions of burden and stress. Dyadic (patient and informal carer) heart failure self-care interventions seek to improve patient self-care such as adherence to medical treatment, exercise training, symptom monitoring and symptom management when needed. Currently, no systematic assessment of dyadic interventions has been conducted with a focus on describing components, examining physical and delivery contexts, or determining the effect on patient and/or carer outcomes. OBJECTIVE: To examine the components, context, and outcomes of dyadic self-care interventions. DESIGN: A systematic review registered in PROSPERO, following PRISMA guidelines with a narrative analysis and realist synthesis. DATA SOURCES: PubMed, EMBASE, Web of Science, PsycINFO, and Cochrane Central Register of Controlled Trials were searched using MeSH, EMTREE terms, keywords, and keyword phrases for the following concepts: dyadic, carers, heart failure and intervention. Eligible studies were original research, written in English, on dyadic self-care interventions in adult samples. REVIEW METHODS: We used a two tiered analytic approach including both completed studies with power to determine outcomes and ongoing studies including abstracts, small pilot studies and protocols to forecast future directions. RESULTS: Eighteen papers - 12 unique, completed intervention studies (two quasi- and ten experimental trials) from 2000 to 2016 were reviewed. Intervention components fell into three groups - education, support, and guidance. Interventions were implemented in 5 countries, across multiple settings of care, and involved 3 delivery modes - face to face, telephone or technology based. Dyadic intervention effects on cognitive, behavioral, affective and health services utilization outcomes were found within studies. However, findings across studies were inconclusive as some studies reported positive and some non-sustaining outcomes on the same variables. All the included papers had methodological limitations including insufficient sample size, mixed intervention effects and counter-intuitive outcomes. CONCLUSIONS: We found that the evidence from dyadic interventions to promote heart failure self care, while growing, is still very limited. Future research needs to involve advanced sample size justification, innovative solutions to increase and sustain behavior change, and use of mixed methods for capturing a more holistic picture of effects in clinical practice. PMID- 29128778 TI - Circadian blood pressure patterns and blood pressure control in patients with chronic kidney disease. AB - BACKGROUND AND AIMS: Hypertension is a major risk factor for chronic kidney disease (CKD), and CKD progression is associated with suboptimal blood pressure (BP) control. Here we evaluate the impact of CKD on the attainment of BP control and the circadian BP profile in older subjects. METHODS: In this observational study, we studied 547 patients referred to the hypertension clinic, of whom 224 (40.9%) had CKD. Blood pressure (BP) control and circadian BP patterns were evaluated by 24-hour ambulatory BP monitoring. Circadian BP variability was measured as the within-subject SD of BP, the percentage of measurements exceeding normal values, hypotension, and dipping status. RESULTS: The attainment of adequate BP control was similar in subjects with or without CKD (around 31%). Logistic regression analysis indicated that CKD was not a determinant of adequate BP control (OR 1.004; 95% CI 0.989-1.019; p = 0.58). Patients with CKD presented as twice as higher prevalence of reverse dipper (night-time peak) for systolic BP and episodes of hypotension during daytime, independently of BP control. CONCLUSIONS: Knowledge of the circadian pattern of BP in hypertensive subjects with CKD could inform better than attainment of BP target about risky condition for CKD progression and cognitive decline and allow a more personalized antihypertensive treatment. PMID- 29128779 TI - Noninvasive ventilation failure in pneumonia patients >=65years old: The role of cough strength. AB - PURPOSE: To explore the association between cough strength and outcomes in elderly patients who received noninvasive ventilation (NIV) due to acute respiratory failure caused by pneumonia. MATERIALS AND METHODS: We enrolled patients >=65years old with acute respiratory failure caused by pneumonia. Just before NIV treatment, cough strength was assessed on a cough-strength scale graded from 0 to 5. Patients graded 0-2 were defined as having no/weak coughs and those graded 3-5 were defined as having moderate/strong coughs. RESULTS: We enrolled 349 patients in this study. The prevalence of no/weak cough was 24% (84/349). Moderate/strong cough patients had lower NIV failure (92/265 [34.7%] vs. 67/84 [79.8%], p<0.01) and lower hospital mortality (85/265 [32.1%] vs. 60/84 [71.4%], p<0.01) than no/weak cough patients. In multivariate logistic regression analysis, we also found that no/weak cough was an independent risk factor for NIV failure (odds ratio=13.83, 95% confidence interval: 6.01-31.81) and death in hospital (odds ratio=4.41, 95% confidence interval: 2.49-7.81). CONCLUSIONS: In pneumonia patients >=65years old, no/weak cough is associated with NIV failure and death in hospital. NIV must be used only with caution in no/weak cough patients. PMID- 29128780 TI - Apnea testing using the oxygen insufflation method for diagnosis of brain death may compromise pulmonary function. AB - INTRODUCTION: The aim of our study was to compare the reliability and safety of the classical I-AT with the continuous positive airway pressure apnea test (CPAP AT). MATERIAL AND METHODS: In the group of 48 patients (group O), an I-AT was performed at the end of BD diagnostic procedures, and approximately 1-1.5h later CPAP-AT with 100% FiO2 and CPAP of 10cm H2O, provided by ventilator in CPAP mode. After pre-oxygenation with 100% FiO2 for 10min, the PaO2/FiO2 ratio was recorded prior to I-AT at time-point one (T1) and prior to CPAP-AT at time-point two (T2). Group O was categorized into subgroup N-H (non-hypoxemic), consisting of 41 patients with good lung function, and subgroup H (hypoxemic) consisting of 7 patients with poor lung function. Within each subgroup PaO2/FiO2 at T1 and T2 were compared. RESULTS: In Group O, PaO2/FiO2 decreased from 321+/-128mmHg at T1 to 291+/-119mmHg at T2 (p=0.004). In subgroup N-H, PaO2/FiO2 declined from 355+/ 103 to 321+/-100mmHg (p=0.008), and in subgroup H, PaO2/FiO2 remained almost unchanged. Additionally, in 4 patients from subgroup N-H, PaO2/FiO2 decreased below 200mmHg at T2. CONCLUSIONS: Our study indicates that I-AT may compromise pulmonary function and this may support the recommendation of safer CPAP-AT alternative. PMID- 29128781 TI - Photosynthesis impairments and excitation energy dissipation on wheat plants supplied with silicon and infected with Pyricularia oryzae. AB - Considering the effect of silicon (Si) in reducing the blast symptoms on wheat in a scenario where the losses in the photosynthetic capacity of the infected plants is lowered, this study investigated the ability of using the incident light, the chloroplastidic pigments (chlorophylls and carotenoids) alterations and the possible role of carotenoids on the process of light dissipation on wheat plants non-supplied (-Si) or supplied (+Si) with Si and inoculated or not with Pyricularia oryzae. For + Si plants, blast severity was reduced compared to -Si plants. Reductions in the concentration of photosynthetic pigments (total chlorophyll, violanxanthin + antheraxanthin + zeaxanthin, beta-carotene and lutein) were greater for inoculated -Si plants than for inoculated + Si ones. The alpha-carotene concentration increased for inoculated -Si and +Si plants in comparison to non-inoculated plants limiting, therefore, lutein production. Higher functional damage to the photosystem II (PSII) was noticed for inoculated Si plants with reductions in the values of maximum quantum quenching, photochemical yield of PSII and electron transport rate, but higher values for quenching non-photochemical. This finding also contributed to reductions in the values of light saturated rate photosynthesis and light saturation point for -Si plants which was attenuated for inoculated + Si plants. Increase in dark respiration values occurred for inoculated plants than for non-inoculated ones. The Si supply to wheat plants, besides reducing blast severity, contributed to their better photosynthetic performance. Moreover, inoculated + Si plants coped with drastic losses of light energy dissipation processes (fluorescence and heat) by increasing the concentration of carotenoids which helped to maintain the structural and functional viability of the photosynthetic machinery minimizing, therefore, lipid peroxidation and the production of reactive oxygen species. PMID- 29128782 TI - Evaluation of the Triple Code Model of numerical processing-Reviewing past neuroimaging and clinical findings. AB - : This review reconciles past findings on numerical processing with key assumptions of the most predominant model of arithmetic in the literature, the Triple Code Model (TCM). This is implemented by reporting diverse findings in the literature ranging from behavioral studies on basic arithmetic operations over neuroimaging studies on numerical processing to developmental studies concerned with arithmetic acquisition, with a special focus on developmental dyscalculia (DD). We evaluate whether these studies corroborate the model and discuss possible reasons for contradictory findings. A separate section is dedicated to the transfer of TCM to arithmetic development and to alternative accounts focusing on developmental questions of numerical processing. We conclude with recommendations for future directions of arithmetic research, raising questions that require answers in models of healthy as well as abnormal mathematical development. WHAT THIS PAPER ADDS: This review assesses the leading model in the field of arithmetic processing (Triple Code Model) by presenting knowledge from interdisciplinary research. It assesses the observed contradictory findings and integrates the resulting opposing viewpoints. The focus is on the development of arithmetic expertise as well as abnormal mathematical development. The original aspect of this article is that it points to a gap in research on these topics and provides possible solutions for future models. PMID- 29128783 TI - Differences in self-advocacy among hard of hearing and typical hearing students. AB - BACKGROUND: Self-advocacy is considered a protective factor of psychosocial and academic problems among students with special needs. AIMS: To asses self-advocacy among students with hearing loss and compare it to that of typical hearing students. METHODS AND PROCEDURE: The current study examined 27 hard of hearing (hh) students and 27 typical hearing students, all studying in mainstream classes. They completed the Hope Scale, a self-esteem scale, a self-efficacy scale, and a measure of self-advocacy statements. Data regarding the hh participants' spoken language abilities were collected through their itinerant teachers. OUTCOMES AND RESULTS: HH students reported lower levels of self-esteem than the typical hearing students. Emotional self-efficacy was positively correlated with age among the hh students, and hope and effort were negatively correlated with age among typical hearing students. Some significant positive correlations emerged among the hh participants between their syntactic and pragmatic abilities and several self-advocacy indicators. CONCLUSIONS AND IMPLICATIONS: Interventions aimed at enhancing self-advocacy among hh students should focus on intensifying their self-esteem as well as their syntactic and pragmatic abilities. PMID- 29128784 TI - Insular subdivisions functional connectivity dysfunction within major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is a mental disorder characterized by cognitive and affective deficits. Previous studies suggested that insula is a crucial node of the salience network for initiating network switching, and dysfunctional connection to this region may be related to the mechanism of MDD. In this study, we systematically investigated and quantified the altered functional connectivity (FC) of the specific insular subdivisions and its relationship to psychopathology of MDD. METHODS: Resting-state FC of insular subdivisions, including bilateral ventral/dorsal anterior insula and posterior insula, were estimated in 19 MDD patients and 19 healthy controls. Abnormal FC was quantified between groups. Additionally, we investigated the relationships between insular connectivity and depressive symptom severity. RESULTS: MDD patients demonstrated aberrant FC for insular subdivisions to superior temporal sulcus, inferior prefrontal gyrus, amygdala and posterior parietal cortex. Moreover, depression symptoms (Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale scorers) were associated with the FC values of insular subdivisions. LIMITATIONS: First, the sample size of our current study is relatively small, which may affect the statistic power. Second, using standardized insular subdivision seeds for FC analyses may neglect subtle natural differences in size and location of functional area across individuals and may thus affect connectivity maps. CONCLUSIONS: Abnormal FC of insular subdivisions to default network and central executive network may represent impaired intrinsic networks switching which may affect the underlying emotional and sensory disturbances in MDD. And our findings can help to understand the pathophysiology and underlying neural mechanisms of MDD. PMID- 29128785 TI - The critical role of internalized HIV-related stigma in the daily negative affective experiences of HIV-positive gay and bisexual men. AB - BACKGROUND: Research suggests that HIV stigma exerts a detrimental impact on the mental health of HIV-positive gay and bisexual men (GBM). We sought to better understand these processes by examining two forms of HIV stigma (i.e., anticipated and internalized) at two levels (i.e., individual and situational) in association with daily negative affective experiences. METHODS: We conducted a 21 day twice-daily ecological momentary assessment study of 51 HIV-positive GBM. Twice-daily stigma measures were disaggregated into individual-level averages and situational fluctuations, and we utilized multilevel models to examine both concurrent and time-lagged effects of HIV stigma on anxious affect, depressed affect, anger, fatigue, and emotion dysregulation. RESULTS: Situational experiences of internalized HIV stigma were associated with increased levels of anxious and depressed affect, anger, and emotion dysregulation in both concurrent and time-lagged analyses. Situational experiences of anticipated HIV stigma were only associated with anger and only within concurrent analyses. Individual-level internalized HIV stigma was associated with anxious affect and emotion dysregulation in both concurrent and time-lagged models, and with depressed affect and fatigue in time-lagged models. LIMITATIONS: The small and high-risk sample limits generalizability and results should be replicated in larger and more diverse samples. CONCLUSIONS: These findings suggest that, independent of the effects of individual-level stigma, situational experiences of internalized HIV stigma are associated with increases in event-level negative affective experiences. A combination of individually-delivered and mobile interventions may be successful at reducing the impact of internalized HIV stigma on negative affect and emotion dysregulation. PMID- 29128786 TI - Green space and cognitive ageing: A retrospective life course analysis in the Lothian Birth Cohort 1936. AB - International evidence suggests that green space has beneficial effects on general and mental health but little is known about how lifetime exposure to green space influences cognitive ageing. Employing a novel longitudinal life course approach, we examined the association between lifetime availability of public parks and cognitive ageing. Lifetime residential information was gathered from the participants of the Lothian Birth Cohort 1936 using a "life-grid" questionnaire at age 78 years. Parks information from 1949, 1969 and 2009 was used to determine a percentage of parks within a 1500 m buffer zone surrounding residence for childhood, adulthood, and later adulthood periods. Linear regressions were undertaken to test for association with age-standardised, residualised change in cognitive function (Moray House Test score) from age 11 to 70 years, and from age 70 to 76 (n = 281). The most appropriate model was selected using the results of a partial F-test, and then stratified by demographic, genetic and socioeconomic factors. The local provision of park space in childhood and adulthood were both important in explaining the change in cognitive function in later life. The association between childhood and adulthood park availability and change in the Moray House Test Score from age 70 to 76 was strongest for women, those without an APOE e4 allele (a genetic risk factor), and those in the lowest socioeconomic groups. Greater neighbourhood provision of public parks from childhood through to adulthood may help to slow down the rate of cognitive decline in later life, recognising that such environmental associations are always sensitive to individual characteristics. PMID- 29128787 TI - Enhancing handwashing frequency and technique of primary caregivers in Harare, Zimbabwe: A cluster-randomized controlled trial using behavioral and microbial outcomes. AB - RATIONALE: Consistent hand hygiene prevents diarrheal and respiratory diseases, but it is often not practiced. The disease burden is highest in low-income settings, which need effective interventions to promote domestic handwashing. To date, most handwashing campaigns have focused on promoting frequent handwashing at key times, whereas specifically promoting handwashing techniques proven to be effective in removing microbes has been confined to healthcare settings. METHODS: We used a cluster-randomized, factorial, controlled trial to test the effects of two handwashing interventions on the behavior of primary caregivers in Harare, Zimbabwe. One intervention targeted caregivers directly, and the other targeted them through their children. Outcome measures were surveyed at baseline and six weeks' follow-up and included observed handwashing frequency and technique and fecal hand contamination before and after handwashing. RESULTS: Combining the direct and indirect interventions resulted in observed handwashing with soap at 28% of critical handwashing times, while the corresponding figure for the non intervention control was 5%. Observed handwashing technique, measured as the number of correctly performed handwashing steps, increased to an average of 4.2, while the control averaged 3.4 steps. Demonstrated handwashing technique increased to a mean of 6.8 steps; the control averaged 5.2 steps. No statistically significant group differences in fecal hand contamination before or after handwashing were detected. CONCLUSIONS: The results provide strong evidence that the campaign successfully improved handwashing frequency and technique. It shows that the population-tailored design, based on social-cognitive theory, provides effective means for developing powerful interventions for handwashing behavior change. We did not find evidence that children acted as strong agents of handwashing behavior change. The fact that the microbial effectiveness of handwashing did not improve despite strong improvements in handwashing technique calls for critical evaluation of existing handwashing recommendations. The aim of future handwashing campaigns should be to promote both frequent and effective handwashing. PMID- 29128788 TI - Inclusion of service robots in the daily lives of frail older users: A step-by step definition procedure on users' requirements. AB - The implications for the inclusion of robots in the daily lives of frail older adults, especially in relation to these population needs, have not been extensively studied. The "Multi-Role Shadow Robotic System for Independent Living" (SRS) project has developed a remotely-controlled, semi-autonomous robotic system to be used in domestic environments. The objective of this paper is to document the iterative procedure used to identify, select and prioritize user requirements. Seventy-four requirements were identified by means of focus groups, individual interviews and scenario-based interviews. The list of user requirements, ordered according to impact, number and transnational criteria, revealed a high number of requirements related to basic and instrumental activities of daily living, cognitive and social support and monitorization, and also involving privacy, safety and adaptation issues. Analysing and understanding older users' perceptions and needs when interacting with technological devices adds value to assistive technology and ensures that the systems address currently unmet needs. PMID- 29128790 TI - The antipsychotic-like effects in rodents of YQA31 involve dopamine D3 and 5-HT1A receptor. AB - BACKGROUND: We previously reported that YQA31 is a dopamine D3 receptor antagonist with modest 5-HT1A receptor affinity and that it exhibits antipsychotic properties in animal models of schizophrenia. However, the contributions of D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31 are not clear. The current study evaluated the role of these two receptors in the effect of YQA31 on the hyperactivity and novel object recognition deficit in mice. METHODS: We used dopamine D3 receptor knockout mice and 5-HT1A receptor antagonist WAY100635 pretreatment, respectively, to investigate the involvement of these receptors in the effects of YQA31. The anti-psychotic effects were tested by inducing hyperlocomotion with methamphetamine or MK-801 and by inducing novel object recognition deficit with MK-801, which are the animal models to represent a positive symptom and a cognitive disorder. RESULTS: YQA31 significantly inhibited MK-801-induced hyperlocomotion and novel object recognition deficit in WT mice, which was significantly inhibited by dopamine D3 receptor knockout. The 5-HT1A receptor antagonist, WAY100635, also blocked the effect of YQA31 in MK-801-induced novel object recognition deficit but not hyperlocomotion. The effect of YQA31 on methamphetamine-induced hyperlocomotion was not reversed by either dopamine D3 receptor knockout or WAY100635 pretreatment. CONCLUSIONS: These results demonstrate the different roles of dopamine D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31. Both dopamine D3 and 5-HT1A receptors contributed to the effects of YQA31 on the inhibition of MK-801-induced novel object recognition deficit, and the dopamine D3 receptor mediated the inhibiting effect of YQA31 on hyperlocomotion induced by MK-801. PMID- 29128789 TI - Diuretic and natriuretic effect of luteolin in normotensive and hypertensive rats: Role of muscarinic acetylcholine receptors. AB - BACKGROUND: Luteolin is a very common phenolic compound found in a wide variety of natural products. Although several biological properties have already been described regarding the beneficial effect of luteolin in the cardiovascular and renal system, no scientific research explored its potential effect as a diuretic agent in experimental trials. METHODS: Groups of male normotensive (NTR) and spontaneously hypertensive rats (SHR) were orally treated with vehicle, hydrochlorothiazide or luteolin. In another experimental set, in order to verify the possible mechanisms of luteolin-induced diuresis, NTR were treated with vehicle, hydrochlorothiazide, amiloride, L-NAME, indomethacin or atropine, 1h before receiving luteolin. The cumulative urine volume, electrolytes excretion, pH and osmolality were measured at the end of the experiment (after 8h). RESULTS: Luteolin, at dose of 3mg/kg, was able to induce both diuretic and natriuretic effect in NTR and SHR groups, without interfering with urinary pH, K+ or Cl- levels. While Ca2+ content remained unchanged in urine from luteolin-treated group of NTR, luteolin reduced Ca2+ excretion in urine from SHR. The treatment with HCTZ and amiloride intensified luteolin-induced diuresis and natriuresis, with an interesting potassium-sparing effect, in addition to an increase in urinary osmolality levels. Moreover, the diuretic and natriuretic action of luteolin was fully avoided in the presence of atropine, a non-selective muscarinic receptor antagonist. CONCLUSIONS: This study revealed the diuretic and natriuretic effect of luteolin in normotensive and hypertensive rats. Our data also showed the involvement of muscarinic acetylcholine receptors for the renal effects of luteolin. PMID- 29128791 TI - ACPA and JWH-133 modulate the vascular tone of superior mesenteric arteries through cannabinoid receptors, BKCa channels, and nitric oxide dependent mechanisms. AB - BACKGROUND: Some cannabinoids, a family of compounds derived from Cannabis sativa (marijuana), have previously shown vasodilator effects in several studies, a feature that makes them suitable for the generation of a potential treatment for hypertension. The mechanism underlying this vasodilator effect in arteries is still controversial. In this report, we explored how the synthetic cannabinoids ACPA (CB1-selective agonist) and JWH-133 (CB2-selective agonist) regulate the vascular tone of rat superior mesenteric arteries. METHODS: To screen the expression of CB1 (Cannabinoid receptor 1) and CB2 (Cannabinoid receptor 2) receptors in arterial rings or isolated smooth muscle cells obtained from the artery, immunocytochemistry, immunohistochemistry, and confocal microscopy were performed. In addition, the effects on vascular tone induced by the two cannabinoids were tested in isometric tension experiments in rings obtained from superior mesenteric arteries. The participation of voltage and calcium-activated potassium channel of big conductance (BKCa) and the role of nitric oxide (NO) release on the vascular effects induced by ACPA and JWH-133 were tested. RESULTS: CB1 and CB2 receptors were highly expressed in the rat superior mesenteric artery, in both smooth muscle and endothelium. The vasodilation effect shown by ACPA was endothelium-dependent through a mechanism involving CB1 receptors, BKCa channel activation, and NO release; meanwhile, the vasodilator effect of JWH-133 was induced by the activation of CB2 receptors located in smooth muscle and by a CB2 receptor-independent mechanism inducing NO release. CONCLUSIONS: CB1 and CB2 receptor activation in superior mesenteric artery causes vasorelaxation by mechanisms involving BKCa channels and NO release. PMID- 29128792 TI - An ApoB100-mimetic vaccine prevents obesity and liver steatosis in ApoE-/- mice. AB - BACKGROUND: Recently, a peptide vaccine (B4T) was developed that prevents high fat diet (HFD)-induced obesity and liver steatosis in wild type mice and appears to target an epitope present in ApoB100 but not ApoB48. Here, we ask whether B4T remains effective in ApoE knockout (ApoE-ko) mice, which exhibit a greatly increased ApoB48/ApoB100 ratio and develop atherosclerosis under HFD. METHODS: HFD-fed male ApoE-ko mice were injected with B4T or vehicle 3 times between 5 and 15 weeks of age. Until 45 weeks of age, they were regularly weighed and antibody titers determined. In the end, adiposity and organ histologies were examined. RESULTS: We find that in the ApoE-ko mice, B4T prevents HFD-induced body weight increases (p<0.01) to a comparable degree as previously shown in wild type mice. Also, liver steatosis was prevented as previously shown in wild type mice. By contrast, atherosclerotic plaque formation was not prevented in any of the vaccinated mice studied, in line with the observation that antibody production paralleled the weight reduction but largely preceded atherogenesis. CONCLUSION: The findings demonstrate effectiveness of B4T despite the increased ApoB48/B100 ratio, but argue against an effect on de novo plaque formation. At least under the current vaccination schedule, the obesity- and atherosclerosis-related roles of ApoB appear to be dissociable. PMID- 29128793 TI - Phytochemicals genistein and capsaicin modulate Kv2.1 channel gating. AB - BACKGROUND: Phytochemicals are a large group of plant-derived compounds that have a broad range of pharmacological effects. Some of these effects are derived from their action on transport proteins, including ion channels. The present study investigates the effects of the phytochemicals genistein and capsaicin on voltage gated potassium Kv2.1 channels. METHODS: The whole-cell patch clamp technique was used to explore the regulation of Kv2.1 channels expressed in HEK293 cells by genistein and capsaicin. RESULTS: Both phytochemicals had a profound effect on the gating properties of Kv2.1 channels; the voltage dependence of activation and inactivation was shifted to hyperpolarized potentials, the closed-state inactivation was accelerated, and the recovery from inactivation was delayed. Moreover, genistein and capsaicin inhibited Kv2.1 currents in a concentration dependent manner. CONCLUSION: This study effectively demonstrated the inhibitory effects of genistein and capsaicin on Kv2.1 channels. As Kv2.1 channels play a prominent role in glucose-stimulated insulin secretion, our findings contribute to our understanding of the putative mechanism by which these phytochemicals exert their reported hypoglycemic effects. PMID- 29128794 TI - Baicalin protects against gastroduodenal ulcers via the modulation of Nrf2 expression: Experimental, biochemical, and histological analyses. AB - BACKGROUND: The present study aimed to determine the mechanisms underlying the gastroprotective effects of baicalin using several animal models of chemically induced gastric ulcers. METHODS: The gastroprotective effects of baicalin against ulcers induced by water immersion stress, alcohol-induced ligation, and indomethacin-induced pylorus ligation were assessed in the present study. Additionally, macroscopic evaluations were performed at the completion of the study and Western blot analyses of Nrf2 were conducted to determine the possible mechanisms of action underlying the effects of baicalin. RESULTS: Compared to the effects of ranitidine in a confirmed model of indomethacin-induced ligation, treatment with various doses of baicalin resulted in significant (p <0.001) increases in protection against ulcers in a dose-dependent manner. Baicalin was 72% effective versus the reference drug and 80% effective against ethanol-induced ulcers. Additionally, in rat stomachs with pylorus ligatures, Western blot analyses revealed that baicalin was 82% protective and that cimetidine was 85% protective. Taken together, the present findings indicate that baicalin is an alternative medicine with the potential to be an effective gastroprotective agent. CONCLUSION: The present findings suggest that the protective effects of baicalin may be regulated via Nrf2-mediated anti-secretory actions. PMID- 29128795 TI - Chemosensitive effects of Astragaloside IV in osteosarcoma cells via induction of apoptosis and regulation of caspase-dependent Fas/FasL signaling. AB - BACKGROUND: The response of conventional chemotherapy for osteosarcoma treatment is usually poor, and chemotherapy-related severe side effects and drug resistance remain a problem. Abundant evidence has shown that Astragaloside IV, extracted from Astragalus membranaceus Bunge, strongly inhibits the growth of many carcinomas. We aimed to investigate the chemosensitive effects of Astragaloside IV in osteosarcoma in vitro and in vivo. METHODS: Human osteosarcoma cell lines MG-63 and 143B, and BALB/c nu/nu mice xenograft were used. MTT, Clonogenic assay, Annexin V/PI assay and Western bloting analysis were carried out. RESULTS: Our present study found that Astragaloside IV was a critical chemosensitizing agent for osteosarcoma treatment. Astragaloside IV suppressed cell proliferation and enhanced chemosensitivity in osteosarcoma cell lines and xenograft. Caspase dependent Fas/FasL signaling was involved in cisplatin-induced apoptosis which was enhanced by Astragaloside IV. CONCLUSION: It indicated that Astragaloside IV might be a promising therapeutic agent for osteosarcoma treatment. PMID- 29128796 TI - Nanomechanical testing of drug activities at the cellular level: Case study for endothelium-targeted drugs. AB - BACKGROUND: The pharmacological treatment of cardiovascular diseases that may potentially be attributed to endothelial dysfunction often requires the application of endothelium-targeted drugs. Simvastatin is one of such drugs currently on the market due to its established anti-inflammatory activities. The nanomechanical response to drug treatment at the cellular level is not yet known. However, this response mechanism is promising as a prospective testing method for newly developing drugs. METHODS: Force spectroscopy was used for in vitro characterization of the elastic properties of human microvascular endothelial cells. Cell dysfunction was caused by the application of tumor necrosis factor alpha. The anti-inflammatory action of the compounds was investigated for the cells incubated with each of the following agents: simvastatin, pyridine derivatives (1,4-dimethylpyridine chloride (1,4-DMP), and 1-methylpyridinium chloride (1-MP)). Moreover, in the case of 1,4-DMP and 1-MP, the measurements were supplemented with F-actin labeling data. RESULTS: We measured the simvastatin influence on the elasticity of human microvascular endothelial cells (HMECs) for concentrations: 1, 10 and 100MUM. Furthermore, we evaluated the therapeutic and preventive effects of 1MUM drug on inflamed cells. Finally, the effect of pyridine derivatives 1,4-dimethylpyridine chloride (1,4-DMP) and 1 methylpyridinium chloride (1-MP) was tested using force spectroscopy. CONCLUSIONS: The anti-inflammatory activity of the simvastatin is well illustrated by the endothelium cell elasticity changes returning from the characteristic inflammation time cycle "soft-stiff-soft" to control values. Furthermore, the elasticity results and F-actin labeling data indicated a preventive effect for 1- MP, whereas 1,4-DMP does not exhibit endothelium activity even at toxic concentrations. PMID- 29128797 TI - Sotalol enhances the anticonvulsant action of valproate and diphenylhydantoin in the mouse maximal electroshock model. AB - BACKGROUND: Sotalol as a drug blocking beta-receptors and potassium KCNH2 channels may interact with different substances that affect seizures. Herein, we present interactions between sotalol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital. METHODS: Effects of sotalol and antiepileptics alone on seizures were determined in the electroconvulsive threshold test, while interactions between sotalol and antiepileptic drugs were estimated in the maximal electroshock test in mice. Motor coordination and long-term memory were evaluated, respectively, in the chimney test and passive-avoidance task. Brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. RESULTS: Sotalol at doses up to 100mg/kg did not affect the electroconvulsive threshold. Applied at doses 60-100mg/kg, sotalol potentiated the antielectroshock action of valproate, while at doses 80-100mg/kg that of phenytoin. Sotalol (up to 100mg/kg) did not affect the action of carbamazepine or phenobarbital in the maximal electroshock. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory in mice. Finally, sotalol did not change brain concentration of valproate and phenytoin, so pharmacokinetic interactions between the drugs are not probable. CONCLUSIONS: As far as obtained data may be extrapolated into clinical conditions, sotalol may be considered as an arrhythmic drug that does not reduce the action of classical antiepileptic drugs and thereby can be used in epileptic patients with cardiac arrhythmias. PMID- 29128799 TI - FTY720 inhibits the Nrf2/ARE pathway in human glioblastoma cell lines and sensitizes glioblastoma cells to temozolomide. AB - BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox sensitive transcription factor regulating the expression of various cytoprotective genes. Constitutive Nrf2 activation in many cancers enhances cell survival and resistance to anti-cancer drugs. Our previous studies have shown that FTY720 induced autophagy-related apoptosis and necroptosis and inhibited invasion and migration in human glioblastoma cells. However, whether FTY720 regulated Nrf2 in glioblastoma cells remained unclear. METHODS: Cell viability assay, western blot, migration and invasion assay, short hairpin RNA (shRNA) were used. RESULTS: We found that FTY720 suppressed the protein and mRNA levels of Nrf2 in human U251MG and U87MG glioblastoma cells lines. In addition, the protein and mRNA levels of heme oxygenase-1 (HO-1) and NADPH:quinine oxidoreductase-1 (NQO-1), two representative target factors of Nrf2, also decreased upon FTY720 treatment. Knockdown of Nrf2 further promoted the anti-cancer effects of FTY720, while activation of Nrf2 exist the opposite effects. In addition, FTY720 significantly sensitized glioblastoma cells to temozolomide (TMZ). However, activation of Nrf2 essentially abolished the induced sensitivity by FTY720. CONCLUSION: Our results indicated the potential application of FTY720 in treatment of glioblastoma and demonstrated that inhibition of Nrf2 can enhance the sensitivity of cancer cells to chemotherapeutic drugs. PMID- 29128798 TI - Mechanistic evaluation of neuroprotective effect of estradiol on rotenone and 6 OHDA induced Parkinson's disease. AB - BACKGROUND: The present study was intended to investigate the protective effect of estradiol against Parkinson's disease through the use of rotenone-induced neurotoxicity model. METHODS: To define the effect on the behavioral function, Tail suspension test, morris water maize test and cylinder tests were performed. Several biochemical and histological markers related to Parkinson's disease was determined in animal and cell culture models. To evaluate the effect of estradiol on the cellular architecture in rotenone-induced brain tissue, the histopathological examination was carried out by using Haemotoxylin and Eosin staining. Moreover, estradiol effect was also been investigated for its protective effect against Parkinson's disease using cell culture model with use of brain endothelial cells. The flowcytometric analysis was carried out to measure apoptosis in cell culture model. RESULTS: The abnormal level of antioxidant enzymes and lipid peroxidation were regulated toward the normal intensity under the influence of estradiol. Furthermore, intracellular ROS level and apoptosis were found to be reduced following estradiol treatment. During the 6-OHDA induced PD, the level of antioxidant marker such as GSH, ROS and TRAP, found to be significantly modulated by the estradiol. CONCLUSION: In view of the above results, it may be suggested that the estradiol may be as a useful therapeutic agent against rotenone-induced neurotoxicity such as Parkinson's disease. PMID- 29128800 TI - Beneficial roles of honey polyphenols against some human degenerative diseases: A review. AB - Honey contains many active constituents and antioxidants such as polyphenols. Polyphenols are phytochemicals, a generic term for the several thousand plant based molecules with antioxidant properties. Many in vitro studies in human cell cultures as well as many animal studies confirm the protective effect of polyphenols on a number of diseases such as cardiovascular diseases (CVD), diabetes, cancer, neurodegenerative diseases, pulmonary diseases, liver diseases and so on. Nevertheless, it is challenging to identify the specific biological mechanism underlying individual polyphenols and to determine how polyphenols impact human health. To date, several studies have attempted to elucidate the molecular pathway for specific polyphenols acting against particular diseases. In this review, we report on the various polyphenols present in different types of honey according to their classification, source, and specific functions and discuss several of the honey polyphenols with the most therapeutic potential to exert an effect on the various pathologies of some major diseases including CVD, diabetes, cancer, and neurodegenerative diseases. PMID- 29128801 TI - Oleuropein protects intracerebral hemorrhage-induced disruption of blood-brain barrier through alleviation of oxidative stress. AB - BACKGROUND: Intracerebral haemorrhage (ICH) as a devastating form of stroke has remained a public health threat due to lack of FDA-approved therapy. Oxidative stress originated from blood cell degradation products plays a crucial role in the ICH pathogenesis. In this study we evaluated oleuropein, a potent natural antioxidant from olive, in a well-established rat ICH model from overall symptoms to detailed molecular mechanism. METHODS: ICH model was established by collagenase injection to the brain of rats, which were randomly divided into groups with vehicle mock treatment, followed by treatment with different doses of oleuropein via daily intraperitoneal injection post-ICH for 3days. The overall neurological deficit, brain edema level and blood-brain barrier (BBB) integrity were then measured in different treatment groups. To understand the protection mechanism of oleuropein in ICH, BBB structural components ZO-1 and occludin, oxidative stress and MAPK signalling pathways were also examined. RESULTS: Oleuropein treatment showed overall alleviation of ICH-associated neurological deficit and brain edema in a dose dependent manner. Consistently, it could preserve the BBB structure and attenuate oxidative stress as well as ICH-induced MAPK activation in brain tissue. CONCLUSION: Our study suggests oleuropein could be used as a promising therapeutic agent for ICH. PMID- 29128802 TI - Chronic social isolation in adaptation of HPA axis to heterotypic stress. AB - BACKGROUND: Social crowding and isolation are recognized as major stressors and risk factors for development of psychiatric disorders. Chronic isolation stress (IS) and crowding stress (CS) activate neuroendocrine and neurochemical mechanisms, that activate the hypothalamic-pituitary-adrenal (HPA) axis. Changes of the plasma level of interleukin-1beta (IL-1beta), ACTH and corticosterone (CORT) after chronic psychosocial IS and CS were investigated. METHODS: Control rats were kept 5 per cage and not stressed. Stressed groups were subjected to either CS for 3, 7, 14days+restraint stress (RS) or IS for (11days) before this treatment was applied. Crowded rats were remained (24 in one cage) and RS rats were restrained for 10min. Total CORT, ACTH and IL-1beta levels were measured using commercially available kits. RESULTS: Social CS for 3days significantly increased plasma IL-1beta level. Social IS increased plasma IL-1beta level after longer period of subsequent CS 7 and 14days, than ACTH and CORT, after 3 and 7days. Prior IS significantly increased plasma IL-1beta level induced by subsequent combined CS for 3days+acute RS, but significantly or totally inhibited the acute stress-induced increase of plasma IL-1beta level after 7 and 14days of combined stress. IS, by contrast, strongly inhibited the increase of plasma ACTH and CORT level induced by combined CS+acute RS. CONCLUSION: Chronic IS augments the changes of IL-1beta level induced by a longer crowding period than ACTH and CORT. Modulatory action of IL-1beta and pituitary-adrenocortical hormones adaptation to chronic social stress is asynchronous. PMID- 29128803 TI - The effect of dehydroglyasperin C on UVB-mediated MMPs expression in human HaCaT cells. AB - BACKGROUND: The ultraviolet B (UVB) from solar radiation increases the generation of reactive oxygen species (ROS), which mediate the production of matrix metalloproteinases (MMPs), and acts mainly on the epidermis layer of the skin. This study was aimed at assessing the anti-photoaging effects of dehydroglyasperin C isolated from Glycyrrhiza uralensis Fisch on MMPs levels in HaCaT human keratinocytes and to elucidate the underlying mechanism. METHODS: The cell viability was measured by MTT assay. Expression, phosphorylation and enzymatic activity of the protein were examined using ELISA, Western blot or gelatin zymography. Intracellular ROS measurement was evaluated by fluorescent ELISA and 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) assay. RESULTS: In the present study, we found that dehydroglyasperin C markedly inhibited UVB mediated expression of collagenase (MMP-1) and gelatinase (MMP-9) by inhibiting ROS generation. Dehydroglyasperin C treatment also decreased the UVB irradiation mediated activation of mitogen-activated protein kinase (MAPK), c-Jun phosphorylation, and c-Fos expression. In addition, the down-regulation of UVB induced c-Jun phosphorylation caused by dehydroglyasperin C treatment was more than the down-regulation of c-Fos expression in the HaCaT human keratinocytes. CONCLUSION: Our results indicated that dehydroglyasperin C may function as a potential anti-photoaging agent by inhibiting UVB-mediated MMPs expression via suppression of MAPK and AP-1 signaling. PMID- 29128804 TI - Hexachlorobenzene as a persistent organic pollutant: Toxicity and molecular mechanism of action. AB - Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. Chronic exposure of humans to HCB leads to a number of effects, such as triggering of porphyria, microsomal enzyme induction, thyroid dysfunctions, neurological symptoms, and immunological disorders. In animals, HCB induced hepatic porphyria, neurotoxic effects, and toxic effects on the thyroid function, reproductive system, and immune system. HCB as a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR) is a hormonal disruptor. HCB is also known to cause tumors of the liver, thyroid and mammary gland in laboratory animals. This review presents HCB toxicity in humans and laboratory animals. The main attention was focused on the mechanisms of HCB toxicity, especially at the molecular level. PMID- 29128805 TI - Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2. AB - BACKGROUND: Ursolic acid has been shown to display antidepressant-like effects in mice through the modulation of monoaminergic systems. In this study, we sought to investigate the involvement of signaling pathways on the antidepressant-like effects of ursolic acid. METHODS: Mice were treated orally with ursolic acid (0.1mg/kg) and, 45min later they received the followings inhibitors by intracerebroventricular route: H-89 (PKA inhibitor, 1MUg/mouse), KN-62 (CAMK-II inhibitor, 1MUg/mouse), chelerythrine (PKC inhibitor, 1MUg/mouse), U0126 (MEK1/2 inhibitor, 5MUg/mouse), PD98059 (MEK1/2 inhibitor, 5MUg/mouse), wortmannin (PI3K irreversible inhibitor, 0.1MUg/mouse) or LY294002 (PI3K inhibitor, 10 nmol/mouse). Immobility time of mice was registered in the tail suspension test (TST). RESULTS: The anti-immobility effect of ursolic acid in the TST was abolished by the treatment of mice with H-89, KN-62, chelerythrine, U0126 or PD98059, but not with wortmannin or LY294002. CONCLUSIONS: These results suggest that activation of PKA, PKC, CAMK-II, MEK1/2 may underlie the antidepressant-like effects of ursolic acid. PMID- 29128806 TI - Emotional disorders induced by Hemopressin and RVD-hemopressin(alpha) administration in rats. AB - BACKGROUND: The endocannabinoid (eCB) system plays an important role in regulating emotional disorders, and is involved, directly or indirectly, in psychiatric diseases, such as anxiety and depression. Hemopressin, a hemoglobin alpha chain-derived peptide, and RVD-hemopressin(alpha), a N-terminally extended form of hemopressin, act as antagonist/inverse agonist and negative allosteric modulator of the cannabinoid 1 (CB1) receptor, respectively. METHODS: Considering the possible involvement of these peptides on emotional behaviour, the aim of our study was to investigate the behavioural effects of a single intraperitoneal (ip) injection of hemopressin (0.05mg/kg) and RVD-hemopressin(alpha) (0.05mg/kg), using a series of validated behavioural tests (locomotor activity/open field test, light-dark exploration test, forced swim test) in rats. Prefrontal cortex levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and the gene expression of monoamine oxidase (MAO-B) and catechol-O methyltransferase (COMT) were measured by high performance liquid chromatography (HPLC) analysis and real-time reverse transcription polymerase chain reaction (RT PCR), respectively. RESULTS: Hemopressin administration induced anxiogenic and depressive behaviour, decreased monoamine steady state levels in prefrontal cortex, and increased the gene expression of the enzymes involved in their catabolism. By contrast, RVD- hemopressin(alpha) induced anxiolytic and antidepressive effects, increased monoamines and decreased the enzymes in prefrontal cortex. CONCLUSION: In conclusion, in the present study we demonstrated behavioral effects induced by peripheral hemopressin and RVD hemopressin(alpha) injections, that could involve modulatory effects on monoaminergic signaling, in the prefrontal cortex. PMID- 29128808 TI - Attenuation of renal damage in type I diabetic rats by umbelliferone - a coumarin derivative. AB - BACKGROUND: It is well known that diabetes is one of the non-communicable disease affecting a large population worldwide. When diabetes remains untreated or uncontrolled, it leads to further serious complications, affecting vital organs like eyes, kidney, heart, etc. The present study was designed to evaluate effects of umbelliferone, a phytochemical, in treatment of diabetic nephropathy. METHODS: Experimental model used was streptozotocin (55mg/kg, ip) induced diabetic nephropathy in male Sprague Dawley rats. After 28days of streptozotocin administration, diabetic animals were treated with umbelliferone at two dose levels, 20 and 40mg/kg for next 28days. RESULTS: The results of the study showed that umbelliferone treatment significantly decreased the elevated plasma creatinine and blood urea nitrogen level while significantly increased the total protein and albumin level in diabetic animals. Creatinine clearance was improved in umbelliferone treated animals. Renal oxidative stress was decreased in umbelliferone treated animals significantly. Histopathological study of the kidney was carried out by specific stains like Hematoxylin-Eosin, Periodic Acid Schiff and Masson Trichrome stain. The sections of the kidney showed that umbelliferone treatment decreased the glomerular damage, mesangial matrix expansion as well as the renal fibrosis. Determination of renal transforming growth factor beta one (TGF-beta1) expression by immunohistochemical analysis, western blotting and circulating TGF-beta1 by ELISA assay showed that umbelliferone decreased the renal tissue and circulating TGF-beta1 level. CONCLUSION: Umbelliferone treatment can significantly reduce the diabetes induced renal damage and can improve the pathological conditions related to the diabetic nephropathy by down regulation of TGF-beta. PMID- 29128807 TI - Apigenin, a novel candidate involving herb-drug interaction (HDI), interacts with organic anion transporter 1 (OAT1). AB - BACKGROUND: Apigenin is a flavonoid compound, widely distributed in natural plants. Various studies have suggested that apigenin has inhibitory effects towards several drug transporters, such as the organic anion transporting (OAT) polypeptides, 1B1 and 1B3 (OATP1B1 and OATP1B3). However, the mechanism by which apigenin interacts with OAT1 has not been well studied. METHODS: MDCK cells stably-expressing OAT1 were used to examine the inhibitory effects of apigenin on OAT1. UPLC-MS/MS was used to evaluate the in vitro and in vivo effects of apigenin on the uptake of acyclovir by OAT1. Cytotoxicity was determined by the cell viability, MTT assays. RESULTS: Apigenin effectively inhibited the activity of OAT1 in a dose-dependent manner with an IC50 value of 0.737MUM. Pre-incubation of cells with apigenin caused a time-dependent inhibition (TDI) of OAT1. Additionally, we examined the interactions between apigenin and acyclovir or adefovir. Data showed that apigenin (1MUM) significantly blocked the uptake of acyclovir by OAT1 in vitro with an inhibition rate of 55%. In vivo, apigenin could increase the concentration of acyclovir in plasma when co-administered with acyclovir. Importantly, the MTT assays showed that, at a dose of 50MUM, apigenin significantly reduced the cytotoxicity of adefovir and substantially increased cell viability from 50.6% to 112.62%. CONCLUSION: Our results demonstrate that apigenin regulates OAT1, and can cause TDI or herb-drug interaction (HDI) when used in combination with acyclovir or adefovir. Therefore, apigenin could be used as a nephroprotective agent when used in combination with the substrates of OAT1. PMID- 29128809 TI - Icariin induces apoptosis in acute promyelocytic leukemia by targeting PIM1. AB - BACKGROUND: Acute promyelocytic leukemia (APL) is one type of acute myeloid leukemia (AML) featured by abnormal, heavily granulated promyelocytes. This study aimed to investigate the antitumor activity of icariin in APL cells. METHODS: APL cell lines (HL-60 and NB4) were used to investigate the effect of icariin in vitro. Cell viability was determined by WST-8 proliferation assay, while cell apoptosis was assessed by flow cytometry. The mRNA and protein expression was determined by quantitative real-time polymerase chain reaction and Western blot, respectively. Moreover, small interfering RNA (siRNA) and overexpressing plasmid were used to manipulate the expression of PIM family kinase 1 (PIM1) to examine the role of PIM1 in icariin-induced apoptosis in APL cells. RESULTS: Icariin could significantly suppress cell growth and induce apoptosis in both model APL cell lines (HL-60 and NB4). It repressed the expression of PIM1 at the molecular level, which was responsible for the antitumor effect of icariin in APL cells. The ectopic overexpression of PIM1 significantly abrogated the inducing effect of icariin on apoptosis. In contrast, the knockdown of PIM1 by siRNA enhanced the antitumor effect of icariin in APL cells. Moreover, the findings indicated that icariin repressed the expression of PIM1 through generating reactive oxygen species and hence modulating the Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3/5 (STAT3/5) signaling pathway. CONCLUSIONS: Icariin potently inhibits the cell growth of APL in vitro through inducing caspase dependent apoptosis. Hence, it can be considered as a promising candidate therapeutic agent for treating APL, although further studies including clinical trials are warranted. PMID- 29128810 TI - Effect of dietary copper nanoparticles versus one copper (II) salt: Analysis of vasoreactivity in a rat model. AB - BACKGROUND: Vascular defects in the mechanical properties of aorta and muscular arteries have been previously reported in animals with copper-deficient feed. However, the interaction between copper nanoparticles (CuNPs) and mechanical properties of arteries has not been reported. Hence, the present study was aimed to evaluate the effect of copper nanoparticles on the vasoreactivity of rat isolated thoracic arteries. METHODS: In this study, 5 week old male Wistar rats were fed a copper-adequate diet (CuA, 6.5mg copper/kg diet), copper-deficient diet (CuD) and copper-modified diets, enriched with copper as a salt (CuS) and as copper nanoparticles (CuNPs) of 40-60nm in diameter. RESULTS: There was a strong relationship between CuNPs and CuS administration in the tensile strength of the thoracic aorta subjected to phenylephrine treatment in the concentration range of 10-7-10-5M. This was also seen between CuNPs and the control diet in the same concentration ranges. In addition vasodilation induced by acetylcholine at the concentration range of 10-7-10-5M was significantly reduced in CuD and NPs feed animals. In CuNPs fed rats, activities of Cu,Zn-SOD, CAT and copper concentration in cardiomyocytes were not influenced when compared with CuS control. In contrast, in CuS-low diet the activities of studied enzymes and copper concentration were pointing towards copper deficiency. CONCLUSIONS: Our results demonstrate for the first time that the observed effects of copper administration in the form of NPs are attributed mainly to the NPs rather than copper itself. Thus another mechanism not related with Cu,Zn-SOD and CAT seems to be involved. PMID- 29128811 TI - Autophagy, mitophagy and apoptotic gene changes in the hippocampal CA1 area in a rat ischemic model of Alzheimer's disease. AB - BACKGROUND: Postichemic brain injury correlates with poor prognosis since selectively vulnerable parts of brain are associated with apoptotic neuronal death. But autophagy has been recognized, as a probable survival mechanism following brain ischemia. METHODS: We have analyzed, by quantitative reverse transcriptase PCR assay protocol, three genes: autophagy, mitophagy and caspase 3 for neuronal death response in ischemic hippocampal CA1 area. RESULTS: We have found that autophagy gene was not significantly modified at all time points after ischemia, whereas mitophagy and caspase 3 genes were upregulated at day 2 and decreased to basal values at days 7 and 30. CONCLUSION: It may be inferred that mitophagy process markedly accompanies apoptosis during delayed neuronal death in hippocampal CA1 area following brain ischemia. PMID- 29128812 TI - Pharmacological evidence for the involvement of adenosine triphosphate sensitive potassium channels in chloroquine-induced itch in mice. AB - BACKGROUND: Chloroquine (CQ) evokes itch in human and scratching behavior in rodents through a histamine-independent pathway. Chloroquine directly excites peripheral sensory neurons which convey itch signals to the central nervous system. It has been revealed that ATP-sensitive potassium channels (KATP channels) are important in regulating neuronal excitability. Thus, we aimed to investigate the involvement of KATP channels in CQ-induced itch which may also reveal a linkage between metabolic state of cells and itch. METHODS: Intradermal (id) injection of CQ at dose of 400MUg/site induces the scratching behavior. KATP channel openers, diazoxide (DZX) and minoxidil (MIN), and a KATP channel blocker, glibenclamide (GLI), were administered intraperitoneally (ip) before CQ. Then the behavior was recorded for 30min, in an unmanned condition, and the scratching bouts were counted by an expert observer who was blinded to the experiments. Furthermore, quantitative reverse transcription-PCR (qRT-PCR) was used to investigate the possible changes in dermal expression of Kcnj8 and Kcnj11, the genes encoding the KATP channels. RESULTS: Our results show that either DZX (10mg/kg, ip) or MIN (10mg/kg, ip) significantly attenuated CQ-induced scratching behavior in mice. Moreover, pretreatment with GLI (3mg/kg, ip) significantly reversed the anti-pruritic effects of DZX and MIN. Our finding of qRT-PCR analysis also show that the expression of Kcnj8 is decreased after CQ injection. CONCLUSIONS: We suggest that KATP channels are possibly involved in CQ-induced itch. While, further studies will be significant to better elucidate the association of metabolic state of cells and itch. PMID- 29128813 TI - Effect of aromatase inhibitors on learning and memory and modulation of hippocampal dickkopf-1 and sclerostin in female mice. AB - BACKGROUND: There has been conflicting reports on the effect of third generation aromatase inhibitors on cognition in estrogen-deficient states. Since aromatase inhibitors themselves cause estrogen deprivation, the present work was designed to evaluate the comparative effect of three aromatase inhibitors on behavioral measures of learning and memory in female mice. Further, in view of the reports of estrogen and Wnt signaling pathway in cognition, the role of two Wnt signaling antagonists (dickkopf-1 and sclerostin) in mediation of cognitive effects of aromatase inhibitors was evaluated. METHODS: Three behavioral paradigms were used for evaluating cognitive functions viz. Morris water maze, active avoidance learning and spontaneous alternation behavior following 10-15days of administration with aromatase inhibitors and the levels of dickkopf-1 and sclerostin were evaluated in hippocampus of female mice. RESULTS: Anastrozole and letrozole (but not exemestane) impaired learning and memory as indicated by increase in escape latency and path length during spatial acquisition, reduction of % quadrant dwell time in Morris water maze, reduction of % avoidance and increase in escape responses in active avoidance learning and decrease in % alternation in a cross maze. The behavioral effects correlated well with the levels of dickkopf-1 and sclerostin in the mouse hippocampus. The highest impairment in learning and memory occurred with letrozole followed by anastrozole while exemestane was without such effects. CONCLUSION: The present study demonstrates that aromatase inhibitors have adverse impact on cognition. Furthermore, modulation of Wnt signaling following estrogen depletion possibly contributed to observed effects in case of anastrozole and letrozole. PMID- 29128814 TI - Amphotericin B-copper (II) complex alters transcriptional activity of genes encoding transforming growth factor-beta family members and related proteins in renal cells. AB - BACKGROUND: Several chemical modifications have been developed to overcome the toxicity of amphotericin B (AmB). Oxidized forms of AmB (AmB-ox), which may occur in patient's circulation during therapy, are as toxic as AmB. Complexes with copper (II) ions (AmB-Cu2+) have been reported to be less toxic to human cells. Previous studies showed that AmB changed the expression of transforming growth factor-beta (TGF-beta). Therefore, the objective of this study was to investigate the influence of AmB and its modified forms on the expression of genes encoding for TGF-beta family members and related proteins in renal cells. METHODS: Human renal proximal tubule cells (RPTEC) were treated with AmB-Cu2+, AmB, or the oxidized form AmB-ox. The expression of TGF-beta family members and related genes was determined using oligonucleotide microarrays. TGF-beta1 protein level was determined using ELISA method. The mRNA level of TGF-beta isoforms, TGF-beta receptors and differentiating genes was evaluated by real-time RT-qPCR. RESULTS: AmB-Cu2+ increased the mRNA levels of TGF-beta1 and TGF-beta2 isoforms and two genes encoding receptors: TGFBR1 and TGFBR2. TGF-beta1 protein level in culture medium was not increased after stimulation with AmB-Cu2+. Microarray analysis revealed changes in both pro-fibrotic and anti-fibrotic genes. CONCLUSIONS: These results suggest that AmB-Cu2+ may induce repair mechanisms in renal proximal tubule cells via changes in the expression of genes involved in intracellular signaling. PMID- 29128815 TI - Troglitazone, a PPAR-gamma agonist, decreases LTC4 concentration in mononuclear cells in patients with asthma. AB - BACKGROUND: Asthma is an inflammatory disorder with multiple mediators involved in the inflammatory response. Despite several attempts, no new anti-inflammatory drugs have been registered for asthma treatment for several years. However, thiazolidinediones, peroxisome proliferator-activated receptor agonists, have demonstrated some anti-inflammatory properties in various experimental settings. The aim of this study was to assess the influence of troglitazone on LTC4 and 15 HETE concentrations. It also evaluates TNF-induced eotaxin synthesis in peripheral blood mononuclear cells from 14 patients with mild asthma and 13 healthy controls. METHODS: PBMCs were isolated from the whole blood of the asthmatics and healthy subjects and pretreated with 0.1, 1 or 10MUM of Troglitazone. The cells were then exposed to 10-6M calcium jonophore or 10ng/ml TNF. The production and release of LTC4, 15-HETE and eotaxin were then assessed. RESULTS: Troglitazone caused a dose-dependent inhibition in LTC4 synthesis in both asthmatics and healthy subjects. Troglitazone did not influence 15-HETE or eotaxin production in either asthmatic patients or in healthy individuals. CONCLUSION: Due to its inhibition of LTC4 synthesis, troglitazone therapy is an interesting potential therapeutic approach in asthma and other LTC4 related inflammatory disorders. PMID- 29128816 TI - Generation of induced pluripotent stem cell line (ZZUi005-A) from a 21-year-old patient with a novel RAB39B gene mutation in X-linked juvenile parkinsonism. AB - Ras-related protein 39B (RAB39B) mutation has been reported as a potential cause of X-linked Parkinson's disease (PD), a rare form of familial PD. Recently, a novel RAB39B mutation was identified in an X-linked juvenile parkinsonism family and the dermal fibroblasts of the patient were obtained and successfully induced to induced pluripotent stem cells (iPSCs) by the human OSKM transcription factors using the Sendai-virus delivery system. Our model may offer a good platform for further research of the pathomechanism, drug testing, and gene therapy of this disease. PMID- 29128817 TI - Generation of induced pluripotent stem cell (iPSC) line from a 21-year-old X linked adrenoleukodystrophy (X-ALD) patient. AB - X-linked Adrenoleukodystrophy (X-ALD) is a genetic disease that caused by mutations in adenosine triphosphate [ATP]-binding-cassette transporter superfamily D member 1 (ABCD1) gene. We generated an induced pluripotent stem cell (iPSC) line from a 21-year-old male X-ALD patient-derived fibroblasts by Sendai virus mediated reprogramming. Established iPSCs stably expanded while maintaining immunoreactivity for various pluripotency markers and alkaline phosphatase, as well as normal 44+XY karyotype. Under the differentiation condition, the cells gave rise to cells of three germ layers. PMID- 29128818 TI - Comparison of 2D and 3D neural induction methods for the generation of neural progenitor cells from human induced pluripotent stem cells. AB - Neural progenitor cells (NPCs) from human induced pluripotent stem cells (hiPSCs) are frequently induced using 3D culture methodologies however, it is unknown whether spheroid-based (3D) neural induction is actually superior to monolayer (2D) neural induction. Our aim was to compare the efficiency of 2D induction with 3D induction method in their ability to generate NPCs, and subsequently neurons and astrocytes. Neural differentiation was analysed at the protein level qualitatively by immunocytochemistry and quantitatively by flow cytometry for NPC (SOX1, PAX6, NESTIN), neuronal (MAP2, TUBB3), cortical layer (TBR1, CUX1) and glial markers (SOX9, GFAP, AQP4). Electron microscopy demonstrated that both methods resulted in morphologically similar neural rosettes. However, quantification of NPCs derived from 3D neural induction exhibited an increase in the number of PAX6/NESTIN double positive cells and the derived neurons exhibited longer neurites. In contrast, 2D neural induction resulted in more SOX1 positive cells. While 2D monolayer induction resulted in slightly less mature neurons, at an early stage of differentiation, the patch clamp analysis failed to reveal any significant differences between the electrophysiological properties between the two induction methods. In conclusion, 3D neural induction increases the yield of PAX6+/NESTIN+ cells and gives rise to neurons with longer neurites, which might be an advantage for the production of forebrain cortical neurons, highlighting the potential of 3D neural induction, independent of iPSCs' genetic background. PMID- 29128819 TI - The 'Saw Tooth' operation for giant fibroadenomas. AB - Fibroadenomas are the most common benign breast lesions affecting adolescents and young women. Cosmesis is an important factor when considering surgical management for these masses. Giant fibroadenomas (>5cm), because of their size, may require larger incisions resulting in significant scarring and scar complications in these young women. Several approaches have been employed, usually involving large incisions, when performing a lumpectomy for giant fibroadenomas. In this report, we highlight a new technique for removal of these masses, which allows the removal of large fibroadenomas through a relatively small, cosmetically acceptable, circumareolar incision. PMID- 29128820 TI - CT guided appendicectomy incision: A prospective case series. AB - OBJECTIVE: Several radiological studies have suggested that the base of the Appendix often does not correspond with Mc Burney's point. The aim of our study is to assess the value of using CT localization of the appendicocaecal junction to guide placement of the appendicectomy incision. DESIGN & METHOD: 32 consecutive patients, booked for open appendicectomy were prospectively included in this study. Coronal and axial CT scans with IV contrast were studied to assess site of the appendicocaecal junction. This information was used to guide placement of the incision. RESULTS: 28 out of 32 patients studied, the appendicocaecal junctions were accurately identified. It was noted that the final incision sites were cephalad to Mc Burney's point in 8, at the point in 3 and caudal in 17. In 1 patient, it was necessary to extend the incision medially by 2cm to retrieve the distal Appendix which had been detached through the site of rupture. CONCLUSION: Mc Burney's point often does not correspond to the base of the appendix. We propose that using CT imaging to guide the appendicectomy incision is safe, facilitates locating the Appendix at surgery, minimizes incision size and decreases the need to extend it. PMID- 29128821 TI - Effects of organic and inorganic compounds of diesel exhaust particles on the mucociliary epithelium: An experimental study on the frog palate preparation. AB - The toxic actions of acute exposition to different diesel exhaust particles (DEPA) fractions on the mucociliary epithelium are not yet fully understood due to different concentrations of organic and inorganic elements. These chemicals elements produce damage to the respiratory epithelium and exacerbate pre-existent diseases. In our study we showed these differences in two experimental studies. Study I (dose-response curve - DRCS): Forty frog-palates were exposed to the following dilutions: frog ringer, intact DEPA diluted in frog-ringer at 3mg/L, 6mg/L and 12mg/L. Study II (DEPF) (DEPA fractions diluted at 12mg/L): Fifty palates - Frog ringer, intact DEPA, DEPA treated with hexane, nitric acid and methanol. Variables analyzed: relative time of mucociliary transport (MCT), ciliary beating frequency (CBF) and morphometric analysis for mucin profile (neutral/acid) and vacuolization. The Results of DRCS: Group DEPA-12mg/L presented a significant increase in the MCT (p<0.05), proportional volume of acid mucus (p<0.05) and decreased proportional volume of neutral mucus and vacuoles (p<0.05). In relation of DEPF: A significant increase in the MCT associated to a decrease in the proportional volume of neutral mucus was founded in nitric acid group. In addition, a significant increase in the proportional volume of acid mucus was found in methanol group. We concluded that: 1) Increasing concentrations of intact DEPA can progressively increase MCT and promote an acidification of intra-epithelial mucins associated to a depletion of neutral mucus. 2) Intact DEPA seem to act as secretagogue substance, promoting mucus extrusion and consequently reducing epithelial thickness. 3) Organic fraction of low polarity seems to play a pivotal role on the acute toxicity to the mucociliary epithelium, by promoting a significant increase in the MCT associated to changes in the chemical profile of the intracellular mucins. PMID- 29128822 TI - A DOC coagulant, gypsum treatment can simultaneously reduce As, Cd and Pb uptake by medicinal plants grown in contaminated soil. AB - The efficiency of gypsum, as a dissolved organic carbon (DOC) coagulator, for the simultaneous immobilization of two heavy metals (Cd and Pb) and one metalloid (As) in agricultural soils near an abandoned mining site was examined. The agricultural soil was defined as long-term contaminated as As (1540mgkg-1), Cd (55mgkg-1) and Pb (1283mgkg-1) concentrations exceeded the Korean guideline values for As (25mgkg-1), Cd (4mgkg-1), and Pb (200mgkg-1). Gypsum was incorporated into the contaminated soil at 3% (w/w). In comparison two commonly using immobilizing agents (lime and compost), together with a mixture (lime+gypsum) were also included in the pot trial for the cultivation of two medical plants (A. gigas and A. macrocephala) and to evaluate the effectiveness of gypsum on As, Cd and Pb immobilization. The results showed that even though pH change-induced immobilizing agents such as lime were more effective than gypsum at immobilizing Cd and Pb, addition of gypsum also effectively reduced heavy metal phytoavailability as indicated by decreases in the concentration of Cd and Pb in medicinal plants. Furthermore, gypsum and gypsum+ lime were also most effective in reducing As concentrations in both plants studied. This was mainly attributed to significant decreases in soil DOC (48-64%) when gypsum and gypsum+lime were applied to the soil. Consequently, it was concluded that enhanced DOC coagulation with gypsum, could be considered as a promising technique for the immobilization of both metals (Cd and Pb) and metalloids (As) in agricultural soils. PMID- 29128823 TI - Immunotoxicity of copper nanoparticle and copper sulfate in a common Indian earthworm. AB - Copper oxide nanoparticles and copper sulfate are established contaminants of water and soil. Metaphire posthuma is a common variety of earthworm distributed in moist soil of Indian subcontinent. Comparative toxicity of copper nanoparticles and copper sulfate were investigated with reference to selected immune associated parameters of earthworm. Total count, phagocytic response, generation of cytotoxic molecules (superoxide anion, nitric oxide), activities of enzymes like phenoloxidase, superoxide dismutase, catalase, acid phosphatase, alkaline phosphatase and total protein of coelomocytes were estimated under the exposures of 100, 500, 1000mg of copper oxide nanoparticles and copper sulfate per kg of soil for 7 and 14 d. A significant decrease in the total coelomocyte count were recorded with maximum depletion as 15.45 +/- 2.2 and 12.5 +/- 2 * 104 cells/ml under the treatment of 1000mg/kg of copper nanoparticles and copper sulfate for 14 d respectively. A significant decrease in generation of nitric oxide and activity of phenoloxidase were recorded upon exposure of both toxins for 7 and 14 d indicating possible decline in cytotoxic status of the organism. A maximum inhibition of superoxide dismutase activity was recorded as 0.083 +/- 0.0039 and 0.055 +/- 0.0057 unit/mg protein/minute against 1000mg/kg of copper nanoparticles and copper sulfate treatment for 14 d respectively. Activities of catalase and alkaline phosphatase were inhibited by all experimental concentrations of both toxins in the coelomocytes of earthworm. These toxins were recorded to be modifiers of the major immune associated parameters of M. posthuma. Unrestricted contamination of soil by sulfate and oxide nanoparticles of copper may lead to an undesirable shift in the innate immunological status of earthworm leading to a condition of immune compromisation and shrinkage in population density of this species in its natural habitat. This article is the first time report of immunological toxicity of nanoparticles and sulfate salt of copper in M.posthuma inhabiting the soil of India, an agriculture based country. PMID- 29128824 TI - A new model based on adiabatic flame temperature for evaluation of the upper flammable limit of alkane-air-CO2 mixtures. AB - For security issue of alkane used in Organic Rankine Cycle, a new model to evaluate the upper flammability limits for mixtures of alkanes, carbon dioxide and air has been proposed in present study. The linear relationship was found at upper flammability limits between molar fraction of diluent in alkane-CO2 mixture and calculated adiabatic flame temperature. The prediction ability of the variable calculated adiabatic flame temperature model that incorporated the linear relationship above is greatly better than the models that adopted the fixed calculated adiabatic flame temperature at upper flammability limit. The average relative differences between results predicted by the new model and observed values are less than 3.51% for upper flammability limit evaluation. In order to enhance persuasion of the new model, the observed values of n-butane-CO2 and isopentane-CO2 mixtures measured in this study were used to confirm the validity of the new model. The predicted results indicated that the new model possesses the capacity of practical application and can adequately provide safe non-flammable ranges for alkanes diluted with carbon dioxide. PMID- 29128825 TI - Toluene and acetaldehyde removal from air on to graphene-based adsorbents with microsized pores. AB - Volatile organic compound (VOC) gases can cause harm to the human body with exposure over the long term even at very low concentrations (ppmv levels); thus, effective absorbents for VOC gas removal are an important issue. In this study, accordingly, graphene-based adsorbents with microsized pores were used as adsorbents to remove toluene and acetaldehyde gases at low concentrations (30ppm). Sufficient amounts of the adsorbents were prepared for use on filters and were loaded uniformly at 0.1-0.5g on a 50*50mm2 area, to evaluate their adsorption features with low gas concentrations. The morphology and chemical composition of the adsorbents were characterized using scanning electron microscopy, N2 adsorption-desorption isotherms, X-ray photoelectron spectroscopy, and Raman spectroscopy. Microwave irradiation and heat treatment near 800 degrees C under KOH activation resulted in enlargement of the pristine graphene surface and its specific surface area; maximum volume capacities of 3510m3/g and 630m3/g were observed for toluene and acetaldehyde gas. The high removal efficiency for toluene (98%) versus acetaldehyde (30%) gas was attributed to pi-pi interactions between the pristine graphene surface and toluene molecules. PMID- 29128826 TI - Redox-sensitive GFP fusions for monitoring the catalytic mechanism and inactivation of peroxiredoxins in living cells. AB - Redox-sensitive green fluorescent protein 2 (roGFP2) is a valuable tool for redox measurements in living cells. Here, we demonstrate that roGFP2 can also be used to gain mechanistic insights into redox catalysis in vivo. In vitro enzyme properties such as the rate-limiting reduction of wild type and mutant forms of the model peroxiredoxin PfAOP are shown to correlate with the ratiometrically measured degree of oxidation of corresponding roGFP2 fusion proteins. Furthermore, stopped-flow kinetic measurements of the oxidative half-reaction of PfAOP support the interpretation that changes in the roGFP2 signal can be used to map hyperoxidation-based inactivation of the attached peroxidase. Potential future applications of our system include the improvement of redox sensors, the estimation of absolute intracellular peroxide concentrations and the in vivo assessment of protein structure-function relationships that cannot easily be addressed with recombinant enzymes, for example, the effect of post-translational protein modifications on enzyme catalysis. PMID- 29128827 TI - A comparison study on a sulfonated graphene-polyaniline nanocomposite coated fiber for analysis of nicotine in solid samples through the traditional and vacuum-assisted HS-SPME. AB - A simple, rapid, and reliable headspace solid-phase microextraction (HS-SPME) procedure, reinforced by applying vacuum in the extraction vial, was developed. It was applied for the extraction of nicotine in solid samples prior to determination by gas chromatography-flame ionization detection (GC-FID). First, the surface of a narrow stainless steel wire was made porous and adhesive by platinization to obtain a durable, higher surface area, and resistant fiber. Then, a thin film of sulfonated graphene/polyaniline (Sulf-G/PANI) nanocomposite was synthesized and simultaneously coated on the platinized fiber using the electrophoretic deposition (EPD) method. It was demonstrated that the extraction efficiency remarkably increased by applying the reduced-pressure condition in the extraction vial. To evaluate the conventional HS-SPME and vacuum-assisted HS-SPME (VA-HS-SPME) platforms, all experimental parameters affecting the extraction efficiency including desorption time and temperature, extraction time and temperature and moisture content of sample matrix were optimized. The highest extraction efficiency was obtained at 60 degrees C, 10min (extraction temperature and time) and 280 degrees C, 2min (desorption condition), for VA-HS-SPME strategy, while for conventional HS-SPME the extraction and desorption conditions found to be 100 degrees C, 30min and 280 degrees C, 2min, respectively. The Sulf G/PANI coated fiber showed high thermal stability, good chemical/mechanical resistance, and long lifetime. For analysis of nicotine in solid samples using VA HS-SPME-GC-FID, linear dynamic range (LDR) was 0.01-30MUgg-1 (R2=0.996), the relative standard deviation (RSD%, n=6), for analyses of 1MUgg-1 nicotine was calculated 3.4% and limit of detection (LOD) found to be 0.002MUgg-1. The VA-HS SPME-GC-FID strategy was successfully carried out for quantitation of nicotine in hair and tobacco real samples. PMID- 29128828 TI - Quantitative assessment of betamethasone dual-acting formulation in urine of patients with rheumatoid arthritis and ankylosing spondylitis after single-dose intramuscular administration and its application to long-term pharmacokinetic study. AB - Quantitative evaluation and assessment of pharmacokinetic parameters of Diprospan(r) (suspension for injection 7mg/mL (2mg+5mg/mL) of betamethasone) were performed in urine samples taken from patients with rheumatoid arthritis or ankylosing spondylitis for 28days after systemic intramuscular administration in routine clinical practice in an open-comparative prospective cohort study. The maximum betamethasone concentration was reached at day 4 of the follow-up; in some cases, beta-phase of elimination of the drug was appeared at day 14 or at day 21 of the follow-up. The deferred beta-phase elimination was likely a consequence of the physiological characteristics of the patients or of the influence of non-steroidal agents. The half-life of betamethasone was 8.5days. The elimination rate constant was 2.49h-1; the mean clearance was 4.72L/d. The recommended frequency of the drug administration to its complete elimination was estimated up to 48days. Mann-Whitney test showed no significant differences in pharmacokinetic characteristics between male and female subjects. The prolonged elimination phase was observed in patients with deviations in their body mass index, continual treatment by diclofenac and nimesulide or, possibly, after consuming an alcohol. The study was recorded in Clinical Trials open source with identifier NCT03119454. PMID- 29128829 TI - Identification of the binding between three fluoronucleoside analogues and fat mass and obesity-associated protein by isothermal titration calorimetry and spectroscopic techniques. AB - In this work, the interactions between fat mass and obesity-associated (FTO) protein and three fluoronucleoside analogues (three-member-ring compound (1a), five-member-ring compound (1b) and six-member-ring compound (1c)) have been investigated by fluorescence, ultraviolet-visible absorption spectroscopy, isothermal titration calorimetric (ITC) and molecular modeling. Analysis of fluorescence data showed that the binding between three analogues and FTO occurred via a static quenching mechanism. Both ITC and fluorescence results indicated that 1b is the strongest quencher. In contrast to spectroscopy techniques, ITC results suggested that there is no binding for 1c. ITC results showed that the binding between FTO and 1a (or 1b) were exothermic. Fluorescence results showed that the binding between three analogues and FTO were endothermic. Results of thermodynamic analysis and molecular modeling suggested that it was entropy driven event between FTO and 1a (or 1b). PMID- 29128830 TI - Metabolism of the synthetic cannabinoid 5F-PY-PICA by human and rat hepatocytes and identification of biliary analytical targets by directional efflux in sandwich-cultured rat hepatocytes using UHPLC-HR-MS/MS. AB - Analytical strategies for detecting drugs in biological samples rely on information on metabolism and elimination. 5F-PY-PICA belongs to the group of synthetic cannabinoids that are known to undergo excretion into the bile. The aims of this study were the in vitro identification of metabolites of 5F-PY-PICA and to determine which analytical targets are excreted into the bile and urine. Metabolites identified after incubation of 5F-PY-PICA with pooled human liver microsomes (pHLM), pooled human hepatocytes (pHH), or suspended and sandwich cultured rat hepatocytes (SCRH). Rat hepatocytes were harvested following a two step perfusion protocol and the SCRH were prepared between layers of rat-tail collagen. The biliary efflux of 5F-PY-PICA and its metabolites was determined in three-day-cultured SCRH by differential efflux into either standard buffer from intact bile canaliculi or standard buffer without divalent cations, which disrupts the bile canaliculi. The metabolites were identified using liquid chromatography-high resolution mass spectrometry/mass spectrometry (LC-HR-MS/MS). The main metabolites were the COOH-omega-metabolite (M4) in pHH, the defluoro-HO omega-metabolite (M3) in pHLM, and the COOH-pyrrolidine-metabolite (M6) in rat hepatocytes. Efflux into standard buffer without divalent cations was significantly higher (p<0.050) for 5F-PY-PICA, M4, and the HO-indole-glucuronide metabolite (M22). M6 did not undergo significant biliary efflux, indicating that basolateral efflux dominates for this metabolite. 5F-PY-PICA, M4, and M22 are proposed as analytical targets for bile analysis in forensic screening protocols, whereas M6 should be one of the main urinary targets for 5F-PY-PICA analysis. PMID- 29128831 TI - Dynamic morphogenesis of dendritic structures formation in hen egg white lysozyme fibrils doped with magnetic nanoparticles. AB - In this research, the dynamic process of aggregation that forms microflower morphology in solution of lysozyme amyloid fibrils doped with spherical or spindle-like magnetic nanoparticles during the process of drying as well as their final microstructures were investigated. The prepared lysozyme amyloid fibrils as well as their mixtures with in-lab synthesized magnetic particles, which were prepared by adding the nanoparticles to the fibrils solution after the process of fibrillation was done, were characterized using brightfield trans-illumination mode optical microscope, atomic force microscopy (AFM) and scanning electron microscope (SEM). Brightfield optical imaging bases upon photoabsorptive property of the fibrils-nanoparticle composites clearly reveals the morphological features in microscale, and additionally, for the in vivo, live action of the time dependent process of self-assembly of such composites composed of fibrillary structure incorporated with magnetic particles was optically elucidated at ambient temperature. Moreover, while results of AFM reveal delicate and peculiar association of fibrils with magnetic nanoparticles of different shapes, SEM images illustrate a stark difference in fine detailed final morphology of microstructures associated with spherical and spindle-like nanoparticles. Our results indicated that the interaction between fibrils solution and the nanoparticles commence right after mixing, the dynamic process of forming dendritic structure resembling microflower morphology is on the order of minutes, and its final structure is highly dependent on the shape of magnetic nanoparticles. PMID- 29128833 TI - Structurally stable N-t-butylacrylamide hydrogel particles for the capture of peptides. AB - Hydrogel particles have proven to be powerful tools for the capture and concentration of low abundance, low molecular weight peptides and proteins from complex biofluids, such as plasma. The primary means of recovering and washing the particles following harvesting is through centrifugation, which can be a very time-consuming process depending on harvest conditions. To improve the process of particle recovery, washing, and elution we have developed new particle formulations: incorporating N-t-butylacrylamide (tBA) in the polymer backbone with monomers bearing more acidic functional groups and higher degrees of cross linking. These particle formulations produce a stable architecture that does not significantly respond to changes in environmental conditions, such as pH and temperature. These two new formulations impart structural stability to the particle, control swelling, and improve pelleting through centrifugation, even at high pH values. These structurally stable microparticles yield improved particle recovery while maintaining the peptide capture properties of the particle. PMID- 29128832 TI - Delivery of paclitaxel using nanoparticles composed of poly(ethylene oxide)-b poly(butylene oxide) (PEO-PBO). AB - An amphiphilic block copolymer poly(ethylene oxide)-b-poly(butylene oxide) (PEO PBO) was evaluated as a carrier for therapeutic delivery of paclitaxel (PTX). PEO PBO and PTX form nanoparticles (NPs) by self-assembly upon hydration. The size of these NPs was about 92.71nm and the zeta potential was -5.06mV, which met the requirements for passive tumor targeting through the enhanced permeability and retention effect. Compared with a commonly used block copolymer poly(ethylene glycol)-b-poly-D,L-(lactic acid) (PEG-PDLLA), PEO-PBO forms nanoparticles with superior pharmacokinetic, biodistribution, and tumor inhibitory properties. Meanwhile, results of hemolysis study and CMC determination showed that PEO-PBO had better biocompatibility and stability than PEG-PDLLA. These data suggest that PEO-PBO has potential for application in drug delivery and warrant further evaluation. PMID- 29128834 TI - Preparation of nano-CaCO3/polystyrene nanocomposite beads for efficient bilirubin removal. AB - A novel nano-CaCO3/polystyrene nanocomposite adsorbent (NPS-8) was synthesized for efficient bilirubin removal from human plasma. A comparison with the polystyrene adsorbent (PS-8), which was without the incorporation of nano-CaCO3, revealed that NPS-8 had superior bilirubin adsorption capacity and mechanical strength. The resulting nano-CaCO3 reinforced PS-8 (NPS-8) was tested by transmission electron microscopy (TEM), scanning electron microscopy (SEM), mechanical strength test, and bilirubin adsorption assays. The adsorption results indicated that NPS-8 displayed better adsorption capacity for bilirubin (91%) than that of PS-8 (75.88%). The mechanical strength of NPS-8 was significantly greater than that of PS-8. In addition, both PS-8 and NPS-8 possessed good blood compatibility properties (a negligible hemolytic activity and platelet adhesion). Therefore, a conclusion could be drawn that NPS-8 has a high potential as an efficient bilirubin adsorbent for blood purification in clinical practice. At the same time, the success of organic-inorganic nanocomposite adsorbents might provide a new insight into the improvement of adsorbents in hemoperfusion. PMID- 29128835 TI - Star poly(epsilon-caprolactone)-based electrospun fibers as biocompatible scaffold for doxorubicin with prolonged drug release activity. AB - In this work, a novel drug delivery system consisting of poly(epsilon caprolactone) (PCL) electrospun fibers containing an ad-hoc-synthesized star polymer made up of a poly(amido-amine) (PAMAM) core and PCL branches (PAMAM-PCL) was developed. The latter system which was synthesized via the ring opening polymerization of epsilon-caprolactone, starting from a hydroxyl-terminated PAMAM dendrimer and characterized by means of 1H NMR, IR and DSC, was found to be compatible with both the polymer matrix and a hydrophilic chemotherapeutic drug, doxorubicin (DOXO), the model drug used in this work. The preparation of the dendritic PCL star product with an average arm length of 2000g/mol was characterized using IR and 1H NMR measurements. The prepared star polymer possessed a higher crystallinity and a lower melting temperature than that of the used linear PCL. Electrospun fibers were prepared starting from solutions containing the neat PCL as well as the PCL/PAMAM-PCL mixture. Electrospinning conditions were optimized in order to obtain defect free fibers, which was proven by the structural FE-SEM study. PAMAM moieties enhanced the hydrophilicity of the fibers, as proved by comparing the water absorption for the PCL/PAMAM-PCL fibers to that neat PCL fibers. The drug-loaded system PCL/PAMAM-PCL was prepared by directly introducing DOXO into the electrospinning solutions. The DOXO-loaded PCL/PAMAM-PCL showed a prolonged release of the drug with respect to the DOXO loaded PCL fibers and elicited effective controlled toxicity over A431 epidermoid carcinoma, HeLa cervical cancer cells and drug resistant MCF-7 breast cancer cells. On the contrary, the drug-free PCL/PAMAM-PCL scaffold demonstrated no toxic effects on human dermal fibroblasts, suggesting the biocompatibility of the proposed system which can be used in cellular scaffold applications. PMID- 29128836 TI - Characterization of liposome-containing SPIONs conjugated with anti-CD20 developed as a novel theranostic agent for central nervous system lymphoma. AB - Despite advances in neuroscience cancer research during the past decades, the survival of cancer patients has only marginally improved and the cure remains unlikely. The blood-brain barrier (BBB) is a major obstacle protecting the entry of therapeutic agents to central nervous system, especially for primary central nervous system lymphoma (PCNSL). Thus, the use of small nanoparticle as a drug carrier may be new strategies to overcome this problem. In this study, we fabricated liposome consisting of superparamagnetic iron oxide nanoparticles (SPIONs) functionalized with anti-CD20 (Rituximab; RTX). The designed nanoparticles have a theranostic property which is not only to improve drug delivery, but also to offer diagnostic and monitoring capabilities. TEM images revealed the spherical shape of liposome with the approximately average diameters about 140-190nm with slightly negatively charge surfaces. Superparamagnetic property of SPIONs-loaded liposomes was confirmed by VSM. Liposome colloidal could be prolonged at 4 degrees C and 25 degrees C storages. RTX conjugated liposome induced cell internalization and apoptosis effect in B-lymphoma cells. Drug targeting and therapeutic effect was investigated in BBB model. The result confirmed that liposome nanocarrier is required as a drug carrier for effectively RTX across the BBB. PMID- 29128837 TI - The effects of ligand valency and density on the targeting ability of multivalent nanoparticles based on negatively charged chitosan nanoparticles. AB - It has been shown that multivalent ligands could significantly enhance the binding avidity compared with the monovalent ones; therefore, once incorporated into nanoparticles, they promote superior targeting ability without increasing the ligand density. Although ligand valency and density play a key role on the targeting ability of corresponding nanoparticles, these facotrs remain largely unexplored and detailed studies are lacking. Herein, a series of multivalent ligands with certain valencies (FAn, n indicates the valency of ligand: n=3, 5, 7) has been conveniently synthesized by conjugating different copies of folate ligands with poly(acrylic acid) (PAA). Negatively charged chitosan nanoparticles (CTS-SA NPs) have been utilized as proper multivalent platforms because they can strongly suppress non-specific protein adsorption and cellular uptake without interfering with the targeting ability of multivalent ligands. Subsequently, the structure of CTS-SA NPs has been modified using different amounts of FAn to form multivalent nanoparticles (FAn-CTS-SA NPs) with various valencies and densities. A series of specific investigations of them suggested that the cellular uptake of multivalent nanoparticles has largely varied with the ligand valency variation even at similar ligand densities; and also largely varied with ligand density variation even at the same ligand valencies. The intermediate valency and density values determined in the current study (ie., 5 and 2.4wt%, respectively) have provided the best cellular uptake, facilitating superior targeting ability at relatively low ligand valency and density. Unexpectedly, no conspicuous difference has been observed during endocytotic inhibition assays with single inhibitors, which may be attributed to the synergetic endocytotic mechanism with multiple pathways of multivalent nanoparticles. The optimal multivalent nanoparticles have also exhibited excellent biocompatibility, long-term stability in vitro and enhanced circulation time in vivo, thus demonstrating their potential for targeted drug delivery. PMID- 29128838 TI - Transfection of plasmid DNA by nanocarriers containing a gemini cationic lipid with an aromatic spacer or its monomeric counterpart. AB - This study performed a biophysical characterization (electrochemistry, structure and morphology) and assessment of the biological activity and cell biocompatibility of GCL/DOPE-pDNA lipoplexes comprised of plasmid DNA and a mixed lipid formed by a DOPE zwitterionic lipid and a gemini cationic lipid N-N'-(1,3 phenylene bis (methylene)) bis (N,N-dimethyl-N-(1-dodecyl) ammonium dibromide (12PH12) containing an aromatic spacer or its monomeric counterpart surfactant, N benzyl-N,N-dimethyl-N-(1-dodecyl) ammonium bromide (12PH). Electrochemical results reveal that i) the gemini cationic lipid (12PH12) and the plasmid pDNA yield effective charges less than their nominal charges (+2 and -2/bp, respectively) and that ii) both vectors (12PH12/DOPE and 12PH/DOPE) could compact pDNA and protect it from DNase I degradation. SAXS and cryo-TEM experiments indicate the presence of a lamellar lyotropic liquid crystal phase represented as alternating layers of mixed lipid and plasmid. Transfection efficiency (by FACS and luminometry) and cell viability assay in COS-7 cells, performed with two plasmid DNAs (pEGFP-C3 and pCMV-Luc VR1216), confirm the goodness of the proposed formulations (12PH12/DOPE and 12PH/DOPE) to transport genetic material, with efficiencies and biocompatibilities comparable to or better than those exhibited by the control Lipofectamine 2000*. In conclusion, although major attention has been paid to gemini cationic lipids in the literature, due to the large variety of modifications that their structures may support to improve the biological activity of the resulting lipoplexes, it is remarkable that the monomeric counterpart surfactant with an aromatic group analyzed in the present work also exhibits good biological activity. The in vitro results reported here indicate that the optimum formulations of the gene vectors studied in this work efficiently transfect plasmid DNA with very low toxicity levels and, thus, may be used in forthcoming in vivo experiments. PMID- 29128839 TI - Enhanced bacterial disinfection by Bi2MoO6-AgBr under visible light irradiation. AB - Bi2MoO6-AgBr hybrid photocatalyst was synthesized via a mixed solvothermal precipitation method. The as-synthesized photocatalysts were well characterized by Powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopic (SEM) equipped with energy-dispersive X-ray spectroscopy (EDX), high resolution transmission electron microscope (HRTEM), UV vis diffuse reflectance spectra (DRS), as well as photoluminescence spectra (PL). The visible light driven (VLD) disinfection activity of Bi2MoO6-AgBr was tested using Escherichia coli as the model bacteria. Complete disinfection of 3*106 CFU mL-1 viable cell density was observed in 90min under visible light irradiation for Bi2MoO6-AgBr with the optimal AgBr amount. Ag+ released from the photocatalysts did not affect the inactivation process due to the low concentration. Whereas, photo-generated holes, H2O2 and O2- were the main active species involved in the photocatalytic disinfection reaction. The presence of O2 and direct contact between photocatalysts and bacterial cells were found to be indispensable for the cell inactivation. In addition, neutral and slight alkaline conditions was beneficial for the disinfection process. PMID- 29128841 TI - Anthropogenic water bodies as drought refuge for aquatic macroinvertebrates and macrophytes. AB - Ecological research associated with the importance of refuges has tended to focus on natural rather than anthropogenic water bodies. The frequency of disturbances, including drought events, is predicted to increase in many regions worldwide due to human-induced climate change. More frequent disturbance will affect freshwater ecosystems by altering hydrologic regimes, water chemistry, available habitat and assemblage structure. Under this scenario, many aquatic biota are likely to rely on permanent water bodies as refuge, including anthropogenic water bodies. Here, macroinvertebrate and macrophyte assemblages from waste-water treatment and raw water storages (i.e. untreated potable water) were compared with nearby natural water bodies during autumn and winter 2013. We expected macroinvertebrate and macrophyte assemblages in raw-water storages to be representative of natural water bodies, while waste-water treatment storages would not, due to degraded water quality. However, water quality in natural water bodies differed from raw water storages but was similar to waste-water treatment storages. Macroinvertebrate patterns matched those of water quality, with no differences occurring between natural water bodies and waste-water treatment storages, but assemblages in raw-water storages differed from the other two water bodies. Unexpectedly, differences associated with raw-water storages were attributable to low abundances of several taxa. Macrophyte assemblages in raw-water storages were representative of natural water bodies, but were less diverse and abundant in, or absent from, waste-water treatment storages. No clear correlations existed between any habitat variables and macroinvertebrate assemblages but a significant correlation between macrophyte assemblages and habitat characteristics existed. Thus, there were similarities in both water quality and macroinvertebrate assemblages between natural water bodies and waste-water treatment storages, and similarities in macrophyte assemblages between raw-water storages and natural water bodies. These similarities illustrate that anthropogenic water storages support representative populations of some aquatic biota across the landscape, and thus, may provide important refuge following disturbance where dispersal capabilities allow. PMID- 29128840 TI - Effect of enrofloxacin on the proteome of earthworms. AB - The environmental and human health risks of veterinary drugs are becoming public health issues. Enrofloxacin (EF) is an extensively used animal-specific antibacterial agent that leaves drug residues in the environment. This study investigated the proteomic response of the earthworm Eisenia fetida to EF exposure. Earthworms were exposed to EF in soil at 1-500mg.kg-1, and samples were collected at intervals during a 28 day period. The extracted proteins were separated by two dimensional electrophoresis to detect differentially expressed proteins (DEPs) in EF-exposed earthworms. In total, 35 unique DEPs were found. These proteins were subjected to MALDI-TOF/TOF-MS analysis and identified through comparison of their mass spectra with those in protein databases. The DEPs were grouped on the basis of their function, into metabolism, stress-related, transport, transcription, and predicted/hypothetical protein categories. Knowledge of proteins that are induced or repressed by EF in earthworms could provide insight into mechanisms of sub-clinical physiological effects of xenobiotic residues in the environment, and may also help understand synergy between pollutants. As several DEPs in E. fetida showed similarity to human protein sequences, E. fetida has potential as an indicator species to assess the environmental and biological risks of drug residues. PMID- 29128842 TI - Application of three-dimensional collagen scaffolds to recapitulate and monitor the dynamics of epithelial-mesenchymal transition during tumor satellite formation of head and neck cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is a worldwide leading malignancy with poor prognoses. Aggressive HNSCC is manifested by forming tumor satellites in the invasive front, which is closely associated with epithelial-mesenchymal transition, local invasion, and metastasis. Limited by the pathological analyses of static cancer specimens conducted in most previous investigations, the dynamic processes and the decisive factors of tumor satellite formation in HNSCC cannot be monitored and studied. The establishment of a system to recapitulate the phenomenon in vitro may be instrumental to explicitly address the question. In this study, we explored the feasibility of establishing an in vitro system to induce tumor satellite formation of different HNSCC cells by applying a system composed of three-dimensional collagen scaffolds. The real-time dynamic process of tumor satellite formation could be monitored in detail, and the pivotal factors accounting for HNSCC tumor satellite formation were evaluated. E-cadherin remodeling, vimentin aggregation, invadopodia formation, and extracellular matrix degradation occurred in the HNSCC cells when they were cultured in an environment created with a low calcium concentration and steric collagen scaffolds, which altogether contributed to tumor satellite formation and spreading. The phenomena of HNSCC cell transition observed in the current system were confirmed in vivo with compatible findings in surgical specimens. Through the use of this system, we illustrated a novel method to study tumor satellite formation in HNSCC. It may serve as a platform for further investigation of underlying mechanisms for tumor satellites of cancer. PMID- 29128843 TI - Shape-controlled magnetic mesoporous silica nanoparticles for magnetically mediated suicide gene therapy of hepatocellular carcinoma. AB - Magnetic nanoparticles (NPs) have emerged as a promising tool for suicide gene therapy. However, the separate delivery of the suicide gene and prodrug in current systems limits their clinical translation. Therefore, improving magnetically mediated suicide gene therapy by exploring higher performance magnetic NP-based hybrid nanoplatforms is an important challenge. In the current study, shape-controlled magnetic mesoporous silica nanoparticles (M-MSNs) were prepared, and their performance in magnetic resonance imaging (MRI)-guided, magnetically targeted and hyperthermia-enhanced suicide gene therapy of hepatocellular carcinoma (HCC) was investigated. Compared with sphere-like MSNs, rod-like MSNs exhibited higher loading capacity, faster prodrug release behavior, stronger magnetically enhanced gene delivery and better magnetic hyperthermia properties. Utilizing the improved magnetic properties of the M-MSNs allowed us to demonstrate highly effective dual magnetically enhanced suicide gene therapy in vivo with decreased systematic toxicity and with the ability to monitor therapeutic outcome by MRI. Because of their magnetic targeting abilities, magnetic hyperthermia performance and MRI properties, these M-MSNs might prove to be a potentially superior candidate for suicide gene therapy of HCC. PMID- 29128844 TI - A biodegradable scaffold enhances differentiation of embryonic stem cells into a thick sheet of retinal cells. AB - Retinal degeneration is a leading cause of blindness in developed countries. Stem cells can be differentiated into retinal organoids to study mechanisms of retinal degeneration, develop therapeutic agents, and potentially serve as replacement tissues. The spherical nature of these retinoids limits their utility, because the investigator lacks ready access to both sides of the neo-tissue. For tissue replacement, spherical retinoids are unable to interact simultaneously with the host retinal pigment epithelium and remaining neurosensory retina. To attempt making a planar retinoid, we developed a biodegradable scaffold that simulates the extracellular matrix of the neurosensory retina. Human embryonic stem cells were seeded on the scaffold. Differentiation into retinal cells was confirmed by quantitative RT-PCR, confocal immunocytochemistry, and immunoblotting. The scaffold favored differentiation into retinal cell types over other anterior forebrain cells, but retinal lamination was rudimentary. The cultures elicited a minimal immune response when implanted into the subretinal space of a mouse model of retinal degeneration. The implants survived for at least 12 weeks, but there was evidence of cytoplasmic transfer rather than implantation into the outer nuclear layer (photoreceptor layer). However, some implanted cells migrated to the inner layers of the retina and established elaborate arbors of neurites. PMID- 29128845 TI - Mitochondrial alkaline pH-responsive drug release mediated by Celastrol loaded glycolipid-like micelles for cancer therapy. AB - Mitochondria, crucial regulators of inducing tumor cells apoptosis, can be treated as the prime target for tumor therapy. The selective and responsive release of proapoptotic therapeutics into mitochondria may notably improve antitumor efficiency. Herein, (4-Carboxybutyl) triphenylphosphonium bromide (CTPP), a lipophilic cation, was conjugated with glucolipid-like conjugates (CSOSA) to produce mitochondria-targeted conjugates (CTPP-CSOSA). Loading with weakly acidic drug Celastrol (Cela), CTPP-CSOSA/Cela micelles could selectively respond to mitochondrial alkaline pH (pH 8.0), controlled by the weaker interaction between hydrophobic core of micelles and Cela with higher solubility at pH 8.0. However, there was a slow drug release behavior at pH 7.4 and pH 5.0. It illustrated that CTPP-CSOSA/Cela could realize mitochondrial fast drug release, and decrease drug leakage in the cytoplasm and lysosome. CTPP-CSOSA/Cela highly enhanced ROS levels, which further induced mitochondria membrane potential decreasing and more Cytochrome C releasing into cytoplasm, then promoted tumor cells apoptosis notably. In vivo, CTPP-CSOSA had an enhanced accumulation in tumor tissue, compared with CSOSA. Moreover, the tumor-inhibition rate of CTPP CSOSA/Cela was 80.17%, which was significantly higher than CSOSA/Cela (58.35%) and Cela (54.89%). Thus, CTPP-CSOSA/Cela micelles with mitochondrial targeting and alkaline pH-responsive release capability could provide a new strategy for tumor therapy. PMID- 29128846 TI - Tissue adhesive FK506-loaded polymeric nanoparticles for multi-layered nano shielding of pancreatic islets to enhance xenograft survival in a diabetic mouse model. AB - This study aims to develop a novel surface modification technology to prolong the survival time of pancreatic islets in a xenogenic transplantation model, using 3,4-dihydroxyphenethylamine (DOPA) conjugated poly(lactide-co-glycolide) poly(ethylene glycol) (PLGA-PEG) nanoparticles (DOPA-NPs) carrying immunosuppressant FK506 (FK506/DOPA-NPs). The functionalized DOPA-NPs formed a versatile coating layer for antigen camouflage without interfering the viability and functionality of islets. The coating layer effectively preserved the morphology and viability of islets in a co-culture condition with xenogenic lymphocytes for 7 days. Interestingly, the mean survival time of islets coated with FK506/DOPA-NPs was significantly higher as compared with that of islets coated with DOPA-NPs (without FK506) and control. This study demonstrated that the combination of surface camouflage and localized low dose of immunosuppressant could be an effective approach in prolonging the survival of transplanted islets. This newly developed platform might be useful for immobilizing various types of small molecules on therapeutic cells and biomaterial surface to improve the therapeutic efficacy in cell therapy and regenerative medicine. PMID- 29128847 TI - Versatile hyaluronic acid modified AQ4N-Cu(II)-gossypol infinite coordination polymer nanoparticles: Multiple tumor targeting, highly efficient synergistic chemotherapy, and real-time self-monitoring. AB - A novel strategy for the preparation of infinite coordination polymer nanoparticles (ICPs) based nanomedicines was developed, with which hyaluronic acid modified AQ4N-Cu(II)-gossypol nanoparticles (HA@AQ4N-Cu(II)-gossypol NPs) were obtained. This is a highly efficient nanomedicine, in which gossypol serves as a chemotherapeutic agent and a self-carrier material; Cu(II) serves as the connecting point and anti-tumor enhancer; AQ4N not only serves as a chemotherapeutic agent and self-carrier material, but also as the self-monitor based on its inherent fluorescence. HA@AQ4N-Cu(II)-gossypol NPs possessed a spherical shape with a dynamic size of 88.7 +/- 7.4 nm, and the total drug loading content and drug encapsulation efficiency are 77.41% and 100%, respectively. This nanomedicine has a multiple tumor-targeting ability caused by HA-receptor mediation and pH-responsive drug release. A significantly low combination index (0.097) of AQ4N and gossypol is ascertained. In vivo experiments indicate that it accumulates and significantly releases drugs at the tumor region. With the use of only one-fiftieth of AQ4N and half of gossypol of the generally administered dose, they can achieve significantly high anti-tumor efficiency with negligible side effects. Importantly, the switching-type changed fluorescence of AQ4N can be used for in vivo real-time self-monitoring of the drug release and distribution, which allows us to adjust the administration dose and time for different tumor types and stages for individual therapy. PMID- 29128848 TI - Antimalarial activity of Malaria Box Compounds against Plasmodium falciparum clinical isolates. AB - Malaria remains a major cause of childhood deaths in resource-limited settings. In the absence of an effective vaccine, drugs and other interventions have played very significant roles in combating the scourge of malaria. The recent reports of resistance to artemisinin necessitate the need for new antimalarial drugs with novel mechanisms of action. Towards the development of new, affordable and easily accessible antimalarial drugs for endemic regions, the Medicines for Malaria Venture (MMV) assembled a total of 400 active antimalarial compounds called the Malaria Box. The potency and the efficacy of the Malaria Box Compounds have been determined mainly using laboratory strains of P. falciparum. This study investigated the potency of twenty compounds from the Malaria Box against four clinical isolates from Ghana, using optimized in vitro growth inhibitory assays. Seven out of the 20 compounds screened had 50% inhibitory concentration (IC50) below 500 nM. The most active among the selected compounds was MMV006087 (average IC50 of 30.79 nM). Variations in the potency of the Malaria Box Compounds were observed between P. falciparum clinical isolates and Dd2 strain. We also investigated the sensitivity of the clinical isolates to chloroquine and artesunate. The N093 clinical isolate was found to be resistant to chloroquine but showed high sensitivity to artesunate. The results underscore the importance of including clinical isolates with different drug-resistant backgrounds, in addition to laboratory strains, in validating potential compounds during antimalarial compound screening programs. PMID- 29128850 TI - Exploring the newborn head diameters in relation to current obstetric forceps' dimensions: A systematic review. AB - OBJECTIVE: The aim of this study was to systematically search the literature for studies that reported term neonate head size and shape, in an attempt to determine the most appropriate dimensions for the obstetric forceps. STUDY DESIGN: We searched the Ovid Medline, Ovid Embase and Ebscohost CINAHL databases from inception to February 2016. We predefined inclusion criteria to identify studies in which head width and length of asymptomatic, term neonates were measured soon after birth using direct, non-photographic methods A bespoke quality assessment score was used to evaluate the identified studies. RESULTS: Seven studies were identified which measured head width (biparietal diameter) in 551 neonates; giving a mean value of 94.0mm (range 90.7mm-95.5mm). We identified one study which measured head length (mentovertical diameter) in 38 neonates; which gave a mean value of 134.5mm (range 129mm-139mm). CONCLUSION: This data, in conjunction with measurements of Neville Barnes' and Wrigley's forceps from our previous study, indicates current obstetric forceps' blades are too long, and close together. Potentially, this could be contributing to neonatal and maternal injuries associated with operational vaginal deliveries. PMID- 29128849 TI - Genetic strategies to tackle neurological diseases in fruit flies. AB - Drosophila melanogaster is a genetic model organism that has contributed to the discovery of numerous genes whose human homologues are associated with diseases. The development of sophisticated genetic tools to manipulate its genome accelerates the discovery of the genetic basis of undiagnosed human diseases and the elucidation of molecular pathogenic events of known and novel diseases. Here, we discuss various approaches used in flies to assess the function of the fly homologues of disease-associated genes. We highlight how systematic and combinatorial approaches based on recently established methods provide us with integrated tool sets that can be applied to the study of neurodevelopmental and neurodegenerative disorders. PMID- 29128851 TI - Study on the PGNAA measurement of heavy metals in aqueous solution by the Monte Carlo-Library Least-Squares (MCLLS) approach. AB - In the present work, a prompt gamma neutron activation analysis (PGNAA) setup, which consists of a 300mCi 241Americium-Beryllium (Am-Be) neutron source and a 4 * 4-in. Bismuth germanium oxide (BGO) detector, was developed for heavy metal detection in aqueous solutions. A series of standard samples with analytical purity were prepared by dissolving heavy metals in deionized water. Quantitative spectrum analysis was performed by the Monte Carlo-Least-Squares (MCLLS) approach to measure the standard samples. The detector response functions of 4 * 4-in. BGO detector were generated by using the CEARDRF code. The element libraries were simulated in silico by the CEARCPG code, which was developed by Dr. Gardner. The simulation results presented were in very good agreement with the experimental results. The correlation coefficients were very close to 1 when the fitted spectrum was compared with the experimental spectrum. By applying the MCLLS approach, the relative deviation of the measurement accuracy was less than 2.27% for Ni, Mn, and Cu and up to 69.33% for Pb. PMID- 29128852 TI - Configuration of gamma detectors in a neutron interrogation system for detection of explosives. AB - This paper investigates the use of a suitable gamma detector array to increase the detectably of explosives in a prompt-gammas neutron activation analysis (PGNAA) system. Monte Carlo simulations (MCNP-4C) were used for analyzing the system. It was found that the system's performance is enhanced by the use of four detectors: three of the are located on the same side as the neutron source and the fourth on the opposite side. Signature-based radiation-scanning, with nine signatures for each detector, is also discussed. PMID- 29128853 TI - Use of Monte Carlo simulation and considerations for PK-PD targets to support antibacterial dose selection. AB - Monte Carlo simulation is used to generate data for pharmacokinetic pharmacodynamic (PK-PD) target attainment analyses to assess antibacterial dosing regimens in early and late stage drug development. Careful consideration of the quality of data for pharmacokinetics, non-clinical PK-PD targets for efficacy, the choice of the bacterial reduction endpoint upon which the PK-PD target is based, variability in the PK-PD target, and effect site exposures ensures optimal dose selection. Relationships between drug exposure and efficacy and/or safety endpoints based on clinical data can also be applied to simulated data to support dose selection. These in silico analyses, conducted throughout drug development, provide the greatest opportunity to de-risk the development of antibacterial agents. PMID- 29128854 TI - Pharmacological management of gastroesophageal reflux disease in infants: current opinions. AB - Gastroesophageal reflux disease (GERD) constitutes a troublesome symptom complex resulting from retrograde passage of gastric contents into the esophagus or extra esophageal regions. Premature-born, high-risk infants and those with neuro-aero digestive pathologies are at increased risk. Critical review over the last 3 years was conducted, and current opinions on pharmacological targets include agents aimed at prevention of transient lower esophageal sphincter relaxation, modification of the physico-chemical composition of gastric contents, modification of gut motility, or altering sensory thresholds to ameliorate the troublesome symptoms. As data from well-designed studies is limited in the infant population, information from adult studies has been cited where potential application may be helpful. PMID- 29128855 TI - Selective inhibition of IDO1, D-1-methyl-tryptophan (D-1MT), effectively increased EpCAM/CD3-bispecific BiTE antibody MT110 efficacy against IDO1hibreast cancer via enhancing immune cells activity. AB - MuS110 and MT110 are BiTE antibodies bispecific for CD3 and EpCAM, which is the most frequently and highly expressed tumor-associated antigen on breast cancer. And pronounced expression of IDO1 has also been reported in breast cancer. Our study aimed to investigate whether IDO1 inhibitor D-1MT combing with MuS110/MT110 had synergistic antitumor effects on IDO expressing EpCAM-positive breast cancer cells in vitro and in vivo. Data suggested that the expression of IDO1 on Epcam positive breast cancer 4T1 and MCF-7 decreased MuS110/MT110 antitumor efficacy by the suppression of T cells activation in vitro. Combining D-1MT with MT110 in IDO+MCF-7 cells, or with MuS110 in IDO+4T1 cells, significantly improved the antitumor efficacy of BiTE antibodies via increasing T cell cytotoxicity and contributing to cytokines releasing. In vivo assay, combination of D-1MT with MT110 in NOD/SCID mice bearing IDOhi MCF-7 xenografts or MuS110 in immune competent BALB/c mice bearing IDOhi 4T1 xenografts suggested the similar synergistic effect. Together, IDO inhibition could reverse the suppression of T cells due to IDO expressing on breast cancer, and improve the antitumor efficacy of EpCAM/CD3-bispecific BiTE antibody. PMID- 29128856 TI - Activation of Nrf2 pathway and inhibition of NLRP3 inflammasome activation contribute to the protective effect of chlorogenic acid on acute liver injury. AB - Chlorogenic acid (CGA), a kind of polyphenol found in coffee, fruits and vegetables, has potent anti-oxidant and anti-inflammatory properties. Our previous studies showed CGA could efficiently alleviate liver fibrosis in rats. However, whether CGA regulates nuclear factor erythroid-2-related factor 2 (Nrf2) anti-oxidant pathway and NLRP3 inflammasome activation and protects against carbon tetrachloride (CCl4)-induced acute liver injury are unknown. We found that CGA could increase Nrf2 activation and expression of Nrf2-related anti-oxidant genes, including HO-1, NQO1 and GCLC. Pretreatment with CGA could reduce CCl4 induced elevation of serum transaminases and alleviate liver pathological abnormalities. CGA also reversed CCl4-induced increase in MDA level and decrease in the levels of GSH, SOD and CAT in liver tissues. Meanwhile, CGA inhibited NLRP3 inflammasome activation, as indicated by the reduced protein expression of NLRP3, Pro-Caspase-1, Caspase-1, Pro-IL-1beta and IL-1beta. Moreover, CGA reduced serum levels and liver mRNA expression of TNF-alpha, IL-6 and IL-1beta. These results demonstrate that CGA protects against CCl4-induced acute liver injury probably through enhancing Nrf2-mediated anti-oxidant pathway and inhibiting NLRP3 inflammasome activation. PMID- 29128857 TI - Emotionally laden impulsivity interacts with affect in predicting addictive use of online sexual activity in men. AB - The interest in studying addictive use of online sexual activities (OSA) has grown sharply over the last decade. Despite the burgeoning number of studies conceptualizing the excessive use of OSA as an addictive disorder, few have tested its relations to impulsivity, which is known to constitute a hallmark of addictive behaviors. To address this missing gap in the literature, we tested the relationships between addictive OSA use, impulsivity traits, and affect among a convenience sample of men (N=182; age, M=29.17, SD = 9.34), building upon a theoretically driven model that distinguishes the various facets of impulsivity. Results showed that negative urgency (an impulsivity trait reflecting the tendency to act rashly in negative emotional states) and negative affect interact in predicting addictive OSA use. These results highlight the pivotal role played by negative urgency and negative affect in addictive OSA use, supporting the relevance of psychological interventions that focus on improving emotional regulation (e.g., to reduce negative affect and learn healthier coping strategies) to mitigate excessive use of OSA. PMID- 29128859 TI - [Vigilance for veterinary medicinal products: Reports of adverse reactions in the year 2016]. AB - INTRODUCTION: A total of 253 reports of adverse reactions to veterinary medicinal products were received during the year 2016 representing a decrease of 13% compared to the previous year (292 reports). The majority of the reports described reactions affecting companion animals (178 dogs and 32 cats) as well as cattle (17 reports) and horses (10 reports). Most of the reactions reported were linked to the use of antiparasitics (145 reports), hormone products (26 reports) and antiinfectives (10 reports). 32 reports were generated from consultations with Tox Info Suisse in Zurich and involved mainly the excessive intake of flavoured tablets and, in some cases, the use of reconverted products (applied to another species than that authorized). Five signals were identified from the reports, which resulted in revisions of the product information in the sections addressing contraindications or adverse reactions. PMID- 29128858 TI - Relation between lifespan polytrauma typologies and post-trauma mental health. AB - BACKGROUND: Most individuals experience more than one trauma. Hence, it is important to consider the count and types of traumas (polytraumatization) in relation to post-trauma mental health. METHOD: The current study examined the relation of polytraumatization patterns to PTSD clusters (intrusions, avoidance, negative alterations in cognitions and mood [NACM], and alterations in arousal and reactivity [AAR]), depression, and impulsivity facets (lack of perseverance, lack of premeditation, negative urgency, sensation seeking) using a web-based sample of 346 participants. Age, gender, race, and ethnicity were covariates. RESULTS: Results of latent class analyses indicated a three-class solution: Low Experience, Moderate Experience - Predominent Threat/Indirect PTEs (Moderate Experience), and High Experience - Predominant Interpersonal PTEs (High/Interpersonal). Multinomial logistic regression results indicated that ethnicity and gender were significant covariates in predicting Low versus High/Interpersonal Class, and Moderate Experience versus High/Interpersonal Class membership, respectively. The High/Interpersonal Class had higher scores on most PTSD clusters, depression, and the impulsivity facets of lack of perseverance and negative urgency compared to the other classes. The Low and Moderate Experience Classes differed on PTSD's avoidance and AAR clusters (lower in the former). CONCLUSIONS: Individuals exposed to multiple PTE types, particularly interpersonal traumas, may be at risk for more severe post-trauma symptoms. PMID- 29128860 TI - Evaluation of different dose rate combinations of ketamine, romifidine and azaperone for castration of 3-4 and 5-6 weeks old piglets. AB - INTRODUCTION: In this study dose rate combinations of ketamine, azaperone and romifidine were tested in 3-4 (G3-4) and 5-6 weeks (G5-6) old piglets according to a dose rate decision tree (DRT) to provide calm anaesthesia induction, reaction-free anaesthesia for castration and smooth recovery within 2 hours. When a combination failed to meet those criteria in 2 piglets, the next dosage of the DRT was tested. In G3-4 four combinations were tested in 14 piglets with dose rates of 10-20 mg/kg ketamine, 3 mg/kg azaperone and 0.15-0.20 mg/kg romifidine IM. Induction was smooth in all piglets, but depth of anaesthesia or recovery (11 and 6 piglets) were insufficient. In G5-6 five combinations were tested in 37 piglets with dose rates of 10-20 mg/kg ketamine, 3-4 mg/kg azaperone and 0.15 0.20 mg/kg romifidine IM. Induction was smooth in all piglets but 2. Depth of anaesthesia or recovery (17 and 7 piglets, respectively) were insufficient. In the present study with 3-4 and 5-6 weeks old piglets, acceptable quality of anaesthesia could not be achieved despite using high drug dose rates. PMID- 29128861 TI - Atrial cardiomyopathy in an adult Labrador retriever dog. AB - INTRODUCTION: A 7-year-old castrated male Labrador retriever was examined for a 10-day history of weakness and syncope. Physical examination revealed bradycardia and a grade III/VI left apical systolic heart murmur. Electrocardiography demonstrated bradycardia, absence of P waves and an atrio-ventricular nodal escape rhythm. Echocardiography revealed marked biatrial enlargement. Thoracic radiographs showed no evidence of pulmonary edema. Routine plasma biochemistry and electrolytes, basal serum cortisol, total thyroxin concentration, and complete blood count were within normal limits. Serum cardiac troponin I concentration was moderately increased. Serological examinations for antibodies against vector-borne diseases were negative. A pacemaker was implanted one month after the initial presentation due to worsening of the dog's clinical condition despite medical treatment. The dog remained asymptomatic for 18 months but was then re-presented with a gastric dilatation volvulus and subsequently euthanized. Necropsy and histology of the heart yielded a diagnosis of atrial cardiomyopathy. PMID- 29128862 TI - [Simple repair of Monteggia fractures in the cat]. AB - INTRODUCTION: Monteggia fractures are rare traumatic injuries in cats and dogs. Ulna repair is mostly achieved by plates. Stable radial head fixation however is challenging. Temporary position screws have to be removed due to rotation forces in the elbow joint causing screw loosening. We present a novel and simple method using a sling technique, which holds the radial head in its physiological position and allows normal elbow movement. PMID- 29128864 TI - Association of alpha2-HS Glycoprotein with Neurogenic Heterotopic Ossification in Patients with Spinal Cord Injury. AB - BACKGROUND The aim of this study was to explore the relationship between the alpha2-HS glycoprotein concentrations in serum and the occurrence of neurogenic heterotopic ossification (NHO) in patients with spinal cord injury (SCI). MATERIAL AND METHODS During the period between January 2011 and January 2012, 75 patients (67 male) with paraplegia caused by spinal cord injury were enrolled. The patients were divided into 2 groups in accordance with the occurrence of heterotopic ossification based on the results high-frequency ultrasound on the bilateral hip joint. The levels of alpha2-HS glycoprotein, C-reactive protein (CRP), D-dimer, and bone morphogenetic protein (BMP) were detected by ELISA. RESULTS We found a significant decrease of alpha2-HS glycoprotein in SCI patients with NHO compared to SCI patients without NHO. In contrast, a significant elevation of serum calcium, D-dimer, BMP, and CRP was observed in SCI patients with NHO. The degree of maturity of NHO did not influence the level of alpha2-HS glycoprotein. Multivariate liner regression analysis showed that the level of serum alpha2-HS glycoprotein was correlated with CRP and spasticity. CONCLUSIONS The decreased level of alpha2-HS glycoprotein may be related to the formation of neurogenic heterotopic ossification in patients with spinal cord injury. Our results suggest that alpha2-HS glycoprotein might be a risk factor for NHO in patients with SCI. PMID- 29128863 TI - Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress Induced (Takotsubo) Cardiomyopathy. AB - BACKGROUND: Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined. METHODS: In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31P-spectroscopy. RESULTS: Participants were predominantly middle-age (64+/-11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24+/-1.3 versus 31+/-1.3 mL/kg/min, P<0.001; increased VE/Vco2 slope, 31+/-1 versus 26+/-1, P=0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, -16+/-1.0 versus -23+/-1.5%, P<0.001; global longitudinal strain, -17+/-1 versus -20+/-1%, P=0.006), increased native T1 mapping values (1264+/-10 versus 1184+/-10 ms, P<0.001), and impaired cardiac energetic status (phosphocreatine/gamma-adenosine triphosphate ratio, 1.3+/-0.1 versus 1.9+/-0.1, P<0.001). CONCLUSIONS: In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02989454. PMID- 29128865 TI - Promoter Methylation of RASSF1A indicates Prognosis for Patients with Stage II and III Colorectal Cancer Treated with Oxaliplatin-Based Chemotherapy. AB - BACKGROUND The purpose of this study was to investigate the prognostic significance of methylation of RAS association domain family protein 1 (RASSF1A) in the promoter region for patients with stage II and III colorectal cancer (CRC) receiving oxaliplatin-based chemotherapy. MATERIAL AND METHODS There were 108 eligible CRC patients and 78 healthy controls included in this study. Methylation specific polymerase chain reaction (MSP) was applied to detect the methylation status of RASSF1A in patients before and after chemotherapy. The effects of RASSF1A methylation on chemotherapy-sensitivity and prognosis for patients were also evaluated in the present study. RESULTS The frequency of RASSF1A methylation was higher in CRC patients than in the healthy controls (48.44% versus 5.13%, p<0.001). After two cycles of chemotherapy, methylation ratio was significantly decreased (21.30%, p<0.001). Promoter methylation of RASSF1A was significantly correlated with tumor stage and pathological differentiation (p=0.008 and p=0.007, respectively). Patients without methylation had a favorable objective response (OR), compared with those with methylation (53.33% versus 25%, p=0.014). Methylation status of RASSF1A could influence progression-free survival and overall survival (log rank test, p<0.05). Cox regression analysis indicated that RASSF1A methylation (HR=2.471, 95% CI=1.125-5.428, p=0.024) and OR (HR=2.678, 95% CI=1.085-6.610, p 0.033) were independently correlated with prognosis for patients treated with oxaliplatin-based chemotherapy. CONCLUSIONS Promoter methylation of RASSF1A can influence sensitivity to oxaliplatin-based chemotherapy, which can be used to predict outcomes for patients with stage II and III CRC. In addition, the aberrant methylation may be a promising target for improving chemotherapy efficacy. PMID- 29128867 TI - The Role of Lipoprotein(a) in Calcific Aortic Valve Disease: Insights From a Large-Cohort Genetic Study. PMID- 29128866 TI - Association of of Atrial Fibrillation Clinical Phenotypes With Treatment Patterns and Outcomes: A Multicenter Registry Study. AB - Importance: Atrial fibrillation (AF) is usually classified on the basis of the disease subtype. However, this characterization does not capture the full heterogeneity of AF, and a data-driven cluster analysis reveals different possible classifications of patients. Objective: To characterize patients with AF based on a cluster analysis and to evaluate the association between these phenotypes, treatment, and clinical outcomes. Design, Setting, and Participants: This cluster analysis used data from an observational cohort that included 9749 patients with AF who had been admitted to 174 US sites participating in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Data analysis was completed from January 2017 to October 2017. Exposure: Patients with diagnosed AF who were included in the registry. Main Outcomes and Measures: Composite of major adverse cardiovascular or neurological events and major bleeding, as defined by the International Society of Thrombosis and Hemostasis criteria. Results: Of 9749 total patients, 4150 (42.6%) were female; 8719 (89.4%) were white and 477 (4.9%) were African American. A cluster analysis was performed using 60 baseline clinical characteristics, and it classified patients with AF into 4 statistically driven clusters: (1) those with considerably lower rates of risk factors and comorbidities than all other clusters (n = 4673); (2) those with AF at younger ages and/or with comorbid behavioral disorders (n = 963); (3) those with AF who had similarities to patients with tachycardia-brachycardia and had device implantation owing to sinus node dysfunction (n = 1651); and (4) those with AF and prior coronary artery disease, myocardial infarction, and/or atherosclerotic comorbidities (n = 2462). Conventional classifications, such as AF subtype and left atrial size, did not drive cluster formation. Compared with the low comorbidity AF cluster, adjusted risks of major adverse cardiovascular or neurological events were significantly higher in the other 3 clusters (behavioral comorbidity cluster: hazard ratio [HR], 1.49; 95% CI, 1.10-2.00; device implantation cluster: HR, 1.39; 95% CI, 1.15-1.68; and atherosclerotic comorbidity cluster: HR, 1.59; 95% CI, 1.31-1.92). For major bleeding, adjusted risks were higher in the behavioral disorder comorbidity cluster (HR, 1.35; 95% CI, 1.05-1.73), those with device implantation (HR, 1.24; 95% CI, 1.05-1.47), and those with atherosclerotic comorbidities (HR, 1.13; 95% CI, 0.96-1.33) compared with the low comorbidity cluster. The same clusters were identified in an external validation in the ORBIT AF II registry. Conclusions and Relevance: Cluster analysis identified 4 clinically relevant phenotypes of AF that each have distinct associations with clinical outcomes, underscoring the heterogeneity of AF and importance of comorbidities and substrates. PMID- 29128868 TI - Association of LPA Variants With Aortic Stenosis: A Large-Scale Study Using Diagnostic and Procedural Codes From Electronic Health Records. AB - Importance: Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between LPA variants and AS, their interactions with risk factors, and the effect of multiple risk alleles is not well established. Objective: To replicate the association between LPA variants with AS and identify subgroups who are at higher risk of developing AS. Design, Setting, and Participants: This case-control study of AS included 44 703 individuals (3469 cases) 55 years or older who were enrolled in the Genetic Epidemiology Research on Aging cohort and who were members of the Kaiser Permanente Northern California health care delivery system. The study leveraged the linkage of administrative health data, electronic medical records, genotypes, and self-reported questionnaire data. The 3469 AS cases were diagnosed between January 1996 and December 2015. Individuals with valvular congenital heart disease were excluded. Exposures: Two single-nucleotide polymorphisms in the LPA locus, rs10455872 and rs3798220, that are known to associate with circulating plasma lipoprotein(a) levels and an LPA risk score. Main Outcomes and Measures: Aortic stenosis or aortic valve replacement. Results: The 44 703 participants were of European ancestry,of whom 22 019 (49.3%) were men. The mean (SD) age for the control group was 69.3 (8.3) years and the mean (SD) age for AS cases was 74.6 (8.5) years. Both LPA variants were associated with AS, with a per risk allele odds ratio of 1.34 (95% CI, 1.23-1.47; P = 1.7 * 10-10) for rs10455872 and 1.31 (95% CI, 1.09-1.58; P = 3.6 * 10-3) for rs3798220 after adjusting for age, age2, and sex. The results remained significant after adjusting for risk factors. The estimates were similar for an LPA risk score. Individuals with 2 risk alleles had a 2-fold or greater odds of AS compared with individuals with no risk alleles (for rs10455872, homozygous odds ratio, 2.05; 95% CI, 1.37-3.07; P = 5.3 * 10-4; for rs3798220, homozygous odds ratio, 3.74; 95% CI, 1.03-13.6; P = .05; and for compound heterygotes, odds ratio, 2.00; 95% CI, 1.17-3.44; P = .01). For rs10455872, the odds ratio for AS was greatest in individuals aged 55 to 64 years and declined with age (interaction P = .03). Each rs10455872 risk allele was also associated with AS that was diagnosed 0.71 years earlier (95% CI, -1.42 to 0; P = .05). Conclusions and Relevance: We provide a large-scale confirmation of the association between 2 LPA variants and AS, reaching genome-wide significance. In addition, individuals with 2 risk alleles have 2-fold or greater odds of developing AS. Age may modify these associations and identify subgroups who are at greater risk of developing AS. PMID- 29128869 TI - Association of the Hospital Readmissions Reduction Program Implementation With Readmission and Mortality Outcomes in Heart Failure. AB - Importance: Public reporting of hospitals' 30-day risk-standardized readmission rates following heart failure hospitalization and the financial penalization of hospitals with higher rates have been associated with a reduction in 30-day readmissions but have raised concerns regarding the potential for unintended consequences. Objective: To examine the association of the Hospital Readmissions Reduction Program (HRRP) with readmission and mortality outcomes among patients hospitalized with heart failure within a prospective clinical registry that allows for detailed risk adjustment. Design, Setting, and Participants: Interrupted time-series and survival analyses of index heart failure hospitalizations were conducted from January 1, 2006, to December 31, 2014. This study included 115 245 fee-for-service Medicare beneficiaries across 416 US hospital sites participating in the American Heart Association Get With The Guidelines-Heart Failure registry. Data analysis took place from January 1, 2017, to June 8, 2017. Exposures: Time intervals related to the HRRP were before the HRRP implementation (January 1, 2006, to March 31, 2010), during the HRRP implementation (April 1, 2010, to September 30, 2012), and after the HRRP penalties went into effect (October 1, 2012, to December 31, 2014). Main Outcomes and Measures: Risk-adjusted 30-day and 1-year all-cause readmission and mortality rates. Results: The mean (SD) age of the study population (n = 115 245) was 80.5 (8.4) years, 62 927 (54.6%) were women, and 91 996 (81.3%) were white and 11 037 (9.7%) were black. The 30-day risk-adjusted readmission rate declined from 20.0% before the HRRP implementation to 18.4% in the HRRP penalties phase (hazard ratio (HR) after vs before the HRRP implementation, 0.91; 95% CI, 0.87-0.95; P < .001). In contrast, the 30-day risk-adjusted mortality rate increased from 7.2% before the HRRP implementation to 8.6% in the HRRP penalties phase (HR after vs before the HRRP implementation, 1.18; 95% CI, 1.10-1.27; P < .001). The 1-year risk adjusted readmission and mortality rates followed a similar pattern as the 30-day outcomes. The 1-year risk-adjusted readmission rate declined from 57.2% to 56.3% (HR, 0.92; 95% CI, 0.89-0.96; P < .001), and the 1-year risk-adjusted mortality rate increased from 31.3% to 36.3% (HR, 1.10; 95% CI, 1.06-1.14; P < .001) after vs before the HRRP implementation. Conclusions and Relevance: Among fee-for service Medicare beneficiaries discharged after heart failure hospitalizations, implementation of the HRRP was temporally associated with a reduction in 30-day and 1-year readmissions but an increase in 30-day and 1-year mortality. If confirmed, this finding may require reconsideration of the HRRP in heart failure. PMID- 29128870 TI - Microbiological and chemical profiles of elephant grass inoculated with and without Lactobacillus plantarum and Pediococcus acidilactici. AB - The study was conducted to evaluate the microbiological and chemical profiles of elephant grass inoculated with and without different wild strains of lactic acid bacteria. Silage was prepared of four treatments and one control with three replicates as control (EKC, adding 2 ml/kg sterilizing water), Lactobacillus plantarum (USA commercial bacteria) (EKP), Lactobacillus plantarum (EKA), Pediococcus acidilactici (EKB), and Pediococcus acidilactici (SKD) isolated from King grass. Silage were prepared using polyethylene terephthalate bottles, and incubated at room temperature for different ensiling days. The pH and acetic acid (AA) were significantly (P < 0.05) reduced and lactic acid (LA), butyric acid (BA), and ethanol were significantly increased (P < 0.05) at 3, 5, 7, and 14 days in treatment groups as compared to control. Water-soluble carbohydrate (WSC) and NH3-N concentration was not affected at days 3, 5, and 7, but significantly (P < 0.05) reduced at 14 days in treatment groups as compared to control. The LA, BA, and ethanol were significantly (P < 0.05) increased and AA, WSC NH3-N, and yeast were significantly (P < 0.05) decreased at 30 days of ensiling in treatment groups as compared to control. It is recommended that the inoculation of LAB could improve the fermentation quality of elephant grass silage and further effort is needed to evaluate these effects on silage produced on farm scale and on animal production performance. PMID- 29128871 TI - Neural substrate of unrelenting negative symptoms in schizophrenia: a longitudinal resting-state fMRI study. AB - Developing a mechanistic insight into the specific brain processes that underpin improvement in negative symptoms can help us design novel chemical and physical treatments against these unrelenting symptoms. The aim of the present study is to explore the longitudinal changes in the brain's regional functional efficiency that accompany improvement in negative symptoms seen in first-episode patients with schizophrenia when treated with antipsychotic for 1 year. Forty-seven first episode patients with schizophrenia were scanned at a drug-naive baseline state and followed up for 1 year to identify negative symptom responders (Rn) and non responders (NRn). Fractional amplitude of low-frequency fluctuations (fALFF) and Granger analysis of effective connectivity (EC) were used to examine the different patterns of regional function and connectivity between Rn and NRn during the 1 year follow-up. Increase of fALFF in the left superior temporal gyrus (STG) and increase of EC from the left STG to the dorsolateral prefrontal cortex (DLPFC) was found in Rn compared to NRn. We further validated that the identified changes in fALFF/EC of STG occur specifically in relation to negative symptoms only (i.e., not pseudo-specific in relation to positive, extrapyramidal or depressive symptoms), and occur irrespective of arbitrary clinical categorization of treatment response. An increase in fALFF in the precuneus and the inferior parietal lobule, and a decrease in EC from the left STG to the occipital cortex, were also found at the 1 year follow-up irrespective of improvement in negative symptoms. Interventions that improve the functional efficiency of left STG and its prefrontal connectivity may show efficacy in alleviating negative symptoms in first-episode schizophrenia. PMID- 29128872 TI - Prenatal kynurenine treatment in rats causes schizophrenia-like broad monitoring deficits in adulthood. AB - RATIONALE: Elevated brain kynurenic acid (KYNA) levels are implicated in the pathology and neurodevelopmental pathogenesis of schizophrenia. In rats, embryonic treatment with kynurenine (EKyn) causes elevated brain KYNA levels in adulthood and cognitive deficits reminiscent of schizophrenia. OBJECTIVES: Growing evidence suggests that people with schizophrenia have a narrowed attentional focus, and we aimed at establishing whether these abnormalities may be related to KYNA dysregulation. METHODS: To test whether EKyn rats display broad monitoring deficits, kynurenine was added to the chow of pregnant Wistar dams on embryonic days 15-22. As adults, 20 EKyn and 20 control rats were trained to stable performance on the five-choice serial reaction time task, requiring the localization of 1-s light stimuli presented randomly across five apertures horizontally arranged along a curved wall, equating the locomotor demands of reaching each hole. RESULTS: EKyn rats displayed elevated omission errors and reduced anticipatory responses relative to control rats, indicative of a lower response rate, and showed reduced locomotor activity. The ability to spread attention broadly was measured by parsing performance by stimulus location. Both groups displayed poorer stimulus detection with greater target location eccentricity, but this effect was significantly more pronounced in the EKyn group. Specifically, the groups differed in the spatial distribution of correct but not incorrect responses. This pattern cannot be explained by differences in response rate and is indicative of a narrowed attentional focus. CONCLUSIONS: The findings suggest a potential etiology of broad monitoring deficits in schizophrenia, which may constitute a core cognitive deficit. PMID- 29128873 TI - Reinforcement enhancement by nicotine in adult rats: behavioral selectivity and relation to mode of delivery and blood nicotine levels. AB - RATIONALE: Reinforcement-enhancing effects of nicotine occur in human subjects and laboratory rats. However, the doses used in animal studies typically exceed smoking-associated levels of exposure, and generalized behavioral activation by nicotine can potentially confound data interpretation. METHODS: During daily 60 min sessions, male adult rats pressed an "active" lever to illuminate a brief cue light. Pressing on either the active or inactive lever retracted both levers for 60 s. Nicotine (0.025-0.2 mg/kg) was given either by continuous intravenous (IV) infusion, or spaced IV pulses (3-s or 30-s/pulse), or pre-session subcutaneous (SC) injection. RESULTS: Almost all rats responded preferentially for the cue light for several weeks. After several home-cage nicotine injections, reinforcement enhancement occurred even within the first nicotine test session. Nicotine increased active lever responding without altering inactive lever responding, with effects reliably observed at doses as low as 0.1 mg/kg SC or 0.1 mg/kg/session IV. Within the session, the 0.1 mg/kg dose maximally increased active lever responding by 2-3-fold, coinciding with serum levels of 25 ng/ml. Intravenous nicotine (tested at 0.1 mg/kg/60-min session) was equally effective whether delivered by continuous infusion or in a series of equally spaced 0.003 mg/kg pulses each of 3-s or 30-s duration. CONCLUSIONS: Low doses of nicotine can potentiate responding for a primary sensory reinforcer without producing a generalized increase in lever pressing. Reinforcer enhancement by nicotine generalized to several modes of drug delivery, appeared to track circulating levels of drug, and occurred even at serum levels within the daytime range of moderate cigarette smokers. PMID- 29128874 TI - The initial prophylactic antibiotic usage and subsequent necrotizing enterocolitis in high-risk premature infants: a systematic review and meta analysis. AB - OBJECTIVE: To investigate the correlation between the initial prophylactic antibiotic use and the subsequent NEC in high-risk premature infants. METHODS: We performed a literature search of PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Web of Science, and nine studies with a total of 5207 infants were selected for inclusion in this study. RESULTS: The pooled estimate for the seven studies combined indicating that prophylactic antibiotic usage was associated with a non-significant trend toward increased incidence of NEC [odds ratio (OR) 0.75; 95% confidence interval (CI) 0.26-2.17], and prolonged exposure to prophylactic antibiotics, compared with limited prophylactic antibiotic use, was associated with a significant trend toward the risk of increasing incidence of NEC (OR 1.31; 95% CI 1.08-1.59). CONCLUSION: Current evidence does not support the use of prophylactic antibiotics to reduce the incidence of NEC for high-risk premature infants. PMID- 29128875 TI - Allowing one quadrant of patellar lateral translation during medial patellofemoral ligament reconstruction successfully limits maltracking without overconstraining the patella. AB - PURPOSE: Graft tensioning during medial patellofemoral ligament (MPFL) reconstruction typically allows for lateral patellar translation within the trochlear groove. Computational simulation was performed to relate the allowed patellar translation to patellofemoral kinematics and contact pressures. METHODS: Multibody dynamic simulation models were developed to represent nine knees with patellar instability. Dual limb squatting was simulated representing the pre operative condition and simulated MPFL reconstruction. The graft was tensioned to allow 10, 5, and 0 mm of patellar lateral translation at 30 degrees of knee flexion. The patellofemoral contact pressure distribution was quantified using discrete element analysis. RESULTS: For the 5 and 10 mm conditions, patellar lateral shift decreased significantly at 0 degrees and 20 degrees . The 0 mm condition significantly decreased lateral shift for nearly all flexion angles. All graft conditions significantly decreased lateral tilt at 0 degrees , with additional significant decreases for the 5 and 0 mm conditions. The 0 mm condition significantly increased the maximum medial pressure at multiple flexion angles, increasing by 57% at 30 degrees , but did not alter the maximum lateral pressure. CONCLUSIONS: Allowing 5 to 10 mm of patellar lateral translation limits lateral maltracking, thereby decreasing the risk of post-operative recurrent instability. Allowing no patellar translation during graft tensioning reduces maltracking further, but can overconstrain the patella, increasing the pressure applied to medial patellar cartilage already fibrillated or eroded from an instability episode. PMID- 29128876 TI - Internal femoral component malrotation in TKA significantly alters tibiofemoral kinematics. AB - PURPOSE: Femoral component malrotation in total knee arthroplasty (TKA) is clinically proven to cause dissatisfaction and impaired function. This study is an attempt to characterize the tibiofemoral kinematics following femoral malrotation in posterior stabilized (PS) TKA. It was hypothesized that internal malrotation would introduce the most pronounced changes. METHODS: Six fresh frozen cadaver specimens were mounted in a kinematic rig. Three motion patterns were applied with the native knee and following PS TKA (passive motion, open chain extension, and squatting) while infrared cameras recorded the trajectories of markers attached to femur and tibia. Three different femoral implants were tested: a conventional posterior stabilized component, and adapted components of the same implant with 5 degrees of intrinsic external and internal rotation, respectively. RESULTS: The implantation of the PS TKA resulted in less tibial internal rotation (squat 33-70 degrees , p < 0.05) and the medial femoral condyle shifted posteriorly especially in deep flexion (squat 84-111 degrees , p < 0.05). Internal component malrotation caused internal rotation and abduction of the tibia in flexion (squat 33-111 degrees , p < 0.05), an elevated (squat 43-111 degrees , p < 0.05) and more anterior (passive 61-126 degrees , p < 0.05) located medial femoral condyle and a lateral femoral condyle located more posterior and inferior (squat 73-111 degrees , p < 0.05) than in the neutrally aligned TKA. External component malrotation caused only little changes under passive motion. Under a squat there was less internal rotation and more adduction to the tibia (33-111 degrees , p < 0.05). The medial femoral condyle was moved more posterior (squat 59-97 degrees , p < 0.05), the lateral femoral condyle more superior (squat 54-105 degrees , p < 0.05) than in the neutrally aligned TKA. CONCLUSION: The greatest differences to the native tibiofemoral kinematics were introduced by internal rotation of the femoral component. Also neutrally and externally rotated femoral components introduce kinematic changes, but to a lesser extent. With respect to the alterations introduced to kinematics internal malrotation should be avoided when performing PS TKA. PMID- 29128877 TI - The location of the medial parapatellar arthrotomy influences intraoperative patella tracking. AB - PURPOSE: The medial parapatellar arthrotomy (MPPA) is a commonly utilized surgical approach; however, the placement of the arthrotomy and its influence on intraoperative patellar tracking has not been evaluated. METHODS: Six knees from three fresh frozen cadavers with transthoracic amputations were operated on. All underwent standard posterior stabilized total knee arthroplasty using a medial parapatellar approach placed at the border of the vastus medialis oblique (VMO) quadriceps junction. Patellae were resurfaced in the standard fashion. All patellae tracked normally with the first arthrotomy placed at the junction of the VMO-quadriceps tendon using the "no touch" technique. Measurement of patellar lift-off from the implant surface of the medial aspect of the trochlea on the femoral component was made at 50 degrees , 75 degrees , and 90 degrees of flexion and a merchant view radiograph taken to evaluate radiographic patellar tilt. To simulate a more lateral placement of the MPPA, a 5-6 mm slice of quadriceps tendon was then removed from the lateral aspect of the tendon from the patellar insertion to the most proximal portion of the arthrotomy. This simulated a 5-6 mm more lateral placement of the parapatellar arthrotomy. The same measurements and radiographs were taken as described previously. Two more times the same size slices was removed from the quadriceps tendon with subsequent measurements and radiographs obtained. RESULTS: The mean patellar lift-off with the first arthrotomy was 0 +/- 0 mm for 50 degrees , 75 degrees , and 90 degrees of flexion. The mean lift with the second arthrotomy was 2 +/- 2, 3 +/- 3, and 4 +/- 3 mm respectively. The third arthrotomy had a mean patellar lift-off of 3 +/- 2, 4 +/- 3, and 8 +/- 2 mm respectively, while the fourth arthrotomy had a mean lift-off of 6 +/- 2, 8 +/- 2, and 9 +/- 4 mm. There was a significant correlation between percentage of quadriceps cut at 1 cm above the superior pole of the patella and patellar lift-off at 50 degrees (R 2 = 0.70; p < 0.0001), 75 degrees (R 2 = 0.68; p < 0.0001), and 90 degrees (R 2 = 0.68; p < 0.0001) of flexion. CONCLUSION: The location of the MPPA has a significant influence on intraoperative assessment of patellar tracking. An MPPA more lateral in the quadriceps tendon may independently influence the patellar tilt observed intraoperatively and should be taken into consideration when evaluating intraoperative patella tracking. An understanding of the independent influence the MPPA has on patellar tracking may decrease the need for lateral release if the surgeon notes the MPPA was made more than 5-10 mm from the junction of the VMO-quadriceps tendon junction. PMID- 29128879 TI - The OARSI core set of performance-based measures for knee osteoarthritis is reliable but not valid and responsive. AB - PURPOSE: The Osteoarthritis Research Society International has identified a core set of performance-based tests of physical function for use in people with knee osteoarthritis (OA). The core set consists of the 30-second chair stand test (30 s CST), 4 * 10 m fast-paced walk test (40 m FPWT) and a stair climb test. The aim of this study was to evaluate the reliability, validity and responsiveness of these performance-based measures to assess the ability to measure physical function in knee OA patients. METHODS: A prospective cohort study of 85 knee OA patients indicated for total knee arthroplasty (TKA) was performed. Construct validity and responsiveness were assessed by testing of predefined hypotheses. A subgroup (n = 30) underwent test-retest measurements for reliability analysis. The Oxford Knee Score, Knee injury and Osteoarthritis Outcome Score-Physical Function Short Form, pain during activity score and knee extensor strength were used as comparator instruments. Measurements were obtained at baseline and 12 months after TKA. RESULTS: Appropriate test-retest reliability was found for all three tests. Intraclass correlation coefficient (ICC) for the 30-s CST was 0.90 (95% CI 0.68; 0.96), 40 m FPWT 0.93 (0.85; 0.96) and for the 10-step stair climb test (10-step SCT) 0.94 (0.89; 0.97). Adequate construct validity could not be confirmed for the three tests. For the 30-s CST, 42% of the predefined hypotheses were confirmed; for the 40 m FPWT, 27% and for the 10-step SCT 36% were confirmed. The 40 m FPWT was found to be responsive with 75% of predefined hypothesis confirmed, whereas the responsiveness for the other tests could not be confirmed. For the 30 s CST and 10-step SCT, only 50% of hypotheses were confirmed. CONCLUSIONS: The three performance-based tests had good reliability, but poor construct validity and responsiveness in the assessment of function for the domains sit-to-stand movement, walking short distances and stair negotiation. The findings of the present study do not justify their use for clinical practice. LEVEL OF EVIDENCE: Level 1. Diagnostic study. PMID- 29128878 TI - Microfracture is more cost-effective than autologous chondrocyte implantation: a review of level 1 and level 2 studies with 5 year follow-up. AB - PURPOSE: Focal cartilage defects in the knee may have devastating effect on the knee joint, where two of the main surgical treatment options are microfracture and autologous chondrocyte implantation. Comparative studies have failed to establish which method yields the best clinical results. A cost-effectiveness analysis of microfracture and autologous chondrocyte implantation would contribute to the clinical decision process. METHODS: A PubMed search identifying level I and level II studies with 5 year follow-up was performed. With the data from these studies, decision trees with associated service provision and costs connected to the two different techniques were designed. In addition to hospital costs, we included costs connected to physiotherapy following surgery. To paint a broader cost picture, we also included indirect costs to the society due to productivity loss caused by work absence. RESULTS: Four high-quality studies, with a follow-up of 5 years, met the inclusion criteria. A total of 319 patients were included, 170 undergoing microfracture and 149 autologous chondrocyte implantation. The re-operation rate was 23 (13.5%) following microfracture, and 18 (12.1%) for autologous chondrocyte implantation. Both groups achieved substantially better clinical scores at 5 years compared to baseline. Microfracture was more cost-effective when comparing all clinical scores. CONCLUSION: Microfracture is associated with both lower costs and lower cost per point increase in patient reported outcome measures. There is a need of well designed, high-quality randomized controlled trials before reliable conclusions regarding cost-effectiveness in the long run is possible. LEVEL OF EVIDENCE: III. PMID- 29128880 TI - The immunophilin repertoire of Plasmodiophora brassicae and functional analysis of PbCYP3 cyclophilin. AB - Plasmodiophora brassicae is a soil-borne pathogen that belongs to Rhizaria, an almost unexplored eukaryotic organism group. This pathogen requires a living host for growth and multiplication, which makes molecular analysis further complicated. To broaden our understanding of a plasmodiophorid such as P. brassicae, we here chose to study immunophilins, a group of proteins known to have various cellular functions, including involvement in plant defense and pathogen virulence. Searches in the P. brassicae genome resulted in 20 putative immunophilins comprising of 11 cyclophilins (CYPs), 7 FK506-binding proteins (FKBPs) and 2 parvulin-like proteins. RNAseq data showed that immunophilins were differentially regulated in enriched life stages such as germinating spores, maturing spores, and plasmodia, and infected Brassica hosts (B. rapa, B. napus and B. oleracea). PbCYP3 was highly induced in all studied life stages and during infection of all three Brassica hosts, and hence was selected for further analysis. PbCYP3 was heterologously expressed in Magnaporthe oryzae gene inactivated DeltaCyp1 strain. The new strain DeltaCyp1+ overexpressing PbCYP3 showed increased virulence on rice compared to the DeltaCyp1 strain. These results suggest that the predicted immunophilins and particularly PbCYP3 are activated during plant infection. M. oryzae is a well-studied fungal pathogen and could be a valuable tool for future functional studies of P. brassicae genes, particularly elucidating their role during various infection phases. PMID- 29128881 TI - Disparities in Geographic Accessibility of National Cancer Institute Cancer Centers in the United States. AB - The National Cancer Institute (NCI) Cancer Centers form the backbone of the cancer care system in the United States since their inception in the early 1970s. Most studies on their geographic accessibility used primitive measures, and did not examine the disparities across urbanicity or demographic groups. This research uses an advanced accessibility method, termed "2-step floating catchment area (2SFCA)" and implemented in Geographic Information Systems (GIS), to capture the degree of geographic access to NCI Cancer Centers by accounting for competition intensity for the services and travel time between residents and the facilities. The results indicate that urban advantage is pronounced as the average accessibility is highest in large central metro areas, declines to large fringe metro, medium metro, small metro, micropolitan and noncore rural areas. Population under the poverty line are disproportionally concentrated in lower accessibility areas. However, on average Non-Hispanic White have the lowest geographic accessibility, followed by Hispanic, Non-Hispanic Black and Asian, and the differences are statistically significant. The "reversed racial disadvantage" in NCI Cancer Center accessibility seems counterintuitive but is consistent with an influential prior study; and it is in contrast to the common observation of co location of concentration of minority groups and people under the poverty line. PMID- 29128882 TI - Early recurrence in patients undergoing curative resection of colorectal liver oligometastases: identification of its clinical characteristics, risk factors, and prognosis. AB - PURPOSE: Oligometastatic disease can potentially be cured when an optimal approach is performed. Early recurrence after liver resection is an intractable problem, and the clinical implications remain unknown in colorectal liver oligometastases (CLOM) patients. This study aimed to investigate the clinical characteristics, risk factors, and prognosis related to early recurrence in these patients. METHODS: A total of 307 consecutive patients with CLOM undergoing curative liver resection were retrospectively reviewed between September 1999 and June 2016. Early recurrence was defined as any recurrence or death from CLOM that occurred within 6 months of liver resection. RESULTS: With a median follow-up time of 31.7 months, the 3-year overall survival (OS) and recurrence-free survival rates were 68.7 and 42.5%, respectively. Forty-nine (16.0%) patients developed early recurrence and showed a poorer 3-year OS than those with non early recurrence (22.3 vs. 75.8%, P < 0.001) or later recurrence (22.3 vs. 52.8 vs. 63.2%, P < 0.001). Moreover, early recurrence was identified as an independent predictor of 3-year OS [hazard ratio (HR) 6.282; 95% confidence interval (CI) 3.980-9.915, P < 0.001]. In multivariate analysis, a node-positive primary tumor [odds ratio (OR) 2.316; 95% CI 1.097-4.892, P = 0.028) and metastatic diameter > 3 cm (OR 2.560; 95% CI 1.290-5.078; P = 0.007) were shown to be risk factors for early recurrence. The salvage liver resection rate for patients with early recurrence was significantly lower than that for patients with later recurrence (4.1 vs. 19.7%, P = 0.010). CONCLUSIONS: Early recurrence should be investigated in routine clinical practice, even in patients with CLOM after curative liver resection. Detailed preoperative comprehensive measurements might help stratify high-risk patients, and a non-surgical treatment for early recurrence might represent an effective alternative. PMID- 29128883 TI - A systematic review and meta-analysis of the effect of low-level laser therapy (LLLT) on chemotherapy-induced oral mucositis in pediatric and young patients. AB - : Oral mucositis is one of the most frequent complications after chemotherapy, occurring in approximately 52 to 80% of children receiving treatment for cancer. Recently, it has been suggested that the use of low-energy laser could reduce the grade of oral mucositis and alleviate the symptoms. In 2014, Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology has recommended low-level laser therapy in prevention of mucositis for hematopoietic stem cell transplantation patients because of its beneficial effects in majority of recent studies. However, the recommendation was made for adult patients, not pediatric patients. Data about the effect of low-level laser therapy in pediatric patients is limited. This study aims to synthesize the available clinical evidences on the effects of low-level laser therapy (LLLT) in the prevention and treatment of chemotherapy-induced oral mucositis (OM). A meta analysis was performed using trials identified through the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Web of Science, China Biology Medicine (CBM), Wanfang Database, and China National Knowledge Infrastructure (CNKI). Data on occurrence, duration, and severity of oral mucositis were collected. All randomized controlled studies and clinical controlled studies comparing LLLT to routine qualified prevention or treatment during or after chemotherapy were critically appraised and analyzed. We found 8 qualified clinical trials with a total of 373 pediatric patients; the methodological quality was acceptable. After prophylactic LLLT, the odds ratio for developing OM was significantly lower compared with placebo(OR = 0.50, 95% CI 0.29 to 0.87, P = 0.01), the odds ratio for developing grade III OM or worse was statistically significantly lower compared with placebo (OR = 0.30, 95% CI (0.10, 0.90), P = 0.03), and the OM severity was statistically significantly lower compared with placebo (SMD = - 0.56, 95% CI (- 0.98, - 0.14), P = 0.009). For therapeutic LLLT, the OM severity was significantly reduced compared to routine care (SMD = - 1.18, 95% CI (- 1.52, - 0.84), P < 0.00001). Oral pain was also reduced after LLLT over routine care (MD = - 0.73, 95% CI (- 1.36, - 0.11), P = 0.02). CONCLUSION: Prophylactic LLLT reduces mucositis and severe mucositis and decreases the average severity of oral mucositis in pediatric and young patients with cancer. Therapeutic LLLT also reduces the average severity of oral mucositis and oral pain. Further research should investigate the optimal parameter of LLLT in pediatric and young patients, and studies with higher methodological quality should be performed. What is known: * Low-level laser therapy (LLLT) was recommended by Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology; however, evidences about LLLT on oral mucositis in pediatric and young patients were insufficient and lack supportive synthesized data. * Recently, there have been several new RCTs or CCTs for pediatric patients or young adults. What is new: * Prophylactic LLLT reduces the occurrence of mucositis and severe mucositis and decreases the average severity of oral mucositis in pediatric and young patients. * Therapeutic LLLT reduces the average severity of oral mucositis and oral pain. PMID- 29128884 TI - Effect of Npt2b deletion on intestinal and renal inorganic phosphate (Pi) handling. AB - BACKGROUND: Hyperphosphatemia is common in chronic kidney disease and is associated with morbidity and mortality. The intestinal Na+-dependent phosphate transporter Npt2b is thought to be an important molecular target for the prevention of hyperphosphatemia. The role of Npt2b in the net absorption of inorganic phosphate (Pi), however, is controversial. METHODS: In the present study, we made tamoxifen-inducible Npt2b conditional knockout (CKO) mice to analyze systemic Pi metabolism, including intestinal Pi absorption. RESULTS: Although the Na+-dependent Pi transport in brush-border membrane vesicle uptake levels was significantly decreased in the distal intestine of Npt2b CKO mice compared with control mice, plasma Pi and fecal Pi excretion levels were not significantly different. Data obtained using the intestinal loop technique showed that Pi uptake in Npt2b CKO mice was not affected at a Pi concentration of 4 mM, which is considered the typical luminal Pi concentration after meals in mice. Claudin, which may be involved in paracellular pathways, as well as claudin-2, 12, and 15 protein levels were significantly decreased in the Npt2b CKO mice. Thus, Npt2b deficiency did not affect Pi absorption within the range of Pi concentrations that normally occurs after meals. CONCLUSION: These findings indicate that abnormal Pi metabolism may also be involved in tight junction molecules such as Cldns that are affected by Npt2b deficiency. PMID- 29128885 TI - Evaluation of the genetic variability found in Brazilian commercial vaccines for infectious bronchitis virus. AB - Infectious bronchitis virus (IBV) is currently one of the most important pathogens in the poultry industry. The H120 and Ma5 are the only viral strains approved by the Brazilian government as the constituent of vaccines. Despite the systematic vaccination in Brazil, IBV has not yet been controlled and diseases associated with this virus have been reported in vaccinated chickens. Here, we investigated the genetic variability of H120 and Ma5 strains present in the IBV vaccines from different Brazilian manufacturers. We performed DNA sequencing analyses of the S1 spike glycoprotein gene to investigate its genetic variability and the presence of viral subpopulations among vaccines, between batches, and also in each vaccine after a single passage was performed in chicken embryonated eggs. Our results revealed up to 13 amino acid substitutions among vaccines and some of them were localized in regions of the S1 glycoprotein that play a role in virus-host interaction. Secondary nucleotide peaks identified in the chromatogram for the S1 gene sequence revealed that all original vaccines (H120 and Ma5) were composed by different subpopulations of IBV. Moreover, new viral subpopulations were also found in vaccines after a single passage in chicken embryonated eggs. These findings indicate that H120 and Ma5 viral strains used in vaccines market in Brazil can still mutate very rapidly during replication, leading to amino acid substitutions in proteins involved in the stimulation of the immune response, such as the S1 glycoprotein. Therefore, our data suggest that the genetic variability of these viral strains should be taken into consideration to ensure an effective immune response against IBV. PMID- 29128886 TI - Mercury in fur of Daubenton's bat (Myotis daubentonii) in Southern Sweden and Comparison to Ecotoxicological Thresholds. AB - To characterise mercury (Hg) exposure in Daubenton's bat (Myotis daubentonii, Kuhl 1817) in southern Sweden, 17 specimens were captured in 2013 and back fur samples were taken for analysis to determine Hg concentrations. The fur Hg levels determined [1.15 +/- 0.27 (mean +/- standard deviation, n = 17) ug Hg g-1 fresh weight (fw)] represent a baseline for comparison in future assessments of Hg exposure in bat populations in northern Europe. Mercury concentrations were close to those reported in fur from other bat species, but were lower than proposed toxicological thresholds in bats (> 30 ug Hg g-1 fw) and mice (5 ug Hg g-1 fw). This is the first study to examine Hg exposure in bats in Scandinavia. PMID- 29128887 TI - The effect of methanogenesis inhibition, inoculum and substrate concentration on hydrogen and carboxylic acids production from cassava wastewater. AB - Manipueira is a carbohydrate-rich agro-industrial waste from cassava processing. It is considered well suitable for biotechnological processes, such as hydrogen and carboxylic acids production, due to the high content of easily degradable organic matter. However, the proper methanogenesis inhibition method, inoculum type, and organic loads are factors still limiting the processes. The objective in this work was to evaluate the effects of such factors on byproducts production in anaerobic reactors. Batch experiments were conducted with 2.3-L flasks during two operational phases. In the first phase (P1), inhibition of methanogens in the sludge was evaluated using acetylene (1% v/v of headspace) and heat treatment (120 degrees C, 1 atm for 30 min). In the second phase (P2), three inoculum types obtained from common anaerobic sludges (bovine rumen and sludges from municipal and textile industrial wastewater treatment plants) were individually assayed. P2 aimed to identify the best inoculum, based on hydrogen production ability, which was tested for three initial concentrations of manipueira in terms of chemical oxygen demand (COD) (10, 20 and 40 g O2/L). Results of P1 indicated that either acetylene or heat treatment efficiently inhibited methanogenesis, with no methane production. However, the maximum H2 production potential by applying heat treatment (~ 563 mL) was more than twice compared with that by acetylene treatment (~ 257 mL); and butyrate was the main carboxylic acid by product (~ 3 g/L). In P2 experiments after sludge heat treatment, the highest hydrogen yield (1.66 +/- 0.07 mol H2/mol glucose) and caproic acid production (~ 2 g/L) were observed at 20 g O2/L of manipueira COD, when bovine rumen was the inoculum. The primary metabolic degradation products in all P2 experiments were ethanol, acetic, butyric, propionic and caproic acids. The finding of caproic acid detection indicated that the applied conditions in manipueira anaerobic degradation favored carbon chain elongation over methanogenesis. PMID- 29128888 TI - Two-dimensional speckle-tracking global longitudinal strain in high-sensitivity troponin-negative low-risk patients with unstable angina: a "resting ischemia test"? AB - With the introduction of high-sensitivity troponin (hsTNI) assays, the clinical significance unstable angina (UA) has become uncertain. We hypothesized that impaired left ventricular (LV) two-dimensional speckle-tracking echocardiography (2D-STE)-derived peak global longitudinal strain (GLS) was able to exclude the presence of significant coronary artery disease (CAD) in UA patients without prior cardiovascular (CV) events and with a normal LV ejection fraction (LVEF). From a cohort of 200 patients admitted with UA, we selected 61 patients without prior CV events and with a normal LVEF; of these, 48 (79%) underwent invasive coronary angiography (ICA) and 24 (39%) had at least >= 1 significant stenosis. 2D-STE LV GLS analysis was performed offline using a dedicated automated software program. The mean patient age was 61 +/- 12 years and 66% were male. Among the 48 patients selected to undergo ICA, those without significant CAD had a better 2D STE GLS (- 19.4 vs. - 15.9%, P < 0.001). A cutoff of - 17.5% had a sensitivity of 87% and a specificity of 82% for differentiating UA patients without significant stenosis (AUC 0.86, P < 0.001). Patients who did not undergo ICA had a better GLS (- 20.2 vs. - 17.7%, P = 0.017). 2D-STE GLS had a significantly better discriminative power compared with LVEF (P < 0.001) and the GRACE score (P < 0.001) for identifying patients with significant CAD. Impaired values of 2D-STE LV GLS were significantly associated with the presence of CAD in hsTnI-negative UA patients and demonstrated better discriminative power than LVEF and the GRACE score. PMID- 29128890 TI - The Alvarado Score is accurate in pregnancy: a retrospective case-control study. AB - BACKGROUND: Acute appendicitis is the most frequent abdominal condition that requires non-obstetric surgical intervention during pregnancy. This study aims to scan pregnant patients operated on for acute appendicitis to evaluate the efficiency of using the Alvarado Score (AS) for diagnosis. METHODS: Our study included 48 pregnant patients who were pre-diagnosed with acute appendicitis and operated on at our department of general surgery from January 2010 to July 2016 and whose files were accessed. Fifty-three non-pregnant female patients of reproductive age who were operated on for appendicitis during the same period were included in the study as the control group. The patients in both groups were divided into two groups based on their AS total score being 7 and >= 7. RESULTS: The mean age of the 48 pregnant patients was 28 (19-42) years, while the mean age of the 53 control patients was 31 (18-45) years. Among pregnant and non-pregnant women, about a third of patients had an AS < 7 (16 of 48 versus 18 of 53). There was no significant difference when the AS scores of both groups were compared (p = 0.947). Using pathology results as reference test, the sensitivity and specificity of the AS in pregnant women was 79 and 80%. CONCLUSIONS: As a result, when the data collected by our study are evaluated, we see that pregnancy does not have a negative effect on the efficacy of AS. Therefore, the AS system can be an easy, non-invasive auxiliary diagnostic tool with high diagnosis accuracy rates that can be used in pregnant patients suspected of having acute appendicitis. PMID- 29128889 TI - The role of neuron-glia interactions in the emergence of ultra-slow oscillations. AB - Ultra-slow cortical oscillatory activity of 1-100 mHz has been recorded in human by electroencephalography and in dissociated cultures of cortical rat neurons, but the underlying mechanisms remain to be elucidated. This study presents a computational model of ultra-slow oscillatory activity based on the interaction between neurons and astrocytes. We predict that the frequency of these oscillations closely depends on activation of astrocytes in the network, which is reflected by oscillations of their intracellular calcium concentrations with periods between tens of seconds and minutes. An increase of intracellular calcium in astrocytes triggers the release of adenosine triphosphate from these cells which may alter transmission at nearby synapses by increasing or decreasing neurotransmitter release. These results provide theoretical support for the emerging awareness of astrocytes as active players in the regulation of neural activity and identify neuron-astrocyte interactions as a potential primary mechanism for the emergence of ultra-slow cortical oscillations. PMID- 29128891 TI - PRMT1 promotes hyperglycemia in a FoxO1-dependent manner, affecting glucose metabolism, during hypobaric hypoxia exposure, in rat model. AB - PURPOSE: High-altitude (HA) environment causes changes in cellular metabolism among unacclimatized humans. Previous studies have revealed that insulin dependent activation of protein kinase B (Akt) regulates metabolic processes via discrete transcriptional effectors. Moreover, protein arginine methyltransferase (PRMT)1-dependent arginine modification of forkhead box other (FoxO)1 protein interferes with Akt-dependent phosphorylation. The present study was undertaken to test the involvement of PRMT1 on FoxO1 activation during hypobaric hypoxia (HH) exposure in rat model. METHODS: Samples were obtained from normoxia control (NC) and HH-exposed (H) rats, subdivided according to the duration of HH exposure. To explore the specific role played by PRMT1 during HH exposure, samples from 1d pair-fed (PF) NC, 1d acute hypoxia-exposed (AH) placebo-treated, and 1d AH TC-E-5003-treated rats were investigated. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) was performed to determine expressions of glycolytic, gluconeogenic enzymes, and insulin response regulating genes. Immuno-blot and enzyme linked immunosorbent assay (ELISA) were used for insulin response regulating proteins. Nuclear translocation of FoxO1 was analyzed using deoxyribonucleic acid (DNA)-binding ELISA kit. RESULTS: We observed HH induced increase in glycolytic enzyme expressions in hepatic tissue unlike hypothalamic tissue. PRMT1 expression increased during HH exposure, causing insulin resistance and resulting increase in FoxO1 nuclear translocation, leading to hyperglycemia. Conversely, PRMT1 inhibitor treatment promoted inhibition of FoxO1 activity and increase in glucose uptake during HH exposure leading to reduction in blood-glucose and hepatic glycogen levels. CONCLUSIONS: PRMT1 might have a potential importance as a therapeutic target for the treatment of HH induced maladies. PMID- 29128893 TI - Regional Biophysics Conference - RBC2016. PMID- 29128892 TI - Trajectories of job demands and control: risk for subsequent symptoms of major depression in the nationally representative Swedish Longitudinal Occupational Survey of Health (SLOSH). AB - PURPOSE: Depression is a global health concern. High job demands, low job control, and the combination (high strain) are associated with depression. However, few longitudinal studies have investigated changed or repeated exposure to demands and control related to depression. We investigated how trajectories of exposure to job demands and control jointly influence subsequent depression. METHODS: We included 7949 subjects from the Swedish Longitudinal Occupational Survey of Health, who completed questionnaires of perceived job demands and control, and depressive symptoms from 2006 to 2014. None of them were depressed between 2006 and 2012. Univariate and joint group-based trajectory models identified groups with similar development of demands and control across 2006 2012. Logistic regression estimated the risk for symptoms of major depression in 2014 according to joint trajectory groups. RESULTS: The joint trajectory model included seven groups, all with fairly stable levels of demands and control over time. Subjects in the high strain and active (high demands and high control) trajectories were significantly more likely to have subsequent major depressive symptoms compared to those having low strain, controlling for demographic covariates (OR 2.15; 95% Cl 1.24-3.74 and OR 2.04; 95% CI 1.23-3.40, respectively). The associations did not remain statistically significant after adjusting for previous depressive symptoms in addition to demographic covariates. CONCLUSIONS: The results indicate that the levels of job demands and control were relatively unchanged across 6 years and suggest that long-term exposure to a high strain or active job may be associated with increased risk for subsequent depression. PMID- 29128894 TI - Behavioural and Emotional Problems in Children and Educational Outcomes: A Dynamic Panel Data Analysis. AB - This study investigates the effects of behavioural and emotional problems in children on their educational outcomes using data from the Longitudinal Survey of Australian Children (LSAC). We contribute to the extant literature using a dynamic specification to test the hypothesis of knowledge accumulation. Further, we apply the system generalised method of moments (GMM) estimator to minimise biases due to unobserved factors. We find that mental disorders in children has a negative effect on the National Assessment Program-Literacy and Numeracy (NAPLAN) test scores. Among all mental disorders, having emotional problems is found to be the most influential with one standard deviation (SD) increase in emotional problems being associated with 0.05 SD reduction in NAPLAN reading, writing and spelling; 0.04 SD reduction in matrix reasoning and grammar; and 0.03 SD reduction in NAPLAN numeracy. PMID- 29128895 TI - Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer. AB - PURPOSE: Deregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER positive breast cancer. METHODS: Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ERalpha-positive cell lines was compared with that in ERalpha-negative cell lines. RESULTS: Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ERalpha signaling, here shown by a coupled increase of ERalpha phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ERalpha-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ERalpha-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up. CONCLUSION: We present a connection between raptor localization to the nucleus and ERalpha-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment. PMID- 29128896 TI - Discordance between oncotype DX recurrence score and RSPC for predicting residual risk of recurrence in ER-positive breast cancer. AB - PURPOSE: Oncotype DX, a gene expression assay widely employed to aid decision making on adjuvant chemotherapy use in patients with primary oestrogen receptor positive (ER+) breast cancer, produces a recurrence score (RS) related to distant disease recurrence (DR) risk (RS%). In node-negative patients, RS can be integrated with clinicopathological parameters to derive RS-pathology-clinical (RSPC) that improves prognostic accuracy. METHODS: Data were collected on patients having clinically indicated tests with an intermediate clinical risk of distant recurrence, and for whom the decision to prescribe chemotherapy remained unclear. Correlation between RS% and RSPC scores was examined. An agreement table was constructed using risk-categorised data. Association between RS%-derived categorical risk assignments and treatment recommendation was evaluated. RESULTS: Data on 171 tests (168 patients) were available. Median DR risk by RS% was 11% (range 3-34%), by RSPC it was 15% (range 4-63%). Correlation between RS% and RSPC was 0.702 (p < 0.001). RS% classified 57.3% of cases as low-, 32.2% intermediate- and 10.5% high-risk for DR; by RSPC proportions were 33.9, 35.7, and 30.4%, respectively. The number of patients receiving chemotherapy recommendations was: 14/87 (16.1%) categorised as low-risk by RS%, 27/49 (55.1%) as intermediate-risk and 12/13 (92.3%) as high-risk. Of 149 patients recommended for endocrine treatment alone, 28 (18.8%) were categorised by RS% as low-risk but by RSPC as intermediate- or high-risk. CONCLUSIONS: In this group of patients, RSPC assessed fewer patients as low-risk and more as high-risk than did RS%. The discordances between the scores indicate that RSPC estimates of risk should be considered when selecting patients for endocrine therapy alone. PMID- 29128897 TI - Speed of processing training in middle-aged and older breast cancer survivors (SOAR): results of a randomized controlled pilot. AB - PURPOSE: Cognitive changes are common among breast cancer survivors. There is limited evidence to guide management of cognitive changes. This randomized controlled pilot evaluated the preliminary efficacy of a speed of processing (SOP) training among middle-aged and older breast cancer survivors. METHODS: Sixty breast cancer survivors with self-reported cognitive changes were recruited to the SOAR study. Participants were randomized to either a home-based SOP training (n = 30) or no-contact control group (n = 30). Primary outcomes were SOP (Useful Field of View Test(r)), and executive function (NIH Toolbox Cognition Battery). Neuropsychological assessments were completed at baseline, 6 weeks, and 6 months post study entry. Data were analyzed using repeated measures t tests, analysis of covariance, and sensitivity analyses. RESULTS: SOP training resulted in improvement in objective measures of SOP and executive function. Immediate (6 week) posttest and 6-month follow-up demonstrated large SOP training effects over time. Large representation of African American women (51.2%) and 96% retention in the SOAR study add to study strengths. CONCLUSION: Home-based SOP training shows promise for remediating cognitive changes following breast cancer treatment, particularly improved SOP, and executive function. PMID- 29128899 TI - A no-touch technique for pulmonary wedge resection of lung cancer. AB - OBJECTIVE: Many of the surgical patients with lung cancer die by metastasis originated from circulating tumor cells (CTCs) which are seeds of metastases. A ring-shaped catching forceps, which generates the great pressure by compression, may reduce the risk of tumor cell spreading. Here, we investigated the efficacy of such forceps based on CTC occurrence. METHODS: Twenty-three patients with clinical stage IA lung cancer who underwent a pulmonary wedge resection were investigated in a clinical-pathological manner. They were divided into those treated using ring forceps catching without tumor release (R group) (n = 16) and non-complete use of ring forceps (N group) (n = 7), then were determined circulating tumor cells (CTCs). RESULTS: Radiographic findings, tumor location, pathological diagnosis, and stapling method were not significantly different between the groups. The risk of detection of CTCs after surgery was significantly lower in group R (12.5 vs. 85.7%, p = 0.02), whereas there were no significant differences found in risk of negative-stapled margin cytology, pre-OP CTC detection, V (+), Ly (+), and Pl (+). CONCLUSIONS: Patients who underwent pulmonary wedge resection of lung cancer had low chance of CTC detection after surgery when they were treated with ring forceps without tumor release, which might become a no-touch isolation technique. PMID- 29128898 TI - 21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology. AB - BACKGROUND: The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen. METHODS: The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years. RESULTS: In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72-1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69-1.47; p = 0.99), 0.84 (95% CI 0.62-1.14; p = 0.26), and 0.81 (95% CI 0.60-1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints. CONCLUSIONS: RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28). PMID- 29128900 TI - Student learning outcomes, perceptions and beliefs in the context of strengthening research integration into the first year of medical school. AB - Research integrated into undergraduate education is important in order for medical students to understand and value research for later clinical practice. Therefore, attempts are being made to strengthen the integration of research into teaching from the first year onwards. First-year students may interpret attempts made to strengthen research integration differently than intended by teachers. This might be explained by student beliefs about learning and research as well as student perceptions of the learning environment. In general, student perceptions of the learning environment play a pivotal role in fostering student learning outcomes. This study aims to determine whether a curriculum change intended to promote research integration fosters student learning outcomes and student perceptions of research integrated into teaching. To serve this purpose, three subsequent cohorts of first-year students were compared, one before and two after a curriculum change. Learning outcomes of these students were measured using scores on a national progress test of 921 students and assessments of a sample of 100 research reports of a first-year student research project. 746 Students filled out the Student Perceptions of Research Integration Questionnaire. The findings suggest that learning outcomes of these students, that is, scores on research related test items of the progress test and the quality of research reports, were better than those of students before the curriculum change. PMID- 29128901 TI - FGL2 knockdown improves heart function through regulation of TLR9 signaling in the experimental autoimmune myocarditis rats. AB - Fibrinogen-like protein 2 (FGL2) is an important immune regulator of both innate and adaptive response. It is present on the surface of macrophages and endothelial cells, and can be constitutively secreted by CD4+CD8+ T cells. Previous studies showed that FGL2 is a potential target for the treatment of experimental autoimmune myocarditis. However, the molecular mechanism of the roles of FGL2 in experimental autoimmune myocarditis is poorly understood. Here, we silenced FGL2 gene by using FGL2-RNAi lentivirus to reveal the heart function in experimental autoimmune myocarditis rats. We found that the cardiac myosin of pigs' hearts induced Lewis rats to come into being as autoimmune myocarditis. TLR9 was upregulated in the heart of experimental autoimmune myocarditis rats. After primary immunization (21 day), the cardiac function of the myocarditis model group improved (P < 0.05). Significantly, the levels of INF-alpha and NF kappaB in the FGL2-RNAi-treated group were lower compared to those in the myocarditis model (EAM) group (P < 0.05). Notably, the inflammation score correspondence with the protein and mRNA levels of TLR9 in myocardial tissues was markedly reduced compared to that in the EAM group (P < 0.05). These results support a role of FGL2 to alleviate inflammatory situation in the myocardium through regulation of the TLR9 signaling pathway in the experimental autoimmune myocarditis rats. PMID- 29128902 TI - Overexpression of 5-Lipoxygenase Worsens the Phenotype of a Mouse Model of Tauopathy. AB - Brain accumulation of increasing amount of phosphorylated microtubule associated tau protein is one the major hallmark lesions of Alzheimer's disease (AD) and related tauopathies. Consistent evidence from clinical and animal studies has shown that neuroinflammation characterizes these diseases. The 5-lipoxygenase (5LO) is an enzyme protein whose metabolic products are lipids with potent inflammatory actions. Previously, we showed that blockade of 5LO activation ameliorates the phenotype of the htau transgenic mice. Here, by employing a vector system to overexpress 5LO in the brain of the same mouse model, we investigated its role and contribution to their behavioral deficits and development of tau neuropathology. Compared with controls, 5LO gene targeted mice manifested significant impairments in their memory and learning ability. On the other hand, brain tissues of the same mice had higher 5LO protein level and activity which resulted in intense neuroinflammation and synaptic pathology. Further, the same mice had a significant elevation of tau phosphorylation, which associated with the activation of the cdk5 kinase and an accumulation of insoluble tau. The functional involvement of this kinase in the 5LO-dependent tau phosphorylation was confirmed in neuronal cells. Taken together, our findings demonstrate that neuronal 5LO is directly involved in tau phosphorylation and tau neuropathology, and for this reason, it should be considered a good therapeutic target for tauopathies. PMID- 29128903 TI - Impairment of Thiamine Transport at the GUT-BBB-AXIS Contributes to Wernicke's Encephalopathy. AB - Wernicke's encephalopathy, a common neurological disease, is caused by thiamine (vitamin B1) deficiency. Neuropathy resulting from thiamine deficiency is a hallmark of Wernicke-Korsakoff syndrome in chronic alcohol users. The underlying mechanisms of this deficiency and progression of neuropathy remain to be understood. To uncover the unknown mechanisms of thiamine deficiency in alcohol abuse, we used chronic alcohol consumption or thiamine deficiency diet ingestion in animal models. Observations from animal models were validated in primary human neuronal culture for neurodegenerative process. We employed radio-labeled bio distribution of thiamine, qualitative and quantitative analyses of the various biomarkers and neurodegenerative process. In the present studies, we established that disruption of thiamine transport across the intestinal gut blood-brain barrier axis as the cause of thiamine deficiency in the brain for neurodegeneration. We found that reduction in thiamine transport across these interfaces was the cause of reduction in the synthesis of thiamine pyrophosphate (TPP), an active cofactor for pyruvate dehydrogenase E1alpha (PDHE1alpha). Our findings revealed that decrease in the levels of PDHE1alpha cofactors switched on the activation of PD kinase (PDK) in the brain, thereby triggering the neuronal phosphorylation of PDHE1alpha (p-PDHE1alpha). Dysfunctional phosphorylated PDHE1alpha causes the reduction of mitochondrial aerobic respiration that led to neurodegeneration. We concluded that impairment of thiamine transport across the gut-BBB-axis that led to insufficient TPP synthesis was critical to Wernicke neuropathy, which could be effectively prevented by stabilizing the thiamine transporters. PMID- 29128904 TI - Pharmacological Rescue of Hippocampal Fear Learning Deficits in Fragile X Syndrome. AB - Fragile X Syndrome (FXS) is the leading cause of autism spectrum disorder and intellectual disability and results from loss of Fragile X mental retardation protein (FMRP). In neurons, FMRP controls the translation of synaptic plasticity proteins that are implicated in learning and memory. FMRP also regulates development- and experience-dependent actin cytoskeleton remodeling within dendritic spines through the small Rho GTPase Rac1. Modulation of Rac1 activity is critical during synaptic plasticity as well as learning and memory. We have previously shown that FXS mouse models exhibit learning and memory deficits as well as hyperactive Rac1 in the hippocampus. To determine whether pharmacological inhibition of Rac1 in FXS improves cognitive impairment, FXS mice were treated with the specific Rac1 inhibitor NSC23766, followed by fear conditioning. Whereas non-cognitive functions were unaffected, hippocampus-related memory improved in FXS mice treated with the Rac1 inhibitor. Furthermore, long-term potentiation in hippocampal slices from FXS mice was increased after incubation with the Rac1 inhibitor. Together, these observations indicate that modulation of Rac1 may provide a novel therapeutic target in the treatment of cognitive impairment in FXS. PMID- 29128906 TI - Toll-Like Receptor-3 Mediates HIV-1-Induced Interleukin-6 Expression in the Human Brain Endothelium via TAK1 and JNK Pathways: Implications for Viral Neuropathogenesis. AB - HIV-1-associated neurocognitive disorders (HAND) is associated with blood-brain barrier (BBB) inflammation, and inflammation involves toll-like receptors (TLRs) signaling. It is not known whether primary human brain microvascular endothelial cells (HBMEC), the major BBB component, express TLRs or whether TLRs are involved in BBB dysfunction and HAND. We demonstrate that HBMEC express TLR3, 4, 5, 7, 9, and 10, and TLR3 was the most abundant. HIV-1 and TLR3 activation increased endothelial TLR3 transcription and expression. HIV-1-positive human subjects showed significantly higher TLR3 expression in brain tissues and blood vessels, with higher TLR3 levels in subjects with HAND. HIV-1 and TLR3 activation increased endothelial IL6 expression by 6-to-127-fold (P < 0.001), activated c jun(serine-63) and SAPK/JNK(Thr183/Tyr185). HIV-1 upregulated IL6 through interleukin-1 receptor-associated-kinase (IRAK)-1/4/TAK1/JNK pathways, via ATP dependent JNK activation. TLR3 activation upregulated IL6 through TAK1/JNK pathways, via ATP-dependent or -independent JNK activation. HIV-1 and TLR3 activation also upregulated transcription factors associated with IL6 and TAK1/JNK pathways (Jun, CEBPA, STAT1). Blocking TLR3 activation prevented HIV-1- and TLR3 ligands-induced upregulation of these transcription factors, prevented IL6 transcription and expression, c-jun and JNK activation. HIV-1 and TLR3 ligands significantly increased monocytes adhesion and migration through the BBB, and decreased endothelial claudin-5 expression. Blocking TLR3 and JNK activation prevented HIV-1- and TLR3 ligands-induced claudin-5 downregulation, monocytes adhesion and transendothelial migration. These data suggest that viral immune recognition via endothelial TLR3 is involved in endothelial inflammation and BBB dysfunction in HIV/AIDS and HAND. Our data provides novel insights into the molecular basis of these HIV-1- and TLR3-mediated effects. PMID- 29128905 TI - Down Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro. AB - Several methods have been used to study the neuropathogenesis of Down syndrome (DS), such as mouse aneuploidies, post mortem human brains, and in vitro cell culture of neural progenitor cells. More recently, induced pluripotent stem cell (iPSC) technology has offered new approaches in investigation, providing a valuable tool for studying specific cell types affected by DS, especially neurons and astrocytes. Here, we investigated the role of astrocytes in DS developmental disease and the impact of the astrocyte secretome in neuron mTOR signaling and synapse formation using iPSC derived from DS and wild-type (WT) subjects. We demonstrated for the first time that DS neurons derived from hiPSC recapitulate the hyperactivation of the Akt/mTOR axis observed in DS brains and that DS astrocytes may play a key role in this dysfunction. Our results bear out that 21 trisomy in astrocytes contributes to neuronal abnormalities in addition to cell autonomous dysfunctions caused by 21 trisomy in neurons. Further research in this direction will likely yield additional insights, thereby improving our understanding of DS and potentially facilitating the development of new therapeutic approaches. PMID- 29128907 TI - A New Conditionally Immortalized Human Fetal Brain Pericyte Cell Line: Establishment and Functional Characterization as a Promising Tool for Human Brain Pericyte Studies. AB - While pericytes wrap around microvascular endothelial cells throughout the human body, their highest coverage rate is found in the brain. Brain pericytes actively contribute to various brain functions, including the development and stabilization of the blood-brain barrier (BBB), tissue regeneration, and brain inflammation. Accordingly, detailed characterization of the functional nature of brain pericytes is important for understanding the mechanistic basis of brain physiology and pathophysiology. Herein, we report on the development of a new human brain pericyte cell line, hereafter referred to as the human brain pericyte/conditionally immortalized clone 37 (HBPC/ci37). Developed via the cell conditionally immortalization method, these cells exhibited excellent proliferative ability at 33 degrees C. However, when cultured at 37 degrees C, HBPC/ci37 cells showed a differentiated phenotype that was marked by morphological alterations and increases in several pericyte-enriched marker mRNA levels, such as platelet-derived growth factor receptor beta. It was also found that HBPC/ci37 cells possessed the facilitative ability of in vitro BBB formation and differentiation into a neuronal lineage. Furthermore, HBPC/ci37 cells exhibited the typical "reactive" features of brain pericytes in response to pro inflammatory cytokines. To summarize, our results clearly demonstrate that HBPC/ci37 cells possess the ability to perform several key brain pericyte functions while also showing the capacity for extensive and continuous proliferation. Based on these findings, it can be expected that, as a unique human brain pericyte model, HBPC/ci37 cells have the potential to contribute to significant advances in the understanding of human brain pericyte physiology and pathophysiology. PMID- 29128908 TI - A phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients. AB - BACKGROUND: Pre-operative chemoradiotherapy using a 5-fluorouracil (5 FU)/cisplatin backbone is widely used to improve surgical outcomes in locoregional oesophageal cancer patients, despite a non-negligible failure rate. OBJECTIVE: We evaluated intensification of this approach to improve patient outcomes by adding cetuximab to induction 5-FU/cisplatin/docetaxel (TPF) and to chemoradiotherapy in a phase II study. PATIENTS AND METHODS: Between November 2006 and April 2009, 50 patients with stage II-IVa squamous cell carcinoma (SCC) or adenocarcinoma of the oesophagus or gastro-oesophageal junction initiated three TPF/cetuximab cycles. Six weeks later, patients with response or stabilisation initiated 6 weeks of cisplatin/cetuximab/radiotherapy, followed by surgery. The primary objective was the clinical complete response (cCR) rate after induction therapy plus chemoradiotherapy in intent-to-treat patients. RESULTS: Thirty-eight patients were evaluable after chemoradiotherapy, 84% of whom showed disease control. Six patients (12%) achieved a cCR, with a 54% overall response rate. Twenty-seven patients underwent surgery, 11 of whom (22%; nine SCC, two adenocarcinoma) had a pathological CR (41%). Fifteen patients were alive after a median follow-up of 23.2 months. Median progression-free survival was 12.2 months (95% confidence interval [CI] 1.7-22.8). Median overall survival was 23.4 months (95% CI 12.2-36.6) and was significantly longer among the 22 patients with complete resection than in the five patients without (42.1 vs. 24.9 months; p = 0.02, hazard ratio: 3.6, 95% CI 1.1-11.6). The toxicity profile was acceptable. CONCLUSIONS: Neoadjuvant cetuximab/TPF followed by chemoradiotherapy in locoregional oesophageal carcinoma patients is feasible and offers a modest response rate in this trial. The results of combining trimodality neoadjuvant treatment with cetuximab are consistent with the literature. Registration: The study is registered at ClinicalTrials.gov (NCT00733889). PMID- 29128909 TI - Central noradrenergic activity affects analgesic effect of Neuropeptide S. AB - BACKGROUND: Neuropeptide S (NPS) is an endogenous neuropeptide controlling anxiolysis, wakefulness, and analgesia. NPS containing neurons exist near to the locus coeruleus (LC) involved in the descending anti-nociceptive system. NPS interacts with central noradrenergic neurons; thus brain noradrenergic signaling may be involved in NPS-induced analgesia. We tested NPS analgesia in noradrenergic neuron-lesioned rats using a selective LC noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). METHODS: A total 66 male Sprague-Dawley rats weighing 350-450 g were used. Analgesic effects of NPS were evaluated using hot-plate and tail-flick test with or without DSP-4. The animal allocated into 3 groups; hot-plate with NPS alone intracerebroventricular (icv) (0.0, 1.0, 3.3, and 10.0 nmol), tail-flick NPS alone icv (0.0 and 10.0 nmol), and hot-plate with NPS and DSP-4 (0 or 50 mg/kg ip). In hot-plate with NPS and DSP-4 group, noradrenaline content in the cerebral cortex, pons, hypothalamus, were measured. RESULTS: NPS 10 nmol icv prolonged hot plate (%MPE) but not tail flick latency at 30 and 40 min after administration. DSP-4 50 mg/kg decreased noradrenaline content in the all 3 regions. The NA depletion inhibited NPS analgesic effect in the hot plate test but not tail flick test. There was a significant correlation between hot plate latency (percentage of maximum possible effect: %MPE) with NPS 10 nmol and NA content in the cerebral cortex (p = 0.017, r 2 = 0.346) which noradrenergic innervation arisen mainly from the LC. No other regions had the correlation. CONCLUSIONS: NPS analgesia interacts with LC noradrenergic neuronal activity. PMID- 29128911 TI - Why the way we look at things in reproductive medicine is changing. PMID- 29128910 TI - Allogeneic ovarian transplantation using immunomodulator preimplantation factor (PIF) as monotherapy restored ovarian function in olive baboon. AB - PURPOSE: Allogeneic ovarian transplantation may be an alternative in the future to oocyte donation in women with premature ovarian failure. The objectives of this study were to (a) evaluate allotransplantation feasibility for restoration of ovarian function and (b) assess efficacy of synthetic preimplantation factor (PIF) monotherapy as sole immune-acceptance regimen. METHODS: This is an experimental animal study using non-human primates (Papio anubis). Allogeneic orthotopic ovarian tissue transplantation was performed in two female olive baboons. PIF was administered as a monotherapy to prevent immune rejection and achieve transplant maintenance and function. Subjects underwent bilateral oophorectomy followed by cross-transplantation of prepared ovarian cortex. Postoperatively, subjects were monitored for clinical and biochemical signs of graft rejection and return of function. Weekly blood samples were obtained to monitor graft acceptance and endocrine function restoration. RESULTS: Postoperatively, there were no clinical signs of rejection. Laboratory parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine) did not indicate organ rejection at any stage of the experiment. Initially, significant loss of follicles was noticed after grafting and serum follicle-stimulating hormone (FSH) and E2 levels were consistent with ovarian failure. Seven months after transplantation, one animal exhibited recurrence of ovarian endocrine function (perineal swelling, E2 rise, FSH decrease, and return of menstruation). CONCLUSIONS: Organ rejection after allogeneic ovarian transplantation was prevented using PIF as monotherapy for the first time and no side effects were recorded. The study suggests the clinical feasibility of ovarian allotransplantation to obtain ovarian function. PMID- 29128912 TI - Ovarian stem cells-resolving controversies. AB - A recent review on ovarian stem cells by Horan and Williams entitled "Oocyte Stem Cells: Fact or Fantasy?" suggests that the debate on ovarian stem cells (OSCs) is still not over. They did not even discuss the presence of two distinct populations of stem cells in the ovary in their review. OSCs are located in the ovary surface epithelium and Tilly's group reported them in the size range of 5-8 MUm whereas Virant-Klun's group has reported pluripotent, 2-4 MUm OSCs. Our group reported OSCs of two distinct sizes including pluripotent very small embryonic like stem cells (VSELs) which are smaller in size than RBCs (similar to those reported by Virant-Klun's group) and slightly bigger (similar to those reported by Tilly's group) tissue committed progenitors (OSCs) that presumably differentiate from VSELs. These stem/progenitor cells express receptors for follicle stimulating hormone (FSH) and are activated by FSH. Our opinion article provides explanation to several open-ended questions raised in the review on OSCs by Horan and Williams. VSELs survive chemotherapy; maintain life-long homeostasis; loss of their function due to a compromised niche results in age related senescence and presence of overlapping pluripotent markers suggest that they may also be implicated in epithelial ovarian cancers. PMID- 29128913 TI - Radiographic markers for measuring tibial rotation based on CT-reconstructed radiographs: an accuracy and feasibility study. AB - OBJECTIVES: Malreduction in the axial plane (malrotation) following tibial fracture surgery is often undiagnosed. A few clinical and radiographic methods have been proposed for measuring tibial rotation intraoperatively, yet have failed to match the accuracy of computed tomography (CT). The aim of this study was to develop radiographic tools for future intraoperative assessment of the tibial shaft rotation profile. METHODS: The setting was a laboratory computerized analysis. Twenty lower limb CT scans were used to construct a three-dimensional (3D) model using AMIRA(c) software. A virtual 3D cylinder was implanted in the posterior condylar line and in the transmalleolar axis. The 3D models were used to simulate four standard knee and ankle plain radiographs. On each radiograph, four landmarks were depicted by two observers and their relation with the cylinder was measured and analyzed for accuracy and reproducibility. A cadaveric lower leg was implanted with two Kirschner wires. A CT scan was performed in addition to 2D fluoroscopy. The simulated radiographs and the fluoroscopy were compared for accuracy. RESULTS: Measurement of the landmarks showed reliability in most of the knee anteroposterior and ankle mortise radiographs (coefficients of variation < 0.01 and = 0.01) respectively. Cadaveric measurement of the landmarks using real fluoroscopy and simulated radiographs were similar. CONCLUSIONS: To date, no reliable and common methods have been reported for the evaluation of tibial axial rotation. We propose a model in which simple radiographic landmarks can be used to calculate a 3D coordinate system that accurately assesses the axial rotation angle of the tibial shaft. PMID- 29128914 TI - Simultaneous determination of tolterodine and its two metabolites, 5 hydroxymethyltolterodine and N-dealkyltolterodine in human plasma using LC-MS/MS and its application to a pharmacokinetic study. AB - Tolterodine is a nonselective muscarinic antagonist that is indicated for the overactive urinary bladder and other urinary difficulties. We developed and validated a simple, rapid and sensitive high-performance liquid chromatography analytical method utilizing tandem mass spectrometry (LC-MS/MS) for the quantitation of tolterodine and its major metabolites, 5-hydroxymethyltolterodine (5-HMT) and N-dealkyltolterodine (NDT), in human plasma. After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of the three analytes was achieved using a reversed-phase Luna Phenyl-hexyl column (100 * 2.0 mm, 3 MUm particles) with a mobile phase of 10 mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in electrospray ionization (ESI) positive ion mode. The retention time of tolterodine, 5-HMT, NDT, and internal standard (IS) were 1.4, 1.24, 1.33, and 1.26 min, respectively. The calibration curves were linear over a range of 0.025-10 ng/ml for tolterodine and 5-HMT, and 0.05-10 ng/ml for NDT. The lower limit of quantifications using 200 MUl of human plasma was 0.025 ng/ml for tolterodine and 5-HMT, and 0.05 ng/ml for NDT. The mean accuracy and precision for intra- and inter-run validation of tolterodine, 5-HMT, and NDT were all within acceptable limits. These results showed that a simple, rapid and sensitive LC-MS/MS method for the quantification of tolterodine and its major metabolites in human plasma was developed. This method was successfully applied to a pharmacokinetic study in humans. PMID- 29128915 TI - MRI kinematic analysis of T1 sagittal motion between cervical flexion and extension positions in 145 patients. AB - PURPOSE: Although the T1 vertebra is considered as an important factor of cervical balance, little is known about its motion between flexion and extension. The purpose of present study was to analyze the T1 sagittal motion using kinematic magnetic resonance imaging (kMRI), and to identify factors that relate to T1 sagittal motion. METHODS: We retrospectively analyzed 145 kMR images taken in weight-bearing neutral, flexion and extension positions. Cervical balance parameters were evaluated in each position. The degree of T1 sagittal motion was defined as [(T1 slope at extension) - (T1 slope at flexion)]. All patients were divided into three groups: Positive group (T1 followed the head motion, T1 sagittal motion > 5 degrees ), Stable group (5 >=, >= - 5) and Negative group (T1 moved in the opposite direction from the head motion, > - 5). The groups were compared and multivariate logistic regression analysis was calculated. RESULTS: There were 57 (40%) patients in the positive, 56 (39%) in the stable and 32 (22%) in the negative group. The positive group had the largest C2-7 sagittal vertical axis in flexion (p < 0.001) and the shortest in the extension (p = 0.023). Similar trends were seen in cranial tilt and cervical tilt. The value of T1 height < 27 mm was a significant independent factor for the negative group (p = 0.008, adjusted odds ratio = 5.958). CONCLUSION: Based on T1 sagittal motion, 40% of the patients were classified in positive group (the T1 vertebra followed the head motion in flexion and extension), and 20% were classified in the negative group (the T1 vertebra moved in the opposite direction from the head motion). T1 height < 27 mm was a potential predictor of negative group. PMID- 29128916 TI - Cardiometabolic Risk in PCOS: More than a Reproductive Disorder. AB - PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is diagnosed by its characteristic reproductive features. However, PCOS is also associated with metabolic abnormalities, including insulin resistance and beta-cell dysfunction. The severity of these abnormalities varies according to the reproductive phenotype, with the so-called NIH or classic phenotype conferring the greatest metabolic risk. The increased risk for type 2 diabetes (T2D) is well established among affected women with the NIH phenotype, but whether PCOS also confers an increased risk for cardiovascular events remains unknown. RECENT FINDINGS: Recent studies in daughters of affected women have found evidence for pancreatic beta cell dysfunction prior to menarche. Further, genetic analyses have provided evidence that metabolic abnormalities such as obesity and insulin resistance contribute to the pathogenesis of PCOS. PCOS increases the risk for T2D. However, the risk for cardiovascular disease has not been quantified, and prospective, longitudinal studies are still critically needed. PMID- 29128919 TI - Genome-Wide Prediction of Potential Vaccine Candidates for Campylobacter jejuni Using Reverse Vaccinology. AB - Campylobacteriosis is a deadly disease which has developed resistance to most of the available chemotherapeutic agents. Although various studies provide evidence of acquired immunity following exposure to Campylobacter jejuni, no effective vaccine has been developed, still. Hence, there is an urgent need to identify potential vaccine candidates for Campylobacter species. In the proposed study, Campylobacter jejuni subsp. jejuni serotype O:2 (strain NCTC 11168) was taken and computational approach was employed to screen C. jejuni genome for promising vaccine candidates. From 1623 protein-coding sequences, 37 potential antigens were screened for epitope prediction based on surface association, consensus antigenicity predictions, solubility, transmembrane domain, and ortholog analysis. Comprehensive immunogenic analysis of these 37 antigens revealed that antigen Q0PA22 shows the greatest potential for experimental immunogenicity analysis. It has several potential CD4+ and CD8+ T-cell epitopes, as well as high probability of B-cell epitope regions as compared to well-characterized antigen Omp18 (Uniprot ID:Q0PC24). Among the highest scoring predicted epitopes, an optimal set of epitopes with respect to overall immunogenicity in target populations for campylobacteriosis viz. Europe, North America and Southwest Asia was determined. An epitope AMLTYMQWL from antigen no. 6(Q0PA22) binds to the most prevalent allele HLA-A*0201, and this epitope has most immunogenicity for all the target populations. In addition, this epitope exhibited highly significant TCR pMHC interactions having a joint Z value of 4.87. Homology mapping studies of the predicted epitope show best homology to a well-studied antigenic peptide from influenza virus H5N1. Therefore, the predicted epitope might be a suitable vaccine candidate. PMID- 29128920 TI - Prospective evaluation of MR overlay on real-time fluoroscopy for percutaneous extremity biopsies of bone lesions visible on MRI but not on CT in children in the interventional radiology suite. AB - Magnetic resonance imaging (MRI) often provides better visualization of bone marrow abnormalities than computed tomography (CT) or fluoroscopy, but bone biopsies are usually performed using conventional CT or, more recently, C-arm CT guidance. Biopsies of bone lesions solely visible on MRI are often challenging to localize and require the operator to review the MRI on a separate console to correlate with MRI anatomical landmarks during the biopsy. The MR overlay technique facilitates such biopsies in the angiographic suite by allowing the pre procedural 3-D MRI to be overlaid on intraprocedural 2-D fluoroscopy. This study describes our initial experience with the MR overlay technique in the angiography suite during pediatric percutaneous extremity bone biopsies of lesions visible on MRI but not on CT or fluoroscopy and demonstrates its utility in relevant clinical cases. PMID- 29128917 TI - Heterologous expression of mitochondrial nicotinamide adenine dinucleotide transporter (Ndt1) from Aspergillus fumigatus rescues impaired growth in Deltandt1Deltandt2 Saccharomyces cerevisiae strain. AB - Our understanding of nicotinamide adenine dinucleotide mitochondrial transporter 1 (Ndt1A) in Aspergillus fumigatus remains poor. Thus, we investigated whether Ndt1A could alter fungi survival. To this end, we engineered the expression of an Ndt1A-encoding region in a Deltandt1Deltandt2 yeast strain. The resulting cloned Ndt1A protein promoted the mitochondrial uptake of nicotinamide adenine dinucleotide (NAD+), generating a large mitochondrial membrane potential. The NAD+ carrier utilized the electrochemical proton gradient to drive NAD+ entrance into mitochondria when the mitochondrial membrane potential was sustained by succinate. Its uptake has no impact on oxidative stress, and Ndt1A expression improved growth and survival of the Deltandt1Deltandt2 Saccharomyces cerevisiae strain. PMID- 29128918 TI - Moderate physical activity reduces 10-year diabetes incidence: the mediating role of oxidative stress biomarkers. AB - OBJECTIVES: To evaluate the effect of physical activity levels on 10-year diabetes incidence and investigate the potential mechanism. METHODS: In 2001 2002, a random sample of apparently healthy 3042 men and women (18-89 years) was selected to participate in the ATTICA study. Several socio-demographic, clinical and lifestyle characteristics were recorded. Physical activity level was recorded through a translated, validated, version of International Physical Activity Questionnaire (IPAQ); MET min/week was calculated and quartiles constructed. Diabetes diagnosis was defined according to the ADA criteria. During 2011-2012, a 10-year follow-up was performed. RESULTS: n = 191 cases were recorded, yielding an incidence of 12.9%. In multivariable analysis, moderate physical activity level (331-1484 MET min/week) was found to decrease 10-year diabetes incidence by 53% compared to very low physical activity (< 150 MET min/week) (OR = 0.47; 95% CI 0.24, 0.93). For high physical activity level (> 1484 MET min/week), the results were not significant. The antidiabetic effect was found to be mediated by oxidized LDL and total antioxidant capacity. CONCLUSIONS: The current work revealed the significant beneficial role of moderate physical activity against diabetes development, potentially through attenuating oxidative stress. PMID- 29128921 TI - A microfluidic in-line ELISA for measuring secreted protein under perfusion. AB - Recent progress in the development of microfluidic microphysiological systems such as 'organs-on-chips' and microfabricated cell culture is geared to simulate organ-level physiology. These tissue models leverage microengineering technologies that provide capabilities of presenting cultured cells with input signals in a more physiologically relevant context such as perfused flow. Proteins that are secreted from cells have important information about the health of the cells. Techniques to quantify cellular proteins include mass spectrometry to ELISA (enzyme-linked immunosorbent assay). Although our capability to perturb the cells in the microphysiological systems with varying inputs is well established, we lack the tools to monitor in-line the cellular responses. User intervention for sample collection and off-site is cumbersome, causes delays in obtaining results, and is especially expensive because of collection, storage, and offline processing of the samples, and in many case, technically impractical to carry out because of limitated sample volumes. To address these shortcomings, we report the development of an ELISA that is carried out in-line under perfusion within a microfluidic device. Using this assay, we measured the albumin secreted from perfused hepatocytes without and under stimulation by IL-6. Since the method is based on a sandwich ELISA, we envision broad application of this technology to not just organs-on-chips but also to characterizing the temporal release and measurement of soluble factors and response to drugs. PMID- 29128922 TI - Causes of renal oligohydramnios: impact on prenatal counseling and postnatal outcome. AB - The presence of renal oligohydramnios (ROH) in a fetus has been associated in the past with a poor prognosis for survival, although recent studies have shown that survival has improved considerably due to the advances in neonatology and pediatric nephrology. In an article recently published in Pediatric Nephrology, evaluation of a large series by Mehler and colleagues confirms the improved prognosis, showing a survival rate of 32 of 38 (84%). In addition, only 12 of 35 (34%) neonates required renal replacement therapy. In five of these 12 children the dialysis could be terminated after the neonatal period. This study has important implications on the decision-making process and counseling of families. While 37% of families of the study opted for termination of pregnancies, palliative care was chosen by 8% of the families, representing an important option when a decision cannot be made rapidly by affected families. A multidisciplinary approach is not only necessary in the active treatment of neonates with a history of ROH but also in antenatal counseling. In this regard future efforts should establish consensus on an ethical framework for the decision-making process in ROH. PMID- 29128924 TI - Correction to: An appraisal of critical effect sizes for the benchmark dose approach to assess dose-response relationships in genetic toxicology. AB - In the original publication, Table 1 was incorrect (differences in the numerators of the fractions). The correct version of Table 1 (sums in the numerators) is given below. PMID- 29128923 TI - Fluid overload independent of acute kidney injury predicts poor outcomes in neonates following congenital heart surgery. AB - BACKGROUND: Fluid overload (FO) is common after neonatal congenital heart surgery and may contribute to mortality and morbidity. It is unclear if the effects of FO are independent of acute kidney injury (AKI). METHODS: This was a retrospective cohort study which examined neonates (age < 30 days) who underwent cardiopulmonary bypass in a university-affiliated children's hospital between 20 October 2010 and 31 December 2012. Demographic information, risk adjustment for congenital heart surgery score, surgery type, cardiopulmonary bypass time, cross clamp time, and vasoactive inotrope score were recorded. FO [(fluid in-out)/pre operative weight] and AKI defined by Kidney Disease Improving Global Outcomes serum creatinine criteria were calculated. Outcomes were all-cause, in-hospital mortality and median postoperative hospital and intensive care unit lengths of stay. RESULTS: Overall, 167 neonates underwent cardiac surgery using cardiopulmonary bypass in the study period, of whom 117 met the inclusion criteria. Of the 117 neonates included in the study, 76 (65%) patients developed significant FO (>10%), and 25 (21%) developed AKI >= Stage 2. When analyzed as FO cohorts (< 10%,10-20%, > 20% FO), patients with greater FO were more likely to have AKI (9.8 vs. 18.2 vs. 52.4%, respectively, with AKI >= stage 2; p = 0.013) and a higher vasoactive-inotrope score, and be premature. In the multivariable regression analyses of patients without AKI, FO was independently associated with hospital and intensive care unit lengths of stay [0.322 extra days (p = 0.029) and 0.468 extra days (p < 0.001), respectively, per 1% FO increase). In all patients, FO was also associated with mortality [odds ratio 1.058 (5.8% greater odds of mortality per 1% FO increase); 95% confidence interval 1.008,1.125;p = 0.032]. CONCLUSIONS: Fluid overload is an important independent contributor to outcomes in neonates following congenital heart surgery. Careful fluid management after cardiac surgery in neonates with and without AKI is warranted. PMID- 29128925 TI - Transcriptome profile analysis reveals cardiotoxicity of maduramicin in primary chicken myocardial cells. AB - Maduramicin, an excellent ionophore antibiotic, is extensively used to control coccidiosis in poultry. Numerous maduramicin intoxications have been reported in farm animal and human due to its relatively narrow safety range, with necrosis or degeneration of cardiac and skeletal muscles as hallmark. To date, the mechanisms of maduramicin-induced cardiotoxicity remain unclear in chicken and other animals. Maduramicin (5 ug/mL)-treated primary chicken myocardial cells were used for RNA sequencing (RNA-Seq) and bioinformatics analysis in this study. A total of 1442 differential expressed genes were identified. 810 genes were up-regulated and the rest 632 genes were down-regulated. Transcriptome analysis revealed that the cytokine-cytokine receptor interaction, apoptosis, calcium signal and cytoplasmic vacuolization pathways were significantly affected. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis showed that gene expression patterns were consistent with RNA-Seq analysis. Pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin-8 (IL 8), apoptosis ratios, cleaved caspase-3, intracellular calcium level and Ca2+ ATPase activity were elevated after maduramicin (0.05, 0.5 and 5 ug/mL) treatment. Massive vacuole formation was found in the cytoplasm by morphology and transmission electron microscopy observation. Taken together, the results suggested that maduramicin exerted its cardiotoxicity by multiple molecular mechanisms in primary chicken myocardial cells. PMID- 29128926 TI - Helminth infections in a pair of sympatric congeneric lizard species. AB - We analyzed parameters of parasitism by helminths in a pair of sympatric congeneric lizard species (Tropidurus hispidus and Tropidurus semitaeniatus). Differences in their supracommunities (richness, composition, and abundance) and the influence of helminthic loads on minimum flight initiation distances and body temperatures were evaluated. We reported new findings of Piratuba digiticauda infecting T. hispidus and Oochoristica bresslaui infecting T. semitaeniatus. Parapharyngodon alvarengai was the most abundant helminth in both host species. Tropidurus hispidus individuals hosted a higher abundance and richness of helminths than T. semitaeniatus, with females of the former having larger helminthic loads than males. Dissimilarities between host species may be attributed to differences in their utilization of niche dimensions (time, food, and structural and thermal space), the occurrence of morphological differences that result in differential exposure to the sources and agents of infection, and/or differential immunological functions. Our data suggests that infection by P. alvarengai led to some limitations in locomotor performance of T. hispidus resulting in decreased minimum flight initiation distance as infection rates increased. Individuals opted for a prolonged period of immobility to avoid capture. There was a negative relationship between helminthic loads and body temperatures in T. semitaeniatus, possibly due to decreased activity and thermoregulation rates, and increased use of shelters by lizards with high infection levels to avoid predation. PMID- 29128927 TI - Toll-like receptors participate in Naegleria fowleri recognition. AB - Naegleria fowleri is a protozoan that invades the central nervous system and causes primary amoebic meningoencephalitis. It has been reported that N. fowleri induces an important inflammatory response during the infection. In the present study, we evaluated the roles of Toll-like receptors in the recognition of N. fowleri trophozoites by human mucoepithelial cells, analyzing the expression and production of innate immune response mediators. After amoebic interactions with NCI-H292 cells, the expression and production levels of IL-8, TNF-alpha, IL 1beta, and human beta defensin-2 were evaluated by RT-PCR, ELISA, immunofluorescence, and dot blot assays, respectively. To determine whether the canonical signaling pathways were engaged, we used different inhibitors, namely, IMG-2005 for MyD88 and BAY 11-7085 for the nuclear factor NFkB. Our results showed that the expression and production of the pro-inflammatory cytokines and beta defensin-2 were induced by N. fowleri mainly through the canonical TLR4 pathway in a time-dependent manner. PMID- 29128928 TI - Serum neuron specific enolase may be a marker to predict the severity and outcome of cerebral venous thrombosis. AB - The objective is to explore the effective of baseline serum neuron specific enolase (NSE) on predicting the severity and outcome in patients with cerebral venous thrombosis (CVT). A total of 156 patients confirmed as CVT in Xuanwu Hospital were enrolled in this retrospective study from March 2011 through September 2016. The severity was evaluated with the National Institutes of Health Stroke Score (NIHSS), intracranial pressure (ICP), and CVT-related complications; the outcome was evaluated by modified Rankin Scale (mRS); the relationship between baseline serum NSE and mRS was analyzed with receiver operating characteristic curve (ROC), logistic regression analysis, and Kaplan-Meier curves. Baseline level of serum NSE was positively associated with baseline NIHSS (r = 0.322, p < 0.001). Among which, patients with high level of serum NSE were also noticed with cerebral venous infarction (p < 0.001), intracranial hemorrhage (p < 0.001), seizure (p = 0.035). Meanwhile, patients in NSE >= 15.05 ng/mL group vs. NSE < 15.05 ng/mL group had large mRS scores (>= 3) at discharge (adjusted OR: 5.40, 95% CI 1.27-22.91; p = 0.022) and higher percentage of mRS scores >= 3 during 40 months of outpatient follow-up (log-rank p < 0.001). Baseline level of serum NSE is positively associated with the severity of CVT. Presumably NSE may be a potential predictor for the clinical outcome of CVT. PMID- 29128929 TI - Freezing of gait in Parkinson's disease: gray and white matter abnormalities. AB - Freezing of gait (FOG) is a disabling disorder that often affects Parkinson's disease (PD) patients in advanced stages of the disease. To study structural gray matter (GM) and white matter (WM) changes in PD patients with and without FOG, twenty-one PD patients with FOG (PD-FOG), 16 PD patients without FOG (PD-nFOG) and 19 healthy subjects (HS) underwent a standardized MRI protocol. For the gray matter evaluation, cortical volume (CV), cortical thickness (CTh), and surface area (SA) were analyzed using the FreeSurfer pipeline. For the white matter evaluation, DTI images were analyzed using tracts constrained by underlying anatomy (TRACULA) toolbox in FreeSurfer. PD-FOG patients exhibited lower CTh than HS in the mesial surface of both cerebral hemispheres, including the superior frontal gyrus, paracentral lobule, posterior cingulate cortex, precuneus and pericalcarine cortex, and in the right dorsolateral prefrontal cortex. Moreover, significant WM changes were observed in PD-FOG patients in comparison with HS in the superior longitudinal fasciculus, uncinate fasciculus, cingulum cingulate gyrus and inferior longitudinal fasciculus (prevalently in the right hemisphere) and in the frontal radiations of the corpus callosum. DTI abnormalities in specific WM bundles correlated significantly with cognitive measures. The damage of multiple cortical areas involved in high-level gait control together with WM disruption between motor, cognitive and limbic structures may represent the anatomical correlate of FOG. PMID- 29128930 TI - Prognostic value of amyloid PET scan in normal pressure hydrocephalus. AB - Amyloid positron emission tomography ([18F] florbetaben (FBB) PET) can be used to determine concomitant Alzheimer's disease (AD) in idiopathic normal pressure hydrocephalus (iNPH) patients. FBB PET scans and the tap test were performed in 31 patients with clinically suspected iNPH, and amyloid positive (iNPH/FBB+) and negative (iNPH/FBB-) groups were compared with respect to clinical characteristics. We evaluated prognostic value of FBB PET scans by analyzing the response to the tap test using a linear mixed model. We also performed a multivariable regression analysis to investigate whether amyloid PET positivity can predict the positive tap test response independent of other AD biomarkers. The results showed that the iNPH/FBB+ group (7/31, 22.6%) had a higher percentage of APOE4 carriers, lower Abeta42, higher CSF t-tau, and p-tau/Abeta42 ratio than the iNPH/FBB- group (24/31, 77.4%), while the two groups did not differ in imaging characteristics. The iNPH/FBB- group had a higher percentage of tap responders and showed a greater improvement in gait scores after the tap test than the iNPH/FBB+ group (group-tap test effect interaction, p = 0.035). A multivariable logistic regression analysis showed that amyloid positivity on PET scans (OR 0.03, p = 0.029) and CSF p-tau (OR 0.87, p = 0.044) were independently associated with the positive tap test response. Among 21 tap responders in the iNPH/FBB- group, 14 patients received shunt surgery and 12/14 (85.7%) patients showed symptom improvement. Our findings suggest that amyloid PET scans can help determine which iNPH patients will benefit from shunt surgery by discriminating concomitant AD. PMID- 29128931 TI - Universal determination of microsatellite instability using BAT26 as a single marker in an Argentine colorectal cancer cohort. AB - Microsatellite instability (MSI) is a hallmark tool for Lynch syndrome (LS) screening and a prognostic marker for sporadic colorectal cancer (CRC). In regions with limited resources and scarce CRC molecular characterization as South America, the implementation of universal MSI screening is under debate for both its purposes. We sought to estimate the frequency of BAT26 in colorectal adenocarcinomas and to determine associated clinical and histological features. Consecutive patients from a CRC registry were included. BAT26 determination was performed in all cases; if instability was found, immunohistochemistry (IHC) and BRAF mutation analyses were done, as appropriate. Differences were assessed by chi-squared or Fisher's exact test, or by T test or Mann-Whitney. Multiple logistic regression was used to identify factors independently associated with BAT26-unstable tumors. We included 155 patients; mean age was 65.6 (SD 14.4) and 56.1% were male. The frequency of BAT26-unstable tumors was 22% (95% CI 15.7 29.3). Factors independently associated with BAT26-unstable tumors were right colon localization (OR 3.4, 95% CI 1.3-8.7), histological MSI features (OR 5.1, 95% CI 1.9-13.6) and Amsterdam criteria (OR 23.2, 95% CI 1.9-286.7). IHC was altered in 85.3% BAT26-unstable tumors and 70.6% lacked MLH1 expression; 47.8% of these harbored BRAF V600E mutation. We provide evidence to link the frequency of BAT26 to an increased diagnostic yield (up to 1.4-folds) of suspected LS cases in comparison to the revised Bethesda guidelines alone. In regions with limited resources, clinical and histological features associated with BAT26-unstable status could be useful to direct MSI screening in sporadic CRCs and may help guide clinical care and future research. PMID- 29128932 TI - Atomic Force Microscopy: A Promising Tool for Deciphering the Pathogenic Mechanisms of Fungi in Cystic Fibrosis. AB - During the past decades, atomic force microscopy (AFM) has emerged as a powerful tool in microbiology. Although most of the works concerned bacteria, AFM also permitted major breakthroughs in the understanding of physiology and pathogenic mechanisms of some fungal species associated with cystic fibrosis. Complementary to electron microscopies, AFM offers unprecedented insights to visualize the cell wall architecture and components through three-dimensional imaging with nanometer resolution and to follow their dynamic changes during cell growth and division or following the exposure to drugs and chemicals. Besides imaging, force spectroscopy with piconewton sensitivity provides a direct means to decipher the forces governing cell-cell and cell-substrate interactions, but also to quantify specific and non-specific interactions between cell surface components at the single-molecule level. This nanotool explores new ways for a better understanding of the structures and functions of the cell surface components and therefore may be useful to elucidate the role of these components in the host-pathogen interactions as well as in the complex interplay between bacteria and fungi in the lung microbiome. PMID- 29128933 TI - Proven Invasive Pulmonary Aspergillosis in Stem Cell Transplant Recipient Due to Aspergillus sublatus, a Cryptic Species of A. nidulans. AB - Invasive fungal disease represents one of the severe complications in haematopoietic stem cell transplant recipients. We describe a case of a patient treated for relapse of chronic lymphoblastic leukaemia 6 years after HSCT. The patient was treated for invasive pulmonary aspergillosis but died 3 months later from multiple organ failures consisting of haemorrhagic necrotizing fungal pneumonia, refractory chronic hepatic graft versus host disease and cytomegalovirus hepatitis. Autopsy samples revealed histopathological evidence of fungal hyphae and an unusual Aspergillus nidulans-like species was isolated in pure culture. More precise identification was achieved by using scanning electron microscopy of ascospores and sequencing of calmodulin gene, and the isolate was subsequently re-identified as A. sublatus (section Nidulantes) and showed good in vitro susceptibility against all classes of antifungals. Commonly used ITS rDNA region and beta-tubulin gene fail to discriminate A. sublatus from related pathogenic species, especially A. quadrilineatus and A. nidulans. Although this is the first case of proven IPA attributed to A. sublatus, we demonstrated that at least some previously reported infections due to A. quadrilineatus were probably caused by this cryptic species. PMID- 29128934 TI - Radiobiological analysis of stereotactic body radiation therapy for an evidence based planning target volume of the lung using multiphase CT images obtained with a pneumatic abdominal compression apparatus: a case study. AB - This study evaluated the efficiency of stereotactic body radiation therapy of lung (SBRT-Lung) in generating a treatment volume using conventional multiple phase three-dimensional computed tomography (3D-CT) of a patient immobilized with pneumatic abdominal compression. The institutional protocol for SBRT-Lung using the RapidArc technique relied on a planning target volume (PTV) delineated using 3D-CT and accounted for linear and angular displacement of the tumor during respiratory movements. The efficiency of the institutional protocol was compared with that of a conventional method for PTV delineation based on radiobiological estimates, such as tumor control probability (TCP) and normal tissue complication probability (NTCP), evaluated using dose-volume parameters. Pneumatic abdominal compression improved the TCP by 15%. This novel protocol improved the TCP by 0.5% but reduced the NTCP for lung pneumonitis (0.2%) and rib fracture (1.0%). Beyond the observed variations in the patient's treatment setup, the institutional protocol yielded a significantly consistent TCP (p < 0.005). The successful clinical outcome of this case study corroborates predictions based on radiobiological evaluation and deserves validation through an increased number of patients. PMID- 29128935 TI - Associations between birthweight, gestational age at birth and subsequent type 1 diabetes in children under 12: a retrospective cohort study in England, 1998 2012. AB - AIMS/HYPOTHESIS: With genetics thought to explain only 40-50% of the total risk of type 1 diabetes, environmental risk factors in early life have been proposed. Previous findings from studies of type 1 diabetes incidence by birthweight and gestational age at birth have been inconsistent. This study aimed to investigate the relationships between birthweight, gestational age at birth and subsequent type 1 diabetes in England. METHODS: Data were obtained from a population-based database comprising linked mother-infant pairs using English national Hospital Episode Statistics from 1998 to 2012. In total, 3,834,405 children, categorised by birthweight and gestational age at birth, were followed up through record linkage to compare their incidence of type 1 diabetes through calculation of multivariable-adjusted HRs. RESULTS: Out of 3,834,405 children, 2969 had a subsequent hospital diagnosis of type 1 diabetes in childhood. Children born preterm (<37 weeks) or early term (37-38 weeks) experienced significantly higher incidence of type 1 diabetes than full term children (39-40 weeks) (HR 1.19 [95% CI 1.03, 1.38] and 1.27 [95% CI 1.16, 1.39], respectively). Children born at higher than average birthweight (3500-3999 g or 4000-5499 g) after controlling for gestational age experienced higher incidence of type 1 diabetes than children born at medium birthweight (3000-3499 g) (HR 1.13 [95% CI 1.03, 1.23] and 1.16 [95% CI 1.02, 1.31], respectively), while children at low birthweight (<2500 g) experienced lower incidence (0.81 [95% CI 0.67, 0.98]), signifying a statistically significant trend (p trend 0.001). CONCLUSIONS/INTERPRETATION: High birthweight for gestational age and low gestational age at birth are both independently associated with subsequent type 1 diabetes. These findings help contextualise the debate about the potential role of gestational and early life environmental risk factors in the pathogenesis of type 1 diabetes, including the potential roles of insulin sensitivity and gut microbiota. PMID- 29128936 TI - Hospital time prior to death and pancreas histopathology: implications for future studies. AB - AIMS/HYPOTHESIS: Diabetes research studies routinely rely upon the use of tissue samples from human organ donors. It remains unclear whether the length of hospital stay prior to organ donation affects the presence of cells infiltrating the pancreas or the frequency of replicating beta cells. METHODS: To address this, 39 organ donors without diabetes were matched for age, sex, BMI and ethnicity in groups of three. Within each group, donors varied by length of hospital stay immediately prior to organ donation (<3 days, 3 to <6 days, or >=6 days). Serial sections from tissue blocks in the pancreas head, body and tail regions were immunohistochemically double stained for insulin and CD45, CD68, or Ki67. Slides were electronically scanned and quantitatively analysed for cell positivity. RESULTS: No differences in CD45+, CD68+, insulin+, Ki67+ or Ki67+/insulin+ cell frequencies were found when donors were grouped according to duration of hospital stay. Likewise, no interactions were observed between hospitalisation group and pancreas region, age, or both; however, with Ki67 staining, cell frequencies were greater in the body vs the tail region of the pancreas (? 0.65 [unadjusted 95% CI 0.25, 1.04]; p = 0.002) from donors <12 year of age. Interestingly, frequencies were less in the body vs tail region of the pancreas for both CD45+ cells (? -0.91 [95% CI -1.71, -0.10]; p = 0.024) and insulin+ cells (? -0.72 [95% CI -1.10, -0.34]; p < 0.001). CONCLUSIONS/INTERPRETATION: This study suggests that immune or replicating beta cell frequencies are not affected by the length of hospital stay prior to donor death in pancreases used for research. DATA AVAILABILITY: All referenced macros (adopted and developed), calculations, programming code and numerical dataset files (including individual-level donor data) are freely available on GitHub through Zenodo at https://doi.org/10.5281/zenodo.1034422. PMID- 29128937 TI - Epigenetics in diabetic nephropathy, immunity and metabolism. AB - When it comes to the epigenome, there is a fine line between clarity and confusion-walk that line and you will discover another fascinating level of transcription control. With the genetic code representing the cornerstone of rules for information that is encoded to proteins somewhere above the genome level there is a set of rules by which chemical information is also read. These epigenetic modifications show a different side of the genetic code that is diverse and regulated, hence modifying genetic transcription transiently, ranging from short- to long-term alterations. While this complexity brings exquisite control it also poses a formidable challenge to efforts to decode mechanisms underlying complex disease. Recent technological and computational advances have improved unbiased acquisition of epigenomic patterns to improve our understanding of the complex chromatin landscape. Key to resolving distinct chromatin signatures of diabetic complications is the identification of the true physiological targets of regulatory proteins, such as reader proteins that recognise, writer proteins that deposit and eraser proteins that remove specific chemical moieties. But how might a diverse group of proteins regulate the diabetic landscape from an epigenomic perspective? Drawing from an ever-expanding compendium of experimental and clinical studies, this review details the current state-of-play and provides a perspective of chromatin-dependent mechanisms implicated in diabetic complications, with a special focus on diabetic nephropathy. We hypothesise a codified signature of the diabetic epigenome and provide examples of prime candidates for chemical modification. As for the pharmacological control of epigenetic marks, we explore future strategies to expedite and refine the search for clinically relevant discoveries. We also consider the challenges associated with therapeutic strategies targeting epigenetic pathways. PMID- 29128941 TI - Measurements of Sexuality-Based Stigma among Gay, Bisexual, and Other Men Who Have Sex with Men (GBMSM) in Resource-Poor Settings: A Review. AB - Gay, bisexual, and other men who have sex with men (GBMSM) in resource-poor settings are disproportionately affected by the HIV/AIDS epidemic. GBMSM living in these settings may face unique barriers to HIV prevention, including legal barriers and increased sexuality-based stigma. It is therefore imperative to tailor HIV prevention and care resources to recognize the lived realities of GBMSM in these settings. Central to this is the accurate measurement of sexuality based stigma. However, there is wide inconsistency in how sexuality-based stigma is measured among GBMSM in resource-poor settings. This paper reviews recent studies of sexuality-based stigma among GBMSM in resource-poor settings, finding great variability in measurements. The results of the review call for greater attention to the development of contextually and culturally specific measures of sexuality-based stigma for GBMSM living in resource-poor settings. PMID- 29128939 TI - Ultra-shortened time-domain HRV parameters at rest and following exercise in athletes: an alternative to frequency computation of sympathovagal balance. AB - PURPOSE: The primary purpose of this study was to determine the accuracy of the standard deviation of normal-to-normal intervals (SDNN) to root mean square of successive normal-to-normal interval differences (RMSSD) ratio from 1-min recordings (SDNN:RMSSD1-min) compared to criterion recordings, as well as its relationship to low-frequency-to-high-frequency ratio (LF:HF) at rest and following maximal exercise in a group of collegiate athletes. METHOD: Twenty athletes participated in the study. Heart rate variability (HRV) data were measured for 5 min before and at 5-10 and 25-30 min following a maximal exercise test. From each 5-min segment, the frequency-domain measures of HF, LF, and LF:HF ratio were analyzed. Time-domain measures of SDNN, RMSSD, and SDNN:RMSSD ratio were also analyzed from each 5-min segment, as well as from randomly selected 1 min recordings. RESULT: The 1-min values of SDNN, RMSSD, and SDNN:RMSSD provided no significant differences and nearly perfect intra-class correlations (ICCs ranged from 0.97 to 1.00, p < 0.001 for all) to the criterion measures from 5-min recordings. In addition, SDNN, RMSSD, and SDNN:RMSSD from the 1-min segments provided very large to nearly perfect correlations (r values ranged from 0.71 to 0.97, p < 0.001 for all) to LF, HF, and LF:HF, respectively, at each time point. CONCLUSION: The findings of the study suggest that ultra-shortened time-domain markers may be useful surrogates of the frequency-domain parameters for tracking changes in sympathovagal activity in athletes. PMID- 29128942 TI - Editorial for innovative clinical investigations: example of a framework for determining the stages of innovation in surgery or other interventional procedures. PMID- 29128938 TI - Liver fibrosis: noninvasive assessment using supersonic shear imaging and FIB4 index in patients with non-alcoholic fatty liver disease. AB - PURPOSE: Shear wave elastography (SWE) has been validated in chronic hepatitis C and B; however, limited data are available in non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the accuracy of SWE and FIB4 index for the diagnosis of fibrosis in a cohort of consecutive patients with biopsy-proven NAFLD, and to evaluate the effects of other histologic parameters on SWE measurement. METHODS: Written informed consent was obtained from all patients, and this study was approved by our internal review board and ethics committee. Seventy-one patients with histologically proven NAFLD (mean age 50.8 years +/- 15.7) were examined. All patients underwent SWE (AixplorerTM; SuperSonic Imagine) and FIB4 index (based on age, aspartate aminotransferase and alanine aminotransferase levels, and platelet counts) measurements. SWE measurements were compared with the histologic features based on the NAFLD activity score and FIB4 index. RESULTS: The area under the ROC curve for the diagnosis of hepatic fibrosis stage 3 or higher was 0.821 (optimal cut-off value 13.1 kPa, sensitivity 62.5%, specificity 57.4%) for SWE and 0.822 (optimal cut-off value 1.41, sensitivity 71.9%, specificity 53.9%) for FIB4 index. The median liver stiffness values measured using SWE showed a stepwise increase with increasing hepatic fibrosis stage (P < 0.001), inflammation score (P = 0.018), and ballooning score (P < 0.001), and showed a stepwise decrease with increasing hepatic steatosis stage (P = 0.046). CONCLUSIONS: SWE and FIB4 index are useful noninvasive tools for estimating the severity of fibrosis in NAFLD patients. However, the presence of severe steatosis may affect the liver stiffness measurement, resulting in underestimations of liver fibrosis. PMID- 29128944 TI - Health risk assessment of instant noodles commonly consumed in Port Harcourt, Nigeria. AB - The current study investigated the levels of some heavy metals [lead (Pb), arsenic (As), nickel (Ni), mercury (Hg), copper (Cu), cadmium (Cd), aluminum (Al), and chromium (Cr)] and polycyclic aromatic hydrocarbons (PAHs) in six brands of instant noodles (CFN, GFC, NGP, GAA, CUN, and FCS) commonly consumed in Port Harcourt, Nigeria. Risks of consumption of contaminated noodles were also assessed. Heavy metal content and PAHs were determined using flame atomic absorption spectrophotometer and gas chromatography, respectively. Concentrations of heavy metals as Pb, Ni, Cu, Al, and Cr were detected while As, Hg, and Cd were not detected in noodles. High average concentrations (mean +/- SD mg/kg) of Pb were observed in brands CFN (3.163 +/- 0.21) and GFC (1.022 +/- 0.08) which were significantly higher (P <= 0.05) than in NGP (0.043 +/- 0.15) and GAA (0.276 +/- 0.18), although all were above WHO permissible limits (0.025 mg/kg). Target Hazard Quotient and Hazard Index for Pb were > 1 in brands CFN and GFC indicating unacceptable risk. Results of PAHs showed brands had total PAHs (mg/kg) in the order CFN > CUN > GAA > NGP > FCS > GFC. Although carcinogenic risks associated with these noodles are within permissible range, consumption of CFN and GFC could pose greater health risk to consumers. Long-term consumption of brands CUN, CFN, and GAA may have higher probability of carcinogenesis among consumers. We therefore recommend more diligent regulatory policies and monitoring by relevant government agencies (WHO, NAFDAC, CPC, and SON) to ensure wholesome noodles get to consumers. PMID- 29128943 TI - Effects of biochar on phytotoxicity and translocation of polybrominated diphenyl ethers in Ni/Fe bimetallic nanoparticle-treated soil. AB - In this study, soil culture experiments were conducted to explore the effects of biochar-supported Ni/Fe nanoparticles on the accumulation and translocation of polybrominated diphenyl ethers (PBDEs) in soil-plant system and its phytotoxicity to Brassica chinensis. Compared with those in BDE209 contaminated soils (S 1) and Ni/Fe nanoparticle-treated soil (S 3), the plant biomass, root, and shoot lengths in biochar-supported Ni/Fe nanoparticle-treated soil (S 4) were increased by 23 mg, 1.35 cm, and 2.08 cm and 27.2 mg, 1.75 cm, and 2.52 cm, respectively, suggesting that the phytotoxicity in S 4 treatment was significantly decreased. Moreover, in all treatments, the contents of BDE209, the total PBDEs, Ni, and Fe in sample plant tissues of S 4 were the lowest. In addition, the superoxide dismutase, peroxidase, and catalase activities in S 4 treatment were found to decrease by 33.8, 47.2, and 24.1%, respectively, compared to those in S 3. Results also showed that biochar addition not only reduced the uptake of PBDEs and heavy metals but also effectively improve soil fertility and reduce the leachability of Ni and Fe caused by Ni/Fe. Finally, the translocation factors (TFs) of PBDEs in four treatments followed the orders as S 1 > S 3 > S 4 > S 2, indicating that biochar has an inhibition effects on PBDE translocation in the plants. In summary, all of the results suggested that the phytotoxicity, translocation of PBDEs, and the negative effects caused by neat Ni/Fe nanoparticles in B. chinensis were decreased as a result of the effects of the biochar. PMID- 29128945 TI - Malathion-induced spermatozoal oxidative damage and alterations in sperm quality of endangered trout Salmo coruhensis. AB - The use of pesticides has been increased along with increasing the farming activities and has caused environmental impacts deleteriously. In particular, non target organisms including fish can be affected by toxic effects of pesticides. Therefore, the impacts of malathion (MTN) on oxidative stress and sperm quality were investigated in vitro. The MTN concentrations used on this study were 0 (control), 75, 100, and 125 MUg/L. Lipid peroxidation (MDA), non-enzymatic (GSH), and enzymatic (SOD, GSH-Px, and CAT) activities in spermatozoa were examined for determination of oxidative stress status. Our findings showed that motility rate and period of sperm cells significantly decreased with exposure to MTN. Biochemical assays revealed that CAT activity and levels of MDA, GSH increased in spermatozoa based on concentration while activity of GSH-Px and SOD decreased. Consequently, spermatozoa were highly sensitive to MTN exposure. MTN has disruptive effects on sperm quality and caused to oxidative stress in spermatozoa. PMID- 29128946 TI - Microscopy in addition to chemical analyses and ecotoxicological assays for the environmental hazard assessment of coal tar-polluted soils. AB - Chemical analysis of soils contaminated with coal tar indicated that most organic compounds, and particularly PAHs, were contained in coarser particles (> 200 MUm). Microscopic observations of this fraction, carried out on polished sections, reported the presence of organic particles in addition to mineral particles. Some organic particles had a very low porosity, and their microstructure did not evolve during biotreatment. Alternatively, other organic particles had a large porosity composed of an interconnected pore network that was open to coal tar surface and thus in contact with soil water. Interconnected porosity seemed to increase during biotreatment in relation to a decrease in the amount of organic compounds. The amount of open porosity in contact with soil water was expected to increase the desorption rate of PAHs. Consequently, the environmental hazard could depend on the amount of open porosity in addition to chemical properties of organic particles, such as their concentration in PAHs. Thus, microscopy can be complementary to chemical analysis and ecotoxicological assays to assess the best strategy for remediation but also to follow the advancement of a biotreatment. PMID- 29128947 TI - T2*-based MR imaging (gradient echo or susceptibility-weighted imaging) in midline and off-midline intracranial germ cell tumors: a pilot study. AB - PURPOSE: The role of T2*-based MR imaging in intracranial germ cell tumors (GCTs) has not been fully elucidated. The aim of this study was to evaluate the susceptibility-weighted imaging (SWI) or T2* gradient echo (GRE) features of germinomas and non-germinomatous germ cell tumors (NGGCTs) in midline and off midline locations. METHODS: We retrospectively evaluated all consecutive pediatric patients referred to our institution between 2005 and 2016, for newly diagnosed, treatment-naive intracranial GCT, who underwent MRI, including T2* based MR imaging (T2* GRE sequences or SWI). Standard pre- and post-contrast T1- and T2-weighted imaging characteristics along with T2*-based MR imaging features of all lesions were evaluated. Diagnosis was performed in accordance with the SIOP CNS GCT protocol criteria. RESULTS: Twenty-four subjects met the inclusion criteria (17 males and 7 females). There were 17 patients with germinomas, including 5 basal ganglia primaries, and 7 patients with secreting NGGCT. All off midline germinomas presented with SWI or GRE hypointensity; among midline GCT, all NGGCTs showed SWI or GRE hypointensity whereas all but one pure germinoma were isointense or hyperintense to normal parenchyma. A significant difference emerged on T2*-based MR imaging among midline germinomas, NGGCTs, and off-midline germinomas (p < 0.001). CONCLUSION: Assessment of the SWI or GRE characteristics of intracranial GCT may potentially assist in differentiating pure germinomas from NGGCT and in the characterization of basal ganglia involvement. T2*-based MR imaging is recommended in case of suspected intracranial GCT. PMID- 29128948 TI - A Dramatic Case of Odynophagia. AB - We report the case of a 77-year-old male with a history of aortic stenosis and interstitial lung disease, who debuted 3 years ago with an outbreak of necrotic and very painful canker sores. The severity of the lesions and their refractory response to treatment led to several hospital admissions and multiple consultations to different specialists (ENT, rheumatology, dermatology, ophthalmology, cardiology, and internal medicine). During this time, the patient received central parenteral nutrition with an episode of catheter-related septicemia, and he came to require psychiatric assistance for autolytic ideation. Numerous diagnostic tests were performed with inconclusive results, including biopsy of the lesion (histological study, immunohistochemistry for CD68 + , CD4 + , CD8 + , CD20 + , MCT +, and cytomegalovirus, PAS, Grocott-Gomori and Zielh Neelsen staining, and in situ hybridization for Epstein Barr virus). Numerous treatments were unsuccessfully tested until thalidomide was administered, thus completely remitting lesions but leaving retractable scarring sequelae. Since then, the patient has had two recurrences, coinciding with the reduction of thalidomide dosages, which were controlled by increasing the dose of the immunomodulator. Recurrent necrotizing major aphthous stomatitis (Sutton's disease) is a clinical variant of recurrent aphthous stomatitis that may have a dramatic course. Unfortunately, the lack of etiopathogenetic uniformity precludes any specific treatment. In severe cases, immunomodulators, including thalidomide, may represent a valid therapeutic option. PMID- 29128949 TI - ElVisML: an open data format for the exchange and storage of electrophysiological data in ophthalmology. AB - PURPOSE: The ISCEV standards and recommendations for electrophysiological recordings in ophthalmology define a set of protocols with stimulus parameters, acquisition settings, and recording conditions, to unify the data and enable comparability of results across centers. Up to now, however, there are no standards to define the storage and exchange of such electrophysiological recordings. The aim of this study was to develop an open standard data format for the exchange and storage of visual electrophysiological data (ElVisML). METHODS: We first surveyed existing data formats for biomedical signals and examined their suitability for electrophysiological data in ophthalmology. We then compared the suitability of text-based and binary formats, as well as encoding in Extensible Markup Language (XML) and character/comma-separated values. RESULTS: The results of the methodological consideration led to the development of ElVisML with an XML encoded text-based format. This allows referential integrity, extensibility, the storing of accompanying units, as well as ensuring confidentiality and integrity of the data. A visualization of ElVisML documents (ElVisWeb) has additionally been developed, which facilitates the exchange of recordings on mailing lists and allows open access to data along with published articles. CONCLUSIONS: The open data format ElVisML ensures the quality, validity, and integrity of electrophysiological data transmission and storage as well as providing manufacturer-independent access and long-term archiving in a future-proof format. Standardization of the format of such neurophysiology data would promote the development of new techniques and open software for the use of neurophysiological data in both clinic and research. PMID- 29128950 TI - Response to "Colonic-Type Adenocarcinoma of the Tongue and Oral Cavity (CATOC)". PMID- 29128951 TI - Insights from the Genomes of Microbes Thriving in Uranium-Enriched Sediments. AB - Elevated uranium dose (4 g kg-1) causes a shift in billabong sediment communities that result in the enrichment of five bacterial species. These taxa include Geobacter, Geothrix and Dyella species, as well as a novel-potentially predatory Bacteroidetes species, and a new member of class Anaerolineae (Chloroflexi). Additionally, a population of methanogenic Methanocella species was also identified. Genomic reconstruction and metabolic examination of these taxa reveal a host of divergent life strategies and putative niche partitioning. Resistance nodulation-division heavy metal efflux (RND-HME) transporters are implicated as potential uranium tolerance strategies among the bacterial taxa. Potential interactions, uranium tolerance and ecologically relevant catabolism are presented in a conceptual model of life in this environment. PMID- 29128952 TI - Effects of acupuncture on cancer-related fatigue: a meta-analysis. AB - PURPOSE: This study was designed to critically evaluate the effect of acupuncture on cancer-related fatigue (CRF). METHODS: Seven databases (Cochrane Library, Embase, Medline, Web of Science, CBM, Wanfang, and CNKI) were systematically reviewed from inception to November 2016 for randomized controlled trials (RCTs). Two reviewers critically and independently assessed the risk of bias using Cochrane Collaboration criteria and extracted correlated data using the designed form. All analyses were performed with Review Manager 5. RESULTS: Ten RCTs, including 1327 patients (acupuncture, 733; control, 594), meeting the inclusion criteria for the meta-analysis were identified. Acupuncture had a marked effect on fatigue in cancer patients, regardless of concurrent anti-cancer treatment, particularly among breast cancer patients. The meta-analysis also indicated that acupuncture could significantly mitigate CRF compared with sham acupuncture or usual care. Acupuncture for 20-30 min/session three times/week for two or three weeks, twice weekly for two weeks and weekly for six weeks, and weekly for six weeks had substantial effects on CRF. Six RCTs reported the occurrence of adverse events, whereas five reported none. The remaining study reported some manageable events, including spot bleeding and bruising. CONCLUSIONS: Acupuncture is effective for CRF management and should be recommended as a beneficial alternative therapy for CRF patients, particularly for breast cancer patients and those currently undergoing anti-cancer treatment. PMID- 29128954 TI - Surgical approach to posterior inferior cerebellar artery aneurysms. AB - BACKGROUND: The far-lateral is a standardised approach to clip aneurysms of the posterior inferior cerebellar artery (PICA). Different variants can be adopted to manage aneurysms that differ in morphology, topography, ruptured status, cerebellar swelling and surgeon preference. METHOD: We distinguished five paradigmatic approaches aimed to manage aneurysms that are: proximal unruptured; proximal ruptured requiring posterior fossa decompression (PFD); proximal ruptured not requiring PFD; distal unruptured; distal ruptured. CONCLUSIONS: Preoperative planning in the setting of PICA aneurysm surgery is of paramount importance to perform an effective and safe procedure, to ensure an adequate PFD and optimal proximal control before aneurysm manipulation. PMID- 29128953 TI - Is the Association of ADHD with Socio-Economic Disadvantage Explained by Child Comorbid Externalizing Problems or Parent ADHD? AB - It has been unclear whether an associations of child ADHD with socio-economic disadvantage (SES) could be accounted for by (a) parental ADHD explaining both low SES and child ADHD, and/or (b) the joint overlap of ODD or CD with low SES and ADHD. Study 1 used a community-recruited case-control sample with detailed evaluation of SES indicators, child ADHD, child externalizing, and parent ADHD symptoms (n = 931 children, 521 ADHD, 577 boys, 354 girls) in a path modeling analysis with latent variables. Study 2 evaluated ADHD and externalizing behavior in a regression model using a poverty index for SES, in 70,927 children (48.2% female) aged 5-17 years from the US 2011-2012 National Survey of Children's Health (NSCH). In Study 1, lower SES was related to the ADHD latent variable, beta = -.18, p < .001; 95%CI [-.25,-.12]. This effect held when parent ADHD and child ODD and CD were in the model, beta = -.11, p < .01, 95% CI [-.09,-.03], equivalent to OR = 1.50, 95% CI[1.12-2.04]). In Study 2, these results replicated. Adjusting only for age and sex, children from families who were below 200% of the federal poverty line were more likely to have moderate or severe ADHD than no ADHD, versus children above that line, OR = 2.13, 95% CI[1.79,2.54], p < .001. The effect held after adjusting for disruptive/externalizing problems, OR = 1.61, p < .01, 95%CI [1.32,1.96]. The effect size for comparable models was similar across both studies, lending higher confidence to the results. It is concluded that the SES association with child ADHD is not explained by artifact and requires a mechanistic explanation. PMID- 29128955 TI - Right Brodmann area 18 predicts tremor arrest after Vim radiosurgery: a voxel based morphometry study. AB - INTRODUCTION: Drug-resistant essential tremor (ET) can benefit from open standard stereotactic procedures, such as deep-brain stimulation or radiofrequency thalamotomy. Non-surgical candidates can be offered either high-focused ultrasound (HIFU) or radiosurgery (RS). All procedures aim to target the same thalamic site, the ventro-intermediate nucleus (e.g., Vim). The mechanisms by which tremor stops after Vim RS or HIFU remain unknown. We used voxel-based morphometry (VBM) on pretherapeutic neuroimaging data and assessed which anatomical site would best correlate with tremor arrest 1 year after Vim RS. METHODS: Fifty-two patients (30 male, 22 female; mean age 71.6 years, range 49 82) with right-sided ET benefited from left unilateral Vim RS in Marseille, France. Targeting was performed in a uniform manner, using 130 Gy and a single 4 mm collimator. Neurological (pretherapeutic and 1 year after) and neuroimaging (baseline) assessments were completed. Tremor score on the treated hand (TSTH) at 1 year after Vim RS was included in a statistical parametric mapping analysis of variance (ANOVA) model as a continuous variable with pretherapeutic neuroimaging data. Pretherapeutic gray matter density (GMD) was further correlated with TSTH improvement. No a priori hypothesis was used in the statistical model. RESULTS: The only statistically significant region was right Brodmann area (BA) 18 (visual association area V2, p = 0.05, cluster size Kc = 71). Higher baseline GMD correlated with better TSTH improvement at 1 year after Vim RS (Spearman's rank correlation coefficient = 0.002). CONCLUSIONS: Routine baseline structural neuroimaging predicts TSTH improvement 1 year after Vim RS. The relevant anatomical area is the right visual association cortex (BA 18, V2). The question whether visual areas should be included in the targeting remains open. PMID- 29128956 TI - Cell Surface Display of MerR on Saccharomyces cerevisiae for Biosorption of Mercury. AB - The metalloregulatory protein MerR which plays important roles in mer operon system exhibits high affinity and selectivity toward mercury (II) (Hg2+). In order to improve the adsorption ability of Saccharomyces cerevisiae for Hg2+, MerR was displayed on the surface of S. cerevisiae for the first time with an alpha-agglutinin-based display system in this study. The merR gene was synthesized after being optimized and added restriction endonuclease sites EcoR I and Mlu I. The display of MerR was indirectly confirmed by the enhanced adsorption ability of S. cerevisiae for Hg2+ and colony PCR. The hydride generation atomic absorption spectrometry was applied to measure the Hg2+ content in water. The engineered yeast strain not only showed higher tolerance to Hg, but also their adsorption ability was much higher than that of origin and control strains. The engineered yeast could adsorb Hg2+ under a wide range of pH levels, and it could also adsorb Hg2+ effectively with Cd2+ and Cu2+ coexistence. Furthermore, the engineered yeast strain could adsorb ultra-trace Hg2+ effectively. The results above showed that the surface-engineered yeast strain could adsorb Hg2+ under complex environmental conditions and could be used for the biosorption and bioremediation of environmental Hg contaminants. PMID- 29128957 TI - Expression of Glut-1 in Malignant Melanoma and Melanocytic Nevi: an Immunohistochemical Study of 400 Cases. AB - The glucose transporter-1 (Glut-1) is a cell membrane glycoprotein involved in glucose uptake. An increased expression of Glut-1 is an important cell adaptation mechanism against hypoxia. An upregulation of Glut-1 can be found in several types of malignant tumors, which are able to reprogram their metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect). However, the data regarding melanocytic lesions is equivocal. We performed comprehensive immunohistochemical analysis of the Glut-1 expression in 225 malignant melanomas (MM) and 175 benign nevi. Only the membranous expression of Glut-1 was regarded as positive. The expression of Glut-1 (the cut-off for positivity was determined as H-score 15) was found in 69/225 malignant melanomas. The number of positive cases and the H-score of Glut-1 increased where there was a higher Breslow thickness (p < 0.00001) when comparing pT1- pT4 MM groups. All benign nevi were classified as negative. In conclusion, the membranous expression of Glut-1 is a common feature of a malignant melanoma but this type of expression is very rare in benign melanocytic nevi. Our results suggest that the membranous expression of Glut-1 can be used as a surrogate marker in the assessing of the biological nature of benign and malignant melanocytic lesions. However, despite its high specificity, the sensitivity of this marker is relatively low. Moreover, due to the fact that the increased expression of Glut-1 correlates with a shorter survival period (10-year disease free survival, recurrence free survival and metastasis free survival and MFS), it can be used as a prognostically adverse factor. PMID- 29128958 TI - D-Proline: Comment to "An overview on D-amino acids". AB - An excellent 2017 review in this journal about D-amino acids by Genchi aims for a comprehensive representation of the current state of knowledge. Unfortunately, information about both D-proline and proline racemase is almost entirely missing. In our investigations into D/L-Pro-containing neuropeptides in cicadas, we have performed literature surveys in this context. Proline racemases in bacteria are known since 1957; their function has been studied mostly in prokaryotes and, more recently, proline racemase was identified in the unicellular eukaryotic parasite Trypanosoma cruzi. Published data on D-proline and/or proline racemase in other species are rare or non-existent. PMID- 29128959 TI - Casino Self- and Forced Excluders' Gambling Behavior Before and After Exclusion. AB - Casino exclusion programs are intended to prevent or limit gambling-related harm. Although previous research showed that self-exclusion is associated with reduced gambling, it remains unknown whether self- and forced excluded subjects show different patterns of gambling behavior and if exclusion from casino gambling affects all gambling activities. The present study retrospectively investigated (1) the role of voluntariness of exclusion for the first time, and (2) general gambling behavior of excluded individuals before and after exclusion. A total of N = 215 casino excluders (self-excluders: n = 187, forced excluders: n = 28) completed an online survey or a face-to-face interview up to 8 years after enrollment. Self- and forced excluders showed similar rates of abstinence (self excluders: 19.3%, forced excluders: 28.6%) and reduction (self-excluders: 67.4%, forced excluders: 60.7%), even though forced excluders reported a significantly greater initial gambling intensity compared to self-excluders (e.g., pre exclusion gambling time; self-excluders: 3.2 days/week, forced excluders: 4.3 days/week). Overall, results indicated that 20.5% of excluders stopped all gambling activities and another 66.5% reduced their gambling. Those who continued gambling significantly reduced this behavior in every segment, except for gambling halls. Findings indicate that self- and forced exclusion are associated with similarly reduced gambling behavior, even in non-excluded segments. However, unchanged gambling in gambling halls emphasizes the importance to implement consistent exclusion programs over all gambling segments. PMID- 29128960 TI - A Proteomics Analysis Reveals 9 Up-Regulated Proteins Associated with Altered Cell Signaling in Colon Cancer Patients. AB - Colorectal cancer is the second most common cancer in women and third most common cancer in men. Cell signaling alterations in colon cancer, especially in aggressive metastatic tumors, require further investigations. The present study aims to compare the expression pattern of proteins associated with cell signaling in paired tumor and non-tumor samples of patients with colon cancer, as well as to define the cluster of proteins to differentiate patients with non-metastatic (Dukes' grade B) and metastatic (Dukes' grade C&D) colon cancer. Frozen tumor and non-tumor samples were collected after tumor resection from 19 patients with colon cancer. The PanoramaTM Antibody Microarray-Cell Signaling kits were used for the analyses. The expression ratios of paired tumor/non-tumor samples were calculated for the each protein. We employed R packages 'samr', 'gplots', 'supclust' (pelora, wilma algorithms), 'glmnet' for the differential expression analysis, supervised clustering and penalized logistic regression. Significance analysis of microarrays revealed 9 significantly up-regulated proteins, including protein kinase C gamma, c-Myc, MDM2, pan cytokeratin, and 1 significantly down regulated protein (GAP1) in tumoral mucosa. Pan-cytokeratin and APP were up regulated in tumor versus non-tumor tissue, and were selected in the predictive cluster to discriminate colon cancer type. Higher levels of S-100b and phospho Tau-pSer199/202 were confirmed as the predictors of non-metastatic colon cancer by all employed regression/clustering methods. Deregulated proteins in colon cancer are involved in oncogenic signal transduction, cell cycle control, and regulation of cytoskeleton/transport. Further studies are needed to validate potential protein markers of colon cancer development and metastatic progression. PMID- 29128961 TI - The relationship between the time until commencement of tolvaptan and the length of hospital stay in heart failure patients. AB - The effect of early use of tolvaptan (TLV) for acute decompensated heart failure (ADHF) is unclear. We investigated the relationship between early use of TLV and the length of hospital stay. 369 consecutive ADHF patients who received TLV during hospitalization between February 2011 and June 2016 were initially enrolled. Patients who died in hospital, transferred hospital or clinical scenario 4 or 5 were excluded. We analyzed 247 ADHF patients. We evaluated the relationship between the length of hospital stay and the following findings: blood pressures, heart rate, New York Heart Association classification, and blood tests on admission. Moreover, we also evaluated treated agents and TLV initiated days from admission. TLV initiated days was statistically associated with the length of hospital stay (r = 0.625, P < 0.001). We compared the early use (within 4 days) vs delayed use of TLV (5 days or later), because the median of time until commencement of TLV from hospitalization was 4 days. The length of hospital stay in the delayed use group was significantly longer than early use group (31.9 +/- 20.4 and 21.0 +/- 12.9 days, P < 0.001). However, there was no difference in the length of hospital stay after initiation of TLV in both groups. Moreover, we investigated the factors related to the long-term hospitalization (hospital stay of median length or more). Multivariate analysis showed that TLV initiated days was independently related to the long-term hospitalization (odds ratio 1.32, 95% confidence interval 1.13-1.53, P < 0.001). Early use of TLV was related to the length of hospital stay for ADHF patients. PMID- 29128962 TI - Good response to tolvaptan shortens hospitalization in patients with congestive heart failure. AB - Tolvaptan has been gradually spread to use as a potent diuretic for congestive heart failure in the limited country. However, the response to this aquaretic drug still is unpredictable. A total of 92 patients urgently hospitalized due to congestive heart failure and treated with tolvaptan in addition to standard treatment was retrospectively analyzed. Responder of tolvaptan treatment was defined as a patient with peak negative fluid balance greater than 500 mL/day, and clinical profiles were compared between 76 responders and 16 non-responders. Responders started to increase daily urine volume (UV) from Day 1 through Day 3. In contrast, non-responders showed no significant increase in daily UV from the baseline up to Day 5. Time between admission and tolvaptan administration was shorter in responders, even without statistical significance (3.3 vs. 4.6 days, p = 0.053). Multivariate analysis revealed that blood urea nitrogen (BUN) [cutoff: 34 mg/dL, odds ratio (OR) 9.0, 95% confidence interval (CI) 1.42-57.3, p < 0.01] and plasma renin activity (PRA) (cutoff: 4.7 ng/mL/h, OR 6.1, 95% CI 1.01-36.4, p < 0.01) at baseline were independent predictors for tolvaptan responsiveness. It suggests that renal perfusion may affect tolvaptan-induced UV. Finally, durations of stay in intensive care unit and total hospitalization were significantly shorter in responders (median: 6.0 vs. 13.0 days, p = 0.022; 15.0 vs. 25.0 days, p = 0.016, respectively). Responders of tolvaptan have lower BUN and renin activity at baseline, and shorten hospitalization period. Trial Registration The study was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) with the identifier UMIN000023594. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024988. PMID- 29128963 TI - The dark sides of fluid administration in the critically ill patient. PMID- 29128964 TI - In vivo assessment of a novel biodegradable ureteral stent. AB - PURPOSE: To perform an in vivo assessment of a newly developed biodegradable ureteral stent (BUS) produced with natural-based polymers. METHODS: The BUS is based on a patented technology combining the injection process with the use of supercritical fluid technology. Study was conducted at ICVS-University of Minho (Braga, Portugal) and a total of ten domestic pigs were used. In seven animals, the experimental BUS stent was inserted, whereas in the remaining a commercially available stent was used (6-Fr Biosoft(r) duo stents, Porges Coloplast, Denmark). Post-stenting intravenous pyelogram was used to evaluate the degree of hydronephrosis. The in vivo stent degradation was measured as function of the weight loss. Moreover, the tensile properties of the BUS were tested during in vivo degradation. After maximum 10 days, animals were killed and necropsy was performed. Tissues were compared between the stented groups as well as between the non-stented contralateral ureters and stented ureters in each group. Biocompatibility was assessed by histopathological grading. RESULTS: In all cases, the BUS was only visible during the first 24 h on X-ray, and in all cases the BUS was completely degraded in urine after 10 days, as confirmed on necropsy. During the degradation process, the mechanical properties of the BUS decreased, while the commercial ureteral stents remained constant. At all time-points after stent insertion, the level of hydronephrosis was minimal. Overall, animals stented with BUS had an average grade of hydronephrosis which was lower compared to the controls. The BUS showed better pathological conditions, and hence better biocompatibility when compared with commercial stents. CONCLUSIONS: Notwithstanding the limitations of the present study, the in vivo testing of our novel natural origin polymer-based BUS suggests this device to feature homogeneous degradation, good urine drainage, and high biocompatibility. Next steps will be to increase its stability, and to improve the radiopacity without compromising its degradation. Ultimately, clinical studies will be required to determine the safety and feasibility of its use in humans. PMID- 29128965 TI - Abemaciclib: First Global Approval. AB - Abemaciclib (VerzenioTM) is an orally administered inhibitor of cyclin-dependent kinases 4 and 6 that is being developed by Eli Lilly and Company. Abemaciclib has been approved in the USA for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, in combination with fulvestrant in women with disease progression following endocrine therapy, and as monotherapy in adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. In addition, abemaciclib is in various stages of development internationally for a variety of cancers. This article summarizes the milestones in the development of abemaciclib leading to its first approval for the treatment of patients with HR-positive, HER2-negative advanced or metastatic breast cancer. PMID- 29128966 TI - Is the DLQI appropriate for medical decision-making in psoriasis patients? AB - Dermatology Life Quality Index (DLQI) is the most commonly applied measure of health-related quality of life (HRQoL) in psoriasis patients. It is among defining criteria of moderate-to-severe psoriasis and present in treatment guidelines. Our objective was to estimate preference-based HRQoL values (i.e., utilities) for hypothetical health states described by the 10 items of the DLQI in psoriasis patients. Moreover, we compare results to findings of a similar study previously conducted among the general public. A cross-sectional survey was carried out among 238 psoriasis patients. Seven hypothetical DLQI-defined health states with total scores of 6, 11, and 16 (3-3 and 1 states, respectively) were evaluated by time trade-off method. The difference in DLQI scores between hypothetical health states was set at 5 points, as it exceeds the minimal clinically important difference (MCID). Utility scores were found to be homogenous across the seven hypothetical health states (range of means for the 6 point states 0.85-0.91, range of means for the 11-point states 0.83-0.85, and mean of 0.84 for the 16-point state). Overall, mean utilities assessed by psoriasis patients were higher for all seven states compared with the general public (mean difference 0.16-0.28; p < 0.001). In 11 out of the 15 comparisons between health states with DLQI scores differing larger than the MCID, there was no statistically significant difference in utility. Thus, in clinical settings, patients with DLQI scores differing more than the MCID may have identical HRQoL. Improving the definition of moderate-to-severe disease and reconsideration of the DLQI in clinical assessment of psoriasis patients are suggested. PMID- 29128967 TI - Early postoperative magnetic resonance imaging findings after arthroscopic rotator cuff repair: T2 hyperintensity of the capsule can predict reduced shoulder motion. AB - INTRODUCTION: The purpose of this study was to investigate whether postoperative shoulder magnetic resonance imaging (MRI) findings correlate with postoperative shoulder range of motion (ROM) at about 4 months after arthroscopic rotator cuff repair (ARCR). MATERIALS AND METHODS: Signal-intensity changes of the capsule, pericapsular soft tissue at the axillary recess, and subcoracoid fat triangle, as well as the thickness of the capsule at the axillary recess and coracohumeral ligament were assessed on preoperative and postoperative MR images of 232 patients. The ROM was evaluated preoperatively and at about 4 months after ARCR. RESULTS: T2 hyperintensity of the capsule, pericapsular soft tissue at the axillary recess, and signal change of the subcoracoid fat triangle were detected in 155, 107, and 89 cases, respectively, on postoperative MRI. Among these cases, 129, 98, and 69 cases, respectively, showed newly developed signal changes. The mean thicknesses of the capsule and coracohumeral ligament were 1.89 +/- 0.69 and 1.64 +/- 0.51 mm, respectively, on preoperative MRI and 3.74 +/- 1.12 and 2.42 +/ 0.56 mm, respectively, on postoperative MRI. At the 4-month follow-up, the mean external rotation (ER), internal rotation (IR), abduction, forward flexion, and extension were 77, 73, 76, 83, and 82%, respectively, of the contralateral side. Newly developed T2 hyperintensity of the capsule and pericapsular soft tissue at the axillary recess on postoperative MRI significantly correlated with the postoperative limitation of ER (p = 0.039) and IR (p = 0.020). CONCLUSIONS: Newly developed signal changes of the capsule, pericapsular soft tissue at the axillary recess, and subcoracoid fat triangle were often detected on postoperative MRI at 4 months after ARCR. Furthermore, newly developed T2 hyperintensity of the capsule and pericapsular soft tissue at the axillary recess correlated with limited ROM in ER and IR at 4 months after ARCR. PMID- 29128968 TI - Involvement of cyclodipeptides in the competition of bacterial communities in the oligotrophic Churince aquatic system of Cuatro Cienegas Basin dominated by Gammaproteobacteria. AB - The Cuatro Cienegas Basin (CCB) within the Chihuahuan Desert in Mexico is an extremely oligotrophic oasis with negligible phosphorous levels, described as a hot spot of biodiversity, not only in stromatolites and microbial mats, but also in living forms in general. The microorganisms possess the capability to produce a wide variety of virulence factors, antibiotics, and quorum-sensing (QS) crosstalk signals such as non-ribosomal cyclodipeptides (CDPs) which enables them to colonize diverse ecological niches. In the aquatic system of CCB known as Churince, a bacterial population was isolated from the Lagunita pond dominated by Gammaproteobacteria. In this work, we determined the relationships between the antagonism and CDPs production in this bacterial population. Results indicate that 68% of isolates showed antagonistic effects over other isolates, correlating with production of CDPs and the antibiotic 2,4-diacetylphloroglucinol (DAPG). Although a minority of the isolates were capable of inducing a QS biosensor strain, bacterial QS interference was not the main mechanism in the antagonism observed. Thus, our results indicate that CDPs primarily, and DAPG to a lesser degree, are involved with the growth-inhibition competition mechanisms of bacterial communities in the Lagunita pond and was associated with a Gammaproteobacteria dominancy phenomena. PMID- 29128969 TI - In vasculitis of small muscular arteries, activation of vessel-infiltrating CD8 T cells seems to be antigen-independent. AB - The etiology of polyarteritis nodosa (PAN) and localized PAN is still unknown, although a T cell-mediated immune mechanism has been considered. CD8 T cells participate not only in the antigen-dependent adaptive immune system, but also in the antigen-independent innate immune system. Non-antigen-activated CD8 T cells express a unique phenotype: granzyme B (GrB) positive /CD25 negative /programmed death-1 (PD-1) negative. The aims of this study were to assess the participation of T cells, especially innate CD8 T cells, in the development of vasculitis. Twenty-eight consecutive cases of skin biopsy specimens with cutaneous vasculitis of small muscular arteries (CVSMA) were retrieved. The series comprises of 21 cases of cutaneous arteritis, three cases of PAN, and four cases of rheumatoid vasculitis. Cases of antineutrophil cytoplasmic antibody-associated vasculitis were excluded. The phenotypes of infiltrating lymphocytes in vasculitis lesions were evaluated by immunohistochemistry. In most cases of CVSMA, the number of CD8 T cells infiltrating the intima was higher than that of CD4 T cells, and significant numbers of GrB-positive cells, which represent activated CD8 T cells, were observed. However, GrB/CD25-double-positive cells, which correspond to antigen-activated T cells, were very few in a small number of cases. Cells positive for PD-1, which is also expressed on antigen-activated CD8 T cells, were not detected. We conclude that a T cell-mediated immune mechanism, involving cytotoxic CD8 T cells, may play a role in the development of CVSMA. Low expression of CD25 in activated CD8 T cells suggests that activation was antigen independent. PMID- 29128970 TI - Cord serum 25-hydroxyvitamin D is not associated with cranial anthropometrics in infants up to 6 months of age. An Odense Child Cohort study. AB - Skull changes are poorly described in vitamin D insufficiency [serum 25 hydroxyvitamin D (s-25(OH)D) 25-50 nmol/L]. We aimed to investigate factors associated with cranial anthropometrics in infants, especially s-25(OH)D. In infants 2.5-6 months old from the Odense Child Cohort, associations between cord and pregnancy s-25(OH)D and anterior fontanel area (n = 765), head circumference (HC, n = 1776) and head shape (n = 1527) were investigated along with other factors. Age was corrected for preterm birth. The mean (SD) s-25(OH)D in early pregnancy was 65.97 (21.33) nmol/L; late pregnancy 78.61 (27.18) nmol/L; and cord 47.1 (21.7) nmol/L. At median (IQR) age 3.7 (2.5-5.9) months, the fontanel area was 225 (0-1690) mm2, and mean (SD) HC was 41.5 (1.5) cm. Asymmetric/flat head shape was present in 846 infants (55.3%). No associations were found between cord, early or late pregnancy s-25(OH)D and any cranial measure by univariate or adjusted analysis. Among significant, independent associations in multivariate analysis, fontanel area was associated inversely with gestational age (GA); HC was associated directly with GA, maternal pre-pregnancy overweight and caesarean section and inversely with smoking; and asymmetrical head shape showed a novel association with male sex: adjusted OR = 1.54 (95% CI 1.25; 1.89), p < 0.001. Other associations with asymmetrical head shape included parity 3+, gestational age and maternal age 30+ years (all protective). In conclusion, neither pregnancy nor cord s-25(OH)D was associated with fontanel size, HC or asymmetrical head shape despite a high prevalence of cord s-25(OH)D < 50 nmol/L. Lower GA was associated with larger fontanel size, lower HC and asymmetrical head shape, and boys more frequently had asymmetrical head shape, probably due to heavier heads. PMID- 29128971 TI - Perampanel-associated self-harm ideation after dosage increase. PMID- 29128972 TI - Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study. AB - PURPOSE: To describe patients initiating dimethyl fumarate (DMF) and measure persistence with DMF, discontinuation, and switching in treatment-naive DMF patients and patients switching to DMF from other multiple sclerosis disease modifying treatments (DMTs). METHODS: A population-based cohort study of all Stockholm County residents initiating DMF from 9 May 2014 until 31 May 2017. All data were derived from a regional database that collects individual-level data on healthcare and drug utilization of all residents. The study outcomes were persistence with DMF and DMF discontinuation and switching to other DMTs. Persistence was measured as the number of days until either DMF discontinuation (treatment gap >= 60 days) or switching to another DMT. RESULTS: The study included 400 patients (median follow-up = 2.5 years). The majority had previously been treated with other DMTs (61%). Throughout the follow-up period, 124 patients (31%) discontinued DMF and 114 patients (29%) switched treatment. Overall, 34% of patients initiating DMF stopped treatment within 1 year and only 43% of patients remained on DMF at 2 years from treatment initiation. CONCLUSIONS: DMF had a rapid market uptake likely due to high expectations held by both patients and clinicians. However, persistence with DMF in routine clinical practice was found to be low. PMID- 29128974 TI - Estimating the fluctuation of Lake Hulun, China, during 1975-2015 from satellite altimetry data. AB - Lake level, area, and volume changes can describe the fluctuation of water bodies. In this study, ICESat/Hydroweb and Landsat data recorded with irregularly time intervals from 1975 to 2015 were used to examine changes in lake level and area which were combined to indirectly estimate water volume variations of Lake Hulun. The time series of lake level, area, and volume variations of Lake Hulun exhibited a fluctuating trend from 1975 to 1984 and the mean value were about 542.57 m, 2065.76 km2, and - 0.045 km3, respectively and an increasing trends showed during 1984-2000. Lake Hulun revealed the fastest decrease in lake level ( 0.42 m/a), volume (- 0.83 km3/a) from 2000 to 2009, and the fastest shrinking in surface area (- 33.88 km2/a) during 2000-2012. There was a seasonal variation of water level and lake volume variations during 2009-2012 and the mean value were 539.98 m and - 5.72 km3, respectively. From 2012 to 2015, a faster increasing trends were shown in water level, area, and volume variations with a rate of 0.73 m/a (the amount of change was 2.92 m), 81.95 km3/a (the amount of change was 327.8 km2), and 0.42 km3/a (the amount of change was1.67 km3), respectively. The lake level and area showed strong correlations for Lake Hulun (R 2 = 0.93). The water volume changes were in very good agreement for lake level changes (R 2 > 0.99) and surface area variations (R 2 = 0.92). Combining with lake level and area changes, the sum of lake volume variation of Lake Hulun was obtained and it showed a positive water budgets of 0.24 km3 during past 40 years. River and groundwater discharge, the pan evaporation, the net pan evaporation, and the water diversion project were reasons for the lake level, area, and volume variations in Lake Hulun. This study demonstrates that remote sensing data can be used as a source of information for monitoring comprehensively the fluctuation of large water bodies. PMID- 29128973 TI - Relevant Features Selection for Automatic Prediction of Preterm Deliveries from Pregnancy ElectroHysterograhic (EHG) records. AB - In this study, we proposed an approach able to predict whether a pregnant woman with contractions would give birth earlier than expected (i.e., before the 37 t h week of gestation (WG)). It only processes non-invasive electrohysterographic (EHG) signals fully automatically without assistance of an expert or an additional medical system. We used term and preterm EHG signals of 30-minutes duration collected between the 27 t h and the 32 n d WG. Preterm deliveries (< 37W G) had occurred in average 4.00 +/- 1.88 weeks since recording dates. Each recording contains three bipolar channels. Using the Huang-Hilbert transform (HHT), we obtained up to twelve intrinsic mode functions (IMFs) for each signal. We found that the most relevant IMFs for both term and preterm records were IMF3 and IMF6. From these two IMFs, we extracted 8 most relevant features targeting EHG signal specificities. We investigated features classifications using support vector machine (SVM) for the 3 single-channels and for all their possible combinations. High discrimination power between term and preterm EHG records was obtained with linear-SVM classifiers. For almost all the cases, mean areas under curves (AUC) exceeded 0.92. A two-channel combination (7 features) achieved the best mean results with A c c u r a c y = 95.70%, S e n s i t i v i t y = 98.40%, S p e c i f i c i t y = 93.00% and A U C = 0.95. Results of the three-channel combination (9 features) were A c c u r a c y = 92.30%, S e n s i t i v i t y = 93.00%, S p e c i f i c i t y = 91.60% and A U C = 0.96. The best single-channel (8 features) gave the mean values: A c c u r a c y = 90.40%, S e n s i t i v i t y = 93.60% and A U C = 0.94. Thus, the advantage of our approach is the high diagnostic performance at low computational cost. PMID- 29128975 TI - Transcutaneous vagus nerve stimulation (tVNS) modulates flow experience. AB - Flow has been defined as a pleasant psychological state that people experience when completely absorbed in an activity. Previous correlative evidence showed that the vagal tone (as indexed by heart rate variability) is a reliable marker of flow. So far, it has not yet been demonstrated that the vagus nerve plays a causal role in flow. To explore this we used transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique that increases activation of the locus coeruleus (LC) and norepinephrine release. A sham/placebo-controlled, randomized cross-over within-subject design was employed to infer a causal relation between the stimulated vagus nerve and flow as measured using the Flow Short-Scale in 32 healthy young volunteers. In both sessions, while being stimulated, participants had to rate their flow experience after having performed a task for 30 min. Active tVNS, compared to sham stimulation, decreased flow (as indexed by absorption scores). The results can be explained by the network reset theory, which assumes that high-phasic LC activity promotes a global reset of attention over exploitation of the current focus of attention, allowing rapid behavioral adaptation and resulting in decreased absorption scores. Furthermore, our findings corroborate the hypothesis that the vagus nerve and noradrenergic system are causally involved in flow. PMID- 29128976 TI - Neurons in the crow nidopallium caudolaterale encode varying durations of visual working memory periods. AB - Adaptive sequential behaviors rely on the bridging and integration of temporally separate information for the realization of prospective goals. Corvids' remarkable behavioral flexibility is thought to depend on the workings of the nidopallium caudolaterale (NCL), a high-level avian associative forebrain area. We trained carrion crows to remember visual items for three alternating delay durations in a delayed match-to-sample task and recorded single-unit activity from the NCL. Sample-selective delay activity, a correlate of visual working memory, was maintained throughout different working memory durations. Delay responses remained selective for the same preferred sample item across blocks with different delay durations. However, selectivity strength decreased with increasing delay durations, mirroring worsened behavioral performance with longer memory delays. Behavioral relevance of delay activity was further evidenced by reduced encoding of the preferred sample item during error trials. In addition, NCL neurons adapted their time-dependent discharges to blocks of different memory durations, so that delay duration could be successfully classified based on population activity a few trials after the delay duration switched. Therefore, NCL neurons not only maintain information from individual trials, but also keep track of the duration for which this information is needed in the context of the task. These results strengthen the role of corvid NCL in maintaining working memory for flexible control of temporally extended goal-directed behavior. PMID- 29128977 TI - Dissociating object-based from egocentric transformations in mental body rotation: effect of stimuli size. AB - The effect of stimuli size on the mental rotation of abstract objects has been extensively investigated, yet its effect on the mental rotation of bodily stimuli remains largely unexplored. Depending on the experimental design, mentally rotating bodily stimuli can elicit object-based transformations, relying mainly on visual processes, or egocentric transformations, which typically involve embodied motor processes. The present study included two mental body rotation tasks requiring either a same-different or a laterality judgment, designed to elicit object-based or egocentric transformations, respectively. Our findings revealed shorter response times for large-sized stimuli than for small-sized stimuli only for greater angular disparities, suggesting that the more unfamiliar the orientations of the bodily stimuli, the more stimuli size affected mental processing. Importantly, when comparing size transformation times, results revealed different patterns of size transformation times as a function of angular disparity between object-based and egocentric transformations. This indicates that mental size transformation and mental rotation proceed differently depending on the mental rotation strategy used. These findings are discussed with respect to the different spatial manipulations involved during object-based and egocentric transformations. PMID- 29128978 TI - On the influence of informational content and key-response effect mapping on implicit learning and error monitoring in the serial reaction time (SRT) task. AB - The present experiment was designed to enhance our understanding of how response effects with varying amounts of useful information influence implicit sequence learning. We recorded event-related brain potentials, while participants performed a modified version of the serial reaction time task (SRTT). In this task, participants have to press one of four keys corresponding to four letters on a computer screen. Unknown to participants, in some parts of the experimental blocks, the stimuli appear in a repetitive (structured) deterministic sequence, whereas in other parts, stimuli were determined randomly. Four groups of participants differing in the presentation of tones after each response performed the SRTT. In the no tone group, no tones were presented after a response. The other three groups differed with respect to the melody generated by the key presses: in the unmelodic group, one out of four different tones was chosen randomly and presented immediately after a response. In the consistent melody group, the press of a response key always resulted in the production of the same tone, resulting in a repetitive melody during structured parts of the sequence (consistent redundant effect). In the inconsistent melody group, the "melody" produced in the sequenced parts of the blocks was identical to the consistent melody group, but the same response could produce two different tones depending on the actual position in the stimulus sequence. Thus, during structured sequences, subjects heard the same melody as in the consistent melody group, but every key press could be followed by one out of two different tones. To disentangle effects of sequence awareness from our experimental manipulations, all analyses were restricted to implicit learners. All four groups showed sequence learning, but to a different degree: in general, every kind of tone improved sequence learning relative to the no tone group. However, unmelodic tones were less beneficial for learning than tones forming a melody. Tones mapped consistently to response keys improved learning faster than tones producing the same melody, but not mapped consistently to keys. However, at the end of the learning phase, the two melody groups did not differ in the amount of sequence learning. The error-related negativity (ERN) increased with sequence learning (larger ERN at the end of the experiment for trials following the sequence compared to random trials) and this effect was more pronounced for the groups that showed more learning. These findings indicate that response effects containing useful information foster sequence learning even if the same response can produce different effects. Furthermore, we replicated earlier results showing that the importance of an error with respect to the task at hand modulates the activity of the human performance monitoring system. PMID- 29128980 TI - Reducing the spread of occult uterine sarcoma at the time of minimally invasive gynecologic surgery. AB - PURPOSE: This review covers the most recent evidence to discuss the incidence of occult uterine sarcoma, whether morcellation increases tumor dissemination or mortality, and whether there is a difference between different types of morcellation. We will also discuss techniques to reduce the spread of an undiagnosed uterine sarcoma. METHOD: A comprehensive literature search was made in Pubmed, Medline, the Cochrane Library, and Google Scholar for articles related to the incidence of occult uterine sarcoma after morcellation. RESULTS: Fibroids are benign uterine tumors and are a common indication for gynecologic surgery. Increasingly, gynecologists are approaching these surgeries with minimally invasive techniques. Uterine sarcomas are rare malignant mesenchymal tumors that are difficult to distinguish preoperatively from uterine fibroids. CONCLUSION: During a minimally invasive surgery, there is a risk of disseminating an occult sarcoma during tissue extraction. Minimally invasive gynecologists are tasked with balancing taking a minimally invasive approach, which is shown to result in better patient outcomes, with minimizing the risk of spreading an occult sarcoma. PMID- 29128979 TI - Critical reviews of 1470-nm laser vaporization on benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is recognized as the common chronic disease that affect majority of men in their elder ages. Nevertheless, there are no effective documents for BPH treatment. Even though great progression has been made on BPH by laser surgery, it also faces several challenges. In this study, our aims were to explore the effects of 1470-nm laser vaporization on BPH. For the research, a total of 170 BPH patients were enrolled. A 1470-nm laser vaporization apparatus was purchased for the surgery. The indicators such as serum sodium, international prostate symptom score (IPSS), Quality of life (QOL), maximum flow rate (Qmax), prostate specific antigen (PSA), and average Post-void Residual Volume (PVR) were detected for evaluating the prostate function. The operation was successful in all 170 patients, neither of whom converted to transurethral resection of the prostate (TURP) nor to open surgery. The surgery time was 52.3 +/- 5.6 min, the laser emission time was 35.6 +/- 3.2 min, the energy consumption was 254.1 +/- 19.3 kJ. The level of serum sodium showed no significant difference between the pre- and post-operation. Qmax was significantly increased in post-operation, while IPSS, QOL, PVR, and PSA were significantly decreased in the post-operation. The 1470-nm laser vaporization treatment protected patients against BPH, indicating that 1470-nm laser vaporization might be important on treating BPH, which provided solid foundation for further clinical treatment. PMID- 29128981 TI - What to eat in a warming world: do increased temperatures necessitate hazardous duty pay? AB - Contemporary climate change affects nearly all biomes, causing shifts in animal distributions and resource availability. Changes in resource selection may allow individuals to offset climatic stress, thereby providing a mechanism for persistence amidst warming conditions. Whereas the role of predation risk in food choice has been studied broadly, the extent to which individuals respond to thermoregulatory risk by changing resource preferences is unclear. We addressed whether individuals compensated for temperature-related reductions in foraging time by altering forage preferences, using the American pika (Ochotona princeps) as a model species. We tested two hypotheses: (1) food-quality hypothesis individuals exposed to temperature extremes should select higher-quality vegetation in return for accepting a physiologically riskier feeding situation; and (2) food-availability hypothesis-individuals exposed to temperature extremes should prioritize foraging quickly, thereby decreasing selection for higher quality food. We quantified the composition and quality (% moisture, % nitrogen, and fiber content) of available and harvested vegetation, and deployed a network of temperature sensors to measure in situ conditions for 30 individuals, during July-Sept., 2015. Individuals exposed to more extreme daytime temperatures showed increased selection for high-nitrogen and for low-fiber vegetation, demonstrating strong support for the food-quality hypothesis. By contrast, pikas that experienced warmer conditions did not reduce selection for any of the three vegetation-quality metrics, as predicted by the food-availability hypothesis. By shifting resource-selection patterns, temperature-limited animals may be able to proximately buffer some of the negative effects associated with rapidly warming environments, provided that sufficient resources remain on the landscape. PMID- 29128982 TI - Actionable secondary findings from whole-genome sequencing of 954 East Asians. AB - Recently, the American College of Medical Genetics (ACMG) recommended the return of actionable secondary findings detected from clinical sequencing. The reported frequency of secondary findings in Asian populations were highly variable and it is unclear whether the uniformity in coverage offered by whole-genome sequencing (WGS) may impact the estimate. In this analysis, we aimed to refine the rate of secondary findings on East Asians through a large-scale WGS study. We classified 1256 protein-altering or splicing variants of the 59 actionable genes detected from WGS of 954 East Asians in strict accordance with the ACMG and the Association for Molecular Pathology guidelines. A total of 21 pathogenic or likely pathogenic variants were detected in 24 of the 954 East Asian genomes with an estimate of 2.5% of East Asians carrying actionable variants. Although the overall estimate of secondary findings was consistent with those reported for non East Asian ethnicities, genetic and allelic heterogeneity was observed. WGS offers a wider breadth of coverage over WES, which highlights the need to further investigate the variable sensitivity of WES and WGS in the detection of secondary findings. Identifying secondary findings in populations underrepresented in previous genetic literature might improve variant interpretation and has a profound impact on local decision-making with regard to the cost-effectiveness of returning the secondary findings from clinical sequencing. PMID- 29128983 TI - Biological control of Echinothrips americanus by phytoseiid predatory mites and the effect of pollen as supplemental food. AB - The poinsettia thrips, Echinothrips americanus Morgan, is an upcoming pest in greenhouse crops, causing serious damage in various vegetable and ornamental crops through extensive foliage feeding. We assessed which stages of E. americanus are attacked and killed by the phytoseiid predatory mites Amblyseius swirskii (Athias-Henriot), Amblydromalus limonicus (Garman and McGregor), Euseius gallicus Kreiter and Tixier and Euseius ovalis (Evans). Both the predation and oviposition rates were assessed in the laboratory to evaluate which mite species is potentially the most effective predator of E. americanus. In two greenhouse trials with non-flowering sweet pepper plants, we compared the efficacy of the predators E. gallicus and E. ovalis with A. swirskii and we assessed how this was affected by the application of cattail pollen. All stages of E. americanus, except adults, were consumed by all species of predatory mites. The highest predation and oviposition rates were recorded for A. limonicus followed by A. swirskii and E. ovalis when first and second larval stages were provided as prey, but E. ovalis appeared to be the best predator of thrips pupae. Euseius gallicus displayed very low predation and oviposition rates compared to the other species of predatory mites. Cattail pollen did not support the population growth of poinsettia thrips, but it strongly increased the predatory mite population densities, particularly those of E. ovalis. Both A. swirskii and E. ovalis significantly reduced thrips densities on plants. The application of pollen significantly enhanced the control of E. americanus by A. swirskii; this was not the case for E. ovalis. Euseius gallicus did not reduce densities of E. americanus on sweet pepper plants, not even at high densities in the presence of pollen. PMID- 29128984 TI - Taxonomic resolution and functional traits in the analysis of tropical oribatid mite assemblages. AB - We analysed species-level datasets representing Oribatida assemblages along a gradient of old-growth primary tropical forests, secondary forests, and plantation forests in Dong Nai Biosphere Reserve, Vietnam. We identified patterns in abundance, species richness and species assemblages of Oribatida, then applied taxonomic sufficiency approach to the datasets. Using three levels of higher taxon aggregation, we evaluated whether aggregated datasets are useful in identifying ecological patterns, in comparison to species-level data. Species level data on Oribatida assemblages clearly separated plantation forests from other forest environments; there was no significant separation between primary and secondary forests. Geographical structuring of species-level assemblages was significant, separating sites from two regions of the reserve. There was a significant concordance between multivariate ordination plots produced for species-level and aggregated (families, suborders/superfamilies) datasets, with Oribatida assemblages of plantation forests consistently separated from two other forest types. Mycobatidae (at family level) and Ceratozetoidea (at suborder/superfamily level) were indicators of plantation forests. The coarsest taxonomic resolution dataset with only four aggregated groups produced no separation of Oribatida assemblages by forest type or region. Moderate level of taxonomic aggregation applied to Oribatida community data did not cause great differences in patterns revealed by multivariate analysis, and therefore could be a valid approach to analysing the structure of tropical Oribatida assemblages. The taxonomic level of suborders and Brachypylina superfamilies appears to be the best compromise for ecological information and ease of identification. Two traits body size and reproductive mode-were recorded for collected Oribatida species. Community-weighted mean trait value, modified Mason's index of functional divergence, and Rao's index of functional diversity were calculated for each trait in each of the sampled Oribatida assemblages. Sexual reproduction was a dominant reproductive mode in soil Oribatida and did not vary across forest types, indicating similar levels of resource limitation for this trait. For body size, lower functional divergence in plantation forests suggests less scope for niche differentiation and higher competition among different body sizes in this forest type. Use of functional traits can enhance and complement the analysis of Oribatida communities, but more data are needed on feeding- and diet-related traits in tropical Oribatida. PMID- 29128985 TI - Resection of melanocytic nevi as a potential treatment of anti-NMDAR encephalitis patients without tumor: report of three cases. AB - The most common underlying tumor associated with anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is ovarian teratoma. Resection of the underlying tumor may decrease exposure of autoantigen and make for faster response of immunotherapy and less relapse frequency. Similar to teratoma, expression of NMDAR in human epidermal melanocytes was suspected recently. The dense melanocytes in melanocytic nevus may serve as potential autoantigens and are prone to increase relapse frequency in the tumor-negative patients. Three patients with confirmed diagnosis of anti-NMDAR encephalitis were described here. They shared common features that the screening tests for an ovarian teratoma or other tumors were all negative, while they were found to have prominent melanocytic nevi on the skin and resection of the nevi likely played a positive effect on their persistent recovery. This is a report on treatment of anti-NMDAR encephalitis patients without underlying tumor through resection of melanocytic nevi. More clinical and experimental investigations are needed to prove its validity. PMID- 29128986 TI - Longitudinal neurophysiological assessment of intramuscular type-A botulin toxin in healthy humans. AB - The aim of this study is to assess the neurophysiological abnormalities of type A botulin toxin-infiltrated human muscle, and their evolution over time. Seried cMAP measurements, 3 and 20 Hz repetitive nerve stimulation, EMG, SFEMG over 3 months from toxin injection. Our findings consist in lack of decrement with 3 Hz repetitive nerve stimulation and facilitation with 20 Hz repetitive nerve stimulation; progressive increasing of jitter; early appearance of fibrillations; small and short motor unit action potential in the first 3 weeks, followed by increasing of MUAP amplitude and duration, with polyphasic morphology. Although claimed as highly specific and sensible, neuromuscular junction facilitation is an inconstant finding in human botulism. Therefore, lack of neuromuscular junction facilitation cannot exclude a diagnosis of botulism. Our findings are compatible with a process of acute denervation followed by distal reinnervation, favored by terminal nerve sprouting. PMID- 29128987 TI - Comparison of olfactory and gustatory disorders in Alzheimer's disease. AB - Patients with Alzheimer's disease (AD) develop olfactory and gustatory disorders. However, the order of failure and relevance of the pathophysiology are unclear. We compared olfactory identification and whole mouth gustation in patients with AD to those with mild cognitive impairment (MCI) and to healthy controls (HC) and assessed correlations with pathophysiology. Patients with AD (n = 40), MCI (n = 34), and HC (n = 40) were recruited. We performed the Odor Stick Identification Test for Japanese (OSIT-J), gustatory test by the intraoral dropping method using taste solutions, Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale Japanese version (ADAS-J cog), Touch Panel type Dementia Assessment Scale (TDAS), and measurement of amyloid beta (Abeta) 42 and phosphorylated tau (p-tau) 181 levels in cerebrospinal fluid (CSF). Patients with AD and MCI had lower OSIT-J scores than did the HC. The OSIT-J score was correlated with the MMSE, ADAS-J cog, TDAS, and Abeta42 results. There were no significant differences in the gustatory test scores among the three groups. The gustatory test score was only correlated with the MMSE, ADAS-J cog, and TDAS results. Olfactory function decreased in AD and MCI patients and was associated with CSF biomarker levels and cognitive disorders. The results suggest that olfactory function is impaired in early stage of AD. Gustatory function was not correlated with CSF biomarkers, which suggests that it may not be impaired in early stage of AD. PMID- 29128988 TI - Employing Community Voices: Informing Practice and Programming through Camden Healthy Start Focus Groups. AB - Objectives Women living in communities with low-socioeconomic status, substandard healthcare, and ongoing exposure to social disparities encounter barriers to healthcare, often making it difficult to access health services. Barriers may stem from provider interactions with clients, conditions of the healthcare facility, or even language barriers. This prompts a call for providers to be keenly aware of the obstacles women encounter when attempting to access services. Methods In an effort to facilitate better access to services, Camden Healthy Start conducted six focus groups. Thirty-nine women between the ages of 22-56 participated. A total of 39 questions were posed to participants about health behavior, health services, pregnancy, reproductive health, and barriers to accessing services. Each 2 h session was audio recorded, translated and transcribed. Following the format of the Women's Health: Attitudes and Practices in North Carolina Focus Group Research, responses were analyzed and themes emerged. Results This article discusses characteristics of healthcare services and cultural insensitivity that impact women's access and act as barriers to care. The results signal the need for Healthy Start to apply a more relational engagement when providing services. Consideration for Practice Relational engagement includes getting to know the client as a person first, respecting their rights to autonomy in the decision making process, and demonstrating an understanding of the client's culture and inclusion of their voices in the conversation. PMID- 29128989 TI - Infant Mortality Lessons Learned from a Fetal and Infant Mortality Review Program. AB - : Objective To review fetal and infant deaths from women enrolled in Indianapolis Healthy Start using the National Fetal and Infant Mortality Review (FIMR) methods to provide strategies for prevention. METHODS: Marion County Public Health Department (MCPHD) FIMR staff identified and reviewed 22 fetal and infant deaths to Indianapolis Healthy Start program participants between 2005 and 2012. Trained FIMR nurses completed 13 of 20 maternal interviews and compiled case summaries of all deaths from the MCPHD FIMR database.. Results Case review teams identified a total of 349 family strengths, 219 contributing factors, and made 220 recommendations for future pregnancies. FIMR deliberation values for Healthy Start program participant deaths were similar to other infant deaths in Marion County during the same time period. Common themes that emerged from the reviews included lack of social support, absence of paternal involvement, substance abuse, non-compliance, and poor health behaviors leading to chronic health conditions that complicated many pregnancies. Conclusions A number of the infant deaths in this review could have been prevented with preconception and inter conception education and by improving the quality and content of prenatal care. PMID- 29128990 TI - Erratum to: Fertility-sparing for young patients with gynecologic cancer: How MRI can guide patient selection prior to conservative management. AB - The original version of this article unfortunately contained mistakes. The figures 7D, 7E and 7F were missing in the article and arrows were missing in the figures 6C, 8B and 11C. The year of publication and volume number for references 19, 79 and 87 have been updated. Also, the Table 2 layout has been improved for better readability. The Publisher apologizes for the mistakes and the inconvenience caused. PMID- 29128991 TI - Renal cancer at unenhanced CT: imaging features, detection rates, and outcomes. AB - PURPOSE: To describe and quantify the rate of detection of renal cancer on unenhanced CT. METHODS: This retrospective, HIPAA-compliant study was approved by the Institutional Review Board. Electronic health records for all patients who underwent unenhanced abdominal CT at our institution between 2000 and 2005 were reviewed to identify patients subsequently diagnosed with renal cancer during a follow-up period of up to 12 years. Images were reviewed to determine if the cancer was visible at index (first) unenhanced CT and their findings recorded. Original radiology reports were reviewed to determine whether the renal cancer was reported; Fisher's Exact Test compared imaging features of detected and missed cancers. Clinical outcomes including time until diagnosis and stage at diagnosis were used to assess the potential impact of missed cancers. RESULTS: Of 15,695 patients, 82 (0.52%) were diagnosed with renal cancer. Of these, 43/82 (52%) cancers were retrospectively detectable on index unenhanced CT. Among retrospectively detectable cancers, 63% (27/43) were originally detected and reported on index CT and 37% (16/43) were missed. Size was the only feature associated with detection; 83% (20/24) of cancers > 3.0 cm were detected versus 37% (7/19) of cancers <= 3.0 cm (p = 0.0036). Although none of the 16 missed renal cancers developed metastases between index CT and time of diagnosis (median 33.5 months), 4 (25%) progressed in stage. CONCLUSIONS: Renal cancer was rare in patients undergoing unenhanced abdominal CT. Over one-third of potentially detectable cancers were missed prospectively. However, missed cancers did not metastasize and infrequently progressed in stage before being diagnosed. PMID- 29128992 TI - Mapping of hepatic vasculature in potential living liver donors: comparison of gadoxetic acid-enhanced MR imaging using CAIPIRINHA technique with CT angiography. AB - PURPOSE: To retrospectively evaluate gadoxetic acid-enhanced magnetic resonance angiography (MRA) using controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) technique for mapping hepatic vascular anatomy in potential living liver donors, with CT angiography (CTA) as reference standard. METHODS: 82 potential living liver donors who underwent MRA and CTA were enrolled in this HIPAA-compliant IRB-approved study. MRA and CTA images were evaluated by two reviewers in consensus with respect to (1) image quality scores for depiction of the hepatic vessels and (2) accuracy of MRA for determining the hepatic vascular variants with CTA as reference standard. The image quality scores were compared using Fisher's exact test between MRA and CTA. RESULTS: The accuracy for determining the hepatic arterial, portal, and hepatic venous variants and segment IV arterial origin was 73, 90, 79, and 55%, respectively, compared to CTA. However, subjective image quality for depiction of hepatic arteries in MRA was significantly lower than CTA (p < 0.001). The portal and hepatic venous image quality was almost equal in both modalities (p = 0.059) except left hepatic vein being depicted better on CT images (p = 0.023). CONCLUSION: Gadoxetic acid enhanced MRA using CAIPIRINHA technique is feasible for mapping hepatic vasculature in potential living liver donors, with moderate accuracy for arterial variants and good to excellent results for hepatic and portal vein variants, compared with CTA. However, the specific delineation of segment IV arterial origin was possible in just over half of the liver donors with MRA. PMID- 29128993 TI - Pancreatic adenocarcinoma: cross-sectional imaging techniques. AB - Pancreatic adenocarcinoma is a common malignancy that has a poor prognosis. Imaging is vital in its detection, staging, and management. Although a variety of imaging techniques are available, MDCT is the preferred imaging modality for staging and assessing the resectability of pancreatic adenocarcinoma. MR also has an important adjunct role, and may be used in addition to CT or as a problem solving tool. A dedicated pancreatic protocol should be acquired as a biphasic technique optimized for the detection of pancreatic adenocarcinoma and to allow accurate local and distant disease staging. Emerging techniques like dual-energy CT and texture analysis of CT and MR images have a great potential in improving lesion detection, characterization, and treatment monitoring. PMID- 29128994 TI - Radiologists' preferences regarding content of prostate MRI reports: a survey of the Society of Abdominal Radiology. AB - PURPOSE: To evaluate radiologist preferences regarding specific content that warrants inclusion in prostate MRI reports. METHODS: Sixty-one members of the Society of Abdominal Radiology responded to a 74-item survey regarding specific content warranted in prostate MRI reports, conducted in August 2016. RESULTS: General items deemed essential report content by >= 50% of respondents were prostate volume (80%), extent of prostate hemorrhage (74%), TURP defects (69%), coil type (64%), BPH (61%), contrast dose (61%), contrast agent (59%), medications administered (59%), and magnet strength (54%). Details regarding lesion description deemed essential by >= 50% were overall PI-RADS category (88%), DCE (+/-) (82%), subjective degree of diffusion restriction (72%), T2WI intensity (72%), T2WI margins (65%), T2WI shape (52%), DWI 1-5 score (50%), and T2WI 1-5 score (50%). Details deemed essential to include in the report Impression by >= 50% of respondents were lymphadenopathy and metastases (100%), EPE (98%), SVI (98%), neurovascular bundle involvement (93%), index lesion location (93%), PI-RADS category of index lesion (82%), number of suspicious lesions (78%), significance of index lesion PI-RADS category (53%), and PI-RADS category of non-index lesions (52%). Preferred methods for lesion localization were slice/image number (68%), 3-part craniocaudal level (68%), zonal location (65%), anterior vs. posterior location (57%), and medial vs. lateral position (56%). Least preferred methods for localization were numeric sector from the PI RADS sector map (8%), annotated screen capture (10%), and graphical schematic of PI-RADS sector map (11%). CONCLUSION: Radiologists generally deemed a high level of detail warranted in prostate MRI reports. The PI-RADS v2 sector map was disliked for lesion localization. PMID- 29128995 TI - A systematic review of dietary interventions for gestational weight gain and gestational diabetes in overweight and obese pregnant women. AB - PURPOSE: The number of overweight and obese women is increasing in the obstetric population. The aim of this study was to review studies that reported results related to the efficacy of dietary interventions on gestational weight gain (GWG) or the prevention of gestational diabetes (GDM) in overweight and obese women. METHODS: The search was performed using the CINAHL, PubMed, Scopus and Medic electronic databases and limited to the years between 2000 and March 2016. This systematic review includes 15 research articles of which 12 were randomized controlled trials, and three were controlled trials. Three main categories emerged as follows: (1) the types of interventions, (2) the contents of the interventions and (3) the efficacy of the intervention on GWG and the prevention of GDM. The quality of the selected studies was evaluated using the AHRQ Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews. RESULTS: Of the selected 15 studies, eight included a specified diet with limited amounts of nutrients or energy, and the others included a dietary component along with other components. Ten studies reported significant differences in the measured outcomes regarding GWG or the prevention of GDM between the intervention and the control groups. CONCLUSIONS: This review confirms the variability in the strategies used to deliver dietary interventions in studies aiming to limit GWG and prevent GDM in overweight and obese women. Inconsistency in the provider as well as the content of the dietary interventions leaves the difficulty of summarizing the components of effective dietary interventions. PMID- 29128996 TI - e-Derma - a Novel Wireless Dermatoscopy System. AB - Cutaneous Melanoma (CM) is a malignant tumour, and is one of the most rapidly growing cancers. Discovering a melanoma in the early stages of the disease is extremely difficult and, as such, only an invasive disease stage can be identified easily with the naked eye. Dermatoscopy is a diagnostic method intended to maximise early detection of CM performed by the dermatoscopy system. To address the limitations of existing systems a novel, wireless digital dermatoscopy system is presented for providing high-resolution images. It integrates a wire-free camera operation and offers a safe transfer of captured images to the computer. The working process of available dermatoscopy systems was studied, which are the most commonly used in everyday dermatology practice. Some findings, like operability, image quality, scalability, user-friendliness, and safeness, were used for the development of an e-Derma dermatoscopy system. An assessment method was performed by a group of dermatoscopy trained dermatologists to evaluate the quality of the testing images. Finally, a laboratory evaluation of images in regard to different parameters like sharpness, colour representation and illumination was performed with the side-by-side comparison of images of available dermatoscopy systems. e-Derma is a novel dermatoscopy system, which eliminates some limitations of existing systems and provides high-quality images. A novel low-budget highly capable dermatoscopy system is presented. The integrated wireless image transfer technology eliminates the movement limitations of a therapist. The image resolution is not limited by the integrated camera; it is easily upgradable with a wide range of on market alternative or improved camera models. PMID- 29128997 TI - PD-1-PD-L1 immune-checkpoint blockade in malignant lymphomas. AB - Tumor cells can evade immune surveillance through overexpressing the ligands of checkpoint receptors on tumor cells or adjacent cells, leading T cells to anergy or exhaustion. Growing evidence of the interaction between tumor cells and microenvironment promoted the emergence of immune-checkpoint blockade. By targeting programmed cell death-1 (PD-1) pathway, cytotoxic activity of T cell is enhanced significantly and tumor cell lysis is induced subsequently. Currently, various antibodies against PD-1 and programmed death-ligand 1 (PD-L1) are under clinical studies in lymphomas. In this review, we outline the rationale for investigation of PD-1-PD-L1 immune-checkpoint blockade in lymphomas and discuss their prospect of applications in clinical treatment. PMID- 29128998 TI - Technology use and its association with health and depressive symptoms in older cancer survivors. AB - PURPOSE: Acknowledging the expanding influence of technology in the promotion of health and wellness, this study assessed the role of information and communication technology (ICT) use in the lives of older cancer survivors. METHODS: A community sample of cancer survivors aged 65 and older (N = 1411) was extracted from a 2011 U.S. National Health and Aging Trends Study dataset. Weighted multiple regression and multinomial logistic regression analyses were performed to explore the relationships between survey respondents' ICT use and their self-rated health status and depressive symptoms. RESULTS: The majority of respondents reported rarely or never engaging in ICT use. Greater use of communication technology such as emailing or texting was associated with decreased risk for severe depressive symptoms and higher self-rated health status. Information technology use was not associated with depressive symptoms and self-rated health status. CONCLUSIONS: Investigation into reasons behind older cancer survivors' apparent low rates of engagement with ICT is warranted, particularly the examination of access as a potential barrier. Findings indicated that frequent use of communication technology was positively linked with mental and physical wellness. The nature of the relationships between communication technology use and physical and mental health merits further research, helping to determine whether community-based educational efforts to improve technology access and skills may benefit the growing population of older cancer survivors. PMID- 29128999 TI - Impact of potentially inappropriate medications and polypharmacy on 3-month readmission among older patients discharged from acute care hospital: a prospective study. AB - BACKGROUND: Polypharmacy and potentially inappropriate medications (PIMs) are known to affect several negative outcomes in older patients. However, studies comparatively assessing polypharmacy and PIMs in relation to readmission are distinctively lacking. AIMS: To compare the impact of polypharmacy and PIMs on 3 month readmission among older patients discharged from acute care hospital. METHODS: Our series consisted of 647 patients consecutively enrolled in a multicenter observational study. The outcome of the study was the occurrence of any admission during the 3-month follow-up after discharge. Polypharmacy was defined as use of more than eight medications. PIMs were identified using 2015 version of Beers and Screening Tool of Older Persons Prescriptions (STOPP) criteria. Statistical analysis was performed using logistic regression models. RESULTS: After adjusting for potential confounders, polypharmacy (OR 2.72, 95% CI 1.48-4.99) was found associated with the outcome, while Beers (OR 0.85, 95% CI 0.46-1.56), STOPP (OR 1.60, 95% CI 0.85-3.01), or combined Beers and STOPP violations (OR 0.99, 95% CI 0.57-1.74) were not. The association between polypharmacy and 3-month readmission was confirmed in logistic regression models including Beers (OR 2.88, 95% CI 1.55-5.34), STOPP (OR 2.64, 95% CI 1.43-4.87), or combined Beers and STOPP violations (OR 2.80, 95% CI 1.51-5.21). DISCUSSION: Besides confirming that polypharmacy should be considered as a marker for readmission risk among older patients discharged from acute care hospital, our findings suggest that the association between polypharmacy and 3-month readmission is substantially independent of use of PIMs. CONCLUSIONS: Polypharmacy, but not PIMs was significantly associated with readmission. Hospitalization should always be considered as a clue to individuate unnecessary polypharmacy and to reduce the burden of medications whenever possible. PMID- 29129000 TI - Health literacy in type 2 diabetes patients: a systematic review of systematic reviews. AB - Aim To summarize, critically review, and interpret the evidence related to the systematic reviews on health literacy (HL) amongst type 2 diabetes mellitus (T2DM). Methods The methodology for this study consisted of a systematic review of systematic reviews, using the PRISMA statement and flowchart to select studies, and searching on PubMed, CINAHL, Scopus, and Cochrane. The search covered the period between January 2006 and June 2016. Results From the 115 identified record by the queries, only six systematic reviews were included, following a quality evaluation using AMSTAR. The included systematic reviews content was analyzed by the independent work of two authors, using a narrative synthesis approach. The findings of this study (i.e., main themes) are areas of consensus and gaps in knowledge. Areas of consensus are HL definition, HL measurement tools, and the relationship between T2DM patient knowledge (or literacy) and his/her HL. The gaps in knowledge were the assessment of the relations between HL and health outcomes and self-efficacy, the gender differences, the effectiveness of interventions to improve HL, the cost effectiveness study of interventions to improve HL, and the understanding of the influence of organizational environment on HL. Conclusion This review provides a current state of knowledge to address clinical practice and research proposals. HL could be useful to personalize patients' follow-up and it should be routinely assessed in its three dimensions (i.e. functional, interactive and critical) to enhance patients' ability to cope with clinical recommendations. Future research should be mainly aimed to test the effectiveness of evidence-based interventions to improve HL amongst T2DM patients. PMID- 29129001 TI - Impact of temperature and storage time on the migration of antimony from polyethylene terephthalate (PET) containers into bottled water in Qatar. AB - Prosperity in Qatar and the consequent stresses on water resources resulted in a sustainable increase in the bottled drinking water market. Reports on health concerns and possible migration of chemicals from the plastic material into the water have driven the current investigation. This study aims to address the extent of antimony (Sb) leaching from polyethylene terephthalate (PET) water bottles subject to temperature variations (24-50 degrees C) due to Qatar's hot climate and improper storage conditions. A representative basket including 66 different imported and locally produced water bottles was considered. The concentrations of Sb in bottled water ranged from 0.168 to 2.263 MUg/L at 24 degrees C and from 0.240 to 6.110 MUg/L at 50 degrees C. Antimony concentrations in PET bottles at 24 degrees C was significantly lower than those at 50 degrees C (p = 0.0142), indicating that the temperature was a principal factor affecting the release of Sb from the plastic into the water. Although the detected Sb amounts were below the guidelines endorsed by WHO and Qatar (standard 5 MUg/L) at 24 degrees C, the concentration measured at 50 degrees C was higher than the recommended WHO values (6.11 MUg/L). PMID- 29129002 TI - Histological characterization of Passiflora pohlii Mast. root tips cryopreserved using the V-Cryo-plate technique. AB - Cryopreservation stands out as the main strategy to ensure safe and cost efficient long-term conservation of plant germplasm, especially for biotechnological materials. However, the injuries associated with the procedure may result in structural damage and low recovery rates after cooling. Histological analysis provides useful information on the effects of osmotic dehydration, LN exposure, and recovery conditions on cellular integrity and tissue organization, allowing the determination of the critical steps of the cryopreservation protocol and, thus, the use of optimized treatments. Passiflora pohlii Mast. (Passifloraceae) is a native species from Brazil with potential agronomic interest. Recent studies showed the presence of saponins in its roots, which presented antioxidant activity. The goal of this work was to develop a cryopreservation technique for root tips of in vitro-derived plants of P. pohlii using the V-Cryo-plate technique and to characterize the anatomical alterations that occurred during the successive steps of the protocol. Root tips were excised from in vitro plants and precultured before adhesion to cryo-plates and then treated for different periods with the plant vitrification solutions PVS2 or PVS3. Treatment with PVS2 for 45 min resulted in higher recovery (79%) when compared with PVS3 (43%). The greatest number of adventitious roots per cryopreserved explant was also observed after a 45-min exposure to PVS2. Plasmolysis levels were higher in cortical cells of cryopreserved explants treated with PVS2, while pericycle and central cylinder cells were not damaged after this treatment. Thirty days after rewarming, no plasmolysis could be detected, regardless of the experimental conditions. PMID- 29129003 TI - Chelation Therapy as a Cardiovascular Therapeutic Strategy: the Rationale and the Data in Review. AB - Chelation therapy, typically used to remove heavy metal toxins, has also been controversially used as a treatment for coronary artery disease. The first Trial to Assess Chelation Therapy (TACT) aimed to provide evidence on chelation therapy's potential for benefit or harm. Although TACT had some significant results, the trial does not provide enough evidence to recommend routine chelation therapy and has limitations. The second TACT was recently funded reigniting a discussion about the value of chelation therapy, its efficacy, and allocation of research resources. Despite limited evidence, patients continue to pursue chelation therapy as a treatment for coronary artery disease. As the medical community has a responsibility to understand all treatments patients pursue, it is important to comprehensively appraise chelation therapy for cardiovascular disease. Understanding the background of heavy metal toxicity, the putative target of chelation therapy, on the cardiovascular system is important to contextualize the role of chelation therapy in cardiovascular disease prevention. We review the clinical evidence of heavy metal toxicity and cardiovascular disease, and available clinical trial data on use of chelation therapy to minimize the cardiovascular burden of heavy metal toxicity. PMID- 29129004 TI - Multiple hereditary osteochondromatosis with spinal cord compression: case report. AB - OBJECTIVE: The purpose of the report is to describe a patient with hereditary osteochondromatosis and spinal cord compression at the thoracic level. CLINICAL FEATURES: An 8-year-old patient with hereditary osteochondromatosis inherited from his father presented paraparesis in the left foot, leading to complete paralysis in both legs. INTERVENTION: In a CT scan, a bony tumor rising from the posterior wall of the T3 body narrowing the spinal canal, and the MRI spinal cord compression at the same level and the hydrosyringomyelic cavity extended to the conus medullaris; with an anterior thoracic approach to T2-T4, the fibro cartilaginous tumor was removed, and the stabilization was completed with bone graft and a plate. Two months after surgery, the patient recovered strength in both legs. CONCLUSIONS: A detailed family history through examination-guided advanced imaging and biopsy provides useful information for diagnosis and appropriate management of occupative lesions in patients affected with multiple hereditary exostosis. PMID- 29129005 TI - Chronic overdrainage syndrome: pathophysiological insights based on ICP analysis: a case-based review. AB - INTRODUCTION: Chronic overdrainage affects shunted patients producing a variety of symptoms that may be misdiagnosed. The best known symptoms are so-called shunt related headaches. There is mounting evidence that changes in cerebrospinal venous system dynamics are a key factor to the pathophysiology of chronic overdrainage syndrome. CLINICAL PRESENTATION: We report the case of a 29-year-old woman with a shunt since the postnatal period suffering from chronic but the most severe intermittent headache attacks, despite an open shunt and with unchanged ventricular width during attacks. Intracranial pressure (ICP) recordings were performed during headache attacks and thereafter. DIAGNOSIS AND MANAGMENT: Massively increased ICPs, a continuous B wave "storm," and severely compromised intracranial compliance despite an open shunt were found, a scenario that was always self-limiting with the resolution of symptoms after several hours. When mobilized to the upright position, her ICPs dropped to - 17 mm Hg, proving shunt overdrainage. OUTCOME AND CONCLUSIONS: Symptomatology can only be explained by sudden venous entrapment following chronic venous distention as a result of chronic overdrainage. Subsequent therapeutic management with an overdrainage preventing shunt and satisfying clinical outcome with complete ceasing of headache attacks adds insight into the pathophysiology of chronic overdrainage syndrome. PMID- 29129007 TI - Association Between Employment and Mental Health Service Use Among Justice Involved Individuals. AB - Using a nationally representative sample of justice-involved persons (N = 1525), the present study examined the extent to which employment status was associated with mental health service use by various service providers. The findings indicate that the rate of mental health service use by general health care providers among the unemployed was higher than that of the employed. Factors associated with mental health service use varied by type of provider. Our findings suggest that employment may be critical for justice-involved people in enhancing their mental health status, which could result in their successful community integration. PMID- 29129006 TI - Preferences for Depression Help-Seeking Among Vietnamese American Adults. AB - Culture impacts help-seeking preferences. We examined Vietnamese Americans' help seeking preferences for depressive symptoms, through a telephone survey (N = 1666). A vignette describing an age- and gender-matched individual with depression was presented, and respondents chose from a list of options and provided open-ended responses about their help-seeking preferences. Results showed that 78.3% would seek professional help, either from a family doctor, a mental health provider, or both; 54.4% preferred to seek help from a family doctor but not from a mental health provider. Most (82.1%) would prefer to talk to family or friends, 62.2% would prefer to look up information, and 50.1% would prefer to get spiritual help. Logistic regression analysis revealed that preferences for non-professional help-seeking options (such as talking to friends or family, looking up information, and getting spiritual help), health care access, and perceived poor health, were associated with increased odds of preferring professional help-seeking. This population-based study of Vietnamese Americans highlight promising channels to deliver education about depression and effective help-seeking resources, particularly the importance of family doctors and social networks. Furthermore, addressing barriers in access to care remains a critical component of promoting professional help-seeking. PMID- 29129008 TI - High levels of oxidized fatty acids in HDL are associated with impaired HDL function in patients with active rheumatoid arthritis. AB - The objective of this study was to evaluate oxidation products of arachidonic acid and linoleic acid in lipoproteins and synovial fluid (SF) from patients with active rheumatoid arthritis (RA) compared to non-RA controls. High-density lipoproteins (HDL) and low-density lipoproteins (LDL) were isolated from plasma using fast protein liquid chromatography and HDL was isolated from SF using dextran sulfate precipitation. 5-Hydroxyeicosatetraenoic acid (HETE), 12-HETE, 15 HETE, 9 hydroxyoctadecadienoic (HODE), and 13-HODE levels were measured in HDL, LDL, and SF by liquid chromatography-tandem mass spectrometry. HDL's anti inflammatory function, cholesterol levels, myeloperoxidase (MPO) and paraoxonase 1 (PON1) activities were determined as previously. 5-HETE, 15-HETE, 9-HODE, and 13-HODE levels were significantly increased in HDL and LDL from patients with active RA (n = 10) compared to healthy controls (n = 8) and correlated significantly with measures of systemic inflammation, particularly in HDL (r = 0.65-0.80, p values < 0.004). Higher HETES and HODES in HDL were also significantly correlated with impaired HDL function as measured by the HDL inflammatory index (HII) (r = 0.54-0.58; p values < 0.03). 15-HETE levels and MPO activity were higher in RA SF (n = 10) compared to osteoarthritis (OA) SF(n = 11), and HDL from RA SF had worse function compared to OA SF HDL (HII = 2.1 +/- 1.9 and 0.5 +/- 0.1), respectively (p < 0.05). Oxidation products of arachidonic acid and linoleic acid are increased in HDL and LDL from patients with active RA compared to healthy controls, and are associated with worse anti-oxidant function of HDL. These results suggest a potential mechanism by which oxidative stress from active RA increases oxidized fatty acids in HDL, promoting HDL dysfunction, and thereby increasing atherosclerotic risk. PMID- 29129010 TI - Social Simulation Models at the Ethical Crossroads. AB - Computational models of group opinion dynamics are one of the most active fields of sociophysics. In recent years, advances in model complexity and, in particular, the possibility to connect these models with detailed data describing individual behaviors, preferences and activities, have opened the way for the simulations to describe quantitatively selected, real world social systems. The simulations could be then used to study 'what-if' scenarios for opinion change campaigns, political, ideological or commercial. The possibility of the practical application of the attitude change models necessitates that the research community working in the field should consider more seriously the moral aspects of their efforts, in particular the potential for their use for unintended goals. The paper discusses these issues, and offers a suggestion for a new research direction: using the attitude models to increase the awareness and detection of social manipulation cases. Such research would offer a scientific challenge and meet the ethical criteria. PMID- 29129009 TI - IRAK2 is associated with susceptibility to rheumatoid arthritis. AB - This study was performed to investigate the association of the single nucleotide polymorphisms of interleukin-1 receptor-associated kinase 2 (IRAK2) rs3844283 and rs708035 with rheumatoid arthritis (RA). IRAK2 rs3844283 and rs708035genotyping was determined by mutagenically separated PCR with specifically designed primers in a cohort of 222 (30 men, 192 women, mean age 49 years) adult RA patients and 224 matched controls. IRAK2 rs3844283 C allele was detected in 66% of RA patients and 74% of controls. The CC genotype was the most frequent genotype in both RA patients (45.5%) and the controls (56.3%). The G allele was found to be associated with RA susceptibility (OR = 1.47, 95% CI = 1.10-1.96, p = 0.008). The GG genotype was found to be associated with RA in the co-dominant and the dominant models (OR = 2.03, 95% CI = 1.08-3.81, p = 0.042 and OR = 1.54, 95% CI = 1.06-2.23, p = 0.023, respectively). IRAK2 rs708035 was found not to be in the Hardy-Weinberg equilibrium. The hyperfunctional IRAK2 rs708035 A allele was more frequent in RA patients than in controls (69.9 versus 62.2%, respectively, p = 0.015). Moreover, IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium and the GA haplotype was significantly more frequent in RA patients than in controls (p = 0.034). This study for the first time ever reports the association of IRAK2 rs3844283, IRAK2 rs708035, and the corresponding haplotypes with RA. Functional studies are recommended to elucidate the risk posed by the GA haplotype for the development of RA. PMID- 29129011 TI - Embodiment and Estrangement: Results from a First-in-Human "Intelligent BCI" Trial. AB - While new generations of implantable brain computer interface (BCI) devices are being developed, evidence in the literature about their impact on the patient experience is lagging. In this article, we address this knowledge gap by analysing data from the first-in-human clinical trial to study patients with implanted BCI advisory devices. We explored perceptions of self-change across six patients who volunteered to be implanted with artificially intelligent BCI devices. We used qualitative methodological tools grounded in phenomenology to conduct in-depth, semi-structured interviews. Results show that, on the one hand, BCIs can positively increase a sense of the self and control; on the other hand, they can induce radical distress, feelings of loss of control, and a rupture of patient identity. We conclude by offering suggestions for the proactive creation of preparedness protocols specific to intelligent-predictive and advisory-BCI technologies essential to prevent potential iatrogenic harms. PMID- 29129012 TI - Need for Controlling of the Filter Bubble Effect. PMID- 29129013 TI - 'Blue Whale Challenge': A Game or Crime? AB - A bewildering range of games are emerging every other day with newer elements of fun and entertainment to woo youngsters. Games are meant to reduce stress and enhance the cognitive development of children as well as adults. Teenagers are always curious to indulge in newer games; and e-gaming is one such platform providing an easy access and quicker means of entertainment. The particular game challenge which has taken the world by storm is the dangerous "Blue Whale Challenge" often involving vulnerable teenagers. The Blue Whale Challenge is neither an application nor internet based game but the users get a link through social media chat groups to enter this "deadly" challenge game. This probably is the only game where the participant has to end his/her life to complete the game. The innocent teenagers are being targeted based on their depressed psychology and are coercively isolated from their social milieux on the pretext of keeping the challenges confidential. To add to the woes, no option is offered to quit the challenge even if the contender is unable to complete the challenge. Blue Whale Challenge in its sheer form could be seen as an illegal, unethical and inhumane endeavor in our present society. The present communication discusses the severe effects of the game on teenagers, the ethical concerns involved and the preventive measures necessary to curb it. PMID- 29129014 TI - Causal Factors of Corruption in Construction Project Management: An Overview. AB - The development of efficient and strategic anti-corruption measures can be better achieved if a deeper understanding and identification of the causes of corruption are established. Over the past years, many studies have been devoted to the research of corruption in construction management (CM). This has resulted in a significant increase in the body of knowledge on the subject matter, including the causative factors triggering these corrupt practices. However, an apropos systematic assessment of both past and current studies on the subject matter which is needful for the future endeavor is lacking. Moreover, there is an absence of unified view of the causative factors of corruption identified in construction project management (CPM). This paper, therefore, presents a comprehensive review of the causes of corruption from selected articles in recognized construction management journals to address the mentioned gaps. A total number of 44 causes of corruption were identified from 37 publications and analyzed in terms of existing causal factors of corruption, annual trend of publications and the thematic categorization of the identified variables. The most identifiable causes were over close relationships, poor professional ethical standards, negative industrial and working conditions, negative role models and inadequate sanctions. A conceptual framework of causes of corruption was established, after categorizing the 44 variables into five unique categories. In descending order, the five constructs are Psychosocial-Specific Causes, Organizational-Specific Causes, Regulatory-Specific Causes, Project-Specific Causes and Statutory-Specific Causes. This study extends the current literature of corruption research in construction management and contributes to a deepened understanding of the causal instigators of corruption identified in CPM. The findings from this study provide valuable information and extended knowledge to industry practitioners and policymakers as well as anti-corruption agencies in the formulation and direction of anti-corruption measures. To corruption researchers in CM, this study is vital for further research. PMID- 29129015 TI - Melanoma Inhibition by Anthocyanins Is Associated with the Reduction of Oxidative Stress Biomarkers and Changes in Mitochondrial Membrane Potential. AB - Anthocyanins are water soluble pigments which have been proved to exhibit health benefits. Several studies have investigated their effects on several types of cancer, but little attention has been given to melanoma. The phytochemical content of nine different berry samples was assessed by liquid chromatography followed by electrospray ionization mass spectrometry (LC-ESI+-MS). Twenty-six anthocyanins were identified, after a previous C18 Sep-pak clean-up procedure. Chokeberry and red grape anthocyanins rich extracts (C-ARE and RG-ARE) were selected to be tested on normal and melanoma cell lines, due to their different chemical pattern. C-ARE composition consists of cyanidin aglycone glycosylated with different sugars; while RG-ARE contains glucosylated derivatives of five different aglycones. Both C-ARE and RG-ARE anthocyanins reduced proliferation, increased oxidative stress biomarkers and diminished mitochondrial membrane potential in melanoma cells, having no negative influence on normal cells. A synergistic response may be attributed to the five different aglycones present in RG-ARE, which proved to exert greater effects on melanoma cells than the mixture of cyanidin derivatives with different sugars (C-ARE). In conclusion, C-ARE and RG-ARE anthocyanins may inhibit melanoma cell proliferation and increase the level of oxidative stress, with opposite effect on normal cells. Therefore, anthocyanins might be recommended as active ingredients for cosmetic and nutraceutical industry. Graphical Abstract ?. PMID- 29129016 TI - Exploring genes involved in benzoic acid biosynthesis in the Populus davidiana transcriptome and their transcriptional activity upon methyl jasmonate treatment. AB - Benzoic acids (BAs) are important structural elements in a wide variety of essential compounds and natural products, and play crucial roles in plant fitness. BA is a precursor of diverse benzenoid compounds, including the hormone salicylic acid (SA) and the aglycone moiety of salicin, which is particularly important in the Salicaceae family. The biosynthetic pathways leading to BA formation in plants are largely unknown. Recently, the CoA-dependent beta oxidative BA biosynthesis pathway, which occurs in peroxisomes, has been characterized in petunia. The core of this pathway is cinnamic acid -> cinnamoyl CoA -> 3-hydroxy-3-phenylpropanoyl-CoA -> 3-oxo-3-phenylpropanoyl-CoA -> benzoyl CoA. Here, we used 454 pyrosequencing to analyze the transcriptome of Populus davidiana and isolate putative genes involved in BA biosynthesis. De novo assembly generated 57,322 unique sequences, including 15,217 contigs and 42,105 singletons. From the unique sequences, we selected six genes exhibiting high similarity to genes encoding L-phenylalanine ammonia lyase, cinnamate:CoA ligase, cinnamoyl-CoA hydratase-dehydrogenase, 3-ketoacyl-CoA thiolase, benzoyl CoA:benzyl alcohol O-benzoyltransferase, and benzaldehyde dehydrogenase. Each of these enzymes might be involved in BA biosynthesis. Real-time PCR (qPCR) analysis revealed that these six genes were highly transcribed in the aerial organs of P. davidiana, particularly in leaves. Treating the leaves of in vitro cultured plants with methyl jasmonate (MeJA) strongly enhanced the mRNA accumulation of all 6 genes, and this treatment also clearly enhanced the accumulation of BA, SA, salicyl alcohol, benzyl alcohol, benzyl benzoate, and benzaldehyde but not salicin. Our study shows that P. davidiana may possess a CoA-dependent beta oxidative BA synthesis pathway. We also identified a relationship between the transcription of these genes and the accumulation of benzenoids, including BA and SA, which are highly responsive to the defense signaling molecule (MeJA). PMID- 29129017 TI - Double-level bone transport for large post-traumatic tibial bone defects: a single centre experience of sixteen cases. AB - PURPOSE: The aim of this study was to evaluate the clinical and functional outcomes of patients with large post-traumatic tibial bone defects managed by double-level bone transport using the Ilizarov technique. METHODS: We retrospectively reviewed 16 patients of 39.1 years (range, 16.0-65.0 years). The bone defects averaged 10.9 +/- 3.8 cm (range: 6.0 cm-20.0 cm) after radical resection and were managed by double-level bone transport. Bone and functional results were evaluated according to the ASAMI criteria. RESULTS: The mean duration of follow-up after frame removal was 29.5 +/- 1.8 months (range, 12.0 36.0 months). All patients achieved complete union in both the regenerates and the docking site and eradication of infection. The mean bone transport time was 55.6 +/- 23.7 days (range, 30.0-125.0 days). The mean external fixation time was 12.0 +/- 3.9 months (range, 5.0-18.0 months), and the mean external fixation index was 1.1 +/- 0.3 months/cm (rang, 0.8-2.0 months/cm). The bone results were excellent in ten patients and poor in six patients. The functional results were excellent in 12 patients and good in four patients. CONCLUSION: Double-level bone transport is a safe, reliable, and successful method for large post-traumatic tibial bone defects. Furthermore, this technique can reduce bone transport time, time in frame, and total treatment time in one stage. PMID- 29129018 TI - A 32-Week Randomized Comparison of Stepwise Insulin Intensification of Biphasic Insulin Aspart (BIAsp 30) Versus Basal-Bolus Therapy in Insulin-Naive Patients with Type 2 Diabetes. AB - INTRODUCTION: This 32-week, open-label, randomized, parallel-group, multinational trial aimed to compare the efficacy and safety of stepwise insulin intensification of biphasic insulin aspart 30 (BIAsp 30) relative to stepwise intensification of a basal-bolus regimen in insulin-naive adults with type 2 diabetes (T2D) who continued pretrial treatment with metformin and sulfonylurea. METHODS: Adults with T2D were randomized into one of two treatment arms for 32 weeks: (1) BIAsp 30 once daily (OD), with the possibility of stepwise treatment intensification up to BIAsp 30 three times daily (TID); (2) insulin glargine OD, with the possibility of stepwise treatment intensification with insulin aspart up to TID. The primary endpoint was change from baseline in HbA1c after 32 weeks. RESULTS: After 32 weeks, the estimated mean change in HbA1c from baseline was statistically significantly lower in the BIAsp 30 arm (- 1.18%) versus basal bolus (- 1.36%) [estimated treatment difference 0.18%; 95% confidence interval (95% CI) 0.01; 0.36; p < 0.05]. The proportion of patients with HbA1c below 7.0% was statistically significantly lower with BIAsp 30 (42.9%) compared with basal bolus (56.9%) (odds ratio 0.58; 95% CI 0.37; 0.89; p = 0.01). The overall rate of severe or blood glucose (BG)-confirmed hypoglycemic events was numerically lower for BIAsp 30 compared with basal-bolus, and a statistically significantly lower rate in nocturnal severe or BG-confirmed hypoglycemia in the BIAsp 30 arm relative to basal-bolus was observed: estimated rate ratio 0.32 (95% CI 0.13; 0.79), p = 0.0131. The proportion of patients with adverse events was similar in both treatment arms. CONCLUSION: Insulin intensification with BIAsp 30 and basal bolus showed an improvement in glycemic control; the change in HbA1c was statistically significantly lower for BIAsp 30 compared to basal-bolus. Basal bolus treatment was accompanied by a numerically, and statistically significantly, higher rate of overall and nocturnal severe or BG-confirmed hypoglycemia, respectively, compared with BIAsp 30. FUNDING: Novo Nordisk A/S. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02453685. PMID- 29129019 TI - Genetic characterization of bank vole virus (BaVV), a new paramyxovirus isolated from kidneys of bank voles in Russia. AB - A genome of bank vole virus (BaVV), isolated from kidney tissues of bank voles (Myodes glareolus) in Russia in 1973, was sequenced. The genomic organization of BaVV (3'-N-P/V/C-M-F-G-L-5', 16,992 nt in length; GenBank accession number MF943130) is most similar to that of Mossman virus (MoV) and Nariva virus (NarPV), two ungrouped paramyxoviruses isolated from rodents in Australia and Trinidad, respectively. The proteins of BaVV have the highest level of sequence identity (ranging from 23-28% for G protein to 66-73% for M protein) to proteins of MoV and NarPV. The results of genetic and phylogenetic analysis suggest that BaVV represents a new species and, together with MoV and NarPV, belongs to a new, yet not established genus of the family Paramyxoviridae. PMID- 29129020 TI - Ethical aspects of medical age assessment in the asylum process: a Swedish perspective. AB - According to European regulations and the legislations of individual member states, children who seek asylum have a different set of rights than adults in a similar position. To protect these rights and ensure rule of law, migration authorities are commonly required to assess the age of asylum seekers who lack reliable documentation, including through various medical methods. However, many healthcare professionals and other commentators consider medical age assessment to be ethically problematic. This paper presents a simplified and amended account of the main findings of a recent ethical analysis of medical age assessment in the asylum process commissioned by the Swedish National Board of Health and Welfare. A number of ethical challenges related to conflicting goals, equality and fairness, autonomy and informed consent, privacy and integrity, and professional values and roles are identified and analysed. It is concluded that most of these challenges can be met, but that this requires a system where the assessment is sufficiently accurate and where adequate safeguards are in place. Two important ethical questions are found to warrant further analysis. The first is whether asylum seekers' consent to the procedure can be considered genuinely voluntary. The second is whether and how medical age assessments could affect negative public attitudes towards asylum seekers or discriminatory societal views more generally. PMID- 29129021 TI - The Effect of Natural or Simulated Altitude Training on High-Intensity Intermittent Running Performance in Team-Sport Athletes: A Meta-Analysis. AB - BACKGROUND: While adaptation to hypoxia at natural or simulated altitude has long been used with endurance athletes, it has only recently gained popularity for team-sport athletes. OBJECTIVE: To analyse the effect of hypoxic interventions on high-intensity intermittent running performance in team-sport athletes. METHODS: A systematic literature search of five journal databases was performed. Percent change in performance (distance covered) in the Yo-Yo intermittent recovery test (level 1 and level 2 were used without differentiation) in hypoxic (natural or simulated altitude) and control (sea level or normoxic placebo) groups was meta analyzed with a mixed model. The modifying effects of study characteristics (type and dose of hypoxic exposure, training duration, post-altitude duration) were estimated with fixed effects, random effects allowed for repeated measurement within studies and residual real differences between studies, and the standard error weighting factors were derived or imputed via standard deviations of change scores. Effects and their uncertainty were assessed with magnitude-based inference, with a smallest important improvement of 4% estimated via between athlete standard deviations of performance at baseline. RESULTS: Ten studies qualified for inclusion, but two were excluded owing to small sample size and risk of publication bias. Hypoxic interventions occurred over a period of 7-28 days, and the range of total hypoxic exposure (in effective altitude-hours) was 4.5-33 km h in the intermittent-hypoxia studies and 180-710 km h in the live-high studies. There were 11 control and 15 experimental study-estimates in the final meta-analysis. Training effects were moderate and very likely beneficial in the control groups at 1 week (20 +/- 14%, percent estimate, +/- 90% confidence limits) and 4-week post-intervention (25 +/- 23%). The intermittent and live-high hypoxic groups experienced additional likely beneficial gains at 1 week (13 +/- 16%; 13 +/- 15%) and 4-week post-intervention (19 +/- 20%; 18 +/- 19%). The difference in performance between intermittent and live-high interventions was unclear, as were the dose of hypoxia and inclusion of training in hypoxia. CONCLUSIONS: Hypoxic intervention appears to be a worthwhile training strategy for improvement in high-intensity running performance in team-sport athletes, with enhanced performance over control groups persisting for at least 4 weeks post-intervention. Pending further research on the type of hypoxia, dose of hypoxia and training in hypoxia, coaches have considerable scope for customising hypoxic training methods to best suit their team's training schedule. PMID- 29129022 TI - Heat Acclimation Decay and Re-Induction: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Although the acquisition of heat acclimation (HA) is well-documented, less is known about HA decay (HAD) and heat re-acclimation (HRA). The available literature suggests 1 day of HA is lost following 2 days of HAD. Understanding this relationship has the potential to impact upon the manner in which athletes prepare for major competitions, as a HA regimen may be disruptive during final preparations (i.e., taper). OBJECTIVE: The aim of this systematic review and meta analysis was to determine the rate of HAD and HRA in three of the main physiological adaptations occurring during HA: heart rate (HR), core temperature (T c), and sweat rate (SR). DATA SOURCES: Data for this systematic review were retrieved from Scopus and critical review of the cited references. STUDY SELECTION: Studies were included when they met the following criteria: HA, HAD, and HRA (when available) were quantified in terms of exposure and duration. HA had to be for at least 5 days and HAD for at least 7 days for longitudinal studies. HR, T c, or SR had to be monitored in human participants. STUDY APPRAISAL: The level of bias in each study was assessed using the McMaster critical review form. Multiple linear regression techniques were used to determine the dependency of HAD in HR, T c, and SR from the number of HA and HAD days, daily HA exposure duration, and intensity. RESULTS: Twelve studies met the criteria and were systematically reviewed. HAD was quantified as a percentage change relative to HA (0% = HA, 100% = unacclimated state). Adaptations in end exercise HR decreased by 2.3% (P < 0.001) for every day of HAD. For end-exercise T c, the daily decrease was 2.6% (P < 0.01). The adaptations in T c during the HA period were more sustainable when the daily heat exposure duration was increased and heat exposure intensity decreased. The decay in SR was not related to the number of decay days. However, protracted HA-regimens seem to induce longer lasting adaptations in SR. High heat exposure intensities during HA seem to evoke more sustained adaptations in SR than lower heat stress. Only eight studies investigated HRA. HRA was 8-12 times faster than HAD at inducing adaptations in HR and T c, but no differences could be established for SR. LIMITATIONS: The available studies lacked standardization in the protocols for HA and HAD. CONCLUSIONS: HAD and HRA differ considerably between physiological systems. Five or more HA days are sufficient to cause adaptations in HR and T c; however, extending the daily heat exposure duration enhances T c adaptations. For every decay day, ~ 2.5% of the adaptations in HR and T c are lost. For SR, longer HA periods are related to better adaptations. High heat exposure intensities seem beneficial for adaptations in SR, but not in T c. HRA induces adaptations in HR and T c at a faster rate than HA. HRA may thus provide a practical and less disruptive means of maintaining and optimizing HA prior to competition. PMID- 29129024 TI - Metabolic regulation of the CCN family genes by glycolysis in chondrocytes. AB - The CCN family consists of 6 genes in the mammalian genome and produces multifunctional proteins involved in a variety of biological processes. Recent reports indicate the profound roles of CCN2 in energy metabolism in chondrocytes, and Ccn2 deficiency is known to alter the expression of 2 other family members including Ccn3. However, almost nothing is known concerning the regulation of the CCN family genes by energy metabolism. In order to gain insight into this critical issue, we initially and comprehensively evaluated the effect of inhibition of glycolysis on the expression of all of the CCN family genes in chondrocytic cells. Upon the inhibition of a glycolytic enzyme, repression of CCN2 expression was observed, whereas CCN3 expression was conversely induced. Similar repression of CCN2 was conferred by the inhibition of aerobic ATP production, which, however, did not induce CCN3 expression. In contrast, glucose starvation significantly enhanced the expression of CCN3 in those cells. The results of a reporter gene assay using a molecular construct containing a CCN3 proximal promoter revealed a dose-dependent induction of the CCN3 promoter activity by the glycolytic inhibitor in chondrocytic cells. These results unveiled a critical role of glycolytic activity in the regulation of CCN2 and CCN3, which activity mediated the mutual regulation of these 2 major CCN family members in chondrocytes. PMID- 29129023 TI - Pathomechanisms of Contact Sensitization. AB - Contact sensitization is the initial process involved in the development of an allergic reaction to xenobiotic environmental substances. Here, we briefly describe the differences between irritant and allergic contact dermatitis. Then, we highlight the essential steps involved in the development of an ACD reaction, i.e., the protein binding of haptens, genetic factors influencing the penetration of sensitizers into the skin, the different mechanisms driving the initial development of an inflammatory cytokine micromilieu enabling the full maturation of dendritic cells, the role of pre- and pro-haptens, antigen presentation and T cell activation via MHC and CD1 molecules, dendritic cell (DC) migration, and potential LC contribution as well as the different T cell subsets involved in ACD. In addition, we discuss the latest publications regarding factors that might influence the sensitizing potential such as repeated sensitizer application, penetration enhancers, humidity of the skin, microbiota, Tregs, and phthalates. Last but not least, we briefly touch upon novel targets for drug development that might serve as treatment options for ACD. PMID- 29129025 TI - Assessment of circulating Wnt1 inducible signalling pathway protein 1 (WISP 1)/CCN4 as a novel biomarker of obesity. AB - WNT1 inducible signaling pathway protein 1 (WISP-1/CCN4) is a novel adipokine, which is upregulated in obesity, and induces a pro-inflammatory response in macrophages in-vitro. Preclinical observations suggested WISP-1/CCN4 as a potential candidate for novel obesity therapy targeting adipose tissue inflammation. Whether circulating levels of WISP-1/CCN4 in humans are altered in obesity and/or type 2 diabetes (T2DM) and in the postprandial state, however, is unknown. This study assessed circulating WISP-1/CCN4 levels in a) paired liquid meal tests and hyperinsulinemic- euglycemic clamps (cohort I, n = 26), b) healthy individuals (cohort II, n = 207) and c) individuals with different stages of obesity and glucose tolerance (cohort III, n = 253). Circulating plasma and serum WISP-1/CCN4 concentrations were measured using a commercially available ELISA. WISP-1/CCN4 levels were not influenced by changes in insulin and/or glucose during the tests. In healthy individuals, WISP-1/CCN4 was detectable in 13% of plasma samples with the intraclass correlation coefficient of 0.93 (95% CI: 0.84 0.96) and in 58.1% of the serum samples in cohort III. Circulating WISP-1/CCN4 positively correlated with body mass index, body fat percentage, leptin and triglyceride levels, hip circumference and fatty liver index. No differences in WISP-1/CCN4 levels between individuals with normal glucose tolerance, impaired glucose tolerance and T2DM were found. The circulating concentrations of WISP 1/CCN4 showed no acute regulation in postprandial state and correlated with anthropometrical obesity markers and lipid profiles. In healthy individuals, WISP 1/CCN4 levels are more often below the detection limit. Thus, serum WISP-1/CCN4 levels may be used as a suitable biomarker of obesity. PMID- 29129026 TI - Micromechanical study of the load transfer in a polycaprolactone-collagen hybrid scaffold when subjected to unconfined and confined compression. AB - Scaffolds are used in diverse tissue engineering applications as hosts for cell proliferation and extracellular matrix formation. One of the most used tissue engineering materials is collagen, which is well known to be a natural biomaterial, also frequently used as cell substrate, given its natural abundance and intrinsic biocompatibility. This study aims to evaluate how the macroscopic biomechanical stimuli applied on a construct made of polycaprolactone scaffold embedded in a collagen substrate translate into microscopic stimuli at the cell level. Eight poro-hyperelastic finite element models of 3D printed hybrid scaffolds from the same batch were created, along with an equivalent model of the idealized geometry of that scaffold. When applying an 8% confined compression at the macroscopic level, local fluid flow of up to 20 [Formula: see text]m/s and octahedral strain levels mostly under 20% were calculated in the collagen substrate. Conversely unconfined compression induced fluid flow of up to 10 [Formula: see text]m/s and octahedral strain from 10 to 35%. No relevant differences were found amongst the scaffold-specific models. Following the mechanoregulation theory based on Prendergast et al. (J Biomech 30:539-548, 1997. https://doi.org/10.1016/S0021-9290(96)00140-6 ), those results suggest that mainly cartilage or fibrous tissue formation would be expected to occur under unconfined or confined compression, respectively. This in silico study helps to quantify the microscopic stimuli that are present within the collagen substrate and that will affect cell response under in vitro bioreactor mechanical stimulation or even after implantation. PMID- 29129027 TI - Factors affecting the efficacy and safety of phosphodiesterase 5 inhibitor and placebo in treatment for lower urinary tract symptoms: meta-analysis and meta regression. AB - PURPOSE: We aimed to investigate the real benefit and safety of phosphodiesterase 5 inhibitor (PDE 5I) for benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) by determining the affecting factors and to overcome the previous meta-analysis studies. METHODS: We conducted a systematic review of improvements in LUTS using International Prostate Symptom Score (IPSS), voiding subscore of IPSS (voiding IPSS), storage subscore of IPSS (storage IPSS), quality of life (QoL), maximal urinary flow rate (Qmax), and post-voided residual volume (PVR), and also investigated adverse events and relevant withdrawal rate. RESULTS: Final included studies were 28 studies with 19,820 subjects (9800 treatment group and 10,020 control group). The overall weighted mean differences of total IPSS, voiding IPSS, storage IPSS, and QoL showed significant improvement. Single placebo group showed significant improvement in all outcomes except PVR. The weighted prevalence of overall withdrawal rate and adverse event specific withdrawal rate was 10 and 3%, respectively. Meta-regression showed that baseline IPSS, dosage of PDE 5I, and country affect clinical improvement compared with placebo. CONCLUSIONS: This study clarifies the efficacy of PDE 5I on treatment of BPH/LUTS as an initial treatment strategy. However, baseline IPSS, dosage of PDE 5I and country affected the clinical improvement. Moreover, adverse event-specific withdrawal rate was not as high as suspected based on the overall withdrawal rate. PMID- 29129029 TI - A game of two halves: inconsistent renal allograft function in two recipients of a split horseshoe kidney. PMID- 29129028 TI - Improved cancer-specific free survival and overall free survival in contemporary metastatic prostate cancer patients: a population-based study. AB - OBJECTIVES: Over the past decade, several systemic agents as docetaxel, cabazitaxel, sipuleucel-T, abiraterone and enzalutamide have improved overall survival (OS) in metastatic prostate cancer (mPCa) patients. However, to date the OS benefit was not demonstrated in population-based analysis. METHODS: Between 2004 and 2014, 19,047 men with de novo mPCa were identified within the Surveillance Epidemiology and End Results database. Median year of diagnosis resulted in two groups: historical (2004-2008) and contemporary (2009-2014). Due to potentially important differences according to year of diagnosis, we relied on propensity score matching. Propensity-score-matched Kaplan-Meier analyses and Cox regression models (CRMs) tested cancer-specific mortality (CSM) free survival and overall mortality (OM) free survival according to treatment period. RESULTS: The propensity-score-matched cohort consisted of 8596 patients with mPCa. Of those, 4298 (50.0%) were historical (2004-2008) and 4298 (50.0%) were contemporary (2009 2014). CSM free survival rates and OM free survival rate were 32 versus 36 months (p < 0.0001) and 26 versus 29 months (p < 0.0001) for, respectively, historical and contemporary patients. In multivariable CRMs, patients diagnosed in contemporary years had lower CSM (HR 0.88; CI 0.82-0.93) and OM (HR 0.88; CI 0.84 0.93) risks compared to historical counterpart (all p < 0.0001). CONCLUSION: This population-based study provides the first evidence of improved CSM free survival and OM free survival in patients with de novo mPCa since the introduction of several systemic agents for CRPC patients. PMID- 29129030 TI - Effects of CPAP and mandibular advancement device treatment in obstructive sleep apnea patients: a systematic review and meta-analysis. AB - The purpose of this review is to conduct a systematic review and meta-analysis comparing the effects of continuous positive airway pressure (CPAP) with a mandibular advancement device (MAD) in improving the quality of life (sleepiness, cognitive, and functional outcomes) in patients diagnosed with obstructive sleep apnea (OSA). Authors identified randomized, placebo-controlled studies from MEDLINE through PubMed, Web of Science, and the Cochrane Library. Studies were assessed for inclusion and exclusion criteria, as well as risk of bias. Initial search yielded 240 unduplicated references, which the authors reduced to 12 relevant studies. Patients with CPAP therapy showed no statistically significant difference in the post-treatment quality of life measured with the SF-36 mental health component (p = .994), or the SF-36 physical functioning component (p = .827). There was no significant improvement in neither Functional Outcomes of Sleep Questionnaire (p = .788) nor cognitive performance (p = .395) compared to patients treated with oral appliances. However, the meta-analyses' overall results showed a significant improvement in the post-treatment apnea-hypopnea index (AHI) in favor of CPAP therapy as compared with the oral appliance group (p < .001). Meta-analyses showed unclear results for sleepiness with no significant differences in average post-treatment Epworth Sleepiness Scale [ESS] (p = .203), but significant differences in change in ESS from baseline favorable to CPAP treatment (p = .047). Further studies are needed. Compliance with treatment was 1.1 h per night significantly lower with CPAP than MAD (p = .004), which could explain why though efficacy (AHI) is better with CPAP, no significant results are shown for quality of life, cognitive, and functional outcomes. Though CPAP is significantly more efficient in reducing AHI (moderate quality of evidence), it has a significantly lower compliance resulting in no differences with MAD in quality of life, cognitive, or functional outcomes. Sleep medicine professionals should monitor treatment compliance and offer patients non-compliant with CPAP an oral appliance for treatment of OSA. PMID- 29129031 TI - Evaluation and management of Staphylococcus aureus bacteriuria: an updated review. AB - BACKGROUND AND AIMS: There is little guidance regarding the evaluation and management of patients with Staphylococcus aureus bacteriuria (SABU). Here, we aimed to provide an up-to-date review of the literature. METHODS: We searched PubMed, Scopus, and clinical trial registries for articles evaluating the epidemiology of SABU, risk factors of SABU, the association of SABU with urinary tract infection, bacteremia and invasive S. aureus infections, and the management of patients with SABU. RESULTS: S. aureus is an uncommon isolate in urine cultures. It is more common among certain patients, e.g., patients with indwelling urinary tract devices or prior urinary tract instrumentation. SABU may represent asymptomatic bacteriuria, primary urinary tract infection, or hematogenous seeding of the urinary tract associated with other foci of infection. SABU may also serve as the focus for subsequent bacteremia and invasive infections. We did not find any clinical trials regarding the management of patients with SABU. CONCLUSIONS: Based on our review, we suggest an algorithmic approach for the evaluation and management of patients with SABU. However, evidence from clinical trials is lacking and there are several gaps in the current literature. These are discussed in this review. PMID- 29129032 TI - Needlestick Injuries Among Emergency Medical Services Providers in Urban and Rural Areas. AB - Through this study, we assessed the knowledge of EMS providers regarding needle stick injuries (NSIs) and examined differences by demographics. This cross sectional study used a random sample of certified EMS providers in West Virginia. The survey consists of three sections: socio-demographic characteristics, whether or not got NSIs in the past 12 months, whether or not received needle stick training before. A total of 248 out of 522 (47.31%) EMS providers completed the survey. The majority of EMS providers (81.99%, n = 202) reported no NSI ever and 18.21% (n = 45) had at least one NSI within past 12 months. Chi square test was used and there was a statistically significant association between NSI occurrence and age (P < 0.01); certification level (P = 0.0005); and years of experience (P < 0.0001). Stratification methods were used and there was high varying proportion in NSIs between urban areas (38.50%) and rural areas (14.70%) among females (OR 0.28, CI 0.075-1.02, P = 0.05). Our survey of NSIs among EMS providers found that older, more highly certified, and more experienced providers reported higher frequencies of NSIs. Female EMS providers are more prone to NSIs in urban areas compared to women in rural areas. The results indicate a need to further examine NSIs and provide information regarding the safety precautions among urban and rural EMS providers. PMID- 29129033 TI - Infant Safe Sleep: A Survey of the Knowledge, Attitudes, and Behaviors of Obstetric Physicians. AB - Obstetricians may be a pregnant woman's primary professional source of information about her infant prior to the birth, but infant safe sleep knowledge, attitudes and behaviors of this population are unknown. This study explores obstetric physicians' knowledge, attitudes, and behaviors related to Sudden Infant Death Syndrome and infant safe sleep and identifies barriers as well as enabling and/or reinforcing factors associated with providing infant safe sleep education in the prenatal environment. A cross-sectional survey was conducted with obstetric physicians who provide prenatal healthcare to women in Ohio. Surveys were sent to all licensed physicians included in the registry of the State Medical Board of Ohio with "obstetrics," "obstetrics and gynecology," or "maternal and fetal medicine" as their primary specialty (n = 1771). The response rate was 30%, with 418 physicians included in the analysis. Many participants were knowledgeable about infant safe sleep recommendations; however, only 55% indicated that it was important for obstetric physicians to discuss Sudden Infant Death Syndrome and/or infant safe sleep with prenatal patients. Many participants (70%) perceived barriers to providing infant safe sleep education, however most (82%) indicated interest in doing so. Participants' knowledge and attitudes were significant predictors of whether they discuss this topic with patients. Obstetric physicians can influence the infant safe sleep decisions that women make. Improving obstetricians' knowledge and attitudes about infant safe sleep and supporting physicians who wish to provide education on this topic may help to ensure that women are receiving frequent and consistent infant safe sleep messaging throughout the prenatal period. PMID- 29129034 TI - Best Practices in Global Health Practicums: Recommendations from the Association of Pacific Rim Universities. PMID- 29129035 TI - Trends and Factors Associated with Breastfeeding and Infant Sleep Practices in Georgia. AB - Breastfeeding benefits both infant and mother, including reducing the risk of Sudden Infant Death Syndrome (SIDS). To further reduce risk of SIDS, the American Academy of Pediatrics recommends infants sleep on their backs on a separate sleep surface. Our objective was to describe trends and factors associated with breastfeeding and infant sleep practices in Georgia. Pregnancy Risk Assessment Monitoring System 2004-2013 data were obtained from the Georgia Department of Public Health. Chi square tests for trends were utilized to determine whether there were significant linear trends in breastfeeding and infant sleep overtime and by survey phase. After exclusions, 4643 cases remained for analysis. From 2004 to 2013, there was a slight (insignificant) decrease in breastfeeding initiation, with the highest proportion in 2010 (79.9%) and the lowest in 2013 (66.9%). Rates of exclusive breastfeeding increased significantly from 2004 (31.3%) to 2013 (81.7%). During that time, the proportion of infants being placed back to sleep slightly decreased (though not significantly), from 59.7 to 48.9%. The proportion of mothers who reported never bed-sharing increased significantly from 26.7 to 45.1% over this period. The decreasing breastfeeding initiation rates in Georgia diverge from national upward trends, however, exclusive breastfeeding rates by survey phase were slightly higher than national trends. Our results suggest the need for targeted education and support for breastfeeding and safe sleep practices. State-level trends data on breastfeeding and infant sleep practices provide valuable information for state-level public health professionals and policy makers, health care providers, and breastfeeding and safe sleep advocates. PMID- 29129036 TI - "Top Performing" US Hospitals and the Health Status of Counties they Serve. AB - This study (a) examined the relationships between "top performing" US hospitals and the health status of counties they serve and (b) compared the health status of "top performing" US hospital counties versus that of remaining US counties. Statistical analyses considered US News and World Report Honor Roll ranking data, as a measure of hospital performance, and County Health Rankings (CHR) data, as a measure of county health status. "Top performing" hospital Honor Roll scores were correlated with measures of Clinical Care (p < 0.001). Counties with "top performing" US hospitals presented greater health status with regard to All Health Outcomes (p < 0.001), Length of Life (p < 0.001), Quality of Life (p < 0.001), All Health Factors (p < 0.001), Health Behaviors (p < 0.001), and Clinical Care (p < 0.001), than compared to remaining US counties. Hospital impact on county health status remains primarily recognized in clinical care and not in overall health. Also, counties that contain a "top performing" US hospital tend to present lower health risks to their citizens than compared to other US counties. PMID- 29129037 TI - Eye movement abnormalities in middle cerebellar peduncle strokes. AB - The middle cerebellar peduncle (MCP) is a major conduit for cortico-ponto cerebellar fibers that convey information related to eye movements. This study aims to elucidate eye movement abnormalities that arise from lesions confined to the MCP. In 23 patients with acute strokes restricted to unilateral MCPs, we investigated the clinical features and ocular motor findings including spontaneous nystagmus, saccades, smooth pursuit, ocular tilt reaction, and head impulse tests. Bithermal caloric tests and audiometry were also performed. Patients with strokes restricted to the MCP usually developed acute vertigo or imbalance, along with few sensorimotor signs or auditory symptoms. Patients frequently showed abnormal eye movements that included spontaneous horizontal/torsional nystagmus, ocular tilt reaction, gaze-evoked nystagmus, abnormal head impulse responses, and bilaterally impaired horizontal smooth pursuit. Unilateral MCP strokes produce acute vertigo and imbalance with distinct ocular motor abnormalities, which are primarily caused by damage to the central vestibular structures and by disruption of the neural pathways responsible for eye-position stabilization and smooth pursuit. PMID- 29129038 TI - Defining the Role of Free Flaps in Partial Breast Reconstruction. AB - BACKGROUND: Free flaps have a well-established role in breast reconstruction after mastectomy; however, their role in partial breast reconstruction remains poorly defined. We reviewed our experience with partial breast reconstruction to better understand indications for free tissue transfer. METHODS: A retrospective review was performed of all patients undergoing partial breast reconstruction at our center between February 2009 and October 2015. We evaluated the characteristics of patients who underwent volume displacement procedures versus volume replacement procedures and free versus pedicled flap reconstruction. RESULTS: There were 78 partial breast reconstructions, with 52 reductions/tissue rearrangements (displacement group) and 26 flaps (replacement group). Bra cup size and body mass index (BMI) were significantly smaller in the replacement group. Fifteen pedicled and 11 free flaps were performed. Most pedicled flaps (80.0%) were used for lateral or upper pole defects. Most free flaps (72.7%) were used for medial and inferior defects or when there was inadequate donor tissue for a pedicled flap. Complications included hematoma, cellulitis, and one aborted pedicled flap. CONCLUSION: Free and pedicled flaps are useful for partial breast reconstruction, particularly in breast cancer patients with small breasts undergoing breast-conserving treatment (BCT). Flap selection depends on defect size, location, and donor tissue availability. Medial defects are difficult to reconstruct using pedicled flaps due to arc of rotation and intervening breast tissue. Free tissue transfer can overcome these obstacles. Confirming negative margins before flap reconstruction ensures harvest of adequate volume and avoids later re-operation. Judicious use of free flaps for oncoplastic reconstruction expands the possibility for breast conservation. PMID- 29129040 TI - Lensless imaging through multiple phase patterns illumination. AB - A stable optical system is required to acquire a high-quality image. A motionless lensless setup is designated to obtain high-resolution and large field of view images. The sample is sequentially illuminated with multiple random phase patterns, and the recorded images are subtracted from the system calibration images correspondingly. The resultant images are propagated to the sample plane. The summation of all images yields a final image with resolution of ~4 MUm, field of view of ~15 mm2, and better signal-to-noise ratio. This technique provides a compact, stable, and cost-effective optical system. PMID- 29129039 TI - Combined diet and exercise interventions for preventing gestational diabetes mellitus. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with a wide range of adverse health consequences for women and their infants in the short and long term. With an increasing prevalence of GDM worldwide, there is an urgent need to assess strategies for GDM prevention, such as combined diet and exercise interventions. This is an update of a Cochrane review that was first published in 2015. OBJECTIVES: To assess the effects of diet interventions in combination with exercise interventions for pregnant women for preventing GDM, and associated adverse health consequences for the mother and her infant/child. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (27 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs, comparing combined diet and exercise interventions with no intervention (i.e. standard care), that reported on GDM diagnosis as an outcome. Quasi-RCTs were excluded. Cross-over trials were not eligible for inclusion. We planned to include RCTs comparing two or more different diet/exercise interventions, however none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, assessed the risk of bias of the included trials and assessed quality of evidence for selected maternal and infant/child outcomes using the GRADE approach. We checked data for accuracy. MAIN RESULTS: In this update, we included 23 RCTs (involving 8918 women and 8709 infants) that compared combined diet and exercise interventions with no intervention (standard care). The studies varied in the diet and exercise programs evaluated and health outcomes reported. None reported receiving funding from a drug manufacturer or agency with interests in the results. Overall risk of bias was judged to be unclear due to the lack of methodological detail reported. Most studies were undertaken in high-income countries.For our primary review outcomes, there was a possible reduced risk of GDM in the diet and exercise intervention group compared with the standard care group (average risk ratio (RR) 0.85, 95% confidence interval (CI) 0.71 to 1.01; 6633 women; 19 RCTs; Tau2 = 0.05; I2 = 42%; P = 0.07; moderate-quality evidence). There was also a possible reduced risk of caesarean section (RR 0.95, 95% CI 0.88 to 1.02; 6089 women; 14 RCTs; moderate-quality evidence). No clear differences were seen between groups for pre-eclampsia (RR 0.98, 95% CI 0.79 to 1.22; 5366 participants; 8 RCTs; low-quality evidence), pregnancy-induced hypertension and/or hypertension (average RR 0.78, 95% CI 0.47 to 1.27; 3073 participants; 6 RCTs; Tau2 = 0.19; I2 = 62%; very low-quality evidence), perinatal mortality (RR 0.82, 95% CI 0.42 to 1.63; 3757 participants; 2 RCTs; low-quality evidence) or large-for-gestational age (RR 0.93, 95% CI 0.81 to 1.07; 5353 participants; 11 RCTs; low-quality evidence). No data were reported for infant mortality or morbidity composite.Subgroup analyses (based on trial design, maternal body mass index (BMI) and ethnicity) revealed no clear differential treatment effects. We were unable to assess the impact of maternal age, parity and specific features of the diet and exercise interventions. Findings from sensitivity analyses (based on RCT quality) generally supported those observed in the main analyses. We were not able to perform subgroup analyses based on maternal age, parity or nature of the exercise/dietary interventions due to the paucity of information/data on these characteristics and the inability to meaningfully group intervention characteristics.For most of the secondary review outcomes assessed using GRADE, there were no clear differences between groups, including for perineal trauma (RR 1.27, 95% CI 0.78 to 2.05; 2733 participants; 2 RCTs; moderate-quality evidence), neonatal hypoglycaemia (average RR 1.42, 95% CI 0.67 to 2.98; 3653 participants; 2 RCTs; Tau2 = 0.23; I2 = 77%; low quality evidence); and childhood adiposity (BMI z score) (MD 0.05, 95% CI 0.29 to 0.40; 794 participants; 2 RCTs; Tau2 = 0.04; I2 = 59%; low-quality evidence). However, there was evidence of less gestational weight gain in the diet and exercise intervention group compared with the control group (mean difference (MD) -0.89 kg, 95% CI -1.39 to -0.40; 5052 women; 16 RCTs; Tau2 = 0.37; I2 = 43%;moderate-quality evidence). No data were reported for maternal postnatal depression or type 2 diabetes; childhood/adulthood type 2 diabetes, or neurosensory disability. AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests reduced risks of GDM and caesarean section with combined diet and exercise interventions during pregnancy as well as reductions in gestational weight gain, compared with standard care. There were no clear differences in hypertensive disorders of pregnancy, perinatal mortality, large-for-gestational age, perineal trauma, neonatal hypoglycaemia, and childhood adiposity (moderate- tovery low quality evidence).Using GRADE methodology, the evidence was assessed as moderate to very low quality. Downgrading decisions were predominantly due to design limitations (risk of bias), and imprecision (uncertain effect estimates, and at times, small sample sizes and low event rates), however two outcomes (pregnancy induced hypertension/hypertension and neonatal hypoglycaemia), were also downgraded for unexplained inconsistency (statistical heterogeneity).Due to the variability of the diet and exercise components tested in the included studies, the evidence in this review has limited ability to inform practice. Future studies could describe the interventions used in more detail, if and how these influenced behaviour change and ideally be standardised between studies. Studies could also consider using existing core outcome sets to facilitate more standardised reporting. PMID- 29129041 TI - Line-scanning confocal microendoscope for nuclear morphometry imaging. AB - Fiber-optic endomicroscopy is a minimally invasive method to image cellular morphology in vivo. Using a coherent fiber bundle as an image relay, it allows additional imaging optics to be placed at the distal end of the fiber outside the body. In this research, we use this approach to demonstrate a compact, low-cost line-scanning confocal fluorescence microendoscope that can be constructed for <$5000. Confocal imaging is enabled without the need for mechanical scanning by synchronizing a digital light projector with the rolling shutter of a CMOS camera. Its axial performance is characterized in comparison with a nonscanned high-resolution microendoscope. We validate the optical sectioning capability of the microendoscope by imaging a two-dimensional phantom and ex vivo mouse esophageal and colon tissues. Results show that optical sectioning using this approach improves visualization of nuclear morphometry and suggest that this low cost line-scanning microendoscope can be used to evaluate various pathological conditions. PMID- 29129043 TI - Economic evaluation of environmental epidemiological projects in national industrial complexes. AB - In this economic evaluation of environmental epidemiological monitoring projects, we analyzed the economic feasibility of these projects by determining the social cost and benefit of these projects and conducting a cost/benefit analysis. Here, the social cost was evaluated by converting annual budgets for these research and survey projects into present values. Meanwhile, the societal benefit of these projects was evaluated by using the contingent valuation method to estimate the willingness-to-pay of residents living in or near industrial complexes. In addition, the extent to which these projects reduced negative health effects (i.e., excess disease and premature death) was evaluated through expert surveys, and the analysis was conducted to reflect the unit of economic value, based on the cost of illness and benefit transfer method. The results were then used to calculate the benefit of these projects in terms of the decrease in negative health effects. For residents living near industrial complexes, the benefit/cost ratio was 1.44 in the analysis based on resident surveys and 5.17 in the analysis based on expert surveys. Thus, whichever method was used for the economic analysis, the economic feasibility of these projects was confirmed. PMID- 29129042 TI - Healthcare worker infected with Middle East Respiratory Syndrome during cardiopulmonary resuscitation in Korea, 2015. AB - OBJECTIVES: During the outbreak of the Middle East Respiratory Syndrome (MERS) in Korea in 2015, the Korea Centers for Disease Control and Prevention (KCDC) confirmed a case of MERS in a healthcare worker in Daejeon, South Korea. To verify the precise route of infection for the case, we conducted an in-depth epidemiological investigation in cooperation with the KCDC. METHODS: We reviewed the MERS outbreak investigation report of the KCDC, and interviewed the healthcare worker who had recovered from MERS. Using the media interview data, we reaffirmed and supplemented the nature of the exposure. RESULTS: The healthcare worker, a nurse, was infected while performing cardiopulmonary resuscitation (CPR) for a MERS patient in an isolation room. During the CPR which lasted for an hour, a large amount of body fluid was splashed. The nurse was presumed to have touched the mask to adjust its position during the CPR. She suggested that she was contaminated with the MERS patient's body fluids by wiping away the sweat from her face during the CPR. CONCLUSIONS: The possible routes of infection may include the following: respiratory invasion of aerosols contaminated with MERS coronavirus (MERS-CoV) through a gap between the face and mask; mucosal exposure to sweat contaminated with MERS-CoV; and contamination during doffing of personal protective equipment. The MERS guidelines should reflect this case to decrease the risk of infection during CPR. PMID- 29129045 TI - Development of S-Methylmethionine Sulfonium Derivatives and Their Skin-Protective Effect against Ultraviolet Exposure. AB - In a previous study, we have demonstrated that S-methylmethionine sulfonium (SMMS) confers wound-healing and photoprotective effects on the skin, suggesting that SMMS can be used as a cosmetic raw material. However, it has an unpleasant odor. Therefore, in the present study, we synthesized odor-free SMMS derivatives by eliminating dimethyl sulfide, which is the cause of the unpleasant odor and identified two derivatives that exhibited skin-protective effects: one derivative comprised (2S,4S)- and (2R,4S)-2-phenylthiazolidine-4-carboxylic acid and the other comprised (2S,4R)-, (2S,4S)-, (2R,4R)-, and (2R,4S)-2-phenyl-1,3-thiazinane 4-carboxylic acid. We performed in vitro proliferation assays using human dermal fibroblasts (hDFs) and an immortalized human keratinocyte cell line (HaCaT). The two SMMS derivatives were shown to increase hDF and HaCaT cell proliferation as well as improve their survival by protecting against ultraviolet exposure. Moreover, the derivatives regulated the expression of collagen type I and MMP mRNAs against ultraviolet exposure in hDFs, suggesting that these derivatives can be developed as cosmetic raw materials. PMID- 29129044 TI - Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress Glioblastoma Tumor Growth. AB - Purpose: Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression. Materials and Methods: We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3AmRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo. Results: By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment. Conclusion: In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework. PMID- 29129046 TI - Acebutolol, a Cardioselective Beta Blocker, Promotes Glucose Uptake in Diabetic Model Cells by Inhibiting JNK-JIP1 Interaction. AB - The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction. PMID- 29129047 TI - Hepaprotective Effect of Standardized Ecklonia stolonifera Formulation on CCl4 Induced Liver Injury in Sprague-Dawley Rats. AB - The liver is an essential organ for the detoxification of exogenous xenobiotics, drugs and toxic substances. The incidence rate of non-alcoholic liver injury increases due to dietary habit change and drug use increase. Our previous study demonstrated that Ecklonia stolonifera (ES) formulation has hepatoprotective effect against alcohol-induced liver injury in rat and tacrine-induced hepatotoxicity in HepG2 cells. This present study was designated to elucidate hepatoprotective effects of ES formulation against carbon tetrachloride (CCl4) induced liver injury in Sprague Dawley rat. Sixty rats were randomly divided into six groups. The rats were treated orally with ES formulation and silymarin (served as positive control, only 100 mg/kg/day) at a dose of 50, 100, or 200 mg/kg/day for 21 days. Seven days after treatment, liver injury was induced by intraperitoneal injection of CCl4 (1.5 ml/kg, twice a week for 14 days). The administration of CCl4 exhibited significant elevation of hepatic enzymes (like AST and ALT), and decrease of antioxidant related enzymes (superoxide dismutase, glutathione peroxidase and catalase) and glutathione. Then, it leaded to DNA damages (8-oxo-2'-deoxyguanosine) and lipid peroxidation (malondialdehyde). Administration of ES formulation inhibited imbalance of above factors compared to CCl4 induced rat in a dose dependent manner. Real time PCR analysis indicates that CYP2E1 was upregulated in CCl4 induced rat. However, increased gene expression was compromised by ES formulation treatment. These findings suggests that ES formulation could protect hepatotoxicity caused by CCl4 via two pathways: elevation of antioxidant enzymes and normalization of CYP2E1 enzyme. PMID- 29129049 TI - DNA Origami Directed Au Nanostar Dimers for Single-Molecule Surface-Enhanced Raman Scattering. AB - We demonstrate the synthesis of Au nanostar dimers with tunable interparticle gap and controlled stoichiometry assembled on DNA origami. Au nanostars with uniform and sharp tips were immobilized on rectangular DNA origami dimerized structures to create nanoantennas containing monomeric and dimeric Au nanostars. Single Texas red (TR) dye was specifically attached in the junction of the dimerized origami to act as a Raman reporter molecule. The SERS enhancement factors of single TR dye molecules located in the conjunction region in dimer structures having interparticle gaps of 7 and 13 nm are 2 * 1010 and 8 * 109, respectively, which are strong enough for single analyte detection. The highly enhanced electromagnetic field generated by the plasmon coupling between sharp tips and cores of two Au nanostars in the wide conjunction region allows the accommodation and specific detection of large biomolecules. Such DNA-directed assembled nanoantennas with controlled interparticle separation distance and stoichiometry, and well-defined geometry, can be used as excellent substrates in single-molecule SERS spectroscopy and will have potential applications as a reproducible platform in single-molecule sensing. PMID- 29129048 TI - Guidance for faecal occult blood testing: quantitative immunochemical method (FIT HB) in colorectal cancer screening programmes. AB - BACKGROUND: in Italy, colorectal cancer screening is included as part of the Italian National Health Service - SSN (Servizio Sanitario Nazionale) Essential Levels of Care - LEA (Livelli Essenziali Assistenziali) and the European Guidelines, which specify quantitative FIT-Hb testing as the best strategy for organised screening programmes. To ensure consistent operating standards in Member States, European regulations require the implementation of certification and accreditation requirements for diagnostic and care-related processes. The requirement, based on ISO 17021 accreditation standards, includes ISO 9001 certification for systems and ISO 15189:2012 accreditation for laboratories. METHODOLOGY: various phases of the analytical process (pre-test, test, post-test) were evaluated in detail and provided operational guidelines for adjusting analytical and managerial procedures using: (a) feedback from members of GISCoR screening labs; (b) performance data obtained via a systematic review of the literature and the Osservatorio Nazionale Screening (ONS) Survey; (c) recommendations for laboratory practice issued by the World Endoscopy Organization "FIT for Screening" Working Group; (d) selected guidelines from the National Guidelines Clearinghouse database; and (e) Canadian, Australian and European screening programme websites. With respect to ISO 15189:2012 standards for accreditation of medical laboratories, GISCoR's guidance has been re evaluated and revised by auditors from the Italian certification body (ACCREDIA) to assess its compliance and completeness with the aim of finalising operating procedures. CONCLUSIONS: the implementation and maintenance of operational standards required by complex systems (e.g. screening programmes) involving constant interaction between facilities and the supporting organisational structure are not easy to achieve. The guide aims to provide laboratories with the necessary guidance for proper process management. PMID- 29129050 TI - Metal-Free Cycloaddition Chemistry Driven Pretargeted Radioimmunotherapy Using alpha-Particle Radiation. AB - The pretargeted radioimmunotherapy approach (PRIT) decouples the administration of tumor targeting monoclonal antibodies (mAbs) from that of the radiolabeled ligand. This multistep strategy allows delivery of high doses of radiation to tumor cells while minimizing nonspecific normal tissue irradiation. In this study, we evaluated the potential of pretargeted alpha-particle radioimmunotherapy based on the inverse electron demand Diels-Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine (Tz). Two tetrazine based chelators, DOTA-Tz and TCMC-Tz, were synthesized and compared for their radiolabeling efficiency with 212Pb, radiochemical stability, and in vivo pharmacokinetics. Dosimetry was determined from pretargeted biodistribution studies. The PRIT study was carried out in LS174T tumor bearing mice pretargeted with CC49-TCO mAb. After removing unbound mAbs from the blood using two doses of clearing agent, mice were treated with various doses of (0, 2.78, 4.63, 7.40, and 2 * 2.78 MBq) of 212Pb-DOTA-Tz. 212Pb-DOTA-Tz displayed better in vivo biodistribution than 212Pb-TCMC-Tz and was selected for PRIT study. All the mouse groups receiving treatment displayed a dose dependent reduction in tumor size, while the control groups showed exponential tumor growth. Treatment with 2.78, 4.63, and 2 * 2.78 MBq of 212Pb-DOTA-Tz resulted in statistically significant improvement in median survival (26, 35, and 39 days, respectively). Groups receiving 7.40 MBq of 212Pb-DOTA-Tz and 0.55 MBq of direct labeled CC49 exhibited acute radiation associated toxicity. This study successfully demonstrated that pretargeted 212Pb alpha-particle therapy resulted in reduced tumor growth rates and improved survival with minimal normal tissue toxicity. PMID- 29129051 TI - Modulation of Charge Recombination in CsPbBr3 Perovskite Films with Electrochemical Bias. AB - The charging of a mesoscopic TiO2 layer in a metal halide perovskite solar cell can influence the overall power conversion efficiency. By employing CsPbBr3 films deposited on a mesoscopic TiO2 film, we have succeeded in probing the influence of electrochemical bias on the charge carrier recombination process. The transient absorption spectroscopy experiments conducted at different applied potentials indicate a decrease in the charge carrier lifetimes of CsPbBr3 as we increase the potential from -0.6 to +0.6 V vs Ag/AgCl. The charge carrier lifetime increased upon reversing the applied bias, thus indicating the reversibility of the photoresponse to charging effects. The ultrafast spectroelectrochemical experiments described here offer a convenient approach to probe the charging effects in perovskite solar cells. PMID- 29129052 TI - Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability. AB - Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX1 potency ( Ke = 5.7 nM) and selectivity (>1,760-fold over OX2) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 MUM), good CNS permeability ( Papp = 14.7 * 10 6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3). PMID- 29129053 TI - Research on Chemical Composition and Biological Properties Including Antiquorum Sensing Activity of Angelica pancicii Vandas Aerial Parts and Roots. AB - The essential oil, different extracts, and isolated compounds of Angelica pancicii Vandas (Apiaceae) were investigated for the first time. The GC-FID and GC-MS analyses revealed sesquiterpenoids as the main constituents of A. pancicii essential oil of aerial parts with bornyl acetate (8.08%), n-octanol (5.82%), kessane (4.26%), and beta-selinene (4.26%) as the main constituents. Analysis of methanol extracts, using an HPLC-DAD/ESI-ToF-MS system, showed a total of 52 compounds in the aerial parts and 53 in the roots, indicating coumarins as the main constituents. In addition, new chromone (1) and six known furanocoumarins (2 7) were isolated from the roots and structurally elucidated by combined spectroscopic methods. The aerial part extracts exhibited higher polyphenolic contents and antioxidant activity evaluated by three radical scavenging assays. Using a microwell dilution method, the strongest antibacterial activity profiles were determined for ethanol and methanol root extracts (minimum bactericidal concentrations (MBCs) = 0.25-3.00 mg/mL), which were comparable to the activity of streptomycin (MBCs = 0.34-1.24 mg/mL), while the strongest antibacterial compound of A. pancicii was oxypeucedanin hydrate (MBCs = 0.50-8.00 mg/mL). Antifungal potential was in moderate extent, and the highest activity was obtained for root methanol extract (minimum fungicidal concentrations (MFCs) = 4.00-14.00 mg/mL). Tested sub-minimum inhibitory concentrations (subMICs) of the extracts and isolated compounds inhibited selected Pseudomonas aeruginosa PAO1 virulence determinants. The most reduced growth of P. aeruginosa colony was in the presence of isolated oxypeucedanin. Ethanol (17.36-46.98%) and methanol (34.54-52.43%) root extracts showed higher anti-biofilm activity compared to streptomycin (49.40-88.36%) and ampicillin (56.46-92.16%). PMID- 29129054 TI - The Mulberry (Morus alba L.) Fruit-A Review of Characteristic Components and Health Benefits. AB - Mulberry (Morus alba L.) fruit has a high yield in one fruiting season in many countries, especially in Asia, and a long history of use as an edible fruit and traditional medicine. A great diversity of nutritive compounds such as fatty acids, amino acids, vitamins, minerals, and bioactive compounds, including anthocyanins, rutin, quercetin, chlorogenic acid, and polysaccharides have been found in mulberry fruit depending on the cultivars and maturity stages. Furthermore, the extracts and active components of mulberry fruit have demonstrated numerous biological activities, including antioxidant, neuroprotective, antiatherosclerosis, immunomodulative, antitumor, antihyperglycemic, and hypolipidemic activities in in vitro and in vivo studies, and they have received increasing interest from researchers and pharmaceutical companies. Although some mechanistic studies further substantiate these potential health benefits of mulberry fruit, a need exists to make a better understanding of the roles of these compounds in traditional medicine and the diet. This review provides recent findings regarding the chemical constituents and biological activities of mulberry fruit, which may be useful for stimulating deep research of mulberry fruit and for predicting their uses as important and safe contributors to benefit human health. PMID- 29129055 TI - Role of Elemental Sulfur in Forming Latent Precursors of H2S in Wine. AB - The level of hydrogen sulfide (H2S) can increase during abiotic storage of wines, and potential latent sources of H2S are still under investigation. We demonstrate that elemental sulfur (S0) residues on grapes not only can produce H2S during fermentation but also can form precursors capable of generating additional H2S after bottle storage for 3 months. H2S could be released from S0-derived precursors by addition of a reducing agent (TCEP), but not by addition of strong brine to induce release of H2S from metal sulfide complexes. The size of the TCEP releasable pool varied among yeast strains. Using the TCEP assay, multiple polar S0-derived precursors were detected following normal-phase preparative chromatography. Using reversed-phase liquid chromatography and high-resolution mass spectrometry, we detected an increase in the levels of diglutathione trisulfane (GSSSG) and glutathione disulfide (GSSG) in S0-fermented red wine and an increase in the levels of glutathione S-sulfonate (GSSO3-) and tetrathionate (S4O62-) in S0-fermented white wine as compared to controls. GSSSG, but not S4O62 , was shown to evolve H2S in the presence of TCEP. Pathways for the formation of GSSSG, GSSG, GSSO3-, and S4O62- from S0 are proposed. PMID- 29129056 TI - Computational Analysis of Transition Metal-Terminal Boride Complexes. AB - A computational analysis of model transition-metal terminal boride [MB(PNPR)] complexes is reported. A combination of density functional theory methods, natural bond orbital analysis, and multiconfiguration self-consistent field calculations were employed to investigate the structure and bonding of terminal boride complexes, in particular, the extent of metal dpi-boron ppi bonding. Comparison of metal-boride, -borylene, and-boryl bond lengths confirms the presence of metal-boron pi bonds, albeit the modest shortening (~3%) of the metal boron bond suggests that the pi-bonding is very weak in terminal borides. Calculated free energies of H2 addition to the boride complexes to yield the corresponding boryl complexes indicate that metal-boride pi-bond strengths are 22 kcal/mol or less as compared to 44 kcal/mol for an analogous nitride complex. It is concluded that, for the boride complexes studied, covering a range of different 4d and 5d metals, that the metal-boride bond consists of a reasonably covalent sigma but two very polarized metal-boron pi bonds. The high polarization of the boron-to-metal pi bonds indicates that the terminal boride is an acceptor or Z-type ligand. PMID- 29129057 TI - Endoplasmic Reticulum-Directed Ratiometric Fluorescent Probe for Quantitive Detection of Basal H2O2. AB - The endoplasmic reticulum (ER) has a central role in the fine-tuning of environmental and internal stimuli. We herein report a ratiometric fluorescent probe, alpha-Naph, capable of determining basal H2O2 in the ER. The probe specifically responds to H2O2. The limit of detection of the probe is as low as 38 nM, making it a feasible sensor to image intracellular basal H2O2. In addition, utilizing its ratiometric property, we are able to measure the concentration of H2O2 in the ER quantitatively, eliminating the error caused by the probe concentration and environment. The intracellular concentration of H2O2 in the ER is calculated to be 0.692 MUM under normal conditions and 1.26 MUM under the stimulation of phorbol myristate acetate. PMID- 29129058 TI - Silicon Nanomembranes with Hybrid Crystal Orientations and Strain States. AB - Methods to integrate different crystal orientations, strain states, and compositions of semiconductors in planar and preferably flexible configurations may enable nontraditional sensing-, stimulating-, or communication-device applications. We combine crystalline-silicon nanomembranes, patterning, membrane transfer, and epitaxial growth to demonstrate planar arrays of different orientations and strain states of Si in a single membrane, which is then readily transferable to other substrates, including flexible supports. As examples, regions of Si(001) and Si(110) or strained Si(110) are combined to form a multicomponent, single substrate with high-quality narrow interfaces. We perform extensive structural characterization of all interfaces and measure charge carrier mobilities in different regions of a 2D quilt. The method is readily extendable to include varying compositions or different classes of materials. PMID- 29129059 TI - Antioxidative Properties and Interconversion of tert-Butylhydroquinone and tert Butylquinone in Soybean Oils. AB - During the process of antioxidation of tert-butylhydroquinone (TBHQ) in oil and fat systems, tert-butylquinone (TQ) can be formed, which has higher toxicity than TBHQ. The changes of TBHQ and TQ in edible oils at room temperature (RT) or under thermal treatment were investigated. Under thermal treatment, volatilization was the main pathway of TBHQ loss in edible oils. TQ was the main oxidation product of TBHQ under thermal treatment as well as at RT. The amount of TQ in thermally treated oils was much less than that in oils stored at RT due to the decreased amount of oxygen dissolved in oils and easy volatilization of TQ at high temperature. In addition, TQ can be reduced to TBHQ by reduction components in edible oils, but the conversion amount was very small. Thus, TQ, theoretically having no antioxidative property, presented a very weak antioxidative activity equivalent to that of BHA due to the presence of insignificant amount of TBHQ formed from TQ in edible oils. The narrow potential difference of 0.059 between oxidation and reduction peaks of TBHQ and TQ resulted in easy interconversion of TBHQ and TQ under the action of common oxidation and reduction substances which have a higher oxidation potential or a lower reduction potential than they have. PMID- 29129060 TI - Alternate Reductants with VB12 to Transform C8 and C6 Perfluoroalkyl Sulfonates: Limitations and Insights into Isomer-Specific Transformation Rates, Products and Pathways. AB - Previous studies evaluating Vitamin B12 (VB12) with Ti(III)-citrate for potential use in in situ remediation of perfluorooctanesulfonate (PFOS) found that linear (L)-PFOS was unaltered. We explored if alternate reductants could overcome this limitation with a primary focus on nanoscale zerovalent zinc (nZn0). Transformation over time with VB12-nZn0 was quantified at 22, 70, and 90 degrees C for PFOS, at 70 degrees C for perfluorohexanesulfonate (PFHxS), and VB12-nFe0 and VB12-Pd0/nFe0 at 70 degrees C for PFOS. Only branched (br-) isomers were transformed generating F- (no SO42-) and polyfluoroalkyl intermediates/products. The absence of L-PFOS transformation by VB12 appears to be due to the inability of L-perfluoroalkyl sulfonates to complex with VB12 and not an activation energy issue that can be overcome by stronger reductants/catalysts. At 90 degrees C, 95% of br-PFOS isomers were transformed within 5 days. Isomer-specific removal rates were positively correlated to the br-CF3's proximity to the terminal CF3. Br-PFHxS transformation was approximately two times slower with less defluorination than br-PFOS. C8/C7 and C6/C5 polyfluorinated sulfonates from br PFOS and br-PFHxS, respectively, were identified as both intermediates and apparent dead-end products. Pathways included 4 F replaced by 2 H and a C?C bond, and serial F replacement by H with up to 12 F atoms removed from br-PFOS. PMID- 29129061 TI - Highly Sensitive and High-Throughput Method for the Analysis of Bisphenol Analogues and Their Halogenated Derivatives in Breast Milk. AB - The structural analogs of bisphenol A (BPA) and their halogenated derivatives (together termed BPs) have been found in the environment, food, and even the human body. Limited research showed that some of them exhibited toxicities that were similar to or even greater than that of BPA. Therefore, adverse health effects for BPs were expected for humans with low-dose exposure in early life. Breast milk is an excellent matrix and could reflect fetuses' and babies' exposure to contaminants. Some of the emerging BPs may present with trace or ultratrace levels in humans. However, existing analytical methods for breast milk cannot quantify these BPs simultaneously with high sensitivity using a small sampling weight, which is important for human biomonitoring studies. In this paper, a method based on Bond Elut Enhanced Matrix Removal-Lipid purification, pyridine-3-sulfonyl chloride derivatization, and liquid chromatography electrospray tandem mass spectrometry was developed. The method requires only a small quantity of sample (200 MUL) and allowed for the simultaneous determination of 24 BPs in breast milk with ultrahigh sensitivity. The limits of quantitation of the proposed method were 0.001-0.200 MUg L-1, which were 1-6.7 times lower than the only study for the simultaneous analysis of bisphenol analogs in breast milk based on a 3 g sample weight. The mean recoveries ranged from 86.11% to 119.05% with relative standard deviation (RSD) <= 19.5% (n = 6). Matrix effects were within 20% with RSD < 10% for six different lots of samples. The proposed method was successfully applied to 20 breast milk samples. BPA, bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF) were detected. BPA was still the dominant BP, followed by BPF. This is the first report describing the occurrence of BPF and BPAF in breast milk. PMID- 29129062 TI - Kinetic Models for the Role of Protein Thiols during Oxidation in Beer. AB - Thiol-containing proteins have been suggested to have antioxidative properties in beer. A kinetic model has been setup for the reactivity of thiols during early stages of oxidative degradation of beer. Kinetic analysis based on the proposed reaction mechanism allowed evaluation of the relative reactivity of beer components, such as bitter acids from hops and polyphenols. The rate constants for the reaction of 1-hydroxyethyl radicals, which are generated during radical mediated oxidation of ethanol in beer, with hop bitter acids and thiols were very similar, and the concentration of these compounds in beer is therefore essential for the relative reactivity. For a standard pilsner beer with 35 international bitter units with typical concentrations of thiols and hop bitter acids, thiols were found to react with ca. 9% of 1-hydroxyethyl radicals, while bitter acids from hops accounted for ca. 88% of the reaction with 1-hydroxyethyl radicals. Polyphenols were not found to account for any major part of the reaction with 1 hydroxyethyl radicals due to low reaction rates and low concentrations in pilsner beer compared to the other components. The kinetic model suggests that the concentration of thiols has to be increased in order to contribute with any significant antioxidative protection and that the fate of thiols during oxidation must be considered since some thiol oxidation products may induce further damage. PMID- 29129063 TI - Pd-Catalyzed Dearomative [3 + 2] Cycloaddition of 3-Nitroindoles with 2 Vinylcyclopropane-1,1-dicarboxylates. AB - A trans-diastereoselective Pd-catalyzed dearomative [3 + 2] cycloaddition between vinylcyclopropane dicarboxylates and 3-nitroindoles has been developed. The reaction provides densely functionalized cyclopenta[b]indolines with versatile vinyl and nitro-groups. The addition of a halide additive was found to be critical for the diastereoselectivity of the reaction, which is proposed to be a result of a rapid pi-sigma-pi interconversion between the intermediates allowing for Curtin-Hammett control. A switch in diastereoselectivity to afford products with the vinyl and nitro groups cis to each other is observed with a 4 substituted 3-nitroindole. PMID- 29129064 TI - Impacts of Combined Cooling, Heating and Power Systems, and Rainwater Harvesting on Water Demand, Carbon Dioxide, and NOx Emissions for Atlanta. AB - The purpose of this study is to explore the potential water, CO2 and NOx emission, and cost savings that the deployment of decentralized water and energy technologies within two urban growth scenarios can achieve. We assess the effectiveness of urban growth, technological, and political strategies to reduce these burdens in the 13-county Atlanta metropolitan region. The urban growth between 2005 and 2030 was modeled for a business as usual (BAU) scenario and a more compact growth (MCG) scenario. We considered combined cooling, heating and power (CCHP) systems using microturbines for our decentralized energy technology and rooftop rainwater harvesting and low flow fixtures for the decentralized water technologies. Decentralized water and energy technologies had more of an impact in reducing the CO2 and NOx emissions and water withdrawal and consumption than an MCG growth scenario (which does not consider energy for transit). Decentralized energy can reduce the CO2 and NOx emissions by 8% and 63%, respectively. Decentralized energy and water technologies can reduce the water withdrawal and consumption in the MCG scenario by 49% and 50% respectively. Installing CCHP systems on both the existing and new building stocks with a net metering policy could reduce the CO2, NOx, and water consumption by 50%, 90%, and 75% respectively. PMID- 29129065 TI - Nonadditive Interactions Mediated by Water at Chemically Heterogeneous Surfaces: Nonionic Polar Groups and Hydrophobic Interactions. AB - We explore how two nonionic polar groups (primary amine and primary amide) influence hydrophobic interactions of neighboring nonpolar domains. We designed stable beta-peptide sequences that generated globally amphiphilic (GA) helices, each with a nonpolar domain formed by six cyclohexyl side chains arranged along one side of the 14-helix. The other side of the helix was dominated by three polar side chains, from beta3-homolysine (K) and/or beta3-homoglutamine (Q) residues. Variations in this polar side chain array included exclusively beta3 hLys (GA-KKK) and beta3-hLys/beta3-hGln mixtures (e.g., GA-QKK and GA-QQK). Chemical force measurements in aqueous solution versus methanol allowed quantification of the hydrophobic interactions of the beta-peptide with the nonpolar tip of an atomic force microscope (AFM). At pH 10.5, where the K side chain is largely uncharged, we measured hydrophobic adhesive interactions mediated by GA-KKK to be 0.61 +/- 0.04 nN, by GA-QKK to be 0.54 +/- 0.01 nN, and by GA-QQK to be 0 +/- 0.01 nN. This finding suggests that replacing an amine group (K side chain) with a primary amide group (Q side chain) weakens the hydrophobic interaction generated by the six cyclohexyl side chains. AFM studies with solid-supported mixed monolayers containing an alkyl component (60%) and a component bearing either a terminal amide or an amine group (40%) revealed analogous trends. These observations from two distinct experiment systems indicate that proximal nonionic polar groups have pronounced effects on hydrophobic interactions generated by a neighboring nonpolar domain, and that the magnitude of the effect depends strongly on polar group identity. PMID- 29129066 TI - AlCl3-Catalyzed Intramolecular Cyclization of N-Arylpropynamides with N Sulfanylsuccinimides: Divergent Synthesis of 3-Sulfenyl Quinolin-2-ones and Azaspiro[4,5]trienones. AB - Switchable ortho/ipso-cyclization of N-arylpropynamides induced with N sulfanylsuccinimides as general sulfur reagents is reported. In the presence of MeOH, para-fluoro N-arylpropynamides exclusively undergo the ipso-cyclization to give 3-sulfenyl azaspiro[4,5]trienones. Two kinds of bioactive heterocycles, benzothieno-[3,2-b]quinoline and -[2,3-c]quinolone, have been directly and efficiently prepared from the corresponding sulfenylated products. PMID- 29129067 TI - One-Pot Construction of Functionalized Spiro-dihydronaphthoquinone-oxindoles via Hauser-Kraus Annulation of Sulfonylphthalide with 3-Alkylideneoxindoles. AB - The Hauser-Kraus annulation of sulfonylphthalide with 3-olefinic oxindole has been performed. This strategy, which involves a cascade Michael addition Dieckmann cyclization-elimination sequence, offers rapid and convenient access to novel spiro-dihydronaphthoquinone-oxindoles in excellent yields with complete selectivity for the enolic form under mild reaction conditions. PMID- 29129068 TI - Structural and Functional Characterization of a Hole-Hole Homodimer Variant in a "Knob-Into-Hole" Bispecific Antibody. AB - Bispecific antibodies have great potential to be the next-generation biotherapeutics due to their ability to simultaneously recognize two different targets. Compared to conventional monoclonal antibodies, knob-into-hole bispecific antibodies face unique challenges in production and characterization due to the increase in variant possibilities, such as homodimerization in covalent and noncovalent forms. In this study, a storage- and pH-sensitive hydrophobic interaction chromatography (HIC) profile change was observed for the hole-hole homodimer, and the multiple HIC peaks were explored and shown to be conformational isomers. We combined traditional analytical methods with hydrogen/deuterium exchange mass spectrometry (HDX MS), native mass spectrometry, and negative-staining electron microscopy to comprehensively characterize the hole-hole homodimer. HDX MS revealed conformational changes at the resolution of a few amino acids overlapping the CH2-CH3 domain interface. Conformational heterogeneity was also assessed by HDX MS isotopic distribution. The hole-hole homodimer was demonstrated to adopt a more homogeneous conformational distribution during storage. This conformational change is likely caused by a lack of CH3 domain dimerization (due to the three "hole" point mutations), resulting in a unique storage- and pH-dependent conformational destabilization and refolding of the hole-hole homodimer Fc. Compared with the hole-hole homodimer under different storage conditions, the bispecific heterodimer, guided by the knob-into-hole assembly, proved to be a stable conformation with homogeneous distribution, confirming its high quality as a desired therapeutic. Functional studies by antigen binding and neonatal Fc receptor (FcRn) binding correlated very well with the structural characterization. Comprehensive interpretation of the results has provided a better understanding of both the homodimer variant and the bispecific molecule. PMID- 29129069 TI - Disentangling Structural Confusion through Machine Learning: Structure Prediction and Polymorphism of Equiatomic Ternary Phases ABC. AB - A method to predict the crystal structure of equiatomic ternary compositions based only on the constituent elements was developed using cluster resolution feature selection (CR-FS) and support vector machine (SVM) classification. The supervised machine-learning model was first trained with 1037 individual compounds that adopt the most populated ternary 1:1:1 structure types (TiNiSi-, ZrNiAl-, PbFCl-, LiGaGe-, YPtAs-, UGeTe-, and LaPtSi-type) and then validated using an additional 519 compounds. The CR-FS algorithm improves class discrimination and indicates that 113 variables including size, electronegativity, number of valence electrons, and position on the periodic table (group number) influence the structure preference. The final model prediction sensitivity, specificity, and accuracy were 97.3%, 93.9%, and 96.9%, respectively, establishing that this method is capable of reliably predicting the crystal structure given only its composition. The power of CR-FS and SVM classification is further demonstrated by segregating the crystal structure of polymorphs, specifically to examine polymorphism in TiNiSi- and ZrNiAl-type structures. Analyzing 19 compositions that are experimentally reported in both structure types, this machine-learning model correctly identifies, with high confidence (>0.7), the low-temperature polymorph from its high-temperature form. Interestingly, machine learning also reveals that certain compositions cannot be clearly differentiated and lie in a "confused" region (0.3-0.7 confidence), suggesting that both polymorphs may be observed in a single sample at certain experimental conditions. The ensuing synthesis and characterization of TiFeP adopting both TiNiSi- and ZrNiAl-type structures in a single sample, even after long annealing times (3 months), validate the occurrence of the region of structural uncertainty predicted by machine learning. PMID- 29129070 TI - Molecular Signatures Associated with Treatment of Triple-Negative MDA-MB231 Breast Cancer Cells with Histone Deacetylase Inhibitors JAHA and SAHA. AB - Jay Amin hydroxamic acid (JAHA; N8-ferrocenylN1-hydroxy-octanediamide) is a ferrocene-containing analogue of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA). JAHA's cytotoxic activity on MDA-MB231 triple negative breast cancer (TNBC) cells at 72 h has been previously demonstrated with an IC50 of 8.45 MUM. JAHA's lethal effect was found linked to perturbations of cell cycle, mitochondrial activity, signal transduction, and autophagy mechanisms. To glean novel insights on how MDA-MB231 breast cancer cells respond to the cytotoxic effect induced by JAHA, and to compare the biological effect with the related compound SAHA, we have employed a combination of differential display-PCR, proteome analysis, and COMET assay techniques and shown some differences in the molecular signature profiles induced by exposure to either HDACis. In particular, in contrast to the more numerous and diversified changes induced by SAHA, JAHA has shown a more selective impact on expression of molecular signatures involved in antioxidant activity and DNA repair. Besides expanding the biological knowledge of the effect exerted by the modifications in compound structures on cell phenotype, the molecular elements put in evidence in our study may provide promising targets for therapeutic interventions on TNBCs. PMID- 29129071 TI - Innovative Polymers for Controlled Release Applications. PMID- 29129072 TI - Organized Peptidic Nanostructures as Functional Materials. PMID- 29129074 TI - From Type-II Triply Degenerate Nodal Points and Three-Band Nodal Rings to Type-II Dirac Points in Centrosymmetric Zirconium Oxide. AB - Using first-principles calculations, we report that ZrO is a topological material with the coexistence of three pairs of type-II triply degenerate nodal points (TNPs) and three nodal rings (NRs), when spin-orbit coupling (SOC) is ignored. Noticeably, the TNPs reside around the Fermi energy with a large linear energy range along the tilt direction (>1 eV), and the NRs are formed by three strongly entangled bands. Under symmetry-preserving strain, each NR would evolve into four droplet-shaped NRs before fading away, producing distinct evolution compared with that in usual two-band NR. When SOC is included, TNPs would transform into type II Dirac points while all of the NRs are gapped. Remarkably, the type-II Dirac points inherit the advantages of TNPs: residing around the Fermi energy and exhibiting a large linear energy range. Both features facilitate the observation of interesting phenomena induced by type-II dispersion. The symmetry protections and low-energy Hamiltonian for the nontrivial band crossings are discussed. PMID- 29129075 TI - Strontium Oxide Tunnel Barriers for High Quality Spin Transport and Large Spin Accumulation in Graphene. AB - The quality of the tunnel barrier at the ferromagnet/graphene interface plays a pivotal role in graphene spin valves by circumventing the impedance mismatch problem, decreasing interfacial spin dephasing mechanisms and decreasing spin absorption back into the ferromagnet. It is thus crucial to integrate superior tunnel barriers to enhance spin transport and spin accumulation in graphene. Here, we employ a novel tunnel barrier, strontium oxide (SrO), onto graphene to realize high quality spin transport as evidenced by room-temperature spin relaxation times exceeding a nanosecond in graphene on silicon dioxide substrates. Furthermore, the smooth and pinhole-free SrO tunnel barrier grown by molecular beam epitaxy (MBE), which can withstand large charge injection current densities, allows us to experimentally realize large spin accumulation in graphene at room temperature. This work puts graphene on the path to achieve efficient manipulation of nanomagnet magnetization using spin currents in graphene for logic and memory applications. PMID- 29129073 TI - Stage Dependence, Cell-Origin Independence, and Prognostic Capacity of Serum Glycan Fucosylation, beta1-4 Branching, beta1-6 Branching, and alpha2-6 Sialylation in Cancer. AB - Glycans represent a promising but only marginally accessed source of cancer markers. We previously reported the development of a molecularly bottom-up approach to plasma and serum (P/S) glycomics based on glycan linkage analysis that captures features such as alpha2-6 sialylation, beta1-6 branching, and core fucosylation as single analytical signals. Based on the behavior of P/S glycans established to date, we hypothesized that the alteration of P/S glycans observed in cancer would be independent of the tissue in which the tumor originated yet exhibit stage dependence that varied little between cancers classified on the basis of tumor origin. Herein, the diagnostic utility of this bottom-up approach as applied to lung cancer patients (n = 127 stage I; n = 20 stage II; n = 81 stage III; and n = 90 stage IV) as well as prostate (n = 40 stage II), serous ovarian (n = 59 stage III), and pancreatic cancer patients (n = 15 rapid autopsy) compared to certifiably healthy individuals (n = 30), nominally healthy individuals (n = 166), and risk-matched controls (n = 300) is reported. Diagnostic performance in lung cancer was stage-dependent, with markers for terminal (total) fucosylation, alpha2-6 sialylation, beta1-4 branching, beta1-6 branching, and outer-arm fucosylation most able to differentiate cases from controls. These markers behaved in a similar stage-dependent manner in other types of cancer as well. Notable differences between certifiably healthy individuals and case-matched controls were observed. These markers were not significantly elevated in liver fibrosis. Using a Cox proportional hazards regression model, the marker for alpha2-6 sialylation was found to predict both progression and survival in lung cancer patients after adjusting for age, gender, smoking status, and stage. The potential mechanistic role of aberrant P/S glycans in cancer progression is discussed. PMID- 29129076 TI - Comprehensive Molecular Characterization of a Cisplatin-Specific Monoclonal Antibody. AB - Despite their immense and rapidly increasing importance as analytical tools or therapeutic drugs, the detailed structural features of particular monoclonal antibodies are widely unknown. Here, an antibody already in use for diagnostic purposes and for molecular dosimetry studies in cancer therapy with very high affinity and specificity for cisplatin-induced DNA modifications was studied extensively. The molecular structure and modifications as well as the antigen specificity were investigated mainly by mass spectrometry. Using nano electrospray ionization mass spectrometry, it was possible to characterize the antibody in its native state. Tandem-MS experiments not only revealed specific fragments but also gave information on the molecular structure. The detailed primary structure was further elucidated by proteolytic treatment with a selection of enzymes and high resolution tandem-MS. The data were validated by comparison with known antibody sequences. Then, the complex glycan structures bound to the antibody were characterized in all detail. The Fc-bound oligosaccharides were released enzymatically and studied by matrix-assisted laser desorption/ionization mass spectrometry. Overall 16 different major glycan structures were identified. The binding specificity of the antibody was investigated by applying synthetic single and double stranded DNA oligomers harboring distinct Pt adducts. The antibody-antigen complexes were analyzed by mass spectrometry under native conditions. The stability of the complex with double stranded DNA was also investigated. PMID- 29129077 TI - Pd-Catalyzed Ortho C-H Hydroxylation of Benzaldehydes Using a Transient Directing Group. AB - The direct Pd-catalyzed ortho C-H hydroxylation of benzaldehydes was achieved using 4-chloroanthranilic acid as the transient directing group, 1-fluoro-2,4,6 trimethylpyridnium triflate as the bystanding oxidant, and p-toluenesulfonic acid as the putative oxygen nucleophile. The unusual C-H chlorination and polyfluoroalkoxylation reactions signaled the importance of external nucleophiles to the outcome of Pd(IV) reductive eliminations. PMID- 29129078 TI - Disparity in Photoexcitation Dynamics between Vertical and Lateral MoS2/WSe2 Heterojunctions: Time-Domain Simulation Emphasizes the Importance of Donor Acceptor Interaction and Band Alignment. AB - Two-dimensional transition metal dichalcogenides (TMDs) heterojunctions are appealing candidates for optoelectronics and photovoltaics. Using time-domain density functional theory combined with nonadiabatic (NA) molecular dynamics, we show that photoexcitation dynamics exhibit a significant difference in the vertical and lateral MoS2/WSe2 heterojunctions arising from the disparity in the donor-acceptor interaction and fundamental band alignment. The obtained electron transfer time scale in the vertical heterojunction shows excellent agreement with experiment. Hole transfer proceeds 1.5 times slower. The electron-hole recombination is 3 orders of magnitude longer than the charge separation, which favors solar cell applications. On the contrary, the lateral heterojunction shows no band offsets steering charge separation. The excited electron is localized at the interface that attracts holes to form an exciton-like state due to Coulomb interaction, suggesting potential applications in light-emitting devices. The coupled electron and hole wave functions increase NA coupling and the coherence time, accelerating electron-hole recombination by a factor of 3 compared with the vertical case. The atomistic studies advance our understanding of the photoinduced charge-phonon dynamics in TMDs heterojunctions. PMID- 29129079 TI - Macroscopic Assembly of Gold Nanorods into Superstructures with Controllable Orientations by Anisotropic Affinity Interaction. AB - Two-dimensional or three-dimensional highly ordered arrays of anisotropic nanoparticles provide attracting properties that are highly desired by the industry. Traditional assembly methods such as evaporation usually produces the nanostructure arrays only up to the millimeter scale with poor control of nanoparticle orientation, making them hardly applicable for industrial needs. Here, we report a facile method to assemble centimeter-scale gold nanorod (Au NR) arrays with highly controlled nanoparticle orientation and high reproducibility. We selectively functionalized the transverse or longitudinal facets of Au NRs with polyethylene glycol (PEG) molecules and utilized the interfacial polymeric affinity between the PEG domains on Au NRs and the PEGylated substrate to achieve the anisotropic self-assembly. The side-PEGylated Au NRs formed closely packed horizontal arrays, whereas the end-PEGylated Au NRs formed vertically standing arrays on the substrate, respectively. The obtained Au NR arrays with different orientations showed anisotropic surface-enhanced Raman scattering (SERS) performance. We showed that the vertically ordered Au NR arrays exhibited 3 times higher SERS signals than the horizontally ordered arrays. PMID- 29129080 TI - Reply to Comment on "Solid-Liquid Work of Adhesion". AB - Extrand's interpretation in his "Comment on "Solid-Liquid Work of Adhesion" by Tadmor and Coworkers" may lead to an important discussion and physical understanding of the problem. Below, we compare the two approaches and elucidate the differences to put them in the right perspective. PMID- 29129081 TI - Identification of Mature Atherosclerotic Plaque Proteome Signatures Using Data Independent Acquisition Mass Spectrometry. AB - Atherosclerosis is a chronic inflammatory disease with complex pathobiology and one of the most common causes of cardiovascular events. The process is characterized by complex vascular remodeling processes that require the actions of numerous proteins. The composition of atherosclerotic plaque is increasingly recognized as a major factor governing the occurrence of cardiovascular or neurological symptoms. To gain deeper insights into the composition of atherosclerotic plaques, we created quantitative proteome profiles of advanced plaque tissues of six male patients undergoing carotid endarterectomy for stroke prevention. Using a quantitative, data-independent proteome approach, we identified 4181 proteins with an average protein coverage of 45%. An analysis of the quantitative composition of the tissue revealed key players of vascular remodeling processes. Moreover, compared with proximal arterial tissue, 20 proteins in mature plaques were enriched, whereas 52 proteins were found in lower quantities. Among the proteins with increased abundance were prominent extracellular matrix proteins such as biglycan and lumican, whereas cytoskeletal markers for contractile smooth muscle cells (SMCs) were decreased. Taken together, this study provides the most comprehensive quantitative assessment of mature human plaque tissue to date, which indicates a central role of SMCs in the structure of advanced atherosclerotic plaques. PMID- 29129082 TI - First-Principles Study of Electron Injection and Defects at the TiO2/CH3NH3PbI3 Interface of Perovskite Solar Cells. AB - We investigated electron injection rates and vacancy defect properties by performing first-principles calculations on the interface of an anatase-TiO2(001) and a tetragonal CH3NH3PbI3(110) (MAPbI3(110)). We found that the coupling matrix element between the lowest unoccupied molecular orbital of MAPbI3 and the TiO2 conduction band (CB) minimum is negligibly small, the indication being that electron-injection times for low-energy excited states are quite long (more than several tens of picoseconds). We also found that higher-lying CB states coupled more strongly; injection was expected to take place on a femtosecond time scale. Furthermore, we found that vacancy defects in the TiO2 layer produced undesired defect levels that caused hole traps and recombination centers. Whereas most of the vacancy defects in the MAPbI3 layer produced no additional states in the MAPbI3 gap, a Pb vacancy (VPb) at the interface created an energy level below the MAPbI3 CB edge and had a lower energy of formation than the VPb defect in bulk because of the interaction with the TiO2 surface. PMID- 29129083 TI - Giant Valley Splitting and Valley Polarized Plasmonics in Group V Transition Metal Dichalcogenide Monolayers. AB - Two-dimensional group VI transition-metal dichalcogenides (TMDs) provide a promising platform to encode and manipulate quantum information in the valleytronics. However, the two valleys are energetically degenerate, protected by time-reversal symmetry (TRS). To lift this degeneracy, one needs to break the TRS by either applying an external magnetic field or using a magnetic rare-earth oxide substrate. Here, we predict a different strategy to achieve this goal. We propose that the ferromagnetic group V TMD monolayer, in which the TRS is intrinsically broken, can produce a larger valley and spin splitting. A polarized ZnS(0001) surface is also used as a substrate, which shifts the valleys to the low-energy regime (near the Fermi level). Moreover, by calculating its collective electronic excitation behaviors, we show that such a system hosts a giant valley polarized terahertz plasmonics. Our results demonstrate a new way to design and use valleytronic devices, which are both fundamentally and technologically significant. PMID- 29129084 TI - Preface on Esophagus Cancer. PMID- 29129085 TI - Radiation techniques for esophageal cancer. AB - Radiotherapy plays a crucial role in the curative management of localized esophageal cancer, both as definitive and preoperative therapy. For definitive therapy, the standard radiation dose is 50.4 Gy in 28 fractions and should be delivered with concurrent chemotherapy. Chemoradiotherapy also has a wellestablished benefit in the preoperative setting, as established in the CROSS randomized trial. Radiation fields are typically generous, to account for subclinical extension of disease along the esophagus and to regional nodes. Three dimensional conformal radiation is the current standard technique for esophageal cancer, though intensity-modulated radiation therapy is increasingly utilized and may improve the outcomes of esophageal radiotherapy by reducing radiation dose to critical normal tissues. PMID- 29129086 TI - The management of localized esophageal squamous cell carcinoma: Western approach. AB - Esophageal cancer remains a significant cause of cancer-related mortality worldwide and carries a poor prognosis both in the locally advanced and metastatic setting. Esophageal squamous cell carcinoma (ESCC) accounts for the majority of esophageal cancers globally, while esophageal adenocarcinoma (EAC) now predominates in the Western world. Historically, clinical trials have not separated the two histologic subtypes, with similar regimens being used for both. This, however, is changing with the recent publication by the Cancer Genome Atlas Research Group confirming that comprehensive analysis reveals ESCC demonstrates frequent genomic amplifications of CCND1 and SOX2 and/or TP63 and biologically are more like head and neck squamous cell carcinomas, whereas EACs strongly resemble the chromosomally unstable variant of gastric cancer. With a lack of viable targets in squamous cell carcinoma, immunotherapeutic approaches are now being investigated in both early stage and metastatic ESCC with promising results being reported in the preliminary data published to date. PMID- 29129087 TI - Surgical management of esophageal cancer. AB - Esophageal cancer (EC) is an aggressive malignancy associated with an overall poor prognosis. The specific risk factors for EC vary by histologic type as well as geographic distribution but there is no widely applicable screening strategy to date. Patients can present with vague symptoms which can prove to be a diagnostic challenge. Furthermore, cases tend to present at a late stage, making therapeutic approach difficult. Despite ongoing changes in management strategy, surgery remains the only viable option for cure in early stage malignancy. Advances in operative and peri-operative management have led to a relatively safe and efficacious procedure that provides durable therapy. Additionally, careful consideration of procedure specific factors can help maximize patient benefit. This review focuses on the surgical approaches to the management of EC and highlights select current trends and recent advances. PMID- 29129088 TI - Systemic therapy for esophagogastric cancer: targeted therapies. AB - The poor prognosis for patients with esophagogastric cancers (EGC) has resulted in an increased focus on the use of targeted agents in this disease. Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), MET, poly (ADP-ribose) polymerase (PARP) and claudin 18.2 (CLDN18.2). Trastuzumab, an anti-Her2 antibody, was approved by the U.S. FDA in 2010 as first-line therapy in combination with chemotherapy for Her2-positive disease. Since then, strategies targeting Her2 that have been successful in Her2-positive breast cancer, have failed in EGC. The one remaining study, the phase III Jacob study with pertuzumab, has yet to be presented. The anti-VEGF receptor 2 antibody, ramucirumab has been investigated as second-line therapy in 2 phase III trials, which resulted in improved survival, with subsequent FDA approval of ramucirumab in the second-line setting. Therapies targeting EGFR have been evaluated in a number of phase III studies, all of which have been negative. Phase III investigation of an mTOR inhibitor did not improve survival, although biomarker studies are awaited which may identify subgroups of patients that may benefit from its use. The results of the trials targeting MET in EGC have been disappointing, raising doubts about the usefulness of further testing agents that inhibit the MET pathway. PARP inhibition with olaparib, warrants further investigation, possibly in combination with other targeted therapies or immune checkpoint inhibition and in a biomarker-selected population. The identification of CLDN18.2 and its targeting with claudiximab is very promising and will be further investigated in a phase III study. PMID- 29129089 TI - Systemic therapy for esophageal cancer: chemotherapy. AB - As one-half of patients with esophagogastric cancer (EGC) present with metastatic disease and the majority of patients with locally advanced disease will eventually develop metastatic disease despite multimodality therapy, most patients will receive palliative chemotherapy at some point. The reference first line regimen consists of a fluoropyrimidine/platinum combination, which is the standard in East Asia, where this disease is endemic. Options include infusional 5-fluorouracil (5-FU), capecitabine, S-1 and other oral 5-FU pro-drugs and cisplatin or oxaliplatin. The addition of docetaxel to 5-FU/cisplatin is an option for young and fit patients, based on a phase III study, but is associated with significant hematologic toxicity and modest benefit. In the UK, epirubicin is added to the doublet, in the absence of phase III data suggesting a clear benefit; in fact, recent studies suggest no benefit. In the second- and third line setting, taxanes and irinotecan are now validated options. Overall, improvements on the basis of chemotherapy have been marginal over the last 30 years and current efforts focus on targeted therapies and immunotherapy. PMID- 29129090 TI - Screening and prevention strategies and endoscopic management of early esophageal cancer. AB - Esophageal cancer is the 8th most common cancer worldwide and the 6th most common cause of cancer-related death. Its two main subtypes, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), have varying incidences globally, but recent decades have seen a demonstrated rise of EAC in Western countries whereas ESCC remains highly prevalent in Eastern Africa, Central Asia, and China. Screening interventions have focused on using endoscopy to identify Barrett's esophagus (BE) as a precursor to EAC, and squamous cell dysplasia prior to onset of ESCC. However, additional cost-effective screening interventions that can be applied to larger populations at risk for esophageal cancer are needed. Advances in endoscopic ablative techniques and endoscopic resection via endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have proven to be effective in eradicating dysplasia and early stage cancer. Preventive strategies involving reduction in tobacco and alcohol consumption as well as regular use of proton pump inhibitors and nonsteroidal anti-inflammatory drugs are aimed at reducing the incidence of dysplasia and esophageal cancer, but require further study before being recommended for widespread use. PMID- 29129091 TI - Issues in the management of esophageal cancer and geriatric patients. AB - Esophageal cancer is a disease occurring in older adults and given the aging population, the incidence of cancer in the elderly will continue to rise. However, older patients are less likely to receive treatment for their cancers based on age alone. There are limited data and guidelines for how to manage the older patient population but elderly patients can derive benefit from treatment. This review will describe issues specific to older patients with esophageal cancer with a focus on the utilization of geriatric assessment (GA) tools and how to apply geriatric principles to this cancer patients. PMID- 29129092 TI - Adenocarcinoma of the esophagus: controversies and consensus. AB - Esophageal cancer, the sixth most common cause of cancer globally, is characterized by the development of early systemic metastatic disease. Adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) is more common in the West. Preoperative chemotherapy or chemoradiotherapy is employed for locally advanced disease with contemporary studies suggesting higher rates of curative resection and reduced rates of local recurrence with the combination of chemotherapy and radiation therapy given prior to surgery. The role of targeted agents and PET scan imaging in preoperative therapy is under active investigation. PMID- 29129093 TI - Systemic therapy for esophagogastric cancer: immune checkpoint inhibition. AB - The poor prognosis for patients with esophagogastric cancers (EGC) requires the development of newer more effective therapies to further improve the treatment outcomes for this disease. Immunotherapy is a novel treatment strategy that is dramatically changing the treatment landscape for several types of cancers. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death the programmed death (PD)-1/PD-ligand are essential immune checkpoint inhibitors that suppress T cell activation. Targeting of these immune checkpoints with monoclonal antibodies has shown clinical efficacy in several solid tumors which has led to their approval and use in routine clinical practice. In EGC early phase evaluation of immune checkpoint inhibitors has yielded encouraging results with multiple phase 3 studies currently ongoing. In this review, the biological rationale for the use of immune checkpoint inhibitors in cancer will briefly be described and the accumulating data concerning their use in EGC will be presented. PMID- 29129094 TI - Rational combination of immunotherapy for triple negative breast cancer treatment. AB - Recent evidence indicates that tumor infiltrating lymphocytes (TILs), including cytotoxic T cells, are present in the tumor microenvironment of triple-negative breast cancers (TNBC). Despite the presence of cytotoxic T cells, these tumors still develop, progress, and metastasize, suggesting evasion of immune response. One mechanism of immunosuppression is the presence of the T cell inhibitory molecule, programmed death protein 1 (PD-1), on infiltrating T cells and its cognate ligand programmed death ligand 1 (PD-L1) on tumor cells, myeloid dendritic cells (DCs), and macrophages, in the tumor microenvironment. Because TNBC is immunologically insensitive, combinatorial strategies may be ideal to increase both anti-proliferation activity and cytotoxic T cells activity in TNBC. On the basis of two recently discovered regulatory mechanisms of PD-L1, we discuss the potential interactions to boost anti-tumor immunity against TNBC in this review and propose therapeutic strategies that could reduce PD-L1 expression by chemotherapeutic drugs or targeted therapies and sensitize TNBC to immunotherapies. PMID- 29129095 TI - Trastuzumab biosimilar in early breast cancer setting: will there be direct patient benefits? PMID- 29129097 TI - [Articles of the Hungarian Medical Journal from April, 1977]. PMID- 29129096 TI - ERAS & Tubeless-Michael Haddock: the past and future of proton beam. PMID- 29129099 TI - [Articles of the Hungarian Medical Journal from July, 1977]. PMID- 29129098 TI - [Articles of the Hungarian Medical Journal from October, 1977]. PMID- 29129100 TI - [Articles of the Hungarian Medical Journal from August, 1977]. PMID- 29129101 TI - [Articles of the Hungarian Medical Journal from November, 1978]. PMID- 29129102 TI - [Articles of the Hungarian Medical Journal from June, 1977]. PMID- 29129103 TI - [Articles of the Hungarian Medical Journal from May, 1977]. PMID- 29129104 TI - [Articles of the Hungarian Medical Journal from August, 1978]. PMID- 29129105 TI - [Articles of the Hungarian Medical Journal from January, 1977]. PMID- 29129106 TI - [Articles of the Hungarian Medical Journal from November, 1977]. PMID- 29129107 TI - Development, Implementation, and Evaluation of a Curriculum to Prepare Volunteer Navigators to Support Older Persons Living With Serious Illness. AB - The purpose of this article is to report the development, implementation, and evaluation of a curriculum designed to prepare volunteer navigators to support community-dwelling older persons with serious chronic illness. The role of the volunteer navigator was to facilitate independence and quality of life through building social connections, improving access to resources, and fostering engagement. A curriculum was constructed from evidence-based competencies, piloted and revised, and then implemented in 7 subsequent workshops. Workshop participants were 51 volunteers and health-care providers recruited through local hospice societies and health regions. Curriculum was evaluated through satisfaction and self-efficacy questionnaires completed at workshop conclusion. Postworkshop evaluation indicated a high degree of satisfaction with the training. One workshop cohort of 7 participants was followed for 1 year to provide longitudinal evaluation data. Participants followed longitudinally reported improved self-efficacy over 12 months and some challenges with role transition. Future improvements will include further structured learning opportunities offered by telephone postworkshop, focusing on advocacy, communication, and conflict management. Overall, volunteers were satisfied with the curriculum and reported good self-perceived efficacy in their new role as navigators. PMID- 29129108 TI - Promoting Mental Health Resource Use on Campus by "Trying Something New". AB - PURPOSE: To design and test a persuasive health promotion campaign that aligns with the qualities of trying something new for the first time. Given that a majority of students have not previously sought/considered professional mental health assistance before, the hypothesis tested in this study asked whether a campaign that takes this into account is effective with this audience. DESIGN: Participants viewed an online informational message (n = 84), information message plus first-time experience banner (n = 99), or 1 of 4 full campaigns, each depicting a student story and photo about a first-time experience (moving from home [n = 48], skydiving [n = 52], acting in a play [n = 48], and exercising with personal trainer [n = 48]). MEASURES: Visual poster items: appeal (visually pleasing, 7 items, alpha = .92), support (value of poster, 5 items, alpha = .86) and behavioral intention items: engagement (participant seek help/pay attention, 3 items, alpha = .86), relevance (content as relevant, 3 items, alpha = .84), and judgment (judgment of others for not seeking help, 2 items, alpha = .87). PARTICIPANTS: College students (N = 380). RESULTS: In comparison to information only messages, framing mental health help seeking as a first-time experience was linked with increased appeal, support, and engagement (Minformationonly = 2.79 [standard deviation, SD = 1.34], Minformationplusbanner = 3.25 [SD = 1.23], Mfullcampaign = 4.07 [SD = 1.28], P < .001, Minformationonly = 4.38 [SD = 1.47], Minformationplusbanner = 4.92 [SD = 1.21], Mfullcampaign = 4.57 [SD = 1.26], P = .014, and Minformationonly = 3.13 [SD = 1.76], Minformationplusbanner = 3.56 [SD = 1.48], Mfullcampaign = 4.02 [SD = 1.42], P < .001, respectively). As anticipated, the full campaign garnered the highest affect and engagement scores. When comparing the 4 first-time experiences, there were main effects on support and engagement (Mtrain = 5.06 [SD = 1.17], Mplane = 4.27 [SD = 1.28], Mhome = 4.59 [SD = 1.19], Mplay = 4.38 [SD = 1.29], P = .009 and Mtrain = 4.50 [SD = 1.27], Mplane = 3.75 [SD = 1.43], Mhome = 4.01 [SD = 1.49], Mplay = 3.84 [SD = 1.39], P = .042, respectively), with the novel experience of "working with a personal trainer" rated highest. CONCLUSION: Findings from this study have implications for the design of health promotion materials on college campuses. Specifically, campaigns that frame seeking help for mental health as a new experience potentially increase student engagement in this behavior. A key finding from the present study is that a campaign in which this behavior is linked to a familiar form of interpersonal help seeking (personal training) can create receptivity to the stigmatized issue of mental health help seeking. PMID- 29129109 TI - Impact of Healthy Vending Machine Options in a Large Community Health Organization. AB - PURPOSE: To determine whether increasing the proportion of healthier options in vending machines decreases the amount of calories, fat, sugar, and sodium vended, while maintaining total sales revenue. DESIGN: This study evaluated the impact of altering nutritious options to vending machines throughout the Banner Health organization by comparing vended items' sales and nutrition information over 6 months compared to the same 6 months of the previous year. SETTING: Twenty-three locations including corporate and patient-care centers. INTERVENTION: Changing vending machine composition toward more nutritious options. MEASURES: Comparisons of monthly aggregates of sales, units vended, calories, fat, sodium, and sugar vended by site. ANALYSIS: A pre-post analysis using paired t tests comparing 6 months before implementation to the equivalent 6 months postimplementation. RESULTS: Significant average monthly decreases were seen for calories (16.7%, P = .002), fat (27.4%, P <= .0001), sodium (25.9%, P <= .0001), and sugar (11.8%, P = .045) vended from 2014 to 2015. Changes in revenue and units vended did not change from 2014 to 2015 ( P = .58 and P = .45, respectively). CONCLUSION: Increasing the proportion of healthier options in vending machines from 20% to 80% significantly lowered the amount of calories, sodium, fat, and sugar vended, while not reducing units vended or having a negative financial impact. PMID- 29129110 TI - Parenting stress and life satisfaction in mothers of children with cerebral palsy: The mediating effect of social support. AB - In this study, we investigated the mediating effect of social support on the relationship between parenting stress and life satisfaction in Chinese mothers of children with cerebral palsy ( N = 369). The results showed that family support and friend support, but not significant-other support, had mediating effects on the relationship between parenting stress and life satisfaction. Moreover, the mediating effect of friend support was equal to family support. These results suggest that the focus should be on reducing parenting stress and increasing support from family and friends to help improve life satisfaction in mothers of children with cerebral palsy. PMID- 29129111 TI - Poor emotional responsiveness in clinical hypertension: Reduced accuracy in the labelling and matching of emotional faces amongst individuals with hypertension and prehypertension. AB - Psychological factors are known to play an important part in the origin of many medical conditions including hypertension. Recent studies have reported elevated blood pressure (even in the normal range of variation) to be associated with a reduced responsiveness to emotions or 'emotional dampening'. Our aim was to assess emotional dampening in individuals with more extreme blood pressure levels including prehypertensives (N = 58) and hypertensives (N = 60) by comparing their emotion recognition ability with normotensives (N = 57). Participants completed novel facial emotion matching and facial emotion labelling tasks following blood pressure measurement and their accuracy of emotion recognition and average response times were compared. The normotensives demonstrated a significantly higher accuracy of emotion recognition than the prehypertensives and the hypertensives in labelling of facial emotions. This difference generalised to the task where two facial halves (upper & lower) had to be matched on the basis of emotions. In neither the labelling nor matching emotion conditions did the groups differ in their speed of emotion processing. Findings of the present study extend reports of 'emotional dampening' to hypertensives as well as to those at-risk for developing hypertension (i.e. prehypertensives) and have important implications for understanding the psychological component of such medical conditions as hypertension. PMID- 29129112 TI - Folate Deficiency and Anemia Among Women of Reproductive Age (15-49 Years) in Senegal: Results of a National Cross-Sectional Survey. AB - BACKGROUND: Widely spread throughout the world, folate and iron deficiencies are risk factors for many diseases. However, contrary to iron deficiency and anemia, which have been documented in depth, the prevalence of folate deficiency among women has not been well-studied. OBJECTIVE: The aim of this study is to determine the prevalence of folate deficiency and anemia and their association among Senegalese women of reproductive age. METHODS: A national cross-sectional survey using a stratified 2-stage cluster sampling was conducted. Data were collected from 1012 women (aged 15-49 years). Plasma folate and hemoglobin (Hb), as well as protein markers of subclinical infections, were equally measured. RESULTS: The mean folate concentration was 8.50 nmol/L (8.16-8.85 nmol/L), and 54.8% of the women were folate deficient (<10 nmol/L). Plasma folate concentration of rural women (7.27 nmol/L [6.89-7.68 nmol/L]) and urban women (10.45 nmol/L [9.88-11.05 nmol/L]) was significantly different ( P < .0001), the highest concentration being observed in women living in Dakar, the capital of Senegal. The breastfeeding women showed lower plasma folate concentration compared to nonbreastfeeding ones: 6.97 nmol/L (6.37-7.63 nmol/L) versus 9.03 nmol/L (8.61 9.46 nmol/L). Overall, 27% of the women were suffering from inflammation/infections. Mean Hb concentration was 116.86 (1.18) g/L, and 47.63% of the women involved in the study were anemic (pregnant women Hb <110 g/L; nonpregnant Hb <120 g/L). Also, a positive and significant correlation was found between plasma folate and Hb concentrations ( r = .07; P = .0167). CONCLUSIONS: This study showed a high prevalence of folate deficiency and anemia among Senegalese women (15-49 years), particularly those living in rural settings and breastfeeding women. PMID- 29129113 TI - Seclusion and Restraint: The Voice of the Patient. PMID- 29129114 TI - Image-guided surgery and therapy for lung cancer: a critical review. AB - Of the many imaging technologies, some have the potential to be used in image guided surgery and therapy (IGS/IGT). This review of relevant papers on IGS/IGT for lung cancer indicates effective localization and IGS/IGT in early endobronchial lesions by fluorescence bronchoscopic technique. Visualization of early peripheral (nodular) tumors at operation can be achieved by a variety of imaging methods and devices which allow identification, localization and provision of intraoperative real-time images. Recent developments employing fluorescence contrasts and near infra-red light have shown encouraging feasibility and outcome in providing reliable methods for the IGS of cancer generally and lung cancer more specifically with provision of real time intraoperative imaging. The concept of the hybrid operating theater is touched upon. PMID- 29129115 TI - Innovative layer genetics to handle global challenges in egg production. AB - 1. In commercial layer breeding, extensive gene pools are tested and selected for market requirements which must be anticipated at least 5 years ahead. Field results confirm a continuous positive genetic trend in egg output and better feed efficiency which can be converted into land savings. 2. Animal welfare and cage free housing dominate future needs of the market. Nesting behaviour and minimal tendency to develop feather-pecking or cannibalism without beak treatment are key trait complexes. Stronger shells for longer production cycles without moulting have to be combined with better bones. 3. No single big gene effect can be expected to control the multifactorial problem of feather-pecking. Adjusting the shape of the beak, with a heritability of .10-.25, can contribute to reducing the risk of severe cannibalism. 4. For better skeletal integrity, the assessment of bone quality in pedigree birds housed in enriched cages is done by keel bone palpation or ultrasound measurement of the humerus. Both traits show similar heritabilities in the range of .15-.30 and can be included in a balanced selection approach for performance, quality and welfare traits. 5. The combination of performance testing and genome-wide DNA marker analysis is a promising tool to generate more progress for a balanced performance and behaviour profile. PMID- 29129116 TI - High HIV prevalence predicts less HIV stigma: a cross-national investigation. AB - Despite substantial global efforts to reduce HIV-related stigma, stigma and discrimination remain widespread and are among the most poorly understood aspects of the epidemic. However, there has been little research on whether HIV stigma in a country is associated with HIV prevalence. This article offers a socioecological perspective for understanding HIV stigma in a context of HIV prevalence. Using two international data sets (the UNAIDS 2009 HIV Epidemiological Report and the World Values Survey), we investigated whether and how HIV prevalence is associated with individual- and country-level HIV stigma. Results showed that in countries with higher HIV prevalence, people reported less HIV stigma (Studies 1 & 2). HIV knowledge mediated the relationship between HIV prevalence and stigma (Study 2). People in countries with higher HIV prevalence reported more knowledge about HIV transmission, which reduced their stigmatizing attitudes. These findings suggest that stigma-reduction programs should incorporate a socioecological perspective and consider the roles of prevalence rate of and knowledge of the disease. PMID- 29129117 TI - Calls to Poison Centers for hookah smoking exposures. AB - Over the past decade, smoking behaviors have changed in the US. Hookah or waterpipe smoking is increasing, especially among youth and young adults. Social media sites describe the "hookah high" or "buzz", which may be related to nicotine, carbon monoxide, or other inhalants in hookah smoke. Most important is the risk of carbon monoxide poisoning. Case reports include a high number of victims presenting with loss of consciousness from either syncope or seizures. Anaphylaxis and a very rare respiratory hypersensitivity reaction, acute eosinophilic pneumonia, have also been reported from hookah smoking in previously healthy young adults. This article provides background information on hookah smoking, describes hookah-induced acute injuries that could precipitate poison center calls, and offers suggestions for exposure characterization. PMID- 29129118 TI - Gene expression of insulin receptor, insulin-like growth factor increases and insulin-like growth factor-binding protein-3 reduces with increase in prostate size in benign prostatic hyperplasia. AB - INTRODUCTION: Although the role of insulin in the development of benign prostatic hyperplasia (BPH) is well established, there are no studies regarding alteration in the gene expression of components of insulin-signaling pathway and their association with prostate size in BPH. Hence, the study was designed to analyze the gene and protein expression of insulin receptor and its related components in patients with BPH. MATERIALS AND METHODS: Twenty-seven BPH patients aged between 55 and 75 years were recruited in the study and prostatic tissues were obtained after transurethral resection of the prostate. Gene expression levels of Insulin receptor (IR), insulin receptor substrate (IRS), insulin-like growth factor (IGF) and insulin-like growth factor-binding protein-3 (IGFBP-3) were assessed by q PCR. RESULTS: Insulin receptor (IR-A and B) and insulin-like growth factors (IGF 1 and IGF-2) gene expression were significantly increased and IGFBP-3 gene expression was reduced in BPH patients with larger prostate size. Also, serum insulin was significantly increased and IGFBP-3 was significantly reduced in patients with larger prostate size. CONCLUSION: Increased expression of IR-A, B and IGF-1, 2 genes and reduced IGFBP-3 gene expression was associated with larger prostate size in BPH. PMID- 29129119 TI - Periodontal inflamed surface area and periodontal case definition classification. AB - OBJECTIVE: To assess whether a higher periodontal inflamed surface area (PISA) may reflect more severe periodontitis, and if so, to calculate which cut-off point should be used to classify a patient as suffering from periodontitis. MATERIAL AND METHODS: Eighty subjects were selected based on their periodontal status and were divided into 4 groups of 20 each; periodontally healthy, mild periodontitis, moderate periodontitis and severe periodontitis. In addition, demographic data, smoking status and socioeconomic status were also recorded. RESULTS: The highest mean PISA value was obtained for the severe periodontitis group (2309.42 +/- 587.69 mm2) and the least for the periodontally healthy (34.30 +/- 16.48 mm2). The PISA values corresponding to the three categories of periodontitis severity were significantly higher than the periodontally healthy group. When receiver operating characteristic (ROC) analysis was performed, a PISA value >=130.33 mm2 predicted the presence of periodontitis with a sensitivity of 98% and a specificity of 100%. CONCLUSIONS: PISA is a periodontal parameter that may be used in conjunction with the Centers for Disease Control and Prevention - American Academy of Periodontology case definition classification in periodontal medicine research. PMID- 29129120 TI - Successful treatment of HIV-/HCV-coinfected patients in the era of direct acting antivirals: is advanced liver disease still a limiting factor? PMID- 29129121 TI - The validity and intra-tester reliability of markerless motion capture to analyse kinematics of the BMX Supercross gate start. AB - The aim of this study was to quantify the validity and intra-tester reliability of a novel method of kinematic measurement. The measurement target was the joint angles of an athlete performing a BMX Supercross (SX) gate start action through the first 1.2 s of movement in situ on a BMX SX ramp using a standard gate start procedure. The method employed GoPro(r) Hero 4 Silver (GoPro Inc., USA) cameras capturing data at 120 fps 720 p on a 'normal' lens setting. Kinovea 0.8.15 (Kinovea.org, France) was used for analysis. Tracking data was exported and angles computed in Matlab (Mathworks(r), USA). The gold standard 3D method for joint angle measurement could not safely be employed in this environment, so a rigid angle was used. Validity was measured to be within 2 degrees . Intra-tester reliability was measured by the same tester performing the analysis twice with an average of 55 days between analyses. Intra-tester reliability was high, with an absolute error <6 degrees and <9 frames (0.075 s) across all angles and time points for key positions, respectively. The methodology is valid within 2 degrees and reliable within 6 degrees for the calculation of joint angles in the first ~1.25 s. PMID- 29129122 TI - Convergence and divergence: An analysis of mechanical restraints. AB - BACKGROUND: Psychiatric nurses are regularly confronted with the uses and effects of control interventions such as mechanical restraints. Although there are evident tensions in the literature regarding the use of mechanical restraints, very little research has focused on the lived and embodied experience of their use, whether from the patient's perspective or the perspective of nursing staff responsible for their application. Research aims: (1) to gain access to the bodily phenomenon of being placed in mechanical restraints; (2) to give voice to the intimate experiential understanding of this experience; and (3) through phenomenological interpretation, to understand the subjective processes and meaning-making of this experience. RESEARCH DESIGN: For this research, we adopted a distinctly ethics-oriented application of the methodology known as interpretative phenomenological analysis, that is, the interpretive dimension of the research focused on ethical practice in mental healthcare - one that is informed by experiential accounts of the lived body. Participants and research context: A total of 40 in-depth semi-structured, nondirected interviews with both nurses (n = 21) and patients (n = 19) we conducted to meet the aims of this article. Participants were recruited from an inpatient psychiatric unit of a Canadian general hospital. Ethical considerations: The research received research ethics board clearance from both the hospital where the study took place and the University of Ottawa. FINDINGS: The comparative analysis is presented under the following headings: (1) context of care, (2) meaning of quality of care, (3) emotional reactions and nurse-patient relationship, (4) meeting the needs and (5) need for alternatives. DISCUSSION/CONCLUSIONS: The research findings are discussed in light of current literature and implications for practice. PMID- 29129123 TI - Opinions of nurses regarding conscientious objection. AB - BACKGROUND: In the last decades, there have been important developments in the scientific and technological areas of healthcare. On certain occasions this provokes conflict between the patients' rights and the values of healthcare professionals which brings about, within this clinical relationship, the problem of conscientious objection. AIMS: To learn the opinions that the Nurses of the Madrid Autonomous Community have regarding conscientious objection. RESEARCH DESIGN: Cross-cutting descriptive study. Participants and research context: The nurses of 9 hospitals and 12 Health Centers in the Madrid Autonomous Community. The study was done by means of an auto completed anonymous questionnaire. The variables studied were social-demographical and their opinions about conscientious objections. Ethical considerations: The study was approved by the Ethical Community of Clinical Research of the University Hospital Principe de Asturias. Participants were assured of maximum confidentiality and anonymity. FINDINGS: A total of 421 nurses answered the questionnaire. In total, 55.6% of the nurses confirmed they were religious believers, and 64.3% declared having poor knowledge regarding conscientious objection. The matters that caused the greatest objections were voluntary abortions, genetic embryo selection, refusal of blood transfusions, and therapy refusal. DISCUSSION: Different authors state that the most significant cases of conscientious objections for health professionals are those regarding carrying out or assisting in abortions, euthanasia, the practice of assisted reproduction and, finally, the prescription and dispensing of the morning-after pill. In our study, the most significant cases in which the nurses would declare conscientious objections would be the refusal to accept treatment, the selection of embryos after genetic diagnosis preimplantation, the patient's refusal to receive blood transfusions due to religious reasons and pregnant women's request for voluntary abortions within the first 14 weeks. CONCLUSION: Nurses' religious beliefs influence their opinions regarding conscientious objection. The nurses who declare themselves as religious believers object in a higher percentage than those without religious beliefs. PMID- 29129124 TI - Haff disease complicated by acute lung injury after crayfish consumption: a case report. PMID- 29129125 TI - Clinical efficacy and safety of a highly conformal, supine, hybrid forward and inverse planned intensity modulated radiation therapy technique for craniospinal irradiation. AB - PURPOSE: To demonstrate the clinical efficacy and safety of a highly conformal, supine, hybrid forward and inverse planned intensity modulated radiation therapy (IMRT) technique for photon craniospinal irradiation (CSI). METHODS: Patients who received supine, hybrid IMRT CSI from 2009 to 2014 were included in this retrospective review. Clinical target volume (CTV) was defined as intracranial contents and thecal sac, including nerve roots. Dose was prescribed such that >99% of CTV received >99% of prescription and >95% of the planning target volume received >95% of prescription, with no attempt to include vertebral bodies. Lateral fields were utilized at the cranium and upper cervical spine. Spine fields were either single posterior or 2-3 obliques. Plans were generated with a hybrid of forward and inverse planned IMRT. Inferior borders of the cranium fields and superior border of the lower spine field were designed with 6-15 cm long, gradual dose gradients by sequential closing of multileaf collimator leaves using forward planned multiple static segment IMRT delivery. The sliding window upper spine IMRT field was created by the inverse planning system to match gradients of the brain and lower spine fields. The lower spine field gradient was similarly completed. RESULTS: The cohort consisted of 34 patients. Median CSI dose was 36 Gy (range: 18-39.6 Gy). With a median follow up of 59.4 months, there were no isolated recurrences or spinal myelopathies at CTV margins or field gradients. Eleven patients had recurrence, all of which were intracranial. CONCLUSIONS: Our hybrid forward and inverse planned IMRT supine CSI technique did not result in any isolated recurrences or myelopathies at CTV margins or field gradients. This suggests our target volumes and blended gradients are appropriate for highly conformal three-dimensional planning. PMID- 29129126 TI - Chronic Circadian Misalignment without Circadian Arrhythmicity or Sleep Deprivation Does Not Impair Adult Hippocampal Neurogenesis. AB - Artificial light in modern society has led to the ubiquity of light exposure at night as individuals work night shifts and use light-emitting electronic devices before bedtime. These aberrant light conditions have detrimental consequences on cognitive and mental health, compelling the need to understand the mechanisms by which light affects brain functions. Although it was believed that aberrant light impairs health by first disrupting circadian rhythms and sleep, we showed that chronic exposure to a light cycle termed T7 (3.5 h of darkness, 3.5 h of light) caused mood and learning dysfunction in adult mice independent of sleep deprivation or circadian arrhythmicity, suggesting the direct effects of aberrant light on brain function. However, the mechanisms by which light directly causes mood and learning dysfunction remain poorly understood. In this study, we sought to determine whether exposure to the T7 cycle disrupts adult hippocampal neurogenesis, given that suppressed neurogenesis has been correlated with mood and learning dysfunction. After exposing adult mice to the T7 light cycle, we analyzed adult hippocampal neurogenesis by examining cellular proliferation and number of adult-born neurons. Contrary to our hypothesis that T7 would suppress neurogenesis, we found that adult mice exposed to 2 or 10 weeks of the T7 light cycle did not exhibit deficits in hippocampal neurogenesis. Our findings suggest that the direct effects of light on mood and learning do not depend on adult hippocampal neurogenesis. PMID- 29129127 TI - A New DAWN for Imaging-Based Selection in the Treatment of Acute Stroke. PMID- 29129128 TI - Convergent Time-Varying Regression Models for Data Streams: Tracking Concept Drift by the Recursive Parzen-Based Generalized Regression Neural Networks. AB - One of the greatest challenges in data mining is related to processing and analysis of massive data streams. Contrary to traditional static data mining problems, data streams require that each element is processed only once, the amount of allocated memory is constant and the models incorporate changes of investigated streams. A vast majority of available methods have been developed for data stream classification and only a few of them attempted to solve regression problems, using various heuristic approaches. In this paper, we develop mathematically justified regression models working in a time-varying environment. More specifically, we study incremental versions of generalized regression neural networks, called IGRNNs, and we prove their tracking properties - weak (in probability) and strong (with probability one) convergence assuming various concept drift scenarios. First, we present the IGRNNs, based on the Parzen kernels, for modeling stationary systems under nonstationary noise. Next, we extend our approach to modeling time-varying systems under nonstationary noise. We present several types of concept drifts to be handled by our approach in such a way that weak and strong convergence holds under certain conditions. Finally, in the series of simulations, we compare our method with commonly used heuristic approaches, based on forgetting mechanism or sliding windows, to deal with concept drift. Finally, we apply our concept in a real life scenario solving the problem of currency exchange rates prediction. PMID- 29129129 TI - In vitro cytotoxicity and genotoxicity of Furia(r)180 SC (zeta-cypermethrin) and Bulldock 125(r)SC (beta-cyfluthrin) pyrethroid insecticides in human peripheral blood lymphocytes. AB - In the present study, human peripheral blood lymphocytes were exposed in vitro to 0, 6, 12, 18, 24, and 30 MUg/mL Furia(r)180 SC (zeta-cypermethrin) and 0, 6.3, 12.5, 18.8, 25, and 31.3 MUg/mL Bulldock(r)125 SC (beta-cyfluthrin). Exposure to 32 ug/mL bleomycin for 24 h served as a positive control. The cytotoxic and genotoxic effects of each insecticide were analyzed using alkaline comet and trypan blue dye exclusion assays. DNA damage was evaluated through three genotoxicity parameters: tail length (TL), tail moment (TM) and tail intensity (TI). Furia(r)180 SC and Bulldock(r)125 SC pyrethroid insecticides and bleomycin significantly increased DNA damage in a concentration-dependent manner. Bulldock(r)125 SC induced more DNA damage than Furia. Lymphocyte viability did not change after exposure to different concentrations of the two pyrethroid insecticides and bleomycin. Moreover, genotoxic results demonstrated that Furia(r)180 SC and Bulldock(r)125 SC insecticides caused in vitro DNA damage in human peripheral lymphocytes. PMID- 29129130 TI - Crystal structures of carboxypeptidase T complexes with transition-state analogs. PMID- 29129131 TI - Increased wound complication with intramedullary screw fixation of clavicle fractures: Is it thermal necrosis? AB - PURPOSE: Adult mid-shaft clavicle fractures are common injuries. For displaced fractures, open reduction with plate or intramedullary (IM) fixation is the widely used techniques. All methods have their own potential drawbacks, especially related to local soft tissue complications. There is little information about outcome and management of local wound complications after clavicle fracture fixations. METHODS: Ninety-seven patients underwent open reduction and internal fixation, 17 were treated with IM screw fixation and 80 with plate fixation. Wound complication occurred in eight patients (8.2%) and rates differed significantly between IM and plate fixations (29.4% vs. 3.8%). Patients were assessed on average 58.3 months with visual analogue pain scores (VASs), Oxford Shoulder Score (OSS), and QuickDash (QD) score. RESULTS: Five patients had wound breakdown and three patients had wound erythema. In seven patients with stable fixation, it was possible to "dress and suppress" with average 3 weeks of oral antibiotics. One patient had unstable fixation and required longer antibiotic treatment with early screw removal. One patient developed a chronic discharging wound, requiring debridement and later plate removal. At final follow-up, all wounds remained healed, bony union was achieved in all. The average scores were: VAS 1, OSS 46, and QD 4.5. CONCLUSIONS: Good function with dry healed wound and united clavicle can be achieved. Further studies are required to investigate the difference in soft tissue complication rates, which may be due to the IM technique of retrograde drilling with a guide wire and due to aseptic thermal bone necrosis, rather than true infection. PMID- 29129132 TI - Reliability of force-velocity relationships during deadlift high pull. AB - This study aimed to evaluate the within- and between-session reliability of force, velocity and power performances and to assess the force-velocity relationship during the deadlift high pull (DHP). Nine participants performed two identical sessions of DHP with loads ranging from 30 to 70% of body mass. The force was measured by a force plate under the participants' feet. The velocity of the 'body + lifted mass' system was calculated by integrating the acceleration and the power was calculated as the product of force and velocity. The force velocity relationships were obtained from linear regression of both mean and peak values of force and velocity. The within- and between-session reliability was evaluated by using coefficients of variation (CV) and intraclass correlation coefficients (ICC). Results showed that DHP force-velocity relationships were significantly linear (R2 > 0.90, p < 0.05). Within sessions and between sessions, mean and peak forces during DHP showed a strong agreement (CV < 3%, ICC > 0.94), mean and peak velocities showed a good agreement (CV < 9%, 0.78 < ICC < 0.92). It was concluded that DHP performance and its force-velocity relationships are highly reliable and can therefore be utilised as a tool to characterise individuals' muscular profiles. PMID- 29129133 TI - Association between hypocapnia and ventilation during the first days of life and brain injury in asphyxiated newborns treated with hypothermia. AB - PURPOSE: Therapeutic hypothermia is the standard treatment for asphyxiated newborns. Since hypocapnia is common in these newborns, the aim of this study was to assess the association among hypocapnia, ventilation, and brain injury. METHODS: We conducted a retrospective cohort study of all asphyxiated newborns treated with hypothermia from 2008 to 2014. Partial pressure of carbon dioxide (pCO2), ventilatory status, and modes of ventilation were recorded during the first 4 days of life. Brain injury was evaluated using brain magnetic resonance imaging. Differences between intubated and nonintubated newborns and between the newborns who developed brain injury or not were assessed. RESULTS: One hundred ninety-eight asphyxiated newborns were treated with hypothermia. During the first 2 days of life, intubated newborns had consistently lower pCO2 levels (respectively, 29.01 +/- 8.55, p < .001 on day 1 of life and 33.65 +/- 7.12, p = .004 on day 2 of life). Fifty-nine percent of the intubated newborns developed brain injury versus only 43% of the nonintubated newborns (p = .046). The lowest pCO2 levels averaged over the first 4 days of life were significantly decreased in newborns developing brain injury (p = .02) and significantly associated with brain injury severity (p = .01). After adjusting for potential cofounders, the lowest pCO2 averaged over days 1-4 of life remained significantly associated with an increased risk of brain injury (odds ratio [95%CI]: 1.07 [1.00-1.14]; p = .04). CONCLUSIONS: Intubated and ventilated asphyxiated newborns experienced more severe hypocapnia, and had higher incidences of brain injury. Hypocapnia during the first 4 days of life was associated with an increased risk of developing (more severe) brain injury. PMID- 29129134 TI - Divided attention during cutting influences lower extremity mechanics in female athletes. AB - Anterior cruciate ligament (ACL) injuries in basketball appear to be more common when players are in possession of the ball. The greater risk of ACL injury when in possession of the ball may result from the athlete's inability to fully attend to their movement. However, it is also possible that having to carry/manipulate the ball restricts the athlete's ability to utilise their upper extremities for stability during a manoeuvre. The purpose of this study was to explore how possession of a basketball and divided attention influence lower extremity mechanics during cutting and landing. Twenty uninjured females with basketball experience performed a baseline lateral cutting task, as well as lateral cuts while carrying a basketball, with and without a subsequent chest pass. Requiring participants to carry the basketball in isolation (i.e., without the additional pass) had minimal influence on lower extremity mechanics compared to baseline. However, participants demonstrated less knee flexion (40.9 degrees vs. 47.3 degrees ) and greater knee abduction (12.2 degrees vs. 10.1 degrees ) for trials that included the additional pass (divided attention condition) compared to trials conducted while carrying the basketball in isolation. Athletes may be at greater risk for ACL injury when they are unable to solely attend to their movement. PMID- 29129135 TI - Precarious Situations of Care Workers in Home-Based Elder Care in Slovenia. AB - Based on policy analysis and individual interviews, the author analyzes the care workers' precarious situations in home-based elder care in Slovenia, a post socialist, European Union country characterized by a rapidly aging population and delays in adapting a long-term care system to this new social risk. Employment and quasi-employment positions which coexist in home-based care can be sorted along two continuums: between public and market service; between formal and informal work. The author argues that working conditions in home-based care differ according to the position of the care worker on these two continuums, that is, being employed in public services, being self-employed, working in informal care markets, holding a status of family assistant, or being an informal family caregiver. Although the working conditions in public services are deteriorating, the analysis shows that precarity is more severe in market and informal care, while formalization and socialization of care bring about less precarious conditions. PMID- 29129137 TI - Citation metrics of excellence in sports biomechanics research. AB - This study extended research on key citation metrics of winners of two career scholar awards in sports biomechanics. Google Scholar (GS) was searched using Harzing's Publish or Perish software for the 13 most recent winners of the ISBS Geoffrey Dyson Award and the ASB Jim Hay Memorial Award. Returned records were corrected for author, and publications excluded for all but peer-reviewed journal articles, proceedings articles, chapters and books in English. These recent award winners had published about 150 publications that had been cited typically 4,082 and 6,648 times over a 26- and 28-year period before receiving these career awards for sports biomechanics research. Estimated median citations at time of their awards were 2,927 and 4,907 for the Dyson and Hay awards, respectively. Award winners had mean Hirsh indexes of 32-45 and mean hi of 19-28. Their mean g indexes (59-84) and their numerous citation classics (C > 100) indicated that they had many influential publications. The citation metrics of these scholars were outstanding and consistent with recent studies of top scholars in biomechanics and kinesiology/exercise science. Careful searching, cleaning and interpretation of several scholar-level citation metrics may provide useful confirmatory evidence for evaluations of awards committees. PMID- 29129138 TI - The electrostatic role of the Zn-Cys2His2 complex in binding of operator DNA with transcription factors: mouse EGR-1 from the Cys2His2 family. AB - The mouse factor Zif268, known also as early growth response protein EGR-1, is a classical representative for the Cys2His2 transcription factor family. It is required for binding the RNA polymerase with operator dsDNA to initialize the transcription process. We have shown that only in this family of total six Zn finger protein families the Zn complex plays a significant role in the protein DNA binding. Electrostatic feature of this complex in the binding of factor Zif268 from Mus musculus with operator DNA has been considered. The factor consists of three similar Zn-finger units which bind with triplets of coding DNA. Essential contacts of the factor with the DNA phosphates are formed by three conservative His residues, one in each finger. We describe here the results of calculations of the electrostatic potentials for the Zn-Cys2His2 complex, Zn finger unit 1, and the whole transcription factor. The potential of Zif268 has a positive area on the factor surface, and it corresponds exactly to the binding sites of each of Zn-finger units. The main part of these areas is determined by conservative His residues, which form contacts with the DNA phosphate groups. Our result shows that the electrostatic positive potential of this histidine residue is enhanced due to the Zn complex. The other contacts of the Zn-finger with DNA are related to nucleotide bases, and they are responsible for the sequence specific binding with DNA. This result may be extended to all other members of the Cys2His2 transcription factor family. PMID- 29129136 TI - Palliative Medicine-Becoming a Subspecialty of the Royal College of Physicians and Surgeons of Canada. AB - The discipline of palliative medicine in Canada started in 1975 with the coining of the term "palliative care." Shortly thereafter, the provision of clinical palliative medicine services started, although the education of the discipline lagged behind. In 1993, the Canadian Society of Palliative Care Physicians (CSPCP) started to explore the option of creating an accredited training program in palliative medicine. This article outlines the process by which, over the course of 20 years, palliative medicine training in Canada went from a mission statement of the CSPCP, to a 1 year of added competence jointly accredited by both the Royal College of Physicians and Surgeons of Canada (Royal College) and the College of Family Physicians of Canada, to a 2-year subspecialty of the Royal College with access from multiple entry routes and a formalized accrediting examination. PMID- 29129139 TI - Effect of using an internal teat sealant at drying-off in cows wintered on forage crops in New Zealand on culling in the dry period and early lactation. AB - AIMS: To determine the impact of treatment with internal teat sealant (ITS) compared to no treatment at drying-off on culling during the dry period and 90 days after calving, for cows wintered on forage crops. METHODS: In four dairy herds in the South Island of New Zealand, cows with no history of clinical mastitis or somatic cell counts >100,000 cells/mL during the 2015-16 season were randomly assigned to treatment with ITS in each quarter (ITS group) or no treatment (Control group). Cows were otherwise treated similarly, wintered on forage crops and transferred to pasture for calving and lactation. Culling was defined as an unplanned exit from the herd, including cows sold for slaughter, cows slaughtered for salvage value and cows that died on farm. Culls and cull dates were recorded between drying-off and 90 days after calving. RESULTS: Between drying-off and 90 days after calving 24/491 (4.9%) cows in the ITS group and 45/473 (9.5%) cows in the Control group were culled (RR=0.51; 95% CI=0.75 0.83), and between 30 days before calving and 90 days after calving 20/491 (4.1%) cows in the ITS group and 40/473 (8.5%) cows in the Control group were culled (RR=0.48; 95% CI=0.29-0.81). In the final multivariable logistic regression model, adjusting for dry-period length, cow age, breed and farm, the OR for culling in the study period was 0.43 (95% CI=0.23-0.81) for cows in the ITS compared with the Control group. For a Friesian/Jersey cow, aged 4-8 years, with a dry period of 30-80 days, dried-off without ITS, the probability of culling in the study period was 0.10 (95% CI=0.06-0.16), and for such a cow treated with ITS the probability was 0.05 (95% CI=0.03-0.08). CONCLUSIONS AND CLINICAL RELEVANCE: In these four herds, the use of ITS at drying-off reduced the incidence of culling between drying-off and 90 days after calving. The use of ITS at drying off in cows prior to wintering on forage crops may provide additional benefit to farmers through reduced incidence of culling and should be considered in any cost benefit analysis of its use. PMID- 29129140 TI - Effects of helix and fingertip mutations on the thermostability of xyn11A investigated by molecular dynamics simulations and enzyme activity assays. AB - Local conformational changes and global unfolding pathways of wildtype xyn11A recombinant and its mutated structures were studied through a series of atomistic molecular dynamics (MD) simulations, along with enzyme activity assays at three incubation temperatures to investigate the effects of mutations at three different sites to the thermostability. The first mutation was to replace an unstable negatively charged residue at a surface beta turn near the active site (D32G) by a hydrophobic residue. The second mutation was to create a disulphide bond (S100C/N147C) establishing a strong connection between an alpha helix and a distal beta hairpin associated with the thermally sensitive Thumb loop, and the third mutation add an extra hydrogen bond (A155S) to the same alpha helix. From the MD simulations performed, MM/PBSA energy calculations of the unfolding energy were in a good agreement with the enzyme activities measured from the experiment, as all mutated structures demonstrated the improved thermostability, especially the S100C/N147C proved to be the most stable mutant both by the simulations and the experiment. Local conformational analysis at the catalytic sites and the xylan access region also suggested that mutated xyn11A structures could accommodate xylan binding. However, the analysis of global unfolding pathways showed that structural disruptions at the beta sheet regions near the N-terminal were still imminent. These findings could provide the insight on the molecular mechanisms underlying the enhanced thermostability due to mutagenesis and changes in the protein unfolding pathways for further protein engineering of the GH11 family xylanase enzymes. PMID- 29129149 TI - Anaesthetic and cardiorespiratory effects of ketamine plus dexmedetomidine for chemical restraint in black capuchin monkeys (Sapajus nigritus). AB - AIMS: To evaluate the quality of anaesthesia and cardiorespiratory effects of ketamine and two doses of dexmedetomidine in captive black capuchin monkeys (Sapajus nigritus) undergoing routine clinical examination. METHODS: Twenty-four animals undergoing routine clinical examination were enrolled in the study. Animals were briefly physically restrained and examined to ensure no obvious illness was present and that they were healthy. Monkeys were randomly allocated to two groups (n=12 per group) and then treated with a combination of I/M 7.5 mg/kg ketamine and either 30 ug/kg or 50 ug/kg dexmedetomidine (Dex30 or Dex50 groups, respectively). Interval to onset and duration of anaesthesia were recorded, and the quality of induction of anaesthesia and recovery were subjectively evaluated. Heart rate, respiratory rate, systolic arterial pressure (SAP), rectal temperature, degree of sedation, analgesia, muscle relaxation and response to auditory stimulus were measured every 5 minutes from onset of anaesthesia until recovery. RESULTS: The mean interval to onset of anaesthesia was 7.3 (SD 6.6) and 9.1 (SD 5.0) minutes for the Dex30 and Dex50 groups, respectively (p=0.208). Mean duration of anaesthesia was longer for monkeys in the Dex50 (85.5 (SD 15.3) minutes) compared to those in Dex30 (63.9 (SD 16.4) minutes) group (p=0.003). Induction was considered excellent in 23/24 animals, and recovery was excellent in all animals. Heart rate, respiratory rate and body temperature decreased in both groups when compared to baseline, with no differences between groups. No differences between groups were found for assessments of sedation, analgesia, muscle relaxation or response to auditory stimulus. CONCLUSION AND CLINICAL RELEVANCE: Administration of ketamine and dexmedetomidine at the two doses produced adequate, dose-dependent chemical restraint, with excellent induction and recovery, and minimal clinically significant cardiorespiratory effects in captive capuchin monkeys. Due to the occurrence of arrhythmias, electrocardiographic monitoring is recommended when this combination is used. The administration of higher doses of dexmedetomidine produced longer lasting anaesthesia without further compromise of cardiorespiratory parameters. PMID- 29129151 TI - False-Positive Diagnosis of Brain Death Following the Pediatric Guidelines: Case Report and Discussion. AB - A 2-year-old boy with severe head trauma was diagnosed brain dead according to the 2011 Pediatric Guidelines. Computed tomographic (CT) scan showed massive cerebral edema with herniation. Intracranial pressures were extremely high, with cerebral perfusion pressures around 0 for several hours. An apnea test was initially contraindicated; later, one had to be terminated due to oxygen desaturation when the Pco2 had risen to 57.9 mm Hg. An electroencephalogram (EEG) was probably isoelectric but formally interpreted as equivocal. Tc-99m diethylene triamine-pentaacetate (DTPA) scintigraphy showed no intracranial blood flow, so brain death was declared. Parents declined organ donation. A few minutes after withdrawal of support, the boy began to breathe spontaneously, so the ventilator was immediately reconnected and the death declaration rescinded. Two hours later, life support was again removed, this time for prognostic reasons; he did not breathe, and death was declared on circulatory-respiratory grounds. Implications regarding the specificity of the guidelines are discussed. PMID- 29129152 TI - Attention-Deficit Hyperactivity Disorder (ADHD) in Epilepsy and Primary ADHD: Differences in Symptom Dimensions and Quality of Life. AB - PURPOSE: We aimed to (1) compare quality of life (QOL) among children with epilepsy, epilepsy and attention-deficit hyperactivity disorder (ADHD), and primary ADHD and (2) compare ADHD symptom dimensions and subtypes between children with epilepsy-ADHD and primary ADHD. METHODS: A total of 140 children; 53 with epilepsy, 35 with epilepsy-ADHD, and 52 with primary ADHD were included. KINDL-R (quality of life measure), Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S), and Conners' Parent Rating Scale (CPRS) were completed. Neurology clinic charts were reviewed for epilepsy-related variables. RESULTS: Children with epilepsy-ADHD had the lowest (poorest) KINDL-R total scores. Epilepsy-ADHD group had more inattentiveness symptoms, whereas primary ADHD group had more hyperactivity/impulsivity symptoms. The frequencies of ADHD combined and inattentiveness subtypes were 60% and 40% in children with epilepsy ADHD and 80.7% and 19.3% in children with primary ADHD, respectively ( P = .034). CONCLUSION: ADHD in epilepsy is associated with a significantly poor quality of life and predominantly inattentiveness symptoms. PMID- 29129153 TI - Skin Biopsy for Diagnosis of Ullrich Congenital Muscular Dystrophy: An Observational Study. AB - The gold standard diagnostic test for Ullrich congenital muscular dystrophy (UCMD) is molecular testing for COL6 mutation. The facility for genetic testing is sparingly available and it is usually diagnosed by muscle biopsy. The latter is an invasive procedure requiring expertise and sedation. Skin biopsy has shown promise as a simpler diagnostic modality. Eleven and 7 cases, respectively, of phenotypically suspected Ullrich congenital muscular dystrophy and dystrophinopathy underwent simultaneous skin and muscle biopsies, which were subjected to hematoxylin and eosin (H&E) and immunohistochemistry staining for collagen VI and dystrophin 1, 2, and 3. Of the 8 and 5 muscle biopsy-confirmed cases of Ullrich congenital muscular dystrophy and dystrophinopathy, 6 Ullrich congenital muscular dystrophy and 5 dystrophinopathy cases showed absent and preserved COL6 staining, respectively, in the skin biopsy. Skin biopsy as a diagnostic option has shown encouraging results in Ullrich congenital muscular dystrophy. These should be evaluated in larger studies. PMID- 29129154 TI - Predictors of Drug-Resistant Epilepsy in Tuberous Sclerosis Complex. AB - Utilizing the multicenter TSC (tuberous sclerosis complex) Natural History Database including 2034 subjects, this study aimed to identify predictors of drug resistant epilepsy in TSC. Basic epilepsy data were available for 1965 individuals in the database. Supplemental data were further collected from 1546 of these subjects through directed site queries, addressing additional epilepsy characteristics including the presence of drug-resistant epilepsy, therapies trialed, and outcomes of specific therapies. Epilepsy was reported in 86.4% of individuals with TSC. Infantile spasms were reported in 45.2% of individuals and focal seizures were reported in 84.4% of individuals. In those with focal epilepsy, drug resistance was reported in 59.6%, with focal seizure onset prior to age 1 year (odds ratio [OR] 1.9, confidence interval [CI] 1.4-2.5, P < .001), infantile spasms (OR 2.0, CI 1.5-2.5, P < 0.001), and infantile spasms incompletely responsive to therapy (OR 47.6, CI 6.7-333.3, P < 0.001) being associated with an increased likelihood of drug resistance. PMID- 29129155 TI - Transgenerational Inheritance of Familial Lipomyelomeningocele. AB - Lipomyelomeningocele is a type of neural tube defect characterized by lipomatous tissue causing a defect in the vertebrae, infiltrating the dura, and tethering the spinal cord. Despite significant neurologic consequences, the underlying etiology remains poorly understood. We present a father and son with remarkably similar presentations of lipomyelomeningocele. Genetic testing did not reveal an underlying cause but whole exome sequencing identified variants in the ARHGAP29 and RADIL genes in the proband and his affected father. Genetic analyses of asymptomatic family members revealed several carriers of the ARHGAP29 or RADIL variants, but only the proband and his father carried both variants, suggesting a possible shared genetic mechanism. Rare cases of siblings affected with lipomyelomeningocele have suggested the possibility of autosomal recessive or germline mosaicism. We present the first documented cases of transgenerational lipomyelomeningocele with important implications for family counseling about the recurrence of lipomyelomeningocele. PMID- 29129156 TI - A Case of KCNQ2-Associated Movement Disorder Triggered by Fever. AB - The differential diagnosis of fever-induced movement disorders in childhood is broad. Whole exome sequencing has yielded new insights into those cases with a suspected genetic basis. We report the case of an 8-year-old boy with a history of neonatal seizures who presented with near-continuous hyperkinetic movements of his limbs during a febrile illness. Initial diagnostic testing did not explain his abnormalities; however, given the suspicion for a channelopathy, whole exome sequencing was performed and it demonstrated a de novo pathogenic heterozygous variant in KCNQ2. There is an expanding phenotypic spectrum of heterozygous alterations in KCNQ2; however, this report provides the first description of a pathogenic KCNQ2 variant fever-induced hyperkinetic movement disorder in childhood. We also review the literature of cases previously published with the same pathogenic variant. PMID- 29129158 TI - Practical gastrointestinal investigation of iron deficiency anaemia. AB - INTRODUCTION: About 10% of oesophagogastroduodenoscopies (OGDs) and colonoscopies are done for investigation of iron deficiency anemia (IDA) . Much of the existing guidance on investigation of IDA predates CRC screening, which has driven significant improvements in colonoscopy quality and completion rates, as well as a reduction in Helicobacter pylori prevalence and increase in PPI usage, and therefore probably needs re-consideration. New investigations, e.g. CT colonography, enteroscopy and capsule endoscopy have also been introduced. Areas covered: This review updates the approach to practical investigation of IDA. Medline was searched using the terms iron deficiency AND anemia AND/OR gastroscopy, colonoscopy, capsule and enteroscopy, together with review of recent relevant published abstracts on the topic. Expert commentary: Gastrointestinal pathology is now a more common cause of IDA than upper GI causes, reflecting better colonoscopy accuracy and completion rates as well as changing disease patterns, and carcinomas are more likely cause IDA than benign adenomas. Increasing use of antiplatelet and anticoagulants is driving greater presentation of IDA. Capsule endoscopy, enteroscopy and CT colonography are increasingly used. Fecal occult blood testing may be a useful simple screening method in the frail, as a negative test can avoid the need for invasive tests. PMID- 29129159 TI - Third trimester ultrasound accuracy and delivery outcome in obese and morbid obese pregnant women. AB - OBJECTIVE: Several studies have highlighted the negative impact of maternal obesity on ultrasound accuracy for fetal weight estimation (EFW). However, the evidence is conflicting. We aimed in our study to find if the ultrasound accuracy for EFW would differ or decrease in obese and morbid obesity classes. We also studied the mode of delivery within the same cohort. METHODS: It is a retrospective study of obese patients with recorded BMI >=30 kg/m2, class I and II (BMI: 30-39.9 kg/m2) compared with extreme obese class III (BMI >=40 kg/m2), who gave birth after 28-week gestation of viable singleton, who had an ultrasound within 7 d of delivery with reported normal amniotic fluid and no major fetal anomaly; the EFW was consistently measured through Hadlock regression formula in the period of 2014-2015 inclusive. Differences between the EFW and actual birth weight (ABW) were assessed by percentage error, accuracy in predictions within +/ 10% of error and the Pearson correlation coefficient were used to correlate EFW with the ABW. The study's secondary outcome was to study the mode of delivery and the rate of cesarean section in obese and morbid obese patients. RESULTS: Total 106 cases fulfilled our criteria. Class I and II as the first group (n = 53). Class III as the second group (n = 53). Maternal and birth characteristics were similar. The Pearson correlation coefficient equal 1 in both groups. The overall mean absolute difference (MAD) in grams of the whole obese cohort was 242 +/- 213. The MAD was 242 +/- 202 and 242 +/- 226 g for the first and second group, respectively (p = 1.0). The overall mean absolute percentage error (MAPE) in this obese cohort was 8%. The MAPE for the first and second group, respectively were 8 and 7% (p = 0.4). The overall rate of cesarean delivery was 60% (64/106) with no differences between the obese and morbid obese BMI classes. Sixty-six percentage (42/64) of these cesarean cases was for repeat cesarean section. CONCLUSION: Despite what has been previously reported about the negative impact of maternal obesity on EFW accuracy, we could not demonstrate this relationship in our obese cohort (MAPE <10%). In addition, we could not illustrate a significant difference in ultrasound accuracy across various obesity classes. However, we found a significantly increased rate of delivery by repeated cesarean section in this obese cohort. PMID- 29129161 TI - Navigation through inter- and intratumoral heterogeneity of endocrine resistance mechanisms in breast cancer: A potential role for Liquid Biopsies? AB - The majority of breast cancers are hormone receptor positive due to the expression of the estrogen and/or progesterone receptors. Endocrine therapy is a major treatment option for all disease stages of hormone receptor-positive breast cancer and improves overall survival. However, endocrine therapy is limited by de novo and acquired resistance. Several factors have been proposed for endocrine therapy failures, which include molecular alterations in the estrogen receptor pathway, altered expression of cell-cycle regulators, autophagy, and epithelial to-mesenchymal transition as a consequence of tumor progression and selection pressure. It is essential to reveal and monitor intra- and intertumoral alterations in breast cancer to allow optimal therapy outcome. Endocrine therapy navigation by molecular profiling of tissue biopsies is the current gold standard but limited in many reasons. "Liquid biopsies" such as circulating-tumor cells and circulating-tumor DNA offer hope to fill that gap in allowing non-invasive serial assessment of biomarkers predicting success of endocrine therapy regimen. In this context, this review will provide an overview on inter- and intratumoral heterogeneity of endocrine resistance mechanisms and discuss the potential role of "liquid biopsies" as navigators to personalize treatment methods and prevent endocrine treatment resistance in breast cancer. PMID- 29129160 TI - Visual but not motor processes predict simple visuomotor reaction time of badminton players. AB - The athlete's brain exhibits significant functional adaptations that facilitate visuomotor reaction performance. However, it is currently unclear if the same neurophysiological processes that differentiate athletes from non-athletes also determine performance within a homogeneous group of athletes. This information can provide valuable help for athletes and coaches aiming to optimize existing training regimes. Therefore, this study aimed to identify the neurophysiological correlates of visuomotor reaction performance in a group of skilled athletes. In 36 skilled badminton athletes, electroencephalography (EEG) was used to investigate pattern reversal and motion onset visual-evoked potentials (VEPs) as well as visuomotor reaction time (VMRT) during a simple reaction task. Stimulus locked and response-locked event-related potentials (ERPs) in visual and motor regions as well as the onset of muscle activation (EMG onset) were determined. Correlation and multiple regression analyses identified the neurophysiological parameters predicting EMG onset and VMRT. For pattern reversal stimuli, the P100 latency and age best predicted EMG onset (r = 0.43; p = .003) and VMRT (r = 0.62; p = .001). In the motion onset experiment, EMG onset (r = 0.80; p < .001) and VMRT (r = 0.78; p < .001) were predicted by N2 latency and age. In both conditions, cortical potentials in motor regions were not correlated with EMG onset or VMRT. It is concluded that previously identified neurophysiological parameters differentiating athletes from non-athletes do not necessarily determine performance within a homogeneous group of athletes. Specifically, the speed of visual perception/processing predicts EMG onset and VMRT in skilled badminton players while motor-related processes, although differentiating athletes from non-athletes, are not associated simple with visuomotor reaction performance. PMID- 29129162 TI - Mesothelioma in Australia: a review. AB - The incidence of malignant mesothelioma in Australia is among the highest in the world as a result of widespread use of asbestos by industry and in construction throughout the 20th century. The risk of developing malignant mesothelioma after asbestos exposure is dose-related; a transient, low dose exposure confers a correspondingly very low risk of disease. Malignant mesothelioma is a heterogeneous disease, partly explaining the limited role of biomarkers in screening and diagnosis. The prognosis remains poor, and early advice on medico legal compensation and a collaborative team approach to managing malignant mesothelioma are both essential. Chemotherapy can have a modest treatment effect in some people. New therapies, such as immunotherapy, do not yet have a defined role in the treatment of malignant mesothelioma. As treatment options for malignant mesothelioma are limited and no cure is available, there is no established role for early detection or screening of at risk populations. A multidisciplinary approach to caring for patients with malignant mesothelioma and their carers is vital. PMID- 29129163 TI - Occupational lung diseases in Australia. AB - Occupational exposures are an important determinant of respiratory health. International estimates note that about 15% of adult-onset asthma, 15% of chronic obstructive pulmonary disease and 10-30% of lung cancer may be attributable to hazardous occupational exposures. One-quarter of working asthmatics either have had their asthma caused by work or adversely affected by workplace conditions. Recently, cases of historical occupational lung diseases have been noted to occur with new exposures, such as cases of silicosis in workers fabricating kitchen benchtops from artificial stone products. Identification of an occupational cause of a lung disease can be difficult and requires maintaining a high index of suspicion. When an occupational lung disease is identified, this may facilitate a cure and help to protect coworkers. Currently, very little information is collected regarding actual cases of occupational lung diseases in Australia. Most assumptions about many occupational lung diseases are based on extrapolation from overseas data. This lack of information is a major impediment to development of targeted interventions and timely identification of new hazardous exposures. All employers, governments and health care providers in Australia have a responsibility to ensure that the highest possible standards are in place to protect workers' respiratory health. PMID- 29129165 TI - The future of health care in Australia. PMID- 29129166 TI - Challenging how tobacco is sold in Australia. PMID- 29129167 TI - Legal does not mean unaccountable: suing tobacco companies to recover health care costs. PMID- 29129168 TI - Spontaneous pneumomediastinum. PMID- 29129169 TI - Spirometry: key to the diagnosis of respiratory disorders. PMID- 29129170 TI - Comprehensive guide to the diagnosis and management of occupational lung diseases. PMID- 29129171 TI - Commentaries and clinical tips for assessing respiratory diseases. PMID- 29129172 TI - Lung health in a changing world. PMID- 29129157 TI - Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. AB - BACKGROUND: The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS: We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or >=80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS: A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00). CONCLUSIONS: Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 .). PMID- 29129173 TI - Youth mental health: building beyond the brand. PMID- 29129174 TI - High flow or titrated oxygen for obese medical inpatients: a randomised crossover trial. AB - OBJECTIVE: To compare the effects on transcutaneous carbon dioxide tension (Ptco2) of high concentration and titrated oxygen therapy in medical inpatients with morbid obesity who were not selected for a pre-existing diagnosis of obesity hypoventilation syndrome. DESIGN: A randomised, crossover trial undertaken between February and September 2015. SETTING: Internal medicine service, Wellington Regional Hospital, New Zealand. PARTICIPANTS: 22 adult inpatients, aged 16 years or more, with a body mass index exceeding 40 kg/m2. INTERVENTIONS: Participants received in random order two 60-minute interventions, with a minimum 30-minute washout period between treatments: titrated oxygen therapy (oxygen delivered, if required, via nasal prongs to achieve peripheral oxygen saturation [Spo2] of 88-92%), and high concentration oxygen therapy (delivered via Hudson mask at 8 L/min, without regard to Spo2). Ptco2 and Spo2 were recorded at 10-minute intervals. MAIN OUTCOME MEASURE: Ptco2 at 60 minutes, adjusted for baseline. RESULTS: Baseline Ptco2 was 45 mmHg or lower for 16 participants with full data (73%). The mean difference in Ptco2 between high concentration and titrated oxygen therapy at 60 minutes was 3.2 mmHg (95% CI, 1.3 5.2 mmHg; P = 0.002). CONCLUSION: High concentration oxygen therapy increases Ptco2 in morbidly obese patients. Our findings support guidelines that advocate oxygen therapy, if required in patients with morbid obesity, be titrated to achieve a target Spo2 of 88-92%. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12610000522011. PMID- 29129175 TI - Patients with thunderstorm asthma or severe asthma in Melbourne: a comparison. PMID- 29129176 TI - Composite reliability of workplace-based assessment of international medical graduates. AB - OBJECTIVE: The fitness to practise of international medical graduates (IMGs) is usually evaluated with standardised assessment tests. The performance rather than the competency of practising doctors should, however, be assessed, for which reason workplace-based assessment (WBA) has gained increasing attention. Our aim was to assess the composite reliability of WBA instruments for assessing IMGs. DESIGN AND SETTING: Between June 2010 and April 2015, 142 IMGs were assessed by 99 calibrated assessors; each was assessed in the workplace over 6 months. The IMGs completed 970 case-based discussions (CBDs), 1741 mini-clinical examination exercises (mini-CEX), and 1020 multi-source feedback (MSF) assessments. PARTICIPANTS: 103 male and 39 female candidates from 28 countries (Africa, Asia, Europe, South America, South Pacific) in urban and rural hospitals of the Hunter New England Health region. MAIN OUTCOME MEASURES: The composite reliability across the three WBA tools, expressed as the standard error of measurement (SEM). RESULTS: In our WBA program, a combination of five CBD and 12 mini-CEX assessments achieved an SEM of 0.33, greater than the threshold 0.26 of a scale point. Adding six MSF results to the assessment package reduced the SEM to 0.24, which is adequately precise. CONCLUSIONS: Combining data from different WBA assessment instruments achieves acceptable reliability for assessing IMGs, provided that the panel of WBA assessment types are carefully selected and the assessors are calibrated. PMID- 29129177 TI - COPD-X Australian and New Zealand guidelines for the diagnosis and management of chronic obstructive pulmonary disease: 2017 update. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterised by persistent respiratory symptoms and chronic airflow limitation, and is associated with exacerbations and comorbidities. Advances in the management of COPD are updated quarterly in the national COPD guidelines, the COPD-X plan, published by Lung Foundation Australia in conjunction with the Thoracic Society of Australia and New Zealand and available at http://copdx.org.au. Main recommendations: Spirometry detects persistent airflow limitation (post-bronchodilator FEV1/FVC < 0.7) and must be used to confirm the diagnosis.Non-pharmacological and pharmacological therapies should be considered as they optimise function (ie, improve symptoms and quality of life) and prevent deterioration (ie, prevent exacerbations and reduce decline).Pulmonary rehabilitation and regular exercise are highly beneficial and should be provided to all symptomatic COPD patients.Short- and long-acting inhaled bronchodilators and, in more severe disease, anti-inflammatory agents (inhaled corticosteroids) should be considered in a stepwise approach.Given the wide range of inhaler devices available, inhaler technique and adherence should be checked regularly.Smoking cessation is essential, and influenza and pneumococcal vaccinations reduce the risk of exacerbations.A plan of care should be developed with the multidisciplinary team. COPD action plans reduce hospitalisations and are recommended as part of COPD self-management.Exacerbations should be managed promptly with bronchodilators, corticosteroids and antibiotics as appropriate to prevent hospital admission and delay COPD progression.Comorbidities of COPD require identification and appropriate management.Supportive, palliative and end-of-life care are beneficial for patients with advanced disease.Education of patients, carers and clinicians, and a strong partnership between primary and tertiary care, facilitate evidence based management of COPD. Changes in management as result of the guideline: Spirometry remains the gold standard for diagnosing airflow obstruction and COPD. Non-pharmacological and pharmacological treatment should be used in a stepwise fashion to control symptoms and reduce exacerbation risk. PMID- 29129178 TI - Cortisone injections for tennis elbow should be an "avoid", rather than a recommended procedure. PMID- 29129179 TI - Euthanasia and physician-assisted suicide: focus on the data. PMID- 29129180 TI - Port Augusta GP on "cloud nine". PMID- 29129182 TI - Integrated (one-stop shop) youth health care: best available evidence and future directions. AB - Although mental health problems represent the largest burden of disease in young people, access to mental health care has been poor for this group. Integrated youth health care services have been proposed as an innovative solution. Integrated care joins up physical health, mental health and social care services, ideally in one location, so that a young person receives holistic care in a coordinated way. It can be implemented in a range of ways. A review of the available literature identified a range of studies reporting the results of evaluation research into integrated care services. The best available data indicate that many young people who may not otherwise have sought help are accessing these mental health services, and there are promising outcomes for most in terms of symptomatic and functional recovery. Where evaluated, young people report having benefited from and being highly satisfied with these services. Some young people, such as those with more severe presenting symptoms and those who received fewer treatment sessions, have failed to benefit, indicating a need for further integration with more specialist care. Efforts are underway to articulate the standards and core features to which integrated care services should adhere, as well as to further evaluate outcomes. This will guide the ongoing development of best practice models of service delivery. PMID- 29129183 TI - Targeting mental health care attributes by diagnosis and clinical stage: the views of youth mental health clinicians. AB - OBJECTIVES: To explore the potential utility of clinical stage and mental disorder categories as a basis for determining which attributes of youth mental health care should be offered to which groups of young people. METHODS: In June 2017, we conducted an online survey of youth mental health clinicians that collected information on the participants' background and areas of expertise, then presented vignettes describing young people with different stages of six mental disorders (disorder-based vignettes were matched to participants' area of expertise). For each vignette, participants were asked to give a quantitative estimate of the proportion of young people with similar mental health problems they thought would clinically benefit from each of twelve attributes of mental health care (other than pharmacological or individual psychological therapies). Survey results were analysed as independent, disorder-based samples, using standard statistical tests of significance, and as a stratified sample using mixed-effects models. RESULTS: A total of 412 clinicians working in 32 countries participated in both parts of the survey. Respondents represented a broad range of clinical disciplines, settings and areas of expertise. Their estimated proportions of young people who would benefit from the mental health care attributes varied by clinical stage and disorder (eg, a mean of 93% [interquartile range (IQR), 90%-100%] of young people with Stage 2 psychosis were estimated to benefit from case management with a multidisciplinary team; while only 15% [IQR, 1%-25%] of young people with Stage 1b generalised anxiety disorder were estimated to benefit from collection and processing of biological samples). Neither the background of the respondents nor the sex of the characters in the vignettes significantly influenced the results. CONCLUSION: A combination of clinical stage and disorder information might be an appropriate basis for ensuring that the right attributes of early intervention mental health care are provided to the right young people at the right time. Policy and research priorities include trialling novel services, preferences research among young people, strengthening service responses to subthreshold disorders and promoting high-fidelity collection of clinical stage data in youth mental health settings. PMID- 29129184 TI - Identifying attributes of care that may improve cost-effectiveness in the youth mental health service system. AB - OBJECTIVE: To identify attributes of youth mental health care for which there is evidence of potential cost-effectiveness. STUDY DESIGN: We performed a literature review of economic evaluations that examined both costs and outcomes for attributes of youth mental health care other than pharmacological or individual psychological therapies for full-threshold disorders. DATA SOURCES: We searched the United Kingdom National Health Service Economic Evaluations Database for evaluations published to the end of 2014; and MEDLINE, Google Scholar and the citation lists of relevant publications for peer-reviewed studies published in English since 1997. DATA SYNTHESIS: Forty economic evaluations met inclusion criteria. Psychosis was the mental disorder with the most developed economic evidence base, with good evidence of cost-effectiveness for first-episode psychosis services. There was a developing cost-effectiveness evidence base for other disorders. The most common attributes of the interventions examined in the included studies were the location of services, engagement and support of families, assessment, prevention, early intervention, group delivery format and information provision. We used our findings to formulate a list of attributes of youth mental health care that may be acceptable to young people and potentially cost-effective. CONCLUSION: There is at least suggestive cost-effectiveness evidence for a range of attributes of youth mental health care. Further economic research is needed to substantiate most cost-effectiveness findings and to improve targeting of care among young people. Future economic evaluations should examine costs from both societal and health care perspectives and incorporate evidence regarding young people's preferences. PMID- 29129185 TI - Combined use of high doses of vasopressin and corticosteroids in a patient with Crohn's disease with refractory septic shock after intestinal perforation: a case report. AB - BACKGROUND: In this article, we present a clinical case of refractory septic shock resulting from intestinal perforation treated with high doses of vasopressin and hydrocortisone during emergency surgery. The use of such high doses of vasopressin for this type of shock is not described in the literature. CASE PRESENTATION: A 49-year-old white woman with grade III obesity, Crohn's disease, and an intestinal perforation presented with refractory septic shock. Initially, a low dose of vasopressin was used. Then, the dosage was increased to 0.4 U/minute; in the literature, this is defined as "salvage therapy." This therapy consists of an initial load followed by a continuous infusion of hydrocortisone. CONCLUSIONS: The significant increase in her cardiac index and stroke volume index resulted in an improvement in peripheral resistance, gas exchange, and urine output and a decrease in her heart rate, interleukin-6 level, and tumor necrosis factor-alpha level. The administration of high doses of vasopressin and corticosteroids was demonstrated to be safe for the immune system, to reduce the systemic inflammatory response, and to have direct cardiovascular effects. Further studies are required to examine the use of vasopressin as an initial vasopressor as well as its use in high dosages and in combination with corticosteroids. PMID- 29129186 TI - An exploration of mortality risk factors in non-severe pneumonia in children using clinical data from Kenya. AB - BACKGROUND: Childhood pneumonia is the leading infectious cause of mortality in children younger than 5 years old. Recent updates to World Health Organization pneumonia guidelines recommend outpatient care for a population of children previously classified as high risk. This revision has been challenged by policymakers in Africa, where mortality related to pneumonia is higher than in other regions and often complicated by comorbidities. This study aimed to identify factors that best discriminate inpatient mortality risk in non-severe pneumonia and explore whether these factors offer any added benefit over the current criteria used to identify children with pneumonia requiring inpatient care. METHODS: We undertook a retrospective cohort study of children aged 2-59 months admitted with a clinical diagnosis of pneumonia at 14 public hospitals in Kenya between February 2014 and February 2016. Using machine learning techniques, we analysed whether clinical characteristics and common comorbidities increased the risk of inpatient mortality for non-severe pneumonia. The topmost risk factors were subjected to decision curve analysis to explore if using them as admission criteria had any net benefit above the current criteria. RESULTS: Out of 16,162 children admitted with pneumonia during the study period, 10,687 were eligible for subsequent analysis. Inpatient mortality within this non-severe group was 252/10,687 (2.36%). Models demonstrated moderately good performance; the partial least squares discriminant analysis model had higher sensitivity for predicting mortality in comparison to logistic regression. Elevated respiratory rate (>=70 bpm), age 2-11 months and weight-for-age Z-score (WAZ) < -3SD were highly discriminative of mortality. These factors ranked consistently across the different models. For a risk threshold probability of 7-14%, there is a net benefit to admitting the patient sub-populations with these features as additional criteria alongside those currently used to classify severe pneumonia. Of the population studied, 70.54% met at least one of these criteria. Sensitivity analyses indicated that the overall results were not significantly affected by variations in pneumonia severity classification criteria. CONCLUSIONS: Children with non-severe pneumonia aged 2-11 months or with respiratory rate >= 70 bpm or very low WAZ experience risks of inpatient mortality comparable to severe pneumonia. Inpatient care is warranted in these high-risk groups of children. PMID- 29129188 TI - Join SDMPH to Advance Global Health Security. PMID- 29129187 TI - Developing the Fourth Evaluation Dimension: A Protocol for Evaluation of Video From the Patient's Perspective During Major Incident Exercises. AB - OBJECTIVE: Presently used evaluation techniques rely on 3 traditional dimensions: reports from observers, registration system data, and observational cameras. Some of these techniques are observer-dependent and are not reproducible for a second review. This proof-of-concept study aimed to test the feasibility of extending evaluation to a fourth dimension, the patient's perspective. METHODS: Footage was obtained during a large, full-scale hospital trauma drill. Two mock victims were equipped with point-of-view cameras filming from the patient's head. Based on the Major Incident Hospital's first experience during the drill, a protocol was developed for a prospective, standardized method to evaluate a hospital's major incident response from the patient's perspective. The protocol was then tested in a second drill for its feasibility. RESULTS: New insights were gained after review of the footage. The traditional observer missed some of the evaluation points, which were seen on the point-of-view cameras. The information gained from the patient's perspective proved to be implementable into the designed protocol. CONCLUSION: Use of point-of-view camera recordings from a mock patient's perspective is a valuable addition to traditional evaluation of trauma drills and trauma care. Protocols should be designed to optimize and objectify judgement of such footage. (Disaster Med Public Health Preparedness. 2017;11:594-599). PMID- 29129189 TI - A review of the economic impact of mental illness. AB - Objective To examine the impact and cost associated with mental illness.Methods A rapid review of the literature from Australia, New Zealand, UK and Canada was undertaken. The review included literature pertaining to the cost-of-illness and impact of mental illness as well as any modelling studies. Included studies were categorised according to impact on education, labour force engagement, earlier retirement or welfare dependency. The well-accepted Drummond 10-point economic appraisal checklist was used to assess the quality of the studies.Results A total of 45 methodologically diverse studies were included. The studies highlight the significant burden mental illness places on all facets of society, including individuals, families, workplaces and the wider economy. Mental illness results in a greater chance of leaving school early, a lower probability of gaining full time employment and a reduced quality of life. Research from Canada suggests that the total economic costs associated with mental illness will increase six-fold over the next 30 years with costs likely to exceed A$2.8 trillion (based on 2015 Australian dollars).Conclusions Mental illness is associated with a high economic burden. Further research is required to develop a better understanding of the trajectory and burden of mental illness so that resources can be directed towards cost-effective interventions.What is known about the topic? Although mental illness continues to be one of the leading contributors to the burden of disease, there is limited information on the economic impact that mental illness imposes on individuals, families, workplaces and the wider economy.What does this paper add? This review provides a summary of the economic impact and cost of mental illness. The included literature highlights the significant burden mental illness places on individuals, families, workplaces, society and the economy in general. The review identified several areas for improvement. For example, only limited information is available on the impact of attention deficit hyperactivity disorder, anxiety, cognitive function, conduct disorder, eating disorder and psychological distress. There was also a dearth of evidence on the intangible elements of pain and suffering of people and their families with depressive disorders. More research is required to better understand the full extent of the impact of mental illness and strategies that may be implemented to minimise this harm.What are the implications for practitioners? Knowing the current and future impact of mental illness highlights the imperative to develop an effective policy response. PMID- 29129190 TI - Moderators of sudden gains after sessions addressing emotion regulation among women in treatment for alcohol use. AB - Sudden gains (SGs) are defined as abrupt and significant improvements in mental health symptoms that occur between two psychotherapy sessions. Preliminary evidence suggests that SGs may be an important pattern of symptom reduction in the treatment of alcohol use disorder (AUD) (i.e., a steep between-session reduction in drinking or alcohol craving frequency or intensity) (Drapkin, Epstein, McCrady, & Eddie, 2015). The current study examined SGs within two randomized clinical trials (RCTs) testing female-specific cognitive behavior therapy (CBT) protocol for AUD (n=146). We tested a priori hypotheses about whether women's baseline depression, anxiety, and confidence to be abstinent while in a negative emotional state would predict attainment of SGs after attending sessions that addressed depression, anxiety, and emotion regulation (i.e., sessions five and six of the 12-session protocol). Data were collected at baseline, within treatment, and 15months after baseline. Results showed that women with high levels of depression and/or anxiety and low confidence to be abstinent in a negative emotional state at baseline were more likely to experience a SG (steep decrease in drinking) after sessions five and six (p=0.02). Further, among women with high levels of depression and/or anxiety at baseline, those who experienced both a SG in drinking after session five/six and had higher confidence to remain abstinent in a negative emotional state at the end of treatment reported lower drinking frequency at 9- but not 15-month follow up [95% CI=(-2.65, -0.86)]. Findings support the value of providing interventions targeting mood and emotion regulation in AUD treatment for women. PMID- 29129191 TI - Alcohol use disorders are associated with increased HIV risk behaviors in cocaine dependent methadone patients. AB - People who inject drugs (PWID) are at increased risk of HIV infection. Although methadone maintenance therapy can help lower this risk, many methadone patients continue to engage in HIV risk behaviors, especially patients who use cocaine and alcohol. The purpose of the current study was to investigate relations between alcohol use disorders and HIV risk behavior in 239 cocaine-dependent methadone patients participating in a randomized controlled trial of a behavioral intervention to promote cocaine abstinence. Past 3-month HIV Risk-taking Behavior Scale (HRBS) scores were compared between cocaine-dependent methadone patients who met DSM-IV-TR diagnostic criteria for alcohol abuse or dependence and those who did not meet these criteria. No significant differences in HRBS drug subscale scores were observed between participants with and without alcohol use disorders, indicating risky drug use was similar between groups. However, alcohol use disorder was significantly associated with HRBS sex subscale scores (t=2.59, p=0.01), indicating participants with alcohol use disorders were more likely to engage in risky sexual behavior. Item-level analyses of the sex-related HRBS questions showed participants with alcohol use disorders were significantly more likely than participants without alcohol use disorders to have unprotected sex, engage in transactional (paid) sex, and have anal sex. Interventions are needed to reduce risky sexual behavior and attenuate the spread of HIV in this high-risk population. PMID- 29129192 TI - HealthCall delivered via smartphone to reduce co-occurring drug and alcohol use in HIV-infected adults: A randomized pilot trial. AB - AIMS: Co-occurrence of drug and alcohol use among people living with HIV is linked to poor medication adherence and lack of viral suppression. HealthCall, a technological enhancement of brief Motivational Interviewing (MI), involves brief daily self-monitoring, positive reinforcement, and personalized feedback. This randomized pilot study among people living with HIV investigated the feasibility and efficacy of reducing non-injection drug and alcohol use with MI+HealthCall as adapted for smartphone technology. DESIGN: An urban, largely-minority community sample of adults living with HIV were screened for eligibility: last 30 day use of non-injection drugs (>=4days of crack/cocaine, methamphetamine, or heroin use) and binge drinking (>=1day of 4+ standard drinks). Those eligible were randomized to one of two groups: MI-only (n=21) and MI+HealthCall-S (n=21). Trained counselors delivered the brief MI at baseline. Drug and alcohol use assessments were completed at baseline, 30 and 60days (end of treatment). Primary outcomes derived from a Timeline Follow Back (TLFB) of the past 30 days included (1) total number of days used primary drug (NumDU) (2) total quantity of primary drug used (dollar amount spent per day; QuantU), (3) total number of drinking days (NumDD) and (4) mean number of drinks per day (QuantDD). Feasibility was determined by HealthCall use rates, patient satisfaction questionnaire (1-5 scale, 5 being best), and retention. FINDINGS: The median daily use rate for HealthCall was 95%, patient satisfaction was excellent (4.5) and retention was high (93%). Both treatment groups reduced drug and alcohol use by end of treatment, with MI+Healthcall-S showing significantly greater reductions than MI-only in QuantU (p=0.01) and NumDU (p=0.046). P-values for reductions in alcohol quantity and frequency in the MI+Healthcall group were 0.09-0.11. CONCLUSIONS: This proof-of concept randomized trial indicates that HealthCall on the smartphone is a highly feasible intervention in urban, minority individuals with HIV, and suggests efficacy in reducing co-occurring drug and alcohol use. Results suggest opportunities for brief behavioral intervention that may be enhanced through interactive mobile technology to address complex alcohol and drug use patterns that interfere with HIV care, medication adherence and ultimately, viral suppression. A larger randomized trial is warranted to replicate and extend present results. PMID- 29129193 TI - Experiences of three states implementing the Medicaid health home model to address opioid use disorder-Case studies in Maryland, Rhode Island, and Vermont. AB - PURPOSE: The United States is facing an unprecedented opioid epidemic. The Affordable Care Act (ACA) included several provisions designed to increase care coordination in state Medicaid programs and improve outcomes for those with chronic conditions, including substance use disorders. Three states-Maryland, Rhode Island, and Vermont - adopted the ACA's optional Medicaid health home model for individuals with opioid use disorder. The model coordinates opioid use disorder treatment that features opioid agonist therapy provided at opioid treatment programs (OTPs) and Office-based Opioid Treatment (OBOT) with medical and behavioral health care and other services, including those addressing social determinants of health. This study examines state approaches to opioid health homes (OHH) and uses a retrospective analysis to identify facilitators and barriers to the program's implementation from the perspectives of multiple stakeholders. METHODS: We conducted 28 semi-structured discussions with 70 discussants across the three states, including representatives from state agencies, OHH providers (OTPs and OBOTs), Medicaid health plans, and provider associations. Discussions were recorded, transcribed, and analyzed using NVivo. In addition, we reviewed state health home applications, policies, regulatory guidance, reporting, and other available OHH materials. We adapted the Exploration, Preparation, Implementation, and Sustainment (EPIS) model as a guiding framework to examine the collected data, helping us to identify key factors affecting each stage of the OHH implementation. RESULTS: Overall, discussants reported that the OHH model was implemented successfully and was responsible for substantial improvements in patient care. Contextual factors at both the state level (e.g., legislation, funding, state leadership, program design) and provider level (OHH provider characteristics, leadership, adaptability) affected each stage of implementation of the OHH model. States took a variety of approaches in designing and implementing the model, with facilitators related to gathering stakeholder input, receiving guidance and technical assistance, and tailoring program design to build on the state's existing care coordination initiatives and provider infrastructure. The OHH model constituted a substantial change for almost all OHH providers in the study, who reported that facilitators to implementation included having goals and workplace culture that were compatible with the OHH model, and having technical support from the state or non-governmental organizations. Some of the main barriers to implementation reported by OHH providers include shortages of primary care providers, dentists, and other providers willing to accept referrals of patients with opioid use disorder; limited community resources to address social determinants of health; challenges related to state-specific program design, such as staffing requirements and reimbursement methodology; care coordination limitations due to confidentiality restrictions and technological barriers; and internal capacity of providers to adopt the new model of care. CONCLUSIONS: The OHH model appears to have the potential to effectively address the complex needs of individuals with opioid use disorder by providing whole-person care that integrates medical care, behavioral health, and social services and supports. The experiences of Maryland, Rhode Island, and Vermont can guide development and implementation of similar OHH initiatives in other states. PMID- 29129195 TI - Barriers to integrating the continuum of care for opioid and alcohol use disorders in primary care: A qualitative longitudinal study. AB - Untreated substance use disorders remain a pervasive public health problem in the United States, especially among medically-underserved and low-income populations, with opioid and alcohol use disorders (OAUD) being of particular concern. Primary care is an underutilized resource for delivering treatment for OAUD, but little is known about the organizational capacity of community-based primary care clinics to integrate treatment for OAUD. The objective of this study was to use an organizational capacity framework to examine perceived barriers to implementing the continuum of care for OAUD in a community-based primary care organization over three time points: pre-implementation (preparation), early implementation (practice), and full implementation. Clinic administrators and medical and mental health providers from two clinics participated in interviews and focus groups. Barriers were organized by type and size, and are presented over the three time points. Although some barriers persisted, most barriers decreased over time, and respondents reported feeling more efficacious in their ability to successfully deliver OAUD treatment. Findings contribute to the needed literature on building capacity to implement OAUD treatment in primary care and suggest that while barriers may be sizable and inevitable, successful implementation is still possible. PMID- 29129198 TI - Corticotropin-Releasing Factor Type 1 Receptor Antagonists for Stress-Related Disorders: Time to Call It Quits? PMID- 29129194 TI - The effects of opioid-agonist treatments on HIV risk and social stability: A mixed methods study of women with opioid use disorder in Ukraine. PMID- 29129197 TI - High prevalence of urine tampering in an office-based opioid treatment practice detected by evaluating the norbuprenorphine to buprenorphine ratio. AB - : The prevalence of urine tampering within office-based opioid treatment (OBOT) is not currently known. This study was a cross-sectional analysis of an OBOT practice in New York City that experienced both a change in provider and a change in electronic medical record software. At that time, every patient in the practice received a urine drug test for "quantitative buprenorphine metabolites." METHODS: Outcomes of the first three urine drug tests were tabulated and analyzed with specific attention to the frequency of buprenorphine-positive (bup+), norbuprenorphine-negative (norbup-) samples, a pattern consistent with urine tampering. RESULTS: On the first sample 6/33 (18%) of patients submitted bup+/norbup- samples, and an additional 3 patients submitted bup+/norbup- samples on subsequent urine tests. Retention to the end of the study period among patients with bup+/norbup- samples was 33%, while in those with bup+/norbup+samples it was 96%. A scatter plot of norbuprenorphine vs. buprenorphine levels estimated that a ratio of <0.2 indicated tampering. CONCLUSION: Testing for buprenorphine metabolites yields valuable clinical information. The prevalence of a result pattern consistent with tampering by "urine spiking," the addition of unconsumed buprenorphine into the urine sample, may be higher than previous estimates. Previous lower cutoffs of the norbuprenorphine:buprenorphine metabolic ratio may miss a substantial proportion of these likely tampered samples. PMID- 29129196 TI - Measuring sustainment of an evidence based treatment for adolescent substance use. AB - BACKGROUND: Measuring the extent a behavioral treatment is sustained in usual care practice settings after initial support for implementation ends is challenging. Oftentimes dichotomous self-report measures are used to measure health program sustainment, but these measures may not adequately capture the quality or extent of behavioral treatment delivery. Using data collected from community based organizations that received support to implement the Adolescent Community Reinforcement Approach (A-CRA), a measure of the extent of sustainment was derived. METHODS: Based on implementation theories and implementation support protocols, a total of 10 core treatment elements were identified to measure the extent of sustainment using information collected from key clinical staff. Item response theory (IRT) and principal component analyses (PCA) were used to further refine the 10 elements into composite measures of sustainment. The association between the 10 elements and the relationships between the comprehensive measures to a dichotomous sustainment measure were also examined. RESULTS: Results from PCA identified two components from the initial 10 elements for measuring the extent of A-CRA treatment sustainment. The two components described different aspects of organizational support for A-CRA treatment implementation, one representing the quality or extent of treatment staffing and delivery and the other representing the quality of or extent of clinical supervision. CONCLUSIONS: Using IRT and PCA, we were able to derive components that could be used to measure the extent of EBT sustainment and also better capture the quality of treatment delivery than the use of simple dichotomous measure. The methodological contribution of our study is that we have demonstrated a general analytic approach that may be applicable for other psychosocial treatments. PMID- 29129199 TI - Associations of Trauma and Posttraumatic Stress Disorder With Inflammation and Endothelial Function: On Timing, Specificity, and Mechanisms. PMID- 29129200 TI - Toward Comprehensive Understanding of the Effects of Intranasal Oxytocin on the Human Amygdala. PMID- 29129201 TI - To Bend and Not Break: The Neurobiology of Stress, Resilience, and Recovery. PMID- 29129202 TI - Stress-Induced Hippocampal Volume Loss Is Adult Neurogenesis Independent. PMID- 29129204 TI - Satnav for cells: Destination membrane fusion. PMID- 29129203 TI - NAADP-evoked Ca2+ signals through two-pore channel-1 require arginine residues in the first S4-S5 linker. AB - Two-pore channels (TPCs) are two-domain members of the voltage-gated ion channel superfamily that localize to acidic organelles. Their mechanism of activation (ligands such as NAADP/PI(3,5)P2 versus voltage) and ion selectivity (Ca2+ versus Na+) is debated. Here we report that a cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4 S5 linker). These residues are conserved between TPC isoforms suggesting a generic role in TPC activation. Accordingly, mutation of residues in TPC1 but not the analogous region in the second domain prevents Ca2+ release by NAADP in intact cells. Our data affirm the role of TPCs in NAADP-mediated Ca2+ signalling and unite differing models of channel activation through identification of common domain-specific residues. PMID- 29129205 TI - The steroid hormone 20-hydroxyecdysone upregulates calcium release-activated calcium channel modulator 1 expression to induce apoptosis in the midgut of Helicoverpa armigera. AB - Animal steroid hormones stimulate extracellular Ca2+ influx into cells; however, the mechanism remains unclear. In this study, we determined that the Ca2+ influx induced by steroid hormone 20-hydroxyecdysone (20E) is mediated by the calcium release-activated calcium channel modulator 1 (CRACM1/Orai1). The Orai1 mRNA is highly expressed during midgut programmed cell death in the lepidopteran insect Helicoverpa armigera. 20E upregulated the expression of Orai1 in H. armigera larvae and in an epidermal cell line (HaEpi). Knockdown of Orai1 in HaEpi cells blocked 20E-induced Ca2+ influx, and the inhibitor of inositol 1, 4, 5 trisphosphate receptor (IP3R) Xestospongin (XeC) blocked 20E-induced Ca2+ influx, suggesting that 20E, via Orai1, induces stored-operated Ca2+ influx. Orai1 interacts with stromal interaction molecule 1(Stim1) to exert its function in 20E induced Ca2+ influx. 20E promotes Orai1 aggregation through G-protein-coupled receptors, phospholipase C gamma 1, and Stim1. Knockdown of Orai1 in the HaEpi cell line repressed apoptosis and maintained autophagy under 20E regulation. Knockdown of Orai1 in larvae delayed pupation, repressed midgut apoptosis, maintained the midgut in an autophagic state, and repressed 20E-pathway gene expression. These results revealed that steroid hormone 20E, via Orai1, induces Ca2+ influx to promote the transition of midgut from autophagy to apoptosis. PMID- 29129206 TI - Differential cytotoxicity and intracellular calcium-signalling following activation of the calcium-permeable ion channels TRPV1 and TRPA1. AB - Several members of the transient receptor channel (TRP) family can mediate a calcium-dependent cytotoxicity. In sensory neurons, vanilloids like capsaicin induce neurotoxicity by activating TRPV1. The closely related ion channel TRPA1 is also activated by irritants, but it is unclear if and how TRPA1 mediates cell death. In the present study we explored cytotoxicity and intracellular calcium signalling resulting from activation of TRPV1 and TRPA1, either heterologously expressed in HEK 293 cells or in native mouse dorsal root ganglion (DRG) neurons. While activation of TRPV1 by the vanilloids capsaicin, resiniferatoxin and anandamide results in calcium-dependent cell death, activation by protons and the oxidant chloramine-T failed to reduce cell viability. The TRPA1-agonists acrolein, carvacrol and capsazepine all induced cytotoxicity, but this effect is independent of TRPA1. Activation of both TRPA1 and TRPV1 triggers a strong influx of external calcium, but also a strong calcium-release from intracellular stores most likely including the endoplasmic reticulum (ER). Activation of TRPV1, but not TRPA1 also results in a strong increase of mitochondrial calcium both in HEK 293 cells and mouse DRG neurons. Our data demonstrate that activation of TRPV1, but not TRPA1 mediates a calcium-dependent cell death. While both receptors mediate a release of calcium from intracellular stores, only activation of TRPV1 seems to mediate a robust and probably lethal increase in mitochondrial calcium. PMID- 29129207 TI - Fusion pore in exocytosis: More than an exit gate? A beta-cell perspective. AB - Secretory vesicle exocytosis is a fundamental biological event and the process by which hormones (like insulin) are released into the blood. Considerable progress has been made in understanding this precisely orchestrated sequence of events from secretory vesicle docked at the cell membrane, hemifusion, to the opening of a membrane fusion pore. The exact biophysical and physiological regulation of these events implies a close interaction between membrane proteins and lipids in a confined space and constrained geometry to ensure appropriate delivery of cargo. We consider some of the still open questions such as the nature of the initiation of the fusion pore, the structure and the role of the Soluble N ethylmaleimide-sensitive-factor Attachment protein REceptor (SNARE) transmembrane domains and their influence on the dynamics and regulation of exocytosis. We discuss how the membrane composition and protein-lipid interactions influence the likelihood of the nascent fusion pore forming. We relate these factors to the hypothesis that fusion pore expansion could be affected in type-2 diabetes via changes in disease-related gene transcription and alterations in the circulating lipid profile. Detailed characterisation of the dynamics of the fusion pore in vitro will contribute to understanding the larger issue of insulin secretory defects in diabetes. PMID- 29129209 TI - The Medicare Annual Wellness Visit. AB - The Medicare Annual Wellness Visit is an annual preventive health benefit, which was created in 2011 as part of the Patient Protection and Affordable Care Act. The visit provides an opportunity for clinicians to review preventive health recommendations and screen for geriatric syndromes. In this article, the authors review the requirements of the Annual Wellness Visit, discuss ways to use the Annual Wellness Visit to improve the care of geriatric patients, and provide suggestions for how to incorporate this benefit into a busy clinic. PMID- 29129208 TI - Augmented gene expression triggered by Na+,K+-ATPase inhibition: Role of Ca2+i mediated and -independent excitation-transcription coupling. AB - In rat vascular smooth muscle cells (RVSMC), 3-h Na+,K+-ATPase inhibition by ouabain or in K+-free medium resulted in the inversion of the [Na+]i/[K+]i ratio and elevation up to 7-fold the content of Egr1, Atf3, Nr4a1 and Ptgs2 mRNAs. Ouabain increased the rate of 45Ca2+ influx by 2-fold that was abolished by L type voltage-gated Ca2+ channel blocker nicardipine, but it was resistant to Na+/Ca2+ exchanger inhibitor KB-R7943. To study the role of Ca2+-mediated signaling in the expression of Na+i/K+i-sensitive genes we used intracellular Ca2+ chelator BAPTA and incubated RVSMC in Ca2+-free medium. The elevation of Nr4a1 and Ptgs2 expression triggered by ouabain was diminished in Ca2+-depeleted cells as well as in the presence of nicardipine and calmodulin antagonists A-7 and W-7. Ptgs2 expression was also suppressed by inhibitor of Ca2+/calmodulin dependent protein kinase (CaMKII) KN-93 whereas increment of Nr4a1 content triggered by ouabain was attenuated by inhibitor of Ca2+/calmodulin-dependent protein phosphatase (calcineurin, CaN) cyclosporin A. Neither Ca2+ depletion nor above listed compounds had any impact on the augmented expression of Egr1 and Atf3 in ouabain-treated RVSMC. Our results strongly suggest that dissipation of transmembrane gradient of monovalent cations increases Ptgs2 and Nr4a1 transcription via augment Ca2+ influx through L-type Ca2+ channels that, in turn, leads to CaMKII-mediated phosphorylation of CREB and calcineurin-mediated dephosphorylation of NFAT, respectively. Additional experiments should be performed to identify intermediates of Na+i,K+i-mediated Ca2+-independent excitation-transcription coupling involved the regulation of Egr1 and Atf3 expression. PMID- 29129210 TI - Driving Dilemmas: A Guide to Driving Assessment in Primary Care. AB - Clinical assessment of fitness to drive can be a challenging part of primary care of older adults. There are no guidelines on screening for driver safety, so it falls to provider judgment on when to assess older drivers. This review offers recommendations on when to assess for driver safety based on red flag conditions, medications, acute events, and patient or family concerns. It reviews how to assess for visual, cognitive, and neuromuscular impairments and what to do as next steps for at-risk drivers once they are identified. Laws regarding driver reporting are also reviewed. PMID- 29129211 TI - Individualized Approach to Cancer Screening in Older Adults. AB - The primary goal of cancer screening is early detection of cancer to reduce cancer-specific mortality and morbidity. The benefits of screening in older adults are uncertain due to paucity of evidence. Extrapolating data from younger populations, evidence suggests that the benefit occurs years later from the time of initial screening and therefore may not be applicable in those older adults with limited life expectancy. Contrast this with the harms of screening, which are more immediate and increase with age and comorbidities. An individualized approach to cancer screening takes these factors into consideration, allowing for thoughtful decision making for older adults. PMID- 29129212 TI - Prevention and Screening of Unhealthy Substance Use by Older Adults. AB - The number of older adults who engage in unhealthy substance use is expected to increase substantially to levels never seen before. Older adults, owing to physiologic changes in aging, are at high risk for the adverse effects of alcohol and illegal drug use. Screening and prevention can help older patients to be better informed of the risks of substance use, and reduce high-risk behaviors and its potential negative outcomes. The authors review the prevalence and trends of substance use and their potential impact on health outcomes, and discuss an approach to screening and prevention for older adults. PMID- 29129213 TI - Vaccinations in Older Adults. AB - Vaccines are important for preventing infections in adults aged >=65 years. Older adults are at increased risk for complications from vaccine-preventable illnesses due to age-associated changes in immune function and chronic medical comorbidities. Vaccination rates for older adults remain low despite widely accepted practice guidelines. Recommended vaccinations for older adults include (1) influenza; (2) pneumococcal; (3) herpes zoster; (4) tetanus, diphtheria, pertussis; and (5) hepatitis B. Cost influences vaccination rates in older adults. PMID- 29129214 TI - Exercise and Older Adults. AB - Regular exercise is essential for healthy aging and offers many health benefits, including reduced risk of all-cause mortality, chronic disease, and premature death. Because physical inactivity is prevalent, greater focus is needed on integrating exercise into care plans and counseling, and developing partnerships that support exercise opportunities. Older adults should be as physically active as their abilities and conditions allow. For substantial health benefits, older adults need to do aerobic, muscle-strengthening, and stretching exercises weekly, and balance activities as needed. Appropriate planning must take account of factors such as prescribed medications, nutrition, injuries, hip and knee arthroplasties, and chronic conditions. PMID- 29129216 TI - Screening for Medication Appropriateness in Older Adults. AB - Older adults are at high risk for inappropriate medication use given their myriad medical conditions and medications. Screening efforts may seem overwhelming, but starting with a focused approach and leveraging a team-based strategy can help practicing clinicians gain initial momentum. Future research is needed to strengthen the evidence base for medication use in older adults and to elucidate effective and scalable interventions to improve medication safety. PMID- 29129215 TI - Frailty Screening and Interventions: Considerations for Clinical Practice. AB - Frailty is recognized as a cornerstone of geriatric medicine. It increases the risk of geriatric syndromes and adverse health outcomes in older and vulnerable populations. Although multiple screening instruments have been developed and validated to improve feasibility in clinical practice, frequent lack of agreement between frailty instruments has slowed broad implementation of these tools. Despite this, interventions to improve frailty-related health outcomes developed to date include exercise, nutrition, multicomponent interventions, and individually tailored geriatric care models. Possible strategies to prevent frailty include lifestyle or behavioral interventions, proper nutrition, and increased activity levels and social engagement. PMID- 29129217 TI - Screening for Geriatric Syndromes: Falls, Urinary/Fecal Incontinence, and Osteoporosis. AB - The geriatric syndromes of falls, incontinence, and osteoporosis are concerns in older adults because of their potential impact on quality of life. Asking about history of falls or a fear of falling should prompt a multifactorial assessment of fall risk and targeted interventions to reduce falls. Urinary and fecal incontinence should be screened because they are common conditions that are underreported due to embarrassment and general perception that incontinence is a normal part of aging. Women over age 65, men over age 70, and younger patients with high-risk characteristics should be screened with bone mineral density testing with dual-energy x-ray absorptiometry. PMID- 29129218 TI - Screening Older Adults for Mental Disorders. AB - Avoidable disability associated with depression, anxiety, and impaired cognition among older adults is pervasive. Incentives for detection of mental disorders in late life include increased reimbursement, reduced cost, and less burden for patients and families. However, screening not aligned with diagnosis, intervention, and outcome assessment has questionable utility. The link between screening, treatment, and outcomes is well established for depression, less so for anxiety and impaired cognition. This article details the use of common instruments to screen and assess depression, anxiety, and cognitive impairment. PMID- 29129219 TI - Cardiovascular Screening and Primary Prevention in Older Adults. AB - Evidence for preventive screening and therapeutic intervention for primary prevention of cardiovascular disease is limited for older adults. In this article, we review screening and prevention strategies, including lifestyle, modifiable risk factors, and medications, that may be considered in older adults, with a focus on those >=75 years, accounting for age, frailty and functional status, medical conditions, and life expectancy. PMID- 29129220 TI - Preoperative Screening. AB - Older adults undergoing elective surgical procedures suffer higher rates of morbidity and mortality than younger patients. A geriatric-focused preoperative evaluation can identify risk factors for complications and opportunities for health optimization and care coordination. Key components of a geriatric preoperative evaluation include (1) assessments of function, mobility, cognition, and mental health; (2) reviews of medical conditions and medications; and (3) discussion of risks, preferences, and goals of care. A geriatric-focused, team based approach can improve surgical outcomes and patient experience. PMID- 29129221 TI - Screening and Prevention in the Modern Era. PMID- 29129223 TI - Infectious pancreatic necrosis virus infection of fish cell lines: Preliminary analysis of gene expressions related to extracellular matrix remodeling and immunity. AB - The pathogenic infectious pancreatic necrosis virus (IPNV) causes high economic losses in fish farming. This virus can modulate several cellular processes during infection, but little is known about the infection mechanism. To investigate gene activation in response to IPNV, CHSE/F and SHK-1 cell line were infected with a cytopathic Sp field isolate of IPNV, and the expression profiles of proinflammatory, antiviral cytokine, and extracellular matrix markers were analyzed. IPNV induced the production of perlecan, fibulin-1, matrix metalloproteinase-2, 14-3-3beta, interleukin-1beta, Mx1, and interferon regulatory factors-1, -3, and -9. Interestingly, IPNV-mediated activity was blocked by pharmacological inhibitors of the NF-kappaB signaling pathway. These results, together with in silico analyses showing the presence of several regulatory consensus-target motifs, suggest that IPNV regulates gene expressions in fish through the activation of several key transcription factors. Collectively, these data indicate that IPNV is a viral regulator of expression for extracellular-matrix and immune markers, even during early infection. Finally, this is the first report in fish to find IPNV modulating the activation of interleukin-1beta production primarily through the NF-kappaB pathway. PMID- 29129222 TI - Both cytopathic and non-cytopathic bovine viral diarrhea virus (BVDV) induced autophagy at a similar rate. AB - : Autophagy is a cellular process that maintains cellular homeostasis by the proteolytic recycling of cytoplasm. Autophagy occurs at basal levels in almost all cells. It is upregulated in cellular stress including starvation, oxidative stress or during infection. Several viruses including flavivirus have developed strategies to subvert or use autophagy for their efficient replication. Bovine viral diarrhea virus (BVDV) is a member of the Flaviviridae family and the pestivirus virus group. BVDV is responsible for significant economic loss in cattle industry worldwide. A unique characteristic of BVDV is the well characterized genetic changes that can result in two different phenotypes (biotypes) in cell culture: cytopathic (cp) or non-cytopathic (ncp) effects. The ncp viruses are the most prevalent and important for clinical disease. This study was carried out to determine the effect of different BVDV phenotypes using the virus pair, cp TGAC and ncp TGAN in autophagy induction, as well as to investigate the role of autophagy in BVDV induced cytopathic effect. RESULTS: showed that both biotypes (cp and ncp) of BVDV induced autophagy in immortal Madin-Darby bovine kidney (MDBK) cell line as well as primary bovine turbinate (Bt) cells following infection. There was no significant difference between cp or ncp strains of BVDV in autophagosome formation (p<0.05) in either MDBK or Bt cells. The autophagy inhibiting drug, 3-methyladenine (3MA) significantly reduced autophagy (p<0.05) as well as viral replication. While autophagy inducing drug rapamycin significantly enhanced autophagy as well as viral replication. The co localization study using, BVDV NS5A, Erns and E1 proteins with autophagy marker, light chain-3 (LC3) revealed that BVDV replication was associated with autophagosomes. This study revealed that both cp and ncp strains of BVDV induced autophagy at similar level and used autophagy machinery for their replication. PMID- 29129224 TI - Quantification and phenotypic characterisation of peripheral IFN-gamma producing leucocytes in chickens vaccinated against Newcastle disease. AB - The aim of this study was to optimise and evaluate an intracellular cytokine staining (ICS) assay for assessment of T cell IFN-gamma responses in chickens vaccinated against Newcastle disease (ND). We aimed to validate currently available antibodies to chicken IFN-gamma using transfected CHO cells. Moreover, this ICS assay was evaluated for use to detect mitogen and antigen induced IFN gamma production in chicken peripheral blood leucocytes. Chickens from an inbred white leghorn line containing two MHC haplotypes, B19 and B21, were divided into three experimental groups; one group was kept as naive controls, one group was vaccinated intramuscularly twice with a commercial inactivated ND virus (NDV) vaccine, and the last group was vaccinated orally twice with a commercial live attenuated NDV vaccine. PBMC were ex vivo stimulated with ConA or with NDV antigen. The ICS assay was used to determine the phenotype and frequency of IFN gamma positive cells. ConA stimulation induced extensive IFN-gamma production in both CD3+TCRgammadelta+ (gammadelta T cells) cells and CD3+TCRgammadelta- cells (alphabeta T cells), but no significant differences were observed between the experimental groups. Furthermore, a large proportion of the IFN-gamma producing cells were CD3- indicating that other cells than classic T cells, secreted this cytokine. NDV antigen stimulation induced IFN-gamma production but to a lower extent than ConA and with a large variation between individuals. The CD3+TCR1gammadelta-CD8alpha+ (CTL) population produced the highest NDV specific IFN-gamma responses, with significantly elevated levels of IFN-gamma producing cells in the B19 chickens vaccinated orally with live attenuated NDV vaccine. This was not the case in the B21 animals, indicating a haplotype restricted variation. In contrast, the CD3+TCR1gammadelta-CD4+ (Th) population did not show a significant increase in IFN-gamma production in NDV stimulated samples which was in part due to a high number of IFN-gamma producing cells after incubation with medium alone. In conclusion, an ICS assay for phenotyping of IFN-gamma producing chicken leukocytes was set up that proved useful in identifying cytokine producing cells upon either mitogen or antigen-specific stimulation. PMID- 29129225 TI - Lipopolysaccharide-induced neutrophil extracellular trap formation in canine neutrophils is dependent on histone H3 citrullination by peptidylarginine deiminase. AB - Neutrophils release neutrophil extracellular traps (NETs), which are extracellular chromatin decorated with histones and antimicrobial proteins. Although known for antimicrobial properties, overzealous production of NETs (NETosis) may lead to cytotoxicity and multiple organ failure in sepsis. Pathogen induced NETosis has been extensively studied in mice but its importance in dogs remains largely unknown. This study sought to characterize in vitro NETosis induced by E.coli LPS, including assessing the role of peptidylarginine deiminase (PAD) in canine NETosis. Neutrophils (1*106 cells/ml) from healthy dogs were isolated and treated with 100MUg/ml LPS, 100nM phorbol 12-myristate 13-acetate (PMA), or buffer for either 90 or 180min. NETs were assessed using fluorescence microscopy of living neutrophils and immunofluorescent microscopy. Supernatant and cellular debris were purified and cell-free DNA was quantified by spectrophotometry. The role of PAD was assessed by treating LPS- and PMA activated neutrophils with 50, 100 or 200MUM of the PAD inhibitor, Cl-amidine. In vitro NETosis was characterized by co-localization of cell-free DNA, citrullinated histone H3, and myeloperoxidase. LPS stimulation resulted in intracellular citrullination of histone H3. Compared to PMA chemically-induced NETosis, LPS resulted in smaller NETs with less extracellular citrullinated histone H3. Cl-amidine decreased citrullination of histones and NET production in either LPS- or PMA-stimulated neutrophils demonstrating that neutrophil PAD is essential for these cellular processes. PMID- 29129227 TI - T and B cell activation profiles from cows with and without Johne's disease in response to in vitro stimulation with Mycobacterium avium subspecies paratuberculosis. AB - Johne's disease (JD) is a chronic wasting disease of ruminants caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP). JD is particularly problematic on US dairy farms: estimates show that over 50% of farms are MAP-contaminated and as many as 91% of dairy herds could be infected. Although estimates vary widely, JD may cost the dairy industry between $200 million and $1.5 billion every year. One major obstacle to JD management is that JD is difficult to detect in many animals, in part due to the variable immunity against MAP demonstrated by JD+ cattle. To characterize the diversity of immune responses against MAP, peripheral blood mononuclear cells from 154 JD test negative and 96 JD test positive cows from the same dairy herds were stimulated with MAP in vitro. The activation of CD4+, CD8+ and gammadelta T cells and surface IgM+ B cells was measured using flow cytometry. CD4+CD45R0+ T cells, gammadelta+MHCII+ and gammadelta+MHCII- T cells and SIgM+ B cells from JD test positive cows all exhibited increased proportions expressing CD25 after MAP stimulation, while CD8+ T cells did not demonstrate increased CD25 expression in response to MAP. PMID- 29129226 TI - Measuring bovine gammadelta T cell function at the site of Mycobacterium bovis infection. AB - Bovine gammadelta T cells are amongst the first cells to accumulate at the site of Mycobacterium bovis infection; however, their role in the developing lesion remains unclear. We utilized transcriptomics analysis, in situ hybridization, and a macrophage/gammadelta T cell co-culture system to elucidate the role of gammadelta T cells in local immunity to M. bovis infection. Transcriptomics analysis revealed that gammadelta T cells upregulated expression of several novel, immune-associated genes in response to stimulation with M. bovis antigen. BCG-infected macrophage/gammadelta T cell co-cultures confirmed the results of our RNAseq analysis, and revealed that gammadelta T cells from M. bovis-infected animals had a significant impact on bacterial viability. Analysis of gammadelta T cells within late-stage M. bovis granulomas revealed significant expression of IFN-gamma and CCL2, but not IL-10, IL-22, or IL-17. Our results suggest gammadelta T cells influence local immunity to M. bovis through cytokine secretion and direct effects on bacterial burden. PMID- 29129228 TI - Preoperative low muscle mass has a strong negative effect on pulmonary function in patients undergoing living donor liver transplantation. AB - OBJECTIVE: This study investigated the effect of preoperative sarcopenia on cardiopulmonary function in patients undergoing living donor liver transplantation (LDLT). METHODS: A retrospective analysis was performed of 207 patients who underwent LDLT between January 2008 and April 2015. The quantity and quality of skeletal muscle were evaluated by the psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC), respectively, using preoperative computed tomography imaging. The correlations between preoperative cardiopulmonary function and sarcopenic factors (PMI, IMAC, and grip strength [GS]) were examined. Moreover, overall survival (OS) rates according to preoperative pulmonary function and risk factors were analyzed. RESULTS: No significant differences were found between ejection fraction (EF) and these sarcopenic factors. In contrast, preoperative vital capacity (VC) and forced expiratory volume (FEV) 1.0 were significantly correlated with PMI (P < 0.001, P < 0.001), IMAC (P = 0.024, P = 0.013), and GS (P = 0.006, P = 0.033) in males. Preoperative VC and FEV1.0 were significantly correlated with IMAC (P = 0.002, P = 0.001) and GS (P = 0.002, P = 0.001) in females. Moreover, %VC, VC, and FEV1.0 in the preoperative low muscle mass group were significantly lower than in the normal muscle mass group (P = 0.004, P < 0.001, P < 0.001, respectively) in males. Multivariate analysis revealed that preoperative low PMI and preoperative restrictive ventilatory impairment were independent risk factors (P = 0.046 and P = 0.014, respectively). CONCLUSIONS: Preoperative low muscle mass was closely involved with pulmonary dysfunction in patients undergoing LDLT. PMID- 29129229 TI - Head injury profoundly affects gut microbiota homeostasis: Results of a pilot study. AB - OBJECTIVES: Head injury (HI) induces a hypercatabolic state, dysimmunity, and septic complications that increase morbidity and mortality. Although compromised immune function is usually incriminated in infection occurrence, gut dysbiosis could also be involved in this phenomenon and, to our knowledge, has never been considered. To assess if HI could affect microbiota, we explored the impact of HI on intestinal microbiota in a rodent model of fluid percussion. METHODS: Nineteen rats were randomly assigned to two groups: Healthy rats fed ad libitum (n = 7) and HI rats (n = 12), which received standard enteral nutrition for 4 d. Four days after HI, rats were euthanized and cecal contents were sampled. Cecal microbiota was assessed using real-time quantitative polymerase chain reaction. RESULTS: HI significantly decreased the cecal content of strict anaerobic groups, Bacteroides/Prevotella group (HI 8.9 versus healthy controls 9.3 median log10 colony forming units [CFU]/g, P = 0.007), Clostridium cluster XIVab (HI 7.9 versus healthy controls 8.9 median log10 CFU/g, P = 0.002), Lactobacillus/Leuconostoc group (HI 8.5 versus healthy controls 9.4 median log10 CFU/g, P = 0.044), and Bifidobacterium sp. (HI 3.0 versus healthy controls 8.2 median log10 CFU/g, P < 0.001). In contrast, colonization by Escherichia coli was dramatically increased (HI 10.5 versus healthy controls 7.0 median log10 CFU/g, P < 0.001). CONCLUSIONS: HI profoundly modified the gut microbiota homeostasis and thus could contribute to infection in head trauma patients. These preliminary results open a new field of research in the management of patients with HI. PMID- 29129230 TI - Prevalence of lifestyle practices that might affect bone health in relation to vitamin D status among female Saudi adolescents. AB - BACKGROUND: Prevention of osteoporosis begins in childhood and adolescence, as most bone mass is accumulated during the first 2 decades of life, with 90% to 95% of an adult's bone mineral content being achieved by the end of adolescence. Therefore, targeting modifiable behaviors among adolescents has an important effect on attaining adequate peak bone mass and minimizing risks for future fractures. OBJECTIVES: The aims of this study were to estimate the prevalence of behaviors affecting bone health and vitamin D status and to identify factors associated with vitamin D deficiency among female Saudi adolescents. METHODS: Several modifiable risk factors that influence bone health include low consumption of dairy products, physical inactivity, insufficient sun exposure, smoking, excessive consumption of soft drinks and caffeine, and vitamin D deficiency. A cross-sectional analytical study was conducted in secondary schools in Jeddah City with 421 randomly selected female adolescents. A predesigned questionnaire was used for data collection, and blood samples were collected to measure levels of vitamin D. A chi2 test and correlation coefficient were used to identify the association between vitamin D and the independent variables. Mean (SD) age was 17.2 y (+1.2 y). Mean vitamin D level was 46 nmol/L (+24.6 nmol/L), ranging from 10.8 to 150.8 nmol/L. RESULTS: The adolescents reported low consumption of dairy products, low prevalence of sun exposure, and low physical inactivity. Prevalence of vitamin D deficiency was 67.5%, and insufficiency was 21%. There were no significant associations between vitamin D status and sociodemographic characteristics; coffee and tea intake; anthropometric measurements; and calcium and/or vitamin D supplementation. Intake of dairy products was significantly positively correlated with vitamin D levels. CONCLUSIONS: This study indicated that female Saudi adolescents are at significant risk for developing osteoporosis on the basis of the prevalence of risky behaviors, including low consumption of dairy products, high consumption of soft drinks, deficiency in physical exercise, low sun exposure, and high prevalence of vitamin D deficiency and insufficiency. PMID- 29129231 TI - The association between the Index of Nutritional Quality (INQ) and breast cancer and the evaluation of nutrient intake of breast cancer patients: A case-control study. AB - OBJECTIVE: Breast cancer (BrCa) is the most frequently diagnosed cancer among females and second cancer after lung cancer in many societies. In Iran, the risk for BrCa is 1 in 35 and each year, 8000 new patients have been diagnosed with BrCa. Studies have shown that dietary components are implicated in the etiology of BrCa. The Index of Nutritional Quality (INQ) is a method of quantitative and qualitative analysis of single foods, meals, and diets. The aim of this study was to determine the usefulness of INQs in predicting BrCa risk. METHODS: Our case control study was conducted from March 2015 to February 2016. The study included 145 cases and 148 controls who attended the Shahid Beheshti University of Medical Sciences Cancer Research Center. INQ scores were computed based on dietary intake using a validated 168-item food frequency questionnaire. Logistic regression models were used to estimate multivariable odds ratios adjusted body mass index, education, employment, marital status, menarche age, childbirth number, smoking, menopause status, and physical activity. RESULTS: Vitamins A, C, B1, B2, and B12 and selenium INQs as a continuous variable in relation to risk for BrCa showed a significant association after multivariate adjustment (odds ratio [OR]vitA, 0.41 [0.27-0.64]; ORvitC, 0.30 [0.20-0.47]; ORvitB1, 0.08 [0.04-0.17]; ORvitB2, 0.19 [0.11-0.34]; ORvitB12, 0.44 [0.31-0.61]; and ORselenium, 0.42 [0.26-0.67]). CONCLUSION: Women who consumed a healthier diet including vitamin A, beta carotene, vitamin C, and folate and low-fat milk were at decreased risk for developing BrCa compared with those whose diet included more high fat and lamb meat. PMID- 29129232 TI - Effect of green tea on plasma leptin and ghrelin levels: A systematic review and meta-analysis of randomized controlled clinical trials. AB - OBJECTIVE: The purpose of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of green tea on serum leptin and ghrelin concentrations. METHODS: We searched PubMed, ISI Web of Science, Scopus, and Google scholar databases up to December 2016. The searches included RCTs conducted in human adults, and studies on the effect of green tea and green tea extract on serum leptin and ghrelin concentrations as outcome variables. Weighted mean differences (WMDs) and standard errors (SEs) of changes in serum ghrelin and leptin levels were calculated. The random effects model was used to derive the summary mean estimates with their corresponding SEs. RESULTS: Eleven RCTs were eligible to be included in the systematic review and the meta-analysis. Our analysis indicated that green tea did not significantly affect leptin and ghrelin concentrations in comparison to placebo (WMD = 1.28 ng/mL, 95% confidence interval: -0.49 to 3.05; P = 0.156, and WMD = 21.49 pg/mL, 95% confidence interval: -40.86 to 83.84; P = 0.499, respectively). However, green tea was associated with an increase in leptin concentration in studies that lasted for more than 12 wk and an increase in ghrelin in women and non-Asians. CONCLUSIONS: Green tea or green tea extract might not be able to change circulatory leptin and ghrelin levels, especially with short-term interventions. More RCTs with longer duration of treatment and higher doses are necessary to assess green tea's effect on fat mass and obesity hormones. PMID- 29129233 TI - Low fermentable, oligo-, di-, mono-saccharides and polyol diet in the treatment of irritable bowel syndrome: A systematic review and meta-analysis. AB - OBJECTIVES: The aim of this review was to systematically assess and meta-analyze the effects of a low fermentable, oligo-, di-, mono-saccharides and polyol (FODMAP) diet (LFD) on the severity of symptoms, quality of life, and safety in patients with irritable bowel syndrome (IBS). METHODS: The MEDLINE/PubMed, Scopus, and Cochrane Library databases were screened through January 19, 2016. Randomized controlled trials (RCTs) that compared LFD to other diets were included if they assessed symptoms of IBS or abdominal pain in patients with IBS. Safety, quality of life, anxiety, depression, and effect on gut microbiota were defined as secondary outcomes. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated. RESULTS: Nine RCTs with a total of 596 subjects were included. Three RCTs compared LFD with a habitual diet, two RCTs provided all meals and compared LFD with a western diet, one RCT each compared LFD with a diet high in FODMAPs or a sham diet, and two RCTs compared with other diet recommendations for IBS. A meta-analysis revealed significant group differences for LFD compared with other diets with regard to gastrointestinal symptoms (SMD = -0.62; 95% CI = -0.93 to -0.31; P = 0.0001), abdominal pain (SMD = -0.50; 95% CI = -0.77 to -0.22; P = 0.008), and health-related quality of life (SMD = 0.36; 95% CI = 0.10-0.62; P = 0.007). Three studies reported a significant reduction in luminal bifidobacteria after LFD. Adverse events were assessed in three RCTs only and no intervention-related adverse events were reported. CONCLUSIONS: This meta-analysis found evidence of the short-term efficacy and safety of LFD in patients with IBS. However, only a preliminary recommendation for LFD can be made until long-term effects are investigated. PMID- 29129234 TI - Whole grain consumption is negatively correlated with obesity-associated aortic stiffness: A hypothesis. AB - OBJECTIVE: Obesity is a risk factor for cardiovascular disease that increases aortic stiffness, which predicts future cardiovascular events. Additionally, obesity is associated with overconsumption, which contributes to aortic stiffening. Recent work has highlighted the role of various foods and nutrients on aortic stiffness among the general population. The objective of the present study was to explore the influence of dietary factors on obesity-associated aortic stiffness, as food choices might be a potential explanation for accelerated aortic stiffening in obesity rather than overconsumption alone. METHODS: Data collected in our laboratory were evaluated in aggregate considering obese men with available measures of aortic stiffness and habitual dietary intake (n = 22). Aortic stiffness was assessed with the gold standard carotid-femoral pulse wave velocity, and habitual dietary intake was determined with the National Institutes of Health's Dietary History Questionnaire-II. RESULTS: Whole grain consumption predicted obesity-associated aortic stiffness in regression analyses (R2 = 0.29, P = 0.010). This correlation remained significant after adjusting for traditional risk factors (age, body mass index, blood pressure) (R2 = 0.27, P = 0.027). Overconsumption determined by daily caloric intake was not predictive of aortic stiffness (R2 = 0.09, P = 0.17) nor was total fiber content (R2 = 0.06, P = 0.29). CONCLUSIONS: These findings suggest a potential role of whole grains to protect against aortic stiffness even when dietary overconsumption is present. Fiber content has been proposed as a major beneficial component in whole grains, but it did not correlate with obesity-related aortic stiffness, suggesting whole grains may have a unique and potentially synergistic role in the protection of obesity-associated aortic health. PMID- 29129235 TI - Effects of intraoperative nutrients administration on energy expenditure during general anesthesia. AB - OBJECTIVES: Recent reports have shown that intraoperative infusions of glucose and amino acids exert anticatabolic effects. The appropriate dosages of these amino acids and glucose during general anesthesia remain unknown. METHODS: Patients who underwent esophagectomy for thoracic esophageal cancer were infused with acetated Ringer's solution that contained glucose and amino acids (B1 group [10 patients]: glucose, 3 g/h; amino acids, 1.2 g/h; B2 group [12 patients]: glucose, 4.5 g/h; amino acids, 1.8 g/h) or did not contain glucose and amino acids (C group, 10 patients). The measured energy expenditure was measured by indirect calorimetry. Nitrogen balance was measured during the anesthesia, and the lengths of the hospital stay were recorded. RESULTS: Resting energy expenditure (B1: 1230 +/- 228; B2: 1317 +/- 282; C: 1012 +/- 153 kcal/h; B2 vs C, P < 0.05) and nitrogen balance (B1: -1.78 +/- 0.78 g; B2: -0.85 +/- 0.98 g; C: 2.94 +/- 2.4 g; B2 vs C, P < 0.05) differed significantly between the B2 and C groups. The lengths of the hospital stay differed between the B2 and C groups (B1: 29 +/- 15 d; B2: 18 +/- 6 d; C: 37 +/- 27 d; B2 vs C, P = 0.06). CONCLUSIONS: The administration of amino acids and glucose increased measured energy expenditure, alleviated nitrogen balance, and may decrease the length of the hospital stay. PMID- 29129236 TI - Effects of betaine supplementation on nitric oxide metabolism, atherosclerotic parameters, and fatty liver in guinea pigs fed a high cholesterol plus methionine diet. AB - OBJECTIVE: The aim of this study was to investigate the effect of high cholesterol (CHOL) and CHOL + methionine (MET) diets on atherogenic and oxidative index parameters and on the factors that influence nitric oxide (NO) bioavailability. Also, attempts were made to determine whether dietary betaine (BET) resulted in any improvement in the changes that occurred after CHOL + MET administration. METHODS: Guinea pigs were fed chow containing 1.5% CHOL with or without 2% MET for 10 wk. A third group received the CHOL + MET + BET diet. Control groups were given standard chow or standard chow + BET. Arginine, NO, nitrotyrosine (NT), and asymmetric dimethylarginine (ADMA) levels; lipid profile; and dimethylarginine dimethylaminohydrolase (DDAH) activity were measured. The liver and aorta were subjected to histopathologic analysis. RESULTS: The CHOL + MET diet caused higher serum CHOL and homocysteine levels, but no further increases were seen in aortic CHOL and diene conjugate (DC) levels and histopathologic lesions as compared with the CHOL group. Hepatic lipids and DC levels were also higher, and histopathologic lesions were more severe. CHOL + MET feeding increased ADMA and NT levels as compared with those of the CHOL-fed group. When BET (1 g/kg body weight/d) was added to the CHOL + MET diet, homocysteine and lipid levels decreased and histopathologic changes were reversed. BET diet decreased serum ADMA and hepatic and aortic DC levels and partly restored DDAH activity. CONCLUSIONS: BET supplementation may be effective in preventing hyperlipidemia, disturbed NO availability, oxidative stress, and the development of fatty liver and atherosclerotic lesions that might result from excess amounts of cholesterol and methionine in the diet. PMID- 29129237 TI - Iron-induced pro-oxidant and pro-lipogenic responses in relation to impaired synthesis and accretion of long-chain polyunsaturated fatty acids in rat hepatic and extrahepatic tissues. AB - OBJECTIVES: Iron is involved in processes involving oxygen transfer and utilization. Excess iron is linked to cardiovascular diseases and some types of cancer. Iron overload is associated with oxidative stress development, and may have important interactions with lipid metabolism in the liver favoring the development and progression of non-alcoholic fatty liver disease. The aim of the study described here was to assess the effect of high intake of iron on oxidative stress-related parameters, lipid metabolism, and levels of long-chain polyunsaturated fatty acids (LCPUFAs) in liver and other tissues of the rat. METHODS: Male Wistar rats (21 d old) were fed an iron-rich diet (200 mg iron/kg diet, IRD) versus a control diet (50 mg iron/kg diet; CD) for 21 d. Samples of erythrocytes, liver, adipose tissue, brain, heart, and testicles were evaluated for fatty acid composition and hepatic biochemical and oxidative stress parameters, Delta-6 and Delta-5 desaturase activities, SREBP-1c and PPAR-alpha mRNA expression and DNA-binding capacity, and lipolytic, lipogenic, and antioxidant enzymatic activities. RESULTS: The IRD caused liver steatosis and increased activity of plasma transaminases, with higher oxidative stress status in plasma and liver. Liver Delta-6 and Delta-5 desaturase exhibited decreased activity, but enhanced expression in response to the IRD compared with the CD, with lower levels of omega-3 and omega-6 LCPUFAs and higher expression and DNA binding of SREBP-1c, whereas expression and DNA-binding activity of PPAR-alpha were diminished. CONCLUSIONS: IRD induced oxidative stress and a reduction in the desaturation capacity of the liver, with LCPUFA depletion in the different tissues studied, thus promoting a pro-steatotic condition in the liver. PMID- 29129238 TI - Diet versus jaw bones: Lessons from experimental models and potential clinical implications. AB - The consumption of different types of diets influences not only body health but the bone remodeling process as well. Nutritional components can directly affect maxillary and mandibular alveolar bone microarchitecture. In this review, we focus on the current knowledge regarding the influence of diets and dietary supplementation on alveolar bone. Accumulating evidence from experimental models suggests that carbohydrate- and fat-rich diets are detrimental for alveolar bone, whereas protective effects are associated with consumption of calcium, omega-3, and bioactive compounds. Little is known about the effects of protein-free and protein-rich diets, boron, vitamin C, vitamin E, zinc, and caffeine on alveolar bone remodeling. Adipokines and direct effects of nutritional components on bone cells are proposed mechanisms linking diet and bone. Results from animal models substantiate the role of nutritional components on alveolar bone. It is a well built starting point for clinical studies on nutritional monitoring and intervention for patients with alveolar bone disorders, especially those who are treatment refractory. PMID- 29129239 TI - An iso-alpha-acid-rich extract from hops (Humulus lupulus) attenuates acute alcohol-induced liver steatosis in mice. AB - OBJECTIVE: Results of in vitro and in vivo studies suggest that consumption of beer is less harmful for the liver than consumption of spirits. It also has been suggested that secondary plant compounds derived from hops such as xanthohumol or iso-alpha-acids may have beneficial effects on the development of liver diseases of various etiologies. The aim of this study was to determine whether iso-alpha acids consumed in doses achieved by "normal" beer consumption have beneficial effects on health. METHODS: Female C57 Bl/6 J mice, pretreated for 4 d with an iso-alpha-acid-rich extract (~30% iso-alpha-acids from hops, 0.75 mg/kg body weight), were fed one bolus of ethanol (6 g/kg body weight intragastric) or an iso-caloric maltodextrin solution. Markers of liver damage, toll-like receptor-4 signaling, and lipid peroxidation were determined. Furthermore, the effect of isohumulone on the lipopolysaccharide-dependent activation of J774 A.1 macrophages, used as a model of Kupffer cells, was determined. RESULTS: In the liver, acute ethanol administration led to a significant accumulation of fat (~10 fold), which was accompanied by significantly higher inducible nitric oxide synthase protein level, elevated nitric oxide production, and increased plasminogen activator inhibitor 1 protein concentration when compared to controls. In mice pretreated with iso-alpha-acids, these effects of alcohol were markedly attenuated. Pretreatment of J774 A.1 macrophages with isohumulone significantly attenuated lipopolysaccharide-induced mRNA expression of inducible nitric oxide synthase and interleukin-6 as well as the release of nitric oxide. CONCLUSION: Taken together, iso-alpha-acids markedly attenuated the development of acute alcohol-induced damage in mice. PMID- 29129240 TI - Maternal methyl donor supplementation during gestation counteracts bisphenol A induced oxidative stress in sows and offspring. AB - OBJECTIVE: Maternal oxidative stress is harmful for embryonic, fetal, and placental development. The aim of this study was to investigate whether methyl donor supplementation during gestation effectively ameliorates maternal and placenta oxidative stress up to offspring. METHODS: Fifty-six Landrace * Yorkshire sows were randomly allocated to receive one of the following four diets during gestation: control diet (CON); control diet supplemented with methyl donor (MET); control diet supplemented with bisphenol A (BPA); and control diet supplemented with BPA and MET (BPA + MET). Blood sample, chorioallantois, and piglets' liver samples were analyzed for antioxidant status and mRNA expression of genes regarding oxidative status. RESULTS: MET diets lowered homocysteine concentration in the plasma of sows. They improved activity of antioxidant enzymes in chorioallantois and piglet plasma and liver (catalase, glutathione peroxidase, and total antioxidant capacity; P < 0.01), and also upregulated mRNA expression of copper, zinc-superoxide dismutase (P < 0.01), and glutathione peroxidase 1 (P < 0.05) in the chorioallantois and catalase (P < 0.01) in piglet liver compared with the control group. In contrast, BPA diets increased malondialdehyde (P < 0.01) levels in sows and piglets and decreased total antioxidant capacity (P < 0.01) concentration in sows and umbilical cord blood plasma, as well as downregulated copper, zinc-superoxide dismutase (P = 0.01) in piglet liver compared with MET group. CONCLUSION: BPA diets fed to sows during gestation aggravated oxidative stress status in sows and piglets, whereas the methyl donor diets enhanced antioxidant capacity of sows and piglets and ameliorated oxidative stress induced by BPA. PMID- 29129241 TI - Zinc and selenium status in critically ill patients according to severity stratification. AB - OBJECTIVE: The aim of this study was to evaluate the concentrations of zinc and selenium in different biological materials and to associate them with the clinical severity score according to the Simplified Acute Physiology Score (SAPS) III. METHODS: The study was conducted in a 10-bed general intensive care unit of the Americo Brasiliense State Hospital/SP, with 95 patients stratified by the SAPS III score cutoff points (63.5 points) as less or more severe and by the diagnosis of sepsis. Analyses of zinc and selenium concentrations in plasma, erythrocytes, and urine were conducted. RESULTS: Plasma concentrations were found to be lower than the reference values for both micronutrients (8.4 +/- 4 and 0.18 +/- 0.06 MUmol/L, respectively, for zinc and selenium), and urinary zinc concentration was higher than the reference (38.6 +/- 35.8 MUmol/24 h). The mean selenium plasma concentration was significantly lower in patients with greater severity, which was not observed for zinc (P > 0.05). The mean selenium plasma and erythrocyte concentrations were significantly different between the groups diagnosed with sepsis, which was not observed in the analysis of zinc. Albumin levels (r = -0.26; P = 0.01) and C-reactive protein (r = 0.40; P < 0.001) correlated with the SAPS III severity score. CONCLUSION: Plasma concentrations of zinc and selenium are low in critically ill patients upon admission to the intensive care unit and may make these patients more susceptible to oxidative stress. The low concentration of erythrocyte selenium may represent an inadequate intake by this population. Additional studies using new biomarkers should be performed with the objective of identifying values for the local population. PMID- 29129242 TI - Intestinal failure as a significant risk factor for renal impairment in children. AB - OBJECTIVE: Although impaired renal function has been a frequent finding among adults with intestinal failure (IF), the data on children is scarce. The aim of this study was to assess renal function in pediatric-onset IF. METHODS: Medical records of 70 patients (38 boys) with pediatric-onset IF due to either short bowel syndrome (n = 59) or primary motility disorder (n = 11) and a history of parenteral nutrition (PN) dependency for >=1 mo were evaluated. Renal function at the most recent follow-up was studied using plasma creatinine, cystatin C, and urea concentrations and estimated glomerular filtration rate (eGFR). RESULTS: At a median age of 5.7 y and after PN duration of 3.2 y, 20 patients (29%) had decreased eGFR and higher cystatin C and urea concentrations. Patients with decreased renal function had significantly longer duration of PN (3.2 versus 0.9 y; P = 0.030) and shorter percentage of age-adjusted small bowel length remaining (22 versus 32%; P = 0.041) compared with patients with preserved renal function. No other predisposing factors for decreased eGFR were identified. CONCLUSIONS: Patients with pediatric-onset IF are at significant risk for impaired renal function, which is associated with the duration of PN and the length of the remaining small bowel. In the present study, no other predisposing factors for decreased eGFR were found. Further studies using measured GFR are needed. PMID- 29129243 TI - Enteral feeding with low-methoxyl pectin accelerates colonic anastomosis healing in rats. AB - OBJECTIVE: Enteral feeding with pectin has proven beneficial for anastomosis healing in rats. The aim of this study was to investigate the effects of low methoxyl pectin (LMP) or high-methoxyl pectin (HMP), on colonic anastomosis healing in rats. METHODS: Male Sprague-Dawley rats (age 7 wk) were fed liquid diets containing LMP, HMP, or no pectin (pectin-free [PF]) for 14 d (n = 10/group). The rats underwent colonic anastomosis surgery on day 7 and were sacrificed on day 14. Bursting pressure, breaking strength, and salt-soluble hydroxyproline at the anastomosis site were used as indices of anastomosis healing. Short-chain fatty acids (SCFAs) in the cecal contents were analyzed. RESULTS: Breaking strength was higher in the LMP group than in the other two groups (P < 0.001). The salt-soluble hydroxyproline content was higher in LMP group than in the PF group (P < 0.01). Bursting pressure did not differ among the three groups. The LMP group produced normal, formed stools, whereas watery stools were observed in HMP and PF groups throughout the experimental period. Cecal SCFAs were highest in LMP group. CONCLUSIONS: These results suggest that LMP promotes healing of colonic anastomosis more effectively than HMP, which may be explained by the mechanical stresses generated by the movement of normally formed stool though the colon. PMID- 29129244 TI - The risk for hypoglycemia during Ramadan fasting in patients with adrenal insufficiency. AB - OBJECTIVES: The risk for hypoglycemia during Ramadan fasting in patients with adrenal insufficiency (AI) is not fully known. The aims of this study were to evaluate this risk objectively and to determine the associated factors. METHODS: This prospective case-crossover study included 25 women and 5 men with known and treated AI and a median age of 38.5 y. Patients underwent clinical examination and a fasting blood sample was collected to measure glucose, urea, creatinine, sodium, potassium, cortisol, growth hormone and free thyroxine. A 24-h continuous glucose monitoring system (CGMS) using iPro2 (Medtronic, Parsippany, NJ, USA) with Enlite sensor (Medtronic) was performed for each patient during a Ramadan fasting day then again during a nonfasting day. RESULTS: Interstitial glucose levels during the 24-h period, the fasting period, and the fasting period after exclusion of the 5 postprandial hours were significantly lower during the fasting day than on the nonfasting day. Hypoglycemia occurred in three patients (10%) during the fasting day but not during the nonfasting day (P = 0.23). Hypoglycemia was asymptomatic in two cases. Male sex was significantly associated with the occurrence of hypoglycemia. CONCLUSION: Interstitial glucose levels were lower during fasting in patients with AI. However, the risk for hypoglycemia was not increased. PMID- 29129245 TI - Resurgence of almost eradicated paediatric diseases and the importance of childhood vaccination. PMID- 29129246 TI - Corrigendum to "Comparative analysis of microRNA and mRNA expression profiles in cells and exosomes under toluene exposure" [Toxicology in Vitro 41. (2017) 92 101]. PMID- 29129247 TI - Association between influenza vaccination and reduced risks of major adverse cardiovascular events in elderly patients. AB - BACKGROUND: This study was conducted to determine the protective effect of influenza vaccine against primary major adverse cardiovascular events (MACEs) in elderly patients, especially those with influenza-like illness (ILI). METHODS: This retrospective, population-based case-control study of an elderly population (age>=65 years) was conducted using Taiwan's National Health Insurance Research Database (2000-2013). One control was selected for each MACE case (n=80,363 each), matched according to age, year of study entry, and predisposing factors for MACEs. ILI and MACEs (myocardial infarction [MI] and ischemic stroke) were defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Odds ratios (ORs) were calculated for the association between MACEs and vaccination. RESULTS: Influenza vaccination received in the previous year was associated with reduced risks of primary MACEs overall (adjusted OR [aOR] 0.80, 95% CI 0.78-0.82, P<.001), MI (aOR 0.80, 95% CI 0.76-0.84, P<.001), and ischemic stroke (aOR 0.80, 95% CI 0.77-0.82, P<.001). ILI diagnosed in the previous year was associated with increased risks of MACEs (aOR 1.24, 95% CI 1.18-1.29, P<.001), MI (aOR 1.46, 95% CI 1.34-1.59, P<.001), and ischemic stroke (aOR 1.16, 95% CI 1.10-1.22, P<.001). Vaccination attenuated the heightened risks associated with ILI (MACEs: aOR 0.99, 95% CI 0.92-1.07, P=.834; MI: aOR 1.05, 95% CI 0.92-1.21, P=.440; ischemic stroke: aOR 0.96, 95% CI 0.89 1.05, P=.398). CONCLUSIONS: Results of this study suggest that influenza vaccination is associated with reduced primary MACE risks in the elderly population, including those with ILI. PMID- 29129248 TI - In-hospital cardiac arrest: Complex clinical challenges in need of unique solutions. PMID- 29129249 TI - Association between hospital rates of early Do-Not-Resuscitate orders and favorable neurological survival among survivors of inhospital cardiac arrest. AB - BACKGROUND: Current guidelines recommend deferring prognostication for 48 to 72 hours after resuscitation from inhospital cardiac arrest. It is unknown whether hospitals vary in making patients who survive an arrest Do-Not-Resuscitate (DNR) early after resuscitation and whether a hospital's rate of early DNR is associated with its rate of favorable neurological survival. METHODS: Within Get With the Guidelines-Resuscitation, we identified 24,899 patients from 236 hospitals who achieved return of spontaneous circulation (ROSC) after inhospital cardiac arrest between 2006 and 2012. Hierarchical models were constructed to derive risk-adjusted hospital rates of DNR status adoption <=12 hours after ROSC and risk-standardized rates of favorable neurological survival (without severe disability; Cerebral Performance Category <=2). The association between hospitals' rates of early DNR and favorable neurological survival was evaluated using correlation statistics. RESULTS: Of 236 hospitals, 61.7% were academic, 83% had >=200 beds, and 94% were urban. Overall, 5577 (22.4%) patients were made DNR <=12 hours after ROSC. Risk-adjusted hospital rates of early DNR varied widely (7.1%-40.5%, median: 22.7% [IQR: 19.3%-26.1%]; median OR of 1.48). Significant hospital variation existed in risk-standardized rates of favorable neurological survival (3.5%-44.8%, median: 25.3% [IQR: 20.2%-29.4%]; median OR 1.72). Hospitals' risk-adjusted rates of early DNR were inversely correlated with their risk-standardized rates of favorable neurological survival (r=-0.179, P=.006). CONCLUSIONS: Despite current guideline recommendations, many patients with inhospital cardiac arrest are made DNR within 12 hours after ROSC, and hospitals vary widely in rates of early DNR. Higher hospital rates of early DNR were associated with worse meaningful survival outcomes. PMID- 29129250 TI - Temporal trends and hospital-level variation of inhospital cardiac arrest incidence and outcomes in the Veterans Health Administration. AB - BACKGROUND: Despite significant attention to resuscitation care by hospitals, national data on trends in the incidence and survival of patients with inhospital cardiac arrest (IHCA) are limited. OBJECTIVE: To determine trends and hospital level variation in the incidence and outcomes associated with IHCA. In exploratory analyses, we evaluated the relationship between hospital-level IHCA incidence and outcomes with general hospital-wide quality improvement activities. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 2,205,123 hospitalizations at 101 Veterans Health Administration (VHA) hospitals between 2008 and 2012. MAIN OUTCOMES: Risk- and reliability-adjusted hospital-level IHCA incidence and survival to hospital discharge. RESULTS: A total of 8821 (0.40%) IHCA occurred between 2008 and 2012, with no significant change in risk-adjusted incidence over this time (P = .77). Hospital-level IHCA incidence varied substantially across facilities, with a median hospital incidence of 4.0 per 1000 hospitalizations and a range from 1.4 to 11.8 per 1000 hospitalizations. Overall, survival to discharge after IHCA was 31.2%. Risk-adjusted odds of survival increased over the study period (2012 vs 2008, OR: 1.49, 95% CI: 1.27, 1.75) but survival varied substantially across facilities from 20.3% to 45.4%. General hospital quality improvement activities were inconsistently associated with IHCA incidence and survival. CONCLUSIONS: Within the VHA, the incidence and outcomes of IHCA showed important trends over time but varied substantially across hospitals with no consistent link to general hospital quality improvement activities. Identification of specific resuscitation practices at hospitals with low incidence and high survival of IHCA may guide further improvements for inhospital resuscitation. PMID- 29129251 TI - The relationship of renal function to outcome: A post hoc analysis from the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study. AB - : The ENSURE-AF study (NCT 02072434) of anticoagulation for electrical cardioversion in nonvalvular atrial fibrillation (NVAF) showed comparable low rates of bleeding and thromboembolism between the edoxaban and the enoxaparin warfarin treatment arms. This post hoc analysis investigated the relationship between renal function and clinical outcomes. METHODS: ENSURE-AF was a multicenter, PROBE evaluation trial of edoxaban 60 mg, or dose reduced to 30 mg/d for weight<=60 kg, creatinine clearance (CrCl; Cockcroft-Gault) <=50 mL/min, or concomitant P-glycoprotein inhibitors compared with therapeutically monitored enoxaparin-warfarin in 2,199 NVAF patients undergoing electrical cardioversion. Efficacy and safety outcomes and time in therapeutic range in the warfarin arm were analyzed in relation to CrCl in prespecified ranges >=15 and <=30, >30 and <=50, >50 and <80, and >=80 mL/min, and an exploratory >=95-mL/min analysis. RESULTS: A total of 1,095 subjects were randomized to edoxaban and 1,104 to enoxaparin-warfarin. Mean age was 64.3+/-10 and 64.2+/-11 years. Mean time in therapeutic range was progressively lower with reducing CrCl strata, being 66.8% in those with CrCl >30 to <=50 compared with 71.8% in those with CrCl >=80. The odds ratios for the primary efficacy and safety end points were comparable for the different predefined renal function strata; given the small numbers, the 95% CI included 1.0. In the subset of those with CrCl >=95, the odds ratios showed consistency with the other CrCl strata. When CrCl was assessed as a continuous variable, there was a nonsignificant trend toward higher major or clinically relevant nonmajor bleeding with reducing CrCl levels, with no significant differences between the 2 treatment arms. When we assessed CrCl at baseline compared with end of treatment, there were no significant differences in CrCl change between the edoxaban and enoxaparin-warfarin arms. The proportions with worsening of renal function (defined as a decrease of >20% from baseline) were similar in the 2 treatment arms. CONCLUSION: Given the small number of events in ENSURE-AF, no effect of renal (dys)function was demonstrated in comparing edoxaban to enoxaparin-warfarin for cardioversion; efficacy and safety of edoxaban remained consistent even in patients with normal or supranormal renal function. PMID- 29129252 TI - Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). AB - BACKGROUND: Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. STUDY DESIGN: This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. CONCLUSION: The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function. PMID- 29129253 TI - Rationale of a novel study design for the BIOFLOW V study, a prospective, randomized multicenter study to assess the safety and efficacy of the Orsiro sirolimus-eluting coronary stent system using a Bayesian approach. AB - BACKGROUND: Traditional study design submitted to the Food and Drug Administration to test newer drug-eluting stents (DES) for marketing approval is the prospective randomized controlled trial. However, several DES have extensive clinical data from trials conducted outside the United States that have led to utilization of a novel design using the Bayesian approach. This design was proposed for testing DES with bioresorbable polymer compared with DES most commonly in use today that use durable polymers for drug elution. STUDY DESIGN AND OBJECTIVES: This prospective, multicenter, randomized, controlled trial is designed to assess the safety and efficacy of the Orsiro bioresorbable polymer sirolimus-eluting stent (BP SES). Up to 1,334 subjects with up to 3 de novo or restenotic coronary artery lesions who qualify for percutaneous coronary intervention with stenting will be randomized 2:1 to the BP SES versus the Xience durable polymer everolimus-eluting stent (DP EES). Data from this trial will be combined with data from 2 similarly designed trials that also randomize subjects to BP SES and DP EES (BIOFLOW II, N=452 and BIOFLOW IV, N=579) by using a Bayesian approach. The primary end point is target lesion failure at 12 months post index procedure, defined as cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization, and the primary analysis is a test of noninferiority of the BP SES versus DP EES on the primary end point according to a noninferiority delta of 3.85%. Secondary end points include stent thrombosis and the individual components of target lesion failure. Subjects will be followed for 5 years after randomization. CONCLUSIONS: The BIOFLOW V trial offers an opportunity to assess clinical outcomes in patients treated with coronary revascularization using the Orsiro BP SES relative to a commonly used DP EES. The use of a Bayesian analysis combines a large randomized cohort of patients 2 two smaller contributing randomized trials to augment the efficiency of the comparison. PMID- 29129254 TI - Does renal function affect the efficacy or safety of a pharmacoinvasive strategy in patients with ST-elevation myocardial infarction? A meta-analysis. AB - BACKGROUND: The efficacy and safety of pharmacoinvasive strategy following fibrinolysis for ST-elevation myocardial infarction (STEMI) in relation to renal function have not been established. METHODS: Using patient-level data from 4 randomized controlled trials, we examined the efficacy and safety of pharmacoinvasive versus standard treatment after fibrinolysis for STEMI. Patients were stratified based on the estimated glomerular filtration rate (eGFR) on presentation (<60 mL/min/1.73 m2 vs >=60 mL/min/1.73 m2). The primary outcome was the composite of death or reinfarction at 30 days. RESULTS: Of 2,029 patients, 457 (23%) had an eGFR<60 mL/min/1.73 m2. Patients with eGFR<60 mL/min/1.73 m2 were older and had higher Thrombolysis in Myocardial Infarction risk scores. Compared with patients with eGFR>=60 mL/min/1.73 m2, patients with renal dysfunction had higher rates of the primary outcome (5.3% vs 11.8%, respectively; P<.001). There was no significant heterogeneity in the treatment effect of pharmacoinvasive strategy on the primary outcome (P heterogeneity=.73) or the rate of death or reinfarction at 1 year (P heterogeneity=.64) in relation to eGFR. Patients with renal dysfunction had higher rates of in-hospital major bleeding compared with patients with eGFR >=60 mL/min/1.73 m2 (7.7% vs 4.3%, respectively; P=.004); however, there was no difference in bleeding events between treatment arms in the overall cohort or in relation to eGFR (P heterogeneity=.67). CONCLUSIONS: Renal impairment is associated with increased rates of adverse events in STEMI patients treated with fibrinolysis. However, the safety and efficacy of pharmacoinvasive strategy are preserved in patients with renal impairment on presentation. PMID- 29129256 TI - Instantaneous wave-free ratio and fractional flow reserve for the assessment of nonculprit lesions during the index procedure in patients with ST-segment elevation myocardial infarction: The WAVE study. AB - BACKGROUND: Functional assessment of non-infarct-related artery lesions during primary percutaneous coronary intervention (PCI) might be useful to avoid revascularization of nonsignificant stenosis and staged procedures, thus reducing hospital stay. We aimed to assess the diagnostic performance of instantaneous wave-free ratio (iFR) as compared with fractional flow reserve (FFR) in this setting. METHODS: In the WAVE study, a prospective, observational, single-center registry (NCT02869906), paired iFR and FFR measurements were performed at the level of non-IRA lesions in patients with ST-segment elevation myocardial infarction both during primary PCI and during staged procedures (5-8 days after). RESULTS: Paired iFR and FFR measurements were available for 66 non-IRA lesions in 50 patients. The iFR and FFR values of non-IRA lesions did not change significantly between the index and staged procedure. Bland-Altman analysis did not show systematic bias for either iFR or FFR repeated measures. Receiver operating characteristic curve analysis showed high accuracy of iFR to identify positive (<=0.80) FFR measurements in the index procedure with an area under the curve of 0.95. A cutoff of <=0.89 for iFR in the index procedure had the best combination of sensitivity (95%) and specificity (90%) with positive and negative predictive values of 86% and 97%, respectively. Finally, iFR measured during the index procedure was significantly correlated with FFR (r=0.71, r2=0.51; P<.0001). CONCLUSIONS: The WAVE study shows that iFR yields similar diagnostic accuracy to FFR in functional evaluation of non-IRA stenosis in patients with STEMI and multivessel CAD, with the advantage of being adenosine free. PMID- 29129257 TI - Temporal changes in infective endocarditis guidelines during the last 12 years: High-level evidence needed. AB - BACKGROUND: Infective endocarditis (IE) is a complex disease necessitating extensive clinical guidelines. The guidelines from the American Heart Association (AHA) and the European Society of Cardiology (ESC) have been markedly extended during the last 12 years. We examined the evidence base for these changes. METHODS: IE guidelines published by AHA and ESC were reviewed. We categorized and combined guidelines into 3 time periods: (1) 2004 (AHA) and 2005 (ESC), (2) 2007 (AHA) and 2009 (ESC), and (3) 2015 (AHA) and 2015 (ESC). Number of recommendations, classes of recommendations (I, II, or III), and levels of evidence (LOE) (A, B, or C) were assessed and the changes over time. RESULTS: From period 1 to period 3, we found a statistically significant increase in total number of IE recommendations from 37 to 253 (P<.01), a 6.8-fold increase. There were a significant decrease in LOE A (from 7 [20.0%] in period 1 to 4 [1.6%] in period 3, P<.0001, a 57% decrease), a nonsignificant decrease in LOE B recommendations (from 17 [48.6%] in period 1 to 115 [45.9%] in period 3, P=.29, a 6.8-fold increase), and a significant increase in LOE C recommendations (from 11 [31.4%] in period 1 to 134 [53.0%] in period 3, P=.02, a 12.2-fold increase). CONCLUSIONS: The number of IE guideline recommendations has increased 6- to 7 fold during the last decade without a corresponding increase in evidence. These results highlight the strong need for more clinical studies to improve the level of evidence in IE guidelines. PMID- 29129255 TI - Regional variation in quality of life in patients with a Fontan circulation: A multinational perspective. AB - BACKGROUND: Impaired quality of life (QOL) is associated with congenital heart disease (CHD) and country of residence; however, few studies have compared QOL in patients with differing complexities of CHD across regional populations. The current study examined regional variation in QOL outcomes in a large multinational sample of patients with a Fontan relative to patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs). METHODS: From the Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease-International Study (APPROACH-IS), 405 patients (163 Fontan and 242 ASD/VSD) across Asia, Europe, and North America provided consent for access to their medical records and completed a survey evaluating QOL (0 to 100 linear analog scale). Primary CHD diagnosis, disease complexity, surgical history, and documented history of mood and anxiety disorders were recorded. Differences in QOL, medical complications, and mood and anxiety disorders between Fontan and ASD/VSD patients, and across geographic regions, were examined using analysis of covariance. Hierarchical regression analyses were conducted to identify variables associated with the QOL ratings. RESULTS: Patients with a Fontan reported significantly lower QOL, and greater medical complications and mood and anxiety disorders relative to patients with ASD/VSD. Inpatient cardiac admissions, mood disorders, and anxiety disorders were associated with lower QOL among patients with a Fontan, and mood disorders were associated with lower QOL among patients with ASD/VSD. Regional differences for QOL were not observed in patients with a Fontan; however, significant differences were identified in patients with ASD/VSD. CONCLUSIONS: Regional variation of QOL is commonplace in adults with CHD; however, it appears affected by greater disease burden. Among patients with a Fontan, regional variation of QOL is lost. Specific attempts to screen for QOL and mood and anxiety disorders among CHD patients may improve the care of patients with the greatest disease burden. PMID- 29129258 TI - Long-term outcomes of bypass grafting versus drug-eluting stenting for left main coronary artery disease: Results from the IRIS-MAIN registry. AB - : There are limited data on comparative outcomes and its determinants following coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for left main coronary artery disease (LMCAD) in a real-world setting. METHODS: A total of 3,504 consecutive patients with LMCAD treated with CABG (n=1,301) or PCI with DES (n=2,203) from the IRIS-MAIN registry were analyzed. The relative treatment effect of one strategy over another was assessed by propensity-score matching method. The primary outcome was a composite of death, myocardial infarction, or stroke. RESULTS: Median follow-up duration was 4.7 years. In the matched cohort, both groups demonstrated a similar risk for the primary outcome (adjusted hazard ratio [HR]: 0.94; 95% CI: 0.77-1.15; P=.54). Compared with CABG, PCI exhibited higher risks of myocardial infarction (HR: 2.11; 95% CI: 1.16-3.83; P=.01) and repeated revascularization (HR: 5.95; 95% CI: 3.94-8.98; P<.001). In the overall population, age, presence of chronic kidney disease, and low ejection fraction (<40%) were key clinical predictors of primary outcome regardless of the treatment strategy. However, factors deemed to be associated with perioperative morbidity were determinants of primary outcome in the CABG group, whereas those generally associated with the severity of atherosclerotic coronary artery disease were strong predictors in the PCI group. CONCLUSIONS: Among patients with significant LMCAD, the long-term risk of the composite outcome of death, myocardial infarction, or stroke was similar between CABG and PCI. Clinical variables that differentially predict adverse outcomes might be useful in triaging appropriate revascularization strategy. PMID- 29129259 TI - Comparison of prevalence and management of left atrial appendage thrombi under old and new anticoagulants prior to left atrial catheter ablation. AB - BACKGROUND: The prevalence and management of left atrial appendage (LAA) thrombi associated with new anticoagulants remain to be elucidated, especially prior to atrial fibrillation (AFib) ablation. This study sought to (1) compare the prevalence of LAA thrombi and/or severe LAA contrast under vitamin K antagonist (VKA) agents and novel oral anticoagulants (NOACs), (2) evaluate the rate of LAA thrombus resolution after anticoagulation modification, and (3) determine the predictive factors of LAA thrombi and severe LAA contrast in patients prior to LA AFib ablation. METHODS: Between January 2013 and March 2016, 576 consecutive patients referred for AFib ablation were included, and the prevalence of transesophageal echocardiography-detected thrombi was similar under NOACs (2.1%) and VKA agents (2.6%). RESULTS: Thrombus resolution was obtained in 50% of cases following anticoagulation modification. Through multivariate exact logistic regression analysis with relevant clinical and echocardiographic features, age (P<.001), LAA hypocontractility (P<.001), and left ventricular ejection fraction (P=.007) were found to be independently associated with the occurrence of LAA thrombus. The relevant factors independently associated with LAA thrombus or severe contrast were LAA hypocontractility (P<.001) and age (P<.001). CONCLUSIONS: The prevalence of transesophageal echocardiography-detected thrombi in patients referred for AFib ablation is similar under NOACs (2.1%) and VKA agents (2.6%). Under VKA therapy with 3-4 international normalized ratio, 50% of thrombi dissolved. Independent predictive factors of procedure contraindication included age, LAA hypocontractility, and left ventricular ejection fraction. PMID- 29129261 TI - Idarucizumab since FDA approval: Use in the real-world. PMID- 29129260 TI - Lipid management in contemporary community practice: Results from the Provider Assessment of Lipid Management (PALM) Registry. AB - BACKGROUND: The latest cholesterol guidelines have shifted focus from achieving low-density lipoprotein cholesterol (LDL-C) targets toward statin use and intensity guided by atherosclerotic cardiovascular disease (ASCVD) risk. METHODS: Statin use and intensity were evaluated in 5,905 statin-eligible primary or secondary prevention patients from 138 PALM Registry practices. RESULTS: Overall, 74.7% of eligible adults were on statins; only 42.4% were on guideline recommended intensity. Relative to primary prevention patients, ASCVD patients were more likely to be on a statin (83.6% vs 63.4%, P<.0001) and guideline recommended intensity (47.3% vs 36.0%, P<.0001). Men were more likely than women to be prescribed recommended intensity for primary (odds ratio [OR] 1.87, 95% CI 1.49-2.34) and secondary (OR 1.47, 95% CI 1.26-1.70) prevention. In primary prevention, increasing age, diabetes, obesity, hypertension, and lower 10-year ASCVD risk were associated with increased odds of receiving recommended intensity. Among ASCVD patients, those with coronary artery disease were more likely to be on recommended intensity than cerebrovascular or peripheral vascular disease patients (OR 1.71, 95% CI 1.41-2.09), as were those seen by cardiologists (OR 1.43, 95% CI 1.12-1.83). Median LDL-C levels were highest among patients not on statins (124.0 mg/dL) and slightly higher among those on lower-than recommended intensity compared with recommended-therapy recipients (88.0 and 84.0 mg/dL, respectively; P<=.0001). CONCLUSIONS: In routine contemporary practice, 1 in 4 guideline-eligible patients was not on a statin; less than half were on the recommended statin intensity. Untreated and undertreated patients had significantly higher LDL-C levels than those receiving guideline-directed statin treatment. PMID- 29129262 TI - Biochemical risk markers and 10-year incidence of atherosclerotic cardiovascular disease: independent predictors, improvement in pooled cohort equation, and risk reclassification. AB - BACKGROUND: The recommendation for statins in primary atherosclerotic cardiovascular disease (ASCVD) prevention begins with risk estimation using the pooled cohort equation (PCE). However, treatment decisions may still remain uncertain after PCE-based assessment. We therefore developed a simple biomarker score that could supplement decision making. METHODS: Using the prospectively collected database of the Multi-Ethnic Study of Atherosclerosis, we identified biochemical risk markers that independently predicted 10-year risk of ASCVD and developed an aggregate biomarker score based on them. Thereafter, we assessed for incremental benefit of these markers over the PCE using C-statistic, net reclassification index (NRI), and integrated discrimination index (IDI). RESULTS: A total of 5,303 adults free of ASCVD at baseline were included in this study. Five biochemical risk markers-high-sensitivity C-reactive protein, homocysteine, albuminuria, N-terminal prohormone of brain natriuretic peptide, and troponin T that predicted 10-year risk of ASCVD were combined into an aggregate biomarker score (CHAN2T3), which demonstrated a graded increase in the rate of incident ASCVD from 2.1% among participants with score of 0 to 25% among participants with score of 5. In addition, a biomarker score of >=2 was associated with improvement in the C-statistic of the PCE (0.748 vs 0.734, P=.02), integrated discrimination index (P<.001), category-free NRI of 45% (95% CI, 31%-57%), and net categorical NRI of 5.4% in the full cohort. Lastly, a biomarker score of >=4 resulted in 6% net reclassification across ASCVD risk cut point of 7.5% among nondiabetic individuals with LDL-C<190mg/dL. CONCLUSIONS: A novel CHAN2T3 biomarker score could supplement risk-based discussion for ASCVD prevention, especially when treatment decision is uncertain. Further validation in other cohorts is however warranted. PMID- 29129263 TI - Variation in post-discharge opioid prescriptions among members of a surgical team. AB - BACKGROUND: Surgeons play a pivotal role in the opioid epidemic but it is unknown how different members of a surgical team vary in the way they prescribe opioids after surgical episodes. STUDY DESIGN: We conducted a retrospective cohort study of all inpatient discharges for 5 common surgeries. Total number of tablets and total milligram equivalents (MME) prescribed were calculated and differences in prescription patterns were determined for attending surgeons, surgical residents and advanced practice providers. Using a generalized ordered logistic regression, we examined factors associated with ordering a higher number of tablets or MME. RESULTS: The median number of tablets (range) prescribed by rank were attending surgeon 30 (6-72), surgical resident 20 (6-189) and advanced care practitioner 40 (5-1000); p < 0.001.The median total MME prescribed by rank were attending surgeon 140 (30-600), surgical resident 200 (30-1600) and advanced practice provider 240 (25-1000); p < 0.001. There was no statistically significant difference by resident postgraduate year (PGY) for both total tablets and total MME prescribed. General surgery residents on average ordered a narrower range of total MME compared to surgical residents in other surgical specialties [20 (50 600) vs 20 (30-1600); p = 0.03]. On regression analysis, residents were less likely to order a higher number of tablets compared to attending surgeons (OR 0.29, p = 0.01). However, surgical residents and advanced care providers were more likely to prescribe a higher total MME compared to attending surgeons (OR 7.12, p < 0.001; OR 3.39, p = 0.01 for surgical resident and OR 6.46, p = 0.01) for advanced practice providers). CONCLUSION: There is wide variation in opioid prescription patterns by surgical providers. More studies are needed to clearly define the ideal number of tablets or MMEs to prescribe for common surgical procedures. PMID- 29129265 TI - Does intra-tumoural fat on MRI predict visibility of small (<=3 cm) hepatocellular carcinomas during ultrasound-guided tumour ablation? AB - AIM: To assess if intra-tumoural fat on magnetic resonance imaging (MRI) affects the ultrasonographic (US) visibility of small (<=3 cm) hepatocellular carcinomas (HCC) during radiofrequency ablation (RFA). MATERIALS AND METHODS: Institutional review board approval was obtained. A retrospective review of all patients who underwent image-guided ablation between 1 January 2010 and 31 April 2015 was performed. Patients with HCC who underwent US RFA were included. Inclusion criteria included small tumours (<=3 cm), treatment-naive cases or new focus of HCC in a different and untreated segment, and pre-procedural MRI. The presence of intra-tumoural fat was determined retrospectively via in-and-out-of-phase MRI. Other factors that potentially affect ultrasonographic visibility, such as background fatty liver, presence of cirrhosis, tumour size, and distance from diaphragm, were recorded. RESULTS: Ninety procedures performed on 74 patients (62 men and 12 women; mean age: 67.3 years; range: 39-88 years). Seventy-two tumours were visible on US (hypoechoic n=35, hyperechoic n=28, heterogeneous n=9). Intra tumoural fat was seen in 23 tumours (25.6%, hyperechoic n=17, hypoechoic n=6). The presence of intra-tumoural fat (p=0.005) and distance from diaphragm (p=0.007) were found to be statistically significant factors affecting tumour visibility on planning US. The presence of background fatty liver (p=0.485), cirrhosis (p=0.48), and tumour size (p=0.15) were not found to be significant. CONCLUSION: The present study shows that the presence of intra-tumoural fat in small HCCs on pre-procedural MRI can accurately predict their visibility on planning US during percutaneous tumour ablation. PMID- 29129264 TI - Lethal infection by Streptococcus group A in thyroid surgery: the importance of an early diagnosis. PMID- 29129266 TI - Single-Cell Defects Cause a Long-Range Mechanical Response in a Confluent Epithelial Cell Layer. AB - Epithelial cells are responsible for tissue homeostasis and form a barrier to maintain chemical gradients and mechanical integrity. Therefore, rapid wound closure is crucial for proper tissue function and restoring homeostasis. In this study, the mechanical properties of cells surrounding a single-cell wound are investigated during closure of the defect. The single-cell wound is induced in an intact layer using micropipette action and responses in neighboring cells are monitored with atomic force microscopy. Direct neighbors reveal a rise in the apparent pretension, which is dominated by cortical tension. The same effect was observed for a single-cell wound induced by laser ablation and during closure of a not fully confluent layer. Moreover, changes in the apparent pretension are far reaching and persist even in cells separated by three cell widths from the defect. This shows that epithelial cells respond to minimal wounds in a collective fashion by increased contractility with substantial reach. PMID- 29129268 TI - Fake news, facts and Nibiru. PMID- 29129267 TI - Does Donor Age and Double Versus Single Lung Transplant Affect Survival of Young Recipients? AB - BACKGROUND: In an effort to expand the donor pool for lung transplants, numerous studies have examined the use of advanced age donors with mixed results, including decreased survival among younger recipients. We evaluated the impact of the use of advanced age donors and single versus double lung transplantation on posttransplant survival. METHODS: The United Network for Organ Sharing database was retrospectively queried between January 2005 and June 2014 to identify lung transplant patients aged at least 18 years. Patients were stratified by recipient age 50 years or less, donor age 60 years or more, and single versus double lung transplantation. Overall survival was assessed using the Kaplan-Meier method. Multivariable survival analysis was performed using a Cox proportional hazards model. RESULTS: In all, 14,222 lung transplants were performed during the study period. With univariate analysis, donor lungs aged 60 years or more were associated with slightly worse 5-year survival (44% versus 52%; p < 0.001). Among recipients aged more than 50 years, this trend was not present in the multivariate model (hazard ratio 1.23, p = 0.055). Among recipients aged 50 years or more, receiving older donor lungs showed worse survival with the use of single lung transplant (5-year survival 15% versus 50%, p = 0.01). No significant difference in survival between young and old donors was seen when double lung transplant was performed (p = 0.491). Cox proportional hazards model showed a trend toward interaction between single lung transplantation and older donors (hazard ratio 2.36, p = 0.057). CONCLUSIONS: Reasonable posttransplant outcomes can be achieved with use of advanced age donors in all recipient groups. Double lung transplantation should be performed when older donors (age more than 60) are used in young recipients (age 50 or less). PMID- 29129269 TI - Partial (two-thirds) nephrectomy in pigs: A comparison of three surgical approaches. AB - Partial (2/3) nephrectomy can be performed via the laparoscopic, retroperitoneal, and transperitoneal approach. Outcomes of the three approaches were compared in this study. 2/3 nephrectomy were performed in 21 healthy Bama miniature pigs (mean bodyweight 20.59+/-2.78kg). Pigs were divided into three groups: those that underwent 2/3 nephrectomy via laparoscopy (LN group, n=7), the retroperitoneal approach (RN group, n=7), or the transperitoneal approach (TN group, n=7). We monitored pre- and postoperative physiologic parameters, blood cell count, and stress and renal function biomarkers. Differences among groups were analyzed. 2/3 nephrectomy was successfully performed in all pigs without any complications. Mean surgical time in the LN group (60.71+/-7.34min) and the TN group (58.57+/ 4.72min) was significantly longer than that in the RN group (41.14+/-5.33min). Warm ischemia in the LN group (38+/-7.57min) was significantly longer than that in the TN group (28.86+/-4.53min), which was significantly longer than that in the RN group (17.86+/-2.34min). The postoperative serum concentration of C reactive protein in the TN group was significantly higher than that in the LN group (p<0.05). So retroperitoneal approach was best choice in case of bilateral renal lesion resulted in shortest ischemia time, and laparoscopic partial nephrectomy should be the primary choice in majority situations resulted in less body stress, smaller surgical incisions and less blood loss. PMID- 29129270 TI - Patient-centeredness of integrated care programs for people with multimorbidity. Results from the European ICARE4EU project. AB - INTRODUCTION: This paper aims to support the implementation of patient-centered care for people with multimorbidity in Europe, by providing insight into ways in which patient-centeredness is currently shaped in integrated care programs for people with multimorbidity in European countries. METHODS: In 2014, expert organizations in 31 European countries identified 200 integrated care practices ('programs') in 25 countries of which 123 were included in our study. Managers of 112 programs from 24 countries completed a questionnaire about characteristics and results of the program, including questions on elements of patient centeredness. Eight programs that were considered especially innovative or promising were analyzed in depth. RESULTS: Programs used various methodologies to involve people with multimorbidity in decision-making, such as motivational interviewing and narrative counseling techniques. In 79 programs individual care plans were developed together with patients. Few programs had already been systematically evaluated, but in one program it was shown that working with individual care plans based on patients' goals and resources resulted in increased patient satisfaction with care. Various barriers to deliver patient centered care were reported, including inadequate knowledge and skills of both patients and professionals. CONCLUSION: In many European countries innovative approaches are applied to increase patient-centeredness of care for people with multimorbidity. To assess their potential benefits and conditions for implementation, thorough process and outcome evaluations of programs are urgently needed. PMID- 29129271 TI - Comparison of keyboard colonization before and after use in an inpatient setting and the effect of keyboard covers. AB - Computer keyboards may contribute to patient infections. We cultured new keyboards, with/without keyboard covers, before placing them in adult inpatient rooms and recultured after 6 months. Nonpathogenic bacteria were present initially but potentially pathogenic bacteria were cultured only after use. Coagulase negative Staphylococcus colonization increased after use (P < .001). Keyboards with a cover had more potentially pathogenic bacteria (22% vs 16%), which although not significant statistically (P = .72), likely due to sample size, trended against covers offering protection. PMID- 29129272 TI - Incidence and risk factors for infection in spine surgery: A prospective multicenter study of 1764 instrumented spinal procedures. AB - BACKGROUND: Surgical site infection (SSI) is a common complication in spinal surgery, imposing a high burden on patients and society. However, information about its characteristics and related risk factors is limited. We designed this prospective, multicenter study to address this issue. METHODS: From January 2015 through February 2016, a total of 1764 patients who had spinal trauma or degenerative spinal diseases were treated with instrumented surgeries and followed up for 1 year with complete data. Data on all patients were abstracted from electronic medical records, and SSIs were prospectively inspected and diagnosed by surgeons in our department. Any disagreement among them was settled by the leader of this study. SPSS 19.0 was used to perform the analyses. RESULTS: A total of 58 patients (3.3%, 58 of 1764) developed SSI; 1.1% had deep SSI, and 2.2% had superficial SSI. Of these, 60.6% (21 of 33) had a polymicrobial cause. Most of them (51 of 58) occurred during hospitalization. The median occurrence time was 3 days after operation (range: 1-123 days). SSI significantly prolonged hospital stays, by 9.3 days on average. The univariate analysis revealed reason for surgery as the only significant risk factor. The multivariate analysis, however, revealed 8 significant risk factors, including higher BMI, surgical site (cervical), surgical approach (posterior), surgery performed in summer, reasons for surgery (degenerative disease), autograft for fusion and fixation, and higher preoperative platelet level. CONCLUSION: Identification of these risk factors aids in stratifying preoperative risk to reduce SSI incidence. In addition, the results could be used in counseling patients and their families during the consent process. PMID- 29129273 TI - Contrasting the potential effects of daytime versus nighttime warming on insects. AB - Mean increases in temperatures associated with climate change are largely driven by increases in minimum (nighttime) temperatures; however, most climate change studies disproportionately increase maximum (daytime) temperatures. We review current literature to compare the potential effects of increasing daytime and nighttime temperatures on insects and their interactions within ecological communities. Although few studies have explicitly addressed the effects of nighttime warming, we draw from broader literature on how insects are affected by temperature to identify possible mechanisms that the timing (day or night) of warming may affect insects. Specifically, we discuss daily temperature variation, thermal performance curves, behaviour and activity patterns, nighttime recovery from hot days, and bottom-up effects mediated by plants. Although limited, the existing evidence suggests nighttime and daytime warming can have different effects, and thus we encourage scientists to use the most realistic warming treatments possible to truly understand how insects and their communities will be affected by climate change. PMID- 29129274 TI - Using artificial diets to understand the nutritional physiology of Drosophila melanogaster. AB - Artificial diets have been in use for rearing insects for more than 100 years. Their composition ranges from completely chemically defined (holidic), to semi defined (meridic) to non-defined (oligidic). Recently, meridic and holidic diets have been used to demonstrate previously unrecognised nutrient-sensitive behaviours and patterns of fitness trait expression in adult Drosophila melanogaster. This article presents a summary of the basic nutritional requirements of Drosophila followed by an account of some of these nutrient modified phenotypes and what they can reveal about fundamental mechanisms. Precisely controlled nutrition, combined with the many advantages of Drosophila present an ideal system for the development of large scale metabolic modelling. PMID- 29129276 TI - Amino acid modulation of lifespan and reproduction in Drosophila. AB - Manipulating amino acid (AA) intake in Drosophila can profoundly affect lifespan and reproduction. Remarkably, AA manipulation can uncouple the commonly observed trade-off between these traits. This finding seems to challenge the idea that this trade-off is due to competitive resource allocation, but here we argue that this view might be too simplistic. We also discuss the mechanisms of the AA response, mediated by the IIS/TOR and GCN2 pathways. Elucidating how these pathways respond to specific AA will likely yield important insights into how AA modulate the reproduction-lifespan relationship. The Drosophila model offers powerful genetic tools, combined with options for precise diet manipulation, to address these fundamental questions. PMID- 29129275 TI - How micronutrients influence the physiology of mosquitoes. AB - Micronutrients or non-energetic nutrients (NEN) are needed in reduced amounts, but are essential for many mosquito physiological processes that influence biological traits from vector competence to reproductive capacity. The NEN include amino acids (AA), vitamins, salts, metals and sterols. Free AA plays critical roles controlling most physiological processes, from digestion to reproduction. Particularly proline connects metabolic pathways in energy production, flight physiology and ammonia detoxification. Metal, in particular iron and calcium, salts, sterol and vitamin homeostasis are critical for cell signaling, respiration, metabolism and reproduction. Micronutrient homeostasis influence the symbiotic relationships with microorganisms, having important implications in mosquitoes' nutrition, physiology and behavior, as well as in mosquito immunity and vector competence. PMID- 29129277 TI - Implications of animal water balance for terrestrial food webs. AB - Recent research has documented shifts in per capita trophic interactions and food webs in response to changes in environmental moisture, from the top-down (consumers to plants), rather than solely bottom-up (plants to consumers). These responses may be predictable from effects of physiological, behavioral, and ecological traits on animal water balance, although predictions could be modified by energy or nutrient requirements, the risk of predation, population-level responses, and bottom-up effects. Relatively little work has explicitly explored food web effects of changes in animal water balance, despite the likelihood of widespread relevance, including during periodic droughts in mesic locations, where taxa may lack adaptations for water conservation. More research is needed, particularly in light of climate change and hydrological alteration. PMID- 29129278 TI - Effects of global change on insect pollinators: multiple drivers lead to novel communities. AB - Global change drivers, in particular climate change, exotic species introduction, and habitat alteration, affect insect pollinators in numerous ways. In response, insect pollinators show shifts in range and phenology, interactions with plants and other taxa are altered, and in some cases pollination services have diminished. Recent studies show some pollinators are tracking climate change by moving latitudinally and elevationally, while others are not. Shifts in insect pollinator phenology generally keep pace with advances in flowering, although there are exceptions. Recent data demonstrate competition between exotic and native bees, along with rapid positive effects of exotic plant removal on pollinator richness. Genetic analyses tie bee fitness to habitat quality. Across drivers, novel communities are a common outcome that deserves more study. PMID- 29129279 TI - Climate change effects on predator-prey interactions. AB - Predator-prey interactions can be very important to community structure and function. A growing body of research demonstrates how climate change can modify these species interactions. Climate change can modify predator-prey interactions by affecting species characteristics, and by modifying consumptive and/or non consumptive predator effects. Current work examines how climate change and predation risk can combine to influence herbivore stoichiometry and feeding ecology. Other recent advances show how climate change can affect chemical signaling of plants and insects, as well as how pollution and other components of the environmental context can modify predator-prey interactions. PMID- 29129280 TI - Daily temperature variation and extreme high temperatures drive performance and biotic interactions in a warming world. AB - We review the major patterns on the effects of daily temperature variation (DTV) and extreme high temperatures (EXT) on performance traits and the resulting outcome of biotic interactions in insects. EXT profoundly affects the outcome of all types of biotic interactions: competitive, predator-prey, herbivore-plant, host-pathogen/parasitoid and symbiotic interactions. Studies investigating effects of DTV on biotic interactions are few but also show strong effects on competitive and host-pathogen/parasitoid interactions. EXT typically reduces predation, and is expected to reduce parasitoid success. The effects of EXT and DTV on the outcome of the other interaction types are highly variable, yet can be predicted based on comparisons of the TPCs of the interacting species, and challenges the formulation of general predictions about the change in biotic interactions in a warming world. PMID- 29129281 TI - The essential roles of metal ions in insect homeostasis and physiology. AB - Metal ions play distinct roles in living organisms, including insects. Some, like sodium and potassium, are central players in osmoregulation and 'blood and guts' transport physiology, and have been implicated in cold adaptation. Calcium is a key player as a second messenger, and as a structural element. Other metals, particularly those with multiple redox states, can be cofactors in many metalloenzymes, but can contribute to toxic oxidative stress on the organism in excess. This short review selects some examples where classical knowledge has been supplemented with recent advances, in order to emphasize the importance of metals as essential nutrients for insect survival. PMID- 29129282 TI - Using plant nutrient landscapes to assess Anthropocene effects on insect herbivores. AB - Global climate change will dramatically affect insect herbivores through changes in plant quality. Linking how multiple climate factors affect plant macronutrient content may be the most accurate way to understand the response of insect herbivores. Studies should embrace the complexity of interacting climate factors in natural systems and characterize shifts in multidimensional plant nutrient landscapes. This nutrient landscape simplifies interpretation of climate effects, although selection of appropriate currencies, scale, and interactions with allelochemicals present challenges. By assessing climate change through the filter of nutrient landscapes we could gain an understanding of how complex interacting climate change drivers affect the 'buffet' available to different insect herbivores. PMID- 29129283 TI - Biological control agents in the Anthropocene: current risks and future options. AB - Global climate change is often expected to disrupt biological control. Predicting the effects of climate change on biological control, and identifying natural enemies that will thrive in future climate scenarios, is thus essential to ensure agricultural sustainability. To promote biological control under climate change, land managers should prioritise the conservation of natural enemy diversity to ensure some effective natural enemies are always present despite often unpredictable climate scenarios. In addition, ecophysiological and habitat domain models should be combined to predict climate change-induced shifts in predation by diverse predator communities. Finally, insights from land managers during extreme weather events, such as droughts and heat waves, may be invaluable in the effort to identify key biological control agents for future scenarios. PMID- 29129284 TI - The B vitamin nutrition of insects: the contributions of diet, microbiome and horizontally acquired genes. AB - Insects generally cannot synthesize eight B vitamins that function as co-enzymes in various required enzymatic reactions. Most insects derive their B vitamin requirements from the diet, microbial symbionts, or a combination of these complementary sources. Exceptionally, the genomes of a few insects bear genes in vitamin B5 (pantothenate) and B7 (biotin) synthesis, horizontally acquired from bacteria. Biomarkers of B vitamin deficiency (e.g. vitamin titers, activity of vitamin-dependent enzymes) offer routes to investigate the incidence and the physiological and fitness consequences of B vitamin deficiency in laboratory and field populations of insects. PMID- 29129285 TI - Mass mortality events and the role of necrophagous invertebrates. AB - Scale is important in understanding and applying concepts in ecology. Historically, the mechanisms regulating necrophagous arthropod community structure have been well explored on a single vertebrate carcass. However, practically nothing is known of whether such findings can be extrapolated to cases where large numbers of carcasses have been introduced into an ecosystem at a single time point. With the increasing incidences of mass mortality events (MMEs), understanding how scale effects community assembly of necrophagous insects and the resulting bottom-up or top-down effects on the impacted ecosystem are of utmost importance. Unfortunately, MMEs are unpredictable, making their study nearly impossible within a robust experimental framework. The objectives of this paper are to provide a brief overview of what is known with regards to ecological responses to carrion, opine on the ramifications of MMEs on local communities, and provide a brief overview of knowledge gaps, avenues for future research, and a potential study systems for rigorous MME experiments. PMID- 29129286 TI - Global change effects on plant-insect interactions: the role of phytochemistry. AB - Natural and managed ecosystems are undergoing rapid environmental change due to a growing human population and associated increases in industrial and agricultural activity. Global environmental change directly and indirectly impacts insect herbivores and pollinators. In this review, we highlight recent research examining how environmental change factors affect plant chemistry and, in turn, ecological interactions among plants, herbivores, and pollinators. Recent studies reveal the complex nature of understanding global change effects on plant secondary metabolites and plant-insect interactions. Nonetheless, these studies indicate that phytochemistry mediates insect responses to environmental change. Future research on the chemical ecology of plant-insect interactions will provide critical insight into the ecological effects of climate change and other anthropogenic disturbances. We recommend greater attention to investigations examining interactive effects of multiple environmental change factors in addition to chemically mediated plant-pollinator interactions, given limited research in these areas. PMID- 29129287 TI - Can agricultural practices that mitigate or improve crop resilience to climate change also manage crop pests? AB - Sustainable agricultural practices that are promoted for mitigating climate change have the potential to also improve pest management. The author highlights recent studies that demonstrate effects of climate-mitigating agricultural practices on arthropod pests and predators in agronomic cropping systems. Promising practices for suppressing pests and/or improving biological control include: plant species diversification, especially via the addition of perennial species; cover cropping; tillage practices that retain crop residue; application of organic fertilizers such as compost and manure; and water management practices such as irrigation and sustainable rice intensification. More research is needed that explicitly tests pest and predator responses to agricultural practices under climate change conditions, if these practices are to be effectively promoted and implemented as agricultural pest management strategies. PMID- 29129288 TI - Overturning dogma: tolerance of insects to mixed-sterol diets is not universal. AB - Insects cannot synthesize sterols de novo, but like all eukaryotes they use them as cell membrane inserts where they influence membrane fluidity and rigidity. They also use a small amount for metabolic purposes, most notably as essential precursors for steroid hormones. It has been a long-held view that most insects require a small amount of specific sterol (often cholesterol) for metabolic purposes, but for membrane purposes (where the bulk of sterols are used) specificity in sterol structure was less important. Under this model, it was assumed that insects could tolerate mixed-sterol diets as long as a small amount of cholesterol was available. In the current paper this dogma is overturned, using data from plant-feeding insects that were fed mixed-sterol diets with different amounts and ratios of dietary sterols. PMID- 29129290 TI - Editorial overview: Global change biology: everything connects to everything else. PMID- 29129289 TI - Craving for the future: the brain as a nutritional prediction system. AB - In the last decades, predictive coding has emerged as an important framework for understanding how the brain processes information. It states that the brain is constantly inferring and predicting sensory data from statistical regularities in its environment. While this framework has been largely applied to sensory processing and motor control, we argue here that it could also serve as framework for a better understanding of how animals regulate nutrient homeostasis. Mechanisms that underlie nutrient homeostasis are commonly described in terms of negative feedback control, which compares current states with a reference point, called setpoint, and counteracts any mismatches. Using concepts from control theory, we explain shortcomings of negative feedback as a purely reactive controller, and how feed-forward mechanisms could be incorporated into feedback control to improve the performance of the control system. We then provide numerous examples to show that many insects, as well as mammals, make use of feed forward, anticipatory mechanisms that go beyond the prevailing view of homeostasis being achieved through reactive negative feedback. The emerging picture is that the brain incorporates predictive signals as well as negative feedback to regulate nutrient homeostasis. PMID- 29129291 TI - Editorial overview: Molecular physiology: Insect nutrition beyond energy. PMID- 29129292 TI - Targeting myeloid cells in the tumor sustaining microenvironment. AB - Myeloid cells are the most abundant cells in the tumor microenvironment (TME). The tumor recruits and modulates endogenous myeloid cells to tumor-associated macrophages (TAM), dendritic cells (DC), myeloid-derived suppressor cells (MDSC) and neutrophils (TAN), to sustain an immunosuppressive environment. Pathologically overexpressed mediators produced by cancer cells like granulocyte macrophage colony-stimulating- and vascular endothelial growth factor induce myelopoiesis in the bone marrow. Excess of myeloid cells in the blood, periphery and tumor has been associated with tumor burden. In cancer, myeloid cells are kept at an immature state of differentiation to be diverted to an immunosuppressive phenotype. Here, we review human myeloid cells in the TME and the mechanisms for sustaining the hallmarks of cancer. Simultaneously, we provide an introduction into current and novel therapeutic approaches to redirect myeloid cells from a cancer promoting to a rather inflammatory, cancer inhibiting phenotype. In addition, the role of platelets for tumor promotion is discussed. PMID- 29129293 TI - The phenotype of peritoneal mouse macrophages depends on the mitochondria and ATP/ADP homeostasis. AB - Different macrophage subtypes have different morphologies/shapes and functions. Naive M0 macrophages are elongated. Pro-inflammatory M1 that produce the bactericidal molecule iNos are round. Anti-inflammatory M2 macrophages that produce the pro-healing enzyme Arg-1 are highly elongated. We showed previously that the morphologies of M0 and M2 but not M1 macrophages are RhoA-dependent. Macrophage-specific deletion of RhoA causes the extreme elongation (hummingbird phenotype) of M0 and M2 but not M1 macrophages. The M1 and M2 macrophages also differ in their metabolic status. Here, we studied the effect of the oxidative phosphorylation inhibitors, antimycin A and oligomycin A, at a suboptimal dose, which depolarizes mitochondria but does not eliminate mitochondrial functions, on the mitochondria/energy production and phenotype of wild-type and RhoA-deleted M0, M1 and M2 peritoneal mouse macrophages. We found that, while untreated M1 macrophages had the lowest and the M2 had the highest level of ATP the ATP/ADP ratio was nearly identical between M0, M1 and M2 macrophages. Inhibitor treatment resulted in approximately 60% increase in ATP level and ATP/ADP ratio in M0 and M2 macrophages, and decrease in the level of filamentous (F) actin, and these changes correlated with a drastic shortening/tail retraction of M0 and M2 macrophages, and decreased expression of Arg-1 in M2 macrophages. The treatment of M1 macrophages caused only a 30% increase in the ATP level and ATP/ADP ratio, and while it did not affect the shape of M1 macrophages, it increased the production of iNos. This indicates that the maintenance of mouse macrophage phenotypes depends on mitochondrial function and ATP/ADP homeostasis. PMID- 29129294 TI - Eosinophilic Esophagitis: Pathophysiology and Definition. AB - Eosinophilic esophagitis is an adaptive immune response to patient-specific antigens, mostly foods. Eosinophilic esophagitis is not solely IgE-mediated and is likely characterized by Th2 lymphocytes with an impaired esophageal barrier function. The key cytokines and chemokines are thymic stromal lymphopoeitin, interleukin-13, CCL26/eotaxin-3, and transforming growth factor-beta, all involved in eosinophil recruitment and remodeling. Chronic food dysphagia and food impactions, the feared late complications, are related in part to dense subepithelial fibrosis, likely induced by interleukin-13 and transforming growth factor-beta. PMID- 29129295 TI - Future Directions in Eosinophilic Esophagitis. AB - Eosinophilic esophagitis advances parallel the increased prevalence. Developments include refining the diagnostic criteria, identifying risk factors, appreciating the contribution of inflammatory pathways, recognizing the importance of subepithelial remodeling, validating trial endpoints, defining a role for biological therapies, and optimizing dietary therapy. Endoscopic outcomes have emerged as endpoints in trials of novel therapeutics. Expanding efforts seek to develop less-invasive methods to assess disease activity thereby reducing the burden of repeated endoscopic procedures during elimination diets. The functional lumen imaging probe is now identified as a determinant of complications with potential utility as a therapeutic endpoint. PMID- 29129296 TI - Eosinophilic Esophagitis: Incidence and Prevalence. AB - Eosinophilic esophagitis (EoE) is a rapidly emerging allergy-mediated condition encountered frequently in clinical practice. It presents with failure to thrive, nausea, and vomiting in children and is a common reason for dysphagia and food impaction in adults. Several institution-based and population-based studies have reported the frequency of EoE over the past few years. The incidence and prevalence of EoE vary depending on the method of data collection. In population based studies using national registries, the incidence appears to be increasing, currently estimated to be approximately 10 cases/100,000 persons annually, whereas the prevalence is reported between 10 and 57 cases/100,000 persons. PMID- 29129297 TI - Demographic Features of Eosinophilic Esophagitis. AB - Eosinophilic esophagitis (EoE) is an increasingly prevalent chronic condition characterized by eosinophilic infiltration of the esophageal epithelium accompanied by esophageal symptoms. The number of new diagnoses is growing worldwide in both pediatric and adult populations. Differences in disease distribution and presentation have been found, varying by gender, race, and other characteristics. This review examines the existing literature and provides insight into the demographic features of EoE. PMID- 29129298 TI - Latest Insights on the Relationship Between Symptoms and Biologic Findings in Adults with Eosinophilic Esophagitis. AB - Patients with eosinophilic esophagitis (EoE) present with symptoms accompanied by behavioral adaptions to living with this condition. These include swallowing- and nonswallowing-associated pain in adulthood. In children, EoE symptoms vary with age and include vomiting, abdominal pain, and dysphagia. Studies using validated patient-reported outcome measures have demonstrated that symptoms in EoE are associated with severe biologic alterations and that patients on the low biologic severity spectrum have few symptoms. This nonlinear nature of the relationship between symptoms and biologic findings has important implications for among other things the length of diagnostic delay, selection of patients for clinical trials, trial duration, and long-term management of EoE patients. PMID- 29129299 TI - Endoscopic and Radiologic Findings in Eosinophilic Esophagitis. AB - Eosinophilic esophagitis (EoE) was first described by Landis in 1978. The disease is characterized by esophageal symptoms, primarily dysphagia in adult patients, and esophageal eosinophilic infiltration. The disease is associated with characteristic endoscopic findings, including edema, rings, furrows, exudates, and strictures. The typical radiographic findings of this disorder are rings, strictures, and small-caliber esophagus. The endoscopic and radiographic findings of EoE are the topic of this review. PMID- 29129300 TI - Eosinophilic Esophagitis in Children and Adults. AB - Adults and children with eosinophilic esophagitis (EoE) have distinct clinical and endoscopic presentations. Recognition of clinical signs, along with laboratory and endoscopic findings, is critical for the identification of patients with EoE because delay in diagnosis has been associated with esophageal remodeling and stricture formation. Clinical presentation varies considerably between adults and children. This is less due to differences in the disease and more due to patient differences. This article describes the similarities and differences in clinical presentation of children and adults with EoE, including areas of epidemiology, clinical and endoscopic presentation, pathophysiology, and treatment. PMID- 29129301 TI - Pharmacologic Treatment of Eosinophilic Esophagitis: An Update. AB - Eosinophilic esophagitis (EoE) is defined as a chronic, immune-medicated or antigen-mediated, esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Food allergens are identified in most patients. Treatment strategies include elimination diets, drugs, and esophageal dilation. This article focuses on pharmacologic treatment. Currently, there is no pharmacologic treatment that has been approved by regulatory authorities. Established pharmacologic options to treat EoE include proton pump inhibitors and swallowed topical steroids. Several biologic therapies are currently under evaluation and some of them have shown promising results in improving biologic endpoints and patient-reported outcomes. PMID- 29129302 TI - Dietary Therapy in Eosinophilic Esophagitis. AB - Eosinophilic esophagitis is characterized by dense mucosal eosinophilia with symptoms of esophageal dysfunction. Because the incidence and prevalence are increasing, understanding the available treatments is imperative. This article highlights evolution and advancements in dietary treatment, supports the notion that food antigens drive this disease, and discusses the advantages, limitations, and future of dietary therapy. Medical and dietary therapies are effective treatments and the optimal approach should be individualized based on patient goals and available local resources. Dietary therapy has been effective and further studies will help identify optimal approaches to dietary therapy. PMID- 29129303 TI - Endoscopic Treatment of Eosinophilic Esophagitis. AB - In eosinophilic esophagitis, the main cause of solid-food dysphagia is tissue remodeling resulting in strictures and narrowed esophagus. Endoscopy and biopsies help to identify the degree of inflammation but often miss the fibrosis. Although initially considered dangerous, esophageal dilation has evolved into an extremely effective and safe treatment in fibrostenotic disease. The key is starting low with small-diameter bougies or balloons, and gradually dilating the esophagus and strictures to 16 to 18 mm. Results in more than 1000 adults and children have shown low rates of complications, especially perforations, and no deaths, but postprocedure chest pain is common. PMID- 29129304 TI - Eosinophilic Esophagitis: New Insights and Management. PMID- 29129305 TI - Eosinophilic Esophagitis. PMID- 29129306 TI - Studies of the cryopreservation condition of Gymnocypris przewalskii spermatozoa. AB - The endemic naked carp (Gymnocypris przewalskii Kessler, 1876) plays an important role in the maintenance of the distinctive ecological system of Lake Qinghai at 3.2km altitude on the Qinghai-Tibet Plateau in China. This study aimed to develop a cryopreservation protocol for Gymnocypris przewalskii spermatozoa. Semen was collected from mature individuals during migration and frozen using the liquid nitrogen vapor method. The influence of different cryoprotectants and three extenders on the post-thaw quality of the sperm was analyzed. The highest sperm motility rate and longest motility time after cryopreservation were achieved by combining Ringer's solution with 15% ethylene glycol (P<0.05). The fertilization rate of this cryopreserved semen was 15.26+/-4.54%. This study thus provides a valuable method for the cryopreservation of the sperm of this important endangered fish species. PMID- 29129307 TI - Changes in asthma self-management knowledge in inner city adolescents following developmentally sensitive self-management training. AB - OBJECTIVE: To evaluate efficacy of a developmentally sensitive curriculum for improving asthma self-management knowledge, attitude, and self-efficacy in adolescents. METHODS: Fourty-two inner-city adolescents (ages 16-20) participated in a 12hour asthma self-management training program. Self-management knowledge, attitude toward asthma, and asthma-related self-efficacy were measured using short-answer tests before and after training. T-Tests were used to evaluate impact and effect sizes were calculated. RESULTS: Mean pretest knowledge was 21.37/46 points; mean posttest was 36.33/46 points. Change from pre- to posttest was highly significant (t=10.34; p<0.0001), with a large effect size (d=1.68). Females improved more than males (18.66+/-8.58 vs. 12.29+/-8.13, p=0.039). Greatest effects were seen in awareness of long-term consequences of uncontrolled asthma (d=2.04), ability to recognize symptoms of life-threatening asthma (d=1.61), correctly monitor symptoms (d=1.49), and tell if asthma was uncontrolled (d=1.39). Asthma self-efficacy also improved significantly (p=0.017), particularly confidence in ability to correctly manage asthma, however improvements in attitude did not achieve statistical significance. CONCLUSION: Developmentally appropriate training is effective in increasing critical self management knowledge and self-efficacy in inner city adolescents, particularly females. PRACTICE IMPLICATIONS: Providers should screen carefully for symptoms and educate using developmentally appropriate training materials on ways to correctly monitor and manage symptom. PMID- 29129308 TI - The probe target mutation G18913A of adenovirus type 5 is not associated with underquantification in a generic adenovirus real-time PCR. PMID- 29129309 TI - Editorial overview: Biophysical methods: behind the scenes of the cryo-EM revolution. PMID- 29129311 TI - Speech disfluencies in children with Down Syndrome. AB - PURPOSE: Speech and language development in individuals with Down syndrome is often delayed and/or disordered and speech disfluencies appear to be more common. These disfluencies have been labeled over time as stuttering, cluttering or both. FINDINGS: were usually generated from studies with adults or a mixed age group, quite often using different methodologies, making it difficult to compare findings. Therefore, the purpose of this study was to analyze and describe the speech disfluencies of a group, only consisting of children with Down Syndrome between 3 and 13 years of age. METHOD: Participants consisted of 26 Dutch speaking children with DS. Spontaneous speech samples were collected and 50 utterances were analyzed for each child. Types of disfluencies were identified and classified into stuttering-like (SLD) and other disfluencies (OD). The criterion of three or more SLD per 100 syllables (cf. Ambrose & Yairi, 1999) was used to identify stuttering. Additional parameters such as mean articulation rate (MAR), ratio of disfluencies, and telescoping (cf. Coppens-Hofman et al., 2013) were used to identify cluttering and to differentiate between stuttering and cluttering. RESULTS & CONCLUSION: Approximately 30 percent of children with DS between 3 and 13 years of age in this study stutter, which is much higher than the prevalence in normally developing children. Moreover, this study showed that the speech of children with DS has a different distribution of types of disfluencies than the speech of normally developing children. Although different cluttering-like characteristics were found in the speech of young children with DS, none of them could be identified as cluttering or cluttering-stuttering. PMID- 29129312 TI - Water adsorption on carbon - A review. AB - Water adsorption on carbonaceous materials has been studied increasingly in the recent years, not only because of its impact on many industrial processes, but also motivated by a desire to understand, at a fundamental level, the distinctive character of directional interactions between water molecules, and between water molecules and other polar groups, such as the functional groups (FGs) at the surfaces of graphene layers. This paper presents an extensive review of recent experimental and theoretical work on water adsorption on various carbonaceous materials, with the aim of gaining a better understanding of how water adsorption in carbonaceous materials relates to the concentration of FGs, their topology (arrangement of the groups) and the structure of the confined space in porous carbons. Arising from this review we are able to propose mechanisms for water adsorption in carbonaceous materials as the adsorbate density increases. The intricate interplay between the roles of FGs and confinement makes adsorption of water on carbon materials very different from that of other simple molecules. PMID- 29129313 TI - Physico-chemistry of bacterial transmission versus adhesion. AB - Bacterial adhesion is a main problem in many biomedical, domestic, natural and industrial environments and forms the onset of the formation of a biofilm, in which adhering bacteria grow into a multi-layered film while embedding themselves in a matrix of extracellular polymeric substances. It is usually assumed that bacterial adhesion occurs from air or by convective-diffusion from a liquid suspension, but often bacteria adhere by transmission from a bacterially contaminated donor to a receiver surface. Therewith bacterial transmission is mechanistically different from adhesion, as it involves bacterial detachment from a donor surface followed by adhesion to a receiver one. Transmission is further complicated when the donor surface is not covered with a single layer of adhering bacteria but with a multi-layered biofilm, in which case bacteria can be transmitted either by interfacial failure at the biofilm-donor surface or through cohesive failure in the biofilm. Transmission through cohesive failure in a biofilm is more common than interfacial failure. The aim of this review is to oppose surface thermodynamics and adhesion force analyses, as can both be applied towards bacterial adhesion, with their appropriate extensions towards transmission. Opposition of surface thermodynamics and adhesion force analyses, will allow to distinguish between transmission of bacteria from a donor covered with a (sub)monolayer of adhering bacteria or a multi-layered biofilm. Contact angle measurements required for surface thermodynamic analyses of transmission are of an entirely different nature than analyses of adhesion forces, usually measured through atomic force microscopy. Nevertheless, transmission probabilities based on Weibull analyses of adhesion forces between bacteria and donor and receiver surfaces, correspond with the surface thermodynamic preferences of bacteria for either the donor or receiver surface. Surfaces with low adhesion forces such as polymer-brush coated or nanostructured surfaces are thus preferable for use as non-adhesive receiver surfaces, but at the same time should be avoided for use as a donor surface. Since bacterial transmission occurs under a contact pressure between two surfaces, followed by their separation under tensile or shear pressure and ultimately detachment, this will affect biofilm structure. During the compression phase of transmission, biofilms are compacted into a more dense film. After transmission, and depending on the ability of the bacterial strain involved to produce extracellular polymeric substances, biofilm left-behind on a donor or transmitted to a receiver surface will relax to its original, pre-transmission structure owing to the viscoelasticity of the extracellular polymeric substances matrix, when present. Apart from mechanistic differences between bacterial adhesion and transmission, the low numbers of bacteria generally transmitted require careful selection of suitably sensitive enumeration methods, for which culturing and optical coherence tomography are suggested. Opposing adhesion and transmission as done in this review, not only yields a better understanding of bacterial transmission, but may stimulate researchers to more carefully consider whether an adhesion or transmission model is most appropriate in the specific area of application aimed for, rather than routinely relying on adhesion models. PMID- 29129314 TI - Tibiotalocalcaneal Arthrodesis With the Hindfoot Arthrodesis Nail: A Prospective Consecutive Series From a Single Institution. AB - Tibiotalocalcaneal arthrodesis (TTCA) is a salvage procedure. We report a series of 20 patients who underwent TTCA using an intramedullary nail. Of the 20 patients, 7 (35%) had diabetes mellitus. The patient experiences and outcomes were analyzed. Their mean age was 61.1 (range 39 to 78) years. The minimum follow up period was 13 (mean 28, range 13 to 49) months. Surgical indications included diabetic Charcot arthropathy in 7 (35%), hindfoot osteoarthritis in 10 (50%), and severe equinovarus deformity in 3 (15%). A calcaneal spiral blade was used in 2 patients (10%). Significant improvements (p < .05) were observed in 5 of 8 Short Form 36-item Health Survey components, the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot scale (p < .001), and visual analog scale for pain (p < .001). The mean length of the hospital stay was 6.7 (range 1 to 27) days. Of the 20 patients, 76.9% had improvement in their activity postoperatively. Also, 81.8% were able to resume their preoperative work after a mean of 7.89 (range 3 to 24) months. Overall, 19 patients (95%) reported favorable outcomes. Superficial wound infection (n = 4; 20%) and deep wound infection (n = 3; 15%) were the most common complications (35%), with 1 case (5%) culminating in a below-the-knee amputation. Radiographic union was achieved in 16 of the tibiotalar joints (80%), 16 subtalar joints (80%), and 4 tibiocalcaneal fusions (20%). In a subgroup analysis of 7 patients with diabetes mellitus (35%), the incidence of wound complications and fusion was comparable to that of the primary cohort. TTCA performed with an intramedullary nail appears to offer a reliable and safe alternative for patients with severe ankle and hindfoot pathologic entities, including those with diabetes mellitus. PMID- 29129315 TI - Fixation Methods for Calcaneus Fractures: A Systematic Review of Biomechanical Studies Using Cadaver Specimens. AB - Calcaneal fractures are notoriously difficult to treat and wound complications occur often. However, owing to the rare nature of these fractures, clinical trials on this subject are lacking. Thus, biomechanical studies form a viable source of information on this subject. With our systematic review of biomechanical studies, we aimed to provide an overview of all the techniques available and guide clinicians in their choice of method of fracture fixation. A literature search was conducted using 3 online databases to find biomechanical studies investigating methods of fixation for calcaneal fractures. A total of 14 studies investigating 237 specimens were identified. Large diversity was found in the tested fixation methods and in the test setups used. None of the studies found a significant difference in favor of any of the fixation methods. All tested methods provided a biomechanically stable fixation. All the investigated methods of fixation for calcaneal fractures seem to be biomechanically sufficient. No clear benefit was found for locking plates in the fixation of calcaneal fractures; however, a subtle mechanical superiority might exist compared with nonlocking plates in the case of fractures in osteoporotic bone. Several of the techniques tested would be suitable for a minimal invasive approach. These should be investigated further in clinical trials. PMID- 29129316 TI - Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells. AB - Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the alpha7 nicotinic acetylcholine receptor (nAChR), has been suggested as a candidate gene for the phenotypes observed. Here, we used induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) derived from individuals with heterozygous 15q13.3 deletions and heterozygous 15q13.3 duplications to investigate the CHRNA7-dependent molecular consequences of the respective CNVs. Unexpectedly, both deletions and duplications lead to decreased alpha7 nAChR associated calcium flux. For deletions, this decrease in alpha7 nAChR-dependent calcium flux is expected due to haploinsufficiency of CHRNA7. For duplications, we found that increased expression of CHRNA7 mRNA is associated with higher expression of nAChR-specific and resident ER chaperones, indicating increased ER stress. This is likely a consequence of inefficient chaperoning and accumulation of alpha7 subunits in the ER, as opposed to being incorporated into functional alpha7 nAChRs at the cell membrane. Here, we showed that alpha7 nAChR-dependent calcium signal cascades are downregulated in both 15q13.3 deletion and duplication NPCs. While it may seem surprising that genomic changes in opposite direction have consequences on downstream pathways that are in similar direction, it aligns with clinical data, which suggest that both individuals with deletions and duplications of 15q13.3 manifest neuropsychiatric disease and cognitive deficits. PMID- 29129317 TI - The Genetic Legacy of the Indian Ocean Slave Trade: Recent Admixture and Post admixture Selection in the Makranis of Pakistan. AB - From the eighth century onward, the Indian Ocean was the scene of extensive trade of sub-Saharan African slaves via sea routes controlled by Muslim Arab and Swahili traders. Several populations in present-day Pakistan and India are thought to be the descendants of such slaves, yet their history of admixture and natural selection remains largely undefined. Here, we studied the genome-wide diversity of the African-descent Makranis, who reside on the Arabian Sea coast of Pakistan, as well that of four neighboring Pakistani populations, to investigate the genetic legacy, population dynamics, and tempo of the Indian Ocean slave trade. We show that the Makranis are the result of an admixture event between local Baluch tribes and Bantu-speaking populations from eastern or southeastern Africa; we dated this event to ~300 years ago during the Omani Empire domination. Levels of parental relatedness, measured through runs of homozygosity, were found to be similar across Pakistani populations, suggesting that the Makranis rapidly adopted the traditional practice of endogamous marriages. Finally, we searched for signatures of post-admixture selection at traits evolving under positive selection, including skin color, lactase persistence, and resistance to malaria. We demonstrate that the African-specific Duffy-null blood group-believed to confer resistance against Plasmodium vivax infection-was recently introduced to Pakistan through the slave trade and evolved adaptively in this P. vivax malaria endemic region. Our study reconstructs the genetic and adaptive history of a neglected episode of the African Diaspora and illustrates the impact of recent admixture on the diffusion of adaptive traits across human populations. PMID- 29129319 TI - Modeling the Interplay Between Neurons and Astrocytes in Autism Using Human Induced Pluripotent Stem Cells. AB - BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unclear etiology and imprecise genetic causes. The main goal of this work was to investigate neuronal connectivity and the interplay between neurons and astrocytes from individuals with nonsyndromic ASD using induced pluripotent stem cells. METHODS: Induced pluripotent stem cells were derived from a clinically well-characterized cohort of three individuals with nonsyndromic ASD sharing common behaviors and three control subjects, two clones each. We generated mixed neural cultures analyzing synaptogenesis and neuronal activity using a multielectrode array platform. Furthermore, using an enriched astrocyte population, we investigated their role in neuronal maintenance. RESULTS: ASD derived neurons had a significant decrease in synaptic gene expression and protein levels, glutamate neurotransmitter release, and, consequently, reduced spontaneous firing rate. Based on co-culture experiments, we observed that ASD derived astrocytes interfered with proper neuronal development. In contrast, control-derived astrocytes rescued the morphological neuronal phenotype and synaptogenesis defects from ASD neuronal co-cultures. Furthermore, after identifying interleukin-6 secretion from astrocytes in individuals with ASD as a possible culprit for neural defects, we were able to increase synaptogenesis by blocking interleukin-6 levels. CONCLUSIONS: Our findings reveal the contribution of astrocytes to neuronal phenotype and confirm previous studies linking interleukin-6 and autism, suggesting potential novel therapeutic pathways for a subtype of individuals with ASD. This is the first report demonstrating that glial dysfunctions could contribute to nonsyndromic autism pathophysiology using induced pluripotent stem cells modeling disease technology. PMID- 29129320 TI - An evaluation of cumulative risks from offshore produced water discharges in the Bass Strait. AB - Chemical analyses and toxicity testing using six marine species were used to characterize the hazard of produced waters (PW) to marine life from twelve Australian offshore platforms. Hazard data were used in conjunction with platform specific plume discharge dilution and species sensitivity distribution modeling to estimate cumulative risks by calculating the multiple substance potentially affected fraction of species in the local marine environment. Results provided two independent lines of evidence demonstrating that cumulative risks to marine life from these discharges meet intended 95% species protection goals at the edge of the mixing zone. A limited number of PW constituents (hydrocarbons, sulphide and ammonia) appeared to dictate risk thereby informing management and providing a rationale for more targeted analyses in future monitoring studies. Based on these findings a tiered framework is proposed to foster consistent screening and potential refinement of cumulative risk evaluations for PW discharges. PMID- 29129321 TI - Distribution, sources, and ecological risk assessment of quinotone antibiotics in the surface sediments from Jiaozhou Bay wetland, China. AB - The distribution, sources, and risk assessment of eight quinotone antibiotics (QNs) in the surface sediments from the wetland in Jiaozhou Bay were investigated. The results showed that QNs were detected in all samples, and the total concentrations of QNs in the sediments ranged from 0.276 to 5.229ng/g. The highest concentration occurred at the entrance to the Yang River wetland. Principal component analysis suggested that the QNs mainly originated from sewage discharges from hospitals, human and aquaculture industries. Risk assessment, based on risk quotients, indicated the current ofloxacin level might be a medium risk level, while other QNs were all low risk. Nevertheless, there should still be concerns due to high consumption of QNs by human beings, animals, and aquatic organisms in the wetland. This investigation provides baseline data that the government can use as a reference guide to control QNs residues in Jiaozhou Bay wetland. PMID- 29129322 TI - Effects of replacing soybean meal with canola meal or treated canola meal on ruminal digestion, omasal nutrient flow, and performance in lactating dairy cows. AB - Extrusion treated canola meal (TCM) was produced in an attempt to increase the rumen-undegraded protein fraction of canola meal (CM). The objective of this study was to evaluate the effects of replacing soybean meal (SBM) with CM or TCM on ruminal digestion, omasal nutrient flow, and performance in lactating dairy cows. To assess performance, 30 multiparous Holstein cows averaging (mean +/- SD) 119 +/- 23 d in milk and 44 +/- 7 kg of milk/d and 15 primiparous cows averaging 121 +/- 19 d in milk and 34 +/- 6 kg of milk/d were blocked in a randomized complete block design with a 2-wk covariate period and 12-wk experimental period (experiment 1). Dietary ingredients differed only in protein supplements, which were SBM, CM, or TCM. All diets were formulated to contain (dry matter basis) 30% alfalfa silage, 30% corn silage, 4% soy hulls, 2.4% mineral-vitamin premix, and 16% CP. The SBM diet contained 25% high-moisture shelled corn and 8.6% SBM; the canola diets contained 22% high-moisture shelled corn and either 11.2% CM or 11.4% TCM. To assess ruminal digestion and omasal nutrient flow, 6 rumen cannulated cows were blocked into 2 squares of 3 cows and randomly assigned within blocks to the same 3 dietary treatments as in experiment 1 in a replicated 3 * 3 Latin square design (experiment 2). Data were analyzed using the MIXED procedure of SAS (SAS Institute, Cary, NC). Orthogonal contrasts were used to compare effects of different protein supplements: SBM versus CM + TCM and CM versus TCM. In experiment 1, compared with SBM, apparent total-tract digestibilities of dry matter and nutrients were greater in cows fed both CM diets, and there was a tendency for nutrient digestibilities to be higher in cows fed CM compared with TCM. Diets did not affect milk yield and milk components; however, both canola diets decreased urinary urea N (% of total urinary N), fecal N (% of total N intake), and milk urea N concentration. In experiment 2, compared with SBM, both canola diets increased N intake and tended to increase rumen degraded protein supply (kg/d) and N truly digested in the rumen (kg/d). Diets did not affect ruminal digestibility, efficiency of microbial protein synthesis, and rumen-undegraded protein flow among diets. Results from this experiment indicate that replacing SBM with CM or TCM in diets of lactating cows improved digestibility and may reduce environmental impact. Moreover, under the conditions of the present study, treating CM by extrusion did not improve CM utilization. PMID- 29129323 TI - Haematological alterations in the cardiac patient after use of an autotransfusion system. AB - OBJECTIVE: There are studies that declare blood recovered with the autotransfusion system that is potentially heparinised and mixed with other drugs, can cause haematological alterations in the patient, according to existing evidence. The proposal was to compare the haematological values of the patients before reinfusing red blood cells from the cell saver and 12h after reinfusion. MATERIAL AND METHODS: Observational analytical study of 479 patients who underwent cardiac surgery where the cell saver was used. Haematological variables were collected before reinfusion and 12h after reinfusion. RESULTS: Statistically significant haematological values before reinfusion and 12h after reinfusion were: haemoglobin (9.5 to 12.5g/dL), haematocrit (26 to 38%), platelets (214.2 to 164.210^3/MUL), total proteins (7.6 to 5.1g/dL), PCR (8.5 to 22.1mg/L) and D dimer (493.3 to 875.5MUg/L) with P<.05. CONCLUSIONS: With the use of the cell saver an increase was observed of haemoglobin, haematocrit, PCR and D-dimer values together with a decrease in platelet and total protein numbers. PMID- 29129324 TI - Dystonia of the soft palate: Mutation of the THAP1 (DYT6) gene in a 42-year-old patient. PMID- 29129318 TI - Does Childhood Trauma Moderate Polygenic Risk for Depression? A Meta-analysis of 5765 Subjects From the Psychiatric Genomics Consortium. AB - BACKGROUND: The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD PRS * CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. METHODS: Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD PRS were based on a discovery sample of ~110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. RESULTS: MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 * 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 * 10-18 and OR = 2.62, p = 1.4 *10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66). CONCLUSIONS: No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT. PMID- 29129325 TI - Protracted febrile myalgia syndrome treated with pulse of corticosteroids. AB - OBJECTIVE: This study describes our 5-year experience treating protracted febrile myalgia syndrome (PFMS) with pulsed doses of corticosteroids. METHODS: Eight patients with PFMS who received pulse corticosteroid therapy were identified from the electronic database of a tertiary pediatric medical center (2011-2016). Their clinical and laboratory data were collected. Differences in continuous variables between hospital admission and discharge were analyzed using Wilcoxon's matched pairs test. RESULTS: There were 6 female and 2 male patients of median age 10.45 years (range 6.2-17.1) Six patients were found to be homozygous for the M694V mutation. In 4 patients, PFMS was the first-ever manifestation of familial Mediterranean fever. Pulse corticosteroid therapy was administered at a dose of 10mg/kg for 3 days. Pain was alleviated (visual analog scale score, 0) within hours of initiation of therapy, although pain flare-ups lasting for minutes to hours were still observed during hospitalization. At discharge, all patients were prescribed continuous oral corticosteroids (1-2mg/kg) with gradual tapering down over 6 weeks. CONCLUSION: Pulse corticosteroid therapy is effective in alleviating PFMS pain; however, it does not completely abort a PFMS episode. PMID- 29129326 TI - Risk factors and clinical characteristics of deep knee infection in patients with intra-articular injections: A matched retrospective cohort analysis. AB - BACKGROUND: Deep knee infection (DKI), consisting of sepsis arthritis (SA) and chronic low-grade infection (CLGI), is a rare but catastrophic adverse event that can result from intra-articular (IA) injections. The purpose of this study was to assess the risk factors for DKI and describe the clinical characteristics of DKI in patients who received IA injections. METHODS: Fifty patients with IA injection induced DKI who underwent surgical treatment between January 2010 and May 2016 served as cases and were matched with non-infected controls who received IA injections in a proportion of 1:5 based on age, gender, and date of admission. All IA injections (both cases and controls) were performed within 6 months of admission at our institution or at a referring institution. Risk factors for injection-induced DKI were analyzed, and the clinical characteristics between SA and CLGI were compared. RESULTS: The final multivariate logistic regression analysis demonstrated that body mass index >=25kg/m2 [odds ratio (OR) = 2.3; 95% confidence interval (CI): 1.1-4.7], corticosteroid injections (OR = 3.21; 95% CI: 1.63-6.31), rheumatoid arthritis (OR = 2.61; 95% CI: 1.20-5.68) and injections performed by general practitioners (OR = 5.23; 95% CI: 2.00-13.67) increased the risk of DKI following IA injections. Of 50 cases, there were 21 SA cases and 29 CLGI cases. SA cases had significantly higher metrics in the categories of fever, local warmth, swelling, rest pain, night pain, limited motion, serum WBC, and CRP levels than CLGI cases. CONCLUSIONS: We identified risk factors and clinical characteristics of injection-induced DKI, which may offer improved guidance on IA injections and knowledge of DKI in patients with IA injections, especially in CLGI patients. PMID- 29129327 TI - Quercetin protects jejunal mucosa from experimental intestinal ischemia reperfusion injury by activation of CD68 positive cells. AB - The aim of our study was to analyse the possible protective effect of quercetin application during the jejunal ischemia-reperfusion injury (IRI) in rats. Quercetin was administered intraperitoneally 30min before 1h ischemia of superior mesenteric artery with following 24h lasting reperfusion period. The male specific pathogen-free (SPF) Charles River Wistar rats were used. In the group with applied quercetin, the significantly increased (p<0.001) levels of anti inflammatory cytokine IL10 were observed both in the blood serum and jejunal tissue. The improvement of the mucosal tissue morphology and proliferating and DNA repairing cell number measured by PCNA activity were recorded by more than 30% higher in the quercetin group. Simultaneously, significant elongation of the intestinal glands (p<0.001) and increase in the number of CD68-positive cells in the lamina propria mucosae (p<0.001) in comparison with control group were found. Based on our results, the preventive application of quercetin before induction of jejunal IRI stimulates faster jejunal mucosa restoration and it seems to have immunomodulatory and anti-inflammatory effects as well. CD68-positive macrophages could have crucial role in this process since they work as both growth factor and cytokine producers. PMID- 29129328 TI - Insight on cytotoxic effects of silver nanoparticles: Alternative androgenic transactivation by adsorption with DHT. AB - Silver nanoparticles (AgNPs) are accumulated in the male reproductive organs for a long time and cause several adverse effects in there. Up to now, there is little of information for the cytotoxic effects in male reproductive cells. In this study, the stable AgNPs with a minimal silver ion (Ag+) dissolution below concentration inducing cytotoxicity in the cell medium were exposed to the human prostate carcinoma cell line 22Rv1. Moreover particle uptake and androgen receptor (AR) transactivation were evaluated. In cell medium, AgNPs exhibited stability in an aqueous environment and minimal Ag+ release. Transmission electron microscopy (TEM) and energy dispersive spectrometer (EDS) analysis demonstrated uptake of AgNPs into cells via endocytosis, and a quantitative Ag assay showed that uptake of AgNPs was size-dependent with the majority of Ag retained in the particle form. To evaluate if the presence of AgNPs can change androgenic potentials of dihydrotestosterone (DHT, strong human androgen), we conducted an AR transactivation assay using the transgenic prostate cell line 22Rv1-MMTV-Hyg and found that AgNPs lowered androgenic transactivation of DHT, which is due to decreased bioavailability of DHT. PMID- 29129329 TI - Influence of nitrogen and phosphorus additions on N2-fixation activity, abundance, and composition of diazotrophic communities in a Chinese fir plantation. AB - Although biological nitrogen (N) fixation (BNF) is an important N input process in subtropical forest ecosystems, how the diazotrophic communities related to this process respond to N and phosphorus (P) inputs is largely unknown. We investigated the effects of exogenous N and/or P inputs on N2-fixation activity, diazotrophic abundance and community composition using a continuous application of fertilizers over 5years experiment in a Chinese fir plantation. The fertilization regimes included control (CK), P treatment (P), low N addition treatment (N1), high N addition treatment (N2), low N and P addition treatment (N1P) and high N with P addition treatment (N2P). N2-fixation activity was determined using the acetylene reduction assay (ARA). Quantitative PCR and Illumina Miseq sequencing of nifH gene were performed to analyze diazotrophic abundance and community composition, respectively. Our results showed that P addition increased N2-fixation activity and nifH gene abundance by 189.07nmol C2H4 and 1.02*107copiesg-1 dry soil, respectively, while were reduced by 1.19nmol C2H4 and 2.04*106copiesg-1 dry soil when N was added. The application of P with low N (N1P) effectively alleviated the inhibitory effect of N input on N2 fixation activity. N-related treatments resulted in significant decreases in operational taxonomic unit (OTU) richness and shifts in diazotrophic community structure. N2-fixation activity and nifH gene abundance were strongly and positively correlated with soil pH and negatively correlated with mineral N (NH4+ N and NO3--N) contents, while mineral N concentrations rather than soil pH appeared to be the main factor altering diazotrophic community structure. These results revealed that P addition played a positive role in regulating biological nitrogen fixation in subtropical forest ecosystems. PMID- 29129330 TI - Surgical procedures and pediatric medical traumatic stress (PMTS) syndrome: Assessment and future directions. AB - INTRODUCTION: Surgical procedures involve traumatic stress. Children may develop chronic psychological distress and dysfunction after surgery, with consequent reluctance to comply with medical follow-up care. A literature review of this topic shows that it has been understudied. Our study aims to assess the frequency and characteristics of symptoms of persistent psychological distress in children following surgery, which have not been documented before, in order to promote its awareness and its early identification. METHODS: Parents of 79 children (aged 1 6) that were hospitalized in a pediatric surgical ward, comprising a representative sample, completed three validated questionnaires assessing their children's psychological symptoms 3-5months after the hospitalization. RESULTS: A significant portion of children suffer from psychological distress 3-5months after hospitalization. Moreover, 10.39% of the children exhibited symptoms of PTSD, and 28.6% of parents reported that the child's distress causes dysfunction. Additionally, our findings emphasize the parents' concerns regarding the child's behavior, function, and health following hospitalization. CONCLUSION: Since a significant prevalence of hospitalization-related traumatic stress is documented, the awareness to it has to be improved, in order to reduce its frequency and increase adherence to medical follow-up care. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: 1. PMID- 29129331 TI - Reply to Letter to the Editor. PMID- 29129332 TI - Aerosol deposition predictions in computed tomography-derived skeletons from severe asthmatics: A feasibility study. AB - BACKGROUND: The authors numerically investigated the correlation between airway skeletons of severe asthmatic human subjects and predicted aerosol deposition to shed light on the effect of environmental factors on asthma risk. We hypothesized that there are asthmatic subjects whose airway skeletal structure can expose the subject to a risk of higher local aerosol deposition compared to subjects with a more common/normal branching pattern. METHODS: From a population of severe asthmatics studied at total lung capacity via computed tomography we randomly selected 8 subjects whose Forced Expiratory Volume in 1s, percent predicted fell below 45% predicted. To simulate aerosol motion in the human lungs, we employed in-house three-dimensional eddy-resolving computational fluid dynamics and particle tracking models utilizing 3 of the 8 severe asthmatic subjects. One of the 3 subjects was found to have a distinct, localized airway narrowing chosen for further investigation. In the simulation, we controlled flow rate and luminal area, i.e., Reynolds and Stokes numbers, in each branch of the computed tomography-derived airway skeletons. FINDINGS: We found a distinct enhancement of aerosol deposition associated with the narrowed branches of one subject even when the luminal area was numerically adjusted from its narrowed state to that of a non-asthmatic subject. The branching angle, freed of luminal narrowing persisted in demonstrating a marginally significant increase in local particle deposition compared with the subjects without the initial constriction. INTERPRETATION: These results demonstrate the possibility that inherent airway structure may influence localized constriction found in severe asthmatics. PMID- 29129333 TI - Pitfalls in the interpretation of specimens from patients with testicular tumours, with an emphasis on variant morphologies. AB - Accurate diagnosis of primary and metastatic tumours is essential in testicular cancer. While many cases are straightforward, some pose difficulties, especially when variant morphologies occur. Seminoma with 'atypical' features, including increased nuclear pleomorphism and crowding and greater cytoplasmic density with loss of membrane definition, mimics embryonal carcinoma, although ancillary features (fibrous septa, lymphocytes) and immunohistochemistry are of great help. Other deceptive seminoma features include prominent to exclusive intertubular growth, microcystic/tubular patterns, and signet-ring tumour cells. Conversely, embryonal carcinomas may have 'seminoma-like' foci, as may Sertoli cell tumours with diffuse growth and pale cytoplasm. Solid pattern yolk sac tumour mimics seminoma and, conversely, microcytic seminoma resembles yolk sac tumour. Other architectural patterns, ancillary yolk sac tumour features (intercellular basement membrane deposits, hyaline cytoplasmic globules) and immunohistochemistry aid in distinction from seminoma. Embryonal carcinomas may show, in addition to 'seminoma-like' foci, pseudoendodermal sinus-like structures, sieve-like patterns, endometrioid-like morphology and prominent zones of stratified columnar tumour cells. These may cause confusion with yolk sac tumour and teratoma, although careful attention to cytological features usually suffices for accurate diagnosis. Recent work has defined 'new' primary trophoblastic tumours, i.e., cystic trophoblastic tumour and epithelioid trophoblastic tumour. The newly termed 'spermatocytic tumour' occasionally consists mostly of a monotonous proliferation of intermediate-sized tumour cells with prominent nucleoli, thereby simulating either seminoma or embryonal carcinoma. Prostatic adenocarcinoma remains the most common tumour to metastasise to the testis and can cause confusion with rete carcinomas and primary germ cell tumours. Post-chemotherapy resections pose their own challenges. Effete tumour cells in areas of necrosis and prominent fibroxanthomatous reactions should not be interpreted as persistent, viable germ cell tumour. 'Fibrosis' often has atypical widely scattered spindle tumour cells in a densely collagenous background but does not merit additional treatment apart from excision. The marked cytological atypia that may occur in metastatic teratoma may be disconcerting but, again, the proper treatment is complete surgical excision rather than more chemotherapy. Glandular and sarcomatoid yolk sac tumours, which are almost exclusively seen after chemotherapy, resemble adenocarcinomas and sarcomas, respectively. Unlike de novo malignancies, they are mostly seen in sites expected for metastases. PMID- 29129334 TI - Calibration of groundwater vulnerability mapping using the generalized reduced gradient method. AB - Groundwater vulnerability assessment studies are essential in water resources management. Overlay-and-index methods such as DRASTIC are widely used for mapping of groundwater vulnerability, however, these methods mainly suffer from a subjective selection of model parameters. The objective of this study is to introduce a calibration procedure that results in a more accurate assessment of groundwater vulnerability. The improvement of the assessment is formulated as a parameter optimization problem using an objective function that is based on the correlation between actual groundwater contamination and vulnerability index values. The non-linear optimization problem is solved with the generalized reduced-gradient (GRG) method, which is numerical algorithm based optimization method. To demonstrate the applicability of the procedure, a vulnerability map for the Tahtali stream basin is calibrated using nitrate concentration data. The calibration procedure is easy to implement and aims the maximization of correlation between observed pollutant concentrations and groundwater vulnerability index values. The influence of each vulnerability parameter in the calculation of the vulnerability index is assessed by performing a single parameter sensitivity analysis. Results of the sensitivity analysis show that all factors are effective on the final vulnerability index. Calibration of the vulnerability map improves the correlation between index values and measured nitrate concentrations by 19%. The regression coefficient increases from 0.280 to 0.485. It is evident that the spatial distribution and the proportions of vulnerability class areas are significantly altered with the calibration process. Although the applicability of the calibration method is demonstrated on the DRASTIC model, the applicability of the approach is not specific to a certain model and can also be easily applied to other overlay-and-index methods. PMID- 29129335 TI - Military human performance optimization and injury prevention: Strategies for the 21st century warfighter. PMID- 29129337 TI - [Acute cataract and surgical complication in a type 1 diabetic]. PMID- 29129336 TI - [Cost of teaching cataract surgery in a public hospital]. AB - INTRODUCTION: The gold standard of cataract surgery, phacoemulsification is the most commonly performed surgical procedure in France. Surgical instruction often takes place in the operating room where residents and fellows perform real surgery, supervised by an experienced surgeon. The goals of this study were double: evaluate surgical times according to the person performing the surgery, in order to quantitate the cost incurred by teaching and compare complication rate between surgeons. METHODS: A retrospective single center study was performed at Simone-Veil Hospital, Eaubonne-Montmorency, France. Over a period of 13 consecutive weeks from January to March 2016, all patients who underwent phacoemulsification for cataract extraction were included. Patients were separated into three groups, according to the primary surgeon: group S for Senior was composed of two experienced surgeons who typically performed over 500 procedures per year; group A for assistant was composed of three residents who performed less than 500 procedures per year; 2 inexperienced interns constituted group I. Surgery duration was recorded by the OR nurse in minutes between the first incision and removal of the lid speculum. The cost of operating room time was estimated at seven euros per minute. The occurrence of complications was determined from the operative report. RESULTS: 408 cataract surgeries were performed during the study period, divided into 156 eyes in group S, 142 in group A and 110 surgeries in group I. The mean age at surgery was 74.1+/-9 years (39 95), comparable in the 3 groups. The operative time was significantly shorter in group S (11.7min) than in A (18.7min; P<0.001) and in I (18.8min; P<0.001). The complication rate was higher in group I than in group S (P=0.03). The average additional cost related to the lengthening of the teaching procedure was 49 euros for Group A and 49.7 euros for Group I. DISCUSSION: The hospital reimbursement for cataract surgery is higher in the public sector than in the private sector; it can absorb the cost of university training. CONCLUSION: Teaching cataract surgery entails an additional financial cost for the hospital. It is also responsible for a higher human cost due to a greater number of operative complications with interns. PMID- 29129338 TI - [The rise of "diets without": From therapeutics to fashions]. PMID- 29129339 TI - Update on the role of endovesical chemotherapy in nonmuscle-invasive bladder cancer. PMID- 29129341 TI - Erratum to 'Rifampicin Lipid-Polymer hybrid nanoparticles (LIPOMER) for enhanced Peyer's patch uptake' [International Journal of Pharmaceutics 532 (2017) 612 622]. PMID- 29129340 TI - Synchronous colorectal cancer and multiple myeloma with chest wall involvement: Is this a coincidence? AB - Multiple primary malignant neoplasms (MPMNs) are rare malignant neoplasms that simultaneously or successively occur in the same patient as 2 or more primary malignancies. Currently, an increasing number of cases are being reported. In general, MPMNs more commonly occur as 2 solid tumors or 2 hematological malignancies. Cases of MPMN that involve a solid tumor and a hematological malignancy are rare. Here, we report a case of synchronous colorectal cancer (CRC) and multiple myeloma (MM) with chest wall involvement. After reviewing the literature, we believe that there may be a distinct syndrome involving CRC and MM. The patient in our case study suffered refractory anemia following surgery and 2 cycles of chemotherapy. Initially, the anemia was considered to be a common manifestation of CRC in this patient. Interestingly, although he received a blood transfusion, his hemoglobin levels remained low. He later developed hematuria, proteinuria, multiple osteoporosis in the costal bones, and thrombocytopenia. These new symptoms drew our attention, and we considered a diagnosis of synchronous primary CRC and MM, with the anemia as a symptom of MM. Based on the results of a bone marrow aspirate, MM was confirmed. Therefore, when CRC is associated with refractory anemia, we should not only assume that anemia is a classical symptom of CRC, a result of chronic blood loss, nutritional deficiencies, or myelosuppression due to chemotherapy, but we should also consider that it may reflect the possibility of a coexisting hematologic malignancy. As the treatment of these 2 malignancies is different, early diagnosis and treatment based on definitive diagnosis as early as possible will be beneficial to overall prognosis. PMID- 29129342 TI - Stature estimation using measurements of the cranium for populations in the United States. AB - Stature estimation is an important component of the biological profile. Human crania are sometimes recovered in the absence of other skeletal material in forensic casework, and stature estimation equations using cranial measurements have not been developed for populations in the United States. Both simple and multiple regression equations for estimating stature were developed from standard cranial measurements taken from both a cranial CT dataset and the Forensic Data Bank, and the resulting equations were tested using a separate dataset. A weak to moderate correlation with stature was found for some of the measurements tested. Tests of the sex- and ancestry-specific equations and pooled sex equations produced accurate estimated stature ranges for most of the individuals in the test dataset, but large 95% confidence intervals (+/-14-16cm) for these equations can produce only an imprecise estimated stature range for an unidentified individual. Pooled ancestry equations also produced accurate estimated stature ranges for many of the individuals in the test dataset, but with even larger 95% confidence intervals (+/-18-20cm). The results of this study indicate that stature can be estimated using cranial measurements, but the resulting 95% confidence intervals produce stature ranges that are too broad to use in most forensic casework. PMID- 29129343 TI - Prognostic Value of Hyperlactatemia and Lactate Clearance After Mitral Valve Surgery. AB - OBJECTIVES: Blood lactate is frequently used to guide management in critically ill patients. In patients undergoing mitral valve surgery, an elevated lactate level is frequently observed; however, overall mortality is low. The authors hypothesized that hyperlactemia is not a useful predictor of poor outcomes in this patient population. The main aim of this study was to explore how blood lactate level and lactate clearance are associated with 30-day mortality and major adverse events in patients undergoing mitral valve surgery. DESIGN: This was a retrospective database review. Logistic regression analysis was performed to assess the associations of perioperative factors with blood lactate in the intensive care unit (ICU). SETTING: Tertiary-care teaching hospital. PARTICIPANTS: The study comprised 917 patients undergoing mitral valve surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The majority of patients (71.8%) had elevated blood lactate >=2 mmol/L on ICU admission; however, within 24 hours, 85.1% of all patients had normal lactate values. Overall 30-day mortality was 2.29% (n = 21). The combination of lactate >=7 mmol/L on ICU admission and a persistent elevated blood lactate level 24 hours after ICU admission provides an excellent prediction of 30-day mortality (C statistic = 0.85). However, even a significantly elevated lactate level on ICU admission was well-tolerated in the majority of patients as long as lactate values normalized within 24 hours. Male sex, longer cardiopulmonary bypass time, blood transfusion in the ICU, and an elevated blood lactate level on ICU admission and 12 hours after ICU admission all were independent risk factors of clearance failure. CONCLUSIONS: An elevated blood lactate level is common after mitral valve surgery and is well-tolerated in the majority of patients. Adding lactate clearance improved the predictive value of the blood lactate level. PMID- 29129344 TI - Transpharyngeal Ultrasonography of Neck Vessels During Antegrade Cerebral Perfusion in a Neonate. PMID- 29129345 TI - Defining Value-Based Care in Cardiac and Vascular Anesthesiology: The Past, Present, and Future of Perioperative Cardiovascular Care. AB - Health care reimbursement models are transitioning from volume-based to value based models. Value-based models focus on patient outcomes both during the hospital admission and postdischarge. These models place emphasis on cost, quality of care, and coordination of multidisciplinary services. Perioperative physicians are challenged to evaluate traditional practices to ensure coordinated, cost-effective, and evidence-based care. With the Centers for Medicare and Medicaid Services planned introduction of bundled payments for coronary artery bypass graft surgery, cardiovascular anesthesiologists are financially responsible for postdischarge outcomes. In order to meet these patient outcomes, multidisciplinary care pathways must be designed, implemented, and sustained, a process that is challenging at best. This review (1) provides a historical perspective of health care reimbursement; (2) defines value as it pertains to quality, service, and cost; (3) reviews the history of value-based care for cardiac surgery; (4) describes the drive toward optimization for vascular surgery patients; and (5) discusses how programs like Enhanced Recovery After Surgery assist with the delivery of value-based care. PMID- 29129346 TI - Bleeding Complications Associated With Percutaneous Tracheostomy Insertion in Patients Supported With Venovenous Extracorporeal Membrane Oxygen Support: A 10 Year Institutional Experience. AB - OBJECTIVES: To evaluate the bleeding complications associated with percutaneous tracheostomy while a patient is receiving venovenous extracorporeal membrane oxygen (VV ECMO) support. DESIGN: Retrospective, observational analysis. SETTING: Single-center, tertiary, academic institution. PARTICIPANTS: All consecutive patients on VV ECMO over a 10 year-period undergoing percutaneous tracheostomy. INTERVENTIONS: Percutaneous tracheostomy. MEASUREMENTS AND MAIN RESULTS: Fifty percutaneous tracheostomies were performed in patients requiring VV ECMO support over the 10-year period. The authors observed a 40% incidence of bleeding, with 32% of these incidences characterized as minor (self-limiting, localized stomal ooze) and 8% characterized as significant (necessitating surgical control and frequent packing or accompanied by a decrease in hemoglobin >20%). CONCLUSIONS: Bleeding is associated with percutaneous tracheostomy and is self-limiting in the majority of patients. PMID- 29129347 TI - International Society for the Study of Vascular Anomalies Classification of Soft Tissue Vascular Anomalies: Survey-Based Assessment of Musculoskeletal Radiologists' Use in Clinical Practice. AB - AIM: There is controversy regarding the diagnosis and classification of vascular anomalies (VA). As torso and extremities are the second most common body part for presentation of VAs, musculoskeletal (MSK) radiologists play a central role in VA classification. The purpose of this study was to evaluate the awareness and clinical use of the International Society for the Study of Vascular Anomalies (ISSVA) classification by MSK radiologists. MATERIALS AND METHODS: A Web-based survey was designed and electronically sent to Society of Skeletal Radiology (SSR) members, with 3 questions on demographics and 7 questions on ISSVA classification use and knowledge. The Z-test for binomial proportions is used to assess for statistical significance between subgroups. RESULTS: The response rate was 12% (130 of 1091), comprised of 64% (83 of 130) academic and 36% (47 of 130) nonacademic MSK radiologists. VAs accounted for only a small (0%-5%) proportion of clinical practice in the majority 92% (119 of 130). Only 17% (22 of 130) of MSK radiologists used the ISSVA classification in practice. Of all respondents, 74% (94 of 127) considered hemangioma a type of vascular malformation (VM). There was no significant difference in the response characteristics between academic and nonacademic radiologists. A greater proportion of MSK radiologists with >5 years' experience provided responses that were discordant with the ISSVA classification compared with less experienced radiologists (0-5 years) in diagnosing hemangiomas in adult patients (P = 0.02), and using the presence of phleboliths to diagnose hemangiomas (P = 0.004). CONCLUSION: Our survey results indicate a lack of familiarity with the ISSVA classification by the MSK radiology community. PMID- 29129348 TI - Performance of the Tinnitus Functional Index as a diagnostic instrument in a UK clinical population. AB - OBJECTIVES: The Tinnitus Functional Index (TFI) has been optimised as a diagnostic tool for quantifying the functional impact of tinnitus in US veteran and civilian groups. However, the TFI has not been fully evaluated for use in other English-speaking clinical populations despite its increasingly popular uptake. Here, a prospective multi-site longitudinal validation study was conducted to evaluate psychometric properties relevant to the UK clinical population. Guided by quality criteria for the measurement properties of health related questionnaires, we specifically evaluated three diagnostic properties relating to the degree to which the TFI (i) covers the eight dimensions proposed to be important for diagnosis, (ii) reliably distinguishes individual differences in severity of tinnitus, and (iii) reliably measures the functional impact of tinnitus. We also examine whether clinically meaningful interpretations of the scores can be produced for the UK population. METHODS: Twelve National Health Service audiology clinics across the UK recruited 255 tinnitus patients to complete questionnaires at four time-intervals, from initial clinical assessment and then over a nine-month period. Patients completed the TFI, the Tinnitus Handicap Inventory (THI), tinnitus case history questions, a Global rating of Perceived Problem with tinnitus and a Clinical Global Impression of perceived change in tinnitus. Baseline TFI data were used to examine the factor structure, construct validity and interpretability of the TFI. Follow-up TFI data were used to examine reliability. RESULTS: Confirmatory factor analysis suggested that of the eight subscales (factors) initially established for the TFI, the 'Auditory' subscale did not contribute to the overall construct 'functional impact of tinnitus', and a modified seven-factor model (TFI-22) better fit the variance in the patient scores. Both the global 25-item TFI and the global TFI-22 scores showed exceptionally high internal consistency (alpha >= 0.95), high construct validity with the THI (r = 0.80) and high test-retest reliability (ICC = 0.87). Test-retest agreement however was only deemed to be borderline acceptable (89%). Receiver Operator Characteristic analysis indicated the 25-item TFI and TFI-22 has excellent ability to distinguish between different levels of impact (Area under the curve > 0.7). CONCLUSION: The TFI was confirmed to cover multiple symptom domains, measuring a multi-domain construct of tinnitus, and satisfies a range of psychometric requirements for a good clinical measure, including having excellent reliability, stability over time and sensitivity to individual differences in tinnitus severity. However, a modified seven-factor structure without the Auditory subscale (TFI-22) is recommended for calculating a global composite score for UK patients. Using patients' experience and Receiver Operator Characteristic analysis, a grading system was presented which identifies the distinct grades of tinnitus impact in the UK clinical population that is broadly comparable to the US-based system. PMID- 29129349 TI - Electrical and mechanical alternans during ventricular tachycardia with moderate chronic heart failure. AB - A chronic heart failure (CHF) rat underwent epicardial programmed electrical stimulation (PES). Ventricular tachycardia (VT) developed during PES. Mechanical alternans was noted despite fixed tachycardia cycle length. Anti-tachycardia pacing attempts initiated a second VT that generated pulse intermittently and then degenerated into pulseless VT with electrical alternans.To our knowledge electrical and mechanical alternans have not been recorded in animal models of CHF during VT. The distinct events of mechanical alternans and electrical alternans may be indicative of progressively worsened calcium handling in the compromised cardiomyocytes.Although ion channel differences between rodents and humans exist, this work attempts to demonstrate this rat model's usefulness in understanding cardiac electrophysiology in CHF. PMID- 29129350 TI - Evaluation of ECG algorithms designed to improve detect of transient myocardial ischemia to minimize false alarms in patients with suspected acute coronary syndrome. AB - BACKGROUND: Patients hospitalized for suspected acute coronary syndrome (ACS) are at risk for transient myocardial ischemia. During the "rule-out" phase, continuous ECG ST-segment monitoring can identify transient myocardial ischemia, even when asymptomatic. However, current ST-segment monitoring software is vastly underutilized due to false positive alarms, with resultant alarm fatigue. Current ST algorithms may contribute to alarm fatigue because; (1) they are not designed with a delay (minutes), rather alarm to brief spikes (i.e., turning, heart rate changes), and (2) alarm to changes in a single ECG lead, rather than contiguous leads. PURPOSE: This study was designed to determine sensitivity, and specificity, of ST algorithms when accounting for; ST magnitude (100MUV vs 200MUV), duration, and changes in contiguous ECG leads (i.e., aVL, I, - aVR, II, aVF, III; V1, V2, V3, V4, V5, V6, V6, I). METHODS: This was a secondary analysis from the COMPARE Study, which assessed occurrence rates for transient myocardial ischemia in hospitalized patients with suspected ACS using 12-lead Holter. Transient myocardial ischemia was identified from Holter using >100MUV ST-segment ? or ?, in >1 ECG lead, >1min. Algorithms tested against Holter transient myocardial ischemia were done using the University of California San Francisco (UCSF) ECG algorithm and included: (1)100MUV vs 200MUV any lead during a 5-min ST average; (2)100MUV vs 200MUV any lead >5min, (3) 100MUV vs 200MUV any lead during a 5-min ST average in contiguous leads, and (4) 100MUV vs 200MUV>5min in contiguous leads (Table below). RESULTS: In 361 patients; mean age 63+12years, 63% male, 56% prior CAD, 43 (11%) had transient myocardial ischemia. Of the 43 patients with transient myocardial ischemia, 17 (40%) had ST-segment elevation events, and 26 (60%) ST-segment depression events. A higher proportion of patients with ST segment depression has missed ischemic events. Table shows sensitivity and specificity for the four algorithms tested. CONCLUSIONS: Sensitivity was highly variable, due to the ST threshold selected, with the 100MUV measurement point being superior to the 200MUV amplitude threshold. Of all the algorithms tested, there was moderate sensitivity and specificity (70% and 68%) using the 100MUV ST-segment threshold, integrated ST-segment changes in contiguous leads during a 5-min average. PMID- 29129352 TI - Pediatric Cardiovascular Morbidity of the Early Term Newborn. AB - OBJECTIVE: To determine whether early term delivery (at 370/7-386/7 weeks of gestation) is associated with long-term pediatric cardiovascular morbidity of the offspring. STUDY DESIGN: A population-based cohort analysis was performed including all term deliveries occurring between 1991 and 2014 at a single tertiary medical center. Gestational age at delivery was subdivided into early term (370/7-386/7), full term (390/7-406/7), late term (410/7-416/7) and post term (>=420/7) delivery. Hospitalizations of children up to the age of 18 years involving cardiovascular morbidity were evaluated, including structural valvular disease, hypertension, arrhythmias, rheumatic fever, ischemic heart disease, pulmonary heart disease, perimyoendocarditis, congestive heart failure, and others. Kaplan-Meier survival curves were used to compare cumulative hospitalization incidence between groups. A multivariable Weibull parametric model was used to control for confounders. RESULTS: During the study period, 223 242 term singleton deliveries met the inclusion criteria. Of them, 24% (n = 53 501) occurred at early term. Hospitalizations involving cardiovascular morbidity were significantly more common in children delivered at early term (0.7%) as compared with those born at full (0.6%), late (0.6%), or post term (0.5%; P = .01). The survival curve demonstrated a significantly higher cumulative incidence of cardiovascular-related hospitalizations in the early term group (log-rank P <.001). In the Weibull model, early term delivery was found to be an independent risk factor for cardiovascular-related hospitalization as compared with full term delivery (adjusted HR, 1.16; 95% CI, 1.01-1.32; P = .02). CONCLUSION: Early term delivery is independently associated with pediatric cardiovascular morbidity of the offspring as compared with offspring born at full term. PMID- 29129351 TI - Is Serum Methylmalonic Acid a Reliable Biomarker of Vitamin B12 Status in Children with Short Bowel Syndrome: A Case Series. AB - We describe 3 patients with short bowel syndrome who had persistently elevated serum methylmalonic acid (MMA) levels while being treated for vitamin B12 deficiency. Following treatment for presumed small bowel bacterial overgrowth, MMA levels normalized. Among patients with short bowel syndrome, MMA levels may have limited specificity for vitamin B12 deficiency. PMID- 29129353 TI - Impact of lymph node dissection at the time of radical nephrectomy with tumor thrombectomy on oncological outcomes: Results from the International Renal Cell Carcinoma-Venous Thrombus Consortium (IRCC-VTC). AB - OBJECTIVES: To study the effect of lymph node dissection (LND) at the time of nephrectomy and tumor thrombectomy on oncological outcomes in patients with renal cell carcinoma (RCC) and tumor thrombus. PATIENTS AND METHODS: The records of 1,978 patients with RCC and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1985 to 2014 at 24 centers were analyzed. None of the patients had distant metastases. Extent and pathologic results of LND were compared with respect to cancer-specific survival (CSS). Multivariable Cox regression models were used to quantify the effect of multiple covariates. RESULTS: LND was performed in 1,026 patients. In multivariable analysis, the presence of LN metastasis, the number of positive LNs, and LN density were independently associated with cancer-specific mortality (CSM). Clinical node negative (cN-) disease was documented in 573 patients, 447 of them underwent LND with 43 cN- patients (9.6%) revealing positive LNs at pathology. LN positive cN- patients showed significantly better CSS when compared to LN positive cN+ patients. In multivariable analysis, positive cN status in LN positive patients was a significant predictor of CSM (HR, 2.923; P = 0.015). CONCLUSIONS: The number of positive nodes harvested during LND and LN density was strong prognostic indicators of CSS, while number of removed LNs did not have a significant effect on CSS. The rate of pN1 patients among clinically node negative patients was relatively high, and LND in these patients suggested a survival benefit. However, only a randomized trial can determine the absolute benefit of LND in this setting. PMID- 29129354 TI - Surgical management and outcomes of patients with bone metastases in germ cell tumors: A case series. AB - OBJECTIVE: To report perioperative and oncological outcomes of patients with nodal and bone involvement treated with postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) and simultaneous bone resection (BR). PATIENTS AND METHODS: Between 2008 and 2016, 14 consecutive unselected TC patients with nodal and bone involvement underwent PC-RPLND and BR. Surgery was performed together with orthopedic surgeons. Standard PC-RPLNDs were performed in 4 patients. Bilateral template PC-RPLND was carried out in 10 patients. Complete BR combined with spacer implantation (XPand Cage) and posterior stabilization was performed in 6 patients. Instead, 8 patients were submitted to partial BR. Perioperative outcomes consisted of operative time, blood loss, length of hospital stay, and complications. Disease recurrence and mortality were registered. RESULTS: Mean operative time, blood loss, and length of hospital stay were 295 minutes, 3.7, l, and 13 days. Additional oncological surgery was performed on 5 patients. Overall, 9 patients had adjunctive surgeries or intraoperative complications. Pathologic report consisted of teratoma in 6, cancer in 5, necrosis in 3 patients. Overall, 2, 5, and 1 patients had Clavien I, II, and IIIA complications, respectively. No perioperative mortality was recorded. Disease recurrence and death occurred in 8 and 7 patients. CONCLUSIONS: PC-RPLND and BR is a safe, feasible, and challenging procedure. Availability of an orthopedic surgeon and stabilization of the spine are mandatory. Complete BR has therapeutic impact on patients harboring teratoma, partial BR seems to be beneficial in patients with necrosis. Patients with vital tumor will relapse irrespectively of the BR approach. PMID- 29129355 TI - A metagenomic approach to dissect the genetic composition of enterotypes in Han Chinese and two Muslim groups. AB - Distinct enterotypes have been observed in the human gut but little is known about the genetic basis of the microbiome. Moreover, it is not clear how many genetic differences exist between enterotypes within or between populations. In this study, both the 16S rRNA gene and the metagenomes of the gut microbiota were sequenced from 48 Han Chinese, 48 Kazaks, and 96 Uyghurs, and taxonomies were assigned after de novo assembly. Single nucleotide polymorphisms were also identified by referring to data from the Human Microbiome Project. Systematic analysis of the gut communities in terms of their abundance and genetic composition was also performed, together with a genome-wide association study of the host genomes. The gut microbiota of 192 subjects was clearly classified into two enterotypes (Bacteroides and Prevotella). Interestingly, both enterotypes showed a clear genetic differentiation in terms of their functional catalogue of genes, especially for genes involved in amino acid and carbohydrate metabolism. In addition, several differentiated genera and genes were found among the three populations. Notably, one human variant (rs878394) was identified that showed significant association with the abundance of Prevotella, which is linked to LYPLAL1, a gene associated with body fat distribution, the waist-hip ratio and insulin sensitivity. Taken together, considerable differentiation was observed in gut microbes between enterotypes and among populations that was reflected in both the taxonomic composition and the genetic makeup of their functional genes, which could have been influenced by a variety of factors, such as diet and host genetic variation. PMID- 29129356 TI - Multilocus sequence analysis of homologous recombination and diversity in Arthrobacter sensu lato named species and glacier-inhabiting strains. AB - Members of the bacterial genus Arthrobacter sensu lato are Gram-positive actinomycetes distributed worldwide and found in numerous environments including soil, water, glacier ice, and sewage. Homologous recombination is an important driving force in bacterial evolution, but its impact on Arthrobacter sensu lato evolution is poorly understood. We evaluated homologous recombination among 41 Arthrobacter sensu lato named species, using multilocus sequence analysis (MLSA). A high level of recombination was found, associated with strong diversification and a reticulate evolutionary pattern of Arthrobacter sensu lato. We also collected a total of 31 cold-adapted Arthrobacter sensu lato strains from two cold glaciers located in northwest China and two temperate glaciers in southwest China, and evaluated their diversity and population structure by MLSA. The glacier strains displayed high diversity, but rates of recombination among the four glacier groups were quite low, indicating that barriers to homologous recombination formed in the past among the populations on different glaciers. Our findings indicate that historical glaciation events shaped the contemporary distributions, taxonomic relationships, and phylogeographic patterns of Arthrobacter sensu lato species on glaciers. PMID- 29129357 TI - In situ neoplasia in lymph node pathology. AB - In situ neoplasia represents the earliest form of malignant progression and is characterized by localization limited to the compartment corresponding to the cell of origin. Like other cancers, lymphoid neoplasms are considered to develop by multistep pathogenetic mechanisms. However, because of the circulating nature of lymphocytes, in situ lymphoid neoplasia may be difficult to identify histopathologically, and the compartment to which it is restricted may be physiological rather than strictly anatomical. The 2016 WHO classification of lymphoid neoplasms recognizes two in situ entities: in situ follicular neoplasia (ISFN) and in situ mantle cell neoplasia (ISMCN). This review summarizes the clinical features, histopathology, genetics, and differential diagnoses of these two entities, including distinction from both their overly malignant counterparts and a variety of reactive processes. PMID- 29129358 TI - Indocyanine green fluorescence-guided parathyroidectomy for primary hyperparathyroidism. AB - BACKGROUND: Our aim was to evaluate the ease and utility of using indocyanine green fluorescence angiography for intraoperative localization of the parathyroid glands. METHODS: Indocyanine green fluorescence angiography was performed during 60 parathyroidectomies for primary hyperparathyroidism during a 22-month period. Indocyanine green was administered intravenously to guide operative navigation using a commercially available fluorescence imaging system. Video files were graded by 3 independent surgeons for strength of enhancement using an adapted numeric scoring system. RESULTS: There were 46 (77%) female patients and 14 (23%) male patients whose ages ranged from 17 to 87 (average 60) years old. Of the 60 patients, 43 (71.6%) showed strong enhancement, 13 (21.7%) demonstrated mild to moderate vascular enhancement, and 4 (6.7%) exhibited little or no vascular enhancement. Of the 54 patients who had a preoperative sestamibi scan, a parathyroid adenoma was identified in 36, while 18 failed to localize. Of the 18 patients who failed to localize, all 18 patients (100%) had an adenoma that fluoresced on indocyanine green imaging. The operations were performed safely with minimal blood loss and short operative times. CONCLUSION: Indocyanine green angiography has the potential to assist surgeons in identifying parathyroid glands rapidly with minimal risk. PMID- 29129359 TI - Discussion. PMID- 29129360 TI - Less is more: cost-effectiveness analysis of surveillance strategies for small, nonfunctional, radiographically benign adrenal incidentalomas. AB - BACKGROUND: Guidelines for management of small adrenal incidentalomas are mutually inconsistent. No cost-effectiveness analysis has been performed to evaluate rigorously the relative merits of these strategies. METHODS: We constructed a decision-analytic model to evaluate surveillance strategies for <4cm, nonfunctional, benign-appearing adrenal incidentalomas. We evaluated 4 surveillance strategies: none, one-time, annual for 2 years, and annual for 5 years. Threshold and sensitivity analyses assessed robustness of the model. Costs were represented in 2016 US dollars and health outcomes in quality-adjusted life years. RESULTS: No surveillance has an expected net cost of $262 and 26.22 quality-adjusted life-years. One-time surveillance costs $158 more and adds 0.2 quality-adjusted life-years for an incremental cost-effectiveness ratio of $778/quality-adjusted life-years. The strategies involving more surveillance were dominated by the no surveillance and one-time surveillance strategies less effective and more expensive. Above a 0.7% prevalence of adrenocortical carcinoma, one-time surveillance was the most effective strategy. The results were robust to all sensitivity analyses of disease prevalence, sensitivity, and specificity of diagnostic assays and imaging as well as health state utility. CONCLUSION: For patients with a < 4cm, nonfunctional, benign-appearing mass, one time follow-up evaluation involving a noncontrast computed tomography and biochemical evaluation is cost-effective. Strategies requiring more surveillance accrue more cost without incremental benefit. PMID- 29129361 TI - Use of emergency surgery score to predict adverse outcomes after emergent laparotomies. PMID- 29129362 TI - Septic predictor index: A novel platform to identify thermally injured patients susceptible to sepsis. AB - BACKGROUND: During the past decades' sepsis has become the major cause of death in severely burned patients. Despite the importance of burn sepsis, its diagnosis, let alone its prediction, is difficult if not impossible. Recently, we have demonstrated burn patients have increased NLRP3 inflammasome activation in white adipose tissue. We aimed to delineate a unique immune profile that can be used to identify septic outcomes in severely burned patients. METHODS: Adult burn patients (n = 37) admitted to our burn center between June 2013-2015 were enrolled in this study. White adipose tissue from the site of injury and plasma were collected from severely burned patients (>20% total body surface area) within 96 hours after thermal injury, indiscriminate of sex or age. RESULTS: We found that patients exhibiting aberrantly high levels of proinflammatory interleukin-1beta and decreased macrophages at the site of injury are highly susceptible to development of sepsis. Septic patients also had increased anti inflammatory (interleukin-10, interleukin-1RA) cytokines in plasma. The Septic Predictor Index was generated as a quotient for the site of injury macrophage proportion and interleukin-1beta production. All patients who eventually develop sepsis had septic predictor index values >0.5. Septic patients with Septic Predictor Index values >1 all had sepsis onset within 12 days post-injury, whereas patients with Septic Predictor Index values between 0.5-1 all had later onset (>12 days). CONCLUSION: The Septic Predictor Index can determine sepsis onset accurately in thermally injured patients a priori and further enables surgeons to develop clinical studies and focused therapies specifically designed for septic cohorts. PMID- 29129363 TI - Decreasing intraoperative delays with meaningful use of the surgical safety checklist. AB - BACKGROUND: Purposeful completion (fidelity) more than simple adherence to items in the surgical safety checklist may improve operating room efficiency and patient safety. The purpose of this study was to evaluate intraoperative delays and correlate them with adherence and fidelity to the preincision surgical safety checklist. METHODS: Trained observers evaluated surgical safety checklist compliance during 3 observation periods from 2014-2016. Degree of adherence, checkpoint verbalization, fidelity, and meaningful completion were assessed. Delays were categorized as missing or malfunctioning equipment, staff error, and medication issues. Descriptive statistics, analysis of variance, logistic regression, chi2 and Student t test were used to analyze results. RESULTS: Of the 591 cases observed, 19% (n = 110) had at least one documented, intraoperative delay. The majority of delays were related to missing (50%) or malfunctioning (30%) equipment. Compared with cases without delays, cases with delays did not have a different mean degree of adherence (96.3 +/- 7.6% vs 95.6 +/- 5.8%, P = .36). Degree of fidelity was different between cases with and without delays (mean fidelity 77.1 +/- 14.9% vs 80.5 +/- 7.14.2%, P = .03). CONCLUSION: The preincision SSC is a communication tool offering an opportunity to discuss potential concerns and anticipated intraoperative needs. Fidelity rather than adherence to the surgical safety checklist seems to diminish intraoperative delays. PMID- 29129364 TI - Diabetes control decreases morbidity and mortality after carotid endarterectomy. AB - BACKGROUND: Single-institution studies have demonstrated a negative effect of diabetes mellitus on outcomes after carotid endarterectomy (CEA). The aim of this study was to compare patients with explicitly controlled and uncontrolled diabetes at the population level. METHODS: Using the National Inpatient Sample 2006-2013, we selected patients undergoing CEA. Rates of stroke, myocardial infarction (MI), and hospital mortality, as well as duration of stay and cost were compared among patients with uncontrolled diabetes (UCDM), well-controlled diabetes (WCDM), and those without diabetes (NDM). RESULTS: We reviewed data from 614,190 patients undergoing CEA. Patients with UCDM, compared with those with WCDM and NDM, had higher rates of stroke (3.27%, 0.93%, and 0.94%, respectively; P < .0001), MI (3.35%, 1.10%, and 0.87%, respectively; P < .0001), and higher hospital mortality (1.43%, 0.25%, and 0.27%, respectively; P < .0001). On multivariate analysis, patients with UCDM compared with WCDM were more likely to develop stroke (odds ratio[OR], 1.45; 95% confidence interval [CI], 1.23-1.71), and MI (OR, 2.26; 95% CI, 1.96-2.60) and were more likely to die (OR, 2.74; 95% CI, 2.19-3.42). Patients with WCDM compared with patients without diabetes had similar likelihoods of stroke (OR, 0.96; 95% CI, 0.90-1.02) and MI (OR, 1.04; 95% CI, 0.98-1.10) but were actually less likely to die (OR, 0.85; 95% CI, 0.76 0.95). CONCLUSION: Patients with uncontrolled diabetes had poorer outcomes after CEA than those with controlled diabetes, whose outcomes were comparable to if not better than individuals without diabetes. PMID- 29129365 TI - Surgical ethics and the future of surgical practice. PMID- 29129366 TI - Contralateral suppression of aldosterone at adrenal venous sampling predicts hyperkalemia following adrenalectomy for primary aldosteronism. AB - BACKGROUND: We aimed to determine whether a greater degree of contralateral suppression of aldosterone secretion at adrenal venous sampling predicted the development of postoperative hyperkalemia after unilateral adrenalectomy for primary aldosteronism. METHODS: A retrospective analysis of patients undergoing unilateral adrenalectomy for primary aldosteronism between 2004-2015 was performed. Clinical and biochemical parameters of patients who developed hyperkalemia (>=5.2 mmol/L) after unilateral adreanlectomy were compared with those who remained normokalemic. The contralateral suppression index was defined as the aldosterone-to-cortisol ratio from the nondominant adrenal vein divided by the aldosterone-to-cortisol ratio from the external iliac vein. RESULTS: Of 192 patients who met criteria for inclusion, 12 (6.3%) developed hyperkalemia (median serum potassium 5.5 mmol/L, range 5.2-6.2 mmol/L), with a median time to onset of 13.5 days (range 7-55 days). Five patients had transiently increased serum potassium concentrations that normalized spontaneously. Four patients received mineralocorticoid replacement therapy with fludrocortisone. On univariate analysis, hyperkalemic patients had slightly greater preoperative serum creatinine levels (1.2 vs 1.0 mg/dL, P = .01), higher postoperative creatinine (1.3 vs 1.0 mg/dL, P = .02), lesser median contralateral suppression index (0.14 vs 0.27, P = .03), and larger adenomas (1.9 vs 1.4 cm, P = .02). On multivariable logistic regression, the contralateral suppression index remained the only significant predictor of postoperative hyperkalemia (P = .04) with an optimal cut off of <0.47. CONCLUSION: Hyperkalemia after unilateral adrenalectomy for primary aldosteronism is uncommon and usually transient, but may require mineralocorticoid supplementation. Patients with a contralateral suppression index of <0.47 require meticulous follow-up and monitoring of serum potassium concentrations after unilateral adrenalectomy. PMID- 29129367 TI - Injection of bulking agents for laryngoplasty. PMID- 29129368 TI - Discussion. PMID- 29129369 TI - Organized atrial arrhythmias after cardiac transplantation: The overlooked value of the 12-lead electrocardiogram and cavotricuspid atrial flutter isthmus. PMID- 29129370 TI - Patient-reported symptoms at hospital discharge independently can predict death and hospitalization burden in advanced heart failure. PMID- 29129371 TI - Comment on "Catheter Ablation of Atrial Flutter following Orthotopic Heart Transplantation". PMID- 29129372 TI - Racial and ethnic disparities in lung transplant listing and waitlist outcomes. AB - BACKGROUND: The United States lung transplant registry data demonstrate differences in adult waitlist mortality by race/ethnicity. It is unknown whether these differences persist after risk adjustment or occur secondary to disparities in disease severity at the time of listing. METHODS: Adult lung transplant waitlist candidates between May 4, 2005 and March 5, 2015 were identified and compared by non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic and Asian race/ethnicity. A competing risk proportional hazards model was used to assess the association of race/ethnicity with the unadjusted and adjusted risk of waitlist death or removal for too sick, transplant, or removal for other reason. Disease illness severity at transplant listing was compared by race/ethnicity. RESULTS: There were 20,684 lung transplant candidates identified (82% NHW, 9% NHB, 6% Hispanic, 2% Asian and 1% other). Non-white candidates had higher unadjusted waitlist mortality, which was fully mitigated by adjusting for other risk factors (NHB: hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.93 to 1.18; Hispanic: HR 1.02, 95% CI 0.99 to 1.18; Asian: HR 0.90, 95% CI 0.70 to 1.16). Adjusted waitlist access to transplant was lower in non-white candidates (NHB: HR 0.88, 95% CI 0.83 to 0.94; Hispanic: HR 0.87, 95% CI 0.81 to 0.94; Asian: HR 0.83, 95% CI 0.73 to 0.96). NHW candidates with obstructive lung disease and pulmonary fibrosis were older with less illness severity at listing than non-white candidates. CONCLUSIONS: Within the current lung allocation system, there is no difference in risk-adjusted waitlist mortality by race/ethnicity, but non-white waitlist candidates have lower risk-adjusted access to lung transplant. Non-white candidates are generally younger with greater disease-specific illness severity at the time of lung transplant listing. PMID- 29129373 TI - Bioresorbable vascular scaffolds to treat coronary allograft vasculopathy: Insights from optical coherence tomography imaging. PMID- 29129374 TI - The Jarvik 2000 left ventricular assist device as a bridge to transplantation: Japanese Registry for Mechanically Assisted Circulatory Support. AB - BACKGROUND: The Jarvik 2000 ventricular assist device features a miniaturized intraventricular pump and an intermittent low-speed function that facilitates aortic valve opening. Despite its long history, little is known about the Jarvik device with regard to post-implantation outcomes. METHODS: Prospectively collected data from 13 participating hospitals were extracted from the Japanese Registry for Mechanically Assisted Circulatory Support database to analyze mortality, morbidity and de-novo aortic regurgitation. Data on 83 patients who underwent implantation of the Jarvik 2000 were reviewed. Median support duration was 191 (maximum 758) days. All recipients underwent implantation as a bridge to transplantation. RESULTS: Overall survival proportions at 1 and 2 years were 85.0% and 79.3%, respectively. Nine patients were in INTERMACS Level 1, and 28 patients were on mechanical circulatory support at the time of implantation. Causes of death included stroke, infection and device malfunction. Three patients had their device removed: 2 at the time of heart transplantation and 1 after recovery of the left ventricle. Common adverse events included major bleeding (27.7%), new infection (31.3%), stroke (20.5%) and device malfunction (20.5%). De novo aortic regurgitation was observed in 17 patients, 6 of whom developed at least moderate regurgitation during follow-up. CONCLUSIONS: Mid-term survival after Jarvik 2000 implantation was satisfactory and comparable to that reported by other national and international registries (INTERMACS and IMACS) for continuous-flow LVADs. De novo aortic regurgitation occurred despite the intermittent low-speed effect of this device, with some recipients experiencing progressive worsening of aortic regurgitation within 2 years post-implantation. PMID- 29129375 TI - Light Controls Protein Localization through Phytochrome-Mediated Alternative Promoter Selection. AB - Alternative promoter usage is a proteome-expanding mechanism that allows multiple pre-mRNAs to be transcribed from a single gene. The impact of this mechanism on the proteome and whether it is positively exploited in normal organismal responses remain unclear. We found that the plant photoreceptor phytochrome induces genome-wide changes in alternative promoter selection in Arabidopsis thaliana. Through this mechanism, protein isoforms with different N termini are produced that display light-dependent differences in localization. For instance, shade-grown plants accumulate a cytoplasmic isoform of glycerate kinase (GLYK), an essential photorespiration enzyme that was previously thought to localize exclusively to the chloroplast. Cytoplasmic GLYK constitutes a photorespiratory bypass that alleviates fluctuating light-induced photoinhibition. Therefore, phytochrome controls alternative promoter selection to modulate protein localization in response to changing light conditions. This study suggests that alternative promoter usage represents another ubiquitous layer of gene expression regulation in eukaryotes that contributes to diversification of the proteome. PMID- 29129377 TI - Kisspeptin as a biomarker for miscarriage: let's wait! PMID- 29129378 TI - Transvaginal natural-orifice transluminal endoscopic surgery: a new approach to myomectomy. AB - OBJECTIVE: To demonstrate a new approach for performing a myomectomy via transvaginal natural-orifice transluminal endoscopic surgery (vNOTES) as an alternative to laparoscopic myomectomy. DESIGN: Stepwise explanation of the technique with the use of original video footage. SETTING: Hospital. PATIENT(S): Eight patients were treated transvaginally for intramural, subserosal, and pedunculated myomas. INTERVENTION(S): In case of a posterior myoma, a 2.5-cm posterior colpotomy was made under general anesthesia. The pouch of Douglas was opened and a vNOTES port was inserted transvaginally. In case of an anterior myoma, an anterior colpotomy was made and the peritoneum was opened between the uterus and the bladder. A vNOTES port was inserted transvaginally. A pneumoperitoneum was created and the myoma was identified. With the use of conventional endoscopic instruments and a standard endoscope, all inserted through the vNOTES port, the uterine serosa was incised over the myoma and the myoma was resected. After achieving hemostasis the uterine scar was sutured in two layers with the use of a standard absorbable suture or an autolocking suture. An adhesion-preventing barrier was applied over the uterine scar. The myoma was removed through the colpotomy in an endobag. The vNOTES port was removed and the colpotomy was sutured with the use of an absorbable suture. The following data were collected: age, body mass index, number of previous abdominal procedures, myoma size, myoma weight, operating time, length of hospital stay, visual analog scale pain score, and serum hemoglobin drop. MAIN OUTCOME MEASURE(S): Successful minimally invasive myomectomy via vNOTES without abdominal scars. RESULT(S): All fibroids were successfully removed via vNOTES without complications or conversions to standard laparoscopy. No peri- or postoperative complications occurred. All patients were discharged within 24 hours, two of them within 12 hours. Anterior myomas can be resected through an anterior colpotomy and posterior myomas can be resected through a posterior colpotomy via the pouch of Douglas. In a low-resource setting, a self-constructed gloveport can be used and the uterine scar can be sutured via vNOTES with the use of a standard absorbable suture. In a first-world setting, the surgical time can be reduced with the use of an autolocking suture and a commercially available vNOTES port. CONCLUSION(S): Myoma types 0-2 can be resected hysteroscopically. Myoma types 3-7 are traditionally resected via laparotomy, laparoscopy, or transabdominal robotic surgery. vNOTES provides a new less invasive approach for the resection of myoma types 3-7. This first IDEAL stage 1 study confirms the feasibility of vNOTES myomectomy. It remains, however, a novel approach that requires further investigation. It can provide better cosmetic results and improved patient comfort. PMID- 29129376 TI - Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum. AB - Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission. PMID- 29129379 TI - Children with epilepsy against their healthy peers and those with headaches: Differences-similarities. AB - INTRODUCTION: Epilepsy, like most chronic diseases, affects bio-psycho-social functioning of children and adolescents. The aim of this work was to assess functioning of children with epilepsy compared with the group of healthy children and those with headaches carried out by children themselves and their mothers. MATERIAL AND METHODS: The study included 209 children with epilepsy and 173 children with headaches and 182 healthy students and their mothers. The research tool was Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQLTM 4.0) questionnaire. RESULTS: Quality of life of healthy children was rated the highest in all areas by both children and mothers. In younger and older children, difference was demonstrated between the assessment of the quality of life of healthy children and the ones with epilepsy or healthy children and the ones with and headaches in all areas of the PedsQLTM 4.0 questionnaire (p<0.05). Children with epilepsy had the most difficulties in subscale School Functioning in their own and their mothers' opinion. Healthy children and their mothers rated the subscale Emotional Functioning lowest. CONCLUSIONS: The functioning of children with epilepsy in the assessment of children and their mothers was the closest to the functioning of children with headaches. Quality of children's life assessment by children with epilepsy and by healthy children differed between the group of girls and boys and between older and younger children in all PedsQLTM 4.0 questionnaire areas. A medium response compatibility between children with epilepsy and their mothers was shown in individual questions. PMID- 29129380 TI - Evaluation of activities of daily living in patients with slowly progressive neuromuscular diseases. AB - Slowly progressive neuromuscular diseases include but are not limited to: facioscapulohumeral muscular dystrophy (FSHD) and limb-girdle muscular dystrophy (LGMD), hereditary motor and sensory neuropathy (HMSN) and spinal muscular atrophy type III (SMA3). The purpose of this study is to present an evaluation of basic and complex activities of daily living in patients suffering from these diseases. The study was conducted on a group of 58 Polish patients: 25 patients with HMSN, 19 with LGMD and FSHD and 14 with SMA3. The research instrument consisted of two parts: a specially designed questionnaire and Nottingham Extended ADL Index. The survey was voluntary, anonymous and self-administered. In our study the highest scores on the NEADL scale were achieved by HMSN patients, and the lowest by patients with SMA3. The research revealed statistically significant differences between all the groups in the total number of points achieved on NEADL scale. The study revealed that for most respondents the most difficult tasks were those in the area of 'mobility'. It is consistent with reports in the literature, which confirm that out of the slowly progressive neuromuscular diseases included in this research, SMA3 is a disease leading to the biggest limitations in performing the activities of everyday life. PMID- 29129381 TI - Cavernous hemangiomas of the third ventricle: Alternative surgical routes in two cases. AB - Cavernous Hemangiomas (CH) arise from any part of the cerebrum. Intraventricular lesions are rare and pure third ventricular localization is rare for CHs. Cavernomas of the ventricles may present with bleeding or signs associated with hydrocephalus. Radical excision is advocated for optimal management of cavernomas. In the present study, we present two cavernomas of the third ventricle which were completely excised via interhemispheric transcallosal transforaminal and Sylvian approaches. Radical excision should be the aim of the surgeon since reoperation for residual cavernomas is more commonly associated with complications and poor outcome. Total excision should be the goal of the treatment due to risk of rebleeding or regrowth. PMID- 29129382 TI - The Cryoelectron Microscopy Structure of the Type 1 Chaperone-Usher Pilus Rod. AB - Adhesive chaperone-usher pili are long, supramolecular protein fibers displayed on the surface of many bacterial pathogens. The type 1 and P pili of uropathogenic Escherichia coli (UPEC) play important roles during urinary tract colonization, mediating attachment to the bladder and kidney, respectively. The biomechanical properties of the helical pilus rods allow them to reversibly uncoil in response to flow-induced forces, allowing UPEC to retain a foothold in the unique and hostile environment of the urinary tract. Here we provide the 4.2 A resolution cryo-EM structure of the type 1 pilus rod, which together with the previous P pilus rod structure rationalizes the remarkable "spring-like" properties of chaperone-usher pili. The cryo-EM structure of the type 1 pilus rod differs in its helical parameters from the structure determined previously by a hybrid approach. We provide evidence that these structural differences originate from different quaternary structures of pili assembled in vivo and in vitro. PMID- 29129383 TI - The Structure of a Conserved Domain of TamB Reveals a Hydrophobic beta Taco Fold. AB - The translocation and assembly module (TAM) plays a role in the transport and insertion of proteins into the bacterial outer membrane. TamB, a component of this system spans the periplasmic space to engage with its partner protein TamA. Despite efforts to characterize the TAM, the structure and mechanism of action of TamB remained enigmatic. Here we present the crystal structure of TamB amino acids 963-1,138. This region represents half of the conserved DUF490 domain, the defining feature of TamB. TamB963-1138 consists of a concave, taco-shaped beta sheet with a hydrophobic interior. This beta taco structure is of dimensions capable of accommodating and shielding the hydrophobic side of an amphipathic beta strand, potentially allowing TamB to chaperone nascent membrane proteins from the aqueous environment. In addition, sequence analysis suggests that the structure of TamB963-1138 is shared by a large portion of TamB. This architecture could allow TamB to act as a conduit for membrane proteins. PMID- 29129384 TI - Radiofrequency ablation for hepatic oligometastatic pancreatic cancer: An analysis of safety and efficacy. AB - OBJECTIVES: This study was to evaluate the value of radiofrequency ablation (RFA) in the treatment of pancreatic cancer with synchronous liver oligometastasis. METHODS: 102 patients diagnosed with pancreatic cancer with synchronous liver oligometastasis undergoing RFA were recruited in this retrospective study between January 2012 and December 2015. Clinical efficacy was evaluated by computed tomography or magnetic resonance imaging 1 month later. All patients were treated with RFA and systemic chemotherapy based on NCCN guideline. RESULTS: The median follow-up was 21 months (range, 4.0-43.8 months). Of all patients, the 1-year survival rate was 47.1% and the median overall survival time was 11.40 months. Complete tumor ablation was achieved in 137 of 145 RFA sessions (94.5%), and in 244 of 254 tumors (96.1%). The incidence of common complications was 9.8%, and no severe complications were reported in any patient. Multivariate Cox regression analysis revealed that primary tumor in the head of the pancreas (HR = 1.868, 95% CI: 1.023-3.409; P = 0.042), maximum diameter of liver metastasis 3-5 cm (HR = 1.801, 95% CI: 1.081-3.001, P = 0.024) and neutrophil/lymphocyte ratio (NLR) >=2.5 (HR = 1.716, 95% CI: 1.047-2.811; P = 0.032) were independent predictors of poorer survival. CONCLUSION: RFA provides a minimally invasive and safe treatment for patients with pancreatic cancer with liver oligometastases. The clinical efficiency of RFA for hepatic oligometastatic pancreatic cancer was easily affected by the following factors: primary tumor location, maximum diameter of liver metastasis and NLR. These factors could be helpful for treatment decision and clinical trial design. PMID- 29129385 TI - Effect-directed fingerprints of 77 botanical extracts via a generic high performance thin-layer chromatography method combined with assays and mass spectrometry. AB - Quantitative effect-directed profiles of 77 industrially and freshly extracted botanicals like herbs, spices, vegetables and fruits, widely used as food ingredients, dietary supplements or traditional medicine, gave relevant information on their quality. It allows the assessment of food, dietary supplements and phytomedicines with regard to potential health-promoting activities. In contrary to sum parameter assays and targeted analysis, chromatography combined with effect-directed analysis allows fast assignment of single active compounds and evaluation of their contribution to the overall activity, originating from a food or botanical sample. High-performance thin layer chromatography was hyphenated with UV/Vis/FLD detection and effect-directed analysis, using the 2,2-diphenyl-1-picrylhydrazyl radical, Gram-negative Aliivibrio fischeri, Gram-positive Bacillus subtilis, acetylcholinesterase and tyrosinase assays. Bioactive compounds of interest were eluted using an elution head-based interface and further characterized by electrospray ionization (high resolution) mass spectrometry. This highly streamlined workflow resulted in a hyphenated HPTLC-UV/Vis/FLD-EDA-ESI+/ESI--(HR)MS method. The excellent quantification power of the method was shown on three compounds. For rosmarinic acid, contents ranged from 4.5mg/g (rooibos) to 32.6mg/g (rosemary), for kaempferol-3-glucoside from 0.6mg/g (caraway) to 4.4mg/g (wine leaves), and for quercetin-3-glucoside from 1.1mg/g (hawthorn leaves) to 17.7mg/g (thyme). Three mean repeatabilities (%RSD) over 18 quantifications for the three compounds were <=2.2% and the mean intermediate precision over three different days (%RSD, n=3) was 5.2%. PMID- 29129386 TI - Atrial fibrillation in patients on haemodialysis in Andalusia. Prevalence, clinical profile and therapeutic management. AB - : Atrial fibrillation (AF) represents an important social and healthcare problem. There is wide variability in the prevalence of this arrhythmia in studies analysing patients on haemodialysis (HD). OBJECTIVE: To investigate the prevalence, clinical profile and therapeutic management of patients with AF on HD in Andalusia. METHODS: We asked the public healthcare system of Andalusia to provide us with the number of patients who were being treated with HD. We asked attending nephrologists from all hospital and outpatient centres in 5 of the 8 Andalusian provinces to perform an electrocardiogram and to fill out a questionnaire on patients selected by simple random sampling. RESULTS: A total of 2,348 patients were being treated with HD in the 5provinces included in the study. The estimated sample size was 285 patients. We obtained an electrocardiogram and information from 252 patients (88.4%); mean age 65.3+/-16 years; 40.9% women. Sixty-three patients (25%) had AF. Of these, 36 (14.3%) had AF in the recorded ECG and in the rest it had been documented previously. In the multivariate analysis, older age (OR: 1.071; 95% CI: 1.036-1.107; P=0.000) and greater time on HD (OR: 1.009; 95% CI: 1.004-1.014; P=0.000) were independently associated with the presence of AF. Of the patients with AF, 41.3% were on anticoagulant treatment at the time of the study; and 41.2% were on antiplatelet agents. CONCLUSIONS: AF in dialysis units is an important finding. Establishing the risk-benefit ratio of anticoagulant treatment constitutes a real challenge. Well-designed clinical trials are pivotal in order to define the rational use of antithrombotic drugs. PMID- 29129387 TI - Socio-sanitary profile and information for living kidney donors and recipients in three Andalusian hospitals. AB - BACKGROUND: Information provided by health professionals to potential donors and recipients is essential for an autonomous and objective decision to make a living kidney donation. OBJECTIVES: To determine the characteristics of the information received by living kidney donors and recipients, to find out their socio-sanitary profile, their socio-demographics, financial and labour characteristics, health and the caregiving activity of these donors and recipients. METHODS: Observational, descriptive and cross-sectional study of the population of living kidney donors and recipients from the University Hospitals Puerta del Mar (Cadiz), Virgen del Rocio (Seville), and the University Hospital Complex of Granada, between 08/04/2014 and 08/06/2015. RESULTS AND CONCLUSIONS: According to the 40 living kidney donors and their 40 recipients surveyed, it is mainly nephrologists who make people aware and provide information about living kidney donation. Almost half of recipients require more information so the evaluation processes and pre-donation information should be updated. In general, the living kidney donor is female, aged 50, with primary/secondary education, lives with a partner and is related to the kidney recipient. Also, the living kidney donor is in paid employment, is overweight, perceives her health as very good or good, and does not smoke or drink alcohol. However, the typical living kidney recipient is male, aged 44 and has completed secondary school studies and vocational training. Furthermore, he does not work, perceives his health as good or regular, and he is an independent person for activities of daily living. PMID- 29129388 TI - IGA nephropathy - Are intravenous steroid pulses more effective than oral steroids in relapse prevention? AB - INTRODUCTION: It is recommended that IgA nephropathy (IgAN) is treated with steroids when the glomerular filtration rate (GFR) is >50ml/min and proteinuria >1g/day. Few studies have been performed comparing the two accepted steroid regimens (1g/day methylprednisolone pulses for 3 consecutive days at the beginning of months 1, 3 and 5, followed by 0.5mg/kg prednisolone on alternate days vs. 1mg/kg/day oral prednisolone). The aim of this study was to compare these two steroid regimens in IgAN treatment. METHODS: We selected 39 patients with biopsy-proven IgAN treated with steroids. Mean age at diagnosis was 37.5 years, 23 males (59%), baseline proteinuria (Uprot) was 2.1 g/day and median serum creatinine (SCr) was 1.5mg/dl. The mean follow-up period was 56 months. Twenty-five patients (64%) were treated with methylprednisolone pulses and 14 (36%) with oral steroids. RESULTS: Patients treated with steroid pulses presented lower relapse risk, defined as the reappearance of Uprot >1g/day and an Uprot increase of more than 50% (incidence rate ratio of 0.18, 95% CI 0.02-0.5). The Kaplan-Meier analysis showed longer relapse-free period (p=0.019). This result was confirmed in a multivariate analysis (p=0.026). However, we did not find other differences between the two steroid regimens. CONCLUSIONS: In comparison to oral steroids, the intravenous pulse regimen was associated with a lower risk of relapse in IgAN, a known independent negative predictor of renal survival. No differences were found regarding the other renal outcomes. PMID- 29129389 TI - Adjuvant therapy in patients with clear cell endometrial carcinoma: An analysis of the National Cancer Database. AB - OBJECTIVE: To assess the impact of adjuvant treatment, sociodemographic and tumor factors on the survival of patients with non-metastatic clear cell endometrial carcinoma (CCC). METHODS: 4298 patients treated from 1998 to 2011 with Stage I IVA CCC were identified within the National Cancer Database. FIGO 2009 staging system was used. Adjuvant groups included: hysterectomy (HYS); HYS+vaginal brachytherapy (VBT); HYS+chemotherapy (CT); HYS+external beam radiation therapy (EBRT); HYS+CT+EBRT; and HYS+CT+VBT. Univariable (UVA) and multivariable (MVA) frailty survival analyses were performed. RESULTS: On UVA, higher stage was associated with an increased risk of death. Compared to stage I-IA, the risk of death for stage IB was HR 1.75 (95% CI, 1.50-2.04; p<0.001), stage II was HR 1.77 (95% CI, 1.50-2.10; p<0.001), stage III-IIIB was HR 3.29 (95% CI, 2.86-3.80; p<0.001), stage IIIC-IIIC2 was HR 3.33 (95% CI: 2.94-3.77; p<0.001), and stage IVA was 8.59 (95% CI: 6.60-11.18; p<0.001). Other meaningful predictors of death included black race (p<0.001), public insurance (p<0.001), geographic education attainment (p=0.001), greater comorbidity score (p=0.001), increasing age (p<0.001), and increasing tumor size (p<0.001). After controlling for stage, insurance, race, education attainment, comorbidity score, age, and tumor size adjuvant treatment was not associated with decreased risk of mortality (p=0.26). CONCLUSION: Adjuvant therapy did not have a meaningful effect on survival in this sample from the National Cancer Center Database. Given the aggressive nature of the disease, clinical trials are required to determine the optimal adjuvant therapy in patients with non-metastatic CCC to improve clinical outcomes. PMID- 29129390 TI - Clinical significance of enlarged cardiophrenic lymph nodes in advanced ovarian cancer: Implications for survival. AB - OBJECTIVE: Advanced ovarian cancer (OC) commonly spreads to cardiophrenic lymph nodes (CPLNs), and is often visible on preoperative imaging. We investigated the prognostic significance of abnormal CPLNs in OC detected by preoperative CT scans using three different definitions. METHODS: Patients undergoing primary debulking surgery for stage IIIC/IV with residual disease (RD) <=1.0cm and a preoperative abdominopelvic CT scan available were included. Scans were reviewed by two blinded radiologists. We characterized abnormal CPLNs using three different definitions: i) qualitative assessment score (QAS); ii) nodes >7mm on the short axis; or, iii) nodes >=10mm on the short axis. We compared overall survival (OS) using the log-rank test. RESULTS: Of the 253 patients (mean age 64.0years), 136 had no gross residual disease (NGR) and 117 had RD. By the QAS definition, CPLNs were abnormal in 28 (11.1%) patients and removed in one case. Among patients with NGR, presence of abnormal CPLNs was associated with worse OS (median OS, 38.4 vs. 69.6months, p=0.08). We observed no association between abnormal CPLNs and OS among patients with RD (median OS, 37.5 vs. 28.5months, p=0.49). OS was significantly better in NGR group without abnormal CPLNs (median OS for NGR vs. RD, 69.6 vs. 28.5months, p<0.001); however, there was no difference in OS between patients with NGR versus RD when abnormal CPLNs were present (median OS, 38.4 vs. 37.5months, p=0.99). Lack of benefit from NGR when abnormal CPLNs were present was observed for all three definitions tested. CONCLUSION: Abnormal CPLNs are an important predictor of survival in advanced stage OC. Management of abnormal CPLNs should be considered in treatment planning when the goal is NGR. PMID- 29129391 TI - Centralization of ovarian cancer in the Netherlands: Hospital of diagnosis no longer determines patients' probability of undergoing surgery. AB - OBJECTIVE: Surgical care for advanced stage epithelial ovarian cancer (EOC) patients has been centralized in the Netherlands since 2012. We evaluated whether the likelihood for patients to undergo surgery depends on the hospital of initial diagnosis before and after centralization of surgical care. METHODS: Patients with EOC FIGO stage IIB-IV, diagnosed in the Netherlands between 2000 and 2015, were identified from the Netherlands Cancer Registry. Multilevel multivariate logistic regression was used to study the association between hospital of diagnosis and patients' likelihood of undergoing surgery in subsequent time periods. Furthermore, changes in overall survival were analyzed by multivariable Cox regression models. RESULTS: 15,314 EOC patients were selected from the NCR. Hospital of diagnosis was identified as a significant level for patients' likelihood of undergoing surgery in 2000-2005 (LR test p<0.001), as well as in 2006-2011 (LR test p=0.002) but not in 2012-2015 (LR test p=0.127). Patients who underwent surgery in 2012-2015 had a better survival when compared to 2006-2011 (HR 0.90(0.84-0.96)). CONCLUSION: This study shows that centralization of surgical care resolved the variation between hospitals in the probability to undergo cytoreductive surgery for patients with advanced EOC. Since centralization was established in 2012, the decision to operate patients seems solely attributable to patient and tumor characteristics. This supports the growing evidence in favor of centralizing (surgical) treatment for complex and heterogeneous diseases such as EOC. PMID- 29129392 TI - Targeting Obesity and Cachexia: Identification of the GFRAL Receptor-MIC-1/GDF15 Pathway. AB - Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) is a divergent transforming growth factor (TGFbeta) superfamily cytokine implicated in biological and disease processes including metabolism, cancer, and chronic inflammation, but whose receptor has remained elusive. Four laboratories have recently identified GFRAL, an orphan receptor of the glial-derived neurotrophic factor (GDNF) receptor alpha family, as the receptor for MIC 1/GDF15, signaling though the coreceptor Ret. These data identify a new systemic to central nervous system (CNS) circuit that regulates metabolism in response to stress and which could be targeted to treat both severe obesity and anorexia/cachexia syndrome. PMID- 29129393 TI - Disulfide-bond-mediated cross-linking of corneous beta-proteins in lepidosaurian epidermis. AB - Corneous beta-proteins (CBPs), formerly referred to as beta-keratins, are major protein components of the epidermis in lepidosaurian reptiles and are largely responsible for their material properties. These proteins have been suggested to form filaments of 3.4nm in thickness and to interact with themselves or with other proteins, including intermediate filament (IF) keratins. Here, we performed immunocytochemical labeling of CBPs in the epidermis of different lizards and snakes and investigated by immunoblotting analysis whether the reduction of disulfide bonds or protein oxidation affects the solubility and mobility of these CBPs. Immunogold labeling suggested that CBPs are partly co-localized with IF keratins in differentiating and mature beta-cells. The chemical reduction of epidermal proteins from lizard and snake epidermis increased the abundance of CBP immunoreactive bands in the size range of CBP monomers on Western blots. Conversely, in vitro oxidation of epidermal proteins reduced the abundance of putative CBP monomers. Some modifications in the IF-keratin range were also noted. These results strongly indicate that CBPs associate with IF-keratins and other proteins via disulfide bonds in the epidermis of lizards and snakes, which likely contributes to the resilience of the cornified beta- and alpha-layers of the lepidosaurian epidermis in live animals and after shedding. PMID- 29129394 TI - Angiotensin II receptor blockers suppress the release of stromal cell-derived factor-1alpha from infarcted myocardium in patients with acute myocardial infarction. AB - BACKGROUND: Although angiotensin II receptor blockers (ARBs) have been shown to have anti-inflammatory effects on infarcted myocardium in experimental models, little is known in humans. Stromal cell-derived factor-1alpha (SDF-1alpha), a pro inflammatory chemokine, is released from infarcted tissue in patients with acute myocardial infarction (AMI). This study examined whether ARBs suppress SDF-1alpha production in the infarcted lesion in patients with AMI. METHODS: SDF-1alpha levels were measured by enzyme-linked immunosorbent assays in plasma obtained from the aortic root (AO) and the anterior interventricular vein (AIV) in 50 patients with an anterior AMI. Measurement of SDF-1alpha levels and left ventriculography were repeated at discharge and 6 months after AMI. Patients were divided into 2 groups according to treatment with ARBs, which were administered at the discretion of the attending physician after admission. RESULTS: The AIV-AO gradient of SDF-1alpha, reflecting SDF-1alpha release from the infarcted myocardial region, decreased between the time of discharge and 6 months after AMI in patients taking an ARB. In contrast, the SDF-1alpha transcardiac gradient did not change in patients not taking an ARB. Among the clinical parameters tested, only the use of ARBs was significantly associated with percent changes in the SDF 1alpha transcardiac gradient from the time of discharge to 6 months after AMI in a linear regression analysis (r=-0.31, p=0.03). The SDF-1alpha transcardiac gradient 6 months after AMI was inversely correlated with the percent change in left ventricular (LV) ejection fraction (r=-0.52, p<0.01) and positively correlated with the percent change in LV end-diastolic volume index (r=0.57, p<0.01) and LV end-systolic volume index (r=0.54, p<0.01) during 6 months after AMI. CONCLUSIONS: ARB treatment suppressed SDF-1alpha release from the infarcted myocardial region, which was associated with improvement in LV dysfunction and adverse remodeling in AMI survivors. PMID- 29129395 TI - Echocardiographic nomograms for upper abdominal aorta Doppler systolic wave values and systo-diastolic diameters variations in children. AB - BACKGROUND: Abdominal aorta pulsatility and blood flow patterns are important diagnostic indicators in congenital heart disease. Reference values for these indexes are lacking. METHODS: We prospectively studied abdominal aorta pulsed wave Doppler systolic peak velocity, deceleration time, and wave duration, and two-dimensional vessel diameters in systole and diastole in healthy Caucasian children. Heteroscedasticity was accounted for by White or Breusch-Pagan test. Age, weight, height, heart rate (HR), and body surface area (BSA) were used as independent variables in different analyses to predict the mean values of each measurement. Structured Z-scores were then computed. RESULTS: In all, 853 subjects (age 0 days to 17 years; 45% females; BSA 0.12-2.12m2) were studied. The predicted values and Z-score boundaries are presented. Data are also presented as mean+/-2 SDs for a given BSA. CONCLUSIONS: We report paediatric echocardiographic nomograms for multiple proximal abdominal aorta parameters including pulsed-wave Doppler systolic velocities, deceleration time, wave duration, and two dimensional vessel diameter variations. Significant variations in these functional indexes with age were found that should be taken into account in clinical practice. At lower ages, steeper and shorter pulsed-wave Doppler peak velocity and limited pulsatility should be expected as physiologic findings. PMID- 29129396 TI - Sex difference between target levels of cholesterol-related parameters and post PCI long-term clinical outcomes: From the FU-Registry. AB - BACKGROUND: Since single lipid parameters are too weak to predict the risk of coronary artery disease, we examined whether the allocation of patients into four groups based on achievement of the target levels set by the Japan Atherosclerosis Guidelines at the time of percutaneous coronary intervention (PCI) would reveal different long-term (5 years) clinical outcomes in males and females. METHODS: The results of a 5-year follow-up study are summarized as FU-Registry, Long-Term Clinical Outcome Results. The subjects consisted of 1158 patients who underwent elective PCI. The male and female patients were separately allocated into four groups: (1) high-density lipoprotein cholesterol (HDL-C>=40mg/dl as well as low density lipoprotein-cholesterol (LDL-C)>=100mg/dl); (2) HDL-C>=40mg/dl as well as LDL-C<100mg/dl; (3) HDL-C<40mg/dl as well as LDL-C>=100mg/dl; (4) HDL-C<40mg/dl as well as LDL-C<100mg/dl, for a comparison of both patient as well as lesion characteristics and the endpoint of major adverse cardiac events (MACEs). RESULTS: Regarding lesion characteristics, significant differences (p<0.05) were detected in the usage rate of a drug-eluting stent (DES) as well as the bend, stent reference diameter, and stent minimum lumen diameter in females by ANOVA, and in severe calcification, the bend, and usage rate of DES (p<0.001) in males. In females, significant differences (p<0.05) were observed in MACEs and target lesion revascularization-PCI. In contrast, among males, the four groups had nearly equivalent outcomes. Uni- and multivariate analyses revealed that HDL-C as well as LDL-C in females were associated with MACEs [OR 3.29 (95% CI 1.05-8.57, p=0.04)], while no association was observed in male multivariate analysis. CONCLUSION: In female patients, HDL-C<40mg/dl and LDL-C>=100mg/dl were even more strongly related to MACEs, whereas the combination of LDL-C and HDL-C was not related to MACEs in male patients. PMID- 29129397 TI - Environmental baselines and reconstruction of Atlantic Water inflow in Bjornoyrenna, SW Barents Sea, since 1800 CE. AB - Metal concentrations, sediment properties and benthic foraminiferal assemblages were investigated in sediment cores in the SW Barents Sea, to reconstruct environmental baselines and natural variability of Atlantic Water inflow since 1800 CE. Metal concentrations correspond to no effect levels and do not influence the foraminifera. Increased Hg and Pb was linked to inflow of Atlantic Water. The data set is considered to reflect the pre-impacted environmental baseline and range in natural variability of the study area. The foraminiferal assemblages in the SW part of the study area showed warming and presence of Atlantic Water towards 1900 CE. The NE part of the region indicate presence of cold Artic Water influenced conditions. Between 1900 and 1980 CE, the SW region indicates reduced inflow of Atlantic Water. From 1980 CE towards the present the assemblages of the entire study area show warming of Atlantic Water and northward retreat of the Arctic Front. PMID- 29129398 TI - Genomic Markers in Prostate Cancer Decision Making. AB - CONTEXT: Although the widespread use of prostate-specific antigen (PSA) has led to an early detection of prostate cancer (PCa) and a reduction of metastatic disease at diagnosis, PSA remains one of the most controversial biomarkers due to its limited specificity. As part of emerging efforts to improve both detection and management decision making, a number of new genomic tools have recently been developed. OBJECTIVE: This review summarizes the ability of genomic biomarkers to recognize men at high risk of developing PCa, discriminate clinically insignificant and aggressive tumors, and facilitate the selection of therapies in patients with advanced disease. EVIDENCE ACQUISITION: A PubMed-based literature search was conducted up to May 2017. We selected the most recent and relevant original articles and clinical trials that have provided indispensable information to guide treatment decisions. EVIDENCE SYNTHESIS: Genome-wide association studies have identified several genetic polymorphisms and inherited variants associated with PCa susceptibility. Moreover, the urine-based assays SelectMDx, Mi-Prostate Score, and ExoDx have provided new insights into the identification of patients who may benefit from prostate biopsy. In men with previous negative pathological findings, Prostate Cancer Antigen 3 and ConfirmMDx predicted the outcome of subsequent biopsy. Commercially available tools (Decipher, Oncotype DX, and Prolaris) improved PCa risk stratification, identifying men at the highest risk of adverse outcome. Furthermore, other biomarkers could assist in treatment selection in castration-resistant PCa. AR-V7 expression predicts resistance to abiraterone/enzalutamide, while poly(ADP ribose) polymerase-1 inhibitor and platinum-based chemotherapy could be indicated in metastatic patients who are carriers of mutations in DNA mismatch repair genes. CONCLUSIONS: Introduction of genomic biomarkers has dramatically improved the detection, prognosis, and risk evaluation of PCa. Despite the progress made in discovering suitable biomarker candidates, few have been used in a clinical setting. Large-scale and multi-institutional studies are required to validate the efficacy and cost utility of these new technologies. PATIENT SUMMARY: Prostate cancer is a heterogeneous disease with a wide variability. Genomic biomarkers in combination with clinical and pathological variables are useful tools to reduce the number of unnecessary biopsies, stratify low-risk from high-risk tumors, and guide personalized treatment decisions. PMID- 29129399 TI - Re: Ken J. Kron, Alexander Murison, Stanley Zhou, et al. TMPRSS2-ERG Fusion Co opts Master Transcription Factors and Activates NOTCH Signaling in Primary Prostate Cancer. Nat Genet 2017;49:1336-45. PMID- 29129400 TI - Re: Woonyoung Choi, Andrea Ochoa, David J. McConkey, et al. Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset. Eur Urol 2017;72:354-65. PMID- 29129401 TI - Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria. AB - The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin. PMID- 29129402 TI - Hepatitis B core antigen based novel vaccine against porcine epidemic diarrhea virus. AB - Porcine epidemic diarrhea Virus (PEDV) is the causative agent of porcine epidemic diarrhea, which is a devastating viral disease and causes severe economic loss to the swine industry. Current vaccine options for PEDV include modified live viruses and killed live viruses. Though these vaccines have shown efficacy, some have side effects including viral shedding. This report details an E. coli based expression and purification process of multiple vaccine candidates for PEDV using Hepatitis B Core Antigen (HBcAg) as a backbone protein. Short linear peptide sequences from PEDV were inserted into the immunodominant region of HBcAg in a novel recombinant vaccine design against PEDV. These peptide sequences were successfully inserted individually as well as all together in a multivalent strategy. Each vaccine candidate was tested in vivo in an intranasal as well as an intraperitoneal administration. Although each candidate was able to elicit a strong immunogenic response specific for the inserted peptide sequences, only two out of five of the test candidates demonstrated an ability to elicit an immune response capable of virus neutralization when delivered via intraperitoneal administration in mice. PMID- 29129403 TI - The future of immunotherapy with individual allergens: Immunotherapy with fungi. PMID- 29129404 TI - New routes of allergen immunotherapy. PMID- 29129405 TI - Neurogenesis and morphological-neural alterations closely related to amyloid beta peptide (25-35)-induced memory impairment in male rats. AB - Memory impairment by the Amyloid-beta 25-35 (Abeta25-35) peptide in animal models has provided an understanding of the causes behind the similar deterioration that occurs in Alzheimer's disease. However, it is uncertain if a decrease of dendritic spines and neurogenesis conduces to cognitive impairment by an impairment in the retrieval of stored memory. The aim of this study was to evaluate the consequences of impairment on spatial memory caused by the administration of the Abeta25-35 peptide in the hippocampus, which is associated whit morphological changes and neurogenesis in the dentate gyrus (DG). The vehicle or Abeta25-35 peptide (0.1MUg/MUL) were bilaterally administered in the CA1 subfield of the rat hippocampus. The animals were tested for spatial learning and memory in the Morris Water Maze. In the day's 11, 18 and 32 after administration of the Abeta25-35 peptide were examined the morphological changes in the DG using a Golgi-Cox stain. In the day 32, the neurogenesis was evaluated by the immunoreactivity to 5-bromo-2'-deoxyuridine (BrdU; 100mg/kg, i.p.) that corresponding to cellular proliferation post damage, the neuronal specific nuclear protein (NeuN) and doublecortin (DCX). This study found a memory retrieval impairment occurring at day 17, a cognitive deficit which had increased significantly at day 31 after the administration of Abeta25-35 peptide. These results are related to morphological changes in the granular cells of the DG, such as a shorter dendritic length and a decrease in the number of dendritic spines. In neurogenesis, the total number of cells positive to BrdU, NeuN and DCX in the hippocampal granule cell layer was found to have declined in animals treated with Abeta25-35. The results suggest that the Abeta25-35 peptide impairs memory retrieval by decreasing the number of dendritic spines and altering neurogenesis in the DG. PMID- 29129407 TI - Finding a place for corifollitropin within the PIVET FSH dosing algorithms. AB - PIVET recombinant FSH (rFSH) dosing algorithms have been designed for rFSH injection pens, providing optimal pregnancy and live birth productivity rates whilst minimizing risk and occurrence of ovarian hyperstimulation syndrome (OHSS). Recently, long-acting recombinant gonadotrophin corifollitropin (Elonva) was approved for use in assisted reproduction, and welcomed by patients as the single injection allowed ovarian stimulation over 7 days without need for multiple injections. Consequently, another rFSH dosing algorithm was devised to incorporate Elonva, and these cycles were compared to standard rFSH agents, Gonal f and Puregon. Initiated Elonva cycles (n = 165) were compared with 972 cycles initiated with standard rFSH. Elonva replaced standard rFSH dosages across the 200-400 IU range, but provided equivalent oocyte retrieval numbers and live birth outcomes. Elonva is considered risky for women whose antral follicle count is >=20 follicles, and was inadvertently administered contra-protocol in 19 cycles with >=20 follicles. However, while oocyte retrieval numbers were higher, raising risk for OHSS, no actual cases ensued. Taken together, this indicated that Elonva was equivalent to standard rFSH stimulation, and consequently has been added to the rFSH algorithms for medium to lower antral follicle counts and represented by green colour coding in the existing PIVET algorithmic charts. PMID- 29129409 TI - [Fertility and deep infiltrating endometriosis]. AB - Deep infiltrating endometriosis is the most severe form of the disease, defined by infiltration beneath the peritoneum greater than 5mm. It affects several anatomical locations including the bladder, the vesico-uterine cul-de-sac, the torus uterinum, the uterosacral ligament, rectovaginal septum and the colon rectum. Deep infiltrating endometriosis is associated with infertility. Surgery performed for deep infiltrating endometriosis in the context of pain offers good pregnancy rates either spontaneously or after assisted reproductive technologies. The results are less favorable when digestive tract is involved. IVF performed in the context of deep infiltrating endometriosis allows very satisfactory results and does not entail risks of aggravation of the pathology. There is currently no clear evidence to support either IVF or surgery to manage infertility associated with deep infiltrating endometriosis, but patients should be informed, although a risk of severe complication exists, that surgery is the only way to increase the chances of spontaneous fertility. PMID- 29129408 TI - Efficiency of decolorization of different dyes using fungal biomass immobilized on different solid supports. AB - Different technologies may be used for decolorization of wastewater containing dyes. Among them, biological processes are the most promising because they seem to be environmentally safe. The aim of this study was to determine the efficiency of decolorization of two dyes belonging to different classes (azo and triphenylmethane dyes) by immobilized biomass of strains of fungi (Pleurotus ostreatus - BWPH, Gleophyllum odoratum - DCa and Polyporus picipes - RWP17). Different solid supports were tested for biomass immobilization. The best growth of fungal strains was observed on the washer, brush, grid and sawdust supports. Based on the results of dye adsorption, the brush and the washer were selected for further study. These solid supports adsorbed dyes at a negligible level, while the sawdust adsorbed 82.5% of brilliant green and 19.1% of Evans blue. Immobilization of biomass improved dye removal. Almost complete decolorization of diazo dye Evans blue was reached after 24h in samples of all strains immobilized on the washer. The process was slower when the brush was used for biomass immobilization. Comparable results were reached for brilliant green in samples with biomass of strains BWPH and RWP17. High decolorization effectiveness was reached in samples with dead fungal biomass. Intensive removal of the dyes by biomass immobilized on the washer corresponded to a significant decrease in phytotoxicity and a slight decrease in zootoxicity of the dye solutions. The best decolorization results as well as reduction in toxicity were observed for the strain P. picipes (RWP17). PMID- 29129410 TI - Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease. AB - Although iron is vital, its free form is likely to be involved in oxidation reduction reactions, leading to the formation of free radicals and oxidative stress. Living organisms have developed protein systems to transport free iron through the cell membranes and biological fluids and store it in a non-toxic and readily mobilizable form to avoid iron toxicity. Hepcidin plays a crucial role in maintaining iron homeostasis. Hepcidin expression is directly regulated by variations in iron intake and its repression leads to an increase in bioavailable serum iron level. However, in pathological situations, prolonged repression often leads to pathological iron overload. In this review, we describe the different molecular mechanisms responsible for the maintenance of iron metabolism and the consequences of iron overload. Indeed, genetic hemochromatosis and post transfusional siderosis are the two main conditions responsible for iron overload. Long-term iron overload is deleterious, and treatment relies on venesection therapy for genetic hemochromatosis and chelation therapy for iron overload resulting from multiple transfusions. PMID- 29129406 TI - Neuropeptide Y Y2 antagonist treated ovariectomized mice exhibit greater bone mineral density. AB - Osteoporosis, a disease characterized by progressive bone loss and increased risk of fracture, often results from menopausal loss of estrogen in women. Neuropeptide Y has been shown to negatively regulate bone formation, with amygdala specific deletion of the Y2 receptor resulting in increased bone mass in mice. In this study, ovariectomized (OVX) mice were injected once daily with JNJ 31020028, a brain penetrant Y2 receptor small molecule antagonist to determine the effects on bone formation. Antagonist treated mice had reduced weight and showed increased whole-body bone mineral density compared to vehicle-injected mice. Micro computerized tomography (micro-CT) demonstrated increased vertebral trabecular bone volume, connectivity density and trabecular thickness. Femoral micro-CT analysis revealed increased bone volume within trabecular regions and greater trabecular number, without significant difference in other parameters or within cortical regions. A decrease was seen in serum P1NP, a measure used to confirm positive treatment outcomes in bisphosphonate treated patients. C terminal telopeptide 1 (CTX-1), a blood biomarker of bone resorption, was decreased in treated animals. The higher bone mineral density observed following Y2 antagonist treatment, as determined by whole-body DEXA scanning, is indicative of either enhanced mineralization or reduced bone loss. Additionally, our findings that ex vivo treatment of bone marrow cells with the Y2 antagonist did not affect osteoblast and osteoclast formation suggests the inhibitor is not affecting these cells directly, and suggests a central role for compound action in this system. Our results support the involvement of Y2R signalling in bone metabolism and give credence to the hypothesis that selective pharmacological manipulation of Y2R may provide anabolic benefits for treating osteoporosis. PMID- 29129411 TI - [Oxacillin-induced DRESS syndrome]. PMID- 29129412 TI - Fatal acute liver failure induced by cyproterone acetate: A new case. PMID- 29129413 TI - [Rickets from vitamin D deficiency and family deficiency]. PMID- 29129414 TI - [Surgical management of deep infiltrating endometriosis with bowel involvement and urinary tract involvement]. AB - Endometriosis is a benign pathology that affects 3% of the general population and about 10% of women of reproductive age. Three anatomoclinical entities are described: peritoneal, ovarian (endometrioma) and deep endometriosis characterized by the infiltration of anatomical structures or organs beyond the peritoneum. Laparoscopic surgery should be performed, as this is associated with a reduction in postoperative complications, length of hospitalization and convalescence. Several surgical techniques allow the removal of deep endometriosis with colorectal involvement: rectal shaving, anterior discoid resection, segmental resection. Deep endometriosis surgery with colorectal involvement is a source of postoperative complications: anastomotic fistula, rectovaginal fistula, intestinal occlusion, digestive haemorrhage, urinary fistula, deep pelvic abscess. Involvement of the urinary tract by endometriosis affects approximately 1% of patients with endometriosis. PMID- 29129415 TI - [IVF and endometriosis, oocyte donation and fertility preservation]. AB - Endometriosis is a common condition, causing pain and infertility. In infertile woman with superficial peritoneal endometriosis and patent tubes, laparoscopy is recommended, followed by ovarian stimulation alone or in combination with intrauterine inseminations. In case of ovarian or deep endometriosis, the indications of surgery and assisted reproductive technologies remain to be defined precisely. In vitro fertilization is generally proposed after the failure of up to three inseminations, directly for ovarian or deep endometriosis, or in case of an associated factor of infertility, mainly male. Before ovarian stimulation in view to in vitro fertilization, a pretreatment by GnRH agonist for 2 to 6 months or combined contraceptive for 6 to 8 weeks would improve the pregnancy rate. Egg donation is effective in patients with advanced ovarian failure or lack of ovarian response to stimulation. Fertility preservation, especially by oocytes vitrified, must be proposed preventively to women with endometriosis at risk of ovarian failure, without close wish to be pregnant. PMID- 29129418 TI - How do we follow up our patients? Reporting outcomes without complete follow-up data renders us on the weak side. PMID- 29129417 TI - [Metronidazole-induced encephalopathy (MIE)]. PMID- 29129419 TI - Is it time to expand the indications for pulmonary embolectomy? PMID- 29129416 TI - Lung transplantation for mitomycin-induced pulmonary veno-occlusive disease. PMID- 29129421 TI - Gathering evidence on rare diseases: Anomalous aortic origin of a coronary artery. PMID- 29129420 TI - Surgical strategy for the treatment of aortoesophageal fistula. AB - OBJECTIVE: To present a surgical strategy for aortoesophageal fistula (AEF). METHODS: From October 1999 to May 2017, 27 patients with AEF were treated at Kobe University Hospital. After 9 patients with malignancies or fish bone penetration were excluded, 18 patients who had AEF secondary to aortic lesions were investigated. The mean age was 67.2 +/- 10.4 years, and the male/female ratio was 16:2. Twelve patients had a nondissection thoracic aneurysm, and 6 patients had a chronic aortic dissection. Six patients were in shock. Seven patients had a previous thoracic endovascular aortic repair (TEVAR) in the descending aorta, 2 patients had descending aorta replacement, 1 had hemiarch replacement, and 2 had total arch replacement. As the first treatment for AEF, 3 patients underwent TEVAR as destination therapy, 3 patients had a bridge TEVAR to open surgery, 1 patient had an extra-anatomical bypass from the ascending aorta to the abdominal aorta, and 11 patients had an in situ reconstruction of the descending aorta. The esophagus was resected in 16 patients, and an omental flap was installed in 16 patients. Additional procedures were extra-anatomical bypass in 2 patients and in situ reconstruction of the aorta in 3 patients. RESULTS: Hospital mortality was noted in 4 patients (22.2% persistent sepsis, n = 3: pneumonia, n = 1). However, since 2007, only 1 of 13 patients has died (pneumonia). Late death occurred in 5 patients, due to pneumonia, cerebral bleeding, diarrhea, sudden death, and persistent infection. Actuarial survival was 42.4 +/- 12.8% at 5 years and freedom from aorta-related death was 59.4 +/- 13.5% at 5 years. Nine patients achieved completed reconstruction of the esophagus 172 +/- 57 days after initial surgery. CONCLUSIONS: Although a comparative study was not performed, 1-stage surgery consisting of resection of an aneurysm and esophagus, in situ reconstruction of the descending aorta, and omental flap installation provided a better outcome in the treatment for AEF. Bridging TEVAR to the open surgery is a useful adjunct in patients with AEF with hemorrhagic shock. Later reconstruction of the esophagus can be performed in the survivors. PMID- 29129422 TI - Do not throw that sternal saw away yet.... PMID- 29129423 TI - The ABCs of autologous blood collection for ex vivo organ preservation. PMID- 29129424 TI - Laparoscopic ligation of cisterna chyli for refractory chylothorax: A case series and review of the literature. AB - OBJECTIVES: We describe an alternative surgical technique for the treatment of chylothorax in patients who have had failure of or are not candidates for transthoracic ligation or embolization by interventional radiology. METHODS: We describe our experience with laparoscopic ligation of the cisterna chyli in 3 such patients and compare our results with published literature. We used a 5-port approach as for foregut surgery. We retracted the liver, transected the gastrohepatic ligament, and retracted the stomach to the left. We exposed the right lateral aspect of the aorta at the level of the celiac trunk and clipped fatty tissue between the aorta and the right crus. We skeletonized the right crus and dissected from the right crus to the inferior vena cava. We then retracted the inferior vena cava laterally, exposed all soft tissue posteriorly, and identified the cisterna chyli posteromedially to the inferior vena cava. Finally, we ligated and clipped all fatty tissue between the right crus and the inferior vena cava. RESULTS: Success rate was 67%; 1 patient with idiopathic chylothorax did not have resolution and eventually died of multisystem organ failure. There were no procedure-related complications. CONCLUSIONS: Laparoscopic ligation of cisterna chyli is an available therapeutic option for patients with chylothorax unresponsive to medical management, embolization, and transthoracic ligation of the thoracic duct. Our series is comparable with other reports of transabdominal approach to chylothorax. PMID- 29129425 TI - Tissue adhesive innovations derived from the natural world. PMID- 29129426 TI - Editorial Comment. PMID- 29129427 TI - Author Reply. PMID- 29129428 TI - Traffic-related distribution of antimony in roadside soils. AB - Vehicular emissions have become one of the main source of pollution of urban soils; this highlights the need for more detailed research on various traffic related emissions and related distribution patterns. Since the banning of asbestos in the European Union, its substitution with antimony (Sb) in brake linings has led to increased inputs of this toxic metalloid to environmental compartments. The objective of this study was to provide detailed information about the spatial distribution patterns of Sb and to assess its mobility and bioavailability. Roadside soils along an arterial road (approx. 9000 vehicles per day) in Cologne (Germany) were studied along five transects, at four soil depths and at seven sampling points set at varying distances from the road (n = 140). For all samples, comprehensive soil characterization was performed and inverse aqua regia-extractable trace metal content was determined being pseudo-total contents. Furthermore, for one transect, also total Sb and a chemical sequential extraction procedure was applied (n = 28). Pseudo-total Sb for all transects decreased significantly with soil depth and distance from the road, reflecting a distribution pattern similar to that of other trace metals associated with brake lining emissions. Conversely, metals associated with exhaust emissions showed a convex distribution. The geochemical fractionation of Sb revealed the following trends: i) non-specifically sorbed Sb was <5%; ii) specifically sorbed Sb was only detected within 1 m distance from the road and decreased with depth; iii) Sb associated with poorly-crystalline Fe oxides decreased with distance from the road; and iv) content of Sb bounded to well-crystalline Fe oxides, and Sb present in the residual fraction remained relatively constant at each depth. Consequently, roadside soils appear to inhibit brake lining-related Sb contamination, with significant but rather low ecotoxicological potential for input into surface and groundwater. PMID- 29129429 TI - Serum concentrations of organochlorine compounds and predictors of exposure in children living in agricultural communities from South-Eastern Spain. AB - BACKGROUND: Information on exposure levels to organochlorine compounds (OCs) in child population is limited, despite their greater vulnerability to the adverse health effects of these chemicals. OBJECTIVE: To determine serum concentrations of 10 OCs (including organochlorine pesticides and polychlorinated biphenyls PCBs-) in children living in agricultural communities from Almeria (South-Eastern Spain), and to identify the main predictors of exposure related to socio-economic characteristics, diet and lifestyle. METHODS: A cross-sectional study was conducted on 133 children aged 6-11 years selected from public schools of the study area. OCs compounds were determined in serum samples by GC/ECD. Anthropometric measures were obtained during sample collection. Information on sociodemographic characteristics, parental occupation, residential history, lifestyle and frequency of food consumption, among other relevant factors, was obtained by questionnaires administered to the mothers. RESULTS: Geometric means of serum concentrations (ng/ml) were 0.11 for beta-hexachloro-cyclohexane (beta HCH), 0.09 for endosulfan, 0.20 for endosulfan-ether, 0.51 for hexachorobenzene (HCB), 0.08 for mirex, 0.06 for oxychlordane, 0.36 for p,p'-DDE, 0.20 for PCB 138, 0.36 for PCB 153, and 0.45 for PCB 180. Percentage of samples above the limit of detection (0.05 ppb) ranged from 32 (beta-HCH) to 100 (HCB). A high variability in OC levels depending on the compound was observed between our results and others found in similar studies carried out in children. Variables related to fish consumption were found to be the major dietary determinant of PCB 138, p,p'-DDE, endosulfan-alpha, beta-HCH, mirex and oxychlordane levels. CONCLUSIONS: Children participating in this study showed detectable levels of many OC, despite these compounds are no longer used. Their presence in children serum can be explained by their high lipophilicity and environmental persistence, leading to contamination of fatty food. In this line, fish consumption seemed to be the most relevant determinant of OC levels found in our study. PMID- 29129430 TI - Relationship of particulate matter and ozone with 3-nitrotyrosine in the atmosphere. AB - The prevalence of allergic diseases has increased in the past few decades. Bio aerosol proteins and their chemical modifications, such as 3-nitrotyrosine (3 NT), in the atmosphere have been attracting attention due to their promotive effects on allergies. 3-NT is generated from the amino acid, tyrosine, through a reaction with ozone (O3) and nitrogen dioxide (NO2). However, the underlying mechanisms have not yet been elucidated in detail. Therefore, we measured 3-NT and evaluated the relationships among 3-NT and various pollutants such as sulfur dioxide (SO2), NOx (NO + NO2), ozone (O3), PM7, total suspended particulate matter (TSP) containing proteins, humidity, and temperature. 3-NT positively correlated with O3, SO2, humidity, and temperature, and negatively correlated with NOx. A multiple regression analysis showed that 3-NT positively associated with O3, humidity, and PM7. O3 positively associated with 3-NT and PM7, and negatively associated with NOx and humidity. These results suggest that 3-NT is generated from PM proteins through a reaction with O3 under high humidity conditions, and that the measurement of 3-NT is important and useful for the research of O3. PMID- 29129431 TI - Ultra-rapid catalytic degradation of 4-nitrophenol with ionic liquid recoverable and reusable ibuprofen derived silver nanoparticles. AB - This study reports a one-pot and eco-friendly method for the synthesis of spherical ibuprofen derived silver nanoparticles (IBU-AgNPs) in aqueous media using ibuprofen analgesics drug as capping as well as reducing agent. Formation of AgNPs occurred within a few min (less than 5 min) at room temperature without resorting to any harsh conditions and hazardous organic solvents. Synthesized AgNPs were characterized with common analytical techniques. Transmission electron microscope (TEM) images confirmed the formation of spherical particles having a size distribution in the range of 12.5 +/- 1.5 nm. Employment of IBU analgesic aided the control of better size distribution and prevented agglomeration of particles. Such AgNPs solution was highly stable for more than two months when stored at ambient temperature. The IBU-AgNPs solution showed excellent ultra rapid catalytic activity for the complete degradation of toxic 4-nitrophenol (4 NPh) into non-toxic 4-aminophenol (4-APh) within 40 s. AgNPs were recovered with the help of water insoluble-room temperature ionic liquid and reused with enhanced catalytic potential. This method provides a novel, rapid and economical alternative for the treatment of toxic organic pollutants to maintain water quality and environmental safety against water pollution. It is extendable for the control of other reducible contaminants in water as well. Furthermore, this catalytic activity for an effective degradation of organic toxins is expected to play a crucial role for achieving the Sustainable Development Goal 6 set by United Nations. PMID- 29129432 TI - Occurrence and human exposure to brominated and organophosphorus flame retardants via indoor dust in a Brazilian city. AB - Indoor dust is considered an important human exposure route to flame retardants (FRs), which has arised concern due the toxic properties of some of these substances. In this study, ten organophosphorus flame retardants (OPFRs), eight polybrominated diphenyl ethers (PBDEs) and four new brominated flame retardants (NBFRs) were determined in indoor dust from different places in Araraquara-SP (Brazil). The sampled places included houses, apartments, offices, primary schools and cars. The analysis of the sample extracts was performed by gas chromatography coupled to mass spectrometry and two ionization techniques were used (electron ionization - EI; electron capture negative ionization - ECNI). OPFRs were the most abundant compounds and tris(2-butoxyethyl) phosphate (TBOEP), tris(phenyl) phosphate (TPHP), tris(1,3-dichloroisopropyl) phosphate (TDCIPP) and tris(2-chloroisopropyl) phosphate (TCIPP) were present at the highest concentrations. Among the brominated FRs, the most ubiquitous compounds were BDE 209, bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP) and decabromodiphenyl ethane (DBDPE). Statistical analysis revealed that there were differences among dust typologies for TBOEP, TDCIPP, ethylhexyl diphenyl phosphate (EHDPHP), BDE 209, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB), BEH-TEBP and DBDPE, which were attributed to different construction materials in each particular environment and to the age of the buildings. The highest levels of brominated FRs were observed in offices, TBOEP was at high concentration in primary schools, and TDCIPP was at high concentration in cars. A preliminary risk assessment revealed that toddlers were exposed to TBOEP levels higher than the reference dose when considering the worst case scenario. The results obtained in this study showed for the first time that although Brazil does not regulate the use of FRs, these substances are present in indoor dust at levels similar to the observed in countries that have strict fire safety standards, and that humans are exposed to complex mixtures of these contaminants via indoor dust. PMID- 29129433 TI - Nanoparticulate-specific effects of silver on teleost cardiac contractility. AB - Silver nanoparticles (nAg), due to their biocidal properties, are common in medical applications and are used in more consumer products than any other engineered nanomaterial. This growing abundance, combined with their ability to translocate across the epithelium and bioaccumulate, suggests that internalized nAg may present a risk of toxicity to many organisms in the future. However, little experimentation has been devoted to cardiac responses to acute nAg exposure, even though nAg is known to disrupt ion channels even when ionic Ag+ does not. In this study, we examined the cardiac response to nAg exposure relative to a sham and an ionic AgNO3 control across cardiomyocyte survival and homeostasis, ventricular contractility, and intrinsic pacing rates of whole hearts. Our results suggest that nAg, but not Ag+ alone, inhibits force production by the myocardium, that Ag in any form disrupts normal pacing of cardiac contractions, and that these responses are likely not due to cytotoxicity. This evidence of nanoparticle-specific effects on physiology should encourage further research into nAg cardiotoxicity and other potential sublethal effects. PMID- 29129434 TI - Mutational Landscape of DDR2 Gene in Lung Squamous Cell Carcinoma Using Next generation Sequencing. AB - BACKGROUND: Lung cancer represents the leading cause of cancer-related death worldwide. Despite great advances in lung cancer management with the recent emergence of molecular targeted therapies for non-squamous non-small-cell lung cancer, no dramatic improvements have been achieved in lung squamous cell carcinoma (SCC). Mutations in discoidin domain receptor 2 (DDR2) gene were recently identified as promising molecular targets in this histology. The aim of this study is to describe the DDR2 mutational landscape of lung SCC and investigate the associated clinical factors. METHODS: Next-generation sequencing of the DDR2 gene was performed on 271 samples of lung SCC. Patients followed in our institution from January 2011 to August 2014 were retrospectively selected for data collection. Other driver gene alterations (EGFR, KRAS, BRAF, HER2, and PI3KCA) were analyzed using pyrosequencing. RESULTS: A total of 11 patients harboring a DDR2 mutation was detected among the 271 sequenced lung SCC samples (4%). We describe 10 unreported mutations, comprising a novel DDR2 exon 7 splice mutant. DDR2 mutations were not mutually exclusive with other driver gene alterations. One hundred thirty-six patients were included for clinical comparison and logistic regression analysis. No difference was detected between DDR2-mutant and DDR2 wild-type lung SCC regarding clinical characteristics or survival. CONCLUSION: DDR2 mutations were observed in 4% of cases of lung SCC of European descent. DDR2-mutated tumors can exhibit other driver gene alterations. No clinical characteristics were significantly associated with DDR2 mutation. PMID- 29129435 TI - Etirinotecan Pegol (NKTR-102) in Third-line Treatment of Patients With Metastatic or Recurrent Non-Small-cell Lung Cancer: Results of a Phase II Study. AB - BACKGROUND: Third-line treatment options are limited for patients with metastatic non-small-cell lung cancer (NSCLC). Etirinotecan pegol (NKTR-102) is a long acting topoisomerase-I inhibitor. We conducted a single-arm phase II trial to evaluate its efficacy in third-line treatment. PATIENTS AND METHODS: Patients aged >= 18 years with histologically proven NSCLC who had received 2 previous systemic therapy regimens, measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status <= 1, and adequate end-organ function were eligible. Etirinotecan pegol was administered at a dose of 145 mg/m2 intravenously once every 3 weeks until progression. The response was assessed every 6 weeks using Response Evaluation Criteria In Solid Tumors, version 1.1. The primary endpoint was the overall objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. A Simon 2 stage design was implemented for futility. RESULTS: From January 2013 to January 2015, 40 patients were enrolled. Their median age was 66 years (range, 19-85 years), 45% were female, 30% had an ECOG performance status of 0, 96% were current and former smokers, and 31 had adenocarcinoma. Patients received a median of 3 cycles (range, 2-15) of protocol therapy. The best response was a partial response in 2 patients. The treatment was well tolerated; 3 patients had grade 3 gastrointestinal toxicity attributable to therapy. The median PFS was 2.3 months (95% confidence interval [CI], 1.3-4.4 months), and the median OS was 7.1 months (95% CI 4.2-11.4 months). CONCLUSIONS: Etirinotecan pegol was well tolerated and led to 2 partial responses and disease stabilization with this third-line treatment of metastatic NSCLC. However, the study failed to meet its prespecified response rate endpoint. PMID- 29129436 TI - Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. AB - BACKGROUND: No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis. METHODS: In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1.50. Participants were randomly assigned to receive 20 MUg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41). FINDINGS: We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5.4%) of 680 patients in the teriparatide group and 64 (12.0%) of 680 patients in the risedronate group (risk ratio 0.44, 95% CI 0.29-0.68; p<0.0001). Clinical fractures occurred in 30 (4.8%) of 680 patients in the teriparatide group compared with 61 (9.8%) of 680 in the risedronate group (hazard ratio 0.48, 95% CI 0.32-0.74; p=0.0009). Non-vertebral fragility fractures occurred in 25 (4.0%) patients in the teriparatide group and 38 (6.1%) in the risedronate group (hazard ratio 0.66; 95% CI 0.39-1.10; p=0.10). INTERPRETATION: Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate. FUNDING: Lilly. PMID- 29129438 TI - Department of Error. PMID- 29129437 TI - Prevention of fractures in patients with osteoporosis. PMID- 29129439 TI - Department of Error. PMID- 29129440 TI - Bosutinib more effective than imatinib in CML. PMID- 29129441 TI - Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. AB - BACKGROUND: In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). METHODS: In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. FINDINGS: Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6.9 (95% CI 3.3 to 10.6) for pembrolizumab and -0.9 (-4.8 to 3.0) for chemotherapy, for a difference of 7.8 (2.9 to 12.8; two-sided nominal p=0.0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8.5 to not reached] vs 5.0 months [3.6 to not reached]; hazard ratio 0.66, 95% CI 0.44-0.97; two-sided nominal p=0.029). INTERPRETATION: Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. FUNDING: Merck & Co. PMID- 29129442 TI - Quality of life: an important element of treatment value. PMID- 29129444 TI - Biomarkers for subtypes of pancreatic ductal adenocarcinoma. PMID- 29129445 TI - Bevacizumab in adjuvant treatment of non-small-cell lung cancer. PMID- 29129443 TI - Adjuvant chemotherapy with or without bevacizumab in patients with resected non small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. AB - BACKGROUND: Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC. METHODS: We did an open-label, randomised, phase 3 trial of adult patients (aged >=18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (>=4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805. FINDINGS: Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50.3 months (IQR 32.9-68.0), the estimated median overall survival in group A has not been reached, and in group B was 85.8 months (95% CI 74.9 to not reached); hazard ratio (group B vs group A) 0.99 (95% CI 0.82-1.19; p=0.90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment. INTERPRETATION: Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early stage NSCLC. FUNDING: National Cancer Institute of the National Institutes of Health. PMID- 29129446 TI - Gut microbiome and immunotherapy response. PMID- 29129447 TI - Amplified hearing device use in acute care settings for patients with hearing loss: A feasibility study. AB - The objective of this study was to assess the feasibility of using amplified hearing devices (AHD) in acute care settings for patients with hearing loss. Secondary objectives include patient and nurse satisfaction, and nursing perceived productivity. Twenty-five adult hard of hearing patients and 15 nurses were evaluated. Patients with a perceived hearing handicap were identified through the Hearing Handicap for the Elderly Screening Version. Patient and staff nurse surveys were used to assess for satisfaction with using the AHD. Nurses were surveyed to evaluate whether they felt the AHD made patient communication more efficient and effective. Twenty-four patients expressed satisfaction with the AHD and would use it in future hospitalizations. Nurses also reported satisfaction, perceived improvement of patient communication and decreased time spent communicating with patients. Results demonstrate the feasibility of using an AHD in acute care inpatient settings where elderly hard of hearing patients are common. PMID- 29129448 TI - Disentangling frailty. PMID- 29129449 TI - Health literacy and its correlates in informal caregivers of adults with memory loss. AB - This secondary analysis examined health literacy among informal caregivers of community-dwelling older adults with memory loss and assessed correlates of caregiver health literacy using the Abilities, Skills and Knowledge Model. Caregiver health literacy (n = 91) was assessed by the Newest Vital Sign. Limited health literacy presented in 38.5% caregivers, with significantly low document literacy. Health literacy was associated bivariately with age, education, global cognitive function, executive function, and working memory (all ps < 0.001), as well as medication knowledge (p = 0.015). Hierarchical regression analyses revealed that older age (p = 0.017), and lower global cognitive function (p < 0.001), working memory (p = 0.001), and academic skills (years of education) (p = 0.004), independently predicted lower health literacy (R2 = 0.54). Medication knowledge, however, was not found to be an independent predictor in the model. Findings suggest limited health literacy is a potential issue among informal caregivers of adults with memory loss. Appropriate assessment and personalized support are needed for informal caregivers who are at high risk for poor health literacy. PMID- 29129450 TI - Resident Choice: A Nursing Home Staff Perspective on Tensions and Resolutions. AB - : A central component of person-centered care, resident choice in daily life, has received little research attention in the U.S. CONTEXT: This study investigated nursing home staff experiences in realizing resident choice. Twenty-six qualitative staff interviews were conducted in an opportunistic sample from two Veterans Health Administration (VHA) Community Living Centers (CLCs, i.e., nursing homes) implementing the Green House Model. Thematic content analysis surfaced several key tensions at the intra-personal, inter-personal, and organizational levels. Most salient were staff mental models within the intra personal level. Staff conveyed a lack of clarity on how to realize resident choice when faced with varying tensions, especially the competing goal of resident medical and safety needs. Staff-employed resolutions to resident choice related tensions also emerged (e.g., preventive practices, staff reinforcement, and staff deliberation). This study offers specific and concrete insights on how resident choice in daily life, and thus resident quality of life, can be advanced. PMID- 29129452 TI - Long-term humoral immunity induced by CVC1302-adjuvanted serotype O foot-and mouth disease inactivated vaccine correlates with promoted T follicular helper cells and thus germinal center responses in mice. AB - Long-lasting humoral immunity is one of the necessary criteria for a successful vaccine. In our previous study, it was demonstrated that the immunopotentiator CVC1302 could improve the humoral immunity induced by the foot and mouth disease virus (FMDV) killed vaccine (KV) with only one dose. Significantly higher FMDV specific antibody titers and more persistent antibody responses were observed in pigs receiving CVC1302-adjuvanted KV (KV-CVC1302) than in those inoculated with KV alone. In this study, we show that CVC1302 enhances murine IgG responses to FMDV by promoting a potent T follicular helper cell (TFH) response, which directly controls the magnitude of the germinal center (GC) B cell response. These results indicate a need for studies to assess the capacity of CVC1302 to enhance the efficacy of FMDV KV immunization in pigs, and provide new insights into the development of FMDV vaccines. PMID- 29129454 TI - Announcing the publication of the WHO immunological basis for immunization series module on pertussis vaccines. AB - In 2017, the World Health Organization (WHO) published an updated document aimed at facilitating the understanding of the immunological basis of pertussis vaccines and their use. The document "The Immunological Basis for Immunization Series: Pertussis Vaccines" is freely available on the WHO website. The main purpose of the module is to provide national immunization managers and vaccination professionals with an overview of the scientific basis of vaccination against pertussis and the immunological basis for the WHO position on pertussis vaccines. The Immunological Basis for Immunization Series was initially developed in 1993. Since then the series was regularly updated and extended. They reflect the biological differences in immune responses to the individual pathogens and the differing strategies employed to create the best possible level of protection that can be provided by vaccination. We invite the immunization community to use these references, and we hope the updated pertussis vaccine module will be a valuable resource. PMID- 29129451 TI - Cost-effectiveness of maternal GBS immunization in low-income sub-Saharan Africa. AB - BACKGROUND: A maternal group B streptococcal (GBS) vaccine could prevent neonatal sepsis and meningitis. Its cost-effectiveness in low-income sub-Saharan Africa, a high burden region, is unknown. METHODS: We used a decision tree model, with Markov nodes to project infants' lifetimes, to compare maternal immunization delivered through routine antenatal care with no immunization. 37 countries were clustered on the basis of economic and health resources and past public health performance. Vaccine efficacy for covered serotypes was ranged from 50% to 90%. The model projected EOGBS (early-onset) and LOGBS (late-onset) cases and deaths, disability-adjusted life years (DALYs), healthcare costs (2014 US$), and cost effectiveness for a representative country in each of the four clusters: Guinea Bissau, Uganda, Nigeria, and Ghana. Maximum vaccination costs/dose were estimated to meet two cost-effectiveness benchmarks, 0.5 GDP and GDP per capita/DALY, for ranges of disease incidence (reported and adjusted for under-reporting) and vaccine efficacy. RESULTS: At coverage equal to the proportion of pregnant women with>=4 antenatal visits (ANC4) and serotype-specific vaccine efficacy of 70%, maternal GBS immunization would prevent one-third of GBS cases and deaths in Uganda and Nigeria, where ANC4 is 50%, 42-43% in Guinea-Bissau (ANC4=65%), and 55 57% in Ghana (ANC4=87%). At a vaccination cost of $7/dose, maternal immunization would cost $320-$350/DALY averted in Guinea-Bissau, Nigeria, and Ghana, less than half these countries' GDP per capita. In Uganda, which has the lowest case fatality ratios, the cost would be $573/DALY. If the vaccine prevents a small proportion of stillbirths, it would be even more cost-effective. Vaccination cost/dose, disease incidence, and case fatality were key drivers of cost/DALY in sensitivity analyses. CONCLUSION: Maternal GBS immunization could be a cost effective intervention in low-income sub-Saharan Africa, with cost-effectiveness ratios similar to other recently introduced vaccines. The vaccination cost at which introduction is cost-effective depends on disease incidence and vaccine efficacy. Clinical Trial registry name and registration number: Not applicable. PMID- 29129453 TI - Hepatitis B virus core particles containing multiple epitopes confer protection against enterovirus 71 and coxsackievirus A16 infection in mice. AB - Human enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two major causative agents of hand-foot-and-mouth disease (HFMD). To investigate novel combined vaccines to prevent EV71 and CA16 infection, we constructed chimeric virus-like particles (tHBc/SPA or tHBc/SP VLPs) displaying conserved epitopes of EV71 (aa 208-222 of VP1 and aa 248-263 of VP2) and CA16 (aa271-285 of VP1) using a truncated hepatitis B virus core carrier (tHBc). Immunization with the chimeric VLPs induced epitope- or virus-specific IgG and neutralization antibodies against EV71 and CA16 in the mice. Compared with inactivated EV71, the chimeric VLPs induced significantly increased Th1 cytokine (IFN-gamma, IL-2) production and decreased Th2 cytokine (IL-4, IL-10) responses. Neonatal mice born to dams immunized with the recombinant particles were completely protected from lethal EV71 and partially protected from CA16 infection. Co-expression of the conserved human MHC class I CD4+ T cell epitope (aa248-263 of VP2) did not improve the antiviral immunity of the chimeric VLP vaccine in mice. Our results demonstrate that experimental combination vaccines comprised of EV71 and CA16 epitopes induce both humoral and cellular immune responses and therefore support further preclinical and clinical development of a bivalent VLP vaccine targeting both CA16 and EV71. PMID- 29129455 TI - Plasma Palmitoyl-Carnitine (AC16:0) Is a Marker of Increased Postprandial Nonesterified Incomplete Fatty Acid Oxidation Rate in Adults With Type 2 Diabetes. AB - OBJECTIVES: Enhanced mitochondrial fatty acid utilization is known to increase radical oxidative stress and induce insulin resistance. An increased level of plasma acylcarnitine (AC) has been proposed to indicate mitochondrial energy substrate overload, a possible mechanism leading to insulin resistance. The aim of our study was to determine fasting and postprandial plasma acetyl-carnitine (AC2:0), palmitoyl-carnitine (AC16:0), oleoyl-carnitine (AC18:1) and linoleoyl carnitine (AC18:2) levels and their relationships with plasma nonesterified fatty acid appearance and oxidation rates and insulin sensitivity in participants with type 2 diabetes and normoglycemic offspring of 2 parents with type 2 diabetes (FH+) compared to healthy participants without family histories of type 2 diabetes (FH-). METHODS: All participants underwent 3 metabolic protocols: 1) a euglycemic hyperinsulinemic clamp at fasting; 2) a 6-hour steady-state oral standard liquid meal and 3) an identical 6-hour steady-state meal intake study with a euglycemic hyperinsulinemic clamp. AC levels were measured by liquid chromatography with tandem mass spectrometry, and fatty acid oxidation (FAO) rates were measured by stable isotopic tracer techniques with indirect respiratory calorimetry. RESULTS: During the insulin clamp at fasting, AC16:0 was significantly higher in the group with type 2 diabetes vs. FH- (p<0.05). In the postprandial state, AC2:0, AC16:0 and AC18:1 decreased significantly, but this reduction was blunted in type 2 diabetes, even during normalization of postprandial glucose levels during the insulin clamp. Fasting AC16:0 correlated with FAO (rho=+0.604; p=0.0002); triacylglycerol (rho=+0.427; p<0.02) and waist circumference (rho=+0.416; p=0.02). CONCLUSIONS: Spillover of AC occurs in type 2 diabetes but is not fully established in FH+. AC16:0 can be a useful biomarker of excessive FAO. PMID- 29129456 TI - A Canadian Cross-Sectional Survey on Psychosocial Supports for Adults Living With Type 1 or 2 Diabetes: Health-Care Providers' Awareness, Capacity and Motivation. AB - OBJECTIVES: Addressing psychosocial issues is critical for diabetes self management. This work explores health-care professionals' (HCPs') 1) perceived relevance of various psychosocial issues in diabetes management and 2) confidence in working on these issues within their services. METHODS: An online cross sectional survey was developed based on the Capacity-Opportunity-Motivation Behaviour Model. It assessed self-rated confidence in supporting patients with psychosocial issues (capability), perceived relevance of these issues (motivation) and facilitators of skill development (opportunity). An e-mail invitation was sent to all Diabetes Canada's professional members, conference delegates and committee members. Qualitative responses were analyzed using thematic analysis. RESULTS: Of the 260 responses received (25% response rate), many were Diabetes Canada professional members (83%) and/or certified diabetes educators (66%). The largest professional groups in the sample were registered nurses (44%) and registered dietitians (33%). All psychosocial issues were perceived as somewhat or extremely important by at least 80% of respondents (range, 80% to 97%). However, HCPs were less confident in supporting their patients with these psychosocial issues; significantly fewer respondents reported that they felt somewhat or extremely confident (range, 26% to 62%). Depression (80%) and anxiety (80%) were the issues in which guidance was most desired. Most respondents wanted some form of formal self-management support training (83%). Preferred training methods included in-person workshops (56%), webinars (56%) and conference sessions (51%). CONCLUSIONS: Motivation to address psychosocial issues in diabetes was high, but capacity to do so and opportunity to learn how were both low. These findings can be used to develop a targeted strategy to help address this gap. PMID- 29129457 TI - Acute Effects of Graduated Elastic Compression Stockings in Patients with Symptomatic Varicose Veins: A Randomised Double Blind Placebo Controlled Trial. AB - OBJECTIVES: To investigate the effectiveness of graduated elastic compression stockings (GECS) below the knee in improving symptoms in patients with varicose veins in the absence of high quality evidence. METHODS: This was a randomised double blind placebo controlled trial. Thirty patients with no experience of elastic stockings, presenting with primary varicose veins causing calf pain or aching were randomised to a GECS (18-21 mmHg at the ankle level, n=15) or a placebo stocking (0 mmHg, n=15). Pain or aching of the index leg after 1 week was the primary outcome measure. In patients with bilateral varicose veins the leg with the most severe pain/aching was considered. Other defined symptoms were secondary outcome measures. All symptoms were scored on a visual analogue scale (VAS). RESULTS: The two study groups were well balanced at baseline. At the completion of the study after 1 week, GECS were more effective than placebo stockings in reducing pain or aching (VAS score 1.7+/-3.0 vs. 4.5+/-2.8 for placebo, p=.02), while non-significant trends were observed for some of the remaining symptoms of the index leg, including feeling of swelling (VAS score 0.9+/-1.9 vs. 3.3+/-3.5 for placebo), paraesthesiae (VAS score 0.2+/-0.6 vs. 2.1+/-3.1 for placebo), and the number of symptoms other than pain or aching (1.3+/-1.1 vs. 2.8+/-1.7 for placebo). Number needed to treat (95% CI) for a 50% or complete improvement of pain or aching in the index leg was 2 (95% CI 1.2-5.5) and 2 (95% CI 1.2-5.3), respectively. Mean daily use of the placebo stockings and GECS was 8.0 hours and 10.2 hours, respectively (p=.13). CONCLUSIONS: Among patients with varicose veins, GECS seem effective in ameliorating symptoms, particularly pain or aching, compared with placebo stockings after 1 week of use. Long-term studies are justified. PMID- 29129458 TI - Commentary on "Surgeons' Perceptions of the Causes of Preventable Harm in Arterial Surgery: A Mixed Methods Study". PMID- 29129459 TI - Reliability and validity of the Youth Leisure-time Sedentary Behavior Questionnaire (YLSBQ). AB - OBJECTIVES: To develop a questionnaire able to assess time spent by youth in a wide range of leisure-time sedentary behaviors (SB) and evaluate its test-retest reliability and criterion validity. DESIGN: Cross-sectional observational. METHODS: The reliability sample included 194 youth, aged 10-18 years, who completed the questionnaire twice, separated by one-week interval. The validity study comprised 1207 participants aged 8-18 years. Participants wore an accelerometer for 7 consecutive days. The questionnaire was designed to assess the amount of time spent in twelve different SB during weekdays and weekends, separately. In order to avoid usual phenomenon of time over reporting, values were adjusted to real available leisure-time (LT) for each participant. Reliability was assessed by using Intraclass Correlation Coefficients (ICC) and weighted (quadratic) kappa (k), and validity was assessed by using Pearson correlation and Bland-Altman plots. RESULTS: The reliability of questionnaire showed a moderate-to-substantial agreement for the most (91%) of items (k=0.43 0.74; ICC=0.41-0.79) with three items (4%) reaching an almost perfect agreement (ICC=0.82-0.83). Only 'sitting and talking' evidenced fair-to-moderate reliability (k=0.27-0.39; ICC=0.34-0.46). The relationship between average sedentary time assessed by the questionnaire and accelerometry was moderate (r=0.36; p<0.001). Systematic biases were not found between questionnaire and accelerometer sedentary time for average day (r=0.05; p=0.11) but Bland-Altman plots suggest moderate discrepancies between both methods of SB measurement (mean=19.86; limits of agreement=-280.04 to 319.76). CONCLUSIONS: The questionnaire showed moderate to good test-retest reliability and a moderate level of validity for assessing SB in youth, similar or slightly better to previously published in this population. PMID- 29129460 TI - The association of novel polymorphisms with stress fracture injury in Elite Athletes: Further insights from the SFEA cohort. AB - OBJECTIVES: To determine, in conjunction with a wider investigation, whether 11 genetic variants in the vicinity of vitamin D, collagen and Wnt signalling pathways were associated with stress fracture injury in the Stress Fracture Elite Athlete (SFEA) cohort. DESIGN: Genotype-phenotype association study. METHODS: Self-reported stress fracture history and demographic data were recorded in 518 elite athletes, 449 male and 69 female (mean age 24.2+/-5.5 years) from the SFEA cohort. Elite athletes were assigned to two groups based on history of stress fracture injury. Data were analysed for the whole cohort and sub-stratified in to male only and multiple stress fracture cases. Genotype was determined using a proprietary fluorescence-based competitive allele-specific polymerase chain reaction assay. RESULTS: SOST SNP rs1877632 and VDR SNPs rs10735810 and rs731236 were associated with stress fracture (p<0.05). In the whole cohort, rs1877632 heterozygotes and homozygotes of the rare allele combined made up 59% of stress fracture sufferers in comparison to 46% in the non-stress fracture group (p=0.05). In the multiple stress fracture cohort, homozygotes of the rare allele of rs10735810 and rs731236 showed an association with stress fracture when compared to those homozygotes for the common allele combined with heterozygotes (p=0.03; p=0.01). No significant associations were shown in the other SNPs analysed (p>0.05). CONCLUSIONS: These data suggest an important role for SOST SNP rs1877632 and VDR SNPs rs10735810 and rs731236 in the pathophysiology of stress fracture. This might be due to the role of the SNPs in the regulation of bone remodelling and adaptation to mechanical loading, with potential implications for the prevention and treatment of stress fracture injuries. PMID- 29129461 TI - [Aspirin: Indications and use during pregnancy]. AB - Aspirin (acetylsalicylic acid) has been used ever since the Antiquity for its painkilling and anti-inflammatory effects. Its antiplatelet properties have then extended its indications to the field of coronaropathy and vascular cerebral disease, and finally to vascular placental disease. Aspirin has been widely prescribed since the 1980's to prevent pre-eclampsia, intra-uterine growth retardation and fetal death of vascular origin. It has also been proposed to prevent unexplained recurrent miscarriages. Its use during pregnancy is considered as safe, provided the daily doses do not exceed 100mg. Aspirin has been proven efficient to prevent pre-eclampsia and fetal growth restriction in high-risk patients. The benefits of prescribing aspirin have been demonstrated neither for vascular placental disease prevention in low risk patients, nor in cases of unexplained recurrent miscarriages. PMID- 29129462 TI - Reply to "Percutaneous bone biopsy is different to the probe to bone test". Comments on "Diabetic foot osteomyelitis: Is conservative treatment possible?". PMID- 29129464 TI - Editorial overview: Cell biology: Membrane dynamics - being at the right place at the right time. PMID- 29129463 TI - Patterns of E-cigarette Use Frequency-National Adult Tobacco Survey, 2012-2014. AB - INTRODUCTION: Accounting for occasional or intermittent e-cigarette use has yielded higher estimates of current use among U.S. adults. However, frequency of e-cigarette use by population subgroups is not well described. This study assessed e-cigarette use frequency by sociodemographic characteristics and other tobacco product use among U.S. adults. METHODS: This study analyzed combined data from the 2012-2013 (n=60,192) and 2013-2014 (n=75,233) National Adult Tobacco Survey, a telephone-based survey of U.S. adults aged >=18 years, to assess frequency of e-cigarette use (daily, some days, rarely) by sex, age, race/ethnicity, education, annual household income, U.S. region, marital status, sexual orientation, and cigarette smoking and other tobacco product use (cigars, cigarillos, little filtered cigars; traditional pipes; water pipes; and chewing tobacco, snuff, dip, snus, and dissolvable tobacco products). Analyses took place in 2016. RESULTS: Among current e-cigarette users, 19.3% used daily, 29.3% used some days, and 51.4% used rarely. Daily use was lowest among younger adults, Hispanics, and those who were single, never married, or not living with a partner; and greatest among non-Hispanic Asians (p<0.0001). Among current e cigarette users, 25.3% were cigarette-only smokers, 52.8% smoked cigarettes and used other tobacco products, 5.5% used other tobacco products only, 6.5% were former cigarette-only smokers, 6.7% were former users of cigarettes and other tobacco products, 1.3% were former other tobacco product users only, and 1.8% never used cigarettes or other tobacco products. CONCLUSIONS: E-cigarette use frequency varies by sociodemographic characteristics and other tobacco use. Further surveillance, particularly related to frequency of e-cigarette use and its impact on cigarette cessation, could inform public health policy, planning, and practice. PMID- 29129465 TI - Developing a model for measuring fear of pain in Norwegian samples: The Fear of Pain Questionnaire Norway. AB - BACKGROUND: Fear of pain is highly correlated with pain report and physiological measures of arousal when pain is inflicted. The Fear of Pain Questionnaire III (FPQ-III) and The Fear of Pain Questionnaire Short Form (FPQ-SF) are self-report inventories developed for assessment of fear of pain (FOP). A previous study assessed the fit of the FPQ-III and the FPQ-SF in a Norwegian non-clinical sample and proved poor fit of both models. This inspired the idea of testing the possibility of a Norwegian FOP-model. AIMS AND METHODS: A Norwegian FOP-model was examined by Exploratory Factor Analysis (EFA) in a sample of 1112 healthy volunteers. Then, the model fit of the FPQ-III, FPQ-SF and the Norwegian FOP model (FPQ-NOR) were compared by Confirmatory Factor Analysis (CFA). Sex neutrality was explored by examining model fit, validity and reliability of the 3 models amongst male and female subgroups. RESULTS: The EFA suggested either a 4-, a 5- or a 6-factor Norwegian FOP model. The eigenvalue criterion supported the suggested 6-factor model, which also explained most of the variance and was most interpretable. A CFA confirmed that the 6-factor model was better than the two 4- and 5-factor models. Furthermore, the CFA used to test the fit of the FPQ-NOR, the FPQ-III and the FPQ-SF showed that the FPQ-NOR had the best fit of the 3 models, both in the whole sample and in sex sub-groups. CONCLUSION: A 6-factor model for explaining and measuring FOP in Norwegian samples was identified and termed the FPQ-NOR. This new model constituted six factors and 27 items, conceptualized as Minor, Severe, Injection, Fracture, Dental, and Cut Pain. The FPQ-NOR had the best fit overall and in male- and female subgroups, probably due to cross-cultural differences in FOP. IMPLICATIONS: This study highlights the importance on exploratory analysis of FOP-instruments when applied to different countries or cultures. As the FPQ-III is widely used in both research and clinical settings, it is important to ensure that the models construct validity is high. Country specific validation of FOP in both clinical and non-clinical samples is recommended. PMID- 29129466 TI - A discrimination model in waste plastics sorting using NIR hyperspectral imaging system. AB - Classification of plastics is important in the recycling industry. A plastic identification model in the near infrared spectroscopy wavelength range 1000-2500 nm is proposed for the characterization and sorting of waste plastics using acrylonitrile butadiene styrene (ABS), polystyrene (PS), polypropylene (PP), polyethylene (PE), polyethylene terephthalate (PET), and polyvinyl chloride (PVC). The model is built by the feature wavelengths of standard samples applying the principle component analysis (PCA), and the accuracy, property and cross validation of the model were analyzed. The model just contains a simple equation, center of mass coordinates, and radial distance, with which it is easy to develop classification and sorting software. A hyperspectral imaging system (HIS) with the identification model verified its practical application by using the unknown plastics. Results showed that the identification accuracy of unknown samples is 100%. All results suggested that the discrimination model was potential to an on line characterization and sorting platform of waste plastics based on HIS. PMID- 29129467 TI - Biocomplex textile as an alternative daily cover for the simultaneous mitigation of methane and malodorous compounds. AB - Space-saving biocomplex textiles, which can be used as covers or rolled up as needed, have been demonstrated as alternative daily covers for the simultaneous mitigation of greenhouse gases (GHGs) and odors in landfills. The biocomplex textiles were made by inserting inorganic biocarriers (perlite (P), tobermolite (T) and their mixture (P/T)) between nonwoven fabrics. Methane (CH4) and dimethyl sulfide (DMS) were used as model compounds for GHGs and odors, and a CH4 and DMS co-degrading microbial consortium was used as an inoculum source. CH4 and DMS could be biologically degraded by methanotrophs and sulfur-oxidizing bacteria in the biocomplex textiles. Both biocomplex textiles made with either P or T were able to maintain the removability for CH4 and DMS after storage for 70 days, although their removal efficiencies for CH4 and DMS were 70-71% and 62-65% of those before storage, respectively. CH4 and DMS were simultaneously removed in lab-scale landfill simulation reactors employed with the biocomplex textiles. After 17 days of starvation, only 2-3 days were needed to recover their removability. Among the 3 kinds of biocarriers evaluated, the biocomplex textile generated using the P/T showed the highest removability and was the most stable. The maximum elimination capacities of the biocomplex textile generated with the P/T were 11.5 g-CH4.m-2-fabric.d-1 and 0.5 g-DMS.m-2-fabric.d-1, respectively. These results suggest that the biocomplex textiles are promising alternative daily covers to mitigate the emission of greenhouse gas and odor in operational landfills. PMID- 29129468 TI - Inhibition of Rac1 ameliorates neuronal oxidative stress damage via reducing Bcl 2/Rac1 complex formation in mitochondria through PI3K/Akt/mTOR pathway. AB - Although the neuroprotective effects of Rac1 inhibition have been reported in various cerebral ischemic models, the molecular mechanisms of action have not yet been fully elucidated. In this study, we investigated whether the inhibition of Rac1 provided neuroprotection in a diabetic rat model of focal cerebral ischemia and hyperglycemia-exposed PC-12 cells. Intracerebroventricular administration of lentivirus expressing the Rac1 small hairpin RNA (shRNA) and specific Rac1 inhibitor NSC23766 not only decreased the infarct volumes and improved neurologic deficits with a correlated significant activation of mitochondrial DNA specific proteins, such as OGG1 and POLG, but also elevated Bcl-2 S70 phosphorylation in mitochondria. Furthermore, the levels of p-PI3K, p-Akt and p-mTOR increased, while 8-OHdG, ROS production and Bcl-2/Rac1 complex formation in mitochondria reduced in both Rac1-shRNA- and NSC23766-treated rats. Moreover, to confirm our in vivo observations, inhibition of Rac1 activity by NSC23766 suppressed the interactions between Bcl-2 and Rac1 in the mitochondria of PC-12 cells cultured in high glucose conditions and protected PC-12 cells from high glucose-induced neurotoxicity. More importantly, these beneficial effects of Rac1 inhibition were abolished by PI3K inhibitor LY294002. In contrast to NSC23766 treatment, LY294002 had little effect on the decrement of p-PTEN level. Taken together, these findings revealed novel neuroprotective roles of Rac1 inhibition against cerebral ischemic reperfusion injury in vivo and high glucose-induced neurotoxicity in PC 12 cells in vitro, by reducing Bcl-2/Rac1 complex formation in mitochondria through the activation of PI3K/Akt/mTOR survival pathway. PMID- 29129469 TI - Does the Use of Volumetric Modulated Arc Therapy Reduce Gastrointestinal Symptoms after Pelvic Radiotherapy? AB - AIMS: Growing numbers of patients with cancer are surviving after treatment with pelvic radiotherapy. We evaluated the technique of volumetric modulated arc therapy (VMAT), which delivers a decreased dose to the organs at risk. We aimed to determine outcomes of this technique in terms of patient-reported acute toxicity and late effects and correlate the frequency of gastrointestinal symptoms with the volume of bowel receiving radiation dose. MATERIALS AND METHODS: Patients who were to receive VMAT for gynaecological malignancy completed patient-reported outcomes at baseline, the end of treatment, 8 weeks and 1 year. The rates of patient-reported toxicity were correlated with the volume of bowel irradiated. RESULTS: The frequencies of patient-reported gastrointestinal symptoms increased in the acute toxicity phase and tended to improve at 1 year, with the exception of faecal incontinence and rectal bleeding (P < 0.05). There was not a strong association between the volume of small bowel that was irradiated (P > 0.05 at all dose levels) and reported toxicity, suggesting that other factors are involved in the development of toxicity. CONCLUSION: Although VMAT decreases the dose delivered to the small bowel, this does not translate into a reduction in patient-reported toxicity. PMID- 29129470 TI - Risk stratification for surgical outcomes in older colorectal cancer patients using ISAR-HP and G8 screening tools. AB - BACKGROUND: Older patients are at risk for adverse outcomes after surgical treatment of cancer. Identifying patients at risk could affect treatment decisions and prevent functional decline. Screening tools are available to select patients for Geriatric Assessment. Until now their predictive value for adverse outcomes in older colorectal cancer patients has not been investigated. OBJECTIVE: To study the predictive value of the Geriatric 8 (G8) and Identification of Seniors at Risk for Hospitalized Patients (ISAR-HP) screening tools for adverse outcomes after elective colorectal surgery in patients older than 70years. Primary outcomes were 30-day complication rates, secondary outcomes were the length of hospital stay and six-month mortality. STUDY DESIGN AND METHODS: Multicentre cohort study from two hospitals in the Netherlands. Frail was defined as a G8 <=14 and/or ISAR-HP >=2. Odds ratio (OR) is given with 95% CI. RESULTS: Overall, 139 patients (52%) out of 268 patients were included; 32 patients (23%) were ISAR-HP-frail, 68 (50%) were G8-frail, 20 were frail on both screening tools. Median age was 77.7years. ISAR-HP frail patients were at risk for 30-day complications OR 2.4 (CI 1.1-5.4, p=0.03), readmission OR 3.4 (1.1 11.0), cardiopulmonary complications OR 5.9 (1.6-22.6), longer hospital stay (10.3 versus 8.9day) and six-months mortality OR 4.9 (1.1-23.4). When ISAR-HP and G8 were combined OR increased for readmission, 30-day and six-months mortality. G8 alone had no predictive value. CONCLUSIONS: ISAR-HP-frail patients are at risk for adverse outcomes after colorectal surgery. ISAR-HP combined with G8 has the strongest predictive value for complications and mortality. KEY POINTS: Patients screening frail on ISAR-HP are at increased risk for morbidity and mortality. Screening results of G8 alone was not predictive for postoperative outcomes. Predictive value increased when G8 and ISAR-HP were combined. PMID- 29129471 TI - Higher intake of fish and fat is associated with lower plasma s adenosylhomocysteine: a cross-sectional study. AB - Several B-vitamins act as co-factors in one-carbon metabolism, a pathway that plays a central role in several chronic diseases. However, there is a lack of knowledge of how diet affects markers in one-carbon metabolism. The aim of this study was to explore dietary patterns and components associated with one-carbon metabolites. We hypothesized that intake of whole-grains and fish would be associated with lower Hcy, and higher SAM:SAH ratio due to their nutrient content. We assessed dietary information using a four-day dietary record in 118 men and women with features of the metabolic syndrome. In addition we assessed whole-blood fatty acid composition and plasma alkylresorcinols. Plasma s adenosylmethionine (SAM), s-adenosylhomocysteine (SAH), homocysteine (Hcy) and vitamin B12 was included as one-carbon metabolism markers. We used principal component analysis (PCA) to explore dietary patterns and multiple linear regression models to examine associations between dietary factors and one-carbon metabolites. PCA separated subjects based on prudent and unhealthy dietary patterns, but the dietary pattern score was not related to the one-carbon metabolites. Whole grain intake was found to be inversely associated to plasma Hcy (-4.7% (-9.3; 0.0), P=.05) and total grain intake tended to be positively associated with SAM and SAH (2.4% (-0.5; 5.5), P=.08; 5.8% (-0.2; 12.1), P=.06, respectively, per SD increase in cereal intake). Fish intake was inversely associated with plasma Hcy and SAH concentrations (-5.4% (-9.7; -0.8), P=.02 and 7.0% (-12.1; -1.5), P=.01, respectively) and positively associated with the SAM:SAH ratio (6.2% (1.6; 11.0), P=.008). In conclusion, intake and fish and whole-grain appear to be associated with a beneficial one-carbon metabolism profile. This indicates that dietary components could play a role in regulation of one-carbon metabolism with a potential impact on disease prevention. PMID- 29129472 TI - Effectiveness of intrapartum antibiotic prophylaxis for early-onset group B Streptococcal infection: An integrative review. AB - BACKGROUND: In some countries, up to 30% of women are exposed to intrapartum antibiotic prophylaxis for prevention of early-onset group B Streptococcal infection. Intrapartum antibiotic prophylaxis aims to reduce the risk of neonatal morbidity and mortality from this infection. The intervention may adversely affect non-pathogenic bacteria which are passed to the newborn during birth and are considered important in optimising health. Since many women are offered intrapartum antibiotic prophylaxis, effectiveness and implications of this intervention need to be established. This review considers clinical trials and observational studies analysing the effectiveness of intrapartum antibiotic prophylaxis. METHODS: An integrative literature review was conducted. One systematic review, three clinical trials and five observational studies were identified for appraisal. FINDINGS: Randomised controlled trials found intrapartum antibiotic prophylaxis effective but all retrieved randomised clinical trials had significant methodological flaws. High quality observational studies reported high rates of effectiveness but revealed less than optimal adherence to screening and administration of the prophylaxis. Scant consideration was given to short term risks, and long-term consequences were not addressed. DISCUSSION: Studies found intrapartum antibiotic prophylaxis to be effective. However, evidence was not robust and screening and prophylaxis have limitations. Emerging evidence links intrapartum antibiotic prophylaxis to adverse short and longer-term neonatal outcomes. CONCLUSION: Our review found high quality evidence of the effectiveness of intrapartum antibiotic prophylaxis was limited. Lack of consideration of potential risks of the intervention was evident. Women should be enabled to make informed decisions about GBS management. More research needs to be done in this area. PMID- 29129473 TI - Dominant-negative loss of function arises from a second, more frequent variant within the SAND domain of autoimmune regulator (AIRE). AB - A genetic variant in the SAND domain of autoimmune regulator (AIRE), R247C, was identified in a patient with type I diabetes mellitus (T1DM) and his mother with rheumatoid arthritis. In vitro, the variant dominantly inhibited AIRE; however, typical features of Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECED) were not seen in the subjects. Rather, early manifestation of autoimmunity appeared to be dependent on additional genetic factors. On a population level, diverse variants were identified in this region. Surprisingly, many likely pathogenic variants were seen disproportionately in Africans when compared to Europeans, reinforcing the importance of these variants in altering the immune repertoire. In light of these findings, we propose that R247C and other variants within the SAND-domain alter protein function in a dominant fashion and hold potential as drivers of autoimmunity. PMID- 29129475 TI - A monoclonal antibody to the reactive centre loop (RCL) of human corticosteroid binding globulin (CBG) is a readout for a functional test of pancreatic elastase sufficiency. PMID- 29129474 TI - [Screening program for tuberculosis among international exchange students in the Department of Isere]. AB - INTRODUCTION: France is a low-incidence country for tuberculosis (TB). Consequently screening is focused on high-risk populations, in particular migrants. The aim of this study was to evaluate the epidemiology of TB among international exchange students in the Department of Isere and the screening programs used. METHODS: We carried out an organizational audit based on interviews with physicians involved in the management of TB in Isere. We conducted a retrospective descriptive study based on a case series of foreign students treated for TB from 2003 to 2013 inclusively. RESULTS: Forty-six international exchange students were treated for active TB during this time, representing an average incidence of 284/100,000. Two thirds of our studied population were Africans, 72% were asymptomatic at the time of screening. A quarter of our cohort developed TB after the initial screening. Thirty-one cases were confirmed bacteriologically, mainly through bronchoscopy. Outcome (radiological and clinical) on quadruple therapy was satisfactory in all patients. Two patients relapsed, one of them with multi-drug resistant TB. CONCLUSION: Our work confirms that international exchange students are a population at high risk of TB and that screening of this population is essential. The significant number of active TB cases diagnosed after the initial screening stresses the importance of diagnosis and follow up of patients with latent TB infection. PMID- 29129476 TI - Pyroptosis and its relationship to atherosclerosis. AB - Pyroptosis is a pro-inflammatory form of regulated cell death and is dependent on the enzymatic activity of inflammatory proteases that belong to the family of cysteine-dependent aspartate-specific proteases (caspases). Pyroptosis is morphologically, mechanistically, and pathophysiologically distinct from other forms of cell death, including apoptosis and necrosis. Pyroptosis is characterized by rapid plasma membrane rupture, with the consequent release of intracellular contents and pro-inflammatory mediators, including interleukin (IL) 1beta, IL-18, and the alarmin HMGB-1.Recent studies have shown that pyroptosis may be involved in atherosclerosis and play an important role in atherosclerotic lesion instability. Here, we review the progress made in understanding the morphological, molecular, and pathophysiological mechanisms of pyroptosis and its potential role in atherosclerosis. PMID- 29129477 TI - Transrectal endoscopic ultrasound-guided paracentesis for diagnosis of malignant ascites in the pelvis. PMID- 29129478 TI - Adalimumab trough levels predict Crohn's disease clinical course. PMID- 29129479 TI - An analysis of anterior scleral shape and its role in the design and fitting of scleral contact lenses. AB - PURPOSE: The purpose of this study was to evaluate the shape of the anterior sclera by measuring the sagittal height and corneoscleral transition angles in the four cardinal and four oblique segments of the eye. MATERIALS AND METHODS: In this study, 78 normal eyes of 39 subjects were evaluated. The sagittal height, corneoscleral angle and scleral angle were measured at three chord lengths (10.0mm, 12.8mm and 15.0mm) in all eight segments of the anterior eye using optical coherence tomography (Zeiss Visante AS-OCT). Scleral toricity was calculated for each eye, defined as the greatest sagittal height difference found between two perpendicular meridians. RESULTS: At a 12.8mm chord length, the shape of the anterior eye was found to be nearly rotationally symmetric, and at a chord of 15.0mm the shape became more asymmetric. The average sagittal heights of the eight segments at a 12.8mm chord ranged from 2890MUm to 2940MUm; at a 15.0mm chord they ranged from 3680MUm to 3790MUm. The average scleral angles at a 15.0mm chord ranged from 35.17 degrees to 38.82 degrees . Significant differences between opposing segments were found in the sagittal height and scleral angle measurements at a chord of 15.0mm (sagittal height p<=0.0021; scleral angle p<=0.0105). The nasal measurements revealed flatter scleral angles and concave corneoscleral transitions, whereas temporal scleral angles were steeper, with tangential or convex corneoscleral transitions. CONCLUSION: These findings are important to consider when designing and fitting contact lenses that rest beyond the boundaries of the limbus, such as scleral lenses. PMID- 29129480 TI - [Takotsubo myocardiopathy: When coronary arteries are silent]. PMID- 29129481 TI - Image processing strategies based on saliency segmentation for object recognition under simulated prosthetic vision. AB - BACKGROUND AND OBJECTIVE: Current retinal prostheses can only generate low resolution visual percepts constituted of limited phosphenes which are elicited by an electrode array and with uncontrollable color and restricted grayscale. Under this visual perception, prosthetic recipients can just complete some simple visual tasks, but more complex tasks like face identification/object recognition are extremely difficult. Therefore, it is necessary to investigate and apply image processing strategies for optimizing the visual perception of the recipients. This study focuses on recognition of the object of interest employing simulated prosthetic vision. METHOD: We used a saliency segmentation method based on a biologically plausible graph-based visual saliency model and a grabCut-based self-adaptive-iterative optimization framework to automatically extract foreground objects. Based on this, two image processing strategies, Addition of Separate Pixelization and Background Pixel Shrink, were further utilized to enhance the extracted foreground objects. RESULTS: i) The results showed by verification of psychophysical experiments that under simulated prosthetic vision, both strategies had marked advantages over Direct Pixelization in terms of recognition accuracy and efficiency. ii) We also found that recognition performance under two strategies was tied to the segmentation results and was affected positively by the paired-interrelated objects in the scene. CONCLUSION: The use of the saliency segmentation method and image processing strategies can automatically extract and enhance foreground objects, and significantly improve object recognition performance towards recipients implanted a high-density implant. PMID- 29129482 TI - Prolonged uninterrupted sitting increases fatigue in type 2 diabetes. AB - Fatigue is a prevalent, costly and disabling clinical complaint among those with type 2 diabetes. In a randomized crossover trial, prolonged uninterrupted sitting increased fatigue by 29% relative to days when sitting was regularly interrupted by brief activity-breaks. This may have implications for diabetes-related quality of life, occupational productivity and self-care. PMID- 29129483 TI - Pharmacological evaluation of new bioavailable small molecules targeting Eph/ephrin interaction. AB - Eph/ephrin system is an emerging target for cancer therapy but the lack of potent, stable and orally bioavailable compounds is impairing the development of the field. Since 2009 our research group has been devoted to the discovery and development of small molecules targeting Eph/ephrin system and our research culminated with the synthesis of UniPR129, a potent but problematic Eph/ephrin antagonist. Herein, we describe the in vitro pharmacological properties of two derivatives (UniPR139 and UniPR502) stemmed from structure of UniPR129. These two compounds acted as competitive and reversible antagonists of all Eph receptors reducing both ephrin-A1 and -B1 binding to EphAs and EphBs receptors in the low micromolar range. The compounds acted as antagonists inhibiting ephrin-A1 dependent EphA2 activation and UniPR139 exerted an anti-angiogenic effect, inhibiting HUVEC tube formation in vitro and VEGF-induced vessel formation in the chick chorioallantoic membrane assay. Finally, the oral bioavailability of UniPR139 represents a step forward in the search of molecules targeting the Eph/ephrin system and offers a new pharmacological tool useful for future in vivo studies. PMID- 29129484 TI - Detection of resistance to fluoroquinolones and injectable drugs among antituberculosis drugs by allele-specific primer extension on a microsphere-based platform. AB - Molecular drug susceptibility testing (DST) for antituberculosis drugs is important for improving the efficacy of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) treatment. In this study, we developed a molecular high-throughput assay system based on allele-specific primer extension (ASPE) and MagPlex-TAG microspheres, referred to here as TAG ASPE, which can detect mutations related to resistance to injectable second-line drugs and fluoroquinolones. Target genes were amplified by multiplex PCR using DNA from H37Rv and 190 clinical Mycobacterium tuberculosis strains and extended by ASPE using 22 ASPE primers. ASPE products were then sorted on the TAG-ASPE array and detected using a Luminex 200 system. The performance of the TAG-ASPE method was compared with that of sequencing and phenotypic DST. Comparison of the TAG-ASPE method with sequencing showed that the sensitivity and specificity of the TAG-ASPE method were 100% [95% confidence interval (CI), 96.38-100%] and 100% (95% CI, 95.70-100%) for the rrs gene and 100% (95% CI, 96.90-100%) and 100% (95% CI, 95.07-100%) for the gyrA gene, respectively. Compared with phenotypic DST, the sensitivity and specificity of the TAG-ASPE method for detecting drug resistance mutations against injectable second-line drugs were 92.52% (95% CI, 85.8-96.72%) and 98.7% (95% CI, 92.98-99.97%), respectively. Additionally, the sensitivity and specificity for fluoroquinolone-resistance detection were 85.4% (95% CI, 78.36-90.85%) and 100% (95% CI, 92.38-100%), respectively. The results of this study demonstrate that the TAG-ASPE method can effectively detect mutations conferring resistance to second-line antituberculosis drugs in numerous clinical specimens. PMID- 29129485 TI - Living systems do not minimize free energy: Comment on "Answering Schrodinger's question: A free-energy formulation" by Maxwell James Desormeau Ramstead et al. PMID- 29129486 TI - A nationwide analysis of re-exploration after liver transplant. AB - BACKGROUND: A retrospective review to investigate rate and outcomes of re exploration following liver transplantation in the United States. METHODS: The NIS database was used to examine outcomes of patients who underwent re exploration following liver transplantation from 2002 to 2012. Multivariate regression analysis was performed to compare outcomes of patients with and without reoperation. RESULTS: We sampled a total of 12,075 patients who underwent liver transplantation. Of these, 1505 (12.5%) had re-exploration during the same hospitalization. Hemorrhagic (67.9%) and biliary tract anastomosis complication (14.8%) were the most common reasons for reoperation. Patients with reoperation had a significantly higher mortality than those who did not (11.6% vs. 3.8%, AOR: 3.01, P < 0.01). Preoperative coagulopathy (AOR: 1.71, P < 0.01) and renal failure (AOR: 1.57, P < 0.01) were associated with hemorrhagic complications. Peripheral vascular disorders (AOR: 2.15, P < 0.01) and coagulopathy (AOR: 1.32, P < 0.01) were significantly associated with vascular complications. Risk of wound disruption was significantly higher in patients with chronic pulmonary disease (AOR: 1.50, P < 0.01). CONCLUSION: Re-exploration after liver transplantation is relatively common (12.5%), with hemorrhagic complication as the most common reason for reoperation. Preoperative coagulation disorders significantly increase hemorrhagic and vascular complications. Further clinical trails should investigate prophylactic strategies in high risk patients to prevent unplanned reoperation. PMID- 29129487 TI - [Evaluation of dysphagia. Results after one year of incorporating videofluoroscopy into its study]. AB - INTRODUCTION: Dysphagia is very common in children with neurological disabilities. These patients usually suffer from respiratory and nutritional problems. The videofluoroscopic swallowing study (VFSS) is the most recommended test to evaluate dysphagia, as it shows the real situation during swallowing. OBJECTIVES: To analyse the results obtained in our centre after one year of the implementation of VFSS, the clinical improvement after confirmation, and the prescription of an individualised treatment for the patients affected. MATERIAL AND METHODS: VFSS performed in the previous were collected. The following variables were analysed: age, pathology, degree of neurological damage, oral and pharyngeal and/or oesophageal dysphagia and its severity, aspirations, prescribed treatment, and nutritional and respiratory improvement after diagnosis. A statistical analysis was performed using SPSS v21. RESULTS: A total of 61 VFSS were performed. Dysphagia was detected in more than 70%, being moderate-severe in 58%. Aspirations and/or penetrations were recorded in 59%, of which 50% were silent. Adapted diet was prescribed to 56%, and gastrostomy was performed on 13 (21%) patients. A statistical association was found between neurological disease and severity of dysphagia. The degree of motor impairment is related to the presence of aspirations. After VFSS evaluation and treatment adjustment, nutritional improvement was found in Z-score of weight (+0.3SD) and BMI (+0.4SD). There was respiratory improvement in 71% of patients with dysphagia being controlled in the Chest Diseases Department. CONCLUSIONS: After implementation of VFSS, a high percentage of patients were diagnosed and benefited from a correct diagnosis and treatment. VFSS is a fundamental diagnostic test that should be included in paediatric centres as a diagnostic method for children with suspected dysphagia. PMID- 29129488 TI - DNA-hypomethylating agents as epigenetic therapy before and after allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and juvenile myelomonocytic leukemia. AB - Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder, typically of older adults, which is characterized by ineffective hematopoiesis, peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm occurring in young children. The common denominator of these malignant myeloid disorders is the limited benefit of conventional chemotherapy and a particular responsiveness to epigenetic therapy with the DNA-hypomethylating agents 5 azacytidine (azacitidine) or decitabine. However, hypomethylating therapy does not eradicate the malignant clone in MDS or JMML and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option. An emerging concept with intriguing potential is the combination of hypomethylating therapy and HSCT. Possible advantages include disease control with good tolerability during donor search and HSCT preparation, improved antitumoral alloimmunity, and reduced risk of relapse even with non-myeloablative regimens. Herein we review the current role of pre- and post-transplant therapy with hypomethylating agents in MDS and JMML. PMID- 29129489 TI - Development and application of a triplex real-time PCR assay for the simultaneous detection of avian influenza virus subtype H5, H7 and H9. AB - Avian influenza virus (AIV), especially subtypes H5, H7 and H9, has contributed to enormous economic losses and poses a potential pandemic threat to global human public health. Early screening of suspected cases is key to controlling the spread of AIVs. In this study, an accurate, rapid, and triplex real-time polymerase chain reaction (PCR) assay was developed for the simultaneous detection of AIV subtypes H5, H7 and H9. The sensitivity of the real-time PCR was at least 100 times higher than that of the conventional PCR, with a detection limit of 50 copies and an EID50 of 1 (50% egg infections dose) for the H5, H7, and H9 subtypes. The lack of cross-reaction with other avian respiratory viruses suggested that the real-time PCR assay was highly specific. The reproducibility of the assay was confirmed using plasmids containing targets genes. Furthermore, 362 clinical field samples were evaluated. Subtypes H5, H7 and H9 were detected in 102 (28.18%) samples by real-time PCR and in 35 (9.67%) samples by conventional virus isolation. These results indicate that the triplex real-time PCR assay has good sensitivity, specificity and reproducibility and that it might be useful for laboratory surveillance and rapid diagnosis of the H5, H7 and H9 subtypes of influenza A viruses. PMID- 29129490 TI - RNAlater(r) is a viable storage option for avian influenza sampling in logistically challenging conditions. AB - Surveillance of wild birds is critical in monitoring for highly pathogenic avian influenza A viruses (AIVs). However, a successful surveillance regime requires proper treatment of samples in the field - rapid placement of samples in -80 degrees C and subsequent maintenance of cold-chain. Given the logistical difficulties of this, many avian taxa and/or geographic locations are not sampled, or, when sampled may result in false negatives due to poor sample treatment in the field. Here, we assessed the utility of RNAlater(r) as a stabilization agent for AIV sampling. We found no difference in real time PCR performance between virus transport media at optimal conditions and RNAlater(r) at -80 degrees C, -20 degrees C, 4 degrees C or room temperature up to two weeks, at either low or high virus load. Not only was RNAlater(r) useful in comparison of spiked samples or those from duck experiments, it was employed successfully in a field study of backyard birds in China. We detected AIV in cloacal and oropharyngeal samples from chickens and a sample with a low Cq was successfully subtyped as H9, although sample storage conditions were suboptimal. Thus, despite limitations in downstream characterization such virus isolation and typing, RNAlater(r) is a viable option for AIV sampling under logistically challenging circumstances. PMID- 29129491 TI - [Population-based analysis of the Healthcare expenditure in Catalonia (Spain): what and who consumes more resources?] AB - OBJECTIVE: To analyse the distribution of the expenditure according to the healthcare services and characteristics of patients, using the microdata of the Catalan population's use of healthcare services. METHODS: A fee or an indirect cost has been applied to all healthcare activities financed by CatSalut during 2014, computing the health expenditure made up by each person and adding it all up for the inhabitants of Catalonia (Spain). RESULTS: The sum of the healthcare expenditure made by all the inhabitants of Catalonia represents 97.0% of the CatSalut budget. Half of the population accounts for 3.6% of total healthcare expenditure (71? per person); 1% of the population spends 23% of the expenditure (22,852? per person). The highest average expenditure, in both women and men, occurs between the age of 80 and 89. The population with a chronic disease has an average annual expenditure of 413?, with 5 of 2,413?, and 10 of 9,626?. The average cost varies according to pathologies, from 2,854? in patients with severe depression to 8,097? in patients with HIV-AIDS. CONCLUSIONS: The results are extremely useful for healthcare planning and for the prioritization of health policy interventions in groups with most needs. PMID- 29129492 TI - Prognostic roles of lymph node micrometastasis in non-small cell lung cancer. AB - OBJECTIVE: This study aimed to confirm the prognostic roles of lymph node (LN) micrometastasis (LNMM) in non-small cell lung cancer (NSCLC) through a meta analysis. METHODS: This study included 2026 NSCLC cases without detection of LN metastasis in histologic examination. We investigated the detection rate of LNMM in early-stage NSCLC and analyzed the correlation between LNMM and the rates of recurrence and survival. RESULTS: The range of detection rates of LNMM was 3.8 68.8% in the eligible studies. The detection rate of LNMM in early-stage NSCLC was 25.3% (95% confidence interval [CI] 19.8-31.6%). In subgroup analysis based on detection method, polymerase chain reaction method had higher detection rate than immunohistochemistry (33.7%, 95% CI 25.5-43.0% vs. 23.1%, 95% CI 18.0 29.0%). The presence of LNMM was significantly correlated with a higher recurrence rate (odds ratio 3.913, 95% CI 1.595-9.600, P=0.003). In addition, there were significant correlations between LNMM and worse overall and disease free survival rates (hazard ratio [HR] 2.345, 95% CI 1.863-2.951, and HR 1.606, 95% CI 1.170-2.206, respectively). CONCLUSION: Taken together, our results showed that LNMM was detected in 25.3% of NSCLCs without nodal disease through ancillary test. In addition, the presence of LNMM was significantly correlated with a higher recurrence rate and worse survival rates in early-stage NSCLC. PMID- 29129493 TI - Overexpression of microRNA-495 improves the intestinal mucosal barrier function by targeting STAT3 via inhibition of the JAK/STAT3 signaling pathway in a mouse model of ulcerative colitis. AB - We aim to investigate the role of microRNA-495 (miR-495) in the intestinal mucosal barrier by indirectly targeting signal transducer and activator of transcription 3 (STAT3) through the Janus kinase-signal transducer and activator of transcription (JAK)/STAT3 signaling pathway in a mouse model of ulcerative colitis (UC). BALB/c mice were selected for establishing mice model of UC, and intestinal tissues of normal and UC mice were collected. ELISA was conducted for detecting levels of TNF-alpha, IL-6, IFN-gamma and IL-10. The levels of SOD, MPO, MDA and NO were tested in the intestinal tissues. Dual luciferase reporter gene assay was applied to determine whether miR-495 directly targets STAT3. Cells were cultured, transfected and assigned into: normal group, blank group, NC group, miR 495 mimic group, miR-495 inhibitor group, siRNA-STAT3 group and miR-495 inhibitor+siRNA-STAT3 group. MTT was used for testing cell proliferation, flow cytometry for cell cycle and apoptosis. Northern blotting and Western blotting were performed to detect miR-495 expression and expressions of STAT3, JAK and Claudin-1. Results show that the UC group had higher expression levels of TNF alpha, IL-6, IFN-gamma, MPO, MDA, NO, STAT3 and JAK and lower expression levels of IL-10, SOD, miR-495 and Claudin-1, compared to the normal group. Dual luciferase reporter gene assay confirmed that STAT3 was the target gene of miR 495. The miR-495 mimic and siRNA-STAT3 groups had higher expressions of Claudin 1, higher cell proliferation and increased amount of cells in S phase, but lower expressions of STAT3 and JAK, decreased amount of cells in G0/G1 phase and cell apoptotic rate compared with the blank, NC groups. We also found that the miR-495 inhibitor+siRNA-STAT3 group had reduced miR-495 expression. No significant differences were found in mRNA and protein expressions of STAT3, JAK and Claudin 1, cell proliferation, apoptosis and cycle amongst the miR-495 inhibitor+siRNA STAT3 groups. Our study provides evidence that miR-495 improves the intestinal mucosal barrier function by targeting STAT3 through inhibiting the JAK/STAT3 signaling pathway in UC mice. PMID- 29129494 TI - Osteoclast-like giant cells in invasive breast cancer predominantly possess M2 macrophage phenotype. AB - Breast carcinoma with osteoclast-like giant cells (OGCs) is a rare tumor; however, their clinicopathological aspects remain unclear. We described the clinicopathological characteristics of 8 patients with breast carcinoma with OGCs. Immuno-phenotypes of the OGCs were comparatively examined with that of foreign body giant cells (FBGCs) in 4 cases of granulomatous reaction (GR) without cancerous elements. In most cancers, tumors displayed cribriform and tubular growth patterns. Three cases showed moderate to high nuclear grade, while all the other tumors had low nuclear grade. Six patients were estrogen receptor (ER) positive, while triple negative phenotype was identified in 2 patients. During the follow-up period, 1 patient had local recurrence of the tumor, and all the patients remained alive. All OGCs and FBGCs expressed CD68, a pan-macrophage marker. OGCs in all the breast cancers showed moderate to high expression of CD163 - a marker of M2-macrophage with pro-tumoral function - whereas its expression in FBGCs was low to moderate (p=0.04). CD86 - a marker of M1 macrophage with a tumoricidal activity - was positive in the OGCs of 3 breast cancers, and in the FBGCs of 3 GR cases (p=0.15). The expression of CD163 was significantly higher than that of CD86 in the OGCs of breast cancer (p<0.001), whereas they were comparable in the FBGCs of GR (p=0.79). In summary, we found that breast carcinoma with OGCs mostly exhibited cribriform and tubular growth pattern, ER positivity, and predominantly possessed the M2-macrophage phenotype. However, the clinical significance of OGCs in breast cancer needs to be elucidated in further studies involving a larger number of cases. PMID- 29129495 TI - Clinicopathological significance and prognostic role of microvessel density in gastric cancer: A meta-analysis. AB - OBJECTIVE: The aim of this study was to elucidate the clinicopathological significance and prognostic role of microvessel density (MVD) in gastric cancer (GC) through a meta-analysis. METHODS: This meta-analysis included 4094 patients from 26 eligible studies. We investigated the correlation between MVD and clinicopathological characteristics, including survival rate. In addition, subgroup analysis based on microscopic magnification among evaluation criteria of MVD was performed. RESULTS: High MVD was significantly correlated with worse overall and disease-free survival rates [hazard ratio (HR), 3.028, 95% confidence interval (CI) 2.105-4.357 and HR 2.045, 95% CI 1.530-2.732, respectively]. MVD was significantly increased in GC with diffuse type of Lauren's classification [mean difference (MD) 3.091, 95% CI 0.615-5.567], lymphatic invasion (MD 8.262, 95% CI 3.310-13.214), lymph node metastasis (MD 5.730, 95% CI 2.444-9.016), higher pT stage (pT3-4) (MD 7.093, 95% CI 0.060-14.126) and higher pTNM stage (III-IV) (MD 3.023, 95% CI 0.181-5.865). However, MD of MVD was not significantly different in regard to vascular invasion (MD 7.430, 95% CI 1.015-15.875), tumor differentiation (MD 5.501, 95% CI 1.353-12.355) and tumor size (MD 4.731, 95% CI 2.003-11.465). CONCLUSION: Taken together, higher MVD was significantly correlated with worse prognosis. In addition, MVD was significantly higher in GC with aggressive tumor behavior than in GC without aggressive features. PMID- 29129496 TI - Runt-related transcription factor 2 (RUNX2) inhibits apoptosis of intestinal epithelial cells in Crohn's disease. AB - Apoptosis in intestinal epithelial cells (IECs) prevents the development of Crohn's disease (CD), a type of inflammatory bowel disease (IBD). Runt-related transcription factor 2 (Runx2) inhibits apoptosis in osteosarcoma-derived U2OS cells via down-regulating the transcriptional activity of p53. However, the expression and function of Runx2 in CD remain unclear. In this study, Runx2 protein levels were decreased in the intestinal epithelial cells (IECs) of CD patients and in a mouse 2, 4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model; in contrast, the expression levels of p53 and Bax, a p53-target gene, were increased. In a TNF-alpha-treated HT29 cell colitis model, the down regulation of Runx2 was accompanied by the up-regulation of apoptotic markers, including cleaved caspase-3 and Bax. Furthermore, Runx2 overexpression effectively decreased TNF-alpha-induced Bax and cleaved caspase-3 expression levels. In conclusion, our data indicated that Runx2 might protect IECs from apoptosis in CD, thus revealing a novel molecular target for treating CD. PMID- 29129497 TI - Frailty and Clinical Outcomes in Advanced Heart Failure Patients Undergoing Left Ventricular Assist Device Implantation: A Systematic Review and Meta-analysis. AB - BACKGROUND: Frailty has been identified as a risk factor for adverse clinical outcomes after cardiac intervention or surgery. However, whether it increases the risk of adverse outcomes in patients undergoing left ventricular assist device (LVAD) therapy has been controversial. Therefore, we conducted a systematic review and meta-analysis of the frailty measures and clinical outcomes of length of stay and mortality in this setting. METHODS: PubMed and Embase were searched until September 11, 2017, for studies evaluating the association between frailty and clinical outcomes in advanced heart failure patients undergoing LVAD implantation. RESULTS: A total of 46 and 79 entries were retrieved from our search strategy. A total of 13 studies involving 3435 patients were included in the final meta-analysis (mean age: 57.7 +/- 15.3 years; 79% male, follow-up duration was 13 +/- 14 months). Compared to nonfrail patients (n = 2721), frail patients (n = 579) had significantly longer time-to-extubation (n = 3; mean difference: 45 +/- 6 hours; I2: 0%) and hospital length of stay (n = 4; mean difference: 2.9 +/- 1.2 days; P = .001; I2: 21%). Frailty was not a predictor of inpatient or short-term mortality [n = 3; hazard ratio (HR): 1.22, 95% confidence interval (CI): 0.66-2.26; P > .05; I2: 0%] but predicted long-term mortality (n = 7; HR: 1.44, 95% CI: 1.15-1.80; P = .001; I2: 0%). CONCLUSIONS: Frailty leads to significantly longer time to extubation, hospital length of stay, and long-term mortality in advanced heart failure patients who have undergone LVAD implantation. Older patients being considered for LVAD implantation should therefore be assessed for frailty status. The risk and benefit of the procedure should be explained to the patient, emphasizing that frailty increases the likelihood of adverse clinical outcomes. PMID- 29129498 TI - A novel double-layer mucoadhesive tablet containing probiotic strain for vaginal administration: Design, development and technological evaluation. AB - Vulvovaginal candidosis caused by Candida spp. is the most prevalent vaginal infection in Europe and the second one in EE.UU, so it has become a major female concern. Probiotics bacteria have been proposed as an alternative treatment with the aim of avoiding the adverse effects associated with conventional therapies including antibiotics and other aggressive drugs for the vaginal mucosa and microbiota. The purpose of this work was to design and develop a novel vaginal tablet that contained Lactobacillus spp. bacteria as a treatment against vulvovaginal infections. A total of 21 two-layers vaginal tablets, which contained different polymeric ratios, were proposed. However, formulation F4 (20mg Na-CMC; 50mg Carbopol(r) 934; 20mg chitosan) was selected as optimal according to its swelling index and dissolution/erosion capability. F4 tablets showed suitable technological properties for vaginal administration as well as mucoadhesion time (24.36+/-0.88h) and force (0.0941N). Disintegration assay in simulated vaginal fluid (SVF, pH5.5) showed that effervescent layer disappeared in 27.48+/-0.05s whilst matrix layer was totally gelled in 1h. Two different release profiles were achieved; on the one hand, a promptly release due to the dissolution of both effervescent layer and matrix layer's surface (1.10*108CFU/g), on the second hand, a prolonged released of the remaining bacteria until 24h (5.48*107CFU/g). For stability and storage study, it was found that bacteria viability was constant until 90days in both ways of storage, in a desiccator and at room temperature, with a final dosage of 108CFU/g which was considered appropriate for vaginal therapy (108-1010CFU/g). PMID- 29129499 TI - D-dimer predicts bleeding complication in out-of-hospital cardiac arrest resuscitated with ECMO. AB - PURPOSE: In out-of-hospital cardiac arrest (OHCA) patients resuscitated with veno arterial extracorporeal membrane oxygenation (VA-ECMO), known as extracorporeal cardiopulmonary resuscitation (ECPR), bleeding is a common complication. The purpose of this study was to assess the risk factors for bleeding complications in ECPR patients. METHODS: We retrospectively analyzed the data for OHCA patients admitted to our hospital and resuscitated with ECPR between October 2009 and December 2016. We compared patients with and without major bleeding (i.e. the Bleeding Academic Research Consortium class>=3 bleeding) within 24h of hospital admission. Patients, whose bleeding complication was not evaluated, were excluded. RESULTS: During the study period, 133 OHCA patients were resuscitated with ECPR, of whom 102 (77%) were included. In total, 71 (70%) patients experienced major bleeding. There were significant differences in age (median 65 vs. 50years, P<0.001), prior antiplatelet therapy (25% vs. 3%, P=0.008), hemoglobin (median 11.6 vs. 12.6g/dL, P=0.003), platelet count (median 125 vs. 155*103/MUL, P=0.001), and D-dimer levels on admission (median 18.8 vs. 6.7MUg/mL, P<0.001) among patients with and those without major bleeding. Multivariate analysis showed significant associations between major bleeding and D-dimer levels (odds ratio, 1.066; 95% confidence interval, 1.018-1.116). Area under receiver-operating characteristic curve, which describes the accuracy of D dimer levels in predicting major bleeding, was 0.76 (95% confidence interval, 0.66-0.87). CONCLUSION: D-dimer levels may predict major bleeding in ECPR patients, suggesting that hyperfibrinolysis may be related to bleeding. PMID- 29129500 TI - Comments on predictive performance of serum S100B for neuronal damage and poor clinical outcomes. PMID- 29129501 TI - [Maternal deaths due to haemorrhage: Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Haemorrhage is the first cause of maternal mortality and morbidity in France and a quality of care marker. Haemorrhage rate in France is around 5 to 10% of deliveries. PPH is defined as a post-partum blood loss>=500mL whatever the delivery route and sometime blood can be concealed inside the pelvis. Between 2010 and 2012 in France, 29 deaths were related to haemorrhage giving a maternal mortality ratio of 1.2/100,000 live births (CI 95% 0.8-1.7). Haemorrhage cases decreased from last triennium (2007-2009) especially for uterine atony cases (12/29) but remains the first leading cause of direct maternal death. Patients with previous cesarean birth were more represented than in general obstetrical population (11/23). Substandard care were mainly due to delays in diagnosis of hemoperitoneum, delays in adequate resuscitation because of reassuring vital signs (normal blood pressure or normal hematocrite at the initial stage of bleeding) or organisational mistakes. PMID- 29129502 TI - A Stressful Situation: Takotsubo Cardiomyopathy. PMID- 29129503 TI - On Learning How to Grow Dahlias. PMID- 29129504 TI - Cognitive therapy of psychosis: Research and implementation. PMID- 29129505 TI - Discontinuing antipsychotic treatment after a first-episode of psychosis: Who, when and how? PMID- 29129506 TI - Clinical insights: Addressing command hallucinations. PMID- 29129507 TI - The use of polygenic risk scores to identify phenotypes associated with genetic risk of schizophrenia: Systematic review. AB - Studying the phenotypic manifestations of increased genetic liability for schizophrenia can increase our understanding of this disorder. Specifically, information from alleles identified in genome-wide association studies can be collapsed into a polygenic risk score (PRS) to explore how genetic risk is manifest within different samples. In this systematic review, we provide a comprehensive assessment of studies examining associations between schizophrenia PRS (SZ-PRS) and several phenotypic measures. We searched EMBASE, Medline and PsycINFO (from August 2009-14th March 2016) plus references of included studies, following PRISMA guidelines. Study inclusion was based on predetermined criteria and data were extracted independently and in duplicate. Overall, SZ-PRS was associated with increased risk for psychiatric disorders such as depression and bipolar disorder, lower performance IQ and negative symptoms. SZ-PRS explained up to 6% of genetic variation in psychiatric phenotypes, compared to <0.7% in measures of cognition. Future gains from using the PRS approach may be greater if used for examining phenotypes that are more closely related to biological substrates, for scores based on gene-pathways, and where PRSs are used to stratify individuals for study of treatment response. As it was difficult to interpret findings across studies due to insufficient information provided by many studies, we propose a framework to guide robust reporting of PRS associations in the future. PMID- 29129508 TI - "Ethnic density of neighbourhood at age 15 modifies the risk for psychosis". So what? PMID- 29129509 TI - Reduced dorsolateral prefrontal cortex activation during affective Go/NoGo in violent schizophrenia patients: An fMRI study. AB - We investigated the influence of anger processing on cognitive control in male schizophrenia patients presenting violent behaviors. We recruited 23 patients without and 24 patients with (SCZ+V) a history of violent behaviors, as well as 22 healthy non-violent men. Participants were administered an affective (angry neutral faces) Go/NoGo task while undergoing functional magnetic resonance imaging. We found a reduced activation in the dorsolateral prefrontal cortex in SCZ+V patients specifically when inhibiting a response while viewing angry faces. These results show an inability of SCZ+V to recruit a core region of the (inhibitory) cognitive control network in the context of anger. PMID- 29129510 TI - Increase in serum HDL level is associated with less negative symptoms after one year of antipsychotic treatment in first-episode psychosis. AB - BACKGROUND: A potential link between increase in total cholesterol and triglycerides and clinical improvement has been observed during antipsychotic drug treatment in chronic schizophrenia patients, possibly due to drug related effects on lipid biosynthesis. We examined whether changes in serum lipids are associated with alleviation of psychosis symptoms after one year of antipsychotic drug treatment in a cohort of first-episode psychosis (FEP) patients. METHODS: A total of 132 non-affective antipsychotic-treated FEP patients were included through the Norwegian Thematically Organized Psychosis (TOP) project. Data on antipsychotic usage, serum lipids (total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (TG)), body mass index (BMI) and clinical state were obtained at baseline and after 12months. The Positive and Negative Syndrome Scale (PANSS) was used to assess psychotic symptoms. Mixed-effects models were employed to examine the relationship between serum lipids and psychotic symptoms while controlling for potential confounders including BMI. RESULTS: An increase in HDL during one year of antipsychotic treatment was associated with reduction in PANSS negative subscores (B=-0.48, p=0.03). This relationship was not affected by concurrent change in BMI (adjusted HDL: B=-0.54, p=0.02). No significant associations were found between serum lipids, BMI and PANSS positive subscores. CONCLUSION: We found that an increase in HDL level during antipsychotic treatment is associated with improvement in negative symptoms in FEP. These findings warrant further investigation to clarify the interaction between lipid pathways and psychosis. PMID- 29129511 TI - DMXAA-pyranoxanthone hybrids enhance inhibition activities against human cancer cells with multi-target functions. AB - Four 5,6-dimethylxanthone-4-acetic acid (D) and pyranoxanthone (P) hybrids (D-P n) were design-synthesized based on multi-target-addressed strategy. D-P-4 was confirmed as the most active agent against HepG-2 cell line growth with an IC50 of 0.216 +/- 0.031 MUM. Apoptosis analysis indicated different contributions of early/late apoptosis/necrosis to cell death for both monomers, the combination (D + P in 1:1 mol ratio) and D-P-4. They all arrested more cells on S phase. Western Blot implied that D-P-4 regulated p53/MDM2 to a better healthy state. Moreover, it improved Bax/Bcl-2 signaling pathway to increase cancer cell apoptosis. In all cases studied, D-P-4 showed the best activity and synergistic effect. All the evidences support that D-P-4 is a better anti-cancer therapy with multi-target functions. PMID- 29129512 TI - Thieno[2,3-b]pyridine derivatives are potent anti-platelet drugs, inhibiting platelet activation, aggregation and showing synergy with aspirin. AB - Drugs which inhibit platelet function are commonly used to prevent blood clot formation in patients with Acute Coronary Syndromes (ACS) or those at risk of stroke. The thieno[3,2-c]pyridine class of therapeutic agents, of which clopidogrel is the most commonly used, target the P2Y12 receptor, and are often used in combination with acetylsalicylic acid (ASA). Six thieno[2,3-b]pyridine were assessed for in vitro anti-platelet activity; all derivatives showed effects on both platelet activation and aggregation, and showed synergy with ASA. Some compounds demonstrated greater activity when compared to clopidogrel. These compounds, therefore, represent potential novel P2Y12 inhibitors for improved treatment for patients. PMID- 29129513 TI - Design, synthesis and biological evaluation of new beta-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors. AB - A series of new beta-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 MUM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV Visible, fluorescence, circular dichroism and molecular docking studies revealed that the beta-carboline-bisindole compounds exhibit combilexin type of interaction with DNA. PMID- 29129514 TI - A green multicomponent synthesis of tocopherol analogues with antiproliferative activities. AB - A one-pot efficient, practical and eco-friendly synthesis of tocopherol analogues has been developed using water or solvent free conditions via Passerini and Ugi multicomponent reactions. These reactions can be optimized using microwave irradiation or ultrasound as the energy source. Accordingly, a small library of 30 compounds was prepared for biological tests. The evaluation of the antiproliferative activity in the human solid tumor cell lines A549 (lung), HBL 100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast), and WiDr (colon) provided lead compounds with GI50 values between 1 and 5 MUM. A structure activity relationship is also discussed. One of the studied compounds comes up as a future candidate for the development of potent tocopherol-mimetic therapeutic agents for cancer. PMID- 29129515 TI - Amygdalin improves microcirculatory disturbance and attenuates pancreatic fibrosis by regulating the expression of endothelin-1 and calcitonin gene-related peptide in rats. AB - BACKGROUND: The pathogenesis of chronic pancreatitis (CP) is a complex process of interaction between tissue injury and repair, which involves microcirculatory disturbance. Amygdalin, an effective component extracted from Semen Persicae (a kind of Chinese herbal medicine), can decrease blood viscosity and improve microcirculation. In this study, we investigated the therapeutic effects of amygdalin on pancreatic fibrosis in rats with CP. METHODS: The rat CP model was induced by injecting dibutyltin dichloride (DBTC) into the right caudal vein. Amygdalin was administrated via the penile vein at a dose of 10 mg/(kg d) from the next day, after the induction of CP, once a day for the previous 3 days, and then once every 2 days, until the end of the experiment. Body weight was observed every 7 days. Pancreatic blood flow and histopathological changes were assessed at 28 days. The activation of pancreatic stellate cells (PSCs) was estimated by the expression of alpha-smooth muscle actin (alpha-SMA). At the same time, the expression of platelet-derived growth factor-BB (PDGF-BB), transforming growth factor beta-1 (TGFbeta-1), endothelin-1 (ET-1), and calcitonin gene-related peptide (CGRP) of pancreatic tissues were detected. RESULTS: Treatment of CP rats with amygdalin improved body weight and pancreatic blood flow, as well as alleviated pancreatic fibrosis and acinar destruction, accompanied by the down regulation of the expressions of alpha-SMA, PDGF-BB, TGFbeta-1, and ET-1, and the up-regulation of the CGRP's expression. CONCLUSION: Amygdalin could reduce the production of pro-fibrotic cytokines, inhibit the activation of PSCs, and attenuate pancreatic fibrosis in a rat with CP. The mechanism probably includes improving microcirculatory disturbance by regulating the production of ET-1 and CGRP. PMID- 29129516 TI - Is there a potential link between vitamin D and pulmonary morbidities in preterm infants? AB - BACKGROUND: There hasn't been conclusive proof about the association between vitamin D and pulmonary morbidities of prematurity. METHODS: 106 preterm infants were retrospectively included into this study. Clinical data and blood samples of all the patients were collected within 24 h of admission. RESULTS: (1) Respiratory distress syndrome (RDS) patients were mainly concentrated in "<=30 weeks" stage when compared with other two gestational age groups. The only significant decrease of vitamin D concentration between RDS and non-RDS patients reflected in "<=30 weeks" stage (RDS vs. non-RDS: 29.48 +/- 13.06 vs. 40.47 +/- 20.52 nmol/l). (2) Bronchopulmonary dysplasia (BPD) patients were also concentrated in "<=30 weeks" stage. Vitamin D concentration showed significant difference both in "<=30 weeks" stage and "30-34 weeks" stage (<=30 weeks stage, BPD vs. non-BPD: 33.20 +/- 16.51 vs. 39.21 +/- 16.65 nmol/l; 30-34 weeks stage, BPD vs. non-BPD: 30.36 +/- 15.50 vs. 41.21 +/- 20.40 nmol/l). (3) Though vitamin D concentration in mechanical ventilation (MV) group was lower than non-MV group, there're no significant differences. (4) Vitamin D concentration in dead cases was significant lower than survival patients at discharge. (5) It showed a good correlation between vitamin D concentration and serum Ca, serum P, duration of MV and duration of oxygen support in "<=30 weeks" stage. CONCLUSION: The significant decrease of vitamin D concentration between RDS and non-RDS patients only reflected in "<=30 weeks" stage. And significant decrease of vitamin D concentration in BPD patients was both showed in "<=30 weeks" stage and "30-34 weeks" stage, which is consistent with "duration of oxygen support". However, the overall effect did not show any difference in all preterm infants. It seems that the appropriate concentration of vitamin D is beneficial to lung maturation of human. Certainly, large sample, multi-center randomized controlled trials are necessary. PMID- 29129517 TI - Comparison of three different hemostatic devices in laparoscopic myomectomy. AB - BACKGROUND: To compare conventional electrosurgery, LigaSure (Valleylab, Boulder, CO), and Harmonic scalpel (Ethicon Endosurgery, Cincinnati, OH) in terms of perioperative and postoperative outcomes during laparoscopic myomectomy (LM). METHODS: We retrospectively studied 817 women with symptomatic fibroids who underwent LM between January 1997 and September 2015. Three different instruments were used separately during surgery. The number and weight of removed fibroids, blood loss, operative time, postoperative decrease in the hemoglobin level, and length of hospital stay were measured for statistical analysis. RESULTS: No significant increase in complications was found in the three groups. Patients in the LigaSure and Harmonic scalpel groups had more numbers of removed fibroids, heavier fibroids removed, and higher rate of pretreatment with GnRH agonist (p < 0.001). These patients also had higher amount of intraoperative bleeding (p = 0.003) and longer operative time (p < 0.001) than those in the conventional electrosurgery group. However, no worse postoperative clinical outcome but shorter length of hospital stay was found in the LigaSure and Harmonic scalpel groups (2.1 +/- 0.6, 2.0 +/- 0.4 vs 2.5 +/- 0.8 days, p < 0.001). CONCLUSION: The use of all three devices is feasible in LM. LigaSure and Harmonic scalpel can reduce the length of hospital stay without worse surgical outcomes. PMID- 29129518 TI - Breast cancer screening with digital breast tomosynthesis - 4 year experience and comparison with national data. AB - BACKGROUND: To determine if mammography combined with digital breast tomosynthesis (DBT), leads to superior performance in screening for breast cancer compared to digital mammography (DM) alone. METHODS: We retrospectively collected data from A) the results of population-based mammography-screening provided by the National Cancer Registry in Taiwan, and B) the results from all screening mammography performed with DBT from 2012 through 2015 at Kaohsiung Veterans General Hospital (VGHKS) since the institution of DBT at the end of 2011. This was compared data from 3 years with DM performed prior to DBT implementation. We calculated the results of medical audit of VGHKS and compared this with national data. Fisher's exact test is applied. RESULTS: VGHKS data demonstrated a higher cancer detection rate (CDR) and positive predictive value 1 (PPV 1) than the national average. Most prominently in the year 2014, our CDR was 120% better than that of the national average. CDR ranged from 6.3 to 8.10/00 prior to the introduction of DBT, and following DBT implementation this improved to 8.5 11.40/00, reflecting a mean increase of 32.2%. Early cancer detection was 50% higher and node negative rate was 25% higher than the national average of latest year. A 17.8% reduction in recall rate (RR) was achieved due to a decrease in unnecessary recall. CONCLUSION: There was a 32.2% increase in CDR and a 17.8% decrease in RR when DBT was used as an adjunct to DM, as compared to DM alone. CDRs were approximately twofold better than national average data. DBT was more effective at detecting cancer in ductal carcinoma in situ and stage 1. PMID- 29129519 TI - SIRT6 protects against hepatic ischemia/reperfusion injury by inhibiting apoptosis and autophagy related cell death. AB - Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury. PMID- 29129520 TI - F2-isoprostanes can mediate bleomycin-induced lung fibrosis. AB - F2-isoprostanes (F2-IsoPs) have been considered markers of oxidative stress in various pulmonary diseases, but little is known about their possible role in pulmonary fibrosis. In this study, we have investigated the potential key role of F2-IsoPs as markers and mediators of bleomycin (BLM)-induced pulmonary fibrosis in rats. During the in vivo study, plasma F2-IsoPs showed a peak at 7 days and remained elevated for the entire experimental period. Lung F2-IsoP content nearly tripled 7 days following the intratracheal instillation of BLM, and by 28 days, the value increased about fivefold compared to the controls. Collagen deposition correlated with F2-IsoP content in the lung. Furthermore, from day 21 onwards, lung sections from BLM-treated animals showed alpha-smooth muscle actin (alpha SMA) positive cells, which were mostly evident at 28 days. In vitro studies performed in rat lung fibroblasts (RLF) demonstrated that either BLM or F2-IsoPs stimulated both cell proliferation and collagen synthesis. Moreover, RLF treated with F2-IsoPs showed a significant increase of alpha-SMA expression compared to control, indicating that F2-IsoPs can readily activate fibroblasts to myofibroblasts. Our data demonstrated that F2-IsoPs can be mediators of key events for the onset and development of lung fibrosis, such as cell proliferation, collagen synthesis and fibroblast activation. Immunocytochemistry analysis, inhibition and binding studies demonstrated the presence of the thromboxane A2 receptor (TP receptor) on lung fibroblasts and suggested that the observed effects may be elicited through the binding to this receptor. Our data added a new perspective on the role of F2-IsoPs in lung fibrosis by providing evidence of a profibrotic role for these mediators in the pathogenesis of pulmonary fibrosis. PMID- 29129521 TI - Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype-phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients. PMID- 29129522 TI - Increasing the safety of surgical treatment for complex Cranio-vertebral anomalies using customized 3D printed models. AB - Surgery for the Cranio-vertebral (CV) junction anomalies using top loading subocciput (C0)/C1-C2 screws is difficult and requires high level of skill and expertise. This is because of complex abnormal anatomy in that region and other issues including the instrumentation. Thorough knowledge of the 3D anatomy of the Craniovertebral junction of the patient is essential for favourable outcome. The customised 3D printed model of CV junction region of the patient can be used for studying the anatomy and relationship of vertebral artery to the C1-C2 joint before the actual surgery. Thirteen patients (includes twelve males and one female) of congenital CV junction anomalies having AAD with or without BI (Basilar Invagination) were included in the study. For all thirteen patients, customised 3D models of CV junction were made based on their CT scan data. The rehearsal of surgical procedure on the model was done a day before the actual surgery. Post surgery, twelve out of thirteen patients showed significant clinical and radiological improvement. We did not had any misplaced screws or vertebral artery injury. 3D models can improve decision making and planning of the surgical procedure in the CV junction region. It unmasks abnormal bony & vascular anatomy effectively. Moreover the rehearsal of the surgical procedure enables the surgical team to be more confident & familiar with the anatomy during the actual surgery. PMID- 29129523 TI - Higher-Order Kidney Organogenesis from Pluripotent Stem Cells. AB - Organogenesis generates higher-order structures containing functional subunits, connective components, and progenitor niches. Despite recent advances in organoid based modeling of tissue development, recapitulating these complex configurations from pluripotent stem cells (PSCs) has remained challenging. In this study, we report assembly of kidney organoids that recapitulate embryonic branching morphogenesis. By studying the distinct origins and developmental processes of the ureteric bud, which contains epithelial kidney progenitors that undergo branching morphogenesis and thereby plays a central role in orchestrating organ geometry, and neighboring mesenchymal nephron progenitors, we established a protocol for differential induction of each lineage from mouse and human PSCs. Importantly, reassembled organoids developed the inherent architectures of the embryonic kidney, including the peripheral progenitor niche and internally differentiated nephrons that were interconnected by a ramified ureteric epithelium. This selective induction and reassembly strategy will be a powerful approach to recapitulate organotypic architecture in PSC-derived organoids. PMID- 29129524 TI - Urban flood mitigation planning for Guwahati: A case of Bharalu basin. AB - Guwahati, the capital city of Assam and the gateway to the seven north-eastern Indian states, is located in the Brahmaputra valley-one of the most flood prone regions of the world. The city receives an average annual rainfall of 1688 mm and is highly vulnerable towards frequent urban floods because of uncontrolled dumping of solid waste and siltation have choked the natural water channels. This coupled with the absence of an integrated drainage network and rapid urbanisation causes floods in many parts of the city, after a quick downpour. Bharalu river is the main natural water channel of the city and Bharalu basin is the most vulnerable one. The present paper is an attempt to plan for urban flood mitigation, by designing an integrated drainage network for the Bharalu basin which includes the low-lying urbanized areas bordered by the Guwahati-Shillong Road, the Radha Gobindo Baruah Road and the Rajgarh Road. Data regarding land use, flood level, rainfall, urban pattern and vulnerability towards urban flood were collected from available literature, field survey to find highest water level for 11.4 km road stretch, expert opinion survey from 18 experts and feedback from 77 community elders who have been residing in the city since the 1980s. The Bharalu basin is divided into seven drainage blocks and storm run-off has been calculated based on the inputs. Seven different trapezoidal drainage sections were designed to form an integrated drainage network which is 'self healing' to a certain extent. This can serve as a template for the other catchment basins and to design a drainage network for the entire Guwahati city, thereby reducing urban flood hazard to a significant extent. The study illustrates the necessity of an urban flood mitigation planning approach in sub Himalayan urban settlements such as Guwahati. PMID- 29129526 TI - Angiogenesis and Microvascular Obstruction: Still a Research Topic or a New Therapeutic Target? PMID- 29129525 TI - Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass. AB - BACKGROUND AND AIMS: The obesity epidemic has led to increased use of Roux-en-Y gastric bypass (RYGB). These patients have an increased incidence of pancreaticobiliary diseases, yet standard ERCP is not possible because of surgically altered gastroduodenal anatomy. Laparoscopy-assisted ERCP (LA-ERCP) has been proposed as an option, but supporting data are derived from single center small case series. Therefore, we conducted a large multicenter study to evaluate the feasibility, safety, and outcomes of LA-ERCP. METHODS: This is a retrospective cohort study of adult patients with RYGB who underwent LA-ERCP in 34 centers. Data on demographics, indications, procedure success, and adverse events were collected. Procedure success was defined when all the following were achieved: reaching the papilla, cannulating the desired duct, and providing endoscopic therapy as clinically indicated. RESULTS: A total of 579 patients (median age, 51; 84% women) were included. Indication for LA-ERCP was biliary in 89%, pancreatic in 8%, and both in 3%. Procedure success was achieved in 98%. Median total procedure time was 152 minutes (interquartile range [IQR], 109-210), with a median ERCP time of 40 minutes (IQR, 28-56). Median hospital stay was 2 days (IQR, 1-3). Adverse events were 18% (laparoscopy related, 10%; ERCP related, 7%; both, 1%) with the clear majority (92%) classified as mild/moderate, whereas 8% were severe and 1 death occurred. CONCLUSIONS: Our large multicenter study indicates that LA-ERCP in patients with RYGB is feasible with a high procedure success rate comparable with that of standard ERCP in patients with normal anatomy. The ERCP-related adverse events rate is comparable with conventional ERCP, but the overall adverse event rate was higher because of the added laparoscopy-related events. PMID- 29129528 TI - Educational Effects of Radiation Reduction During Fluoroscopic Examination of the Adult Gastrointestinal Tract. AB - RATIONALE AND OBJECTIVES: This study aimed to evaluate the effects of educating radiology residents and radiographers about radiation exposure on reduction of dose area product (DAP) and fluoroscopy time in diagnostic fluoroscopy of the gastrointestinal (GI) tract in adult patients. MATERIALS AND METHODS: In April 2015, we offered 1 hour of education to radiology residents and radiographers on how to reduce radiation doses during fluoroscopic examinations. Fluoroscopic examinations of the GI tracts of adult patients performed from June 2014 to February 2016 were evaluated. A total of 2326 fluoroscopic examinations (779 and 1547 examinations before and after education, respectively) were performed, including 10 kinds of examinations. Fluoroscopy time and DAP were collected. A radiologist evaluated the number of spot images, captured images, cine video, captured video, and the use of collimation or magnification. We used the Mann Whitney U test to assess the difference in fluoroscopy-related factors before and after education. RESULTS: Median DAP decreased significantly after education, from 21.1 to 18.2 Gy?cm2 (P < .001) in all examinations. After education DAP decreased significantly in defecography (P < .001) and fluoroscopy time decreased significantly in upper gastrointestinal series with water-soluble contrast (P < .001). Spot and cine images that increased the radiation dose were used less frequently after education than before in some kinds of examinations, especially in defecography (P < .001). More images were collimated after education in barium swallow than before (P < .001). CONCLUSIONS: Educating radiologist residents and radiographers could reduce DAP in fluoroscopy examinations of the GI tract in adult patients. PMID- 29129527 TI - Identification of measles virus genotype B3 associated with outbreaks in Islamabad, Pakistan, 2013-2015. AB - BACKGROUND: Measles virus infection remains a significant cause of childhood mortality and morbidity despite continued global efforts and the availability of a safe and effective vaccine. Molecular analysis of indigenous measles viruses could provide critical information on outbreak linkages and transmission pathways that can aid the implementation of appropriate control programs in Pakistan. METHODS: Blood samples and throat swabs were collected from subjects suspected with measles in Islamabad, Pakistan from 2013 to 2015. Serum samples were tested for the presence of measles immunoglobulin M (IgM) antibodies using enzyme-linked immunosorbent assay (ELISA) while throat swabs were used for the isolation (Vero/SLAM cell line) and subsequent characterization and phylogenetic analysis of measles strains. RESULTS: Of 373 blood samples, 66% tested positive for measles IgM. Male subjects were more often infected (58%) than female (42%) with the highest frequency of positive cases (63%) in the 0-5-years age group. Among the positive cases, only 13% had received one or two doses of the measles vaccine, while 87% were unvaccinated. Of 80 throat swabs, 29 (36%) showed a measles virus-specific cytopathic effect (CPE) and were characterized as genotype B3 through partial sequencing of the nucleoprotein (N) gene. Phylogenetic analysis revealed the Pakistani B3 strains to be closely related to strains from neighboring countries (Iran and Afghanistan) as well as with B3 viruses from the USA, Germany, and the UK. CONCLUSIONS: The study results showed that despite the availability of an effective vaccine, the burden of measles infections is very high in Pakistan due to poor routine immunization coverage even in major cities, including the capital city of Islamabad. It is imperative that national health authorities take urgent strategic steps to improve routine immunization and implement adequate molecular identification methods to tackle future measles outbreaks. PMID- 29129529 TI - Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis. AB - Profilin is an abundant actin monomer-binding protein with critical actin regulatory roles in vivo [1, 2]. However, profilin also influences microtubule dynamics in cells, which may be mediated in part through its interactions with formins that in turn bind microtubules [3, 4]. Specific residues on human profilin-1 (PFN1) are mutated in patients with amyotrophic lateral sclerosis (ALS) [5, 6]. However, the observation that some ALS-linked PFN1 mutants fail to alter cellular actin organization or dynamics [5-8] or in vitro actin-monomer affinity [9] has been perplexing, given that profilin is best understood as an actin regulator. Here, we investigated direct effects of profilin on microtubule dynamics and whether ALS-linked mutations in PFN1 disrupt such functions. We found that human, fly, and yeast profilin homologs all directly enhance microtubule growth rate by several-fold in vitro. Microtubule stimulatory effects were unaffected by mutations in the canonical actin- or poly-proline-binding sites of profilin. Instead, microtubule activities depended on specific surface residues on profilin mutated in ALS patients. Furthermore, microtubule effects were attenuated by increasing concentrations of actin monomers, suggesting competition between actin and microtubules for binding profilin. Consistent with these biochemical observations, a 2-fold increase in the expression level of wild type PFN1, but not the ALS-linked PFN1 mutants, increased microtubule growth rates in cells. Together, these results demonstrate that profilin directly enhances the growth rate of microtubules. They further suggest that ALS-linked mutations in PFN1 may perturb cellular microtubule dynamics and/or the coordination between the actin and microtubule cytoskeletons, leading to motor neuron degeneration. PMID- 29129530 TI - Glutamylation Regulates Transport, Specializes Function, and Sculpts the Structure of Cilia. AB - Ciliary microtubules (MTs) are extensively decorated with post-translational modifications (PTMs), such as glutamylation of tubulin tails. PTMs and tubulin isotype diversity act as a "tubulin code" that regulates cytoskeletal stability and the activity of MT-associated proteins such as kinesins. We previously showed that, in C. elegans cilia, the deglutamylase CCPP-1 affects ciliary ultrastructure, localization of the TRP channel PKD-2 and the kinesin-3 KLP-6, and velocity of the kinesin-2 OSM-3/KIF17, whereas a cell-specific alpha-tubulin isotype regulates ciliary ultrastructure, intraflagellar transport, and ciliary functions of extracellular vesicle (EV)-releasing neurons. Here we examine the role of PTMs and the tubulin code in the ciliary specialization of EV-releasing neurons using genetics, fluorescence microscopy, kymography, electron microscopy, and sensory behavioral assays. Although the C. elegans genome encodes five tubulin tyrosine ligase-like (TTLL) glutamylases, only ttll-11 specifically regulates PKD-2 localization in EV-releasing neurons. In EV-releasing cephalic male (CEM) cilia, TTLL-11 and the deglutamylase CCPP-1 regulate remodeling of 9+0 MT doublets into 18 singlet MTs. Balanced TTLL-11 and CCPP-1 activity fine-tunes glutamylation to control the velocity of the kinesin-2 OSM-3/KIF17 and kinesin-3 KLP-6 without affecting the intraflagellar transport (IFT) kinesin-II. TTLL-11 is transported by ciliary motors. TTLL-11 and CCPP-1 are also required for the ciliary function of releasing bioactive EVs, and TTLL-11 is itself a novel EV cargo. Therefore, MT glutamylation, as part of the tubulin code, controls ciliary specialization, ciliary motor-based transport, and ciliary EV release in a living animal. We suggest that cell-specific control of MT glutamylation may be a conserved mechanism to specialize the form and function of cilia. PMID- 29129532 TI - Idiosyncratic Genome Degradation in a Bacterial Endosymbiont of Periodical Cicadas. AB - When a free-living bacterium transitions to a host-beneficial endosymbiotic lifestyle, it almost invariably loses a large fraction of its genome [1, 2]. The resulting small genomes often become stable in size, structure, and coding capacity [3-5], as exemplified by Sulcia muelleri, a nutritional endosymbiont of cicadas. Sulcia's partner endosymbiont, Hodgkinia cicadicola, similarly remains co-linear in some cicadas diverged by millions of years [6, 7]. But in the long lived periodical cicada Magicicada tredecim, the Hodgkinia genome has split into dozens of tiny, gene-sparse circles that sometimes reside in distinct Hodgkinia cells [8]. Previous data suggested that all other Magicicada species harbor complex Hodgkinia populations, but the timing, number of origins, and outcomes of the splitting process were unknown. Here, by sequencing Hodgkinia metagenomes from the remaining six Magicicada and two sister species, we show that each Magicicada species harbors Hodgkinia populations of at least 20 genomic circles. We find little synteny among the 256 Hodgkinia circles analyzed except between the most closely related cicada species. Gene phylogenies show multiple Hodgkinia lineages in the common ancestor of Magicicada and its closest known relatives but that most splitting has occurred within Magicicada and has given rise to highly variable Hodgkinia gene dosages among species. These data show that Hodgkinia genome degradation has proceeded down different paths in different Magicicada species and support a model of genomic degradation that is stochastic in outcome and nonadaptive for the host. These patterns mirror the genomic instability seen in some mitochondria. PMID- 29129531 TI - The Diversity, Structure, and Function of Heritable Adaptive Immunity Sequences in the Aedes aegypti Genome. AB - The Aedes aegypti mosquito transmits arboviruses, including dengue, chikungunya, and Zika virus. Understanding the mechanisms underlying mosquito immunity could provide new tools to control arbovirus spread. Insects exploit two different RNAi pathways to combat viral and transposon infection: short interfering RNAs (siRNAs) and PIWI-interacting RNAs (piRNAs) [1, 2]. Endogenous viral elements (EVEs) are sequences from non-retroviral viruses that are inserted into the mosquito genome and can act as templates for the production of piRNAs [3, 4]. EVEs therefore represent a record of past infections and a reservoir of potential immune memory [5]. The large-scale organization of EVEs has been difficult to resolve with short-read sequencing because they tend to integrate into repetitive regions of the genome. To define the diversity, organization, and function of EVEs, we took advantage of the contiguity associated with long-read sequencing to generate a high-quality assembly of the Ae. aegypti-derived Aag2 cell line genome, an important and widely used model system. We show EVEs are acquired through recombination with specific classes of long terminal repeat (LTR) retrotransposons and organize into large loci (>50 kbp) characterized by high LTR density. These EVE-containing loci have increased density of piRNAs compared to similar regions without EVEs. Furthermore, we detected EVE-derived piRNAs consistent with a targeted processing of persistently infecting virus genomes. We propose that comparisons of EVEs across mosquito populations may explain differences in vector competence, and further study of the structure and function of these elements in the genome of mosquitoes may lead to epidemiological interventions. PMID- 29129533 TI - Sounds of Modified Flight Feathers Reliably Signal Danger in a Pigeon. AB - In his book on sexual selection, Darwin [1] devoted equal space to non-vocal and vocal communication in birds. Since then, vocal communication has become a model for studies of neurobiology, learning, communication, evolution, and conservation [2, 3]. In contrast, non-vocal "instrumental music," as Darwin called it, has only recently become subject to sustained inquiry [4, 5]. In particular, outstanding work reveals how feathers, often highly modified, produce distinctive sounds [6-9], and suggests that these sounds have evolved at least 70 times, in many orders [10]. It remains to be shown, however, that such sounds are signals used in communication. Here we show that crested pigeons (Ochyphaps lophotes) signal alarm with specially modified wing feathers. We used video and feather removal experiments to demonstrate that the highly modified 8th primary wing feather (P8) produces a distinct note during each downstroke. The sound changes with wingbeat frequency, so that birds fleeing danger produce wing sounds with a higher tempo. Critically, a playback experiment revealed that only if P8 is present does the sound of escape flight signal danger. Our results therefore indicate, nearly 150 years after Darwin's book, that modified feathers can be used for non-vocal communication, and they reveal an intrinsically reliable alarm signal. PMID- 29129534 TI - Mechanical Shielding of Rapidly Growing Cells Buffers Growth Heterogeneity and Contributes to Organ Shape Reproducibility. AB - A landmark of developmental biology is the production of reproducible shapes, through stereotyped morphogenetic events. At the cell level, growth is often highly heterogeneous, allowing shape diversity to arise. Yet, how can reproducible shapes emerge from such growth heterogeneity? Is growth heterogeneity filtered out? Here, we focus on rapidly growing trichome cells in the Arabidopsis sepal, a reproducible floral organ. We show via computational modeling that rapidly growing cells may distort organ shape. However, the cortical microtubule alignment along growth-derived maximal tensile stress in adjacent cells would mechanically isolate rapidly growing cells and limit their impact on organ shape. In vivo, we observed such microtubule response to stress and consistently found no significant effect of trichome number on sepal shape in wild-type and lines with trichome number defects. Conversely, modulating the microtubule response to stress in katanin and spiral2 mutant made sepal shape dependent on trichome number, suggesting that, while mechanical signals are propagated around rapidly growing cells, the resistance to stress in adjacent cells mechanically isolates rapidly growing cells, thus contributing to organ shape reproducibility. PMID- 29129535 TI - Genetic Influence on Eye Movements to Complex Scenes at Short Timescales. AB - Where one looks within their environment constrains one's visual experiences, directly affects cognitive, emotional, and social processing [1-4], influences learning opportunities [5], and ultimately shapes one's developmental path. While there is a high degree of similarity across individuals with regard to which features of a scene are fixated [6-8], large individual differences are also present, especially in disorders of development [9-13], and clarifying the origins of these differences is essential to understand the processes by which individuals develop within the complex environments in which they exist and interact. Toward this end, a recent paper [14] found that "social visual engagement"-namely, gaze to eyes and mouths of faces-is strongly influenced by genetic factors. However, whether genetic factors influence gaze to complex visual scenes more broadly, impacting how both social and non-social scene content are fixated, as well as general visual exploration strategies, has yet to be determined. Using a behavioral genetic approach and eye tracking data from a large sample of 11-year-old human twins (233 same-sex twin pairs; 51% monozygotic, 49% dizygotic), we demonstrate that genetic factors do indeed contribute strongly to eye movement patterns, influencing both one's general tendency for visual exploration of scene content, as well as the precise moment to-moment spatiotemporal pattern of fixations during viewing of complex social and non-social scenes alike. This study adds to a now growing set of results that together illustrate how genetics may broadly influence the process by which individuals actively shape and create their own visual experiences. PMID- 29129536 TI - Event Boundaries Trigger Rapid Memory Reinstatement of the Prior Events to Promote Their Representation in Long-Term Memory. AB - Although everyday experiences unfold continuously over time, shifts in context, or event boundaries, can influence how those events come to be represented in memory [1-4]. Specifically, mnemonic binding across sequential representations is more challenging at context shifts, such that successful temporal associations are more likely to be formed within than across contexts [1, 2, 5-9]. However, in order to preserve a subjective sense of continuity, it is important that the memory system bridge temporally adjacent events, even if they occur in seemingly distinct contexts. Here, we used pattern similarity analysis to scalp electroencephalographic (EEG) recordings during a sequential learning task [2, 3] in humans and showed that the detection of event boundaries triggered a rapid memory reinstatement of the just-encoded sequence episode. Memory reactivation was detected rapidly (~200-800 ms from the onset of the event boundary) and was specific to context shifts that were preceded by an event sequence with episodic content. Memory reinstatement was not observed during the sequential encoding of events within an episode, indicating that memory reactivation was induced specifically upon context shifts. Finally, the degree of neural similarity between neural responses elicited during sequence encoding and at event boundaries correlated positively with participants' ability to later link across sequences of events, suggesting a critical role in binding temporally adjacent events in long-term memory. Current results shed light onto the neural mechanisms that promote episodic encoding not only for information within the event, but also, importantly, in the ability to link across events to create a memory representation of continuous experience. PMID- 29129538 TI - Pneumonia in the tropics: Report from the Task Force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. AB - The aetiology of community acquired pneumonia varies according to the region in which it is acquired. This review discusses those causes of CAP that occur in the tropics and might not be readily recognizable when transplanted to other sites. Various forms of pneumonia including the viral causes such as influenza (seasonal and avian varieties), the coronaviruses and the Hantavirus as well as bacterial causes, specifically the pneumonic form of Yersinia pestis and melioidosis are discussed. PMID- 29129537 TI - A Moving Source of Matrix Components Is Essential for De Novo Basement Membrane Formation. AB - The basement membrane (BM) is a thin layer of extracellular matrix (ECM) beneath nearly all epithelial cell types that is critical for cellular and tissue function. It is composed of numerous components conserved among all bilaterians [1]; however, it is unknown how all of these components are generated and subsequently constructed to form a fully mature BM in the living animal. Although BM formation is thought to simply involve a process of self-assembly [2], this concept suffers from a number of logistical issues when considering its construction in vivo. First, incorporation of BM components appears to be hierarchical [3-5], yet it is unclear whether their production during embryogenesis must also be regulated in a temporal fashion. Second, many BM proteins are produced not only by the cells residing on the BM but also by surrounding cell types [6-9], and it is unclear how large, possibly insoluble protein complexes [10] are delivered into the matrix. Here we exploit our ability to live image and genetically dissect de novo BM formation during Drosophila development. This reveals that there is a temporal hierarchy of BM protein production that is essential for proper component incorporation. Furthermore, we show that BM components require secretion by migrating macrophages (hemocytes) during their developmental dispersal, which is critical for embryogenesis. Indeed, hemocyte migration is essential to deliver a subset of ECM components evenly throughout the embryo. This reveals that de novo BM construction requires a combination of both production and distribution logistics allowing for the timely delivery of core components. PMID- 29129539 TI - Leptospirosis: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. AB - Leptospirosis is a zoonosis caused by a gram negative aerobic spirochete of the genus Leptospira. It is acquired by contact with urine or reproductive fluids from infected animals, or by inoculation from contaminated water or soil. The disease has a global distribution, mainly in tropical and subtropical regions that have a humid, rainy climate and is also common in travelers returning from these regions. Clinical suspicion is critical for the diagnosis and it should be included in the differential diagnosis of any patient with a febrile hepatorenal syndrome in, or returning from endemic regions. The leptospiremic phase occurs early and thereafter there is an immunologic phase in which the most severe form, Weil's disease, occurs. In the latter, multiple organ dysfunction predominates. The appropriate diagnostic test depends on the stage of the disease and consists of direct and indirect detection methods and cultures. Severely ill patients need to be monitored in an ICU with appropriate anti-bacterial agents and early, aggressive and effective organ support. Antibiotic therapy consists of penicillins, macrolides or third generation cephalosporins. PMID- 29129540 TI - Inhibitory role of oxytocin on TNFalpha expression assessed in vitro and in vivo. AB - AIM: Oxytocin administration to diet-induced obese (DIO) rodents, monkeys and humans decreases body weight and fat mass with concomitant improvements in glucose metabolism. Moreover, several studies show an immunomodulatory role of oxytocin in a number of settings (such as atherosclerosis, injury, sepsis). This study aims to shed some light on the effects of oxytocin on macrophage polarization and cytokine production, as well as its possible impact on these parameters in adipose tissue in DIO mice with impaired glucose metabolism. METHODS: Mouse bone marrow cells were differentiated into macrophages and treated with oxytocin. Macrophage proliferation, cytokine secretion and macrophage populations were determined. For experiments in vivo, DIO mice were treated with oxytocin for 2 weeks. Body weight and composition and glucose tolerance were subsequently followed. At the end of treatment, adipose tissue macrophage populations, plasma cytokine levels and cytokine expression in adipose tissue were determined. RESULTS: In bone marrow-derived macrophages, oxytocin induced an anti-inflammatory phenotype (decreased M1/M2 ratio). In M1-derived macrophages, oxytocin decreased TNFalpha secretion, with no effects on the other cytokines tested nor any effect on cytokine secretion by M2-derived macrophages. Oxytocin treatment in DIO mice in vivo led to decreased body weight accompanied by an improvement in glucose tolerance, with no changes in plasma cytokine levels. In adipose tissue, oxytocin decreased Tnfalpha expression without modifying the M1/M2 macrophage ratio. CONCLUSION: Oxytocin treatment decreases TNFalpha production both in vitro (in bone marrow-derived macrophages) and in vivo (in epididymal adipose tissue) in DIO mice. This effect may also be contributory to the observed improvement in glucose metabolism. PMID- 29129541 TI - Weight gain in early pregnancy and risk of gestational diabetes mellitus among Latinas. AB - AIM: To evaluate the association between gestational weight gain (GWG) in early pregnancy and incidence of abnormal glucose tolerance (AGT) and gestational diabetes mellitus (GDM) among Latinas. METHODS: We conducted a retrospective cohort study of 2039 Latinas using pooled data from two medical centres in Massachusetts. Gestational weights were abstracted from medical records and GWG was categorized as low, appropriate and excessive according to 2009 Institute of Medicine Guidelines. Diagnosis of AGT and GDM was confirmed by study obstetricians. RESULTS: A total of 143 women (7.0%) were diagnosed with GDM and 354 (17.4%) with AGT. After adjusting for age and study site, women with low GWG up to the time of GDM screen had a lower odds of GDM (OR: 0.51, 95% CI: 0.29 0.92). Among overweight women, women with excessive first-trimester GWG had 2 fold higher odds of AGT (OR: 1.96, 95% CI: 1.17-3.30) and GDM (OR: 2.07, 95% CI: 1.04-4.12) compared to those with appropriate GWG; however, these findings were not significant among normal weight or obese women. CONCLUSION: Among Latinas, low GWG up to the time of GDM screen was associated with lower odds of AGT and GDM, while excessive GWG among overweight women was associated with higher odds. Findings highlight need for interventions in early pregnancy to help women meet GWG guidelines and to moderate GWG among overweight Latinas. PMID- 29129542 TI - Tumor-infiltrating T lymphocytes and morphogenesis of follicular lymphoma. PMID- 29129543 TI - Idiopathic elastosis perforans serpiginosa with satisfactory response after 5-ALA photodynamic therapy. AB - Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents, light, and oxygen for the treatment of malignant or benign diseases. Topical photosensitizers employed in dermatology are 5-aminolevulinic acid (5 ALA) and methyl aminolevulinate, classically used for the treatment of superficial non-melanoma skin cancer and their precursors. Recently the efficacy of PDT has been introduced in other benign diseases. Elastosis perforans serpiginosa (EPS) is a rare skin disorder characterized by transepidermal elimination of abnormal elastic fibers. Management of this condition is complicated, various methods have been used but with limited success. We report a case of EPS in a 30-yeard-old woman treated with 5 ALA-PDT. After 4 sessions the lesions have almost completely disappeared with no residual side effects. Therefore we present an effective and safe alternative for the treatment of EPS. PMID- 29129544 TI - Diffusion imaging study of the Corpus Callosum in bipolar disorder. AB - Structural and diffusion imaging studies have provided some evidence of abnormal organization of Corpus Callosum (CC) in Bipolar Disorder (BD). Therefore, by using Diffusion Weighted Imaging (DWI), which allows to build subtle prediction models of fiber integrity for white matter (WM) tracts, this study aims to further explore the microstructure integrity of CC in BD patients compared to matched healthy controls. Twenty-four chronic patients with BD and 35 healthy controls were included in the study. Circular regions of interest were placed, on diffusion images, in the left and right side of callosal regions (i.e. rostrum/genu, anterior body, posterior body, splenium) and the Apparent Diffusion Coefficient (ADC) was then calculated. Significantly increased ADC values were found in right anterior body and in right splenium in BD patients compared to healthy controls (all p < 0.05, Bonferroni corrected). In this study, we found abnormally increased ADC callosal values in BD suggesting microstructural anomalies specifically in the right hemisphere. Interestingly, this finding further supports the presence of an altered inter-hemispheric communication between frontal and temporo-parietal association areas in patients with BD, which may ultimately result in clinical symptoms and cognitive deficits. PMID- 29129545 TI - Predicting progression of amnesic MCI: The integration of episodic memory impairment with perfusion SPECT. AB - The present study aimed at assessing if the ability to predict progression from amnesic Mild Cognitive Impairment (aMCI) to dementia is improved by considering the presence at the baseline of Single Photon Emission Computed Tomography (SPECT) perfusion abnormalities in addition to a defect of long term memory. The Episodic Memory Score (EMS), a global index which integrates results obtained in subtests of the Rey's Verbal Learning Test and the Rey-Osterrieth Figure recall, were taken into account to evaluate defects of long term memory. The study sample consisted of 42 subjects affected by aMCI, who were followed-up during a two-year period. At the final follow-up 15 subjects progressed to AD. The EMS predicted progression from aMCI to dementia with a high level of sensitivity and a lower level of specificity, but the association of neuropsychological (EMS) and SPECT data (hypoperfusion in the Posterior Cingulate Cortex) increased the accuracy in predicting conversion from aMCI to AD. The association of results obtained by aMCI patients on memory tests and perfusion SPECT may improve the accuracy in detecting subjects who will progress to dementia. The use of currently available and low-cost investigations could be advantageous in terms of public health policies. PMID- 29129546 TI - Solitary intraosseous myofibroma of the ilium in an adult patient: A case report and literature review. AB - BACKGROUND: Myofibroma is a rare benign tumor typically occurring in the skin and subcutaneous tissues of the head and neck in infants and young children. The incidence of solitary intraosseous and adult myofibroma is extremely low. Although there have been a few reported cases of solitary intraosseous myofibroma in adult patients, most of these cases involved the craniofacial bones. METHODS: We present the case of a 64-years-old woman presenting with minimal pain of the right buttock and groin. RESULT: Radiographs and computed tomography showed a huge tumor spreading around the ilium, and non-uniform calcifications were noted inside the tumor. Iliac tumor biopsy was conducted, and intraosseous myofibroma was suspected. We performed surgical resection of the mass, and a final diagnosis of myofibroma with metaplastic bone production was made. CONCLUSION: We have presented an extremely rare case of solitary intraosseous myofibroma in an adult patient. PMID- 29129547 TI - A mathematical model of nutrient influence on fungal competition. AB - Fungi have a well-established role in nutrient cycling and are widely used as agents in biological control and in the remediation of polluted landscapes. Competition for resources between different fungal communities is common in these contexts and its outcome impacts on the success of such biotechnological applications. In this investigation a mathematical model is constructed to represent competition between two fungal colonies that have access to different resources. It is shown that the model equations display a multitude of travelling wave solutions and that the outcome of competition between two fungal biomasses can be controlled through the simple manipulation of the nutrient resources available to each. The model equations are also numerically integrated to illustrate the range of outcomes arising from fungal competition and these results are placed in context of established experimental observations. PMID- 29129548 TI - Bifurcation of a delayed Gause predator-prey model with Michaelis-Menten type harvesting. AB - In this paper, a Gause predator-prey model with gestation delay and Michaelis Menten type harvesting of prey is proposed and analyzed by considering Holling type III functional response. We first consider the local stability of the interior equilibrium by investigating the corresponding characteristic equation. In succession, we derive some sufficient conditions on the occurrence of the stability switches of the positive steady state by taking the gestation delay as a bifurcation parameter. It is shown that the delay can induce instability and small amplitude oscillations of population densities via Hopf bifurcations. Furthermore, the stability and direction of the Hopf bifurcations are determined by employing the center manifold argument. Finally, computer simulations are performed to illustrate our analytical findings, and the biological implications of our analytical findings are also discussed. PMID- 29129550 TI - Use of newer technologies with existing service for family reintegration of unknown psychiatric patients: A case series. AB - Homeless Mentally Ill (HMI) patients pose a challenge in treatment, management and rehabilitation services. HMI patients are often difficult to engage in treatment, and associated with relapse and rehospitalization, even after recovery. Family plays an important role in treatment engagement and care of the mentally ill person in India. Here, we report two unknown psychiatric patients who were reintegrated to their families using newer technologies with existing service. Newer technologies have helped in early identification of HMI families and reintegration into them. The early reintegration reduced the unnecessary detention of HMI patients inside the hospital after recovery. PMID- 29129549 TI - Application of ACOSOG Z1071: Effect of Results on Patient Care and Surgical Decision-Making. AB - BACKGROUND: The ACOSOG (American College of Surgeons Oncology Group) Z1071 assessed the feasibility of performing sentinel lymph node biopsy (SLNB) in node positive patients who completed neoadjuvant chemotherapy (NACT). Historically, adoption of clinical research into practice takes years. The goal of this study was to determine the effect of Z1071 on our practice. MATERIALS AND METHODS: This is a retrospective review of Z1071's influence on a single institution's practice. Patients with biopsy-proven positive axillary lymph nodes before NACT were eligible for the study. After NACT, patients with nodal response according to imaging and exam were candidates for SLNB. Two cohorts were stratified according to diagnosis date before and after Z1071 results were presented on December 5, 2012 at the San Antonio Breast Cancer Symposium. Fisher exact tests and nonparametric rank tests were used to compare cohorts. RESULTS: The pre-Z1071 cohort included 74 patients and the post-Z1071 cohort 56 for a total of 130 patients. Post-Z1071, 73% (41/56) underwent a SLNB with an average of 4 nodes removed. Moreover, 27% (15/56) of patients had an axillary lymph node dissection as first intervention post-Z1071, compared with 99% (73/74) pre-Z1071. Axillary pathologic complete response pre-Z1071 was 35% (26/74) and post-Z1071 was 27% (15/56) (P = .35). CONCLUSION: This report shows that meaningful practice changes can be implemented rapidly. Changes in practice generated by clinical trial results should be monitored and outcomes followed. PMID- 29129551 TI - Response to the letter: "Efficacy and tolerability of long acting injectable antipsychotics (LAI) over oral formulations". PMID- 29129552 TI - Clinical characteristics of suicidal behavior in an intensive care unit at a university hospital in Japan: A 7-year observational study. AB - BACKGROUND: Suicidal behavior accounts for at least 40,000 admissions per year to emergency departments in Japan; however, little is known about emergency admissions owing to suicidal behavior in metropolitan areas. Therefore, we examined the clinical characteristics of suicidal behavior using psychosocial assessments performed by experienced psychiatrists in an intensive care unit. METHODS: Participants were 971 patients admitted to a university hospital's intensive care unit for suicidal behavior between July 2006 and June 2013. Physicians and psychiatrists regularly assessed the participants using a standard data extraction form while the participants were in the intensive care unit. As suicidal behavior involving drug overdose is generally less fatal than other methods, we predicted that clinical characteristics would differ between patients with and without overdose. We classified participants into drug overdose or other method groups (ns=732 and 239, respectively) to compare suicide methods. RESULTS: In the overdose group, participants' median age was approximately 5 years lower, and the following proportions were larger: female participants (77%) and participants with borderline personality disorders (21% vs. 10%), no clear suicidal ideation (30% vs. 15%), impulsively attempted self-harm (86% vs. 62%), and interpersonal problems (26% vs. 16%). CONCLUSION: Ameliorating interpersonal problems and improving stress coping skills would benefit people who attempt suicide via overdose. PMID- 29129553 TI - MitoepigenomeKB a comprehensive resource for human mitochondrial epigenetic data. AB - Epigenetic modifications in the mitochondrial genome has been an emerging area of interest in the recent years in the field of mitochondrial biology. The renewed interest in the area has been largely fueled by a number of reports in the recent years suggesting the presence of epigenetic modifications in human mitochondrial genome and their associations with exposure to environmental factors and human diseases and or traits. Nevertheless there has been no systematic effort to curate, organize this information to enable cross-comparison between studies and datasets. We compiled 62 datasets from 9 studies on the epigenetic modifications in human mitochondrial genome to create a comprehensive catalog. This catalog is available as a user friendly interface - mitoepigenomeKB, where the data could be searched, browsed or visualized. The resource is available at URL: http://clingen.igib.res.in/mitoepigenome/. We hope mitoepigenomeKB would emerge as a central resource for datasets on epigenetic modifications in human mitochondria and would serve as the starting point to understanding the biology of human mitochondrial epigenome. PMID- 29129554 TI - Development of a novel observer reported outcome tool as the primary efficacy outcome measure for a rare disease randomized controlled trial. AB - We developed an Observer-Reported Outcome (ObsRO) survey instrument to be applied in a multicenter, placebo-controlled, crossover randomized controlled trial of dichloroacetate in children with pyruvate dehydrogenase complex deficiency. The instrument quantifies a subject's at-home level of functionality, as reported by a parent/caregiver, who were instrumental in providing the clinical descriptors and domains that formed the instrument's content. Feasibility testing of the ObsRO tool showed it to be easy to use and comprehensive in capturing the major clinical functional limitations of affected children and requires less than 5min for a parent/caregiver to complete daily. PMID- 29129555 TI - Nicotine delivery efficiency of first- and second-generation e-cigarettes and its impact on relief of craving during the acute phase of use. AB - Knowledge about the change in blood nicotine concentrations during the first five minutes (acute phase) of e-cigarette vaping is important to determine whether the used product has a dependence potential or may be an efficient nicotine replacement product. To address this issue, we monitored blood nicotine levels during the acute phase in volunteers using disposable cigalikes (CLs) and a tank model (TM) and compared them with blood nicotine levels in subjects using a tobacco cigarette (TC). In parallel, heart rate changes were continually measured and withdrawal symptoms and craving were assessed with the Questionnaire on Smoking Urges before and immediately after the vaping/smoking sessions. Additionally, at the end of each session negative health effects were rated on a visual analog scale. After five minutes of e-cigarette or TC use, the mean nicotine plasma concentrations were as follows: CLs, 5.5ng/ml; TM, 9.3ng/ml; TC, 17.1ng/ml. Nicotine levels increased significantly faster in the first 4min of consuming a TC than with the CLs and the TM. The highest rate of increase in nicotine concentration was found with the TC (6.8ng/ml) and TM (2.3ng/ml) between the 1st and 2nd minute, whereas the CLs showed comparatively small changes in the amount delivered over the five minutes. Withdrawal and craving for smoking decreased with the TM by the same amount as with the TC, even though less nicotine was delivered to the blood and considerably fewer side effects occurred. The heart rate of TM users was also markedly lower than that of the TC users. Unlike CLs, TM e-cigarettes represent an effective source of nicotine and might be used as an alternative nicotine replacement product to aid smoking cessation. However, nicotine plasma levels observed in TM users after short-time vaping have also the potential to produce and sustain nicotine addiction. PMID- 29129556 TI - Mechanisms of RhoA inactivation and CDC42 and Rac1 activation during zebrafish optic nerve regeneration. AB - When axons of the mammalian central nervous system (CNS) are injured, they fail to regenerate, while those of lower vertebrates undergo regeneration after injury. Wingless-type MMTV integration site family (Wnt) proteins play important roles in the CNS, and are reported to be activated after mammalian spinal cord or brain injury. Moreover, for axon growth to proceed, it is thought that small G proteins, such as CDC42 and Rac1, need to be activated, whereas RhoA must be inactivated. However, the cell and molecular mechanisms involved in optic nerve regeneration remain unclear. In this study, we investigated axonal regeneration after injury using the zebrafish optic nerve as a model system. We sought to clarify the role of Wnt proteins and the mechanisms involved in the activation and inactivation of small G-proteins in nerve regeneration. After optic nerve injury, mRNA levels of Wnt5b, TAX1BP3 and ICAT increased in the retina, while those of Wnt10a decreased. These changes were associated with a reduction in beta catenin in nuclei. We found that Wnt5b activated CDC42 and Rac1, leading to the inactivation of RhoA, which appeared to be dependent on increased TAX1BP3 mRNA levels. Furthermore, we found that mRNA levels of Daam1a and ARHGEF16 decreased. We speculate that the decrease in beta-catenin levels, which also further reduces levels of active RhoA, might contribute to regeneration in the zebrafish. Collectively, our novel results suggest that Wnt5b, Wnt10a, ICAT and TAX1BP3 participate in the activation and inactivation of small G-proteins, such as CDC42, Rac1 and RhoA, during the early stage of optic nerve regeneration in the zebrafish. PMID- 29129557 TI - Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. AB - Metabolic and behavioural effects of, and interactions between Delta9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications. PMID- 29129558 TI - Time and psychostimulants: Opposing long-term structural effects in the adult ADHD brain. A longitudinal MR study. AB - Long-term effects of psychostimulants such as methylphenidate on ADHD patients have been proved to be difficult to capture in cross-sectional studies comparing medicated and non-medicated samples and in longitudinal studies with children, with age-related maturational processes possibly confounding independent effects of medication. However, chronic psychostimulant administration at therapeutic doses has been proven to yield profound neuroadaptive changes in rodent models. Here, we present for the first time the effect of psychostimulant treatment on brain volumes in a sample of medication-naive adult ADHD patients. We investigated grey matter volume changes in a sample of 41 medication-naive adult ADHD patients before and after three years of psychostimulant treatment (N = 25) or no treatment (N = 16) compared to healthy adults (N = 25). We found a significant group x time interaction effect on left putamen grey matter volumes, with a decrease in left putamen volumes in the non-medicated group compared to both the medicated group and controls, and no differences between the medicated group and controls. Our results suggest a normalizing effect of psychostimulant treatment on the left putamen volume loss detected in non-medicated ADHD patients. PMID- 29129559 TI - Treatment and Survival Outcome of BRAF-Mutated Metastatic Colorectal Cancer: A Retrospective Matched Case-Control Study. AB - BACKGROUND: Somatic v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation, present in approximately 10% of metastatic colorectal cancer (mCRC) cases, is associated with poor prognosis. Patient outcome outside of clinical trials has only been reported in small series. We report real-world data on treatment and survival for BRAF-mutated (MT) patients at a single tertiary center, compared with a matched BRAF wild type (WT) control group. PATIENTS AND METHODS: All colorectal cancer patients tested for BRAF mutation, from October 2010 to November 2014 were identified. BRAF-MT mCRC cases were compared with an age and sex-matched BRAF-WT control group. Clinicopathological data were collected and survival calculated using the Kaplan-Meier method and comparisons made using Cox regression. RESULTS: Forty-three of 503 patients (8.5%) tested had BRAF-MT mCRC and were compared with 88 BRAF-WT controls. Median overall survival (mOS) was 18.2 months for BRAF-MT and 41.1 months for BRAF-WT mCRC patients (hazard ratio, 2.74; 95% confidence interval, 1.60-4.70; P < .001). Progression free survival for BRAF-MT and WT patients, respectively, was: 8.1 months versus 9.2 months (P = .571) first-line, 5.5 months versus 8.3 months (P = .074) second line, and 1.8 months versus 5.6 months (P = .074) third-line. Treatment using sequential fluoropyrimidine-based doublet chemotherapy was similar between both groups. Anti-epidermal growth factor receptor (EGFR) therapy was mainly given third-line with progressive disease in 90% (n = 9 of 10) of BRAF-MT patients at first restaging. CONCLUSION: In this case-control study, the poor mOS of BRAF-MT mCRC was associated with reduced treatment benefit beyond first-line. Sequential doublet chemotherapy remains a reasonable option in appropriately selected patients. BRAF-MT patients did not benefit from anti-EGFR therapy in this study. Recruitment to clinical trials is recommended to improve outcomes in BRAF-MT mCRC. PMID- 29129560 TI - The Role of Holter Monitoring in the Diagnosis of Early Repolarisation Pattern. AB - BACKGROUND: A slower heart rate can exaggerate J-point elevation in a 12-lead ECG. This study examined the role of Holter monitoring in the diagnosis of early repolarisation pattern (ERP). METHODS: We examined 24-hour Holter recordings of 4000 consecutive patients seen at an outpatient clinic, and found 500 patients (12.5%) with ERP (based on J-point elevation magnitude maximum value>=0.1mV on the Holter recording). The highest magnitude of J-point elevation, R wave amplitude, the ratio between J-point elevation magnitude and R-wave amplitude on the same ECG lead (J/R ratio), QRS interval, and QT/QTc interval were measured on the Holter recording and on a surface 12-lead ECG of the 500 patients with ERP. The magnitude of J-point elevation, J/R ratio, and QT/QTc interval were compared between three groups: nighttime Holter recording, daytime Holter recording, and daytime surface 12-lead ECG. RESULTS: The magnitude of J-point elevation of the nighttime Holter (0.20+/-0.10mV) was higher than that of the daytime in Holter (0.12+/-0.07mV, p<0.001) and the 12-lead ECG (0.12+/-0.06mV, p<0.001). There was no statistical difference in magnitude of J-point elevation between daytime Holter and surface 12-lead ECG. While all 500 patients were diagnosed with ERP based on J-point elevation maximum value J-point on Holter monitoring, only 425 (85%) patients could be diagnosed with ERP based on the surface 12-lead ECG. The J-point elevation maximum value on the nighttime Holter was negatively correlated with heart rate (r=-0.15, p=0.0007) and QTc (r=-0.13, p=0.0043), and positively correlated with R wave amplitude (r=0.46, p<0.0001), J/R ratio (r=0.69, p<0.0001), and QRS interval (r=0.29, p<0.0001). CONCLUSIONS: The J-point elevation on nighttime Holter recording was higher than that on daytime Holter and daytime surface 12-lead ECG, and there was misdiagnosis of ERP based on daytime surface 12-lead ECG. Holter monitoring has a complementary role in the diagnosis of ERP, especially in patients with a suspected diagnosis of ERP based on daytime surface 12-lead ECG. PMID- 29129561 TI - Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy: A 16-Year Australian Single Centre Experience. AB - BACKGROUND: Alcohol septal ablation (ASA), is a well-established treatment for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). We report the acute, short and long-term clinical and echocardiographic outcomes of our experience in a single Australian centre over 16 years. METHODS: We retrospectively analysed consecutive patients presenting to our centre for ASA between March 2000 and July 2016. Local databases were interrogated along with direct patient or physician contact occurred where required. RESULTS: Alcohol septal ablation was performed in 80 patients with symptomatic, medication refractory HOCM (mean age 61+/-15 years; range 22-84 years; 50% male). All patients had transthoracic echocardiography prior to the procedure, within 48hours of the procedure, 6 weeks, 6 months, 1 year and yearly thereafter to a median follow-up of 80+/ 40months. At baseline, mean resting and provoked LVOT gradients were 80+/-49mmHg and 97+/-40mmHg respectively. Compared with baseline, ASA led to a reduction in resting LVOT gradients at all time points, particularly at 2 days-52+/-41mmHg, p<0.001; 12 months-29+/-34mmHg, p<0.001; and last follow-up 12+/-21mmHg, p<0.001. Provoked LVOT gradients were also reduced at 2 days-64+/-44mmHg and last follow up of 19+/-29mmHg, p<0.001. Compared to baseline (19.8+/-4.2mm), ASA was associated with a reduction in interventricular septal (IVS) thickness at all time intervals with last echocardiographic follow-up at 80 months being 16.0+/ 4.9mm, (=1 MUg/L per h) had no significant excess risk. INTERPRETATION: The current practice of MR antagonist therapy in primary aldosteronism is associated with significantly higher risk for incident cardiometabolic events and death, independent of blood pressure control, than for patients with essential hypertension. Titration of MR antagonist therapy to raise renin might mitigate this excess risk. FUNDING: US National Institutes of Health. PMID- 29129577 TI - Pelvic bone anatomy vs implanted gold seed marker registration for image-guided intensity modulated radiotherapy for prostate carcinoma: Comparative analysis of inter-fraction motion and toxicities. AB - OBJECTIVES: We compared the prostate motion variability and toxicities between patients treated with gold marker registration based IG-IMRT (IG-IMRT-M) and bony landmark registration based IG-IMRT (IG-IMRT-B). METHODS: T1c-T3b (node negative), intermediate and high risk (non-metastatic) adenocarcinoma of prostate, age >=18years, Karnofsky Performance Status of >=70 were included in this retrospective study. The prostate motion variability, acute and late radiation toxicities between the two treatment arms (IG-IMRT-M versus IG-IMRT-B) were compared. RESULTS: Total of 35 patients (17 for IG-IMRT-M and 18 for IG-IMRT B) were treated with a median radiotherapy dose of 76 Gray. The prostate variability observed with and without markers in millimeter was 4.1+/-2.3 vs 3.7+/-2.1 [Antero-Posterior (A-P); p=0.001], 2.3+/-1.5 vs 2.1+/-1.2 [Superior Inferior (S-I); p=0.095] and 1.1+/-1.7 vs 0.4+/-1.4 [Left-Right (L-R); p=0.003]. There was higher acute toxicity in IG-IMRT-B arm compared to IG-IMRT-M arm in terms of grade >=2 diarrhea [50% vs 11% OR=7.5 (1.3-42.7); p=0.02] and grade >=2 proctitis [38% vs 5.8%, OR=10.1 (1.09-94.1); p=0.04]. At a median follow up of 36months, the late genitourinary toxicities grade >=2 [27% vs 0%; p=0.04] were higher in the IG-IMRT-B arm compared to IG-IMRT-M arm. CONCLUSIONS: IG-IMRT-M detects higher prostate motion variability as compared to IG-IMRT-B, inferring a significant prostate motion inside fixed pelvic bony cavity. The addition of marker based image guidance results in higher precision of prostate localization and lesser acute and late toxicities. PMID- 29129579 TI - Epidemiology of REM sleep behavior disorder: both study design and measurement tool count. PMID- 29129578 TI - Cryptococcosis in an Infectious Diseases Hospital of Buenos Aires, Argentina. Revision of 2041 cases: Diagnosis, clinical features and therapeutics. AB - BACKGROUND: Cryptococcosis is still a life-threatening mycosis that continues to be of serious concern in Latin American countries, especially among HIV+positive population. However, there is not any reliable information about the prevalence of this disease in this region. AIMS: The aim of this study is to report data of 2041 patients with cryptococcosis that were attended at the Infectious Diseases Hospital F. J. Muniz over a 30 year-period. METHODS: Information about demographic and clinical data, survival time and the applied treatment, was taken from the Mycology Unit database. Mycological exams from different clinical samples were performed. Cryptococcal capsular antigen in serum and cerebrospinal fluid was detected through the latex agglutination technique. Cryptococcus isolates were phenotypically identified and the genotype was determined in some of them. Susceptibility tests were carried out following M27-A3 document. RESULTS: Seventy five percent of HIV+positive patients and 50% of the HIV negative population were males. Mean ages were 34.1 in HIV+positive patients and 44.8 in the HIV-negative. Cryptococcosis was associated with AIDS in 98% of the cases. Meningeal compromise was seen in 90% of the patients. Although cerebrospinal fluid rendered more positive results, blood culture was the first diagnostic finding in some cases. Cryptococcal antigen showed positive results in 96.2% of the sera samples and in the 93.1% of the cerebrospinal fluid samples. Most of the isolates were Cryptococcus neoformans and belonged to genotype VNI. Minimal inhibitory concentration values were mostly below the epidemiological cutoff values. CONCLUSIONS: We observed that thanks to a high level of clinical suspicion, early diagnosis, combined therapy and intracranial pressure control by daily lumbar punctures, the global mortality rate has markedly decreased through the years in the analyzed period. PMID- 29129580 TI - The beta and alpha2delta auxiliary subunits of voltage-gated calcium channel 1 (Cav1) are required for TH2 lymphocyte function and acute allergic airway inflammation. AB - BACKGROUND: T lymphocytes express not only cell membrane ORAI calcium release activated calcium modulator 1 but also voltage-gated calcium channel (Cav) 1 channels. In excitable cells these channels are composed of the ion-forming pore alpha1 and auxiliary subunits (beta and alpha2delta) needed for proper trafficking and activation of the channel. Previously, we disclosed the role of Cav1.2 alpha1 in mouse and human TH2 but not TH1 cell functions and showed that knocking down Cav1 alpha1 prevents experimental asthma. OBJECTIVE: We investigated the role of beta and alpha2delta auxiliary subunits on Cav1 alpha1 function in TH2 lymphocytes and on the development of acute allergic airway inflammation. METHODS: We used Cavbeta antisense oligonucleotides to knock down Cavbeta and gabapentin, a drug that binds to and inhibits alpha2delta1 and alpha2delta2, to test their effects on TH2 functions and their capacity to reduce allergic airway inflammation. RESULTS: Mouse and human TH2 cells express mainly Cavbeta1, beta3, and alpha2delta2 subunits. Cavbeta antisense reduces T-cell receptor-driven calcium responses and cytokine production by mouse and human TH2 cells with no effect on TH1 cells. Cavbeta is mainly involved in restraining Cav1.2 alpha1 degradation through the proteasome because a proteasome inhibitor partially restores the alpha1 protein level. Gabapentin impairs the T-cell receptor-driven calcium response and cytokine production associated with the loss of alpha2delta2 protein in TH2 cells. CONCLUSIONS: These results stress the role of Cavbeta and alpha2delta2 auxiliary subunits in the stability and activation of Cav1.2 channels in TH2 lymphocytes both in vitro and in vivo, as demonstrated by the beneficial effect of Cavbeta antisense and gabapentin in allergic airway inflammation. PMID- 29129582 TI - Ventilation defect percent in helium-3 magnetic resonance imaging as a biomarker of severe outcomes in asthma. PMID- 29129583 TI - Identification of atopic dermatitis subgroups in children from 2 longitudinal birth cohorts. AB - BACKGROUND: Atopic dermatitis (AD) is a prevalent disease with variable natural history. Longitudinal birth cohort studies provide an opportunity to define subgroups on the basis of disease trajectories, which may represent different genetic and environmental pathomechanisms. OBJECTIVES: We sought to investigate the existence of distinct longitudinal phenotypes of AD and test whether these findings are reproducible in 2 independent cohorts. METHODS: The presence of AD was examined in 2 birth cohort studies including 9894 children from the United Kingdom (ALSPAC) and 3652 from the Netherlands (PIAMA). AD was defined by parental report of a typical itchy and/or flexural rash. Longitudinal latent class analysis was used to investigate patterns of AD from birth to the age of 11 to 16 years. We investigated associations with known AD risk factors, including FLG null mutations, 23 other established AD-genetic risk variants, and atopic comorbidity. RESULTS: Six latent classes were identified, representing subphenotypes of AD, with remarkable consistency between the 2 cohorts. The most prevalent class was early-onset-early-resolving AD, which was associated with male sex. Two classes of persistent disease were identified (early-onset persistent and early-onset-late-resolving); these were most strongly associated with the AD-genetic risk score as well as personal and parental history of atopic disease. A yet unrecognized class of mid-onset-resolving AD, not associated with FLG mutations, but strongly associated with asthma, was identified. CONCLUSIONS: Six classes based on temporal trajectories of rash were consistently identified in 2 population-based cohorts. The differing risk factor profiles and diverse prognoses demonstrate the potential importance of a stratified medicine approach for AD. PMID- 29129584 TI - High salt loading induces urinary storage dysfunction via upregulation of epithelial sodium channel alpha in the bladder epithelium in Dahl salt-sensitive rats. AB - We aimed to investigate whether high salt intake affects bladder function via epithelial sodium channel (ENaC) by using Dahl salt-resistant (DR) and salt sensitive (DS) rats. Bladder weight of DR + high-salt diet (HS, 8% NaCl) and DS + HS groups were significantly higher than those of DR + normal-salt diet (NS, 0.3% NaCl) and DS + NS groups after one week treatment. We thereafter used only DR + HS and DS + HS group. Systolic and diastolic blood pressures were significantly higher in DS + HS group than in DR + HS group after the treatment period. Cystometrogram showed the intercontraction intervals (ICI) were significantly shorter in DS + HS group than in DR + HS group during infusion of saline. Subsequent infusion of amiloride significantly prolonged ICI in DS + HS group, while no intra-group difference in ICI was observed in DR + HS group. No intra- or inter-group differences in maximum intravesical pressure were observed. Protein expression levels of ENaCalpha in the bladder were significantly higher in DS + HS group than in DR + HS group. ENaCalpha protein was localized at bladder epithelium in both groups. In conclusion, high salt intake is considered to cause urinary storage dysfunction via upregulation of ENaC in the bladder epithelium with salt-sensitive hypertension, suggesting that ENaC might be a candidate for therapeutic target for urinary storage dysfunction. PMID- 29129585 TI - Re: Strategies for pH regulation during organ preservation. PMID- 29129581 TI - Eosinophilic esophagitis (EoE) genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is an esophageal inflammatory disease associated with atopic diseases. Thymic stromal lymphopoietin (TSLP) and calpain 14 (CAPN14) genetic variations contribute to EoE, but how this relates to atopy is unclear. OBJECTIVE: The purpose of this study was to explore the relationship between EoE, atopy, and genetic risk. METHODS: EoE-atopy enrichment was tested by using 700 patients with EoE and 801 community control subjects. Probing 372 single nucleotide polymorphisms (SNPs) in 63 atopy genes, we evaluated EoE associations using 412 nonatopic and 868 atopic disease control subjects. Interaction and stratified analyses of EoE-specific and atopy-related SNPs were performed. RESULTS: Atopic disease was enriched in patients with EoE (P < .0001). Comparing patients with EoE and nonatopic control subjects, EoE associated strongly with IL-4/kinesin family member 3A (IL4/KIF3A) (P = 2.8 * 10-6; odds ratio [OR], 1.87), moderately with TSLP (P = 1.5 * 10-4; OR, 1.43), and nominally with CAPN14 (P = .029; OR, 1.35). Comparing patients with EoE with atopic disease control subjects, EoE associated strongly with ST2 (P = 3.5 * 10-6; OR, 1.77) and nominally with IL4/KIF3A (P = .019; OR, 1.25); TSLP's association persisted (P = 4.7 * 10-5; OR, 1.37), and CAPN14's association strengthened (P = .0001; OR, 1.71). Notably, there was gene-gene interaction between TSLP and IL4 SNPs (P = .0074). Children with risk alleles for both genes were at higher risk for EoE (P = 2.0 * 10-10; OR, 3.67). CONCLUSIONS: EoE genetic susceptibility is mediated by EoE-specific and general atopic disease loci, which can have synergistic effects. These results might aid in identifying potential therapeutics and predicting EoE susceptibility. PMID- 29129586 TI - Mannose-binding lectin and its roles in immune responses in grass carp (Ctenopharyngodon idella) against Aeromonas hydrophila. AB - The complement system is a crucial component of the innate immune system that links innate and adaptive immunity via four pathways. Mannose-binding lectin (MBL), the initiating molecule of the lectin pathway, plays a significant role in the innate immune system in mammals and fish. Herein, we identified an MBL homolog (gcMBL) in grass carp (Ctenopharyngodon idella). The full-length 948 bp gcMBL cDNA includes a 741 bp open reading frame encoding a 246 amino acid protein with a signal peptide, collagen triple helix repeat domain, and a C-type lectin like/link domain. The gcMBL protein shares low similarity with MBL counterparts in other species, and is most closely related to Cyprinus carpio MBL. Transcription of gcMBL was widely distributed in different tissues, and was induced by Aeromonas hydrophila in vivo and in vitro. Expression of gcMBL was also affected by LPS and flagellin stimulation in vitro. In cells over-expressing gcMBL, transcripts of almost all components except gcC5 were up-regulated, and gcMBL, gcIL1beta, gcTNF-alpha, gcIFN, gcCD59, gcC5aR and gcITGbeta-2 were significantly up-regulated following exposure to A. hydrophila or stimulation by bacterial PAMPs. Meanwhile, gcMBL deficiency achieved by RNAi down-regulated transcript levels following A. hydrophila challenge, and gcMBL induced NF-kappaB signalling. These findings indicate a vital role of gcMBL in innate immunity in grass carp. PMID- 29129587 TI - Thighplasty: improving aesthetics through revival of the medial, horizontal procedure: A safe and scar-saving option. AB - INTRODUCTION: Thighplasty is a common bodycontouring procedure, but also associated with a high complication rate. The purpose of this study was to access the outcome of the medial horizontal thigh lift as it is a common surgical technique regarding thigh deformity correction performed at the authors' department. Surgical keysteps, clinical applications, advantages and disadvantages of the procedure are shown. Postoperative evaluation took place with special focus on individual patient satisfaction. METHODS: Retrospective analysis of 25 bilateral thigh lifts with single medial horizontal incision line was performed. Evaluated data include patient age, sex, body mass index, combined procedures, additional liposuction, weight loss, former bariatric surgery, comorbidities, smoking status and surgical complications. Follow-up was performed with a standardized protocol and the scar was accessed according to the Vancouver Scare-Scale. Additionally the patients were asked to complete a questionnaire divided into the sections 'scars', 'postoperative result' and 'sexuality'. RESULTS: Average patient-age was 43 years. Average follow-up was 2 years and 8 months. Average weight loss before surgery was 57 kg. 36% of all patients additionally received a liposuction of the medial thigh. In six cases (24%), we observed complications, which were designated as 'minor complications' in five times (conservative management without problems) and 'major complication' in one time (surgical revision). Postoperative patient-satisfaction was high. DISCUSSION AND CONCLUSION: Compared to the horizontal and vertical combined thigh lift with the classic T-shaped incision lines we observed fewer complications and a reduction of postoperative morbidity. Additionally patient satisfaction was very high. We estimate that the main reason therefore is the avoidance of the vertical scar and its associated short- and longterm problems. The evaluated data confirm the medial horizontal thighplasty as a good and valuablesurgical option for the management of thigh deformities with moderate skin and tissue excess, localized in the upper part of the thigh. PMID- 29129588 TI - Optimizing donor site closure following bilateral breast reconstruction with abdominal-based free flaps. PMID- 29129590 TI - Concluding Editorial / Abschlusseditorial. PMID- 29129589 TI - Behavior of detoxifying enzymes of Aedes aegypti exposed to girgensohnine alkaloid analog and Cymbopogon flexuosus essential oil. AB - Because mosquito control depend on the use of commercial insecticides and resistance has been described in some of them, there is a need to explore new molecules no resistant. In vivo effects of girgensohnine analog 2-(3,4 dimethoxyphenyl)-2-(piperidin-1-yl)acetonitrile DPPA and Cymbopogon flexuosus essential oil CFEO, on the detoxifying enzymes acetylcholinesterase (AChE), glutathione-S-transferase (GST), nonspecific esterases (alpha- and beta-), mixed function oxidases (MFO) and p-NPA esterases were evaluated on a Rockefeller (Rock) and wild Aedes aegypti population from Santander, Colombia (WSant). The action was tested after 24h of exposure at concentrations of 20.10, 35.18 and 70.35mgL-1 of DPPA and 18.45, 30.75 and 61.50mgL-1 of CFEO, respectively. It was found that AChE activity of Rock and WSant was not influenced by the evaluated concentration of DPPA and CFEO (p>0.05), while MFO activity was significantly affected by all CFEO concentrations in WSant (p<0.05). GST, alpha- and beta esterase activities were affected in Rock exposed at the highest CFEO concentration, this concentration also modified beta-esterases activity of WSant. DPPA and CFEO sublethal doses induced inhibition of AChE activity on untreated larvae homogenate from 12 to 20% and 18 to 26%, respectively. For untreated adult homogenate, the inhibition activity raised up to 14 to 27% for DPPA and 26 to 34% for CFEO. Elevated levels of detoxifying enzymes, found when CFEO was evaluated, showed a larval sensitivity not observed by the pure compound suggesting that DPPA, contrary to CFEO, was not recognized, transformed or eliminated by the evaluated detoxifying enzymes. PMID- 29129591 TI - Patient involvement in a systematic review: Development and pilot evaluation of a patient workshop. AB - Patient involvement (PI) in research is increasingly required as a means to improve relevance and meaningfulness of research results. PI has been widely promoted by the National Institute for Health Research in England in the last years. In Germany, widespread involvement of patients in research is still missing. The methods used to realize PI have been developed mainly in English research contexts, and detailed information on how to involve patients in systematic reviews is rare. Therefore, the aim of the study was that patients contribute and prioritize clinically relevant outcomes to a systematic review on meta-cognitive interventions, and to evaluate a patient workshop as well as patients' perceptions of research involvement. Seven patients with experience in psychiatric care participated in our workshop. They focused on outcomes pre defined in the review protocol (e.g., meta-cognitive or cognitive changes, symptomatology, quality of life), neglected other outcomes (like satisfaction with treatment, acceptability), and added relevant new ones (e.g., scope of action/autonomy, applicability). Altogether, they valued the explicit workshop participation positively. However, some suggested to involve patients at an earlier stage and to adapt the amount of information given. Further systematic reviews would benefit from the involvement of patients in the definition of other components of the review question (like patients or interventions), in the interpretation of key findings or in drafting a lay summary. PMID- 29129592 TI - ? PMID- 29129593 TI - Emotional priming depends on the degree of conscious experience. AB - Most experiments in consciousness research assume that awareness is a dichotomous 'either/or' phenomenon. However, participants can distinguish multiple levels of subjective experience of simple features (colour, shape etc.), which correlate with their performance in different tasks. As experiments showing multiple levels of perceptual awareness question the widespread idea that many forms of perception can occur unconsciously, we investigated emotional priming combined with methods able to measure small variations in subjective experience. We show awareness of emotional faces is gradual rather than dichotomous, and that the effects of emotional priming are predicted by the level of perceptual awareness of emotional faces, with no effects when reported unseen. The results question how much unconscious perceptions can influence behaviour. As priming is one of the most well-established phenomena believed to occur unconsciously, the results expand the growing body of evidence that questions the contributions of unconscious processing on behaviour. PMID- 29129594 TI - Are resting state spectral power measures related to executive functions in healthy young adults? AB - Resting-state electroencephalogram (rsEEG) has been found to be associated with psychopathology, intelligence, problem solving, academic performance and is sometimes used as a supportive physiological indicator of enhancement in cognitive training interventions (e.g. neurofeedback, working memory training). In the current study, we measured rsEEG spectral power measures (relative power, between-band ratios and asymmetry) in one hundred sixty five young adults who were also tested on a battery of executive function (EF). We specifically focused on upper Alpha, Theta and Beta frequency bands given their putative role in EF. Our indices enabled finding correlations since they had decent-to-excellent internal and retest reliability and very little range restriction relative to a nation-wide representative large sample. Nonetheless, Bayesian statistical inference indicated support for the null hypothesis concerning lack of monotonic correlation between EF and rsEEG spectral power measures. Therefore, we conclude that, contrary to the quite common interpretation, these rsEEG spectral power measures do not indicate individual differences in the measured EF abilities. PMID- 29129595 TI - The economic case for improved coverage of public mental health interventions. PMID- 29129596 TI - Amyloid toxicity is enhanced after pharmacological or genetic invalidation of the sigma1 receptor. AB - The sigma-1 receptor (S1R) is a molecular chaperone which activity modulates several intracellular signals including calcium mobilization at mitochondria associated endoplasmic reticulum membranes. S1R agonists are potent neuroprotectants against neurodegenerative insults and particularly in rodent models of Alzheimer's disease (AD). We here analyzed whether S1R inactivation modifies vulnerability to amyloid toxicity in AD models. Two strategies were used: (1) amyloid beta[25-35] (Abeta25-35) peptide (1, 3, 9nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE 100 or in S1RKO mice, and (2) WT, APPSweInd, S1RKO, and APPSweInd/S1RKO mice were created and female littermates analyzed at 8 months of age. Learning deficits, oxidative stress, Bax level and BDNF content in the hippocampus were analyzed. Abeta25-35 induced learning impairment, oxidative stress, Bax induction and BDNF alteration at lower dose in NE-100-treated mice or S1RKO mice as compared to WT animals. The extent of learning deficits and biochemical alterations were also higher in APPSweInd/S1RKO mice as compared to WT, APPSweInd, and S1RKO animals. S1R inactivation or altered S1R expression augmented the pathological status in pharmacologic and genetic AD mouse models. These observations, in relation with the well-known protective effects of S1R agonists, are coherent with a role of signal amplifier in neurodegeneration and neuroprotection proposed for S1R in AD and related neurodegenerative disorders. PMID- 29129598 TI - POLB: A new role of DNA polymerase beta in mitochondrial base excision repair. AB - The mitochondrial genome is a matrilineally inherited DNA that encodes numerous essential subunits of the respiratory chain in all metazoans. As such mitochondrial DNA (mtDNA) sequence integrity is vital to organismal survival, but it has a limited cadre of DNA repair activities, primarily base excision repair (BER). We have known that the mtDNA is significantly oxidized by both endogenous and exogenous sources, but this does not lead to the expected preferential formation of transversion mutations, which suggest a robust base excision repair (BER) system. This year, two different groups reported compelling evidence that what was believed to be exclusively nuclear DNA repair polymerase, POLB, is located in the mitochondria and plays a significant role in mitochondrial BER, mtDNA integrity and mitochondrial function. In this commentary, we review the findings and highlight remaining questions for the field. PMID- 29129599 TI - ITK and RLK Inhibitor PRN694 Improves Skin Disease in Two Mouse Models of Psoriasis. AB - The chronic and highly prevalent skin disorder psoriasis vulgaris is characterized by a hyperproliferative epidermis and aberrant immune activity. Many studies have highlighted the role of differentiated T lymphocytes in psoriasis progression. Several biologics are currently available that target proinflammatory cytokines produced by T lymphocytes, but the need for improved therapies persists. The small molecule PRN694 covalently binds ITK and RLK, two Tec kinases activated downstream of T-lymphocyte activation, both of which are up regulated in psoriatic skin. These Tec kinases are involved in signaling cascades mediating T-lymphocyte proliferation, differentiation, and migration and proinflammatory cytokine production. In vitro analysis showed that PRN694 effectively inhibited IL-17A production from murine T helper type 17 differentiated T lymphocytes. Additionally, PRN694 effectively reduced the psoriasis-like phenotype severity and reduced epidermal proliferation and thickness in both the Rac1V12 and imiquimod mouse models of psoriasis. PRN694 also inhibited CD3+ T-cell and gammadelta T-cell infiltration into skin regions. Inhibition of ITK and RLK attenuated psoriasis-associated signaling pathways, indicating that PRN694 is an effective psoriasis therapeutic. PMID- 29129597 TI - Cocaine and desipramine elicit distinct striatal noradrenergic and behavioral responses in selectively bred obesity-resistant and obesity-prone rats. AB - Previous studies have demonstrated a role for norepinephrine (NE) in energy regulation and feeding, and basal differences have been observed in hypothalamic NE systems in obesity-prone vs. obesity-resistant rats. Differences in the function of brain reward circuits, including in the nucleus accumbens (NAc), have been shown in obesity-prone vs. obesity-resistant populations, leading many researchers to explore the role of striatal dopamine in obesity. However, alterations in NE transmission also affect NAc mediated behaviors. Therefore, here we examined differences in striatal NE and the response to norepinephrine transporter blockers in obesity-prone and obesity-resistant rats. We found that striatal NE levels increase following systemic cocaine administration in obesity prone, but not obesity-resistant rats. This could result from either blockade of striatal norepinephrine transporters (NET) by cocaine leading to reduced NE reuptake, or circuit-based responses following cocaine administration resulting in increased NE release. Retrodialysis of the NET inhibitor, desipramine, into the ventral striatum did not cause selective increases in striatal NE levels in obesity-prone rats, suggesting that circuit-based mechanisms underlie NE increases following systemic cocaine administration. Consistent with this, systemic desipramine treatment decreased locomotor activity in obesity-prone, but not obesity-resistant rats. Furthermore, obesity-prone rats were also more sensitive to desipramine-induced reductions in food intake compared to obesity resistant rats. Taken together, these data expand our understanding of differences in NE systems of obesity-prone vs. resistant rats, and provide new insights into basal differences in striatal systems that may influence feeding behavior. PMID- 29129600 TI - MABp1 Targeting IL-1alpha for Moderate to Severe Hidradenitis Suppurativa Not Eligible for Adalimumab: A Randomized Study. AB - Patients with moderate to severe hidradenitis suppurativa failing adalimumab therapy, or those ineligible to receive it, remain a population with an unmet need. Twenty patients not eligible for adalimumab were randomized to receive 12 weeks of blind treatment with placebo or MABp1, a true human antibody targeting IL-1alpha. Hidradenitis suppurativa clinical response score at week 12 was the primary endpoint. The primary endpoint was met in 10% and 60% of placebo- and MABp1-treated patients, respectively (odds ratio = 13.50, 95% confidence interval = 1.19-152.51). Clinical efficacy was maintained at 24 weeks in 0% and 40%. Improvement in the visual analog scale was reported by 20% and 85.7%, respectively, of patients failing previous anti-TNF treatment. Ultrasonography showed decreased neovascularization and lesion skin depth in the MABp1 group. MABp1 treatment was associated with decrease of circulating IL-8 and of stimulated production of IL-8 by whole blood. Whole blood production for hBD-2 was negatively associated with changes on ultrasonography in the placebo group but not in the MABp1 group. MABp1 is a promising treatment for patients with hidradenitis suppurativa not eligible for adalimumab. Inhibition of neovascularization and modulation of the production of IL-8 and hBD-2 are suggested mechanisms of action. PMID- 29129601 TI - On-chip signal amplification of magnetic bead-based immunoassay by aviating magnetic bead chains. AB - In this work, a Lab-on-a-Chip (LOC) platform is used to electromagnetically actuate magnetic bead chains for an enhanced immunoassay. Custom-made electromagnets generate a magnetic field to form, rotate, lift and lower the magnetic bead chains (MBCs). The cost-effective, disposable LOC platform was made with a polymer substrate and an on-chip electrochemical sensor patterned via the screen-printing process. The movement of the MBCs is controlled to improve the electrochemical signal up to 230% when detecting beta-type human chorionic gonadotropin (beta-hCG). Thus, the proposed on-chip MBC-based immunoassay is applicable for rapid, qualitative electrochemical point-of-care (POC) analysis. PMID- 29129602 TI - Standardized fraction of Xylocarpus moluccensis fruits improve vascular relaxation and plaque stability in dyslipidemic models of atherosclerosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xylocarpus moluccensis (Lamk.) M. Roem of family Meliaceae has triterpenoids rich fruits. Triterpenoids have been known to possess cardioprotection and anti-atherosclerotic activities (Han and Bakovic, 2015; Wu et al., 2009). Standardized fraction of these fruits exhibited anti-dyslipidemic (Srivastava et al., 2015), anti-inflammatory (Ravangpai et al., 2011) and CNS depressant activity (Sarker et al., 2007). However, there is no report in the literature on its cardiovascular effects. AIM OF THE STUDY: The present study was undertaken to assess vasoprotective, anti-atherosclerotic and further examine the anti-dyslipidemic effect of the standardized fraction of Xylocarpus moluccensis (F018) fruits in the mechanical injury and high fat diet (HFD) induced dyslipidemic/ atherosclerosis models. MATERIALS AND METHODS: Guinea pigs were fed 0.08% cholesterol + 15% fat diet for 3 weeks, while ApoE KO mice were fed high fat diet for 18 weeks to induce dyslipidemia and atherosclerosis. A combination of balloon injury and high fat diet (1% cholesterol, 6% peanut oil) for 5 weeks was used to accelerate atherosclerosis in NZW rabbits. F018 was administered once daily by oral route in guinea pigs (10, 25 or 50mg/kg/day for 3 weeks), ApoE KO mice (50mg/kg/day for 6 weeks) and in NZW rabbit (25mg/kg/day for 5 weeks) to monitor its effect on dyslipidemia, vasoreactivity and plaque composition by using standard methodologies. RESULTS: F018 treatment in guinea pigs (25 and 50mg/kg/day), ApoE mice (50mg/kg/day) and rabbits (25mg/kg/day) significantly reduced plasma lipids and improved ACh induced vasorelaxation. Anti-dyslipidemic effect of F018 seems to be due to the modulation of enterohepatic genes involved in the cholesterol absorption and excretion. Moreover, significant improvement in the acetylcholine (ACh) induced vasorelaxation was accompanied with reduced inflammatory burden and enhanced activation of eNOS in ApoE mice aortic tissue. Similarly inflammatory cytokines, immunolabeling of macrophage marker (CD68) and MMP-9 were reduced along with augmentation in vascular smooth muscle cells and collagen type I and III in the mechanically injured iliac artery segment in the rabbits. CONCLUSIONS: Altogether, F018 preserved vasoreactivity, reduced atherosclerotic plaque progression and enhanced plaque stability by reducing lipids, inflammatory cytokines, improving endothelial function and collagen content. PMID- 29129603 TI - A rapid quantitative analysis of bile acids, lysophosphatidylcholines and polyunsaturated fatty acids in biofluids based on ultraperformance liquid chromatography coupled with triple quadrupole tandem massspectrometry. AB - Much evidence suggested that quantitative analysis of bile acids (BAs), lysophosphatidylcholines (LPCs), and polyunsaturated fatty acids (PUFAs) in biofluids may be very useful for diagnosis and prevention of hepatobiliary disease with a non-invasive manner. However, simultaneously fast analysis of these metabolites has been challenging for their huge differences of physicochemical properties and concentration levels in biofluids. In this study, we present a liquid chromatography-mass spectrometry method with a high throughput analytical cycle (10min) to fast and accurately quantify fifteen potential biomarkers (eight BAs, four LPCs and three PUFAs) of hepatobiliary disease. The accuracy for the fifteen analytes in plasma and urine matrices was 80.45%-118.99% and 84.55%-112.66%, respectively. The intra- and inter- precisions for the fifteen analytes in plasma and urine matrices were all less than 20% and the lower limit of quantification (LLOQ) of analytes is up to 0.0283 8.2172nmol/L. Therefore, this method is fast, sensitive and accurate for the quantitative analysis of BAs, LPCs and PUFAs in biofluids. Moreover, the stability and concentration differences of the analytes in plasma and serum were evaluated, and the results demonstrated that LPCs is stable, but PUFAs is very unstable in freeze and thaw cycles, and the concentrations of the analytes in serum were slightly higher than those in plasma. We suggested plasma may be a kind of better bio-sample than serum using for quantitative analysis of metabolites in blood, due to the characteristics of plasma are more close to blood than those of serum. PMID- 29129604 TI - Simultaneous determination of nine kinds of dominating bile acids in various snake bile by ultrahigh-performance liquid chromatography with triple quadrupole linear iontrap mass spectrometry. AB - Snake bile is one of the most expensive traditional Chinese medicines (TCMs). However, due to the complicated constitutes of snake bile and the poor ultraviolet absorbance of some trace bile acids (BAs), effective analysis methods for snake bile acids were still unavailable, making it difficult to solve adulteration problems. In present study, ultrahigh-performance liquid chromatography with triple quadrupole linear ion trap mass spectrometry (UHPLC QqQ-MS/MS) was applied to conduct a quantitative analysis on snake BAs. The mass spectrometer was monitored in the negative ion mode, and multiple-reaction monitoring (MRM) program was used to determine the contents of BAs in snake bile. In all, 61 snake bile from 17 commonly used species of three families (Elapidae, Colubridae and Viperidae), along with five batches of commercial snake bile from four companies, were collected and detected. Nine components, Tauro 3alpha,12alpha-dihydroxy-7-oxo-5beta-cholenoic acid (T1), Tauro 3alpha,7alpha,12alpha,23R-tetrahydroxy-5beta-cholenoic acid (T2), taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), cholic acid (CA), Tauro-3alpha,7alpha-dihydroxy-12 oxo-5beta-cholenoic acid (T3), and Tauro-3alpha,7alpha,9alpha,16alpha tetrahydroxy-5beta-cholenoic acid (T4) were simultaneously and rapidly determined for the first time. In these BAs, T1 and T2, self-prepared with purity above 90%, were first reported with their quantitative determination, and the latter two (T3 and T4) were tentatively determined by quantitative analysis multi-components by single marker (QAMS) method for roughly estimating the components without reference. The developed method was validated with acceptable linearity (r2>=0.995), precision (RSD<6.5%) and recovery (RSD<7.5%). It turned out that the contents of BAs among different species were also significantly different; T1 was one of the principle bile acids in some common snake bile, and also was the characteristic one in Viperidae and Elapidae; T2 was the dominant components in Enhydris chinensis. This quantitative study of BAs in snake bile is a remarkable improvement for clarifying the bile acid compositions and evaluating the quality of snake bile. PMID- 29129605 TI - Evolution and adaptation of single-pass transmembrane proteins. AB - A comparative analysis of 6039 single-pass (bitopic) membrane proteins from six evolutionarily distant organisms was performed based on data from the Membranome database. The observed repertoire of bitopic proteins is significantly enlarged in eukaryotic cells and especially in multicellular organisms due to the diversification of enzymes, emergence of proteins involved in vesicular trafficking, and expansion of receptors, structural, and adhesion proteins. The majority of bitopic proteins in multicellular organisms are located in the plasma membrane (PM) and involved in cell communication. Bitopic proteins from different membranes significantly diverge in terms of their biological functions, size, topology, domain architecture, physical properties of transmembrane (TM) helices and propensity to form homodimers. Most proteins from eukaryotic PM and endoplasmic reticulum (ER) have the N-out topology. The predicted lengths of TM helices and hydrophobic thicknesses, stabilities and hydrophobicities of TM alpha helices are the highest for proteins from eukaryotic PM, intermediate for proteins from prokaryotic cells, ER and Golgi apparatus, and lowest for proteins from mitochondria, chloroplasts, and peroxisomes. Tyr and Phe residues accumulate at the cytoplasmic leaflet of PM and at the outer leaflet of membranes of bacteria, Golgi apparatus, and nucleus. The propensity for dimerization increases from unicellular to multicellular eukaryotes, from enzymes to receptors, and from intracellular membrane proteins to PM proteins. More than half of PM proteins form homodimers with a 2:1 ratio of right-handed to left-handed helix packing arrangements. The inverse ratio (1:2) was observed for dimers from the ER, Golgi and vesicles. PMID- 29129606 TI - Transgenerational blunting of morphine-induced corticosterone secretion is associated with dysregulated gene expression in male offspring. AB - A number of parental experiences, even when occurring prior to conception, have been shown to induce transgenerational effects beyond the first generation. In the case of exposure to drugs of abuse, studies in rodents suggest that offspring demonstrate significant differences in how they respond to the drug to which their parent was exposed. We have previously observed significant alterations in morphine analgesia, conditioned place preference and self-administration in the offspring of females exposed to morphine during adolescent development. In addition to effects on pain perception and reward, morphine also modulates the hypothalamic pituitary adrenal (HPA) axis. The purpose of the current study was to determine whether female adolescent morphine exposure results in transgenerational effects on regulation of the HPA axis by morphine in future generations. Adolescent morphine was administered to female Sprague Dawley rats using a 10 day, escalating dose regimen of morphine (5-25 mg/kg; from 30 to 39 days of age). Control animals received saline. Both saline and morphine exposed females (SAL-F0 and MOR-F0, respectively) were mated with drug naive males beginning at least 3 weeks after the final injection. Plasma corticosterone levels were measured in male and female offspring (F1) during adulthood following 0, 0.1, or 10 mg/kg morphine. In addition, expression of corticotropin releasing hormone (Crh) and mu opioid receptor (Oprm1) in the paraventricular nucleus (PVN) were measured using quantitative PCR. MOR-F1 males, but not females, had blunted morphine-induced corticosterone secretion. This effect was specific to offspring from females exposed to morphine during adolescence as those exposed during adulthood produced offspring in which the effect was absent. In addition, MOR-F1 males had significantly lower levels of PVN Crh following saline. These effects were not driven by PVN oprm1 in the F1 males as there were no differences based on maternal adolescent exposure. To determine the persistence of the blunted morphine-induced corticosterone effect, SAL-F2 and MOR-F2 males were examined. Blunted morphine-induced corticosterone secretion extended into the MOR-F2 generation, as well as effects on Crh. In addition, there was additional dysregulation ofOprm1 expression in the PVN in MOR-F2 compared with SAL-F2 males. These findings suggest that sex-specific alterations in opioid-mediated regulation of the HPA axis are transgenerationally transmitted for at least two generations following female adolescent morphine exposure. These effects may play a role in the previously observed changes in morphine analgesia and reward related behaviors observed in this phenotype. In addition, alterations in HPA functioning such as these may play a broad role in transgenerational epigenetic transmission. PMID- 29129607 TI - Polymorphisms in HLA-C and KIR alleles are not associated with HAM/TSP risk in HTLV-1-infected subjects. AB - INTRODUCTION: Several genetic polymorphisms may be related to susceptibility or resistance to viral disease outcomes. Immunological or genetic factors may act as major triggers of the immune pathogenesis of HAM/TSP. This study investigated the association of immune related genetic polymorphisms with viral and immunological markers. METHODS: 247 HTLV-1-infected volunteers, drawn from a larger group of HTLV-infected subjects followed at the Institute of Infectious Diseases "Emilio Ribas" (IIER) for up to 19 years, participated in this study, which ran from June 2011 to July 2016. The subjects were classified according to their neurological status into two groups: Group 1 (160 asymptomatic individuals) and Group 2 (87 HAM/TSP patients). Samples were tested for spontaneous lymphocyte proliferation (LPA) and HTLV-1 proviral load (PVL) and for IFN-lambda4, HLA-C and KIR genotypes using qPCR. RESULTS: We found associations between LPA (p=0.0001) with HAM/TSP and confirmed the IFN-lambda4 polymorphism rs8099917, allele GG, as a protective factor using a recessive model (OR=3.22, CI=1.10-9.47). Polymorphisms in HLA-C and KIR alleles were not associated with risk of developing HAM/TSP. CONCLUSION: We demonstrated that age, LPA and an IFN-lambda4 polymorphism were associated with progression to HAM/TSP. Understanding HAM/TSP pathogenesis can provide important markers of prognostic value for clinical management, and contribute to the discovery of new therapeutic interventions in the future. PMID- 29129608 TI - No Exacerbation of Knee Joint Pain and Effusion Following Preoperative Progressive Resistance Training in Patients Scheduled for Total Knee Arthroplasty: Secondary Analyses From a Randomized Controlled Trial. AB - BACKGROUND: Preoperative progressive resistance training (PRT) is controversial in patients scheduled for total knee arthroplasty (TKA), because of the concern that it may exacerbate knee joint pain and effusion. OBJECTIVE: To examine whether preoperative PRT initiated 5 weeks prior to TKA would exacerbate pain and knee effusion, and would allow a progressively increased training load throughout the training period that would subsequently increase muscle strength. DESIGN: Secondary analyses from a randomized controlled trial (NCT01647243). SETTING: University Hospital and a Regional Hospital. PATIENTS: A total of 30 patients who were scheduled for TKA due to osteoarthritis and assigned as the intervention group. METHODS: Patients underwent unilateral PRT (3 sessions per week). Exercise loading was 12 repetitions maximum (RM) with progression toward 8 RM. The training program consisted of 6 exercises performed unilaterally. MAIN OUTCOME MEASURES: Before and after each training session, knee joint pain was rated on an 11-point scale, effusion was assessed by measuring the knee joint circumference, and training load was recorded. The first and last training sessions were initiated by 1 RM testing of unilateral leg press, unilateral knee extension, and unilateral knee flexion. RESULTS: The median pain change score from before to after each training session was 0 at all training sessions. The average increase in knee joint effusion across the 12 training sessions was a mean 0.16 cm +/- 0.23 cm. No consistent increase in knee joint effusion after training sessions during the training period was found (P = .21). Training load generally increased, and maximal muscle strength improved as follows: unilateral leg press: 18% +/- 30% (P = .03); unilateral knee extension: 81% +/- 156% (P < .001); and unilateral knee flexion: 53% +/- 57% (P < .001). CONCLUSION: PRT of the affected leg initiated shortly before TKA does not exacerbate knee joint pain and effusion, despite a substantial progression in loading and increased muscle strength. Concerns for side effects such as pain and effusion after PRT seem unfounded. LEVEL OF EVIDENCE: I. PMID- 29129609 TI - Hydrodilatation With Corticosteroid for the Treatment of Adhesive Capsulitis: A Systematic Review. AB - BACKGROUND: Current evidence suggests that corticosteroid injection alone expedites the recovery of pain-free range of motion (ROM) in patients with adhesive capsulitis compared to physiotherapy or placebo. However, it remains unclear whether the addition of hydrodilatation with corticosteroid provides improvement in pain-free ROM as well as pain relief. OBJECTIVE: A review of the literature was conducted to determine whether the combined intervention of hydrodilatation and corticosteroid injection expedites restoration of pain-free ROM compared to a control treatment of corticosteroid injection in patients with adhesive capsulitis. METHODS: EMBASE, MEDLINE, and CINAHL were searched from database inception to January 2017. Relevant studies were determined as randomized controlled trials written in English, comparing the outcomes of hydrodilatation and corticosteroid injection to a control group treated with corticosteroid injection alone in patients with adhesive capsulitis. Two independent reviewers assessed manuscripts for study inclusion and extracted data. RESULTS: A total of 2276 studies were identified through the search, of which 6 randomized controlled studies (involving 410 shoulders) met criteria for inclusion in this review. Mean age ranged from 51-61 years, with mean symptom duration of 4-9 months. Studies varied significantly regarding the volume of injectate, anatomical injection approach, symptom duration, and the method of glenohumeral capsule distension (capsular rupture versus preservation). Two studies demonstrated clinically and statistically significant improvement in the combination group at 3-month follow-up, and one study demonstrated clinically significant improvement only in ROM and/or pain/functional scales, compared to 3 studies demonstrating no benefit when compared to corticosteroid injection alone. CONCLUSION: Combining hydrodilatation with corticosteroid injection potentially expedites recovery of pain-free ROM. The greatest benefit is experienced within the first 3 months of intervention. Differences in hydrodilatation techniques, inclusion of capsular preservation, anatomical approach, and length of symptoms may explain the variability in efficacy demonstrated. Further trials using larger sample sizes, better anatomical approaches, image guidance, and hydrodilatation techniques are required to determine the true nature of benefits of hydrodilatation with corticosteroid injection. LEVEL OF EVIDENCE: II. PMID- 29129610 TI - The effect of rat strain and stress exposure on performance in touchscreen tasks. AB - Patients suffering from depression-associated cognitive impairments often recover incompletely after remission from the core symptoms of depression (lack of energy, depressed mood and anhedonia). This study aimed to set the basis for clinically relevant testing of cognitive impairments in a preclinical model of depression. Hence, we used the chronic mild stress (CMS) model of depression, which provokes the core symptom of anhedonia in a fraction of the stress exposed animals, while others remain resilient, and assessed the entire CMS groups' cognitive performance on the touchscreen operant platform. Specifically, we applied the pairwise discrimination (PD) and reversal task including a retention phase on Wistar and Long Evans controls and CMS exposed Long Evans rats. We observed differences between the albino Wistar and the pigmented Long Evans strain regarding performance in the PD and reversal task as well as in memory consolidation. CMS exposure did not alter learning and memory in the PD and reversal task, even though it altered affective behaviours in the elevated plus maze and open field test. This is likely due to the heterogeneity of the CMS group, in which stress exposure elicited the expected range of phenotypes from anhedonic-like to resilient shown with the sucrose consumption test. Thus, our study suggests that pigmented rat strains, such as Long Evans, are superior to albino rats in the vision-based touchscreen studies. Furthermore, we propose investigation of the CMS subgroups in more complex, hippocampus-dependent tasks to refine a translational preclinical model of depression-induced cognitive impairments. Hence, this study increased awareness of strain-specific differences in touchscreen performance and added to the literature regarding the sensitivity of the PD and reversal task to stress-induced cognitive alterations. PMID- 29129611 TI - Effect of sleep curtailment on dietary behavior and physical activity: A randomized crossover trial. AB - Our objective was to clarify the effect of sleep curtailment on energy intake (EI) and physical activity under free-living conditions. Participants were 16 healthy women aged 21-22years. A randomized crossover trial design was used to compare a short sleep condition (SS): 4h/night (2:00-6:00) and a control sleep condition (CS): 7h/night (23:00-6:00). Each condition comprised 3 consecutive nights. Sleep duration was assessed using a wristwatch-type accelerometer at home. All living activities except sleeping were free-living. Physical activity was assessed using a tri-axial accelerometer, and was categorized by intensity level (sedentary; sedentary to light; moderate to vigorous). Participants were asked to purchase and consume meals with visible nutrient information. EI was evaluated by adding values from these food labels. Mean sleep duration in the two conditions was significantly different (4.3+/-0.3 vs. 7.1+/-0.4h, p<0.01). For the shared wakefulness period in the two conditions (6:00-23:00), step counts and physical activity were not significantly different. Sedentary time (878+/-61 vs. 727+/-40min, p<0.01), and sedentary to light-intensity activity time (1122+/-18 vs. 932+/-63min, p<0.01) were significantly increased in SS (waking time, 06:00 02:00) compared with CS (waking time, 06:00-23:00). However, these significant effects were clearly attenuated after adjustment for awake time (p>0.05). Total EI was not significantly different between conditions (8.64+/-0.82 vs. 8.46+/ 1.28MJ, p>0.05), nor were leptin levels (p>0.05), but insulin and cortisol levels after SS were significantly higher than after CS (p<0.05). In this study, physical activity was increased in the SS condition and attributed to differences in awake time between conditions. However, there were no differences in EI. Further studies to investigate the effect of sleep curtailment on weight gain through stress and insulin resistance are necessary. PMID- 29129612 TI - Why lipostatic set point systems are unlikely to evolve. AB - OBJECTIVES: Body fatness is widely assumed to be regulated by a lipostatic set point system, which has evolved in response to trade-offs in the risks of mortality. Increasing fatness makes the risk of starvation lower but increases the risk of predation. Yet other models are available. The aim of this work is to evaluate using mathematical modeling whether set-point systems are more likely to evolve than the alternatives. METHODS: I modeled the trade-off in mortality risks using a simple mathematical model, which generates an optimum level of fatness that is presumed to be the driver for the evolution of a set-point. I then mimicked the likely errors in this optimum level, that derive from the variation in the component parameters of the mortality curves using Markov Chain Monte Carlo (MCMC) simulation by Bayesian inference Using Gibbs Sampling (BUGS). RESULTS: The error propagation generated by the simulations showed that even very small errors in the model parameters were magnified enormously in the location of the optimum fatness level. If the model parameters had coefficients of variation of just 1% then the coefficient of variation in the optimum level of fatness was between 20 and 90%. In that situation, a set-point centered at the mathematical optimum from the component curves would be at the correct level of fatness that minimizes mortality, and hence maximizes fitness, on less than 8% of occasions. CONCLUSIONS: Set-point regulation of body fatness is hence highly unlikely to evolve where there is any realistic level of variation in the parameters that define mortality risks. Using further MCMC modeling, I show that a dual intervention point system is more likely to evolve. This mathematical simulation work has important implications for how we interpret molecular work concerning regulation of adiposity. PMID- 29129614 TI - Mid-Term Clinical, Functional, and Radiographic Outcomes of 105 Gender-Specific Patellofemoral Arthroplasties, With or Without the Association of Medial Unicompartmental Knee Arthroplasty. AB - BACKGROUND: The purpose of this study is to evaluate clinical and radiographic outcomes after gender-specific patellofemoral arthroplasty (PFA) either isolated or combined with unicompartmental knee arthroplasty (UKA). METHODS: A total of 105 PFAs in 85 patients were reviewed: 64 knees had isolated patellofemoral osteoarthritis and received an isolated PFA, and 41 knees with bicompartmental osteoarthritis were treated with medial UKA and PFA. Preoperative and postoperative clinical and functional assessment included knee range of motion, Knee Society Score, University of California Los Angeles Activity Score, Tegner Activity Level Scale, and visual analogue scale pain. Preoperative and postoperative radiographs were evaluated for patellofemoral and tibiofemoral compartment osteoarthritis, trochlear dysplasia, changes in patellar height, and signs of osteolysis. RESULTS: At a mean follow-up of 5.5 +/- 1.6 years, both groups showed improvement in knee joint range of motion (P < .001), clinical and functional Knee Society Score (P < .001), University of California Los Angeles Activity Score (P < .001 in the PFA group and P = .004 in the UKA + PFA group), and visual analogue scale pain (P < .001). There were no statistically significant postoperative differences between the 2 groups. No signs of osteolysis or subsidence were recorded. Survivorship of these 105 implants was 95.2%. CONCLUSION: Excellent clinical and radiographic outcomes were achieved after PFA with a gender-specific implant both as isolated replacement and when combined with medial UKA. Bicompartmental replacement with small implants can be considered in patients with bicompartmental osteoarthritis and intact anterior cruciate ligament. PMID- 29129615 TI - Patients With Major Depressive Disorder Experience Increased Perception of Pain and Opioid Consumption Following Total Joint Arthroplasty. AB - BACKGROUND: Pain in the immediate postoperative period following total joint arthroplasty is influenced by various patient factors, including major depressive disorder (MDD). Therefore, this study aimed to compare the patient perception of pain and opioid consumption between patients with and without MDD who received either a total knee arthroplasty (TKA) or total hip arthroplasty (THA). Specifically, we compared (1) pain intensity, (2) lengths of stay, (3) opioid consumption, and (4) patient perception of pain control. METHODS: We reviewed our institutional Press Ganey database to identify patients with a diagnosis of MDD who received a THA (n = 48) and TKA (n = 68) between 2012 and 2016. An independent samples t-test and chi-square analyses were conducted to assess continuous and categorical variables, respectively. Analysis of covariance assessed the effects of depression on postoperative pain intensity. Mixed-design analysis of variance assessed the difference in opioid consumption between groups. RESULTS: Patients with MDD who received THA or TKA demonstrated a higher mean pain intensity score when compared to those without MDD; however, this was not statistically different (235.6 vs 207.7; P = .264 and 214.8 vs 185.1; P = .055, respectively). Patients with MDD who received THA or TKA consumed more opioids when compared to those without MDD (P = .048 and P = .038, respectively). CONCLUSION: Patients with MDD undergoing total joint arthroplasty consume more opioids compared to their matched cohort during the immediate postoperative period. Identifying patient-specific factors, such as MDD, could help arthroplasty surgeons modulate patients' course of recovery. These findings warrant more cooperation between arthroplasty surgeons and primary care providers to optimize outcome. PMID- 29129616 TI - Risk of Periprosthetic Joint Infection in Patients With Multiple Arthroplasties. AB - BACKGROUND: Risk of subsequent periprosthetic joint infection (PJI) in a second prosthetic joint following initial PJI has been shown to be 19%-20%. We sought to identify (1) the risk of developing a second PJI for our patients with multiple prosthetic joints and (2) the effect of bacteremia on development of a subsequent PJI. METHODS: We retrospectively reviewed all patients treated surgically for PJI by a single surgeon from 2003 to 2014. Time between initial and subsequent infection, bacteremia, and risk factors for PJI were identified. RESULTS: Of 167 patients treated for PJI, 76 had multiple prosthetic joints. Thirteen percent (10/76) developed a PJI in a second location. Excluding simultaneous infections, the rate was 8.3% (6/72), despite having a 57% incidence of immunosuppression, diabetes, renal failure, smoking, or steroid use. Average follow-up for patients with 1 PJI was 4.6 years (range 0.03-13.6). Seventy percent (7/10) of patients with multiple infections were bacteremic at the time of initial infection compared to 18.1% (12/66) of patients with a single infection (P = .0004). Excluding the 4 simultaneous infections (all bacteremic), the risk of developing an infection in a second joint was 20% if bacteremic and 5.2% if not bacteremic. CONCLUSION: Our study identified the risk of developing a subsequent PJI to be one half of previous studies. Bacteremia at the time of PJI is an important factor for developing subsequent PJI. Multiple prosthetic joints may be less hazardous than previously thought for patients with PJI suggesting that suppressive antibiotics may only be necessary in cases with bacteremia. PMID- 29129613 TI - PGC-1alpha functions as a co-suppressor of XBP1s to regulate glucose metabolism. AB - OBJECTIVE: Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) promotes hepatic gluconeogenesis by activating HNF4alpha and FoxO1. PGC-1alpha expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC 1alpha and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1alpha and XBP1s and its role in glucose metabolism. METHODS: We investigated the biochemical interaction between PGC-1alpha and XBP1s and examined the role of their interaction in glucose homeostasis using animal models. RESULTS: We show that PGC-1alpha interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1alpha and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1alpha expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1alpha levels in obese and diabetic mouse liver restores XBP1s protein induction. CONCLUSIONS: Our findings reveal a novel function of PGC-1alpha as a suppressor of XBP1s function, suggesting that hepatic PGC-1alpha promotes gluconeogenesis through multiple pathways as a co-activator for HNF4alpha and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s. PMID- 29129617 TI - Computed Tomographic Evaluation of Bone Stock in Patients With Crowe Type III Developmental Dysplasia of the Hip: Implications for Guiding Acetabular Component Placement Using the High Hip Center Technique. AB - BACKGROUND: We evaluated acetabular cup coverage (CC) and rim contact (RC) to evaluate the bone stock above the acetabulum for guiding acetabular component placement using the high hip center technique in patients with Crowe type III developmental dysplasia of the hip. METHODS: Using hip computed tomography and image processing software, pelvises were reconstructed digitally in 20 hips with Crowe type III developmental dysplasia of the hip. Mimicked cup was placed with anteversion angles of 0 degrees (group I), 5 degrees (group II), and 10 degrees (group III) respectively. In each group, the cup was placed at the anatomical hip center at first, and then the cup was moved up to 40 mm vertically about the native rotation center with an increment of 2.5 mm at each step. CC and RC were calculated and documented with each movement. RESULTS: CC was 65.87%, 67.77%, and 68.98% for group I, group II, and group III at the native rotation center, and increased progressively to 86.45%, 85.85%, and 84.71% at 25 mm above. RC was 49.17%, 50.25%, and 51.92% for group I, group II, and group III at the native rotation center, and increased progressively to 86.87%, 86.39%, and 84.94% at 22.5 mm above. CC and RC were positively correlated, despite the different anteversion angles (r = 0.687 at 0 degrees , 0.683 at 5 degrees , and 0.645 at 10 degrees ; P < .001). CONCLUSION: Computed tomography analysis and computer stimulation demonstrate that it is feasible to use high hip center technique in Crowe type III hips. PMID- 29129618 TI - Rotating Hinge Implants for Complex Primary and Revision Total Knee Arthroplasty. AB - BACKGROUND: Contemporary rotating hinge knee (RHK) prosthesis has shown improved survival rates over earlier generations. However, reports of high complication and mechanical failure rates highlight the need for more clinical outcome data in the complex primary and revision setting. The purpose of this study is to report our results of using a contemporary rotating hinge for complex primary and revision total knee arthroplasty. METHODS: Using a prospectively maintained surgical database, 79 knees in 76 patients who underwent an RHK of a single design for either a complex primary (14 knees) or revision total knee arthroplasty (65 knees) were identified. This included 19% undergoing an RHK for periprosthetic joint infection and 32.9% who had concomitant extensor mechanism repair. The cohort consisted of 60 women and 16 men with a mean age of 66.7 years (range 39-89) at the time of surgery. Patient outcomes were assessed using Knee Society Scores and radiographs were reviewed for signs of wear and loosening. Failure rates were estimated using Kaplan-Meier survival curves. RESULTS: At a minimum of 2 years, 13 patients had died and 4 were lost to follow-up, leaving 62 knees in 59 patients who were followed for a mean of 55.2 months (range 24-146). The mean Knee Society Scores improved from 35.7 to 66.2 points (P < .01). The incidence of complications was 38.7%. The most common complications were periprosthetic fracture, extensor mechanism rupture, and periprosthetic infection. Estimated survival was 70.7% at 5 years. CONCLUSION: Despite improvements in design and biomaterials, there remains a relatively high complication rate associated with the use of a modern RHK implant. While aseptic loosening was rare, periprosthetic fracture, infection, and extensor mechanism failure were substantial emphasizing the complex nature of these cases. PMID- 29129619 TI - Transcriptional profiling validates involvement of extracellular matrix and proteinases genes in mouse gonad development. AB - Extracellular matrix (ECM) plays an important scaffolding role in the establishment of organs structure during development. A great number of ECM components and enzymes (proteinases) regulating formation/degradation of ECM during organ remodeling have been identified. In order to study the role of ECM in the mouse gonad development, especially during sexual differentiation of the gonads when the structure of the testis and ovary becomes established, we performed a global analysis of transcriptome in three main cell types of developing gonad (supporting, interstitial/stromal and germ cells) using transgenic mice, cell sorting and microarray. The genes coding for ECM components were mostly expressed in two gonadal cell lines: supporting and interstitial/stromal cells. These two cell lines differed in the expression pattern of ECM components, which suggests that ECM components might be crucial for differentiation of gonad compartments (for example testis cords vs. interstitium in XY gonads). Collagens and proteoglycans coding genes were mainly expressed in the interstitium/stromal cells, while non-collagen glycoproteins and matricellular coding genes were expressed in both cell lines. We also analyzed the expression of genes encoding ECM enzymes that are secreted to the ECM where they remodel the scaffolding of developing organs. We found that the ECM enzyme genes were also mostly expressed in supporting and interstitial/stromal cells. In contrast to the somatic cells, the germ cells expressed only limited number of ECM components and enzymes. This suggests that the germ line cells do not participate, or play only a minor role, in the sculpting of the gonad structure via ECM synthesis and remodeling. Importantly, the supporting cells showed the sex-specific pattern of expression of ECM components. However, the pattern of expression of most ECM enzymes in the somatic and germ cells is independent on the sex of the gonad. Further studies are required to elucidate the exact roles of identified genes in sexual differentiation of the gonads. PMID- 29129620 TI - Human adipose-derived stem cells (ADSC) and human periodontal ligament stem cells (PDLSC) as cellular substrates of a toxicity prediction assay. AB - With the increasing need to develop in vitro assays to replace animal use, human stem cell-derived methods are emerging and showing outstanding contributions to the toxicological screening of substances. Adult human stem cells such as adipose derived stem cells (ADSC) and periodontal ligament stem cells (PDLSC) were used as cell substrates for a cytotoxicity assay and toxicity prediction using the neutral red uptake (NRU) assay. First, primary cell cultures from three independent donors, from each tissue source, were characterized as mesenchymal stem cells (MSC) by plastic adherence and appropriate immunophenotype for MSC markers (positive for CD90, CD73, and CD105 and negative for CD11b, CD34, CD45, HLADR, and CD19). Furthermore, ADSC and PDLSC were able to differentiate into adipocytes and osteoblasts when maintained under the same culture conditions previously established for the NRU assay. NRU assays for three reference test substances were performed. R2 was higher than 0.85 for all conditions, showing the feasibility to calculate IC50 values. The IC50 values were then used to predict the LD50 of the test substances, which were comparable to previous results and the ICCVAM standard test report. Primary ADSC and PDLSC showed the potential to be considered as additional models for use in cytotoxicity assays. PMID- 29129621 TI - TDCPP protects cardiomyocytes from hypoxia-reoxygenation injury induced apoptosis through mitigating calcium overload and promotion GSK-3beta phosphorylation. AB - TDCPP, Tris (1, 3-dichloro-2-propyl) phosphate belongs to a group of chemicals known as triester organophosphate flame retardants, It can alter calcium homeostasis at much lower concentrations in normal conditions, but the mechanism is unclear till now. Calcium overload is a leading cause of apoptosis in myocardial ischemia/reperfusion (I/R) injury, thus how to mitigate Ca2+-overload is deserved to be investigated. We therefore hypothesized that TDCPP could attenuate cardiomyocytes apoptosis in I/R injury. H/R (hypoxia/reoxygenation) experiments in vitro were used to simulate in vivo I/R injury. The present study aimed to explore the potential effect of TDCPP in cardiomyocytes after H/R injury, Ca2+ imaging technique was used to explore SOCE(store-operated calcium entry) and Ca2+-overload levels, western blot technique was used to explore the potential target, the cell morphology, cell viability and mitochondrial membrane potential were also detected. The results have shown that: TDCPP could decrease SOCE, restore H9c2 cell viability, mitigate Ca2+-overload in H/R injury and reduce the mitochondrial membrane potential. Furthermore, TDCPP decreased STIM1 expression and promoted GSK3beta phosphorylation. Collectively, for the first time, this study suggest the antiapoptosis roles of TDCPP in H/R injury are via mitigation Ca2+-overload and promoting GSK-3beta phosphorylation. PMID- 29129622 TI - Personalized long-term prediction of cognitive function: Using sequential assessments to improve model performance. AB - Prediction of onset and progression of cognitive decline and dementia is important both for understanding the underlying disease processes and for planning health care for populations at risk. Predictors identified in research studies are typically accessed at one point in time. In this manuscript, we argue that an accurate model for predicting cognitive status over relatively long periods requires inclusion of time-varying components that are sequentially assessed at multiple time points (e.g., in multiple follow-up visits). We developed a pilot model to test the feasibility of using either estimated or observed risk factors to predict cognitive status. We developed two models, the first using a sequential estimation of risk factors originally obtained from 8 years prior, then improved by optimization. This model can predict how cognition will change over relatively long time periods. The second model uses observed rather than estimated time-varying risk factors and, as expected, results in better prediction. This model can predict when newly observed data are acquired in a follow-up visit. Performances of both models that are evaluated in10-fold cross-validation and various patient subgroups show supporting evidence for these pilot models. Each model consists of multiple base prediction units (BPUs), which were trained using the same set of data. The difference in usage and function between the two models is the source of input data: either estimated or observed data. In the next step of model refinement, we plan to integrate the two types of data together to flexibly predict dementia status and changes over time, when some time-varying predictors are measured only once and others are measured repeatedly. Computationally, both data provide upper and lower bounds for predictive performance. PMID- 29129623 TI - Alterations of brain volumes in women with early life maltreatment and their associations with oxytocin. AB - Early life maltreatment (ELM) is associated with different neurobiological alterations. Lower oxytocin and altered grey matter volumes (GMV) in brain regions associated with the central oxytocin system, such as the hypothalamus, amygdala, and nucleus accumbens, have been reported in women with ELM. However, the association between peripheral oxytocin and brain morphometry in women with ELM has not been studied yet. We therefore collected blood samples from 33 women with and 25 women without ELM, all without current mental disorders to measure and compare oxytocin levels between the two groups. Furthermore, T1-weighted high resolution structural magnetic resonance brain images of a subsample of these women were collected, analyzed with voxel-based morphometry, compared between the two groups, and correlated with oxytocin levels. There were no differences in oxytocin levels between the groups. However, oxytocin levels were associated with different brain regions in women with ELM compared with control women without ELM: A positive association between GMV in the nucleus accumbens and oxytocin was specific for control women but not for women with ELM. For the hypothalamus, there was a positive association between GMV and oxytocin in control women. However, the same region was negatively associated with oxytocin in women with ELM and it showed larger GMV compared to control women without ELM. For the amygdala, a negative association between GMV and oxytocin was specific for women with ELM. Results are discussed with regard to previous research on endocrine and neurostructural alterations in individuals with ELM. PMID- 29129624 TI - Women's preferences for men's beards show no relation to their ovarian cycle phase and sex hormone levels. AB - According to the ovulatory shift hypothesis, women's mate preferences for male morphology indicative of competitive ability, social dominance, and/or underlying health are strongest at the peri-ovulatory phase of the menstrual cycle. However, recent meta-analyses are divided on the robustness of such effects and the validity of the often-used indirect estimates of fertility and ovulation has been called into question in methodological studies. In the current study, we test whether women's preferences for men's beardedness, a cue of male sexual maturity, androgenic development and social dominance, are stronger at the peri-ovulatory phase of the menstrual cycle compared to during the early follicular or the luteal phase. We also tested whether levels of estradiol, progesterone, and the estradiol to progesterone ratio at each phase were associated with facial hair preferences. Fifty-two heterosexual women completed a two-alternative forced choice preference test for clean-shaven and bearded male faces during the follicular, peri-ovulatory (validated by the surge in luteinizing hormone or the drop in estradiol levels) and luteal phases. Participants also provided for one entire menstrual cycle daily saliva samples for subsequent assaying of estradiol and progesterone. Results showed an overall preference for bearded over clean shaven faces at each phase of the menstrual cycle. However, preferences for facial hair were not significantly different over the phases of menstrual cycle and were not significantly associated with levels of reproductive hormones. We conclude that women's preferences for men's beardedness may not be related to changes in their likelihood of conception. PMID- 29129625 TI - Comparison of fasting and non-fasting lipid profiles in a large cohort of patients presenting at a community hospital. AB - OBJECTIVE: To compare the fasting and non-fasting lipid profile including ApoB in a cohort of patients from a community setting. Our purpose was to determine the proportion of results that could be explained by the known biological variation in the fasting state and to examine the additional impact of non-fasting on these same lipid parameters. METHODS: 1093 adult outpatients with fasting lipid requests were recruited from February to September 2016 at the blood collection sites of the Moncton Hospital. Participants were asked to come back in the next 3 4days after having eaten a regular breakfast to have their blood drawn for a non fasting lipid profile. RESULTS: 91.6% of patients in this study had a change in total cholesterol that fell within the biological variation expected for this parameter. Similar results were seen for HDL-C (94.3%) non-HDL-C (88.8%) and ApoB (93.0%). A smaller number of patients fell within the biological variation expected for TG (78.8%) and LDL-C (74.6%). An average TG increase of 0.3mmol/L was observed in fed patients no matter the level of fasting TG. A gradual widening in the range of change in TG concentration was observed as fasting TG increased. Similar results were seen in diabetic patients. CONCLUSION: Outside of LDL-C and TG, little changes were seen in lipid parameters in the postprandial state. A large part of these changes could be explained by the biological variation. We observed a gradual widening in the range of increase in TG for patients with higher fasting TG. Non-HDL-C and ApoB should be the treatment target of choice for patients in the non-fasting state. PMID- 29129626 TI - Clinical significance of the serum biomarker index detection in children with Henoch-Schonlein purpura. AB - OBJECTIVE: To explore a panel of serum biomarkers for laboratory diagnosis of pediatric Henoch-Schonlein purpura (HSP). METHODS: The blood white blood cells (WBC) and serum levels of serum amyloid A (SAA), interleukin 6 (IL-6), immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin E (IgE), C-reactive protein (CRP), complement component 3 (C3), complement component 4 (C4), and ASO (anti-streptolysin O) were detected in 127 patients with Henoch-Schonlein purpura (HSP), 110 cases of septicemia patients, and 121 healthy volunteers. The diagnostic ability of biomarkers selected from HSP and septicemia patients was analyzed by ROC curve. By designing the calculation model, the biomarker index was calculated for laboratory diagnosis of HSP and differential diagnosis between HSP and septicemia. RESULTS: The levels of serum WBC, CRP, IL-6 and SAA in the septicemia patients were significantly higher than those in the control group (p<0.05). Compared with the healthy individuals, serum levels of WBC, CRP, IL-6, SAA, IgA and IgM were significantly increased in patients with HSP (p<0.05). The area under the curve (AUC) of SAA, IgA, IgM, WBC, IL-6, and CRP in the patients with HSP was 0.964, 0.855, 0.849, 0.787, 0.765, and 0.622, respectively. The values of SAA, IgA, IgM, WBC, IL-6, and CRP in septicemia patients were 0.700, 0.428, 0.689, 0.682, 0.891, and 0.853, respectively. Biomarker index=SAA+IgA/4000+IgM/4000*0.4CRPmean valueCRPi. The biomarker index in HSP patients was significantly higher than that of the healthy controls. However, the biomarker index in septicemia patients was significantly lower than the control. CONCLUSION: The biomarker index of HSP patients is higher than that of the control group. While in the infectious disease represented by septicemia, it is decreased. The detection of biomarker index could exclude the interference of infection as the auxiliary examination to HSP patients. PMID- 29129627 TI - Serum reference interval of ARCHITECT alpha-fetoprotein in healthy Chinese Han adults: Sub-analysis of a prospective multi-center study. AB - OBJECTIVES: Alpha-fetoprotein (AFP) has been widely used in clinical practice for decades. However, large-scale survey of serum reference interval for ARCHITECT AFP is still absent in Chinese population. This study aimed to measure serum AFP levels in healthy Chinese Han subjects, which is a sub-analysis of an ongoing prospective, cross-sectional, multi-center study (ClinicalTrials.gov Identifier: NCT03047603). METHODS: This analysis included a total of 530 participants (41.43+/-12.14years of age on average, 48.49% males), enrolled from 5 regional centers. Serum AFP level was measured by ARCHITECT immunoassay. Statistical analysis was performed using SAS 9.4 and R software. RESULTS: AFP distribution did not show significant correlation with age or sex. The overall median and interquartile range of AFP was 2.87 (2.09, 3.83) ng/mL. AFP level did not show a trend of increasing with age. The new reference interval was 2.0-7.07ng/mL (LOQ- 97.5th percentiles). CONCLUSIONS: The reference interval for ARCHITECT AFP is updated with the data of adequate number of healthy Han adults. This new reference interval is more practical and applicable in Chinese adults. PMID- 29129628 TI - The combinatorial effects of osmolytes and alcohols on the stability of pyrazinamidase: Methanol affects the enzyme stability through hydrophobic interactions and hydrogen bonds. AB - Inside the cells, proteins are surrounded by mixtures of different osmolytes. However, our current understanding of the combinatorial effects of such mixtures on the stability of proteins remains elusive. In the present study, the stability and structure of recombinant pyrazinamidase (PZase) from Mycobacterium tuberculosis were analyzed in the presence of stabilizing osmolytes (sorbitol, sucrose and glycerol) and alcohols (methanol, ethanol, isopropanol and n propanol). The far-UV and near-UV circular dichroism (CD), intrinsic fluorescence and thermostability results indicated that methanol, unexpectedly, has stronger effect on destabilization of the enzyme compared to ethanol which has larger log P. Interestingly, the relative half-life of PZase was longer in mixtures methanol with the osmolytes, sorbitol or sucrose (expectedly), or glycerol (unexpectedly), compared to other alcohols. Molecular dynamics simulation results showed that methanol increases the flexibility of region 5-40 and loop 51-71 in the PZase, which are potentially crucial for the stability and activity of the enzyme, respectively. Our results indicated that methanol can interact with PZase via hydrophobic interactions and hydrogen bonds, and therefore resulting in destabilization of the structure of the enzyme. In addition, glycerol probably increases the stability of the enzyme in methanol by disrupting the unfavorable hydrophobic interactions and hydrogen bonds. PMID- 29129629 TI - Phenolic compounds based conjugates from dextran aldehyde and BSA: Preparation, characterization and evaluation of their anti-cancer efficacy for therapeutic applications. AB - Here, we have synthesized phenolic compounds (pc) based on conjugates from dextran aldehyde (dex-ald) and bovine serum albumin (BSA) and screening their potential activity as therapeutic agents in cancer disease. The synthesized conjugates were analyzed by UV-vis, FT-IR, XRD and SEM analysis. UV-vis spectra of conjugates showed the shifting of spectral peak at UV to visible region revealed the enhanced conjugation due to formation of linkage. The XRD peaks of conjugates found broader and indicating the amorphous phase of conjugating materials in compared to free components. The SEM images showed that the conjugated materials having numerous pores on its surface, which proved its porous nature. The amount of phenolic compounds conjugated with (dex-ald-pc) and (BSA-pc) were found to be 65.4 and 73.91mg/g of conjugates, respectively. Cells viability was significantly decreased approximately 80-85% at concentration of 100MUg conjugates whereas the free polymers or phenolics did not affect the viability of cancer cells. Generation of high quantity of reactive oxygen species (ROS) in cells treated with conjugate materials, which may caused cell apoptosis in cancer cell line. The results clearly showed that conjugation of phenolic compounds were an effective method to improve the functional properties for therapeutic applications. PMID- 29129630 TI - Antibacterial, antifungal and anticoagulant activities of chicken PLA2 group V expressed in Pichia pastoris. AB - Secretory class V phospholipase A2 (PLA2-V) has been shown to be involved in inflammatory processes in cellular studies, but the biochemical and physical properties of this important enzyme have been unclear. As a first step towards understanding the structure, function and regulation of this PLA2, we report the expression and characterization of PLA2-V from chicken (ChPLA2-V). The ChPLA2-V cDNA was synthesized from chicken heart polyA mRNA by RT-PCR, and an expression construct containing the PLA2 was established. After expression in Pichia pastoris cells, the active enzyme was purified. The purified ChPLA2-V protein was biochemically and physiologically characterized. The recombinant ChPLA2-V has an absolute requirement for Ca2+ for enzymatic activity. The optimum pH for this enzyme is pH 8.5 in Tris-HCl buffer with phosphatidylcholine as substrate. ChPLA2 V was found to display potent Gram-positive and Gram-negative bactericidal activity and antifungal activity in vitro. The purified enzyme ChPLA2-V with much stronger anticoagulant activity compared with the intestinal and pancreatic chicken PLA2-V was approximately 10 times more active. Chicken group V PLA2, like mammal one, may be considered as a future therapeutic agents against fungal and bacterial infections and as an anticoagulant agent. PMID- 29129631 TI - Binding of calcium and target peptide to calmodulin-like protein CML19, the centrin 2 of Arabidopsis thaliana. AB - Calmodulin-like protein 19 (CML19) is an Arabidopsis centrin that modulates nucleotide excision repair (NER) by binding to RAD4 protein, the Arabidopsis homolog of human Xeroderma pigmentosum complementation group C protein. Although the necessity of CML19 as a part of the RAD4 plant recognition complex for functional NER is known at a cellular level, little is known at a molecular level. Herein, we used a combination of biophysical and biochemical approaches to investigate the structural and ion and target-peptide binding properties of CML19. We found that CML19 possesses four Ca2+-specific binding sites, two of high affinity in the N-terminal domain and two of low affinity in the C-terminal domain. Binding of Ca2+ to CML19 increases its alpha-helix content, stabilizes the tertiary structure, and triggers a conformational change, resulting in the exposure of a hydrophobic patch instrumental for target protein recognition. Using bioinformatics tools we identified a CML19-binding site at the C-terminus of RAD4, and through in vitro binding experiments we analyzed the interaction between a 17-mer peptide representing this site and CML19. We found that the peptide shows a high affinity for CML19 in the presence of Ca2+ (stoichiometry 1:1) and the interaction primarily involves the C-terminal half of CML19. PMID- 29129632 TI - Synthesis, characterization of ZnO-chitosan nanocomposites and evaluation of its antifungal activity against pathogenic Candida albicans. AB - In this study, we investigated the antifungal activity and cytotoxicity of ZnO chitosan nanocomposites (ZnO-C NCs) against Candida albicans and human epithelial type 2 (HEp2) cells, respectively. The crystalline phase, morphology, composition, particle size and optical absorption properties of the synthesized ZnO-C NCs were systematically investigated by various contemporary methods. The X ray diffraction analysis results showed characteristic diffraction peaks corresponding to both ZnO and chitosan, while field-emission scanning electron microscopy (FESEM) displayed clusters of spherical shaped particulate morphology. UV-vis absorption spectra showed a shift in the optical absorption towards lower wavelength for ZnO-C NCs when compared to ZnO nanoparticles (NPs). The antifungal activity results (against C. albicans) showed that the minimum inhibitory concentration of ZnO NPs and ZnO-C NCs were 200MUg/mL and 75MUg/mL, respectively, suggesting the greater therapeutic potential of ZnO-C NCs. FESEM analysis results showed the substantial change in the external morphology of C. albicans after treatment with both ZnO NPs and ZnO-C NCs due to the fungal cell membrane damage. ZnO-C NCs displayed lower cytotoxicity with HEp2 cells indicating the good cytocompatibility of the synthesized ZnO-C NCs. It is expected that ZnO and chitosan complement each other and exhibit synergistic effects potential for antimicrobial and biomedical applications. PMID- 29129633 TI - Sequence and structure insights of kazal type thrombin inhibitor protein: Studied with phylogeny, homology modeling and dynamic MM/GBSA studies. AB - Despite the wide medical importance of serine protease inhibitors, many of kazal type proteins are still to be explored. These thrombin inhibiting proteins are found in the digestive system of hematophagous organisms mainly Arthropods. We studied one of such protein i.e. Kazal type-1 protein from sand-fly Phlebotomus papatasi as its structure and interaction with thrombin is unclear. Initially, Dipetalin a kazal-follistasin domain protein was run through PSI-BLAST to retrieve related sequences. Using this set of sequence a phylogenetic tree was constructed, which identified a distantly related kazal type-1 protein. A three dimensional structure was predicted for this protein and was aligned with Rhodniin for further evaluation. To have a comparative understanding of it's binding at the thrombin active site, the aligned kazal model-thrombin and rhodniin-thrombin complexes were subjected to molecular dynamics simulations. Dynamics analysis with reference to main chain RMSD, H-chain residue RMSF and total energy showed rhodniin-thrombin complex as a more stable system. Further, the MM/GBSA method was applied that calculated the binding free energy (DeltaGbinding) for rhodniin and kazal model as -220.32kcal/Mol and 90.70kcal/Mol, respectively. Thus, it shows that kazal model has weaker bonding with thrombin, unlike rhodniin. PMID- 29129634 TI - Immunostimulatory effects of sulfated chitosans on RAW 264.7 mouse macrophages via the activation of PI3K/Akt signaling pathway. AB - To investigate the immunostimulatory effects of chitosan sulfates, we prepared alpha- and beta-chitosan sulfates with different molecular weights and compared their immunostimulatory activities in RAW 264.7 macrophages. Results suggest that beta-chitosan sulfates were more active than alpha-chitosan in promoting nitric oxide (NO) production. Further study show that beta-chitosan sulfate significantly promoted the production of NO, prostaglandin E2, tumor necrosis factor (TNF)-alpha, interleukin-6 and interleukin-1beta at the levels of transcription and translation. Moreover, Western blots revealed that it induced the phosphorylation of p85 and Akt, and the nuclear translocation of p50/p65 and c-Fos/c-Jun. The luciferase activity of cells pretreated with beta-chitosan sulfate further confirmed the nuclear translocation of p50/p65 and c-Fos/c-Jun. Determination of Toll-like receptor (TLR) 4 expression suggested that beta chitosan sulfate at least partly bound to TLR4. In conclusion, beta-chitosan sulfates activate RAW 264.7 cells through the PI3K-Akt pathway, which is dependent on activator protein-1 and nuclear factor-kappaB activation. PMID- 29129635 TI - Three-dimensional and non-destructive characterization of nerves inside conduits using laboratory-based micro computed tomography. AB - BACKGROUND: Histological assessment of peripheral nerve regeneration in animals is tedious, time-consuming and challenging for three-dimensional analysis. NEW METHOD: The present study reports on how and to what extent micro computed tomography of paraffin-embedded samples can provide a reliable three-dimensional approach for quantitative analysis of peripheral nerves. RESULTS: Rat sciatic nerves were harvested, formalin-fixated, positioned into nerve conduits (NC), paraffin-embedded, and imaged using a laboratory-based X-ray microtomography system with an isotropic voxel length of 4MUm. Suitable quantitative measures were identified and automatically evaluated, i.e. nerve length, cross-sectional area and volume, as well as vascular structures, to be used as an assessment and comparison indicator of regeneration quality. COMPARISON WITH EXISTING METHODS: Compared to imaging using contrast agents, the investigated specimens can subsequently undergo the conventional histological analysis without requiring additional preparation steps. Contrast and spatial resolution are also increased significantly. CONCLUSIONS: We demonstrate the potential of the micro computed tomography for non-destructive monitoring of peripheral nerves inside the conduits. PMID- 29129636 TI - Inflammation-mediated muscle metabolic dysregulation local and remote to the site of major abdominal surgery. AB - BACKGROUND & AIMS: Postoperative hyperglycaemia is common in patients having major surgery and is associated with adverse outcomes. This study aimed to determine whether bacteraemia contributed to postoperative systemic inflammation, and whether increases in the expression of muscle mRNAs and proteins reflecting increased muscle inflammation, atrophy and impaired carbohydrate oxidation were evident at the time of surgery, and both local and distant to the site of trauma, and could be associated with impaired glucoregulation. METHODS: Fifteen adult patients without diabetes undergoing major abdominal surgery participated in this observational study set in a university teaching hospital. Arterialised-venous blood samples and muscle biopsies were obtained before and after major elective abdominal surgery, from sites local (rectus abdominis - RA) and remote to the site of surgery (vastus lateralis - VL). The main outcome measures included blood glucose concentrations, gut permeability and changes in expression of muscle mRNAs and proteins linked to inflammation and glucose regulation. RESULTS: Immediately postoperatively, RA demonstrated markedly increased mRNA expression levels of cathepsin-L (7.5-fold, P < 0.05), FOXO1 (10.5-fold, P < 0.05), MAFbx (11.5-fold, P < 0.01), PDK4 (7.8-fold, P < 0.05), TNF-alpha (16.5-fold, P < 0.05) and IL-6 (1058-fold, P < 0.001). A similar, albeit blunted, response was observed in VL. Surgery also increased expression of proteins linked to inflammation (IL 6; 6-fold, P < 0.01), protein degradation (MAFbx; 4.5-fold, P < 0.5), and blunted carbohydrate oxidation (PDK4; 4-fold, P < 0.05) in RA but not VL. Increased systemic inflammation (TNF-alpha, P < 0.05; IL-6, P < 0.001), and impaired postoperative glucose tolerance (P < 0.001), but not bacteraemia (although gut permeability was increased significantly, P < 0.05) or increased plasma cortisol, were noted 48 h postoperatively. CONCLUSIONS: A systemic postoperative proinflammatory response was accompanied by muscle inflammation and metabolic dysregulation both local and remote to the site of surgery, and was not accompanied by bacteraemia. CLINICAL TRIAL REGISTRATION: Registered at http://clinicaltrials.gov (NCT01134809). PMID- 29129637 TI - A multicentre qualitative study assessing implementation of an Enhanced Recovery After Surgery program. AB - BACKGROUND & AIMS: The existence of enhanced recovery specific guidelines (ERAS) is not enough to change patient management practice since many barriers exist to successful ERAS implementation. The present survey aimed to analyse motivations for implementation as well as encountered difficulties and challenges. Further, relevance and importance of perioperative care items and postoperative recovery targets were assessed. METHODS: A multicentre qualitative study was conducted between August and December 2016 among surgeons, anaesthesiologists and nurses from implemented ERAS centres in Switzerland (n = 16) and Sweden (n = 14). An online survey (31 closed questions) was sent by email, with reminders at 4, 8 and 12 weeks. RESULTS: Seventy-seven out of 146 experts completed the survey (response rate 52.7%). Main motivations to implement ERAS were the expectation to reduce complications (91%), higher patient satisfaction (73%) and shorter hospital stay (62%). The application of ERAS program represented major changes in clinical practice for 57% of participants without significant differences between various specialities (surgeons: 63%, nurses: 63%, anaesthesiologists: 36%, p = 0.185). The most important barriers for straightforward implementation were time restraints (69%), opposing colleagues (68%) and logistical reasons (66%). The 3 most frequently cited patient-related barriers to adopt ERAS were opposing personality (52%), co-morbidities (49%) and language barriers (31%). CONCLUSIONS: Implementing ERAS care into practice was challenging and required important changes in clinical practice for all involved specialities. Main reasons for implementation were the expectation to reduce complications and hospital stay with improved patients' satisfaction. Main barriers were time restraints, reluctance to change and logistics. PMID- 29129638 TI - An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint. AB - The spindle assembly checkpoint (SAC) generates a diffusible protein complex that prevents anaphase until all chromosomes are properly attached to spindle microtubules. A key step in SAC initiation is the recruitment of MAD1 to kinetochores, which is generally thought to be governed by the microtubule kinetochore (MT-KT) attachment status. However, we demonstrate that the recruitment of MAD1 via BUB1, a conserved kinetochore receptor, is not affected by MT-KT interactions in human cells. Instead, BUB1:MAD1 interaction depends on BUB1 phosphorylation, which is controlled by a biochemical timer that integrates counteracting kinase and phosphatase effects on BUB1 into a pulse-generating incoherent feedforward loop. We propose that this attachment-independent timer serves to rapidly activate the SAC at mitotic entry, before the attachment sensing MAD1 receptors have become fully operational. The BUB1-centered timer is largely impervious to conventional anti-mitotic drugs, and it is, therefore, a promising therapeutic target to induce cell death through permanent SAC activation. PMID- 29129639 TI - Determinants of Histone H3K4 Methylation Patterns. AB - Various factors differentially recognize trimethylated histone H3 lysine 4 (H3K4me3) near promoters, H3K4me2 just downstream, and promoter-distal H3K4me1 to modulate gene expression. This methylation "gradient" is thought to result from preferential binding of the H3K4 methyltransferase Set1/complex associated with Set1 (COMPASS) to promoter-proximal RNA polymerase II. However, other studies have suggested that location-specific cues allosterically activate Set1. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments show that H3K4 methylation patterns on active genes are not universal or fixed and change in response to both transcription elongation rate and frequency as well as reduced COMPASS activity. Fusing Set1 to RNA polymerase II results in H3K4me2 throughout transcribed regions and similarly extended H3K4me3 on highly transcribed genes. Tethered Set1 still requires histone H2B ubiquitylation for activity. These results show that higher-level methylations reflect not only Set1/COMPASS recruitment but also multiple rounds of transcription. This model provides a simple explanation for non-canonical methylation patterns at some loci or in certain COMPASS mutants. PMID- 29129640 TI - The Stress Granule Transcriptome Reveals Principles of mRNA Accumulation in Stress Granules. AB - Stress granules are mRNA-protein assemblies formed from nontranslating mRNAs. Stress granules are important in the stress response and may contribute to some degenerative diseases. Here, we describe the stress granule transcriptome of yeast and mammalian cells through RNA-sequencing (RNA-seq) analysis of purified stress granule cores and single-molecule fluorescence in situ hybridization (smFISH) validation. While essentially every mRNA, and some noncoding RNAs (ncRNAs), can be targeted to stress granules, the targeting efficiency varies from <1% to >95%. mRNA accumulation in stress granules correlates with longer coding and UTR regions and poor translatability. Quantifying the RNA-seq analysis by smFISH reveals that only 10% of bulk mRNA molecules accumulate in mammalian stress granules and that only 185 genes have more than 50% of their mRNA molecules in stress granules. These results suggest that stress granules may not represent a specific biological program of messenger ribonucleoprotein (mRNP) assembly, but instead form by condensation of nontranslating mRNPs in proportion to their length and lack of association with ribosomes. PMID- 29129641 TI - Cohesin Ubiquitylation and Mobilization Facilitate Stalled Replication Fork Dynamics. AB - Replication fork integrity is challenged in conditions of stress and protected by the Mec1/ATR checkpoint to preserve genome stability. Still poorly understood in fork protection is the role played by the structural maintenance of chromosomes (SMC) cohesin complex. We uncovered a role for the Rsp5Bul2 ubiquitin ligase in promoting survival to replication stress by preserving stalled fork integrity. Rsp5Bul2 physically interacts with cohesin and the Mec1 kinase, thus promoting checkpoint-dependent cohesin ubiquitylation and cohesin-mediated fork protection. Ubiquitylation mediated by Rsp5Bul2 promotes cohesin mobilization from chromatin neighboring stalled forks, likely by stimulating the Cdc48/p97 ubiquitin selective segregase, and its timely association to nascent chromatids. This Rsp5Bul2 fork protection mechanism requires the Wpl1 cohesin mobilizer as well as the function of the Eco1 acetyltransferase securing sister chromatid entrapment. Our data indicate that ubiquitylation facilitates cohesin dynamic interfacing with replication forks within a mechanism preserving stalled-fork functional architecture. PMID- 29129642 TI - Synthetic Approach to biomolecular science by cyborg supramolecular chemistry. AB - BACKGROUND: To imitate the essence of living systems via synthetic chemistry approaches has been attempted. With the progress in supramolecular chemistry, it has become possible to synthesize molecules of a size and complexity close to those of biomacromolecules. Recently, the combination of precisely designed supramolecules with biomolecules has generated structural platforms for designing and creating unique molecular systems. Bridging between synthetic chemistry and biomolecular science is also developing methodologies for the creation of artificial cellular systems. SCOPE OF REVIEW: This paper provides an overview of the recently expanding interdisciplinary research to fuse artificial molecules with biomolecules, that can deepen our understanding of the dynamical ordering of biomolecules. MAJOR CONCLUSIONS AND GENERAL SIGNIFICANCE: Using bottom-up approaches based on the precise chemical design, synthesis and hybridization of artificial molecules with biological materials have been realizing the construction of sophisticated platforms having the fundamental functions of living systems. The effective hybrid, molecular cyborg, approaches enable not only the establishment of dynamic systems mimicking nature and thus well-defined models for biophysical understanding, but also the creation of those with highly advanced, integrated functions. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato. PMID- 29129643 TI - TGFbeta pathway inhibition in the treatment of non-small cell lung cancer. AB - Advanced non-small cell lung cancer (NSCLC) continues to be an incurable family of thoracic malignancies that is chronically managed with chemotherapy, targeted therapy, and immunotherapy. While the discovery of driver oncogenes and the advent of targeted and immunotherapies in the last decade have vastly improved clinical disease management for patients harboring druggable mutations, the mainstay treatment for the majority of NSCLC patients remains cytotoxic chemotherapy. The clinical efficacy of targeted, immune, and cytotoxic therapies is limited by the development of drug resistance. Transforming growth factor beta (TGFbeta) signaling, a crucial mediator of embryonic development and peripheral immune tolerance, may be dysregulated in some malignant contexts, including lung cancer, and has been correlated with poor prognosis in advanced cancers. Aberrant upregulation of TGFbeta expression in the tumor microenvironment has also been implicated in promoting NSCLC progression and metastasis, as well as driving the development of resistance to cytotoxic, targeted, and immunomodulatory therapeutic interventions. Here, we examine the mechanisms underlying TGFbeta mediated drug resistance in NSCLC, and consider TGFbeta as a combinatorial therapeutic intervention to circumvent or delay the development of NSCLC treatment resistance. PMID- 29129644 TI - Role of kinase-coupled TRP channels in mineral homeostasis. AB - Transient receptor potential (TRP) proteins TRPM6 and TRPM7 are alpha-kinase coupled divalent cation-selective channels activated upon a reduction of cytosolic levels of Mg2+ and Mg.ATP. Emerging evidence indicate that one of the main physiological functions of TRPM6 and TRPM7 is maintaining of cellular metabolism of Mg2+ and likely other essential metals such as Ca2+ and Zn2+. Recent experiments with genetic animal models have shown that TRPM6 and TRPM7 are essential for epithelial Mg2+ transport in the placenta and intestine. In addition, mutations in TRPM6 or TRPM7 have been linked to Mg2+ deficiency in humans. However, many key functional aspects of these remarkable proteins as well as mechanisms of the associated channelopathies remain incompletely understood. The present review article highlights the recent significant progress in the field with the focus on the vital roles of TRPM7 and TRPM7 in mineral homeostasis. PMID- 29129645 TI - Incretins modulate progesterone biosynthesis by regulating bone morphogenetic protein activity in rat granulosa cells. AB - The effects of incretins on ovarian steroidogenesis have not been clarified. In this study, we investigated the effects of incretins, including GIP and GLP-1, on ovarian steroidogenesis using rat primary granulosa cells. Treatment with incretins significantly suppressed progesterone synthesis in the presence of FSH, and the effect of GIP was more potent than that of GLP-1. In contrast, incretins had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of incretins on steroidogenesis, GIP and GLP-1 suppressed the expression of progesterogenic factors and enzymes, including StAR, P450scc, 3betaHSD, but not P450arom, and cellular cAMP synthesis induced by FSH. In addition, incretins moderately increased FSHR mRNA expression in granulosa cells. Of note, treatment with GIP, but not treatment with GLP-1, augmented Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1 induced by BMP-6 stimulation, suggesting that GIP upregulates BMP receptor signaling that can inhibit FSH-induced progesterone synthesis in rat granulosa cells. On the other hand, BMP-6 treatment suppressed the expression of GIP receptor but not that of GLP-1 receptor. Expression of the BMP type-I receptor ALK-3 was upregulated by treatment with GIP and GLP-1 and that of ALK-6 was also increased by GIP, while inhibitory Smad6 expression was impaired by GIP and GLP-1 in rat granulosa cells. Collectively, the results indicate that incretins, particularly GIP, impair FSH-induced progesterone production, at least in part, by upregulating BMP signaling in rat granulosa cells. The modulatory effects of incretins on endogenous BMP activity may be applicable to treatment of dysregulated steroidogenesis such as polycystic ovary syndrome. PMID- 29129646 TI - Extracellular volume depletion and resultant hypotonic hyponatremia: A novel translational approach. AB - Although several methods currently exist to determine that a person is hypovolemic, it often remains very challenging to accurately estimate the effective circulating volume or amount of intravascular volume depletion in a non controlled setting. This depletion of intravascular volume can have many causes and is frequently accompanied by hypotonic hyponatremia as a result of hypovolemia-induced release of arginine vasopressin (AVP) from the posterior pituitary gland. Here, we derive a novel, comprehensible equation that provides a theoretical insight into the complex interrelationship between the degree of isotonic volume depletion and the resultant change in plasma sodium concentration. We believe that the presented model can prove to be a valuable tool for the analysis of fluid and electrolyte imbalances. PMID- 29129647 TI - Salivary biomarker combination prediction model for the diagnosis of periodontitis in a Taiwanese population. AB - BACKGROUND/PURPOSE: This study aimed at screening the diagnostic potential of salivary biomarkers and pairing them to establish a prediction model with higher accuracy in diagnosing periodontitis in the Taiwanese population. METHODS: Fifty seven participants were divided into a non-periodontitis group and a periodontitis group. Salivary biomarkers CRP, IL-6, IL-8, IL-1beta, IL-1ra, lactoferrin, MMP-8, MMP-9, PDGF-BB, TNF-alpha, and VEGF, were analyzed. The potential and reliability of the biomarkers for diagnosing periodontitis were analyzed dichotomously. The correlation of individual biomarkers with periodontitis was assessed using the Spearman rank correlation coefficient with logistic regression. The combinational prediction model was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Regarding individual biomarkers, IL-1beta and MMP-9 levels were significantly higher, and TNF-alpha was significantly lower in the periodontitis group. IL-1beta, MMP-8, and MMP-9 exhibited a greater odds ratio with statistical significance in the dichotomous table. The combination of three biomarkers yielded AUCs of 0.821 0.853, and the combination of IL-1beta, IL-1ra, and MMP-9 exhibited the highest AUC (0.853), with high sensitivity (73.3%) and specificity (88.9%). CONCLUSION: Regarding individual biomarkers, IL-1beta, MMP-8, and MMP-9 showed potential for identifying patients with periodontitis. The combination of IL-1beta, IL-1ra, and MMP-9 might be feasible for developing a future point-of-care device for diagnosing periodontitis. PMID- 29129648 TI - HLA genes in Barranquilla (North Colombia): Searching for cryptic Amerindian genes. AB - America First Inhabitants population (Amerindians, Na Dene and Eskimos) underwent a drastic population reduction and gene exchange after Europeans and Africans arrival after 1492 AD. Barranquilla population may be a good model to study present day population admixture in South America. HLA-A, -B and -DRB1 DNA typing has been performed in 188 unrelated individuals originated in the area and speak Spanish language; they showed apparent European/African and mixed characters. HLA genetic European/African features were found and only 1.85% Amerindian one. This contrasts with neighboring Cuban population where 10% HLA Amerindian characters appear. PMID- 29129650 TI - Forecasting the future burden of opioids for osteoarthritis. AB - OBJECTIVE: To quantify the current national burden of opioids for osteoarthritis (OA) pain in Australia in terms of number of dispensed opioid prescriptions and associated costs, and to forecast the likely burden to the year 2030/31. DESIGN: Epidemiological modelling. METHODS: Published data were obtained on rates of opioid prescribing for people with OA and national OA prevalence projections. Trends in opioid dispensing from 2006 to 2016, and average costs for common opioid subtypes were obtained from the Pharmaceutical Benefits Scheme and Medicare Australia Statistics. Using these inputs, a model was developed to estimate the likely number of dispensed opioid prescriptions and costs to the public healthcare system by 2030/31. RESULTS: In 2015/16, an estimated 1.1 million opioid prescriptions were dispensed in Australia for 403,954 people with OA (of a total 2.2 million Australians with OA). Based on recent dispensing trends and OA prevalence projections, the number of dispensed opioid prescriptions is expected to nearly triple to 3,032,332 by 2030/31, for an estimated 562,610 people with OA. The estimated cost to the Australian healthcare system was $AUD25.2 million in 2015/16, rising to $AUD72.4 million by 2030/31. CONCLUSION: OA-related opioid dispensing and associated costs are set to increase substantially in Australia from 2015/16 to 2030/31. Use of opioids for OA pain is concerning given joint disease chronicity and the risk of adverse events, particularly among older people. These projections represent a conservative estimate of the full financial burden given additional costs associated with opioid-related harms and out-of-pocket costs borne by patients. PMID- 29129651 TI - Dendritic cells in the cornea during Herpes simplex viral infection and inflammation. AB - Herpes simplex keratitis is commonly caused by Herpes simplex virus type 1, which primarily infects eyelids, corneas, or conjunctiva. Herpes simplex virus type 1 through sophisticated interactions with dendritic cells (DCs), a type of antigen presenting cell)-initiates proinflammatory responses in the cornea. Corneas were once thought to be an immune-privileged region; however, with the recent discovery of DCs that reside in the cornea, this long-held conjecture has been overturned. Therefore, evaluating the clinical, preclinical, and cell-based studies that investigate the roles of DCs in corneas infected with Herpes simplex virus is critical. With in vivo confocal microscopy, animal models, and cell culture experiments, we may further the understanding of the sophisticated interactions of Herpes simplex virus with DCs in the cornea and the molecular mechanism associated with it. It has been shown that specific differentiation of DCs using immunohistochemistry, flow cytometry, and polymerase chain reaction analysis in both human and mice tissues and viral tissue infections are integral to increasing understanding. As for in vivo confocal microscopy, it holds promise as it is the least invasive and a real-time investigation. These tools will facilitate the discovery of various targets to develop new treatments. PMID- 29129649 TI - TSG-6 - a double-edged sword for osteoarthritis (OA). AB - PURPOSE: To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression. METHODS: TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids (SFs). Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of Inter-alpha-Inhibitor (IalphaI) and TSG-6 activity +/- spiked in IalphaI. Primary chondrocyte cultures (n=5) +/- IL1beta or TNFalpha were evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix (ECM) assembly were explored using quantitative hyaluronan (HA)-aggrecan binding assays. RESULTS: TSG-6 activity was significantly associated (R > 0.683, P < 0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IalphaI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect. CONCLUSIONS: TSG 6 activity is a global inflammatory biomarker in knee OA SF. IalphaI, supplied from outside cartilage, only penetrates the cartilage surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression. PMID- 29129652 TI - Engineering strategies for enhanced production of protein and bio-products in Pichia pastoris: A review. AB - Pichia pastoris has been recognized as one of the most industrially important hosts for heterologous protein production. Despite its high protein productivity, the optimization of P. pastoris cultivation is still imperative due to strain- and product-specific challenges such as promoter strength, methanol utilization type and oxygen demand. To address the issues, strategies involving genetic and process engineering have been employed. Optimization of codon usage and gene dosage, as well as engineering of promoters, protein secretion pathways and methanol metabolic pathways have proved beneficial to innate protein expression levels. Large-scale production of proteins via high cell density fermentation additionally relies on the optimization of process parameters including methanol feed rate, induction temperature and specific growth rate. Recent progress related to the enhanced production of proteins in P. pastoris via various genetic engineering and cultivation strategies are reviewed. Insight into the regulation of the P. pastoris alcohol oxidase 1 (AOX1) promoter and the development of methanol-free systems are highlighted. Novel cultivation strategies such as mixed substrate feeding are discussed. Recent advances regarding substrate and product monitoring techniques are also summarized. Application of P. pastoris to the production of biodiesel and other value-added products via metabolic engineering are also reviewed. P. pastoris is becoming an indispensable platform through the use of these combined engineering strategies. PMID- 29129653 TI - Targeting ncRNAs by plant secondary metabolites: The ncRNAs game in the balance towards malignancy inhibition. AB - The current trend of combining state of the art technologies with quondam treatments in order to overcome existing gaps in the clinical area determined an increased interest into polyphenols, common dietary phytochemicals, for the prevention and treatment of chronic diseases, especially cancer. The reemergence of polyphenols in the cancer field is sustained by advanced-omics technologies able to identify coding and non-coding genes and their related signaling pathways modulated by natural compounds. Identification of the structural correspondence between interacting molecules will allow the development of more targeted and informed therapeutic strategies for cancer management. PMID- 29129654 TI - Corrigendum to "Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases" [Mol. Genet. Metab. 118 (2016) 206-213]. PMID- 29129655 TI - Relevance and uncertainty jointly influence reward anticipation at the level of the SPN ERP component. AB - The stimulus-preceding negativity (SPN) component reflects the anticipatory phase of reward processing. Its amplitude is usually larger for informative compared to uninformative upcoming stimuli, as well as for uncertain relative to predictable ones. In this study, we sought to assess whether these two effects, when combined together, produced a synergistic effect or rather independent ones on the SPN during performance monitoring. Participants performed a speeded Go/NoGo task while 64-channel EEG was recorded concurrently. We focused on the SPN activity generated in anticipation of feedback, which was either positive (for correct and fast reactions) or negative (for correct but slow responses). Further, the feedback's informativeness about the satisfaction status of goals was alternated across blocks. When uncertainty about the action outcome was low (in conditions where positive feedback was either less or more frequent than negative feedback), the SPN amplitude (measured at fronto-central electrodes) did not vary as a function of feedback's relevance or valence. By comparison, when positive and negative feedback were equiprobable (uncertainty was high), the SPN was more pronounced for relevant compared to irrelevant feedback. Interestingly, in this condition, it was also larger at right fronto-central sites for positive than negative feedback. These ERP results suggest that both factors-relevance and uncertainty- combine and influence reward anticipation at the SPN level. PMID- 29129656 TI - Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor alpha expression induced by dexamethasone and valproic acid. PMID- 29129657 TI - Transport mechanism of lipid covered saquinavir pure drug nanoparticles in intestinal epithelium. AB - Pure drug nanoparticles (NPs) represent a promising formulation for improved drug solubility and controlled dissolution velocity. However, limited absorption by the intestinal epithelium remains challenge to their clinical application, and little is known about how these NPs within the cells are transported. To improve cellular uptake and transport of pure nanodrug in cells, here, a lipid covered saquinavir (SQV) pure drug NP (Lipo@nanodrug) was designed by modifying a pure SQV NP (nanodrug) with a phospholipid bilayer. We studied their endocytosis, intracellular trafficking mechanism using Caco-2 cell model. Uptake of Lipo@nanodrug by Caco-2 cells was 1.91-fold greater than that of pure nanodrug via processes involving cell lipid raft. The transcellular transport of Lipo@nanodrug across Caco-2 monolayers was 3.75-fold and 1.92-fold higher than that of coarse crystals and pure nanodrug, respectively. Within cells, Lipo@nanodrug was mainly localized in the endoplasmic reticulum and Golgi apparatus, leading to transcytosis of Lipo@nanodrug across intestinal epithelial cells, whereas pure nanodrug tended to be retained and to dissolve in cell and removed by P-gp-mediated efflux. In rats, the oral bioavailability of the model drug SQV after Lipo@nanodrug administration was 4.29-fold and 1.77-fold greater than after coarse crystal and pure nanodrug administration, respectively. In conclusion, addition of a phospholipid bilayer to pure drug NP increased their cellular uptake and altered their intracellular processing, helping to improve drug transport across intestinal epithelium. To our knowledge, this is the first presentation of the novel phospholipid bilayer covered SQV pure drug NP design, and a mechanistic study on intracellular trafficking in in vitro cell models has been described. The findings provide a new platform for oral delivery of poorly water-soluble drugs. PMID- 29129658 TI - Overcoming antibiotic resistance: Is siderophore Trojan horse conjugation an answer to evolving resistance in microbial pathogens? AB - Comparative study of siderophore biosynthesis pathway in pathogens provides potential targets for antibiotics and host drug delivery as a part of computationally feasible microbial therapy. Iron acquisition using siderophore models is an essential and well established model in all microorganisms and microbial infections a known to cause great havoc to both plant and animal. Rapid development of antibiotic resistance in bacterial as well as fungal pathogens has drawn us at a verge where one has to get rid of the traditional way of obstructing pathogen using single or multiple antibiotic/chemical inhibitors or drugs. 'Trojan horse' strategy is an answer to this imperative call where antibiotic are by far sneaked into the pathogenic cell via the siderophore receptors at cell and outer membrane. This antibiotic once gets inside, generates a 'black hole' scenario within the opportunistic pathogens via iron scarcity. For pathogens whose siderophore are not compatible to smuggle drug due to their complex conformation and stiff valence bonds, there is another approach. By means of the siderophore biosynthesis pathways, potential targets for inhibition of these siderophores in pathogenic bacteria could be achieved and thus control pathogenic virulence. Method to design artificial exogenous siderophores for pathogens that would compete and succeed the battle of intake is also covered with this review. These manipulated siderophore would enter pathogenic cell like any other siderophore but will not disperse iron due to which iron inadequacy and hence pathogens control be accomplished. The aim of this review is to offer strategies to overcome the microbial infections/pathogens using siderophore. PMID- 29129659 TI - Generation of conditional Acvrl1 knockout mice by CRISPR/Cas9-mediated gene targeting. AB - OBJECTIVES: This study aimed to generate mutant mice containing the Acvrl1 gene flanked with LoxP sequences to allow conditional deletion of Acvrl1 by the LoxP/Cre system. Such mice may facilitate the development of brain arteriovenous malformation (BAVM) models. METHODS: The CRISPR/Cas9 technique was used to edit Acvrl1. Two single guide RNAs (sgRNAs) with recognition sites on intron 3 and 8 and a donor vector that was homologous with the targeted gene and contained two LoxP sequences were designed and constructed. The in vitro-synthesized sgRNA, Cas9 mRNA and donor vectors were injected into mouse zygotes, which were then transferred into pseudopregnant mice. Neonatal mutant mice were identified by genotyping and sequencing. RESULTS: Two mice with a floxed Acvrl1 allele were generated at a success rate of 8.7%. The target mice, which were healthy and fertile, were obtained through interbreeding. CONCLUSION: CRISPR/Cas9 is a reliable gene-editing tool, and is able to efficiently modify Acvrl1 and create the target mice. PMID- 29129660 TI - Microduplication of 10q26.3 in a Chinese hypertriglyceridemia patient. AB - Hypertriglyceridemia (HTG) plays an important role in the development and progression of atherosclerosis. It is inherited in an autosomal dominant pattern with a frequency of approximately 1:1,000,000 worldwide. Previous study has demonstrated that more than six genes underlie this disorder. In addition, copy number variants (CNVs) including disease-causing genes also play a crucial role in it. In this study, we have employed SNP-ARRAY chip technology to detect the pathogenic CNVs in a HTG patient who carried no meaningful mutations in HTG candidate genes. And we identified a de novo CNV interstitial 134.7 kb duplication of chromosome region 10q26.3 containing CYP2E1. And this CNV also has been confirmed by Real-time PCR. CYP2E1 is a member of cytochrome P450 superfamily of enzymes which play an important role in fatty acid metabolism. Our study is consistent with previous research and further claimes that CNVs containing CYP2E1 may be related to HTG and obesity. Our study not only further confirmes the hypothesis that the CYP2E1 is a plausible candidate gene for HTG, but also may contribute to the diagnosis and treatment of these genomic diseases. PMID- 29129661 TI - Going Viral and Interacting with the Press. PMID- 29129662 TI - Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application. AB - NAD(P)H-dependent oxidoreductases catalyze the reduction or oxidation of a substrate coupled to the oxidation or reduction, respectively, of a nicotinamide adenine dinucleotide cofactor NAD(P)H or NAD(P)+. NAD(P)H-dependent oxidoreductases catalyze a large variety of reactions and play a pivotal role in many central metabolic pathways. Due to the high activity, regiospecificity and stereospecificity with which they catalyze redox reactions, they have been used as key components in a wide range of applications, including substrate utilization, the synthesis of chemicals, biodegradation and detoxification. There is great interest in tailoring NAD(P)H-dependent oxidoreductases to make them more suitable for particular applications. Here, we review the main properties and classes of NAD(P)H-dependent oxidoreductases, the types of reactions they catalyze, some of the main protein engineering techniques used to modify their properties and some interesting examples of their modification and application. PMID- 29129663 TI - Compensation Strategies in Voice Production With Glottal Insufficiency. AB - OBJECTIVES: This study evaluates potential compensation strategies under conditions of glottal insufficiency. METHODS: Using a numerical respiratory laryngeal model of voice production, voice production under conditions of glottal insufficiency is investigated across a large range of voice conditions, and compared with normal voice production. RESULTS: This study shows that glottal insufficiency leads to increased noise production, reduced fundamental frequency range, and inability to produce very low-intensity voice. Glottal insufficiency also leads to significantly increased respiratory effort of phonation and difficulty in maintaining a normal breath group duration, which restricts high intensity voice production and falsetto-like voice production. Although compensation strategies exist to alleviate these undesirable voice changes, they often require hyperfunctional laryngeal and respiratory muscle activities and thus are more likely to result in vocal fatigue. CONCLUSIONS: The laryngeal and respiratory subsystems need to be considered as a whole to fully understand the effect of glottal insufficiency on voice production. Strategies that compensate for laryngeal weakness at the cost of compromising the normal function of the respiratory subsystem are undesirable and may impose additional constraints on voice production and the effectiveness of available compensation strategies. PMID- 29129664 TI - Hemistepsin A ameliorates acute inflammation in macrophages via inhibition of nuclear factor-kappaB and activation of nuclear factor erythroid 2-related factor 2. AB - Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata (Bunge) Bunge. We investigated the anti-inflammatory effects of HsA and sought to determine its mechanisms of action in macrophages. HsA pretreatment inhibited nitric oxide production, and reduced the expression of iNOS and COX-2 in Toll like receptor ligand-stimulated RAW 264.7 cells. Additionally, HsA decreased the secretion of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated Kupffer cells as well as in RAW 264.7 cells. HsA inhibited phosphorylation of IKKalpha/beta and degradation of IkappaBalpha, resulting in decreased nuclear translocation of nuclear factor-kappaB (NF-kappaB) and its transcriptional activity. Moreover, HsA phosphorylated nuclear factor erythroid 2-related factor 2 (Nrf2), increased expression levels of antioxidant genes, and attenuated LPS stimulated H2O2 production. Phosphorylation of p38 and c-Jun N-terminal kinase was required for HsA-mediated Nrf2 phosphorylation. In a D-galactosamine/LPS induced liver injury model, HsA ameliorated D-galactosamine/LPS-induced hepatocyte degeneration and inflammatory cells infiltration. Moreover, immunohistochemical analyses using nitrotyrosine, 4-hydroxynonenal, and cleaved poly (ADP-ribose) polymerase antibodies revealed that HsA protected the liver from oxidative stress. Furthermore, HsA reduced the numbers of proinflammatory cytokine-positive cells in hepatic tissues. Thus, these results suggest HsA may be a promising natural product to manage inflammation-mediated tissue injuries through inhibition of NF-kappaB and activation of Nrf2. PMID- 29129666 TI - Effect of soy isoflavone supplementation on plasma lipoprotein(a) concentrations: A meta-analysis. AB - BACKGROUND: Soy supplementation has been shown to reduce total and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol. However, contradictory effects of soy isoflavone supplementation on lipoprotein(a) [Lp(a)] have been reported suggesting the need for a meta-analysis to be undertaken. OBJECTIVE: The aim of the study was to investigate the impact of supplementation with soy isoflavones on plasma Lp(a) levels through a systematic review and meta-analysis of eligible randomized placebo-controlled trials. METHODS: The search included PubMed-Medline, Scopus, ISI Web of Knowledge, and Google Scholar databases (by March 26, 2017), and quality of studies was evaluated according to Cochrane criteria. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. RESULTS: Ten eligible studies comprising 11 treatment arms with 973 subjects were selected for the meta-analysis. Meta-analysis did not suggest any significant alteration of plasma Lp(a) levels after supplementation with soy isoflavones (standardized mean difference: 0.08, 95% confidence interval: -0.05, 0.20, P = .228). The effect size was robust in the leave-one-out sensitivity analysis. In meta-regression analysis, neither dose nor duration of supplementation with soy isoflavones was significantly associated with the effect size. CONCLUSION: This meta-analysis of the 10 available randomized placebo controlled trials revealed no significant effect of soy isoflavones treatment on plasma Lp(a) concentrations. PMID- 29129665 TI - Intravasation of SW620 colon cancer cell spheroids through the blood endothelial barrier is inhibited by clinical drugs and flavonoids in vitro. AB - Mechanisms how colorectal cancer (CRC) cells penetrate blood micro-vessel endothelia and metastasise is poorly understood. To study blood endothelial cell (BEC) barrier breaching by CRC emboli, an in vitro assay measuring BEC-free areas underneath SW620 cell spheroids, so called "circular chemorepellent induced defects" (CCIDs, appearing in consequence of endothelial retraction), was adapted and supported by Western blotting, EIA-, EROD- and luciferase reporter assays. Inhibition of ALOX12 or NF-kappaB in SW620 cells or BECs, respectively, caused attenuation of CCIDs. The FDA approved drugs vinpocetine [inhibiting ALOX12 dependent 12(S)-HETE synthesis], ketotifen [inhibiting NF-kappaB], carbamazepine and fenofibrate [inhibiting 12(S)-HETE and NF-kappaB] significantly attenuated CCID formation at low MUM concentrations. In the 5-FU-resistant SW620-R/BEC model guanfacine, nifedipine and proadifen inhibited CCIDs stronger than in the naive SW620/BEC model. This indicated that in SW620-R cells formerly silent (yet unidentified) genes became expressed and targetable by these drugs in course of resistance acquisition. Fenofibrate, and the flavonoids hispidulin and apigenin, which are present in medicinal plants, spices, herbs and fruits, attenuated CCID formation in both, naive- and resistant models. As FDA-approved drugs and food flavonoids inhibited established and acquired intravasative pathways and attenuated BEC barrier-breaching in vitro, this warrants testing of these compounds in CRC models in vivo. PMID- 29129667 TI - Prevalence of Functional Gastrointestinal Disorders in Children and Adolescents in the Mediterranean Region of Europe. AB - BACKGROUND & AIMS: Little is known about the prevalence of functional gastrointestinal disorders (FGIDs) in children from the Mediterranean area of Europe. We aimed to assess the prevalence of FGIDs in children and adolescents in this region. METHODS: We collected data on 13,750 children (4-18 years old) enrolled in the Mediterranean-European Area Project, a school-based health study performed in Croatia, Greece, Israel, Italy, Jordan, Lebanon, Macedonia, Serbia, and Spain. Data were collected from March to June and in September of 2016. We analyzed data from 6602 students 4 to 10 years old (group A; mean age, 7.7 +/- 1.9 y), and 7148 subjects 11 to 18 years old (group B; mean age, 13.8 +/- 2.1 y). Children with FGIDs were identified based on answers to questionnaires on pediatric gastrointestinal symptoms, selected based on Rome III criteria. RESULTS: In group A, the prevalence of FGIDs was 20.7%. The most frequent disorders were functional constipation (11.7%), irritable bowel syndrome (IBS, 4%), aerophagia (3.5%), and abdominal migraine (3.1%). The prevalence of abdominal migraine was significantly higher in girls than in boys (P = .007). In group B, the overall prevalence of FGIDs was 26.6%. The most frequent disorders were functional constipation (13.1%), abdominal migraine (7.8%), aerophagia (6.3%), and IBS (5.6%). In group B, FGIDs had a higher prevalence among girls than boys (P < .001). In both groups, we found significant differences in the prevalence of specific disorders among specific countries. CONCLUSIONS: In an analysis of data on children 4 to 18 years old from the Mediterranean-European Area Project, we found FGIDs to be more frequent in girls. Functional constipation, aerophagia, abdominal migraine, and IBS are the most common disorders. However, the prevalence of FGIDs varies significantly among countries. PMID- 29129669 TI - Effect of application score strategy on interviews offered to postgraduate year 1 pharmacy residency applicants. AB - OBJECTIVES: Residency programs may need to spend a large amount of time on the application review process in order to invite the best candidates for interviews. By using a different scoring strategy, this process could be made more efficient while still resulting in selection of the most appropriate candidates to interview. The objective of this study was to explore hypothetical scoring strategies for past residency applicants and to determine the percentage of these applicants that would have received an interview offer compared with the program's standard scoring strategy. METHODS: Two years of residency applications to a postgraduate year 1 (PGY1) program providing the majority of clinical experience in ambulatory care were analyzed. Four models were explored: 1) standard model (original method); 2) simplified model (derived from statistical methods); 3) intuition model (criteria thought to best exemplify program success); and 4) objective model (criteria easy to objectively record, e.g., grade point average). All 3 new models were compared with the standard model to determine the percentage of candidates who would have received an interview if their applications had been scored according to the new model. RESULTS: A total of 110 applications were reviewed (42 interviews offered). After a multivariable analysis, academics, leadership, interest in ambulatory care, and professionalism were included in the simplified model, which predicted 81% of the interviews offered through the standard model. The intuition and objective models predicted 71% and 48% of interviews offered through the standard model, respectively. CONCLUSION: Models scoring only 4 of the initial 12 criteria would have likely predicted 71% to 81% of original interview offers. Residency programs should consider periodically reviewing their application review processes to determine areas for improved efficiency. PMID- 29129668 TI - Characterization of actions taken during the delivery of medication therapy management: A time-and-motion approach. AB - OBJECTIVES: To characterize actions performed by pharmacists and support staff during provision of medication therapy management (MTM) and to compare actions performed according to practice characteristics. METHODS: A purposeful sample of 7 MTM practices (2 call centers and 5 community practices) was identified and visited by investigators. Pharmacists and support staff were observed during their routine provision of MTM. Investigators characterized "major" (e.g., preparation for a comprehensive medication review) and "minor" (i.e., specific steps in overarching major action) actions with the use of a time-and-motion approach. RESULTS: A total of 32 major and 469 minor actions were observed. Practices were characterized as Later Maturity Level or Early Maturity Level on the basis of their self-reported MTM appointment volume, self-assessment of the extent of integration of chronic care model principles, and payer mix. Later Maturity Level practices were more likely to deliver follow-up medication therapy reviews and comprehensive medication reviews (CMRs) as opposed to targeted medication reviews (TMRs) and to receive physician referrals for MTM. Later Maturity Level practices were also more likely to use paid interns than pharmacy rotation students. CMR activities observed at Later Maturity Level practices lasted a median of 30.8 minutes versus 20.3 minutes for CMR activities at Early Maturity Level practices. Similarly, TMR activities observed at Later Maturity Level practices were longer: a median of 31.0 minutes versus 12.3 minutes. At Later Maturity Level practices, pharmacists spent a greater proportion of time providing patient education, while support staff spent a greater proportion of time on tasks such as capturing demographics and introducing or explaining MTM. CONCLUSION: MTM activities were longer at Later Maturity Level practices, and these practices were more likely to use paid pharmacy interns and to receive physician referrals for MTM. This work provides a foundation for future research. PMID- 29129670 TI - Microalgae-derived oxylipins decrease inflammatory mediators by regulating the subcellular location of NFkappaB and PPAR-gamma. AB - Oxylipins (OXLs) are bioactive molecules generated by the oxidation of fatty acids that promote the resolution of acute inflammation and prevent chronic inflammatory processes through molecular mechanisms that are not well known. We have previously reported the anti-inflammatory activity of microalgae-derived OXLs and OXL-containing biomass in two inflammatory bowel disease (IBD) models: 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute colitis and TNBS-induced recurrent colitis. In this study, we examined the in vitro anti-inflammatory mechanism of action of the most abundant OXLs isolated from Chlamydomonas debaryana (13S-HOTE and 13S-HODE) and Nannochloropsis gaditana (15S-HEPE). These OXLs decreased IL-1beta and IL-6 pro-inflammatory cytokines production as well as iNOS and COX-2 expression levels in THP-1 macrophages. In addition, OXLs decreased IL-8 production in HT-29 colon cells, the major chemokine produced by these cells. The interaction of OXLs with NFkappaB and PPAR-gamma signaling pathways was studied by confocal microscopy. In THP-1 macrophages and HT-29 colon cells, stimulated by LPS and TNFalpha respectively, a pre-treatment with 13S HOTE, 13S-HODE and 15S-HEPE (100MUM) resulted in a lower nuclear presence of NFkappaB in both cell lines. The study of the subcellular localization of PPAR gamma showed that the treatment of THP-1 and HT-29 cells with these OXLs caused the migration of PPAR-gamma into the nucleus. Colocalization analysis of both transcription factors in LPS-stimulated THP-1 macrophages showed that the pre treatment with 13S-HOTE, 13S-HODE or 15S-HEPE lowered nuclear colocalization similar to control value, and increased cytosolic localization above control level. These results indicate that these OXLs could act as agonist of PPAR-gamma and consequently inhibit NFkappaB signaling pathway activation, thus lowering the production of inflammatory markers, highlighting the therapeutic potential of these OXLs in inflammatory diseases such as IBD. PMID- 29129671 TI - The semantic system is involved in mathematical problem solving. AB - Numerous studies have shown that the brain regions around bilateral intraparietal cortex are critical for number processing and arithmetical computation. However, the neural circuits for more advanced mathematics such as mathematical problem solving (with little routine arithmetical computation) remain unclear. Using functional magnetic resonance imaging (fMRI), this study (N = 24 undergraduate students) compared neural bases of mathematical problem solving (i.e., number series completion, mathematical word problem solving, and geometric problem solving) and arithmetical computation. Direct subject- and item-wise comparisons revealed that mathematical problem solving typically had greater activation than arithmetical computation in all 7 regions of the semantic system (which was based on a meta-analysis of 120 functional neuroimaging studies on semantic processing). Arithmetical computation typically had greater activation in the supplementary motor area and left precentral gyrus. The results suggest that the semantic system in the brain supports mathematical problem solving. PMID- 29129672 TI - The absence of restricted water pool in brain white matter. AB - Understanding diffusion-weighted MR signal in brain white matter (WM) has been a long-sought-after goal. Modern research pursues this goal by focusing on the biological compartments that contributes essentially to the signal. In this study, we experimentally address the apparent presence of a compartment in which water motion is restricted in all spatial directions. Using isotropic diffusion encoding, we establish an upper bound on the fraction of such a compartment, which is shown to be about 2% of the unweighted signal for moderate diffusion times. This helps to eliminate such a compartment that have been assumed in literature on biophysical modeling. We also used the diffusion decay curve obtained from the isotropic encoding to establish a lower limit on the mean diffusivities of either of intra- or extra-axonal compartment as a function of their relative water fraction. PMID- 29129673 TI - Making an unknown unknown a known unknown: Missing data in longitudinal neuroimaging studies. AB - The analysis of longitudinal neuroimaging data within the massively univariate framework provides the opportunity to study empirical questions about neurodevelopment. Missing outcome data are an all-to-common feature of any longitudinal study, a feature that, if handled improperly, can reduce statistical power and lead to biased parameter estimates. The goal of this paper is to provide conceptual clarity of the issues and non-issues that arise from analyzing incomplete data in longitudinal studies with particular focus on neuroimaging data. This paper begins with a review of the hierarchy of missing data mechanisms and their relationship to likelihood-based methods, a review that is necessary not just for likelihood-based methods, but also for multiple-imputation methods. Next, the paper provides a series of simulation studies with designs common in longitudinal neuroimaging studies to help illustrate missing data concepts regardless of interpretation. Finally, two applied examples are used to demonstrate the sensitivity of inferences under different missing data assumptions and how this may change the substantive interpretation. The paper concludes with a set of guidelines for analyzing incomplete longitudinal data that can improve the validity of research findings in developmental neuroimaging research. PMID- 29129674 TI - Cytotoxic T Lymphocyte Granzyme-b mediates neuronal cell death during Plasmodium berghei ANKA induced experimental cerebral malaria. AB - Cerebral malaria is a complex, acute, neurological disease characterised by a sudden onset of cerebral symptoms. This disease is manifested as initial arousable stage that is followed by an unarousable coma and eventually death. Parasite burden and CD8+ T cell count in the brain determines the disease outcome. Cytotoxic CD8+ T cell-derived Granzyme-b is required for the development of experimental cerebral malaria (ECM), but the mechanism of pathogenesis is not known. Here, we show that CD8+ T cells infiltrate in to the brain during ECM releasing Granzyme-b that is cytotoxic to neuronal cells. Granzyme-b kills neuronal cells through direct cytotoxicity and also by activating neuronal caspase-3 and calpain1 via cytoskeletal breakdown. Our results showed the increased expression of cell adhesion molecules and chemokine receptors in the brain and their associated infiltration of T cells during ECM. PMID- 29129675 TI - Alpha-synuclein dimerization in erythrocytes of patients with genetic and non genetic forms of Parkinson's Disease. AB - BACKGROUND: Variations of alpha-synuclein levels or species have been reported in Parkinson's Disease (PD). There has been little systematic examination of erythrocytes, a rich source of alpha-synuclein. METHODS: Erythrocyte membranes were obtained from PD patients (mutation carriers in the alpha-synuclein gene (A53T-PD) and glucocerebrosidase gene (GBA-PD) (n=18 each), and patients without known mutations (GU-PD, n=56)), and age-/sex-matched controls (n=56). Levels of monomeric and dimeric alpha-synuclein were assessed using Western immunoblotting. RESULTS: A statistically significant increase of alpha-synuclein dimer and dimer to monomer ratio was found in GBA-PD and GU-PD. In contrast, dimer levels of A53T PD were not different from controls. No difference was found in alpha-synuclein monomer levels. CONCLUSIONS: The increased alpha-synuclein dimer in GBA-PD and GU PD is suggestive of an apparent systemic dysfunction causing the dimerization, and potentially oligomerization, of alpha-synuclein. These results may have implications for PD pathogenesis and biomarker development. PMID- 29129676 TI - Exercise enhances cognitive function and neurotrophin expression in the hippocampus accompanied by changes in epigenetic programming in senescence accelerated mice. AB - Aerobic exercise is known to increase expression of neurotrophins, particularly brain-derived neurotrophic factor (BDNF), in the hippocampus and to improve cognitive function. Exercise exerts neuroprotective effects in the hippocampus by inducing epigenetic changes, which play crucial roles in aging and neurodegenerative diseases. Specifically, the activity levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate histone acetylation and modulate gene transcription. The objective of the present study was to assess the interactive effects of exercise and aging on cognitive function, expression of neurotrophins (BDNF and neurotrophin-4) and their receptors (tyrosine receptor kinase B and p75), and epigenetic regulations, including the activity of HATs and HADCs in the hippocampus. We used the senescence-accelerated mouse (SAM) model, specifically 13-month-old SAM resistant 1(SAMR1) and SAM prone 1 (SAMP1) lines. Mice were distributed into four groups based on accelerated senescence and exercise status. Mice in the exercise groups exercised on a treadmill for approximately 60min a day, 5days a week. Aerobic exercise for 4 weeks improved cognitive function, accompanied by an increase in BDNF expression and a decrease in p75 transcription in both SAMR1 and SAMP1. In addition, the exercise regimen activated both HAT and HDAC in the hippocampus. Therefore, the present study reveals that despite accelerated senescence, long term exercise improved cognitive function, upregulated the expression of BDNF, and downregulated p75, a receptor involved in apoptotic signaling. Furthermore, long-term exercise enhanced activity of both HAT and HDAC, which may contribute to the transcriptional regulation underlying the improvement of cognitive function. PMID- 29129677 TI - Upregulated BMP6 pathway involved in the pathogenesis of Abeta toxicity in vivo. AB - In our previous work, we demonstrated the protective effect of BMP6 on neuron against Abeta toxicity in vitro. In the present study, our aim was to determine the effects of BMP6 in Abeta toxicity in vivo. Firstly, we evaluated the levels and localization of endogenous BMP6 in APP/PS1 transgenic mice. Secondly, dose response effects of exogenous BMP6 and BMP6 pathway antagonists were tested in transgenic CL2006C. elegans (expressing Abeta3-42) lifespan and locomotor activity. We have three findings: 1) BMP6 was upregulated in the hippocampus in APP/PS1 mice. 2) The endogenous BMP6 is mainly expressed in the cytoplasm of neuron and nuclear of microglia, not in astrocyte in APP/PS1 mice. 3) BMP6 supplementation did not benefit transgenic worms, even toxic at certain concentrations, and antagonizing BMP downstream pathways including Smad and LIMK1 could alleviate the toxicity caused by 0.1MUg/ml BMP6. The results suggest there is elevated BMP6 pathway in Abeta toxicity, and normalization of BMPs may be an important target for therapeutic intervention of AD. PMID- 29129678 TI - Pathophysiological mechanisms of migraine and epilepsy: Similarities and differences. AB - Migraine and epilepsy are episodic disorders with distinct features, but they have some clinical and pathophysiological overlaps. We review here clinical overlaps between seizures and migraine attacks, activities of neuronal networks observed during seizures and migraine attacks, and molecular and cellular mechanisms of migraine identified in genetic forms, focusing on genetic variants identified in hemiplegic migraine and their functional effects. Epilepsy and migraine can be generated by dysfunctions of the same neuronal networks, but these dysfunctions can be disease-specific, even if pathogenic mutations target the same protein. Studies of rare monogenic forms have allowed the identification of some molecular/cellular dysfunctions that provide a window on pathological mechanisms: we have begun to disclose the tip of the iceberg. PMID- 29129679 TI - Pecularities of the structure of glycogen as an indicator of the functional state of mauthner neurons in fish Percsottus glehni during wintering. AB - Mauthner neurons (MN)*, specific multifunctional neurons of fish, are a unique object for investigating the adaptive potentialities of the cell. The goal of the work was to study the structure of MN of fish Percsottus glehni during wintering under the conditions of hypothermia and deficit of oxygen and energy substrates. It was shown using a light microscope that the volume of the somatic moiety of neurons changes slightly at the beginning of wintering and is significantly reduced by the termination of wintering. It was found on the ultrastructural level that, at the beginning of wintering, glycogen exists in the central cytoplasm of MN in the form of large concentrated fields consisting of separate granules, whereas in the summer period the granules are distributed diffusely throughout the cell. In the vicinity of glycogen fields, lamellar structures of the smooth reticulum were seen. At the boundaries of glycogen fields, the aggregation of mitochondria and their active intrusion into glycogen fields were evident. By the end of wintering, the amount of glycogen significantly decreased, which was accompanied by a reduction of the smooth reticulum and rare contacts of mitochondria with glycogen fields. We assume that, because MN have a broader range of metabolic and functional possibilities than usual neurons in which glycogen is lacking or its content is negligible, they possess their own systems of glycolysis, glyconeogenesis, and deposition of glycogen. This allows them to maintain a sufficient level of energy supply under anaerobic conditions for performing the function of "guard neurons" during wintering. PMID- 29129680 TI - Existential Issues in Sexual Medicine: The Relation Between Death Anxiety and Hypersexuality. AB - INTRODUCTION: Current sex therapy and sexual medicine protocols often ignore the existential dilemmas associated with sexual dysfunction and other problematic sexual problems. This oversight is especially apparent when assessing and treating the controversial phenomenon of hypersexuality, or "sexual addiction." A deeper understanding of the existential concept of death anxiety could offer an alternative treatment paradigm that might lead to a more effective treatment outcome. AIM: To explore the relation between the existential phenomenon of death anxiety and hypersexuality (ie, sexual addiction) and present an evaluation and treatment paradigm that is rooted in existential psychotherapy, a form of psychotherapy that is a deeply life-affirming and dynamic approach to therapy that focuses on concerns rooted in the individual's existence. METHODS: A review of the literature focusing on the topics of hypersexuality, death anxiety, and existential psychotherapy was undertaken and a treatment paradigm is offered. MAIN OUTCOME MEASURES: Current treatment protocols for hypersexuality and sexual addiction were reviewed, as were current concepts in existential therapy. These were integrated into an assessment and treatment paradigm. RESULTS: Although sexual medicine and traditional sex therapy techniques can often alleviate sexual suffering, there are times when a more in-depth psychotherapy is needed to get to the root cause and ultimate assuagement of the presenting sexual symptoms. Existential psychotherapy is one such form of treatment that allows clinicians to probe the subterranean depths of the human psyche and make meaning of one's sexual behavior and its vagaries. CONCLUSION: Although certainly not all cases of hypersexuality are precipitated by a confrontation with mortality and death, there are cases in which sex is imbued with meaning as an antidote to the fear of death. Existential therapy is a form of treatment that could be particularly effective in many of these cases. Watter DN. Existential Issues in Sexual Medicine: The Relation Between Death Anxiety and Hypersexuality. Sex Med Rev 2018;6:3-10. PMID- 29129681 TI - Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons. AB - Mitochondrial changes have long been implicated in the pathogenesis of Parkinson's disease (PD). The glycine to serine mutation (G2019S) in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause for PD and has been shown to impair mitochondrial function and morphology in multiple model systems. We analyzed mitochondrial function in LRRK2 G2019S induced pluripotent stem cell (iPSC)-derived neurons to determine whether the G2019S mutation elicits similar mitochondrial deficits among central and peripheral nervous system neuron subtypes. LRRK2 G2019S iPSC-derived dopaminergic neuron cultures displayed unique abnormalities in mitochondrial distribution and trafficking, which corresponded to reduced sirtuin deacetylase activity and nicotinamide adenine dinucleotide levels despite increased sirtuin levels. These data indicate that mitochondrial deficits in the context of LRRK2 G2019S are not a global phenomenon and point to distinct sirtuin and bioenergetic deficiencies intrinsic to dopaminergic neurons, which may underlie dopaminergic neuron loss in PD. PMID- 29129682 TI - Spatial and Sex-Dependent Responses of Adult Endogenous Neural Stem Cells to Alcohol Consumption. AB - Chronic alcohol abuse results in alcohol-related neurodegeneration, and critical gaps in our knowledge hinder therapeutic development. Neural stem cells (NSCs) are a subpopulation of cells within the adult brain that contribute to brain maintenance and recovery. While it is known that alcohol alters NSCs, little is known about how NSC response to alcohol is related to sex, brain region, and stage of differentiation. Understanding these relationships will aid in therapeutic development. Here, we used an inducible transgenic mouse model to track the stages of differentiation of adult endogenous NSCs and observed distinct NSC behaviors in three brain regions (subventricular zone, subgranular zone, and tanycyte layer) after long-term alcohol consumption. Particularly, chronic alcohol consumption profoundly affected the survival of NSCs in the subventricular zone and altered NSC differentiation in all three regions. Significant differences between male and female mice were further discovered. PMID- 29129684 TI - RHOA GTPase Controls YAP-Mediated EREG Signaling in Small Intestinal Stem Cell Maintenance. AB - RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage. Mechanistically, RHOA loss reduces YAP signaling of the Hippo pathway and affects YAP effector epiregulin (EREG) expression in the crypts. Expression of an active YAP (S112A) mutant rescues ISC marker expression, ISC regeneration, and ISC-associated Wnt signaling, but not defective epithelial polarity, in RhoA knockout mice, implicating YAP in RHOA-regulated ISC function. EREG treatment or active beta catenin Catnblox(ex3) mutant expression rescues the RhoA KO ISC phenotypes. Thus, RHOA controls YAP-EREG signaling to regulate intestinal homeostasis and ISC regeneration. PMID- 29129683 TI - Non-monotonic Changes in Progenitor Cell Behavior and Gene Expression during Aging of the Adult V-SVZ Neural Stem Cell Niche. AB - Neural stem cell activity in the ventricular-subventricular zone (V-SVZ) decreases with aging, thought to occur by a unidirectional decline. However, by analyzing the V-SVZ transcriptome of male mice at 2, 6, 18, and 22 months, we found that most of the genes that change significantly over time show a reversal of trend, with a maximum or minimum expression at 18 months. In vivo, MASH1+ progenitor cells decreased in number and proliferation between 2 and 18 months but increased between 18 and 22 months. Time-lapse lineage analysis of 944 V-SVZ cells showed that age-related declines in neurogenesis were recapitulated in vitro in clones. However, activated type B/type C cell clones divide slower at 2 to 18 months, then unexpectedly faster at 22 months, with impaired transition to type A neuroblasts. Our findings indicate that aging of the V-SVZ involves significant non-monotonic changes that are programmed within progenitor cells and are observable independent of the aging niche. PMID- 29129685 TI - Small RNA Sequencing Reveals Dlk1-Dio3 Locus-Embedded MicroRNAs as Major Drivers of Ground-State Pluripotency. AB - Ground-state pluripotency is a cell state in which pluripotency is established and maintained through efficient repression of endogenous differentiation pathways. Self-renewal and pluripotency of embryonic stem cells (ESCs) are influenced by ESC-associated microRNAs (miRNAs). Here, we provide a comprehensive assessment of the "miRNome" of ESCs cultured under conditions favoring ground state pluripotency. We found that ground-state ESCs express a distinct set of miRNAs compared with ESCs grown in serum. Interestingly, most "ground-state miRNAs" are encoded by an imprinted region on chromosome 12 within the Dlk1-Dio3 locus. Functional analysis revealed that ground-state miRNAs embedded in the Dlk1 Dio3 locus (miR-541-5p, miR-410-3p, and miR-381-3p) promoted pluripotency via inhibition of multi-lineage differentiation and stimulation of self-renewal. Overall, our results demonstrate that ground-state pluripotency is associated with a unique miRNA signature, which supports ground-state self-renewal by suppressing differentiation. PMID- 29129686 TI - Naive-like ESRRB+ iPSCs with the Capacity for Rapid Neural Differentiation. AB - Several groups have reported the existence of a form of pluripotency that resembles that of mouse embryonic stem cells (mESCs), i.e., a naive state, in human pluripotent stem cells; however, the characteristics vary between reports. The nuclear receptor ESRRB is expressed in mESCs and plays a significant role in their self-renewal, but its expression has not been observed in most naive-like human induced pluripotent stem cells (hiPSCs). In this study, we modified several methods for converting hiPSCs into a naive state through the transgenic expression of several reprogramming factors. The resulting cells express the components of the core transcriptional network of mESCs, including ESRRB, at high levels, which suggests the existence of naive-state hiPSCs that are similar to mESCs. We also demonstrate that these cells differentiate more readily into neural cells than do conventional hiPSCs. These features may be beneficial for their use in disease modeling and regenerative medicine. PMID- 29129687 TI - Coatomer subunit beta 2 (COPB2), identified by label-free quantitative proteomics, regulates cell proliferation and apoptosis in human prostate carcinoma cells. AB - Label-free quantitative proteomics has broad applications in the identification of differentially expressed proteins. Here, we applied this method to identify differentially expressed proteins (such as coatomer subunit beta 2 [COPB2]) and evaluated the functions and molecular mechanisms of these proteins in prostate cancer (PCA) cell proliferation. Proteins extracted from surgically resected PCA tissues and adjacent tissues of 3 patients were analyzed by label-free quantitative proteomics. The target protein was confirmed by bioinformatics and GEO dataset analyses. To investigate the role of the target protein in PCA, we used lentivirus-mediated small-interfering RNA (siRNA) to knockdown protein expression in the prostate carcinoma cell line, CWR22RV1 cells and assessed gene and protein expression by reverse transcription quantitative polymerase chain reaction and western blotting. CCK8 and colony formation assays were conducted to evaluate cell proliferation. Cell cycle distributions and apoptosis were assayed by flow cytometry. We selected the differentiation-related protein COPB2 as our target protein based on the results of label-free quantitative proteomics. High expression of COPB2 was found in PCA tissue and was related to poor overall survival based on a public dataset. Cell proliferation was significantly inhibited in COPB2-knockdown CWR22RV1 cells, as demonstrated by CCK8 and colony formation assays. Additionally, the apoptosis rate and percentage of cells in the G1 phase were increased in COPB2-knockdown cells compared with those in control cells. CDK2, CDK4, and cyclin D1 were downregulated, whereas p21 Waf1/Cip1 and p27 Kip1 were upregulated, affecting the cell cycle signaling pathway. COPB2 significantly promoted CWR22RV1 cell proliferation through the cell cycle signaling pathway. Thus, silencing of COPB2 may have therapeutic applications in PCA. PMID- 29129688 TI - Identification of protein kinase C isozymes involved in the anti-proliferative and pro-apoptotic activities of 10-Methyl-aplog-1, a simplified analog of debromoaplysiatoxin, in several cancer cell lines. AB - 10-Me-aplog-1 is a simplified analog of the tumor-promoting compound debromoaplysiatoxin (DAT) and a unique protein kinase C (PKC) activator with limited tumor-promoting and pro-inflammatory activities. 10-Me-aplog-1 inhibits the growth of several cancer cell lines, but the inhibitory mechanism involving PKC isozymes remains unclear. We quantified the amount of PKC isozymes in nine human cancer cell lines that differ in 10-Me-aplog-1 sensitivity. PKCalpha and delta were the predominant isozymes expressed in all cell lines, but there was no significant correlation between expression levels and anti-proliferative activity. Knocking down PKCalpha, and/or PKCdelta in the three aplog-sensitive cell lines indicated their involvement in the anti-proliferative and pro apoptotic activities of 10-Me-aplog-1. This finding suggests that PKCalpha and/or PKCdelta activation could be effective for treating certain cancers. Since the mechanism underlying 10-Me-aplog-1's anti-proliferative activities resembles that of DAT, 10-Me-aplog-1 may be regarded as a special key derived from pleiotropic DAT as a bunch of keys. PMID- 29129689 TI - Ascorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin. AB - BACKGROUND: Increased endothelial permeability is central to shock and organ dysfunction in sepsis but therapeutics targeted to known mediators of increased endothelial permeability have been unsuccessful in patient studies. We previously reported that cell-free hemoglobin (CFH) is elevated in the majority of patients with sepsis and is associated with organ dysfunction, poor clinical outcomes and elevated markers of oxidant injury. Others have shown that Vitamin C (ascorbate) may have endothelial protective effects in sepsis. In this study, we tested the hypothesis that high levels of CFH, as seen in the circulation of patients with sepsis, disrupt endothelial barrier integrity. METHODS: Human umbilical vein endothelial cells (HUVEC) were grown to confluence and treated with CFH with or without ascorbate. Monolayer permeability was measured by Electric Cell-substrate Impedance Sensing (ECIS) or transfer of 14C-inulin. Viability was measured by trypan blue exclusion. Intracellular ascorbate was measured by HPLC. RESULTS: CFH increased permeability in a dose- and time-dependent manner with 1 mg/ml of CFH increasing inulin transfer by 50% without affecting cell viability. CFH (1 mg/ml) also caused a dramatic reduction in intracellular ascorbate in the same time frame (1.4 mM without CFH, 0.23 mM 18 h after 1 mg/ml CFH, p < 0.05). Pre treatment of HUVECs with ascorbate attenuated CFH induced permeability. CONCLUSIONS: CFH increases endothelial permeability in part through depletion of intracellular ascorbate. Supplementation of ascorbate can attenuate increases in permeability mediated by CFH suggesting a possible therapeutic approach in sepsis. PMID- 29129690 TI - Monoterpenoid perillyl alcohol impairs metabolic flexibility of Candida albicans by inhibiting glyoxylate cycle. AB - The metabolic pathway such as glyoxylate cycle (GC) enables Candida albicans, to survive under glucose deficient conditions prevalent in the hostile niche. Thus its key enzymes (Isocitrate lyase; ICL and malate synthase; MLS) represent attractive targets against C. albicans. We have previously reported the antifungal potential of a natural monoterpenoid perillyl alcohol (PA). The present study uncovers additional role of PA as a potent GC inhibitor. We explored that PA phenocopied ICL1 deletion mutant and were hypersensitive under low carbon utilizing conditions. The effect of PA on GC was substantiated by molecular docking analyses, which reveals the in-silico binding affinity of PA with ICL and MLS and explored that PA binds to the active sites of both proteins with better binding energy in comparison to their known inhibitors 3 nitropropionate and bromopyruvate respectively. Enzyme kinetics by Lineweaver Burk plot unravels that PA inhibits ICL and MLS enzymes in competitive and non competitive manner respectively. Moreover, semi-quantitative RT-PCR indicated that PA inhibits ICL1 and MLS1 mRNA expressions. Lastly, we demonstrated the antifungal efficacy of PA by enhanced survival of Caenorhabditis elegans model and less hemolytic activity (10.6%) on human blood cells. Further studies are warranted for PA to be considered as viable drug candidate. PMID- 29129691 TI - RecBCD (Exonuclease V) is inhibited by DNA adducts produced by cisplatin and ultraviolet light. AB - The presence of adducts on the DNA double-helix can have major consequences for the efficient functioning of DNA repair enzymes. E. coli RecBCD (exonuclease V) is involved in recombinational repair of double-strand breaks that are caused by defective DNA replication, DNA damaging agents and other factors. The holoenzyme possesses a bipolar helicase activity which helps unwind DNA from both 3'- and 5' directions and is coupled with a potent exonuclease activity that is also capable of digesting DNA from both 3'- and 5'-ends. In this study, DNA sequences were damaged with cisplatin or UV followed by RecBCD treatment. DNA damaging agents such as cisplatin and UV induce the formation of intrastrand adducts in the DNA template. It was demonstrated that RecBCD degradation was inhibited by either cisplatin-damaged or UV-damaged DNA sequences. This is the first occasion that RecBCD has been demonstrated to be inhibited by DNA adducts induced by cisplatin or UV. In addition, we quantified the amounts of DNA remaining after RecBCD treatment and observed that the level of inhibition was concentration and dose dependent. A DNA-targeted 9-aminoacridinecarboxamide cisplatin analogue was also found to inhibit RecBCD activity. PMID- 29129692 TI - PRMT1 mediates podocyte injury and glomerular fibrosis through phosphorylation of ERK pathway. AB - Diabetic nephropathy (DN) is characterized by a change of glomerular structure and dysfunction of filtration barrier, which significantly accompanied by podocytes apoptosis and glomerular fibrosis. Angiotensin II(Ang II) induced activation of ERK1/2 signaling plays important roles in causing apoptosis of podocytes in DN kidneys. Previous studies have shown that PRMT1 have a pro inflammatory function through activating ERK1/2 signaling pathway during development of chronic pulmonary disease, however, its role in DN development has not been investigated. Here, we detected a higher expression of PRMT1 in podocytes of kidneys from DN patients compared with normal kidneys. High glucose administration induced elevation of PRMT1 expression in podocytes, accompanied with higher phosphorylation of ERK and cleaved caspase-3. AMI-1, a selective inhibitor for PRMT1, could block these effects caused by glucose treatment. Administration of AMI-1 also attenuated apoptosis of podocytes during DN development of high-fatty diet-induced diabetic mice. Epithelial to mesenchymal transition during DN development, which characterized by extracellular matrix deposition in podocytes, was also restrained by AMI-1 treatment. Collectively, this study firstly demonstrated that PRMT1 exert podocyte-injury effects in mouse glomerulus through Ang II/ERK pathway, which reveals a potential therapeutic target for DN. PMID- 29129693 TI - FOXJ1 promotes bladder cancer cell growth and regulates Warburg effect. AB - Forkhead Box J1 (FOXJ1) which belongs to Fox gene family, plays complex and crucial roles in processes of development, organogenesis, regulation of the immune system, as well as progression of several malignancies. However, how FOXJ1 functions in bladder cancer remains unclear. Here, we report that FOXJ1 is upregulated in most bladder cancer patients, and predicts poor clinical outcomes. FOXJ1 facilitates bladder cancer cell proliferation and colony formation. FOXJ1 knockdown suppresses bladder tumor growth in nude mice. Mechanistically, FOXJ1 enhances glycolysis by increasing glucose uptake, lactate production and extracellular acidification rate (ECAR), and decreasing ATP generation and oxygen consumption rate (OCR) in bladder cancer cells. Our findings provide clues regarding the role of FOXJ1 as a tumor inducer in bladder cancer and an enhancer in glycolysis. Targeting FOXJ1 could be a potential therapeutic strategy in bladder cancer. PMID- 29129694 TI - Mitochondrial tRNAThr 15909A>G mutation associated with hypertension in a Chinese Han pedigree. AB - Mitochondrial DNA mutations are one of the molecular genetic bases of hypertension. Here, we performed clinical, genetic and mutational evaluation, molecular characterization as well as biochemical analysis of a Chinese Han family with maternally inherited hypertension. The m.15909A > G variant in tRNAThr was identified. This mutation abolished a highly conserved base pairing (11U-24A) in the D-stem of tRNAThr and affected the structure and function of mitochondrial tRNAThr. As a result, the overall levels of mitochondrial translation products was decreased. The reduced mitochondrial protein synthesis resulted in the decrease in the activity of complex, and in turn, the production of ATP decreased and the generation of ROS increased. The m.15909A > G mutation maybe an inherited factor leading to the development of hypertension in this Chinese Han pedigree. PMID- 29129695 TI - Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3beta pathway in cells and in APP/PS1 transgenic mice. AB - Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Abeta) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3beta pathway. We found GSK3beta increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT GSK3beta signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment. PMID- 29129696 TI - The making of a mushroom: Mitosis, nuclear migration and the actin network. AB - Basidiomycetes feature a prolonged dikaryotic life stage. A dispute over open versus closed mitosis could be solved using in vivo fluorescence videomicroscopy of histone 2B::EGFP and Lifeact labeled Schizophyllum commune. It revealed nuclei to condense to approximately one fifth in diameter during mitotic prophase. In addition, the specifics of clamp cell formation typical of many basidiomycetes included an actin network at the future site of nuclear division, which allowed for cessation of nuclear movement and re-localization of one nucleus towards the emerging clamp cell, while the other divided along the hyphal axis. Subsequent fusion of the clamp cell to form the clamp connection restored the close association of the two nuclei in a very fast process after clamp fusion. Septation was preceded by actin patches and vesicles involved in formation of the actin ring. PMID- 29129697 TI - Dual Mechanisms for Balancing Th17 and Treg Cell Fate by CREB. AB - Th17 cells, which express the cytokine IL-17A, and master regulator RORgammat, are important in the inflammatory response to fungal and bacterial pathogens, but also have a pathogenic role in many inflammatory disorders. In contrast, regulatory T cells (Treg), expressing the Foxp3 transcription factor, have a suppressive function and can dampen an immune response. The appropriate balance of these distinct effector functions is critical for an effective immune response and autoimmunity can arise if this process goes awry. In this issue, Wang et al. demonstrate a critical role for the transcription factor CREB (cyclic AMP responsive element binding protein) in regulating the balance between inflammatory Th17 and suppressive Treg cells with implications for autoimmunity. PMID- 29129699 TI - Deguelin, an Aurora B Kinase Inhibitor, Exhibits Potent Anti-Tumor Effect in Human Esophageal Squamous Cell Carcinoma. AB - Aurora B kinase has emerged as a key regulator of mitosis and deregulation of Aurora B activity is closely related to the development and progression of human cancers. In the present study, we found that Aurora B is overexpressed in human esophageal squamous cell carcinoma (ESCC), high levels of Aurora B protein were associated with a worse overall survival rate in ESCC patients. Depleting of Aurora B blunted the malignant phenotypes in ESCC cells. Importantly, we demonstrated that a natural compound, deguelin, has a profound anti-tumor effect on ESCC via inhibiting Aurora B activity. Deguelin potently inhibited in vitro Aurora B kinase activity. The in silico docking study further indicated that deguelin was docked into the ATP-binding pocket of Aurora B. Inhibition of Aurora B activity attenuated growth of ESCC cells, resulted in G2/M cell cycle arrest, polyploidy cells formation, and apoptosis induction. Knocking down of Aurora B decreased the sensitivity of ESCC cells to deguelin. The in vivo results showed that deguelin blocked the phosphorylation of histone H3 and inhibited the growth of ESCC tumor xenografts. Overall, we identified deguelin as an effective Aurora B inhibitor, which deserves further studies in other animal models and ESCC treatment. PMID- 29129698 TI - Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates. AB - As the HIV/AIDS pandemic still progresses, understanding the mechanisms governing viral transmission as well as protection from HIV acquisition is fundamental. In this context, cohorts of HIV serodiscordant heterosexual couples (SDC) represent a unique tool. The present study was aimed to evaluate specific parameters of innate, cellular and humoral immune responses in SDC. Specifically, plasma levels of cytokines and chemokines, HIV-specific T-cell responses, gp120-specific IgG and IgA antibodies, and HIV-specific antibody-dependent cellular cytotoxicity (ADCC) activity were assessed in nine HIV-exposed seronegative individuals (ESN) and their corresponding HIV seropositive partners (HIV+-P), in eighteen chronically infected HIV subjects (C), nine chronically infected subjects known to be HIV transmitters (CT) and ten healthy HIV- donors (HD). Very low magnitude HIV-specific cellular responses were found in two out of six ESN. Interestingly, HIV+-P had the highest ADCC magnitude, the lowest IgA levels and the highest IgG/IgA ratio, all compared to CT. Positive correlations between CD4+ T-cell counts and both IgG/IgA ratios and %ADCC killing uniquely distinguished HIV+-P. Additionally, evidence of IgA interference with ADCC responses from HIV+-P and CT is provided. These data suggest for the first time a potential role of ADCC and/or gp120-specific IgG/IgA balance in modulating heterosexual transmission. In sum, this study provides key information to understand the host factors that influence viral transmission, which should be considered in both the development of prophylactic vaccines and novel immunotherapies for HIV-1 infection. PMID- 29129701 TI - Biomarkers for Treatment Monitoring in Tuberculosis: A New Hope. PMID- 29129700 TI - Paracetamol Medication During Pregnancy: Insights on Intake Frequencies, Dosages and Effects on Hematopoietic Stem Cell Populations in Cord Blood From a Longitudinal Prospective Pregnancy Cohort. AB - BACKGROUND: Paracetamol is the first choice for antipyretic or analgesic treatment throughout pregnancy. Products with Paracetamol are readily available over the counter and therefore easily accessible for self-medication. Epidemiological data on Paracetamol intake pattern during pregnancy and its potential immunological effects are sparse. We aimed to analyze a possible association between Paracetamol medication and numbers of hematopoietic stem cells (HSC) in cord blood. METHODS: The objective was addressed in the PRINCE (PRENATAL DETERMINANTS OF CHILDREN'S HEALTH) study, a population-based prospective pregnancy cohort study initiated in 2011 at the University Medical Center in Hamburg, Germany. 518 healthy pregnant women with singleton pregnancies were recruited during the first trimester. Three examinations were scheduled at the end of the 1st (gestational week 12-14), the 2nd (gestational week 22-24) and the 3rd trimester (gestational week 34-36). For 146 of these women, cord blood flow cytometry data were available. Paracetamol intake was assessed for each trimester of pregnancy. FINDINGS: Among the 518 enrolled women, 40% took Paracetamol as main analgesic treatment during pregnancy. The intake frequency and dosage of Paracetamol varied between the women and was overall low with a tendency towards higher frequencies and higher dosages in the third trimester. Paracetamol intake, particularly during the third trimester, resulted in decreased relative numbers of HSCs in cord blood, independent of maternal age, first-trimester BMI, parity, gestational age and birth weight (-0.286 (95% CI 0.592, 0.021), p=0.068). INTERPRETATION: Prenatal Paracetamol intake, especially during the third trimester, may be causally involved in decreasing HSCs in cord blood. PMID- 29129702 TI - FKBP8 protects the heart from hemodynamic stress by preventing the accumulation of misfolded proteins and endoplasmic reticulum-associated apoptosis in mice. AB - Protein quality control in cardiomyocytes is crucial to maintain cellular homeostasis. The accumulation of damaged organelles, such as mitochondria and misfolded proteins in the heart is associated with heart failure. During the process to identify novel mitochondria-specific autophagy (mitophagy) receptors, we found FK506-binding protein 8 (FKBP8), also known as FKBP38, shares similar structural characteristics with a yeast mitophagy receptor, autophagy-related 32 protein. However, knockdown of FKBP8 had no effect on mitophagy in HEK293 cells or H9c2 myocytes. Since the role of FKBP8 in the heart has not been fully elucidated, the aim of this study is to determine the functional role of FKBP8 in the heart. Cardiac-specific FKBP8-deficient (Fkbp8-/-) mice were generated. Fkbp8 /- mice showed no cardiac phenotypes under baseline conditions. The Fkbp8-/- and control wild type littermates (Fkbp8+/+) mice were subjected to pressure overload by means of transverse aortic constriction (TAC). Fkbp8-/- mice showed left ventricular dysfunction and chamber dilatation with lung congestion 1week after TAC. The number of apoptotic cardiomyocytes was dramatically elevated in TAC operated Fkbp8-/- hearts, accompanied with an increase in protein levels of cleaved caspase-12 and endoplasmic reticulum (ER) stress markers. Caspase-12 inhibition resulted in the attenuation of hydrogen peroxide-induced apoptotic cell death in FKBP8 knockdown H9c2 myocytes. Immunocytological and immunoprecipitation analyses indicate that FKBP8 is localized to the ER and mitochondria in the isolated cardiomyocytes, interacting with heat shock protein 90. Furthermore, there was accumulation of misfolded protein aggregates in FKBP8 knockdown H9c2 myocytes and electron dense deposits in perinuclear region in TAC operated Fkbp8-/- hearts. The data suggest that FKBP8 plays a protective role against hemodynamic stress in the heart mediated via inhibition of the accumulation of misfolded proteins and ER-associated apoptosis. PMID- 29129703 TI - Identification of novel mitochondrial localization signals in human Tafazzin, the cause of the inherited cardiomyopathic disorder Barth syndrome. AB - Mutations in the gene tafazzin (TAZ) result in Barth syndrome (BTHS). Patients present with hypotonia, cyclic neutropenia, 3-methyglutaconic aciduria, and cardiomyopathy, which is the major cause of mortality. The recessive, X-linked TAZ gene encodes a mitochondrial membrane-associated phospholipid modifying enzyme, which adds unsaturated fatty acid species to monolysocardiolipin to generate mature cardiolipin in the mitochondrial membrane that is essential for mitochondrial morphology and function. To identify intrinsic mitochondrial localization sequences in the human TAZ protein, we made sequential TAZ peptide eGFP fusion protein expression constructs and analyzed the localization of eGFP fluorescence by confocal microscopy. We assessed these fusion proteins for mitochondrial localization through cotransfection of H9c2 cells with plasmids encoding organellar markers linked to TdTomato. We have identified two peptides of TAZ that are independently responsible for mitochondrial localization. Using CRISPR-generated TAZ knock out cell lines, we found that these peptides are able to direct proteins to mitochondria in the absence of endogenous TAZ. These peptides are not located within the predicted enzymatic clefts of TAZ, implying that some BTHS disease causing mutations may affect mitochondrial localization without affecting transacylase activity. These novel peptides improve our understanding of TAZ intracellular trafficking, provide insight into the molecular basis of BTHS and provide molecular reagents for developing targeted mitochondrial therapies. PMID- 29129704 TI - Wearable activity monitors in oncology trials: Current use of an emerging technology. AB - BACKGROUND: Physical activity is an important outcome in oncology trials. Physical activity is commonly assessed using self-reported questionnaires, which are limited by recall and response biases. Recent advancements in wearable technology have provided oncologists with new opportunities to obtain real-time, objective physical activity data. The purpose of this review was to describe current uses of wearable activity monitors in oncology trials. METHODS: We searched Pubmed, Embase, and the Cochrane Central Register of Controlled Trials for oncology trials involving wearable activity monitors published between 2005 and 2016. We extracted details on study design, types of activity monitors used, and purpose for their use. We summarized activity monitor metrics including step counts, sleep and sedentary time, and time spent in moderate-to-vigorous activity. RESULTS: We identified 41 trials of which 26 (63%) involved cancer survivors (post-treatment) and 15 trials (37%) involved patients with active cancer. Most trials (65%) involved breast cancer patients. Wearable activity monitors were commonly used in exercise (54%) or behavioral (29%) trials. Cancer survivors take between 4660 and 11,000 steps/day and those undergoing treatment take 2885 to 8300steps/day. CONCLUSION: Wearable activity monitors are increasingly being used to obtain objective measures of physical activity in oncology trials. There is potential for their use to expand to evaluate and predict clinical outcomes such as survival, quality of life, and treatment tolerance in future studies. Currently, there remains a lack of standardization in the types of monitors being used and how their data are being collected, analyzed, and interpreted. PRECIS: Recent advancements in wearable activity monitor technology have provided oncologists with new opportunities to monitor their patients' daily activity in real-world settings. The integration of wearable activity monitors into cancer care will help increase our understanding of the associations between physical activity and the prevention and management of the disease, in addition to other important cancer outcomes. PMID- 29129706 TI - Design, synthesis, and biological evaluation of novel 7-deazapurine nucleoside derivatives as potential anti-dengue virus agents. AB - Dengue fever, caused by four distinct serotypes of dengue virus (DENV-1 to -4), has become the fastest spreading human infectious disease in recent years. Despite extensive efforts, there is no specific antiviral treatment approved for dengue until now. Nucleoside inhibitors represent an actively pursued area to develop small-molecule anti-dengue virus agents. In this study, we designed and synthesized a series of 7-deazapurine nucleoside derivatives and evaluated their anti-DENV activity. Our design strategy and structure activity relationship studies revealed 6e as the most potent inhibitor (EC50 = 2.081 +/- 1.102 MUM) of DENV replication. 6e suppressed RNA levels and DENV E protein expression, without causing any apparent cytotoxicity in A549 and HepG2 cells (CC50 = 150.06 +/- 11.42 MUM, SI = 72.11 in A549 cells, and CC50 = 146.47 +/- 11.05 MUM and SI = 63.7 in HepG2 cells). In addition, 6e showed similar inhibition potency against four serotypes of DENV, suggesting that it restrains some evolutionarily conserved targets essential for DENV replication. We conceive that 6e may serve as a promising lead compound for anti-DENV drug development. PMID- 29129705 TI - A virus-like particle of the hepatitis B virus preS antigen elicits robust neutralizing antibodies and T cell responses in mice. AB - The preS antigen of hepatitis B virus (HBV) corresponds to the N-terminal polypeptide in the large (L) antigen in addition to the small (S) antigen. The virus-like particle (VLP) of the S antigen is widely used as a vaccine to protect the population from HBV infection. The presence of the S antigen and its antibodies in patient blood has been used as markers to monitor hepatitis B. However, there is very limited knowledge about the preS antigen. We generated a preS VLP that is formed by a chimeric protein between preS and hemagglutinin (HA), and the matrix protein M1 of influenza virus. The HBV preS antigen is displayed on the surface of preS VLP. Asn112 and Ser98 of preS in VLP were found to be glycosylated and O-glycosylation of Ser98 has not been reported previously. The preS VLP shows a significantly higher immunogenicity than recombinant preS, eliciting robust anti-preS neutralizing antibodies. In addition, preS VLP is also capable of stimulating preS-specific CD8+ and CD4+ T cell responses in Balb/c mice and HBV transgenic mice. Furthermore, preS VLP immunization provided protection against hydrodynamic transfection of HBV DNA in mice. The data clearly suggest that this novel preS VLP could elicit robust immune responses to the HBV antigen, and can be potentially developed into prophylactic and therapeutic vaccines. PMID- 29129707 TI - APOBEC3B edits HBV DNA and inhibits HBV replication during reverse transcription. AB - Hepatitis B virus is a partially double-stranded DNA virus that replicates by reverse transcription, which occurs within viral core particles in the cytoplasm. The cytidine deaminase APOBEC3B is a cellular restriction factor for HBV. Recently, it was reported that APOBEC3B can edit HBV cccDNA in the nucleus, causing its degradation. However, whether and how it can edit HBV core-associated DNAs during reverse transcription is unclear. Our studies to address this question revealed the following: First, silencing endogenous APOBEC3B in an HBV infection system lead to upregulation of HBV replication. Second, APOBEC3B can inhibit replication of HBV isolates from genotypes (gt) A, B, C, and D as determined by employing transfection of plasmids expressing isolates from four different HBV genotypes. For HBV inhibition, APOBEC3B-mediated inhibition of replication primarily depends on the C-terminal active site of APOBEC3B. In addition, employing the HBV RNaseH-deficient D702A mutant and a polymerase deficient YMHA mutant, we demonstrated that APOBEC3B can edit both the HBV minus- and plus-strand DNAs, but not the pregenomic RNA in core particles. Furthermore, we found by co-immunoprecipitation assays that APOBEC3B can interact with HBV core protein in an RNA-dependent manner. Our results provide evidence that APOBEC3B can interact with HBV core protein and edit HBV DNAs during reverse transcription. These data suggest that APOBEC3B exerts multifaceted antiviral effects against HBV. PMID- 29129709 TI - Sialolithiasis removal under general anesthesia: A descriptive retrospective study in the maxillofacial surgery department in Lille University Hospital. AB - INTRODUCTION: Since the beginning of the use of sialendoscopy and extracorporeal lithotripsy, recommendations have changed. The purpose of this retrospective study was to evaluate the efficiency of our treatment protocol, without a lithotripter, under general anaesthesia in the Stomatology and Maxillofacial Surgery Department of Lille University Hospital. The secondary goals were to evaluate patient tolerance and satisfaction. MATERIALS AND METHODS: All patients treated with sialendoscopy alone, sialendoscopy with a combined surgical approach or a transoral approach (TOA) (sialolithotomy) between January 2013 and December 2015 were included. Efficiency was judged by the number and size of the extracted calculi compared to those found on the preoperative CTS, the symptoms mentioned during the one month postoperative examination and the recurrence within 6 months (telephone follow-up). Success was attained when the calculus was completely eliminated and the patient was symptom free after one month and without recurrence through six months. On the other hand, failure was attained when the calculus could not be completely removed, there was remaining debris, the patient was still symptomatic after one month or if there was a recurrence before six months. RESULTS: The sialendoscopy success rate was 78.57% for the submandibular gland and 92.3% for the parotid gland. We had a 100% success rate with the combined approach for the parotid gland, we had a 96.7% success rate with TOA and we had a 100% success rate with TOA assisted with sialendoscopy. CONCLUSION: Our results conform with the literature and prompt us to suggest a protocol without a lithotripter. PMID- 29129710 TI - Benign symmetric lipomatosis with lingual involvement: Case report and literature review. AB - Benign symmetrical lipomatosis (BSL) is a rare disorder characterized by diffuse, multiple, symmetric and non-encapsulated fat masses generally localized in the face, neck and upper trunk. An uncommon case of lingual affliction in BSL, presented with macroglossia, sleep apnea, dysphagia and dysartria is described. Bilateral partial glossectomy was performed, with an improvement in initial symptoms one year after surgery. Only seven other BSL cases with lingual involvement have been reported in the literature. This case report and literature review highlights that BSL with lingual affliction is extremely rare, almost exclusive for BSL Type I and affects predominantly middle-aged males from Mediterranean countries. Surgical treatment with unilateral or bilateral partial glossectomy usually restores normal tongue function, but most be accompanied with a postoperative follow up to assure that recurrence does not occur. PMID- 29129708 TI - Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice. AB - Chronic hepatitis B virus infection cannot be cured by current therapies, so new treatments are urgently needed. We recently identified novel inhibitors of the hepatitis B virus ribonuclease H that suppress viral replication in cell culture. Here, we employed immunodeficient FRG KO mice whose livers had been engrafted with primary human hepatocytes to ask whether ribonuclease H inhibitors can suppress hepatitis B virus replication in vivo. Humanized FRG KO mice infected with hepatitis B virus were treated for two weeks with the ribonuclease H inhibitors #110, an alpha-hydroxytropolone, and #208, an N-hydroxypyridinedione. Hepatitis B virus viral titers and S and e antigen plasma levels were measured. Treatment with #110 and #208 caused significant reductions in plasma viremia without affecting hepatitis B virus S or e antigen levels, and viral titers rebounded following treatment cessation. This is the expected pattern for inhibitors of viral DNA synthesis. Compound #208 suppressed viral titers of both hepatitis B virus genotype A and C isolates. These data indicate that Hepatitis B virus replication can be suppressed during infection in an animal by inhibiting the viral ribonuclease H, validating the ribonuclease H as a novel target for antiviral drug development. PMID- 29129711 TI - Double palatal flap for oro-nasal fistula closure. AB - INTRODUCTION: The management of oral fistula to the nose depends on its etiology, its size and its location. Here, we describe a simple technique, inspired by the ones initially developed by Bardach for cleft palates repair. The surgical alternatives are discussed. TECHNICAL NOTE: The double palatal flap is a simple technique, allowing closure in a single session of a central or centro-lateral palate fistula. The key of this technique is the dissection between nasal and palate mucous layers, providing a sufficient amount of laxity to close the defect without tension. DISCUSSION: The double palatal flap can cover centro-lateral palate mucosal fistulae. It provides both aesthetic and functional results in a single stage. Reliability, simplicity and quickness are its main advantages. Outcomes are usually simple; Velar insufficiency may occur, that can be corrected by speech therapy. PMID- 29129712 TI - Estimating the annual risk of HIV transmission within HIV sero-discordant couples in sub-Saharan Africa. AB - OBJECTIVE: To estimate the annual risk of HIV transmission (phi) within HIV sero discordant couples in 23 countries in sub-Saharan Africa (SSA), by utilizing newly available national population-based data and accounting for factors known to potentially affect this estimation. METHODS: We used a recently developed pair based mathematical model that accommodates for HIV-dynamics temporal variation, sexual risk-behavior heterogeneity, and antiretroviral therapy (ART) scale-up. RESULTS: Estimated country-specific phi (in absence of ART) ranged between 4.2% (95% uncertainty interval (UI): 1.9%-6.3%) and 47.4% (95% UI: 37.2%-69.0%) per person-year (ppy), with a median of 12.4%. phi was strongly associated with HIV prevalence, with a Pearson correlation coefficient of 0.92, and was larger in high- versus low-HIV-prevalence countries. phi increased by 1.31% (95% confidence interval: 1.00%-1.55%) ppy for every 1% increase in HIV prevalence. CONCLUSIONS: phi estimates were similar to earlier estimates, and suggested considerable heterogeneity in HIV infectiousness across SSA. This heterogeneity may explain, partly, the differences in epidemic scales. PMID- 29129713 TI - Quantification of sexual HIV transmission risk in Africa. PMID- 29129714 TI - Noninvasive Diagnosis of Pancreatic Cancer Through Detection of Volatile Organic Compounds in Urine. PMID- 29129715 TI - Reducing barriers to healthy weight: Planned and responsive adaptations to a lifestyle intervention to serve people with impaired mobility. AB - BACKGROUND: People with impaired mobility (IM) disabilities have a higher prevalence of obesity and obesity-related chronic conditions; however, lifestyle interventions that address the unique needs of people with IM are lacking. OBJECTIVE: This paper describes an adapted evidence-based lifestyle intervention developed through community-based participatory research (CBPR). METHODS: Individuals with IM, health professionals, disability group representatives, and researchers formed an advisory board to guide the process of thoroughly adapting the Diabetes Prevention Program Group Lifestyle Balance (DPP GLB) intervention after a successful pilot in people with IM. The process involved two phases: 1) planned adaptations to DPP GLB content and delivery, and 2) responsive adaptations to address issues that emerged during intervention delivery. RESULTS: Planned adaptations included combining in-person sessions with conference calls, providing arm-based activity trackers, and adding content on adaptive cooking, adaptive physical activity, injury prevention, unique health considerations, self advocacy, and caregiver support. During the intervention, participants encountered numerous barriers, including health and mental health issues, transportation, caregivers, employment, adjusting to disability, and functional limitations. We addressed barriers with responsive adaptations, such as supporting electronic self-monitoring, offering make up sessions, and adding content and activities on goal setting, problem solving, planning, peer support, reflection, and motivation. CONCLUSIONS: Given the lack of evidence on lifestyle change in people with disabilities, it is critical to involve the community in intervention planning and respond to real-time barriers as participants engage in change. A randomized controlled trial (RCT) is underway to examine the usability, feasibility, and preliminary effectiveness of the adapted intervention. PMID- 29129717 TI - A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader. AB - Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable. This set of kinases is only a fraction of the intracellular targets bound by the degrader, demonstrating that successful degradation requires more than target engagement. The results guided us to develop selective degraders for FLT3 and BTK, with potentials to improve disease treatment. Together, this study demonstrates an efficient approach to triage a gene family of interest to identify readily degradable targets for further studies and pre-clinical developments. PMID- 29129716 TI - The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. AB - Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach. PMID- 29129718 TI - Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. AB - Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small molecule inhibitors. PMID- 29129719 TI - Non-protein amino acid derivatives of 25-methoxylprotopanaxadiol/25 hydroxyprotopanaxadioland their anti-tumour activity evaluation. AB - As active components of ginseng, 25-methoxylprotopanaxadiol and 25 hydroxyprotopanaxadiol exhibited an ability to inhibit the growth and proliferation or to induce the differentiation and apoptosis of tumour cells. We modified 25-OCH3-PPD and 25-OH-PPD with non-protein amino acids and a series of derivatives was obtained by chromatographic separation, purification and spectroscopy analysis. Thirteen derivatives of 25-OCH3-PPD (compounds 1-13) and 12 derivatives of 25-OH-PPD (compounds 14-25) were synthesised. The anti-cancer activities of the derivatives were evaluated on HCT-116 and BGC-823 cell lines by MTT assay. Compound 9 and compound 14 exhibited considerable anti-tumour activity for HCT-116 and BGC-823 cell lines, exhibited higher cytotoxic activity than 25 OCH3-PPD and 25-OH-PPD. Therefore, these ginsenoside derivatives could be used as potential lead for the development of a new type of anticancer agent. PMID- 29129721 TI - Immunological considerations underlying heat shock protein-mediated cancer vaccine strategies. AB - The success of active immunotherapies in the prevention of many infectious diseases over the course of over 200 years has lead scientists to wonder if the same principles could be applied to cancer. Antigen-specific active immunotherapies for the treatment of cancer have been researched for over two decades, however, the overwhelming majority of these studies have failed to stimulate robust clinical responses. It is clear that current active immunotherapy research should incorporate methods to increase the immunostimulatory capacity of these therapies. To directly address this need, we propose the addition of the immunostimulatory heat shock proteins (HSPs) to active immunotherapeutic strategies to augment their efficacy. Heat shock proteins are a family of highly conserved intracellular chaperone proteins, and are the most abundant family proteins inside cells. This ubiquity, and their robust immunostimulatory capacity, points to their importance in regulation of intracellular processes and, therefore, indicators of loss of cellular integrity if found extracellularly. Thus, we emphasize the importance of taking into consideration the location of vaccine-derived HSP/tumor-antigen complexes when designing active immunotheraputic strategies. PMID- 29129722 TI - An extended history of drug self-administration results in multiple sources of control over drug seeking behavior. AB - It is widely recognized that across the development of drug addiction, cues associated with drug use come to exert increasing control over drug seeking and taking behaviors. However, there remain gaps in our knowledge regarding how the different types of drug related cues affect drug seeking and taking behaviors, and how the emergence of cue control over these behaviors relates to the onset of drug seeking compulsions. This paper reviews the literature on drug self administration in animals to address these gaps. It first identifies the different types of cues that acquire control over reward seeking behavior generally, and examines whether the same types of cues acquire control over drug seeking behavior specifically. It then examines how the role of drug related cues in motivating and reinforcing drug seeking behavior changes across an extended drug-taking history, with a particular focus on the case of nicotine. The evidence reviewed shows that, after an extended history of drug taking, drug seeking behaviors are controlled by contextual cues associated with the development of drug seeking habits, response contingent cues that accompany delivery of the drug, as well as internal states that correlate with levels of drug intake. These multiple sources of control over drug seeking are discussed in relation to the generation of an addicted phenotype in animal models and the hypothesized progression from internal control over drug use to compulsive drug seeking. PMID- 29129720 TI - Glucocorticoid receptor signaling in the eye. AB - Glucocorticoids (GCs) are essential steroid hormones that regulate numerous metabolic and homeostatic functions in almost all physiological systems. Synthetic glucocorticoids are among the most commonly prescribed drugs for the treatment of various conditions including autoimmune, allergic and inflammatory diseases. Glucocorticoids are mainly used for their potent anti-inflammatory and immunosuppressive activities mediated through signal transduction by their nuclear receptor, the glucocorticoid receptor (GR). Emerging evidence showing that diverse physiological and therapeutic actions of glucocorticoids are tissue , cell-, and sex-specific, suggests more complex actions of glucocorticoids than previously anticipated. While several synthetic glucocorticoids are widely used in the ophthalmology clinic for the treatment of several ocular diseases, little is yet known about the mechanism of glucocorticoid signaling in different layers of the eye. GR has been shown to be expressed in different cell types of the eye such as cornea, lens, and retina, suggesting an important role of GR signaling in the physiology of these ocular tissues. In this review, we provide an update on the recent findings from in vitro and in vivo studies reported in the last 5 years that aim at understanding the role of GR signaling specifically in the eye. Advances in studying the physiological effects of glucocorticoids in the eye are vital for the elaboration of optimized and targeted GC therapies with potent anti inflammatory potential while minimizing adverse effects. PMID- 29129723 TI - Neural correlates of impaired self-regulation in male youths with autism spectrum disorder: A voxel-based morphometry study. AB - Although recent studies revealed impaired self-regulation (dysregulation) in autism spectrum disorder (ASD), neural correlates of dysregulation and its impacts on autistic neuroanatomy remain unclear. Voxel-based morphometry was applied on structural MRI images in 81 ASD and 61 typically developing (TD) boys aged 7-17years. Dysregulation was defined by the sum of T-scores of Attention, Aggression, and Anxiety/Depression subscales in the Child Behavior Checklist>180. There were 53 and 28 boys in the ASD+Dysregulation and ASD-Dysregulation groups, respectively. First, we compared regional gray matter (GM) volume for ASD and TD. Second, we investigated regional GM volumetric differences among the ASD+Dysregulation, ASD-Dysregulation and TD groups. Lastly, shared and distinct neurostructural correlates of dysregulation were investigated in the ASD and TD groups. The ASD-TD difference on neuroanatomy no longer existed after controlling the dysregulation severity. ASD+Dysregulation had larger regional GM volumes in the right fusiform gyrus, and smaller GM volumes in the anterior prefrontal cortex than ASD-Dysregulation and TD, respectively. ASD+Dysregulation had smaller GM volumes in the left lateral occipital/superior parietal cortex than TD boys. No GM difference was identified between ASD-Dysregulation and TD. ASD and TD had a shared association between GM volumes in the orbitofrontal cortex and dysregulation levels. Our findings suggest that atypical neuroanatomy associated with ASD might partially reflect a disproportionate level of impaired self regulation. Categorical and dimensional considerations of dysregulation should be implemented in future ASD studies. PMID- 29129724 TI - Retinal vasculature development in health and disease. AB - Development of the retinal vasculature is based on highly coordinated signalling between different cell types of the retina, integrating internal metabolic requirements with external influences such as the supply of oxygen and nutrients. The developing mouse retinal vasculature is a useful model system to study these interactions because it is experimentally accessible for intra ocular injections and genetic manipulations, can be easily imaged and develops in a similar fashion to that of humans. Research using this model has provided insights about general principles of angiogenesis as well as pathologies that affect the developing retinal vasculature. In this review, we discuss recent advances in our understanding of the molecular and cellular mechanisms that govern the interactions between neurons, glial and vascular cells in the developing retina. This includes a review of mechanisms that shape the retinal vasculature, such as sprouting angiogenesis, vascular network remodelling and vessel maturation. We also explore how the disruption of these processes in mice can lead to pathology such as oxygen induced retinopathy - and how this translates to human retinopathy of prematurity. PMID- 29129725 TI - Changes in turn alternation pattern in response to substrate-borne vibrations in terrestrial isopods. AB - The present study focuses on the relationship existing between the phenomenon of turn alternation and substrate-borne vibrations in woodlice. Armadillo officinalis was utilized as a behavioral model in comparison to Armadillidium vulgare so as to assess its capability of perceiving external vibrations too. A T maze with multiple exits was used to collect information on the pattern of turn alternation in i) adult individuals of A. officinalis exposed, and ii) not exposed to micro-vibrations, and iii) adult individuals of A. vulgare exposed to micro-vibrations. Turn alternation was assessed as the number of times that an animal turned on the opposite side in the T-maze. Our results showed a statistically significant association between turn alternation pattern and both exposure to micro-vibrations and species of the animals. According to our best fitting model, A. officinalis not exposed and A. vulgare exposed to substrate borne vibrations have 97% and 98% lower odds, respectively of being in a higher category of turn alternations compared to a lower category than exposed individuals of A. officinalis. A. officinalis seems to be very reactive to substrate-borne vibrations, unlike A. vulgare. This different reactivity might be related to a more complex defense mechanism developed as an evolutionary adaptation to the xeric environment, and/or to a means of communication mediated by substrate-borne vibrations, like in insects. PMID- 29129726 TI - Examining object recognition and object-in-Place memory in plateau zokors, Eospalax baileyi. AB - Recognition memory is important for the survival and fitness of subterranean rodents due to the barren underground conditions that require avoiding the burden of higher energy costs or possible conflict with conspecifics. Our study aims to examine the object and object/place recognition memories in plateau zokors (Eospalax baileyi) and test whether their underground life exerts sex-specific differences in memory functions using Novel Object Recognition (NOR) and Object in-Place (OiP) paradigms. Animals were tested in the NOR with short (10min) and long-term (24h) inter-trial intervals (ITI) and in the OiP for a 30-min ITI between the familiarization and testing sessions. Plateau zokors showed a strong preference for novel objects manifested by a longer exploration time for the novel object after 10min ITI but failed to remember the familiar object when tested after 24h, suggesting a lack of long-term memory. In the OiP test, zokors effectively formed an association between the objects and the place where they were formerly encountered, resulting in a higher duration of exploration to the switched objects. However, both sexes showed equivalent results in exploration time during the NOR and OiP tests, which eliminates the possibility of discovering sex-specific variations in memory performance. Taken together, our study illustrates robust novelty preference and an effective short-term recognition memory without marked sex-specific differences, which might elucidate the dynamics of recognition memory formation and retrieval in plateau zokors. PMID- 29129727 TI - Mouth-licking by dogs as a response to emotional stimuli. AB - Dogs are able to perceptually discriminate emotional displays of conspecifics and heterospecifics and possess the cognitive prototypes for emotional categorisation, however, it remains unclear whether dogs can respond appropriately to this information. One way to assess associations between specific behaviours and the perception of emotionally competent stimuli is to look at other reliable measures that are related to cognitive and physiological processing. Using a cross-modal preferential looking paradigm (Albuquerque et al., 2016), we presented dogs with pairs of facial expressions (positive and negative) combined with an emotionally charged vocalisation (positive or negative) or a control sound (neutral) and coded their mouth-licking behaviour. We found an effect of the valence of the face image dogs were seeing on the onset of the mouth-licking, with higher frequencies of this behaviour in response to the negative faces compared to images with positive valence. However, neither the sound being played nor the interaction between image valence and sound affected the behaviour. We also found an effect of species with mouth-licking occurring more often towards human stimuli. This spontaneous differential behavioural response, combined with previous evidence of cognitive emotional processing in these animals, suggests that dogs may have a functional understanding of emotional expressions. PMID- 29129728 TI - PAKs in the brain: Function and dysfunction. AB - p21-Activated kinases (PAKs) comprise a family of proteins covering a central role in signal transduction. They are downstream effectors of Rho GTPases and can affect a variety of processes in different cell types and tissues by remodeling the cytoskeleton and by promoting gene transcription and cell survival. Given the relevance of cytoskeletal organization in neuronal development as well as synaptic function and the importance of pro-survival signals in controlling neuronal cell fate, accumulating studies investigated the role of PAKs in the nervous system. In this review, we provide a critical overview of the role of PAKs in the nervous system, both in neuronal and non-neuronal cells, and discuss their potential link with neurodegenerative diseases. PMID- 29129729 TI - Life course, sociocultural factors and disordered eating in adult Mexican women. AB - Disordered eating (DE) can appear in women of all ages and in diverse sociocultural contexts, however most research focuses on younger women in higher income countries. The purpose of this article was to explore the association of life course markers with DE, considering the effects of sociocultural factors, in a sample of adult women in Tijuana, Mexico. We employed data from a household survey (n = 2322) conducted in 2014, to evaluate the associations of DE with age, occupation, marital status and having children (life course markers), and indicators of social position and exposure to modernization (sociocultural factors). The prevalence of weight preoccupation was 69.2% (CI95% 67.3,71.1), the prevalence of dieting 24.8% (CI95% 22.4,27.3), and 2.0% (CI95% 1.4,3.0) had a probable eating disorder according to the questionnaire cutoff score. In the adjusted model, younger age, being employed, higher social position and indicators of exposure to modernization had positive associations with DE. There were interactions between marital status and body mass index, and between age and region of birth. The interaction terms showed that overweight was positively associated with DE among single and cohabiting participants, but not among the married ones; and that the negative association between DE and age was apparent from younger age groups in women born in less developed regions of Mexico. Our results replicate others in showing DE to be present in women through the life course, and point to at-risk groups in the confluences of life course, social position and modernization. PMID- 29129730 TI - How post-saccadic target blanking affects the detection of stimulus displacements across saccades. AB - When a visual stimulus is displaced during a saccade the displacement is often not noticed unless it is large compared to the amplitude of the eye movement. Displacement detection is improved, however, if a blank intervenes between saccade target offset and the presentation of the displaced post-saccadic stimulus. This has been interpreted as evidence that precise information about eye position and accurate memory for the position of the pre-saccadic target are available immediately after saccade offset, but are overridden by the presence of the post-saccadic stimulus if it is present when the eyes land. In the current set of experiments we examined in more detail how blanking contributes to the increase in displacement sensitivity. In two experiments we showed that the presentation of a blank interval between saccade offset and the presentation of the displaced stimulus improved people's ability to detect that the stimulus had been displaced and also their ability to judge the direction that it had been displaced, but only for displacements opposite to the direction of the saccade (backward displacements). A third experiment suggested that this improvement in the detection of backward displacements was due in part to subjects misremembering the saccade target location as being closer to the initial fixation point than it actually was immediately after the saccade but remembering its location more veridically 50 ms later. This has the effect of improving the detection of displacements as well as their direction of displacement, but preferentially for backwards vs. forward displacements. PMID- 29129732 TI - Chromatic summation and receptive field properties of blue-on and blue-off cells in marmoset lateral geniculate nucleus. AB - The "blue-on" and "blue-off" receptive fields in retina and dorsal lateral geniculate nucleus (LGN) of diurnal primates combine signals from short wavelength sensitive (S) cone photoreceptors with signals from medium/long wavelength sensitive (ML) photoreceptors. Three questions about this combination remain unresolved. Firstly, is the combination of S and ML signals in these cells linear or non-linear? Secondly, how does the timing of S and ML inputs to these cells influence their responses? Thirdly, is there spatial antagonism within S and ML subunits of the receptive field of these cells? We measured contrast sensitivity and spatial frequency tuning for four types of drifting sine gratings: S cone isolating, ML cone isolating, achromatic (S + ML), and counterphase chromatic (S - ML), in extracellular recordings from LGN of marmoset monkeys. We found that responses to stimuli which modulate both S and ML cones are well predicted by a linear sum of S and ML signals, followed by a saturating contrast-response relation. Differences in sensitivity and timing (i.e. vector combination) between S and ML inputs are needed to explain the amplitude and phase of responses to achromatic (S + ML) and counterphase chromatic (S - ML) stimuli. Best-fit spatial receptive fields for S and/or ML subunits in most cells (>80%) required antagonistic surrounds, usually in the S subunit. The surrounds were however generally weak and had little influence on spatial tuning. The sensitivity and size of S and ML subunits were correlated on a cell-by-cell basis, adding to evidence that blue-on and blue-off receptive fields are specialised to signal chromatic but not spatial contrast. PMID- 29129733 TI - Doxorubicin synergism and resistance reversal in human neuroblastoma BE(2)C cell lines: An in vitro study with dextran-catechin nanohybrids. AB - Hybrid nanocarrier consisting in nanographene oxide coated by a dextran-catechin conjugate was proposed in the efforts to find more efficient Neuroblastoma treatment with Doxorubicin chemotherapy. The dextran-catechin conjugate was prepared by immobilized laccase catalysis and its peculiar reducing ability exploited for the synthesis of the hybrid carrier. Raman spectra and DSC thermograms were recorded to check the physicochemical properties of the nanohybrid, while DLS measurements, SEM, TEM, and AFM microscopy allowed the determination of its morphological and dimensional features. A pH dependent Doxorubicin release was observed, with 30 and 75% doxorubicin released at pH 7.4 and 5.0, respectively. Viability assays on parental BE(2)C and resistant BE(2)C/ADR cell lines proved that the high anticancer activity of dextran catechin conjugate (IC50 19.9 +/- 0.6 and 18.4 +/- 0.7 ug mL-1) was retained upon formation of the nanohybrids (IC50 24.8 +/- 0.7 and 22.9 +/- 1 ug mL-1). Combination therapy showed a synergistic activity between doxorubicin and either bioconjugate or nanocarrier on BE(2)C. More interestingly, on BE(2)C/ADR we recorded both the reversion of doxorubicin resistance mechanism as a consequence of decreased P-gp expression (Western Blot analysis) and a synergistic effect on cell viability, confirming the proposed nanohybrid as a very promising starting point for further research in neuroblastoma treatment. PMID- 29129731 TI - Individual differences in visual science: What can be learned and what is good experimental practice? AB - We all pass out our lives in private perceptual worlds. The differences in our sensory and perceptual experiences often go unnoticed until there emerges a variation (such as 'The Dress') that is large enough to generate different descriptions in the coarse coinage of our shared language. In this essay, we illustrate how individual differences contribute to a richer understanding of visual perception, but we also indicate some potential pitfalls that face the investigator who ventures into the field. PMID- 29129734 TI - Ciprofloxacin-loaded sodium alginate/poly (lactic-co-glycolic acid) electrospun fibrous mats for wound healing. AB - Wound dressings should ideally be able to maintain high humidity, remove excess wound exudate, permit thermal insulation, provide certain mechanical strength, and in some cases deliver antibiotics to prevent infections. Until now, none of the existing wound dressing products can meet all these requirements. To design a wound dressing with as many of the aforementioned features as possible, in this study, we attempted to prepare ciprofloxacin (CIP), an antibiotic, loaded electrospun hydrophobic poly (lactic-co-glycolic acid) (PLGA) fibrous mats modified with hydrophilic sodium alginate (ALG) microparticles. The results showed that ALG could improve the wettability, water absorption capacity, and enhance the release rate of ciprofloxacin from the PLGA fibrous mats. In addition, the addition of ALG reduced the stiffness of PLGA fibrous mats for better protection of the injured area as indicated by the Young's modulus. Moreover, the burst release of CIP resulted from the addition of ALG seemed to provide an improved antimicrobial effect to the PLGA mats. This study demonstrated the potential of combining hydrophilic and hydrophobic polymers to design the desired wound dressings via the electrospinning process. PMID- 29129735 TI - Arterial stiffness and cerebral hemodynamic pulsatility during cognitive engagement in younger and older adults. AB - : This study examined central artery stiffness and hemodynamic pulsatility during cognitive engagement in younger and older adults. METHODS: Vascular-hemodynamic measures were completed in 19 younger (age 35+/-1yrs) and 20 older (age 69+/ 2yrs) adults at rest and during a Stroop task. Aortic stiffness (carotid-femoral pulse wave velocity, PWV) and carotid pulse pressure (PP) were assessed using applanation tonometry. Carotid stiffness was assessed as a single-point PWV using Doppler Ultrasound. Middle cerebral artery (MCA) mean flow and flow pulsatility index (PI) were assessed using transcranial Doppler. Cognitive function was assessed as accuracy and reaction time from the Stroop task. RESULTS: Older adults had lower accuracy scores and longer reaction times on the Stroop task compared to younger adults (p<0.05). Both age groups had similar increases in MCA mean flow during Stroop (p<0.05). There were significant increases in aortic PWV, carotid PWV, carotid PP and MCA PI during Stroop in older but not younger adults (p<0.05). Carotid PP and MCA PI assessed during Stroop were statistical mediators of the association between age group and Stroop performance metrics (accuracy and reaction time, p<0.05), while aortic and carotid PWV were indirect statistical mediators of MCA PI through carotid PP (p<0.05). CONCLUSIONS: Older adults experience increases in large artery stiffness during cognitive engagement possibly preventing effective buffering of pulsatile hemodynamic energy entry into the cerebrovasculature. This is important as pulsatile flow during cognitive engagement, and not mean flow per se, was related to overall cognitive performance. PMID- 29129736 TI - Role of D-galactose-induced brain aging and its potential used for therapeutic interventions. AB - Aging is a phenomenon that all living organisms inevitably face. Every year, 9.9million people, globally, suffer from dementia, an indicator of the aging brain. Brain aging is significantly associated with mitochondrial dysfunction. This is characterized by a decrease in the activity of respiratory chain enzymes and ATP production, and increased free radical generation, mitochondrial deoxyribonucleic acid (DNA) mutations, and impaired mitochondrial structures. To get a better understanding of aging and to prevent its effects on many organs, chronic systemic administration of D-galactose was used to artificially create brain senescence in animal models and established to be beneficial for studies of anti-aging therapeutic interventions. Several studies have shown that D-galactose induced brain aging which does so not only by causing mitochondrial dysfunction, but also by increasing oxidative stress, inflammation, and apoptosis, as well as lowering brain-derived neurotrophic factors. All of these defects finally lead to cognitive decline. Various therapeutic approaches which act on mitochondria and cognition were evaluated to assess their effectiveness in the battle to reverse brain aging. The aim of this article is to comprehensively summarize and discuss the underlying mechanisms involved in D-galactose-induced brain aging, particularly as regards alterations in brain mitochondria and cognitive function. In addition, the aim is to summarize the different therapeutic approaches which have been utilized to address D-galactose-induced brain aging. PMID- 29129737 TI - Endotoxemia is modulated by quantity and quality of dietary fat in older adults. AB - BACKGROUND: Aging is an important determinant of the rate of atherosclerosis development, mainly through low-grade inflammation. Diet, and particularly its fat content, modulates the inflammatory response in fasting and postprandial states. OBJECTIVE: We aimed to study the effects of dietary fat on endotoxemia in healthy older adults. MATERIALS AND METHODS: Twenty healthy older adults were randomized to three diets, lasting three-weeks each, using a crossover design: 1. A Mediterranean diet enriched in MUFA with virgin olive oil. 2. An SFA-rich diet. 3. A low-fat high-carbohydrate diet enriched in n-3 PUFA (alpha-linolenic acid of plant origin) (CHO-PUFA diet). At the end of each period, after a 12-h fast, the subjects received a meal with a composition similar to the dietary period just completed. We determined the fasting and the postprandial plasma levels of lipopolysaccharide (LPS) and LPS-binding protein (LBP). RESULTS: In the fasting state, we observed lower LPS plasma levels after the consumption of the CHO-PUFA diet (P=0.046) in comparison with the consumption of the Med and SFA-rich diets. In the postprandial measurements, we observed a statistically significant increase in plasma levels of LPS (P=0.044) and a decrease in LBP (P=0.003) after the intake of the CHO-PUFA meal, whereas no postprandial changes were observed after the ingestion of the Med and SFA-rich meals. CONCLUSION: Our results, together with those obtained in a previous study, support the concept that the consumption of the Med Diet, in contrast to a low-fat PUFA diet, constitutes a more suitable dietary lifestyle for preventing the development of atherosclerosis in a population at risk, such as older adults. PMID- 29129738 TI - Timing of Referral and Characteristics of Uninsured, Medicaid, and Insured Patients Referred to the Outpatient Supportive Care Center at a Comprehensive Cancer Center. AB - CONTEXT: Low-income patients face barriers to palliative care access, which might negatively influence symptom management and advanced care planning. OBJECTIVE: Our aim was to compare time of referral and characteristics (level of symptom distress) among uninsured (indigent), low-insured (Medicaid), and insured patients presenting to our supportive care center (SCC). METHODS: We conducted a retrospective review of randomly selected 100 indigent, 100 Medicaid, and 300 insured outpatients referred during the same five-year period. We reviewed demographic and clinical characteristics including date of diagnosis of advanced cancer and of first visit to SCC, symptom assessment (Edmonton Symptom Assessment System), type and dose of opioid medication, number of total outpatient visits, and date of last contact with palliative care team. RESULTS: Among 482 evaluable patients, indigent, Medicaid, and insured patients, respectively, had mean (SD) ages of 48 (11), 50 (12), and 63 (13) years (P < 0.001); Edmonton Symptom Assessment System pain scores at first visit of 6.7 (2.5), 5.6 (3.2), and 4.9 (3.2) (P < 0.001); nonwhite race in 60%, 49%, and 25% of cases (P < 0.001); unmarried status in 68%, 64%, and 33% of cases (P < 0.001), while 63%, 87%, and 54% of patients (P < 0.001) were on opioids with median number of encounters per month of 0.6, 0.8, and 0.5 (P = 0.001). Median survival (95% CI) from first visit to last contact was 4.6 (2.8-6.2), 5.4 (3.5-7), and 5.6 (4.7-7.3) months (P = 0.036). CONCLUSION: Patients with limited or no insurance had significantly higher pain and were more frequently on opioids, younger, nonwhite, and not married. They required higher number of SCC follow-up visits. Insurance status did not affect timing of SCC referral or follow-ups at our cancer center. PMID- 29129739 TI - What Do "None," "Mild," "Moderate," "Severe," and "Very Severe" Mean to Patients With Cancer? Content Validity of PRO-CTCAETM Response Scales. PMID- 29129740 TI - Survey on Neonatal End-of-Life Comfort Care Guidelines Across America. AB - CONTEXT: Infants of age less than one year have the highest mortality rate in pediatrics. The American Academy of Pediatrics published guidelines for palliative care in 2013; however, significant variation persists among local protocols addressing neonatal comfort care at the end-of-life (EOL). OBJECTIVES: The purpose of this study was to evaluate current neonatal EOL comfort care practices and clinician satisfaction across America. METHODS: After institutional review board approval (516005), an anonymous, electronic survey was sent to members of the American Academy of Pediatrics Section on Neonatal-Perinatal Medicine. Members of the listserv include neonatologists, neonatal fellow physicians, neonatal nurses, and neonatal nurse practitioners from across America (U.S. and Canada). RESULTS: There were 346/3000 (11.5%) responses with wide geographic distribution and high levels of intensive care responding (46.1% Level IV, 50.9% Level III, 3.0% Level II). Nearly half (45.2%) reported that their primary institution did not have neonatal comfort care guidelines. Of those reporting institutional neonatal comfort care guidelines, 19.1% do not address pain symptom management. Most guidelines also do not address gastrointestinal distress, anxiety, or secretions. Thirty-nine percent of respondents stated that their institution did not address physician compassion fatigue. Overall, 91.8% of respondents felt that their institution would benefit from further education/training in neonatal EOL care. CONCLUSION: Across America, respondents confirmed significant variation and verified many institutions do not formally address neonatal EOL comfort care. Institutions with guidelines commonly appear to lack crucial areas of palliative care including patient symptom management and provider compassion fatigue. The overwhelming majority of respondents felt that their institutions would benefit from further neonatal EOL care training. PMID- 29129741 TI - Risk of second cancer following radiotherapy. PMID- 29129742 TI - The sequence preference of DNA cleavage by T4 endonuclease VII. AB - The enzyme T4 endonuclease VII is a resolvase that acts on branched DNA intermediates during genetic recombination, by cleaving DNA with staggered cuts approximately 3-6 bp apart. In this paper, we investigated the sequence preference of this cleavage reaction utilising two different DNA sequences. For the first time, the DNA sequence preference of T4 endonuclease VII cleavage sites has been examined without the presence of a known DNA substrate to mask any inherent nucleotide preference. The use of the ABI3730 platform enables the cleavage site to be determined at nucleotide resolution. We found that T4 endonuclease VII cleaves DNA with a sequence preference. We calculated the frequency of nucleotides surrounding the cleavage sites and found that following nucleotides had the highest incidence: AWTAN*STC, where N* indicates the cleavage site between positions 0 and 1, N is any base, W is A or T, and S is G or C. An A at position -1 and T at position +2 were the most predominant nucleotides at the cleavage site. Using a Sequence Logo method, the sequence TATTAN*CT was derived at the cleavage site. Note that A and T nucleotides were highly preferred 5' to the cleavage sites in both methods of analysis. It was proposed that the enzyme recognises the narrower minor groove of these consecutive AT base pairs and cleaves DNA 3' to this feature. PMID- 29129743 TI - Comprehensive identification of proteins binding to RNA G-quadruplex motifs in the 5' UTR of tumor-associated mRNAs. AB - G-quadruplex structures in the 5' UTR of mRNAs are widely considered to suppress translation without affecting transcription. The current study describes the comprehensive analysis of proteins binding to four different G-quadruplex motifs located in mRNAs of the cancer-related genes Bcl-2, NRAS, MMP16, and ARPC2. Following metabolic labeling (Stable Isotope Labeling with Amino acids in Cell culture, SILAC) of proteins in the human cell line HEK293, G-quadruplex binding proteins were enriched by pull-down assays and identified by LC-orbitrap mass spectrometry. We found different patterns of interactions for the G-quadruplex motifs under investigation. While the G-quadruplexes in the mRNAs of NRAS and MMP16 specifically interacted with a small number of proteins, the Bcl-2 and ARPC2 G-quadruplexes exhibited a broad range of proteinaceous interaction partners with 99 and 82 candidate proteins identified in at least two replicates, respectively. The use of a control composed of samples from all G-quadruplex forming sequences and their mutated controls ensured that the identified proteins are specific for RNA G-quadruplex structures and are not general RNA-binding proteins. Independent validation experiments based on pull-down assays and Western blotting confirmed the MS data. Among the interaction partners were many proteins known to bind to RNA, including multiple heterogenous nuclear ribonucleoproteins (hnRNPs). Several of the candidate proteins are likely to reflect stalling of the ribosome by RNA G-quadruplex structures. Interestingly, additional proteins were identified that have not previously been described to interact with RNA. Gene ontology analysis of the candidate proteins revealed that many interaction partners are known to be tumor related. The majority of the identified RNA G-quadruplex interacting proteins are thought to be involved in post-transcriptional processes, particularly in splicing. These findings indicate that protein-G-quadruplex interactions are not only important for the fine-tuning of translation but are also relevant to the regulation of mRNA maturation and may play an important role in tumor biology. Proteomic data are available via ProteomeXchange with identifier PXD005761. PMID- 29129744 TI - Upregulation of aquaporin 3 expression by diterpenoids in Euphorbia pekinensis is associated with activation of the NF-kappaB signaling pathway in the co-culture system of HT-29 and RAW 264.7 cells. AB - This study was designed to evaluate the toxic effects of diterpenoids separated from the roots of Euphorbia pekinensis, a type of widely used traditional Chinese medicine. This herb has intestinal toxicity associated with its complex diterpenoids. In this study, the diterpenoids (pekinenin A, pekinenin C, pekinenin F, pekinenin G, yuexiandajisu A, (-)-(1S)-15-hydroxy-18 carboxycembrene) elevated the expression of interleukin 1 beta and tumor necrosis factor alpha in a dose-dependent manner at doses of 6.25, 12.5, and 25 MUM in RAW264.7 monocultures. Pekinenin C increased the expression of phosphorylated IkappaB and phosphorylated p65 in RAW264.7 monocultures, indicating that it stimulated a substantial inflammatory response and activated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathway. A co-culture model of RAW 264.7 mouse macrophage cells and HT-29 human intestinal epithelial cells was established to study the correlation between inflammation and aquaporin (AQP) expression and to evaluate the toxicity of different diterpenoids from E. pekinensis. Pekinenin C (6.25, 12.5, and 25 MUM) increased AQP3 mRNA and protein expression of HT-29 cells in the co-culture system in a dose-dependent manner but not in HT-29 monocultures. AQP3 mRNA and protein expression peaked at 2 and 3 h of HT-29 cells in the co-culture system, respectively. In contrast, their expression peaked more slowly in the monoculture system. After the specific NF-kappaB inhibitor BAY11-7082 (5, 10, and 20 MUM) was added to the co-culture system, the release of cytokines and increased AQP3 expression caused by pekinenin C were inhibited. Comparisons of the representative monomeric compound pekinenin C, diterpenoid monomer mixtures, and total diterpenoids from E. pekinensis showed that the monomer mixtures had the most toxicity. In conclusion, this study demonstrated that E. pekinensis induces inflammation and increases the expression of AQP3, causing disorders of water metabolism, which may lead to gastrointestinal side effects such as diarrhea. PMID- 29129745 TI - Fluorescent light-up acridine orange derivatives bind and stabilize KRAS-22RT G quadruplex. AB - KRAS is often found mutated in lethal cancers and should be an important target for anticancer drug development. However, no effective inhibitor has been reported so far, prompting the scientific community to describe the RAS proteins as nearly "undruggable". Recent approaches developed to modulate KRAS protein expression comprises the targeting of G-quadruplex (G4) structures formed within the nuclease hypersensitive element of KRAS promoter region, by designing small and specific ligands to stabilize the tertiary fold and reduce gene expression. In this work, we report in vitro and in silico studies of novel acridine orange (AO) derivatives (C3-C8), developed as G4 stabilizing agents. The results show that the ligands bind with high affinity and stabilize KRAS22-RT G4 with modest specificity over duplex DNA. The most promising ligand C8 stabilizes the structure by ~ 40 degrees C. Molecular docking using NMR-derived distance restraints reveal atomic details about the ligand structural features in the interaction with KRAS22-RT G4. In vitro studies with HeLa cells show that the ligands are cytotoxic with IC50 values between 0.9 MUM and 5.7 MUM. Moreover, the ligands tend to localize in the nucleus as shown by confocal fluorescence microscopy. Overall, these results show that the reported AO ligands display favourable properties as G4 ligands and this study provides structural detail for the development of lead KRAS G4 ligands. PMID- 29129746 TI - Caspase signaling, a conserved inductive cue for metazoan cell differentiation. AB - Caspase signaling pathways were originally discovered as conveyors of programmed cell death, yet a compendium of research over the past two decades have demonstrated that these same conduits have a plethora of physiologic functions. Arguably the most extensive non-death activity that has been attributed to this protease clade is the capacity to induce cell differentiation. Caspase control of differentiation is conserved across diverse metazoan organisms from flies to humans, suggesting an ancient origin for this form of cell fate control. Here we discuss the mechanisms by which caspase enzymes manage differentiation, the targeted substrates that may be common across cell lineages, and the countervailing signals that may be essential for these proteases to 'execute' this non-death cell fate. PMID- 29129747 TI - Mitochondrial SIRT3 and neurodegenerative brain disorders. AB - Sirtuins are highly conserved NAD+ dependent class III histone deacetylases and catalyze deacetylation and ADP ribosylation of a number of non-histone proteins. Since, they require NAD+ for their activity, the cellular level of Sirtuins represents redox status of the cells and thereby serves as bona fide metabolic stress sensors. Out of seven homologues of Sirtuins identified in mammals, SIRT3, 4 & 5 have been found to be localized and active in mitochondria. During recent past, clusters of protein substrates for SIRT3 have been identified in mitochondria and thereby advocating SIRT3 as the main mitochondrial Sirtuin which could be involved in protecting stress induced mitochondrial integrity and energy metabolism. As mitochondrial dysfunction underlies the pathogenesis of almost all neurodegenerative diseases, a role of SIRT3 becomes an arguable speculation in such brain disorders. Some recent findings demonstrate that SIRT3 over expression could prevent neuronal derangements in certain in vivo and in vitro models of aging and neurodegenerative brain disorders like; Alzheimer's disease, Huntington's disease, stroke etc. Similarly, loss of SIRT3 has been found to accelerate neurodegeneration in the brain challenged with excitotoxicity. Therefore, it is argued that SIRT3 could be a relevant target to understand pathogenesis of neurodegenerative brain disorders. This review is an attempt to summarize recent findings on (1) the implication of SIRT3 in neurodegenerative brain disorders and (2) whether SIRT3 modulation could ameliorate neuropathologies in relevant models. PMID- 29129748 TI - Cellular calcium signaling in the aging brain. AB - Aging in the biological system is an irreversible process. In the initial stages of lifespan aging improves survival skills of an organism while in the later stages aging reduce the survival skills. Aging is associated with changes in several cellular and molecular functions among which calcium signaling is a prominent one. Calcium signaling is essential for many vital functions of the brain and even minor impairments in calcium signaling can lead to deleterious consequences including neuronal death. Calcium signaling proteins are pursued as promising drug targets for many aging related diseases. This review attempts to summarize changes in calcium signaling in the brain as a result of aging. PMID- 29129749 TI - Quantitative proteomic analysis of deciduous molars during cap to bell transition in miniature pig. AB - : Taking advantage of genetic manipulation tools and accessibility, almost all molecular knowledge on vertebrate tooth development was obtained from rodent models that only have one dentition in their entire lives. Whether the tooth development in other vertebrates such as swine or human follows the same rules remains elusive. Rodent dentitions differ considerably from human dentitions, therefore limiting the application of knowledge from rodent tooth to human tooth. Signal-mediated communication between cells and complex gene and protein regulatory networks are key components of tooth development. By combining isobaric tandem mass tag (TMT) labeling with liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) technology, we constructed the proteomic profile of deciduous molars at embryonic days 40 and 50 in miniature pig (Sus scrofa). During the ten days of prenatal development of the miniature pig, the morphology of the lower deciduous molar moves from the early cap to the bell stage. Thus, we identified proteins that are associated with these developing stages and identified differentially regulated proteins (DRPs) that are potential or novel drivers of tooth morphogenesis. Three candidate proteins were validated via qRT-PCR, western blotting analysis, and the location of those proteins in tooth germ were observed by immunohistochemical staining. Multiple signaling pathways and protein interaction network revealed potential mechanisms of early tooth programming in a large mammal. Bioinformatic analysis also showed that cross interaction of Wnt and Sonic hedgehog pathways may play a key role in deciduous development during cap to bell transition in miniature pig. SIGNIFICANCE: We performed the most comprehensive study of the whole tooth germ proteome in mammals to date. The high-throughput proteomic analysis identifies differentially regulated proteins and pathways that will help elucidate the mechanisms of tooth development. PMID- 29129750 TI - K-complex morphological features in male obstructive sleep apnea-hypopnea syndrome patients. AB - This study characterized the differences in K-complex (KC) morphology features between obstructive sleep apnea-hypopnea syndrome (OSAHS) patients and healthy controls and analyzed the effect of respiratory events on KC morphology. We enrolled 42 male subjects (21 OSAHS patients and 21 age-matched healthy controls) who underwent overnight polysomnography. KCs in stage N2 were manually identified. We found that KCs in healthy controls had larger negative and whole amplitudes, longer durations, and smoother positive waves than OSAHS patients but smaller positive amplitudes. Most features showed highly significant differences after Bonferroni correction (p<0.001/3). After separating out the KCs associated with respiratory events in OSAHS patients, the differences between the groups remained but were relatively smaller. In OSAHS patients, compared with the spontaneous KCs not evoked by obvious factors, the KCs occurring after respiratory events had larger amplitudes, steeper slopes, larger negative wave amplitude and duration ratios. KCs occurring during respiratory events showed lower amplitudes and shorter durations. These results may reveal the impact of respiratory events on sleep and brain function. PMID- 29129751 TI - Hypoglossal motoneurons are endogenously activated by serotonin during the active period of circadian cycle. AB - In obstructive sleep apnea patients, contraction of lingual muscles protects the pharyngeal airway from collapse. Hypoglossal (XII) motoneurons innervate the muscles of the tongue and are themselves under wake-related excitatory drives, including that mediated by serotonin (5-HT). Estimates of endogenous 5-HT activation vary among different studies. We tested whether endogenous drive mediated by 5-HT is present in rat XII motoneurons when measured during the active period of the circadian cycle. We monitored sleep-wake states and lingual and nuchal electromyograms (EMGs) while perfusing the XII nucleus with a vehicle or a 5-HT2 receptor antagonist (mianserin, 0.2mM) at the active period onset. EMG levels were measured during each behavioral state and normalized by the mean EMG activity during wakefulness at 4-7am. Wake-related lingual EMG was significantly lower during mianserin perfusion than with the vehicle (53.0+/-9.7% vs. 84.5+/ 8.7%; p=0.002). Mianserin had no effect on nuchal EMG or sleep-wake behavior. Thus, rat XII motoneurons receive endogenous serotonergic activation during wakefulness when measured during the dark period. This indicates that XII motoneuronal activity is enhanced by 5-HT output during the active period of the circadian cycle. PMID- 29129752 TI - Larval development of the symbiotic pea crab Pinnaxodes chilensis (H. Milne Edwards, 1837) (Decapoda, Brachyura, Pinnotheridae) reared in laboratory. AB - The complete larval development of Pinnaxodes chilensis (including four zoeal stages and a megalopa stage) is described and illustrated in detail for the first time. The descriptions are based on laboratory-reared larvae obtained from ovigerous females found inside specimens of the sea urchin Loxechinus albus collected in the coast of Valparaiso, Chile. In order to allow the correct differentiation of specimens from plankton samples, the larval stages of P. chilensis are compared with those from other Pinnotheridae species, whose larval development is known for the Chilean continental waters (Calyptraeotheres politus). The morphological characters described for P. chilensis larvae, as well as the comparison with the remaining larval development descriptions available for the genus Pinnaxodes, are used to discuss the heterogeneity within this genus. PMID- 29129753 TI - Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway. AB - PURPOSE: Nitrogen mustard (NM), which simulates the effects of sulfur mustard (SM), is a potent vesicant known to cause irreversible corneal damage. This study investigates the mechanisms by which NM induces corneal damage by examining the impact of NM exposure on the morphology and lipidome of the cornea. METHODS: Intact ex vivo rabbit eyes were placed in serum-free DMEM organ culture. NM (0, 1, 2.5, 5 or 10 mg/ml) was applied to the central cornea for 5, 10 or 15 min using a 5 mm filter disk and subsequently rinsed with DMEM. Corneas were then cultured for 3, 24, or 48 h before being fixed for morphological analysis or for 24 h before being snap frozen for lipidomic analysis. RESULTS: No morphological changes were detected 3 h after NM exposure. Twenty-four h after exposure, 1 mg/ml NM caused erosion of the corneal epithelium, but no damage to the underlying stroma. Damage caused by 2.5 mg/ml NM extended almost two thirds through the corneal stroma, while 5 mg/ml completely penetrated the corneal stroma. An altered lipid profile occurred 24 h after corneas were exposed to NM. Specific sphingomyelins, ceramides, and diacylglycerols were increased up to 9-, 60- and 10-fold, respectively. CONCLUSIONS: NM induces concentration- and exposure time-dependent damage to the cornea that increases in severity over time. Alterations in the sphingomyelin-ceramide pathway may contribute to the damaging effects of NM exposure. PMID- 29129754 TI - CD44 targeting hyaluronic acid coated lapatinib nanocrystals foster the efficacy against triple-negative breast cancer. AB - Lapatinib (LPT) is an orally administered drug for the treatment of metastatic breast cancer. For expanding its therapeutic horizon, we have prepared its nanocrystals (LPT-NCs) that were subsequently coated with hyaluronic acid (HA) to produce LPT-HA-NCs. The detailed in-vitro and in-vivo investigation of LPT-HA-NCs showed the superior anticancer activity due to active targeting to CD44 receptors than the counterparts LPT-NCs and free LPT. In the triple negative 4T1 cells induced breast tumor bearing female Balb/C mice; LPT-HA-NCs treatment caused significant retardation of tumor growth and overall increase in animal survival probability because of their higher tumor localization, increased residence time. Our findings clearly suggest that HA coated LPT-NCs formulation enhances the activity of LPT against triple negative breast cancer. It exhibited magnificent therapeutic outcome at low dose thus presenting a strategy to reduce dose administrations and minimize dose related toxicity. PMID- 29129755 TI - Phylogenetic analysis predicts structural divergence for proteobacterial ClpC proteins. AB - Regulated proteolysis is required in all organisms for the removal of misfolded or degradation-tagged protein substrates in cellular quality control pathways. The molecular machines that catalyze this process are known as ATP-dependent proteases with examples that include ClpAP and ClpCP. Clp/Hsp100 subunits form ring-structures that couple the energy of ATP binding and hydrolysis to protein unfolding and subsequent translocation of denatured protein into the compartmentalized ClpP protease for degradation. Copies of the clpA, clpC, clpE, clpK, and clpL genes are present in all characterized bacteria and their gene products are highly conserved in structure and function. However, the evolutionary relationship between these proteins remains unclear. Here we report a comprehensive phylogenetic analysis that suggests divergent evolution yielded ClpA from an ancestral ClpC protein and that ClpE/ClpL represent intermediates between ClpA/ClpC. This analysis also identifies a group of proteobacterial ClpC proteins that are likely not functional in regulated proteolysis. Our results strongly suggest that bacterial ClpC proteins should not be assumed to all function identically due to the structural differences identified here. PMID- 29129756 TI - Assessment of Oncological Outcomes After Radical Prostatectomy According to Preoperative and Postoperative Cancer of the Prostate Risk Assessment Scores: Results from a Large, Two-center Experience. AB - BACKGROUND: Among prostate cancer (PCa) patients undergoing radical prostatectomy (RP) and with virtually identical unfavorable pathological characteristics, those deemed at low risk (LR) preoperatively had better oncological outcomes than those with intermediate (IR) or high risk (HR) preoperatively. OBJECTIVE: To examine if this phenomenon still applies when preoperative Cancer of the Prostate Risk Assessment (CAPRA) scores are compared to postoperative scores (CAPRA-S) in RP patients. DESIGN, SETTING, AND PARTICIPANTS: We evaluated 10 290 PCa patients who underwent RP at tertiary care centers in Hamburg (Germany) and Milan (Italy) during 1991-2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All patients were classified as CAPRA/CAPRA-S LR, IR, or HR (<=2, 3-5, and >=6 points, respectively). Kaplan-Meier and Cox regression analyses were performed to assess the risk of biochemical recurrence (BCR) and metastatic disease (metD). RESULTS AND LIMITATIONS: Overall, 59.6%, 29.3%, and 11.1% patients were CAPRA-S LR, IR, and HR respectively. For CAPRA-S LR patients, 5-yr BCR-free and metD-free rates for preoperative CAPRA LR versus IR/HR patients were 93.1% versus 85.7% (p<0.001) and 99.7% versus 98.9% (p=0.017), respectively. For CAPRA-S IR/HR patients, the corresponding rates were 69.9% versus 57.2% and 98.2 versus 93.7% (both p<0.001). On multivariable Cox regression analyses, a combination of CAPRA-S and preoperative CAPRA resulted in increases in predictive accuracy for BCR (from 76.0% to 78.3%) and metD (from 82.0% to 84.0%). Specifically, biopsy Gleason patterns and the percentage of positive cores added information to the CAPRA-S score. Long-term follow-up is needed to discern clinical metD differences between preoperative CAPRA risk groups. CONCLUSIONS: CAPRA-S LR patients in the CAPRA IR/HR group had higher BCR/metD risk. Conversely, CAPRA-S IR/HR patients in the CAPRA LR group had lower BCR/metD risk. Future tools should incorporate better tumor and Gleason quantification to optimize prediction. PATIENT SUMMARY: We demonstrated that among 10290 European patients with prostate cancer who underwent radical prostatectomy, those deemed at low risk preoperatively had better oncological outcomes than their peers with intermediate or high risk, despite virtually identical unfavorable pathological characteristics. PMID- 29129757 TI - Respiration-based monitoring of metabolic rate following cold-exposure in two invasive Anoplophora species depending on acclimation regime. AB - The Asian and Citrus longhorned beetles, Anoplophora glabripennis (ALB) and A. chinensis (CLB) respectively, are two closely related invasive species with overlapping native ranges. Although both species have rather similar biological characteristics, they differ in their invasion patterns. ALB shows numerous, but local, outbreaks in urban areas of North-East America, Western and Central Europe, whereas CLB has colonized a large part of Northern Italy. Temperature is pivotal in setting distribution limits of ectotherms. Low temperature may be limiting for larvae since they are the main overwintering stage for both species. To investigate whether differential cold tolerance may contribute to setting the respective limits of the range invaded by each species, we monitored larval metabolic rate before and after exposure to a one-week ecologically relevant moderate cold stress (-2/+2 degrees C, 14/10h). We tested two distinctive fluctuating regimes before the cold exposure to check whether larval acclimation significantly altered their cold tolerance. Survival was high in all conditions for both species. Visual examination showed temporary locomotor inactivity during the stress but respiration rates were not altered after the stress suggesting that larvae could rapidly resume their initial metabolic activity. The respiration rate was globally higher in ALB than in CLB. Together, these results tend to indicate that both species have similar tolerance to the moderate cold stress tested, but also that ALB may be better at maintaining metabolic activity at cold than CLB. These observed differences could affect phenology in both species and in turn their establishment potential. PMID- 29129758 TI - Impact of Nivolumab versus Docetaxel on Health-Related Quality of Life and Symptoms in Patients with Advanced Squamous Non-Small Cell Lung Cancer: Results from the CheckMate 017 Study. AB - INTRODUCTION: In the phase III CheckMate 017 study, nivolumab prolonged overall survival versus docetaxel in previously treated patients with advanced squamous NSCLC. Study objectives included health-related quality of life (HRQoL) and symptom assessments. METHODS: Patients serially completed the Lung Cancer Symptom Scale (LCSS) and European Quality of Life Five Dimensions (EQ-5D) questionnaires. The LCSS average symptom burden index (ASBI) (mean score for six lung cancer specific symptoms; range 0-100), LCSS three-item global index, EQ-5D utility index, and EQ-5D visual analog scale scores were analyzed. The proportion of patients exhibiting clinically meaningful improvement (a >=10-point decrease) in ASBI scores by week 12 was a secondary end point. Mixed-effect model repeated measures analysis of HRQoL changes from baseline and analyses of time to HRQoL deterioration were conducted. RESULTS: Baseline mean plus or minus SD LCSS ASBI scores were similar in the nivolumab (29.6 +/- 16.4) and docetaxel (29.6 +/- 14.7) groups. By week 12, the proportions of patients (95% confidence interval) with clinically meaningful improvement in ASBI scores were 20.0% (13.6-27.7) with nivolumab and 21.9% (15.3-29.8) with docetaxel. At weeks 16 to 54, significant improvements in ASBI scores from baseline were seen with nivolumab; clinically meaningful improvements were observed at weeks 42 to 84. No significant changes in ASBI scores from baseline were observed with docetaxel; at week 36, a clinically meaningful deterioration was seen. Improvements in HRQoL with nivolumab versus with docetaxel were supported by other measures, and time to first HRQoL deterioration was longer. CONCLUSION: Nivolumab alleviates symptom burden and improves health status versus docetaxel as second-line squamous NSCLC treatment. PMID- 29129759 TI - Dampening of the bone formation response following repeat dosing with sclerostin antibody in mice is associated with up-regulation of Wnt antagonists. AB - Administration of antibodies to sclerostin (Scl-Ab) has been shown to increase bone mass, bone mineral density (BMD) and bone strength by increasing bone formation and decreasing bone resorption in both animal studies and human clinical trials. In these studies, the magnitude and rate of increase in bone formation markers is attenuated upon repeat dosing with Scl-Ab despite a continuous and progressive increase in BMD. Here, we investigated whether the attenuation in the bone formation response following repeated administration of Scl-Ab was associated with increased expression of secreted antagonists of Wnt signalling and determined how the circulating marker of bone formation, P1NP, responded to single, or multiple doses, of Scl-Ab four days post-dosing. Female Balb/c mice were treated with Scl-Ab and we demonstrated that the large increase in serum P1NP observed following the first dose was reduced following administration of multiple doses of Scl-Ab. This dampening of the P1NP response was not due to a change in the kinetics of the bone formation marker response, or differences in exposure to the drug. The abundance of transcripts encoding several secreted Wnt antagonists was determined in femurs collected from mice following one or six doses of Scl-Ab, or vehicle treatment. Compared with vehicle controls, expression of SOST, SOST-DC1, DKK1, DKK2, SFRP1, SFRP2, FRZB, SFRP4 and WIF1 transcripts was significantly increased (approximately 1.5-4.2 fold) following a single dose of Scl-Ab. With the exception of SFRP1, these changes were maintained or further increased following six doses of Scl-Ab and the abundance of SFRP5 was also increased. Up-regulation of these Wnt antagonists may exert a negative feedback to increased Wnt signalling induced by repeated administration of Scl-Ab and could contribute to self-regulation of the bone formation response over time. After an antibody-free period of four weeks or more, the P1NP response was comparable to the naive response, and a second phase of treatment with Scl-Ab following an antibody-free period elicited additional gains in BMD. Together, these data demonstrate that the rapid dampening of the bone formation response in the immediate post-dose period which occurs after repeat dosing of Scl-Ab is associated with increased expression of Wnt antagonists, and a treatment-free period can restore the full bone formation response to Scl-Ab. PMID- 29129760 TI - The key role of proinflammatory cytokines, matrix proteins, RANKL/OPG and Wnt/beta-catenin in bone healing of hip arthroplasty patients. AB - INTRODUCTION: We still lack understanding of why some implants fail while most remain stable after decades of use. Proinflammatory cytokines, matrix proteins and bone regulating cytokines of the RANKL/OPG (receptor activator of nuclear factor kappa B ligand/osteoprotegerin) and Wnt/beta-catenin pathways are mandatory for normal bone repair but their spatial and temporal role in the healing of primary total hip arthroplasties (THA) has not been previously shown. MATERIALS AND METHODS: Twenty-four osteoarthritis patients with one-sided well fixed primary THA were prospectively monitored during 18years (18Y) with repeated blood samples, clinical variables and radiographs. Eighty-one healthy donors divided in three age- and gender-matched groups and twenty osteoarthritis patients awaiting THA and serving as control of the validity of stored plasma in THA patients, were included. Plasma was analyzed for C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor (TNF)-alpha, osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC/osteonectin), osteocalcin (OC), bone specific alkaline phosphatase (BALP), N-terminal propeptide of collagen type I (P1NP), RANKL, OPG, the Wnt agonistic ligands (Wnt)-1 and Wnt-3a, and the Wnt antagonists sclerostin, Dickkopf (Dkk)-1, Dkk-3, Dkk-4, secreted frizzled related protein (sFRP)-1, sFRP-3 and Wnt inhibitory factor-1 (Wif-1). RESULTS: Inflammatory mediators in arthroplasty patients (CRP, IL-6, OPN) increased significantly on day one after surgery vs preoperative value (PR) and healthy subjects and returned to baseline at 6W. TNF alpha did not change relative preoperative level or healthy subjects. SPARC and OC increased in a biphasic fashion with the primary phase beginning shortly after surgery and lasting 3M (SPARC) and 2Y (OC) while the secondary phase peaked at 1Y (SPARC) and 13Y (OC), with both returning to basal level at 15Y. BALP peaked at 3M after surgery with a return to basal level at 2Y followed by a continuous increase from 5Y until 18Y. P1NP increased immediately after surgery and returned to basal level at 6W followed by a new peak at 10Y returning to basal at 13Y. IL 8 and IL-1beta peaked at 5Y post-THA and returned to basal level at 10Y. RANKL/OPG and Wnt/beta-catenin remained at preoperative levels until 5Y post-THA when a sustained increase in OPG level, paralleled by a sustained decrease in sclerostin, started and lasted until 18Y. Despite a strong increase by RANKL at 13Y, the OPG/RANKL-ratio remained high between 5Y and 18Y. Dkk-1 and sFRP-1 remained at basal level until 5Y followed by a peak at 7Y and a return to basal level at 15Y. Similarly, RANKL increased after 5Y, peaked at 13Y and returned to basal levels at 18Y, thus coinciding with Wnt-1. In contrast, Wnt3a, Dkk-3, Dkk 4, sFRP-3 and Wif-1 did not differ from preoperative levels or healthy subjects during the course of the follow-up. CONCLUSION: The primary peak of proinflammatory cytokines involved in the initiation of bone healing after trauma is in line with previous results. The primary phase of increased matrix proteins, P1NP and BALP paralleled by RANKL, OPG and Wnt/beta-catenin remaining at preoperative level until 5Y, support a strong formation of mineralized matrix and to a lesser degree bone during this phase. The secondary proinflammatory peak at 5Y is likely a trigger of coupled bone remodeling and neosynthesis as it is followed by increased levels of the bone anabolic turnover marker, BALP, and mediators of the RANKL/OPG and Wnt/beta-catenin pathways. A continuous increase by OPG level and the bone turnover marker, BALP, lasting from 5Y until 18Y and paralleled by a similar decrease in sclerostin level support their being key regulators of bone anabolism, whereas the transient and opposed activities of RANKL, Wnt-1, Dkk-1 and sFRP-1 serve as fine tuning tools during the coupled remodeling phase. PMID- 29129761 TI - Are Antiplatelet and Anticoagulants Drugs A Risk Factor for Bleeding in Mild Traumatic Brain Injury? AB - OBJECTIVE: Facing mild traumatic brain injury, clinicians must decide whether to perform a computed tomography (CT) scan to detect a potential intracranial hemorrhage. Many useful guidelines have been developed for the general population, but there is no general consensus about the best practice to adopt when dealing with patients on antiplatelet or anticoagulation drugs. The relatively recent introduction of new anticoagulants and second-generation antiplatelet drugs poses new challenges in this field. There are no data in the literature about the relative risk of intracranial bleeding in such categories. METHODS: We enrolled 2773 consecutive patients presenting at our emergency department with mild traumatic brain injury as chief complaint and evaluated the results of their head CT scans, stratifying their anticoagulation and/or antiplatelet drug regime. RESULTS: Of these patients, 1608 matched the criteria for head CT scan and had a Glasgow Coma Scale (GCS) score of 15; 517 were on antiplatelet drugs, whereas 213 were on anticoagulants. The risk of developing intracranial bleeding was significantly higher for patients on antiplatelet drugs, whereas the risk of anticoagulated patients overlapped with that of the general population. The trend for second-generation drugs was of higher risk of bleeding only for antiplatelets. CONCLUSIONS: Patients with a GCS score of 15 on long-term anticoagulation therapy seem to be at no higher risk for intracranial hemorrhage than are nonanticoagulated patients. On the contrary, patients with a GCS score of 15 on antiplatelet therapy seem to be more prone to developing intracranial bleeding than are the general population, with a trend to be more at risk when it comes to second-generation drugs. PMID- 29129762 TI - Risk Factors for the Rupture of Intracranial Aneurysms Using Computed Tomography Angiography. AB - OBJECTIVE: To study the clinical and morphologic characteristics associated with risk factors for the rupture of intracranial aneurysms (IAs). METHODS: A total of 1115 consecutive patients with 1282 IAs were reviewed from August 2011 to February 2016. The patients and IAs were divided into ruptured and unruptured groups. Based on the clinical and morphologic findings, the risk factors for IA rupture were assessed using statistical methods. RESULTS: Age, hypertension, diabetes mellitus, and cerebral atherosclerosis were associated with ruptured IAs. IAs located in the anterior cerebral artery, the anterior communicating artery, the posterior communicating artery, and the internal carotid artery were associated with ruptured IAs. Ruptures were also associated with arterial bifurcations, irregular aneurysm shapes, and all continuous data, except neck width. Binary logistic regression showed that IAs located at bifurcations (odds ratio [OR], 1.804), with irregular shapes (OR, 4.677), with high aspect ratios (ARs) (OR, 5.037) or with small mean diameters (MDs) (OR, 0.495) are more prone to rupture. Receiver operating characteristic analysis showed that the threshold values of the AR and MD were 1 and 3.70 mm, respectively. CONCLUSIONS: Morphologic characteristics, such as being located at bifurcations, being irregularly shaped, having a high AR (>1), and having a small MD (<3.70 mm), were better predictors of rupture. PMID- 29129763 TI - Mammillothalamic and Mammillotegmental Tracts as New Targets for Dementia and Epilepsy Treatment. AB - BACKGROUND: Recently, neuromodulation through deep brain stimulation (DBS) has appeared as a new surgical procedure in the treatment of some types of dementia and epilepsy. The mammillothalamic and mammillotegmental tracts are involved among the new targets. To our knowledge, a review article focused specifically on these mammillary body efferents is lacking in the medical literature. Their contribution to memory is, regrettably, often overlooked. METHODS: A review of the relevant literature was conducted. RESULTS: There is evidence that mammillary bodies can contribute to memory independently from hippocampal formation, but the mechanism is not yet known. Recent studies in animals have provided evidence for the specific roles of these mammillary body efferents in regulating memory independently. In animal studies, it has been shown that the disruption of the mammillothalamic tract inhibits seizures and that electrical stimulation of the mammillary body or mammillothalamic tract raises the seizure threshold. In humans, DBS targeting the mammillary body through the mammillothalamic tract or the stimulation of the anterior thalamic nucleus, especially in the areas closely related to the mammillothalamic tract, has been found effective in patients with medically refractory epilepsy. Nonetheless, little knowledge exists on the functional anatomy of the mammillary body efferents, and their role in the exact mechanism of epileptogenic activity and in the memory function of the human brain. CONCLUSIONS: A comprehensive knowledge of the white matter anatomy of the mammillothalamic and mammillotegmental tracts is crucial since they have emerged as new DBS targets in the treatment of various disorders including dementia and epilepsy. PMID- 29129764 TI - Decompressive Craniectomy for Spontaneous Intracerebral Hemorrhage: A Systematic Review and Meta-analysis. AB - BACKGROUND: Spontaneous intracerebral hemorrhage (sICH) is a devastating disease with high mortality and morbidity, and the application of decompressive craniectomy (DC) in sICH is controversial. We conducted a systematic review to verify the effects of DC on improving outcome in sICH. METHODS: Through searching several electronic databases, we screened eligible publications. Respective risk ratio (RR) and its 95% confidence interval (CI) were calculated, data were synthesized with a fixed-effect model, and sensitivity analyses and subgroup analyses were performed. Publication bias was measured with Begg and Egger tests. RESULTS: Overall effect showed that DC significantly reduced the poor outcome compared with the control group (RR, 0.91; 95% CI, 0.84-0.99; P = 0.03). But in the subgroup analyses, only studies published after 2010, studies using hematoma evacuation as control, and studies measuring outcome with Glasgow outcome score showed better outcomes in the DC group than in the control group. The other subgroup analyses and sensitivity analyses achieved inconsistent results. Compared with the control group, DC effectively decreased mortality (RR, 0.67; 95% CI, 0.53-0.85; P = 0.0008). The sensitivity analyses and subgroup analyses achieved consistent results. CONCLUSIONS: The application of DC effectively reduced mortality in patients with sICH. DC might improve functional outcomes in certain populations and needs further verification. DC is not associated with increased incidences of postoperative rebleeding and hydrocephalus. PMID- 29129765 TI - C2 Body as "Keystone" in Management of C1-C2-C3 Dislocation Secondary to Congenital Absence of C2 Posterior Elements. AB - BACKGROUND: Congenital absence of C2 posterior arch may present with C2-C3 dislocation. Previously these cases were managed by fusing occiput-C1-C4 without including C2 in the construct. Such constructs are likely to immobilize the long segment of the cervical spine, and exclusion of C2 may not yield the best result. CASE DESCRIPTION: We report a case with congenital absence of posterior arch of axis with C2-3 and C1-C2 dislocation who presented with progressive spastic quadriparesis. The inferior facets of C2 were rudimentary. In our patient the C1 C2-C3 dislocations were stabilized with C1 and C3 lateral mass along with C2 pedicle screws. Clinical improvement with radiologic realignment occurred. CONCLUSION: Absence of the posterior arch of axis may be associated with adjacent C1-C2 along with C2-C3 dislocation, so both levels need to be addressed. The radiology should be critically evaluated for other structures developing from the C2 neural arch. It is important to include C2 to achieve a stable construct without compromising adjacent-level mobility. PMID- 29129766 TI - Treatment of Spontaneous Dissecting Aneurysm in Extracranial Vertebral Artery with Covered Stent. AB - OBJECTIVE: To treat a 13-year-old boy with a spontaneous vertebrobasilar artery dissecting aneurysm in the extracranial artery, which was only 1 mm away from the initial segment of subclavian artery. METHODS: A covered stent was inserted to block the artery of the vertebrobasilar artery dissecting aneurysm. RESULTS: The vertebrobasilar artery dissecting aneurysm was successfully treated without complications. CONCLUSIONS: The procedure is a fast, reliable, effective, and economical technique, particularly suitable for surgeries in settings with limited resources. PMID- 29129767 TI - Low-Grade Glioma with Foci of Early Transformation Does Not Necessarily Require Adjuvant Therapy After Radical Surgical Resection. AB - BACKGROUND: Low-grade glioma (LGG) is a slow-growing tumor often found in young adults with minimal or no symptoms. As opposed to true low-grade lesions such as dysembryoplastic neuroepithelial tumors, they are associated with continuous growth and inevitable malignant transformation. METHODS: Case series of patients who have had en bloc resection of LGG with foci of anaplasia found embedded within the tumor specimen and not at margins. Patients were offered and agreed to a conservative approach avoiding adjuvant therapy. RESULTS: In the current case series, we describe a small subset of LGG that have shown foci of high-grade glioma but have shown behavior and growth tendencies similar to LGG after radical surgical resection. No patient to date has shown recurrent disease requiring adjuvant therapy. CONCLUSIONS: This case series supports the use of early aggressive surgical treatment of grade II gliomas that are premalignant. It acts as proof of concept that after radical resection, the presence of small foci of transformation embedded within grade II tumor may be treated with close radiologic surveillance rather than immediate adjuvant therapy. PMID- 29129768 TI - What's New in Spinal Coccidioidomycosis? PMID- 29129769 TI - Retrosigmoid Intradural Suprameatal-Inframeatal Approach for Complete Surgical Removal of a Giant Recurrent Vestibular Schwannoma with Severe Petrous Bone Involvement: Technical Case Report. AB - BACKGROUND: Surgical removal of giant vestibular schwannomas with severe petrous bone involvement remains challenging due to the high risk of complications. The retrosigmoid intradural suprameatal-inframeatal approach (RISIA) allows for safe exposure extending from Meckel's cave to the petrous internal carotid artery (ICA). CASE DESCRIPTION: A 27-year-old man presented with recurrence of a giant vestibular schwannoma (4.5 cm) invading Meckel's cave and the left petrous ICA. Symptoms included complete left facial palsy and hearing loss due to tumor invasion and previous operations, as well as left-sided trigeminal hypesthesia, abducens nerve palsy, and lower cranial nerve dysfunction due to tumor compression. The patient also exhibited severe discoordination and ataxia. The tumor was completely resected via the RISIA, which involved drilling of the suprameatal and inframeatal portions of the petrous bone. No approach-related complications were observed. Full recovery of cranial nerve functions (with the exception of those related to the facial and cochlear nerves) and balance were observed postoperatively. CONCLUSIONS: The RISIA allows for safe and effective surgical access during complete tumor resection, even when severe involvement of Meckel's cave and the petrous ICA are observed. The present report is the first to demonstrate the usefulness of this approach in patients with recurrent giant vestibular schwannoma. PMID- 29129770 TI - Nerve Transfers in Patients with Brown-Sequard Pattern of Spinal Cord Injury: Report of 2 Cases. AB - BACKGROUND: Use of distal nerve transfer for improving upper limb function has been well described for patients with tetraplegic spinal cord injury and brachial plexus injuries but has not previously been described for Brown-Sequard type spinal cord injury. We describe our experience with 2 cases of combined Brown Sequard injury and unilateral brachial amyotrophy. CASE DESCRIPTION: Patient 1, a 43-year-old woman, was involved in a motor vehicle accident and sustained left side C5-7 level hemicord injury causing ipsilateral proximal arm weakness and sensory loss with contralateral hemisensory changes, neuropathic pain, and spasms. At 6 months after injury, she underwent a spinal accessory to suprascapular nerve, radial nerve triceps branch to axillary nerve, and ulnar fascicle to biceps transfer. At 2-year follow-up, she had improved function with Medical Research Council grade 4 power of shoulder abduction, elbow flexion, and internal and external rotation. Patient 2, a 38-year-old man, sustained a C4-5 fracture-dislocation in a motor vehicle accident and associated right-side hemicord injury involving the C5 and C6 myotomes with relatively preserved distal function. At 9 months after injury, he underwent radial nerve triceps branch to axillary nerve division and ulnar nerve fascicle to musculocutaneous nerve brachialis branch transfer. At 8 months after surgery, electromyography demonstrated evidence of further reinnervation of the deltoid muscle. CONCLUSIONS: Our early experience of nerve transfer with 2 patients with combined Brown-Sequard cord injury and brachial amyotrophy indicated acceptable surgical safety and demonstrated encouraging results. PMID- 29129771 TI - Effects of Antarctic krill docosahexaenoic acid on MCF-7 cell migration and invasion induced by the interaction of CD95 with caveolin-1. AB - Tumor metastasis leads to a poor prognosis in breast cancer, yet the mechanisms remain unclear. Docosahexaenoic acid (DHA) extracted from Antarctic krill is an optical isomer of common DHA and has a much stronger anti-neoplastic effect. In this work, the migration and invasion abilities of MCF-7 cells treated with low concentrations of Antarctic krill DHA were evaluated. Low concentrations of Antarctic krill DHA significantly reduced the numbers of migrating and invasive MCF-7 cells, whereas the cell numbers decreased slowly in the CD95-silenced MCF-7 cells, which implies that CD95 might be involved in cell migration and invasion. Additionally, co-immunoprecipitation and Western blotting demonstrated that Antarctic krill DHA induced the accumulation of CD95 and caveolin-1 interaction, resulting in the down-regulation of MMP2 expression through the FAK/SRC/PI3K/AKT signaling pathway. In conclusion, Antarctic krill DHA enhanced the interaction between CD95 and caveolin-1, which may led to an inhibitory effect on cell migration and invasion via the FAK/SRC/PI3K/AKT signaling pathway. Our study indicates that Antarctic krill DHA has great potential for tumor therapy and has revealed a new metastatic mechanism mediated by the interaction of CD95 with caveolin-1. PMID- 29129772 TI - Glycyrrhizin ameliorates high fat diet-induced obesity in rats by activating NrF2 pathway. AB - AIM: Obesity based on insulin resistance is a state of chronic oxidative stress and inflammation that are highly regulated through nuclear factor Erythroid 2 related factor 2 (NrF2) pathway. MATERIALS AND METHODS: 70 male Wistar rats were randomized into two models. The prophylactic model was 10weeks and rats were grouped into: normal group, GL group (received glycyrrhizin 50mg/kg/day orally along with normal pellet diet), HFD group and HFD+ GL group (received glycyrrhizin along with HFD). The treatment model was 14weeks and rats were grouped into: normal group, HFD group and HFD+GL group (received glycyrrhizin from the week 10). KEY FINDINGS: Glycyrrhizin decreased significantly rat weights and insulin resistance, normalized lipid profile and reduced significantly the adipocytes size in adipose tissue and lipid deposition in the liver tissue through histopathologic examination. Furthermore, glycyrrhizin ameliorated obesity-induced oxidative stress which indicated by significant decrease in liver malondialdehyde level (P<0.001) and increase in the total antioxidant capacity (P<0.001). Interestingly, molecular mechanism of glycyrrhizin was explored, that included significant reduction of liver gluconeogenic enzymes mRNA expression (P<0.001), a significant increase of liver insulin receptor, NrF2 and homooxygenase-1 mRNA expressions (P<0.001) and significant increase and nuclear translocation of NrF2 in liver tissue. SIGNIFICANCE: Glycyrrhizin ameliorates HFD induced obesity in rats that may be attributed to its ability to increase insulin receptor expression and to activate NrF2 and subsequent homooxygenase-1 pathway. Thus, this work represents a safe natural compound (glycyrrhizin) that has a great role either as prophylaxis or treatment for insulin resistance related to obesity. PMID- 29129773 TI - Gambogic acid ameliorates diabetes-induced proliferative retinopathy through inhibition of the HIF-1alpha/VEGF expression via targeting PI3K/AKT pathway. AB - AIMS: Gambogic acid (GA) is one of active components of Chinese medicine gamboges resin. Diabetic retinopathy (DR) is a most serious microvascular complication of diabetes and also the leading cause of blindness. The aim of this study is to evaluate the beneficial effect of GA on diabetes-induced retinal angiogenesis and further explore the potential mechanisms. MATERIAL AND METHODS: High glucose (HG) treated RF/6A cells and STZ-induced diabetic mice were used as in vitro and in vivo models. Then the effects of GA on proliferation, migration and tube formation in RF/6A cells and pathomorphological changes in STZ-induced diabetic mice were determined. The activation of HIF-1alpha/VEGF and PI3K/AKT signaling pathways was assessed by various molecular biological experiments. KEY FINDINGS: According to our results, GA inhibited HG-induced proliferation, migration and tube formation in choroid-retinal endothelial RF/6A cells. The upregulation of HIF-1alpha and VEGF induced by HG in RF/6A cells was restrained by GA treatment significantly. Moreover, GA suppressed retinal pathomorphological changes and angiogenesis in STZ-induced diabetic mice in vivo, and also inhibited the activation of HIF-1alpha/VEGF pathway induced by diabetics. Finally, GA suppressed the activation of PI3K/AKT signaling pathway in STZ-induced diabetic mice in vivo and in HG-induced RF/6A cells in vitro. Further activation of PI3K/AKT pathway by IGF-1 restrained the beneficial effect of GA in RF/6A cells. SIGNIFICANCE: Our results provide evidence that GA may ameliorate diabetes induced retinal angiogenesis, which are proofs that GA may be developed as a potential drug for treating DR. PMID- 29129774 TI - Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer's disease. AB - While most often noted for its cognitive symptoms, Alzheimer's disease (AD) is, at its core, a disease of protein misfolding/aggregation, with an intriguing inflammatory component. Defective clearance and/or abnormal production of the amyloid-beta peptide (Abeta), and its ensuing accumulation and aggregation, underlie two hallmark features of AD: brain accumulation of insoluble protein deposits known as amyloid or senile plaques, and buildup of soluble Abeta oligomers (AbetaOs), diffusible toxins linked to synapse dysfunction and memory impairment. In neurons, as in typical eukaryotic cells, the endoplasmic reticulum (ER) serves as a main compartment for the folding, maturation, trafficking and quality control of newly synthesized proteins. The ER lumen, a calcium-rich, oxidizing environment, provides favorable conditions for these physiological functions to occur. These conditions, however, also favor protein aggregation. Several stressors, including metabolic/nutrient stress and certain pathologies, may upset the ER homeostasis, e.g., by affecting calcium levels or by causing the accumulation of unfolded or misfolded proteins. Whatever the underlying cause, the result is what is commonly known as "ER stress". This, in turn, triggers a conserved cellular response mechanism known as the "unfolded protein response" (UPR). The UPR comprises three pathways involving transcriptional or translational regulators aimed at normalizing ER function, and each of them results in pro-inflammatory signaling. A positive feedback loop exists between ER stress and inflammation, with clear implications for neurodegeneration and AD. Here, we explore recent findings on the role of ER stress and the UPR in inflammatory processes leading to synapse failure and memory impairment in AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29129775 TI - Connecting Alzheimer's disease to diabetes: Underlying mechanisms and potential therapeutic targets. AB - Alzheimer's disease (AD) is a risk factor for type 2 diabetes and vice versa, and a growing body of evidence indicates that these diseases are connected both at epidemiological, clinical and molecular levels. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and type 2 diabetes. Impaired neuronal insulin signaling and endoplasmic reticulum (ER) stress are present in animal models of AD, similar to observations in peripheral tissue in T2D. These findings shed light into novel diabetes-related mechanisms leading to brain dysfunction in AD. Here, we review the literature on selected mechanisms shared between these diseases and discuss how the identification of such mechanisms may lead to novel therapeutic targets in AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29129776 TI - Glucagon-like Peptide-1 (GLP-1) and neurotransmitters signaling in epilepsy: An insight review. AB - Epilepsy is one of the most prevalent neurological disorder affecting more than 50 million people worldwide. Numerous studies have suggested that an imbalance in glutamatergic (excitatory) and GABAergic (inhibitory) neurotransmitter system is one of the dominating pathophysiological mechanisms underlying the occurrence and progression of seizures. Further, this alteration in GABAergic and glutamatergic system disrupts the delicate balance of other neurotransmitters system in the brain. Emerging strides have documented the protective role of GLP-1 signaling on altered neurotransmitters signaling in Epilepsy and associated co-morbidities. GLP-1 is neuropeptide and synthesized by preproglucagon (PPG) neurons in the brain. GLP-1 receptors are widely distributed throughout the brain including hippocampus (CA3 and CA1 region) and implicated in various neurological disorders like Epilepsy. A complete understanding of alteration in neurotransmitters signaling will provide essential insight into the basic pathogenic mechanisms of epilepsy and may uncover novel targets for future drug therapies. Presently, treatment of epilepsy is palliative in nature, providing only symptomatic relief to patients. The apparent or traditional approach of treating epileptic subjects with anti-epileptic drugs is associated with variety of adverse effects. Therefore, alternative approaches that can restore altered neurotransmitter signaling are being tried and adopted. Present review is an attempt to highlight the emerging protective role of GLP-1 signaling on altered neurotransmitters signaling in epilepsy. Authors have made significant efforts to discuss effect of various GLP-1 analogs on various neurotransmitters system and associated molecular and cellular pathways as a potential drug target for the management of epilepsy and associated co-morbidities. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29129778 TI - In vitro effect of clindamycin against Bacteroides and Parabacteroides isolates in Poland. AB - OBJECTIVES: The aims of this study were (i) to analyse strains of the genera Bacteroides and Parabacteroides isolated from clinical specimens for phenotypic resistance to clindamycin, (ii) to detect erm genes in the isolates and (iii) to determine any correlation between in vitro resistance and the presence of erm genes. METHODS: The Bacteroides and Parabacteroides isolates analysed were obtained from patients hospitalised at teaching hospitals in Poland. Antimicrobial susceptibility testing was performed by Etest and the results were interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. All isolates were analysed by PCR for the presence of the resistance genes ermF, ermB and ermG. RESULTS: Resistance to clindamycin was detected in 31.0% (62/200) of all evaluated isolates, with the ermF and ermB genes detected in 31.0% (62/200) and 0.5% (1/200) of isolates, respectively. No isolates with ermG were detected among the evaluated strains. Pearson's test showed an almost perfect correlation between clindamycin minimum inhibitory concentrations (MICs) and the presence of ermF in Bacteroides spp. and Parabacteroides distasonis isolates, although the ermF gene was also present in 10 clindamycin-susceptible isolates of Bacteroides spp. CONCLUSIONS: This study demonstrated a substantial proportion of Bacteroides (22.5-100% depending on the species) and 50.0% of Parabacteroides strains exhibiting resistance to clindamycin. The clindamycin MIC for resistant strains in each case was >=256mg/L. Resistance to clindamycin in Bacteroides and Parabacteroides species is correlated mainly with the presence of the ermF gene. PMID- 29129779 TI - Global, Regional and National Burden of Prostate Cancer, 1990 to 2015: Results from the Global Burden of Disease Study 2015. AB - PURPOSE: Data on the incidence, mortality and burden of prostate cancer as well as changing trends are necessary to provide policy makers with the evidence needed to allocate resources appropriately. This study presents estimates of prostate cancer incidence, mortality and burden from 1990 to 2015 by patient age, country and developmental status using the results of the Global Burden of Disease 2015 study. MATERIALS AND METHODS: Data from vital registration systems and cancer registries were used to generate mortality estimates. Cause specific mortality served as the basis for estimating incidence, prevalence and disability adjusted life years. The global number of incident cases, deaths and disability adjusted life years attributable to prostate cancer are reported as well as age standardized rates. RESULTS: Incident cases of prostate cancer increased 3.7-fold from 1990 to 2015. The age standardized incidence rate also increased 1.7-fold during the study period and in 2015 it reached 56.71/100,000 person-years (95% uncertainty interval 45.86-78.45). Global estimates of the age standardized death rate decreased slightly to 14.24 deaths (95% uncertainty interval 11.8-17.95) per 100,000 person-years in 2015. The decline in the age standardized death rate was more prominent in high income countries. Disability adjusted life years attributable to prostate cancer increased by 90% during the study period. CONCLUSIONS: The prostate cancer mortality rate is decreasing in high income countries. However, the incidence and burden of disease are steadily increasing globally, resulting in further challenges in the allocation of limited health care resources. The current study provides comprehensive knowledge of the local burden of disease and help with appropriate allocation of resources for prostate cancer prevention, screening and treatment. PMID- 29129777 TI - Trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine induces lipid peroxidation-associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first-trimester placental cell line. AB - Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)-l cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast cell line, HTR-8/SVneo. We exposed the cells in vitro to 10-100MUM DCVC for various time points up to 24h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p<0.05). DCVC also significantly stimulated caspase 3, 7, 8 and 9 activities after 12h (p<0.05), suggesting that DCVC stimulates the activation of both the intrinsic and extrinsic apoptotic signaling pathways simultaneously. Pre-treatment with the tBID inhibitor Bl-6C9 partially reduced DCVC-stimulated caspase 3 and 7 activity, signifying crosstalk between the two pathways. Additionally, DCVC treatment increased lipid peroxidation in a concentration-dependent manner. Co-treatment with the antioxidant peroxyl radical scavenger (+/-)-alpha-tocopherol attenuated caspase 3 and 7 activity, suggesting that lipid peroxidation mediates DCVC induced apoptosis in extravillous trophoblasts. Our findings suggest that DCVC induced apoptosis and lipid peroxidation in extravillous trophoblasts could contribute to poor placentation if similar effects occur in vivo in response to TCE exposure, indicating that further studies into this mechanism are warranted. PMID- 29129780 TI - Prior Radiation Therapy Decreases Time to Idiopathic Erosion of Artificial Urinary Sphincter: A Multi-Institutional Analysis. AB - PURPOSE: Substantial controversy and conflicting data exist regarding the survival of the artificial urinary sphincter in patients with prior radiation therapy. We present data from a multi-institutional analysis examining the effect of prior radiation for prostate cancer on device survival. MATERIALS AND METHODS: A database was compiled of patients with artificial urinary sphincter cuff erosion, which included demographic and comorbid patient characteristics, functional analyses and interventions. We identified 80 patients with iatrogenic or idiopathic artificial urinary sphincter erosion. Idiopathic erosion cases were further analyzed to determine factors influencing device survival with specific stratification for radiation therapy. RESULTS: A total of 56 patients were identified with idiopathic artificial urinary sphincter erosion. Of those men 33 (58.9%) had not undergone radiation treatment while 23 (41.1%) had a history of brachytherapy or external beam radiotherapy. In patients without radiation erosion-free median device survival was 3.15 years (95% CI 1.95-5.80), in contrast to the median device survival of only 1.00 year (95% CI 0.36-3.00) in irradiated patients. The erosion-free survival experience of patients with vs without radiation differed significantly (Wilcoxon-Breslow test for equality of survivor functions p = 0.03). CONCLUSIONS: Radiation therapy in patients with known idiopathic cuff erosion in this contemporary analysis correlated with significantly increased time to erosion. Mean time to idiopathic cuff erosion was accelerated by approximately 2 years in irradiated cases. To our knowledge these data represent the first demonstration of substantial outcome differences associated with radiation in patients with an artificial urinary sphincter who present specifically with cuff erosion. PMID- 29129781 TI - Effect of Sperm Morphology on Pregnancy Success via Intrauterine Insemination: A Systematic Review and Meta-Analysis. AB - PURPOSE: Men with abnormal sperm morphology are often counseled that natural conception and intrauterine insemination are ineffective, and in vitro fertilization is the only option. Our objective was to determine the effect of sperm morphology on the pregnancy success of intrauterine insemination. MATERIALS AND METHODS: We systematically searched for studies published prior to January 2017 that 1) reported ultrasound verified clinical pregnancies per intrauterine insemination cycle, 2) assessed sperm morphology using the Kruger strict criteria and 3) described morphology at the greater than 4% and 4% or less and/or the 1% or greater and less than 1% thresholds. In all studies mean female age was between 25 and 40 years and mean total motile sperm count was greater than 10 million. Estimates were pooled using random effects meta-analysis. RESULTS: Data were extracted from 20 observational studies involving a total of 41,018 cycles. When comparing men at the greater than 4% and 4% or less thresholds, the rate of ultrasound verified pregnancy per intrauterine insemination cycle was not statistically or clinically different (14.2% vs 12.1%, p = 0.06) and the risk difference was 3.0% (95% CI 1.4-4.6), indicating 3.0 additional pregnancies per 100 intrauterine insemination cycles. When comparing men at the 1% or greater and the less than 1% thresholds, there were no statistical or clinical differences in the rate of ultrasound verified pregnancy per cycle of intrauterine insemination (14.0% vs 13.9%, p = 0.97) or in the risk difference (1.6%, 95% CI -4.5-7.6). CONCLUSIONS: There appears to be no clinical difference in intrauterine insemination pregnancy success among men with normal and abnormal sperm morphology when accounting for total motile sperm count and female age. Abnormal sperm morphology alone should not exclude couples from attempting intrauterine insemination. PMID- 29129782 TI - Reactive oxygen species production triggers green tea-induced anti-leukaemic effects on acute promyelocytic leukaemia model. AB - Green tea (GT) has been consumed as a beverage for thousands of years because of its therapeutic properties observed over time. Because there is no sufficient evidence supporting the protective role of tea intake during the development of acute myeloid leukaemia, we herein study GT extract effects on an acute promyelocytic leukaemia model. Our results demonstrated that GT reduces leucocytosis and immature cells (blasts) in peripheral blood, bone marrow (BM), and spleen of leukaemic mice, parallel with an increase of mature cells in the BM. In addition, GT induces apoptosis of cells in the BM and spleen, confirmed by activation of caspase-3, -8 and -9; GT reduces the malignant clones CD34+ and CD117+ in the BM and reduces CD117+ and Gr1+ immature myeloid cells in the spleen; GT increases intracellular reactive oxygen species (ROS) in the BM Gr1+ cells while reducing CD34+ and CD117+ cells; GT reduces CXCR4 expression on CD34+ and CD117+ cells, and reduces the nuclear translocation of HIF-1alpha. GT has anti-proliferative effects in leukaemia in vivo by inhibiting malignant clone expansion, probably by modulating the intracellular production of ROS. PMID- 29129783 TI - Hypoxia-induced miR-214 expression promotes tumour cell proliferation and migration by enhancing the Warburg effect in gastric carcinoma cells. AB - miR-214 is an important oncomiRNA and is upregulated in various types of cancer, including gastric cancer. However, the molecular mechanism underlying the ectopic expression and function of miR-214 in gastric cancer is largely undefined. In this study, we found that miR-214 induces the Warburg effect and promotes the migration and proliferation of human gastric cancer cells. According to the mechanistic analysis, miR-214 expression is induced by environmental hypoxia, and miR-214 mediates hypoxia-induced functions. We then explored the molecular mechanism by which miR-214 enhances the Warburg effect in gastric cancer cells and identified the adenosine A2A receptor (A2AR) and PR/SET domain 16 (PRDM16) genes as the direct targets of miR-214. In conclusion, miR-214 inhibits A2AR and PRDM16 expression and enhances the Warburg effect in gastric cancer cells, thus promoting the proliferation and migration of gastric cancer cells. This study highlights an important role for the hypoxia-miR-214-PRDM16/A2AR pathway in the tumourigenesis of gastric cancer and may facilitate the development of new therapeutics against hypoxic tumours. PMID- 29129784 TI - Impact of prosthodontic rehabilitation on the masticatory performance of partially dentate older patients: Can it predict nutritional state? Results from a RCT. AB - OBJECTIVES: With a decreased number of teeth, a reduction in chewing function can contribute to changes in food choices and ultimately impact on overall nutritional status. This study compared the impact of two tooth replacement strategies for partially dentate older patients on masticatory performance and nutritional status. METHODS: Patients aged 65 years and older were randomly allocated to two different treatment groups. For the RPDP-group (removable partial dental prostheses) each participant was restored to complete dental arches with cobalt-chromium removable prostheses. For the SDA-group (shortened dental arch), participants were restored to 10 occluding pairs of natural and replacement teeth using adhesive bridgework. Masticatory performance was assessed with a colour-mixing ability test. Each patient provided haematological samples that were screened for biochemical markers of nutritional status. Patients were also assessed using the Mini Nutritional Assessment (MNA). RESULTS: Eighty-nine patients completed the test for masticatory performance and provided blood samples and MNA scores at baseline (BL) and after 12 months (12m). Masticatory performance (p<0.001) and MNA (p<0.05) increased significantly in both groups, but no significant between group differences were noted. A mixed picture was observed for nutrition biomarkers. Mixed-effect linear regression models did not demonstrate that nutritional status could be predicted from masticatory performance. CONCLUSIONS: These results indicate that prosthodontic rehabilitation according to the principles of the SDA is equivalent to RPDPs in terms of restoration of chewing capacity for partially dentate older patients. However, masticatory performance may only have minor associations with nutritional status for this patient group. CLINICAL SIGNIFICANCE: Replacing teeth with either RPDPs or SDA provides a prerequisite for efficient chewing. Further research is required to determine the impact of oral rehabilitation coupled with nutritional counselling for this patient population. PMID- 29129785 TI - Advances in Hypoxia-Inducible Factor Biology. AB - Hypoxia-inducible factor (HIF), a central regulator for detecting and adapting to cellular oxygen levels, transcriptionally activates genes modulating oxygen homeostasis and metabolic activation. Beyond this, HIF influences many other processes. Hypoxia, in part through HIF-dependent mechanisms, influences epigenetic factors, including DNA methylation and histone acetylation, which modulate hypoxia-responsive gene expression in cells. Hypoxia profoundly affects expression of many noncoding RNAs classes that have clinicopathological implications in cancer. HIF can regulate noncoding RNAs production, while, conversely, noncoding RNAs can modulate HIF expression. There is recent evidence for crosstalk between circadian rhythms and hypoxia-induced signaling, suggesting involvement of molecular clocks in adaptation to fluxes in nutrient and oxygen sensing. HIF induces increased production of cellular vesicles facilitating intercellular communication at a distance-for example, promoting angiogenesis in hypoxic tumors. Understanding the complex networks underlying cellular and genomic regulation in response to hypoxia via HIF may identify novel and specific therapeutic targets. PMID- 29129786 TI - Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes. AB - Caloric restriction rapidly reverses type 2 diabetes (T2D), but the mechanism(s) of this reversal are poorly understood. Here we show that 3 days of a very-low calorie diet (VLCD, one-quarter their typical intake) lowered plasma glucose and insulin concentrations in a rat model of T2D without altering body weight. The lower plasma glucose was associated with a 30% reduction in hepatic glucose production resulting from suppression of both gluconeogenesis from pyruvate carboxylase (VPC), explained by a reduction in hepatic acetyl-CoA content, and net hepatic glycogenolysis. In addition, VLCD resulted in reductions in hepatic triglyceride and diacylglycerol content and PKCE translocation, associated with improved hepatic insulin sensitivity. Taken together, these data show that there are pleotropic mechanisms by which VLCD reverses hyperglycemia in a rat model of T2D, including reduced DAG-PKCE-induced hepatic insulin resistance, reduced hepatic glycogenolysis, and reduced hepatic acetyl-CoA content, PC flux, and gluconeogenesis. PMID- 29129788 TI - A new formulation of poly(MAOTIB) nanoparticles as an efficient contrast agent for in vivo X-ray imaging. AB - : Polymeric nanoparticles (PNPs) are gaining increasing importance as nanocarriers or contrasting material for preclinical diagnosis by micro-CT scanner. Here, we investigated a straightforward approach to produce a biocompatible, radiopaque, and stable polymer-based nanoparticle contrast agent, which was evaluated on mice. To this end, we used a nanoprecipitation dropping technique to obtain PEGylated PNPs from a preformed iodinated homopolymer, poly(MAOTIB), synthesized by radical polymerization of 2 methacryloyloxyethyl(2,3,5-triiodobenzoate) monomer (MAOTIB). The process developed allows an accurate control of the nanoparticle properties (mean size can range from 140 nm to 200 nm, tuned according to the formulation parameters) along with unprecedented important X-ray attenuation properties (concentration of iodine around 59 mg I/mL) compatible with a follow-up in vivo study. Routine characterizations such as FTIR, DSC, GPC, TGA, 1H and 13C NMR, and finally SEM were accomplished to obtain the main properties of the optimal contrast agent. Owing to excellent colloidal stability against physiological conditions evaluated in the presence of fetal bovine serum, the selected PNPs suspension was administered to mice. Monitoring and quantification by micro-CT showed that iodinated PNPs are endowed strong X-ray attenuation capacity toward blood pool and underwent a rapid and passive accumulation in the liver and spleen. STATEMENT OF SIGNIFICANCE: The design of X-ray contrast agents for preclinical imaging is still highly challenging. To date, the best contrast agents reported are based on iodinated lipids or inorganic materials such as gold. In literature, several attempts were undertaken to create polymer-based X-ray contrast agents, but their applicability in vivo was limited to their low contrasting properties. Polymer based contrast agents present the advantages of an easy surface modification for future application in targeting. Herein, we develop a novel approach to design polymer-based nanoparticle X-ray contrast agent (polymerization of a highly iodine-loaded monomer (MAOTIB)), leading to an iodine concentration of 59 mg/mL. We showed their high efficiency in vivo in mice, in terms of providing a strong signal in blood and then accumulating in the liver and spleen. PMID- 29129787 TI - CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. AB - Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD+ dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD+ axis could increase the efficacy of anti-tumor adoptive T cell therapy. PMID- 29129791 TI - Resting State Networks Mediate the Effect of Genotype by Environment Interaction on Mental Health. AB - A number of studies have shown that the presence of short (S) allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with a higher risk for depression following exposure to stressful life events. These findings are in line with neuroimaging studies showing that 5-HTTLPR polymorphism has an effect on the connectivity among key areas involved in emotion regulation. Here using mediated moderation analysis, we show that electrophysiological manifestations of resting state networks in the alpha frequency band mediate the effect of 5-HTTLPR by stress interaction on depression/anxiety symptoms in a nonclinical sample. Specifically, at the brain level, both L-allele homozygotes and S-allele carriers are similarly responsive to stress exposure. However, these brain responses seem to act as triggers of psychopathological symptoms in S allele carriers, but as suppressors in L-allele homozygotes. This finding implies that the interpretation of the effect of gene by environment interaction on psychopathology seems more complicated than behavioral results alone would imply. It is not just differential sensitivity to stress, but rather different ways of coping with stress, which distinguish S-allele carriers and L-allele homozygotes. PMID- 29129789 TI - Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy. AB - : In the present study, a dual pH-responsive multifunctional nanoparticle system was designed for combining immunotherapy and chemotherapy to treat breast cancer through targeting immune cells and cancer cells. A proven anti-tumor immune regulator, R848, was encapsulated with poly(L-histidine) (PHIS) to form PHIS/R848 nanocores. Doxorubicin (DOX) was conjugated to hyaluronic acid (HA) through an acid-cleavable hydrazone bond linkage to synthesize polymeric prodrug HA-DOX, which was subsequently coated outside PHIS/R848 nanocores to form HA DOX/PHIS/R848 nanoparticles. Ionization of PHIS around pH 6.5 (a pH value close to that of tumor microenvironment) switched the nature of this material from hydrophobic to hydrophilic, and thus triggered the release of R848 to exert immunoregulatory action. The rupture of hydrazone bond in HA-DOX at about pH 5.5 (pH of endo/lysosomes) accelerated the release of DOX to exert cytotoxic effects. In immune cells, PHIS/R848 nanocores exhibited strong immunoregulatory activities similar to those induced by free R848. In breast cancer cells overexpressing CD44, HA-DOX was specially internalized by CD44-mediated endocytosis and significantly inhibited the cell growth. In 4T1 tumor-bearing mice, HA DOX/PHIS/R848 nanoparticles showed excellent tumor-targeting ability and remarkably inhibited the tumor growth by regulating tumor immunity and killing tumor cells. In summary, this multifunctional nanoparticle system could deliver R848 and DOX respectively to tumor microenvironment and breast cancer cells to achieve synergistic effects of immunotherapy and chemotherapy against breast cancer. STATEMENT OF SIGNIFICANCE: Combination of immunotherapy and chemotherapy is becoming a promising new treatment for cancer. The major challenge is to target cancer and immune cells simultaneously and specifically. In this study, a dual pH-responsive multifunctional nanoparticle system based on poly(L-histidine) and hyaluronic acid was designed for co-loading R848 (immune-regulator) and doxorubicin (chemotherapeutic drug) through different encapsulation modes. By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer. PMID- 29129792 TI - The Hypoxia Mimetic Protocatechuic Acid Ethyl Ester Inhibits Synaptic Signaling and Plasticity in the Rat Hippocampus. AB - During hypoxia a number of physiological changes occur within neurons including the stabilization of hypoxia-inducible factors (HIFs). The activity of these proteins is regulated by O2, Fe2+, 2-OG and ascorbate-dependant hydroxylases which contain prolyl-4-hydroxylase domains (PHDs). PHD inhibitors have been widely used and have been shown to have a preconditioning and protective effect against a later and more severe hypoxic insult. In this study we have investigated the neuroprotective effects of the PHD inhibitor, protocatechuic acid ethyl ester (ethyl 3,4, dihydroxybenzoate: EDHB), as well as its effects on synaptic transmission and plasticity in the rat hippocampus using electrophysiological techniques. We report for the first time, an acute concentration-dependent and reversible inhibitory effect of EDHB (10-100 MUM) on synaptic transmission in the dentate gyrus but not Cornu Ammonis 1 (CA1) region which does not affect cell viability. This effect was attenuated through the application of the NMDA or GABAA receptor antagonists, AP-5 and picrotoxin in the dentate gyrus. There were no changes in the ratio of paired responses after EDHB application suggesting a post-synaptic mechanism of action. EDHB (100 MUM), was found to inhibit synaptic plasticity in both the dentate gyrus and CA1 regions. Application of exogenous Fe2+ (100 MUM) or digoxin (100 nM) did not reverse EDHB's inhibitory effect on synaptic transmission or plasticity in both regions, suggesting that its effects may be HIF-independent. These results highlight a novel modulatory role for the PHD inhibitor EDHB in hippocampal synaptic transmission and plasticity. A novel post-synaptic mechanism of action may be involved, possibly involving NMDA and GABAA receptor activation. PMID- 29129790 TI - In vitro osteogenesis by intracellular uptake of strontium containing bioactive glass nanoparticles. AB - : Monodispersed strontium containing bioactive glass nanoparticles (Sr-BGNPs) with two compositions were synthesised, through a modified sol-gel Stober process, wherein silica nanoparticles (SiO2-NPs) were formed prior to incorporation of calcium and strontium, with diameters of 90 +/- 10 nm. The osteogenic response of a murine preosteoblast cell line, MC3T3-E1, was investigated in vitro for a nanoparticle concentration of 250 ug/mL with compositions of 87 mol% SiO2, 7 mol% CaO, 6 mol% SrO and 83 mol% SiO2, 3 mol% CaO, 14 mol% SrO. Dissolution studies in minimum essential media (alpha-MEM) at pH 7.4 and artificial lysosomal fluid (ALF) at pH 4.5 showed that the particles dissolved and that Sr2+ ions were released from Sr-BGNPs in both environments. Both particle compositions and their ionic dissolution products enhanced the alkaline phosphatase (ALP) activity of the cells and calcium deposition. Immunohistochemistry (IHC) staining of Col1a1, osteocalcin (OSC) and osteopontin (OSP) showed that these proteins were expressed in the MC3T3-E1 cells following three weeks of culture. In the basal condition, the late osteogenic differentiation markers, OSC and OSP, were more overtly expressed by cells cultured with Sr-BGNPs with 14 mol% SrO and their ionic release products than in the control condition. Col1a1 expression was only slightly enhanced in the basal condition, but was enhanced further by the osteogenic supplements. These data demonstrate that Sr-BGNPs accelerate mineralisation without osteogenic supplements. Sr-BGNPs were internalised into MC3T3-E1 cells by endocytosis and stimulated osteogenic differentiation of the pre-osteoblast cell line. Sr-BGNPs are likely to be beneficial for bone regeneration and the observed osteogenic effects of these particles can be attributed to their ionic release products. STATEMENT OF SIGNIFICANCE: We report, for the first time, that monodispersed bioactive glass nanoparticles (~90 nm) are internalised into preosteoblast cells by endocytosis but by unspecific mechanisms. The bioactive nanoparticles and their dissolution products (without the particles present) stimulated the expression of osteogenic markers from preosteoblast cells without the addition of other osteogenic supplements. Incorporating Sr into the bioactive glass nanoparticle composition, in addition to Ca, increased the total cation content (and therefore dissolution rate) of the nanoparticles, even though nominal total cation addition was constant, without changing size or morphology. Increasing Sr content in the nanoparticles and in their dissolution products enhanced osteogenesis in vitro. The particles therefore have great potential as an injectable therapeutic for bone regeneration, particularly in patients with osteoporosis, for which Sr is known to be therapeutic agent. PMID- 29129794 TI - Is Hand Selection Modulated by Cognitive-perceptual Load? AB - Previous studies proposed that selecting which hand to use for a reaching task appears to be modulated by a factor described as "task difficulty". However, what features of a task might contribute to greater or lesser "difficulty" in the context of hand selection decisions has yet to be determined. There has been evidence that biomechanical and kinematic factors such as movement smoothness and work can predict patterns of selection across the workspace, suggesting a role of predictive cost analysis in hand-selection. We hypothesize that this type of prediction for hand-selection should recruit substantial cognitive resources and thus should be influenced by cognitive-perceptual loading. We test this hypothesis by assessing the role of cognitive-perceptual loading on hand selection decisions, using a visual search task that presents different levels of difficulty (cognitive-perceptual load), as established in previous studies on overall response time and efficiency of visual search. Although the data are necessarily preliminary due to small sample size, our data suggested an influence of cognitive-perceptual load on hand selection, such that the dominant hand was selected more frequently as cognitive load increased. Interestingly, cognitive perceptual loading also increased cross-midline reaches with both hands. Because crossing midline is more costly in terms of kinematic and kinetic factors, our findings suggest that cognitive processes are normally engaged to avoid costly actions, and that the choice not-to-cross midline requires cognitive resources. PMID- 29129793 TI - The Interval Between VNS-Tone Pairings Determines the Extent of Cortical Map Plasticity. AB - Repeatedly pairing vagus nerve stimulation (VNS) with a tone or movement drives highly specific and long-lasting plasticity in auditory or motor cortex, respectively. Based on this robust enhancement of plasticity, VNS paired with rehabilitative training has emerged as a potential therapy to improve recovery, even when delivered long after the neurological insult. Development of VNS delivery paradigms that reduce therapy duration and maximize efficacy would facilitate clinical translation. The goal of the current study was to determine whether primary auditory cortex (A1) plasticity can be generated more quickly by shortening the interval between VNS-tone pairing events or by delivering fewer VNS-tone pairing events. While shortening the inter-stimulus interval between VNS tone pairing events resulted in significant A1 plasticity, reducing the number of VNS-tone pairing events failed to alter A1 responses. Additionally, shortening the inter-stimulus interval between VNS-tone pairing events failed to normalize neural and behavioral responses following acoustic trauma. Extending the interval between VNS-tone pairing events yielded comparable A1 frequency map plasticity to the standard protocol, but did so without increasing neural excitability. These results indicate that the duration of the VNS-event pairing session is an important parameter that can be adjusted to optimize neural plasticity for different clinical needs. PMID- 29129795 TI - Orexin-A/hypocretin-1 Immunoreactivity in the Lateral Hypothalamus is Reduced in Genetically Obese but not in Diet-induced Obese Mice. AB - The mechanisms that link diet and body weight are not fully understood. A diet high in fat often leads to obesity, and this in part is the consequence of diet induced injury to specific hypothalamic nuclei. It has been suggested that a diet high in fat leads to cell loss in the lateral hypothalamus, which contains specific populations of neurons that are essential for regulating energy homoeostasis; however, we do not know which cell types are affected by the diet. We studied the possibility that high-fat diet leads to a reduction in orexin A/hypocretin-1 (Hcrt1) and/or melanin-concentrating hormone (MCH) immunoreactivity in the lateral hypothalamus. We quantified immuno-labeled Hcrt1 and MCH cells in brain sections of mice fed a diet high in fat for up to 12 weeks starting at 4 weeks of age and found that this diet did not modify the number of Hcrt1- or MCH-immunoreactive neurons. By contrast, there were fewer Hcrt1- (but not MCH-) immunoreactive cells in genetically obese db/db mice compared to wild type mice. Non-obese, heterozygous db/+ mice also had fewer Hcrt1-immunoreactive cells. Differences in the number of Hcrt1-immunoreactive cells were only a function of the db genotype but not of diet or body weight. Our findings show that the lateral hypothalamus is affected differently in the db genotype and in diet-induced obesity, and support the idea that not all hypothalamic neurons involved in energy balance regulation are sensitive to the effects of diet. PMID- 29129796 TI - Comprehensive profiling of prostaglandins in human ovarian follicular fluid using mass spectrometry. AB - Prostaglandins are formed by enzymatic and non-enzymatic mechanisms. They have been detected in human ovarian follicular fluid (HFF), a medium rich in growth factors and nutrients important for oocyte growth and fertility. However, the comprehensive identification of HFF prostaglandins has not been addressed. Here we use hybrid triple quadrupole time-of-flight and triple quadrupole mass spectrometers to comprehensively analyze prostaglandins in HFF. We identified PGE1, PGE2, PGF2alpha, and other prostaglandins synthesized via prostaglandin endoperoxide synthase (i.e. Cox) cascades. We also identified specific PGF2alpha isomers (F2-isoprostanes) and PGF3alpha analogs whose structures are inconsistent with Cox-dependent formation. A prospective cohort pilot study of infertility patient subtypes revealed two potential associations. F2-isoprostanes are decreased in the diminished ovarian reserve subtype and elevated PGF2alpha may be associated with decreased live birth. Other than PGF2alpha, only body mass index >25kg/m2 correlated with poor in vitro fertilization outcome. Our studies suggest that HFF contains prostaglandins formed from at least two mechanisms, which may correlate with distinct clinical parameters. PMID- 29129797 TI - Microglia and alcohol meet at the crossroads: Microglia as critical modulators of alcohol neurotoxicity. AB - Alcohol use disorders affect millions of people worldwide causing huge social and economic burden on modern society. Excessive alcohol consumption or intoxication provokes severe damage to the body inducing immune suppression, liver damage and neurological disorder. In the central nervous system (CNS), alcohol exposure can lead to neuronal loss, cognitive decline, motor dysfunction, inflammation and impairment of neuroimmune responses. Glial cells, from which microglia represent roughly 10-15%, are primary modulators of the neuroimmune responses and inflammation in the CNS. Here we overview literature relating alcohol exposure with microglia activation and brain inflammation, highlighting that microglia are critical regulators of alcohol responses in the CNS. Different studies indicate that alcohol intake alters the microglial activation spectrum, with the microglial response varying according to the dose, duration, and pattern of alcohol administration. Presently, further investigation is required to establish whether microglia dysfunction initiates or simply amplifies the neurotoxicity of alcohol in the brain. Such knowledge can be greatly facilitated by the use of microglia-specific genetic targeting in animal models and will be critical for the development of better therapeutics for mitigating the neurotoxicity induced by alcohol. PMID- 29129798 TI - The efficacy of HI-6 DMS in a sustained infusion against percutaneous VX poisoning in the guinea-pig. AB - Post-exposure nerve agent treatment usually includes administration of an oxime, which acts to restore function of the enzyme acetylcholinesterase (AChE). For immediate treatment of military personnel, this is usually administered with an autoinjector device, or devices containing the oxime such as pralidoxime, atropine and diazepam. In addition to the autoinjector, it is likely that personnel exposed to nerve agents, particularly by the percutaneous route, will require further treatment at medical facilities. As such, there is a need to understand the relationship between dose rate, plasma concentration, reactivation of AChE activity and efficacy, to provide supporting evidence for oxime infusions in nerve agent poisoning. Here, it has been demonstrated that intravenous infusion of HI-6, in combination with atropine, is efficacious against a percutaneous VX challenge in the conscious male Dunkin-Hartley guinea-pig. Inclusion of HI-6, in addition to atropine in the treatment, improved survival when compared to atropine alone. Additionally, erythrocyte AChE activity following poisoning was found to be dose dependent, with an increased dose rate of HI-6 (0.48mg/kg/min) resulting in increased AChE activity. As far as we are aware, this is the first study to correlate the pharmacokinetic profile of HI-6 with both its pharmacodynamic action of reactivating nerve agent inhibited AChE and with its efficacy against a persistent nerve agent exposure challenge in the same conscious animal. PMID- 29129799 TI - Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques. AB - Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.g. pralidoxime, to reactivate the OP-inhibited AChE. However, commonly used oximes inefficiently cross the bloodbrain barrier and are rapidly cleared and their benefit is debated. Recent findings have demonstrated the ability of a novel zwitterionic, centrally acting, brain penetrating oxime (RS194B) to reverse severe symptoms and rapidly reactivate sarin-inhibited AChE in macaques, but it has not been tested following OP pesticide poisoning. In the present study, the symptoms following a lethal dose of inhaled paraoxon (100ug/kg), were shown to mimic those in insecticide poisoned individuals and were also rapidly reversed in macaques by post-exposure IM administration of 80mg/kg of RS194B. This occurred with a concomitant reactivation of AChE to 40 100% in<1hr and BChE (40% in 8h). These findings will be used to develop a macaque model with RS194B as a post-exposure treatment for insecticide poisoning and generate efficacy data for approval under the FDA Animal rule. PMID- 29129800 TI - Saikosaponin-d-mediated downregulation of neurogenesis results in cognitive dysfunction by inhibiting Akt/Foxg-1 pathway in mice. AB - Saikosaponin-d (SSd), one of the main constituents of the total saikosaponins extracted from Bupleurum falcatum L, possesses anti-inflammatory and anti apoptosis effect. Recently, SSd was proved to improve depressive symptoms although exhibit hepatotoxicity in animals, but the central nervous system (CNS) toxicity of SSd remains unclear. The present study investigated the SSd-induced impairment in hippocampal cognitive function and explored the possible mechanisms involved. After intragastric administration of SSd (4mg/kg, 8mg/kg) for 7days, the learning and memory abilities of mice were evaluated by behavioral experiments. In the step-down passive avoidance test, we found that the mice treated with SSd showed a significant decrease of step-down latency and increase of the frequency of errors. In the Morris water maze task, both the escape latency and swimming distance of the mice treated with SSd were increased, correspondingly, both the time of mice staying in the target zone and the frequency of crossing platform were decreased. These neurobehavioral changes were accompanied by the reduction of the expression of 5-bromo-2'-deoxyuridine (BrdU), nestin, doublecortin (Dcx) and microtubule associated protein 2 (MAP2). Moreover, SSd significantly inhibited the expression of p-Akt, Foxg-1 and fibroblast growth factor 2 (FGF2) in the hippocampus of mice. These results indicated that SSd had a toxic effect on cognitive function in mice, which was associated with inhibiting the hippocampal neurogenesis via Akt/Foxg1 pathway. PMID- 29129801 TI - Activating prostaglandin E2 receptor subtype EP4 increases secreted mucin from airway goblet cells. AB - Prostaglandin E2 (PGE2) is a ligand of the E-type prostanoid receptors, EP1-4. PGE2 secretion is increased in the airways of patients with asthma by secretory phospholipases A2, which also increases MUC5AC mucin in goblet cells. We hypothesized that PGE2 would also increase MUC5AC mRNA and secreted protein through specific EP receptor activation. We sought to assess the effect of specific EP receptor activation on MUC5AC secretion from ciliated-enriched cells or goblet-enriched cells induced by IL-13. We develop an enriched goblet cell epithelium by growing normal human bronchial epithelial cells at air liquid interface for 14 days in the presence of IL-13. We examined exposure to 4 specific EP receptor agonists at 24 h and 14 days in cells grown with or without IL-13 exposure, and measured MUC5AC mRNA and secreted protein, as well as airway culture morphology, and EP receptor expression. In ciliated-enriched cells grown in the absence of IL-13, the EP4 receptor agonist modestly increased both MUC5AC mRNA and secretion (p < 0.001, 241% increase of transcripts and p < 0.01, 86% increase of secreted protein) but did not visibly change cell morphology. In goblet-enriched cells grown in the presence of IL-13, the EP4 receptor agonist greatly increased both MUC5AC mRNA and protein (p < 0.001, 315% increase of transcripts and 92% increase of secreted protein). Specific activation of the other EP receptor had no effect on secreted mucin. EP4 receptor mRNA and protein were significantly increased in goblet-enriched cells, while the other receptor mRNA were decreased. We conclude that PGE2 stimulates airway mucin production predominantly by EP4 receptor activation in association with increased EP4 receptor expression. This may contribute to mucus hypersecretion as seen in severe asthma. PMID- 29129802 TI - Treatment of Paget-Schroetter syndrome with a three-stage approach including thoracoscopic rib resection at the second stage. AB - OBJECTIVE: Young, active persons may suffer lifelong consequences of subclavian vein thrombosis, but the best treatment options remain unclear. On introduction of more active pharmacomechanical thrombus removal and thoracoscopic rib resection in our institution, we planned a diagnostic and treatment protocol and aimed to analyze the early, midterm, and intermediate-term results. METHODS: The study included 72 patients who were diagnosed with an upper limb deep venous thrombosis and underwent phlebography between 2006 and 2013. After the initial treatment, control phlebography was performed and a thoracoscopic first rib resection was considered. Postoperative balloon angioplasty was performed when appropriate, and 1-year follow-up phlebography was carried out. RESULTS: After the initial thrombus removal, 60 patients were treated with thoracoscopic first rib resection and subsequent phlebography with or without balloon angioplasty. The median time from symptom to surgery was 124 days, and six (10%) patients had a reocclusion before surgery. Ten (16.7%) patients experienced complications, which were treated mainly with a chest tube (n = 3) or thoracoscopic re exploration (n = 4). Three months after surgery, 98.3% (59/60) experienced an overall relief of symptoms. No recurrence of clinical thrombosis or residual compression due to incomplete rib resection was seen, and 96.6% (56/58) of the patients reported an overall improvement of symptoms at 13 months. Two patients (3.4%) were treated for chronic pain and had electroneuromyography-verified nerve plexus damage. In both cases, the pain was relieved in the long run. CONCLUSIONS: A combination of early thrombus removal, thoracoscopic first rib resection, and postoperative venous balloon angioplasty seems to yield acceptable intermediate term results after Paget-Schroetter thrombosis. PMID- 29129803 TI - Symptomatic, unilateral, isolated, complete persistent sciatic vein. AB - Persistent sciatic vein is a rare anomaly of mesodermal development. When found, it is often associated with varicosities in abnormal distributions, pain, limb congestion, and hypertrophy. In this report, we describe a case of an isolated, complete persistent sciatic vein with an atypical anatomy and onset. PMID- 29129804 TI - Recent advances in galactose-engineered nanocarriers for the site-specific delivery of siRNA and anticancer drugs. AB - Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand-receptor mediated delivery of drug carriers. PMID- 29129805 TI - Rare genetic diseases: update on diagnosis, treatment and online resources. AB - Rare genetic diseases collectively impact a significant portion of the world's population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computer-aided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how the collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases. PMID- 29129806 TI - Treatment of chronic spontaneous urticaria: Immunomodulatory approaches. AB - This paper summarizes and reviews the mechanisms of action and data concerning efficacy of recommended treatments as well as other treatments that have been tested, independently of the outcomes, in the management of chronic spontaneous urticaria. Due to the central role of mast cells, basophils and histamine in the pathophysiology of this disease, H1-antihistamines remain the first-line treatment. However, current knowledge about this complex disease, also recognizes an important role for T lymphocytes, B lymphocytes, and autoantibodies. Implications of these others mediators thus provide further targets for treatment. Indeed, agents previously used to treat other autoimmune and inflammatory diseases, have demonstrated efficacy in chronic spontaneous urticaria and are therefore potential therapeutic alternatives for antihistamine unresponsive patients. PMID- 29129807 TI - The long noncoding RNA expression profiles of paroxysmal atrial fibrillation identified by microarray analysis. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) represent a novel class of noncoding RNAs that are involved in a variety of biological processes and human diseases. Recent evidence suggested that lncRNAs were associated with cardiac disorders. However, the roles of lncRNAs in paroxysmal atrial fibrillation (PAF) remain elusive. The purpose of the present study was to identify differentially expressed lncRNAs in PAF and predict their potential functions. METHODS: Between May 2014 and December 2015, a total of 67 patients, including 34 patients with PAF and 33 patients without PAF were recruited in this study. Of these participants, 3 PAF patients and 3 controls were used for the microarray analysis and a separate cohort (31 PAF patients and 30 controls) were used for further validation. LncRNA profiles in the leukocytes were detected by microarray. RESULTS: A total of 2095 and 1584 differentially expressed lncRNAs and mRNAs, respectively, were identified between the PAF patients and controls. Four lncRNAs (uc002nvy.3, ENST00000561094, uc004aef.3, ENST00000559960) were randomly selected for quantitative real-time PCR (qRT-PCR) in a separate cohort, validating that ENST00000559960 was upregulated and uc004aef.3 was downregulated in the PAF patients. uc002nvy.3 and ENST00000561094 showed no significant difference between PAF and the controls. Multiple logistic analyses showed that ENST00000559960 (OR 1.47; 95% CI 1.09 to 2.00; P=0.01) and uc004aef.3 (OR 0.63; 95% CI 0.41 to 0.96; P=0.03) were independently associated with PAF. Receiver operating characteristic (ROC) curves analyses revealed that ENST00000559960 and uc004aef.3 were modest predictors of PAF. The area under the curve (AUC) was 0.67+/-0.07 (95% CI 0.54 0.81; P=0.02) for uc004aef.3 and 0.70+/-0.07 (95% CI 0.56-0.83; P<0.01) for ENST00000559960. Bioinformatic analyses (lncRNAs classification and subgroup, gene ontology analysis, pathway analysis and gene co-expression network construction) were performed for predicting the role of lncRNAs. CONCLUSIONS: Our results demonstrated that lncRNA profiles were differentially expressed in the PAF leukocytes, and two lncRNAs (ENST00000559960 and uc004aef.3) may help in prediction of PAF. This motivates further investigation of the role of lncRNAs for PAF. PMID- 29129808 TI - Overexpression of FOXA1 inhibits cell proliferation and EMT of human gastric cancer AGS cells. AB - The lack of effective medical treatment for advanced stages of gastric cancer mainly contributes to the high mortality rate. The association of forkhead box protein A1 (FOXA1) with tumor progression has been reported in different human cancers. However, the function of FOXA1 in gastric cancer is largely unknown. In the present study, FOXA1 protein showed a significant reduction in gastric cancer samples comparing with matched control samples. In addition, the higher expression of FOXA1 in transcription level was observed in gastric cancer cell lines as compared with that in normal gastric cell line, while the contrary result was observed in protein level. Then we studied the effects of FOXA1 on gastric cancer cells in vitro and in vivo based on FOXA1-overexpression AGS cells. We found that up-regulation of FOXA1 was notably inhibited the cell proliferation and tumor formation, and induced cell apoptosis. Moreover, overexpression of FOXA1 was able to increase the E-cadherin protein level and decreased the Vimentin protein level, which implicates that FOXA1 probably plays as an inhibitor of epithelial mesenchymal transition. In conclusion, these data suggests that FOXA1 may function as a novel anti-oncogene in gastric cancer cells. PMID- 29129809 TI - Characterization and spatiotemporal expression analysis of nine bone morphogenetic protein family genes during intermuscular bone development in blunt snout bream. AB - Intermuscular bones (IBs) only exist in the myosepta of lower teleosts and its molecular mechanism remains to be clarified. Bone morphogenetic proteins (BMPs) have been demonstrated to be involved in various physiological processes, including bone and cartilage formation. In this study, we firstly obtained and characterized nine bmp genes for Megalobrama amblycephala, which belongs to Cyprinidae and have a certain amount of IBs. Sequence alignment and phylogenetic analysis both documented that the mature proteins of M. amblycephala bmp genes were highly conserved with other corresponding homologs, respectively, indicating that the function of each bmp gene has been conserved throughout evolution. As a step to characterize potential involvement of bmp genes in IB formation and development, spatiotemporal expressions of nine bmp genes (bmp2a, bmp2b, bmp3, bmp4, bmp5, bmp7b, bmp8a, bmp14 and bmp16) were investigated during the key development stages of IBs. During the ossification process from stage I (the IBs haven't emerged) to stage IV (all of the IBs ossified in the tail with the mature morphology), the expression profiles revealed that bmp16 was the most abundant transcript while bmp4 had the lowest abundance. The mRNA levels of bmp3, bmp4, bmp5 and bmp8a increased significantly at stage II, suggesting their roles in stimulating IB formation. The expression of bmp7b reached the highest level at stage III (the rapid period of IB development), suggesting potential involvement of bmp7b in promoting osteoblast differentiation. With the exception of bmp7b and bmp16, most bmp genes appeared a significant increase at IB maturation phase (stage IV), which means that they may play important roles in maintenance of IB morphogenesis. Spatial tissue distribution of bmp genes showed that most bmp genes were observed at the highest level in developing IBs at one year old fish. Spatiotemporal expression patterns suggest the potential key roles of these bmp genes in IBs formation and maintenance in fish, being as possible promoters or inhibitors. PMID- 29129810 TI - Discerning molecular interactions: A comprehensive review on biomolecular interaction databases and network analysis tools. AB - Computational analysis of biomolecular interaction networks is now gaining a lot of importance to understand the functions of novel genes/proteins. Gene interaction (GI) network analysis and protein-protein interaction (PPI) network analysis play a major role in predicting the functionality of interacting genes or proteins and gives an insight into the functional relationships and evolutionary conservation of interactions among the genes. An interaction network is a graphical representation of gene/protein interactome, where each gene/protein is a node, and interaction between gene/protein is an edge. In this review, we discuss the popular open source databases that serve as data repositories to search and collect protein/gene interaction data, and also tools available for the generation of interaction network, visualization and network analysis. Also, various network analysis approaches like topological approach and clustering approach to study the network properties and functional enrichment server which illustrates the functions and pathway of the genes and proteins has been discussed. Hence the distinctive attribute mentioned in this review is not only to provide an overview of tools and web servers for gene and protein-protein interaction (PPI) network analysis but also to extract useful and meaningful information from the interaction networks. PMID- 29129811 TI - Transcriptome - Scale characterization of salt responsive bean TCP transcription factors. AB - TEOSINTE-BRANCHED1/CYCLOIDEA/PCF (TCP) proteins are important regulators of growth and developmental processes including branching, floral organ morphogenesis and leaf growth as well as stress response. This study identified 27 TCP genes of Phaseolus vulgaris (common bean), which were divided into three clusters based on phylogenetic relationship. In addition, this study showed that some of TCP genes such as Pvul-TCP-4 and Pvul-TCP-15 located on chromosomes 3 and 7, Pvul-TCP-7 and Pvul-TCP-20 located on chromosome 7 and 9, were segmentally duplicated. On the other hand, a total of 20 Pvul-TCP genes have predicted to be targeted by microRNAs (miRNA). Most of the miRNA-target genes were Pvul-TCP-1, 11, -13 and -27, which were targeted by 13, 17, 22 and 13 plant miRNAs, respectively. miR319 was one of the highly represented regulatory miRNAs to target TCP transcripts. Promoter region analysis of TCP genes resulted that the GT-1 motif, which was related to salt stress, was found in 14 different Pvul-TCP genes. Expression profiling of 10 Pvul-TCP genes based on RNA-sequencing data further confirmed with quantitative real-time RT-PCR measurements identified that Pvul-TCP genes under salt stress are expressed in a cultivar- and tissue-specific manner. PMID- 29129812 TI - Influence of LGALS3 gene polymorphisms on susceptibility and prognosis of dilated cardiomyopathy in a Northern Han Chinese population. AB - BACKGROUND: Galectin-3 plays an important role in modulating cardiac inflammation and fibrosis. It also takes part in the pathways underlying cardiac remodeling. Therefore, LGALS3 gene, encoding galectin-3 protein, is a promising candidate for the genetic study of dilated cardiomyopathy (DCM). To date, there has been no research evaluating the association between LGALS3 gene polymorphisms and the susceptibility and prognosis of DCM. METHODS AND RESULTS: Genotyping of 4 single nucleotide polymorphisms (SNPs) in the LGALS3 gene, which were reported to be functional in the literature, was performed in 279 unrelated clinically diagnosed DCM patients and 363 apparently healthy controls from Northern Han Chinese population using iPLEX SNP Genotyping analysis on a Sequenom MassARRAY System. The frequency of G allelic polymorphism of rs1009977 and the C allelic polymorphism of rs4652 were lower in DCM patients (OR=0.77, 95% CI [0.60-0.99], P=0.045; OR=0.79, 95% CI [0.63-0.99], P=0.042, respectively). The minor variants of rs1009977 and rs4652 were associated with low susceptibility of DCM under additive genetic models (P=0.045 and P=0.040, respectively). The AA genotype of both rs2274273 and rs4644 was associated with lower left ventricular ejection fraction (recessive model, P=0.018 for both; additive model, P=0.039 for both). The G variant of rs1009977 was related with lower serum galectin-3 level in DCM patients under three genetic models (additive model, P=0.020, dominant model, P=0.020, recessive model, P=0.037). The A variant of both rs2274273 and rs4644 was associated with lower level of galectin-3 in DCM patients under additive model (P=0.032 for both) and dominant model (P=0.012 for both). None of the 4 SNPs was associated with the cardiovascular or all-cause death rate of DCM. In Conclusion, LGALS3 gene polymorphisms might be associated with the susceptibility of DCM in a Northern Han Chinese population. PMID- 29129813 TI - A novel duplication downstream of BMP2 in a Chinese family with Brachydactyly type A2 (BDA2). AB - BACKGROUND: Brachydactyly type A2 (BDA2) is an autosomal dominant disease characterized by the deformation of the middle phalanx of the second fingers and toes. It has been reported to be associated with three genes regulating the osteogenesis, including BMPR1B, GDF5 and BMP2. MATERIALS AND METHODS: 10 BDA2 patients and 7 unaffected individuals in a Chinese family were identified through clinical signs and radiographs. The mutation analyses of BMPR1B, GDF5 and BMP2 gene was performed in all the available family members and 100 control subjects. The duplication analysis for the downstream of BMP2 was also performed in all the samples. RESULTS: A novel 4671bp duplication downstream the BMP2 gene was identified in all the patients undergoing molecular analysis but not in the unaffected individuals and healthy controls, with a 28bp microhomology flanking it. There was no mutation in all the exons of BMPR1B, GDF5 and BMP2 in all the tested family members. CONCLUSION: The novel duplication has different breakpoints compared with the previous ones but highly overlapped with them. The duplication narrows the range of the potential cis-regulatory sequence, and further supports the association between BDA2 and the duplication downstream BMP2. PMID- 29129814 TI - Zinc deficiency promotes cystitis-related bladder pain by enhancing function and expression of Cav3.2 in mice. AB - Cav3.2 T-type Ca2+ channel activity is suppressed by zinc that binds to the extracellular histidine-191 of Cav3.2, and enhanced by H2S that interacts with zinc. Cav3.2 in nociceptors is upregulated in an activity-dependent manner. The enhanced Cav3.2 activity by H2S formed by the upregulated cystathionine-gamma lyase (CSE) is involved in the cyclophosphamide (CPA)-induced cystitis-related bladder pain in mice. We thus asked if zinc deficiency affects the cystitis related bladder pain in mice by altering Cav3.2 function and/or expression. Dietary zinc deficiency for 2 weeks greatly decreased zinc concentrations in the plasma but not bladder tissue, and enhanced the bladder pain/referred hyperalgesia (BP/RH) following CPA at 200mg/kg, a subeffective dose, but not 400mg/kg, a maximal dose, an effect abolished by pharmacological blockade or gene silencing of Cav3.2. Acute zinc deficiency caused by systemic N,N,N',N'-tetrakis (2-pyridylmethyl)-ethylendiamine (TPEN), a zinc chelator, mimicked the dietary zinc deficiency-induced Cav3.2-dependent promotion of BP/RH following CPA at 200mg/kg. CPA at 400mg/kg alone or TPEN plus CPA at 200mg/kg caused Cav3.2 overexpression accompanied by upregulation of Egr-1 and USP5, known to promote transcriptional expression and reduce proteasomal degradation of Cav3.2, respectively, in the dorsal root ganglia (DRG). The CSE inhibitor, beta-cyano-l alanine, prevented the BP/RH and upregulation of Cav3.2, Egr-1 and USP5 in DRG following TPEN plus CPA at 200mg/kg. Together, zinc deficiency promotes bladder pain accompanying CPA-induced cystitis by enhancing function and expression of Cav3.2 in nociceptors, suggesting a novel therapeutic avenue for treatment of bladder pain, such as zinc supplementation. PMID- 29129815 TI - Biological effects of adipocytes in sulfur mustard induced toxicity. AB - Sulphur mustard (2,2'-dichloroethyl sulfide; SM) is a vesicant chemical warfare agent whose mechanism of acute or chronic action is not known with any certainty and to date there is no effective antidote. SM accumulation in adipose tissue (AT) has been originally verified in our previous study. To evaluate the biological effect caused by the presence of abundant SM in adipocyte and assess the biological role of AT in SM poisoning, in vitro and in vivo experiments were performed. High content analysis revealed multi-cytotoxicity in SM exposed cells in a time and dose dependent manner, and adipocytes showed a relative moderate damage compared with non-adipocytes. Cell co-culture model was established and revealed the adverse effect of SM-exposed adipocyte supernatant on the growth of co-cultured cells. The pathological changes in AT from 10mg/kg SM percutaneously exposed rats were checked and inflammation phenomena were observed. The mRNA and protein levels of inflammation-related adipokines secreted from AT in rats exposed to 1, 3 and 10mg/kg doses of SM were determined by reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assays. The expressions of proinflammatory and anti-inflammatory adipokines together promoted the inflammation development in the body. The positive correlations between AT and serum adipokine levels were explored, which demonstrated a substantial role of AT in systemic inflammation responding to SM exposure. Thus, AT is not only a target of SM but also a modulator in the SM toxicity. PMID- 29129816 TI - Fever and rash in a traveler returning to Europe from Colombia - Don't just think arboviral. PMID- 29129817 TI - Outbreaks caused by Aedes aegyptis due to El Nino in a coastal area of Peru. PMID- 29129818 TI - Inter- and intra-subject variability of nitric oxide levels in leukocyte subpopulations. AB - Assessment of nitric oxide (NO) dynamics in immune cells, commonly measured using NO surrogates such as inducible nitric oxide synthase (iNOS) rather than NO itself, has been effective in understanding pathophysiology across a wide range of diseases. Although the intracellular measurement of NO is now feasible, many technical issues remain unresolved. The principle aim of our study was to determine the effect of storage time of whole blood on nitric oxide (NO) level expression in leukocytes. This is important because immune cells remain chemically dynamic even after they are removed from the circulation, and the impact of storage time must be known to optimally quantify the effect of a disease or condition on NO dynamics in circulating leukocytes. We measured NO levels using the fluorescent probe, diaminofluorescein (DAF-2DA), and flow cytometry in monocytes, neutrophils, and natural killer cells from healthy subjects immediately after blood draw (Time 0) and 30, 60, and 120 min following the blood draw. There was no significant difference among the 4 study time points in NO (DAF-2) levels, though there was wide intra-subject variability at all time points. Using LPS stimulation, we compared iNOS (the more traditional surrogate marker of NO dynamics) with NO (by DAF-2) in natural killer cells and monocytes and, we found no difference in the response patterns. In summary, we did find that within a 2-hour interval from blood draw to sample processing, there was a remarkably wide intra-subject variability in expression of intracellular NO (DAF 2) in leukocytes of healthy individuals at baseline and over time. The mechanism(s) for these differences are not known but could clearly confound efforts to detect changes in NO metabolism in white blood cells. We speculate that rapid pulsatility of NO could explain the wide variability seen. PMID- 29129819 TI - Nicotinic acetylcholine receptor alpha7 subunit improves energy homeostasis and inhibits inflammation in nonalcoholic fatty liver disease. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide; yet, the pathogenesis of the disorder is not completely understood. The nicotinic acetylcholine receptor alpha7 subunit (alpha7nAChR) plays an indispensable role in the vagus nerve-regulated cholinergic anti inflammatory pathway. METHODS: In the present study, we investigated the key role of alpha7nAChR in NAFLD development. Male wild-type (WT) and alpha7nAChR knockout (alpha7nAChR-/-) mice were fed a normal chow or a high-fat diet (HFD) for 16weeks to induce NAFLD. RESULTS: We found that both the mRNA and protein levels of alpha7nAChR in the liver tissue of NAFLD mice were significantly higher than those in mice fed normal chow. There were no differences in food intake, body weight, hepatic cholesterol and triglyceride contents, and insulin sensitivity between WT and alpha7nAChR-/- mice under normal condition. When the WT and alpha7nAChR-/- mice were challenged with HFD, the body weight of alpha7nAChR-/- mice became higher than that of WT mice. The oxygen consumption and energy expenditure in HFD-fed alpha7nAChR-/- mice were significantly lower than that in HFD-fed WT mice. The HFD-fed alpha7nAChR-/- mice also showed more aggravated hepatic lipid accumulation, steatosis and oxidative stress than HFD-fed WT mice. Macrophage infiltration; mRNA levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta; and liver fibrosis were significantly accelerated in HFD-fed alpha7nAChR-/- mice compared to that in HFD-fed WT mice. In addition, the bolus insulin injection-activated insulin signaling pathway, which was reflected by the phosphorylation of insulin receptor at Tyr1162/Tyr1163 site (p-IRTyr1162/Tyr1163), insulin receptor substrate-1 at Tyr612 site (p-IRS 1Tyr612) and Akt at Ser473 (p-AktSer473), was significantly compromised in liver tissues of HFD-fed alpha7nAChR-/- mice relative to HFD-fed WT mice. Finally, pharmacologically activation of alpha7nAChR in HFD-fed mice, with a selective agonist PNU-282987, remarkably ameliorated the hepatic steatosis, inflammatory cell infiltration and fibrosis. CONCLUSION: In conclusion, our results demonstrate that activation of alpha7nAChR improves energy homeostasis and inhibits inflammation in nonalcoholic fatty liver disease. PMID- 29129820 TI - Deactivation of the NLRP3 inflammasome in infiltrating macrophages by duodenal jejunal bypass surgery mediates improvement of beta cell function in type 2 diabetes. AB - OBJECTIVE: Bariatric surgery could improve pancreatic beta cell function, thereby leading to the remission of the type 2 diabetes mellitus (T2DM). However, the specific mechanism underlying this phenomenon is yet to be revealed. The aim of this study is to test the hypothesis that Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in infiltrating macrophages plays an important role in the modulation of beta cell function after duodenal-jejunal bypass (DJB) surgery. METHODS: DJB and sham surgery were performed in diabetic Sprague-Dawley (SD) rats induced by high-fat diet (HFD) and streptozotocin (STZ). Body weight, food intake, and glucose tolerance test (GTT) were measured at indicated time points. Apoptosis of the beta cells was measured by Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) assay. We also assessed the macrophage content and NLRP3 expression in the rat model. Furthermore, macrophage reconstitution was performed after DJB surgery. Beta cell function and NLRP3 inflammasome pathway were re-evaluated in wild-type macrophage reconstitution group and NLRP3-knockdown macrophage reconstitution group. RESULTS: DJB surgery group rats displayed rapid and sustained improvement in glucose tolerance. Decreased apoptosis and improved secretion function of the beta cells were observed in DJB surgery group. NLRP3 inflammasome pathway in infiltrating macrophages was also suppressed after DJB surgery. Moreover, diabetic remission acquired by DJB sustained in NLRP3-knockdown macrophage reconstitution group, while extinguished in group reconstituted with wild-type macrophage. CONCLUSIONS: NLRP3 inflammasome deactivation in infiltrating macrophages is involved in marked beta cell function improvement after DJB surgery. PMID- 29129821 TI - Association between lipoprotein (a) and proprotein convertase substilisin/kexin type 9 in patients with heterozygous familial hypercholesterolemia: A case control study. AB - BACKGROUND: Recent data have suggested an important role of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) in the development of atherosclerotic cardiovascular disease (ASCVD) in both general population and family hypercholesterolemia (FH), while the relation of Lp(a) to PCSK9 has not been examined. OBJECTIVE: The aim of the present study was to investigate the association between plasma PCSK9 and Lp(a)in patients with heterozygous FH (HeFH). METHODS: Two hundred and fifty-five molecularly confirmed patients with HeFH were compared to 255 age- and gender-matched non-FH controls. Plasma PCSK9 and Lp(a) concentrations were measured using ELISA and immunoturbidimetric method respectively, and finally their association was assessed. RESULTS: Both plasma PCSK9 and Lp(a) levels were significantly higher in patients with HeFH compared to control group (p<0.001). Besides, the Lp(a) concentration and percentage of Lp(a)>=300mg/L were increased by PCSK9 tertiles in HeFH group (both p<0.05) while not in control group. In partial correlation analysis, Lp(a) was associated with PCSK9 (r=0.254, p<0.001) in HeFH group but not in control, which were further confirmed by multivariable linear regression analysis. Furthermore, significant associations between Lp(a) and PCSK9 were also found in subgroups of HeFH group irrespective of definite or probable FH, with and without coronary artery disease (CAD), and with statin or not. CONCLUSIONS: Plasma Lp(a) level was associated with PCSK9 in patients with HeFH alone, suggesting that much about the interaction of PCSK9 with Lp(a) in FH need further explorations. PMID- 29129822 TI - A hyperbolastic type-I diffusion process: Parameter estimation by means of the firefly algorithm. AB - A stochastic diffusion process, whose mean function is a hyperbolastic curve of type I, is presented. The main characteristics of the process are studied and the problem of maximum likelihood estimation for the parameters of the process is considered. To this end, the firefly metaheuristic optimization algorithm is applied after bounding the parametric space by a stagewise procedure. Some examples based on simulated sample paths and real data illustrate this development. PMID- 29129823 TI - Autonomous control of metabolic state by a quorum sensing (QS)-mediated regulator for bisabolene production in engineered E. coli. AB - Inducible gene expression systems are widely used in microbial host strains for protein and commodity chemical production because of their extensive characterization and ease of use. However, some of these systems have disadvantages such as leaky expression, lack of dynamic control, and the prohibitively high costs of inducers associated with large-scale production. Quorum sensing (QS) systems in bacteria control gene expression in response to population density, and the LuxI/R system from Vibrio fischeri is a well-studied example. A QS system could be ideal for biofuel production strains as it is self regulated and does not require the addition of inducer compounds, which reduce operational costs for inducer. In this study, a QS system was developed for inducer-free production of the biofuel compound bisabolene from engineered E. coli. Seven variants of the Sensor plasmid, which carry the luxI-luxR genes, and four variants of the Response plasmid, which carry bisabolene producing pathway genes under the control of the PluxI promoter, were designed for optimization of bisabolene production. Furthermore, a chromosome-integrated QS strain was engineered with the best combination of Sensor and Response plasmid and produced bisabolene at a titer of 1.1g/L without addition of external inducers. This is a 44% improvement from our previous inducible system. The QS strain also displayed higher homogeneity in gene expression and isoprenoid production compared to an inducible-system strain. PMID- 29129824 TI - Impact of Fluorescent In Situ Hybridization Aberrations and CLLU1 Expression on the Prognosis of Chronic Lymphocytic Leukemia: Presentation of 156 Patients from Turkey. AB - OBJECTIVE: This study evaluates the impact of CLLU1 expression and fluorescent in situ hybridization (FISH) analysis of a group of Turkish chronic lymphocytic leukemia (CLL) patients. MATERIALS AND METHODS: A total of 156 CLL patients were analyzed by FISH method; 47 of them were also evaluated for CLLU1 expression. Results were correlated with clinical parameters. RESULTS: FISH aberrations were found in 62% of patients. These aberrations were del13q14 (67%), trisomy 12 (27%), del11q22 (19%), del17p (8%), and 14q32 rearrangements (20%). Overall del11q22 and del17p were associated with the highest mortality rates, shortest overall survival (OS), and highest need for medication. Homozygous del13q14, 14q32 rearrangements, and higher CLLU1 expression correlated with shorter OS. CONCLUSION: Cytogenetics/FISH analysis is still indicated for routine evaluation of CLL. Special consideration is needed for the poor prognostic implications of del11q22, del17p, 14q32 rearrangements, and homozygous del13q14. The impact of CLLU1 expression is not yet clear and it requires more data before becoming routine in genetic testing in CLL patients. PMID- 29129825 TI - NPM1 Mutation Analysis in Acute Myeloid Leukemia: Comparison of Three Techniques Sanger Sequencing, Pyrosequencing, and Real-Time Polymerase Chain Reaction. AB - OBJECTIVE: Nucleophosmin-1 (NPM1) mutations have prognostic importance in acute myeloid leukemia (AML) patients with intermediate-risk karyotype at diagnosis. Approximately 30% of newly diagnosed cytogenetically normal AML (CN-AML) patients harbor the NPM1 mutation in India. In this study we compared the efficiency of three molecular techniques in detecting NPM1 mutation in peripheral blood and bone marrow samples. MATERIALS AND METHODS: In a single-center cohort we analyzed 165 CN-AML bone marrow/peripheral blood samples for NPM1 mutation analysis. About 30% of the CN-AML samples revealed NPM1 mutations. For the detection, three methods were compared: Sanger sequencing, pyrosequencing, and real-time polymerase chain reaction (PCR). RESULTS: NPM1 exon 12 mutations were observed in 52 (31.51%) of all CN-AML cases. The sensitivity of Sanger sequencing, pyrosequencing, and real-time PCR was 80%, 90%, and 95%, whereas specificity was 95%, 100%, and 100%, respectively. The minimum limit of mutation detection was 20%-30% for Sanger sequencing, 1%-5% for pyrosequencing, and 0.1%-1% for real time PCR. CONCLUSION: The sequencing method, which is the reference method, has the lowest sensitivity and is sometimes difficult to interpret. Real-time PCR is a highly sensitive method for mutation detection but is limited for specific mutation types. In our study, pyrosequencing emerged as the most suitable technique for the detection of NPM1 mutations on the basis of its easy interpretation and less time-consuming processes than Sanger sequencing. PMID- 29129826 TI - Invasive Aspergillosis in Refractory Angioimmunoblastic T-Cell Lymphoma. PMID- 29129827 TI - Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation. AB - BACKGROUND: The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. METHODS: We estimated the lifetime risk of AF in individuals from the community based Framingham Heart Study. Polygenic risk for AF was derived using a score of ~1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. RESULTS: Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF >55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4-9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3-55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P<0.001). CONCLUSIONS: In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long term AF risk. PMID- 29129828 TI - Contemporary Epidemiology of Heart Failure in Fee-For-Service Medicare Beneficiaries Across Healthcare Settings. AB - BACKGROUND: To assess the current landscape of the heart failure (HF) epidemic and provide targets for future health policy interventions in Medicare, a contemporary appraisal of its epidemiology across inpatient and outpatient care settings is needed. METHODS AND RESULTS: In a national 5% sample of Medicare beneficiaries from 2002 to 2013, we identified a cohort of 2 331 939 unique fee for-service Medicare beneficiaries >=65-years-old followed for all inpatient and outpatient encounters over a 10-year period (2004-2013). Preexisting HF was defined by any HF encounter during the first year, and incident HF with either 1 inpatient or 2 outpatient HF encounters. Mean age of the cohort was 72 years; 57% were women, and 86% and 8% were white and black, respectively. Within this cohort, 518 223 patients had preexisting HF, and 349 826 had a new diagnosis of HF during the study period. During 2004 to 2013, the rates of incident HF declined 32%, from 38.7 per 1000 (2004) to 26.2 per 1000 beneficiaries (2013). In contrast, prevalent (preexisting + incident) HF increased during our study period from 162 per 1000 (2004) to 172 per 1000 beneficiaries (2013) (Ptrend <0.001 for both). Finally, the overall 1-year mortality among patients with incident HF is high (24.7%) with a 0.4% absolute decline annually during the study period, with a more pronounced decrease among those diagnosed in an inpatient versus outpatient setting (Pinteraction <0.001) CONCLUSIONS: In recent years, there have been substantial changes in the epidemiology of HF in Medicare beneficiaries, with a decline in incident HF and a decrease in 1-year HF mortality, whereas the overall burden of HF continues to increase. PMID- 29129829 TI - Developmental-behavioral pediatrics education in the United States: challenges in the midst of healthcare evolution. PMID- 29129830 TI - Psychological stress exposure to aged mice causes abnormal feeding patterns with changes in the bout number. AB - Stress responses are affected by aging. However, studies on stress-related changes in feeding patterns with aging subject are minimal. We investigated feeding patterns induced by two psychological stress models, revealing characteristics of stress-induced feeding patterns as "meal" and "bout" (defined as the minimum feeding behavior parameters) in aged mice. Feeding behaviors of C57BL/6J mice were monitored for 24 h by an automatic monitoring device. Novelty stress reduced the meal amount over the 24 h in both young and aged mice, but as a result of a time course study it was persistent in aged mice. In addition, the decreased bout number was more pronounced in aged mice than in young mice. The 24 h meal and bout parameters did not change in either the young or aged mice following water avoidance stress (WAS). However, the meal amount and bout number increased in aged mice for 0-6 h after WAS exposure but remained unchanged in young mice. Our findings suggest that changes in bout number may lead to abnormal stress-related feeding patterns and may be one tool for evaluating eating abnormality in aged mice. PMID- 29129832 TI - Multiphoton minimal inertia scanning for fast acquisition of neural activity signals. AB - OBJECTIVE: Multi-photon laser scanning microscopy provides a powerful tool for monitoring the spatiotemporal dynamics of neural circuit activity. It is, however, intrinsically a point scanning technique. Standard raster scanning enables imaging at subcellular resolution; however, acquisition rates are limited by the size of the field of view to be scanned. Recently developed scanning strategies such as travelling salesman scanning (TSS) have been developed to maximize cellular sampling rate by scanning only select regions in the field of view corresponding to locations of interest such as somata. However, such strategies are not optimized for the mechanical properties of galvanometric scanners. We thus aimed to develop a new scanning algorithm which produces minimal inertia trajectories, and compare its performance with existing scanning algorithms. APPROACH: We describe here the adaptive spiral scanning (SSA) algorithm, which fits a set of near-circular trajectories to the cellular distribution to avoid inertial drifts of galvanometer position. We compare its performance to raster scanning and TSS in terms of cellular sampling frequency and signal-to-noise ratio (SNR). MAIN RESULTS: Using surrogate neuron spatial position data, we show that SSA acquisition rates are an order of magnitude higher than those for raster scanning and generally exceed those achieved by TSS for neural densities comparable with those found in the cortex. We show that this result also holds true for in vitro hippocampal mouse brain slices bath loaded with the synthetic calcium dye Cal-520 AM. The ability of TSS to 'park' the laser on each neuron along the scanning trajectory, however, enables higher SNR than SSA when all targets are precisely scanned. Raster scanning has the highest SNR but at a substantial cost in number of cells scanned. To understand the impact of sampling rate and SNR on functional calcium imaging, we used the Cramer-Rao Bound on evoked calcium traces recorded simultaneously with electrophysiology traces to calculate the lower bound estimate of the spike timing occurrence. SIGNIFICANCE: The results show that TSS and SSA achieve comparable accuracy in spike time estimates compared to raster scanning, despite lower SNR. SSA is an easily implementable way for standard multi-photon laser scanning systems to gain temporal precision in the detection of action potentials while scanning hundreds of active cells. PMID- 29129833 TI - The Metaphysical Itch. PMID- 29129831 TI - Identification of new genetic variants of HLA-DQB1 associated with human longevity and lipid homeostasis-a cross-sectional study in a Chinese population. AB - Healthy longevity has been an unremitting pursuit of human, but its genetic and the environment causes are still unclear. As longevity population is a good healthy aging model for understanding how the body begin aging and the process of aging, and plasma lipids metabolism and balance is a very important to life maintain and physiologic functional turnover. It is important to explore how the effect of genetic variants associated long-life individuals on lipids metabolism and balance. Therefore, we developed a comparative study based population which contains 2816 longevity and 2819 control. Through whole-exome sequencing and sanger sequencing genotypes, we identified four new single nucleotide polymorphisms of HLA-DQB1(major histocompatibility complex, class II, DQ beta 1), rs41542812 rs1049107 rs1049100 rs3891176(Prange=0.048-2.811*10-8 for allele frequencies), associated with longevity in Chinese Longevity Cohort. Further, by analysis of the longevity-variants linked to blood lipids, we identified HLA-DQB1 rs1049107, T-carriers (PHDL=0.006, OR: 11.277; PTG=9.095*10-7, OR: 0.025; PLDL/HDL=0.047, OR: 1.901) and HLA-DQB1 rs1049100, T-carriers (PTG=1.799*10-6, OR: 0.028) associated with lipid homeostasis in long lived individuals. Our finding showed that longevity and lipid homeostasis were associated with HLA-DQB1 and suggested that immune gene variants could act on both new function of maintaining the homeostasis and anti-aging in longevity. PMID- 29129834 TI - The Relationship Between Cochlear Implants and Deaf Identity. AB - The degree to which individuals with cochlear implants (CIs) experience communication difficulties has implications for social participation and identity development. However, few studies have examined the relationship between cochlear implantation, identity, and social participation. Using data from a Danish national survey of deaf adults, the authors examined the significance of having (or not having) a CI in regard to identity (categorized as deaf, hearing, bicultural, and marginal) and various related factors concerning social participation and experiences of being deaf. Cochlear implantation was found to be associated with type of identity, type and quality of friendships and social activities, and feelings of limitation attributed to hearing loss. Age was a significant factor: These associations were mainly found among participants older than age 25 years. The authors discuss the results in dialogue with the concept of social identity and the history of the bilingual/bicultural tradition in Denmark. PMID- 29129835 TI - How Do Deaf Adults Define Quality of Life? AB - Six deaf adults defined quality of life (QOL) in personal interviews. Questions were based on an eight-domain QOL framework: physical well-being, emotional well being, interpersonal relations, social inclusion, personal development, material well-being, self-determination, and rights (Schalock & Alonso, 2002). The interview process had three phases. First, a pilot study (N = 3) evaluated the questions for logic, clarity, and applicability. Next, six deaf adults participated in videotaped, structured interviews. Then four deaf adults participated in videotaped, structured follow-up interviews. Interpretive coding was used in data analysis to establish themes across participants. Five QOL themes, as explained by the participants, emerged from the interviews: (a) Being deaf was integral to who the study participants were. (b) Friends and family were important. (c) Independence was valued. (d) The local vocational rehabilitation services department hindered QOL. (e) Multiple problems existed with interpreters and interpreting in the medical field. PMID- 29129836 TI - Debating Futures in Flemish Deaf Parliament: Deaf Epistemologies, Participatory Citizenship, and Sustainable Development. PMID- 29129837 TI - Enabling Pedagogy and Andragogy for 21st-Century Sign Language Users and Learners. PMID- 29129838 TI - Sign Language Legislation as a Tool for Sustainability. PMID- 29129839 TI - Council on the Education of the Deaf (CED) Accredited Teacher Preparation Programs (as of 7/1/2017). PMID- 29129840 TI - Erratum. PMID- 29129841 TI - Genetic Risk Assessment of Elastin Gene Polymorphisms with Intracranial Aneurysm in Koreans. AB - Elastin encoded by elastin gene (ELN) is a crucial extracellular matrix protein responsible for arterial resilience. The objective of this study was to identify single nucleotide polymorphisms (SNPs) of ELN gene susceptible to intracranial aneurysm (IA) in Korean population. Two SNPs of ELN gene, rs2071307 (Gly422Ser) and rs2856728 (intron), were genotyped in 90 patients with IA and 90 age and frequency matched controls. Fisher's exact test was conducted to evaluate allelic association with IA. Of the two SNPs in ELN gene, T allele of rs2856728 (intron) showed statistically significant association with increased development of IA (odds ratio [OR]: 2.34, 95% confidence interval [CI]: 1.44-3.81, P = 7.6 * 10-4). However, G allele of rs2071307 (Gly422Ser) had no significant association with the development of IA (OR: 1.27, 95% CI: 1.44-3.81, P = 0.607). Interestingly, the odds of having rs2856728 variant was approximately 2-fold higher in males than that in females (OR: 3.46 vs. 1.88, P < 0.05). However, none of SNPs showed difference between single and multiple IA in this study. This preliminary study implies that the rs2856728 variant in ELN gene polymorphisms might play crucial roles in the development and pathogenesis of IA in Korean population. PMID- 29129842 TI - Association of Perioperative Redox Balance on Long-Term Outcome in Patients Undergoing Lung Resection. AB - PURPOSE: We examined whether redox balance during the perioperative period is associated with long-term survival of patients after undergoing lung resection. METHODS: Patients who underwent surgery for lung cancer from January to June 2013 at our institution were investigated. Serum was collected during the operation, and on postoperative day (POD) 3 and 7, and the levels of derivatives of reactive oxygen metabolites (d-ROMs) and biologic antioxidant potential (BAP) were measured. RESULTS: In all, 21 patients (69 +/- 7 years old) were enrolled, of whom 9 underwent video-assisted thoracoscopic surgery. Comorbidities in the patients included chronic obstructive pulmonary disease in eight and idiopathic pulmonary fibrosis in five. d-ROM values on POD 3 and 7 were significantly increased as compared to those obtained during the operation (p <0.001), whereas BAP did not change after surgery. Patients with a value below a d-ROM cutoff value of 327 during the operation showed significantly superior 3-year overall survival as compared to those with a value above the cutoff (87.5% vs. 20.0%, p <0.001). CONCLUSION: In the present patients, surgical stress caused an increase in d-ROM during the postoperative course. The d-ROM value obtained during the operation was correlated with long-term survival following resection for lung cancer. PMID- 29129843 TI - Large Arterial Ring Formed between the M1 and M2 Segments of the Right Middle Cerebral Artery Diagnosed with MR Angiography. PMID- 29129844 TI - Spatial Restriction within Intracranial Epidermoid Cysts Observed Using Short Diffusion-time Diffusion-weighted Imaging. AB - We report two cases of pathologically proven intracranial epidermoid cysts. Both cases were scanned with diffusion-weighted imaging using pulsed gradient spin echo (PGSE) and oscillating gradient spin-echo (OGSE; 50 Hz) prototype sequences with diffusion times of 47.3 ms and 8.5 ms, respectively. The apparent diffusion coefficient measured by OGSE was higher than that measured by PGSE, indicating the spatial restriction of water diffusion in the laminated keratin layers within the cyst as demonstrated by histopathology. PMID- 29129845 TI - Microalbuminuria Is Associated with Lower Weight and Taller Height in Adolescence. AB - Microalbuminuria (MA) is a well-known predictor of cardiovascular disease and mortality in adults. However, these relationships remain unclear in adolescents. A few studies on association between MA and obesity have been conducted in adolescents. However, the association between MA and growth parameters such as height has not been studied, despite the fact that adolescence is a period of rapid physiological change. We, therefore, aimed to evaluate the association between MA and growth parameters, and the association between MA and obesity related cardiovascular risk factors after adjusting for growth. The study included 1,459 adolescents (847 boys and 612 girls) aged 12-18 years who participated in the Korean National Health and Nutrition Examination Survey (2011 2013). A urine albumin/creatinine ratio (UACR) of 30-299 mg/g in a morning urine sample was considered to reflect MA. MA was detected in 53 (3.6%) including 24 girls. Height z-score of adolescents with MA was greater than that of normoalbuminuric adolescents (0.87 vs. 0.38; P < 0.01). Upon multiple regression analysis, UACR was associated with lower weight z-score (beta = -0.100, P < 0.01) and higher height z-score (beta = 0.069, P < 0.01). In term of cardiovascular risk factors, the UACR was not associated with fasting glucose, high-density lipoprotein cholesterol, or triglyceride levels. Adolescents with MA tend to be thin and tall. MA is not a useful screening method for obesity-related cardiovascular risk in adolescents, but instead MA is associated with taller height and lower weight, growth-related parameters in adolescence. PMID- 29129846 TI - The IL18 Promoter Polymorphism, rs1946518, Is Associated with the Risk of Periodontitis in Japanese Women: The Kyushu Okinawa Maternal and Child Health Study. AB - Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in periodontitis and its polymorphisms might modulate the individual susceptibility to periodontitis. Only a limited number of studies on the association between IL18 single-nucleotide polymorphisms (SNPs) and the risk of periodontitis have been realized, however. The aim of this case-control study among young post-partum Japanese women (18 to 45 years) was to determine the impact of SNPs, rs1946518 (-607 C/A) and rs187238 (-137G/C), on periodontitis. The two SNPs may be located within a transcription factor-binding element, thereby influencing transcription from the IL18 promoter. Subjects were 131 cases who had at least one tooth with a probing pocket depth of >= 4.0 mm and 1,017 periodontally healthy controls. Probing pocket depth measurements were performed between 1 and 12 months post-partum. In this population, the A allele of rs1946518 and the C allele of rs187238 are more common. After adjustment for age, education, smoking, and use of an interdental brush, compared with subjects with the AA or AC genotype of SNP rs1946518, those with the CC genotype had a significantly reduced risk of periodontitis (adjusted odds ratio = 0.54, 95% confidence interval = 0.29-0.97). No significant association was observed between rs187238 and the risk of periodontitis. Our study did not reveal any evidence of interaction between the IL18 polymorphisms and smoking. Our findings indicate that the IL18 promoter SNP, rs1946518, is a potential risk factor of periodontitis among young Japanese women. PMID- 29129847 TI - Effects of ketoconazole on cyclophosphamide metabolism: evaluation of CYP3A4 inhibition effect using the in vitro and in vivo models. AB - Cyclophosphamide (CP) is widely used in anticancer therapy regimens and 2 dechloroethylcyclophosphamide (DECP) is its side-chain dechloroethylated metabolite. N-dechloroethylation of CP mediated by the enzyme CYP3A4 yields nephrotoxic and neurotoxic chloroacetaldehyde (CAA) in equimolar amount to DECP. This study aimed to evaluate the inhibitory effect of ketoconazole (KTZ) on CP metabolism through in vitro and in vivo drug-drug interaction (DDI) research. Long-term treatment of KTZ induces hepatic injury; thus single doses of KTZ at low, middle, and high levels (10, 20, and 40 mg/kg) were investigated for pharmacokinetic DDI with CP. Our in vitro human liver microsome modeling approach suggested that KTZ inhibited CYP3A4 activity and then decreased DECP exposure. In addition, an UHPLC-MS/MS method for quantifying CP, DECP, and KTZ in rat plasma was developed and fully validated with a 4 min analysis coupled with a simple and reproducible one-step protein precipitation. A further in vivo pharmacokinetic study demonstrated that combination use of CP (10 mg/kg) and KTZ (10, 20, and 40 mg/kg) in rats caused a KTZ dose-dependent decrease in main parameters of DECP (Cmax, Tmax, and AUC0-infinity) and provided magnitude exposure of DECP (more than a 50% AUC decrease) as a consequence of CYP3A inhibition but had only a small effect on the CP plasma concentration. Our results suggested that combination usage of a CYP3A4 inhibitor like KTZ may decrease CAA exposure and thus intervene against CAA-induced adverse effects in CP clinical treatment. PMID- 29129848 TI - Significance of functional disease-causal/susceptible variants identified by whole-genome analyses for the understanding of human diseases. AB - Human genome variation may cause differences in traits and disease risks. Disease causal/susceptible genes and variants for both common and rare diseases can be detected by comprehensive whole-genome analyses, such as whole-genome sequencing (WGS), using next-generation sequencing (NGS) technology and genome-wide association studies (GWAS). Here, in addition to the application of an NGS as a whole-genome analysis method, we summarize approaches for the identification of functional disease-causal/susceptible variants from abundant genetic variants in the human genome and methods for evaluating their functional effects in human diseases, using an NGS and in silico and in vitro functional analyses. We also discuss the clinical applications of the functional disease causal/susceptible variants to personalized medicine. PMID- 29129851 TI - Ancient Chinese capital models - Measurement system in urban planning. AB - Measurement systems are very important in urban design. This article reviews the theories of grid plans, particularly with respect to the spatial formations of ancient capital cities in Asia, and clarifies three Chinese Capital Models. The "Zhou li" Capital Model (Z) is based on the ancient text "Zhou li" that makes mention of the ideal city. However, because the description of the physical plan of the city is very brief and includes contradictory elements, conclusions regarding the specifics of the city design are extremely difficult to reach. This article proposes the most appropriate Model (Z) as an architype of the ideal Chinese city. Interestingly, there are no excavated examples of Model (Z). The two existing models, the Chang'an Capital Model (C), which is well known as the model for ancient Japanese capitals like Heiankyo (the present Kyoto) and the Da Yuan (Dadu) Capital Model (D), the model for the city that is today Beijing, are described as Variants I and II, with a focus on the land division system of bo (street blocks). PMID- 29129852 TI - One-year eGFR decline rate is a good predictor of prognosis of renal failure in patients with type 2 diabetes. AB - It is difficult to distinguish the onset of renal function decline from the typical variation in estimated glomerular filtration rate (eGFR) measurements in clinical practice. In this study, we used data analysis incorporating smoothing techniques to identify significant trends despite large amounts of noise. We identified the starting points of meaningful eGFR decline based on eGFR trajectories. This was a retrospective observational study of 2533 type 2 diabetes patients. We calculated 1-year eGFR decline rates from the difference between each eGFR value and that of the previous year. We examined the prediction capacity of 1-year eGFR decline rate for renal prognosis. When we performed receiver operating characteristic analysis, the area under the curve of 1-year eGFR decline rate was 0.963 (95% confidence interval: 0.953-0.973). With a cut off value of more than 7.5% eGFR decline during a 1-year period, the sensitivity was 98.8% and specificity was 82.3%. The predictive accuracy of 1-year eGFR decline rate for renal prognosis was high. PMID- 29129853 TI - Erratum to "Biological control for grapevine crown gall using nonpathogenic Rhizobium vitis strain ARK-1". PMID- 29129849 TI - Lipoquality control by phospholipase A2 enzymes. AB - The phospholipase A2 (PLA2) family comprises a group of lipolytic enzymes that typically hydrolyze the sn-2 position of glycerophospholipids to give rise to fatty acids and lysophospholipids. The mammalian genome encodes more than 50 PLA2s or related enzymes, which are classified into several subfamilies on the basis of their structures and functions. From a general viewpoint, the PLA2 family has mainly been implicated in signal transduction, producing bioactive lipid mediators derived from fatty acids and lysophospholipids. Recent evidence indicates that PLA2s also contribute to phospholipid remodeling for membrane homeostasis or energy production for fatty acid beta-oxidation. Accordingly, PLA2 enzymes can be regarded as one of the key regulators of the quality of lipids, which I herein refer to as lipoquality. Disturbance of PLA2-regulated lipoquality hampers tissue and cellular homeostasis and can be linked to various diseases. Here I overview the current state of understanding of the classification, enzymatic properties, and physiological functions of the PLA2 family. PMID- 29129850 TI - Prostaglandin terminal synthases as novel therapeutic targets. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory and anti-tumor effects by reducing prostaglandin (PG) production via the inhibition of cyclooxygenase (COX). However, the gastrointestinal, renal and cardiovascular side effects associated with the pharmacological inhibition of the COX enzymes have focused renewed attention onto other potential targets for NSAIDs. PGH2, a COX metabolite, is converted to each PG species by species-specific PG terminal synthases. Because of their potential for more selective modulation of PG production, PG terminal synthases are now being investigated as a novel target for NSAIDs. In this review, I summarize the current understanding of PG terminal synthases, with a focus on microsomal PGE synthase-1 (mPGES-1) and PGI synthase (PGIS). mPGES-1 and PGIS cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis. mPGES-1 and PGIS are expected to be attractive alternatives to COX as therapeutic targets for several diseases, including inflammatory diseases and cancer. PMID- 29129856 TI - Single Cell Analysis. PMID- 29129857 TI - Estimation of Retention Time in GC/MS of Volatile Metabolites in Fragrant Rice Using Principle Components of Molecular Descriptors. AB - A quantitative structure-retention relationship (QSRR) study was applied for an estimation of retention times of secondary volatile metabolites in Thai jasmine rice. In this study, chemical components in rice seed were extracted using solvent extraction, then separated and identified by gas chromatography-mass spectrometry (GC-MS). A set of molecular descriptors was generated for these substances obtained from GC-MS analysis to numerically represent the molecular structure of such compounds. Principal component analysis (PCA) and principal component regression analysis (PCR) were used to model the retention times of these compounds as a function of the theoretically derived descriptors. The best fitted regression model was obtained with R-squared of 0.900. The informative chemical properties related to retention time were elucidated. The results of this study demonstrate clearly that the combination of molecular weight and autocorrelation functions of two dimensional interatomic distance, which are molecular polarizability, atom identity, sigma charge, sigma electronegativity and polarizability, can be considered as comprehensive factors for predicting the retention times of volatile compounds in rice. PMID- 29129854 TI - Update on the Therapeutic Strategy of Type B Aortic Dissection. AB - Stanford type B aortic dissection (TBAD) is a life-threatening disease. Current therapeutic guidelines recommend medical therapy with aggressive blood pressure lowering for patients with acute TBAD unless they have fatal complications. Although patients with uncomplicated TBAD have relatively low early mortality, aorta-related adverse events during the chronic phase worsen the long-term clinical outcome. Recent advances in thoracic endovascular aortic repair (TEVAR) can improve clinical outcomes in patients with both complicated and uncomplicated TBAD. According to present guidelines, complicated TBAD patients are recommended for TEVAR. However, the indication in uncomplicated TBAD remains controversial. Recent results of randomized trials, which compared the clinical outcome in patients treated with optimal medical therapy and those treated with TEVAR, suggest that preemptive TEVAR should be considered in uncomplicated TBAD with suitable aortic anatomy. However, these trials failed to show improvement in early mortality in patients treated with TEVAR compared with patients treated with optimal medical therapy, which suggest the importance of patient selection for TEVAR. Several clinical and imaging-related risk factors have been shown to be associated with early disease progression. Preemptive TEVAR might be beneficial and should be considered for high-risk patients with uncomplicated TBAD. However, an interdisciplinary consensus has not been established for the definition of patients at high-risk of TBAD, and it should be confirmed by experts including physicians, radiologists, interventionalists, and vascular surgeons. This review summarizes the current understanding of the therapeutic strategy in patients with TBAD based on evidence and expert consensus. PMID- 29129858 TI - Green Electroanalytical Method for Fast Measurement of Xanthine Oxidase Inhibitor Febuxostat. AB - The electrooxidation of xanthine oxidase inhibitor febuxostat was investigated on a boron-doped diamond electrode in aqueous solution. The oxidation of the drug molecule was irreversible and exhibited a diffusion-controlled form. A green electroanalytical method for simple and fast measurements of febuxostat was developed at the unmodified electrode surface. The analyses were performed using square-wave voltammetric peak current at 1.38 V. The linear response was obtained in the range of 7.5 * 10-7 - 2.0 * 10-5 M with the detection limit of 9.5 * 10-8 M. The practical analytical value of the method is demonstrated by quantitative determination of febuxostat in film-coated tablets with excellent recovery of 99.6%. Interference studies reveal that uric acid shows a well-developed voltammetric response at +0.64 V. In view of this, the electroanalytical performances of the boron-doped diamond electrode can open up new possibilities for development of the method for simultaneous clinical analysis of febuxostat and uric acid. PMID- 29129859 TI - Membrane Introduction Mass Spectrometry Combined with an Orthogonal Partial-Least Squares Calibration Model for Mixture Analysis. AB - The emerging membrane introduction mass spectrometry technique has been successfully used to detect benzene, toluene, ethyl benzene and xylene (BTEX), while overlapped spectra have unfortunately hindered its further application to the analysis of mixtures. Multivariate calibration, an efficient method to analyze mixtures, has been widely applied. In this paper, we compared univariate and multivariate analyses for quantification of the individual components of mixture samples. The results showed that the univariate analysis creates poor models with regression coefficients of 0.912, 0.867, 0.440 and 0.351 for BTEX, respectively. For multivariate analysis, a comparison to the partial-least squares (PLS) model shows that the orthogonal partial-least squares (OPLS) regression exhibits an optimal performance with regression coefficients of 0.995, 0.999, 0.980 and 0.976, favorable calibration parameters (RMSEC and RMSECV) and a favorable validation parameter (RMSEP). Furthermore, the OPLS exhibits a good recovery of 73.86 - 122.20% and relative standard deviation (RSD) of the repeatability of 1.14 - 4.87%. Thus, MIMS coupled with the OPLS regression provides an optimal approach for a quantitative BTEX mixture analysis in monitoring and predicting water pollution. PMID- 29129860 TI - Removal of Trace Levels of Cu(II) from Seawater by Co-precipitation with Humic Acids. AB - To maintain performance related to fuel consumption and maneuverability, the bottom of ships are painted with antifouling paint that contains Cu2O as a biocidal pigment. However, in enclosed coastal areas around dockyards, some of the Cu(II) contained in the paint is eluted into the surrounding water. The present study examined the removal of Cu from seawater by co-precipitation with humic acids (HAs). After precipitating the HA in seawater, the amount of Cu(II) in the supernatant was colorimetrically measured by a colorimetry using bathocuproine. The removal efficiency (RE%) for micromolar Cu(II) increased with increasing initial concentrations of HAs. An RE of 90% was obtained using an HA derived from hardwood bark compost. Aromatic components in the HA that contained highly substituted acidic functional groups appeared to enhance the removal of Cu(II). The findings reported herein indicate that HAs represent a useful material for removing trace levels of Cu from seawater. PMID- 29129861 TI - Detection of Scopolamine Hydrobromide via Surface-enhanced Raman Spectroscopy. AB - Surface-enhanced Raman spectroscopy (SERS) was used to measure scopolamine hydrobromide. First, the Raman characteristic peaks of scopolamine hydrobromide were assigned, and the characteristic peaks were determined. The optimal aggregation agent was potassium iodide based on a comparative experimental study. Finally, the SERS spectrum of scopolamine hydrobromide was detected in aqueous solution, and the semi-quantitative analysis and the recovery rate were determined via a linear fitting. The detection limit of scopolamine hydrobromide in aqueous solution was 0.5 MUg/mL. From 0 - 10 MUg/mL, the curve of the intensity of the Raman characteristic peak of scopolamine hydrobromide at 1002 cm 1 is y = 4017.76 + 642.47x. The correlation coefficient was R2 = 0.983, the recovery was 98.5 - 109.7%, and the relative standard deviation (RSD) was about 5.5%. This method is fast, accurate, non-destructive and simple for the detection of scopolamine hydrobromide. PMID- 29129862 TI - Effects of the pH and Concentration on the Stability of Standard Solutions of Proteinogenic Amino Acid Mixtures. AB - To prepare metrologically traceable amino acid mixed standard solutions, it is necessary to determine the stability of each amino acid present in the mixed solutions. In the present study, we prepared amino acid mixed solutions using certified reference standards of 17 proteinogenic amino acids, and examined the stability of each of these amino acids in 0.1 N HCl. We found that the concentration of glutamic acid decreased significantly during storage. LC/MS analysis indicated that the instability of glutamic acid was due to the partial degradation of glutamic acid to pyroglutamic acid in 0.1 N HCl. Using accelerated degradation tests, we investigated several solvent compositions to improve the stability of glutamic acid in amino acid mixed solution, and determined that the change of the pH by diluting the mixed solution improved the stability of glutamic acid. PMID- 29129863 TI - Origin of the Optical Response of a Dye-doped Plasticized Poly(vinyl chloride) based Photonic Crystal Ion Sensor. AB - We investigated the origin of the optical responses of a two-dimensional photonic crystal (2D-PhC) optode membrane ion sensor based on plasticized poly(vinyl chloride) (PVC) containing lipophilic dye. We previously developed a highly sensitive potassium ion sensor. However, the contributions of various factors to the sensor's optical response could not be distinguished. Here, we synthesized a lipophilic dye with spectral changes that do not overlap with those of propagated light in the PhC. Using this synthesized dye excluded the contribution of light absorption by the dye to the peak intensity change of the ion sensor. In refractive index standard solutions, the bulk refractive index change upon ion extraction contributed negligibly. The contribution of diffracted light scattering by optical transparency change of the plasticized PVC upon ion extraction accounted for approximately 45% of the ion sensor's total response. These findings are important for the development of highly sensitive plasticized PVC-based 2D-PhC ion sensors. PMID- 29129864 TI - Analysis of Fresh Sap Collected from Ryukyu Lacquer Tree. AB - The chemical structure of fresh lacquer sap collected from a lacquer tree growing in Nago City of Okinawa, Japan, was analyzed by gas chromatography/mass spectrometry (GC/MS) and nuclear magnetic resonance (NMR). The results showed that Nago lacquer is laccol lacquer and its major components are 3-(heptadeca 10Z,13E,15E-trienyl)catechol, 3-(heptadeca-10Z,13E-dienyl)catechol, 3-(heptadeca 14Z-enyl)catechol, and 3-(heptadeca-12Z-enyl)catechol, which are similar to the components of Vietnamese lacquer. It showed higher laccase activity at pH 5 - 8 and better low temperature adaptability than Vietnamese lacquer. The Nago lacquer reached a dust free dry (DF) condition after 6 h, but Vietnamese lacquer did not. However, both were able to achieve harden dry (HD) in 24 h at 25 degrees C, 80% relative humidity. In order to identify the lacquer provenance, the strontium isotope ratio was analyzed. The strontium isotope ratio (87Sr/86Sr) of Nago lacquer was 0.7110, which is different from the 0.7450 of Vietnamese lacquer. PMID- 29129865 TI - Flow Injection-Chemiluminescence Method for Determination of Hyoscine Butylbromide Using Silver(III) as Oxidizing Agent. AB - Diperiodatoargentate(III) (DPA)/silver(III) complex, [Ag(HIO6)2]5-, in sulfuric acid medium has been used to determine hyoscine butylbromide (HBB) by flow injection (FI) coupled with chemiluminescence (CL) detector. A linear standard curve between the CL intensity and concentration range from 0.005 to 20 mg L-1 was obtained. The determination coefficient (R2), limit of detection (3s * blank), relative standard deviation (RSD) for 0.5 mg L-1 HBB and analytical throughput were 0.9992 (n = 8), 5 * 10-4 mg L-1, 1.5% (n = 10) and 160 injections h-1, respectively. The developed method was applied for the determination of HBB in pharmaceutical formulations with recoveries from 92 +/- 4 to 108 +/- 3%. For comparison, a spectrophotometric method was used and the results obtained by both methods were in good agreement at a 95% confidence level. The effect of key chemical and physical variables (reagent concentration, flow rate, sample volume, PMT voltage) and interfering species (pharmaceutical excipients and inorganic ions) on the determination of HBB was examined. The possible CL mechanism of HBB on silver(III) complex in sulfuric acid medium was also discussed in brief. PMID- 29129866 TI - Determination of Trace Fission Products Associated with Thorium and HCl Matrix by Inductively Coupled Plasma Mass Spectrometry after Anion Exchange Separation. AB - For the determination of MUg-mg L-1 of FPs in 100 g L-1 of thorium matrix with HCl medium, a method, including anion-exchange pre-separation, evaporation and inductively coupled plasma mass spectrometry (ICP-MS) measurement, was developed. The procedure parameters, such as the matrix effect of thorium, the acidity of separation, the elution curve of thorium and FPs and the temperature of evaporation were optimized by batch equilibration, column elution and evaporation experiments. It was found that the average recovery of the FPs was in the range 80 - 110%, and the RSD values were in the range 2 - 15% utilizing prior anion exchange separation of FPs from thorium samples. Furthermore, the detection limit of the method was also investigated. PMID- 29129867 TI - A Non-invasive Monitoring of Propofol Concentration in Blood by a Virtual Surface Acoustic Wave Sensor Array. AB - Propofol (2,6-diisopropylphenol) is widely used in total intravenous anesthesia. An unknown drug concentration in blood always leads to some side effects in patients with propofol injection. However, the drug concentration in the blood is hard to be continuously measured since invasive sampling causes a loss of blood at each measurement. Here, we introduced a virtual surface acoustic wave sensor array (VSAWSA) to non-invasively detect the propofol concentration in blood through exhaled gases. Calibration was conducted by a parallel test using gas chromatography and mass spectrometry (GC-MS) with solid-phase micro-extraction (SPME) for preconcentration. The limit of detection of VSAWSA reached 0.15 nmol/L for propofol. Six cases of clinical trials was conducted to compare the exhaled propofol concentrations to the plasma concentrations controlled by target controlled infusion (TCI). The calibration by GC-MS ensured the feasibility, reliability, and accuracy of the VSAWSA (R = 0.9904, p <0.001). The clinical monitoring data by VSAWSA showed an excellent consistency with TCI. PMID- 29129868 TI - Analysis of Fluorine in Drinking Water by ICP-QMS/QMS with an Octupole Reaction Cell. AB - The analysis of fluorine was carried out by measuring BaF+ ions with an inductively coupled plasma tandem quadrupole mass spectrometer (ICP-QMS/QMS). After optimization, a radio frequency power of 1300 W was found to benefit for the production of BaF+ ions while suppressing the production of BaOH3+ ions. After optimization of the reaction cell gas, it was found that the best performance for measuring BaF+ could be achieved at a flow rate of O2 in the range from 0.65 to 0.75 mL min-1. The signal intensity of BaF+ depended linearly on the concentration of Ba when it was not higher than 100 mg kg-1. The co existence of metallic cations, such as Na in the sample, might suppress the generation of BaF+ ions in the plasma, while anions might not cause such a kind of interferences. The background equivalent concentration (BEC) and the lower detection limit (LDL) of fluorine were 0.4 and 0.06 mg kg-1, respectively, by adjusting the samples to a 10 mg kg-1 Ba matrix. The concentration of fluorine in a certified reference material (ERM-CA015a) was determined with the present method, for which the observed value was (1.36 +/- 0.05)mg kg-1, which agreed with the certified value (1.3 +/- 0.1)mg kg-1, where both values were shown as (mean value +/- expanded uncertainty) with a coverage factor of (k = 2) for calculating the expanded uncertainty giving a level of confidence of approximately 95%. The present method was applied to the analysis of a tap water sample collected in the laboratory, for which the results of recovery tests gave a recovery around 100% with good reproducibility. PMID- 29129869 TI - Fast Determination of Biodiesel Content in Commercial Diesel/Biodiesel Blends by Using Digital Images and Multivariate Calibration. AB - A new simple, rapid and inexpensive analytical method was developed to determine the biodiesel percentage in biodiesel/diesel blends through simple digital images of samples obtained by scanning with a commercial scanner. Soybean biodiesel and petroleum diesel samples were acquired from refineries currently in operation. There were prepared several mixtures within the range 1.5 to 12.0% of biodiesel in diesel oil, using the same procedure as is done in industry. The analytical signals were images recorded with a scanner. This data was decomposed with different color systems: RGB, HSV, HLS, CMYK and Grayscale. Chemometrics models based on color signals obtained from different mixtures of biodiesel/diesel were built. The quantification by using partial least squares (PLS) resulted in a RMSEP value for biodiesel of 0.9% (w/w); this load approximately 10-times smaller than the corresponding calibration range, with a correlation of 0.96 between predicted and reference values. PMID- 29129870 TI - Portable Microplate Analyzer with a Thermostatic Chamber Based on a Smartphone for On-site Rapid Detection. AB - A microplate method provides an efficient way to use modern detection technology. However, there are some difficulties concerning on-site detection, such as being non-portable and time-consuming. In this work, a novel portable microplate analyzer with a thermostatic chamber based on a smartphone was designed for rapid on-site detection. An analyzer with a wide-angle lens and an optical filter provides a proper environment for the microplate. A smartphone app-iPlate Monitor was used for RGB analyze of image. After a consistency experiment with a microtiter plate reader (MTPR), the normalized calibration curves were y = 0.7276x + 0.0243 (R2 = 0.9906) and y = 0.3207x + 0.0094 (R2 = 0.9917) with a BCA protein kit as well as y = 0.182x + 0.0134 (R2 = 0.994) and y = 0.0674x + 0.0003 (R2 = 0.9988) with a glucose kit. The times for obtaining the detection requirement were 15 and 10 min for the BCA protein kit and the glucose kit at 37 degrees C; in contrast, it required more than 30 and 20 min at ambient temperature. Meanwhile, it also showed good repeatability for detections. PMID- 29129871 TI - Change in Plasma Total, Esterified and Non-esterified Capric Acid Concentrations during a Short-term Oral Administration of Synthetic Tricaprin in Dogs. AB - We studied change in the plasma total, esterified and non-esterified capric acid (FA10:0) and its effect on longer fatty acid concentrations during the short-term oral administration of synthetic tricaprin in dogs. We administered 150 and 1500 mg tricaprin/kg body weight per day orally to dogs for 7 consecutive days. Blood samples were collected at 0, 0.5, 1, 2, 4, 8, and 24 h on the 1st and 7th days for measuring the total-, esterified- and non-esterified-FA10:0. The total-FA10:0 concentration increased in a dose-dependent manner, reaching a peak at 1 h on the 1st day and at 2 to 4 h on the 7th day; it then mostly disappeared within 24 h. The mean esterified FA10:0 concentration was found be 75.5 and 60.3% of total FA10:0 in dogs fed 150 and 1500 mg of tricaprin/kg body weight, respectively. The plasma level of FA10:0 depends on the duration and dose of tricaprin administration, but are rapidly cleared from circulation within several hours. PMID- 29129872 TI - Comparison of the Extractabilities of Tetrachloro- and Tetrabromopalladate(II) Ions with a Thiodiglycolamide Compound. AB - Using N,N,N',N'-tetra-2-ethylhexyl-thiodiglycolamide (TEHTDGA) in n-dodecane as the extractant, we compared the percentages of Pd(II) extracted from HCl and HBr solutions, and analyzed the structures of the Pd(II)-extractant complexes. For comparison, similar experiments were performed with di-n-hexyl sulfide (DHS), a well-known sulfide-type extractant. TEHTDGA extracted Pd(II) from both HCl and HBr solutions much faster than DHS. The Pd(II)/(TEHTDGA or DHS) stoichiometry in the organic phase was 1:2. For TEHTDGA, the extractability of Pd(II) from HBr solution was inferior to that from HCl solution, whereas the opposite was true for DHS. However, FT-IR spectroscopy and EXAFS measurements indicated that the inner-sphere structure of Pd(II) in the TEHTDGA complex was almost the same as that in the DHS system: in both cases, two of the halide ions in the tetrachloro- or tetrabromopalladate(II) ion were replaced by the sulfur atoms of two extractant molecules. PMID- 29129873 TI - Competitive ELISA-like Label-free Detection of Lysozyme by Using a Fluorescent Monomer-doped Molecularly Imprinted Hydrogel. AB - We report on a molecularly imprinted hydrogel for the selective fluorescent detection of a targeting protein. To achieve the fluorescent detection of proteins, a fluorescent functional monomer was synthesized with fluorescein isothiocyanate and allylamine. The monomer (FITC-AA) provided a gradable alteration of the absorption spectrum, and a decrease of the fluorescent intensity due to an interaction with the model protein, lysozyme. Also, the imprinted hydrogel (PI-gel) was simply prepared with FITC-AA, the anionic functional monomers, poly(ethylene glycol) dimethacrylate, and lysozyme by radical photo polymerization. The PI-gel showed selective adsorption for lysozyme and the imprinting factor reached to 2.7. Additionally, the PI-gel indicated a gradual decrease of the fluorescent intensity corresponding to the lysozyme concertation similar to a competitive enzyme-linked immunosorbent assay detection. PMID- 29129875 TI - Prediction Models - Why Are They Used or Not Used? PMID- 29129877 TI - Evaluation of the chemiluminescent enzyme immunoassay system for the measurement of testosterone in the serum and whole blood of stallions. AB - Testosterone (T) concentration is a useful indicator of reproductive function in male animals. However, T concentration is not usually measured in veterinary clinics, partly due to the unavailability of reliable and rapid assays for animal samples. In this study, a rapid chemiluminescent enzyme immunoassay system (CLEIA system) that was developed for the measurement of T concentration in humans use was validated for stallion blood samples. First, serum T concentrations were measured using the CLEIA system and compared with those measured by a fluoroimmunoassay that has been validated for use in stallions. The serum T concentrations measured by the two methods were highly correlated (r = 0.9865, n = 56). Second, to validate the use of whole blood as assay samples, T concentrations in whole blood and in the serum were measured by the CLEIA system. T concentrations in both samples were highly correlated (r = 0.9665, n = 64). Finally, to evaluate the practical value of the CLEIA system in clinical settings, T concentrations were measured in three stallions with reproductive abnormalities after the administration of human chorionic gonadotropin (hCG). Two stallions with small or absent testes in the scrotum showed an increase in T production in response to hCG administration and one stallion with seminoma did not. In conclusion, the CLEIA system was found to be a rapid and reliable tool for measuring T concentrations in stallions and may improve reproductive management in clinical settings and in breeding studs. PMID- 29129878 TI - Elevated Expression Levels of Long Non-Coding RNA, Loc554202, Are Predictive of Poor Prognosis in Cervical Cancer. AB - Cervical cancer remains one of the most common causes of gynecological cancer associated death. Long non-coding RNA Loc554202 (lncRNA Loc554202) has been reported to be involved in the development of several types of cancer. However, the role of Loc554202 in cervical cancer remains unclear. In this study, we measured the expression levels of Loc554202 in cervical cancer tissues from 120 patients. The quantitative real-time PCR analysis showed the expression levels of Loc554202 were significantly higher in cervical cancer tissues compared with the adjacent non-tumor tissues. Elevated expression levels of Loc554202 were significantly associated with tumor size (p = 0.006), FIGO stage (p = 0.015), HPV (p = 0.001), and lymph node metastasis (p = 0.002). Kaplan-Meier analysis clearly illustrated that patients with high expression levels of Loc554202 had a lower overall survival rate compared to patients with lower expression (p = 0.0013). Furthermore, we show that Loc554202 is an independent poor prognostic factor through multivariate analysis. Subsequently, using cervical cancer cell lines, HeLa and ME-180, we decreased the expression levels of Loc554202 with siRNA. As results, the proliferation ability of cervical cancer cells was inhibited and apoptosis was induced after Loc554202 knockdown, as judged by viability assay, colony formation, and flow cytometry. Moreover, knockdown of Loc554202 expression down-regulated Bcl-2 expression and conversely up-regulated Bax expression in cervical cancer cells using Western blotting analysis. In conclusion, elevated levels of Loc554202 are predictive of poor prognosis in cervical cancer. We suggest that Loc554202 may serve as a potential therapeutic target for cervical cancer. PMID- 29129879 TI - Transcatheter Aortic Valve Implantation for Degenerated 19-mm Aortic Bioprosthetic Valve. AB - BACKGROUND: The valve-in-valve procedure, in which a transcatheter heart valve (THV) is implanted over a prosthetic valve, has been shown to be safe and therapeutically effective, depending on the size of the replacement valve.Methods and Results:We report 3 cases of successful valve-in-valve procedure to replace a degenerated 19-mm stented prosthetic aortic valve. Balloon-expanding THVs were implanted: 20-mm in the 1st case and 23-mm in the next 2. Aortic stenosis was almost completely resolved in all patients, who recovered promptly and without cardiac adverse events. CONCLUSIONS: Using the valve-in-valve procedure for a 19 mm degenerated bioprosthesis was feasible and safe. PMID- 29129880 TI - ? PMID- 29129881 TI - ? PMID- 29129876 TI - Microbial Ecology along the Gastrointestinal Tract. AB - The ecosystem of the human gastrointestinal (GI) tract traverses a number of environmental, chemical, and physical conditions because it runs from the oral cavity to the anus. These differences in conditions along with food or other ingested substrates affect the composition and density of the microbiota as well as their functional roles by selecting those that are the most suitable for that environment. Previous studies have mostly focused on Bacteria, with the number of studies conducted on Archaea, Eukarya, and Viruses being limited despite their important roles in this ecosystem. Furthermore, due to the challenges associated with collecting samples directly from the inside of humans, many studies are still exploratory, with a primary focus on the composition of microbiomes. Thus, mechanistic studies to investigate functions are conducted using animal models. However, differences in physiology and microbiomes need to be clarified in order to aid in the translation of animal model findings into the context of humans. This review will highlight Bacteria, Archaea, Fungi, and Viruses, discuss differences along the GI tract of healthy humans, and perform comparisons with three common animal models: rats, mice, and pigs. PMID- 29129883 TI - [THE ROLES AND TRAINING SYSTEM OF NEW SPECIALISTS FOR ALLERGY IN INTERNAL MEDICINE]. PMID- 29129882 TI - Plasticity in Glioma Stem Cell Phenotype and Its Therapeutic Implication. AB - The marked heterogeneity in glioblastoma (GBM) may be induced through dynamic differentiation and dedifferentiation process of glioma cells. The hypothesis that environmental stimuli induce these phenotypic changes, including dedifferentiation into the stem cell phenotype which contributes to the high invasiveness and resultant poor outcome in GBM patients, is recently being proven. In the process of cancer invasion and metastasis, the phenotypic change has also been described as epithelial-mesenchymal transition (EMT). This biological process is mainly dependent on hypoxic stimuli and also on transforming growth factor-beta (TGF-beta) released from glioma stem cells, mesenchymal stem cells, and myeloid cells recruited by hypoxia. The tumor microenvironment, especially hypoxia, inducing such dynamic phenotypic changes can be a good therapeutic target in the treatment of GBM. PMID- 29129884 TI - [JAPANESE PEDIATRIC GUIDELINE FOR FOOD ALLERGY 2016-DIETARY INSTRUCTION AND ORAL IMMUNOTHERAPY]. PMID- 29129885 TI - [AIRWAY EPITHELIAL CELL DIFFERENTIATION AND HYPERSECRETION -THE ROLE OF IL-13, CLCA1 AND TMEM16A]. PMID- 29129886 TI - [MANAGEMENT OF CONNECTIVE TISSUE DISEASE-ASSOCIATED INTERSTITIAL LUNG DISEASE]. PMID- 29129887 TI - [ANALYSIS OF BACKGROUNDS AND LEVEL OF UNDERSTANDING OF TREATMENT OF POOR ADHERENCE AND DROPOUT CASES ON SUBLINGUAL IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP YEAR]. AB - BACKGROUND: We considered the factors of poor adherence to and dropout from sublingual immunotherapy (SLIT) by verifying patient backgrounds 1 year after start of treatment. METHODS: We recruited 38 patients who began SLIT between November 2014 and September 2015. We analyzed their attributes and level of understanding of the treatment, and conducted a self-reported survey on factors behind dropout cases and poor adherence cases. RESULTS: Four patients dropped out 1 year after start of treatment. Three left for reasons related to anxiety about side effects. There were five cases of poor adherence. There was no significant difference between good adherence, poor adherence, and dropout regarding level of understanding of the treatment (p=0.59). In the comparison between good and poor adherence groups, except four dropout patients, the adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients. Continuous rate of SLIT achieved about 90%, suggesting relatively high level of adherence. CONCLUSION: It appears possible that anxiety related to side effects could be a factor affecting dropout from SLIT. There was no significant difference regarding level of understanding of the treatment. The adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients. PMID- 29129888 TI - [CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN THE THIRD TREATED YEAR WITH JAPANESE CEDAR POLLINOSIS IN 2017]. AB - : It past 3 years in 2017 after the first purchase of the drug for sublingual immunotherapy (SLIT) for Japanese Cedar pollinosis (JCP). We reported the clinical efficacy of SLIT in the first and the second treated year. PURPOSE: The purpose of this study is to clear the clinical efficacy of SLIT in the third treated year by comparing with other therapies, such as subcutaneous immunotherapy (SCIT), or other pharmacotherapy. METHODS: We compared the clinical efficacy in 2017, of 112 SLIT in the third treated year with 38 SCIT, 364 primary pharmacotherapy that started therapies before pollen dispersal, 254 pharmacotherapy that started therapies after pollen disposal, or 333 non treatment. The clinical efficacy was evaluated with symptom scores, total nasal symptom scores and combined total nasal symptom-medication scores (TNSMS), symptoms of nose and eye by visual analog scale (VAS), quality of life (QOL) scores by Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No1). RESULTS: Both SCIT and SLIT showed good clinical efficacy without significant difference in every assessment. Both SCIT and SLIT were significantly better than other pharmacotherapy in most assessment. Patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 9 and 24% of total SLIT, respectively. CONCLUSION: SLIT in the third treated year showed good clinical efficacy in reducing symptoms and TNSMS of JCP, and in improving QOL. SLIT was significantly effective compared with other pharmacotherapies. PMID- 29129889 TI - [AN ADULT CASE OF EGG ALLERGY TREATED WITH RUSH ORAL IMMUNOTHERAPY]. AB - A 26-year-old female patient exhibited symptoms associated with egg allergy, which had been present since early childhood. The patient requested the treatment of egg allergy and was admitted to our hospital for rush oral immunotherapy. The threshold was determined by an oral food challenge test, after positive results on a double-blind food challenge test. The patient ingested dry powder of raw egg white 5 times per day starting with a tenth of the threshold dose (3.0mg), followed by a 1.2-times increase every time. When the amount of powder reached 1g, it was replaced with 8g of scrambled egg, after then subsequent doses were increased 1.5 times every time. The target of one chicken egg (60g) was reached on the 18th day. During treatment, minor allergic symptoms of urticarial and dyspnea were observed on two occasions, but they disappeared after oral administration of antihistamines. The result of an exercise challenge test after ingestion of egg was negative, and no allergic symptoms were observed by the ingestion of processed foods that contained egg. The patient currently receives ongoing maintenance treatment, consisting of the ingestion of one chicken egg per day; no allergic symptoms have been observed during a period of 2 year while receiving this treatment. Rush oral immunotherapy is a treatment option to be considered for adults with food allergy who were not able to acquire immune tolerance during childhood. PMID- 29129890 TI - ? PMID- 29129891 TI - CDHR3. PMID- 29129892 TI - ? PMID- 29129893 TI - [Erratum : ALLERGIC CONJUNCTIVAL DISORDERS AND THE BARRIER FUNCTION OF CONJUNCTIVA, FOCUSING ON TEARS AND CALT [Japanese Journal of Allergology Vol.66 (2017) No.8 p.1001-1006]]. PMID- 29129894 TI - Motivating Mothers to Recommend Their 20-Year-Old Daughters Receive Cervical Cancer Screening: A Randomized Study. AB - BACKGROUND: In Japan, the rate of cervical cancer screening is remarkably low, especially among women in their twenties and thirties, when cervical cancer is now increasing dramatically. The aim of this study was to test whether a modified government reminder for 20-year-old women to engage in cervical cancer screening, acting through maternal education and by asking for a maternal recommendation to the daughter to receive the screening, could increase their participation rate. METHODS: In two Japanese cities, 20-year-old girls who had not received their first cervical cancer screening before October of fiscal year 2014 were randomized into two study arms. One group of 1,274 received only a personalized daughter-directed reminder leaflet for cervical cancer screening. In the second group of 1,274, the daughters and their mothers received a combination package containing the same reminder leaflet as did the first group, plus an additional informational leaflet for the mother, which requested that the mother recommend that her daughter undergo cervical cancer screening. The subsequent post-reminder screening rates of these two study arms were compared. RESULTS: The cervical cancer screening rate of 20-year-old women whose mothers received the information leaflet was significantly higher than that for women who received only a leaflet for themselves (11% vs 9%, P = 0.0049). CONCLUSIONS: An intervention with mothers, by sending them a cervical cancer information leaflet with a request that they recommend that their daughter receive cervical cancer screening, significantly improved their daughters' screening rate. PMID- 29129896 TI - Extraction and the Fatty Acid Profile of Rosa acicularis Seed Oil. AB - Rosa acicularis seed oil was extracted from Rosa acicularis seeds by the ultrasonic-assisted aqueous enzymatic method using cellulase and protease. Based on a single experiment, Plackett-Burman design was applied to ultrasonic-assisted aqueous enzymatic extraction of wild rose seed oil. The effects of enzyme amount, hydrolysis temperature and initial pH on total extraction rate of wild rose seed oil was studied by using Box-Behnken optimize methodology. Chemical characteristics of a sample of Rosa acicularis seeds and Rosa acicularis seed oil were characterized in this work. The tocopherol content was 200.6+/-0.3 mg/100 g oil. The Rosa acicularis seed oil was rich in linoleic acid (56.5%) and oleic acid (34.2%). The saturated fatty acids included palmitic acid (4%) and stearic acid (2.9%). The major fatty acids in the sn-2 position of triacylglycerol in Rosa acicularis oil were linoleic acid (60.6%), oleic acid (33.6%) and linolenic acid (3.2%). According to the 1,3-random-2-random hypothesis, the dominant triacylglycerols were LLL (18%), LLnL (1%), LLP (2%), LOL (10%), LLSt (1.2%), PLP (0.2%), LLnP (0.1%), LLnO (0.6%) and LOP (1.1%). This work could be useful for developing applications for Rosa acicularis seed oil. PMID- 29129895 TI - Impact of Alcohol Intake and Drinking Patterns on Mortality From All Causes and Major Causes of Death in a Japanese Population. AB - BACKGROUND: We examined the associations of alcohol consumption and liver holidays with all-cause mortality and with mortality due to cancer, heart disease, cerebrovascular disease, respiratory disease, and injury using a large scale prospective study in Japan. METHODS: We followed 102,849 Japanese who were aged between 40 and 69 years at baseline for 18.2 years on average, during which 15,203 deaths were reported. Associations between alcohol intake and mortality risk were assessed using a Cox proportional hazards model, with analysis by the number of liver holidays (in which a person abstains from drinking for several days a week). RESULTS: A J-shaped association was observed between alcohol intake and total mortality in men (nondrinkers: reference; occasional drinkers: hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.68-0.80; 1-149 g/week: HR 0.76; 95% CI, 0.71-0.81; 150-299 g/week: HR 0.75; 95% CI, 0.70-0.80; 300-449 g/week: HR 0.84; 95% CI, 0.78-0.91; 450-599 g/week: HR 0.92; 95% CI, 0.83-1.01; and >=600 g/week: HR 1.19; 95% CI, 1.07-1.32) and in women (nondrinkers: reference; occasional: HR 0.75; 95% CI, 0.70-0.82; 1-149 g/week: HR 0.80; 95% CI, 0.73-0.88; 150-299 g/week: HR 0.91; 95% CI, 0.74-1.13; 300-449 g/week: HR 1.04; 95% CI, 0.73 1.48; and >=450 g/week: HR 1.59; 95% CI, 1.07-2.38). In current drinkers, alcohol consumption was associated with a linear, positive increase in mortality risk from all causes, cancer, and cerebrovascular disease in both men and women, but not heart disease in men. Taking of liver holidays was associated with a lower risk of cancer and cerebrovascular disease mortality in men. CONCLUSIONS: Alcohol intake showed J-shaped associations with the risk of total mortality and three leading causes of death. However, heavy drinking increases the risk of mortality, which highlights the necessity of drinking in moderation coupled with liver holidays. PMID- 29129897 TI - Production of Phytosteryl Ester from Echium Oil in a Recirculating Packed Bed Reactor Using an Immobilized Lipase. AB - The synthesis of phytosteryl ester via the lipase-catalyzed esterification of phytosterol with fatty acid from echium oil was performed in a recirculating packed bed reactor. A commercial lipase from Candida rugosa was immobilized and then used to optimize the reaction conditions for the synthesis of the phytosteryl ester. The parameters investigated were temperature, molar ratio of phytosterol to fatty acid, retention time, and amount of solvent. The optimum conditions were determined as the temperature of 40C, the molar ratio of 1:3 (phytosterol to fatty acid), the retention time of 3 min, and the solvent amount of 40 mL. The maximum conversion of phytosteryl ester was ca. 90 mol% under the optimum conditions. The major fatty acid in phytosteryl ester synthesized was alpha-linolenic acid (ca. 38 mol%). PMID- 29129898 TI - Aggregation Behavior of Disulfide Linked Gemini Surfactants Compared to that of Double Tailed Surfactants. AB - Disulfide linked gemini surfactant having a long spacer chain, [C10H21N(CH3)2(CH2)11SS(CH2)11N(CH3)2C10H21]2Br (2C1011SS), was prepared by the hydrolysis and oxidation process of thioester group for [C10H21N(CH3)2(CH2)11SCOCH3]Br. The critical vesicle concentrations of double tailed surfactants such as dialkyldimethylammonium bromide were observed by the conductivity and light scattering methods. The disulfide bonds of gemini surfactant, [C12H25N(CH3)2CH2CH2SSCH2CH2N(CH3)2C12H25]2Br (2C12SS), were rapidly cleaved by the addition of water-soluble dithiothreitol. However, it took long time to cleave the disulfide bonds of so-called double tailed surfactants 2C1011SS due to vesicle formation. The dynamic light scattering method showed that the diameters of 2C12SS micelles were increased with the cleavage of disulfide bonds, whereas those of 2C1011SS aggregates remained almost constant at 17.6 +/-1.3 nm in similar size with dialkyldimethylammonium bromide vesicles. The time course of disulfide cleavage was examined by the conductivity and HPLC analysis. The produced thiol surfactants were returned to their original gemini surfactants by the addition of H2O2. PMID- 29129899 TI - Selective Production of Acid-form Sophorolipids from Glycerol by Candida floricola. AB - Biosurfactants (BSs) are produced in abundance from various feedstocks by diverse microorganisms, and are used in various applications. In this paper, we describe a new yeast isolate that produces glycolipid-BSs from glycerol, with the aim of enhancing the utilization of the surplus glycerol produced by the oleo-chemical industry. As a result of the screening, strain ZM1502 was obtained as a potential producer of BS from glycerol. Based on TLC analysis, the strain produced glycolipid BSs. According to structural analyses (NMR, MALDI-TOF MS, and GC-MS), the main component of the glycolipids was 6',6"-di-O-acetylated acid-form sophorolipid (SL). Interestingly, the strain produced only acid-form SL, without lactone-form SLs, although the conventional SL-producing yeast, Starmerella bombicola, produces lactone-form SLs with small amounts of the acid-form. Based on taxonomy, the strain was identified as Candida floricola. It produced 3.5 g L 1 of acid-form SLs in 20% (w/v) glycerol. In addition, C. floricola CBS7290 and NBRC10700T also produced only acid-form SLs from glycerol. These results suggest that C. floricola would enhance the utilization of waste glycerol as a fermentation feedstock and facilitate a broad range of applications for SLs. PMID- 29129900 TI - Homochiral Asymmetric Triacylglycerol Isomers in Egg Yolk. AB - The composition of triacylglycerol (TAG) positional isomer (-PI) and enantiomer ( E) in immature chicken egg yolk, mature chicken yolk, and chicken meat was examined. POO (consisting of one palmitic acid (P) and two oleic acids (Os)), PPO (consisting of two Ps and one O), and PPL (consisting of two Ps and one linoleic acid (L)) were treated as representative TAG molecular species in all the analytical samples because P, O, and L were the major fatty acids comprising egg and chicken meat. sn-POO (binding P at sn-1 position) was predominant in egg yolks, while sn-OOP and sn-OPO were present in chicken meat. This difference was ascribed to the different roles of these isomers as nutrients, because TAG in egg yolk is important for new born organisms and TAG in chicken meat is used for fat accumulation. The compositions of the TAG isomers in PPO and PPL in egg yolk were similar, and O and L did not bind at the sn-1 position. In contrast, all the isomers of PPO and PPL were found in chicken meat. These results imply that the TAG structure could be modified so that the nutrient requirement is fulfilled in egg yolk and chicken meat. PMID- 29129901 TI - The Inhibitory Effects of Anthocyanin-Rich Sunrouge Tea on Pancreatic Lipase Activity. AB - This study investigated the in vitro and in vivo effects of Sunrouge (SR), which is an anthocyaninrich green tea. Hot and cold water extracts (CWEX) of Yabukita (YK; regular green tea), SR second crop (SR2), and SR third crop (SR3) were prepared. The 50% inhibitory concentrations for YK, SR2, and SR3 CWEXs against pancreatic lipase in vitro were 12.3+/-2.8, 6.2+/-0.3, and 4.0+/-1.1 mg/mL, respectively. Epigallocatechin gallate (EGCG) accounted for 4.3%, 6.0%, and 6.3% of YK, SR2, and SR3 CWEXs, respectively. SR2 had the highest anthocyanin content of these three samples. In vivo, the increase in the plasma triacylglycerol (TG) concentration following oral administration of oil to mice was significantly suppressed at 60 and 120 min in animals treated with SR2. No significant differences were observed between the plasma TG concentration in the YK and control groups. These results suggested that concomitant administration of SR with oil may suppress lipid absorption and that EGCG may exert this effect. PMID- 29129902 TI - Quantification of Fraglide-1, a New Functional Ingredient, in Vinegars. AB - Vinegar is a widely used condiment in the world, and is produced from ethanol by acetic acid fermentation. Different fruits, vegetables, cereals, and wines can be used as ingredients for vinegar production. It is known that vinegar has many nutrient components such as organic acids, polyphenols, and aromatic compounds. Because of these bioactive components, it has many health benefits. China has a long history of producing vinegar and has been using it for health products and as medicine. Chinese aromatic Zhenjiang vinegar (Kozu) is produced from sticky rice. It is famous for its special flavor and health benefits. 5-Hydroxy-4-phenyl butenolide (Fraglide-1) is a functional compound discovered in Kozu and has anti fungal and anti-obesity effects. In this study, the Fraglide-1 content of different kinds of vinegars and ingredients, including Kozu samples and ingredients, was investigated. Fraglide-1 analysis was carried out via LC-MS/MS in multiple reaction monitoring mode. It was found that all the Kozu samples, as well as brown rice vinegar (Kurosu) samples, and the Chinese sticky rice husk used for the production of Kozu, contained Fraglide-1. Kozu production requires a 6-month- to 8-year-long aging process for its special flavor and aroma. Because of this long aging process, Fraglide-1 is thought to move from the sticky rice husk to Kozu. PMID- 29129903 TI - Utility of eye-tracking technology for preparing medical students in Spain for the summative objective structured clinical examination. PMID- 29129904 TI - Perception survey on the introduction of clinical performance examination as part of the national nursing licensing examination in Korea. AB - PURPOSE: The purpose of this study was to analyze opinions about the action plan for implementation of clinical performance exam as part of the national nursing licensing examination and presents the expected effects of the performance exam and aspects to consider regarding its implementation. METHODS: This study used a mixed-methods design. Quantitative data were collected by a questionnaire survey, while qualitative data were collected by focus group interviews with experts. The survey targeted 200 nursing professors and clinical nurses with more than 5 years of work experience, and the focus group interviews were conducted with 28 of professors, clinical instructors, and nurses at hospitals. RESULTS: First, nursing professors and clinical specialists agreed that the current written tests have limitations in evaluating examinees' ability, and that the introduction of a clinical performance exam will yield positive results. Clinical performance exam is necessary to evaluate and improve nurses' work ability, which means that the implementation of a performance exam is advisable if its credibility and validity can be verified. Second, most respondents chose direct performance exams using simulators or standardized patients as the most suitable format of the test. CONCLUSION: In conclusion, the current national nursing licensing exam is somewhat limited in its ability to identify competent nurses. Thus, the time has come for us to seriously consider the introduction of a performance exam. The prerequisites for successfully implementing clinical performance exam as part of the national nursing licensing exam are a professional training process and forming a consortium to standardize practical training. PMID- 29129905 TI - Change of Oral to Topical Corticosteroid Therapy Exacerbated Glucose Tolerance in a Patient with Plaque Psoriasis. AB - BACKGROUND Psoriasis is known as the most frequent disease treated by long-term topical steroids. It is also known that patients with thick, chronic plaques require the highest potency topical steroids. However, the treatment is limited to up to four weeks due to risk of systemic absorption. CASE REPORT An 80-year old man was diagnosed with type 2 diabetes 16 years before, and was being administered insulin combined with alpha glucosidase inhibitor. He was diagnosed with plaque psoriasis and his oral steroid treatment was switched to topical steroid treatment due to lack of improvement and poorly controlled blood glucose level. The hypoglycemic events improved after the psoriatic lesions improved. CONCLUSIONS Control of blood glucose level is difficult at the very beginning of topical steroid treatment for psoriasis especially if a patient is receiving insulin treatment. Intense monitoring of blood glucose level during initiation of topical steroid treatment is necessary to prevent unfavorable complications. PMID- 29129907 TI - Balancing activity, stability and conductivity of nanoporous core-shell iridium/iridium oxide oxygen evolution catalysts. AB - The selection of oxide materials for catalyzing the oxygen evolution reaction in acid-based electrolyzers must be guided by the proper balance between activity, stability and conductivity-a challenging mission of great importance for delivering affordable and environmentally friendly hydrogen. Here we report that the highly conductive nanoporous architecture of an iridium oxide shell on a metallic iridium core, formed through the fast dealloying of osmium from an Ir25Os75 alloy, exhibits an exceptional balance between oxygen evolution activity and stability as quantified by the activity-stability factor. On the basis of this metric, the nanoporous Ir/IrO2 morphology of dealloyed Ir25Os75 shows a factor of ~30 improvement in activity-stability factor relative to conventional iridium-based oxide materials, and an ~8 times improvement over dealloyed Ir25Os75 nanoparticles due to optimized stability and conductivity, respectively. We propose that the activity-stability factor is a key "metric" for determining the technological relevance of oxide-based anodic water electrolyzer catalysts. PMID- 29129906 TI - Correlation of Maternal Serum Homocysteine in the First Trimester with the Development of Gestational Hypertension and Preeclampsia. AB - BACKGROUND This study investigated the relationship of serum homocysteine in early pregnancy with the risk of gestational hypertension (GH) and preeclampsia (PE) and with the severity of preeclampsia. MATERIAL AND METHODS In a retrospective cohort study, we identified 147 confirmed cases of preeclampsia (103 with mild PE and 44 with severe PE) and 147 confirmed cases of GH; 4418 women who remained normotensive and nonproteinuric throughout pregnancy served as controls. Maternal blood samples were collected at between 11 and 13 weeks of gestation to test serum concentrations of homocysteine (Hcy), folic acid, and VitB12. A logistic regression model was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS Women who subsequently developed GH and PE were older and had higher body mass indexes (BMIs) than those in the control group. Compared with the control group, women who developed PE were less educated (P=0.031), and more of those who developed GH were primiparas (P=0.012). The serum levels of Hcy in severe PE were significantly higher than those in the control group (median: 8.50 MUmol/L vs. 7.33 MUmol/L, P<0.001). After logistic regression analyses for potential confounding factors, the adjusted odds ratios (aORs) of Hcy was 1.12 for severe PE (95% CI 1.06-1.20). The serum concentrations of folic acid and VitB12 in those with GH and PE were not significantly different from controls. CONCLUSIONS A high level of Hcy in the first trimester is an independent risk factor for severe PE, although it is not a useful marker for the subsequent development of GH and mild PE. PMID- 29129908 TI - TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma. AB - Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac) binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Our findings uncover a pathway in which TRIM24 functions as a signal relay for oncogenic EGFR signaling and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation. PMID- 29129911 TI - The role of Nrf2 in NLRP3 inflammasome activation. PMID- 29129910 TI - Thermostable exoshells fold and stabilize recombinant proteins. AB - The expression and stabilization of recombinant proteins is fundamental to basic and applied biology. Here we have engineered a thermostable protein nanoparticle (tES) to improve both expression and stabilization of recombinant proteins using this technology. tES provides steric accommodation and charge complementation to green fluorescent protein (GFPuv), horseradish peroxidase (HRPc), and Renilla luciferase (rLuc), improving the yields of functional in vitro folding by ~100 fold. Encapsulated enzymes retain the ability to metabolize small-molecule substrates, presumably via four 4.5-nm pores present in the tES shell. GFPuv exhibits no spectral shifts in fluorescence compared to a nonencapsulated control. Thermolabile proteins internalized by tES are resistant to thermal, organic, chaotropic, and proteolytic denaturation and can be released from the tES assembly with mild pH titration followed by proteolysis. PMID- 29129909 TI - RNA editing by ADAR1 leads to context-dependent transcriptome-wide changes in RNA secondary structure. AB - Adenosine deaminase acting on RNA 1 (ADAR1) is the master RNA editor, catalyzing the deamination of adenosine to inosine. RNA editing is vital for preventing abnormal activation of cytosolic nucleic acid sensing pathways by self-double stranded RNAs. Here we determine, by parallel analysis of RNA secondary structure sequencing (PARS-seq), the global RNA secondary structure changes in ADAR1 deficient cells. Surprisingly, ADAR1 silencing resulted in a lower global double stranded to single-stranded RNA ratio, suggesting that A-to-I editing can stabilize a large subset of imperfect RNA duplexes. The duplexes destabilized by editing are composed of vastly complementary inverted Alus found in untranslated regions of genes performing vital biological processes, including housekeeping functions and type-I interferon responses. They are predominantly cytoplasmic and generally demonstrate higher ribosomal occupancy. Our findings imply that the editing effect on RNA secondary structure is context dependent and underline the intricate regulatory role of ADAR1 on global RNA secondary structure. PMID- 29129913 TI - Volcanism in slab tear faults is larger than in island-arcs and back-arcs. AB - Subduction-transform edge propagators are lithospheric tears bounding slabs and back-arc basins. The volcanism at these edges is enigmatic because it is lacking comprehensive geological and geophysical data. Here we present bathymetric, potential-field data, and direct observations of the seafloor on the 90 km long Palinuro volcanic chain overlapping the E-W striking tear of the roll-backing Ionian slab in Southern Tyrrhenian Sea. The volcanic chain includes arc-type central volcanoes and fissural, spreading-type centers emplaced along second order shears. The volume of the volcanic chain is larger than that of the neighbor island-arc edifices and back-arc spreading center. Such large volume of magma is associated to an upwelling of the isotherms due to mantle melts upraising from the rear of the slab along the tear fault. The subduction transform edge volcanism focuses localized spreading processes and its magnitude is underestimated. This volcanism characterizes the subduction settings associated to volcanic arcs and back-arc spreading centers. PMID- 29129914 TI - Dendritic cells: Managing migration. PMID- 29129912 TI - Reflective imaging improves spatiotemporal resolution and collection efficiency in light sheet microscopy. AB - Light-sheet fluorescence microscopy (LSFM) enables high-speed, high-resolution, and gentle imaging of live specimens over extended periods. Here we describe a technique that improves the spatiotemporal resolution and collection efficiency of LSFM without modifying the underlying microscope. By imaging samples on reflective coverslips, we enable simultaneous collection of four complementary views in 250 ms, doubling speed and improving information content relative to symmetric dual-view LSFM. We also report a modified deconvolution algorithm that removes associated epifluorescence contamination and fuses all views for resolution recovery. Furthermore, we enhance spatial resolution (to <300 nm in all three dimensions) by applying our method to single-view LSFM, permitting simultaneous acquisition of two high-resolution views otherwise difficult to obtain due to steric constraints at high numerical aperture. We demonstrate the broad applicability of our method in a variety of samples, studying mitochondrial, membrane, Golgi, and microtubule dynamics in cells and calcium activity in nematode embryos. PMID- 29129915 TI - MHC molecules: Immune editing shapes the cancer landscape. PMID- 29129916 TI - A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells. AB - While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA binding protein CSDE1 (cold shock domain containing E1) is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post transcriptional regulator of hESC identity and neurogenesis. PMID- 29129919 TI - Functional genomics: Shining a light on genetic screen strategies. PMID- 29129917 TI - Dengue virus-reactive CD8+ T cells mediate cross-protection against subsequent Zika virus challenge. AB - Zika virus (ZIKV) and dengue virus (DENV) are antigenically related flaviviruses that share cross-reactivity in antibody and T cell responses, and co-circulate in increasing numbers of countries. Whether pre-existing DENV immunity can cross protect or enhance ZIKV infection during sequential infection of the same host is unknown. Here, we show that DENV-immune Ifnar1 -/- or wild-type C57BL/6 mice infected with ZIKV have cross-reactive immunity to subsequent ZIKV infection and pathogenesis. Adoptive transfer and cell depletion studies demonstrate that DENV immune CD8+ T cells predominantly mediate cross-protective responses to ZIKV. In contrast, passive transfer studies suggest that DENV-immune serum does not protect against ZIKV infection. Thus, CD8+ T cell immunity generated during primary DENV infection can confer protection against secondary ZIKV infection in mice. Further optimization of current DENV vaccines for T cell responses might confer cross-protection and prevent antibody-mediated enhancement of ZIKV infection. PMID- 29129920 TI - Transcription: Putting R loops firmly on the map. PMID- 29129918 TI - Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. AB - CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8+ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8+ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8+ T cells, and an increased ratio of intratumoral CD8+ T cells to CD4+ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain. PMID- 29129921 TI - Towards a genomics-informed, real-time, global pathogen surveillance system. AB - The recent Ebola and Zika epidemics demonstrate the need for the continuous surveillance, rapid diagnosis and real-time tracking of emerging infectious diseases. Fast, affordable sequencing of pathogen genomes - now a staple of the public health microbiology laboratory in well-resourced settings - can affect each of these areas. Coupling genomic diagnostics and epidemiology to innovative digital disease detection platforms raises the possibility of an open, global, digital pathogen surveillance system. When informed by a One Health approach, in which human, animal and environmental health are considered together, such a genomics-based system has profound potential to improve public health in settings lacking robust laboratory capacity. PMID- 29129924 TI - Hypertension: Peripheral control of the systemic hypoxic response. PMID- 29129923 TI - Ist1 regulates ESCRT-III assembly and function during multivesicular endosome biogenesis in Caenorhabditis elegans embryos. AB - Degradation of most integral membrane proteins is directed by the endosomal sorting complex required for transport (ESCRT) machinery, which selectively targets ubiquitin-modified cargoes into intralumenal vesicles (ILVs) within multivesicular endosomes (MVEs). To better understand the mechanisms underlying ESCRT-mediated formation of ILVs, we exploited the rapid, de novo biogenesis of MVEs during the oocyte-to-embryo transition in C. elegans. In contrast to previous models suggesting that ILVs form individually, we demonstrate that they remain tethered to one another subsequent to internalization, arguing that they bud continuously from stable subdomains. In addition, we show that membrane bending and ILV formation are directed specifically by the ESCRT-III complex in vivo in a manner regulated by Ist1, which promotes ESCRT-III assembly and inhibits the incorporation of upstream ESCRT components into ILVs. Our findings underscore essential actions for ESCRT-III in membrane remodeling, cargo selection, and cargo retention, which act repetitively to maximize the rate of ILV formation. PMID- 29129922 TI - Statistical and integrative system-level analysis of DNA methylation data. AB - Epigenetics plays a key role in cellular development and function. Alterations to the epigenome are thought to capture and mediate the effects of genetic and environmental risk factors on complex disease. Currently, DNA methylation is the only epigenetic mark that can be measured reliably and genome-wide in large numbers of samples. This Review discusses some of the key statistical challenges and algorithms associated with drawing inferences from DNA methylation data, including cell-type heterogeneity, feature selection, reverse causation and system-level analyses that require integration with other data types such as gene expression, genotype, transcription factor binding and other epigenetic information. PMID- 29129926 TI - Tubular disease: Anti-LRP2 nephropathy. PMID- 29129927 TI - Nephrotic syndrome: AVIL mutations reduce podocyte migration rate in SRNS. PMID- 29129928 TI - Self-probing spectroscopy of XUV photo-ionization dynamics in atoms subjected to a strong-field environment. AB - Single-photon ionization is one of the most fundamental light matter interactions in nature, serving as a universal probe of the quantum state of matter. By probing the emitted electron, one can decode the full dynamics of the interaction. When photo-ionization is evolving in the presence of a strong laser field, the fundamental properties of the mechanism can be signicantly altered. Here we demonstrate how the liberated electron can perform a self-probing measurement of such interaction with attosecond precision. Extreme ultraviolet attosecond pulses initiate an electron wavepacket by photo-ionization, a strong infrared field controls its motion, and finally electron-ion collision maps it into re-emission of attosecond radiation bursts. Our measurements resolve the internal clock provided by the self-probing mechanism, obtaining a direct insight into the build-up of photo-ionization in the presence of the strong laser field. PMID- 29129925 TI - The neural basis of homeostatic and anticipatory thirst. AB - Water intake is one of the most basic physiological responses and is essential to sustain life. The perception of thirst has a critical role in controlling body fluid homeostasis and if neglected or dysregulated can lead to life-threatening pathologies. Clear evidence suggests that the perception of thirst occurs in higher-order centres, such as the anterior cingulate cortex (ACC) and insular cortex (IC), which receive information from midline thalamic relay nuclei. Multiple brain regions, notably circumventricular organs such as the organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), monitor changes in blood osmolality, solute load and hormone circulation and are thought to orchestrate appropriate responses to maintain extracellular fluid near ideal set points by engaging the medial thalamic-ACC/IC network. Thirst has long been thought of as a negative homeostatic feedback response to increases in blood solute concentration or decreases in blood volume. However, emerging evidence suggests a clear role for thirst as a feedforward adaptive anticipatory response that precedes physiological challenges. These anticipatory responses are promoted by rises in core body temperature, food intake (prandial) and signals from the circadian clock. Feedforward signals are also important mediators of satiety, inhibiting thirst well before the physiological state is restored by fluid ingestion. In this Review, we discuss the importance of thirst for body fluid balance and outline our current understanding of the neural mechanisms that underlie the various types of homeostatic and anticipatory thirst. PMID- 29129930 TI - An unusual endo-selective C-H hydroarylationof norbornene by the Rh(I)-catalyzed reactionof benzamides. AB - Hydroarylation is an environmentally attractive strategy which incorporates all of the atoms contained in the substrates into the desired products. Almost all the hydroarylations of norbornene reported to date involve an exo-selective reaction. Here we show the endo-selective hydroarylation of norbornene in the Rh(I)-catalyzed reaction of aromatic amides. The addition of sterically bulky carboxylic acids enhances the endo-selectivity of the reaction. The results of deuterium-labeling experiments show that both the ortho-carbon and the ortho hydrogen atoms of aromatic amides were attached to the same carbon atom of the norbornane skeleton in the hydroarylation product. These results clearly suggest that hydrometalation or carbometalation, which are commonly accepted mechanisms for the catalytic hydroarylation of C-H bonds, are not involved as the key step in the present reaction, and suggest that the reaction involves a rhodium carbene complex generated from norbornene as the key intermediate. PMID- 29129931 TI - Mapping functional diversity from remotely sensed morphological and physiological forest traits. AB - Assessing functional diversity from space can help predict productivity and stability of forest ecosystems at global scale using biodiversity-ecosystem functioning relationships. We present a new spatially continuous method to map regional patterns of tree functional diversity using combined laser scanning and imaging spectroscopy. The method does not require prior taxonomic information and integrates variation in plant functional traits between and within plant species. We compare our method with leaf-level field measurements and species-level plot inventory data and find reasonable agreement. Morphological and physiological diversity show consistent change with topography and soil, with low functional richness at a mountain ridge under specific environmental conditions. Overall, functional richness follows a logarithmic increase with area, whereas divergence and evenness are scale invariant. By mapping diversity at scales of individual trees to whole communities we demonstrate the potential of assessing functional diversity from space, providing a pathway only limited by technological advances and not by methodology. PMID- 29129929 TI - IL-2 imprints human naive B cell fate towards plasma cell through ERK/ELK1 mediated BACH2 repression. AB - Plasma cell differentiation is a tightly regulated process that requires appropriate T cell helps to reach the induction threshold. To further understand mechanisms by which T cell inputs regulate B cell fate decision, we investigate the minimal IL-2 stimulation for triggering human plasma cell differentiation in vitro. Here we show that the timed repression of BACH2 through IL-2-mediated ERK/ELK1 signalling pathway directs plasma cell lineage commitment. Enforced BACH2 repression in activated B cells unlocks the plasma cell transcriptional program and induces their differentiation into immunoglobulin M-secreting cells. RNA-seq and ChIP-seq results further identify BACH2 target genes involved in this process. An active regulatory region within the BACH2 super-enhancer, under ELK1 control and differentially regulated upon B-cell activation and cellular divisions, helps integrate IL-2 signal. Our study thus provides insights into the temporal regulation of BACH2 and its targets for controlling the differentiation of human naive B cells. PMID- 29129933 TI - Atomically-precise colloidal nanoparticles of cerium dioxide. AB - Synthesis of truly monodisperse nanoparticles and their structural characterization to atomic precision are important challenges in nanoscience. Success has recently been achieved for metal nanoparticles, particularly Au, with diameters up to 3 nm, the size regime referred to as nanoclusters. In contrast, families of atomically precise metal oxide nanoparticles are currently lacking, but would have a major impact since metal oxides are of widespread importance for their magnetic, catalytic and other properties. One such material is colloidal CeO2 (ceria), whose applications include catalysis, new energy technologies, photochemistry, and medicine, among others. Here we report a family of atomically precise ceria nanoclusters with ultra-small dimensions up to ~1.6 nm (~100 core atoms). X-ray crystallography confirms they have the fluorite structure of bulk CeO2, and identifies surface features, H+ binding sites, Ce3+ locations, and O vacancies on (100) facets. Monodisperse ceria nanoclusters now permit investigation of their properties as a function of exact size, surface morphology, and Ce3+:Ce4+ composition. PMID- 29129934 TI - Improved shape for refinable surfaces with singularly parameterized irregularities. AB - To date, singularly-parameterized surface constructions suffer from poor highlight line distributions, ruling them out as a surface representation of choice for primary design surfaces. This paper explores graded, many-piece, everywhere C1 singularly-parameterized surface caps that mimic the shape of a high-quality guide surface. The approach illustrates the trade-off between polynomial degree and surface quality. For bi-degree 5, minor flaws in the highlight line distribution are still visible when zooming in on the singularity, but the distribution is good at the macroscopic level. Constructions of degree bi 4 or bi-3 may require one or more steps of guided subdivision to reach the same macroscopic quality. Akin to subdivision surfaces, singularly-parameterized functions on the surfaces are straightforward to refine. PMID- 29129932 TI - The vaccinia virus DNA polymerase structure provides insights into the mode of processivity factor binding. AB - Vaccinia virus (VACV), the prototype member of the Poxviridae, replicates in the cytoplasm of an infected cell. The catalytic subunit of the DNA polymerase E9 binds the heterodimeric processivity factor A20/D4 to form the functional polymerase holoenzyme. Here we present the crystal structure of full-length E9 at 2.7 A resolution that permits identification of important poxvirus-specific structural insertions. One insertion in the palm domain interacts with C-terminal residues of A20 and thus serves as the processivity factor-binding site. This is in strong contrast to all other family B polymerases that bind their co-factors at the C terminus of the thumb domain. The VACV E9 structure also permits rationalization of polymerase inhibitor resistance mutations when compared with the closely related eukaryotic polymerase delta-DNA complex. PMID- 29129935 TI - Antimalarial Use of Malagasy Plants is Poorly Correlated with Performance in Antimalarial Bioassays. AB - Bioassay screening of plant extracts can identify unique lead compounds for drug development, but the "hit rate" from random screening is very low. Targeted screening of medicinal plants has been repeatedly reported to increase the percentage of samples displaying bioactivity. Contrarily, Maranz (2012) suggested that African antimalarial plants were unsuitable sources of antimalarial drugs because high prevalence of malaria would result in rapid evolution of resistance to active compounds that directly targeted the parasite. As malaria is highly prevalent in much of Madagascar, it was of interest to determine whether Malagasy antimalarial plants would outperform randomly selected plants in conventional antimalarial assays being conducted as part of a discovery program. Of 1294 plant samples screened for antimalarial activity, 39.6% had an IC50 <50 MUg/ml and 21.1% had an IC50 <20 MUg/ml (the minimum to qualify as a first-pass "hit"). Ethnobotanical uses were coded at both the generic and the species level, as neither samples nor use reports in literature were always identifiable to species level. The 526 samples belonging to genera having reported uses for malaria were slightly more likely than average to display activity (44.3% with IC50 <50 MUg/ml, p < .01; 23.2% with IC50 <20 MUg/ml). Of these, 67 samples from individual species with documented use were still more likely to be modestly active (49.3% with IC50 <50 MUg/ml), yet less likely to be highly active (17.9% with IC50 <20 MUg/ml). Thus, in this specific context, ethnobotanically directed screening would not have substantially improved screening efficiency, and would have missed most of the potential hits. PMID- 29129936 TI - Infrared Energy Harvesting in Millimeter-Scale GaAs Photovoltaics. AB - The design and characterization of mm-scale GaAs photovoltaic cells are presented and demonstrate highly efficient energy harvesting in the near infrared. Device performance is improved dramatically by optimization of the device structure for the near-infrared spectral region and improving surface and sidewall passivation with ammonium sulfide treatment and subsequent silicon nitride deposition. The power conversion efficiency of a 6.4 mm2 cell under 660 nW/mm2 NIR illumination at 850 nm is greater than 30 %, which is higher than commercial crystalline silicon solar cells under similar illumination conditions. Critical performance limiting factors of sub-mm scale GaAs photovoltaic cells are addressed and compared to theoretical calculations. PMID- 29129938 TI - Growth and properties of wide bandgap (MgSe)n(ZnxCd1-xSe)m short-period superlattices. AB - We report the molecular beam epitaxy (MBE) growth and properties of (MgSe)n(ZnxCd1-x Se)m short-period superlattices(SPSLs) for potential application in II-VI devices grown on InP substrates. SPSL structures up to 1 MUm thick with effective bandgaps ranging from 2.6 eV to above 3.42 eV are grown and characterized, extending the typical range possible for the ZnxCdyMg1-x-ySe random alloy beyond 3.2 eV. Additionally, ZnxCd1-xSe single and multiple quantum well structures using the SPSL barriers are also grown and investigated. The structures are characterized utilizing reflection high-energy electron diffraction, X-ray reflectance, X-ray diffraction and photoluminescence. We observed layer-by-layer growth and smoother interfaces in the QWs grown with SPSL when compared to the ZnxCdyMg1-x-ySe random alloy. The results indicate that this materials platform is a good candidate to replace the random alloy in wide bandgap device applications. PMID- 29129937 TI - Cerebrospinal Fluid Proteins as Regulators of Beta-amyloid Aggregation and Toxicity. AB - Amyloid disorders, such as Alzheimer's, are almost invariably late-onset diseases. One defining diagnostic feature of Alzheimer's disease is the deposition of beta-amyloid as extracellular plaques, primarily in the hippocampus. This raises the question: are there natural protective agents that prevent beta-amyloid from depositing, and is it loss of this protection that leads to onset of disease? Proteins in cerebrospinal fluid (CSF) have been suggested to act as just such natural protective agents. Here, we describe some of the early evidence that led to this suggestion, and we discuss, in greater detail, two CSF proteins that have garnered the bulk of the attention. PMID- 29129939 TI - Indigenous migration dynamics in the Ecuadorian Amazon: a longitudinal and hierarchical analysis. AB - Amazonian indigenous populations are approaching a critical stage in their history in which increasing education and market integration, rapid population growth and degradation of natural resources threaten the survival of their traditions and livelihoods. A topic that has hardly been touched upon in this context is migration and population mobility. We address this by analysing a unique longitudinal dataset from the Ecuadorian Amazon on the spatial mobility of five indigenous groups and mestizo co-residents. Analyses reveal traditional and new forms of population mobility and migrant selectivity, including gendered forms of marriage migration and rural-urban moves driven by education. These results illustrate a dynamic present and an uncertain future for indigenous populations in which rural, natural-resource-based lifeways may well be sustained but with increasing links to urban areas. PMID- 29129941 TI - Understanding context effects for a measure of life evaluation: how responses matter. PMID- 29129940 TI - Early Women, Late Men: Timing Attitudes and Gender Differences in Marriage. AB - Around the world, women marry earlier than men, but it is not well understood why this gender gap exists. Using panel data collected in Nepal, the authors investigate whether attitudes about marital timing held by unmarried youth and their parents account for women marrying earlier than men. They also examine whether the influence of timing attitudes differs by gender. On average, unmarried youth and their parents viewed 20 to 25 as acceptable ages for women to marry, while ages 23 to 30 were appropriate for men. In turn, women entering the acceptable marriage age range earlier than men accounted for a third of the gender gap in marital timing. The influence of youth and parents' timing attitudes did differ by gender, but only at the extreme. When they were much too young for marriage, both genders were less likely to marry, but this dampening effect was substantially larger for women. PMID- 29129943 TI - Neighborhood Violent Crime and Academic Growth in Chicago: Lasting Effects of Early Exposure. AB - A large body of research documents the importance of early experiences for later academic, social, and economic success. Exposure to an unsafe neighborhood is no exception. Living in a violent neighborhood can influence the stress levels, protective behaviors, and community interactions of both parents and children in ways that generate cumulative educational disadvantage. Using nine years (2002 2011) of detailed crime data from the Chicago Police Department and longitudinal administrative data from the Chicago Public Schools, I estimate the influence of early exposure to neighborhood violence on growth in standardized test scores over time. Student fixed-effects are included to remove any bias due to constant differences between students. The results show that children from more violent neighborhoods fall farther behind their peers from safer neighborhoods as they progress through school. These effects are comparable in size to the independent association with socioeconomic disadvantage and an annual measure of more recent neighborhood violence exposure. PMID- 29129944 TI - Verbenanone, an octahydro-5H-chromen-5-one from a Hawaiian-Plant Associated Fungus FT431. AB - A new secondary metabolite verbenanone (1) with a unique (4aS,8aS)-octahydro-5H chromen-5-one moiety has been obtained from the endophytic fungus FT431, which was isolated from the native Hawaiian plant Verbena sp. The structure of compound 1 was characterized based on NMR and MS spectroscopic analysis. The absolute configuration (AC) of compound 1 was determined by Mosher acids. Compound 1 was tested against A2780 and A2780cisR, but it was inactive. PMID- 29129942 TI - Priorities for research in soil ecology. AB - The ecological interactions that occur in and with soil are of consequence in many ecosystems on the planet. These interactions provide numerous essential ecosystem services, and the sustainable management of soils has attracted increasing scientific and public attention. Although soil ecology emerged as an independent field of research many decades ago, and we have gained important insights into the functioning of soils, there still are fundamental aspects that need to be better understood to ensure that the ecosystem services that soils provide are not lost and that soils can be used in a sustainable way. In this perspectives paper, we highlight some of the major knowledge gaps that should be prioritized in soil ecological research. These research priorities were compiled based on an online survey of 32 editors of Pedobiologia - Journal of Soil Ecology. These editors work at universities and research centers in Europe, North America, Asia, and Australia.The questions were categorized into four themes: (1) soil biodiversity and biogeography, (2) interactions and the functioning of ecosystems, (3) global change and soil management, and (4) new directions. The respondents identified priorities that may be achievable in the near future, as well as several that are currently achievable but remain open. While some of the identified barriers to progress were technological in nature, many respondents cited a need for substantial leadership and goodwill among members of the soil ecology research community, including the need for multi-institutional partnerships, and had substantial concerns regarding the loss of taxonomic expertise. PMID- 29129945 TI - Solid-phase synthesis of cyclic hexapeptides wollamides A, B and desotamide B. AB - Solid-phase synthesis of antibacterial cyclohexapeptides including wollamides A, B and desotamide B has been developed. Briefly, the protected linear hexapeptides were assembled on 2-chlorotrityl chloride resin using standard Fmoc chemistry and diisopropylcarbodiimide/hydroxybenzotriazole coupling reagents, cleaved off-resin with hexafluoroisopropanol/dichloromethane to keep side-chain protecting groups intact, and cyclized in solution. Final global removal of all protecting groups using a cocktail of trifluoroacetic acid/triisopropylsilane/dichloromethane afforded the desired cyclic hexapeptides, which were characterized by 1H, 13C NMR, and HRMS. Subsequent investigation of macrocyclization parameters such as terminal residues, coupling reagents, and cyclization concentration revealed the optimized conditions for the synthesis of this class of cyclic hexapeptides. PMID- 29129947 TI - Microcredit and willingness to pay for environmental quality: Evidence from a randomized-controlled trial of finance for sanitation in rural Cambodia. AB - Low willingness to pay (WTP) for environmental quality in developing countries is a key research question in environmental economics. One explanation is that missing credit markets may suppress WTP for environmental improvements that require large up-front investments. We test the impact of microloans on WTP for hygienic latrines via a randomized controlled trial in 30 villages in rural Cambodia. We find that microcredit dramatically raises WTP for improved latrines, with 60% of households in the Financing arm willing to purchase at an unsubsidized price, relative to 25% in the Non-financing arm. Effects on latrine installation are positive but muted by several factors, including a negative peer effect: randomly induced purchases by neighbors reduce a household's probability of installing its own latrine. On methodological grounds, this paper shows that a "decision-focused evaluation" can be integrated into academic analysis to provide insight into questions of general interest. PMID- 29129948 TI - Health externalities of India's expansion of coal plants: Evidence from a national panel of 40,000 households. AB - Coal power generation is expanding rapidly in India and other developing countries. In addition to consequences for climate change, present-day health externalities may also substantially increase the social cost of coal. Health consequences of air pollution have proven important in studies of developed countries, but, despite clear importance, similarly well-identified estimates are less available for developing countries, and no estimates exist for the important case of coal in India. We exploit panel data on Indian households, matched to local changes in exposure to coal plants. Increased exposure to coal plants is associated with worse respiratory health. Consistent with a causal mechanism, the effect is specific: no effect is seen on diarrhea or fever, and no effect on respiratory health is seen of new non-coal plants. Our result is not due to endogenous avoidance behavior, or to differential trends in determinants of respiratory health, either before the period studied or simultaneously. PMID- 29129949 TI - The Effects of Malpractice Non-Economic Damage Caps on the Supply of Physician Labor: Heterogeneity by Physician Age and Risk. AB - We explore the impact of malpractice caps on non-economic damages that were enacted between 2003 and 2006 on the supply of physician labor, separately for high-malpractice risk and low-malpractice risk physician specialty types, and separately by young and old physicians. We use physician data from the Area Resource File for 2000-2011 and malpractice policy data from the Database of State Tort Law Reforms. We study the impact of these caps using a reverse natural experiment, comparing physician supply in nine states enacting new caps to physician supply in ten states that had malpractice caps in place throughout the full time period. We use an event study to evaluate changes in physician labor compared to the prior year. We find evidence that non-economic damage caps increased the supply of high-risk physicians <35 years of age by 0.93 physicians per 100,000 people in the year after the caps were enacted. Non-economic damage caps were cumulatively associated with an increase of 2.1 high-risk physicians <35 years of age per 100,000 people. Stronger non-economic damage caps generally had a larger impact on physical supply. PMID- 29129950 TI - Response to 'Letter to the Editor: regarding Sylvetsky et al. 2017 Plasma concentrations of sucralose in children and adults'. PMID- 29129946 TI - Application of Materials as Medical Devices with Localized Drug Delivery Capabilities for Enhanced Wound Repair. AB - The plentiful assortment of natural and synthetic materials can be leveraged to accommodate diverse wound types, as well as different stages of the healing process. An ideal material is envisioned to promote tissue repair with minimal inconvenience for patients. Traditional materials employed in the clinical setting often invoke secondary complications, such as infection, pain, foreign body reaction, and chronic inflammation. This review surveys the repertoire of surgical sutures, wound dressings, surgical glues, orthopedic fixation devices and bone fillers with drug eluting capabilities. It highlights the various techniques developed to effectively incorporate drugs into the selected material or blend of materials for both soft and hard tissue repair. The mechanical and chemical attributes of the resultant materials are also discussed, along with their biological outcomes in vitro and/or in vivo. Perspectives and challenges regarding future research endeavors are also delineated for next-generation wound repair materials. PMID- 29129951 TI - A scalable correlator for multichannel diffuse correlation spectroscopy. AB - Diffuse correlation spectroscopy (DCS) is a technique which enables powerful and robust non-invasive optical studies of tissue micro-circulation and vascular blood flow. The technique amounts to autocorrelation analysis of coherent photons after their migration through moving scatterers and subsequent collection by single-mode optical fibers. A primary cost driver of DCS instruments are the commercial hardware-based correlators, limiting the proliferation of multi channel instruments for validation of perfusion analysis as a clinical diagnostic metric. We present the development of a low-cost scalable correlator enabled by microchip-based time-tagging, and a software-based multi-tau data analysis method. We will discuss the capabilities of the instrument as well as the implementation and validation of 2- and 8-channel systems built for live animal and pre-clinical settings. PMID- 29129952 TI - Association of ABO Blood Types and Clinicopathological Features of Prostate Cancer. AB - Purpose: To investigate the association between ABO blood types and clinicopathological characteristics in patients with prostate cancer (PC). Methods: A total of 237 pathologically diagnosed PC patients were enrolled. All patients were classified as low-middle or high-risk group. The correlation of ABO blood types with high-risk PC was determined by univariate and multivariate regression analysis. Results: Data indicated 144 (85.7%) patients were stratified as high risk in the non-O group, while 50 (72.5%) patients in the O group (p = 0.025). However, there was no significant difference regarding PSA, Gleason score, stage, or metastasis between O and non-O group (p > 0.05). Univariate logistic regression analyses revealed PSA, Gleason score, and blood type non-O were all correlated with high-risk PC (OR = 1.139, p < 0.001; OR = 9.465, p < 0.001; OR = 2.280, p = 0.018, resp.). In the stepwise multivariate regression analysis, the association between blood type non-O and high-risk PC remained significant (OR = 33.066, 95% CI 2.391-457.323, and p = 0.009) after adjusting for confounding factors as well as PSA and Gleason score. Conclusion: The present study firstly demonstrated that non-O blood type was at higher risk of aggressive PC compared with O type, suggesting that PC patients with non-O blood type should receive more attention in clinical practice. PMID- 29129953 TI - A weak instrument [Formula: see text]-test in linear IV models with multiple endogenous variables. AB - We consider testing for weak instruments in a model with multiple endogenous variables. Unlike Stock and Yogo (2005), who considered a weak instruments problem where the rank of the matrix of reduced form parameters is near zero, here we consider a weak instruments problem of a near rank reduction of one in the matrix of reduced form parameters. For example, in a two-variable model, we consider weak instrument asymptotics of the form [Formula: see text] where [Formula: see text] and [Formula: see text] are the parameters in the two reduced form equations, [Formula: see text] is a vector of constants and [Formula: see text] is the sample size. We investigate the use of a conditional first-stage [Formula: see text]-statistic along the lines of the proposal by Angrist and Pischke (2009) and show that, unless [Formula: see text], the variance in the denominator of their [Formula: see text]-statistic needs to be adjusted in order to get a correct asymptotic distribution when testing the hypothesis [Formula: see text]. We show that a corrected conditional [Formula: see text]-statistic is equivalent to the Cragg and Donald (1993) minimum eigenvalue rank test statistic, and is informative about the maximum total relative bias of the 2SLS estimator and the Wald tests size distortions. When [Formula: see text] in the two-variable model, or when there are more than two endogenous variables, further information over and above the Cragg-Donald statistic can be obtained about the nature of the weak instrument problem by computing the conditional first-stage [Formula: see text]-statistics. PMID- 29129954 TI - THROUGH THE LENS OF RACE: BLACK AND WHITE WOMEN'S PERCEPTIONS OF WOMANHOOD. AB - The intersection of race and gender may create unique experiences for Black and White women in terms of work, family, domestic roles, and interpersonal relationships. Dissimilar gender-role norms may foster different perceptions of gender for these two groups of women. In the current study, we examined similarities and differences in Black and White women's perceptions of their gender using qualitative focus group methodology and grounded theory data analysis. The results identified five themes that were common to Black and White women: Gender-Based Mistreatment, Perceived Advantage, Friendships and Community, Caretaking, and Work and Family Options. One additional theme, Inner Strength, emerged only for Black women. Although many of the broad perceptions of womanhood were similar for Black and White women, analysis of the content within each theme highlighted important differences. We discuss the results in terms of how they may reflect socio-historical factors, gender discrimination, stereotypes, and gender-role norms. PMID- 29129955 TI - A COMPARATIVE ANALYSIS OF BIOETHICAL ISSUES FROM VIEW POINTS OF RELIGIOUS AFFAIRS ADMINISTRATION IN TURKEY, ROMAN CATHOLICISM AND ORTHODOX JUDAISM. AB - The arguments set forth by religious authority are important since they play a crucial role in shaping the social values of the public and influence the decision of individuals in practice pertaining to bioethical issues. The Religious Affairs Administration (RAA) was established at the inception of the Republic of Turkey in 1924 to guide religious considerations moving out of the Ottoman caliphate to a secular bioethical framework. In this article, the bioethical views of the RAA under Islamic tradition is examined and contrasted with those influenced by the Roman Catholic and Orthodox Judaic traditions. On bioethical deliberations related to the beginning and end-of-life, all three religious traditions justify sacredness of life and that of God's will in its preservation it. Assisted reproduction techniques between spouses is considered to be appropriate, although third party involvement is explicitly forbidden. Organ transplantation is approved by all three religious traditions, except uterine transplantation. Contraceptive practices are approved under certain conditions - views differ most on approaches to contraception and the appropriateness of methods. The RAA judgement on cloning is to prohibit it, like Roman Catholicism and Orthodox Judaism. In other topics, cosmetic surgery and gender determination are approved only for treatment. PMID- 29129956 TI - Relationship between Provider Stigma and Predictors of Staff Turnover among Addiction Treatment Providers. AB - To further our knowledge about feasible targets for improving quality of addiction treatment services, the current study provides preliminary assessment of the relationship between provider stigma and indicators of staff turnover. As predicted, results suggest that higher provider stigma was significantly related to lower ratings of job satisfaction and workplace climate. However, provider stigma was not significantly related to burnout. Our preliminary findings, if replicated, suggest the importance of considering provider stigma as a risk factor for future staff turnover and job dissatisfaction. Promising provider stigma interventions do exist and offer viable opportunity for improving quality of addiction treatment. PMID- 29129957 TI - Illusions of face memory: Clarity breeds familiarity. AB - When people perform a recognition memory task, they may avail themselves of different forms of information. For example, they may recall specific learning episodes, or rely on general feelings of familiarity. Although subjective familiarity is often valid, it can make people vulnerable to memory illusions. Research using verbal materials has shown that "old" responses are often increased by enhancing perceptual fluency, as when selected words are shown with relatively higher contrast on a computer. Conversely, episodic memory can create an erroneous sense of perceptual advantages for recently studied words. In this investigation, symmetric fluency effects were tested in face memory, a domain that is often considered neurologically and psychologically unique. In eight experiments involving over 800 participants, we found consistent memorial and perceptual illusions-fluency created feelings of familiarity, and familiarity created feelings of fluency. In both directions, these effects were manifested as response biases, suggesting effects based on memorial and perceptual attributions. PMID- 29129958 TI - Executive function predicts artificial language learning. AB - Previous research suggests executive function (EF) advantages among bilinguals compared to monolingual peers, and these advantages are generally attributed to experience controlling two linguistic systems. However, the possibility that the relationship between bilingualism and EF might be bidirectional has not been widely considered; while experience with two languages might improve EF, better EF skills might also facilitate language learning. In the current studies, we tested whether adults' and preschool children's EF abilities predicted success in learning a novel artificial language. After controlling for working memory and English receptive vocabulary, adults' artificial language performance was predicted by their inhibitory control ability (Study 1) and children's performance was predicted by their attentional monitoring and shifting ability (Study 2). These findings provide preliminary evidence suggesting that EF processes may be employed during initial stages of language learning, particularly vocabulary acquisition, and support the possibility of a bidirectional relationship between EF and language acquisition. PMID- 29129959 TI - Cancer-Targeting Ultrasmall Silica Nanoparticles for Clinical Translation: Physicochemical Structure and Biological Property Correlations. AB - Although a large body of literature exists on the potential use of nanoparticles for medical applications, the number of probes translated into human clinical trials is remarkably small. A major challenge of particle probe development and their translation is the elucidation of safety profiles associated with their structural complexity, not only in terms of size distribution and heterogeneities in particle composition but also their effects on biological activities and the relationship between particle structure and pharmacokinetics. Here, we report on the synthesis, characterization, and long-term stability of ultrasmall (<10 nm diameter) dual-modality (optical and positron emission tomography) and integrintargeting silica nanoparticles (cRGDY-PEG-Cy5-C' dots and 124I-(or 131I-) cRGDY-PEG-Cy5-C'dots) and the extent to which their surface ligand density differentially modulates key in vitro and in vivo biological activities in melanoma models over a range of ligand numbers (i.e., ~6-18). Gel permeation chromatography, established as an important particle characterization tool, revealed a two-year shelf life for cRGDY-PEG-Cy5-C' dots. Radiochromatography further demonstrated the necessary radiochemical stability for clinical applications. The results of subsequent ligand density-dependent studies elucidate strong modulations in biological response, including statistically significant increases in integrin-specific targeting and particle uptake, cellular migration and adhesion, renal clearance, and tumor-to-blood ratios with increasing ligand number. We anticipate that nanoprobe characteristics and a better understanding of the structure-function relationships determined in this study will help guide identification of other lead nanoparticle candidates for in vitro and in vivo biological assessments and product translation. PMID- 29129960 TI - Processing-Size Correlations in the Preparation of Magnetic Alginate Microspheres Through Emulsification and Ionic Crosslinking. AB - Magnetic alginate microspheres are biocompatible due to their alginate matrix, and motion-controllable by applied magnetic fields due to their magnetic character. Therefore, they have the potential of being used as vessels to a broad variety of materials, including drugs and therapeutic agents, facilitating entry to biological systems in a relatively non-invasive manner. Here, magnetic alginate microspheres were prepared through an emulsification and ionic cross linking process, where a mixture of alginate and iron oxide magnetic nanoparticles was initially dispersed in a continuous phase, followed by gelation of this dispersed phase into microspheres by cross-linking the dispersion with calcium ions. The resulting magnetic alginate microspheres were found to be superparamagnetic and to respond to applied magnetic fields by chain formation. The effect of shear rate, alginate concentration, and magnetic nanoparticle concentration on microsphere size was investigated with the aim to control the size of microspheres with respect to process and formulation parameters. Two of these parameters, shear rate and alginate concentration, were used to correlate experimental results with a theoretical model for the case where the dispersed phase is more viscous than the continuous phase. PMID- 29129961 TI - Enhancement of intrinsic optical signal recording with split spectrum optical coherence tomography. AB - Functional optical coherence tomography (OCT) of stimulus-evoked intrinsic optical signal (IOS) promises to be a new methodology for high-resolution mapping of retinal neural dysfunctions. However, its practical applications for non invasive examination of retinal function have been hindered by the low signal-to noise ratio (SNR) and small magnitude of IOSs. Split spectrum amplitude decorrelation has been demonstrated to improve the image quality of OCT angiography. In this study, we exploited split spectrum strategy to improve the sensitivity of IOS recording. The full OCT spectrum was split into multiple spectral bands and IOSs from each sub-band were calculated separately and then combined to generate a single IOS image sequence. The algorithm was tested on in vivo images of frog retinas. It significantly improved both IOS magnitude and SNR, which are essential for practical applications of functional IOS imaging. PMID- 29129962 TI - A Three-factor Structure of Emotion Understanding in Third-grade Children. AB - Theoretical conceptualizations of emotion understanding generally imply a two factor structure comprised of recognition of emotional expressions and understanding emotion-eliciting situations. We tested this structure in middle childhood and then explored the unique predictive value of various facets of emotion understanding in explaining children's socioemotional competence. Participants were 201 third-grade children and their mothers. Children completed five different measures, which provided eight distinct indices of emotion understanding. Mothers completed two questionnaires assessing children's socioemotional skills and problems. Results indicated that: (a) emotion understanding in third-grade children was differentiated into three unique factors: Prototypical Emotion Recognition, Prototypical Emotion Knowledge, and Advanced Emotion Understanding, (b) skills within factors were modestly related, (c) factors varied in complexity, supporting theoretical and empirical models detailing developmental sequencing of skills, and (d) skills in Prototypical Emotion Knowledge were uniquely related to mothers' reports of third-grade children's socioemotional competence. Implications regarding elementary-school age children's social cognitive development are discussed. PMID- 29129963 TI - 'If I was a different ethnicity, would she treat me the same?': Latino parents' experiences obtaining autism services. AB - This article reports on an ethnographic study with 12 Latino families of children on the autism spectrum related to obtaining autism services in Los Angeles County. Using critical discourse analysis of interviews, observations, and records, we consider the experiences of the Latino families in relation to: 1) A discursively constructed 'autism parent' subject position that mandates 'fighting' service systems to 'win' autism services for children, originating from White middle-class parents' socio-economic resources and social capital; 2) A neoliberal social services climate that assumes scarcity of available resources and prioritizes austerity in their authorization; and 3) A media and institutional 'cultural deficit' discourse that attributes disparities in autism services for Latino children to their parents' presumed culturally-based 'passivity.' We argue that parental discourse about fighting, or not fighting, for autism services is engendered by a tension between a parental logic of care, and the logic of competition of the economic market. PMID- 29129964 TI - A Likelihood-Free Approach for Characterizing Heterogeneous Diseases in Large Scale Studies. AB - We propose a non-parametric approach for characterizing heterogeneous diseases in large-scale studies. We target diseases where multiple types of pathology present simultaneously in each subject and a more severe disease manifests as a higher level of tissue destruction. For each subject, we model the collection of local image descriptors as samples generated by an unknown subject-specific probability density. Instead of approximating the probability density via a parametric family, we propose to side step the parametric inference by directly estimating the divergence between subject densities. Our method maps the collection of local image descriptors to a signature vector that is used to predict a clinical measurement. We are able to interpret the prediction of the clinical variable in the population and individual levels by carefully studying the divergences. We illustrate an application this method on simulated data as well as on a large scale lung CT study of Chronic Obstructive Pulmonary Disease (COPD). Our approach outperforms classical methods on both simulated and COPD data and demonstrates the state-of-the-art prediction on an important physiologic measure of airflow (the forced respiratory volume in one second, FEV1). PMID- 29129965 TI - Green light given to more research on health disparities in LGBT elders. PMID- 29129966 TI - Root growth in field-grown winter wheat: Some effects of soil conditions, season and genotype. AB - This work compared root length distributions of different winter wheat genotypes with soil physical measurements, in attempting to explain the relationship between root length density and soil depth. Field experiments were set up to compare the growth of various wheat lines, including near isogenic lines (Rht-B1a Tall NIL and Rht-B1c Dwarf NIL) and wheat lines grown commercially (cv. Battalion, Hystar Hybrid, Istabraq, and Robigus). Experiments occurred in two successive years under rain fed conditions. Soil water content, temperature and penetrometer resistance profiles were measured, and soil cores taken to estimate vertical profiles of pore distribution, and root number with the core-break method and by root washing. Root length distributions differed substantially between years. Wetter soil in 2014/2015 was associated with shallower roots. Although there was no genotypic effect in 2014/2015, in 2013/2014 the dwarf wheat had the most roots at depth. In the shallower layers, some wheat lines, especially Battalion, seemed better at penetrating non-structured soil. The increase in penetrometer resistance with depth was a putative explanation for the rapid decrease in root length density with depth. Differences between the two years in root profiles were greater than those due to genotype, suggesting that comparisons of different genotypic effects need to take account of different soil conditions and seasonal differences. We also demonstrate that high yields are not necessarily linked to resource acquisition, which did not seem to be limiting in the low yielding dwarf NIL. PMID- 29129967 TI - Single Particle Analyzer of Mass: A Charge Detection Mass Spectrometer with a Multi-Detector Electrostatic Ion Trap. AB - A new charge detection mass spectrometer that combines array detection and electrostatic ion trapping to repeatedly measure the masses of single ions is described. This instrument has four detector tubes inside an electrostatic ion trap with conical electrodes (cone trap) to provide multiple measurements of an ion on each pass through the trap resulting in a signal gain over a conventional trap with a single detection tube. Simulations of a cone trap and a dual ion mirror trap design indicate that more passes through the trap per unit time are possible with the latter. However, the cone trap has the advantages that ions entering up to 2 mm off the central axis of the trap are still trapped, the trapping time is less sensitive to the background pressure, and only a narrow range of energies are trapped so it can be used for energy selection. The capability of this instrument to obtain information about the molecular weight distributions of heterogeneous high molecular weight samples is demonstrated with 8 MDa polyethylene glycol (PEG) and 50 and 100 nm amine modified polystyrene nanoparticle samples. The measured mass distribution of the PEG sample is centered at 8 MDa. The size distribution obtained from mass measurements of the 100 nm nanoparticle sample is similar to the size distribution obtained from transmission electron microscopy (TEM) images, but most of the smaller nanoparticles observed in TEM images of the 50 nm nanoparticles do not reach a sufficiently high charge to trigger the trap on a single pass and be detected by the mass spectrometer. With the maximum trapping time set to 100 ms, the charge uncertainty is as low as +/-2 charges and the mass uncertainty is approximately 2% for PEG and polystyrene ions. PMID- 29129968 TI - Bleaching response of coral species in the context of assemblage response. AB - Caribbean coral reefs are declining due to a mosaic of local and global stresses, including climate change-induced thermal stress. Species and assemblage responses differ due to factors that are not easily identifiable or quantifiable. We calculated a novel species-specific metric of coral bleaching response, taxon alpha and -beta, which relates the response of a species to that of its assemblages for 16 species over 18 assemblages. By contextualizing species responses within the response of their assemblages, the effects of environmental factors are removed and intrinsic differences among taxa are revealed. Most corals experience either a saturation response, overly-sensitive to weak stress (alpha > 0) but under-responsive compared to assemblage bleaching (beta < 1), or a threshold response, insensitive to weak stress (alpha < 0) but over-responsive compared to assemblage bleaching (beta > 1). This metric may help reveal key factors of bleaching susceptibility and identify species as targets for conservation. PMID- 29129970 TI - Word Learning in Infant- and Adult-Directed Speech. AB - Infant-directed speech (IDS), compared with adult-directed speech (ADS), is characterized by a slower rate, a higher fundamental frequency, greater pitch variations, longer pauses, repetitive intonational structures, and shorter sentences. Despite studies on the properties of IDS, there is no direct demonstration of its effects for word learning in infants. This study examined whether 21- and 27-month-old children learned novel words better in IDS than in ADS. Two major findings emerged. First, 21-month-olds reliably learned words only in the IDS condition, although children with relatively larger vocabulary than their peers learned in the ADS condition as well. Second, 27-month-olds reliably learned the words in the ADS condition. These results support the implicitly held assumption that IDS does in fact facilitate word mapping at the start of lexical acquisition and that its influence wanes as language development proceeds. PMID- 29129969 TI - Statistical Contributions to Bioinformatics: Design, Modeling, Structure Learning, and Integration. AB - The advent of high-throughput multi-platform genomics technologies providing whole-genome molecular summaries of biological samples has revolutionalized biomedical research. These technologiees yield highly structured big data, whose analysis poses significant quantitative challenges. The field of Bioinformatics has emerged to deal with these challenges, and is comprised of many quantitative and biological scientists working together to effectively process these data and extract the treasure trove of information they contain. Statisticians, with their deep understanding of variability and uncertainty quantification, play a key role in these efforts. In this article, we attempt to summarize some of the key contributions of statisticians to bioinformatics, focusing on four areas: (1) experimental design and reproducibility, (2) preprocessing and feature extraction, (3) unified modeling, and (4) structure learning and integration. In each of these areas, we highlight some key contributions and try to elucidate the key statistical principles underlying these methods and approaches. Our goals are to demonstrate major ways in which statisticians have contributed to bioinformatics, encourage statisticians to get involved early in methods development as new technologies emerge, and to stimulate future methodological work based on the statistical principles elucidated in this article and utilizing all availble information to uncover new biological insights. PMID- 29129971 TI - networksis: A Package to Simulate Bipartite Graphs with Fixed Marginals Through Sequential Importance Sampling. AB - The ability to simulate graphs with given properties is important for the analysis of social networks. Sequential importance sampling has been shown to be particularly effective in estimating the number of graphs adhering to fixed marginals and in estimating the null distribution of graph statistics. This paper describes the networksis package for R and how its simulate and simulate_sis functions can be used to address both of these tasks as well as generate initial graphs for Markov chain Monte Carlo simulations. PMID- 29129972 TI - Inflammation and Colorectal Cancer. AB - : Colorectal cancer (CRC) is the fourth most common cancer in both men and women in the United States, resulting in over 55,000 deaths annually. Environmental and genetic factors influence the development of CRC, and inflammation is a critical hallmark of cancer that may arise from a variety of factors. Purpose of review: While patients with inflammatory bowel disease (IBD) have a higher risk of developing CRC, sporadic CRCs may engender or be potentiated by inflammation as well. In this review, we focus on recent advances in basic and translational research utilizing murine models to understand the contribution of inflammatory signaling pathways to CRC. Recent findings: We discuss advances in the utility of three-dimensional enteroid/colonoid/tumoroid cultures to understand immune epithelial interactions in CRC, as well as the potential for utilizing patient derived tumoroids for personalized therapies. Summary: This review underscores the importance of understanding the complex molecular mechanisms underlying inflammation in sporadic CRC and highlights up-and-coming or new avenues for CRC biomarkers or therapies. PMID- 29129973 TI - Are the Symptoms of an NSAID-Induced Ulcer Truly Milder Than Those of an Ordinary Ulcer? AB - Objective: The percentage of patients with nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin- (LDA-) induced ulcers who complain of gastrointestinal symptoms has generally been considered to be low. The aim of this study was to examine and compare the symptoms and quality of life (QOL) at peptic ulcer onset. Methods: This study involved 200 patients who were confirmed by endoscopy to be in the acute stage of gastroduodenal ulcer (A1-H1). Patients completed a self-administered questionnaire (Global Overall Symptom score and SF 8) at ulcer onset, and data were compared between NSAIDs/LDA ulcers and non NSAIDs/LDA ulcers. Results: The upper gastrointestinal symptoms score was significantly lower for patients using LDA only (20.5 +/- 9.4 in the nonusing group, 19.6 +/- 8.6 in the NSAIDs-only group, 16.7 +/- 11.6 in the LDA-only group, and 18.5 +/- 7.2 in the NSAIDs/LDA group, P < 0.05). The QOL score (physical summary) was significantly lower in the NSAID group (42.1 +/- 9.9) than in the nonusing group (47.6 +/- 7.6) (P < 0.05). Patients' characteristics showed no significant differences among the groups, with the exception of age. Conclusion: The severity of upper abdominal symptoms at peptic ulcer onset was similar between NSAID users and nonusers. PMID- 29129974 TI - Screening of Pesticides with the Potential of Inducing DSB and Successive Recombinational Repair. AB - A study was realized to ascertain whether eight selected pesticides would induce double strand breaks (DSB) in lymphocyte cultures and whether this damage would induce greater levels of proteins Rad51 participating in homologous recombination or of p-Ku80 participating in nonhomologous end joining. Only five pesticides were found to induce DSB of which only glyphosate and paraoxon induced a significant increase of p-Ku80 protein, indicating that nonhomologous end joining recombinational DNA repair system would be activated. The type of gamma-H2AX foci observed was comparable to that induced by etoposide at similar concentrations. These results are of importance since these effects occurred at low concentrations in the micromolar range, in acute treatments to the cells. Effects over longer exposures in actual environmental settings are expected to produce cumulative damage if repeated events of recombination take place over time. PMID- 29129975 TI - Forensic Age Estimation of Chinese Malaysian Adults by Evaluating Occlusal Tooth Wear Using Modified Kim's Index. AB - Background and Objective: Evaluation of dental attrition is an easy and relatively accurate approach to estimating the age of an adult either ante- or postmortem for some specific population. Dental attrition represents a progressive physiological age change that can be measured using variety of indices to aid as an adjunct in forensic age estimation. Some of the previously proposed indices have their own practical limitations. This paper focuses on using modified Kim's criteria to score dental attrition to estimate the age of Chinese Malaysian adults and validate it. Methodology: Tooth wear was evaluated on 190 dental models of Chinese Malaysian adults (age range: 20-60 years) using modified Kim's index to custom-derive a population specific linear equation. The same equation was validated further on new 60 dental casts. Results and Conclusion: Regression analysis revealed good correlation between age and teeth wear and lower standard error of estimate. Test of regression on a test sample (n = 30 pairs, age range: 20-60 years) showed insignificant difference between predicted versus the actual age with statistically acceptable mean absolute difference. These data suggest that modified Kim's index can be used effectively in forensic age estimation. PMID- 29129976 TI - Using Odd-Alkanes as a Carbon Source to Increase the Content of Nutritionally Important Fatty Acids in Candida krusei, Trichosporon cutaneum, and Yarrowia lipolytica. AB - We investigated the possibility of utilizing unusual carbon sources by three yeast strains: Candida krusei DBM 2136, Trichosporon cutaneum CCY 30-5-10, and Yarrowia lipolytica CCY 30-26-36. These strains are characterized by high biomass yield, ability to accumulate high amounts of lipids, and their potential as producers of dietetically important fatty acids. The aim of this work was the production of nutritionally important fatty acids by utilization of n-alkanes with an odd number of carbon atoms, alone and in combination with glucose and subsequent analysis of microbial lipids accumulation and fatty acid profile. All three yeast strains were able to grow and produce high amounts of the fatty acids of interest. Yarrowia lipolytica was found as the most suitable strain for the growth on n-alkanes (n-pentadecane and n-heptadecane) as the only source of carbon. The addition of biosurfactants rhamnolipids into the cultivation increased the ratio of heptadecenoic acid (up to 17.9% of total FAs in Y. lipolytica CCY 30-26-36, 14.9% in T. cutaneum CCY 30-5-10, and 17.5% in C. krusei DBM 2136) and the total biomass yield. The results show that, by manipulation of the initial cultivation conditions, the ratio of important fatty acids may be increased. PMID- 29129977 TI - Preinoculation of Soybean Seeds Treated with Agrichemicals up to 30 Days before Sowing: Technological Innovation for Large-Scale Agriculture. AB - The cultivation of soybean in Brazil experienced an expressive growth in the last decades. Soybean is highly demanding on nitrogen (N) that must come from fertilizers or from biological fixation. The N supply to the soybean crop in Brazil relies on the inoculation with elite strains of Bradyrhizobium japonicum, B. elkanii, and B. diazoefficiens, which are able to fulfill the crop's N requirements and enrich the soil for the following crop. The effectiveness of the association between N2-fixing bacteria and soybean plants depends on the efficacy of the inoculation process. Seed treatment with pesticides, especially fungicides or micronutrients, may rapidly kill the inoculated bacteria, affecting the establishment and outcome of the symbiosis. The development of technologies that allow inoculation to become a successful component of industrial seed treatment represents a valuable tool for the seed industry, as well as for the soybean crop worldwide. In this article, we report the results of new technologies, developed by the company Total Biotecnologia Industria e Comercio S/A of Brazil, for preinoculation of soybean seeds with bradyrhizobia, in the presence of agrichemicals. Our results demonstrate improved bacterial survival for up to 30 days after inoculation, without compromising nodulation, N2-fixation, and yield in the field. PMID- 29129978 TI - A Case of Peripheral Ulcerative Keratitis Associated with Autoimmune Hepatitis. AB - Purpose: To describe a case of peripheral ulcerative keratitis in the setting of autoimmune hepatitis and possible overlap syndrome with primary sclerosing cholangitis. Case Report: A 48-year-old African American female with autoimmune hepatitis with possible overlap syndrome with primary sclerosing cholangitis presented with tearing, irritation, and injection of the left eye that was determined to be peripheral ulcerative keratitis. The patient was treated with topical and systemic steroids, immunosuppressant drugs (azathioprine and mycophenolate mofetil), a biologic (rituximab), and surgery (conjunctival resection), and the peripheral ulcerative keratitis epithelialized but ultimately led to corneal perforation. Conclusion: In this unique case, a patient with peripheral ulcerative keratitis who underwent treatment ultimately had a corneal perforation. This case may suggest a possible relationship between autoimmune hepatitis and peripheral ulcerative keratitis. PMID- 29129979 TI - Hair Germ Model In Vitro via Human Postnatal Keratinocyte-Dermal Papilla Interactions: Impact of Hyaluronic Acid. AB - Hair follicle (HF) reconstruction in vitro is a promising field in alopecia treatment and human HF development research. Here, we combined postnatal human dermal papilla (DP) cells and skin epidermal keratinocytes (KCs) in a hanging drop culture to develop an artificial HF germ. The method is based on DP cell hair-inducing properties and KC self-organization. We evaluated two protocols of aggregate assembling. Mixed HF germ-like structures demonstrated the initiation of epithelial-mesenchymal interaction, including WNT pathway activation and expression of follicular markers. We analyzed the influence of possible DP cell niche components including soluble factors and extracellular matrix (ECM) molecules in the process of the organoid assembling and growth. Our results demonstrated that soluble factors had little impact on HF germ generation and Ki67+ cell score inside the organoids although BMP6 and VD3 maintained effectively the DP identity in the monolayer culture. Aggrecan, biglycan, fibronectin, and hyaluronic acid (HA) significantly stimulated cell proliferation in DP cell monolayer culture without any effect on DP cell identity. Most of ECM compounds prevented the formation of cell aggregates while HA promoted the formation of larger organoids. In conclusion, our model could be suitable to study cell-cell and cell-niche interactions during HF reconstruction in vitro. PMID- 29129981 TI - The Spatial and Career Mobility of China's Urban and Rural Labor Force. AB - This paper provides a comprehensive examination of the spatial and career mobility of China's labor population. The paper integrates theories on stratification and social change and exploits the innovative design and measurement of the China Labor-force Dynamics Survey to minimize the under coverage problem of the rural-urban migratory experience. Our analysis provides several fresh findings: (1) at-birth rural household registration (hukou) status leads to a greater probability of spatial mobility and career advancement than at birth urban hukou status does; (2) education and gender differentiates rural origin people, increasing the heterogeneity of urban labor and decreasing the heterogeneity of rural labor; (3) hukou policy relaxation favors later cohorts over earlier cohorts; and (4) among demographically comparable people, having experienced spatial mobility is correlated with having career advancement experience. Work organizations are found to be the arena where the two dimensions of mobility can happen jointly. Our findings provide a rich context for understanding the management and organization of Chinese labor. PMID- 29129980 TI - Quality of Care of Patients with Diabetes in Primary Health Services in Southeast Brazil. AB - Background: Diabetes management involves multiple aspects that go beyond drug therapy as a way of providing high quality care. The objective of this study was to describe quality of care indicators for individuals with diabetes in southeast Brazil and to explore associations among these indicators. Methods: In this cross sectional, observational study, health care providers filled out a questionnaire addressing health care structure and processes at 14 primary health care units (PHCUs). Clinical and laboratory data of diabetic patients attending the PHCUs and from patients referred to a secondary health care (SHC) center were collected. Results: There was a shortage of professionals in 53.8% of the PHCUs besides a high proportion of problems regarding referrals to SHC. At the PHCU, glycated hemoglobin results were available only in half of the medical records. A low rate of adequate glycemic control was also observed. An association between structure and process indicators and the outcomes analyzed was not found. Conclusion: Major deficiencies were found in the structure and processes of the PHCUs, in addition to unsatisfactory diabetes care outcomes. However, no association between structure, process, and outcomes was found. PMID- 29129982 TI - Antioxidant capacity and major phenol compounds of horticultural plant materials not usually used. AB - Horticultural plant materials not usually used from onion, carrot, beetroot, sea buckthorn, black and red currants as well as a wastewater powder from olive oil production were analyzed for total phenols content (FC), ferric reducing ability of plasma (FRAP), radical scavenging capacity (ABTS), and for major phenolic compounds by HPLC-MS. Antioxidant capacity and phenol content varied significantly between species and cultivars, with extracts of sea buckthorn leaves being superior. In different species, different phenolic compounds were closely associated with FRAP, ABTS and FC. For instance, hydrolysable tannins were major antioxidants in sea buckthorn whereas quercetin was the major antioxidant in onion peel and skin. This study shows that horticultural plant materials usually left in the field or waste materials from processing may have high antioxidant properties, and that extracts of these materials therefore could be of potential interest for development of antioxidant food additives. PMID- 29129983 TI - The impact of oat structure and beta-glucan on in vitro lipid digestion. AB - Oat beta-glucan has been shown to play a positive role in influencing lipid and cholesterol metabolism. However, the mechanisms behind these beneficial effects are not fully understood. The purpose of the current work was to investigate some of the possible mechanisms behind the cholesterol lowering effect of oat beta glucan, and how processing of oat modulates lipolysis. beta-Glucan release, and the rate and extent of lipolysis measured in the presence of different sources of oat beta-glucan, were investigated during gastrointestinal digestion. Only a fraction of the original beta-glucan content was released during digestion. Oat flakes and flour appeared to have a more significant effect on lipolysis than purified beta-glucan. These findings show that the positive action of beta-glucan is likely to involve complex processes and interactions with the food matrix. This work also highlights the importance of considering the structure and physicochemical properties of foods, and not just the nutrient content. PMID- 29129984 TI - Intercultural competency development of health professions students during study abroad in India. AB - Objective: Short-term international health-related study abroad seminars for health-professions students are increasingly popular because of a focus in higher education on global awareness and intercultural competency. This study describes a study abroad strategy to teach students intercultural communication skills and knowledge, and evaluated the effectiveness of a 3-week health-related study abroad program and intercultural competency curriculum in increasing skills and knowledge of health-profession students. Methods: This was a mixed methods study, with a pretest-posttest, within-subjects design, and content analysis of student reflection journals. The curriculum was designed to increase students' sensitivity to different cultural worldviews and support attitudes such as curiosity and openness that lead to relational abilities such as flexibility and adaptability. Students completed the Intercultural Sensitivity Scale (ISS) and Intercultural Effectiveness Scale (IES) both 3 months prior to and immediately following the trip. Means and standard deviations were calculated and a paired t test was performed. Results: Qualitative analysis of students' reflections presented evidence of developing awareness of their own cultural worldview, openness to Indian culture, and the use of skills to develop intercultural competence. There was a non-statistically significant improvement in ISS and IES scores. Conclusions: Students' reflections demonstrated personal growth through the acquisition of knowledge and skills needed for further intercultural competence development. Students indicated that the curriculum helped them make meaning out of their experiences. Short-term health-related study abroad seminars may help students develop self-awareness and cultural openness by providing theoretically based curriculum before departure and while in the host country, including structured reflections and cultural mentoring, engagement with locals, and a balance of challenge with support. PMID- 29129985 TI - Orientation of Methylguanidinium Ions at the Water-Air Interface. AB - We use heterodyne-detected vibrational sum-frequency generation (HD-VSFG) to determine the orientation of the molecular plane of methylguanidinium ions at the surface of aqueous solutions. We measure the VSFG response of the symmetric and antisymmetric methyl stretch vibrations of the methylguanidinium ion with different polarization combinations. We find that for at least 50% of the methylguanidinium ions the molecular plane is at an angle >20 degrees with respect to the surface plane. Hence, for only a minor fraction of the ions does the molecular plane have an orientation (near-)parallel to the surface plane, in contrast to the predictions of recent molecular dynamics simulation studies. PMID- 29129986 TI - Ghrelin Protects Human Lens Epithelial Cells against Oxidative Stress-Induced Damage. AB - Oxidative stress has been recognized as an important mediator in the pathogenesis of age-related cataracts; using antioxidant supplements is one plausible strategy to protect the antioxidative defense system against oxidative stress. Ghrelin administration is expected to reduce ROS, preventing the onset of different diseases. The role of ghrelin, if any, in protecting against oxidative stress in HLECs has never been examined. In the present study, we investigated the effects of ghrelin against H2O2-induced oxidative stress and the associated molecular mechanisms in HLECs and rat lenses. The results showed that pretreatment with ghrelin reduced H2O2-induced cellular apoptosis and ROS accumulation, increased the expression levels of SOD and CAT, and decreased the expression level of MDA. The morphological examination showed that the ghrelin-treated lens organ culture maintained transparency. This is the first report to show that ghrelin can protect HLECs from H2O2-induced oxidative stress. Our findings suggest that ghrelin may prevent the progression of cataracts, which has treatment value for ophthalmologists. PMID- 29129988 TI - Effect of ALDH2 on High Glucose-Induced Cardiac Fibroblast Oxidative Stress, Apoptosis, and Fibrosis. AB - Our study aimed firstly to observe whether ALDH2 was expressed in neonate rat cardiac fibroblasts, then to investigate the effect of activation of ALDH2 on oxidative stress, apoptosis, and fibrosis when cardiac fibroblasts were subjected to high glucose intervention. Cultured cardiac fibroblasts were randomly divided into normal (NG), NG + Alda-1, high glucose (HG), HG + Alda-1, HG + Alda-1 + daidzin, HG + daidzin, and hypertonic groups. Double-label immunofluorescence staining, RT-PCR, and Western blot revealed ALDH2 was expressed in cardiac fibroblasts. Compared with NG, ALDH2 activity and protein expression were reduced, and cardiac fibroblast proliferation, ROS releasing, 4-HNE protein expression, collagen type I and III at mRNA levels, and the apoptosis rate were increased in HG group. While in HG + Alda-1 group, with the increases of ALDH2 activity and protein expression, the cardiac fibroblast proliferation and ROS releasing were decreased, and 4-HNE protein expression, collagen type I and III at mRNA levels, and apoptosis rate were reduced compared with HG group. When treated with daidzin in HG + Alda-1 group, the protective effects were inhibited. Our findings suggested that ALDH2 is expressed in neonate rat cardiac fibroblasts; activation of ALDH2 decreases the HG-induced apoptosis and fibrosis through inhibition of oxidative stress. PMID- 29129987 TI - Increasing the Fungicidal Action of Amphotericin B by Inhibiting the Nitric Oxide Dependent Tolerance Pathway. AB - Amphotericin B (AmB) induces oxidative and nitrosative stresses, characterized by production of reactive oxygen and nitrogen species, in fungi. Yet, how these toxic species contribute to AmB-induced fungal cell death is unclear. We investigated the role of superoxide and nitric oxide radicals in AmB's fungicidal activity in Saccharomyces cerevisiae, using a digital microfluidic platform, which enabled monitoring individual cells at a spatiotemporal resolution, and plating assays. The nitric oxide synthase inhibitor L-NAME was used to interfere with nitric oxide radical production. L-NAME increased and accelerated AmB induced accumulation of superoxide radicals, membrane permeabilization, and loss of proliferative capacity in S. cerevisiae. In contrast, the nitric oxide donor S nitrosoglutathione inhibited AmB's action. Hence, superoxide radicals were important for AmB's fungicidal action, whereas nitric oxide radicals mediated tolerance towards AmB. Finally, also the human pathogens Candida albicans and Candida glabrata were more susceptible to AmB in the presence of L-NAME, pointing to the potential of AmB-L-NAME combination therapy to treat fungal infections. PMID- 29129989 TI - Inhibitory Effect of Propolis on Platelet Aggregation In Vitro. AB - Platelet hyperactivity plays an important role in arterial thrombosis and atherosclerosis. The present study was aimed to investigate the effects of different extracts of propolis and components of flavonoids on platelet aggregation. Platelet-rich plasma was prepared and incubated in vitro with different concentrations of the tested extracts and components of flavonoids. Platelets aggregation was induced by different agonists including adenosine diphosphate (ADP, 10 MUM), thrombin receptor activator peptide (TRAP, 50 MUM), and collagen (5 MUg/mL). At 25 mg/L to 300 mg/mL, the water extract propolis (WEP) inhibited three agonists-induced platelet aggregations in a dose-dependent manner. The flavonoids isolated from the propolis also showed markedly inhibited platelet aggregation induced by collagen, ADP, and TRAP, respectively. The components including caffeic acid phenethyl ester (CAPE), galangin, apigenin, quercetin, kaempferol, ferulic acid, rutin, chrysin, pinostrobin, and pinocembrin and their abilities of inhibiting platelet aggregation were studied. It was concluded that propolis had an antiplatelet action in which flavonoids were mainly implicated. PMID- 29129990 TI - Tripodal Amine Ligands for Accelerating Cu-Catalyzed Azide-Alkyne Cycloaddition: Efficiency and Stability against Oxidation and Dissociation. AB - Ancillary ligands, especially the tripodal ligands such as tris(triazolylmethyl)amines, have been widely used to accelerate the Cu-catalyzed azide-alkyne cycloaddition (CuAAC, a "click" reaction). However, the relationship between the activity of these Cu(I) complexes and their stability against air oxidation and ligand dissociation/exchange was seldom studied, which is critical for the applications of CuAAC in many biological systems. In this work, we synthesized twenty-one Cu(I) tripodal ligands varying in chelate arm length (five to seven atoms), donor groups (triazolyl, pyridyl and phenyl), and steric hindrance. The effects of these variables on the CuAAC reaction, air oxidation, and ligand dissociation were evaluated. Reducing the chelate arm length to five atoms, decreasing steric hindrance, or using a relatively weakly-binding ligand can significantly increase the CuAAC reactivity of the Cu(I) complexes, but the concomitant higher degree of oxidation cannot be avoided, which leads to rapid degradation of a histidine-containing peptide as a model of proteins. The oxidation of the peptide can be reduced by attaching oligo(ethylene glycol) chains to the ligands as sacrificing reagents. Using electrospray ionization mass spectrometry (ESI-MS), we directly observed the tri- and di-copper(I)-acetylide complexes in CuAAC reaction in the [5,5,5] ligand system and a small amount of di Cu(I)-acetylide in the [5,5,6] ligand system. Only the mono-Cu(I) ligand adducts were observed in the [6,6,6] and [5,6,6] ligand systems. PMID- 29123642 TI - Supporting evidence-based analysis for modified risk tobacco products through a toxicology data-sharing infrastructure. AB - The US FDA defines modified risk tobacco products (MRTPs) as products that aim to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products. Establishing a product's potential as an MRTP requires scientific substantiation including toxicity studies and measures of disease risk relative to those of cigarette smoking. Best practices encourage verification of the data from such studies through sharing and open standards. Building on the experience gained from the OpenTox project, a proof-of-concept database and website ( INTERVALS) has been developed to share results from both in vivo inhalation studies and in vitro studies conducted by Philip Morris International R&D to assess candidate MRTPs. As datasets are often generated by diverse methods and standards, they need to be traceable, curated, and the methods used well described so that knowledge can be gained using data science principles and tools. The data-management framework described here accounts for the latest standards of data sharing and research reproducibility. Curated data and methods descriptions have been prepared in ISA-Tab format and stored in a database accessible via a search portal on the INTERVALS website. The portal allows users to browse the data by study or mechanism (e.g., inflammation, oxidative stress) and obtain information relevant to study design, methods, and the most important results. Given the successful development of the initial infrastructure, the goal is to grow this initiative and establish a public repository for 21 st-century preclinical systems toxicology MRTP assessment data and results that supports open data principles. PMID- 29123644 TI - RNAi targeting Caenorhabditis elegans alpha-arrestins has small or no effects on lifespan. AB - Background: alpha-arrestins are a family of proteins that are implicated in multiple biological processes, including metabolism and receptor desensitization. Methods: Here, we sought to examine the roles of alpha-arrestins in the longevity of Caenorhabditis elegans through an RNA interference screen. Results: We found that knocking down each of 24 out of total 29 C. elegans alpha-arrestins had small or no effects on lifespan. Thus, individual C. elegans alpha-arrestins may have minor effects on longevity. Conclusions: This study will provide useful information for future research on the functional role of alpha-arrestins in aging and longevity. PMID- 29123645 TI - BeerDeCoded: the open beer metagenome project. AB - Next generation sequencing has radically changed research in the life sciences, in both academic and corporate laboratories. The potential impact is tremendous, yet a majority of citizens have little or no understanding of the technological and ethical aspects of this widespread adoption. We designed BeerDeCoded as a pretext to discuss the societal issues related to genomic and metagenomic data with fellow citizens, while advancing scientific knowledge of the most popular beverage of all. In the spirit of citizen science, sample collection and DNA extraction were carried out with the participation of non-scientists in the community laboratory of Hackuarium, a not-for-profit organisation that supports unconventional research and promotes the public understanding of science. The dataset presented herein contains the targeted metagenomic profile of 39 bottled beers from 5 countries, based on internal transcribed spacer (ITS) sequencing of fungal species. A preliminary analysis reveals the presence of a large diversity of wild yeast species in commercial brews. With this project, we demonstrate that coupling simple laboratory procedures that can be carried out in a non professional environment with state-of-the-art sequencing technologies and targeted metagenomic analyses, can lead to the detection and identification of the microbial content in bottled beer. PMID- 29118975 TI - Interfacial microscopic examination and chemical analysis of resin-dentin interface of self-adhering flowable resin composite. AB - Background: The newly introduced self-adhering flowable resin-composites decrease the required time for application by incorporation of an acidic adhesive monomer, thus reducing the number of the steps, but its bonding is still uncertain. The aim of this study was to evaluate the interfacial microscopic examination and chemical analysis at the resin-dentin interface of a self-adhering flowable resin composite (Vertise-Flow) versus a total-etch (Te-Econom Plus) resin composite, using an etching agent (Eco-Etch gel) and bonding agent (Single Bond Universal). Methods: Sixteen freshly extracted sound human posterior teeth were used. The teeth were randomly divided into two groups: 8 specimens per type of composite. Standard-shaped class V cavities were prepared on the buccal surface. One group was restored by Te-Econom Plus resin composite by total-etch technique using Eco Etch gel, which was applied to dentine for 15 seconds, followed by rinsing, drying and bonding agent application (Single Bond Universal). The other group restored directly with self-adhering resin composite (Vertise-Flow) without application of etch or bond. Curing was done for 20 seconds using a light emitting diode light curing unit. Evaluation of the resin-dentin interface was done microscopically by examination of marginal gap distance in MUm using scanning electron microscope (SEM), and chemical analysis of silver particles was observed using SEM with energy-dispersive X-ray spectrometry after 24 hours of specimen storage in ammoniacal silver nitrate. Results: Regarding marginal gap distance (um) and silver atomic % mean values, teeth restored with self-adhering resin composite (Vertise-Flow) showed significantly higher mean values than the multi-step etch and rinse resin composite group (5.2 vs 0; 12.2 vs 8.2, respectively). Conclusions: Resin-dentin bonding using total-etch resin composite technique was more effective than self-adhering flowable resin composite (Vertise Flow) regarding marginal gap formation and penetration of silver particles. Further studies for bond strength could be performed. PMID- 29118975 TI - Interfacial microscopic examination and chemical analysis of resin-dentin interface of self-adhering flowable resin composite. AB - Background: The newly introduced self-adhering flowable resin-composites decrease the required time for application by incorporation of an acidic adhesive monomer, thus reducing the number of steps, but its bonding is still uncertain. The aim of this study was to evaluate the interfacial microscopic examination and chemical analysis at the resin-dentin interface of a self-adhering flowable resin composite (VertiseTMFlow Self-Adhering Flowable Composite, Kerr Dental, USA) versus a total-etch (Te-Econom Plus) resin composite, using an etching agent (Eco Etch gel) and bonding agent (Single Bond Universal). Methods: Sixteen freshly extracted sound human posterior teeth were used. The teeth were randomly divided into two groups: 8 specimens per type of composite. Standard-shaped class V cavities were prepared on the buccal surface. One group was restored by Te-Econom Plus resin composite by total-etch technique using Eco-Etch gel, which was applied to dentine for 15 seconds, followed by rinsing, drying and bonding agent application (Single Bond Universal). The other group restored directly with self adhering resin composite (Vertise-Flow) without application of etch or bond. Curing was done for 20 seconds using a light emitting diode light curing unit. Evaluation of the resin-dentin interface was done microscopically by examination of marginal gap distance in MUm using scanning electron microscope (SEM), and chemical analysis of silver particles was observed using SEM with energy dispersive X-ray spectrometry after 24 hours of specimen storage in ammoniacal silver nitrate. Results: Regarding marginal gap distance (um) and silver atomic % mean values, teeth restored with self-adhering resin composite (Vertise-Flow) showed significantly higher mean values than the multi-step etch and rinse resin composite group (5.2 vs 0; 12.2 vs 8.2, respectively). Conclusions: Resin-dentin bonding using total-etch resin composite technique was more effective than self adhering flowable resin composite (Vertise-Flow) regarding marginal gap formation and penetration of silver particles. Further studies for bond strength could be performed. PMID- 29129996 TI - ADDRESSING HYPERTENSION IN THE PATIENT WITH TYPE 2 DIABETES MELLITUS: PATHOGENESIS, GOALS, AND THERAPEUTIC APPROACH. AB - Hypertension is considered a powerful cardiovascular risk factor and is present in up to two-thirds of patients who suffer from diabetes. In the background of an established epidemiological association between lower blood pressure (BP) and improvement in long-term clinical outcomes, several large landmark trials and analyses have attempted to examine the possible benefit of tighter BP control in patients with Type 2 diabetes mellitus. Although aggressive BP targets in patients with diabetes have been advocated for a long time, currently accepted evidence from these studies has led to a general recommendation of systolic BP <140 mmHg and diastolic BP <90 mmHg. Therapy consists of lifestyle management, including weight loss if overweight or obese, a Dietary Approaches to Stop Hypertension (DASH)-style based nutrition counselling, and reduced sodium intake. Timely initiation and subsequent titration of antihypertensive medications to achieve individualised BP goals is recommended. A therapeutic agent that acts on the renin-angiotensin-aldosterone pathway, such as an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, should generally be included in the pharmacologic therapy for hypertension in patients with Type 2 diabetes mellitus. A multi-drug combination, particularly including a thiazide diuretic, is very often necessary and should be started early in the course of management. Finally, an accurate and standardised method of BP measurement in the outpatient setting is essential to ensure proper monitoring and gauge the effectiveness of treatment. PMID- 29129998 TI - Changes in Retinal and Choroidal Vascular Blood Flow after Oral Sildenafil: An Optical Coherence Tomography Angiography Study. AB - Purpose: To describe changes in the retina and choroidal flow by optical coherence tomography angiography (OCT-A) after a single dose of oral sildenafil. Method: A case-control study. Patients in the study group received 50 mg of oral sildenafil. Patients in the control group received a sham pill. Retinal and choroidal images were obtained at baseline (before pill ingestion) and 1 hour after ingestion. Central macular and choroidal thickness, choroidal and outer retina flow, and the retinal and choroidal vascular density were compared using a Mann-Whitney U test. Results: Twenty eyes were enrolled into the study group and 10 eyes in the control group. There was a significant difference in central choroidal thickness and outer retina blood flow between groups after 1 hour of sildenafil ingestion (p < 0.01). There were no differences in central macular thickness, choroidal flow, and retinal vascular density among groups. Conclusions: A single dose of oral sildenafil increases choroidal thickness, probably due to sildenafil-induced vasodilation. PMID- 29129997 TI - Trichloroethylene-induced alterations in DNA methylation were enriched in polycomb protein binding sites in effector/memory CD4+ T cells. AB - Exposure to industrial solvent and water pollutant trichloroethylene (TCE) can promote autoimmunity, and expand effector/memory (CD62L) CD4+ T cells. In order to better understand etiology reduced representation bisulfite sequencing was used to study how a 40-week exposure to TCE in drinking water altered methylation of ~337 770 CpG sites across the entire genome of effector/memory CD4+ T cells from MRL+/+ mice. Regardless of TCE exposure, 62% of CpG sites in autosomal chromosomes were hypomethylated (0-15% methylation), and 25% were hypermethylated (85-100% methylation). In contrast, only 6% of the CpGs on the X chromosome were hypomethylated, and 51% had mid-range methylation levels. In terms of TCE impact, TCE altered (>= 10%) the methylation of 233 CpG sites in effector/memory CD4+ T cells. Approximately 31.7% of these differentially methylated sites occurred in regions known to bind one or more Polycomb group (PcG) proteins, namely Ezh2, Suz12, Mtf2 or Jarid2. In comparison, only 23.3% of CpG sites not differentially methylated by TCE were found in PcG protein binding regions. Transcriptomics revealed that TCE altered the expression of ~560 genes in the same effector/memory CD4+ T cells. At least 80% of the immune genes altered by TCE had binding sites for PcG proteins flanking their transcription start site, or were regulated by other transcription factors that were in turn ordered by PcG proteins at their own transcription start site. Thus, PcG proteins, and the differential methylation of their binding sites, may represent a new mechanism by which TCE could alter the function of effector/memory CD4+ T cells. PMID- 29129999 TI - Expression of Genes and Their Polymorphism Influences the Risk of Knee Osteoarthritis. AB - Introduction: Genetic factors including the level of expression of the fingerprint of genes involved in the development of bones and cartilage such as GDF-5 or ESR-alpha or CALM-1 are known to be strong determinants of the osteoarthritis (OA) in Caucasian and Oriental populations. Because of high prevalence of OA in Indian population and availability of limited genetic data, we determined whether similar genetic factors are involved in Indians as well. Methods: A case control study was carried out involving 500 patients of knee OA and equal number of healthy controls. Genotyping analyses in whole blood, mRNA, and protein expressions in peripheral blood lymphocytes (PBLs) were performed using established protocols. Results: Our results showed a significantly decreased level of mRNA and protein expressions for GDF-5, ESR-alpha, and CALM-1 genes in PBLs of OA cases when compared to healthy controls. The frequency of variant genotypes of these genes was also increased significantly in cases of OA compared to controls. Conclusion: Our results demonstrated that the decrease in expression of GDF-5, ESR-alpha, and CALM-1 in PBLs and association of polymorphism in these genes may be important in predicting the severity and thereby the progression of OA in Indian population. PMID- 29130000 TI - Knowledge of Stroke Risk Factors and Warning Signs in Patients with Recurrent Stroke or Recurrent Transient Ischaemic Attack in Thailand. AB - Stroke is a global burden. It is not known whether patients who are most at risk of stroke (recurrent stroke or recurrent transient ischaemic attack) have enough knowledge of stroke risk factors and warning signs. The aim of this study was to assess the knowledge of stroke risk factors and warning signs in this high-risk population. We performed a cross-sectional questionnaire-based study of patients with recurrent stroke or recurrent TIA admitted to Srinagarind Hospital and Khon Kaen Hospital, Thailand. A total of 140 patients were included in the study (age 65.6 +/- 11.3 years [mean +/- SD], 62 females). Using an open-ended questionnaire, nearly one-third of patients (31.4%) could not name any risk factors for stroke. The most commonly recognized risk factors were hypertension (35%), dyslipidemia (28.6%), and diabetes (22.9%). Regarding stroke warning signs, the most commonly recognized warning signs were sudden unilateral weakness (61.4%), sudden trouble with speaking (25.7%), and sudden trouble with walking, loss of balance, or dizziness (21.4%). Nineteen patients (13.6%) could not identify any warning signs. The results showed that knowledge of stroke obtained from open-ended questionnaires is still unsatisfactory. The healthcare provider should provide structured interventions to increase knowledge and awareness of stroke in these patients. PMID- 29130001 TI - Are Patients Traveling for Intraoperative Radiation Therapy? AB - Purpose: One benefit of intraoperative radiation therapy (IORT) is that it usually requires a single treatment, thus potentially eliminating distance as a barrier to receipt of whole breast irradiation. The aim of this study was to evaluate the distance traveled by IORT patients at our institution. Methods: Our institutional prospective registry was used to identify IORT patients from 10/2011 to 2/2017. Patient's home zip code was compared to institution zip code to determine travel distance. Characteristics of local (<50 miles), regional (50 100 miles), and faraway (>100 miles) patients were compared. Results: 150 were patients included with a median travel distance of 27 miles and mean travel distance of 121 miles. Most were local (68.7%), with the second largest group living faraway (20.0%). Subset analysis of local patients demonstrated 20.4% traveled <10 miles, 34.0% traveled 10-20 miles, and 45.6% traveled 20-50 miles. Six patients traveled >1000 miles. The local, regional, and faraway patients did not differ with respect to age, race, tumor characteristics, or whole breast irradiation. Conclusions: Breast cancer patients are traveling for IORT, with 63% traveling >20 miles for care. IORT is an excellent strategy to promote breast conservation in selected patients, particularly those who live remote from a radiation facility. PMID- 29130002 TI - Right Atrial Fibroelastoma Presenting as Typical Atrial Flutter: Rare Disease in Unusual Location. AB - Typical atrial flutter as initial presentation of papillary fibroelastoma involving the cavotricuspid isthmus is not described before in literature. To our knowledge only 14 cases have been reported in literature involving the right atrium. Very unusual location is at the junction between inferior vena cava (IVC) and right atria as only 1 case has been reported. PMID- 29130003 TI - Spontaneous Tumor Lysis Syndrome due to Uterine Leiomyosarcoma with Lung Metastases. AB - Tumor lysis syndrome (TLS) is an oncologic emergency characterized by a combination of metabolic derangements (hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia) caused by rapid turnover from cell destruction in certain cancers. These metabolic derangements can lead to seizures, cardiac arrhythmias, renal failure, and death. TLS is usually seen after the initiation of chemotherapy for hematologic malignancies. TLS occurring spontaneously, without initiation of chemotherapy, is rare and its occurrence in solid tumors is rarer still. We report a case of spontaneous TLS in a patient with leiomyosarcoma of the uterus, with metastasis to lung. Such a case has never been reported before. PMID- 29130004 TI - Gastrointestinal Involvement of Testicular Germ Cell Tumor: A Case Report and Literature Review. AB - Testicular germ cell tumors (GCT) are the commonest solid tumors in young men. Typical presentation is with painless scrotal swelling; however, symptoms related to complications or metastasis may be the initial presentation. Gastrointestinal (GI) metastasis is seen in about 5% of patients with germ cell tumors and presentation is commonly with GI bleed. It is important to have GCT as a differential diagnosis of GI bleed in young men presenting with unexplained anemia as direct questioning about scrotal swelling and genital examination when appropriate will guide further investigation and facilitate prompt diagnosis. We present a case of a 26-year-old man with testicular germ cell tumor and severe anemia secondary to extension and perforation of duodenum by retroperitoneal metastasis and a review of the literature on the gastrointestinal manifestations of testicular germ cell tumors. PMID- 29130005 TI - A Case of Haematometra Secondary to Cervical Stenosis after Vesicle Vaginal Fistula Surgical Repair. AB - Background. Haematometra is a rare postobstetrics fistula surgical repair outcome complication; however the condition can be misinterpreted especially in limited resource areas that lack routine ultrasound guidance and with a slowly progressed increase in size of abdomen accompanied with a history of amenorrhoea together with a history of having unprotective sexual intercourse which may increase the possibility of being controversial to full-term gravid uterus. The causes of haematometra might be either due to congenital abnormality of the vaginal canal or acquired iatrogenically. However, any other cause that involved vaginal canal can be a predisposing factor of haematometra. We present a case of a 32-year-old female patient, who had obstetric fistula which was successfully repaired over the past two years. She presented with one-year-and-two-month history of an amenorrhoea that was progressive accompanied with distended abdomen to the extent of looking typically as the gravid uterus. Explorative laparotomy was performed successfully and surgical incision managed by hysterotomy and salpingotomy, whereby approximately ten liters of serosanguinous blood fluid mixed with blood clots was completely suctioned. Despite being a rare condition after vesicle vaginal fistula repair complication outcome, haematometra remains to be relatively common gynaecological condition among female adolescence during postpubertal period. PMID- 29130006 TI - Incidental Laparoscopic Discovery of an Intraperitoneal Plastic Catheter 16 Years after an Unsafe Abortion: A Case Report from the Gynecologic, Obstetric, and Pediatric Hospital of Yaounde (Cameroon). AB - In many developing countries like Cameroon, unsafe abortion is a major public health problem. It can be responsible for severe complications including damage to the digestive and/or urinary tract, sepsis, and uterine perforation. Uterine perforation could be caused by most of the instruments that are used to evacuate the uterus. We report a case of apparent uterine perforation and subsequent migration of the plastic or rubber catheter into the peritoneal cavity during an abortion procedure performed in a setting that may have been unsafe. The discovery was made during a diagnostic laparoscopy indicated for secondary infertility of tubal origin 16 years after the abortion procedure. This is a rare clinical finding which is of therapeutic and diagnostic importance. To the best of our knowledge, a single similar case has been reported so far in the literature. PMID- 29130007 TI - Adult Sporadic Burkitt's Lymphoma Presenting with Rapid Development of Peritoneal Lymphomatosis. AB - Sporadic Burkitt's Lymphoma (BL) is a highly aggressive form of non-Hodgkin's lymphoma which requires prompt diagnosis and treatment. Though usual presentation involves abdominal lymphadenopathy with possible solid organ involvement, sporadic BL can rarely present with peritoneal lymphomatosis. We present a unique case with rapid evolution of BL presenting as peritoneal and omental lymphomatosis with hepatic lesions and pelvic and pericardial adenopathy. PMID- 29130008 TI - A Rare Association of Autoimmune Hemolytic Anemia with Gastric Adenocarcinoma. AB - An 80-year-old male presented with dyspnea on exertion for at least two months. He also complained of progressive dysphagia and weight loss of 35 pounds over the last eight months. Initial blood tests showed hemoglobin of 6.1 g/dl, reticulocytes count of 19.7%, total bilirubin of 3.2 mg/dl, lactate dehydrogenase of 600 U/L, and haptoglobin of less than 8 mg/dl, and direct Coombs test was positive for warm immunoglobulin G. The impression was autoimmune hemolytic anemia (AIHA). The evaluation of dysphagia with esophagogastroduodenoscopy revealed a single irregular 4 cm malignant appearing ulcerated mass at the incisura angularis of the stomach. The mass was confirmed as adenocarcinoma on biopsy. Diagnostic laparoscopy was positive for malignant cells and he was diagnosed with stage IV adenocarcinoma of the stomach. Other extensive workup to determine the etiology of AIHA was negative (described in detail below). Surgery was deferred primarily due to metastasis of cancer. Initially, hemoglobin was stabilized by intravenous methylprednisolone, high dose immunoglobulins, and packed red blood cell transfusions. After a few weeks, hemoglobin started trending down again. The patient was weaned off steroids and paradoxically IgG mediated autohemolysis was controlled with the initiation of palliative chemotherapy. Our case highlights a rare occurrence of AIHA in association with gastric adenocarcinoma. PMID- 29130009 TI - Optical Coherence Tomography Angiography of Two Choroidal Nevi Variants. AB - Optical coherence tomography angiography (OCT-A) is a recently established noninvasive technology for evaluation of the retinal and choroidal vasculature. The literature regarding the findings in choroidal nevi is scarce. We report the OCT-A findings associated with two different variants. Subject one had decreased vascular flow signal in the choroidal, choriocapillaris, deep retinal, and superficial retinal layers. Subject two had decreased vascular flow signal in the choroidal, choriocapillaris, and deep retinal layers with a normal vascular flow signal in the superficial retinal layer. To our knowledge, these patterns of decreased vascular flow signals have not been previously reported using OCT-A. This may be due to blockage from the choroidal nevus, true diminished blood flow (ischemia), or other factors. PMID- 29130010 TI - Spontaneous Bilateral Sternoclavicular Joint Septic Arthritis and Lumbar Discitis: An Unusual Case in a Healthy Adult. AB - Introduction: Septic arthritis of the sternoclavicular (SC) joint is a rare condition. Typically, it presents in patients with risk of infection and is usually unilateral. In this report, we describe a case of spontaneous bilateral sternoclavicular joint infection of an otherwise healthy adult. Case Presentation: A 67-year-old man presented in our hospital complaining of 2-week history of neck and chest pain which was radiating to his shoulders bilaterally. Clinical examination revealed erythema and swelling of the sternoclavicular area. Inflammatory markers were raised. Image investigation with CT and MRI was undertaken and verified the presence of bilateral sternoclavicular joint infection. The patient received prolonged course of intravenous antibiotics since his admission. The patient was discharged in a good condition and followed up in clinic. Conclusion: High index of clinical suspicion of SC joint infection is important for early diagnosis to avoid further complications. PMID- 29130011 TI - Successful Pelvic Resection for Acetabular Hydatidosis. AB - Background: Hydatidosis of the bone is a rare occurrence (0.9 to 2.5% of all localization of the disease). In those occurrences, the pelvic bone is the second most frequent localization. Curative treatment of pelvic bone hydatidosis is difficult and a consensus is yet to be found. Clinical Case: We report a case of hydatidosis of the ischium, extended to the homolateral hip. The patient was treated through hip resection using patient-specific cutting guides, followed by total hip reconstruction. Albendazole was administered to the patient for two months before the surgery and for three months following the surgery. Conclusions: In a young patient, hydatidosis of the pelvic bone can be treated with satisfying results through wide resection of the hip coupled with an antiparasitic treatment administered before and after the surgery. Prosthetic reconstruction, similar to what is done in cancer surgery, restores good functions. PMID- 29130012 TI - 10-Year-Old Female with Acute Abdominal Pain with Pancreatic Mass. AB - A previously healthy 10-year-old female presented to a local emergency department following three days of nausea and vomiting diagnosed with a solid pseudopapillary tumor. Solid pseudopapillary neoplasms are a rare form of pancreatic cystic neoplasm that typically presents in young females in their 20 30s and are very rare in children. These neoplasms often present as an asymptomatic tumor found on incidental imaging. When symptomatic they most commonly present with abdominal pain and can also cause a palpable abdominal mass, weight loss, gastrointestinal obstruction, and nausea and vomiting. Timely diagnosis of this rare neoplasm is very important because complete resection of the tumor is the definitive treatment and leads to an excellent long-term survival. PMID- 29130013 TI - An Unusual Mechanism of Closure of Muscular Ventricular Septal Defects. AB - Ventricular septal defects (VSDs) are the most common congenital heart defects. Most of the small or moderate size (<6 mm) muscular VSDs close spontaneously within the first two years of life. The usual mechanism of spontaneous closure involves muscular tissue encroachment with superimposed fibrosis or primary fibrous tissue formation around the margins of the defect. We describe an unusual mechanism of spontaneous closure of a muscular VSD. PMID- 29130014 TI - A Case of Probable Amisulpride Induced Mania after Eight Months of Therapy. AB - Development of manic symptoms during treatment with atypical antipsychotics can be a troublesome side effect that has been described with most atypical antipsychotics. However, reports of amisulpride induced mania have been rare. Here, we report the case of an 18-year-old male patient diagnosed with schizophrenia, who developed manic symptoms while on treatment with amisulpride. While previous reports have described occurrence of mania within days to three months of treatment with amisulpride, we report a case where manic symptoms occurred after around eight months of therapy. We have also attempted to describe the possible risk factors based on the available case studies. PMID- 29130015 TI - Jejunal Diverticular Perforation Causing Small Bowel Obstruction in a Type 4 Hiatal Hernia: A Rare Case Report of a Nonagenarian Patient and Review of Relevant Literature. AB - Type IV paraesophageal hernia (PEH) is very rare and is characterized by the intrathoracic herniation of the abdominal viscera other than the stomach into the chest. We describe a case of a 90-year-old male patient who presented at our emergency department complaining of epigastric pain that he had experienced over the past few hours and getting progressively worse. On the day after admission, his pain became severe. Chest radiography revealed an intrathoracic intestinal gas bubble; emergency exploratory laparotomy identified a type IV PEH with herniation of only the jejunum with perforated diverticula on mesenteric side through a hiatal defect into mediastinum. There are a few published cases of small bowel herniation into the thoracic cavity in the literature. Our patient represents a rare case of an individual diagnosed with type IV PEH with herniation of jejunum with perforated diverticula. PMID- 29130016 TI - Incidental Eosinophilic Chromophobe Renal Cell Carcinoma in Renal Allograft. AB - The incidence of renal cell carcinoma (RCC) in renal allograft in transplant recipients is 0.22-0.25%. De novo clear cell, papillary, and chromophobe RCCs and RCCs with sarcomatoid differentiation originating in renal allograft have been reported. Routine surveillance for graft tumours is not routinely practiced and these tumours are commonly asymptomatic and incidentally discovered. We describe a case of incidental, eosinophilic chromophobe RCC in a 31-year-old, long-term renal transplant male recipient, who presented with acute gastroenteritis 11 years after transplantation. The graft was nonfunctional at the time of presentation. Abdominal ultrasound and computed tomography scan demonstrated 1.8 cm well-defined, round enhancing lesion, confined to the renal allograft and suspicious for malignancy. Pathological examination of graft nephrectomy specimen showed gross, histopathological, and immunohistochemical features of eosinophilic chromophobe RCC. Fifty-five months after surgery, the patient was alive and free of malignancy. To the best of our knowledge, only five chromophobe RCCs originating in a renal allograft were previously described in English literature. We suggest that chromophobe RCC should be considered in the differential diagnosis of renal allograft mass, including eosinophilic tumours, and emphasise the importance of periodic screening of renal allograft in all renal transplant recipients. PMID- 29130017 TI - Clinical Characteristics, Management, and Outcomes of Suspected Poststroke Acute Coronary Syndrome. AB - Background: Acute coronary syndrome (ACS) can complicate acute ischemic stroke, causing significant morbidity and mortality. To date, literatures that describe poststroke acute coronary syndrome and its morbidity and mortality burden are lacking. Methods: This is a single center, retrospective study where clinical characteristics, cardiac evaluation, and management of patients with suspected poststroke ACS were compared and analyzed for their association with inpatient mortality and 1-year all-cause mortality. Results: Of the 82 patients, 32% had chest pain and 88% had ischemic ECG changes; mean peak troponin level was 18, and mean ejection fraction was 40%. The medical management group had older individuals (73 versus 67 years, p < 0.05), lower mean peak troponin levels (12 versus 49, p < 0.05), and lower mean length of stay (12 versus 25 days, p < 0.05) compared to those who underwent stent or CABG. Troponin levels were significantly associated with 1-year all-cause mortality. Conclusion: Age and troponin level appear to play a role in the current clinical decision making for patient with suspected poststroke ACS. Troponin level appears to significantly correlate with 1-year all-cause mortality. In the management of poststroke acute coronary syndrome, optimal medical therapy had similar inpatient and all-cause mortality compared to PCI and/or CABG. PMID- 29130018 TI - Virulence and Antimicrobial Resistance in Campylobacter spp. from a Peruvian Pediatric Cohort. AB - The presence of virulence factors (VFs) and mechanisms of quinolones and macrolide resistance was analyzed in Campylobacter spp. from a pediatric cohort study in Lima. In 149 isolates (39 Campylobacter jejuni and 24 Campylobacter coli from diarrheic cases; 57 C. jejuni and 29 C. coli from controls), the presence of the cdtABC and cadF genes and iam marker was established. Nalidixic acid, ciprofloxacin, erythromycin, and azithromycin susceptibilities were established in 115 isolates and tetracycline-susceptibility was established in 100 isolates. The presence of mutations in the gyrA, parC, and 23S rRNA genes was determined. The cadF gene and all genes from the cdtABC operon were significantly more frequent among C. jejuni (P < 0.0001); the iam marker was more frequent in C. coli (P < 0.0001). No differences were observed in VFs between cases and controls. Almost all isolates were tetracycline-resistant; nalidixic acid and ciprofloxacin resistance reached levels of 90.4% and 88.7%, respectively. Resistance to macrolides was 13% (C. jejuni 4.3%; C. coli 26.1%). Resistance to ciprofloxacin was related to GyrA Thr86 substitutions, while 13 of 15 macrolide resistant isolates possessed a 23S rRNA mutation (A2075G). Differences in the presence of VFs and alarming levels of resistance to tested antimicrobial agents were observed among C. jejuni and C. coli. PMID- 29130019 TI - Patients' Knowledge and Attitude toward the Disposal of Medications. AB - Background: Safe disposal of medications is of high concern as malpractice may lead to harmful consequences such as undesirable effects, prescription drug abuse, overstocking, self-medication, accidental overdose, and even death. There is a lack of uniform and nationwide guidance on how patients should safely dispose their leftover medications. This study aims to assess patients' knowledge and attitude regarding the disposal of medications. Method: This research is a cross-sectional study. A self-administered questionnaire was used to collect data from various outpatient pharmaceutical services in King Abdulaziz Medical City (KAMC), Jeddah. Results: The study revealed that 73% of the respondents throw the medications in the trash, 14% return the medications to a pharmacy, 5% never dispose them, and 3% donate the medications to a friend or charity centers. More than 80% of the respondents never received any information or advice from healthcare providers about safe and proper disposal of medications. Conclusion: Our findings suggest that there is an immediate requirement for the establishment of collaborative and uniform guidelines for the safe disposal of leftover medications. A policy for drug donation needs to be included in routine patient education as well as educational and collective programs for the public. PMID- 29130020 TI - What do we know from clinical trials on exercise and Alzheimer's disease? AB - Alzheimer's disease (AD) is the most common form of dementia in elderly with major symptoms of a general term for memory loss and other intellectual abilities impairment which are serious enough to interfere with daily life. While there is no treatment can prevent and revise the cognitive function impairment in AD, physical activity becomes a potential beneficial intervention for AD. Multiple evidences suggested that exercise in general plays beneficial roles in improving brain function. Most common mechanisms of exercise-induced enhancement of brain function are including alteration of neurogenesis, neuron plasticity, neuronal signaling and receptors, as well as neuronal networks. This mini review includes most recent clinical studies and focuses on the effects of physical exercise, cognitive stimulation, and combination of both physical and cognitive training on protection and rescue cognitive decline in people with AD. PMID- 29130021 TI - Transgenic Overexpression of Steroid Sulfatase Alleviates Cholestasis. AB - Background and Aim: Sulfotransferase (SULT)-mediated sulfation and steroid sulfatase (STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules. STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids. Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor (LXR), a nuclear receptor with anti cholestasis activity, whereas the sulfated oxysterols antagonize LXR signaling. The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS. The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR. Methods: Liver-specific STS transgenic mice were created and subject to the lithocholic acid (LCA)-induced model of cholestasis. Results: Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCA-induced cholestasis. The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes, likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols. Conclusions: STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands. PMID- 29130022 TI - Evaluation of Postgraduates Following Implementation of a Focus Assessed Transthoracic Echocardiography (FATE) Training Course-A Pilot Study. AB - At our institution, implementation of a formal training course in Basic Focus Assessed Transthoracic Echocardiography (FATE) was associated with an improvement in anesthesia trainees' ability to obtain transthoracic echocardiography (TTE) images. Total image acquisition scores improved by a median (Q1, Q3) 9.1 (2.9,14.7) percentage points from pre-to post-hands-on FATE course (n=20; p=0.001). Participants who returned for a subsequent assessment 5 months following the course demonstrated a median (Q1, Q3) 18.0 (9.1,22.1) percentage point improvement from their pre-course total image acquisition scores (n=11; p=0.002). This pilot study established the feasibility of our program and results suggest that the basic FATE course can be used to teach trainees TTE quickly, effectively, and with significant retention. PMID- 29130024 TI - Chained Kullback-Leibler Divergences. AB - We define and characterize the "chained" Kullback-Leibler divergence min w D(p||w) + D(w||q) minimized over all intermediate distributions w and the analogous k-fold chained K-L divergence min D(p||wk-1) + ... + D(w2||w1) + D(w1||q) minimized over the entire path (w1,...,wk-1). This quantity arises in a large deviations analysis of a Markov chain on the set of types - the Wright Fisher model of neutral genetic drift: a population with allele distribution q produces offspring with allele distribution w, which then produce offspring with allele distribution p, and so on. The chained divergences enjoy some of the same properties as the K-L divergence (like joint convexity in the arguments) and appear in k-step versions of some of the same settings as the K-L divergence (like information projections and a conditional limit theorem). We further characterize the optimal k-step "path" of distributions appearing in the definition and apply our findings in a large deviations analysis of the Wright Fisher process. We make a connection to information geometry via the previously studied continuum limit, where the number of steps tends to infinity, and the limiting path is a geodesic in the Fisher information metric. Finally, we offer a thermodynamic interpretation of the chained divergence (as the rate of operation of an appropriately defined Maxwell's demon) and we state some natural extensions and applications (a k-step mutual information and k-step maximum likelihood inference). We release code for computing the objects we study. PMID- 29130023 TI - Anxiety and Mood Clinical Profile following Sport-related Concussion: From Risk Factors to Treatment. AB - Conceptual models for assessing and treating sport-related concussion (SRC) have evolved from a homogenous approach to include different clinical profiles that reflect the heterogeneous nature of this injury and its effects. There are six identified clinical profiles, or subtypes from SRC, and one such clinical profile is the anxiety/mood profile. Athletes with this profile experience predominant emotional disturbance and anxiety following SRC. The purpose of this targeted review was to present an overview of the empirical evidence to support factors contributing to the anxiety/mood profile, along with methods of evaluation and treatment of this clinical profile following SRC. We discuss the potential underlying mechanisms and risk factors for this clinical profile, describe comprehensive assessments to evaluate concussed athletes with an anxiety/mood clinical profile, and explore behavioral and other interventions for treating these athletes. Although there is limited, but growing empirical evidence for the anxiety/mood clinical profile following SRC, understanding this clinical profile is germane for clinicians who are treating athletes with emotional sequelae after SRC. PMID- 29130025 TI - Epidemiology of Keratinocyte Carcinoma. AB - Purpose of the review: To provide a synopsis of recent research advances in the epidemiology of keratinocyte carcinoma (KC), with a focus on indoor tanning and known risk factors for other forms of cancer such as cigarette smoking and alcohol drinking. Recent findings: The evidence is strong enough to infer that use of UVR-emitting indoor tanning devices cause KC. Epidemiologic studies of cigarette smoking, alcohol drinking, and menopausal hormone therapy all show some suggestion for increased risk of KC but the evidence is not yet strong enough to determine if there is a true etiologic role. Body mass index is clearly inversely associated with KC risk but this is more likely to be due to lower UVR exposure in overweight and obese individuals than it is due to a true etiologic role. Summary: The epidemic of KC continues unabated, and the causal role of indoor tanning is contributing to this unfavorable trend in KC incidence rates. Advances in understanding the etiology of KC should not divert attention away from the fact that the primary public health strategy to prevent KC is known: minimize population exposure to UVR from the sun and from UVR-emitting indoor tanning devices, particularly among those with sun-sensitive phenotypes. PMID- 29130026 TI - Recent Developments in Pd(0)-Catalyzed Alkene Carboheterofunctionalization Reactions. AB - This review summarizes recent developments in palladium-catalyzed alkene carboalkoxylation and carboamination reactions. New synthetic methods that have been reported in the past four years are described, along with mechanistic issues and the influence of mechanism on product stereochemistry. The applications of these transformations to the synthesis of natural products and other biologically relevant compounds are also discussed. PMID- 29130027 TI - Cryptococcosis today: It is not all about HIV infection. AB - Purpose of the review: Cryptococcal disease is most often thought of in the context of HIV infection. Much of our knowledge of the disease originates from its management in the HIV-positive population over the last 30 years. While the majority of cases globally continue to occur in the setting of advanced HIV, Cryptococcus species is increasingly responsible for disease in HIV-negative populations including those considered normal hosts and these HIV-negative populations will be the focus of this review. Recent findings: Currently available data indicated that significant differences exist in epidemiology, clinical presentation, management and outcomes of cryptococcal disease in HIV negative populations when compared to those living with HIV. Summary: Further research is required to improve our knowledge of cryptococcal disease in particular in HIV-negative cohorts so as to optimise management of the disease in the future. PMID- 29130029 TI - Turking Overtime: How Participant Characteristics and Behavior Vary Over Time and Day on Amazon Mechanical Turk. AB - Online experiments allow researchers to collect datasets at times not typical of laboratory studies. We recruit 2,336 participants from Amazon Mechanical Turk to examine if participant characteristics and behaviors differ depending on whether the experiment is conducted during the day versus night, and on weekdays versus weekends. Participants make incentivized decisions involving prosociality, punishment, and discounting, and complete a demographic and personality survey. We find no time or day differences in behavior, but do find that participants at nights and on weekends are less experienced with online studies; on weekends are less reflective; and at night are less conscientious and more neurotic. These results are largely robust to finer grained measures of time and day. We also find that those who participated earlier in the course of the study are more experienced, reflective, and agreeable, but less charitable than later participants. PMID- 29130028 TI - Sphingosine Kinases/Sphingosine 1-Phosphate Signaling in Hepatic Lipid Metabolism. AB - The ever-increasing prevalence of metabolic diseases such as dyslipidemia and diabetes in the western world continues to be of great public health concern. Biologically active sphingolipids, such as sphingosine 1-phosphate (S1P) and ceramide, are important regulators of lipid metabolism. S1P not only directly functions as an active intracellular mediator, but also activates multiple signaling pathways via five transmembrane G-protein coupled receptors (GPCRs), S1PR1-5. S1P is exclusively formed by sphingosine kinases (SphKs). Two isoforms of SphKs, SphK1 and SphK2, have been identified. Recent identification of the conjugated bile acid-induced activation of S1PR2 as a key regulator of SphK2 opened new directions for both the sphingolipid and bile acid research fields. The role of SphKs/S1P-mediated signaling pathways in health and various human diseases has been extensively reviewed elsewhere. This review focuses on recent findings related to SphKs/S1P-medaited signaling pathways in regulating hepatic lipid metabolism. PMID- 29130030 TI - A review of engineered zirconia surfaces in biomedical applications. AB - Zirconia is widely used for load-bearing functional structures in medicine and dentistry. The quality of engineered zirconia surfaces determines not only the fracture and fatigue behaviour but also the low temperature degradation (ageing sensitivity), bacterial colonization and bonding strength of zirconia devices. This paper reviews the current manufacturing techniques for fabrication of zirconia surfaces in biomedical applications, particularly, in tooth and joint replacements, and influences of the zirconia surface quality on their functional behaviours. It discusses emerging manufacturing techniques and challenges for fabrication of zirconia surfaces in biomedical applications. PMID- 29130031 TI - The use of tobacco tax revenues to fund the Guam Cancer Registry: A double win for cancer control. AB - Cancer registries that provide reliable data on cancer incidence, mortality and burden are essential to cancer control. However, establishing sustainable local funding mechanisms to support cancer registries remains a challenge in many countries. Guam, an unincorporated Territory of the United States of America in the Western Pacific, enacted a bill that raised tobacco taxes, and earmarked a percentage of tobacco tax revenues to support its Cancer Registry. This provided a reliable funding stream for the Registry, allowing for continued staffing and capacity building; at the same time, youth tobacco consumption decreased following the tax increase. Linking tobacco tax revenues to cancer registry support is a feasible strategy with a double benefit: higher tobacco prices from higher tobacco taxes reduce tobacco-related cancer risk while assuring the long term viability of systematic cancer data collection and dissemination. PMID- 29130032 TI - SUCCESSFUL TREATMENT OF A SOLITARY SKULL METASTASIS IN A CHILD WITH WILMS' TUMOR. AB - This report presents the successful treatment of a child with a solitary metastatic lesion to the calvarium following treatment for Stage III anaplastic Wilms' Tumor. PMID- 29130034 TI - The effects of disease-related symptoms on daily function in Wolfram Syndrome. AB - OBJECTIVE: To investigate daily function among individuals with Wolfram Syndrome (WFS) and examine whether any limitations are related to disease-related symptoms. METHODS: WFS (n = 31), Type 1 diabetic (T1DM; n = 25), and healthy control (HC; n = 29) participants completed the Pediatric Quality of Life Questionnaire (PEDSQL) Self and Parent Report. PEDSQL domain scores were compared among these groups and between WFS patients with and without specific disease related symptoms. Relationships between PEDSQL scores and symptom severity as assessed by the Wolfram Unified Rating Scale (WURS) Physical Scale were also examined. RESULTS: Across most domains, the WFS group had lower PEDSQL Self and Parent Report scores than the T1DM and HC groups. WFS participants with urinary, sleep, and temperature regulation problems had lower PEDSQL scores than those without. The WURS Physical Scale correlated with Self and Parent Report PEDSQL domains. WFS group Self and Parent Reports correlated with each other. CONCLUSIONS: The WFS group reported lower daily function compared to T1DM and HC groups. Within WFS, worse symptom severity and the specific symptoms of sleep, temperature regulation, and urinary problems were associated with poorer daily function. These findings provide rationale for an increased emphasis on identifying, treating and understanding these less well-known symptoms of WFS. PMID- 29130035 TI - Demography and Risk Factors of Suicide in Bangladesh: A Six-Month Paper Content Analysis. AB - Background: Suicide is a global public health problem too often neglected by researchers and Bangladesh is not an exception. There is no suicide surveillance and nationwide study is yet to be conducted in the country. Objectives: This paper aimed to look into suicide based on newspaper reporting in Bangladesh focusing on the demographic variables and risk factors. Methods: 6 national newspapers were scrutinized from November 2016 to April 2017. Data were checked, cross-checked, and then analyzed with SPSS software. Results: In a duration of six months, a total of 271 cases were reported; age was found to be in the range of 11-70 years (26.67 +/- 13.47). 61% of the reported cases were below 30 years of age, 58% were female, 24% were students, 17% were house makers, 61% were from rural background, and 45% were married. Hanging was found to be the commonest method (82.29%); marital and familial discord remained a noticeable risk factor (34.32%). Family members and neighbors noticed 103 cases, and only 3 cases were found to have suicide notes. Conclusion: Suicide is an underattended public health problem in Bangladesh with few researches and paucity of literature. Establishment of national suicide surveillance is now a time demanded step. PMID- 29130033 TI - Danger of frustrated sensors: Role of Toll-like receptors and NOD-like receptors in aseptic and septic inflammations around total hip replacements. AB - The innate immune sensors, Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), can recognize not only exogenous pathogen-associated molecular patterns (PAMPs), but also endogenous molecules created upon tissue injury, sterile inflammation, and degeneration. Endogenous ligands are called damage-associated molecular patterns (DAMPs), and include endogenous molecules released from activated and necrotic cells as well as damaged extracellular matrix. TLRs and NLRs can interact with various ligands derived from PAMPs and DAMPs, leading to activation and/or modulation of intracellular signalling pathways. Intensive research on the innate immune sensors, TLRs and NLRs, has brought new insights into the pathogenesis of not only various infectious and rheumatic diseases, but also aseptic foreign body granuloma and septic inflammation of failed total hip replacements (THRs). In this review, recent knowledge is summarized on the innate immune system, including TLRs and NLRs and their danger signals, with special reference to their possible role in the adverse local host response to THRs. PMID- 29130036 TI - Accuracy, Precision, and Trending Ability of Electrical Cardiometry Cardiac Index versus Continuous Pulmonary Artery Thermodilution Method: A Prospective, Observational Study. AB - Introduction: Evaluation of accuracy, precision, and trending ability of cardiac index (CI) measurements using the AesculonTM bioimpedance electrical cardiometry (Aesc) compared to the continuous pulmonary artery thermodilution catheter (PAC) technique before, during, and after cardiac surgery. Methods: A prospective observational study with fifty patients with ASA 3-4. At six time points (T), measurements of CI simultaneously by continuous cardiac output pulmonary thermodilution and thoracic bioimpedance and standard hemodynamics were performed. Analysis was performed using Bland-Altman, four-quadrant plot, and polar plot methodology. Results: CI obtained with pulmonary artery thermodilution and thoracic bioimpedance ranged from 1.00 to 6.75 L min-1 and 0.93 to 7.25 L min 1, respectively. Bland-Altman analysis showed a bias between CIBIO and CIPAC of 0.52 liters min-1 m-2, with LOA of [-2.2; 1.1] liters min-1 m-2. Percentage error between the two techniques was above 30% at every time point. Polar plot methodology and 4-quadrant analysis showed poor trending ability. Skin incision had no effect on the results. Conclusion: CI obtained by continuous PAC and CI obtained by Aesculon bioimpedance are not interchangeable in cardiac surgical patients. No effects of skin incision were found. International clinical trial registration number is ISRCTN26732484. PMID- 29130037 TI - Posttraumatic Psychiatric Disorders and Resilience in Healthcare Providers following a Disastrous Earthquake: An Interventional Study in Taiwan. AB - Background: Posttraumatic psychiatric disorders (PTPDs) are common in disaster workers; however, their incidence and resilience in healthcare providers (HCPs) following a disastrous earthquake are still unclear. Therefore, we conducted an interventional study to clarify this issue. Methods: After a medical response to the scene of a collapsed huge building, we conducted an assessment of the HCPs using an immediate self-administered questionnaire and a follow-up questionnaire 1 month later. Psychological support after the operation was implemented. We performed analysis of the risk for PTPDs and comparison between immediate and follow-up questionnaires. Results: The mean age (standard deviation) of the HCPs was 32.7 (5.2) years, with 33.5 (5.8) years for nurses and 32.4 (4.4) years for physicians. The proportion of females among the nurses and physicians was 94.3% and 12.5%, respectively. In total, 16.4% (11/67) of HCPs fit the criteria of PTPDs. Nurses had a trend of higher incidence than physicians. Female HCPs had a trend of higher incidence than male HCPs. After intervention, none of the HCPs reported PTPDs in the follow-up questionnaire (p < 0.05). Conclusion: This study delineated that PTPDs were common in HCPs following medical response to an earthquake; however, the resilience was good after the early intervention. PMID- 29130038 TI - Nanomedicine for Inner Ear Diseases: A Review of Recent In Vivo Studies. AB - Nanoparticles are promising therapeutic options for inner ear disease. In this report, we review in vivo animal studies in the otologic field using nanoparticles over the past 5 years. Many studies have used nanoparticles to deliver drugs, genes, and growth factors, and functional and morphological changes have been observed. The constituents of nanoparticles are also diversifying into various biocompatible materials, including poly(lactic-co glycolic acid) (PLGA). The safe and effective delivery of drugs or genes in the inner ear will be a breakthrough for the treatment of inner ear diseases, including age-related hearing loss. PMID- 29130039 TI - A Sustained-Release Membrane of Thiazolidinedione-8: Effect on Formation of a Candida/Bacteria Mixed Biofilm on Hydroxyapatite in a Continuous Flow Model. AB - Thiazolidinediones (TZDs) have been found to act as effective quorum sensing quenchers, capable of preventing biofilm formation. Our previous studies demonstrated a profound antibiofilm effect of the TZD derivative thiazolidinedione-8 (S-8), either in solution or incorporated into a sustained release membrane (SRM-S-8) under batch conditions. In the present study, we used a constant depth film fermenter model in order to investigate the impact of SRM-S 8 on mixed C. albicans-S. mutans biofilm development, under flow conditions. We found that essential parameters of cospecies biofilm maintenance and maturation, such as metabolic activity, biofilm thickness, roughness, extracellular polysaccharides production, and morphology of both pathogens, were altered by SRM S-8 in the flow system. We propose that prolonged and sustained release of S-8 in a flow-through system allows better penetration of the active agent to deeper layers of the mixed biofilm, thereby increasing its activity against both pathogens. In conclusion, the use of a locally applied sustained-release drug delivery system of S-8 can affect the dental polymicrobial biofilm, resulting in clinical improvements and a better patient compliance. PMID- 29130040 TI - Effect of Computer Navigation on Accuracy and Reliability of Limb Alignment Correction following Open-Wedge High Tibial Osteotomy: A Meta-Analysis. AB - Background: It is unclear whether computer navigation can improve the accuracy and reliability of targeted lower limb alignment correction following open-wedge high tibial osteotomy (HTO). This meta-analysis was designed to compare the accuracy and reliability of limb alignment correction between computer navigated and conventional open-wedge HTOs. Methods: Studies that compared postoperative coronal alignment, including mechanical axis (MA) and weight bearing line (WBL) ratio, outliers of alignment correction, and change in tibial posterior slope, following open-wedge HTO performed using computer navigated and conventional methods were included. Results: Ten studies were included in the meta-analysis. The MA (0.93 degrees ; 95% confidence interval [CI]: 0.45-1.41 degrees ; P < 0.001) and WBL ratio (1.5%; 95% CI: 0.03-2.98%; P = 0.048) were significantly greater for computer navigated HTO than for conventional HTO. Outliers of alignment correction after surgery were significantly lower in patients who underwent computer navigated HTO than in those who underwent conventional HTO (odds ratio: 0.25; 95% CI: 0.08-0.79; P = 0.02). Changes in posterior tibial slope from before to after surgery, however, were similar for the two approaches. Conclusion: Computer navigated HTO resulted in slightly more valgus postoperative alignment and effectively reduced outliers of alignment correction but had no effect on change in posterior tibial slope when compared with conventional HTO. PMID- 29130041 TI - Long-Term Sleep Duration as a Risk Factor for Breast Cancer: Evidence from a Systematic Review and Dose-Response Meta-Analysis. AB - Sleep patterns have been associated with the development of cancers, although the association between sleep duration and breast cancer remains controversial. The purpose of our study was to explore the relationship between sleep duration and breast cancer risk. The PubMed and Web of Science databases were searched, and restricted cubic splines were used to explore the dose-response relationship. Data from 415,865 participants were derived from 10 studies. A J-shaped nonlinear trend was found between sleep duration and breast cancer incidence (Pnon-linear = 0.012); compared with the reference hours (6 h or 7 h), with increasing sleep hours, the risk of breast cancer increased (Ptrend = 0.028). Moreover, a nonlinear relationship was found between sleep duration and estrogen receptor positive breast cancer (Pnon-linear = 0.013); the risk of estrogen receptor positive breast cancer increased with increasing sleep hours compared to the reference hours (Ptrend = 0.024). However, no nonlinear relationship was found between sleep duration and estrogen receptor-negative breast cancer; the risk of estrogen receptor-negative breast cancer was 1.035 for every additional sleep hour. Compared to women with the reference number of sleep hours, women with a longer sleep duration might have a significantly increased risk of breast cancer, especially estrogen receptor-positive breast cancer. PMID- 29130042 TI - Out-of-Hospital Administration of Medication without Prescription and Associated Factors among Preschool Children. AB - The increasing trend of administering nonprescribed medicines in children is a significant public health issue. The aim of the present study was to assess the use of medication without a prescription (MWP), including both nonprescribed medication (NPM) and prescription-only medication (POM), and identify associated factors, among preschoolers in Athens, Greece. A predesigned questionnaire was distributed to parents from May through June 2011. Multivariable binary logistic regression analysis models were used to assess associations of interest. Results showed that 95.1% of parents reported administering at least one MWP, during the previous 12 months. Antipyretics (91%) were the most commonly NPM and bronchodilators (24.8%) and antibiotics (16.4%) the most common POM dispensed. Child's increased age group, lack of parental information, higher paternal education, and mother's foreign nationality were associated with increased antipyretic use (p < 0.05), while father's foreign nationality and parental age were positive predictors of antibiotic administration (p < 0.05). The likelihood of consuming antipyretics and antibiotics significantly increased when information was provided by a pharmacist (p = 0.017 and p = 0.054, resp.). Conclusively, most parents have administered at least one MWP, including antibiotics, to address symptoms of common childhood diseases, highlighting the need of information campaigns concerning the consequences of their improper use. PMID- 29130043 TI - Nonuniform Internal Structure of Fibrin Fibers: Protein Density and Bond Density Strongly Decrease with Increasing Diameter. AB - The major structural component of a blood clot is a meshwork of fibrin fibers. It has long been thought that the internal structure of fibrin fibers is homogeneous; that is, the protein density and the bond density between protofibrils are uniform and do not depend on fiber diameter. We performed experiments to investigate the internal structure of fibrin fibers. We formed fibrin fibers with fluorescently labeled fibrinogen and determined the light intensity of a fiber, I, as a function of fiber diameter, D. The intensity and, thus, the total number of fibrin molecules in a cross-section scaled as D1.4. This means that the protein density (fibrin per cross-sectional area), rhop , is not homogeneous but instead strongly decreases with fiber diameter as D-0.6. Thinner fibers are denser than thicker fibers. We also determined Young's modulus, Y, as a function of fiber diameter. Y decreased strongly with increasing D; Y scaled as D-1.5. This implies that the bond density, rhob , also scales as D 1.5. Thinner fibers are stiffer than thicker fibers. Our data suggest that fibrin fibers have a dense, well-connected core and a sparse, loosely connected periphery. In contrast, electrospun fibrinogen fibers, used as a control, have a homogeneous cross-section. PMID- 29130044 TI - The Effect of Pterygomasseteric Sling's Area in the Postoperative Stability after Mandibular Setback Surgery. AB - Purpose: The purpose of the present study was to investigate the correlation between the postoperative stability and area of pterygomasseteric sling (PMS). Materials and Methods: Forty patients of mandibular prognathism were treated by isolated mandibular setback. Serial lateral cephalograms were collected (preoperatively [T1], immediately after surgery [T2], and more than 1 year postoperatively [T3]). The postoperative stability (T32) was divided into 3 groups (total, forward, and backward movements). The areas of PMS, immediate surgical changes (T21), postoperative stability (T32), and final surgical change (T31) were analyzed by Student's t-test, Pearson's correlation coefficient, and multiple linear regression analysis. Results: The amount of mean setback (T21) was 12.6 mm in total group, 13.8 mm in forward group, and 10.8 mm in backward group. In the total group, postoperative stability (T32) was 0.6 mm forward and reduction area of PMS (T31) was 291 mm2 (17.2%). The reduction area of PMS (T31) was 298.2 mm2 (18%) and 263.1 (15.3%) mm2 in the forward group (3 mm) and backward group (2.4 mm), respectively. However, reduction area of PMS (T31) showed weak correlation with postoperative stability (T32) in all groups. Conclusion: Total and forward groups presented significant correlations between postoperative stability (T32) and amount of setback (T21). PMID- 29130045 TI - The PDZ-Binding Motif of HPV16-E6 Oncoprotein Modulates the Keratinization and Stemness Transcriptional Profile In Vivo. AB - Objective: The aim of this work was to compare the early gene expression profiles in the skin of HPV16-E6 transgenic mice regulated by the E6 PDZ-binding motif. Materials and Methods: The global transcriptional profiles in dorsal skin biopsies from K14E6 and K14E6Delta146-151 transgenic mice were compared using microarrays. Relevant genes obtained from the most differentially expressed processes were further examined by RT-qPCR, in situ RT-PCR, Western blot, or immunofluorescence. Results: The transcriptomic landscape of K14E6 versus K14E6Delta146-151 shows that the most affected expression profiles were those related to keratinocyte differentiation, stem cell maintenance, and keratinization. Additionally, downregulation of epidermal stemness markers such as K15 and CD34, as well as the upregulation of cytokeratin 6b, appeared to be dependent on the E6 PDZ-binding motif. Finally, wound healing, a physiological process linked to stemness, is impaired in the K14E6 mice compared to K14E6Delta146-151. Conclusion: The E6 PDZ-binding motif appears to affect stemness and keratinization during early stages of skin carcinogenesis. As E6 plays a significant role in HPV-induced skin carcinogenesis, the K14E6 versus K14E6Delta146-151 transcriptional profile provides a source of valuable data to uncover novel E6 functions in the skin. PMID- 29130046 TI - A Comparison of the Device-Related Complications of Intramedullary Lengthening Nails Using a New Classification System. AB - The purpose of this study was to understand the pros and cons of the lengthening nails which have their own mechanical mechanism; we propose a classification for "device-related complications" arising from mechanical properties of the nail itself. From March 2010 to March 2014, 115 segments of lower limb lengthening were performed using intramedullary lengthening nails (35 ISKD, 34 PRECICE1, and 46 PRECICE2). Device-related complications were sorted into three categories according to a new classification: distraction control-related (type I), stability related (type II), and other device-related (type III); these were subdivided using Paley's concept of problems (a), obstacles (b), and sequel (c). Most common complications were distraction mechanism issues (type I) in ISKD and mechanical strength related ones (type II) in PRECICE1 and PRECICE2. Sixty percent (21/35) of ISKD had device-related problems. In PRECICE1 group, 8.8% (3/34) had device-related problems, and 8.8% (3/34) showed device-related obstacle. In PRECICE2, forty-four percent (20/46) had device-related problems. In conclusion, a new classification showed more clearly the differences of mechanical characteristics of different nails. The most essential thing of future lengthening nail development is minimizing the types I and II complications. Further study is necessary to compare the mechanical strength and stability of lengthening nails. PMID- 29130047 TI - Bending Properties of Fiber-Reinforced Composites Retainers Bonded with Spot Composite Coverage. AB - Orthodontic and periodontal splints are prepared with round or flat metallic wires. As these devices cannot be used in patients with allergy to metals or with aesthetic demands, fiber-reinforced composite (FRC) retainers have been introduced. Stiffness of FRC materials could reduce physiologic tooth movement. In order to lower rigidity of conventional FRC retainers, a modified construction technique that provided a partial (spot) composite coverage of the fiber has been tested and compared with metallic splints and full-bonded FRCs. Flat (Bond-a Braid, Reliance Orthodontic Products) and round (Penta-one 0155, Masel Orthodontics) stainless steel splints, conventional FRC splints, and experimental spot-bonded FRC retainers (Everstick Ortho, StickTech) were investigated. The strength to bend the retainers at 0.1 mm deflection and at maximum load was measured with a modified Frasaco model. No significant differences were reported among load values of stainless steel wires and experimental spot-bonded FRC retainers at 0.1 mm deflection. Higher strength values were recoded for conventional full-bonded FRCs. At maximum load no significant differences were reported between metallic splints (flat and round) and experimental spot-bonded FRCs, and no significant differences were reported between spot- and full-bonded FRC splints. These results encourage further tests in order to evaluate clinical applications of experimental spot-bonded FRC retainers. PMID- 29130048 TI - Is Health Education at University Associated with Students' Health Literacy? Evidence from Cross-Sectional Study Applying HLS-EU-Q. AB - Background: Despite the large number of studies assessing health literacy, little research has been conducted with young adults. Since health literacy is related to the setting in which health information is provided, our study aim was to measure health literacy competencies in a sample of university students and to evaluate the relationships between these competencies and their university health education. Methods: A total of 912 university students (aged 18-24 years) completed the 47-item European Health Literacy Survey Questionnaire (HLS-EU-Q47). Results: Perceived difficulties with health information were related to gender, with male students reporting significantly lower health literacy scores. Studying more health education-related subjects was associated with a higher health literacy competency, due to these students' higher rates of accessing and understanding health information in the health promotion domain. Conclusion: Health literacy among young adult university students is insufficient. The subjects they study are related to their university health education; in particular, the number of health-related subjects they study is positively related to students' health promotion domain-based competencies. PMID- 29130049 TI - Risk Factors of Allergic Disease: A Study with a Large Data Set. PMID- 29130050 TI - Evaluating the Use of Serum Inflammatory Markers for Preoperative Diagnosis of Infection in Patients with Nonunions. AB - Purpose: The aim of this study is to evaluate the effectiveness of laboratory serum tests in the diagnosis of infected nonunion. Methods: Forty-two patients suspected of having infected nonunion were investigated in the study. The serum levels of white blood-cell count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin-6 (IL-6) were measured. A positive diagnosis of infection was made on the basis of the positive culture results. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each test were calculated. Results: The sensitivity and specificity of CRP both were higher than IL-6: 60.0% versus 57.1% and 85.7% versus 57.1%, respectively. With one, two, three, and four positive tests, the predicted probabilities of infection were 66.7%, 90.9%, 100%, and 100%, respectively, but the number of patients who had three or four positive tests was small. Conclusions: The diagnostic utility of IL-6 is inferior to CRP and the finding conflicts with previous conclusions drawn from periprosthetic infections. Laboratory analysis of serum inflammatory markers alone is not an effective screening tool for patients suspected of having an infected nonunion. PMID- 29130052 TI - The Diabetic Foot. PMID- 29130051 TI - The Effect of a 12-Week Health Training Program on Selected Anthropometric and Biochemical Variables in Middle-Aged Women. AB - Regular moderate physical activity positively affects health, fitness, and body composition; it regulates the pro- and anti-inflammatory cytokines levels. Vitamin D plays an important regulatory role; its adequate levels correlate with low values of inflammation markers and an increase in muscle strength and fitness in exercising people. The study's aim was to evaluate changes in somatic variables, oxidative stress, and inflammation markers, as well as blood calcidiol concentration in middle-aged healthy women after 12 weeks of aerobics classes endurance exercises, including choreographic sequences, aiming to improve fitness and motor coordination. The training led to a significant reduction of body mass and fat tissue; it induced an increase in lean body mass. After the 12-week training program, plasma antioxidant status increased (0.65 +/- 0.21, p < 0.01) and the concentration of lipid peroxidation products decreased (0.07 +/- 0.02, p < 0.001). A significant increase in plasma antioxidant status associated with training could have reduced the level of proinflammatory interleukin as indicated by a positive correlation between these variables (rs = 0.64, p < 0.05). The study proved that a 12-week health training program in physically inactive middle aged women might provide improvements in their anthropometric parameters and selected biochemical indicators. PMID- 29130053 TI - Treatment Gaps Found in the Management of Type 2 Diabetes at a Community Health Centre in Johannesburg, South Africa. AB - Aims: The management of cardiometabolic goals or "ABCs" (HbA1c, blood pressure (BP), and cholesterol) ultimately determines the morbidity and mortality outcomes in patients with type 2 diabetes mellitus (T2DM). We sought to determine if patients with T2DM attending an urbanized public sector community health centre (CHC) were having their ABCs measured, were treated with appropriate cardioprotective agents and finally, were achieving guideline-based targets. Methods and Results: A cross-sectional record review of 519 patients was conducted between May and August 2015. The mean age was 54 years (SD: +/-11.5) and 54% (n = 280) were females. Testing of ABCs occurred in 68.8% (n = 357) for HbA1c, 95.4% (n = 495) for BP, and 58.6% (n = 304) for LDL-C. Achievement of ABC targets was as follows: 19.3% (HbA1c < 7%), 22.0% (BP < 140/80 mmHg), and 56.3% (LDL-C < 2.5 mmol/l). Conclusion: There were a significant number of patients who were not tested nor received adequate pharmacotherapy or achieved their ABC targets. This places these patients at an increased risk for the development of diabetes-related complications. Although the realities of resource constraints exist in South Africa's public sector settings, a wider implementation of evidence-based guidelines must be instituted in order to ensure better patient outcomes. PMID- 29130054 TI - Multimodal integration of spontaneously produced representational co-speech gestures: an fMRI study. AB - To examine whether more ecologically valid co-speech gesture stimuli elicit brain responses consistent with those found by studies that relied on scripted stimuli, we presented participants with spontaneously produced, meaningful co-speech gesture during fMRI scanning (n = 28). Speech presented with gesture (versus either presented alone) elicited heightened activity in bilateral posterior superior temporal, premotor, and inferior frontal regions. Within left temporal and premotor, but not inferior frontal regions, we identified small clusters with superadditive responses, suggesting that these discrete regions support both sensory and semantic integration. In contrast, surrounding areas and the inferior frontal gyrus may support either sensory or semantic integration. Reduced activation for speech with gesture in language-related regions indicates allocation of fewer neural resources when meaningful gestures accompany speech. Sign language experience did not affect co-speech gesture activation. Overall, our results indicate that scripted stimuli have minimal confounding influences; however, they may miss subtle superadditive effects. PMID- 29130056 TI - The Bell Curve Revisited: Testing Controversial Hypotheses with Molecular Genetic Data. AB - In 1994, the publication of Herrnstein's and Murray's The Bell Curve resulted in a social science maelstrom of responses. In the present study, we argue that Herrnstein's and Murray's assertions were made prematurely, on their own terms, given the lack of data available to test the role of genotype in the dynamics of achievement and attainment in U.S. society. Today, however, the scientific community has access to at least one dataset that is nationally representative and has genome-wide molecular markers. We deploy those data from the Health and Retirement Study in order to test the core series of propositions offered by Herrnstein and Murray in 1994. First, we ask whether the effect of genotype is increasing in predictive power across birth cohorts in the middle twentieth century. Second, we ask whether assortative mating on relevant genotypes is increasing across the same time period. Finally, we ask whether educational genotypes are increasingly predictive of fertility (number ever born [NEB]) in tandem with the rising (negative) association of educational outcomes and NEB. The answers to these questions are mostly no; while molecular genetic markers can predict educational attainment, we find little evidence for the proposition that we are becoming increasingly genetically stratified. PMID- 29130055 TI - Gene therapy with HSV encoding p55TNFR gene for HIV neuropathic pain: an evidence based mini-review. AB - While effective antiretroviral treatment makes human immunodeficiency virus (HIV) related death decreased dramatically, neuropathic pain becomes one of the most common complications in patients with HIV/acquired immunodeficiency syndrome (AIDS). The exact mechanisms of HIV-related neuropathic pain are not well understood yet, and no effective therapy is for HIV-pain. Evidence has shown that proinflammatory factors (e.g., tumor necrosis factor alpha (TNFalpha)) released from glia, are critical to contributing to chronic pain. Preclinical studies have demonstrated that non-replicating herpes simplex virus (HSV)-based vector expressing human enkephalin reduces inflammatory pain, neuropathic pain, or cancer pain in animal models. In this review, we describe recent advances in the use of HSV-based gene transfer for the treatment of HIV pain, with a special focus on the use of HSV-mediated soluble TNF receptor I (neutralizing TNFalpha in function) in HIV neuropathic pain model. PMID- 29130057 TI - Differentiation of Myeloid-derived Suppressor Cells from Murine Bone Marrow and Their Co-culture with Splenic Dendritic Cells. AB - Myeloid-derived suppressor cells (MDSCs) possess the ability to suppress the immune response, and to amplify the regulatory properties of other immune cells, i.e., dendritic cells. Here we describe a protocol in which MDSCs were differentiated from murine bone marrow cells, and CD11c+ dendritic cells were purified from murine spleens. MDSCs and CD11c dendritic cells can be co-cultured and the immunoregulatory phenotype of the MDSCs-conditioned dendritic cells could be assessed by means of a specific functional in vivo experiment, i.e., a skin test as a measure of the delayed-type hypersensitivity reaction toward a poorly immunogenic antigen. PMID- 29130058 TI - Bioluminescence Monitoring of Neuronal Activity in Freely Moving Zebrafish Larvae. AB - The proof of concept for bioluminescence monitoring of neural activity in zebrafish with the genetically encoded calcium indicator GFP-aequorin has been previously described (Naumann et al., 2010) but challenges remain. First, bioluminescence signals originating from a single muscle fiber can constitute a major pitfall. Second, bioluminescence signals emanating from neurons only are very small. To improve signals while verifying specificity, we provide an optimized 4 steps protocol achieving: 1) selective expression of a zebrafish codon-optimized GFP-aequorin, 2) efficient soaking of larvae in GFP-aequorin substrate coelenterazine, 3) bioluminescence monitoring of neural activity from motor neurons in free-tailed moving animals performing acoustic escapes and 4) verification of the absence of muscle expression using immunohistochemistry. PMID- 29130059 TI - Inter- and Intra-Individual Variation in Emotional Complexity: Methodological Considerations and Theoretical Implications. AB - The degree of relationship between positive and negative emotional states or emotional complexity is a topic of ongoing methodological and theoretical debate. At issue is whether positive and negative emotions are opposite ends of a bipolar continuum or independent dimensions in a bivariate distribution with little degree of overlap. In this review, we summarize a body of work suggesting that the distinction between positive and negative emotions varies both between and within individuals over time as a function of cognition and changes in informational demands, a perspective called the Dynamic Model of Affect (DMA). In addition to providing a unifying theoretical model that specifies the conditions under which both bivariate and bipolar models of affect may be valid, the DMA offers an integrative, multidimensional affective framework through which models of resilience and stress adaptation may be articulated. Future work should continue to explore the contextual factors, especially those that have relevance for the complexity of information processing, as potential moderators of the dynamic interplay between positive and negative emotions. PMID- 29130060 TI - Models of spatial and temporal dimensions of memory. AB - Episodic memory involves coding of the spatial location and time of individual events. Coding of space and time is also relevant to working memory, spatial navigation, and the disambiguation of overlapping memory representations. Neurophysiological data demonstrate that neuronal activity codes the current, past and future location of an animal as well as temporal intervals within a task. Models have addressed how neural coding of space and time for memory function could arise, with both dimensions coded by the same neurons. Neural coding could depend upon network oscillatory and attractor dynamics as well as modulation of neuronal intrinsic properties. These models are relevant to the coding of space and time involving structures including the hippocampus, entorhinal cortex, retrosplenial cortex, striatum and parahippocampal gyrus, which have been implicated in both animal and human studies. PMID- 29130062 TI - Human spatial navigation: Representations across dimensions and scales. AB - Humans, like many other species, employ three fundamental forms of strategies to navigate: allocentric, egocentric, and beacon. Here, we review each of these different forms of navigation with a particular focus on how our high-resolution visual system contributes to their unique properties. We also consider how we might employ allocentric and egocentric representations, in particular, across different spatial dimensions, such as 1-D vs. 2-D. Our high acuity visual system also leads to important considerations regarding the scale of space we are navigating (e.g., smaller, room-sized "vista" spaces or larger city-sized "environmental" spaces). We conclude that a hallmark of human spatial navigation is our ability to employ these representations systems in a parallel and flexible manner, which differ both as a function of dimension and spatial scale. PMID- 29130061 TI - Episodic Future Thinking: Mechanisms and Functions. AB - Episodic future thinking refers to the capacity to imagine or simulate experiences that might occur in one's personal future. Cognitive, neuropsychological, and neuroimaging research concerning episodic future thinking has accelerated during recent years. This article discusses research that has delineated cognitive and neural mechanisms that support episodic future thinking as well as the functions that episodic future thinking serves. Studies focused on mechanisms have identified a core brain network that underlies episodic future thinking and have begun to tease apart the relative contributions of particular regions in this network, and the specific cognitive processes that they support. Studies concerned with functions have identified several domains in which episodic future thinking produces performance benefits, including decision making, emotion regulation, prospective memory, and spatial navigation. PMID- 29130063 TI - Stress, self-regulation, and context: Evidence from the Health and Retirement Survey. AB - Health-related behaviors, such as smoking, alcohol use, exercise, and diet, are major determinants of physical health and health disparities. However, a growing body of experimental research in humans and animals also suggests these behaviors can impact the ways our bodies respond to stress, such that they modulate (that is, serve as a means to self-regulate or cope with) the deleterious impact of stressful experiences on mental health. A handful of epidemiologic studies have investigated the intersection between stress and health behaviors on health disparities (both mental and physical), with mixed results. In this study we use a novel instrument designed to explicitly measure the self-regulatory motivations and perceived effectiveness of eight health-related self-regulatory behaviors (smoking, alcohol, drug use, overeating, prayer, exercise, social support, talking with a councilor) in a subset of the Health and Retirement Study (N=1,354, Mean age=67, 54% female). We find that these behaviors are commonly endorsed as self-regulatory stress-coping strategies, with prayer, social support, exercise, and overeating used most frequently. The likelihood of using particular behaviors as self-regulatory strategies varied significantly by sex, but not by race/ethnicity, education, or wealth. We also find that greater stress exposure is associated with higher likelihood of using these behaviors to self regulate feelings of emotional distress, particularly health-harming behaviors like smoking, alcohol, and overeating. These findings provide an important link between sociological and psychological theoretical models on stress and empirical epidemiological research on social determinants of health and health disparities. PMID- 29130064 TI - Phylogenetic Group of Escherichia coli Isolates from Broilers in Brazilian Poultry Slaughterhouse. AB - The aim of the study was to determine the phylogenetic groups of E. coli strains isolated from seemingly healthy broiler and broiler condemned suspected of colibacillosis in a Brazilian slaughterhouse. Samples from respiratory tract and edible giblets (liver and heart) of broilers with and without macroscopic lesions of colibacillosis were collected at slaughter. There were 84 strains isolated from broilers condemned of which 11 were obtained from swabs of the heart, 7 from the liver, and 66 from the respiratory tract. Of the 53 E. coli strains isolated from broilers not condemned, 5 were isolated from the heart, 4 from the liver, and 44 from the respiratory tract. E coli strains were tested via PCR for phylogenetic groups A, B1, B2, C, D, E, and F. Phylogroups A and B1 were the most common phylogroups of E. coli obtained from healthy and sick-appearing broiler carcasses. The results of the study showed that phylogroups B2 and E were associated with the heart samples and phylogroup A was associated with respiratory tract samples, phylogroup B1 with not condemned carcass, and phylogroup D with liver samples. PMID- 29130065 TI - Metabolic Syndrome in Apparently "Healthy" Ghanaian Adults: A Systematic Review and Meta-Analysis. AB - Background: Metabolic syndrome (MetS) is a major public health problem in Sub Saharan Africa. We systematically reviewed the literature towards estimating the prevalence of MetS among apparently "healthy" Ghanaian adults. Methods: We searched PubMed, Web of Science, Scopus, Africa Journals Online, African Index Medicus, and Google scholar as well as the websites of the Ministry of Health and Ghana Health service through September 2016. Only studies conducted among apparently "healthy" (no established disease, e.g., diabetes and hypertension) adults aged >= 18 years were considered. Only studies that utilised the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP), World Health Organization (WHO), or International Diabetes Federation (IDF) classifications for MetS were included. Results: Data from nine studies involving 1,559 individuals were pooled. The prevalence of MetS based on NCEP-ATP, WHO, and IDF classifications was 12.4% (95% confidence interval [CI] = 8.3-17.4%), 6.0% (95% CI = 1.4-13.1%), and 21.2% (95% CI = 12.4-30.9), respectively. Prevalence of MetS was higher among women than men. Conclusion: Among a population of adult Ghanaians deemed "healthy," there is a high prevalence of MetS. Preventive measures are required to address the risk components of MetS such as obesity and hypertension which are rapidly rising in Ghana. PMID- 29130067 TI - Gaussian Process Regression for Sensorless Grip Force Estimation of Cable Driven Elongated Surgical Instruments. AB - Haptic feedback is a critical but a clinically missing component in robotic Minimally Invasive Surgeries. This paper proposes a Gaussian Process Regression(GPR) based scheme to address the gripping force estimation problem for clinically commonly used elongated cable-driven surgical instruments. Based on the cable-driven mechanism property studies and surgical robotic system properties, four different Gaussian Process Regression filters were designed and analyzed, including: one GPR filter with 2-dimensional inputs, one GPR filter with 3-dimensional inputs, one GPR Unscented Kalman Filter (UKF) with 2 dimensional inputs, and one GPR UKF with 3-dimensional inputs. The four proposed methods were compared with the dynamic model based UKF filter on a 10mm gripper on the Raven-II surgical robot platform. The experimental results demonstrated that the four proposed methods outperformed the dynamic model based method on precision and reliability without parameter tuning. And surprisingly, among the four methods, the simplest GPR Filter with 2-dimensional inputs has the best performance. PMID- 29130066 TI - Creativity, Comprehension, Conversation and the Hippocampal Region: New Data and Theory. AB - Present findings indicate that hippocampal region (HR) damage impairs aspects of everyday language comprehension and production that require creativity ___ defined as the ability to form new internal representations that satisfy relevant constraints for being useful or valuable in the real world. In two studies, seventeen people participated in extensive face-to-face interviews: sixteen normal individuals and H.M., an amnesic with cerebellar and HR damage but virtually no neocortical damage. Study 1 demonstrated deficits in H.M.'s comprehension of creative but not routine aspects of the interviews ___ extending to the real world twelve prior demonstrations that H.M. understands routine but not novel aspects of experimentally constructed sentences, deficits that reflected his HR damage, but not his cerebellar damage, his explicit or declarative memory problems, inability to comprehend or recall the instructions, forgetting, poor visual acuity, motoric slowing, time pressure, deficits in visual scanning or attentional allocation, lack of motivation, and excessive memory load in the tasks. Study 2 demonstrated similar deficits in H.M.'s ability to produce creative but not routine aspects of conversational discourse, extending findings in five prior sentence production experiments to real-world creativity. We discuss conceptual frameworks for explaining relations between new and-useful creativity and the HR. PMID- 29130068 TI - Diet and Physical Activity Behaviors in Primary Care Patients with Recent Intentional Weight Loss. AB - Purpose: Lifestyle habits of primary care patients with recent, intentional weight loss are unclear and need to be better understood to aid in translational health promotion efforts. We aimed to characterize diet and exercise habits in primary care patients with recent, intentional weight loss, comparing those with greater (>=10%) vs. lesser (5 to <10%) weight loss. Methods: This was a cross sectional analysis of baseline data from a randomized trial comparing weight loss maintenance interventions. The study included primary care patients, 18-75 years old, with >=5% intentional weight loss via lifestyle change in the past 2 years. Participants (74% female, 87% white) had mean age 53 (12) years, body mass index 30.4 (5.9) kg/m2, and recent weight loss of 11 (8)%. Dietary habits were measured by the Diet Habits Survey. Physical activity and sedentary behavior were measured by self-report and objectively by pedometer. Results: On average, participants reported high fruits and vegetables intake (5 servings/day), and low intake of fried foods (1 serving/week), desserts (1 serving/week) and sugar-sweetened beverages (0 servings/week). Those with greater vs. lesser weight loss had higher intake of fruits and vegetables (p=0.037) and low fat foods or recipes (p=0.019). Average self-reported moderate-vigorous physical activity was 319 (281) minutes/week, with significant differences between greater (374 (328) minutes/week) vs. lesser (276 (230) minutes/week) weight loss groups (p=0.017). By pedometer, 30% had >=7,500 steps/day; the proportion was higher in greater (43%) vs. lesser (19%) weight loss groups (p=0.005). Conclusions: For weight loss, clinical patients typically employ simple strategies such as 5+ fruits and vegetables per day, fried foods and desserts <=1 per week, elimination of sugary drinks, choosing low fat foods/recipes, and physical activity 45-60 min/day. PMID- 29130069 TI - Label-free nanopore single-molecule measurement of trypsin activity. AB - Trypsin is the most important digestive enzyme produced in the pancreas, and is a useful biomarker for pancreatitis. In this work, a rapid and sensitive method for the quantitative determination of trypsin activity is developed by using a biological alpha-hemolysin protein nanopore. Due to its much larger molecular diameter than the narrow pore constriction, trypsin itself cannot transport through the alpha-hemolysin channel. Hence, an indirect trypsin detection method is developed by monitoring its proteolytic cleavage of a lysine-containing peptide substrate. Based on the current modulations produced by the translocation of the substrate degradation products in the nanopore, the activity levels of trypsin could be determined. The method is rapid and highly sensitive, with picomolar concentrations of trypsin detected in minutes. In addition, the effects of cation and temperature on the sensor sensitivity, trypsin inhibition, and serum sample analysis are also investigated. PMID- 29130070 TI - Perceptual confidence neglects decision-incongruent evidence in the brain. PMID- 29130071 TI - The Electrophysiological Substrate of Early Repolarization Syndrome: Noninvasive Mapping in Patients. AB - Background: The early repolarization (ER) pattern is a common ECG finding. Recent studies established a definitive clinical association between ER and fatal ventricular arrhythmias. However, the arrhythmogenic substrate of ER in the intact human heart has not been characterized. Objectives: To map the epicardial electrophysiological (EP) substrate in ER syndrome patients using noninvasive Electrocardiographic Imaging (ECGI), and to characterize substrate properties that support arrhythmogenicity. Methods: Twenty-nine ER syndrome patients were enrolled, 17 of which had a malignant syndrome. Characteristics of the abnormal EP substrate were analyzed using data recorded during sinus rhythm. The EP mapping data were analyzed for electrogram morphology, conduction and repolarization. Seven normal subjects provided control data. Results: The abnormal EP substrate in ER syndrome patients has the following properties: (1) Abnormal epicardial electrograms characterized by presence of J-waves in localized regions; (2) Absence of conduction abnormalities, including delayed activation, conduction block, or fractionated electrograms; (3) Marked abbreviation of ventricular repolarization in areas with J-waves. The action potential duration (APD) was significantly shorter than normal (196+/-19 vs. 235+/-21 ms, p<0.05). Shortening of APD occurred heterogeneously, leading to steep repolarization gradients compared to normal control (45+/-17 vs.7+/-5 ms/cm, p<0.05). Premature ventricular contractions (PVCs) were recorded in 2 patients. The PVC sites of origin were closely related to the abnormal EP substrate with J-waves and steep repolarization gradients. Conclusions: Early Repolarization is associated with steep repolarization gradients caused by localized shortening of APD. Results suggest association of PVC initiation sites with areas of repolarization abnormalities. Conduction abnormalities were not observed. PMID- 29130073 TI - Patterns of mortality by occupation in the UK, 1991-2011: a comparative analysis of linked census and mortality records. AB - Background: Detailed assessments of mortality by occupation are scarce. We aimed to assess mortality by occupation in the UK, differences in rates between England and Wales and Scotland, and changes over time in Scotland. Methods: We analysed adults of working age (20-59 years) using linked census and death records. Main occupation was coded into more than 60 groups in the 2001 census, with mortality follow-up until Dec 31, 2011. Comparable occupation data were available for Scotland in 1991, allowing assessment of trends over time. We calculated age standardised all-cause mortality rates (per 100 000 person-years), stratified by sex. We used Monte Carlo simulation to derive p values and 95% CIs for the difference in mortality over time and between England and Wales and Scotland. Findings: During 4.51 million person-years of follow-up, mortality rates by occupation differed by more than three times between the lowest and highest observed rates in both men and women. Among men in England and Wales, health professionals had the lowest mortality (225 deaths per 100 000 person-years [95% CI 145-304]), with low rates also shown in managers and teachers. The highest mortality rates were in elementary construction (701 deaths per 100 000 person years [95% CI 593-809]), and housekeeping and factory workers. Among women, teachers and business professionals had low mortality, and factory workers and garment trade workers had high rates. Mortality rates have generally fallen, but have stagnated or even increased among women in some occupations, such as cleaners (337 deaths per 100 000 person years [95% CI 292-382] in 1991, rising to 426 deaths per 100 000 person years in 2001 [371-481]). Findings from simulation models suggested that if mortality rates by occupation in England and Wales applied to Scotland, 631 fewer men (95% CI 285-979; a 9.7% decrease) and 273 fewer women (26-513; 6.7% decrease) of working age would die in Scotland every year. Excess deaths in Scotland were concentrated among lower skilled occupations (eg, female cleaners). Interpretation: Mortality rates differ greatly by occupation. The excess mortality in Scotland is concentrated among low-skilled workers and, although mortality has improved in men and women in most occupational groups, some groups have experienced increased rates. Future research investigating the specific causes of death at the detailed occupational level will be valuable, particularly with a view to understanding the health implications of precarious employment and the need to improve working conditions in very specific occupational groups. Funding: None. PMID- 29130072 TI - Prediction of Chronic Kidney Disease Stage 3 by CKD273, a Urinary Proteomic Biomarker. AB - Introduction: CKD273 is a urinary biomarker, which in advanced chronic kidney disease predicts further deterioration. We investigated whether CKD273 can also predict a decline of estimated glomerular filtration rate (eGFR) to <60 ml/min per 1.73 m2. Methods: In analyses of 2087 individuals from 6 cohorts (46.4% women; 73.5% with diabetes; mean age, 46.1 years; eGFR >= 60 ml/min per 1.73 m2, 100%; urinary albumin excretion rate [UAE] >=20 MUg/min, 6.2%), we accounted for cohort, sex, age, mean arterial pressure, diabetes, and eGFR at baseline and expressed associations per 1-SD increment in urinary biomarkers. Results: Over 5 (median) follow-up visits, eGFR decreased more with higher baseline CKD273 than UAE (1.64 vs. 0.82 ml/min per 1.73 m2; P < 0.0001). Over 4.6 years (median), 390 participants experienced a first renal endpoint (eGFR decrease by >=10 to <60 ml/min per 1.73 m2), and 172 experienced an endpoint sustained over follow-up. The risk of a first and sustained renal endpoint increased with UAE (hazard ratio >= 1.23; P <= 0.043) and CKD273 (>= 1.20; P <= 0.031). UAE (>=20 MUg/min) and CKD273 (>=0.154) thresholds yielded sensitivities of 30% and 33% and specificities of 82% and 83% (P <= 0.0001 for difference between UAE and CKD273 in proportion of correctly classified individuals). As continuous markers, CKD273 (P = 0.039), but not UAE (P = 0.065), increased the integrated discrimination improvement, while both UAE and CKD273 improved the net reclassification index (P <= 0.0003), except for UAE per threshold (P = 0.086). Discussion: In conclusion, while accounting for baseline eGFR, albuminuria, and covariables, CKD273 adds to the prediction of stage 3 chronic kidney disease, at which point intervention remains an achievable therapeutic target. PMID- 29130074 TI - Does Noise Weighting Matter in CT Iterative Reconstruction? AB - This paper uses a computer simulation to investigate whether a more accurate noise model always results in less noisy images in CT iterative reconstruction. We start with a hypothetic non-realistic noise model for the CT measurements, by assuming that the attenuation coefficient is energy independent and there is no scattering. A variance formula for this model is derived and presented. Based on this model, computer simulations are conducted with 12 different ad hoc noise weighting methods, and their results are compared. The simple Poisson noise model performs better than other more accurate models, when the projection data are generated with the hypothetical noise model. A more accurate noise model does not necessarily produce a less-noisy image. In this counter example, modeling the system's electronic noise during reconstruction does not help reducing the image noise. A simpler noise model sometimes can outperform the complicated and more accurate noise model. PMID- 29130075 TI - Association Between Cytokines and Liver Histology in Children with Nonalcoholic Fatty Liver Disease. AB - Background: Reliable non-invasive markers to characterize inflammation, hepatocellular ballooning, and fibrosis in nonalcoholic fatty liver disease (NAFLD) are lacking. We investigated the relationship between plasma cytokine levels and features of NAFLD histology to gain insight into cellular pathways driving NASH and to identify potential non-invasive discriminators of NAFLD severity and pattern. Methods: Cytokines were measured from plasma obtained at enrollment in pediatric participants in NASH Clinical Research Network studies with liver biopsy-proven NAFLD. Cytokines were chosen a priori as possible discriminators of NASH and its components. Minimization of Akaike Information Criterion (AIC) was used to determine cytokines retained in multivariable models. Results: Of 235 subjects, 31% had "Definite NASH" on liver histology, 43% had "Borderline NASH", and 25% had NAFLD but not NASH. Total plasminogen activator inhibitor 1 (PAI1) and activated PAI1 levels were higher in pediatric participants with Definite NASH and with lobular inflammation. Interleukin-8 (IL 8) was higher in those with stage 3-4 fibrosis and lobular inflammation. sIL 2ralpha was higher in children with stage 3-4 fibrosis and portal inflammation. In multivariable analysis, PAI1 variables were discriminators of Borderline/Definite NASH, definite NASH, lobular inflammation and ballooning. IL 8 increased with steatosis and fibrosis severity; sIL-2ralpha increased with fibrosis severity and portal inflammation. IL-7 decreased with portal inflammation and fibrosis severity. Conclusions: Plasma cytokines associated with histology varied considerably among NASH features, suggesting promising avenues for investigation. Future, more targeted analysis is needed to identify the role of these markers in NAFLD and to evaluate their potential as non-invasive discriminators of disease severity. PMID- 29130076 TI - CRISPR Correction of a Homozygous Low-Density Lipoprotein Receptor Mutation in Familial Hypercholesterolemia Induced Pluripotent Stem Cells. AB - : Familial hypercholesterolemia (FH) is a hereditary disease primarily due to mutations in the low-density lipoprotein receptor (LDLR) that lead to elevated cholesterol and premature development of cardiovascular disease. Homozygous FH patients (HoFH) with two dysfunctional LDLR alleles are not as successfully treated with standard hypercholesterol therapies, and more aggressive therapeutic approaches to control cholesterol levels must be considered. Liver transplant can resolve HoFH, and hepatocyte transplantation has shown promising results in animals and humans. However, demand for donated livers and high-quality hepatocytes overwhelm the supply. Human pluripotent stem cells can differentiate to hepatocyte-like cells (HLCs) with the potential for experimental and clinical use. To be of future clinical use as autologous cells, LDLR genetic mutations in derived FH-HLCs need to be corrected. Genome editing technology clustered regularly-interspaced-short-palindromic-repeats/CRISPR-associated 9 (CRISPR/Cas9) can repair pathologic genetic mutations in human induced pluripotent stem cells. Conclusion: We used CRISPR/Cas9 genome editing to permanently correct a 3-base pair homozygous deletion in LDLR exon 4 of patient-derived HoFH induced pluripotent stem cells. The genetic correction restored LDLR-mediated endocytosis in FH-HLCs and demonstrates the proof-of-principle that CRISPR-mediated genetic modification can be successfully used to normalize HoFH cholesterol metabolism deficiency at the cellular level. PMID- 29130077 TI - Study of the Factors Leading to Fetal and Neonatal Dysthyroidism in Children of Patients With Graves Disease. AB - Context: Neonatal hyperthyroidism was first described in 1912 and in 1964 was shown to be linked to transplacental passage of maternal antibodies. Few multicenter studies have described the perinatal factors leading to fetal and neonatal dysthyroidism. Objective: To show how fetal dysthyroidism (FD) and neonatal dysthyroidism (ND) can be predicted from perinatal variables, in particular, the levels of anti-thyrotropin receptor antibodies (TRAbs) circulating in the mother and child. Design and Patients: This was a retrospective multicenter study of data from the medical records of all patients monitored for pregnancy from 2007 to 2014. Setting: Among 280,000 births, the medical records of 2288 women with thyroid dysfunction were selected and screened, and 417 women with Graves disease and positive for TRAbs during pregnancy were included. Results: Using the maternal TRAb levels, the cutoff value of 2.5 IU/L best predicted for FD, with a sensitivity of 100% and specificity of 64%. Using the newborn TRAb levels, the cutoff value of 6.8 IU/L best predicted for ND, with a sensitivity of 100% and a specificity of 94%. In our study, 65% of women with a history of Graves disease did not receive antithyroid drugs during pregnancy but still had infants at risk of ND. Conclusions: In pregnant women with TRAb levels >=2.5 IU/L, fetal ultrasound monitoring is essential until delivery. All newborns with TRAb levels >=6.8 IU/L should be examined by a pediatrician with special attention for thyroid dysfunction and treated, if necessary. PMID- 29130079 TI - Enabling Machine Learning in Critical Care. AB - Critical care units are home to some of the most sophisticated patient technology within hospitals. In parallel, the field of machine learning is advancing rapidly and increasingly touching our lives. To facilitate the adoption of machine learning approaches in critical care, we must become better at sharing and integrating data. Greater emphasis on collaboration- outside the traditional "multidisciplinary" realm and into the engineering, mathematical, and computer sciences-will help us to achieve this. Meanwhile, those at the forefront of the health data revolution must earn and maintain society's trust and demonstrate that data sharing and reuse is a necessary step to improve patient care. PMID- 29130078 TI - Hepatic Adaptations to a High Fat Diet in the MRL Mouse Strain are Associated with an Inefficient Oxidative Phosphorylation System. AB - The MRL mice are resistant to a 12-week high fat diet (HFD) feeding protocol, with the proximal cause being an increased basal pAMPKT172 expression in the skeletal muscle. Here, we test if this lack of pathology extends to the liver at both the tissue and cellular levels and its correlation to pAMPKT172 levels. MRL and B6 mice were subjected to 12 weeks of diet intervention and tissues were either fixed for histology or snap-frozen for further processing (n= 3-6, per group). The HFD MRL mice remain insulin and glucose sensitive after 12 weeks of HFD. This phenomenon is correlated to increased liver pAMPKT172. The HFD-fed B6 control strain demonstrates the opposite trend with decreased pAMPKT172 expression after the HFD period. We have found further evidence of differential MRL metabolic adaptations. These differences include reduced glycogen content, reduced ectopic fat storage, and increased expression of Complex II (CII) and Complex V of the Electron Transport Chain (ETC). Whereas, B6 HFD control show unchanged glycogen content, increased ectopic fat and increased expression of Complex I and Complex V of the ETC. Taken together, the MRL adaptations point to an inefficient energy-producing phenotype that leads to glycogen depletion and attenuation of ectopic fat as secondary consequences with AMPK as the signaling mediator of these HFD- hepatic adaptations. PMID- 29130080 TI - Solution-processed single crystal microsheets of a novel dimeric phthalocyanine involved triple-decker for high-performance ambipolar organic field effect transistors. AB - Well-defined single crystal microsheets of a novel dimeric phthalocyanine involved sandwich-type triple-decker complex [Pc(SC6H13)8]2Eu2[BiPc(SC6H13)12]Eu2[Pc(SC6H13)8]2 (1) are successfully prepared via a facile solution process. High-performance single crystal OFETs with a hole mobility of 18 cm2 V-1 s-1 and an electron mobility of 0.3 cm2 V-1 s-1 are obtained. PMID- 29130081 TI - A nanostructured Fc(COCH3)2 film prepared using silica monolayer colloidal crystal templates and its electrochromic properties. AB - Since oxidation and reduction reactions mainly take place on surfaces, enlarging the specific surface of redox materials is the key to achieving excellent electrochemical performance. In this work, by using silica monolayer colloidal crystal templates (MCCTs), a nanostructured Fc(COCH3)2 film is prepared successfully, and such a nanostructure could exhibit the following unique electrochemical properties: the MCCTs could impede the aggregation tendency of Fc(COCH3)2 and possess high electrochemical activity; Fc(COCH3)2 enlarges the contact area and offers more active sites and faster electronic transmission channels. The structure, optical and electrochemical properties of the nanostructured Fc(COCH3)2 were tested and then compared with those of compact Fc(COCH3)2 films to evaluate the role of the nanoarchitecture. The unique structure design of the Fc(COCH3)2 film enables outstanding performance, showing a large transmittance change (DeltaT) of 37% at 550 nm when switched between 0.5 V and -2.5 V, which is approximately ninefold higher than that of the compact Fc(COCH3)2 film (approximately 4%). Response times of coloration and bleaching are found to be only 16.15 s and 5.56 s. Furthermore, the nanostructured Fc(COCH3)2 film shows much better cycling stability than the compact one. The results indicate that the nanostructure could significantly improve the electrochemical performance of the Fc(COCH3)2 film due to the increase in electrochemical active sites and the enhancement of the "D-to-A" redox switch of ferrocene. PMID- 29130082 TI - A solid phase-assisted approach for the facile synthesis of a highly water soluble zirconium-89 chelator for radiopharmaceutical development. AB - Nuclear medicine has seen impressive growth in recent years. An important development in this field occurred through the application of new radionuclides, e.g., 89Zr (t1/2 = 78.4 h, beta+ 0.396 MeV), the physical properties of which allow the use of antibodies as biological vectors for specific cancer targeting in combination with high resolution imaging by positron emission tomography (PET). The most commonly used chelator for 89Zr-based PET imaging is the hexadentate desferrioxamine (DFO) chelator. However, due to the instability of this complex, there has been a strong push towards the development of octadentate chelators. We report an ether derivative, oxoDFO*, resembling the motif of DFO with four hydroxamic acid groups for the binding of the radiometal and four ether linkages to increase the water solubility. Very importantly, the synthesis of this chelator follows a solid phase-assisted approach allowing for the development of an attractive synthetic methodology and widening the scope for the access to DFO-like chelators in highly efficient synthetic sequences. PMID- 29130083 TI - Metallic Fe nanoparticles trapped in self-adapting nanoreactors: a novel high capacity anode for aqueous Ni-Fe batteries. AB - Metallic Fe nanoparticles trapped in thick carbon nanoreactors are realized in situ via conventional gas-phase reactions. These derived nanohybrids exhibit unique self-adapting properties, with prominent anodic performance in terms of both stored capacity and cyclic durability when serving as anodes for Ni-Fe batteries. PMID- 29130084 TI - Welsh onion extract inhibits PCSK9 expression contributing to the maintenance of the LDLR level under lipid depletion conditions of HepG2 cells. AB - Statins mediate the transactivation of PCSK9, which in turn limits their cholesterol-lowering effects via LDL receptor (LDLR) degradation. The objective of the present study was to investigate the mechanism of action by which Welsh onion (Allium fistulosum L. [family Amaryllidaceae]) extract (WOE) regulates LDLR and PCSK9. HepG2 cells were cultured under lipid depletion conditions using a medium supplemented with delipidated serum (DLPS). WOE (50, 100, 200, and 400 MUg ml-1) significantly attenuated the DLPS-mediated increases in LDLR, PCSK9, and SREBP2 gene expression. While WOE treatment maintained the DLPS-mediated increases in LDLR protein expression, it dose-dependently and significantly attenuated the DLPS-mediated increases in the protein content of PCSK9. The suppression of PCSK9 was associated with the WOE-mediated reductions in SREBP2, but not HNF1alpha. WOE also dose-dependently reduced PCSK9 protein expression that was otherwise markedly induced by concomitant statin treatment. WOE-mediated PCSK9 inhibition contributed to LDLR lysosomal degradation suppression, and subsequent LDLR protein stabilization. HPLC analysis indicated that WOE contains kaempferol, quercetin, ferulic acid, and p-coumaric acid. Kaempferol and p coumaric acid contributed to the maintenance of LDLR expression by inhibiting PCSK9 in lipid depleted HepG2 cells. Altogether, these findings suggest that WOE inhibits PCSK9 transcription and protein expression via the reduction of SREBP2, and decreased PCSK9 further contributes to LDLR degradation prevention and LDLR protein stabilization under conditions of lipoprotein deficiency. The PCSK9 inhibition-mediated mechanism of WOE was likely attributed to the action of kaempferol and p-coumaric acid present in WOE. PMID- 29130085 TI - C-H nickellation of phenol-derived phosphinites: regioselectivity and structures of cyclonickellated complexes. AB - This report describes the results of a study on the ortho-C-H nickellation of the aryl phosphinites i-Pr2P(OAr) derived from the following four groups of substituted phenols: 3-R-C6H4OH (R = F (b), Me (c), MeO (d), Cl (e)); 3,5-R2 C6H3OH (R = F (f), Me (g), Cl (h), OMe (i)); 2-R-C6H4OH (R = Me (j), Ph(k)); and 2,6-R2-C6H3OH (R = Me (l), Ph (m)). No nickellation was observed with the phosphinites derived from the 3,5-disubstituted phenols g and h, and the 2,6 disubstituted phenols l and m; in all other cases nickellation occurred at an ortho-C-H to generate either the Br-bridged dimers [{kappaP,kappaC-(i Pr)2POAr}Ni(MU-Br)]2 (1b-1f, 1j, and 1k) or the monomeric acetonitrile adduct {kappaP,kappaC-ArOP(i-Pr)2}Ni(Br)(NCMe) (1i-NCMe). Analysis of C-H nickellation regioselectivity with 3-R-C6H4OH pointed to the importance of substituent sterics, not electronics: nickellation occurred at the least hindered position either exclusively (for R = Me (c), MeO(d), and Cl (e)) or predominantly (for R = F (b); 6 : 1). This conclusion is also consistent with the observation that C-H nickellation is possible with the 3,5-disubstituted aryl phosphinites bearing F and OMe, but not with the more bulky substituents Me or Cl. For the 2-substituted aryl phosphinites, C-H nickellation occurs at the unsubstituted ortho-C-H and not on the R substituent, regardless of whether the alternative C-H moiety of the substituent is sp3 (R = Me (j)) or sp2 (R = Ph (k)). The system thus reveals a strong preference for formation of 5-membered metallacycles. Consistent with this reactivity, no nickellation occurs with (2,6-R2-C6H3O)P(i-Pr)2. Tests with the parent dimer derived from i-Pr2P(OPh) showed that conversion to the monomeric acetonitrile adduct is highly favored, going to completion with only a small excess of MeCN. All new cyclonickellated complexes reported in this study were fully characterized, including by single crystal X-ray diffraction studies. The solid state structures of the dimers 1b and 1d showed an unexpected feature: two halves of the dimers displayed non-coplanar conformations that place the two Ni(ii) centers at shortened distances from each other (2.94-3.16 A). Geometry optimization studies using DFT have shown that such non-coplanar conformations stabilize the complex, implying that the "bending" observed in these complexes is not caused by packing forces. Indeed, it appears that the occurrence of coplanar conformations in the solid state structures of these dimers is a simple consequence of packing forces rather than an intrinsic property of the compound. PMID- 29130086 TI - A new ruthenium black dye design with improved optical properties for transparent dye sensitized solar devices. AB - We report here on the preparation and on the electronic properties of a panchromatic Ru(ii) sensitizer based on a new ligand which allows for higher molar extinction coefficients in the visible and better performances (32% efficiency improvement) over conventional "black dye" in transparent DSSC. PMID- 29130087 TI - Polyethylenimine-coated Fe3O4 nanoparticles effectively quench fluorescent DNA, which can be developed as a novel platform for protein detection. AB - We report a novel assembly of polyethyleneimine (PEI)-coated Fe3O4 nanoparticles (NPs) with single-stranded DNA (ssDNA), and the fluorescence of the dye labeled in the DNA is remarkably quenched. In the presence of a target protein, the protein-DNA aptamer mutual interaction releases the ssDNA from this assembly and hence restores the fluorescence. This feature could be adopted to develop an aptasensor for protein detection. As a proof-of-concept, for the first time, we have used this proposed sensing strategy to detect thrombin selectively and sensitively. Furthermore, simultaneous multiple detection of thrombin and lysozyme in a complex protein mixture has been proven to be possible. PMID- 29130088 TI - Universal behaviour of the glass and the jamming transitions in finite dimensions for hard spheres. AB - We investigate the glass and the jamming transitions of hard spheres in finite dimensions d, through a revised cell theory, that combines the free volume and the Random First Order Theory (RFOT). Recent results show that in infinite dimension the ideal glass transition and jamming transitions are distinct, while based on our theory we argue that they indeed coincide for finite d. As a consequence, jamming results into a percolation transition described by RFOT, with a static length diverging with exponent nu = 2/d, which we verify through finite size scaling, and standard critical exponents alpha = 0, beta = 0 and gamma = 2 independent on d. PMID- 29130089 TI - Rubidium containing thin films by atomic layer deposition. AB - The application range for atomic layer deposition (ALD) has now been extended to include the deposition of rubidium-containing films, enabling the deposition of new and exploratory types of compounds by ALD. The properties of rubidium t butoxide as an ALD precursor are promising, revealing similar behavior as its lithium, sodium and potassium counterparts. The deposition of rubidium containing films is reported as proof of concept through the Rb-Ti-O and Rb-Nb-O systems. Rubidium content in the doping level range of Rb is controllably achieved in Rb:TiOx up to 20%, whereas Rb can be introduced as a major component in Rb:NbOx. Perovskite RbNbO3, otherwise unattainable in bulk systems under ambient conditions, is shown to be stabilized on SrTiO3 (100) substrates. This report opens up the investigation of thin films of new and unexplored systems, not only in the world of ALD, but in materials chemistry in general. PMID- 29130090 TI - Arrested and temporarily arrested states in a protein-polymer mixture studied by USAXS and VSANS. AB - We investigate the transition of the phase separation kinetics from a complete to an arrested liquid-liquid phase separation (LLPS) in mixtures of bovine gamma globulin with polyethylene glycol (PEG). The solutions feature LLPS with upper critical solution temperature phase behavior. At higher PEG concentrations or low temperatures, non-equilibrium, gel-like states are found. The kinetics is followed during off-critical quenches by ultra-small angle X-ray scattering (USAXS) and very-small angle neutron scattering (VSANS). For shallow quenches a kinetics consistent with classical spinodal decomposition is found, with the characteristic length (xi) growing with time as xi ~ t1/3. For deep quenches, xi grows only very slowly with a growth exponent smaller than 0.05 during the observation time, indicating an arrested phase separation. For intermediate quench depths, a novel growth kinetics featuring a three-stage coarsening is observed, with an initial classical coarsening, a subsequent slowdown of the growth, and a later resumption of coarsening approaching again xi ~ t1/3. Samples featuring the three-stage coarsening undergo a temporarily arrested state. We hypothesize that, while intermittent coarsening and collapse might contribute to the temporary nature of the arrested state, migration-coalescence of the minority liquid phase through the majority glassy phase may be the main mechanism underlying this kinetics, which is also consistent with earlier simulation results. PMID- 29130091 TI - Donor-acceptor interaction-driven self-assembly of amphiphilic rod-coil molecules into supramolecular nanoassemblies. AB - Rigid-flexible amphiphilic molecules consisting of an aromatic segment based on pyrene and biphenyl units and hydrophilic polyethylene oxide chains self-assemble into lamellar, hexagonal columnar, and two-dimensional columnar nanostructures in the bulk state. In aqueous solution, these molecules self-assemble into nanofibers, spherical micelles, and multilayer nanotubes, depending on the chain or rod length of the molecules. Notably, ordered nanostructures of supramolecular polymers, such as single-layer curving fragments, nanofibers, and nanosheets, were constructed through charge-transfer interactions between the nanoobjects and an electron-acceptor molecule, 2,4,5,7-tetranitrofluorenone. These experimental results reveal that diverse supramolecular morphologies can be controlled by tuning rod-coil molecular interactions or charge-transfer interactions between the donor and acceptor molecules. PMID- 29130092 TI - Unveiling the relative stability and proton binding of non-classical Wells-Dawson isomers of [(NaF6)W18O54(OH)2]7- and [(SbO6)W18O54(OH)2]9-: a DFT study. AB - Density functional theory calculations combined with the energy and building block decomposition analyses have been carried out to investigate the structures, stability orders, redox potentials and proton binding of the six Baker-Figgis isomers (alpha, beta, gamma, alpha*, beta* and gamma*) of [(SbO6)W18O54(OH)2]9- {H2SbW18} and [(NaF6)W18O54(OH)2]7- {H2NaW18} anions at the level of PBEsol D3/TZP. Both bonding energy and Gibbs free energy analyses exhibit that the two non-classical Wells-Dawson (WD) species behave quite differently from each other. The pyroanimonate {H2SbW18}, with a stability order of gamma* > beta* > alpha > alpha* > beta > gamma, is a non-classical WD species, while the hexafluoride {H2NaW18} (alpha > beta > gamma > gamma* > beta* > alpha*) is a transition intermediate between classical and non-classical WD types, possessing both non classical ([XW18O60(OH)2]n-, X = I, Te and W) and classical [Si2W18O62]8- properties. Energy decomposition analyses (EDA) reveal that spatial arrangement (Ehost), host-guest fragment interaction energy (FIE), and structural distortion energy (DE) are three key factors governing the relative stability of isomers; among these, DE is always dominant, while FIE and Ehost are subordinated but are still important. Building-block decomposition analyses (BDA) disclose that the octahedral {MO6} units of the equatorial belt, particularly the staggered belt, are always more distorted than those of the two polar caps inside each structure. The theoretical redox potentials demonstrate that the oxidizing power increases with a trend of alpha < beta < gamma and alpha* < beta* < gamma* for both species, and the first redox potential is closely related to the energy level of the LUMO of each anion. Evaluation of the proton inclusion energies suggests that {H2NaW18} can only embed two protons, while {H2SbW18} may encapsulate four; the number of embedded protons is controlled by both the charge of the heteroatom X and the volume of the tetrahedral {O4}/{OF3} cavity. PMID- 29130093 TI - Catalytic CO oxidation over Pd70Au30(111) alloy surfaces: spectroscopic evidence for Pd ensemble dependent activity. AB - Catalytic CO oxidation over Pd(111) and Pd70Au30(111) surfaces was investigated by in situ spectroscopic observations to understand the alloying effect. The reaction behaviour on Pd70Au30(111) is greatly different from that on Pd(111). Pd monomer and dimer ensembles can act as active centers, whereas triangular-shaped trimers and larger ensembles are inactive. PMID- 29130094 TI - Irregular model DNA particles self-assemble into a regular structure. AB - DNA nanoparticles with three-fold coordination have been observed to self assemble in experiment into a network equivalent to the hexagonal (6.6.6) tiling, and a network equivalent to the 4.8.8 Archimedean tiling. Both networks are built from a single type of vertex. Here we use analytic theory and equilibrium and dynamic simulation to show that a model particle, whose rotational properties lie between those of the vertices of the 6.6.6 and 4.8.8 networks, can self-assemble into a network built from three types of vertex. Important in forming this network is the ability of the particle to rotate when bound, thereby allowing the formation of more than one type of binding motif. The network in question is equivalent to a false tiling, a periodic structure built from irregular polygons, and possesses 40 particles in its unit cell. The emergence of this complex structure, whose symmetry properties are not obviously related to those of its constituent particles, highlights the potential for creating new structures from simple variants of existing nanoparticles. PMID- 29130095 TI - An efficient supramolecular adsorbent for co-adsorption of dyes and metal ions from wastewater and its application in self-healing materials. AB - Herein, a novel type of two-component supramolecular adsorbent, 2-OA, was developed based on non-covalent interactions using tetrazolyl derivative with octadecylamine (OA) and fully characterized using a number of structural and spectral techniques. The self-assembled 2-OA gels displayed remarkable stimuli responsiveness as well as shape-persistent and self-healing properties. In addition, it was found that the adsorbent 2-OA was able to remove dyes (10 kinds of cationic and anionic dyes) and metal ions (Cu2+ and Fe2+) simultaneously from wastewater owing to synergistic electrostatic attraction, hydrogen-bonding, and hydrophobic and coordination interactions. It also exhibited excellent co adsorption capability to dye mixtures and binary mixtures of dyes and metal ions. In particular, the dye/metal-loaded adsorbents could be obtained easily from the aqueous phase, and recycling of the adsorbents could thus be achieved. These results suggest that the supramolecular gel 2-OA not only has great potential application in wastewater treatment but also provides a strategy for the development of intriguing self-healing materials. PMID- 29130096 TI - Structuring polymer gels via catalytic reactions. AB - We use computer simulations to investigate how a catalytic reaction in a polymer sol can induce the formation of a polymer gel. To this aim we consider a solution of homopolymers in which freely-diffusing catalysts convert the originally repulsive A monomers into attractive B ones. We find that at low temperatures this reaction transforms the polymer solution into a physical gel that has a remarkably regular mesostructure in the form of a cluster phase, absent in the usual homopolymer gels obtained by a quench in temperature. We investigate how this microstructuring depends on catalyst concentration, temperature, and polymer density and show that the dynamics for its formation can be understood in a semi quantitative manner using the interaction potentials between the particles as input. The structuring of the copolymers and the AB sequences resulting from the reactions can be discussed in the context of the phase behaviour of correlated random copolymers. The location of the spinodal line as found in our simulations is consistent with analytical predictions. Finally, we show that the observed structuring depends not only on the chemical distribution of the A and B monomers but also on the mode of formation of this distribution. PMID- 29130097 TI - c-Fos mediates alpha1, 2-fucosyltransferase 1 and Lewis y expression in response to TGF-beta1 in ovarian cancer. AB - FUT1 is a key rate-limiting enzyme in the synthesis of Lewis y, a membrane associated carbohydrate antigen. The aberrant upregulation of FUT1 and Lewis y antigen is related to proliferation, invasion and prognosis in malignant epithelial tumors. A c-Fos/activator protein-1 (AP-1) binding site was found in the FUT1 promoter. However, the mechanisms of transcriptional regulation of FUT1 remain poorly understood. TGF-beta1 is positively correlated to Lewis y. In the present study, we investigated the molecular mechanism of FUT1 gene expression in response to TGF-beta1. We demonstrated that c-Fos was highly expressed in 77.50% of ovarian epithelial carcinoma cases and was significantly correlated with Lewis y. Using luciferase activity and chromatin immunoprecipitation (ChIP) assay, we further revealed that c-Fos interacted with the FUT1 promoter in ovarian cancer cells and transcriptional capacity of the heterodimer formed by c-Fos and c-Jun was stronger than that of the c-Fos or c-Jun homodimers. Then, we demonstrated that TGF-beta1 induced dose-dependent c-Fos expression, which was involved in TGF beta1-induced ovarian cancer cell proliferation. In addition, inhibition of MAPK activation or TGF-beta1 receptor by pharmacological agents prevented TGF-beta1 induced c-Fos and Lewis y expression. Silencing of c-Fos prevented TGF-beta1 induced Lewis y expression. Collectively, the results of these studies demonstrated that TGF-beta1 regulated FUT1 and Lewis y expression by activating the MAPK/c-Fos pathway. PMID- 29130098 TI - Ursodeoxycholic acid suppresses epithelial-mesenchymal transition and cancer stem cell formation by reducing the levels of peroxiredoxin II and reactive oxygen species in pancreatic cancer cells. AB - Reactive oxygen species (ROS) play a key role in cancer development and progression. Ursodeoxycholic acid (UDCA) may possess antioxidant, anti inflammatory and chemoprophylatic effects. Therefore, we aimed to investigate the effects and mechanisms of UDCA treatment on pancreatic cancer cells. The pancreatic cancer cell lines HPAC and Capan-1 were treated with 0.2 mM UDCA. To examine alterations in the levels of intracellular ROS, the DCF-DA stain was used and both stemness and epithelial-mesenchymal transition (EMT)-related genes were quantified using qRT-PCR and western blot analysis. The pancreatic cancer sphere culture was performed following seven days of treatment with 0.2 mM UDCA, as an indicator of stemness. Following treatment with UDCA, the level of intracellular ROS was decreased in the pancreatic cancer cells. UDCA decreased both the phosphorylation of STAT3 and the expression of peroxiredoxin II (Prx2). Furthermore, the treatment resulted in the upregulation of E-cadherin and in the downregulation of N-cadherin. In addition, UDCA decreased the expression of sex determining region Y-box 2 (Sox2) and it diminished the number of pancreatic cancer spheres formed. In conclusion UDCA suppressed the levels of intracellular ROS and Prx2 and it decreased EMT and stem cell formation in pancreatic cancer cells. Therefore, UDCA may provide favorable therapeutic benefits, through its antioxidant effects, for patients with pancreatic cancer. PMID- 29130099 TI - Upregulation of miR-542-3p inhibits the growth and invasion of human colon cancer cells through PI3K/AKT/survivin signaling. AB - The present study was designed to assess the expression of microRNA-542-3p (miR 542-3p) in human colon cancer and investigate the possible molecular mechanisms underlying the effect of miR-542-3p on the growth and invasion of colon cancer cells. We found that miR-542-3p expression was downregulated in colon cancer patient tissues, compared with that observed in the control group. Silencing of miR-542-3p expression significantly promoted cell viability and inhibited apoptosis. In addition, overexpression of miR-542-3p significantly reduced cell viability and promoted apoptosis in colon cancer cells. Meanwhile, silencing of miR-542-3p expression significantly suppressed PI3K and p-AKT and survivin protein expression, while overexpression of miR-542-3p significantly induced PI3K and p-AKT and survivin protein expression in colon cancer cells. PI3K inhibitor (LY294002) or survivin inhibitor (YM155) suppressed PI3K/AKT/survivin signaling and increased the anticancer effects of miR-542-3p on the apoptosis in colon cancer. The present study demonstrated that upregulation of miR-542-3p inhibited the growth and invasion of colon cancer cells through PI3K/AKT/survivin signaling, highlighting a novel therapeutic approach for the treatment of colon cancer. PMID- 29130100 TI - Immature colon carcinoma transcript-1 promotes cell growth of hepatocellular carcinoma via facilitating cell cycle progression and apoptosis resistance. AB - Immature colon carcinoma transcript-1 (ICT1) is a newly identified oncogene, which regulates proliferation, cell cycle progression and apoptosis of cancer cells. However, the clinical significance, biological function and underlying mechanisms of ICT1 in hepatocellular carcinoma (HCC) remain poorly known. In the present study, we showed that the expression of ICT1 in HCC tissues were notably overexpressed compared to corresponding non-tumor tissues. Accordingly, the relative levels of ICT1 were upregulated in HCC cell lines compared with LO2 cells. The positive expression of ICT1 was correlated with large tumor size and advanced TNM tumor stage. Kaplan-Meier plots indicated that ICT1-positive expression in HCC patients showed a prominent shorter survival. In addition, ICT1 knockdown inhibited proliferation and cell cycle progression, and induced apoptosis in HepG2 cells. While, ICT1 overexpression showed opposite effects on these cellular processes of Hep3B cells. In vivo experiments demonstrated that ICT1 deficiency reduced the growth of subcutaneous HCC in nude mice. Notably, ICT1 knockdown reduced the levels of CDK1, cyclin B1 and Bcl-2 and increased the expression of Bax in HepG2 cells. ICT1 overexpression resulted in upregulation of CDK1, cyclin B1 and Bcl-2, and downregulation of Bax in Hep3B cells. Furthermore, microRNA-134 (miR-134) was recognized as a direct upstream regulator and inversely modulated ICT1 abundance in HCC cells. Altogether, our data support that miR-134 regulation of ICT1 facilitates malignant phenotype of HCC cells probably via cell cycle and apoptosis-associated proteins including CDK1, cyclin B1, Bcl-2 and Bax. PMID- 29130101 TI - The recombinant EGFR/CD13 bi-targeted fusion protein induces apoptosis and blocks tube formation. AB - Previously it was shown that the recombinant EGFR/CD13 bi-targeted fusion protein ER(Fv)-LDP-NGR which consists of an anti-EGFR scFv antibody fragment, a tri cyclic NGR peptide, and a lidamycin-derived apoprotein, inhibited the proliferation of cancer cells and markedly suppressed tumor growth of breast carcinoma MCF-7 xenografts in athymic mice. This study investigated the mechanism of action of the fusion protein. Human breast cancer MCF-7 cells, lung adenocarcinoma A549 cells, and microvascular endothelial HMEC-1 cells were used for a series of assays and determinations. ER(Fv)-LDP-NGR downregulated the transcription and expression of the target proteins EGFR and CD13, and interfered with the intracellular EGFR signaling pathway, cell cycle signaling pathway and apoptotic pathway. It induced apoptosis, inhibited proliferation, caused cell cycle G2/M phase arrest, and suppressed cell migration. Accompanied by weakening the capability to degrade extracellular matrix, ER(Fv)-LDP-NGR depressed the invasion capacity of cancer cells. In addition, ER(Fv)-LDP-NGR prevented microvascular endothelial cells from tube formation, which is closely related to angiogenesis. In conclusion, the EGFR/CD13 bi-targeted fusion protein ER(Fv)-LDP NGR displays multi-functional characteristics, acting on both cancer cells and endothelial cells. It might be an effective agent for targeted cancer therapy. PMID- 29130102 TI - Knockdown of lncRNA-XIST enhances the chemosensitivity of NSCLC cells via suppression of autophagy. AB - Drug resistance is the major factor contributing to the failure of chemotherapy in non-small cell lung cancer (NSCLC) patients. Emerging evidence suggests that autophagy plays a vital role in the chemoresistance of many types of tumors. However, the exact mechanism underlying the chemoresistance of NSCLC is still elusive, and it is unclear whether lncRNA-XIST is involved in autophagy and chemoresistance of NSCLC. In the present study, we demonstrated that lncRNA-XIST was overexpressed in NSCLC tumor samples, and knockdown of lncRNA-XIST significantly decreased autophagy by regulation of ATG7 as determined by qPCR and by western blotting. Furthermore, we found that miR-17 was upregulated following knockdown of lncRNA-XIST, and miR-17 mimics decreased the protein levels of ATG7 by directly targeting the 3'-untranslated region of ATG7 mRNA as determined by RT qPCR and by western blotting. Furthermore, we found that the expression level of lncRNA-XIST was markedly increased in cisplatin-resistant A549 cells as determined by q-PCR. Knockdown of lncRNA-XIST restored the chemosensitivity of cisplatin-resistant A549 cells to cisplatin, which was reversed by miR-17 inhibitor and overexpression of ATG7 as determined by CCK8 assays. This study provides evidence that lncRNA-XIST may be a potential marker of poor response to cisplatin chemotherapy in NSCLC patients and the pathway 'lncRNA-XIST/miR 17/autophagy' may be a promising target for patients with chemoresistant NSCLC. PMID- 29130103 TI - Hypoxia-induced inhibition of the endocannabinoid system in glioblastoma cells. AB - The endocannabinoid system plays an important role in the regulation of physiological and pathological conditions, including inflammation and cancer. Hypoxia is a fundamental phenomenon for the establishment and maintenance of the microenvironments in various physiological and pathological conditions. However, the influence of hypoxia on the endocannabinoid system is not fully understood. In the present study, we investigated the effects of hypoxia on the endocannabinoid system in malignant brain tumors. We subjected U-87 MG cells, derived from malignant glioblastoma, to hypoxia (1.5% O2) for 3 days, and evaluated their viability and expression of endocannabinoid-related genes. Hypoxia decreased the expression of cannabinoid receptor 1 and the astrocyte marker glial fibrillary acidic protein, and increased the expression of vascular endothelial growth factor and cyclooxygenase-2, the enzyme responsible for the metabolism of endocannabinoids, in U-87 MG cells. Although cannabinoid receptor (CB) engagement induces cell death in U-87 MG cells in normoxic conditions, CB agonist-induced death was attenuated in hypoxic conditions. These results suggest that hypoxia modifies the endocannabinoid system in glioblastoma cells. Hypoxia induced inhibition of the endocannabinoid system may aid the development of glioblastoma. PMID- 29130104 TI - Expression of fatty acid synthase is regulated by PGC-1alpha and contributes to increased cell proliferation. AB - We previously demonstrated that overexpression of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) promotes increased cell proliferation and tumorigenic potential through upregulation of specificity protein 1 (Sp1) and acyl-CoA-binding protein (ACBP). Fatty acid synthase (FASN) is a key enzyme in fatty acid biosynthesis, and its expression in various cancers is associated with survival, poor prognosis and cancer recurrence. In the present study, we evaluated whether PGC-1alpha regulated FASN expression in human colorectal cancer (SNU-C4 and HT-29) cells. We also examined whether cell proliferation was inhibited by shRNA-induced FASN knockdown in SNU-C4 and HT-29 cells. In all tested cell lines, FASN-shRNA knockdown inhibited cell proliferation, decreased antioxidant enzyme expression, and increased apoptosis and production of H2O2-induced reactive oxygen species (ROS). These findings indicated that FASN expression may enhance cell proliferation by regulating antioxidant enzyme production and resistance to ROS-induced apoptosis. We further provided evidence that FASN expression was regulated indirectly through upregulation of Sp1 and SREBP-1c by PGC-1alpha. Overall, our results revealed that FASN expression, mediated by PGC-1alpha, may play a positive role in cancer cell proliferation. PMID- 29130105 TI - Tumor molecular profiling of NSCLC patients using next generation sequencing. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a tumor with a broad spectrum of targeted therapies already available or in clinical trials. Thus, molecular characterization of the tumor using next generation sequencing (NGS) technology, has become a key tool for facilitating treatment decisions and the clinical management of NSCLC patients. The performance of a custom 23 gene multiplex amplification hot spot panel, based on Ion AmpliSeqTM technology, was evaluated for the analysis of tumor DNA extracted from formalin-fixed and paraffin-embedded (FFPE) tissues. Furthermore, the Ion AmpliSeqTM RNA Fusion Lung Cancer Research Panel was used for fusion RNA transcript analysis. The mutation spectrum of the tumors was determined in a cohort of 502 patients with NSCLC using the aforementioned targeted gene panels. The panel used for tumor DNA analysis in this study exhibited high rates (100%) of sensitivity, specificity and reproducibility at a mutation allelic frequency of 3%. At least one DNA mutation was detected in 374 patients (74.5%) and an RNA fusion was identified in 16 patients, (3.2%). In total, alterations in a cancer driver gene were identified (including point mutations, gene rearrangements and MET amplifications) in 77.6% of the tumors tested. Among the NSCLC patients, 23% presented a mutation in a gene associated with approved or emerging targeted therapy. More specifically, 13.5% (68/502) presented a mutation in a gene with approved targeted therapy (EGFR, ALK, ROS1) and 9.4% (47/502) had an alteration in a gene related to emerging targeted therapies (ERBB2, BRAF, MET and RET). Furthermore, 51.6% of the patients had a mutation in a gene that could be related to an off label therapy or indicative for access to a clinical trial. Thus, the targeted NGS panel used in this study is a reliable approach for tumor molecular profiling and can be applied in personalized treatment decision making for NSCLC patients. PMID- 29130106 TI - Molecular alterations of the NF2 gene in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. AB - Neurofibromatosis type 2 with mutations in the neurofibromin 2 (NF2) gene, encoding the Merlin protein, is an autosomal dominant disorder characterized by enhanced cancer predisposition, particularly tumors of the central nervous system. Recent animal studies indicate that disruption of NF2/Merlin function in oval cells, which are hepatic progenitor cells, may lead to the development of primary liver cancers including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its role in human primary liver cancer remains unclear. In the present study, we explored the role of NF2/Merlin in human primary liver cancers. Tumor tissues (n=144) were used for the screening of NF2 mutation, while whole blood samples from 219 HCC and 194 healthy control cases were used for analysis of single nucleotide polymorphisms (SNPs) in liver cancer. The expression and amplification of NF2/Merlin and its downstream gene in the Hippo pathway, Yes-associated protein (YAP), were also analyzed. Missense NF2 mutations were identified in 2 of 106 (1.9%) HCCs and 2 of 38 (5.3%) ICCs. Allele frequency of NF2 IVS4-39 A/A was significantly higher in the HCCs than that in the healthy controls. Noteworthy, NF2/Merlin showed a dual role as a tumorigenic gene and tumor-suppressor gene; Merlin was expressed at higher levels in tumors than in adjacent non-tumor tissues of HCC; while the rate of Merlin upregulation was significantly lower in poorly differentiated ICCs. In addition, a significant negative correlation between Merlin and YAP expression was observed in ICC. In conclusion, we provide initial evidence of human primary liver cancers characterized by molecular alterations of NF2/Merlin and the involvement of the Hippo pathway in the pathogenesis of human liver cancer. PMID- 29130108 TI - miR-149 suppresses human non-small cell lung cancer growth and metastasis by inhibiting the FOXM1/cyclin D1/MMP2 axis. AB - Valid evidence has demonstrated that microRNAs have critical functions in cancer genesis and tumor progression. In the present study, aberrant expression of microRNA-149 (miR-149) was confirmed in non-small cell lung cancer (NSCLC) tissues. Low expression of miR-149 was associated with malignant clinical features and poor survival. Gain- and loss-of-function experiments demonstrated that miR-149 inhibited NSCLC tumor growth and metastasis in vitro and in vivo. Furthermore, oncogenic transcription factor FOXM1 was confirmed as a direct target of miR-149 in NSCLC. Cyclin D1 and MMP2 served as downstream targets of FOXM1 and were also inhibited by miR-149. In summary, the present study indicated that downregulation of miR-149 in NSCLC predicted poor clinical outcomes. miR-149 suppresses tumor growth and metastasis in NSCLC by inhibiting the FOXM1/cyclin D1/MMP2 signaling pathway. PMID- 29130107 TI - A seven-gene prognostic signature for rapid determination of head and neck squamous cell carcinoma survival. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and displays divergent clinical outcomes. Prognostic biomarkers might improve risk stratification and survival prediction. We aimed to investigate the prognostic genes associated with overall survival. A two-step gene selection method was used to develop a seven-gene-based prognostic model based on the training set collected from The Cancer Genome Atlas (TCGA). In addition, the prognostic model was validated in an independent testing set from Gene Expression Omnibus (GEO). The score based on the model successfully distinguished HNSCC survival into high risk and low-risk groups in the training set (HR, 2.79; 95% CI, 1.98-3.92; P=4.05x10-9) and the testing set (HR, 2.05; 95% CI, 1.35-3.11; P=7.98x10-4). In addition, the score could significantly predict 5-year survival by ROC curves (AUCs for training set, 0.73; testing set, 0.66). Combining risk scores with clinical characteristics improved the AUCs beyond using clinical characteristics alone (training set, from 0.57 to 0.75; testing set, from 0.63 to 0.72). A subgroup sensitivity analysis with HPV status and tumor sites revealed that the risk score was significant in all subgroups except oral cavity tumors of the testing set. Furthermore, HPV-positive status improves survival in oropharyngeal HNSCC but not non-oropharyngeal HNSCC. In conclusion, the seven-gene prognostic signature is a reliable and practical prognostic tool for HNSCC. This approach can add prognostic value to clinical characteristics and provides a new possibility for individualized treatment. PMID- 29130109 TI - Deubiquitinase USP9X promotes cell migration, invasion and inhibits apoptosis of human pancreatic cancer. AB - Ubiquitin specific peptidase 9, X-linked (USP9X), a significant regulatory protease in protein ubiquitination, has been proven to act as a proto-oncogene in several types of cancers, such as cervix, colon, breast, brain and lung cancers. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to its high invasive and metastatic abilities. Nevertheless, whether USP9X acts as a proto-oncogene or a tumor-suppressor gene in PDAC is controversial and the mechanism of metastasis remains unknown. The present study focused on the effect of USP9X on the migration, invasion and apoptosis of PADC cells. We analyzed the expression of USP9X in pancreatic cancer tissues of different pathologic grades by immunohistochemical analysis. USP9X expression in the pancreatic cancer tissues was markedly increased in contrast to that noted in the adjacent non-tumor tissues. USP9X expression in PANC-1 cells was downregulated after transfection of shRNA-USP9X. Knockdown of endogenous USP9X expression evidently inhibited the migration and invasion of PANC-1 cells, and promoted cell apoptosis. Meanwhile, expression levels of Snail, Twist, N-cadherin and vimentin were downregulated. E-cadherin expression was negatively correlated with USP9X expression and the expression of survivin was also downregulated in the PANC-1 cells. In brief, USP9X promoted the migration and invasion of PANC-1 cells probably by provoking epithelial-mesenchymal transition, and also inhibited apoptosis. We believe that USP9X is a major oncogene that may play a significant role in the treatment and prognosis of PDAC. PMID- 29130110 TI - Epimedium koreanum Nakai inhibits PMA-induced cancer cell migration and invasion by modulating NF-kappaB/MMP-9 signaling in monomorphic malignant human glioma cells. AB - Previously, we showed that the herbal extract EYK (Epimedium koreanum Nakai) can regulate the immune response. Other studies showed that EYK has beneficial effects in human lung cancer, angiogenesis and Alzheimer's disease (AD). However, it remains unknown whether EYK can affect cancer cell migration and invasion in human brain cancer cell lines. In the present study, we found that pre- or post treatment with EYK inhibited phorbol 12-myristate 13-acetate (PMA)-induced cancer cell migration and invasion in A172 cells, but not in U373MG or T98G cells. Additionally, pre- or post-treatment with PMA followed by EYK decreased MMP-9 activity in A172 cells. Moreover, treatment with a NF-kappaB inhibitor significantly decreased cell migration in A172 cells pre- or post-treated with EYK and PMA, suggesting that EYK requires NF-kappaB to alter cancer cell migration. Either pre- or post-treatment with EYK significantly decreased NF kappaB nuclear translocation in comparison with PMA treatment. Taken together, our results suggest that EYK suppresses PMA-induced cancer cell migration in monomorphic malignant human glioma cells by downregulating the NF-kappaB pathway and decreasing MMP-9 activity. PMID- 29130111 TI - MicroRNA-433 inhibits cervical cancer progression by directly targeting metadherin to regulate the AKT and beta-catenin signalling pathways. AB - Cervical cancer is one of the most common female malignancies worldwide. Emerging data have shown that microRNAs (miRNAs) play significant roles in various human cancers, including cervical cancer. Aberrantly expressed miRNAs in cervical cancer contribute to tumour occurrence and development as either tumour suppressors or promoters. Research suggests that miRNA-433 (miR-433) possibly plays an important role in the development of various cancer types. However, no study has explored the expression patterns, roles and underlying mechanisms of miR-433 in cervical cancer. In the present study, we demonstrated significant downregulation of miR-433 in cervical cancer tissues and cell lines. Low miR-433 expression was found to significantly correlate with patient characteristics including tumour size, International Federation of Gynecology and Obstetrics stage, lymph node and distant metastases. Functional studies showed that restoration of miR-433 inhibited cell proliferation and invasion and increased apoptosis in cervical cancer cells. Metadherin (MTDH) was also validated as a direct target gene of miR-433. MTDH mRNA expression was upregulated in cervical cancer tissues and was inversely correlated with miR-433 expression. MTDH knockdown showed similar tumour-suppressive roles as miR-433 overexpression in regards to cervical cancer cell proliferation, invasion and apoptosis. Rescue experiments revealed that MTDH overexpression markedly reversed the effects of miR-433 overexpression in regards to proliferation, invasion and apoptosis of cervical cancer cells. Further investigations revealed that miR-433 inactivated AKT and beta-catenin pathways in cervical cancer. Collectively, these findings indicate the essential roles of miR-433 in suppressing cervical cancer progression and suggest its potential as a therapeutic target for the treatment of cervical cancer. PMID- 29130112 TI - Infection risk assessment in patients undergoing primary total knee arthroplasty. AB - PURPOSE: To determine the incidence and to identify potential risk factors for in hospital and late infections, as well as for deep periprosthetic joint infection (PJI) following TKA. METHODS: We identified 17,959 patients treated with primary TKA between 2000 and 2009. We recorded patient demographics, comorbidities and in hospital complications. The rates of in-hospital, late, and deep PJIs were determined. Different logistic regression models were built to identify risk factors for each of the above types of infection. RESULTS: The rates for in hospital, post-discharge, and deep PJI were 0.65%, 0.41%, and 0.26%, respectively. Younger age, allogeneic blood transfusion, liver disease, and unilateral or staged bilateral TKA were risk factors for in-hospital infection. Renal and pulmonary disease, urinary tract infection, wound dehiscence, and prior in-hospital infection were risk factors for post-discharge infection. Male gender, history of in-hospital infection, prolonged length of stay, and pulmonary disease were identified as risk factors for deep PJI. CONCLUSION: Despite low infection rates after primary TKA, there are patients at higher risk that would benefit by addressing modifiable risk factors for both in-hospital or post discharge infections, including deep PJIs. PMID- 29130113 TI - Long-term results of closed reduction for developmental dislocation of the hip in children of walking age under eighteen months old. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) diagnosed in older postnatal children can be effectively treated by closed reduction (CR) alone. However, no prospective or comparative trial to explore the differential effectiveness of CR between non-walking and walking postnatal children has yet been reported. This study investigated the clinical and radiologic outcomes of CR in the age range of interest (12-18 months old) via a prospective trial and compared these results with those of a younger age group who also underwent CR. PATIENTS AND METHODS: Between 1999 and 2009, 56 children diagnosed with DDH were enrolled. Of these, 45 were followed after CR for a period of at least seven years. The anatomical parameters of the hip/pelvis, including arthrograms, were evaluated and compared before and after CR. The final radiologic status, including the occurrence of avascular necrosis (AVN), and clinical outcomes were evaluated and compared. RESULTS: The mean ages at the start of treatment were 6.11 and 15.29 months old in group 1 and group 2, respectively. None of the children required surgical open reduction during the follow-up period. The final status of hips were classified according to the Bucholz-Ogden system. Two type II hips and one type I hip were found in group 1. In group 2, two type I hips and one type III hip were observed at the final follow-up. The overall clinical outcomes were satisfactory in both groups, according to McKay's criteria. No significant differences in clinical outcomes between the two groups were found (P = 0.382). Surgery was performed for just one patient in group 2 at seven years old. CONCLUSIONS: CR in DDH for postnatal children 12-18 months old may provide similar results to the non walking age group if performed with preliminary traction, gentle CR under general anaesthesia, percutaneous adductor tenotomy, and the minimization of forceful abduction. PMID- 29130114 TI - Workplace bullying and violence as risk factors for type 2 diabetes: a multicohort study and meta-analysis. AB - AIMS/HYPOTHESIS: The aim of this multicohort study was to examine whether employees exposed to social stressors at work, such as workplace bullying and violence, have an increased risk of type 2 diabetes. METHODS: The study included 45,905 men and women (40-65 years of age and free of diabetes at baseline) from four studies in Sweden, Denmark and Finland. Workplace bullying and violence were self-reported at baseline. Incident diabetes was ascertained through national health and medication records and death registers. Marginal structural Cox models adjusted for age, sex, country of birth, marital status and educational level were used for the analyses. RESULTS: Nine per cent of the population reported being bullied at work and 12% were exposed to workplace violence or threats of violence. Bullied participants had a 1.46 (95% CI 1.23, 1.74) times higher risk of developing diabetes compared with non-bullied participants. Exposure to violence or threats of violence was also associated with a higher risk of diabetes (HR 1.26 [95% CI 1.02, 1.56]). The risk estimates attenuated slightly when taking BMI into account, especially for bullying. The results were similar for men and women, and were consistent across cohorts. CONCLUSIONS/INTERPRETATION: We found a higher risk of incident type 2 diabetes among employees exposed to bullying or violence in the workplace. Further research is needed to determine whether policies to reduce bullying and violence at work may reduce the incidence of type 2 diabetes in working populations. Research on the mechanisms is also highly warranted. PMID- 29130115 TI - Correction to: 18F-NaF PET/CT: EANM procedure guidelines for bone imaging. AB - The original version of this article unfortunately contained an error. The name and affiliation of "Frederic Paycha" needs to be corrected. Given in this article is the correct author name and affiliation. PMID- 29130116 TI - Hearing loss and renal syndromes. AB - The association between ear and kidney abnormalities has long been recognized; however, the connection between these two disparate organs is not always straightforward. Although Alport syndrome is the most well-known, there are over 20 disorders that need to be considered in the differential diagnosis of patients with both ear and kidney abnormalities. Commonalities are present between the kidney and ear in a number of structural proteins, developmentally important transcription factors, ciliary proteins, and channel proteins, and mutations in these pathways can lead to disease in both organ systems. This manuscript reviews the congenital disorders with both hearing and kidney manifestations. PMID- 29130117 TI - Correction to: The metabolic cost of nesting: body condition and blood parameters of Caiman crocodilus and Melanosuchus niger in Central Amazonia. AB - Although nesting ecology is well studied in several crocodilian species, it is not known how nest attendance influences physiology and body condition of nesting females. In this study, we describe body condition and serum biochemical values of nesting female, non-nesting female and male spectacled caiman (Caiman crocodilus) and black caiman (Melanosuchus niger) in two areas of Central Amazonia. We also evaluated the effect of nest age and nest distance to water on body condition and blood parameters of nesting females. Body condition and plasmatic concentrations of glucose, triglycerides, lactate and uric acid of nesting females were significantly different from those of non-nesting females and males in C. crocodilus, but not in M. niger. Our study also demonstrated that nest age and distance to water had a negative effect on female body condition in C. crocodilus, but not in M. niger. Female C. crocodilus attending older nests or nests built further away from permanent water bodies tended to have lower body condition. Our results demonstrate that the nesting strategy of C. crocodilus has a metabolic cost associated with nest attendance for nesting females, which appear to depend on accumulated energetic reserves during nest attendance. In contrast, nest attendance had little effect on the physiology of female M. niger. PMID- 29130118 TI - SOX10-positive cells emerge in the rat pituitary gland during late embryogenesis and start to express S100beta. AB - In the pituitary gland, S100beta-positive cells localize in the neurohypophysis and adenohypophysis but the lineage of the two groups remains obscure. S100beta is often observed in many neural crest-derived cell types. Therefore, in this study, we investigate the origin of pituitary S100beta-positive cells by immunohistochemistry for SOX10, a potent neural crest cell marker, using S100beta green fluorescence protein-transgenic rats. On embryonic day 21.5, a SOX10 positive cell population, which was also positive for the stem/progenitor cell marker SOX2, emerged in the pituitary stalk and posterior lobe and subsequently expanded to create a rostral-caudal gradient on postnatal day 3 (P3). Thereafter, SOX10-positive cells appeared in the intermediate lobe by P15, localizing to the boundary facing the posterior lobe, the gap between the lobule structures and the marginal cell layer, a pituitary stem/progenitor cell niche. Subsequently, there was an increase in SOX10/S100beta double-positive cells; some of these cells in the gap between the lobule structures showed extended cytoplasm containing F actin, indicating a feature of migration activity. The proportion of SOX10 positive cells in the postnatal anterior lobe was lower than 0.025% but about half of them co-localized with the pituitary-specific progenitor cell marker PROP1. Collectively, the present study identified that one of the lineages of S100beta-positive cells is a SOX10-positive one and that SOX10-positive cells express pituitary stem/progenitor cell marker genes. PMID- 29130119 TI - P85 regulates neuronal migration through affecting neuronal morphology during mouse corticogenesis. AB - In mammalian developing embryonic cortex, projection neurons migrate from the ventricular zone to the cortical plate, guided by radial glial cells with a transformation between bipolar and multipolar morphology. Previous studies have demonstrated that the PI3K-Akt-mTOR signal plays a critical role in brain development. However, the function of P85 in cortical development is still unclear. In the present study, we found that overexpression of P85 impaired cortical neuronal migration. Using in utero electroporation, we revealed that the length of the leading process in P85 overexpressed neurons became shorter than that in the control group but with more branches. Using markers for new-born neurons, we further found that overexpression of P85 did not affect the ultimate fate of these cortical neurons. These findings indicated that the P85 subunit plays an essential role in neuronal migration and neuronal morphology during mouse corticogenesis. PMID- 29130120 TI - Responses of rubber leaf phenology to climatic variations in Southwest China. AB - The phenology of rubber trees (Hevea brasiliensis) could be influenced by meteorological factors and exhibits significant changes under different geoclimates. In the sub-optimal environment in Xishuangbanna, rubber trees undergo lengthy periods of defoliation and refoliation. The timing of refoliation from budburst to leaf aging could be affected by powdery mildew disease (Oidium heveae), which negatively impacts seed and latex production. Rubber trees are most susceptible to powdery mildew disease at the copper and leaf changing stages. Understanding and predicting leaf phenology of rubber trees are helpful to develop effective means of controlling the disease. This research investigated the effect of several meteorological factors on different leaf phenological stages in a sub-optimal environment for rubber cultivation in Jinghong, Yunnan in Southwest China. Partial least square regression was used to quantify the relationship between meteorological factors and recorded rubber phenologies from 2003 to 2011. Minimum temperature in December was found to be the critical factor for the leaf phenology development of rubber trees. Comparing the delayed effects of minimum temperature, the maximum temperature, diurnal temperature range, and sunshine hours were found to advancing leaf phenologies. A comparatively lower minimum temperature in December would facilitate the advancing of leaf phenologies of rubber trees. Higher levels of precipitation in February delayed the light green and the entire process of leaf aging. Delayed leaf phenology was found to be related to severe rubber powdery mildew disease. These results were used to build predictive models that could be applied to early warning systems of rubber powdery mildew disease. PMID- 29130121 TI - Chiari I malformation: surgical technique, indications and limits. AB - BACKGROUND: Chiari malformation type I (CM-I) is a rare disease characterised by herniation of cerebellar tonsils below the foramen magnum with associated anomalies of posterior fossa. We describe here the surgical technique, indications and limits of surgical treatment. METHOD: The authors describe the surgical technique, including: posterior fossa decompression, opening of the foramen of Magendie and duraplasty in case of CM-I. CONCLUSIONS: Posterior fossa decompression plus duraplasty is a safe and effective procedure for patients with CM-I malformation. PMID- 29130122 TI - ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation. AB - ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice. PMID- 29130123 TI - Informal value chain actors' knowledge and perceptions about zoonotic diseases and biosecurity in Kenya and the importance for food safety and public health. AB - Zoonotic diseases, transmitted from animals to humans, are a public health challenge in developing countries. Livestock value chain actors have an important role to play as the first line of defence in safeguarding public health. However, although the livelihood and economic impacts of zoonoses are widely known, adoption of biosecurity measures aimed at preventing zoonoses is low, particularly among actors in informal livestock value chains in low and middle income countries. The main objective of this study was to investigate knowledge of zoonoses and adoption of biosecurity measures by livestock and milk value chain actors in Bura, Tana River County, in Kenya, where cattle, camels, sheep and goats are the main livestock kept. The study utilised a mixed methods approach, with a questionnaire survey administered to 154 value chain actors. Additional information was elicited through key informant interviews and participatory methods with relevant stakeholders outside the value chain. Our results found low levels of knowledge of zoonoses and low levels of adherence to food safety standards, with only 37% of milk traders knowing about brucellosis, in spite of a sero-prevalence of 9% in the small ruminants tested in this study, and no slaughterhouse worker knew about Q fever. Actors had little formal education (between 0 and 10%) and lacked training in food safety and biosecurity measures. Adoption of biosecurity measures by value chain actors was very low or non-existent, with only 11% of butchers wearing gloves. There was a gendered dimension, evidenced by markedly different participation in value chains and lower adoption rates and knowledge levels among female actors. Finally, cultural and religious practices were shown to play an important role in exposure and transmission of diseases, influencing perceptions and attitudes to risks and adoption of biosecurity measures. PMID- 29130124 TI - Systemic autoimmune diseases complicated with hydrocephalus: pathogenesis and management. AB - Systemic autoimmune diseases (SAIDs) represent a group of syndromes involving at least two organ systems. Classical SAIDs include connective tissue diseases, vasculitis, and granulomatous diseases, many of which involve the nervous system and result in different neurological manifestations. Hydrocephalus can be a rare but lethal complication of various SAIDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), sarcoidosis, and primary vasculitis. However, the pathogenesis of SAIDs complicated with different types of hydrocephalus is varied and difficult to determine using the existing published data, and various manifestations and expressive forms of the conditions bring a substantial challenge to a timely clinical diagnosis and treatment. The commonly used medical management programs based on the etiology of hydrocephalus are anti-inflammatory or anti-infectious therapies, while surgical management such as ventriculoperitoneal shunts is effective most of the time. Further research should be directed toward improving our understanding of the pathogenesis of these conditions and determining the most effective method for treating this life threatening condition. PMID- 29130125 TI - Towards the Womb of Neonatal Intensive Care. AB - Within the mother's womb, life finds its first stirrings. The womb shelters the fetus, the growing child within. We recognize the existential traces of a wombed existence when a newborn calms in response to being held; when a newborn stills in response to his or her mother's heartbeat; and, when a newborn startles in the presence of bright light. Yet, how does experiential human life begin within another human being? What are the conditions and paths of becoming for the fetus within the womb? And for the child born early, what "womb" welcomes the premature child in neonatal intensive care? PMID- 29130126 TI - Bodies in Genres of Practice: Johann Ulrich Bilguer's Fight to Reduce Field Amputations. AB - This paper examines Johann Ulrich Bilguer's 1761 dissertation on the inutility of amputation practices, examining reasons for its influence despite its nonconformance to genre expectations. I argue that Bilguer's narratives of patient suffering, his rhetorical likening of surgeons to soldiers, and his attention to the horrific experiences of war surgeons all contribute to the dissertation's wide impact. Ultimately, the dissertation offers an example of affective rhetorics employed during the Enlightenment, demonstrating how bodies and environments-those "ambient rhetorics" made visible in a text-can contribute to an analysis of genre deviations and widen the scope of genre studies. PMID- 29130127 TI - Predictability of orthodontic movement with orthodontic aligners: a retrospective study. AB - BACKGROUND: The aim of this study was to evaluate the predictability of F22 aligners (Sweden & Martina, Due Carrare, Italy) in guiding teeth into the positions planned using digital orthodontic setup. METHODS: Sixteen adult patients (6 males and 10 females, mean age 28 years 7 months) were selected, and a total of 345 teeth were analysed. Pre-treatment, ideal post-treatment-as planned on digital setup-and real post-treatment models were analysed using VAM software (Vectra, Canfield Scientific, Fairfield, NJ, USA). Prescribed and real rotation, mesiodistal tip and vestibulolingual tip were calculated for each tooth and, subsequently, analysed by tooth type (right and left upper and lower incisors, canines, premolars and molars) to identify the mean error and accuracy of each type of movement achieved with the aligner with respect to those planned using the setup. RESULTS: The mean predictability of movements achieved using F22 aligners was 73.6%. Mesiodistal tipping showed the most predictability, at 82.5% with respect to the ideal; this was followed by vestibulolingual tipping (72.9%) and finally rotation (66.8%). In particular, mesiodistal tip on the upper molars and lower premolars were achieved with the most predictability (93.4 and 96.7%, respectively), while rotation on the lower canines was the least efficaciously achieved (54.2%). CONCLUSIONS: Without the use of auxiliaries, orthodontic aligners are unable to achieve programmed movement with 100% predictability. In particular, although tipping movements were efficaciously achieved, especially at the molars and premolars, rotation of the lower canines was an extremely unpredictable movement. PMID- 29130128 TI - Effect of Cys, GSH, and pH on Mercury Release from Tibetan Medicine Zuotai, beta HgS, and alpha-HgS in Artificial Gastrointestinal Juices. AB - Zuotai, also named as "gTso thal", a known Tibetan medicinal mixture containing insoluble cubic crystal mercuric sulfide (beta-HgS), has been used to treat diseases with long history. The mercury release ratio from Zuotai in gastrointestinal environment is one determinant factor for its bioavailability and biological effect. However, the information is still scarce now. Therefore, the study was designed to investigate the effect of sulfhydryl biomolecules [L cysteine (Cys) and glutathione (GSH)] and pH on mercury dissociation from Zuotai, beta-HgS, and hexagonal crystal mercuric sulfide (alpha-HgS) in artificial gastrointestinal juices or pure water with a 1:100 solid-liquid ratio. And, the digestion and peristalsis of gastrointestinal tract were simulated in vitro. The results showed the following trend for the mercury release ratio of Zuotai, artificial gastric juice > artificial intestinal juice > pure water, whereas the trend for beta-HgS and alpha-HgS was as follows, artificial intestinal fluid > artificial gastric fluid > pure water. The mercury release ratios of Zuotai, beta HgS, and alpha-HgS significantly increased in artificial intestinal juice containing L-Cys or GSH compared to those without sulfhydryl biomolecules in the juice. However, in contrast to the results observed for beta-HgS and alpha-HgS, the mercury release ratio of Zuotai was reduced remarkably in pure water and artificial gastric juice with Cys or GSH. And, we found that strong acidic or strong alkaline environments promoted the dissociation of mercury from Zuotai, beta-HgS, and alpha-HgS. Taken together, current findings may contribute to other studies regarding clinical safety and bioavailability of the traditional drug Zuotai containing beta-HgS. PMID- 29130129 TI - Impact of on-site sanitation systems on groundwater sources in a coastal aquifer in Chennai, India. AB - On-site sanitation is the most preferred mode of sanitation due to expensive off site sanitation. The increasing population especially in the peri-urban areas has led to increasing use of on-site sanitation systems in India. However, the habitations in the vicinity of these systems do not have centralised water supply and are dependent on groundwater sources. However, there is concern about leaching of faecal coliforms and nitrate from the septic tanks to the underlying aquifer. The present study is attempted at two sites in the coastal city of Chennai where on-site sanitation is prevailing. The sample locations (16 nos.) are selected in such a way that groundwater sources are situated in the vicinity of on-site sanitation systems. The groundwater sources are the bore wells installed by the private agencies. It is observed that parameters considered key parameters to study the impact of the on-site sanitation systems, namely Na2+, Cl , NO3-, faecal coliform and total dissolved solids, exceed the concentration limits recommended by the Bureau of Indian Standards. The piper diagram analysis identifies that the predominant cations and anions are respectively Na+, and Cl-, SO4- and HCO3-.The Gibbs plot shows ground water quality is dominated by the evaporation process in both the seasons. The Cl/HCO3 ratio in many samples confirms the seawater intrusion in the study area. Elevated concentrations of faecal coliforms in all the samples (16 nos.) confirm the significant amount of groundwater pollution from the on-site sanitation systems. It is desired that policy planners and implementation agencies should undertake detailed scientific and hydrogeological studies of the region in order to examine the feasibility of implementing on-site sanitation systems. PMID- 29130130 TI - Heavy metal distribution in Tiaoxi River's sediment. AB - According to current study, seven surface sediments and three sediment cores were collected from three typical areas of Tiaoxi River, which were living area, agricultural area, and industrial area. The water quantity into the Lake Taihu from the Tiaoxi River accounted for almost one third of the total water quantity by all rivers into the Lake Taihu. To study geochemical features and pollution history of heavy metals in three typical areas of Tiaoxi River, total content and chemical fractionations of Cu, Pb, Cd, Cr, Mn, Zn, Fe, As, and Hg were analyzed for surface and core sediments using the speciation extraction procedure, proposed by the Commission of the European Communities Bureau of Reference (BCR), together with grain size and organic carbon measurements. The results showed that the concentration of nine heavy metals and the variation characteristics of Zn, Cu, Fe, Mn, and Cr are different among five cores, which has shown that the river responses to natural and anthropogenic activities were dissimilar in various areas. BCR sequential extraction showed contents of Cr, Fe, and Cu were dominated in the remaining parts. Non-residual fractions for Zn and Mn contained major portions. Based on RAC (risk assessment core), the risk of Mn was high to very high in the three typical areas, and the risk of Zn was medium in the three typical areas. PMID- 29130131 TI - Distinctive accumulation patterns of heavy metals in Sardinella aurita (Clupeidae) and Mugil cephalus (Mugilidae) tissues. AB - The present study assessed the impact of metal pollution on two widely consumed types of wild fish Sardinella aurita and Mugil cephalus captured from the Gulf of Gabes (Tunisia) which is currently experiencing acute environmental problems. A study of the Cd, Cu, Zn, and Pb levels present in the studied site and vital in fish tissues (gills, liver, gonad, and muscle) was undertaken. As expected, muscle, liver, and gonad tissues contained the highest concentrations of all metals except for Zn. The metal levels showed a significant variation of accumulation between species with overall effects of the tested tissues. In addition, the results address the significant effects of the species/tissue interaction. Liver sections showed structural alterations consisting mainly of a significant desquamation of the tissue, a fibroblast proliferation, and a lipid droplet accumulation in both species. Additionally, the presence of skeletal abnormalities affecting the vertebral column was observed in the M. cephalus specimens. As a whole, our data provide the first evidence of distinctive metal accumulation patterns in vital fish tissues as well as the interspecific difference that can be correlated with the biological habits of the two selected models, S. aurita and M. cephalus, known respectively as pelagic and benthopelagic species. PMID- 29130132 TI - In vivo assessment of polydatin, a natural polyphenol compound, on arsenic induced free radical overproduction, gene expression, and genotoxicity. AB - Arsenic (As) is a well-known contaminant of global groundwater. Its exposure causes several hazardous effects on animals and human via oxidative stress. The present study examined the effect of polydatin (PD) on free radical overproduction in rats exposed to As. Thirty-five male rats randomly allocated into five equal groups. To the control group, physiological saline was given orally and to the second group only 100 mg/L As was given by drinking water for 60 days. The other groups were treated with As (100 mg/L) and PD orally at 50, 100, and 200 mg/kg/day, respectively. Treatment with As enhanced malondialdehyde level but decreased glutathione level in blood, liver, kidney, brain, lung, and heart of rats. Also, As decreased superoxide dismutase and catalase activities of erythrocyte, liver, kidney, brain, lung, and heart in rats. Furthermore, As treatment gave rise to increased DNA damage and gene expressions of interleukin 1 beta (IL-1beta), nuclear factor kappa beta (NFkappaB), p53, and tumor necrosis factor-alpha (TNF-alpha) in the lung, brain, kidney, and liver. However, treatment of PD ameliorated As-exposed lipid peroxidation, antioxidant enzymes activities, DNA damage, gene expressions, and histopathological changes in tissues. In conclusion, PD has a dose-dependent protective effect on lipid peroxidation and antioxidant defense mechanism in rats against As exposure. PMID- 29130133 TI - Infusion of leukocytes from HLA haplo-identical familial donors as an adjuvant in the HLH-2004 protocol to treat the virus-associated adult hemophagocytic lymphohistiocytosis: a retrospective study of 26 patients. AB - Adult hemophagocytic lymphohistiocytosis (HLH) is a fatal disease with poor survival and a limited role of drug therapies. To help to recognize virus and enhance survival, we infused leukocytes derived from human leukocyte antigen (HLA) haplo-identical familial donors to patients. We retrospectively investigated 26 adult virus-associated hemophagocytic syndrome (VAHS) patients' medical records from 2006-2017. Eleven of the 26 patients accepted relatives' derived leukocytes infusions in addition to drug therapies recommended in the HLH 2004 protocol. The leukocyte doses ranged from 0.75 to 3.30*108 per kilogram of body weight. The other 15 patients accepted immunosuppressive and supportive therapies referred to in the HLH-2004 protocol. We compared the treatment outcomes of the two groups of patients. Patients in the cell infusion group had a lower viral load (P = 0.023) and better laboratory results and prolonged overall survival (60.44 vs. 20.18 weeks, P = 0.047). A factor that might relate to overall survival is platelet count (P = 0.032), except for the leukocyte infusions (P = 0.012). For patients without acceptable donors, infusions of leukocytes from HLA haplo-identical familial donors could be a feasible treatment to prolong overall survival as an adjuvant to drug therapies. PMID- 29130134 TI - Is it possible to improve prognostic value of NCCN-IPI in patients with diffuse large B cell lymphoma? The prognostic significance of comorbidities. AB - The prognostic value of the International Prognostic Index (IPI) has been re evaluated in the rituximab-treated diffuse large B cell lymphoma (DLBCL) patients. Accordingly, National Comprehensive Cancer Network-IPI (NCCN-IPI) has been introduced to estimate prognosis of DLBCL patients. However, comorbidities that frequently affect elderly DLBCL patients were not analyzed. The aim of this study was to evaluate the prognostic significance of comorbidities using Charlson Comorbidity Index (CCI) in 962 DLBCL patients. According to CCI, majority of patients (73.6%) did not have any comorbidity, while high CCI (>= 2) was observed in 71/962 (7.4%) patients, and in 55/426 (12.9%) of the elderly patients aged >= 60 years. When the CCI was analyzed in a multivariate model along with the NCCN IPI parameters, it stood out as a threefold independent risk factor of a lethal outcome. Also, we have developed a novel comorbidity-NCCN-IPI (cNCCN-IPI) by adding additional 3 points if the patient had a CCI >= 2. Four risk groups emerged with the following patient distribution in low, low-intermediate, high intermediate, and high group: 3.4, 34.3, 49.4, and 12.5%, respectively. The prognostic value of the new cNCCN-IPI was 2.1% improved compared to that of the IPI, and 1.3% improved compared to that of the NCCN-IPI (p < 0.05). This difference was more pronounced in elderly patients, in whom the cNCCN-IPI showed a 5.1% better discriminative power compared to that of the IPI, and 3.6% better compared to the NCCN-IPI. The NCCN-IPI enhanced by the CCI and combined with redistributed risk groups is better for differentiating risk categories in unselected DLBCL patients, especially in the elderly. PMID- 29130135 TI - A patient with acquired factor X deficiency and metastatic transitional cell carcinoma of the bladder: is there a link between metastasis and factor deficiency in solid tumors? PMID- 29130136 TI - Correction to: Quantitative topographic anatomy of the femoral ACL footprint: a micro-CT analysis. AB - An author has corrected their first name and updated their email address - see the affiliation section below. Daniel G. Norman should now be Danielle G. Norman as shown in the authorgroup section above. PMID- 29130137 TI - Assessment of the equivalent dipole layer source model in the reconstruction of cardiac activation times on the basis of BSPMs produced by an anisotropic model of the heart. AB - Promising results have been reported in noninvasive estimation of cardiac activation times (AT) using the equivalent dipole layer (EDL) source model in combination with the boundary element method (BEM). However, the assumption of equal anisotropy ratios in the heart that underlies the EDL model does not reflect reality. In the present study, we quantify the errors of the nonlinear AT imaging based on the EDL approximation. Nine different excitation patterns (sinus rhythm and eight ectopic beats) were simulated with the monodomain model. Based on the bidomain theory, the body surface potential maps (BSPMs) were calculated for a realistic finite element volume conductor with an anisotropic heart model. For the forward calculations, three cases of bidomain conductivity tensors in the heart were considered: isotropic, equal, and unequal anisotropy ratios in the intra- and extracellular spaces. In all inverse reconstructions, the EDL model with BEM was employed: AT were estimated by solving the nonlinear optimization problem with the initial guess provided by the fastest route algorithm. Expectedly, the case of unequal anisotropy ratios resulted in larger localization errors for almost all considered activation patterns. For the sinus rhythm, all sites of early activation were correctly estimated with an optimal regularization parameter being used. For the ectopic beats, all but one foci were correctly classified to have either endo- or epicardial origin with an average localization error of 20.4 mm for unequal anisotropy ratio. The obtained results confirm validation studies and suggest that cardiac anisotropy might be neglected in clinical applications of the considered EDL-based inverse procedure. PMID- 29130138 TI - Automated 3D method for the construction of flexible and reconfigurable numerical breast models from MRI scans. AB - Anatomically realistic numerical breast models are essential tools for microwave breast imaging, supporting feasibility analysis, performance verification, and design improvements. Patient-specific models also assist in interpreting the results of the patient studies conducted on microwave imaging prototype systems. The proposed method employs automated and robust 3D processing techniques to construct flexible and reconfigurable breast models. These techniques include noise and artifact suppression with a principal component analysis (PCA) approach, and oversampling of the magnetic resonance imaging (MRI) data to enhance the intensity continuity. The k-means clustering segmentation identifies fatty and fibroglandular tissues and further segments these regions into a selected number of tissues, providing reconfigurable models. A peak Gaussian fitting technique maps the model clusters to the dielectric properties. The robustness of the proposed method is verified by applying it to both 1.5- and 3-T MRI scans as well as to scans of varying breast densities. PMID- 29130139 TI - Portable abdomen radiography: moving to thickness-based protocols. AB - BACKGROUND: Default pediatric protocols on many digital radiography systems are configured based on patient age. However, age does not adequately characterize patient size, which is the principal determinant of proper imaging technique. Use of default pediatric protocols by inexperienced technologists can result in patient overexposure, inadequate image quality, or repeated examinations. OBJECTIVE: To ensure diagnostic image quality at a well-managed patient radiation exposure by transitioning to thickness-based protocols for pediatric portable abdomen radiography. MATERIALS AND METHODS: We aggregated patient thickness data, milliamperes (mAs), kilovoltage peak (kVp), exposure index (EI), source-to detector distance, and grid use for all portable abdomen radiographs performed in our pediatric hospital in a database with a combination of automated and manual data collection techniques. We then analyzed the database and used it as the basis to construct thickness-based protocols with consistent image quality across varying patient thicknesses, as determined by the EI. RESULTS: Retrospective analysis of pediatric portable exams performed at our adult-focused hospitals demonstrated substantial variability in EI relative to our pediatric hospital. Data collection at our pediatric hospital over 4 months accumulated roughly 800 portable abdomen exams, which we used to develop a thickness-based technique chart. CONCLUSION: Through automated retrieval of data in our systems' digital radiography exposure logs and recording of patient abdomen thickness, we successfully developed thickness-based techniques for portable abdomen radiography. PMID- 29130140 TI - Transforaminal intrathecal delivery of nusinersen using cone-beam computed tomography for children with spinal muscular atrophy and extensive surgical instrumentation: early results of technical success and safety. AB - BACKGROUND: Nusinersen, the only treatment approved by the United States Food and Drug Administration for spinal muscular atrophy (SMA), is delivered intrathecally. Many children with SMA have extensive spinal instrumentation and deformities, often precluding the use of standard approaches for gaining intrathecal access. Furthermore the anatomical distortion that often occurs with rotoscoliosis can complicate the use of fluoroscopic guidance. Compared to fluoroscopy, CT affords superior guidance for complex needle placements. This opens up alternatives to the posterior (interlaminar) technique, including transforaminal and caudal approaches. OBJECTIVE: This study describes the early results of technical success, complications and radiation dose of intrathecal delivery of nusinersen using cone-beam CT guidance with two-axis fluoroscopic navigational overlay. MATERIALS AND METHODS: We conducted a retrospective review of 15 consecutive nusinersen injections performed in four children with SMA and extensive spinal hardware precluding standard posterior lumbar puncture techniques. These children were treated using transforaminal thecal access employing cone-beam CT with navigational overlay. We analyzed results including technical success, complications and total fluoroscopy time. RESULTS: All procedures were technically successful. No major complications and one minor complication were reported; the minor complication was a post-procedural neuropathic headache that was attributed to procedural positioning and was treated successfully with gabapentin. The average procedural fluoroscopy time and air kerma were 1.9 min and 55.8 mGy, respectively. CONCLUSION: Cone-beam CT guidance with two-axis navigational overlay is a safe, effective method for gaining transforaminal intrathecal access in children with spinal abnormalities and hardware precluding the use of standard techniques. PMID- 29130142 TI - Radiotherapy for Gastric Bleeding from Tumor Invasion of Recurrent Colon Cancer with Liver Metastasis After Resection. PMID- 29130141 TI - Sjogren's syndrome initially presented as thrombotic thrombocytopenic purpura in a male patient: a case report and literature review. AB - Thrombotic thrombocytopenic purpura (TTP) is a potentially lethal multisystem disorder which could be caused by autoimmune diseases. However, the concomitant occurrence of TTP and Sjogren's syndrome (SS) is an extremely uncommon scenario, especially in male patients. A 56-year-old Chinese male was admitted for the appearance of diffuse ecchymosis. Then he gradually developed transient slurred speech, progressive confusion, agitation, extremity weakness, and fever. Laboratory investigations suggested anemia, thrombocytopenia, significantly increased lactic dehydrogenase, schistocytes in peripheral blood smear, and a disintegrin-like metalloproteinase with thrombospondin motif type 1 member 13 (ADAMTS13) activity deficiency with high inhibitor titers. TTP was thus diagnosed. The patient also had positive anti-nuclear antibody, anti-SSA, and anti-SSB; however, anti-double stranded DNA (dsDNA) was negative. These drove us to perform ocular and dental sicca evaluation and the finial diagnosis was TTP secondary to SS. Plasma exchange and corticosteroid therapy were effective to control TTP. Cyclophosphamide was subsequently added when the platelet count was stable. The total duration of corticosteroid and cyclophosphamide was 8 and 6 months, respectively. The patient recovered without relapse at 1-year follow-up. To our knowledge, this was the first case of SS initially presented as TTP in a male patient. The case also elucidated the importance of autoantibody screen in the workup of TTP and the benefits of adjunctive immunosuppressive therapy in relapse prevention. PMID- 29130143 TI - Incorporating Social Media into your Support Tool Box: Points to Consider from Genetics-Based Communities. AB - Patients with newly-described or rare genetic findings are turning to social media to find and connect with others. Blogs, Facebook groups, and Twitter have all been reported as tools for patients to connect with one another. However, the preferences for social media use and privacy among patients, their families, and these communities have not been well characterized. To explore preferences about privacy and membership guidelines, an online survey was administered to two web based patient registries, Simons Variation in Individuals Project ( www.simonsvipconnect.org ) and GenomeConnect ( www.genomeconnect.org ). Over a three-month period, invitations were sent to 2524 individuals and 103 responses (4%) were received and analyzed. Responses indicate that Facebook is the most popular resource accessed within this sample population (99%). Participants used social media to look for information about their diagnosis or test results (83%), read posts from rare disease groups or organizations (73%), participate in conversations about their diagnosis (67%), and connect with others to find support (58%). Focusing on privacy issues in social media, respondents indicate that membership and access impact the level of comfort in sharing personal or medical information. Nearly 60% of respondents felt uncomfortable sharing photos or medical information within a public Facebook group, whereas only 12% of respondents felt uncomfortable sharing in private group targeted to families alone. Using this preliminary data concerning social media use and privacy, we developed points for genetic counselors to incorporate when discussing available support resources for patients with a new, or rare, genetic diagnosis or genetic test result. Genetic counselors are trained to provide anticipatory guidance to families adapting to new genetic information, and are well-equipped to help patients consider their preferences about using social media as a source of information and support. PMID- 29130144 TI - Preparation of biosorbents from the Jatoba (Hymenaea courbaril) fruit shell for removal of Pb(II) and Cd(II) from aqueous solution. AB - In this study, the biosorption properties of Jatoba (Hymenaea courbaril) fruit shell for removal of Pb(II) and Cd(II) ions from aqueous solutions, and its potential as a low-cost biosorbent for water treatment, were investigated. The Jatoba fruit shell (JBin) was subjected to different treatments with heated water (JBH2O) and sodium hydroxide (JBNaOH) to modify its surfaces and improve its adsorption properties. The chemical modification of the surfaces of the resulting materials was confirmed by analyzing the compositions and structural features of the raw material and the chemically treated materials using SEM, FTIR, 13C NMR, and pHpzc. The ability of the biosorbents to remove the metal ions was investigated with batch adsorption procedures. The adsorption data were then examined in detail by applying adsorption models of Langmuir, Freundlich, and Dubinin-Radushkevich. The results showed that the experimental data were best described by the Langmuir model for the Pb-JBin and Cd-JBNaOH systems, the Freundlich model for the Pb-JBH2O and Pb-JBNaOH systems, and the Dubinin Radushkevich model for Cd-JBin and Cd-JBH2O systems. The maximum adsorption capacities of JBNaOH obtained using the Langmuir model reached values of 30.27 and 48.75 mg g-1 for Cd(II) and Pb(II), respectively. The adsorption kinetic studies showed that the pseudo-second-order model was the best fitted to the experimental data, and adsorptions for Pb-JBH2O and Cd-JBH2O are controlled by intraparticle diffusion mechanism. PMID- 29130145 TI - Late-Onset ADHD: Understanding the Evidence and Building Theoretical Frameworks. AB - PURPOSE OF REVIEW: The traditional definition of Attention-Deficit/Hyperactivity Disorder (ADHD), assuming onset in childhood, has been challenged by evidence from four recent birth-cohort studies that reported most adults with ADHD lacked a childhood categorical ADHD diagnosis. RECENT FINDINGS: Late onset of symptoms was evaluated in the long-term follow-up of the Multimodal Treatment study of ADHD (MTA). In most cases, other factors were present that discounted the late onset of ADHD symptoms and excluded the diagnosis of ADHD. We offer two theoretical frameworks for understanding the ADHD trajectory throughout the life cycle: (1) the complex phenotype model, and (2) the restricted phenotype model. We conclude that (a) late onset (after age 12) is a valid trajectory for ADHD symptoms, (b) the percentage of these cases with onset after adolescence is yet uncertain, and PMID- 29130146 TI - Recent Developments in the Search for Urinary Biomarkers in Bladder Cancer. AB - PURPOSE OF REVIEW: This review aims to evaluate research surrounding the utility of urinary biomarkers to detect bladder cancer and predict recurrence. RECENT FINDINGS: Recent research has focussed on the evaluation of genetic markers found in urine to provide diagnostic and prognostic information. Furthermore, the isolation and characterisation of extracellular vesicles (EVs) from the urine patients with bladder cancer provide an exciting new development in biomarker research that is set to expand in the coming years. Current urinary biomarker research is a broad field that encompasses the evaluation of urinary proteins, DNA, RNA and EVs to detect signatures that can be used to predict the presence of bladder cancer and provide prognostic information. EVs in particular offer an exciting and novel perspective in the search for accurate bladder cancer biomarkers. PMID- 29130147 TI - Callous-Unemotional Traits Modulate Brain Drug Craving Response in High-Risk Young Offenders. AB - Adults with psychopathy have a high propensity for substance abuse, generally starting from a young age. This investigation tested hypotheses about differences in the neural responses associated with drug craving among high-risk young offenders with histories of abuse of stimulants and other drugs as a function of psychopathic traits. Fifty-four male adolescents (44 with a history of stimulant abuse and 10 controls) incarcerated at a maximum-security facility (M age = 17.08 years) completed a drug-cue exposure task while brain hemodynamic activity was monitored using functional magnetic resonance imaging (fMRI) with a mobile MRI scanner stationed at the facility. Psychopathic traits were assessed using the Hare Psychopathy Checklist: Youth Version (PCL:YV). In the stimulant abuser group, drug cues elicited activity in classic reward circuitry. Consistent with studies of adult psychopathic traits and substance abuse, there was a negative association between PCL-YV scores and hemodynamic response related to drug craving in the amygdala and ACC in youth with a history of stimulant abuse. However, there were considerably more negative associations between the PCL:YV and hemodynamic response among youth than adults and this was primarily due to callous-unemotional traits rather than interpersonal or behavioral traits. The implications for how personality traits modulate motivations for drug-seeking behavior among adolescent offenders are discussed. PMID- 29130148 TI - Interaction of zearalenone with bovine serum albumin as determined by fluorescence quenching. AB - The major aim of this study was to examine the binding of zearalenone (ZEN) to bovine serum albumin (BSA) by measuring the quenching of the intrinsic fluorescence of the protein under aqueous conditions. The results suggest that ZEN has a strong ability to quench the intrinsic fluorescence of BSA through a static mechanism. The hydrophobicity of the microenvironment around the tyrosine (Tyr) residues in BSA was increased in the presence of ZEN. The quenching constants, ratio of protein with ZEN, and thermodynamic parameters were determined. The collaborative action of hydrophobic and electrostatic interactions was involved in the binding process and the formation of the complex was mainly enthalpy-driven. The average binding distance between ZEN and BSA was calculated to be 2.20 nm. This is much closer in magnitude than the distance reported for the binding of most toxins to HSA and most pharmaceuticals to BSA, indicating a strong affinity. PMID- 29130149 TI - Is Lipidomic the Answer to the Search of a Biomarker for Organ Preservation Protocol in Head and Neck Squamous Cell Carcinoma? AB - In the last decade organ preservation protocols based on chemoradiotherapy (CRT) has been showing the possibility of preserving function without jeopardizing survival for locally advanced head and neck squamous cell carcinoma (HNSCC). Still, only a percentage of the patients will benefit from this approach and, to date, no biomarkers are known to correctly predict these patients. More recently, modern mass spectrometry method has been used to determine metabolic profiles, and lipidomics, in particular, emerged as a new field of study in oncology and other diseases. This study aimed to analyze the lipid profile on saliva from patients undergoing to a prospective, single center, open-label, non-randomized phase II trial for organ preservation on HNSCC. The lipid analysis was performed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Multivariate statistical analyses based on principal component analysis and orthogonal partial least square-discriminant analysis were applied to MALDI-TOF-MS data to visualize differences between the lipid profiles and identify potential biomarkers. The results assisted on distinguishing complete responders from non-responders to the treatment protocol. In conclusion, we demonstrated that a group of lipids is differentially abundant in saliva from HNSCC patients submitted to an organ preservation protocol, being able to differentiate responders from non-responders. These results suggest the potential use of lipid biomarkers to identify patients who may benefit from this treatment. Also, we showed that saliva testing might be routinely used in clinical practice, for being a non-invasive alternative to blood testing, besides inexpensive and easy to obtain. PMID- 29130150 TI - Predictors of adverse psychological experiences surrounding genome-wide profiling for disease risk. AB - This study aimed to identify predictors of adverse psychological experiences among direct-to-consumer (DTC) genomic test consumers. We performed a secondary analysis on data from the Scripps Genomic Health Initiative (SGHI), which studied 2037 individuals tested with commercially available tests yielding personalized risk estimates for 23 common, genetically complex diseases. As part of the original study, the participants completed baseline and follow-up survey measures assessing demographics, personal and family health history, attitudes toward genetic testing, anxiety (State-Trait Anxiety Inventory (STAI)), test-related distress (Impact of Event Scale-Revised (IES-R)), and reactions to receipt of results. To further describe the participants who had an adverse psychological outcome, this secondary analysis defined two different variables ("distress response" and "psychologically sensitive participants") and examined their relationship to various demographic variables and other survey responses. One hundred thirty participants (6.4%) were defined as having a "distress response" to receipt of results based on changes in STAI and/or IES. Four hundred thirty one participants (21.2%) were defined as being "psychologically sensitive" based on high STAI scores both pre- and post-receipt of results. For psychologically sensitive subjects, younger age emerged as a predictor (p < 0.0005). Family history and personal history were only significant predictors for Alzheimer's disease in the psychologically sensitive participants (p = .03) and restless leg syndrome in those with a distress response (p = .03). Psychologically sensitive participants were more likely to indicate a number of pre-test concerns than were controls, but neither group of participants were any more likely to follow up with their physician or a free genetic counseling service after the return of results. PMID- 29130151 TI - Viral Vectors, Engineered Cells and the CRISPR Revolution. AB - Over the past few decades the ability to edit human cells has revolutionized modern biology and medicine. With advances in genome editing methodologies, gene delivery and cell-based therapeutics targeted at treatment of genetic disease have become a reality that will become more and more essential in clinical practice. Modifying specific mutations in eukaryotic cells using CRISPR-Cas systems derived from prokaryotic immune systems has allowed for precision in correcting various disease mutations. Furthermore, delivery of genetic payloads by employing viral tropism has become a crucial and effective mechanism for delivering genes and gene editing systems into cells. Lastly, cells modified ex vivo have tremendous potential and have shown effective in studying and treating a myriad of diseases. This chapter seeks to highlight and review important progress in the realm of the editing of human cells using CRISPR-Cas systems, the use of viruses as vectors for gene therapy, and the application of engineered cells to study and treat disease. PMID- 29130153 TI - From Reductionism to Holism: Toward a More Complete View of Development Through Genome Engineering. AB - Paradigm shifts in science are often coupled to technological advances. New techniques offer new roads of discovery; but, more than this, they shape the way scientists approach questions. Developmental biology exemplifies this idea both in its past and present. The rise of molecular biology and genetics in the late twentieth century shifted the focus from the anatomical to the molecular, nudging the underlying philosophy from holism to reductionism. Developmental biology is currently experiencing yet another transformation triggered by '-omics' technology and propelled forward by CRISPR genome engineering (GE). Together, these technologies are helping to reawaken a holistic approach to development. Herein, we focus on CRISPR GE and its potential to reveal principles of development at the level of the genome, the epigenome, and the cell. Within each stage we illustrate how GE can move past pure reductionism and embrace holism, ultimately delivering a more complete view of development. PMID- 29130152 TI - Combining Engineered Nucleases with Adeno-associated Viral Vectors for Therapeutic Gene Editing. AB - With the recent advent of several generations of targeted DNA nucleases, most recently CRISPR/Cas9, genome editing has become broadly accessible across the biomedical community. Importantly, the capacity of these nucleases to modify specific genomic loci associated with human disease could render new classes of genetic disease, including autosomal dominant or even idiopathic disease, accessible to gene therapy. In parallel, the emergence of adeno-associated virus (AAV) as a clinically important vector raises the possibility of integrating these two technologies towards the development of gene editing therapies. Though clear challenges exist, numerous proof-of-concept studies in preclinical models offer exciting promise for the future of gene therapy. PMID- 29130154 TI - A Transgenic Core Facility's Experience in Genome Editing Revolution. AB - The use of animal models, particularly rodents, has been immensely important to nearly all aspects of biomedical research, from basic science exploration to translational discoveries into clinical applications. The transgenic core facility that provides animal model production, preservation, and recovery services has been fundamental to the success of research efforts using animals. Recent advances in genome editing technologies, especially the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) enzyme system, have transformed the tedious animal model production into a simple and effective procedure. We, as a transgenic core facility established in 1993, adopted the CRISPR/Cas9 technology in early 2014 and have experienced the dramatic shift in the practice of animal model production, from the conventional embryonic stem cell approach to the direct genomic editing in rodent embryos. In this chapter, we describe the lessons that we learned from more than 200 genome editing projects performed in this core facility within the past 3 years. We also provide the practical guidelines for efficient generation of animal models using this technology and the insights into where new technologies lead us. PMID- 29130155 TI - Genome Editing to Study Ca2+ Homeostasis in Zebrafish Cone Photoreceptors. AB - Photoreceptors are specialized sensory neurons with unique biological features. Phototransduction is well understood due in part to the exclusive expression and function of the molecular components of this cascade. Many other processes are less well understood, but also extremely important for understanding photoreceptor function and for treating disease. One example is the role of Ca2+ in the cell body and overall compartmentalization and regulation of Ca2+ within the cell. The recent development of CRISPR/Cas9 genome editing techniques has made it possible to rapidly and cheaply alter specific genes. This will help to define the biological function of elusive processes that have been more challenging to study. CRISPR/Cas9 has been optimized in many systems including zebrafish, which already has some distinct advantages for studying photoreceptor biology and function. These new genome editing technologies and the continued use of the zebrafish model system will help advance our understanding of important understudied aspects of photoreceptor biology. PMID- 29130156 TI - CRISPR: From Prokaryotic Immune Systems to Plant Genome Editing Tools. AB - The clustered regularly interspaced short palindromic repeats (CRISPR) system is a prokaryotic adaptive immune system that has the ability to identify specific locations on the bacteriophage (phage) genome to create breaks in it, and internalize the phage genome fragments in its own genome as CRISPR arrays for memory-dependent resistance. Although CRISPR has been used in the dairy industry for a long time, it recently gained importance in the field of genome editing because of its ability to precisely target locations in a genome. This system has further been modified to locate and target any region of a genome of choice due to modifications in the components of the system. By changing the nucleotide sequence of the 20-nucleotide target sequence in the guide RNA, targeting any location is possible. It has found an application in the modification of plant genomes with its ability to generate mutations and insertions, thus helping to create new varieties of plants. With the ability to introduce specific sequences into the plant genome after cleavage by the CRISPR system and subsequent DNA repair through homology-directed repair (HDR), CRISPR ensures that genome editing can be successfully applied in plants, thus generating stronger and more improved traits. Also, the use of the CRISPR editing system can generate plants that are transgene-free and have mutations that are stably inherited, thus helping to circumvent current GMO regulations. PMID- 29130157 TI - Target Discovery for Precision Medicine Using High-Throughput Genome Engineering. AB - Over the past few years, programmable RNA-guided nucleases such as the CRISPR/Cas9 system have ushered in a new era of precision genome editing in diverse model systems and in human cells. Functional screens using large libraries of RNA guides can interrogate a large hypothesis space to pinpoint particular genes and genetic elements involved in fundamental biological processes and disease-relevant phenotypes. Here, we review recent high-throughput CRISPR screens (e.g. loss-of-function, gain-of-function, and targeting noncoding elements) and highlight their potential for uncovering novel therapeutic targets, such as those involved in cancer resistance to small molecular drugs and immunotherapies, tumor evolution, infectious disease, inborn genetic disorders, and other therapeutic challenges. PMID- 29130158 TI - CRISPR in the Retina: Evaluation of Future Potential. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) has been gaining widespread attention for its ability for targeted genome surgery. In treating inherited retinal degenerations, gene therapies have had varied results; the ones effective in restoring eye sight are limited by transiency in its effect. Genome surgery, however, is a solution that could potentially provide the eye with permanent healthy cells. As retinal degenerations are irreversible and the retina has little regenerative potential, permanent healthy cells are vital for vision. Since the retina is anatomically accessible and capable of being monitored in vivo, the retina is a prime location for novel therapies. CRISPR technology can be used to make corrections directly in vivo as well as ex vivo of stem cells for transplantation. Current standard of care includes genetic testing for causative mutations in expectation of this potential. This chapter explores future potential and strategies for retinal degenerative disease correction via CRISPR and its limitations. PMID- 29130159 TI - The Future of CRISPR Applications in the Lab, the Clinic and Society. AB - CRISPR (clustered regularly interspaced short palindromic repeats) has emerged as one of the premiere biological tools of the century. Even more so than older genome editing techniques such as TALENs and ZFNs, CRISPR provides speed and ease of-use heretofore unheard of in agriculture, the environment and human health. The ability to map the function of virtually every component of the genome in a scalable, multiplexed manner is unprecedented. Once those regions have been explored, CRISPR also presents an opportunity to take advantage of endogenous cellular repair pathways to change and precisely edit the genome [1-3]. In the case of human health, CRISPR operates as both a tool of discovery and a solution to fundamental problems behind disease and undesirable mutations. PMID- 29130160 TI - Use of Whole-Cell Bioassays for Screening Quorum Signaling, Quorum Interference, and Biofilm Dispersion. AB - In most bacteria, a global level of regulation, termed quorum sensing (QS), exists involving intercellular communication via the production and response to cell density-dependent signal molecules. QS has been associated with a number of important features in bacteria including virulence regulation and biofilm formation. Consequently, there is considerable interest in understanding, detecting, and inhibiting QS. N-acylated homoserine lactones (AHLs) are used as extracellular QS signals by a variety of Gram-negative bacteria. Chromobacterium violaceum, commonly found in soil and water, produces the characteristic purple pigment violacein, regulated by AHL-mediated QS. Based on this readily observed pigmentation phenotype, C. violaceum strains can be used to detect various aspects of AHL-mediated QS activity. In another commonly used bioassay organism, Agrobacterium tumefaciens, QS can be detected by the use of a reporter gene such as lacZ. Here, we describe several commonly used approaches incorporating C. violaceum and A. tumefaciens that can be used to detect AHL and QS inhibitors. Due to the inherent low susceptibility of biofilm bacteria to antimicrobial agents, biofilm dispersion, whereby bacteria reenter the planktonic community, is another increasingly important area of research. At least one signal, distinct from traditional QS, has been identified and there are a variety of other environmental factors that also trigger dispersion. We describe a microtiter based experimental strategy whereby potential biofilm dispersion compounds can be screened. PMID- 29130161 TI - Detection of 2-Alkyl-4-Quinolones Using Biosensors. AB - 2-Alkyl-4-quinolones (AQs) such as 2-heptyl-3-hydroxy-4-quinolone (PQS) and 2 heptyl-4-hydroxyquinoline (HHQ) are quorum-sensing signal molecules. Here we describe two methods for AQ detection and quantification that employ thin-layer chromatography (TLC) and microtiter plate assays in combination with a lux-based Pseudomonas aeruginosa AQ biosensor strain. For TLC detection, organic solvent extracts of bacterial cells or spent culture supernatants are chromatographed on TLC plates, which are then dried and overlaid with the AQ biosensor. After detection by the bioreporter, AQs appear as both luminescent and green (from pyocyanin) spots. For the microtiter assay, either spent bacterial culture supernatants or extracts are added to a growth medium containing the AQ biosensor. Light output by the bioreporter correlates with the AQ content of the sample. The assays described are simple to perform, do not require sophisticated instrumentation, and are highly amenable to screening large numbers of bacterial samples. PMID- 29130162 TI - "Hot Stuff": The Many Uses of a Radiolabel Assay in Detecting Acyl-Homoserine Lactone Quorum-Sensing Signals. AB - Many Proteobacteria synthesize acyl-homoserine lactone (AHL) molecules for use as signals in cell density-dependent gene regulation known as quorum sensing (QS) and response. AHL detection protocols are essential to QS researchers and several techniques are available, including a 14C-AHL radiolabel assay. This assay is based on the uptake of radiolabeled methionine by living cells and conversion of the radiolabel into S-adenosylmethionine (SAM). The radiolabeled SAM is then incorporated into AHL signal by an AHL synthase enzyme. Here we describe a methodology to perform the AHL radiolabel assay, which is unbiased, relatively fast, and very sensitive compared to other AHL detection protocols. PMID- 29130163 TI - Liquid Chromatography/Mass Spectrometry (LC/MS) for the Detection and Quantification of N-Acyl-L-Homoserine Lactones (AHLs) and 4-Hydroxy-2 Alkylquinolines (HAQs). AB - High-performance liquid chromatography (HPLC) coupled in-line with mass spectrometry (MS) permits rapid and specific identification and quantification of N-acyl-L-homoserine lactones (AHLs) and 4-hydroxy-2-alkylquinolines (HAQs). We are presenting here methods for the analysis of these molecules directly from biological samples using LC/MS. PMID- 29130164 TI - Detection of the Bacterial Quorum-Sensing Signaling Molecules N-Acyl-Homoserine Lactones (HSL) and N-Acyl-Homoserine (HS) with an Enzyme-Linked Immunosorbent Assay (ELISA) and via Ultrahigh-Performance Liquid Chromatography Coupled to Mass Spectrometry (UHPLC-MS). AB - Quick and reliable quantitative methods requiring low amounts of sample volume are needed for the detection of N-acyl-homoserine lactones (HSL) and their degradation products N-acyl-homoserines (HS) in order to elucidate the occurrence and dynamics of these prevalent quorum-sensing molecules of Gram-negative bacteria in natural samples and laboratory model experiments. A combination of ELISA and UHPLC-MS is presented here which has proven to meet these requirements. Both methods can not only precisely detect and quantify HSLs but also their degradation products HS and thereby enable studying signaling dynamics in quorum sensing, which have been identified to play an essential role in bacterial communication. PMID- 29130165 TI - Biosensors for the Detection and Quantification of AI-2 Class Quorum-Sensing Compounds. AB - Intercellular small-molecular-weight signaling molecules modulate a variety of biological functions in bacteria. One of the more complex behaviors mediated by intercellular signaling molecules is the suite of activities regulated by quorum sensing molecules. These molecules mediate a variety of population-dependent responses including the expression of genes that regulate bioluminescence, type III secretion, siderophore production, colony morphology, biofilm formation, and metalloprotease production. Given their central role in regulating these responses, the detection and quantification of QS molecules have important practical implications. Until recently, the detection of QS molecules from Gram negative bacteria has relied primarily on bacterial reporter systems. These bioassays though immensely useful are subject to interference by compounds that affect bacterial growth and metabolism. In addition, the reporter response is highly dependent on culture age and cell population density. To overcome such limitations, we developed an in vitro protein-based assay system for the rapid detection and quantification of the furanosyl borate diester (BAI-2) subclass of autoinducer-2 (AI-2) QS molecules. The biosensor is based on the interaction of BAI-2 with the Vibrio harveyi QS receptor LuxP. Conformation changes associated with BAI-2 binding to the LuxP receptor change the orientation of cyan and yellow variants of GFP (CFP and YFP) fused to the N- and C-termini, respectively, of the LuxP receptor. LuxP-BAI2 binding induces changes in fluorescence resonance energy transfer (FRET) between CFP and YFP, whose magnitude of change is ligand concentration dependent. Ligand-insensitive LuxP mutant FRET protein sensors were also developed for use as control biosensors. The FRET-based BAI-2 biosensor responds selectively to both synthetic and biologically derived BAI-2 compounds. This report describes the use of the LuxP-FRET biosensor for the detection and quantification of BAI-2. PMID- 29130166 TI - Detection of Agr-Type Autoinducing Peptides Produced by Staphylococcus aureus. AB - Strains of the Gram-positive pathogen Staphylococcus aureus can be divided into four quorum sensing (QS) groups. Membership of each group is defined by the amino acid sequence of the autoinducing peptide (AIP) QS signal molecule that is encoded within the agrBDCA genetic locus and specifically within agrD. This chapter describes the use of simple, in-cell, lux-based, bio-reporters that can be used to identify/confirm the specific agr group to which a particular S. aureus isolate belongs, as well as to assess the timing and quantity of AIP produced. PMID- 29130167 TI - Ultra-Performance Liquid Chromatography/Mass Spectrometry for the Detection and Quantification of Diffusible Signal Factor (DSF) Family Quorum-Sensing Signals. AB - Molecules of the diffusible signal factor (DSF) family represent a class of widely conserved quorum-sensing signals used by many Gram-negative bacterial pathogens. The measurement of DSF family signals is essential for understanding their biological roles, signaling pathway, and regulatory network. We are presenting here methods for extraction and purification of DSF family signals from culture supernatants, and further quantification of members of DSF family signals using an ultra-performance liquid chromatographic system (UPLC) coupled with an accurate time-of-flight mass spectrometry (TOF-MS) analysis. PMID- 29130168 TI - Rapid Electrochemical Detection of Pseudomonas aeruginosa Signaling Molecules by Boron-Doped Diamond Electrode. AB - As the leading cause of morbidity and mortality of cystic fibrosis (CF) patients, early detection of Pseudomonas aeruginosa (PA) is critical in the clinical management of this pathogen. Herein, we describe rapid and sensitive electroanalytical methods using differential pulse voltammetry (DPV) at a boron doped diamond (BDD) electrode for the detection of PA signaling biomolecules. Monitoring the production of key signaling molecules in bacterial cultures of P. aeruginosa PA14 over 8 h is described, involving sample pretreatment by liquid liquid and solid-phase extraction. In addition, direct electrochemical detection approach of PA signaling molecules is also reported in conjunction with hexadecyltrimethylammonium bromide (CTAB) to disrupt the bacterial membrane. PMID- 29130169 TI - Detection and Quantification of Butyrolactones from Streptomyces. AB - In Streptomyces, the onset of antibiotic production and sporulation is coordinated through small diffusible molecules known as gamma-butyrolactones (GBLs). These are active in very low amounts, and their extraction and characterization are challenging. Here we describe a rapid, small-scale method for the extraction of GBL from Streptomyces coelicolor, from both solid and liquid cultures, which provides sufficient material for subsequent bioassays and partial characterization. We also present two different bioassay techniques for the detection and quantification of the GBL content in the extracts: the antibiotic bioassay and the kanamycin bioassay. PMID- 29130170 TI - Fluorescence Quenching Studies of gamma-Butyrolactone-Binding Protein (CprB) from Streptomyces coelicolor A3(2). AB - Fluorescence spectroscopy is an important analytical tool which is widely employed to study biological systems. This technique can be applied to qualitatively and quantitatively probe protein-ligand interactions primarily because of its sensitivity, selectivity, nondestructive and rapid form of analysis. In this chapter we describe the utility of this technique to establish a label-free, universal screening protocol for putative gamma-butyrolactone (GBL) receptors by exploiting the intrinsic fluorescence of a highly conserved tryptophan residue that constitutes the hydrophobic pocket for GBL binding, a unique feature possessed by this family of receptors. Here we demonstrate this technique using a combination of steady-state fluorescence quenching methods and fluorescence lifetime decay kinetics using CprB protein from Streptomyces coelicolor A3(2) as a model system. Interaction data between CprB and two chemically synthesized GBLs involved in quorum sensing, Cp1 and Cp2, have been used as example. PMID- 29130171 TI - Methods to Study Solo/Orphan Quorum-Sensing Receptors. AB - LuxR solos/orphans are very widespread among Proteobacteria; however they are surprisingly understudied given that they are likely to play a major role in cell cell communication in bacteria. Here we describe three simple methodologies/approaches that can be used in order to begin to study this subgroup of quorum sensing-related LuxR receptors. PMID- 29130173 TI - Global Expression Analysis of Quorum Sensing-Controlled Genes by RNAseq. AB - RNA sequencing (RNAseq) enables transcriptional profiling of many organisms. This chapter describes the use of RNAseq in prokaryotes to identify quorum sensing (QS)-controlled transcripts by comparing samples from QS-induced and -uninduced conditions. Briefly, each RNA sample is converted to ds-cDNA in a method that limits amplification of ribosomal RNA species. The ds-cDNA contains adapters that enable sequencing and quantification by next-generation sequencing (NGS). PMID- 29130172 TI - Enzymatic Assays to Investigate Acyl-Homoserine Lactone Autoinducer Synthases. AB - Bacteria use chemical molecules called autoinducers as votes to poll their numerical strength in a colony. This polling mechanism, commonly referred to as quorum sensing, enables bacteria to build a social network and provide a collective response for fighting off common threats. In Gram-negative bacteria, AHL synthases synthesize acyl-homoserine lactone (AHL) autoinducers to turn on the expression of several virulent genes including biofilm formation, protease secretion, and toxin production. Therefore, inhibiting AHL signal synthase would limit quorum sensing and virulence. In this chapter, we describe four enzymatic methods that could be adopted to investigate a broad array of AHL synthases. The enzymatic assays described here should accelerate our mechanistic understanding of quorum-sensing signal synthesis that could pave the way for discovery of potent antivirulence compounds. PMID- 29130174 TI - Identification of AHL- and BDSF-Controlled Proteins in Burkholderia cenocepacia by Proteomics. AB - We used comparative proteome analysis to determine the target genes of the two quorum sensing (QS) circuits in the opportunistic pathogen Burkholderia cenocepacia: the N-acyl homoserine lactone (AHL)-based CepIR system and the BDSF (B urkholderia diffusible signal factor, cis-2-dodecenoic acid)-based RpfFR system. In this book chapter, we focus on the description of the practical procedure we currently use in the laboratory to perform a sensitive GeLC-MS/MS shotgun proteomics experiment; we also briefly describe the downstream bioinformatic data analysis. PMID- 29130175 TI - Imaging N-Acyl Homoserine Lactone Quorum Sensing In Vivo. AB - In order to study N-acyl homoserine lactone (AHL)-based quorum sensing in vivo, we present a protocol using an Escherichia coli strain equipped with a luxR-based monitor system, which in the presence of exogenous AHL molecules expresses a green fluorescent protein (GFP). Lungs from mice challenged intratracheally with alginate beads containing both a Pseudomonas aeruginosa strain together with the E. coli monitor strain can be investigated at different time points postinfection. Epifluorescent or confocal scanning laser microscopy (CSLM) is used to detect the GFP-expressing E. coli monitor strain in the lung tissues, indicating production and excretion of AHLs in vivo by the infecting P. aeruginosa. PMID- 29130176 TI - Assessing Pseudomonas aeruginosa Autoinducer Effects on Mammalian Epithelial Cells. AB - The human mucosal environment in the gut is rich with interactions between microbiota and mammalian epithelia. Microbes such as the Gram-negative bacterium Pseudomonas aeruginosa may use quorum sensing to communicate with other microorganisms and mammalian cells to alter gene expression. Here, we present methodologies to evaluate the effects of P. aeruginosa N-(3-oxo-dodecanoyl)-L homoserine lactone (3O-C12-HSL) on Caco-2 cell monolayers. First, we describe a method for assessing barrier function and permeability of epithelial cells when exposed to 3O-C12-HSL by measuring transepithelial electrical resistance (TER) and paracellular flow using fluorescently labeled dextran. Secondly, we detail methods to investigate the effect of 3O-C12-HSL on protein-protein interactions of epithelial junction proteins. Lastly, we will detail imaging techniques to visualize Caco-2 barrier disruption following exposure to 3O-C12-HSL through the use of confocal laser scanning microscopy (CLSM) and a super resolution technique, stimulated emission depletion (STED) microscopy, to achieve nanoscale visualization of Caco-2 monolayers. PMID- 29130177 TI - Animal Models for Pseudomonas aeruginosa Quorum Sensing Studies. AB - Quorum sensing (QS) systems play global regulatory roles in bacterial virulence. They synchronize the expression of multiple virulence factors and they control and modulate bacterial antibiotic tolerance systems and host defense mechanisms. Therefore, it is important to obtain knowledge about QS modes of action and to test putative therapeutics that may interrupt QS actions in the context of infections. This chapter describes methods to study bacterial pathogenesis in murine acute and persistent/relapsing infection models, using the Gram-negative bacterial pathogen Pseudomonas aeruginosa as an example. These infection models can be used to probe bacterial virulence functions and in mechanistic studies, as well as for the assessment of the therapeutic potential of antibacterials, including anti-virulence agents. PMID- 29130178 TI - Methods to Study Quorum Sensing-Dependent Virulence and Movement of Phytopathogens In Planta. AB - Cell-to-cell communication mediated by the diffusible signal factor (DSF) is a common form of gene regulation and plays an important role in virulence of many plant pathogenic bacteria including Xanthomonas spp. Here we describe several approaches to study the involvement of DSF-dependent QS system of the plant pathogenic bacteria Xanthomonas campestris pv. pelargonii (Xhp) as an example of the Xanthomonas spp. The methods described include detection and measurement of DSF, movement in planta, colonization, and aggregate formation. PMID- 29130179 TI - Differential Equations Models to Study Quorum Sensing. AB - Mathematical models to study quorum sensing (QS) have become an important tool to explore all aspects of this type of bacterial communication. A wide spectrum of mathematical tools and methods such as dynamical systems, stochastics, and spatial models can be employed. In this chapter, we focus on giving an overview of models consisting of differential equations (DE), which can be used to describe changing quantities, for example, the dynamics of one or more signaling molecule in time and space, often in conjunction with bacterial growth dynamics. The chapter is divided into two sections: ordinary differential equations (ODE) and partial differential equations (PDE) models of QS. Rates of change are represented mathematically by derivatives, i.e., in terms of DE. ODE models allow describing changes in one independent variable, for example, time. PDE models can be used to follow changes in more than one independent variable, for example, time and space. Both types of models often consist of systems (i.e., more than one equation) of equations, such as equations for bacterial growth and autoinducer concentration dynamics. Almost from the onset, mathematical modeling of QS using differential equations has been an interdisciplinary endeavor and many of the works we revised here will be placed into their biological context. PMID- 29130180 TI - Qualitative and Quantitative Determination of Quorum Sensing Inhibition In Vitro. AB - The formation of biofilms in conjunction with quorum sensing (QS) regulated expression of virulence by opportunistic pathogens contributes significantly to immune evasion and tolerance to a variety of antimicrobial treatments. The present protocol describes methods to determine the in vitro efficacy of potential QS inhibitors (QSIs). Work on Pseudomonas aeruginosa has shown that chemical blockage of QS is a promising new antimicrobial strategy. Several live bacterial reporter systems have been developed to screen extracts and pure compounds for QSI activity. Here we describe the usage of reporter strains consisting of a lasB-gfp or rhlA-gfp fusion in P. aeruginosa for qualitative and quantitative evaluation of the inhibition of two of the major QS pathways, monitored as reduced expression of green fluorescence. By the use of an in vitro flow cell system it is possible to study the QSI activity by monitoring its ability to interfere with the protective functions of bacterial biofilm. For evaluation of the global effects of QSI compounds, we present a protocol for the DNA microarray based transcriptomics. Using these in vitro methods it is possible to evaluate the potential of various QSI compounds. PMID- 29130182 TI - A Culture-Dependent Method for the Identification of Quorum Quenching Enzymes of Microbial Origin. AB - Although it has been more than a decade since the first discovery of AHL lactonase AiiA in Bacillus sp. 240B1, we are only beginning to understand the diversity of quorum quenching (QQ) enzymes. Most of the previously identified QQ enzymes are derived from nonmarine microorganisms. A novel marine-derived secretory AHL lactonase, MomL, was found in Muricauda olearia in our previous work and represents a novel type of AHL lactonase widespread in the ocean. Herein, we describe a culture-dependent method for the identification of microbial QQ enzymes, especially the high-throughput method for screening QQ bacteria from cultivable bacterial strains. This method should be capable of efficiently identifying QQ enzymes from various microbial origins. The discovery of more QQ enzymes will help us to understand their ecological roles and may provide potential as therapeutic agents. PMID- 29130181 TI - A Coculture-Based Approach for Screening Campaigns Aimed at Identifying Novel Pseudomonas aeruginosa Quorum Sensing Inhibitors. AB - Quorum sensing (QS) is recognized as a promising target for the identification of anti-virulence drugs hampering Pseudomonas aeruginosa adaptability to the host environment and pathogenicity. Consequently, a number of studies in the last decade focused on the identification of small molecules or proteins with anti-QS activity, mainly targeting the las QS system, which is based on N-3-oxododecanoyl homoserine lactone (3OC12-HSL) as signal molecule. Different experimental approaches have been successfully used to identify QS blockers interfering with the activity/stability of the 3OC12-HSL receptor LasR, with the functionality of the 3OC12-HSL synthase LasI, or with the stability/bioavailability of the 3OC12 HSL signal molecule itself.Here we describe the use of a high-throughput screening system for the identification of novel las QS inhibitors based on the cocultivation of P. aeruginosa wild type and the P. aeruginosa-derived biosensor strain PA14-R3, in which light emission relies on the ability of the wild type strain to synthesize 3OC12-HSL and of the biosensor strain to perceive this signal molecule. With respect to other screening systems, this method has the advantage of being cost-effective and allowing the identification of compounds targeting, besides 3OC12-HSL reception, any cellular process critical for the functionality of the las QS system, including 3OC12-HSL synthesis and secretion. PMID- 29130183 TI - Directed Evolution of Quorum-Quenching Enzymes: A Method for the Construction of a Directed Evolution Platform and Characterization of a Quorum-Quenching Lactonase from Geobacillus kaustophilus. AB - A thermostable quorum-quenching lactonase from Geobacillus kaustophilus (GKL) was used as a template for in vitro directed evolution experiments. Here we describe the overexpression and purification of wild-type GKL, the construction of a quorum-quenching directed evolution platform using bioluminescence as a reporter, and the in vitro kinetic assay for the determination of kinetic parameters of wild-type GKL and its mutants. PMID- 29130184 TI - Generation of High-Sensitivity Monoclonal Antibodies Specific for Homoserine Lactones. AB - A number of bacteria use a class of chemical compounds called acyl-homoserine lactones (AHLs) as quorum sensing (QS) signals to coordinate their behavior at the population level, including pathogens like Pseudomonas aeruginosa. Blocking QS using antibodies is an attractive strategy for infection control as this process takes a central role in P. aeruginosa infections. Here the methods involved in the generation of high sensitivity anti-QS monoclonal antibodies from an immunized sheep phage display antibody library are described. A panel of AHL compounds conjugated to carrier proteins are used for sheep immunization and a phage display antibody library is constructed using the immune repertoire of sheep as a source of antibody genes. High sensitivity single chain antibody fragments (scFv) are isolated from the library using "smart selection strategies" and reformatted into single chain antibodies (scAbs). The resultant monoclonal antibodies: (1) recognize HSL compounds at low nanomolar concentrations; (2) have the potential to reduce virulence gene expression in P. aeruginosa; and (3) offer protection in a nematode model of infection. PMID- 29130185 TI - Identification of AI-2 Quorum Sensing Inhibitors in Vibrio harveyi Through Structure-Based Virtual Screening. AB - Quorum sensing (QS) is a cell-to-cell communication system that regulates gene expression as a result of the production and perception of signal molecules called autoinducers (AIs). AI-2 is a QS autoinducer produced by both Gram negative and Gram-positive bacteria, in which it regulates intraspecies and interspecies communication. The identification of QS inhibitors is considered a promising strategy for the development of anti-virulence drugs with reduced selective pressure for resistance. Here we describe a high-throughput virtual screening approach to identify AI-2 quorum sensing inhibitors on the basis of Vibrio harveyi LuxPQ crystal structure. Seven potent inhibitors with IC50 values in the micromolar range were selected with no effect or low effect on V. harveyi growth rate. PMID- 29130186 TI - Identification of Staphylococcal Quorum Sensing Inhibitors by Quantification of o Hemolysin with High Performance Liquid Chromatography. AB - Quorum sensing plays a major role in regulation of virulence factor production by staphylococci. Chemical inhibitors that block this process and prevent the production of exotoxins and exoenzymes could have medical utility for infection prophylaxis and therapy. Here, we describe a high performance liquid chromatography method amenable to medium throughput screening for staphylococcal quorum sensing inhibitors by quantification of o-hemolysin, a direct protein output of this system. PMID- 29130187 TI - The Secret Life of RNA: Lessons from Emerging Methodologies. AB - The last past decade has witnessed a revolution in our appreciation of transcriptome complexity and regulation. This remarkable expansion in our knowledge largely originates from the advent of high-throughput methodologies, and the consecutive discovery that up to 90% of eukaryotic genomes are transcribed, thus generating an unanticipated large range of noncoding RNAs (Hangauer et al., 15(4):112, 2014). Besides leading to the identification of new noncoding RNA species, transcriptome-wide studies have uncovered novel layers of posttranscriptional regulatory mechanisms controlling RNA processing, maturation or translation, and each contributing to the precise and dynamic regulation of gene expression. Remarkably, the development of systems-level studies has been accompanied by tremendous progress in the visualization of individual RNA molecules in single cells, such that it is now possible to image RNA species with a single-molecule resolution from birth to translation or decay. Monitoring quantitatively, with unprecedented spatiotemporal resolution, the fate of individual molecules has been key to understanding the molecular mechanisms underlying the different steps of RNA regulation. This has also revealed biologically relevant, intracellular and intercellular heterogeneities in RNA distribution or regulation. More recently, the convergence of imaging and high throughput technologies has led to the emergence of spatially resolved transcriptomic techniques that provide a means to perform large-scale analyses while preserving spatial information. By generating transcriptome-wide data on single-cell RNA content, or even subcellular RNA distribution, these methodologies are opening avenues to a wide range of network-level studies at the cell and organ-level, and promise to strongly improve disease diagnostic and treatment.In this introductory chapter, we highlight how recently developed technologies aiming at detecting and visualizing RNA molecules have contributed to the emergence of entirely new research fields, and to dramatic progress in our understanding of gene expression regulation. PMID- 29130188 TI - Quantification of 2'-O-Me Residues in RNA Using Next-Generation Sequencing (Illumina RiboMethSeq Protocol). AB - RNA 2'-O-methylation is one of the ubiquitous nucleotide modifications found in many RNA types from bacteria, archaea, and eukarya. We and others have recently published accurate and sensitive detection of these modifications on native RNA at a single base resolution by high-throughput sequencing technologies. Relative quantification of these modifications is still under progress and would probably reduce the number of false positives due to 3D RNA structure. Therefore, here, we describe a reliable and optimized protocol for quantification of 2'-O Methylations based on alkaline fragmentation of RNA coupled to a commonly used ligation approach followed by Illumina sequencing. For this purpose, we describe how to prepare in vitro transcribed yeast 18S and 25S rRNA used as a reference for unmodified rRNAs and to compare them to purified 18S and 25S rRNA from yeast total RNA preparation. These reconstructed rRNA mixes were combined at different ratios and processed for RiboMethseq protocol.This technique will be applicable for routine parallel treatment of biological and clinical samples to decipher the functions of 2'-O-methylations in normal and pathologic processes or during development. PMID- 29130189 TI - Identifying the m6A Methylome by Affinity Purification and Sequencing. AB - N 6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA, and is newly emerging as a key posttranscriptional mRNA regulator. Recent research has uncovered insight into the location and function of m6A sites on a large scale, in part due to the transcriptome-wide identification of m6A sites by high-throughput sequencing (m6A-seq). Here, we present a protocol for m6A-seq, which maps the m6A methylome by affinity purification and sequencing. PMID- 29130191 TI - Axon-TRAP-RiboTag: Affinity Purification of Translated mRNAs from Neuronal Axons in Mouse In Vivo. AB - Translating ribosome affinity purification (TRAP) is a widely used technique to analyze ribosome-bound mRNAs in particular target cells that express a tagged ribosomal protein. We developed axon-TRAP-RiboTag, a TRAP-based method that allows purification and identification of translated mRNAs from distal neuronal axons in mouse, and identified more than 2000 of translated mRNAs in retinal ganglion cell (RGC) axons in vivo. The use of Cre-negative littermate control to filter out false-positive signals allows unbiased detection, and combining TRAP with in vitro ribosome run-off enables identification of actively translated mRNAs. Here, we describe a detailed protocol to identify translated mRNAs in RGC axons in mouse in vivo. This method can be applied to any neurons whose cell bodies and distal axons are anatomically separated. PMID- 29130190 TI - PARIS: Psoralen Analysis of RNA Interactions and Structures with High Throughput and Resolution. AB - RNA has the intrinsic propensity to form base pairs, leading to complex intramolecular and intermolecular helices. Direct measurement of base pairing interactions in living cells is critical to solving transcriptome structure and interactions, and investigating their functions (Lu and Chang, Curr Opin Struct Biol 36:142-148, 2016). Toward this goal, we developed an experimental method, PARIS (Psoralen Analysis of RNA Interactions and Structures), to directly determine transcriptome-wide base pairing interactions (Lu et al., Cell 165(5):1267-1279, 2016). PARIS combines four critical steps, in vivo cross linking, 2D gel purification, proximity ligation, and high-throughput sequencing to achieve high-throughput and near-base pair resolution determination of the RNA structurome and interactome in living cells. In this chapter, we aim to provide a comprehensive discussion on the principles behind the experimental and computational strategies, and a step-by-step description of the experiment and analysis. PMID- 29130192 TI - LCM-Seq: A Method for Spatial Transcriptomic Profiling Using Laser Capture Microdissection Coupled with PolyA-Based RNA Sequencing. AB - LCM-seq couples laser capture microdissection of cells from frozen tissues with polyA-based RNA sequencing and is applicable to single neurons. The method utilizes off-the-shelf reagents and direct lysis of the cells without RNA purification, making it a simple and relatively cheap method with high reproducibility and sensitivity compared to previous methods. The advantage with LCM-seq is also that tissue sections are kept intact and thus the positional information of each cell is preserved. PMID- 29130193 TI - Spatial Transcriptomics: Constructing a Single-Cell Resolution Transcriptome-Wide Expression Atlas. AB - The method described here aims at the construction of a single-cell resolution gene expression atlas for an animal or tissue, combining in situ hybridization (ISH) and single-cell mRNA-sequencing (scRNAseq).A high resolution and medium coverage gene expression atlas of an animal or tissue of interest can be obtained by performing a series of ISH experiments, followed by a process of image registration and gene expression averaging. Using the overlapping fraction of the genes, concomitantly obtained scRNAseq data can be fitted into the spatial context of the gene expression atlas, complementing the coverage by genes. PMID- 29130194 TI - Single mRNA Molecule Detection in Drosophila. AB - Single molecule fluorescent in situ hybridization (smFISH) enables quantitative measurements of gene expression and mRNA localization. The technique is increasingly popular for analysis of cultured cells but is not widely applied to intact organisms. Here, we describe a method for labeling and detection of single mRNA molecules in whole embryos of the fruit fly Drosophila melanogaster. This method permits measurements of gene expression in absolute units, enabling new studies of transcriptional mechanisms underlying precision and reproducibility in cell specification. PMID- 29130195 TI - Detection and Automated Analysis of Single Transcripts at Subcellular Resolution in Zebrafish Embryos. AB - Single molecule fluorescence in situ hybridization (smFISH) is a method to visualize single mRNA molecules. When combined with cellular and nuclear segmentation, transcripts can be assigned to different cellular compartments resulting in quantitative information on transcript levels at subcellular resolution. The use of smFISH in zebrafish has been limited by the lack of protocols and an automated image analysis pipeline for samples of multicellular organisms. Here we present a protocol for smFISH on zebrafish cryosections. The protocol includes a method to obtain high-quality sections of zebrafish embryos, an smFISH protocol optimized for zebrafish cryosections, and a user-friendly, automated analysis pipeline for cell segmentation and transcript detection. The software is freely available and can be used to analyze sections of any multicellular organism. PMID- 29130196 TI - Super-Resolution Single Molecule FISH at the Drosophila Neuromuscular Junction. AB - The lack of an effective, simple, and highly sensitive protocol for fluorescent in situ hybridization (FISH) at the Drosophila larval neuromuscular junction (NMJ) has hampered the study of mRNA biology. Here, we describe our modified single molecule FISH (smFISH) methods that work well in whole mount Drosophila NMJ preparations to quantify primary transcription and count individual cytoplasmic mRNA molecules in specimens while maintaining ultrastructural preservation. The smFISH method is suitable for high-throughput sample processing and 3D image acquisition using any conventional microscopy imaging modality and is compatible with the use of antibody colabeling and transgenic fluorescent protein tags in axons, glia, synapses, and muscle cells. These attributes make the method particularly amenable to super-resolution imaging. With 3D Structured Illumination Microscopy (3D-SIM), which increases spatial resolution by a factor of 2 in X, Y, and Z, we acquire super-resolution information about the distribution of single molecules of mRNA in relation to covisualized synaptic and cellular structures. Finally, we demonstrate the use of commercial and open source software for the quality control of single transcript expression analysis, 3D-SIM data acquisition and reconstruction as well as image archiving management and presentation. Our methods now allow the detailed mechanistic and functional analysis of sparse as well as abundant mRNAs at the NMJ in their appropriate cellular context. PMID- 29130197 TI - Detection of mRNA and Associated Molecules by ISH-IEM on Frozen Sections. AB - The use of tagged RNA probes to directly hybridize frozen sections of chemically fixed tissues, followed by the tag detection with specific antibodies and gold conjugates form the core of the in situ hybridization (ISH)-immunoelectron microscopy (IEM) method that we have developed and successfully used to detect endogenous gurken and bicoid mRNAs in Drosophila oocytes. PMID- 29130198 TI - Hybridization Chain Reaction for Direct mRNA Detection Without Nucleic Acid Purification. AB - Hybridization chain reaction (HCR) provides a feasible solution for nucleic acid detection without target amplification. By highly specific sandwich hybridization, target RNA can be directly captured onto solid support and detected using HCR with fluorescent dyes. Here, we describe a novel method for malaria RNA detection based on sandwich hybridization and two-dimensional HCR, without involving nucleic acid purification or any enzymatic reaction, using ordinary oligonucleotides without labeling or modification. PMID- 29130199 TI - In Situ Detection of MicroRNA Expression with RNAscope Probes. AB - Elucidating the spatial resolution of gene transcripts provides important insight into potential gene function. MicroRNAs are short, singled-stranded noncoding RNAs that control gene expression through base-pair complementarity with target mRNAs in the 3' untranslated region (UTR) and inhibiting protein expression. However, given their small size of ~22- to 24-nt and low expression levels, standard in situ hybridization detection methods are not amendable for microRNA spatial resolution. Here, I describe a technique that employs RNAscope probe design and propriety amplification technology that provides simultaneous single molecule detection of individual microRNA and its target gene. This method allows for rapid and sensitive detection of noncoding RNA transcripts in frozen tissue sections. PMID- 29130200 TI - Padlock Probes to Detect Single Nucleotide Polymorphisms. AB - Rapid development of high-throughput DNA analyzation methods has enabled global characterization of genetic landscapes and aberrations in study subjects in a time and cost effective fashion. In most methods, however, spatial tissue context is lost since sample preparation requires isolation of nucleic acids out of their native environment. We hereby present the most recent protocol for multiplexed, in situ detection of mRNAs and single nucleotide polymorphisms using padlock probes and rolling circle amplification. We take advantage of a single nucleotide variant within conserved ACTB mRNA to successfully differentiate human and mice cocultured cells and apply presented protocol to genotype PCDH X and Y homologs in human brain. We provide a method for automated characterization and quantitation of target mRNA in single cells or chosen tissue area. mRNA of interest, harboring a polymorphism, is first reverse-transcribed to cDNA. Allele specific padlock probes are hybridized to the cDNA target and enzymatically circularized maintaining a physical link with the parent mRNA molecule. Lastly, circularized probes are replicated in situ, using rolling circle amplification mechanism to facilitate detection. PMID- 29130201 TI - Quantifying Gene Expression in Living Cells with Ratiometric Bimolecular Beacons. AB - Molecular beacons (MBs), a class of oligonucleotide-based probes, have enabled researchers to study various RNA molecules in their native live-cell contexts. However, it is also increasingly recognized that, when delivered into cells, MBs have the tendency to be sequestered into the nucleus where they may generate false positive signals. In an attempt to overcome this issue, MBs have been synthesized with chemically modified oligonucleotide backbones to confer greater biostability. Alternatively, strategies have been developed to minimize nuclear entry. In the latter approach, we have combined functional elements of MBs with functional elements of siRNAs that facilitate nuclear export to create a new RNA imaging platform called ratiometric bimolecular beacons (RBMBs). We showed that RBMBs exhibited long-term cytoplasmic retention, and hence a marginal level of false positive signals in living cells. Subsequent studies demonstrated that RBMBs could sensitively and accurately quantify mRNA transcripts engineered to contain multiple tandem repeats of an MB target sequence at the single-molecule level. In this chapter, we describe the synthesis of RBMBs and their applications for absolute quantification and tracking of single mRNA transcripts in cells. PMID- 29130202 TI - Optimizing Molecular Beacons for Intracellular Analysis of RNA. AB - Conventional molecular beacons (MBs) have been used extensively for imaging specific endogenous RNAs in living cells, but their tendency to generate false positive signals as a result of nuclease degradation and/or nonspecific binding limits sensitive and accurate imaging of intracellular RNAs. In an attempt to overcome this limitation, MBs have been synthesized with various chemically modified oligonucleotide backbones to confer greater biostability. We have recently developed a new MB architecture composed of 2'-O-methyl RNA (2Me), a fully phosphorothioate (PS) modified loop domain and a phosphodiester stem (2Me/PSLOOP MB). We showed that this new MB exhibits a marginal level of false positive signals and enables accurate single-molecule imaging of target RNA in living cells. In this chapter, we describe detailed methods that led us to conclude that, among various PS-modified configurations, the 2Me/PSLOOP MB is an optimal design for intracellular RNA analysis. PMID- 29130203 TI - Live Imaging of Nuclear RNPs in Mammalian Complex Tissue with ECHO-liveFISH. AB - Multiplex RNA detection with fluorescence microscopy offers high spatial and temporal resolution required for addressing complex behaviors of RNA in living cells. Using chemically engineered linear oligonucleotide probes that emit fluorescence upon hybridization to target RNA, we have devised an imaging method suitable for studies of the dynamic regulation of nuclear RNPs, an important and yet poorly understood cellular pathway of gene expression. This new method labels specific sequences of RNA components in RNPs and thus avoids overexpression of fluorescent marker proteins that may result in entangled experimental results. Using this method, we observe in living brain tissue spatially constrained nuclear RNA foci under dynamic regulation in response to cellular transcriptional activity with individual cell heterogeneity. PMID- 29130204 TI - In Vivo Visualization and Function Probing of Transport mRNPs Using Injected FIT Probes. AB - Fluorogenic hybridization methods, such as the use of FIT probes, enable the in vivo detection of specific mRNAs transcribed from their endogenous, genetically nonmodified loci. Here, we describe the design, synthesis and injection of nuclease resistant FIT probes into developing Drosophila oocytes to detect endogenous localizing mRNAs as wells as to probe function of structural RNA elements. PMID- 29130206 TI - Method for Imaging Live-Cell RNA Using an RNA Aptamer and a Fluorescent Probe. AB - Live-cell imaging of mRNA dynamics is increasingly important to understanding spatially restricted gene expression. We recently developed a convenient and versatile method that uses a gene-specific RNA aptamer and a fluorescent probe to enable spatiotemporal imaging of endogenous mRNAs in living cells. The method was validated by live-cell imaging of the endogenous mRNA of beta-actin. The new RNA imaging technology might be useful for live-cell imaging of any RNA molecules. PMID- 29130207 TI - RNA Live Imaging in the Model Microorganism Ustilago maydis. AB - An essential feature of protein expression is the tight regulation of when and where a protein is translated from its cognate mRNA. This spatiotemporal expression is particularly important in guaranteeing the correct and efficient targeting of proteins to defined subcellular sites. In order to achieve local translation, mRNAs must be deposited at specific locations. A common mechanism is the active transport of mRNAs along the actin or microtubule cytoskeleton. To study such dynamic transport processes in vivo RNA live imaging is the method of choice. This method is based on the principle that defined binding sites for a heterologous RNA-binding protein (RBP) are inserted in the 3' UTR of target mRNAs. Coexpression of the RBP fused to a fluorescent protein enables mRNA detection in vivo using fluorescence microscopy techniques. In this chapter we describe the well-established method of studying microtubule-dependent mRNA transport in the eukaryotic model microorganism Ustilago maydis. The presented experimental design and the microscopic techniques are applicable to a broad range of other organisms. PMID- 29130205 TI - Visualizing RNA in Live Bacterial Cells Using Fluorophore- and Quencher-Binding Aptamers. AB - To elucidate the roles, dynamics, and regulation of RNAs, it is vital to be able to visualize the RNA of interest (ROI) in living cells noninvasively. Here, we describe a novel live-cell RNA imaging method using fluorophore- and quencher binding aptamers, which can be genetically fused to the ROI. In this method, new membrane permeable and nonfluorescent fluorophore-quencher conjugates were utilized, and we showed that their fluorescence increases dramatically upon binding to fluorophore- or quencher-binding aptamers. This phenomenon allowed for labeling the ROI with many different colored fluorophores and also dual-color imaging of two distinct RNAs in live bacteria. Our approach uses small RNA tags and small molecule fluorophores for labeling, thereby minimal perturbation on the function and dynamics of the RNA of interest is expected. PMID- 29130208 TI - Real-Time Fluorescence Imaging of Single-Molecule Endogenous Noncoding RNA in Living Cells. AB - Visualizing RNA in living cells is increasingly important to facilitate accumulation of knowledge about the relation between specific RNA dynamics and physiological events. Single-molecule fluorescence imaging of target RNAs is an excellent approach to analyzing intracellular RNA motion, but it requires special techniques for probe design and microscope setup. Herein, we present a principle and protocol of an RNA visualization probe based on an RNA binding protein of the Pumilio homology domain (PUM-HD). We also describe the setup and operation of a microscope, and introduce an application to visualize telomeric repeats containing RNA with telomeres and a telomere-related protein: hnRNPA1. This imaging technique is applicable to visualization of different RNAs, especially including repetitive sequences, in living cells. PMID- 29130210 TI - Imaging Newly Transcribed RNA in Cells by Using a Clickable Azide-Modified UTP Analog. AB - Robust RNA labeling and imaging methods that enable the understanding of cellular RNA biogenesis and function are highly desired. In this context, we describe a practical chemical labeling method based on a bioorthogonal reaction, namely, azide-alkyne cycloaddition reaction, which facilitates the fluorescence imaging of newly transcribed RNA in both fixed and live cells. This strategy involves the transfection of an azide-modified UTP analog (AMUTP) into mammalian cells, which gets specifically incorporated into RNA transcripts by RNA polymerases present inside the cells. Subsequent posttranscriptional click reaction between azide labeled RNA transcripts and a fluorescent alkyne substrate enables the imaging of newly synthesized RNA in cells by confocal microscopy. Typically, 50 MUM to 1 mM of AMUTP and a transfection time of 15-60 min produce significant fluorescence signal from labeled RNA transcripts in cells. PMID- 29130209 TI - Live Imaging of mRNA Synthesis in Drosophila. AB - mRNA synthesis is one of the earliest readouts of the activity of a transcribed gene, which is of particular interest in the context of metazoan cell fate specification. These processes are intrinsically dynamic and stochastic, which makes in vivo single-cell measurements inevitable. Here, we present the application of a technology that has been widely used in single celled organisms to measure transcriptional activity in developing embryos of the fruit fly Drosophila melanogaster. The method allows for quantification of instantaneous polymerase occupancy of active gene loci and thereby enables the development and testing of models of gene regulation in development. PMID- 29130211 TI - Detection of the First Round of Translation: The TRICK Assay. AB - Quantitative fluorescence microscopy techniques are frequently applied to answer fundamental biological questions. Single-molecule RNA imaging methods have enabled the direct observation of the initial steps of the mRNA life cycle in living cells, however, the dynamic mechanisms that regulate mRNA translation are still poorly understood. We have developed an RNA biosensor that can assess the translational state of individual mRNA transcripts with spatiotemporal resolution in living cells. In this chapter, we describe how to perform a TRICK (translating RNA imaging by coat protein knock-off) experiment and specifically focus on a detailed description of our image processing and data analysis procedure. PMID- 29130212 TI - Imaging Translation Dynamics of Single mRNA Molecules in Live Cells. AB - mRNA translation is a key step in decoding the genetic information stored in DNA. Regulation of translation efficiency contributes to gene expression control and is therefore important for cell fate and function. Here, we describe a recently developed microscopy-based method that allows for visualization of translation of single mRNAs in live cells. The ability to measure translation dynamics of single mRNAs will enable a better understanding of spatiotemporal control of translation, and will provide unique insights into translational heterogeneity of different mRNA molecules in single cells. PMID- 29130213 TI - Systematic Detection of Poly(A)+ RNA-Interacting Proteins and Their Differential Binding. AB - RNA-binding proteins are dynamic posttranscriptional regulators of gene expression. Identification of mRNA-binding proteins in a given experimental setting is thus of great importance. We describe a procedure to enrich for direct poly(A)+ RNA protein binders by 4-thiouridine-enhanced UV cross-linking and oligo(dT) purification. Subsequent nuclease-mediated release of RNA-binding proteins (RBPs) from mRNA allows for detection of eluted proteins by mass spectrometry. In addition, we provide a comparative approach to detect differences in RBP binding activity upon a biological stimulus. PMID- 29130215 TI - Individual Nucleotide Resolution UV Cross-Linking and Immunoprecipitation (iCLIP) to Determine Protein-RNA Interactions. AB - RNA-binding proteins (RBPs) interact with and determine the fate of many cellular RNA transcripts. In doing so they help direct many essential roles in cellular physiology, while their perturbed activity can contribute to disease etiology. In this chapter we detail a functional genomics approach, termed individual nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP), that can determine the interactions of RBPs with their RNA targets in high throughput and at nucleotide resolution. iCLIP achieves this by exploiting UV-induced covalent cross-links formed between RBPs and their target RNAs to both purify the RBP-RNA complexes under stringent conditions, and to cause reverse transcription stalling that then identifies the direct cross-link sites in the high throughput sequenced cDNA libraries. PMID- 29130214 TI - Isolation and Characterization of Endogenous RNPs from Brain Tissues. AB - Identification of physiological target RNAs and protein interactors bound to RNA binding proteins is a key prerequisite to understand the underlying mechanisms of posttranscriptional expression control and RNA granule assembly. Here, we describe a multistep biochemical approach to isolate endogenous ribonucleoprotein particles from brain tissues by exploiting differential centrifugation and gradient fractionation followed by immunoprecipitation with monospecific, affinity-purified antibodies directed against selected RNA-binding proteins. This protocol results in highly enriched endogenous ribonucleoprotein particles that then can be analyzed by mass spectrometry (for proteins composition) and microarray or RNA sequencing technologies (for target mRNAs). PMID- 29130216 TI - RNA Tagging: Preparation of High-Throughput Sequencing Libraries. AB - Protein-RNA networks, in which a single protein binds and controls multiple mRNAs, are central in biological control. As a result, methods to identify protein-RNA interactions that occur in vivo are valuable. The "RNA Tagging" approach enables the investigator to unambiguously identify global protein-RNA interactions in vivo and is independent of protein purification, cross-linking, and radioactive labeling steps. Here, we provide a protocol to prepare high throughput sequencing libraries for RNA Tagging experiments. PMID- 29130217 TI - RAP-MS: A Method to Identify Proteins that Interact Directly with a Specific RNA Molecule in Cells. AB - RNA molecules interact with proteins to perform a variety of functions in living cells. The binding partners of many RNAs, in particular the newly discovered class of long noncoding RNAs (lncRNAs), remain largely unknown. RNA antisense purification coupled with mass spectrometry (RAP-MS) is a method that enables the identification of direct and specific protein interaction partners of a specific RNA molecule. Because RAP-MS uses direct RNA-protein cross-linking methods coupled along with highly denaturing purification conditions, RAP-MS provides a short list of high confidence protein interactors. PMID- 29130218 TI - [Clinical significance and practice points of conversion therapy for gastric cancer with peritoneal metastasis]. AB - Gastric cancer with peritoneal dissemination is usually considered to be oncologically unresectable and is known to have a very poor prognosis. Despite recent advances in systemic chemotherapy, peritoneal dissemination due to advanced gastric cancer (AGC) still remains the most life-threatening type of metastasis and recurrence, which usually causes ascites accumulation, intestinal obstruction, or hydronephrosis, and then seriously impairs the quality of life. In general, the median survival time of these cases is reported to be just only 6 9 months. Recently, conversion therapy for gastric cancer with peritoneal dissemination has been highly concerned. It is defined as a conversion surgery aiming at an R0 resection after chemotherapy for both primary gastric cancer and distant metastatic cancerous foci including peritoneal dissemination, which were originally unresectable due to technical and/or oncological reasons. In numerous clinical practices, the results of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) have been reported to be more satisfactory in comparison with traditional systemic chemotherapy alone. Some clinical trials have demonstrated the clinical efficacy of intravenous and intraperitoneal administration of paclitaxel (PTX) combined with oral S-1 for peritoneal dissemination of gastric cancer with or without malignant ascites. Particularly, a longer period of survival can be expected when conversion R0 gastrectomy is successfully performed after observing significant responses of NIPS. Some clinical practice key points of conversion therapy for AGC patients with peritoneal dissemination are reviewed, including the importance of intraperitoneal and systemic synchronous chemotherapy, the reasonable choice of intraperitoneal chemotherapy drugs, the evaluation of primary gastric cancer and metastatic foci before and after conversion therapy, some special complications of NIPS, the indications of conversion surgery and the adjuvant therapy after conversion surgery, ect. PMID- 29130219 TI - [Colorectal cancer heterogeneity: genotype, phenotype and clinical manifestation]. AB - Colorectal cancer is the third high-incidence of malignant tumors in the world, and also a kind of tumor with good biological behavior and good efficacy. Colorectal cancer heterogeneity is a very important trait of its biological behavior, which can be reflected in many different aspects, including tumor type, pathogenesis, molecular phenotyping and time-space heterogeneity. Different pathogenesis produces different tumor phenotypes, which are generated in the process of natural evolution and intervention. Various phenotypes show the difference among different individuals of colorectal cancer, in terms of clinical characteristics, treatment response and prognosis. Understanding the heterogeneity of colorectal cancer has important clinical value for individualized treatment. PMID- 29130220 TI - [Current research progress and thinking of fecal microbiota transplantation for the treatment of gastrointestinal disorders]. AB - Fecal microbiota transplantation (FMT), also known as fecal bacteriotherapy or fecal infusion, consists of injection of a liquid filtrate of feces from a healthy donor into the gastrointestinal tract of a recipient individual. FMT has been proposed as a therapeutic approach for functional diseases of the gastrointestinal tract by reestablishment of a wide diversity of intestinal flora. Clostridium difficile infection (CDI) treatment guideline from American Gastroenterology Association (AGA) recommends that FMT can be used as the treatment protocols of relapse CDI. Numerous case reports, retrospective case series, and randomized controlled trials have shown the benefit of FMT in patients with functional bowel disorders, including inflammatory bowel disease, irritable bowel syndrome and constipation, etc. Evidence regarding the safety of FMT is relatively limited because the very rapid adoption of FMT as a therapeutic modality for CDI occurred before the performance of large, long prospective trials that are typically conducted to assess the safety of new interventions. Potential adverse events can be categorized as short-term and long-term, and short-term events can further be divided into those related to the method of FMT delivery (colonoscopy, sedation) and those related to the FMT itself. Due to the recent emergence of FMT, little data exist regarding long-term events and many safety concerns are speculative. Capsulized FMT therapy solves the clinical problems associated with the use of fresh FMT suspensions for long-term maintenance i.e. repeat transplantation and invasive procedures, which is of great significance to optimize the traditional FMT clinical strategy. Future work will focus on establishing best practices and more robust safety data than exist currently, as well as refining FMT beyond current "whole-stool" transplants to increase safety and tolerability. Encapsulated formulations, full-spectrum stool based products, and defined microbial consortia are all in the immediate future. Although challenges exist, regulatory agencies have been willing to work with stakeholders and will continue to evolve and adapt policy as therapeutics based on human gut microbiota research emerge. PMID- 29130221 TI - [Development and progress of diagnosis and treatment for gastric cancer in China- what inspiration we gained from Japan and Korea]. AB - The incidence of gastric cancer in East Asia is highest in the world. Level of screening and inspection in high risk population, diagnosis and treatment in early stage, standardized surgery, minimally invasive techniques and clinical research always reach the international lead. In the past few years, the surgeons and researchers from China have already made considerable progress by learning the experience from Japan and Korea. The early detection of gastric cancer increases annually, the minimally invasive surgeries including endoscopic or laparoscopic operations are widely used, the standard surgical procedure and lymphadenectomy are popularized, meanwhile the clinical research for gastric cancer has also started. In the future, as long as following this way, we will definitely achieve better improvement in diagnosis and treatment of gastric cancer in China. PMID- 29130222 TI - [Selection and appraisal of digestive tract reconstruction after totally laparoscopic gastrectomy for gastric cancer]. AB - In recent years, with the development of laparoscopic technology, more and more totally laparoscopic gastrectomy has been applied. The reconstruction of digestive tract is the key procedure of laparoscopic gastrectomy and is associated with the postoperative quality of life. Each method of digestive tract reconstruction has its own characteristic, however, unified consensus on how to choose the optimal method for digestive tract reconstruction has not yet been reached till today. In this article, we will discuss and evaluate the advantages, disadvantages and indications of these reconstruction methods after totally laparoscopic distal gastrectomy, total gastrectomy and proximal gastrectomy combined with relative literatures and our practical experience in order to provide the reference to choose the reasonable reconstruction method at the premise of radical resection, which may decrease the morbidity of postoperative complication, increase the quality of life, and bring benefits to patients definitely. PMID- 29130223 TI - [Metabolic changes in patients with short bowel syndrome and the nutritional support therapy]. AB - Patients with short bowel syndrome suffer from fluid and electrolyte imbalance and malabsorption due to poor nutrient processing capability of the residual intestine. Nutritional support therapy has been considered as one of the important treatments for short bowel syndrome. For patients with short bowel syndrome, a deep understanding of metabolic changes, and then rational application of nutritional support therapy and intestinal rehabilitation program can save many patients' lives, improve quality of life, and even achieve independence from parenteral nutrition, and return to a normal life. PMID- 29130224 TI - [Interpretation of 2017 National Comprehensive Cancer Network (NCCN) guidelines for the diagnosis and treatment of esophageal squamous cell carcinoma through the new TNM staging of esophageal carcinoma (eighth edition) by the Union for International Cancer Control (UICC) and the American Cancer Commission (AJCC)]. AB - The eighth edition of Union for International Cancer Control (UICC) and the American Joint Committee on Cancer(AJCC) announced in 2017 the new staging of esophageal cancer, focusing on the prognostic significance of accurate staging and lymph node metastasis before treatment of esophageal carcinoma, the rationality of early tumor therapy, and the importance of induction therapy. The modified 2017 edition of the National Comprehensive Cancer Network (NCCN) guidelines, based on above contents matching UICC/AJCC eighth edition of the new staging of esophageal cancer, added preoperative clinical staging to guide the selection of treatment, and re-defined the indications of endoscopic resection and operation for early esophageal squamous cell carcinoma, meanwhile emphasized once again the importance of preoperative induction therapy for locally advanced esophageal squamous cell carcinoma. While there are still many pendent problems that need to be explored further, the knowledge of the law of progression in esophageal cancer and the factors related to prognosis, launching targeted researches for solving practical problems, and the emphasis of standardized diagnosis and treatment are the basic strategies to improve the efficacy of esophageal carcinoma. PMID- 29130225 TI - [Conversion therapy of advanced gastric cancer]. AB - There are 30% to 40% of advanced gastric cancer patients who lose the opportunity of curative surgery at initial diagnosis, so chemotherapy is recommended as the main treatment modality, however, the overall prognosis is poor. Recently, a number of phase II( studies show an enormously ideal potential of conversion therapy in these patients. Conversion therapy uses rational chemotherapy, radiotherapy and targeted therapy and so on combined with MDT assessment to translate initial unresectable case to resectable one, which obviously prolongs survival time and improves quality of life. In this review, we address the indications, development and our experiences of conversion therapy in advanced GC, which looks forward to providing the reference to clinical diagnosis and treatment. PMID- 29130227 TI - [Recognition of the diagnosis and treatment of small intestinal obstruction]. AB - Small intestinal obstruction is a common and frequent disease in general surgery. Delayed diagnosis and surgical timing, and inaccurate treatment strategy will lead to life-threatening complications. Therefore, how to diagnose and treat quickly and accurately is still a difficult problem in current gastrointestinal surgery. This paper summarizes and analyzes the diagnosis and treatment strategies of small intestinal obstruction based on current laboratory technology, medical imaging technology, perioperative management and improvement of surgical concepts. At the same time, early postoperative inflammatory small bowel obstruction, radioactive enteritis with intestinal obstruction, primary abdominal cocoon, primary pseudo obstruction are discussed according to the long term experience of the author's department. The aim is to establish a reasonable and effective strategy for the diagnosis and treatment of common and special small intestinal obstruction. PMID- 29130226 TI - [Prevention and treatment of perioperative non-surgery-related complications in elderly patients with gastric cancer]. AB - The incidence of elderly gastric cancer patients is increasing, since the average life span is longer than ever before and the medical management is improved. Elderly patients usually have more comorbidities due to gradual loss of immunonutritional and functional status, leading to a higher rate of non-surgery related postoperative morbidity and mortality. Along with the development of surgical and nursing technique, more and more surgeons would perform surgical procedures on elderly gastric cancer patients without hesitation. Moreover, recent studies showed that surgery would be an effective way to improve the prognosis of elderly gastric cancer patients, while the surgery-related complications were not increased significantly. Therefore, it is important to elucidate some specific issues of prevention and treatment of postoperative non surgery-related complications in elderly gastric cancer patients. The topic of this review will cover coronary complications, pulmonary complications, nutrition related complications, and some other postoperative issues. PMID- 29130228 TI - [Valuation and prospect of function preserving gastrectomy]. AB - Preserving gastric function and improving quality of life (QOL) is the tendency of surgery for early gastric cancer. Function preserving gastrectomy (FPG) is applied to modify the extent of surgery and to achieve better quality of life at the premise of radical resection. Pylorus-preserving gastrectomy is the most favorable approach of FPG with oncological safety, which can improve nutritional status and QOL via preserving pylorus and vagal nerve. Proximal gastrectomy is widely accepted as FPG for early upper 1/3 gastric cancer. However, the most optimal way of anastomosis is not yet solved. Sentinel node navigation is currently the most accurate approach for intraoperative diagnosis of lymph node metastasis, which stimulates the development of many kinds of FPG procedures for individual treatment. Nevertheless, more efforts should be made to reduce false negative rate of sentinel node biopsy. Herein we discuss the valuation and prospect of FPG. PMID- 29130230 TI - [Protective measures in laparoscopic resection for upper or mid rectal cancer and sigmoid colon cancer with transrectal specimen extraction surgery]. AB - OBJECTIVE: To introduce the use of a self-made specimen protective sleeve in laparoscopic resection for upper or mid rectal cancer and sigmoid colon cancer with transrectal specimen extraction surgery and the improvement of implantation method, so as to avoid and reduce bacterial contamination and tumor cell dissemination in abdominal cavity. METHODS: During June 2015 and May 2017, 48 cases of high located rectal or sigmoid colon cancer were operated laparoscopically with natural orifices specimen extraction surgery (NOSES) using a self-made specimen protecting sleeve. Operation indication: (1) Rectum and sigmoid colon cancer with the distance of more than 6 cm from tumor inferior margin to dentate line. (2) The maximum diameter of intestine together with mesangial and tumor <7 cm by intraoperative judgment. (3) No anal and distal rectal surgery, no anorectal stenosis or lack of expansion capacity caused by trauma. (4) No ulcerative colitis, Crohn's disease or radiation proctitis. After transecting the rectum, the specimen protective sleeve was inserted through the right lower 12 mm main Trocar (This sleeve was tailored from the laparoscopic protective sleeve produced by China 3L Corporation, which was intercepted with 25 35 cm from one end of the sleeve according to the length of distal rectal retention. One end was ligated and the other was open with a ligature band. About 5 ml paraffin oil was used to rinse and lubricate during the operation). The rectal stump retained 7-8 cm in abdominal cavity. The transanal ligation part of the protective sleeve was cut off, then the stapler nail seat was inserted and specimen was pull out through the sleeve and rectum. RESULTS: There were 30 males and 18 females. The average age was (64.5+/-14.1) years, the BMI was (25.4+/-3.9) kg/m2, the tumor diameter was (3.3+/-1.1) cm, the maximum diameter of specimen was (5.4+/-1.5) cm and the length of specimen was (18.6+/-4.3) cm. Among these 48 cases, specimens of 36 patients were pulled out through inside of the sleeve easily, while specimens of 12 patients were quite difficult with resistance. Of 12 cases, 7 needed the help of transverse forceps, 4 needed to make 1 cm incision in pull-through bowel and insert a suction to decrease the volume of large specimens with gathering of gas and fluid, and 1 received small abdominal incision to remove specimen and perform intestinal reconstruction due to big specimen (the diameter of tumor and mesentery was 7.5 cm). Specimen tears of 6 patients didn't result in dissemination thanks to the specimen protecting sleeve. The operation time was (113.2+/-76.1) min, the bleeding amount was (38.5+/-17.3) ml, the time to first oral intake was (47.9+/-4.4) h, and the postoperative hospitalization length was (8.5+/-1.7) d. Anastomotic leakage occurred in 1 case (2.1%). No intra-abdominal and trocar infection, and obstruction were found. CONCLUSION: The use of protective sleeve and the improvement of the method of intraperitoneal implantation can effectively reduce the abdominal contamination during the specimen extraction. It can be applied to big specimens as well. PMID- 29130229 TI - [Discovery, anatomy and clinical significance of the mesorectal finish line of total mesorectal excision]. AB - OBJECTIVE: To investigate the surgical endpoint of separation of mesorectum during total mesorectal excision (TME), suggesting the concept of "terminal line", in order to perform above separation better for middle-low rectal cancer. METHODS: Gross anatomy of mesorectum endpoint from 81 surgical specimens of low anterior resection (LAR, 5 to 6 cm of distance from low margin of cancer to anal edge) and 71 surgical specimens of abdominal perineal resection(APR, <5 cm of distance from low margin of cancer to anal edge) was observed. Clinicopathological, magnetic resonance imaging(MRI) morphological and operative video data of 108 low rectal cancer patients undergoing TME at Department of Colorectal Surgery of Affiliated Union Hospital of Fujian Medical University between March 2016 and March 2017 were retrospectively analyzed. Rates of the "terminal line" exposure of TME between different surgical procedures(robot or laparoscope) and different anatomical instruments (ultrasonic knife or electric hook) were compared for evaluating the site of separation endpoint. RESULTS: The gross anatomical findings of specimens from LAR showed that the rectal wall below the levator hiatus level had no mesorectum attachment, and gross anatomical finding of specimens from APR showed that the levator hiatus was the most terminal attachment margin of the mesorectum whose thickness was only 2 millimeters in levator hiatus level. MRI morphological findings of 108 low rectal cancer patients showed that high signal intensity of mesorectal tissue on T2 MRI gradually thinned to the level of levator hiatus. High quality laparoscopic and robotic operation revealed a white linear structure formed by pelvic fascia, which covered and surrounded levator hiatus, so the "terminal line" of TME was defined. The operation video of 108 revealed that the overall exposure rate of the "terminal line" was 45.4%, the exposure rate of "terminal line" in robotic surgery was similar to that in laparoscopic surgery [(60.0%(18/30) vs. 39.7%(31/78), P=0.058], while such rate in ultrasonic knife was superior to electric hook [55.4%(41/74) vs. 23.5%(8/34), P=0.002]. Laparoscopy combined with ultrasonic knife can also obtained a high exposure rate of 52.3%(23/44). CONCLUSIONS: The white linear structure referring to pelvic fascia which covers and surrounds levator hiatus is the "terminal line" of TME. The use of an ultrasonic knife is easier to expose this structure and to guarantee the quality of TME. PMID- 29130231 TI - [Effect of postoperative hyperglycemia on clinical outcome of gastrointestinal fistula patients undergoing gastrointestinal reconstruction]. AB - OBJECTIVE: To investigate the effect of hyperglycemia within postoperative 48 hours on gastrointestinal (GI) fistula patients without preoperative diagnosis of diabetes undergoing selective GI reconstruction. METHODS: Clinical data of GI fistula patients with age of 18 to 70 years and without diffuse peritonitis and systemic infection undergoing definitive GI reconstruction at Intestinal Fistula Center of Jinling Hospital from September 2012 to December 2015 were retrospectively analyzed. According to the highest blood glucose (BG) value detected within postoperative 48 hours, patients were divided into normoglycemia (BG<6.9 mmol/L), mild hyperglycemia (6.9 to 11.4 mmol/L) and severe hyperglycemia (BG>=11.5 mmol/L) groups. Clinical manifestations were compared among three groups. Effects of postoperative hyperglycemia on associated parameters, including postoperative surgical site infection, anastomotic leakage, intestinal nutrition recovery, hospital stay and hospitalization cost were investigated. RESULTS: A total of 314 patients were enrolled, of whom postoperative gastric fistula occurred in 6 cases, small intestinal fistula in 95 cases, ileocolonic anastomotic fistula in 116, and colorectal fistula in 97 cases. One hundred and ninety-three (61.5%) patients experienced hyperglycemia, including 148 cases of mild hyperglycemia group and 45 cases of severe hyperglycemia group, the other 121 cases were of normoglycemia group. There were no significant differences in gender, BMI, ratio of smoking, ratio of alcohol user and primary diseases among 3 groups (all P>0.05). Older patients were vulnerable to postoperative hyperglycemia and patients who developed hyperglycemia were also prone to have increased ASA score (all P=0.000). Hyperglycemia patients had significantly higher ratio of postoperative ileocolonic anastomotic fistula (mild hyperglycemia group: 40.5%, 60/148; severe hyperglycemia group: 44.4%, 20/45) than normoglycemia cases (29.8%,36/121). Compared to normoglycemia group, ratio of intra-operative transfusion case was higher (P=0.001), operative time was longer (P=0.026), ratio of number of anastomosis >2 was higher (P=0.001), ratio of receiving laparoscopic-assisted operation was lower (P=0.005), ratio of postoperative surgical site infection was higher (P=0.006), incidence of anastomotic leakage was higher (P=0.004), ratio of re-operation was higher (P=0.004), intestinal nutrition recovery time was longer (P=0.001), ICU stay was longer (P=0.001), total hospitalization time was longer (P=0.000) and hospitalization cost was more expensive (P=0.000) in both two hyperglycemia groups. Multivariate regression analysis showed that mild hyperglycemia and severe hyperglycemia were independent risk factors to predict surgical site infection (OR=1.99, 95%CI: 1.12 to 3.54, P=0.019; OR=3.02, 95%CI: 1.36 to 6.70, P=0.007) and anastomotic leakage (OR=7.59, 95%CI: 1.68 to 34.34, P=0.009; OR=13.4, 95%CI: 2.50 to 71.65, P=0.002). Multivariate linear regression analysis indicated that intestinal recovery time of normoglycemia group was 2 days shorter and 3 days shorter, and hospitalization time of normoglycemia group was 2 days shorter and 10 days shorter as compared with mild hyperglycemia and severe hyperglycemia group, respectively. CONCLUSIONS: Elevated postoperative BG is common in GI fistula patients receiving selective GI reconstruction. Postoperative hyperglycemia is significantly associated with surgical site infection, anastomotic leakage and prolonged intestinal recovery. BG control treatment should be recommended for those patients with postoperative hyperglycemia. PMID- 29130232 TI - [Clinical study of preserving left colic artery during laparoscopic total mesorectal excision for the treatment of rectal cancer]. AB - OBJECTIVE: To evaluate the feasibility, safety, radicality and short-term outcome of preserving left colic artery (LCA) during laparoscopic total mesorectal excision (TME) for the treatment of rectal cancer. METHODS: From January 2013 to December 2016,136 patients with mid-lower rectal cancer received laparoscopic TME in the Gastrointestinal Surgery Department of Taizhou People's Hospital of Jiangsu Province. Patients with rectal tumor within 10 cm to the anal verge were enrolled into the study. All the enrolled patients had complete data of pathology and follow-up. Those receiving neoadjuvant chemoradiotherapy, with severe base diseases, multifocal tumor, tumor invasion of surrounding tissues, fixation of tumor, recurrent tumor, complications such as acute ileus, bleeding, perforation were excluded. In this study, 72 patients did not undergo preservation of LCA (high ligation group) and 64 patients underwent preservation of LCA (low ligation group). Operative parameters, clinicopathological data and short-term outcome were collected and compared between two groups. RESULTS: The baseline data including gender, age, body mass index, tumor stage, and distance of tumor from anal verge of two groups were comparable (P>0.05). The differences between two groups about the mean time of operation and the operative blood loss were not significant [(164.0+/-12.6) min vs. (167.3+/-9.4) min, (30.0+/-3.6) ml vs. (30.1+/-3.0) ml, all P>0.05]. There was no operative death in both groups. Differences in the lymph node dissection (13.7+/-2.6 vs. 13.3+/-2.1) and the specimen length of proximal resection margin [(16.4+/-1.9) cm vs. (16.7+/-2.1) cm] or distal resection margins [(3.9+/-0.6) cm vs. (4.1+/-0.9) cm] between high and low ligation groups were not significant (all P>0.05). Compared with high ligation group, the low ligation group had higher rate of sphincter preservation [92.2% (59/64) vs. 79.2% (57/72), chi2=4.580, P=0.032], lower rate of anastomotic leakage [1.6% (1/64) vs. 9.7% (7/72), chi2=4.075, P=0.044], anastomotic stenosis [3.1% (2/64) vs. 12.5%(9/72), chi2=4.006, P=0.045], and voiding and sexual dysfunction [6.3%(4/64) vs. 18.1%(13/72), chi2=4.317, P=0.038]. Mean time of follow-up was 19 months. In high ligation group, the local recurrent rate was 5.56%, distant metastasis rate was 13.89%, overall survival rate was 90.28%, disease-free survival rate was 80.56%, while in low ligation group, the local recurrence rate was 4.69%, distant metastasis rate was 12.50%, overall survival rate was 90.63%, disease-free survival rate was 82.81%, whose differences between two groups were not significant (all P>0.05). CONCLUSION: Preservation of LCA during laparoscopic TME for the treatment of rectal cancer is safe and feasible, which can reduce the incidence of anastomotic leakage and stenosis, and voiding and sexual dysfunction. PMID- 29130233 TI - [Clinical features and prognosis analysis of 21 gastric cancer patients with pathological complete response after neoadjuvant chemotherapy]. AB - OBJECTIVE: To evaluate the clinical features and prognosis of gastric cancer patients with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). METHODS: Clinical data of 159 gastric cancer patients who received NAC followed by surgical resection between January 2012 and December 2014 at the Affiliated Tumor Hospital of Zhengzhou University were collected and clinical features of those with pCR were analyzed retrospectively. Kaplan-Meier method was used to estimate 3-year overall survival (OS) rate and recurrence-free survival (RFS) rate. Recurrence factors were analyzed by univariate and multivariate analysis with Cox proportional hazard model. RESULTS: A total of 21 patients(13.2%) achieved pCR, including 13 male and 8 female cases, with the median age at diagnosis of 56 (40 to 70) years. Eleven cases were differentiated tumor and 10 were undifferentiated. Six cases were in clinical baseline stage II(, and 15 were in III(. Five cases received the mFOLFOX6 (oxaliplatin + leucovorin +5-FU), 6 received the SOX (oxaliplatin +S-1), 4 received the XELOX (oxaliplatin + capecitabine), 2 received the EOX (epirubicin + oxaliplatin +capecitabine) and 4 received the DOX (docetaxel + oxaliplatin +capecitabine) chemotherapy regimens. Two cases achieved CR, 18 achieved PR, and 1 was SD after NAC. The median (range) course of preoperative and postoperative chemotherapy were 4(2 to 5) and 2(0 to 5) . All the patients underwent R0 resection plus D2 lymphadenectomy, and 4 cases were performed with proximal gastrectomy, 3 cases were performed with distal gastrectomy, 13 cases were performed with total gastrectomy, and one case was performed with total gastrectomy plus pancreatic splenectomy. Pneumonia, abdominal bleeding and infection, anastomotic leakage, and gastroplegia occurred respectively in one case, who all were cured by conservative treatment. The median follow-up of the survivors was 39.3 (range 22.7 to 56.9) months. Three cases died of recurrence: 1 case in the liver, 1 in the lung, and 1 in the brain. Two cases developed recurrence and survived: 1 in the liver and 1 in celiac lymph nodes. The overall survival and 3-year recurrence free survival rates were 90.2%(95%CI: 100 to 77.3) and 90.5%(95%CI: 100 to 78.0). Fourteen cases did not complete scheduled chemotherapy course, and the overall 3 year survival rate was 85.1%. Older age(>50 years old)(P=0.028, RR=0.063, 95%CI: 0.005 to 0.743) and no postoperative complication (P=0.023, RR=0.065, 95%CI: 0.006 to 0.689) were identified as independent prognostic factors with Cox multivariate analysis. CONCLUSION: Patients diagnosed as gastric cancer with pCR after NAC have good prognosis, but the pCR ratio is low, and those with younger age and more postoperative complications may have higher risk for recurrence and metastasis. PMID- 29130234 TI - [Expression of acetyl coenzyme A synthetase 2 in colorectal cancer and its biological role]. AB - OBJECTIVE: To investigate the expression of acetyl coenzyme A synthetase short chain family member 2 (ACSS2) in patients with colorectal cancer (CRC) and its biological role. METHODS: A total of 74 CRC tissue samples and 40 normal colorectal tissues were tested by immunohistochemical staining to detect the expression of ACSS2 (cell staining intensity score: 0 points: without staining, 1 points: weak staining, 2 points: intensity staining, 3 point: strong staining; the percentage of positive cells in tumor or negative score: 0 points: negative, 1 point: <25% positive cells, 2 points: 25%-50% positive cells, 3 points: 50%-75% positive cells, 4 points: >75% positive cells. The product of above two scores was the final score.). Association of ACSS2 expression with clinicopathological characteristics was analyzed. Small interfering RNA (siRNA, including A and B group) was used to knock down the expression of ACSS2 in colorectal cell lines (Lovo, HCT116) and their proliferation, migration and epithelial-mesenchymal transition (E-cadherin and Snail as markers) after knocking down were observed. RESULTS: The expression of ACSS2 was significant higher in CRC tissue than that in normal colorectal tissue (tumor average score 6.284, normal tissue average score 3.625, P<0.01) and the percentage of positive cell was higher than that in normal tissue (tumor 69.9%, normal tissue 45.1%, P=0.000). The use of ACSS2 siRNA successfully knocked down the expression of ACSS2 in Lovo and HCT116 cells. A mild suppression of cell proliferation was observed 5 days after planked (A450 value: Lovo-NC 1.758+/-0.041, Lovo-ACSS2-siA 1.485+/-10.026, Lovo-ACSS2-siB 1.371+/-0.049; HCT116-NC 2.609+/-0.038, HCT116-ACSS2-siA 2.260+/-0.042, HCT116 ACSS2-siB 2.295+/-0.029). While a remarkable ability decline of cell migration was found (Lovo-NC 225+/-5/field, Lovo-ACSS2-siA 40+/-5/field, Lovo-ACSS2-siB 79+/-3/field; HCT116-NC 198+/-7/field, HCT116-ACSS2-siA 96+/-7/field, HCT116 ACSS2-siB 77+/-9/field, P<0.05). Real-time quantitative PCR detection showed that in Lovo cells, expression of E-cadherin up-regulated and expression of Snail down regulated, while in HCT116 cells, E-cadherin up-regulated slightly [E-cadherin: Lovo NC 1.000+/-0.211, Lovo-siA 3.403+/-0.207, Lovo-siB 2.658+/-0.420 (P<0.05); HCT116 NC 1.000+/-0.121, HCT116-siA 1.349+/-0.197, HCT116-siB 1.528+/ 0.147(P>0.05); Snail: Lovo NC 1.000+/-0.085, Lovo-siA 0.468+/-0.030, Lovo-siB 0.499+/-0.088 (P<0.05); HCT116 NC 1.000+/-0.118, HCT116-siA 0.265+/-0.020, HCT116 siB 0.194+/-0.017 (P<0.05)]. CONCLUSION: CRC tissues have high expression of ACSS2, which may be associated with cell migration and epithelial-mesenchymal transition. PMID- 29130235 TI - [A meta-analysis on risk factors of postoperative perineal wound complications after abdominoperineal resection for rectal cancer]. AB - OBJECTIVE: To investigate the risk factors of postoperative perineal wound complications after abdominoperineal resection for rectal cancer. METHODS: The databases of Medline, Embase, Web of Science, Ovid, Cochrane Library, CBM, CNKI, VIP and WANFANG were searched for the studies of abdominoperineal resection up to October 2016. The quality of the included studies was assessed by using "Cochrane collaboration's tool for assessing risk of bias" and "the Newcastle-Ottawa Scale". The meta-analyses were performed with Review Manager 4.3 software. RESULTS: Eight randomized controlled trials and 33 non-randomized controlled trials with 15 287 patients were enrolled. Meta-analyses showed that neoadjuvant radiotherapy (OR=2.55, 95%CI: 1.66 to 3.93, P<0.01) and obesity (OR=2.12, 95%CI: 1.05 to 4.26, P=0.04) significantly increased the morbidity of perineal wound complication after abdominoperineal resection for rectal cancer; omentoplasty(OR=0.30, 95%CI: 0.14 to 0.67, P=0.003), presacral space clysis (OR=0.11, 95%CI: 0.01 to 0.94, P=0.04), abdominal drainage (OR=0.36, 95%CI: 0.21 to 0.63, P<0.01), perineal skin drainage(OR=41.72, 95%CI: 2.39 to 727.90, P=0.01) and local application of antibiotics (OR=0.17,95%CI: 0.07 to 0.40, P<0.01) significantly decreased the morbidity of perineal wound complication; however, extralevator abdominoperineal excision (OR=0.88, 95%CI: 0.57 to 1.35, P=0.56), laparoscopic procedure (OR=1.02, 95%CI: 0.47 to 2.21, P=0.96), biologic mesh reconstruction (OR=1.81, 95%CI: 0.95 to 3.46, P=0.07), myocutaneous flap reconstruction (OR=1.32, 95%CI: 0.18 to 9.91, P=0.79) and negative pressure drainage(OR=0.69, 95%CI: 0.35 to 1.34, P=0.27) had no influence on the healing of perineal wound. CONCLUSIONS: Numerous factors can affect the occurrence of perineal wound complication after abdominoperineal resection for rectal cancer. Due to the limitations of enrolled studies, multicenter large scale and high quality randomized controlled trials are required to validate the current results. PMID- 29130236 TI - [Occurrence, diagnosis and treatment of de novo gastrointestinal malignancies after organ transplantation]. AB - With the continuous use of immunosuppressive agents routinely, the long-term survival rate of organ transplant recipients has been incessantly improved. However, the risk of de novo malignancies is also increasing, which has become the second cause of death after organ transplantation. De novo gastrointestinal malignancies are common after liver or kidney transplantation, mostly with advanced stage when diagnosed and poor prognosis. There is a significant trend in the development of de novo malignancies in transplant recipients, which is probably related to factors, including direct or indirect effects of immunosuppressive agents, precancerosis and survival time of transplanted grafts and recipients. Long-term postoperative use of immunosuppressive agents can keep the recipient's immune system in the inhibitory state, which provides the conditions for tumor cells to escape immune surveillance and to proliferate. In addition, some immunosuppressive agents [such as calcium phosphatase inhibitor (CNI)] are carcinogenic and the use of anti-tumor combined with immunosuppressive drugs can be considered [such as mycophenolate mofetil (MMF), mammalian rapamycin target protein (mTOR) inhibitors]. De novo gastrointestinal malignancy has no specific clinical manifestations. It is suggested that the recipients need to strictly comply with the follow-up time, avoid exposure to carcinogens, treat the precancerosis positively and have a medical examination carefully. At present, there are no literatures and guidelines about a standard treatment for de novo gastrointestinal malignancies after transplantation. The primary treatment of de novo malignancies should be adjusting the dosage of immunosuppressive agents to ensure that their minimum dose can effectively maintain the graft function. For patients with stable postoperative organ function and without acute or chronic rejection, the dosage of immunosuppressive agents can be reduced gradually to avoid an excessive immunosuppressive effect. Thereafter, the incidence of de novo malignancies is reduced to a minimum. Minimization of using CNI as soon as possible after transplantation has been widely recognized, and CNI plus mTOR inhibitor or MMF has become a relatively reasonable method. PMID- 29130237 TI - In situ forming oxidised hyaluronic acid/adipic acid dihydrazide hydrogel for prevention of epidural fibrosis after laminectomy. AB - Post-operative epidural fibrosis is a biological response after laminectomy that may lead to clinical symptoms, such as radicular pain. An ideal material for prevention of epidural fibrosis should be able to inhibit fibroblast adhesions and reduce formation of scar tissue. An injectable hydrogel would be the material of choice for this purpose, since it could fill an irregular surgical defect completely, gelate in situ and be delivered in a minimally-invasive manner. The objective of this study was to evaluate, in vitro and in vivo, the cytocompatibility and anti-adhesive effect of an oxidised hyaluronic acid/adipic acid dihydrazide (oxi-HA/ADH) hydrogel. Different cell types present in the spine were used to test the cytocompatibility of the hydrogel. The hydrogel extraction medium had no deleterious effects on neural cells (PC-12), but reduced fibroblasts viability (NIH/3T3). Although the hydrogel did not change the release of lactate dehydrogenase from myoblasts (C2C12) and Schwann cells (RSC96), the extraction medium concentration slightly affected the mitochondrial activity of these two cell types. qPCR showed that the hydrogel down-regulated S100a and P4hb expression in NIH/3T3 cells, supporting the hypothesis that the hydrogel might inhibit fibroblast activity. The animal study showed a reduction of scar tissue formation as well as severity of adhesion between scar tissue and the dura mater in a rat laminectomy model. Superficially, the peel-off test showed significantly decreased tenacity. In conclusion, the oxi-HA/ADH hydrogel is a promising injectable and thermosensitive material for prevention of post-operative epidural fibrosis. PMID- 29130239 TI - Fifty-Seventh Annual Meeting of the Society for Psychophysiological Research The Hofburg, Vienna, Austria October 11-15, 2017 Website: www.sprweb.org. PMID- 29130240 TI - VI: ACADEMIC FUNCTIONING. PMID- 29130238 TI - Society for Psychophysiological Research, Abstracts for the Fifty-Seventh Annual Meeting, The Hofburg, Vienna, Austria, October 11-15, 2017. PMID- 29130241 TI - ISSUE INFORMATION - CURRENT MONOGRAPHS LISTING. PMID- 29130242 TI - X: INTEGRATIVE SUMMARY. PMID- 29130243 TI - III: PRELIMINARY ANALYSES AND ANALYTIC PLAN. PMID- 29130246 TI - IX: PEER CHARACTERISTICS. PMID- 29130247 TI - II: METHOD. PMID- 29130244 TI - V: R/E IDENTITY AND DISCRIMINATION. PMID- 29130248 TI - COMMENTARY ON "MOVING THROUGH ADOLESCENCE: DEVELOPMENTAL TRAJECTORIES OF AFRICAN AMERICAN AND EUROPEAN AMERICAN YOUTH". AB - This commentary discusses Gutman et al.'s monograph on developmental trajectories of African American and European American youth. Conceptual and methodological strengths of the monograph are highlighted, and the historical context of the study, including societal and technological changes that have altered the experience of adolescence and advances in developmental science that have occurred since the MADICS was conducted, are discussed. Finally, several suggestions are offered for ways Gutman et al.'s analyses could be elaborated to address further questions about adolescent development in context. PMID- 29130249 TI - IV: PSYCHOLOGICAL WELL-BEING. PMID- 29130251 TI - VIII: FAMILY CHARACTERISTICS. PMID- 29130257 TI - 27th congress of the European Childhood Obesity Group, ECOG abstracts in 2017, 15 17 November 2017, Rome, Italy. PMID- 29130252 TI - I. INTRODUCTION: MOVING THROUGH ADOLESCENCE: DEVELOPMENTAL TRAJECTORIES OF AFRICAN AMERICAN AND EUROPEAN AMERICAN YOUTH. AB - In this monograph, we investigate the developmental trajectories of a predominantly middle-class, community-based sample of European American and African American adolescents growing up in urban, suburban, and rural areas in Maryland, United States. Within risk-protection and positive youth development frameworks, we selected developmental measures based on the normative tasks of adolescence and the most widely studied indicators in the three major contexts of development: families, peer groups, and schools. Using hierarchical linear growth models, we estimated adolescents' growth trajectories from ages 12 to 20 with variation accounted for by socioeconomic status (SES), gender, race/ethnicity, and the gender by race/ethnicity interaction. In general, the results indicate that: (a) periods of greatest risk and positive development depended on the time frame and outcome being examined and (b) on average, these adolescents demonstrated much stronger evidence of positive than problematic development, even at their most vulnerable times. Absolute levels of their engagement in healthy behaviors, supportive relationships with parents and friends, and positive self-perceptions and psychological well-being were much higher than their reported angry and depressive feelings, engagement in risky behaviors, and negative relationships with parents and peers. We did not find evidence to support the idea that adolescence is a time of heightened risk. Rather, on average, these adolescents experienced relatively stable and developmentally healthy trajectories for a wide range of characteristics, behaviors, and relationships, with slight increases or decreases at different points in development that varied according to domain. Developmental trajectories differed minimally by SES but in some expected ways by gender and race/ethnicity, although these latter differences were not very marked. Overall, most of the young people navigated through their adolescence and arrived at young adulthood with good mental and physical health, positive relationships with their parents and peers, and high aspirations and expectations for what their future lives might hold. PMID- 29130255 TI - VII: PROBLEM BEHAVIORS. PMID- 29130258 TI - Letter from the Editor. PMID- 29130259 TI - Research ethics and the Zika legacy in Brazil. PMID- 29130261 TI - Localising the 'ethical' in stem cell science: Case studies from Asia, North America and Europe. PMID- 29130262 TI - Zika, contraception and the non-identity problem. AB - The 2016 outbreak of the Zika arbovirus was associated with large numbers of cases of the newly-recognised Congenital Zika Syndrome (CZS). This novel teratogenic epidemic raises significant ethical and practical issues. Many of these arise from strategies used to avoid cases of CZS, with contraception in particular being one proposed strategy that is atypical in epidemic control. Using contraception to reduce the burden of CZS has an ethical complication: interventions that impact the timing of conception alter which people will exist in the future. This so-called 'non-identity problem' potentially has significant social justice implications for evaluating contraception, that may affect our prioritisation of interventions to tackle Zika. This paper combines ethical analysis of the non-identity problem with empirical data from a novel survey about the general public's moral intuitions. The ethical analysis examines different perspectives on the non-identity problem, and their implications for using contraception in response to Zika. The empirical section reports the results of an online survey of 93 members of the US general public exploring their intuitions about the non-identity problem in the context of the Zika epidemic. Respondents indicated a general preference for a person-affecting intervention (mosquito control) over an impersonal intervention (contraception). However, their responses did not appear to be strongly influenced by the non identity problem. Despite its potential philosophical significance, we conclude from both theoretical considerations and analysis of the attitudes of the community that the non-identity problem should not affect how we prioritise contraception relative to other interventions to avoid CZS. PMID- 29130263 TI - Public Health Spending and Medicare Resource Use: A Longitudinal Analysis of U.S. Communities. AB - OBJECTIVE: To examine whether local expenditures for public health activities influence area-level medical spending for Medicare beneficiaries. DATA SOURCES AND SETTING: Six census surveys of the nation's 2,900 local public health agencies were conducted between 1993 and 2013, linked with contemporaneous information on population demographics, socioeconomic characteristics, and area level Medicare spending estimates from the Dartmouth Atlas of Health Care. DATA COLLECTION/EXTRACTION: Measures derive from agency survey data and aggregated Medicare claims. STUDY DESIGN: A longitudinal cohort design follows the geographic areas served by local public health agencies. Multivariate, fixed effects, and instrumental-variables regression models estimate how area-level Medicare spending changes in response to shifts in local public health spending, controlling for observed and unmeasured confounders. PRINCIPAL FINDINGS: A 10 percent increase in local public health spending per capita was associated with 0.8 percent reduction in adjusted Medicare expenditures per person after 1 year (p < .01) and a 1.1 percent reduction after 5 years (p < .05). Estimated Medicare spending offsets were larger in communities with higher rates of poverty, lower health insurance coverage, and health professional shortages. CONCLUSIONS: Expanded financing for public health activities may provide an effective way of constraining Medicare spending, particularly in low-resource communities. PMID- 29130264 TI - The Economic Cost of Communicable Disease Surveillance in Local Public Health Agencies. AB - OBJECTIVE: We identify economic costs associated with communicable disease (CD) monitoring/surveillance in Colorado local public health agencies and identify possible economies of scale. DATA SOURCES/STUDY SETTING: Data were collected via a survey of local public health employees engaged in CD work. Survey respondents logged time spent on CD surveillance for 2-week periods in the spring of 2014 and fall of 2014. Forty-three of the 54 local public health agencies in Colorado participated. STUDY DESIGN: We used a microcosting approach. We estimated a statistical cost function using cost as a function of the number of reported investigable diseases during the matched 2-week period. We also controlled for other independent variables, including case mix, characteristics of the agency, the community, and services provided. DATA COLLECTION/EXTRACTION METHODS: Data were collected from a microcosting survey using time logs. PRINCIPAL FINDINGS: Costs increased at a decreasing rate as cases increased, with both cases (beta = 431.5, p < .001) and cases squared (beta = -3.62, p = .05) statistically significant. CONCLUSIONS AND IMPLICATIONS: The results of the model suggest economies of scale. Cost per unit is estimated to be one-third lower for high volume agencies as compared to low-volume agencies. Cost savings could potentially be achieved if smaller agencies shared services. PMID- 29130265 TI - The Economics of Public Health: Missing Pieces to the Puzzle of Health System Reform. AB - The United States continues to experiment with health care delivery and financing innovations, but relatively little attention is given to the public health system and its capacity for improving health status in the U.S. population at large. The public health system operates as a multisector enterprise in which government agencies work in conjunction with private and voluntary organizations to identify health risks in the population and to mobilize community-wide actions that prevent and contain these risks. The Affordable Care Act and related health reform initiatives are generating new interest in the question of how best to expand and integrate public health approaches into the larger U.S. health system. The research articles featured in this issue of Health Services Research cluster around two broad topics: how public health agencies can deliver services efficiently and how public health agencies can interact productively with other elements of the health system. The results suggest promising avenues for aligning medical care and public health practices. PMID- 29130266 TI - School-Based Influenza Vaccination: Health and Economic Impact of Maine's 2009 Influenza Vaccination Program. AB - OBJECTIVE: To estimate the societal economic and health impacts of Maine's school based influenza vaccination (SIV) program during the 2009 A(H1N1) influenza pandemic. DATA SOURCES: Primary and secondary data covering the 2008-09 and 2009 10 influenza seasons. STUDY DESIGN: We estimated weekly monovalent influenza vaccine uptake in Maine and 15 other states, using difference-in-difference-in differences analysis to assess the program's impact on immunization among six age groups. We also developed a health and economic Markov microsimulation model and conducted Monte Carlo sensitivity analysis. DATA COLLECTION: We used national survey data to estimate the impact of the SIV program on vaccine coverage. We used primary data and published studies to develop the microsimulation model. PRINCIPAL FINDINGS: The program was associated with higher immunization among children and lower immunization among adults aged 18-49 years and 65 and older. The program prevented 4,600 influenza infections and generated $4.9 million in net economic benefits. Cost savings from lower adult vaccination accounted for 54 percent of the economic gain. Economic benefits were positive in 98 percent of Monte Carlo simulations. CONCLUSIONS: SIV may be a cost-beneficial approach to increase immunization during pandemics, but programs should be designed to prevent lower immunization among nontargeted groups. PMID- 29130268 TI - Best of the 2017 AcademyHealth Annual Research Meeting. PMID- 29130267 TI - Long-Term Impact of a Postdischarge Community Health Worker Intervention on Health Care Costs in a Safety-Net System. AB - OBJECTIVE: Patient navigators (PNs) may represent a cost-effective strategy to improve transitional care and reduce hospital readmissions. We evaluated the impact of a PN intervention on health system costs in the 180 days after discharge for high-risk patients in a safety-net system. DATA SOURCE/SETTING: Primary and secondary data from an academic safety-net health system. STUDY DESIGN: We compared per-patient utilization and costs, overall and by age, for high-risk, medical service patients randomized to the PN intervention relative to usual care between October 2011 and April 2013. Intervention patients received hospital visits and telephone outreach from PNs for 30 days after every qualifying discharge. DATA COLLECTION/EXTRACTION METHODS: We used administrative and electronic encounter data, and a survey of nurses; costs were imputed from the Medicare fee schedule. PRINCIPAL FINDINGS: Total costs per patient over the 180 days postindex discharge for those aged >=60 years were significantly lower for PN patients compared to controls ($5,676 vs. $7,640, p = .03); differences for patients aged <60 ($9,942 vs. $9,046, p = .58) or for the entire cohort ($7,092 vs. $7,953, p = .27) were not significant. CONCLUSIONS: Patient navigator interventions may be useful strategies for specific groups of patients in safety net systems to improve transitional care while containing costs. PMID- 29130269 TI - Medicare Advantage and Fee-for-Service Performance on Clinical Quality and Patient Experience Measures: Comparisons from Three Large States. AB - OBJECTIVE: To compare performance between Medicare Advantage (MA) and Fee-for Service (FFS) Medicare during a time of policy changes affecting both programs. DATA SOURCES/STUDY SETTING: Performance data for 16 clinical quality measures and 6 patient experience measures for 9.9 million beneficiaries living in California, New York, and Florida. STUDY DESIGN: We compared MA and FFS performance overall, by plan type, and within service areas associated with contracts between CMS and MA organizations. Case mix-adjusted analyses (for measures not typically adjusted) were used to explore the effect of case mix on MA/FFS differences. DATA COLLECTION/EXTRACTION METHODS: Performance measures were submitted by MA organizations, obtained from the nationwide fielding of the Medicare Consumer Assessment of Healthcare Providers and Systems (MCAHPS) Survey, or derived from claims. PRINCIPAL FINDINGS: Overall, MA outperformed FFS on all 16 clinical quality measures. Differences were large for HEDIS measures and small for Part D measures and remained after case mix adjustment. MA enrollees reported better experiences overall, but FFS beneficiaries reported better access to care. Relative to FFS, performance gaps were much wider for HMOs than PPOs. Excluding HEDIS measures, MA/FFS differences were much smaller in contract-level comparisons. CONCLUSIONS: Medicare Advantage/Fee-for-Service differences are often large but vary in important ways across types of measures and contracts. PMID- 29130273 TI - Don't quote me on this, but.... PMID- 29130270 TI - State Prescription Contraception Insurance Mandates: Effects on Unintended Births. AB - OBJECTIVE: To test the effects of state prescription contraception insurance mandates on unintended, mistimed, and unwanted births in a sample of privately insured recent mothers. DATA: We pooled Pregnancy Risk Assessment Monitoring System (PRAMS) data from 1997 to 2012 to study 209,964 privately insured recent mothers in 24 states, 11 of which implemented prescription contraception coverage mandates between 2000 and 2008. STUDY DESIGN: Individual-level difference-in differences models compare the probability of unintended birth among privately insured recent mothers in state-years with mandates to those in state-years without mandates. Additional models use aggregate data to estimate the effect of mandates on states' number of unintended births. PRINCIPAL FINDINGS: State mandates are associated with decreased probability of unintended birth (1.58 percentage points) among privately insured women in the second year of implementation, driven by decreased probability of mistimed birth (1.37 percentage points or 614 births per state-year) in the second year of implementation. We find no effects in the first year of implementation or on the probability of unwanted birth. Unexpectedly, recent mothers without private insurance experienced declines in unintended birth, but among unwanted, rather than mistimed, births. CONCLUSIONS: State prescription contraception insurance mandates are associated with reduced probability of unintended and mistimed births among privately insured women. PMID- 29130274 TI - Rescue oxygenation in small infants. PMID- 29130271 TI - The Impact of State Medical Malpractice Reform on Individual-Level Health Care Expenditures. AB - BACKGROUND: Past studies of the impact of state-level medical malpractice reforms on health spending produced mixed findings. Particularly salient is the evidence gap concerning the effect of different types of malpractice reform. This study aims to fill the gap. It extends the literature by examining the general population, not a subgroup or a specific health condition, and controlling for individual-level sociodemographic and health status. METHODS: We merged the Database of State Tort Law Reforms with the Medical Expenditure Panel Survey between 1996 and 2012. We took a difference-in-differences approach to specify a two-part model for analyzing individual-level health spending. We applied the recycled prediction method and the bootstrapping technique to examining the difference in health spending growth between states with and without a reform. All expenditures were converted to 2010 U.S. dollars. RESULTS: Only two of the 10 major state-level malpractice reforms had significant impacts on the growth of individual-level health expenditures. The average annual expenditures in states with caps on attorney contingency fees increased less than that in states without the reform (p < .05). Compared with states with traditional contributory negligence rule, the average annual expenditures increased more in both states with a pure comparative fault reform (p < .05) and states with a comparative fault reform that barred recovery if the plaintiff's fault was equal to or greater than the defendant's (p < .05). CONCLUSIONS: A few state-level malpractice reforms had significantly affected the growth of individual-level health spending, and the direction and magnitude of the effects differed by type of reform. PMID- 29130275 TI - Feng shui And Emotional Response in the Critical care Environment (FARCE) study. AB - The aim of this study was to investigate the relationship between nursing staff emotions and their surrounding environment, using the ancient system of feng shui. Two orientations of critical care bed spaces (wind and water groups, respectively) were mapped using a western bagua. Energy or 'chi' scores for nine emotions were calculated based on the positive or negative flow of chi in each of the two groups. During a two-week period, nursing staff were allocated to work in a bed space in either the wind or water groups; nursing staff who were not allocated to a study bed space acted as a control group. Participating nursing staff completed a questionnaire, ranking nine emotional states and their overall inner harmony, using a 11-point chi scale. In total, 108 questionnaires were completed. Critical bed space orientation according to feng shui principles was not related to nurse-reported chi scores or inner harmony (p > 0.05 for all measurements). There was also poor correlation between the bagua-predicted and reported chi scores for both the wind and water groups (R2 = 0.338 and 0.093, respectively). The use of feng shui to guide the layout of critical care bed spaces does not improve the emotional well-being of nursing staff. PMID- 29130272 TI - Effects of Guideline and Formulary Changes on Statin Prescribing in the Veterans Affairs. AB - OBJECTIVE: To compare the effects of two sequential policy changes-the addition of a high-potency statin to the Department of Veterans Affairs (VA) formulary and the release of the American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines-on VA provider prescribing. DATA SOURCES/STUDY SETTING: Retrospective analysis of 1,100,682 VA patients, 2011-2016. STUDY DESIGN: Interrupted time-series analysis of changes in prescribing of moderate-to high-intensity statins among high-risk patients and across high-risk subgroups. We also assessed changes in prescribing of atorvastatin and other statin drugs. We estimated marginal effects (ME) of formulary and guideline changes by comparing predicted and observed statin use. DATA COLLECTION/EXTRACTION METHODS: Data from VA Corporate Data Warehouse. PRINCIPAL FINDINGS: The use of moderate-to high-intensity statins increased by 2 percentage points following the formulary change (ME, 2.4, 95% confidence interval [CI], 2.2 to 2.6) and less than 1 percentage point following the guideline change (ME, 0.8, 95% CI, 0.6 to 0.9). The formulary change led to approximately a 12 percentage-point increase in the use of moderate-to-high-intensity atorvastatin (ME, 11.5, 95% CI, 11.3 to 11.6). The relatively greater provider response to the formulary change occurred across all patient subgroups. CONCLUSIONS: Addition of a high-potency statin to formulary affected provider prescribing more than the ACC/AHA guidelines. PMID- 29130276 TI - Trainee fatigue - time for a culture change? A reply. PMID- 29130277 TI - MTP block and paravertebral spread. PMID- 29130278 TI - Neuromuscular monitoring and the cost of antagonism: when will we learn? PMID- 29130279 TI - Recognising obstructive sleep apnoea in pregnancy - a survey of UK obstetric anaesthetists. PMID- 29130280 TI - Comparing times in clinical studies with a finite ending. PMID- 29130281 TI - An unusual failure of sevoflurane QuikFil PEN bottles. PMID- 29130282 TI - MTP block anatomy. PMID- 29130283 TI - Trainee fatigue - time for a culture change? PMID- 29130284 TI - The 'cost' of sugammadex. PMID- 29130285 TI - Neuromuscular monitoring and the cost of antagonism: when will we learn? A reply. PMID- 29130286 TI - What is the real oximeter gap? PMID- 29130287 TI - MTP block anatomy and paravertebral spread - a reply. PMID- 29130288 TI - Optimising early neonatal nutrition using translational research methodology. AB - AIM: Preterm birth has been described as a 'nutritional emergency', with these infants often born with minimal nutrition reserves. Failure to provide adequate early nutrition jeopardises growth and neurodevelopment. Consensual nutrition guidelines exist for infants who weigh <1500 g; however, audits have identified shortfalls in their adherence, consequently highlighting an evidence-practice gap. This work aimed to identify the barriers to the delivery of early optimal nutrition in a tertiary-level Neonatal Critical Care Unit to inform an implementation project to ensure best practice care. METHODS: A total of 19 medical and nursing staff participated in semistructured interviews. Transcripts underwent qualitative content analysis to examine barriers to early infant feeding. Barriers were categorised into domains from the Theoretical Domains Framework (TDF), and potential interventions were identified using evidence-based strategy selection guides that articulates with the TDF. RESULTS: Four main themes, with associated sub-themes, emerged, including: (i) Roles and responsibilities, (ii) decision making, (iii) disconnect between beliefs and the application of evidence and (iv) monitoring and awareness. Eight barrier 'domains' were identified using TDF-Knowledge; memory, attention and decision processes; skills; professional/social role and identity; beliefs about capabilities; beliefs about consequences; environmental context and resources; and social influences. CONCLUSIONS: Using a systematic approach to analysing barriers to early nutrition and mapping through the TDF and behaviour change wheel, the most effective interventions to modify practice have been identified. These will be monitored in ongoing audits. PMID- 29130289 TI - Development and pilot testing of a parent-reported health-related quality of life measure for children on the ketogenic diet: The KetoQoL. AB - AIM: The aim of the present study was to develop a parent-reported tool that will measure health-related quality of life (HRQoL) in children following ketogenic diet (KD) therapies for refractory epilepsy once it has been pilot tested and analysed. METHODS: Parents of children following KD therapies for epilepsy were recruited through a public hospital in Queensland, Australia, in 2012 and 2014. Qualitative semistructured interviews were conducted in 2012 with 13 parents who described changes seen in their child's HRQoL while on the KD. A quality of life tool (QoL) was developed by adapting the Quality of Life in Childhood Epilepsy tool based on results and themes analysed from the interviews. The KetoQoL was pilot tested with 18 parents recruited in 2014. Interrelationships between variables and questions were explored with exploratory factor analysis (EFA) to determine which questions had the greatest effect on QoL. RESULTS: The first iteration of the KetoQoL consisted of five main domains: physical, cognitive, social, intrapersonal and effects on the family. The domains were subdivided into 18 variables, totalling 54 items. EFA demonstrated that items from the physical and effects on the family domains had the greatest effect on QoL. CONCLUSIONS: KetoQoL is an HRQoL tool developed using a range of methods and assessed for both face and content validity. Further testing of KetoQoL is required to refine and confirm the factors. This work will enhance the evaluation of treatment effectiveness in children with epilepsy following the KD. PMID- 29130291 TI - Exploring nutrition capacity in Australia's charitable food sector. AB - AIM: The primary aim of this study was to explore the capacity of community organisations within Australia's charitable food sector to provide nutritious food to people experiencing food insecurity. A secondary aim was to explore their capacity to provide food in an environment that encourages social interaction. METHODS: This qualitative research used an exploratory case study design and was informed by a nutrition capacity framework. Participants were recruited through SecondBite, a not-for-profit food rescue organisation in Australia. Convenience sampling methods were used. Semi-structured interviews were conducted to explore the knowledge, attitudes and experiences of people actively involved in emergency food relief provision. Transcripts were thematically analysed using an open coding technique. RESULTS: Nine interviews were conducted. The majority of participants were female (n = 7, 77.8%) and worked or volunteered at organisations within Victoria (n = 7, 77.8%). Results suggest that the capacity for community organisations to provide nutritious food to their clients may be limited by resource availability more so than the nutrition-related knowledge and attitudes of staff members and volunteers. CONCLUSIONS: Australia's charitable food sector plays a vital role in addressing the short-term needs of people experiencing food insecurity. To ensure the food provided to people experiencing food insecurity is nutritious and provided in an environment that encourages social interaction, it appears that the charitable food sector requires additional resources. In order to reduce demand for emergency food relief, an integrated policy approach targeting the underlying determinants of food insecurity may be needed. PMID- 29130290 TI - Parent, patient and health professional perspectives regarding enteral nutrition in paediatric oncology. AB - AIM: Enteral tube feeding (ETF) is an important part of treatment for paediatric cancer patients. Without nutritional therapy, the prevalence of under-nutrition during treatment for childhood cancer may be as high as 50%. To ensure that the appropriate initiation of ETF is optimised, information on the views of key stakeholders regarding ETF is needed. METHODS: In total, 48 interviews were conducted with parents of paediatric cancer patients (n = 20), patients (n = 10) and members of the paediatric oncology health-care team (n = 18). Semistructured interviews were used to elicit information from participants, and the data were analysed using a content analysis approach. The interviews focused on views regarding: (i) attitude toward, and impact of, ETF; (ii) information and support regarding ETF; and (iii) clinical management of ETF. RESULTS: There was agreement between stakeholders on the impact of ETF on patients, both positive (good nutrition, weight gain and decreased anxiety) and negative (physical appearance, invasive insertion procedure and comfort). There were discordant perceptions regarding the timing and type of information provided on the use of ETF, as well as the decision-making process used. CONCLUSIONS: By standardising the information given to parents and enhancing understanding of parent, patient and health-care worker perceptions about ETF, the initiation of tube feeding may be optimised. This may positively impact patient outcomes in the future. PMID- 29130292 TI - Scoping study investigating stakeholder perceptions and use of school canteens in an Australian city. AB - AIM: To investigate stakeholder perceptions of healthy food availability in school canteens, the promotion of healthy foods and canteen policy compliance. METHODS: This is a cross-sectional study of Catholic and independent primary and high schools comprising three investigative phases: (i) survey of 39 schools, (ii) survey of canteen managers and parents from 10 schools and (iii) an audit of school menus against National Healthy School Canteen Guidelines. RESULTS: Total participants included: 6 principals, no canteen mangers and 86 parents from two schools; 24 menus were audited. Schools are committed to supporting healthy eating, with participants agreeing canteens should follow the National Health School Canteen Guidelines. A total of 94% of parents (n = 81/86) indicated that their children buy food from the school canteen, with commonly purchased items mostly classified as 'red'. Despite this food choice, parents (n = 32/48) indicated they had a responsibility to encourage healthy eating. No school canteen menu comprised +50% 'green' foods and thus did not comply with the National Healthy School Canteen Guidelines. CONCLUSIONS: Despite the intense focus on school canteens to sell healthy food, little has changed in terms of student's food choices and the barriers to providing healthy options. The external environment and divided parental buy-in impact the canteen's ability to comply with guidelines. A holistic approach involving all stakeholder levels is required to successfully achieve a healthy school canteen environment and positively influence student's food habits and choices. PMID- 29130293 TI - Hand-to-foot bioelectrical impedance analysis to measure fat mass in healthy children: A comparison with air-displacement plethysmography. AB - AIM: To identify children at risk of overweight, assessing children's body composition in a valid way is crucial. The present cross-sectional study examines the comparability of children's fat mass percentage obtained by hand-to-foot bioelectrical impedance analysis (BIA) versus BodPod air-displacement plethysmography as a reference method. METHODS: The body composition of 206 Belgian children (7-13 years; 7.7% overweight) was measured with BodPod and hand to-foot BIA (Tanita BC418 with built-in formula). RESULTS: Overall, comparability was the highest in girls. Good ranking agreement (rho = 0.819) and interchangeability (intra-class correlation (ICC) = 0.757) were found in girls but not in boys (rho = 0.568; ICC = 0.512). Although bioelectrical impedance resulted in an overall overestimation of only 0.5 fat%, it underestimated and overestimated fat% in children with, respectively, higher and lower fat%. The 95% limits of agreement distance was around 17 fat%, and there was a significant difference from the line of identity (intercept ? 0; slope ? 1). CONCLUSIONS: Despite good ranking agreement, the use of BIA as an alternative for the BodPod is not recommended because of over-/underestimation and wide limits of agreement. It is not possible to calculate a simple correction factor for the whole fat% range to make the two approaches interchangeable. PMID- 29130295 TI - Bridging the gap in paediatric nutrition: Dietetic practice research to improve knowledge translation. PMID- 29130294 TI - Food insecurity increases the odds of obesity among Iranian women: A population based study of northwestern Iran. AB - AIM: The main objective of the present study was to evaluate the association between obesity and food security status. The sample comprised of Iranian adults with an age range of 15-64 years. METHODS: In this cross-sectional study (n = 1277), the short form of the Household Food Security Scale was used to determine food security status. Height, weight and waist and hip circumferences were measured, and body mass index, waist-to-hip ratio, waist-to-height ratio and conicity index (CI) were also calculated. One-way analysis of variance and logistic regression were used for statistical analyses. RESULTS: There were no statistically significant differences in the mean anthropometric measurements of males and females with different food security status (P > 0.05). After adjusting for covariates, there was no statistically significant association between food security status and anthropometric measurements in men. However, the low food secure females were 72% more likely to be overweight in comparison with very low food-secure women (P = 0.04). Moreover, food-secure females were 32% less likely to have CI >1.25 compared with very low food-secure females (P = 0.04). CONCLUSIONS: The results showed that there is an association between food insecurity and overweight, which is consistent with the finding of prior researches. In addition, for the first time, we showed the significant association between low food security and CI. PMID- 29130296 TI - Supporting dietitians to work in Aboriginal health: Qualitative evaluation of a Community of Practice mentoring circle. AB - AIM: This paper explores the experience of dietitians participating in a Community of Practice designed to support their work with Aboriginal communities. METHODS: The Community of Practice for dietitians working with Aboriginal communities ran for 12 months, starting in May 2014. Six-weekly mentoring sessions were held using Skype, with conversation aided by a facilitator. In depth, semi-structured interviews were held with all participants at the conclusion of the Community of Practice. Data were analysed using thematic analysis. RESULTS: Thirteen dietitians participated in the Community of Practice and an in-depth, semi-structured interview. Four key themes were identified: (i) Aboriginal health practice requires a different way of 'knowing', 'being' and 'working'; (ii) Community of Practice is a safe place to discuss, debrief and explore ideas that are not safe elsewhere; (iii) participation in Community of Practice contributed to workforce retention in the Aboriginal health sector; and (iv) participation in Community of Practice contributed to dietitians changing their practice and feeling confident to do so. CONCLUSIONS: By increasing confidence and opportunities for safe discussion, Community of Practice appears to be a useful model of Continuing Professional Development to support dietitians working in Aboriginal health. PMID- 29130297 TI - SCIENTISTS and SCIENCE ADVOCATES: Professor David Y. Graham: A Brilliant Scientist and a Compassionate Mentor PMID- 29130298 TI - Role of microRNAs (miRNAs) in the pathophysiology of diabetes mellitus. AB - Diabetes mellitus is becoming the critical problem among the entire world and it is difficult to understand the molecular mechanism representing the concept of diabetic pathology. Recently the knowledge of the involvement of genetics in type 2 diabetes mellitus (T2DM) susceptibility has sketched a great concentration towards the transcriptional activity of beta cells within the pancreas. This disease becomes the leading cause of death, so it is necessary to study the molecular pathogenesis, phenotypes, and characteristics to design the therapeutic parameters. Here in this review role of miRNA is being illustrated as it plays a crucial role in the pathogenesis, progression, and fate of beta cells of pancreas regulating the insulin secretion. Here in this review, we try to include the effects and pathophysiology of various miRNA in diabetes mellitus and on the various sites of the human body. PMID- 29130299 TI - [The role of vitamin D in assisted reproduction techniques]. AB - Vitamin D or calcitriol, which was first identified back in 1920, has a key role in bone metabolism and mineralization, and in calcium and magnesium homeostasis. A nuclear receptor (VDR) mediates vitamin D actions in a lot of organs like bowel, bone, kidney, breast, gonads, pancreas, brain, cardiovascular and immune systems. In all these tissues the 1,25(OH)2D play a fundamental role in reduction of chronic pathologies, in modulation of cellular growth, neuromuscular, immune and inflammation actions. Vitamin D is important in reproduction physiology and in development gynecological and obstetric disorders like polycystic ovarian syndrome, endometriosis, myomatosis, gestational diabetes and preeclampsia. Over the last few years, vitamin D has been suggested to have a role in assisted reproduction techniques. PMID- 29130300 TI - pSite: Amino Acid Confidence Evaluation for Quality Control of De Novo Peptide Sequencing and Modification Site Localization. AB - MS-based de novo peptide sequencing has been improved remarkably with significant development of mass-spectrometry and computational approaches but still lacks quality-control methods. Here we proposed a novel algorithm pSite to evaluate the confidence of each amino acid rather than the full-length peptides obtained by de novo peptide sequencing. A semi-supervised learning approach was used to discriminate correct amino acids from random one; then, an expectation maximization algorithm was used to adaptively control the false amino-acid rate (FAR). On three test data sets, pSite recalled 86% more amino acids on average than PEAKS at the FAR of 5%. pSite also performed superiorly on the modification site localization problem, which is essentially a special case of amino acid confidence evaluation. On three phosphopeptide data sets, at the false localization rate of 1%, the average recall of pSite was 91% while those of Ascore and phosphoRS were 64 and 63%, respectively. pSite covered 98% of Ascore and phosphoRS results and contributed 21% more phosphorylation sites. Further analyses show that the use of distinct fragmentation features in high-resolution MS/MS spectra, such as neutral loss ions, played an important role in improving the precision of pSite. In summary, the effective and universal model together with the extensive use of spectral information makes pSite an excellent quality control tool for both de novo peptide sequencing and modification site localization. PMID- 29130301 TI - Omni-Purpose Stretchable Strain Sensor Based on a Highly Dense Nanocracking Structure for Whole-Body Motion Monitoring. AB - Here, we report an omni-purpose stretchable strain sensor (OPSS sensor) based on a nanocracking structure for monitoring whole-body motions including both joint level and skin-level motions. By controlling and optimizing the nanocracking structure, inspired by the spider sensory system, the OPSS sensor is endowed with both high sensitivity (gauge factor ~ 30) and a wide working range (strain up to 150%) under great linearity (R2 = 0.9814) and fast response time (<30 ms). Furthermore, the fabrication process of the OPSS sensor has advantages of being extremely simple, patternable, integrated circuit-compatible, and reliable in terms of reproducibility. Using the OPSS sensor, we detected various human body motions including both moving of joints and subtle deforming of skin such as pulsation. As specific medical applications of the sensor, we also successfully developed a glove-type hand motion detector and a real-time Morse code communication system for patients with general paralysis. Therefore, considering the outstanding sensing performances, great advantages of the fabrication process, and successful results from a variety of practical applications, we believe that the OPSS sensor is a highly suitable strain sensor for whole-body motion monitoring and has potential for a wide range of applications, such as medical robotics and wearable healthcare devices. PMID- 29130302 TI - A Cell-Mimicking Structure Converting Analog Volume Changes to Digital Colorimetric Output with Molecular Selectivity. AB - We herein report a three-component cell-mimicking structure with a peroxidase like iron oxide nanozyme as the nucleus, a molecularly imprinted hydrogel shell as cytoplasm, and a lipid bilayer membrane. The structure was characterized by cryo and negative stain TEM and also by a calcein leakage test. By introducing charged monomers, the gel shell can swell or shrink in response to salt concentration. By lowering the salt concentration, the gradual "analog" gel volume change was reflected in a switch-like "digital" colorimetric output by the burst of membrane and oxidation of substrates such as 3,3',5,5' tetramethylbenzidine (TMB). Controlled access was also achieved by using melittin to insert channels cross the membrane, and selective molecular transport was realized by the molecularly imprinted gel. The functions of each component are coupled, and this sophisticated tripartite structure provides a new platform for modular design of new materials. Our cell-mimicking structure is functional and it is complementary to the current protocell work that aims to understand the origin of life. PMID- 29130303 TI - Assembly of RGD-Modified Hydrogel Micromodules into Permeable Three-Dimensional Hollow Microtissues Mimicking in Vivo Tissue Structures. AB - Fabricated microscale tissues that replicate in vivo architectures have shown huge potential in regenerative medicine and drug discovery. Owing to the spatial organization of cell-encapsulated hydrogel microstructures, three-dimensional (3D) tissue structures have been broadly applied as novel pathological or pharmacological models. However, the spatial reorganization of arbitrary microstructures with tissue-specific shapes into 3D in vitro microtissues that mimic the physiological morphology and nutrient diffusion of native tissues presents a major challenge. Here, we develop a versatile method that engineers permeable 3D microtissues into tissue-specific microscopic architectures. The customized, arbitrarily shaped hollow micromodules are prepared by photocopolymerizing poly(ethylene glycol) diacrylate (PEGDA) with acryloyl-PEG Arg-Gly-Asp-Ser (RGDS). These micromodules are spatially reorganized and self aligned by a facile assembly process based on hydrodynamic interactions, forming an integrated geometry with tissue-specific morphology and a vessel-mimetic lumen. The RGD linkages create cell-adhesive structures in the PEGDA hydrogel, greatly increasing the long-term cell viability in 3D microtissue cultures. Meanwhile, the mechanical properties for fast cell spreading inside the microstructures can be optimized by modulating the PEGDA concentration. The 3D microtissues, with their different geometries and permeable tubular lumens, maintained cell proliferation over 14 days. The cell viabilities exceeded 98%. We anticipate that our method will regenerate complex tissues with physiological importance in future tissue engineering. PMID- 29130304 TI - Interface-Engineered Charge-Transport Properties in Benzenedithiol Molecular Electronic Junctions via Chemically p-Doped Graphene Electrodes. AB - In this study, we fabricated and characterized vertical molecular junctions consisting of self-assembled monolayers of benzenedithiol (BDT) with a p-doped multilayer graphene electrode. The p-type doping of a graphene film was performed by treating pristine graphene (work function of ~4.40 eV) with trifluoromethanesulfonic (TFMS) acid, producing a significantly increased work function (~5.23 eV). The p-doped graphene-electrode molecular junctions statistically showed an order of magnitude higher current density and a lower charge injection barrier height than those of the pristine graphene-electrode molecular junctions, as a result of interface engineering. This enhancement is due to the increased work function of the TFMS-treated p-doped graphene electrode in the highest occupied molecular orbital-mediated tunneling molecular junctions. The validity of these results was proven by a theoretical analysis based on a coherent transport model that considers asymmetric couplings at the electrode molecule interfaces. PMID- 29130305 TI - Tuning the Sensing Performance of Multilayer Plasmonic Core-Satellite Assemblies for Rapid Detection of Targets from Lysed Cells. AB - Optical sensors based on discrete plasmonic nanostructures are invaluable for probing biomolecular interactions when applied as plasmonic rulers or reconfigurable multinanoparticle assemblies. However, their adaptation as a versatile sensing platform is limited by the research-grade instrumentation required for single-nanostructure imaging and/or spectroscopy and complex data fitting and analysis. Additionally, the dynamic range is often too narrow for the quantitative analysis of targets of interest in biodiagnostics, food safety, or environmental monitoring. Herein we present plasmonic assembly comprising a core nanoparticle surrounded by multiple layers of satellite nanoparticles through aptamer linker. The layer-by-layer assembly of the satellite nanoparticles yields uniform discrete nanoparticle clusters on a substrate with enhanced optical properties. Binding of the model target (adenosine 5'-triphosphate, ATP) induces disassembly and leads to a dramatic decrease in the scattering intensity that can be analyzed readily from darkfield images. We demonstrate that the sensing performance, such as detection limit, dynamic range, and sensitivity, can be tuned by controlling the size of the assembly. The substrate-anchored nanoparticle assemblies are selective to only ATP, and not other adenine containing compounds. By adapting the methodology to a flexible support, cellular ATP can be directly detected by lysing adherent cells in close contact with the plasmonic assemblies-a process that does not require any sample preparation or purification. Enhancing the optical detection signal via designing and engineering nanoparticle assemblies could enable their use with low-cost portable imaging systems and broaden their applicability beyond the study of biomolecular interaction. PMID- 29130306 TI - Evaluating in Vitro Culture Medium of Gut Microbiome with Orthogonal Experimental Design and a Metaproteomics Approach. AB - In vitro culture based approaches are time- and cost-effective solutions for rapidly evaluating the effects of drugs or natural compounds against microbiomes. The nutritional composition of the culture medium is an important determinant for effectively maintaining the gut microbiome in vitro. This study combines orthogonal experimental design and a metaproteomics approach to obtaining functional insights into the effects of different medium components on the microbiome. Our results show that the metaproteomic profile respond differently to medium components, including inorganic salts, bile salts, mucin, and short chain fatty acids. Multifactor analysis of variance further revealed significant main and interaction effects of inorganic salts, bile salts, and mucin on the different functional groups of gut microbial proteins. While a broad regulating effect was observed on basic metabolic pathways, different medium components also showed significant modulations on cell wall, membrane, and envelope biogenesis and cell motility related functions. In particular, flagellar assembly related proteins were significantly responsive to the presence of mucin. This study provides information on the functional influences of medium components on the in vitro growth of microbiome communities and gives insight on the key components that must be considered when selecting and optimizing media for culturing ex vivo microbiotas. PMID- 29130307 TI - Unveiling Mechanism of a Quinine-Squaramide Catalyzed Enantioselective Aza Friedel-Crafts Reaction between Cyclic Trifluoromethyl Ketimine and Naphthol: A DFT Study. AB - A mechanism study of quinine-squaramide catalyzed enantioselective aza-Friedel Crafts (aza-F-C) reaction is described using density functional theory (DFT). The most favorable pathway is obtained through the discussions of four possible modes of hydrogen bond interactions, in which the nucleophile is activated by the squaramide N-H groups (N-Ha and N-Hb) and the electrophile binds to the protonated amine by hydrogen bonding. Meanwhile, we have also studied the energy barrier of the stereocontrolling transition states that might play a role of stereoselectivity. In addition, noncovalent interaction (NCI) analyses show a series of favorable cooperative noncovalent interactions, including N-H...O and C H...F hydrogen-bonding, and pi...pi interactions. The strong interactions and lower barrier were found for TS3R, indicating the preference for the R configuration adduct, which is in good agreement with the experimental observations. PMID- 29130308 TI - Highly Enhanced Light-Outcoupling Efficiency in ITO-Free Organic Light-Emitting Diodes Using Surface Nanostructure Embedded High-Refractive Index Polymers. AB - We develop the high-performance internal light-outcoupling (HRLOC) system based on the high-refractive index polyimide (PI) and metal oxide nanoparticles for organic light-emitting diodes (OLEDs) with silver nanowires (AgNWs). The spontaneously formed nanobump structures, high refractive index, and light scattering properties of HRLOC significantly enhance the light-extraction efficiency of OLEDs. Not only do the outcoupling structures improve the light extraction efficiency, but also remarkably enhance the electrical properties of OLEDs. HRLOC leads to the regular and smooth formation of AgNWs, resulting in the improvement of the electrical properties of devices by preventing electrical shorts and leakage currents. The power efficiency of the AgNW-based OLEDs with PI is improved by a factor of 1.31 compared to the reference device with indium tin oxide (ITO) transparent electrode at a luminance of 20 000 cd/m2. The efficiency is further improved by incorporating TiO2 nanoparticles into the PI matrix by a factor of 1.69. To our knowledge, the optically and electrically enhanced OLEDs show one of the highest enhancement factors reported for ITO-free OLEDs with internal outcoupling structures. In addition, the outcoupling structures are solution processable, thermally stable, and can be scaled up to 200 * 200 mm2 for large-area applications. We believe that the light-outcoupling structures developed here have great potential for efficient, low-cost, and flexible ITO free OLEDs. PMID- 29130309 TI - Impact of Chemical Doping on Optical Responses in Bismuth-Doped CH3NH3PbBr3 Single Crystals: Carrier Lifetime and Photon Recycling. AB - We studied the optical responses of organic-inorganic halide perovskite CH3NH3PbBr3 single crystals doped with heterovalent Bi3+ ions (electron densities up to 2.3 * 1012 cm-3). The Bi doping causes no significant changes in the band gap energy but leads to an enhanced Urbach tail and photoluminescence blue shift. On the basis of the time-resolved photoluminescence measurements, we attribute the PL response to a shorter carrier lifetime induced by Bi doping, which results in a reduced photon recycling effect (i.e., the repeated emission and reabsorption of photons inside the crystal). We discuss the physical relation between Bi concentration and the optical and electric properties of Bi-doped CH3NH3PbBr3 and reveal the unique nature of the Bi3+ ion as a dopant in halide perovskites. PMID- 29130310 TI - 2,1,3-Benzothiadiazole-5,6-dicarboxylicimide-Based Polymer Semiconductors for Organic Thin-Film Transistors and Polymer Solar Cells. AB - A series of polymer semiconductors incorporating 2,1,3-benzothiadiazole-5,6 dicarboxylicimide (BTZI) as strong electron-withdrawing unit and an alkoxy functionalized head-to-head linkage containing bithiophene or bithiazole as highly electron-rich co-unit are designed and synthesized. Because of the strong intramolecular charge transfer characteristics, all three polymers BTZI-TRTOR (P1), BTZI-BTOR (P2), and BTZI-BTzOR (P3) exhibit narrow bandgaps of 1.13, 1.05, and 0.92 eV, respectively, resulting in a very broad absorption ranging from 350 to 1400 nm. The highly electron-deficient 2,1,3-benzothiadiazole-5,6 dicarboxylicimide and alkoxy-functionalized bithiophene (or thiazole) lead to polymers with low-lying lowest unoccupied molecular orbitals (-3.96 to -4.28 eV) and high-lying highest occupied molecular orbitals (-5.01 to -5.20 eV). Hence, P1 and P3 show substantial and balanced ambipolar transport with electron mobilities/hole mobilities of up to 0.86/0.51 and 0.95/0.50 cm2 V-1 s-1, respectively, and polymer P2 containing the strongest donor unit exhibited unipolar p-type performance with an average hole mobility of 0.40 cm2 V-1 s-1 in top-gate/bottom-contact thin-film transistors with gold as the source and drain electrodes. When incorporated into bulk heterojunction polymer solar cells, the narrow bandgap (1.13 eV) polymer P1 shows an encouraging power conversion efficiency of 4.15% with a relatively large open-circuit voltage of 0.69 V, which corresponds to a remarkably small energy loss of 0.44 eV. The power conversion efficiency of P1 is among the highest reported to date with such a small energy loss in polymer:fullerene solar cells. PMID- 29130311 TI - Decoding Apparent Ferroelectricity in Perovskite Nanofibers. AB - Ferroelectric perovskites are an important group of materials underpinning a wide variety of devices ranging from sensors and transducers to nonvolatile memories and photovoltaic cells. Despite the progress in material synthesis, ferroelectric characterization of nanoscale perovskites is still a challenge. Piezoresponse force microscopy (PFM) is one of the most popular tools for probing and manipulating nanostructures to study the ferroelectric properties. However, the interpretation of hysteresis data and alternate signal origins are critical. Here, we use a family of scanning probe microscopy (SPM) techniques to systematically investigate the ferroelectric behavior of electrospun potassium niobate (KNbO3) nanofibers. Band Excitation (BE) SPM scans reveal that PFM signals are dominated by changes in resonant frequency due to rough nanofiber surfaces, rather than the actual local piezoelectric strength. We investigate the bias-induced charge injection properties and electrostatic interactions on the PFM response of the nanofiber using contact mode Kelvin probe force microscopy (cKPFM). Furthermore, the impact of relative humidity on the KNbO3 nanofiber's piezoresponse, switching behavior, and tip-induced charges are explored. The resultant data from BE scans were utilized to estimate the piezoelectric constants of the KNO nanofiber. These observations will provide clarity in studying newly developed ferroelectric nanostructures and unambiguously interpreting the PFM data. PMID- 29130312 TI - Protein S-Nitrosylation: Determinants of Specificity and Enzymatic Regulation of S-Nitrosothiol-Based Signaling. AB - SIGNIFICANCE: Protein S-nitrosylation, the oxidative modification of cysteine by nitric oxide (NO) to form protein S-nitrosothiols (SNOs), mediates redox-based signaling that conveys, in large part, the ubiquitous influence of NO on cellular function. S-nitrosylation regulates protein activity, stability, localization, and protein-protein interactions across myriad physiological processes, and aberrant S-nitrosylation is associated with diverse pathophysiologies. Recent Advances: It is recently recognized that S-nitrosylation endows S-nitroso-protein (SNO-proteins) with S-nitrosylase activity, that is, the potential to trans-S nitrosylate additional proteins, thereby propagating SNO-based signals, analogous to kinase-mediated signaling cascades. In addition, it is increasingly appreciated that cellular S-nitrosylation is governed by dynamically coupled equilibria between SNO-proteins and low-molecular-weight SNOs, which are controlled by a growing set of enzymatic denitrosylases comprising two main classes (high and low molecular weight). S-nitrosylases and denitrosylases, which together control steady-state SNO levels, may be identified with distinct physiology and pathophysiology ranging from cardiovascular and respiratory disorders to neurodegeneration and cancer. CRITICAL ISSUES: The target specificity of protein S-nitrosylation and the stability and reactivity of protein SNOs are determined substantially by enzymatic machinery comprising highly conserved transnitrosylases and denitrosylases. Understanding the differential functionality of SNO-regulatory enzymes is essential, and is amenable to genetic and pharmacological analyses, read out as perturbation of specific equilibria within the SNO circuitry. FUTURE DIRECTIONS: The emerging picture of NO biology entails equilibria among potentially thousands of different SNOs, governed by denitrosylases and nitrosylases. Thus, to elucidate the operation and consequences of S-nitrosylation in cellular contexts, studies should consider the roles of SNO-proteins as both targets and transducers of S nitrosylation, functioning according to enzymatically governed equilibria. Antioxid. Redox Signal. 00, 000-000. PMID- 29130313 TI - The Role of Biomarkers in Research on Caregivers for Cancer Patients: A Scoping Review. AB - BACKGROUND: Biomarkers can be used as prognostic, predictive, or monitoring indicators of an associated outcome. The purpose of this review was to provide a comprehensive summary of the research examining the use of biomarkers as surrogate end points for clinical outcomes in family caregivers for cancer patients, identify gaps, and make recommendations for future research. METHODS: A scoping review, a process of mapping the existing literature, was conducted. Studies comparing biomarkers across caregivers and controls and/or examining relationships between biomarkers and psychological health were reviewed. RESULTS: The studies ( N = 18) of caregivers for cancer patients who were identified used biomarkers to predict outcomes ( n = 13) and to monitor the efficacy of interventions ( n = 6). Biomarkers were divided into two categories based on physiological systems involved: (1) neuroendocrine function (sympathetic-adrenal medullary axis activity, hypothalamic-pituitary-adrenal axis activity) and (2) immune function. Predictive biomarkers were sensitive to differences between caregivers and controls. The biomarkers were used to evaluate outcomes frequently associated with stress, depression, and anxiety. Cortisol was the biomarker most commonly measured to monitor the efficacy of interventions. DISCUSSION: Biomarkers are most commonly incorporated into caregiver studies to predict group membership and psychological health. Neuroendocrine biomarkers, specifically cortisol, are most frequently assessed. Future research should include biomarkers of other physiologic functions (e.g., cardiovascular function, cognitive dysfunction, and cell aging) and those that serve as multisystem indicators. Expanding the scientific study of biomarkers will contribute to our understanding of the mechanisms through which stress may influence caregiver health. PMID- 29130314 TI - Determining Psychoneuroimmunologic Markers of Yoga as an Intervention for Persons Diagnosed With PTSD: A Systematic Review. AB - There is a growing body of research on yoga as a therapeutic intervention for psychological symptoms of post-traumatic stress disorder (PTSD) accompanied by speculations on underlying physiologic mechanisms. The purpose of this systematic review is to identify, qualitatively evaluate, and synthesize studies of yoga as an intervention for PTSD that measured physiologic outcomes in order to gain insights into potential mechanisms. The focus is on studies evaluating yoga as a therapeutic intervention for PTSD rather than for trauma exposure, PTSD prevention, or subclinical PTSD. Multiple databases were searched for publications from the past two decades using terms derived from the question, "In people with PTSD, what is the effect of yoga on objective outcomes?" Eligibility criteria included yoga-only modalities tested as an intervention for formally diagnosed PTSD with at least one physiologic outcome. Results of this review confirmed that, though much of the published literature proposes physiological mechanisms underlying yoga's effects on PTSD, very few studies ( n = 3) have actually evaluated physiological evidence. Additionally, several studies had methodological limitations. In light of the limited data supporting yoga's beneficial effects on autonomic nervous system dysregulation, we present a theoretical model of the psychoneuroimmunologic processes associated with PTSD and the effects yoga may have on these processes to guide future research. Gaps in the literature remain for mechanisms related to activation of the hypothalamic pituitary-adrenal axis and inflammation. Additional rigorous mechanistic studies are needed to guide development of effective yoga interventions for PTSD to augment existing evidence-based PTSD treatments. PMID- 29130316 TI - Correlation of Leukocyte and Coronary Lesion Severity of Acute Myocardial Infarction. AB - Leukocytes play a pivotal role in the onset and progression of acute myocardial infarction (AMI). We evaluated the relationship between leukocyte count and coronary lesion severity of AMI. We carried out a retrospective study involving 815 patients with AMI undergoing primary percutaneous coronary intervention from 2005 to 2014 at a cardiovascular center. We recorded their risk factors, routine blood parameters, and cardiovascular events during hospitalization. When thrombus and nonthrombus burden groups were compared, leukocyte count (9.55 [7.80, 12.29] vs 10.70 [8.67, 13.04]*109/L, P = .005), neutrophil count (7.48 [5.65, 10.18] vs 8.61 [6.61, 10.80]*109/L, P = .001), and neutrophil-lymphocyte ratio (NLR; 4.99 [2.97, 7.16] vs 10.70 [8.67, 13.04], P = .003) were significantly different. Patients in the total occlusion group showed higher leukocyte count, neutrophil count, and NLR compared to the nontotal occlusion group. After multivariate logistic analysis, a neutrophil count >=8.355 * 109/L was independently associated with high thrombus burden and total coronary occlusion. Leukocyte count, neutrophil count, or NLR was not significantly related to cardiovascular events during hospitalization. In conclusion, the neutrophil count might be an independent predictor of high thrombus burden and total coronary occlusion. PMID- 29130315 TI - Incorrect intraarterial insertion of a catheter. PMID- 29130317 TI - Impact of Diabetes Mellitus on Percutaneous Coronary Intervention Outcomes: Real World Lessons From a Large Chinese Single-Center Registry. PMID- 29130324 TI - Bonjour et Adieu: Reflections on a Decade at the Helm of Our Journal / Bonjour et adieu: Reflexions sur une decennie a la barre de notre journal. PMID- 29130323 TI - Analysis: A Step Toward Standardizing Diabetic Foot Images. AB - In this issue of Journal of Diabetes Science and Technology Yap and coauthors report on the design and present results from a reliability study of the application called FootSnap that is intended for standardization of the distance and the orientation of the camera relative to the diabetic foot that is photographed. To produce standardized photographs FootSnap uses a straightforward, yet original and useful method. However, other systems have been reported and clinically tested earlier, in which the same parameters of foot images might be standardized and which are free of some limitations of FootSnap. Nevertheless, FootSnap should contribute to increase clarity of documenting changes in the diabetic foot shape, texture color and lesions, and it should facilitate application of automatic image processing algorithms. PMID- 29130325 TI - The Plasma Levels of ADAMTS-13, von Willebrand Factor, VWFpp, and Fibrin-Related Markers in Patients With Systemic Sclerosis Having Thrombosis. AB - This study aimed to examine the hemostatic abnormalities in patients with systemic sclerosis (SSc) and the relationship between these abnormalities and thrombotic events (THEs), focusing on the difference in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). The plasma levels of ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13), von Willebrand factor (VWF), VWF propeptide (VWFpp), d-dimer, and soluble fibrin (SF) were measured in 233 patients with SSc. The relationship between their levels and organ involvement, including THEs and interstitial lung disease (ILD), was evaluated. The plasma levels of VWF and VWFpp were significantly elevated and ADAMTS-13 activity was significantly decreased in patients with SSc compared to healthy participants. The VWFpp in dcSSc was significantly higher than in lcSSc. Twelve patients with SSc were complicated with acute THE, and 25 patients with SSc were complicated with past THE. The plasma levels of d-dimer and SF were significantly elevated in patients with SSc having THE. The plasma levels of VWF and VWFpp were significantly elevated in patients with SSc having ILD. The plasma levels of d-dimer were elevated in patients with SSc having other connective tissue diseases (CTDs). The plasma levels of ADAMTS-13 were significantly decreased and VWF, VWFpp, and SF were increased in patients with a d-dimer level of >=1 MUg/mL. Systemic sclerosis carries a high risk of THE, especially in patients with other CTDs. Plasma hemostasis-related markers are closely related to ILD and THE. These markers are important as markers of organ involvement as well as THE. PMID- 29130326 TI - Resting-State Network Functional Connectivity Patterns Associated with the Mindful Attention Awareness Scale. AB - Mindfulness refers to attending to moment-to-moment experiences with acceptance and no judgment. Several scales have been developed to quantify different components of mindfulness. The Mindful Attention Awareness Scale (MAAS) is particularly sensitive to trait mindfulness and is proposed to measure the attentional component of mindfulness. The purpose of this study was to identify the neural correlates of the MAAS in four resting-state networks related to attention-the default mode network (DMN), the salience network (SN), and the left and right central executive network (CEN). Thirty-two university students naive to mindfulness completed the MAAS and later underwent a resting-state functional magnetic resonance imaging scan. Resting-state data were analyzed using an independent component analysis; the scores from the MAAS were covaried to the connectivity maps in an analysis of covariance. The results indicate that variations in MAAS scores correlated with variations in functional connectivity patterns in resting-state networks. Specifically, within the SN and CEN, the MAAS was negatively correlated with functional connectivity in the precuneus, even though the precuneus is a key component of the DMN. Negative correlations in the DMN between the MAAS and the insula and negative correlations in the SN between the MAAS and the posterior cingulate cortex were also observed. These results suggest that MAAS scores (1) are correlated with the functional connectivity of several brain structures related to attention and (2) involve cross-network functional connectivity. PMID- 29130329 TI - Investigating the differential effects of social networking site addiction and Internet gaming disorder on psychological health. AB - Background and aims Previous studies focused on examining the interrelationships between social networking site (SNS) addiction and Internet gaming disorder (IGD) in isolation. Moreover, little is known about the potential simultaneous differential effects of SNS addiction and IGD on psychological health. This study investigated the interplay between these two technological addictions and ascertained how they can uniquely and distinctively contribute to increasing psychiatric distress when accounting for potential effects stemming from sociodemographic and technology-related variables. Methods A sample of 509 adolescents (53.5% males) aged 10-18 years (mean = 13.02, SD = 1.64) were recruited. Results It was found that key demographic variables can play a distinct role in explaining SNS addiction and IGD. Furthermore, it was found that SNS addiction and IGD can augment the symptoms of each other, and simultaneously contribute to deterioration of overall psychological health in a similar fashion, further highlighting potentially common etiological and clinical course between these two phenomena. Finally, the detrimental effects of IGD on psychological health were found to be slightly more pronounced than those produced by SNS addiction, a finding that warrants additional scientific scrutiny. Discussion and conclusion The implications of these results are further discussed in light of the existing evidence and debates regarding the status of technological addictions as primary and secondary disorders. PMID- 29130328 TI - Established risk factors for addiction fail to discriminate between healthy gamers and gamers endorsing DSM-5 Internet gaming disorder. AB - Background and aims The DSM-5 includes criteria for diagnosing Internet gaming disorder (IGD) that are adapted from substance abuse and widely used in research and clinical contexts, although evidence supporting their validity remains scarce. This study compared online gamers who do or do not endorse IGD criteria regarding self-control-related abilities (impulsivity, inhibitory control, and decision-making), considered the hallmarks of addictive behaviors. Method A double approach was adopted to distinguish pathological from recreational gamers: The first is the classic DSM-5 approach (>=5 criteria required to endorse the IGD diagnosis), and the second consists in using latent class analysis (LCA) for IGD criteria to distinguish gamers' subgroups. We computed comparisons separately for each approach. Ninety-seven volunteer gamers from the community were recruited. Self-reported questionnaires were used to measure demographic- and game-related characteristics, problematic online gaming (with the Problematic Online Gaming Questionnaire), impulsivity (with the UPPS-P Impulsive Behavior Scale), and depression (with the Beck Depression Inventory-II). Experimental tasks were used to measure inhibitory control (Hybrid-Stop Task) and decision-making abilities (Game of Dice Task). Results Thirty-two participants met IGD criteria (33% of the sample), whereas LCA identified two groups of gamers [pathological (35%) and recreational]. Comparisons that used both approaches (DSM-5 and LCA) failed to identify significant differences regarding all constructs except for variables related to actual or problematic gaming behaviors. Discussion The validity of IGD criteria is questioned, mostly with respect to their relevance in distinguishing high engagement from pathological involvement in video games. PMID- 29130330 TI - Psychometric validation of the Persian Bergen Social Media Addiction Scale using classic test theory and Rasch models. AB - Background and aims The Bergen Social Media Addiction Scale (BSMAS), a six-item self-report scale that is a brief and effective psychometric instrument for assessing at-risk social media addiction on the Internet. However, its psychometric properties in Persian have never been examined and no studies have applied Rasch analysis for the psychometric testing. This study aimed to verify the construct validity of the Persian BSMAS using confirmatory factor analysis (CFA) and Rasch models among 2,676 Iranian adolescents. Methods In addition to construct validity, measurement invariance in CFA and differential item functioning (DIF) in Rasch analysis across gender were tested for in the Persian BSMAS. Results Both CFA [comparative fit index (CFI) = 0.993; Tucker-Lewis index (TLI) = 0.989; root mean square error of approximation (RMSEA) = 0.057; standardized root mean square residual (SRMR) = 0.039] and Rasch (infit MnSq = 0.88-1.28; outfit MnSq = 0.86-1.22) confirmed the unidimensionality of the BSMAS. Moreover, measurement invariance was supported in multigroup CFA including metric invariance (DeltaCFI = -0.001; DeltaSRMR = 0.003; DeltaRMSEA = -0.005) and scalar invariance (DeltaCFI = -0.002; DeltaSRMR = 0.005; DeltaRMSEA = 0.001) across gender. No item displayed DIF (DIF contrast = -0.48 to 0.24) in Rasch across gender. Conclusions Given the Persian BSMAS was unidimensional, it is concluded that the instrument can be used to assess how an adolescent is addicted to social media on the Internet. Moreover, users of the instrument may comfortably compare the sum scores of the BSMAS across gender. PMID- 29130331 TI - Pasture, multi-enzymes, benzoic acid and essential oils positively influence performance, intestinal organ weight and egg quality in free-range laying hens. AB - 1. The objective of this study was to investigate the effect of range type, multi enzyme applications, and a combination of benzoic acid (BA) and essential oils (EO) on the productive performance, organ weight and egg quality of free-range laying hens. 2. Three hundred laying hens were evaluated for the short-term (6 weeks) and long-term (12 weeks) effects of range type (G = no pasture, P = pasture) and feed additives (T1 = control; T2 = betaglucanase/pectinase/protease; T3 = BA/EO). Body weight, feed intake (FI), feed conversion ratio (FCR), egg production (EP), digestive organ weight, and egg quality (EQ) were evaluated. Data were analysed using SPSS 2.2 in a 2*2*3 factorial arrangement. 3. Hens that ranged on pasture were significantly heavier (2043 g vs. 1996 g; p < 0.001), laid heavier eggs (61.9 g vs. 60.3 g; p < 0.001) and produced darker yolk colour (4.3 vs. 7.0; p < 0.001) compared to hens ranged on gravel. Hens fed T2 were significantly heavier (2050 g) compared to hens fed T1 (2005 g) or T3 (2008 g). Organ weights (gizzard, liver and pancreas) were significantly heavier in hens ranged on pasture (16.8 g/kg BW, 22.3 g/kg BW and 1.89 g/kg BW, respectively) compared to hens ranged on gravel (14.2 g/kg BW, 21.7 g/kg BW and 1.83 g/kg BW, respectively). Over time, body weight (1970-2070 g; p < 0.001) and egg weight (59.5-62.8 g; p < 0.001) increased, FI (123-120 g; p = 0.024) was reduced and FCR (2.36-2.10; p = 0.002) improved 4. In conclusion, hens housed on pasture and fed multi-enzyme supplemented diets had significantly heavier body weight and produced heavier eggs with darker yolk colour. Pasture intake and enzyme supplementation increased digestive organ weight significantly. PMID- 29130335 TI - Erratum. AB - The following corrections applies to "The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO)" by K Murakami, J Wada, D Ogawa, CS Horiguchi, T Miyoshi, M Sasaki, HA Uchida, Y Nakamura and H Makino. Diabetes and Vascular Disease Research 2013; 10(1): 93-96. DOI: 10.1177/1479164112444640 . PMID- 29130333 TI - Non-disclosure to male partners and incomplete PMTCT regimens associated with higher risk of mother-to-child HIV transmission: a national survey in Kenya. AB - Health worker experience and community support may be higher in high HIV prevalence regions than low prevalence regions, leading to improved prevention of mother-to-child HIV transmission (PMTCT) programs. We evaluated 6-week and 9 month infant HIV transmission risk (TR) in a high prevalence region and nationally. Population-proportionate-to-size sampling was used to select 141 clinics in Kenya, and mobile teams surveyed mother-infant pairs attending 6-week and 9-month immunizations. HIV DNA testing was performed on HIV-exposed infants. Among 2521 mother-infant pairs surveyed nationally, 2423 (94.7%) reported HIV testing in pregnancy or prior diagnosis, of whom 200 (7.4%) were HIV-infected and 188 infants underwent HIV testing. TR was 8.8% (4.0%-18.3%) in 6-week and 8.9% (3.2%-22.2%) in 9-month cohorts including mothers with HIV diagnosed postpartum, of which 53% of infant infections were due to previously undiagnosed mothers. Of 276 HIV-exposed infants in the Nyanza survey, TR was 1.4% (0.4%-5.3%) at 6-week and 5.1% (2.5%-9.9%) at 9-months. Overall TR was lower in Nyanza, high HIV region, than nationally (3.3% vs. 7.2%, P = 0.02). HIV non-disclosure to male partners and incomplete ARVs were associated with TR in both surveys [aOR = 12.8 (3.0-54.3); aOR = 5.6 (1.2-27.4); aOR = 4.5 (1.0-20.0), aOR = 2.5, (0.8-8.4), respectively]. TR was lower in a high HIV prevalence region which had better ARV completion and partner HIV disclosure, possibly due to programmatic efficiencies or community/peer/partner support. Most 9-month infections were among infants of mothers without prior HIV diagnosis. Strategies to detect incident or undiagnosed maternal infections will be important to achieve PMTCT. PMID- 29130334 TI - Pulsed Electron Paramagnetic Resonance Imaging: Applications in the Studies of Tumor Physiology. AB - SIGNIFICANCE: Electron paramagnetic resonance imaging (EPRI) is capable of generating images of tissue oxygenation using exogenous paramagnetic probes such as trityl radicals or nitroxyl radicals. The spatial distribution of the paramagnetic probe can be generated using magnetic field gradients as in magnetic resonance imaging and, from its spectral features, spatial maps of oxygen can be obtained from live objects. In this review, two methods of signal acquisition and image formation/reconstruction are described. The probes used and its application to study tumor physiology and monitor treatment response with chemotherapy drugs in mouse models of human cancer are summarized. Recent Advances: By implementing phase encoding/Fourier reconstruction in EPRI in time domain mode, the frequency contribution to the spatial resolution was avoided and images with improved spatial resolution were obtained. The EPRI-generated pO2 maps in tumor were useful to detect and evaluate the effects of various antitumor therapies on tumor physiology. Coregistration with other imaging modalities provided a better understanding of hypoxia-related alteration in physiology. CRITICAL ISSUES: The high radiofrequency (RF) power of EPR irradiation and toxicity profile of radical probes are the main obstacles for clinical application. The improvement of RF low power pulse sequences may allow for clinical translation. FUTURE DIRECTIONS: Pulsed EPR oximetry can be a powerful tool to research various diseases involving hypoxia such as cancer, ischemic heart diseases, stroke, and diabetes. With appropriate paramagnetic probes, it can also be applied for various other purposes such as detecting local acid-base balance or oxidative stress. Antioxid. Redox Signal. 28, 1378-1393. PMID- 29130336 TI - Antiproliferative and cytotoxic secondary metabolites from fruits of Leplaea mayombensis. AB - Two new seco-lanostane-type triterpenes, named mayomlactones A (1) and B (2) were isolated from the fruits of Leplaea mayombensis together with 10 known compounds (3-12). Structures of the new compounds were elucidated by extensive spectroscopic studies. Except compounds 11 and 12, all the other chemical compounds are newly reported from Leplaea genus. From the results of this investigation, compounds 1-10 were examined for antiproliferative activity against HeLa cells as well as cytotoxicity against 3T3 cell line. Compounds 3 and 4 showed moderate antiproliferative activity with IC50 values of 10.4 +/- 0.1 and 18.6 +/- 0.2 MUM, respectively. On the other hand, compounds 1, 4 and 9 showed weak cytotoxicity with IC50 values 44.1 +/- 0.5, 55.8 +/- 0.7 and 55.1 +/- 0.5 MUM. Overall, none of the tested compounds showed good selectivity (SI ranging from 0.51 to 3.06) but high toxicity against the 3T3 cell line. PMID- 29130337 TI - Trienic alpha-pyrone and ochratoxin derivatives from a sponge-derived fungus Aspergillus ochraceopetaliformis. AB - A new trienic alpha-pyrone derivative asteltoxin G (1) bearing a tetrahydrofuran ring and a new ochratoxin derivative named ochratoxin A1 (5), along with seven known compounds, were isolated from a sponge-derived fungus Aspergillus ochraceopetaliformis. The compounds (1-9) were evaluated on the basis of spectroscopic analyses and comparison with those of the reported data. The new compound ochratoxin A1 (5) exhibited anti-inflammatory activity against IL-6 and TNF-alpha expression of the LPS-induced THP-1 cells with inhibitory rates of 74.4 and 67.7% at concentration of 10 MUM, respectively. PMID- 29130339 TI - Ethyl lucidenates A reverses P-glycoprotein mediated vincristine resistance in K562/A02 cells. AB - Multidrug resistance is a major unresolved obstacle to successful cancer chemotherapy. It is often associated with an elevated efflux of a variety of anticancer drugs by ATP-binding cassette transporters including P-glycoprotein, BCRP and MRP1. In this study, the reversal effect of Ethyl lucidenates A on K562/A02 cells was investigated. At concentrations of 10 MUM, Ethyl lucidenates A could reverse the resistance of K562/A02 to vincristine up to 7.59 folds. Mechanistically, Ethyl lucidenates A could increase the intracellular accumulation of vincristine in K562/A02 cells through inhibiting the P glycoprotein mediated drug-transport activity by rhodamine accumulation assay and cell cycle analysis. Further mechanistic investigation found that Ethyl lucidenates A did not alter P-glycoprotein expression. In conclusion, Ethyl lucidenates A could reverse the multidrug resistance of K562/A02 cells via its influence on P-glycoprotein drug-transport activity and thus, be a potential multidrug resistance reversal agent. PMID- 29130338 TI - Colonic hydrogen sulfide produces portal hypertension and systemic hypotension in rats. AB - Hydrogen sulfide, a toxic gas, at low concentrations is also a biological mediator in animals. In the colon, hydrogen sulfide is produced by intestinal tissues and gut sulfur bacteria. Gut-derived molecules undergo liver metabolism. Portal hypertension is one of the most common complications contributing to the high mortality in liver cirrhosis. We hypothesized that the colon-derived hydrogen sulfide may affect portal blood pressure. Sprague-Dawley rats were maintained either on tap water (controls) or on water solution of thioacetamide to produce liver cirrhosis (CRH-R). Hemodynamics were measured after administration of either saline or Na2S, a hydrogen sulfide donor, into (1) the colon, (2) the portal vein, or (3) the femoral vein. Expression of enzymes involved in hydrogen sulfide metabolism was measured by RT-PCR. CRH-R showed a significantly higher portal blood pressure but a lower arterial blood pressure than controls. Saline did not affect hemodynamic parameters. In controls, intracolonic hydrogen sulfide decreased arterial blood pressure and portal blood flow but increased portal blood pressure. Similarly, hydrogen sulfide administered into the portal vein decreased arterial blood pressure but increased portal blood pressure. In contrast, hydrogen sulfide administered into the systemic vein decreased both arterial and portal blood pressures. CRH-R showed significantly greater responses to hydrogen sulfide than controls. CRH-R had a significantly higher liver concentration of hydrogen sulfide but lower expression of rhodanese, an enzyme converting hydrogen sulfide to sulfate. In conclusion, colon-administered hydrogen sulfide increases portal blood pressure while decreasing the systemic arterial blood pressure. The response to hydrogen sulfide is more pronounced in cirrhotic rats which show reduced hydrogen sulfide liver metabolism. Therefore, colon-derived hydrogen sulfide may be involved in the regulation of portal blood pressure, and may contribute to portal hypertension. Impact statement Accumulating evidence suggests that gut-derived molecules affect the control of the circulatory system. Mechanisms controlling liver circulation have been profoundly studied; however, the effects of gut bacteria-derived molecules on portal blood pressure have not been established. In the colon, hydrogen sulfide is produced by intestinal tissues and gut sulfur bacteria. We found that colon-administered hydrogen sulfide increases portal blood pressure while decreasing the systemic arterial blood pressure. The hemodynamic response to hydrogen sulfide was more pronounced in cirrhotic rats which showed reduced hydrogen sulfide liver metabolism, i.e. lower expression of rhodanese, an enzyme converting hydrogen sulfide to sulfate. We propose that colon-derived hydrogen sulfide may affect the regulation of portal and arterial blood pressures and may be involved in portal hypertension. PMID- 29130340 TI - Adherence to the Mediterranean diet in a Sicilian student population. AB - Since the last decades, socio-economic changes have a key role on eating habits affecting the nutritional status and health of people, in particular children and adolescents. The aim of this study was to compare the diet of student population both normal weight and overweight and obese in order to understand their eating habits by comparing the different diets of the student referring to the Mediterranean diet. The study comprised 337 Sicilian students aged 9 to 13 years, 96 in primary schools and 241 in secondary schools, respectively, in three Sicilian cities namely, Messina, San Piero Patti and Ragusa. The variables studied were height, weight, body mass index (BMI) and adherence to the Mediterranean Adequacy Index (MAI) diet quality indicator. Interestingly, the results highlighted 2.67 MAI mean value for normal weight students while 1.27 MAI mean value indicating a decreased adherence to the Mediterranean diet in overweight students. PMID- 29130341 TI - Topoisomerases inhibitory activities and DNA binding properties of 9 methoxycamptothecin from Nothapodytes nimmoniana (J. Graham) Mabberly. AB - We have reported previously that 9-methoxycamptothecin (MCPT) showed significant antitumor activity in vitro. Here, agarose gel electrophoresis experiments were performed to evaluate MCPT's unwinding ability toward plasmid DNA and inhibitory activities against topoisomerases (Topo) I and II. Binding properties of MCPT to calf thymus DNA (CT-DNA) were evaluated by UV-vis, melting temperature, fluorescence, circular dichroism methodologies and molecular docking technique. Results showed that MCPT at 100 MUM inhibited Topo I activity, but had no effect on Topo II. Studies on the binding properties indicated that minor groove binding was the most probable binding mode of MCPT to DNA. The abilities of MCPT to act as Topo I inhibitor and minor groove binding agent may be related to its strong antitumor activity. PMID- 29130342 TI - Nivolumab in recurrent/metastatic head and neck cancers. AB - Head and neck cancer is an immunosuppressive disease, with a high proportion expressing PD-L1. Until recently, options were lacking in second line. Prognosis is poor especially for patients who progress during chemotherapy with survival often inferior to 6 months. Nivolumab is the only anti-PD-1 agent to prolong survival in the second-line setting and is now the standard option since the CheckMate-141 trial. Treatment is generally well tolerated, patients seem to have a better quality of life when compared with chemotherapy. Markers of efficacy are lacking even if some data are emerging. Different combinations of immunotherapy are ongoing. Hyperprogression is a phenomenon associated with poor outcome and might be the consequence of anti-PD-1 treatment but this is yet to be proven. PMID- 29130344 TI - Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant. AB - Chemotherapy-induced nausea and vomiting (CINV) remains a challenge in cancer care. Improved understanding of CINV pathophysiology has triggered the development of new antiemetic therapeutic options, such as selective neurokinin-1 (NK1) receptor antagonists (RAs), which effectively prevent CINV when added to a standard antiemetic regimen (serotonin-3 RA and dexamethasone). Aprepitant and its water-soluble prodrug, fosaprepitant dimeglumine, are the most widely used NK1 RAs, with extensive clinical use worldwide. Recently, a Phase III trial prospectively evaluated fosaprepitant-based antiemetic therapy for CINV prevention in a large, well-defined nonanthracycline- and cyclophosphamide-based moderately emetogenic chemotherapy population. Fosaprepitant demonstrated significantly improved efficacy outcomes compared with a control regimen and was generally well tolerated, indicating that NK1 RAs are a valuable therapeutic option in this setting. PMID- 29130345 TI - MiR-199a targeting ROCK1 to affect kidney cell proliferation, invasion and apoptosis. AB - Renal cell carcinoma (RCC) is one of the three most common cancers of urinary tract cancer, accounting for 2-3% of all systemic cancers. Recent studies have found that miR-199a is lowly expressed in RCC, may act as a tumour suppressor gene to induce the occurrence of kidney cancer. In the present study, we investigated the role of miR-199a in the progression and metastasis of RCC. The results showed that miR-199a significantly downregulated in RCC and cell lines. Overexpression of miR-199a in RCC cell lines significantly inhibited cell proliferation, migration and invasion. Furthermore, the qRT-PCR and western blot results showed that miR-199a overexpression significantly downregulated ROCK-1 mRNA and protein levels. ROCK1 was identified as a target of miR-199a, and ectopic expression of miR-199a downregulated ROCK1 by direct binding to its 3' untranslated region. Together, these findings indicate that miR-199a acts as a tumour suppressor and its downregulation in tumour tissues may contribute to the progression and metastasis of RCC through a mechanism involving ROCK1, suggesting miR-199a as a potential new diagnostic and therapeutic target for the treatment of RCC. PMID- 29130343 TI - Defining baseline epigenetic landscapes in the rat liver. AB - AIM: Characterization of the hepatic epigenome following exposure to chemicals and therapeutic drugs provides novel insights into toxicological and pharmacological mechanisms, however appreciation of genome-wide inter- and intra strain baseline epigenetic variation, particularly in under-characterized species such as the rat is limited. Material & methods: To enhance the utility of epigenomic endpoints safety assessment, we map both DNA modifications (5-methyl cytosine and 5-hydroxymethyl-cytosine) and enhancer related chromatin marks (H3K4me1 and H3K27ac) across multiple male and female rat livers for two important outbred laboratory rat strains (Sprague-Dawley and Wistar). Results & conclusion: Integration of DNA modification, enhancer chromatin marks and gene expression profiles reveals clear gender-specific chromatin states at genes which exhibit gender-specific transcription. Taken together this work provides a valuable baseline liver epigenome resource for rat strains that are commonly used in chemical and pharmaceutical safety assessment. PMID- 29130346 TI - Chemical composition and evaluation of antinociceptive activity of the essential oil of Stevia serrata Cav. from Guatemala. AB - The composition and the antinociceptive activity of the essential oil of Stevia serrata Cav. from a population located in the west highlands of Guatemala were evaluated. A yield of 0.2% (w/w) of essential oil was obtained by hydrodistillation of the dried aerial parts of the plant. The essential oil analysed by GC-FID and GC-MS showed a high content of sesquiterpenoids, with chamazulene (60.1%) as the major component and 91.5% of the essential oil composition was identified. To evaluate antinociceptive activity in mice, the essential oil of S. serrata Cav. was administered as gavage, using three different doses. In the formalin test, the animals were pre-treated with oral doses of the essential oil before the administration of formalin. Oral administration of S. serrata Cav. essential oil produced a marked antinociceptive activity. Therefore, the plant could be domesticated as a source of essential oil rich in chamazulene for developing medicinal products. PMID- 29130347 TI - Editorial Comment on: Ureteroscopic Laser Lithotripsy: A Review of Dusting vs Fragmentation with Extraction by Matlaga et al. PMID- 29130348 TI - Tryptophan-Containing Non-Cationizable Opioid Peptides - a new chemotype with unusual structure and in vivo activity. AB - Recently, a new family of opioid peptides containing tryptophan came to the spotlight for the absence of the fundamental protonable tyramine 'message' pharmacophore. Structure-activity relationship investigations led to diverse compounds, characterized by different selectivity profiles and agonist or antagonist effects. Substitution at the indole of Trp clearly impacted peripheral/central antinociceptivity. These peculiarities prompted to gather all the compounds in a new class, and to coin the definition 'Tryptophan-Containing Non-Cationizable Opioid Peptides', in short 'TryCoNCOPs'. Molecular docking analysis suggested that the TryCoNCOPs can still interact with the receptors in an agonist-like fashion. However, most TryCoNCOPs showed significant differences between the in vitro and in vivo activities, suggesting that opioid activity may be elicited also via alternative mechanisms. PMID- 29130350 TI - Podocyturia as an early diagnostic marker of preeclampsia: a literature review. AB - CONTEXT: Preeclampsia (PE) is a pregnancy-related disease, and it is a leading cause of maternal and neonatal morbidity and mortality. It is characterized by the new onset of hypertension after 20 weeks of gestation together with signs of organ damage, most commonly the kidneys. The treatment of PE is symptomatic and final intervention requires delivery, regardless of the gestational age of the foetus. Furthermore, PE is a risk factor for developing cardiovascular disease and chronic kidney disease - even many years after the delivery. OBJECTIVE: Current research of PE has revealed that detection of podocytes in urine (podocyturia) could be a useful method for both confirmation of PE diagnosis and for the prediction of the severity of the disease. CONCLUSION: The main aim of this review is to summarize the current state of available methods for podocyte detection and to discuss their relevance in clinical practice. PMID- 29130352 TI - Medicinal properties of alpha-santalol, a naturally occurring constituent of sandalwood oil: review. AB - Alpha-santalol is a naturally occurring sesquiterpene that is derived from sandalwood oil. Its wide range of health benefits have been attributed to the modulation of various signalling pathways involved in the development of a particular disease. For example, the antitumour and cancer preventive properties of alpha-santalol have been shown to involve cell death induction through apoptosis and cell cycle arrest in various cancer models. A marked decrease in inflammatory markers have also been shown with alpha-santalol administration in skin tissue models. The current review is aimed at bringing the most recent advances of alpha-santalol against various disease-specific models and highlighting its associated mechanistic details. PMID- 29130349 TI - Regenerating beta cells of the pancreas - potential developments in diabetes treatment. AB - INTRODUCTION: The etiology of diabetes is mainly attributed to insulin deficiency due to the lack of beta cells (type 1), or to insulin resistance that eventually results in beta cell dysfunction (type 2). Therefore, an ultimate cure for diabetes requires the ability to replace the lost insulin-secreting beta cells. Strategies for regenerating beta cells are under extensive investigation. Areas covered: Herein, the authors first summarize the mechanisms underlying embryonic beta cell development and spontaneous adult beta cell regeneration, which forms the basis for developing beta cell regeneration strategies. Then the rationale and progress of each beta cell regeneration strategy is reviewed. Current beta cell regeneration strategies can be classified into two main categories: in vitro beta cell regeneration using pluripotent stem cells and in vivo reprogramming of non-beta cells into beta cells. Each has its own advantages and disadvantages. Expert opinion: Regenerating beta cells has shown its potential as a cure for the treatment of insulin-deficient diabetes. Much progress has been made, and beta cell regeneration therapy is getting closer to a clinical reality. Nevertheless, more hurdles need to be overcome before any of the strategies suggested can be fully translated from bench to bedside. PMID- 29130353 TI - For the greater credibility: Jesuit science and education in modern Portugal (1858-1910). AB - Upon the restoration of the Society of Jesus in Portugal in 1858, the Jesuits founded two important colleges that made significant efforts in the promotion of hands-on experimental teaching of the natural sciences. At the Colegio de Campolide (Lisbon, 1858-1910) and the Colegio de Sao Fiel (Lourical do Campo, 1863-1910) the Jesuits created modern chemistry and physics laboratories, organized significant botanical, zoological and geological collections, promoted scientific expeditions with their students to observe eclipses and to collect novel species of animals and plants, and engaged in original research work in physics, botany, and zoology. The successful implementation of modern scientific practices gained these colleges public recognition as the most prominent secondary institutions in nineteenth-century Portugal, and this made a major contribution to countering the widespread and commonly accepted anti-Jesuit accusations of obscurantism and scientific backwardness. PMID- 29130351 TI - The Gene Therapy Resource Program: A Decade of Dedication to Translational Research by the National Heart, Lung, and Blood Institute. AB - Over a 10-year period, the Gene Therapy Resource Program (GTRP) of the National Heart Lung and Blood Institute has provided a set of core services to investigators to facilitate the clinical translation of gene therapy. These services have included a preclinical (research-grade) vector production core; current Good Manufacturing Practice clinical-grade vector cores for recombinant adeno-associated virus and lentivirus vectors; a pharmacology and toxicology core; and a coordinating center to manage program logistics and to provide regulatory and financial support to early-phase clinical trials. In addition, the GTRP has utilized a Steering Committee and a Scientific Review Board to guide overall progress and effectiveness and to evaluate individual proposals. These resources have been deployed to assist 82 investigators with 172 approved service proposals. These efforts have assisted in clinical trial implementation across a wide range of genetic, cardiac, pulmonary, and blood diseases. Program outcomes and potential future directions of the program are discussed. PMID- 29130354 TI - Delivery of Adeno-Associated Virus Vectors in Adult Mammalian Inner-Ear Cell Subtypes Without Auditory Dysfunction. AB - Hearing loss, including genetic hearing loss, is one of the most common forms of sensory deficits in humans with limited options of treatment. Adeno-associated virus (AAV)-mediated gene transfer has been shown to recover auditory functions effectively in mouse models of genetic deafness when delivered at neonatal stages. However, the mouse cochlea is still developing at those time points, whereas in humans, the newborn inner ears are already fully mature. For effective gene therapy to treat genetic deafness, it is necessary to determine whether AAV mediated therapy can be equally effective in the fully mature mouse inner ear without causing damage to the inner ear. This study tested several AAV serotypes by canalostomy in adult mice. It is shown that most AAVs transduce the sensory inner hair cells efficiently, but are less efficient at transducing outer hair cells. A subset of AAVs also transduces non-sensory cochlear cell types. Neither the surgical procedure of canalostomy nor the AAV serotypes damage hair cells or impair normal hearing. The studies indicate that canalostomy can be a viable route for safe and efficient gene delivery, and they expand the repertoire of AAVs to target diverse cell types in the adult inner ear. PMID- 29130355 TI - Adherence and outcomes: a systematic review of palivizumab utilization. AB - INTRODUCTION: Palivizumab is a humanized monoclonal antibody used for respiratory syncytial virus (RSV) prophylaxis. RSV is the primary cause of lower respiratory tract infection in children aged <2 years, and can give rise to high-burden hospitalization and respiratory complications in later life. Adherence to a monthly dosing regimen, both in timing and injection number, is essential to sustain therapeutic levels of palivizumab and maintain protective status. Deviation from the approved dosing schedule may reduce the efficacy of palivizumab and increase the risk of breakthrough RSV infection and hospitalization. Areas covered: There is no standardized definition of adherence to palivizumab treatment. This review addresses the wide variability in defining and reporting adherence to palivizumab prophylaxis across different studies. The review assesses whether a relationship exists in the outcomes reported in studies relative to the monthly adherence protocol as defined in published randomized controlled trials of the efficacy and safety of palivizumab. Expert commentary: Standardized detailed reporting of adherence to palivizumab prophylaxis using consistent definitions will help provide a more robust level of evidence. This information may be important when considering variations in effectiveness, alterations to recommendations and guidelines, and cost-effectiveness of treatment. PMID- 29130356 TI - Authors reply: the effect of physical activity, body mass index and waist circumference on incident diabetes. PMID- 29130357 TI - Biological effects of metal degradation in hip arthroplasties. AB - Metals and metal alloys are the most used materials in orthopedic implants. The focus is on total hip arthroplasty (THA) that, though well tolerated, may be associated with local and remote adverse effects in the medium-long term. This review aims to summarize data on the biological consequences of the metal implant degradation that have been attributed predominantly to metal-on-metal (MoM) THA. Local responses to metals consist of a broad clinical spectrum ranging from small asymptomatic tissue lesions to severe destruction of bone and soft tissues, which are designated as metallosis, adverse reactions to metal debris (ARMD), aseptic lymphocytic vasculitis associated lesion (ALVAL), and pseudotumors. In addition, the dissemination of metal particles and ions throughout the body has been associated with systemic adverse effects, including organ toxicity, cancerogenesis, teratogenicity, and immunotoxicity. As proved by the multitude of studies in this field, metal degradation may increase safety issues associated with THA, especially with MoM hip systems. Data collection regarding local, systemic and long-term effects plays an essential role to better define any safety risks and to generate scientifically based recommendations. PMID- 29130358 TI - Gelatinase inhibitors: a patent review (2011-2017). AB - INTRODUCTION: Gelatinase represents a promising biotarget in new drug development as it is closely related to various pathological events, including but not limited to neoplasm, aging, respiratory and neurological disorders. Gelatinase inhibitors are thereby designated as chemotherapeutics or as mechanistic probe to figure out the unrecognized functions of MMP members. Areas covered: The focus of this article is to highlight recently issued patents concerning the naturally available or synthetic gelatinase inhibitors (2011-2017), where the chemical structures, SAR investigation, biological application. Besides, the binding modes of representative inhibitors with gelatinase are also briefly described. Expert opinion: The access of crystallographic structure of inhibitor complexed with gelatinase, the availability of pharmacophoric features of gelatinase inhibitors, together with the proper use of drug design protocols, have paved the way for developing more selective and potent modulators. Moreover, considering typical bio-assessment was primarily concentrated on the antitumor effect, the other bioactivity outcomes should also be concerned to look for new application of gelatinase inhibitors. PMID- 29130359 TI - Necessity of admission to improve the hearing-recovery rate in idiopathic sudden sensorineural hearing loss. AB - OBJECTIVES: The purpose of this study was to determine the prognostic potential of admission of a patient for idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY DESIGN: Retrospective clinical study. METHODS: We conducted a retrospective study of 301 patients with ISSNHL. The patients were divided into a study (57 patients at out-patients department (OPD) based treatment, using systemic steroids and intra-tympanic (IT) steroid injection) and a control groups (301 patients at admission, using systemic steroids and IT steroid injection). We compared the success rate (15 dB cut off), Siegel's criteria and hearing gain decibels between two groups. RESULTS: The overall recovery rate of the OPD based treatment group (29.8%) was poor than that of the admission group (52.9%) (p = .002). The odd ratio of OPD based treatment factor was 2.035 when the OPD based treatment and poor prognostic factors were analyzed at logistic regression test (Duration of delayed treatment, 1.073; average hearing loss level, 0.972) (p = .041). CONCLUSION: Admission must be strongly recommended when the patients with ISSNHL asked about the necessity of admission. We hypothesized that resting, getting out of their social stress, and relief of anxiety might be helpful to their hearing recoveries. PMID- 29130360 TI - Autophagy and innate immunity: Insights from invertebrate model organisms. AB - Macroautophagy/autophagy is a fundamental intracellular degradation process with multiple roles in immunity, including direct elimination of intracellular microorganisms via 'xenophagy.' In this review, we summarize studies from the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans that highlight the roles of autophagy in innate immune responses to viral, bacterial, and fungal pathogens. Research from these genetically tractable invertebrates has uncovered several conserved immunological paradigms, such as direct targeting of intracellular pathogens by xenophagy and regulation of autophagy by pattern recognition receptors in D. melanogaster. Although C. elegans has no known pattern recognition receptors, this organism has been particularly useful in understanding many aspects of innate immunity. Indeed, work in C. elegans was the first to show xenophagic targeting of microsporidia, a fungal pathogen that infects all animals, and to identify TFEB/HLH-30, a helix-loop-helix transcription factor, as an evolutionarily conserved regulator of autophagy gene expression and host tolerance. Studies in C. elegans have also highlighted the more recently appreciated relationship between autophagy and tolerance to extracellular pathogens. Studies of simple, short-lived invertebrates such as flies and worms will continue to provide valuable insights into the molecular mechanisms by which autophagy and immunity pathways intersect and their contribution to organismal survival. Abbreviations Atg autophagy related BECN1 Beclin 1 CALCOCO2 calcium binding and coiled-coil domain 2 Cry5B crystal toxin 5B Daf abnormal dauer formation DKF-1 D kinase family-1 EPG-7 Ectopic P Granules-7 FuDR fluorodeoxyuridine GFP green fluorescent protein HLH-30 Helix Loop Helix-30 Imd immune deficiency ins-18 INSulin related-18; LET-363, LEThal-363 lgg-1 LC3, GABARAP and GATE-16 family-1 MAPK mitogen-activated protein kinase MATH the meprin and TRAF homology MTOR mechanistic target of rapamycin NBR1 neighbor of BRCA1 gene 1 NFKB nuclear factor of kappa light polypeptide gene enhancer in B cells NOD nucleotide-binding oligomerization domain containing OPTN optineurin PAMPs pathogen-associated molecular patterns Park2 Parkinson disease (autosomal recessive, juvenile) 2, parkin pdr-1 Parkinson disease related PFTs pore-forming toxins PGRP peptidoglycan-recognition proteins PIK3C3 phosphatidylinositol 3- kinase catalytic subunit type 3 pink-1 PINK (PTEN-I induced kinase) homolog PRKD protein kinase D; PLC, phospholipase C PRKN parkin RBR E3 ubiquitin protein ligase PRRs pattern-recognition receptors PtdIns3P phosphatidylinositol-3 phosphate rab-5 RAB family-5 RB1CC1 RB1-inducible coiled-coil 1 RNAi RNA interference sqst SeQueSTosome related SQSTM1 sequestosome 1 TBK1 TANK-binding kinase 1 TFEB transcription factor EB TGFB/TGF-beta transforming growth factor beta TLRs toll-like receptors unc-51 UNCoordinated-51 VPS vacuolar protein sorting; VSV, vesicular stomatitis virus VSV-G VSV surface glycoprotein G Wipi2 WD repeat domain, phosphoinositide interacting 2. PMID- 29130361 TI - MTA1 is a novel regulator of autophagy that induces tamoxifen resistance in breast cancer cells. AB - Tamoxifen is commonly used to treat patients with ESR/ER-positive breast cancer, but its therapeutic benefit is limited by the development of resistance. Recently, alterations in macroautophagy/autophagy function were demonstrated to be a potential mechanism for tamoxifen resistance. Although MTA1 (metastasis associated 1) has been implicated in breast tumorigenesis and metastasis, its role in endocrine resistance has not been studied. Here, we report that the level of MTA1 expression was upregulated in the tamoxifen resistant breast cancer cell lines MCF7/TAMR and T47D/TR, and knockdown of MTA1 sensitized the cells to 4 hydroxytamoxifen (4OHT). Moreover, knockdown of MTA1 significantly decreased the enhanced autophagy flux in the tamoxifen resistant cell lines. To confirm the role of MTA1 in the development of tamoxifen resistance, we established a cell line, MCF7/MTA1, which stably expressed MTA1. Compared with parental MCF7, MCF7/MTA1 cells were more resistant to 4OHT-induced growth inhibition in vitro and in vivo, and showed increased autophagy flux and higher numbers of autophagosomes. Knockdown of ATG7 or cotreatment with hydroxychloroquine, an autophagy inhibitor, restored sensitivity to 4OHT in both the MCF7/MTA1 and tamoxifen resistant cells. In addition, AMP-activated protein kinase (AMPK) was activated, probably because of an increased AMP:ATP ratio and decreased expression of mitochondrial electron transport complex components. Finally, publicly available breast cancer patient datasets indicate that MTA1 levels correlate with poor prognosis and development of recurrence in patients with breast cancer treated with tamoxifen. Overall, our findings demonstrated that MTA1 induces AMPK activation and subsequent autophagy that could contribute to tamoxifen resistance in breast cancer. PMID- 29130362 TI - Is serum bilirubin associated with the severity of Guillain-Barre syndrome? AB - OBJECTIVE: Our aim was to assess the correlation between serum bilirubin levels and Guillain-Barre syndrome (GBS). PATIENTS AND METHODS: One hundred and one newly diagnosed patients with Guillain-Barre syndrome and 111 healthy age- and sex-matched individuals in the First Affiliated Hospital of Guangxi Medical University (Guangxi, China) from June 2012 to May 2017 were included in this study. Clinical characteristics and laboratory parameters of Guillain-Barre syndrome patients and healthy controls were retrospectively analysed. RESULTS: Serum bilirubin levels in Guillain-Barre syndrome patients were significantly lower as compared with those in healthy controls (p < 0.001); besides, log C reactive protein and erythrocyte sedimentation rate were significantly higher. We found that there was a negative correlation between GBS disability scale scores and total bilirubin, direct bilirubin, indirect bilirubin (r = -0.541, P < 0.001; r = -0.403, P < 0.001; r = -0.526, P < 0.001), respectively. Among patients with GBS, serum total bilirubin, direct bilirubin, and indirect bilirubin levels were independently associated with Guillain-Barre syndrome disability scale scores in multiple linear regression analysis, respectively. CONCLUSIONS: We observed that serum bilirubin levels were lower in patients with Guillain-Barre syndrome, and suggested total bilirubin, direct bilirubin, and indirect bilirubin were independently and inversely associated with Guillain-Barre syndrome severity. PMID- 29130364 TI - Fluorescent Labeling and 2-Photon Imaging of Mouse Tooth Pulp Nociceptors. AB - Retrograde fluorescent labeling of dental primary afferent neurons (DPANs) has been described in rats through crystalline fluorescent DiI, while in the mouse, this technique was achieved with only Fluoro-Gold, a neurotoxic fluorescent dye with membrane penetration characteristics superior to the carbocyanine dyes. We reevaluated this technique in the rat with the aim to transfer it to the mouse because comprehensive physiologic studies require access to the mouse as a model organism. Using conventional immunohistochemistry, we assessed in rats and mice the speed of axonal dye transport from the application site to the trigeminal ganglion, the numbers of stained DPANs, and the fluorescence intensity via 1) conventional crystalline DiI and 2) a novel DiI formulation with improved penetration properties and staining efficiency. A 3-dimensional reconstruction of an entire trigeminal ganglion with 2-photon laser scanning fluorescence microscopy permitted visualization of DPANs in all 3 divisions of the trigeminal nerve. We quantified DPANs in mice expressing the farnesylated enhanced green fluorescent protein (EGFPf) from the transient receptor potential cation channel subfamily M member 8 (TRPM8EGFPf/+) locus in the 3 branches. We also evaluated the viability of the labeled DPANs in dissociated trigeminal ganglion cultures using calcium microfluorometry, and we assessed the sensitivity to capsaicin, an agonist of the TRPV1 receptor. Reproducible DiI labeling of DPANs in the mouse is an important tool 1) to investigate the molecular and functional specialization of DPANs within the trigeminal nociceptive system and 2) to recognize exclusive molecular characteristics that differentiate nociception in the trigeminal system from that in the somatic system. A versatile tool to enhance our understanding of the molecular composition and characteristics of DPANs will be essential for the development of mechanism-based therapeutic approaches for dentine hypersensitivity and inflammatory tooth pain. PMID- 29130363 TI - Antioxidant role of autophagy in maintaining the integrity of glomerular capillaries. AB - Autophagy is a lysosomal degradation system by which cytosolic materials and damaged organelles are broken down into basic components. To explore the physiological role of autophagy in glomerular endothelial cells (GEnCs), we compared the autophagic flux among cells in the kidney under starvation. Inhibition of autophagy by chloroquine administration significantly increased the number of autophagosomes or autolysosomes in GEnCs and proximal tubular cells, but not in podocytes, suggesting that the GEnCs exhibit substantial autophagic activity. Next, we analyzed endothelial and hematopoietic cell-specific atg5 deficient mice (atg5-conditional KO [cKO] mice). Glomeruli of 4-wk-old atg5-cKO mice exhibited slightly distended capillary loops accompanied by an accumulation of reactive oxygen species (ROS). Glomeruli of 8-wk-old atg5-cKO mice showed a lobular pattern with thickening of the capillary loops and mesangial matrix expansion; however, the vasculature of other organs was preserved. The atg5-cKO mice died by 12 wk of age, presumably due to pancytopenia resulting from the defect in their hematopoietic lineages. Therefore, we subjected 4-wk atg5-cKO mice to irradiation followed by bone marrow transplantation from normal littermates. Transplanted mice recapitulated the glomerular phenotypes of the atg5-cKO mice with no obvious histological changes in other organs. Twelve-mo-old transplanted mice developed mesangiolysis and glomerulosclerosis with significant deterioration of kidney function. Administration of N-acetyl-l-cysteine, a ROS scavenger, to atg5-cKO mice rescued the glomerular phenotypes. These data suggest that endothelial autophagy protects glomeruli from oxidative stress and maintains the integrity of glomerular capillaries. Enhancing endothelial autophagy may provide a novel therapeutic approach to minimizing glomerular diseases. PMID- 29130365 TI - Lupane triterpenoids, antioxidant potential and antimicrobial activity of Myrciaria floribunda (H. West ex Willd.) O. Berg. AB - Chemical composition of the methanol extract of Myrciaria floribunda leaves was investigated. The nor-lupane triterpenoids platanic acid and messagenic I acid were identified, along with other known triterpenoids (betulinic aldehyde, ursolic acid acetate and betulinic acid), a new lupane triterpenoid (2alpha,6alpha,30-trihydroxybetulinic acid) and the flavonoids catechin, quercetrin and mirycitrin. The structures were determined by spectroscopic methods (NMR, LC-MS, GC-MS). The major isolated compound was betulinic acid. The methanol extract and 2alpha,6alpha,30-trihydroxybetulinic acid were evaluated for their DPPH scavenging potential. The tested triterpenoid was one hundred times more active than betulinic acid, but less active than the extract. Screening for antimicrobial activity showed that the methanol extract was active against Staphylococcus aureus and Escherichia coli, but inactive against Candida albicans and Candida krusei, while 2alpha,6alpha,30-trihydroxybetulinic acid was inactive to all tested microorganisms. PMID- 29130368 TI - Blocked vs. interleaved presentation and proactive interference in episodic memory. AB - Although a number of theoretical accounts of proactive interference (PI) in episodic memory have been proposed, existing empirical evidence does not support conclusively a single view yet. In two experiments we tested the predictions of the temporal discrimination theory of PI against alternative accounts by manipulating the presentation schedule of study materials (lists blocked by category vs. interleaved). In line with the temporal discrimination theory, we observed a clear buildup of (and release from) PI in the blocked condition, in which all the lists of the same category were presented sequentially. In the interleaved condition, with alternating lists of different categories, a more gradual and smoother buildup of PI was observed. When participants were left free to choose their presentation schedule, they spontaneously adopted an interleaved schedule, resulting again in more gradual PI. After longer delays, we observed recency effects at the list level in overall recall and, in the blocked condition, PI-related effects. The overall pattern of findings agrees with the predictions of the temporal discrimination theory of PI, complemented with categorical processing of list items, but not with alternative accounts, shedding light on the dynamics and underpinnings of PI under diverse presentation schedules and over different time scales. PMID- 29130367 TI - Development and evaluation of the Dignity Talk question framework for palliative patients and their families: A mixed-methods study. AB - BACKGROUND: Effective patient-family communication can reduce patients' psychosocial distress and relieve family members' current suffering and their subsequent grief. However, terminally ill patients and their family members often experience great difficulty in communicating their true feelings, concerns, and needs to each other. AIM: To develop a novel means of facilitating meaningful conversations for palliative patients and family members, coined Dignity Talk, explore anticipated benefits and challenges of using Dignity Talk, and solicit suggestions for protocol improvement. DESIGN: A convergent parallel mixed-methods design. Dignity Talk, a self-administered question list, was designed to prompt end-of-life conversations, adapted from the Dignity Therapy question framework. Participants were surveyed to evaluate the Dignity Talk question framework. Data were analyzed using qualitative and quantitative methods. SETTING/PARTICIPANTS: A total of 20 palliative patients, 20 family members, and 34 healthcare providers were recruited from two inpatient palliative care units in Winnipeg, Canada. RESULTS: Most Dignity Talk questions were endorsed by the majority of patients and families (>70%). Dignity Talk was revised to be convenient and flexible to use, broadly accessible, clearly stated, and sensitively worded. Participants felt Dignity Talk would be valuable in promoting conversations, enhancing family connections and relationships, enhancing patient sense of value and dignity, promoting effective interaction, and attending to unfinished business. Participants suggested that patients and family members be given latitude to respond only to questions that are meaningful to them and within their emotional capacity to broach. CONCLUSION: Dignity Talk may provide a gentle means of facilitating important end-of-life conversations. PMID- 29130366 TI - Autophagy and inflammation in chronic respiratory disease. AB - Persistent inflammation within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic inflammation in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary inflammation and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD chronic obstructive pulmonary disease CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor. PMID- 29130369 TI - From moths to caterpillars: Ideal conditions for Galleria mellonella rearing for in vivo microbiological studies. AB - Galleria mellonella is a well-accepted insect model for the study of pathogen host interactions and antimicrobial compounds. The main advantages of this model include the low cost of maintenance, the fast life cycle, the possibility of using a large number of caterpillars and the innate immune system, which is evolutionarily conserved relative to mammals. Because of these advantages, different research groups have been working to implement the rearing of G. mellonella in laboratory conditions. This protocol describes our experience in the rearing of G. mellonella caterpillars for experimental infection models and the influence of different artificial diets on developmental and physiological parameters. Here, we suggest a diet composition that benefits the life cycle of G. mellonella by accelerating the larval phase length and increasing the caterpillar weight. This diet also stimulated the immune system of G. mellonella by increasing the hemolymph volume and hemocyte concentration. In addition, our rearing protocol generated caterpillars that are more resistant to infection by Staphylococcus aureus, Escherichia coli and Candida albicans. A standard G. mellonella rearing protocol is fundamental to minimize external influences on the results, and this simple and easy protocol can support researchers starting to rear G. mellonella. PMID- 29130370 TI - Normal adult and adolescent performance on TASIT-S, a short version of The Assessment of Social Inference Test. AB - There is a need for short, reliable, sensitive assessment tools to measure social cognition. The Awareness of Social Inference Test (TASIT) is an ecologically valid instrument that uses videos of actors engaged in everyday conversations to assess emotion perception, the ability to detect lies, sarcasm and sincerity, and the ability to judge what others are thinking, intending, feeling, and saying. A recently developed short version of TASIT retains the structure of the original test and its clinical sensitivity. In this paper, we compare TASIT-S performance in healthy adolescents, adults, and older adults as well as the effects of country (U.S.A. and Australia), English familiarity and gender. In this study 616 Australians including 226 adolescents (13-19) and 390 adults aged 20-75 + along with 180 U.S. residents (aged 20-74) completed one, two, or three parts of TASIT S either face to face (Australians) or on-line (US residents). Results indicated that there were minor differences in TASIT-S performance (Part 3 only) based on country of residence and no significant effects for English familiarity in adolescents (not examined in adults). There were no gender effects. Young and middle aged adults (20-59) tended to perform better than adolescents and older adults on most parts of TASIT-S. In general, TASIT-S scores decreased moderately with advancing age. In conclusion, TASIT-S is a useful screen for social cognitive impairment in English speakers that is appropriate for use from adolescence through to older age. It produces comparable scores in the U.S.A. and Australia. PMID- 29130372 TI - 'Motility Psychoses', by Erik Stromgren (1940). AB - The motility psychoses are a group of acute psychiatric conditions characterized by salient disorders of movement (increased, decreased and disorganized), psychotic experiences, confusion and good prognosis. The debate on whether they are just atypical forms of schizophrenia or manic-depressive insanity or constitute an independent group of psychoses has not yet been settled. Erik Stromgren's classical chapter deals with the history and clinical aspects of the motility psychoses. Based on a historical analysis and an empirical study of a patient cohort, the author draws conclusions on the nature of this clinical group that has stood the test of time well. PMID- 29130371 TI - "Lost in translation: Seeing the forest by focusing on the trees". AB - A complex process translates messenger RNA (mRNA) base sequence into protein amino acid sequence. Transfer RNAs must recognize 3-base codons in the mRNA to insert the correct amino acids into the growing protein. Codon degeneracy makes decoding complicated in that multiple (synonymous) triplets can encode a single amino acid and multiple tRNAs can have the same anticodon. Over the last twenty years, new developments in structural biology, genome sequencing and bioinformatics has elucidated the intricacies of the ribosome structure and the details of the translation process. High throughput analyses of sequence information support the idea that mRNA folding has a major effect on expression for codons at the 5'-end of mRNA (N-terminal region of a polypeptide). Despite a forest of sequence data, significant details of the complex translation process can escape detection. However, a sensitive translation assay has allowed a single tree in this forest to be revealing. PMID- 29130376 TI - The Cuticle Mutant eca2 Modifies Plant Defense Responses to Biotrophic and Necrotrophic Pathogens and Herbivory Insects. AB - We isolated previously several Arabidopsis thaliana mutants with constitutive expression of the early microbe-associated molecular pattern-induced gene ATL2, named eca (expresion constitutiva de ATL2). Here, we further explored the interaction of eca mutants with pest and pathogens. Of all eca mutants, eca2 was more resistant to a fungal pathogen (Botrytis cinerea) and a bacterial pathogen (Pseudomonas syringae) as well as to a generalist herbivorous insect (Spodoptera littoralis). Permeability of the cuticle is increased in eca2; chemical characterization shows that eca2 has a significant reduction of both cuticular wax and cutin. Additionally, we determined that eca2 did not display a similar compensatory transcriptional response, compared with a previously characterized cuticular mutant, and that resistance to B. cinerea is mediated by the priming of the early and late induced defense responses, including salicylic acid- and jasmonic acid-induced genes. These results suggest that ECA2-dependent responses are involved in the nonhost defense mechanism against biotrophic and necrotrophic pathogens and against a generalist insect by modulation and priming of innate immunity and late defense responses. Making eca2 an interesting model to characterize the molecular basis for plant defenses against different biotic interactions and to study the initial events that take place in the cuticle surface of the aerial organs. PMID- 29130377 TI - Negotiating horizontality in medical South-South cooperation: The Cuban mission in Rio de Janeiro's urban peripheries. AB - For more than 50 years, Cuba has been one of the most important players in the field of international medical cooperation in the Global South. Between 2013 and 2016, Cuba maintained one of its largest cooperations with Brazil: nearly 11,400 Cuban physicians were sent to work within the framework of the Brazilian health programme 'More-Doctors-for-Brazil', which was implemented to improve Brazil's precarious public health sector. This paper inquires into the manifold challenges of horizontal connectivity in this medical South-South cooperation. We will trace these back to deep-rooted contentions about the epistemological approaches to medical practice and professional recognition within and between Cuban and Brazilian arenas of public health, which do not, however, conform to a simplistic socialism-capitalism dichotomy. Rather, this particular South-South cooperation reveals significant differences in how powerful the postcolonial legacies of medical assistance remain in Global Health settings. This paper explores how these legacies may impact on the moral and professional legitimacy of the individuals involved in South-South partnership. Using ethnographic findings in newly established family clinics situated in urban poverty regions in Rio de Janeiro's North, we will also show how prolonged local interactions may create new spaces of horizontal encounters and connectivity in international medical cooperation. PMID- 29130378 TI - The experiences of patients with advanced cancer and caregivers presenting to Emergency Departments: A qualitative study. AB - BACKGROUND: Despite being a common event in the course of an advanced cancer illness, there is little understanding of patients' perceptions of hospital Emergency Department presentations. AIM: To explore the experiences and perceptions of Emergency Departments held by patients with advanced cancer and their informal caregivers. DESIGN: Cross-sectional study involving semi structured interviews with advanced cancer patients and their informal caregivers. Qualitative data analysis was underpinned by a phenomenological approach utilising a data-driven inductive thematic frame. SETTING/PARTICIPANTS: In total, 19 patients with advanced cancer who presented to Emergency Departments in the previous 6 months and 10 informal caregivers from an Australian public hospital and community palliative care service were interviewed. RESULTS: Patients reported that Emergency Department presentations were largely prompted by worsening symptoms or were a means to expedite hospital admission, with many instructed to attend by their health care provider. The experience in the Emergency Department was described as a time of anxiety and uncertainty with concerns over communication, the general environment and delays in the symptom management highlighted. Long waits were common. Despite this, patients described relief at receiving care. While the Emergency Department was viewed as a safety net for the health system, many believed advanced cancer patients should have alternative options. CONCLUSION: Relatively simple changes of regular communication updates and early symptom relief would improve patient experience of Emergency Department care. However, since an Emergency Department presentation is frequently serving as a default to access medical care, a significant re orientation of the health care system is required to meet patient needs. PMID- 29130379 TI - Trauma complexity and child abuse: A qualitative study of attachment narratives in adult refugees with PTSD. AB - The present study aimed to identify trauma types over the life course among adult refugees and to explore their accounts of childhood maltreatment. A sample of 43 Arabic-speaking refugees with posttraumatic stress disorder (PTSD) attending a treatment context in Denmark were interviewed. Using a "Trauma Coding Manual" developed for this study, trauma types were identified in interview transcripts. In both men and women with Iraqi and Palestinian-Lebanese backgrounds, high levels of trauma complexity and high rates of childhood maltreatment were found (63%, n = 27). A number of concepts and categories emerged in the domains childhood physical abuse (CPA), childhood emotional abuse (CEA), and neglect. Participants articulated wide personal impacts of child abuse in emotional, relational, and behavioral domains in their adult lives. These narratives contribute valuable clinical information for refugee trauma treatment providers. PMID- 29130380 TI - Measuring the quality of end-of-life care: Development, testing, and cultural validation of the Danish version of Views of Informal Carers' Evaluation of Services-Short Form. AB - BACKGROUND: The perspectives of patients and relatives are important in the improvement of the quality of health care. However, the quality of end-of-life care has not been systematically evaluated in Scandinavia. AIM: To develop or adapt and subsequently validate a questionnaire assessing the quality of end-of life care in Denmark. The questionnaire was intended for bereaved relatives in order to assess the quality of care in the last 3 months of the patient's life and the circumstances surrounding death. DESIGN AND DATA SOURCES: Based on the literature and interviews with 15 bereaved relatives and 17 healthcare professionals, relevant topics to include in a questionnaire were identified. The topics were prioritized by 100 bereaved relatives and subsequently compared to existing questionnaires. The chosen questionnaire was tested by cognitive interviews with 36 bereaved relatives. RESULTS: Most of the important topics were covered by the Views of Informal Carers' Evaluation of Services-Short Form, but not all Danish settings (e.g. home care by a palliative team) were covered. These settings were added to the Views of Informal Carers' Evaluation of Services-Short Form, and a few adaptations were made before a Danish version of the Views of Informal Carers' Evaluation of Services-Short Form was tested by cognitive interviews. This cultural validation showed that the slightly adapted Danish version was perceived as relevant, understandable, and acceptable. Furthermore, the cognitive interviews gave insight in the comprehension and interpretation of Views of Informal Carers' Evaluation of Services-Short Form items. CONCLUSION: With a few adaptations, the British Views of Informal Carers' Evaluation of Services-Short Form was relevant in a Danish setting. PMID- 29130381 TI - Lymph node metastases as only qualifier for stage IV serous ovarian cancer confers longer survival than other sites of distant disease - a Swedish Gynecologic Cancer Group (SweGCG) study. AB - BACKGROUND: The International Federation of Gynecology and Obstetrics (FIGO) ovarian cancer staging system includes no sub-stage for lymph nodes (LN) as only distant disease manifestation. We explore the prognostic implication of LN as only stage IV classifier in serous ovarian cancer. METHOD: This is a nation-wide, population-based study on 551 women with serous stage IV cancers diagnosed between 2009-2014. We compare overall survival (OS) in women with LN as only distant metastatic site to those with pleural metastases only and to patients with other/multiple stage IV manifestations. Cox regression models were used for uni- and multivariable estimations. RESULTS: Of 551stage IV cases, distant metastatic site was registered in 433. Median OS for women with LN (n = 51) was 41.4 months, compared to 25.2 and 26.8 months for patients with pleural (n = 195) or other/multiple (n = 187) distant metastases (p = .0007). The corresponding five-year survival rates were 32, 11 and 22%, respectively. Multivariable analyzes confirmed shorter survival for women with pleural (HR 2.99, p = .001) or other/multiple distant sites (HR 2.67, p = .007), as compared to LN cases. LN only patients lived 9.1 months longer after primary than after interval surgery, but this difference was not significant (p = .245). CONCLUSION: Women with stage IV serous ovarian cancer having lymph nodes as only distant metastatic site live longer than other stage IV patients. PMID- 29130382 TI - Less-Affected Hand Function in Children With Hemiparetic Unilateral Cerebral Palsy: A Comparison Study With Typically Developing Peers. AB - BACKGROUND: Neurorehabilitation interventions in children with unilateral cerebral palsy (UCP) target motor abilities in daily life yet deficits in hand skills persist. Limitations in the less-affected hand may affect overall bimanual hand skills. OBJECTIVE: To compare hand function, by timed motor performance on the Jebsen-Taylor Test of Hand Function (JTTHF) and grip strength of children with UCP to children with typical development (CTD), aged 8 to 18 years old. Exploratory analyses compared hand function measures with regard to neurophysiological outcomes measured by transcranial magnetic stimulation and between group comparisons of hemispheric motor threshold. METHODS: Baseline hand skills were evaluated in 47 children (21 UCP; 26 CTD). Single-pulse transcranial magnetic stimulation testing assessed corticospinal tract and motor threshold. RESULTS: The mean difference of the less-affected hand of children with UCP to the dominant hand of CTD on the JTTHF was 21.4 seconds (95% CI = 9.32-33.46, P = .001). The mean difference in grip strength was -30.8 N (95% CI = -61.9 to 0.31, P = .052). Resting motor thresholds between groups were not significant, but age was significantly associated with resting motor threshold ( P < .001; P = .001). Children with UCP ipsilateral pattern of motor representation demonstrated greater mean differences between hands than children with contralateral pattern of motor representation ( P < .001). All results were adjusted for age and sex. CONCLUSIONS: The less-affected hand in children with UCP underperformed the dominant hand of CTD. Limitations were greater in children with UCP ipsilateral motor pattern. Rehabilitation in the less-affected hand may be warranted. Bilateral hand function in future studies may help identify the optimal rehabilitation and neuromodulatory intervention. PMID- 29130384 TI - Characterising the growth in palliative care prescribing 2011-2015: Analysis of national medical and non-medical activity. AB - BACKGROUND: The role of non-medical prescribers working in palliative care has been expanding in recent years and prescribers report improvements in patient care, patient safety, better use of health professionals' skills and more flexible team working. Despite this, there is a lack of empirical evidence to demonstrate its clinical and economic impact, limiting our understanding of the future role of non-medical prescribers within a healthcare system serving an increasing number of people with palliative care needs. AIM: We developed a unique methodology to establish the level of non-medical prescribers' activity in palliative care across England and consider the likely overall contribution these prescribers are making at a national level in this context in relation to medical prescribing. SETTING/PARTICIPANTS: All prescriptions for 10 core palliative care drugs prescribed by general practitioners, nurses and pharmacists in England and dispensed in the community between April 2011 and April 2015 were extracted from the Prescribing Analysis Cost Tool system. DESIGN: The data were broken down by prescriber and basic descriptive analysis of prescription frequencies by opioid, non-opioids and total prescriptions by year were undertaken. To evaluate the yearly growth of non-medical prescribers, the total number of prescriptions was compared by year for each prescribing group. RESULTS: Non-medical prescribers issued prescriptions rose by 28% per year compared to 9% in those issued by medical prescribers. Despite this, the annual growth in non-medical prescribers prescriptions was less than 1% a year in relation to total community palliative care prescribing activity in England. Impact on medical prescribing is therefore minimal. PMID- 29130383 TI - Identification of a novel gene in ROD9 island of Salmonella Enteritidis involved in the alteration of virulence-associated genes expression. AB - Salmonella enterica subsp. I serovar Enteritidis (S. Enteritidis), one of the causative agents for non-typhoidal gastrointestinal diseases in humans is an intracellular bacterium and mechanism for its invasion into host cells is critical to cause infection. The virulence of the pathogen is explained by the expression of genes located on its pathogenicity islands, mostly encoded under SPI-1 and SPI-2. However, S. Typhimurium SL1344, despite sharing ~98% of its genome with S. Enteritidis P125109, lacks few regions of differences (ROD) that are hypothesized to impart virulence potential to S. Enteritidis. In this study, we created different mutants in the ROD9 island of S. Enteritidis, also referred as SPI-19 and identified a novel locus, SEN1005, encoding a hypothetical protein that is involved in its pathogenesis. DeltaSEN1005 displayed significantly reduced entry into cultured epithelial cells as well as uptake by macrophages and failed to cause acute colitis in C57BL/6 mice at day 3 post-infection (p.i.). Additionally, the global transcriptome analysis revealed a highly repressed SPI-1 and other down-regulated genes responsible for flagellar assembly, chemotaxis and motility in the mutant which correlated with decreased invasion and abated inflammation as compared to the wild-type. Therefore, our findings revealed that DeltaSEN1005 was attenuated in vitro as well as in vivo and we propose this hypothetical protein to play a role in altering the expression of genes involved in Salmonella virulence. PMID- 29130385 TI - Developing awareness of confabulation through psychological formulation: A case report and first-person perspective. AB - Confabulation, or the unintentional production of false, distorted or displaced memories, is commonly seen in people who have brain injury. However, it is most common in the acute phase, with persistent confabulation being comparatively rare. In this paper, we describe the case of Joe, a 24-year-old man who showed confabulation in the chronic phase of his rehabilitation, three years after traumatic brain injury. We describe our approach to therapy for this confabulation, and in particular how collaborative formulation enabled Joe to understand his confabulation, and then to manage it effectively, using a diary and "detective" procedure to identify whether or not evidence existed to support potentially confabulated memories. Furthermore, we include Joe's own perspective on what it is like to be confabulating, and on his experience of rehabilitation. This is an example of a successful insight-based therapeutic intervention, which is rare in this domain. To the best of our knowledge, this is also the first example of a first-person perspective on confabulation. PMID- 29130386 TI - Searching for God: Illness-Related Mortality Threats and Religious Search Volume in Google in 16 Nations. AB - We tested predictions about religiosity and terror management processes in 16 nations. Specifically, we examined weekly variation in Google search volume in each nation for 12 years (all weeks for which data were available). In all 16 nations, higher than usual weekly Google search volume for life-threatening illnesses (cancer, diabetes, and hypertension) predicted increases in search volume for religious content (e.g., God, Jesus, prayer) in the following week. This effect held up after controlling for (a) recent past and annual variation in religious search volume, (b) increases in search volume associated with religious holidays, and (c) variation in searches for a non-life-threatening illness ("sore throat"). Terror management threat reduction processes appear to occur across the globe. Furthermore, they may occur over much longer periods than those studied in the laboratory. Managing fears of death via religious belief regulation appears to be culturally pervasive. PMID- 29130387 TI - Palliative care in patients with haematological neoplasms: An integrative systematic review. AB - BACKGROUND: Palliative care was originally intended for patients with non haematological neoplasms and relatively few studies have assessed palliative care in patients with haematological malignancies. AIM: To assess palliative care interventions in managing haematological malignancies patients treated by onco haematology departments. DESIGN: Integrative systematic review with data extraction and narrative synthesis (PROSPERO #: CRD42016036240). DATA SOURCES: PubMed, CINAHL, Cochrane, Scopus and Web-of-Science were searched for articles published through 30 June 2015. Study inclusion criteria were as follows: (1) published in English or Spanish and (2) containing data on palliative care interventions in adults with haematological malignancies. RESULTS: The search yielded 418 articles; 99 met the inclusion criteria. Six themes were identified: (1) end-of-life care, (2) the relationship between onco-haematology and palliative care departments and referral characteristics, (3) clinical characteristics, (4) experience of patients/families, (5) home care and (6) other themes grouped together as 'miscellany'. Our findings indicate that palliative care is often limited to the end-of-life phase, with late referral to palliative care. The symptom burden in haematological malignancies patients is more than the burden in non-haematological neoplasms patients. Patients and families are generally satisfied with palliative care. Home care is seldom used. Tools to predict survival in this patient population are lacking. CONCLUSION: Despite a growing interest in palliative care for haematological malignancies patients, the evidence base needs to be strengthened to expand our knowledge about palliative care in this patient group. The results of this review support the need to develop closer cooperation and communication between the palliative care and onco haematology departments to improve patient care. PMID- 29130388 TI - Evaluation of ascitic soluble human leukocyte antigen-G for distinguishing malignant ascites from benign ascites. AB - The overexpression of soluble human leukocyte antigen-G is associated with malignant tumours. The purpose of our study was to detect soluble human leukocyte antigen-G concentrations in ascites and to evaluate the value of ascitic soluble human leukocyte antigen-G for the diagnosis of malignant ascites. Enzyme-linked immunosorbent assay was used to detect soluble human leukocyte antigen-G levels in 64 patients with malignant ascites and 30 patients with benign ascites. Receiver operating characteristic curves were used to evaluate the diagnostic efficacy of ascitic soluble human leukocyte antigen-G for the detection of malignant ascites. Ascitic soluble human leukocyte antigen-G levels were significantly higher in the malignant ascites group than in the benign ascites group (20.718 +/- 3.215 versus 12.467 +/- 3.678 ug/L, t = 7.425, p < 0.001). The area under the receiver operating characteristic curve for ascitic soluble human leukocyte antigen-G was 0.957 (95% confidence interval, 0.872-0.992). At a cut off value of 19.60 ug/L, the sensitivity and specificity of ascitic soluble human leukocyte antigen-G were 87.5% (95% confidence interval, 71.0%-96.5%) and 100% (95% confidence interval, 88.4%-100%), respectively. With respect to area under the receiver operating characteristic curve, sensitivity and specificity, ascitic carcinoembryonic antigen (0.810, 68.75% and 83.33%, respectively) and carbohydrate antigen 19-9 (0.710, 65.63% and 70%, respectively) significantly differed (all p < 0.05). In malignant ascites that were cytology-negative and biopsy-positive, the rate of positivity for ascitic soluble human leukocyte antigen-G was 75%, which was higher than the corresponding rates for ascitic carcinoembryonic antigen (31.25%) and carbohydrate antigen 19-9 (6.25%; both p < 0.05). In conclusion, The detection of ascitic soluble human leukocyte antigen-G exhibited good performance for diagnosing malignant ascites, and particularly those that were cytology-negative and biopsy-positive. PMID- 29130389 TI - Anti-cancer effects of F16: A novel vascular endothelial growth factor receptor specific inhibitor. AB - Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancers. This study was aimed to explore the anti-angiogenic activity of a novel vascular endothelial growth factor receptor specific inhibitor named F16 in both in vitro and in vivo experimental models. This compound effectively reduced cell proliferation, tube formation, and migration of human umbilical vein endothelial cells in a concentration-dependent manner by directly inhibiting vascular endothelial growth factor binding and subsequent vascular endothelial growth factor receptor-2 phosphorylation. The F16 was also able to inhibit the phosphoinositide 3-kinase/protein kinase B-mediated survival and migration pathways in cancer in addition to inhibiting the focal adhesion kinase and mitogen-activated protein kinases-mediated signaling in GI 101A cancer cells. The chorioallantoic membrane assay followed by tumor growth inhibition measurements with GI-101A breast cancer xenograft implanted athymic nude mice confirmed the in vivo tumor reductive effects of F16. It was interesting to observe a decrease in tumor burden after F16 treatment which correlated very well with the decrease in the plasma levels of mucin-1 (MUC-1). Our studies so far have confirmed that F16 is a specific inhibitor of angiogenesis in both in vitro and in vivo models. The F16 also works very efficiently with Taxol in combination by limiting the tumor growth that is better than the monotherapy with any one of the drugs that were tested individually. Thus, F16 offers a promising anti-proliferative and anti-angiogenic effects with better specificity than some of the existing multi-kinase inhibitors. PMID- 29130390 TI - Investigation of the differences between the Tibetan and Han populations in the hemoglobin-oxygen affinity of red blood cells and in the adaptation to high altitude environments. AB - OBJECTIVE: High altitude is characterized by low oxygen pressure, resulting in multiple adaptive responses. Tibetans who have lived in the plateau for thousands of years have developed unique phenotypes, such as downregulation of the HIF pathway through EPAS1 and EGLN1 gene mutation. However, the changes of hemoglobin oxygen affinity under hypoxia environment remain elusive. METHODS: A blood cell analyzer and a blood oxygen analyzer were used to conduct routine blood tests and measure the oxygen affinity P50 in in the Han population that rapidly entered the plateau (for 3-7 days), the plateau-acclimatized Han population (residing for 30 days on the plateau), the plateau Han population (more than 10 years on the plateau), and the Tibetan population. RESULTS: The Han population that rapidly entered the plateau had increasing higher P50 values, RBCs counts and hemoglobin (HGB) levels, while the acclimatized Han population, the plateau Han population and Tibetan all had significantly lower P50 values. However, there were no significant differences in the RBCs counts and HGB levels between the plateau Han, Tibetan populations and the Han population of the plains. DISCUSSION: The adaptability of the Tibetan and plateau Han populations to the plateau was mainly due to the strong affinity of HGB for oxygen, which provided sufficient oxygen for tissues and organs. CONCLUSIONS: The change of P50 could be a feature of the adaptation to the plateau and to avoid altitude sickness, such as high-altitude polycythemia and dyspnea. PMID- 29130392 TI - A novel hybrid multichannel biphasic calcium phosphate granule-based composite scaffold for cartilage tissue regeneration. AB - The objective of the present study was to develop a novel hybrid multichannel biphasic calcium phosphate granule (MCG)-based composite system for cartilage regeneration. First, hyaluronic acid-gelatin (HG) hydrogel was coated onto MCG matrix (MCG-HG). Poly(lactic-co-glycolic acid) (PLGA) microspheres was separately prepared and modified with polydopamine subsequent to BMP-7 loading (B). The surface-modified microspheres were finally embedded into MCG-HG scaffold to develop the novel hybrid (MCG-HG-PLGA-PD-B) composite system. The newly developed MCG-HG-PLGA-PD-B composite was then subjected to scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier Transform infrared spectroscopy, porosity, compressive strength, swelling, BMP-7 release and in-vitro biocompatibility studies. Results showed that 60% of BMP-7 retained on the granular surface after 28 days. A hybrid MCG-HG-PLGA-PD-B composite scaffold exhibited higher swelling and compressive strength compared to MCG-HG or MCG. In vitro studies showed that MCG-HG-PLGA-PD-B had improved cell viability and cell proliferation for both MC3T3-E1 pre-osteoblasts and ATDC5 pre-chondrocytes cell line with respect to MCG-HG or MCG scaffold. Our results suggest that a hybrid MCG-HG-PLGA-PD-B composite scaffold can be a promising candidate for cartilage regeneration applications. PMID- 29130391 TI - The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. AB - Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity. PMID- 29130393 TI - Wound-healing effects of human dermal components with gelatin dressing. AB - There have been numerous investigations regarding various types of dressings and artificial dermis of solid form, yet limited research and development on paste types, such as hydrogels with dermal powder, have ensued. In this study, we compared the in vivo wound healing effects of gelatin paste containing dermal powder to a collagen type I/chondroitin 6-sulfate (coll/chondroitin) sponge and gelatin alone, after 48 days post grafting, in a skin wound rat model. In the dermis powder/gelatin paste-treated group, wound area contraction was minimized 50%, while in the gelatin and coll/chondroitin sponge groups, the initial area contracted 83-85% and 79-85%, respectively. Histological analysis revealed the wounds treated with dermal powder/gelatin were associated with many fibroblasts, which infiltrated the wound bed, as well as thick collagen bundles that were arranged in dendritic arrays, resembling normal skin. Furthermore, in contrast to the gelatin- and coll/chondroitin sponge-treated groups, the powder/gelatin paste treated wounds exhibited an abundance of elastic fibers (Victoria blue staining) and extensive formation of blood vessels around the dermis (CD31 staining). Therefore, the dermis powder/gelatin paste not only renders convenience to users but also has prominent wound-healing effects on full-thickness wounds. PMID- 29130394 TI - Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B. AB - Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration. PMID- 29130396 TI - Upper Limb Coordination in Individuals With Stroke: Poorly Defined and Poorly Quantified. AB - BACKGROUND: The identification of deficits in interjoint coordination is important in order to better focus upper limb rehabilitative treatment after stroke. The majority of standardized clinical measures characterize endpoint performance, such as accuracy, speed, and smoothness, based on the assumption that endpoint performance reflects interjoint coordination, without measuring the underlying temporal and spatial sequences of joint recruitment directly. However, this assumption is questioned since improvements of endpoint performance can be achieved through different degrees of restitution or compensation of upper limb motor impairments based on the available kinematic redundancy of the system. Confusion about adequate measurement may stem from a lack a definition of interjoint coordination during reaching. METHODS AND RESULTS: We suggest an operational definition of interjoint coordination during reaching as a goal oriented process in which joint degrees of freedom are organized in both spatial and temporal domains such that the endpoint reaches a desired location in a context-dependent manner. CONCLUSIONS: In this point-of-view article, we consider how current approaches to laboratory and clinical measures of coordination comply with our definition. We propose future study directions and specific research strategies to develop clinical measures of interjoint coordination with better construct and content validity than those currently in use. PMID- 29130397 TI - HIPK3 modulates autophagy and HTT protein levels in neuronal and mouse models of Huntington disease. AB - Macroautophagy/autophagy is an important cellular protein quality control process that clears intracellular aggregate-prone proteins. These proteins may cause neurodegenerative disorders such as Huntington disease (HD), which is mainly caused by the cytotoxicity of the mutant HTT/Hdh protein (mHTT). Thus, autophagy modulators may regulate mHTT levels and provide potential drug targets for HD and similar diseases. Meanwhile, autophagy function is also impaired in HD and other neurodegenerative disorders via unknown mechanisms. In a recent study, we identified a positive feedback mechanism that may contribute to mHTT accumulation and autophagy impairment in HD. Through genome-scale screening, we identified a kinase gene, HIPK3, as a negative modulator of autophagy and a positive regulator of mHTT levels in HD cells. Knocking down or knocking out HIPK3 reduces mHTT levels via enhancing autophagy in HD cells and in vivo in an HD knock-in mouse model. Interestingly, mHTT positively regulates HIPK3 mRNA levels in both HD cells and HD mouse brains, and this forms a positive feedback loop between mHTT and HIPK3. This loop potentially contributes to autophagy inhibition, mHTT accumulation, and disease progression in HD. The modulation of mHTT by HIPK3 is dependent on its kinase activity and its known substrate DAXX, providing potential HD drug targets. Collectively, our data reveal a novel kinase modulator of autophagy in HD cells, providing therapeutic entry points for HD and similar diseases. PMID- 29130398 TI - Corrigendum. PMID- 29130395 TI - Pneumococcal whole-cell and protein-based vaccines: changing the paradigm. AB - INTRODUCTION: Epidemiologic evaluations of Streptococcus pneumoniae nasopharyngeal (NP) colonization and pneumococcal disease suggest that newer serotypes in future formulations of pneumococcal conjugate vaccines (PCVs) are needed and there may need to be continued reformulations because there are many new emerging serotypes expressed by pneumococci. Areas covered: Mechanisms of protection by next-generation whole-cell vaccine (WCV) and/or multi-component pneumococcal purified protein vaccines (PPVs) in development for prevention of pneumococcal infections. Expert commentary: A long-term strategy for prevention of pneumococcal disease will likely include WCV and PPVs. However these vaccines will impact disease pathogenesis in a different manner than PCVs. Prevention of pneumococcal NP colonization should not be expected, nor is it desirable because risks for NP colonization by other replacement organisms into the ecological niche vacated by all pneumococci may have consequences. The expression biology of capsule and surface protein antigens are phase dependent. Therefore, the immune response will be different and the mechanism of protection divergent. WCVs and PPVs may be alternative strategies in low income developing countries to protect against invasive disease and reduce NP carriage load. PMID- 29130399 TI - Recent trends in publications of US vascular surgery program directors. AB - Objective In order to examine the academic productivity of US vascular surgery program directors, the number of vascular publications listed in PubMed from 2001 to 2015 for US vascular surgery program directors was reviewed. We suggest that this can be used as a benchmark for academic productivity. Methods The names of the program directors were taken from the Accreditation Council for Graduate Medical Education (ACGME) website at two time points: December 2009 (Independent Programs) and December 2015 (Independent + Integrated). This was used to query PubMed, which listed 5196 publications: 3284 from 2001 to 2009 and 1912 from 2010 to 2015. Results There were 104 program directors (2001-2009) and 114 program directors (2010-2015) with average number of publications in PubMed per program director as 3.68/year (SD +/- 2.31) and 2.80/year (SD +/- 2.73), respectively ( P = .01). From 2001 to 2009, 1215 (37%) and in 2010 to 2015, 860 (45%) of the publications were from Journal of vascular surgery. The top third produced 67% and 69% of publications in the two time-points. No statistical difference was ascertained regionally: northeast, southeast, midwest and west ( P = .46). The numbers of publications/year decreased by 17% compared to first 10 years. From 2001 to 2009, there were no programs with no publications which increased to five and three with no Journal of Vascular Surgery publications which increased to 21 in 2010-2015. The independent and integrated program directors published average of 2.85 (SD +/- 2.69) and 3.47 (SD +/- 3.1) total publications; 1.25 (SD +/- 1.4) and 3.47 (SD +/- 1.7) Journal of Vascular Surgery papers/year, respectively ( P = .28, P = .23). Changes in the study subject were noted by percentage of total publications: endovascular lower extremity arterial (4.7% to 8.9%), Thoracic Endovascular Aortic Repair (TEVAR) (4.5% to 9.9%), Arterio-Venous (AV) access (0.0% to 3.0%), basic science (14.7% to 6.8%), open thoracic (3.0% to 0.6%). Conclusion There seems to be a significant decline in the number of publications over the last 15 years. Yet, the subject of the publications has progressed from Open to TEVAR with an increase in endovascular publications. However, basic science publications reduced by half. PMID- 29130400 TI - A randomized-controlled trial of cognitive-behavioral therapy for depression with integrated techniques from emotion-focused and exposure therapies. AB - BACKGROUND: Emotional processing (EP) is hypothesized to be a key mechanism of change in psychotherapy that may enhance its long-term efficacy. To study the effects of fostering EP in psychotherapy for depression, this randomized controlled clinical trial compares the efficacy and pattern of change of a cognitive-behavioral therapy that integrates emotion-focused techniques within an exposure framework (Exposure-Based Cognitive Therapy for depression; EBCT-R) to a standard cognitive-behavioral therapy (CBT). METHODS: One hundred and forty-nine depressed outpatients were randomized to a maximum of 22 sessions of manualized EBCT-R (N = 77) or CBT (N = 72). Primary outcomes were self-reported and clinician-rated depressive symptoms at posttreatment and 12-month follow-up. Secondary outcomes were self-esteem, interpersonal problems, and avoidance thoughts and behaviors. RESULTS: Depressive symptoms improved significantly over therapy in both treatments, with large within-group effect sizes for CBT (d = 1.95) and EBCT-R (d = -1.77). The pattern of depression change during treatment did not differ between treatments. Symptom relief lasted over 12 months and did not differ between EBCT-R and CBT. CONCLUSIONS: Results suggest that both treatments produced significant short- and long-term improvement in depression symptoms, but the integration of emotion-focused techniques within an exposure framework did not have added benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01012856. PMID- 29130401 TI - Combined Single-Tract of Minimally Percutaneous Nephrolithotomy and Flexible Ureteroscopy for Staghorn Calculi in Oblique Supine Lithotomy Position. AB - PURPOSE: To present our experience of combined single-percutaneous tract minimally invasive percutaneous nephrolithotomy (MPCNL) and flexible ureteroscopic lithotripsy (FURL) in managing staghorn calculi (SC) in oblique supine lithotomy position and to define the safety, efficiency, and feasibility of this approach. PATIENTS AND METHODS: Eighty-seven patients with SC treated with surgery in our hospital from March 2014 to January 2016 were retrospectively analyzed. The 87 patients were divided into 2 groups according to operative type: MPCNL combined with FURL (Group 1, n = 44) and MPCNL (Group 2, n = 43). The clinical data, perioperative parameters, and postoperative complications of the 2 groups were compared and analyzed. RESULTS: There were no significant differences in age, gender, stone type, and size ( P = .873, .570, .448, and .593, respectively). The average operative time, the average hospitalization time after surgery, the hemoglobin level, and the complication rate of Group 1 were lower than that of Group 2 ( P < .05 each). The first and second time stone free rates of Group 1 were higher than that of Group 2 ( P < .05 each). CONCLUSION: Single tract MPCNL combined with FURL in the oblique supine lithotomy position to treat SC could improve stone free rates, reduce operative time and length of hospital stay, decrease renal hemorrhage, and avoid other complications. We think this is an efficient and safe operative approach to manage SC. PMID- 29130402 TI - Assessing the performance and microbial community of hybrid moving bed and conventional membrane bioreactors treating municipal wastewater. AB - A conventional (SB-CMBR) and a hybrid moving-bed (SB-HMBR) sequencing batch membrane bioreactor treating municipal wastewater were compared during their start-up in terms of organic matter and nutrient removal, membrane fouling characteristics and microbial community. Both systems exhibited similar COD, ammonium, total nitrogen (TN) and phosphorus removal efficiency, amounting up to 96%, 99%, 70% and 85%, respectively. Results from cycle tests revealed that the contribution of attached biomass to the overall ammonium removal in the hybrid reactor was marginal. Moreover, higher despite the similar phosphorus removal efficiency attained in both reactors, nitrate-dosing activity batch assays specifically revealed that the anoxic phosphate uptake rate (PUR) in the SB-HMBR was 1.71 times higher than in the SB-CMBR. Moreover, a higher frequency of Candidatus Accumulibacter-related polyphosphate-accumulating organisms was observed in the biofilm carriers of the hybrid reactor. These findings may explain why the overall PUR was almost 50% higher in the SB-HMBR. By operating the reactors in sequencing batch mode, adhesion of particles on the membrane surface was reduced while fouling was mitigated as compared to continuous MBR systems. Better filterability conditions with lower fouling rate were found in the SB-HMBR, important features of the hybrid reactor for reducing membrane cleaning-related energy demand. PMID- 29130403 TI - Urinary Iodine, Perchlorate, and Thiocyanate Concentrations in U.S. Lactating Women. AB - BACKGROUND: Iodine is an essential micronutrient for thyroid hormone production. Adequate iodine intake and normal thyroid function are important during early development, and breastfed infants rely on maternal iodine excreted in breast milk for their iodine nutrition. The proportion of women in the United States of childbearing age with urinary iodine concentration (UIC) <50 MUg/L has been increasing, and a subset of lactating women may have inadequate iodine intake. UIC may also be influenced by environmental exposure to perchlorate and thiocyanate, competitive inhibitors of iodine transport into thyroid, and lactating mammary glands. Data regarding UIC in U.S. lactating women are limited. To adequately assess the iodine sufficiency of lactating women and potential associations with environmental perchlorate and thiocyanate exposure, we conducted a multicenter, cross-sectional study of urinary iodine, perchlorate, and thiocyanate concentrations in healthy U.S. lactating women. METHODS: Lactating women >=18 years of age were recruited from three U.S. geographic regions: California, Massachusetts, and Ohio/Illinois from November 2008 to June 2016. Demographic information and multivitamin supplements use were obtained. Iodine, perchlorate, and thiocyanate levels were measured from spot urine samples. Correlations between urinary iodine, perchlorate, and thiocyanate levels were determined using Spearman's rank correlation. Multivariable regression models were used to assess predictors of urinary iodine, perchlorate, and thiocyanate levels, and UIC <100 MUg/L. RESULTS: A total of 376 subjects (>=125 from each geographic region) were included in the final analyses [mean (SD) age 31.1 (5.6) years, 37% white, 31% black, and 11% Hispanic]. Seventy-seven percent used multivitamin supplements, 5% reported active cigarette smoking, and 45% were exclusively breastfeeding. Median urinary iodine, perchlorate, and thiocyanate concentrations were 143 MUg/L, 3.1 MUg/L, and 514 MUg/L, respectively. One-third of women had UIC <100 MUg/L. Spot urinary iodine, perchlorate, and thiocyanate levels all significantly positively correlated to each other. No significant predictors of UIC, UIC <100 MUg/L, or urinary perchlorate levels were identified. Smoking, race/ethnicity, and marital status were significant predictors of urinary thiocyanate levels. CONCLUSION: Lactating women in three U.S. geographic regions are iodine sufficient with an overall median UIC of 143 MUg/L. Given ubiquitous exposure to perchlorate and thiocyanate, adequate iodine nutrition should be emphasized, along with consideration to decrease these exposures in lactating women to protect developing infants. PMID- 29130404 TI - Differences in neural pathways are related to the short- or long-term benefits of constraint-induced movement therapy in patients with chronic stroke and hemiparesis: a pilot cohort study. AB - Background No previous studies have determined how the post-stroke integrity of non-corticospinal neural pathways relates to the efficacy of constraint-induced movement therapy (CIMT). Objectives We aimed to clarify the relationship between several non-corticospinal neural pathway integrities and the short- and long-term benefits of CIMT. Methods This was a pilot cohort study (UMIN registration number: R00027136UMIN000023566), for which we enrolled 13 patients with chronic stroke and hemiparesis who had undergone CIMT. We assessed patients' motor function improvement by comparing the Fugl-Meyer Assessment (FMA) scores, as well as the Amount of Use (AOU) and Quality of Movement (QOM) scales of the Motor Activity Log before, immediately after (short-term), and 6 months after (long term) CIMT. We assessed neural pathway integrity by calculating fractional anisotropy (FA) in diffusion tensor images acquired before CIMT. We then assessed correlations between FA and short- and long-term post-CIMT motor function improvements. Results The patients showed significant improvements in all functional assessments at both short- and long-term follow-ups. Immediate FMA score improvements were significantly correlated with FA of the affected anterior limb of the internal capsule (ALIC), body of the corpus callosum, column and body of the fornix (CBF), cingulate cortex (CgC), cerebral peduncle (CP), and posterior limb of the internal capsule. Six-month FMA score improvements were significantly correlated with FA of the affected ALIC, CgC, CBF, CP, and superior frontooccipital fasciculus. Conclusions The integrity of the affected corticospinal and non-corticospinal motor pathways was associated with CIMT induced motor learning at least 6 months after CIMT. PMID- 29130405 TI - What is the role of community at the end of life for people dying in advanced age? A qualitative study with bereaved family carers. AB - BACKGROUND: New public health approaches to palliative care prioritise the role of community at end of life. However, little is known about community support for the increasing numbers of people dying in advanced age. AIM: To explore the role of community at end of life for people dying in advanced age from the perspective of their bereaved family caregivers. DESIGN: A constructionist framework underpinned a qualitative research design. Data were analysed using critical thematic analysis. SETTING/PARTICIPANTS: A total of 58 participants (19 Maori and 39 non-Maori) who cared for 52 family members who died at >80 years of age participated in semi-structured interviews. RESULTS: A reduction in the social networks and community engagement of the older person was identified in the end of-life period. Numerous barriers to community engagement in advanced age were identified, including poor health (notably dementia), moving into an aged care facility and lack of access due to transport difficulties. An active withdrawal from community at end of life was also noted. Carers felt limited support from community currently, but identified that communities could play a particular role in reducing social isolation and loneliness among people of advanced age prior to death. CONCLUSION: Our study provides strong support for public health approaches to palliative care that advocate building social networks around people who are dying and their family carers. However, it also indicates that strategies to do so must be flexible enough to be responsive to the unique end-of-life circumstances of people in advanced age. PMID- 29130406 TI - Pubic hair removal and Phthirus pubis infestation. PMID- 29130407 TI - HIV and other STIs in male sex workers: Findings from a sexual health promotion intervention in Vietnam. AB - Male sex workers (MSWs) in Vietnam are at high risk for acquisition and transmission of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs), yet are extremely disengaged from the healthcare system. This contributes to large numbers of untreated or late-treated infections and increased secondary transmission. We enrolled 995 MSWs in Hanoi and Ho Chi Minh City (HCMC) in a Sexual Health Promotion intervention that included face-to-face delivery of seven content modules, a clinical examination and testing for HIV, syphilis, gonorrhea and Chlamydia. Onsite treatment was provided for STIs, and those who tested positive for HIV were referred to local treatment centers. While 64.6% of participants had never been to a health service and fewer than half (41.2%) had ever been tested for HIV, 67.1% returned for test results. This testing identified 109 (11.0%) participants who were HIV-positive and 312 (31.4%) who tested positive for at least one other STI. Substantive differences were seen in MSWs from different cities, with those from Hanoi more likely to have ever visited a health service (57.8% vs. 24.9%) and to have taken a prior HIV test (54.1% vs. 37.9%) than those in HCMC. Sexual health promotion is a promising approach to engaging MSWs in health services. PMID- 29130411 TI - The Implant Conundrum. PMID- 29130414 TI - Occlusal Angles of Equine Incisors. AB - The angulation of equine incisors is frequently used as a parameter for dental corrections. However, the term incisor angle is only vaguely defined, and no studies exist presenting a series of reliable measurements in individual incisors of multiple horses. The aim of this study was to establish an exact method to determine incisor angles and to test whether clinically accessible landmarks (facial crest and bars) are suitable to estimate incisor angles. Eighteen horses were used to create 3-dimensional (3D) reconstructions of the skulls from computed tomography (CT) data sets. Reference planes (median and transverse plane) were calculated using defined anatomical landmarks. Subsequently, occlusal planes for incisors and for incisor quadrants were calculated. Occlusal table angles were measured in relation to the reference planes. For each incisor, sagittal and transverse angles were measured. Mean values of individual incisor angles ranged from 3.5 degrees to 6.8 degrees (transverse angle) and from 32.6 degrees to 44.9 degrees (sagittal angle). No significant differences were detected in mean between the left and the right side when teeth in same Triadan positions were compared. However, in individual horses, marked differences between the left and the right side of the jaws occurred. Mandibular incisors showed significantly steeper sagittal angles than maxillary incisors. Furthermore, angles of opposing incisors were correlated with each other. The facial crest and the upper jaw bars featured a curved shape and were therefore of limited use to estimate the angulation of the upper incisors. In contrast, the lower jaw bars were suitable to determine the angulations of lower incisors. PMID- 29130416 TI - Prevalence, incidence and associated factors of pressure ulcers in home palliative care patients: A retrospective chart review. AB - BACKGROUND: Terminally ill patients are at high risk of pressure ulcers, which have a negative impact on quality of life. Data about pressure ulcers' prevalence, incidence and associated factors are largely insufficient. AIM: To document the point prevalence at admission and the cumulative incidence of pressure ulcers in terminally ill patients admitted to an Italian home palliative care unit, and to analyse the patients' and caregivers' characteristics associated with their occurrence. DESIGN: Retrospective chart review. SETTING/PARTICIPANTS: Patients ( n = 574) with a life expectancy ?6 months admitted to a palliative home care service were included in this study. RESULTS: The prevalence and incidence rates were 13.1% and 13.0%, respectively. The logistic regression models showed body mass index ( p < 0.001), Braden score at risk ( p < 0.001), Karnofsky Performance Scale index <30 ( p < 0.001), patients' female gender, patients' age >70 and >1 caregiver at home as the dichotomous variables predictors of presenting with a pressure ulcer at time of admission and during home palliative care. CONCLUSION: The notable pressure ulcers' incidence and prevalence rates suggest the need to include this issue among the main outcomes to pursue during home palliative care. The accuracy of body mass index, Braden Scale and Karnofsky Performance Scale in predicting the pressure ulcers risk is confirmed. Therefore, they appear as essential tools, in combination with nurses' clinical judgment, for a structured approach to pressure ulcers prevention. Further research is needed to explore the home caregivers' characteristics and attitudes associated with the occurrence of pressure ulcers and the relations between their strategies for pressure ulcer prevention and gender-related patient's needs. PMID- 29130415 TI - Mechanisms and function of autophagy in intestinal disease. AB - The discovery of numerous genetic variants in the human genome that are associated with inflammatory bowel disease (IBD) has revealed critical pathways that play important roles in intestinal homeostasis. These genetic studies have identified a critical role for macroautophagy/autophagy and more recently, lysosomal function, in maintaining the intestinal barrier and mucosal homeostasis. This review highlights recent work on the functional characterization of IBD-associated human genetic variants in cell type-specific functions for autophagy. PMID- 29130417 TI - Systems biology: mathematical modeling and model analysis. PMID- 29130418 TI - Caregiver quality of life in advanced cancer: Qualitative results from a trial of early palliative care. AB - BACKGROUND: Early involvement of palliative care improves patient quality of life; however, quantitative studies have not yet demonstrated a similar effect for caregivers, for whom the construct of quality of life is less well developed. AIM: To conceptualise quality of life of caregivers from their own perspective and to explore differences in themes between those who did or did not receive an early palliative care intervention. DESIGN: Qualitative grounded theory study. SETTING: Tertiary comprehensive cancer centre. PARTICIPANTS: Following participation in a cluster-randomised trial of early palliative care, 23 caregivers (14 intervention and 9 control) of patients with advanced cancer participated in semi-structured interviews to discuss their quality of life. RESULTS: The core category was 'living in the patient's world'. Five related themes were 'burden of illness and caregiving', 'assuming the caregiver role', 'renegotiating relationships', 'confronting mortality' and 'maintaining resilience'. There was thematic consistency between trial arms, except for the last two themes, which had distinct differences. Participants in the intervention group engaged in open discussion about the end of life, balanced hope with realism and had increased confidence from a range of professional supports. Controls tended to engage in 'deliberate ignorance' about the future, felt uncertain about how they would cope and lacked knowledge of available supports. CONCLUSIONS: Caregiver quality of life is influenced profoundly by the interaction with the patient and should be measured with specific questionnaires that include content related to confronting mortality and professional supports. This would improve delineation of quality of life for caregivers and allow greater sensitivity to change. Registration: clinicaltrials.gov NCT01248624. PMID- 29130419 TI - Recapitulation of Native Dermal Tissue in a Full-Thickness Human Skin Model Using Human Collagens. AB - OBJECTIVE: Full-thickness skin models comprise a three-dimensional dermal equivalent based on an animal-derived collagen matrix that harbors fibroblasts and an epidermal equivalent formed by keratinocytes. The functionality of both equivalents is influenced by many factors, including extracellular matrix composition and resident cell type. Animal-derived collagens differ in amino acid composition and physicochemical properties from human collagens. This composition could alter the functionality of the dermal equivalent and epidermal morphogenesis with the barrier formation in full-thickness models (FTMs). By replacement of animal-derived collagen for human collagen, we generated and characterized the animal material-free human collagen full-thickness models (hC FTMs) that better mimic native dermal tissue. MATERIALS AND METHODS: An isolation procedure to obtain soluble collagen from human abdominal dermis was developed. Both FTMs and hC-FTMs were generated with primary human fibroblasts and keratinocytes. Immunohistochemical analyses with biomarkers for the dermal matrix composition, basement membrane (BM) formation, epidermal proliferation, differentiation, and activation were performed. The stratum corneum (SC) lipid composition was studied with liquid chromatography-mass spectrometry. Lipid lamellar organization was determined by small-angle X-ray diffraction. RESULTS: The FTMs and hC-FTMs exhibit many similarities, including the dermal matrix structure, BM formation, epidermal basal layer proliferation, and execution of differentiation programs. The SC contains a similar number of corneocyte layers and the same level of lipids. The ceramide chain length distribution and ceramide subclass profile showed only minor differences. Subsequently, this led to an unaltered lamellar organization. CONCLUSION: The animal material-free hC-FTM is generated successfully using collagens isolated from human abdominal dermis. Utilization of human collagens revealed that (epi-)dermal morphogenesis and lipid barrier formation resembled that of original FTMs. The hC-FTMs contain a dermal equivalent that mimics the native stromal tissue to a higher extent. Therefore these in vitro skin models can be used as promising tool for research purposes that contribute to animal-free experimentation. PMID- 29130420 TI - "There are more things in heaven and earth!" How knowledge about traditional healing affects clinical practice: interviews with conventional health personnel. AB - People with Sami and Norwegian background are frequent users of traditional folk medicine (TM). Traditional healing, such as religious prayers of healing (reading) and the laying on of hands, are examples of commonly used modalities. The global aim of this study is to examine whether health personnel's knowledge, attitudes and experiences of traditional healing affect their clinical practice. Semi-structured individual interviews (n=32) and focus group interviews (n=2) were conducted among health personnel in two communities in Northern Norway. The text data was transcribed verbatim and analysed based on the criteria for content analysis. Six themes were identified. The participants had acquired their knowledge of traditional healing through their childhood, adolescence and experience as health personnel in the communities. They all expressed that they were positive to the patients' use of traditional healing. They justified their attitudes, stating that "there are more things in heaven and earth" and they had faith in the placebo effects of traditional healing. The health personnel respected their patients' faith and many facilitated the use of traditional healing. In some cases, they also applied traditional healing tools if the patients asked them to do so. The health personnel were positive and open-minded towards traditional healing. They considered reading as a tool that could help the patients to handle illness in a good way. Health personnel were willing to perform traditional healing and include traditional tools in their professional toolkit, even though these tools were not documented as evidence-based treatment. In this way they could offer their patients integrated health services which were tailored to the patients' treatment philosophy. PMID- 29130423 TI - Re: "Suitability of a 7-F ExoSeal Vascular Closure Device for Femoral Artery Punctures Made by 8-F or 9-F Introducer Sheaths". PMID- 29130422 TI - Factors Influencing Decision Making in the Treatment of Complex Pararenal Aortic Pathologies: The APPROACH Concept. PMID- 29130421 TI - High tobacco use prevalence with significant regional and sex differences in smokeless tobacco use among Western Alaska Native people: the WATCH study. AB - Tobacco use prevalence among Alaska Native (AN) people living in Alaska is greater than the general population prevalence statewide and nationally. Better understanding of regional tobacco use is needed to improve cessation efforts and reduce prevalence. Using self-reported baseline data from the Western Alaska Tribal Collaborative for Health study, we describe tobacco use patterns among AN people in two western Alaska regions. Data were stratified by age group and sex. Dual- and multi-product use in the Yukon-Kuskokwim (Y-K) region was stratified by concurrent vs sequential use. Overall, 87% of the cohort reported having used tobacco. In Norton Sound, cigarette (98%) was the predominant tobacco type. In Y K 71% smoked, 76% used smokeless tobacco (ST), with 47% reporting use of both products. ST use in Y-K consisted of commercial ST and homemade iqmik. Y-K women reported more ST product use, while men reported more cigarette use. Among dual- and multi-product users, the majority reported concurrent use, with no significant differences between men and women. Distinct regional differences include high smoking prevalence in Norton Sound and frequent use of smoking and ST products in Y-K. Findings support modification of cessation programmes to address regional variations in tobacco use patterns. PMID- 29130424 TI - Clifford J. Buckley, MD (1936-2017). PMID- 29130425 TI - Communication about palliative care: A phenomenological study exploring patient views and responses to its discussion. AB - BACKGROUND: Communication about palliative care is a complex task frequently delayed until otherwise unavoidable. There is a need for discussion of palliative care to be viewed as a distinct communication task that is guided by empirical data. However, little is known of patient views and responses to these encounters. AIM: To explore patient views surrounding communication about palliative care and their responses to its discussion. DESIGN: Cross-sectional, prospective, exploratory qualitative design, involving narrative-style interviews and underpinned by an interpretative phenomenological framework. SETTING/PARTICIPANTS: Purposively sampled, English-speaking, adult patients with advanced cancer ( n = 30) recruited from cancer services at a tertiary metropolitan hospital in Melbourne, Australia. RESULTS: Three major themes evolved. (1) Death as unspeakable: death was expressed using only implicit, ambiguous or technical terms and perceived to be outside the parameters of medical interactions. (2) Palliative care as a euphemism for death: the term 'palliative care' was perceived to be used by health professionals as a tool to talk about dying and understood by patients as a euphemism for death. (3) Palliative care as unspeakable: 'palliative care' was personified by patients to mean not just death, but my death, in turn, also becoming unspeakable. CONCLUSION: This study provides important new patient insights and responses to the discussion of palliative care. Results demonstrate that the task of discussing palliative care remains complex, difficult and limited by our language. Greater consistency, sensitivity and sophistication are required when talking about palliative care to patients who may benefit from this care. PMID- 29130427 TI - Reduction of anxiety sensitivity in relation to nicotine withdrawal symptoms during smoking cessation: an examination among successful quitters. AB - Anxiety sensitivity has been implicated as a potential risk factor for post-quit withdrawal symptoms. The present study examined relations between the extent of change in anxiety sensitivity and the course of nicotine withdrawal symptoms experienced during the initial two weeks of a quit attempt among treatment seeking smokers. The sample consisted of 29 adult daily smokers (34% female; Mage = 47.7, SD = 13.1) who successfully quit and maintained their abstinence. After adjusting for the effects of gender, treatment condition, use of nicotine replacement therapy, nicotine dependence, alcohol use problems, baseline levels of anxiety sensitivity, and reductions in negative affect, greater reductions in anxiety sensitivity were related to faster decreases in withdrawal symptoms. The current data suggest that there may be merit to employ anxiety sensitivity reduction methods for the management of emergent withdrawal symptoms in smoking cessation treatment. PMID- 29130426 TI - NUPR1 maintains autolysosomal efflux by activating SNAP25 transcription in cancer cells. AB - In the advanced stages of cancer, autophagy is thought to promote tumor progression through its ability to mitigate various cellular stresses. However, the details of how autophagy is homeostatically regulated in such tumors are unknown. Here, we report that NUPR1 (nuclear protein 1, transcriptional regulator), a transcriptional coregulator, is aberrantly expressed in a subset of cancer cells and predicts low overall survival rates for lung cancer patients. NUPR1 regulates the late stages of autolysosome processing through the induction of the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE associated protein VAMP8. NUPR1 depletion deregulates autophagic flux and impairs autolysosomal clearance, inducing massive cytoplasmic vacuolization and premature senescence in vitro and tumor suppression in vivo. Collectively, our data show that NUPR1 is a potent regulator of autolysosomal dynamics and is required for the progression of some epithelial cancers. PMID- 29130428 TI - A Scoping Review of Physical Rehabilitation in Long-Term Care: Interventions, Outcomes, Tools. AB - Residents in long-term care (LTC) often require physical rehabilitation (PR) to maintain/improve physical function. This scoping review described the breadth of literature regarding PR in LTC to date, synthesizing PR interventions that have been evaluated, outcomes used, and tools for determining service eligibility. A structured search, conducted in six licensed databases and grey literature, identified 381 articles for inclusion. Most interventions were delivered and evaluated at the resident level and typically were multicomponent exercise programs. Performance-based measures, activities of daily living, and mood were the most frequently reported outcomes. A key knowledge gap was PR in relation to goals, such as quality of life. Future studies should reflect medically complex residents who live in LTC, and length of residents' stay should be differentiated. Intervention studies should also explore realistic delivery methods; moreover, tool development for determining service eligibility is necessary to ensure equality in rehabilitative care across the LTC sector. PMID- 29130429 TI - Izhakiella australiensis sp. nov. isolated from an Australian desert soil. AB - A Gram-stain-negative, rod-shaped, non-motile bacterium, designated D4N98T, was isolated from a desert soil near Glendambo, Australia. The taxonomic position of strain D4N98T was investigated using a polyphasic approach. Strain D4N98T shared 97 % 16S rRNA gene sequence similarity with the only reference strain of the genus Izhakiella (Izhakiella capsodis N6PO6T), and less than 96 % similarity with other species of genera in the family Enterobacteriaceae with validly published names. Phylogenetic analysis, based on 16S rRNA, rpoB, atpD, gyrB genes and a concatenated sequence comprising 37 single copy marker genes, as well as chemotaxonomic data (major polar lipids: phosphatidyl ethanolamine, phosphatidylglycerol, diphosphatidylglycerol, a neutral lipid, and a glycolipid. Major fatty acids (>10 %): C16 : 0, C17 : 0 cyclo, summed feature 2 (C14 : 0 3-OH and/or iso-C16 : 1 I), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) support the affiliation of this strain to the genus Izhakiella. The results of in silico DNA-DNA hybridisation plus physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain D4N98T from the other species of the genus Izhakiellawith validly published names. Therefore, strain D4N98T represents a novel species, for which the name Izhakiella australiensis sp. nov. is proposed. The type strain is D4N98T (LMG 30066T=DSM 105030T). PMID- 29130430 TI - Kuraishia mediterranea sp. nov., a methanol-assimilating yeast species from olive oil and its sediment. AB - Six yeast strains isolated from olive oil sediments and spoiled olive oils originating from Slovenia and Portugal, respectively, proved to represent an undescribed yeast species based on DNA sequence comparisons. The analysis of gene sequences for internal transcribed spacer regions and the large subunit rRNA gene D1/D2 domain placed the novel species in the genus Kuraishia in a subclade containing Kuraishiacapsulata, the type species of the genus. Although the novel species is well separated genetically from the recognized species of the genus, only a minor phenotypic difference differentiating it from Kuraishia capsulata and K. molischiana was observed. Relevant to its isolation source, no lipolytic activity was detected in the strains of the novel species. To accommodate the above-noted strains, Kuraishia mediterranea sp. nov. (holotype: ZIM 2473T; isotype: CBS 15107T; MycoBank no.: MB 822817) is proposed. PMID- 29130431 TI - Erratum: Rugosibacter aromaticivorans gen. nov., sp. nov., a bacterium within the family Rhodocyclaceae, isolated from contaminated soil, capable of degrading aromatic compounds. PMID- 29130432 TI - Corrigendum: Proposal to reclassify Propionibacterium acnes type I as Propionibacterium acnes subsp. acnes subsp. nov. and Propionibacterium acnes type II as Propionibacterium acnes subsp. defendens subsp. nov. PMID- 29130433 TI - List of new names and new combinations previously effectively, but not validly, published. PMID- 29130434 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 67, part 8, of the IJSEM. PMID- 29130435 TI - Remote Hearing Healthcare. PMID- 29130436 TI - Hearing Technology Use and Management in School-Age Children: Reports from Data Logs, Parents, and Teachers. AB - BACKGROUND: Consistency of hearing aid and remote microphone system use declines as school-age children with hearing loss age. One indicator of hearing aid use time is data logging, another is parent report. Recent data suggest that parents overestimate their children's hearing aid use time relative to data logging. The potential reasons for this disparity remain unclear. Because school-age children spend the majority of their day away from their parents and with their teachers, reports from teachers might serve as a valuable and additional tool for estimating hearing aid use time and management. PURPOSE: This study expands previous research on factors influencing hearing aid use time in school-age children using data logging records. Discrepancies between data logging records and parent reports were explored using custom surveys designed for parents and teachers. Responses from parents and teachers were used to examine hearing aid use, remote microphone system use, and hearing aid management in school-age children. STUDY SAMPLE: Thirteen children with mild-to-moderate hearing loss between the ages of 7 and 10 yr and their parents participated in this study. Teachers of ten of these children also participated. DATA COLLECTION AND ANALYSIS: Parents and teachers of children completed written surveys about each child's hearing aid use, remote microphone system use, and hearing aid management skills. Data logs were read from hearing aids using manufacturer's software. Multiple linear regression analysis and an intraclass correlation coefficient were used to examine factors influencing hearing aid use time and parent agreement with data logs. Parent report of hearing aid use time was compared across various activities and school and nonschool days. Survey responses from parents and teachers were compared to explore areas requiring potential improvement in audiological counseling. RESULTS: Average daily hearing aid use time was ~6 hr per day as recorded with data logging technology. Children exhibiting greater degrees of hearing loss and those with poorer vocabulary were more likely to use hearing aids consistently than children with less hearing loss and better vocabulary. Parents overestimated hearing aid use by ~1 hr per day relative to data logging records. Parent-reported use of hearing aids varied across activities but not across school and nonschool days. Overall, parents and teachers showed excellent agreement on hearing aid and remote microphone system use during school instruction but poor agreement when asked about the child's ability to manage their hearing devices independently. CONCLUSIONS: Parental reports of hearing aid use in young school-age children are largely consistent with data logging records and with teacher reports of hearing aid use in the classroom. Audiologists might find teacher reports helpful in learning more about children's hearing aid management and remote microphone system use during their time at school. This supplementary information can serve as an additional counseling tool to facilitate discussion about remote microphone system use and hearing aid management in school-age children with hearing loss. PMID- 29130437 TI - Remote Hearing Aid Support: The Next Frontier. AB - BACKGROUND: In an effort to reduce health-care disparities, there has been a recent surge of interest in the remote provision of care. Audiologists have begun to provide screening, diagnostic, and rehabilitative services via telehealth technologies. PURPOSE: To evaluate the feasibility and perceived benefits of providing remote hearing aid follow-up appointments in a controlled clinical environment and in participants' homes. RESEARCH DESIGN: A descriptive quasi experimental study was completed. STUDY SAMPLE: The study consisted of two phases. The in-clinic phase included 50 adults with hearing loss who participated in remote hearing aid follow-up appointments at Vanderbilt University Medical Center. A subgroup of 21 adults from the original in-clinic phase plus one additional participant completed the in-home appointments. DATA COLLECTION AND ANALYSIS: All participants completed the Montreal Cognitive Assessment and study designed questionnaires. All participants were asked to install proprietary distance support (DS) client software on a laptop or desktop computer and participate in hearing aid follow-up appointments. RESULTS: The majority of participants in both groups installed the DS client software with no assistance other than written instructions, and indicated a preference for DS appointments over face-to-face appointments. CONCLUSION: On average, participants and the study audiologist were satisfied with remote hearing aid follow-up visits. Additional support might be needed for older patients with little confidence in their ability to interact with technology. PMID- 29130439 TI - Cochlear Implantation in Children with Postlingual Progressive Steeply Sloping High-Frequency Hearing Loss. AB - BACKGROUND: Children with steeply sloping sensorineural hearing loss (SNHL) lack access to critical high-frequency cues despite the use of advanced hearing aid technology. In addition, their auditory-only aided speech perception abilities often meet Food and Drug Administration criteria for cochlear implantation. PURPOSE: The objective of this study was to describe hearing preservation and speech perception outcomes in a group of young children with steeply sloping SNHL who received a cochlear implant (CI). RESEARCH DESIGN: Retrospective case series. STUDY SAMPLE: Eight children with steeply sloping postlingual progressive SNHL who received a unilateral traditional CI at Seattle Children's Hospital between 2009 and 2013 and had follow-up data available up to 24 mo postimplant were included. DATA COLLECTION AND ANALYSIS: A retrospective chart review was completed. Medical records were reviewed for demographic information, preoperative and postoperative behavioral hearing thresholds, and speech perception scores. Paired t tests were used to analyze speech perception data. Hearing preservation results are reported. RESULTS: Rapid improvement of speech perception scores was observed within the first month postimplant for all participants. Mean monosyllabic word scores were 76% and mean phoneme scores were 86.7% at 1-mo postactivation compared to mean preimplant scores of 19.5% and 31.0%, respectively. Hearing preservation was observed in five participants out to 24-mo postactivation. Two participants lost hearing in both the implanted and unimplanted ear, and received a sequential bilateral CI in the other ear after progression of the hearing loss. One participant had a total loss of hearing in only the implanted ear. Results reported in this article are from the ear implanted first. Bilateral outcomes are not reported. CONCLUSIONS: CIs provided benefit for children with steeply sloping bilateral hearing loss for whom hearing aids did not provide adequate auditory access. In our cohort, significant improvements in speech understanding occurred rapidly postactivation. Preservation of residual hearing in children with a traditional CI electrode is possible. PMID- 29130438 TI - Segmental and Suprasegmental Perception in Children Using Hearing Aids. AB - BACKGROUND: Suprasegmental perception (perception of stress, intonation, "how something is said" and "who says it") and segmental speech perception (perception of individual phonemes or perception of "what is said") are perceptual abilities that provide the foundation for the development of spoken language and effective communication. While there are numerous studies examining segmental perception in children with hearing aids (HAs), there are far fewer studies examining suprasegmental perception, especially for children with greater degrees of residual hearing. Examining the relation between acoustic hearing thresholds, and both segmental and suprasegmental perception for children with HAs, may ultimately enable better device recommendations (bilateral HAs, bimodal devices [one CI and one HA in opposite ears], bilateral CIs) for a particular degree of residual hearing. Examining both types of speech perception is important because segmental and suprasegmental cues are affected differentially by the type of hearing device(s) used (i.e., cochlear implant [CI] and/or HA). Additionally, suprathreshold measures, such as frequency resolution ability, may partially predict benefit from amplification and may assist audiologists in making hearing device recommendations. PURPOSE: The purpose of this study is to explore the relationship between audibility (via hearing thresholds and speech intelligibility indices), and segmental and suprasegmental speech perception for children with HAs. A secondary goal is to explore the relationships among frequency resolution ability (via spectral modulation detection [SMD] measures), segmental and suprasegmental speech perception, and receptive language in these same children. RESEARCH DESIGN: A prospective cross-sectional design. STUDY SAMPLE: Twenty-three children, ages 4 yr 11 mo to 11 yr 11 mo, participated in the study. Participants were recruited from pediatric clinic populations, oral schools for the deaf, and mainstream schools. DATA COLLECTION AND ANALYSIS: Audiological history and hearing device information were collected from participants and their families. Segmental and suprasegmental speech perception, SMD, and receptive vocabulary skills were assessed. Correlations were calculated to examine the significance (p < 0.05) of relations between audibility and outcome measures. RESULTS: Measures of audibility and segmental speech perception are not significantly correlated, while low-frequency pure-tone average (unaided) is significantly correlated with suprasegmental speech perception. SMD is significantly correlated with all measures (measures of audibility, segmental and suprasegmental perception and vocabulary). Lastly, although age is not significantly correlated with measures of audibility, it is significantly correlated with all other outcome measures. CONCLUSIONS: The absence of a significant correlation between audibility and segmental speech perception might be attributed to overall audibility being maximized through well-fit HAs. The significant correlation between low-frequency unaided audibility and suprasegmental measures is likely due to the strong, predominantly low-frequency nature of suprasegmental acoustic properties. Frequency resolution ability, via SMD performance, is significantly correlated with all outcomes and requires further investigation; its significant correlation with vocabulary suggests that linguistic ability may be partially related to frequency resolution ability. Last, all of the outcome measures are significantly correlated with age, suggestive of developmental effects. PMID- 29130440 TI - Development and Pilot Evaluation of a Novel Theory-Based Intervention to Encourage Help-Seeking for Adult Hearing Loss. AB - BACKGROUND: Health behavior theories can provide an understanding of hearing health behaviors and, more importantly, can be used to develop theoretically based strategies to change these health behaviors. PURPOSE: To develop a theory based brief intervention to increase help-seeking for adult hearing loss and to conduct a pilot study to evaluate its feasibility, effectiveness, and impact on hearing beliefs and behaviors. RESEARCH DESIGN: An intervention was designed that could be easily administered by a health-care provider who does not have expertise in audiology-such as a primary care physician, community nurse, or social worker. The intervention aims to alter perceived benefit, severity, cues to action, and self-efficacy for seeking help by providing experiential/affective messaging and simultaneously providing intrinsic motivation for the recipient to seek hearing help. To first determine whether this intervention changed beliefs and increased help-seeking behavior, this study was conducted in a hearing research laboratory setting. STUDY SAMPLE: A total of 101 adults aged 50-89 yr were recruited within 6 months of having attended an appointment at a primary care clinic at the VA Portland Health Care System. All were sent a letter inviting them to participate in a study if they had trouble with their hearing but had not had a scheduled hearing test or worn hearing aids in the prior 5 yr and also had functional oral and written English. Data from 87 individuals were available for analysis. INTERVENTION: The intervention is designed for use in any health-care setting in which a health-care provider can facilitate a conversation about hearing. On arrival at a health-care facility, recipients are provided with nine emotionally evocative color photographs to prompt reflection on ways in which hearing difficulties impact them. A discussion with a health-care provider (facilitator) follows, during which recipients may identify the negative impacts of their hearing loss. If the recipient identifies negative impacts, the facilitator suggests that he or she consider having a hearing test and provides a list of local hearing-health professionals. DATA COLLECTION AND ANALYSIS: Participants completed baseline questionnaires assessing hearing beliefs and attitudes. They were then randomly assigned either to the group receiving the study intervention or to a control group. Six months after study enrollment, participants reported whether they had sought help for their hearing and completed a second set of questionnaires. RESULTS: Twelve of 41 individuals (29.3%) in the intervention group and 7 of 46 individuals (15.2%) in the control group sought help within the 6-month follow-up period. A chi2 test showed these numbers did not differ significantly; however, the odds ratio of having had a hearing test were 2.3 times greater for those who received the intervention than for those who did not. CONCLUSIONS: Despite not reaching statistical significance, the odds ratio suggests that the theory-based brief intervention is worthy of additional examination. We intend to work with health-care providers to conduct a larger study to investigate whether the intervention has value in the real world. PMID- 29130441 TI - Is the Device-Oriented Subjective Outcome (DOSO) Independent of Personality? AB - BACKGROUND: Self-report questionnaires are a frequently used method of evaluating hearing aid outcomes. Studies have shown that personality can account for 5-20% of the variance in response to self-report measures. As a result, these influences can impact results and limit their generalizability when the purpose of the study is to examine the technological merit of hearing aids. To reduce personality influences on self-report outcome data, the Device-Oriented Subjective Outcome (DOSO) was developed. The DOSO is meant to demonstrate outcomes of the amplification device relatively independent of the individual's personality. Still, it is unknown if the DOSO achieves its original goal. PURPOSE: The purpose of this study was to examine the relationship between personality and the DOSO. The relationship between personality and several widely used hearing-related questionnaires was also examined. RESEARCH DESIGN: This is a nonexperimental study using a correlational design. STUDY SAMPLE: A total of 119 adult hearing aid wearers participated in the study. DATA COLLECTION AND ANALYSIS: The NEO Five-Factor Inventory was used to measure five personality traits (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). The initial (unaided) hearing disablement, residual (aided) hearing disablement, and hearing aid benefit and satisfaction was measured using the DOSO, Hearing Handicap Inventory for the Elderly/Adult, Abbreviated Profile of Hearing Aid Benefit, and Satisfaction with Amplification in Daily Life. The relationship between personality and each questionnaire was examined using a correlation analysis. RESULTS: All of the DOSO subscales were found to be significantly correlated to personality, regardless of whether age and better-ear hearing thresholds were controlled. Individuals who reported poorer hearing aid outcomes tended to have higher Neuroticism scores, while those who scored higher in Extraversion, Openness, and Agreeableness were more likely to report better outcomes. Across DOSO subscales, the maximum variance explained by personality traits ranged from 6% to 11%. Consistent with the literature, ~3-18% of the variance of other hearing-related questionnaires was attributable to personality. CONCLUSIONS: The degree to which personality affects the DOSO is similar to other hearing-related questionnaires. Although the variance accounted for by personality is not large, researchers and clinicians should not assume that the results of the DOSO are independent of personality. PMID- 29130442 TI - Outcomes of Hearing Aid Use by Individuals with Unilateral Sensorineural Hearing Loss (USNHL). AB - BACKGROUND: Unilateral sensorineural hearing loss (USNHL) can have a negative impact on functions associated with the advantages of balanced, binaural hearing. Although single-sided deafness, which is a complete loss of audibility in one ear, has gained increased interest in the published research, there is a gap in the literature concerning hearing aid outcomes for individuals with residual, or otherwise "aidable," hearing in the affected ear. PURPOSE: To assess hearing aid outcomes for a group of individuals with USNHL with residual, aidable function. RESEARCH DESIGN: A quasi-experimental study of hearing aid outcomes with paired comparisons made between unaided and aided test conditions. STUDY SAMPLE: A convenience sample of twenty-two individuals with USNHL, with sufficient residual hearing in the affected ear as to receive audibility from use of a hearing aid, were recruited into the study from September 2011 to August 2012. INTERVENTION: Each participant was fit with a digital behind-the-ear hearing aid coupled to a custom ear mold. DATA COLLECTION AND ANALYSIS: Assessments were performed at baseline (unaided) and after a three-month field trial (aided) with primary outcomes involving objective measures in sound field yielding signal-to-noise ratio loss (SNR Loss) via the Quick Speech-in-Noise Test and word recognition scores (WRS) via the Northwestern University Auditory Test, No. 6. Outcomes also involved the administration of two well-established subjective benefit questionnaires: The Abbreviated Profile of Hearing Aid Benefit (APHAB) and the 49 item Speech, Spatial, and Qualities of Hearing Scale (SSQ49). RESULTS: As a group, participants showed significantly improved median SNR Loss thresholds when aided in a test condition that included spatial separation of speech and noise, with speech stimuli directed toward the worse ear and noise stimuli directed toward the better ear (diff. = -4.5; p < 0.001). Hearing aid use had a small, though statistically significant, negative impact on median SNR Loss thresholds, when speech and noise stimuli originated from the same 0 degrees azimuth (diff. = 1.0; p = 0.018). This was also evidenced by the median WRS in sound field (diff. = -6.0; p = 0.006), which was lowered from 98% in the unaided state to 92% in the aided state. Results from the SSQ49 showed statistically significant improvement on all subsection means when participants were aided (p < 0.05), whereas results from the APHAB were generally found to be unremarkable between unaided and aided conditions as benefit was essentially equal to the 50th percentile of the normative data. At the close of the study, it was observed that only slightly more than half of all participants chose to continue use of a hearing aid after their participation. CONCLUSIONS: We observed that hearing aid use by individuals with USNHL can improve the SNR Loss associated with the interference of background noise, especially in situations when there is spatial separation of the stimuli and speech is directed toward the affected ear. In addition, hearing aid use by these individuals can provide subjective benefit, as evidenced by the APHAB and SSQ49 subjective benefit questionnaires. PMID- 29130444 TI - Erratum. AB - [This corrects the article DOI: 10.3766/jaaa.15105.]. PMID- 29130443 TI - Unraveling the Mystery of Auditory Brainstem Response Corrections: The Need for Universal Standards. AB - BACKGROUND: The auditory brainstem response (ABR) is used to estimate behavioral hearing thresholds in infants and difficult-to-test populations. Differences between the toneburst ABR and behavioral thresholds exist making the correspondence between the two measures less than perfect. Some authors have suggested that corrections be applied to ABR thresholds to account for these differences. However, because there is no agreed upon universal standard, confusion regarding the use of corrections exists. PURPOSE: The primary purpose of this article is to review the reasoning behind and use of corrections when the toneburst ABR is employed to estimate behavioral hearing thresholds. We also discuss other considerations that all audiologists should be aware of when obtaining and reporting ABR test results. RESULTS: A review of the purpose and use of corrections reveals no consensus as to whether they should be applied or which should be used. Additionally, when ABR results are adjusted, there is no agreement as to whether additional corrections for hearing loss or the age of the client are necessary. This lack of consensus can be confusing for all individuals working with hearing-impaired children and their families. CONCLUSIONS: Toneburst ABR thresholds do not perfectly align with behavioral hearing thresholds. Universal protocols for the use of corrections are needed. Additionally, evidence based procedures must be employed to obtain valid ABRs that will accurately estimate hearing thresholds. PMID- 29130446 TI - The role of mucin-educated platelet activation in tumor invasiveness: An unfolding concern in the realm of cancer biology. AB - Metastasis is a complex and well-coordinated phenotypic transformation of cancer cells governed by aberrant genetic and molecular pathways. It has been approved as the most consistent cause of cancer death. With emerging insight into the genomics, transcriptomics and proteomics, progress has been made and reasonably large number of molecular pathways of metastasis has been forwarded, but our understanding of precise underlying molecular mechanisms remains largely scarce. It has been well-known for around a decade and more that platelets are intriguingly contributing to the cancer metastasis. However, it is only recently that cancer cells can activate platelets have started to become apparent. Surprisingly, platelets in response to cancer cell activation, supported by research observations, allow cancer cells to escape immune removal, prolong survival in vascular compartment, increased cellular adhesion and develop new cellular niches which eventually help to favor cancer metastasis. Although a widely acknowledged plausible explanation that cancer cells activate platelets to facilitate in their distant spread, the description of this remains to be confirmed. In recent years, mucins, heavily glycosylated peptide structure, have been introduced to be released by several types of cancer cells. They account for poor prognosis in wide array of malignancies, because of their significant ability to induce metastatic process. The mechanism responsible for their increased metastatic propensity remains uncharacterized, but recent work suggested the role of cancer expressed mucins in initiating platelet thrombus. The association of cancer yield mucins, platelets and metastasis therefore suggests a pressing need to explore novel molecular mechanisms and therapeutic targets thereafter. PMID- 29130447 TI - Only lasers can be used for low level laser therapy. AB - The question of lasers' exclusivity, as well as the degree of influence of special properties of low-intensity laser illumination (LILI), such as coherence, polarity and monochromaticity, on the effectiveness of low level laser therapy (LLLT) continues to cause arguments. The study analyzes publications from 1973 to 2016, in which laser and conventional light sources are compared, and the following conclusions are drawn. First, there are a lot of publications with incorrect comparison or unfounded statements. Secondly, other sources of light are often meant by LILI without any justification. Thirdly, all studies, in which the comparison is carried out correctly and close parameters of the impact and the model are used, have a firm conclusion that laser light is much more effective. Fourthly, it is uniquely identified that the most important parameter that determines the efficiency of lasers is monochromaticity, i.e., a much narrower spectral width than for all other light sources. Only laser light sources can be used for LLLT! PMID- 29130449 TI - The antioxidant activity and nitric oxide production of extracts obtained from the leaves of Chenopodium quinoa Willd. AB - BACKGROUND: Most reports have indicated the antioxidant capacity of quinoa seeds. However, the leaves of Quinoa (Chenopodium quinoa Willd.) are usually worthless and little known about their biological activities. In this study, the antioxidant and immunomodulatory potential of the quinoa leaf extracts were explored. METHODS: The crude leaf extracts of quinoa were extracted using water, 50% ethanol or 95% ethanol as solvent, denoted WQL, 50% EQL and 95% EQL, respectively. The antioxidant activities of quinoa leaf extracts were assessed by the ability of 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging and iron chelating. The total phenolic content was determined. Inhibition of nitric oxide (NO) production in the lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells was examined to gauge the anti-inflammatory activity. RESULTS: The 95% EQL showed a higher level of total phenolic content (569.5 mg GAE/g extract) and better DPPH scavenging activity. The WQL exhibited a better iron chelating capacity (28.9% at 10 mg/ml). The iron chelating activity of the 95% EQL increased in a concentration-dependent manner, which ranged from 10.9% up to 53.9%. The 50% EQL and 95% EQL significantly inhibited NO production in the LPSstimulated RAW 264.7 cells. CONCLUSION: We demonstrate that the extracts of quinoa leaves possess the biological activities of antioxidant and anti inflammatory. Our finding suggests that the leaf extract of quinoa has potential to be utilized for natural health products. PMID- 29130450 TI - Lower risk of end stage renal disease in diabetic nurse. AB - OBJECTIVES: As professional medical caregivers, nurses have extensive medical knowledge and information than general population. However, they may use their professional knowledge and networks to seek prompt health services. In this study, we aimed to determine susceptibility of nurses with diabetes to developing end-stage renal disease requiring dialysis compared to diabetes patients in the general population. METHODS: This retrospective longitudinal study extracted data of nurses with newly diagnosed diabetes and general patients with diabetes from the National Health Insurance Database between 1998 and 2006 and follow-up to December 2009, satisfied the participant inclusion criteria was 518,058. Nurses and general population were matched with propensity score method in a 1:10 ratio. Basic characteristics and health status were similar between groups. Cox proportional hazards model was used to compare relative risks and dialysis factors between groups. RESULTS: Nurses were younger than general population with diabetes (42.01 years vs. 59.29 years) and had lower risk of dialysis (adjusted hazard ratio = 0.36, 95% confidence interval 0.16-0.81). Nurses with Diabetes Complications Severity Index (DCSI)?3 had dialysis risk up to 83.53 times higher than that of the reference group (DCSI < 3). DCSI was the only variable determined to be a related factor affecting dialysis risk in nurses with diabetes. CONCLUSIONS: Nurses with diabetes have lower risk of dialysis. This suggests that nurses may have more knowledge regarding chronic disease control and change their lifestyles than general diabetes patients. Results of this study may serve as a reference for developing health education. PMID- 29130448 TI - A review on the effects of current chemotherapy drugs and natural agents in treating non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer deaths worldwide, and this makes it an attractive disease to review and possibly improve therapeutic treatment options. Surgery, radiation, chemotherapy, targeted treatments, and immunotherapy separate or in combination are commonly used to treat lung cancer. However, these treatment types may cause different side effects, and chemotherapy-based regimens appear to have reached a therapeutic plateau. Hence, effective, better-tolerated treatments are needed to address and hopefully overcome this conundrum. Recent advances have enabled biologists to better investigate the potential use of natural compounds for the treatment or control of various cancerous diseases. For the past 30 years, natural compounds have been the pillar of chemotherapy. However, only a few compounds have been tested in cancerous patients and only partial evidence is available regarding their clinical effectiveness. Herein, we review the research on using current chemotherapy drugs and natural compounds (Wortmannin and Roscovitine, Cordyceps militaris, Resveratrol, OSU03013, Myricetin, Berberine, Antroquinonol) and the beneficial effects they have on various types of cancers including non-small cell lung cancer. Based on this literature review, we propose the use of these compounds along with chemotherapy drugs in patients with advanced and/or refractory solid tumours. PMID- 29130451 TI - Population-based cohort study investigating the association between weight loss and pyogenic liver abscesses. AB - BACKGROUND AND AIM: Few systematic studies focus on the association between weight loss and pyogenic liver abscesses. The objective of the study was to assess the association between weight loss and pyogenic liver abscesses in adults in Taiwan. METHODS: This population-based cohort study utilized the database of the Taiwan National Health Insurance Program. Totally, 8453 subjects aged 20 to 84 years with newly diagnosed weight loss between 2000 and 2012 were assigned as the weight loss group, and 33777 randomly selected subjects without weight loss were assigned as the non-weight loss group. Both the weight loss and the non weight loss groups were matched according to sex, age, and comorbidities. The incidence of pyogenic liver abscesses at the end of 2013 was measured in both groups. RESULTS: A multivariable Cox proportional hazards regression model was done and presented evidence that the adjusted HR of pyogenic liver abscess was 2.47 (95 %CI 1.21, 5.02) for those subjects with weight loss and without comorbidities, as compared with those subjects without weight loss and without comorbidities. Among the weight loss group, 5% developed pyogenic liver abscesses within 3 months. CONCLUSION: Weight loss is associated with pyogenic liver abscesses in adults. Yet weight loss might not be an early clinical symptom of undiagnosed pyogenic liver abscesses. PMID- 29130453 TI - A binary motor imagery tasks based brain-computer interface for two-dimensional movement control. AB - OBJECTIVE: Two-dimensional movement control is a popular issue in brain-computer interface (BCI) research and has many applications in the real world. In this paper, we introduce a combined control strategy to a binary class-based BCI system that allows the user to move a cursor in a two-dimensional (2D) plane. Users focus on a single moving vector to control 2D movement instead of controlling vertical and horizontal movement separately. APPROACH: Five participants took part in a fixed-target experiment and random-target experiment to verify the effectiveness of the combination control strategy under the fixed and random routine conditions. Both experiments were performed in a virtual 2D dimensional environment and visual feedback was provided on the screen. MAIN RESULTS: The five participants achieved an average hit rate of 98.9% and 99.4% for the fixed-target experiment and the random-target experiment, respectively. SIGNIFICANCE: The results demonstrate that participants could move the cursor in the 2D plane effectively. The proposed control strategy is based only on a basic two-motor imagery BCI, which enables more people to use it in real-life applications. PMID- 29130454 TI - Recent trends in spin-resolved photoelectron spectroscopy. AB - Since the discovery of the Rashba effect on crystal surfaces and also the discovery of topological insulators, spin- and angle-resolved photoelectron spectroscopy (SARPES) has become more and more important, as the technique can measure directly the electronic band structure of materials with spin resolution. In the same way that the discovery of high-Tc superconductors promoted the development of high-resolution angle-resolved photoelectron spectroscopy, the discovery of this new class of materials has stimulated the development of new SARPES apparatus with new functions and higher resolution, such as spin vector analysis, ten times higher energy and angular resolution than conventional SARPES, multichannel spin detection, and so on. In addition, the utilization of vacuum ultra violet lasers also opens a pathway to the realization of novel SARPES measurements. In this review, such recent trends in SARPES techniques and measurements will be overviewed. PMID- 29130455 TI - Structure, magnetism and electronic properties in 3d-5d based double perovskite ([Formula: see text]Y x )2FeIrO6. AB - The 3d-5d based double perovskites are of current interest as they provide model systems to study the interplay between electronic correlation (U) and spin-orbit coupling (SOC). Here, we report detailed structural, magnetic and transport properties of doped double perovskite material ([Formula: see text]Y x )2FeIrO6 with [Formula: see text]. With substitution of Y, the system retains its original crystal structure but structural parameters change with x in nonmonotonic fashion. The magnetization data for Sr2FeIrO6 show antiferromagnetic type magnetic transition around 45 K; however, a close inspection of the data indicates a weak magnetic phase transition around 120 K. No change of structural symmetry has been observed down to low temperature, although the lattice parameters show sudden changes around the magnetic transitions. Sr2FeIrO6 shows an insulating behavior over the whole temperature range, which nevertheless does not change with Y substitution. The nature of charge conduction is found to follow thermally activated Mott's variable range hopping and power law behavior for parent and doped samples, respectively. Interestingly, evolution of structural, magnetic and transport behavior in ([Formula: see text]Y x )2FeIrO6 is observed to reverse with [Formula: see text], which is believed to arise due to a change in the transition metal ionic state. PMID- 29130452 TI - Augmenting intracortical brain-machine interface with neurally driven error detectors. AB - OBJECTIVE: Making mistakes is inevitable, but identifying them allows us to correct or adapt our behavior to improve future performance. Current brain machine interfaces (BMIs) make errors that need to be explicitly corrected by the user, thereby consuming time and thus hindering performance. We hypothesized that neural correlates of the user perceiving the mistake could be used by the BMI to automatically correct errors. However, it was unknown whether intracortical outcome error signals were present in the premotor and primary motor cortices, brain regions successfully used for intracortical BMIs. APPROACH: We report here for the first time a putative outcome error signal in spiking activity within these cortices when rhesus macaques performed an intracortical BMI computer cursor task. MAIN RESULTS: We decoded BMI trial outcomes shortly after and even before a trial ended with 96% and 84% accuracy, respectively. This led us to develop and implement in real-time a first-of-its-kind intracortical BMI error 'detect-and-act' system that attempts to automatically 'undo' or 'prevent' mistakes. The detect-and-act system works independently and in parallel to a kinematic BMI decoder. In a challenging task that resulted in substantial errors, this approach improved the performance of a BMI employing two variants of the ubiquitous Kalman velocity filter, including a state-of-the-art decoder (ReFIT KF). SIGNIFICANCE: Detecting errors in real-time from the same brain regions that are commonly used to control BMIs should improve the clinical viability of BMIs aimed at restoring motor function to people with paralysis. PMID- 29130456 TI - Strain coupling of oxygen non-stoichiometry in perovskite thin films. AB - The effects of strain and oxygen vacancies on perovskite thin films have been studied in great detail over the past decades and have been treated separately from each other. While epitaxial strain has been realized as a tuning knob to tailor the functional properties of correlated oxides, oxygen vacancies are usually regarded as undesirable and detrimental. In transition metal oxides, oxygen defects strongly modify the properties and functionalities via changes in oxidation states of the transition metals. However, such coupling is not well understood in epitaxial films, but rather deemed as cumbersome or experimental artifact. Only recently it has been recognized that lattice strain and oxygen non stoichiometry are strongly correlated in a vast number of perovskite systems and that this coupling can be beneficial for information and energy technologies. Recent experimental and theoretical studies have focused on understanding the correlated phenomena between strain and oxygen vacancies for a wide range of perovskite systems. These correlations not only include the direct relationship between elastic strain and the formation energy of oxygen vacancies, but also comprise highly complex interactions such as strain-induced phase transitions due to oxygen vacancy ordering. Therefore, we aim in this review to give a comprehensive overview on the coupling between strain and oxygen vacancies in perovskite oxides and point out the potential applications of the emergent functionalities strongly coupled to oxygen vacancies. PMID- 29130457 TI - Gene dosage reductions of Trf1 and/or Tin2 induce telomere DNA damage and lymphoma formation in aging mice. AB - This corrects the article DOI: 10.1038/leu.2015.173. PMID- 29130458 TI - Erratum. AB - [This corrects the article DOI: 10.1002/2211-5463.12286.]. PMID- 29130459 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/ams2.198.]. PMID- 29130460 TI - A two-dimensional TiB4 monolayer exhibits planar octacoordinate Ti. AB - At present, the concept of planar hypercoordination in chemistry meets the fast development of two-dimensional (2D) nanomaterials, leading to considerable interest in searching for 2D materials with planar hypercoordinate atoms. In this work, by means of the swarm-intelligence structure search method and first principles calculations, we predict a hitherto unknown 2D TiB4 monolayer with a planar octacoordinate Ti moiety, in which each Ti atom binds to eight B atoms with equal distances in a perfect plane, and has the highest coordination of Ti known for 2D materials thus far. Systematic ab initio calculations demonstrate the superior thermodynamic and dynamic stabilities of the predicted TiB4 monolayer, indicating the high feasibility for experimental synthesis. The stabilization of this perfect planar structure originates from the geometric fit between the atomic radius of Ti and the size of the 8-membered B ring, as well as the electron transfer from Ti to B atoms which compensates the electron deficiency of the full sp2 hybridized B network. Motivated by the unforeseen geometry of the TiB4 monolayer, a series of other 2D transition metal borides (TMB4, TM = V, Cr, Mo, W and Os) with quasi-planar octacoordinate TM atoms are further designed and discussed. The present work provides a useful roadmap for the discovery of 2D hypercoordinate materials. PMID- 29130461 TI - Intracellular coassembly boosts the anti-inflammation capacity of dexamethasone. AB - Dexamethasone (Dex) is one of the essential medicines used to treat inflammation diseases but an overdose of Dex leads to severe adverse effects. The development of a new strategy to boost the anti-inflammation efficacy of Dex is, therefore, important but remains challenging. Herein, by employing an enzyme-instructed self assembly system, we developed an intracellular coassembly strategy to boost the anti-inflammation efficacy of Dex. Under the catalysis of alkaline phosphatase (ALP), the hydrogelator precursor Nap-Phe-Phe-Tyr(H2PO3)-OH (1p) self-assembled to form Gel 1 but dexamethasone sodium phosphate (Dp) only yielded Dex precipitates. However, subjecting equivalent amounts of 1p and Dp together to ALP triggered coassembly was found to result in the formation of Gel 2. Cell experiments indicated that intracellular ALP-triggered coassembly of Dp with 1p extensively boosted the anti-inflammation efficacy of Dex on two types inflammatory cell models. We envision that, in the near future, our strategy of intracellular coassembly could be widely employed to boost the therapeutic effects of more drugs, while in the meantime used to alleviate the undesired adverse effects of these drugs. PMID- 29130462 TI - A three-dimensional graphene aerogel containing solvent-free polyaniline fluid for high performance supercapacitors. AB - Conducting polymer based supercapacitors usually suffer from the difficulty of achieving high specific capacitance and good long-term stability simultaneously. In this communication, a long-chain protonic acid doped solvent-free self suspended polyaniline (S-PANI) fluid and reduced graphene oxide (RGO) were used to fabricate a three-dimensional RGO/S-PANI aerogel via a simple self-assembled hydrothermal method, which was then applied as a supercapacitor electrode. This 3D RGO/S-PANI composite exhibited a high specific capacitance of up to 480 F g-1 at a current density of 1 A g-1 and 334 F g-1 even at a high discharge rate of 40 A g-1. An outstanding cycling performance, with 96.14% of the initial capacitance remaining after 10 000 charging/discharging cycles at a rate of 10 A g-1, was also achieved. Compared with the conventional conducting polymer materials, the 3D RGO/S-PANI composite presented more reliable rate capability and cycling stability. Moreover, S-PANI possesses excellent processability, thereby revealing its enormous potential in large scale production. We anticipate that the solvent free fluid technique is also applicable to the preparation of other 3D graphene/polymer materials for energy storage. PMID- 29130463 TI - Correction: Dynamic properties of dipeptidyl peptidase III from Bacteroides thetaiotaomicron and the structural basis for its substrate specificity - a computational study. AB - Correction for 'Dynamic properties of dipeptidyl peptidase III from Bacteroides thetaiotaomicron and the structural basis for its substrate specificity - a computational study' by M. Tomin et al., Mol. BioSyst., 2017, 13, 2407-2417. PMID- 29130465 TI - Manipulating the stereoselectivity of the thermostable Baeyer-Villiger monooxygenase TmCHMO by directed evolution. AB - Baeyer-Villiger monooxygenases (BVMOs) and evolved mutants have been shown to be excellent biocatalysts in many stereoselective Baeyer-Villiger transformations, but industrial applications are rare which is partly due to the insufficient thermostability of BVMOs under operating conditions. In the present study, the substrate scope of the recently discovered thermally stable BVMO, TmCHMO from Thermocrispum municipale, was studied. This revealed that the wild-type (WT) enzyme catalyzes the oxidation of a variety of structurally different ketones with notable activity and enantioselectivity, including the desymmetrization of 4 methylcyclohexanone (99% ee, S). In order to induce the reversal of enantioselectivity of this reaction as well as the transformations of other substrates, directed evolution based on iterative saturation mutagenesis (ISM) was applied, leading to (R)-selectivity (94% ee) without affecting the thermostability of the biocatalyst. PMID- 29130464 TI - Boronic acid recognition of non-interacting carbohydrates for biomedical applications: increasing fluorescence signals of minimally interacting aldoses and sucralose. AB - To address carbohydrates that are commonly used in biomedical applications with low binding affinities for boronic acid based detection systems, two chemical modification methods were utilized to increase sensitivity. Modified carbohydrates were analyzed using a two component fluorescent probe based on boronic acid-appended viologen-HPTS (4,4'-o-BBV). Carbohydrates normally giving poor signals (fucose, l-rhamnose, xylose) were subjected to sodium borohydride (NaBH4) reduction in ambient conditions for 1 h yielding the corresponding sugar alcohols from fucose, l-rhamnose and xylose in essentially quantitative yields. Compared to original aldoses, apparent binding affinities were increased 4-25 fold. The chlorinated sweetener and colon permeability marker sucralose (Splenda), otherwise undetectable by boronic acids, was dechlorinated to a detectable derivative by reactive oxygen and hydroxide intermediates by the Fenton reaction or by H2O2 and UV light. This method is specific to sucralose as other common sugars, such as sucrose, do not contain any carbon-chlorine bonds. Significant fluorescence response was obtained for chemically modified sucralose with the 4,4'-o-BBV-HPTS probe system. This proof of principle can be applied to biomedical applications, such as gut permeability, malabsorption, etc. PMID- 29130466 TI - [Safinamide from daily clinical practice: first clinical steps]. AB - INTRODUCTION: The management of motor complications in Parkinson's disease (PD) is still limited. Safinamide, a new drug that has MAO-B inhibition and antiglutamatergic effects through inhibition of sodium channels, has shown efficacy for the treatment of fluctuations at doses of 50-100 mg/day. PATIENTS AND METHODS: From daily clinical practice, we describe the efficacy and tolerability of safinamide at three months in PD patients with motor complications. Efficacy was assessed by the Clinical Global Impression of Change scale and change in 'off' time during the daytime. All reported adverse events were recorded. RESULTS: Fifty patients were recruited. 57.4% reported to be much better or moderately better at three months, improving both motor and non-motor fluctuations. Significant decrease of 0.9 +/- 0.6 h/day was achieved at three months. In 13 patients (27.6%), levodopa equivalent daily dose was reduced in 132 mg/day. In patients with dyskinesias, safinamide 100 mg/day was better for controlling fluctuations and dyskinesias. 19% of patients had mild adverse events. Seven patients stopped treatment after development of confusional syndrome. CONCLUSIONS: The dopaminergic and non-dopaminergic action of safinamide exerts a good control of motor fluctuations. In patients with fluctuations and dyskinesias the dose of 100 mg/day of safinamide is preferred. Tolerability was good, except for patients older than 75 years or in advanced stages of the disease. PMID- 29130467 TI - [A comparative study of three systems for quantifying the spike and wave index in patients with continuous spikes and waves during slow sleep]. AB - INTRODUCTION: Continuous spikes and waves during slow sleep (CSWS) is an epileptic encephalopathy of childhood with a pattern of epileptiform discharges during sleep, which, if prolonged over time, produce severe neuropsychological impairment. Quantification of the paroxysms by means of a spike and wave index (SWI) > 85% establishes a presumptive diagnosis and allows early therapy to be started to prevent such impairment. AIMS: To compare the results of the classic method for calculating the SWI against two proposals that optimise the relation between the analysis time employed and the diagnostic sensitivity. PATIENTS AND METHODS: The nocturnal electroencephalographic registers of 17 patients with CSWS were studied. Two observers calculated the SWI with the classic method, as well as with two other methods, M2 and M3, first in the active phase and then in the remission phase. The time required by each method, the individual SWI values and the agreement between methods and observers were compared. RESULTS: With M3 two of the patients failed to reach the cut-off point of SWI > 85%. Agreement in the active phase of CSWS after M2 and M3 was 0.762 and 0.704, respectively, while in the remission phase it was 0.951 and 0.830. Inter-observer agreement exceeded 0.905 in all cases. CONCLUSIONS: The two abbreviated methods can be used in both the active and the remission phases, with a substantial reduction in the analysis time that is needed. Our results support the current tendency to consider SWI > 60% as suggestive of CSWS. Method M2 yields results that are closer to those of the classic method than those of M3. PMID- 29130468 TI - [Efficacy of group reminiscence therapy for people with dementia. Systematic literature review and meta-analysis]. AB - INTRODUCTION: Reminiscence therapy is one of the most effective psychosocial interventions for people with dementia. AIMS: To analyse the effectiveness of group reminiscence therapy in people with dementia and to check their involvement in the design and evaluation of the interventions. PATIENTS AND METHODS: CINHAL, PubMed, Psicodoc and PsycINFO databases were searched for the period of 2004 to 2016. A systematic search was performed, as well as a quality assessment and a meta-analysis of the articles. RESULTS: The 14 studies selected had a moderate risk of bias. People with dementia who received group reminiscence therapy experienced an improvement in cognition (dMR = 0.26; 95% CI: 0.11-0.40; p = 0.0006; I2 = 0%) which was larger than the one observed in the control group (dc = 0.37; 95% CI: 0.11-0.63; p = 0.005; I2 = 0%). There was no improvement in mood, quality of life, behaviour or activities of daily living. People with dementia were not included in the design nor in the evaluation of the interventions. CONCLUSIONS: Group reminiscence therapy for people with dementia has favourable effects in cognition. There is a need for the inclusion of people with dementia in the design and planning of the interventions and for more randomised controlled trials. PMID- 29130469 TI - [Heparan sulphates, amyloidosis and neurodegeneration]. AB - INTRODUCTION: A number of neurodegenerative disorders have been linked directly to the accumulation of amyloid fibres. These fibres are made up of proteins or peptides with altered structures and which join together in vivo in association with heparan sulphate-type polysaccharides. AIMS: To examine the most recent concepts in the biology of heparan sulphates and their role in the aggregation of the peptide Abeta, of tau protein, of alpha-synuclein and of prions. The study also seeks to analyse their implications in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and prion diseases. DEVELOPMENT: In vitro, heparan sulphates have played an important role in the process of oligomerisation and fibrillation of amyloidogenic proteins or peptides, in the stabilisation of these bodies and their resistance to proteolysis, thereby participating in the formation of a wide range of amyloid fibres. Heparan sulphates have also been related to the internalisation of pro-amyloid fibres during the process of intercellular propagation (spreading), which is considered to be crucial in the development of proteinopathies, the best example of which is Alzheimer's disease. CONCLUSION: This study suggests that the fine structures of heparan sulphates, their localisation in cells and tissues, together with their local concentration, may regulate the amyloidosis processes. The advances made in the understanding of this area of glyconeurobiology will make it possible to improve the understanding of the cell and molecular mechanisms underlying the neurodegenerative process. PMID- 29130470 TI - [The influence of social stress on the reinforcing effect of ecstasy under the conditioned place preference paradigm: the role played by age, dose and type of stress]. AB - INTRODUCTION: Addiction to drugs is a chronic illness with severe repercussions for those that consume them and to date has no known cure. Psychostimulants, such as ecstasy, are the most widely consumed illegal drugs among adolescents and young adults. AIMS: To describe and to analyse the different variables that can influence the effects of social stress and the reinforcing properties of ecstasy. Likewise, it also seeks to evaluate whether the effects of social stress on conditioned place preference (induced by ecstasy) are similar to those deriving from other psychostimulants, such as cocaine. DEVELOPMENT: Social defeat evaluated in the short term has an effect only on adult animals by diminishing sensitivity to the conditioned reinforcing effects of ecstasy. Conversely, long term social stress increases the reinforcing effects of this drug in adolescent and adult animals. The dose of ecstasy employed has little influence on the effects of social defeat on conditioned place preference. In comparison to the effects of social stress on the reinforcing properties of cocaine, a different effect is only observed when defeat is evaluated in the short term. CONCLUSIONS: Different variables modulate the reinforcing effects of ecstasy, such as the age of the animals, the dose employed or exposure to stress. It is essential to study these variables in order to determine the neurobiological and environmental vulnerability factors that can have an influence on the development of addiction to ecstasy. PMID- 29130471 TI - [Involvement of the spinal cord in rheumatoid arthritis]. PMID- 29130472 TI - [Androgen deprivation therapy: does the risk of dementia increase?] PMID- 29130474 TI - Interventions for the reduction of prescribed opioid use in chronic non-cancer pain. AB - BACKGROUND: This is the first update of the original Cochrane Review published in 2013. The conclusions of this review have not changed from the 2013 publication. People with chronic non-cancer pain who are prescribed and are taking opioids can have a history of long-term, high-dose opioid use without effective pain relief. In those without good pain relief, reduction of prescribed opioid dose may be the desired and shared goal of both patient and clinician. Simple, unsupervised reduction of opioid use is clinically challenging, and very difficult to achieve and maintain. OBJECTIVES: To investigate the effectiveness of different methods designed to achieve reduction or cessation of prescribed opioid use for the management of chronic non-cancer pain in adults compared to controls. SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, and Embase in January 2017, as well as bibliographies and citation searches of included studies. We also searched one trial registry for ongoing trials. SELECTION CRITERIA: Included studies had to be randomised controlled trials comparing opioid users receiving an intervention with a control group receiving treatment as usual, active control, or placebo. The aim of the study had to include a treatment goal of dose reduction or cessation of opioid medication. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We sought data relating to prescribed opioid use, adverse events of opioid reduction, pain, and psychological and physical function. We planned to assess the certainty of the evidence using the GRADE approach, however, due to the heterogeneity of studies, we were unable to combine outcomes in a meta-analysis and therefore we did not assess the evidence with GRADE. MAIN RESULTS: Three studies are new to this update, resulting in five included studies in total (278 participants). Participants were primarily women (mean age 49.63 years, SD = 11.74) with different chronic pain conditions. We judged the studies too heterogeneous to pool data in a meta-analysis, so we have summarised the results from each study qualitatively. The studies included acupuncture, mindfulness, and cognitive behavioral therapy interventions aimed at reducing opioid consumption, misuse of opioids, or maintenance of chronic pain management treatments. We found mixed results from the studies. Three of the five studies reported opioid consumption at post-treatment and follow-up. Two studies that delivered 'Mindfulness-Oriented Recovery Enhancement' or 'Therapeutic Interactive Voice Response' found a significant difference between groups at post-treatment and follow-up in opioid consumption. The remaining study found reduction in opioid consumption in both treatment and control groups, and between-group differences were not significant. Three studies reported adverse events related to the study and two studies did not have study-related adverse events. We also found mixed findings for pain intensity and physical functioning. The interventions did not show between-group differences for psychological functioning across all studies. Overall, the risk of bias was mixed across studies. All studies included sample sizes of fewer than 100 and so we judged all studies as high risk of bias for that category. AUTHORS' CONCLUSIONS: There is no evidence for the efficacy or safety of methods for reducing prescribed opioid use in chronic pain. There is a small number of randomised controlled trials investigating opioid reduction, which means our conclusions are limited regarding the benefit of psychological, pharmacological, or other types of interventions for people with chronic pain trying to reduce their opioid consumption. The findings to date are mixed: there were reductions in opioid consumption after intervention, and often in control groups too. PMID- 29130475 TI - Immunological interaction between Giardia cyst extract and experimental toxoplasmosis. AB - Toxoplasmosis is mostly associated with other intestinal parasitic infections especially Giardia due to shared mode of peroral infection. Toxoplasma and Giardia induce a strong T-helper 1- immune response. Our aim was to induce a protective immune response that results in significant impact on intestinal and extra-intestinal phases of Toxoplasma infection. This study was conducted in experimental animals and assessment of Giardia cyst extract effect on Toxoplasma infection was investigated by histopathological examination of small intestine and brain, Toxoplasma cyst count and iNOS staining of the brain, measurement of IFN-gamma and TGF-beta in intestinal tissues. Results showed that the brain Toxoplasma cyst number was decreased in mice infected with Toxoplasma then received Giardia cyst extract as compared to mice infected with Toxoplasma only. This effect was produced because Giardia cyst extract augmented the immune response to Toxoplasma infection as evidenced by severe inflammatory reaction in the intestinal and brain tissues, increased levels of IFN-gamma and TGF-beta in intestinal tissues and strong iNOS staining of the brain. In conclusion, Giardia cyst extract generated a protective response against T. gondii infection. Therefore, Giardia antigen will be a suitable candidate for further researches as an immunomodulatory agent against Toxoplasma infection. PMID- 29130476 TI - Graft versus host disease in a pediatric multiple organ transplant recipient with trichohepatoenteric syndrome - a unique case report. PMID- 29130478 TI - Systolic Blood Pressure and Mortality: Role of Reverse Causation. PMID- 29130477 TI - Transcranial Doppler and Lower Extremity Function in Older Adults: Einstein Aging Study. AB - OBJECTIVES: To determine whether transcranial Doppler ultrasound (TCD) measures of mean blood flow velocity (MBFV) in the major cerebral arteries are associated with measures of lower extremity function in community-dwelling older adults. DESIGN: Cross-sectional study. SETTING: Community sample. PARTICIPANTS: Individuals aged 70 and older (mean 79.5, 54% female) without dementia participating in the Einstein Aging Study (N = 200). MEASUREMENTS: All participants underwent TCD assessments and tests of lower extremity function at an annual clinic visit. Average MBFV for anterior (left and right anterior and middle cerebral arteries (MCAs)) and posterior (vertebral (VA) and basilar (BA) artery) circulation was measured using a standardized TCD protocol. Lower extremity function was characterized according to gait speed (cm/s) measured using an instrumented walkway, balance according to unipedal stance time (UPST, seconds), and lower extremity strength according to timed repeated chair rise (seconds). RESULTS: Multiple regression models adjusted for age, sex, race, education, and medical comorbidities showed that lower MBFV in the MCA was associated with slower gait speed and chair rise time but not with UPST. Ordinal regression models showed that lower MBFV in the VA and BA is associated with shorter UPST. CONCLUSION: Low MBFV in the anterior and posterior cerebral circulation was associated with worse lower extremity function and balance in older adults. This might be indicative of the importance of age-related changes in cerebral hemodynamics in the function of brain regions involved in specific aspects of physical performance. PMID- 29130479 TI - Implementing Models of Geriatric Care-Behind the Scenes. AB - Innovative geriatric clinical programs have proliferated in the 21st century, and many have been highlighted in the Journal of the American Geriatrics Society (JAGS). The Affordable Care Act has supported the accelerated innovation of publicized and unpublicized program development, adaptation, and implementation. Many JAGS articles report work conducted in programs with significant improvements in quality; high satisfaction for patients and providers; and for some, reductions in costs. Despite considerable detail, enabling implementers to attempt to adopt reported programs or adapt them to local environments, much less is typically conveyed about the subtleties of the implementation process that led to a successful outcome. Moreover, where we have been given a window into successful initiatives, far less is known about those that failed and even less about why some succeeded but others failed. With a focus on our shared needs as a geriatrics community, to foster the exchange of more-comprehensive models of successful and failed implementation, we propose publications that address implementation itself-a second layer of reporting about the "hidden" elements that may have been decisive factors in taking an efficacious test, treatment, or model and putting it into real-world practice. We propose a new platform for sharing a broader range of healthcare quality improvement initiatives-successes and failures. We include several salient characteristics that could be measured and described in support of dynamic, sustainable, evidence-based implementation of geriatrics programs. PMID- 29130480 TI - Antidesmoglein 1 and 3 antibodies in healthy subjects of a population in the Peruvian high amazon. AB - BACKGROUND: The objective of this study was to determine the presence of anti Dsg1 and Dsg3 antibodies in healthy subjects of the high Peruvian Amazon (Tuemal, Rodriguez de Mendoza province, department of Amazonas) to establish the theoretical presence of environmental factors or triggers in the area. MATERIALS AND METHODS: Cross-sectional study. The study population included persons of any age or gender, clinically healthy, who were evaluated by a dermatologist to confirm the absence of blistering diseases. Blood samples were analyzed by indirect immunofluorescence (IIF), immunoprecipitation (IP), anti-Dsg1 IgM antibody (Ab) enzyme-linked immunosorbent assay (ELISA), as well as anti-Dsg1 and anti-Dsg3 IgG Ab ELISA. RESULTS: Participants included 21 healthy subjects comprised of 61.9% males and 38.1% females; 47.6% had a positive anti-Dsg1 Ab ELISA for total IgG (or any subclasses). IIF detected antibodies against intercellular spaces in one subject. Anti-Dsg1 Ab IP was mildly positive in 33.3% of the subjects. Anti-Dsg1 IgG subclasses found positive were: IgG1 (19.0%), IgG2 (33.3%), and IgG3 (28.6%); none of the samples were positive for anti-Dsg1 Ab IgM ELISA, and 23.8% of the subjects were positive for anti-Dsg3 Ab ELISA. The age distribution was similar for subjects positive for anti-Dsg1 and anti-Dsg3 Ab ELISA, with higher frequencies found among the 20-29 and 40-49 year-old age groups. CONCLUSION: A fraction of healthy subjects of the high Peruvian Amazon developed anti-Dsg1 and anti-Dsg3 antibodies, demonstrating the possible presence of environmental factors for endemic pemphigus (EP) at a higher altitude than previously described. PMID- 29130481 TI - Reply to: Systolic Blood Pressure and Mortality: Role of Reverse Causation. PMID- 29130483 TI - Contributions of infant vagal regulation at 1 month to subsequent joint attention abilities. AB - Since birth, humans develop an ability to regulate their inner states and behaviors, when facing demanding situations, in order to restore calmness and engage with other persons and the surrounding environment. The present study analyzed whether 1-month infant vagal regulation to auditory stimuli was associated with later joint attention abilities-responding to and initiating joint attention-in interaction with their mothers. Twenty-three infants were assessed and measures of respiratory sinus arrhythmia-RSA (baseline and vagal tone change during auditory stimulation) were used as index of vagal regulation. At 12-months, joint attention behaviors were assessed in a 10-min toy-play mother infant interaction. Correlational analyses showed that lower baseline RSA and larger increases in vagal tone during auditory stimulation were related to more instances of joint attention behaviors at 12 months, especially responding to joint attention. Results suggest that distinct profiles of autonomic functioning may contribute to joint attention skills. PMID- 29130482 TI - Longitudinal observational study of hidradenitis suppurativa: impact of surgical intervention with adjunctive biologic therapy. AB - BACKGROUND: Hidradenitis supppurativa (HS) is a chronic inflammatory disease of the apocrine sweat glands affecting 1-4% of the population. While surgical excision is a mainstay of therapy, lesions often recur. Biologic therapies, including tumor necrosis factor-alpha and IL-12/23 inhibitors, are effective for mild to moderate HS. However, longitudinal studies investigating biologic therapy in conjunction with surgery are limited. The purpose of this analysis was to investigate impact of surgery and biologic therapy on HS disease activity. METHODS: Data from 68 HS patients were analyzed. Outcome measures included hidradenitis suppurativa Sartorius Score (HSS), active nodule (AN) count, Hurley stage, and probability of achieving 75% reduction in active nodule count (AN75). RESULTS: Mean age was 40 +/- 14 years; 66% were female and 72% were African American. Mean disease duration was 10 years, and Hurley stage III disease was seen in 63% of patients. Patients who received biologics had a larger drop in HSS and AN count than those who never received biologics (P = 0.002). Biologic treatment was associated with average reduction in 22 (15-29) HSS points (P < 0.0001). The effect of biologics was greater in patients who also underwent surgery (P = 0.013). Timing of biologics relative to surgery did not impact efficacy. Patients who received HS surgery with biologic therapy were most likely to achieve the AN75 (P = 0.017). CONCLUSIONS: In this diverse cohort of patients with severe HS, biologic therapy was associated with a more rapid decline in disease activity, with the greatest effect in patients who also underwent HS surgery. PMID- 29130484 TI - PRN473, an inhibitor of Bruton's tyrosine kinase, inhibits neutrophil recruitment via inhibition of macrophage antigen-1 signalling. AB - BACKGROUND AND PURPOSE: Following inflammatory stimuli, neutrophils are recruited to sites of inflammation and exert effector functions that often have deleterious effects on tissue integrity, which can lead to organ failure. Bruton's tyrosine kinase (Btk) is expressed in neutrophils and constitutes a promising pharmacological target for neutrophil-mediated tissue damage. Here, we evaluate a selective reversible inhibitor of Btk, PRN473, for its ability to dampen neutrophil influx via inhibition of adhesion receptor signalling pathways. EXPERIMENTAL APPROACH: In vitro assays were used to assess fMLP receptor 1 (Fpr 1)-mediated binding of ligands to the adhesion receptors macrophage antigen-1 (Mac-1) and lymphocyte function antigen-1. Intravital microscopy of the murine cremaster was used to evaluate post-adhesion strengthening and endoluminal crawling. Finally, neutrophil influx was visualized in a clinically relevant model of sterile liver injury in vivo. Btk knockout animals were used as points of reference for Btk functions. KEY RESULTS: Pharmacological inhibition of Btk by PRN473 reduced fMLP-induced phosphorylation of Btk and Mac-1 activation. Biochemical experiments demonstrated the specificity of the inhibitor. PRN473 (20 mg.kg-1 ) significantly reduced intravascular crawling and neutrophil recruitment into inflamed tissue in a model of sterile liver injury, down to levels seen in Btk-deficient animals. A higher dose did not provide additional reduction of intravascular crawling and neutrophil recruitment. CONCLUSIONS AND IMPLICATIONS: PRN473, a highly selective inhibitor of Btk, potently attenuates sterile liver injury by inhibiting the activation of the beta2 -integrin Mac-1 and subsequently neutrophil recruitment into inflamed tissue. PMID- 29130485 TI - Sophocarpine attenuates wear particle-induced implant loosening by inhibiting osteoclastogenesis and bone resorption via suppression of the NF-kappaB signalling pathway in a rat model. AB - BACKGROUND AND PURPOSE: Aseptic prosthesis loosening, caused by wear particles, is one of the most common causes of arthroplasty failure. Extensive and over activated osteoclast formation and physiological functioning are regarded as the mechanism of prosthesis loosening. Therapeutic modalities based on inhibiting osteoclast formation and bone resorption have been confirmed to be an effective way of preventing aseptic prosthesis loosening. In this study, we have investigated the effects of sophocarpine (SPC, derived from Sophora flavescens) on preventing implant loosening and further explored the underlying mechanisms. EXPERIMENTAL APPROACH: The effects of SPC in inhibiting osteoclastogenesis and bone resorption were evaluated in osteoclast formation, induced in vitro by the receptor activator of NF-kappaB ligand (RANKL). A rat femoral particle-induced peri-implant osteolysis model was established. Subsequently, micro-CT, histology, mechanical testing and bone turnover were used to assess the effects of SPC in preventing implant loosening. KEY RESULTS: In vitro, we found that SPC suppressed osteoclast formation, bone resorption, F-actin ring formation and osteoclast associated gene expression by inhibiting NF-kappaB signalling, specifically by targeting IkappaB kinases. Our in vivo study showed that SPC prevented particle induced prosthesis loosening by inhibiting osteoclast formation, resulting in reduced periprosthetic bone loss, diminished pseudomembrane formation, improved bone-implant contact, reduced bone resorption-related turnover and enhanced stability of implants. Inhibition of NF-kappaB signalling by SPC was confirmed in vivo. CONCLUSION AND IMPLICATIONS: SPC can prevent implant loosening through inhibiting osteoclast formation and bone resorption. Thus, SPC might be a novel therapeutic agent to prevent prosthesis loosening and for osteolytic diseases. PMID- 29130487 TI - A case of mucous membrane pemphigoid with IgG antibodies against the beta3 and gamma2 subunits of laminin-332, and the C-terminal domain of BP180. PMID- 29130488 TI - C-reactive protein is linked to disease activity, impact, and response to treatment in patients with chronic spontaneous urticaria. AB - BACKGROUND: Elevated levels of C-reactive protein (CRP), a sensitive marker of inflammation, have been consistently reported in chronic spontaneous urticaria (CSU). Here, we retrospectively analyzed data from 1253 CSU patients from 2 centers to answer the following questions: (i) What is the prevalence of elevated levels of CRP in CSU? (ii) Why do CSU patients show elevated levels of CRP? (iii) Are elevated CRP levels relevant? METHODS: Serum levels of CRP were measured by the nephelometric method. We collected information regarding various laboratory tests including ESR, CBC with differential, D-dimer, fibrinogen, C3, C4, IL-6, etc. For most patients, we also collected data on age, gender, duration of CSU, presence of angioedema, activity (UAS at the time of blood sampling and for 7 days), quality of life (CU-Q2oL and/or DLQI), comorbidities and possible causes of CSU, and autologous serum skin test (ASST) response. The efficacy of second generation antihistamines was evaluated on the day of blood collecting. RESULTS: One-third of CSU patients had elevated levels of CRP. Higher levels of CRP were associated with ASST positivity (P = .009) and arterial hypertension (P = .005), but not with other possible causes or comorbidities of CSU. C-reactive protein correlated with urticaria activity (P < .001), quality of life impairment (P = .026), and inflammatory and coagulation markers (P < .001). C-reactive protein levels were significantly higher in nonresponders to antihistamines as compared to responders (P < .001). CONCLUSION: Elevated levels of CRP are common and relevant in CSU patients. The assessment of CRP levels may help to optimize the management of patients with CSU. PMID- 29130486 TI - RTP801 is a critical factor in the neurodegeneration process of A53T alpha synuclein in a mouse model of Parkinson's disease under chronic restraint stress. AB - BACKGROUND AND PURPOSE: Recently, the incidence of Parkinson's disease has shown a tendency to move to a younger population, linked to the constantly increasing stressors of modern society. However, this relationship remains obscure. Here, we have investigated the contribution of stress and the mechanisms underlying this change. EXPERIMENTAL APPROACH: Ten-month-old alpha-synuclein A53T mice, a model of Parkinson's disease (PD), were treated with chronic restraint stress (CRS) to simulate a PD-sensitive person with constant stress stimulation. PD-like behavioural tests and pathological changes were evaluated. Differentiated PC12 A53T cells were treated with corticosterone in vitro. We used Western blot, microRNA expression analysis, immunofluorescence staining, dual luciferase reporter assay and HPLC electrochemical detection to assess cellular and molecular networks after stress treatment. In vivo, stereotaxic injection of shRNA lentivirus was used to confirm our in vitro results. KEY RESULTS: The protein RTP801 is encoded by DNA-damage-inducible transcript 4, and it was specifically increased in dopaminergic neurons of the substantia nigra after CRS treatment. RTP801 was post-transcriptionally inhibited by the down-regulation of miR-7. Delayed turnover of RTP801, through the inhibition of proteasome degradation also contributed to its high content. Elevated RTP801 blocked autophagy, thus increasing accumulation of oligomeric alpha-synuclein and aggravating endoplasmic reticulum stress. RTP801 inhibition alleviated the symptoms of neurodegeneration during this process. CONCLUSIONS AND IMPLICATIONS: RTP801 is a promising target for the treatment of PD, especially for PD-sensitive patients who live under increased social pressure. Down-regulation of RTP801 could inhibit the current tendency to an earlier onset of PD. PMID- 29130489 TI - Angiotensin 1-7 modulates electrophysiological characteristics and calcium homoeostasis in pulmonary veins cardiomyocytes via MAS/PI3K/eNOS signalling pathway. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia, and pulmonary veins (PVs) play a critical role in triggering AF. Angiotensin (Ang)-(1 7) regulates calcium (Ca2+ ) homoeostasis and also plays a critical role in cardiovascular pathophysiology. However, the role of Ang-(1-7) in PV arrhythmogenesis remains unclear. MATERIALS AND METHODS: Conventional microelectrodes, whole-cell patch-clamp and the fluo-3 fluorimetric ratio technique were used to record ionic currents and intracellular Ca2+ in isolated rabbit PV preparations and in single isolated PV cardiomyocytes, before and after administration of Ang-(1-7). RESULTS: Ang (1-7) concentration dependently (0.1, 1, 10 and 100 nmol/L) decreased PV spontaneous electrical activity. Ang-(1-7) (100 nmol/L) decreased the late sodium (Na+ ), L-type Ca2+ and Na+ -Ca2+ exchanger currents, but did not affect the voltage-dependent Na+ current in PV cardiomyocytes. In addition, Ang-(1-7) decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. A779 (a Mas receptor blocker, 3 MUmol/L), L-NAME (a NO synthesis inhibitor, 100 MUmol/L) or wortmannin (a specific PI3K inhibitor, 10 nmol/L) attenuated the effects of Ang-(1-7) (100 nmol/L) on PV spontaneous electric activity. CONCLUSION: Ang-(1-7) regulates PV electrophysiological characteristics and Ca2+ homoeostasis via Mas/PI3K/eNOS signalling pathway. PMID- 29130491 TI - Teaching & Learning Tips 2: Cognitive load theory. AB - Challenge: Dermatology trainees include medical students, residents, and fellows. Variability in level of experience and background knowledge can make clinical teaching challenging. Research also shows novices have different ways of thinking than experts, which must be acknowledged in the preceptor-trainee interaction for optimal teaching and learning to occur. Herein we explore how "cognitive load" varies with learner level and how reducing cognitive load can enhance learning, especially for novice learners. PMID- 29130490 TI - Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families. AB - BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders. PMID- 29130492 TI - Flat-topped papules arising in a young woman's tattoo. PMID- 29130493 TI - Trajectories of resting frontal brain activity and psychopathology in female adolescents exposed to child maltreatment. AB - Resting frontal electroencephalogram (EEG) alpha asymmetry patterns reflecting different affective and motivational tendencies have been proposed as a putative mechanism underlying resilience among maltreated youth. This 2-year prospective study examined whether developmental stability of resting frontal alpha asymmetry moderated the relation between child maltreatment severity and psychopathology in female adolescents (n = 43; ages 12-16) recruited from child protection agencies. Results identified two trajectories of resting frontal asymmetry: 60.5% displayed stable right and 39.5% displayed stable left frontal alpha asymmetry. Although individuals with these alpha asymmetry profiles experienced comparable childhood trauma severity, adolescents with stable left alpha asymmetry and lower levels of trauma were less likely to present symptoms or an episode of posttraumatic stress disorder (PTSD) and depression over 2 years than those with stable right alpha asymmetry and lower levels of trauma. These findings suggest that developmental patterns of resting left frontal brain activity may buffer against psychopathology in maltreated female youth. PMID- 29130494 TI - Variability in iodine in temperate seaweeds and iodine accumulation kinetics of Fucus vesiculosus and Laminaria digitata (Phaeophyceae, Ochrophyta). AB - The biogeochemistry of iodine in temperate coastal ecosystems is largely mediated by macroalgae, which act as a major biological sink and source of iodine. Their capacity to accumulate, retain and release iodine has been associated with abiotic and biotic stressors, but quantitative information is limited. We evaluated the seasonal iodine retention capacity of eleven macroalgal species belonging to different systematic groups, collected from two sites in Ireland. Iodine accumulation and retention were then further quantified in Fucus vesiculosus and Laminaria digitata in relation to I- concentrations in seawater and temperature. In general, iodine contents were ~101 -102 MUmol . (g dw)-1 for Laminariales, 100 -101 MUmol . (g dw)-1 for Fucales, 10-1 -100 MUmol . (g dw)-1 for Rhodophyta, and 10-1 MUmol . (g dw)-1 for Chlorophyta. Typically, algal iodine contents were above average in winter and below average in summer. Iodine accumulation in F. vesiculosus and L. digitata depended on I- availability and followed the Michaelis-Menten kinetic. The ratio of maximum accumulation rate to half accumulation coefficient (rhomax : Kt ) was 2.4 times higher for F. vesiculosus than for L. digitata, suggesting that F. vesiculosus was more efficient in iodine accumulation. Both species exhibited a temperature-dependent net loss of iodine, and only an exposure to sufficient external I- concentrations compensated for this loss. This study revealed that both environmental (e.g., I- in seawater, temperature) and organismal (e.g., the status of the iodine storage pool) variables determine retention and variability in iodine in temperate seaweeds. PMID- 29130495 TI - Matrine reversed multidrug resistance of breast cancer MCF-7/ADR cells through PI3K/AKT signaling pathway. AB - Matrine is an alkaloid extracted from a Chinese herb Sophora flavescens Ait, and has been used clinically for breast cancer with marked therapeutic efficacy in China. However, the mechanism has not been well known. Thus, the present study was to explore whether Matrine reverses multidrug resistance for breast cancer cells through the regulation of PI3K/AKT signaling pathway. Methyl thiazolyl tetrazolium (MTT) assay was used to detect the inhibitory action; Annexin V to detect apoptosis; fluorospectrophotometry to examine intracellular adriamycin (ADR) accumulation; and Western blot to label the proteins of P-glycoprotein (P gp), MRP1, PTEN, p-AKT, Bcl-2, Bax, and Caspase-3. Matrine (0-2.5 mg/mL) inhibited MCF-7/ADR cell growth and induced apoptosis (P < 0.01). A total of 0.2 mg/mL Matrine could increase the intracellular concentration of ADR; the accumulation in MCF-7/ADR cells increased 3.56 times. Compared with control group, 0.6, 1.2 mg/mL Matrine reduced protein expressions of P-gp, MRP1, p-AKT, Bcl-2, but increased PTEN, Bax, and cleaved caspase-3 gradually, and unchanged caspase-3. Matrine was more likely to reduce the expression of P-gp, MRP1, and p AKT at the same inhibition radio of Matrine, (0.6 mg/mL) and MK2206 (0.05 MUmol/L). Matrine inhibited MCF-7/ADR cell growth, induced apoptosis, and reversed multidrug resistance for breast cancer cells through the regulation of downstream apoptosis factors of PI3K/AKT signaling pathway by decreasing cell phosphorylation of AKT level. PMID- 29130496 TI - Using SMART design to improve symptom management among cancer patients: A study protocol. AB - In this in-progress sequential multiple assignment randomized trial (SMART), dyads of solid tumor cancer patients and their caregivers are initially randomized to 4 weeks of reflexology or meditative (mindfulness) practices provided by/with their caregiver in the patient's home or to a control group. After 4 weeks, intervention group dyads in which patients do not show improvement in fatigue (non-responders) are re-randomized to either receive additional time with the same therapy during weeks 5-8 or to add the other therapy. The aims are (1) to compare reflexology and meditative practices groups during weeks 1-4 on patients' fatigue severity, summed symptom inventory score, depressive symptoms, and anxiety, so as to determine the relative effectiveness of these therapies and the characteristics of responders and non-responders to each therapy. (2) Among reflexology non-responders based on fatigue score at week 4, to determine patient symptom outcomes when meditative practices are added during weeks 5-8, versus continuing with reflexology alone. (3) Among meditative practices non-responders based on fatigue score at week 4, to determine patient symptom outcomes when reflexology is added during weeks 5-8, versus continuing with meditative practices alone. (4) To compare improvements in patient symptom outcomes among the three groups created by the first randomization. (5) To explore which dyadic characteristics are associated with optimal patient symptom outcomes, to determine tailoring variables for decision rules of future interventions. The trial has a target of 331 dyads post-attrition and has 150 dyads enrolled. We are overcoming challenges with dyadic recruitment and retention while maintaining fidelity. PMID- 29130497 TI - UBC-Nepal expedition: acclimatization to high-altitude increases spinal motoneurone excitability during fatigue in humans. AB - KEY POINTS: Acute exposure and acclimatization to hypoxia are associated with an impairment and partial recovery, respectively, of the capability of the central nervous system to drive muscles during prolonged efforts. Motoneurones play a vital role in muscle contraction and in fatigue, although the effect of hypoxia on motoneurone excitability during exercise has not been assessed in humans. We studied the impact of fatigue on motoneurone excitability in normoxia, acute and chronic exposure (5050 m) to hypoxia. Performance was worse in acute hypoxia but recovered to the normoxic standard in chronic hypoxia, in parallel with an increased excitability of the motoneurones compared to acute exposure to hypoxia. These findings reveal that prolonged hypoxia causes a heightened motoneurone responsiveness during fatiguing exercise; such an adaptation might favour the restoration of performance where low pressures of oxygen are chronically present. ABSTRACT: The fatigue-induced failure of the motor cortex to drive muscles maximally increases in acute hypoxia (AH) compared to normoxia (N) but improves with acclimatization (chronic hypoxia; CH). Despite their importance to muscle output, it is unknown how locomotor motoneurones in humans are affected by hypoxia and acclimatization. Eleven participants performed 16 min of submaximal [25% maximal torque (maximal voluntary contraction, MVC)] intermittent isometric elbow flexions in N, AH (environmental chamber) and CH (7-14 days at 5050 m) (PI O2 = 140, 74 and 76 mmHg, respectively). For each minute of the fatigue protocol, motoneurone responsiveness was measured with cervicomedullary stimulation delivered 100 ms after transcranial magnetic stimulation (TMS) used to transiently silence voluntary drive. Every 2 min, cortical voluntary activation (cVA) was measured with TMS. After the task, MVC torque declined more in AH (~20%) than N and CH (~11% and 14%, respectively, P < 0.05), with no differences between N and CH. cVA was lower in AH than N and CH at baseline (~92%, 95% and 95%, respectively) and at the end of the protocol (~82%, 90% and 90%, P < 0.05). During the fatiguing task, motoneurone excitability in N and AH declined to ~65% and 40% of the baseline value (P < 0.05). In CH, motoneurone excitability did not decline and, late in the protocol, was ~40% higher compared to AH (P < 0.05). These novel data reveal that acclimatization to hypoxia leads to a heightened motoneurone responsiveness during fatiguing exercise. Positive spinal and supraspinal adaptations during extended periods at altitude might therefore play a vital role for the restoration of performance after acclimatization to hypoxia. PMID- 29130498 TI - Peripheral nerve ultrasound in Friedreich ataxia. AB - INTRODUCTION: Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes. METHODS: The ultrasound cross-sectional area of median, ulnar, tibial, and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population. RESULTS: The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs. DISCUSSION: Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role. Muscle Nerve 57: 852-856, 2018. PMID- 29130499 TI - Combined metabolomic and correlation networks analyses reveal fumarase insufficiency altered amino acid metabolism. AB - Fumarase catalyzes the interconversion of fumarate and l-malate in the tricarboxylic acid cycle. Fumarase insufficiencies were associated with increased levels of fumarate, decreased levels of malate and exacerbated salt-induced hypertension. To gain insights into the metabolism profiles induced by fumarase insufficiency and identify key regulatory metabolites, we applied a GC-MS based metabolomics platform coupled with a network approach to analyze fumarase insufficient human umbilical vein endothelial cells (HUVEC) and negative controls. A total of 24 altered metabolites involved in seven metabolic pathways were identified as significantly altered, and enriched for the biological module of amino acids metabolism. In addition, Pearson correlation network analysis revealed that fumaric acid, l-malic acid, l-aspartic acid, glycine and l-glutamic acid were hub metabolites according to Pagerank based on their three centrality indices. Alanine aminotransferase and glutamate dehydrogenase activities increased significantly in fumarase deficiency HUVEC. These results confirmed that fumarase insufficiency altered amino acid metabolism. The combination of metabolomics and network methods would provide another perspective on expounding the molecular mechanism at metabolomics level. PMID- 29130500 TI - Purification, characterization and application of a novel antimicrobial peptide from Andrias davidianus blood. AB - : The Andrias davidianus has been known as a traditional Chinese medicine for a long time. Its blood is considered as a waste or by-product of the meat production industry. Although there are reports on isolation of the antimicrobial peptides from different resources, there are no reports of their isolation from A. davidianus blood. In this work, an antimicrobial peptide, andricin B, was isolated from the blood of A. davidianus by an innovative method in which the magnetic liposome adsorption was combined with reversed-phase high-performance liquid chromatography. The structure, antimicrobial activity and safety of andricin B were further investigated. Amino acid sequence was determined by N terminal sequencing and found to be Gly-Leu-Thr-Arg-Leu-Phe-Ser-Val-Ile-Lys. Circular dichroism (CD) spectra and prediction of three-dimensional structure by bioinformatics software suggested the presence of a well-defined random coil conformation. Andricin B was found to be active against all bacteria tested in this study as well as some fungi. The minimum inhibitory concentrations (MICs) were in the range 8-64 MUg ml-1 . Moreover, the haemolytic testing also suggested that andricin B could be considered safe at the MICs. Finally, andricin B was shown to inhibit the growth of Staphylococcus aureus in the cooked meat of A. davidianus. This study shows that andricin B is a promising novel antimicrobial peptide that may provide further insights towards the development of new drugs. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the pioneer study on screening and isolation of antimicrobial peptide from the blood of Andrias davidianus. Here, we have developed a novel method by combining magnetic liposomes adsorption with reversed-phase high-performance liquid chromatography to purify and screen the antimicrobial peptides. From this screen, we identified a novel antimicrobial peptide which we name as andricin B. Andricin B is unique as it checks the growth of both Gram-positive and Gram-negative bacteria as well as few fungal species. PMID- 29130501 TI - Telomerase reverse transcriptase promoter hypermethylation is associated with metastatic disease in abdominal paraganglioma. PMID- 29130502 TI - Cardiac involvement in the muscular dystrophies. AB - Cardiac disease is a common clinical manifestation present in a variety of neuromuscular disorders, most notably the muscular dystrophies. Heart disease may produce the presenting or predominant symptoms in these disorders but more often not does not result in clinical features at the time of initial presentation. Cardiac involvement in the muscular dystrophies results from pathologic changes in the myocardium and the cardiac conduction system, leading to cardiomyopathy and/or rhythm disturbances including supraventricular arrhythmias, life threatening ventricular arrhythmias, and sudden cardiac death. This Review covers the spectrum of cardiac dysfunction in these inherited muscle disorders and proposes practical recommendations for monitoring and management. Muscle Nerve 57: 707-715, 2018. PMID- 29130504 TI - Mass spectrometry-based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders. AB - Metabolomics seeks to take a "snapshot" in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry-based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry-based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the investigation of underlying mechanism of therapeutic strategies. PMID- 29130503 TI - Association of teen mothers' and grandmothers' parenting capacities with child development: A study protocol. AB - Children born to teen mothers may experience less responsive and supportive parenting and are at heightened risk for a range of social, developmental, and health issues. There is literature to support the positive impact of grandmothers on teen parents and their children. However, what if the teen's mother is also limited in her parenting capacities? How do parenting capacities across these two generations of mothers affect the developing child? In this ongoing study we are examining two important aspects of parenting capacities, attachment quality and executive functioning, in teen mothers (TM) and their biological, co- residing mothers or grandmothers (GM or GGM). Both are essential components of effective parenting, but little is known about their impact on young children's development when raised by two generations of parents. In a cross- sectional, descriptive design, a convenience sample of 50 TM/GM dyads with children 1 to 3 years old is being recruited from two urban teen-tot clinics. Participants complete a paper and-pencil measure of attachment quality and a computerized measure of multiple aspects of executive function (working memory, inhibitory control, cognitive flexibility). A standardized maternal report measure is used to assess child developmental status. The biggest challenges of the study thus far include recruitment and transience of the study population. Progress to date and experiences from recruitment and data collection are discussed, as well as successful strategies to address challenges. PMID- 29130505 TI - Muscle membrane properties in A pig sepsis model: Effect of norepinephrine. AB - INTRODUCTION: Sepsis-induced myopathy and critical illness myopathy are common causes of muscle weakness in intensive care patients. This study investigated the effect of different mean arterial blood pressure (MAP) levels on muscle membrane properties following experimental sepsis. METHODS: Sepsis was induced with fecal peritonitis in 12 of 18 anesthetized and mechanically ventilated pigs. Seven were treated with a high (75-85 mmHg) and 5 were treated with a low (>=60 mmHg) MAP target for resuscitation. In septic animals, resuscitation was started 12 h after peritonitis induction, and muscle velocity recovery cycles were recorded 30 h later. RESULTS: Muscles in the sepsis/high MAP group showed an increased relative refractory period and reduced early supernormality compared with the remaining septic animals and the control group, indicating membrane depolarization and/or sodium channel inactivation. The membrane abnormalities correlated positively with norepinephrine dose. DISCUSSION: Norepinephrine may contribute to sepsis induced abnormalities in muscle by impairing microcirculation. Muscle Nerve 57: 808-813, 2018. PMID- 29130506 TI - Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis. AB - In many patients who suffer from epilepsies, recurrent epileptic seizures do not start at birth but develop later in life. This holds particularly true for epilepsies with a focal seizure origin including focal cortical dysplasias and temporal lobe epilepsy (TLE). TLE most frequently has its seizure onset in the hippocampal formation. Hippocampal biopsies of pharmacoresistant TLE patients undergoing epilepsy surgery for seizure control most frequently reveal the damage pattern of hippocampal sclerosis, that is, segmental neuronal cell loss and concomitant astrogliosis. Many TLE patients report on transient brain insults early in life, which is followed by a 'latency' period lacking seizure activity of months or even years before chronic recurrent seizures start. The plethora of structural and cellular mechanisms that convert the hippocampal formation to become chronically hyperexcitable after a transient insult to the brain are summarized under the term epileptogenesis. In contrast to the obstacles arising for experimental studies of epileptogenesis aspects in human surgical hippocampal tissue, recent animal model approaches allow insights into mechanisms of epileptogenesis. Relevant models of transient brain insults in this context comprise several distinct types of lesions including excitoxic status epilepticus (SE), electrical seizure induction, traumatic brain injury, induction of inflammatory processes by hyperthermia and viral inflammation and others. In pathogenetic terms, aberrant transcriptional and epigenetic reprogramming, acquired channel- and synaptopathies, neuronal network and blood-brain barrier dysfunction as well as innate and adaptive immunity-mediated damage play major roles. In subsequent steps, respective animal models have been used in order to test whether this dynamic process can be either retarded or even abolished by interfering with epileptogenic mechanisms. Well-controlled subsequent analyses of epileptogenic cascades characterized in animal models using carefully stratified human hippocampal biopsies to exploit the unique opportunities given by these rare and precious brain tissue samples aim to translate into novel antiepileptogenic approaches. Respective preclinical tests can open entirely new perspectives for tailor-made treatments in patients with the potential to avoid the emergence of chronic focal seizure events. PMID- 29130507 TI - Neurofascin-155 IGG4 Neuropathy: Pathophysiological Insights, Spectrum of Clinical Severity and Response To treatment. AB - INTRODUCTION: Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor. METHODS: From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound. RESULTS: Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal. DISCUSSION: A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018. PMID- 29130509 TI - ARFHPV E7 oncogene, lncRNA HOTAIR, miR-331-3p and its target, NRP2, form a negative feedback loop to regulate the apoptosis in the tumorigenesis in HPV positive cervical cancer. AB - The objective of this study was to explore the role of HOTAIR in the development of cervical cancer, as well as its downstream signaling pathway. We conducted computational analysis, luciferase assay to explore downstream of HOTAIR and miR 331-3p. Real-time PCR and Western blot were carried out to detect the relationship among E7, HOTAIR, miR-331-3p, NRP2, and P53. Finally, MTT assay and flow cytometry analysis were performed to validate the effect of E7 and miR-331 3p on cell apoptosis and proliferation. NRP2 was identified as a virtual target gene of miR-331-3p with a binding site of miR-331-3p, and HOTAIR was directly sponged to miR-331-3p, miR-331-3p reduced luciferase activity of wild-type of NRP2 3'UTR and HOTAIR, but not those of mutant NRP2 3'UTR and HOTAIR. MiR-331-3p down-regulated NRP2 and E7 expression levels, and further promoted cell apoptosis, while inhibited cell proliferation. Cell transfected with HPV16 E7 displayed lower levels of HOTAIR, NRP2 and P53, a higher level of miR-331-3p, over-expression of E7 further repressed cell apoptosis, while improved cell proliferation compared with control. Normal HPV (+) group exhibited a higher miR 331-3p, and lower mRNA levels of HOTAIR and NRP2 than HPV (-) group. According to the result of IHC (immunohistochemistry), we found that NRP2 protein was highly expressed in HPV (-) group compared to that in HPV (+) group. E7-HOTAIR-miR-331 3p-NRP2-E7 formed a regulatory loop, and could be involved in the pathogenesis of cervical cancer. PMID- 29130508 TI - Review: Electric field driven pumping in microfluidic device. AB - Pumping of fluids with precise control is one of the key components in a microfluidic device. The electric field has been used as one of the most popular and efficient nonmechanical pumping mechanism to transport fluids in microchannels from the very early stage of microfluidic technology development. This review presents fundamental physics and theories of the different microscale phenomena that arise due to the application of an electric field in fluids, which can be applied for pumping of fluids in microdevices. Specific mechanisms considered in this report are electroosmosis, AC electroosmosis, AC electrothermal, induced charge electroosmosis, traveling wave dielectrophoresis, and liquid dielectrophoresis. Each phenomenon is discussed systematically with theoretical rigor and role of relevant key parameters are identified for pumping in microdevices. We specifically discussed the electric field driven body force term for each phenomenon using generalized Maxwell stress tensor as well as simplified effective dipole moment based method. Both experimental and theoretical works by several researchers are highlighted in this article for each electric field driven pumping mechanism. The detailed understanding of these phenomena and relevant key parameters are critical for better utilization, modulation, and selection of appropriate phenomenon for efficient pumping in a specific microfluidic application. PMID- 29130511 TI - A decade as Executive Editor of the American Journal of Primatology. PMID- 29130512 TI - Hepatocyte-generated 27-hydroxycholesterol promotes the growth of melanoma by activation of estrogen receptor alpha. AB - Cholesterol plays an important role in maintaining normal physiological function of human body. However, excessive intake will induce a series of diseases including cancer. For melanoma, the relationship between hypercholesterolemia and its incidence remains unknown. The cholesterol metabolite 27-hydroxy cholesterol (27-HC) catalyzed by CYP27A1 has been reported to activate estrogen receptor (ER). As studies have indicated that melanoma expresses ER, we designed experiments to explore whether 27-HC could link hypercholesterolemia and melanoma. In this study, hepatocyte-specific CYP27A1-/- mice were generated by CRISPR/Cas9 technology. The results revealed that high-cholesterol diet induced metabolism disorder and promoted the melanoma growth through 27-HC. Further study found that 27-HC promoted the growth of melanoma cells by activating ERalpha and eliciting the AKT and MAPK signaling pathway. This study puts forward the important role of 27-HC in the development of melanoma for the first time, links hypercholesterolemia with melanoma progression. The research also provides the rationale for the use of tamoxifen in melanoma therapy. The levels of 27-HC in blood could act as a novel biomarker for tamoxifen treatment in melanoma patients. PMID- 29130510 TI - Heterogenous migraine aura symptoms correlate with visual cortex functional magnetic resonance imaging responses. AB - OBJECTIVE: Migraine aura is sparsely studied due to the highly challenging task of capturing patients during aura. Cortical spreading depression (CSD) is likely the underlying phenomenon of aura. The possible correlation between the multifaceted phenomenology of aura symptoms and the effects of CSD on the brain has not been ascertained. METHODS: Five migraine patients were studied during various forms of aura symptoms induced by hypoxia, sham hypoxia, or physical exercise with concurrent photostimulation. The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal response to visual stimulation was measured in retinotopic mapping-defined visual cortex areas V1 to V4. RESULTS: We found reduced BOLD response in patients reporting scotoma and increased response in patients who only experienced positive symptoms. Furthermore, patients with bilateral visual symptoms had corresponding bihemispherical changes in BOLD response. INTERPRETATION: These findings suggest that different aura symptoms reflect different types of cerebral dysfunction, which correspond to specific changes in BOLD signal reactivity. Furthermore, we provide evidence of bilateral CSD recorded by fMRI during bilateral aura symptoms. Ann Neurol 2017;82:925-939. PMID- 29130513 TI - Falls and hip fractures associated with urinary incontinence among older men and women with complex needs: A national population study. AB - AIMS: To determine if urinary incontinence (UI) was an independent risk factor for falls and hip fractures in community-dwelling older men and women with complex needs, after controlling for confounders. METHODS: Since 2012, all community care recipients in New Zealand have undergone standardized needs assessments using the Home Care International Residential Assessment Instrument (interRAI-HC). The interRAI-HC elicits information over multiple domains, including UI frequency and falls. Those aged 65+ years with assessment between July 1, 2012 and May 31, 2014 without collection devices or indwelling catheters were matched to hospital, mortality, and pharmaceutical databases, and apposite regression models applied. RESULTS: Overall, 25 257 (37.5%) men and 42 032 (62.5%) women were eligible, with average age of 82.7 years (range: 65, 106 years). Incontinence was reported by 34.3% of men and 42.6% of women, falls within 90 days by 42.7% of men and 39.1% of women; and fractures recorded for 2.5% of men and 3.7% of women. In multivariable analysis, UI was significantly associated with falls (P < 0.001), and differentially related by sex (P < 0.001). Compared to continent participants, the odds of increasing falls risk was 1.69 (95% CI: 1.57, 1.82) for men with frequent incontinence and 1.53 (95% CI: 1.43, 1.64) for men with occasional continence; higher than the 1.39 (95% CI: 1.32, 1.46) and 1.33 (95% CI: 1.26, 1.39), respectively, for women. UI was not associated with hip fractures. CONCLUSION: UI is a common independent risk factor for falls but not hip fractures. Patterns are different between men and women with complex needs. PMID- 29130514 TI - Involvement of Src signaling in the synergistic effect between cisplatin and digoxin on cancer cell viability. AB - Cisplatin and other platinum-containing drugs have played a crucial role in anticancer treatments for over 30 years. However, treatment with cisplatin may cause serious side effects, such as myelosuppression, nausea, ototoxicity, nephrotoxicity, and cell resistance processes. In addition, cardiotonic steroids, particularly digoxin, have recently been suggested to exert potent anticancer effects. Therefore, it is possible that the combined treatment of HeLa cells with cisplatin and digoxin can ameliorate the cytotoxic effects and decrease the side effects of cisplatin. In this study, we demonstrated that the interaction between cisplatin and digoxin had a synergistic effect on cervical cancer cells and a significantly positive cytotoxic and antiproliferative effect on this cell line compared to the control and single cisplatin treatments. Although a decrease in the Na,K-ATPase alpha1 subunit expression was observed in total extracts, its expression remains unchanged in the membrane, as does the Na,K-ATPase activity. The antiproliferative effect of the synergistic treatment appears to depend on Src kinase activation, indicating the possible involvement of the Scr-EGFR-ERK1/2 pathway in the antitumor effect. The inhibition of ERK1/2 provoked the same synergism with 1 MUM cisplatin as that observed with 1 nM digoxin plus 1 MUM cisplatin but not with 1 nM digoxin. Pretreatment with PP2 during combined treatment abolished the synergistic effect on the antiproliferative activity. Cisplatin and digoxin are already used in the clinical setting; therefore, this study opens possibilities for future clinical trials of combined treatments to improve treatment outcomes with a lower incidence of toxicity and side effects. PMID- 29130515 TI - Spectral decomposition for resolving partial volume effects in MRSI. AB - PURPOSE: Estimation of brain metabolite concentrations by MR spectroscopic imaging (MRSI) is complicated by partial volume contributions from different tissues. This study evaluates a method for increasing tissue specificity that incorporates prior knowledge of tissue distributions. METHODS: A spectral decomposition (sDec) technique was evaluated for separation of spectra from white matter (WM) and gray matter (GM), and for measurements in small brain regions using whole-brain MRSI. Simulation and in vivo studies compare results of metabolite quantifications obtained with the sDec technique to those obtained by spectral fitting of individual voxels using mean values and linear regression against tissue fractions and spectral fitting of regionally integrated spectra. RESULTS: Simulation studies showed that, for GM and the putamen, the sDec method offers < 2% and 3.5% error, respectively, in metabolite estimates. These errors are considerably reduced in comparison to methods that do not account for partial volume effects or use regressions against tissue fractions. In an analysis of data from 197 studies, significant differences in mean metabolite values and changes with age were found. Spectral decomposition resulted in significantly better linewidth, signal-to-noise ratio, and spectral fitting quality as compared to individual spectral analysis. Moreover, significant partial volume effects were seen on correlations of neurometabolite estimates with age. CONCLUSION: The sDec analysis approach is of considerable value in studies of pathologies that may preferentially affect WM or GM, as well as smaller brain regions significantly affected by partial volume effects. Magn Reson Med 79:2886-2895, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29130516 TI - MicroRNA-329 inhibits cell proliferation and tumor growth while facilitates apoptosis via negative regulation of KDM1A in gastric cancer. AB - Altered expression of microRNA (miRNA) is strongly implicated in gastric cancer (GC). Here, we demonstrated a decreased expression of miRNA-329 in GC. Then we explored the regulatory mechanisms responsible for its effect on GC cells. GC tissues and their adjacent non-tumor tissues were collected. Complete follow-up was updated. A series of inhibitors, mimics, and siRNA against KDM1A were introduced to validate regulatory mechanisms for miR-497 and KDM1A in BGC-823 cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay were employed for evaluating the expressions of miRNA-329, KDM1A, H3K4me1, and H3K4me2. Cell proliferation, cycle progression, and apoptosis were assessed by means of an MTT assay and flow cytometry. Cell colony formation was assessed. uman gastric cancer xenotransplanted into nude mice was studied. As opposed to adjacent tissues and gastritis tissues, miRNA-329 was highly expressed and KDM1A was low expressed in GC tissues. The patients with high miRNA-329 expression or low KDM1A expression had longer survival periods. The miRNA-329 mimics and siRNA against KDM1A decreased KDM1A expression and increased H3K4me1 and H3K4me2 expressions. Forced expression of miRNA-329 in gastric cancer cells significantly promotes their capacity of apoptosis but reduces proliferation, migration, and invasion. KDM1A is a direct downstream target for miRNA-329. In a nude mouse subcutaneous tumor system, in vivo tumor growth of BGC-823 was significantly inhibited after treatment of miRNA-329 mimics or siRNA against KDM1A. We conclude that miRNA-329 functions as a tumor suppressor in GC, which could be achieved via transcriptional suppression of KDM1A. PMID- 29130517 TI - Mesenchymal splice isoform of CD44 (CD44s) promotes EMT/invasion and imparts stem like properties to ovarian cancer cells. AB - Increased metastasis and a precipitous recurrence contribute to the lethality of ovarian cancer (OC). Several molecular mechanisms including aberrant-splicing have been closely associated with the extent of cancer progression. Numerous gene transcripts are differentially spliced in cancer cells, CD44 being one of them. CD44 splice isoforms contribute to the aggressiveness and gain of stem-like properties in different cancer types, but their role in ovarian cancer remains to be elucidated. We observed augmented CD44 levels in human ovarian cancer patient samples correlated with enhanced expression of the mesenchymal spliced variant CD44s (standard) and a concurrent decrease in the epithelial variants (CD44v). Moreover, CD44s was upregulated upon TGFbeta1-induced EMT, which was mediated through the downregulation of the splicing factor, ESRP1. Furthermore, overexpression of this mesenchymal isoform in the OC cells induced EMT and invasion, followed by the gain of stem-like characteristics and chemoresistance. Since all these phenomena render lethality to this disease type, CD44s can be attributed for playing a major role in deregulated-splicing mediated ovarian cancer progression. PMID- 29130518 TI - Automated red blood cell exchange in preparation for filgrastim mobilization of autologous peripheral blood hematopoietic progenitor cells in a patient with sickle cell anemia. AB - Increasing survival of patients with sickle cell anemia (SCA) well into adulthood results in a rising likelihood of developing hematological malignancy. High-dose chemotherapy with autologous hematopoietic progenitor cell (HPC) rescue is standard of care for several hematological malignancies, but the risk of severe or life-threatening vaso-occlusive phenomena during filgrastim mobilization of HPC for collection poses a potential barrier to this approach. We report the use of automated red cell exchange in preparation for filgrastim mobilization in a patient with homozygous SCA. Red cell exchange was repeated just prior to high dose chemotherapy to mitigate the need for red cell transfusion during bone marrow reconstitution. The patient experienced no vaso-occlusive phenomena throughout the entire episode of care and did not become iron overloaded. This approach should be considered for all patients with homozygous or compound heterozygous sickle cell disease who are candidates for auto-HPC rescue therapy. PMID- 29130519 TI - Velocity reconstruction with nonconvex optimization for low-velocity-encoding phase-contrast MRI. AB - PURPOSE: To introduce and demonstrate a nonconvex optimization method for reconstructing velocity data from low-velocity-encoding (Venc ) phase-contrast MRI data. THEORY AND METHODS: Solving for velocity values from phase-contrast MRI data was formulated as a nonconvex optimization problem. Weighting was added to account for intravoxel dephasing, and a Laplacian-based regularization was used to account for residual velocity aliasing. The reconstruction was tested with two low-Venc schemes: dual-Venc and a multidirectional high-moment encoding. The reconstruction method was tested in a digital simulation, in flow phantoms, and in healthy volunteers (N = 5). RESULTS: The nonconvex-optimization reconstruction velocity error was lower than the conventional reconstruction in simulations (4.6 versus 3.0 cm/s for multidirectional high moment, 8.3 versus 3.8 cm/s for dual Venc ) and in flow phantoms (23.9 versus 5.9 cm/s for multidirectional high moment, 15.2 versus 6.4 cm/s for dual-Venc ). Qualitative assessment of velocity fields in all experiments, including healthy volunteers, showed decreased apparent noise in the velocity fields and fewer phase wraps. No additional velocity bias in measured velocities was seen in volunteers with the proposed method. CONCLUSIONS: The proposed nonconvex-optimization reconstruction method incorporates additional information to solve for velocities when using any type of low-Venc (high-moment) acquisition. The method reduces the amount of residual phase aliasing, and decreases velocity errors that result from intravoxel dephasing. These improvements allow for more robust acquisitions, and for Venc to be lowered 2 to 4 times relative to conventional acquisitions, thereby increasing the velocity-to-noise ratio. Magn Reson Med, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. Magn Reson Med 80:42-52, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29130520 TI - Narrated video demonstrating the procedure of videourodynamics. AB - AIMS: To present a narrated video designed to demonstrate the steps involved in the procedure of videourodynamics. METHODS: The technique shown and described in this teaching video is that performed in the urogynaecology Department at King's College Hospital, London. The equipment utilizes fluid filled lines and external pressure transducers which provide accurate and consistent results. RESULTS: The advantage of videocystourolodraphy is that as well as incorporating screening fluoroscopy with a cystometric trace, simultaneous assessment of lower urinary tract anatomy and morphology and function is possible. CONCLUSION: Videourodynamics or videocystourogrpahy is a diagnostic tool that incorporates urodynamics with imaging of the lower urinary tract which occurs simultaneously. Thus both functional anatomy and physiology can be assessed. PMID- 29130521 TI - A variant in PPP4R3A protects against alzheimer-related metabolic decline. AB - OBJECTIVES: A reduction in glucose metabolism in the posterior cingulate cortex (PCC) predicts conversion to Alzheimer's disease (AD) and tracks disease progression, signifying its importance in AD. We aimed to use decline in PCC glucose metabolism as a proxy for the development and progression of AD to discover common genetic variants associated with disease vulnerability. METHODS: We performed a genome-wide association study (GWAS) of decline in PCC fludeoxyglucose F 18 ([18 F] FDG) positron emission tomography measured in Alzheimer's Disease Neuroimaging Initiative participants (n = 606). We then performed follow-up analyses to assess the impact of significant single nucleotide polymorphisms (SNPs) on disease risk and longitudinal cognitive performance in a large independent data set (n = 870). Last, we assessed whether significant SNP influence gene expression using two RNA sequencing data sets (n = 210 and n = 159). RESULTS: We demonstrate a novel genome-wide significant association between rs2273647-T in the gene, PPP4R3A, and reduced [18 F] FDG decline (p = 4.44 * 10-8 ). In a follow-up analysis using an independent data set, we demonstrate a protective effect of this variant against risk of conversion to MCI or AD (p = 0.038) and against cognitive decline in individuals who develop dementia (p = 3.41 * 10-15 ). Furthermore, this variant is associated with altered gene expression in peripheral blood and altered PPPP4R3A transcript expression in temporal cortex, suggesting a role at the molecular level. INTERPRETATIONS: PPP4R3A is a gene involved in AD risk and progression. Given the protective effect of this variant, PPP4R3A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for AD therapies. Ann Neurol 2017;82:900-911. PMID- 29130522 TI - RhoJ promotes hypoxia induced endothelial-to-mesenchymal transition by activating WDR5 expression. AB - Endothelial-to-mesenchymal transition (EndMT) contributes to the pathogenesis of a host of human diseases. RhoJ, a small G protein, is abundantly expressed in endothelial cells. In the present study, we investigated the potential role RhoJ plays in EndMT. We report that RhoJ depletion by small interfering RNA attenuated hypoxia induced EndMT in both immortalized endothelial cells and human primary microvascular endothelial cells. RhoJ knockdown blocked the recruitment of TWIST and SNAIL, two transcriptional repressors, to the promoter region of VE-CADHERIN, a prominent endothelial marker. RhoJ mediated the induction of TWIST and SNAIL expression, under hypoxic conditions, by promoting the binding of HIF-1alpha to the gene promoters and by enhancing the accumulation of trimethylated histone H3K4. Further analysis revealed that RhoJ was essential for the up-regulation of WDR5, a key component of the mammalian H3K4 methyltransferase, by hypoxia thereby leading to the trans-activation of TWIST and SNAIL. Finally, lentivirus mediated over-expression of WDR5 compensated for the loss of TWIST and SNAIL and allowed EndMT to proceed despite the absence of RhoJ in hypoxia-challenged endothelial cells. In conclusion, we propose that RhoJ-dependent induction of WDR5 may be essential for hypoxia-induced EndMT. PMID- 29130523 TI - Subclinical thinning of macular ganglion cell layer in Leber optic neuropathy carriers. PMID- 29130524 TI - Psychometric properties and validation of two global impression questionnaires (PGI-S, PGI-I) for stress incontinence in a German-speaking female population. AB - AIMS: The Patient Global Index of Severity (PGI-S) and the Patient Global Index of Improvement (PGI-I) are global impression questionnaires developed in English and validated in women with stress urinary incontinence (SUI). This validation study tested the psychometric properties of German-language versions of the two questionnaires in German-speaking women with SUI. METHODS: The German-language PGI-S and PGI-I were psychometrically tested and validated using the SF-12 questionnaire, the Kings Health Questionnaire (KHQ), clinical parameters, incontinence episode frequency and pad use in 311 patients before and 3 months after receiving a TVT-O or TVT tape for SUI. RESULTS: At baseline and 3 months postoperatively there was a positive correlation between PGI-S response categories and clinical parameters, IEF and pad use, and nearly all KHQ subscales. There were no correlations between response categories of PGI-S at baseline and PGI-I at 3 months and the SF-12 scales PCS-12 and MCS-12. CONCLUSION: Our results demonstrated good psychometric properties of the German language PGI-S and PGI in German-speaking women with SUI. PMID- 29130525 TI - The integral theory of female stress urinary incontinence is not scientifically sound. PMID- 29130526 TI - Phase processing for quantitative susceptibility mapping of regions with large susceptibility and lack of signal. AB - PURPOSE: Phase processing impacts the accuracy of quantitative susceptibility mapping (QSM). Techniques for phase unwrapping and background removal have been proposed and demonstrated mostly in brain. In this work, phase processing was evaluated in the context of large susceptibility variations (Deltachi) and negligible signal, in particular for susceptibility estimation using the iterative phase replacement (IPR) algorithm. METHODS: Continuous Laplacian, region-growing, and quality-guided unwrapping were evaluated. For background removal, Laplacian boundary value (LBV), projection onto dipole fields (PDF), sophisticated harmonic artifact reduction for phase data (SHARP), variable-kernel sophisticated harmonic artifact reduction for phase data (V-SHARP), regularization enabled sophisticated harmonic artifact reduction for phase data (RESHARP), and 3D quadratic polynomial field removal were studied. Each algorithm was quantitatively evaluated in simulation and qualitatively in vivo. Additionally, IPR-QSM maps were produced to evaluate the impact of phase processing on the susceptibility in the context of large Deltachi with negligible signal. RESULTS: Quality-guided unwrapping was the most accurate technique, whereas continuous Laplacian performed poorly in this context. All background removal algorithms tested resulted in important phase inaccuracies, suggesting that techniques used for brain do not translate well to situations where large Deltachi and no or low signal are expected. LBV produced the smallest errors, followed closely by PDF. CONCLUSION: Results suggest that quality-guided unwrapping should be preferred, with PDF or LBV for background removal, for QSM in regions with large Deltachi and negligible signal. This reduces the susceptibility inaccuracy introduced by phase processing. Accurate background removal remains an open question. Magn Reson Med 79:3103-3113, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29130527 TI - The utility of oral brush cytology in the early detection of oral cancer and oral potentially malignant disorders: A systematic review. AB - OBJECTIVES: This systematic review aimed to analyze the published evidence for the use of oral brush cytology for the early detection of oral cancer and oral potentially malignant disorders (OPMDs). METHODS: Literature was systematically searched through several databases: MEDLINE, EMBASE, PubMed, SCOPUS, Cochrane Library, and Web of Science. Additional review was performed through cross-checks on the bibliographies of selected articles. The inclusion criteria involved studies assessing the utility of oral brush cytology on human tissues and its applications in the diagnosis, screening, or surveillance of oral cancer or OPMDs. RESULTS: The search strategy resulted in 343 abstracts or full-text articles, of which 36 met the inclusion criteria. The year of publication ranged from 1994 to 2017, and a total of 4302 samples from OPMDs, oral squamous cell carcinoma, and healthy controls have been investigated. Baby toothbrush, cytobrush, OralCDx(r) , and Orcellex(r) are the brushes that were used to obtain transepithelial mucosal samples for conventional and liquid-based cytology evaluation. CONCLUSIONS: Findings from this study indicate that meaningful evidence-based recommendations for the implementation of a minimally invasive technique to be utilized as an adjunctive tool for screening and early detection of oral cancer and OPMDs are complicated from the reported studies in the literature. There is need for well-designed clinical studies to assess the accuracy of oral brush cytology utilizing validated cytological assessment criteria for the diagnosis and prediction of OPMDs. PMID- 29130528 TI - Relationship between extensibility and collagen expression in immobilized rat skeletal muscle. AB - INTRODUCTION: This study investigated longitudinal changes in muscle extension and collagen expression in an immobilized rat soleus muscle, and assessed the relationship between both elements. METHODS: Soleus muscles of the control and immobilization groups (1, 2, 4, 8, and 12 weeks) were used for analysis of muscle extensibility and collagen expression. RESULTS: The slope value/physiological cross-sectional area (PCSA; a parameter for muscle extensibility) and hydroxyproline (a parameter for collagen expression) were significantly higher in the immobilization group than in the control group for all experimental time points. In the immobilization group, both factors were significantly higher at 4, 8, and 12 weeks than at 1 and 2 weeks after immobilization. A significant positive correlation was observed between the slope value/PCSA and hydroxyproline expression. DISCUSSION: The present study indicated that a decrease in muscle extensibility depended on collagen overexpression in immobilized rat soleus muscles. Muscle Nerve 57: 672-678, 2018. PMID- 29130529 TI - Anterior segment morphology after laser iridotomy in primary angle closure suspects. AB - PURPOSE: To evaluate and compare the changes in anterior segment parameters in primary angle closure suspects before and after laser peripheral iridotomy and intrasession repeatability of measurements before laser iridotomy as assessed by Scheimpflug-Placido disc topographer. METHODS: Before laser iridotomy, 56 eyes of 56 primary angle closure suspect patients underwent anterior segment analysis with the Sirius Scheimpflug-Placido disc topographer system using glaucoma analysis mode, which was repeated a week after iridotomy. Anterior segment parameters such as central anterior chamber depth, central corneal thickness, anterior chamber volume and iridocorneal angle were analysed before and after laser iridotomy and compared with paired t-test. Three consecutive scans were obtained to assess the intrasession repeatability of measurements before iridotomy by a single examiner and intraclass correlation co-efficient was calculated. Multivariate regression analysis was performed to evaluate the predictors associated with iridocorneal angle narrowing. RESULTS: Intraclass correlation co-efficient values ranged from 0.982 for anterior chamber volume to 0.998 for the iridocorneal angle. After laser iridotomy, mean central anterior chamber depth increased from 2.14 +/- 0.29 mm to 2.21 +/- 0.28 mm (p = 0.04), mean anterior chamber volume increased from 96.2 +/- 16.98 mm3 to 98.14 +/- 15.87 mm3 (p < 0.0001) and mean iridocorneal angle widened from 33.38 +/- 3.96 degrees to 34.82 +/- 4.27 degrees (p = 0.01), compared with pre-iridotomy status. There was no change in central corneal thickness, intraocular pressure or pupil diameter. Multivariate regression analysis model showed that at one week after iridotomy, iridocorneal angle opening was positively correlated with age (beta = 0.773, p = 0.005) and anterior chamber volume (beta = 1.308, p < 0.0001). CONCLUSIONS: Laser peripheral iridotomy induces significant changes in the 3-D anterior segment morphology in primary angle closure suspect patients. The Scheimpflug-Placido disc topographer provides reproducible measurements of the iridocorneal angle and other parameters measured and hence, may become clinically useful for non-invasive detection of potentially occludable angles. Predictors of iridocorneal angle widening after iridotomy were older age and anterior chamber volume. PMID- 29130530 TI - Erratum: "Reference-based MRI" [Med. Phys. Vol 43, Issue 10, pages 5357-5369, October 2016]. PMID- 29130531 TI - Acute hypoxic preconditioning prevents palmitic acid-induced cardiomyocyte apoptosis via switching metabolic GLUT4-glucose pathway back to CD36-fatty acid dependent. AB - Metabolic syndrome is a risk factor for the development of cardiovascular diseases. Myocardial cell damage leads to an imbalance of energy metabolism, and many studies have indicated that short-term hypoxia during myocardial cell injury has a protective effect. In our previous animal studies, we found that short-term hypoxia in the heart has a protective effect, but long-term hypoxia increases myocardial cell injury. Palmitic acid (PA)-treated H9c2 cardiomyoblasts and neonatal rat ventricle cardiomyocytes were used to simulate hyperlipidemia model, which suppress cluster of differentiation 36 (CD36) and activate glucose transporter type 4 (GLUT4). We exposed the cells to short- and long-term hypoxia and investigated the protective effects of hypoxic preconditioning on PA-induced lipotoxicity in H9c2 cardiomyoblasts and neonatal rat cardiomyocytes. Preconditioning with short-term hypoxia enhanced both CD36 and GLUT4 metabolism pathway protein levels. Expression levels of phospho-PI3K, phospho-Akt, phospho AMPK, SIRT1, PGC1alpha, PPARalpha, CD36, and CPT1beta induced by PA was reversed by short-term hypoxia in a time-dependent manner. PA-induced increased GLUT4 membrane protein level was reduced in the cells exposed to short-term hypoxia and si-PKCzeta. Short-term hypoxia, resveratrol and si-PKCzeta rescue H9c2 cells from apoptosis induced by PA and switch the metabolic pathway from GLUT4 dependent to CD36 dependent. We demonstrate short-term hypoxic preconditioning as a more efficient way as resveratrol in maintaining the energy metabolism of hearts during hyperlipidemia and can be used as a therapeutic strategy. PMID- 29130532 TI - The impact of argan oil on plasma lipids in humans: Systematic review and meta analysis of randomized controlled trials. AB - The study aims to investigate the effect of argan oil on plasma lipid concentrations through a systematic review of the literature and a meta-analysis of available randomized controlled trials. Randomized controlled trials that investigated the impact of at least 2 weeks of supplementation with argan oil on plasma/serum concentrations of at least 1 of the main lipid parameters were eligible for inclusion. Effect size was expressed as the weighted mean difference (WMD) and 95% confidence interval (95% CI). Meta-analysis of data from 5 eligible trials with 292 participants showed a significant reduction in plasma concentrations of total cholesterol (WMD: -16.85 mg/dl, 95% CI [-25.10, -8.60], p < .001), low-density lipoprotein cholesterol (WMD: -11.67 mg/dl, 95% CI [-17.32, 6.01], p < .001), and triglycerides (WMD: -13.69 mg/dl, 95% CI [-25.80, -1.58], p = .027) after supplementation with argan oil compared with control treatment, and plasma concentrations of high-density lipoprotein cholesterol (WMD: 4.14 mg/dl, 95% CI [0.86, 7.41], p = .013) were found to be increased. Argan oil supplementation reduces total cholesterol, low-density lipoprotein cholesterol, and triglycerides and increases high-density lipoprotein cholesterol levels. Additionally, larger clinical trials are needed to assess the impact of argan oil supplementation on other indices of cardiometabolic risk and on the risk of cardiovascular outcomes. PMID- 29130533 TI - Liver mitochondrial oxygen consumption and efficiency of milk production in lactating Holstein cows supplemented with copper, manganese and zinc. AB - The objective of this study was to examine the relationship between mitochondrial proton leak and feed efficiency with supplementation of different levels of Cu, Mn and Zn (Bioplex, Alltech) at levels above Nutrient Requirements of Dairy Cattle (NRC, 2001). Milk yield and composition, mineral excretion in milk and faeces, feed efficiency and liver mitochondrial proton leak were measured in 60 Holstein dairy cows at approximately 70 days in milk on a commercial dairy. Treatments reflect total Cu, Mn and Zn intake/day and are as follows: (i) High: 444 mg/day Cu, 3492 mg/day Mn, 2234 mg/day Zn; (ii) Med: 436 mg/day Cu, 3002 mg/day Mn, 2047 mg/day Zn; (iii) Low: 420 mg/day Cu, 2764 mg/day Mn, 2186 mg/day Zn; (iv) LowMn: 391 mg/day Cu, 2617 mg/day Mn, 1849 mg/day Zn; and (v) Control: 264 mg/day Cu, 2850 mg/day Mn, 1593 mg/day Zn. Proton leak-dependent respiration was lowest in Control (p < .10). However, measures of efficiency were greatest in Med and least in High (p < .10). Therefore, measures of efficiency did not reflect efficiency due to low proton leak and there appears to be an upper limit to beneficial supplementation of Cu, Mn and Zn. PMID- 29130534 TI - Skin squames contribute to ammonia and volatile fatty acid production from bacteria colonizing in air-cooling units with odor complaints. AB - One of the most notable Indoor Air Quality problems is odor emission. This study investigated the potential contribution of skin squames to the production of ammonia (NH3 ) and volatile organic acids (VFAs) by 7 bacteria isolated from air cooling (AC) units with complaints of urine and body odors. Our previous study showed that keratinolytic activity is higher in AC units with odor complaints than those without. In the offices where these units are located, the most likely source of keratins is from human skin squames. Most bacteria can produce NH3 and VFAs in the skin squame culture. Some correlations between the levels of NH3 , NH4+, VFAs, and keratinolytic activity were found. The odor production pathway with skin squames was proposed. Staphylococcus haemolyticus was abundant in the AC units with odor problems and had a high level of keratinolytic activity in addition to odor production. For long-term odor control, it is important to reduce the level of skin squames entering the AC units. PMID- 29130535 TI - Between-center disparities in access to heart transplantation in France: contribution of candidate and center factors - A comprehensive cohort study. AB - Transplantation represents the last option for patients with advanced heart failure. We assessed between-center disparities in access to heart transplantation in France 1 year after registration and evaluated the contribution of factors to these disparities. Adults (n = 2347) registered on the French national waiting list between January 1, 2010, and December 31, 2014, in the 23 transplant centers were included. Associations between candidate and transplant center characteristics and access to transplantation were assessed by proportional hazards frailty models. Candidate blood groups O and A, sensitization, and body mass index >=30 kg/m2 were independently associated with lower access to transplantation, while female gender, severity of heart failure, and high serum bilirubin levels were independently associated with greater access to transplantation. Center factors significantly associated with access to transplantation were heart donation rate in the donation service area, proportion of high-urgency candidates among listed patients, and donor heart offer decline rate. Between-center variability in access to transplantation increased by 5% after adjustment for candidate factors and decreased by 57% after adjustment for center factors. After adjustment for candidate and center factors, five centers were still outside of normal variability. These findings will be taken into account in the future French heart allocation system. PMID- 29130536 TI - Adoption and use of an injury prevention exercise program in female football: A qualitative study among coaches. AB - This study focuses on an injury prevention exercise program (IPEP), Knee Control, which has been shown to reduce the incidence of acute knee injury in female adolescent football players. The aim was to explore the factors influencing coaches' adoption and use of Knee Control within female football in Sweden. This was a qualitative study involving interviews with 20 strategically selected coaches for female football teams, predominantly adolescent teams. The semi structured interview guide was influenced by the Health Belief Model, and an ecological perspective was adopted during the interviews. Interviews were analyzed with qualitative content analysis. The results illustrate the different influences that interact on adoption and use of Knee Control by coaches. The coaches described themselves as crucial for Knee Control adoption and use, but external facilitators and barriers such as resources for training, social support from other coaches, clubs and football associations and player buy-in were also described as important. Knee Control characteristics, such as how well the program fit the team, also influenced use of Knee Control. Many coaches modified the program to improve player buy-in and Knee Control fit. Such modifications may risk compromising the preventive effect but may increase feasibility, that is the ease of using Knee Control, and thereby long-term use. These findings may guide the design and delivery of future IPEPs, and improve use of Knee Control, for example, by expanding the program to fit different target groups and supporting coaches and players in the use of Knee Control. PMID- 29130537 TI - Evaluation of renal metabolic response to partial ureteral obstruction with hyperpolarized 13 C MRI. AB - Hyperpolarized 13 C magnetic resonance imaging (MRI) may be used to non invasively image the transport and chemical conversion of 13 C-labeled compounds in vivo. In this study, we utilize hyperpolarized 13 C MRI to evaluate metabolic markers in the kidneys longitudinally in a mouse model of partial unilateral ureteral obstruction (pUUO). Partial obstruction was surgically induced in the left ureter of nine adult mice, leaving the right ureter as a control. 1 H and hyperpolarized [1-13 C]pyruvate MRI of the kidneys was performed 2 days prior to surgery (baseline) and at 3, 7 and 14 days post-surgery. Images were evaluated for changes in renal pelvis volume, pyruvate, lactate and the lactate to pyruvate ratio. After 14 days, mice were sacrificed and immunohistological staining of both kidneys for collagen fibrosis (picrosirius red) and macrophage infiltration (F4/80) was performed. Statistical analysis was performed using a linear mixed effects model. Significant kidney * time interaction effects were observed for both lactate and pyruvate, indicating that these markers changed differently between time points for the obstructed and unobstructed kidneys. Both kidneys showed an increase in the lactate to pyruvate ratio after obstruction, suggesting a shift towards glycolytic metabolism. These changes were accompanied by marked hydronephrosis, fibrosis and macrophage infiltration in the obstructed kidney, but not in the unobstructed kidney. Our results show that pUUO is associated with increased pyruvate to lactate metabolism in both kidneys, with injury and inflammation specific to the obstructed kidney. The work also demonstrates the feasibility of the use of hyperpolarized 13 C MRI to study metabolism in renal disease. PMID- 29130538 TI - "What if this is my chance to save my life?" A semistructured interview study on the motives and experiences of end-stage renal disease patients who engaged in public solicitation of a living kidney donor. AB - The increase in patients using public solicitation (PS) to find a living kidney donor has generated a debate about the ethical complexities of PS. To investigate why patients engaged in PS and what they experienced during PS, we conducted semistructured interviews with 20 Dutch patients with end-stage renal disease who had publicly solicited a living donor. Transcripts were thematically analyzed. We identified ten themes on patients' considerations preceding PS: cautiousness in discussing living donation within social network; reluctance to accept a kidney from loved ones; rejection/withdrawal of related donor candidates; moral objections to paid donation; the ease of social media; encouraged by others; ends justifying the means; despair and urge to take action; public disclosure of vulnerability; fear of being (perceived to be) selfish. We identified nine themes on patients' experiences: positive emotions and support generated by action; genuine and ulterior motives for donation; patients acting as educators and screeners; time- and energy-consuming process; emotionally taxing process; positive interactions with donor candidates; feeling of dependency and obligation; limited cooperation from health professionals; demands a proactive attitude and media strategy. These results can inform and complement (existing) policies on PS and provide content for education of patients who are considering PS. PMID- 29130539 TI - Sources of systematic error in proton density fat fraction (PDFF) quantification in the liver evaluated from magnitude images with different numbers of echoes. AB - The purpose of this work was to investigate sources of bias in magnetic resonance imaging (MRI) liver fat quantification that lead to a dependence of the proton density fat fraction (PDFF) on the number of echoes. This was a retrospective analysis of liver MRI data from 463 subjects. The magnitude signal variation with TE from spoiled gradient echo images was curve fitted to estimate the PDFF using a model that included monoexponential R2 * decay and a multi-peak fat spectrum. Additional corrections for non-exponential decay (Gaussian), bi-exponential decay, degree of fat saturation, water frequency shift and noise bias were introduced. The fitting error was minimized with respect to 463 * 3 = 1389 subject-specific parameters and seven additional parameters associated with these corrections. The effect on PDFF was analyzed, notably the dependence on the number of echoes. The effects on R2 * were also analyzed. The results showed that the inclusion of bias corrections resulted in an increase in the quality of fit (r2 ) in 427 of 463 subjects (i.e. 92.2%) and a reduction in the total fitting error (residual norm) of 43.6%. This was largely a result of the Gaussian decay (57.8% of the reduction), fat spectrum (31.0%) and biexponential decay (8.8%) terms. The inclusion of corrections was also accompanied by a decrease in the dependence of PDFF on the number of echoes. Similar analysis of R2 * showed a decrease in the dependence on the number of echoes. Comparison of PDFF with spectroscopy indicated excellent agreement before and after correction, but the latter exhibited lower bias on a Bland-Altman plot (1.35% versus 0.41%). In conclusion, correction for known and expected biases in PDFF quantification in liver reduces the fitting error, decreases the dependence on the number of echoes and increases the accuracy. PMID- 29130540 TI - Anti-inflammatory and analgesic activities of cupressuflavone from Cupressus macrocarpa: Impact on pro-inflammatory mediators. AB - Hit, Lead & Candidate Discovery Inflammation is a complex biological process that is generally occurs in response to pathological triggers. Both neurodegenerative diseases and cancer have been linked to inflammation. The analgesic and anti inflammatory effects of cupressuflavone (CUF) isolated from Cupressus macrocarpa were examined. The analgesic effects of CUF (40, 80 and 160 mg/kg po) were assessed in the acetic acid-induced writhing and hot plate models in mice with diclofenac sodium as the reference standard (100 mg/kg). CUF dose-dependently inhibited the writhing response in mice by 25, 48, and 62%, at the three CUF doses with 160 mg/kg being equivalent to the diclofenac control. CUF dose dependently increased the hot plate model reaction time with a maximal effect after 120 min. In the carrageenan-induced paw edema model of inflammation, CUF demonstrated anti-inflammatory activity by inhibiting paw edema by 55, 60, and 64% at doses of 40, 80, and 160 mg/kg po, respectively. CUF also reduced the plasma pro-inflammatory mediators PGE2 (44, 54, and 58%), TNF-alpha (26, 37, and 53%), IL-1beta (19, 33, and 41%), and IL-6 (32, 44, and 55%) at the three doses tested with the highest dose having similar effects to diclofenac sodium (100 mg/kg). This finding from this study indicates that CUF has both analgesic and anti-inflammatory effects. PMID- 29130541 TI - Depression, social support, and clinical outcomes following lung transplantation: a single-center cohort study. AB - Depressive symptoms are common among lung transplant candidates and have been associated with poorer clinical outcomes in some studies. Previous studies have been plagued by methodologic problems, including small sample sizes, few clinical events, and uncontrolled confounders, particularly perioperative complications. In addition, few studies have examined social support as a potential protective factor. We therefore examined the association between pretransplant depressive symptoms, social support, and mortality in a large sample of lung transplant recipients. As a secondary aim, we also examined the associations between psychosocial factors, perioperative outcomes [indexed by hospital length of stay (LOS)], and mortality. We hypothesized that depression would be associated with longer LOS and that the association between depression, social support, and mortality would be moderated by LOS. Participants included lung transplant recipients, transplanted at Duke University Medical Center from January 2009 to December 2014. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI-II) and social support using the Perceived Social Support Scale (PSSS). Medical risk factors included forced vital capacity (FVC), partial pressure of carbon dioxide (PCO2 ), donor age, acute rejection, and transplant type. Functional status was assessed using six-minute walk distance (6MWD). We also controlled for demographic factors, including age, gender, and native disease. Transplant hospitalization LOS was examined as a marker of perioperative clinical outcomes. Participants included 273 lung recipients (174 restrictive, 67 obstructive, 26 cystic fibrosis, and six "other"). Pretransplant depressive symptoms were common, with 56 participants (21%) exhibiting clinically elevated levels (BDI-II >= 14). Greater depressive symptoms were associated with longer LOS [adjusted b = 0.20 (2 days per 7-point higher BDI-II score), P < 0.01]. LOS moderated the associations between depressive symptoms (P = 0.019), social support (P < 0.001), and mortality, such that greater depressive symptoms and lower social support were associated with greater mortality only among individuals with longer LOS. For individuals with LOS >= 1 month, clinically elevated depressive symptoms (BDI-II >= 14) were associated with a threefold increased risk of mortality (HR = 2.97). Greater pretransplant depressive symptoms and lower social support may be associated with greater mortality among a subset of individuals with worse perioperative outcomes. PMID- 29130542 TI - Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: A clinical study. AB - Extracts of bitter orange (BOE, Citrus aurantium L.) and its primary protoalkaloid p-synephrine are extensively consumed as dietary supplements. p Synephrine is also present in foods and juices prepared from various Citrus species. The safety of p-synephrine has been questioned as a result of structural similarities with ephedrine. This study assessed the cardiovascular (stimulant) and hemodynamic effects of BOE (49 mg p-synephrine) daily given to 16 healthy subjects for 15 days in a placebo-controlled, cross-over, double-blinded study. A physical evaluation by a cardiologist, as well as heart rates, blood pressures, and electrocardiograms were determined, and blood samples were drawn at baseline, and Days 5, 10, and 15. Serum levels for caffeine and p-synephrine were measured at 1 and 2 weeks. Subjects completed a 10-item health and metabolic questionnaire at baseline and on Day 15. No significant changes occurred in heart rate, electrocardiograms, systolic blood or diastolic pressures, blood cell counts, or blood chemistries in either the control or p-synephrine treated groups at any time point. No adverse effects were reported in response to the bitter orange (p synephrine). Caffeine consumed by the participants varied markedly. Under these experimental conditions, BOE and p-synephrine were without stimulant (cardiovascular) and adverse effects. PMID- 29130543 TI - Medicinal plants of the genus Macleaya (Macleaya cordata, Macleaya microcarpa): A review of their phytochemistry, pharmacology, and toxicology. AB - In the genus Macleaya, Macleaya cordata and Macleaya microcarpa have been recognized as traditional herbs that are primarily distributed in China, North America, and Europe and have a long history of medicinal usage. These herbs have been long valued and studied for detumescence, detoxification, and insecticidal effect. This review aims to provide comprehensive information on botanical, phytochemical, pharmacological, and toxicological studies on plants in the genus Macleaya. Plants from the genus of Macleaya provide a source of bioactive compounds, primarily alkaloids, with remarkable diversity and complex architectures, thereby having attracted attention from researchers. To date, 291 constituents have been identified and/or isolated from this group. These purified compounds and/or crude extract possess antitumor, anti-inflammatory, insecticidal, and antibacterial activities in addition to certain potential toxicities. Macleaya species hold potential for medicinal applications. However, despite the pharmacological studies on these plants, the mechanisms underlying the biological activities of active ingredients derived from Macleaya have not been thoroughly elucidated to date. Additionally, there is a need for research focusing on in vivo medical effects of Macleaya compounds and, eventually, for clinical trials. PMID- 29130544 TI - Identification of gene expression signatures across different types of neural stem cells with the Monte-Carlo feature selection method. AB - Adult neural stem cells (NSCs) are a group of multi-potent, self-renewing progenitor cells that contribute to the generation of new neurons and oligodendrocytes. Three subtypes of NSCs can be isolated based on the stages of the NSC lineage, including quiescent neural stem cells (qNSCs), activated neural stem cells (aNSCs) and neural progenitor cells (NPCs). Although it is widely accepted that these three groups of NSCs play different roles in the development of the nervous system, their molecular signatures are poorly understood. In this study, we applied the Monte-Carlo Feature Selection (MCFS) method to identify the gene expression signatures, which can yield a Matthews correlation coefficient (MCC) value of 0.918 with a support vector machine evaluated by ten-fold cross validation. In addition, some classification rules yielded by the MCFS program for distinguishing above three subtypes were reported. Our results not only demonstrate a high classification capacity and subtype-specific gene expression patterns but also quantitatively reflect the pattern of the gene expression levels across the NSC lineage, providing insight into deciphering the molecular basis of NSC differentiation. PMID- 29130547 TI - miR-140-5p-mediated regulation of the proliferation and differentiation of human dental pulp stem cells occurs through the lipopolysaccharide/toll-like receptor 4 signaling pathway. AB - Human dental pulp stem cells (DPSCs) are oral mesenchymal stem cells with potential to differentiate into various cell types. Recent studies of DPSCs have focused on microRNAs (miRNAs), a class of small noncoding RNAs that play crucial roles in regulating DPSC phenotypes. In the current study, the expression of miR 140-5p was significantly decreased during lipopolysaccharide (LPS)-mediated differentiation of DPSCs in vitro. Overexpression of miR-140-5p enhanced proliferation of DPSCs and inhibited DPSC differentiation, whereas suppression of miR-140-5p produced the opposite effect. Moreover, the expression of toll-like receptor 4 (TLR-4), a critical regulator of DPSCs, was negatively correlated with the levels of miR-140-5p. A luciferase reporter analysis confirmed that miR-140 5p could regulate TLR-4 by directly binding to the 3'-untranslated region (3' UTR) of the TLR4 mRNA. Additionally, we suppressed TLR-4 expression by treating cells with a TLR-4 inhibitor, CLI-095, and demonstrated that the effect of the miR-140-5p inhibitor on DPSC proliferation and differentiation could be partially reversed by blocking TLR-4. Taken together, our data suggest that miR-140-5p is a novel miRNA that regulates DPSC proliferation and differentiation. PMID- 29130548 TI - Reliability and validity of the Arabic PTSD Checklist Civilian Version (PCL-C) in women survivors of intimate partner violence. AB - Although intimate partner violence (IPV) survivors are at high risk for developing posttraumatic stress disorder (PTSD), PTSD has been considered a disorder specific to Western culture. There is a lack of reliable and valid measures of PTSD symptomology available in the Arab world, and there is still no clear evidence about the underlying factor structure of PTSD symptomology in the context of IPV. Thus, in the present study we investigated the construct validity (factor structure), internal consistency, and concurrent validity of a translated version of the PTSD Checklist Civilian Version (PCL-C) in a sample of 299 Saudi women who had experienced IPV. Four competing models (DSM-IV, Emotional Numbing, Dysphoria, and Dysphoric Arousal) were specified and estimated using confirmatory factor analysis (CFA). The five-factor Dysphoric Arousal model provided superior fit with the data compared to the alternative models, supporting construct validity of the Arabic PCL-C. The factor loadings for the five-factor Dysphoric Arousal model ranged from .31 to .83. A relatively high correlation between the Arabic PCL-C and Arabic Center for Epidemiologic Studies-Depression (CES-D) Scale (r = .78, p < .05) provided evidence of concurrent validity. The total scale also demonstrated internal consistency reliability (alpha = .89). Overall, the study supports the Dysphoric Arousal model in representing PTSD symptoms among IPV survivors, the reliability and validity of the Arabic version of PCL-C, and the cross-cultural applicability of PTSD symptoms. PMID- 29130549 TI - Concomitant IDH wild-type glioblastoma and IDH1-mutant anaplastic astrocytoma in a patient with constitutional mismatch repair deficiency syndrome. PMID- 29130550 TI - 1 H NMRS of carnosine combined with 31 P NMRS to better characterize skeletal muscle pH dysregulation in Duchenne muscular dystrophy. AB - In recent years, quantitative nuclear magnetic resonance imaging and spectroscopy (NMRI and NMRS) have been used more systematically as outcome measures in natural history and clinical trial studies for Duchenne muscular dystrophy (DMD). Whereas most of these studies have emphasized the evaluation of the fat fraction as an assessment for disease severity, less focus has been placed on metabolic indices measured by NMRS. 31 P NMRS in DMD reveals an alkaline inorganic phosphate (Pi ) pool, originating from either leaky dystrophic myocytes or an increased interstitial space. 1 H NMRS, exploiting the pH-sensitive proton resonances of carnosine, an intracellular dipeptide, was used to distinguish between these two hypotheses. NMR data were obtained in 23 patients with DMD and 14 healthy subjects on a 3-T clinical NMR system. Both 31 P and 1 H NMRS data were acquired at the level of the gastrocnemius medialis muscle. A multi-slice multi-echo imaging acquisition was performed for the determination of water T2 and fat fraction in the same region of interest. Whereas nearly all patients with DMD showed an elevated pH compared with healthy controls when using 31 P NMRS, 1 H NMRS-determined pH was not systematically increased. As expected, the carnosine based intracellular pH was never found to be alkaline in the absence of a concurrent Pi -based pH elevation. In addition, abnormal intracellular pH, based on carnosine, was never associated with normal water T2 values. We conclude that, in one group of patients, both 1 H and 31 P NMRS showed an alkaline pH, originating from the intracellular compartment and reflecting ionic dysregulation in dystrophic myocytes. In the other patients with DMD, intracellular pH was normal, but an alkaline Pi pool was still present, suggesting an extracellular origin, probably revealing an expanded interstitial volume fraction, often associated with fibrotic changes. The data demonstrate that 1 H NMRS could serve as a biomarker to assess the normalization of intramyocytic pH and sarcolemmal permeability following therapy inducing dystrophin expression in patients with DMD. PMID- 29130551 TI - A localized pallidal physiomarker in cervical dystonia. AB - OBJECTIVE: Deep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinson's disease, a disease-specific physiomarker was identified that is now used to investigate adaptive closed-loop stimulation in first studies. In dystonia, such a physiomarker is missing. METHODS: Pallidal oscillations were recorded from 153 contact pairs in 27 patients. We investigated whether power amplitudes in theta and beta bands correlate with dystonic symptom severity across patients. We then projected theta power from each contact pair onto standard subcortical anatomy. In this way, we defined a theta hot spot on a group level and investigated whether proximity of the active DBS contacts to it correlated with clinical improvement. RESULTS: Dystonic symptom severity significantly correlated with theta but not beta oscillatory amplitudes (rho = 0.4, p = 0.009) and interhemispheric coherence (rho = 0.5, p = 0.002). The sweet spot of theta activity localized to the posterior third of the internal pallidum and theta power correlated with proximity to this location (rho = 0.23, p = 0.002), which coincided with 3 previously published coordinates describing optimal stimulation targets. Finally, motor improvement through pallidal long-term DBS correlated with theta peak amplitude (rho = 0.38, p = 0.018). INTERPRETATION: Our findings suggest that theta oscillations in the internal pallidum are robustly associated with dystonic symptoms in cervical dystonia and may be a useful biomarker for adaptive closed-loop stimulation. Furthermore, theta oscillatory activity may have a predictive value for the clinical benefit after chronic DBS that could be used to improve intraoperative neurophysiological target mapping during electrode implantation. Ann Neurol 2017;82:912-924. PMID- 29130552 TI - Resveratrol pretreatment enhanced homing of SDF-1alpha-preconditioned bone marrow derived mesenchymal stem cells in a rat model of liver cirrhosis. AB - Stromal cell-derived factor-1alpha (SDF-1alpha) has been known to implicate in homing of MSCs, and resveratrol has been reported to have a positive influence on SDF-1 level in the site of injury. In this study, a combined strategy was applied to evaluate bone marrow-derived MSCs (BMSCs) homing to the rat model of liver cirrhosis induced by common bile duct ligation (CBDL): (1) pretreatment delivery of resveratrol into the cirrhotic liver, and (2) transplantation of ex vivo BMSC preconditioning with SDF-1alpha. BMSCs were preconditioned with 10 ng/uL SDF 1alpha for 1 h and then labeled with the CM-Dil. Cirrhosis was induced by CBDL. Animals received intraperitoneal injection of resveratrol for 7 days, started on day 28 of CBDL post-operative. On day 36 post-operative, 1 * 106 of SDF-1alpha preconditioned BMSCs was injected via caudal vein. Animals were sacrificed at 72 h post-cell transplantation. Immunofluorescence and flow cytometry assessments showed that the BMSC+SDF+RV group had an increased rate of homing into the liver, but it had a decreased rate of homing into the lung and spleen, as compared with the other groups (P < 0.05). The BMSC+SDF+RV group showed high protein expression of SIRT1, but low protein expression of p53 in the liver (P < 0.05 vs other groups). CXCR4 and matrix metalloproteinase (MMP)-9 highly expressed in SDF 1alpha-preconditioned BMSCs in vitro, and that AKTs and CXCL12 expressed in injured liver undergoing resveratrol injection. Our findings suggest that reseveratrol pretreatment prior to SDF-1alpha preconditioning could be a promising strategy for designing cell-based therapies for liver cirrhosis. PMID- 29130553 TI - The Akkermansia muciniphila is a gut microbiota signature in psoriasis. AB - Psoriasis is an immune-mediated chronic inflammatory skin disease. Although its pathogenesis is not fully understood, Th17 cells and the cytokines they produce, such as IL-17, IL-22 and IL-23, play critical roles in the pathogenesis of psoriasis. Evidence has demonstrated that psoriasis has some common features, including immune responses (due to Th17 cells) and inflammatory cytokine profiles, with systematic diseases including inflammatory bowel diseases (IBDs) and obesity. Recently, studies have demonstrated that the gut microbiota plays a crucial role in host homoeostasis and immune response, particular in Th17 cells, but the role of the gut microbiota in psoriasis remains unclear. To study the relationship between gut microbiota and psoriasis, we analysed microbiota profiles in psoriasis using a 16S rDNA sequencing platform, and we found that the abundance of Akkermansia muciniphila was significantly reduced in patients with psoriasis. A. muciniphila is believed to have an important function in the pathogenesis of IBD and obesity; therefore, A. muciniphila, which is an indicator of health status, may be a key node for psoriasis as well as IBD and obesity. Taken together, our study identified that gut microbiota signature and function are significantly altered in the gut of patients with psoriasis, which provides a novel angle to understanding the pathogenesis of psoriasis. PMID- 29130554 TI - Sensory recovery of myomucosal flap oral cavity reconstructions. AB - BACKGROUND: Sensory restoration of the oral cavity is a primary aim of reconstructive surgery in posttraumatic or postablative defects. Sensitivity plays a key role in oral function, whose impairment strongly affects the patient's quality of life. Cheek myomucosal flaps provide a reliable and tissue like reconstruction of these regions but their sensitive recovery, which we still know little about, deserves thorough assessment. METHODS: In this retrospective study, the myomucosal cheek flaps were tested for different aspects of sensory recovery: touch; 2-point discrimination; pain; sharp/smooth discrimination; ability to feel hot/cold stimulus; stereognosis; and taste. RESULTS: Fifty-two myomucosal flap reconstructions were investigated. All sensitivity tests showed positive results. When comparison was possible, sensitivity seemed significantly close to the contralateral healthy side. Sensory recovery proved to be even better than that reported on reinnervated microvascular free flap reconstructions of the oral cavity. CONCLUSION: Myomucosal flap reconstruction demonstrated a high degree of sensory recovery. PMID- 29130555 TI - Ethmoidal adenocarcinoma treated by exclusive endoscopic approach: Focus on learning curve and modification of management. AB - BACKGROUND: The purpose of this study was to investigate the outcome and recurrences for ethmoidal adenocarcinomas treated by exclusive endoscopic surgery in curative intent and investigate the role of the learning curve. METHODS: We conducted a single-center retrospective study, including 60 patients separated in 2 groups (2002-2011 n = 28 and 2012-2015 n = 32). RESULTS: The global survival rate at 5 years was 72.6%, and the global and local recurrence rates were 21.6% and 13.3%, respectively. The learning curve had significant impact on global survival at 2 years (93.8% vs 77.8%) and on overall and local recurrences, despite the higher rate of T4 classifications in the latter group. This learning curve could be explained by the evolution toward large endoscopic resection, bilateral, with resection of the cribriform plate, and eventually medial maxillectomy, and started on the healthy side. CONCLUSION: For selected cases, exclusive endoscopic resection of ethmoid adenocarcinoma achieves results at least as good as craniofacial resection when performed by an experienced cranial base team and including a large endoscopic resection. PMID- 29130556 TI - Effect of novel chelating agents on the push-out bond strength of calcium silicate cements to the simulated root-end cavities. AB - To compare the effects of different chelating agents on the push-out bond strength of calcium silicate-based cements to the simulated root-end cavities. Root-end cavities were prepared on the roots of fifty extracted maxillary anterior teeth. The specimens were then randomly divided into 5 groups (n = 10) based on the final irrigation regimen: Group 1: 17% EDTA, Group 2: 7% maleic acid, Group 3: QMix, Group 4: 2.25% peracetic acid (PAA), Group 5: 0.9% saline. Then, the samples from each group were subdivided into two groups (n = 5) based on the apical filling material. In group 1, root-end cavities of all samples were filled with Biodentine and in group 2, with MTA. Each sample was horizontally sectioned to produce two discs of ~1 mm thick per specimen. The maximum load required for the dislodgement of 100 retrofillings was recorded. The specimens were examined under scanning electron microscope after debonding to assess the type of bond failure. Data were statistically analyzed using Kruskal Wallis and Mann Whitney U tests. Irrigation with saline resulted in higher bond strength compared to the other irrigants in the retrograde cavities obturated with MTA or Biodentine (p < .05). In MTA group, there was no significant difference between the test irrigants (p > .05). EDTA and PAA groups showed higher dislodgement resistance values than the other test irrigants, when Biodentine was used as a filling. The type of irrigation solution influences the bond strength of the root end fillings. PMID- 29130557 TI - Out of sight, out of mind: perforated distal stump appendicitis. PMID- 29130558 TI - Right lobe donor hepatectomy: is it safe? A retrospective study. AB - Donor safety is utmost important in Living donor liver transplantation (LDLT). Small for size syndrome in some recipients with left lobe donors led to the evolution of right lobe LDLT. The aim of the study was to analyze the safety of large series of right lobe (RL) donor hepatectomies and compare outcomes with left lobe (LL) and left lateral segment (LLS) donations. A consecutive cohort of 726 donors from January 2011 to January 2014 were studied; RL (n = 641, 88.3%), LL (n = 36, 4.9%) or LLS (n = 49, 6.8%) depending on the type of donation. The mean age was 34.6 +/- 10 years. The overall complication rate was 22.3%. Most were Clavien grade I and II. Clavien grade IIIa, IIIb, IV and V were noted in 4.2% donors. The incidence of these major complications were comparable among RL (n = 28, 4.2%), LL (n = 1, 2.7%) and LLS (n = 2, 4.08%) (P = 0.89). Bile leak was seen in 20 donors (2.7%) and 13 were managed conservatively with prolonged or additional intra-abdominal drainage. Seven underwent re-exploration for bile leak. In centres experienced in right lobe LDLT, morbidity after RL donation is similar to that of LL donation; and with adequate GRWR, same 1-year recipient outcomes. PMID- 29130559 TI - Effect of general anesthesia and intubation on parathyroid levels in normal patients and those with hyperparathyroidism. AB - BACKGROUND: Induction of general anesthesia and endotracheal intubation may precipitate parathyroid hormone (PTH) elevation in patients with primary hyperparathyroidism (HPT). The purposes of this study were to revisit this observation and to study its impact in healthy patients. METHODS: Patients with primary HPT who underwent parathyroidectomy were retrospectively studied. The PTH was sampled and compared: before, immediately after general anesthesia and endotracheal intubation, and 15 minutes after parathyroidectomy. Healthy adults who underwent elective operations were prospectively studied. The PTH was sampled before general anesthesia and endotracheal intubation, immediately after, and 15 minutes later. RESULTS: Thirty-one patients, aged 28-89 years (mean 60.1 +/- 13 years), were retrospectively studied. The PTH was significantly elevated after general anesthesia and endotracheal intubation (P = .014). Fifty patients, aged 21-86 years (mean 54 +/- 15 years), were prospectively studied. The PTH elevation after general anesthesia and endotracheal intubation was not significant. CONCLUSION: General anesthesia and endotracheal intubation causes an immediate, steep, and significant PTH elevation in patients with primary HPT but only a minor change in healthy adults. The difference may be attributed to an impaired adrenergic response in patients with primary HPT. PMID- 29130560 TI - Patterns of vascularization and surgical morbidity in juvenile nasopharyngeal angiofibroma: A case series, systematic review, and meta-analysis. AB - BACKGROUND: Vascular patterns of juvenile nasopharyngeal angiofibroma (JNA) are poorly defined. We performed both institutional and systematic literature reviews to characterize the relationship between arterial supply patterns of JNA with intraoperative blood loss and tumor recurrence. METHODS: A retrospective review of 26 patients with JNA treated at our institution from 1995 to 2015 with available angiograms, and systematic reviews and meta-analyses of 828 JNA cases undergoing angiographic embolization published between 1995 and 2015 were completed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: The systematic review (828 cases) found internal carotid artery (ICA) supply in 35.6% of tumors, and 30.8% of tumors received bilateral vascular supply. Our institutional data (n = 26) indicated 69% had bilateral supply. Meta-analysis of data from 5 studies demonstrated ICA/bilateral arterial supply is predictive of increased operative blood loss (P < .01). CONCLUSION: Complex vascular contributions to JNA are frequent, underreported, and portends increased blood loss. This information can justifiably be included in staging systems to enhance prognostic counseling of patients. PMID- 29130561 TI - Mechanism of action of camphoryl-benzene sulfonamide derivative on glucose uptake in adipose tissue. AB - The aim of the present study was to investigate the mechanism of action of a sulfonamide derivative on glucose uptake in adipose tissue, as well as to characterize the effects of this compound on intestinal disaccharidases and advanced glycation end-products (AGEs) formation. Camphoryl-benzene sulfonamide (CS) was able to stimulate glucose uptake in isolated adipocytes, adipose tissue, and in soleus muscle. The stimulatory effect of the compound (10 MUM) on glucose uptake on adipose tissue was blocked by diazoxide, wortmannin, U73122, colchicine, and N-ethylmaleimide. On the other hand, the effects of CS were not blocked by glibenclamide, an inhibitor of the K+ -ATP channel, or even by the inhibitor of protein p38 MAPK, SB 203580. In vivo, this compound reduced intestinal disaccharidase activity, while, in vitro, CS reduced the formation of AGEs at 7, 14, and 28 days of incubation. The stimulatory effect of CS on glucose uptake requires the activation of the K+ -ATP channel, translocation, and fusion of GLUT4 vesicles to the plasma membrane on adipocytes for glucose homeostasis. In addition, the inhibition of disaccharidase activity contributes to the glucose homeostasis in a short-term as well as the remarkable reduction in AGE formation indicates that the CS may prevent of complications of late diabetes. PMID- 29130564 TI - Effect of non-thermal atmospheric plasma on the dentin-surface topography and composition and on the bond strength of a universal adhesive. AB - This study investigated the effect of application of non-thermal atmospheric plasma (NTAP) on the topography and composition of the dentin surface, as well as the microtensile bond strength (MUTBS) of a universal adhesive to NTAP-treated dentin. Exposed flat dentin surfaces from human third molars were either treated with NTAP for 10 and 30 s or untreated (control). The dentin-surface topography and chemical composition were characterized by atomic force microscopy (n = 3) and Raman confocal spectroscopy (n = 5), respectively. The MUTBS (n = 8) of Scotchbond Universal to dentin was determined after storage for 24 h and 1 yr, either by direct water exposure or under simulated pulpal pressure. In-situ zymography was used to evaluate the influence of NTAP on the dentin-enzymatic activity. Non-thermal atmospheric plasma produced no remarkable topographical or chemical alterations at the dentin surface; only the amount of phosphate decreased following 10 s of treatment with NTAP. After 1 yr of direct water exposure, the MUTBS of NTAP-treated specimens did not differ statistically significantly from that of untreated controls, whereas simulated pulpal pressure aging resulted in a significantly higher MUTBS for NTAP-treated dentin. The dentin-enzymatic activity appeared to be treatment-dependent, but the untreated controls showed more intense fluorescence within the hybrid layer. Scotchbond Universal maintained its MUTBS strength after 1 yr of direct water exposure and simulated pulpal pressure, although remarkable statistical differences between treatments were observed depending on the aging condition. PMID- 29130563 TI - Serum lipoprotein and RBC rigidity index to predict cerebral infarction in patients with carotid artery stenosis. AB - OBJECTIVE: This study aims to determine the risk factors and to predict the occurrence of cerebral infarction in patients with carotid artery stenosis. METHODS: Two hundred and one subjects with carotid artery stenosis were retrospectively selected from Jinshan Branch of Shanghai Sixth People's Hospital, 115 cases of which with cerebral infarction and 86 without it. Clinical tests were performed including coagulation indices, fasting glucose, serum lipid, and blood rheology. Logistic regression analyses were used to identify the risk factors. Regression model was established, and receiver operating characteristic (ROC) curve was applied to analyze its diagnostic value. RESULTS: Our data indicated that apolipoprotein AI (OR = 0.051, 95% CI: 0.009-0.295), lipoprotein (a) (OR = 1.003, 95% CI: 1.001-1.005), and RBC rigidity index (OR = 0.383, 95% CI: 0.209-0.702) were independent risk factors. Area under the curve (AUC) of the regression model = 0.78, with the sensitivity of 73.9% (95% CI: 64.9%-81.7%) and specificity of 69.2% (95% CI: 52.4%-83.0%). Prediction probability was determined while logistic regression score >0.748 defaulted as high-risk status. High-risk ratios were 80% in progressive cerebral infarction and 72% in nonprogressive cerebral infarction (P > .05), respectively, while significant differences were found when both compared with controls (P < .001). CONCLUSIONS: We show herein that the regression model based on apolipoprotein AI, lipoprotein (a), and RBC IR is a promising tool to predict the occurrence of cerebral infarction in patients with carotid artery stenosis. However, identification of novel diagnostic markers for progressive cerebral infarction is still necessary. PMID- 29130562 TI - The prognostic significance of pneumothorax in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Pneumothorax is a co-morbidity in patients with idiopathic pulmonary fibrosis (IPF). However, its incidence, risk factors and prognostic significance in IPF remain unclear. The aim of this study was to clarify the incidence and prognostic significance of pneumothorax in patients with IPF, and to further investigate the risk factors for its onset. METHODS: Eighty-four consecutive patients with IPF based on the consensus guideline were included in this study. We retrospectively reviewed the medical records, pulmonary function tests and chest high-resolution computed tomography images, and determined the incidence of pneumothorax. The prognostic significance of pneumothorax was evaluated using the Cox proportional hazards model analysis with time-dependent covariates. We also assessed the cumulative incidence and the risk factors for pneumothorax. RESULTS: Of the 84 patients, 17 (20.2%) developed pneumothorax. The cumulative incidence of pneumothorax was 8.5%, 12.5% and 17.7% at 1, 2 and 3 years, respectively. Univariate analysis demonstrated that pneumothorax was significantly related to poor prognosis (hazards ratio, 2.99; P = 0.002). Multivariate analysis, adjusting for sex, age and forced vital capacity (% predicted), revealed that pneumothorax was an independent predictor of poor outcome in IPF (hazards ratio, 2.85; P = 0.006). Lower BMI and the presence of extensive reticular abnormalities were significantly associated with developing pneumothorax. CONCLUSION: These results confirm that patients with IPF often develop pneumothorax during their clinical course and that the onset of pneumothorax predicts a poor outcome. PMID- 29130565 TI - Dose-finding and efficacy confirmation trial of the superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for locally advanced maxillary sinus cancer (Japan Clinical Oncology Group 1212): Dose-finding phase. AB - BACKGROUND: We are currently undertaking a multi-institutional prospective trial of the superselective intra-arterial infusion of high-dose cisplatin with concomitant radiotherapy for patients with T4aN0M0 or T4bN0M0 locally advanced maxillary sinus squamous cell carcinomas (SCC). We herein report the results of the dose-finding phase. METHODS: The dose-finding phase sought to evaluate the incidence of dose-limiting toxicities and determine the recommended number of cycles of the intra-arterial infusion of cisplatin. In this phase, 100 mg/m2 of cisplatin was administered intra-arterially weekly for 7 weeks with concomitant radiotherapy (70 Gy). RESULTS: All 18 patients received a full dose of radiotherapy. The number of cycles of cisplatin was 7 in 13 patients and 6 in 5 patients. The dose-limiting toxicities were observed in 5 patients. CONCLUSION: These results indicated that this therapy is safe and well-tolerated at 7 cycles of cisplatin, which was determined to be the recommended number of cycles for locally advanced maxillary sinus SCC. PMID- 29130566 TI - Cisplatin-conjugated gold nanoparticles as a theranostic agent for head and neck cancer. AB - BACKGROUND: The purpose of this study was to develop a nanoplatform, which simultaneously acts as radiosensitizer, drug carrier, and tumor imaging agent for head and neck cancer. METHODS: We synthesized 20 nm gold nanoparticles, coated with glucose and cisplatin (CG-GNPs). Their penetration into tumor cells and their cellular toxicity were evaluated in vitro. In vivo experiments were conducted to evaluate their impact on tumor growth and their imaging capabilities. RESULTS: The CG-GNPs showed efficient penetration into tumor cells and similar cellular toxicity as cisplatin alone. Combined with radiation, CG GNPs led to greater tumor reduction than that of radiation alone and radiation with free cisplatin. The CG-GNPs also demonstrated efficient tumor imaging capabilities. CONCLUSION: Our CG-GNPs have a great potential to increase antitumor effect, overcome resistance to chemotherapeutics and radiation, and allow imaging-guided therapy. PMID- 29130567 TI - Treatment strategies in coronary microvascular dysfunction: a systematic review of interventional studies. AB - Coronary microvascular dysfunction has been associated with a wide spectrum of diseases and conditions, and it has proven to be a strong prognostic marker of morbidity and mortality. Despite increased attention guideline-based treatment recommendations are lacking. We performed a systematic review of pharmacological and non-pharmacological interventions to improve coronary perfusion, assessed by intracoronary Doppler, transthoracic Doppler echocardiography, positron emission tomography, cardiac magnetic resonance imaging, transthoracic contrast perfusion echocardiography and dilution techniques. No restrictions were made regarding the study design (randomized, placebo-controlled/ randomized with active comparators/ non-randomized with or without a control group), the cardiac condition studied or the coronary microvascular function at baseline. An electronic database search yielded 4,485 records of which 80 studies met our inclusion criteria. Included studies were sorted according to intervention and study design. Studies were small and heterogeneous in methodology and only few were placebo controlled. Although some treatments looked promising, we found that no specific treatment was sufficiently well-documented to be recommended in any patient groups. There is a need for larger well-designed clinical trials and we suggest that future studies stratify study populations according to pathogenic mechanisms, thereby investigating whether an individualized treatment approach would be more successful. This article is protected by copyright. All rights reserved. PMID- 29130568 TI - Flexible next-generation robotic surgical system for transoral endoscopic hypopharyngectomy: A comparative preclinical study. AB - BACKGROUND: The purpose of this cadaveric study was to determine the efficacy of a flexible, next-generation robotic surgical system for transoral robotic hypopharyngectomy. METHODS: A comparative evaluation study of the flexible versus rigid robotic surgical systems for the hypopharynx was conducted using 3 cadavers. Endpoints for assessment were visualization of the hypopharynx, access to the hypopharynx, and difficulty of dissection. Hypopharyngectomy was performed on 3 other cadavers using the da Vinci Sp surgical system. RESULTS: Access to the apex of the pyriform sinus and the esophageal inlet was easier with the da Vinci Sp than with the da Vinci Si. Dissection with the da Vinci Sp was easier in all areas of the hypopharynx than with the da Vinci Si. Robotic hypopharyngectomy was successfully completed on all cadavers using the da Vinci Sp surgical system. CONCLUSION: Preclinical testing in human cadavers suggests that flexible robotic surgery may facilitate successful transoral hypopharyngectomy. PMID- 29130569 TI - A re-adjustable sling for female recurrent stress incontinence and intrinsic sphincteric deficiency: Long-term results in 205 patients using the Remeex sling system. AB - AIMS: To evaluate the outcomes and complications at long-term follow-up after a Remeex re-adjustable sling for recurrent stress urinary incontinence (rSUI) and intrinsic sphincteric deficiency (ISD) in women. METHODS: Two hundred thirty women with SUI were evaluated after undergoing a re-adjustable sling operation. Twenty-five patients were lost to follow-up, 205 were classified by Q-tip, urodynamic, and clinical criteria into ISD (109) and rSUI (96). Outcome measures included number of pads, 1 h pad-test, urodynamics and subjective satisfaction index with the procedure. RESULTS: After a mean follow-up of 89 months (26-159), 165 patients were cured of SUI (71.7% in the intention to treat analysis (itt), 80.5% in per protocol analysis (pp)). Forty patients remained incontinent (17.4% in itt, 19.5 in pp). Thirty-one patients (15.1%) had detrusor overactivity (DH) incontinence, 21 (10.2%) with de-novo DH and 10 with previous urodynamic mixed incontinence. Eighty-eight patients required re-adjustment of the sling during the follow-up. The tension was increased in 82 cases due to recurrence of SUI and reduced in six due to outlet obstruction. The overall complications rate was 28.8%, (3.4% clavien III). CONCLUSIONS: The Remeex re-adjustable sling provides a good cure rate for rSUI and ISD at long-term follow-up. The complications rate is acceptable since most complications are clavien II. The ability to re-adjust the sling tension during the follow-up allowed us to achieve cure for recurrence after the initial procedure, and to relieve obstruction in every case attempted. PMID- 29130570 TI - Cold-water or partial-body cryotherapy? Comparison of physiological responses and recovery following muscle damage. AB - The aim of this study is to compare (a) the physiological responses following cold-water immersion (CWI) and partial-body cryotherapy (PBC) and (b) the effects on recovery following a muscle-damaging protocol (5 * 20 drop jumps). Nineteen healthy males were randomly allocated into either a CWI (10 degrees C for 10 minutes; n = 9) or a PBC (-60 degrees C for 30 seconds, -135 degrees C for 2 minutes; n = 10) group. The physiological variables (thigh muscle oxygen saturation [SmO2 ], cutaneous vascular conductance [CVC], mean arterial pressure [MAP], and local skin temperature) were assessed immediately prior and up to 60 minutes post-treatment (10-minutes intervals). The recovery variables (thigh muscle swelling, maximum voluntary contraction [MVC] of the right knee extensors, vertical jump performance [VJP], and delayed onset of muscle soreness [DOMS]) were measured immediately prior and up to 72 hours post-treatment (24-hours intervals). Compared to PBC values, CVC (at 30 minutes), SmO2 (at 40 minutes), and lower extremity skin temperature (thigh/shin at 60 minutes) were significantly reduced in the CWI group after the treatment (all P < .05). Only lower extremity skin temperature was significantly reduced in the PBC group directly post-treatment (all P < .05). MAP significantly increased in both groups after the treatments (both P < .05). DOMS did not differ between groups. MVC and VJP returned to baseline in both groups after 24 hours (P > .05). CWI had a greater impact on the physiological response compared to PBC. However, both treatments resulted in similar recovery profiles during a 72-hours follow-up period. PMID- 29130571 TI - How to do breast reconstruction using free flaps with short pedicles: a stepwise technique for easier, safer anastomoses. PMID- 29130572 TI - Ischemic Optic Neuropathy in a Dog with Acute Bilateral Blindness and Primary Systemic Hypertension. AB - A 6-year-old neutered female Jack Russell terrier was investigated for sudden onset prechiasmatic bilateral blindness, left circling, reduced proprioception in the right pelvic limb and right facial allodynia. Electroretinography was normal. Magnetic resonance imaging (MRI) examination revealed that the right optic nerve and the optic chiasm were hyperintense on diffusion weighted imaging and hypointense on apparent diffusion coefficient map consistent with ischemic optic neuropathy. A concurrent lacunar infarct was detected in the left rostral colliculus. Primary systemic hypertension was diagnosed based on blood pressure measurement and no detectable abnormalities on hematology, comprehensive serum biochemistry, urinalysis including protein/creatinine and cortisol/creatinine ratios and thoracic/abdominal imaging. Prednisolone for 10 days and amlodipine long-term were administered. Vision was not recovered after 7 months. Repeat MRI supported the diagnosis of ischemic lesions and revealed a recent striatocapsular infarct. Ischemic optic neuropathy is a well-recognized cause of blindness in humans and should be included as a differential diagnosis for acute prechiasmatic blindness in dogs. PMID- 29130573 TI - Planned angiographic control versus clinical follow-up for patients with unprotected left main stem stenosis treated with second generation drug-eluting stents: A propensity score with matching analysis from the FAILS (failure in left main with second generation stents-Cardiogroup III Study). AB - BACKGROUND: The value of angiographic follow-up in unprotected left main (ULM) stenting remains undefined. METHODS: The FAILS-2 registry included consecutive patients presenting with a critical lesion of an ULM treated with second generation drug eluting stents in 6 centers from June 2007 to January 2015. Patients were stratified into two groups: those discharged with planned angiographic follow-up and those with clinical follow-up. MACE (Major Adverse Clinical Events, a composite end point of death, myocardial infarction, TLR, and ST) was the primary end point, while each component was a secondary endpoint Sensitivity analysis was performed for patients treated with a provisional or a two-stent strategy. A propensity score analysis was used to compare the outcomes in the two groups. RESULTS: After multivariate adjustment, 220 patients per group were selected. Planned angiographic follow up was performed after a median of 7 (6-10) months. After 16 (14-21) months, rates of MACE were similar between the two groups (24 vs. 21%, P = 0.29) with lower rates of all cause and cardiovascular death in the angiographic control group (6 vs. 14%, P = 0.01 and 3 vs. 6%, P = 0.04) but with higher rates of TLR (15 vs. 5%, P < 0.001). The same trend was seen irrespective of the stent strategy. CONCLUSION: planned angiographic control results in more TLR but may reduce mortality. These findings need to be confirmed by adequately powered randomized controlled trial. PMID- 29130574 TI - Drug interactions between rifamycin antibiotics and hormonal contraception: a systematic review. AB - BACKGROUND: Rifamycin antibiotics are commonly used for treatment of tuberculosis, but may reduce the effectiveness of hormonal contraception (HC). OBJECTIVES: To determine whether interactions between rifamycins and HC result in decreased effectiveness or increased toxicity of either therapy. SEARCH STRATEGY: We searched MEDLINE, Embase, Cochrane and clinicaltrials.gov through May 2017. SELECTION CRITERIA: We included trials, cohort, and case-control studies addressing pregnancy rates, pharmacodynamics or pharmacokinetic (PK) outcomes when HC and rifamycins were administered together versus apart. Of 7291 original records identified, 11 met inclusion criteria after independent review by two authors. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted study details and assessed study quality using the United States Preventive Services Task Force grading system. Findings are reported descriptively. MAIN RESULTS: Studies only addressed combined oral contraceptives (COCs) and none reported pregnancy rates. Quality ranged from good to poor. Rifampin increased the frequency of ovulation in two of four studies, and reduced estrogen and/or progestin exposure in five studies. Rifabutin led to smaller PK changes than rifampin in two studies. In one study each, rifaximin and rifalazil did not alter hormone PK. CONCLUSIONS: No studies evaluated pregnancy risk or non-oral HCs. PK and ovulation outcomes support a clinically concerning drug interaction between COCs and rifampin, and to a lesser extent rifabutin. Data are limited for other rifamycins. TWEETABLE ABSTRACT: Rifampin and rifabutin reduce systemic exposure of oral contraceptives, but no studies have evaluated pregnancy risk. PMID- 29130576 TI - Quinke's triad: haemobilia secondary to hepatic artery aneurysm. PMID- 29130575 TI - A prospective investigation to evaluate risk factors for lower extremity injury risk in male youth soccer players. AB - There is an inherent risk of injury in male youth football; however, pertinent risk factors for injury have yet to be examined. This study used a prospective cohort design with 357 elite male youth football players (aged 10-18 years) assessed during the preseason period and then monitored during the season recording all non-contact lower extremity injuries. Screening tests included single leg hop for distance (SLHD); 75% of maximum hop and stick (75%Hop); single leg countermovement jump (SLCMJ); and the tuck jump assessment (TJ). Players were divided into subgroups based on chronological age. SLCMJ peak landing vertical ground reaction force (pVGRF) asymmetry was the most prominent risk factor (U11 U12s, OR 0.90, P = .04; and U15-U16s, OR 0.91, P < .001). Maturational offset (OR 0.58, P = .04), lower right leg SLCMJ pVGRF relative to body weight (OR 0.36, P = .03), and advanced chronological age (OR 3.62, P = .04) were also significantly associated with heightened injury risk in the U13-U14s, U15-U16s, and U18s, respectively. Univariate analyses showed combinations of anthropometric and movement screening risk factors were associated with heightened risk of lower extremity injury; however, there was variability across the different chronological age groups. Greater SLCMJ pVGRF asymmetry, lower right leg SLCMJ pVGRF %BW, later maturation, and advanced chronological age are potential risk factors for injury in elite male youth football players, although the strength of these relationships was often low to moderate. In addition, risk factors are likely to change at different stages of development. PMID- 29130577 TI - Factors affecting the patency of arteriovenous fistulas for hemodialysis: Single center experience. AB - INTRODUCTION: Arteriovenous fistulas (AVFs) are the preferred form vascular access for hemodialysis (HD), as they have a low rate of complications and durable function. The aim of our investigation was to analyze the factors that might influence the function of AVFs. METHODS: Data were taken from the computerized patient record system in the Clinic of Urology and Nephrology, Clinical Center, Kragujevac, Serbia, for a 2-year period. We analyzed patients who had requested re-creation of AVFs as a secondary procedure. During this period 112 patients, 73 (65%) men and 39 (35%) women, had AVF thromboses. All relevant clinical and laboratory parameters that could affect the function and survival of AVF were evaluated. FINDINGS: In univariate logistic regression analysis, statistically significant predictors influencing the duration of the fistula were magnesium (P < 0.001), triglycerides (P = 0.041), smoking (P = 0.001), antiplatelet therapy (P < 0.001), and type of HD (bicarbonate vs. hemodiafiltration) (P < 0.001). In the multiple logistic regression model, high concentrations of magnesium (B = 7434; P < 0.001) and antiplatelet therapy (B - 1.042; P = 0.04) were significantly associated with the length of AVF function. DISCUSSION: After successful establishment of an AVF, there is a compelling need to maintain fistula patency. Factors that affect functioning of the AVFs are presently under intense scrutiny. According to our results, some clinical factors may determine long term fistula duration, such as concentration of the magnesium and antiplatelet therapy. PMID- 29130578 TI - SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease. AB - Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD-dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac-p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53-induced mitochondrial dysfunction and neuronal damage in a deacetylase activity-dependent manner. Notably, mitochondrially targeted p53 (mito-p53) directly reduced mitochondria DNA-encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53 ChIP analysis verified the presence of p53-binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito-p53 activity. Our results indicate that SIRT3 dysfunction leads to p53-mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD. PMID- 29130580 TI - Stent use for hemodialysis access: What a general nephrologist needs to know. AB - Recurrent stenosis due to neo-intimal hyperplasia leads to loss of patency in an established hemodialysis access. The current treatment strategy to maintain patency involves percutaneous transluminal angioplasty with or without stent placement. There are several key points that an interventionalist needs to weigh before deciding to place a stent. These include appropriateness of stent placement, the long term consequences, the type of stent to be deployed, the size of stent and finally the impact on cannulation during dialysis. A general nephrologist needs to be aware of the various benefits and pitfalls of stent placement. The current review provides basic information that will educate the dialysis provider about stents and its use in treating dysfunctional hemodialysis access using commonly encountered clinical scenarios. PMID- 29130581 TI - Oxygen, animals and aquatic bioturbation: An updated account. PMID- 29130579 TI - A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness. AB - The primary cilium is a key organelle in numerous physiological and developmental processes. Genetic defects in the formation of this non-motile structure, in its maintenance and function, underlie a wide array of ciliopathies in human, including craniofacial, brain and heart malformations, and retinal and hearing defects. We used exome sequencing to study the molecular basis of disease in an 11-year-old female patient who suffered from growth retardation, global developmental delay with absent speech acquisition, agenesis of corpus callosum and paucity of white matter, sensorineural deafness, retinitis pigmentosa, vertebral anomalies, patent ductus arteriosus, and facial dysmorphism reminiscent of STAR syndrome, a suspected ciliopathy. A homozygous variant, c.870_871del, was identified in the CDK10 gene, predicted to cause a frameshift, p.Trp291Alafs*18, in the cyclin-dependent kinase 10 protein. CDK10 mRNAs were detected in patient cells and do not seem to undergo non-sense mediated decay. CDK10 is the binding partner of Cyclin M (CycM) and CDK10/CycM protein kinase regulates ciliogenesis and primary cilium elongation. Notably, CycM gene is mutated in patients with STAR syndrome. Following incubation, the patient cells appeared less elongated and more densely populated than the control cells suggesting that the CDK10 mutation affects the cytoskeleton. Upon starvation and staining with acetylated tubulin, gamma-tubulin, and Arl13b, the patient cells exhibited fewer and shorter cilia than control cells. These findings underscore the importance of CDK10 for the regulation of ciliogenesis. CDK10 defect is likely associated with a new form of ciliopathy phenotype; additional patients may further validate this association. PMID- 29130582 TI - Periprocedural transfusion in patients undergoing transfemoral transcatheter aortic valve implantation. AB - OBJECTIVES: The aim of this investigation was to identify patient's characteristics and periprocedural variables related to periprocedural transfusion in transfemoral Transcatheter Aortic Valve Implantation (tf-TAVI). BACKGROUND: Transfusion of allogenic red-blood cells (RBC) in tf-TAVI and the number of transfused units has been linked to an increased 30-day mortality. In line with the trend of minimization and cost-effectiveness, transfusion should be avoided, wherever possible. METHODS: Between 2007 and 2015, 1,734 procedures were analyzed from our prospective registry for RBC-transfusion. Multiple logistic regression analysis was used to identify the dependent variables. RESULTS: Transfusion was considered necessary in 14% (n = 243) of the patients. Female gender (OR [95% CI]) (1.680 [1.014-2.783]) and preprocedural moderate (7.594 [4.404-13.095]) and severe anemia (8.202 [0.900-74.752]) according to WHO were the most important preprocedural variables. Periprocedural, pericardial effusion (12.109 [3.753-39.063]), emergency extracorporeal circulation (54.5288 [6.178 481.259]) and major vascular injury (2.647 [1.412-4.962]) were related to transfusion. The same applies to moderate (4.255 [1.859-9.740]) and severe anemia (31.567 [8.560-116.416]) as well as periprocedural experience (0.072 [0.035 0.149] - 0.141[0.079-0.251], P < 0.001) CONCLUSION: Procedural experience, serious adverse events, low pre- and periprocedural Hb levels and female gender were the main variables relating to transfusion. Even in experienced high-volume centers, transfusion is still necessary in a considerable number of patients. PMID- 29130583 TI - Endoscopic retrograde cholangio-pancreatography in the management of biliary complications after paediatric liver transplantation - a retrospective study. AB - The published paediatric experience with endoscopic retrograde cholangio pancreatography (ERCP) in the diagnosis and management of biliary complications following liver transplantation (LT) is limited. We describe our experience with ERCP in the management of children following LT who presented with biliary complications, over a 20-year period (1995-2014). The retrospectively reviewed data are summarized descriptively. Of 94 children (47 boys) who received 102 liver transplants at our centre, seven children (five boys, two girls) underwent ERCP after liver transplantation. In total, 25 ERCP procedures were carried out in these patients. The median age at liver transplantation was 10.7 (3.9-16.2) years. The median interval between LT and the first ERCP was 28 days (12 days-6.8 years). All patients were on standard calcineurin-inhibitor-based immunosuppression regimens. Six of the seven patients underwent ERCP on more than one occasion [median number of ERCP sessions per patient- 4, (1-6)]. Seventeen procedures were carried out under conscious sedation, remaining eight under general anaesthesia. Sedation was achieved employing a standard regimen (Midazolam 5 mg with Pethidine 50 mg) and occasionally Fentanyl. ERCP is an effective and safe intervention from both diagnostic and therapeutic point of view, in the management of post-LT biliary complications in children. PMID- 29130584 TI - Long-term outcomes after reirradiation in nasopharyngeal carcinoma with intensity modulated radiotherapy: A meta-analysis. AB - BACKGROUND: The purpose of this clinical review was to summate the published data for the long-term outcomes of reirradiation with intensity-modulated radiotherapy (IMRT) for locally recurrent nasopharyngeal carcinoma (NPC). METHODS: We searched biomedical literature databases for eligible studies published from January 2005 to September 2016. Outcomes of interests were 5-year local failure-free survival, distant failure-free survival, overall survival (OS), and toxicities. Meta analysis was performed using a random effects model. RESULTS: We found 4 comparative and 8 noncomparative studies (n = 1768). Reirradiation was associated with pooled event rates of 72% (95% confidence interval [CI] 66%-78%; I2 = 84%), 85% (95% CI 82%-88%; I2 = 69%), and 41% (95% CI 36%-47%; I2 = 80%) for 5-year local failure-free survival, distant failure-free survival, and OS, respectively, with significant heterogeneity among the study results. The pooled event rate for grade 5 toxicities was 33% (95% CI 30%-35%; I2 = 0%) with minimal heterogeneity. CONCLUSION: Reirradiation with IMRT for locally recurrent NPC could confer long term disease control and survival but is associated with significant mortality. PMID- 29130585 TI - Exploring patient-reported outcomes following percutaneous coronary intervention: A qualitative study. AB - BACKGROUND: Percutaneous coronary intervention (PCI) is a common cardiac procedure used to treat obstructive coronary artery disease. Patient-centred care is a priority in cardiovascular health having been shown to increase patient satisfaction, engagement with rehabilitation activities and reduce anxiety. Evidence indicates that patient-centred care is best achieved by routine collection of patient-reported outcomes (PROs). However, existing patient reported outcome measures (PROMs) have limited the patient involvement in their development. AIMS: To identify and explore outcomes, patients perceive as important following PCI. METHODS: A qualitative design was adopted. Eight focus groups and five semi-structured interviews were conducted with 32 patients who had undergone PCI in the previous 6 months. Outcomes were identified and mapped under the U.S. Food and Drug Administration (FDA) patient-reported outcome (PROs) domains of feeling (physical and psychological outcomes), function and evaluation. Inductive and deductive analysis methods were used with open, axial and thematic coding. RESULTS: Consistent with prior studies, patients identified feeling and function outcomes such as reductions in physical and psychological symptoms and the ability to perform usual activities as important. Participants also identified a range of new outcomes, including confidence to return to usual activities and evaluation domains such as adverse effects of medications and the importance of patient communication. CONCLUSION: The findings of this research should be considered in the design of a cardiac PROM for PCI patients. A PROM which adequately assesses these outcomes can provide clinicians and hospital staff with a foundation in which to address these concerns or symptoms. PMID- 29130587 TI - Pushing boundaries: Implantation of the 34 mm Medtronic CoreValve in patients with a large aortic annulus. AB - The relationship between adherence to the recommended CoreValve sizing parameters and clinical outcomes is not well known for the recently released 34 mm valve, which is currently the largest available transcatheter valve. There is a presumed temporal reduction in paravalvular regurgitation in patients who receive an in range valve, however, certain patients possess annular dimensions that are too large. We therefore describe two patients with annular dimensions larger than the manufacturer recommended range for the 34 mm CoreValve, who despite this underwent transcatheter aortic valve replacement with excellent clinical outcomes. PMID- 29130586 TI - Prognostic implication of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with recurrent papillary thyroid cancer. AB - BACKGROUND: Fluorine-18 fluorodeoxyglucose positron emission tomography/CT (18 F FDG PET/CT) has been widely accepted as an effective method for detecting recurrent papillary thyroid cancer (PTC) in patients with increased serum thyroglobulin (Tg) or Tg antibody (TgAb) levels and negative whole-body scintigraphy (WBS) results. The role of WBS as a diagnostic tool in detecting recurrence has relatively decreased recently. However, only a few studies have examined the usefulness of 18 F-FDG PET/CT for evaluating patients with recurrent PTC, regardless of the WBS results. The purpose of this analysis was to evaluate the diagnostic value and prognostic role of 18 F-FDG PET/CT for patients with recurrent PTC, irrespective of their WBS results. METHODS: Sixty-six patients with locoregional recurrent PTC who underwent 18 F-FDG PET/CT and neck CT within 6 months before surgical treatment were included in this retrospective analysis. Imaging findings were compared with postoperative histopathologic results. The diagnostic values of 18 F-FDG PET/CT and neck CT were compared according to the serum Tg and TgAb levels and cervical levels. Each patient's status at the last follow-up was also reviewed, and survival probabilities were estimated using the Kaplan-Meier plot. RESULTS: The sensitivity, specificity, and diagnostic accuracy of 18 F-FDG PET/CT for the entire patient group were 38.5%, 90.2%, and 58.3%, respectively. The corresponding neck CT values were 55.0%, 85.7%, and 66.7%, respectively. According to the serum Tg and TgAb levels, except for the specificity, most diagnostic values of 18 F-FDG PET/CT were worse than those of the neck CTs, with or without statistical significance. For the high maximum standardized uptake value (SUVmax) group (SUVmax >10) and the low SUVmax group, the median locoregional disease-free survival times were 33.3 months and 81.8 months, respectively (P < .001). CONCLUSION: The diagnostic value of 18 F-FDG PET/CT for localizing recurrent lesions was worse than that of the neck CT, irrespective of the WBS results. However, patients with a higher SUVmax showed a significantly worse prognosis than did those with a lower SUVmax. Therefore, we suggest that, in patients with recurrent PTC, 18 F-FDG PET/CT should be considered for prognostication rather than diagnosis. PMID- 29130588 TI - Effects of Astragalus Extract Mixture HT042 on Height Growth in Children with Mild Short Stature: A Multicenter Randomized Controlled Trial. AB - HT042 is a standardized functional food ingredient approved by Korean Food and Drug Administration with a claim 'HT042 can help height growth of children'. We aimed to evaluate the safety and efficacy of HT042 on height growth in children with mild short stature. A multicenter, randomized, double-blind, placebo controlled parallel study was performed on children aged 6-8 years with height ranked below the 25th percentile. In 129 children, height gain was significantly higher in HT042 group than placebo group after 24 weeks (mean difference, 0.29 cm; 95% CI, 0.01 to 0.57 cm; p = 0.027). The difference was elevated when the efficacy analysis was restricted to children below the 10th percentile (mean difference, 0.45 cm; 95% CI, 0.04 to 0.87 cm; p = 0.031). Because bone age advancement was lower in HT042 group, height standard deviation score gain for bone age was higher in HT042 group and the difference was significant in children below the 10th percentile (mean difference, 0.20 score; 95% CI, 0.00 to 0.39 points; p = 0.045). Serum IGF-1 and IGFBP-3 levels were significantly increased compared with baseline within HT042 group, but group difference was not significant. HT042 supplementation helped to increase height growth in children without skeletal maturation and was more effective in much shorter children. The effects might be mediated by increases in serum IGF-1 and IGFBP-3 levels. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29130589 TI - Australia's Health Star Rating policy process: Lessons for global policy-making in front-of-pack nutrition labelling. AB - AIM: This study explored factors that shaped the development of Australia's Health Star Rating system for front-of-pack labelling (FoPL) on packaged foods and whether insights could be drawn from this experience to inform the development of global FoPL standards. METHODS: Ten individual semi-structured interviews were conducted with public health or consumer advocates, academics in the field of nutrition labelling and policy, a food industry employee, and Australian public servants. Thematic analysis was undertaken, guided by Kingdon's Multiple Streams Framework, to identify factors which shaped Australian and international FoPL policy processes. RESULTS: Senior Australian bureaucrats played the policy entrepreneur role to facilitate the development of the Health Star Rating system. The public health and consumer advocacy groups formed an alliance to counter-balance the influence of the food industry in the Health Star Rating development process. Public health and consumer groups have less influence at Codex Alimentarius, where policy-making is constrained by political alliances and consensus voting structures. CONCLUSIONS: Strong leadership, policy entrepreneurship and a coherent alliance between public health and consumer groups enabled the development of a FoPL system in Australia and could contribute to advancing FoPL standards at the international level. PMID- 29130590 TI - Quantification of GABA, glutamate and glutamine in a single measurement at 3 T using GABA-edited MEGA-PRESS. AB - gamma-Aminobutyric acid (GABA) and glutamate (Glu), major neurotransmitters in the brain, are recycled through glutamine (Gln). All three metabolites can be measured by magnetic resonance spectroscopy in vivo, although GABA measurement at 3 T requires an extra editing acquisition, such as Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS). In a GABA-edited MEGA-PRESS spectrum, Glu and Gln co edit with GABA, providing the possibility to measure all three in one acquisition. In this study, we investigated the reliability of the composite Glu + Gln (Glx) peak estimation and the possibility of Glu and Gln separation in GABA edited MEGA-PRESS spectra. The data acquired in vivo were used to develop a quality assessment framework which identified MEGA-PRESS spectra in which Glu and Gln could be estimated reliably. Phantoms containing Glu, Gln, GABA and N acetylaspartate (NAA) at different concentrations were scanned using GABA-edited MEGA-PRESS at 3 T. Fifty-six sets of spectra in five brain regions were acquired from 36 healthy volunteers. Based on the Glu/Gln ratio, data were classified as either within or outside the physiological range. A peak-by-peak quality assessment was performed on all data to investigate whether quality metrics can discriminate between these two classes of spectra. The quality metrics were as follows: the GABA signal-to-noise ratio, the NAA linewidth and the Glx Cramer-Rao lower bound (CRLB). The Glu and Gln concentrations were estimated with precision across all phantoms with a linear relationship between the measured and true concentrations: R1 = 0.95 for Glu and R1 = 0.91 for Gln. A quality assessment framework was set based on the criteria necessary for a good GABA-edited MEGA PRESS spectrum. Simultaneous criteria of NAA linewidth <8 Hz and Glx CRLB <16% were defined as optimum features for reliable Glu and Gln quantification. Glu and Gln can be reliably quantified from GABA-edited MEGA-PRESS acquisitions. However, this reliability should be controlled using the quality assessment methods suggested in this work. PMID- 29130591 TI - Familial choreoathetosis due to novel heterozygous mutation in PDE10A. AB - PDE10A encodes a dual cAMP-cGMP phosphodiesterase that is enriched in the medium spiny neurons of the corpus striatum in the brain and plays an important role in basal ganglia circuitry. Three unrelated patients with childhood onset chorea and striatal abnormalities on MRI brain with heterozygous de novo variants in PDE10A have been described previously. Two families with eight affected individuals with biallelic mutations in PDE10A have also been described previously. We report a family with multiple affected individuals with childhood onset chorea, striatal abnormalities, and a novel heterozygous mutation, c.1001T>G(p.F334C) in PDE10A which was identified by exome sequencing. PMID- 29130592 TI - Accounting for measurement error in human life history trade-offs using structural equation modeling. AB - OBJECTIVES: Revealing causal effects from correlative data is very challenging and a contemporary problem in human life history research owing to the lack of experimental approach. Problems with causal inference arising from measurement error in independent variables, whether related either to inaccurate measurement technique or validity of measurements, seem not well-known in this field. The aim of this study is to show how structural equation modeling (SEM) with latent variables can be applied to account for measurement error in independent variables when the researcher has recorded several indicators of a hypothesized latent construct. METHODS: As a simple example of this approach, measurement error in lifetime allocation of resources to reproduction in Finnish preindustrial women is modelled in the context of the survival cost of reproduction. In humans, lifetime energetic resources allocated in reproduction are almost impossible to quantify with precision and, thus, typically used measures of lifetime reproductive effort (e.g., lifetime reproductive success and parity) are likely to be plagued by measurement error. These results are contrasted with those obtained from a traditional regression approach where the single best proxy of lifetime reproductive effort available in the data is used for inference. RESULTS: As expected, the inability to account for measurement error in women's lifetime reproductive effort resulted in the underestimation of its underlying effect size on post-reproductive survival. CONCLUSIONS: This article emphasizes the advantages that the SEM framework can provide in handling measurement error via multiple-indicator latent variables in human life history studies. PMID- 29130593 TI - Chylomicronemia risk factors ranked by importance for the individual and community in 108 711 women and men. AB - BACKGROUND: Hypertriglyceridemia prevalence is increasing as more individuals become obese, and chylomicronemia risk factors for the individual and community have not been described previously. OBJECTIVE: To describe chylomicronemia risk factors in the general population for individuals and community. METHODS: A total of 108 711 individuals from the Copenhagen General Population Study were grouped as unlikely chylomicronemia (nonfasting triglycerides <2 mmol L-1 (177 mg dL-1 )), possible chylomicronemia (2-4.99 mmol L-1 (177-442 mg dL-1 )), probable chylomicronemia (5-9.99 mmol L-1 (443-885 mg dL-1 )) and definite chylomicronemia (>=10 mmol L-1 (>= 886 mg dL-1 )). Relative risk (RR) from Poisson regression ranked dichotomized chylomicronemia risk factors for individuals, and population attributable fractions (PAF) for the community: type 2 diabetes, alcohol intake, obesity, fat intake, hypothyroidism, kidney function, education, sedentary lifestyle, menopause and hormone replacement (women). RESULTS: For women and men, chylomicronemia was unlikely in 81% and 64%, possible in 18% and 33%, probable in 1% and 3% and definite in 0.03% and 0.14%, respectively. For the individual, the three top-ranked risk factors for probable/definite versus unlikely chylomicronemia in women were type 2 diabetes (RR: 4.21; 95% confidence interval: 3.30-5.36), menopause (RR: 3.74; 2.62-5.36) and obesity (RR: 3.44; 2.81-4.21). Corresponding top-ranked risk factors in men were obesity (RR: 3.86; 3.46-4.30), type 2 diabetes (RR: 1.88; 1.61-2.19) and reduced kidney function (RR: 1.86; 1.48 2.34). For the community, top-ranked risk factors in women were menopause (PAF: 63%), obesity (PAF: 29%) and type 2 diabetes (PAF: 15%). Corresponding top-ranked risk factors in men were obesity (PAF: 29%), type 2 diabetes (PAF: 6.4%) and sedentary lifestyle (PAF: 6.0%). CONCLUSIONS: Obesity and type 2 diabetes were the most important modifiable chylomicronemia risk factors in women and men, both for the individual and community. This could influence chylomicronemia prevention and help design randomized trials aimed at reducing triglycerides. PMID- 29130594 TI - DNA damage and circulating cell free DNA in greenhouse workers exposed to pesticides. AB - Pesticides widely used in agriculture and other applications have been linked to cancer and other diseases through several potential mechanisms. The goals of this study were to assess DNA damage in lymphocytes by the cytokinesis-block micronucleus assay (CBMN), and to measure circulating cell free DNA (ccf-DNA) in the blood of pesticide-exposed greenhouse workers and matched controls living in the same area. CBMN was applied to peripheral blood lymphocyte samples taken at different times (spring and autumn) for each individual. We measured plasma ccf DNA levels using a Qubit(r) fluorometer. The results indicated that the MNL, BNMN, and NBUDs frequencies of pesticide-exposed individuals were significantly higher than non-exposed individuals. Apart from MNL, BNMN and CBPI, a season related effect was found for the NPB and NBUD frequencies. With MNL and BNMN as the dependent variables, multiple regression analysis showed that age and gender affected MN formation. The ccf-DNA level in the pesticide-exposed group was significantly higher than the control group. There was no seasonal variation regarding the free DNA amount. Ccf-DNA in males was found to be higher than females. The MNL, BNMN, NPB, and CBPI did not correlate with the ccf-DNA amount. It can be concluded that pesticide exposure can modulate DNA integrity via different mechanisms. Also, elevated levels of ccf-DNA could be recommended as a biomarker of pesticide exposure. Environ. Mol. Mutagen. 59:161-169, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29130595 TI - Naphthoquinones: A continuing source for discovery of therapeutic antineoplastic agents. AB - Naturally occurring naphthoquinones, usually in forms of botanical extracts, have been implicated with human life since ancient time, far earlier than their isolation and identification in modern era. The long use history of naphthoquinones has witnessed their functional shift from the original purposes as dyes and ornaments toward medicinal benefits. Hitherto, numerous studies have been carried out to elucidate the pharmacological profile of both natural and artificial naphthoquinones. A number of entities have been identified with promising therapeutic potential. Apart from the traditional effects of wound healing, anti-inflammatory, hemostatic, antifertility, insecticidal and antimicrobial, etc., the anticancer potential of naphthoquinones either in combination with other treatment approaches or on their own is being more and more realized. The molecular mechanisms of naphthoquinones in cells mainly fall into two categories as inducing oxidant stress by ROS (reactive oxygen species) generation and directly interacting with traditional therapeutic targets in a non oxidant mechanism. Based on this knowledge, optimized agents with naphthoquinones scaffold have been acquired and further tested. Hereby, we summarize the explored biological mechanisms of naphthoquinones in cells and review the application perspective of promising naphthoquinones in cancer therapies. PMID- 29130596 TI - Evaluation of a bioengineered construct for tissue engineering applications. AB - Effective biomaterial options for tissue repair and regeneration are limited. Current biologic meshes are derived from different tissue sources and are generally sold as decellularized tissues. This work evaluated two collagen based bioengineered constructs and a commercial product in a model of abdominal full thickness defect repair. To prepare the bioengineered construct, collagen type 1 from porcine skin was isolated using an acid solubilization method. After purification, the collagen was formed into collagen sheets that were physically bonded to form a mechanically robust construct that was subsequently laser micropatterned with pores as a means to promote tissue integration (collagen only construct). A second engineered construct consisted of the aforementioned collagen construct embedded in an RGD-functionalized alginate gel that serves as a bioactive interface (collagen-alginate construct). The commercial product is a biologic mesh derived from bovine pericardium (Veritas(r) ). We observed enhanced vascularization in the midportion of the engineered collagen-alginate construct 2 weeks after implantation. Overall, the performance of the bioengineered constructs was similar to that of the commercial product with comparable integration strength at 8 weeks. Bioengineered constructs derived from monomeric collagen demonstrate promise for a variety of load bearing applications in tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2345-2354, 2018. PMID- 29130598 TI - Filling the periorbital hollows with hyaluronic acid gel: Long-term review of outcomes and complications. AB - INTRODUCTION: Hyaluronic acid gel has been used for rejuvenation of the periorbital tissues since 2004. The in-office, nonsurgical procedural nature has resulted in the growing popularity of the use of fillers. The periorbital region poses unique challenges to the cosmetic surgeon. Malar edema, blue-gray dyschromia, and contour irregularities are well reported short-term complications. We present a long-term follow-up review of complications associated with periocular injection of hyaluronic acid gel fillers. METHODS: Retrospective review of 147 patients with at least a 5-year follow-up period since the first injection. Five senior masked reviewers were asked to grade photographs of patients in comparison with preinjection photographs. Grading was based on a reference photographic key looking specifically at the presence and severity of malar edema, blue-gray dyschromia, and contour irregularity. RESULTS: Malar edema (11%), blue-gray dyschromia (31.3%), and contour irregularities (30.5%) continue to be problems in longer term follow-up of patients. The vast majority (90%) of these complications were mild and required no intervention. There is no statistically significant difference in the mean volumes injected by severity grading of each measured complication. CONCLUSION: Hyaluronic acid gel fillers of the periorbital region are well tolerated in our long-term follow-up experience. The vast majority of cases of malar edema, blue-gray dyschromia, and contour irregularities are mild and do not require intervention. Conservative treatment and tailored treatment approaches, in terms of volume and frequency of injections, may decrease the tendency of these adverse effects to occur. PMID- 29130597 TI - Co-occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines. AB - Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co-occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight-obesity, sleep apnea, congenital heart disease, and osteopenia-osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision-making and management of these medically complex individuals. The development of evidence-based clinical guidance will require an expanded clinical knowledge-base in order to move forward. PMID- 29130599 TI - Interstitial microdeletion of 17q11.2 is associated with hypotonia, fatigue, intellectual disability, and a subtle facial phenotype in three unrelated patients. AB - Over the past decade chromosomal microarray analysis (array CGH) has allowed the discovery of many novel disease-causing recurrent microdeletion and microduplication syndromes. Here we present three unrelated patients (2F; 1M) from three different countries, with developmental delay, intellectual disability, hypotonia, fatigue, and highly similar dysmorphic facial features. Shared facial features are a broad and wide forehead, similar shape of the eyes with long palpebral fissures, a bulbous tip of the nose and thick lips. Intellectual disabilities range from mild to severe. One female patient and the male patient were investigated in childhood for significant hypotonia thought to be suggestive of a neuromuscular disorder. The two female patients also show excessive fatigue with daytime somnolence. The patients carry overlapping, de novo microdeletions of chromosome 17q11.2, with sizes ranging from 0.97 to 1.18 Mb. The smallest region of overlap (SRO) between the three patients is 863 kb, and contains seven genes, five of which are predicted to exhibit haploinsufficiency (CDK5R1, PSMD11, RHOT1, SUZ12, ZNF207) although none has yet been associated with genetic syndromes. Of these five genes, the brain expressed CDK5R1 gene constitutes a good candidate for the developmental delay, while the RHOT1 gene, involved in mitochondrial trafficking, might underlie the hypotonia and the excessive fatigue. PMID- 29130600 TI - Opioid dependence and pregnancy in early twentieth-century America. AB - BACKGROUND AND AIMS: Research on Neonatal Abstinence Syndrome has prompted discussion over how to ensure best outcomes for pregnant women who use drugs and for drug-dependent newborns. Before Neonatal Abstinence Syndrome and the 1980s panic of "crack babies," turn-of-the-century American medical journals discussed infants born to drug-using mothers. This paper aimed to determine whether women who used drugs while pregnant in early twentieth-century America were subject to the stigma many face today. METHODS: Records from early twentieth century medical journals, narcotic maintenance clinics, prisons that held drug users, and conferences on narcotics were examined. Dr. Charles Terry's outspokenness on drug addiction and pregnancy merited closer examination of his work, particularly The Opium Problem. RESULTS: Some physicians saw drug-dependent newborns as scientific proof that addiction was a physiological disease and not subject to questions of morality. This theory was discarded in the 1920s. In that decade, beliefs that children born to drug-using parents threatened national well-being proliferated. Following formal medicine's retreat from addiction treatment, research on drug addiction and pregnancy fell into obscurity until decades later. CONCLUSIONS: The precedent that women who use drugs while pregnant deserve humane treatment extends to the early twentieth century in the US. From 1910 to 1930, perceptions of infants of drug-using women changed from hopeful to fearful. PMID- 29130602 TI - Synthetic piperine amide analogs with antimycobacterial activity. AB - Piperine amide analogs are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene derived fragments. The compounds are screened for activity against Mycobacterium tuberculosis H37Rv. The most potent compounds are the 1-adamantyl and the monoterpene-derived hybrids, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells. The presence of quaternary carbon atom as main structural requirement for anti-TB activity is pointed out by a QSAR study. The most promising compound is the (+)-isopinocampheylamine-derived amide which is characterized with selectivity index of 1387.8. PMID- 29130601 TI - Scaling up HIV viral load - lessons from the large-scale implementation of HIV early infant diagnosis and CD4 testing. AB - INTRODUCTION: The scale-up of effective HIV viral load (VL) testing is an urgent public health priority. Implementation of testing is supported by the availability of accurate, nucleic acid based laboratory and point-of-care (POC) VL technologies and strong WHO guidance recommending routine testing to identify treatment failure. However, test implementation faces challenges related to the developing health systems in many low-resource countries. The purpose of this commentary is to review the challenges and solutions from the large-scale implementation of other diagnostic tests, namely nucleic-acid based early infant HIV diagnosis (EID) and CD4 testing, and identify key lessons to inform the scale up of VL. DISCUSSION: Experience with EID and CD4 testing provides many key lessons to inform VL implementation and may enable more effective and rapid scale up. The primary lessons from earlier implementation efforts are to strengthen linkage to clinical care after testing, and to improve the efficiency of testing. Opportunities to improve linkage include data systems to support the follow-up of patients through the cascade of care and test delivery, rapid sample referral networks, and POC tests. Opportunities to increase testing efficiency include improvements to procurement and supply chain practices, well connected tiered laboratory networks with rational deployment of test capacity across different levels of health services, routine resource mapping and mobilization to ensure adequate resources for testing programs, and improved operational and quality management of testing services. If applied to VL testing programs, these approaches could help improve the impact of VL on ART failure management and patient outcomes, reduce overall costs and help ensure the sustainable access to reduced pricing for test commodities, as well as improve supportive health systems such as efficient, and more rigorous quality assurance. These lessons draw from traditional laboratory practices as well as fields such as logistics, operations management and business. CONCLUSIONS: The lessons and innovations from large-scale EID and CD4 programs described here can be adapted to inform more effective scale-up approaches for VL. They demonstrate that an integrated approach to health system strengthening focusing on key levers for test access such as data systems, supply efficiencies and network management. They also highlight the challenges with implementation and the need for more innovative approaches and effective partnerships to achieve equitable and cost-effective test access. PMID- 29130603 TI - Proteogenomic Re-Annotation of Coccidioides posadasii Strain Silveira. AB - The aims of this study are to provide protein-based evidence upon which to reannotate the genome of Coccidiodes posadasii, one of two closely related species of Coccidioides, a dimorphic fungal pathogen that causes coccidioidomycosis, also called Valley fever. Proteins present in lysates and filtrates of in vitro grown mycelia and parasitic phase spherules from C. posadasii strain Silveira are analyzed using a GeLC-MS/MS method. Acquired spectra are processed with a proteogenomics workflow comprising a Silveira proteome database, a six-frame translation of the Silveira genome and an ab initio gene prediction tool prior to validation against published ESTs. This study provides evidence for 837 genes expressed at the protein level, of which 169 proteins (20.2%) are putative proteins and 103 (12.3%) are not annotated in the Silveira genome. Additionally, 275 novel peptides are derived from intragenic regions of the genome and 13 from intergenic regions, resulting in 172 gene refinements. Additionally, we are the first group to report translationally active retrotransposon elements in a Coccidioides spp. Our study reveals that the currently annotated genome of C. posadasii str. Silveira needs refinement, which is likely to be the case for many nonmodel organisms. PMID- 29130604 TI - Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins. AB - Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay-Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series. PMID- 29130605 TI - Community-driven demand creation for the use of routine viral load testing: a model to scale up routine viral load testing. AB - INTRODUCTION: HIV treatment outcomes are dependent on the use of viral load measurement. Despite global and national guidelines recommending the use of routine viral load testing, these policies alone have not translated into widespread implementation or sufficiently increased access for people living with HIV (PLHIV). Civil society and communities of PLHIV recognize the need to close this gap and to enable the scale up of routine viral load testing. METHODS: The International Treatment Preparedness Coalition (ITPC) developed an approach to community-led demand creation for the use of routine viral load testing. Using this Community Demand Creation Model, implementers follow a step-wise process to capacitate and empower communities to address their most pressing needs. This includes utlizing a specific toolkit that includes conducting a baseline assessment, developing a treatment education toolkit, organizing mobilization workshops for knowledge building, provision of small grants to support advocacy work and conducting benchmark evaluations. RESULTS AND DISCUSSION: The Community Demand Creation Model to increase demand for routine viral load testing services by PLHIV has been delivered in diverse contexts including in the sub-Saharan African, Asian, Latin American and the Caribbean regions. Between December 2015 and December 2016, ITPC trained more than 240 PLHIV activists, and disbursed US$90,000 to network partners in support of their national advocacy work. The latter efforts informed a regional, community-driven campaign calling for domestic investment in the expeditious implementation of national viral load testing guidelines. CONCLUSIONS: HIV treatment education and community mobilization are critical components of demand creation for access to optimal HIV treatment, especially for the use of routine viral load testing. ITPC's Community Demand Creation Model offers a novel approach to achieving this goal. PMID- 29130606 TI - Oral administration of Lactobacillus plantarum CJLP133 and CJLP243 alleviates birch pollen-induced allergic rhinitis in mice. AB - AIMS: In this study, we evaluated the therapeutic efficacy of selected probiotics in a mouse model of birch pollen (BP)-induced allergic rhinitis. METHODS AND RESULTS: Oral administration of Lactobacillus plantarum CJLP133 and CJLP243 ameliorated the symptoms of BP-induced allergic rhinitis by reducing airway hyperresponsiveness, and both the histological scores and the number of infiltrated cells in the nasal cavities and lungs. Compared with those from vehicle-treated mice, bronchoalveolar lavage fluid and draining lymph node samples from CJLP133 and CJLP243-administrated mice showed diminished numbers of immune cells, increased secretion of a Th1-type cytokine (IFN-gamma) and decreased production of Th2-type cytokines (IL-4, IL-5 and IL-13). Consistent with these results, levels of IL-4, IL-5, IL-13, serum IgE and BP-specific serum IgG1 were decreased, whereas secretion of IFN-gamma and BP-specific serum IgG2a was augmented upon administration of CJLP133 and CJLP243 in mice. CONCLUSION: Oral administration of L. plantarum CJLP133 and CJLP243 alleviates symptoms of BP induced allergic rhinitis in mice by recovering Th1/Th2 balance via enhancement of the Th1-type immune response. SIGNIFICANCE AND IMPACT OF THE STUDY: Lactobacillus plantarum CJLP133 and CJLP243 have therapeutic effects on BP induced allergic rhinitis in an animal model. PMID- 29130607 TI - Qualitative experiences of disengagement in assertive outreach teams, in particular for "black" men: Clinicians' perspectives. AB - : This study is a follow-on study to a study into the experiences of disengagement from mental health services for men who described their ethnic identity as "black." The aim of this study was to understand the same phenomenon from a clinician's perspective. WHAT IS KNOWN ON THE SUBJECT?: Literature highlights that people from ethnic minority backgrounds experience some difficulties engaging with mental health services; Disengagement from mental health services is a complex phenomenon that occurs for a variety of different reasons; Only one paper previously has investigated clinicians' perspective on disengagement from mental health services; WHAT THE STUDY ADDS TO EXISTING KNOWLEDGE?: This study demonstrates that clinicians are aware that stigma and medication impact upon engagement with mental health services, which were also important components of the patients experience. A finding of the former study was that patients' attitudes towards mental health services change over time, with patients engaging more as they get older, a finding was supported by wider literature. However, in this study, the participants were not certain that this was the case. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The implications for practice from this study are that staff should persist with efforts to reduce the stigma surrounding mental health, carefully consider the significance and impact of medication and have an awareness of how patients' attitudes towards mental illness and mental health services change and develop over time. Continued support for an AO approach to practice for people who find it difficult to engage with services, where a multidisciplinary "team" approach can focus on service user-centred recovery goals and a positive space for collaboration. ABSTRACT: Introduction Engagement with services is often poor amongst people with severe mental health problems, yet key to improving clinical outcomes. Aims This study explores the perception of clinicians on patients with severe mental health problems, in particular the experiences of black men, who disengage from mental health services. Method Two focus groups consisting of a combined total of twelve, mainly white, experienced clinicians in the UK were recruited. Transcripts were analysed using interpretative phenomenological analysis. Results Clinicians understood that patients' awareness of stigma impacted upon engagement with mental health services. Clinicians were aware that medication negatively impacted on engagement. The passage of time was perceived as impacting upon engagement. Discussion The perspectives of the clinicians in this study and the experiences of the patients in a former study converged. The participants had an understanding of the complexities that black men faced when engaging with mental health services. Implications for practice This is the first study to highlight that AOT staff need to be aware of the key role that stigma plays in engagement in treatment, continue to focus on efforts to reduce the stigma surrounding mental health, consider the significance medication and be aware of how patients' attitudes towards mental health services develop over time. PMID- 29130608 TI - Impact of web-based clinical practice guidelines on paediatric fracture clinics. AB - BACKGROUND: In an effort to standardize management and reduce over-treatment of uncomplicated paediatric fractures, the Victorian Pediatric Orthopaedic Network and the Royal Children's Hospital, Melbourne, created publically available web based paediatric fracture pathways. The aim of this study was to determine the impact of web-based fracture pathways on the clinic volume at a tertiary-care paediatric fracture clinic. METHODS: A comparative retrospective review was performed at a large, urban, tertiary-care children's hospital. Fracture clinic data from two 12-week periods before and after implementation of the fracture pathways were compared. For each study period, data collected included: total number of emergency department visits, number of fracture clinic visits, number of fracture clinic visits for patients that presented with upper extremity fractures for which web-based fracture pathways were available, number of radiology department visits for X-rays, and number of fracture clinic visits for patients requiring orthopaedic intervention in the operating room (closed or open reductions). RESULTS: The number of fracture clinic visits for patients with upper extremity fractures decreased 12% post-pathway implementation, from 954 visits to 842 visits. The number of radiology department visits for patients with upper extremity fractures decreased 24% post-pathway implementation, from 714 to 544 visits. CONCLUSION: The implementation of web-based fracture pathways for upper extremity paediatric fractures was associated with a decrease in clinic resource utilization at a tertiary-care children's hospital. PMID- 29130609 TI - Impact of body fat percentage change on future diabetes in subjects with normal glucose tolerance. AB - The aim of the work was to determine the effect of body fat change on risk of diabetes in normal glucose tolerance (NGT) population. A total of 1,857 NGT subjects were included and followed up for an average period of 44.57 months. Body fat percentage (BF%) was measured by bioelectrical impedance analysis. Subjects were grouped based on the BF% and/or body mass index (BMI) state. Among all subjects, 28 developed diabetes after follow-up. Compared with subjects with stable normal BF% (control), subjects who became obesity at follow-up were defects in insulin secretion and had a higher risk of developing diabetes (7.102, 95% confidence intervals [CI] 1.740-28.993), while no difference in diabetic risk could be viewed between subjects with abnormal BF% at baseline but normal at the end of follow-up and control subjects after adjustment of confounding factors. Moreover, compared with those keeping normal BF% and BMI both at baseline and follow-up, subjects who had normal BMI at baseline and follow-up, but abnormal BF% at baseline or/and follow-up still had a higher risk to develop diabetes (4.790, 95% CI 1.061-21.621), while those with normal BF% at baseline and follow up, but abnormal BMI at baseline or/and follow-up had not. Subjects from normal BF% at baseline to obese at follow-up are associated with an increased risk of diabetes. Maintaining normal body fat is more relevant than BMI in preventing diabetes. (c) 2017 IUBMB Life, 69(12):947-955, 2017. PMID- 29130610 TI - The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study. AB - OBJECTIVE: This study was intended to investigate the effects of icariin on the healing of tooth extraction sites under the systemic administration of zoledronic and dexamethasone. METHOD: Thirty female rats underwent bilateral ovariectomy and were randomly assigned to 5 groups: SS group received a weekly injection of saline, while ZD, ZD + LICA, ZD + MICA, and ZD + HICA groups received zoledronic with dexamethasone for 8 weeks. One week later, mandibular first molars were extracted in all groups. Then, 30, 60, and 120 mg/kg icariin were intragastrically given to ZD + LICA, ZD + MICA, and ZD + HICA groups daily for 10 weeks, while saline was given to SS group and ZD group. Blood samples and mandibles were harvested for examinations after 10 weeks. RESULTS: Significantly smaller wound area was noted in SS and ZD + HICA groups, but the incidence of bisphosphonate-related osteonecrosis of the jaws (BRONJ) was not significantly different. Groups injected with zoledronic and dexamethasone had higher C terminal cross-linked telopeptide of type 1 collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP 5b), and the number of osteoclast cells, with less vascular endothelial growth factor (VEGF) and osteocalcin (OCN). In contrast, CTX 1, TRACP 5b, and the number of osteoclast cells declined after using icariin and promoted VEGF and OCN were noted and the effects were in a dosage-dependent manner. CONCLUSION: Concurrent use of zoledronic and dexamethasone inhibits the expression of VEGF, OCN, and wound healing and increases the number of osteoclast cells, serum CTX-1, and TRACP-5b after discontinuation for 10 weeks. Icariin weakens those effects in a dose-dependent manner but does not influence the onset of BRONJ. PMID- 29130611 TI - Usefulness of exosome-encapsulated microRNA-451a as a minimally invasive biomarker for prediction of recurrence and prognosis in pancreatic ductal adenocarcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) encapsulated in the exosomes of plasma is of interest as stable and minimally invasive biomarkers for recurrence and prognosis in cancer patients. The aim of this study was to clarify the predictive and prognostic value of plasma exosomal microRNA-451a (miR-451a) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Microarray-based expression profiling of miRNAs derived from exosomes in the plasma of six PDAC patients with UICC stage II was employed to identify a biomarker to distinguish between patients with and without recurrence. For validation analysis, plasma exosome samples of other 50 PDAC patients were measured by TaqMan MicroRNA assays. RESULTS: In the miRNA microarray analyses, miR-451a showed the highest upregulation in the stage II patients who showed recurrence after surgery. In the relationship to pathological factors, exosomal miR-451a showed a significant association with tumor size and stage. The overall survival (OS) and disease-free survival rates (DFS) of the high exosomal miR-451a patients were significantly worse than those of the low miR-451a patients. In Cox proportional hazards model analysis, exsomal miR-451a showed significance to OS and DFS. CONCLUSIONS: Plasma exosomal miR-451a levels may be a useful minimally invasive biomarker for the prediction of recurrence and prognosis in PDAC patients. PMID- 29130612 TI - Caliber and fitness of the axillary artery as a conduit for large-bore cardiovascular procedures. AB - OBJECTIVES: We sought to describe the caliber and vascular health of the subclavian and axillary arteries as related to their potential utilization in complex cardiovascular procedures. BACKGROUND: Patients referred for advanced catheter-based therapies frequently have lower extremity peripheral vascular disease that may prohibit the use of large bore arterial catheters. Utilization of the upper extremity peripheral vasculature is rarely considered as an alternative access strategy. This may be due in part to a lack of familiarity with the thoracic vasculature. METHODS AND RESULTS: 208 consecutive patients undergoing routine CTA prior to transcatheter aortic valve replacement were retrospectively evaluated in a systematic analysis of upper and lower extremity vasculature. Minimal luminal diameters (MLDs) for the axillary arteries and iliofemoral arteries were 6.0 +/- 1.1 mm and 6.6 +/- 1.8 mm respectively. Compared to the iliofemoral arteries, the axillary arteries demonstrated substantially lower rates of significant stenosis (2% vs. 12%, p < 0.01) and significantly lower rates of moderate to severe calcification disease (9% vs. 64%, p < 0.01). Diabetes and tobacco use were independently associated with smaller axillary artery caliber by MLD (p < 0.01) but not with significant stenotic disease. CONCLUSIONS: The axillary arteries are slightly smaller but less frequently diseased than the corresponding iliofemoral vessels. PMID- 29130613 TI - Impact of anemia on long-term outcomes after percutaneous coronary intervention for chronic total occlusion. AB - OBJECTIVES: A single-centre, observational study was performed in order to investigate the relationship between anemia and outcomes after percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). BACKGROUND: Anemia has been identified as adverse predictor in patients with coronary artery disease undergoing coronary revascularization. Data on the impact of anemia on outcomes in patients undergoing PCI for CTO lesions are lacking. METHODS: A total of 1,964 patients undergoing CTO PCI were stratified according to the presence/absence of anemia (hemoglobin of <13 g/dl for men and <12 g/dl for women). The primary endpoint was all-cause mortality. Median follow-up was 2.6 (interquartile range 1.1-3.1) years. RESULTS: Of the 1,964 patients, 297 (15.1%) had anemia. Anemic as compared to nonanemic patients had and an increased all-cause mortality (27.9% versus 9.1%, P < 0.001), and associations remained significant after multivariable adjustments (adjusted HR 2.26, 95% CI 1.71-2.98, P < 0.001). All cause mortality decreased with increasing hemoglobin tertiles (T1: 18.6%, T2: 8.6%, T3: 8.2%, log rank P < 0.001). Procedural success was associated with reduced all-cause mortality both in anemic (21.8% versus 47.2%, adjusted HR 0.59, 95% CI 0.37-0.93, P = 0.02) and nonanemic patients (7.8% versus 16.3%, adjusted HR 0.64, 95% CI 0.42-0.98, P = 0.02, interaction P = 0.69). CONCLUSIONS: Although anemia is associated with an increased all-cause mortality in patients undergoing CTO PCI, the survival benefit associated with successful CTO recanalization is maintained. PMID- 29130614 TI - Panax notoginseng saponins attenuate cardiomyocyte apoptosis through mitochondrial pathway in natural aging rats. AB - Panax notoginseng saponins (PNS) have been widely used in the cardiovascular system for the treatment of cardiovascular diseases and stroke in China. In this study, we investigated the anti-apoptotic effect of PNS on cardiomyocytes in the natural aging rat and explored the potential mechanisms regarding oxidative stress and mitochondrial function signaling pathways. Male Sprague-Dawley rats were randomly divided into five groups: adult control (3-month old), aging control (24-month old), and different doses of PNS-treated aging rat groups (10, 30, 60 mg/kg/day, orally). After treatment of PNS or saline for 6 months, the effects of PNS on the cardiomyocytes were evaluated. Results showed that PNS significantly improved the morphological changes in myocardium, prevented the increase of cardiomyocyte apoptosis in the aging rats, and improved mitochondrial dysfunction associated aging in a dose-dependent manner. PNS also significantly reversed the down-regulation of FoxO3a and Mn-SOD and up-regulated PGC-1alpha, LC3beta, and Beclin-1 levels. Our data demonstrated that during aging, mitochondrial dysfunction caused an increase of oxidative damage, which played a key role in cardiomyocyte apoptosis. PNS exerted an anti-apoptotic effect via attenuating oxidative damage through oxidative stress- and mitochondrial function related signaling pathways. PMID- 29130615 TI - In-office bleaching efficacy on stain removal from CAD/CAM and direct resin composite materials. AB - OBJECTIVE: To evaluate the efficacy of in-office bleaching on stain removal from stained resin composite and ceramic computer-assisted design/computer-assisted manufacturing (CAD/CAM) blocks and direct resin composites. METHODS: Forty disk shaped samples were fabricated from each of nine materials: six CAD/CAM (VITABLOCS Mark II, Paradigm MZ100, Exp Vita Hybrid Ceramic, VITA ENAMIC, Exp Kerr, and LAVA Ultimate) and three direct resin composites (Filtek Supreme, Venus Diamond, and Filtek Silorane). Samples were randomly divided into five groups (n = 8), each stained with a particular staining solution. Using a calibrated spectrophotometer and a black background, L*a*b* values were assessed before and after 120 days of staining. Samples were subjected to in-office bleaching using 40% hydrogen peroxide gel for one hour. At subsequent assessment, color change (DeltaE) was calculated as the difference between L*a*b* values. Both ANOVA and the Duncan test were used to identify differences between groups (alpha = 0.05). RESULTS: Bleaching resulted in significant differences in DeltaE values for all materials (P < .001). Bleaching efficacy was highly influenced by material composition and staining solution. Residual color values after bleaching for ceramic and hybrid ceramics ranged from -0.49 to 2.35, within the clinically acceptable maximum of 3.3. Values after bleaching for resin-based CAD/CAM ranged from -0.7 to 7.08 while direct resin composites values ranged from -1.47 to 25.13. Coffee left the greatest residual color on all materials. CONCLUSIONS: Based on material nature, 40% hydrogen peroxide bleaching can remove staining. The new resin-based CAD/CAM blocks showed promising results in terms of color stability. CLINICAL SIGNIFICANCE: Bleaching using 40% hydrogen peroxide can be an effective method to remove stains from dental restorations. In this way, restoration replacement as a result of discoloration may no longer be necessary. PMID- 29130616 TI - Emergency extracorporeal membrane oxygenation in transcatheter aortic valve implantation: A two-center experience of incidence, outcome and temporal trends from 2010 to 2015. AB - BACKGROUND: Although the incidence of periprocedural complications has decreased in transcatheter aortic valve implantation (TAVI), life-threatening complications occur and emergency veno-arterial extracorporeal membrane oxygenation (vaECMO) can provide immediate circulatory stabilization. We report our two-center experience of vaECMO during life-threatening complications in TAVI. METHODS: From January 2010 to December 2015, 1,810 consecutive patients underwent TAVI at two centers. Clinical characteristics, type of complication, outcome and temporal trends in the requirement of emergency vaECMO were evaluated. RESULTS: Life threatening complications requiring vaECMO occurred in 1.8% of cases (33 patients; 22 transfemoral, 11 transapical). Indications for vaECMO were ventricular rupture (30%, 10/33), low output (15%, 5/33), bleeding (12%, 4/33), coronary artery impairment (9%, 3/33), ventricular arrhythmias (6%, 2/33), severe aortic regurgitation (6%, 2/33), aortic annular rupture (6%, 2/33), and aortic dissection (3%, 1/33). In 4 cases, no definite cause for hemodynamic instability was identified. Conversion to open heart surgery was necessary in 42% of patients (14/33). Percutaneous coronary intervention was performed in all cases with coronary artery impairment (9%, 3/33). Patients with severe aortic regurgitation (6%, 2/33) underwent emergency valve-in-valve implantation. Other patients received, in addition to vaECMO support conservative treatment (42%, 14/33). In hospital mortality and 30-day mortality were 46% (15/33). Of patients discharged, 67% (12/18) had no neurological impairment, whereas mild and severe neurological impairment was found in 11% (2/18) and 22% (4/18), respectively. From 2010 to 2015, with increasing procedures (from n = 43 to n = 553) requirement of vaECMO decreased from 9.3% to 0.9% (P for the trend <0.001). CONCLUSION: Over a 6-year period, need for emergency vaECMO during TAVI significantly decreased over time. Despite high in-hospital mortality, vaECMO represents a feasible strategy for hemodynamic support in case of life-threatening complications. PMID- 29130617 TI - Dendritic cell phenotype in severe asthma reflects clinical responsiveness to glucocorticoids. AB - BACKGROUND: Subsets of patients with severe asthma remain symptomatic despite prolonged, high-dose glucocorticoid therapy. We hypothesized that the clinical glucocorticoid sensitivity of these asthmatics is reflected in differences in peripheral blood dendritic cell subsets. OBJECTIVE: To compare peripheral blood leucocyte populations using flow cytometry at baseline and after 2 weeks of systemic glucocorticoid (steroid) treatment to identify immunological differences between steroid-sensitive (SS) and steroid-resistant (SR) asthmatics. METHODS: Adult severe asthmatics (SS n = 12; SR n = 23) were assessed for their response to 2 weeks of therapy with oral prednisolone. Peripheral blood was obtained before and after therapy and stained for lymphocyte (CD3, CD19, CD4, CD8 and Foxp3) and dendritic cell markers (Lineage negative [CD3, CD14, CD16, CD19, CD20, CD56], HLA-DR+, CD304, CD11c, ILT3 and CD86). RESULTS: A higher median frequency of myeloid DCs (mDCs) but not plasmacytoid DCs (pDCs) was observed in the blood of SR as compared to SS asthmatics (P = .03). Glucocorticoid therapy significantly increased median B cell, but not T cell numbers in both cohorts, with a trend for increased numbers of Foxp3+ Tregs in SS (P = .07), but not SR subjects. Oral prednisolone therapy significantly reduced the median numbers and frequencies of total DCs and pDCs in both SS and SR asthmatics. Interestingly, the expression of HLA-DR and ILT3 was also reduced on pDCs in all patients. In contrast, therapy increased the median frequency of mDCs in SS, but reduced it in SR asthmatics. CONCLUSIONS: Myeloid DC frequency is elevated in SR compared with SS asthmatics, and mDC shows a differential response to oral prednisolone therapy. PMID- 29130618 TI - The taste of toxicity: A quantitative analysis of bitter and toxic molecules. AB - The role of bitter taste-one of the few basic taste modalities-is commonly assumed to signal toxicity and alert animals against consuming harmful compounds. However, it is known that some toxic compounds are not bitter and that many bitter compounds have negligible toxicity while having important health benefits. Here we apply a quantitative analysis of the chemical space to shed light on the bitterness-toxicity relationship. Using the BitterDB dataset of bitter molecules, The BitterPredict prediction tool, and datasets of toxic compounds, we quantify the identity and similarity between bitter and toxic compounds. About 60% of the bitter compounds have documented toxicity and only 56% of the toxic compounds are known or predicted to be bitter. The LD50 value distributions suggest that most of the bitter compounds are not very toxic, but there is a somewhat higher chance of toxicity for known bitter compounds compared to known nonbitter ones. Flavonoids and alpha acids are more common in the bitter dataset compared with the toxic dataset. In contrast, alkaloids are more common in the toxic datasets compared to the bitter dataset. Interestingly, no trend linking LD50 values with the number of activated bitter taste receptors (TAS2Rs) subtypes is apparent in the currently available data. This is in accord with the newly discovered expression of TAS2Rs in several extra-oral tissues, in which they might be activated by yet unknown endogenous ligands and play non-gustatory physiological roles. These results suggest that bitter taste is not a very reliable marker for toxicity, and is likely to have other physiological roles. (c) 2017 IUBMB Life, 69(12):938-946, 2017. PMID- 29130619 TI - A feasibility study of transaxillary TAVI with the lotus valve. AB - OBJECTIVES: To assess the feasibility of axillary transcatheter aortic valve implantation (TAVI) using the Lotus valve. BACKGROUND: TAVI is used to treat patients with severe aortic stenosis, with transfemoral (TF) access being the safest and most widely used route. In patients unsuitable for this, there are reports that the axillary artery may be safest alternative access route. The Lotus device is a fully retrievable 2nd generation transcatheter heart valve which is licensed for femoral and transaortic access. There are limited data on the suitability of this valve for axillary access. METHODS: We assessed the feasibility of transaxillary TAVI with the Lotus valve in patients unsuitable for TF TAVI. Between January and October 2016, we identified 10 patients who underwent transaxillary TAVI with the Lotus valve. This cohort was compared with 347 (85%) patients who underwent TF TAVI, 45 (11%) patients who underwent and trans-apical or direct-aortic TAVI and the total group of 16 (4%) patients who underwent axillary TAVI. RESULTS: Ten patients aged 75 years (69-83) underwent attempted TAVI with the Lotus via axillary access. Device success was 100%. In hospital and 30-day mortality was zero. There were no neurological events, no major vascular complications and no myocardial infarctions. Four of 10 patients required a pacemaker post-TAVI. No patient was left with moderate or greater aortic regurgitation. Median length of stay was 3 days CONCLUSIONS: TAVI with the Lotus valve is feasible via the axillary artery and appears safe in our small cohort of patients. PMID- 29130620 TI - Electro-optic probe for real-time assessments of RF electric field produced in an MRI scanner: Feasibility tests at 3 and 4.7 T. AB - During magnetic resonance imaging (MRI) examinations, the average specific absorption rate (SAR) of the whole body is calculated as an index of global energy deposition in biological tissue without taking into account the presence of metallic implants or conductive materials. However, this global SAR calculation is not sufficient to ensure patient safety and a local SAR measurement should be carried out. Several measurement techniques have already been used to evaluate the local SAR, in particular electric field (E-field) probes, but the accuracy of the measurements and the resolutions (spatial and temporal) depend strongly on the measurement method/probe. This work presents an MR-compatible, subcentimeter probe based on an electro-optic (EO) principle enabling a real-time measurement of the local E-field during MRI scans. The experiments using these probes were performed on two different MR systems (preclinical and clinical) having different static magnetic field strengths and with different volume coil geometries. The E-field was measured with unloaded (in air) and loaded volume coils in order to assess the sensing characteristics of the optical probe. The results show an excellent linearity between the measured E field and the radiofrequency (RF) magnetic field in both experimental conditions. Moreover, the distribution of the E-field throughout the volume coil was experimentally determined and was in good agreement with numerical simulations. Finally, we demonstrate through our measurements that the E-field depends strongly on the dielectric properties of the medium. PMID- 29130621 TI - Realizing the potential of routine viral load testing in sub-Saharan Africa. PMID- 29130622 TI - Patent processus vaginalis as a conduit for tumoral seeding: a rare presentation of port site metastasis. PMID- 29130623 TI - Body fatness at a young age, body fatness gain and risk of breast cancer: systematic review and meta-analysis of cohort studies. AB - Higher body fatness in adulthood has been consistently associated with an increased risk of postmenopausal breast cancer, as well as a tendency towards a lower risk of premenopausal breast cancer. However, the association between body fatness at a young age (<=30 years), body fatness gain and the risk of breast cancer is less defined. PubMed and Web of Science databases were searched to identify relevant publications. Risk estimates with 95% confidence intervals from each study were transformed into a continuous variable for each 5 kg m-2 increase in body mass index (BMI) and were pooled under a random-effects model. Each 5 kg m-2 increase in BMI was significantly associated with a 14%, 12% and 17% lower risk of breast cancer later in life among all women, premenopausal women and postmenopausal women, respectively. Significant heterogeneity and publication bias were observed. The results remained unchanged after the trim and fill method was applied to correct the bias. Each 5 kg m-2 increase in BMI from a young age until cohort entry was significantly associated with a 13% and 14% higher risk of breast cancer in all women and postmenopausal women, respectively. In summary, higher body fatness at a young age may have a protective role in the later development of breast cancer in both premenopausal and postmenopausal women. However, this potential benefit should not be overemphasized, as our findings suggest that increased body fatness gain from a young age is positively associated with postmenopausal breast cancer risk. These findings further justify the need to maintain a steady weight throughout life. PMID- 29130625 TI - Comparative evaluation of 68 Ga-labeled NODAGA, DOTAGA, and HBED-CC-conjugated cNGR peptide chelates as tumor-targeted molecular imaging probes. AB - The biological behavior of 68 Ga-based radiopharmaceuticals can be significantly affected by the chelators' attributes (size, charge, lipophilicity). Thus, this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on the distribution pattern of 68 Ga-labeled NGR peptides targeting CD13 receptors. 68 Ga-DOTAGA-c(NGR), 68 Ga-NODAGA-c(NGR), and 68 Ga HBED-CC-c(NGR) were observed to be hydrophilic with respective log p values being -3.5 +/- 0.2, -3.3 +/- 0.08, and -2.8 +/- 0.14. The three radiotracers exhibited nearly similar uptake in human fibrosarcoma HT-1080 tumor cells with 86%, 63%, and 33% reduction during blocking studies with unlabeled cNGR peptide for 68 Ga DOTAGA-c(NGR), 68 Ga-NODAGA-c(NGR), and 68 Ga-HBED-CC-c(NGR), respectively, indicating higher receptor specificity of the first two radiotracers. The neutral radiotracer 68 Ga-NODAGA-c(NGR) demonstrated better target-to-non-target ratios during in vivo studies compared to its negatively charged counterparts, 68 Ga DOTAGA-c(NGR) and 68 Ga-HBED-CC-c(NGR). The three radiotracers had similar HT 1080 tumor uptake and being hydrophilic exhibited renal excretion with minimal uptake in non-target organs. Significant reduction (p < .005) in HT-1080 tumor uptake of the radiotracers was observed during blocking studies. It may be inferred from these studies that the three radiotracers are promising probes for in vivo imaging of CD13 receptor expressing cancer sites; however, 68 Ga-NODAGA c(NGR) is a better candidate. PMID- 29130624 TI - Efficiency of electrochemotherapy with reduced bleomycin dose in the treatment of nonmelanoma head and neck skin cancer: Preliminary results. AB - BACKGROUND: In the present study, effectiveness of electrochemotherapy was compared in patients with nonmelanoma skin cancer (NMSC) of the head and neck using standard and reduced doses of bleomycin. METHODS: Twenty-eight patients older than 65 years were prospectively treated with electrochemotherapy for nonmelanoma head and neck skin cancer. In the experimental group (n = 12 patients; 24 lesions), reduced bleomycin doses (10 000 IU/m2 ) were used. In the control group (n = 16 patients; 28 lesions), the standard bleomycin doses (15 000 IU/m2 ) were used. Tumor responses and side effects were monitored. These two groups were pair matched for the characteristics of patients (age, gender) and their tumors (diameter, histology type, recurrent lesions). RESULTS: Complete tumor response at 2 months post-electrochemotherapy with the reduced bleomycin dose was 100% and with the standard bleomycin dose it was 96%. No statistically significant difference regarding skin toxicity was observed between the 2 groups (P = .20). Skin toxicity of grade 3 or less was recorded only in the control group (7% of treated lesions). CONCLUSION: Presented results show the comparable antitumor effectiveness of electrochemotherapy when using standard or reduced bleomycin dose in elderly patients with nonmelanoma head and neck skin cancer. PMID- 29130626 TI - Age-related macular degeneration: using morphological predictors to modify current treatment protocols. AB - To assess predictors of treatment response in neovascular age-related macular degeneration (AMD) in an attempt to develop a patient-centric treatment algorithm. We conducted a systematic search using PubMed, EMBASE and Web of Science for prognostic indicators/predictive factors with the key words: 'age related macular degeneration', 'neovascular AMD', 'choroidal neovascular membrane (CNV)', 'anti-vascular endothelial growth factor (anti-VEGF)', 'aflibercept', 'ranibizumab', 'bevacizumab', 'randomized clinical trials', 'post-hoc', 'prognostic', 'predictive', 'response' 'injection frequency, 'treat and extend (TAE), 'pro re nata (PRN)', 'bi-monthly' and 'quarterly'. We only included studies that had an adequate period of follow-up (>1 year), a single predefined treatment regimen with a predetermined re-injection criteria, an adequate number of patients, specific morphological [optical coherence tomography (OCT)] criteria that predicted final visual outcomes and injection frequency and did not include switching from one drug to the other. We were able to identify seven prospective studies and 16 retrospective studies meeting our inclusion criteria. There are several morphological and demographic prognostic indicators that can predict response to therapy in wet AMD. Smaller CNV size, subretinal fluid (SRF), retinal angiomatous proliferation (RAP) and response to therapy at 12 weeks (visual, angiographic or OCT) can all predict good visual outcomes in patients receiving anti-VEGF therapy. Patients with larger CNV, older age, pigment epithelial detachment (PED), intraretinal cysts (IRC) and vitreomacular adhesion (VMA) achieved less visual gains. Patients having VMA/VMT required more intensive treatment with increased treatment frequency. Patients with both posterior vitreous detachment (PVD) and SRF require infrequent injections. Patients with PED are prone to recurrences of fluid activity with a reduction in visual acuity (VA). A regimen that involves less intensive therapy and extended follow-up intervals (4 weekly) can be suggested for patients who show adequate visual response and have both SRF and PVD at baseline. In addition, patients with poor prognostic indicators such as IRC, VMA, large CNV size, older age and poor response at 12 weeks should be extended very cautiously with the possibility of fixed monthly/bimonthly (every 2 months) treatments if they fail to achieve dryness. Patients with PED at baseline should receive monthly/bimonthly injections of anti-VEGF therapy or can be extended very cautiously (two weekly intervals) using a TAE protocol. PMID- 29130627 TI - Temporal trends (2002-2014) of incidence and shockable status of adult emergency medical service attended out-of-hospital cardiac arrest of presumed cardiac aetiology in Queensland. AB - OBJECTIVE: To describe trends in incidence and shockable status of adult out-of hospital cardiac arrest (OHCA) of presumed cardiac aetiology attended by Queensland Ambulance Service (QAS) paramedics between 2002 and 2014. METHODS: The QAS cardiac arrest registry was used to collect data. Analyses included age standardised rates by gender for all adults and older adults only (65 years+); age-specific incidence rates of young adults (18-49), middle age adults (50-64) and five groups of older adults (65-69, 70-74, 75-79, 80-84 and 85+); and proportions of shockable versus non-shockable initial rhythm together and by age group (young, middle age and older adults). Temporal trends were analysed. RESULTS: Over the 13 years, 32 346 cases of adult OHCA of presumed cardiac aetiology were recorded on the QAS OHCA registry. Age-standardised incidence reduced significantly over time overall and in males only, in all adults and independently in older adults. A significant reduction independently in females was observed only in older adults. Age-specific rates reduced in the 18-49, 70 74, 75-79 and 80-84 year age groups, increased in the 50-64 age group (largely attributable to females) and no significant trends were found in the 65-69 and 85+ age groups. The proportion of cases with an initially shockable rhythm significantly decreased overall. This trend was observed independently in older adults, but not in young or middle age adults. CONCLUSION: Age-standardised incidence has reduced with a period of stagnation in the middle age and early older years. These factors require consideration in data interpretation and strategy planning. PMID- 29130629 TI - In reply to "Mast Cell Disorders in Ehlers-Danlos Syndrome". PMID- 29130628 TI - Characterization of genetic intratumor heterogeneity in colorectal cancer and matching patient-derived spheroid cultures. AB - Patient-derived in vitro cultures of colorectal cancer (CRC) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from CRCs and see how well intratumor heterogeneity (ITH) was recapitulated in matching patient-derived spheroids. Three to five biopsies were collected from six CRC tumors. Each biopsy was split in two; one half was used for spheroid culturing, while the other half was used for DNA and RNA purification. For two patients, lymph node metastases were analyzed. Somatic mutations were called from whole exome sequencing data. Each tumor contained mutations shared across all biopsies and spheroids, including major CRC drivers such as APC, KRAS, and TP53. At the same time, all tumors exhibited ITH on both mutation and copy number level. The concordance between biopsies and spheroids ranged between 40 and 70% for coding mutations. For three patients, the biopsy and spheroid from matching areas clustered together, meaning that the spheroid resembled the area of origin more than the other areas. However, all biopsies and spheroids contained private mutations. Therefore, multiple cultures from spatially distinct sites of the tumor increase the insight into the genetic profile of the entire tumor. Molecular subtypes were called from RNA sequencing data. When based on transcripts from both cancer and noncancerous cells, the subtypes were largely independent of sampling site. In contrast, subtyping based on cancer cell transcripts alone was dependent on sample site and genetic ITH. In conclusion, all examined CRC tumors showed genetic ITH. Spheroid cultures partly reflected this ITH, and having multiple cultures from distinct tumor sites improved the representation of the genetic tumor subclones. This should be taken into account when establishing patient derived models for drug screening. PMID- 29130630 TI - A structure-based strategy toward the development of novel candidates for antimycobacterial activity: Synthesis, biological evaluation, and docking study. AB - Bacterial resistance to most of the available antibiotics has stimulated the discovery of novel efficacious antibacterial agents. Bedaquiline is first of its type that has been specifically introduced for the management of MDR-TB in combination with other drugs. In this study, a series of isoniazid/ethambutol/pyrazinamide/-quinoline conjugates based on the structures of bedaquiline were designed and synthesized. Biological activity tests revealed that some of isoniazid/ethambutol/quinoline conjugates have useful antibiotic activity against MTB H37Rv (MIC: 2.0-8.0 MUg/ml). Furthermore, molecular docking calculations were performed for the most potent inhibitor to show its binding interactions within the active site of the possible target protein. Overall, these compounds represent novel valuable starting point with potent antimycobacterial activity and deserve further structural modifications. PMID- 29130631 TI - Short rib syndrome Beemer-Langer type, a short history. PMID- 29130632 TI - DOCK3-related neurodevelopmental syndrome: Biallelic intragenic deletion of DOCK3 in a boy with developmental delay and hypotonia. AB - Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6-12 of the DOCK3 gene at 3p21.2. Symptoms of our proband resembles a phenotype of Dock3 knockout mice exhibiting sensorimotor impairments. Furthermore, our proband has clinical similarities with two siblings with compound heterozygous loss-of-function mutations of DOCK3 reported in [Helbig, Mroske, Moorthy, Sajan, and Velinov (); https://doi.org/10.1111/cge.12995]. Biallelic DOCK3 mutations cause a neurodevelopmental disorder characterized by unsteady gait, hypotonia, and developmental delay. PMID- 29130634 TI - Synthesis of thermo-responsive bovine hemoglobin imprinted nanoparticles by combining ionic liquid immobilization with aqueous precipitation polymerization. AB - Surface molecular imprinting over functionalized nanoparticles has proved to be an effective approach for construction of artificial nanomaterials for protein recognition. Herein, we report a strategy for synthesis of core-shell protein imprinted nanoparticles by the functionalization of nano-cores with ionic liquids followed by aqueous precipitation polymerization to build thermo-responsive imprinted polymer nano-shells. The immobilized ionic liquids can form multiple interactions with the protein template. The polymerization process can produce thermo-reversible physical crosslinks, which are advantageous to enhancing imprinting and facilitating template removal. With bovine hemoglobin as a model template, the imprinted nanoparticles showed temperature-sensitivity in both dispersion behaviors and rebinding capacities. Compared with the ionic-liquid modified core nanoparticles, the imprinted particles exhibited greatly increased selectivity and two orders of magnitude higher binding affinity for the template protein. The imprinted nanoparticles achieved relatively high imprinting factor up to 5.0 and specific rebinding capacity of 67.7 mg/g, respectively. These nanoparticles also demonstrated rapid rebinding kinetics and good reproducibility after five cycles of adsorption-regeneration. Therefore, the presented approach may be viable for the fabrication of high-performance protein-imprinted nanoparticles with temperature sensitivity. PMID- 29130635 TI - Prospective role of indigenous Exiguobacterium profundum PT2 in arsenic biotransformation and biosorption by planktonic cultures and biofilms. AB - AIMS: The aim of this study was to analyse arsenic (As) transformation and biosorption by indigenous As-resistant bacteria both in planktonic and biofilm modes of growth. METHODS AND RESULTS: As-resistant bacteria were isolated from industrial waste water and strain PT2, and identified as Exiguobacterium profundum through 16S rRNA gene sequencing was selected for further study. As transformation and biosorption by E. profundumPT2 was determined by HPLC-ICP-MS analysis. Planktonic cultures reduced 3.73 mmol l-1 As5+ into As3+ from artificial waste water effluent after 48-h incubation. In case of biosorption, planktonic cultures and biofilms exhibited 25.2 and 29.4 mg g-1 biomass biosorption, respectively. As biosorption kinetics followed Freundlich isotherm and pseudo second-order model. Biofilm formation peaked after 3 days of incubation, and in the presence of As stress, biofilm formation was significantly affected in contrast to control (P < 0.05). Homogeneous nature of mature biofilms with an increased demand of nutrients was revealed by minimum roughness and maximum surface to biovolume ratio measured through CLSM analysis. CONCLUSION: Indigenous As-resistant E. profundumPT2 was found capable of As transformation and biosorption both in the form of planktonic cultures and biofilms. SIGNIFICANCE AND IMPACT OF THE STUDY: Indigenous biofilm forming E. profundum PT2 revealing As biosorption and biotransformation potential is presented an eco friendly and cost-effective source for As remediation that can be implemented for waste water treatment. PMID- 29130633 TI - The mitochondrial metabolic reprogramming agent trimetazidine as an 'exercise mimetic' in cachectic C26-bearing mice. AB - BACKGROUND: Cancer cachexia is characterized by muscle depletion and exercise intolerance caused by an imbalance between protein synthesis and degradation and by impaired myogenesis. Myofibre metabolic efficiency is crucial so as to assure optimal muscle function. Some drugs are able to reprogram cell metabolism and, in some cases, to enhance metabolic efficiency. Based on these premises, we chose to investigate the ability of the metabolic modulator trimetazidine (TMZ) to counteract skeletal muscle dysfunctions and wasting occurring in cancer cachexia. METHODS: For this purpose, we used mice bearing the C26 colon carcinoma as a model of cancer cachexia. Mice received 5 mg/kg TMZ (i.p.) once a day for 12 consecutive days. A forelimb grip strength test was performed and tibialis anterior, and gastrocnemius muscles were excised for analysis. Ex vivo measurement of skeletal muscle contractile properties was also performed. RESULTS: Our data showed that TMZ induces some effects typically achieved through exercise, among which is grip strength increase, an enhanced fast-to slow myofibre phenotype shift, reduced glycaemia, PGC1alpha up-regulation, oxidative metabolism, and mitochondrial biogenesis. TMZ also partially restores the myofibre cross-sectional area in C26-bearing mice, while modulation of autophagy and apoptosis were excluded as mediators of TMZ effects. CONCLUSIONS: In conclusion, our data show that TMZ acts like an 'exercise mimetic' and is able to enhance some mechanisms of adaptation to stress in cancer cachexia. This makes the modulation of the metabolism, and in particular TMZ, a suitable candidate for a therapeutic rehabilitative protocol design, particularly considering that TMZ has already been approved for clinical use. PMID- 29130636 TI - Efficacy of subcutaneous injection of platelet-rich plasma in alopecia: A clinical and histological pilot study on a rat model with a six-month long-term follow-up experience. AB - PURPOSE: To assess the potential of platelet-rich plasma (PRP) subcutaneous injection of to treat alopecia and to evaluate local toxicity. MATERIALS-METHODS: Twelve Hairless rats were used. At D0, we performed systematic clinical examination and divided the rat back into four quadrants (Q). We initiated subcutaneous injection using either PRP in PRPQ+, platelet-poor plasma (PPP) in PPPQ+, physiological serum (PS) in PSQ+, or no treatment (Q4). At D7, D14, D21, and D28 but also second month (M2), M3, M4, M5, rats had exactly the same injection procedure. Follow-up with PRP efficacy and toxicity at D28 and M6 using clinical and histological evaluation was performed. RESULTS: Hair density was significantly improved at D28 and at M6 for PRPQ+ vs PSQ+ (respectively, P = .0156 and P = .0313), PPPQ+ (respectively, P = .042 and P = .046). Significant histological improvement was observed between D28 and M6, for PRPQ+ vs PPPQ+ and PSQ+ for vessels (respectively, P = .0160 and P = .021), collagen (respectively, P = .0036 and P = .032), and epithelium (respectively, P = .0138 and P = .022) with no local toxicity. CONCLUSION: Our study suggests that subcutaneous PRP injections using controlled concentration of platelets and leukocytes improve hair growth. PMID- 29130637 TI - How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome. AB - A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3. PMID- 29130638 TI - Thromboembolism after WATCHMANTM in a clopidogrel non-responder: A case for concern? AB - Atrial fibrillation (AF) is associated with an increased risk of stroke and thromboembolism (TE). The WATCHMANTM left atrial appendage (LAA) closure device is indicated to reduce the risk of TE from the LAA in patients with non-valvular AF. Here, we present a case of a patient with device-related thrombus who suffered a TE event two months after WATCHMANTM LAA closure and two weeks after switching from aspirin plus warfarin to aspirin plus clopidogrel therapy. Laboratory investigation identified the patient to be hypercoagulable and to be a non-responder to clopidogrel therapy. We discuss the potential role of platelet function testing to prevent device-related thrombi. PMID- 29130639 TI - Calvarial mass as a presenting feature of neurofibromatosis type 2 in a pediatric patient. PMID- 29130640 TI - Asthma prevalence trends by weight status among US children aged 2-19 years, 1988 2014. AB - BACKGROUND: Obesity is a risk factor for asthma. However, it is unclear if increased obesity prevalence contributed to rising childhood asthma prevalence. OBJECTIVE: To assess if population-level changes in weight status impacted asthma prevalence over time. METHODS: Using nationally representative 1988-2014 National Health and Nutrition Examination Survey data for 40 644 children aged 2-19 years, we analyzed asthma trends by weight status (body mass index age-specific percentiles determined using measured weight and height). Logistic regression and population attributable fraction were used to assess the association between obesity and asthma prevalence. RESULTS: Although obesity was a risk factor for asthma throughout the period, asthma prevalence increased only among children with normal weight; there was no interaction between weight status and time. The population attributable fraction for overweight/obesity rose from 8.5% in 1988 1994 to 11.9% in 2011-2014, but this increase was not significant (P = 0.44). CONCLUSIONS: Together, these data do not support a contribution of obesity trends to asthma prevalence trends. PMID- 29130641 TI - UNBS5162 inhibits the proliferation of human A549 non-small-cell lung cancer cells by promoting apoptosis. AB - BACKGROUND: Lung cancer is one of the most frequently diagnosed malignancies in the world, thus developing novel anticancer reagents for lung cancer treatment is critical. METHODS: We performed cell counting kit-8 and cell colony formation assays to investigate the role of UNBS5162 in the proliferation of A549 cells. Invasion and migration assays were applied to study the inhibitory effect of UNBS5162 on non-small cell lung cancer cells. To detect the effect of UNBS5162 on A549 cell apoptosis, Annexin-V fluorescein isothiocyanate and propidium iodide staining methods were used. Protein expression was analyzed using Western blot assay. RESULTS: UNBS5162 not only inhibited proliferation but also decreased invasion and migration in A549 cells. Most cells were intact (96.93%) under control conditions, but the number of intact cells decreased (84.8%) after 24 hours of treatment with UNBS5162, and the number of early and late apoptotic cells significantly increased (P < 0.05). Anti-apoptotic protein Bcl-2 expression in the UNBS5162 group was significantly decreased (P < 0.05), and expression of proapoptotic proteins Bim, Bax, and active caspase-3 were significantly increased (P < 0.05) compared to the control. In the PI3K signaling pathway, phospo-AKT and phospo-mTOR levels were significantly decreased (P < 0.05), while S6K and Cyclin D1 protein levels were significantly decreased in UNBS5162 treated A549 cells (P < 0.05). CONCLUSION: These findings suggest that UNBS5162 could inhibit A549 cell proliferation and metastasis by inhibiting PI3K pathway mediated apoptosis. PMID- 29130643 TI - Pilot study on preventing anastomotic leakage in stapled gastroesophageal anastomosis. AB - BACKGROUND: This study explored how to improve the surgical technique to reduce or avoid anastomotic leakage. METHODS: From January 2012 to December 2016, 101 consecutive patients with cancer of the esophagus or gastroesophageal junction underwent stapled gastroesophageal anastomosis. The procedure included creating a tube-type stomach, fixing an inserted anvil, inspecting mucosa-to-mucosa alignment in the lumen under direct vision after firing the stapler, and, if found, manually repairing a rupture of the mucous membrane of the anastomosis. RESULTS: A rupture of the mucous membrane of the anastomosis was found in four out of the 101 patients and manually repaired. No postsurgical anastomotic leakage occurred. All patients recovered well and the average postoperative stay was 10.4 days. There was no mortality within 30 days after surgery. CONCLUSION: It is critical to inspect the integrality of the luminal mucous membrane of the anastomosis under direct vision in order to prevent anastomotic leakage in surgical resection of esophageal and gastroesophageal junction malignancies. PMID- 29130642 TI - Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner. AB - Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide resistant (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance. By assessing genome-wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD resistance is associated with an increase in genome-wide DNA methylation and an even greater reduction in chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD-resistant cell lines. Moreover, we show that these changes are potentially reversible, as combination of 5-azacytidine and EPZ-6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl transferases and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs. PMID- 29130645 TI - Distributed decision making in action: diagnostic imaging investigations within the bigger picture. AB - INTRODUCTION: Decision making in the health care system - specifically with regard to diagnostic imaging investigations - occurs at multiple levels. Professional role players from various backgrounds are involved in making these decisions, from the point of referral to the outcomes of the imaging investigation. The aim of this study was to map the decision-making processes and pathways involved when patients are referred for diagnostic imaging investigations and to explore distributed decision-making events at the points of contact with patients within a health care system. METHOD: A two-phased qualitative study was conducted in an academic public health complex with the district hospital as entry point. The first phase included case studies of 24 conveniently selected patients, and the second phase involved 12 focus group interviews with health care providers. Data analysis was based on Rapley's interpretation of decision making as being distributed across time, situations and actions, and including different role players and technologies. RESULTS: Clinical decisions incorporating imaging investigations are distributed across the three vital points of contact or decision-making events, namely the initial patient consultation, the diagnostic imaging investigation and the post investigation consultation. Each of these decision-making events is made up of a sequence of discrete decision-making moments based on the transfer of retrospective, current and prospective information and its transformation into knowledge. CONCLUSION: This paper contributes to the understanding of the microstructural processes (the 'when' and 'where') involved in the distribution of decisions related to imaging investigations. It also highlights the interdependency in decision-making events of medical and non-medical providers within a single medical encounter. PMID- 29130644 TI - Progress towards the United Nations 90-90-90 and 95-95-95 targets: the experience in British Columbia, Canada. AB - INTRODUCTION: Antiretroviral therapy (ART) scale-up is central to the global strategy to control the HIV/AIDS pandemic. To accelerate efforts towards ending the AIDS epidemic, the Joint United Nations Programme on HIV/AIDS released the 90 90-90 and 95-95-95 targets, which have recently been approved by the United Nations (UN). This study characterizes the province of British Columbia (BC)'s progress towards achieving the UN targets, predicts a trajectory up to 2030 according to each of the individual steps (i.e. %Diagnosed, %On ART and %Virologically Suppressed), and identifies the population sub-groups at higher risk of not achieving these targets. METHODS: The analyses were based on linked individual-level datasets of people living with HIV (PLWH) in BC, aged >=18 months, from 2000 to 2013. Using past trends in HIV prevalence and of each individual UN targets, we forecasted these outcomes until 2030 via generalized additive models. We ran a second set of analyses to assess the associations between individual demographic and behavioural factors and each of the individual steps of the UN targets. Lastly, we performed sensitivity analyses to account for uncertainty associated with prevalence estimates and suppression definitions. RESULTS: Among the estimated 10666 PLWH in BC in 2013, 82% were diagnosed, 76% of those diagnosed were on ART and 83% of those on ART were virologically suppressed. We identified that females, PLWH aged <30 years and those with unknown risk or who self-identify as having a history of injection drug use were the population subgroups that experienced the most challenge in engaging on ART and achieving viral suppression. Our model projections suggest that BC will achieve 90%-91%-90% and 97%-99%-97% by 2020 and 2030 respectively. CONCLUSIONS: As we approach 2020, BC is rapidly moving towards achieving the UN targets. However, region-specific challenges persist. Identification of remaining regional challenges will be essential to achieving the proposed UN targets and therefore fulfilling the promise to end AIDS as a pandemic by 2030. PMID- 29130646 TI - Investigating the expression of MMPs and TIMPs in preterm placenta and role of CpG methylation in regulating MMP-9 expression. AB - Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are crucial to the processes of normal labor and parturition. We have previously reported aberrant protein levels of MMPs in placenta of women delivering preterm as compared to term. In this study, we examine the mRNA levels of MMPs (MMP-1, MMP-2, and MMP-9) and TIMPs (TIMP-1, TIMP-2) in the placenta from women delivering preterm as compared with term and further study the promoter DNA methylation of the MMP-9 gene in a sub-sample of term and preterm placentae. A total of 110 women were included in the study; 56 delivered term and 54 delivered preterm. MMP and TIMP mRNA levels were determined by Taqman-based qPCR. Promoter CpG methylation of MMP-9 gene was studied on a subset of 10 term and 8 preterm placenta using Epitect Methyl-II PCR assay kit. The mRNA levels of MMP-1,-2 were higher and those of TIMP-1,-2 were lower in the placentae of women delivering preterm. MMP-9 levels were comparable between the two groups. Among women undergoing spontaneous vaginal deliveries, higher mRNA levels of MMP-1, -2 and -9 were seen in the placentae of those delivering preterm as compared to term. Similar results were seen in women undergoing preterm labor as compared to term. MMP-9 gene promoter was hypomethylated in preterm placenta as compared to term placenta, while the mRNA levels were comparable between the two groups. The observed imbalance between MMP and TIMP expression may have prematurely triggered the signaling cascade leading to preterm birth. (c) 2017 IUBMB Life, 69(12):985 993, 2017. PMID- 29130648 TI - Emergent percutaneous therapy for left ventricular assist device retrograde flow. AB - With the number of heart transplants being performed each year stagnating due to lack of donors the left ventricular assist device (LVAD) patient population will continue to grow. As more and more patients are living longer with LVADs, either as a bridge to transplant or destination therapy, we will continue to see an increased number of complications related to assist device therapy. One of the common challenges physicians face are patients who suffer from both bleeding and thrombotic complications. When bleeding complications occur anticoagulation is usually reduced or discontinued and then the thrombosis risk increases. Once a pump thrombosis occurs there are limited percutaneous treatment strategies available, especially in the setting of a recent bleeding event. Surgical exchange is the only definitive therapy and that can be a high risk and difficult operation. Turning off an LVAD may become necessary, as it did in our case, but that can lead to significant retrograde flow through the device and rapid patient decline. A prompt percutaneous therapy is needed to stabilize these patients. PMID- 29130647 TI - Randomized controlled trial of electro-stimulation therapies to modulate retinal blood flow and visual function in retinitis pigmentosa. AB - PURPOSE: We examined changes in visual function and ocular and retinal blood flow (RBF) among retinitis pigmentosa (RP) participants in a randomized controlled trial of electro-stimulation therapies. METHODS: Twenty-one RP participants were randomized (1:1:1) to transcorneal electrical stimulation (TES) at 6 weekly half hour sessions, electro-acupuncture or inactive laser acupuncture (sham control) at 10 half-hour sessions over 2 weeks. Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA), quick contrast sensitivity function, Goldmann visual fields, AdaptDx scotopic sensitivity, spectral flow and colour Doppler imaging of the central retinal artery (CRA), and RBF in macular capillaries were measured twice pre-treatment, after 2 TES sessions, within a week and a month after intervention completion. RESULTS: We measured a significant improvement in retrobulbar CRA mean flow velocity for both the TES (p = 0.038) and electro acupuncture groups (p = 0.001) on average after 2 weeks of treatment when compared to sham controls. Transcorneal electrical simulation (TES) and electro acupuncture subjects had significant 55% and 34% greater increases, respectively, in RBF in the macular vessels when compared to sham controls (p < 0.001; p = 0.008) within a week of completing six TES sessions or a month after electro acupuncture. There was a significant difference in the proportion of eyes that had improved visual function when comparing the three intervention groups (p = 0.038): four of seven TES subjects (57%), two of seven electro-acupuncture subjects (29%) and none of the seven control subjects (0%) had a significant visual improvement outside of typical test-retest variability at two consecutive post-treatment visits. CONCLUSION: Increased blood flow following electro stimulation therapies is an objective, physiological change that occurred in addition to visual function improvements in some RP patients. PMID- 29130649 TI - Sino-Nasal Outcome Test-22 quality-of-life patterns in patients presenting with nasal septal perforation. AB - OBJECTIVES: To assess the impact of nasal septal perforation (NSP) on quality of life. DESIGN: Retrospective cohort study. SETTING: Rhinology clinics from two hospitals in Liverpool, United Kingdom. PARTICIPANTS: Patients diagnosed with NSP. MAIN OUTCOME MEASURES: Patients (n = 26) diagnosed with NSP completed the Sino-Nasal Outcome Test-22 (SNOT-22). The collated data were compared with SNOT 22 scores from a cohort of healthy volunteers (n = 34) and a cohort of patients (n = 30) diagnosed with chronic rhinosinusitis (CRS). RESULTS: The mean total SNOT-22 score of NSP and CRS cohorts was higher than that observed in healthy volunteers. The mean total SNOT-22 score in the CRS cohort (57.2, standard deviation SD 10.3) was the higher than NSP (50.2, SD 23.5), although this difference did not achieve statistical significance. The mean score for the rhinologic-specific domains (rhinologic symptoms, extranasal rhinologic symptoms), ear/facial symptoms and psychological dysfunction domain was higher in the CRS cohort compared to NSP, although statistical significance was only observed in the extranasal rhinologic symptoms domain (11.2, SD 2.4 vs 6.4, SD 4.1). Conversely, the mean sleep dysfunction domain score for NSP (12.7, SD 7.5) was higher than CRS (10.0, SD 4.9, respectively) although this was not statistically significant. CONCLUSIONS: This study has assessed the clinimetric and psychometric properties of patients suffering from symptomatic NSP. Future reports should consider inclusion of SNOT-22 data but with the addition of perforation-specific symptoms (nasal crusting, epistaxis, whistling noise). PMID- 29130650 TI - Coming of age: A time for transition. PMID- 29130651 TI - Further delineation of the GDF6 related multiple synostoses syndrome. AB - A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome. PMID- 29130652 TI - Ginsenoside Rb1 improves leptin sensitivity in the prefrontal cortex in obese mice. AB - AIM: Obesity impairs leptin-induced regulation of brain-derived neurotrophic factor (BDNF) expression and synaptogenesis, which has been considered to be associated with the incidence of neuronal degenerative diseases, cognitive decline, and depression. Ginsenoside Rb1 (Rb1), a major bioactive component of ginseng, is known to have an antiobesity effect and improve cognition. This study examined whether Rb1 can improve central leptin effects on BDNF expression and synaptogenesis in the prefrontal cortex during obesity using an in vivo and an in vitro model. RESULT: Ginsenoside Rb1 (Rb1) chronic treatment improved central leptin sensitivity, leptin-JAK2-STAT3 signaling, and leptin-induced regulation of BDNF expression in the prefrontal cortex of high-fat diet-induced obese mice. In cultured prefrontal cortical neurons, palmitic acid, the saturated fat, impaired leptin-induced BDNF expression, reduced the immunoreactivity and mRNA expression of synaptic proteins, and impaired leptin-induced neurite outgrowth and synaptogenesis. Importantly, Rb1 significantly prevented these pernicious effects induced by palmitic acid. CONCLUSION: These results indicate that Rb1 reverses central leptin resistance and improves leptin-BDNF-neurite outgrowth and synaptogenesis in the prefrontal cortical neurons. Thus, Rb1 supplementation may be a beneficial avenue to treat obesity-associated neurodegenerative disorders. PMID- 29130653 TI - [Advances in Diagnosis and Treatment of Posterior Distal Injury of Pelvic Fracture]. AB - Pelvic fracture is one of the common diseases of traumatic orthopedics. With the increase of accidents such as traffic accidents,high craters and crush injuries in China,the incidence of pelvic fractures is also increasing year by year. Since pelvic bones and the ligament structure are close to neurovascular,cavity organs and the urogenital structure,early diagnosis and treatment of pelvic fractures is essential for preventing early complications and late sequelae. The treatment of pelvic ring injury has been the focus of pelvic fracture treatment,which determines the outcome of treatment. The application of external fixation and internal fixation to pelvic fracture is still subject to ongoing debate. For unstable pelvic ring injury,emergency external fixation plays a very important role. Pelvic ring injury is often accompanied with nerve injury (lumbosacral plexus injury),which often leads to pain,dysfunction and other complications. Because of its refractory,extensive studies have been undertaken to identify clinical innovations that may be able to repair nerve damage and reduce complications. These research advances can help improve the diagnosis and treatment of pelvic fractures and patient survival and prognosis. PMID- 29130654 TI - [Classification and Treatment of Sacroiliac Joint Dislocation]. AB - OBJECTIVE: To develop a renewed classification and treatment regimen for sacroiliac joint dislocation. METHODS: According to the direction of dislocation of sacroiliac joint,combined iliac,sacral fractures,and fracture morphology,sacroiliac joint dislocation was classified into 4 types. Type I (sacroiliac anterior dislocation): main fracture fragments of posterior iliac wing dislocated in front of sacroiliac joint. Type II (sacroiliac posterior dislocation): main fracture fragments of posterior iliac wing dislocated in posterior of sacroiliac joint. Type III (Crescent fracturedislocation of the sacroiliac joint): upward dislocation of posterior iliac wing with oblique fracture through posterior iliac wing. Type IIIA: a large crescent fragment and dislocation comprises no more than onethird of sacroiliac joint,which is typically inferior. Type IIIB: intermediatesize crescent fragment and dislocation comprises between one and twothirds of joint. Type IIIC: a small crescent fragment where dislocation comprises most,but not the entire joint. Different treatment regimens were selected for different types of fractures. Treatment for type I sacroiliac joint dislocation: anterior iliac fossa approach pry stripping reset; sacroiliac joint fixed with sacroiliac screw through percutaneous. Treatment for type II sacroiliac joint dislocation: posterior sacroiliac joint posterior approach; sacroiliac joint fixed with sacroiliac screw under computer guidance. Treatment for type IIIA and IIIB sacroiliac joint dislocation: posterior sacroiliac joint approach; sacroiliac joint fixed with reconstruction plate. Treatment for type IIIC sacroiliac joint dislocation: sacroiliac joint closed reduction; sacroiliac joint fixed with sacroiliac screw through percutaneous. Treatment for type IV sacroiliac joint dislocation: posterior approach; sacroiliac joint fixed with spinal pelvic fixation. RESULTS: Results of 24 to 72 months patient follow-up (mean 34.5 months): 100% survival,100% wound healing,and 100% fracture healing. Two cases were identified as type I sacroiliac joint dislocation,including one with coexistence of nerve injury. Patients recovered completely 12 months after surgery. Eight cases were identified as type II sacroiliac joint dislocation; none had obvious nerve injury during treatments. Twelve cases were identified as type III sacroiliac joint dislocation,including one with coexistence of nerve injury. Patients recovered completely 12 months after surgery. Three cases were identified as type IV sacroiliac joint dislocation with coexistence of nerve injury. Two patients fully recovered 12 months after surgery. One had partial recovery of neurological function. CONCLUSION: The classification and treatment regimen for sacroiliac joint dislocation have achieved better therapeutic effect,which is worth promoting. PMID- 29130655 TI - [Efficacy of Sacroiliac Joint Anterior Approach with Double Reconstruction Plate and Computer Assisted Navigation Percutaneous Sacroiliac Screw for Treating Tile C1 Pelvic Fractures]. AB - OBJECTIVE: To compare the efficacy of sacroiliac joint anterior approach with double reconstruction plate and computer assisted navigation percutaneous sacroiliac screw for treating Tile C1 pelvic fractures. METHODS: Fifty patients with pelvic Tile C1 fractures were randomly divided into two groups ( n=25 for each) in the orthopedic department of West China Hospital of Sichuan University from December 2012 to November 2014. Patients in group A were treated by sacroiliac joint dislocation with anterior plate fixation. Patients in group B were treated with computerized navigation for percutaneous sacroiliac screw. The operation duration,intraoperative blood loss,incision length,and postoperative complications (nausea,vomiting,pulmonary infection,wound complications,etc.) were compared between the two groups. The postoperative fracture healing time,postoperative patient satisfaction,and postoperative fractures MATTA scores (to evaluate fracture reduction),postoperative MAJEED function scores,and SF36 scores of the patients were also recorded and compared. RESULTS: No significant differences in baseline characteristics were found between the two groups of patients. All of the patients in both groups had their operations successfully completed. Patients in group B had significantly shorter operations and lower intraoperative blood loss,incision length and postoperative complications than those in group A ( P<0.05). Patients in group B also had higher levels of satisfaction than those in group A ( P<0.05). No significant differences were found between the two groups in postoperative followup time,fracture healing time,postoperative MATTA scores,postoperative MAJEED function scores and SF36 scores ( P>0.05). CONCLUSION: Sacroiliac joint anterior approach with double reconstruction plate and computer assisted navigation percutaneous sacroiliac screws are both effective for treating Tile C1type pelvic fractures,with similar longterm efficacies. However,computer assisted navigation percutaneous sacroiliac screw has the advantages of less trauma,less bleeding,and quicker. PMID- 29130656 TI - [Design of Minimal Invasive Screw on Posterior Pelvis Ring and Pelvic Finite Element Analysis]. AB - OBJECTIVE: To design minimal invasive screw on posterior pelvic ring and perform threedimensional finite element analysis based on a pelvis finite element model. METHODS: We measured the pelvic anatomical data of 20 healthy volunteers and identified potential designs for minimal invasive screw on posterior pelvic ring. A finite element model of pelvis was then established. Threedimensional finite element analyses were performed under static and dynamic mechanical loading,respectively. RESULTS: Three screw tracks on ilium (A,B and C) were identified based on a threedimensional reconstruction of pelvis. Nail track B and C had greater length and width,but shorter distance between nailing and soft tissue compared with nail track A. Static loading under an external rotation load of 500 N generated a maximum Mises Von stress of 582.05 Pa and sacral iliac complex of 107.38 Pa. The greatest strain was located at the articular cartilage on the side of the nail,followed by lateral sacral joint cartilage and symphysis pubis. The largest displacement was located at the ilium on the side of the nail,with a gradient decrease to the opposite side. The largest displacement of the anterior superior iliac spine was 0.35 cm on the side of the nail. The dynamic loading identified displacement of the anterior superior iliac spine with 1.5 mm in Z axis,1.8 mm in X axis and -0.2 mm in Y axis; and displacement of the pubic bone with 0.8 mm in Z axis,1.0 mm in X axis and 0.03 mm in Y axis. The maximum displacement appeared along the impact direction: Y axis. Relatively large equivalent stress was found in pubis and ischium,anterior superior iliac spine,sacrum,acetabular that are prone to fracture. With increased impact force,the stress of pelvis increased over time. The maximum impact force,stress and displacement of the pelvis occurred at 10 ms when peak force was reached. Under the impact of 4 000 N and 5 000 N,the bone was subject to a stress level of over 200 MPa,exceeding its average yield strength,which suggests a possibility of pelvic fracture. CONCLUSION: Taking B/C as a main screw track and A as an auxiliary screw track is a reasonable choice. The pelvic finite element model lays a foundation for further studies into sacral fracture and design of screw tracks. PMID- 29130657 TI - [Comparison of USS Combined with Sacroiliac Screw and CMAS Iliosacral Fixation in the Treatment of Unstable Sacral Fracture]. AB - OBJECTIVE: To compare the effectiveness of two lumbopelvic fixation procedures for treating unstable sacral fractures. METHODS: The clinical data of 47 patients were treated for unstable sacral fractures in the West China Hospital of Sichuan University from January 2010 to December 2014 were reviewed. Twentytwo patients (28 sides) were treated with USS combined with iliosacral screw (group A),while 25 patients (39 sides) were treated with closed multiaxial screws (CMAS) iliosacral fixation system combined with Posterior Segmental Spinal Fixation system (group B). The outcomes of the two procedures were compared using the following indicators: length of operations,amount of intraoperative blood loss,MATTA score of fracture reduction,MAJEED function score one year postoperation,postoperative complications,and GIBBONS Classification of sacral nerve injury in patients with sacral nerve symptoms. RESULTS: Group A had longer operations [(121.4+/-5.1) min] than group B [(110.6+/-4.5) min, P<0.05]. Group A had larger intraoperative blood loss [(618+/-45) mL] than group B [(570+/-40) mL, P<0.05]. Both groups had two cases of wound infection after operations that were cured by debridement and antibiotic therapy. According to the MATTA scoring criteria,group A had 92.9% excellent and good fracture reduction,compared with 97.5% in group B ( P<0.05). According to the MAJEED functional scoring criteria,group A had 86.4% excellent and good clinical functions,compared with 92.0% in group A ( P<0.05). The GIBBONS criteria indicated that neurological functions of both groups improved significantly after operations ( P<0.05),but no significant difference appeared between the two groups ( P>0.05). CONCLUSION: CMAS iliosacral fixation system is better for treating unstable sacral fractures compared with USS combined with iliosacral screws. PMID- 29130658 TI - [Vein Nerve Conduit Supported by Vascular Stent in the Regeneration of Peripheral Nerve in Rabbits]. AB - OBJECTIVE: To evaluate the effectiveness of autologous vein nerve conduit supported by vascular stent in repairing a 10 mm gap peroneal nerve in white New Zealand rabbits. METHODS: 30 New Zealand rabbits were randomly divided into three groups: autologous nerve group (group A),conventional autologous vein nerve conduit group (group B),autologous vein nerve conduit supported by vascular stent group (group C). 10 mm common peroneal nerve was cut off. In groups A,the peroneal nerve was turned 180 degrees before suturing. In group B and group C,20 mm long external jugular vein was cut and removed. After dilution of venous retraction,the venous bridge filled the gap of the nerve defect in group B. In group C,a blood vessel stent was placed for accessing the external jugular vein,and then connected to the nerve defect. Ulnar ulcer was observed after operations. Reflex score of left foot toe was recorded. The nerve regeneration and functional recovery was assessed through electrophysiological examinations,comparison of wet mass ratio between the left and right hind limb gastrocnemius,morphological observations,transmission electron microscopy 12 weeks after operations. RESULTS: Group B had the lowest scoring of toespreading reflex,whereas Group A had the highest scoring of toespreading reflex. There was a statistically significant difference in the scoring of toespreading reflex between group A and group C. In terms of the diameter of regenerated nerve fiber and the thickness of regenerated myelin sheath,no statistically significant ( P>0.05) difference was found between group A and group C,whereas the difference was significant ( P<0.05) between groups A/C and group B. The presence of peripheral nerves found in light microscopic examinations revealed normal characteristics of myelinated fibers in all groups. The myelinated axon profile was almost equal between group B and group C under electron microscopic examinations. However,more degenerated axons with disturbed contoursin were found in group B compared with group C. CONCLUSION: Autologous vein nerve conduit supported by vascular stent increases regeneration of nerves. PMID- 29130659 TI - [DNA Repair Function and Mutation of an H2B Monoubiquitination Factor WDR70 in Ovarian Cancer]. AB - OBJECTIVE: To investigate the roles of enzyme DCAF proteinDNA damagebinding protein 1 (DDB1)/cullin4 (CRL4) complex family members CRL4WD40 repeat domain protein 70 (WDR70) in DNA repair process and its mutation in ovarian cancer. METHODS: Immunofluorescent assay was employed to measure H2AX (gammaH2AX) and phosphorylated replication protein A2 (RPA32) formed in siDDB1 or siWDR70 ovarian cancer cells after the treatments of chemical medicine and radioactive threapy. 5Brdu immunohistochemical staining was used to explore the function of WDR70 in DNA replication. The expressions of WDR70 and histone protein H2B monoubiquitination (uH2B) was measured by immunohistochemistry,the function of DNA repair,expression and mutations of CRL4 in ovarian cancer were detected by semiquantitative PCR and DNA sequencing. RESULTS: Immunofluorescent assay indicated that distinct subunits of CRL4 played different roles in checkpoint activation and H2Bmonoubiquitinationdepedendent homologous recombination,while the scaffold subunit DDB1 participated in both processes,WDR70 was only required for DNA end resection,chromatin loading of RPA32 and HR. The dose of WDR70 was not effect on DNA replication. Ovarian cancer had different expression of WDR70 and uH2B compared with normal tissue,transcripts of WDR70 was diminished or truncated in 50% of ovarian cancer,which corresponded to multiple mutations. CONCLUSION: CRL4 ubiquitin ligase plays multiple roles in DNA repair and is critical for genome stability. It may be an potential anticancer barrier against ovarian malignancies. PMID- 29130660 TI - [Viability of Colon Tumor Cells in Insufficient-nutritional Condition is Reduced by MiR-133b Through Regulating Expression of GSTP1]. AB - OBJECTIVE: To determine the expression level of GSTP1 in colon tumor tissues at different stages and the effects of GSTP1 expression on colon tumor cells,and to identify miR that regulate the expression of GSTP1. METHODS: Realtime PCR and western blot were used to detect the expression level of GSTP1 in colon tumor tissues. pcDNA3.1GSTP1 was constructed and transfected into human colon tumor cell line HCT116. The apoptosis rate and viability of HCT116 were measured. TargetScan and MicroCosm Targets programs were used to measure GSTP1 3'UTR and identify GSTP1targeting miR. pGL3GSTP13'UTR was constructed and transfected with the selected miR into human kidney epithelial cell line HEK293. Dualluciferase reporter assay were performed to detect the regulation effect of the selected miR on GSTP1 expressions. The selected miR was transfected into HCT116,and their levels of GSTP1 expression and reactive oxygen species (ROS) were measured. The selected miR and pcDNA3.1GSTP1 were then transfected together into HCT116. The viability and ROS level of the transfected cells were measured. RESULTS: The expression levels of GSTP1 increased in colon tumor tissues at all stages. Overexpression of GSTP1 decreased apoptosis and increased viability of HCT116 in insufficientnutritional condition. miR133b could target GSTP1 3'UTR and repressively regulate GSTP1 expressions in HCT116. The overexpression of miR133b rapidly decreased viability and increased ROS level in HCT116 in insufficientnutritional condition. But such effects were absent in normal nutritional condition. In addition,in insufficient nutrition condition,when the HCT116 overexpress miR133b and GSTP1 at the same time,the extent of viability decrease and ROS level increase are shortened. CONCLUSION: In insufficientnutritional condition,miR133b decreases viability of colon tumor cells by repressively regulating GSTP1 expressions. PMID- 29130661 TI - [Effects of Genistein on Whole Genome Expression Profiles of Mice Testes Tissue Cultured in vitro]. AB - OBJECTIVE: To investigate the effects of Genistein (Gen) on the whole expression profiles of testes in mice by using the gene chip technology,and analyze the mechanism how Gen exerts testis on gene level. METHODS: The testicular tissues of suckling mice were cultured in vitro,and separated into control group and Gen group with the dose of 5 MUmol/L. After 72 h of culture,we extracted the total RNA and purified it,then detected the gene expression by using Agilent gene array. RESULTS: Compared with the control,there were 84 genes expressed differently in Gen group,including 47 upregulated genes and 37 downregulated genes. We classified these genes as 14 categories in Gen group by GO ( P<0.05),including cell proliferation,cell death,the immune system and reproductive development. CONCLUSION: The whole gene chip test found that Gen can mainly affect the functions of testes by regulating the expression of gene related to cell development,proliferation and cell cycle function, which can influence the spermatogenesis and change the testis cell proliferation and apoptosis. PMID- 29130662 TI - [The Role of Bone Morphogenic Protein-4 in the Progression of Vein Graft Hyperplastic Remodeling under Hyperglycemic Condition]. AB - OBJECTIVE: This study was designed to assess the vessel wall characteristics and the expression levels of bone morphogenic protein4(BMP4) and proliferating cell antigen Ki67 in vein grafts harvested from diabetic rats,and to investigate the role of BMP4 in progression of vein graft hyperplastic remodeling under hyperglycemic condition. METHODS: 48 male SpragueDawky rats [body mass (194+/-16) g] aged 8 weeks were randomly divided into diabetes mellitus (DM) group ( n=24) and nondiabetes mellitus (NDM) group ( n=24). The DM rats were induced by streptozotocin in combination with highsugar and highfat diet. The unilateral external jugular vein was interposition grafted into the common carotid arteries in the two groups. The vein grafts were harvested at preoperatively and 1,2 and 4 weeks postoperatively ( n=6) in each group. The morphological characteristics of the venous graft wall were evaluated by hematoxylineosin staining,and the expression levels and the distribution of Ki67 and BMP4 were assessed by immunohistochemistry analysis,then the expression of BMP4 gene and protein was measured by realtime polymerase chain reaction (RTPCR) and Western blot assay respectively. RESULTS: In the progression of rats vein grafts hyperplastic remodeling,the venous wall thickness of rats thickened with time increasing,and the intimal and medial thickness of the vein grafts harvested from DM rats were significantly higher than those from NDM rats at the same time postoperatively ( P<0.05). Ki-67 was highly xpressed in smooth muscle cells nucleus located in the rats vein grafts,and its expression level was up-regulated gradually in the progression of vein graft failure,and the Ki 67 positive cells of vein grafts from DM rats were significantly higher than those from NDM controls at the same period ( P<0.05). Immunohistochemistry analysis showed that BMP4 was expressed in smooth muscle cells cytoplasmof the rats vein grafts,combined with the results of RT-PCR and Western blot assay,there was a little BMP4 expression could be seen in venous wall of NDM rats,while BMP4 positive cells and the expression level of BMP4 gene and protein from DM rats vein grafts was increasing with obvious time dependence and significantly higher than the NDM rats ( P<0.05). CONCLUSION: The morphological and pathological changes within the venous wall were significantly correlated with the high expression levels of BMP4 in vein grafts harvested from diabetic rats,implying a potential role of BMP4 in the progression of accelerated vein graft failure under hyperglycemic condition. PMID- 29130663 TI - [Capsaicin Alleviate Myocardial Ischemia Reperfusion Injury Through Attenuating Mitochondrial Oxidative Stress]. AB - OBJECTIVE: To investigate the role of capsaicin (CAP) in myocardial ischemia reperfusion injury and its underlying mechanisms. METHODS: Twentyfour adult male SD rats were randomized into 4 groups,namely the control group,ischemia reperfusion group,ischemia reperfusion with CAP group,and ischemia reperfusion with CAPZ and CAP group. Isolated rat hearts underwent Langendorff perfusion. Left ventricular enddiastolic pressure (LVEDP) andleft ventricular developed pressure (LVDP) was calculated to evaluate myocardial performance at 30 min of reperfusion.Triphenyltetrazolium chloride staining was used to measure the infarct size of myocardium at 120 min reperfusion. The morphological changes in myocardial fiber was analyzed by HE staining at the end of reperfusion. Lactate dehydrogenase (LDH) content in the coronary flow was determined during the first 5 min reperfusion. The myocardial mitochondria was isolated and extracted for measuring a series of indicators of mitochondrial oxidative stress,including superoxide dismutase (SOD),methane dicarboxylic aldehyde (MDA) at the end of reperfusion. Western blot was used to determine the expression of caspase3 and cytochrome c at 10 min reperfusion. RESULTS: Compared with the control group,IR group significantly decreased in cardiac function,the level of LVDP and SOD activity and induced an enlarged infarct size ( P<0.01),accompanied by the disordered arrangement of myocardial cells,the content of MDA was increased ( P<0.01),the content of caspase3 and cytochrome c were also upregulated ( P<0.01).10 MUmol/L CAP significantly attenuated these effects induced by ischemia reperfusion injury,levels of LVDP and infarct size at the end of reperfusion were significantly improved( P<0.01),nevertheless levels of LVEDP and MDA at the end of reperfusion and LDH were down-regulated markedly ( P<0.01),the content of caspase-3 and cytochrome c were also decreased ( P<0.01). CONCLUSION: These results demonstrate that CAP can suppresses cell apoptosis and necrosis,and alleviate heart function and cell survival from ischemia reperfusion injury through attenuating mitochondrial oxidative stress. PMID- 29130664 TI - [Prediction Value of TWEAK/Fn14 in Crohn's Disease with Intestinal Fibrosis]. AB - OBJECTIVE: To investigate the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/ fibroblast growth factorinducible 14 (Fn14) in the serum and colon tissue of Crohn's disease (CD) and to elucidate whether the expression of TWEAK/Fn14 can be used as an indicator for intestinal fibrosis. METHODS: Blood samples from 67 CD patients and 33 healthy controls were collected to measure the level of TWEAK by ELISA. Meanwhile,colon samples from 29 CD patients received colectomy and the normal colon tissues from 15 patients with colon cancer were included. The expression of TWEAK and Fn14 in colon samples was analyzed by immunohistochemistry (IHC). The number of the cells with Fn14,alphasmooth muscle actin (alphaSMA) double positive was measured by immunofluorescent double staining. RESULTS: The level of serum TWEAK in CD patients was higher than that in healthy controls ( P<0.01),which was positive correlated with colectomy ( r=0.295, P=0.015),intestinal stenosis ( r=0.290, P=0.017) and intestinal obstruction ( r=0.453,P=0.000 1). ROC analysis displayed the area under the curve of serum TWEAK for predicting intestinal stenosis in CD patients was 0.67 (95%CI 0.540.80, P=0.020). IHC results showed that the expression of TWEAK and Fn14 were increased in colon samples from CD patients with intestinal obstruction ( P<0.05). The number of Fn14 and alphaSMA positive cells was significantly increased in CD patients with intestinal obstruction ( P<0.05). CONCLUSION: TWEAK/Fn14 pathway may play an important role in CD related intestinal fibrosis. PMID- 29130665 TI - [Effects and Its Mechanism of IGF-1R on the Synthesis of Hyaluronic Acid in Orbital Fibroblasts of Thyroid Associated Ophthalmopathy]. AB - OBJECTIVE: To explore the effects of insulin-like growth factor1 (IGF1) receptor (IGF1R) on the synthesis of hyaluronic acid (HA) in orbital fibroblasts of thyroid associated ophthalmopathy (TAO) and its signal pathway. METHODS: Orbital fibroblasts were harvested from TAO ( n=19) and normal control ( n=5),then were primary cultured and treated with recombinant human IGF1 in different concentrations. Before the treatment of IGF1,the cells were pretreated respectively with 1H7,LY294002 or AKT inhibitor IV for 24 h. The production of HA was measured using a commercial ELISA kit,and the synthesis of PI3K,Akt and pAkt was measured by Western blot. RESULTS: Along with the increase of recombinant human IGF1 concentration,the synthesis of HA by TAO orbital fibroblasts were increased as well,the synthesis of HA peaked at the concentration of 10 nmol/L in IGF1 in TAO group ( P<0.01). Compared with the normal control,orbital fibroblasts from TAO had the synthesis of HA increased after the treatment of IGF1 ( P<0.01). The pretreatment of 1H7 or AKT inhibitor IV significantly decreased the HA concentration in culture media ( P<0.01),while the decrease of HA synthesis in the group pretreated with LY294002 was not statistically significant ( P=0.390). IGF1 treatment increased the level of pAkt expression,but it seems no effects on PI3K and Akt expression. 1H7 and LY294002 decreased the expression of PI3K and pAkt protein,but no obvious inhibitory effect on total Akt protein. Akt inhibitor IV decreased the expression of PI3K,Akt and pAkt. CONCLUSION: The synthesis of HA by orbital fibroblasts could be increased in TAO,which may partially via phosphoinositide 3kinase/Akt pathway. PMID- 29130666 TI - [Application of Chromosomal Microarray Analysis for Chromosomal Abnormalities of Spontaneously Aborted Fetuses]. AB - OBJECTIVE: To evaluate the clinical significance of chromosomal microarry analysis (CMA) for detection of chromosomal abnormalities in spontaneously aborted fetuses. METHODS: Chorionic villi samples from 431 spontaneously aborted fetuses were detected on the chromosomal abnormalities by CMA in our department form September 2014 to April 2016. RESULTS: The overall success rate of CMA was 100%,and 283 cases were detected with abnormalities (65.67%). Of these 283 cases with abnormal results,126 were common aneuploidies (trisomy 13,16,18,21,22 as well as X and Y aneuploidies) (44.52%),72 were uncommon aneuploidies (25.44%),10 were composited aneuploidies (3.53%),9 were partial aneuploidies (3.18%),29 were polyploidy (10.25%),4 were mosaicism (1.41%),31 were with multiple duplications and deletions (10.96%),and 2 were microduplication/microdeletion syndromes. CONCLUSION: CMA has great advantage for the detection of chromosomal abnormalities in spontaneously aborted fetuses comparing with fluorescence in situ hybridization (FISH). It is of great clinical significance for etiological diagnosis of spontaneous abortion and guidance on reproduction. PMID- 29130667 TI - [Pregnant Outcomes of Multiparae in Women with Advanced Age (>=35 years)after the 2008 Wenchuan Earthquake]. AB - OBJECTIVE: To evaluate pregnancy outcomes of multiparae in women with advanced age (>=35 yr.) after the 2008 Wenchuan earthquake. METHODS: Clinical data of 542 pregnant women with prenatal care in Wenchuan during 20082013 were reviewed,comparing preconception conditions,pregnant rates,pregnant complications,and perinatal outcomes between those younger ( n=176) and older ( n=366) than 35 years. RESULTS: In the 542 women,622 conceptions were reported,with 517 deliveries and 522 live births. The women with advanced age had lower cumulative pregnancy rate (twoyear),higher incidence of hypertensive disorders of pregnancy,gestational diabetes,multiple pregnancy,fetal distress,low birth weight and birth defects than their younger counterparts. The younger women also had higher term live birth rate and lower miscarriage rate. But the differences showed no statistical significance. CONCLUSION: Prenatal care brings similar pregnant outcomes to multiparae in women with advance aged and younger aged. PMID- 29130668 TI - [Analysis on Clinical Characteristic and Risk Factors of Patients Coexistence of Cerebral Artery Stenosis with Unruptured Intracranial Aneurysm]. AB - OBJECTIVE: To analyze the incidence of intracranial unruptured aneurysms in patients with intracranial artery stenosis,clinical features,and investigate the risk factors for unruptured intracranial aneurysms. METHODS: Medical records from all patients performed with digital subtraction angiography (DSA) who had been treated at Peking University Third Hospital,China,from January 2012 to December 2015 were retrospectively reviewed to identify cases coexistence with cerebral artery stenosis and unruptured intracranial aneurysm. RESULTS: Of 273 patients with cerebral artery stenosis (>=50%),intracranial unruptured aneurysms was observed in 17 cases (6.23%) from age of 45 to 78,among them 8 (47.06%) were female and 9 (52.94%) were male. The incidence of unruptured intracranial aneurysm in male patients was 4.17% (9/216),and that of female was 14.4% (8/57). There was statistically significant difference between the male and female incidence of intracranial aneurysm ( P<0.05). Of these 17 patients,16 (94.12%) aneurysms were located in the internal carotid artery (ICA) system,1 (5.88%) aneurysm was located at the tip of the basilar artery. In 11 cases (64.71%),aneurysms were located at the distal of the stenotic vessels,2 (11.76%) were located at the proximal of the stenotic vessels,and 4 cases (23.53%) of which the aneurysm and stenosis were not in the same artery. Logistic multivariate analysis showed that gender was an independent risk factor for aneurysms in patients with cerebral arterial stenosis. CONCLUSION: In the intracranial artery stenosis atients,the possibility of the occurrence of the aneurysm is much higher than the general population,and women were more prominent than man. Sex is an independent risk factor for aneurysms in patients with cerebral arterial stenosis. PMID- 29130669 TI - [A Preliminary Analysis of Bifidobacterial Species Dependent Influence on the Health of the Elderly]. AB - OBJECTIVE: To analyze the species dependent effect of bifidobacteria to the heath of the middle and elderly. METHODS: Total 148 healthy volunteers living in Chengdu with 5074 years old were recruited in 2015. The blood samples were collected from them and analyzed physiologically and immunologically. The fecal bifidobacterial were also analyzed by realtime fluorescence quantitative PCR (qPCR) using 16S rRNA targeting designed gene and species specific primers. RESULTS: Bifidobacterium can be detected in feces of the elderly,the detection rate was 100%,108/g fecal. Especially,more species predominated in the infants were found the tested subjects. Bifidobacterium was positively associated with urea nitrogen ( r=0.214, P<0.05). B. adolescentis was negatively associated with body mass index (BMI) ( r=-0.311, P<0.05),while B.catenulatum was positive to BMI ( r=0.167, P<0.05). B.breve and high density lipoproteincholesterol (HDLC) were negatively correlated ( r=-0.247, P<0.05). Bifidobacterium infantis and HDLC were positively correlated ( r=0.350, P<0.05). Among tested immune parameters,only B.bifidum was found to be positive associated with IgA ( r=0.365, P<0.05). CONCLUSION: Bifidobacterium might affect the host physiologically and immunology in the species dependent manner. Keeping intestinal bifidobacteria in the ideal species composition might be one of effective ways to slow immune senescence,and promote the health of the elderly. PMID- 29130670 TI - [Risk Factors Associated with the Outcomes of Heart Valve Replacement]. AB - OBJECTIVE: To determine risk factors associated with the outcomes of heart valve replacement,especially in the patients with rheumatic heart disease (RHD). METHODS: Data were extracted from 2 696 patients who received valve replacement from August 2012 to January 2015. Spearman correlation analyses were performed to identify potential risk factors. Logistic regression models were established to determine risk factors associated with deaths and complications. RESULTS: Duration of cardiopulmonary bypass (CPB) [standard partial regression coefficient ( B')=0.418],heart function ( B'=0.344) and pulmonary hypertension ( B'=0.285) were significant predictors of deaths in hospitals. The prevalence of complications was associated with heart function ( B'=0.520),pulmonary hypertension ( B'=0.365),CPB duration ( B'=0.306),diabetes ( B'=0.129),left ventricular diameter ( B'=0.118) and pulmonary regurgitation B'=0.071). For patients with RHD,significant predictors of complications included heart function ( B'=0.578),pulmonary hypertension ( B'=0.401),CPB duration ( B'=0.305) and diabetes ( B'=0.143). Left ventricular ejection fraction was not significant in the regression models. CONCLUSION: Chronic renal failure,heart function and CPB duration are associated with postoperative deaths in patients with heart valve replacement,while diabetes,heart function and pulmonary hypertension are significant predictors of postoperative complications. For RHD patients,diabetes,heart function and pulmonary hypertension are major risk factors associated with postoperative complications. PMID- 29130671 TI - [Clinical Study on the Correlation Between Tinnitus and Hearing Loss in 400 Patients]. AB - OBJECTIVE: To investigate the correlation between tinnitus and hearing loss. METHODS: Clinical data of 400 patients presented with tinnitus as the first chief complain were analyzed. The relationship between tinnitus and hearing loss was categorized based on sites,onset time of tinnitus and hearing loss,for the purpose of provideing clinical evidence to explore the etiology,treatment and prognosis of tinnitus. RESULTS: Among the 400 patients,61% of them did not show the correlation of tinnitus with hearing loss (52.05% with normal hearing,and 47.95% with hearing loss),while only 39% had the relationship (70.51% related,29.49% possibly related). CONCLUSION: In this study,no absolute correlation between tinnitus and hearing loss was observed. Tinnitus and hearing loss may not be treated in the same way. PMID- 29130672 TI - [Effects of Cellular Density on the Induction of Suspension Globe of Ovarian Cancer Stem Cells]. AB - OBJECTIVE: To determine the effect of cellular density on the separation and identification of cancer stem cells from human ovarian clear cell carcinoma cell line ES-2 and adenocarcinoma cell line A2780. METHODS: ES-2 and A2780 cells were cultured with human recombinant epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) and bovine serum albumin and insulin in serum free medium. The cancer stem cells were obtained through serial passages. Changes in cell morphology,expressions of surface marker CD133 and CD44,and soft AGAR clone forming in the stem cells were examined under different cell density,either in serum-supplemented medium (SSM group) or in serum free medium (SFM group). RESULTS: Under the density of 2*104 mL-1,ES-2 cells survived in SFM,but did not form stem cells. When the density increased to 5*104 mL-1 or 1*105 mL-1,ES-2 cells survived in SFM,proliferated and formed stem cells. Compared with adherent cells,the suspension globe of stem cells expressed high levels of CD133 and CD44 ( P<0.05),with proliferation and clone forming ability after serial passages. The stem cell balls under the density of 5*104 mL-1 had stronger ability of tumor formation. A2780 cells formed suspension globe under the density of 1*104 mL-1 and 3*104 mL-1,but larger and more transparent balls were observed under the density of 3*104 mL-1 density. No suspension globe was formed under the density of 5*104 mL-1. More CD133+/CD44+cells were detected by flow cytometry under the density of 3*104 mL-1,compared with that under the density of 1*104 mL-1 ( P<0.05). Tumor stem cells grew faster under the density of 3*104 mL-1. CONCLUSION: The optimal density for identifying stem cells from human ovarian cancer is 5*104 mL-1 for ES-2 and 3*104 mL-1 for A2780,respectively. PMID- 29130673 TI - [Detection of 11 Organophosphate Pesticides and Atrazine in Water by Dispersive Liquid-Liquid Microextraction Combined with Gas Chromatography Mass Spectrometry]. AB - OBJECTIVE: To develop a method for detecting 11 organophosphate pesticides and atrazine in water samples by dispersive liquidliquid microextraction combined with gas chromatographymass spectrometry (DLLMEGC/MS) . METHODS: DLLME and GCMS parameters were optimized for efficient extraction of chemicals. The proposed method was used for detecting organophosphate pesticides in tap water and river water samples,with 200 MUL of dimethylbenzene as extractant and 800 MUL of methanol as dispersant. They were mixed,emulsified and dispersed into 10 mL of water samples. The extractant (1 MUL) from centrifugation was injected into the GC/MS system for analyses. GC separation was performed on HP5 column (30 m*0.25 mm,0.25 MUm) by temperature programming. Mass spectrometric analysis was done with EI and selected ion monitoring (SIM) mode was used for quantitative analysis. RESULTS: Good linear ranges for detecting the 11 pesticides and atrazine appeared from 2.0 ng/mL to 50 ng/mL,with a limit of 0.121.38 ng/mL. The relative standard derivations (RSDs) ranged from 5.57% to 9.85%. The average recoveries ranged from 75.5% to 107%. CONCLUSION: The method is sensitive and rapid,with simultaneous extraction and concentration procedures. The lowdensity organic solvent after extraction is easy to isolate. The method fits for analyses of organophosphate pesticides and atrazine in water samples. PMID- 29130674 TI - [Efficacy of Superior Rectus and Lateral Rectus Muscle Belly Union Surgery for Myopic Strabismus Fixus]. AB - OBJECTIVE: To evaluate the effectiveness of superior rectus (SR) and lateral rectus (LR) union suture without scleral fixation for the treatment of myopic strabismus fixus. METHODS: A retrospective review was performed on 27 eyes of 16 patients who underwent lateral part of SR and superior part of LR muscle belly union between January 2010 and October 2015. We collected the ocular data including: best corrected visual acuity,axial length,CT or MRI images,orthoptic measurements (by prism test),and eye movements pre- and postoperatively. RESULTS: The follow up time varied from 3-12 months. All of the patients got satisfactory results except two severe cases. A statistical change of prism test value and eye movement was noticed ( P<0.01). Orthoptic measurements showed that the mean esotropia was improved from (92.50+/-18.17)Delta preoperatively to (9.19+/ 4.39)Delta postoperatively ( P<0.01). In regards for the vertical deviation,the mean residual hypotropia was (2.38+/-3.10)Delta postoperatively compared to (21.88+/-5.74)Delta preoperatively ( P<0.01). At the last follow-up,mean abduction limitation was improved from -3.19+/-0.62 to -1.15+/-0.52 ( P<0.01),mean elevation limitation was improved from -2.85+/-0.82 to -0.78+/-0.51 ( P<0.01). No special complications were noted. CONCLUSION: Muscle belly suture of SR and LR was an effective surgery to correct ocluar misalignment and motility in myopic strabismus fixus. PMID- 29130675 TI - [Severe Adverse Pregnancy Outcomes in Placenta Previa and Prior Cesarean Delivery]. AB - OBJECTIVE: To investigate the severe adverse pregnancy outcomes in pregnancies with placenta previa and prior cesarean delivery and its risk factors. METHODS: This retrospective casecontrol study reviewed all pregnancies with placenta previa and prior cesarean delivery delivered by repeat cesarean section in our institution between January 2005 and June 2015,and investigated the incidence of severe adverse pregnancy outcome. A composite of severe adverse pregnancy outcomes (including transfusion of 10 units or more red blood cells,maternal ICU admission,unanticipated injuries,repeat operation,hysterectomy,and maternal death) and other maternal and neonatal outcomes were described. Univariate and multivariable logistic regression analysis were used to quantify the effects of risk factors on severe adverse pregnancy outcomes. RESULTS: There were 478 women with placenta previa and prior cesarean delivery in our hospital over the last decade. The average age of them was 32.5+/-4.8 years old,most women were beyond 30 years old,the average gravidity and parity were 4 and 1,131 cases (27.4%) had severe adverse pregnancy outcomes. Transfusion of 10 units or more red blood cells happened in 75 cases (15.7%,75/478); 44 cases (9.2%,44/478) necessitated maternal ICU admission; unanticipated bladder injury occurred in 11 cases,but non ureter or bowel injury happened; All 4 repeat operations were due to delayed hemorrhage after conservative management during cesarean delivery,and an emergent hysterectomy was performed for all of the 4 cases. Hysterectomy (107 cases,22.4%) was the most common severe adverse pregnancy outcome. Among all 311 morbidly adherent placenta cases finally confirmed by pathological or surgical findings or both,only 172 (55.3%) were suspected before delivery. Multivariable logistic regression analysis showed that the risk of severe adverse pregnancy outcomes was significantly increased by pernicious placenta previa (i.e. anterior placenta overlying the prior cesarean scar),suspicion of morbidly adherent placenta before delivery and hemoglobin before delivery lower than 100 g/L,and the corresponding odds ratios and 95% confidence intervals were 2.4 (1.5-3.8),3.6 (2.3-5.6) and 2.5 (1.6-3.9),respectively. CONCLUSION: Pernicious placenta previa,suspicion of morbidly adherent placenta before delivery and hemoglobin before delivery lower than 100 g/L were associated with severe adverse pregnancy outcomes in women with placenta previa and prior cesarean delivery . PMID- 29130676 TI - [The Feasibility of CT Attenuation Value to Predict the Composition of Upper Urinary Calculi and Success Rate of Extracorporeal Shock Wave Lithotripsy]. AB - OBJECTIVE: To explore the feasibility of CT attenuation value (CTvalue) to predict the composition of upper urinary calculi and the number of shock waves (NSW) and success rate (SR) of extracorporeal shock wave lithotripsy (ESWL). METHODS: A total of 146 patients with upper urinary calculi treated by ESWL were included. CT scan was performed before ESWL. Upper urinary calculi with the maximum diameters of less than or equal to 2 cm were included. Infrared spectroscopy was used to analyze the composition of calculi. The effect of ESWL was estimated at 1 month followup. The factors that influence NSW and SR of ESWL were analyzed by correlation analysis. RESULTS: The CTvalue of calcium calculi were larger than that of noncalcium calculi ( P<0.001). The differences of NSW,SR of ESWL and CTvalues of calculi between the patients with different ages,skintostone distances and genders were not statistically significant. The partial correlation analysis found that CTvalue and long diameter of calculi were positively correlated with the NSW ( P<0.05). This result was consistent in subgroup analysis (stone site: kidney or ureter). CTvalue and long diameter of calculi were negatively correlated with SR of ESWL ( P<0.05). However,the CTvalue of ureteral calculi was not correlated with SR of ESWL in subgroup analysis. CONCLUSION: The power of CTvalue to predict upper urinary calculi composition is insufficient. Higher CTvalue suggests more NSW in ESWL,but CTvalue is not suitable to predict SR of ESWL. PMID- 29130677 TI - [Dermoscopy Study on the Effects of Gold Microacupuncture,Hyaluronic Acid Injection,and rb-bFGF to Treat Facial Rejuvenation]. AB - OBJECTIVE: To explore the dermoscopic changes facial rejuvenation after the combination therapy of gold microacupuncture,Hyaluronic acid (HA) injection,and recombinant bovine alkaline fibroblast growth factor (rbbFGF). METHODS: Twenty cases of patients (age from 30 to 55 yearold) with facial skin naturally aging were included. The patients received multisource radio frequency therapeutic apparatus for injection at the subbermaldermal levels from 1316 W. Noncrosslinking HA of 2 mL was injected in the upper dermis. rbbFGF was externally applied 3 to 5 times a day for a week according to the dry skin issues,humanlike collagen mask was applied once a day for a week. Dermoscopy was used to observe the changes of skin,such as olor spot,wrinkle,skin texture and pore. RESULTS: The patients were found facial contour tighten,skin quality improved obviously after two phase combination therapy,the Objective evaluation of dermoscopy delicated skin mirror,skin texture,skin moisture condition improved obviously,while the subjective satisfaction degree was increased. CONCLUSION: Golden microacupuncture combined with HA injection and rbbFGF could provide better joint treatment for facial rejuvenation. PMID- 29130678 TI - [Expression of LOX in Colorectal Cancer Tissues and Its Relationship with Progress and Prognosis]. AB - OBJECTIVE: To analyze the expression of lysyl oxidase (LOX) in colorectal cancer and its relationship with clinicopathological characteristics, prognosis, and its progress. METHODS: 82 cases of colorectal tumor paraffin-embedded specimens and paired tumor-adjacent tissues were collected, and data of clinicopathological characteristics and prognosis of these patients were also recorded from 2009.1 to 2010.5. Expressions of LOX, hypoxia inducible factor-1alpha (HIF-1alpha), matrix metalloproteinase (MMP)-2, MMP-7 were determined by immunohistochemistry. Then relationship between LOX and clinicopathological characteristics and prognosis was explored, and relationship between LOX and HIF-1alpha, MMP-2, MMP-7 were investigated. RESULTS: Expressions of LOX was stronger in tumors than in tumor adjacent tissues (P<0.05). Cancer tissues with overexpressed LOX had later clinical stages, deeper tumor invasion, and more metastatic lymph nodes (all P<0.05). The result also showed that patients with overexpression of LOX had poorer prognosis, and overexpression of LOX was independent factor for prognosis in COX survival analysis. Expression of HIF-1alpha, MMP-2, MMP-7 in colorectal cancer was stronger than in tumor-adjacent tissues (P<0.05). Positive relationship was found between LOX and HIF-1alpha, MMP-2, MMP-7 proteins (P<0.05). CONCLUSION: LOX was overexpressed in colorectal cancer tissues, and was associated with the progression of colorectal cancer. LOX may be involved in the progress of colorectal cancer by regulating HIF-1alpha, MMP-2, MMP-7 protein expression. PMID- 29130679 TI - 681 Progress report on the elimination of human onchocerciasis, 2016-2017. PMID- 29130680 TI - Country Immunization Information System Assessments (IISAs), in Kenya (2015) and Ghana (2016). PMID- 29130681 TI - Nodular glomerulosclerosis: not always diabetic nephropathy. PMID- 29130682 TI - High-Performance Piezoelectric Nanogenerators via Imprinted Sol-Gel BaTiO3 Nanopillar Array. AB - We report high-performance piezoelectric nanogenerators (PENGs) with nanoimprinted sol-gel BaTiO3 (BTO) nanopillar array polarized under high electric field and ultraviolet. The PENGs fabricated using this method demonstrate greatly enhanced output voltage of ~10 V and current density of ~1.2 MUA cm-2, respectively, in comparison to that of flat PENG. Further, the PENG demonstrates uniform output characteristics over the entire device area thanks to uniform nanoimprint pillar array. The approach introduced here is simple, effective, reliable, and reproducible way to fabricate high-performance sol-gel-based PENGs and electronic devices. PMID- 29130683 TI - Triplet Ground-State-Bridged Photochemical Process: Understanding the Photoinduced Chiral Inversion at the Metal Center of [Ru(phen)2(l-ser)]+ and Its Bipy Analogues. AB - One of the main concerns in the photochemistry and photophysics of ruthenium complexes is the de-excitation of the triplet metal centered ligand-field state 3MC. To understand the mechanism by which the 3MC states in some reversible photochemical reactions could avoid the fate of fast decay and ligand dissociations, the photoinduced chiral inversion at the metal center of the complexes [Ru(diimine)2(l-ser)]+ (diimine = 1,10-phenanthroline or 2,2' bipyridine, l-ser = l-serine) has been analyzed at the first principle level of theory. The calculated equilibrium constants and ECD curves for the photoinduced equilibrium mixtures are in agreement with the observed ones. The results showed that the reversible photochemical process Delta(deltaS) ? Lambda(deltaS) on the potential surface of the lowest triplet excited state proceeds in three steps: 3CTDelta <-> 3MCDelta, 3MCDelta <-> 3MCLambda, 3MCLambda <-> 3CTLambda, where the first and the third steps involve mainly the elongation and compression of the octahedral core of the reactant Delta(deltaS) and product Lambda(deltaS), respectively. The chiral inversion Delta <-> Lambda takes place in the second step through a much distorted square-pyramid-like transition state, and actually proceeds on the triplet ground state 3MC due to the crossover of the triplet T1 and singlet S0 states. Inspecting the transient structures at the crossing points, we found that they become less distorted and their lowest or imaginary frequency displacement vectors in triplet state still dominate the reaction path, which makes the reaction reversible without ligand release. Thus, the triplet ground-state-bridged photoinduced mechanism offers a new angle of view to understand the related reversible photochemical reactions. PMID- 29130684 TI - Influence of Proton Acceptors on the Proton-Coupled Electron Transfer Reaction Kinetics of a Ruthenium-Tyrosine Complex. AB - A polypyridyl ruthenium complex with fluorinated bipyridine ligands and a covalently bound tyrosine moiety was synthesized, and its photo-induced proton coupled electron transfer (PCET) reactivity in acetonitrile was investigated with transient absorption spectroscopy. Using flash-quench methodology with methyl viologen as an oxidative quencher, a Ru3+ species is generated that is capable of initiating the intramolecular PCET oxidation of the tyrosine moiety. Using a series of substituted pyridine bases, the reaction kinetics were found to vary as a function of proton acceptor concentration and identity, with no significant H/D kinetic isotope effect. Through analysis of the kinetics traces and comparison to a control complex without the tyrosine moiety, PCET reactivity was found to proceed through an equilibrium electron transfer followed by proton transfer (ET PT) pathway in which irreversible deprotonation of the tyrosine radical cation shifts the ET equilibrium, conferring a base dependence on the reaction. Comprehensive kinetics modeling allowed for deconvolution of complex kinetics and determination of rate constants for each elementary step. Across the five pyridine bases explored, spanning a range of 4.2 pKa units, a linear free-energy relationship was found for the proton transfer rate constant with a slope of 0.32. These findings highlight the influence that proton transfer driving force exerts on PCET reaction kinetics. PMID- 29130685 TI - Daptomycin-Phosphatidylglycerol Domains in Lipid Membranes. AB - Daptomycin is an acidic, 13-amino acid, cyclic polypeptide that contains a number of nonproteinogenic residues and is modified at its N-terminus with a decanoyl chain. It has been in clinical use since 2003 against selected drug-resistant Staphylococcus aureus and Enterococcus spp infections. In vitro, daptomycin is active against Gram-positive pathogens at low concentrations but its antibiotic activity depends critically on the presence of calcium ions. This dependence has been thought to arise from binding of one or two Ca2+ ions to daptomycin as a required step in its interaction with the bacterial membrane. Here, we investigated the interaction of daptomycin with giant unilamellar vesicles (GUVs) composed 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and 1-palmitoyl-2 oleoylphosphatidylglycerol (POPG). We used fluorescence confocal microscopy to monitor binding of the peptide to GUVs and follow its effect on the membrane of the vesicle. We found that in the absence of POPG or Ca2+ daptomycin does not bind measurably to the lipid membrane. In the presence of 20-30% PG in the membrane and 2 mM Ca2+, daptomycin induces the formation of membrane domains rich in acidic lipids. This effect is not induced by Ca2+ alone. In addition, daptomycin causes GUV collapse, but it does not translocate across the membrane to the inside of intact POPC/POPG vesicles. We conclude that pore formation is probably not the mechanism by which the peptide functions. On the other hand, we found that daptomycin coclusters with the anionic phospholipid POPG and the fluorescent probes used, leading to extensive formation of daptomycin-POPG domains in the membrane. PMID- 29130686 TI - Thioamide Substitution Selectively Modulates Proteolysis and Receptor Activity of Therapeutic Peptide Hormones. AB - Peptide hormones are attractive as injectable therapeutics and imaging agents, but they often require extensive modification by mutagenesis and/or chemical synthesis to prevent rapid in vivo degradation. Alternatively, the single-atom, O to-S modification of peptide backbone thioamidation has the potential to selectively perturb interactions with proteases while preserving interactions with other proteins, such as target receptors. Here, we use the validated diabetes therapeutic, glucagon-like peptide-1 (GLP-1), and the target of clinical investigation, gastric inhibitory polypeptide (GIP), as proof-of-principle peptides to demonstrate the value of thioamide substitution. In GLP-1 and GIP, a single thioamide near the scissile bond renders these peptides up to 750-fold more stable than the corresponding oxopeptides toward cleavage by dipeptidyl peptidase 4, the principal regulator of their in vivo stability. These stabilized analogues are nearly equipotent with their parent peptide in cyclic AMP activation assays, but the GLP-1 thiopeptides have much lower beta-arrestin potency, making them novel agonists with altered signaling bias. Initial tests show that a thioamide GLP-1 analogue is biologically active in rats, with an in vivo potency for glycemic control surpassing that of native GLP-1. Taken together, these experiments demonstrate the potential for thioamides to modulate specific protein interactions to increase proteolytic stability or tune activation of different signaling pathways. PMID- 29130687 TI - Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C via Convergent Fragment Coupling Using a Tertiary Carbon Radical. AB - The development of a convergent fragment coupling strategy for the enantioselective total syntheses of a group of rearranged spongian diterpenoids that harbor the cis-2,8-dioxabicyclo[3.3.0]octan-3-one unit is described. The key bond disconnection relies on a late-stage fragment coupling between a tertiary carbon radical and an electron-deficient alkene to unite two ring systems and form two new stereocenters, one of which is quaternary, in a stereoselective and efficient manner. This strategy is applied toward scalable 14-15 step syntheses of three rearranged spongian diterpenoids, cheloviolenes A and B, and dendrillolide C. PMID- 29130688 TI - From Classification to Regression Multitasking QSAR Modeling Using a Novel Modular Neural Network: Simultaneous Prediction of Anticonvulsant Activity and Neurotoxicity of Succinimides. AB - Succinimides, which contain a pharmacophore responsible for anticonvulsant activity, are frequently used antiepileptic drugs and the synthesis of their new derivatives with improved efficacy and tolerability presents an important task. Nowadays, multitarget/tasking methodologies focused on quantitative-structure activity relationships (mt-QSAR/mtk-QSAR) have an important role in the rational design of drugs since they enable simultaneous prediction of several standard measures of biological activities at diverse experimental conditions and against different biological targets. Relating to this very topic, the mt-QSAR/mtk-QSAR methodology can give only binary classification models, and as such, in this study a regression mtk-QSAR (rmtk-QSAR) model based on a novel modular neural network (MNN) has been proposed. The MNN uses standard classification mtk-QSAR models as input modules, while the regression is performed by the output module. The rmtk-QSAR model has been successfully developed for the simultaneous prediction of anticonvulsant activity and neurotoxicity of succinimides, with a satisfactory accuracy in testing (R2 = 0.87). Thus, the proposed mtk-QSAR regression method can be regarded as a viable alternative to the standard QSAR methodology. PMID- 29130689 TI - Mechanochemical Ruthenium-Catalyzed Hydroarylations of Alkynes under Ball-Milling Conditions. AB - Under solventless grinding conditions, mechanochemical ruthenium-catalyzed hydroarylations of alkynes with acetanilides lead to trisubstituted alkenes. Only catalytic amounts of pivalic acid or copper acetate are required, and without the need for external heating, the reaction times are shorter than those of their solution-based counterpart. Mechanochemical oxidative annulations through palladium-catalyzed intramolecular amination convert the products into N acetylindoles. PMID- 29130690 TI - DPPF-Catalyzed Atom-Transfer Radical Cyclization via Allylic Radical. AB - A general iron-catalyzed strategy for the atom-transfer radical cyclization (ATRC) of allylic halide is reported. Critical to this strategy is the use of DPPF [1,1'-bis(diphenylphosphino)ferrocene] as catalyst, which allows for efficient generation of the allylic radical species via a single-electron transfer (SET) process. The feasibility of achieving ATRC reactions of propargyl chlorides is also demonstrated, which affords products with an exocyclic allene moiety. PMID- 29130691 TI - Insertion of a Transient Tin Nitride into Carbon-Carbon and Boron-Carbon Bonds. AB - A simple exchange reaction between [AriPr4Sn(MU-Cl)]2 (1) and sodium azide afforded the doubly bridged Sn(II) azide, [AriPr4Sn(MU-N3)]2 (2) (AriPr4 = C6H3 2,6(C6H3-2,6-iPr2)2) in 85% yield. Photolysis of a diethyl ether solution of 2 for ca. 16 h yielded an azepinyl-substituted insertion product, [C6H3-2-(C6H3-2,6 iPr2)-6-(C6H3N-3,7-iPr2)Sn]2 (3). The reaction of the Lewis acid, B(C6F5)3 (BCF), or the Lewis base, pyridine, with 2 dissociates the dimer to afford the corresponding complexed monomeric Sn(II) azide, AriPr4SnN3BCF (4) in which BCF coordinates the alpha-nitrogen, or AriPr4Sn(pyridine)N3 (6) in which pyridine coordinates to the tin atom. Photolysis of 4 in diethyl ether for 12 h results in the insertion of the alpha-nitrogen of the azide group into one of the B-C bonds of the BCF acceptor to yield the tin(II) amide, AriPr4SnN(C6F5)B(C6F5)2 (5). In contrast, photolysis of 6 for over 36 h afforded no apparent reaction. A highly reactive Sn nitride intermediate, AriPr4Sn=N, is proposed as part of the mechanistic pathway for the formation of 3 and 5 as a result of trapping the tin centered radical isomers. This was effected by immediate freezing the samples of 2 or 4 after ca. 30 min of UV photolysis and recording their electron paramagnetic resonance spectra. These exhibited a rhombic g tensor of [g1, g2, g3] = [2.029, 1.978, 1.933]. This radical intermediate could be related to the valence isomers of the nitride [-SnIV=N] intermediate, in isomeric equilibrium with the nitrene [-SnII-N] and nitridyl [-SnIII?N.] forms, but with the spin density on the nitrogen being quenched, possibly by the H atom abstraction to form an S = 1/2 species of formula -Sn.?N(H). PMID- 29130692 TI - Uptake of Long Protein-Polyelectrolyte Nanotubes by Dendritic Cells. AB - Anisotropic nanostructures, such as nanotubes, incorporating bioactive molecules present interesting features for application as drug delivery carriers. Here, we present the synthesis of layer-by-layer (LbL) nanotubes including protein (ovalbumin) layers and go from simple to more complex synergetic combinations of synthetic and natural polyelectrolytes, leading to structures with tunable properties. The rigidity in organic and aqueous media, the stability in buffer solution and the uptake of different LbL tubes by dendritic cells (DCs) are analyzed to contrast size and chemistry. The most rigid studied systems appear as the best candidates to be internalized by cells, regardless of the chemistry of their outermost layers. The successful transport of long protein-loaded robust rigid nanotubes to the cytoplasm of DCs paves the way for their use as new cargo for the delivery of large amounts of antigen to such cells. PMID- 29130693 TI - Putting bandits into context: How function learning supports decision making. AB - The authors introduce the contextual multi-armed bandit task as a framework to investigate learning and decision making in uncertain environments. In this novel paradigm, participants repeatedly choose between multiple options in order to maximize their rewards. The options are described by a number of contextual features which are predictive of the rewards through initially unknown functions. From their experience with choosing options and observing the consequences of their decisions, participants can learn about the functional relation between contexts and rewards and improve their decision strategy over time. In three experiments, the authors explore participants' behavior in such learning environments. They predict participants' behavior by context-blind (mean tracking, Kalman filter) and contextual (Gaussian process and linear regression) learning approaches combined with different choice strategies. Participants are mostly able to learn about the context-reward functions and their behavior is best described by a Gaussian process learning strategy which generalizes previous experience to similar instances. In a relatively simple task with binary features, they seem to combine this learning with a probability of improvement decision strategy which focuses on alternatives that are expected to lead to an improvement upon a current favorite option. In a task with continuous features that are linearly related to the rewards, participants seem to more explicitly balance exploration and exploitation. Finally, in a difficult learning environment where the relation between features and rewards is nonlinear, some participants are again well-described by a Gaussian process learning strategy, whereas others revert to context-blind strategies. (PsycINFO Database Record PMID- 29130695 TI - A test of the empirical profile and coherence of the DSM-5 psychopathy specifier. AB - The Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5; American Psychiatric Association, 2013) introduced a psychopathy specifier (DSM-5 PS) as part of the Section III diagnostic model of antisocial personality disorder. Designed to capture the construct of fearless dominance/boldness, the DSM-5 PS is assessed on the basis of the presence of low scores on traits of withdrawal and anxiousness, and high scores on attention seeking. These constructs have garnered attention in the past decade but are the subject of substantial debate as to their role in the conceptualization and assessment of psychopathy, given their limited relations to the maladaptive outcomes typically associated with this personality disorder. In the current study (N = 340 undergraduates; 170 informants), we examined the DSM-5 PS, both in composite form and its trait subscales, to investigate the degree to which the DSM-5 PS manifested empirical profiles associated with psychopathy and its maladaptive correlates. Consistent with prior fearless dominance/boldness research, the DSM-5 PS manifested limited relations with other components of psychopathy, symptoms of DSM-5 Section II and III antisocial personality disorder, and self- and informant related impairment scores. When examined at the individual subscale level, the 3 DSM-5 PS subscales manifested only partially overlapping profiles and only 1 of the 3-Attention Seeking-demonstrated an association with maladaptivity (e.g., externalizing behaviors). These findings raise important concerns about the coherence and utility of the DSM-5 PS as a diagnostic specifier included in a psychiatric nosology. (PsycINFO Database Record PMID- 29130694 TI - Initial validation of brief measures of suicide risk factors: Common data elements used by the Military Suicide Research Consortium. AB - The Military Suicide Research Consortium (MSRC) developed a 57-item questionnaire assessing suicide risk factors, referred to as the Common Data Elements (CDEs), in order to facilitate data sharing and improve collaboration across independent studies. All studies funded by MSRC are required to include the CDEs in their assessment protocol. The CDEs include shortened measures of the following: current and past suicide risk, lethality and intent of past suicide attempts, hopelessness, thwarted belongingness, anxiety sensitivity, posttraumatic stress disorder symptoms, traumatic brain injury, insomnia, and alcohol abuse. This study aimed to evaluate the psychometric properties of the CDE items drawn from empirically validated measures. Exploratory factor analysis was used to examine the overall structure of the CDE items, and confirmatory factor analyses were used to evaluate the distinct properties of each scale. Internal consistencies of the CDE scales and correlations with full measures were also examined. Merged data from 3,140 participants (81.0% military service members, 75.6% male) across 19 MSRC-funded studies were used in analyses. Results indicated that all measures exhibited adequate internal consistency, and all CDE shortened measures were significantly correlated with the corresponding full measures with moderate to strong effect sizes. Factor analyses indicated that the shortened CDE measures performed well in comparison with the full measures. Overall, our findings suggest that the CDEs are not only brief but also provide psychometrically valid scores when assessing suicide risk and related factors that may be used in future research. (PsycINFO Database Record PMID- 29130696 TI - [Single nucleotide polymorphisms and clinical nutrition]. PMID- 29130697 TI - [Preferences for the attributes of home enteral nutrition (HEN) in Spain. Do caregivers know their patients' preferences?] AB - INTRODUCTION: Establishing a home enteral nutrition (HEN) that is adapted to the patient's needs and preferences can improve their quality of life and adherence, contributing to a higher treatment efficiency, better prognosis and cost reduction. As in most cases, patients need total or partial help from their caregivers, and there is a need for evaluating how well do caregivers know their patients' priorities. OBJECTIVES: Exploring patients' preferences for HEN characteristics in Spain, and the concordance between patients and caregivers. METHODS: A cross-sectional observational study based on the discrete choice experiment methodology. A set of eight choice scenarios generated from six attributes with two levels each was presented along with an ad hoc questionnaire on the importance and satisfaction with HEN. The relative importance (RI) of each attribute and the patient-caregiver concordance was estimated in every question. RESULTS: One hundred and forty-eight patients participated, and in 77 cases both the patient and the caregiver took the survey. The most important attributes (RI) for HEN were adaptation to comorbidities (33%), tolerability (33%), nutrients and calories (26%) and package characteristics (8%). Patients showed a high degree of satisfaction with the assistance received. Concordance between patient and caregiver was found in every question, being it moderate to good. CONCLUSIONS: According to patients, an ideal HEN product would be adaptable to comorbidities, easy to tolerate, providing the necessary nutrients and calories, with an easy to handle package. Caregivers know well their patients' preferences. PMID- 29130698 TI - Preoperative metabolic status is associated with different evolution of resting energy expenditure after liver transplant in adults. AB - INTRODUCTION: The resting energy expenditure (REE) evolution after liver transplantation is not fully understood. OBJECTIVE: To assess longitudinally the REE evolution in adults undergoing liver transplantation, in association with other nutritional measurements that characterize the metabolic profile. METHODS: A single-center cohort of consecutive end-stage liver disease patients with indication for liver transplantation was recruited. REE, subjective global assessment (SGA), handgrip strength and body composition measurements were assessed before transplantation (T0) and at median nine (T1) and 36 (T2) days after transplantation. Mixed effects regression models were used for analysis. RESULTS: Fifty-six patients with a mean age of 53.7 (8.5) years were included; 87.5% were males. In T0, 41% of patients were normometabolic, 37.5% were hypometabolic and 21.4% were hypermetabolic. After transplantation, the mean REE decreased progressively in patients initially hypermetabolic and the opposite occurred in those initially hypometabolic. The REE evolution was positively associated with body weight (beta = 9.6, p < 0.001) and energy intake (beta= 13.6, p = 0.005) in the whole sample; it was positively associated with body weight (beta= 7.1, p = 0.018) and percentage of energy intake from lipids (beta= 18.9, p = 0.003) in initially hypometabolic patients, and positively associated with body weight (beta= 14.1, p < 0.001) and negatively associated with SGA undernourishment (beta = -171, p = 0.007) in initially normometabolic patients. CONCLUSION: Different REE evolutions after liver transplantation are associated with the preoperative metabolic status. In patients initially hypometabolic, the REE evolution is positively associated with body weight and percentage of energy intake from lipids, and in those initially normometabolic, it is positively associated with body weight and negatively associated with SGA-undernourishment. PMID- 29130699 TI - Inflammation and insulin resistance according to body composition in European adolescents: the HELENA study. AB - INTRODUCTION: Inflammation is related to insulin resistance in adults, especially on those individuals with high levels of body composition. OBJECTIVES: The aim of this study is to assess the relationship between a set of inflammatory biomarkers and insulin resistance by levels of body composition in a sample of European adolescents. MATERIAL AND METHODS: Nine hundred and sixty-two adolescents (442 boys and 520 girls) from nine European countries met the inclusion criteria of having measurements for the homeostasis model assessment (HOMA) and a set of inflammation-related biomarkers: C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), interleukin (IL-6), complement factors C3 and C4 and selected cell adhesion molecules. Body mass index (BMI), fat mass index (FMI) and waist circumference (WC) were categorized using tertiles. To assess the associations stratifying by body composition indexes, ANOVA and linear regression models were performed. RESULTS: Mean biomarkers' concentrations differed across BMI, FMI and WC tertiles (p < 0.05) by sex. In both sexes, insulin, HOMA, CRP, C3 and C4 were significantly different between categories (p < 0.001), always showing the highest mean concentration in the upper category of BMI, FMI and WC. The most consistent finding was an association between insulin resistance and C3 concentrations (p < 0.05), in the adolescents in the highest tertile of BMI, FMI and WC, except in the case of FMI in girls. CONCLUSION: Inflammatory and glucose metabolism markers differed by tertiles of body composition, being usually higher in the highest tertile. C3 complement factor was associated with insulin resistance in adolescents, especially those with high total and abdominal adiposity. PMID- 29130700 TI - [Dissatisfaction with body image and its relation to nutritional status, cardiometabolic risk and cardiorespiratory capacity in public school children]. AB - INTRODUCTION: The increase in abdominal fat and excess weight are related to dissatisfaction with body image, which nowadays is highly prevalent nationally and internationally. AIM: The purpose of the study was to relate dissatisfaction levels to body image, nutritional status, cardiometabolic risk and cardiorespiratory capacity in pre-adolescent students. MATERIAL AND METHODS: Three hundred and thirty-nine students participated in the study, 165 girls (11.29 +/- 0.69 years) and 174 boys (11.22 +/- 0.72 years). Anthropometric data were collected: BMI, percentage of body fat (%BF), waist circumference (WC), height-to-weight ratio (HWR), VO2max and body image. RESULTS: In the comparison by sex, we found higher V02max values in boys (p < 0.001). No significant differences were found for the variables BMI, WC, HWR, blood pressure and body image (p > 0.05); 27.7% of the study sample were overweight and 29.2% were obese. The subjects with obesity had the lowest VO2max levels. Dissatisfaction with body image was found to be associated with nutritional status (p < 0.001). In addition, 8.1% of the obese students presented extreme dissatisfaction with their body image and 19.4% of the children with cardiometabolic risk exhibited some type of dissatisfaction; the two variables were related (p = 0.008). CONCLUSIONS: The study provides evidence that children with malnutrition by excess present disorders associated with body dissatisfaction and other health indicators that limit integral growth in pre-adolescence. PMID- 29130701 TI - Patient-Generated Subjective Global Assessment of nutritional status in pediatric patients with recent cancer diagnosis. AB - BACKGROUND: The subjective global assessment (SGA) is a simple, sensitive tool used to identify nutritional risk. It is widely used in the adult population, but there is little evidence on its effectiveness in children with cancer. OBJECTIVE: This cross-sectional study was undertaken to demonstrate significant correlation between a simplified version of the Patient-Generated SGA (PG-SGA) and anthropometric assessment to identify nutritional status in children recently diagnosed with cancer. METHODS: The nutritional status of 70 pediatric cancer patients was assessed with the PG-SGA and anthropometric measurements. The relation between the assessments was tested with ANOVA, independent samples t test, Kappa statistic, and non-parametric Spearman and Kendall correlation coefficient. The PG-SGA divided the patients into four groups: well nourished, mildly, moderately and severely malnourished. RESULTS: The prevalence of malnutrition according to the PG-SGA was 21.4%. The correlations (r >= 0.300, p < 0.001) and the concordance (k >= 0.327, p < 0.001) between the PG-SGA and anthropometric indicators were moderate and significant. CONCLUSIONS: The results indicate that the PG-SGA is a valid tool for assessing nutritional status in hospitalized children recently diagnosed with cancer. It is important to emphasize that the subjective assessment does not detect growth retardation, overweight or obesity. PMID- 29130702 TI - [Short, medium and long-term benefits of human milk intake in very-low-birth weight infants]. AB - AIM: The aim of the present study is to evaluate the effect of human milk feeding during the first weeks of life in very low birth weight infants on weight gain at discharge, length of hospitalization, postmenstrual age at discharge and nutritional assessment, growth and neurodevelopment at two and five years. MATERIAL AND METHODS: Longitudinal study of very-low-birth-weight infants (< 1,500 grams) admitted to the Neonatal Intensive Care Unit of La Paz University Hospital, from January 1st 2009 to December 31st 2009, followed in the follow-up clinic. Their parents agreed to perform a more exhaustive anthropometric study at five years, classified according to the type of feeding at the time of discharge (exclusive human milk, formula milk or mixed). Initial hospital duration and anthropometry at discharge were evaluated. At two years of age, anthropometric data (weight, height and head circumference) were collected and neurodevelopment was assessed according to the Bayley scale of child development. Data at five years were collected prospectively. Measurements of weight, height and head circumference, waist circumference, hip, relaxed and contracted arm, thigh and middle leg, bicipital, triceps, subscapular, suprailiac and leg skin folds were performed. For patients older than five years, the Kaufman test battery for children was used. The effect of human milk on the variables of interest was investigated using a multivariate analysis correcting for gestational age and weight at birth. RESULTS: One hundred and fifty-two infants born in 2009 were discharged from our unit: exclusive breast milk (59), formula (55) or mixed milk (38). More detailed follow-up was carried out for 61 of them. Human milk during the first admission decreases the initial hospital stay, and is associated with a higher head circumference at two and five years, and a better score in the global and verbal cognitive area at five years. CONCLUSIONS: Our results suggest that maternal milk feeding during initial admission should be encouraged because it can improve neurodevelopment at five years of age. PMID- 29130703 TI - Nutritional practices in very low birth weight infants: a national survey. AB - BACKGROUND: Significant efforts have been made to improve the nutritional support of very preterm infants. Large surveys may help to know the nutritional practices for preterm infants in neonatal units and identify if they are in line with the current guidelines. METHODS: A multicentre nationwide web-based survey on clinical feeding practices in very low birth weight (VLBW) infants was conducted in tertiary neonatal hospitals that admit infants with a birth weight < 1,500 g and/or a gestational age of < 32 weeks. RESULTS: The questionnaire was completed by 53 units (response rate, 59%). Over 90% of the units surveyed start amino-acid administration immediately after birth and more than half use novel intravenous fish oil-based lipid emulsions. Enteral nutrition is started within 24 hours of birth in 65% of units and 86% of these are medium-sized or large. Feeding volumes are increased at a rate of 10-30 ml/kg/day in > 90% of units. Monitoring of serum phosphorus was measured more frequently than albumin (p = 0.009) or triglycerides (p = 0.037), but only 28% of centres regularly measure pre-albumin as a nutritional biomarker. Human milk fortification and iron supplementation, starting at four weeks of age, are almost universal. However, only 30% of units administer 800 IU/day of vitamin D. Nearly 50% of the units discharge infants on preterm formula. CONCLUSION: Most Spanish neonatology units use early amino-acid supplementation and over half use novel fish oil-based lipid emulsions. Post discharge nutrition practices and vitamin administration vary greatly. PMID- 29130704 TI - [Relationship between anthropometric health indexes with food consumption in physically active elderly]. AB - INTRODUCTION: Programs focused on active aging do not always have actions to guide the elderly about healthy eating. Therefore, the concordance between the feeding habits and the morphological characteristics of this population group is little known. OBJECTIVE: To correlate the anthropometric health indexes with the frequency of food consumption in physically active elderly (PAE). METHODS: The sample consisted of 307 physically active Chilean elders of both sexes (8.4% males), with a mean age of 70.2 years. The studied variables corresponded to nutritional status, abdominal adiposity, cardiovascular risk and frequency of food consumption. A logistic regression model was applied, considering alpha < 0.05. RESULTS: Fruit intake (OR = 0.12; 95% CI, 0.02-0.92) and water consumption (OR = 0.20; CI 95%, 0.04-0.90) are shown as protective factors for obesity; on the other hand, alcohol consumption (OR = 4.19; 95% CI, 1.03-17.02) and sweet snacks (OR = 10.68; 95% CI, 1.85-61.74) are presented as risk factors for obesity. In addition, vegetable intake (OR = 0.32; 95% CI, 0.11-0.92) was associated as a protective factor against abdominal adiposity and sweet snack consumption (OR = 6.45; 95% CI, 1.08-38.43) as a factor to present cardiovascular risk. CONCLUSION: The PAE that are more frequent in the consumption of healthy foods also show better nutritional status, abdominal adiposity and lower cardiovascular risk than active Chilean elderly who exhibit less healthy eating behavior. PMID- 29130705 TI - Disability and its influence in nutritional assessment tools in elderly people living in nursing homes. AB - INTRODUCTION: Poor nutritional status is associated with increased morbidity and mortality, especially in older people. OBJECTIVE: The aim of this study was to assess nutritional status in elderly nursing home residents with different nutritional test, and to determine which parameters used for nutritional assessment can be carried out in this population, which usually have a high prevalence of functionally dependent residents. METHODS: A cross-sectional study was performed in 383 elderly. The nutritional assessment tools used were the Mini Nutritional Assessment (MNA), the new ESPEN consensus definition of malnutrition, and the tool for Controlling Nutritional Status (CONUT). Moreover, the ability to perform basic activities of daily living was assessed with the Barthel index (BI). RESULTS: According to BI, 78.9% had a total dependence and only 20.9% could be weighed and heighed. The prevalence of malnutrition with MNA, ESPEN and CONUT was 21.3%, 17.6% and 20.7%, respectively. The agreement between MNA vs ESPEN criteria was moderate (kappa = 0.483), but with CONUT was low. CONCLUSIONS: Nursing homes had a high percentage of totally dependent residents. This high degree of functional dependence made difficult to obtain some anthropometric parameters such as weight and height, which are essential to carry out most nutritional tests. MNA, CONUT and the new ESPEN criteria of malnutrition showed a high prevalence of malnutrition and risk of malnutrition in subjects in which they could be performed. PMID- 29130706 TI - Androgen receptor gene polymorphisms and maximal fat oxidation in healthy men. A longitudinal study. AB - INTRODUCTION: Androgens play a major role in fat oxidation; however, the effects of androgens depend, among other factors, on the intrinsic characteristics of the androgen receptor (AR). Lower repetitions of CAG and GGN polymorphism appear to have a protective effect on fat accumulation in the transition from adolescent to mid-twenties. Whether a similar protective effect is present later in life remains unknown. The aims of this study were: a) to evaluate if extreme CAG and GGN repeat polymorphisms of the androgen receptors influence body fat mass, its regional distribution, resting metabolic rate (RMR), maximal fat oxidation capacity (MFO) and serum leptin, free testosterone and osteocalcin in healthy adult men; and b) to determine the longitudinal effects on fat tissue accumulation after 6.4 years of follow-up. METHODS: CAG and GGN repeats length were measured in 319 healthy men (mean +/- standard deviation [SD]: 28.3 +/- 7.6 years). From these, we selected the subjects with extreme short (CAGS < or equal 19; n = 7) and long (CAGL > or equal 24; n = 10) CAG repeats, and the subjects with short (GGNS < or equal to 22; n = 9) and long (GGNL > or equal to 25; n = 10) GGN repeats. Body composition was assessed by DXA and serum levels of leptin, free testosterone and osteocalcin by ELISA. After 6.4 years of follow-up, DXA was repeated, and resting metabolic rate (RMR), MFO and VO2max determined by indirect calorimetry. RESULTS: CAGS and CAGL subjects had similar RMR and accumulated comparable amounts of fat tissue over 6.4 +/- 1.0 years of follow-up. However, CAGL had higher MFO and total lean mass than CAGS (p < 0.05). Men with GGNS accumulated greater amount of total fat mass than men with GGNL, particularly in the trunk region seven years later. This concurred with a greater MFO in the GGNL group (p < 0.05), who accumulated less fat mass. Free testosterone was associated with MFO in absolute values (r = 0.45; p < 0.05) and MFO per kg of lower extremity lean mass per height squared (r = 0.35; p < 0.05). CONCLUSIONES: CAG and GGN repeat polymorphisms may influence muscle fat oxidation capacity and may have a role in the accumulation of fat over the years. PMID- 29130707 TI - [Sarcopenic obesity in elderly women: influence of I/D polymorphism of the angiotension converter enzyme]. AB - INTRODUCTION: Sarcopenic obesity (SO) is a term that refers to an increase of fat mass together with a decrease of muscle mass, which is suffered by a high percentage of elderly population. Physical activity seems to be a good strategy to prevent it getting worse. However, genetic factors related to the aging process and to elderly's physical fitness could have an influence on it. AIM: To determine if elderly women > 60 who practice physical activity regularly had differences in sarcopenic obesity according to the I/D polymorphism from the ACE (angiotensin converter enzyme) gen. METHODS: Cross-sectional study of 300 elderly women who have practiced physical exercise at least twice a week for the past two years. Anthropometric data, physical activity and sedentary behaviour questionnaire, sarcopenic obesity (determining the percentage of fat mass and total muscle mass by electrical impedance and grouping the quintiles of these values into four groups) and physical fitness assessment, as well as ACE gen genotype measured by oral mucosa sample, were evaluated. RESULTS: There were significant differences (p < 0.05) in sarcopenic obesity according to ACE I/D genotype (SO values: 2.18 ACE DD vs 2.48 ACE II + ACE ID). CONCLUSIONS: Women who were ACE DD presented lower risk of sarcopenic obesity than those in the ACE II and ACE ID groups. PMID- 29130708 TI - [Association between birth weight and cardiometabolic risk factors in children of Bucaramanga, Colombia>]. AB - BACKGROUND: Birth weight could be a medium-term risk factor in the development of overweight and obesity and a long-term risk factor of cardio-metabolic diseases. OBJECTIVE: To evaluate the association between birth weight and cardio-metabolic risk factors in children from Bucaramanga, Colombia. METHODS: This cross sectional study included 1,282 children between five and eleven years of age in Bucaramanga. Dependent variables: arterial hypertension, arterial prehypertension, overweight/obesity, glucose intolerance, insulin resistance, dyslipidemia. The main independent variable: birth weight (grams). The association between the independent and dependent variables was evaluated through logistic and multiple linear regression. Data analysis was performed using Stata v. 12.0 software. RESULTS: The overweight prevalence (overweight or obesity) was 22.93% (95% CI 20.64%-25.33%), while the low birth weight prevalence was 3.70% (95% CI 2.65%-5.00%). The most prevalent cardiovascular risk factor was overweight, followed by high LDL-cholesterol levels (17.24%, 95% CI 15.20 19.41%). Following an adjustment by age, sex, socioeconomic level and physical activity and obstetric maternal history, overweight, BMI Z-scores for age and systolic blood pressure had a statistically significant association with birth weight (OR: 1.44; 95% CI 1.10-1.89; p = 0.006, beta= 0.23, 95% CI: 0.10-0.36, p = 0.001 and beta= 1.18, CI 95%: 0.24-2.12, p = 0.013, respectively). CONCLUSIONS: Children with higher birth weight showed more likely to develop overweight or obesity during childhood. PMID- 29130709 TI - Body shape as body image determinant in university students. AB - INTRODUCTION AND OBJECTIVES: Body shape (BSP) and body image (BI) are part of the external physical structure, then modifications in body shape necessarily affect body image; however, both combined have not been studied. The purpose of the study was to evaluate the statistical relationship between BSP and BI in university students. METHOD: Two hundred and ninety-six participants (17-35 years) were included in this study. Different anthropometric measurements were used to define their somatotype (BSP), body mass index (BMI), waist to hip ratio (WHR) and waist circumference (WC). In addition, a questionnaire on body image perception was applied (McElhone et al.), regarding "how do I look?", "how do I think others see me?", "how do others see me?", and "how do I want to look like?". RESULTS: On average, men perceived themselves in normal weight; in contrast, women perceived themselves as overweight. Men were meso-endomorphic, while women were endo-mesomorphic as an average. CONCLUSION: Body shape measured as somatotype as well as WC and WHR were excellent determinants of body image. Participants who presented a higher endomorphy, WC and WHR and a lower ectomorphy had a higher appreciation of being overweight or obese and wish to become thinner. PMID- 29130710 TI - Body fat percentage comparisons between four methods in young football players: are they comparable? AB - INTRODUCTION: Dual X-ray absorptiometry (DXA), air displacement plethysmography (ADP), bioelectrical impedance analysis (BIA) and anthropometry are four body composition methods that have been frequently used for the assessment of body fat percentage (%BF) in athletes. However, the agreement between these methods has not been studied yet in adolescent football players. OBJECTIVES: The aim of this study was to compare %BF calculated by DXA, ADP, BIA and anthropometry in 92 participants. METHODS: Sixty-four males (13.4 +/- 0.6 years of age) and 28 females (13.4 +/- 0.6 years) participated in this study. %BF was measured with four methods: DXA, ADP, BIA, and anthropometry. ADP %BF was calculated by using Siri's equation. The equation proposed by Slaughter et al. was used to calculate %BF by anthropometry. Paired t-test was used to compare %BF means. The heteroscedasticity was calculated by Bland-Altman analyses. RESULTS AND CONCLUSIONS: Both in males and females, DXA, ADP, BIA and Slaughter et al. equation demonstrated significant %BF differences when compared to each other (p < 0.05); 95% limits of agreements ranged from 5.13 to 15.09% points. Only BIA showed heteroscedasticity compared to the other methods in both genders (p < 0.05). Although DXA, ADP, BIA, and anthropometry have been used in the scientific literature in order to assess %BF in adolescent football players, these results demonstrate that these body composition methods are not interchangeable in this population. PMID- 29130711 TI - Combined assessment of nutritional status in patients with peritoneal dialysis using bioelectrical impedance vectors and malnutrition inflammation score. AB - BACKGROUND AND OBJECTIVE: Protein energy wasting (PEW) is a common syndrome in patients with chronic kidney disease, related to changes in hydration status, decreased food intake and inflammation. There are several tools for the assessment and diagnosis of such alterations. Bioimpedance vector analysis (BIVA) assess the state of nutrition and hydration, but not the inflammatory component, while the malnutrition inflammation score (MIS) comprises the inflammatory and nutritional factors, but not the state of hydration. The aim of the study was to determine the concordance between MIS and BIVA to assess nutritional status in peritoneal dialysis patients. METHODS: We studied 50 patients on peritoneal dialysis which underwent bioelectrical impedance measurements with an empty peritoneal cavity, also MIS was applied and biochemical parameters were evaluated. RESULTS: The prevalence of malnutrition with VIBE and MIS was 38% and 24% respectively. Statistically significant differences in body mass index (BMI) and phase angle between normally nourished and wasted patients by both methods were found. Body composition, biochemical parameters and impedance vectors were not statistically different between normally nourished and wasted patients. Concordance between methods was 0.314 (p = 0.019). CONCLUSIONS: Combined nutritional assessment with MIS and BIVA is necessary for the diagnosis of protein energy wasting syndrome in patients undergoing peritoneal dialysis. PMID- 29130712 TI - [Development of a food composition database for valoration of dietary intake in Peruvian Amazon]. AB - AIM: The aim of this study was the development of a specific food composition database of Peruvian Amazonia with which value the dietary intake of the population. METHODOLOGY: An observational surveying study has been performed at which 303 individuals aged 3-83 years were selected. To compiling a register of basic food reminders of 24 hours (R24) and frequency foods consumption questionnaires (FFQ) over a four-year period were collected, and were complemented by the National Household Budget Survey. The database was formulated on the basis of guidelines described by Greenfiel and Southgate and those proposed by INFOODS. RESULTS: A food composition database was developed using the indirect method with 135 foods provided information on the content in energy, macronutrients, sodium, potassium, phosphorus, calcium, iron, thiamine, riboflavin, folic acid, B12, B6, C, A y D. The references used were those of composition of Peruvian foods, Central America's, McCance and Widdowson's and USDA's tables, among others. CONCLUSIONS: The database development was indispensable for the dietary model valuation in this community, because the Composition of Peruvian Foods Tables do not provide sufficiently complete information on nutrient composition of foods the most consumed in Amazonia. PMID- 29130713 TI - [Gestational weight gain and postpartum weight retention in a cohort of women in Aragon, Spain]. AB - OBJECTIVES: To describe gestational weight gain and postpartum weight retention in women classified by pre-pregnancy body mass index BMI). METHODS: Prospective cohort study with a sample of 301 women. Weight was evaluated throughout pregnancy and puerperium. Multilinear regression models were performed to assess determinants of gestational weight gain and postpartum weight retention by pre gestationalBMI categories. RESULTS: During pregnancy, 36.5% of the participants gained more weight than recommended, and 90% retained weight at six months after childbirth. Slim women had greater weight gain during pregnancy and retained more postpartum weight. Age, parity, miscarriage history, pre-gestational BMI, origin and place of residence were independently associated with gestational weight gain. Postpartum weight retention was directly related to gestational weight gain and inversely with breastfeeding duration. CONCLUSIONS: Pre-gestational BMI is a predictor of gestational weight gain. Also, gestational weight gain is a predictor of postpartum weight retention. Educational programs focused on promoting healthy behaviors are needed both in pregnancy and postpartum. PMID- 29130714 TI - Intake of fibers and its association with cardiometabolic risk factors in individuals on a secondary prevention for cardiovascular diseases: a multicenter study. AB - INTRODUCTION: Among the non-pharmacologic measures for the prevention and treatment of cardiovascular diseases (CVD), which are the first cause of death worldwide, the adequate intake of dietary fibers (DF) has shown an important role. OBJECTIVE: To evaluate the association between the intake of DF and the cardio-metabolic risk factors in individuals on a secondary prevention for CVD. METHODS: Transversal study with basal data of the study's DICA Br participants belonging to collaborative centers in the states of Maranhao (MA), Bahia (BA) and Rio de Janeiro (RJ). Sociodemographic and clinical data were used, as well as the daily intake of DF in individuals of both sexes, with age >= 45 years and manifest evidence of arteriosclerosis. The association between the intake of dietary fibers and the cardio-metabolic risk factors was obtained through Poisson's regression model. RESULTS: With 141 evaluated individuals, high frequency of non-appropriateness of DF intake was observed. The participants in the centers of RJ (PR = 0.63; CI 95% = 0.49-0.80) and BA (PR = 0.79; CI 95% = 0.66-0.95), former smokers (PR = 0.59; CI 95% = 0.45-0.78) and non-smokers (PR = 0.62; CI 95% = 0.66-0.95) had fewer chances of having non appropriate intake of DF. On the other hand, overweight individuals showed 28.0% more chances of non appropriate intake of DF. CONCLUSION: Results showed that the majority of the observed population presented non-appropriate intake of DF and that this low intake was significantly associated with overweight, smoking and location of the collaborative center. PMID- 29130715 TI - Relationship of long-term macronutrients intake on anabolic-catabolic hormones in female elite volleyball players. AB - INTRODUCTION: Specific macronutrient distribution and training can alter acute and chronic hormone behavior and, subsequently, sport performance. OBJECTIVE: The main aim was to examine relationships between dietary intake and anabolic/catabolic hormone response in elite female volleyball players during a 29-week season. METHODS: Twenty-two elite female volleyballers (26.4 +/- 5.6 years; 178 +/- 9 cm; 67.1 +/- 7.5 kg) had dietary intake (seven-day dietary recall and food frequency questionnaire), blood concentration of anabolic/catabolic hormones concentration, physical performance, and body composition assessed at four time points: a) T1: baseline/pre-testing; b) T2: eleven weeks after T1; c) T3: ten weeks after T2; and d) T4: eight weeks after T3. Hormones evaluated were: total testosterone (TT), free testosterone (FT) adrenocorticotropic hormone (ACTH), and cortisol (C), along with hormone ratios. RESULTS: Positive correlations were observed between carbohydrate/protein ratio with DeltaFT (r = 0.955; p < 0.001), DeltaTT/C ratio (r = 0.638; p = 0.047), and DeltaFT/C ratio (r = 0.909; p < 0.001). Significant and negative correlations were found between protein intake with DeltaTT (r = -0.670; p = 0.034), and FT (r = -0.743; p < 0.001), carbohydrate intake and DeltaACTH (r = -0.658; p = 0.006). No relationships were observed regarding Deltacortisol. On the other hand, there was no change (p > 0.05) in body mass or body mass index at any time point, and the sum of six skinfolds improved (p < 0.05) from T1 (86.5 +/- 6.9 mm) to T4 (75.2 +/- 5.6 mm) as did muscle mass (T1: 28.9 +/- 0.7 kg vsT4: 30.1 +/- 0.8 kg). Vertical jump, spike-jump and speed improved (p < 0.05) from T1 to T4. CONCLUSIONS: A high carbohydrate/protein ratio was associated with positive changes in anabolism, while high protein and low carbohydrates (CHO) were associated with an attenuated anabolic response. PMID- 29130716 TI - [Effect of quinua (Chenopodium quinoa)consumption as a coadjuvant in nutritional intervention in prediabetic subjects]. AB - INTRODUCTION: Quinoa is a pseudocereal containing low glycemic index carbohydrates, dietary fiber, high biological value protein, phytosterols, and n 3 and n-6 fatty acids, which has generated interest in prediabetes nutritional interventions. This randomized (2:1), placebo-controlled, double-blind study evaluated the effects of processed quinoa on body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG) and the satiation and fullness (complete) degree in prediabetic patients. MATERIAL AND METHOD: Thirty patients were randomized (2:1) in two study arms: Kuska Active product (processed quinoa) and placebo (maltodextrin), with an intake period of 28 days. BMI, HbA1c and FPG were determined before starting treatment and at 28-day intake. Satiety and fullness sensation were just assessed by visual analog scale (VAS) at the day 28. ANOVA was performed for repeated measures with two factors to study (within subject factor: time; intersubject factor: product consumed) to demonstrate the effectiveness of processed quinoa on the study variables. RESULTS: Twenty-nine patients (placebo, n = 10; quinoa, n = 19) completed the study, and the quinoa group shows a significant decrease in BMI (p < 0.05) and HbA1c values (p < 0.001), and an increase in the satiation and fullness (complete) degree (p < 0.001). No significant differences were found in FPG levels from baseline to post intake period. CONCLUSIONS: The results show that processed quinoa intake during 28 days decreases BMI and HbA1c levels, maintains FPG levels, and incr eases the satiation and fullness (complete) degree in prediabetic patients. PMID- 29130717 TI - Effect of the implementation of the mixed cafeteria system in a hospital nutrition and dietetic service. AB - INTRODUCTION: The type of service offered by the nutrition and dietetics service (NDS) of a hospital has a direct impact on food waste. OBJECTIVE: To evaluate waste in the transition from a simple to a mixed cafeteria service. METHODOLOGY: The study was carried out in a NDS of a University Hospital during 60 days (30 days for each type of service). The meals prepared and distributed and the leftovers of lunch and dinner were weighed. RESULTS: Per capita values of non usable leftovers were below the acceptable range (7-25 g), not varying with the service transition (p = 0.3) at lunch. At dinner, on the contrary, values were above the acceptable range, with a median of 190 g and 202 g, also showing no difference with the service modification (p = 0.5). At lunch, with the transition, there was a reduction in the plate waste-ingestion (p < 0.0001), percentage of plate waste-ingestion (p < 0.0001) and percentage of non-usable foods (p = 0.007). At dinner, there was a reduction in the plate waste-ingestion (p < 0.0001) and in the percentage of plate waste-ingestion (p = 0.0001). CONCLUSION: The modification of the service type was effective in reducing the plate waste-ingestion, but did not lead to operational modifications of the service, since the amount of non-usable leftovers remained high at dinner. Greater control of the production and distribution of meals is suggested, as well as training of food handlers and supervisors, implementation of standardized operating procedures and cost control in order to reduce waste, which has an economic, social and political impact. PMID- 29130718 TI - Eating disorders during the adolescence: personality characteristics associated with anorexia and bulimia nervosa. AB - INTRODUCTION: Previous studies provide relevant information about the relationship between personality and eating disorders (ED). The involvement of personality factors in the etiology and maintenance of ED indicates the need of emphasizing the study of the adolescent's personality when diagnosed of ED. OBJECTIVES: The aims of this study were to analyze the adolescent's personality profiles that differ significantly in anorexia nervosa (AN) and bulimia nervosa (BN), and to explore the most common profiles and their associations with those subtypes of eating disorders (ED). METHODS: A total of 104 patients with AN and BN were studied by means of the Millon Adolescent Clinical Inventory (MACI). RESULTS: The personality profiles that differ significantly in both AN and BN were submissive, egotistic, unruly, forceful, conforming, oppositional, self demeaning and borderline. The most frequent profiles in AN were conforming (33.33%), egotistic (22.72%) and dramatizing (18.18%) while in the case of BN those profiles were unruly (18.42%), submissive (18.42%) and borderline (15.78%). We did not find any associations between the diagnostic subgroup (AN, BN) and the fact of having personality profiles that could become dysfunctional. CONCLUSIONS: Bearing in mind these results, it may be concluded that there are relevant differences between personality profiles associated with AN and BN during adolescence, so tailoring therapeutic interventions for this specific population would be important. PMID- 29130719 TI - [Prevalence of modifiable behavioral risk factors associated to non-communicable diseases in Latin American college students: a systematic review]. AB - INTRODUCTION: Physical inactivity, smoking, harmful use of alcohol and an unhealthy diet are considered by the World Health Organization (WHO) as the four main behavioral risk factors that increase the risk of suffering non-communicable diseases. OBJECTIVE: To describe the prevalence of the behavioral risk factors in college students according to the scientific database analyzed. MATERIALS AND METHODS: A systematic review was carried out with 585 articles analyzed through electronic search in academic databases. After the analysis, 93 studies that fulfill the inclusion criteria were selected. RESULTS: The final mean of the prevalence found in the articles analyzed was of 52,57% +/- 22,53% for physical inactivity, 22,61% +/- 12,91% for smoking, 26,2 (RI 24,5) for harmful use of alcohol and 81,3% +/- 16,3% for low intake of fruits and vegetables. CONCLUSIONS: The results show the existence of an unhealthy lifestyle in Latin-American college students. PMID- 29130720 TI - [Relationship between quality of life, physical activity, nutrition, glycemic control and sarcopenia in older adults with type 2 diabetes mellitus]. AB - INTRODUCTION: The term sarcopenia is defined as age-related loss of skeletal muscle mass and function, with a consequent impact on quality of life. However, there is a lack of studies examining the prevalence of sarcopenia in patients with type 2 diabetes mellitus (DM). OBJECTIVES: To analyze the prevalence of sarcopenia in patients over 65 years with type 2 DM and the influence of physical activity, diet, glycemic control, sex, age, and quality of life. METHODS: A total of 279 patients (155 females), aged 76.6 +/- 6.27 years, participated in this study in order to analyze body circumferences (waist, hip, calf, and arm), body mass index, handgrip strength, physical activity level, nutritional status, quality of life, and glycemic control. The cut-off value for sarcopenia was defined as the body mass index lower than 9.2 or 7.4 kg/m2 for males and females, respectively. RESULTS: In participants, the prevalence of sarcopenia was 8.33%. Moreover, the level of sarcopenia was negatively associated with quality of life (r = -0.130, p = 0.030), physical activity (r = -0.164, p = 0.006), nutritional status (r = -0.274, p < 0.001), and male sex (r = -0.137, p = 0.022); and positively associated with age (r = 0.183, p = 0.002). CONCLUSIONS: The prevalence of sarcopenia in patients with type 2 DM is moderate, and it is related to relevant health factors, such as lower quality of life, lower physical exercise level, and increased malnutrition, especially in older adult males. PMID- 29130721 TI - The nutritional limitations of plant-based beverages in infancy and childhood. AB - Breastfeeding, infant formula and cow's milk are basic foods in infant nutrition. However, they are being increasingly replaced either totally or partially by plant-based beverages.The composition of 164 plant-based beverages available in Spain was reviewed based on the nutritional labeling of the package and the manufacturers' webpages. This was compared to the composition of cow's milk and infant formula. In addition, the nutritional disease associated with consumption of plant-based beverages in infants and children was reviewed by means of a literature search in Medline and Embase since 1990 based on the key words "plant based beverages" or "rice beverages" or "almond beverages" or "soy beverages" and "infant" or "child".The nutritional composition of 54 soy beverages, 24 rice beverages, 22 almond beverages, 31 oat beverages, 6 coconut beverages, 12 miscellaneous beverages and 15 mixed beverages was described. At least 30 cases of nutritional disease in children associated with nearly exclusive consumption of plant-based beverages have been published. A characteristic association has been observed between soy beverage and rickets, rice beverage and kwashiorkor, and almond-based beverage and metabolic alkalosis.The nutritional quality of plant-based beverages is lower than that of cow's milk and infant formula, therefore they are not a nutritional alternative. Predominant or exclusive use of these beverages in infant feeding can lead to serious nutritional risks. In the case of nonexclusive feeding with these beverages, the pediatrician should be aware of the nutritional risks and limitations of these beverages in order to complement their deficiencies with other foods. PMID- 29130722 TI - ? AB - INTRODUCTION: Malnutrition is a health problem which affects a high percentage of old people since the physical and psychosocial changes common to this period of life favor it in this group. In addition, aging population has a high prevalence of chronic illnesses and acute pathologies which can affect their nutritional state negatively, leading to malnutrition related to illness. OBJECTIVE: The aim of this systematic revision was to analyze the economic costs related to malnutrition in old people and to discover whether there were differences between economic costs of pre-existing malnutrition prior to illness and malnutrition because of disease. METHOD: A bibliographic search was carried out in the databases of Pubmed, Web of Science and Scopus, for the period between 2000 and 2016. RESULTS: A total of 1,001 articles were found and 19 were selected using inclusion criteria. Of these, eleven analyzed the costs of pre-existing malnutrition prior to illness, seven analyzed the costs of malnutrition related to illness and one, both situations. CONCLUSIONS: In general, malnutrition increased health costs as a result of hospital admissions, greater number of readmissions and greater demand on health resources. Moreover, in the studies analyzed, pre-existing malnutrition prior to illness implied greater costs than those related to the actual illness; therefore, it would be convenient to establish selection and preventive policies on malnutrition in old people. PMID- 29130723 TI - [Telomeres and diet quality]. AB - BACKGROUND: Few studies have evaluated the relationship between diet quality and telomere integrity in humans. Telomeres are regions of non-coding DNA localized at the end of each chromosome whose length, in addition to indicating life expectancy, indicates an overall health status. The objective of this systematic review is to compile the existing evidence on the relationship between telomere length and diet quality to further explore the impact that some nutrients, foods and dietary patterns may have on telomere homeostasis and therefore, in precision nutrition strategies. MATERIAL AND METHODS: A bibliographic review was performed in the PubMed database to identify published articles (in English or Spanish) until December 2016 that met the following criteria: included human subjects; cross-sectional studies; case-control studies; prospective cohort studies or intervention studies; evaluating the relationship of nutrients, foods or dietary patterns on telomere integrity. The search strategy included the following keywords: nutrients or food OR food groups OR diet OR dietary pattern OR eating pattern OR dietary habits OR diet type AND telomere attrition OR telomere length. In total, 19 cross-sectional studies, five case-control studies, five prospective cohort studies, and two intervention studies were included, including those articles that were found for being listed in other publications. RESULTS: Positive associations were found between telomere length and adherence to the Mediterranean diet and consumption of vegetables and fruits. The results observed for other nutrients, foods or dietary patterns were incoherent although it seems that processed meats, cereals, alcohol and sweetened beverages could be associated with shorter telomeres. CONCLUSIONS: Dietary intervention, and in particular the promotion of a Mediterranean-style diet, may play a role in the protection of telomere integrity. PMID- 29130724 TI - Probiotics for fibromyalgia: study design for a pilot double-blind, randomized controlled trial. AB - BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic, generalized and diffuse pain disorder accompanied by other symptoms such as emotional and cognitive deficits. The FMS patients show a high prevalence of gastrointestinal symptoms. Recently it has been found that microbes in the gut may regulate brain processes through the gut-microbiota-brain axis, modulating thus affection, motivation and higher cognitive functions. Therefore, the use of probiotics might be a new treatment that could improve the physical, psychological and cognitive state in FMS; however, no evidence about this issue is available. METHODS: This paper describes the design and protocol of a double-blind, placebo-controlled and randomized pilot study. We use validated questionnaires, cognitive task through E Prime and biological measures like urine cortisol and stool fecal samples. The trial aim is to explore the effects of eight weeks of probiotics therapy in physical (pain, impact of the FMS and quality of life), emotional (depression, and anxiety) and cognitive symptoms (attention, memory, and impulsivity) in FMS patients as compared to placebo. CONCLUSION: This pilot study is the first, to our knowledge, to evaluate the effects of probiotics in FMS. The primary hypothesis was that FMS patients will show a better performance on cognitive tasks, and an improvement in emotional and physical symptoms. These results will contribute to a better understanding in the gut-brain axis. Here we present the design and protocol of the study. PMID- 29130725 TI - [Eighth Jesus Culebras Lecture. Critical Care, nutrition and hyperglycemia: a close relationship]. AB - Critically ill patients show a metabolic response to injury that affects carbohydrate metabolism, causing hyperglycemia and an increase in glycemic variability that makes the critically ill patient susceptible to infection, resulting in morbidity and mortality increase. Also, severe hypoglycemia was detected as a consequence of intensive insulin treatment that provokes deleterious effects in their clinical evolution, so a correct monitoring of plasma glucose would contribute to reduce morbidity and mortality. In critically ill patients, glucose metabolism is in allostasis stage as a consequence of metabolic stress, producing an increase in peripheral resistance to insulin that causes an imbalance with the pancreatic beta-cell function, increasing insulin secretion to maintain plasma glucose levels within normality ranges. Numerous studies have been published about treatments with insulin and glycemic variability, whereas there are very few about nutrometabolic treatment of hyperglycemia in critically ill patients. Of all of them we can conclude that it is always recommended to keep glucose levels under 180 mg/dl, and when possible, not over 150 mg/dl, establishing a lower range of 110-140 mg/dl. Moreover, tight glycemic control increases the risk of severe hypoglycemia (<= 40 mg/dl) and its subsequent mortality, so we advise against it. Besides, glycemic variability has been independently associated with an increase of mortality in critically ill patients and, consequently, protocols should aim at avoiding it. Nutritional treatment with diabetes-specific diets not only improves hyperglycemic control and decreases insulin needs, but also decreases glycemic variability and could reduce the incidence of infectious complications. Therefore, they are recommended, at least during the first week of stay. Finally, diabetes seems to modulates the consequences of hyperglycemia in critically ill patients, so diabetic patients could benefit from a higher glycemic target than those without diabetes but with stress hyperglycemia. PMID- 29130726 TI - [Importance of selection criteria for the determination of sugar-sweetened beverage consumption in children and adolescents]. PMID- 29130727 TI - [Correlation attenuation and low reliability: does it really matter?] PMID- 29130728 TI - [Importance of differentiating cutoff points from BMI according to age]. PMID- 29130734 TI - The Rare Lateral Cuneo-Cuboid Coalition: A Case Report. AB - BACKGROUND: Tarsal coalitions typically occur at the talocalcaneal or calcaneonavicular joints. Common findings are pain, limited range of motion, and a pes planus deformity. METHODS: The focus of this case report will include the presentation, imaging, treatment, and outcomes for a 21-year-old female diagnosed with a rare lateral cuneo-cuboid coalition with chronic pain. Clinical and radiographic examinations, typically utilized to diagnose the common coalition, were unremarkable. An MRI was diagnostic of the lateral cuneo-cuboid coalition and was successfully treated with surgical resection. RESULTS: At 6-year follow up, she reports resolution of symptoms and has returned to her normal pre surgical activity level pain-free. CONCLUSIONS: This case is only the third lateral cuneo-cuboid coalition reported in the literature. The rarity of this coalition and unsuspecting clinical presentation makes it worthy of acknowledgement. PMID- 29130735 TI - Evaluation of the Pharmacodynamic Effects of the Potassium Binder RDX7675 in Mice. AB - INTRODUCTION: Hyperkalemia is a common complication in patients with heart failure or chronic kidney disease, particularly those who are taking inhibitors of the renin-angiotensin-aldosterone system. RDX7675, the calcium salt of a reengineered polystyrene sulfonate-based resin, is a potassium binder that is being investigated as a novel treatment for hyperkalemia. This study evaluated the pharmacodynamic effects of RDX7675 in mice, compared to 2 current treatments, sodium polystyrene sulfonate (SPS) and patiromer. METHODS: Seven groups of 8 male CD-1 mice were given either standard chow (controls) or standard chow containing 4.0% or 6.6% active moiety of RDX7675, patiromer, or SPS for 72 hours. Stool and urine were collected over the final 24 hours of treatment for ion excretion analyses. RESULTS: RDX7675 increased stool potassium (mean 24-hour excretion: 4.0%, 9.19 mg; 6.6%, 18.11 mg; both P < .0001) compared with controls (4.47 mg) and decreased urinary potassium (mean 24-hour excretion: 4.0%, 12.05 mg, P < .001; 6.6%, 6.68 mg, P < .0001; vs controls, 20.38 mg). The potassium-binding capacity of RDX7675 (stool potassium/gram of resin: 4.0%, 1.14 mEq/g; 6.6%, 1.32 mEq/g) was greater (all P < .0001) than for patiromer (4.0%, 0.63 mEq/g; 6.6%, 0.48 mEq/g) or SPS (4.0%, 0.73 mEq/g; 6.6% 0.55 mEq/g). RDX7675 and patiromer decreased urinary sodium (mean 24-hour excretion: 0.07-1.38 mg; all P < .001) compared to controls (5.01 mg). In contrast, SPS increased urinary sodium excretion (4.0%, 13.31 mg; 6.6%, 17.60 mg; both P < .0001) compared to controls. CONCLUSIONS: RDX7675 reduced intestinal potassium absorption and had a greater potassium-binding capacity than patiromer or SPS in mice. The calcium-based resins RDX7675 and patiromer reduced intestinal sodium absorption, unlike sodium based SPS. These results support further studies in humans to confirm the potential of RDX7675 for the treatment of patients with hyperkalemia. PMID- 29130736 TI - The ISBER Strategic Plan: Growing Stronger Through International Cooperation. PMID- 29130738 TI - Ethylene Glycol and Dimethyl Sulfoxide Combination Reduces Cryoinjuries and Apoptotic Gene Expression in Vitrified Laying Hen Ovary. AB - Successful cryopreservation of avian gonads is important not only for avian breeding but is also crucial for preservation of species, especially of endangered birds. The aim of this study was to evaluate the effect of vitrification by several cryoprotectants on the ovarian tissues of laying hens. Ovarian tissues were randomly divided into six groups: control (nonvitrified: C), dehydrated using ethylene glycol (EG), dehydrated with propylene glycol (PROH), dehydrated using dimethyl sulfoxide (DMSO), and two combined groups, EG+DMSO and EG+PROH. The composition of vitrification solutions was as follows: EG group: V1 = 7.5% EG and V2 = 15% EG +0.5 M sucrose, DMSO group: V1 = 7.5% DMSO and V2 = 15% DMSO +0.5 M sucrose, PROH group: V1 = 7.5% PROH and V2 = 15% PROH +0.5 M sucrose, EG+DMSO group: V1 = 7.5% EG +7.5% DMSO and V2 = 15% EG +15% DMSO +0.5 M sucrose and EG+PROH group: V1 = 7.5% EG +7.5% PROH and V2 = 15% EG +15% PROH +0.5 M sucrose. Ovarian tissues of each group were dehydrated for 10 minutes with V1 solution and 2 minutes with V2. Among the vitrified groups, intact primordial and primary follicles showed significant increase in EG+DMSO, but follicular attrition had the highest rate in the PROH group (p < 0.05). Immunohistochemical analysis showed that the percentage of active caspase 3-positive cells was lower (p < 0.05) when using EG+DMSO versus PROH. Further gene expression of caspase 3, 8, and 9 was highest in the PROH group (p < 0.05). Vitrification of ovaries of laying hens using EG+DMSO can afford effective protection of primordial and primary follicles during preservation and may therefore be successfully used for storing avian gonadal tissues. PMID- 29130739 TI - Trans-umbilical laparoscopic-assisted appendectomy in the pediatric population: comparing single-incision and 2-trocar techniques. AB - INTRODUCTION: Trans-umbilical laparoscopic-assisted appendectomy (TULAA) combines advantages of open surgery with benefits of laparoscopy and can be performed either by single-incision or with two trocars; the present study aims to compare outcomes and cost of these techniques in a pediatric serie. MATERIAL AND METHODS: Patients undergoing TULAA between July 2013 and June 2014 were retrospectively reviewed. There were two groups: A (single-incision) - one umbilical trocar for a telescope with inbuilt working channel; and B (2-trocar) - one umbilical trocar for a 'standard' telescope plus a supra-pubic trocar for instruments. RESULTS: One-hundred and eighty-nine patients (112 males, age: 12[2-17] years) underwent TULAA; 32(17%) presented with perforated appendicitis. Group A encompassed 157 and group B 32 patients; age, gender, proportion of perforated appendicitis, and follow-up were similar. Operative time was 46 [21-145] min in group A, and 54.5[30-111] in group B (A vs B, p = 0.087). Length of hospital stay was 2 [1;22] days in group B, and 2 [0;24] in group A (A vs B, p = 0.136). The prevalence of post-operative complications was similar: 11 (7%) cases in group A and 2 (6.3%) intra-abdominal abscesses in group B. Using disposable trocars, the more expensive starting point of single-incision technique may be reversed after 27 procedures. CONCLUSION: Single-incision and 2-trocar TULAA are effective techniques with low complication rates and similar outcomes. Despite being technically more demanding, single incision may be advantageous because there are no visible scars, and potentially cheaper in hospitals where disposable trocars are used. PMID- 29130740 TI - A student perspective on preparing for difficult consultations in the clinical environment. PMID- 29130743 TI - Clarification. AB - Nodzo SR, Miladore MP, Kaplan NB, Ritter CA. Short to Midterm Clinical and Radiographic Outcomes of the Salto Total Ankle Prosthesis. Foot Ankle Int. 2014;35(1): 22-29. (Original DOI: 10.1177/1071100713510497 ). PMID- 29130742 TI - Internal roosting location is associated with differential use of the outdoor range by free-range laying hens. AB - 1. In commercial free-range systems for laying hens, popholes to the outdoor range are often installed on one side of the house only. In multi-tier systems, it is possible that some individuals fail to access the range due to internal barriers to movement. 2. Five commercial multi-tier flocks from different units were studied. For each flock, two different colour markers were used to distinguish 200 birds roosting near the popholes (NP-Roost) and 200 birds roosting far from the popholes (FP-Roost) at night. The following day, counts of marked birds on the range and inside the house were performed. 3. Significantly more NP-Roost birds were observed in all areas of the outdoor range than FP-Roost birds the next day. Distance of FP area from the popholes was very strongly positively correlated with effect size in the adjacent range area. 4. Additionally, in the indoor area far from the popholes (FP) more FP-Roost birds were observed the next day than NP-Roost birds. In the indoor area near to the popholes (NP) more NP-Roost birds were observed the next day than FP-Roost birds. 5. These results suggest that roosting location is associated with differential range use when popholes are only available on one side of the shed as birds that roosted far from the popholes used the range less. PMID- 29130746 TI - Corrigendum. AB - Kestner CJ, Glisson RR, Nunley JA. A Biomechanical Analysis of Two Anterior Ankle Arthrodesis Systems. Foot Ankle Int. 2013;34(7):1006-1011. (Original DOI: 10.1177/1071100713484007 ). PMID- 29130747 TI - Influence of Storage and Inter- and Intra-Assay Variability on the Measurement of Inflammatory Biomarkers in Population-Based Biobanking. AB - BACKGROUND: In the present study, we examined the effect of sample storage on the reproducibility of several inflammatory biomarkers, including high-sensitivity C reactive protein (hsCRP), high-sensitivity interleukin-6 (hsIL6), and high sensitivity tumor necrosis factor alpha (hsTNFalpha). In addition, we assessed inter- and intra-assay variability between collaborating biobanks. METHODS: In total, 240 fasting plasma samples were obtained from the LifeLines biobank. Samples had been stored for less than 2 or more than 4 years at -80 degrees C. Measurements were performed at three different laboratories. hsCRP was measured by immunonephelometry and ELISA, hsIL6, and hsTNFalpha samples were measured with ELISAs from two different manufacturers. For confirmation, similar analyses were performed on samples obtained from a subpopulation of 80 obese individuals. Passing-Bablok regression analysis and Bland-Altman plots were used to compare the results. RESULTS: We observed good stability of samples stored at -80 degrees C. hsCRP measured on the day of blood draw was similar to levels measured after more than 4 years of storage. There were small interlaboratory differences with the R&D ELISAs for hsIL6 and hsTNFalpha. We found a linear correlation between the Bender Medsystems ELISA and the R&D ELISA for hsIL6, with significantly higher levels measured with the R&D ELISA. Over 90% of hsTNFalpha samples measured with the IBL ELISA were below the detection limit of 0.13 ng/L, rendering this assay unsuitable for large-scale analysis. Similar results were found in the confirmation study. CONCLUSION: In summary, plasma hsCRP showed good stability in samples stored for either less than 2 years or more than 4 years at 80 degrees C. Both the R&D and Bender Medsystems for hsIL6 measurement yielded similar results. The IBL hsTNFalpha assay is not suited for use in biobanking samples. Assays for the measurement of inflammatory biomarker assays should be rigorously tested before large sample sets are measured. PMID- 29130748 TI - Evaluation of Two Matrices for Long-Term, Ambient Storage of Bacterial DNA. AB - BACKGROUND: Culture-independent molecular analyses allow researchers to identify diverse microorganisms. This approach requires microbiological DNA repositories. The standard for DNA storage is liquid nitrogen or ultralow freezers. These use large amounts of space, are costly to operate, and could fail. Room temperature DNA storage is a viable alternative. In this study, we investigated storage of bacterial DNA using two ambient storage matrices, Biomatrica DNAstable(r) Plus and GenTegra(r) DNA. METHODS: We created crude and clean DNA extracts from five Streptococcus pneumoniae isolates. Extracts were stored at -30 degrees C (our usual DNA storage temperature), 25 degrees C (within the range of temperatures recommended for the products), and 50 degrees C (to simulate longer storage time). Samples were stored at -30 degrees C with no product and dried at 25 degrees C and 50 degrees C with no product, in Biomatrica DNAstable Plus or GenTegra DNA. We analyzed the samples after 0, 1, 2, 4, 8, 16, 32, and 64 weeks using the Nanodrop 1000 to determine the amount of DNA in each aliquot and by real-time PCR for the S. pneumoniae genes lytA and psaA. Using a 50 degrees C storage temperature, we simulated 362 weeks of 25 degrees C storage. RESULTS: The average amount of DNA in aliquots stored with a stabilizing matrix was 103%-116% of the original amount added to the tubes. This is similar to samples stored at 30 degrees C (average 102%-121%). With one exception, samples stored with a stabilizing matrix had no change in lytA or psaA cycle threshold (Ct) value over time (Ct range <=2.9), similar to samples stored at -30 degrees C (Ct range <=3.0). Samples stored at 25 degrees C with no stabilizing matrix had Ct ranges of 2.2-5.1. CONCLUSION: DNAstable Plus and GenTegra DNA can protect dried bacterial DNA samples stored at room temperature with similar effectiveness as at -30 degrees C. It is not effective to store bacterial DNA at room temperature without a stabilizing matrix. PMID- 29130749 TI - Does Maternal Synbiotic Supplementation Affect Conjugated Linoleic Acid Level in Breast Milk? A Randomized Placebo-Controlled Clinical Trial. AB - AIM: As conjugated linoleic acid (CLA)is a potential growth promotor in newborns, the present pilot study aimed at measuring the effect of synbiotic supplementation on breast milk CLA level. MATERIALS AND METHODS: Sixty lactating mothers were randomly allocated to take either synbiotic (n = 31) or placebo (n = 29) for 30 days. Maternal anthropometric indices were measured at the onset and end of the study by standard methods and body mass index was calculated. Information on food intake was collected by using a 24 hours 24-hour recall method for 2 days and food record questionnaire for 1 day. Breast milk lipids were extracted and CLA level was quantified by gas chromatography. RESULTS: No significant differences were observed in the baseline mean breast milk concentrations of Fatty acids (FAs) between the synbiotic and placebo groups (p > 0.05). The CLA content of breast milk increased significantly by 58% (from 0.19 +/- 0.15 to 0.30 +/- 0.22 mmol/L) in the supplemented group, whereas it decrease decreased slightly but not significantly by 14% (from 0.22 +/- 0.14 to 0.19 +/- 0.10 mmol/L) in the placebo group. After adjustment for covariates, the CLA content of breast milk was significantly higher in the supplemented group compared with placebo group after the intervention (p = 0.03). The ratio of total n - 6:3 increased significantly over time in both groups, but was not different among groups (p < 0.05). CONCLUSIONS: This pilot study showed that supplementation of lactating women with synbiotic, resulted in increased breast milk CLA composition. Further research using different species of probiotic bacteria and analysis of maternal and infant plasma FAs would be beneficial. PMID- 29130751 TI - A Guide for Understanding Health Education and Promotion Programs. AB - Planning, Implementing & Evaluating Health Promotion Programs: A Primer is a versatile and comprehensive resource on the theoretical and practical underpinnings of successful health promotion programs. The requirements for effective health promotion program development are presented with frequent use of practical planning examples, pedagogical devices, and expert rationale. Ideal for undergraduate and graduate students in health education, promotion, and planning courses, this 15-chapter textbook is organized in a manner that specifically addresses the responsibilities and competencies required of health education specialists as published in the Health Education Specialist Practice Analysis of 2015. The authors of this textbook are leaders in the field and provide readers with the skills necessary to carry out the full process of health promotion program execution, while also offering direct preparation for CHES and MCHES licensing exams. PMID- 29130752 TI - Self-reported difficulty and preferences of wheeled mobility device users for simulated low-floor bus boarding, interior circulation and disembarking. AB - BACKGROUND: Low ridership of public transit buses among wheeled mobility device users suggests the need to identify vehicle design conditions that are either particularly accommodating or challenging. The objective of this study was to determine the effects of low-floor bus interior seating configuration and passenger load on wheeled mobility device user-reported difficulty, overall acceptability and design preference. METHODS: Forty-eight wheeled mobility users evaluated three interior design layouts at two levels of passenger load (high vs. low) after simulating boarding and disembarking tasks on a static full-scale low floor bus mockup. RESULTS: User self-reports of task difficulty, acceptability and design preference were analyzed across the different test conditions. Ramp ascent was the most difficult task for manual wheelchair users relative to other tasks. The most difficult tasks for users of power wheelchairs and scooters were related to interior circulation, including moving to the securement area, entry and positioning in the securement area and exiting the securement area. Boarding and disembarking at the rear doorway was significantly more acceptable and preferred compared to the layouts with front doorways. CONCLUSION: Understanding transit usability barriers, perceptions and preferences among wheeled mobility users is an important consideration for clinicians who recommend mobility-related device interventions to those who use public transportation. Implications for Rehabilitation In order to maximize community participation opportunities for wheeled mobility users, clinicians should consider potential public transit barriers during the processes of wheelchair device selection and skills training. Usability barriers experienced by wheeled mobility device users on transit vehicles differ by mobility device type and vehicle configurations. Full-scale environment simulations are an effective means of identifying usability barriers and design needs in people with mobility impairments and may provide an alternative model for determining readiness for using fixed route buses or eligibility for paratransit. PMID- 29130753 TI - In vitro and in vivo evaluation of controlled-release matrix tablets of highly water-soluble drug applying different mw polyethylene oxides (PEO) as retardants. AB - The aim of the work presented is to prepare a controlled-release hydrophilic matrix tablet (CMT) controlling release of highly water-soluble drug applying pure combination of high- and low-Mw PEO as matrix materials, to avoid the lag time of drug release, and to overcome incomplete release in later stages. The influences of types and amounts of different Mw PEOs used, drug loading, pH of release medium and agitation rate on drug release were evaluated. The study of uptake and erosion of matrix was conducted and mechanism of improving drug release was discussed. In vivo pharmacokinetics of the CMT and reference preparation self-made controlled-release osmotic pump tablets (COPT) were performed in beagle dogs. The optimized formulation containing 43% PEO WSR 303 and 32% PEO N750 showed a zero order release from 1 h to 12 h. In vivo results demonstrated that the CMT had similar AUC0-48 h and Cmax with the COPT but smaller Tmax than the COPT and provided a more stable therapeutic concentration compared to the COPT. In conclusion, hydrophilic matrix tablet combining only different Mw PEOs as matrix materials had very good potential to be developed into a controlled-release drug delivery system for highly water-soluble drug. Besides, its manufacturing processes were succinct which would be preferable for modern medicine industry. PMID- 29130755 TI - Scientific abstracts from the 7th International Barcode of Life Conference / Resumes scientifiques du 7e Conference internationale " Barcode of Life ". PMID- 29130754 TI - Corrigendum. PMID- 29130756 TI - Scientific abstracts from the 7th International Barcode of Life Conference / Resumes scientifiques du 7e Conference internationale " Barcode of Life ". PMID- 29130757 TI - International Barcode of Life: Focus on big biodiversity in South Africa. AB - Participants in the 7th International Barcode of Life Conference (Kruger National Park, South Africa, 20-24 November 2017) share the latest findings in DNA barcoding research and its increasingly diversified applications. Here, we review prevailing trends synthesized from among 429 invited and contributed abstracts, which are collated in this open-access special issue of Genome. Hosted for the first time on the African continent, the 7th Conference places special emphasis on the evolutionary origins, biogeography, and conservation of African flora and fauna. Within Africa and elsewhere, DNA barcoding and related techniques are being increasingly used for wildlife forensics and for the validation of commercial products, such as medicinal plants and seafood species. A striking trend of the conference is the dramatic rise of studies on environmental DNA (eDNA) and on diverse uses of high-throughput sequencing techniques. Emerging techniques in these areas are opening new avenues for environmental biomonitoring, managing species-at-risk and invasive species, and revealing species interaction networks in unprecedented detail. Contributors call for the development of validated community standards for high-throughput sequence data generation and analysis, to enable the full potential of these methods to be realized for understanding and managing biodiversity on a global scale. PMID- 29130758 TI - Proniosomes derived niosomes: recent advancements in drug delivery and targeting. AB - Vesicular drug delivery systems have gained wide attention in the field of nanotechnology. Among them proniosomes become the superior over other vesicular carriers. Proniosomes are dry formulations of water soluble nonionic surfactant coated carrier system which immediately forms niosomes upon hydration. They have the capability to overcome the instability problems associated with niosomes and liposomes and have the potential to improve solubility, bioavailability, and absorption of various drugs. Furthermore, they offer versatile drug delivery concept for enormous number of hydrophilic and hydrophobic drugs. They have the potential to deliver drugs effectively through different routes at specific site of action to achieve controlled release action and reduce toxic effects associated with drugs. This review discusses the general preparation techniques of proniosomes and mainly focus on the applications of proniosomes in drug delivery and targeting. Moreover, this review demonstrates critical appraisal of the literature for proniosomes. Additionally, this review extensively explains the potential of proniosomes in delivering drugs via different routes, such as oral, parenteral, dermal and transdermal, ocular, oral mucosal, vaginal, pulmonary, and intranasal. Finally, the comparison of proniosomes with niosomes manifests the clear distinction between them. Moreover, proniosomes need to be explored for proteins and peptide delivery and in the field of nutraceuticals and develop pilot plant scale up studies to investigate them in industrial set up. PMID- 29130759 TI - Preeclampsia in pregnancies complicated by systemic lupus erythematosus (SLE) nephritis: prophylactic treatment with multidisciplinary approach are important keys to prevent adverse obstetric outcomes. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) commonly affects women of childbearing age. Hypertension, antiphospholipid syndrome, and lupus nephritis are risk factors for adverse maternal/fetal outcome. The aim of this retrospective cohort study is to compare pregnancy outcomes in patients with and without SLE nephritis, using a multidisciplinary approach and a broad prophylaxis protocol. MATERIALS AND METHODS: Data were collected from 86 pregnancies complicated by SLE. Twenty-seven women with nephropathy before pregnancy stated as the study group and 59 formed the control group. Each group received a prophylactic treatment based on their clinical characteristics. Results were expressed as mean +/- SD, percentage and chi2-test (significant values when p < .05). RESULTS: The prophylactic treatment (60.4% of the patients) significantly controlled the complications related to some risk factors, such as antiphospholipid antibodies (aPL) and nephritis. Preeclampsia occurred in 14.8% of patients. Patients with pregestational hypertension showed a 2.75 odds ratio of adverse events when compared to the group without chronic hypertension. The presence of proteinuria was associated with a risk of preeclampsia 2.45 times greater, as well as serum creatinine >1.2 mg/dL, which was related to a risk 1.25 times higher than the risk observed in patients with serum creatinine <1.2 mg/dL. A 6-month inactive disease was associated with a better outcome. A value of Estimated Glomerular Filtration Rate (eGFR) < 90 mL/min/1.73 m2 resulted in a 18.73 times greater risk of preeclampsia, intrauterine growth restriction (IUGR), and preterm delivery. DISCUSSION: A multidisciplinary approach in a tertiary care center and a broad prophylactic treatment protocol to patients affected by SLE and complicated by nephritis may definitively foster a successful pregnancy. PMID- 29130760 TI - Risk factors for premature birth in French Guiana: the importance of reducing health inequalities. AB - OBJECTIVES: French Guiana has the highest birth rate in South America. This French territory also has the highest premature birth rate and perinatal mortality rate of all French territories. The objective was to determine the premature birth rate and to identify the prevalence of risk factors of premature birth in French Guiana. METHODS: A retrospective study of all births in French Guiana was conducted between January 2013 and December 2014 using the computerized registry compiling all live births over 22 weeks of gestation on the territory. RESULTS: During this period 12 983 live births were reported on the territory. 13.5% of newborns were born before 37 (1755/12 983). The study of the registry revealed that common sociodemographic risk factors of prematurity were present. In addition, past obstetrical history was also important: a scarred uterus increased the risk of prematurity adjusted odds ratio =1.4, 95%CI (1.2 1.6). Similarly, obstetrical surveillance, the absence of preparation for birth or of prenatal interview increased the risk of prematurity by 2.4 and 2.3, the excess fraction in the population was 69% and 72.2%, respectively. CONCLUSIONS: Known classical risk factors are important. In the present study excess fractions were calculated in order to prioritize interventions to reduce the prematurity rate. PMID- 29130761 TI - Systematic review: advice lines for patients with inflammatory bowel disease. AB - OBJECTIVE: Advice lines for patients with inflammatory bowel diseases (IBD) have been introduced internationally. However, only a few publications have described the advice line service and evaluated the efficiency of it with many results presented as conference posters. A systematic synthesis of evidence is needed and the aim of this article was to systematically review the evidence of IBD advice lines. MATERIALS AND METHODS: A broad systematic literature search was performed to identify relevant studies addressing the effect of advice lines. The process of selection of the retrieved studies was undertaken in two phases. In phase one, all abstracts were review by two independent reviewers. In phase two, the full text of all included studies were independently reviewed by two reviewers. The included studies underwent quality assessment and data synthesis. RESULTS: Ten published studies and 10 congress abstracts were included in the review. The studies were heterogeneous both in scientific quality and in the focus of the study. No rigorous evidence was found to support that advice lines improve disease activity in IBD and correspondingly no studies reported worsening in disease activity. Advice lines were found to be health economically beneficial with clear indications of the positive impact of advice lines from the patient perspective. CONCLUSION: The levels of evidence of the effect of advice lines in IBD are low. However, the use of advice lines was found to be safe, and cost effective. Where investigated, patients with IBD overwhelmingly welcome an advice line with high levels of patient satisfaction reported. PMID- 29130763 TI - Comparative Evaluation of a Novel Phage Protein Ligand Assay and Immunomagnetic Separation Method To Isolate the Seven Top Serogroups of Escherichia coli (O157, O26, O103, O145, O111, O45, and O121) in Foods at Risk. AB - The presence of Shiga toxin-producing Escherichia coli (STEC) in food is a major concern for food safety authorities and industries. Methods for detecting these pathogenic bacteria are crucial. Enrichment of foods for STEC identification has been optimized, but selective concentration of bacteria before isolation still needs to be improved. In the present study, we tested the performance of the VIDAS ESPT detection method against that of the immunomagnetic separation (IMS) method. A preenrichment inoculation was performed to provide a realistic scenario of the contamination that occurs in foods, and the methods were then compared. Results obtained were then confirmed in naturally contaminated foods. Preenrichment inoculation assays revealed that the novel concentration method using phage recombinant proteins or the selective capture of the target top seven STEC serogroups is as specific and sensitive as IMS. Subsequent evaluation of naturally contaminated samples confirmed that the novel concentration method and IMS are equivalent in performance under the conditions tested. PMID- 29130764 TI - Efficacy of a Blend of Sulfuric Acid and Sodium Sulfate against Shiga Toxin Producing Escherichia coli, Salmonella, and Nonpathogenic Escherichia coli Biotype I on Inoculated Prerigor Beef Surface Tissue. AB - A study was conducted to investigate the efficacy of a sulfuric acid-sodium sulfate blend (SSS) against Escherichia coli O157:H7, non-O157 Shiga toxin producing E. coli (STEC), Salmonella, and nonpathogenic E. coli biotype I on prerigor beef surface tissue. The suitability of using the nonpathogenic E. coli as a surrogate for in-plant validation studies was also determined by comparing the data obtained for the nonpathogenic inoculum with those for the pathogenic inocula. Prerigor beef tissue samples (10 by 10 cm) were inoculated (ca. 6 log CFU/cm2) on the adipose side in a laboratory-scale spray cabinet with multistrain mixtures of E. coli O157:H7 (5 strains), non-O157 STEC (12 strains), Salmonella (6 strains), or E. coli biotype I (5 strains). Treatment parameters evaluated were two SSS pH values (1.5 and 1.0) and two spray application pressures (13 and 22 lb/in2). Untreated inoculated beef tissue samples served as controls for initial bacterial populations. Overall, the SSS treatments lowered inoculated (6.1 to 6.4 log CFU/cm2) bacterial populations by 0.6 to 1.5 log CFU/cm2 (P < 0.05), depending on inoculum type and recovery medium. There were no main effects (P >= 0.05) of solution pH or spray application pressure when SSS was applied to samples inoculated with any of the tested E. coli inocula; however, solution pH did have a significant effect (P < 0.05) when SSS was applied to samples inoculated with Salmonella. Results indicated that the response of the nonpathogenic E. coli inoculum to the SSS treatments was similar (P >= 0.05) to that of the pathogenic inocula tested, making the E. coli biotype I strains viable surrogate organisms for in-plant validation of SSS efficacy on beef. The application of SSS at the tested parameters to prerigor beef surface tissue may be an effective intervention for controlling pathogens in a commercial beef harvest process. PMID- 29130765 TI - Microbiological Profile of Three Commercial Poultry Processing Plants in Colombia. AB - Poultry meat production in Colombia has significant growth potential to fulfill national demands and to become an important global exporter. Entering export markets requires compliance with international food safety standards and the support of a rigorous national inspection system. To support the development of national standards, information about the microbiological profiles of poultry operations is needed, and no official microbiological baseline is currently available. A total of 480 chicken carcass rinses and 64 fecal samples were collected at different process sites from three commercial poultry processing establishments located in different regions of Colombia. Samples were analyzed to determine the prevalence of Salmonella and the levels of Escherichia coli in chicken rinse. Six steps were selected for sampling in the slaughter, evisceration, and chilling processes. The overall Salmonella prevalence after water immersion chilling at the three establishments was 12.5% (73 of 584 samples). E. coli levels were 1.2 to 2.2 log CFU/mL (mean, 1.65 log CFU/mL) after the chilling process. Significant differences (P < 0.05) were found for E. coli levels among the processing sites at the three establishments; however, there were no significant differences in the distribution of Salmonella-positive samples through the sites at each plant. These results can be used as reference data for microorganisms in chicken meat facilities in Colombia and will help the poultry industry and regulators in the design of new prevention programs and food safety management systems. PMID- 29130766 TI - Molecular Characterization of Salmonella from Beef Carcasses and Fecal Samples from an Integrated Feedlot and Abattoir in Mexico. AB - Nontyphoid Salmonella strains are some of the leading causes of foodborne illnesses worldwide; however, there is very limited information on the presence and characteristics of Salmonella in the food production chain in developing countries. In this study, pulsed-field gel electrophoresis (PFGE) was used for molecular subtyping and for monitoring the ecology and transmission of Salmonella isolates in a slaughter facility in Mexico in an attempt to determine specific steps that need to be improved to reduce Salmonella contamination in beef carcasses. A total of 94 isolates from a Salmonella stock culture collection originally obtained from a single vertically integrated feedlot and beef abattoir in Mexico were analyzed. A total of 26 unique PFGE patterns were identified, 38.5% of them corresponding to a single serotype. High concordance (88.4%) was found between serotype and PFGE banding subtype. Salmonella Kentucky and Salmonella Give were the most clonal subtypes in this study, and Salmonella Muenster was the most diverse, with 11 banding patterns identified. A total of 73.7, 70.6, and 85.7% of the PFGE subtypes identified from preevisceration, precooler, and chilled carcasses, respectively, were identified only at those specific points and not at any previous or subsequent steps of the slaughter process, suggesting that each step is in itself a source of Salmonella contamination. Salmonella Mbandaka was more likely to be recovered from feces than from any of the steps of the slaughter process. The genetic diversity and distribution of PFGE subtypes in the processing facility highlight the need to implement antimicrobial interventions and improve sanitation procedures at various points to avoid further Salmonella dissemination into the meat supply. PMID- 29130767 TI - Using the International Classification of Functioning, Disability, and Health to identify outcome domains for a core outcome set for aphasia: a comparison of stakeholder perspectives. AB - PURPOSE: This study synthesised the findings of three separate consensus processes exploring the perspectives of key stakeholder groups about important aphasia treatment outcomes. This process was conducted to generate recommendations for outcome domains to be included in a core outcome set for aphasia treatment trials. MATERIALS AND METHODS: International Classification of Functioning, Disability, and Health codes were examined to identify where the groups of: (1) people with aphasia, (2) family members, (3) aphasia researchers, and (4) aphasia clinicians/managers, demonstrated congruence in their perspectives regarding important treatment outcomes. Codes were contextualized using qualitative data. RESULTS: Congruence across three or more stakeholder groups was evident for ICF chapters: Mental functions; Communication; and Services, systems, and policies. Quality of life was explicitly identified by clinicians/managers and researchers, while people with aphasia and their families identified outcomes known to be determinants of quality of life. CONCLUSIONS: Core aphasia outcomes include: language, emotional wellbeing, communication, patient-reported satisfaction with treatment and impact of treatment, and quality of life. International Classification of Functioning, Disability, and Health coding can be used to compare stakeholder perspectives and identify domains for core outcome sets. Pairing coding with qualitative data may ensure important nuances of meaning are retained. Implications for rehabilitation The outcomes measured in treatment research should be relevant to stakeholders and support health care decision making. Core outcome sets (agreed, minimum set of outcomes, and outcome measures) are increasingly being used to ensure the relevancy and consistency of the outcomes measured in treatment studies. Important aphasia treatment outcomes span all components of the International Classification of Functioning, Disability, and Health. Stakeholders demonstrated congruence in the identification of important outcomes which related Mental functions; Communication; Services, systems, and policies; and Quality of life. A core outcome set for aphasia treatment research should include measures relating to: language, emotional wellbeing, communication, patient-reported satisfaction with treatment and impact of treatment, and quality of life. Coding using the International Classification of Functioning, Disability, and Health, presents a novel methodology for the comparison of stakeholder perspectives to inform recommendations for outcome constructs to be included in a core outcome set. Coding can be paired with qualitative data to ensure nuances of meaning are retained. PMID- 29130768 TI - Screening of six polymorphisms related with folate metabolism in parents of individuals with Down syndrome. AB - OBJECTIVE: The study aim to investigate MTHFR C677T, MTHFR A1298C, RFC1 A80G, MTR A2756G, CBS 844ins68, MTRR A66G polymorphisms in Down syndrome (DS) parents. METHODS: Polymorphisms were evaluated in 35 mothers and 24 fathers of individuals with free trisomy of chromosome 21 confirmed by karyotype. The control group included 26 mothers and 26 fathers who had no children with DS. The molecular analysis was performed by polymerase chain reaction and restriction fragment length polymorphism (reaction chain polymerase restriction fragment length polymorphism) or polymerase chain reaction. The chi2 test (chi-square) was used to compare allele's differences among the study and the control group. Hardy Weinberg equilibrium model was performed by chi2 testing. Multiple logistic regression models and binary logistic regression used to determine the association between polymorphisms and parental DS risk. RESULTS: This study did not reveal any significant difference in frequencies of polymorphisms. The haplotype analysis did not reveal linkage disequilibrium. The logistic regression analysis did not demonstrate differences between the groups. However, the binary logistic regression showed a higher frequency of the polymorphic homozygote genotype in DS parent group to codominant and dominant model in the RFC1 A80G. CONCLUSION: In conclusion, although the screening results were significant only to the RFC1 A80G polymorphism, the other determinations of the genetic factors associated with abnormal chromosome segregation could be helpful in future studies, including other polymorphisms involved in folate metabolism. PMID- 29130769 TI - Neuroprotective effects and UPLC-Q-TOF/MS-based active components identification of external applied a novel Wen-Luo-Tong microemulsion. AB - Chemotherapy induced neuropathy causes excruciating pain to cancer patients. Wen Luo-Tong (WLT), a traditional Chinese medicinal compound, has been used to alleviate anti-cancer drug such as oxaliplatin-induced neuropathic pain for many years. However, the current route of administration of WLT is inconvenient and the active ingredients and mechanism of action of WLT are still unclear. To address these issues, we developed a novel formulation of WLT (W/O microemulsion) for the ease of application. New ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) methods were employed for analysis of the ingredients. We identified seven ingredients that penetrated through the skin into the Franz cell receptor solution and four of those ingredients were retained in skin tissue when WLT microemulsion was applied. We tested the microemulsion formulation on an oxaliplatin-induced neuropathy rat model and showed that this formulation significantly decreased oxaliplatin induced mechanical hyperalgesia responses. Schwann cells (SCs) viability experiment in vitro was studied to test the protective effect of the identified seven ingredients. The result showed that Hydroxysafflor Yellow A, icariin, epimedin B and 4-dihydroxybenzoic acid significantly increased the viability of SCs after injured by Oxaliplatin. Our report presents the first novel formulation of WLT with neuroprotective effect and ease of use, which has potential for clinical applications. PMID- 29130770 TI - Transition state analogue imprinted polymers as artificial amidases for amino acid p-nitroanilides: morphological effects of polymer network on catalytic efficiency. AB - The morphology of the polymer network - porous/less porous - plays predominant role in the amidase activities of the polymer catalysts in the hydrolytic reactions of amino acid p-nitroanilides. Polymers with the imprints of stable phosphonate analogue of the intermediate of hydrolytic reactions were synthesized as enzyme mimics. Molecular imprinting was carried out in thermodynamically stable porogen dimethyl sulphoxide and unstable porogen chloroform, to investigate the morphological effects of polymers on catalytic amidolysis. It was found that the medium of polymerization has vital influence in the amidase activities of the enzyme mimics. The morphological studies of the polymer catalysts were carried out by scanning electron microscopy and Bruner-Emmett Teller analysis. The morphology of the polymer catalysts and their amidase activities are found to be dependent on the composition of reaction medium. The polymer catalyst prepared in dimethyl sulphoxide is observed to be efficient in 1:9 acetonitrile (ACN)-Tris HCl buffer and that prepared in chloroform is noticed to be stereo specifically and shape-selectively effective in 9:1 ACN-Tris HCl buffer. The solvent memory effect in catalytic amidolysis was investigated using the polymer prepared in acetonitrile. PMID- 29130771 TI - Return-to-work success despite conflicts: an exploration of decision-making during a work rehabilitation program. AB - PURPOSE: Collective decision-making by stakeholders appears important to return to-work success, yet few studies have explored the processes involved. This study aims to explore the influence of decision-making on return-to-work for workers with musculoskeletal or common mental disorders. METHOD: This study is a secondary analysis using data from three earlier multiple-case studies that documented decision-making during similar and comparable work rehabilitation programs. Individual interviews were conducted at the end of the program with stakeholders, namely, the disabled workers and representatives of health care professionals, employers, unions and insurers. Verbatims were analysed inductively. RESULTS: The 28 decision-making processes (cases) led to 115 different decisions-making instances and included the following components: subjects of the decisions, stakeholders' concerns and powers, and types of decision-making. No differences were found in decision-making processes relative to the workers' diagnoses or return-to-work status. However, overall analysis of decision-making revealed that stakeholder agreement on a return-to-work goal and acceptance of an intervention plan in which the task demands aligned with the worker's capacities were essential for return-to-work success. CONCLUSION: These results support the possibility of return-to-work success despite conflictual decision-making processes. In addition to facilitating consensual decisions, future studies should be aimed at facilitating negotiated decisions. Implications for rehabilitation Facilitating decision-making, with the aim of obtaining agreement from all stakeholders on a return-to-work goal and their acceptance of an intervention plan that respects the worker's capacities, is important for return-to-work success. Rehabilitation professionals should constantly be on the lookout for potential conflicts, which may either complicate the reach of an agreement between the stakeholders or constrain return-to-work possibilities. Rehabilitation professionals should also be constantly watching for workers' and employers' return-to-work concerns, as they may change during work rehabilitation, potentially challenging a reached agreement. PMID- 29130772 TI - Assessment of left ventricular function using the Myocardial Performance Index in term fetuses that develop intrapartum compromise. AB - OBJECTIVE: To investigate the relationship between the prelabour left ventricular Myocardial Performance Index (LVMPI) and intrapartum fetal compromise (IFC) in low-risk term pregnancies. METHODS: A blinded, prospective observational cohort study at the Mater Mother's Hospital, Brisbane, Australia. A cohort of 284 women with uncomplicated singleton pregnancies underwent fortnightly ultrasound from 36 weeks until delivery. The LVMPI was assessed by conventional Doppler ultrasound and correlated with intrapartum outcomes. The LVMPI was also correlated with other Doppler indices of fetal wellbeing. RESULTS: Two hundred and seventy-three women were included in the final analysis, the median LVMPI was higher in fetuses that required any emergency operative delivery for IFC (0.56, 0.52-0.60 versus 0.54, 0.50-0.58, p = .007). The left ventricular cardiac output (LVCO) and cerebroplacental ratio (CPR) were lower in fetuses that required any emergency operative delivery for IFC compared to those that did not (164 +/- 19 ml/min/kg versus 181 +/- 30 ml/min/kg, p < .001) (1.63 + 0.30 versus 1.90 + 0.50, p < .001), respectively. The LVMPI was inversely correlated with the CPR (r = -0.20, p < .01), MCA PI (r = -0.29, p < .01), and LVCO (r = -0.22, p < .01). CONCLUSIONS: Higher global LVMPI is associated with a higher risk for IFC and poorer condition of the newborn. PMID- 29130773 TI - Alteration of salivary glycopatterns in oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP) is one of the most common oral mucosal lesions affecting 0.5-2% of the adult population. It is difficult to distinguish between OLP and other oral mucosal diseases. Structural changes in the glycans of saliva proteins might be reliable indicators of OLP. However, little is known about the alteration of salivary glycopatterns during OLP. OBJECTIVE: We aimed to investigate the alterations of salivary protein glycosylation related to OLP. MATERIAL AND METHODS: Twenty-eight patients with OLP and 30 age- and sex-matched healthy volunteers (HVs) were enrolled in the test group to probe the difference of salivary glycopatterns using lectin microarrays. The lectin blotting were further utilized to validate the expression of certain glycans. RESULTS: The glycoproteins recognized by three lectins [Aleuria aurantia lectin (AAL); Phytolacca americana (PWM); Phaseolus vulgaris agglutinin (E + L), (PHA-E + L)] were mainly increasing in the saliva of OLP. Meanwhile, these glycoproteins also exhibited significant age-associated alterations. CONCLUSIONS: This study provided a new basic insight into salivary glycopatterns in OLP and helped to develop new potential biomarkers for diagnosis of OLP. PMID- 29130774 TI - The sweet spot for biologics: recent advances in characterization of biotherapeutic glycoproteins. AB - INTRODUCTION: Glycosylation is recognized as a Critical Quality Attribute for therapeutic glycoproteins such as monoclonal antibodies, fusion proteins and therapeutic replacement enzymes. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for their discovery, development and quality control. The aim of this review is to highlight relevant and recent advances in analytical technologies for characterization of biotherapeutic glycoproteins. Areas covered: The review gives an overview of the glycosylation trends of biotherapeutics approved in 2016 and 2017 by FDA. It describes current and novel analytical technologies for characterization of therapeutic glycoproteins and is explored in the context of released glycan, glycopeptide or intact glycoprotein analysis. Ultra performance liquid chromatography, mass spectrometry and capillary electrophoresis technologies are explored in this context. Expert commentary: There is a need for the biopharmaceutical industry to incorporate novel state of the art analytical technologies into existing and new therapeutic glycoprotein workflows for safer and more efficient biotherapeutics and for the improvement of future biotherapeutic design. Additionally, at present, there is no 'gold-standard' approach to address all the regulatory requirements and as such this will involve the use of orthogonal glycoanalytical technologies with a view to gain diagnostic information about the therapeutic glycoprotein. PMID- 29130775 TI - Results of native and transplant kidney biopsies of children in a single center over a 15 years period. AB - Renal biopsy is an important diagnostic procedure in pediatric nephrology. This study retrospectively investigates the indications, results and complications in a single tertiary children's hospital in Turkey. We evaluated the native and transplant kidney biopsies in Gazi University Pediatric Nephrology Department between 2001 and 2015. A total of 196 biopsies (144 natives and 52 transplants) were included into the study. The mean age of the patients was respectively 10.8 +/- 3.5, 13.9 +/- 1.5 years. The main indication for a biopsy was non-nephrotic proteinuria with or without hematuria (n= 35), followed by steroid-resistance nephrotic syndrome (SRNS) (n = 34) and Henoch-Schonlein purpura (HSP)-related proteinuria (n = 20) for native kidneys. We found that focal segmental glomerulosclerosis (FSGS) (11.7%) was the most common histopathologic diagnosis for native kidneys, but acute cellular rejection (7.6%) was the most common histopathologic diagnosis for transplant kidneys. The complication rate in our study was founded 6.6% totally. Different complication rates were found in other studies; however, we think that this difference comes from the inspecting methodology of the complications. Hence, we wanted to share our own experience in the context of other studies in the literature. PMID- 29130776 TI - New Insights into Effects of Aromatic Amino Acids on Hydroxyapatite. AB - Biomimetics inspired by superstructures and extraordinary properties of teeth have resulted in tooth repair and the generation of novel materials. However, little attention has been paid to tooth color, whose origin remains unknown. Based on recent studies, fluorophores-mainly aromatic amino acids (AAAs) in proteins-might be responsible for tooth color. We synthesized carbonated hydroxyapatite (HA; the mineral phase of teeth) in the presence of different amino acids (AAs; the basic units of protein matrix of teeth) as a simplified model of teeth to explore the color source at the AA level. After measuring the fluorescence and color characteristics of HA-AAs before and after bleaching treatment, we found that only HA, synthesized in the presence of AAAs, exhibited remarkable fluorescence and color property. Furthermore, linearly increased fluorescence intensity and deeper color were observed with an increase in AAA content in HA-AAAs. Similarly, significantly decreased absorbance of HA-AAAs between 250 and 300 nm in ultraviolet spectra, declined fluorescence intensity, and decolored performance of HA-AAAs were observed after bleaching treatment. The results showed that AAAs contributed to the fluorescence and color properties of HA and that hydrogen peroxide might whiten HA-AAAs by oxidizing the benzene ring in AAAs. These findings are of great significance in promoting the synthesis of advanced tooth-colored materials and furthering our understanding of the possible mechanisms of hydrogen peroxide. Moreover, our study shed light on the importance of AAAs and might provide new ideas for investigations of biomineralization and biomimetics. PMID- 29130777 TI - Hole in the Air. PMID- 29130778 TI - Lack of induced mutagenesis in E. coli or human lymphoblast cell line upon long term sub-culturing in medium from irradiated meat. AB - PURPOSE: Current study was aimed to enhance the confidence of consumers as well as entrepreneurs towards food irradiation program. MATERIALS AND METHODS: In this work, safety of high dose (25 kGy) irradiated meat samples (HDIMS) was ascertained by scoring mutation frequency through a long-term sub-culturing study in Escherichia coli MG1655 cells (ATCC 700926) up to 1500 generations (at 1%), 250 generations (at 5% and 10%) and human lymphoblast thymidine kinase heterozygote (TK6) cell line (ATCC CRL-8015) [at two gene loci, tk-/+ (thymidine kinase) and hprt+ (Hypoxanthine Phosphoribosyltransferase)] up to 156 generations using goat meat sample. Also these samples were assayed at further radiation doses of 10, 45 and 70 kGy at 2% concentration (in cell line), and 1% (in E. coli). Study was also performed with other meat samples such as chicken, fishes (pomfret and rohu) and shrimps by carrying out limited long-term sub-culturing trials in human lymphoblast cell line. Mutation analysis was also carried out using a novel DPAR (Differential loss of Plasmid Antibiotic Resistance) assay followed by sequencing of tcR (tetracycline resistance) gene of pBR322 plasmid isolated from E. coli cells grown for 1500 generations on HDIMS medium and RAPD (Random Amplified Polymorphic DNA) analysis of the genome. RESULTS AND CONCLUSION: None of the assays exhibited any induced mutation when analyzed at regular time intervals. RAPD analysis also did not indicate any change in its nucleotide sequence, ruling out the occurrence of any silent mutation. Thus, the present findings report absence of mutagenic effect of high dose irradiated meat samples. PMID- 29130780 TI - Obituary-Omar Khan, MD, Professor and Chair of Neurology and Neurologist-in-Chief of the Detroit Medical Center. PMID- 29130779 TI - Experimentally constrained circuit model of cortical arteriole networks for understanding flow redistribution due to occlusion and neural activation. AB - Computations are described which estimate flows in all branches of the cortical surface arteriole network from two-photon excited fluorescence (2PEF) microscopy images which provide the network topology and, in selected branches red blood cell (RBC) speeds and lumen diameters. Validation is done by comparing the flow predicted by the model with experimentally measured flows and by comparing the predicted flow redistribution in the network due to single-vessel strokes with experimental observations. The model predicts that tissue is protected from RBC flow decreases caused by multiple occlusions of surface arterioles but not penetrating arterioles. The model can also be used to study flow rerouting due to vessel dilations and constrictions. PMID- 29130781 TI - Article Commentary: High-Fat Diet Determines the Composition of the Murine Gut Microbiome Independently of Obesity. PMID- 29130783 TI - Article Commentary: Intestinal Dysbiosis: A Possible Mechanism of Alcohol-Induced Endotoxemia and Alcoholic Steatohepatitis in Rats. PMID- 29130784 TI - Erratum. AB - Rollins MD, Scaife E, Jackson W, Mulroy C, Book L, Meyers R. Elimination of Soybean Lipid Emulsion in Parenteral Nutrition and Supplementation With Enteral Fish Oil Improve Cholestasis in Infants With Short Bowel Syndrome. Nutr Clin Pract. 2010;25:199-204. (Original DOI: 10.1177/0884533610361477 ) In the above article, on page 202, 2 amounts in Table 2 appear incorrectly. Under "20% soybean lipid emulsion," in the "linoleic" line, the amount should be 0.1 g/mL instead of 1.1 g/mL. In the "total fat(kcal/ml)" line, the amount should be 2.0 g/mL instead of 0.2 g/mL. PMID- 29130786 TI - Production of eurycomanone from cell suspension culture of Eurycoma longifolia. AB - CONTEXT: Eurycomanone is found in the Eurycoma longifolia Jack (Simaroubaceae) tree, exhibits significant antimalarial activity, improves spermatogenesis, suppresses expression of lung cancer cell tumour markers and regulates signalling pathways involved in proliferation, cell death and inflammation. OBJECTIVES: Establishment of cell suspension culture of E. longifolia to determine the eurycomanone accumulation during cultures. MATERIALS AND METHODS: Callus of E. longifolia was cultured in MS medium supplemented with 0.8% agar, 30/L sucrose, 1.25 mg/L NAA and 1 mg/L KIN for biomass production. Cell suspension culture was established by transferring friable calli to the same medium without agar. Eurycomanone content during cell culture was determined by HPLC with a C18 column, flow rate of 0.8 mL/min, run time of 17.5 min, detector wavelength of 254 nm. The stationary phase was silica gel and the mobile phase was acetonitric:H2O. Roots of 5 year-old trees were used as the control. RESULTS: The cells from 3 g of inoculum increased in biomass with a maximum value of 16 g fresh weight (0.7 g dry weight) at 14th day of culture. The cell growth then decreased from day 14 to day 20. Eurycomanone was produced during culture from the beginning to 20th day, its highest content (1.7 mg/g dry weight) also obtained at 14th day (the control is 2.1 mg/g dry weight). DISCUSSION AND CONCLUSIONS: Cell suspension culture of E. longifolia is a suitable procedure to produce eurycomanone. The yield of eurycomanone biosynthesis in 14 days-old cells are relatively high, approximately 0.8 times the control. PMID- 29130787 TI - miR-19a and miR-424 target TGFBR3 to promote epithelial-to-mesenchymal transition and migration of tongue squamous cell carcinoma cells. AB - Previous studies indicate that TGFBR3 (transforming growth factor type III receptor, also known as betaglycan), a novel suppressor of progression in certain cancers, is down-regulated in tongue squamous cell carcinoma (TSCC). However, the role of this factor as an upstream regulator in TSCC cells remains to be elucidated. The present study was designed to elucidate whether TGFBR3 gene expression is regulated by two microRNA molecules, miR-19a and miR-424. The study also aimed to determine if these microRNAs promote migration of CAL-27 human oral squamous cells. Immunohistochemistry (IHC) and western blot analyses demonstrated that TGFBR3 protein levels were dramatically down-regulated in clinical TSCC specimens. Conversely, bioinformatics analyses and qRT-PCR results confirmed that both miR-19a and miR-424 were markedly up-regulated in clinical TSCC specimens. In this study, we observed that transfection of a TGFBR3-containing plasmid dramatically inhibited epithelial-to-mesenchymal transition (EMT) and migration in CAL-27 cells. Co-immunoprecipitation analyses also revealed that TGFBR3 forms a complex with the beta-arrestin 2 scaffolding protein and IkappaBalpha. Furthermore, overexpression of TGFBR3 decreased p-p65 expression and increased IkappaBalpha expression; these effects were subsequently abolished following knockdown of beta-arrestin 2. Moreover, over-expression of miR-19a and miR-424 promoted migration and EMT in CAL-27 cells. We also observed that the promotion of EMT by miR-19a and miR-424 was mediated by the inhibition of TGFBR3. Our study provides evidence that miR-19a and miR-424 play important roles in the development of TSCC. These results expand our understanding of TGFBR3 gene expression and regulatory mechanisms pertaining to miRNAs. PMID- 29130789 TI - The evaluation of radiologic methods for access guidance in percutaneous nephrolithotomy: a systematic review of the literature. AB - INTRODUCTION: Percutaneous nephrolithotomy (PNL) is the treatment of choice for larger and complex renal calculi. First step in performing PNL is to obtain access to the renal cavity using either fluoroscopy or ultrasound (US) guidance or a combination of both. Which guiding method to choose is controversial? A systematic review of the literature was performed comparing image guidance modalities for obtaining access in PNL. Evidence acquisition and synthesis: A PubMed, Scopus and Cochrane search for peer-reviewed studies was performed using the keywords "ultrasound" AND "fluoroscopy" AND "Percutaneous nephrolithotomy". Eligible articles were reviewed according to PRISMA criteria. Two hundred and forty records were identified using the keywords. Of these twelve studies were considered relevant. RESULTS: US guidance seems to be associated with a slightly lower complication rate, which may be related to fewer puncture attempts needed for obtaining access and to better peri-renal organ visualization. On the other hand, US-guidance alone needs the adjunct of fluoroscopy in a significant number of cases for achieving access. Stone free rate (SFR) was comparable between groups. Using US for renal access unequivocally reduces radiation exposure. CONCLUSION: Current evidence indicates that both fluoroscopy and US guidance may be successfully used for obtaining percutaneous renal access. Combining the image guiding modalities - US and fluoroscopy - seems to increase outcome in PNL both with regard to success in achieving access and reducing complications. Furthermore, including US in the access strategy of PNL reduces radiation exposure to surgeon and staff as well as patients. PMID- 29130788 TI - Complex action of tyramine, tryptamine and histamine on native and recombinant ASICs. AB - Proton-gated channels of the ASIC family are widely distributed in the mammalian brain, and, according to the recent data, participate in synaptic transmission. However, ASIC-mediated currents are small, and special efforts are required to detect them. This prompts the search for endogenous ASIC ligands, which can activate or potentiate these channels. A recent finding of the potentiating action of histamine on recombinant homomeric ASIC1a has directed attention to amine-containing compounds. In the present study, we have analyzed the action of histamine, tyramine, and tryptamine on native and recombinant ASICs. None of the compounds caused potentiation of native ASICs in hippocampal interneurons. Furthermore, when applied simultaneously with channel activation, they produced voltage-dependent inhibition. Experiments on recombinant ASIC1a and ASIC2a allowed for an interpretation of these findings. Histamine and tyramine were found to be inactive on the ASIC2a, while tryptamine demonstrated weak inhibition. However, they induce both voltage-dependent inhibition of open channels and voltage-independent potentiation of closed/desensitized channels on the ASIC1a. We suggest that the presence of an ASIC2a subunit in heteromeric native ASICs prevents potentiation but not inhibition. As a result, the inhibitory action of histamine, which is masked by a strong potentiating effect on the ASIC1a homomers, becomes pronounced in experiments with native ASICs. PMID- 29130790 TI - Performance evaluation of a miniature magnetic sector mass spectrometer onboard a satellite in space. AB - With the rapid development of space technology in China, it is urgent to use mass spectrometer to detect the space environment. In this work, a space miniature magnetic sector mass spectrometer is evaluated, which consists of three subsystems: (1) physical unit, (2) electric control unit, (3) and high voltage power. It has 90 degrees magnetic sector-field analyzer with double trajectory, in which a trajectory measurement range is from 1 to 12 amu, the other range is from 6 to 90 amu.The mass spectrometer has two work models, one is used to measure space neutral gas when the filament of mass spectrometer ion source turned on, the other is used to measure space charged ions when the filament turned off. The absolute resolution of this device is less than 1 amu, the minimum detectable ion current is about 10-13 A, and the sensitivity is 10-6 A/Pa (N2). Its overall size is 170 mm * 165 mm * 170 mm, its weight is 4.5 kg, and its power consumption is 18 W. A series of environmental adaptability tests, including high and low temperature cycle, shock, vibration, thermal vacuum cycle, were carried out on the ground before launching, and sensitivity and peak position were also calibrated on the ground. In November 2012, the mass spectrometer was carried by an experimental satellite to 499 km sun synchronization and is still working right now. It successfully detected the atmosphere compositions both in the satellite orbit and gas-emitted from satellite, including O, He, 12CO2, 13CO2, H2, N2, O2, H2O, and so on. PMID- 29130791 TI - The Sexual Health of Women in Lebanon: Are There Differences by Sexual Orientation? AB - PURPOSE: From studies conducted in Western countries (United States, United Kingdom, and Australia), we know that the sexual health of sexual minority women (SMW) differs in key ways from that of heterosexual women (HSW). To date, the sexual health of SMW living in the Middle East and North Africa region has not been studied. The purpose of this study was to compare the sexual health of SMW and HSW living in Lebanon. METHODS: SMW and HSW living in Lebanon (N = 95) completed an anonymous, self-administered survey. SMW's risk perceptions and health promoting and sexual behaviors were compared to those of HSW. We examined differences by sexual orientation by using t tests and Fisher's exact tests. RESULTS: The 45 SMW and 50 HSW had similar demographic characteristics. Significantly more SMW had heard of human papillomavirus, but only 22% of women from both groups knew of its association with abnormal Papanicolaou tests. Cervical cancer screening rates were similar in SMW and HSW, although remarkably low (42%) compared with rates in Western countries. Significantly more SMW (18%) reported difficulty with access to care than HSW (0%). Forty-four percent of SMW reported discomfort in disclosing their sexual orientation to their healthcare provider and 61% reported that healthcare providers lacked sensitivity toward lesbian, gay, bisexual, and transgender needs. Unwanted sexual contact occurred more frequently in SMW (53%) than HSW (23%). CONCLUSION: The sexual health of women is affected by sociocultural factors. SMW living in Lebanon have unique health needs that should be addressed within their sociocultural context. PMID- 29130792 TI - So long, farewell, Auf Wiedersehen, Adieu.... PMID- 29130793 TI - From genomes to diaries: a 3-year prospective, real-life study of ragweed specific sublingual immunotherapy. AB - During the last decades, the prevalence of allergy has dramatically increased. Allergen-specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease, but there are still many questions and unmet needs hindering its widespread use to fulfill its treatment potential and maximize its benefits for the society. To provide a comprehensive phenome-wide overview in sublingual immunotherapy, using ragweed allergy as a target, we planned and carried out a longitudinal, prospective, observational, open-label study (DesensIT). In this paper we present challenges of using deep and comprehensive phenotypes embracing biological, clinical and patient-reported outcomes in allergen-specific immunotherapy and show how we designed the DesensIT project to optimize data collection, processing and evaluation. PMID- 29130794 TI - Allergen immunotherapy for birch-apple syndrome: what do we know? AB - Apple allergy is common in patients allergic to birch pollen, and this is defined as 'birch-apple syndrome'. Allergens responsible for cross-reactivity belong to the pathogenesis-related-10 family, and high homology in the amino acid sequences of the major allergens Bet v 1 from birch and Mal d 1 from apple has been demonstrated. Here we review the literature on the treatment of birch-apple syndrome by allergen immunotherapy. The only allergen immunotherapy method available thus far is based on the administration of birch-pollen extracts, through the subcutaneous or sublingual route, to induce tolerance to Bet v1 and to the homologous allergen Mal d 1. However, the studies performed thus far show modest efficacy, and thus other methods of immunotherapy should be investigated. PMID- 29130796 TI - Allergen immunotherapy. PMID- 29130795 TI - Comparison of two different assays and the predictive value of allergen components in house dust mite allergy. AB - AIM: In house dust mite (HDM) allergy diagnostics, the IMMULITE, ImmunoCAP and assays for allergen components (nDer p 1 and rDer p 2) are available. METHODS: Serum sIgE levels were compared and the predictive values for the detection of an early asthmatic response (EAR) were calculated with receiver operating characteristics and a log-logistic regression model. RESULTS: sIgE levels of IMMULITE and ImmunoCAP were similar (Dermatophagoides pteronyssinus [D. pter.] 47.3 +/- 35.7 and 42.9 +/- 34.4 kU.l-1; p = 0.23). ImmunoCAP slgEs exhibited similar accuracy in detecting an EAR, area under the curves (AUCs): D. pter. (0.76); Dermatophagoides farinae (0.79); nDer p 1 (0.69); and rDer p 2 (0.72). At low sIgE concentrations (3.5 kU.l-1), rDer p 2 was more specific and better predicted an EAR (probability rDer p 2: 62%; D. pter.: 19%). PMID- 29130797 TI - Dose-finding study of carbamylated monomeric allergoid tablets in grass-allergic rhinoconjunctivitis patients. AB - AIM: To determine the optimal effective and safe dose of sublingual immunotherapy tablets containing carbamylated monomeric allergoids in patients with grass pollen-induced allergic rhinoconjunctivitis. METHODS: In this prospective, randomized, double-blind, active-controlled, multicenter, Phase II study, four different daily doses were applied preseasonally for 12 weeks. RESULTS: Of 158 randomized adults, 155 subjects (safety population) received 300 units of allergy (UA)/day (n = 36), 600 UA/day (n = 43), 1000 UA/day (n = 39), or 2000 UA/day (n = 37). After treatment, 54.3, 47.6, 59.0 and 51.4% of patients, respectively, ceased to react to the highest allergen concentration in a conjunctival provocation test. Furthermore, the response threshold improved in 70.4, 62.9, 76.7 and 66.7% of patients, respectively. No serious adverse events occurred. CONCLUSION: This study found 1000 UA/day to be the optimal effective and safe dose. PMID- 29130798 TI - Baked milk and baked egg oral immunotherapy. PMID- 29130800 TI - The role of the microbiome in childhood asthma. AB - It is now well established that the healthy bronchial tree contains a microbiome distinct from that of the upper respiratory tract and that the lung microbiome may be dysregulated in individuals with a chronic respiratory disease, such as asthma. In addition, after birth, gut microbes interact with the host tissue, especially with the lymphatic tissue, thereby guaranteeing efficient immune activation. This review focuses on the available literature on the relationships between the gut microbiome, immune function and asthma in childhood, as well as the therapeutic strategies aimed at acting on the modulation of the microbiome. PMID- 29130799 TI - Allergen immunotherapy modulates sensitivity of Treg cells to apoptosis in a rat model of allergic asthma. AB - AIM: To study the apoptosis of Foxp3+ Treg cells following Alstonia scholaris pollen sensitization-challenge and following allergen immunotherapy. MATERIALS & METHODS: Wistar rats were sensitized-challenged with Alstonia scholaris pollen and were further given intranasal immunotherapy. For the analysis of the apoptotic proteins on Treg cells by flow cytometry, multiple gating procedures were followed. RESULTS: Allergen sensitization-challenge increases Annexin-V, Fas, FasL, caspases-8, 9, 3 cytochrome-C, APAF-1, Bax, perforin-1 and granzyme-B on Treg cells which is decreased following intranasal immunotherapy. On the other hand, Bcl-2 expression is decreased in allergy and increased by immunotherapy. CONCLUSION: Apoptosis of Treg cells is increased following allergen sensitization challenge via extrinsic, intrinsic and perforin/granzyme pathways and allergen immunotherapy decreased the sensitivity to apoptosis of Treg cells. PMID- 29130801 TI - The relevance of house dust mites allergy in clinical practice: the epidemiological impact on allergen immunotherapy. AB - House dust mite (HDM) is the most common cause of respiratory allergy worldwide. The impact of HDM allergy is influenced by a number of factors, including local climate. We investigated such issue in Italy, using a real-life setting, including outpatients visited at allergy clinics. In 9143 patients (7873 adults and 1270 children) who were evaluated in 15 allergy clinics, investigating as well the rate of prescription of allergen immunotherapy. The present study confirms that Mediterranean climate is associated with a higher prevalence of mite allergy than continental climate. This significant difference may have an impact on allergen immunotherapy prescription, which should be more common in areas with higher prevalence of HDM allergy. PMID- 29130802 TI - Oral immunotherapy using polymeric nanoparticles loaded with peanut proteins in a murine model of fatal anaphylaxis. AB - BACKGROUND: Peanut allergy is the most common cause of anaphylaxis and food related death. However, there is currently no approved immunotherapy treatment. Hence, this warrants the need for relevant and convenient animal models to test for adequate immunotherapies. MATERIALS & METHODS: In this study, we compared three mouse strains: CD1, BALB/c and C57, to select a model of peanut allergy. After that, we conducted then a therapeutic study using an immunogenic peanut extract encapsulated in nanoparticles made with polymer Gantrez(r) following the solvent displacement method. RESULTS & CONCLUSION: After implementing a dosing schedule with oral commercial peanut butter, the antibody responses, cytokine profiles and, above all, the anaphylaxis induced after a challenge with peanut proteins, showed that the outbred CD1 strain was the most susceptible to peanut sensitization. CD1 sensitized mice were orally immunized with three doses of the nanoparticle formulation capable of protecting them against the severe anaphylactic symptoms induced by the peanut challenge. PMID- 29130803 TI - Steroid sparing effect of sublingual immunotherapy: real life study in mono/polisensitized children with asthma. AB - AIM: Steroid-sparing effect of sublingual immunotherapy (SLIT) in mono/polisensitized asthmatic children were evaluated. MATERIALS AND METHODS: Children undergoing allergen-specific SLIT between 2010 and 2014 were included. Asthma control and usage/dose of inhaled corticosteroid (ICS) in the previous year was determined. Asthma control without ICS need >=6 months was defined as 'ICS avoidance'. RESULTS: 90 children (mean +/- SD age 8.92 +/- 4.17 years) were enrolled, 56.7% (n = 60) being polysensitized. Mono, 2-simultaneous and multiple pollen-mix allergen SLIT were prescribed in 84.4, 17.8 and 7.8%, respectively. ICS was avoided in 70%, with no significant difference in mono- versus poly sensitized patients. ICS-avoidance rates in mono-allergen, pollen-mixture and 2 simultaneous-allergen SLIT were 93.6, 83.3 and 73.7%, respectively. Longer duration SLIT resulted in significantly more ICS-avoidance (p:0.0001). CONCLUSION: SLIT with mono/multiple-mixed/simultaneous allergens in childhood asthma resulted in retained-avoidance of ICS. Steroid-sparing effect of SLIT in polysensitized children warrants further investigation. PMID- 29130804 TI - Is Metal Particle Release Associated with Peri-implant Bone Destruction? An Emerging Concept. AB - Peri-implant diseases affecting the surrounding structures of endosseous dental implants include peri-implant mucositis and peri-implantitis. The prevalence of peri-implantitis ranges between 15% and 20% after 10 y, highlighting the major challenge in clinical practice in the rehabilitation of dental implant patients. The widespread nature of peri-implant bone loss poses difficulties in the management of biological complications affecting the long-term success of osseointegrated implant reconstructions. Metal and titanium particles have been detected in peri-implant supporting tissues. However, it remains unclear what mechanisms could be responsible for the elicitation of particle and ion release and whether these released implant-associated materials have a local and/or systemic impact on the peri-implant soft and hard tissues. Metal particle release as a potential etiologic factor has been intensively studied in the field of orthopedics and is known to provoke aseptic loosening around arthroplasties and is associated with implant failures. In dental medicine, emerging information about metal/titanium particle release suggests that the potential impact of biomaterials at the abutment or bone interfaces may have an influence on the pathogenesis of peri-implant bone loss. This mini-review highlights current evidence of metal particle release around dental implants and future areas for research. PMID- 29130806 TI - Erratum. PMID- 29130805 TI - Rehabilitative Success After Brain Trauma by Augmenting a Subtherapeutic Dose of Environmental Enrichment With Galantamine. AB - BACKGROUND: Environmental enrichment (EE) confers benefits after traumatic brain injury (TBI) when provided daily for > 6 hours, but not 2 or 4 hours, which more accurately reflects the daily amount of clinical rehabilitation. The lack of benefit with sub-therapeutic EE suggests that augmentation with galantamine (GAL), which enhances cognition after TBI, may be indicated to confer benefits. OBJECTIVE: To test the hypothesis that 2 and 4 hours of EE paired with GAL will provide benefits comparable to 24 hours of EE alone. Moreover, all EE groups will perform better than the standard (STD)-housed GAL group. METHODS: Anesthetized rats received a TBI or sham injury and then were randomized to receive intraperitoneal injections of GAL (2 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 hours after surgery and once daily while receiving EE for 2, 4, or 24 hours. Motor and cognitive assessments were conducted on postoperative days 1 5 and 14-19, respectively. RESULTS: Motor function was significantly improved in the TBI + 24-hour EE group versus the TBI + STD + VEH and TBI + STD + GAL groups ( P < .05). Cognitive performance was enhanced in all EE groups as well as in the TBI + STD + GAL versus TBI + STD + VEH ( P < .05). Moreover, the 2- and 4-hour EE groups receiving GAL did not differ from the 24-hour EE group ( P > .05) and performed better than GAL alone ( P < .05). CONCLUSIONS: The findings support the hypothesis and have clinical relevance because, often, only brief rehabilitation may be available in the clinic and, thus, augmenting with a pharmacotherapy such as GAL may lead to outcomes that are significantly better than either therapy alone. PMID- 29130807 TI - Corrigendum. AB - Byrd JK, Smith KJ, de Almeida JR, et al. Transoral robotic surgery and the unknown primary: a cost-effectiveness analysis. Otolaryngol Head Neck Surg. 2014;150:976-982. (Original DOI: 10.1177/0194599814525746 ). PMID- 29130809 TI - Corrigendum. AB - Coughlin MJ, Jones CP, Viladot R, Golano P, Grebing BR, Kennedy MJ, Shurnas PS, Alvarez F. Hallux valgus and first ray mobility: a cadaveric study. Foot Ankle Int. 2004;25(8):537-544. (Original doi: 10.1177/107110070402500805 ). PMID- 29130811 TI - Corrigendum. AB - Rosenfeld RM, Schwartz SR, Cannon CR, et al. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2014; 150(1S): S1-S24. (Original doi: 10.1177/0194599813517083 ). PMID- 29130812 TI - Mutual point-winning probabilities (MPW): a new performance measure for table tennis. AB - We propose a new performance measure for table tennis players: the mutual point winning probabilities (MPW) as server and receiver. The MPWs quantify a player's chances to win a point against a given opponent, and hence nicely complement the classical match statistics history between two players. These new quantities are based on a Bradley-Terry-type statistical model taking into account the importance of individual points, since a rally at 8-2 in the first set is less crucial than a rally at the score of 9-9 in the final set. The MPWs hence reveal a player's strength on his/her service against a given opponent as well as his/her capacity of scoring crucial points. We estimate the MPWs by means of maximum likelihood estimation and show via a Monte Carlo simulation study that our estimation procedure works well. In order to illustrate the MPWs' versatile use, we have organized two round-robin tournaments of ten respectively eleven table tennis players from the Belgian table tennis federation. We compare the classical final ranking to the ranking based on MPWs, and we highlight how the MPWs shed new light on strengths and weaknesses of the players. PMID- 29130813 TI - Museums, health and wellbeing research: co-developing a new observational method for people with dementia in hospital contexts. AB - AIMS: The aim of this article is to present a new observational tool for assessing the impacts of museum object handling for people with moderate-to severe dementia in hospital settings, focusing on wellbeing, social interaction, level of engagement and agitation. This article presents a four-step approach to collaboration towards co-developing the tool, which involved a range of academics, museums professionals, and health and social care partners, and describes the process of integrating multiple perspectives towards common research methodologies. METHODS: The research team organised a series of meetings and workshops with museum and healthcare partners to identify commonly used assessments and their perspectives on the objectives and possible outcomes of museum object handling activities. These were integrated with findings from a review of current conceptualisations of engagement in people with dementia (PWD) to produce a fit-for-purpose video evaluation method of the health and wellbeing impacts of the museum object handling programmes. RESULTS: This article presents the Museum Engagement Observation Tool for use in hospital settings for people with moderate-to-severe dementia. CONCLUSION: This article suggests that collaborative approaches can inform the development of future methods for creative health research and evaluation initiatives and to support this, it outlines the process of development of a new observational tool for people with dementia. PMID- 29130814 TI - Erratum. AB - Boiger, M., Mesquita, B., Uchida, Y., & Barrett, L. F. (2013). Condoned or Condemned: The Situational Affordance of Anger and Shame in the United States and Japan. Personality and Social Psychology Bulletin, 39(4), 540-553. doi: 10.1177/0146167213478201 This article contained the following errors that were introduced during the production process. Below is how these sentences should have appeared: On page 544, instead of "the relationship between of the actors involved," the sentence should read: "the relationship between the actors involved" On page 545, instead of "and the positive association between power and likelihood of occurrence was stronger for shame situations from Japan (b = .07, Z = 2.00, p = .04) than shame situations from Japan (b = -.02, Z = 0.71, p = .47) from the U.S., chi2(1) = 4.16, p = .04.," the sentence should read: "and the positive association between power and likelihood of occurrence was stronger for shame situations from Japan (b = .07, Z = 2.00, p = .04) than from the U.S. (b = .02, Z = 0.71, p = .47), chi2(1) = 4.16, p = .04." On page 550, instead of "Americans perceived situations in which their personal flaws were revealed as more shameful, whereas Japanese perceived situations that implied a loss of public face as more shameful chi2(1) = 6.26, p = .01 Japanese and American students also differed substantially in terms of the source of agency eliciting shame: Americans perceived situations in which others' actions caused them to feel shame as more shameful, while Japanese perceived situations in which they themselves were responsible as more shameful chi2(1) = 51.33, p = .001.," the sentence should read: "Americans perceived situations in which their personal flaws were revealed as more shameful, whereas Japanese perceived situations that implied a loss of public face as more shameful, chi2(1) = 38.86, p < .001. Japanese and American students also differed substantially in terms of the source of agency eliciting shame: Americans perceived situations in which others' actions caused them to feel shame as more shameful, while Japanese perceived situations in which they themselves were responsible as more shameful, chi2(1) = 51.33, p = .001." On page 551, instead of "In both cultures, it were interactions with close others that made people particularly angry involved interactions with close others.," the sentence should read: "In both cultures, it were interactions with close others that made people particularly angry." On page 551, instead of "Thus, angering situations in the United States are promoted in line with the necessary concerns and tasks of an independent self that needs to cultural negotiate personal autonomy within close relationships.," the sentence should read: "Thus, angering situations in the United States are promoted in line with the cultural tasks of an independent self that needs to negotiate personal autonomy within close relationships." PMID- 29130815 TI - Aspergillus Infection in an Immunocompetent Host With Supravalvular Aortic Stenosis. AB - Supravalvular aortic stenosis is the rarest form of left ventricular outflow tract obstruction. Aspergillus endocarditis is also rare and generally reported in immunocompromised hosts. Here we present a case of an immunocompetent patient with supravalvular aortic stenosis complicated by aortic mycotic pseudoaneurysm due to invasive aspergillosis. PMID- 29130817 TI - Response to "A Critical Review of the Interior Shape of the Ear Canal," From Kuo Wei Huang and Men-Shen Tsai. PMID- 29130816 TI - The role of perceived family social support and parental solicitous responses in adjustment to bothersome pain in young people with physical disabilities. AB - PURPOSE: Family social support and parental solicitous responses have been hypothesised to play an important role in paediatric pain. However, research testing the hypothesised associations between these social domains and measures of adjustment to pain in youths with disabilities and chronic pain is non existent. METHODS: About 111 youths with physical disabilities and bothersome pain were interviewed and asked to complete measures of average pain intensity, pain interference, family social support, parent solicitous responding, and catastrophising. RESULTS: Children's perceptions of pain-related solicitous responses from their parent/guardian were associated both with more pain interference and greater pain-related catastrophising; perceived social support was negatively associated with pain interference. CONCLUSIONS: The findings provide new information regarding the role that psychosocial factors have in predicting function and adjustment, and have important implications as to how youth with physical disabilities with pain might be most effectively treated. Implications for rehabilitation Little is known about the role of perceived family social support or parental solicitous responses in the adjustment to chronic pain in young people with physical disabilities. This study provides new and important findings that have significant theoretical and practical implications that could help to understand and manage function in these patients. Results show that it matters how parents respond to their children with disabilities who have pain, and raise the possibility that interventions which target these responses may result in significant benefits for the children. PMID- 29130818 TI - Response to: "Severe Tinnitus and Depressive Symptoms: A Complex Interaction," From Berthold Langguth et al. PMID- 29130820 TI - ENRC 1st European NeuroRehabilitation Congress October 20-22, 2011 The Kurhaus Meran, Merano, Italy Abstracts. PMID- 29130819 TI - Correction to: Photomed Laser Surg 2016;34:263-271 DOI: 10.1089/pho.2016.4094. PMID- 29130822 TI - Corrigendum. AB - Moller, A. C., Deci, E. L., Ryan, R. M. (2006). Choice and ego-depletion: The moderating role of autonomy. Personality and Social Psychology Bulletin, 32(8), 1024-1036. (Original DOI: 10.1177/0146167206288008 ). PMID- 29130824 TI - Longitudinal Structural and Functional Differences Between Proportional and Poor Motor Recovery After Stroke. AB - BACKGROUND: Evolution of motor function during the first months after stroke is stereotypically bifurcated, consisting of either recovery to about 70% of maximum possible improvement ("proportional recovery, PROP") or in little to no improvement ("poor recovery, POOR"). There is currently no evidence that any rehabilitation treatment will prevent POOR and favor PROP. OBJECTIVE: To perform a longitudinal and multimodal assessment of functional and structural changes in brain organization associated with PROP. METHODS: Fugl-Meyer Assessments of the upper extremity and high-density electroencephalography (EEG) were obtained from 63 patients, diffusion tensor imaging from 46 patients, at 2 and 4 weeks (T0) and at 3 months (T1) after stroke onset. RESULTS: We confirmed the presence of 2 distinct recovery patterns (PROP and POOR) in our sample. At T0, PROP patients had greater integrity of the corticospinal tract (CST) and greater EEG functional connectivity (FC) between the affected hemisphere and rest of the brain, in particular between the ventral premotor and the primary motor cortex. POOR patients suffered from degradation of corticocortical and corticofugal fiber tracts in the affected hemisphere between T0 and T1, which was not observed in PROP patients. Better initial CST integrity correlated with greater initial global FC, which was in turn associated with less white matter degradation between T0 and T1. CONCLUSIONS: These findings suggest links between initial CST integrity, systems-level cortical network plasticity, reduction of white matter atrophy, and clinical motor recovery after stroke. This identifies candidate treatment targets. PMID- 29130825 TI - Late-preterm infants, early-term infants, and timing of elective deliveries; current status in a Korean medical center. AB - OBJECTIVE: The aim of this study was to examine the current perinatal outcomes among infants born late-preterm and early-term compared to those born full-term and evaluate the optimal gestational age for delivery. METHODS: We performed a retrospective cohort study for births occurred at Seoul St. Mary's Hospital over the past 7 years. Statistical comparison was performed using chi2 test and multivariable logistic regression models. RESULTS: A total of 7580 women met the study criteria. Compared to 39 weeks, delivery at late-preterm and early-term had higher risk of composite morbidity, including respiratory morbidities, intracranial hemorrhage (ICH), and admission to neonatal intensive care unit (NICU) (34 weeks adjusted odds ratio [aOR]: 132.54; 95% confidence interval (CI): 74.00-240.10; 37 weeks aOR: 2.14; 95%CI: 1.65-2.77). The risks of sepsis and necrotizing enterocolitis in deliveries before 36 weeks and the risk of feeding difficulty in deliveries before 37 weeks were significantly higher than those of 39 weeks. Neonatal morbidity at deliveries was not significantly different between 38 and 39 weeks. CONCLUSIONS: Neonatal morbidities at late-preterm births are significant and surveillance for them seems increasing. Obstetricians should recognize the risk of respiratory morbidity, ICH, and NICU admission for deliveries before 38 weeks' gestation. PMID- 29130826 TI - Corrigendum. AB - Vanek VW, Borum P, Buchman A, et al. A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract. 2012;27:440-491. (Original DOI: 10.1177/0884533612446706 ). PMID- 29130828 TI - Corrigendum. AB - Choi SJ, Lee JB, Lim HJ, et al. Clinical features of recurrent or persistent benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg. 2012;147:919 924. doi: 10.1177/0194599812454642 . PMID- 29130829 TI - Comparison of conventional phototherapy and phototherapy along with Kangaroo mother care on cutaneous bilirubin of neonates with physiological jaundice. AB - BACKGROUND: One of the adjuvant and desirable therapies is skin contact between mother and baby or Kangaroo mother care (KMC) that is a cheap, accessible, relaxing, noninvasive and easy method. This study aimed to compare the effect of conventional phototherapy method and phototherapy along with KMC on cutaneous bilirubin in neonates with physiological jaundice. MATERIALS AND METHODS: In this randomized clinical trial, all infants with physiological jaundice who referred for phototherapy to Mofid Hospital of Shahid Beheshti University of Medical Sciences, Tehran, Iran were selected by convenience sampling based on inclusion criteria and were randomly assigned into two groups of conventional phototherapy (n = 35) and phototherapy along with KMC (n = 35). RESULTS: The results showed that there was a significant difference in the average volume of skin bilirubin before treatment with cutaneous bilirubin every 24 h after treatment (p < .001). This significant difference was present in both intervention and control groups. Although the average volume of skin bilirubin every 24 h after treatment was lower in the intervention group than the control group, this difference was not statistically significant (p = .236). Mean duration of hospitalization of infants in the intervention group was significantly lower than the control group (2.09 versus 3.03 d, p < .001). CONCLUSION: Although KMC along with phototherapy has a favorable effect on the reduction of cutaneous bilirubin in neonates with physiological jaundice, there are not significant differences in routine care. This may need to do KMC for a longer time (more than 1 h) which must be surveyed in the future studies. KMC was effective in reduction of the duration of hospitalization in jaundiced infants. PMID- 29130827 TI - Association of Single-Nucleotide Polymorphisms in Immune-Related Genes with Development of Dengue Hemorrhagic Fever in a Mexican Population. AB - Single-nucleotide polymorphisms (SNPs) occurring in immune-related genes have been associated with risk or protection for development of dengue, depending on ethnicity. Here, we genotyped seven SNPs located in immune response-related genes to identify their association with severe forms of dengue in patients from an endemic region in Mexico. One hundred and thirty-eight patients with dengue fever (DF), thirty-one dengue hemorrhagic fever (DHF) patients, as well as 304 healthy donors were genotyped by using a TaqMan-based approach. SNP analysis, including rs1800629 (TNF), rs4804803 (CD209), rs2780831 (JAK1), rs1801274 (FCGR2A), rs231775 (CTLA4), rs12979860, and rs8099917 (IFNL3), was performed. The rs1800629 A-allele in the TNF gene was associated with an increased risk of DHF (OR = 3.4, CI = 1.235-9.284 p = 0.0212) whereas SNPs rs4804803, rs2780831, rs1801274, rs231775, rs12979860, and rs8099917 showed no association in this cohort. These results show that allelic variations in TNF can play an important role in the development of DHF. However, the lack of association between all remaining SNPs and DHF suggests that the genetic background might directly modify the role of these immune-related molecules, leading to the milder illness often observed in a Mexican population. PMID- 29130830 TI - Enhanced CD103 Expression and Reduced Frequencies of Virus-Specific CD8+ T Cells Among Airway Lymphocytes After Influenza Vaccination of Mice Deficient in Vitamins A + D. AB - Previous research has evaluated antibody responses toward an influenza virus vaccine in the context of deficiencies for vitamins A and D (VAD+VDD). Results showed that antibodies and antibody-forming cells in the respiratory tract were reduced in VAD+VDD mice. However, effectors were recovered when oral supplements of vitamins A + D were delivered at the time of vaccination. Here we address the question of how vaccine-induced CD8+ T cell responses are affected by deficiencies for vitamins A + D. VAD+VDD and control mice were vaccinated with an intranasal, cold-adapted influenza virus A/Puerto Rico/8/34 vaccine, with or without oral supplements of vitamins A + D. Results showed that the percentages of vaccine-induced CD8+ T cell and total CD4+ T cell responses were low among lymphocytes in the airways of VAD+VDD animals compared to controls. The CD103 membrane marker, a protein that binds e-cadherin (expressed on respiratory tract epithelial cells), was unusually high on virus-specific T cells in VAD+VDD mice compared to controls. Interestingly, when T cells specific for the PA224-233/Db epitope were compared with T cells specific for the NP366-374/Db epitope, the former population was more strongly positive for CD103. Preliminary experiments revealed normal or above-normal percentages for vaccine-induced T cells in airways when VAD+VDD animals were supplemented with vitamins A + D at the time of vaccination and on days 3 and 7 after vaccination. Our results suggest that close attention should be paid to levels of vitamins A and D among vaccine recipients in the clinical arena, as low vitamin levels may render individuals poorly responsive to vaccines. PMID- 29130831 TI - A Predominant Oxidative Renal Metabolite of Empagliflozin in Male Mice Is Cytotoxic in Mouse Renal Tubular Cells but not Genotoxic. AB - In a previously reported CD-1 mouse 2-year carcinogenicity study with the sodium glucose cotransporter-2 inhibitor empagliflozin, an increased incidence of renal tubular adenomas and carcinomas was identified only in the male high-dose group. Follow-up investigative studies have shown that the renal tumors in male high dose mice were preceded by a number of renal degenerative/regenerative findings. Prior cross-species in vitro metabolism studies using microsomes identified an oxidative metabolite (M466/2) predominantly formed in the male mouse kidney and which spontaneously degrades to a metabolite (M380/1) and reactive 4-OH crotonaldehyde (CTA). In order to further evaluate potential modes of action for empagliflozin-associated male mouse renal tumors, we report here a series of in vitro investigative toxicology studies conducted to evaluate the cytotoxic and genotoxic potential of empagliflozin and M466/2. To assess the cytotoxic potential of empagliflozin and M466/2, a primary mouse renal tubular epithelial (mRTE) cell model was used. In mRTE cells, M466/2-derived in vitro 4-OH CTA exposure was cytotoxic, while empagliflozin was not cytotoxic or mitogenic. Empagliflozin and M466/2 were not genotoxic, supporting an indirect mode of action for empagliflozin-associated male mouse renal tumorigenesis. In conclusion, these in vitro data show that M466/2-derived 4-OH CTA exposure is associated with cytotoxicity in renal tubule cells and may be involved in promoting compound-related in vivo renal metabolic stress and chronic low-level renal injury, in turn supporting a nongenotoxic mode of tumor pathogenesis specific to the male mouse. PMID- 29130832 TI - Developmental Toxicity Assay for Food Additive Tartrazine Using Zebrafish ( Danio rerio) Embryo Cultures. AB - Tartrazine (TTZ) is an azo dye used as a colorant in food products, drugs, and cosmetics. The present study evaluates the impacts of TTZ on embryonic development of zebrafish ( Danio rerio). Laboratory-raised D. rerio embryos (n = 20/concentration) were exposed to graded dilutions of TTZ (0, 0.1, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 75, and 100 mM) from gastrulation stage (5.25 hours postfertilization [hpf]) until hatching and developmental trajectory was traced up to day 7. The no observed effect concentration (NOEC), median lethal concentration (LC50), median effective concentration (EC50), and teratogenic index (TI) were calculated. Exposure of embryos to < 10 mM TTZ had no effects; 20 to 30 mM TTZ caused tail bending, cardiac and yolk sac edema in 50% of larvae; in 30 to 50 mM TTZ-exposed embryos the heart rates declined along with the above mentioned deformities, causing mortality within 96 to 144 hpf; development ceased completely at 75 to 100 mM concentration. The NOEC and LC50 were recorded at 5 and 29.4 mM dose, respectively. The EC50 values for heart rate, cardiac edema, tail bending, and hatching success were at 59.60, 53.81, 98.28, and 58.97 mM with TI quotient 0.49, 0.54, 0.29, and 0.49, respectively. We conclude that TTZ is not embryo toxic/teratogenic for zebrafish embryos up to a dose level of 10 mM concentration. PMID- 29130810 TI - Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine. AB - BACKGROUND: Intravenous sodium bicarbonate and oral acetylcysteine are widely used to prevent acute kidney injury and associated adverse outcomes after angiography without definitive evidence of their efficacy. METHODS: Using a 2-by 2 factorial design, we randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention-to-treat analysis. The primary end point was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast-associated acute kidney injury was a secondary end point. RESULTS: The sponsor stopped the trial after a prespecified interim analysis. There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary end point (P=0.33). The primary end point occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group as compared with 116 of 2482 (4.7%) in the sodium chloride group (odds ratio, 0.93; 95% confidence interval [CI], 0.72 to 1.22; P=0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group as compared with 112 of 2498 (4.5%) in the placebo group (odds ratio, 1.02; 95% CI, 0.78 to 1.33; P=0.88). There were no significant between-group differences in the rates of contrast-associated acute kidney injury. CONCLUSIONS: Among patients at high risk for renal complications who were undergoing angiography, there was no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebo for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of contrast-associated acute kidney injury. (Funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia; PRESERVE ClinicalTrials.gov number, NCT01467466 .). PMID- 29130833 TI - Changes in the Pharmacokinetics of Phenytoin in Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice. AB - We previously demonstrated that the expression levels of drug-metabolizing enzymes, cytochrome P450 (CYP) enzymes, in the liver are significantly decreased in a murine model of ulcerative colitis (UC). In this study, we investigated changes in the pharmacokinetics of phenytoin, a CYP2C substrate drug, in the presence of UC. Colitis was induced by feeding male mice 3.5% dextran sulfate sodium (DSS) dissolved in drinking water for 10 days. The messenger RNA (mRNA) expression of CYP2C29 and CYP2C37 and the protein expression of CYP2C in the liver were evaluated via real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. In DSS-treated animals, both mRNA and protein expression levels of CYP2C in the liver were significantly reduced relative to those in control animals (by 20%-40%). Phenytoin (30 mg/kg) was administered orally in a single dose to mice, and plasma concentrations were measured. Plasma concentrations of phenytoin were higher in the DSS-treated group than in the control group at 12, 24, and 36 hours after administration. Animals given DSS also exhibited a higher area under the plasma concentration-time curve extrapolated to infinity (AUCinf, 315 MUg.h/mL), a delayed elimination half-life ( T1/2, 8.1 hours), and a decreased body clearance (CL/F, 3.52 mL/h) compared with that of control animals (AUCinf, 215 MUg.h/mL; T1/2, 3.6 h; CL/F, 5.58 mL/h). This study indicated that the presence of UC decreases CYP2C expression levels in the liver, thereby delaying the metabolism of CYP2C substrates, including phenytoin, and increasing blood concentrations of these substrates. PMID- 29130835 TI - Corrigendum. AB - Capra GG, Ge X, Balough BJ, Shah AN, Turner S, Mullin DP, Pfannenstiel TJ. Management of the incus body in ossiculoplasty. Otolaryngol Head Neck Surg. 2013;148(3):482-487. (Original doi: 10.1177/0194599812472641 ). PMID- 29130834 TI - The Relationship between Intuitive Action Choices and Moral Reasoning on Animal Ethics Issues in Students of Veterinary Medicine and Other Relevant Professions. AB - With growing understanding of animals' capabilities, and public and organizational pressures to improve animal welfare, moral action by veterinarians and other relevant professionals to address animal issues is increasingly important. Little is known about how their action choices relate to their moral reasoning on animal ethics issues. A moral judgment measure, the VetDIT, with three animal and three non-animal scenarios, was used to investigate the action choices of 619 students in five animal- and two non-animal-related professional programs in one Australian university, and how these related to their moral reasoning based on Personal Interest (PI), Maintaining Norms (MN), or Universal Principles (UP) schemas. Action choices showed significant relationships to PI, MN, and UP questions, and these varied across program groups. Having a previous degree or more experience with farm animals had a negative relationship, and experience with horses or companion animals a positive relationship, with intuitive action choices favoring life and bodily integrity of animals. This study helps to explain the complex relationship between intuitive moral action choices and moral reasoning on animal ethics issues. As a useful research and educational tool for understanding this relationship, the VetDIT can enhance ethical decision making. PMID- 29130837 TI - Corrigendum. AB - DeLegge MH, Kelly AT. State of nutrition support teams. Nutr Clin Pract. 2013;28:691-697. (Original DOI: 10.1177/0884533613507455 ). PMID- 29130838 TI - The Psychology of Rituals: An Integrative Review and Process-Based Framework. AB - Traditionally, ritual has been studied from broad sociocultural perspectives, with little consideration of the psychological processes at play. Recently, however, psychologists have begun turning their attention to the study of ritual, uncovering the causal mechanisms driving this universal aspect of human behavior. With growing interest in the psychology of ritual, this article provides an organizing framework to understand recent empirical work from social psychology, cognitive science, anthropology, behavioral economics, and neuroscience. Our framework focuses on three primary regulatory functions of rituals: regulation of (a) emotions, (b) performance goal states, and (c) social connection. We examine the possible mechanisms underlying each function by considering the bottom-up processes that emerge from the physical features of rituals and top-down processes that emerge from the psychological meaning of rituals. Our framework, by appreciating the value of psychological theory, generates novel predictions and enriches our understanding of ritual and human behavior more broadly. PMID- 29130836 TI - Composite 3D printed scaffold with structured electrospun nanofibers promotes chondrocyte adhesion and infiltration. AB - Additive manufacturing, also called 3D printing, is an effective method for preparing scaffolds with defined structure and porosity. The disadvantage of the technique is the excessive smoothness of the printed fibers, which does not support cell adhesion. In the present study, a 3D printed scaffold was combined with electrospun classic or structured nanofibers to promote cell adhesion. Structured nanofibers were used to improve the infiltration of cells into the scaffold. Electrospun layers were connected to 3D printed fibers by gluing, thus enabling the fabrication of scaffolds with unlimited thickness. The composite 3D printed/nanofibrous scaffolds were seeded with primary chondrocytes and tested in vitro for cell adhesion, proliferation and differentiation. The experiment showed excellent cell infiltration, viability, and good cell proliferation. On the other hand, partial chondrocyte dedifferentiation was shown. Other materials supporting chondrogenic differentiation will be investigated in future studies. PMID- 29130839 TI - Exploring Palliative Care Competency Standards for Medical Education in China: A Survey of National Hospice Service Program Providers. PMID- 29130841 TI - Ultrastructural Pathology joins forces with the Society for Ultrastructural Pathology. PMID- 29130840 TI - What works for wellbeing? A systematic review of wellbeing outcomes for music and singing in adults. AB - AIMS: The role of arts and music in supporting subjective wellbeing (SWB) is increasingly recognised. Robust evidence is needed to support policy and practice. This article reports on the first of four reviews of Culture, Sport and Wellbeing (CSW) commissioned by the Economic and Social Research Council (ESRC) funded What Works Centre for Wellbeing ( https://whatworkswellbeing.org/ ). OBJECTIVE: To identify SWB outcomes for music and singing in adults. METHODS: Comprehensive literature searches were conducted in PsychInfo, Medline, ERIC, Arts and Humanities, Social Science and Science Citation Indexes, Scopus, PILOTS and CINAHL databases. From 5,397 records identified, 61 relevant records were assessed using GRADE and CERQual schema. RESULTS: A wide range of wellbeing measures was used, with no consistency in how SWB was measured across the studies. A wide range of activities was reported, most commonly music listening and regular group singing. Music has been associated with reduced anxiety in young adults, enhanced mood and purpose in adults and mental wellbeing, quality of life, self-awareness and coping in people with diagnosed health conditions. Music and singing have been shown to be effective in enhancing morale and reducing risk of depression in older people. Few studies address SWB in people with dementia. While there are a few studies of music with marginalised communities, participants in community choirs tend to be female, white and relatively well educated. Research challenges include recruiting participants with baseline wellbeing scores that are low enough to record any significant or noteworthy change following a music or singing intervention. CONCLUSIONS: There is reliable evidence for positive effects of music and singing on wellbeing in adults. There remains a need for research with sub-groups who are at greater risk of lower levels of wellbeing, and on the processes by which wellbeing outcomes are, or are not, achieved. PMID- 29130844 TI - Corrigendum. AB - White L, Bly RA, D'Auria D, et al. Cricothyrotomy simulator with computational skill assessment for procedural skill training in the developing world. Otolaryngol Head Neck Surg. 2013;149:P60. (Original DOI: 10.1177/0194599813495815a83 ) In the September 2013 supplement to the journal, 2013 Official Program Abstracts, an author's name was misspelled. The third author, Daniella D'Auria, should have been listed as Daniela D'Auria. PMID- 29130843 TI - Correction to: Photomed Laser Surg 2015;34:516-524; DOI: 10.1089/pho.2015.3988. PMID- 29130846 TI - Response to "Anthropometric Indicators Predict Metabolic Syndrome Diagnosis in Maintenance Hemodialysis Patients: Methodological and Statistical Issues". PMID- 29130848 TI - Editor's Note. PMID- 29130847 TI - Anthropometric Indicators Predict Metabolic Syndrome Diagnosis in Maintenance Hemodialysis Patients: Methodological and Statistical Issues. PMID- 29130849 TI - Response to Dr Rhee. PMID- 29130850 TI - CORRECTION. PMID- 29130851 TI - Correction. PMID- 29130852 TI - Highlights from the Current Issue: March 2015. PMID- 29130853 TI - Endovascular Treatment of 12 Cases of Renal Arteriovenous Malformations: The Experience of 1 Center and an Overview of the Literature. AB - OBJECTIVES: Congenital renal arteriovenous malformations (rAVMs) represent rare vascular diseases. The heterogeneous vascular architecture of each rAVM determines the endovascular treatment techniques employed. We reported our experience with the endovascular treatment of a series of rAVMs. MATERIALS: This retrospective study consisted of 12 patients with 12 rAVMs who underwent renal arterial embolization (RAE) in our hospital. Embolic materials, including particles, liquid embolic agents (n-butyl 2-cyanoacrylate, Onyx, and ethanol), and coils, were selectively used based on the decisions of interventional radiologists. Technical success was defined as the complete occlusion of the feeding arteries and nidus on postprocedure renal arteriography. Clinical success was defined as the resolution of hematuria or the disappearance of rAVM-relevant symptoms. RESULTS: The median follow-up period was 13.5 months (range: 4-72). The technical success based on 12 procedures in 12 patients was 83.3% (10 of 12). In the 2 procedures that technically failed, the existence of multiple fine feeding arteries arising from the proximal portion of different segmental renal arteries explains the incomplete embolization. One of the 2 patients achieved clinical success without additional RAE. The other patient had recurrent hematuria 25 months after initial treatment, which was successfully managed conservatively with hemostatic agents. Thus, the clinical success was 91.7% (11 of 12). CONCLUSIONS: Renal artery embolization with the selective use of various embolic materials is an effective treatment for patients with rAVMs. The existence of multiple fine feeding vessels arising from the proximal portion of different segmental renal arteries is likely to affect the technical success of treatment. PMID- 29130854 TI - Transarterial Embolization of a Renal Artery Aneurysm Concomitant With Renal Arteriovenous Fistula. AB - Congenital renal artery aneurysm is uncommon. Moreover, renal artery aneurysm concomitant with a congenital renal arteriovenous fistula is extremely rare. Transarterial embolization is the first-line treatment for these conditions. We report a case of a patient with congenital renal artery aneurysm concomitant with a congenital renal arteriovenous fistula of the upper polar left renal artery which was successfully treated by transarterial embolization with coil, glue, and Amplatzer vascular plug. PMID- 29130855 TI - Management of Chronic Massive Traumatic Popliteal Artery Pseudoaneurysm: A Case Series With Different Treatment Strategies. AB - Giant traumatic popliteal artery (PA) pseudoaneurysms (PSA) are rare but limb threatening if untreated. Management can be challenging, as no standardized approach exists. This report evaluates our experience with 3 cases treated differently. Treatment is individualized based on patient disease and comorbidities. Endovascular and local patch arterial repair are safe alternatives to graft bypass when feasible. PMID- 29130857 TI - Information for Readers. PMID- 29130856 TI - Table of Contents 4/c (CMYK) on All 3 Pages of Toc. PMID- 29130845 TI - Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. AB - BACKGROUND: The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS: In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. RESULTS: The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .). PMID- 29130858 TI - Head and Neck Cancer: Emerging Perspectives. PMID- 29130859 TI - Sponsors. PMID- 29130860 TI - Editors. PMID- 29130863 TI - On the Move Box. PMID- 29130864 TI - Prokinetic Therapy for Feed Intolerance in Critical Illness: One Drug or Two? AB - OBJECTIVE: To compare the efficacy of combination therapy, with erythromycin and metoclopramide, to erythromycin alone in the treatment of feed intolerance in critically ill patients. DESIGN: Randomized, controlled, double-blind trial. SETTING: Mixed medical and surgical intensive care unit. PATIENTS: Seventy-five mechanically ventilated, medical patients with feed intolerance (gastric residual volume >=250 mL). INTERVENTIONS: Patients received either combination therapy (n = 37; 200 mg of intravenous erythromycin twice daily + 10 mg of intravenous metoclopramide four times daily) or erythromycin alone (n = 38; 200 mg of intravenous erythromycin twice daily) in a prospective, randomized fashion. Gastric feeding was re-commenced and 6-hourly gastric aspirates performed. Patients were studied for 7 days. Successful feeding was defined as a gastric residual volume <250 mL with the feeding rate >=40 mL/hr, over 7 days. Secondary outcomes included daily caloric intake, vomiting, postpyloric feeding, length of stay, and mortality. MEASUREMENTS AND MAIN RESULTS: Demographic data; use of inotropes, opioids, or benzodiazepines; and pretreatment gastric residual volume were similar between the two groups. The gastric residual volume was significantly lower after 24 hrs of treatment with combination therapy, compared with erythromycin alone (136 +/- 23 mL vs. 293 +/- 45 mL, p = .04). Over the 7 days, patients treated with combination therapy had greater feeding success, received more daily calories, and had a lower requirement for postpyloric feeding, compared with erythromycin alone. Tachyphylaxis occurred in both groups but was less with combination therapy. Sedation, higher pretreatment gastric residual volume, and hypoalbuminemia were significantly associated with a poor response. There was no difference in the length of hospital stay or mortality rate between the groups. Watery diarrhea was more common with combination therapy (20 of 37 vs. 10 of 38, p = .01) but was not associated with enteric infections, including Clostridium difficile. CONCLUSIONS: In critically ill patients with feed intolerance, combination therapy with erythromycin and metoclopramide is more effective than erythromycin alone in improving the delivery of nasogastric nutrition and should be considered as the first-line treatment. ( Crit Care Med. 2007;35:2561-2567.) NQ Nguyen, M Chapman, RJ Fraser, LK Bryant, C Burgstad, RH Holloway. PMID- 29130865 TI - Probiotic Prophylaxis in Predicted Severe Acute Pancreatitis: A Randomised, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Infectious complications and associated mortality are a major concern in acute pancreatitis. Enteral administration of probiotics could prevent infectious complications, but convincing evidence is scarce. Our aim was to assess the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis. METHODS: In this multicenter randomized, double-blind, placebo-controlled trial, 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic Health Evaluation [APACHE II] score >=8, Imrie score >=3, or C-reactive protein> 150 mg/L) were randomly assigned within 72 h of onset of symptoms to receive a multispecies probiotic preparation (n = 153) or placebo (n = 145), administered enterally twice daily for 28 days. The primary endpoint was the composite of infectious complications-i.e., infected pancreatic necrosis, bacteremia, pneumonia, urosepsis, or infected ascites-during admission and 90-day follow-up. Analyses were by intention to treat. This study is registered, number ISRCTN38327949. FINDINGS: One person in each group was excluded from analyses because of incorrect diagnoses of pancreatitis; thus, 152 individuals in the probiotics group and 144 in the placebo group were analysed. Groups were much the same at baseline in terms of patients' characteristics and disease severity. Infectious complications occurred in 46 (30%) patients in the probiotics group and 41 (28%) of those in the placebo group (relative risk 1.06, 95% CI 0.75-1.51). 24 (16%) patients in the probiotics group died, compared with nine (6%) in the placebo group (relative risk 2.53, 95% CI 1.22-5.25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p = 0.004). INTERPRETATION: In patients with predicted severe acute pancreatitis, probiotic prophylaxis with this combination of probiotic strains did not reduce the risk of infectious complications and was associated with an increased risk of mortality. Probiotic prophylaxis should therefore not be administered in this category of patients. ( Lancet. 2008;371(9613):651-659) MGH Besselink, HC van Santvoort, E Buskens, et al, for the Dutch Acute Pancreatitis Study Group. PMID- 29130866 TI - Enteral Feeding Misconnections: A Consortium Position Statement. AB - An invitation from the American Hospital Association (AHA) brought together a number of representatives from various organizations in Washington, D.C., on October 11, 2006, to (1) discuss the current state of practice pertaining to enteral feedings and (2) patient safety risks associated with medical misconnections involving enteral feeding systems. Although the initial focus was on Luer fittings, the scope of the discussion was expanded to the entire enteral feeding system to identify areas where misconnections could occur. This article presents the issues associated with enteral feeding misconnections and proposes a set of solutions. ( The Joint Commission Journal on Quality and Patient Safety. 2008;34:285-292) P Guenter, RW Hicks, D Simmons, et al. PMID- 29130867 TI - Using the experience-sampling method to examine the psychological mechanisms by which participatory art improves wellbeing. AB - AIMS: To measure the immediate impact of art-making in everyday life on diverse indices of wellbeing ('in the moment' and longer term) in order to improve understanding of the psychological mechanisms by which art may improve mental health. METHODS: Using the experience-sampling method, 41 artists were prompted (with a 'beep' on a handheld computer) at random intervals (10 times a day, for one week) to answer a short questionnaire. The questionnaire tracked art-making and enquired about mood, cognition and state of consciousness. This resulted in 2,495 sampled experiences, with a high response rate in which 89% of questionnaires were completed. RESULTS: Multi-level modelling was used to evaluate the impact of art-making on experience, with 2,495 'experiences' (experiential-level) nested within 41 participants (person-level). Recent art making was significantly associated with experiential shifts: improvement in hedonic tone, vivid internal imagery and the flow state. Furthermore, the frequency of art-making across the week was associated with person-level measures of wellbeing: eudemonic happiness and self-regulation. Cross-level interactions, between experiential and person-level variables, suggested that hedonic tone improved more for those scoring low on eudemonic happiness, and further that, those high in eudemonic happiness were more likely to experience phenomenological features of the flow state and to experience inner dialogue while art-making. CONCLUSION: Art-making has both immediate and long-term associations with wellbeing. At the experiential level, art-making affects multiple dimensions of conscious experience: affective, cognitive and state factors. This suggests that there are multiple routes to wellbeing (improving hedonic tone, making meaning through inner dialogue and experiencing the flow state). Recommendations are made to consider these factors when both developing and evaluating public health interventions that involve participatory art. PMID- 29130868 TI - Corrigendum. PMID- 29130869 TI - Effects of a museum-based social prescription intervention on quantitative measures of psychological wellbeing in older adults. AB - AIMS: To assess psychological wellbeing in a novel social prescription intervention for older adults called Museums on Prescription and to explore the extent of change over time in six self-rated emotions ('absorbed', 'active', 'cheerful', 'encouraged', 'enlightened' and 'inspired'). METHODS: Participants ( n = 115) aged 65-94 years were referred to museum-based programmes comprising 10 weekly sessions, by healthcare and third sector organisations using inclusion criteria (e.g. socially isolated, able to give informed consent, not in employment, not regularly attending social or cultural activities) and exclusion criteria (e.g. unable to travel to the museum, unable to function in a group situation, unlikely to be able to attend all sessions, unable to take part in interviews and complete questionnaires). In a within-participants' design, the Museum Wellbeing Measure for Older Adults (MWM-OA) was administered pre-post session at start-, mid- and end-programme. A total of 12 programmes, facilitated by museum staff and volunteers, were conducted in seven museums in central London and across Kent. In addition to the quantitative measures, participants, carers where present, museum staff and researchers kept weekly diaries following guideline questions and took part in end-programme in-depth interviews. RESULTS: Multivariate analyses of variance showed significant participant improvements in all six MWM-OA emotions, pre-post session at start-, mid- and end-programme. Two emotions, 'absorbed' and 'enlightened', increased pre-post session disproportionately to the others; 'cheerful' attained the highest pre-post session scores whereas 'active' was consistently lowest. CONCLUSION: Museums can be instrumental in offering museum-based programmes for older adults to improve psychological wellbeing over time. Participants in the study experienced a sense of privilege, valued the opportunity to liaise with curators, visit parts of the museum closed to the public and handle objects normally behind glass. Participants appreciated opportunities afforded by creative and co-productive activities to acquire learning and skills, and get to know new people in a different context. PMID- 29130870 TI - Modern technology to support carers of care recipients with dementia or functional mental illness: promising progress, but a long road ahead. AB - There is no doubt that family carers who look after a family member with dementia or with a functional mental illness fulfill an important role, not only for their loved one, but also for the health and aged care systems of the countries they live in. Due to increasing life expectancy, but also improved healthcare the number of family carers supporting older care recipients with functional mental illness or dementia is on the rise. While the carer role often can offer rewarding experiences caregivers are at increased risk of stress, depression, sleep problems, and often experience poor health outcomes with increased morbidity and mortality (Oyebode, 2003). Next to the stressors directly associated with the carer role, they often do not have the time to engage in healthy behavior to protect their physical, mental, and cognitive health (Loi et al., 2014). There is a wealth of literature providing evidence about effective strategies to support carers and the recent Lancet Commission on Dementia prevention, intervention, and care highlighted the importance of exploring how the use of technological innovations could support carers better (Livingston et al., 2017). The use of modern technology in this context can mean a variety of approaches, such as internet-based programs to provide education and skill building, virtual support to assist with monitoring and managing challenging behavior, online support groups, and the use of assistive or therapeutic technology to improve safety, enable positive activities, and support communication between carer and care recipient, to name just a few (D'Onofrio et al., 2017; Ienca et al., 2017; Livingston et al., 2017). More specifically, telehealth approaches via videoconferences have the potential to better support carers who live in rural or remote regions (O'Connell et al., 2014) or who cannot attend face-to-face support programs for other reasons such as inability to leave the care recipient alone at home, being a multiple carer or having a disability themselves to give just some examples. PMID- 29130871 TI - Burnout and Stress in Medicine in the 21st Century: Catastrophe or Opportunity? PMID- 29130872 TI - A Retrospective Comparative Analysis of the Use of Implantable Bone Stimulators in Nonunions. AB - This study details the use of implantable bone stimulators in the setting of nonunion. A retrospective comparative analysis was used to evaluate the efficacy of implantable bone stimulators in achieving union in the setting of atrophic or oligotrophic nonunion by two fellowship-trained orthopaedic trauma surgeons. Initially, 72 patients underwent surgical intervention for nonunion. Twenty-one patients had an implantable bone stimulator placed at the time of nonunion surgery. Thirty-eight patients had a minimum of 1-year follow-up. An implantable bone stimulator was used in 13 patients and 25 patients did not have a bone stimulator. The use of implantable bone stimulators was found to be significantly associated with increased union rates (p = .042). (Journal of Surgical Orthopaedic Advances. PMID- 29130873 TI - Influence of Body Mass Index on Clinical Outcomes in Reverse Total Shoulder Arthroplasty. AB - The purpose of this study was to compare reverse total shoulder arthroplasty (RTSA) outcomes in normal weight, overweight, and obese patients. A RTSA outcomes registry was reviewed for rotator cuff-deficient patients with a minimum 2-year follow-up. Fractures, rheumatoid arthritis, and revisions were excluded. Based on World Health Organization body mass index (BMI) classification, there were 29 normal weight, 50 overweight, and 51 obese patients. All groups demonstrated significant improvements from preoperative to most recent follow-up in function scores, pain, and forward elevation. Obese and overweight groups had significantly worse preoperative rotation than the normal weight group. Postoperatively, there was no significant difference in absolute values or degree of improvement of rotation between groups. There was no significant difference in the incidence of radiographic or clinical complications between groups. Results of this study suggest that BMI has little influence on outcomes or risk of complication following RTSA. Longer-term studies are needed to determine if these results are maintained. (Journal of Surgical Orthopaedic Advances. PMID- 29130874 TI - Do Routine Radiographs Obtained at Initial Outpatient Postoperative Visit Change Management? AB - Routine postoperative radiographs are commonly obtained at the initial postoperative visit. The purpose of this study was to demonstrate the clinical utility of routine postoperative radiographs and quantify the radiation exposure and cost to the health care system. All orthopaedic surgeries performed during 2007 at a level I trauma center were retrospectively analyzed. Surgical procedures that were likely to require follow-up radiographs were included. Analysis demonstrated 878 procedures with 471 procedures (54%) receiving initial postoperative radiographs. Routine radiographs were performed in 455 (96.6%) procedures with 4/455 (0.879%) resulting in a change in management. Nonroutine radiographs were performed in 16 (3.40%) procedures with 2/16 (12.5%) triggering a change in management. Subjects receiving radiographs at the initial postoperative visit obtained a mean of 2.54 radiographs per procedure with a mean exposure of 0.199 mSv with a median cost of $29.98 per radiographic series in 2013 Medicare reimbursement dollars. (Journal of Surgical Orthopaedic Advances. PMID- 29130875 TI - Predictors of Acute Ischemic Stroke After Total Knee Arthroplasty. AB - Although acute ischemic stroke (AIS) is a feared medical complication after total knee arthroplasty (TKA), little is known about its incidence and risk factors. The purpose of this retrospective populationbased study using the Nationwide Inpatient Sample (2008-2011) was to determine the incidence and predictors of AIS following TKA. The rate of perioperative AIS was 0.08%. Patients undergoing bilateral TKA were almost three times more likely to develop AIS compared with unilateral TKA patients. The age group with the highest odds of AIS was >=85 years. Sex and race and ethnicity were not independently associated with AIS. The comorbidity with the highest risk for AIS was history of stroke, followed by cardiac valvular disease, peripheral vascular disease, atrial fibrillation, complicated diabetes, coagulopathy, and ischemic heart disease. The data in this article might prove useful for preoperative counseling and decision making, resource allocation, and implementation of strategies to minimize the occurrence of AIS after TKA. (Journal of Surgical Orthopaedic Advances. PMID- 29130876 TI - Efficacy of Arthroscopic Teaching Methods: A Prospective Randomized Controlled Study. AB - Arthroscopic education research recently has been focused on the use of skills labs to facilitate resident education and objective measure development to gauge technical skill. This study evaluates the effectiveness of three different teaching methods. Medical students were randomized into three groups. The first group received only classroom-based lecture. The second group received the same lecture and 28 minutes of lab-based hands-off arthroscopy instruction using a cadaver and arthroscopy setup. The final group received the same lecture and 7 minutes of hands-on arthroscopy instruction in the lab on a cadaver knee. The arthroscopic knee exam that followed simulated a diagnostic knee exam and subjects were measured on task completion and by the number of look downs. The number of look downs and the number of tasks completed did not achieve statistical significance between groups. Posttest survey results revealed that the hands-on group placed significantly more value on their educational experience as compared with the other two groups. (Journal of Surgical Orthopaedic Advances. PMID- 29130877 TI - Reduction Loss After Distal Radius Fracture Fixation With Locked Volar Plates. AB - Distal radius fractures are among the most common injuries in the upper extremity. While many studies have looked at the maintenance of reduction with volar locking plates, there is a paucity of literature comparing the ability of different plates to maintain reduction over time. This study reviews the ability of various plates to maintain radiographic reduction at union after distal radius fracture treatment. Loss of some aspect of fracture reduction was routinely observed following locked volar plating regardless of implant. However, choice of implant did have a significant impact on final radiographic alignment, particularly with respect to volar tilt and ulnar variance. Yet, selecting between a fixed angle versus a variable angle was not found to make a difference in maintaining reduction. The authors recommend that surgeons take these findings into consideration when selecting a volar locking plate. (Journal of Surgical Orthopaedic Advances. PMID- 29130878 TI - A Novel Technique Utilizing a Vastus Lateralis Anchor in Treatment of Chronic Patellar Dislocation After Total Knee Arthroplasty. AB - Extensor mechanism complications involving the patella frequently result in total knee arthroplasty (TKA) failure. Postoperative patellar dislocation may be caused by soft tissue imbalance, improper sizing, and position of the prosthesis. This report describes a case of revision TKA requiring several rounds of soft tissue releases in an effort to treat the patient's chronic patellar dislocation. In the process, a novel surgical approach was developed for the surgical management of refractory chronic patellar dislocations. Postoperative follow-up at 1, 2, 6, 12, and 24 months indicated no complaints of patellar subluxation or dislocation. Plain films also demonstrated no effusion, fracture, or patellar dislocation on sunrise, anteroposterior, and lateral views. This novel anatomic repositioning of the vastus lateralis around the quadriceps tendon converted a pathologic lateralizing force into a medial stabilizer. On follow-up evaluations, successful patellar tracking without dislocation has been demonstrated. (Journal of Surgical Orthopaedic Advances. PMID- 29130879 TI - Vascularized Medial Femoral Condyle Graft for Manubrium Nonunion: Case Report and Review of the Literature. AB - Fractures of the sternum are rare. Persistent nonunions, however, can lead to chronic pain and significant functional limitations. The vascularized medial femoral condyle is a versatile tool in the surgeon's armamentarium. Traditionally, it has been used as a thin corticoperiosteal graft in the treatment of nonunion of tubular bones. Its use as a structural corticocancellous graft has also been expanding. This report presents a case of a patient with a recalcitrant symptomatic nonunion of the manubrium treated with the unique combined corticoperiosteal and corticocancellous vascularized bone graft from the medial femoral condyle and reviews the literature concerning these uncommon nonunions. (Journal of Surgical Orthopaedic Advances. PMID- 29130880 TI - Two Patients and Two Knee Cysts. AB - Differential diagnosis of a cystic lesion adjacent to menisci can be a challenge even when the case presents as seemingly straightforward. To "tell the story" as accurately as possible, the radiologist must be familiar with the natural history of these lesions as well as distinctive imaging features and must take all relevant factors into consideration, such as patient's age, activity level, and surgical history. This article presents two cases to illustrate how imaging features affect the report and management plan. (Journal of Surgical Orthopaedic Advances. PMID- 29130881 TI - Distal Radius Skyline View: How to Prevent Dorsal Cortical Penetration. AB - Volar locked plating has become a standard treatment for operative stabilization of distal radius fractures. It is assumed that volar plating portends a low risk of extensor tendon irritation and rupture, especially when compared with dorsal plating constructs; however, extensor tendon tenosynovitis and rupture is a well described complication after volar plating of the distal radius. Dorsal cortical penetration of screws may go unnoticed with traditional intraoperative fluoroscopic techniques and may contribute to extensor tendon irritation. This article presents the authors' experience with an additional fluoroscopic dorsal tangential radiograph helping the surgeon ascertain dorsal screw prominence following volar plate fixation. (Journal of Surgical Orthopaedic Advances. PMID- 29130882 TI - Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. AB - Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research (http://epic.gfellerlab.org). PMID- 29130883 TI - Regulatory network structure determines patterns of intermolecular epistasis. AB - Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. PMID- 29130885 TI - Animal thermoregulation: a review of insulation, physiology and behaviour relevant to temperature control in buildings. AB - Birds and mammals have evolved many thermal adaptations that are relevant to the bioinspired design of temperature control systems and energy management in buildings. Similar to many buildings, endothermic animals generate internal metabolic heat, are well insulated, regulate their temperature within set limits, modify microclimate and adjust thermal exchange with their environment. We review the major components of animal thermoregulation in endothermic birds and mammals that are pertinent to building engineering, in a world where climate is changing and reduction in energy use is needed. In animals, adjustment of insulation together with physiological and behavioural responses to changing environmental conditions fine-tune spatial and temporal regulation of body temperature, while also minimizing energy expenditure. These biological adaptations are characteristically flexible, allowing animals to alter their body temperatures to hourly, daily, or annual demands for energy. They exemplify how buildings could become more thermally reactive to meteorological fluctuations, capitalising on dynamic thermal materials and system properties. Based on this synthesis, we suggest that heat transfer modelling could be used to simulate these flexible biomimetic features and assess their success in reducing energy costs while maintaining thermal comfort for given building types. PMID- 29130886 TI - Au nanowire junction breakup through surface atom diffusion. AB - Metallic nanowires are known to break into shorter fragments due to the Rayleigh instability mechanism. This process is strongly accelerated at elevated temperatures and can completely hinder the functioning of nanowire-based devices like e.g. transparent conductive and flexible coatings. At the same time, arranged gold nanodots have important applications in electrochemical sensors. In this paper we perform a series of annealing experiments of gold and silver nanowires and nanowire junctions at fixed temperatures 473, 673, 873 and 973 K (200 degrees C, 400 degrees C, 600 degrees C and 700 degrees C) during a time period of 10 min. We show that nanowires are especially prone to fragmentation around junctions and crossing points even at comparatively low temperatures. The fragmentation process is highly temperature dependent and the junction region breaks up at a lower temperature than a single nanowire. We develop a gold parametrization for kinetic Monte Carlo simulations and demonstrate the surface diffusion origin of the nanowire junction fragmentation. We show that nanowire fragmentation starts at the junctions with high reliability and propose that aligning nanowires in a regular grid could be used as a technique for fabricating arrays of nanodots. PMID- 29130887 TI - Axial p-n junction and space charge limited current in single GaN nanowire. AB - The electrical characterizations of individual basic GaN nanostructures, such as axial nanowire (NW) p-n junctions, are becoming indispensable and crucial for the fully controlled realization of GaN NW based devices. In this study, electron beam induced current (EBIC) measurements were performed on two single axial GaN p n junction NWs grown by plasma-assisted molecular beam epitaxy. I-V characteristics revealed that both ohmic and space charge limited current (SCLC) regimes occur in GaN p-n junction NW. Thanks to an improved contact process, both the electric field induced by the p-n junction and the SCLC in the p-part of GaN NW were disclosed and delineated by EBIC signals under different biases. Analyzing the EBIC profiles in the vicinity of the p-n junction under 0 V and reverse bias, we deduced a depletion width in the range of 116-125 nm. Following our previous work, the acceptor N a doping level was estimated to be 2-3 * 1017 at cm-3 assuming a donor level N d of 2-3 * 1018 at cm-3. The hole diffusion length in n-GaN was determined to be 75 nm for NW #1 and 43 nm for NW #2, demonstrating a low surface recombination velocity at the m-plane facet of n-GaN NW. Under forward bias, EBIC imaging visualized the electric field induced by the SCLC close to p-side contact, in agreement with unusual SCLC previously reported in GaN NWs. PMID- 29130884 TI - Ubiquitin turnover and endocytic trafficking in yeast are regulated by Ser57 phosphorylation of ubiquitin. AB - Despite its central role in protein degradation little is known about the molecular mechanisms that sense, maintain, and regulate steady state concentration of ubiquitin in the cell. Here, we describe a novel mechanism for regulation of ubiquitin homeostasis that is mediated by phosphorylation of ubiquitin at the Ser57 position. We find that loss of Ppz phosphatase activity leads to defects in ubiquitin homeostasis that are at least partially attributable to elevated levels of Ser57 phosphorylated ubiquitin. Phosphomimetic mutation at the Ser57 position of ubiquitin conferred increased rates of endocytic trafficking and ubiquitin turnover. These phenotypes are associated with bypass of recognition by endosome-localized deubiquitylases - including Doa4 which is critical for regulation of ubiquitin recycling. Thus, ubiquitin homeostasis is significantly impacted by the rate of ubiquitin flux through the endocytic pathway and by signaling pathways that converge on ubiquitin itself to determine whether it is recycled or degraded in the vacuole. PMID- 29130889 TI - Electron trap states at InGaAs/oxide interfaces under inversion through constant Fermi-level ab initio molecular dynamics. AB - We employ constant-Fermi-level ab initio molecular dynamics to investigate defects at the InGaAs/oxide interface upon inversion. We adopt a substoichiometric amorphous model for modelling the structure at the interface and investigate the formation of defect structures upon setting the Fermi-level above the conduction band minimum. The defect formation is detected through both an analysis of the atomic structure and a Wannier-decomposition of the electronic structure. This computer driven approach is able to retrieve In and Ga lone-pair defects and As-As dimer/dangling bond defects, in agreement with previous studies based on physical intuition. In addition, the present simulation reveals hitherto unidentified defect structures consisting of metallic In-In, In-Ga, and Ga-Ga bonds. The defect charge transition levels of such metallic bonds in Al2O3 are then determined through a hybrid functional scheme and found to be consistent with the defect density measured at InGaAs/Al2O3 interfaces. Hence, we conclude that both In and Ga lone pairs dangling bonds and metallic In-In bonds are valid candidate defects for charge trapping at InGaAs/oxide interfaces upon charge carier inversion. This study demonstrates the effectiveness of constant-Fermi level ab initio molecular dynamics in revealing and identifying defects at InGaAs/oxide interfaces. PMID- 29130888 TI - Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy. AB - Polymeric biomaterials that can be smartly disassembled through the cleavage of the covalent bonds in a controllable way upon an environmental stimulus such as pH change, redox, special enzymes, temperature, or ultrasound, as well as light irradiation, but are otherwise stable under normal physiological conditions have attracted great attention in recent decades. The 2-(4-aminophenyl) benzothiazole molecule (CJM-126), as one of the benzothiazole derivatives, has exhibited a synergistic effect with cisplatin (CDDP) and restrains the bioactivities of a series of human breast cancer cell lines. In our study, novel NIR-responsive targeted binary-drug-loaded nanoparticles encapsulating indocyanine green (ICG) dye were prepared as a new co-delivery and combined therapeutic vehicle. The prepared drug-loaded polymeric nanoparticles (TNPs/CDDP-ICG) are stable under normal physiological conditions, while burst drugs release upon NIR laser irradiation in a mild acidic environment. The results further confirmed that the designed co-delivery platform showed higher cytotoxicity than the single free CDDP due to the synergistic treatment of CJM-126 and CDDP in vitro. Taken together, the work might provide a promising approach for effective site-specific antitumor therapy. PMID- 29130890 TI - Memristive Effects in Oxygenated Amorphous Carbon Nanodevices. AB - Computing with resistive-switching (memristive) memory devices has shown much recent progress and offers an attractive route to circumvent the von-Neumann bottleneck, i.e. the separation of processing and memory, which limits the performance of conventional computer architectures. Due to their good scalability and nanosecond switching speeds, carbon-based resistive-switching memory devices could play an important role in this respect. However, devices based on elemental carbon, such as tetrahedral amorphous carbon or t-aC, typically suffer from a low cycling endurance. A material that has proven to be capable of combining the advantages of elemental carbon-based memories with simple fabrication methods and good endurance performance for binary memory applications is oxygenated amorphous carbon, or a-COx. Here, we examine the memristive capabilities of nanoscale a-COx devices, in particular their ability to provide the multilevel and accumulation properties that underpin computing type applications. We show the successful operation of nanoscale a-COx memory cells for both the storage of multilevel states (here 3-level) and for the provision of an arithmetic accumulator. We implement a base-16, or hexadecimal, accumulator and show how such a device can carry out hexadecimal arithmetic and simultaneously store the computed result in the self-same a-COx cell, all using fast (sub-10 ns) and low-energy (sub-pJ) input pulses. PMID- 29130891 TI - Nonlinear modeling of crystal system transition of black phosphorus using continuum-DFT model. AB - In this paper, the nonlinear behavior of black phosphorus crystals is investigated in tandem with dispersion-corrected density functional theory (DFT D) analysis under uniaxial loadings. From the identified anisotropic behavior of black phosphorus due to its morphological anisotropy, a hyperelastic anisotropic (HA) model named continuum-DFT is established to predict the nonlinear behavior of the material. In this respect, uniaxial Cauchy stresses are employed on both the DFT-D and HA models along the zig-zag and armchair directions. Simultaneously, the transition of the crystal system is recognized at about 4.5 GPa of the applied uniaxial tensile stress along the zig-zag direction on the DFT D simulation in the nonlinear region. In order to develop the nonlinear continuum model, unknown constants are surveyed with the optimized least square technique. In this regard, the continuum model is obtained to reproduce the Cauchy stress stretch and density of strain-stretch results of the DFT-D simulation. Consequently, the modified HA model is introduced to characterize the nonlinear behavior of black phosphorus along the zig-zag direction. More importantly, the specific transition of the crystal system is successfully predicted in the new modified continuum-DFT model. The results reveal that the multiscale continuum DFT model is well defined to replicate the nonlinear behavior of black phosphorus along the zig-zag and armchair directions. PMID- 29130892 TI - Surface effects on ionic Coulomb blockade in nanometer-size pores. AB - Ionic Coulomb blockade in nanopores is a phenomenon that shares some similarities but also differences with its electronic counterpart. Here, we investigate this phenomenon extensively using all-atom molecular dynamics of ionic transport through nanopores of about one nanometer in diameter and up to several nanometers in length. Our goal is to better understand the role of atomic roughness and structure of the pore walls in the ionic Coulomb blockade. Our numerical results reveal the following general trends. First, the nanopore selectivity changes with its diameter, and the nanopore position in the membrane influences the current strength. Second, the ionic transport through the nanopore takes place in a hopping-like fashion over a set of discretized states caused by local electric fields due to membrane atoms. In some cases, this creates a slow-varying 'crystal like' structure of ions inside the nanopore. Third, while at a given voltage, the resistance of the nanopore depends on its length, the slope of this dependence appears to be independent of the molarity of ions. An effective kinetic model that captures the ionic Coulomb blockade behavior observed in MD simulations is formulated. PMID- 29130893 TI - A highly efficient flocculant for graphene oxide recycling and its applications. AB - In this study, we found a novel and efficient way of recycling graphene oxide (GO) by adding ZnO colloid into the GO solution. GO flocculates immediately when mixed with ZnO colloids. Interestingly, the flocculation would disappear and disperse homogeneously in solution if a certain amount of HCl is added. The study offers a solution to recover and reuse GO throughout its production procedures. More importantly, in the obtained reduced GO/ZnO (rGO/ZnO) flocculant, ZnO nanorods are observed self-assembled into an ordered structure in between the rGO sheets. This prevents the rGO sheets from re-stacking and facilitates the movement of the electrolyte into ZnO if the prepared rGO/ZnO is used as an electrode for supercapacitor. Electrochemical measurements have proved that the rGO/ZnO composite with a weight ratio of 1:1 exhibits a gravimetric specific capacitance of 175 F g-1 and the rGO/ZnO electrode maintains 89.6% of the initial capacitance after 5000 cycles of uses. PMID- 29130894 TI - A comparison of the role of beamwidth in biological and engineered sonar. AB - Sonar is an important sensory modality for engineers as well as in nature. In engineering, sonar is the dominating modality for underwater sensing. In nature, biosonar is likely to have been a central factor behind the unprecedented evolutionary success of bats, a highly diverse group that accounts for over 20% of all mammal species. However, it remains unclear to what extent engineered and biosonar follow similar design and operational principles. In the current work, the key sonar design characteristic of beamwidth is examined in technical and biosonar. To this end, beamwidth data has been obtained for 23 engineered sonar systems and from numerical beampattern predictions for 151 emission and reception elements (noseleaves and ears) representing bat biosonar. Beamwidth data from these sources is compared to the beamwidth of a planar ellipsoidal transducer as a reference. The results show that engineered and biological both obey the basic physical limit on beamwidth as a function of the ratio of aperture size and wavelength. However, beyond that, the beamwidth data revealed very different behaviors between the engineered and the biological sonar systems. Whereas the beamwidths of the technical sonar systems were very close to the planar transducer limit, the biological samples showed a very wide scatter away from this limit. This scatter was as large, if not wider, than what was seen in a small reference data set obtained with random aluminum cones. A possible interpretation of these differences in the variability could be that whereas sonar engineers try to minimize beamwidth subject to constraints on device size, the evolutionary optimization of bat biosonar beampatterns has been directed at other factors that have left beamwidth as a byproduct. Alternatively, the biosonar systems may require beamwidth values that are larger than the physical limit and differ between species and their sensory ecological niches. PMID- 29130895 TI - Ceramic core with polymer corona hybrid nanocarrier for the treatment of osteosarcoma with co-delivery of protein and anti-cancer drug. AB - For the treatment of metastatic bone cancer, local delivery of therapeutic agents is preferred compared to systemic administration. Delivery of an anti-cancer drug and a protein that helps in bone regeneration simultaneously is a challenging approach. In this study, a nanoparticulate carrier which delivers a protein and an anti-cancer drug is reported. Bovine serum albumin (BSA) as a model protein was loaded into hydroxyapatite (HA) nanoparticles (NPs) and methotrexate (MTX) conjugated to poly(vinyl alcohol) was coated onto BSA-loaded HA NPs. Coating efficiency was in the range of 10-17 wt%. In vitro drug release showed that there was a steady increase in the release of both BSA and MTX with 76% of BSA and 88% of MTX being released in 13 days. Cytotoxicity studies of the NPs performed using human osteosarcoma (OMG-63) cell line showed the NPs were highly biocompatible and exhibited anti-proliferative activity in a concentration-dependent manner. PMID- 29130896 TI - Characterisation of flattening filter free (FFF) beam properties for initial beam set-up and routine QA, independent of flattened beams. AB - Flattening filter free (FFF) beams have reached widespread use for clinical treatment deliveries. The usual methods for FFF beam characterisation for their quality assurance (QA) require the use of associated conventional flattened beams (cFF). Methods for QA of FFF without the need to use associated cFF beams are presented and evaluated against current methods for both FFF and cFF beams. Inflection point normalisation is evaluated against conventional methods for the determination of field size and penumbra for field sizes from 3 cm * 3 cm to 40 cm * 40cm at depths from dmax to 20 cm in water for matched and unmatched FFF beams and for cFF beams. A method for measuring symmetry in the cross plane direction is suggested and evaluated as FFF beams are insensitive to symmetry changes in this direction. Methods for characterising beam energy are evaluated and the impact of beam energy on profile shape compared to that of cFF beams. In plane symmetry can be measured, as can cFF beams, using observed changes in profile, whereas cross-plane symmetry can be measured by acquiring profiles at collimator angles 0 and 180. Beam energy and 'unflatness' can be measured as with cFF beams from observed shifts in profile with changing beam energy. Normalising the inflection points of FFF beams to 55% results in an equivalent penumbra and field size measurement within 0.5 mm of conventional methods with the exception of 40 cm * 40 cm fields at a depth of 20 cm. New proposed methods are presented that make it possible to independently carry out set up and QA measurements on beam energy, flatness, symmetry and field size of an FFF beam without the need to reference to an equivalent flattened beam of the same energy. The methods proposed can also be used to carry out this QA for flattened beams, resulting in universal definitions and methods for MV beams. This is presented for beams produced by an Elekta linear accelerator, but is anticipated to also apply to other manufacturers' beams. PMID- 29130897 TI - Synthesis of carbon nanotube (CNT)-entangled CuO nanotube networks via CNT catalytic growth and in situ thermal oxidation as additive-free anodes for lithium ion batteries. AB - We demonstrated the utility of carbon nanotubes (CNTs) as a catalyst and conductive agent to synthesize CNT-entangled copper nanowire (CuNW-CNT) networks within a melted mixture of hexadecylamine and cetyltrimethy ammounium bromide. The CuNW-CNT networks were further in situ thermally oxidized into CuO nanotube CNT (CuONT-CNT) with the high retention of network structure. The binder- and conducting-additive-free anodes constructed using the CuONT-CNT networks exhibited high performance, such as high capability (557.7 mAh g-1 at 0.2 degrees C after 200 cycles), high Coulombic efficiency (near 100%), good rate performance (385.5 mAh g-1 at 5 degrees C and 310.3 mAh g-1 at 10 degrees C), and long cycling life. PMID- 29130899 TI - Semiconductor quantum dot super-emitters: spontaneous emission enhancement combined with suppression of defect environment using metal-oxide plasmonic metafilms. AB - We demonstrate that a metal-oxide plasmonic metafilm consisting of a Si/Al oxide junction in the vicinity of a thin gold layer can quarantine excitons in colloidal semiconductor quantum dots against their defect environments. This process happens while the plasmon fields of the gold layer enhance spontaneous emission decay rates of the quantum dots. We study the emission dynamics of such quantum dots when the distance between the Si/Al oxide junction and the gold thin layer is varied. The results show that for distances less than a critical value the lifetime of the quantum dots can be elongated while they experience intense plasmon fields. This suggests that the metal-oxide metafilm can keep photo excited electrons in the cores of the quantum dots, suppressing their migration to the surface defect sites. This leads to suppression of Auger recombination, offering quantum dot super-emitters with emission that is enhanced not only by the plasmon fields (Purcell effect), but also by strong suppression of the non radiative decay caused by the defect sites. PMID- 29130900 TI - Aggregate frequency width, nuclear hyperfine coupling and Jahn-Teller effect of Cu2+ impurity ion ESR in SrLaAlO4 dielectric resonator at 20 millikelvin. AB - The impurity paramagnetic ion, [Formula: see text] substitutes Al in the [Formula: see text] single crystal lattice, this results in a [Formula: see text] elongated octahedron, and the resulting measured g-factors satisfy four-fold axes variation condition. The aggregate frequency width of the electron spin resonance with the required minimum level of impurity concentration has been evaluated in this single crystal [Formula: see text] at 20 millikelvin. Measured parallel hyperfine constants, [Formula: see text], were determined to be [Formula: see text] and [Formula: see text] at [Formula: see text] for the nuclear magnetic quantum number [Formula: see text], and [Formula: see text] respectively. The anisotropy of the hyperfine structure reveals the characteristics of the static Jahn-Teller effect. The second-order-anisotropy term, [Formula: see text], is significant and cannot be disregarded, with the local strain dominating over the observed Zeeman-anisotropy-energy difference. The Bohr electron magneton, [Formula: see text], (within [Formula: see text] so-called experimental error) has been found using the measured spin-Hamiltonian parameters. Measured nuclear dipolar hyperfine structure parameter [Formula: see text] shows that the mean inverse third power of the electron distance from the nucleus is [Formula: see text] a.u. for [Formula: see text] ion in the substituted [Formula: see text] ion site assuming nuclear electric quadruple moment [Formula: see text] barn. PMID- 29130898 TI - Single-step synthesis of Er3+ and Yb3+ ions doped molybdate/Gd2O3 core-shell nanoparticles for biomedical imaging. AB - Nanostructures as color-tunable luminescent markers have become major, promising tools for bioimaging and biosensing. In this paper separated molybdate/Gd2O3 doped rare earth ions (erbium, Er3+ and ytterbium, Yb3+) core-shell nanoparticles (NPs), were fabricated by a one-step homogeneous precipitation process. Emission properties were studied by cathodo- and photoluminescence. Scanning electron and transmission electron microscopes were used to visualize and determine the size and shape of the NPs. Spherical NPs were obtained. Their core-shell structures were confirmed by x-ray diffraction and energy-dispersive x-ray spectroscopy measurements. We postulated that the molybdate rich core is formed due to high segregation coefficient of the Mo ion during the precipitation. The calcination process resulted in crystallization of delta/xi (core/shell) NP doped Er and Yb ions, where delta-gadolinium molybdates and xi-molybdates or gadolinium oxide. We confirmed two different upconversion mechanisms. In the presence of molybdenum ions, in the core of the NPs, Yb3+-[Formula: see text] (?2F7/2, 3T2>) dimers were formed. As a result of a two 980 nm photon absorption by the dimer, we observed enhanced green luminescence in the upconversion process. However, for the shell formed by the Gd2O3:Er, Yb NPs (without the Mo ions), the typical energy transfer upconversion takes place, which results in red luminescence. We demonstrated that the NPs were transported into cytosol of the HeLa and astrocytes cells by endocytosis. The core-shell NPs are sensitive sensors for the environment prevailing inside (shorter luminescence decay) and outside (longer luminescence decay) of the tested cells. The toxicity of the NPs was examined using MTT assay. PMID- 29130901 TI - Quantification of fat fraction in lumbar vertebrae: correlation with age and implications for bone marrow dosimetry in molecular radiotherapy. AB - Absorbed dose to active bone marrow is a predictor of hematological toxicity in molecular radiotherapy. Due to the complex composition of bone marrow tissue, the necessity to improve the personalized dosimetry has led to the application of non conventional imaging methods in nuclear medicine. The aim of this study is to apply magnetic resonance imaging (MRI) for quantification of the fat fraction in lumbar vertebrae and to analyze its implications for bone marrow dosimetry. First, a highly accelerated two-point Dixon MRI sequence for fat-water separation was validated in a 3T system against the magnetic resonance spectroscopy (MRS) gold standard. The validation was performed in a fat-water phantom composed of 11 vials with different fat fractions between 0% and 100%, and subsequently repeated in the lumbar vertebrae of three healthy volunteers. Finally, a retrospective study was performed by analyzing the fat fraction in five lumbar vertebrae of 44 patients scanned with the two-point Dixon sequence. The two-point Dixon phantom acquisition showed a good agreement (maximum difference = 2.9%) between the nominal fat fraction and MRS. In the volunteers, a statistical analysis showed a non-significant difference (p = 0.19) between MRI and MRS. In the patients, gender-specific linear fits for female and male data indicated that the age dependent marrow conversion (red -> yellow marrow) is slower in males (0.3% per year) than in females (0.5% per year). Lastly, the fat fraction values showed a considerable variability in patients of similar ages and the same gender. Two point Dixon MRI enables a non-invasive and spatially resolved quantification of the fat fraction in bone marrow. Our study provides important evidence on the differences in marrow conversion between females and males. In addition, differences were observed in the cellularity values of the International Commission on Radiological Protection (ICRP) reference man (0.7) and the median values obtained in our patient group. These observations lead to the conclusion that the fat fraction in bone marrow should be considered as a patient-specific variable in clinical dosimetry procedures. PMID- 29130902 TI - Dielectrophoresis-based multi-step nanowire assembly on a flexible superstrate. AB - Nanowire assembly based on dielectrophoresis (DEP) could be a useful and efficient tool for fabricating nanowire-based devices. Although there have been extensive reports on the DEP nanowire assembly, the new approaches that make DEP more facile and affordable are still desirable. Herein, we present an approach using the reusable electrodes to assemble silver nanowires onto a removable, independent polyethylene terephthalate (PET) film. The PET film is placed on the reusable electrodes, and a sinusoidal AC voltage is applied to the electrodes to induce DEP force for nanowire assembly upon the flexible film. We explore the influences of voltage, frequency and film thickness on nanowire assembly and further realize the assembly of silver nanowire arrays. In addition, the induced electric field is rotated in two consecutive steps to assemble the rectangular mesh-like nanowire networks. This reusable and facile approach for DEP nanowire assembly could provide a low-cost, precise, rapid and convenient tool for applications in the fields of flexible electronics. PMID- 29130903 TI - A Half-Century of Excellence. PMID- 29130905 TI - JPO Interviews Dr. Charles H. Tweed. PMID- 29130904 TI - The Possibility of Skeletal Anchorage. PMID- 29130906 TI - The Straight-Wire Appliance. PMID- 29130908 TI - Common Sense Mechanics. PMID- 29130907 TI - Bio-Progressive Therapy. PMID- 29130909 TI - The Vari-Simplex Discipline. PMID- 29130910 TI - Nonextraction Treatment. PMID- 29130911 TI - Air-Rotor Stripping. PMID- 29130912 TI - Knowing Your Practice: A Cost Comparative Basis for Practice Management. PMID- 29130914 TI - JCO Interviews Dr. Bjorn U. Zachrisson on Excellence in Finishing. PMID- 29130913 TI - Precision Lingual Arches. PMID- 29130916 TI - The Pendulum Appliance for Class II Non-Compliance Therapy. PMID- 29130915 TI - An Orthopedic Approach to the Treatment of Class III Malocclusion in Young Patients. PMID- 29130917 TI - Statically Determinate Transpalatal Arches. PMID- 29130918 TI - JCO Roundtable: The Temporomandibular Joint and Craniomandibular Disorders. PMID- 29130920 TI - Orthodontic Fees. PMID- 29130919 TI - The Pseudo-Class I: A Newly Defined Type of Malocclusion. PMID- 29130921 TI - Orthodontic Office Design: Creating Your Next Office. PMID- 29130922 TI - Clinical Applications of the Miniscrew Anchorage System. PMID- 29130923 TI - "Surgery First" Skeletal Class III Correction Using the Skeletal Anchorage System. PMID- 29130924 TI - Smile Analysis and Design in the Digital Era. PMID- 29130925 TI - Esthetic Treatment Planning for Orthognathic Surgery. PMID- 29130926 TI - Complex Orthodontic Treatment Using a New Protocol for the Invisalign Appliance. PMID- 29130927 TI - A Strategic Orthodontic Marketing Plan. PMID- 29130928 TI - Overview: Intraoral Digital Scanners. PMID- 29130929 TI - TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies. AB - The NLRP3 inflammasome is a protein complex responsible for caspase-1-dependent maturation of the proinflammatory cytokines IL-1beta and IL-18. Gain-of-function missense mutations in NLRP3 cause the disease spectrum known as the cryopyrin associated periodic syndromes (CAPS). In this study, we generated Nlrp3-knockin mice on various KO backgrounds including Il1b/Il18-, caspase-1-, caspase-11- (Casp1/11-), and Tnf-deficient strains. The Nlrp3L351P Il1b-/- Il18-/- mutant mice survived and grew normally until adulthood and, at 6 months of age, exhibited marked splenomegaly and leukophilia. Injection of these mice with low dose LPS resulted in elevated serum TNF levels compared with Nlrp3L351P Casp1/11 /- mice and Il1b-/- Il18-/- littermates. Treatment of Nlrp3A350V mice with the TNF inhibitor etanercept resulted in all pups surviving to adulthood, with normal body and spleen/body weight ratios. Nlrp3A350V Tnf-/- mice showed a similar phenotypic rescue, with marked reductions in serum IL-1beta and IL-18, reduced myeloid inflammatory infiltrate in the skin and spleen, and substantial decreases in splenic mRNA expression of both inflammasome components (Nlrp3, Pycard, pro Casp1) and pro-cytokines (Il1b, Il18). Likewise, we observed a reduction in the expression of both pro-Casp1 and pro-Il1b in cultured Nlrp3A350V Tnf-/- BM derived DCs. Our data show that TNF is an important transcriptional regulator of NLRP3 inflammasome components in murine inflammasomopathies. Moreover, these results may have therapeutic implications for CAPS patients with partial responses to IL-1-targeted therapies. PMID- 29130930 TI - Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis. AB - Abnormal activity of the renin-angiotensin-aldosterone system plays a causal role in the development of hypertension, atherosclerosis, and associated cardiovascular events such as myocardial infarction, stroke, and heart failure. As both a vasoconstrictor and a proinflammatory mediator, angiotensin II (Ang II) is considered a potential link between hypertension and atherosclerosis. However, a role for Ang II-induced inflammation in atherosclerosis has not been clearly established, and the molecular mechanisms and intracellular signaling pathways involved are not known. Here, we demonstrated that the RhoA GEF Arhgef1 is essential for Ang II-induced inflammation. Specifically, we showed that deletion of Arhgef1 in a murine model prevents Ang II-induced integrin activation in leukocytes, thereby preventing Ang II-induced recruitment of leukocytes to the endothelium. Mice lacking both LDL receptor (LDLR) and Arhgef1 were protected from high-fat diet-induced atherosclerosis. Moreover, reconstitution of Ldlr-/- mice with Arhgef1-deficient BM prevented high-fat diet-induced atherosclerosis, while reconstitution of Ldlr-/- Arhgef1-/- with WT BM exacerbated atherosclerotic lesion formation, supporting Arhgef1 activation in leukocytes as causal in the development of atherosclerosis. Thus, our data highlight the importance of Arhgef1 in cardiovascular disease and suggest targeting Arhgef1 as a potential therapeutic strategy against atherosclerosis. PMID- 29130931 TI - Confounding role of tumor necrosis factor in cryopyrin-associated periodic syndromes. AB - The NLRP3 inflammasome is a critical component of the innate immune system and can be activated in response to microbial and endogenous danger signals. Activation of the NLRP3 inflammasome results in caspase-1-dependent secretion of the proinflammatory cytokines IL-1beta and IL-18. Gain-of-function missense mutations in NLRP3 result in a group of autoinflammatory diseases collectively known as the cryopyrin-associated periodic syndromes (CAPS). CAPS patients have traditionally been successfully treated with therapeutics targeting the IL-1 pathway; however, there are a number of identified CAPS patients who show only a partial response to IL-1 blockade. In this issue of the JCI, McGeough et al. demonstrated that TNF-alpha, in addition to IL-1beta, plays an important role in promoting NLRP3 inflammasomopathies. PMID- 29130933 TI - Histamine-releasing factor: a promising therapeutic target for food allergy. AB - The prevalence of food allergies has been increasing at an alarming rate over the last few decades. Despite the dramatic increase in disease prevalence, the development of effective therapies has not kept pace. In this issue of the JCI, Ando et al. provide a causal link between histamine-releasing factor (HRF) interactions with IgE and food allergy in a murine model. Successful oral immunotherapy of both egg-allergic human patients and food-allergic mice was associated with sustained suppression of HRF-reactive IgE levels. These results support a role for HRF-IgE interactions in the amplification of intestinal inflammation and suggest HRF as a therapeutic target in food allergy. PMID- 29130932 TI - p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia. AB - p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor derived organoid cultures, elimination of both p120 alleles resulted in caspase-3 dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly assess the tumorigenic impact of p120 haploinsufficiency relative to other candidate drivers. Remarkably, p120 ranked third among the 919 drivers identified. Cofactors alpha-catenin and epithelial cadherin (E-cadherin) were also among the highest scoring candidates, indicating a mechanism at the level of the intact complex that may play an important role at very early stages of of intestinal tumorigenesis while simultaneously restricting outright loss via synthetic lethality. PMID- 29130934 TI - Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C. AB - Transcriptional repression of ubiquitin B (UBB) is a cancer-subtype-specific alteration that occurs in a substantial population of patients with cancers of the female reproductive tract. UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. UBB is repressed in approximately 30% of high-grade serous ovarian cancer (HGSOC) patients and is a recurrent lesion in uterine carcinosarcoma and endometrial carcinoma. We identified ovarian tumor cell lines that retain UBB in a repressed state, used these cell lines to establish orthotopic ovarian tumors, and found that inducible expression of a UBC targeting shRNA led to tumor regression, and substantial long-term survival benefit. Thus, we describe a recurrent cancer-specific lesion at the level of ubiquitin production. Moreover, these observations reveal the prognostic value of UBB repression and establish UBC as a promising therapeutic target for ovarian cancer patients with recurrent UBB silencing. PMID- 29130935 TI - Histamine-releasing factor enhances food allergy. AB - Food allergy occurs due to IgE- and mast cell-dependent intestinal inflammation. Previously, we showed that histamine-releasing factor (HRF), a multifunctional protein secreted during allergy, interacts with a subset of IgE molecules and that the HRF dimer activates mast cells in an HRF-reactive IgE-dependent manner. In this study, we investigated whether HRF plays any role in food allergy. Specifically, we determined that prophylactic and therapeutic administration of HRF inhibitors that block HRF-IgE interactions reduces the incidence of diarrhea and mastocytosis in a murine model of food allergy. Food allergy-associated intestinal inflammation was accompanied by increased secretion of the HRF dimer into the intestine in response to proinflammatory, Th2, and epithelial-derived cytokines and HRF-reactive IgE levels at the elicitation phase. Consistent with these data, patients with egg allergy had higher blood levels of HRF-reactive IgE compared with individuals that were not hypersensitive. Successful oral immunotherapy in egg-allergy patients and food-allergic mice reduced HRF-reactive IgE levels, thereby suggesting a pathological role for HRF in food allergy. Together, these results suggest that antigen and HRF dimer amplify intestinal inflammation by synergistically activating mast cells and indicate that HRF has potential as a therapeutic target in food allergy. PMID- 29130936 TI - JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. AB - Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M- and IL-6-triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease. PMID- 29130938 TI - Ubiquitin levels: the next target against gynecological cancers? AB - Ubiquitylation is a tightly regulated process that is essential for appropriate cell survival and function, and the ubiquitin pathway has shown promise as a therapeutic target for several forms of cancer. In this issue of the JCI, Kedves and colleagues report the identification of a subset of gynecological cancers with repressed expression of the polyubiquitin gene UBB, which renders these cancer cells sensitive to further decreases in ubiquitin production by inhibition of the polyubiquitin gene UBC. Moreover, inducible depletion of UBC in mice harboring tumors with low UBB levels dramatically decreased tumor burden and prolonged survival. Together, the results of this study indicate that there is a synthetic lethal relationship between UBB and UBC that has potential to be exploited as a therapeutic strategy to fight these devastating cancers. PMID- 29130937 TI - Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation. AB - Regulation of skeletal muscle development and organization is a complex process that is not fully understood. Here, we focused on amphiphysin 2 (BIN1, also known as bridging integrator-1) and dynamin 2 (DNM2), two ubiquitous proteins implicated in membrane remodeling and mutated in centronuclear myopathies (CNMs). We generated Bin1-/- Dnm2+/- mice to decipher the physiological interplay between BIN1 and DNM2. While Bin1-/- mice die perinatally from a skeletal muscle defect, Bin1-/- Dnm2+/- mice survived at least 18 months, and had normal muscle force and intracellular organization of muscle fibers, supporting BIN1 as a negative regulator of DNM2. We next characterized muscle-specific isoforms of BIN1 and DNM2. While BIN1 colocalized with and partially inhibited DNM2 activity during muscle maturation, BIN1 had no effect on the isoform of DNM2 found in adult muscle. Together, these results indicate that BIN1 and DNM2 regulate muscle development and organization, function through a common pathway, and define BIN1 as a negative regulator of DNM2 in vitro and in vivo during muscle maturation. Our data suggest that DNM2 modulation has potential as a therapeutic approach for patients with CNM and BIN1 defects. As BIN1 is implicated in cancers, arrhythmia, and late-onset Alzheimer disease, these findings may trigger research directions and therapeutic development for these common diseases. PMID- 29130939 TI - Open the gates: vascular neurocrine signaling mobilizes hematopoietic stem and progenitor cells. AB - Mobilization of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) into the peripheral blood is a complex process that is enhanced dramatically under stress-induced conditions. A better understanding of how the mobilization process is regulated will likely facilitate the development of improved clinical protocols for stem cell harvesting and transplantation. In this issue of the JCI, Singh et al. (1) showed that the truncated cleaved form of neurotransmitter neuropeptide Y (NPY) actively promotes a breach of BM vascular sinusoidal portals, thereby augmenting HSPC trafficking to the circulation. The authors report a previously unrecognized axis, in which expression of the enzyme dipeptidylpeptidase-4 (DPP4)/CD26 by endothelial cells activates NPY-mediated signaling by increasing the bioavailability of the truncated form of NPY. These findings underscore the importance of and urgency to develop pharmacological therapies that target the vasculature and regulate diverse aspects of hematopoiesis, such as HSPC trafficking, in steady-state and stress-induced conditions. PMID- 29130940 TI - Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells. AB - Endothelial cells (ECs) are components of the hematopoietic microenvironment and regulate hematopoietic stem and progenitor cell (HSPC) homeostasis. Cytokine treatments that cause HSPC trafficking to peripheral blood are associated with an increase in dipeptidylpeptidase 4/CD26 (DPP4/CD26), an enzyme that truncates the neurotransmitter neuropeptide Y (NPY). Here, we show that enzymatically altered NPY signaling in ECs caused reduced VE-cadherin and CD31 expression along EC junctions, resulting in increased vascular permeability and HSPC egress. Moreover, selective NPY2 and NPY5 receptor antagonists restored vascular integrity and limited HSPC mobilization, demonstrating that the enzymatically controlled vascular gateway specifically opens by cleavage of NPY by CD26 signaling via NPY2 and NPY5 receptors. Mice lacking CD26 or NPY exhibited impaired HSPC trafficking that was restored by treatment with truncated NPY. Thus, our results point to ECs as gatekeepers of HSPC trafficking and identify a CD26-mediated NPY axis that has potential as a pharmacologic target to regulate hematopoietic trafficking in homeostatic and stress conditions. PMID- 29130941 TI - Remote Ischemia Preconditioning Attenuates Blood-Spinal Cord Barrier Breakdown in Rats Undergoing Spinal Cord Ischemia Reperfusion Injury: Associated with Activation and Upregulation of CB1 and CB2 Receptors. AB - BACKGROUND/AIMS: Remote ischemic preconditioning (RIPC) has protective effects on spinal cord ischemia reperfusion (I/R) injury, but the potential mechanisms remain unclear. In our study, the effects and underlying mechanisms of RIPC on blood-spinal cord barrier (BSCB) breakdown following I/R injury were investigated. METHODS: animals underwent intraperitoneal administration with cannabinoid-1 (CB1) receptor antagonist AM251, cannabinoid-2 (CB2) receptor antagonist AM630 or vehicle 15 minutes before three 3-minute occlusion reperfusion cycles on the right femoral artery or a sham operation. 30 minutes after the preconditioning, aortic arch was exposed with or without 14-minute occlusion. Neurological function was assessed with Tarlov scoring system. The disruption of BSCB was assessed by measuring Evans Blue (EB) extravasation. The expression of tight junction protein occludin was determined by western blot analyses. The expression and localization of CB1 and CB2 receptors were assessed by western blot and immunofluorescence. RESULTS: RIPC attenuated the motor dysfunction, BSCB disruption and downregulation of occludin after I/R injury, which were impaired by blocking CB1 and CB2 receptors. Moreover, RIPC upregulated the elevated perivascular expression of CB1 and CB2 receptors following I/R injury. CONCLUSIONS: These results indicated that RIPC, through activation and upregulation of CB1 and CB2 receptors, was involved in preserving the integrity of BSCB after spinal cord I/R injury. PMID- 29130942 TI - High-Grade Urothelial Carcinoma on Urine Cytology Resembling Umbrella Cells. AB - CONTEXT: High-grade urothelial carcinoma (UC) cells have many appearances on urine cytology, but according to The Paris System, they can be easily distinguished from umbrella cells. OBJECTIVE: We aimed to define the incidence and appearance of high-grade UC cells that resemble umbrella cells in Cytospin preparations on urine cytology. RESULTS: Cytospin preparations from 331 cases with biopsy follow-up (230 benign/low-grade and 101 malignant [22 carcinoma in situ, 52 papillary, 19 invasive UC, 8 other] cases) were reviewed. A total of 18 cases with malignant cells resembling umbrella cells were identified (17.8% of the malignant cases) and were the only type of malignant cell in 3% of the cases. Two patterns were identified. Tumor cells were either identifiable by at least 20 abnormal cells which were large, had abundant cytoplasm but an elevated nuclear to-cytoplasmic ratio, and markedly enlarged, round-to-elongated nucleoli, or else rare cells with abundant cytoplasm but obviously malignant nuclei. Cells without nucleoli or obviously malignant nuclei were not specific. CONCLUSIONS: Malignant cells resembling umbrella cells can be seen in up to 17% of urine cytology specimens. PMID- 29130943 TI - Effect of a Shortened Duration of FOLFOX Chemotherapy on the Survival Rate of Patients with Stage II and III Colon Cancer. AB - BACKGROUND: FOLFOX chemotherapy is widely used as an adjuvant treatment for advanced colon cancer. The duration of adjuvant chemotherapy is usually set to 6 months, which is based on a former study of 5-fluorouracil/leucovorin chemotherapy. However, the FOLFOX regimen is known to have complications, such as peripheral neuropathy. The aim of this study was to compare the survival rates and complications experienced by patients receiving either 4 or 6 months of FOLFOX chemotherapy. METHODS: Retrospective data analysis was performed for stage II and III patients who underwent radical resection of colon cancer. We compared the 5-year survival rates and the occurrence of complications in patients who completed only 8 cycles of FOLFOX chemotherapy with patients who completed 12 cycles of chemotherapy. RESULTS: Among 188 patients who underwent adjuvant FOLFOX chemotherapy for stage II or III colon cancer, 83 (44.1%) completed 6 months of FOLFOX chemotherapy and 64 (34.0%) patients discontinued after 4 months of chemotherapy. The 5-year overall survival and disease-free survival rates did not show a significant difference. Patients in the 6-month group had peripheral neuropathy more frequently (p = 0.028). CONCLUSIONS: Five-year overall and disease-free survival were not significantly different between the 2 groups. Large-scale prospective studies are necessary for the analysis of complications and survival rates. PMID- 29130944 TI - Cholecystokinin Expression in the Development of Postinfarction Heart Failure. AB - BACKGROUND/AIMS: Cholecystokinin (CCK) is expressed in cardiomyocytes and may also play an important role in cardiovascular regulation. Clinical studies have shown that plasma CCK levels are an independent marker of cardiovascular mortality in cardiac disease. However, whether the development of postinfarction heart failure is associated with changes in CCK expression is unknown. METHODS: To investigate CCK expression patterns and the association between CCK expression and heart functional parameters, we randomized male Sprague-Dawley rats into myocardial infarction (MI) or sham operation (SO) groups. CCK expression levels were assessed by western blotting, immunohistochemistry, real-time polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA) at different time points (2, 4 or 6 weeks) after surgery. Brain natriuretic peptide (BNP) concentrations were determined using Western blotting and ELISA, myocardial morphology was assessed by microscopy. RESULTS: Plasma CCK and BNP levels were significantly increased in all the MI groups compared with the corresponding SO groups. However, the degree to which myocardial CCK mRNA and protein expression levels were increased the MI groups compared with the SO groups was greater in the 4- and 6-week groups than in the 2-week group. Furthermore, plasma CCK levels were positively correlated with BNP concentrations and left ventricular end systolic diameter (LVDs) and significantly negatively correlated with the ejection fraction (EF) and shortening fraction (SF) in model animals. CONCLUSIONS: Heart failure progression after infarction is associated with upregulated CCK levels; thus, CCK may be useful as a novel marker of heart failure. PMID- 29130945 TI - Maternally Expressed Gene 3 (MEG3) Enhances PC12 Cell Hypoxia Injury by Targeting MiR-147. AB - BACKGROUND/AIMS: Cerebral ischemia often leads to breakdown of blood-brain barrier (BBB) and vasogenic edema. It remains to be established whether MEG3 is responsible for the hypoxic damage in neural cells. This study aimed to investigate the role of MEG3 in the hypoxia-induced injuries of PC12 cells. METHODS: The PC12 cells were seeded and cultured under hypoxia and normoxia culture conditions. The cell viability determined by trypan blue exclusion, apoptosis using propidium iodide (PI) and fluorescein isothiocynate (FITC) conjugated Annexin V staining, cell-migration using a modified two-chamber migration assay with a pore size of 8 uM and invasion using 24-well Millicell Hanging Cell Culture inserts with 8 uM PET membranes. RESULTS: Cell viability, relative migration and relative invasion decreased significantly in PC12 cells injured due to hypoxia as compared to control cells. An increase in apoptosis was also observed. The expression of MEG3 was up-regulated in hypoxia-injured PC12 cells. MEG3 overexpression enhanced hypoxia injuries, while MEG3 suppression attenuated the injuries. Meanwhile, MEG3 negatively regulated miR-147 expression. In addition, we found that the expression of Sox2 was increased in PC12 cells after hypoxia and miR-147 negatively regulated Sox2 expression through targets its 3'-UTR. Interesting, Sox2 activated NF-kappaB pathway and Wnt/beta-catenin pathway in PC12 cells. CONCLUSION: Considering the observations in our study, we can conclude that MEG3 aggravated the hypoxial injury in PC12 cells by down regulating miR-147 gene and miR-147 further negatively regulated Sox2 expression. PMID- 29130946 TI - Considerations about the Use of a Loading Dose of Daptomycin in a Neutropenic Murine Thigh Infection Model with Methicillin-Resistant Staphylococcus aureus Infection. AB - Previous clinical studies have showed the clinical benefits of the initiation of treatment with a daptomycin (DAP) loading dose, but only a few studies have evaluated its antimicrobial benefits. We evaluated the efficacy of a DAP loading dose against methicillin-resistant Staphylococcus aureus (MRSA) infections in a neutropenic murine thigh infection model. Three MRSA isolates (DAP MIC: 0.5, 1, and 2 mg/L) were tested. Four DAP regimens simulating human concentration-time profiles, i.e., (i) day 1: 8 mg/kg and day 2: 6 mg/kg, (ii) days 1 and 2: 6 mg/kg/day, (iii) day 1: 8 mg/kg and day 2: 4 mg/kg, and (iv) days 1 and 2: 4 mg/kg/day, were administered to the mice. Efficacy was calculated as the change in bacterial density. DAP loading-dose regimen iii showed greater antimicrobial activity against MRSA with MIC 1 mg/L than nonloading regimen iv (-3.10 +/- 0.63 vs. -0.71 +/- 0.34 log10 CFU; p < 0.01). Loading-dose regimen iii achieved greater log10 CFU changes than nonloading regimen ii, while the total DAP dose for 2 days was the same (-3.10 +/- 0.63 vs. -1.46 +/- 0.48 log10 CFU; p < 0.05). DAP loading-dose regimen iii showed enhanced antimicrobial activity against MRSA with DAP MIC 0.5 mg/L when compared with nonloading regimen iv. However, loading dose regimens i and iii did not reduce bacterial density for MRSA with DAP MIC 2 mg/L. Our data suggest that a DAP loading-dose regimen would be an advantageous procedure for patients infected with MRSA with DAP MIC <=1 mg/L. PMID- 29130947 TI - Application of Digital PCR in Detecting Human Diseases Associated Gene Mutation. AB - Gene mutation has been considered a research hotspot, and the rapid development of biomedicine has enabled significant advances in the evaluation of gene mutations. The advent of digital polymerase chain reaction (dPCR) elevates the detection of gene mutations to unprecedented levels of precision, especially in cancer-associated genes. dPCR has been utilized in the detection of tumor markers in cell-free DNA (cfDNA) samples from patients with different types of cancer in samples such as plasma, cerebrospinal fluid, urine and sputum, which confers significant value for dPCR in both clinical applications and basic research. Moreover, dPCR is extensively used in detecting pathogen mutations related to typical features of infectious diseases (e.g., drug resistance) and mutation status of heteroplasmic mitochondrial DNA, which determines the manifestation and progression of mtDNA-related diseases, as well as allows for the prenatal diagnosis of monogenic diseases and the assessment of the genome editing effects. Compared with real-time PCR (qPCR) and sequencing, the higher sensitivity and accuracy of dPCR indicates a great advantage in the detection of rare mutation. As a new technique, dPCR has some limitations, such as the necessity of highly allele-specific probes and a large sample volume. In this review, we summarize the application of dPCR in the detection of human disease-associated gene mutations. PMID- 29130948 TI - Mapping Genomic Scaffolds to Chromosomes Using Laser Capture Microdissection in Application to Hawaiian Picture-Winged Drosophila. AB - Next-generation sequencing technologies have led to a decreased cost and an increased throughput in genome sequencing. Yet, many genome assemblies based on short sequencing reads have been assembled only to the scaffold level due to the lack of sufficient chromosome mapping information. Traditional ways of mapping scaffolds to chromosomes require a large amount of laboratory work and time to generate genetic and/or physical maps. To address this problem, we conducted a rapid technique which uses laser capture microdissection and enables mapping scaffolds of de novo genome assemblies directly to chromosomes in Hawaiian picture-winged Drosophila. We isolated and sequenced intact chromosome arms from larvae of D. differens. By mapping the reads of each chromosome to the recently assembled scaffolds from 3 Hawaiian picture-winged Drosophila species, at least 67% of the scaffolds were successfully assigned to chromosome arms. Even though the scaffolds are not ordered within a chromosome, the fast-generated chromosome information allows for chromosome-related analyses after genome assembling. We utilize this new information to test the faster-X evolution effect for the first time in these Hawaiian picture-winged Drosophila species. PMID- 29130949 TI - Performance of the Surprise Question Compared to Prediction Models in Hemodialysis Patients: A Prospective Study. AB - BACKGROUND: The surprise question (SQ) ("Would you be surprised if this patient were still alive in 6 or 12 months?") is used as a mortality prognostication tool in hemodialysis (HD) patients. We compared the performance of the SQ with that of prediction models (PMs) for 6- and 12-month mortality prediction. METHODS: Demographic, clinical, laboratory, and dialysis treatment indicators were used to model 6- and 12-month mortality probability in a HD patients training cohort (n = 6,633) using generalized linear models (GLMs). A total of 10 nephrologists from 5 HD clinics responded to the SQ in 215 patients followed prospectively for 12 months. The performance of PM was evaluated in the validation (n = 6,634) and SQ cohorts (n = 215) using the areas under receiver operating characteristics curves. We compared sensitivities and specificities of PM and SQ. RESULTS: The PM and SQ cohorts comprised 13,267 (mean age 61 years, 55% men, 54% whites) and 215 (mean age 62 years, 59% men, 50% whites) patients, respectively. During the 12 month follow-up, 1,313 patients died in the prediction model cohort and 22 in the SQ cohort. For 6-month mortality prediction, the GLM had areas under the curve of 0.77 in the validation cohort and 0.77 in the SQ cohort. As for 12-month mortality, areas under the curve were 0.77 and 0.80 in the validation and SQ cohorts, respectively. The 6- and 12-month PMs had sensitivities of 0.62 (95% CI 0.35-0.88) and 0.75 (95% CI 0.56-0.94), respectively. The 6- and 12-month SQ sensitivities were 0.23 (95% CI 0.002-0.46) and 0.35 (95% CI 0.14-0.56), respectively. CONCLUSION: PMs exhibit superior sensitivity compared to the SQ for mortality prognostication in HD patients. PMID- 29130950 TI - Characteristics of False-Negative Thyroid Fine-Needle Aspirates. AB - INTRODUCTION: False-negative thyroid fine-needle aspirates (FNA) are not well characterized. METHODS: We correlated the results of all thyroid aspirations from 1997 to 2016 with histologic follow-up. RESULTS: There were 13,733 aspirates, 2,112 (15.3%) resections, and 678 malignancies (32.1%). Eighteen (2.7%) false negative cases were identified (interpretation, n = 6; sampling, n = 7; and new nodules, n = 5). Interpretive false-negative cases were significantly less likely when the indeterminate rate was greater than 13% (p = 0.01). Interpretive errors involved rare cells with poorly developed features of malignancy. Sampling errors were not associated with scant cellularity in the specimen. The majority of false negative cases were not resected because of a clinical suspicion of malignancy. The sensitivity of FNA for 9-mm papillary carcinomas was 44.3%. CONCLUSION: In this cohort, the false-negative rate of thyroid FNA was 2.7% and the risk of malignancy for a benign diagnosis was 3.5%. Interpretative errors involved rare cells with poorly developed features of malignancy. There is little evidence that either the false-negative rate or the risk of malignancy of a benign thyroid FNA is different in patients who do and do not undergo resection. PMID- 29130951 TI - Prehospital Computed Tomography Angiography in Acute Stroke Management. AB - BACKGROUND: An ambulance equipped with a computed tomography (CT) scanner, a point-of-care laboratory, and telemedicine capabilities (mobile stroke unit [MSU]) has been shown to enable the delivery of thrombolysis to stroke patients directly at the emergency site, thereby significantly decreasing time to treatment. However, work-up in an MSU that includes CT angiography (CTA) may also potentially facilitate triage of patients directly to the appropriate target hospital and specialized treatment, according to their individual vascular pathology. METHODS: Our institution manages a program investigating the prehospital management of patients with suspicion of acute stroke. Here, we report a range of scenarios in which prehospital CTA could be relevant in triaging patients to the appropriate target hospital and to the individually required treatment. RESULTS: Prehospital CTA by use of an MSU allowed to detect large vessel occlusion of the middle cerebral artery in one patient with ischemic stroke and occlusion of the basilar artery in another, thereby allowing rational triage to comprehensive stroke centers for immediate intra-arterial treatment. In complementary cases, prehospital imaging not only allowed diagnosis of parenchymal hemorrhage with a spot sign indicating ongoing bleeding in one patient and of subarachnoid hemorrhage in another but also clarified the underlying vascular pathology, which was relevant for subsequent triage decisions. CONCLUSION: Defining the vascular pathology by CTA directly at the emergency site may be beneficial in triaging patients with various cerebrovascular diseases to the most appropriate target hospital and specialized treatment. PMID- 29130952 TI - Efferent Axonal Projections of the Habenular Complex in the Fire-Bellied Toad Bombina orientalis. AB - The habenular complex and its associated axonal pathways are often thought of as phylogenetically conserved features of the brain among vertebrates despite the fact that detailed studies of this brain region are limited to a few species. Here, the gross morphology and axonal projection pattern of the habenular complex of an anuran amphibian, the fire-bellied toad Bombina orientalis, was studied to allow comparison with the situation in other vertebrates. Axonal pathways were traced using biocytin applications in dissected brain preparations. The results show that the rostral part of the left dorsal nucleus is enlarged in this species, while the rostral ventral nucleus and caudal parts do not show left right size differences. Biocytin applications revealed widespread axonal projections of the habenular complex to the posterior tuberculum/dorsal hypothalamic region, ventral tegmentum, interpeduncular nucleus (IPN), and raphe median. Additionally, axons targeting the lateral hypothalamus originated from the ventral habenular nuclei. The results also suggest an asymmetrical pattern of projection to the IPN in the rostral part of the habenular complex, where the left habenula preferentially targeted the dorsal IPN while the right habenula preferentially targeted the ventral IPN. The caudal habenular nuclei showed no asymmetry of projections as both sides targeted the ventral IPN. Comparison of the habenular complex axonal connectivity across vertebrates argues against strong phylogenetic conservation of the axonal projection patterns of different habenular nuclei. PMID- 29130953 TI - Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer. PMID- 29130955 TI - Tinnitus and Hearing Survey: A Polish Study of Validity and Reliability in a Clinical Population. AB - This study investigates the psychometric properties of the Polish version of the Tinnitus and Hearing Survey (THS-POL), which is a tool for evaluating what proportion of patients' tinnitus is due to hearing problems and what proportion is specifically due to the tinnitus. The THS-POL was created using the translation-backtranslation method. Study participants completed the THS-POL twice over a period of 3 days. The test-retest analysis shows excellent strength of correlations (THS-POL subscale A r = 0.89, subscale B r = 0.9). For subscales A and B, reliability measured using Cronbach's alpha was alpha = 0.86 and 0.95, respectively, in the first administration and alpha = 0.91 and 0.94 in the second administration. Confirmatory factor analysis confirmed a good 2-factor structure of the THS. Convergent validity evaluated using the Pearson product-moment correlation between subscale A (tinnitus) and the Tinnitus Handicap Inventory shows good correlations. In conclusion, the THS-POL is a valid and reliable screening tool to assist in deciding about the optimal management approach. PMID- 29130954 TI - Effects of Tolvaptan Addition to Furosemide in Normo- and Hyponatremia Patients with Heart Failure and Chronic Kidney Disease Stages G3b-5: A Subanalysis of the K-STAR Study. AB - BACKGROUND: Tolvaptan increases free water clearance (aquaresis) and thereby improves hyponatremia. Although hyponatremia on admission is common in patients with congestive heart failure (CHF), little is known regarding the response to tolvaptan in those who also have chronic kidney disease (CKD) with or without hyponatremia. The aim of this subanalysis was to investigate the differences in treatment response between normo- and hyponatremia patients with CHF and CKD stages G3b-5. METHODS: The Kanagawa Aquaresis Investigators Trial of Tolvaptan on HF Patients with Renal Impairment (K-STAR) was a multicenter, open-label, randomized, controlled prospective clinical trial that included 81 Japanese patients with CHF and residual signs of congestion despite oral furosemide treatment (>=40 mg/day). All patients were randomly assigned to 7-day treatment with either <=15 mg/day of new add-on tolvaptan or <=40 mg/day of increased furosemide. A subanalysis was conducted for 73 patients, who were classified into 2 groups according to their assigned treatment, then further stratified into 2 subgroups according to their serum sodium concentration [Na+]. The differences between the urine and serum parameters from day 1 to 3 were compared between the groups and between the subgroups in each group. RESULTS: The change (Delta) in urine volume (DeltaUV) and Deltaurine osmolality were greater in the tolvaptan group than in the furosemide group; however, DeltaUV and Deltaurine osmolality did not show significant differences between the normonatremia subgroup and the hyponatremia subgroup in each group. In addition, Deltaserum [Na+] was greater in the tolvaptan group, although the change was not clinically significant. In contrast, Deltaserum [Na+] did not show significant differences between the normo and hyponatremia subgroups in each group. CONCLUSION: Tolvaptan added to furosemide resulted in a greater diuretic effect than increased furosemide, even in normonatremia patients with CHF complicated by CKD stages G3b-5 in the very early treatment phase. PMID- 29130956 TI - Ischemic Stroke: Histological Thrombus Composition and Pre-Interventional CT Attenuation Are Associated with Intervention Time and Rate of Secondary Embolism. AB - BACKGROUND AND PURPOSE: The introduction of stent retrievers has made the complete extraction and histological analysis of human thrombi possible. A number of large randomized trials have proven the efficacy of thrombectomy for ischemic stroke; however, thrombus composition could have an impact on the efficacy and risk of the intervention. We therefore investigated the impact of histologic thrombus features on interventional outcome and procedure-related embolisms. For a pre-interventional estimation of histologic features and outcome parameters, we assessed the pre-interventional CT attenuation of the thrombi. METHODS: We prospectively included all consecutive patients with occlusion of the middle cerebral artery who underwent thrombectomy between December 2013 and February 2016 at our university medical center. Samples were histologically analyzed (H&E, Elastica van Gieson, Prussian blue); additionally, immunohistochemistry for CD3, CD20, and CD68/KiM1P was performed. Main thrombus components (fibrin, erythrocytes, and white blood cells) were determined and compared to intervention time, frequency of secondary embolisms, as well as additional clinical and interventional parameters. Additionally, we assessed the pre-interventional CT attenuation of the thrombi in relation to the unaffected side (rHU) and their association with histologic features. RESULTS: One hundred eighty patients were included; of these, in 168 patients (93.4%), complete recanalization was achieved and 27 patients (15%) showed secondary embolism in the control angiogram. We observed a significant association of high amounts of fibrin (p < 0.001), low percentage of red blood cells (p < 0.001), and lower rHU (p < 0.001) with secondary embolism. Higher rHU values were significantly associated with higher amounts of fibrin (p <= 0.001) and low percentage of red blood cells (p <= 0.001). Additionally, high amounts of fibrin were associated with longer intervention times (p <= 0.001), whereas thrombi with high amounts of erythrocytes correlated with shorter intervention times (p <= 0.001). ROC analysis revealed reliable prediction of secondary embolisms for low rHU (AUC = 0.746; p <= 0.0001), low amounts of RBC (AUC = 0.764; p <= 0.0001), and high amounts of fibrin (AUC = 0.773; p <= 0.0001). CONCLUSIONS: Fibrin-rich thrombi with low erythrocyte percentage are significantly associated with longer intervention times. Embolisms in the thrombectomy process occur more often in thrombi with a small fraction of red blood cells and a low CT-density, suggesting a higher fragility of these thrombi. PMID- 29130957 TI - Clinical Disease Patterns in a Regional Swiss Cohort of 34 Pyoderma Gangrenosum Patients. AB - BACKGROUND/AIM: Pyoderma gangrenosum (PG) is a rare, neutrophilic dermatosis often associated with an underlying disease, and clinical data or larger studies are rare. METHODS: In this retrospective study, disease characteristics, clinical manifestations, and treatment response were evaluated in a Swiss cohort of PG patients. RESULTS: In participating centers, 34 cases (21 females) of PG were analyzed based on clinical and histological presentation between 2002 and 2012. The mean age at diagnosis was 61.2 years; 50% of the patients experienced only 1 episode of PG. In 13 cases (out of 20), recurrences occurred during PG therapy; 64.1% showed only 1 lesion simultaneously. The predominant localization was the lower limb (67%). The lesions were disseminated in 26.6%. At the time of diagnosis or recurrence, the mean diameter was 37.6 mm and the mean ulcer size was 10.3 cm2. C-reactive protein (CRP) was elevated in 73.2%; leukocytosis was present in 58.9% and neutrophilia in 50.9%. At least 1 associated comorbidity was present in 85% (the most prominent being cardiovascular disease). The most often used systemic treatments were steroids (68.3%), cyclosporine A (31.7%), dapsone (31.7%), and infliximab (13.3%), and the most often used topicals were tacrolimus 0.1% (48.3%) and corticosteroids (35%). PG healed completely at discharge in 50.8%. The average time to diagnosis was 8 months, and the mean duration to healing was 7.1 months. CONCLUSION: PG is a difficult-to-diagnose skin disease. Here, markers for inflammation such as CRP, leukocytosis, and neutrophilia were elevated in 50-73% of the PG patients. PMID- 29130958 TI - Propofol Through Upregulating Caveolin-3 Attenuates Post-Hypoxic Mitochondrial Damage and Cell Death in H9C2 Cardiomyocytes During Hyperglycemia. AB - BACKGROUND/AIMS: Hearts from diabetic subjects are susceptible to myocardial ischemia reperfusion (I/R) injury. Propofol has been shown to protect against myocardial I/R injury due to its antioxidant properties while the underlying mechanism remained incompletely understood. Thus, this study aimed to determine whether or not propofol could attenuate myocardial I/R injury by attenuating mitochondrial dysfunction/damage through upregulating Caveolin (Cav)-3 under hyperglycemia. METHODS: Cultured rat cardiomyocyte H9C2 cells were subjected to hypoxia/reoxygenation (H/R) in the absence or presence of propofol under high glucose (HG), and cell viability, lactate dehydrogenase (LDH) and mitochondrial viability as well as creatine kinase-MB (CK-MB), cardiac troponin I (cTnI) and intracellular adenosine triphosphate (ATP) content were measured with colorimetric Enzyme-Linked Immunosorbent Assays. Intracellular levels of oxidative stress was assessed using 2,7-dichlorodihydrofluorescein diacetate (DCF DA) fluorescent staining and mitochondrial-dependent apoptosis was assessed by detecting mitochondrial membrane potential and the activation of apoptotic caspases 3 and 9. RESULTS: Exposure of cells to HG without or with H/R both significantly increased cell injury, cell apoptosis and enhanced oxidative stress that were associated with mitochondrial dysfunction and decreased Cav-3 protein expression. All these changes were further exacerbated following H/R under HG. Administration of propofol at concentrations from 12.5 to 50 uM but not 100 uM significantly attenuated H/R injury that was associated with increased Cav-3 expression and activation of the prosurvival proteins Akt and STAT3 with the optimal protective effects seen at 50 uM of propofol (P25). The beneficial effects of propofol(P25) were abrogated by Cav-3 disruption with beta-methyl cyclodextrin. CONCLUSION: Propofol counteracts cardiomyocyte H/R injury by attenuating mitochondrial damage and improving mitochondrial biogenesis through upregulating Cav-3 during hyperglycemia. PMID- 29130959 TI - Ginsenoside Rg1 Protects Cardiomyocytes Against Hypoxia/Reoxygenation Injury via Activation of Nrf2/HO-1 Signaling and Inhibition of JNK. AB - BACKGROUND/AIMS: Excessive reactive oxygen species (ROS) disturb the physiology of H9c2 cells, which is regarded as a major cause of H9c2 cardiomyocyte apoptosis. Ginsenoside Rg1 is the main active extract of ginseng, which has important antioxidant properties in various cell models. This project investigated the role of ginsenoside Rg1 in hypoxia/reoxygenation (H/R)-induced oxidative stress injury in cultured H9c2 cells to reveal the underlying signaling pathways. METHODS: H9c2 cells were pretreated with ginsenoside Rg1 for 12 h before exposure to H/R. In the absence or presence of Nrf2siRNA, HO-1 inhibitor (ZnPP-IX), and inhibitors of the MAPK pathway (SB203580, PD98059, SP600125), H9c2 cells were subjected to H/R with Rg1 treatment. The effects and mechanisms of H/R induced cardiomyocyte injury were measured. RESULTS: Ginsenoside Rg1 treatment suppressed H/R-induced apoptosis and caspase-3 activation. Ginsenoside Rg1 treatment decreased ROS production and mitochondrial membrane depolarization by elevating the intracellular antioxidant capacity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH). Furthermore, ginsenoside Rg1 stimulation appeared to result in nuclear translocation of NF-E2 related factor 2 (Nrf2), along with enhanced expression of the downstream target gene heme oxygenase-1 (HO-1) in a dose-dependent manner. However, ginsenoside Rg1 mediated cardioprotection was abolished by Nrf2-siRNA and HO-1 inhibitor. H/R treatment increased the levels of phosphorylated c-Jun N-terminal kinases (p JNK), which was dramatically attenuated by ginsenoside Rg1 and SP600125 (a specific JNK inhibitor). CONCLUSION: These observations indicate that ginsenoside Rg1 activates the Nrf2/HO-1 axis and inhibits the JNK pathway in H9c2 cells to protect against oxidative stress. PMID- 29130960 TI - PIWI Proteins and PIWI-Interacting RNA: Emerging Roles in Cancer. AB - P-Element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a type of noncoding RNAs (ncRNAs) and interact with PIWI proteins. piRNAs were primarily described in the germline, but emerging evidence revealed that piRNAs are expressed in a tissue-specific manner among multiple human somatic tissue types as well and play important roles in transposon silencing, epigenetic regulation, gene and protein regulation, genome rearrangement, spermatogenesis and germ stem cell maintenance. PIWI proteins were first discovered in Drosophila and they play roles in spermatogenesis, germline stem-cell maintenance, self-renewal, retrotransposons silencing and the male germline mobility control. A growing number of studies have demonstrated that several piRNA and PIWI proteins are aberrantly expressed in various kinds of cancers and may probably serve as a novel biomarker and therapeutic target for cancer treatment. Nevertheless, their specific mechanisms and functions need further investigation. In this review, we discuss about the biogenesis, functions and the emerging role of piRNAs and PIWI proteins in cancer, providing novel insights into the possible applications of piRNAs and PIWI proteins in cancer diagnosis and clinical treatment. PMID- 29130961 TI - Endothelial Cell-Derived Microparticles from Patients with Obstructive Sleep Apnea Hypoxia Syndrome and Coronary Artery Disease Increase Aortic Endothelial Cell Dysfunction. AB - BACKGROUND/AIMS: Obstructive sleep apnea hypoxia syndrome (OSAHS) is an independent risk factor for coronary artery disease (CAD). Treatment of OSAHS improves clinical outcome in some CAD patients, but the relationship between OSAHS and CAD is complex. Microparticles (MPs) are shed by the plasma membrane by either physiologic or pathologic stimulation. In the current study, we investigated the role of MPs in the context of OSAHS. METHODS AND RESULTS: 54 patients with both suspected coronary artery stenosis and OSAHS were recruited and underwent both coronary arteriography and polysomnography. Circulating MPs were isolated and analyzed by flow cytometry. CAD+OSAHS patients exhibited greater levels of total MPs (Annexin V+), erythrocyte-derived MPs (CD235+ Annexin V+), platelet-derived MPs (CD41+ Annexin V+), and leukocyte-derived MPs (CD45+ Annexin V+) compared to CAD alone patients or control. CAD+OSAHS patients expressed the greatest level of endothelial-derived MPs of all cellular origin types (CD144+ Annexin V +). Treatment of human aortic endothelial cells (HAECs) with MPs isolated from CAD+OSAHS patients markedly increased HAEC permeability (as detected by FITC-dextran), and significantly upregulated mRNA levels of ICAM 1, VCAM-1, and MCP-1. CONCLUSION: OSAHS+CAD patients harbor increased levels of MPs, particularly the endothelial cell-derived subtype. When administered to HAECs, OSAHS+CAD patients MPs increase endothelial cell permeability and dysfunction. PMID- 29130963 TI - Shift Work and the Risk of Coronary Artery Disease: A Cardiac Computed Tomography Angiography Study. AB - AIMS: Shift work disrupts the normal circadian rhythm and is associated with risk factors for coronary artery disease (CAD) and a higher incidence of CAD morbidity and mortality. Cardiac computed tomography angiography (CCTA) is a robust noninvasive modality for assessing the presence, extent, and severity of CAD. We sought to investigate whether shift workers are prone to a higher burden of CAD compared to non-shift workers. METHODS: We conducted a historically prospective study in consecutive patients who underwent CCTA and answered a telephonic questionnaire. Due to significant differences in age and gender, we compared 89 well-matched pairs of shift workers and non-shift workers with the use of propensity scores. RESULTS: Our cohort consisted of 349 participants, of whom 94 (26.9%) were shift workers. The mean age was 50.7 years, and 62.5% were males. After pairing, we showed that shift workers had a higher prevalence of CAD than non-shift workers (74.2 vs. 53.9%, respectively, p = 0.01), and a lower prevalence of coronary calcium scores of zero (46.8 vs. 63.4%, respectively, p = 0.034). Stenosis >50% was more prevalent in shift workers than in non-shift workers (20.2 vs. 11.2%, respectively, p = 0.006), and the extent of CAD (defined as the presence of >=1-vessel disease) tended to be higher in shift workers than in non-shift workers (25.8 vs. 13.5%, respectively, p = 0.06). CONCLUSIONS: In this CCTA study, we showed in a well-matched cohort of consecutive patients that shift workers had a higher prevalence and extent of CAD than non-shift workers. PMID- 29130962 TI - Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction. AB - BACKGROUND/AIM: Plasma trimethylamine-N-oxide (TMAO), a product of intestinal microbial metabolism of dietary phosphatidylcholine has been recently associated with atherosclerosis and increased risk of cardiovascular diseases (CVD) in rodents and humans. However, the molecular mechanisms of how TMAO induces atherosclerosis and CVD progression are still unclear. The present study tested whether TMAO induces NLRP3 inflammasome formation and activation and thereby contributes to endothelial injury initiating atherogenesis. METHODS: Inflammasome formation and activation was determined by confocal microscopy, caspase-1 activity was measured by colorimetric assay, IL-1beta production was measured using ELISA, cell permeability was determined by microplate reader and ZO-1 expression was determined by western blot analysis and confocal microscopy. In in vivo experiments, TMAO was infused by osmotic pump implantation. RESULTS: TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase-1, caspase-1 activity, IL-1beta production, cell permeability in carotid artery endothelial cells (CAECs) compared to control cells. Pretreatment with caspase-1 inhibitor, WEHD or Nlrp3 siRNA abolished the TMAO-induced inflammasome formation, activation and cell permeability in these cells. In addition, we explored the mechanisms by which TMAO activates NLRP3 inflammasomes. TMAO-induced the activation of NLRP3 inflammasomes was associated with both redox regulation and lysosomal dysfunction. In animal experiments, direct infusion of TMAO in mice with partially ligated carotid artery were found to have increased NLRP3 inflammasome formation and IL-1beta production in the intima of wild type mice. CONCLUSION: The formation and activation of NLRP3 inflammasomes by TMAO may be an important initiating mechanism to turn on the endothelial inflammatory response leading to endothelial dysfunction. PMID- 29130964 TI - Changes in the Proliferation/Apoptosis Balance in the Bovine Ovary: A Key Early Event in Follicular Persistence. AB - The objective of this work was to evaluate proliferation and apoptosis in the bovine ovary in a model of follicular persistence induced by low levels of progesterone to detect incipient changes during cystic ovarian disease development on the expected day of ovulation (day 0) and after 5, 10, and 15 days of follicular persistence. We analyzed cell proliferation by evaluating the expression of Ki-67 and apoptosis by evaluating caspase-3, BAX, and BCL2 expression. Proliferation was similar in the granulosa and theca cells of antral follicles in the P0 group (treated with progesterone up to the expected day of ovulation) and in the control group. A decrease in cell proliferation was detected after 5 days of persistence (P5) in relation to P0 (p < 0.05). Similar changes were found in the granulosa cells of the persistent follicles in relation to the control group (p < 0.05). Caspase-3 expression was similar in granulosa cells of antral follicles at early stages of persistence, with an increase after 15 days of persistence (p < 0.05). In the granulosa cells of group P10 (10 days of persistence), caspase-3 expression was reduced relative to that of antral follicles from the control group (p < 0.05). BCL2 expression was higher in granulosa cells of the persistent follicles of group P0 relative to the control follicles, with no changes in BAX expression, which was increased in persistent follicles of group P15 (p < 0.05). Similar results were observed in theca cells at initial stages of persistence. The results show that, initially, proliferation is maintained with low apoptosis and an increase in cell survival. PMID- 29130965 TI - Calciphylaxis: Another Piece of the Puzzle. PMID- 29130966 TI - iTRAQ-Based Proteomic Analysis of Neonatal Kidney from Offspring of Protein Restricted Rats Reveals Abnormalities in Intraflagellar Transport Proteins. AB - BACKGROUND: It is well recognized that adverse events in utero can impair fetal development and lead to the development of kidney injury and hypertension in adulthood. We previously reported a lower kidney index, glomeruli number, and decreased glomerular filtration rate in intrauterine growth restriction (IUGR) offspring induced by maternal protein malnutrition. To explore the molecular mechanisms linking impaired fetal growth to renal diseases, we investigated differentially expressed proteins (DEPs) in the IUGR neonatal kidneys by isobaric tags for relative and absolute quantitation (iTRAQ) analysis. METHODS: We induced IUGR through maternal protein malnutrition. Neonatal kidneys were collected; the protein was extracted; pooled before iTRAQ labeling, and subjected to mass spectrometric analysis. Mass spectrometry results were then further confirmed by assessing five representative proteins in individual specimens with quantitative PCR (qPCR), immunohistochemical (IHC) and / or western blot analysis. RESULTS: A total of 367DEPs (263 up-regulated, 104 down-regulated.) with a threshold of a 1.2-fold change and a P value <= 0.05 between IUGR kidneys and control kidneys were identified. Further bioinformatics analysis revealed that these proteins play important roles in oxidative phosphorylation, purine metabolism, pyrimidine metabolism, RNA small body, spliceosome assembly and intraflagellar transport (IFT). IFT family proteins (IFT80, 88,144) and PKD2 were shown to be up-regulated in IUGR kidneys, confirmed by western blotting, IHC and Q-PCR. Epigenetic modulating factors SET and MYND domain containing 3 (SMYD3), a histone-lysine N methyltransferase, and H3K4me3 level were also remarkably enhanced in IUGR neonatal kidneys. CONCLUSIONS: This first comprehensive analysis of the neonatal kidney proteome reveals new insights in nephridial development, and may make a valuable contribution towards the identification of the pathological mechanisms involved in the developmental origins of adult disease. PMID- 29130967 TI - Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells. AB - BACKGROUND/AIMS: Lung cancer (LC) continues to be one of the most prevalent cancers around the world. During this study we aimed to investigate the involvement of endoplasmic reticulum stress (ERS) in autophagy, apoptosis, and chemotherapy resistance of mutant p53 LC cells. METHODS: Immunohistochemistry was employed to help determine the p53 mutation status of cancer cells from 92 primary LC patients, who were subsequently assigned to either the mutant p53 (n = 39) or wild-type p53 group (n = 53). RESULTS: Mutant p53 cells exhibited increased expression of the C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme-1alpha (IRE1alpha). The Mutant p53 cells were also found to be sensitive to chemotherapy and displayed decreased expression of PI3K, Akt, and mTOR. The mutant p53 cell lines were treated with tunicamycin to induce ERS and rapamycin in order to inhibit mTOR. Both agents increased the expression of CHOP, GRP78, IRE1alpha, LC3-II/LC3-I, Atg5, Atg7, caspase-3, caspase-12, cleaved caspase-3, cleaved caspase-12, as well as decreases in cell proliferation as well as the expression levels of PI3K, Akt, and mTOR. Enhanced levels of cell apoptosis and reduced chemotherapy resistance were also detected. CONCLUSION: The findings of our study suggest that ERS promotes autophagy and apoptosis, while acting to reduce chemotherapy resistance in mutant p53 LC cells by downregulating the PI3K/Akt/mTOR signaling pathway. PMID- 29130968 TI - Immunohistochemical Localization of Calbindin D28k, Parvalbumin, and Calretinin in the Superior Olivary Complex of Circling Mice. AB - The circling mouse serves as a hearing loss model. It has spontaneous tmie gene mutations that cause hair cell and cochlear degeneration. However, little is known about the role of the tmie gene in superior olivary complex (SOC) regions, in which sound information from the two ears is integrated and primarily relayed to the nuclei of the lateral lemniscus and inferior colliculus. Several studies have reported that abnormal calcium (Ca2+) homeostasis is associated with the pathology of hearing loss. This study investigated the distribution of Ca2+ binding proteins (CaBPs), such as calbindin D28k, parvalbumin, and calretinin, in the SOC of the circling mouse on postnatal day 16. A comparison of wild-type (+/+), heterozygous (+/cir), and homozygous (cir/cir) mice showed that CaBP immunoreactivity was significantly decreased in the auditory nucleus of the SOC of homozygous (cir/cir) mice. A decline in the CaBPs level in the SOC may be the result of hearing loss through hair cell and cochlear degeneration following tmie gene mutation. PMID- 29130969 TI - Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly. AB - BACKGROUND/AIMS: Mechanisms underlying the relationship between systemic inflammation and age-related decline in muscle mass are poorly defined. The purpose of this work was to investigate the relationship between the systemic inflammatory marker CRP and muscle mass in elderly and to identify mechanisms by which CRP mediates its effects on skeletal muscle, in-vitro. METHODS: Muscle mass and serum CRP level were determined in a cohort of 118 older women (67+/-1.7 years). Human muscle cells were differentiated into myotubes and were exposed to CRP. The size of myotubes was determined after immunofluorescent staining using troponin. Muscle protein synthesis was assessed using stable isotope tracers and key signalling pathways controlling protein synthesis were determined using western-blotting. RESULTS: We observed an inverse relationship between circulating CRP level and muscle mass (beta= -0.646 (95% CI: -0.888, -0.405) p<0.05) and demonstrated a reduction (p < 0.05) in the size of human myotubes exposed to CRP for 72 h. We next showed that this morphological change was accompanied by a CRP-mediated reduction (p < 0.05) in muscle protein fractional synthetic rate of human myotubes exposed to CRP for 24 h. We also identified a CRP-mediated increased phosphorylation (p<0.05) of regulators of cellular energy stress including AMPK and downstream targets, raptor and ACC-beta, together with decreased phosphorylation of Akt and rpS6, which are important factors controlling protein synthesis. CONCLUSION: This work established for the first time mechanistic links by which chronic elevation of CRP can contribute to age related decline in muscle function. PMID- 29130970 TI - Physiological Signatures of Dual Embryonic Origins in Mouse Skull Vault. AB - BACKGROUND/AIMS: The mammalian skull vault is a highly regulated structure and consists of several membrane bones of different tissue origins (e.g. neural crest derived frontal bone and mesoderm derived parietal bone). Although membrane bones form through intramembranous ossification, neural crest derived frontal bone has superior osteoblast activity and bone regeneration ability, triggering a novel conception for craniofacial reconstruction and bone regeneration called endogenous calvarial regeneration. However, a comprehensive landscape of the genes and signaling pathways involved in this process is not clear. METHODS: Transcriptome analysis within the two bone elements is firstly performed to determine the physiological signatures of differential gene expressions in mouse skull vault. RESULTS: Frontal bone tissues and parietal bone tissues maintain tissue origin through special gene expression similar to neural crest vs mesoderm tissue, and physiological functions between these two tissues are also found in differences related to proliferation, differentiation and extracellular matrix production and clustered signaling pathways. CONCLUSION: Our data provide novel insights into the potential gene regulatory network in regulating the development of neural crest-derived frontal bone and mesoderm-derived parietal bone. PMID- 29130971 TI - Can the Ki-67 Labeling Index in Biopsy Specimens Predict the World Health Organization Grade of Rectal Neuroendocrine Tumors? AB - BACKGROUND: Being grade 2 is a known risk factor for metastasis in rectal neuroendocrine tumors (R-NETs). We aimed to identify the efficacy of the Ki-67 labeling index (LI) in endoscopic biopsy specimens to predict the World Health Organization (WHO) grade of R-NETs. METHODS: A total of 59 patients with 60 R NETs (43 WHO grade 1 and 17 WHO grade 2), treated between October 2002 and December 2014, were retrospectively evaluated. The patients included in the study underwent biopsies followed by endoscopic submucosal resection with a ligation device, trans-anal full-thickness surgical resection, or radical surgery with lymph node dissection. The Ki-67 LI in the biopsy and resected specimens were compared between the 2 tumor grade groups, and the diagnostic sensitivity, specificity, and positive and negative predictive values for the detection of WHO grade 2 tumors were evaluated. RESULTS: The sensitivity, specificity, and positive and negative predictive values of the Ki-67 LI in biopsy specimens for predicting grade 2 tumors were 53% (9 of 17), 95% (41 of 43), 100% (9 of 9), and 87% (41 of 47), respectively. Pearson's rank correlation coefficient between the Ki-67 LI in the biopsy and resected specimens was 0.92. CONCLUSIONS: The Ki-67 LI of the biopsy specimen is useful for determining the appropriate treatment for R NETs. PMID- 29130972 TI - Human Dendritic Cells with Th2-Polarizing Capacity: Analysis Using Label-Free Quantitative Proteomics. AB - BACKGROUND: Dendritic cells (DCs) are the sentinels of the immune system. Upon recognition of a pathogen, they mature and migrate to draining lymph nodes to prime and polarize T cell responses. Although it is known that helminths and helminth-derived molecules condition DCs to polarize T helper (Th) cells towards Th2, the underlying mechanisms remain incompletely understood. OBJECTIVES: The aim of this study was to conduct a proteome analysis of helminth antigen stimulated DCs in order to gain more insight into the cellular processes associated with their ability to polarize immune responses. METHODS: We analyzed the maturation and polarization of monocyte-derived DCs from 9 donors at 2 different time points after stimulation with different Th1- and Th2-polarizing pathogen-derived molecules. The samples were measured using liquid chromatography Fourier transform ion cyclotron resonance mass spectrometry for relative quantitation. RESULTS: Lipopolysaccharide-induced maturation promoted the expression of proteins related to metabolic, cellular, and immune system processes. Th1-polarizing DCs, conditioned by IFN-gamma during maturation, displayed accelerated maturation by differentially expressing cytoskeletal proteins and proteins involved in immune regulation. The stimulation of DCs with soluble egg antigens and omega-1 derived from Schistosoma mansoni, which are both Th2-inducing stimuli, increased 60S acidic ribosomal protein P2, and vesicle amine transferase 1 while decreasing the expression of proteins related to antigen processing and presentation. CONCLUSION: Our data indicate that not only proteins involved in the interaction between T cells and DCs at the level of the immunological synapse, but also those related to cellular metabolism and stress, may promote Th2 polarization. PMID- 29130973 TI - Frequency, Aetiology, and Outcome of Small Cerebellar Infarction. AB - BACKGROUND AND PURPOSE: Strokes due to small (<2 cm) cerebellar infarction are under-recognised, and their profile and aetiology have not been well characterised. We aimed to determine the frequency, clinical features, aetiology, and outcome of small as compared to large cerebellar infarction. METHODS: This study is a retrospective analysis of clinical and imaging features of a prospectively assessed series of 108 consecutive patients with acute cerebellar infarction admitted to Liverpool Hospital, Sydney, NSW, Australia, during 2011 2015. RESULTS: The mean age of the patients was 67 years, and 33 (31%) had small cerebellar infarction. Compared to large cerebellar infarction, those with small cerebellar infarction had a comparable distribution of vascular risk factors but significantly less nausea and vomiting, gait disturbance, limb ataxia, and dysarthria. The posterior (n = 22, 67%) lobe was most commonly affected, followed by the anterior (n = 9, 27%) and flocculonodular (n = 2) lobes. Dizziness, limb ataxia, and nystagmus were significantly more common in patients with anterior lobe infarction. Vertebrobasilar disease was the presumed aetiology in 40 patients (37%), and was less commonly seen in small as compared to large cerebellar infarction. Cardioembolism affected 37% of the patients, irrespective of the size or topography of the cerebellar infarction, and there was no relation of supratentorial white matter lucencies (WMLs) to the size of cerebellar infarction. At 3 months, 65% of the patients were functionally independent (according to modified Rankin Scale scores of 0-2), and having a poor outcome was significantly related to moderate-to-severe supratentorial WML and large cerebellar infarction. CONCLUSIONS: Small cerebellar infarction accounted for one third of the ischaemic strokes in this location, most often involved the posterior lobe, causing fewer clinical features, and had a better clinical outcome than large cerebellar infarction. Patients with small cerebellar infarction require appropriate vascular management including investigation for a cardioembolic source. PMID- 29130974 TI - Atypical Squamous Cells in Liquid-Based Cervical Cytology: Microbiology, Inflammatory Infiltrate, and Human Papillomavirus-DNA Testing. AB - OBJECTIVE: The aim of this study was to assess the correlation between atypical squamous cells (ASC) and inflammatory infiltrate and vaginal microbiota using cervical liquid-based cytological (SurePath(r)) and high-risk human papillomavirus (HR-HPV) tests. STUDY DESIGN: A cross-sectional study was conducted using a 6-year database from a laboratory in Fortaleza (Brazil). Files from 1,346 ASC cases were divided into subgroups and results concerning inflammation and vaginal microorganisms diagnosed by cytology were compared with HR-HPV test results. RESULTS: An absence of specific microorganisms (ASM) was the most frequent finding (ASC of undetermined significance, ASC-US = 74%; ASC - cannot exclude high-grade squamous intraepithelial lesion, ASC-H = 68%), followed by bacterial vaginosis (ASC-US = 20%; ASC- H = 25%) and Candida spp. (ASC-US = 6%; ASC-H = 5%). Leukocyte infiltrate was present in 71% of ASC-US and 85% of ASC H (p = 0.0040), and in these specific cases HR-HPV tests were positive for 65 and 64%, respectively. A positive HR-HPV test was relatively more frequent when a specific microorganism was present, and Candida spp. was associated with HR-HPV positive results (p = 0.0156), while an ASM was associated with negative HR-HPV results (p = 0.0370). CONCLUSION: ASC-US is associated with an absence of inflammation or vaginosis, while ASC-H smears are associated with Trichomonas vaginalis and inflammatory infiltrate. A positive HR-HPV is associated with Candida spp. in ASC cytology. PMID- 29130975 TI - Karyotypes versus Genomes: The Nymphalid Butterflies Melitaea cinxia, Danaus plexippus, and D. chrysippus. AB - The number of sequenced lepidopteran genomes is increasing rapidly. However, the corresponding assemblies rarely represent whole chromosomes and generally also lack the highly repetitive W sex chromosome. Knowledge of the karyotypes can facilitate genome assembly and further our understanding of sex chromosome evolution in Lepidoptera. Here, we describe the karyotypes of the Glanville fritillary Melitaea cinxia (n = 31), the monarch Danaus plexippus (n = 30), and the African queen D. chrysippus (2n = 60 or 59, depending on the source population). We show by FISH that the telomeres are of the (TTAGG)n type, as found in most insects. M. cinxia and D. plexippus have "conventional" W chromosomes which are heterochromatic in meiotic and somatic cells. In D. chrysippus, the W is inconspicuous. Neither telomeres nor W chromosomes are represented in the published genomes of M. cinxia and D. plexippus. Representation analysis in sequenced female and male D. chrysippus genomes detected an evolutionarily old autosome-Z chromosome fusion in Danaus. Conserved synteny of whole chromosomes, so called "macro synteny", in Lepidoptera permitted us to identify the chromosomes involved in this fusion. An additional and more recent sex chromosome fusion was found in D. chrysippus by karyotype analysis and classical genetics. In a hybrid population between 2 subspecies, D. c. chrysippus and D. c. dorippus, the W chromosome was fused to an autosome that carries a wing colour locus. Thus, cytogenetics and the present state of genome data complement one another to reveal the evolutionary history of the species. PMID- 29130976 TI - Discontinued Information and Communication Technology Usage among Older Adults in Continuing Care Retirement Communities in the United States. AB - BACKGROUND: Older adults are increasingly using information and communication technologies (ICTs). Recent studies show beneficial effects of using ICTs for older adults, particularly in terms of reducing loneliness and depression. However, little is known about the factors that may prevent discontinued ICT use in populations that may be at greater risk, such as those in continuing care retirement communities (CCRCs). OBJECTIVES: The purpose of this study is to examine a range of factors that may influence discontinued (1) ICT use, (2) searching for health information, and (3) searching for general information over time among CCRC residents. METHODS: We use longitudinal data from a randomized controlled trial conducted with residents of 19 CCRCs. We use flexible parametric models to estimate the hazard ratio or hazard rate over 5 waves of data to determine what factors significantly predict discontinued (1) ICT use, (2) health information searching, and (3) general information searching. RESULTS: The analysis reveals that independent living residents who took part in an 8-week ICT training intervention were less likely to stop using ICTs. Age and the number of instrumental activities of daily living (IADL) impairments significantly predicted an increased likelihood of stopping ICT use. When examining specific ICT-related activities, the analysis reveals that independent living residents who took part in the ICT training intervention were less likely to stop searching for health information and general information online. In addition, age and the number of IADL impairments were associated with increased likelihood of discontinued health information searches and discontinued general information searches. CONCLUSION: ICT training interventions may motivate residents of CCRCs to stay connected by increasing the ICT skill level and promoting confidence, thus decreasing the probability that they will discontinue using ICTs and searching for general information. However, the effects of ICT training on motivating continued ICT usage may be more pronounced among independent living residents. Limitations in the number of IADL impairments is a key factor leading to discontinued use of ICTs among CCRC residents, suggesting that designers of ICTs should be cognizant of the cognitive and physical limitations among this group. PMID- 29130977 TI - Effects of Wearable Sensor-Based Balance and Gait Training on Balance, Gait, and Functional Performance in Healthy and Patient Populations: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Wearable sensors (WS) can accurately measure body motion and provide interactive feedback for supporting motor learning. OBJECTIVE: This review aims to summarize current evidence for the effectiveness of WS training for improving balance, gait and functional performance. METHODS: A systematic literature search was performed in PubMed, Cochrane, Web of Science, and CINAHL. Randomized controlled trials (RCTs) using a WS exercise program were included. Study quality was examined by the PEDro scale. Meta-analyses were conducted to estimate the effects of WS balance training on the most frequently reported outcome parameters. RESULTS: Eight RCTs were included (Parkinson n = 2, stroke n = 1, Parkinson/stroke n = 1, peripheral neuropathy n = 2, frail older adults n = 1, healthy older adults n = 1). The sample size ranged from n = 20 to 40. Three types of training paradigms were used: (1) static steady-state balance training, (2) dynamic steady-state balance training, which includes gait training, and (3) proactive balance training. RCTs either used one type of training paradigm (type 2: n = 1, type 3: n = 3) or combined different types of training paradigms within their intervention (type 1 and 2: n = 2; all types: n = 2). The meta-analyses revealed significant overall effects of WS training on static steady-state balance outcomes including mediolateral (eyes open: Hedges' g = 0.82, CI: 0.43 1.21; eyes closed: g = 0.57, CI: 0.14-0.99) and anterior-posterior sway (eyes open: g = 0.55, CI: 0.01-1.10; eyes closed: g = 0.44, CI: 0.02-0.86). No effects on habitual gait speed were found in the meta-analysis (g = -0.19, CI: -0.68 to 0.29). Two RCTs reported significant improvements for selected gait variables including single support time, and fast gait speed. One study identified effects on proactive balance (Alternate Step Test), but no effects were found for the Timed Up and Go test and the Berg Balance Scale. Two studies reported positive results on feasibility and usability. Only one study was performed in an unsupervised setting. CONCLUSION: This review provides evidence for a positive effect of WS training on static steady-state balance in studies with usual care controls and studies with conventional balance training controls. Specific gait parameters and proactive balance measures may also be improved by WS training, yet limited evidence is available. Heterogeneous training paradigms, small sample sizes, and short intervention durations limit the validity of our findings. Larger studies are required for estimating the true potential of WS technology. PMID- 29130978 TI - Peritoneal Seeding after Gastric Perforation during Endoscopic Submucosal Dissection for Gastric Cancer. AB - BACKGROUND/AIMS: Since the risk of cancer cells seeding the peritoneum after perforation during endoscopic submucosal dissection (ESD) is unclear, we retrospectively examined peritoneal relapse after gastric perforation during ESD for gastric cancer at a single institution. METHODS: Of 876 patients who underwent ESD for early gastric cancer between January 2002 and December 2015, 22 patients (2.5%) experienced gastric perforation during ESD at the Osaka National Hospital in Osaka, Japan. Clinical data from these 22 patients were reviewed for information on pathology, clinical course, and evidence of peritoneal dissemination. RESULTS: Patients were followed for a median of 55 (range 2-108) months. Two patients had peritoneal seeding following perforation during ESD. Multivariate analysis to explore the influence of clinical factors on the peritoneal seeding revealed that an intra-abdominal fluid collection on the CT imaging just after ESD, tumor location at the upper lesion of stomach, and pathologically marginal invasion were independently associated with an incidence of peritoneal relapse. CONCLUSION: Although rare, we should recognize the possibility of cancer cells seeding the peritoneum after perforation during gastric ESD. PMID- 29130979 TI - 18F-FAMT PET Is Useful to Distinguish between Specific Uptake and Nonspecific Uptake Compared to 18F-Flourodeoxyglucose Position Emission Tomography in Esophageal Cancer Patients. AB - BACKGROUND: L-[3-18F]-alpha-methyltyrosine (18F-FAMT) solely accumulates in tumor cells via an amino acid transport system. This selective uptake pattern results in a very high tumor-to-background ratio, enabling clear delineation of the tumor. The purpose of the present study was to assess the significance of 18F FAMT PET, which shows little nonspecific uptake compared to 18F flourodeoxyglucose position emission tomography (FDG PET) in esophageal cancer patients. METHODOLOGY: PET-CT studies with 18F-FAMT and 18F-FDG were performed as part of pretreatment work-up in 82 patients with histologically confirmed esophageal cancer. We evaluated nonspecific uptakes of 18F-FDG and 18F-FAMT PET. RESULTS: The nonspecific uptake of 18F-FAMT PET was lower than that of 18F-FDG PET (p = 0.282). In the operation group, 26.1% demonstrated nonspecific uptake in 18F-FDG PET, whereas only 2.38% (1 case) demonstrated nonspecific uptake in 18F FAMT PET (p = 0.433). In the inoperable group, 47.5% showed nonspecific uptake in 18F-FDG PET, whereas 5.0% showed nonspecific uptake in 18F-FAMT PET (p = 0.079). CONCLUSION: A crucial point for the diagnostic value of PET is distinguishing specific and nonspecific uptake. 18F-FAMT-PET is a very superior modality with regard to the lower rate of nonspecific uptake in esophageal cancer. PMID- 29130980 TI - Circulating LncRNAs Serve as Diagnostic Markers for Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: Circulating (serous or plasmic) long non-coding RNA (lncRNA) as biomarkers for predicting the diagnosis or prognosis of human disease have been well documented. Due to the sensibility or specificity limitation of Alpha Fetoprotein (AFP), a cluster lncRNAs were revealed as fingerprints for hepatocellular carcinoma (HCC). In this study, we enrolled all the reported circulating lncRNAs in HCC as candidate targets and examined in an independent cohort. METHODS: The candidate lncRNAs were determined by qRT-PCR divided into training and validation sets. The risk score analysis was employed to evaluate the potential diagnosis ability of the lncRNAs independently or combining with AFP value. The receiver operating characteristic curve (ROC) was applied for presentation of sensibility or specificity. RESULTS: Among the ten candidate circulating lncRNA, LINC00152, RP11-160H22.5, XLOC014172 and LOC149086 were screened with significant difference in training set. Further investigation in validation set indicated LINC00152, RP11-160H22.5 and XLOC014172 might be the fingerprints for HCC comparing with chronic hepatitis (CH) patients or healthy controls. The risk score analysis revealed the combination of three lncRNAs with AFP could distinguish the HCC from either CH or healthy control with the area under curve value (AUC) of 0.986 and 0.985, respectively. CONCLUSION: The three lncRNAs may act as novel biomarkers for acting as fingerprint in HCC combining with AFP. PMID- 29130981 TI - Endocranial Casts of Pre-Mammalian Therapsids Reveal an Unexpected Neurological Diversity at the Deep Evolutionary Root of Mammals. AB - The origin and evolution of the mammalian brain has long been the focus of scientific enquiry. Conversely, little research has focused on the palaeoneurology of the stem group of Mammaliaformes, the Permian and Triassic non mammaliaform Therapsida (NMT). This is because the majority of the NMT have a non ossified braincase, making the study of their endocranial cast (sometimes called the "fossil brain") problematic. Thus, descriptions of the morphology and size of NMT endocranial casts have been based largely on approximations rather than reliable determination. Accordingly, here we use micro-CT scans of the skulls of 1 Dinocephalia and 3 Biarmosuchia, which are NMT with a fully ossified braincase and thus a complete endocast. For the first time, our work enables the accurate determination of endocranial shape and size in NMT. This study suggests that NMT brain size falls in the upper range of the reptilian and amphibian variation. Brain size in the dicynodont Kawingasaurus is equivalent to that of early Mammaliaformes, whereas the Dinocephalia show evidence of a secondary reduction of brain size. In addition, unlike other NMT in which the endocast has a tubular shape and its parts are arranged in a linear manner, the biarmosuchian endocast is strongly flexed at the level of the midbrain, creating a near right angle between the fore- and hindbrain. These data highlight an unexpected diversity of endocranial size and morphology in NMT, features that are usually considered conservative in this group. PMID- 29130982 TI - Aphasia Following Left Putaminal Hemorrhage at a Rehabilitation Hospital. AB - OBJECTIVE: We aimed to clarify the relationship between aphasia and hematoma type/volume in patients with left putaminal hemorrhage admitted to a rehabilitation facility. METHODS: We evaluated the relationship between the presence, type, and severity of aphasia and hematoma type/volume in 92 patients with putaminal hemorrhage aged 29-83 years. Hematoma type and volume were evaluated on the basis of CT images obtained at stroke onset. The Standard Language Test for Aphasia was conducted as part of the initial assessment. RESULTS: Aphasia was observed in 79 of 92 patients. A total of 31 patients had fluent aphasia, while 48 had non-fluent aphasia. Non-fluent aphasia often involved hematoma on the anterior limb of the internal capsule, while fluent aphasia often involved hematoma on the posterior limb of internal capsule. When the hematoma volume exceeded 20 mL, patients experienced difficulty in repeating spoken words. When hematoma volume exceeded 40 mL, non-fluent aphasia was observed in all patients. CONCLUSION: Our findings suggest that hematoma type and volume not only influence the development of aphasia following putaminal hemorrhage but also play a major role in determining the patient's fluency and repetition ability. PMID- 29130983 TI - Prevalence and Clinical Characteristics of Local Allergic Rhinitis in Children Sensitized to House Dust Mites. AB - OBJECTIVE: The prevalence of local allergic rhinitis (LAR) in nonatopic children remains unknown. This study aimed to determine the prevalence, clinical characteristics, and severity of LAR in children in comparison to classical allergic rhinitis (AR) and nonallergic rhinitis (NAR). STUDY DESIGN: A total of 145 children (aged 1-18 years) were enrolled and classified into 3 groups (AR, NAR, and LAR) based on a skin prick test (SPT) and a nasal provocation test (NPT) with house dust mite, i.e., Dermatophagoides pteronyssinus. NPT positivity was defined as a symptom score >=2 standard deviations (SDs) above the healthy control score. RESULTS: Eighty-one children had AR (55.9%), and 64 (44.1%) had symptoms of rhinitis with negative SPT; 59 NAR (40.7%) and 5 LAR (3.4%) children were identified. The kappa score for agreement between the SPT and the NPT results was 0.778 (95% CI 0.726-0.830, p < 0.001). A significant correlation was observed between wheal diameter and maximum nasal symptom score provoked by D.pteronyssinus (rho = 0.589, p < 0.001). Nasal severity according to the ARIA guideline did not show any differences in the 3 groups (p = 0.693). The AR group was older than the LAR and NAR groups (AR > LAR > NAR, p = 0.003). CONCLUSIONS: Despite the evidence to support the existence of LAR in pediatric populations, we found that its prevalence was relatively low, possibly due to the high rate of agreement between SPT and NPT. Further investigations are needed to identify immunological as well as clinical implications of LAR. PMID- 29130985 TI - Heptamethoxyflavone Reduces Phosphodiesterase Activity and T-Cell Growth in vitro. AB - In a previous study, we reported that interleukin-4 production was reduced in spleen cells of mice administered 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF), which is a polymethoxyflavone found at high concentrations in the peel of various citrus fruits. In this study, we investigated the function of HMF on the growth of T cells cultured from the spleens of mice. HMF decreased the reduction of 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) by anti-CD3/CD28 antibody-stimulated mouse spleen cells. HMF inhibited the activities of phosphodiesterase (PDE) enzymes prepared from bovine brain and human PDE4B and PDE3B enzymes. The cyclic AMP (cAMP) content in anti-CD3/CD28 antibody-stimulated spleen cells increased after HMF treatment in vitro. These results suggest that HMF inhibits T-cell growth and affects immune function via reduced PDE activity and increased cAMP content. PMID- 29130984 TI - Lymphocyte Cell Ratios and Mortality among Incident Hemodialysis Patients. AB - BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been previously suggested as oncologic prognostication markers. These are associated with malnutrition and inflammation, and hence, may provide benefit in predicting mortality among hemodialysis patients. METHODS: Among 108,548 incident hemodialysis patients in a large U.S. dialysis organization (2007-2011), we compared the mortality predictability of NLR and PLR with baseline and time varying covariate Cox models using the receiver operating characteristic curve (AUROC), net reclassification index (NRI), and adjusted R2. RESULTS: During the median follow-up period of 1.4 years, 28,618 patients died. Median (IQR) NLR and PLR at baseline were 3.64 (2.68-5.00) and 179 (136-248) respectively. NLR was associated with higher mortality, which appeared stronger in the time-varying versus baseline model. PLR exhibited a J-shaped association with mortality in both models. NLR provided better mortality prediction in addition to demographics, comorbidities, and serum albumin; DeltaAUROC and NRI for 1-year mortality (95% CI) were 0.010 (0.009-0.012) and 6.4% (5.5-7.3%) respectively. Additionally, adjusted R2 (95% CI) for the Cox model increased from 0.269 (0.262 0.276) to 0.283 (0.276-0.290) in the non-time-varying model and from 0.467 (0.461 0.472) to 0.505 (0.500-0.512) in the time-varying model. There was little to no benefit of adding PLR to predict mortality. CONCLUSIONS: High NLR in incident hemodialysis patients predicted mortality, especially in the short-term period. NLR, but not PLR, added modest benefit in predicting mortality along with demographics, comorbidities, and serum albumin, and should be included in prognostication approaches. PMID- 29130986 TI - Skin Test Reactivity to Hymenoptera Venom after Venom Immunotherapy Correlates Inversely with the IgG/IgE Ratio. AB - BACKGROUND: Skin test reactivity to hymenoptera venom and venom-specific IgE are important for diagnosing venom allergy and deciding on the appropriate allergen for venom immunotherapy (VIT). Longitudinal data on skin test reactivity during VIT and their correlation with venom-specific immunoglobulin (Ig)E and IgG are scarce. METHODS: We retrospectively analyzed shifts in skin test reactivity and serum levels of venom-specific IgE and IgG in patients allergic to hymenoptera venom before the initiation of VIT with ultrarush therapy and after >=3 years of VIT. RESULTS: Fifty-four patients received ultrarush desensitization and subsequent VIT with wasp venom, 26 with honeybee venom, and 8 with both wasp and honeybee venom. Hymenoptera-specific skin test reactivity decreased during VIT in most patients, and became negative in 8% of the wasp-allergic patients and in 25% of the honeybee-allergic patients. Serum levels of venom-specific IgE positively correlated to skin test reactivity before VIT, but did not change significantly during VIT. IgG serum levels and the IgG/IgE ratio increased during VIT in most patients. A high IgG/IgE ratio correlated with low skin test reactivity after >=3 years of VIT. CONCLUSIONS: The correlation between a high venom-specific IgG/IgE ratio and low skin test reactivity after VIT may be interesting for future investigations that assess its role as a potential marker for VIT efficacy. PMID- 29130987 TI - Relationship between RAS Association Domain Family Protein 1A Promoter Methylation and the Clinicopathological Characteristics in Patients with Ovarian Cancer: A Systematic Meta-Analysis. AB - BACKGROUND: To investigate the relationship between RAS association domain family protein 1A (RASSF1A) promoter methylation and the clinical features, and the survival of ovarian cancer patients. METHODS: A comprehensive literature search was conducted in the PubMed, Embase, EBSCO, and Cochrane Library databases. The overall ORs with their 95% CIs were calculated in this meta-analysis. RESULTS: Finally 17 relevant publications with 1,108 ovarian cancer samples were available for the current meta-analysis. RASSF1A promoter methylation had a significantly higher level in ovarian cancer than in low malignant potential (LMP) tumors. No significant relationship was observed between RASSF1A promoter methylation and the clinicopathological characteristics in ovarian cancer. Two studies reported that RASSF1A promoter methylation was not correlated with the survival of patients with ovarian cancer. CONCLUSIONS: Our findings suggest that the use of RASSF1A promoter methylation could distinguish ovarian cancer and LMP tumors. RASSF1A promoter methylation may not be correlated with the clinical features and the survival of ovarian cancer patients. More studies with large sample sizes are essential in the future. PMID- 29130988 TI - Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause. AB - BACKGROUND/AIMS: Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause. METHODS: We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature. RESULTS: We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause. CONCLUSION: CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause. PMID- 29130989 TI - Preoperative Nutritional Optimization for Crohn's Disease Patients Can Improve Surgical Outcome. AB - BACKGROUND: Preoperative preparation of patients with Crohn's disease is challenging and there are no specific guidelines regarding nutritional support. The aim of this study was to assess whether preoperative nutritional support influenced the postoperative outcome. METHODS: A retrospective, cohort study including all Crohn's disease patients who underwent abdominal surgery between 2008 and 2014 was conducted. Patients' characteristics and clinical and surgical data were recorded and analyzed. RESULTS: Eighty-seven patients were included in the study. Thirty-seven patients (42.5%) received preoperative nutritional support (mean albumin level 3.14 vs. 3.5 mg/dL in the non-optimized group; p < 0.02) to optimize their nutritional status prior to surgery. Preoperative albumin level, after adequate nutritional preparation, was similar between the 2 groups. The 2 groups differ neither in demographic and surgical data, overall post-op complication (p = 0.85), Clavien-Dindo score (p = 0.42), and length of stay (p = 0.1). Readmission rate was higher in the non-optimized group (p = 0.047). CONCLUSION: Nutritional support can minimize postoperative complications in patients with low albumin levels. Nutritional status should be optimized in order to avoid hazardous complications. PMID- 29130990 TI - Increased Bone Morphogenetic Protein Signaling in the Cutaneous Vasculature of Patients with Calciphylaxis. AB - BACKGROUND: The objective of this study was to investigate the role of bone morphogenetic protein (BMP) signal transduction in the pathogenesis of calciphylaxis. METHODS: Skin biopsy specimens were obtained from 18 patients with, and 12 patients without, calciphylaxis. Tissue sections were stained with antibodies directed against BMP effector proteins phosphorylated-SMAD (p-SMAD) 1/5/9, inhibitor of DNA 1 (Id1), inhibitor of DNA 3 (Id3), and Runx2. The intensity of staining was scored semi-quantitatively as strong versus weak or absent. RESULTS: Of the 18 patients with calciphylaxis (mean age: 59 +/- 8 years), 9 were women and 15 had end-stage renal disease. Of the 12 control patients (mean age: 57 +/- 10 years), 8 were women and 8 had end-stage renal disease. Strong staining for p-SMAD 1/5/9 was detected in blood vessels from all calciphylaxis patients. In 1 patient with calciphylaxis, strong staining for p SMAD 1/5/9 was detected in a blood vessel that did not have evidence of calcification. Id1 and Id3 immunoreactivity was detected in blood vessels from all 12 patients with calciphylaxis that were tested. Runx2 staining was detected in all 6 patients with calciphylaxis who were tested. p-SMAD 1/5/9 immunoreactivity was weak or absent in blood vessels of 10 of the 12 control samples. CONCLUSIONS: The BMP signal transduction pathway is activated in the cutaneous vasculature of calciphylaxis patients. The ability to detect p-SMAD 1/5/9, Id1, and Id3 in cutaneous vasculature may assist in the diagnosis of calciphylaxis. As BMP signaling inhibitors become available, this pathway may serve as a future therapeutic target for calciphylaxis. PMID- 29130993 TI - Extranodal Lymphoproliferative Processes. PMID- 29130992 TI - Genetic Determinants of C1 Inhibitor Deficiency Angioedema Age of Onset. AB - BACKGROUND: In view of the large heterogeneity in the clinical presentation of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), great efforts are being made towards detecting measurable biological determinants of disease severity that can help to improve the management of the disease. Considering the central role that plasma kallikrein plays in bradykinin production, we investigated the contribution of the functional polymorphism KLKB1-428G/A to the disease phenotype. METHODS: We studied 249 C1-INH-HAE patients from 114 European families, and we explored possible associations of C1-INH-HAE clinical features with carriage of KLKB1-428G/A, combined or not with that of the functional F12 46C/T polymorphism. RESULTS: Carriers of the G allele of the KLKB1-428G/A polymorphism exhibited a significantly delayed disease onset (i.e., by 4.1 years [p < 0.001], depending on the zygocity status), while carriers of both the KLKB1 428G/A and the F12-46C/T polymorphism displayed an 8.8-year delay in disease onset (p < 0.001) and a 64% lower probability of needing long-term prophylactic treatment (p = 0.019). CONCLUSIONS: These findings support our initial hypothesis that functional alterations in genes of proteins involved in bradykinin metabolism and function affect the clinical phenotype and possibly contribute to the pathogenesis of C1-INH-HAE. Given that an earlier onset of symptoms is inversely correlated with the subsequent course of the disease and, eventually, the need for long-term prophylaxis, these polymorphisms may be helpful prognostic biomarkers of disease severity. PMID- 29130991 TI - Pre-End-Stage Renal Disease Hemoglobin Variability Predicts Post-End-Stage Renal Disease Mortality in Patients Transitioning to Dialysis. AB - BACKGROUND: Hemoglobin variability (Hb-var) has been associated with increased mortality both in non-dialysis dependent chronic kidney disease (NDD-CKD) and end stage renal disease (ESRD) patients. However, the impact of Hb-var in advanced NDD-CKD on outcomes after dialysis initiation remains unknown. METHODS: Among 11,872 US veterans with advanced NDD-CKD transitioning to dialysis between October 2007 through September 2011, we assessed Hb-var calculated from the residual SD of at least 3 Hb values during the last 6 months before dialysis initiation (prelude period) using within-subject linear regression models, and stratified into quartiles. Outcomes included post-transition all-cause, cardiovascular, and infection-related mortality, assessed in Cox proportional hazards models and adjusted for demographics, comorbidities, length of hospitalization, medications, estimated glomerular filtration rate (eGFR), type of vascular access, Hb parameters (baseline Hb [i.e., intercept] and change in Hb [i.e., slope]), and number of Hb measurements. RESULTS: Higher prelude Hb-var was associated with use of iron and antiplatelet agents, tunneled dialysis catheter use, higher levels of baseline Hb, change in Hb, eGFR, and serum ferritin. After multivariable adjustment, higher prelude Hb-var was associated with higher post ESRD all-cause and infection-related mortality, but not cardiovascular mortality (adjusted hazard ratios [95% CI] for the highest [vs. lowest] quartile of Hb-var, 1.10 [1.02-1.19], 1.28 [0.93-1.75], and 0.93 [0.79-1.10], respectively). CONCLUSIONS: High pre-ESRD Hb-var is associated with higher mortality, particularly from infectious causes rather than cardiovascular causes. Further research is required to clarify the underlying mechanisms and true causal nature of the observed association. PMID- 29130994 TI - Enhancement of Anti-Leukemia Immunity by Leukemia-Derived Exosomes Via Downregulation of TGF-beta1 Expression. AB - BACKGROUND/AIMS: Minimal residual leukemia cells (MRLs) are difficult to eradicate through traditional treatment and therefore remain to be a major threat to the long-term survival of leukemia patients. Tumor-derived exosomes (TEXs), which carry tumor associated antigens (TAA), may be a potential cell-free tumor vaccine for the specific eradication of MRLs. However, TEXs are intended to be less immunogenic due to exosomal TGF-beta1. To further optimize the efficacy of TEX-based vaccines, we investigated whether exosomes from TGF-beta1 silenced leukemia cells (LEXTGF-beta1si) had an increased potential to induce a specific antitumor effect compared with non-modified exosomes. METHODS: Exosomal TGF-beta1 was downregulated via lentiviral shRNA silencing of TGF-beta1 in leukemia cells. The characteristics of LEXTGF-beta1si were determined via electron microscopy, western blot analysis, and flow cytometry. The antitumor effect of LEXTGF-beta1si was evaluated by detecting the properties of LEXTGF-beta1si-pulsed dendritic cells (DCs), CD4+ T-cell proliferation, Th1 cytokine secretion, specific CTL activity, and NK cell function. Moreover, to verify the superiority of LEXTGF beta1si immunization, LEXTGF-beta1si was subcutaneously injected into DBA/2 mice: either followed by tumor challenge or tumor bearing. RESULTS: The lentiviral shRNA silencing of TGF-beta1 in parental leukemia cells successfully downregulated the TGF-beta1 level in leukemia cell derived exosomes (LEX). LEXTGF beta1si was uptaken by DCs and was more potent in promoting DC function by upregulating the surface expression of costimulatory factors and MHC class II molecules, while inducing the secretion of IL-12p70 and TNF-alpha. Furthermore, immunization with LEXTGF-beta1si facilitated CD4+ T-cell proliferation and Th1 cytokine secretion, and stimulated stronger specific cytotoxic lymphocyte (CTL) response and nature killer (NK) cell cytotoxicity more efficiently compared to non-modified LEX. In mice models, immunization with LEXTGF-beta1si resulted in a more potent capability to inhibit tumor growth and to prolong survival, suggesting that LEXTGF-beta1si was more effective in both protective and therapeutic antitumor tests than non-modified LEX. CONCLUSIONS: These data suggested that down-regulation of exosomal TGF-beta1 effectively induced potent anti-tumor immunity. Our strategy of optimizing exosome vaccine may have promising potential for leukemia immunotherapy. PMID- 29130996 TI - Preliminaries. PMID- 29130995 TI - LncRNA UCA1 Promotes Mitochondrial Function of Bladder Cancer via the MiR 195/ARL2 Signaling Pathway. AB - BACKGROUND/AIMS: This study aims to identify whether Urothelial Cancer Associated 1 (UCA1) regulates mitochondrial metabolic reprogramming in bladder cancer, and to explore how UCA1 participates in mitochondrial metabolism by the UCA1/miR 195/ARL2 signaling pathway; these findings may be aid in the development of tumor diagnostic and therapeutic strategies. METHODS: Bladder tissues were obtained from patients. Stable cell lines were constructed, with ectopic expression of UCA1 in UMUC2 cells and knockdown of UCA1 in 5637 cells. The expression levels of UCA1, miR-195, and ARL2 were detected by real-time PCR, western blotting, and immunohistochemistry Cell viability was detected by Cell Counting Kit-8 (CCK8) assay; mitochondrial DNA copy numbers were tested by realtime PCR; ATP level was evaluated by ATP assay kit; mitochondrial membrane potential was analyzed by 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolylcarbocyanine iodide (JC 1) fluorescent probe. miRNAs between UCA1 and ARL2 were predicted by TargetScan and RNAHybrid, and then determined by real-time PCR. Dual-luciferase activity assay and RNA immunoprecipitation (RIP) assay were used to verify the relationship between UCA1 and miR-195. The expression level of ARL2 was silenced by small interfering RNA(siRNA). For in vivo experiments, UCA1-silencing 5637 cells were subcutaneously injected into BALB/C nude mice to evaluate the effects of UCA1 on tumor progression by the regulation of miR-195 and ARL2. RESULTS: We demonstrate here that UCA1 enhances mitochondrial function in bladder cancer cells. UCA1 contributes to ARL2-induced mitochondrial activity, which plays an important role in mitochondrial function. UCA1, as a competing endogenous RNA (ceRNA), regulates mitochondrial function through upregulating ARL2. In this way, it inhibited the miR-195 signaling pathway to enhance mitochondrial function in bladder cancer. Additionally, ARL2 is a direct target of miR-195 and can be repressed by either miR-195 overexpression or UCA1 inhibition. Knockdown of ARL2 was analogous to the inhibition of UCA1 and the upregulation of miR-195. Animal experiments further indicated that UCA1 promoted bladder tumor growth by regulating miR-195 /ARL2. CONCLUSION: These data suggest that UCA1 enhanced mitochondrial function and cell viability through the UCA1/miR-195/ARL2 axis in vitro and in vivo. The elucidation of this signaling network provides a more adequate theoretical basis for understanding the molecular pathology of bladder cancer, and also UCA1 as a potential diagnosis and treatment target for bladder cancer. PMID- 29130997 TI - Non-Diabetic Kidney Disease in Type 2 Diabetic Patients: Prevalence, Clinical Predictors and Outcomes. AB - BACKGROUND/AIMS: Diabetic kidney disease (DKD) is one of the most frequent microvascular complications of diabetes and is the leading cause of end-stage kidney disease worldwide. In patients with diabetes, non-diabetic kidney disease (NDKD) can also occur. NDKD can be either alone or superimposed with the DKD. In this study, we aimed to investigate the utility of kidney biopsy in patients with type 2 diabetes mellitus (T2DM) and the predictability of diagnosing DKD versus NDKD from clinical and laboratory data. We also evaluated the prevalence and etiology of NDKD in patients with T2DM. METHODS: We retrospectively reviewed type 2 diabetic patients who had kidney biopsy in the last 10 years for diagnosing possible NDKD in our center. In all patients kidney biopsies were performed because of atypical clinical features and biopsy samples were examined by light and immunofluorescence microscopy. Clinical parameters, laboratory workup and office blood pressures were recorded for each patient at the time of biopsy. RESULTS: Eight patients were excluded due to missing data. A total of 48 patients (female/male: 26/22 and mean age: 59+/-8 years) were included in the study. According to the biopsy findings, 24 (50%) patients had NDKD alone, 20 (41.7%) had DKD alone and 4 (8.3%) had coexisting DKD and NDKD. The most common NDKD diagnoses were membranous nephropathy (29.2%), tubulointerstitial nephritis (20.8%) and IgA nephropathy (12.5%). There were no significant differences in three groups with respect to the duration of diabetes, proteinuria, hematuria and glycated hemoglobin A1c levels. Diabetic retinopathy (DR) was the most significant finding, which was associated with DKD. Positive and negative predictive values of DR for DKD were 88 and 81%, respectively. CONCLUSION: This study demonstrated a high prevalence of NDKD in patients with T2DM. The absence of DR strongly predicted NDKD. Clinical decision alone can lead to wrong diagnosis and delay in appropriate therapy. Clinicians should consider the kidney biopsy more liberally when there is uncertainty on the exact etiology of the kidney disease. However, prospective multicenter studies are needed to clarify the prognosis and outcomes of patients with diabetics. PMID- 29130999 TI - Selection of Character Coding Method Is Not Phylogenetically Neutral: A Test Case Using Hominoids. AB - The early stages of phylogenetic inference from morphological data involve a sequence of choices about which analytical methods to employ. At each stage, the selection of one method over another can dramatically impact tree inference. Phylogenetic hypotheses are sensitive to decisions relating to which taxa and characters to select for analysis, whether and how to delimit character states, which taxa to use as outgroups, and how to account for character dependence. Using extant hominoids as a test case, I quantify the degree to which phylogenetic inferences are sensitive to the choice of method used to transform continuously scaled variables into categorical traits. I demonstrate that the character coding strategy significantly impacts hypotheses of character state identity and phylogenetic branching patterns. To avoid biasing evolutionary hypotheses, I recommend that continuously scaled characters be analyzed without prior discretization. PMID- 29130998 TI - Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke. AB - BACKGROUND: The present study aims to investigate the protective effects of the SOCS1-JAK2-STAT3 signaling pathway on neurons in a rat model of ischemic stroke. METHODS: Our study was conducted using an ischemic stroke rat model. After the microglia were extracted, 40 neonatal Sprague-Dawley (SD) rats were assigned into the blank, AG490, model and negative control (NC) groups. The neurological function of all the rats was evaluated. Histopathological changes were observed. qRT-PCR and western blotting were applied to measure the expression of genes and proteins in the SOCS1-JAK2-STAT3 signaling pathway and related to apoptosis. The TUNEL assay was conducted to calculate the cellular morphology and apoptosis of neuronal cells. Cell viability was detected using the MTT assay. In addition, immunoassays were used to measure the content of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) as well as the levels of oxidative stress. RESULTS: Compared with the blank group, the model and NC groups showed higher neurological function scores-the cytoplasm of the neurons were cavitated, the organelles were reduced with unclear margins, some of the neurons were necrotic, and apoptosis was increased. In addition, the NC and model groups exhibited decreased cell viability, lower mRNA and protein expression of SOCS1 SOCS3 and bcl-2 and reduced SOD and GSH levels but higher mRNA and protein expression levels of AK2, STAT3,Bax and caspase-3 as well as increased protein expression of P-JAK2, P-STAT3 and activated caspase-3 (c-caspase-3). Moreover, the MDA levels were up-regulated in the NC and model groups. In contrast, opposing trends were found in the AG490 group compared with the NC and model groups. CONCLUSION: These data demonstrate that inhibiting the SOCS1-JAK2-STAT3 signaling pathway can reduce the loss of nerve function and apoptosis of neuronal cells, which provides a new target for the clinical treatment of ischemic stroke. PMID- 29131000 TI - Immunodeficiency-Associated Lymphoproliferative Disorders. PMID- 29131001 TI - Atorvastatin Calcium Inhibits PDGF-betabeta-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRbeta-PI3K-Akt Signaling Cascade. AB - BACKGROUND/AIMS: Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular lesions, such as atherosclerosis and restenosis. PDGF betabeta, an isoform of PDGF (platelet-derived growth factor), has been demonstrated to induce proliferation and migration of VSMCs. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has favorable protective effects on VSMCs. This study examined the effects of atorvastatin calcium on the proliferation and migration of PDGF betabeta-treated VSMCs, as well as its underlying mechanisms. METHODS: MTT assays, Edu imaging, cell cycle analysis, wound healing assays, transwell migration assays, and western blot analysis were performed. RESULTS: Atorvastatin calcium significantly inhibited cell proliferation, DNA synthesis and cell migration of PDGF-betabeta-treated VSMCs. We demonstrated that atorvastatin calcium induced cell cycle arrest in the G0/G1 phase in response to PDGF-betabeta stimulation and decreased the expression of G0/G1-specific regulatory proteins, including proliferating cell nuclear antigen (PCNA), CDK2, cyclin D1, cyclin E and CDK4 in PDGF-betabeta-treated VSMCs. Moreover, pretreatment with atorvastatin calcium inhibited the PDGF-betabeta-treated phosphorylation of PDGFRbeta and Akt, whereas atorvastatin calcium did not affect the phosphorylation of PLC-gamma1 or (ERK) 1/2. CONCLUSION: Our data suggested that atorvastatin calcium inhibited abnormal proliferation and migration of VSMCs through G0/G1 cell cycle arrest and suppression of the PDGFRbeta-Akt signaling cascade. PMID- 29131003 TI - Lymph Nodal Structure and Cytological Patterns. PMID- 29131002 TI - Low Tidal Volume Positive End-Expiratory Pressure versus High Tidal Volume Zero Positive End-Expiratory Pressure and Postoperative Pulmonary Functions in Robot Assisted Laparoscopic Radical Prostatectomy. AB - OBJECTIVE: The aim was to compare the effects of low tidal volume (VT) and moderate positive end-expiratory pressure (PEEP) with high VT and zero end expiratory pressure (ZEEP) on postoperative pulmonary functions and oxygenation in patients undergoing robot-assisted laparoscopic radical prostatectomy. SUBJECTS AND METHODS: Forty-four patients were randomized into low VT-PEEP and high VT-ZEEP groups. The patients were ventilated with a VT of 6 mL/kg and 8 cm H2O PEEP in the low VT-PEEP group and a VT of 10 mL/kg and 0 cm H2O PEEP in the high VT-ZEEP group. Preoperative and postoperative spirometric measurements were done and chest X-rays were evaluated using the radiological atelectasis score (RAS). p < 0.05 was considered statistically significant. RESULTS: The intraoperative and postoperative arterial partial pressure of oxygen and arterial oxygen saturation values were significantly higher in the low VT-PEEP group than in the high VT-ZEEP group. At all times, the arterial-to-alveolar oxygenation gradients were significantly lower in the low VT-PEEP group than in the high VT ZEEP group. Preoperative RAS were similar in both groups, but the postoperative RAS was significantly lower in the low VT-PEEP group (p < 0.001). Forced vital capacity, forced expiratory volume in 1 s, and peak expiratory flow rate recorded postoperatively were significantly lower in the high VT-ZEEP group (p < 0.001). CONCLUSIONS: Postoperative pulmonary functions were less impaired in patients ventilated with a VT of 6 mL/kg and 8 cm H2O PEEP than in patients ventilated with a VT of 10 mL/kg and ZEEP. PMID- 29131004 TI - Metastases. PMID- 29131005 TI - A Review of Anesthetic Effects on Renal Function: Potential Organ Protection. AB - BACKGROUND: Renal protection is a critical concept for anesthesiologists, nephrologists, and urologists, since anesthesia and renal function are highly interconnected and can potentially interfere with one another. Therefore, a comprehensive understanding of anesthetic drugs and their effects on renal function remains fundamental to the success of renal surgeries, especially transplant procedures. Some experimental studies have shown that some anesthetics provide protection against renal ischemia/reperfusion (IR) injury, but there is limited clinical evidence. SUMMARY: The effects of anesthetic drugs on renal failure are particularly important in the context of kidney transplantation, since the conditions of preservation following removal profoundly influence the recovery of organ function. Currently, preservation procedures are typically based on the usage of a cold-storage solution. Some anesthetic drugs induce anti inflammatory, anti-necrotic, and anti-apoptotic effects. A more thorough understanding of anesthetic effects on renal function can present a novel approach for developing organ-protective strategies. The aim of this review is to discuss the effects of different anesthetic drugs on renal function, with particular focus on IR injury. Many studies have demonstrated the organ protective effects of some anesthetic drugs, specifically propofol, which indicate the potential of some anesthetics to introduce novel organ protective targets. This is not surprising, since lipid emulsions are major components of propofol, which accumulating data show provide organ protective effects against IR injury. Key Messages: Thorough understanding of the interaction between anesthetic drugs and renal function remains fundamental to the delivery of safe perioperative care and to optimizing outcomes after renal surgeries, particularly transplant procedures. Anesthetics can be repurposed for organ protection with more information about their effects, especially during transplant procedures. Here, we review the effects of different anesthetic drugs - specifically those that contain lipids in their structure, with special reference to IR injury. PMID- 29131006 TI - Lymph Node Haematopoietic, Histiocytic, Dendritic Proliferations and Other Lymphoid Organs. PMID- 29131007 TI - Proteinase-Activated Receptor-2 Sensitivity of Amplified TRPA1 Activity in Skeletal Muscle Afferent Nerves and Exercise Pressor Reflex in Rats with Femoral Artery Occlusion. AB - BACKGROUND/AIMS: Limb ischemia occurs in peripheral artery disease (PAD). Sympathetic nerve activity (SNA) that regulates blood flow directed to the ischemic limb is exaggerated during exercise in this disease, and transient receptor potential channel A1 (TRPA1) in thin-fiber muscle afferents contributes to the amplified sympathetic response. The purpose of the present study was to determine the role of proteinase-activated receptor-2 (PAR2) in regulating abnormal TRPA1 function and the TRPA1-mediated sympathetic component of the exercise pressor reflex. METHODS: A rat model of femoral artery ligation was employed to study PAD. Dorsal root ganglion (DRG) tissues were obtained to examine the protein levels of PAR2 using western blot analysis. Current responses induced by activation of TRPA1 in skeletal muscle DRG neurons were characterized using whole-cell patch clamp methods. The blood pressure response to static exercise (i.e., muscle contraction) and stimulation of TRPA1 was also examined after a blockade of PAR2. RESULTS: The expression of PAR2 was amplified in DRG neurons of the occluded limb, and PAR2 activation with SL-NH2 (a PAR2 agonist) increased the amplitude of TRPA1 currents to a greater degree in DRG neurons of the occluded limb. Moreover, FSLLRY-NH2 (a PAR antagonist) injected into the arterial blood supply of the hindlimb muscles significantly attenuated the pressor response to muscle contraction and TRPA1 stimulation in rats with occluded limbs. CONCLUSIONS: The PAR2 signal in muscle sensory nerves contributes to the amplified exercise pressor reflex via TRPA1 mechanisms in rats with femoral artery ligation. These findings provide a pathophysiological basis for autonomic responses during exercise activity in PAD, which may potentially aid in the development of therapeutic approaches for improvement of blood flow in this disease. PMID- 29131008 TI - Elevated FOXC2 Expression Promotes Invasion of HCC Cell Lines and is Associated with Poor Prognosis in Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: Increasing evidence has indicated that Forkhead box protein C2 (FOXC2) plays an important role in carcinogenesis. However, the expression and the role of FOXC2 in hepatocellular carcinoma (HCC) have not been extensively studied. METHODS: FOXC2 expression was analyzed by quantitative real-time polymerase chain reaction, Western blot analysis and immunohistochemistry in HCC tissue and cells. The relationship between FOXC2 expression and patient clinical significance and survival were assessed by Pearson's correlation and Kaplan-Meier analysis, respectively. Cell proliferation assays, colony formation assays, flow cytometric analysis and Transwell assays were employed to measure the effects of FOXC2 on HCC cells in vitro. RESULTS: The expression of FOXC2 was increased in HCC tissue, and high FOXC2 expression was associated with worse patient survival. Knockdown of FOXC2 inhibited HCC cell growth, migration, and invasion in vitro, as well as tumor growth. Furthermore, we found that activation of AKT-mediated MMP-2 and MMP-9 was involved in FOXC2 promoting an aggressive phenotype. CONCLUSIONS: Taken together, these findings demonstrate that FOXC2 is upregulated in HCC tissue and is associated with tumor size, vascular invasion and advanced TNM stage. Further investigation suggested that FOXC2 may play a vital role in promoting proliferation and invasion in HCC and serves as a novel therapeutic target in HCC. PMID- 29131009 TI - Effects of MicroRNA-499 On the Inflammatory Damage of Endothelial Cells During Coronary Artery Disease Via the Targeting of PDCD4 Through the NF-Kappabeta/TNF alpha Signaling Pathway. AB - BACKGROUND/AIMS: This study aimed to analyze the impact of microRNA-499 (miR-499) on the inflammatory damage of endothelial cells during coronary artery disease (CAD) via the targeting of PDCD4 through the NF-kB/ TNF-alpha signaling pathway. METHODS: A total of 216 CAD patients (CAD group) and 90 healthy people (normal group) were enrolled in our study. Endothelial cells were collected and assigned into normal, OX-LDL, negative control (NC), miR-499 inhibitor, miR-499 mimic, PDCD4 siRNA, and miR-499 inhibitor + PDCD4 siRNA groups. The qRT-PCR and western blotting were performed to detect the mRNA and protein expression levels of PDCD4 and miR-499. The MTT assay was performed to determine cell viability, ELISA was performed to determine the expression levels of inflammatory factors, and flow cytometry assay to evaluate cell apoptosis. RESULTS: Increased miR-499 expression and decreased PDCD4 expression in the plasma were observed in the CAD group compared with the normal group, demonstrating a negative correlation between miR 499 and PDCD4. Compared to the normal and miR-499 inhibitor groups, the survival rate of cells and PDCD4 expression were decreased; and the expressions of miR 499, IL-6, IL-8, IL-1beta, TNF-alpha, NF-kB, VCAM-1, ICAM-1 and MCP-1 and the apoptosis rate were all elevated in the OX-LDL, NC, miR-499 mimic, PDCD4 siRNA and miR-499 inhibitor + PDCD4 siRNA groups. Compared to the OX-LDL, NC and miR 499 inhibitor + PDCD4 siRNA groups, PDCD4 expression and the survival rate of cells were increased; and the IL-6, IL-8, IL-1beta, TNF-alpha, NF-kappaB, VCAM-1, ICAM-1 and MCP-1 expression levels and the apoptosis rate were all reduced in the miR-499 inhibitor group. In the PDCD4 siRNA group, PDCD4 expression and the survival rate of cells were lower, and the expression levels of IL-6, IL-8, IL 1beta, TNF-alpha, NF-kappaB, VCAM-1, ICAM-1 and MCP-1 and the apoptosis rate were all higher compared with the miR-499 mimic group. In the miR-499 inhibitor + PDCD4 siRNA group, PDCD4 expression and the survival rate of cells were higher, and the expression levels of IL-6, IL-8, IL-1beta, TNF-alpha, NF-kappaB, VCAM-1, ICAM-1, and MCP-1 and the apoptosis rate were all lower than those in the PDCD4 siRNA group. CONCLUSION: Down-regulated miR-499 expression increased PDCD4 expression and protected endothelial cells from inflammatory damage during CAD by inhibiting the NF-kappaB/TNF-alpha signaling pathway. PMID- 29131010 TI - Blockade of Experimental Multiple Sclerosis by Inhibition of the Acid Sphingomyelinase/Ceramide System. AB - BACKGROUND: Multiple sclerosis (MS) is a severe and common autoimmune disorder of the central nervous system. Despite the availability of several novel treatment options, the disease is still poorly controlled, since the pathophysiological mechanisms are not fully understood. METHODS: We tested the role of the acid sphingomyelinase/ceramide system in a model of MS, i.e. experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin-oligodendrocyte glycoprotein and the development of the disease was analyzed by histology, immunological tests and clinical assessment in wildtype and acid sphingomyelinase (Asm)-deficient mice. RESULTS: Genetic deficiency of acid sphingomyelinase (Asm) protected against clinical symptoms in EAE and markedly attenuated the characteristic detrimental neuroinflammatory response. T lymphocyte adhesion, integrity of tight junctions, blood-brain barrier disruption and subsequent intracerebral infiltration of inflammatory cells were blocked in Asm-deficient mice after immunization. This resulted in an almost complete block of the development of disease symptoms in these mice, while wildtype mice showed severe neurological symptoms typical for EAE. CONCLUSION: Activation of the Asm/ceramide system is a central step for the development of EAE. Our findings may serve to identify novel therapeutic strategies for MS patients. PMID- 29131011 TI - Dizziness and the Acute Vestibular Syndrome at the Emergency Department: A Population-Based Descriptive Study. AB - BACKGROUND: Dizziness is a common occurrence witnessed at emergency departments (EDs). This study aims to describe the epidemiology and management of dizzy patients with and without an acute vestibular syndrome (AVS) in the ED at Umea University Hospital. METHODS: A total of n = 2,126 ED dizziness visits during 3 years were identified. Data were obtained through retrospective review of medical records. Cases were stratified based on presentation, including AVS and neurological deficits. The outcomes analyzed included cerebrovascular causes of dizziness. A Poisson distribution was assumed when calculating incidence CIs. RESULTS: Dizziness accounted for 2.1% of all ED visits, incidence 477/100,000 inhabitants (95% CI 457-498). Among dizzy patients, 19.2% had an AVS, incidence 92/100,000 inhabitants (95% CI 74-113). Top medical diagnostic groups were otovestibular (15.1%), cardiovascular (8.7%) and neurological diseases (7.7%), including stroke and transitory ischemic attack (4.8%). Cerebrovascular causes of dizziness were more common among those with an AVS (10.0%) vs. those without (3.6%), p < 0.01. CONCLUSION: The risk for cerebrovascular causes of dizziness, although low in an unselected cohort, increases with the presence of neurological signs and an AVS. These population-based data may be useful when planning and implementing dizziness and AVS management algorithms at EDs. PMID- 29131013 TI - A New Baltic Population-Specific Human Genetic Marker in the PMCA4 Gene. AB - OBJECTIVES: The PMCA gene family consists of 4 genes and at least 21 splice variants; among these, the Ca2+ ATPase 4 (PMCA4) gene encodes a plasma membrane protein abundantly expressed in several tissues, including the kidney, heart, and sperm. Knockout of PMCA4 causes infertility due to immotile sperm in mouse models. We therefore investigated variants in this gene for potential association with infertility in groups of Estonian (n = 191) and Latvian (n = 92) men with reduced sperm motility. METHODS: All exons, exon-intron boundaries, 5' and 3' untranslated regions, and the promoter region of the PMCA4 gene were analysed by direct sequencing for a group of Estonian infertile men. Genotyping of guanine and adenine alleles of rs147729934 was performed, using a custom-designed TaqMan(r) probe for a group of Latvian infertile men as well as additional groups from Latvia and several groups of people with proven ethnicity from the Baltic region. RESULTS: Although we did not identify any significant associations between variants in the gene and infertility, our results indicated that in all studied Latvian and Estonian groups the adenine allele of the variant rs147729934 was present at a higher frequency than expected. Analysis of additional samples indicated that the adenine allele of rs147729934 likely originated once in the modern-day Baltic or western Russia area, as the frequency of the minor adenine allele observed in this region is remarkably higher than that in the general European population. CONCLUSIONS: Our results revealed no significant difference in frequencies of genetic variants in PMCA4 gene between men with normal and those with reduced sperm motility. The adenine allele of the variant rs147729934 is potentially an informative tool for future population studies concerning ancient Baltic and Finno-Ugric history. PMID- 29131012 TI - Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer. AB - BACKGROUND/AIMS: Our study aims to investigate the role, effect and mechanisms of ESRP1 (epithelial splicing regulatory protein 1) in epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer (EOC). METHODS: Microarray and immunohistochemical analysis of ESRP1 expression were performed in EOC cases. The correlations between ESRP1 expression and clinical factors on EOC were assessed. Lentivirus-mediated RNA interference and EGFP vector which contains ESRP1 gene were used to down-regulate and up-regulate ESRP1 expression in human EOC cell lines. Roles of ESRP1 in cell growth, migration and invasion of EOC cells were also measured by Cell Counting Kit-8 and Transwell systems in vitro and by a nude mice intraperitoneal transplantation model in vivo. RESULTS: By the analysis of Gene Expression Omnibus (GEO) (p<0.05) and our own microarray data (p<0.001), ESRP1 expression in EOC was significantly different from normal ovarian tissue. It was abundant in the nuclei of cancer cells and in malignant lesions. However, it was weakly expressed or negative in both normal and benign lesions. High ESRP1 expression in EOC was associated with poor clinical outcomes. Decreased ESRP1 expression significantly increased cell migration and invasion both in vivo and in vitro. Snail strongly repressed ESRP1 transcription through binding to the ESRP1 promoter in EOC cells. Furthermore, ESRP1 regulated the expression of CD44s. Down-regulated ESRP1 resulted in an isoform switching from CD44v to CD44s, which modulated epithelial-mesenchymal transition (EMT) program in EOC. Up regulatin of ESRP1 was detected in mesenchymal to epithelial transition (MET) in vivo. CONCLUSIONS: ESRP1 regulates CD44 alternative splicing during the EMT process which plays an important role in EOC carcinogenesis. In addition, ESRP1 is associated with disease prognosis in EOC. PMID- 29131014 TI - Early Nutrition and Growth until the Corrected Age of 2 Years in Extremely Preterm Infants. AB - BACKGROUND: Extremely preterm birth is associated with a high risk of extrauterine growth retardation, which has been linked with adverse developmental outcomes. OBJECTIVE: We investigated whether nutritional management during the first 7 days of life affects growth patterns until the corrected age of 2 years in extremely preterm infants. STUDY DESIGN: A retrospective study of 78 extremely preterm (<28 weeks' gestation) neonates was conducted. Data regarding parenteral and enteral intake of energy, protein, lipids, and carbohydrates during the first 7 days of life were collected from patient records. The outcome measures included weight, height, and head circumference with Z scores at term-equivalent age and the corrected ages of 1 and 2 years. Analyses were performed with hierarchical linear mixed models. RESULTS: Nutritional intake during the first week of life did not reach the current recommendations. The total energy intake during the first 7 days of life was statistically significantly associated with weight, length, and head circumference until the corrected age of 2 years after adjusting for potential confounding factors. Individual macronutrient intake displayed no association with growth patterns. CONCLUSIONS: Energy intake during the first 7 days of life is associated with growth until the corrected age of 2 years. These results provide support for the aggressive early nutritional management of extremely preterm infants. PMID- 29131015 TI - Therapeutic Response to Paroxetine in Major Depressive Disorder Predicted by DNA Methylation. AB - BACKGROUND: Antidepressants have variable therapeutic effects, depending on genetic and environmental factors. Approximately 30% of major depressive disorder (MDD) patients do not respond significantly to antidepressants such as paroxetine, a selective serotonin reuptake inhibitor (SSRI). However, the biological mechanisms behind this phenomenon are mostly unknown. Here, we examined the role of patients' epigenetic background in SSRI efficacy. METHODS: Genome-wide DNA methylation analysis of the peripheral blood of Japanese MDD patients was performed by using the Infinium HumanMethylation450 BeadChip. RESULTS: We compared the results of the 10 patients who best responded to paroxetine (BR) with the 10 worst responders (WR), and found 623 CpG sites with a >10% difference in DNA methylation level. Among them, 218 sites were nominally significant between BR and WR (p < 0.05), and 2 sites (cg00594917 and cg07260927) were significantly different after false discovery rate (FDR) correction (q < 0.05). The methylation difference was greatest at cg00594917, located in the first exon of the PPFIA4 gene, which codes for liprin-alpha (p = 0.00012). Hierarchical cluster analysis of 23 CpG sites in the PPFIA4 gene distinguished BR and WR, except for 1 WR patient. The cg07260927 site was located in the 5'UTR of the heparin sulfate-glucosamine 3-sulfotransferase 1 (HS3ST1) gene (p = 0.00013). Hierarchical cluster analysis of 28 CpG sites in HS3ST1 distinguished BR and WR, except for 1 WR and 2 BR patients. CONCLUSION: Our results suggest that patients' DNA methylation profile at specific genes such as PPFIA4 and HS3ST1 is associated with individual variations in therapeutic responses to paroxetine. PMID- 29131016 TI - Focal Transplantation of Aberrant Glial Cells Carrying the SOD1G93A Mutation into Rat Spinal Cord Induces Extensive Gliosis. AB - OBJECTIVE: We aimed to determine the potential of aberrant glial cells (AbAs) isolated from the spinal cord of adult SOD1G93A symptomatic rats to induce gliosis and neuronal damage following focal transplantation into the lumbar spinal cord of wild-type rats. METHODS: AbAs were obtained from the spinal cords of SOD1G93A symptomatic rats. One hundred thousand cells were injected using a glass micropipette into the lumbar spinal cords (L3-L5) of syngeneic wild-type adult rats. Equal volumes of culture medium or wild-type neonatal microglia were used as controls. Seven days after transplantation, immunohistochemistry analysis was carried out using astrocytic and microglia cell markers. Transplanted SOD1G93A AbAs were recognized by specific antibodies to human SOD1 (hSOD1) or misfolded human SOD1. RESULTS: Seven days after transplantation, AbAs were mainly detected in the medial region of the lumbar ventral horn as a well-limited cell cluster formed at the site of injection by their immunoreactivity to either misfolded SOD1 or normally folded hSOD1. Compared with controls, transplanted AbAs were surrounded by marked microgliosis and reactive astrocytes. Marked microgliosis was observed to extend bilaterally up to the cervical cord. Motor neurons close to AbA transplants were surrounded by activated glial cells and displayed ubiquitin aggregation. CONCLUSIONS: AbAs bearing mutant SOD1G93A have the potential to induce neuroinflammation along the spinal cord and incipient damage to the motor neurons. The emergence of AbAs during amyotrophic lateral sclerosis pathogenesis may therefore be a mechanism to boost neuroinflammation and spread motor neuron damage along the neuroaxis. PMID- 29131017 TI - Initial Presentation of Type 2 Diabetes in Adolescents Predicts Durability of Successful Treatment with Metformin Monotherapy: Insights from the Pediatric Diabetes Consortium T2D Registry. AB - BACKGROUND/AIMS: Many adolescents with type 2 diabetes (T2D) have rapid deterioration of glycemic control on metformin monotherapy within 2 years of diagnosis. METHODS: Enrollment data from the Pediatric Diabetes Consortium T2D Registry were used to categorize 276 youth with a T2D duration >=2 years into two groups: (1) participants with HbA1c <7.5% on metformin monotherapy (group 1, n = 75) and (2) participants treated with insulin +/- metformin (group 2, n = 201). The characteristics of the groups were compared. RESULTS: At enrollment, groups 1 and 2 did not differ in age (16.2 vs. 16.8 years) or BMI percentile (99 vs. 98%); group 2 had higher HbA1c (9.9% [85 mmol/mol] vs. 5.9% [41 mmol/mol], p < 0.001). Lower HbA1c and metformin monotherapy at diagnosis were associated with a greater likelihood of adequate control with metformin alone (p < 0.001). In multivariable analysis, HbA1c at diagnosis (p = 0.001) and diabetes duration (p = 0.009) were associated with adequate control on metformin. The HbA1c trajectory after diagnosis was worse in group 2. CONCLUSION: Durable metabolic control of T2D with metformin monotherapy is most likely in youth presenting with lower HbA1c and with shorter diabetes duration, independent of age, race-ethnicity, and BMI. Elevated HbA1c levels in those on insulin therapy highlight the importance of early diagnosis and a better understanding of glycemic control barriers. PMID- 29131018 TI - Next-Generation Sequencing in Diagnostic Pathology. AB - Interrogation of tissue informs on patient management through delivery of a diagnosis together with associated clinically relevant data. The diagnostic pathologist will usually evaluate the morphological appearances of a tissue sample and, occasionally, the pattern of expression of a limited number of biomarkers. Recent developments in sequencing technology mean that DNA and RNA from tissue samples can now be interrogated in great detail. These new technologies, collectively known as next-generation sequencing (NGS), generate huge amounts of data which can be used to support patient management. In order to maximize the utility of tissue interrogation, the molecular data need to be interpreted and integrated with the morphological data. However, in order to interpret the molecular data, the pathologist must understand the utility and the limitations of NGS data. In this review, the principles behind NGS technologies are described. In addition, the caveats in the interpretation of the data are discussed, and a scheme is presented to "classify" the types of data which are generated. Finally, a glossary of new terminology is included to help pathologists become familiar with the lexicon of NGS-derived molecular data. PMID- 29131019 TI - Utility of Autonomic Function Tests to Differentiate Dementia with Lewy Bodies and Parkinson Disease with Dementia from Alzheimer Disease. AB - OBJECTIVE: We studied autonomic disturbance in patients with dementia with Lewy bodies (DLB), Parkinson disease with dementia (PDD), Alzheimer disease (AD), to determine whether autonomic function tests can be used to distinguish these disorders. METHODS: Autonomic function was tested in 56 patients with DLB, 37 patients with PDD, and 59 patients with AD by using the sympathetic skin response, coefficient of variation in R-R interval, the head-up tilt test, serum norepinephrine concentration, and 123I-meta-iodobenzylguanidine cardiac scintigraphy. Symptoms of autonomic dysfunction, such as constipation, urinary symptoms, and orthostatic hypotension, were also noted. RESULTS: The groups did not differ on baseline characteristics other than those associated with Parkinsonism and dementia. All patients with DLB and PDD had some dysautonomia, whereas rates were much lower for patients with AD (19%). Significantly more DLB and PDD patients than AD patients showed abnormalities on autonomic function tests. CONCLUSIONS: Autonomic function tests might be quite useful to distinguish DLB and PDD from AD. PMID- 29131020 TI - Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer. AB - BACKGROUND/AIMS: Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. METHODS: We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. RESULTS: CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. CONCLUSION: AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors. PMID- 29131021 TI - A Novel Color Fluorescence Navigation System for Intraoperative Transcutaneous Lymphatic Mapping and Resection of Sentinel Lymph Nodes in Breast Cancer: Comparison with the Combination of Gamma Probe Scanning and Visible Dye Methods. AB - BACKGROUND: This study evaluated the clinical efficacy of a novel imaging system (HyperEye Medical System [HEMS]; Mizuho Corp., Tokyo, Japan) that uses the near infrared (NIR) fluorescence of indocyanine green to analyze sentinel lymph node (SLN) biopsies for the staging of breast cancer. METHODS: This study enrolled 91 patients with histologically confirmed breast cancer that was clinically node negative with a tumor size <3 cm. We compared SLN identification rates between HEMS and conventional methods (gamma probe scanning using a colloidal radioisotope [RI] and a blue dye method) by analyzing the relationships of lymphatic to axillary lesions and SLNs. RESULTS: The identification rate of SLNs was 100% using HEMS, 97.8% using the RI method, and 95.6% using the blue dye method. Two types of lymphatic pathway (LP) were detected in 39 patients (42.9%) and also clearly identified using HEMS-captured color and NIR fluorescence. The incidence of two or more SLNs was significantly higher in patients with a two route LP to the axilla group than in those with only one route (p < 0.001; 43.6 vs. 9.6%). CONCLUSIONS: The HEMS NIR fluorescence color imaging method is a promising potential modality for higher-level identification of SLNs than a standard combination of the RI and blue dye methods. PMID- 29131022 TI - An Echocardiographic Screening Program Helps to Identify Pulmonary Hypertension in Extremely Low Birthweight Infants with and without Bronchopulmonary Dysplasia: A Single-Center Experience. AB - BACKGROUND: Pulmonary hypertension (PH) affects 1 in 6 infants with a birthweight <1,000 g (extremely low birthweight; ELBW) and is frequently associated with bronchopulmonary dysplasia (BPD). If untreated, the mortality rates of the disease are high. OBJECTIVES: The aim of this study was to characterize risk factors for PH in ELBW infants and to describe the timing of onset of the disease by setting up a screening program. METHODS: ELBW infants treated at the Department of Neonatology (level III neonatal intensive care unit at the University of Cologne Medical Centre, Germany) between January 2010 and March 2015 were included. Echocardiography screening for PH was performed either before discharge or if BPD was diagnosed. Additionally, infants had at least 1 echocardiographic scan after discharge. Survival with PH, age at diagnosis of PH, and risk factors associated with PH were assessed. RESULTS: In total, 34/188 (18%) infants had PH. Of these, 14 (41%) were identified after discharge. Another 11 (32%) were diagnosed with PH without suffering from moderate or severe BPD. The risk factors for diagnosis of PH were moderate (odds ratio, OR 4 [2-8]) or severe BPD (OR 13 [2-71]), prolonged rupture of membranes >7 days (OR 5 [1-19]), and birthweight below the 3rd percentile (OR 3 [1-9]). All infants with PH before discharge and 50% diagnosed after discharge were treated with sildenafil (2.0 mg/kg/day). PH resolved and sildenafil was discontinued in all patients after a median duration of 13 months (IQR 8-20). CONCLUSIONS: An echocardiographic screening program may help to identify infants with PH. Examinations should include all ELBW infants irrespective of the presence of BPD and be continued after discharge. PMID- 29131023 TI - Evaluation of Serum Nidogen-2 as a Screening and Diagnostic Tool for Ovarian Cancer. AB - INTRODUCTION: Ovarian cancer is a relatively common occurrence with the formation of a tumour in the ovaries and is the leading cause of death in the gynecological field. Despite enormous efforts, there are no successful screening methods developed until now to decrease mortality in this regard. AIM: To evaluate nidogen-2 as a new tumour marker combined with higher sensitivity, specificity and accuracy than carbohydrate antigen (CA-125) and Doppler ultrasound to improve early diagnosis of ovarian cancer. PATIENTS AND METHODS: One hundred and forty four qualified women with a preliminary diagnosis of adnexal mass were subjected to history, examination, transvaginal Doppler ultrasound and Quantitative assessment of serum level of CA-125 and nidogen-2 followed by the resection of the masses, which were sent for histopathological examination. RESULTS: One hundred and sixteen cases were benign and 28 cases were malignant. The surgical procedures ranged from limited resection to radical hysterectomy. There was a highly significant correlation between both serum nidogen-2 and CA-125 and the results of histopathological examination (p = 0.0001). Serum nidogen-2 had 91.6% sensitivity, 62% specificity, 37.1% positive predictive value, 97.9% negative predictive value and 68% accuracy (p < 0.05). CONCLUSION: Nidogen-2 is a new promising ovarian malignancy biomarker that correlates closely with ultrasound and CA125. It did improve the accuracy of diagnosis, but further studies are needed. PMID- 29131024 TI - Evaluation of Anastomotic Leak after Esophagectomy for Esophageal Cancer: Typical Time Point of Occurrence, Mode of Diagnosis, Value of Routine Radiocontrast Agent Studies and Therapeutic Options. AB - BACKGROUND: Data on the typical time point of occurrence of anastomotic leak (AL) after esophagectomy for esophageal cancer are currently scarce. Therefore, the usefulness of routine radiocontrast agent studies (RRCS) for testing proper healing of the anastomosis after esophagectomy remains unclear. Furthermore, preferred available tools to diagnose postoperative AL and therapeutic options are still under debate. METHODS: We present a retrospective analysis of 328 consecutive patients who underwent esophagectomy for esophageal cancer between 2005 and 2015. A RRCS has been performed to date in our center on the fifth postoperative day (POD), before returning to normal oral intake. RESULTS: In total, 49 of 328 patients developed AL after esophagectomy (15%). A total of 11 patients (23%) developed AL before the RRCS and 34 patients (69%) after an unremarkable RRCS; and 4 patients (8%) with AL were diagnosed by RRCS, resulting in overall sensitivity of 16%. The median time point of occurrence of AL was POD 9, the majority of AL (84%) occurred between POD 1 and 19. Computed tomography led to the diagnosis of AL in 41% of patients. The most frequent therapy of AL was stenting in 47% of patients. Endoscopic vacuum therapy was used in 4 patients. CONCLUSIONS: The majority of AL occurred within the first 3 weeks after esophagectomy without a typical time point. In our series, RRCS on the fifth POD had a low sensitivity of 16%. Therefore, standardized RRCS and fasting till the examination cannot be generally recommended. In case of clinical suspicion of AL, computed tomography of the chest and abdomen with oral contrast agent should be performed, followed by endoscopy. Endoscopic stent placement remains the standard therapy of AL in our center. Endoscopic vacuum therapy evolves as it is an interesting alternative therapeutic option and can be combined with stenting in selected cases. PMID- 29131025 TI - TMEM106a is a Novel Tumor Suppressor in Human Renal Cancer. AB - BACKGROUND/AIMS: In recent years the diagnosis and management of renal cancer has changed greatly, although the mechanism is still elusive. TMEM106a is a conserved type II transmembrane protein which is a key factor to regulate macrophage activation. Its inactivation in gastric cancer is frequently observed to be associated with poor prognosis. The role of TMEM106a in renal cancer remained unclear. METHODS: TMEM106a expression profiling was performed in a panel of renal cancer cell lines and primary renal tissue cells. Then TMEM106a was overexpressed by a viral system in a renal cancer cell line with low level of TMEM106a. This stable cell line was assessed in multiple cell growth and migration assays. The results from TMEM106a overexpressing cell line were then confirmed with primary renal cells by siRNA knockdown of TMEM106a. RESULTS: TMEM106a expression level was reduced in renal cancer cells compared to normal primary renal cells. Restoration of TMEM106a expression in TMEM106a-low renal cancer cells resulted in attenuated proliferation, reduced cell migration and enhanced caspase 3 dependent apoptosis compared to control cells. TMEM106a knockdown in primary renal cells led to increased colony formation compared to the control cells with scrambled siRNA transfection. CONCLUSION: TMEM106a is a novel tumor suppressor in renal cancer. PMID- 29131026 TI - TRPML1 Participates in the Progression of Alzheimer's Disease by Regulating the PPARgamma/AMPK/Mtor Signalling Pathway. AB - BACKGROUND: TRPML1 is reported to be involved in the pathogenesis of Alzheimer's disease (AD) by regulating autophagy; however, the underlying mechanism is not completely clear. METHODS: We developed an APP/PS1 transgenic animal model that presents with AD. TRPML1 was also overexpressed in these mice. Protein expression levels were determined by Western blot. Morris water maze (MWM) and recognition tasks were performed to characterize cognitive ability. TUNEL assays were analysed for the detection of neuronal apoptosis. Primary neurons were isolated and treated with the vehicle, Abeta1-42 or Abeta1-42 + mTOR activator, as well as infected with the recombinant adenovirus TRPML1 overexpression vector in vitro. Cell viability was measured by the MTS assay, and lysosomal Ca2+ was also measured. RESULTS: In the APP/PS1 transgenic mice, TRPML1 was downregulated, the PPARgamma/AMPK signalling pathway was activated, the mTOR/S6K signalling pathway was suppressed, and autophagic lysosome reformation (ALR)-related proteins were upregulated. TRPML1 overexpression or treatment with PPARgamma and AMPK inhibitors or an mTOR activator reduced the expression levels of ALR-related proteins, rescued the memory and recognition impairments and attenuated neuronal apoptosis in mice with the APP/PS1 transgenes. In vitro experiments showed that TRPML1 overexpression or treatment with the mTOR activator propranolol attenuated the Abeta1-42-suppressed cell viability and the Abeta1-42-decreased lysosomal [Ca2+] ion concentration in primary neurons. TRPML1 overexpression or treatment with the mTOR activator propranolol also attenuated the Abeta1-42-inhibited mTOR/S6K signalling pathway and the Abeta1-42-induced ALR-related protein expression levels. CONCLUSION: TRPML1 is involved in the pathogenesis of AD by regulating autophagy at least in part through the PPARgamma/AMPK/mTOR signallingpathway. PMID- 29131027 TI - MicroRNA-194 Regulates Lipopolysaccharide-Induced Cell Viability by Inactivation of Nuclear Factor-kappa B Pathway. AB - The present study explored the functional role of microRNA (miR)-194 in lipopolysaccharide (LPS) induced lung cell injury, along with the underlying mechanisms and to reveal the potential role in infantile pneumonia. Human fibroblasts WI38 cells were transfected with miR-194 mimic or miR-194 inhibitor, and the transfection efficiency was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Thereafter, the cells were treated with or without LPS, and then cell viability, cell apoptosis and mRNA and protein expressions of key proteins of nuclear factor kappa B (NF-kappaB) pathway including inhibitor of NF-kappaB (IkappaB) alpha, p-65, and B-cell CLL/lymphoma (Bcl) 3 were analyzed. Results showed that overexpression and suppression of miR 194 was effective. Administration of LPS significantly decreased the cell viability and statistically promoted the percentages of apoptotic cells and increased the mRNA and protein expressions of p-65 and Bcl-3 but downregulated IkappaBalpha compared to the control group (P < 0.05 or P < 0.01). LPS in combination with miR-194 suppression further enhanced the effects of LPS on cell viability and cell apoptosis compared to the LPS group (P < 0.05). In contrast, LPS in combination with miR-194 overexpression observably reversed the effects of LPS on cell viability, cell apoptosis and mRNA and protein expressions of the key proteins (P < 0.05 or P < 0.01). In conclusion, miR-194 increases the LPS-induced the inhibition of cell viability and increasing of the cell apoptosis by inhibition of NF-kappaB pathway in WI38 cells. MiR-194 might be a potential targeted therapy for treatment of infantile pneumonia. PMID- 29131028 TI - MiR-142-5p Suppresses Tumorigenesis by Targeting PIK3CA in Non-Small Cell Lung Cancer. AB - BACKGROUND/AIMS: Numerous studies have demonstrated that aberrant microRNA (miRNA) expression is involved in human disease including cancer. To date, the potential miRNAs regulating lung cancer growth and progression are not fully identified yet. METHODS: In this study, the expression of miR-142-5p was measured in non-small cell lung cancer tissue and cell lines by qRT-PCR. The functional assays including the cell viability, colony formation, cell migration and invasion were performed in miR-142-5p mimic or inhibitor transfected cell lines (in vitro) and the cell tumorigenesis in nude mice (in vivo). The fluorescence ratios of cell viability were recorded using a multi-plate reader (Synergy 2, BioTek, Winooski, VT, USA) and the colonies were counted using an ELIspot Bioreader 5000 (BIO-SYS, Karben, GE). RESULTS: MiR-142-5p was significantly downregulated in non-small cell lung cancer tissue and cell lines compared to normal human lung tissues. Overexpression of miR-142-5p resulted in decreased expression of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) at both mRNA and protein levels. We found that miR-142-5p overexpression markedly suppressed cell proliferation in vitro and in vivo. Conversely, inhibition of miR-142-5p promoted lung cancer growth. Mechanistic studies showed that PIK3CA was a potential target of miR-142-5p and it mediated reduction of PIK3CA resulting in suppression of PI3K/Akt pathway. CONCLUSIONS: Our results demonstrate that miR-142-5p functions as a growth suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA in non-small cell lung cancer. PMID- 29131029 TI - Rapid Induction of Osteogenic Markers in Mesenchymal Stem Cells by Adipose Derived Stromal Vascular Fraction Cells. AB - BACKGROUND/AIMS: Stromal vascular fraction (SVF) cells are a mixed cell population, and their regenerative capacity has been validated in various therapeutic models. The purpose of this study was to investigate the regenerative mechanisms utilized by implanted SVF cells. Using an in vitro co-culture system, we sought to determine whether SVF implantation into impaired tissue affects endogenous mesenchymal stem cell (MSC) differentiation; MSCs can differentiate into a variety of cell types, and they have a strong regenerative capacity despite their low numbers in impaired tissue. METHODS: Adipose-derived SVF cells obtained from four donors were co-cultured with bone marrow-derived MSCs, and the differential expression of osteogenic markers and osteogenic differentiation inducers over time was analyzed in mono-cultured MSCs and MSCs co-cultured with SVF cells. RESULTS: The co-cultivation of MSCs with SVF cells significantly and mutually induced the expression of osteogenic-specific markers via paracrine and/or autocrine regulation but did not induce adipocyte, chondrocyte or myoblast marker expression. More surprisingly, subsequent osteogenesis and/or comparable effects were rapidly induced within 48 h. CONCLUSION: To the best of our knowledge, this is the first study in which osteogenesis and/or comparable effects were rapidly induced in bone marrow-derived MSCs and adipose-derived SVF cells through co-cultivation. Our findings suggest that the positive effects of SVF implantation into impaired bone may be attributed to the rapid induction of MSC osteogenesis, and the transplantation of co-cultured and preconditioned SVF cells and/or MSCs may be more effective than the transplantation of untreated cells for the treatment of bone defects. PMID- 29131031 TI - International College of Psychosomatic Medicine News. PMID- 29131030 TI - N-Cadherin-Mediated Activation of PI3K/Akt-GSK-3beta Signaling Attenuates Nucleus Pulposus Cell Apoptosis Under High-Magnitude Compression. AB - BACKGROUND/AIMS: Mechanical overloading-induced nucleus pulposus (NP) apoptosis plays an important role in the pathogenesis of intervertebral disc degeneration. N-cadherin (N-CDH)-mediated signaling preserves normal NP cell phenotype. This study aims to investigate the effects of N-CDH on NP cell apoptosis under high magnitude compression and the underlying mechanism behind this process. METHODS: Rat NP cells seeded on scaffold were perfusion-cultured using a self-developed perfusion bioreactor for 5 days and experienced different magnitudes (2% and 20% compressive deformation, respectively) of compression at a frequency of 1.0 Hz for 4 hours once per day. The un-loaded NP cells were used as controls. Lentivirus-mediated N-CDH overexpression and inhibitor LY294002 were used to further investigate the role of N-CDH and PI3K/Akt pathway under high-magnitude compression, respectively. NP cell apoptosis was evaluated by caspase-3 activity measured using a commercial kit, flow cytometry, and expression of apoptosis related molecules analyzed by real-time PCR and western blotting assays. RESULTS: High-magnitude compression significantly increased apoptotic NP cells, caspase-3 activity and expression of pro-apoptotic molecules (Bax and caspase-3/cleaved caspase-3), but decreased expression of anti-apoptotic molecule (Bcl-2). High magnitude compression decreased expression of N-CDH, p-Akt and p-GSK-3beta. However, N-CDH overexpression attenuated NP cell apoptosis and increased expression of p-Akt and p-GSK-3beta under high-magnitude compression. Further analysis showed that inhibition of the PI3K/Akt pathway suppressed NP cell apoptosis and decreased expression of p-GSK-3beta, but had no significant effects on N-CDH expression under high-magnitude compression. CONCLUSION: N-CDH can attenuate NP cell apoptosis through activating the PI3K/Akt-GSK-3beta signaling under high-magnitude compression. PMID- 29131032 TI - Anti-Psoriasis Effects and Mechanisms of Alpha-(8-Quinolinoxy) Zinc Phthalocyanine-Mediated Photodynamic Therapy. AB - BACKGROUND/AIMS: The aim of this study was to determine the anti-psoriasis effects of alpha-(8-quinolinoxy) zinc phthalocyanine (ZnPc-F7)-mediated photodynamic therapy (PDT) and to reveal its mechanisms. METHODS: HaCaT cells were used to observe the influence of ZnPc-F7-PDT on cell proliferation in vitro. The in vivo anti-psoriasis effects of ZnPc-F7-PDT were evaluated using a mouse vagina model, a propranolol-induced cavy psoriasis model and an imiquimod (IMQ) induced nude mouse psoriasis model. Flow cytometry was carried out to determine T lymphocyte levels. Western blotting was performed to determine protein expression, and a reverse transcription-polymerase chain reaction test was performed to determine mRNA expression. RESULTS: The results showed that ZnPc-F7 PDT significantly inhibited the proliferation of HaCaT cells in vitro; when the light doses were fixed, changing the irradiation time or output power had little influence on the inhibition rate. ZnPc-F7-PDT significantly inhibited the hyperproliferation of mouse vaginal epithelium induced by diethylstilbestrol and improved propranolol- and IMQ-induced psoriasis-like symptoms. ZnPc-F7-PDT inhibited IMQ-induced splenomegaly and T lymphocyte abnormalities. ZnPc-F7-PDT did not appear to change T lymphocytes in the mouse vagina model. ZnPc-F7-PDT down-regulated the expression of proliferating cell nuclear antigen (PCNA), B cell lymphoma-2 (Bcl-2), interleukin (IL)-17A mRNA and IL-17F mRNA, and up regulated the expression of Bax. CONCLUSION: In conclusion, ZnPc-F7-PDT exhibited therapeutic effects in psoriasis both in vitro and in vivo and is a potential approach in the treatment of psoriasis. Potential mechanisms of these effects included the inhibition of hyperproliferation; regulation of PCNA, Bcl-2, Bax, IL 17A mRNA and IL-17F mRNA expression; and immune regulation. PMID- 29131033 TI - Adverse Reactions to Biologics in Psoriasis. AB - Psoriasis is a chronic autoimmune disease which affects millions of people worldwide. Not only can psoriasis itself be debilitating and significantly reduce an individual's quality of life, but it is also a risk factor for other systemic disorders, such as metabolic syndrome, cardiovascular disease, and malignancy. Tremendous strides were made in the treatment of psoriasis during the mid-to-late 20th century, including the emergence of topical corticosteroids and vitamin D analogs, methotrexate, systemic retinoids, and phototherapy. However, it was not until 2004 with the advent of systemic biologic agents, which precisely target components of the immune system involved in the pathophysiological process of psoriasis, that the primary treatment benchmark increased from 50% improvement in the Psoriasis Area and Severity Index (PASI 50) to PASI 75, PASI 90, and even PASI 100, or complete resolution of cutaneous disease. Today, many patients receiving biologic therapy routinely experience greater than 75% or 90% reduction in cutaneous disease burden and a significant improvement in overall quality of life. These biologic agents are generally well-tolerated and safe but, like any medication, have associated adverse effects, some of which are predictable based on the effects of immune modulation, animal model studies, and human populations with known cytokine deficiencies. Going forward, it will be important to carefully monitor the safety profiles of these agents in both clinical trials and post-marketing surveillance registries to ensure long-term safety. It is reassuring that large safety registries are consistent in demonstrating an improved safety profile with newer and emerging biologic therapies. PMID- 29131034 TI - Clinical Trial and Registry Data. AB - Physicians rely on safety and efficacy data from pivotal trials to guide treatment decisions and manage patients. Even with robust clinical trial data, there remain questions regarding rare safety events and generalizability. Registries complement clinical trials. By evaluating effectiveness and safety in broad patient populations and often providing longer term or larger numbers of patients or both compared to clinical trials, registries consolidate and may extend the safety observations derived from pivotal trials. Our review of phase 3 clinical trial data, long-term extension studies and biologics registries shows biologics to be a safe option for short- and long-term use. Tumor necrosis factor (TNF)-, interleukin (IL)-12/23- and IL-17-antagonists yield similar safety profiles regarding infections, malignancy and major adverse cardiovascular events. The known risk of tuberculosis activation with TNF agonists appears to be readily handled by screening. Mild to moderate candida infections and potential exacerbation or de novo onset of inflammatory bowel disease are associated with IL-17 blockade. PMID- 29131035 TI - Immunosuppression/Infections across Indications. AB - There is increasing use of cytokine inhibitors (including biologics) in the treatment of psoriasis as their efficacy and safety have been demonstrated. Cytokines are important signaling molecules evolved to coordinate a response to infectious threat. In this study, we review available trial, registry and cohort study data pertaining to the immunosuppressive effects of these medications when used to treat psoriasis. The risk of infection associated with these medications is small. Special considerations include the use of these agents in the setting of granulomatous infections, viral hepatitis, human immunodeficiency virus infection, fungal infection and in the perioperative state. PMID- 29131036 TI - The Immunogenicity of Biologic Therapies. AB - Virtually all therapeutic proteins (biologics) elicit an immune response with the consequent production of anti-drug antibodies (ADA). The majority of ADA to therapeutic monoclonal antibodies (mAbs) are directed against the antigen-binding site of the therapeutic mAb, and hence are neutralizing. This nature of the ADA response explains why fully human antibodies can still be highly immunogenic. The detection of ADA is technically challenging and all assays have limitations, namely a limited capacity in detecting ADA in the presence of a drug due to immune complex (IC) formation, which may underestimate the ADA incidence. Refined assays, able to disrupt drug-ADA ICs, have revealed the presence of ADA in a higher proportion of patients. The great heterogeneity among ADA assays prevents a direct comparison of immunogenicity between different molecules and across studies. The formation of drug-ADA ICs can significantly alter pharmacokinetics and directly reduce drug efficacy if the ADA titer (i.e., concentration) is sufficiently high and persistent. In patients with low ADA titer, free drug concentrations may remain high enough to be effective, while in patients developing high ADA titer a substantial part of the drug will be neutralized and clinical non-response is likely to occur. ADA can also increase the risk of adverse events, namely hypersensitivity reactions. Several studies have revealed the presence of ADA before a clinically overt adverse reaction, highlighting their predictive value. Algorithms integrating therapeutic drug monitoring and immunogenicity information in the current clinical evaluation of patients receiving biologics are today available to guide therapeutic decisions in clinical practice, helping us to design safer and more cost-effective therapeutic strategies. PMID- 29131037 TI - Paradoxical Reactions: Anti-Tumor Necrosis Factor Alpha Agents, Ustekinumab, Secukinumab, Ixekizumab, and Others. AB - Paradoxical reactions during treatment with a biologic agent can be defined as the appearance or exacerbation of a pathological condition that usually responds to this class of drug while treating a patient for another condition, which usually remains under control (even though there may be a change in morphology or phenotype). Paradoxical reactions were initially described as isolated case reports or case series in patients treated with anti-tumor necrosis factor (TNF) alpha agents, first in inflammatory rheumatic diseases, later in psoriasis and inflammatory bowel disease. Paradoxical reactions have subsequently been reported with other biological drugs or classes (e.g., tocilizumab), even though in some cases insufficient efficacy or phenotype switch may be difficult to differentiate from true paradoxical reactions. This chapter will deal with the most frequently reported variants of paradoxical reactions: palmoplantar pustular and psoriasiform reactions, psoriatic arthritis, hidradenitis, inflammatory bowel disease, uveitis, pyoderma gangrenosum, granulomatous reactions, and vasculitis. The underlying pathomechanism in these complex diseases with involvement of multiple immunological pathways is most likely a cytokine imbalance, and substitution of the anti-TNFalpha agent by an alternative anti-p40 or anti-IL-17A biologic may be extremely helpful. Paradoxical reactions can cause serious handicap, and early recognition and treatment of these drug class effects is of paramount importance, especially when the primary disease is relatively devoid of therapeutic alternatives and its reactivation may have catastrophic consequences. Close surveillance of patients treated with newly available biologic drugs is necessary to detect and describe new paradoxical reactions. PMID- 29131038 TI - Bullous Diseases. AB - Autoimmune bullous diseases are a heterogeneous group of blistering diseases affecting the skin and/or mucous membrane. Systemic corticosteroids, which are often associated with immunosuppressants, are the main treatment option for these diseases. The 2 main biologics used in the treatment of autoimmune bullous diseases are rituximab, especially in pemphigus and mucous membrane pemphigoid, and omalizumab in bullous pemphigoid. Rituximab is a promising therapeutic option in pemphigus and mucous membrane pemphigoid. Its tolerance is rather good, although rare but potentially severe side effects can occur. Omalizumab has not been robustly evaluated in the treatment of bullous pemphigoid. Some case reports suggest that this drug might be of interest in a few patients with recalcitrant BP and high immunoglobulin E serum levels. Interestingly, this drug is generally well tolerated. PMID- 29131039 TI - Adverse Reactions of Antibody-Therapy for Primary Cutaneous Lymphomas: Rituximab, Brentuximab Vedotin, Alemtuzumab, and Mogamulizumab. AB - Treatment of advanced PCLs is limited and rarely reaches complete remission despite aggressive treatment modalities, such as polychemotherapy with various adverse effects. However, several monoclonal antibodies drug agents in patients with advanced primary cutaneous lymphomas demonstrate promising efficacy and manageable safety profiles. The monoclonal antibodies drug agents have favourable tolerability compared with multi-agent cytotoxic chemotherapy. However, adverse effects manifest with a broad clinical spectrum, hence the markers of targeted therapies are not limited to tumour cells but found on tumour cells and also on benign T and/or B cells. Moreover, the safety profile and direct causal association of drug and adverse effects should be interpreted with caution because many of the patients in clinical studies have received multiple treatments. Here, we focus on the safety profile of mAbs therapies that have recently been approved or are currently under preclinical or clinical investigation for CBCLs (rituximab) and CTCLs (brentuximab, mogamulizumab, and alemtuzumab). Further studies to define clinical safety profile in the patient cohort with cutaneous lymphomas are needed. PMID- 29131040 TI - Adverse Reactions to Biologics: Melanoma (Ipilimumab, Nivolumab, Pembrolizumab). AB - With increasing use of immunotherapies such as anti-cytotoxic T cell lymphocyte antigen-4 and anti-programmed cell death 1 antibodies, various skin toxicities have emerged. Severity of skin toxicities varies from mild lichenoid reaction to severe toxic epidermal necrolysis. Appropriate diagnosis and management of these skin toxicities are essential for optimal patient care and to avoid unnecessary cessation of anti-cancer therapies. This review summarises a wide range of cutaneous manifestations associated with immunotherapy usage in patients with metastatic melanoma. PMID- 29131041 TI - Skin Manifestations of Targeted Antineoplastic Therapy. AB - The management of oncology patients has changed significantly over recent years, with the development of new targeted anticancer therapies. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents; their intensity can be dose-limiting or lead to the discontinuation of therapy. Tyrosine kinase inhibitors can cause maculopapular rash and hand-foot reaction, whereas papulopustular rash, paronychia, regulatory changes in hair, and dryness are caused by epidermal growth factor receptor inhibitors. SMO inhibitors, vismodegib and sonidegib, may result in muscle spasms and alopecia. PMID- 29131043 TI - Non-Hodgkin Lymphoma. PMID- 29131042 TI - Bystander Cells Taking Action. PMID- 29131044 TI - Sustainability of Treatment Effects of Trauma-Focused Cognitive-Behavioral Therapy for Children and Adolescents: Findings from 6- and 12-Month Follow-Ups. PMID- 29131046 TI - Contents Vol. 105, 2017. PMID- 29131045 TI - Initial Results of Prompt Mental Health Care, the Norwegian Version of Improving Access to Psychological Therapies. PMID- 29131047 TI - Erratum. PMID- 29131048 TI - The Correlation of Serum Brain Natriuretic Peptide and Interleukin-6 with Quality of Life Using the Chronic Obstructive Pulmonary Disease Assessment Test. AB - OBJECTIVE: The aim of this study was to determine the levels of serum pro-brain natriuretic peptide (pro-BNP) and interleukin (IL)-6 in patients with stable chronic obstructive pulmonary disease (COPD) and to correlate these markers with health-related quality of life using the COPD assessment test (CAT). MATERIALS AND METHODS: Serum pro-BNP and IL-6 levels were measured in 82 patients with stable COPD. Serum pro-BNP and serum IL-6 levels, pulmonary function, and oxygen saturation (SpO2) were measured according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and CAT score. Also, the associations of both pro-BNP and IL-6 with the clinical parameters of patients were tested. RESULTS: The serum levels of IL-6 (7.57 [5-11.16] pg/mL) and pro-BNP (120.55 [92.89-144.20] pg/mL) were higher with enhancing disease severity based on the GOLD classification (p = 0.034 and 0.068, respectively). Also, serum levels of pro-BNP (120.55 [89.50-147.90] pg/mL) and IL-6 (6.68 [4.40-11.97] pg/mL) were increased in patients with high CAT scores (p = 0.004 and 0.017, respectively). There was a significant positive correlation between plasma pro-BNP and IL-6 levels (r = 0.332, p = 0.002). CONCLUSION: The results demonstrated that with increased severity of obstruction based on the GOLD criteria both IL-6 and pro BNP were elevated. This increase in inflammatory markers was associated with a reduced quality of life and the severity of hypoxia. These findings indicated that lowering IL-6 and pro-BNP could be useful in the management of COPD patients. PMID- 29131050 TI - The Clinical Inadequacy of the Placebo Model and the Development of an Alternative Conceptual Framework. AB - Placebo effects are often attributed to clinical interactions and contextual factors that affect expectations of the patient about the treatment and result in symptom changes. The prevailing conceptualization consists of an undifferentiated placebo response that needs to be minimized in controlled investigations and maximized in clinical practice. However, treatment outcome is the cumulative result of the interaction of several classes of variables with a selected treatment: living conditions (housing, nutrition, work environment, social support), patient characteristics (age, sex, genetics, general health conditions, personality, well-being), illness features and previous therapeutic experience, self-management, and treatment setting (physician's attitude and attention, illness behavior). Such variables may be therapeutic or countertherapeutic, and are unlikely to be simply additive. In certain patients their interactive combination may lead to clinical improvement, whereas in other cases it may produce no effect, and, in a third group, it may lead to worsening of the condition. Maximizing patients' expectations does not necessarily result in sustained effects and, in due course, may actually lead to worsening of the condition (violation of expectations). In this paper, we outline a multifactorial conceptual model that may have implications for the design of clinical trials as well as for clinical practice, with special reference to psychopharmacology and psychotherapy. The effects of drug treatment may be potentiated by specific nonpharmacological treatment strategies, and this synergism may disclose significant differences against placebo. Medical outcomes may be unsatisfactory not because technical interventions are missing, but because our conceptual models and thinking are inadequate. PMID- 29131049 TI - Changing Characteristics of Obese Children and Adolescents Entering Pediatric Lifestyle Intervention Programs in Germany over the Last 11 Years: An Adiposity Patients Registry Multicenter Analysis of 65,453 Children and Adolescents. AB - OBJECTIVE: To examine whether characteristics of children and adolescents who start lifestyle intervention (LI) for obesity in Germany changed over the last decade. METHODS: 65,453 subjects (<21 years) from the APV database (Adiposity Patients Registry) with a BMI >= 90th percentile were included (years 2005-2015). Logistic regression models (confounders: age, sex, migration background) were created for overweight, obesity, extreme obesity, and obesity-related comorbidities. Comorbidities were further adjusted for weight category. Results were stratified by inpatient or outpatient care. RESULTS: Extreme obesity was found to be more frequent at the onset of LI (2005: 11.6; 2015: 12.7%) with a similar trend in subgroups (p < 0.001). Obesity increased (2005: 50.3%; 2015: 55.1%), and overweight decreased (2005: 34.1%; 2015: 29.0%) in the whole study population. Trends were similar for inpatient or outpatient care (all p < 0.001). Hypertension increased from 45.7% to 49.2% in the whole study population, and similar data were obtained in the subgroup of inpatients (both p < 0.0001). Dyslipidemia increased in all patients (2005: 21.9%; 2015: 28.0%) and in inpatients (2005: 20.2%; 2015: 25.7%; both p < 0.0001). Abnormal carbohydrate metabolism rose in all patients (from 5.2 to 6.4%; p = 0.0002) without significant trends in subgroups. CONCLUSION: During the last decade, children and adolescents presented with higher BMI SDS at the onset of LI and the proportion with obesity-related comorbidities increased. Particularly the presence of comorbidities differed between outpatients and inpatients. PMID- 29131051 TI - Interocular Symmetry of Choroidal Thickness and Volume in Healthy Eyes on Optical Coherence Tomography. AB - BACKGROUND: We aimed to determine the physiological symmetry, with spectral domain optical coherence tomography, of choroidal measurements in a healthy population in all the areas defined in the Early Treatment Diabetic Retinopathy Study (ETDRS). METHODS: One hundred and fifty-four eyes of 77 healthy young adults between the ages of 19 and 32 years were enrolled. Differences in choroidal thickness (CT) and volume (CV) between the left and right eyes were calculated. Normal ranges of absolute interocular differences were established as the 95th percentile. RESULTS: The mean +/- SD subfoveal CT (SFCT) and total CV values in the right and left eyes were 342.03 +/- 77.38 versus 361.64 +/- 76.45 um (correlation coefficient rho = 0.820; p < 0.001) and 0.27 +/- 0.06 versus 0.28 +/- 0.06 mm3 (rho = 0.830; p < 0.001), respectively. Differences in 5 of the 9 areas of the ETDRS map were statistically significant (p < 0.05), but with a strong interocular correlation (rho > 0.8; p < 0.001). The 95th percentile of interocular tolerance limits for CT in the 1-, 3-, and 6-mm areas were 97, 70, and 57 MUm, respectively; the 95th percentile for the volume values were 0.06, 0.51, and 1.73 mm3. CONCLUSIONS: CT and CV are highly correlated between eyes, statistically significant differences between them can be found, and absolute interocular differences may reach 97 um in SFCT, and 1.73 mm3 in total CV. PMID- 29131052 TI - Prenatal Screening for 22q11.2 Deletion Using a Targeted Microarray-Based Cell Free DNA Test. AB - OBJECTIVE: To determine the performance of a targeted microarray-based cell-free DNA (cfDNA) test (Harmony Prenatal Test(r)) for the identification of pregnancies at increased risk for 22q11.2 deletion. METHODS: Test performance was determined in 2 steps including a total of 1,953 plasma samples. Analytical validation was performed in 1,736 plasma samples. Clinical verification of performance was performed in an additional 217 prospectively ascertained samples from pregnancies with fetal deletion status determined by diagnostic testing. RESULTS: Analytical sensitivity was 75.4% (95% CI: 67.1-82.2%) based on 122 samples with deletions ranging from 1.96 to 3.25 Mb. In 1,614 presumed unaffected samples, specificity was determined to be at least 99.5% (95% CI: 99.0-99.7%). In the clinical cohort, 5 of 7 samples from pregnancies affected with 22q11.2 deletion were determined to have a high probability of deletion. There were no false positive results in the 210 unaffected samples in this cohort. These clinical data are consistent with the performance demonstrated in the analytical validation. CONCLUSIONS: cfDNA testing using a targeted microarray-based technology is able to identify pregnancies at increased risk for 22q11.2 deletions of 3.0 Mb and smaller while maintaining a low false positive rate. PMID- 29131053 TI - An Experimental Study to Measure the Mechanical Properties of the Human Liver. AB - BACKGROUND: Since the liver is one of the most important organs of the body that can be injured during trauma, that is, during accidents like car crashes, understanding its mechanical properties is of great interest. Experimental data is needed to address the mechanical properties of the liver to be used for a variety of applications, such as the numerical simulations for medical purposes, including the virtual reality simulators, trauma research, diagnosis objectives, as well as injury biomechanics. However, the data on the mechanical properties of the liver capsule is limited to the animal models or confined to the tensile/compressive loading under single direction. Therefore, this study was aimed at experimentally measuring the axial and transversal mechanical properties of the human liver capsule under both the tensile and compressive loadings. METHODS: To do that, 20 human cadavers were autopsied and their liver capsules were excised and histologically analyzed to extract the mean angle of a large fibers population (bundle of the fine collagen fibers). Thereafter, the samples were cut and subjected to a series of axial and transversal tensile/compressive loadings. RESULTS: The results revealed the tensile elastic modulus of 12.16 +/- 1.20 (mean +/- SD) and 7.17 +/- 0.85 kPa under the axial and transversal loadings respectively. Correspondingly, the compressive elastic modulus of 196.54 +/- 13.15 and 112.41 +/- 8.98 kPa were observed under the axial and transversal loadings respectively. The compressive axial and transversal maximum/failure stress of the capsule were 32.54 and 37.30 times higher than that of the tensile ones respectively. The capsule showed a stiffer behavior under the compressive load compared to the tensile one. In addition, the axial elastic modulus of the capsule was found to be higher than that of the transversal one. CONCLUSIONS: The findings of the current study have implications not only for understanding the mechanical properties of the human capsule tissue under tensile/compressive loading, but also for providing unprocessed data for both the doctors and engineers to be used for diagnosis and simulation purposes. PMID- 29131054 TI - Heritability of End-Stage Renal Disease: A Swedish Adoption Study. AB - BACKGROUND/AIMS: The heritability of end-stage renal disease (ESRD) among adoptees has not been examined so far. By studying adoptees and their biological and adoptive parents, it is possible to differentiate between the genetic causes and environmental causes of familial aggregation. This nationwide study aimed to disentangle the genetic and shared environmental contribution to the familial transmission of ESRD. METHODS: We performed a family study for Swedish-born adoptees (born between 1945 until 1995) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the National Patient Registry for the period 1964-2012. ESRD was defined as patients in active uremic care, that is, chronic dialysis or kidney transplantation. OR for ESRD was determined for adoptees with an affected biological parent with ESRD compared with adoptees without a biological parent with ESRD. The OR for ESRD was also calculated in adoptees with an adoptive parent with ESRD compared with adoptees with an adoptive parent without ESRD. Moreover, heritability for ESRD was estimated with Falconer's regression. RESULTS: A total of 111 adoptees, 463 adoptive parents, and 397 biological parents were affected by ESRD. The OR for ESRD was 6.41 in adoptees (95% CI 2.96-13.89) of biological parents diagnosed with ESRD. The OR for ESRD was 2.40 in adoptees (95% CI 0.76-7.60) of adoptive parents diagnosed with ESRD. The heritability of ESRD was 59.5 +/- 18.2%. CONCLUSION: The family history of ESRD in a biological parent is an important risk factor for ESRD. The high heritability indicates that genetic factors play an important role in understanding the etiology of ESRD. PMID- 29131055 TI - BMI Is a Better Body Proportionality Measure than the Ponderal Index and Weight for-Length for Preterm Infants. AB - BACKGROUND: Clinicians have observed preterm infants in the neonatal intensive care unit growing disproportionally; however, the only growth charts that have been available were from preterm infants born in the 1950s which utilized the ponderal index. Prior to creating the recently published BMI curves, we found only 1 reference justifying the use of the ponderal index. OBJECTIVES: To determine the best measure of body proportionality for assessing growth in US preterm infants. METHODS: Using a dataset of 391,681 infants, we determined the body proportionality measure that was most correlated with weight and least correlated with length. We examined the sex-specific overall correlations and then stratified further by gestational age (GA). We then plotted the body proportionality measures versus length to visualize apparent discrepancies in the appropriate measure. RESULTS: The overall correlations showed weight/length3 (ponderal index) was the best measure but stratification by GA indicated that BMI (weight/length2) was the best measure. This seeming inconsistency was due to negative correlations between ponderal index and length at each GA. BMI, on the other hand, had a correlation with length across GAs, but was uncorrelated with length within GAs. Both ponderal index and BMI were positively correlated with weight. CONCLUSIONS: BMI is the appropriate measure of body proportionality for preterm infants, contrary to current practice. PMID- 29131056 TI - Chloride Intracellular Channel 4 Overexpression in the Proximal Tubules of Kidneys from the Spontaneously Hypertensive Rat: Insight from Proteomic Analysis. AB - BACKGROUND: Hypertensive nephropathy, a leading cause of declining kidney function, is a multifactorial process not well understood. In order to elucidate biological processes and identify novel macromolecular components crucially involved in the process of kidney damage, the application of system biology approaches, like proteomics, is required. METHODS: Proteomic studies were performed using the renal parenchyma of spontaneously hypertensive rats (SHR) and their normotensive Wistar Kyoto controls. Animals were sacrificed at early time intervals (6, 13, and 20 weeks after birth), the renal tissue extract was subjected to two-dimensional gel electrophoresis, differential expressed proteins were identified, and altered pathways were evaluated. One specific protein, chloride intracellular channel 4 (CLIC4), not implicated so far in the development of hypertension and nephrosclerosis, was further studied by Western blotting, immunohistochemistry and immunofluorescence. RESULTS: Proteomic analysis identified several pathways/processes and organelles (mitochondria) as being affected from the early stages of hypertension. CLIC4 was overexpressed in SHR at all 3 time intervals examined. This finding was confirmed by Western blotting and by immunohistochemistry and immunofluorescence; these morphological techniques demonstrated that CLIC4 was almost exclusively localized at the apical surface of the proximal tubular epithelial cells. CONCLUSIONS: Our studies provide evidence that major changes occur in the renal parenchyma from early stages of the development of hypertension. The overexpression of CLIC4 suggests that alterations in the proximal tubular compartment during hypertension should be further examined and that CLIC4 may be a useful early marker of renal tubular alterations due to elevated blood pressure. PMID- 29131057 TI - Unaided Smoking Cessation in Healthy Employees. AB - BACKGROUND: According to guidelines, behavioral and pharmacological assistance should be offered to all smokers willing to quit. However, a large proportion of ex-cigarette smokers are self-quitters. OBJECTIVES: To identify characteristics of long-term, unaided self-quitters, as compared to recurrent smokers among health care employees. METHODS: University hospital employees (n = 5,218) were addressed through a 17-question questionnaire inquiring about past and current smoking behavior. Questions included daily cigarette consumption, pack-years, previous quit attempts, smoking-free period, and utilization of pharmacological therapies and counseling. RESULTS: 2,574 (49.3%) questionnaires were returned. 791 subjects declared to have successfully quit smoking. A complete data set was available for 763 cases. Patients remained smoking free for a mean period of 11.8 +/- 9.7 years. The most common smoking cessation method in these subjects was unaided (77.2%), followed by alternative approaches (15.4%), nicotine replacement therapy (4.5%), counseling (1.7%), and bupropion (1.2%). Smoking cessation was achieved with 1 attempt in 53% of the cases, 2 in 19%, 3 in 13%, and more than 3 attempts in 15%, respectively. On average, 2.4 +/- 3.02 attempts led to successful smoking cessation. After 2 or more unsuccessful attempts, the odds ratio for a further unsuccessful smoking cessation was 2.58 (95% CI 1.94-3.45). CONCLUSION: The majority of the ex-smokers quitted smoking without any behavioral or pharmacological support. The chance to successfully quit smoking without any help in a first or second attempt is considerably high. The risk for smoking recurrence after 2 ineffective quit attempts is markedly increased (OR 2.58). PMID- 29131058 TI - Nonfunctional Redundant Acts Characterize OCD, Even in OCD-Unrelated Tasks: A Demonstration in Questionnaire Completion. AB - BACKGROUND: Ethological methods used to analyze human obsessive-compulsive disorder (OCD) rituals demonstrated excess of unnecessary repetitions as well as irrelevant, idiosyncratic acts (additions) compared to normal activity. A question that still remains is whether these well-known repetitions and additions are manifested in behaviors unrelated to the OCD rituals. Our objectives were to: (1) assess whether OCD-related repetitions and additions as found in previous studies also affect the patients' activity of filling out questionnaires and (2) evaluate the specificity of these behaviors to OCD as opposed to other anxiety disorders and healthy controls. SAMPLING AND METHODS: Several standardized disorder-specific self-report questionnaires were used in order to assess the patient's psychopathologies. The style of filling-out these questionnaires by OCD and non-OCD anxiety outpatients and normal controls was analyzed. Four categories were used: omissions, repetitions, corrections, and additions. RESULTS: The OCD group scored significantly higher on the number of additions as compared with both the anxiety group and the nonclinical group, and significantly higher on the number of corrections and repetitions as compared with the nonclinical group. CONCLUSIONS: The hallmarks of OCD, repetitions and additions, are manifested not only in the patient's rituals and thoughts, but in apparently "neutral" tasks that do not a priori involve the intrusive thoughts, urges, and images typical of obsessive-compulsive behavior. Additions seem to be more specific to OCD than repetitions. These two executive faults impede routine functionality of OCD patients in tasks related and unrelated to their rituals. Our study delineates simple, observable behavioral characteristics that distinguish between OCD and non-OCD anxiety patients as well as healthy individuals. These symptomatic behaviors may offer a clue to personality traits or deficits in executive functions that possibly play a part in the pathophysiology of OCD. Our results are an additional indication that nonfunctionality in obsessive-compulsive behavior deserves full attention for a better understanding of the psychopathological mechanisms of OCD. PMID- 29131059 TI - Risk Factors and Outcomes of Emergency Room Visits in Intestinal Behcet's Disease. AB - BACKGROUND/AIMS: Intestinal Behcet's disease (BD) is a chronic recurring intestinal vasculitic disorder that can lead to emergency room (ER) visits. We aimed to investigate the independent risk factors associated with intestinal BD related ER visits. METHODS: We retrospectively reviewed 606 patients with intestinal BD registered at the Inflammatory Bowel Disease Clinic of Severance Hospital, Seoul, Korea. RESULTS: One hundred eighty-five patients (30.5%) visited the ER at least once (total visits, 510). In multivariate analysis, lower socioeconomic status (hazard ratio [HR] 1.884), higher comorbidity index (HR 1.548), corticosteroid use (HR 1.459), higher C-reactive protein (CRP; HR 1.375), and higher disease activity index for intestinal BD (DAIBD) score (HR 1.013) were independent risk factors. However, older age (HR 0.982), disease duration (HR 0.850), opioid use (HR 0.528), and higher hemoglobin level (HR 0.944) were significantly associated with decreased ER visits. CONCLUSIONS: The ER attendance rate of patients with intestinal BD was 30.5%. Lower socioeconomic status, higher comorbidity index, corticosteroid use, higher CRP, and higher DAIBD score were positively associated with ER visits. Older age, disease duration, opioid use, and higher hemoglobin level were significantly associated with decreased ER visits. PMID- 29131060 TI - Aging-Induced Modulation of Pituitary Adenylate Cyclase-Activating Peptide- and Vasoactive Intestinal Peptide-Induced Vasomotor Responses in the Arteries of Mice. AB - Pituitary adenylate cyclase-activating peptide (PACAP; 1-38 and 1-27) and vasoactive intestinal peptide (VIP) are related neuropeptides of the secretin/glucagon family. Overlapping signaling through G-protein-coupled receptors mediates their vasomotor activity. We previously showed that PACAP deficiency (PACAP-KO) shifts the mechanisms of vascular response and maintains arterial relaxation through the VIP backup mechanism and (mainly) its VPAC1R, but their age-dependent modulation is still unknown. We hypothesized that backup mechanisms exist, which maintain the vasomotor activity of these peptides also in older age. Thus, we investigated the effects of exogenous VIP and PACAP peptides in isolated carotid arteries of 2- and 15-month-old wild-type (WT) and PACAP-KO mice. All peptides induced relaxation in the arteries of young WT mice, whereas in young PACAP-KO mice PACAP1-27 and VIP, but not PACAP1-38, induced relaxation. Unlike VIP, PACAP-induced vasomotor responses were reduced in aging WT mice. However, in the arteries of aging PACAP-KO mice, PACAP1-27- and VIP-induced responses were reduced, but PACAP1-38 showed a greater vasomotor response compared to that of young PACAP-KO animals. There were no significant differences between the vasomotor responses of aging WT and PACAP-KO mice. Our data suggest that, in the absence of PACAP both in young and old ages, the vascular response is mediated through backup mechanisms, most likely VIP, maintaining proper vascular relaxation in aging-induced PACAP insufficiency. PMID- 29131061 TI - Kinetic Aspects of Verapamil Binding (On-Rate) on Wild-Type and Six hKv1.3 Mutant Channels. AB - BACKGROUND/AIMS: The human-voltage gated Kv1.3 channel (hKv1.3) is expressed in T and B lymphocytes. Verapamil is able to block hKv1.3 channels. We characterized the effect of verapamil on currents through hKv1.3 channels paying special attention to the on-rate (kon) of verapamil. By comparing on-rates obtained in wild-type (wt) and mutant channels a binding pocket for verapamil and impacts of different amino acid residues should be investigated. METHODS: Using the whole cell patch clamp technique the action of verapamil on currents through wild-type and six hKv1.3 mutant channels in the open state was investigated by measuring the time course of the open channel block in order to calculate kon of verapamil. RESULTS: The on-rate of verapamil to block current through hKv1.3_T419C mutant channels is similar to that obtained for hKv1.3_wt channels whereas the on-rate of verapamil to block currents through hKv1.3_L417C and hKv1.3_L418C mutant channels was ~ 3 times slower compared to in wt channels. The on-rate of verapamil to block currents through hKv1.3_L346C and the double mutant hKv1.3_L346C_L418C channel was ~ 2 times slower compared to that obtained in the wt channel. The hKv1.3_I420C mutant channel reduced the on-rate of verapamil to block currents ~ 6 fold. CONCLUSIONS: We conclude that position 420 in hKv1.3 channels maximally interferes with verapamil reaching its binding site to block the channel. Positions 417 and 418 in hKv1.3 channels partially hinder verapamil reaching its binding site to block the channel whereas position 419 may not interfere with verapamil at all. Mutant hKv1.3_L346C and hKv1.3_L346C_L418C mutant channels might indirectly influence the ability of verapamil reaching its binding site to block current. PMID- 29131064 TI - Historical Background, Clinical Applications, Controversies. PMID- 29131063 TI - Changing Paradigms in Acute Kidney Injury: From Mechanisms to Management. PMID- 29131062 TI - Cardiorenal Determinants of Erectile Dysfunction in Primary Prevention: A Cross Sectional Study. AB - OBJECTIVE: The aim of this study was to investigate the association between the severity of erectile dysfunction (ED), cardiovascular risk, and target organ damage (heart, renal, vascular) in men free of cardiovascular diseases (CVD). SUBJECTS AND METHODS: ED was assessed using the International Index of Erectile Function (IIEF-5). The study included 182 men: 100 with ED (IIEF mean score <=21) and 82 without ED (IIEF mean score >21). Ultrasound was used to evaluate carotid plaques and left ventricular mass, geometry, and diastolic function. Cardiovascular anamnesis, CVD risk factors, and anthropometric and biochemical parameters were obtained. The European Society of Cardiology-Systematic Coronary Risk Evaluation Score (ESC-SCORE) was used to calculate total patient cardiovascular risk. Continuous variables between groups were compared using the Student t test and Mann-Whitney U test, while categorical data were compared using the chi2 test. Multiple linear regression was used to test the association between the severity of ED and presence of target organ damage. RESULTS: The following parameters were significantly higher in the ED group compared to the controls: family history of coronary heart disease (43.7 vs. 26.7%, p = 0.047), ESC-SCORE (2.27 +/- 1.79 vs. 1.61 +/- 1.13, p = 0.012), and waist circumference (109.28 +/- 10.82 vs. 106.17 +/- 10.07, p = 0.047). Impaired renal function (p = 0.081), albuminuria (p = 0.545), vascular damage (p = 0.602), and diastolic function (p = 0.724) were similar in both groups. However, left ventricular hypertrophy (LVH; odds ratio 2.231, 95% CI 1.069-4.655, p = 0.22) was more frequent in the ED group (29.9 vs. 16.0%). The multiple linear regression analysis revealed that LVH (beta = 1.761, p = 0.002) and impaired renal function assessed using the estimated glomerular filtration rate (<60 mL/min/1.73 m2; beta = 6.207, p = 0.0001) were the independent risk factors for severity of ED. CONCLUSION: This study showed that LVH and impaired renal function are associated with ED severity. PMID- 29131065 TI - Suicidal Ideation and Suicide Attempts in the Elderly Associated with Opioid Use and Pain Sensitivity. PMID- 29131066 TI - Human Washington University Polyomavirus in Patients with Respiratory Tract Infection in Kuwait. AB - OBJECTIVE: To determine Washington University (WU) polyomavirus strains circulating among hospitalized patients with respiratory tract infections (RTI) in Kuwait. MATERIALS AND METHODS: Samples from 459 hospitalized children and adult RTI patients were screened for respiratory viruses by polymerase chain reaction from April 2013 to April 2016. The VP2 gene from WU virus (WUV)-positive samples was sequenced and subjected to phylogenetic analysis. RESULTS: Of the 459 hospitalized RTI patients, 18 (3.9%) patients were positive for WUV infection. WUV infection was common among children aged <=11 years (9 patients, 50%). Among the 18 WUV-infected hospitalized patients, viral co-infection was detected in 9 patients (50%). The most common viruses associated with mixed infection were respiratory syncytial virus and human rhinovirus (2 patients, 11.1% each). Of the 18 WUV-infected patients, 4 were sequenced and subjected to phylogenetic analysis. The circulating strains belong to type Ia and IIIb. CONCLUSION: This study enabled us to detect WUV among hospitalized RTI patients. Co-infection with other respiratory viruses was notable. Two circulating WUV genotypes (Ia and IIIb) were identified among hospitalized RTI patients in Kuwait. PMID- 29131067 TI - Estimation of Trait-Model Parameters in a MOD Score Linkage Analysis. AB - BACKGROUND/AIMS: Theoretically, the trait-model parameters (disease allele frequency and penetrance function) can be estimated without bias in a MOD score linkage analysis. We aimed to practically evaluate the MOD score approach regarding its ability to provide unbiased trait-model parameters for various pedigree-type and trait-model scenarios. We further investigated the ability of the MOD score approach to detect imprinting using affected sib pairs (ASPs) and affected half-sib pairs (AHSPs) when all parental genotypes are missing. METHODS: Simulated pedigree data were analyzed using the GENEHUNTER-MODSCORE software package. Parameter estimation performance in terms of bias and variability was evaluated with regard to trait-model type and pedigree complexity. RESULTS: Generally, parameters were estimated with lower bias and variability with increasing pedigree complexity, especially for recessive and overdominant models. However, dominant and additive models could hardly be distinguished even when using 3-generation pedigrees. Imprinting could clearly be detected for mixtures of mainly ASPs and only few AHSPs with the common parent of the imprinted sex, even though no parental genotypes were available. CONCLUSION: Our results provide guidance to researchers regarding the possibility to estimate trait-model parameters by a MOD score analysis, including the degree of imprinting, with certain types of pedigrees. PMID- 29131069 TI - Paediatric Lymphadenopathies. PMID- 29131068 TI - Maternal Cannabinoid Use Alters Cannabinoid (CB1) and Endothelin (ETB) Receptor Expression in the Brains of Dams but Not Their Offspring. AB - According to the 2015 National Survey on Drug Use and Health, cannabis (marijuana) is the most commonly used recreational drug in the US. Among pregnant women aged 14-55 years, 3.4% were cannabis users. Presently, little is known about the neurodevelopmental effect of cannabis use during pregnancy and/or nursing on neonates. Endothelin (ET) is essential for normal development of the central nervous system (CNS). Decreases in ETB receptor expression correlate with a decline in nerve growth factor (NGF) and an increase in vascular endothelial growth factor (VEGF) in postnatal brain. Activation of ETB and cannabinoid 1 (CB1) receptors each promote neurogenesis and enhance angiogenesis, indicating that both ET and CB systems play a critical role during early CNS development. Hence the purpose of this study was to determine whether maternal CB abuse during pregnancy and lactation alters the expression of ETB receptors, CB1 receptors, VEGF, and NGF in the postnatal rat brain. Sixteen pregnant Sprague-Dawley rats were administered either saline or anandamide (AEA) at a dose of 3 mg/kg/day i.p. from gestational day 7 and continued through weaning on postnatal day (PND) 21. Rat pups were subdivided into 4 subgroups and sacrificed on PND 2, 7, 14, and 28. Brain tissue of the pups and dams (sacrificed on PND 21) was analyzed via Western blot for the expression of ETB receptors, CB1 receptors, VEGF, and NGF. AEA exposed dams had significantly fewer live births (p = 0.027), and their pups presented with significantly lower body weights on PND 7 (p = 0.013) and PND 28 (p = 0.018). There was no significant difference noted in ETB receptor, CB1 receptor, NGF, or VEGF expression in the pup brains. In all pups, brain ETB receptor expression decreased and CB1 receptor expression increased with age. In the AEA-exposed dam brain, however, there was a decrease in ETB receptor (p = 0.043) and an increase in CB1 receptor expression (p = 0.033). AEA exposure during pregnancy appears to affect fetal viability and postnatal weight gain in offspring while not altering the expression patterns of ETB receptors, CB1 receptors, NGF, or VEGF in the pup brain. The observed trend to an increase in CB1 receptor expression concurrent with a decrease in ETB receptor expression in both dams and pups may point to a homeostatic regulation between these 2 systems in CNS development and neuroprotection. PMID- 29131070 TI - Pathophysiology of Post Transplant Hypertension in Kidney Transplant: Focus on Calcineurin Inhibitors Induced Oxidative Stress and Renal Sodium Retention and Implications with RhoA/Rho Kinase Pathway. AB - Post-transplant hypertension is a common occurrence during treatment with calcineurin inhibitors (CNIs) in kidney transplant population. The pathogenesis of vasoconstriction induced by CNIs involves vascular tone alterations and kidney sodium transport regulation. Among the factors involved a key role is played by the activation of intrarenal renin-angiotensin system with enhanced release of Angiotensin II (Ang II) and increase of oxidative stress. A common pathway between oxidative stress and hypertension induced by CNIs may be identified in the involvement of the activation of RhoA/Rho kinase pathway, key for the induction of hypertension and cardiovascular-renal remodeling, of the oxidative stress mediated increased nitric oxide (NO) metabolism and increased renal sodium retention via increased activity of thiazide-sensitive sodium chloride cotransporter (NCC) in the distal tubule. We examined literature data including those coming from our group regarding the role of oxidative stress and sodium retention in CNIs induced hypertension and their involvement in cardiovascular renal remodeling. Based on the available data, we have provided support to the activation of RhoA/Rho kinase pathway as an important effector in the pathophysiology of CNIs induced post-transplant hypertension via activation of oxidative stress and sodium retention. Clarification of how the biochemical and molecular mechanisms that regulate the processes involved in CNIs induced post transplant hypertension work and interact, would provide further insights not only into the comprehension of the pathophysiology of CNIs induced post transplant hypertension but could also have a positive impact on the clinical ground through the identification of significant targets. Their specific pharmacologic targeting might have multiple beneficial effects on the whole cardiovascular-renal function. The demonstration that in kidney transplanted patients with CNIs induced post-transplanted hypertension, the treatment of hypertension with different antihypertensive drugs inducing a comparable blood pressure reduction but different effects for example on oxidative stress and oxidative stress related proteins and/or Rho kinase and sodium retention, could be helpful for the choice of the antihypertensive treatment in these patients which takes advantage from effects of these drugs beyond blood pressure reduction. PMID- 29131071 TI - Highly Selective Endothelin-1 Receptor A Inhibition Prevents Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice. AB - BACKGROUND: Pulmonary fibrosis is a chronic disease, which progressively leads to respiratory failure and ultimately death. Endothelin-1 (ET-1), a vasoconstrictor secreted by endothelial cells, promotes vasoconstriction by activation of its receptors A and B. OBJECTIVES: We addressed the role of highly selective ET-1 receptor A (ETA) inhibition in the pathogenesis of experimental pulmonary fibrosis by bleomycin (BLM). METHODS: BLM sulfate (2 U/mL) or saline was intratracheally administered to C57/Bl6 mice (4 groups; n = 5-11/group). Pretreatment with the highly selective ETA receptor inhibitor sitaxentan (15 mg/kg/day) was started 1 day prior to BLM injection and continued for the duration of the experiment. Lung mechanics were assessed prior to sacrifice at days 7, 14, and 21 after BLM, followed by procurement of bronchoalveolar lavage fluid (BALF), blood, and lung tissue samples. RESULTS: Time-dependent effects of BLM exposure included decreased static compliance and increased lung elastance, airspace inflammation and microvascular permeability, histological acute lung injury and fibrosis, and lung collagen deposition. Pretreatment with highly selective ETA receptor inhibitor had no adverse effect on control mice but improved lung mechanics and lung injury score in addition to decreasing BALF pleocytosis, protein content, and collagen deposition in BLM-treated mice. Mortality from BLM reached 40% and occurred primarily during the inflammatory stage of the model but was abrogated by sitaxentan pretreatment. CONCLUSIONS: We conclude that in our BLM-induced pulmonary fibrosis model, prophylactic highly selective ETA inhibition improves survival, preserves lung function, attenuates lung injury, and reduces collagen deposition. PMID- 29131073 TI - An Introduction to Contrast-Enhanced Ultrasound for Nephrologists. AB - Contrast-enhanced ultrasound (CEUS) is an emerging technology with no known nephrotoxicity. CEUS has been utilized in cardiac and abdominal imaging for decades in Asia and Europe and has recently received greater attention in the United States with its approval for characterization of indeterminate liver lesions. Emerging data suggest that CEUS has potential as a diagnostic imaging tool among individuals who have contraindications to CT and MRI. Few nephrologists are aware of CEUS and even fewer are aware of its potential applications among individuals with kidney disease. This review introduces CEUS to the nephrology community and provides a basic overview of CEUS technology. Knowledge of the applications, advantages, and disadvantages of CEUS provides the framework for nephrologists to make informed decisions regarding this emerging imaging test in appropriate circumstances. This review focuses on the use of CEUS for the characterization of indeterminate kidney lesions and summarizes the most recent data, some of which specifically includes patients with chronic kidney disease (CKD). The results demonstrate that CEUS has high sensitivity and moderate specificity for detecting malignancy in indeterminate kidney lesions among individuals with and without CKD. In conclusion, CEUS is an emerging imaging technique that may have clinically useful applications for detecting malignant kidney lesions, specifically in patients with CKD. However, most of the current data come from small, single-center studies, and larger, multicenter studies are needed. PMID- 29131072 TI - IL-21 Is Increased in Nasal Polyposis and after Stimulation with Staphylococcus aureus Enterotoxin B. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory disease associated with lymphoid aggregates and local IgE production related to Staphylococcus aureus enterotoxins. T-follicular helper cells and their effector cytokine interleukin (IL)-21 play an important role in germinal center proliferation. METHODS: IL-21 was determined on the mRNA level by qPCR in nasal tissue of 3 groups of patients: control (n = 17), chronic rhinosinusitis without nasal polyposis (CRSsNP; n = 23), and CRSwNP (n = 35). The expression of IL-21 by CD4+ T cells was analyzed in tissue at baseline and after 24-h stimulation of tissue fragments with S. aureus enterotoxin B (SEB) using flow cytometry. Finally, human nasal IL-21+CXCR5+CD4+ T cells were isolated and coincubated with human blood naive B cells to investigate their functionality. RESULTS: IL-21 mRNA expression was increased in the CRSwNP group (p < 0.05) compared to the control group, and B-cell lymphoma-6 and B-lymphocyte-induced maturation protein-1 were upregulated in CRSwNP versus CRSsNP. Furthermore, SEB was able to increase IL-21 mRNA expression significantly (p < 0.01) in nasal polyps. Flow cytometry revealed that the source of IL-21 was predominantly CD4+ T cells and that IL-21+CD4+ T cells were significantly increased in polyp tissue and further increased after SEB stimulation. Finally, tissue CXCR5+CD4+ T cells derived from nasal polyp tissue were able to induce maturation of human naive B cells. CONCLUSIONS: IL-21- and IL-21-producing CD4+ T cells were increased in CRSwNP. In addition, SEB induced an increase in IL-21 and IL-21+CD4+ T cells, suggesting that S. aureus can modulate the function of Tfh cells in nasal polyps. We speculate that T-follicular helper cells and IL-21 are important in the pathophysiology of CRSwNP. PMID- 29131074 TI - Tranexamic Acid Failed to Reverse the Anticoagulant Effect and Bleeding by an Oral Direct Factor Xa Inhibitor Edoxaban. AB - BACKGROUND/AIMS: Agents to reverse the anticoagulant effect of edoxaban, an oral direct factor Xa inhibitor, would be desirable in emergency situations. The aim of this study is to determine the effect of tranexamic acid, an antifibrinolytic agent, on the anticoagulant activity and bleeding by edoxaban in rats. METHODS: A supratherapeutic dose of edoxaban (3 mg/kg) was intravenously administered to rats. Three minutes after dosing, tranexamic acid (100 mg/kg) was given intravenously. Bleeding was induced by making an incision with a blade on the planta 8 min after edoxaban injection and bleeding time was measured. Prothrombin time (PT) and clot lysis were examined. RESULTS: A supratherapeutic dose of edoxaban significantly prolonged PT and bleeding time. Tranexamic acid did not affect PT or bleeding time prolonged by edoxaban, although tranexamic acid significantly inhibited clot lysis in rat plasma. CONCLUSION: An antifibrinolytic agent tranexamic acid failed to reverse the anticoagulant effect and bleeding by edoxaban in rats. PMID- 29131075 TI - The Cerebellar-Cerebral Microstructure Is Disrupted at Multiple Sites in Very Preterm Infants with Cerebellar Haemorrhage. AB - BACKGROUND: Recent advances in magnetic resonance imaging (MRI) techniques have prompted reconsideration of the anatomical correlates of adverse outcomes in preterm infants. The importance of the contribution made by the cerebellum is now increasingly appreciated. The effect of cerebellar haemorrhage (CBH) on the microstructure of the cerebellar-cerebral circuit is largely unexplored. OBJECTIVES: To investigate the effect of CBH on the microstructure of cerebellar cerebral connections in preterm infants aged <32 gestational weeks. METHODS: Infants underwent diffusion tensor MRI at term-equivalent age. MRI was evaluated for CBH and additional supratentorial brain injury using a validated scoring system. Region of interest-based measures of brain microstructure (fractional anisotropy [FA] and apparent diffusion coefficient) were quantified in 5 vulnerable regions (the centrum semiovale, posterior limb of the internal capsule, corpus callosum, and superior and middle cerebellar peduncles). Group differences between infants with CBH and infants without CBH were assessed. RESULTS: There were 267 infants included in the study. Infants with CBH (isolated and combined) had significantly lower FA values in all regions investigated. Infants with isolated CBH showed lower FA in the middle and superior cerebellar peduncles and in the posterior limb of the internal capsule. CONCLUSIONS: This study provides evidence that CBH causes alterations in localised and remote WM pathways in the developing brain. The disruption of the cerebellar-cerebral microstructure at multiple sites adds further support for the concept of developmental diaschisis, which is propagated as an explanation for the consequences of early cerebellar injury on cognitive and affective domains. PMID- 29131077 TI - Book Discussions: A Novel Format for Transporting Classic Works into Present-Day Phonetics Research. PMID- 29131078 TI - Role of Sexuality in the Outcome of Anorexia Nervosa and Bulimia Nervosa: A 3 Year Follow-Up Study. PMID- 29131079 TI - Are Inflammatory Cytokines Associated with Pain during Acute Myocardial Infarction? AB - OBJECTIVE: Pain and inflammation during acute myocardial infarction (AMI) have been associated with the development of posttraumatic stress disorder and may also impact negatively on somatic outcome. We investigated the relationship between pain during AMI and levels of circulating proinflammatory (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6) and anti-inflammatory (IL-33 and tissue growth factor [TGF]-beta1) cytokines. METHODS: Data were collected as part of the Myocardial Infarction - Stress Prevention Intervention (MI-SPRINT) study. We included 140 patients (mean age 59.6 years, 82.1% male) with high acute psychological distress within 48 h after MI. Fasting blood samples were drawn thereafter to measure cytokine levels. Sociodemographic factors, psychological and medical data, as well as cardiometabolic markers were assessed with questionnaires and patient interviews. RESULTS: Linear regression models showed a significant positive correlation of pain with TGF-beta1 (b = 770.91, p = 0.031) and a significant inverse correlation of pain with IL-33 (b = -0.11, p = 0.015) after controlling for age, gender, body mass index, lifetime depression, acute stress disorder symptoms, and the prognostic Global Registry of Acute Coronary Events (GRACE) score. Pain was not associated with IL-6 but with the GRACE score (b = 0.01, p = 0.003). Pain showed no significant association with TNF-alpha. CONCLUSION: Pain during MI was associated with anti- but not proinflammatory cytokines. As IL-33 has been shown to be cardioprotective, lower IL-33 levels with more intense pain may suggest a pathway through which increased pain during MI may have an impact on the medical prognosis. PMID- 29131080 TI - Complete Static Repopulation of Decellularized Porcine Tissues for Heart Valve Engineering: An in vitro Study. AB - To date, a completely in vitro repopulated tissue-engineered heart valve has not been developed. This study focused on sequentially seeding 2 cell populations onto porcine decellularized heart valve leaflets (HVL) and pericardia (PER) to obtain fully repopulated tissues. For repopulation of the interstitium, porcine valvular interstitial cells (VIC) and bone marrow-derived mesenchymal stem cells (BM-MSC) or adipose tissue-derived stem cells (ADSC) were used. In parallel, the culture medium was supplemented with ascorbic acid 2-phosphate (AA) and its effect on recolonization was investigated. Subsequently and in order to obtain an endothelial surface layer similar to those in native HVL, valvular endothelial cells (VEC) were seeded onto the scaffolds. It was shown that VIC efficiently recolonized HVL and partially also PER. On the other hand, stem cells only demonstrated limited or no subsurface cell infiltration of HVL and PER. Interestingly, the addition of AA increased the migratory capacity of both stem cell populations. However, this was more pronounced for BM-MSC, and recolonization of HVL appeared to be more efficient than that of PER tissue. VEC were demonstrated to generate a new endothelial layer on HVL and PER. However, scanning microscopy revealed that these endothelial cells were not allowed to fully spread onto PER. This study provided a proof of concept for the future generation of a bioactive tissue-engineered heart valve by showing that bioactive HVL could be generated in vitro within 14 days via complete repopulation of the interstitium with BM-MSC or VIC and subsequent generation of an entirely new endothelium. PMID- 29131081 TI - Overexpression of the Transmembrane Protein IQGAP3 Is Associated with Poor Survival of Patients with Gastric Cancer. AB - OBJECTIVE: Spheroid colony formation is a useful method of cancer stem cell (CSC) characterization. We previously showed that the IQ motif containing the GTPase activating protein 3 gene (IQGAP3) is upregulated in spheroid body-forming gastric cancer (GC) cells compared with parental cells. We investigated IQGAP3 expression in GC. METHODS: IQGAP3 protein expression was analyzed by immunohistochemistry in 165 GC cases. RNA interference was used to inhibit IQGAP3 expression in GC cell lines. RESULTS: In non neoplastic gastric mucosa, weak staining of IQGAP3 was observed in the foveolar epithelium, while GC tissue showed stronger, more extensive staining. Of the 165 GC cases, 34 (21%) were positive for IQGAP3 expression. GC cases positive for IQGAP3 were found more frequently in stage II/III/IV cases than in stage I cases. Univariate and multivariate analyses demonstrated that IQGAP3 expression is an independent prognostic classifier of GC patients. Both the number and size of the spheres formed by MKN-74 cells were significantly reduced by knockdown of IQGAP3. The phosphorylation of Akt and Erk1/2 was inhibited by knockdown of IQGAP3. CONCLUSION: These results suggest that IQGAP3 plays an important role in gastric CSCs. The location of IQGAP3 on the cell membrane makes it a potential therapeutic target for GC. PMID- 29131082 TI - Aspirin Inhibits Platelet-Derived Sphingosine-1-Phosphate Induced Endothelial Cell Migration. AB - BACKGROUND: Aspirin plays a crucial role in the prevention of cardiovascular diseases. We previously described that aspirin has effects beyond inhibition of platelet aggregation, as it inhibited thrombin-mediated release of sphingosine-1 phosphate (S1P) from human platelets. S1P is a bioactive lipid with important functions on inflammation and apoptosis. In endothelial cells (EC), S1P is a key regulator of cell migration. In this study, we aimed to analyze the effects of aspirin on platelet-induced EC migration. METHODS: Human umbilical EC migration was measured by Boyden chamber assay. EC migration was induced by platelet supernatants of thrombin receptor-activating peptide-1 (AP1) stimulated platelets. To investigate the S1P receptor subtype that promotes EC migration, specific inhibitors of S1P receptor subtypes were applied. RESULTS: S1P induced EC migration in a concentration-dependent manner. EC migration induced by AP1 stimulated platelet supernatants was reduced by aspirin. S1P1 receptor inhibition almost completely abolished EC migration induced by activated platelets. The inhibition of S1P2 or S1P3 receptor had no effect. CONCLUSION: Aspirin inhibits EC migration induced by activated platelets that is in part due to S1P and mediated by the endothelial S1P1 receptor. The clinical significance of this novel mechanism of aspirin action has to be investigated in future studies. PMID- 29131083 TI - The Effect of Nutritive and Non-Nutritive Sweeteners on the Growth, Adhesion, and Biofilm Formation of Candida albicans and Candida tropicalis. AB - OBJECTIVE: To determine the effect of glucose, sucrose, and saccharin on growth, adhesion, and biofilm formation of Candida albicans and Candida tropicalis. MATERIALS AND METHODS: The growth rates of mono-cultures of planktonic C. albicans and C. tropicalis and 1:1 mixed co-cultures were determined in yeast nitrogen broth supplemented with 5% (30 mM) and 10% (60 mM) glucose, sucrose, and saccharin, using optical density measurements at 2-h intervals over a 14-h period. Adhesion and biofilm growth were performed and the growth quantified using a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The biofilm architecture was visualized using scanning electron microscopy. One- and two-way analysis of variance (ANOVA) was performed to analyse the differences among multiple means. RESULTS: The highest planktonic growth was noted in 5% glucose after 14 h (p < 0.05). No significant planktonic growth was observed in either concentration of saccharin. Both the concentrations of glucose and sucrose elicited significantly increased adhesion from MTT activity of 0.017 to >0.019 in mono- as well as co-cultures (p < 0.05), whilst the lower concentration of saccharin significantly dampened the adhesion. Maximal biofilm growth was observed in both species with the lower concentration of sucrose (5%), although a similar concentration of saccharin abrogated biofilm development: the highest MTT value (>0.35) was obtained for glucose and the lowest (>0.15) for saccharin. CONCLUSION: In this study, glucose and sucrose accelerated the growth, adhesion, and biofilm formation of Candida species. However, the non-nutritive sweetener saccharin appeared to dampen, and in some instances suppress, these virulent attributes of Candida. PMID- 29131084 TI - Mindfulness-Based Cognitive Therapy as a Treatment for Chronic Tinnitus: A Randomized Controlled Trial. AB - BACKGROUND: Tinnitus is experienced by up to 15% of the population and can lead to significant disability and distress. There is rarely a medical or surgical target and psychological therapies are recommended. We investigated whether mindfulness-based cognitive therapy (MBCT) could offer an effective new therapy for tinnitus. METHODS: This single-site randomized controlled trial compared MBCT to intensive relaxation training (RT) for chronic, distressing tinnitus in adults. Both treatments involved 8 weekly, 120-min sessions focused on either relaxation (RT) or mindfulness meditation (MBCT). Assessments were completed at baseline and at treatment commencement 8 weeks later. The primary outcomes were tinnitus severity (Tinnitus Questionnaire) and psychological distress (Clinical Outcomes in Routine Evaluation - Non-Risk, CORE-NR), 16 weeks after baseline. The analysis utilized a modified intention-to-treat approach. RESULTS: A total of 75 patients were randomly allocated to MBCT (n = 39) or RT (n = 36). Both groups showed significant reductions in tinnitus severity and loudness, psychological distress, anxiety, depression, and disability. MBCT led to a significantly greater reduction in tinnitus severity than RT, with a mean difference of 6.3 (95% CI 1.3-11.4, p = 0.016). Effects persisted 6 months later, with a mean difference of 7.2 (95% CI 2.1-2.3, p = 0.006) and a standardized effect size of 0.56 (95% CI 0.16-0.96). Treatment was effective regardless of initial tinnitus severity, duration, or hearing loss. CONCLUSIONS: MBCT is effective in reducing tinnitus severity in chronic tinnitus patients compared to intensive RT. It also reduces psychological distress and disability. Future studies should explore the generalizability of this approach and how outcome relates to different aspects of the intervention. PMID- 29131085 TI - Lymphadenitis and Lymphadenopathy. PMID- 29131086 TI - Intracranial Epidural Haematoma following Surgical Removal of a Giant Lumbosacral Schwannoma: A Case Report and Literature Review. AB - Postoperative intracranial epidural haematoma (EDH) is an extremely rare complication following spinal surgery, with only a handful of cases described in the literature. We report the case of a 16-year-old girl who underwent a successful subtotal resection of a giant lumbosacral schwannoma (L2-S2 level). Recovery from general anaesthesia was uneventful; however, her neurological status deteriorated rapidly within 24 h after surgery. A head computed tomography scan revealed a large right frontoparietal EDH with midline shift. An immediate frontotemporoparietal osteoplastic craniotomy and evacuation of the EDH were performed. At 1 year postoperatively, the patient regained full neurological recovery with no radiological signs of growth of the residual tumour. PMID- 29131087 TI - Deferoxamine-Induced Migration and Odontoblast Differentiation via ROS-Dependent Autophagy in Dental Pulp Stem Cells. AB - BACKGROUND/AIMS: As a vital degradation and recycling system, autophagy plays an essential role in regulating the differentiation of stem cells. We previously showed that iron chelator deferoxamine (DFO) could promote the repair ability of dental pulp stem cells (DPSCs). Here, we investigated the effect of DFO in autophagy and the role of autophagy in regulating the migration and odontoblast differentiation of DPSCs. METHODS: Transmission electron microscopy, immunofluorescence staining and western blotting were performed to evaluate the autophagic activity of DPSCs. Transmigration assay, alkaline phosphatase staining/activity, alizarin red S staining and quantitative PCR were performed to examine the migration and odontoblast differentiation of DPSCs. Reactive oxygen species (ROS) levels and the effects of ROS scavenger in autophagy induction were also detected. Autophagy inhibitors (3-MA and bafilomycin A1) and lentiviral vectors carrying ATG5 shRNA sequences were used for autophagy inhibition. RESULTS: Early exposure to DFO promoted the mineralization of DPSCs and increased autophagic activity. Autophagy inhibition suppressed DFO-induced DPSC migration and odontoblast differentiation. Furthermore, DFO treatment could induce autophagy partly through hypoxia-inducible factor 1alpha/B cell lymphoma 2/adenovirus E1B 19K-interacting protein 3 (HIF-1alpha/BNIP3) pathway in a ROS dependent manner. CONCLUSION: DFO increased DPSC migration and differentiation, which might be modulated through ROS-induced autophagy. PMID- 29131088 TI - Development and Evaluation of Lipid Nanoparticles Containing Natural Botanical Oil for Sun Protection: Characterization and in vitro and in vivo Human Skin Permeation and Toxicity. AB - The use of sunscreen products is widely promoted by schools, government agencies, and health-related organizations to minimize sunburn and skin damage. In this study, we developed stable solid lipid nanoparticles (SLNs) containing the chemical UV filter octyl methoxycinnamate (OMC). In parallel, we produced similar stable SLNs in which 20% of the OMC content was replaced by the botanical urucum oil. When these SLNs were applied to the skin of human volunteers, no changes in fluorescence lifetimes or redox ratios of the endogenous skin fluorophores were seen, suggesting that the formulations did not induce toxic responses in the skin. Ex vivo (skin diffusion) tests showed no significant penetration. In vitro studies showed that when 20% of the OMC was replaced by urucum oil, there was no reduction in skin protection factor (SPF), suggesting that a decrease in the amount of chemical filter may be a viable alternative for an effective sunscreen, in combination with an antioxidant-rich vegetable oil, such as urucum. There is a strong trend towards increasing safety of sun protection products through reduction in the use of chemical UV filters. This work supports this approach by producing formulations with lower concentrations of OMC, while maintaining the SPF. Further investigations of SPF in vivo are needed to assess the suitability of these formulations for human use. PMID- 29131089 TI - Human Chorionic Gonadotropin Test: Old Uncertainties, New Perspectives, and Value in 46,XY Disorders of Sex Development. AB - The human chorionic gonadotropin (hCG) test represents a key step in assessing Leydig cell function in prepubertal males, but differences in terms of hCG doses, number of injections, and sequence of blood drawing are published in the literature, showing poor standardization. The few available data in healthy boys are summarized here. A recombinant hCG (rhCG) formulation might permit overcoming some controversies as well as avoid the potential biological risk related to the injection of extractive hormones. Studies in humans are scarce, but they indicate that 250 ug rhCG in a single dose may represent a useful scheme for the dynamic evaluation of Leydig cell function in children as well as in adults. The main indication for hCG testing in childhood is the investigation of 46,XY disorders of sex differentiation. The test must also be considered in order to investigate the presence of functional testicular tissue when gonadal peptide hormones cannot be measured. PMID- 29131090 TI - Online Self-Help as an Add-On to Inpatient Psychotherapy: Efficacy of a New Blended Treatment Approach. AB - BACKGROUND: Depression is one of the most frequent and costly mental disorders. While there is increasing evidence for the efficacy of online self-help to improve depression or prevent relapse, there is little evidence in blended care settings, especially combined with inpatient face-to-face psychotherapy. Therefore, we evaluated whether an evidence-based online self-help program improves the efficacy of inpatient psychotherapy. METHODS: A total of 229 depressed patients were randomly allocated either to an online self-help program (intervention group [IG]; Deprexis) or an active control group (CG; weekly online information on depression) in addition to inpatient psychodynamic psychotherapy. Both groups had access to their respective experimental intervention for 12 weeks, regardless of inpatient treatment duration. Reduction of depressive symptoms, as measured with the Beck Depression Inventory-II, was the primary outcome at the end of the intervention (T2). RESULTS: Depressive symptoms were statistically significantly lower in the IG compared to the active CG at T2 with a moderate between-group effect size of d = 0.44. The same applied to anxiety (d = 0.33), quality of life (d = 0.34), and self-esteem (d = 0.38) at discharge from inpatient treatment (T1). No statistically significant differences were found regarding dysfunctional attitudes (d = 0.14) and work ability (d = 0.08) at T1. CONCLUSIONS: This is the first evidence for blended treatment combining online self-help with inpatient psychotherapy. The study opens new and promising avenues for increasing the efficacy of inpatient psychotherapy. Future studies should determine how integration of online self-help into the therapeutic process can be developed further. PMID- 29131091 TI - Apathy Profile in Parkinson's and Huntington's Disease: A Comparative Cross Sectional Study. AB - BACKGROUND/AIMS: Apathy is one of the most frequent, disabling and difficult-to treat symptoms that show up in many neurodegenerative disorders. The aim of this study was to assess and compare apathy profile in Parkinson's and Huntington's patients using the same comprehensive instruments to measure apathy, cognition and depressive symptoms. MATERIALS AND METHODS: We consecutively assessed Parkinson's disease (PD) and Huntington's disease (HD) patients recruited from a Movement Disorders Unit. In all patients, information related to demographics, clinical data, motor score (Movement Disorders Society-Unified Parkinson Disease Rating Scale; Unified Huntington Disease Rating Scale), cognition (Montreal Cognitive Assessment scale), depressive symptoms (Beck Depression Inventory II) and apathy (Apathy Evaluation Scale - clinical version) was collected. Patients with dementia or major depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised criteria were excluded from the study. RESULTS: Seventy-five patients were enrolled, 45 with PD and 30 with HD. Apathy was present in 42.5% of PD patients and 51.7% of HD patients. In PD patients, apathy was associated with motor score, shorter duration of disease, lower dose of levodopa equivalent daily dose and depressive symptomatology, whereas in HD patients, apathy was related to disease duration, motor score and cognitive impairment. CONCLUSIONS: We found a similar prevalence of apathy in PD and HD patients but with different clinical correlations and different apathy domains involved, and this may warrant the development of different therapeutic approaches. PMID- 29131092 TI - Value of Intraoperative Parathyroid Hormone Assay during Parathyroidectomy in Dialysis and Renal Transplant Patients with Secondary and Tertiary Hyperparathyroidism. AB - BACKGROUND: In dialysis and renal transplant patients with secondary and tertiary hyperparathyroidism (HPT), the value of intraoperative parathyroid hormone (ioPTH) during parathyroidectomy (PTX) and its association with long-term PTH levels are unknown. The present study aims at evaluating the relationship of ioPTH with long-term PTH levels post-PTX in dialysis and renal transplant patients in a single-center study. METHODS: The ioPTH was measured in 57 dialysis patients (33 females and 24 males) and 18 renal transplant recipients (12 males and 6 females) who underwent PTX from 2005 to 2015 for refractory HPT. Near-total PTX was performed in 56 patients and total PTX with autotransplantation in 20 patients. The PTH monitoring included 3 samples: pre-intubation, 10- and 20-min (pre-ioPTH, 10-ioPTH, and 20-ioPTH) post parathyroid gland excision. Patients were followed up for up to 5 years. RESULTS: In the dialysis group, the median (25th-75th percentile) pre-, 10-, and 20-ioPTH levels were 1,447 pg/mL (938 2,176), 143 pg/mL (78-244) and 112 pg/mL (59-153) respectively. In the renal transplant group, pre-, 10-, and 20-ioPTH levels were 273 pg/mL (180-403), 42 pg/mL (25-72), and 34 pg/mL (23-45) respectively. All patients in the transplant group had a functional kidney transplant at the time of PTX with a median serum creatinine of 1.3 mg/dL (1.2-1.7) and estimated glomerular filtration rate of 55 mL/min (40-60). The median time between renal transplant and PTX surgeries was 22 months (7-81). The last median follow-up PTH level was 66 pg/mL (15-201) in the dialysis group and 54 pg/mL (17-72) in the transplant group (p = 0.438). The mean time for last PTH post-PTX was 2.3 +/- 2.0 years. In both groups, there was no significant difference between 20-ioPTH and any-time post-PTX PTH levels (p = 0.6 and p = 0.9). Nineteen patients (25%) were readmitted within 90 days because of hypocalcemia. One patient in the dialysis group was readmitted for post-PTX hematoma evacuation. No patient required repeat PTX because of recurrent HPT that was refractory to medical therapy. Only one dialysis patient required repeat PTX because the first procedure failed. CONCLUSIONS: The 20-ioPTH is a good indicator of long-term PTH levels in dialysis and renal transplant patients. Hypocalcemia is a common complication, particularly in dialysis patients, and it is the main reason for readmission after PTX. Hypoparathyroidism is a potential concern after PTX in dialysis patients. PMID- 29131093 TI - Metformin for Rapidly Maturing Girls with Central Adiposity: Less Liver Fat and Slower Bone Maturation. AB - BACKGROUND/AIMS: Girls with low-birth weight (LBW) and postnatal weight catch-up tend to develop visceral and hepatic fat excess, which may be accompanied by an upregulated adrenarche with precocious pubarche (PP) and by a rapidly progressive puberty with early menarche and shorter stature. A pilot study suggested that metformin treatment for 4 years reduces central adiposity in LBW-PP girls and normalizes puberty and adult height. In this cohort, we studied the relationship between metformin treatment, bone maturation, and body composition. METHODS: Longitudinal hand X-rays (0-4 years, analyzed by BoneXpert) were available from 34 LBW-PP girls (89% of the original cohort; n = 17 untreated, n = 17 metformin treated; age at the start of treatment 8 years) along with body composition (0-4 years, by DXA), hepatic fat, and abdominally subcutaneous and visceral fat (posttreatment, by MRI). RESULTS: The tempo of bone aging was accelerated in untreated girls (~16% faster vs. chronological aging) and normal in metformin treated girls (~20% slower vs. untreated girls). Metformin-treated girls gained more height per bone-age year and had less visceral and hepatic fat. The tempo of bone maturation was associated (R = 0.55; p < 0.001) with hepatic fat. CONCLUSION: Metformin treatment in rapidly maturing girls with central adiposity normalized bone maturation. This normalization was accompanied by less central fat and was related closely to hepatic fat. PMID- 29131094 TI - Pleurodesis Using Mistletoe Extract Delivered via a Spray Catheter during Semirigid Pleuroscopy for Managing Symptomatic Malignant Pleural Effusion. AB - BACKGROUND: Talc poudrage during thoracoscopy is considered the standard procedure for patients with symptomatic malignant pleural effusion (MPE). Until now, no alternative technique other than talc poudrage for pleurodesis during medical thoracoscopy has been proposed. Liquid sclerosants, such as mistletoe extract, have been sprayed evenly into the pleural cavity during semirigid pleuroscopy for chemical pleurodesis. OBJECTIVE: We conducted a retrospective study using the database of semirigid pleuroscopy to identify the usefulness of pleurodesis using a mistletoe extract delivered via a spray catheter during semirigid pleuroscopy for symptomatic MPE. METHODS: All consecutive patients with symptomatic MPE who underwent semirigid pleuroscopy from October 2015 to September 2016 were registered. The responses were evaluated using chest X- ray or computed tomography 4 weeks after pleurodesis. RESULTS: The study included 43 patients who underwent pleurodesis with mistletoe extract via a spray catheter during semirigid pleuroscopy. Complete and partial responses were seen in 21 (49%) and 19 (44%) patients, respectively. The median duration of chest tube placement after pleurod-esis was 7 days (range 6-8 days) in the 40 patients with complete or partial responses. No cases of severe hemorrhage, empyema formation, respiratory failure, or procedure-related mortality were observed in the subjects at 4 weeks after semirigid pleuroscopy. CONCLUSION: Pleurodesis with mistletoe extract delivered via a spray catheter during semirigid pleuroscopy is a safe and effective procedure for managing symptomatic MPE. PMID- 29131095 TI - Intracranial Internal Carotid Artery Wall Calcification in Ischemic Strokes Treated with Thrombolysis. AB - BACKGROUND: Calcifications are an important element of atherosclerotic plaques and have been used as a marker of atherosclerosis and clinical outcome predictor in different vascular territories. CT-scan, performed in the acute ischemic stroke setting, can reliably detect intracranial arterial calcifications. OBJECTIVES: To investigate the association between intracranial internal carotid artery calcification and functional outcome, symptomatic intracerebral hemorrhage (sICH), recanalization, and death. METHODS: We included 396 consecutive ischemic stroke patients submitted to recombinant tissue plasminogen activator treatment between January 2011 and September 2014. Admission CT-scans were reviewed to calculate the Total Carotid Syphon Calcification score. Patients were followed for up to at least 6 months post-stroke or until death. Outcome measures included evaluation of recanalization on the first 24 h (transcranial color coded Doppler or angio-CT), sICH, and assessment of functional outcome at 3 months after stroke (using modified Rankin scale). RESULTS: Carotid artery wall calcification did not predict sICH, recanalization or any good outcome. However, it was a statistically significant predictor of death (OR 1.102, 95% CI [1.004-1.211], p = 0.042). DISCUSSION: Intracranial carotid artery calcification does not increase the risk of thrombolysis-induced sICH. Patients with higher grade of carotid artery wall calcification may have a higher mortality rate. PMID- 29131096 TI - Women Serum Concentrations of the IL-10 Family of Cytokines and IFN-gamma Decrease from the Third Trimester of Pregnancy to Active Labor. AB - Labor is regarded as increased myometrial activity with a regular contractility pattern. At this final stage of pregnancy, myometrial quiescence is lost, accompanied by altered immune homeostasis. It is well known that the interleukin (IL)-10 family of cytokines modulates immunological responses mainly in epithelial cells, including the endometrium. To investigate their inflammatory profile during labor, we performed a longitudinal study in a group of healthy pregnant women (n = 20) with uncomplicated pregnancies in the third trimester of pregnancy and during active labor. Blood was sampled from pregnant women in the third trimester (gestational age 32-38 weeks, mean 36 +/- 2 weeks) and during active labor (39-41 weeks of gestation, mean 40 +/- 1 weeks). Serum levels of several cytokines were measured using multiplex immunoassays for both stages, indicating that the concentrations of IL-10, IL-20, IL-22, IL-28A, and interferon (IFN)-gamma were significantly decreased during active labor in comparison with third-trimester levels (p < 0.05). Our analysis did not find significant correlations between IL-10, IL-20, IL-22, IL-28A, and IFN-gamma levels and gestational age. However, our data suggest that the systemic downregulation of several members of the IL-10 family of cytokines plays an important role in the activation of myometrial smooth cells associated with uterine contractions during active labor. Downregulation of this IL-10 family of cytokines seems to coincide with the well-reported functional progesterone withdrawal during labor. Likewise, lower plasma IFN-gamma concentrations may indicate a role for IFN-gamma in active labor. PMID- 29131098 TI - Implementation of a New High-Volume Circular Stapler in Stapled Anopexy for Hemorrhoidal Disease: Is Patient's Short-Term Outcome Affected by a Higher Volume of Resected Tissue? AB - BACKGROUND: Stapled anopexy is a safe technique for the treatment of hemorrhoids but carries a higher risk of recurrence, which might be caused due to the limited volume of resected tissue. In this study, we investigated the introduction of a high-volume circular stapling device; in particular whether an increased amount of resected tissue could affect patients' short-term postoperative outcome. METHODS: Between 2011 and 2015, stapled anopexy was performed for hemorrhoids and/or anal prolapse in 141 patients (n = 25 conventional PPH-3(c)-stapler versus n = 116 high-volume CHEX(c)-stapler). In this prospectively collected dataset, operation details and short-term postoperative outcome were compared. RESULTS: With the high-volume stapler, a significantly higher amount of tissue was resected: 9.8 g (range 6.2-11.4) vs. 6.4 g (range 4.9-8.8) with the conventional stapler, p < 0.01. Postoperative short-term outcome did not differ in terms of readmission and complication rates. In all 5 patients who underwent a redo operation for residual hemorrhoids or prolapse, the high-volume stapler was used in the primary operation. CONCLUSION: A high-volume stapling device for stapled anopexy was introduced safely with a significantly higher amount of resected tissue without a worse short-term outcome. However, it remains unclear whether higher stapling volumes may lead to improved long-term outcome with less reinterventions. PMID- 29131097 TI - Fluoxetine Treatment in Rats Increases the Rate of Taurine Transport in Mononuclear Cells. AB - : Fluoxetine, a selective serotonin reuptake inhibitor antidepressant, modulates the mitogen-induced proliferation of lymphocytes. Lymphocytes contain taurine and express taurine transporter (TauT). Among the effects of taurine on lymphocytes are protection against oxidants and regulation of the inflammatory aspects of the immune response. Our aim was to determine the influence of fluoxetine treatment on taurine transport, and to determine the presence of TauT in the mononuclear cells of rats. METHODS: Male adult Sprague-Dawley rats were treated with fluoxetine 10 mg/kg i.p. for 1, 2, and 3 weeks. The cells were obtained by density gradients. [3H]Taurine was used for transport assays. Amino acid levels were determined by high-performance liquid chromatography. Immunolabeling of CD4+, CD8+, and TauT was performed. The mRNA of TauT was evaluated by RT-PCR. Controls were included for each protocol. RESULTS: The transport of taurine, after 1 week of treatment, was significantly augmented compared to controls. The affinity significantly increased at 1 and 2 weeks. While the percentage of CD4+ cells decreased and that of CD8+ cells increased, the percentage of TauT in CD4+ and CD8+ cells was not affected. Reduction of levels of aspartic acid, glutamic acid, threonine, alanine, glycine, and arginine occurred at 1 and 2 weeks. The taurine concentration significantly decreased after 2 and 3 weeks of treatment. The estimation of mRNA of TauT was not different. CONCLUSION: Taurine transport increases with fluoxetine treatment, and so this could be related to an immunomodulatory role of fluoxetine through TauT. Inhibition of serotonin reuptake might be involved in the regulation of taurine transport in mononuclear cells. PMID- 29131099 TI - The Prevalence of Periodontitis Is Increased in Psoriasis and Linked to Its Inverse Subtype. AB - Periodontitis and psoriasis are suggested to be co-occurring, chronic inflammatory conditions with overlapping characteristics. However, respective evidence is rare and data on risk factors of periodontitis in psoriasis patients are minimal. The aim of this study was to expand the evidence of psoriasis associated periodontitis and establish a potential risk profile for periodontitis. In total, data from 209 exacerbated psoriasis patients were retrospectively analyzed on recordings of periodontitis and compared with those of 91 patients with chronic spontaneous urticaria (CSU). Analysis showed a significantly increased prevalence of periodontitis in psoriasis compared to CSU patients with an odds ratio of 3.76 (95% CI = 1.60-10.27, p = 0.001). Within the psoriatic subtypes, the presence of the inverse type (affecting intertriginous body areas) was strongly linked to periodontitis with an odds ratio of 5.11 (95% CI = 1.36-20.38, p = 0.006). These results are enlarging the evidence for psoriasis-associated periodontitis and identify a link between the inverse type of psoriasis and periodontitis. PMID- 29131100 TI - Association of p53 Codon 72 Polymorphism with Breast Cancer in a Rwandese Population. AB - BACKGROUND AND AIMS: A common polymorphism in the tumor suppressor gene p53 at codon 72 has been suggested to play a role in the development of a number of cancers. This polymorphism has been studied in many populations worldwide, with conflicting results. The present study was planned to assess the association of p53 codon 72 polymorphism with breast cancer development in a Rwandese population. METHODS: In this study, the polymorphism was examined by allele specific PCR analysis in 40 patients with breast cancer and 39 healthy controls. RESULTS: The heterozygous genotype Pro/Arg prevailed in both breast cancer patients and controls, and was present in 80% (32/40) and 92.3% (36/39) of cases, respectively. No statistically significant association was observed between p53 codon 72 polymorphism and breast cancer risk. Distribution of p53 genotypes was also studied according to familial history, tumor grade, and clinical stage, and results clearly showed no statistically significant difference. CONCLUSION: These results suggest that p53 codon 72 polymorphism could not be assessed as a risk factor marker for predisposition to breast cancer in Rwanda. However, further studies using larger sample sizes are needed to provide more conclusive results and to investigate other genetic mutations affecting the activity of p53. PMID- 29131101 TI - Outcomes and Prognostic Factors in Pediatric Oligodendroglioma: A Population Based Study. AB - BACKGROUND/AIMS: Pediatric oligodendroglioma (pODG) is a rare primary brain tumor that remains poorly understood. Demographics, outcomes, and prognostic factors were analyzed in 346 pODG cases from the Surveillance, Epidemiology, and End Results database. METHODS: Gender, race, age, tumor location, tumor size, tumor grade, extent of resection, and use of radiotherapy were evaluated with respect to overall survival (OS) by univariate and multivariate analysis. These factors were assessed in the pediatric cohort and 5,753 adult oligodendroglioma cases for comparison. RESULTS: The mean OS in pODG was 199.6 months. Five- and 10-year survival rates were 85 and 81%. pODG arose less frequently in the frontal lobe than adult tumors (53 vs. 22%) but was more common in the temporal lobe (32 vs. 18%) and extracortical regions (19 vs. 5%, p < 0.0001). pODG presented with smaller size (55 vs. 24%, p < 0.0001) and lower grade (72 vs. 54%, p < 0.0001) than adult tumors. Tumor location, size, grade, use of radiotherapy, and extent of resection were significant prognostic factors. Size and grade were much stronger prognostic factors in children than adults. While children with oligodendroglioma survive much longer than adults on the whole, there was no difference in outcome between children with high-grade tumors and adults with high-grade tumors. CONCLUSION: pODG differs significantly from adult oligodendroglioma along a number of demographic and tumor factors at a population level, and key prognostic factors influence survival differently in pODG than in adult disease. PMID- 29131103 TI - Hodgkin Lymphoma. PMID- 29131102 TI - A Case of a 4-Year-Old Female with a Primary Spinal Malignancy Presenting with Froin's Syndrome. AB - We report the case of a 4-year-old female with a primary extradural intramedullary atypical teratoid/rhabdoid tumor (AT/RT) leading to a middle cerebral artery (MCA) infarct and Froin's syndrome. She presented with a 6-pound weight loss over the previous week, as well as a decreased urinary output and an altered mental status. She underwent a brain MRI that revealed a left MCA infarct, mild ventriculomegaly, and bilateral internal carotid artery, M1, and A1 stenosis. An external ventricular drain (EVD) was placed due to increased intracranial pressure. Cerebrospinal fluid (CSF) was analyzed via lumbar puncture that revealed extremely elevated protein. However, CSF sampled from the EVD was completely normal, a phenomenon called Froin's syndrome. The following day, she developed a right MCA infarct. Her grim prognosis was discussed with her family and care was eventually withdrawn. The patient underwent an autopsy which confirmed a spinal AT/RT. To our knowledge, this is the first reported case of stroke and Froin's syndrome as the initial manifestations of a primary spinal AT/RT with a late onset of spinal cord compression due to tumor obstruction. PMID- 29131105 TI - Survival Rates in Closed and Open Vitrification for Human Mature Oocyte Cryopreservation: A Meta-Analysis. AB - BACKGROUND/AIMS: Survival of warmed oocytes is the first part and is one of the most important aspects of in vitro fertilization following oocyte cryopreservation. There is no definite conclusion about the difference in survival rates between closed and open vitrification for oocyte cryopreservation. This study aimed to investigate whether there is a difference in survival rates between closed and open vitrification for cryopreservation of human mature oocytes. METHODS: A literature search was performed using the MEDLINE, Cochrane Central Register of Controlled Trials, and Embase databases. A total of 4 studies were included in the meta-analysis. RESULTS: In the frequentist meta-analysis, the random effects model showed no statistically significant difference in survival rates between closed and open vitrification (risk ratio [RR] 0.8873, 95% confidence interval [CI] 0.7658-1.0280). However, an effect size deviation of the RR from 1.0 and a borderline trend of the 95% CI were noted. In the Bayesian meta analysis, the posterior probability that closed vitrification would decrease the survival rate when compared to that with open vitrification was 83.04% for the random effects model. CONCLUSION: It is not yet possible to conclude that closed vitrification is an aseptic alternative to open vitrification in human mature oocyte cryopreservation. PMID- 29131106 TI - Gut Microbiota-Dependent Modulation of Energy Metabolism. AB - The gut microbiota has emerged as an environmental factor that modulates the host's energy balance. It increases the host's ability to harvest energy from the digested food, and produces metabolites and microbial products such as short chain fatty acids, secondary bile acids, and lipopolysaccharides. These metabolites and microbial products act as signaling molecules that modulate appetite, gut motility, energy uptake and storage, and energy expenditure. Several findings suggest that the gut microbiota can affect the development of obesity. Germ-free mice are leaner than conventionally raised mice and they are protected against diet-induced obesity. Furthermore, obese humans and rodents have an altered gut microbiota composition with less phylogeneic diversity compared to lean controls, and transplantation of the gut microbiota from obese subjects to germ-free mice can transfer the obese phenotype. Taken together, these findings indicate a role for the gut microbiota in obesity and suggest that the gut microbiota could be targeted to improve metabolic diseases like obesity. This review focuses on the role of the gut microbiota in energy balance regulation and its potential role in obesity. PMID- 29131107 TI - An Evolutionary Approach to Clinical Pharmacopsychology. PMID- 29131108 TI - Genetic and Pathological Assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in Familial and Sporadic Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Mutations in the genes encoding the heterogeneous nuclear ribonucleoproteins hnRNPA1 and hnRNPA2/B1 have been reported in a multisystem proteinopathy that includes amyotrophic lateral sclerosis (ALS) and inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia. Mutations were also described in the prion-like domain of hnRNPA1 in patients with classic ALS. Another hnRNP protein, hnRNPA3, has been found to be associated with the ALS/frontotemporal dementia protein C9orf72. OBJECTIVE: To further assess their role in ALS, we examined these hnRNPs in spinal cord tissue from sporadic (SALS) and familial ALS (FALS) patients, including C9orf72 repeat expansion-positive patients, and controls. We also sought to determine the prevalence of HNRNPA1, HNRNPA2B1, and HNRNPA3 mutations in Australian ALS patients. METHODS: Immunostaining was used to assess hnRNPs in ALS patient spinal cords. Mutation analysis of the HNRNPA1, HNRNPA2B1, and HNRNPA3 genes was performed in FALS and of their prion-like domains in SALS patients. RESULTS: Immunostaining of spinal motor neurons of ALS patients with the C9orf72 repeat expansion showed significant mislocalisation of hnRNPA3, and no differences in hnRNPA1 or A2/B1 localisation, compared to controls. No novel or known mutations were identified in HNRNPA1, HNRNPA2B1, or HNRNPA3 in Australian ALS patients. CONCLUSIONS: hnRNPA3 pathology was identified in motor neurons of ALS patients with C9orf72 repeat expansions, implicating hnRNPA3 in the pathogenesis of C9orf72-linked ALS. hnRNPA3 warrants further investigation into the pathogenesis of ALS linked to C9orf72. This study also determined that HNRNP mutations are not a common cause of FALS and SALS in Australia. PMID- 29131109 TI - Histological Assessment of Gonads in DSD: Relevance for Clinical Management. AB - Malignant gonadal germ cell tumors, referred to as germ cell cancers (GCC), occur with increased frequency in individuals who have specific types of differences (disorders) of sex development (DSD). Recent population-based studies have identified new environmental and genetic risk factors that have led to a 'genvironment' hypothesis, which may potentially be helpful in risk assessment in DSD-related GCC. In DSD, the malignancy risk is highly heterogeneous, but recent studies allow now to discriminate between high- and low-risk conditions. Gonadal biopsy is in some cases the best procedure of choice to assess the risk, and with the availability of immunohistochemical biomarkers [OCT3/4 (POU5F1), TSPY, SOX9, FOXL2 and KITLG (SCF)], a reliable classification of GCC and its precursors can be made. The opportunities in the field of virtual diagnostic pathology will be presented, having possibilities for rare diseases in general and DSD specifically. It is expected that the International DSD Registry will stimulate international collaborations, facilitating better diagnostic procedures as well as research. PMID- 29131110 TI - Long-Term and Short-Term Antidepressant Use in General Practice: Data from a Large Cohort in the Netherlands. AB - BACKGROUND: Antidepressant use is highly prevalent. Research has mainly focused on efficacy during short periods of use for depression and anxiety. There is a relative paucity of data regarding the frequency of long-term use. METHODS: To determine the prevalence and possible increase of long-term use of antidepressants over recent years, we analyzed routine general practice care data in a large cohort of patients (n = 156,620) in and around Amsterdam, The Netherlands. Additionally, predictors of long-term use were studied. RESULTS: Prevalence of long-term use of antidepressants is substantial, and such use appears to be increasing: 30.3% of use was long-term over the period 1995-2005 compared to 43.7% for the period 2005-2015. Higher age, a registered diagnosis of anxiety or depression, and the use of SSRIs or SNRIs were associated with long term use in multivariate analysis. In addition, specific antidepressants were differentially associated with long-term use. CONCLUSIONS: Long-term antidepressant use is substantial and appears to be on the rise. Awareness of this phenomenon should be increased, such use should be prevented when possible, and reasons for long-term use need to be examined. PMID- 29131112 TI - Spurious Hyperchloremia in the Presence of Elevated Plasma Salicylate: A Cohort Study. AB - BACKGROUND: Acute metabolic acidosis is rarely associated with a reduced or negative anion gap (AG), but several case reports have described such an abnormality occurring in the setting of acute salicylate intoxication. The underlying cause of this phenomenon is unclear. METHODS: In this retrospective cohort study, we reviewed our institutional database to identify all patients admitted for salicylate intoxication at Mayo Clinic (Rochester, MN, USA) from January 2010 through December 2012. Serum chloride was measured with the Cobas INTEGRA 400 plus electrode (expedited laboratory test) or Cobas 6000 (routine laboratory test). We compared blood chloride levels measured by the 2 devices in the presence of positive blood salicylate level. RESULTS: Twelve adult patients with salicylate levels >20 mg/dL had markedly elevated chloride concentrations. The median (interquartile range) chloride level at admission was 120 (107-145) mmol/L on their initial laboratory studies, resulting in reduced or even negative AGs. None of the patients had bromide toxicity, nor did they have any other identifiable cause of hyperchloremia or decreased AG. Further testing of the same blood samples with an alternative measurement system (Roche Cobas 6000) yielded normal chloride values, indicating that falsely elevated chloride values with the initial testing led to the diminished or negative AG values. CONCLUSION: Circulating levels of salicylate can interfere with chloride measured by using routine techniques, resulting in spurious hyperchloremia outcomes and erroneous AG values. In patients with acute metabolic acidosis and abnormally reduced or negative AG, salicylate interference with chloride measurement should be suspected. PMID- 29131111 TI - Physical Activity and Fatigue in Patients with Sarcoidosis. AB - BACKGROUND: Little is known about physical activity in daily life among patients with sarcoidosis. Fatigue is a frequent and disabling symptom that might negatively affect physical activity levels. METHODS: In patients with sarcoidosis, we measured physical activity (steps per day) by accelerometry (SenseWear Armband) for 1 week. We assessed lung function (DLCO, FVC), exercise capacity (6-min walking distance [6MWD]), health-related quality of life (St George's Respiratory Questionnaire [SGRQ]), generic quality of life (12-Item Short-Form Health Survey [SF-12]), and fatigue (Multidimensional Fatigue Inventory [MFI-20]). RESULTS: We investigated 57 patients with sarcoidosis (mean age 50 years, 56% male, mean DLCO 73% predicted, mean FVC 91% predicted, mean 6MWD 525 m, mean steps per day 7,490), of whom n = 14 (25%) had severe fatigue. The MFI-20 subscales "reduced activity" and "physical fatigue" were weakly associated with steps per day on a bivariate level (Spearman rho = -0.274 and rho = -0.277, respectively; p < 0.05), while the other subscales and the total score were not. 6MWD, SGRQ score, and SF-12 (physical health) score showed stronger associations with steps per day in bivariate analyses (Pearson r = 0.499, r = 0.386, and r = 0.467, respectively; p < 0.01), and were independent predictors of steps per day in multivariate linear regression analyses adjusting for confounders (p < 0.05). In ROC curve analyses, 6MWD, SGRQ score, and SF-12 (physical health) score properly identified sedentary patients (steps per day <5,000; AUROC 0.90, 0.81, and 0.80, respectively; p < 0.01). Fatigue was less predictive (MFI-20 subscale "general fatigue," AUROC 0.70; p = 0.03). CONCLUSION: While exercise capacity and quality of life measurements were robust predictors of physical activity in patients with sarcoidosis, associations of objectively measured physical activity with fatigue were surprisingly weak. In sarcoidosis, fatigue might not preclude affected patients from being physically active, although this symptom is subjectively perceived as highly disabling. PMID- 29131113 TI - Speech Production Quality of Cochlear Implant Users with Respect to Duration and Onset of Hearing Loss. AB - PURPOSE: To assess whether postlingual onset and shorter duration of deafness before cochlear implant (CI) provision predict higher speech intelligibility results of CI users. METHODS: For an objective judgement of speech intelligibility, we used an automatic speech recognition system computing the word recognition rate (WR) of 50 adult CI users and 50 age-matched control individuals. All subjects were recorded reading a standardized text. Subjects were divided into three groups: pre- or perilingual deafness (A), both >2 years before implantation, postlingual deafness <2 years before implantation (B), or postlingual deafness >2 years before implantation (C). RESULTS: CI users with short duration of postlingual deafness (B) had a significantly higher WR (median 74%) than CI users with long duration of postlingual deafness (C; 68%, p < 0.001) or pre-/perilingual onset (A; 56%, p < 0.001). Compared to their control groups only CI users with short duration of postlingual deafness reached similar WR, others showed significantly lower WR. Other factors such as hearing loss onset, duration of CI use, or duration of amplified hearing showed no consistent influence on speech quality. CONCLUSIONS: The speech production quality of adult CI users shows dependencies on the onset and duration of deafness. These features need to be considered while planning rehabilitation. PMID- 29131115 TI - Fine-Needle Cytology: Technical Procedures and Ancillary Techniques. PMID- 29131114 TI - Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3. AB - OBJECTIVE: The present study evaluated the ability of rosmarinic acid (RA) to inhibit microglia activation induced by lipopolysaccharide (LPS) in the N9 murine microglial cell line, and investigated the putative mechanisms involved in this process. METHODS: In all tests, N9 murine microglial cells were pretreated with RA (0.1, 1.0, and 10 MUM) for 20 h and exposed to LPS (1 MUM/mL) for 4 h. Cell viability was measured by Trypan blue exclusion assay. Flow cytometry was used to detect reactive oxygen species (ROS), quantify cleaved caspase-3, and analyze the mitochondrial electrochemical potential. iNOS, Arg-1, TNF-alpha, IL-1beta, and IL 6 proteins were analyzed by Western blotting, and their antigens were detected using the chemiluminescence technique. The effect of RA on DNA was evaluated by the Comet assay. RESULTS: RA attenuated the expression of the M1 marker iNOS and the levels of proinflammatory factors, including TNF-alpha, IL-1beta, and IL-6; it increased the expression of the M2 marker Arg-1, and inhibited, at least in part, ROS generation and loss of mitochondrial outer membrane permeabilization through the inhibition of cleaved caspase-3 activation. RA also inhibited DNA damage, reassuring cell protection. CONCLUSIONS: The results suggested a protective effect of RA through downregulation of inflammatory cytokines and cleaved caspase-3. PMID- 29131116 TI - Detection of a Splice Site Variant in a Patient with Glomerulopathy and Fibronectin Deposits. AB - BACKGROUND/AIMS: Glomerulopathy with fibronectin deposits (GFND; OMIM: 601894) is a very rare inherited kidney disease caused by pathogenic variants in the FN1 gene. Only 9 exonic pathogenic variants in FN1, 9 at the heparin-binding site, and 1 at the integrin-binding site have been reported. No intronic variants in FN1 have been detected. METHODS: We found a pathogenic intronic variant in intron 36 (c.5888-2A>G) located at the heparin-binding site. To determine whether this mutation influences splicing processes, we conducted RT-PCR analysis and an in vitro splicing assay using minigene construction. RESULTS: RT-PCR using RNA extracted from leukocytes of the proband failed because of the low expression of FN1 mRNA in leukocytes. We conducted in vitro functional splicing analysis using minigenes and found that c.5888-2A>G caused a 12 bp deletion at exon 37 by the activation of a novel splicing acceptor site within exon 37. We were able to detect the same abnormal transcript in mRNA extracted from the patient's urinary sediment and confirmed the pathogenicity of c.5888-2A>G by both RT-PCR using the patient sample and an in vitro splicing assay. CONCLUSION: Intronic variants can cause GFND. Minigene analysis is useful for determining the pathogenicity of the intronic variants and could be used for all inherited kidney diseases. PMID- 29131117 TI - Significant Hemorrhage Rate Reduction after Gamma Knife Radiosurgery in Symptomatic Cavernous Malformations: Long-Term Outcome in 95 Case Series and Literature Review. AB - BACKGROUND: The natural history of cavernous malformations (CMs) has remained unclear. This lack of knowledge has made treatment decisions difficult. Indeed, the use of stereotactic radiosurgery is nowadays controversial. The purpose of this paper is to throw light on the effectiveness of Gamma Knife radiosurgery (GKRS) therapy. METHODS: The authors reviewed data collected from a prospectively maintained database. A total of 95 patients (57 female and 38 male) underwent GKRS for high-surgical-risk CMs. A total of 76 cavernomas were deeply located (64 lesions in the brainstem and 12 lesions in the thalamus). All of them were located in eloquent regions. The median malformation volume was 1,570 mm3. The median tumor margin dose was 11.87 Gy, and the mean tumor maximum dose was 19.56 Gy. RESULTS: Ninety-five cavernous CMs were managed from 1994 to 2014. All patients had experienced at least 1 symptomatic bleeding incident before treatment (only 1 hemorrhage event in 81%). The median length of follow-up review was 78 months. The pretreatment annual hemorrhage rate was 3.06% compared with 1.4% during the first 3-year latency interval, and 0.16% thereafter (p = 0.004). Four patients developed new location-dependent neurological deficits, and 3 patients had edema-related headache after radiosurgery. All of them presented full recovery. CONCLUSIONS: The best dosage range for preventing bleeding was identified as between 11 and 12 Gy in our series. Although the efficacy of radiosurgery in CMs remains impossible to quantify, a very significant reduction in the bleeding rate occurs after a 3-year latency interval. No permanent neurological morbidity is reported in our series. These results defend the safety of GKRS in surgical high-risk CM from the first bleeding event. PMID- 29131119 TI - R.H. Stetson, Motor Phonetics: A Study of Speech Movements in Action, 2nd ed., Amsterdam, North Holland Publishing Co., 1951. PMID- 29131120 TI - A Prospective Study to Evaluate a Diagnostic Algorithm for the Use of Fluid Lymphocyte Subset Analysis in Undiagnosed Unilateral Pleural Effusions. AB - BACKGROUND: Haematological malignancy is an important cause of pleural effusion. Pleural effusions secondary to haematological malignancy are usually lymphocyte predominant. However, several other conditions such as carcinoma, tuberculosis, and chronic heart failure also cause lymphocytic effusions. Lymphocyte subset (LS) analysis may be a useful test to identify haematological malignancy in patients with lymphocytic effusions. However, research into their utility in pleural effusion diagnostic algorithms has not yet been published. OBJECTIVES: We aimed to determine the clinical utility of pleural fluid LS analysis and whether it can be applied to a diagnostic algorithm to identify effusions secondary to haematological malignancy. The secondary aim was to evaluate the diagnostic value of pleural fluid differential cell count. METHODS: Consecutive consenting patients presenting to our pleural service between 2008 and 2013 underwent thoracentesis and differential cell count analysis. We proposed an algorithm which selected patients with lymphocytic effusions (>50%) to have further fluid sent for LS analysis. Two independent consultants agreed on the cause of the original effusion after a 12-month follow-up period. RESULTS: A total of 60 patients had samples sent for LS analysis. LS analysis had an 80% sensitivity (8/10) and a 100% specificity for the diagnosis of haematological malignancy. The positive and negative predictive values were 100 and 96.1%, respectively. Overall 344 differential cell counts were analysed; 16% of pleural effusions with a malignant aetiology were neutrophilic or eosinophilic at presentation. A higher neutrophil and eosinophil count was associated with benign diagnoses, whereas a higher lymphocyte count was associated with malignant diagnoses. CONCLUSIONS: LS analysis may identify haematological malignancy in a specific cohort of patients with undiagnosed pleural effusions. A pleural fluid differential cell count provides useful additional information to streamline patient pathway decisions. PMID- 29131121 TI - Emerging Insights and New Perspectives on the Nature of Hydrocephalus. PMID- 29131122 TI - Response to "An Evolutionary Approach to Clinical Pharmacopsychology". PMID- 29131123 TI - Exploring Factors Associated with Depression and Anxiety among Hospitalized Patients with Type 2 Diabetes Mellitus. AB - OBJECTIVES: The aims of the current study were to determine the prevalence and severity of anxiety and depression, and to explore associated factors among hospitalized patients with type 2 diabetes mellitus. SUBJECTS AND METHODS: All patients with type 2 diabetes (160 patients) who were admitted to the Internal Medicine Wards of the King Abdulaziz Medical City, Riyadh, Saudi Arabia, from January to August 2015 were asked to participate, and 158 patients agreed to do so. A self-administered questionnaire consisting of 2 parts was used. The first part was on sociodemographic information, and the second part was a validated screening tool for assessing depression and anxiety. The severity of anxiety and depression was classified as normal, mild, moderate, and severe. Logistic regression was carried out to identify variables that were independently associated with anxiety and depression. RESULTS: Using the screening tool, 85 (53.8%) and 80 (50.6%) study patients were identified as patients who suffered from depression and anxiety, respectively. The severity of distress was moderate/severe in 36 (42.4%) patients with depression and 41 (51.3%) patients with anxiety. The factors independently associated with the risk for anxiety in hospitalized patients with diabetes were physical inactivity and staying 8 days or longer in the hospital. On the other hand, factors that were independently associated with the risk for depression were older age, low income, and nephropathy. CONCLUSION: The majority of hospitalized patients with diabetes developed moderate/severe anxiety or depression, or both, during hospitalization. Hence, screening for anxiety and depression in high-risk hospitalized diabetic patients is recommended during hospitalization. PMID- 29131124 TI - Comparison of Helicobacter pylori Eradication Rates of 2-Week Levofloxacin Containing Triple Therapy, Levofloxacin-Containing Bismuth Quadruple Therapy, and Standard Bismuth Quadruple Therapy as a First-Line Regimen. AB - OBJECTIVE: The aim of this study was to compare the efficacy and safety of 2-week levofloxacin-containing triple therapy, levofloxacin-containing bismuth quadruple therapy, and standard bismuth-containing quadruple therapy as a first-line regimen for the eradication of Helicobacter pylori. METHODS: A total of 329 patients with H. pylori infection were randomly divided into 3 groups to receive one of the following regimens: (a) levofloxacin-containing bismuth quadruple therapy, RBAL (rabeprazole 20 mg, b.i.d., bismuth subsalicylate 562 mg, b.i.d., amoxicillin 1 g, b.i.d, levofloxacin 500 mg, once daily), (b) standard bismuth quadruple therapy, RBMT (rabeprazole 20 mg, b.i.d, subsalicylate 562 mg, b.i.d., metronidazole 500 mg, t.i.d, tetracycline 500 mg, q.i.d), or (c) levofloxacin containing triple therapy, RAL (rabeprazole 20 mg, b.i.d., amoxicillin 1 g, b.i.d, levofloxacin 500 mg, once daily). The primary outcome was the eradication rate in the intention-to-treat (ITT) and per protocol (PP) analysis. RESULTS: The eradication rates of the above 3 groups using ITT analysis were RBAL 83.8%, RBMT 88.3%, and RAL 74.8% compared with 91.2, 92.5, and 79.2%, respectively, using PP analysis. The eradication rate using RBMT was significantly higher than that of RAL (p = 0.029 in ITT analysis and p = 0.017 in PP analysis). Several side effects occurred in 156 patients (54.1%) in the RBAL group, 215 (52.3%) in the RBMT group, and 56 (26.2%) in the RAL group (p > 0.05, RBAL vs. RBMT; p < 0.001, RBMT vs. RAL; p < 0.001, RBAL vs. RAL). CONCLUSION: All bismuth-containing quadruple therapies had acceptable eradication rates, but levofloxacin-containing triple therapy was not as good as quadruple therapies. Hence, quadruple therapies should be considered the preferred first-line therapy for H. pylori infections. PMID- 29131126 TI - Extending the Neuroanatomic Territory of Diffuse Midline Glioma, K27M Mutant: Pineal Region Origin. AB - Diffuse midline glioma, H3-K27M mutant (DMG-K27M) is a newly described, molecularly distinct infiltrative glioma that almost exclusively arises in midline CNS structures, including the brain stem, especially the pons, as well as the thalamus and spinal cord with rare examples seen in the cerebellum, third ventricle, and hypothalamus. To our knowledge, only 1 case of a molecularly confirmed DMG-K27M arising in the pineal region has been previously reported. We present the second occurrence of a tissue-confirmed DMG-K27M of the pineal region, which, to our knowledge, is the first case reported in a child and the first case with documented preoperative MRI. This case, in addition to a prior report described in an adult, defines the lower end of a broad age range of DMG K27M onset (12-65 years) and establishes the pineal gland as a bona fide site of origin for this newly codified midline glioma. PMID- 29131125 TI - Splanchnic-Cerebral Oxygenation Ratio Decreases during Enteral Feedings in Anemic Preterm Infants: Observations under Near-Infrared Spectroscopy. AB - BACKGROUND: Anemia is common in premature infants. Due to risks with red blood cell transfusions, many anemic infants are not transfused. The implications of this pathophysiologic status, especially at times of increased metabolic demand (enteral feedings), is not well understood. Near-infrared spectroscopy (NIRS) allows for the noninvasive determination of regional oxygen saturations (rSO2) in tissues such as the brain and mesentery, giving insight into their oxygen sufficiency. OBJECTIVE: We tested the hypothesis that during enteral feedings very low birth weight (VLBW) infants with a hematocrit <=28% will experience a decrease in splanchnic rSO2 and splanchnic-cerebral oxygenation ratio (SCOR). METHODS: This prospective, observational, 2-centered study included VLBW infants receiving full enteral feedings with a hematocrit <=28%. Cerebral and splanchnic rSO2 were monitored via NIRS for 24 h. Average values were calculated for periods immediately preceding, during, and after each feeding. SCOR was calculated from these values (rSO2 splanchnic/rSO2 cerebral), and data were analyzed using a linear mixed effect model. RESULTS: Fifty neonates with a median gestational age of 28 weeks (range 23-32), a birth weight of 1,118 +/- 284 g (mean +/- SD), and a hematocrit of 26 +/- 2% (mean +/- SD) were studied. During feedings, SCOR decreased significantly from baseline (0.72 +/- 0.17 to 0.69 +/- 0.17, p = 0.043). With feedings, there was a trend of decreased splanchnic rSO2 (47 +/- 11 to 45 +/- 10, p = 0.057) and no change in cerebral rSO2 (66 +/- 8 to 66 +/- 7, p = 0.597). CONCLUSIONS: VLBW infants with a hematocrit <=28% had a decrease in SCOR and a trend towards decreased splanchnic rSO2 with enteral feedings. PMID- 29131127 TI - Pleiotropic Effects of White Willow Bark and 1,2-Decanediol on Human Adult Keratinocytes. AB - BACKGROUND: Acne vulgaris is a common skin defect, usually occurring during adolescence, but often it can persist in adults leaving permanent face scarring. Acne is usually treated with topical drugs, oral antibiotics, retinoids, and hormonal therapies, but medicinal plants are increasingly employed. OBJECTIVE: To investigate the protective role of white willow bark (WWB) and 1,2-decanediol (DD) on the damage caused by lipopolysaccharides (LPS) on human adult keratinocytes (HaCaT). METHODS: HaCaT were exposed to LPS alone or in association with WWB and DD. Epidermal viability, metabolic modulation, inflammatory activity, and cell migration were assessed with both common standardized protocols or high-throughput screening systems. RESULTS: The preincubation of HaCaT with WWB and DD (used separately or in combination) differently prevented the alterations induced by LPS on HaCaT in terms of growth factor release (IGF, EGF, VEGF), cytokine production (IL-1alpha, IL-6, IL-8), or expression of the transcription factor FOXO-I. Moreover, they partially restore wound repair lowered by LPS. CONCLUSIONS: These results suggest that both natural compounds were able to differently affect several functions of LPS-stressed keratinocytes suggesting their potential role for the prevention of acne vulgaris, without adverse effects. PMID- 29131128 TI - Clinical Factor 2016. PMID- 29131129 TI - Effect of Diazepam on 24-Hour Blood Pressure and Heart Rate in Healthy Young Volunteers. AB - AIM: To assess the effects of evening chronic administration of diazepam on 24-h blood pressure (BP) and heart rate (HR) in healthy young adults. METHODS: This randomized double blind, cross-over study evaluated the effects of diazepam 5 mg or placebo, both ingested in the evening, on 24-h ambulatory BP and HR in healthy subjects aged 21-30. RESULTS: A total of 30 subjects were included in the analysis. At the end of 4-week diazepam intake, an increase in 24-h HR mean values was found (+5.2 beats/min, p < 0.05). Analysis of subperiods showed that diazepam produced a 10.1% increase in night-time HR (+6.1 beats/min, p < 0.01) without affecting BP. A significant HR rise (+4.9 beats/min, p < 0.05) and SBP reduction (-3.8 mm Hg, p < 0.05) were observed in the morning hours. The HR increase persisted in day-time hours (+4.6 beats/min, p < 0.05), while BP values resulted unaffected. CONCLUSIONS: In healthy subjects, diazepam taken as a hypnotic agent induces a significant HR increase, possibly mediated by a decrease in vagal tone. This effect might be of clinical relevance due to the role that HR plays as an independent cardiovascular risk factor. PMID- 29131130 TI - Prediction of Intraoperative Urinary Collecting System Entry in Patients with Peripheral Renal Tumors Undergoing Partial Nephrectomy: Usefulness of Tumor Centered Multiplanar Reconstruction. AB - OBJECTIVE: To assess the usefulness of tumor-centered multiplanar reconstruction (TC-MPR) for predicting intraoperative urinary collecting system (UCS) entry in patients with peripheral renal tumors undergoing partial nephrectomy (PN). METHODS: Dynamic computed tomography images of 50 peripheral cT1 renal tumors treated with laparoendoscopic PN were analyzed. TC-MPR generated a digital cross sectional image showing the tumor center and the closest calyx on a same plane. Patients and tumor characteristics including the distance from the tumor margin to the closest calyx (MPR-distance), and the angle formed by 2 tangent lines from the closest calyx to the tumor (MPR-angle) were assessed. RESULTS: Intraoperative UCS entry was observed in 15 patients (30%). The patients who experienced intraoperative UCS entry had a higher RENAL score, wider MPR-angle, and shorter MPR-distance than those who did not (p = 0.04, p = 0.001, p < 0.001, respectively). Multivariate analysis identified MPR-angle as an independent factor for intraoperative UCS entry (p < 0.001). CONCLUSIONS: The spatial information assessed using TC-MPR serves as a predictive factor for intraoperative UCS entry during PN. PMID- 29131131 TI - Gamma Knife Stereotactic Radiosurgery for the Treatment of Primary and Metastatic Ocular Malignancies. AB - BACKGROUND: Gamma knife radiosurgery (GKR) can be used for precise targeting of malignant lesions of the CNS when brachytherapy is not an appropriate option. OBJECTIVES: This study reports treatment technique, efficacy, and radiation induced adverse effects in patients with primary and metastatic ocular lesions treated with Leksell GKR. METHODS: A retrospective, single-institution review was conducted of 28 patients with primary or metastatic ocular disease, treated from 2000 to 2014. The dose to margin was 17-27 Gy (maximum dose 28-54 Gy). Primary outcomes included overall survival (OS), local control, progression-free survival (PFS), and enucleation. RESULTS: The median age at diagnosis was 70 years, and the median follow-up was 26.4 months. Of the 28 patients, 11 (39%) had metastatic ocular disease, and 17 (61%) were diagnosed with primary ocular melanoma (stage T2a-T4e). The average maximum dose and dose to margin were 41 and 21 Gy, respectively. The mean dose to the optic nerve was 12.6 Gy. The 5-year OS was 46% (95% CI: 23.6-68.4%) for the entire cohort; the 5-year PFS for M0 patients who presented with primary ocular melanoma lesions was 90% (95% CI: 71-100%). Only 1 patient required enucleation after radiation treatment. CONCLUSION: GKR is an effective option, with acceptable levels of toxicity, in the treatment of primary and metastatic ocular lesions. PMID- 29131132 TI - Points of Concern in Post Acute Kidney Injury Management. AB - The incidence of acute kidney injury (AKI) will in the future remain high, partly due to an increase in comorbidities and other AKI favoring factors such as the rise in high-risk diagnostic and therapeutic interventions. AKI has emerged as a major public health concern with high human and financial costs. It has recently been demonstrated that patients surviving an AKI episode show increased all-cause mortality, chronic kidney disease (CKD), ESRD, cardiovascular events, and reduced quality of life. Although it is important to acknowledge that, after an AKI episode, the risk of dying by far exceeds the risk of developing incident or progressive CKD and/or entering a maintenance renal replacement therapy (RRT) program, currently only a minority of patients are referred for renal follow-up, even after AKI-requiring RRT. On the other hand, renal follow-up for all AKI survivors might not be necessary and would represent an overwhelming work load for the health care system. There are at present no clear guidelines on which patients should be referred and on the elements of post AKI care that may improve non-renal and renal outcomes. In this review, we discuss several points of concern in post-AKI management and propose an algorithm on post-AKI care, mainly based on the renal recovery pattern at discharge from the hospital. Potential opportunities to improve care include appropriate risk stratification, close monitoring of kidney function, management of CKD complications, blood pressure control, medication reconciliation, and education of patients and non nephrologists on AKI and its downstream complications. PMID- 29131133 TI - Sulphonated Formononetin Induces Angiogenesis through Vascular Endothelial Growth Factor/cAMP Response Element-Binding Protein/Early Growth Response 3/Vascular Cell Adhesion Molecule 1 and Wnt/beta-Catenin Signaling Pathway. AB - BACKGROUND: Sodium formononetin-3'-sulphonate (Sul-F) is a derivative of the isoflavone formononetin. In this study, we investigated whether Sul-F can regulate angiogenesis and the potential mechanism in vitro. METHODS: We examined the effects of Sul-F on cell proliferation, cell invasion, and tube formation in the human umbilical vein endothelial cell line (HUVEC). To better understand the mechanism involved, we investigated effects of the following compounds: cAMP response element-binding protein (CREB) inhibitor 2-naphthol-AS-E-phosphate (KG 501), early growth response 3 (Egr-3) siRNA, vascular endothelial growth factor (VEGF) antagonist soluble VEGF receptor 1 (sFlt-1), VEGF receptor 2 blocker SU 1498, Wnt5a antagonist WIF-1 recombinant protein (WIF-1), and inhibitor of Wnt/beta-catenin recombinant Dickkopf-1 protein (DKK-1). HUVEC proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A scratch adhesion test was used to assess cell invasion ability. Matrigel tube formation assay was performed to test capillary tube formation ability. Activation of the VEGF/CREB/Egr-3/Vascular cell adhesion molecule 1 (VCAM-1) pathway in HUVEC was tested by Western blot analysis. RESULTS: Our results suggest that Sul-F induced angiogenesis in vitro by enhancing cell proliferation, invasion, and tube formation. The increase in proliferation and tube formation by Sul-F was counteracted by DKK-1, WIF-1, SU1498, KG-501, sFlt-1, and Egr-3 siRNA. CONCLUSIONS: These results may suggest that Sul-F induces angiogenesis in vitro via a programed Wnt/beta-catenin pathway and VEGF/CREB/Egr-3/VCAM-1 signaling axis. PMID- 29131134 TI - Mannose-Binding Lectin Does Not Act as a Biomarker for the Progression of Preinvasive Lesions of Invasive Cervical Cancer. AB - OBJECTIVE: To evaluate serum concentrations of mannose-binding lectin (MBL) in women presenting with different human papillomavirus (HPV)-associated cervical lesions. SUBJECTS AND METHODS: A total of 364 women, who underwent screening for cervical cancer or treatment at the Erasto Gaertner Cancer Hospital (HEG), Curitiba, Brazil, were enrolled in the study. Based on the latest cervical colposcopy-guided biopsy results, the women were divided into 4 groups: cervical intraepithelial neoplasia CIN-I (n = 54), CIN-II (n = 72), CIN-III (n = 145), and invasive cancer (n = 93). A time-resolved immunofluorometric assay was used to measure the MBL concentrations in serum. The statistical analysis was done using GraphPad Prism 6.0. Comparisons were performed by Kruskal-Wallis and Mann-Whitney tests and analyzed by chi2 test; continuous variables are presented as medians and categorical variables as frequencies. RESULTS: The median MBL concentrations in decreasing order were as follows: invasive cancer: 1,452 ng/mL, CIN-I: 1,324 ng/mL, CIN-II: 1,104 ng/mL, and CIN-III 1,098 ng/mL. However, no statistical significance was found among the 4 groups with HPV-associated lesions (p = 0.11). Equally, the MBL levels did not show a significant association between the age of the patients and the severity of the cervical lesions (p = 0.68). No statistical significance was found in the median values of MBL or in the status of MBL deficient (<100 ng/mL) and high producers (>1,000 ng/mL) among the women in each group (p = 0.77). CONCLUSION: In this study, there was no statistically significant difference in MBL serum levels among the groups with CIN. Hence MBL serum concentration appeared not to have influenced the progression of HPV related preinvasive cervical lesions into invasive cancer. PMID- 29131135 TI - Interhemispheric and Infratentorial Subdural Empyema with Preseptal Cellulitis as Complications of Sinusitis: A Case Report. AB - Intracranial complications of paranasal sinusitis have become rare due to the use of antibiotics nowadays. However, several cases have been reported due the ability of paranasal sinusitis to cause serious complications. Once the infection spreads over the cranial structure, it could infect the orbits, underlying bones, meninges, adjacent veins, and brain. Subdural empyema is a rare but potentially life-threatening complication following paranasal sinusitis and should be considered as a neurological emergency. The location where subdural empyema may appear is a challenge in diagnosis and treatment. We report the case of a 17-year old boy who presented in a state of somnolence due to interhemispheric and infratentorial subdural empyema with preseptal cellulitis secondary to pansinusitis. Early diagnosis and aggressive antibiotic treatment combined with neurosurgical operation were mandatorily implemented. The case was managed using a multidisciplinary approach including the ENT, eye, and nutrition departments. The boy achieved clinical improvement, with impairment of eye movement as the only persistent symptom before discharge. Daily supervision at the primary health care center with continuous antibiotic treatment was recommended to the patient. Pertinent literature with controversies in the management of subdural empyema will be briefly discussed in this case report. PMID- 29131136 TI - Malignant Pleural Effusions: Mistletoe Spray Instead of Talc Poudrage? PMID- 29131137 TI - Georges Millardet, Etudes de dialectologie landaise. Le developpement des phonemes additionnels, Toulouse, Edouard Privat, 1910, 224 Pages. PMID- 29131138 TI - Impact of Altered WNT2B Expression on Bladder Wall Fibroblasts: Implications for Apoptosis Regulation in the Stroma of the Lower Urinary Tract. AB - BACKGROUND: Little is known about the role of WNT signalling in pathological processes involving the urinary tract stroma. Here the impact of WNT signalling on bladder wall fibroblasts (BWFs) was studied using integrated expression profiling. MATERIAL AND METHODS: WNT ligand and downstream WNT pathway component expression was profiled in human BWFs using qRT-PCR. Highly expressed WNT2B was knocked down using siRNA in BWFs. The expression of 730 mRNAs and 800 miRNAs was analyzed on the nCounter MAX platform in #WNT2B and control transfected BWFs. qRT PCR was used for validation in vitro and in matched scar and healthy bladder wall tissue samples of 12 patients with vesico-urethral anastomotic stricture (VUAS). RESULTS: Thirteen genes and 9 miRNAs showed differential expression in #WNT2B cells. Among these were TNFSF10, a key apoptosis inductor, (0.22fold, p = 0.011) and miR-1246 (36.2fold, p = 0.031). miRNA target prediction indicated TNFSF10 to be regulated by miR-1246. qRT-PCR analysis confirmed differential expression of miR-1246 and TNFSF10 in #WNT2B BWFs. Furthermore, TNFSF10 was significantly underexpressed in VUAS tissue (p = 0.009). CONCLUSION: Perturbation of WNT signalling results in an altered expression of the apoptosis inductor TNFSF10. Similar changes are observed in VUAS. Further studies investigating the crosslink between WNT signalling and apoptosis regulation in the urinary tract stroma are warranted. PMID- 29131139 TI - Capsaicin Used on Skin Influences Ion Transport Pathways: An in vitro Study. AB - Acute, adverse skin effects to capsaicin can be activated by inhibition of sodium transport not only in nociceptive neurons, but also in keratinocytes. The aim of the current study was to describe and compare immediate (15 s) and prolonged (30 min) effects of capsaicin on epidermal (not neural) sodium transport using a rabbit skin model. Skin fragments (n = 169) were incubated in 4 conditions: undisturbed ion transport (U; n = 48); inhibited sodium transport (INa; n = 34) with amiloride used as sodium transport blocker; long-term irritation by capsaicin with undisturbed ion transport (CAPSA-U; n = 43) and with inhibited sodium transport (CAPSA-INa; n = 35). After 30 min of incubation, a solution of capsaicin was applied directly to the skin fragments. The study demonstrated that sodium transport inhibition eliminated the effects of both immediate and prolonged capsaicin application. The results could be the basis for future research considering selective sodium transport inhibitors for human skin to reduce the side effects of capsaicin, related to activation of sodium channels in keratinocytes. PMID- 29131140 TI - A transient pool of nuclear F-actin at mitotic exit controls chromatin organization. AB - Re-establishment of nuclear structure and chromatin organization after cell division is integral for genome regulation or development and is frequently altered during cancer progression. The mechanisms underlying chromatin expansion in daughter cells remain largely unclear. Here, we describe the transient formation of nuclear actin filaments (F-actin) during mitotic exit. These nuclear F-actin structures assemble in daughter cell nuclei and undergo dynamic reorganization to promote nuclear protrusions and volume expansion throughout early G1 of the cell cycle. Specific inhibition of this nuclear F-actin assembly impaired nuclear expansion and chromatin decondensation after mitosis and during early mouse embryonic development. Biochemical screening for mitotic nuclear F actin interactors identified the actin-disassembling factor cofilin-1. Optogenetic regulation of cofilin-1 revealed its critical role for controlling timing, turnover and dynamics of F-actin assembly inside daughter cell nuclei. Our findings identify a cell-cycle-specific and spatiotemporally controlled form of nuclear F-actin that reorganizes the mammalian nucleus after mitosis. PMID- 29131141 TI - Programming asynchronous replication in stem cells. AB - Many regions of the genome replicate asynchronously and are expressed monoallelically. It is thought that asynchronous replication may be involved in choosing one allele over the other, but little is known about how these patterns are established during development. We show that, unlike somatic cells, which replicate in a clonal manner, embryonic and adult stem cells are programmed to undergo switching, such that daughter cells with an early-replicating paternal allele are derived from mother cells that have a late-replicating paternal allele. Furthermore, using ground-state embryonic stem (ES) cells, we demonstrate that in the initial transition to asynchronous replication, it is always the paternal allele that is chosen to replicate early, suggesting that primary allelic choice is directed by preset gametic DNA markers. Taken together, these studies help define a basic general strategy for establishing allelic discrimination and generating allelic diversity throughout the organism. PMID- 29131143 TI - Nonimmune cells equipped with T-cell-receptor-like signaling for cancer cell ablation. AB - The ability to engineer custom cell-contact-sensing output devices into human nonimmune cells would be useful for extending the applicability of cell-based cancer therapies and for avoiding risks associated with engineered immune cells. Here we have developed a new class of synthetic T-cell receptor-like signal transduction device that functions efficiently in human nonimmune cells and triggers release of output molecules specifically upon sensing contact with a target cell. This device employs an interleukin signaling cascade, whose OFF/ON switching is controlled by biophysical segregation of a transmembrane signal inhibitory protein from the sensor cell-target cell interface. We further show that designer nonimmune cells equipped with this device driving expression of a membrane-penetrator/prodrug-activating enzyme construct could specifically kill target cells in the presence of the prodrug, indicating its potential usefulness for target-cell-specific, cell-based enzyme-prodrug cancer therapy. Our study also contributes to the advancement of synthetic biology by extending available design principles to transmit extracellular information to cells. PMID- 29131142 TI - A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state. AB - Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high-density lipoprotein (HDL) structure and metabolism, probably mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood, as lipid-free apoA-I has been notoriously resistant to high-resolution structural study. Published models from low-resolution techniques share certain features but vary considerably in shape and secondary structure. To tackle this central issue in lipoprotein biology, we assembled a team of structural biologists specializing in apolipoproteins and set out to build a consensus model of monomeric lipid-free human apoA-I. Combining novel and published cross-link constraints, small-angle X ray scattering (SAXS), hydrogen-deuterium exchange (HDX) and crystallography data, we propose a time-averaged model consistent with much of the experimental data published over the last 40 years. The model provides a long-sought platform for understanding and testing details of HDL biogenesis, structure and function. PMID- 29131144 TI - Top-down characterization of endogenous protein complexes with native proteomics. AB - Protein complexes exhibit great diversity in protein membership, post translational modifications and noncovalent cofactors, enabling them to function as the actuators of many important biological processes. The exposition of these molecular features using current methods lacks either throughput or molecular specificity, ultimately limiting the use of protein complexes as direct analytical targets in a wide range of applications. Here, we apply native proteomics, enabled by a multistage tandem MS approach, to characterize 125 intact endogenous complexes and 217 distinct proteoforms derived from mouse heart and human cancer cell lines in discovery mode. The native conditions preserved soluble protein-protein interactions, high-stoichiometry noncovalent cofactors, covalent modifications to cysteines, and, remarkably, superoxide ligands bound to the metal cofactor of superoxide dismutase 2. These data enable precise compositional analysis of protein complexes as they exist in the cell and demonstrate a new approach that uses MS as a bridge to structural biology. PMID- 29131145 TI - Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. AB - Endogenous metabolites play essential roles in the regulation of cellular identity and activity. Here we have investigated the process of oligodendrocyte precursor cell (OPC) differentiation, a process that becomes limiting during progressive stages of demyelinating diseases, including multiple sclerosis, using mass-spectrometry-based metabolomics. Levels of taurine, an aminosulfonic acid possessing pleotropic biological activities and broad tissue distribution properties, were found to be significantly elevated (~20-fold) during the course of oligodendrocyte differentiation and maturation. When added exogenously at physiologically relevant concentrations, taurine was found to dramatically enhance the processes of drug-induced in vitro OPC differentiation and maturation. Mechanism of action studies suggest that the oligodendrocyte differentiation-enhancing activities of taurine are driven primarily by its ability to directly increase available serine pools, which serve as the initial building block required for the synthesis of the glycosphingolipid components of myelin that define the functional oligodendrocyte cell state. PMID- 29131146 TI - Synthetic microbial consortia enable rapid assembly of pure translation machinery. AB - Assembly of recombinant multiprotein systems requires multiple culturing and purification steps that scale linearly with the number of constituent proteins. This problem is particularly pronounced in the preparation of the 34 proteins involved in transcription and translation systems, which are fundamental biochemistry tools for reconstitution of cellular pathways ex vivo. Here, we engineer synthetic microbial consortia consisting of between 15 and 34 Escherichia coli strains to assemble the 34 proteins in a single culturing, lysis, and purification procedure. The expression of these proteins is controlled by synthetic genetic modules to produce the proteins at the correct ratios. We show that the pure multiprotein system is functional and reproducible, and has low protein contaminants. We also demonstrate its application in the screening of synthetic promoters and protease inhibitors. Our work establishes a novel strategy for producing pure translation machinery, which may be extended to the production of other multiprotein systems. PMID- 29131147 TI - Accurate assembly of transcripts through phase-preserving graph decomposition. AB - We introduce Scallop, an accurate reference-based transcript assembler that improves reconstruction of multi-exon and lowly expressed transcripts. Scallop preserves long-range phasing paths extracted from reads, while producing a parsimonious set of transcripts and minimizing coverage deviation. On 10 human RNA-seq samples, Scallop produces 34.5% and 36.3% more correct multi-exon transcripts than StringTie and TransComb, and respectively identifies 67.5% and 52.3% more lowly expressed transcripts. Scallop achieves higher sensitivity and precision than previous approaches over a wide range of coverage thresholds. PMID- 29131149 TI - Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules. AB - The bone marrow (BM) microenvironment contains many types of cells and molecules with roles in hematopoiesis, osteogenesis, angiogenesis and metabolism. The spatial distribution of the different bone and BM cell types remains elusive, owing to technical challenges associated with bone imaging. To map nonhematopoietic cells and structures in bone and BM, we performed multicolor 3D imaging of osteoblastic, vascular, perivascular, neuronal and marrow stromal cells, and extracellular-matrix proteins in whole mouse femurs. We analyzed potential interactions between cells and molecules on the basis of colocalization of markers. Our results shed light on the markers expressed by different osteolineage cell types; the heterogeneity of vascular and perivascular cells; the neural subtypes innervating marrow and bone; the diversity of stromal cells; and the distribution of extracellular-matrix components. Our complete imaging data set is available for download and can be used in research in bone biology, hematology, vascular biology, neuroscience and extracellular-matrix biology. PMID- 29131148 TI - Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing. AB - Efficient genome editing with Cas9-sgRNA in vivo has required the use of viral delivery systems, which have limitations for clinical applications. Translational efforts to develop other RNA therapeutics have shown that judicious chemical modification of RNAs can improve therapeutic efficacy by reducing susceptibility to nuclease degradation. Guided by the structure of the Cas9-sgRNA complex, we identify regions of sgRNA that can be modified while maintaining or enhancing genome-editing activity, and we develop an optimal set of chemical modifications for in vivo applications. Using lipid nanoparticle formulations of these enhanced sgRNAs (e-sgRNA) and mRNA encoding Cas9, we show that a single intravenous injection into mice induces >80% editing of Pcsk9 in the liver. Serum Pcsk9 is reduced to undetectable levels, and cholesterol levels are significantly lowered about 35% to 40% in animals. This strategy may enable non-viral, Cas9-based genome editing in the liver in clinical settings. PMID- 29131151 TI - Combined intensive immunosuppression and eculizumab for aplastic anemia in the context of hemolytic paroxysmal nocturnal hemoglobinuria: a retrospective analysis. PMID- 29131150 TI - Neurologic complications after allogeneic hematopoietic stem cell transplantation: risk factors and impact. AB - Neurologic complications (NCs) may be a significant source of morbidity and mortality after hematopoietic cell transplantation (HCT). We performed a retrospective study of 263 consecutive patients undergoing allogeneic HCT for hematological malignancies to determine the incidence, risk factors and clinical impact of NCs in the first 5 years after HCT. We determined the incidence of central nervous system (CNS) infection, intracranial hemorrhage, ischemic stroke, metabolic encephalopathy, posterior reversal encephalopathy syndrome, seizure and peripheral neuropathy. In all, 50 patients experienced 63 NCs-37 early (?day +100), 21 late (day +101 to 2 years) and 5 very late (2 to 5 years). The 1- and 5 year cumulative incidences of all NCs were 15.6% and 19.2%, respectively, and of CNS complication (CNSC; all of the above complications except peripheral neuropathy) were 12.2 and 14.5%. Risk factors for CNSC were age (hazard ratio (HR)=1.06 per year, P=0.0034), development of acute GvHD grade III-IV (HR=2.78, P=0.041), transfusion-dependent thrombocytopenia (HR=3.07, P=0.025) and delayed platelet engraftment (>90th centile; HR=2.77, P=0.043). CNSCs negatively impacted progression-free survival (HR=2.29, P=0.0001), overall survival (HR=2.63, P<0.0001) and non-relapse mortality (HR=8.51, P<0.0001). NCs after HCT are associated with poor outcomes, and usually occur early after HCT. PMID- 29131152 TI - Elevated pre-transplant C-reactive protein identifies a high-risk subgroup in multiple myeloma patients undergoing delayed autologous stem cell transplantation. AB - The significance of elevated C-reactive protein (CRP) prior to autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has not been studied. We analyzed 1111 MM patients who underwent ASCT at Mayo Clinic from 2007 to 2015. A total of 840 patients (76%) received early ASCT (?12 months from diagnosis) and 271 patients (24%) received delayed ASCT (>12 months from diagnosis). Elevated CRP (> upper normal limit (8 mg/L)) was seen in 14% and 22% of patients undergoing early and delayed ASCT, respectively (P=0.003). There was no correlation of CRP with pre-transplant response, bone marrow plasma cell percentage or labeling index. Patients with an elevated CRP had a higher likelihood of having circulating plasma cells prior to ASCT (33 vs 19%; P<0.001). In the early ASCT cohort, the median overall survival (OS) in patients with normal and elevated CRP was not reached and 91 months respectively (P=0.011). In the delayed ASCT cohort, the median OS in respective groups were 73 and 30 months respectively (P<0.001), with elevated CRP being an independent prognostic marker on multivariate analysis (hazard ratio 2.0; 95% confidence interval, 1.0-3.8; P=0.045). Elevated pre-transplant CRP identifies a high-risk population especially in patients undergoing delayed ASCT and should be incorporated in the pre-transplant evaluation. PMID- 29131153 TI - Reduced-toxicity conditioning for allogeneic hematopoietic cell transplantation in elderly or comorbid patients with AML using fludarabine, BCNU and melphalan: disease stage at transplant determines outcome. PMID- 29131154 TI - Impact of HLA-G polymorphism on the outcome of allogeneic hematopoietic stem cell transplantation for metastatic renal cell carcinoma. AB - Renal cell carcinoma (RCC) is particularly sensitive to immune intervention. HLA G, a non-classical HLA class I molecule with immunomodulatory properties, has been studied with regard to outcome after hematopoietic stem cell transplantation (HSCT), in particular the 14 bp insertion/deletion polymorphism in the 3' untranslated region. Here we analyzed n=56 patients affected by metastatic RCC who received an allogeneic HSCT between 1998 and 2006 in Milano, Marseille, Clermont-Ferrand and Stockholm. The 14 bp polymorphism was analyzed in correlation with overall survival (OS), PFS, acute and chronic GvHD. With a median follow-up of 13 years, a trend towards better outcome was observed when homozygosity for the 14bp-del allele was present: multivariate hazard ratio was 0.50 (95% confidence interval (CI): 0.23-1.13; P=0.10) and 0.57 (95% CI: 0.26 1.26; P=0.17) for OS and PFS, respectively, when 14bp-del/del was compared with 14bp-ins/X. Further exploratory analysis revealed a significant association between T/C at p3003 and improved OS (P=0.05) and PFS (P=0.006) compared with T/T. To our knowledge this is the first study on HLA-G and outcome after HSCT for a solid malignancy. After a coordinated multicenter study, we found that the more tolerogenic polymorphisms (14bp-del/del) is associated with better PFS and OS. The finding on p3003 deserves further investigation. PMID- 29131155 TI - Treatment intensity and symptom burden in hospitalized adolescent and young adult hematopoietic cell transplant recipients at the end of life. AB - Adolescent and young adult (AYA) oncology patients experience many physical and psychological symptoms at the end of life (EOL); however, data on these experiences for AYA patients who have undergone hematopoietic cell transplantation (HCT) remains sparse. We sought to investigate the characteristics of AYA patients aged 15-25 years who received allogeneic HCT and subsequently died while inpatient at our institution between the years 2008 and 2014. A standardized data extraction tool was used to collect information about patient demographics, treatment and symptoms. We found that during this time frame, 34 AYA patients had received HCT and died while inpatient at our institution, 23 (68%) of whom died because of treatment-related complications. Compared with non-HCT AYA oncology patients (n=35), patients who received HCT (n=34) were more likely to have died in the intensive care unit (71% vs 23%, P<0 .0001) and to have received mechanical ventilation (68% vs 17%, P<0.0001) or hemodialysis (53% vs 0%, P<0.0001) in the last 30 days of life. These findings demonstrate that AYA patients who receive allogeneic HCT receive intensive EOL treatment, suggesting that these patients may benefit from early integration of expert interdisciplinary services to prospectively assess and manage distressing symptoms. PMID- 29131156 TI - Impact of choice, timing, sequence and combination of broad-spectrum antibiotics on the outcome of allogeneic haematopoietic stem cell transplantation. AB - Recent data link the incidence of intestinal GvHD (iGvHD) after allogeneic haematopoietic stem cell transplantation (aSCT) to exposure with piperacillin tazobactam or imipenem-cilastatin. To assess relevance of timing, duration, sequence and combination of antibiotic treatment in this setting, we applied a time-dependent model to our aSCT cohort. Patients from the prospective Cologne Cohort of Neutropenic Patients (CoCoNut) undergoing aSCT from January 2007 to April 2013 were included into a time-dependent multivariate Cox proportional hazards regression model with backward-stepwise selection. In 399 eligible patients, cumulative antibiotic exposure (hazard ratio (HR) 2.46; 95% confidence interval (95% CI) 1.59-3.81; P<0.001) and exposure to sequential treatment with penicillin derivatives and carbapenems (HR 6.22, 95% CI 1.27-30.31), but not to the individual classes, were associated with iGvHD at day 100. Glycopeptides were assessed as a risk factor (HR 3.73, 95% CI 1.51-9.19), but not considered independent, since their use was dependent on previous exposure to penicillin derivatives and carbapenems. Patients with iGvHD presented with increased non relapse mortality at day 365 (HR 3.51; 95% CI 2.10-5.89; P<0.001). We identified sequential exposure to penicillin derivatives and carbapenems as well as overall exposure to antibiotics as independent risk factors for iGVHD. Confirmation of these findings in larger, prospective cohorts is necessary. PMID- 29131157 TI - Targeting the T cell receptor beta-chain constant region for immunotherapy of T cell malignancies. AB - Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1+ and TRBC2+ compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1+, but not TRBC2+, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity. PMID- 29131158 TI - UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. AB - Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1 independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of alpha1- and/or beta3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling. PMID- 29131159 TI - Enhancing the precision of genetic lineage tracing using dual recombinases. AB - The Cre-loxP recombination system is the most widely used technology for in vivo tracing of stem or progenitor cell lineages. The precision of this genetic system largely depends on the specificity of Cre recombinase expression in targeted stem or progenitor cells. However, Cre expression in nontargeted cell types can complicate the interpretation of lineage-tracing studies and has caused controversy in many previous studies. Here we describe a new genetic lineage tracing system that incorporates the Dre-rox recombination system to enhance the precision of conventional Cre-loxP-mediated lineage tracing. The Dre-rox system permits rigorous control of Cre-loxP recombination in lineage tracing, effectively circumventing potential uncertainty of the cell-type specificity of Cre expression. Using this new system we investigated two topics of recent debates-the contribution of c-Kit+ cardiac stem cells to cardiomyocytes in the heart and the contribution of Sox9+ hepatic progenitor cells to hepatocytes in the liver. By overcoming the technical hurdle of nonspecific Cre-loxP-mediated recombination, this new technology provides more precise analysis of cell lineage and fate decisions and facilitates the in vivo study of stem and progenitor cell plasticity in disease and regeneration. PMID- 29131161 TI - Rapid virtual hematoxylin and eosin histology of breast tissue specimens using a compact fluorescence nonlinear microscope. AB - Up to 40% of patients undergoing breast conserving surgery for breast cancer require repeat surgeries due to close to or positive margins. The lengthy processing required for evaluating surgical margins by standard paraffin-embedded histology precludes its use during surgery and therefore, technologies for rapid evaluation of surgical pathology could improve the treatment of breast cancer by reducing the number of surgeries required. We demonstrate real-time histological evaluation of breast cancer surgical specimens by staining specimens with acridine orange (AO) and sulforhodamine 101 (SR101) analogously to hematoxylin and eosin (H&E) and then imaging the specimens with fluorescence nonlinear microscopy (NLM) using a compact femtosecond fiber laser. A video-rate computational light absorption model was used to produce realistic virtual H&E images of tissue in real time and in three dimensions. NLM imaging could be performed to depths of 100 MUm below the tissue surface, which is important since many surgical specimens require subsurface evaluation due to contamination artifacts on the tissue surface from electrocautery, surgical ink, or debris from specimen handling. We validate this method by expert review of NLM images compared to formalin-fixed, paraffin-embedded (FFPE) H&E histology. Diagnostically important features such as normal terminal ductal lobular units, fibrous and adipose stromal parenchyma, inflammation, invasive carcinoma, and in situ lobular and ductal carcinoma were present in NLM images associated with pathologies identified on standard FFPE H&E histology. We demonstrate that AO and SR101 were extracted to undetectable levels after FFPE processing and fluorescence in situ hybridization (FISH) HER2 amplification status was unaffected by the NLM imaging protocol. This method potentially enables cost effective, real-time histological guidance of surgical resections. PMID- 29131160 TI - Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. AB - Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease. PMID- 29131162 TI - The 3D OrbiSIMS-label-free metabolic imaging with subcellular lateral resolution and high mass-resolving power. AB - We report the development of a 3D OrbiSIMS instrument for label-free biomedical imaging. It combines the high spatial resolution of secondary ion mass spectrometry (SIMS; under 200 nm for inorganic species and under 2 MUm for biomolecules) with the high mass-resolving power of an Orbitrap (>240,000 at m/z 200). This allows exogenous and endogenous metabolites to be visualized in 3D with subcellular resolution. We imaged the distribution of neurotransmitters gamma-aminobutyric acid, dopamine and serotonin-with high spectroscopic confidence in the mouse hippocampus. We also putatively annotated and mapped the subcellular localization of 29 sulfoglycosphingolipids and 45 glycerophospholipids, and we confirmed lipid identities with tandem mass spectrometry. We demonstrated single-cell metabolomic profiling using rat alveolar macrophage cells incubated with different concentrations of the drug amiodarone, and we observed that the upregulation of phospholipid species and cholesterol is correlated with the accumulation of amiodarone. PMID- 29131163 TI - Profiling the transcriptome with RNA SPOTs. AB - Single-molecule FISH (smFISH) has been the gold standard for quantifying individual transcript abundances. Here, we scale up multiplexed smFISH to the transcriptome level and profile 10,212 different mRNAs from mouse fibroblast and embryonic stem cells. This method, called RNA sequential probing of targets (SPOTs), provides an accurate, flexible, and low-cost alternative to sequencing for profiling transcriptomes. PMID- 29131165 TI - Self-recalibration of a robot-assisted structured-light-based measurement system. AB - The structured-light-based measurement method is widely employed in numerous fields. However, for industrial inspection, to achieve complete scanning of a work piece and overcome occlusion, the measurement system needs to be moved to different viewpoints. Moreover, frequent reconfiguration of the measurement system may be needed based on the size of the measured object, making the self recalibration of extrinsic parameters indispensable. To this end, this paper proposes an automatic self-recalibration and reconstruction method, wherein a robot arm is employed to move the measurement system for complete scanning; the self-recalibration is achieved using fundamental matrix calculations and point cloud registration without the need for an accurate calibration gauge. Experimental results demonstrate the feasibility and accuracy of our method. PMID- 29131164 TI - An improved MS2 system for accurate reporting of the mRNA life cycle. AB - The MS2-MCP system enables researchers to image multiple steps of the mRNA life cycle with high temporal and spatial resolution. However, for short-lived mRNAs, the tight binding of the MS2 coat protein (MCP) to the MS2 binding sites (MBS) protects the RNA from being efficiently degraded, and this confounds the study of mRNA regulation. Here, we describe a reporter system (MBSV6) with reduced affinity for the MCP, which allows mRNA degradation while preserving single molecule detection determined by single-molecule FISH (smFISH) or live imaging. Constitutive mRNAs (MDN1 and DOA1) and highly-regulated mRNAs (GAL1 and ASH1) endogenously tagged with MBSV6 in Saccharomyces cerevisiae degrade normally. As a result, short-lived mRNAs were imaged throughout their complete life cycle. The MBSV6 reporter revealed that, in contrast to previous findings, coordinated recruitment of mRNAs at specialized structures such as P-bodies during stress did not occur, and mRNA degradation was heterogeneously distributed in the cytoplasm. PMID- 29131166 TI - Achieving electric field focusing using annular metal-dielectric multilayers. AB - We present studies on an electric field focuser comprised of annular epsilon-near zero metamaterials (ENZMs) and inner free space. According to effective medium theory, annular ENZMs can be realized via annular metal-dielectric multilayers. In practice, we choose silver and air to design the focuser. Our numerical simulations demonstrate that the electric field can be focused on a fixed point, regardless of the number and location of electromagnetic sources in annular multilayers, which might be helpful for laser ignition. PMID- 29131167 TI - Analysis and elimination of bias error in a fiber-optic current sensor. AB - Bias error, along with scale factor, is a key factor that affects the measurement accuracy of the fiber-optic current sensor. Because of polarization crosstalk, the coherence of parasitic interference signals could be rebuilt and form an output independent of the current to be measured, i.e., the bias error. The bias error is a variable of the birefringence optical path difference. Hence, when the temperature changes, the bias error shows a quasi-periodical tendency whose envelope curve reflects the coherence function of light source. By identifying the key factors of bias error and setting the propagation directions of a super luminescent diode, polarization-maintaining coupler and polarizer to fast axis, it is possible to eliminate the coherence of parasitic interference signals. Experiments show that the maximum bias error decreases by one order of magnitude at temperatures between -40 degrees C to 60 degrees C. PMID- 29131168 TI - Learning-based single-shot superresolution in diffractive imaging. AB - We present a method of retrieving a superresolved object field from a single captured intensity image in diffraction-limited diffractive imaging based on machine learning. In this method, the inverse process of diffractive imaging is regressed by using a number of pairs, each consisting of object and captured images. The proposed method is experimentally demonstrated by using a lensless imaging setup with or without scattering media. PMID- 29131169 TI - Analysis of illumination uniformity affected by small-scale self-focusing of a pump beam in the radial smoothing scheme. AB - In the radial smoothing (RS) scheme, small-scale self-focusing (SSSF) can degrade beam quality of a pump beam with a Gaussian pulse train, resulting in the degradation of the smoothing performance of the RS scheme. Considering SSSF of the pump beam in an optical Kerr medium (OKM), the propagation model of the laser beam in the RS scheme has been developed, and the effects of the characteristics of the pump beam and the thickness of the optical Kerr medium on the RS performance have further been numerically simulated and analyzed. The results show that SSSF decreases the illumination uniformity in the RS scheme by inducing distorted wavefront modulation of the pump beam. Consequently, the beam quality of the pump beam should be controlled to avoid the degradation of the RS performance affected by SSSF. In addition, the peak intensity of the pump beam and the thickness of the OKM should be reasonable to ensure RS performance while mitigating the impact of SSSF. PMID- 29131170 TI - Co-phasing experiment of a segmented mirror using a combined broadband and two wavelength algorithm. AB - In this paper, a broadband phasing algorithm is combined with a two-wavelength phasing algorithm to detect the piston error of a segmented mirror with the advantages of long range, high precision, and fast detection. Moreover, an active optics co-phasing experimental system of the segmented mirror is built to verify the algorithm's effectiveness. The segmented mirror consists of four hexagonal segments, with flat-to-flat lengths of 100 mm and radii of curvature of 2000 mm. First, a Shack-Hartmann sensor and piezoelectric actuators are used to finely co focus the segmented mirror. Then, the broadband phasing algorithm is used to reduce the piston error of the segmented mirror to several micrometers. Finally, the two-wavelength phasing algorithm is used to reduce the piston error of the segmented mirror to zero. The experimental results show that the measurement accuracy is better than 26 nm, and the adjustment accuracy is approximately 55 nm, which demonstrates that the combined algorithm is valuable for segmented mirror co-phasing measurement and adjustment. PMID- 29131171 TI - Application of spatially modulated near-infrared structured light to study changes in optical properties of mouse brain tissue during heatstress. AB - Heat stress (HS) is a medical emergency defined by abnormally elevated body temperature that causes biochemical, physiological, and hematological changes. The goal of the present research was to detect variations in optical properties (absorption, reduced scattering, and refractive index coefficients) of mouse brain tissue during HS by using near-infrared (NIR) spatial light modulation. NIR spatial patterns with different spatial phases were used to differentiate the effects of tissue scattering from those of absorption. Decoupling optical scattering from absorption enabled the quantification of a tissue's chemical constituents (related to light absorption) and structural properties (related to light scattering). Technically, structured light patterns at low and high spatial frequencies of six wavelengths ranging between 690 and 970 nm were projected onto the mouse scalp surface while diffuse reflected light was recorded by a CCD camera positioned perpendicular to the mouse scalp. Concurrently to pattern projection, brain temperature was measured with a thermal camera positioned slightly off angle from the mouse head while core body temperature was monitored by thermocouple probe. Data analysis demonstrated variations from baseline measurements in a battery of intrinsic brain properties following HS. PMID- 29131172 TI - Performance analysis of UV multiple-scatter communication system with height difference. AB - Based on the Monte Carlo (MC) method, a non-coplanar ultraviolet (UV) multiple scatter propagation model with a height difference between the transmitter (Tx) and receiver (Rx) was presented. We focused on the relationship between bit error rate (BER) and the height difference between the Tx and Rx. We also studied the impact of the elevation angle and the off-axis angle of the Tx and Rx on the BER under the condition that the height difference is not zero. In addition, an outdoor UV communication testbed was set up to provide support for the validity of the MC model. The simulation results show that when the height difference between the Tx and Rx increases, the BER first decreases and then increases, the BER can be reduced by adjusting the transceiver elevation angle, and the bigger the off-axis angle is, the bigger BER is. The experimental results are in good agreement with the simulation results. PMID- 29131173 TI - Dielectric metalenses with engineered point spread function. AB - High-index silicon nanoblocks support excitation of both electric and magnetic resonance modes at telecommunication wavelengths. At frequencies where both electric and magnetic resonance modes are excited simultaneously, changing the geometrical dimensions of the silicon cubes creates a 2pi full span over the phase of the transmitted light in different amplitude ranges. We take advantage of the additional power-flux modulation of the scattered signal to focus the incident light with desired full width at half maximum (FWHM) and side lobe levels (SLLs) in both the lateral and axial directions. By implementing proper amplitude filters within the telecommunication working wavelength (1.55 MUm), a FWHM less than half of the wavelength (0.42lambdaeff) and apodization with nearly faded SLLs are achievable. Our approach introduced in this paper provides a new way to design high efficiency metalenses with desired FWHM and SLL of focal spot. PMID- 29131174 TI - Tunable graphene plasmonic Y-branch switch in the terahertz region using hexagonal boron nitride with electric and magnetic biasing. AB - A tunable graphene plasmonic Y-branch switch at THz wavelengths is proposed. The effects of magnetic and electric biasing are studied to harness the transmission of the transverse electric and magnetic guided mode resonances. In the structure, hexagonal boron nitride is utilized as a substrate for graphene. The application of hexagonal boron nitride, with the advantages of high mobility and ultralow ohmic loss, introduces a promising alternative substrate for graphene. Analytical and numerical results show that, by slight variation of the doping level in graphene through magnetic and electric biasing, the characteristics of the propagation of the guided mode resonances can be manipulated. A large extinction ratio of 40 dB at a wavelength of 60 MUm is obtained. Besides, the proposed switch shows a low insertion loss of about 1 dB and a relatively large optical bandwidth of 1 MUm. The electric biasing is of the order of 0.1 mV. Additionally, with the presence of magnetic biasing, a compact switch with a size of 25 MUm is achieved. Showing a high extinction ratio, low insertion loss, and compact size, the proposed switch can find potential applications in graphene plasmonics integrated devices. PMID- 29131175 TI - Speckle pattern sequential extraction metric for estimating the focus spot size on a remote diffuse target. AB - The speckle pattern (line by line) sequential extraction (SPSE) metric is proposed by the one-dimensional speckle intensity level crossing theory. Through the sequential extraction of received speckle information, the speckle metrics for estimating the variation of focusing spot size on a remote diffuse target are obtained. Based on the simulation, we will give some discussions about the SPSE metric range of application under the theoretical conditions, and the aperture size will affect the metric performance of the observation system. The results of the analyses are verified by the experiment. This method is applied to the detection of relative static target (speckled jitter frequency is less than the CCD sampling frequency). The SPSE metric can determine the variation of the focusing spot size over a long distance, moreover, the metric will estimate the spot size under some conditions. Therefore, the monitoring and the feedback of far-field spot will be implemented laser focusing system applications and help the system to optimize the focusing performance. PMID- 29131176 TI - Automatic, high-accuracy image registration in confocal microscopy. AB - We proposed a high-accuracy image registration method of confocal microscopy for a large field of view and high resolution. The spatial information (edge information) and the entropy correlation coefficient have been both taken into account for higher accuracy of registration. The edge information is introduced to calculate the normalization correlation coefficient of the image. Then the normalization correlation coefficient and the entropy correlation coefficient of the original image have been used to improve the proposed similarity measures, the normalized mutual information with edge information (called EMI). Meanwhile, a parallel particle swarm optimization (pa-PSO) with the idea of conditional initialization and parallel cooperation is developed to speed up the convergence rate and further reduce the mismatch. Experiments verified that the registration accuracy can be up to 0.2 pixel and has better robustness to the noise. PMID- 29131177 TI - High-power continuous-wave narrow-linewidth 253.7 nm deep-ultraviolet laser. AB - A 760 mW stable continuous-wave narrow-linewidth 253.7 nm deep-ultraviolet laser is developed for laser cooling of mercury atoms. It is based on a high-power 1014.8 nm room-temperature fiber laser amplifier and two cascaded efficient frequency-doubling stages. The saturated absorption spectrum of Hg202 on the 6S01 6P13 transition is demonstrated with a high signal-to-noise ratio. This deep ultraviolet laser has significant applications in quantum optics and laser cooling of mercury atoms in 2D and 3D magneto-optical traps. PMID- 29131178 TI - Carrier frequency tuning of few-cycle light pulses by a broadband attenuating mirror. AB - We demonstrate the performance of a novel multilayer dielectric reflective thin film attenuator capable of reshaping the super-octave spectrum of near-single cycle visible laser pulses without deteriorating the phase properties of the reflected light. These novel broadband attenuating mirrors reshape in a virtually dispersion-free manner the incident spectrum such that the carrier wavelength of the reflected pulses shifts from ~700 nm (Egamma=1.77 eV) to ~540 nm (Egamma=2.25 eV) or beyond while maintaining their initial near-single-cycle pulse duration. This constitutes a viable approach to convert a number of established few-cycle ultrafast laser systems into sources with a selectable excitation wavelength to meet the requirements of single-color/multicolor high temporal resolution spectroscopic experiments. PMID- 29131179 TI - Improved back-projection method for circular-scanning-based photoacoustic tomography with improved tangential resolution. AB - While photoacoustic computed tomography (PACT) is generally built with planar transducers of finite size, most current reconstruction algorithms assume the transducer to be an ideal point, which leads to a spinning blur in the consequently obtained PACT images due to the model mismatch. In this work, we put forward an improved back-projection method that factors in the geometry of the transducers to improve the tangential resolution for the reconstruction of 2D circular-scanning-based photoacoustic tomography. Extensive simulations and experiments were carried out to study the adaptability and stability of the proposed method. Results show that this method can effectively restore the tangential distortion of the PACT image for both simulated and experimental data. Results indicated that the improvement of the tangential resolution is more obvious for transducers with larger size. We also demonstrated the application of this method to transducers other than planar, and results show that the reconstructed image quality can be significantly affected by the shape and position of the transducers used. This study may help to guide the selection of transducer and design of scanning strategy in PACT. PMID- 29131180 TI - Comparison of photoemission characteristics between square and circular wire array GaAs photocathodes. AB - Two types of negative electron affinity gallium arsenide (GaAs) wire array photocathodes were fabricated by reactive ion etching and inductively coupled plasma etching of bulk GaAs material. High density GaAs wire arrays with high periodicity and good morphology were verified using scanning electron microscopy, and photoluminescence spectra confirmed the wire arrays had good crystalline quality. Reflection spectra showed that circular GaAs wire arrays had superior light trapping compared with square ones. However, after Cs/O activation, the square GaAs wire array photocathodes showed enhanced spectral response. The integral sensitivity of the square wire array photocathodes was approximately 2.8 times that of the circular arrays. PMID- 29131181 TI - Generation of long-range curved-surface plasmonic modes and their propagation through thin metal films in a tandem array. AB - We describe the generation of plasmonic modes that propagate in a curved trajectory. This is performed by masking a metal surface with two screens containing a randomly distributed set of holes that follow a Gaussian statistic. The diameter of the holes is less than the wavelength of the illuminating plane wave. By implementing scaling and rotations on each screen, we control the correlation trajectory and generate long-range curved plasmonic modes. The study is generalized for the transmission of a plasmonic mode propagating in a tandem array of thin metal films using the evanescent character of the electric field. PMID- 29131182 TI - Edge effect correction using ion beam figuring. AB - The edge effect is regarded as one of the most difficult technical issues for fabricating large primary mirrors, as it can greatly reduce the key performance of the optical system. Ion beam figuring (IBF) has the advantage of no edge effect, so we can use it to remove high points on the edge and improve surface accuracy. The edge local correction method (ELCM) of IBF processes only the surface edge zone, and is very different from the current full caliber figuring method (FCFM). Therefore, it is necessary to study the ELCM of IBF. In this paper, the key factors of ELCM are analyzed, such as dwell time algorithm, edge data extension methods, and the outward dimension of the starting figuring point. At the same time, the distinctions between ELCM and FCFM are compared. Finally, a 142 mm diameter fused silica mirror is fabricated to verify the validity of the theoretical of ELCM. The experimental results indicate that the figuring precision and efficiency can be obviously improved by ELCM. PMID- 29131183 TI - Efficient signal design and optimal power allocation for visible light communication attocell systems. AB - In this paper, we investigate visible light communication (VLC) attocell systems in which any two neighboring attocells overlap. An efficient signal design for VLC called time superposition reuse (TSR) is proposed to mitigate interference and improve spectral efficiency. In the scheme, two neighboring cells are allocated with two time slots that have superposition in the time domain. By adjusting superposition between time slots, the system can achieve a flexible spectral efficiency and system performance. Further, we develop an optimal power allocation strategy for TSR in the system. The strategy is given according to the position of the user and the level of superposition, and then the corresponding optimal Euclidean distance is derived. In addition, we analyze the system performance and prove that the optimal Euclidean distance is an increasing function of the delay between signals and a decreasing function of the sampling period. Simulation results demonstrate that the optimal power allocation has a better performance than uniform power allocation and TSR outperforms time division multiple access significantly for the user in VLC attocell systems. PMID- 29131184 TI - Two-dimensional coherent random laser in photonic crystal fiber with dye-doped nematic liquid crystal. AB - A random laser of a photonic crystal fiber (PCF) with holes filled with laser dye doped nematic liquid crystal (NLC) is reported. When the excitation polarization was along the PCF axis, the measured laser threshold was 80 MUJ/mm2 per pulse, which is much lower than the previously reported random laser of PCF filled with laser dye-doped organic solvent. This low threshold is due to the high refractive index of the NLC, which produces a greater scattering efficiency. In contrast, when the excitation polarization is perpendicular to the PCF axis, the threshold was much higher or the laser oscillation was absent. This is because of the lower refractive index of the NLC for the perpendicular polarization. The laser oscillation was absent in the isotropic phase because of a low fluorescence efficiency at high temperatures. PMID- 29131185 TI - Refractive index measurement of suspended cells using opposed-view digital holographic microscopy. AB - Opposed-view digital holographic microscopy (OV-DHM) with autofocusing and out-of focus background suppression was demonstrated and applied to measure the refractive index (RI) of suspended HeLa cells. In OV-DHM, a specimen is illuminated from two sides in a 4pi-like configuration. The generated two opposite-view object waves, which have orthogonal polarization orientations, interfere with a common reference wave, and the generated holograms are recorded by a CMOS camera. The image plane of the sample was determined by finding the minimal variation between the two object waves. The out-of-focus background was suppressed by averaging the two object waves. Simultaneous determination of both the cell thickness and the phase retardation was avoided by using a spheroidal model for the detached cell obtained from confocal microscopy. Thus, the RI of suspended HeLa cells was measured from phase images of OV-DHM, with the thickness of the cells estimated by using a constant axial-to-lateral ratio. This measurement strategy reveals the RI with an accuracy of ~10% of the RI difference between cells and surrounding medium. PMID- 29131186 TI - Improvement of temperature-induced spectrum characterization in a holographic sensor based on N-isopropylacrylamide photopolymer hydrogel. AB - A novel thermo-sensitive N-isopropylacrylamide photopolymer was developed for improving the temperature and humidity responses of holographic sensors. Diffraction spectra of holographic volume gratings recorded in the materials were characterized to explore the sensing response capacity. A dependence of peak wavelength on the temperature was observed and provided a quantitative strategy for holographic sensing applications. Expansion of the humidity range induced a strong extension of wavelength shift. Finally, the temperature response reversibility was demonstrated experimentally. Our sensing results were completely different from the reported typical acrylamide polymer system. Compared with the former, we obtained a more sensitive temperature response and an evident shift expansion (>200 nm) at a relative humidity of 70% or higher. These results can obviously improve the thermo-sensitivity of a holographic sensor and expand the practical application area of the holographic sensing strategy. PMID- 29131187 TI - Automatic obscuration elimination for off-axis mirror systems. AB - The degree of automation in optical design has always been improving, and several human-competitive automatic lens design programs have been developed. However, to the best of our knowledge, no such work on off-axis systems has been reported, which we think is largely due to the complicated unfeasible conditions caused by obscuration. Here, we propose a model to detect and evaluate the degree of obscuration for off-axis mirror systems and also a method to automatically eliminate the obscuration by structural optimization. This effect of obscuration elimination is demonstrated by several examples. It can greatly facilitate the design of off-axis mirror systems. Particularly, the method can be applied in the search for feasible off-axis structures from on-axis ones. This work may provide insight for further study of human-competitive automatic design of off-axis systems. PMID- 29131188 TI - Laser display system for multi-depth screen projection scenarios. AB - Proposed is a laser projection display system that uses an electronically controlled variable focus lens (ECVFL) to achieve sharp and in-focus image projection over multi-distance three-dimensional (3D) conformal screens. The system also functions as an embedded distance sensor that enables 3D mapping of the multi-level screen platform before the desired laser scanned beam focused/defocused projected spot sizes are matched to the different localized screen distances on the 3D screen. Compared to conventional laser scanning and spatial light modulator (SLM) based projection systems, the proposed design offers in-focus non-distorted projection over a multi-distance screen zone with varying depths. An experimental projection system for a screen depth variation of 65 cm is demonstrated using a 633 nm laser beam, 3 KHz scan speed galvo-scanning mirrors, and a liquid-based ECVFL. As a basic demonstration, an in-house developed MATLAB based graphic user interface is deployed to work along with the laser projection display, enabling user inputs like text strings or predefined image projection. The user can specify projection screen distance, scanned laser linewidth, projected text font size, projected image dimensions, and laser scanning rate. Projected images are shown highlighting the 3D control capabilities of the display, including the production of a non-distorted image onto two-depths versus a distorted image via dominant prior-art projection methods. PMID- 29131189 TI - 3D shape, deformation, and vibration measurements using infrared Kinect sensors and digital image correlation. AB - Consumer-grade red-green-blue and depth (RGB-D) sensors, such as the Microsoft Kinect and the Asus Xtion, are attractive devices due to their low cost and robustness for real-time sensing of depth information. These devices provide the depth information by detecting the correspondences between the captured infrared (IR) image and the initial image sent to the IR projector, and their essential limitation is the low accuracy of 3D shape reconstruction. In this paper, an effective technique that employs the Kinect sensors for accurate 3D shape, deformation, and vibration measurements is introduced. The technique involves using the RGB-D sensors, an accurate camera calibration scheme, and area- and feature-based image-matching algorithms. The IR speckle pattern projected from the Kinect projector considerably facilitates the digital image correlation analysis in the regions of interest with enhanced accuracy. A number of experiments have been carried out to demonstrate the validity and effectiveness of the proposed technique and approach. It is shown that the technique can yield measurement accuracy at the 10 MUm level for a typical field of view. The real time capturing speed of 30 frames per second makes the proposed technique suitable for certain motion and vibration measurements, such as non-contact monitoring of respiration and heartbeat rates. PMID- 29131190 TI - Tailoring lens functionality by 3D laser printing. AB - Conversion of a Gaussian beam into a top-hat beam or to an annular beam is demonstrated using 3D direct laser printing. Micron-scale refractive phase elements were designed and printed directly on standard commercially available lenses. These structures modify the phase of the incoming beam into either three intensity-flattened profiles, having line, square, or circular shapes, or to an annular beam profile. This method to functionalize lenses opens new and exciting opportunities for compact and robust beam shaping, as well as for reduction of the aberrations of the lens itself. PMID- 29131191 TI - Effect of graded bandgap structure on photoelectric performance of transmission mode AlxGa1-xAs/GaAs photocathode modules. AB - The graded bandgap AlxGa1-xAs/GaAs photocathode with graded composition and exponential doping structure has shown great potential for improving photoemission capability. In order to better study the performance of transmission-mode AlxGa1-xAs/GaAs photocathode with the complex graded bandgap structure, the experimental optical properties and quantum efficiency are measured by comparison with uniform composition and exponential doping Al0.7Ga0.3As/GaAs photocathode. The theoretical optical properties of the multilayer AlxGa1-xAs/GaAs photocathode modules are calculated by matrix formula on the basis of thin-film optical principles. The effect of cathode thickness and aluminum proportion on optical properties are analyzed by simulation. The results show that these parameters have complicated effects on the optical properties. Different parameters are presented as the changes of peak and valley of the optical property curves. Meanwhile, the emission layer has a significant effect on the absorptivity values of the photocathode modules, which will obviously influence photoemission performance. By using the optical properties via calculation, a better fit of the experimental data with the theoretical model can be achieved, which would make reasonable guidance for further investigation of these complex graded bandgap photoemitters. PMID- 29131192 TI - Wide area mapping of liquid crystal devices with passive and active command layers. AB - We track the non-uniformity of a wide area liquid crystal device using multiple cross-polarized intensity measurements. They give us not only accurate estimates of the core physical liquid crystal parameters, such as elastic constants, but also spatial maps of the device properties, including the liquid crystal thickness and pretilt angle. A bootstrapping statistical analysis, coupled with the multiple measurements, gives us reliable error bars on all the measured parameters. PMID- 29131193 TI - Frequency and timing stability of an airborne injection-seeded Nd:YAG laser system for direct-detection wind lidar. AB - We report on the design and performance of the laser deployed in the airborne demonstrator Doppler wind lidar for the Aeolus mission of the European Space Agency (ESA). The all-solid-state, diode-pumped and frequency-tripled Nd:YAG laser is realized as a master oscillator power amplifier (MOPA) system, generating 60 mJ of single-frequency pulses at 355 nm wavelength, 50 Hz repetition rate and 20 ns pulse duration. For the measurement of the Doppler frequency shift over several accumulated laser shots, the frequency stability of the laser is of crucial importance. Injection-seeding, in combination with an active cavity control based on the Ramp-Delay-Fire technique, provides a pulse-to pulse frequency stability of 0.25 MHz measured at 1064 nm under laboratory conditions. This value increases to 0.31 MHz for airborne operation in a vibration environment that has been characterized by multiple acceleration sensors during different flight conditions. In addition, a pure Ramp-Fire setting was tested for comparison leading to a frequency stability of 0.16 MHz both in airborne operation and on ground. The laser cavity control electronics also have to provide a trigger signal for the lidar detection electronics, about 60 MUs prior to the expected laser pulse emission and with high timing stability. An in flight timing stability of below 100 ns was measured decreasing to 20 ns for a shorter pre-trigger time of 10 MUs. PMID- 29131194 TI - Elimination of self-mode-locking pulses in high-power continuous-wave Yb-doped fiber lasers with external feedback. AB - Sustained self-pulsing and self-mode-locking (SML) are detrimental to the performance of continuous-wave (CW) fiber lasers. We demonstrate an all-fiber method to eliminate SML pulsing by employing a low-reflectivity fiber Bragg grating (FBG) outside of a laser cavity to provide feedback. A narrow-bandwidth FBG is used to form an external cavity with the output coupler FBG, which suppresses the SML up to a certain output power level, at which point, the laser emission linewidth is still within the bandwidth of the FBG. On the other hand, a broad-bandwidth FBG forms a chirped cavity with the output coupler FBG, which can suppress the SML at a much higher power level, tested up to 50 W. This method provides a simple effective all-fiber solution for suppressing self-pulsing in CW fiber lasers at high pump levels with no need to change the laser configuration. PMID- 29131195 TI - Compact single-shot d-scan setup for the characterization of few-cycle laser pulses. AB - We present a compact implementation of the ultrashort pulse measurement technique based on dispersion scans (d-scan), allowing single-shot measurement of few-cycle pulses. The main novelty in our design, making our setup extremely compact and simple, is the use, after a prism, of a spherical mirror in an off-axis geometry. The intentionally introduced strong astigmatism makes it possible to image the output of the crystal in one direction while focusing it in the other direction, resulting in the output face of the prism being imaged into a line in the second harmonic crystal. The technique is validated by comparing measured dispersion scans, retrieved spectral phases and temporal profiles of this single-shot system with standard d-scan results. PMID- 29131196 TI - Multi-element direct design using a freeform surface for a compact illumination system. AB - An iterative optimization algorithm is introduced to address the surface iterative errors as well as source extension issues in a freeform illumination system for producing satisfactory illumination distribution. A unique two parameter coordinate system is utilized to represent the emitted ray directions. Then, the direction vector for the incident rays, which propagate through several surfaces, is obtained using ray-tracing techniques. Based on the mapping between the incoming rays and a target grid, a freeform surface is generated as a good starting design. An iterative optimization strategy is further employed to alleviate the deterioration of illumination distribution on the target region, and the uniformity of the illumination system is evaluated during optimization. Very few variables are demanded, and more flexibility in the design of the freeform surface is offered. Successive iterations can be performed until the desired result is attained. An optical system is used as an example to demonstrate the validity of the proposed method, and numerical simulations are carried out to evaluate the optical performance. The simulation results show that a small angular intensity distribution and prescribed rectangular illumination pattern can be achieved simultaneously. PMID- 29131197 TI - Astigmatism-free Czerny-Turner compact spectrometer with cylindrical mirrors. AB - A modified optical design for a broadband, high resolution, astigmatism-free Czerny-Turner spectrometer is proposed. Astigmatism is corrected by using cylindrical mirrors over a broad spectral range. The theory and method for astigmatism correction are thoroughly analyzed. The comparison between the modified Czerny-Turner spectrometer and the traditional Czerny-Turner spectrometer is also described in detail. The ray-tracing results show that the RMS spot radius has decreased to 4.2 MUm at the central wavelength and 17 MUm at the wedge wavelength. PMID- 29131198 TI - Microwave photonic filter-based interrogation system for multiple fiber Bragg grating sensors. AB - Fiber optic sensors based on fiber Bragg gratings (FBGs) find potential use in condition monitoring because their spectral properties change according to external environmental and/or physical factors. We propose and demonstrate a technique for interrogating multiple FBG-based sensors based on microwave photonic (MWP) filtering. In particular, we exploit the spectrum-slicing properties of two different FBG Fabry-Perot cavities to implement a double passband MWP filter. Each sensor spectrum results in a unique MWP filter passband. As temperature is applied to a sensor, the corresponding MWP filter passband will shift in frequency; we track such shifts by monitoring the detected power at a fixed radio frequency. We discuss the use of a ratiometric approach for enhancing the sensitivity and the impact of cross-talk from the MWP filter responses in terms of simultaneous multi-sensor operation. Results show that we can monitor local temperatures at two (or multiple) different locations simultaneously and independently using a single measurement system. PMID- 29131199 TI - Positive dwell time algorithm with minimum equal extra material removal in deterministic optical surfacing technology. AB - In deterministic computer-controlled optical surfacing, accurate dwell time execution by computer numeric control machines is crucial in guaranteeing a high convergence ratio for the optical surface error. It is necessary to consider the machine dynamics limitations in the numerical dwell time algorithms. In this paper, these constraints on dwell time distribution are analyzed, and a model of the equal extra material removal is established. A positive dwell time algorithm with minimum equal extra material removal is developed. Results of simulations based on deterministic magnetorheological finishing demonstrate the necessity of considering machine dynamics performance and illustrate the validity of the proposed algorithm. Indeed, the algorithm effectively facilitates the determinacy of sub-aperture optical surfacing processes. PMID- 29131200 TI - Impact of the scattering phase function on the bulk reflectance of a turbid medium with large-scale inhomogeneities. AB - We study the total bulk reflectance of a turbid medium with large (as compared to the light wavelength) inhomogeneities at grazing angles of light incidence. To model highly forward scattering in the medium, we take advantage of the Reynolds McCormick scattering phase function. Using the scaling analysis for the small angle radiative transfer equation, we derive simple analytical formulas for the total reflectance. For grazing incidence angles, we find a range of values of the medium transport coefficients where the total reflectance proves to be a universal function of a single parameter, which is expressed in terms of the incidence angle, the absorption coefficient, and the transport scattering one. The explicit form of this function is governed by the specific angular profile of the scattering phase function. The results obtained are verified by comparison with results of a direct numerical integration of the radiative transfer equation. PMID- 29131201 TI - Watt-level tunable 1.5 MUm narrow linewidth fiber ring laser based on a temperature tuning pi-phase-shifted fiber Bragg grating. AB - A watt-level tunable 1.5 MUm narrow linewidth fiber ring laser using a temperature tuning pi-phase-shifted fiber Bragg grating (pi-PSFBG) is demonstrated here, to the best of our knowledge, for the first time. The pi-PSFBG is employed as both a narrow band filter and a wavelength tuning component, and its central wavelength is thermally tuned by a thermo-electric cooler. The maximum laser power is about 1.1 W with a linewidth of ~318 MHz (~2.57 pm) and a power fluctuation of less than 3%. The wavelength tuning range of the laser is about 1.29 nm with a sensitivity of ~14.33 pm/ degrees C, and the wavelength fluctuation is about 0.2 pm. This work provides important reference for tunable fiber lasers with both high power and narrow linewidth. PMID- 29131202 TI - Manipulating and detecting the chirpiness of spatial chirp signals via fractional Fourier lenses designed by transformation optics. AB - Estimating the chirpiness of a spatial chirp signal is important in many optical engineering applications. With the help of transformation optics, a new kind of fractional Fourier transform lens is designed by deforming the conventional graded index lens through conformal mapping, which can manipulate the chirpiness of the input chirp signal. The low-input chirpiness is magnified by the transformation material, and the error of the detection is kept approximately the same; thus, the designed lens has enhanced chirpiness detection precision and distinguishability for low chirpiness. The design is validated by numerical simulations. PMID- 29131203 TI - Computer-generated hologram using binary phase with an aperture. AB - Computer-generated holograms (CGHs) have attracted more and more attention in some application fields, such as 3D displays, optical security, and beam shaping. In this paper, a strategy is presented for optical information verification based on CGH using binary phase (1 bit) with an aperture. The input is encoded into the cascaded phase-only masks based on CGH via iterative phase retrieval, and one extracted phase mask is binarized in which one part is selected according to an aperture and further embedded into a random binary-phase host mask. It is numerically illustrated that the reconstructed image can be effectively verified when system parameters, such as aperture and phase-only masks, are correctly applied. It is demonstrated that the proposed method can provide a promising strategy for CGH-based optical verification. PMID- 29131204 TI - Voltage dependent admittance spectroscopy for the detection of near interface defect states for thin film solar cells. AB - Recently recorded efficiencies of Cu(In,Ga)Se2 based solar cells were mainly achieved by surface treatment of the absorber that modifies the buffer-absorber interface region. However, only little is known about the electronic properties within this region. In this manuscript voltage dependent admittance spectroscopy is applied to low temperature grown Cu(In,Ga)Se2 based solar cells to detect near interface defect states in the absorber. Under non-equilibrium conditions even defect states close to the interface may cross the Fermi level and hence are detectable using capacitance based measurement methods, in contrast to the case of zero bias conditions. Such defects are of potential importance for understanding device limitations and hence, adequate characterization is necessary. A SCAPS model is developed including a near interface deep acceptor state, which explains the frequency and voltage dependence of the capacitance. Using the same model, also the experimental apparent doping density is explained. PMID- 29131205 TI - Mechanism of enhancement of ferroelectricity of croconic acid with temperature. AB - A detailed study of the thermal behaviour of atomic motions in the organic ferroelectric croconic acid is presented in the temperature range 5-300 K. Using high-resolution inelastic neutron scattering and first-principles electronic structure calculations within the framework of density functional theory and a quasiharmonic phonon description of the material, we find that the frequencies of the well defined doublet in inelastic neutron scattering spectra associated with out-of-plane motions of hydrogen-bonded protons decrease monotonically with temperature indicating weakening of these bonding motifs and enhancement of proton motions. Theoretical mean-square displacements for these proton motions are within 5% of experimental values. A detailed analysis of this observable shows that it is unlikely that there is a facile proton transfer along the direction of ferroelectric polarization in the absence of an applied electric field. Calculations predict constrained thermal motion of proton along crystallographic lattice direction c retaining the hydrogen bond motif of the crystal at high temperature. Using the Berry-phase method, we have also calculated the spontaneous polarization of temperature dependent cell structures, and find that our computational model provides a satisfactory description of the anomalous and so far unexplained rise in bulk electric polarization with temperature. Correlating the thermal motion induced lattice strain with temperature dependent spontaneous polarizations, we conclude that increasing thermal strain with temperatures combined with constrained thermal motion along the hydrogen bond motif are responsible of this increase in ferroelectricity at high temperature. PMID- 29131206 TI - A continuous luminescence assay for monitoring kinase activity: signalling the ADP/ATP ratio using a discrete europium complex. AB - We report the application of a stable cationic europium complex [Eu.1]+ in a continuous-read luminescence assay for kinase activity. [Eu.1]+ binds reversibly to ATP and ADP in water, at neutral pH, in the presence of Mg2+ ions, providing distinctive luminescence responses that permits the kinase-catalysed conversion of ATP to ADP to be monitored in real-time. PMID- 29131207 TI - Imaging cellular trafficking processes in real time using lysosome targeted up conversion nanoparticles. AB - beta-NaYF4:Yb,Gd up-conversion nanoparticles, UCNPs, surface functionalized with suitable targetting peptides function as nontoxic lysosome-specific imaging probes. PMID- 29131208 TI - G-Quartet hydrogels for effective cell growth applications. AB - Functional G-quartet hydrogels formed from natural guanosine cross linked with benzene-1,4-diboronic acid and Mg2+ support cell growth with no visible signs of gel degradation. PMID- 29131209 TI - Bulk double emulsification for flow cytometric analysis of microfluidic droplets. AB - Droplet microfluidics is valuable for applications in chemistry and biology, but generates massive numbers of droplets that must be analyzed and sorted. Here, we describe a simple approach to bulk double emulsify microfluidic emulsions for analysis and sorting with commercial flow cytometers. We illustrate the method by using it to identify droplets based on nucleic acid content. Though simple, our method provides a general approach for analyzing and sorting microfluidic droplets without custom microfluidic double emulsifiers or sorters. PMID- 29131211 TI - Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action. AB - Resistance to platinum drugs (used in >50% of cancer chemotherapies) is a clinical problem. Other precious metal complexes with distinct mechanisms of action might overcome this. Half-sandwich organometallic complexes containing arene or cyclopentadienyl (Cp) ligands show promise. We screened two iridium(iii) complexes [Ir(CpXbiph)(ppy)Cl] (ZL49, 1, ppy = phenylpyridine) and [Ir(CpXph)(azpyNMe2)Cl]PF6 (ZL109, 2, azpyNMe2 = N,N-dimethylphenylazopyridine) in 916 cancer cell lines from 28 tissue types. On average, complex 2 was 78* more potent than 1, 36* more active than cisplatin (CDDP), and strongly active (nanomolar) in patient-derived ovarian cancer cell lines. RNA sequencing of A2780 ovarian cells revealed upregulation of antioxidant responses (NRF2, AP-1) consistent with observed induction of reactive oxygen species (ROS). Protein microarrays, high content imaging and cell cycle analysis showed S/G2 arrest, and late-stage DNA damage response without p53 requirement. The triple-negative breast cancer cell line OCUB-M was highly sensitive to 2 as were cell lines with KIT mutations. Complex 2 exhibits a markedly different pattern of antiproliferative activity compared to the 253 drugs in the Sanger Cancer Genome database, but is most similar to osmium(ii) arene complexes which share the same azopyridine ligand. Redox modulation and DNA damage can provide a multi-targeting strategy, allowing compounds such as 2 to overcome cellular resistance to platinum anticancer drugs. PMID- 29131214 TI - Ni nanoparticles@Ni-Mo nitride nanorod arrays: a novel 3D-network hierarchical structure for high areal capacitance hybrid supercapacitors. AB - Because of the advanced nature of their high power density, fast charge/discharge time, excellent cycling stability, and safety, supercapacitors have attracted intensive attention for large-scale applications. Nevertheless, one of the obstacles for their further development is their low energy density caused by sluggish redox reaction kinetics, low electroactive electrode materials, and/or high internal resistance. Here, we develop a facile and simple nitridation process to successfully synthesize hierarchical Ni nanoparticle decorated Ni0.2Mo0.8N nanorod arrays on a nickel foam (Ni-Mo-N NRA/NF) from its NiMoO4 precursor, which delivers a high areal capacity of 2446 mC cm-2 at a current density of 2 mA cm-2 and shows outstanding cycling stability. The superior performance of the Ni-Mo-N NRA/NF can be ascribed to the metallic conductive nature of the Ni-Mo nitride, the fast surface redox reactions for the electrolyte ions and electrode materials, and the low contacted resistance between the active materials and the current collectors. Furthermore, a hybrid supercapacitor (HSC) is assembled using the Ni-Mo-N NRA/NF as the positive electrode and reduced graphene oxide (RGO) as the negative electrode. The optimized HSC exhibits excellent electrochemical performance with a high energy density of 40.9 W h kg-1 at a power density of 773 W kg-1 and a retention of 80.1% specific capacitance after 6000 cycles. These results indicate that the Ni-Mo-N NRA/NF have a promising potential for use in high-performance supercapacitors. PMID- 29131216 TI - Detection of the electronic structure of iron-(iii)-oxo oligomers forming in aqueous solutions. AB - The nature of the small iron-oxo oligomers in iron-(iii) aqueous solutions has a determining effect on the chemical processes that govern the formation of nanoparticles in aqueous phase. Here we report on a liquid-jet photoelectron spectroscopy experiment for the investigation of the electronic structure of the occurring iron-oxo oligomers in FeCl3 aqueous solutions. The only iron species in the as-prepared 0.75 M solution are Fe3+ monomers. Addition of NaOH initiates Fe3+ hydrolysis which is followed by the formation of iron-oxo oligomers. At small enough NaOH concentrations, corresponding to approximately [OH]/[Fe] = 0.2 0.25 ratio, the iron oligomers can be stabilized for several hours without engaging in further aggregation. Here, we apply a combination of non-resonant as well as iron 2p and oxygen 1s resonant photoelectron spectroscopy from a liquid microjet to detect the electronic structure of the occurring species. Specifically, the oxygen 1s partial electron yield X-ray absorption (PEY-XA) spectra are found to exhibit a peak well below the onset of liquid water and OH- (aq) absorption. The iron 2p absorption gives rise to signal centered between the main absorption bands typical for aqueous Fe3+. Absorption bands in both PEY-XA spectra are found to correlate with an enhanced photoelectron peak near 20 eV binding energy, which demonstrates the sensitivity of resonant photoelectron (RPE) spectroscopy to mixing between iron and ligand orbitals. These various signals from the iron-oxo oligomers exhibit maximum intensity at [OH]/[Fe] = 0.25 ratio. For the same ratio, we observe changes in the pH as well as in complementary Raman spectra, which can be assigned to the transition from monomeric to oligomeric species. At approximately [OH]/[Fe] = 0.3 we begin to observe particles larger than 1 nm in radius, detected by small-angle X-ray scattering. PMID- 29131217 TI - Brownian dynamics simulations of analytical ultracentrifugation experiments exhibiting hydrodynamic and thermodynamic non-ideality. AB - Hydrodynamic and thermodynamic non-ideality are important phenomena when studying concentrated and interacting systems in analytical ultracentrifugation (AUC). Here we present an extended Brownian Dynamics (BD) based algorithm which incorporates hydrodynamic and thermodynamic non-ideality. It can serve as an independent and versatile approach for the theoretical description of interparticulate interactions in AUC, as it allows tracking the trajectory of individual particles. Concentration dependencies of the sedimentation and diffusion coefficient have been implemented and validated for the extended BD model. For monodisperse systems, it is shown that profiles obtained by BD are in excellent agreement with well-established Lamm equation solvers. Moreover, important limits and restrictions of current Lamm equation based analysis methods are discussed. In particular, BD allows modeling and evaluation of AUC data of non-ideal polydisperse systems. This is relevant as most nanoparticulate systems are polydisperse in size. Here, a simulation for a polydisperse system including concentration effects is presented for the first time. PMID- 29131220 TI - Highly regioselective gold-catalyzed formal hydration of propargylic gem difluorides. AB - Herein, we report a highly regioselective gold-catalyzed formal hydration of propargylic gem-difluorides. Not only does this transformation provide access to versatile fluorinated building blocks that were difficult or hardly possible to access beforehand, but it also represents a rare case of a highly regioselective gold-catalyzed hydroalkoxylation of internal alkynes and puts forward the utility of the difluoromethylene unit as a directing group in catalysis. PMID- 29131221 TI - Organocatalysis using aldehydes: the development and improvement of catalytic hydroaminations, hydrations and hydrolyses. AB - Organocatalysis has emerged as a powerful approach to facilitate and accelerate various difficult reactions. This Feature article presents recent developments and improvements using aldehydes as catalysts in difficult Cope-type intermolecular hydroamination, hydration and hydrolysis reactions. Most reactions exploit temporary intramolecularity. In catalytic Cope-type hydroaminations of allylic amines, aldehydes act as tethering catalysts, and allow room temperature reactions and high enantio- or diastereoselectivities if chiral aldehydes or reagents are used. Mechanistic studies showed that simpler catalysts such as formaldehyde are more active due to an improved ability to form the temporary tether, which translated in an improved reaction scope. Gratifyingly, improved catalytic efficiency and broad reaction scope were also observed in the aldehyde catalyzed hydration of alpha-amino nitriles. Since destabilized aldehydes often favor temporary intramolecularity, this led to a comparison of the catalytic activity of several carbohydrates, and to experiments relevant in the prebiotic "origin of life" chemistry context. Studies on catalytic hydrolysis reactions of organophosphorous reagents are also presented, in which o-phthalaldehyde performs electrophilic activation of phosphinic amides, and other substrates possessing the P([double bond, length as m-dash]O)NH motif. Overall, this Feature article shows that aldehydes can be efficient catalysts in a variety of reactions, and highlights the efficiency of destabilized aldehydes such as formaldehyde and simple carbohydrates in this context. PMID- 29131222 TI - Cu-Catalyzed asymmetric Friedel-Crafts propargylic alkylation of phenol derivatives. AB - A copper-catalyzed asymmetric Friedel-Crafts propargylic alkylation of electron rich phenol derivatives with a variety of propargylic esters has been described. With Cu(OTf)2 decorated with a chiral tridentate ketimine P,N,N-ligand as the catalyst, asymmetric Friedel-Crafts propargylic alkylation of 3,5-dialkoxyphenol derivatives proceeded smoothly in high yields and with good to excellent enantioselectivities. The present study suggested that the presence of an electron-rich substituent on the meta-position of phenol is essential for the promotion of Friedel-Crafts propargylic alkylation, and the substrate bearing two electron-rich groups on both the 3,5-positions of phenol tends to give a satisfactory performance. PMID- 29131223 TI - Enhancing the sensitivity of DNA detection by structurally modified solid-state nanopore. AB - Solid-state nanopore is an ionic current-based biosensing platform, which would be a top candidate for next-generation DNA sequencing and a high-throughput drug screening tool at single-molecular-scale resolution. There have been several approaches to enhance the sensitivity and reliability of biomolecule detection using the nanopores particularly in two aspects: signal-to-noise ratio (SNR) and translocation dwell time. In this study, an additional nano-well of 100-150 nm diameter and the aspect ratio of ~5 called 'guide structure' was inserted in conventional silicon-substrate nanopore device to increase both SNR and dwell time. First, the magnitude of signals (conductance drop (DeltaG)) increased 2.5 times under applied voltage of 300 mV through the guide-inserted nanopore compared to the conventional SiN/Si nanopore in the same condition. Finite element simulation was conducted to figure out the origin of DeltaG modification, which showed that the guide structure produced high DeltaG due to the compartmental limitation of ion transports through the guide to the sensing nanopore. Second, the translocation velocity decreased in the guide-inserted structure to a maximum of 20% of the velocity in the conventional device at 300 mV. Electroosmotic drag formed inside the guide structure, when directly applied to the remaining segment of translocating DNA molecules in cis chamber, affected the DNA translocation velocity. This study is the first experimental report on the effect of the geometrical confinement to a remnant DNA on both SNR and dwell time of nanopore translocations. PMID- 29131224 TI - Single nanoparticles magnetization curves by controlled tip magnetization magnetic force microscopy. AB - The development of high spatial resolution and element sensitive magnetic characterization techniques to quantitatively measure magnetic parameters of individual nanoparticles (NPs) and deeply understand and tune their magnetic properties is a hot topic in nanomagnetism. Magnetic force microscopy (MFM), thanks to its high lateral resolution, appears as a promising technique for the magnetic characterization of single nano-sized materials although it is still limited by some drawbacks, especially by the presence of electrostatic artifacts. Recently, these limitations have been overcome by the development of a particular MFM based technique called controlled magnetization - MFM (CM-MFM) allowing, in principle, a quantifiable correlation between the measured magnetic signal and the magnetization of the object under investigation. Here we propose an experimental procedure, based on the use of CM-MFM technique, to measure the magnetization curve of single magnetic NPs individuating their saturation magnetization, magnetic field, and coercivity. We measured, for the first time, the magnetization curves of individual Fe3O4 nanoparticles with diameters in the range of 18-32 nm by using a MFM instrument. Results are in very good agreement with the quantitative data obtained by SQUID analysis on a macroscopic sample, showing the high potential of the technique in the field of nanomagnetometry. PMID- 29131226 TI - A new general approach to synthesizing filled and yolk-shell structured metal oxide microspheres by applying a carbonaceous template. AB - New mechanisms were found for the formation of metal oxide microspheres with yolk shell and filled structures by applying carbonaceous template microspheres with high porosity. Repeated impregnation first adopted to achieve a high loading rate of metal precursor in the carbonaceous template provided the breakthrough. The carbonaceous template with an appropriate loading rate of the metal precursor produced metal oxide microspheres with filled and yolk-shell structure depending on the ramping rate and oxygen concentration during the post-treatment process. Combustion of the carbonaceous template-which occurs during the moderate post treatment process in air with a high oxygen concentration-must occur to form yolk shell structured microspheres. On the other hand, the decomposition of carbon by post-treatment at a slow ramping rate in an atmosphere with a low oxygen concentration without burning produced filled-structured metal oxide microspheres. The carbonaceous template with a high loading rate of the metal precursor produced metal oxide microspheres with filled structures even at a fast ramping rate and high oxygen concentration during the post-treatment process. The new strategy was applied to synthesize various metal oxide microspheres including SnO2, Fe2O3, NiO, and Mn2O3 microspheres. PMID- 29131227 TI - Controlling electron and energy transfer paths by selective excitation in a zinc porphyrin-BODIPY-C60 multi-modular triad. AB - A multi-modular donor-acceptor triad composed of zinc porphyrin, BF2-chelated dipyrromethene (BODIPY), and C60 was newly synthesized, with the BODIPY entity at the central position. Using absorbance and emission spectral, electrochemical redox, and computational optimization results, energy level diagrams for the ZnP BODIPY dyad and ZnP-BODIPY-C60 triad were constructed to envision the different photochemical events upon selective excitation of the BODIPY and ZnP entities. By transient absorption spectral studies covering a wide femtosecond-to-millisecond time scale, evidence for the different photochemical events and their kinetic information was secured. Efficient singlet-singlet energy transfer from 1BODIPY* to ZnP with a rate constant kENT = 1.7 * 1010 s-1 in toluene was observed in the case of the ZnP-BODIPY dyad. Interestingly, in the case of the ZnP-BODIPY-C60 triad, the selective excitation of ZnP resulted in electron transfer leading to the formation of the ZnP+-BODIPY-C60- charge-separated state. Owing to the distal separation of the radical cation and radical anion species (edge-to-edge distance of 18.7 A), the radical ion-pair persisted for microseconds. By contrast, the selective excitation of BODIPY resulted in an ultrafast energy transfer to yield ZnP-BODIPY-1C60* as the major product. The 1C60* populated the low-lying 3C60* via intersystem crossing prior to returning to the ground state. The present study successfully demonstrates the importance of supramolecular geometry and selection of excitation wavelength in regulating the different photoprocesses. PMID- 29131228 TI - 3D printing in chemical engineering and catalytic technology: structured catalysts, mixers and reactors. AB - Computer-aided fabrication technologies combined with simulation and data processing approaches are changing our way of manufacturing and designing functional objects. Also in the field of catalytic technology and chemical engineering the impact of additive manufacturing, also referred to as 3D printing, is steadily increasing thanks to a rapidly decreasing equipment threshold. Although still in an early stage, the rapid and seamless transition between digital data and physical objects enabled by these fabrication tools will benefit both research and manufacture of reactors and structured catalysts. Additive manufacturing closes the gap between theory and experiment, by enabling accurate fabrication of geometries optimized through computational fluid dynamics and the experimental evaluation of their properties. This review highlights the research using 3D printing and computational modeling as digital tools for the design and fabrication of reactors and structured catalysts. The goal of this contribution is to stimulate interactions at the crossroads of chemistry and materials science on the one hand and digital fabrication and computational modeling on the other. PMID- 29131229 TI - Phonon coupling and transport in individual polyethylene chains: a comparison study with the bulk crystal. AB - Using the first-principles-based anharmonic lattice dynamics, we calculate the thermal conductivities (kappa) of both bulk and single-chain polyethylene (PE) and characterize the mode-wise phonon transport and scattering channels. A significantly higher room-temperature axial thermal conductivity in single-chain PE (1400 W m-1 K-1) is observed compared to bulk PE crystals (237 W m-1 K-1). The reduction of scattering phase space caused by the diminished inter-chain van der Waals interactions explains the much larger kappa in single-chain PE. Different from many previous studies, the thermal conductivity of single-chain PE is predicted to converge at a chain length of ~1 mm at 300 K. The convergence is explained by the indirect thermal resistance from momentum-conserving scatterings of long-wavelength phonons. It is also found that longitudinal phonon modes dominate the thermal transport in PE chains, while transverse phonon branches with quadratic dispersions contribute little to kappa due to their vanishing group velocities and limited lifetimes in the long wavelength limit. The predicted high kappa of bulk crystalline and single-chain PE show great potential for use of polymers in thermal management, and the unveiled phonon transport mechanisms offer guides for their molecule-level design. PMID- 29131231 TI - A strain-induced exciton transition energy shift in CdSe nanoplatelets: the impact of an organic ligand shell. AB - We study the influence of surface passivating ligands on the optical and structural properties of zinc blende CdSe nanoplatelets. Ligand exchange of native oleic acid with aliphatic thiol or phosphonic acid on the surface of nanoplatelets results in a large shift of exciton transition energy for up to 240 meV. Ligand exchange also leads to structural changes (strain) in the nanoplatelet's core analysed by wide-angle X-ray diffraction. By correlating the experimental data with theoretical calculations we demonstrate that the exciton energy shift is mainly caused by the ligand-induced anisotropic transformation of the crystalline structure altering the well width of the CdSe core. Further the exciton reduced mass in these CdSe quantum wells is determined by a new method and this agrees well with the expected values substantiating that ligand-strain induced changes in the colloidal quantum well thickness are responsible for the observed spectral shifts. Our findings are important for theoretical modeling of other anisotropically strained systems and demonstrate an approach to tune the optical properties of 2D semiconductor nanocrystals over a broad region thus widening the range of possible applications of AIIBVI nanoplatelets in optics and optoelectronics. PMID- 29131232 TI - Homogenous graphene oxide-peptide nanofiber hybrid hydrogel as biomimetic polysaccharide hydrolase. AB - Cellulose, an impressive potential sustainable fuel, is difficult to hydrolyze because of the protection of beta-1,4-glycosidic bonds through the tight hydrogen bonding network. In this study, homogenous graphene oxide (GO)-peptide nanofiber hybrid hydrogels (GO-PNFs) were designed as a beta-glycosyl hydrolase mimetic to achieve efficient degradation of cellobiose and cellopentaose. For comparison, free peptides, graphene oxide mixed with free peptides (GO-peptdies) and self assembled peptide nanofibers (PNFs) were also studied for their activity as a hydrolase mimetics for degradation of cellobiose. Among these materials, GO-PNFs showed the highest hydrolysis activity. Transmission electron microscopy, atomic force microscopy, fluorescence analysis, circular dichroism spectroscopies, X-ray diffraction, Raman spectra and computational modeling were used to interpret the difference in activity mechanism in these artificially designed enzymes. These investigations suggested that high catalytic performance of GO-PNFs toward cellobiose and cellopentaose hydrolysis could be attributed to the formation of nanofiber structures of peptides, optimal molecular conformation and less steric hindrance to access the substrate. More importantly, GO not only served as a platform for attaching PNFs, but also created a hydrophobic microenvironment and facilitated proton transfer, an essential step in catalytic hydrolysis, thus enhancing catalytic activity. All these provided insights into the potential use of peptides and GO hybrid composite nanoenzymes in efficient cellulose hydrolysis. PMID- 29131233 TI - Comparison of TOF MRA, Contrast-Enhanced MRA and Subtracted CTA from CTP in Residue Evaluation of Treated Intracranial Aneurysms. AB - AIM: To compare effectiveness of contrast-enhanced MRA (CE-MRA), 3D-Time-of flight MRA (3D-TOF-MRA) and subtracted CTA from CTP (sub-CTA) in residue evaluation of intracranial aneurysms treated either with coiling or clipping. MATERIAL AND METHODS: Sixteen treated aneurysms, which were evaluated with three methods within two weeks after the operation, were enrolled. The success of each imaging techniques in demonstration of residue aneurysm and nearby vessels was compared by Fisher?'s Exact Test. The differences among three was evaluated by Cochran?'s Q test (p <= 0.05). RESULTS: Perfusion abnormality was noted in % 81 of clipped and none of coiled patients. Vessel visualization in the vicinity of aneurysm was better in sub-CTA, followed by CE-MRA. In clipped aneurysms, sub-CTA revealed residue aneurysms in % 16,7 of the patients while 3D-TOF-MRA and CE-MRA revealed none. In coiled aneurysms, CE-MRA revealed residue aneurysms in 100 %, and TOF-MRA in 33,3 % while sub-CTA revealed none. Although dramatic differences were noted in the evaluation of residue aneurysm as well as nearby vessel visualization, no statistical significance noted due to very few patients in subcategories Conclusion: This is first study comparing the effectiveness of CE MRA, 3D-TOF MRA and sub-CTA in residue aneurysms evaluation. Vessel visualization in the vicinity of aneurysm was better in sub-CTA in all regardless of coiling or clipping. Residue aneurysms were more commonly revealed by CE-MRA in coiled patients and more commonly and better shown by sub-CTA in clipped patients in addition of showing perfusion abnormality that's is more common in clipped patients. PMID- 29131234 TI - The Role of Triangular Vertebral Canal Shape in Surgical Management of Patients with Lumbar Spinal Stenosis: A Cross-Sectional Study. AB - AIM: We assessed the role of triangular vertebral canal shape (VCS) in pain severity, pain-related findings, and postoperative satisfaction in patients with lumbar spinal stenosis (LSS) who had undergone decompressive surgery. MATERIAL AND METHODS: This cross-sectional study conducted at a single center included 61 consecutive patients who had undergone surgical treatment for LSS. By comparing pre- and postoperative data, the role of triangular VCS in pain severity [assessed using a visual analog scale (VAS)], pain-related findings, and postoperative satisfaction of patients was examined. VCS was determined to be triangular, oval, or circular based on magnetic resonance imaging (MRI) and magnetic resonance myelography (MRM) findings. RESULTS: Preoperative VAS scores of patients with triangular VCS were significantly higher than those of patients with oval and circular VCSs (P 0.05). No significant difference was found in postoperative VAS scores among patients with triangular, oval, and circular VCSs. In all subgroups, postoperative VAS scores were significantly lower than preoperative scores (P 0.05). This postoperative decrease in VAS scores was significantly higher among patients with triangular VCS than in those with oval or circular VCS (P 0.05). CONCLUSION: Combined use of MRI and MRM can be recommended for symptomatic patients when planning surgery. Although pain severity decreased postoperatively in all patients, this decrease was more pronounced in patients with triangular VCS than in those with oval or circular VCS. During preoperative counseling of patients with LSS, the presence of triangular VCS should be considered. This may improve surgical outcome and patient satisfaction. PMID- 29131235 TI - Anatomical variations of brachial plexus in fetal cadavers. AB - AIM: The plexus brachialis is a complex structure with anatomical variations and connections with neighboring tissues. These variations may cause disparity in the motor and sensorial innervations of the upper extremity. The knowledge of anatomy and probable variations are important for performing surgical procedures in the neck, shoulder and axilla. This study was planned to demonstrate the anatomical variations of infantile brachial plexus. MATERIAL AND METHODS: A total of 20 plexus brachialis from 11 fetal cadavers were dissected and examined microscopically. The branching patterns and variations were evaluated. The width of the nerves was assessed at the level of the nerve root, trunk and cord on the basis of all brachial plexuses and they were arranged in terms of thickness. RESULTS: Half of the brachial plexuses were found to be prefixed, while 15% were found to be postfixed. Truncus superior, medial cord and nervus ulnaris were found in normal formation, whereas anatomical variations were detected in the rest of the structures. The plexus brachialis elements were arranged in the following order from large to small according to their average thicknesses: C7 C6 C8 C5 = T1; TS TI TM; PC LC MC. CONCLUSION: Since the risk of injury for variated branches is higher, understanding the anatomical variations of plexus brachialis and its extensions are significant importance during surgical intervention. PMID- 29131236 TI - Chronic subdural hematoma associated with arachnoid cyst of the middle fossa : Surgical treatment and mid-term results in fifteen patients. AB - AIM: We report the neurological and radiological features, surgical management and Mid-term outcome in a series of patients with chronic subdural hematoma (CSDH) and associated ipsilateral arachnoid cyst (AC) of the middle fossa. MATERIAL AND METHODS: Between August 2004 and August 2012, 453 patients were treated with diagnosis of CSDH in our clinic. Of those, 15 patients had ipsilateral arachnoid cyst in the middle fossa. A single burr hole craniostomy was performed to drain the hematoma and the AC left intact at first in 14 patients, one patient had no surgical intervention. Follow-up period ranged from 13 months to 88 months (mean 43.07 +/- 23.23 months). RESULTS: The patients having CSDH with AC were found to be younger than the patients with CSDH alone, the mean age was 13.93 +/-12.37 years Eleven patients had head trauma 21 to 50 days before admission. Hematoma evacuation through a single burr hole and closed system subdural drainage 2 to 4 days after surgery improved the symptoms in all patients. Two patients developed subdural fluid collection which is treated by subduroperitoneal shunt placement. CONCLUSION: Greater prevalence of ACs in patients with CSDHs has been reported in the literature. We recommend the drainage of the hematoma via a single craniostomy and to leave the AC intact as the first choice of treatment if the associated AC is a Galassi type I or II. Additional subduroperitoneal shunting may be performed in patients with Galassi type III cyst. PMID- 29131237 TI - Editorial - Non AIDS-defining malignancies: a new epidemic in HIV-infected population for the upcoming decades? PMID- 29131238 TI - The role of prasugrel in the management of acute coronary syndromes: a systematic review. AB - OBJECTIVE: Dual antiplatelet therapy (DAPT) is the treatment of choice in the medical management of patients with acute coronary syndrome (ACS). The combination of aspirin and a P2Y12 inhibitor in patients who receive a coronary stent reduces the rate of stent thrombosis and the rates of major adverse cardiovascular events. However, patients with acute coronary syndrome remain at risk of recurrent cardiovascular events despite the advance of medical therapy. The limitations of clopidogrel with variable antiplatelet effects and delayed onset of action are well established and lead to the development of newer P2Y12 inhibitors. Prasugrel is a selective adenosine diphosphate (ADP) receptor antagonist indicated for use in patients with ACS. Prasugrel provides greater inhibition of platelet aggregation than clopidogrel and has a rapid onset of action. We have conducted a systematic review to retrieve current evidence regarding the role of prasugrel in the management of ACS. Evidence comparing prasugrel, clopidogrel, and ticagrelor remain scant. MATERIALS AND METHODS: A complete literature survey was performed using PubMed database search to gather available information regarding management of acute coronary syndromes and prasugrel. An explorative comparison of the safety and efficacy of prasugrel, clopidogrel, and ticagrelor was also conducted. RESULTS: Prasugrel and ticagrelor are more efficacious than clopidogrel in reducing the occurrence of non-fatal myocardial infarction, stroke, or cardiovascular (CV) death but they have also an increased risk of major bleeding in comparison to clopidogrel. CONCLUSIONS: Prasugrel and ticagrelor are today the recommended first-line agents in patients with ACS. The estimation of which drug is superior over the other cannot be reliably established from the current trials. PMID- 29131239 TI - Effectiveness of a novel boswellic acids delivery form (Casperome(r)) in the management of grade II ankle sprains due to sport trauma - a registry study. AB - OBJECTIVE: In this study, we evaluated a novel delivery form of boswellic acids (Casperome(r)) in the management of signs and symptoms associated with ankle sprain grade II due to sport trauma. PATIENTS AND METHODS: In this supplement registry study, 72 otherwise healthy subjects with grade II ankle sprain induced by sport activities were advised to either follow a standard management (SM, 37 subjects) for the condition or the SM with the additional daily intake of 1 tablet containing 250 mg Casperome(r) (35 subjects). Subjects were allowed to use rescue medications (ketoprofen tablets, 25 mg/tablet), and their intake was measured at the end of the management period of 7 days. Each individual was subjected to several non-invasive examinations (self-reported pain at rest and under moderate exercise, range of active and passive movement, presence of local hematomas by ultrasonography) at the following time periods: at inclusion, to evaluate the basal conditions of the subject before the beginning of the study, at day 3 and at the end of the week to evaluate the response differences between the two groups. Additionally, a blood sample from the Casperome(r) treated subjects (34 out of 35 subjects) was taken at day 7 and analyzed for the systemic concentration of boswellic acids. RESULTS: The 72 individuals recruited in this study spontaneously decided which management to follow, either SM (n=37) or SM+Casperome(r) (n=35). Supplementation with Casperome(r) 250 mg/day showed beneficial effects in the reduction of signs and symptoms of ankle sprains evaluated at day 3 and day 7, and was shown to induce measurable plasma level of boswellic acids. Moreover, the supplementary use of Casperome(r) was well tolerated and devoid of side effects. CONCLUSIONS: Our pilot registry study showed the effectiveness of Casperome(r) supplementation in improving recovery after ankle sprain of mild severity (grade II), suggesting a potentially beneficial role in relieving the trauma associated with sport activities and in decreasing the use of rescue drugs. PMID- 29131240 TI - Mirtogenol(r) supplementation in association with dorzolamide-timolol or latanoprost improves the retinal microcirculation in asymptomatic patients with increased ocular pressure. AB - OBJECTIVE: Supplementation with Mirtogenol(r) improves the retinal microcirculation and reduces intraocular pressure (IOP) in ocular hypertension, when administrated either alone or in association with an ophthalmic solution (latanoprost). In this study, microcirculatory parameters (perfusion of the circle of Zinn-Haller and retinal circulation) and oxidative stress were tested to assess the effects of Mirtogenol(r) plus traditional antihypertensive drugs in patients with elevated IOP. PATIENTS AND METHODS: 88 otherwise healthy patients with increased IOP were followed-up in a supplement registry for 12 weeks. Three groups received; (a) dorzolamide-timolol plus Mirtogenol(r); (b) latanoprost drops plus Mirtogenol(r) or (c) latanoprost only. Oral supplementation consisted of two tablets/day of Mirtogenol(r) (80 mg of bilberry extract, Mirtoselect(r) plus 40 mg of Pycnogenol(r)). IOP, retinal blood flow, perfusion of the circle of Zinn-Haller, and oxidative stress were measured during the registry period. RESULTS: The three study groups were comparable; IOP and ocular blood flow velocity at inclusion were also comparable. Over the study period the decrease in IOP and the improvements in retinal microcirculation were statistically significant for all management groups, with a marginally more evident benefit in Mirtogenol(r)+latanosprost-treated patients. At 12 weeks, the altered perfusion at the circle of Zinn-Haller was improved in all groups; patients using Mirtogenol(r) showed a better perfusional pattern compared with subjects using only latanoprost. A reduction in oxidative stress was observed in supplemented subjects at the end of the study period; no significant change was seen in non supplemented patients. All managements were well-tolerated without side effects. CONCLUSIONS: Supplementation with Mirtogenol(r), in addition to local ophthalmic treatments, is safe and may contribute as a supplementary management to reach a normal IOP and ocular microcirculatory parameters. PMID- 29131241 TI - Insulin-like growth factor I reduces the occurrence of necrotizing enterocolitis by reducing inflammatory response and protecting intestinal mucosal barrier in neonatal rats model. AB - OBJECTIVE: To observe the effect of enteral supplement of insulin-like growth factor I (IGF-1) on dynamic changes of TLR4, NF-kappaB, IL-6, SIgA and MUC2 in intestinal tissues of neonatal rats, and to investigate the protective effects and possible mechanisms of IGF-1 on necrotizing enterocolitis (NEC). MATERIALS AND METHODS: Specific pathogen free (SPF) neonatal Sprague Dawley (SD) rats aged 3 days old were randomly divided into 3 groups, namely, normal control group, NEC model group and IGF-1 intervention group. In NEC group, the neonatal NEC rat models were established using artificial feeding, hypoxia and cold stimulation. In IGF-1 intervention group, the models were established by means of artificial feeding plus hypoxia and cold stimulation, and IGF-1 (22 ug/L) at a physiological concentration similar to the breast milk was added to milk replacer for intervention. The rats in the three groups were killed after the blood was collected from the heart at 24, 48 and 72 h, respectively, following the establishment of models; then, 3 cm of the terminal ilea were dissected and used for histopathological examination, RT-PCR and ELISA studies after hematoxylin and eosin (HE) staining. RESULTS: Symptoms in IGF-1 intervention group were significantly relieved, and the incidence rate of NEC was lowered remarkably. In NEC model group, the peak expression of TLR4 mRNA occurred later than that of NF kappaB mRNA and IL-6, and the expressions of TLR4 mRNA, NF-kappaB mRNA and IL-6 were decreased at 72 h after IGF-1 intervention. In NEC model group, the expression of MUC2 showed a transient decrease, the expression of SIgA was on the decline, but the expressions of MUC2 and SIgA were increased after IGF-1 intervention. CONCLUSIONS: The enteral administration of IGF-1 at a physiological concentration can ameliorate the clinical symptoms in neonatal NEC rat models and decrease the occurrence rate. The possible mechanism is that IGF-1 down-regulates the TLR4 mRNA expression to inhibit the production of inflammatory mediators, and it up-regulates the expressions of MUC2 and SIgA to protect the mechanical and immuno-barrier functions of the intestinal mucous. PMID- 29131242 TI - Synergistic effects of chlorambucil and TRAIL on apoptosis and proliferation of Raji cells. AB - OBJECTIVE: Tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL) can induce the apoptosis of tumor cells, but leaving its effect on malignant lymphoma largely insignificant, as these tumors may develop drug resistance. Chlorambucil (CLB) had definitive treatment efficacy on low-malignant non-Hodgkin lymphoma (NHL), but with unclear efficacy on highly malignant Burkitt lymphoma. A study has been shown that CLB could enhance the sensitivity of chronic lymphatic leukemia cells against TRAIL. This work aims to investigate the effect of CLB combined with TRAIL on in vitro proliferation and apoptosis of Raji cells. MATERIALS AND METHODS: TRAIL (0, 20, 40 and 80 ng/ml) or CLB (0, 2.5 5 and 10 MUM) was used to treat Raji cells. Cell counting kit 8 (CCK-8) was used to test proliferation whilst flow cytometry was employed to examine the apoptosis. The effect of TRAIL or CLB treatment on expression of death receptor 4 (DR4) and DR5 was tested. Combined treatment (80 ng/ml TRAIL and 10 MUM CLB) was adopted for observing Raji cell proliferation and apoptosis. RESULTS: Single treatment of TRAIL or CLB has weak effects of inducing apoptosis or inhibiting proliferation. TRAIL concentration has no significant effects on DR4/DR5 expression in Raji cells, whilst CLB treatment elevated those gene expressions. Combined treatment of TRAIL and CLB had more potent effects regarding cell proliferation inhibition or apoptosis induction compared to single treatment. CONCLUSIONS: TRAIL or CLB has weak inhibitor effects on Raji cell proliferation or induction of apoptosis. Via up-regulating DR4 and DR5 expression, CLB has synergistic effects with TRAIL to potentiate the apoptotic induction and proliferation inhibition role. PMID- 29131243 TI - Photodynamic therapy with 5-aminolevulinic acid suppresses IFN-gamma-induced K17 expression in HaCaT cells via MAPK pathway. AB - OBJECTIVE: Psoriasis is a chronic inflammatory skin disorder that greatly affects the patient's quality of life. Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) has recently been applied for inflammatory dermatoses including psoriasis. However, the therapeutic effect of ALA-PDT is yet to be validated, and the underlying mechanisms remain unclear. MATERIALS AND METHODS: In this study, a psoriatic model was established by treating HaCaT cells with 250 U/ml IFN-gamma for 48 h. The effect of ALA-PDT treatment on HaCaT cell viability was assessed using MTT assay. The levels of p38, JNK, and ERK, as well as their phosphorylation status (P-p38, P-JNK, P-ERK), were assessed by immunoblotting. RESULTS: Our data indicate that ALA-PDT can significantly inhibit the proliferation of IFN-g-treated HaCaT cells and the expression of keratin 17, both in a dose- and time-dependent manner. Furthermore, ALA-PDT can activate the MAPK pathway, and promote the expression of p38, JNK, and ERK. ALA-PDT showed pro apoptotic effects by enhancing cell apoptosis and upregulating the apoptotic genes PARP and caspase 3. CONCLUSIONS: Taken together, these findings indicate the possible pathways involved in ALA-PDT-mediated effects and highlight the potential of ALA-PDT in the development of novel therapeutic strategies. PMID- 29131244 TI - A review on irisin, a new protagonist that mediates muscle-adipose-bone-neuron connectivity. AB - Physical activity improves the quality of life and decreases the risk of several diseases (i.e. stroke, hypertension, myocardial infarction, obesity, and malignancies). Skeletal muscles are considered as an endocrine organ that produces myokines characterized by a paracrine or endocrine activity. Irisin is a circulating hormone-like myokine and is secreted as a product of fibronectin type III domain-containing protein 5 from skeletal muscle in response to exercise. This molecule regulates the energy metabolism and acts in adipose tissue, bones, and nervous system. As both animal and clinical studies confirmed the action of irisin in muscle and adipocytes, this protein is considered as adipomyokine. In adipose tissue, irisin stimulates the process of browning of beige precursor fat cells, which are present in white fat cells, and promotes energy expenditure. It affects bone metabolism by increasing osteoblast differentiation and reducing osteoclast maturation. In the nervous system, irisin influences hippocampal neurogenesis and neural differentiation of embryonic stem cells in mice and is considered as a messenger between exercise and brain function. However, the existence of this protein and its role in humans is a matter of debate. This study presents irisin as a new champion of the molecule, which could be considered as the messenger in the muscle-fat-bone-brain axis. PMID- 29131245 TI - Expression of the Wnt/beta-catenin signal pathway in patients with acute renal injury. AB - OBJECTIVE: The purpose of this investigation is to determine if the protein expression of the Wnt/beta-catenin signal pathway is induced after acute renal injury in patients with acute tubular necrosis. PATIENTS AND METHODS: Sixty patients in who met inclusion criteria underwent renal biopsy. Based on the result of the biopsy, patients were divided into two groups: one with nephrotic syndrome with mini-change disease (MCD group, 30 patients), the other one with minor lesions and acute tubular necrosis (ATN, 30 patients). Biopsy sections were stained with either periodic acid-Schiff (PAS) or Masson stain and examined under light microscopy to determine the degree of tubulointerstitial injury and renal tubular interstitial fibrosis, respectively. The expression of Wnt/beta-catenin signal proteins in renal tissue was resolved immunohistochemically using protein specific antisera. RESULTS: The typically silent Wnt/beta-catenin signal pathway in normal kidneys was noted to be upregulated in patients in either the MCD and ATN groups; that expression was statistically significantly higher in the ATN group as compared to the MCD group (p < 0.05). The degree of renal tissue injury was statistically significantly higher in the ATN group as compared to the MCD group (p < 0.05). Also, the degree of tubulointerstitial fibrosis was significantly higher in the ATN group as compared to the MCD group (p < 0.05). CONCLUSIONS: Results of this investigation confirm the expression of Wnt/beta catenin signal pathway in renal tissue in patients with acute renal injury and nephrotic syndrome, which appear to be important in the host biological response to necrosis, fibrosis, and proliferation. PMID- 29131246 TI - Study on the distribution of CD8+ memory T cell subsets and IFN-gamma level during the spontaneous clearance of hepatitis B virus in patients with chronic hepatitis B virus infection. AB - OBJECTIVE: To study the alteration of CD8+ memory T cell subsets under different immune statuses during the spontaneous clearance of hepatitis B virus (HBV) in Chinese patients with chronic HBV infection. PATIENTS AND METHODS: We analyzed Chinese patients with chronic HBV infection including 10 patients with Hepatitis B surface Antigen (HBsAg) spontaneous seroconversion, 25 patients with Hepatitis B virus e Antigen (HBeAg) spontaneous seroconversion, 25 patients with chronic hepatitis B (CHB), and 25 chronic HBV carriers. The CD8+ T cells in peripheral blood were isolated, and flow cytometry was used to determine the percent change of CD8+ T memory cell subsets. ELISA was used to measure the levels of Interferon gamma (IFN-gamma) secretion from CD8+ T cells. RESULTS: (1) The percentage of CD8+ TN cells in peripheral blood was lower in the HBsAg seroconversion group than in the HBeAg seroconversion group (p<0.01), and higher in the CHB group and chronic HBV carrier group (p<0.01, 0.01); (2) The percentage of CD8+ TEM-2 memory T cells in peripheral blood was higher in the HBsAg seroconversion group than the HBeAg seroconversion group (p<0.05), CHB group, and chronic HBV carrier group (p<0.01, 0.01); (3) The percentage of CD8+ TEM-1 and CD8+ TCM cells in peripheral blood was higher in the CHB group and HBV carrier group than the HBsAg seroconversion group and HBeAg group, but there were no significant differences between groups (p>0.05); (4) IFN-gamma production from CD8+ T cells in peripheral blood was higher in the HBsAg seroconversion group than the HBeAg seroconversion group (p<0.05), CHB group, and chronic HBV carrier group (p<0.05, 0.01). CONCLUSIONS: The consistent increase of CD8+ TEM-2 cell subsets may be an important cause of spontaneous clearance of HBV. The disorder of CD8+ memory T cell differentiation may be an important mechanism of chronic HBV infection. PMID- 29131247 TI - Comparison of cholecystectomy and percutaneous cholecystostomy in acute cholecystitis: results of a retrospective study. AB - OBJECTIVE: To retrospectively compare the clinical outcomes of percutaneous cholecystostomy (PC) and cholecystectomy in patients with acute cholecystitis admitted to an urban University Hospital. PATIENTS AND METHODS: We studied 646 patients with acute cholecystitis. Ninety patients had placement of a PC at their index hospitalization, and 556 underwent cholecystectomy. Of the 90 patients with PC, 13 underwent subsequent elective cholecystectomy. RESULTS: Overall, in hospital mortality and postoperative complications were significantly higher in patients who received PC than in those who underwent cholecystectomy. In the ASA score 1-2 group, patients with PC were significantly older and had a longer postoperative stay while their mortality and morbidity were similar to patients who underwent cholecystectomy. In patients with ASA score of 3, PC and cholecystectomy did not differ significantly for demographic variables and clinical outcomes such as hospital stay, in-hospital mortality, postoperative complications and distribution of complications according to the classification of Clavien-Dildo. In mild, moderate, and severe cholecystitis, patients who underwent PC were significantly older than those who received cholecystectomy. In general, in mild, moderate and severe cholecystitis, the clinical outcomes did not differ significantly between patients who received PC and cholecystectomy. Morbidity was higher in patients with mild cholecystitis who underwent PC. Of the 77 patients dismissed from the hospital with drainage, 12 (15.6%) developed biliary complications and 5 needed substitutions of the drainage itself. CONCLUSIONS: PC does not offer advantages compared to cholecystectomy in the treatment of acute cholecystitis. Its routine use is therefore questioned. There is need of an adequate, randomized study that compares PC and cholecystectomy in high-risk patients with moderate-severe cholecystitis. PMID- 29131248 TI - Body mass index and metabolic syndrome impact differently on major clinical events in renal transplant patients. AB - OBJECTIVE: Kidney transplant recipients (KTRs) are bound to develop cardiovascular disease (CVD), and obesity represents a well-known risk factor for CVD. It has been reported that the metabolic syndrome (MetS) is a frequent finding in KTRs, and MetS could develop even if body mass index (BMI) is only mildly increased. We compared the impact of BMI and MetS on the development of major clinical events (MCEs) in a cohort of 107 KTRs during a follow-up of 63 +/- 31 months. PATIENTS AND METHODS: Clinical characteristics were recorded at the time of enrollment and patients were classified on the basis of MCEs development. In a Cox model, MCEs were the dependent variable while age, sex, history of CVD, glomerular filtration rate, length of dialysis pre-transplantation, BMI classes and diagnosis of MetS were independent variables. Patients were classified into 3 groups: normal (BMI < 25 kg/m2), overweight (BMI of 25 to 30 kg/m2) and obese (BMI > 30 kg/m2). RESULTS: During follow-up, 55 MCEs were recorded: 16 patients died (15%), 19 (18%) had major cardiovascular events (CVEs), and 20 (19%) started dialysis due to graft failure. KTRs who had MCEs (n = 42) were older, had a lower renal function, longer dialysis vintage pre-transplantation, higher prevalence of history of CVD and higher BMI than those without MCEs. Cox regression analysis showed that length of dialysis pre-transplantation, renal function, previous CVD, and BMI classes (overweight and obesity) were related to MCEs. CONCLUSIONS: BMI, but not MetS, predicted MCEs in KTRs as well as non-traditional CVD risk factors such as length of dialysis pre-transplantation and graft function. Thus, a simple evaluation during clinic visits could identify KTRs at high risk for MCEs. PMID- 29131249 TI - Study on the expression and mechanism of plasma microRNA-21 in patients with ischemic cardiomyopathy. AB - OBJECTIVE: To investigate the expression and mechanism of plasma microRNA-21 in patients with ischemic cardiomyopathy (ICM). PATIENTS AND METHODS: 56 cases of ICM patients were selected in our hospital from February 2010 to March 2016 as the observation group, and 60 cases of healthy patients were selected as control group. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of microRNA-21 in two groups. Then, differences of the total cholesterol (TC), triglycerides (TG), left ventricular ejection fraction (LVEF), high and low density lipoprotein cholesterol (HDL-C, LDL-C), left ventricular end-diastolic volume (LVEDV), N terminal B type brain natriuretic peptide (NT-proBNP) and other clinical indicators of the two groups, were compared. The correlation between the plasma microRNA-21 level and the clinical indices was analyzed, and the value of microRNA-21 in the diagnosis and treatment of ICM was evaluated. RESULTS: The levels of LDL-C, HDL-C and LVEF in the observation group were lower than those in the control group (p<0.05). Plasma microRNA-21, TG, NT-proBNP and LVEDV were higher than those in the control group; the difference was statistically significant (p<0.05). Logistic regression analysis showed that the plasma microRNA-21 level was positively correlated with NT-proBNP and LVEDV (p<0.05). CONCLUSIONS: The expression of microRNA-21 in plasma of patients with ICM was significantly increased. And the expression of micro RNA-21 in plasma was positively correlated with NT-proBNP and LVEDV. Through the ventricular remodeling in ICM patients, it can be used as a new target for the diagnosis and treatment of ICM and a new biomarker for risk assessment. PMID- 29131250 TI - Effects of remote ischemic preconditioning on myocardial injury and endothelial function and prognosis after percutaneous coronary intervention in patients with acute coronary syndrome. AB - OBJECTIVE: To explore the effects of remote ischemic preconditioning on myocardial injury and prognosis after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome. PATIENTS AND METHODS: The study was a single center, prospective, randomized, controlled study. A total of 184 patients with unstable angina undergoing elective PCI were randomly assigned to remote ischemic preconditioning group (induced by four times of 5-min inflations of a blood pressure cuff to 200 mmHg around the upper arm, followed by 5-min intervals of reperfusion at 1 h before PCI therapy) or control group (an uninflated cuff around the arm). Successful completion of the PCI eventually included 130 cases of patients, including 72 cases in the remote ischemic preconditioning group and 58 cases in the control group. CK-MB, cTnI, sICAM-1, sVCAM-1 and Hs-CRP levels were measured at 6 am. of the day operating PCI and at 24 h after PCI in the two groups. Major adverse cardiac events were recorded of two groups of patients in the postoperative 6 months. (MACE, including recurrence of angina pectoris, myocardial infarction and death). RESULTS: There were no statistically significant differences in baseline indicators between the 2 groups. CK - MB, cTnI, sICAM-1, sVCAM-1 and Hs-CRP levels in patients with remote ischemic preconditioning group were significantly lower than those form the control group after PCI (p < 0.05), but there were no significant differences between the occurrence of MACE in the postoperative 6 months (p > 0.05). CONCLUSIONS: Remote ischemic preconditioning can reduce PCI related myocardial injury and protect vascular endothelial function. PMID- 29131251 TI - Ischemic stroke and ST-elevation myocardial infarction revealing infective endocarditis. AB - In this clinical scenario, we report the case of a patient who presented multiple embolic complications due to mitral infective endocarditis (IE). A 68-year-old woman had extended right hepatectomy for hilar cholangiocarcinoma. Unfortunately, she had multiple postoperative complications and had to be transferred to the Intensive Care Unit. During this stay, we have diagnosed an Enterococcus faecium IE after the occurrence of multiple embolic complications (myocardial infarction, ischemic stroke, digital emboli, splenic emboli, and renal emboli). The case is presented hereunder with illustrative imagings. While embolism is a known complication of IE, the presence of multiple emboli in various organs is rare. PMID- 29131252 TI - YAP1 up-regulation inhibits apoptosis of aortic dissection vascular smooth muscle cells. AB - OBJECTIVE: Elevated apoptosis of vascular smooth muscle cell (VSMC) is correlated with the occurrence of aortic dissection (AD). Yes-associated protein 1 (YAP1) is the major effector in Hippo-YAP signal pathway, which facilitates cell proliferation and suppressing apoptosis. Several studies have been performed regarding the relationship between YAP1 and AD pathogenesis. This study established the AD rat model to investigate possible roles of YAP1 in regulating VSMC apoptosis and AD pathogenesis. MATERIALS AND METHODS: Cell apoptosis and YAP1 expression were compared between AD vascular tissues and normal rats. In vitro studies with rat thoracic VSMCs were divided into control, cyclic stretch, cyclic stretch + pIRES2-blank and cyclic stretch + pIRES2-YAP1 groups. Cell apoptosis rate, YAP1 and survivin expressions were measured. AD rats were divided into model, Ad-NC injection, and Ad-YAP1 injection group for the detection of AD formation rate, expressions of YPA1 and survivin, and VSMCs apoptosis. RESULTS: Compared to control group, vascular cell apoptosis was increased, and YAP1 expression was reduced in AD rats. Cyclic stretch significantly induced VSMCs apoptosis. The over-expression of YAP1 up-regulated survivin and impeded the cell apoptosis induced by cyclic stretch. The treatment with Ad-YAP1 up-regulated the levels of YAP1 and survivin in AD model rat vascular tissues, and decreased apoptosis and AD formation rate/AD diameter/length. CONCLUSIONS: YAP1 played a critical role in affecting VSMC apoptosis and AD pathogenesis. Up-regulation of YAP1 decreased VSMC apoptosis and AD formation. PMID- 29131253 TI - LncRNA SNHG7 promotes the proliferation and inhibits apoptosis of gastric cancer cells by repressing the P15 and P16 expression. AB - OBJECTIVE: To investigate the relative expression of long non-coding small nucleolar RNA host gene 7 (lncRNA SNHG7) in gastric cancer tissues and cells, the effect of lncRNA SNHG7 on proliferation and apoptosis of gastric cancer cells in vivo and in vitro experiments, and the relevant mechanism. PATIENTS AND METHODS: Real-time quantitative polymerase chain reaction (qRT-PCR) experiment was performed to detect the relative expressions of SNHG7 in the gastric cancer tissues and cells. In presence of lip2000, SNHG7 interference sequence was transiently transfected into the gastric cancer cells followed by transfection efficiency detection by qRT-PCR. Cell count kit 8 (CCK-8) and clone formation assay were also carried out to detect the effect of SNHG7 on the proliferation of gastric cancer cells, flow cytometry (FCM) to detect the effect of SNHG7 on the cycle and apoptotic rate of gastric cancer cells, in vivo experiment to detect the effect of SNHG7 on biological behaviors of gastric cancer cells, and Western blotting assay to detect the variations in expression of downstream proteins after SNHG7 expression was interfered. RESULTS: The qRT-PCR experiment showed that in a total of 68 cases of cancer tissues and tumor-adjacent tissues, the relative expression of SNHG7 was upregulated in 48 cases of gastric cancer tissues and 5 gastric cancer cell lines. The in vitro experiments showed that after SNHG7 expression was interfered, the proliferation of gastric cancer cells was inhibited with an increase in apoptotic rate and arrest of cell cycle in G1/G0 phase. Experiment on nude-mouse transplanted tumor model confirmed that after SNHG7 expression was interfered, in vivo tumor growth was inhibited, and the Western blotting assay revealed that regulation of p15 and p16 expressions constituted a part of the potential molecular mechanism. CONCLUSIONS: Relative expression of SNHG7 is upregulated in gastric cancer tissues and cells, and partially contributes to the development and progression of gastric cancer through regulation of p15 and p16 expressions. Thus, interference on expression of SNHG7 can provide critical the theoretical basis for inverting the malignant phenotype of gastric cancer in clinical practice. PMID- 29131254 TI - Excess of weight: is it a modifiable predictive and prognostic factor in locally advanced rectal cancer? AB - OBJECTIVE: To evaluate the relationship between body mass index (BMI) and rates of treatment tolerance and clinical outcomes in patients with locally advanced rectal cancer treated with a multimodality approach. PATIENTS AND METHODS: This study was conducted on 56 patients with histologically proven rectal adenocarcinoma, staged T3-4, and/or node-positive tumor, which underwent intensified radiochemotherapy (RT-CHT) treatment before surgery. We calculated adiposity indices and analyzed their influence on treatment tolerance and clinical outcomes. RESULTS: Distribution of the 56 patients according to BMI was BMI < 25 kg/m2 (n = 19; 33.9%), BMI 25-29 kg/m2 (n = 29; 51.8%) and BMI >= 30 kg/m2 (n = 8; 14.3%). BMI had no significant influence on neo-adjuvant treatment related toxicity. With a median follow-up of 23 months (range 11-47), the 2-year survival was 85.7%. We did not observe any significant difference among the three BMI categories for any of the outcomes. CONCLUSIONS: This study suggested no evident links between overweight and survival in patients with locally advanced rectal carcinoma treated with neo-adjuvant RT-CHT. Overweight patients tolerate treatment as normal-weight patients. PMID- 29131255 TI - The correlation between the expression of ADAM17, EGFR and Ki-67 in malignant gliomas. AB - OBJECTIVE: The aim of this study was to analyze the depolymerization in metalloproteinase (ADAM17), epidermal growth factor receptor (EGFR), the expression of Ki-67 of glioma patients and the correlations with malignancy. PATIENTS AND METHODS: 53 brain glioma samples resected from patients who had surgery from April 2015 to May 2016 at Chinese People's Armed Police Force General Hospital were selected. According to the degree of malignancy: 22 patients were divided into a deterioration group (stage I to II); 31 patients in highly deteriorated group (stage III to IV); 14 brain tissue samples of traumatic decompression from the hospital as control group. The immunohistochemical method was used to detect the expression of ADAM17, EGFR, and Ki-67 in three groups, and the correlation between the expression of ADAM17, EGFR, and Ki-67. Thus, the stages of malignancy were analyzed. RESULTS: ADAM17, EGFR, and Ki-67 had no expression or weak expression in the control group, and increased in the low stage of deterioration group; the differences were statistically significant (p < 0.05). The positive expression rates of ADAM17, EGFR, and KI-67 were significantly higher in the high deterioration group than that in the control group (p < 0.05). Moreover, the analysis showed that the expression of ADAM17, EGFR, and Ki-67 were positively correlated with the stage of malignancy (R = 0.823, p = 0.000; R = 0.804, p = 0.000; R = 0.811, p = 0.000). CONCLUSIONS: The results suggested that there was a significant positive correlation between ADAM17, EGFR, and Ki-67 with the stage of malignancy. PMID- 29131256 TI - The expression of OCT4 and its clinical significance in laryngeal squamous carcinoma tissues. AB - OBJECTIVE: To investigate the expression of OCT4 and its clinical significance in laryngeal squamous carcinoma tissues. PATIENTS AND METHODS: Immunohistochemical staining was used to analyze the expression of OCT4 in 61 cases of laryngeal squamous carcinoma and 10 cases of the adjacent normal laryngeal tissues. RESULTS: The expression of OCT4 was not detected in normal laryngeal tissues, but could be detected in the nucleus of laryngeal carcinoma. The positive expression rates of OCT4 in well-moderately differentiated and poorly differentiated laryngeal squamous carcinoma tissues were 25.6% (11/43) and 66.7% (12/18) respectively, and there were significant differences (p < 0.01). The expression of the OCT4 protein was related to lymph node metastasis and TNM stage (p < 0.05), but not to gender, age and position of the tumor (p > 0.05). CONCLUSIONS: OCT4 is expressed in laryngeal squamous carcinoma tissues and is closely related to the cell differentiation of laryngeal carcinoma, lymph node metastasis and clinical stage. PMID- 29131257 TI - Long noncoding RNA CASC2 inhibits metastasis and epithelial to mesenchymal transition of lung adenocarcinoma via suppressing SOX4. AB - OBJECTIVE: Recently, long non-coding RNAs (lncRNAs) have caught more attention for their role in tumor progression. Lung adenocarcinoma (LAC) is one of these ordinary malignant tumors. This study aims to identify whether lncRNA CASC2 (cancer susceptibility candidate 2) can regulate the metastasis of LAC, and find out its potential mechanism. PATIENTS AND METHODS: RT-qPCR was conducted to detect CASC2 expression level in 63 LAC tissues and 4 LAC cells. Besides, statistical methods were applied to analyze clinical data and prognosis in the 63 patients. Furthermore, function experiments were performed to determine the effect of CASC2 on LAC metastasis in vitro. The potential mechanism was further explored by RT-qPCR and Western blot assay. RESULTS: In our study, CASC2 expression level was lower in LAC tissues than that in corresponding tissues. CASC2 expression was associated with lymph node metastasis, clinical stage and survival time of these patients. Moreover, overexpression of CASC2 inhibited migrated and invaded ability of LAC cells. Then, epithelial to mesenchymal transition (EMT) process of LAC cells and SOX4 expression was suppressed by upregulating CASC2. CONCLUSIONS: These results indicate that CASC2 could inhibit metastasis and EMT of LAC via suppressing SOX4, which may offer a new vision for interpreting the mechanism of LAC metastasis. PMID- 29131258 TI - Correlation of RGS4 and P16 expressions with pediatric nephroblastoma and its significance on prognosis. AB - OBJECTIVE: To investigate the correlation of regulator of G-protein signaling 4 (RGS4) and P16 expressions with pediatric nephroblastoma and its significance on prognosis. PATIENTS AND METHODS: A total of 80 children with primary nephroblastoma who underwent surgical resection in our hospital from March 2009 to March 2012 were selected as objects of study. The expressions of RGS4 and P16 in cancer and cancer-adjacent tissues of patients were detected by reverse transcription-polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry. All patients were followed up for 5 years. The relationship of RGS4 and P16 to nephroblastoma staging and patients' prognosis was analyzed. RESULTS: The results of RT-PCR and Western blot displayed that the expressions of RGS4, P16 mRNA and protein in cancer tissue, were significantly lower than those in cancer-adjacent tissue (p < 0.05). Immunohistochemistry result revealed that the positive rates of RGS4 and P16 in cancer tissue were distinctly lower than those in cancer-adjacent tissue (76.54% vs. 34.32%, p < 0.05). RGS4 and P16 protein expressions were not associated with tumor, node metastasis (TNM) and pathological typing of nephroblastoma, but they were lowly expressed in patients with high metastasis (p < 0.05). The expressions of RGS4 and P16 were absent in pediatric nephroblastoma, and overall survival (OS) was significantly reduced (p < 0.05). CONCLUSIONS: The absence of RGS4 and P16 in pediatric nephroblastoma tissue is correlated with poor prognosis of patients. RGS4 and P16 are of significance for the prognosis of pediatric nephroblastoma. PMID- 29131259 TI - MicroRNA-21 functions as an oncogene and promotes cell proliferation and invasion via TIMP3 in renal cancer. AB - OBJECTIVE: Renal cell carcinoma (RCC) displays an increasing incidence and mortality rate worldwide in recent years. More and more evidence identified microRNAs function as positive or negative regulatory factors in many cancers, but the role of miR-21 in RCC remains unclear. PATIENTS AND METHODS: Relative expression levels of miR-21 in human RCC tissue samples and RCC-derived cell lines were measured using quantitative real-time Polymerase Chain Reaction (PCR). Clinical features were collected to further study the relationship between the miR-21 level and clinicopathologic variables. Loss- and gain- of miR-21 experiments were employed to measure the influence of miR-21 in cell proliferation, apoptosis, invasion and migration. Downstream target gene was confirmed by using luciferase and Western blotting assays. RESULTS: MiR-21 significantly over-expressed in RCC tissues and cell lines than normal groups. Higher miR-21 expression level indicated larger tumor sizes, more lymph metastasis and advanced tumor node metastasis (TNM) stage. Knocking down miR-21 inhibited the cell growth, invasion and migration abilities but promoted the cell apoptosis, while over-expressing miR-21 promoted cell growth and metastasis. Furthermore, TIMP3 was confirmed as a direct target of moR-21 and inhibition of TIMP3 reserved the effect of down-regulating miR-21 in RCC cells. CONCLUSIONS: Our study demonstrated miR-21 was significantly over-expressed and functioned as a tumor oncogene via TIMP3 in RCC, which could provide a potential target for RCC diagnosis and therapy. PMID- 29131260 TI - MicroRNA-645 promotes cell metastasis and proliferation of renal clear cell carcinoma by targeting GK5. AB - OBJECTIVE: To dissect the functioning mode of miR-645 on renal clear cell carcinoma cell metastasis and growth, and provide therapeutic targets for renal clear cell carcinoma. PATIENTS AND METHODS: Quantitative Real-time PCR (qRT-PCR) assay was employed to detect miR-645 expression level. Wound healing assay and transwell assay were performed to investigate metastasis capacity of renal clear cell carcinoma cells. Cell Counting Kit 8 (CCK8) assay was incorporated to assess cell proliferation capacity. Flow cytometry was used to identify cell apoptosis and cell cycle distribution. Protein levels were assessed by Western blotting assay. The target gene was predicted and verified by bioinformatics analysis and luciferase assay. RESULTS: MiR-645 was upregulated in renal clear cell carcinoma tissues when compared with para-carcinoma tissues (n=32). Downregulated miR-645 could attenuate cell migration and invasion capacities, as well as inhibited cell proliferation capacity, promoted cell apoptosis and cell cycle arrest at G0/G1 phase. GK5 was chosen as the target gene of miR-645 by bioinformatics analysis and luciferase reporter assay. Moreover, silence of GK5 could rescue tumor suppression role of downregulated miR-645 on renal clear cell carcinoma metastasis. CONCLUSIONS: Knockdown of miR-645 exerted tumor-suppressive effects on renal clear cell carcinoma metastasis and growth via targeting GK5 in vitro, which provided an innovative and candidate target for diagnose and treatment of renal clear cell carcinoma. PMID- 29131261 TI - MiR-96 expression in prostate cancer and its effect on the target gene regulation. AB - OBJECTIVE: Previous studies showed that miR-96 was associated with a carcinogenic effect. To investigate the expression of miR-96 and related target genes in the regulation of prostatic cancer, we compared the expression of miR-96 in both prostatic cancer and adjacent normal tissues, and explored the role of miR-96 in prostate cancer. PATIENTS AND METHODS: PC-3 cell line originated from human prostatic cancer tissues was prepared. RNA was extracted for examination of miR 96 expression. The expressional alternation of miR-96 target genes, forkhead box O1 (FOXO1) and forkhead box O3a (FOXO3a), in prostatic cancer, was confirmed by PC-3 cells transfected with miR-96 and anti miR-96. RESULTS: Compared with control group, levels of FOXO1 and FOXO3a in PC-3 cells treated with anti miR-96 were 1.584 times and 1.637 times higher, respectively. Further, PC-3 cells were transfected with siRNA targeting FOXO1 and FOXO3a, resulting in a significant decrease of FOXO1 and FOXO3a expression, as verified by qPCR and Western blot analyses. Compared with untreated groups, proliferation and cell clonal formation exhibited a marked increase in PC-3 cells under transfection with both siR-FOXO1 and siR-FOXO3a. CONCLUSIONS: As target genes of miR-96, FOXO1 and FOXO3a confer protection against prostatic cancer, while the inhibition of FOXO1 and FOXO3a enhances cancer proliferation. PMID- 29131262 TI - MiR-630 promotes epithelial ovarian cancer proliferation and invasion via targeting KLF6. AB - OBJECTIVE: MicroRNAs play critical roles in post-translational gene expression. The current study was to investigate the effects of miR-630 in epithelial ovarian cancer. PATIENTS AND METHODS: Thirty epithelial ovarian cancer tissue and thirty normal ovarian tissue samples were collected and were detected miR-630 expression level with qRT-PCR. MiR-630 mimics, inhibitors and negative controls were transfected into SKOV3 and Cell Counting Kit-8 (CCK-8) assay, and transwell experiment were performed to detect the proliferation rate and migration, respectively. The luciferase reporter assay was utilized to identify miR-630's target gene. Balb/c nude mice were utilized to verify the effect of miR-630 in vivo. RESULTS: QRT-PCR showed a significantly high miR-630 expression in epithelial ovarian cancer relative to normal ovarian tissue. The miR-630 overexpression promoted epithelial ovarian cancer cell SKOV3 proliferation and migration. Kruppel-like factor 6 (KLF6) was predicted as the target of miR-630. In vivo study also verified that miR-630 overexpression stimulated ovarian cancer growth. CONCLUSIONS: We propose that targeting miR-630 might be a promising therapeutic approach for ovarian cancer. PMID- 29131263 TI - Research on application value of combined detection of serum CA125, HE4 and TK1 in the diagnosis of ovarian cancer. AB - OBJECTIVE: To explore the diagnostic value of joint examination of cancer antigen 125 (CA125), thymidine kinase-1 (TK1) and human epididymis protein 4 (HE4) in the serum of patients with ovarian cancer. PATIENTS AND METHODS: A total of 75 ovarian cancer specimens (ovarian cancer group), 40 benign ovarian specimens (benign group) and 35 ovarian specimens of healthy women (normal control group) were collected. The serum levels of HE4, CA125 and TK1 and the positive detection rates in the three groups were compared. Meanwhile, the sensitivity and specificity of the three tumor markers in the diagnosis of ovarian cancer in the three groups were compared. RESULTS: The levels of HE4, CA125 and TK1 in the ovarian cancer group were significantly higher than those in the control group (p<0.05), and those in the ovarian cancer group were significantly higher than those in the benign group (p<0.05). The positive rates of CA125 as well as TK1 in the ovarian cancer group and the benign group were significantly higher than those in the control group (p<0.05), and those in the ovarian cancer group were significantly higher than those in the benign group (p<0.05). In the detection of an individual tumor marker, the sensitivity of CA125 was the highest, followed by HE4. The specificity of HE4 was the highest, followed by TK1. For the combination of two tumor markers, the sensitivity of CA125+HE4 ranked the first (92.18%), and the specificity of TK1+HE4 ranked the first (88.37%). The sensitivity and specificity of the joint detection of CA125+HE4+TK1 were 94.18% and 79.53%, respectively. The sensitivity of the joint detection of CA125+HE4+TK1 was significantly higher than that of the detection of a single tumor marker and that of joint detection of two tumor markers (p<0.05). CONCLUSIONS: Combined detection of CA125, HE4 and TK1 can significantly improve the sensitivity in the diagnosis of ovarian cancer. PMID- 29131264 TI - Upregulation of LncRNA PANDAR predicts poor prognosis and promotes cell proliferation in cervical cancer. AB - OBJECTIVE: To investigate the expression level of long non-coding RNA promoter of CDKN1A antisense DNA damage activated RNA (lncRNA PANDAR) in cervical cancer and to analyze the effects of PANDAR on biological behaviors of cervical cancer and the clinical significance of PANDAR. PATIENTS AND METHODS: A total of 68 pairs of cervical cancer and paired cancer-adjacent tissue specimens were collected. The relative expression of PANDAR in tissues was detected by quantitative Real-time polymerase chain reaction (qRT-PCR) so as to analyze the relationship between PANDAR and clinicopathological factors of cervical cancer and evaluate its clinical significance. qRT-PCR was used to detect the relative expression of PANDAR in cervical cancer cells. Interference in PANDAR was conducted. Cell counting kit-8 (CCK-8) assay was used to detect the changes in cell proliferation capacity. RESULTS: The results of qRT-PCR showed that the expression level of PANDAR was significantly up-regulated in cervical cancer tissues compared with that in cancer-adjacent tissues. Statistical analysis showed that PANDAR expression was correlated with International Federation of Gynecology and Obstetrics (FIGO) staging, tumor size and tumor invasion degree. Kaplan-Meier survival analysis showed that the survival time of patients with highly expressed PANDAR was shorter than that of patients with lowly expressed PANDAR. Cox multivariate regression analysis showed that PANDAR could be used as an independent prognostic factor for patients with cervical cancer. CCK-8 results showed that interference in PANDAR significantly inhibited tumor cell proliferation. CONCLUSIONS: The expression level of PANDAR is up-regulated in cervical cancer tissues and cells, and PANDAR promotes tumor growth. PANDAR may be a biomarker for the early diagnosis of cervical cancer and a potential therapeutic target for reversing the malignant phenotype of tumors. PMID- 29131265 TI - Metformin reduces SATB2-mediated osteosarcoma stem cell-like phenotype and tumor growth via inhibition of N-cadherin/NF-kB signaling. AB - OBJECTIVE: To investigate the role of SATB2 in stem cell-like properties of osteosarcoma and identify new strategies to eliminate cancer stem cells of osteosarcoma. MATERIALS AND METHODS: Osteosarcoma cancer stem cells were derived by sarcosphere generation or chemo drug enrichment. SATB2 and pluripotency associated gene expression in osteosarcoma CSCs were analyzed using qRT-PCR and Western blotting. The sphere formation assay, cell counting kit-8 assay and anti chemotherapy proteins were used to measure the effects of altered SATB2, N cadherin expression or metformin treatment in CSCs. Nude mice were injected with SATB2-deficient U2OS/MTX cells to assess the role of SATB2 in osteosarcoma growth and chemoresistance in vivo. Bioinformatics analyses were performed to identify SATB2 downstream target genes and immunochemistry to determine the correlation between SATB2 expression and patient outcome. Western blotting and luciferase reporter assays were used to examine the effects of N-cadherin and SATB2 inhibition on the NF-kB pathway. RESULTS: SATB2 was upregulated in osteosarcoma stem cells. Knockdown of SATB2 decreased sarcosphere formation, cell proliferation and stem cell-like gene expression in vitro, meanwhile reduced tumor growth and chemoresistance in vivo. High SATB2 expression in osteosarcoma patient samples was associated with poor clinical outcome. N-cadherin was one critical downstream target gene of SATB2 that mediated the stem cell-like phenotype. Reduction of SATB2 or N-cadherin resulted in NF-kB inactivation, which led to impaired osteosarcoma sphere formation and tumor cell proliferation. Metformin treatment of osteosarcoma cells enhanced the effects of chemotherapy via suppression of N-cadherin. CONCLUSIONS: SATB2 plays an important role in regulating osteosarcoma stem cell-like properties and tumor growth. The combination of conventional chemotherapy and metformin may be a promising therapeutic strategy for osteosarcoma patients. PMID- 29131266 TI - Reactive oxygen species downregulate ARID1A expression via its promoter methylation during the pathogenesis of endometriosis. AB - OBJECTIVE: Oxidative stress caused by reactive oxygen species (ROS) plays an important role in the pathogenesis of endometriosis. The gene AT-rich interactive domain 1A (ARID1A), is frequently down regulated and inactivated in endometriosis. This report is focused on the molecular mechanism of the correlation between oxidative stress and ARID1A gene expression in endometrial cell oxidative damage model. PATIENTS AND METHODS: In this study, the ARID1A gene expression level and its promoter methylation level were detected in 30 endometriosis and normal tissues. The primary endometrial cell was co-cultured with H2O2. Then, MDA and Gpx level were used to test the ROS level, RT-PCR was employed to detect the expression level of ARID1A. At last, the ARID1A gene promoter methylation level was detected by methylation-specific PCR (MSP). Finally, the expression level of DNMT1 was detected by both RT-PCR and Western blot. RESULTS: The expression level of ARID1A gene was down regulated in endometriosis compared with normal tissues. The low expression level of ARID1A gene was associated with its promoter hyper-methylation. In H2O2 simulated endometrial cells, ARID1A gene expression level was decreased. Finally, ROS regulated ARID1A gene expression by changing the methylation level of ARID1A gene promoter. Finally, both the mRNA level and protein level of DNMT1 increased in H2O2 simulated endometrial cells. CONCLUSIONS: In endometriosis, the down regulated ofARID1A gene was highly correlated with its promoter hyper methylation. ROS decreased the expression level of ARID1A gene via regulating methylation of its promoter which contributing to the understanding of the pathogenesis of endometriosis. The possible mechanism of ARID1A gene promoter hyper-methylation is ROS up-regulated DNMT1gene expression. PMID- 29131267 TI - Interleukin-33 promotes the inflammatory reaction in chronic rhinosinusitis with nasal polyps by NF-kappaB signaling pathway. AB - OBJECTIVE: Interleukin (IL)-33 promotes T helper (Th2) immune response and may be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Using murine and human specimens, we evaluated the role of IL-33 in CRSwNP. MATERIALS AND METHODS: To establish CRSwNP, Balb/c mice were sensitized with house dust mite, followed up by intranasal exposure to Staphylococcus aureus to stimulate the inflammatory response of nasal mucosa. The hematoxylin-eosin staining and total serum IgE were used to the successful construction of CRSwNP model. For mechanistic studies, we blocked mice with IL-33 and the Th2 cells counts in tissue were detected. Th2 cytokine expression of IL-4, IL-5, IL-13, IL 22, CCL-11, and CCL-24 in control group, CRSwNP group and IL-33 blockade group at 12 weeks after CRSwNP model establishment, were analyzed by qRT-PCR. Meanwhile, the relative mRNA and protein expression levels of NF-kappaB, MyD88 and TLR7 were detected after IL-33 blockade. To document the inflammatory response in patients with CRSwNP, The relative mRNA expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 in control individuals and patients with CRSwNP (chronic rhinosinusitis with nasal polyps) were analyzed by qRT-PCR. RESULTS: The CRSwNP model was successfully constructed. After IL-33 blocked, the relative expression of IL-33 and Th2 cells counts were reduced significantly. CRSwNP mice showed overproduction of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 and IL-33 blockade inhibited the expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24. Furthermore, IL-33 blockade decreased the mRNA levels of NF-kappaB, MyD88 and TLR7, and also restrained the protein expression of them. On the other hand, patients' specimens with CRSwNP showed high levels of Th2 cytokines including IL 33, IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24. CONCLUSIONS: CRSwNP is associated with overexpression of IL-33, with subsequent activation of Th2 immune response by NF-kappaB signaling pathway. PMID- 29131268 TI - Correlation of insulin-like growth factor 1 and osteoarthritic cartilage degradation: a spontaneous osteoarthritis in guinea-pig. AB - OBJECTIVE: The pathogenesis of osteoarthritis centers on the imbalance between catabolic and anabolic processes in cartilage metabolism. Insulin growth factor 1 (IGF-1) has been shown to have anabolic effects in cartilage in vitro. This study aim to determine whether IGF-1 on cartilage is associated with loss of chondrocyte and extracellular matrix breakdown using the Hartley guinea pig model. MATERIALS AND METHODS: Cartilage from the medial and lateral tibial plateau of 6-month and 12-month old Hartley guinea pigs were used for this study. Histological analysis was performed with hematoxylin-eosin (HE) and toluidine blue staining. Safranin-O staining was used to quantify proteoglycan (PG) loss and the extent of cartilage damage by Modified Mankin score. Distribution of IGF 1 was demonstrated with in situ hybridization techniques. IGF-1 mRNA levels were assessed using Real-time PCR. RESULTS: Histological loss of chondrocytes, and cartilage matrix and decreased IGF-1 distribution were demonstrated in a temporal and spatial manner. Compared to the 6-month old samples, the 12-month specimens had significantly cartilage degeneration and less cartilage matrix and PGs staining. Decreased level of IGF-1 was also observed in the 12-month samples. These observations were more pronounced in the medial tibial plateau when compared to the lateral plateau. CONCLUSIONS: The decreased level of IGF-1 may play a critical role for maintaining the balance between catabolic and anabolic processes in cartilage metabolism during the development of osteoarthritis. Thus, the increase of IGF-1 may be applicable to developing OA therapy. PMID- 29131269 TI - Clinical analysis of urinary tract infection in patients undergoing transurethral resection of the prostate. AB - OBJECTIVE: To analyze the related influencing factors of urinary tract infection in patients undergoing transurethral resection of the prostate (TURP). PATIENTS AND METHODS: A total of 343 patients with benign prostatic hyperplasia admitted to this hospital from January 2013 to December 2016, were selected and treated by TURP. Patients were divided into infection group and non-infection group according to the occurrence of urinary tract infection after operation. The possible influencing factors were collected to perform univariate and multivariate logistic regression analysis. RESULTS: There were 53 cases with urinary tract infection after operation among 343 patients with benign prostatic hyperplasia, accounting for 15.5%. The univariate analysis displayed that the occurrence of urinary tract infection in patients undergoing TURP was closely associated with patient's age >= 65 years old, complicated diabetes, catheterization for urinary retention before operation, no use of antibiotics before operation and postoperative indwelling catheter duration >= 5 d (p < 0.05). Multivariate logistic regression analysis revealed that age >= 65 years old, complicated diabetes, catheterization before operation, indwelling catheter duration >= 5 d and no use of antibiotics before operation were risk factors of urinary tract infection in patients receiving TURP (p < 0.05). CONCLUSIONS: The patient's age >= 65 years old, catheterization before operation, complicated diabetes and long-term indwelling catheter after operation, can increase the occurrence of urinary tract infection after TURP, while preoperative prophylactic utilization of anti-infective drugs can reduce the occurrence of postoperative urinary tract infection. PMID- 29131270 TI - Imaging assessment of portal venous system: pictorial essay of normal anatomy, anatomic variants and congenital anomalies. AB - The purpose of this pictorial essay is to describe anatomic variants and congenital anomalies of portal venous system and related liver parenchymal alterations. The imaging findings of some of these entities have been previously described in other articles, however this work encompasses all congenital anomalies of portal venous system with attention to their features on various imaging modalities; in particular we illustrated with detailed pictures all the main portal vein variants, congenital extra- and intra-hepatic porto-systemic venous shunts and portal vein aneurysm. Variants of portal branches and intrahepatic portosystemic shunts are quite uncommon, however, when present, they should be recognized before performing surgery or interventional procedures. Congenital absence of the portal vein is an important finding as the complete loss of portal perfusion predisposes the liver to focal or diffuse hyperplastic or dysplastic changes. Portal vein aneurysm is a rare clinical entity that can affect intra- and extra-hepatic portal branches; although usually asymptomatic, thrombosis can occur. Awareness of congenital variants of portal venous system among radiologists should allow a more confident diagnosis and permit an accurate planning of surgical procedures and percutaneous interventions; identification of portal system anomalies also suggest an accurate evaluation of associated hepatic parenchymal anomalies such as nodular regenerative hyperplasia, focal nodular hyperplasia (FNH), and adenomas with high risk of malignant transformation. PMID- 29131271 TI - Reply to the letter: HIPEC and the necessary hyperthermia: do we still need the open abdomen? PMID- 29131272 TI - HIPEC and the necessary hyperthermia: do we still need the open abdomen? PMID- 29131273 TI - Diagnostic value of joint detection of homocysteine and RDW CV on acute myocardial infarction. AB - The article "Diagnostic value of joint detection of homocysteine and RDW CV on acute myocardial infarction" by G.-X. Hu, J. Zhang, Y.-G. Tian, Y.-H. Li, L. Mou, L.-J. Qiao, published in Eur Rev Med Pharmacol Sci 2016; 20 (19): 4124-4128 has been withdrawn. PMID- 29131274 TI - Expression level and clinical significance of IL-2, IL-6 and TGF-beta in elderly patients with goiter and hyperthyroidism. AB - OBJECTIVE: To investigate the level of expression and the clinical significance of IL-2 (interleukin-2), IL-6 (interleukin-6) and TGF-beta (transforming growth factor-beta) in elderly patients with goiter and hyperthyroidism. PATIENTS AND METHODS: Gender, age, course of disease, BMI (Body Mass Index), serum FT3 (Free triiodothyronine-3), FT4 (Free triiodothyronine-4), TT3 (Total triiodothyronine 3), TT4 (Total triiodothyronine-4), TSH (Thyroid Stimulating Hormone) and clinical manifestations on admission and other general clinical data and laboratory examination results were collected and statistically analyzed as case group in 128 elderly patients with goiter and hyperthyroidism. Additional 128 over 60-year-old patients with hyperthyroidism were selected as control group. The thyroid tissue of these patients and the control group were examined by fine needle aspiration biopsy. The expressions of IL-2, IL-6, TGF-beta of the thyroid tissue in all patients were detected by immunohistochemistry, qRT-PCR (Real-time Quantitative Polymerase Chain Reaction) and Western blot method respectively, and the statistical analysis was carried out. p < 0.05 indicated that the difference had statistical significance. RESULTS: Compared with the control group, the expressions of IL-2, IL-6 and TGF-beta in the group of patients were significantly higher (p < 0.05). The significantly higher expression of IL-2, IL 6, and TGF-beta was mainly concentrated in the thyroid follicular cells of patients with hyperthyroidism and thyroid enlargement (p < 0.05). In the patients with goiter, hyperthyroidism, and symptoms of exophthalmos, the level of expression of IL-6 was significantly higher than that of patients without exophthalmos (p < 0.05). In the patients with goiter, hyperthyroidism and symptoms of exophthalmos, and the patients with goiter, hyperthyroidism without symptoms of exophthalmos, IL-2 and TGF-beta expression level were not different (p > 0.05). CONCLUSIONS: The expression levels of IL-2, IL-6, and TGF-beta were significantly increased in the patients with senile goiter and hyperthyroidism, but in the senile patients with goiter, hyperthyroidism and exophthalmos symptoms, IL-6 levels were significantly higher than those without exophthalmos. The use of IL-2, IL-6, and TGF-beta is of great significance in the diagnosis of goiter with hyperthyroidism, especially for elderly patients with atypical clinical symptoms of hyperthyroidism. PMID- 29131275 TI - Expression, correlation and prognostic significance of CD133, P57 and HSF1 in meningioma. AB - OBJECTIVE: The present study investigated the expressions of CD133, P57 and HSF1 in meningioma so as to explore their protagonists in the prognosis of meningioma. PATIENTS AND METHODS: The subjects in the present study included 57 cases of pathologically diagnosed patients with meningioma and 38 cases of non-meningioma patients. The immunofluorescence method was used to detect CD133, p57, and HSF1 expressions in the meningioma tissue. The reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used for expression studies in both the normal as well as meningioma tissues. RESULTS: Immunofluorescence results showed high levels of expression of CD133, P57 and HSF1 in meningioma tissues. Further, the results of variance analyses confirmed that the expressions of CD133, P57, and HSF1 in meningioma tissues and normal brains tissue were significantly different (p < 0.01). CONCLUSIONS: Expressions of CD133, p57, and HSF1 in meningioma are exceptionally high. The above observation could be exploited for the development of a novel treatment for a brain tumor and better clinical diagnosis as well. PMID- 29131276 TI - The expression of MMP-7 in serum and aneurysm tissues of patients with abdominal aortic aneurysm associated with hypertension and the clinical efficacy of endovascular exclusion. AB - OBJECTIVE: To investigate the expression of matrix metalloproteinase-7 (MMP-7) in abdominal aortic aneurysm (AAA) with hypertension, and the clinical efficacy of endovascular exclusion. PATIENTS AND METHODS: Seventy-two cases of AAA with hypertension were retrospectively analyzed. Patients were divided into the observation group (34 cases) and control group (38 cases). The control group was treated by AAA incision with artificial vascular replacement, while the observation group was treated by endovascular graft exclusion. Over the same period, 72 age- and sex-matched healthy adults and 72 patients with hypertension were selected. MMP-7 expression in patients with hypertension, aneurysm associated with hypertension, and healthy controls were measured by ELISA and immunohistochemical staining. RESULTS: ELISA showed that serum MMP-7 levels of patients with an aneurysm were significantly higher than those of patients with simple hypertension and healthy controls (p<0.05). The operative time, blood loss, and blood transfusion in the observation group were significantly lower than those in the control group (p<0.05). At the 1-month follow-up, the prevalence of pulmonary infection, incision infection, lower limb thrombosis, and lower limb weakness in the observation group were significantly lower than in the control group (p<0.05). The quality of life scores in the observation group after 1 and 3 months was significantly higher than those in the control group (p<0.05). Immunohistochemistry showed that the expression of MMP-7 in aneurysm tissue was significantly higher than in normal tissue. The expression of MMP-7 in the two groups was significantly decreased compared with before surgery (p<0.05). CONCLUSIONS: The detection of MMP-7 expression in hypertensive patients is an early marker of the occurrence of AAA. The use of endovascular exclusion for the treatment of AAA with hypertension is minimally invasive and safe. Furthermore, postoperative vital signs of patients are stable, and the quality of life is improved. PMID- 29131277 TI - Communications of the median nerve in foetuses. AB - BACKGROUND: Communications between the median, ulnar and musculocutaneous nerves in the arm, forearm and hand were reported in adult cadaveric and electrophysiological studies. These communicant branches may lead conflicting clinical and electrodiagnostic outcomes. While there are many studies on adult patients or cadavers, there is poor regarding foetuses. The present study was conducted to examine the frequencies of these communications and their coexistences in human foetuses. MATERIALS AND METHODS: Anterior aspect of the forearms of 50 foetuses (29 females, 20 males, and 1 unknown) were dissected bilaterally (totally 100 sides) for this purpose. RESULTS: Communications between the median and the musculocutaneous nerves in the arm were found unilaterally in 4%. Communications from the median to the ulnar nerve in the forearm were encountered unilaterally in 22%, and bilaterally in 12%; from the ulnar to the median nerve in the hand unilaterally in 28%, and bilaterally in 12%. Coexistence of all these variations was not encountered in any foetus. But coexistence of two different types of communicant branch was encountered in 4%. CONCLUSIONS: Precise knowledge of nerve communications, variations and rate of coexistences in foetuses may have significance for clinicians and researchers dealing with subjects in foetal period. PMID- 29131278 TI - Fractal and stereological analyses of insulin-induced rat exocrine pancreas remodelling. AB - BACKGROUND: The effect of insulin on the endocrine pancreas has been the subject of extensive study, but quantitative morphometric investigations of the exocrine pancreas are scarce. This study was therefore undertaken to investigate the effect of acute and chronic insulin administration (two doses, 0.4 IU and 4 IU) on the morphology of rat pancreas acini. MATERIALS AND METHODS: Semi-fine sections stained with methylene blue and basic fuchsine or haematoxylin and eosin stained 5-micrometer thick paraffin sections were used for fractal and stereological analysis of exocrine acini. Acute insulin treatment, independent of applied doses increased fractal dimension in line with decreased lacunarity of pancreas acini. Chronic low dose insulin decreased fractal dimension and increased lacunarity of pancreas acini, but a high dose had the opposite effect. The volume densities (Vv) of cytoplasm, granules and nucleus are affected differently: acute low dose and high chronic dose significantly decreased granules Vv, and in line increased cytoplasmic Vv, whereas other examined structures showed slight changes without statistical significance. RESULTS: The results obtained from this investigation indicate that insulin treatment induced structural remodelling of the exocrine pancreas suggesting a substantial role of insulin in its functioning. CONCLUSIONS: Additionally, we showed that fine architectural changes in acini could be detected by fractal analysis, suggesting this method as an alternative or addition to routine stereology. PMID- 29131279 TI - Electron microscope study of the advanced tendinopathy process of the long head of the biceps brachii tendon treated arthroscopically. AB - BACKGROUND: The ultrastructural alterations related to tendinopathy have not been well described. Most studies on this subject have been conducted many years ago and focused on material from the Achilles tendon. It was demonstrated that various comorbidities can affect ultrastructural alterations in the advanced tendinopathy; however, there is very little data on ultrastructural morphology in tendinopathies related to mechanical overload as in case of the long head of the biceps brachii tendon (LHBT). The aim was to determine intermediate ultrastructural alterations in middle to severe grade the LHBT tendinopathy and to establish if they are different than those reported in the literature for other anatomical locations. MATERIALS AND METHODS: In this study we examined the ultrastructure of a series of the LHBT fragments arthroscopically removed due to tendinopathy and inve-stigated the morphology of tenocytes and collagen fibres in cases of the LHBT tendinopathy. RESULTS: In pathological samples tenocytes were randomly scattered, their shape was round and the shape of nuclei was also disrupted. The presence of apoptotic--like features in tenocytes' nuclei was noted. All samples showed replacement of collagen fibrils by non-collagen extracellular matrix and diffuse collagen disorganisation. CONCLUSIONS: It was demonstrated at ultrastructural level that the LHBT tendino-pathy is not simply a wear and tear phenomenon, since chronic degeneration of the extracellular matrix and tenocytes were present, similarly as in tendinopathies, in other anatomical locations. (Folia Morphol 2018; 77, 2: 371-377). PMID- 29131280 TI - The sphenopalatine foramen in man: anatomical, radiological and endoscopic study. AB - BACKGROUND: Epistaxis is a frequent problem otorhinolaryngologists faces of in their practice. The variations of the sphenopalatine foramen (SPF) and consequ ently the artery may be one of the major sources of such bleeding. The present work aimed to localise the site of SPF and also to illustrate its different shapes, number and any other variation. MATERIALS AND METHODS: In the current study, 20 adult skulls of both sexes with total 40 half skulls were used in addition to 20 heads of adult living subjects of both sexes aged between 30 and 60 years examined with multislice helical com-puted tomography with 3-dimensional reconstruction of SPF. Then, examination of another ten dried skulls with endoscope was performed. RESULTS: The number of the SPF is varied being single in nearly 80% and multiple in 20% of examined cases. The shape of the foramen also is varied; regular in 67.5% and irregular in 32.5% of all cases. The site of the foramen on the lateral nasal wall is placed in the superior meatus in most of examined skulls (62.5%) while in the rest (37.5%) they are found in the superior meatus and extending to the middle one. CONCLUSIONS: There are variation of the number, shape and site of the SPF, and consequently of the branches of the sphenopalatine artery, and this may explain the surgical failure in management of severe epistaxis. The data obtained from the current work support the predication of more than one sphenopalatine ar-teries and gives ample knowledge on the endoscopic study of the lateral nasal wall and consequently the surgical treatment of severe epistaxis. (Folia Morphol 2018; 77, 2: 345-355). PMID- 29131281 TI - Immunohistochemical study on roe deer haemal nodes. AB - BACKGROUND: The aim of this study was to investigate the immunohistochemical characteristics of the haemal nodes located in the abdominal and thoracic cavities in roe deer (Capreolus capreolus). MATERIALS AND METHODS: In this study, 2 adult male and 2 adult female roe deers in addition to 2 roe deer foetuses at the late foetal stages were used. The avidin-biotin-peroxidase technique was applied to anti-CD3, anti-CD79acy, anti--macrophage, anti-S100 primary antibodies. RESULTS: Positive results were gained for all the antibodies used. Many CD3 positive T-lymphocytes were seen in the lymphoid tissue areas of the foetal haemal nodes, in the germinal centre of the lymph follicles of the adult haemal nodes and in their lymphatic cords. CD79acy positive cells were less in number while S-100 protein was positive in both lymph follicles and in sinuses of the adult haemal nodes. In foetal haemal nodes, cells positive for S-100 protein were more prevalent in the sinuses. For the MAC387 primary antibody, there were positive macrophages seen in the capsule and trabeculae of the haemal nodes, located denser in males. Macrophage cells in the lymphoid structures and granulocytes in the sinuses of the haemal nodes of both adults and foetuses were positive for MAC387. CONCLUSIONS: This study is the first one to define the detailed structural features immunohistochemically in the haemal nodes of the roe deer. Even it's concluded that the results were similar with the other ruminants, it's also pointed out that there are certain differences among the foetal, adult male and female haemal nodes of the roe deer. (Folia Morphol 2018; 77, 2: 266 271). PMID- 29131282 TI - Prognostic value of daytime heart rate, blood pressure, their products and quotients in chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) is an important epidemiological and therapeuthic issue with poor prognosis. The aim of the study was to estimate the prognostic value of daytime heart rate (HR), blood pressure (BP), their products and quotients in patients with CHF. METHODS: The study included 80 stable patients with CHF and reduced left ventricular ejection fraction (LVEF <= 35%). Physical examination, laboratory blood tests, electrocardiogram, chest X-ray, echocardiography, 6-minute walk test (6MWT), telemetry monitoring and BP measurements were performed in all participants. We estimated mean daytime: BP, HR, their products and quotients. The follow-up period was 6 months. Major adverse cardiac events (MACE) included: death, cardiovascular death, hospitalization due to CHF exacerbation. RESULTS: The analysis involved all recruited patients with CHF (91% men) aged 59 +/- 12 years, in New York Heart Association class 2.15 +/- 0.57 and reduced LVEF (mean LVEF: 23 +/- 6%). The 3 month and 6-month mortality rates were 4% and 6% respectively. There was a significant correlation between diastolic blood pressure (DBP), all-cause mortality (p = 0.048) and CHF decompensation (p = 0.0004) after 3-month observation period. No relationship was found between HR or systolic blood pressure (SBP) and MACE. Both higher SBP * HR and DBP * HR products were related to lower risk of heart failure exacerbations during 6-month follow-up. None of the analyzed products or ratios had an impact on mortality in this study group. CONCLUSIONS: Diastolic blood pressure, SBP * HR and DBP * HR products may be useful in subsequent heart failure exacerbation risk stratification. Moreover, DBP value may predict short-term mortality in patients with CHF. PMID- 29131283 TI - Quantitative myocardial Blush score (QuBE) allows the prediction of heart failure development in long-term follow-up in patients with ST-elevation myocardial infarction: Proof of concept study. AB - BACKGROUND: Acute myocardial infarction (AMI) might lead to left ventricular remodeling. Adequate myocardial perfusion is critical to prevent this adverse remodeling. Quantitative myocardial blush evaluator (QuBE) software, available on line, is a simple analysis tool which enables the precise quantification of myocardial perfusion in the infarct area immediately after interventional treatment. The aim of this study was to assess whether the results of QuBE analysis might predict the development of HF in AMI patients in 3 year-long follow-up. METHODS: 95 patients with first AMI, single vessel coronary artery disease, Killip class I at presentation were enrolled in the study. Angiograms were reanalyzed using the on-line QuBE software. Data on heart failure development (ICD 10 codes I50) provided by the National Health Fund were considered as primary outcome. RESULTS: QuBE values ranged from 0.0 to 25.3 arbitrary units, mean value was 9.9 +/- 5.2 arbitrary units. QuBE correlated positively with myocardial blush grade (MBG; Spearman R = 0.342 at p < 0.05). Multivariate Cox proportional hazard modeling, adjusted for initial TIMI flow, and TIMI thrombus grade indicated QuBE score (1 unit increase - HR 0.919, 95% CI 0.846-0.999, p = 0.049) and left ventricular ejection fraction at discharge (1% increase - HR 0.936, 95% CI 0.902-0.971, p = 0.000) as independent predictors of HF development. CONCLUSIONS: The QuBE assessment of myocardial perfusion allows the prediction of HF development in the post-infarction period in this highly selective group of patients. PMID- 29131284 TI - Usefulness of cutting balloon angioplasty for the treatment of congenital heart defects. AB - BACKGROUND: Patients with complex congenital heart defects may have different hemodynamic prob-lems which require a variety of interventional procedures including angioplasty which involves using high-pressure balloons. After failure of conventional balloon angioplasty, cutting balloon angioplasty is the next treatment option available. The purpose of this study was to evaluate the safety and efficacy of cutting balloon angioplasty in children with different types of congenital heart defects. METHODS: Cutting balloon angioplasty was performed in 28 children with different congenital heart defects. The indication for cutting balloon angioplasty was: pulmonary artery stenosis in 17 patients, creating or dilatation of interatrial communication in 10 patients, and stenosis of left subclavian artery in 1 patient. RESULTS: In the pulmonary arteries group there was a significant decrease in systolic blood pressure (SBP) in the proximal part of the artery from the average 74.33 +/- 20.4 mm Hg to 55 +/- 16.7 mm Hg (p < 0.001). Distal to the stenosis there was an increase in SBP from 19.8 +/- 3.82 mm Hg to 30.3 +/- +/- 13.3 mm Hg (p = 0.04). This result remained constant in the follow-up. In atrial septal defect/fenestra-tion group, cutting balloon angioplasty was performed after an unsuccessful classic Rashkind procedure. After cutting balloon angioplasty there was a significant widening of the interatrial communication. CONCLUSIONS: Cutting balloon angioplasty is a feasible and effective treatment option in different con-genital heart defects. PMID- 29131285 TI - Favourable hypotensive effect after standardised tomato extract treatment in hypertensive subjects at high cardiovascular risk: a randomised controlled trial. AB - BACKGROUND: Cardiovascular (CV) diseases remain a leading global cause of death. Lowering blood pressure (BP) reduces the risk of CV complications, especially stroke and acute coronary events, and it delays the progression of kidney disease. Adequate non-pharmacological treatment improves the effectiveness of the antihypertensive therapy. A Mediterranean diet with high content of vegetables (rich in tomatoes) is associated with a reduced CV risk. AIM: The main objective of the present study was to assess whether the addition of standardised tomato extract (STE) or acetylsalicylic acid (ASA) to standard antihypertensive therapy can improve BP control in patients with arterial hypertension (HT). METHODS: The study involved 82 high-risk hypertensive patients. Patients with primary HT at high to a very high total CV risk were randomised in a blinded fashion to one of two groups, i.e. the ASA and STE group. The patients had two visits, a baseline visit and one after four weeks of treatment. In all the patients, during each visit, clinical BP and ambulatory BP measurements (ABPM) were performed. Platelet aggregation was determined using the VerifyNow analyser. RESULTS: After four weeks of treatment in the STE group, there was a statistically significant reduction in 24-h systolic BP, diastolic BP, and mean arterial pressure values measured in ABPM (p < 0.001). After four weeks of treatment in the STE group there was a statistically significant reduction in pulse pressure (PP) during the daytime and during 24 h (p < 0.05). Interestingly, it was found that the use of STE in obese patients significantly decreased the day PP (p < 0.05). After four weeks of treatment in the ASA group there was no statistically significant reduction in BP values measured in ABPM. CONCLUSIONS: The results of this study show that the addition of STE to standard antihypertensive therapy improves BP control in hypertensive patients with high CV risk. This effect, together with the anti-aggregatory effect, may indicate the pleiotropic effect of tomato extract. This fact justifies further research into functional foods and gives new insights into STE as a food supplement that could have new therapeutic and prophylactic uses for the treatment of hypertensive patients with high CV risk and especially with obesity. PMID- 29131286 TI - Conscious sedation for transcatheter implantation of atrial septal occluders with two- and three-dimensional transoesophageal echocardiography guidance - a feasibility and safety study. AB - BACKGROUND: General anaesthesia may have negative impact on patient mortality and morbidity, as well as overall procedure costs, in atrial septal occluder (ASO) implantation. AIM: We sought to evaluate the safety, efficacy, and feasibility of conscious sedation for transcatheter implantation of ASOs. METHODS: A total of 122 patients referred for transcatheter implantation of ASO were included. Mean patient age was 51 +/- 15 years, and 43 (35%) patients were male. The initial dose of midazolam was 2 mg and fentanyl dose was 25 MUg. Additional doses of midazolam and fentanyl were administered, if necessary. Patient responsiveness was assessed every 10 min, and the sedatives doses were titrated in order not to exceed grade 3 sedation in the Ramsey scale. RESULTS: Atrial septal occluders were successfully implanted in the majority of patients (98.4%). In two (1.6%) cases the proce-dure failed because of too small patent foramen ovale (PFO) diameter (n = 1, 0.8%) or device instability (n = 1, 0.8%). The mean duration of procedure was 47.6 +/- 28.4 min and was similar for ASD and PFO closure (p = 0.522). The overall mean dose of midazolam was 4.7 +/- 2.2 mg (63.9 +/- 32.5 MUg/kg) and fentanyl was 30.0 +/- 11.9 MUg (0.43 +/- 0.17 MUg/kg). Median entrance dose of radiation at the patient plane was 25 (interquartile range: 16 57) mGy, and did not differ between ASD and PFO procedures (p = 0.614). The majority of patients were free of complications (91.0%). The following early complications were observed: transient ischaemic attack (n = 2, 1.6%), supraventricular arrhythmias (n = 4, 3.3%), left atrial thrombus formation (n = 1, 0.8%), symptomatic bradycardia (n = 1, 0.8%), and femoral venous bleeding (n = 5, 4.1%). After mean follow-up of 386 days residual shunt was observed in eight (6.6%) patients. CONCLUSIONS: Conscious sedation for transcatheter implantation of ASO is a feasible, safe, and efficient technique, allowing successful PFO and ASD closure in the majority of patients. PMID- 29131287 TI - The relationship between ischaemia-modified albumin and good coronary collateral circulation. AB - BACKGROUND: It is important to determine the grade of the coronary collateral circulation (CCC) in patients with stable coronary artery disease. AIM: In this study, we aimed to investigate the relationship between the ischaemia-modified albumin (IMA) level and good CCC. METHODS: A total of 95 patients with coronary angiography and at least one epicardial coronary artery obstruction were included in the study. The Rentrop classification was used with CCC grading, where 0 and 1 were defined as poor collateral, and 2 and 3 were defined as good collateral. The IMA level of the patients was measured using an enzyme-linked immunosorbent assay (ELISA). The receiver-operating characteristic curve was used to show the sensitivity and specificity of IMA levels and the optimal cut-off value for predicting good CCC. RESULTS: The multiple logistic regression analysis revealed that the IMA level in the good CCC group was higher (p < 0.045). Conversely, the high-sensitivity C-reactive protein level was lower in the good CCC group (p < 0.023). We found an IMA cut-off value (4.7 ng/mL) that indicated good CCC level, and this shows good CCC with 70.2% sensitivity and 60.3% specificity. CONCLUSIONS: The IMA level could serve as a simple and useful predictor of well developed CCC. PMID- 29131288 TI - Mechanisms of cardioembolic stroke revisited. Atrial cardiopathy. PMID- 29131289 TI - Negative predictors of treatment success in outpatient therapy of arterial hypertension in Poland. Results of the CONTROL NT observational registry. AB - BACKGROUND: Identification of factors interfering with adequate control of arterial hypertension (HT) in the course of antihypertensive therapy is necessary to reduce the incidence of cardiovascular disorders and optimise clinical practice guidelines. AIM: The study objective was to conduct a screening assessment of the rate of uncontrolled hypertension among hypertensive patients coming to a routine follow-up visit, and to characterise patients with inadequate control of HT in the aspect of their cardiovascular risk profile and therapeutic strategies used. METHODS: The CONTROL NT registry was a nationwide observational study performed by physicians in the outpatient setting in Poland. Patient data were collected twice: between April and September 2011 and between January and August 2012. Dur-ing screening, the physician completed a questionnaire with patient basic clinical information. The impact of the selected demographic and clinical parameters on treatment success defined as blood pressure (BP) lowering to < 140/90 mmHg when measured in the office at the second visit was investigated with univariate and multivariate logistic regression models. RESULTS: In total 1288 outpatient physicians participated in the CONTROL NT registry. In the screened group of 34,919 patients with a history of HT, 66.9% had abnormal BP readings in the office. In 15,262 patients with inadequate control of hypertension included in further analysis, the mean age was 59.3 +/- 11.9 years, 47.9% were women, the disease duration was 8.2 +/- 6.5 years and antihypertensive therapy was used for 7.4 +/- 6.0 years. At least three cardiovascular risk factors were found in 46% of patients, with the most common dyslipidaemia (77.4%) and abdominal obesity (74.8%). In 56.6% of patients at least one concomitant disease was diagnosed, the most common being diabetes (29.8%). At the time of enrolment 21.5% of patients received no antihypertensive drugs, one, two, three (or more) drug combinations and fixed-dose combina-tions were received by 16.8%, 28.5%, 31.5% and 4.0% of patients, respectively. The most commonly used drug class was angiotensin-converting enzyme inhibitors (50%), followed by beta blockers (42%) and diuretics (39%). Significant negative predictors of BP control included: body mass index >= 30 kg/m2, heart rate >= 70 bpm, history of hypertension >= 7 years, and kidney disease (the odds ratios adjusted by age and gender - 0.61; 0.76; 0.79; and 0.76, respectively). CONCLUSIONS: The percentage of Polish outpatients with adequate HT control is unsatisfactory. Patients with diabetes, chronic kidney disease, dyslipidaemia, overweight or obesity, longer disease and treatment duration and poor treatment compliance require a particularly careful assessment of risk factors and comorbidities, appropriate therapy intensification, and more frequent use of antihypertensive fixed-dose combinations. PMID- 29131290 TI - Nesfatin-1 levels in patients with slow coronary flow. AB - BACKGROUND: Nesfatin-1 is a novel anorectic neuropeptide with potent metabolic regulatory effects. AIM: We aimed to evaluate the relationship between nesfatin-1 levels and slow coronary flow (SCF). METHODS: A total of 60 consecutive patients with SCF and 60 consecutive patients with normal coronary flow (NCF) were enrolled into the study. Nesfatin-1 level was measured from blood serum samples using enzyme-linked immunosorbent assay test. RESULTS: Serum nesfatin-1 levels were significantly lower in the SCF group compared to the NCF group (p < 0.001). Low levels of nesfatin-1 were found to be significantly and independently associated with the SCF (odds ratio 0.982, 95% confidence interval 0.969-0.995, p = 0.005). CONCLUSIONS: The results of this study showed that serum nesfatin-1 level was lower in the SCF group than in the NCF group. Nesfatin-1 could play a role in the pathogenesis of SCF phenomenon with mechanisms such as inflammation and endothelial dysfunction. Further studies are needed to determine the relation between SCF and nesfatin-1. PMID- 29131291 TI - Risk assessment according to the SCORE risk chart - from history, through present, to the future. PMID- 29131292 TI - In-hospital sudden cardiac arrest protocol analysis. AB - BACKGROUND: In-hospital sudden cardiac arrest (SCA) is an event that is linked to high mortality. Data analysis of SCA and the course of in-hospital cardiopulmonary resuscitation (CPR) allows for its better understanding and improvement. AIM: Analysis of cases of SCA and the procedures taken by the medical staff of University Hospital. METHODS: A retrospective analysis of 104 protocols of SCA, from May 2014 to December 2015. Actions taken by medical staff before the arrival of the resuscitation team (RT) and RT proceedings. Data are presented as median and mean +/- standard deviation. RESULTS: 52.88% of cases were women, and their mean age was 70.82 +/- 13.32 years. Resuscitation activities (basic life support: 48.08%, advance life support: 42.31%) were performed before the RT arrival, and no action was taken in 5.77% of cases. The cardiac arrest occurred most commonly in the afternoons hours, and the Emergency Room was the place of CPR in 41.35% of cases. The waiting time for RT was on average 4.47 +/- 5.85 min. Non-defibrillation rhythms occurred in 79.80%, and the efficacy of resuscitation was 40%. CONCLUSIONS: Resuscitation protocols should be registered not only as an important part of medical records, but also as a source of information during the CPR training of staff. The lack of rescue activities before the arrival of the RT indicates the urgent need to identify the cause of the problem and eliminate these negative behaviours. PMID- 29131293 TI - Dynamic thiol/disulphide homeostasis and its prognostic value in patients with non-ST elevation-acute coronary syndromes. AB - BACKGROUND: Cardiovascular diseases are still one of the leading causes of death in industrialised countries, and oxidative stress plays an important role in the pathogenesis of acute coronary syndromes (ACS). The dynamic thiol/disulphide homeostasis plays an important role in maintaining the oxidant-antioxidant balance. AIM: We aimed to demonstrate the relationship between dynamic thiol/disulphide homeostasis parameters and non-ST elevation ACS (NSTE-ACS). METHODS: Patients with NSTE-ACS (n = 210) and a control group (n = 185) were included in the study. The GRACE risk score and the development of major adverse cardiovascular event (MACE) were used to evaluate the prognosis. RESULTS: Native thiol, total thiol, disulphide/native thiol, disulphide/total thiol, and native thiol/total thiol levels were found to be lower in the NSTE-ACS group (p < 0.001). There was a statistically significant difference between native and total thiol levels in the GRACE risk score subgroups (p < 0.001). There was a correlation between MACE and native thiol levels (p = 0.04). CONCLUSIONS: Consequently, the dynamic thiol/disulphide homeostasis parameters were significantly different in the NSTE-ACS group and may be used to predict prognosis in this patient group. PMID- 29131294 TI - Clinical, echocardiographic, and pacing parameters affecting atrial fibrillation burden in patients with tachycardia-bradycardia syndrome. AB - BACKGROUND: The influence of various factors on atrial fibrillation (AF) development in the population of tachycardia-bradycardia syndrome (TBS) patients remains unclear. There are no data on the impact of different right ventricular pacing percentage (RVp%) profiles. AIM: The purpose of the study was to evaluate the relationship between the AF burden (AFB) and various clinical, echocardiographic, and pacing parameters in TBS patients. METHODS: We performed a prospective, one-year registry of TBS patients with documented AF referred for dual-chamber pacemaker (DDD) implantation. RESULTS: The data of 65 patients were analysed. The median 12-month RVp% and AFB was 9.4% and 1.0%, respectively. During the follow-up 14% of patients had no AF (p = 0.003), and the withdrawal of AF symptoms was observed in 49% of patients (p < 0.0001). The AFB was related to the left atrium diameter (r = 0.31, p = 0.02), especially in the subjects with left ventricular ejection fraction < 60% (r = 0.44, p = 0.04). Based on the relative change of RVp%, three groups of various RVp% profile were established: stable, decreasing, and increasing RVp%. In the stable RVp% group (n = 21) there was a quadratic correlation between the 12-month RVp% and AFB (r = 0.71, p = 0.0003). In the stable RVp% > 20% subgroup there was a significant increase of AFB in comparison to the RVp% <= 20% subgroup (DeltaAFB 1.8% vs. 0.0%, p = 0.03, respectively). In the increasing RVp% group (n = 28) the AFB increased whereas in the decreasing RVp% (n = 16) it remained stable (DeltaAFB 0.67% vs. 0.0%, p = 0.034, respectively). CONCLUSIONS: DDD implantation in TBS patients is related to a significant reduction in AF symptoms, and left atrial diameter correlates with cumulative AFB in the mid-term observation. Stable RVp% > 20% is associated with AF progression whereas lower stable RVp% may stabilise AF development. Increasing RVp% may be associated with the AFB increase in comparison to the decreasing RVp% subgroup in which AFB remains stable. PMID- 29131295 TI - The intracardiac concentrations of the N-terminal-pro B-type natriuretic peptide (NT-proBNP) and the determinants of its secretion in patients with atrial fibrillation. AB - BACKGROUND: N-terminal-pro B-type natriuretic peptide (NT-proBNP) is elevated not only in heart failure (HF) but also in atrial fibrillation (AF). The role and secretion pattern of NT-proBNP in AF is still undetermined. AIM: The study aimed to assess NT-proBNP concentrations in patients with and without preserved left ventricular ejection fraction (LVEF) depending on the type of AF. It was also intended to define the main source of NT-proBNP production within the heart. In addition, it aimed to study the relation of NT-proBNP with some echocardiographic parameters reflecting the stretch of heart chambers as well as with the chosen parameters of physical capacity. METHODS: Blood samples were collected from the right atrium (RA), left atrium (LA), and femoral artery (FA) in 53 patients referred for occlusion of the LA appendage. Thirty patients were assigned into Group I (LVEF >= 50%, no HF symptoms) and the remaining 23 patients to Group II (LVEF < 50%, HF symptoms). NT-proBNP concentrations were determined using the ELISA test. RESULTS: In Group I, the lowest NT-proBNP level was found in RA (460.47 +/- 723.15 pg/mL and 1097.72 +/- 851.42 pg/mL for paroxysmal and permanent AF, respectively), higher in LA (481.5 +/- 724.56 pg/mL and 1188.06 +/- 851.42 pg/mL for paroxysmal and permanent AF), and the highest values in FA (537.77 +/- 808.49 pg/mL and 1188.04 +/- 798.28 pg/mL for paroxysmal and permanent AF). In Group II the NT-proBNP values were significantly higher compared to Group I (p < 0.01), but similarly values in RA were the lowest (183.47 +/- 1826.08 pg/mL and 2141.68 +/- 1801.69 pg/mL for paroxysmal and permanent AF), intermediate values were observed in LA (1857.57 +/- 2221.39 pg/mL and 2386.81 +/- 2067.2 pg/mL for paroxysmal and permanent AF), and the highest were seen in FA (1936.27 +/- 2149.85 and 2437.33 +/- 1999.37 pg/mL for paroxysmal and permanent AF, respectively). In Group I, NT-proBNP from LA best correlated with LA area (r = 0.56) and RA area (r = 0.56). In Group II, the strongest correlations were found between NT-proBNP from LA and left ventricular end systolic dimension (r = 0.57) and volume (r = 0.6). CONCLUSIONS: NT-proBNP is markedly elevated in the majority of patients with AF even in the absence of HF. LA secretion of NT-proBNP is an important contributor to the overall increase of NT-proBNP also in HF patients. In AF patients, the concentration of NT-proBNP correlates with the remodelling of heart chambers, but not with physical capacity. PMID- 29131297 TI - Gut bacteria-derived molecules as mediators and markers in cardiovascular diseases. The role of the gut-blood barrier. PMID- 29131296 TI - Complete percutaneous approach versus surgical access in transfemoral transcatheter aortic valve implantation: results from a multicentre registry. AB - BACKGROUND: Although the femoral approach is the most common route utilised in transcatheter aortic valve implantation (TAVI), it still carries a substantial risk of severe bleeding and vascular complications. AIM: The aim of our study was to compare the safety and efficacy of the complete percutaneous (CPC) approach with surgical cut-down and closure (SCC) in TAVI patients. METHODS: The study population comprised 683 patients with severe aortic stenosis, who underwent transfemoral TAVI. Bleeding and vascular complications were defined according to the Valve Academic Research Consortium (VARC-2) criteria. Propensity-matched cohorts were created to reduce the potential bias of non-random assignment to the type of vascular access technique (SSC, n = 203 vs. CPC, n = 203). RESULTS: The rate of minor vascular complications was higher in the CPC cohort (18.2% vs. 9.9%, p = 0.02). There were no differences in major vascular complications or in any type of bleedings between the two groups. Age (odds ratio [OR] 1.044; 95% confidence interval [CI] 1.003-1.09, p = 0.046), preprocedural haemoglobin (OR 0.849; 95% CI 0.760-0.944, p = 0.03), and baseline estimated glomerular filtration rate < 30 mL/min (OR 3.216; 95% CI 1.176-8.741, p = 0.021) were independent predictors of life-threatening/disabling and major bleedings. Diabetes remained the only independent predictor of major vascular complications (OR 1.695; 95% CI 1.014-3.156, p = 0.046). CONCLUSIONS: In this retrospective analysis both vascular access and closure techniques were associated with a similar risk of severe bleeding and major vascular events. However, these findings should be further confirmed in a multicentre, randomised study. PMID- 29131298 TI - Decellularized kidney matrix as functional material for whole organ tissue engineering. AB - Renal transplantation is currently the most effective treatment for end-stage renal disease, which represents one of the major current public health problems. However, the number of available donor kidneys is drastically insufficient to meet the demand, causing prolonged waiting lists. For this reason, tissue engineering offers great potential to increase the pool of donated organs for kidney transplantation, by way of seeding cells on supporting scaffolding material. Biological scaffolds are prepared by removing cellular components from the donor organs using a decellularization process with detergents, enzymes or other cell lysing solutions. Extracellular matrix which makes up the scaffold is critical to directing the cell attachment and to creating a suitable environment for cell survival, proliferation and differentiation. Researchers are now studying whole intact scaffolds produced from the kidneys of animals or humans without adversely affecting extracellular matrix, biological activity and mechanical integrity. The process of recellularization includes cell seeding strategies and the choice of the cell source to repopulate the scaffold. This is the most difficult phase, due to the complexity of the kidney. Indeed, no studies have provided sufficient results of complete renal scaffold repopulation and differentiation. This review summarizes the research that has been conducted to obtain decellularized kidney scaffolds and to repopulate the scaffolds, evaluating the best cell sources, the cell seeding methods and the cell differentiation in kidney scaffolds. PMID- 29131299 TI - Corrosion of titanium: Part 1: aggressive environments and main forms of degradation. AB - Titanium has outstanding corrosion resistance due to the external natural oxide protective layer formed when it is exposed to an aerated environment. Despite this, titanium may suffer different forms of corrosion in severe environments: uniform corrosion, pitting and crevice corrosion, hydrogen embrittlement, stress corrosion cracking, fretting corrosion and erosion. In this first review, forms of corrosion affecting titanium are analyzed based on a wide literature review. For each form of corrosion, the mechanism and most severe environment are reported according to the current understanding.In the second part, this review will address the possible surface treatments that can increase corrosion resistance on commercially pure titanium: Electrochemical anodizing, thermal oxidation, chemical oxidation and bulk treatments such as alloying will be considered, highlighting the advantages of each technique. PMID- 29131300 TI - Engineered scaffolds and cell-based therapy for periodontal regeneration. AB - BACKGROUND: The main objective of regenerative periodontal therapy is to completely restore the periodontal tissues lost. This review summarizes the most recent evidence in support of scaffold- and cell-based tissue engineering, which are expected to play a relevant role in next-generation periodontal regenerative therapy. METHODS: A literature search (PubMed database) was performed to analyze more recently updated articles regarding periodontal regeneration, scaffolds and cell-based technologies. RESULTS: Evidence supports the importance of scaffold physical cues to promote periodontal regeneration, including scaffold multicompartmentalization and micropatterning. The in situ delivery of biological mediators and/or cell populations, both stem cells and already differentiated cells, has shown promising in vivo efficacy. CONCLUSIONS: Porous scaffolds are pivotal for clot stabilization, wound compartmentalization, cell homing and cell nutrients delivery. Given the revolutionary introduction of rapid prototyping technique and cell-based therapies, the fabrication of custom-made scaffolds is not far from being achieved. PMID- 29131302 TI - Highly active spore biocatalyst by self-assembly of co-expressed anchoring scaffoldin and multimeric enzyme. AB - We report a spore-based biocatalysis platform capable of producing and self assembling active multimeric enzymes on a spore surface with a high loading density. This was achieved by co-expressing both a spore surface-anchoring scaffoldin protein containing multiple cohesin domains and a dockerin-tagged enzyme of interest in the mother cell compartment during Bacillus subtilis sporulation. Using this method, tetrameric beta-galactosidase was successfully displayed on the spore surface with a loading density of 1.4 * 104 active enzymes per spore particle. The resulting spore biocatalysts exhibited high conversion rates of transgalactosylation in water/organic emulsions. With easy manufacture, enhanced thermostability, excellent reusability, and long-term storage stability at ambient temperature, this approach holds a great potential in a wide range of biocatalysis applications especially involving organic phases. PMID- 29131301 TI - Genome-wide identification of tolerance mechanisms toward p-coumaric acid in Pseudomonas putida. AB - The soil bacterium Pseudomonas putida KT2440 has gained increasing biotechnological interest due to its ability to tolerate different types of stress. Here, the tolerance of P. putida KT2440 toward eleven toxic chemical compounds was investigated. P. putida was found to be significantly more tolerant toward three of the eleven compounds when compared to Escherichia coli. Increased tolerance was for example found toward p-coumaric acid, an interesting precursor for polymerization with a significant industrial relevance. The tolerance mechanism was therefore investigated using the genome-wide approach, Tn-seq. Libraries containing a large number of miniTn5-Km transposon insertion mutants were grown in the presence and absence of p-coumaric acid, and the enrichment or depletion of mutants was quantified by high-throughput sequencing. Several genes, including the ABC transporter Ttg2ABC and the cytochrome c maturation system (ccm), were identified to play an important role in the tolerance toward p coumaric acid of this bacterium. Most of the identified genes were involved in membrane stability, suggesting that tolerance toward p-coumaric acid is related to transport and membrane integrity. PMID- 29131303 TI - Population-based incidence rate of inpatient and outpatient surgical procedures in a high-income country. AB - BACKGROUND: The WHO and the World Bank ask countries to report the national volume of surgery. This report describes these data for Sweden, a high-income country. METHODS: In an 8-year population-based observational cohort study, all inpatient and outpatient care in the public and private sectors was detected in the Swedish National Patient Register and screened for the occurrence of surgery. The entire Swedish population was eligible for inclusion. All patients attending healthcare for any disease were included. Incidence rates of surgery and likelihood of surgery were calculated, with trends over time, and correlation with sex, age and disease category. RESULTS: Almost one in three hospitalizations involved a surgical procedure (30.6 per cent). The incidence rate of surgery exceeded 17 480 operations per 100 000 person-years, and at least 58.5 per cent of all surgery was performed in an outpatient setting (range 58.5 to 71.6 per cent). Incidence rates of surgery increased every year by 5.2 (95 per cent c.i. 4.2 to 6.1) per cent (P < 0.001), predominantly owing to more outpatient surgery. Women had a 9.8 (95 per cent c.i. 5.6 to 14.0) per cent higher adjusted incidence rate of surgery than men (P < 0.001), mainly explained by more surgery during their fertile years. Incidence rates peaked in the elderly for both women and men, and varied between disease categories. CONCLUSION: Population requirements for surgery are greater than previously reported, and more than half of all surgery is performed in outpatient settings. Distributions of age, sex and disease influence estimates of population surgical demand, and should be accounted for in future global and national projections of surgical public health needs. PMID- 29131304 TI - Costs of reproduction are reflected in women's faces: Post-menopausal women with fewer children are perceived as more attractive, healthier and younger than women with more children. AB - OBJECTIVES: The costs associated with reproduction (i.e., gestation, lactation, childcare) have long-term negative consequences by elevating risk of disease and reducing lifespan. We tested the hypotheses that high parity, and thus high reproductive costs bear by women, is perceived by other people when they evaluate facial appearance of health, attractiveness and age of mothers. MATERIALS AND METHODS: Using computer software we created average facial images based on real photographs of post-menopausal women with varying number of children; 3 parity categories were created (1-2, 4-5, and 7-9 children). Study participants (N = 571) were asked to choose the face they perceived as more attractive, younger and healthier via two-alternative forced choice questions asked in three randomized blocks. RESULTS: Women who had given birth to fewer children were judged both by men and women as more attractive, younger and healthier than women with more children. In each category the lowest scores were received by women from highest parity category (7-9 children). DISCUSSION: Mechanisms behind the observed variation in facial appearance are not known but higher levels of oxidative stress among women with high parity may explain their faster aging and lower attractiveness in older age. These results suggest that costs of reproduction might affect women's physical appearance. PMID- 29131305 TI - Quality of information about success rates provided on assisted reproductive technology clinic websites in Australia and New Zealand. AB - BACKGROUND: Many factors influence the chance of having a baby with assisted reproductive technologies (ART). A 2016 Australian Competition and Consumer Commission (ACCC) investigation concluded that ART clinics needed to improve the quality of information they provide about chance of ART success. AIM: To evaluate changes in the quality of information about success rates provided on the websites of ART clinics in Australia and New Zealand before and after the ACCC investigation. MATERIALS AND METHOD: Desktop audits of websites of ART clinics in Australia and New Zealand were conducted in 2016 and 2017 and available information about success rates was scored using a matrix with eight variables and a possible range of scores of 0-9. RESULTS: Of the 54 clinic websites identified in 2016, 32 had unique information and were eligible to be audited. Of these, 29 were also eligible to be audited in 2017. While there was a slight improvement in the mean score from 2016 to 2017 (4.93-5.28), this was not statistically significantly different. Of the 29 clinics, 14 had the same score on both occasions, 10 had a higher and five a lower information quality score in 2017. CONCLUSIONS: To allow people who consider ART to make informed decisions about treatment they need comprehensive and accurate information about what treatment entails and what the likely outcomes are. As measured by a scoring matrix, most ART clinics had not improved the quality of the information about success rates following the ACCC investigation. PMID- 29131306 TI - Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer's Disease: Systematic Review and Network Metaanalysis. AB - BACKGROUND/OBJECTIVES: To examine the comparative effectiveness and safety of cognitive enhancers for Alzheimer's disease (AD). DESIGN: Systematic review and Bayesian network metaanalysis (NMA). SETTING: MEDLINE, EMBASE, Cochrane Library, CINAHL, Ageline (inception-March 2016). PARTICIPANTS: Individuals with AD in randomized controlled trials (RCTs), quasi-RCTs, and nonrandomized studies. INTERVENTION: Any combination of donepezil, rivastigmine, galantamine, or memantine. MEASUREMENTS: Two reviewers independently screened titles, abstracts, and full-texts; abstracted data; and appraised risk of bias. RESULTS: Twenty thousand three hundred forty-three citations were screened, and 142 studies were included (110 RCTs, 21 non-RCTs, 11 cohort studies). NMA found that donepezil (Mini-Mental State Examination: mean difference (MD) = 1.39, 95% credible interval (CrI) = 0.53-2.24), donepezil+memantine (2.59, 95% CrI = 0.12-4.98), and transdermal rivastigmine (2.02, 95% CrI = 0.02-4.08) improved cognition more than placebo. NMA found that donepezil (Alzheimer's Disease Assessment Scale cognitive: MD = -3.29, 95% CrI = -4.57 to -1.99) and galantamine (MD = -2.13, 95% CrI = -3.91 to -0.27) improved cognition more than placebo. NMA found that donepezil+memantine (MD = -5.23, 95% CrI = -8.72 to -1.56) improved behavior more than placebo. NMA found that donepezil (MD = -0.32, 95% CrI = -0.46 to -0.19), donepezil+memantine (MD = -0.57, 95% CrI = -0.95 to -0.21), oral rivastigmine (MD = -0.38, 95% CrI = -0.56 to -0.17), and galantamine (MD = -3.79, 95% CrI = -6.98 to -0.59) improved global status more than placebo. NMA found that galantamine decreased the odds of mortality (odds ratio = 0.56, 95% CrI = 0.36-0.87). No agent increased risk of serious adverse events, falls, or bradycardia. Some increased risk of headache (oral rivastigmine), diarrhea (oral rivastigmine, donepezil), nausea (oral rivastigmine, donepezil, galantamine), and vomiting (oral rivastigmine, donepezil, galantamine). CONCLUSION: An exhaustive review of the literature involving 142 studies demonstrated that cognitive enhancers in general have minimal effects on cognition according to minimal clinically important difference and global ratings. The drugs appear safe, but this must be interpreted cautiously because trial participants may have less comorbidity and fewer adverse effects than those treated with these drugs in clinical practice. PMID- 29131307 TI - Breastfeeding, weaning, and dietary practices during the Western Zhou Dynasty (1122-771 BC) at Boyangcheng, Anhui Province, China. AB - OBJECTIVES: Here we investigate breastfeeding and weaning practices and adult dietary habits at the Western Zhou Dynasty (1122-771 BC) site of Boyangcheng () located in Anhui Province, China. In addition, we utilize the differences in bone collagen turnover rates between rib and long bones from the same individual to examine past life histories, such as changes in diet or residence. MATERIALS AND METHODS: Bone collagen from both the rib and long bones (either femora or humeri) of 42 individuals was measured for stable isotope ratios of carbon (delta13 C) and nitrogen (delta15 N). In addition, delta13 C and delta15 N values are reported for 35 animals (dogs, cows, horses, pigs, and deer). RESULTS: The human delta13 C values range from -20.70/00 to -12.00/00 with a mean value of -18.8 +/- 1.60/00. The human delta15 N values range from 9.10/00 to 13.40/00 with a mean value of 10.9 +/- 1.00/00. The animals display a wide range of delta13 C ( 21.50/00 to -8.20/00; -15.8 +/- 4.50/00) and delta15 N values (4.00/00 to 9.50/00; 6.5 +/- 1.80/00). CONCLUSIONS: The adult delta13 C and delta15 N results indicate that mixed C3 (rice) and C4 (millet) terrestrial diets with varying levels of animal protein (mostly pigs and deer) were consumed. The elevated subadult delta15 N results return to adult levels by approximately 3-4 years of age, indicating that the weaning process was completed during this period. Individuals between 2 and 10 years old, with lower delta13 C and delta15 N results than the adult mean, possibly consumed more plant-based diets, and this is consistent with Chinese medical teachings ~1500 years later during the Tang Dynasty (AD 618-907). The isotopic offsets between the ribs and long bones revealed that five adults experienced dramatic dietary shifts in their later lives, switching from predominately C3 /C4 to C3 diets. This research provides the first isotopic information about ancient Chinese breastfeeding and weaning practices and establishes a foundation for future studies to examine diachronic trends. PMID- 29131308 TI - Glycosyltransferase cascades made fit for chemical production: Integrated biocatalytic process for the natural polyphenol C-glucoside nothofagin. AB - Glycosyltransferase cascades are promising tools of biocatalysis for natural product glycosylation, but their suitability for actual production remains to be shown. Here, we demonstrate at a scale of 100 g isolated product the integrated biocatalytic production of nothofagin, the natural 3'-C-beta-D-glucoside of the polyphenol phloretin. A parallel reaction cascade involving coupled C glucosyltransferase and sucrose synthase was optimized for the one-pot glucosylation of phloretin from sucrose via an UDP/UDP-glucose shuttle. Inclusion complexation with the highly water soluble 2-hydroxypropyl-beta-cyclodextrin pushed the phloretin solubility to its upper practical limit (~120 mM) and so removed the main bottleneck on an efficient synthesis of nothofagin. The biotransformation thus intensified had excellent performance metrics of 97% yield and ~50 gproduct /L at a space-time yield of 3 g/L/hr. The UDP-glucose was regenerated up to ~220 times. A scalable downstream process for efficient recovery of nothofagin (>=95% purity; >=65% yield) was developed. A tailored anion-exchange chromatography at pH 8.5 was used for capture and initial purification of the product. Recycling of the 2-hydroxypropyl-beta-cyclodextrin would also be possible at this step. Product precipitation at a lowered pH of 6.0 and re-dissolution in acetone effectively replaced desalting by size exclusion chromatography in the final step of nothofagin purification. This study therefore, reveals the potential for process intensification in the glycosylation of polyphenol acceptors by glycosyltransferase cascades. It demonstrates that, with up- and downstream processing carefully optimized and suitably interconnected, a powerful biocatalytic technology becomes available for the production of an important class of glycosides difficult to prepare otherwise. PMID- 29131309 TI - Deaths from Resident-to-Resident Aggression in Australian Nursing Homes. AB - OBJECTIVES: To describe the frequency and nature of deaths from resident-to resident aggression (RRA) in nursing homes in Australia. DESIGN: National population-based retrospective cohort study. SETTING: Accredited nursing homes in Australia. PARTICIPANTS: Residents whose deaths resulted from RRA and were reported to the coroner between July 1, 2000, and December 31, 2013. MEASUREMENTS: Cases were identified using the National Coronial Information System, and data on individual, interpersonal, organizational, and societal factors were collected through review of the paper-based coroners' files. RESULTS: This research identified 28 deaths from RRA over a 14-year study period (0.004 per 100,000 bed days). Most exhibitors of aggression were male (n = 24, 85.7%), and risk of death from RRA was twice as high for male as for female nursing home residents (relative risk (RR) = 2.13, 95% confidence interval (CI) = 0.93-4.80, P = .05). Almost 90% of residents involved in RRA had a diagnosis of dementia, and three-quarters had a history of behavioral problems, including wandering and aggression. Dyad analysis showed that exhibitors of aggression were often younger and more recently admitted to the nursing home than targets. RRA incidents commonly occurred in communal areas and during the afternoon and involved a "push and fall." Seven (25%) RRA deaths had a coronial inquest; criminal charges were rarely filed. CONCLUSION: This is the first national study in Australia, and the largest internationally, to examine RRA deaths using medicolegal data. This generates hypotheses for future research on the effect of environmental and organizational factors on the frequency and preventability of RRA. PMID- 29131310 TI - Tests of fit of historically-informed models of African American Admixture. AB - OBJECTIVES: African American populations in the U.S. formed primarily by mating between Africans and Europeans over the last 500 years. To date, studies of admixture have focused on either a one-time admixture event or continuous input into the African American population from Europeans only. Our goal is to gain a better understanding of the admixture process by examining models that take into account (a) assortative mating by ancestry in the African American population, (b) continuous input from both Europeans and Africans, and (c) historically informed variation in the rate of African migration over time. MATERIALS AND METHODS: We used a model-based clustering method to generate distributions of African ancestry in three samples comprised of 147 African Americans from two published sources. We used a log-likelihood method to examine the fit of four models to these distributions and used a log-likelihood ratio test to compare the relative fit of each model. RESULTS: The mean ancestry estimates for our datasets of 77% African/23% European to 83% African/17% European ancestry are consistent with previous studies. We find admixture models that incorporate continuous gene flow from Europeans fit significantly better than one-time event models, and that a model involving continuous gene flow from Africans and Europeans fits better than one with continuous gene flow from Europeans only for two samples. Importantly, models that involve continuous input from Africans necessitate a higher level of gene flow from Europeans than previously reported. DISCUSSION: We demonstrate that models that take into account information about the rate of African migration over the past 500 years fit observed patterns of African ancestry better than alternative models. Our approach will enrich our understanding of the admixture process in extant and past populations. PMID- 29131311 TI - Hemiparasites can transmit indirect effects from their host plants to herbivores. AB - Parasitic plants can serve as critical intermediaries between their hosts and other organisms; however these relationships are not well understood. To investigate the relative importance of plant traits in such interactions, we studied the role of the root hemiparasite, Castilleja levisecta (Orobanchaceae), as a mediator of interactions between the host plants it parasitizes and the lepidopteran herbivore Euphydryas editha (Nymphalidae), whose caterpillars feed on Castilleja and sequester iridoid glycosides from it. We tested whether the hemiparasite's size, leaf N concentration, and iridoid glycoside concentrations were influenced by the identity of its host plant, and then whether these traits influenced outcomes for the herbivore. We found that the hemiparasite's size and leaf N depended on the host it parasitized, and these traits in turn affected outcomes for E. editha. Specifically, Euphydryas editha survival increased with hemiparasite size and caterpillar mass increased with leaf N; caterpillars with greater mass were more likely to survive during diapause. We also found preliminary evidence that host identity influenced iridoid glycoside sequestration by the herbivore. Mean iridoid glycoside concentrations in caterpillars ranged from 1-12% depending on the host being parasitized by Castilleja. This study demonstrates that root parasitism can result in strong indirect effects on higher trophic levels, influencing organisms' survival, growth, and chemical interactions. PMID- 29131312 TI - Gross total resection and adjuvant radiotherapy most significant predictors of improved survival in patients with atypical meningioma. AB - BACKGROUND: Atypical and malignant meningiomas are far less common than benign meningiomas. As aggressive lesions, they are prone to local recurrence and may lead to decreased survival. Although malignant meningiomas typically are treated with maximal surgical resection and adjuvant radiotherapy (RT), to the authors' knowledge the optimal treatment for atypical lesions remains to be defined. There are limited prospective data in this setting. METHODS: The National Cancer Data Base was queried to investigate cases of histologically confirmed meningiomas diagnosed from 2004 to 2014. This included 7811 patients with atypical meningiomas (World Health Organization grade 2) and 1936 patients with malignant meningiomas (World Health Organization grade 3); during the same period, a total of 60,345 patients were diagnosed with benign meningiomas (World Health Organization grade 1). Data collected included patient and tumor characteristics, extent of surgical resection, and use of RT. Survival analysis was performed using Kaplan-Meier estimates with the log-rank test of significance and Cox univariate and multivariate regression. Logistic regression was used to determine factors associated with use of RT. RESULTS: The 5-year overall survival rate was 85.5% in patients with benign meningiomas, 75.9% in patients with atypical meningiomas, and 55.4% in patients with malignant meningiomas (P<.0001). In patients with atypical meningiomas, gross (macroscopic) total resection (GTR) and adjuvant RT were found to be associated with significantly improved survival, independently and especially in unison (GTR plus RT: hazard ratio, 0.47; P = .002). On multivariate analysis, the combination of GTR plus RT was found to be the most important factor for improved survival. However, GTR was associated with significantly lower rates of RT use. CONCLUSIONS: GTR and adjuvant RT appear to be highly associated with improved survival, independent of other factors, in patients with atypical meningiomas. Cancer 2018;124:734-42. (c) 2017 American Cancer Society. PMID- 29131313 TI - Risk score to predict biliary leakage after elective liver resection. AB - BACKGROUND: Biliary leakage remains a major cause of morbidity after liver resection. Previous prognostic studies of posthepatectomy biliary leakage (PHBL) lacked power, population homogeneity, and model validation. The present study aimed to develop a risk score for predicting severe PHBL. METHODS: In this multicentre observational study, patients who underwent liver resection without hepaticojejunostomy in one of nine tertiary centres between 2012 and 2015 were randomly assigned to a development or validation cohort in a 2 : 1 ratio. A model predicting severe PHBL (International Study Group of Liver Surgery grade B/C) was developed and further validated. RESULTS: A total of 2218 procedures were included. PHBL of any severity and severe PHBL occurred in 141 (6.4 per cent) and 92 (4.1 per cent) patients respectively. In the development cohort (1475 patients), multivariable analysis identified blood loss of at least 500 ml, liver remnant ischaemia time 45 min or more, anatomical resection including segment VIII, transection along the right aspect of the left intersectional plane, and associating liver partition and portal vein ligation for staged hepatectomy as predictors of severe PHBL. A risk score (ranging from 0 to 5) was built using the development cohort (area under the receiver operating characteristic curve (AUROC) 0.79, 95 per cent c.i. 0.74 to 0.85) and tested successfully in the validation cohort (AUROC 0.70, 0.60 to 0.80). A score of at least 3 predicted an increase in severe PHBL (19.4 versus 2.6 per cent in the development cohort, P < 0.001; 15 versus 3.1 per cent in the validation cohort, P < 0.001). CONCLUSION: The present risk score reliably predicts severe PHBL. It represents a multi institutionally validated prognostic tool that can be used to identify a subset of patients at high risk of severe PHBL after elective hepatectomy. PMID- 29131314 TI - Electron shuttling to ferrihydrite selects for fermentative rather than Fe3+ reducing biomass in xylose-fed batch reactors derived from three different inoculum sources. AB - Reports suggest that ferric iron and electron shuttling molecules will select for Fe3+ -reducer dominated microbial biomass. We investigated the influence of the redox mediators anthraquinone-2,6-disulfonate (AQDS) and riboflavin using xylose as the sole fermentation substrate, with or without ferric iron. Electron shuttling to insoluble ferrihydrite enhanced solventogenesis, acidogenesis, hydrogen production, and xylose consumption, relative to the cells plus xylose controls in fermentations inoculated with woodland marsh sediment, wetwood disease, or raw septic liquid, over multiple transfers in 15-day batch fermentations. 16S rRNA gene based community analyses indicated that ferrihydrite alone, and AQDS/riboflavin plus ferrihydrite, immediately shifted native heterogeneous communities to those predominantly belonging to the Clostdridiales, rather than stimulating Fe3+ respiring populations. Data were similar irrespective of the inoculum source, suggesting that Fe3+ and/or electron shuttling compounds select for rapid proliferation of fermentative genera when fermentable substrates are present, and increases the extent of xylose consumption and solvent production. PMID- 29131315 TI - TXNDC5 contributes to rheumatoid arthritis by down-regulating IGFBP1 expression. AB - The thioredoxin domain-containing 5 (TXNDC5) gene is associated with susceptibility to rheumatoid arthritis (RA) and exhibits increased expression in the synovial tissues. TXNDC5 is also associated strongly with diabetes, a metabolic disease characterized by interrupted insulin signalling. This study investigated whether TXNDC5 contributes to RA via the insulin signalling pathway. In this study, RA synovial fibroblast-like cells (RASFs) transfected with an anti TXNDC5 small interfering RNA (siRNA) were analysed with an insulin signaling pathway RT2 profiler polymerase chain reaction (PCR) array and an insulin resistance RT2 profiler PCR array. The PCR arrays detected significantly increased expression of insulin-like growth factor binding protein 1 (IGFBP1) in RASFs with suppressed TXNDC5 expression. The result was verified using real-time PCR and Western blot analyses. Significantly elevated IGFBP1 expression and decreased interleukin (IL)-6 secretion were also detected in culture medium of transfected RASFs. Furthermore, decreased IGFBP1 mRNA and protein expression levels were detected in RA synovial tissues. Additionally, significantly increased apoptosis and decreased cell proliferation and cell migration were observed in RASFs transfected with the anti-TXNDC5 siRNA, whereas transfection with the anti-IGFBP1 siRNA or a mixture of the anti-IGFBP1 and anti-TXNDC5 siRNAs restored normal cell proliferation, migration and IL-6 level in RASFs. Insulin like growth factor (IGF) has potent prosurvival and anti-apoptotic functions, and IGFBP1 can suppress IGF activity. Based on the results of the present study, we suggest that TXNDC5 contributes to abnormal RASF proliferation, migration and IL 6 production by inhibiting IGFBP1 expression. PMID- 29131316 TI - Efficacy of a community-based participatory and multilevel intervention to enhance hepatitis B virus screening and vaccination in underserved Korean Americans. AB - BACKGROUND: The primary objective of the current study was to evaluate the efficacy of a community-based participatory intervention program in improving hepatitis B virus (HBV) screening and vaccination among Korean Americans who were not previously screened. METHODS: A cluster randomized trial involving 32 Korean church-based community organizations (1834 participants) was conducted. Sixteen churches were randomly assigned to an HBV screening and vaccination multicomponent intervention condition (972 participants) and 16 were assigned to a general cancer education control condition (862 participants). The main components of the intervention program included interactive group education; patient navigation; and the engagement of health care providers, church leadership, and church members in the medical field. The application of community based participatory research principles was monitored and evaluated. HBV screening and vaccination rates (self-reported and medical record verification) were assessed at 6-month and 12-month follow-ups, respectively. RESULTS: The results of the current study demonstrated significant efficacy in the HBV screening rate (92.5% in the intervention group vs 5.5% in the control group), 3 series HBV vaccination completion rate (84% in the intervention group vs 17.6% in the control group), and overall screening and vaccination compliance rate (87% in the intervention group vs 3.8% in the control group). Participants in the intervention group were significantly more likely to receive HBV screening (92.5%) compared with those in the control group (5.5%). In multivariate mixed effect logistic regression analysis, the odds ratio for an intervention effect on HBV screening was 512.3 after adjusting for cluster effect and other demographic variables. With regard to vaccination rates, of the 332 participants who were screened with no immunity in the intervention group, 308 (92.8%) received at least 1 HBV vaccination, 300 (90.4%) received at least 2 shots, and 279 participants (84%) received all 3 shots. CONCLUSIONS: A combination of community based participatory research and a multilevel approach may produce the most optimal results and be essential in producing a considerable effect for enhancing HBV screening and vaccination, particularly for Korean American populations with limited language proficiency and insurance coverage. Cancer 2018;124:973-82. (c) 2017 American Cancer Society. PMID- 29131318 TI - A critical role of pentraxin 3 in severe sepsis and septic shock. PMID- 29131317 TI - Molecular photoprotection of human keratinocytes in vitro by the naturally occurring mycosporine-like amino acid palythine. AB - BACKGROUND: Solar ultraviolet radiation (UVR) induces molecular and genetic changes in the skin, which result in skin cancer, photoageing and photosensitivity disorders. The use of sunscreens is advocated to prevent such photodamage; however, most formulations contain organic and inorganic UVR filters that are nonbiodegradable and can damage fragile marine ecosystems. Mycosporine like amino acids (MAAs) are natural UVR-absorbing compounds that have evolved in marine species for protection against chronic UVR exposure in shallow-water habitats. OBJECTIVES: To determine if palythine, a photostable model MAA, could offer protection against a range of UVR-induced damage biomarkers that are important in skin cancer and photoageing. METHODS: HaCaT human keratinocytes were used to assess the photoprotective potential of palythine using a number of end points including cell viability, DNA damage (nonspecific, cyclobutane pyrimidine dimers and oxidatively generated damage), gene expression changes (linked to inflammation, photoageing and oxidative stress) and oxidative stress. The antioxidant mechanism was investigated using chemical quenching and Nrf2 pathway activation assays. RESULTS: Palythine offered statistically significant protection (P < 0.005) against all end points tested even at extremely low concentrations (0.3% w/v). Additionally, palythine was found to be a potent antioxidant, reducing oxidatively generated stress, even when added after exposure. CONCLUSIONS: Palythine is an extremely effective multifunctional photoprotective molecule in vitro that has potential to be developed as a natural and biocompatible alternative to currently approved UVR filters. PMID- 29131319 TI - Optimizing active surveillance strategies to balance the competing goals of early detection of grade progression and minimizing harm from biopsies. AB - BACKGROUND: Active surveillance (AS) for prostate cancer includes follow-up with serial prostate biopsies. The optimal biopsy frequency during follow-up has not been determined. The goal of this investigation was to use longitudinal AS biopsy data to assess whether the frequency of biopsy could be reduced without substantially prolonging the time to the detection of disease with a Gleason score >= 7. METHODS: With data from 1375 men with low-risk prostate cancer enrolled in AS at Johns Hopkins, a hidden Markov model was developed to estimate the probability of undersampling at diagnosis, the annual probability of grade progression, and the 10-year cumulative probability of reclassification or progression to Gleason score >= 7. It simulated 1024 potential AS biopsy strategies for the 10 years after diagnosis. For each of these strategies, the model predicted the mean delay in the detection of disease with a Gleason score >= 7. RESULTS: The model estimated the 10-year cumulative probability of reclassification from a Gleason score of 6 to a Gleason score >= 7 to be 40.0%. The probability of undersampling at diagnosis was 9.8%, and the annual progression probability for men with a Gleason score of 6 was 4.0%. On the basis of these estimates, a simulation of an annual biopsy strategy estimated the mean time to the detection of disease with a Gleason score >= 7 to be 14.1 months; however, several strategies eliminated biopsies with only small delays (<12 months) in detecting grade progression. CONCLUSIONS: Although annual biopsy for low-risk men on AS is associated with the shortest time to the detection of disease with a Gleason score >= 7, several alternative strategies may allow less frequent biopsying without sizable delays in detecting grade progression. Cancer 2018;124:698-705. (c) 2017 American Cancer Society. PMID- 29131320 TI - A translational evidence for cholesteryl ester transfer protein modulation by glucocorticoids: A time for reflection. PMID- 29131321 TI - Ty1-fused protein-body formation for spatial organization of metabolic pathways in Saccharomyces cerevisiae. AB - Metabolite production through a multistep metabolic pathway can often be increased by efficient substrate channeling created by spatial sequestration of the metabolic reactions. Here, Tya, a structural component in the Ty1 retrotransposon element that forms virus-like particles (VLPs) in Saccharomyces cerevisiae, was used to spatially organize enzymes involved in a metabolic pathway into a multi-enzyme protein body in yeast. As a proof of principle, Tya fusion to three key enzymes involved in biosynthesis of the isoprenoids farnesene and farnesol was tested to assess its potential to improve productivity. The Tya fusion protein resulted in three and fourfold increases in farnesene and farnesol production, respectively, as compared with that observed in a non-fused control. Specifically, two-phase partitioning fed-batch fermentations of S. cerevisiae ATCC200589 overexpressing Tya-fused enzymes (tHmg1, IspA, and alpha-farnesene synthase) yielded 930 +/- 40 mg/L of farnesene after 7 days. Additionally, we observed that the Tya-fusion proteins tended to partition into particulate fractions upon 100,000g ultracentrifugation, suggesting the formation of large aggregates of protein bodies, with their particulate structure also observed by transmission electron microscopy. The dramatic increase in the biosynthetic productivity of metabolites via use of a Tya-fusion protein suggested that this approach might be useful for the creation of multi-enzyme complexes to improve metabolic engineering in yeast. PMID- 29131322 TI - Effects of achievement differences for internal/external frame of reference model investigations: A test of robustness of findings over diverse student samples. AB - BACKGROUND: Achievement in math and achievement in verbal school subjects are more strongly correlated than the respective academic self-concepts. The internal/external frame of reference model (I/E model; Marsh, 1986, Am. Educ. Res. J., 23, 129) explains this finding by social and dimensional comparison processes. We investigated a key assumption of the model that dimensional comparisons mainly depend on the difference in achievement between subjects. We compared correlations between subject-specific self-concepts of groups of elementary and secondary school students with or without achievement differences in the respective subjects. AIMS: The main goals were (1) to show that effects of dimensional comparisons depend to a large degree on the existence of achievement differences between subjects, (2) to demonstrate the generalizability of findings over different grade levels and self-concept scales, and (3) to test a rarely used correlation comparison approach (CCA) for the investigation of I/E model assumptions. SAMPLES: We analysed eight German elementary and secondary school student samples (grades 3-8) from three independent studies (Ns 326-878). METHOD: Correlations between math and German self-concepts of students with identical grades in the respective subjects were compared with the correlation of self concepts of students having different grades using Fisher's Z test for independent samples. RESULTS: In all samples, correlations between math self concept and German self-concept were higher for students having identical grades than for students having different grades. Differences in median correlations had small effect sizes for elementary school students and moderate effect sizes for secondary school students. CONCLUSIONS: Findings generalized over grades and indicated a developmental aspect in self-concept formation. The CCA complements investigations within I/E-research. PMID- 29131323 TI - Validity and usefulness of a single-item measure of patient-reported bother from side effects of cancer therapy. AB - BACKGROUND: The improving efficacy of cancer treatment has resulted in an increasing array of treatment-related symptoms and associated burdens imposed on individuals undergoing aggressive treatment of their disease. Often, clinical trials compare therapies that have different types, and severities, of adverse effects. Whether rated by clinicians or patients themselves, it can be difficult to know which side effect profile is more disruptive or bothersome to patients. A simple summary index of bother can help to adjudicate the variability in adverse effects across treatments being compared with each other. METHODS: Across 4 studies, a total of 5765 patients enrolled in cooperative group studies and industry-sponsored clinical trials were the subjects of the current study. Patients were diagnosed with a range of primary cancer sites, including bladder, brain, breast, colon/rectum, head/neck, hepatobiliary, kidney, lung, ovary, pancreas, and prostate as well as leukemia and lymphoma. All patients were administered the Functional Assessment of Cancer Therapy-General version (FACT G). The single item "I am bothered by side effects of treatment" (GP5), rated on a 5-point Likert scale, is part of the FACT-G. To determine its validity as a useful summary measure from the patient perspective, it was correlated with individual and aggregated clinician-rated adverse events and patient reports of their general ability to enjoy life. RESULTS: Analyses of pharmaceutical trials demonstrated that mean GP5 scores ("I am bothered by side effects of treatment") significantly differed by maximum adverse event grade (P<.001) in all trials, with a clear trend toward increasing GP5 scores with level of increasing adverse event grade. Effect sizes ranged from 0.13 to 0.46. Analyses of cooperative group trials demonstrated a significant correlation between GP5 and item GF3 ("I am able to enjoy life") in the predicted direction. CONCLUSIONS: The single FACT-G item "I am bothered by side effects of treatment" is significantly associated with clinician-reported adverse events and with patients' ability to enjoy their lives. It has promise as an overall summary measure of the burden of a given set of treatment toxicities compared with another. Future research can identify the contribution of individual side effects compared with one another in terms of how each may contribute to overall bother. Cancer 2018;124:991-7. (c) 2017 American Cancer Society. PMID- 29131324 TI - Advanced Imaging Reduces Cost Compared to Standard of Care in Emergency Department of Triage of Acute Chest Pain. AB - OBJECTIVE: To evaluate medical costs of novel therapies in complex medical settings using registry data. DATA SOURCE/STUDY SETTING: Primary data, from 2008 to 2010. We used patient registry data to evaluate cost and quality performance of coronary computed tomography angiography (CCTA) in triaging chest pain patients in our tertiary care emergency department and to model financial performance under Medicare's two midnight rule. STUDY DESIGN: Using generalized linear modeling, we retrospectively compared estimated expenditures for evaluation of low-to-intermediate-risk chest pain for demographic and medically risk matched samples of 894 patients each, triaged with CCTA or local standard of care (SOC) using Medicare reimbursement as a proxy. DATA COLLECTION/EXTRACTION METHODS: Predefined data elements were downloaded from the hospital mainframe into the CCTA registry, where they were validated and maintained electronically. PRINCIPLE FINDINGS: We found that predicted standard of care costs were 2.5 times higher on the initial visit and 1.98 times higher over 30 days (p < .001) than those using CCTA. Predicted cost was 1.6 times higher when we applied our two midnight rule model (p < .001). CONCLUSION: Rapid assessment of treatment using registry data is a promising means of analyzing cost performance in complex health care environments. PMID- 29131325 TI - Panel Report, IPA Congress Buenos Aires 2017: Pleasure and intimacy. PMID- 29131326 TI - Magnesium in Migraine Prophylaxis-Is There an Evidence-Based Rationale? A Systematic Review. AB - OBJECTIVE: The primary objective was to systematically evaluate the existing evidence base on magnesium in migraine prophylaxis. METHODS: The search for clinical trials published from 1990 to 2016 was separately conducted by AvL and FR using standard search terms as well as MeSh terms on PubMed and EMBASE. Randomized, double-blind, placebo-controlled trials investigating prophylactic magnesium administration in migraineurs aged 18-65 were considered eligible. In a mutual effort, the studies found were sorted and analyzed under consideration of the guidelines for controlled trials for drugs in migraine by the International Headache Society and using predefined eligibility criteria. The resulting clinical trials were jointly analyzed by FR and AvL applying the evidence classification scheme by the American Academy of Neurology and the Cochrane bias tool to assess the evidence-base. In accordance with the guidelines for controlled trials, the number of migraine days and number of migraine attacks were chosen as primary efficacy parameters. The present review was not registered. RESULTS: Out of 204 search results, five clinical trials fulfilling the selection procedure were found. One out of two Class I evidence trials showed a significant reduction of the number of migraine attacks compared with placebo, while two out of three Class III trials evinced a statistically significant reduction of the primary efficacy parameters compared with placebo. CONCLUSION: This systematic review provides Grade C (possibly effective) evidence for prevention of migraine with magnesium. Prophylactic treatment of migraine by means of high levels of magnesium dicitrate (600 mg) seems to be a safe and cost efficient strategy in clinical use. PMID- 29131328 TI - Headache Education Active-Waiting Directive: A Program to Enhance Well-Being During Long Referral Wait Times. AB - OBJECTIVE: The aim of this initiative was to evaluate the clinical impact, patient acceptability, and sustainability of implementing a newly developed evidence-guided migraine education program in an academic headache center. BACKGROUND: Headache is the fifth most common reason for emergency department (ED) visits and accounts for more than 10 million physician visits annually. Successful management of headaches presents a challenge to both primary care providers and neurologists. The catchment area for an academic headache specialty center in a large metropolitan area is over 6 million with an average wait time of over 15 months. This delays diagnosis and impacts patients, thus a Headache Education Active-Waiting Directive (HEAD) was developed to improve patient knowledge and self-care skills among migraine patients awaiting an initial appointment. METHODS: This was a prospective pre- and post-intervention study. English-speaking adults, aged 18-65 years, referred to the Center for Headache at the University of Toronto for headache consultation between May and December 2012, who had not previously been assessed by a headache specialist, were consented and enrolled. Data on Migraine Disability Assessment (MIDAS) with additional questions on emergency visits, lifestyle, and self-efficacy were collected premigraine and postmigraine education program session. RESULTS: Two hundred and forty-eight patients attended the HEAD program and 177 (71%) consented to the study. Detailed predata and postdata were available for 152 participants (mean age 42.5 +/- 11.9 years, 86% females); 117/150 (78%) presented with depressive symptoms and 90/146 (62%) presented with anxiety symptoms. One hundred and thirty-seven of 143 (96%) were using headache treatment. Eighty of 137 (58%) were overusing over-the-counter medications and only 21/137 (15%) were on preventative treatment. There was a decrease in the MIDAS scores of participants at postsession testing prior to neurological consultation (pre-MIDAS mean 50.0 +/- 64.6 vs post-MIDAS mean 43.2 +/- 50.8, P = .046), as well as a decrease in the number of patients requiring ED visit (presession 33 [22%] vs postsession 17 [11%], P = .001). A significant decrease in medication and narcotic overuse after the HEAD program was also observed. Hydration (water intake), morning protein intake, and routine sleep frequency also significantly improved postsession. Controlling for pre-MIDAS score, poor outcome defined as higher post-MIDAS score was statistically associated with lower education level [F(2,149) = 10.88, P = .001]. The majority (144/167, 86%) of the participants found the HEAD program helpful, with 70/167 (42%) very satisfied and 74/167 (44%) somewhat satisfied. One hundred and thirty-two of 167 (79%) felt empowered after attending the education session, and 152/167 (91%) felt that other patients with headache would benefit from this program. CONCLUSIONS: The HEAD program, created to help manage lengthy appointment wait times, was associated with lowering migraine-associated disability, decreasing ED visits, reducing medication and narcotic use and overuse. Education empowers patients to take an active role in their care, especially in regards to improving treatment timing and modifiable lifestyle behaviors. This education program can potentially play a role in early intervention for headache patients especially with chronic migraine and medication overuse headache. PMID- 29131327 TI - CGRP and PTX3 as Predictors of Efficacy of Onabotulinumtoxin Type A in Chronic Migraine: An Observational Study. AB - OBJECTIVE: The aim of this study is to find a relation between several biomarkers in peripheral blood and outcome after treatment with onabotulinumtoxin A (OnabotA). BACKGROUND: OnabotA is an effective treatment in chronic migraine (CM). Different studies have tried to find predictors of response to treatment, either with clinical characteristics, neuroimaging features, or molecular biomarkers; however, it is still not possible to predict the individual outcome. METHODS: We measured serum levels of biomarkers of inflammation (IL-6, IL-10, TNF alpha, and hs-CRP), endothelial dysfunction (PTX3 and sTWEAK), blood-brain barrier disruption (cFN), brain damage (S100b, NSE), and trigemino-vascular activation (CGRP) by ELISA in a group of CM patients treated with OnabotA and healthy controls. After 24 weeks, patients were classified in two groups according to their outcome considering variations in headache frequency: nonresponders (nonimprovement or improvement <50%) and responders (improvement >50%). We compared baseline levels of biomarkers between these groups. RESULTS: Sixty-two patients diagnosed with CM (IHS 2013 criteria) who fulfilled criteria for treatment with OnabotA and 24 healthy controls were included. Fifteen patients did not respond to treatment (24.2%) and 47 were responders (75.8%). Pentraxin 3 (PTX3) serum levels (1455.4 +/- 487.5 pg/mL versus 720.3 +/- 334.1 pg/mL, P < .0001) and calcitonin gene-related peptide (CGRP) serum levels (133.1 +/- 86.6 ng/mL versus 58.2 +/- 91.7 ng/mL, P = .004) were significantly higher in responders than nonresponders. Serum basal levels of PTX3 >1000 pg/mL (AUC 0.908; 95% CI: 0.827-0.990) and CGRP >50 ng/mL (AUC 0.800; 95% CI: 0.652-0.947) were associated with good response to OnabotA treatment. CONCLUSIONS: These results show that molecular markers of trigeminovascular activation (CGRP) and endothelial dysfunction (PTX3) are associated with response to OnabotA and may act as new biomarkers for the selection of treatment in chronic migraineurs. PMID- 29131329 TI - Function and structure relationships of a beta-1,2-glucooligosaccharide-degrading beta-glucosidase. AB - BT_3567 protein, a putative beta-glucosidase from Bacteroides thetaiotaomicron, exhibits higher activity toward Sop3-5 (Sopn , n: degree of polymerization of beta-1,2-glucooligosaccharides) than toward Sop2 , unlike a known beta glucosidase from Listeria innocua which predominantly prefers Sop2 . In the complex structure determined by soaking of a D286N mutant crystal with Sop4 , a Sop3 moiety was observed at subsites -1 to +2. The glucose moiety at subsite +2 forms a hydrogen bond with Asn81, which is replaced with Gly in the L. innocua beta-glucosidase. The Km values of the N81G mutant for Sop3-5 are much higher than those of the wild-type, suggesting that Asn81 contributes to the binding to substrates longer than Sop3 . PMID- 29131331 TI - Contextual influence over deriving others' true beliefs using a relational triangulation perspective-taking protocol (RT-PTP-M1). AB - This paper introduces the relational triangulation framework as a functional contextual expansion of the established Relational Frame Theory (Hayes, Barnes Holmes, & Roche, 2001) account of perspective-taking. Initial support for the new framework is provided through data collected with a novel relational triangulation perspective-taking protocol configured in the present study to show contextual influence over deriving true belief in others following the direct training of a "seeing leads to knowing" repertoire (Leslie & Frith, 1988). Eight verbally competent adults were directly trained to make operant discriminations on a first set of target stimuli (i.e., the identities of three distinct figurines) and then directly trained to make contextually controlled deictic pointing responses to a second set of target stimuli (i.e., to the relative location of a target beacon according to the signaled spatial perspective of the self vs. two others). The test for derivation was whether the stimuli that had directly acquired contextual control over deictic perspective-taking during training would spontaneously exert contextual control over figurine discrimination relative to the spatial perspective of the two others. That is, passing the test for derivation required participants to infer that the others would "report what they were seeing" the same way that the self would if the self were in their position, suggesting coordination of the self and others. Seven of the eight participants exhibited the intended derivation of the others' "true beliefs," confirming successful relational triangulation perspective-taking protocol configuration for this purpose. PMID- 29131332 TI - The impact of rape acknowledgment on survivor outcomes: The moderating effects of rape myth acceptance. AB - OBJECTIVE: Little is known about how rape acknowledgment relates to posttrauma functioning; recent research suggests the effect may depend on additional factors. In the current study, the moderating effect of rape myth acceptance (RMA) on the relationships between rape acknowledgment and mental health outcomes was examined. METHOD: A sample of 181 female rape survivors recruited from a university completed an online survey assessing RMA, rape acknowledgment, depression symptoms, and alcohol use. RESULTS: Generally, the results supported that RMA moderated the influence of rape acknowledgment on depression symptoms and average quantity per drinking episode, but not frequency of alcohol use. The findings demonstrated that when individuals endorsed high levels of RMA, acknowledged rape survivors reported worse outcomes than unacknowledged rape survivors. Among individuals low on RMA, unacknowledged rape survivors reported worse outcomes than acknowledged rape survivors. CONCLUSION: It is recommended that clinicians recognize the role of survivor beliefs, such as RMA, in the relationship between labeling sexual assault experiences and mental health consequences. PMID- 29131330 TI - Shifting Patterns in Cesarean Delivery Scheduling and Timing in Oregon before and after a Statewide Hard Stop Policy. AB - OBJECTIVES: To assess the use and timing of scheduled cesareans and other categories of cesarean delivery and the prevalence of neonatal morbidity among cesareans in Oregon before and after the implementation of Oregon's statewide policy limiting elective early deliveries. DATA SOURCES: Oregon vital statistics records, 2008-2013. STUDY DESIGN: Retrospective cohort study, with multivariable logistic regression, regression controlling for time trends, and interrupted time series analyses, to compare the odds of different categories of cesarean delivery and the odds of neonatal morbidity pre- and postpolicy. DATA COLLECTION/EXTRACTION METHODS: We analyzed vital statistics data on all term births in Oregon (2008-2013), excluding births in 2011. PRINCIPAL FINDINGS: The odds of early-term scheduled cesareans decreased postpolicy (adjusted odds ratio [aOR], 0.70; 95 percent confidence interval [CI], 0.66-0.74). In the postpolicy period, there were mixed findings regarding assisted neonatal ventilation and neonatal intensive care unit admission, with regression models indicating higher postpolicy odds in some categories, but lower postpolicy odds after controlling for time trends. CONCLUSIONS: Oregon's hard stop policy limiting elective early term cesarean delivery was associated with lower odds of cesarean delivery in the category of women who were targeted by the policy; more research is needed on impact of such policies on neonatal outcomes. PMID- 29131333 TI - Examining the characteristics and clinical features of in- and between-session suicide risk assessments among psychiatric outpatients. AB - OBJECTIVE: To evaluate the characteristics of suicide risk assessments completed using the Decision Tree framework both in and between psychotherapy sessions, clinical features of patients for whom between-session assessments are indicated, and data collected across assessments. METHOD: Data were collected from 1,358 suicide risk assessments conducted with psychiatric outpatients (N = 41) at elevated suicide risk engaged in care at a psychology training clinic. RESULTS: Participants completed an average of 4.75 (standard deviation = 4.95) suicide risk assessments (2.81 +/- 4.43 between-session assessments) per each month in treatment. Assessment frequency and patient ratings of suicidal desire and intent were each significantly associated with therapist risk level categorizations. CONCLUSION: The Decision Tree framework's in- and between-session assessments have the potential to be implemented in a routinized format among psychiatric outpatients at elevated suicide risk. Additional research is needed to establish the feasibility and clinical utility of this framework across samples and providers. PMID- 29131334 TI - Antioxidant Activities of Lactic Acid Bacteria for Quality Improvement of Fermented Sausage. AB - : Lactobacillus curvatus (SR6) and Lactobacillus paracasei (SR10-1) were assessed for their antioxidant activities and inoculated into sausages to investigate their effects on quality during fermentation. The results showed that L. curvatus SR6 had better DPPH* scavenging activity (59.67% +/- 6.68%) and reducing power (47.31% +/- 4.62%) and L. paracasei SR10-1 had better OH* scavenging activity (285.67% +/- 2.00%) and anti-lipid peroxidation capacity (63.89% +/- 0.93%). The superoxide dismutase activity of the cell culture fluid was greater than 47.00 U/mL, and the catalase activity of the cell-free extracts was greater than 1.00 U/mL. In the sausage model, lactic acid bacteria rapidly became the dominant microflora and reduced the moisture content, water activity, nitrite, and pH. The bacteria significantly enhanced the antioxidant activity of the sausage extracts, which improved the sensory characteristics and safety of the sausages. These results illustrate that both strains have excellent antioxidant activities and can be used as antioxidant starters in fermented meat products. PRACTICAL APPLICATION: The study illustrated the antioxidant and antioxidase activities of Lactobacillus curvatus SR6 and Lactobacillus paracasei SR10-1 and demonstrated the changes in the quality characteristics and antioxidant activities of fermented sausages. The findings provide valuable information for the meat industry on the application of functional starters in fermented meat products. PMID- 29131335 TI - Shelf life characteristics of bread produced from ozonated wheat flour. AB - : The objective of this work was to study the effect of ozone treatment on the quality of bread and its shelf life. Flour was treated with ozone gas a rate of 5 L/min for 5, 15, 25, 35, and 45 min. Baking studies showed that bread made from flour treated with ozone for 15 min exhibited improved quality properties (in terms of specific volume, bread color, and crumb cell numbers). Exposure to ozone for shorter times did not cause obvious changes in the major volatile compounds of bread. A shelf life tests showed that ozone gas treatment influenced the extent of starch crystallinity. The relative starch crystallinity of bread made from flour treated with ozone for 15 min was lower than the control value, as were the hardness, springiness, and cohesiveness. Microscopic examination of crumb structure revealed remarkable differences between control and treated breads. PRACTICAL APPLICATIONS: Although ozone is a naturally occurring substance found in the atmosphere, ozone can also be produced synthetically. Recently, ozone has come to be regarded as a new treatment for flour. Especially in countries where the chlorination is forbidden, ozone treatment may be of a great interest if it were associated with significant and reliable changes in flour. Ozone treatment of wheat flour tends to improve bread shelf life and quality in terms of physiochemical, baking properties, X-ray diffraction data, volatile compound levels, crumb structure, and textural characteristics. Given such findings, desirable shelf life and bread qualities may be achieved when ozone is used as a flour oxidant prior to bread baking. Analyses of the effects of ozone gas on treatment of flour on bread shelf life and quality would aid the production of high quality and extend the shelf life of bread. PMID- 29131337 TI - Effect of farming system on donkey milk composition. AB - BACKGROUND: Donkey milk is considered as a functional food for sensitive consumers, such as children who are allergic to cow milk. No information is available regarding the effect of farming systems on the quality of donkey milk. The present study aimed to evaluate the effect of the farming system and lactation stage on donkey milk with respect to gross composition, as well as fat soluble vitamins and fatty acids (FA). RESULTS: Individual milk samples were collected from lactating jennies (n = 53) on the six of the largest farms located in North West Italy. The performance of lactating jennies, herd characteristics and feeding strategies were recorded at each milk sampling. The gross composition of the milk, along with the fat-soluble vitamin content, differed in accordance with the farming system. The lactation stage had limited effects on milk quality. A higher milk fat content corresponded to a higher amount of fresh herbage proportion in the diet, with the highest polyunsaturated fatty acid (PUFA), C18:1c9, C18:3n-3, n-3 FA, retinol and alpha-tocopherol content and the lowest concentrations of the FA that are less favorable for human health in the milk of animals fed on only forage diets. CONCLUSION: Extensive farming of dairy donkeys increased the fat content and fat-soluble vitamin concentration of milk and also altered the FA composition to a more favorable profile for human nutrition. (c) 2017 Society of Chemical Industry. PMID- 29131336 TI - Molecular function of alpha7 nicotinic receptors as drug targets. AB - Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric alpha7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non-neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation. Its diverse physiological actions and associated disorders have made of alpha7 an attractive novel target for drug modulation. Potentiation of the alpha7 receptor has emerged as a novel therapeutic strategy for several neurological diseases, such as Alzheimer's and Parkinson's diseases, and inflammatory disorders. In contrast, increased alpha7 activity has been associated with cancer cell proliferation. The presence of different drug target sites offers a great potential for alpha7 modulation in different pathological contexts. In particular, compounds that target allosteric sites offer significant advantages over orthosteric agonists due to higher selectivity and a broader spectrum of degrees and mechanisms of modulation. Heterologous expression of alpha7, together with chaperone proteins, combined with patch clamp recordings have provided important advances in our knowledge of the molecular basis of alpha7 responses and their potential modulation for pathological processes. This review gives a synthetic view of alpha7 and its molecular function, focusing on how its unique activation and desensitization features can be modified by pharmacological agents. This fundamental information offers insights into therapeutic strategies. PMID- 29131338 TI - Characterization of Volatile Sulfur Compounds in Moutai Liquors by Headspace Solid-Phase Microextraction Gas Chromatography-Pulsed Flame Photometric Detection and Odor Activity Value. AB - : This study investigated the aroma contribution of volatile sulfur compounds (VSCs) in Moutai liquors. The VSCs were analyzed using headspace solid-phase microextraction-gas chromatography-pulsed flame photometric detection (HS-SPME-GC PFPD). The influences of SPME fibers, ethanol content in the sample, pre incubation time, and extraction temperature and time on the extraction of VSCs were optimized. The VSCs were optimally extracted using a divinylbenzene/carboxen/polydimethylsiloxane fiber, by incubating 10 mL diluted Chinese liquor (5% vol.) with 3 g NaCl at 30 degrees C for 15 min, followed by a subsequent extraction for 40 min at 30 degrees C. The optimized method was further validated. A total of 13 VSCs were identified and quantified in Moutai liquors. The aroma contribution of these VSCs were evaluated by their odor activity values (OAVs), with the result that 7 of 13 VSCs had OAVs > 1. In particular, 2-furfurylthiol, methanethiol, dimethyl trisulfide, ethanethiol, and methional had relatively high OAVs and could be the key aroma contributors to Moutai liquors. PRACTICAL APPLICATION: In this study, a method for analyzing volatile sulfur compounds in Chinese liquors has been developed. This method will allow an in-depth study the aroma contribution of volatile sulfur compounds in Chinese liquors. Seven volatile sulfur compounds were identified as potential key aroma contributors for Moutai liquors, which can help to the quality control of Moutai liquors. PMID- 29131339 TI - Geographic Disparities in Access to Nursing Home Services: Assessing Fiscal Stress and Quality of Care. AB - OBJECTIVE: We test whether nursing homes serving predominately low-income and racial minority residents (compositional explanation) or located in neighborhoods with higher concentrations of low-income and racial minority residents (contextual explanation) have worse financial outcomes and care quality. DATA SOURCES: Healthcare Cost Report Information System, Nursing Home Compare, Online Survey Certification and Reporting Certification, and American Community Survey. STUDY DESIGN: A cross-sectional study design of nursing homes within U.S. metropolitan areas. DATA COLLECTION/EXTRACTION METHODS: Data were obtained from Centers for Medicare & Medicaid Services and U.S. Census Bureau. PRINCIPAL FINDINGS: Medicaid-dependent nursing homes have a 3.5 percentage point lower operating ratio. Those serving primarily racial minorities have a 2.64-point lower quality rating. A 1 percent increase in the neighborhood population living in poverty is associated with a 1.20-point lower quality rating, on a scale from 10 to 50, and a 1 percent increase in the portion of neighborhood black residents is associated with a 0.8 percentage point lower operating ratio and a 0.37 lower quality rating. CONCLUSIONS: Medicaid dependency (compositional effect) and concentration of racial minority residents in neighborhoods (contextual effect) are associated with higher fiscal stress and lower quality of care, indicating that nursing homes' geographic location may exacerbate long-term care inequalities. PMID- 29131340 TI - Convergent and divergent evolution in carnivorous pitcher plant traps. AB - Contents Summary 1035 I. Introduction 1035 II. Evolution of the pitcher 1036 III. Convergent evolution 1036 IV. Divergent evolution 1038 V. Adaptive radiation and speciation 1040 VI. Conclusions and perspectives 1040 Acknowledgements 1040 References 1040 SUMMARY: The pitcher trap is a striking example of convergent evolution across unrelated carnivorous plant lineages. Convergent traits that have evolved across pitcher plant lineages are essential for trap function, suggesting that key selective pressures are in action. Recent studies have also revealed patterns of divergent evolution in functional pitcher morphology within genera. Adaptations to differences in local prey assemblages may drive such divergence and, ultimately, speciation. Here, we review recent research on convergent and divergent evolution in pitcher plant traps, with a focus on the genus Nepenthes, which we propose as a new model for research into adaptive radiation and speciation. PMID- 29131341 TI - Multiple strategies for pathogen perception by plant immune receptors. AB - Contents Summary 17 I. Introduction 17 II. Pathogen perception by NLRs: from direct recognition to integrated decoys 18 III. Multiple activation and signaling pathways for NLRs 18 IV. How to engineer NLR-mediated disease resistance? 21 V. Conclusion 23 Acknowledgements 23 References 23 SUMMARY: Plants have evolved a complex immune system to protect themselves against phytopathogens. A major class of plant immune receptors called nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) is ubiquitous in plants and is widely used for crop disease protection, making these proteins critical contributors to global food security. Until recently, NLRs were thought to be conserved in their modular architecture and functional features. Investigation of their biochemical, functional and structural properties has revealed fascinating mechanisms that enable these proteins to perceive a wide range of pathogens. Here, I review recent insights demonstrating that NLRs are more mechanistically and structurally diverse than previously thought. I also discuss how these findings provide exciting future prospects to improve plant disease resistance. PMID- 29131342 TI - Strain-volume loops in severe aortic valve disease. PMID- 29131343 TI - Extracting Wair from the electron beam measurements of Domen and Lamperti. AB - PURPOSE: The average energy expended by an energetic electron to create an ion pair in dry air, Wair , is a key quantity in radiation dosimetry. Although Wair is well established for electron energies up to about 3 MeV, there is limited data for higher energies. The measurements by Domen and Lamperti [Med. Phys. 3, 294-301 (1976)] using electron beams in the energy range from 15 to 50 MeV can, in principle, be used to deduce values for Wair , if the electron stopping power of graphite and air are known. A previous analysis of these data revealed an anomalous variation of 2% in Wair as a function of the electron energy. We use Monte Carlo simulation techniques to reanalyze the original data and obtain new estimates for Wair , and to investigate the source of the reported anomaly. METHODS: Domen and Lamperti (DL) reported the ratio of the response of a graphite calorimeter to that of a graphite ionization chamber for broad beams of electrons with energies between 15 and 50 MeV and at different depths in graphite (including depths well beyond the range of the primary electrons, i.e., in the bremsstrahlung photon regime). Using a detailed EGSnrc model of the DL apparatus, as well as up-to-date stopping powers, we compute the dose ratio between the ionization chamber cavity and the calorimeter core, for plane-parallel electron beams. This dose ratio, multiplied by the DL measured ratio, provides a direct estimate for Wair . RESULTS: Despite an improved analysis of the original work, the extracted values of Wair still exhibit an increase as the mean electron energy at the point of measurement decreases below about 15 MeV. This anomalous trend is dubious physically, and inconsistent with extensive data for Wair obtained at lower energies. A thorough sensitivity analysis indicates that this trend is unlikely to stem from errors in extrapolation and correction procedures, uncertainties in electron stopping powers, or bias in calorimetry or ionization chamber measurements. However, we find that results are quite sensitive to the intrinsic graphite mass thickness of the detectors and to the incident beam energy. CONCLUSIONS: The DL experiment provides data in an energy regime where the electron stopping power is insensitive to the mean excitation energy of graphite - an issue plaguing Wair experiments at lower energies. Unfortunately, state-of-the-art scrutiny of the original data cannot explain the anomalous trend in terms of perturbation effects or extrapolation bias. It can only be understood in terms of speculative offsets in graphite mass thickness or beam energy. Therefore higher accuracy measurements for electron energies above 15 MeV are recommended to further resolve the value of Wair . PMID- 29131344 TI - Aerrow: A probe-format graphite calorimeter for absolute dosimetry of high-energy photon beams in the clinical environment. AB - PURPOSE: In this work, the design, operation, initial experimental evaluation, and characterization of a small-scale graphite calorimeter probe - herein referred to as the Aerrow - developed for routine use in the clinical environment, are described. Similar in size and shape to a Farmer type cylindrical ionization chamber, the Aerrow represents the first translation of calorimetry intended for direct use by clinical physicists in the radiotherapy clinic. METHODS: Based on a numerically optimized design obtained in previous work, a functioning Aerrow prototype capable of two independent modes of operation (quasi-adiabatic and isothermal) was constructed in-house. Reference dose measurements were performed using both Aerrow operation modes in a 6 MV photon beam and were directly compared to results obtained with a calibrated reference-class ionization chamber. The Aerrow was then used to quantify the absolute output of five clinical linac-based photon beams (6 MV, 6 MV FFF, 10 MV, 10 MV FFF, and 15 MV; 63.2% < %dd(10)* < 76.3%). Linearity, dose rate, and orientation dependences were also investigated. RESULTS: Compared to an ion chamber-derived dose to water of 76.3 +/- 0.7 cGy, the average doses measured using the Aerrow were 75.6 +/- 0.7 and 74.7 +/- 0.7 cGy/MU for the quasi adiabatic and isothermal modes, respectively. All photon beam output measurements using the Aerrow in water-equivalent phantom agreed with chamber-based clinical reference dosimetry data within combined standard uncertainties. The linearity of the Aerrow's response was characterized by an adjusted R2 value of 0.9998 in the dose range of 80 cGy to 470 cGy. For the dose-rate dependence, no statistically significant effects were observed in the range of 0.5 Gy/min to 5.4 Gy/min. A relative photon beam quality dependence of 1.7% was calculated in the range of 60 Co to 24 MV (58.4% < %dd(10)* < 86.8%) using Monte Carlo. Finally, the angular dependence (gantry stationary and detector rotated) of the Aerrow's response was found to be insignificant to within +/-0.5%. CONCLUSIONS: This work demonstrates the feasibility of using an ion chamber-sized calorimeter as a practical means of measuring absolute dose to water in the radiotherapy clinic. The potential introduction of calorimetry as a mainstream device into the clinical setting is powerful, as this fundamental technique has formed the basis of absorbed dose standards in many countries for decades and could one day form the basis of a new local absorbed dose standard for clinics. PMID- 29131345 TI - Pursuing an Ethical, Socially Just Classroom: Searching for Community Psychology Pedagogy. AB - Discussions of community psychology (CP) ethics often examine how we might best uphold CP values in community-based practice. However, for many community psychologists in faculty positions, our main domain of practice is the undergraduate classroom. Teaching is essential to the growth and sustainability of our field as prospective students tend to discover CP during their undergraduate studies. University-based work is also a key site of CP practice. Universities are contested spaces where interlocking forms of oppression manifest in many ways, including teaching (e.g., what is taught, how, by whom, to whom). CP values compel us to treat our classrooms as more than just information transmission spaces; just as there is no value-neutral research, there is no value-neutral course content or classroom practice. This first-person narrative explores ethical issues that arise when we put CP values, specifically social justice, respect for diversity, participation, and wellness, in conversation with pedagogical best practices and course content in higher education. It presents interrelated ethical dilemmas and the authors' conflicted responses. We conclude with a four-part call to the field for dedicated scholarly spaces and supports focused on the development and study of undergraduate CP pedagogy. PMID- 29131346 TI - Technical Note: Evaluation of the latency and the beam characteristics of a respiratory gating system using an Elekta linear accelerator and a respiratory indicator device, Abches. AB - PURPOSE: To evaluate the basic performance of a respiratory gating system using an Elekta linac and an Abches respiratory-monitoring device. METHODS: The gating system was comprised of an Elekta Synergy linac equipped with a ResponseTM gating interface module and an Abches respiratory-monitoring device. The latencies from a reference respiratory signal to the resulting Abches gating output signal and the resulting monitor-ion-chamber output signal were measured. Then, the flatness and symmetry of the gated beams were measured using a two-dimensional ionization chamber array for fixed and arc beams, respectively. Furthermore, the beam quality, TPR20,10 , and the output of the fixed gated beams were also measured using a Farmer chamber. Each of the beam characteristics was compared with each of those for nongated irradiation. RESULTS: The full latencies at beam-on and beam-off for 6-MV gated beams were 336.4 +/- 23.4 ms and 87.6 +/- 7.1 ms, respectively. The differences in flatness between the gated and nongated beams were within 0.91% and 0.87% for the gun-target and left-right directions, respectively. In the same manner, the beam symmetries were within 0.68% and 0.82%, respectively. The percentage differences in beam quality and beam output were below 1% for a beam-on time range of 1.1-7 s. CONCLUSION: The latency of the Elekta gating system combined with Abches was found to be acceptable using our measurement method. Furthermore, we demonstrated that the beam characteristics of the gating system using our respiratory indicator were comparable with the nongated beams for a single-arc gated beam delivery. PMID- 29131347 TI - Critical care ultrasound: A national survey across specialties. AB - PURPOSE: Management of the critically ill patient requires rapid assessment and differentiation. Point-of-care ultrasound (POCUS) improves diagnostic accuracy and guides resuscitation. This study sought to describe the use of critical care related POCUS amongst different specialties. METHODS: This study was conducted as an online 18-question survey. Survey questions queried respondent demographics, preferences for POCUS use, and barriers to implementation. RESULTS: 2735 recipients received and viewed the survey with 416 (15.2%) responses. The majority of respondents were pulmonary and critical care medicine (62.5%) and emergency medicine (19.9%) providers. Respondents obtained training through educational courses (26.5%), fellowship (23.9%), residency (21.6%), or self guided learning (17.2%). POCUS use was common for diagnostic and procedural guidance. Emergency medicine providers were more likely to utilize POCUS to evaluate undifferentiated hypotension (98.5%, P < .001), volume status and fluid responsiveness (88.2%, P = .005), and cardiopulmonary arrest (94.1%, P < .001) compared to other specialties. Limited training, competency, or credentialing were the most common barriers, in up to 39.4% of respondents. CONCLUSION: Study respondents utilize POCUS in a variety of clinical applications. However, a disparity in utilization still exists among clinicians who care for critically ill patients. Overcoming barriers, such as a lack of formalized training, competency, or credentialing, may lead to increased utilization. PMID- 29131348 TI - The value of contrast-enhanced laparoscopic ultrasound during robotic-assisted surgery for primary colorectal cancer. AB - AIM: The aim of this study was to assess the potential clinical value of contrast enhanced laparoscopic ultrasonography (CE-LUS) as a screening modality for liver metastases during robotic assisted surgery for primary colorectal cancer (CRC). METHOD: A prospective, descriptive (feasibility) study including 50 consecutive patients scheduled for robotic assisted surgery for primary CRC. CE-LUS was performed by 2 experienced specialists. Only patients without metastatic disease were included. Follow-up was obtained with contrast-enhanced CT imaging at 3 and 12 months postoperatively. RESULTS: Fifty patients were included; 45 patients were available for final analysis. The patients were equally distributed between stage I, II, and III according to the TNM classification system. No liver metastasis was detected during LUS and CE-LUS. CE-LUS was easy to perform and there was no complication. Follow-up revealed no liver metastasis in any of the patients. CONCLUSION: CE-LUS did not increase the detection rate of occult liver metastasis during robotic assisted primary CRC surgery. The use of CE-LUS as a screening modality for detection of liver metastasis cannot be recommended based on this study, but larger controlled studies on high-risk patients seem relevant. PMID- 29131349 TI - Peer victimization and social-emotional outcomes: The role of teacher and peer support. AB - The relation between peer victimization, risk of social, emotional, and behavioral difficulties, and school-based sources of social support for students in elementary and middle school were examined. Participants included 656 students in third to eighth grade from one school district. Results indicated that peer support mediated the relation between peer victimization and risk of social, emotional, and behavioral difficulties, but teacher support did not mediate this relation. Conditional indirect effects analyses revealed that the indirect effect of peer support varied as a function of school level (i.e., intermediate and middle school). The implications and limitations of the current study are discussed, as well as directions for future research. PMID- 29131350 TI - Leiomyosarcoma of the inferior vena cava presenting as a cardiac mass. AB - Primary tumors of the inferior vena cava (IVC) are rare. The most common primary malignancy is leiomyosarcoma (LMS), with a severe prognosis. Right-atrium (RA) involvement is seen in about 20 percent of cases. We report the case of a 53-year old woman admitted to the intensive care unit because of progressive dyspnea with lower limb edema. Echocardiography demonstrated a large mass in the RA. At open heart surgery, the tumor appeared located in the IVC infrahepatic segment, completely obstructing the lumen and extending into the suprahepatic portion and the RA. Histopathological examination concluded to LMS. PMID- 29131351 TI - Ion recombination and polarity correction factors for a plane-parallel ionization chamber in a proton scanning beam. AB - PURPOSE: To evaluate the effect on charge collection in the ionization chamber (IC) in proton pencil beam scanning (PBS), where the local dose rate may exceed the dose rates encountered in conventional MV therapy by up to three orders of magnitude. METHODS: We measured values of the ion recombination (ks ) and polarity (kpol ) correction factors in water, for a plane-parallel Markus TM23343 IC, using the cyclotron-based Proteus-235 therapy system with an active proton PBS of energies 30-230 MeV. Values of ks were determined from extrapolation of the saturation curve and the Two-Voltage Method (TVM), for planar fields. We compared our experimental results with those obtained from theoretical calculations. The PBS dose rates were estimated by combining direct IC measurements with results of simulations performed using the FLUKA MC code. Values of ks were also determined by the TVM for uniformly irradiated volumes over different ranges and modulation depths of the proton PBS, with or without range shifter. RESULTS: By measuring charge collection efficiency versus applied IC voltage, we confirmed that, with respect to ion recombination, our proton PBS represents a continuous beam. For a given chamber parameter, e.g., nominal voltage, the value of ks depends on the energy and the dose rate of the proton PBS, reaching c. 0.5% for the TVM, at the dose rate of 13.4 Gy/s. For uniformly irradiated regular volumes, the ks value was significantly smaller, within 0.2% or 0.3% for irradiations with or without range shifter, respectively. Within measurement uncertainty, the average value of kpol , for the Markus TM23343 IC, was close to unity over the whole investigated range of clinical proton beam energies. CONCLUSION: While no polarity effect was observed for the Markus TM23343 IC in our pencil scanning proton beam system, the effect of volume recombination cannot be ignored. PMID- 29131352 TI - GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. AB - BACKGROUND: The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting. METHODS: In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a "clamp" procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol. RESULTS: For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C "risk" allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect (p = 0.0044) such that subjects with 2 copies of the GRIK1 C "risk" allele reported the greatest sedative response to the higher alcohol dose. CONCLUSIONS: This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans. PMID- 29131354 TI - Effect of status epilepticus on expression of brain UDP-glucuronosyltransferase 1a in rats. AB - Status epilepticus (SE) involves severe epileptic seizures that cause oxidative stress in the brain. Oxidative stress is known to influence uridine 5'-diposphate glucuronosyltransferase (UGT) 1A expression. The present study aimed at elucidating the effect of SE on Ugt1a1, Ugt1a6 and Ugt1a7 expression in the rat brain. Kainic acid was used to create an animal model of SE. Sprague-Dawley rats were treated intraperitoneally with 10 mg/kg kainic acid. Ugt1a1 and Ugt1a7 mRNA levels were increased by SE in the cortex and hippocampus (Ugt1a1: 4.0- and 5.3 fold, respectively; Ugt1a7: 2.8- and 2.5-fold, respectively). Moreover, the induction degree of heme oxygenase-1 mRNA, an oxidative stress marker, was high in these regions, suggesting that oxidative stress could be involved in Ugt1a1 and Ugt1a7 induction. Ugt1a6 was elevated by 1.8-fold in the cortex in both SE and non-response (non-epileptic seizure response) rats, implying that Ugt1a6 induction may be independent from SE. An intraperitoneal single administration of 25 mg/kg diazepam (DZP) for the treatment of SE could attenuate heme oxygenase-1 induction in the cortex, whereas Ugt1a1 was decreased in the hippocampus, but not in the cortex, suggesting that there likely exists an alternative mechanism for Ugt1a1 reduction by DZP treatment. Continuous 14-day administration of DZP inhibited Ugt1a1 induction in the cortex, but did not have an effect on Ugt1a7 induction. This study indicated that SE altered the expression of brain Ugt1a1 and Ugt1a7, which could alter glucuronidation in the brain. PMID- 29131353 TI - Technical note: Accelerated nonrigid motion-compensated isotropic 3D coronary MR angiography. AB - PURPOSE: To develop an accelerated and nonrigid motion-compensated technique for efficient isotropic 3D whole-heart coronary magnetic resonance angiography (CMRA) with Cartesian acquisition. METHODS: Highly efficient whole-heart 3D CMRA was achieved by combining image reconstruction from undersampled data using compressed sensing (CS) with a nonrigid motion compensation framework. Undersampled acquisition was performed using a variable-density Cartesian trajectory with radial order (VD-CAPR). Motion correction was performed in two steps: beat-to-beat 2D translational correction with motion estimated from interleaved image navigators, and bin-to-bin 3D nonrigid correction with motion estimated from respiratory-resolved images reconstructed from undersampled 3D CMRA data using CS. Nonrigid motion fields were incorporated into an undersampled motion-compensated reconstruction, which combines CS with the general matrix description formalism. The proposed approach was tested on 10 healthy subjects and compared against a conventional twofold accelerated 5-mm navigator-gated and tracked acquisition. RESULTS: The proposed method achieves isotropic 1.2-mm Cartesian whole-heart CMRA in 5 min +/- 1 min (~8* acceleration). The proposed approach provides good-quality images of the left and right coronary arteries, comparable to those of a twofold accelerated navigator-gated and tracked acquisition, but scan time was up to about four times faster. For both coronaries, no significant differences (P > 0.05) in vessel sharpness and length were found between the proposed method and reference scan. CONCLUSION: The feasibility of a highly efficient motion-compensated reconstruction framework for accelerated 3D CMRA has been demonstrated in healthy subjects. Further investigation is required to assess the clinical value of the method. PMID- 29131355 TI - Interaction of albumins and heparinoids investigated by affinity capillary electrophoresis and free flow electrophoresis. AB - A fast and precise affinity capillary electrophoresis (ACE) method has been applied to investigate the interactions between two serum albumins (HSA and BSA) and heparinoids. Furthermore, different free flow electrophoresis methods were developed to separate the species which appears owing to interaction of albumins with pentosan polysulfate sodium (PPS) under different experimental conditions. For ACE experiments, the normalized mobility ratios (?R/Rf ), which provided information about the binding strength and the overall charge of the protein ligand complex, were used to evaluate the binding affinities. ACE experiments were performed at two different temperatures (23 and 37 degrees C). Both BSA and HSA interact more strongly with PPS than with unfractionated and low molecular weight heparins. For PPS, the interactions can already be observed at low mg/L concentrations (3 mg/L), and saturation is already obtained at approximately 20 mg/L. Unfractionated heparin showed almost no interactions with BSA at 23 degrees C, but weak interactions at 37 degrees C at higher heparin concentrations. The additional signals also appeared at higher concentrations at 37 degrees C. Nevertheless, in most cases the binding data were similar at both temperatures. Furthermore, HSA showed a characteristic splitting in two peaks especially after interacting with PPS, which is probably attributable to the formation of two species or conformational change of HSA after interacting with PPS. The free flow electrophoresis methods have confirmed and completed the ACE experiments. PMID- 29131356 TI - Gluten sensitivities and the allergist: Threshing the grain from the husks. AB - "Gluten sensitivity" has become commonplace among the public. Wheat allergy (WA) and celiac disease (CD) are well-defined entities, but are becoming a fraction of individuals following a gluten-free diet (GFD). Wheat allergy has a prevalence of <0.5%. Wheat, specifically its omega-5 gliadin fraction, is the most common allergen implicated in food-dependent, exercise-induced anaphylaxis. CD is a non IgE hypersensitivity to certain cereal proteins: gluten in wheat, secalin in rye, hordein in barley, and to a lesser extent avenin in oat. It is a rare disease, with an estimated prevalence that varied widely geographically, being higher in Northern Europe and the African Saharawi region than in South-East Asia. In addition to suggestive symptoms, serologic testing has high diagnostic reliability and biopsy is a confirmatory procedure. Patients with CD have extra intestinal autoimmune comorbid conditions more frequently than expected. A third entity is nonceliac gluten sensitivity, which has been created because of the increasing number of subjects who claim a better quality of life or improvement of their variety of symptoms on switching to a GFD. The phenomenon is being fueled by the media and exploited by the industry. The lack of a specific objective test has been raising substantial controversy about this entity. Allergists and gastroenterologists need to pay attention to the multitudes of individuals who elect to follow a GFD. Many such subjects might have WA, CD, or another illness. Providing them with appropriate evaluation and specific management would be of great advantages, medically and economically. PMID- 29131358 TI - DIY in The Lab: How Necessity Can Make us Creative.... PMID- 29131357 TI - Zika virus: what we need to know? AB - Zika virus is one of the emerging viruses and is of significant threat to human health globally. It is a mosquito borne flavivirus similar to dengue, yellow fever, and West Nile viruses. It was reported about 5 decades ago and then it spreads to different parts of the world. Large outbreaks were reported on Yap Islands in 2007. Now it has gained wide attention globally by health communities. Major vector for virus transmission is Aedes aegypti mosquito. ZIKV infection is mostly asymptomatic but it is also responsible to cause mild influenza like illness to serious manifestations. There is no specific anti-viral treatment is available for ZIKV infection. The virus disseminates very fast due to which it possesses a serious threat especially in those areas where there is lack of specific immunity against virus. Little knowledge is available on its transmission and pathogenicity. Although virus was discovered years ago but its genomic structure is not clearly understood yet. In this review we focus on the current knowledge of epidemiology of ZIKV, its transmission, its structural biology, different aspects of diagnosis and diagnostic challenges as well as highlighted appropriates antiviral drugs and vaccines regarding treatment. PMID- 29131359 TI - Conductance-based profiling of nanopores: Accommodating fabrication irregularities. AB - Solid-state nanopores are nanoscale channels through otherwise impermeable membranes. Single molecules or particles can be passed through electrolyte-filled nanopores by, e.g. electrophoresis, and then detected through the resulting physical displacement of ions within the nanopore. Nanopore size, shape, and surface chemistry must be carefully controlled, and on extremely challenging <10 nm-length scales. We previously developed a framework to characterize nanopores from the time-dependent changes in their conductance as they are being formed through solution-phase nanofabrication processes with the appeal of ease and accessibility. We revisited this simulation work, confirmed the suitability of the basic conductance equation using the results of time-dependent experimental conductance measurements during nanopore fabrication by Yanagi et al., and then deliberately relaxed the model constraints to allow for (i) the presence of defects; and (ii) the formation of two small pores instead of one larger one. Our simulations demonstrated that the time-dependent conductance formalism supports the detection and characterization of defects, as well as the determination of pore number, but with implementation performance depending on the measurement context and results. In some cases, the ability to discriminate numerically between the correct and incorrect nanopore profiles was slight, but with accompanying differences in candidate nanopore dimensions that could yield to post-fabrication conductance profiling, or be used as convenient uncertainty bounds. Time-dependent nanopore conductance thus offers insight into nanopore structure and function, even in the presence of fabrication defects. PMID- 29131360 TI - Bacterial diversity and community structure during fermentation of Chinese sauerkraut with Lactobacillus casei 11MZ-5-1 by Illumina Miseq sequencing. AB - : The bacterial diversity and community structure involved in Chinese sauerkraut is one of the most important factors shaping the final characteristics of traditional foods. In this research, Lactobacillus casei 11MZ-5-1 was applied in Chinese sauerkraut fermentation as a starter culture. Illumina Miseq sequencing analysis was used to reveal the bacterial diversity and community structure during Chinese sauerkraut fermentation. A total of 177 283 high-quality reads of 16S rRNA V4 regions were obtained. The inoculation of L. casei 11MZ-5-1 decreased considerably the bacterial richness and bacterial diversity. This inoculum led to the replacement of Lactococcus by Lactobacillus. The levels of Pseudomonas and Enterobacter bacteria decreased. These findings reveal the evolution of important bacterial groups that are involved in fermentation and will facilitate improvements in the Chinese sauerkraut fermentation process. SIGNIFICANCE AND IMPACT OF THE STUDY: This research thoroughly revealed the effects of Lactobacillus casei 11MZ-5-1 starter cultures on bacterial communities during Chinese sauerkraut fermentation. Illumina Miseq sequencing was effective technique to monitor the bacterial diversity and community structure. The inoculation of L. casei 11MZ-5-1 led to the decline of bacterial richness and diversity together with a consistent predominance of Lactobacillus during spontaneous fermentation. The result collectively suggested L. casei 11MZ-5-1 is a promising starter in Chinese sauerkraut manufacturing. PMID- 29131361 TI - Modeling the frequency-dependent detective quantum efficiency of photon-counting x-ray detectors. AB - PURPOSE: To find a simple model for the frequency-dependent detective quantum efficiency (DQE) of photon-counting detectors in the low flux limit. METHODS: Formula for the spatial cross-talk, the noise power spectrum and the DQE of a photon-counting detector working at a given threshold are derived. Parameters are probabilities for types of events like single counts in the central pixel, double counts in the central pixel and a neighboring pixel or single count in a neighboring pixel only. These probabilities can be derived in a simple model by extensive use of Monte Carlo techniques: The Monte Carlo x-ray propagation program MOCASSIM is used to simulate the energy deposition from the x-rays in the detector material. A simple charge cloud model using Gaussian clouds of fixed width is used for the propagation of the electric charge generated by the primary interactions. Both stages are combined in a Monte Carlo simulation randomizing the location of impact which finally produces the required probabilities. The parameters of the charge cloud model are fitted to the spectral response to a polychromatic spectrum measured with our prototype detector. RESULTS: Based on the Monte Carlo model, the DQE of photon-counting detectors as a function of spatial frequency is calculated for various pixel sizes, photon energies, and thresholds. CONCLUSION: The frequency-dependent DQE of a photon-counting detector in the low flux limit can be described with an equation containing only a small set of probabilities as input. Estimates for the probabilities can be derived from a simple model of the detector physics. PMID- 29131362 TI - Sex discordance identification following non-invasive prenatal testing. AB - OBJECTIVE: The objectives of this study were to characterise genotype-phenotype discordance identified in the routine clinical setting and to explore the associated diagnostic and counselling challenges. METHOD: Cases were derived from a cohort of pregnant women who attended a multisite specialist prenatal screening and ultrasound service for non-invasive prenatal testing by cell-free DNA analysis and midtrimester fetal morphology assessment. RESULTS: Seven cases of genotype-phenotype discordance were identified from a cohort of 12 919 women between June 2013 and March 2017 (incidence 1/1845 pregnancies). A variety of disorders of sexual differentiation were subsequently diagnosed. CONCLUSION: Sex chromosomes are the basis of sexual differentiation during embryonic development. Variations of the traditional XX or XY karyotype may result in conditions where the genotype is discordant with the phenotype. Detection of these conditions in the past typically occurred during adolescence, due to delayed puberty, or during adulthood, due to infertility. With the increasing availability of non-invasive prenatal testing and high-resolution ultrasound, more cases of genotype-phenotype sex discordance are being identified in routine clinical practice during early pregnancy. These discordant results present significant diagnostic and counselling challenges, and their potential should be included in increasingly complex pre-NIPT counselling. PMID- 29131363 TI - Automatic renal lesion segmentation in ultrasound images based on saliency features, improved LBP, and an edge indicator under level set framework. AB - PURPOSE: Segmentation of lesions in ultrasound images is widely used for preliminary diagnosis. In this paper, we develop an automatic segmentation algorithm for multiple types of lesions in ultrasound images. The proposed method is able to detect and segment lesions automatically as well as generate accurate segmentation results for lesion regions. METHODS: In the detection step, two saliency detection frameworks which adopt global image information are designed to capture the differences between normal and abnormal organs as well as these between lesions and the normal tissues around them. In the segmentation step, three types of local information, i.e., image intensity, improved local binary patterns (LBP) features, and an edge indicator, are embedded into a modified level set framework to carry out the segmentation task. RESULTS: The cyst and carcinoma regions in the ultrasound images of the human kidneys can be automatically detected and segmented by using the proposed method. The efficiency and accuracy of the method are validated by quantitative evaluations and comparative measurements with three well-recognized segmentation methods. Specifically, the average precision and dice coefficient of the proposed method in segmenting renal cysts are 95.33% and 90.16%, respectively, while those in segmenting renal carcinomas are 94.22% and 91.13%, respectively. The average precision and dice coefficient of the proposed method are higher than those of three compared segmentation methods. CONCLUSIONS: The proposed method can efficiently detect and segment the renal lesions in ultrasound images. In addition, since the proposed method utilizes the differences between normal and abnormal organs as well as these between lesions and the normal tissues around them, it can be possibly extended to deal with lesions in other organs of ultrasound images as well as lesions in medical images of other modalities. PMID- 29131364 TI - Quality of life is significantly impaired in nonallergic rhinitis patients. AB - BACKGROUND: In contrast to the well-known significant impairment of quality of life (QoL) in allergic rhinitis (AR), the degree of impairment in QoL in nonallergic rhinitis (NAR) remained unknown for a long time, due to a lack of a validated questionnaire to assess QoL in the NAR patient group. In this study, a validation of the mini-RQLQ questionnaire in NAR patients was performed, followed by an assessment of QoL in NAR patients compared to AR and healthy controls. Secondly, use of medication and treatment satisfaction in AR and NAR was assessed. METHODS: The study was an observational cohort study in 287 AR and 160 NAR patients. Patients with symptoms of rhinitis were recruited from a tertiary care outpatient clinic of the Otorhinolaryngology Department. Allergic rhinitis (AR) was defined as one or more positive results on skin prick testing and clinically relevant symptoms of rhinitis related to their sensitization. Nonallergic rhinitis (NAR) was defined as clinically relevant symptoms of rhinitis but without positive results on skin prick testing. The mini-RQLQ was successfully validated in this study for NAR patients. RESULTS: Quality of life (QoL) in NAR patients was equally-and for some aspects even more-impaired compared to AR. More than half of both AR and NAR patients were unsatisfied with treatment. CONCLUSION: These results demonstrate a significant impairment in both AR and NAR patients in their QoL combined with a low treatment satisfaction, emphasizing the need for adequate treatment, especially in the NAR patient group. PMID- 29131365 TI - Gut microbiota and body composition in anorexia nervosa inpatients in comparison to athletes, overweight, obese, and normal weight controls. AB - OBJECTIVES: Anorexia nervosa (AN) is a heterogeneous eating disorder associated with alterations of body structure and the gut microbiome. We aimed to investigate the gut microbiota composition of a large female cohort including different BMI groups and activity levels along with body composition parameters. METHOD: 106 female participants were included in this cross-sectional study: AN patients (n = 18), athletes (n = 20), normal weight (n = 26), overweight (n = 22), and obese women (n = 20). DNA was extracted from stool samples and subjected to 16S rRNA gene analysis. The software Quantitative Insights Into Microbial Ecology (QIIME) was used to analyze data. Additionally, we performed anthropometric assessments, ultrasound measurements of subcutaneous adipose tissue thickness, bioimpedance analysis, administered depression inventories, and ascertained laboratory parameters and dietary intakes. RESULTS: Alpha diversity was particularly lower in AN patients and obese participants compared to other groups, while athletes showed highest alpha diversity. Several categories significantly associated with community structure were identified: body fat parameters, serum lipids, CRP, depression scales and smoking. Comparative analysis revealed Coriobacteriaceae as the only enriched phylotype in AN compared to other entities (LDA score >3.5). DISCUSSION: This study provides further evidence of intestinal dysbiosis in AN and sheds light on characteristics of the gut microbiome in different BMI and physical activity groups. These insights point to new modulation possibilities of the gut microbiota which could improve the standard therapy of AN. PMID- 29131366 TI - Successful and safe use of Q-switched lasers in the treatment of nevus of Ota in children with phototypes IV-VI. AB - OBJECTIVE: Nevus of Ota represents congenital dermal melanocytosis in a trigeminal distribution, most commonly occurring in Asian individuals and other individuals with skin of color. Evidence suggests early treatment is beneficial. Multiple reports have shown efficacy and safety of Q-switched laser treatment in adults. There is little data on children and in non-Asian skin types. This series was done to demonstrate safe and effective use of Q-switched laser therapy in children of multiple skin types. STUDY DESIGN: Retrospective case series. METHODS: This was a chart review of patients under 18 years old who presented to our practice from 2002 to 2015 with a clinical diagnosis of nevus of Ota who were treated with Q-switched lasers (694 and 1,064 nm). Patients were treated without the use of general anesthesia or sedation, and corneal shields were used in appropriate cases. Percentage of improvement as well as side effects were rated by five physicians independently. Improvement, when present, was rated in quartiles (1-25%, 26-50%, 51-75%, and 76-100% improvement). RESULTS: Twenty-four children were included. The average age at the start of treatment was 3.9 years old (range of 3 months to 12.4 years), and patients had Fitzpatrick skin types IV through VI. The mean number of treatments was 9.3. Assessment revealed excellent response (76-100% improvement) in 70% of patients and good to excellent response (51-100% improvement) in 86%. Two patients (8%) had post-inflammatory hyperpigmentation, one of whom also had focal hypopigmentation. CONCLUSION: Treatment of nevus of Ota with Q-switched lasers in children with skin of color, without general anesthesia or sedation, is safe and effective. Early intervention should be encouraged for better efficacy and to prevent psychosocial distress in later childhood and adulthood. Lasers Surg. Med. 50:56-60, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29131368 TI - Models of Chinese Reading: Review and Analysis. AB - Our understanding of the cognitive processes involved in reading has been advanced by computational models that simulate those processes (e.g., see Reichle, 2015). Unfortunately, most of these models have been developed to explain the reading of English and other alphabetic languages, with relatively fewer efforts to examine whether or not the assumptions of these models also explain what has been learned from other languages and, in particular, non alphabetic writing systems like Chinese (e.g., see Li, Zang, Liversedge, & Pollatsek, 2015). In this article, we will review those computational models that have been developed to explain the reading of Chinese, with the goal of comparing their theoretical assumptions to those of models that explain the reading of English. Our analysis indicates that there are both points of convergence and divergence between the theoretical assumptions of Chinese versus English models, suggesting that the cognitive systems supporting reading may be differentially influenced by features of the languages and/or writing systems, or that certain theoretical assumptions developed to explain the reading of one language might be adapted to explain the reading of others. PMID- 29131367 TI - Influence of the neural microenvironment on prostate cancer. AB - BACKGROUND: Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. METHOD: We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. RESULT: Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non neoplastic epithelial cells. CONCLUSION: Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. PMID- 29131370 TI - Mental ill-health among adult patients at healthcare centres in Sweden: district nurses experiences. AB - BACKGROUND: Mental ill-health among the general population is increasing in Sweden. Primary Health Care (PHC) and Healthcare Centres (HCC), where district nurses (DNs) work, bear the basic responsibility for treatment of mental ill health, while severe mental ill-health fall under the responsibility of psychiatric specialist care. The increased prevalence of mental ill-health in the community means that DNs increasingly encounter people with mental health problems - not least as a comorbidity. How well DNs are equipped to deal with mental ill-health is currently unclear. AIM: The purpose of this study was to explore district nurses' experience of encountering and dealing with mental ill health among adult patients at healthcare centres. DESIGN: A qualitative explorative approach was used to capture the experiences of the phenomena under study. METHODS: Individual interviews were conducted with 10 DNs working at six HCCs. The interviews were transcribed and analysed by qualitative content analysis. RESULTS: The result emerged as several subcategories captured by three categories: (i) having competence - a prerequisite for feeling confident; (ii) nursing mental ill-health requires time and commitment; and (iii) working in an organisation without preparedness, encompassed by the synthesising theme; nursing mental ill-health requires specific competence and organisational support. CONCLUSION: Working as a DN requires formal and informal competence when encountering patients with complex health needs. The findings revealed that the DNs could feel insecure regarding how to deal with patients with mental ill health due to lack of knowledge. Assessment of patients with mental ill-health is time- and energy-consuming and calls for improved teamwork at HCCs as well as effective collaboration with psychiatric specialist care and other care givers. The DNs responsibility to fulfil their work considering the increasing number of mental ill-health among people that seeks help at HCCs needs to be acknowledged and met by the PHC organisation. PMID- 29131369 TI - Photobiomodulation for traumatic brain injury and stroke. AB - There is a notable lack of therapeutic alternatives for what is fast becoming a global epidemic of traumatic brain injury (TBI). Photobiomodulation (PBM) employs red or near-infrared (NIR) light (600-1100nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow, and tissue oxygenation. PBM can also act to reduce swelling, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate microglial activation state. All these mechanisms of action strongly suggest that PBM delivered to the head should be beneficial in cases of both acute and chronic TBI. Most reports have used NIR light either from lasers or from light-emitting diodes (LEDs). Many studies in small animal models of acute TBI have found positive effects on neurological function, learning and memory, and reduced inflammation and cell death in the brain. There is evidence that PBM can help the brain repair itself by stimulating neurogenesis, upregulating BDNF synthesis, and encouraging synaptogenesis. In healthy human volunteers (including students and healthy elderly women), PBM has been shown to increase regional cerebral blood flow, tissue oxygenation, and improve memory, mood, and cognitive function. Clinical studies have been conducted in patients suffering from the chronic effects of TBI. There have been reports showing improvement in executive function, working memory, and sleep. Functional magnetic resonance imaging has shown modulation of activation in intrinsic brain networks likely to be damaged in TBI (default mode network and salience network). PMID- 29131372 TI - Reading Emotion From Mouse Cursor Motions: Affective Computing Approach. AB - Affective computing research has advanced emotion recognition systems using facial expressions, voices, gaits, and physiological signals, yet these methods are often impractical. This study integrates mouse cursor motion analysis into affective computing and investigates the idea that movements of the computer cursor can provide information about emotion of the computer user. We extracted 16-26 trajectory features during a choice-reaching task and examined the link between emotion and cursor motions. Participants were induced for positive or negative emotions by music, film clips, or emotional pictures, and they indicated their emotions with questionnaires. Our 10-fold cross-validation analysis shows that statistical models formed from "known" participants (training data) could predict nearly 10%-20% of the variance of positive affect and attentiveness ratings of "unknown" participants, suggesting that cursor movement patterns such as the area under curve and direction change help infer emotions of computer users. PMID- 29131371 TI - Utility of Gram staining for diagnosis of Malassezia folliculitis. AB - Malassezia folliculitis (MalF) mimics acne vulgaris and bacterial folliculitis in clinical presentations. The role of Gram staining in rapid diagnosis of MalF has not been well studied. In our study, 32 patients were included to investigate the utility of Gram staining for MalF diagnosis. The final diagnoses of MalF were determined according to clinical presentation, pathological result and treatment response to antifungal agents. Our results show that the sensitivity and specificity of Gram staining are 84.6% and 100%, respectively. In conclusion, Gram staining is a rapid, non-invasive, sensitive and specific method for MalF diagnosis. PMID- 29131373 TI - Differentially expressed miRNA-210 during follicular-luteal transition regulates pre-ovulatory granulosa cell function targeting HRas and EFNA3. AB - Ovarian folliculogenesis, ovulation, and luteinization are an important prerequisite for fertility performance in mammals. Spatial and temporal key factors and proteins for their regulation are well known. Recent advancement in the field of molecular biology led to the discovery of another class of gene regulators, microRNA (miRNA). Previous studies on profiling of miRNA in buffalo ovaries revealed that miRNA-210 (miR-210) is differently expressed in follicular luteal transition. Therefore, the present study was planned to ascertain the role of miR-210 in buffalo granulosa cells. Cultured granulosa cells were transfected with miR-210 mimic. Effect of overexpression of miR-210 was analyzed on granulosa cell marker genes (CYP19A1 and PCNA) which were significantly downregulated (P < 0.05). Further, target genes of miR-210 were screened using Target Scan software v7.1 and a list of 37 genes with cumulative weight context score (CWCS) > 0.5 was sorted followed by their functional annotation and network analyses using PANTHER and STRING software. Bioinformatics analyses identified HRas gene as a potential hub gene of miR-210 targeted genes. HRas has been shown to be involved in diverse biological pathways regulating ovarian functions. An expression analysis of HRas was further validated both in vitro and in vivo. EFNA3 (EFHRIN-A3), another identified target of miR-210 known to be involved in angiogenesis, was also downregulated in miR-210 transfected granulosa cells. In conclusion, the present study demonstrated that miR-210 can regulate granulosa cell function at preovulatory stage through HRas and EFNA3. Further studies are needed to find the mechanism how miR-210 regulates the granulosa cells function through these targets. PMID- 29131374 TI - Social capital's role in recovery: evidence from communities affected by the 2010 Pakistan floods. AB - Pakistan suffered large-scale flooding in summer 2010 that caused damage amounting to approximately USD 43 billion, claimed the lives of at least 1,700 people, and negatively affected some 20 million others. Observers have debated the degree to which social capital plays a role in recovery after a catastrophe of this magnitude. Using new survey data on 450 residents impacted by the disaster, this study found that, controlling for various confounding factors, the social capital levels of victims serve as robust correlates of life recovery. Other important variables connected with recovery include education and income, family size, occupation, material damage suffered, stability of home, and trauma experience. The findings point to a number of relevant policy recommendations, most notably that during and following major shocks, disaster managers should work to keep the social networks of victims intact so that they can benefit from interaction with family, friends, and neighbours. PMID- 29131375 TI - Keratosis follicularis squamosa (Dohi) successfully treated with benzoyl peroxide 2.5% gel. PMID- 29131376 TI - Method development for quantification of quizartinib in rat plasma by liquid chromatography/tandem mass spectrometry for pharmacokinetic application. AB - Quizartinib is a highly potent inhibitor of the fms-like tyrosine kinase receptor, which is one of the most commonly mutated genes in acute myeloid leukemia. Quizartinib has shown a significant antileukemic clinical influence among relapsed/refractory acute myeloid leukemia patients. This study aimed at developing and validating an analytical method for the measurement of quizartinib in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was validated according to US Food and Drug Administration guidelines, and the results obtained in this work met the set criteria. Liquid-liquid extraction was used and chromatographic separation was achieved on a BEHTM C18 column. Detection of quizartinib was achieved in multiple reaction monitoring mode using positive-ion mode electrospray ionization. The MS/MS ion transitions at mass-to-charge ratios (m/z) of 561.129/114.09 and 441.16/84.03 were monitored for quizartinib and ibrutinib, respectively. The linear detection range was 2 1000 ng/mL (r > 0.998), with intra- and inter-day assay precisions <=13.07 and 13.17%, respectively. This rapid, simple and sensitive method was validated and successfully applied to the pharmacokinetic study of quizartinib in rat samples. PMID- 29131377 TI - New insights of subfertility among transplanted women: Immunosuppressive drug FK506 leads to calcium leak and oocyte activation before fertilization. AB - FKBP12, known as FK506 binding protein, binds to immunosuppressive drug FK506, which must be taken by patients who received organ transplant. The side effect of FK506 is that women have difficulties in bearing a baby, so it is important to find the reason of their subfertility. This research explored the expression of FKBP12 in pre-implantation embryos and investigated its potential effect on reproduction. The results demonstrate that FKBP12 had good co-localization with endoplasmic reticulum and inositol-1, 4, 5- trisphosphate receptor in pre implantation stages. Inhibiting FKBP12 by FK506 significantly increased the rate of 1-cell and fragmented embryos, greatly reduced the rate of 2-cell embryos during in vitro fertilization. When the mice received FK506 by gavage for 21 days, the calcium intensity of oocytes was decreased, these mice were subfertile and gave birth to significantly less pups during 6-month breeding period. QPCR demonstrated that Fbxo43 and P27kip, which are related to the release of MII oocyte arrest, and calcium channel partner protein Orai1 were downregulated, while Cdc2 and Ca2+ sensor at ER, stromal interaction molecule 1 (Stim1) were upregulated for a short time after adding FK506. Further exploration discovered that FK506 treatment increased Ca2+ concentration in the cytoplasm and caused pronucleus formation, however, the rate of parthenogenetic activation was lower compared to SrCl2 group. These findings identify the previously unknown role of FKBP12 in female reproduction which contributes to the release of calcium via IP3 R channel and might open up new strategies for women who want to bear a baby after transplantation. PMID- 29131378 TI - Physiological benefits to parents from undertaking skin-to-skin contact with their neonate, in a neonatal intensive special care unit. AB - There has been increased focus on the use of family-centred care interventions, such as skin-to-skin contact (SSC) in Neonatal Intensive Special Care (NISC) Units over the past two decades. SSC between a parent and their neonate has previously shown to promote positive mental and emotional health in parents and assist in bonding and attachment between parent and neonate. The purpose of this study was to investigate the effect that SSC between parent and their neonate has on the parent's heart rate (HR) and blood pressure (BP). There has been a lack of prior research investigating the physiological responses from SSC on parents, hence the need to conduct this study. The study was conducted as an observational cohort study at The Royal Women's Hospital NISC Unit in Melbourne, Australia. One SSC between parent and neonate was recorded, and three repeated measures analysis of variance (anova) were conducted to investigate the relationship between SSC and the parent's HR, systolic BP and diastolic BP. The study found statistically significant differences between the parent's initial HR and BP, to measurements taken during the SSC (p < 0.05). This may suggest that parents' find SSC with their neonate to be a stress-reducing intervention, whilst they are in a NISC Unit. This may in turn promote associated benefits, such as a decrease in parental depression and anxiety, whilst they are in the NISC Unit, physical health benefits, as well as increased feelings of bonding between parent and their neonate. Based on the findings, it is suggested that SSC should be promoted in NISC Units as a family-centred care intervention that lowers parent's HR and BP and may provide associated health benefits. PMID- 29131379 TI - Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors. AB - Novel series of phthalazine derivatives 6-11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT 116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR 2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 +/- 0.30, 13.22 +/- 0.22, 18 +/- 0.20, and 35 +/- 0.45 MUM, respectively, and MCF-7 breast cancer cells with IC50 of 8.8 +/- 0.45, 17.9 +/- 0.50, 25.2 +/- 0.55, and 44.3 +/ 0.49 MUM, respectively, in comparison to sorafenib as reference drug with IC50 of 5.47 +/- 0.3 and 7.26 +/- 0.3 MUM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC50 of 0.11 +/- 0.01, 0.31 +/- 0.03, 0.72 +/- 0.08, and 0.91 +/- 0.08 MUM, respectively, in comparison to sorafenib as reference ligand with IC50 of 0.1 +/- 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way. PMID- 29131380 TI - Upregulation of PRMT6 by LPS suppresses Klotho expression through interaction with NF-kappaB in glomerular mesangial cells. AB - Lipopolysaccharide (LPS) released from gram-negative bacteria stimulates immune responses in infected cells. Epigenetic modifications such as DNA methylation and protein methylation modulate LPS-induced innate immune gene expressions. Expression of the Klotho protein decreased with LPS treatment in rats. In a cellular model, information regarding the effect of LPS on Klotho expression was meager. In the present study, we demonstrated that LPS triggered global DNA and protein methylation in glomerular mesangial MES-13 cells. LPS upregulated protein expressions of enzymes central to cellular methylation reactions, especially protein arginine methyltransferase 6 (PRMT6) in MES-13 cells. Expression of the Klotho protein was diminished by LPS and was restored by 5-Aza-2'-deoxycytidine (5-Aza-2'-dc), AMI-1, and ammonium pyrrolidinedithiocarbamate (PDTC), but not adenosine aldehyde (AdOx). NF-kappaB was identified as a substrate for arginine methylation and interacted with PRMT6 in MES-13 cells. Inhibition of PRMT activity by AMI-1 blocked LPS-induced NF-kappaB nuclear translocation in MES-13 cells. Our data indicate that NF-kappaB negatively regulated Klotho expression with an interaction with PRMT6, which was upregulated by LPS in MES-13 cells. PMID- 29131382 TI - A simple and effective crepe bandage splinting method to decrease tension after large superficial circumflex iliac artery perforator (SCIP) flap donor site closure. PMID- 29131381 TI - Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization. AB - Macrophages have been shown to demonstrate a high level of plasticity, with the ability to undergo dynamic transition between M1 and M2 polarized phenotypes. We investigate long non-coding RNA (lncRNA) cox-2 in macrophage polarization and the regulatory mechanism functions in hepatocellular carcinoma (HCC). Lipopolysaccharide (LPS) was used to induce RAW264.7 macrophages into M1 type, and IL-4 was to induce RAW264.7 macrophages into M2 type. We selected mouse hepatic cell line Hepal-6 and hepatoma cell line HepG2 for co-incubation with M1 or M2 macrophages. Quantitative real-time PCR was used to detect the expressions of lncRNA cox-2 and mRNAs. ELISA was conducted for testing IL-12 and IL-10 expressions; Western blotting for epithelial mesenchymal transition related factors (E-cadherin and Vimentin). An MTT, colony formation assay, flow cytometry, transwell assay, and stretch test were conducted to test cell abilities. The M1 macrophages had higher lncRNA cox-2 expression than that in the non-polarized macrophages and M2 macrophages. The lncRNA cox-2 siRNA decreased the expression levels of IL-12, iNOS, and TNF-alpha in M1 macrophages, increased the expression levels of IL-10, Arg-1, and Fizz-1 in M2 macrophages (all P < 0.05). The lncRNA cox-2 siRNA reduces the ability of M1 macrophages to inhibit HCC cell proliferation, invasion, migration, EMT, angiogenesis and facilitate apoptosis while strengthening the ability of M2 macrophages to promote proliferation HCC cell growth and inhibit apoptosis. These findings indicate that lncRNA cox-2 inhibits HCC immune evasion and tumor growth by inhibiting the polarization of M2 macrophages. PMID- 29131383 TI - Rational Optimization of Tumor Suppressor-Derived Peptide Inhibitor Selectivity between Oncogene Tyrosine Kinases ErbB1 and ErbB2. AB - The tumor-suppressor protein Mig-6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2. Despite their highly homologous nature, these two kinases are separately involved in the development of different types of human cancer. Here, we utilized a rational strategy to iteratively optimize the interaction specificity of the two kinases with a Mig-6 derived peptide by exploiting structural diversity space. Instead of traditionally improving the peptide binding potency, the optimization attempts to maximize the affinity difference between peptides binding to ErbB1 and ErbB2. The computational design was also substantiated by using fluorescence-based assays. Consequently, we successfully designed three peptides, HSLTPTQSF, THLMNLLRI, and NSGCPMHK, with high or moderate selectivity for ErbB1 over ErbB2 (3.1-, 6.3-, and 3.0-fold, respectively) and two peptides, PCMTDFLFT and WVIFPSQTN, with moderate or modest selectivity for ErbB2 over ErbB1 (3.5- and 1.6-fold, respectively). The method is expected to be used for the rational molecular design of selective peptide entities for other protein systems. PMID- 29131385 TI - Rural community birth: Maternal and neonatal outcomes for planned community births among rural women in the United States, 2004-2009. AB - BACKGROUND: Approximately 22% of women in the United States live in rural areas with limited access to obstetric care. Despite declines in hospital-based obstetric services in many rural communities, midwifery care at home and in free standing birth centers is available in many rural communities. This study examines maternal and neonatal outcomes among planned home and birth center births attended by midwives, comparing outcomes for rural and nonrural women. METHODS: Using the Midwives Alliance of North America Statistics Project 2.0 dataset of 18 723 low-risk, planned home, and birth center births, rural women (n = 3737) were compared to nonrural women. Maternal outcomes included mode of delivery (cesarean and instrumental delivery), blood transfusions, severe events, perineal lacerations, or transfer to hospital and a composite (any of the above). The primary neonatal outcome was a composite of early neonatal intensive care unit or hospital admissions (longer than 1 day), and intrapartum or neonatal deaths. Analysis involved multivariable logistic regression, controlling for sociodemographics, antepartum, and intrapartum risk factors. RESULTS: Rural women had different risk profiles relative to nonrural women and reduced risk of adverse maternal and neonatal outcomes in bivariable analyses. However, after adjusting for risk factors and confounders, there were no significant differences for a composite of maternal (adjusted odds ratio [aOR] 1.05 [95% confidence interval {CI} 0.93-1.19]) or neonatal (aOR 1.13 [95% CI 0.87-1.46]) outcomes between rural and nonrural pregnancies. CONCLUSION: Among this sample of low-risk women who planned midwife-led community births, no increased risk was detected by rural vs nonrural status. PMID- 29131384 TI - Extent and consequences of inadequate disease control among adults with a history of moderate to severe atopic dermatitis. AB - Since control of atopic dermatitis (AD) remains challenging but has not been adequately characterized, the objective of this study was to characterize disease control among patients with a history of moderate to severe AD. Data were from the 2014 Adelphi US AD Disease Specific Programme, a cross-sectional survey of physicians (n = 202) and their patients with history of moderate to severe AD (n = 1064, 54% female, 75% white, mean age 40 years). Inadequately controlled AD as rated by the physician was defined as currently flaring; deteriorating/changeable AD; or physician dissatisfaction with current control. The overall inadequate control rate was 58.7% (n = 625), which increased with current AD severity and was observed in 53.4% and 83.4% of patients receiving immunosuppressants and systemic corticosteroids, respectively. Relative to controls, inadequately controlled patients had poorer disease-specific quality of life, higher level of work impairment, greater itch and sleep interference with daily living (all P < 0.05). Multivariate analysis showed factors significantly associated with inadequate control (all P < 0.05), including Hispanic race, symptoms on the head/neck or lower limbs, itch and sleep interference with daily living. A limitation of the study was reliance on accuracy of reporting, potential selection bias and cross-sectional study design. In summary, there was a high rate and substantial impact of physician-rated inadequately controlled disease among patients with a history of moderate to severe AD, suggesting the need for more effective therapies. PMID- 29131386 TI - Education, school type and screen time were associated with overweight and obesity in 2930 adolescents. AB - AIM: This cross-sectional study analysed the influence of socio-economic factors on screen time, overweight and obesity. METHODS: We asked adolescents aged 10, 14 and 17 from 10 school types in urban and rural regions in Upper Austria to complete questionnaires from December 2012 to February 2013. Their parents were also asked to complete questionnaires. RESULTS: The questionnaires were completed by 2930 adolescents and 2209 parents. Total weekend screen time was significantly associated with a higher body mass index (BMI) in 10-year-old boys (p < 0.005) and 10-year-old girls (p = 0.002), and there were significant associations between higher BMI and television time and longer weekend video game use in subjects aged 10 and 14. Higher education levels were associated with shorter daily video game use and longer computer use. Males (p < 0.0001) and adolescents from immigrant families (p < 0.0001) reported longer screen times at all ages. Lower parental education and higher parental BMI correlated significantly with longer screen time and BMI in the youngest age group. CONCLUSION: The greatest weight problems were in younger adolescents, despite shorter screen times, and boys and adolescents from immigrant families reported the longest screen times. Prevention strategies need to start early. PMID- 29131387 TI - Laparoscopic mesh repair of a labial hernia. AB - AIMS: To present a narrated video designed to demonstrate the steps involved in a laparoscopic mesh repair of a labial hernia. METHODS: This was in a 76-year-old woman who presented with a small bowel hernia in to her left labium majus. In 2014 she had a robotically assisted radical cystectomy for bladder cancer with anterior exenteration. She developed the hernia in February 2015 and initially a vaginal approach was attempted to repair the hernia (with layered non-absorbable sutures to close the fascia over the defect) at her local hospital, although this was unsuccessful. A laparoscopic repair with mesh on the 10 May 2016 was undertaken at our unit. RESULTS: This was a complex case requiring a multi disciplinary approach and individualised care. The need for a mesh was obvious: however, the use of both synthetic and biological meshes to achieve an optimum result was unique and highly successful. CONCLUSION: In this instance a minimally invasive laparoscopic approach where initial adhesiolysis was performed and then a synthetic mesh sandwiched in between two biological porcine meshes provided a unique management solution. The patient was seen 8 weeks post operatively and at 14 months after the procedure. She had complete resolution of her symptoms with no residual hernia. PMID- 29131388 TI - Saccharomyces interspecies hybrids as model organisms for studying yeast adaptation to stressful environments. AB - The strong development of molecular biology techniques and next-generation sequencing technologies in the last two decades has significantly improved our understanding of the evolutionary history of Saccharomyces yeasts. It has been shown that many strains isolated from man-made environments are not pure genetic lines, but contain genetic materials from different species that substantially increase their genome complexity. A number of strains have been described as interspecies hybrids, implying different yeast species that under specific circumstances exchange and recombine their genomes. Such fusing usually results in a wide variety of alterations at the genetic and chromosomal levels. The observed changes have suggested a high genome plasticity and a significant role of interspecies hybridization in the adaptation of yeasts to environmental stresses and industrial processes. There is a high probability that harsh wine and beer fermentation environments, from which the majority of interspecies hybrids have been isolated so far, influence their selection and stabilization as well as their genomic and phenotypic heterogeneity. The lessons we have learned about geno- and phenotype plasticity and the diversity of natural and commercial yeast hybrids have already had a strong impact on the development of artificial hybrids that can be successfully used in the fermentation-based food and beverage industry. The creation of artificial hybrids through the crossing of strains with desired attributes is a possibility to obtain a vast variety of new, but not genetically modified yeasts with a range of improved and beneficial traits. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29131389 TI - A new porcine vascularized tibial bone allotransplantation model. Anatomy and surgical technique. AB - INTRODUCTION: Vascularized bone allotransplantation may provide new options for reconstruction of segmental defects if problems of long-term immune modulation can be solved. The current literature lacks an orthotopic large animal model, limited to bone and without the confounding effects of other tissue types, permitting a multifaceted evaluation before new methods are used clinically. The purpose of this study was to develop a large animal model for vascularized bone allotransplantation. MATERIALS AND METHODS: Eight porcine hind limbs were dissected. Length, diameter, and location of all hindlimb vessels were measured and a single nutrient vessel supplying the tibial diaphysis identified enabling its use as a vascularized bone allotransplant. Four Yucatan minipigs were divided into two pairs with a major swine leukocyte antigen mismatch. A 3.5 cm tibial segment including its nutrient pedicle was raised simultaneously from each pig and transplanted into the matched defect of the other animal. Microarterial anastomosis of the pedicle and 3-drug immunosuppression maintained VCA viability. Bone healing and limb function were followed for 16 weeks. RESULTS: A consistent tibia diaphyseal nutrient artery arose from the caudal tibial artery to enter bone a mean 2.8 mm distal to the tibial tubercle with a pedicle length of 6.6 +/- 3.3 mm and diameter of 1.6 +/- 0.2 mm. Using this pedicle, we reconstructed a 3.5 cm tibial defect with a vascularized bone allotransplant in four animals. Immediate weightbearing as well as progressive bone healing was demonstrated. CONCLUSION: We have developed a vascularized tibial bone allotranplantation large animal model suitable for future bone-only allotranplantation research in mini pigs. PMID- 29131391 TI - Complex genetics of Tourette's Syndrome: Piecing the puzzle. PMID- 29131390 TI - Immune Function in Critically Ill Dogs. AB - BACKGROUND: People with critical illness (CI) commonly develop various forms of immune dysfunction, however, there is limited information concerning immune dysfunction in dogs with CI. HYPOTHESIS: The immune response in CI dogs differs from that of healthy dogs. ANIMALS: Immunologic variables were compared between 14 dogs with CI, defined as APPLEfast score of >20 points, admitted to the University of Missouri Veterinary Health Center Small Animal Clinic Intensive Care Unit and healthy controls (n = 15). METHODS: Cohort study evaluating constitutive and lipopolysaccharide (LPS)-stimulated TNF-alpha, IL-6, and IL-10 production, phagocytosis of opsonized E. coli and respiratory burst capacity after opsonized E. coli or phorbol 12-myristate 13-acetate (PMA) stimulation, peripheral blood lymphocyte phenotype, and monocyte expressions of HLA-DR and TLR 4. RESULTS: Lipopolysaccharide-stimulated leukocyte TNF-alpha (median, Q1, Q3; CI, 49, 49, 120; control, 655, 446, 1174 pg/mL; P = < 0.001), IL-6 (median, Q1, Q3; CI, 49, 49, 64; control, 100, 49, 166 pg/mL; P = 0.029), and IL-10 (CI, 49, 49, 56; control, 96, 49, 203 pg/mL; P = 0.014) production and both E. coli (median, Q1, Q3; CI, 60.5, 43, 88.5; control, 86.6, 81, 89.2%; P = 0.047) and PMA (CI, 40, 11.7, 70; control, 93, 83, 97.6%; P = < 0.001)-stimulated respiratory burst capacity significantly decreased in CI dogs. Percentage of monocytes expressing TLR-4 greater in the CI dogs (median, Q1, Q3; CI, 46.9, 24.3, 64.2; control, 16.4, 9.4, 26.2%; P = 0.005). CONCLUSION: These findings suggest dogs with CI develop immune system alterations that result in reduced respiratory burst function and cytokine production despite upregulation of TLR-4. PMID- 29131392 TI - Virus detection in critically ill children with acute respiratory disease: a new profile in view of new technology. AB - AIM: To describe the epidemiology of critically ill children admitted to a paediatric intensive care unit (PICU) with acute respiratory disease. The association with intubation was analysed for the three most prevalent viruses and in those with and without viral co-infection. METHODS: Patients admitted to the PICU (2004-2014) with acute respiratory disease were included. Analyses were performed utilising each respiratory viral infection or multiple viral infections as an exposure. RESULTS: There were 1766 admissions with acute respiratory disease of which 1372 had respiratory virus testing and 748 had one or more viruses detected. The risk of intubation before or during the PICU stay was higher if parainfluenza virus was detected compared to respiratory syncytial virus (RSV) (OR: 2.20; 95% CI: 1.06-4.56). Sixty-three admissions had two or more viruses detected, and the combination of RSV and Rhinovirus/enterovirus was the most common. No significant difference was observed in the risk of intubation between patients with multiple and single viral infections. CONCLUSION: Higher risk of intubation was found in patients with parainfluenza as compared to RSV. The risk of intubation comparing parainfluenza virus to other viruses and for patients with multiple versus single virus needs to be further studied. PMID- 29131394 TI - Shaken or Stirred? Evaluating the combination of budesonide-surfactant for survival free of bronchopulmonary dysplasia. PMID- 29131393 TI - Flap monitoring with continuous oxygen partial tension measurement in breast reconstructive surgery: A preliminary report. AB - BACKGROUND: The best method for the postoperative monitoring of flaps in reconstructive surgery is still a matter of debate. The aim of this study is to evaluate the usefulness of an oxygen partial tension monitoring system for the postoperative follow-up of a series of breast flaps, in addition to the traditional periodical clinical evaluations. PATIENTS AND METHODS: Twenty-one consecutive female patients (mean age: 61 years) who underwent free- or pedicled flap reconstruction of the breast were included in the study. Fifteen patients had a deep inferior epigastric perforator flap breast reconstruction, while the remaining six patients underwent a transverse rectus abdominus myocutaneous flap reconstruction. The Licox(r) Recon (Integra LifeSciences Corp, Plainsboro, New Jersey) system was used for the monitoring of the flaps. The oxygen partial tension (PtO2 ) values were displayed on the system monitor and registered with appropriate software for statistical analysis. RESULTS: A decreasing trend in the mean PtO2 values was observed over the first five postoperative days. The mean values registered in the first postoperative day were higher than those observed in the subsequent four days. Three patients were lost due to misplacement of the probe. Among the remaining 18 flaps, 3 (17%) reported a remarkable decrease in PtO2 values, with the mean PtO2 registered in the second postoperative day being significantly lower than in the other flaps (7.3 +/- 0.7 vs. 17.0 +/- 0.9; P value <.05). These three flaps have been promptly re-explored, with a final flap failure rate of 5.5% (1 flap). CONCLUSIONS: The continuous oxygen tension evaluation represents a promising method for the postoperative monitoring of breast reconstructive surgery flaps when used in combination with the traditional periodic clinical evaluations. PMID- 29131395 TI - Do fidgety general movements predict cerebral palsy and cognitive outcome in clinical follow-up of very preterm infants? PMID- 29131396 TI - Ractopamine in particulate matter emitted from beef cattle feedyards and playa wetlands in the Central Plains. AB - Beef cattle in the United States are routinely administered ractopamine, a beta adrenergic receptor agonist, to enhance growth. The present study is the first to quantify ractopamine in feedyard-emitted particulate matter and playa wetlands near feedyards. Ractopamine was present in 92% of particulate matter samples, 16% of playa sediment samples, and 3% of playa water samples, at maximum concentrations of 4.7 MUg/g, 5.2 ng/g (dry wt), and 271 ng/L, respectively. These data suggest that aerial transmission and deposition of particulate matter is a transport mechanism for ractopamine between feedyards and aquatic systems in the region. Environ Toxicol Chem 2018;37:970-974. (c) 2017 SETAC. PMID- 29131397 TI - A Double-blind, Placebo-controlled, Multicenter, Prospective, Randomized Study of Beraprost Sodium Treatment for Cats with Chronic Kidney Disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a common progressive and irreversible disease in cats. The efficacy and safety of beraprost sodium (BPS) in cats with CKD have not been evaluated. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy and safety of BPS in the treatment of cats with CKD, as compared to placebo. ANIMALS: Seventy-four client-owned cats with naturally occurring CKD. METHODS: Double blind, placebo-controlled, multicenter, prospective, randomized trial. The cats received BPS (55 MUg/cat) or a placebo PO q12 h for 180 days. The primary endpoint was prospectively defined as a change in the serum creatinine (sCr), serum phosphorus-to-calcium ratio or urine specific gravity (USG). RESULTS: The sCr increased significantly (P = 0.0030) in the placebo group (mean +/- SD: 2.8 +/- 0.7 to 3.2 +/- 1.3 mg/dL) but not in the BPS group (2.4 +/- 0.7 to 2.5 +/- 0.7 mg/dL). The difference between the groups at day 180 was significant (0.8 mg/dL, 95% CI: 0.2 to 1.3 mg/dL, P = 0.0071). The serum phosphorus-to-calcium ratio was significantly (P = 0.0037) increased in the placebo group (0.46 +/- 0.10 to 0.52 +/- 0.21 mg/dL) but not in the BPS group (0.50 +/- 0.08 to 0.51 +/- 0.11 mg/dL). There was no significant change in the USG in either group. An adverse event judged as being treatment-related included vomiting that occurred in 1 case in the placebo group. No clinically relevant change was observed in the CBC and other blood chemistry tests. CONCLUSIONS AND CLINICAL IMPORTANCE: Beraprost sodium treatment was well tolerated and safe in cats with CKD. BPS inhibited the reduction in renal filtration function as measured by sCr increase. PMID- 29131398 TI - Response to Cognitive Processing Therapy in Veterans With and Without Obstructive Sleep Apnea. AB - Recent studies have called attention to the need for enhancing treatment outcome in trauma-focused psychotherapies, such as cognitive processing therapy (CPT), with veterans. Given the prevalence of posttraumatic-related sleep disturbances, and the role of sleep in emotional learning and processing, sleep quality may be a target for improving CPT outcome. Elevated rates of obstructive sleep apnea (OSA) have been reported in samples of veterans with posttraumatic stress disorder (PTSD); however, the impact of OSA on response to CPT is unclear. In this study, CPT outcome was examined in veterans with and without a diagnosis of OSA. Following chart review, 68 OSA-positive and 276 OSA-negative veterans were identified. Generalized estimating equations were used to compare between-group differences in weekly self-reported PTSD symptomatology. The OSA-positive veterans reported greater PTSD severity over the course of treatment and at posttreatment compared with veterans without OSA (B = -0.657). Additionally, OSA positive veterans with access to continuous positive airway pressure (CPAP) therapy reported less PTSD severity relative to OSA-positive veterans without access to CPAP (B = -0.421). Apnea appears to be a contributing factor to the reduced effectiveness of evidence-based psychotherapy for veterans with PTSD; however, preliminary evidence indicates that CPAP therapy may help mitigate the impact of OSA on treatment outcome. PMID- 29131399 TI - Cholangitis and Cholangiohepatitis in Dogs: A Descriptive Study of 54 Cases Based on Histopathologic Diagnosis (2004-2014). AB - BACKGROUND: Cholangitis in dogs appears to be more common than previously thought, but understanding of the disease remains incomplete. OBJECTIVE: To describe a population of dogs with cholangitis or cholangiohepatitis. ANIMALS: Fifty-four client-owned dogs with cholangitis or cholangiohepatitis. METHODS: Medical records of dogs with cholangitis or cholangiohepatitis confirmed by histopathology between January 2004 and December 2014 were identified using a computer-based search and retrospectively reviewed. RESULTS: Clinical signs included vomiting (72.2%), lethargy (70.4%), and inappetence (64.8%). Most dogs (49/50) had increased liver enzyme activities, hyperbilirubinemia (32/50), and hypercholesterolemia (24/43). Ultrasonographic abnormalities of the hepatobiliary system were seen in 84% of cases. On histopathology, 53 of 54 affected dogs had neutrophilic cholangitis (NC) or cholangiohepatitis, whereas 1 dog had lymphocytic cholangitis. Most cases (42/54) were chronic. Evidence of concurrent biliary disease (46.2%) and biliary tract obstruction (42.6%) was common. Seventeen of 36 biliary and 11 of 25 liver cultures were positive for bacterial growth; Escherichia coli and Enterococcus spp. were most common. Median patient survival was 671 days (95% confidence interval [CI]: 114-1,426). On Cox regression, dogs that did not have a cholecystectomy performed had a 2.1 greater hazard for death (P = 0.037; 95% CI: 1.0-4.3) compared to cholecystectomized dogs. Dogs >13 years old had a 5.0 greater hazard for death (P = 0.001; 95% CI: 1.9-13.2) compared to younger dogs. CONCLUSIONS AND CLINICAL SIGNIFICANCE: Chronic NC or cholangiohepatitis was most common. Cholecystitis and biliary tract obstruction often occurred in conjunction with cholangitis. Cholecystectomized dogs had decreased risk of death; thus, cholecystectomy may improve patient outcome. PMID- 29131402 TI - The neonatal transport index could be used as a reference tool for the Italian perinatal care regionalisation plan. PMID- 29131401 TI - Non-alcoholic fatty liver disease and the development of reflux esophagitis: A cohort study. AB - BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, is associated with gastroesophageal reflux disease in cross-sectional studies, but a prospective association has not been evaluated. The current study aimed to determine whether NAFLD increases the risk of incident reflux esophagitis in a large cohort study. METHODS: We conducted a cohort study of 34 063 men and women without reflux esophagitis or other upper gastrointestinal disease at baseline who underwent health checkup examinations between January 2003 and December 2013. Fatty liver was diagnosed by ultrasound based on standard criteria. Reflux esophagitis was defined by the presence of at least grade A mucosal break on esophagogastroduodenoscopy. RESULTS: The prevalence of NAFLD at baseline was 33.2%. During 153 520.2 person years of follow-up, the cumulative incidences of reflux esophagitis for participants without and with NAFLD were 9.6% and 13.8%, respectively (P < 0.001). The age-adjusted and sex-adjusted hazard ratio for the risk of reflux esophagitis development in participants with NAFLD compared with those without NAFLD was 1.15 (95% confidence interval 1.07-1.23; P < 0.001). However, this association disappeared after adjusting for body mass index and other metabolic factors (hazard ratio 1.01, 95% confidence interval 0.94-1.09; P = 0.79). Similarly, in multivariable-adjusted models, there was no significant association between NAFLD severity and the risk of developing reflux esophagitis. CONCLUSIONS: Non-alcoholic fatty liver disease is not independently associated with the risk of the development of reflux esophagitis, but rather, reflux esophagitis is primarily the consequence of increased body mass index commonly associated with NAFLD. PMID- 29131403 TI - Does a procalcitonin-guided approach to term and late-preterm neonates with suspected early-onset sepsis safely decrease unnecessary antibiotic exposure? PMID- 29131400 TI - Evaluation of 3 Serological Tests for Early Detection Of Leptospira-specific Antibodies in Experimentally Infected Dogs. AB - BACKGROUND: Leptospirosis in dogs is a disease of global importance. Early detection and appropriate therapeutic intervention are necessary to resolve infection and prevent zoonotic transmission. However, its diagnosis is hindered by nonspecific clinical signs and lack of rapid diagnostic tests of early infection. Recently, 2 rapid point-of-care tests (WITNESS Lepto [WITNESS Lepto, Zoetis LLC, Kalamazoo, MI, USA] and SNAP Lepto [SNAP Lepto, IDEXX Laboratories, Westbrook, ME, USA]) for detection of Leptospira-specific antibodies in canine sera were developed. HYPOTHESIS: Immunoglobulin M-based WITNESS Lepto containing multiple detection antigens can detect Leptospira-specific antibodies to common leptospiral serovars earlier in the course of infection as compared to microscopic agglutination test (MAT) and SNAP Lepto. ANIMALS: Four groups of 8 6- to 8-month-old male Beagle dogs were used. METHODS: Thirty-two healthy seronegative dogs were inoculated experimentally with serovars Canicola, Grippotyphosa, Icterohaemorrhagiae, and Pomona (8 dogs/serovar). Acute-phase sera were collected at regular intervals and monitored for Leptospira-specific antibodies by WITNESS Lepto, MAT, and SNAP Lepto. RESULTS: Seroconversion was detected in all dogs by day 10 by WITNESS Lepto and in 30 of 32 dogs by day 14 by MAT. The SNAP Lepto test detected seroconversion in 3 dogs during the 2 weeks postchallenge. CONCLUSIONS: Immunoglobulin M-based WITNESS Lepto detected immune responses specific to multiple leptospiral serovars early in the course of infection and identified seroconversion in all animals earlier than did the gold standard MAT. The SNAP Lepto test displayed considerably lower and inconsistent performance during the study period. At the point-of-care, WITNESS Lepto should be the test of choice for rapid and reliable screening of acutely ill dogs suspected to have leptospirosis. PMID- 29131404 TI - Efficacy of Radiation Therapy for the Treatment of Sialocele in Dogs. AB - BACKGROUND: Sialocele is a collection of saliva that has leaked from a damaged salivary gland or duct and is surrounded by granulation tissue. Surgery is the recognized first-line treatment. Recurrence rate after surgery is 5-14%. Salivary gland tissue is very sensitive to radiation therapy (RT). HYPOTHESIS/OBJECTIVES: Radiation therapy will be useful for the treatment of sialocele. The aims were to characterize response rate and clinical course of dogs with sialocele treated with RT and to determine a starting dose for clinical use. ANIMALS: Eleven dogs with sialocele. METHODS: Retrospective study of response and outcome after RT. RESULTS: All dogs had cervical sialocele. Seven dogs (63.6%) were treated with 3 weekly fractions of 4 Gray (Gy); (total dose, 12 Gy). Three dogs (27.3%) received 4 fractions of 4 Gy (16 Gy) and 1 dog received 5 fractions of 4 Gy (20 Gy) on a Monday-Wednesday-Friday schedule. Six dogs (54%) achieved a complete response (CR), and 5 dogs (45%) achieved a partial response (PR). Three dogs had progression of their sialocele 2, 3, and 9 months after RT; all three had received 12 Gy initially and 2 received 2 additional fractions of 4 Gy (cumulative total dose, 20 Gy) and subsequently achieved remission for >2 years. CONCLUSIONS AND CLINICAL IMPORTANCE: Radiation therapy is useful for the treatment of recurrent sialocele refractory to surgical management and a minimum total dose of 16 or 20 Gy in 4 Gy fractions appears effective. PMID- 29131405 TI - The Role of Interfaces in Polyethylene/Metal-Oxide Nanocomposites for Ultrahigh Voltage Insulating Materials. AB - Recent progress in the development of polyethylene/metal-oxide nanocomposites for extruded high-voltage direct-current (HVDC) cables with ultrahigh electric insulation properties is presented. This is a promising technology with the potential of raising the upper voltage limit in today's underground/submarine cables, based on pristine polyethylene, to levels where the loss of energy during electric power transmission becomes low enough to ensure intercontinental electric power transmission. The development of HVDC insulating materials together with the impact of the interface between the particles and the polymer on the nanocomposites electric properties are shown. Important parameters from the atomic to the microlevel, such as interfacial chemistry, interfacial area, and degree of particle dispersion/aggregation, are discussed. This work is placed in perspective with important work by others, and suggested mechanisms for improved insulation using nanoparticles, such as increased charge trap density, adsorption of impurities/ions, and induced particle dipole moments are considered. The effects of the nanoparticles and of their interfacial structures on the mechanical properties and the implications of cavitation on the electric properties are also discussed. Although the main interest in improving the properties of insulating polymers has been on the use of nanoparticles, leading to nanodielectrics, it is pointed out here that larger microscopic hierarchical metal-oxide particles with high surface porosity also impart good insulation properties. The impact of the type of particle and its inherent properties (purity and conductivity) on the nanocomposite dielectric and insulating properties are also discussed based on data obtained by a newly developed technique to directly observe the charge distribution on a nanometer scale in the nanocomposite. PMID- 29131406 TI - Testicular vein thrombosis: Incidence of recurrent venous thromboembolism and survival. AB - PURPOSE: Testicular vein thrombosis (TVT) etiology, recurrence, and survival were compared with lower extremity deep vein thrombosis (DVT) in order to determine whether treatment guidelines for DVT could be applied to TVT. PATIENTS AND METHODS: An inception cohort of patients with confirmed TVT (January 1995-October 2015) was compared to a control group of patients with lower extremity DVT matched by age, gender, and diagnosis date. RESULTS: Thirty-nine men with TVT were identified; 15 (38%) with isolated TVT. Left testicular vein was affected in 77% patients; there were no cases of bilateral TVT. Cancer was over twofold more common in TVT patients (59% vs 28%, P = .01). Most cancers (78%) involved organs in proximity to the testicular vein. Although TVT patients were less frequently treated with anticoagulants (49% vs 97%, P = .0001), recurrence rates were similar to DVT group (TVT 4.2 vs DVT 1.1 per 100 patient-years, P = .11). Despite higher cancer prevalence, survival rates were similar between groups (31% vs 28%; P = .34). Major bleeding events were rare (one patient per group). CONCLUSIONS: Identifying TVT should prompt a search for a regional malignancy. Despite the high cancer prevalence and low utilization of anticoagulants, recurrent venous thrombosis and mortality rates are similar to DVT patients. PMID- 29131407 TI - Posttraumatic Stress Disorder, Gender, and Risk Factors: World Trade Center Tower Survivors 10 to 11 Years After the September 11, 2001 Attacks. AB - Ten to eleven years after the September 11, 2001 terrorist attacks, probable posttraumatic stress disorder (PTSD) was evaluated in 1,755 World Trade Center (WTC) evacuees based on data from the WTC Health Registry. Characteristics of men and women were compared and factors associated with PTSD symptom severity were examined using the PTSD Checklist (PCL). Compared with men (n = 1,015, 57.8%), women (n = 740, 42.2%) were younger and of lower socioeconomic status. Ten to eleven years after September 11, 2001, 13.7% of men and 24.1% of women met criteria for PTSD. Results indicated that when considered with all other variables (i.e., demographic, socioeconomic and social resources, exposure to the attacks, life events), gender was not a significant predictor of PTSD symptom severity. Being younger on September 11, 2001, unemployed, less educated, and/or having higher exposure to the attacks, unmet mental health care needs, and less social support predicted higher PCL scores for both genders (betas = .077 to .239). Demographic characteristics and socioeconomic resources (DeltaR2 = .113) accounted for the largest amount of variance in PCL scores over and above exposure/evacuation, mental healthcare needs, and social support variables (DeltaR2 = .093 to .102). When trends of unmet mental healthcare needs were analyzed, the most prevalent response for men was that they preferred to manage their own symptoms (15.1%), whereas the most prevalent response for women was that they could not afford to pay for mental health care (14.7%). Although the prevalence of probable PTSD in women tower survivors was approximately twice as high as it was for men, this is attributable largely to demographic and socioeconomic resource factors and not gender alone. Implications for treatment and interventions are discussed. PMID- 29131408 TI - Parent and Child Trauma Symptoms During Child-Parent Psychotherapy: A Prospective Cohort Study of Dyadic Change. AB - Five randomized controlled trials have shown that child-parent psychotherapy (CPP) improves trauma symptoms in children. Less is known about parent symptoms or moderators of symptom change. In a sample of 199 parent (81% biological mother; 54% Latina/o) and child (aged 2 to 6 years; 52% male; 49% Latina/o) dyads who participated in an open treatment study of CPP, this study investigated whether parent and child symptoms similarly decreased during treatment and whether improvement was moderated by parent, child, and treatment characteristics. Parents completed baseline and posttreatment interviews regarding exposure to traumatic events, posttraumatic stress symptomatology (PTSS), and other mental health indices. Latent difference score analysis showed that PTSS significantly decreased by more than 0.5 SD for parents and children. The PTSS improvement in parents was associated with reductions in child avoidance, r = .19, p = .040, and hyperarousal, r = .33, p < .001. Girls showed a greater reduction than boys in reexperiencing, beta = -.13, p = .018, and hyperarousal, beta = -.20, p = .001. Contrary to expectations, parent and child improvement in PTSS was greater for those with fewer parental lifetime stressors, betarange = .15 to .33, and for those who participated in fewer treatment sessions, betarange = .15 to .21. The extent of improvement in parent PTSS varied based on clinician expertise, beta = -.20, p = .009. Significant reductions in parent and child PTSS were observed during community-based treatment, with CPP and symptom improvement varying according to child, parent, and treatment characteristics. PMID- 29131409 TI - Field-size correction factors of a radiophotoluminescent glass dosimeter for small-field and intensity-modulated radiation therapy beams. AB - PURPOSE: We evaluated the energy responses of a radiophotoluminescent glass dosimeter (RPLD) to variations in small-field and intensity-modulated radiation therapy (IMRT) conditions using experimental measurements and Monte Carlo simulation. METHODS: Several sizes of the jaw and multileaf collimator fields and various plan-class IMRT-beam measurements were performed using the RPLD and an ionization chamber. The field-size correction factor for the RPLD was determined for 6- and 10-MV x rays. This correction factor, together with the perturbation factor, was also calculated using Monte Carlo simulation with the EGSnrc/egs_chamber user code. In addition, to evaluate the response of the RPLD to clinical-class-specific reference fields, the field-size correction factor for the clinical IMRT plan was measured. RESULTS: The calculated field-size correction factor ranged from 1.007 to 0.981 (for 6-MV x rays) and from 1.012 to 0.990 (for 10-MV x rays) as the jaw-field size ranged from 1 * 1 cm2 to 20 * 20 cm2 . The atomic composition perturbation factor for these jaw fields decreased by 3.2% and 1.9% for the 6- and 10-MV fields, respectively. The density perturbation factor was unity for field sizes ranging from 3 * 3 cm2 to 20 * 20 cm2 , whereas that for field sizes ranging from 3 * 3 cm2 to 1 * 1 cm2 decreased by 3.2% (for 6-MV x rays) and 4.3% (for 10-MV x rays). The volume-averaging factor rapidly increased for field sizes below 1.6 * 1.6 cm2 . The results for the MLC fields were similar to those for the jaw fields. For plan-class IMRT beams, the field-size correction and perturbation factors were almost unity. The difference between the doses measured using the RPLD and ionization chamber was within 1.2% for the clinical IMRT plan at the planning-target volume (PTV) region. CONCLUSIONS: For small fields of size 1.6 * 1.6 cm2 or less, it was clarified that the volume averaging and density perturbation were the dominant effects responsible for the variation in the RPLD response. Moreover, perturbation correction is required when measuring a field size 1.0 * 1.0 cm2 or less. Under the IMRT conditions, the difference in the responses of the RPLD between the reference conditions and the PTV region calculated by Monte Carlo simulation did not exceed 0.8%. These results indicate that it is feasible to measure IMRT dosage using an RPLD at the PTV region. PMID- 29131410 TI - Primary antibiotic resistance of Helicobacter pylori strains among adults and children in a tertiary referral centre in Lithuania. AB - The study evaluated primary antibiotic resistance of Helicobacter pylori within the period 2013-2015 and trends of antibiotic consumption over the last decade in Lithuania; 242 adults and 55 children were included in the study. E-tests were performed for amoxicillin, metronidazole, clarithromycin, ciprofloxacin, rifampicin and tetracycline. The presence of H. pylori and clarithromycin resistance was additionally tested by PCR. Helicobacter pylori culture was positive in 67 of 242 (28%) adult and in 12 of 55 (21.8%) children samples. Resistance rates among adults by E-tests were as follows: metronidazole - 32.8% (95% confidence interval (CI): 22.7-44.7%), ciprofloxacin - 7.5% (95% CI: 3.2 16.3%), rifampicin - 7.5% (95% CI: 3.2-16.3%), amoxicillin - 0%, whereas resistance rates in children were as follows: metronidazole - 25% (95% CI: 8.9 53.2%), rifampicin - 8.3% (CI: 1.5-35.4%), amoxicillin and ciprofloxacin - 0%. Accumulated clarithromycin resistance rates by E-tests and PCR were 8.2% (95% CI: 4.1-16.0%) in adults and 17.7% (95% CI: 6.2-41.0%) in children. Total use of macrolides and lincosamides in Lithuania increased from 1.26 to 1.86 defined daily dose (DDD)/1000 inhabitants/day among adults, while it has doubled from 1.10 to 2.22 DDD/1000/children/day in children within 2003-2015. There are no significant changes in the susceptibility of H. pylori to the most widely used antibiotics in adults over the last years in Lithuania; however, clarithromycin resistance among children exceeds 15% and mandates further larger-scale studies in paediatric population. PMID- 29131411 TI - The Salt Matters: Enhanced Reversibility of Li-O2 Batteries with a Li[(CF3 SO2 )(n-C4 F9 SO2 )N]-Based Electrolyte. AB - The safety hazards and cycle instability of lithium metal anodes (LMA) constitute significant barriers to progress in lithium metal batteries. This situation is worse in Li-O2 batteries because the LMA is prone to be chemically attacked by O2 shuttled from the cathode. Notwithstanding, efforts on LMA are much sparse than those on the cathode in the realm of Li-O2 batteries. Here, a novel lithium salt of Li[(CF3 SO2 )(n-C4 F9 SO2 )N] (LiTNFSI) is reported, which can effectively suppress the parasitic side reactions and dendrite growth of LMA during cycling and thereby significantly enhance the overall reversibility of Li-O2 batteries. A variety of advanced research tools are employed to scrutinize the working principles of the LiTNFSI salt. It is revealed that a stable, uniform, and O2 resistive solid electrolyte interphase is formed on LMA, and hence the "cross talk" between the LMA and O2 shuttled from the cathode is remarkably inhibited in LiTNFSI-based Li-O2 batteries. PMID- 29131412 TI - Oxidation of Polynuclear Aromatic Hydrocarbons using Ruthenium-Ion-Catalyzed Oxidation: The Role of Aromatic Ring Number in Reaction Kinetics and Product Distribution. AB - Oxidation of aromatic hydrocarbons with differing numbers of fused aromatic rings (2-5), have been studied in two solvent environments (monophasic and biphasic) using ruthenium-ion-catalyzed oxidation (RICO). RICO reduces the aromaticity of the polyaromatic core of the molecule in a controlled manner by selective oxidative ring opening. Moreover, the nature of the solvent system determines the product type and distribution, for molecules with more than two aromatic rings. Competitive oxidation between substrates with different numbers of aromatic rings has been studied in detail. It was found that the rate of polyaromatic hydrocarbon oxidation increases with the number of fused aromatic rings. A similar trend was also identified for alkylated aromatic hydrocarbons. The proof of-concept investigation provides new insight into selective oxidation chemistry for upgrading of polyaromatic molecules. PMID- 29131414 TI - Oral health-related quality of life, measured using the five-item version of the Oral Health Impact Profile, in relation to socio-economic status: a population survey in Sweden. AB - Oral health-related quality of life (OHRQoL) is an important patient-reported outcome measure in dental research. This study was conducted to analyse the association between OHRQoL, as measured using the five-item version of the Oral Health Impact Profile (OHIP-5), and different socio-economic indices. A national survey of randomly selected adult individuals in Sweden (n = 3,500) was performed using telephone interviews. The questions asked for the purpose of this study were defined by the items of the OHIP-5, just as questions were asked regarding socio-economic variables, including education, income, and economic resources. Poor OHRQoL, as identified by an OHIP-5 score of 3 or higher on at least two of the five items, was statistically significantly associated in multivariate analysis with low income (OR = 1.84) and having no economic resources (OR = 2.19). The statistical models were adjusted for age, gender, ethnicity, marital status, dental-care utilization, dental anxiety, and smoking. The OHIP-5 may be used in larger epidemiological surveys because it demonstrates the ability to discriminate for a range of important areas of measurement in dental public health, including social determinants. PMID- 29131413 TI - The effect of epitope-based ligation of ICAM-1 on survival and retransplantation of pig islets in nonhuman primates. AB - BACKGROUND: Pig islet xenotransplantation is a promising alternative to allogeneic transplantation. However, the wide immunologic barrier between pigs and primates limits the long-term survival of the graft. MD-3, a novel monoclonal antibody (mAb) that recognizes a particular epitope of human ICAM-1, can render T cells tolerant to a xenograft by arresting dendritic cell maturation. We report the long-term survival of adult wild-type pig islets and successful retransplantation in nonhuman primates using a protocol comprising induction with MD-3 mAb and maintenance with anti-CD154 mAb and sirolimus. METHODS: Eleven rhesus monkeys were assigned to three groups. Group 1 (n = 4) involved treatment with MD-3 induction, short-term (<4 months) administration of anti-CD154 mAb, and maintenance therapy with sirolimus. Group 2 (n = 4) involved treatment with MD-3 induction and long-term maintenance therapy with anti-CD154 mAb and sirolimus. Group 3 (n = 3) involved only maintenance therapy with anti-CD154 mAb and sirolimus. Diabetes was induced in monkeys by streptozotocin, and pig islets (61 000-112 000 IEQ/kg for each transplant; up to 280 000 IEQ/kg per recipient) were infused through the portal vein. The in vivo functional potency of the isolated islets was tested by minimal model transplant in streptozotocin-induced diabetic NOD/SCID mice, and the mean AUC of blood glucose level divided by the number of follow-up days was calculated. RESULTS: The islet grafts survived more than 6 months (between 225 and 727 days) in nine of 12 transplants of MD-3-treated groups 1 and 2, whereas in the absence of MD-3 mAb, survival was <40 days. In three transplants of the MD-3-treated Group 2, functional graft survival was only for 104, 125, and 154 days. In these cases, a retrospective analysis suggested that the relatively short survival duration was associated with the relatively high AUC value in the NOD/SCID bioassay. Notably, when retransplantation was performed in Group 3, blood glucose control was extended up to 956 days, which was supported by MD-3 mAb-based suppression of adaptive immunity. No replication of cytomegalovirus genes was observed. CONCLUSIONS: Long-term survival of pig islet xenografts and successful retransplantation were achieved with MD-3 mAb based immunosuppression regimen in this pig-to-monkey transplantation model. It should be emphasized that these encouraging results were achieved following the transplantation of islets from pigs that had not been genetically modified. Considering that it is possible to further substantially reduce the destruction of grafted islet using genetically modified pig islet, the islet requirement could be reduced and much longer graft survival can be achieved. PMID- 29131415 TI - Superior Toughness and Fast Self-Healing at Room Temperature Engineered by Transparent Elastomers. AB - The most important properties of self-healing polymers are efficient recovery at room temperature and prolonged durability. However, these two characteristics are contradictory, making it difficult to optimize them simultaneously. Herein, a transparent and easily processable thermoplastic polyurethane (TPU) with the highest reported tensile strength and toughness (6.8 MPa and 26.9 MJ m-3 , respectively) is prepared. This TPU is superior to reported contemporary room temperature self-healable materials and conveniently heals within 2 h through facile aromatic disulfide metathesis engineered by hard segment embedded aromatic disulfides. After the TPU film is cut in half and respliced, the mechanical properties recover to more than 75% of those of the virgin sample within 2 h. Hard segments with an asymmetric alicyclic structure are more effective than those with symmetric alicyclic, linear aliphatic, and aromatic structures. An asymmetric structure provides the optimal metathesis efficiency for the embedded aromatic disulfide while preserving the remarkable mechanical properties of TPU, as indicated by rheological and surface investigations. The demonstration of a scratch-detecting electrical sensor coated on a tough TPU film capable of auto repair at room temperature suggests that this film has potential applications in the wearable electronics industry. PMID- 29131416 TI - Characterization of sweat induced with pilocarpine, physical exercise, and collected passively by metabolomic analysis. AB - BACKGROUND/PURPOSE: The elimination of the pain associated with needle picking is a strong motivation for the development of clinical non-invasive diagnostic methods. Sweat has been described as an alternative biological sample that may have a direct relation to the plasma composition. MATERIALS AND METHODS: In this study, analysis of sweat of human volunteers obtained by induction with pilocarpine is compared with sweat samples obtained by physical exercise and by passive collection along 7 hours. The sweat samples have been analyzed by 1H nuclear magnetic resonance spectroscopy. RESULTS: A range of 34 different metabolites has been detected in sweat samples, including lactate, several amino acids, pyroglutamate, and urocanate. Most of the metabolites identified were quantified. The majority of the amino acids detected in sweat seem to have origin in the epidermis surface. No significant differences in sweat samples from female and male were observed by 1H NMR metabolomic analysis. CONCLUSIONS: Principal component analysis (PCA) shows that both physical exercise and pilocarpine methods seem to be equally reproducible methods in terms of sweat metabolite composition presenting better repeatability than natural sweat collection. Nevertheless, this difference is mainly originated from amino acids with origin from the skin surface. PMID- 29131417 TI - Culturing with modified EGM2 medium enhances porcine neonatal islet-like cell clusters resistance to apoptosis in islet xenotransplantation. AB - BACKGROUND: Neonatal pig islet-like cell clusters (NICC) are an attractive source of insulin-producing tissue for potential transplantation treatment of type 1 diabetic patients. However, a considerable loss of NICC after their transplantation due to apoptosis resulted from islet isolation and instant blood mediated inflammatory reaction remains to be overcome. METHODS: EGM2 medium depleted with hydrocortisone and supplemented with 50 mmol/L isobutylmethylxanthine, 10 mmol/L nicotinamide, and 10 mmol/L glucose was used to culture NICC at day 1, the day after isolation and changed every other day. NICC cultured with EGM2 or control Ham's F-10 medium were collected at day 7 of culture for the following assays. The viability of NICC was evaluated by AO/EB staining and FACS. Static assay and oxygen consumption rate analysis were performed to assess the function of NICC. Insulin and glucagon gene expression were measured by real-time PCR. Tubing loops model and TUNEL assay were performed to confirm the apoptosis-resistant ability of NICC cultured with modified EGM2 medium. Serum starvation and hypoxia treatment were used to test the tolerant capability of NICC in the microenvironment of hypoxia/nutrient deficiency in vitro. The molecules involved in apoptosis pathways in NICC were analyzed by Western blotting. RESULTS: Compared with Ham's F-10 medium, culturing NICC with EGM2 medium led to increased number and viability of NICC with higher stimulation index, upregulated gene expression of both insulin and glucagon, and enhanced mitochondria function. Furthermore, fewer modified EGM2 medium cultured NICC were found under apoptosis when evaluated in an in vitro tubing loop model of IBMIR. Moreover, EGM2 medium cultured NICC demonstrated much less apoptotic cells under either serum starvation or hypoxia condition than their Ham's F-10 medium cultured counterparts. The enhanced capability of EGM2 cultured NICC to resist apoptosis was associated with their elevated protein levels of anti-apoptotic Bcl 2 family member Mcl-1. CONCLUSION: Culturing NICC with EGM2 provides a simple and effective approach not only to increase NICC yield, viability, and maturation but also to enhance their resistance to apoptosis to preserve the initial graft mass for successful islet xenotransplantation. PMID- 29131418 TI - Stereoselective Nanozyme Based on Ceria Nanoparticles Engineered with Amino Acids. AB - Stereoselectivity towards substrates is one of the most important characteristics of enzymes. Amino acids, as cofactors of many enzymes, play important roles in stereochemistry. Herein, chiral nanozymes were constructed by grafting a series of d- or l-amino acids onto the surfaces of ceria (cerium oxide) nanoparticles. We selected the most commonly used drug for combating Parkinson's disease, that is, 3,4-dihydroxyphenylalanine (DOPA) enantiomers, as examples for chiral catalysis. Through detailed kinetic studies of cerium oxide nanoparticles (CeNPs) modified with different eight amino acids, we found that phenylalanine-modified CeNP was optimal for the DOPA oxidation reaction and showed excellent stereoselectivity towards its enantiomers. l-Phenylalanine-modified CeNPs showed higher catalytic ability for oxidation of d-DOPA, while d-phenylalanine-modified CeNPs were more effective towards l-DOPA. Taken together, the results indicated that stereoselective nanozyme can be constructed by grafting nanoparticles with chiral molecules. This work may inspire better design of chiral nanozymes. PMID- 29131419 TI - Potential Therapeutic Applications of MnSODs and SOD-Mimetics. AB - Natural as well as synthetic antioxidants are constantly being investigated for their efficiency in combatting the effects of oxidative stress, which appears to be the responsible cause of several diseases, including cancer, central nervous system disorders, ischaemia-reperfusion disorders, cardiovascular conditions, and diabetes. Superoxide dismutases (SODs) constitute the ubiquitous antioxidant defences against oxidative stress that underlies numerous pathological conditions. Therefore, the development of therapeutics aimed at either delivering MnSOD more effectively to target tissues in the body in the form of MnSOD gene therapy, or the synthesis of molecules that mimic the activity of superoxide dismutase is constantly being explored. Classes that have been developed as SOD mimetics include the Mn-metalloporphyrins, Mn-cyclic polyamines, Mn-salen complexes, MnPLED derivatives as well as the nitroxides. Thus far, SOD mimetics have shown remarkable efficacy in several animal models suffering from oxidative stress injuries. A promising approach for the future of SOD and SOD mimic therapeutics appears to involve combination treatment of the antioxidants with radiotherapy or chemotherapy. PMID- 29131420 TI - Chromatographic analysis of VOC patterns in exhaled breath from smokers and nonsmokers. AB - Cigarette smoking harms nearly every organ of the body and causes many diseases. The analysis of exhaled breath for exogenous and endogenous volatile organic compounds (VOCs) can provide fundamental information on active smoking and insight into the health damage that smoke is creating. Various exhaled VOCs have been reported as typical of smoking habit and recent tobacco consumption, but to date, no eligible biomarkers have been identified. Aiming to identify such potential biomarkers, in this pilot study we analyzed the chemical patterns of exhaled breath from 26 volunteers divided into groups of nonsmokers and subgroups of smokers sampled at different periods of withdrawal from smoking. Solid-phase microextraction technique and gas chromatography/mass spectrometry methods were applied. Many breath VOCs were identified and quantified in very low concentrations (ppbv range), but only a few (toluene, pyridine, pyrrole, benzene, 2-butanone, 2-pentanone and 1-methyldecyclamine) were found to be statistically significant variables by Mann-Whitney test. In our analysis, we did not consider the predictive power of individual VOCs, as well as the criterion of uniqueness for biomarkers suggests, but we used the patterns of the only statistically significant compounds. Probit prediction model based on statistical relevant VOCs patterns showed that assessment of smoking status is heavily time dependent. In a two-class classifier model, it is possible to predict with high specificity and sensitivity if a subject is a smoker who respected 1 hour of abstinence from smoking (short-term exposure to tobacco) or a smoker (labelled "blank smoker") after a night out of smoking (long-term exposure to tobacco). On the other side, in our study "blank smokers" are more like non-smokers so that the two classes cannot be well distinguished and the corresponding prediction results showed a good sensitivity but low selectivity. PMID- 29131421 TI - Voltage-Controlled On/Off Switching of Ferromagnetism in Manganite Supercapacitors. AB - The ever-growing technological demand for more advanced microelectronic and spintronic devices keeps catalyzing the idea of controlling magnetism with an electric field. Although voltage-driven on/off switching of magnetization is already established in some magnetoelectric (ME) systems, often the coupling between magnetic and electric order parameters lacks an adequate reversibility, energy efficiency, working temperature, or switching speed. Here, the ME performance of a manganite supercapacitor composed of a ferromagnetic, spin polarized ultrathin film of La0.74 Sr0.26 MnO3 (LSMO) electrically charged with an ionic liquid electrolyte is investigated. Fully reversible, rapid, on/off switching of ferromagnetism in LSMO is demonstrated in combination with a shift in Curie temperature of up to 26 K and a giant ME coupling coefficient of ~226 Oe V-1 . The application of voltages of only ~2 V results in ultralow energy consumptions of about 90 uJ cm-2 . This work provides a step forward toward low power, high-endurance electrical switching of magnetism for the development of high-performance ME spintronics. PMID- 29131422 TI - Translation and validation of the Danish version of the brief family assessment measure III in a sample of acutely admitted elderly medical patients. AB - RATIONALE AND OBJECTIVE: Family functioning plays a pivotal role in the adaptation to illness of both individuals and families, especially among elderly patients. The Brief Family Assessment Measure Third Edition (Brief FAM-III) is among the most frequently used self-report instruments that measures family functioning. However, no Danish translation or measure of its psychometric properties in a Danish population is available. The purpose of this study was to translate the Brief FAM-III into Danish and then evaluate its psychometric properties in elderly patients. METHODS: The Brief FAM-III was translated into Danish using the forward-backward translation procedure and examined its psychometric properties in 60 elderly patients (aged over 65) consecutively admitted to an acute medical ward. Internal consistency reliability was assessed by Cronbach's alpha coefficients, and confirmatory factor analysis was used to examine the construct validity of the Brief FAM-III. RESULTS: Evaluation of the Danish version of the Brief FAM-III confirmed the three-factor structure (General Scale, Self-Rating Scale and Dyadic Relationships Scale) identified in the original instrument. However, goodness-of-fit indicators showed a relatively poor model fit. Cronbach's alpha for the total scales of Brief FAM-III was 0.94 suggesting good internal consistency. CONCLUSIONS: The Danish version of the Brief FAM-III demonstrated satisfactory validity and reliability to assess family functioning among acutely admitted elderly Danish patients. We suggest that it may also be useful for monitoring family functioning over time or determining the effects of therapeutic interventions in elderly medical patients; however, further testing is recommended. PMID- 29131423 TI - Rh-Catalyzed Denitrogenative Reaction of N-Sulfonyl-1,2,3-triazoles with Isatoic Anhydrides and Oxadiazolones. AB - A convenient and simple, RhII -catalyzed denitrogenative method for the synthesis of biologically interesting 2-amino-benzoxazinones and 5-amino-oxadiazoles from readily available isatoic anhydrides and oxadiazolones has been developed. These reactions proceed via an O-H insertion onto alpha-imino RhII -carbenoid species followed by a rearrangement. The scope of the reaction can also be extended to benzoxazinones to access amino-substituted benzoxazines. PMID- 29131424 TI - Influences of age, ethnic group, and skin sites on a provisory skin marking, experimentally induced, in vivo. AB - BACKGROUND: To study capacity of skin to being imprinted by a marking head rapidly applied (10 seconds) onto the skin under a standardized pressure (15 kPa). MATERIAL AND METHODS: Referential photographs of skin markings, resulting from different times of application serve at grading the extent of skin imprints. The imprinting tool, equipped with 5 linear bulbs of different sizes but same thickness (1 mm), was applied onto the cheeks of 641 women of different ages (18 80 years) of 3 different ethnic groups. In the cohort of 198 Caucasian women, the marking head was pressed onto 3 different sites (outer arm, cheek, and dorsal forearm) and the kinetics of skin recovery from cheek marking was recorded on a smaller and younger part of this Caucasian cohort, ie, 141 Caucasian women, aged 18-59 years. RESULTS: The recorded intensities of skin markings were found highly correlated with age in all 3 studied ethnic groups (Chinese, African-American, and Caucasian). Caucasian women seem more sensitive to the marking and the kinetics of recovery from such imprint was found highly dependent from its intensity, ie, the higher the grades, the slower the recovery. In Caucasian women, intensities were different between skin sites, where arm showed higher resistance to marking. Possible impact of photo-aging on the decreased skin resistance to such provoked deformation is likely of minor amplitude, as compared to the one induced by chronological aging. CONCLUSION: This method offers a new vision on skin aging, in its variable response to a standard deformation that appears mostly driven by chronological aging. PMID- 29131425 TI - Stage of diagnosis of prostate, breast and colorectal cancer in farm residents compared with other rural and urban residents in New South Wales. AB - OBJECTIVE: To determine if stage at diagnosis of prostate, breast and colorectal cancers differs between farm, rural non-farm and urban residents. DESIGN: Data linkage of baseline survey information from a large cohort study, with state cancer registry records from 2006 to 2009. SETTING: New South Wales, Australia. PARTICIPANTS: New South Wales residents enrolled in the 45 and Up Study cohort. MAIN OUTCOME MEASURES: Adjusted odds ratio of non-localised cancer stage was modelled using binary logistic regression, controlling for commonly known cancer risk factors. RESULTS: Overall differences in the odds ratios for later stage prostate, breast and colorectal cancer diagnosis in farm men and women compared with rural non-farm and urban counterparts were not statistically significant, although farm men had twice the odds of either group of being diagnosed at later stage colorectal cancer. The odds of later stage prostate cancer for farm and urban men were similar, but rural non-farm men were significantly less likely than urban men to be diagnosed at later stage. Higher household income was associated with later stage breast and prostate cancer; and private health insurance with extras was negatively associated with later stage prostate cancer. CONCLUSIONS: Differences in stage of cancer diagnosis, particularly between farm and rural non-farm men, remain unexplained but were not statistically significant. Farm men may be at higher risk of later stage colorectal cancer diagnosis, which if confirmed has implications for research on possible reasons, and for the delivery of appropriate cancer diagnostic services in rural areas. PMID- 29131426 TI - Heterogeneous Acid-Catalyzed Racemization of Tertiary Alcohols. AB - Tertiary alcohols are important structural motifs in natural products and building blocks in organic synthesis but only few methods are known for their enantioselective preparation. Chiral resolution is one of these approaches that leaves one enantiomer (50 % of the material) unaffected. An attractive method to increase the efficiency of those resolutions is to racemize the unaffected enantiomer. In the present work, we have developed a practical racemization protocol for tertiary alcohols. Five different acidic resin materials were tested. The Dowex 50WX8 was the resin of choice since it was capable of racemizing tertiary alcohols without any byproduct formation. Suitable solvents and a biphasic system were investigated, and the optimized system was capable of racemizing differently substituted tertiary alcohols. PMID- 29131427 TI - Optimal fabrication methods for miniature coplanar ion traps. AB - RATIONALE: Ion trap mass spectrometers are beneficial due to their intrinsic sensitivity and specificity. Therefore, a portable version for in situ analysis of various compounds is very attractive. Miniaturization of ion traps is paramount for the portability of such mass spectrometers. METHODS: We developed an optimized design for a planar linear ion trap mass spectrometer, consisting of two trapping plates with photolithographically patterned electrodes. Each plate is constructed using a machined glass substrate and standard microfabrication procedures. The plates are attached to a patterned circuit board via wire bonds then positioned approximately 5 mm apart. RESULTS: Trapped ions are detected by ejecting them through tapered slits, which alleviate charge buildup. Mass analysis can be performed through either boundary or resonant ion ejection. Better than unit mass resolution is demonstrated with resonant ejection. CONCLUSIONS: The optimized planar linear ion trap provides good resolution and the potential for further miniaturization. This was accomplished by vigorously testing variables associated with ion trap design including electrical connections, substrate materials, and electrode designs. PMID- 29131428 TI - Control of Enantioselectivity in Rhodium(I) Catalysis by Planar Chiral Dibenzo[a,e]cyclooctatetraenes. AB - Planar chiral 5,11-disubstiuted dibenzo[a,e]cyclo-octatetraenes (dbCOTs) have been developed as the first useful chiral homologs to dbCOT-ligands for asymmetric applications. Methods enabling the preparation of such compounds on a gram-scale in enantiomerically pure form are described. Evaluated as ligands in rhodium(I)-catalyzed 1,4- and 1,2-arylation reactions, tertiary and quarternary stereogenic centers were formed with excellent yields and selectivities of up to >99 % ee. A catalytic asymmetric synthesis of a key cyclization precursor to (-) penifulvin A highlights the system in an applied context. PMID- 29131429 TI - Highly Efficient Porphyrin-Based OPV/Perovskite Hybrid Solar Cells with Extended Photoresponse and High Fill Factor. AB - Employing a layer of bulk-heterojunction (BHJ) organic semiconductors on top of perovskite to further extend its photoresponse is considered as a simple and promising way to enhance the efficiency of perovskite-based solar cells, instead of using tandem devices or near infrared (NIR)-absorbing Sn-containing perovskites. However, the progress made from this approach is quite limited because very few such hybrid solar cells can simultaneously show high short circuit current (JSC ) and fill factor (FF). To find an appropriate NIR-absorbing BHJ is essential for highly efficient, organic, photovoltaics (OPV)/perovskite hybrid solar cells. The materials involved in the BHJ layer not only need to have broad photoresponse to increase JSC , but also possess suitable energy levels and high mobility to afford high VOC and FF. In this work, a new porphyrin is synthesized and blended with [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) to function as an efficient BHJ for OPV/perovskite hybrid solar cells. The extended photoresponse, well-matched energy levels, and high hole mobility from optimized BHJ morphology afford a very high power conversion efficiency (PCE) (19.02%) with high Voc , JSC , and FF achieved simultaneously. This is the highest value reported so far for such hybrid devices, which demonstrates the feasibility of further improving the efficiency of perovskite devices. PMID- 29131430 TI - Readily Exfoliated TiSe2 Nanosheets for High-Performance Sodium Storage. AB - Materials with sheet-like morphologies are highly desirable candidates for energy storage and conversion applications, due to the confined atomic thickness and high surface area, which would largely improve the electrochemical reaction kinetics. In this work, the sodium storage performance of TiSe2 nanosheets and corresponding sodiation/desodiation reaction mechanism are studied for the first time. TiSe2 nanosheets are readily exfoliated from bulk TiSe2 after quick ultrasonication or grinding. The TiSe2 nanosheets exhibit a reversible capacity of 147 mAh g-1 at 0.1 A g-1 , and show excellent rate capability with a capacity of 103 mAh g-1 at an ultra-high current density of 10.0 A g-1 . The combined in situ XRD and ex-situ HRTEM results suggest that sodium storage in TiSe2 is achieved through a multi-step intercalation/deintercalation mechanism. Besides, TiSe2 might be a promising 2D nanomaterial platform for other energy and electronic applications due to its easy exfoliation and unique physicochemical properties. PMID- 29131431 TI - Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents. AB - Fucosylated chondroitin sulfate (FuCS) is a structurally distinct glycosaminoglycan with excellent anticoagulant activity. Studies show that FuCS and its depolymerized fragments exhibit a different anticoagulant mechanism from that of heparin derivatives, with decreased risks of adverse effects and bleeding. However, further exploitation has been hindered by the scarcity of structurally defined oligosaccharides. Herein, facile method is reported for the synthesis of the repeating trisaccharide unit of FuCS based on the degradation of chondroitin sulfate polymers. A series of simplified FuCS glycomimetics that have highly tunable structures, controllable branches, and defined sulfation motifs were generated by copper-catalyzed alkyne-azide cycloaddition. Remarkable improvement in activated partial thromboplastin time (APTT) assay activities was observed as the branches increased, but no significant influences were observed for prothrombin time (PT) and thrombin time (TT) assay activities. Further FXase inhibition tests suggested that glycoclusters 33 b-40 b selectively inhibited intrinsic anticoagulant activities, but had little effect on the extrinsic and common coagulation pathways. Notably, glycoclusters with the 2,4-di-O-sulfated fucosyl residue displayed the most potency, which was in consistent with that of natural polysaccharides. These FuCS clusters demonstrated potency to mimic linear glycosaminoglycans and offer a new framework for the development of novel anticoagulant agents. PMID- 29131432 TI - Water-Lubricated Intercalation in V2 O5 .nH2 O for High-Capacity and High-Rate Aqueous Rechargeable Zinc Batteries. AB - Low-cost, environment-friendly aqueous Zn batteries have great potential for large-scale energy storage, but the intercalation of zinc ions in the cathode materials is challenging and complex. Herein, the critical role of structural H2 O on Zn2+ intercalation into bilayer V2 O5 .nH2 O is demonstrated. The results suggest that the H2 O-solvated Zn2+ possesses largely reduced effective charge and thus reduced electrostatic interactions with the V2 O5 framework, effectively promoting its diffusion. Benefited from the "lubricating" effect, the aqueous Zn battery shows a specific energy of ~144 Wh kg-1 at 0.3 A g-1 . Meanwhile, it can maintain an energy density of 90 Wh kg-1 at a high power density of 6.4 kW kg-1 (based on the cathode and 200% Zn anode), making it a promising candidate for high-performance, low-cost, safe, and environment-friendly energy-storage devices. PMID- 29131433 TI - Suppressive effects of morphine injected into the ventral bed nucleus of the stria terminalis on the affective, but not sensory, component of pain in rats. AB - Pain is a complex experience with both sensory and affective components. Clinical and preclinical studies have shown that the affective component of pain can be reduced by doses of morphine lower than those necessary to reduce the sensory component. Although the neural mechanisms underlying the effects of morphine on the sensory component of pain have been investigated extensively, those influencing the affective component remain to be elucidated. The bed nucleus of the stria terminalis (BNST) has been implicated in the regulation of various negative emotional states, including aversion, anxiety and fear. Thus, this study aimed to clarify the role of the ventral part of the BNST (vBNST) in the actions of morphine on the affective and sensory components of pain. First, the effects of intra-vBNST injections of morphine on intraplantar formalin-induced conditioned place aversion (CPA) and nociceptive behaviors were investigated. Intra-vBNST injections of morphine reduced CPA without affecting nociceptive behaviors, which suggests that intra-vBNST morphine alters the affective, but not sensory, component of pain. Next, to examine the effects of morphine on neuronal excitability in type II vBNST neurons, whole-cell patch-clamp recordings were performed in brain slices. Bath application of morphine hyperpolarized type II vBNST neurons. Thus, the suppressive effects of intra-vBNST morphine on pain induced aversion may be due to its inhibitory effects on neuronal excitability in type II vBNST neurons. These results suggest that the vBNST is a key brain region involved in the suppressive effects of morphine on the affective component of pain. PMID- 29131434 TI - Five-year impact of catheter ablation for atrial fibrillation in patients with a prior history of stroke. AB - BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach. Patients with a prior history of a stroke (CVA) represent a unique high-risk population for recurrent thromboembolic events. The role of antiarrhythmic treatment on the natural history of stroke recurrence in these patients is not fully understood. METHODS: Three patient groups with a prior CVA and 5 years of follow-up were matched 1:3:3 by propensity score (+/ 0.01): AF ablation patients receiving their first ablation (n = 139), AF patients that did not receive an ablation (n = 416), and CVA patients without clinical AF (n = 416). Prior CVA was determined by medical chart review. Patients were followed for outcomes of recurrent CVA, heart failure, and death. RESULTS: The average age of the population was 69 +/- 11 years and 51% male. AF ablation patients had higher rates of hypertension and heart failure (P < 0.0001), but diabetes prevalence was similar between the groups (P = 0.5). Note that 5-year risk of CVA (HR = 2.26, P < 0.0001) and death (HR = 2.43, P < 0.0001) were higher in the AF, no ablation group compared those that were ablated. When comparing AF, ablation to no AF patients, there was not a significant difference in 5-year risk of for CVA (HR = 0.82, P = 0.39) and death (HR = 0.92, P = 0.70); however, heart failure risk was increased (HR = 3.08, P = 0.001). CONCLUSION: In patients with AF and a prior CVA, patients undergoing ablation have lower rates of recurrent stroke compared to AF patients not ablated. Although the full mechanisms of benefit are unknown, as CVA rates are similar to patients without AF these data are suggestive of a potential altering of the natural history of disease progression. PMID- 29131436 TI - GABAB receptors in neocortical and hippocampal pyramidal neurons are coupled to different potassium channels. AB - Classically, GABAB receptors are thought to regulate neuronal excitability via G protein-coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABAB receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABAB receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 MUm) abolished outward currents evoked by GABAB receptors in CA1 pyramidal, but only partially blocked GABAB responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin-Q, a specific GIRK channel blocker. Tertiapin-Q partially blocked GABAB responses in CA1 pyramidal neurons, but was ineffective in blocking GABAB responses in neocortical layer 5 neurons. Consistent with the idea that GABAB receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABAB responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABAB responses mediated by two-pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABAB receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABAB inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity. PMID- 29131435 TI - Transgenic characterization of two silkworm tissue-specific promoters in the haemocyte plasmatocyte cells. AB - Haemocytes play crucial roles in insect metabolism, metamorphosis, and innate immunity. As a model of lepidopteran insects, the silkworm is a useful model to study the functions of both haematopoiesis and haemocytes. Tissue-specific promoters are excellent tools for genetic manipulation and are widely used in fundamental biological research. Herein, two haemocyte-specific genes, Integrin beta2 and Integrin beta3, were confirmed. Promoter activities of Integrin beta2 and Integrin beta3 were evaluated by genetic manipulation. Quantitative real-time PCR and western blotting suggested that both promoters can drive enhanced green fluorescent protein (EGFP) specifically expressed in haemocytes. Further evidence clearly demonstrated that the transgenic silkworm exhibited a high level of EGFP signal in plasmatocytes, but not in other detected haemocyte types. Moreover, EGFP fluorescence signals were observed in the haematopoietic organ of both transgenic strains. Thus, two promoters that enable plasmatocytes to express genes of interest were confirmed in our study. It is expected that the results of this study will facilitate advances in our understanding of insect haematopoiesis and immunity in the silkworm, Bombyx mori. PMID- 29131437 TI - Dichromatic Photocatalytic Substitutions of Aryl Halides with a Small Organic Dye. AB - Photocatalytic bond activations are generally limited by the photon energy and the efficiency of energy and electron transfer processes. Direct two-photon processes provide sufficient energy but the ultra-short lifetimes of the excited states prohibit chemical reactions. The commercial dye 9,10-dicyanoanthracene enabled photocatalytic aromatic substitutions of non-activated aryl halides. This reaction operates under VIS-irradiation via sequential photonic, electronic, and photonic activation of the simple organic dye. The resultant highly reducing excited photocatalyst anion readily effected C-H, C-C, C-P, C-S, and C-B bond formations. Detailed synthetic, spectroscopic, and theoretical studies support a biphotonic catalytic mechanism. PMID- 29131438 TI - Melanoma tumors exhibit a variable but distinct metabolic signature. AB - The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient respiration due to mitochondrial defects, and concomitant enhancement of lactate production due to increased aerobic glycolysis. We analysed 48 melanoma samples by immunohistochemistry and found that 38% of melanomas are characterized by areas of isolated or combined deficiencies of complexes of the oxidative phosphorylation (OXPHOS) system, whereby the incidence of OXPHOS-deficient areas is associated with an increased Breslow index; 62% of melanomas showed high expression of all OXPHOS complexes. Expression of carbonic anhydrase IX was low, indicating that melanomas generally are well-oxygenated. Expression of HIF-1alpha and MCT4 was high, which might be a consequence of increased lactate dehydrogenase A levels in melanomas. Our data indicate that there are two types of melanomas: one that features a classic Warburg effect, whereas the other one, despite being glycolytic, maintains a high level of OXPHOS complexes. PMID- 29131439 TI - Usability of advanced pneumatic compression to treat cancer-related head and neck lymphedema: A feasibility study. AB - BACKGROUND: This functional usability study assessed ease of use, fit, comfort, and potential clinical benefits of advanced pneumatic compression treatment of cancer-related head and neck lymphedema. METHODS: Patient-reported comfort and other treatment aspects were evaluated and multiple face and neck measurements were obtained on 44 patients with head and neck lymphedema before and after 1 treatment session to assess usability and treatment-related lymphedema changes. RESULTS: A majority of the patients (82%) reported the treatment was comfortable; most patients (61%) reported feeling better after treatment, and 93% reported that they would be likely to use this therapy at home. One treatment produced overall small but highly statistically significant reductions in composite metrics (mean +/- SD) of the face (82.5 +/- 4.3 cm vs 80.9 +/- 4.1 cm; P < .001) and neck (120.4 +/- 12.2 cm vs 119.2 +/- 12.1 cm; P < .001) with no adverse events. CONCLUSION: Results found the treatment to be safe, easy to use, and well tolerated while demonstrating edema reduction after a single initial treatment. PMID- 29131440 TI - miR-193b availability is antagonized by LncRNA-SNHG7 for FAIM2-induced tumour progression in non-small cell lung cancer. AB - OBJECTIVES: Long non-coding RNAs have identified to involve into the tumour cell proliferation, apoptosis and metastasis. We previously found that up-regulated LncRNA-SNHG7 (SNHG7) positively correlated to the Fas apoptosis inhibitory molecule 2 (FAIM2) in lung cancer cells with unclear mechanism. METHODS: Non small cell lung cancer (NSCLC) and relative normal tissues (n = 25) were collected. The SNHG7 expression and function in NSCLC was determined. The SNHG7 miR 193b-FAIM2 network was analysed in vitro and vivo. RESULTS: We reported that oncogene SNHG7 predicted a poor clinical outcome and functioned as competitive endogenous RNA (ceRNA) antagonized microRNA-193b (miR-193b) to up-regulate the FAIM2 level in NSCLC. Bioinformatic analysis predicted that SNHG7 harboured miR 193b-binding sites, and we found decreased miR-193b levels in NSCLC tissues when compared to relative normal tissues. Luciferase assays indicated that overexpression of miR-193b inhibited the Ruc expression of plasmid with miR-193b binding sites of SNHG7 in a dose-dependent manner. Ectopically expressed SNHG7 also as a molecular sponge sequestered endogenous miR-193b. Besides, FAIM2 was found to be directly targeted by miR-193b. The restoration of miR-193b levels in NSCLC cell lines A549 and H125 suppressed the expression of FAIM2 and related tumour proliferation, metastasis and induced apoptosis. However, forced expression of SNHG7 could down-regulate miR-193b to elevate the FAIM2 level of tumour cells, leading to impaired miR-193b/FAIM2-induced tumour progression. Knockdown of SNHG7 in vivo significantly delayed the tumour growth with decreased tumour volume, which accompanied with enhanced miR-193b expression and reduced FAIM2 levels. CONCLUSION: The results indicated that miR-193b is indispensible for the ceRNA role of SNHG7 in FAIM2-supported tumourigenesis of lung cancer. PMID- 29131442 TI - Increased rates of atrial fibrillation recurrence following pulmonary vein isolation in overweight and obese patients. AB - INTRODUCTION: Catheter ablation is common for patients with symptomatic, drug refractory atrial fibrillation (AF). Obesity is a known risk factor for incident AF. The impact of obesity on AF ablation outcomes is incompletely understood. We sought to determine the impact of elevated body mass index (BMI) on pulmonary vein isolation (PVI) procedural outcomes and associated complications. METHODS AND RESULTS: We evaluated patients undergoing PVI from 2001 to 2015, dividing them into four groups: normal weight (BMI >= 18.5 to < 25), overweight (BMI >= 25 to < 30), obese (BMI > 30 to < 40), and morbidly obese (BMI >= 40). Demographic and procedural characteristics, complications, and ablation outcomes were compared among groups. A total of 701 patients (146 time-matched controls, 227 overweight, 244 obese, and 84 morbidly obese) with complete demographic, procedural, and follow-up data were included. Increasing BMI correlated positively with HTN, OSA, CHA2 DS2 -VASC score, and persistent AF (P <= 0.001 for all associations). Radiofrequency application time and intraprocedural heparin dose increased with BMI (P <= 0.001). Arrhythmia recurrence at 1 year was 39.9% in controls, while higher in all high-BMI groups (overweight, 51.3%; obese, 57%; morbidly obese, 58.1 %; P = 0.007 for all versus controls). Impact of BMI on AF recurrence was not seen in persistent AF patients. Complication rates across groups were similar. CONCLUSIONS: AF recurrence after catheter ablation is higher in overweight, obese, and morbidly obese patients comparing to normal weight controls, driven primarily by outcomes differences in paroxysmal AF patients. Complications were not associated with increased BMI. PMID- 29131441 TI - Genetic and epigenetic regulation of major histocompatibility complex class I gene expression in bovine trophoblast cells. AB - PROBLEM: The regulatory mechanisms governing differential expression of classical major histocompatibility complex (MHC) class I (MHC-Ia) and non-classical MHC class I (MHC-Ib) genes are poorly understood. METHOD OF STUDY: Quantitative reverse transcription- polymerase chain reaction (PCR) was used to compare the abundance of MHC-I transcripts and related transcription factors in peripheral blood mononuclear cells (PBMC) and placental trophoblast cells (PTC). Methylation of MHC-I CpG islands was detected by bisulfite treatment and next-generation sequencing. Demethylation of PBMC and PTC with 5'-aza-deoxycytidine was used to assess the role of methylation in gene regulation. RESULTS: MHC-I expression was higher in PBMC than PTC and was correlated with expression of IRF1, class II MHC transactivator (CIITA), and STAT1. The MHC-Ia genes and BoLA-NC1 were devoid of CpG methylation in PBMC and PTC. In contrast, CpG sites in the gene body of BoLA NC2, -NC3, and -NC4 were highly methylated in PBMC but largely unmethylated in normal PTC and moderately methylated in somatic cell nuclear transfer PTC. In PBMC, demethylation resulted in upregulation of MHC-Ib by 2.8- to 6-fold, whereas MHC-Ia transcripts were elevated less than 2-fold. CONCLUSION: DNA methylation regulates bovine MHC-Ib expression and is likely responsible for the different relative levels of MHC-Ib to MHC-Ia transcripts in PBMC and PTC. PMID- 29131443 TI - A systematic review of randomized controlled trials with herbal medicine on chronic rhinosinusitis. AB - Chronic rhinosinusitis (CRS) is a common disease with evidence to show that its incidence and prevalence are increasing. Medicinal plants are commonly used to treat CRS. This systematic review aimed to assess the effectiveness and safety of herbal preparations for treatment of the patients with CRS. Cochran, Embase, ISI, PubMed, and Scopus databases were searched until August 1, 2016. Only randomized controlled trials were included. Four randomized controlled trials were included in this systematic review. Various medicinal plants were studied in each article. Inclusion and exclusion criteria, and outcome measures varied among different articles. The results of this trials showed that this special medicinal plants may be effective in the treatment of CRS. No serious reactions were reported during the administration of herbal remedies in the 4 studies. However, trials with a well-designed approach are needed to study the actual safety and efficacy of herbs in the treatment of CRS. PMID- 29131445 TI - Airyscan super-resolution microscopy of mitochondrial morphology and dynamics in living tumor cells. AB - Mitochondrial morphology is regulated by continuous fusion-and-fission events that are essential for maintaining normal function. Despite the prominence of mitochondrial function in energy generation and cell signaling, understanding of processes of fusion and fission dynamics has been hampered by the lack of high resolution optical systems that accommodate live-cell imaging. We have examined different confocal modalities in terms of resolution and signal-to-noise ratio (SNR) in a point scanning confocal microscope with Airyscan super-resolution (AS SR). Results indicated that Airyscan (AS) provided speed, super-resolution, and high SNR. This modality was then used for monitoring mitochondrial dynamics in live tumor cells modified to harbor green-fluorescent protein localized to mitochondria. We then compared regular AS and fast-Airyscan modalities in terms of gentleness on the live-cell samples. The fast mode provided unprecedented imaging speed that permits monitoring dynamics both in 2D and also in three dimensional dataset with time lapses (4D). Alterations to the mitochondrial network in U87 glioblastoma cells occurred within seconds and the cells were not affected by modest inhibition of fission. The super-resolution permitted quantitative measurements of mitochondrial diameter with a precision that enabled detection of significant differences in mitochondrial morphology between cell lines. We have observed swelling of mitochondrial tubules in A549 lung cancer cells after 2 hr treatment with deoxynyboquinone, an ROS-generating pharmacologic drug. We also tested different 3D analytical parameters and how they can affect morphometric quantitation. The AS-SR imaging enabled high-speed imaging of mitochondrial dynamics without the compromise to cell morphology or viability that is common with conventional fluorescence imaging due to photo-oxidation. PMID- 29131446 TI - Food provision among food relief agencies in rural Australia, and perceived barriers and enablers to provide healthy food. AB - OBJECTIVE: Food insecurity affects 4-14% of Australians, and up to 82% of vulnerable groups. Food relief agencies commonly provide food parcels or food vouchers. Little research has been undertaken on food relief agencies within rural Australia. This study determined the type of food assistance provided by rural food relief agencies, and barriers and enablers to provide healthy food. DESIGN: Cross-sectional study, using telephone questionnaires with qualitative and quantitative aspects. Data were analysed using descriptive statistics and thematic analysis. SETTING: Rural New South Wales, Australia. PARTICIPANTS: Representatives of 10 food relief agencies. MAIN OUTCOME MEASURE(S): Types of food assistance and food provided, and the barriers and enablers to provide healthy food to clients. RESULT: Most agencies provided food hampers and perishable and non-perishable food. Rural food relief agencies had a greater capacity to provide non-perishable compared to perishable food. Grains, breads and cereals, and canned fruit and vegetables were most popular. Nine key themes emerged including 'Ability to purchase and provide healthy food', 'Ability to regulate food purchased or chosen by clients', 'Financial constraints of the agency' and 'Lack of storage'. CONCLUSION: There are many variables to consider in order to understand the capacity of rural food relief agencies to provide healthy food. There are also opportunities for food relief agencies to appraise current practices and make changes. Initiatives to improve storage facilities and food availability are key and include networking with local businesses, community organisations and government. Rural food relief agency clients could benefit from accessing food literacy and health programs like FoodREDi, OzHarvest NEST and SecondBite Fresh NED. PMID- 29131444 TI - Native T1 reference values for nonischemic cardiomyopathies and populations with increased cardiovascular risk: A systematic review and meta-analysis. AB - BACKGROUND: Although cardiac MR and T1 mapping are increasingly used to diagnose diffuse fibrosis based cardiac diseases, studies reporting T1 values in healthy and diseased myocardium, particular in nonischemic cardiomyopathies (NICM) and populations with increased cardiovascular risk, seem contradictory. PURPOSE: To determine the range of native myocardial T1 value ranges in patients with NICM and populations with increased cardiovascular risk. STUDY TYPE: Systemic review and meta-analysis. POPULATION: Patients with NICM, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and patients with myocarditis (MC), iron overload, amyloidosis, Fabry disease, and populations with hypertension (HT), diabetes mellitus (DM), and obesity. FIELD STRENGTH/SEQUENCE: (Shortened) modified Look-Locker inversion-recovery MR sequence at 1.5 or 3T. ASSESSMENT: PubMed and Embase were searched following the PRISMA guidelines. STATISTICAL TESTS: The summary of standard mean difference (SMD) between the diseased and a healthy control populations was generated using a random-effects model in combination with meta-regression analysis. RESULTS: The SMD for HCM, DCM, and MC patients were significantly increased (1.41, 1.48, and 1.96, respectively, P < 0.01) compared with healthy controls. The SMD for HT patients with and without left-ventricle hypertrophy (LVH) together was significantly increased (0.19, P = 0.04), while for HT patients without LVH the SMD was zero (0.03, P = 0.52). The number of studies on amyloidosis, iron overload, Fabry disease, and HT patients with LVH did not meet the requirement to perform a meta analysis. However, most studies reported a significantly increased T1 for amyloidosis and HT patients with LVH and a significant decreased T1 for iron overload and Fabry disease patients. DATA CONCLUSIONS: Native T1 mapping by using an (Sh)MOLLI sequence can potentially assess myocardial changes in HCM, DCM, MC, iron overload, amyloidosis, and Fabry disease compared to controls. In addition, it can help to diagnose left-ventricular remodeling in HT patients. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:891-912. PMID- 29131447 TI - Effect of Various Treatment Modalities on Surface Characteristics and Shear Bond Strengths of Polyetheretherketone-Based Core Materials. AB - PURPOSE: To investigate the effect of different surface treatments on the surface roughness (Ra), wettability, and shear bond strength of polyetheretherketone (PEEK) to composite resin. MATERIALS AND METHODS: One hundred ninety eight PEEK specimens were divided into six groups (n = 33). Specimen surfaces were treated with the following surface treatment modalities: silicoating (CoJet), acetone treatment, acid etching (H2 SO4 ), airborne particle abrasion (Al2 O3 ), laser irradiation (Yb:PL laser), and the nontreated surface serving as the control. Surface roughness was measured with an profilometer (n = 11) and a goniometer was used to measure the surface wettability through contact angle (theta)(n = 11). PEEK surfaces were veneered with a composite resin (n = 11). The specimens were then thermocycled for 10,000 cycles at 5 to 55 degrees C. Shear bond strengths between the PEEK and composite resin were measured with an universal test machine. One-way ANOVA was used to analyze the data. Tukey's post-hoc test was used to determine significant differences between groups (alpha = 0.05). RESULTS: Surface roughness and wettability of PEEK surfaces along with shear bond strength of PEEK to composite resin were influenced by the surface treatments. (p < 0.01) Highest mean Ra values were obtained for PEEK surfaces treated by laser irradiation (2.85 +/- 0.2 um) followed by airborne particle abrasion (2.26 +/- 0.33 um), whereas other surface treatment modalities provided similar Ra values, with the acid-etched PEEK surfaces having the lowest mean Ra values (0.35 +/- 0.14 um). Silicoating provided the most wettable PEEK surfaces (48.04 +/- 6.28o), followed by either acetone treatment (70.19 +/- 4.49o) or acid treatment (76.07 +/- 6.61o). Decreased wettability was observed for airborne particle abraded (84.83 +/- 4.56o) and laser-treated PEEK surfaces (103.06 +/- 4.88o). The highest mean shear bond strength values were observed for acid-etched PEEK surfaces (15.82 +/- 4.23 MPa) followed by laser irradiated (11.46 +/- 1.97 MPa), airborne particle abraded (10.81 +/- 3.06 MPa), and silicoated PEEK surfaces (8.07 +/- 2.54 MPa). Acetone-treated (5.98 +/- 1.54 MPa) and untreated PEEK surfaces (5.09 +/- 2.14 MPa) provided the lowest mean shear bond strengths. CONCLUSIONS: The highest mean shear bond strengths were observed for acid-etched PEEK surfaces, followed by laser-irradiated, airborne particle abraded, and silicoated PEEK surfaces providing similar mean shear bond strengths. Since shear bond strengths higher than 10 MPa are considered acceptable, acid etching, laser irradiation, and airborne particle abrasion of PEEK surfaces may be considered viable surface treatment modalities for the PEEK material tested. PMID- 29131448 TI - Saccharomyces cerevisiae * Saccharomyces uvarum hybrids generated under different conditions share similar winemaking features. AB - Interspecific hybrids among species in the Saccharomyces genus are frequently detected in anthropic habitats and can also be obtained easily in the laboratory. This occurs because the most important genetic barriers among Saccharomyces species are post-zygotic. Depending on several factors, including the involved strains, the hybridization mechanism and stabilization conditions, hybrids that bear differential genomic constitutions, and hence phenotypic variability, can be obtained. In the present study, Saccharomyces cerevisiae * Saccharomyces uvarum hybrids were constructed using genetically and physiologically different S. uvarum parents at distinct temperatures (13 and 20 degrees C). The effect of those variables on the main oenological features of the wines obtained with these hybrids was evaluated. Hybrids were successfully obtained in all cases. However, genetic stabilization based on successive fermentations in white wine at 13 degrees C was significantly longer than that at 20 degrees C. Our results demonstrated that, irrespective of the S. uvarum parent and temperature used for hybrid generation and stabilization, similar physicochemical and aromatic features were found in wines. The hybrids generated herein were characterized by low ethanol production, high glycerol synthesis and the capacity to grow at low temperature and to produce malic acid with particular aroma profiles. These features make these hybrids useful for the new winemaking industry within the climate change era frame. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29131449 TI - Mechanical power sheath mediated recanalization and lead implantation in patients with venous occlusion: Technique and results. AB - INTRODUCTION: Chronic venous occlusion hampers lead revisions and upgrades in patients with a cardiac implantable electronic devices (CIEDs). This can make cardiothoracic surgery, venoplasty, or contra-lateral implantation of leads with tunneling necessary. A technique using venous recanalization may be a preferred alternative. We assessed the efficacy and safety of this new technique. METHODS AND RESULTS: From 2009 to 2016, all consecutive patients planned for lead revision or upgrade with known chronic venous occlusion were studied. All patients underwent extraction of an existing malfunctional or functional CIED lead with the Cook Evolution mechanical power sheath. By using the lumen of the sheath, endovascular access to the heart was obtained for new leads. Forty-two patients (107 leads, 2.6 +/- 1.1) were included. The indication for this procedure was replacement of malfunctional leads (n = 35, 83%) or device upgrade (n = 7, 17%). In total, 77 leads were extracted (30 leads stayed in situ) with a mean age at time of extraction of 8.4 years. Because of damage to bystander leads during extraction, two additional leads (one RA lead, one LV lead) were extracted. Clinical success was achieved in 41 patients (97%) and complete success in 39 patients (93%). There were two minor complications (two pocket hematomas, managed conservatively) and one major complication (tamponade, needing thoracotomy). Mean procedure time was 3.0 hours (median, 2.0; range, 1:28-5:35 hours) with a mean fluoroscopy time of 14.9 +/- 12.5 minutes. CONCLUSIONS: The technique of Evolution-mediated recanalization in case of lead revisions or upgrades is feasible with an acceptable safety profile and high efficacy. PMID- 29131450 TI - Potential for health care cost savings with preoperative gastrostomy tube placement in the head and neck cancer population. AB - BACKGROUND: The purpose of this study was to examine the cost differences between preoperative and postoperative placement of gastrostomy tubes (G-tubes) in patients with head and neck cancer. METHODS: We conducted a retrospective chart review of patients with aerodigestive tract cancers from 2010 to 2015. Data included inpatient and postdischarge costs, demographics, tumor characteristics, surgical treatment, length of stay (LOS), time spent in the intensive care unit (ICU), and readmissions. RESULTS: Five hundred ninety patients were included in this study. There was a $7624 inpatient cost savings (P = .002) for those G-tubes placed preoperatively ($26 060) versus postoperatively ($33 754). Postdischarge costs did not differ significantly between groups (P = .60). There was a $9248 total costs savings (P = .009) for those patients with G-tubes placed preoperatively ($39 751) versus postoperatively ($48 999), despite patients with preoperative G-tubes having lower body mass index (BMI; P = .009), higher Association of Anesthesiologist (ASA) class (P = .02), more preoperative radiation (P < .001), and more free tissue transfer reconstruction (P = .007). CONCLUSION: There is potential for savings by placing G-tubes preoperatively, possibly driven by decreased LOS, despite data suggesting that patients with G tubes placed preoperatively are higher risk. PMID- 29131451 TI - What we do and do not know about women and kidney diseases - questions unanswered and answers unquestioned: Reflection on World Kidney Day and International Woman's Day. AB - Chronic kidney disease affects approximately 10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health and specifically their kidney health, on the community, and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for child bearing, and on the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29131454 TI - Emerging roles of MicroRNAs in osteonecrosis of the femoral head. AB - Osteonecrosis of the femoral head (ONFH) is one of the most common orthopaedic diseases. The exact pathogenic mechanism of ONFH is still unknown. MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively modulate gene expression at post-transcriptional level. An increasing number of studies have shown that miRNAs play crucial roles in different physiological processes, including development, cell proliferation, differentiation and metabolism. Recently, multiple studies demonstrated that miRNAs are involved in the pathogenesis of ONFH. In this review, we summarize dysregulated miRNAs and their functions in ONFH. Furthermore, we discuss their potential clinical applications for diagnosis and treatment of ONFH. PMID- 29131453 TI - Mechanistic Insights on Human Phosphoglucomutase Revealed by Transition Path Sampling and Molecular Dynamics Calculations. AB - Human alpha-phosphoglucomutase 1 (alpha-PGM) catalyzes the isomerization of glucose-1-phosphate into glucose-6-phosphate (G6P) through two sequential phosphoryl transfer steps with a glucose-1,6-bisphosphate (G16P) intermediate. Given that the release of G6P in the gluconeogenesis raises the glucose output levels, alpha-PGM represents a tempting pharmacological target for type 2 diabetes. Here, we provide the first theoretical study of the catalytic mechanism of human alpha-PGM. We performed transition-path sampling simulations to unveil the atomic details of the two catalytic chemical steps, which could be key for developing transition state (TS) analogue molecules with inhibitory properties. Our calculations revealed that both steps proceed through a concerted SN 2-like mechanism, with a loose metaphosphate-like TS. Even though experimental data suggests that the two steps are identical, we observed noticeable differences: 1) the transition state ensemble has a well-defined TS region and a late TS for the second step, and 2) larger coordinated protein motions are required to reach the TS of the second step. We have identified key residues (Arg23, Ser117, His118, Lys389), and the Mg2+ ion that contribute in different ways to the reaction coordinate. Accelerated molecular dynamics simulations suggest that the G16P intermediate may reorient without leaving the enzymatic binding pocket, through significant conformational rearrangements of the G16P and of specific loop regions of the human alpha-PGM. PMID- 29131455 TI - Effects of supplementary amino acids on available energy of soybean meal determined by difference and regression methods fed to growing pigs. AB - This study was conducted to evaluate effects of inclusion level and supplementary amino acids (AAs) on digestible energy (DE) and metabolizable energy (ME) values of soybean meal (SBM) fed to growing pigs, determined by difference and regression methods. Sixty pigs were fed 10 diets according to a 5 * 2 factorial arrangement. Two control diets contained 97.34% corn without supplementary AAs or 95.61% corn with supplementary AAs. Eight diets were formulated by replacing corn and AAs in control diets with 8%, 15%, 25% and 31% SBM. There was no difference in DE and ME values of SBM determined by difference method as inclusion level of SBM increased or crystalline AAs were added. No difference was observed in DE and ME values of SBM determined by the two methods in diets without supplementary AAs, but the values determined by the difference method were greater (P < 0.05) than those determined by regression method when crystalline AAs were added in diets. In conclusion, inclusion level and supplementary AAs did not affect DE and ME values of SBM calculated by difference or regression methods. There were differences in DE and ME values of SBM determined by the difference method and the regression method when crystalline AAs were added in diets. PMID- 29131456 TI - Performance and hemtochemical parameters of buck-kids fed concentrate partially replaced with tropical Piliostigma thonningii foliage. AB - Fifteen 5-month-old Red Sokoto buck-kids, (6.6 +/- 0.71 kg body weight (BW)) randomly distributed into three groups of five animals per group, were used to study the effects of supplementary concentrate partially replaced with Piliostigma thonningii (PT) foliage on the growth performance, economic benefit and blood profile in a completely randomized design using analysis of variance. The goats in group 1 received 100% supplementary concentrates (PT0), groups 2 and 3 received 25% (PT25) and 50% (PT50), respectively, of concentrate replaced with an equal amount (dry matter basis) of Piliostigma foliage. The goats were fed a basal diet of threshed sorghum top (TST). Intake of concentrate, hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, total feeding cost and cost/kg BW were greater (P < 0.05) for PT0 than for PT25 and PT50. Consumption of P. thonningii foliage was greater (P < 0.05) for PT50 relative to PT25. Tannin consumption of the treatment diets were greater (P < 0.05) than that of the control concentrate diet. Serum urea N reduced (P < 0.05) with increasing level of concentrate replacement, while serum glucose was higher (P < 0.05) in PT0 than in PT50. However, means of all blood measurements were within normal ranges for goats. Net benefit showed this rank order: PT0 < PT50 < PT25 (all P < 0.05). Both differential and relative benefits were higher (P < 0.05) for PT25 than for PT50. P. thonningii foliage can replace 50% of supplemental concentrate without impairing feed intake, growth performance and health of buck-kids. PMID- 29131457 TI - Neurodevelopmental outcome of HIV-exposed but uninfected infants in the Mother and Infants Health Study, Cape Town, South Africa. AB - OBJECTIVES: To compare neurodevelopmental outcomes of HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) infants in a peri-urban South African population. HEU infants living in Africa face unique biological and environmental risks, but uncertainty remains regarding their neurodevelopmental outcome. This is partly due to lack of well-matched HUU comparison groups needed to adjust for confounding factors. METHODS: This was a prospective cohort study of infants enrolled at birth from a low-risk midwife obstetric facility. At 12 months of age, HEU and HUU infant growth and neurodevelopmental outcomes were compared. Growth was evaluated as WHO weight-for-age, length-for-age, weight-for-length and head-circumference-for-age Z-scores. Neurodevelopmental outcomes were evaluated using the Bayley scales of Infant Development III (BSID) and Alarm Distress Baby Scale (ADBB). RESULTS: Fifty-eight HEU and 38 HUU infants were evaluated at 11-14 months of age. Performance on the BSID did not differ in any of the domains between HEU and HUU infants. The cognitive, language and motor scores were within the average range (US standardised norms). Seven (12%) HEU and 1 (2.6%) HUU infant showed social withdrawal on the ADBB (P = 0.10), while 15 (26%) HEU and 4 (11%) HUU infants showed decreased vocalisation (P = 0.06). There were no growth differences. Three HEU and one HUU infant had minor neurological signs, while eight HEU and two HUU infants had macrocephaly. CONCLUSIONS: Although findings on the early neurodevelopmental outcome of HEU infants are reassuring, minor differences in vocalisation and on neurological examination indicate a need for reassessment at a later age. PMID- 29131458 TI - Image analysis is an excellent tool for quantifying Ki-67 to predict the prognosis of gastrointestinal stromal tumor patients. AB - We investigated the quantification of Ki-67 staining using digital image analysis (IA) as a complementary prognostic factor to the modified National Institutes of Health (NIH) classification in patients with gastrointestinal stromal tumor (GIST). We examined 92 patients, focusing on the correlation between age, sex, primary tumor site, tumor size, predominant histologic type, mitotic index, modified NIH classification (low/intermediate vs high), Ki-67 quantitation, and recurrence-free survival (RFS). We compared two IA processes for whole slide imaging (WSI) and manually captured image (MCI) methods. A Ki-67 quantitation cutoff was determined by receiver operator characteristics curve analysis. In the survival analysis, the high-risk group of a modified NIH classification, a mitotic count >5 per 20 high-powered fields, and Ki-67 cutoffs of >=6% and >=8% obtained by IA of the WSI and MCI methods, respectively, had an adverse impact on RFS. On multivariate analysis, each Ki-67 quantitation method strongly predicted prognosis, more strongly than the modified NIH classification. In addition, Ki-67 quantitation using IA of the MCI method could stratify low or intermediate risk and high risk GIST patients. Thus, IA is an excellent tool for quantifying Ki-67 to predict the prognosis of GIST patients, and this semiautomated approach may be preferable for patient care. PMID- 29131459 TI - Differential contribution of interleukin-10 promoter variants in malaria and schistosomiasis mono- and co-infections among Nigerian children. AB - OBJECTIVE: Interleukin-10 (IL-10) is an anti-inflammatory cytokine produced by Th1 cells and macrophages. The rationale of this study was to examine and validate possible contributions of IL-10 promoter polymorphisms in sub-Saharan Africa in children infected with either Plasmodium falciparum or Schistosoma haematobium and in children co-infected with both parasites. MATERIALS AND METHODS: A total of 309 Nigerian children aged 4-15 years were recruited. The study group consisted of individuals infected either with P. falciparum (n = 76) or S. haematobium (n = 94) in mono-infections, a group of children co-infected with both P. falciparum and S. haematobium (n = 62) and matched healthy controls (n = 77). The IL-10 promoter polymorphisms -1082G/A, -819C/T and -592C/A were genotyped by direct sequencing. RESULTS: The frequencies of the IL-10 -1082GG genotype, the -1082G allele and haplotype GCC (positions -1082, -819 and -592) were higher in children infected with P. falciparum than in healthy controls, indicating that the -1082GG genotype and the -1082G allele and the GCC haplotype are associated with increased susceptibility to malaria infection (OR = 3.4, 95% CI = 1.2-10.8, P = 0.02; OR = 2.5, 95% CI = 1.1-3.4, P = 0.02; OR = 3.8, 95% CI = 2.0-7.2, P = 0.0001, respectively). Children with the -1082GG genotype had a higher parasitaemia than children with the -1082AA or -1082AG genotypes (P = 0.0017). Haplotype GCC occurred more frequently in children infected with S. haematobium, while haplotype GTA was less frequent than in controls (OR = 2.2, 95% CI = 1.2-4.4, P = 0.017 and OR = 0.1, 95% CI = 0.02-0.5, P = 0.0004, respectively). No differences in the frequencies of IL-10 promoter polymorphisms were observed between children with P. falciparum-S. haematobium co-infections and healthy controls. CONCLUSION: Although IL-10 promoter polymorphisms are not associated with P. falciparum and S. haematobium co-infection, variant -1082G/A and haplotype GCC are associated with malaria, whereas the IL-10 haplotypes GCC and GTA are associated with schistosomiasis. PMID- 29131460 TI - Pilot study on the effectiveness and students' attitude towards undergraduate training provided by industry. AB - INTRODUCTION: Rapid developments in CAD/CAM technology necessitate the adaptation of curriculum content. Limited resources hinder institutions in holding state of the art equipment available for student training. MATERIALS AND METHODS: A workshop given by an industry partner was organised as part of the final pre clinical course in prosthodontics for the academic years 2015 and 2016. The workshop on dental ceramics and CAD/CAM technology comprised of lectures and practical demonstrations. Multiple-choice examinations prior to and after the workshop as well as questionnaires were used for assessing effectiveness and students' perception. The test scores and evaluation results were compared using Fisher's exact test of homogeneity (alpha = 0.05). RESULTS: The workshop improved students' performance in the written examination. With the exception of 1 question, students having attended the workshop performed significantly better (P < .05). The majority of students felt that the workshop fostered their knowledge in the field of dental ceramics and CAD/CAM. Whilst only a small portion (<10%) disapproved industry-supported education, up to 45% of the participants considered the workshop as sales promotion. The students were undecided on whether or not competitor companies should be invited to present on the same topic and whether or not more industry-supported courses would be beneficial. DISCUSSION: Industry-supported education appears to be a necessity in the field of CAD/CAM dentistry, but care has to be taken to select adequate partners, and the content of courses has to be controlled. PMID- 29131461 TI - Somatosensory profile of patients with haemophilia. AB - INTRODUCTION: Patients with haemophilia (PwH) suffer from an enhanced pain sensitivity due to repetitive joint bleedings. A comprehensive, quantitative examination of the somatosensory system has not been performed in this population to date. MATERIAL AND METHODS: Thirty patients with moderate or severe haemophilia A or B and 30 healthy controls were examined by means of Quantitative Sensory Testing to assess the function of the somatosensory system. Detection (DT) and pain thresholds (PT) were determined, amounting to a total of 13 parameters. Both knee joints and the hand as reference were examined in order to assess both joint-specific as well as general changes in the somatosensory profile. RESULTS: Analysing DT and PT, a significant main effect was found for group * stimulus interaction (P <= .001). Post hoc tests revealed significant differences in DT between PwH and controls for thermal stimuli across both knees (cold DT: P < .001; warm DT: P < .01) and the hand (cold DT: P < .01; warm DT: P < .05). Mechanical DT was increased in PwH at both knee joints (left knee: P <= .05; right knee: P <= .01). Furthermore, pressure PT was decreased in PwH at both knees (P <= .001). CONCLUSION: Haemophilic arthropathy leads to alterations of the somatosensory profile in PwH. Our results reveal initial evidence of a combination of peripheral sensitization, indicated by decreased pressure PT and mechanical DT at the knee joints, as well as general changes of the somatosensory system, shown by reduced thermal DT at affected sites and remote from these. Therefore, both mechanisms have to be considered regarding the pain management in PwH. PMID- 29131462 TI - Outcomes of liver transplantation in pediatric recipients with cardiovascular disease. AB - LT exerts considerable stress on the heart perioperatively. Limited data exist on impact of cardiovascular diseases on LT children. This study evaluated the outcomes of children with CVD who underwent LT and compared with pretransplant findings. From 518 LT recipients, 82 (15.8%) had CVD. Sixty patients were classified as low-risk adjustment for congenital heart surgery 1 (RACHS 1 and 2). Five patients were classified as RACHS >=3. The most common echocardiographic finding in the CVD patients (25/82) was ASD. CVD patients had more abnormal EKG (32.4% vs 14.5%, P < .001), abnormal chest X-ray (11.8% vs 1.4%, P < .001), and altered echocardiography (89.7% vs 15.4%, P < .001) findings compared with the No CVD group pretransplant. Post-transplant, significant differences between groups were observed related to abnormal EKG (14.7% vs 7.0%, P = .03) and echocardiography (48.5% vs 3.2%, P < .01) findings. Pretransplant ASD spontaneously closed in 22 patients. At 1 and 5 years post-transplant, there was no difference in the survival rate between groups (P = .96). The prevalence of CVD in recipients of LT was high, and its presence was associated with significantly higher cardiac decompensation before and after LT. Minor and moderate cardiovascular disease did not impact the long-term survival. PMID- 29131463 TI - Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9, editorial commentary. PMID- 29131465 TI - Psychometric analysis of subjective sedation scales used for critically ill paediatric patients. AB - AIMS: This study evaluated the psychometric properties of subjective sedation scales using one psychometric scoring system to identify the appropriate scale that is most suitable for clinical care practice. BACKGROUND: A number of published sedation assessment scales for paediatric patients are currently used to attempt to achieve a moderate depth of sedation to avoid the undesirable effects caused by over- or undersedation. However, there has been no systematic review of these scales. SEARCH STRATEGY: We searched the Cochrane Library, PubMed, EMBASE, the Cumulative Index to Nursing and Allied Health Literature, etc., to obtain relevant articles. The quality of the selected studies was evaluated according to the Consensus-based Standards for the Selection of Health Measurement Instruments checklist. INCLUSION CRITERIA: Articles that had been published or were in press and discussed the psychometric properties of sedation scales were included. The population comprised critically ill infants and non verbal children ranging in age from 0 to 18 years who underwent sedation in an intensive care unit. FINDINGS: Data were independently extracted by two investigators using a standard data extraction checklist: 43 articles were included in this review, and 13 sedation scales were examined. The quality of the psychometric evidence for the Comfort Scale and Comfort Behaviour Scale was 'very good', with the Comfort Scale having a higher quality (total weighted scores, Comfort Scale = 17.3 and Comfort Behaviour Scale = 15.5). CONCLUSIONS: We suggest that the scales be systematically and comprehensively tested in terms of development method, reliability, validation, feasibility and correlation with clinical outcome. The Comfort Scale and Comfort Behaviour Scale are useful tools for measuring sedation in paediatric patients. RELEVANCE TO CLINICAL PRACTICE: Nursing staff should choose one subjective sedation scale that is suitable for assessing paediatric patients' depth of sedation. We recommend the Comfort Scale and Comfort Behaviour Scale as optimal choices if the clinical environment permits. PMID- 29131464 TI - Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice. AB - Microglial activation is a key element in initiating and perpetuating inflammatory responses to stroke. Interferon regulatory factor 5 (IRF5) and IRF4 signaling have been found critical in mediating macrophage pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, respectively, in peripheral inflammation. We hypothesize that the IRF5/4 regulatory axis also mediates microglial activation after stroke. C57BL6 mice of 8-12 weeks were subject to a 90-min middle cerebral artery occlusion, and the brains evaluated at 24 h, 3, 10 and 30 days after reperfusion. Flow cytometry was utilized to examine microglial activation and cytokine expression. RT-PCR was performed for mRNA levels of IRF5/4 in sorted microglia. Microglial expression of IRF5/4 was examined by immunohistochemistry, and brain cytokine levels were determined by ELISA. Our results revealed that the IRF5 mRNA level in sorted microglia increased at 3 days of stroke; whereas IRF4 mRNA level exhibited biphasic increases, with a transient rise at 24 h and a peak at 10 days. The same pattern was seen in IRF5/4 protein colocalization with Iba-1+ cells by IHC. Intracellular levels of TNF-alpha and IL 1beta in microglia peaked at 3 days of stroke, and IL-4+ IL-10+ double-positive microglia significantly increased at day 10. Brain levels of these cytokines were consistent with microglial cytokine changes. Worse behavior test results were seen at 3 days vs. 10 days of stroke. We conclude that microglia phenotypes are dynamic to ischemic stroke, and IRF5/4 signaling may regulate microglial M1/M2 activation and impact on stroke outcomes. PMID- 29131466 TI - Understanding the Reactive Adsorption of H2 S and CO2 in Sodium-Exchanged Zeolites. AB - Purifying sour natural gas streams containing hydrogen sulfide and carbon dioxide has been a long-standing environmental and economic challenge. In the presence of cation-exchanged zeolites, these two acid gases can react to form carbonyl sulfide and water (H2 S+CO2 ?H2 O+COS), but this reaction is rarely accounted for. In this work, we carry out reactive first-principles Monte Carlo (RxFPMC) simulations for mixtures of H2 S and CO2 in all-silica and Na-exchanged forms of zeolite beta to understand the governing principles driving the enhanced conversion. The RxFPMC simulations show that the presence of Na+ cations can change the equilibrium constant by several orders of magnitude compared to the gas phase or in all-silica beta. The shift in the reaction equilibrium is caused by very strong interactions of H2 O with Na+ that reduce the reaction enthalpy by about 20 kJ mol-1 . The simulations also demonstrate that the siting of Al atoms in the framework plays an important role. The RxFPMC method presented here is applicable to any chemical conversion in any confined environment, where strong interactions of guest molecules with the host framework and high activation energies limit the use of other computational approaches to study reaction equilibria. PMID- 29131468 TI - Oxidative Dissolution of Resoles: A Versatile Approach to Intricate Nanostructures. AB - Resoles are resins obtained by base-catalyzed phenol-formaldehyde condensation with a three-dimensional cross-linked framework. They are considered as highly chemical-resistant, and calcination is thus generally used in the treatment of resole-type resins, which significantly limits the diversity of nanostructured materials that can be derived from resole-type resins. Herein, we report that selected metal nitrate solutions can be used to dissolve various types of nanostructured resoles through an oxidative dissolution process. This strategy not only enables the controlled dissolution of resoles, but more importantly provides a new approach to selectively etch resole-based nanocomposites to give rise to a variety of nanostructured materials with unprecedented architectures and great potential in bioapplications. PMID- 29131467 TI - Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report. AB - Central mucoepidermoid carcinoma (MEC) poses a diagnostic challenge because of its rarity and histological overlap with glandular odontogenic cyst (GOC). In MEC of both salivary glands and jaws, MAML2 arrangement has been well known as the specific gene alteration. We report a case of central MEC arising from GOC diagnosed by MAML2 fusion gene. A 57-year-old male presented a multilocular cystic lesion in left molar region of the mandible. Histopathologically, multiple cysts lined by thin cuboidal or non-keratinized squamous epithelium with small duct-like structures, mucous cells and ciliated cells were present. It was diagnosed as GOC. The recurrent lesion after nine years showed the proliferation of many cystic and solid nests composed of epidermoid, mucous and intermediated cells. Nested PCR revealed CRTC3-MAML2 fusion gene in the recurrent lesion, but not in the primary one. Similarly, MAML-2 rearrangement by FISH analysis was positive in the recurrent lesion, while negative for the primary one, thus confirming the diagnosis of central MEC arising from GOC. Analysis of MAML2 rearrangement can be used as a supportive evidence to distinguish central MEC from GOC. PMID- 29131469 TI - Do programs for Aboriginal and Torres Strait Islander people leaving prison meet their health and social support needs? AB - The objective of this review was to synthesise evidence on the health and social support needs of Aboriginal and Torres Strait Islander people leaving prison and on programs which aid successful community re-entry. A systematic literature review was undertaken of peer-reviewed and grey literature published between 2001 and 2013, focusing on the post-release needs of Aboriginal and Torres Strait Islander adults and pre- and post-release programs. Aboriginal and Torres Strait Islander people have high health and social support needs on leaving prison. There is little literature evidence that re-entry programs commonly consider health needs, support linkages with primary care or Aboriginal Medical Services, or are designed in consideration of the particular needs of Aboriginal and Torres Strait Islander people. In the absence of evaluative evidence on re-entry programs in this group, we have synthesised the best practice recommendations. Re entry programs must be culturally competent in design and delivery, holistic, take a long-term view, involve families and communities, demonstrate interagency coordination and promote linkages between prison and community-based services. There is an urgent need for accessible pre- and post-release programs which meet the particular needs of Aboriginal and Torres Strait Islander people, including their health needs. Programs must be flexible, comprehensive and accessible to those on remand or with short sentences. Stronger linkage with primary care and Aboriginal and Torres Strait Islander community controlled health organisations is recommended. PMID- 29131470 TI - Synthesis of some novel pyridine compounds containing bis-1,2,4 triazole/thiosemicarbazide moiety and investigation of their antioxidant properties, carbonic anhydrase, and acetylcholinesterase enzymes inhibition profiles. AB - Some novel derivatives of thiosemicarbazide and 1,2,4-triazole-3-thiol were synthesized and evaluated for their biological activities. The title compounds were prepared starting from readily available pyridine-2,5-dicarboxylic acid. The reaction carboxylic acid with absolute ethanol afforded the corresponding dimethyl pyridine-2,5-dicarboxylate (1). The reaction of dimethyl-2,5 pyridinedicarboxylate (1) with hydrazine hydrate good yielded pyridine-2,5 dicarbohydrazide (2). Refluxing compound 2 with alkyl/aryl isothiocyanate derivatives for 3-8 h afforded 1,4-disubstituted thiosemicarbazides (3a-e). Base catalyzed intra-molecular dehydrative cyclization of these intermediates furnished the 4,5-disubstituted bis-mercaptotriazoles (4a-e) in good yield (85% 95%). Among the target compounds, 2,2'-(pyridine-2,5-diyldicarbonyl)bis[N-(p methoxyphenyl)hydrazinecarbothioamide] (3c) showed very high activity with value of 72.93% against 1,1-diphenyl-2-picrylhydrazyl free radical at the concentration of 25 MUg/mL. The inhibitory effects of the target compounds against acetylcholinesterase (AChE), hCA I, and II were studied. AChE, cytosolic hCA I and II isoforms were potently inhibited by synthesized these derivatives with Ki s in the range of 3.07 +/- 0.76-87.26 +/- 29.25 nM against AChE, in the range of 1.47 +/- 0.37-10.06 +/- 2.96 nM against hCA I, and in the range of 3.55 +/- 0.57 7.66 +/- 2.06 nM against hCA II, respectively. PMID- 29131472 TI - Total Syntheses of the Monoterpenoid Indole Alkaloids (+/-)-Alstoscholarisine B and C. AB - Total syntheses of the monoterpenoid indole alkaloids (+/-)-alstoscholarisine B and C were accomplished starting from a readily available indole-2-acetic ester and an alpha,beta-unsaturated N-sulfonyllactam. PMID- 29131471 TI - The toxicological effects of some avermectins on goat liver carbonic anhydrase enzyme. AB - Avermectins are used worldwide as antiparasitic drugs in the field of veterinary medicine and as agricultural pesticides and insecticides. Carbonic anhydrase (CA, E.C. 4.2.1.1) is a zinc-containing metalloenzyme that catalyzes the reversible hydration of carbon dioxide (CO2 ) to yield protons (H+ ) and bicarbonate (HCO3- ). In this study, some avermectins, including abamectin, doramectin, eprinomectin, and moxidectin, were investigated for in vitro inhibitory effects on the CA enzyme purified from goat liver, which was purified (125.00-fold) using sepharose 4B-l-tyrosine-sulfanilamide affinity chromatography, with a yield of 68.27% and a specific activity of 21765.31 EU/mg proteins. The inhibition results obtained from this study showed Ki values of 0.283, 0.153, 0.232, and 0.317 nM for abamectin, doramectin, eprinomectin, and moxidectin, respectively. On the other hand, acetazolamide, well-known clinically established CA inhibitor, possessed a Ki value of 0.707 nM against goat liver CA. PMID- 29131473 TI - Production of Hydroxynitrile Lyase from Davallia tyermannii (DtHNL) in Komagataella phaffii and Its Immobilization as a CLEA to Generate a Robust Biocatalyst. AB - Hydroxynitrile lyase from the white rabbit's foot fern Davallia tyermannii (DtHNL) catalyzes the enantioselective synthesis of alpha-cyanohydrins, which are key building blocks for pharmaceutical and agrochemical industries. An efficient and competitive process necessitates the availability and robustness of the biocatalyst. Herein, the recombinant production of DtHNL1 in Komagataella phaffii, yielding approximately 900 000 U L-1 , is described. DtHNL1 constitutes approximately 80 % of the total protein content. The crude enzyme was immobilized. Crosslinked enzyme aggregates (CLEAs) resulted in significant enhancement of the biocatalyst stability under acidic conditions (activity retained after 168 h at pH 2.4). The DtHNL1-CLEA was employed for (R) mandelonitrile synthesis (99 % conversion, 98 % enantiomeric excess) in a biphasic system, and evaluated for the synthesis of (R)-hydroxypivaldehyde cyanohydrin under reaction conditions that immediately inactivated non immobilized DtHNL1. The results show the DtHNL1-CLEA to be a stable biocatalyst for the synthesis of enantiomerically pure cyanohydrins under acidic conditions. PMID- 29131474 TI - Photodynamic therapy with double duration for circumscribed choroidal haemangioma: functional and anatomical results based on initial parameters. AB - IMPORTANCE: Pre-treatment symptoms longer than 12 months and foveal cystoid changes are indicators for poor anatomical and functional outcome after photodynamic therapy (PDT). BACKGROUND: To evaluate the prognostic factors on the effectiveness of PDT with double duration for treatment of exudative circumscribed choroidal haemangioma. DESIGN: Retrospective study. PARTICIPANTS: Twenty-seven patients with symptomatic exudative circumscribed choroidal haemangioma treated with PDT. METHODS: Clinical charts of patients with exudative circumscribed choroidal haemangioma treated with PDT were analysed with regard to visual acuity, duration of symptoms, subfoveal fluid, foveal cystoid changes and foveal thickness in optical coherence tomography. MAIN OUTCOME MEASURES: Change of best-corrected visual acuity, sub- and intrafoveal fluid and foveal thickness measured with optical coherence tomography from baseline to last follow-up. RESULTS: Mean visual acuity improved by 0.05 from 0.42 logMAR (standard deviation [SD] 0.34) to 0.37 logMAR (SD 0.47). In 70% of the patients, PDT stopped exudation and revealed a dry fovea. The recurrence or persistence of sub- or intrafoveal fluid was significantly associated with pre-therapeutic symptoms existing for more than 12 months (P = 0.046). Mean foveal thickness in optical coherence tomography decreased from 324 MUm (SD 223 MUm) to 209 MUm (SD 109 MUm). CONCLUSIONS AND RELEVANCE: PDT proved to be a safe and effective treatment procedure for exudative circumscribed choroidal haemangioma in our series, with few side effects. We observed a more successful treatment with regard to anatomical and functional results in cases with pre-existing symptoms less than 12 months and in cases without pre-therapeutic foveal cystoid changes. PMID- 29131475 TI - General health and well-being among primary care patients aged 75+ years: Associations with living conditions, oral health and dependency. AB - OBJECTIVE: Our aim was to examine the associations between general health and well-being with living conditions, oral health and degree of dependency. METHODS: We surveyed people from a primary care service and collected data on sociodemographic characteristics, general health, health utility, well-being, activities, living conditions and oral health impact. RESULTS: Overall, 459 participated (78% response rate). Poor general health was associated with decreased instrumental activities of daily living scores (18% of those with poor general health were independent vs 60% with good general health). Greater oral health impact was also related to poor general health. Health utility was lower for some dependency, for renting and oral health impact. Well-being was also lower for some dependency, for renting, not speaking English and oral health impact. CONCLUSION: In addition to the well-known association of poor general health with dependency, our results also illustrate the potential importance of living conditions and oral health. PMID- 29131476 TI - Authors' reply re: Perinatal and maternal morbidity and mortality among term singletons following midcavity operative vaginal delivery versus caesarean delivery. PMID- 29131477 TI - A Risk Assessment Score and Initial High-sensitivity Troponin Combine to Identify Low Risk of Acute Myocardial Infarction in the Emergency Department. AB - OBJECTIVES: Early discharge of patients with presentations triggering assessment for possible acute coronary syndrome (ACS) is safe when clinical assessment indicates low risk, biomarkers are negative, and electrocardiograms (ECGs) are nonischemic. We hypothesized that the Emergency Department Assessment of Chest Pain Score (EDACS) combined with a single measurement of high-sensitivity cardiac troponin (hs-cTn) could allow early discharge of a clinically meaningful proportion of patients. METHODS: We pooled data from four patient cohorts from New Zealand and Australia presenting to an emergency department with symptoms suggestive of ACS. The primary outcome was major adverse cardiac events (MACE) within 30 days of presentation. In patients with a nonischemic ECG we evaluated the sensitivity for MACE and percentage low risk of every combination of high sensitivity cardiac troponin T (hs-cTnT) concentration and high-sensitivity cardiac troponin I (hs-cTnI) concentration with EDACS. We used a standard smoothing technique on the probability density function for hs-cTn and EDACS and applied bootstrapping to determine the optimal threshold combinations, namely, the combination that maximized the percentage low risk with >=98.5% sensitivity for MACE. RESULTS: From 2,536 patients, 2,258 presented without an ischemic ECG of whom 272 (12.1%) had a MACE within 30 days. The optimal threshold for hs-cTnI was 7 ng/L combined with an EDACS threshold of 16 (36.8% patients low risk). The optimal thresholds for hs-cTnT were 8 ng/L combined with an EDACS threshold of 15 (30.2% patients low risk). CONCLUSION: Single measurements of both hs-cTnI and hs cTnT at presentation combined with EDACS to identify over 30% of patients as low risk and therefore eligible for safe early discharge after only one blood draw. PMID- 29131478 TI - Gene isolation using degenerate primers targeting protein motif: A laboratory exercise. AB - Structures and functions of protein motifs are widely included in many biology based course syllabi. However, little emphasis is placed to link this knowledge to applications in biotechnology to enhance the learning experience. Here, the conserved motifs of nucleotide binding site-leucine rich repeats (NBS-LRR) proteins, successfully used for the isolation and characterization of many plant resistance gene analogues (RGAs), is featured in the development of a series of laboratory experiments using important molecular biology techniques. A set of previously isolated RGA sequences is used as the model for performing sequence alignment and visualising 3D protein structure using current bioinformatics programs (Clustal Omega and Argusdock software). A pair of established degenerate primer sequences is provided for the prediction of targeted amino acids sequences in the RGAs. Reverse transcription-polymerase chain reaction (RT-PCR) is used to amplify RGAs from total RNA samples extracted from the tropical wild relative of black pepper, Piper colubrinum (Piperaceae). This laboratory exercise enables students to correlate specific DNA sequences with respective amino acid codes and the interaction between conserved motifs of resistance genes with putatively targeted proteins. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):47-53, 2018. PMID- 29131480 TI - Corrigendum. PMID- 29131479 TI - Measuring the success of Medical Emergency Teams: potentially preventable deaths versus total cardiac arrest deaths. A single centre observational study. AB - BACKGROUND: Rapid response systems have been implemented with the aim of preventing patient deterioration, in-hospital cardiac arrests (IHCA) and related deaths. Not all 'unexpected deaths' are preventable, thus compromising the use of unexpected deaths as an outcome measure. AIMS: To assess temporal trends in potentially preventable deaths as a subset of total unexpected death rates over a 4-year period. METHODS: A single centre, cohort study of all unexpected deaths between 1 January 2010 and 31 December 2013. Unexpected deaths were identified from the rapid response systems database and patients' case histories were reviewed to reclassify the deaths into one of three categories: potentially preventable: if earlier MET activation may have prevented death; missed not for resuscitation opportunity; and not preventable. Total bed days were obtained from the hospital's patient administration system. RESULTS: The rate of potentially preventable deaths decreased from 5.3 to 0.7 per 100 000 bed days (incident rate ratio (IRR) 0.53 (95% CI 0.31-0.90), P = 0.02). The rate of total unexpected deaths was unchanged (IRR 0.96 (0.80-1.16), P = 0.70), as were the rates of non preventable deaths (IRR 1.06 (0.78-1.42), P = 0.72) and missed NFR deaths (IRR 1.1 (0.83-1.42), P = 0.56). CONCLUSION: The rate of potentially preventable deaths has decreased by 47% per year over a 4-year period without any change in the overall rate of unexpected deaths. Distinguishing between potentially preventable deaths in contrast to total unexpected deaths enables more targeted evaluation of rapid response systems. PMID- 29131482 TI - The case for publishing case reports. PMID- 29131481 TI - Role of capillary ketone testing in the diagnosis and monitoring of diabetic ketoacidosis. PMID- 29131483 TI - Fluorinated Vinylsilanes from the Copper-Catalyzed Defluorosilylation of Fluoroalkene Feedstocks. AB - Herein, a copper-catalyzed C-F bond defluorosilylation reaction of tetrafluoroethylene and other polyfluoroalkenes is described. Mechanistic studies, based on a series of stoichiometric reactions with copper complexes, revealed that the key steps of this defluorosilylation reaction are 1) the 1,2 addition of a silylcopper intermediate to the polyfluoroalkene and 2) a subsequent selective beta-fluorine elimination, which generates a Cu-F species. The beta-fluorine elimination is facilitated by Lewis acidic F-Bpin, which is generated in situ during the defluorosilylation. PMID- 29131484 TI - The major cellulases CBH-1 and CBH-2 of Neurospora crassa rely on distinct ER cargo adaptors for efficient ER-exit. AB - Filamentous fungi are native secretors of lignocellulolytic enzymes and are used as protein-producing factories in the industrial biotechnology sector. Despite the importance of these organisms in industry, relatively little is known about the filamentous fungal secretory pathway or how it might be manipulated for improved protein production. Here, we use Neurospora crassa as a model filamentous fungus to interrogate the requirements for trafficking of cellulase enzymes from the endoplasmic reticulum to the Golgi. We characterized the localization and interaction properties of the p24 and ERV-29 cargo adaptors, as well as their role in cellulase enzyme trafficking. We find that the two most abundantly secreted cellulases, CBH-1 and CBH-2, depend on distinct ER cargo adaptors for efficient exit from the ER. CBH-1 depends on the p24 proteins, whereas CBH-2 depends on the N. crassa homolog of yeast Erv29p. This study provides a first step in characterizing distinct trafficking pathways of lignocellulolytic enzymes in filamentous fungi. PMID- 29131485 TI - In Vitro Effects of Serotonin, Melatonin, and Other Related Indole Compounds on Amyloid-beta Kinetics and Neuroprotection. AB - SCOPE: Amyloid-beta peptide is the main component of senile plaques in Alzheimer's disease. The inhibition of amyloid-beta peptide assembly, the destabilization of amyloid-beta peptide aggregates, and the decrease of its cytotoxicity for the prevention of neuronal death are considered neuroprotective effects. In this work, the protective effects against amyloid-beta peptide aggregation and cytotoxicity of eight indolic compounds are evaluated: tryptophan, tryptamine, serotonin, tryptophol, N-acetylserotonin, 3-indoleacetic acid, tryptophan ethyl ester, and melatonin. METHODS AND RESULTS: Thioflavin T spectroscopic assay, transmission electron microscopy, western blotting, circular dichroism, NMR, cell viability (thiazolyl blue tetrazolium bromide assay), quantitative PCR, and heme oxygenase activity are used. Serotonin is the most effective compound for inhibiting amyloid-beta peptide aggregation. Almost all the indolic compounds tested prevent amyloid-beta peptide-induced and increase cell viability, being between 9 and 25%. Melatonin and serotonin are the most active. Moreover, serotonin increased the expression of SIRT-1 and 2, heat shock protein 70, and heme oxygenase activity, this being a possible mechanism underlying the observed neuroprotective effect. CONCLUSION: Melatonin and other related indolic compounds, mainly serotonin, show an inhibitory and destabilizing effect on amyloid-beta peptide fibril formation and they possess neuroprotective properties related to the vitagenes system. PMID- 29131486 TI - Free amino acids, biogenic amines, and ammonium profiling in tobacco from different geographical origins using microwave-assisted extraction followed by ultra high performance liquid chromatography. AB - This work describes a rapid, stable, and accurate method for determining the free amino acids, biogenic amines, and ammonium in tobacco. The target analytes were extracted with microwave-assisted extraction and then derivatized with diethyl ethoxymethylenemalonate, followed by ultra high performance liquid chromatography analysis. The experimental design used to optimize the microwave-assisted extraction conditions showed that the optimal extraction time was 10 min with a temperature of 60 degrees C. The stability of aminoenone derivatives was improved by keeping the pH near 9.0, and there was no obvious degradation during the 80 degrees C heating and room temperature storage. Under optimal conditions, this method showed good linearity (R2 > 0.999) and sensitivity (limits of detection 0.010-0.081 MUg/mL). The extraction recoveries were between 88.4 and 106.5%, while the repeatability and reproducibility ranged from 0.48 to 5.12% and from 1.56 to 6.52%, respectively. The newly developed method was employed to analyze the tobacco from different geographical origins. Principal component analysis showed that four geographical origins of tobacco could be clearly distinguished and that each had their characteristic components. The proposed method also showed great potential for further investigations on nitrogen metabolism in plants. PMID- 29131487 TI - Glaucoma patient follow-up time at Waikato Hospital, New Zealand. PMID- 29131488 TI - Dorsal Root Ganglion Stimulation Used for the Treatment of Chronic Neuropathic Pain in the Groin: A Single-Center Study With Long-Term Prospective Results in 34 Cases. AB - OBJECTIVE: Chronic neuropathic pain in the groin is a severe condition and difficult to treat. Dorsal root ganglion stimulation (DRGS) covers discrete painful areas precisely with its stimulation power in comparison to spinal cord stimulation (SCS). It was our hypothesis that DRGS provides a long-term relief of chronic groin pain over a period of more than three years. MATERIALS AND METHODS: Patients (age >18 years) with chronic neuropathic groin pain were prospectively examined. After a successful test-trial (duration of 3-10 days, pain decrease >50%) a permanent generator was implanted. The patients were re-examined after three months, then after one year, two, and three years. We used the Visual Analogue Scale (VAS), the Pain Disability Index (PDI), the Pain Catastrophizing Scale (PCS), the Brief Pain Inventory (BPI), and the Beck Depression Inventory (BDI) for the assessment. RESULTS: We included 34 consecutive patients (13 female, 21 male, mean age 50.4 years, range of age 24-84 years, 30/34 trial to permanent conversion) during the time period from 2012 until 2016. Thirty patients had a successful test-trial and a generator was subsequently implanted. Results after three years: the preoperative VAS dropped from Mdn = 8 to Mdn = 4.5 (p = 0.001). The PDI decreased from Mdn = 48 to Mdn = 23 (p = 0.004). The PCS changed from Mdn = 31 to Mdn = 16 (p = 0.006). The BPI dropped from Mdn = 76 to Mdn = 30 (p = 0.003). The BDI decreased from Mdn = 17 to Mdn = 7 (p = 0.010). Five patients showed complications (16.7%). CONCLUSION: In this study, DRGS proved an efficient long-term method for the treatment of chronic neuropathic groin pain and we strongly recommend its use. PMID- 29131490 TI - EU-40 Materials Prize: B V. Lotsch / Honorary Membership of the Polish Chemical Society: H.-U. Reissig / Welch Award: J. B. Goodenough. PMID- 29131489 TI - Evaluation of the serum zinc level in adult patients with melasma: Is there a relationship with serum zinc deficiency and melasma? AB - BACKGROUND: Melasma is a common acquired hypermelanosis of sun-exposed skin, particularly on the face, which presents as symmetric, light- to gray-brown colored macules and patches. There are several studies of serum zinc levels in cutaneous disorders. So far, no studies have been carried out to assess the serum zinc level in patients with melasma. The aim of this study is to determine the serum zinc level in patients with melasma compared to healthy subjects. MATERIALS AND METHODS: A total of 118 patients with melasma and 118 healthy controls were enrolled in this prospective cross-sectional study. The two groups were matched for age and sex. Atomic absorption spectrophotometry was used to measure serum zinc levels. The statistical analysis was performed using SPSS software. RESULTS: The mean serum level of zinc in melasma patients and controls was 77.4+/-23.2 MUg/dL and 82.2+/-23.9 MUg/dL, respectively (P-value=.0001). Serum zinc deficiency was found in 45.8% and 23.7% of melasma patients and control subjects, respectively. A positive family history of melasma in first-degree relatives was present in 46 (39%) of the cases, and a history of taking oral contraceptive pill was found in 95 (81%) of women with melasma. The aggravating factors for melasma were stated as: sun exposure (11.1%), pregnancy (15.3%), nutrition (2.5%), oral contraceptive pills (18.6%), and emotional stress (5.9%). The malar and centrofacial patterns were seen in 3.4% and 72% of cases, respectively, whereas 24.6% of the patients had both centrofacial distribution and malar distribution, and there was no patient with mandibular pattern. Among patients with melasma, 20.3% had thyroid dysfunction, while in the control subjects, 8.4% had thyroid dysfunction (P=.001). CONCLUSION: There is a significant relationship between low levels of zinc and melasma. Zinc deficiency may be involved in the pathogenesis of melasma. Also, treatment with oral zinc supplements can be tried in these patients to see the outcome. However, to make recommendations on screening for zinc deficiency in patients with melasma, future research of good methodological quality is needed. PMID- 29131491 TI - The polygonal model: A simple representation of biomolecules as a tool for teaching metabolism. AB - Metabolism involves numerous reactions and organic compounds that the student must master to understand adequately the processes involved. Part of biochemical learning should include some knowledge of the structure of biomolecules, although the acquisition of such knowledge can be time-consuming and may require significant effort from the student. In this report, we describe the "polygonal model" as a new means of graphically representing biomolecules. This model is based on the use of geometric figures such as open triangles, squares, and circles to represent hydroxyl, carbonyl, and carboxyl groups, respectively. The usefulness of the polygonal model was assessed by undergraduate students in a classroom activity that consisted of "transforming" molecules from Fischer models to polygonal models and vice and versa. The survey was applied to 135 undergraduate Biology and Nursing students. Students found the model easy to use and we noted that it allowed identification of students' misconceptions in basic concepts of organic chemistry, such as in stereochemistry and organic groups that could then be corrected. The students considered the polygonal model easier and faster for representing molecules than Fischer representations, without loss of information. These findings indicate that the polygonal model can facilitate the teaching of metabolism when the structures of biomolecules are discussed. Overall, the polygonal model promoted contact with chemical structures, e.g. through drawing activities, and encouraged student-student dialog, thereby facilitating biochemical learning. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):66-75, 2018. PMID- 29131492 TI - Hastening treatment development in bipolar disorder: Evaluation of consensus based recommendations for cognition trials. PMID- 29131493 TI - Gaming to improve vision: 21st century self-monitoring for patients with age related macular degeneration. AB - IMPORTANCE: Improved vision self-monitoring tools are required for people at risk of neovascular complications from age related macular degeneration (AMD). BACKGROUND: to report the self-monitoring habits of participants with intermediate AMD using the Amsler grid chart, and the use of personal electronic devices and gameplay in this over 50 year old cohort. DESIGN: single-centre descriptive study carried out at the Centre for Eye Research (CERA), Melbourne, Australia. PARTICIPANTS: 140 participants over 50 years of age, with a diagnosis of intermediate AMD and best-corrected visual acuity (BCVA) of >=6/12 in each eye. METHODS: structured questionnaire survey of participants who were enrolled in natural history of AMD studies at CERA. MAIN OUTCOME MEASURES: frequency of vision self-monitoring using the Amsler grid chart, and frequency of general use of personal electronic devices and gameplay. RESULTS: Of 140 participants with mean age of 70.5 years, 83.6% used an Amsler grid chart, but only 39.3% used it once per week. Most participants (91.4%) used one or more personal electronic devices. Of these, over half (54.7%) played games on them, among whom 39% played games once a day. Of participants aged 50-69 years, 92% (95%CI 85.1-98.9) were willing to play a game to monitor their vision, compared to 78% (95%CI 69.0-87.0) of those aged 70 years and older (P < 0.05). CONCLUSIONS AND RELEVANCE: a large proportion of AMD patients already use personal electronic devices. Gamification techniques are likely to increase compliance with self-monitoring, leading to earlier detection in the next generation of patients with neovascular AMD. PMID- 29131494 TI - Antimicrobial Emulsifier-Glycerol Monolaurate Induces Metabolic Syndrome, Gut Microbiota Dysbiosis, and Systemic Low-Grade Inflammation in Low-Fat Diet Fed Mice. AB - SCOPE: Glycerol monolaurate (GML) is widely consumed worldwide in the food industry and is considered safe, but for chronic diseases, supporting scientific data remain sparse. This study investigates whether dietary GML induces metabolic syndrome, gut microbiota dysbiosis, and systemic low-grade inflammation. METHODS AND RESULTS: GML-induced occurrence of metabolic syndrome, gut microbiota alterations, and systemic low-grade inflammation are investigated. The results demonstrate that GML induced metabolic syndrome by significantly increasing the body weight, weight gain, food intake, body fat, fat droplet size and percentage of epididymal fat, serum triglycerides (TG), LDL, and atherogenic index, and decreasing the body muscle ratio, liver weight, and HDL, compared to the control (CON) group. Meanwhile, GML significantly changed the beta-diversity and composition of gut microbiota and upregulated the circulating levels of serum LPS, IL-1beta, IL-6, and TNF-alpha. Importantly, GML significantly decreased Akkermansia muciniphila and Lupinus luteus, and increased Bacteroides acidifaciens, Escherichia coli and the microbial DNA abundance of the ten predicated metabolism pathways involved in carbohydrate, amino acid, and lipid metabolism. CONCLUSION: Our results indicate that relatively low-dose GML consumption promotes metabolic syndrome, gut microbiota dysbiosis, and systemic low-grade inflammation, thereby calling for a reassessment of GML usage. PMID- 29131495 TI - Old treatment and new curiosity: Lithium in drinking water. PMID- 29131496 TI - Suboptimal initiation predicts short-term prognosis and vulnerability among very elderly patients who start hemodialysis. AB - AIM: A recent, growing concern regarding hemodialysis in Japan is a sustained increase in the elderly population. Among very elderly people who start hemodialysis, the prognosis is considered to be poor; however, this has not been fully elucidated. This study aimed to discover the short-term prognosis and related factors in very elderly patients who commence hemodialysis. METHODS: Between January 2008 and December 2013, 122 patients aged >=85 years at hemodialysis initiation were documented in our hospital. Predictors of 90-day and 1-year mortality after hemodialysis initiation were assessed with Cox proportional hazards regression analysis. Selection of covariates for the multivariate model was based on forward stepwise selection using the probability of a likelihood ratio statistics. RESULTS: The subjects' mean age was 87.4 +/- 2.5 years, and 48% were female. The most common cause of death was infection (41% of patients) and the leading cause of infectious death was pneumonia. The 90-day and 1-year survival rates were 81% and 62%, respectively. Suboptimal initiation was a significant prognostic factor for 90-day [hazard ratio (HR) 3.98, 95% confidence interval (CI) 1.18-13.43] and 1-year [HR 3.19, 95% CI 1.51-6.76] mortality after adjusting for confounders in multivariate analysis. CONCLUSION: Very elderly patients who started hemodialysis had a poor prognosis, and suboptimal initiation significantly predicted outcome. Shared decision-making with patients and their families is needed for initiating hemodialysis on the conditions that appropriate information on the expected prognosis is provided. PMID- 29131497 TI - Development of Endothelial Cell Networks in 3D Tissues by Combination of Melt Electrospinning Writing with Cell-Accumulation Technology. AB - A remaining challenge in tissue engineering approaches is the in vitro vascularization of engineered constructs or tissues. Current approaches in engineered vascularized constructs are often limited in the control of initial vascular network geometry, which is crucial to ensure full functionality of these constructs with regard to cell survival, metabolic activity, and potential differentiation ability. Herein, the combination of 3D-printed poly-epsilon caprolactone scaffolds via melt electrospinning writing with the cell accumulation technique to enable the formation and control of capillary-like network structures is reported. The cell-accumulation technique is already proven itself to be a powerful tool in obtaining thick (50 um) tissues and its main advantage is the rapid production of tissues and its ease of performance. However, the applied combination yields tissue thicknesses that are doubled, which is of outstanding importance for an improved handling of the scaffolds and the generation of clinically relevant sample volumes. Moreover, a correlation of increasing vascular endothelial growth factor secretion to hypoxic conditions with increasing pore sizes and an assessment of the formation of neovascular like structures are included. PMID- 29131498 TI - Wavy Architecture Thin-Film Transistor for Ultrahigh Resolution Flexible Displays. AB - A novel wavy-shaped thin-film-transistor (TFT) architecture, capable of achieving 70% higher drive current per unit chip area when compared with planar conventional TFT architectures, is reported for flexible display application. The transistor, due to its atypical architecture, does not alter the turn-on voltage or the OFF current values, leading to higher performance without compromising static power consumption. The concept behind this architecture is expanding the transistor's width vertically through grooved trenches in a structural layer deposited on a flexible substrate. Operation of zinc oxide (ZnO)-based TFTs is shown down to a bending radius of 5 mm with no degradation in the electrical performance or cracks in the gate stack. Finally, flexible low-power LEDs driven by the respective currents of the novel wavy, and conventional coplanar architectures are demonstrated, where the novel architecture is able to drive the LED at 2 * the output power, 3 versus 1.5 mW, which demonstrates the potential use for ultrahigh resolution displays in an area efficient manner. PMID- 29131499 TI - Self-Organization of Amorphous Carbon Nanocapsules into Diamond Nanocrystals Driven by Self-Nanoscopic Excessive Pressure under Moderate Electron Irradiation without External Heating. AB - Phase transformation between carbon allotropes usually requires high pressures and high temperatures. Thus, the development of low-temperature phase transition approaches between carbon allotropes is highly desired. Herein, novel amorphous carbon nanocapsules are successfully synthesized by pulsed plasma glow discharge. These nanocapsules are comprised of highly strained carbon clusters encapsulated in a fullerene-like carbon matrix, with the formers serving as nucleation sites. These nucleation sites favored the formation of a diamond unit cell driven by the self-nanoscopic local excessive pressure, thereby significantly decreasing the temperature required for its transformation into a diamond nanocrystal. Under moderate electron beam irradiation (10-20 A cm-2 ) without external heating, self organization of the energetic carbon clusters into diamond nanocrystals is achieved, whereas the surrounding fullerene-like carbon matrix remains nearly unchanged. Molecular dynamics simulations demonstrate that the defective rings as the active sites dominate the phase transition of amorphous carbon to diamond nanocrystal. The findings may open a promising route to realize phase transformation between carbon allotropes at a lower temperature. PMID- 29131500 TI - Columnar Liquid Crystals from a Giant Macrocycle Mesogen. AB - Columnar liquid crystals composed of a giant macrocyclic mesogen were prepared. The giant macrocyclic mesogen has a square hollow with a 2.5 nm diagonal, which was bounded by diindolo[3,2-b:2',3'-h]carbazole (diindolocarbazole) moieties as the edges and bis(salicylidene)-o-phenylenediamine (salphen) moieties as the corners. The shape and size of the macrocycle were directly observed by scanning tunneling microscopy (STM). Each side of the bright square in the STM image corresponds to a diindolocarbazole moiety, and the length of the sides was consistent with the result of the single crystal analysis of diindolocarbazole. Finally, we successfully obtained a giant macrocycle with long and branched side chains, which exhibited a rectangular columnar LC phase over a wide temperature range. To the best of our knowledge, it contained the largest discrete inner space of any thermotropic columnar liquid crystal composed of macrocyclic mesogens. PMID- 29131501 TI - Authors' reply re: Perinatal and maternal morbidity and mortality among term singletons following midcavity operative vaginal delivery versus caesarean delivery. PMID- 29131502 TI - Racial identity, aesthetic surgery and Yoruba African Values. AB - The question of racial identity in the process and outcome of aesthetic surgery is gaining increasing attention in bioethical discourse. This paper attempts an ethical examination of the racial identity issues involved in aesthetic surgery. Dominant moral values in Western culture are explored in the evaluation of aesthetic surgery. The paper argues that African values are yet to receive the universal attention they arguably deserve especially in the rethinking of values underlying aesthetic surgery as racial transformation. Through a consideration of some moral-aesthetic values in the Yoruba-African culture, this paper further re evaluates the ethics of aesthetic surgery. The paper contends against the propagation of aesthetic surgery as a new form of bolstering racial divides and identity in the evolving cosmopolitan age. The position defended in the paper is that some values from Yoruba-African culture are useful in the consideration of the ethics of aesthetic surgery and more importantly, in avoiding the racial identity bias embedded in aesthetic surgery. The paper concludes that if due consideration is perhaps given to some African moral-aesthetic values in the global aesthetic surgery industry, some of the evolving moral and racial complexities would be better mediated. PMID- 29131504 TI - Balloon pin-hole rupture during percutaneous coronary intervention for recurrent, calcified in-stent restenosis: A case report. AB - Percutaneous coronary intervention (PCI) for patients with in-stent restenosis (ISR) is generally considered safe and effective. However, due to increased tissue hardness, PCI for calcified intra-stent ISR is technically challenging. Here, we report severe angioplasty-related complications in a patient presenting with calcified, recurrent ISR following PCI. After receiving drug-coated balloon (DCB) angioplasty for an initial ISR, the patient developed recurrent ISR during the follow-up period. Intravascular imaging revealed intra-stent calcifications and balloon angioplasty was subsequently performed. During the angioplasty, a pin hole balloon rupture occurred, consequently causing coronary dissection as visualized by intravascular imaging. To prevent acute coronary occlusion, stent implantation was required. The present case report suggests that, following detection of intra-stent calcified stenosis, both careful balloon inflation as well as optimal ablation device selection are required to prevent potential complications and obtain successful procedural outcomes. PMID- 29131503 TI - Association between plasma fibrinogen and survival in patients with small-cell lung carcinoma. AB - BACKGROUND: Elevated plasma fibrinogen (Fbg) levels contribute to tumor progression and metastasis; however, limited research on Fbg in small cell lung cancer (SCLC) has been conducted. This study evaluated the prognostic value of Fbg levels in patients with SCLC. METHODS: Data on plasma Fbg level, clinical features, and overall survival were retrospectively collected. Kaplan-Meier estimates and log-rank tests were used to analyze the relationship between Fbg level and survival. Multivariate analyses were performed to determine independent prognostic factors. Subgroup analyses were performed based on extensive/limited disease and Eastern Cooperative Oncology Group status. RESULTS: A total of 120 patients with SCLC were included. The one, three, and five-year survival rates for the entire cohort were 48.3%, 9.2%, and 1.7%, respectively. Univariate analyses revealed that age, alcohol use, clinical stage, pleural effusion, Eastern Cooperative Oncology Group grade, and Fbg and lactate dehydrogenase levels were associated with survival (P < 0.05). The median survival time for patients with high Fbg levels (> 400 mg/dL) was shorter than for those with low Fbg levels (8 vs. 14 months; P = 0.013). Furthermore, multivariate analysis revealed that Fbg was negatively and independently associated with SCLC prognosis (hazard ratio 1.505, 95% confidence interval 1.018-2.226; P = 0.041). Higher Fbg levels were associated with shorter survival in the extensive disease subgroup (7 vs. 12 months; P = 0.004). CONCLUSIONS: Elevated plasma Fbg was an independent factor associated with poor outcomes in SCLC patients and could serve as a prognostic biomarker. PMID- 29131505 TI - Naevus lightening in melanoma patients under BRAF/MEK inhibitor combination therapy versus checkpoint immunotherapy: A histological and immunohistochemistry analysis. PMID- 29131506 TI - Development of a capillary electrophoresis method for the determination of the chiral purity of dextromethorphan by a dual selector system using quality by design methodology. AB - Dextromethorphan is a centrally acting antitussive drug, while its enantiomer levomethorphan is an illicit drug with opioid analgesic effects. As capillary electrophoresis has been proven as an ideal technique for enantiomer analysis, the present study was conducted in order to develop a capillary electrophoresis based limit test for levomethorphan. The analytical target profile was defined as a method that should be able to determine levomethorphan with acceptable precision and accuracy at the 0.1 % level. From initial scouting experiments, a dual selector system consisting of sulfated beta-cyclodextrin and methyl-alpha cyclodextrin was identified. The critical process parameters were evaluated in a fractional factorial resolution IV design followed by a central composite face centered design and Monte Carlo simulations for defining the design space of the method. The selected working conditions consisted of a 30/40.2 cm, 50 MUm id fused-silica capillary, 30 mM sodium phosphate buffer, pH 6.5, 16 mg/mL sulfated beta-cyclodextrin, and 14 mg/mL methyl-alpha-cyclodextrin at 20 degrees C and 20 kV. The method was validated according to ICH guideline Q2(R1) and applied to the analysis of a capsule formulation. Furthermore, the apparent binding constants between the enantiomers and the cyclodextrins as well as complex mobilities were determined to understand the migration behavior of the analytes. PMID- 29131507 TI - The disruptive effect of lysozyme on the bacterial cell wall explored by an in silico structural outlook. AB - The bacterial cell wall, a structural unit of peptidoglycan polymer comprised of glycan strands consisting of a repeating disaccharide motif [N-acetylglucosamine (NAG) and N-acetylmuramylpentapeptide (NAM pentapeptide)], encases bacteria and provides structural integrity and protection. Lysozymes are enzymes that break down the bacterial cell wall and disrupt the bacterial life cycle by cleaving the linkage between the NAG and NAM carbohydrates. Lab exercises focused on the effects of lysozyme on the bacterial cell wall are frequently incorporated in biochemistry classes designed for undergraduate students in diverse fields as biology, microbiology, chemistry, agronomy, medicine, and veterinary medicine. Such exercises typically do not include structural data. We describe here a sequence of computer tasks designed to illustrate and reinforce both physiological and structural concepts involved in lysozyme effects on the bacterial cell-wall structure. This lab class usually lasts 3.5 hours. First, the instructor presents introductory concepts of the bacterial cell wall and the effect of lysozyme on its structure. Then, students are taught to use computer modeling to visualize the three-dimensional structure of a lysozyme in complex with bacterial cell-wall fragments. Finally, the lysozyme inhibitory effect on a bacterial culture is optionally proposed as a simple microbiological assay. The computer lab exercises described here give students a realistic understanding of the disruptive effect of lysozymes on the bacterial cell wall, a crucial component in bacterial survival. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):83-90, 2018. PMID- 29131508 TI - An interactive computer lab of the galvanic cell for students in biochemistry. AB - We describe an interactive module that can be used to teach basic concepts in electrochemistry and thermodynamics to first year natural science students. The module is used together with an experimental laboratory and improves the students' understanding of thermodynamic quantities such as Deltar G, Deltar H, and Deltar S that are calculated but not directly measured in the lab. We also discuss how new technologies can substitute some parts of experimental chemistry courses, and improve accessibility to course material. Cloud computing platforms such as CoCalc facilitate the distribution of computer codes and allow students to access and apply interactive course tools beyond the course's scope. Despite some limitations imposed by cloud computing, the students appreciated the approach and the enhanced opportunities to discuss study questions with their classmates and instructor as facilitated by the interactive tools. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):58-65, 2018. PMID- 29131509 TI - Emission Tuning with Size-Controllable Polymer Dots from a Single Conjugated Polymer. AB - Two conjugated polymers (CPs) with various compositions of phenylene and benzoselenadiazoben (BSD) are synthesized to have a special emitting property; different fluorescence colors in solution and in the solid states, allowing the resulting conjugated polymer dots (Pdots) to emit different fluorescence colors upon their size variation. The photophysical property of such different-sized Pdots is investigated using fluorescence spectra and fluorescence lifetimes. A decrease in the fluorescence lifetime of Pdots is observed with an increase in the size of Pdots, caused by quantitative change in energy transfer from phenylene (energy donor) to the BSD unit (energy acceptor). The results provide that any CP can be used for the fabrication of Pdots with size-tunable emission, as long as the CP shows different emissions according to its phases. Such emission of Pdots can even be observed when in the solid solution in polymer matrix, which emits different fluorescence colors depending on the size of embedded Pdots in the polymer matrix. PMID- 29131510 TI - Pulmonary pleomorphic carcinoma with few PD-1-positive immune cells and regulatory T cells that showed a complete response to nivolumab. AB - Pulmonary pleomorphic carcinoma has been shown to respond remarkably to PD-1 inhibitors; however, the biomarkers for this therapy have not been fully proven. We report a case of pulmonary pleomorphic carcinoma with overexpressed PD-L1, in which a complete response to nivolumab was sustained for >14 months. Immunohistochemical analysis revealed few PD-1+ immune cells and regulatory T cells in the tumor, in addition to predominant infiltration of CD8+ cells and macrophages. Our findings suggest that the presence of a small number of PD-1+ immune cells and regulatory T cells should be investigated as candidate therapeutic biomarkers. PMID- 29131512 TI - The Role of the Anterior Cingulate Cortex in Prediction Error and Signaling Surprise. AB - In the past two decades, reinforcement learning (RL) has become a popular framework for understanding brain function. A key component of RL models, prediction error, has been associated with neural signals throughout the brain, including subcortical nuclei, primary sensory cortices, and prefrontal cortex. Depending on the location in which activity is observed, the functional interpretation of prediction error may change: Prediction errors may reflect a discrepancy in the anticipated and actual value of reward, a signal indicating the salience or novelty of a stimulus, and many other interpretations. Anterior cingulate cortex (ACC) has long been recognized as a region involved in processing behavioral error, and recent computational models of the region have expanded this interpretation to include a more general role for the region in predicting likely events, broadly construed, and signaling deviations between expected and observed events. Ongoing modeling work investigating the interaction between ACC and additional regions involved in cognitive control suggests an even broader role for cingulate in computing a hierarchically structured surprise signal critical for learning models of the environment. The result is a predictive coding model of the frontal lobes, suggesting that predictive coding may be a unifying computational principle across the neocortex. PMID- 29131511 TI - Magnetic Actuation of Drops and Liquid Marbles Using a Deformable Paramagnetic Liquid Substrate. AB - The magnetic actuation of deposited drops has mainly relied on volume forces exerted on the liquid to be transported, which is poorly efficient with conventional diamagnetic liquids such as water and oil, unless magnetosensitive particles are added. Herein, we describe a new and additive-free way to magnetically control the motion of discrete liquid entities. Our strategy consists of using a paramagnetic liquid as a deformable substrate to direct, using a magnet, the motion of various floating liquid entities, ranging from naked drops to liquid marbles. A broad variety of liquids, including diamagnetic (water, oil) and nonmagnetic ones, can be efficiently transported using the moderate magnetic field (ca. 50 mT) produced by a small permanent magnet. Complex trajectories can be achieved in a reliable manner and multiplexing potential is demonstrated through on-demand drop fusion. Our paramagnetofluidic method advantageously works without any complex equipment or electric power, in phase with the necessary development of robust and low-cost analytical and diagnostic fluidic devices. PMID- 29131513 TI - Role of vascular ultrasound scanning in repeated trans-radial coronary artery intervention (prospective randomized study). AB - OBJECTIVES: We aimed to detect if pre-procedure vascular ultrasound scanning (VUS) of radial arteries (RAs) can increase the radial access success (RAS) rate and/or reduce the vascular access time (VAT), by guiding the choice of the proper access site for repeated trans-radial interventions (TRIs). BACKGROUND: Currently, repeated-TRIs are encountered more frequently in most of the cath. labs. However, structural changes of the RAs after TRA may hinder it is usage for repeated-TRI. VUS is the most accurate noninvasive test for assessing RAs, nonetheless, its role in the setting of repeated-TRIs has not been studied before. MATERIAL AND METHODS: We randomly assigned 300 patients undergoing repeated-TRI, to either planning the vascular access site based upon the result of VUS that was performed pre-procedural (group A, 150 patients) or to be left to the operator's discretion (group B, 150 patients). RESULTS: In group A (143/145 [98.6%]), RAS rate was only numerically higher than group B (143/150 [95.3%]), P = 0.08. There was a statistically significant differences between both groups in VAT [(1.25 +/- 0.17 min), vs. (4.95 +/- 0.87 min) for group A and B, respectively, P = 0.02] and in procedure duration [(37.2 +/- 19.8 min) vs. (51.8 +/- 18.6 min) for group A and B, respectively, P = 0.04]. RA spasm was more common in group B [18% (27/150)] than group A [2% (3/145)], P = 0.001. CONCLUSION: VUS of RAs prior to repeated-TRI is associated with significant reduction in VAT, procedure duration, RA spasm and a mild increase in the RAS rate. PMID- 29131514 TI - Quantitative trait loci associated with soybean seed weight and composition under different phosphorus levels. AB - Seed size and composition are important traits in food crops and can be affected by nutrient availability in the soil. Phosphorus (P) is a non-renewable, essential macronutrient, and P deficiency limits soybean (Glycine max) yield and quality. To investigate the associations of seed traits in low- and high-P environments, soybean recombinant inbred lines (RILs) from a cross of cultivars Fiskeby III and Mandarin (Ottawa) were grown under contrasting P availability environments. Traits including individual seed weight, seed number, and intact mature pod weight were significantly affected by soil P levels and showed transgressive segregation among the RILs. Surprisingly, P treatments did not affect seed composition or weight, suggesting that soybean maintains sufficient P in seeds even in low-P soil. Quantitative trait loci (QTLs) were detected for seed weight, intact pods, seed volume, and seed protein, with five significant QTLs identified in low-P environments and one significant QTL found in the optimal-P environment. Broad-sense heritability estimates were 0.78 (individual seed weight), 0.90 (seed protein), 0.34 (seed oil), and 0.98 (seed number). The QTLs identified under low P point to genetic regions that may be useful to improve soybean performance under limiting P conditions. PMID- 29131515 TI - Enhanced resolution and speckle-free three-dimensional printing of macular optical coherence tomography angiography. PMID- 29131516 TI - Performance in a Collaborative Search Task: The Role of Feedback and Alignment. AB - When people communicate, they coordinate a wide range of linguistic and non linguistic behaviors. This process of coordination is called alignment, and it is assumed to be fundamental to successful communication. In this paper, we question this assumption and investigate whether disalignment is a more successful strategy in some cases. More specifically, we hypothesize that alignment correlates with task success only when communication is interactive. We present results from a spot-the-difference task in which dyads of interlocutors have to decide whether they are viewing the same scene or not. Interactivity was manipulated in three conditions by increasing the amount of information shared between interlocutors (no exchange of feedback, minimal feedback, full dialogue). We use recurrence quantification analysis to measure the alignment between the scan-patterns of the interlocutors. We found that interlocutors who could not exchange feedback aligned their gaze more, and that increased gaze alignment correlated with decreased task success in this case. When feedback was possible, in contrast, interlocutors utilized it to better organize their joint search strategy by diversifying visual attention. This is evidenced by reduced overall alignment in the minimal feedback and full dialogue conditions. However, only the dyads engaged in a full dialogue increased their gaze alignment over time to achieve successful performances. These results suggest that alignment per se does not imply communicative success, as most models of dialogue assume. Rather, the effect of alignment depends on the type of alignment, on the goals of the task, and on the presence of feedback. PMID- 29131517 TI - A Postmortem Study of Frontal and Temporal Gyri Thickness and Cell Number in Human Obesity. AB - OBJECTIVE: This study aimed to compare cortex thickness and neuronal cell density in postmortem brain tissue from people with overweight or obesity and normal weight. METHODS: The cortex thickness and neuron density of eight donors with overweight or obesity (mean = 31.6 kg/m2 ; SD = 4.35; n = 8; 6 male) and eight donors with normal weight (mean = 21.8 kg/m2 ; SD = 1.5; n = 8; 5 male) were compared. All participants were Mexican and lived in Mexico City. Randomly selected thickness measures of different cortex areas from the frontal and temporal lobes were analyzed based on high-resolution real-size photographs. A histological analysis of systematic-random fields was used to quantify the number of neurons in postmortem left and right of the first, second, and third gyri of frontal and temporal lobe brain samples. RESULTS: No statistical difference was found in cortical thickness between donors with overweight or obesity and individuals with normal weight. A smaller number of neurons was found among the donors with overweight or obesity than the donors with normal weight at different frontal and temporal areas. CONCLUSIONS: A lower density of neurons is associated with overweight or obesity. The morphological basis for structural brain changes in obesity requires further investigation. PMID- 29131518 TI - Metabolic profile of Kudiezi injection in rats by UHPLC coupled with Fourier transform ion cyclotron resonance mass spectrometry. AB - In this study, a reliable and sensitive ultra-high performance liquid chromatography coupled with fourier transform ion cyclotron resonance mass spectrometry method was developed for the systematic study of the metabolic profile of Kudiezi injection in rat plasma, bile, urine, and feces after intravenous administration of a single dose. The chromatographic separation was performed on an Agilent Eclipse Plus C18 column (4.6 mm * 50 mm, 1.8 MUm) and the identification of prototype components and metabolites was achieved on a Bruker Solarix 7.0 T ultra-high resolution spectrometer in negative ion mode. Results indicated that a total of 76 constituents including 29 prototype compounds and 47 metabolites (10 phase I metabolites and 37 phase II metabolites) were tentatively identified. And the metabolic pathways of these prototype compounds including hydroxylation, dehydrogenation, glucuronidation, and sulfate conjugation. In conclusion, the developed method with high resolution and sensitivity was effective for screening and identification of prototypes and metabolites of Kudiezi injection in vivo. Moreover, these results would provide significant information for further pharmacokinetic and pharmacological research of Kudiezi injection in vivo. PMID- 29131519 TI - Displaying Tetra-Membrane Spanning Claudins on Enveloped Virus-Like Particles for Cancer Immunotherapy. AB - Virus-like particles (VLPs) displaying foreign antigens have become an important tool in vaccination including the induction of immune responses against self antigens. Claudin 6 (CLDN6) has been identified as tumor-associated antigen and is therefore a potential target for tumor vaccination strategies. However, as tetra-membrane spanning protein its incorporation into VLPs while preserving a native fold is challenging. Here, we attempted the incorporation of a panel of engineered CLDN6 variants into the membrane of retrovirus-derived VLPs. Interestingly, wild-type CLDN6 revealed the most efficient display. VLPs presenting CLDN6 or CLDN9 derived from different donor species were produced and preservation of their native confirmation was demonstrated by antibody binding assays. VLPs displaying murine CLDN6 were used to immunize mice. Antibodies recognizing native CLDN6 as displayed on cell surfaces and mediating complement dependent cytotoxicity were elicited in vaccinated animals. The data suggest applications of CLDN6 displaying VLPs in cancer immunotherapy. PMID- 29131520 TI - Near-infrared human finger measurements based on self-calibration point: Simulation and in vivo experiments. AB - Near-infrared light allows measuring tissue oxygenation. These measurements relay on oxygenation-dependent absorption spectral changes. However, the tissue scattering, which is also spectral dependent, introduces an intrinsic error. Most methods focus on the volume reflectance from a semi-infinite sample. We have proposed examining the full scattering profile (FSP), which is the angular intensity distribution. A point was found, that is, the iso-path length (IPL) point, which is not dependent on the tissue scattering, and can serve for self calibration. This point is geometric dependent, hence in cylindrical tissues depends solely on the diameter. In this work, we examine an elliptic tissue cross section via Monte Carlo simulation. We have found that the IPL point of an elliptic tissue cross section is indifferent to the input illumination orientation. Furthermore, the IPL point is the same as in a circular cross section with a radius equal to the effective ellipse radius. This is despite the fact that the FSPs of the circular and elliptical cross sections are different. Hence, changing the orientation of the input illumination reveals the IPL point. In order to demonstrate this experimentally, the FSPs of a few female fingers were measured at 2 perpendicular orientations. The crossing point between these FSPs was found equivalent to the IPL point of a cylindrical phantom with a radius similar to the effective radius. The findings of this work will allow accurate pulse oximetry assessment of blood saturation. PMID- 29131521 TI - High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer. AB - Heat shock factor 4 (HSF4) is a member of the HSF family. In this study, by using data from the Cancer Genome Atlas-Colorectal Cancer (TCGA-CRC), we investigated the expression profile and the prognostic value of the HSF4 in terms of overall survival (OS) and recurrence free survival (RFS) in CRC patients. RNA-Seq data showed that HSF4 RNA expression was significantly higher in CRC tissues (N = 380) than in the corresponding normal tissues (N = 51) (mean +/- SD: 3.56 +/- 1.28 vs. 1.85 +/- 0.87, P < 0.0001). High HSF4 expression group had significantly higher ratio of stages III/IV patients (52/86, 60.5%) than low HSF4 expression group (110/264, 41.7%; P = 0.0024). Besides, the high HSF4 expression group also had significantly increased expression of CEA (CEA >= 5, 26/51, 51.0% vs. 64/186, 34.4%), higher proportion of recurrence (32/86, 37.2% vs. 48/254, 18.9%, P = 0.0005) and death (36/90, 40.0% vs. 49/277, 17.7%, P < 0.0001) compared with the low HSF4 expression group. Multivariate analysis confirmed that high HSF4 expression was an independent prognostic factor of poor OS (HR = 2.111, 95%CI: 1.350-3.302, P = 0.001) and RFS (HR = 1.958, 95%CI: 1.224-3.131, P = 0.005). Bioinformatic analysis showed that HSF4 can directly interact with DUSP26, ZBED8, and MAPK14. It is also coexpressed with PTGER1, COL11A2, CLPS, and ARSA and colocalized with PTGER1, ADRB1, PEX12, CLPS, PSEN2, KCNJ5, CPA1, ARSA, PNLIP, IRX4, CPA2, IDUA, BCKDHA, and CTRL. We hypothesized that HSF4 might exert its oncogenic effects in CRC via some of these genes. (c) 2017 IUBMB Life, 69(12):956 961, 2017. PMID- 29131522 TI - When Do Two-Stage Processes Outperform One-Stage Processes? AB - Apart from product yield and titer, volumetric productivity is a key performance indicator for many biotechnological processes. Due to the inherent trade-off between the production of biomass as catalyst and of the actual target product, yield and volumetric productivity cannot be optimized simultaneously. Therefore, in combination with genetic techniques for dynamic regulation of metabolic fluxes, two-stage fermentations (TSFs) with separated growth and production phase have recently gained much interest because of their potential to improve the productivity of bioprocesses while still allowing high product yields. However, despite some successful case studies, so far it has not been discussed and analyzed systematically whether or under which conditions a TSF guarantees superior productivity compared to one-stage fermentation (OSF). In this study, we use mathematical models to demonstrate that the volumetric productivity of a TSF is not automatically better than of a corresponding OSF. Our analysis reveals that the sharp decrease of the specific substrate uptake rate usually observed in (non-growth) production phases severely impacts the volumetric productivity and thus raises a big challenge for designing competitive TSF processes. We discuss possible approaches such as enforced ATP wasting to improve substrate utilization rates in the production phase by which TSF processes can become superior to OSF. We also analyze additional factors influencing the relative performance of OSF and TSF and show that OSF processes can be more appropriate if a high product yield is an economic constraint. In conclusion, a careful assessment of the trade offs between substrate uptake rates, yields, and productivity is necessary when deciding for OSF vs. TSF processes. PMID- 29131523 TI - Assessment of tissue polarimetric properties using Stokes polarimetric imaging with circularly polarized illumination. AB - Tissue-depolarization and linear-retardance are the main polarization characteristics of interest for bulk tissue characterization, and are normally interpreted from Mueller polarimetry. Stokes polarimetry can be conducted using simpler instrumentation and in a shorter time. Here, we use Stokes polarimetric imaging with circularly polarized illumination to assess the circular depolarization and linear-retardance properties of tissue. Results obtained were compared with Mueller polarimetry in transmission and reflection geometry, respectively. It is found that circular-depolarization obtained from these 2 methods is very similar in both geometries, and that linear-retardance is highly quantitatively similar for transmission geometry and qualitatively similar for reflection geometry. The majority of tissue circular-depolarization and linear retardance image information (represented by local image contrast features) obtained from Mueller polarimetry is well preserved from Stokes polarimetry in both geometries. These findings can be referred to for further understanding tissue Stokes polarimetric data, and for further application of Stokes polarimetry under the circumstances where short acquisition time or low optical system complexity is a priority, such as polarimetric endoscopy and microscopy. PMID- 29131524 TI - Multi-Scale Contingencies During Individual and Joint Action. AB - The present paper describes a joint action paradigm in which individuals or pairs utilized two computer keys to keep a dot stimulus moving inside a larger rectangle. Members of a pair could neither see nor hear each other. This paradigm allowed us to combine the discrete-trial type dependent variables (e.g., reaction time) commonly utilized by representational theorists, with the continuous, temporal dependence variables (e.g., RQA) utilized by dynamical theorists. Analysis revealed that individuals kept the dot in the rectangle longer than dyads and did so by moving it back and forth within the rectangle. Dyads, however, pressed their individual buttons as quickly as possible in order to keep the dot near the middle of the rectangle. These findings indicate that joint action constitutes a multi-scale phenomena that is best investigated via multiple, complementary methodologies versus single-measure, competing theories. PMID- 29131525 TI - Modified dispersive liquid-phase microextraction based on sequential injection solidified floating organic drop combined with HPLC for the determination of phenobarbital and phenytoin. AB - A modified dispersive liquid phase microextraction based on sequential injection solidified floating organic drop was developed for simultaneous separation/preconcentration of trace amounts of phenobarbital and phenytoin. The important factors affecting on the extraction recovery including pH, the volume of extraction solvent, ionic strength, and the number of injections were investigated and optimized by Box-Behnken design and desirability function. Under the optimum experimental conditions, the calibration graph was linear in the concentration range of 1.0-300.0 MUg/L (r2 = 0.997) for phenobarbital and 2.0 400.0 MUg/L (r2 = 0.996) for phenytoin. The limit of detection and limit of quantification were 0.35 and 1.2 MUg/L for phenobarbital and 0.65 and 2.2 MUg/L for phenytoin, respectively. The relative standard deviation for six replicate determinations at 10 MUg/L was 3.3 and 4.1% for phenobarbital and phenytoin, respectively. The developed method was successfully applied to the determination of phenobarbital and phenytoin in urine and plasma samples. PMID- 29131526 TI - Amniotic mesenchymal stem cells mitigate osteoarthritis progression in a synovial macrophage-mediated in vitro explant coculture model. AB - Osteoarthritis (OA) is a disease of the synovial joint marked by chronic, low grade inflammation leading to cartilage destruction. Regenerative medicine strategies for mitigating OA progression and/or promoting cartilage regeneration must be assessed using models that mimic the hallmarks of OA. More specifically, these models should maintain synovial macrophage phenotype in their native micro environment. Herein, an in vitro coculture model of patient-matched human OA cartilage and synovium was assessed for viability, macrophage phenotype, and progressive cartilage destruction in the presence of an inflammatory milieu. Additionally, the influence of synovial macrophages and their polarization within the model was defined using depletion studies. Finally, the model was used to compare the ability of human amniotic stem cells (hAMSCs) and human adipose stem cells (hADSCs) to mitigate OA progression. OA cocultures demonstrated progressive and significant reductions in chondrocyte viability and cartilage glycosaminoglycan content within a proinflammatory environment. Selective depletion of synovial macrophages resulted in significant decreases in M1:M2 percentage ratio yielding significant reductions in concentrations of interleukin 1 beta, matrix metalloproteinase-13 and attenuation of cartilage damage. Finally, hAMSCs were found to be more chondroprotective versus hADSCs as indicated by significantly improved OA chondrocyte viability (89.8 +/- 2.4% vs. 58.4 +/- 2.4%) and cartilage glycosaminoglycan content (499.0 +/- 101.9 MUg/mg dry weight vs. 155.0 +/- 26.3 MUg/mg dry weight) and were more effective at shifting OA synovial macrophage M1:M2 ratio (1.3:1 vs. 5:1), respectively. Taken together, the coculture model mimics salient features of OA, including macrophage-mediated cartilage destruction that was effectively abrogated by hAMSCs but not hADSCs. PMID- 29131527 TI - 3D matrix-embedding inhibits cycloheximide-mediated sensitization to TNF-alpha induced apoptosis of human endothelial cells. AB - The programmed form of cell death (apoptosis) is essential for normal development of multicellular organisms. Dysregulation of apoptosis has been linked with embryonal death and is involved in the pathophysiology of various diseases. Others and we previously demonstrated endothelial biology being intertwined with biochemical and structural composition of the subendothelial basement membrane. We now demonstrate that a three-dimensional growing environment significantly shields endothelial cells from cytokine-induced apoptosis. Detailed analysis reveals differences in intracellular signaling pathways in naive endothelial cells and cytokine-stimulated endothelial cells when cells are grown within a three-dimensional collagen-based matrix compared to cells grown on two dimensional tissue culture plates. Main findings are significantly reduced p53 expression and level of p38-phosphorylation in three-dimensional grown endothelial cells. Despite similar concentrations of focal adhesion kinase, three dimensional matrix-embedded endothelial cells express significantly less tyrosine phosphorylated focal adhesion kinase. Pretreatment with antibodies against integrin alphav beta3 partially reversed the protective effect of three dimensional matrix-embedding on endothelial apoptosis. Our findings provide detailed insights into the mechanisms of endothelial apoptosis with respect to the spatial matrix environment. These results enhance our understanding of endothelial biology and may otherwise help in the design of tissue-engineered materials. Furthermore, findings on focal adhesion kinase phosphorylation might enhance our understanding of clinical studies with tyrosine kinase inhibitors. PMID- 29131528 TI - The design of a Social Cost-Benefit Analysis of preventive interventions for toxoplasmosis: An example of the One Health approach. AB - Toxoplasma gondii infections cause a large disease burden in the Netherlands, with an estimated health loss of 1,900 Disability Adjusted Life Years and a cost of-illness estimated at ?44 million annually. Infections in humans occur via exposure to oocysts in the environment and after eating undercooked meat containing tissue cysts, leading to asymptomatic or mild symptoms, but potentially leading to the development of ocular toxoplasmosis. Infection in pregnant women can lead to stillbirth and disorders in newborns. At present, prevention is only targeted at pregnant women. Cat vaccination, freezing of meat destined for undercooked consumption and enhancing biosecurity in pig husbandries are possible interventions to prevent toxoplasmosis. As these interventions bear costs for sectors in society that differ from those profiting from the benefits, we perform a social cost-benefit analysis (SCBA). In an SCBA, costs and benefits of societal domains affected by the interventions are identified, making explicit which stakeholder pays and who benefits. Using an epidemiological model, we consider transmission of T. gondii after vaccination of all owned cats or cats at livestock farms. To identify relevant high-risk meat products that will be eaten undercooked, a quantitative microbial risk assessment model developed to attribute predicted T. gondii infections to specific meat products will be used. In addition, we evaluate serological monitoring of pigs at slaughter followed by an audit and tailor made advice for farmers in case positive results were found. The benefits will be modelled stochastically as reduction in DALYs and monetized in Euro's following reference prices for DALYs. If the balance of total costs and benefits is positive, this will lend support to implementation of these preventive interventions at the societal level. Ultimately, the SCBA will provide guidance to policy makers on the most optimal intervention measures to reduce the disease burden of T. gondii in the Netherlands. PMID- 29131529 TI - Clinicopathological characteristics and survival outcomes in pleomorphic lobular breast carcinoma of the breast: a SEER population-based study. AB - The purpose of this study was to explore the clinicopathological features and survival outcome of pleomorphic lobular carcinoma (PLC) of breast, we identified 131 PLC patients and 460,109 invasive ductal carcinoma (IDC) patients in the Surveillance, Epidemiology, and End Result (SEER) database. PLCs presented with increased lymph node involvement, older age, higher AJCC stage and grade, and lower median survival months (PLC 84 +/- 51.03 vs. IDC 105.2 +/- 64.39 P < 0.01). Compared to IDC patients, PLC patients were more inclined to be treated with mastectomy. In univariate analysis, PLC patients showed a worse disease-specific survival (DSS) than that of IDC patients (hazard ratio = 0.691, 95% confidence interval 0.534-0.893, P < 0.01). In multivariate analysis, we took into account other prognostic factors and found that the histology types were no longer an independent prognostic factor (P = 0.120). DSS have no difference between matched IDC and PLC groups (P = 0.615). This result may be due to PLCs presenting higher tumor stage, higher tumor grade, and higher rate of LN metastasis than IDCs. Our conclusion is that PLC and IDC have many different characteristics, but there is not enough difference on the DSS. PMID- 29131530 TI - Biomarkers for immune checkpoint inhibitors: The importance of tumor topography and the challenges to cytopathology. AB - The recent emergence of immune checkpoint inhibitors for cancer therapy has created much excitement among cancer patients, drug and diagnostic developers, and health care professionals. This is due largely to the dramatic and sustained responses among some advanced cancers that were previously refractory to therapy. Unfortunately, these responses are difficult to predict, so the goal of the right drug for the right patient at the right time remains elusive. This is in part due to the complexity of the tumor immune microenvironment and its role in drug efficacy. The application of biomarkers to pathologic specimens to predict responses to therapy remains one of the key roles for pathologists in precision medicine. For the new immune checkpoint inhibitors, the emerging class of biomarkers revolves around the immunohistochemical detection of the drug target (or its ligand), programmed cell death ligand 1, on tumor cells or associated immune cells. The diagnostic terrain is already complex because of the involvement of different technology platforms, antibody clones, scoring systems, and indications for their use. The application of these biomarkers to cytologic specimens is critical because the current drug indications are for advanced-stage cancers that are often sampled by minimally invasive cytologic means rather than surgical resection. This review summarizes the current state of biomarkers for immune checkpoint inhibitors with an emphasis on the opportunities for and threats to cytologic samples. Cancer Cytopathol 2018;126:11-9. (c) 2017 American Cancer Society. PMID- 29131531 TI - Modifying Expression Modes of Human Neurotensin Receptor Type 1 Alters Sensing Capabilities for Agonists in Yeast Signaling Biosensor. AB - Neurotensin receptor type 1 (NTSR1), a member of the G-protein-coupled receptor (GPCR) family, is naturally activated by binding of a neurotensin peptide, leading to a variety of physiological effects. The budding yeast Saccharomyces cerevisiae is a proven host organism for assaying the agonistic activation of human GPCRs. Previous studies showed that yeast cells can functionally express human NTSR1 receptor, permitting the detection of neurotensin-promoted signaling using a ZsGreen fluorescent reporter gene. However, the fluorescence intensity (sensitivity) of NTSR1-expressing yeast cells is low compared to that of yeast cells expressing other human GPCRs (e.g., human somatostatin receptors). The present study sought to increase the sensitivity of the NTSR1-expressing yeast for use as a fluorescent biosensor, including modification of the expression of human NTSR1 in yeast. Changes in the transcription, translation, and transport of the receptor are attempted by altering the promoter, consensus Kozak-like sequence, and secretion signal sequences of the NTSR1-encoding gene. The resulting yeast cells exhibited increased sensitivity to exogenously added peptide. The cells are further engineered by using cell-surface display technology to ensure that the agonistic peptides are secreted and tethered to the yeast cell wall, yielding cells with enhanced NTSR1 activation. This yeast biosensor holds promise for the identification of agonists to treat NTSR1-related diseases. PMID- 29131532 TI - Reply to GATA3 differential expression in neuroblastoma and nephroblastoma. PMID- 29131534 TI - Universal target-enrichment baits for anthozoan (Cnidaria) phylogenomics: New approaches to long-standing problems. AB - Anthozoans (e.g., corals, anemones) are an ecologically important and diverse group of marine metazoans that occur from shallow to deep waters worldwide. However, our understanding of the evolutionary relationships among the ~7,500 species within this class is hindered by the lack of phylogenetically informative markers that can be reliably sequenced across a diversity of taxa. We designed and tested 16,306 RNA baits to capture 720 ultraconserved element loci and 1,071 exon loci. Library preparation and target enrichment were performed on 33 taxa from all orders within the class Anthozoa. Following Illumina sequencing and Trinity assembly, we recovered 1,774 of 1,791 targeted loci. The mean number of loci recovered from each species was 638 +/- 222, with more loci recovered from octocorals (783 +/- 138 loci) than hexacorals (475 +/- 187 loci). Parsimony informative sites ranged from 26 to 49% for alignments at differing hierarchical taxonomic levels (e.g., Anthozoa, Octocorallia, Hexacorallia). The per cent of variable sites within each of three genera (Acropora, Alcyonium, and Sinularia) for which multiple species were sequenced ranged from 4.7% to 30%. Maximum likelihood analyses recovered highly resolved trees with topologies matching those supported by other studies, including the monophyly of the order Scleractinia. Our results demonstrate the utility of this target-enrichment approach to resolve phylogenetic relationships from relatively old to recent divergences. Redesigning the baits with improved affinities to capture loci within each subclass will provide a valuable toolset to address systematic questions, further our understanding of the timing of diversifications and help resolve long-standing controversial relationships in the class Anthozoa. PMID- 29131535 TI - Artificial Photosynthesis: Beyond Mimicking Nature. AB - In this Editorial, Guest Editors Holger Dau, Etsuko Fujita, and Licheng Sun introduce the Special Issue of ChemSusChem on "Artificial Photosynthesis for Sustainable Fuels". They discuss the need for non-fossil based fuels, introduce both biological and artificial photosynthesis, and outline various important concepts in artificial photosynthesis, including molecular and solid-state catalysts for water oxidation and hydrogen evolution, catalytic CO2 reduction, and photoelectrochemical systems. PMID- 29131533 TI - A phase I/II pharmacokinetics/pharmacodynamics study of irinotecan combined with S-1 for recurrent/metastatic breast cancer in patients with selected UGT1A1 genotypes (the JBCRG-M01 study). AB - S-1 and irinotecan combination is attractive for breast cancer refractory to anthracyclines and taxanes. Patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer previously treated with anthracyclines and taxanes were eligible. Patients with brain metastases and homozygous for UGT1A1 *6 or *28 or compound heterozygous (*6/*28) were excluded. A dose escalation design was chosen for the phase I portion (level 1: irinotecan 80 mg/m2 days 1-8 and S-1 80 mg/m2 days 1-14 every 3 weeks; level 2: irinotecan 100 mg/m2 and S-1 80 mg/m2 ). Study objectives included determination of the recommended dose for phase II, response rate, progression-free survival (PFS), and safety. Pharmacokinetics and CD34+ circulating endothelial cells (CECs) as pharmacodynamics were also analyzed. Thirty-seven patients were included. One patient at each level developed dose-limiting toxicities; therefore, level 2 was the recommended dose for phase II. Diarrhea was more common in patients possessing a *6 or *28 allele compared with wild-type homozygous patients (46% and 25%). Among 29 patients treated at level 2, PFS was longer for UGT1A1 wt/*6 and wt/*28 patients than for wt/wt patients (12 vs. 8 months, P = 0.06). PFS was significantly longer in patients with a larger-than-median SN-38 area under the curve (AUC) than in those with a smaller AUC (P = 0.039). There was an association between clinical benefit and reduction in baseline CD34+ CECs by S-1 (P = 0.047). The combination of irinotecan and S-1 is effective and warrants further investigation. PMID- 29131536 TI - Non-invasive ventilation use in status asthmaticus: 16 years of experience in a tertiary intensive care. AB - OBJECTIVE: To describe the use of non-invasive ventilation (NIV) in adults presenting with status asthmaticus to Middlemore Hospital Critical Care Complex (CCC, South Auckland, New Zealand) from 2000 to 2015. METHOD: Retrospective review of all adult asthma admissions to the Hospital CCC between 2000 and 2015. Demographic, physiological, treatment data and blood gas results were recorded. RESULTS: There were 265 asthma admissions to Middlemore Hospital CCC during the study period. The median age was 34 years; 64% were female. NIV was used in 186 admissions, of which eight went on to require intubation and invasive mechanical ventilation (IMV). Twenty-three other admissions received IMV without a trial of NIV and a further 58 were managed with medical care only. The average pH for all admissions was 7.23 and the IMV group had an average pH of 6.99. Forty-five admissions presented with a Glasgow Coma Scale (GCS) score of <=10. Twenty-five of these were managed with NIV with only one requiring subsequent intubation. The mean duration of NIV in this group was 5 h (range 1-17 h) with a mean ICU and hospital length of stay of 17 h and 3.5 days, respectively. All patients in this group effectively lowered the pCO2 over a 2 h period with NIV having an average drop of 5.9 kPa and IMV 3.4 kPa. CONCLUSION: The use of NIV appears to be safe and effective in patients with severe asthma, including selected patients with an altered level of consciousness. NIV was well tolerated with a low need for subsequent intubation. PMID- 29131537 TI - Health information needs of pregnant women: information sources, motives and barriers. AB - BACKGROUND: Pregnant women should be provided with relevant and useful information to manage this specific period of their lives. Assessing information needs of this group is a prerequisite for providing this information. OBJECTIVE: The aim of this study was to assess the information needs of pregnant women during their pregnancy and childbirth. METHODS: This descriptive study was conducted on the pregnant women who attended antenatal clinics and obstetricians/gynaecologists' offices in Kerman, Iran, in 2015. Data were collected using a self-administered, valid and reliable questionnaire. A total of 400 women participated in the study. FINDINGS: Most pregnant women needed information about care of the foetus (n = 344, 86%), physical and psychological complications after delivery (n = 333, 83%), development and growth of the foetus (n = 330, 82.5%), pregnancy nutrition (n = 327, 82%) and special tests during pregnancy (n = 326, 81.5%). They mostly (n = 195, 49%) looked for information when they were suffering from a disease or pregnancy complications. CONCLUSIONS: As pregnant women need extensive information to be able to take care of themselves and their babies, their information needs should be identified and taken into consideration when planning educational programmes for this group of women. PMID- 29131538 TI - Flexible and Accessible Automated Operation of Miniature Chromatography Columns on a Liquid Handling Station. AB - The High Throughput (HT) investigation of chromatographic separations is an important element of downstream bioprocess development due to the importance of chromatography as a technique for achieving stringent regulatory requirements on product purity. Various HT formats for chromatography exist, but the miniature column approach has characteristics resembling large scale packed bed column chromatography the most. The operation of such columns on robotic stations can be automated, but this is not always a straightforward procedure; the robotic manipulations are highly dependent on the settings of each experiment and the standard commands of the supporting software may not provide readily the required flexibility and accessibility for "plug and play" functionality. These can limit the potential of this technique in laboratories engaging on HT activities. In this work, we present an application which aims to overcome this challenge by providing end-users with a flexible operation of the miniature column technique on an automated liquid handler. The application includes a script which is written on Freedom EVOware, and is supplemented by custom compiled executables. Here, the manipulations carried out by the application are described in detail and its functionality is demonstrated through typical experiments based on bind and elute miniature column chromatography. The application is shown to allow for the unsupervised "on-the-fly" programming of the robotic station and to ultimately make the technique accessible to non-automation experts. This application is therefore well suited to simplifying development activities based on the robotic deployment of the miniature column chromatography technique. PMID- 29131540 TI - Equivalence in outcomes between Draf 2B vs Draf 3 frontal sinusotomy for refractory chronic frontal rhinosinusitis. AB - BACKGROUND: Endoscopic Draf 2B and Draf 3 frontal sinusotomies are frequently performed for chronic refractory frontal rhinosinusitis. The purpose of this study was to compare outcomes between Draf 2B and Draf 3 procedures. METHODS: A retrospective cohort study was conducted comparing patients undergoing bilateral Draf 2B vs Draf 3 procedures from 2000 to 2016. Patients with neoplasia, dysplasia, mucocele, cystic fibrosis, or ciliary dyskinesia were excluded. Preoperative disease parameters included number of prior surgeries, presence of polyps, preoperative 22-item Sino-Nasal Outcome Test (SNOT-22) score, frontal Lund-Mackay score, anterior-posterior diameter of the frontal ostium, and Global Osteitis Scoring Scale (GOSS). Postoperative outcomes included SNOT-22 score, neo ostium patency, surgical revision rates, and complications. RESULTS: A total of 21 patients with bilateral Draf 2B and 17 patients with Draf 3 surgeries were compared. Mean follow-up time was 15.6 months. No significant differences were seen between groups for any preoperative disease parameter. Both cohorts showed statistically significant (p = 0.0001 [Draf 2B]; p = 0.0001 [Draf 3]) and clinically meaningful (Delta = 24.1; Delta = 24.9) improvements in SNOT-22 at last follow-up vs preoperatively. The Draf 2B group had greater improvement in SNOT-22 score than the Draf 3 group at 1 to 3 months (p = 0.003), but the magnitude of improvement equalized at 5 to 9 months (p = 0.66) and last follow-up (p = 0.90). No significant differences were noted between groups regarding patency, revision rates, or complications. CONCLUSION: Both Draf 2B and Draf 3 procedures offer durable symptomatic improvement for patients with refractory frontal CRS. The Draf 2B is associated with earlier postoperative symptom improvement and overall shows comparable long-term outcomes to the Draf 3 sinusotomy. PMID- 29131541 TI - Rhombic-Shaped Nanostructures and Mechanical Properties of 2D DNA Origami Constructed with Different Crossover/Nick Designs. AB - DNA origami methods enable the fabrication of various nanostructures and nanodevices, but their effective use depends on an understanding of their structural and mechanical properties and the effects of basic structural features. Frequency-modulation atomic force microscopy is introduced to directly characterize, in aqueous solution, the crossover regions of sets of 2D DNA origami based on different crossover/nick designs. Rhombic-shaped nanostructures formed under the influence of flexible crossovers placed between DNA helices are observed in DNA origami incorporating crossovers every 3, 4, or 6 DNA turns. The bending rigidity of crossovers is determined to be only one-third of that of the DNA helix, based on interhelical electrostatic forces reported elsewhere, and the measured pitches of the 3-turn crossover design rhombic-shaped nanostructures undergoing negligible bending. To evaluate the robustness of their structural integrity, they are intentionally and simultaneously stressed using force controlled atomic force microscopy. DNA crossovers are verified to have a stabilizing effect on the structural robustness, while the nicks have an opposite effect. The structural and mechanical properties of DNA origami and the effects of crossovers and nicks revealed in this paper can provide information essential for the design of versatile DNA origami structures that exhibit specified and desirable properties. PMID- 29131539 TI - Molecular testing on endobronchial ultrasound (EBUS) fine needle aspirates (FNA): Impact of triage. AB - BACKGROUND: Endobronchial ultrasound (EBUS)-guided fine needle aspiration (FNA) is performed to diagnose and stage lung cancer. Multiple studies have described the value of Rapid On-Site Evaluation (ROSE), but often the emphasis is upon diagnosis than adequacy for molecular testing (MT). The aim was to identify variable(s), especially cytology-related, that can improve MT. METHODS: A search for EBUS-FNAs with ROSE was conducted for lung adenocarcinomas or when this diagnosis could not be excluded. All such cases underwent reflex MT on cell blocks. The impact of cytology-related variables [i.e., number of pass(es), dedicated pass(es) directly into media, cytotechnologist (CT), laboratory technician (LT) and triage with 1 or >1 cytologist] was evaluated. The latter category was divided into Group A [ROSE, triage and slide preparation by cytopathologist (CP) and CT at start of the procedure] and Group B (ROSE only by CT or by CT/CP after start of procedure; triage and slide preparation by CT or clinical staff). The impact of all these variables on MT was assessed. RESULTS: A total of 100 cases were identified, and 79 had sufficient tissue for MT. Of all variables evaluated, MT was positively affected by performing a direct dedicated pass (P = 0.013) and ROSE by Group A (P = 0.033). CONCLUSIONS: ROSE with appropriate triage, including performing a dedicated pass and proper slide preparation, improves MT, and this is enhanced by having >1 cytologist at the start of the procedure. In the era of personalized medicine, "adequate" should denote sufficient tissue for diagnosis and MT. PMID- 29131542 TI - The 3 D Structure of Twisted Benzo[ghi]perylene-Triimide Dimer as a Non-Fullerene Acceptor for Inverted Perovskite Solar Cells. AB - Here, we introduced benzo[ghi]perylenetriimide (BPTI) derivatives including monomer and twisted dimer (t-BPTI) as an alternative electron-transport layer (ETL) material to replace the commonly used PC61 BM in inverted planar heterojunction perovskite solar cells (PSCs). Moreover, the double ETL was applied in our PSCs with structure of glass/ITO/PEDOT:PSS/perovskite/BPTI/C60 or PDI-C4/BCP/Al. The use of a double ETL structure can effectively eliminate the leakage current. The devices with the t-BPTI/C60 double ETL yield an average power conversion efficiency of 10.73 % and a maximum efficiency of 11.63 %. The device based on the complete non-fullerene electron acceptors of t-BPTI/PDI-C4 as double ETL achieved maximum efficiency of 10.0 %. Moreover, it was found that the utilization of alloy t-BPTI+BPTI as ETL can effectively reduce the hysteresis effect of PSCs. The results suggest that BPTI-based electron-transport materials are potential alternatives for widely used fullerene acceptors in PSCs. PMID- 29131543 TI - HLA class II polymorphism in Saudi patients with multiple sclerosis. AB - Several studies have investigated the association of different HLA antigens with multiple sclerosis (MS). However, only few studies have considered the association of high-resolution HLA type and MS with none yet from Saudi Arabia. The aim of this study was to investigate the association of HLA class II alleles with MS in the Saudi population. We used next-generation sequencing to investigate HLA association with MS. This study was conducted at King Abdulaziz Medical City in Riyadh, Saudi Arabia. We found that several HLA-DRB1 and DQB1 alleles were associated with MS. These alleles included HLA-DRB1*15:01 (odds ratio [OR]: 3.01; 95%, confidence interval [CI]: 1.68-5.54; P = .0001), HLA DQB1*02:01 (OR: 1.76; 95% CI: 1.20-2.58; P = .0022), HLA-DQB1*06:02 (OR: 3.52; 95% CI: 1.87-6.86; P < .0001), and HLA-DQB1*06:03 (OR: 2.42; 95% CI: 1.16-5.25; P = 0.01). Interestingly, HLA-DRB1*15:01 was associated with increased risk of previous relapses. In addition, HLA-DRB1*15:01 and HLA-DQB1*06:02 were found to be associated with lower vitamin D levels. This study provides insights on the association of different HLA alleles with clinical characteristics and outcome of MS among Saudis. These insights can have future implications for the clinical management of MS based on the patient genetic profile. PMID- 29131544 TI - Synthesis and Properties of Open Fullerenes Encapsulating Ammonia and Methane. AB - We describe the synthesis and characterisation of open fullerene (1) and its reduced form (2) in which CH4 and NH3 are encapsulated, respectively. The 1 H NMR resonance of endohedral NH3 is broadened by scalar coupling to the quadrupolar 14 N nucleus, which relaxes rapidly. This broadening is absent for small satellite peaks, which are attributed to natural abundance 15 N. The influence of the scalar relaxation mechanism on the linewidth of the 1 H ammonia resonance is probed by variable temperature NMR. A rotational correlation time of tauc =1.5 ps. is determined for endohedral NH3 , and of tauc =57+/-5 ps. for the open fullerene, indicating free rotation of the encapsulated molecule. IR spectroscopy of NH3 @2 at 5 K identifies three vibrations of NH3 (nu1 , nu3 and nu4 ) redshifted in comparison with free NH3 , and temperature dependence of the IR peak intensity indicates the presence of a large number of excited translational/ rotational states. Variable temperature 1 H NMR spectra indicate that endohedral CH4 is also able to rotate freely at 223 K, on the NMR timescale. Inelastic neutron scattering (INS) spectra of CH4 @1 show both rotational and translational modes of CH4 . Energy of the first excited rotational state (J=1) of CH4 @1 is significantly lower than that of free CH4 . PMID- 29131545 TI - A double point mutation at residues Ile14 and Val15 of Bcl-2 uncovers a role for the BH4 domain in both protein stability and function. AB - B-cell lymphoma 2 (Bcl-2) protein is the archetype apoptosis suppressor protein. The N-terminal Bcl-2-homology 4 (BH4) domain of Bcl-2 is required for the antiapoptotic function of this protein at the mitochondria and endoplasmic reticulum (ER). The involvement of the BH4 domain in Bcl-2's antiapoptotic functions has been proposed based on Gly-based substitutions of the Ile14/Val15 amino acids, two hydrophobic residues located in the center of Bcl-2's BH4 domain. Following this strategy, we recently showed that a BH4-domain-derived peptide in which Ile14 and Val15 have been replaced by Gly residues, was unable to dampen proapoptotic Ca2+ -release events from the ER. Here, we investigated the impact of these mutations on the overall structure, stability, and function of full-length Bcl-2 as a regulator of Ca2+ signaling and cell death. Our results indicate that full-length Bcl-2 Ile14Gly/Val15Gly, in contrast to wild-type Bcl 2, (a) displayed severely reduced structural stability and a shortened protein half-life; (b) failed to interact with Bcl-2-associated X protein (BAX), to inhibit the inositol 1,4,5-trisphosphate receptor (IP3 R) and to protect against Ca2+ -mediated apoptosis. We conclude that the hydrophobic face of Bcl-2's BH4 domain (Ile14, Val15) is an important structural regulatory element by affecting protein stability and turnover, thereby likely reducing Bcl-2's ability to modulate the function of its targets, like IP3 R and BAX. Therefore, Bcl-2 structure/function studies require pre-emptive and reliable determination of protein stability upon introduction of point mutations at the level of the BH4 domain. PMID- 29131546 TI - Polymeric Nanoparticles Induce NLRP3 Inflammasome Activation and Promote Breast Cancer Metastasis. AB - Polymeric nanoparticles gain enormous interests in cancer therapy. Polyethylenimine (PEI) 25 kD is well known for its high transfection efficiency and cytotoxicity. PEI-CyD (PC) was previously synthesized by conjugating low molecular PEI (M w 600) with beta-cyclodextrin (beta-CyD), which is shown to induce lower cytotoxicity than PEI 25 kD. In the current study, the in vivo immune response of branched PEI 25 kD and PC is investigated. Compared to PC/pDNA, exposure of PEI 25kD/pDNA induces higher level of immune-stimulation evidenced by the increased spleen weight, phagocytic capacity of peritoneal macrophage, and proinflammatory cytokines in serum and liver. Importantly, administration of PEI 25 kD can greatly promote breast cancer metastasis in liver and lung tissues, which correlates with its ability to induce high oxidative stress and NLRP3-inflammasome activation. These results suggest that polymeric nanocarriers have the potential to induce immune-stimulation and cancer metastasis, which may affect their efficiency for cancer therapy. PMID- 29131548 TI - Diversity of Thermogenic Capacity Predicts Divergent Obesity Susceptibility in a Wild Rodent. AB - OBJECTIVE: The objective of the present study was to examine whether wild rodents exhibit diverse obesity susceptibility and what factors predispose subjects to this divergence in response to a high-fat diet (HFD). METHODS: Sixty male and female Brandt's voles (Lasiopodomys brandtii) were fed an HFD for 8 weeks, and the upper (obesity prone [OP]) and lower (obesity resistant [OR]) one-third for mass gain were selected. Energy budgets and pathologic changes were measured. Another 30 males were fed a low-fat control diet (LFD) for 10 weeks and then fed an HFD for 12 weeks. The energetic parameters of the rodents on an LFD were analyzed for the correlation with body mass of the rodents on an HFD. RESULTS: OP voles had higher energy intakes, higher levels of noradrenaline-induced nonshivering thermogenesis, and a greater impairment of insulin tolerance than OR voles. Unlike laboratory rodents, there were no differences in physical activity or resting metabolic rate between these groups of voles. The thermogenic capacity during LFD feeding was the strongest predictor for mass gain during HFD feeding. CONCLUSIONS: This study suggests that a wild rodent species of Brandt's voles exhibits diverse obesity susceptibility in reaction to an HFD, providing a natural model to give insight into the mechanisms for divergent obesity susceptibility. This study also indicates that maximum thermogenic capacity has a predictive power for the development of obesity when an HFD was available. PMID- 29131547 TI - Publishing in a heart failure journal-where lies the scientific interest? PMID- 29131549 TI - Diagnosis of Kawasaki disease. AB - Kawasaki disease (KD) is a medium vessel vasculitis with predilection for coronary arteries. Due to lack of a reliable confirmatory laboratory test, the diagnosis of KD is based on a constellation of clinical findings that appear in a typical temporal sequence. These diagnostic criteria have been modified from time to time and the most recent guidelines have been proposed by the American Heart Association (AHA) in 2017. However, several children may have incomplete or atypical forms of KD and the diagnosis can often be difficult, especially in infants and young children. In this review, we have detailed the steps involved in arriving at a diagnosis of KD and also highlight the important role of echocardiography in diagnosis and management of children with KD. PMID- 29131551 TI - beta-Cryptoxanthin Inhibits Angiogenesis in Human Umbilical Vein Endothelial Cells Through Retinoic Acid Receptor. AB - SCOPE: beta-Cryptoxanthin is an abundant carotenoid in fruits and vegetables that can be quantified in human blood serum. Yet, contrary to other carotenoids, its effects on endothelial cells and angiogenesis remain unknown. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVEC) are treated with 0.01, 0.1, or 1 MUm of beta-cryptoxanthin. Antioxidant activity is determined by its free radical scavenging and oxygen-radical absorbance capacity. The effect on migration and formation of tubular structures is studied. Additionally, effect on angiogenesis is also analyzed using an in vivo model. beta-Cryptoxanthin exhibits scavenging ability, having an antioxidant effect on HUVEC. Interestingly, beta cryptoxanthin reduces their migration and angiogenesis, even in the presence of vascular endothelial growth factor (VEGF). Additionally, such carotenoid inhibits in vivo angiogenesis induced by VEGF. In addition, treatment of HUVEC with LE540 (retinoic acid receptor [RAR] panantagonist) inhibits beta-cryptoxanthin antiangiogenic effect on HUVEC. CONCLUSION: beta-Cryptoxanthin inhibits angiogenesis through RAR. Thus, this carotenoid and food containing it may be useful for the prevention and treatment of angiogenic pathologies. That includes tumoral growth and wet macular degeneration associated with aging. To the best of our knowledge, this is the first report of the antioxidant effect and antiangiogenic activity of this carotenoid on HUVEC, both in vitro and in vivo. PMID- 29131553 TI - GATA3 differential expression in neuroblastoma and nephroblastoma. PMID- 29131552 TI - Activation of the Wnt Pathway by Small Peptides: Rational Design, Synthesis and Biological Evaluation. AB - A computational analysis of the X-ray structure of the low-density lipoprotein receptor-related protein 6 (LRP6) with the Dickkopf-1 (DKK1) C-terminal fragment has allowed us to rationally design a small set of decapeptides. These compounds behave as agonists of the canonical Wnt pathway in the micromolar range when tested on a dual luciferase Wnt functional assay in glioblastoma cells. Two of the oligopeptides showed a lack of cytotoxicity in human primary osteoblasts isolated from sponge bone tissue (femoral heads or knees of elderly patients). According to the mechanism of action, the studies revealed a dose- and time dependent increase in the viability of human osteoblasts. These results may indicate a potential therapeutic application of this class of compounds in the treatment of bone diseases related to aging, such as osteoporosis. PMID- 29131550 TI - Innate and acquired immune surveillance in the postdissemination phase of metastasis. AB - Metastasis is responsible for the majority of death in cancer patients. Of the different steps in the metastasis cascade, the postdissemination phase is perhaps one of the least understood. Many factors, both from the disseminated tumor cells and the microenvironment, impact the success of the metastatic outgrowth. In this article, we discuss the interactions between colonizing cancer cells and immune cells in the period between vascular arrest in a secondary organ and metastatic outgrowth. We address the ambiguity in the findings of current research regarding the role of immune cells in regulating the metastatic microenvironment, and their hand in determining cancer cell fate. PMID- 29131554 TI - The pathophysiology, incidence, impact, and treatment of opioid-induced nausea and vomiting. AB - PURPOSE: Opioid medications are integral in managing acute moderate-to-severe pain. Opioid analgesics bind to MU (mu), kappa (kappa), or delta (delta) opioid receptors in the brain, spinal cord, and digestive tract. However, opioids cause adverse effects that may interfere with their therapeutic use. Some adverse effects wane over time, but patients using opioids for acute pain struggle with opioid-induced nausea and vomiting (OINV) the entire time they take the opioid. This article discusses the underlying mechanisms, clinical implications, and treatment strategies of OINV. DATA SOURCES: Systematic search and review of Medline, PubMed, and Google Scholar for articles relating to OINV. In addition, package inserts provided pharmacologic data and dose recommendations as needed. CONCLUSIONS: Research suggests approximately 40% of patients may experience nausea and 15%-25% of patients may experience vomiting after opioid administration. Nausea often precedes vomiting, although they can occur separately. Many patients receiving opioids rate the nausea and vomiting as worse than their pain. Nausea and vomiting can lead to complications including electrolyte imbalances, malnutrition, and volume depletion, and can also negatively affect quality of life and postoperative recovery. IMPLICATIONS FOR PRACTICE: There are several medications that can be used to treat OINV including serotonin receptor antagonists, dopamine receptor antagonists, and neurokinin-1 receptor antagonists. Healthcare providers should be proactive about discussing OINV with patients, as this may improve patient outcomes and pain relief. PMID- 29131556 TI - Home Alone - It's not a movie, it's reality. PMID- 29131555 TI - AANP News. PMID- 29131557 TI - Comparison of self-made cryopreservative fibrin glue and commercial fibrin glue kit in pterygium surgery: 1-year follow-up. AB - PURPOSE: To assess long-term efficacy and safety of self-made cryopreservative fibrin glue (SMC) applied in pterygium surgery. METHODS: Prospective, comparative, interventional case series. Forty eyes of 40 patients with nasal primary pterygium, 24 male and 16 female, were enrolled. The patients were assigned to two groups and each contained 12 male and eight female based on the pterygium area encroaching onto the cornea. In one group, the conjunctival autograft was attached to the sclera with SMC stored for 2 months, and in the other group, commercial fibrin glue kit (CK) was applied after the pterygium was removed. All the patients were followed up postoperatively on days 1, 3, 7 and 14 then at months 1, 3, 6, 12. The main outcome measures included operating time, postoperative discomfort, recurrence rate and complications. RESULTS: There were no significant differences in surgery time (p = 0.713) and postoperative discomfort (day 1, 3, 7; p = 0.747, p = 0.766, p = 0.983, respectively) between the two groups. By the end of 1-year follow-up, the recurrence rate was 0% in the SMC group and 5% in the CK group (p = 1.000). There were no infections and severe visual acuity (VA) threatening complications in either group. CONCLUSION: Self made cryopreservative fibrin glue (SMC) is as effective as standard CK for autograft fixation in pterygium surgery and it also has good safety after long term follow-up. For its convenience and low cost, this new methods should be popularized, especially in underdeveloped area. PMID- 29131558 TI - Cytologic findings of an adult rhabdomyoma in the parapharyngeal space: A report of a case and review of the literature. AB - Adult extracardiac rhabdomyomas are rare benign mesenchymal tumor arising from skeletal muscle. While they are often located in the larynx and pharynx, the incidence in the parapharyngeal area is extremely rare with only 1 documented cytology case report to date. We report a case of an adult extracardiac rhabdomyoma in the parapharyngeal space diagnosed cytologically with subsequent histologic confirmation. The patient is a 57-year-old man with history of weight loss, hematuria, dysphagia, and airway encroachment. Computerized tomography of his abdomen showed a large left renal mass. While the patient was in the operating room for the resection of his renal mass, a fine-needle aspiration from left the parapharyngeal mass was performed. The smears showed uniform bland polygonal cells with abundant eosinophilic cytoplasm and peripherally located nuclei. Immunohistochemical stains performed on the cell block showed the tumor cells were desmin positive and negative for S-100 and PAX-8, supporting the diagnosis of an adult rhabdomyoma. Subsequent resection of the mass confirmed the diagnosis of an adult extracardiac rhabdomyoma. PMID- 29131559 TI - Diagnostic challenges and problem cases in salivary gland cytology: A 20-year experience. AB - BACKGROUND: Fine-needle aspiration (FNA) is routinely performed to evaluate salivary gland lesions, and provides valuable information regarding the cytomorphologic features of the lesions. Occasionally, there are overlaps between benign and malignant conditions due to heterogeneity of the cell types, metaplastic changes, and sampling issues. Herein, the authors present a retrospective study of diagnostic pitfalls in salivary gland cytology and the simulating conditions. METHODS: A 20-year retrospective review (1995-2015) of medical records was performed searching for the cytology reports of patients who underwent FNA of the salivary gland with the words "amendment" or "revision." Medical records of the revised cases were reviewed for the subsequent surgical follow-up. All cases with a diagnostic discrepancy between the primary cytologic diagnosis and the final histology diagnosis were included in the current study. The histologic diagnosis was considered the gold standard. RESULTS: A total of 19 cases were included in the current study. The cases were divided into 7 categories based on their cytologic diagnoses: 1) nondiagnostic (1 case); 2) benign, nonneoplastic lesion (2 cases); 3) benign salivary gland neoplasm (2 cases); 4) salivary gland neoplasm (4 cases); 5) epithelial neoplasm, not otherwise specified (1 case); 6) markedly atypical cells suspicious for a malignant neoplasm (1 case); and 7) malignant neoplasms (8 cases). CONCLUSIONS: The interpretation of salivary gland FNA can be influenced by several factors including prominent metaplasia, focal atypia, cystic changes, variable cellular components within the lesions, scant cellularity, variants of neoplasms, and a prior history of malignancy. Multiple passes representing the entire mass, imaging findings, and familiarity with salivary gland cytomorphology may improve the diagnostic accuracy. Cancer Cytopathol 2018;126:101-11. (c) 2017 American Cancer Society. PMID- 29131560 TI - The Effects of Rate Regulation on Demand for Supplemental Health Insurance PMID- 29131561 TI - Did Medicare Induce Pharmaceutical Innovation? PMID- 29131562 TI - Health and Democracy. PMID- 29131563 TI - Sustained Codelivery of Cisplatin and Paclitaxel via an Injectable Prodrug Hydrogel for Ovarian Cancer Treatment. AB - The sustained release of both the hydrophilic drug and hydrophobic drug from one delivery system remains challenging in pharmaceutics and biomaterials science. The combination of hydrophilic cisplatin and hydrophobic paclitaxel (PTX) exhibits a clinical survival advantage compared with the individual drug therapy against various tumors such as ovarian cancer. In this study, a localized, long term codelivery system of cisplatin and PTX was developed using an injectable and thermosensitive polymer-platinum(IV) conjugate hydrogel as the carrier. The thermosensitive Bi(mPEG-PLGA)-Pt(IV) (PtGel) conjugate was synthesized via covalently linking two mPEG-PLGA copolymers onto a Pt(IV) prodrug, and its concentrated aqueous solution exhibited a reversible sol-gel transition upon heating. Meanwhile, the core-corona micelles formed by the amphiphilic conjugates in water could serve as a reservoir for the solubilization of PTX, and thus an injectable binary drug-loaded hydrogel formulation was obtained. We also found that the introduction of PTX into the conjugate hydrogel decreased its sol-gel transition temperature and improved its gel strength. In vitro release experiments showed that both of the loaded drugs were released in a sustained manner for as long as 2.5 months, which was the longest combination delivery of these two drugs ever reported. In vitro cellular assays revealed that the dual drug system exhibited a synergistic anticancer effect against ovarian cancer cells. Finally, using the SKOV-3 ovarian cancer xenograft mouse model, we demonstrated that a single injection of the PTX-loaded conjugate hydrogel system resulted in enhanced anticancer efficacy and significantly reduced the side effects, when compared with the multiple injections of the free drug combination. PMID- 29131564 TI - Light-Emitting Photon-Upconversion Nanoparticles in the Generation of Transdermal Reactive-Oxygen Species. AB - Common photosensitizers used in photodynamic therapy do not penetrate the skin effectively. In addition, the visible blue and red lights used to excite such photosensitizers have shallow penetration depths through tissue. To overcome these limitations, we have synthesized ultraviolet- and visible-light-emitting, energy-transfer-based upconversion nanoparticles and coencapsulated them inside PLGA-PEG (methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)) nanoparticles with the photosensitizer protoporphyrin IX. Nd3+ has been introduced as a sensitizer in the upconversion nanostructure to allow its excitation at 808 nm. The subcytotoxic doses of the hybrid nanoparticles have been evaluated on different cell lines (i.e., fibroblasts, HaCaT, THP-1 monocytic cell line, U251MG (glioblastoma cell line), and mMSCs (murine mesenchymal stem cells). Upon NIR (near infrared)-light excitation, the upconversion nanoparticles emitted UV and VIS light, which consequently activated the generation of reactive oxygen species (ROS). In addition, after irradiating at 808 nm, the resulting hybrid nanoparticles containing both upconversion nanoparticles and protoporphyrin IX generated 3.4 times more ROS than PLGA-PEG nanoparticles containing just the same dose of protoporphyrin IX. Their photodynamic effect was also assayed on different cell cultures, demonstrating their efficacy in selectively killing treated and irradiated cells. Compared to the topical application of the free photosensitizer, enhanced skin permeation and penetration were observed for the nanoparticulate formulation, using an ex vivo human-skin permeation experiment. Whereas free protoporphyrin IX remained located at the outer layer of the skin, nanoparticle-encapsulated protoporphyrin IX was able to penetrate through the epidermal layer slightly into the dermis. PMID- 29131565 TI - Protein-Based 3D Microstructures with Controllable Morphology and pH-Responsive Properties. AB - The microtechnology of controlling stimuli-responsive biomaterials at micrometer scale is crucial for biomedical applications. Here, we report bovine serum albumin (BSA)-based three-dimensional (3D) microstructures with tunable surface morphology and pH-responsive properties via two-photon polymerization microfabrication technology. The laser processing parameters, including laser power, scanning speed, and layer distance, are optimized for the fabrication of well-defined 3D BSA microstructures. The tunable morphology of BSA microstructures and a wide range of pH response corresponding to the swelling ratio of 1.08-2.71 have been achieved. The swelling behavior of the microstructures can be strongly influenced by the concentration of BSA precursor, which has been illustrated by a reasonable mechanism. A panda face-shaped BSA microrelief with reversible pH-responsive properties is fabricated and exhibits unique "facial expression" variations in pH cycle. We further design a mesh sieve shaped microstructure as a functional device for promising microparticle separation. The pore sizes of microstructures can be tuned by changing the pH values. Therefore, such protein-based microstructures with controllable morphology and pH-responsive properties have potential applications especially in biomedicine and biosensors. PMID- 29131566 TI - New Class of LAGP-Based Solid Polymer Composite Electrolyte for Efficient and Safe Solid-State Lithium Batteries. AB - Inorganic solid electrolytes (SEs) possess substantial safety and electrochemical stability, which make them as key components of safe rechargeable solid-state Li batteries with high energy density. However, complicated integrally molding process and poor wettability between SEs and active materials are the most challenging barriers for the application of SEs. In this regard, we explore composite SEs of the active ceramic Li1+xAlxGe2-x(PO4)3 (LAGP) as the main medium for ion conduction and the polymer P(VDF-HFP) as a matrix. Meanwhile, for the first time, we choice high chemical, thermal, and electrochemical stability of ionic liquid swelled in polymer, which significantly ameliorate the interface in the cell. In addition, a reduced crystallinity degree of the polymer in the electrolyte can also be achieved. All of these lead to good ionic conductivity of the composite electrolyte (LPELCE), at the same time, good compatibility with the lithium electrode. Especially, high mechanical strength and stable solid electrolyte interphase which suppressed the growth of lithium dendrites and high thermal safety stability can also be observed. For further illustration, the solid-state lithium battery of LiFePO4/LPELCE/Li shows relatively satisfactory performance, indicating the promising potentials of using this type of electrolyte to develop high safety and high energy density solid-state lithium batteries. PMID- 29131567 TI - Highly Efficient Antibacterial Surfaces Based on Bacterial/Cell Size Selective Microporous Supports. AB - We report on the fabrication of efficient antibacterial substrates selective for bacteria, i.e., noncytotoxic against mammalian cells. The strategy proposed is based on the different size of bacteria (1-4 MUm) in comparison with mammalian cells (above 20 MUm) that permit the bacteria to enter in contact with the inner part of micrometer-sized pores where the antimicrobial functionality are placed. On the contrary, mammalian cells, larger in terms of size, remain at the top surface, thus reducing adverse cytotoxic effects and improving the biocompatibility of the substrates. For this purpose, we fabricated well-ordered functional microporous substrates (3-5 MUm) using the breath figures approach that enabled the selective functionalization of the pore cavity, whereas the rest of the surface remained unaffected. Microporous surfaces were prepared from polymer blends comprising a homopolymer (i.e., polystyrene) and a block copolymer (either polystyrene-b-poly(dimethylaminoethyl methacrylate) (PDMAEMA) or a quaternized polystyrene-b-poly(dimethylaminoethyl methacrylate)). As a result, porous surfaces with a narrow size distribution and a clear enrichment of the PDMAEMA or the quaternized PDMAEMA block inside the pores were obtained that, in the case of the quaternized PDMAEMA, provided an excellent antimicrobial activity to the films. PMID- 29131568 TI - Diisonitrile Natural Product SF2768 Functions As a Chalkophore That Mediates Copper Acquisition in Streptomyces thioluteus. AB - A nonribosomal peptide synthetase (NRPS) gene cluster (sfa) was identified in Streptomyces thioluteus to direct the biosynthesis of the diisonitrile antibiotic SF2768. Its biosynthetic pathway was reasonably proposed based on bioinformatics analysis, metabolic profiles of mutants, and the elucidation of the intermediate and shunt product structures. Bioinformatics-based alignment found a putative ATP binding cassette (ABC) transporter related to iron import within the biosynthetic gene cluster, which implied that the product might be a siderophore. However, characterization of the metal-binding properties by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), metal-ligand titration, thin-layer chromatography (TLC), and chrome azurol S (CAS) assays revealed that the final product SF2768 and its diisonitrile derivatives specifically bind copper, rather than iron, to form stable complexes. Inductively coupled plasma mass spectrometry (ICP-MS) analysis revealed that the intracellular cupric content of S. thioluteus significantly increased upon incubation with the copper-SF2768 complex, direct evidence for the copper acquisition function of SF2768. Further in vivo functional characterization of the transport elements for the copper-SF2768 complexes not only confirmed the chalkophore identity of the compound but also gave initial clues into the copper uptake mechanism of this nonmethanotrophic microorganism. PMID- 29131569 TI - Efficient and Lightweight Electromagnetic Wave Absorber Derived from Metal Organic Framework-Encapsulated Cobalt Nanoparticles. AB - Porous-carbon-based nanocomposites are gaining tremendous interest because of good compatibility, lightweight, and strong electromagnetic wave absorption. However, it is still a great challenge to design and synthesize porous-carbon based composites with strong absorption capability and broad frequency bandwidth. Herein, a facile and effective method was developed to synthesize Co magnetic nanoparticles/metal organic framework (MOF) (Co NPs/ZIF-67) nanocomposites. Co NPs/porous C composites were subsequently obtained by annealing Co NPs/ZIF-67 nanocomposites at different temperatures under an inert atmosphere. The carbonized nanocomposites showed highly efficient electromagnetic wave absorption capability. Specifically, the optimal composite (i.e., Co/C-700) possessed a maximum reflection loss (RL) value of -30.31 dB at 11.03 GHz with an effective absorption bandwidth (RL <= -10 dB) of 4.93 GHz. The electromagnetic parameters and the absorption performance of the composites are readily tunable by adjusting the carbonization temperature and the concentration of Co NPs in the composites. Because of the combination of good impedance matching, dual-loss mechanism, and the synergistic effect between Co NPs and porous carbon composites, these Co NPs/MOF-derived composites are attractive candidates for electromagnetic wave absorbers. PMID- 29131570 TI - Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating Enzyme Subfamily. AB - The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to targeting this so far undruggable oncogene. Here, we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and while displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases (DUBs). The utility of these compounds as valuable probes to investigate and further explore cellular DUB biology is highlighted by the demonstration of target engagement against both USP25 and USP28 in cells. Furthermore, we demonstrate that these inhibitors are able to elicit modulation of both the total levels and the half-life of the c-Myc oncoprotein in cells and also induce apoptosis and loss of cell viability in a range of cancer cell lines. We however observed a narrow therapeutic index compared to a panel of tissue-matched normal cell lines. Thus, it is hoped that these probes and data presented herein will further advance our understanding of the biology and tractability of DUBs as potential future therapeutic targets. PMID- 29131571 TI - Nanostructure of Fully Injectable Hydrazone-Thiosuccinimide Interpenetrating Polymer Network Hydrogels Assessed by Small-Angle Neutron Scattering and dSTORM Single-Molecule Fluorescence Microscopy. AB - Herein, we comprehensively investigate the internal morphology of fully injectable interpenetrating networks (IPNs) prepared via coextrusion of functionalized precursor polymer solutions based on thermoresponsive poly(N isopropylacrylamide) (PNIPAM) and nonthermoresponsive poly(vinyl pyrrolidone) (PVP) by reactive mixing using kinetically orthogonal hydrazone and thiosuccinimide cross-linking mechanisms. Small-angle neutron scattering, probing both the full IPN as well as the individual constituent networks of the IPN using index-matching, suggests a partially mixed internal structure characterized by PNIPAM-rich domains entrapped in a clustered PVP-rich phase. This interpretation is supported by super-resolution fluorescence microscopy (direct stochastic optical reconstruction microscopy) measurements on the same gels on a different length scale, which show both the overall phase segregation typical of an IPN as well as moderate mixing of PNIPAM into the PVP-rich phase. Such a morphology is consistent with the kinetics of both gelation and phase separation in this in situ gelling system, in which gelation effectively traps a fraction of the PNIPAM in the PVP phase prior to full phase separation; by contrast, such interphase mixing is not observed in semi-IPN control hydrogels. This knowledge has significant potential for the design of an injectable hydrogel with internal morphologies optimized for particular biomedical applications. PMID- 29131572 TI - In Vivo Optical Detection and Spectral Triangulation of Carbon Nanotubes. AB - In the first in vivo demonstration of spectral triangulation, biocompatible composites of single-walled carbon nanotubes in Matrigel have been surgically implanted into mouse ovaries and then noninvasively detected and located. This optical method deduces the three-dimensional position of a short-wave IR emission source from the wavelength-dependent attenuation of fluorescence in tissues. Measurements were performed with a second-generation optical scanner that uses a light-emitting diode matrix emitting at 736 nm for diffuse specimen excitation. The intrinsic short-wave IR fluorescence of the nanotubes was collected at various positions on the specimen surface, spectrally filtered, and detected by a photon-counting InGaAs avalanche photodiode. Sensitivity studies showed a detection limit of ~120 pg of nanotubes located beneath ~3 mm of tissue. In addition, the mass and location of implanted nanotubes could be deduced through spectral triangulation with sub-millimeter accuracy, as validated with the aid of magnetic resonance imaging (MRI) data. Dual-modality imaging combining spectral triangulation with computed tomography or MRI will allow accurate registration of emission centers with anatomical features. These results are a step toward the future use of probes with targeting agents such as antibodies linked to nanotube tags for the noninvasive detection and imaging of tumors in preclinical research on small animals. Translation to the clinic could aid in early detection of ovarian cancer and identification of metastases for resection during primary surgery. PMID- 29131573 TI - Flexible and Lightweight Pressure Sensor Based on Carbon Nanotube/Thermoplastic Polyurethane-Aligned Conductive Foam with Superior Compressibility and Stability. AB - Flexible and lightweight carbon nanotube (CNT)/thermoplastic polyurethane (TPU) conductive foam with a novel aligned porous structure was fabricated. The density of the aligned porous material was as low as 0.123 g.cm-3. Homogeneous dispersion of CNTs was achieved through the skeleton of the foam, and an ultralow percolation threshold of 0.0023 vol % was obtained. Compared with the disordered foam, mechanical properties of the aligned foam were enhanced and the piezoresistive stability of the flexible foam was improved significantly. The compression strength of the aligned TPU foam increases by 30.7% at the strain of 50%, and the stress of the aligned foam is 22 times that of the disordered foam at the strain of 90%. Importantly, the resistance variation of the aligned foam shows a fascinating linear characteristic under the applied strain until 77%, which would benefit the application of the foam as a desired pressure sensor. During multiple cyclic compression-release measurements, the aligned conductive CNT/TPU foam represents excellent reversibility and reproducibility in terms of resistance. This nice capability benefits from the aligned porous structure composed of ladderlike cells along the orientation direction. Simultaneously, the human motion detections, such as walk, jump, squat, etc. were demonstrated by using our flexible pressure sensor. Because of the lightweight, flexibility, high compressibility, excellent reversibility, and reproducibility of the conductive aligned foam, the present study is capable of providing new insights into the fabrication of a high-performance pressure sensor. PMID- 29131574 TI - Complex Phase Behavior and Network Characteristics of Midblock-Solvated Triblock Copolymers as Physically Cross-Linked Soft Materials. AB - In the presence of a midblock-selective solvent, triblock copolymers not only self-organize but also form a molecular network. Thermoplastic elastomer gels constitute examples of such materials and serve as sealants and adhesives, as well as ballistic, microfluidic, and electroactive media. We perform Monte Carlo and dissipative particle dynamics simulations to investigate the phase behavior and network characteristics of these materials. Of particular interest is the existence of a truncated octahedral morphology that resembles the atomic arrangement of various inorganic species. Both simulation approaches quantify the midblock bridges responsible for network development and thus provide a detailed molecular picture of these composition-tunable soft materials. PMID- 29131575 TI - Halogenation of Biotin Protein Ligase Inhibitors Improves Whole Cell Activity against Staphylococcus aureus. AB - We report the synthesis and evaluation of 5-halogenated-1,2,3-triazoles as inhibitors of biotin protein ligase from Staphylococcus aureus. The halogenated compounds exhibit significantly improved antibacterial activity over their nonhalogenated counterparts. Importantly, the 5-fluoro-1,2,3-triazole compound 4c displays antibacterial activity against S. aureus ATCC49775 with a minimum inhibitory concentration (MIC) of 8 MUg/mL. PMID- 29131576 TI - Pharmacological Characterization of [3H]ATPCA as a Substrate for Studying the Functional Role of the Betaine/GABA Transporter 1 and the Creatine Transporter. AB - The betaine/gamma-aminobutyric acid (GABA) transporter 1 (BGT1) is one of the four GABA transporters (GATs) involved in the termination of GABAergic neurotransmission. Although suggested to be implicated in seizure management, the exact functional importance of BGT1 in the brain is still elusive. This is partly owing to the lack of potent and selective pharmacological tool compounds that can be used to probe its function. We previously reported the identification of 2 amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (ATPCA), a selective substrate for BGT1 over GAT1/GAT3, but also an agonist for GABAA receptors. With the aim of providing new functional insight into BGT1, we here present the synthesis and pharmacological characterization of the tritiated analogue, [3H]ATPCA. Using traditional uptake assays at recombinant transporters expressed in cell lines, [3H]ATPCA displayed a striking selectivity for BGT1 among the four GATs ( Km and Vmax values of 21 MUM and 3.6 nmol ATPCA/(min * mg protein), respectively), but was also found to be a substrate for the creatine transporter (CreaT). In experiments with mouse cortical cell cultures, we observed a Na+ dependent [3H]ATPCA uptake in neurons, but not in astrocytes. The neuronal uptake could be inhibited by GABA, ATPCA, and a noncompetitive BGT1-selective inhibitor, indicating functional BGT1 in neurons. In conclusion, we report [3H]ATPCA as a novel radioactive substrate for both BGT1 and CreaT. The dual activity of the radioligand makes it most suitable for use in recombinant studies. PMID- 29131577 TI - Electronic Structure Reconfiguration toward Pyrite NiS2 via Engineered Heteroatom Defect Boosting Overall Water Splitting. AB - Developing highly active and low-cost heterogeneous catalysts toward overall electrochemical water splitting is extremely desirable but still a challenge. Herein, we report pyrite NiS2 nanosheets doped with vanadium heteroatoms as bifunctional electrode materials for both hydrogen- and oxygen-evolution reaction (HER and OER). Notably, the electronic structure reconfiguration of pyrite NiS2 is observed from typical semiconductive characteristics to metallic characteristics by engineering vanadium (V) displacement defect, which is confirmed by both experimental temperature-dependent resistivity and theoretical density functional theory calculations. Furthermore, elaborate X-ray absorption spectroscopy measurements reveal that electronic structure reconfiguration of NiS2 is rooted in electron transfer from doped V to Ni sites, consequently enabling Ni sites to gain more electrons. The metallic V-doped NiS2 nanosheets exhibit extraordinary electrocatalytic performance with overpotentials of about 290 mV for OER and about 110 mV for HER at 10 mA cm-2 with long-term stability in 1 M KOH solutions, representing one of the best non-noble-metal bifunctional electrocatalysts to date. This work provides insights into electronic structure engineering from well-designed atomic defect metal sulfide. PMID- 29131578 TI - Optically Detected Magnetic Resonance for Selective Imaging of Diamond Nanoparticles. AB - While there is great interest in understanding the fate and transport of nanomaterials in the environment and in biological systems, the detection of nanomaterials in complex matrices by fluorescence methods is complicated by photodegradation, blinking, and the presence of natural organic material and other fluorescent background signals that hamper detection of fluorescent nanomaterials of interest. Optically detected magnetic resonance (ODMR) of nitrogen-vacancy (NV) centers in diamond nanoparticles provides a pathway toward background-free fluorescence measurements, as the application of a resonant microwave field can selectively modulate the intensity from NV centers in nanodiamonds of various diameters in complex materials systems using on-resonance and off-resonance microwave fields. This work represents the first investigation showing how nanoparticle diameter impacts the NV center lifetime and thereby directly impacts the accessible contrast and signal-to-noise ratio when using ODMR to achieve background-free imaging of NV-nanodiamonds in the presence of interfering fluorophores. These results provide new insights that will guide the choice of optimum nanoparticle size and methodology for background-free imaging and sensing applications, while also providing a model system to explore the fate and transport of nanomaterials in the environment. PMID- 29131579 TI - Binding and Energetics of Electron Transfer between an Artificial Four-Helix Mn Protein and Reaction Centers from Rhodobacter sphaeroides. AB - The ability of an artificial four-helix bundle Mn-protein, P1, to bind and transfer an electron to photosynthetic reaction centers from the purple bacterium Rhodobacter sphaeroides was characterized using optical spectroscopy. Upon illumination of reaction centers, an electron is transferred from P, the bacteriochlorophyll dimer, to QA, the primary electron acceptor. The P1 Mn protein can bind to the reaction center and reduce the oxidized bacteriochlorophyll dimer, P+, with a dissociation constant of 1.2 MUM at pH 9.4, comparable to the binding constant of c-type cytochromes. Amino acid substitutions of surface residues on the Mn-protein resulted in increases in the dissociation constant to 8.3 MUM. The extent of reduction of P+ by the P1 Mn protein was dependent on the P/P+ midpoint potential and the pH. Analysis of the free energy difference yielded a midpoint potential of approximately 635 mV at pH 9.4 for the Mn cofactor of the P1 Mn-protein, a value similar to those found for other Mn cofactors in proteins. The linear dependence of -56 mV/pH is consistent with one proton being released upon Mn oxidation, allowing the complex to maintain overall charge neutrality. These outcomes demonstrate the feasibility of designing four-helix bundles and other artificial metalloproteins to bind and transfer electrons to bacterial reaction centers and establish the usefulness of this system as a platform for designing sites to bind novel metal cofactors capable of performing complex oxidation-reduction reactions. PMID- 29131581 TI - Template-Assisted Enzymatic Synthesis of Oligopeptides from a Polylactide Chain. AB - Peptides are often attached to polymer materials, as bioactive components, for the control of interactions between the material and its surrounding proteins and cells. However, synthesizing peptides and attaching them to polymers can be challenging and laborious. Herein, we describe the grafting of oligopeptides to an aliphatic polyester, using a one-step chemo-enzymatic synthesis with papain as the biocatalyst. To enable enzyme-mediated functionalization of the polyester, ethyl hept-6-enoylalaninate (grafter) was synthesized and attached to polylactide chains using thiol-ene click reactions. The oligopeptides were grafted onto the polylactide chains using two different synthetic routes: the grafting from strategy, in which the grafter was attached to the polyester prior to oligopeptide synthesis, or the grafting to strategy, in which oligopeptides were synthesized on the grafter first, then attached to the polymer chain. The final products were analyzed and their structures were confirmed using nuclear magnetic resonance (NMR). The peptide attachment was evaluated using size exclusion chromatography (SEC), contact angle measurement and energy-dispersive X-ray spectroscopy-scanning electron microscopy (EDS-SEM). Furthermore, the mechanistic aspects of the synthesis of the oligopeptides on the grafter were studied using molecular dynamics (MD) simulations. The simulation revealed that hydrogen bonding (between the P1 amide nitrogen of the grafter backbone and the carbonyl oxygen of D158 in the papain) maintain the grafter in a productive conformation to stabilize the transition state of nitrogen inversion, a key step of the biocatalytic mechanism. Apart from being biologically relevant, both experimental and computational results suggest that the designed grafter is a good template for initiating chemo-enzymatic synthesis. The results also showed that the grafting to strategy was more successful compared to the grafting from strategy. Overall, a successful synthesis of predefined peptide functionalized polylactide was prepared, where the oligopeptides were grafted in an easy, time efficient, and environmentally friendly way. PMID- 29131580 TI - Modular Self-Assembly of Protein Cage Lattices for Multistep Catalysis. AB - The assembly of individual molecules into hierarchical structures is a promising strategy for developing three-dimensional materials with properties arising from interaction between the individual building blocks. Virus capsids are elegant examples of biomolecular nanostructures, which are themselves hierarchically assembled from a limited number of protein subunits. Here, we demonstrate the bio inspired modular construction of materials with two levels of hierarchy: the formation of catalytically active individual virus-like particles (VLPs) through directed self-assembly of capsid subunits with enzyme encapsulation, and the assembly of these VLP building blocks into three-dimensional arrays. The structure of the assembled arrays was successfully altered from an amorphous aggregate to an ordered structure, with a face-centered cubic lattice, by modifying the exterior surface of the VLP without changing its overall morphology, to modulate interparticle interactions. The assembly behavior and resultant lattice structure was a consequence of interparticle interaction between exterior surfaces of individual particles and thus independent of the enzyme cargos encapsulated within the VLPs. These superlattice materials, composed of two populations of enzyme-packaged VLP modules, retained the coupled catalytic activity in a two-step reaction for isobutanol synthesis. This study demonstrates a significant step toward the bottom-up fabrication of functional superlattice materials using a self-assembly process across multiple length scales and exhibits properties and function that arise from the interaction between individual building blocks. PMID- 29131582 TI - Nanotransplantation Printing of Crystallographic-Orientation-Controlled Single Crystalline Nanowire Arrays on Diverse Surfaces. AB - The fabrication of a highly ordered array of single-crystalline nanostructures prepared from solution-phase or vapor-phase synthesis methods is extremely challenging due to multiple difficulties of spatial arrangement and control of crystallographic orientation. Herein, we introduce a nanotransplantation printing (NTPP) technique for the reliable fabrication, transfer, and arrangement of single-crystalline Si nanowires (NWs) on diverse substrates. NTPP entails (1) formation of nanoscale etch mask patterns on conventional low-cost Si via nanotransfer printing, (2) two-step combinatorial plasma etching for defining Si NWs, and (3) detachment and transfer of the NWs onto various receiver substrates using an infiltration-type polymeric transfer medium and a solvent-assisted adhesion switching mechanism. Using this approach, high-quality, highly ordered Si NWs can be formed on almost any type of surface including flexible plastic substrates, biological surfaces, and deep-trench structures. Moreover, NTPP provides controllability of the crystallographic orientation of NWs, which is confirmed by the successful generation of (100)- and (110)-oriented Si NWs with different properties. The outstanding electrical properties of the NWs were confirmed by fabricating and characterizing Schottky junction field-effect transistors. Furthermore, exploiting the highly flexible nature of the NWs, a high-performance piezoresistive strain sensor, with a high gauge factor over 200 was realized. PMID- 29131583 TI - Constant pH Accelerated Molecular Dynamics Investigation of the pH Regulation Mechanism of Dinoflagellate Luciferase. AB - The bioluminescence reaction in dinoflagellates involves the oxidation of an open chain tetrapyrrole by the enzyme dinoflagellate luciferase (LCF). The activity of LCF is tightly regulated by pH, where the enzyme is essentially inactive at pH ~8 and optimally active at pH ~6. Little is known about the mechanism of LCF or the structure of the active form of the enzyme, although it has been proposed that several intramolecularly conserved histidine residues in the N-terminal region are important for the pH regulation mechanism. Here, constant pH accelerated molecular dynamics was employed to gain insight into the conformational activation of LCF induced by acidification. PMID- 29131584 TI - Mechanically Driven Grain Boundary Formation in Nickel Nanowires. AB - Metallic nanomaterials are widely used in micro/nanodevices. However, the mechanically driven microstructure evolution in these nanomaterials is not clearly understood, particularly when large stress and strain gradients are present. Here, we report the in situ bending experiment of Ni nanowires containing nanoscale twin lamellae using high-resolution transmission electron microscopy. We found that the large, localized bending deformation of Ni nanowires initially resulted in the formation of a low-angle tilt grain boundary (GB), consisting of randomly distributed dislocations in a diffuse GB layer. Further bending intensified the local plastic deformation and thus led to the severe distortion and collapse of local lattice domains in the GB region, thereby transforming a low-angle GB to a high-angle GB. Atomistic simulations, coupled with in situ atomic-scale imaging, unravelled the roles of bending-induced strain gradients and associated geometrically necessary dislocations in GB formation. These results offer a valuable understanding of the mechanically driven microstructure changes in metallic nanomaterials through GB formation. The work also has implications for refining the grains in bulk nanocrystalline materials. PMID- 29131585 TI - Antibody-Templated Assembly of an RNA Mimic of Green Fluorescent Protein. AB - One of the most intriguing ways through which nature achieves regulation of biological pathways encompasses the coordination of noncovalent interactions that bring biomolecules to be colocalized in a designated restricted space. Inspired by this mechanism, we have explored the possibility of using antibodies as bivalent biomolecular substrates for the templated assembly of a functional RNA structure. We have developed a biosupramolecular complementation assay by assembling a fluorescent Spinach aptamer, which is a synthetic RNA mimic of the Green Fluorescent Protein, from its split segments. We have employed two antigen tagged RNA strands that, upon binding to the target antibody, are colocalized in a confined space and can reassemble into the native Spinach conformation, yielding a measurable fluorescence emission as a function of the templating antibody concentration. We have demonstrated the generality of our approach using two different antigen/antibody systems and found that both platforms show high binding affinity, specificity for the target antibody, and enough selectivity to work in crude cellular extracts. This study highlights the potential of biosupramolecular RNA engineering for the development of innovative biomimetic tools for nanobiotechnology and bioanalytical assays. PMID- 29131586 TI - Single-Walled Carbon Nanotubes Probed with Insulator-Based Dielectrophoresis. AB - Single-walled carbon nanotubes (SWNTs) offer unique electrical and optical properties. Common synthesis processes yield SWNTs with large length polydispersity (several tens of nanometers up to centimeters) and heterogeneous electrical and optical properties. Applications often require suitable selection and purification. Dielectrophoresis is one manipulation method for separating SWNTs based on dielectric properties and geometry. Here, we present a study of surfactant and single-stranded DNA-wrapped SWNTs suspended in aqueous solutions manipulated by insulator-based dielectrophoresis (iDEP). This method allows us to manipulate SWNTs with the help of arrays of insulating posts in a microfluidic device around which electric field gradients are created by the application of an electric potential to the extremities of the device. Semiconducting SWNTs were imaged during dielectrophoretic manipulation with fluorescence microscopy making use of their fluorescence emission in the near IR. We demonstrate SWNT trapping at low-frequency alternating current (AC) electric fields with applied potentials not exceeding 1000 V. Interestingly, suspended SWNTs showed both positive and negative dielectrophoresis, which we attribute to their zeta potential and the suspension properties. Such behavior agrees with common theoretical models for nanoparticle dielectrophoresis. We further show that the measured zeta potentials and suspension properties are in excellent agreement with a numerical model predicting the trapping locations in the iDEP device. This study is fundamental for the future application of low-frequency AC iDEP for technological applications of SWNTs. PMID- 29131587 TI - Cell Migration and Bone Formation from Mesenchymal Stem Cell Spheroids in Alginate Hydrogels Are Regulated by Adhesive Ligand Density. AB - The adhesion and migration of cells entrapped in engineered materials is regulated by available adhesive ligands. Although mesenchymal stem cell (MSC) spheroids injected into damaged tissues promote repair, their transplantation in biomaterials which regulate cell migration from the aggregate may further enhance their therapeutic potential. Alginate hydrogels were modified with Arginine Glycine-Aspartic acid (RGD) at increasing concentrations, and osteogenically induced human MSC spheroids were entrapped to assess cell migration, survival, and differentiation. Cell migration was greater from MSC spheroids in alginate modified with low RGD levels, while the osteogenic potential was higher for spheroids entrapped in unmodified or high RGD density gels in vitro. Upon ectopic implantation, microCT and immunohistochemistry revealed extensive osteogenesis in unmodified and high RGD density gels compared to low RGD density gels. These data suggest that restriction of MSC migration from spheroids correlates with enhanced spheroid osteogenic potential, representing a novel tool for bone tissue engineering. PMID- 29131588 TI - Kinetic Isotope Effects and Transition State Structure for Hypoxanthine-Guanine Xanthine Phosphoribosyltransferase from Plasmodium falciparum. AB - Plasmodium falciparum parasites are purine auxotrophs that rely exclusively on the salvage of preformed purines from their human hosts to supply the requirement for purine nucleotides. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) catalyzes the freely reversible Mg2+-dependent conversion of 6-oxopurine bases to their respective nucleotides and inorganic pyrophosphate. The phosphoribosyl group is derived from 5-phospho-alpha-d-ribosyl 1-pyrophosphate (PRPP). The enzyme from malaria parasites (PfHGXPRT) is essential as hypoxanthine is the major precursor in purine metabolism. We used specific heavy atom labels in PRPP and hypoxanthine to measure primary (1-14C and 9-15N) and secondary (1-3H and 7-15N) intrinsic kinetic isotope effect (KIE) values for PfHGXPRT. Intrinsic isotope effects contain information for understanding enzymatic transition state properties. The transition state of PfHGXPRT was explored by matching KIE values predicted from quantum mechanical calculations to the intrinsic values determined experimentally. This approach provides information about PfHGXPRT transition state bond lengths, geometry, and atomic charge distribution. The transition state structure of PfHGXPRT was determined in the physiological direction of addition of ribose 5-phosphate to hypoxanthine by overcoming the chemical instability of PRPP. The transition state for PfHGXPRT forms nucleotides through a well-developed and near-symmetrical DN*AN, SN1-like transition state. PMID- 29131589 TI - Using Tryptophan Mutants To Probe the Structural and Functional Status of BsSCO, a Copper Binding, Cytochrome c Oxidase Assembly Protein from Bacillus subtilis. AB - The synthesis of cytochrome c oxidase protein from Bacillus subtilis (i.e., BsSCO) binds copper with picomolar affinity, which increases the protein's melting temperature (i.e., TM) by 20 degrees C. Here two native tryptophans (i.e., W36 and W101) are identified as major contributors to BsSCO's structural form, and their contributions to the stability, intrinsic fluorescence, and copper binding properties of BsSCO are explored. Single mutations of tryptophan to phenylalanine decrease the TM by 10 degrees C and the folding free energy by 3-4 kcal/mol. A more severe change to alanine (i.e., W36A BsSCO) decreases the TM by 20 degrees C and the stability by 9 kcal/mol. However, these mutants bind copper with high affinity and assemble cytochrome c oxidase in vivo. Replacing phenylalanine at a position near (~5 A) the copper binding site with tryptophan (i.e., F42W) increases the TM of apo-BsSCO by 3 degrees C but diminishes the effect of copper binding. When both native tryptophans are changed to alanine, apo-BsSCO is unfolded in vitro and is not functional in cytochrome c oxidase assembly in vivo. A double-mutant of BsSCO in which W36A is combined with F42W exhibits a form of metastability. Apo-W36A/F42W BsSCO melts at 37 degrees C, which upon binding of copper shifts to 65 degrees C. B. subtilis expressing W36A/F42W BsSCO and grown at 37 degrees C does not assemble cytochrome c oxidase. However, when these cells are cooled to 25 degrees C, cytochrome c oxidase activity is recovered. Our results illustrate the subtle relationship between the structural stability and functional properties of BsSCO in the assembly of cytochrome c oxidase. PMID- 29131590 TI - Environmental Nuclear Magnetic Resonance Spectroscopy: An Overview and a Primer. AB - NMR spectroscopy is a versatile tool for the study of structure and interactions in environmental media such as air, soil, and water as well as monitoring the metabolic responses of living organisms to an ever changing environment. Part review, part perspective, and part tutorial, this Feature is aimed at nonspecialists who are interested in learning more about the potential and impact of NMR spectroscopy in environmental research. PMID- 29131591 TI - Colloidal Dual-Diameter and Core-Position-Controlled Core/Shell Cadmium Chalcogenide Nanorods. AB - To capitalize on shape- and structure-dependent properties of semiconductor nanorods (NRs), high-precision control and exquisite design of their growth are desired. Cadmium chalcogenide (CdE; E = S or Se) NRs are the most studied class of such, whose growth exhibits axial anisotropy, i.e., different growth rates along the opposite directions of {0001} planes. However, the mechanism behind asymmetric axial growth of NRs remains unclear because of the difficulty in instant analysis of growth surfaces. Here, we design colloidal dual-diameter semiconductor NRs (DDNRs) under the quantum confinement regime, which have two sections along the long axis with different diameters. The segmentation of the DDNRs allows rigorous assessment of the kinetics of NR growth at a molecular level. The reactivity of a terminal facet passivated by an organic ligand is governed by monomer diffusivity through the surface ligand monolayer. Therefore, the growth rate in two polar directions can be finely tuned by controlling the strength of ligand-ligand attraction at end surfaces. Building on these findings, we report the synthesis of single-diameter CdSe/CdS core/shell NRs with CdSe cores of controllable position, which reveals a strong structure-optical polarization relationship. The understanding of the NR growth mechanism with controllable anisotropy will serve as a cornerstone for the exquisite design of more complex anisotropic nanostructures. PMID- 29131592 TI - Paper-Plastic Hybrid Microfluidic Device for Smartphone-Based Colorimetric Analysis of Urine. AB - In this work, a disposable paper-plastic hybrid microfluidic lab-on-a-chip (LOC) has been developed and successfully applied for the colorimetric measurement of urine by the smartphone-based optical platform using a "UrineAnalysis" Android app. The developed device was cost-effectively implemented as a stand-alone hybrid LOC by incorporating the paper-based conventional reagent test strip inside the plastic-based LOC microchannel. The LOC device quantitatively investigated the small volume (40 MUL) of urine analytes for the colorimetric reaction of glucose, protein, pH, and red blood cell (RBC) in integration with the finger-actuating micropump. On the basis of our experiments, the conventional urine strip showed large deviation as the reaction time goes by, because dipping the strip sensor in a bottle of urine could not control the reaction volume. By integrating the strip sensor in the LOC device for urine analysis, our device significantly improves the time-dependent inconstancy of the conventional dipstick-based urine strip, and the smartphone app used for image analysis enhances the visual assessment of the test strip, which is a major user concern for the colorimetric analysis in point-of-care (POC) applications. As a result, the user-friendly LOC, which is successfully implemented in a disposable format with the smartphone-based optical platform, may be applicable as an effective tool for rapid and qualitative POC urinalysis. PMID- 29131593 TI - Formulation and Composition Effects in Phase Transitions of Emulsions Costabilized by Cellulose Nanofibrils and an Ionic Surfactant. AB - Cellulose nanofibrils (CNF) offer great prospects as a natural stabilizer of colloidal dispersions and complex fluids for application in food, pharma, and cosmetics. In this study, an ionic surfactant (sodium dodecyl sulfate, SDS) was used as emulsifier of oil-in-water and water-in-oil emulsions that were further costabilized by addition of CNF. The adsorption properties of SDS in both, CNF dispersions and emulsions, as well as the influence of composition (CNF and SDS concentration) and formulation (ionic strength, oil, and CNF types) on the phase behavior were elucidated and described in the framework of Windsor systems. At low salinity, the phase transition of emulsions containing CNF and SDS at low concentrations was controlled by molecular transfer in the oil-in-water system. Irregular droplets and "bi-continuous" morphologies were observed at medium and high salinity for systems containing high CNF and SDS concentrations. Water-in oil emulsions were only possible at high salinity and SDS concentrations in the presence of small amounts of CNF. The results revealed some subtle differences in CNF interfacial activity, depending on the method used for their isolation via fiber deconstruction, either from microfluidization or aqueous counter collision. Overall, we propose that the control of emulsion morphology and stability by addition of CNF opens the possibility of developing environmentally friendly complex systems that display high stability and respond to ionic strength following the expectations of classical emulsion systems. PMID- 29131594 TI - Primary Amine-Clustered DNA Aptamer for DNA-Protein Conjugation Catalyzed by Microbial Transglutaminase. AB - DNA-protein conjugates are promising biomolecules for use in areas ranging from therapeutics to analysis because of the dual functionalities of DNA and protein. Conjugation requires site-specific and efficient covalent bond formation without impairing the activity of both biomolecules. Herein, we have focused on the use of a microbial transglutaminase (MTG) that catalyzes the cross-linking reaction between a glutamine residue and a primary amine. In a model bioconjugation, a highly MTG-reactive Gln (Q)-donor peptide (FYPLQMRG, FQ) was fused to enhanced green fluorescent protein (FQ-EGFP) and a primary amine-clustered DNA aptamer was enzymatically synthesized as a novel acyl-acceptor substrate of MTG, whose combination leads to efficient and convenient preparation of DNA-protein conjugates with high purity. Dual functionality of the obtained DNA-EGFP conjugate was evaluated by discrimination of cancer cells via c-Met receptor recognition ability of the DNA aptamer. The DNA aptamer-EGFP conjugate only showed fluorescence toward cells with c-Met overexpression, indicating the retention of the biochemical properties of the DNA and EGFP in the conjugated form. PMID- 29131595 TI - Variability in Toxin Profiles of the Mediterranean Ostreopsis cf. ovata and in Structural Features of the Produced Ovatoxins. AB - Fifty-five strains of Ostreopsis were collected in the Mediterranean Sea and analyzed to characterize their toxin profiles. All the strains were grown in culture under the same experimental conditions and identified by molecular PCR assay based on the ITS-5.8S rDNA. A liquid chromatography-high resolution multiple stage mass spectrometry (LC-HRMSn) approach was used to analyze toxin profiles and to structurally characterize the detected toxins. Despite morphological and molecular characterization being consistent within the species O. cf. ovata, a certain degree of toxin variability was observed. All the strains produced ovatoxins (OVTXs), with the exception of only one strain. Toxin profiles were quite different from both qualitative and quantitative standpoints: 67% of the strains contained OVTX-a to -e, OVTX-g, and isobaric PLTX, in 25% of them only OVTX-a, -d, -e and isobaric PLTX were present, while 4% produced only OVTX-b and -c. None of the strains showed a previously identified profile, featuring OVTX-f as dominant toxin, whereas OVTX-f was a minor component of very few strains. Toxin content was mostly in the range 4-70 pg/cell with higher levels (up to 238 pg/cell) being found in strains from the Ligurian and South Adriatic Sea. Structural insights into OVTX-b, -c, -d, and -e were gained, and the new OVTX-l was detected in 36 strains. PMID- 29131596 TI - Dioxygenation Reaction of a Cobalt-Nitrosyl: Putative Formation of a Cobalt Peroxynitrite via a {CoIII(NO)(O2-)} Intermediate. AB - A cobalt-nitrosyl complex, [(BPI)Co(NO)(OAc)], 1 {BPI = 1,3-bis(2' pyridylimino)isoindol} was prepared and characterized. Structural characterization revealed that the cobalt center has a distorted square pyramidal geometry with the NO group coordinated from the apical position in a bent fashion. The addition of dioxygen (O2) to the dichloromethane solution of complex 1 resulted in the formation of nitro complex, [(BPI)Co(NO2)(OAc)], 2. It was characterized structurally. Kinetic studies suggested the involvement of an associative mechanism. FT-IR spectroscopic studies suggested the formation of the intermediate 1a [(BPI)CoIII(NO)(O2-)(OAc)] in the reaction. The intermediate 1a decomposed to complex 2 via a presumed peroxynitrite intermediate which was implicated by its characteristic phenol ring nitration reaction. PMID- 29131597 TI - Facile Low-Temperature Synthesis of Cellulose Nanocrystals Carrying Buckminsterfullerene and Its Radical Scavenging Property in Vitro. AB - Buckminsterfullerene (C60), known for its strong radical scavenging properties, has been studied extensively for its biomedical applications. Its clinical use would be promoted by novel functionalization of C60 with the aid of drug delivery carriers based on nanoparticle technologies. Cellulose nanocrystals (CNCs) have recently been exploited as a promising nanoplatform for drug delivery, owing to their intriguing attributes such as nanoscale dimensions, low toxicity, broad chemical-modifying capacity, and biocompatibility. Herein, cellulose nanocrystals carrying buckminsterfullerene (CNC-C60) have been synthesized via amine functionalization of CNCs and subsequent grafting of C60 onto the surface of amine-terminated CNCs. FTIR and XPS measurements confirmed the success of the synthesis, which was further evidently supported by TGA analysis. Given atomic compositions of samples by elemental analysis, we figured out a C60 content of 0.17 mmol/g of CNC-C60, equivalent to 34 C60 molecules/1000 anhydroglucose units (AGU). Afterward, CNC-C60 was evaluated for its antiradical effects on scavenging hydroxyl radicals in vitro. The ease of synthesis and significant radical scavenging activity make CNC-C60 a promising novel antioxidant agent for biomedical use. PMID- 29131598 TI - Speciation of CuCl and CuCl2 Thiol-Amine Solutions and Characterization of Resulting Films: Implications for Semiconductor Device Fabrication. AB - Thiol-amine mixtures are an attractive medium for the solution processing of semiconducting thin films because of their remarkable ability to dissolve a variety of metals, metal chalcogenides, metal salts, and chalcogens. However, very little is known about their dissolution chemistry. Electrospray ionization high-resolution tandem mass spectrometry and X-ray absorption spectroscopy were employed to identify the species formed upon dissolution of CuCl and CuCl2 in 1 propanethiol and n-butylamine. Copper was found to be present exclusively in the 1+ oxidation state for both solutions. The copper complexes detected include copper chlorides, copper thiolates, and copper thiolate chlorides. No complexes of copper with amines were observed. Additionally, alkylammonium ions and alkylammonium chloride adducts were observed. These findings suggest that the dissolution is initiated by proton transfer from the thiol to the amine, followed by coordination of the thiolate anions with copper cations. Interestingly, the mass and X-ray absorption spectra of the solutions of CuCl and CuCl2 in thiol amine were essentially identical. However, dialkyl disulfides were identified by Raman spectroscopy as an oxidation product only for the copper(II) solution, wherein copper(II) had been reduced to copper(I). Analysis of several thiol-amine pairs suggested that the dissolution mechanism is quite general. Finally, analysis of thin films prepared from these solutions revealed persistent chlorine impurities, in agreement with previous studies. These impurities are explained by the mass spectrometric finding that chloride ligands are not completely displaced by thiolates upon dissolution. These results suggest that precursors other than chlorides will likely be preferred for the generation of high-efficiency copper chalcogenide films, despite the reasonable efficiencies that have been obtained for films generated from chloride precursors in the past. PMID- 29131599 TI - Radical Multicomponent Carboamination of [1.1.1]Propellane. AB - Three-dimensional, small-ring scaffolds are very important in modern drug discovery to expand the available drug-like chemical space and to optimize drug candidates. Among them, bicyclo[1.1.1]pentane (BCP) is regarded as a high-value bioisostere for a phenyl ring or tert-butyl group; it provides an option to generate drug-like molecules with good passive permeability, high aqueous solubility, and improved metabolic stability, though the lack of methodology to functionalize BCP remains a significant challenge. Here we present an efficient method, developed with the aid of density functional theory calculations, for the synthesis of multifunctionalized BCP derivatives by means of a radical multicomponent carboamination of [1.1.1]propellane. This reaction features mild conditions, one-pot operation, and gram-scale synthetic capability, and opens up a unique and highly efficient route for the synthesis of multifunctionalized BCP derivatives, including synthetically useful 3-substituted BCP-amines. PMID- 29131600 TI - Environmental DNA (eDNA) Shedding and Decay Rates to Model Freshwater Mussel eDNA Transport in a River. AB - Freshwater mussels are vital components of stream ecosystems, yet remain threatened. Thus, timely and accurate species counts are critical for proper conservation and management. Mussels live in stream sediments and can be challenging to survey given constraints related to water depth, flow, and time of year. The use of environmental DNA (eDNA) to monitor mussel distributions and diversity is a promising tool. Before it can be used as a monitoring tool, however, we need to know how much eDNA mussels shed into their environment and how long the eDNA persists. Here, we present a novel application of eDNA to estimate both the presence/absence and abundance of a freshwater mussel species, Lampsilis siliquoidea. The eDNA shedding and decay rates reported within are the first for freshwater mussels. We determined that eDNA shedding was statistically similar across mussel densities, but that first-order decay constants varied between experimental treatments. Finally, we effectively modeled downstream transport of eDNA and present a model that can be used as a complementary tool to estimate mussel density. Our results suggest that eDNA has the potential to be a complementary tool to survey mussels and enhance current efforts to monitor and protect freshwater mussel biodiversity. PMID- 29131601 TI - Highly Efficient Rh(I) Homo- and Heterogeneous Catalysts for C-N Couplings via Hydrogen Borrowing. AB - Rhodium(I) complexes were explored as catalysts for the hydrogen borrowing reactions of amines and alcohols. Bidentate carbene-triazole ligands were readily synthesized via "click" reactions which allowed a diversity of ligand backbones to be accessed. The catalytic transformations are highly efficient, able to reach completion in under 6 h, and promote C-N bond formation across a range of primary alcohol and amine substrates. Moreover, site-selective catalysis can be achieved using substrates with more than one reactive site. A rhodium(I) complex covalently attached to a carbon black surface was also deployed in the hydrogen borrowing coupling reaction of aniline with benzyl alcohol. This represents the first report of a heterogeneous rhodium catalyst used for hydrogen borrowing. PMID- 29131602 TI - Electrodeposition of Isolated Platinum Atoms and Clusters on Bismuth Characterization and Electrocatalysis. AB - We describe a method for the electrodeposition of an isolated single Pt atom or small cluster, up to 9 atoms, on a bismuth ultramicroelectrode (UME). This deposition was immediately followed by electrochemical characterization via the hydrogen evolution reaction (HER) that occurs readily on the electrodeposited Pt but not on Bi. The observed voltammetric current plateau, even for a single atom, which behaves as an electrode, allows the estimation of deposit size. Pt was plated from solutions of femtomolar PtCl62-, which allowed precise control of the arrival of ions and thus the plating rate on the Bi UME, to one ion every few seconds. This allowed the atom-by-atom fabrication of isolated platinum deposits, ranging from single atoms to 9-atom clusters. The limiting currents in voltammetry gave the size and number of atoms of the clusters. Given the stochasticity of the plating process, we show that the number of atoms plated over a given time (10 and 20 s) follows a Poisson distribution. Taking the potential at a certain current density as a measure of the relative rate of the HER, we found that the potential shifted positively as the size increased, with single atoms showing the largest overpotentials compared to bulk Pt. PMID- 29131603 TI - Toward an Understanding of Selective Alkyne Hydrogenation on Ceria: On the Impact of O Vacancies on H2 Interaction with CeO2(111). AB - Ceria (CeO2) has recently been found to be a promising catalyst in the selective hydrogenation of alkynes to alkenes. This reaction occurs primarily on highly dispersed metal catalysts, but rarely on oxide surfaces. The origin of the outstanding activity and selectivity observed on CeO2 remains unclear. In this work, we show that one key aspect of the hydrogenation reaction-the interaction of hydrogen with the oxide-depends strongly on the presence of O vacancies within CeO2. Through infrared reflection absorption spectroscopy on well-ordered CeO2(111) thin films and density functional theory (DFT) calculations, we show that the preferred heterolytic dissociation of molecular hydrogen on CeO2(111) requires H2 pressures in the mbar regime. Hydrogen depth profiling with nuclear reaction analysis indicates that H species stay on the surface of stoichiometric CeO2(111) films, whereas H incorporates as a volatile species into the volume of partially reduced CeO2-x(111) thin films (x ~ 1.8-1.9). Complementary DFT calculations demonstrate that oxygen vacancies facilitate H incorporation below the surface and that they are the key to the stabilization of hydridic H species in the volume of reduced ceria. PMID- 29131604 TI - From Zn(II)-Carboxylate to Double-Walled Zn(II)-Carboxylato Phosphate MOF: Change in the Framework Topology, Capture and Conversion of CO2, and Catalysis of Strecker Reaction. AB - The ligand H2L has been built by linking an imidazole moiety to the 5-position of isophthalic acid. It forms two types of porous frameworks, {[Zn(L)].2DMF.2H2O}n (1) and {[(CH3)2NH2][Zn2(L)(H2O)PO4].2DMF}n (2). 1 is a porous neutral framework and has rtl rutile 3,6-conn topology, while 2 is an organo-metallophosphate anionic porous framework with double-walled hexagonal channels. Framework 1' (desolvated) exhibits moderate CO2 adsorption (58 cc g-1 at 273 K, 1 bar), whereas 2' (desolvated) shows a microporous nature with a high adsorption of CO2 (111.7 cc g-1 or 22 wt % at 273 K, 1 bar). Interestingly, this adsorbed CO2 could be converted very efficiently to cyclic carbonates under mild conditions using 2' as the catalyst in the presence of tetrabutylammonium bromide as the cocatalyst. The presence of open metal sites in 2' makes it an efficient heterogeneous catalyst for solvent-free three-component Strecker reaction using various aldehydes/ketones together with amines and trimethylsilyl cyanide in high yields at room temperature. The straightforward experimental and product isolation procedure along with easy recovery and reusability of the catalyst provided an attractive route for the synthesis of alpha-amino nitriles. PMID- 29131605 TI - Poly(omega-methoxyalkyl acrylate)s: Nonthrombogenic Polymer Family with Tunable Protein Adsorption. AB - A series of polyacrylates with different n-alkyl side chain lengths (1 to 6, and 12 carbons) and a omega-methoxy terminal group (poly(omega-methoxyalkyl acrylate): PMCxA) were prepared to study their nonthrombogenicity using human platelet adhesion, micro bicinchoninic acid (micro BCA) protein assay, and enzyme linked immunosorbent assay (ELISA) tests. In all cases, human platelet adhesion was suppressed on the PMCxA-coated substrates, and the number of human platelets adhered to the PMC3A (poly(3-methoxypropyl acrylate))-coated surface was comparable to that of commercialized nonthrombogenic coating agent poly(2 methoxyethyl acrylate) (PMEA, equal to PMC2A). The amount of protein adsorbed onto the PMCxA was investigated by micro BCA using bovine serum albumin (BSA) and human fibrinogen (hFbn), revealing that PMC3A exhibited significantly high resistance to nonspecific BSA adsorption. Additionally, the amount of hFbn adsorbed onto the PMC3A was suppressed to the same extent as PMEA. The exposure degree of platelet adhesion sites in adsorbed hFbn was evaluated using an ELISA test, and the degree on the PMCxA with three to six methylene carbons was comparable to the PMEA. The hydration water structure in the hydrated PMCxA was also characterized using differential scanning calorimetry (DSC). The amount of intermediate water, which is the hydration water molecules that moderately interact with the polymer matrix, was maximum in the PMEA with two methylene run lengths, whereas the amount decreased by increasing the number of methyelnes in the side chain. The amount of adsorbed protein increased with a decrease in the amount of intermediate water, suggesting that the protein adsorption amount is tunable by simply changing the number of methylene carbons in the side chain. The present study revealed that poly(omega-methoxyalkyl acrylate)s are useful for blood-contacting medical devices, and PMC3A is the best mode of PMCxA to apply as an antiprotein adsorption coating agent. PMID- 29131606 TI - First Chemical Characterization of Refractory Black Carbon Aerosols and Associated Coatings over the Tibetan Plateau (4730 m a.s.l). AB - Refractory black carbon (rBC) aerosol is an important climate forcer, and its impacts are greatly influenced by the species associated with rBC cores. However, relevant knowledge is particularly lacking at the Tibetan Plateau (TP). Here we report, for the first time, highly time-resolved measurement results of rBC and its coating species in central TP (4730 m a.s.l), using an Aerodyne soot particle aerosol mass spectrometer (SP-AMS), which selectively measured rBC-containing particles. We found that the rBC was overall thickly coated with an average mass ratio of coating to rBC (RBC) of ~7.7, and the coating species were predominantly secondarily formed by photochemical reactions. Interestingly, the thickly coated rBC was less oxygenated than the thinly coated rBC, mainly due to influence of the transported biomass burning organic aerosol (BBOA). This BBOA was relatively fresh but formed very thick coating on rBC. We further estimated the "lensing effect" of coating semiquantitatively by comparing the measurement data from a multiangle absorption photometer and SP-AMS, and found it could lead to up to 40% light absorption enhancement at RBC > 10. Our findings highlight that BBOA can significantly affect the "lensing effect", in addition to its relatively well known role as light-absorbing "brown carbon." PMID- 29131607 TI - Carbon Papers and Aerogels Based on Graphene Layers and Chitosan: Direct Preparation from High Surface Area Graphite. AB - In this work, carbon papers and aerogels based on graphene layers and chitosan were prepared. They were obtained by mixing chitosan (CS) and a high surface area nanosized graphite (HSAG) in water in the presence of acetic acid. HSAG/CS water dispersions were stable for months. High resolution transmission electron microscopy revealed the presence of few graphene layers in water suspensions. Casting or lyophilization of such suspensions led to the preparation of carbon paper and aerogel, respectively. In X-ray spectra of both aerogels and carbon paper, peaks due to regular stacks of graphene layers were not detected: graphene with unaltered sp2 structure was obtained directly from graphite without the use of any chemical reaction. The composites were demonstrated to be electrically conductive thanks to the graphene. Chitosan thus makes it possible to obtain monolithic carbon aerogels and flexible and free-standing graphene papers directly from a nanosized graphite by avoiding oxidation to graphite oxide and successive reduction. Strong interaction between polycationic chitosan and the aromatic substrate appears to be at the origin of the stability of HSAG/CS adducts. Cation-pi interaction is hypothesized, also on the basis of X-ray photoelectron spectroscopy findings. This work paves the way for the easy large scale preparation of carbon papers through a method that has a low environmental impact and is based on a biosourced polymer, graphene, and water. PMID- 29131609 TI - Li7(TeO3)3F: A Lithium Fluoride Tellurite with Large Second Harmonic Generation Responses and a Short Ultraviolet Cutoff Edge. AB - Here, the combination of the strong electropositive lithium and the most electronegative fluorine with the TeO3 group afforded the first lithium fluoride tellurite, namely, Li7(TeO3)3F (P63), which was synthesized by solid-state reactions. Its structure features a novel three-dimensional anionic framework of [Li7O9F]12- composed of LiO3F and LiO4 tetrahedra with one-dimensional hexagonal tunnels of 12-membered rings along the c-axis, filled by the "isolated" psi-TeO3 tetrahedra. Notably, this compound displays the largest band gap of 4.75 eV among all of the non-centrosymmetric metal-tellurites reported so far, as well as strong second harmonic generation (SHG) responses (3 * KH2PO4 @1064 nm, 0.2 * beta-BaB2O4 @532 nm) and a large laser damage threshold (73 * AgGaS2). Furthermore, theoretical calculations reveal that the LiO4 and LiO3F tetrahedra also contribute significantly to the SHG response (~30%). PMID- 29131608 TI - Metabolism and Photolysis of 2,4-Dinitroanisole in Arabidopsis. AB - New insensitive munitions explosives, including 2,4-dinitroanisole (DNAN), are replacing traditional explosive compounds to protect soldiers and simplify transport logistics. Despite the occupational safety benefits of these new explosives, feasible strategies for cleaning up DNAN from soil and water have not been developed. Here, we evaluate the metabolism of DNAN by the model plant Arabidopsis to determine whether phytoremediation can be used to clean up contaminated sites. Furthermore, we evaluate the role of photodegradation of DNAN and its plant metabolites within Arabidopsis leaves to determine the potential impact of photolysis on the phytoremediation of contaminants. When exposed to DNAN for three days, Arabidopsis took up and metabolized 67% of the DNAN in hydroponic solution. We used high resolution and tandem mass spectrometry in combination with stable-isotope labeled DNAN to confirm ten phase II DNAN metabolites in Arabidopsis. The plants separately reduced both the para- and ortho-nitro groups and produced glycosylated products that accumulated within plant tissues. Both DNAN and a glycosylated metabolite were subsequently photolyzed within leaf tissue under simulated sunlight, and [15N2]DNAN yielded 15NO2- in leaves. Therefore, photolysis inside leaves may be an important, yet under-explored, phytoremediation mechanism. PMID- 29131610 TI - Real-Time Imaging of Single-Molecule Enzyme Cascade Using a DNA Origami Raft. AB - The dynamics of enzymes are directly associated with their functions in various biological processes. Nevertheless, the ability to image motions of single enzymes in a highly parallel fashion remains a challenge. Here, we develop a DNA origami raft-based platform for in-situ real-time imaging of enzyme cascade at the single-molecule level. The motions of enzymes are rationally controlled via different tethering modes on a two-dimensional (2D) supported lipid bilayer (SLB). We construct an enzyme cascade by anchoring catalase on cholesterol labeled double-stranded (ds) DNA and glucose oxidase on cholesterol-labeled origami rafts. DNA functionalized with cholesterol can be readily incorporated in SLB via the cholesterol-lipid interaction. By using a total internal reflection fluorescence microscope (TIRFM), we record the moving trajectory of fluorophore labeled single enzymes on the 2D surface: the downstream catalase diffuses freely in SLB, whereas the upstream glucose oxidase is relatively immobile. By analyzing the trajectories of individual enzymes, we find that the lateral motion of enzymes increases in a substrate concentration-dependent manner and that the enhanced diffusion of enzymes can be transmitted via the cascade reaction. We expect that this platform sheds new light on studying dynamic interactions of proteins and even cellular interactions. PMID- 29131611 TI - Synthesis and in Vitro Evaluation of Monodisperse Amino-Functional Polyester Dendrimers with Rapid Degradability and Antibacterial Properties. AB - Amine functional polymers, especially cationically charged, are interesting biomacromolecules for several reasons, including easy cell membrane entrance, their ability to escape endosomes through the proton sponge effect, spontaneous complexation and delivery of drugs and siRNA, and simple functionalization in aqueous solutions. Dendrimers, a subclass of precision polymers, are monodisperse and exhibit a large and exact number of peripheral end groups in relation to their size and have shown promise in drug delivery, biomedical imaging and as antiviral agents. In this work, hydroxyl functional dendrimers of generation 1 to 5 based on 2,2-bis(methylol)propionic acid (bis-MPA) were modified to bear 6 to 96 peripheral amino groups through esterification reactions with beta-alanine. All dendrimers were isolated in high yields and with remarkable monodispersity. This was successfully accomplished utilizing the present advantages of fluoride promoted esterification (FPE) with imidazole-activated monomers. Straightforward postfunctionalization was conducted on a second generation amino-functional dendrimer with tetraethylene glycol through NHS-amidation and carbonyl diimidazole (CDI) activation to full conversion with short reaction times. Fast biodegradation of the dendrimers through loss of peripheral beta-alanine groups was observed and generational- and dose-dependent cytotoxicity was evaluated with a set of cell lines. An increase in neurotoxicity compared to hydroxyl-functional dendrimers was shown in neuronal cells, however, the dendrimers were slightly less neurotoxic than commercially available poly(amidoamine) dendrimers (PAMAMs). Additionally, their effect on bacteria was evaluated and the second generation dendrimer was found unique inhibiting the growth of Escherichia coli at physiological conditions while being nontoxic toward human cells. Finally, these results cement a robust and sustainable synthetic route to amino-functional polyester dendrimers with interesting chemical and biological properties. PMID- 29131612 TI - Functional Characterization of Epitheaflagallin 3-O-Gallate Generated in Laccase Treated Green Tea Extracts in the Presence of Gallic Acid. AB - Epitheaflagallin (ETFG) and epitheaflagallin 3-O-gallate (ETFGg) are minor polyphenols in black tea extract that are enzymatically synthesized from epigallocatechin (EGC) and epigallocatechin gallate (EGCg), respectively, in green tea extract via laccase oxidation in the presence of gallic acid. The constituents of laccase-treated green tea extract in the presence of gallic acid are thus quite different from those of nonlaccase-treated green tea extract: EGC and EGCg are present in lower concentrations, and ETFG and ETFGg are present in higher concentrations. Additionally, laccase-treated green tea extract contains further polymerized catechin derivatives, comparable with naturally fermented teas such as oolong tea and black tea. We found that ETFGg and laccase-treated green tea extracts exhibit versatile physiological functions in vivo and in vitro, including antioxidative activity, pancreatic lipase inhibition, Streptococcus sorbinus glycosyltransferase inhibition, and an inhibiting effect on the activity of matrix metalloprotease-1 and -3 and their synthesis by human gingival fibroblasts. We confirmed that these inhibitory effects of ETFGg in vitro match well with the results obtained by docking simulations of the compounds with their target enzymes or noncatalytic protein. Thus, ETFGg and laccase-treated green tea extracts containing ETFGg are promising functional food materials with potential antiobesity and antiperiodontal disease activities. PMID- 29131613 TI - Proton-Coupled Electron Transfer and Substituent Effects in Catechol-Based Deep Eutectic Solvents: Gross and Fine Tuning of Redox Activity. AB - The 1,2-diol moiety in a variety of substituted catechols allows formation of room temperature ionic melts in a 2:1 ratio with choline chloride or choline dihydrogen citrate. These deep eutectic solvents were 4.3-6.6 M in redox active catechols. Substituents on 3- and 4-substituted catechols shift both E degrees and pKa such that Hammett parameters predict the observed Ep for oxidation in square wave voltammetry. The proton acceptor for the proton-coupled oxidation shifts the observed Ep more strongly than the substituents within the substituents and acceptors reported here. The shift is predicted well by the pKa of the conjugate acid of the proton acceptor, i.e., water in aqueous solutions or chloride or dihydrogen citrate in the DESs in this study. Together, the substituent and the proton acceptor allow gross and fine-tuning of the oxidation potential for catechol over 750 mV, the first demonstration of control of the thermodynamics of proton-coupled electron transfer in deep eutectic solvents. Changing the substituents on the HBD affords fine control in tens of millivolts, while changing the base strength of the anion of the organic salt affords gross control across hundreds of millivolts. PMID- 29131614 TI - Halloysite Tubes as Nanocontainers for Herbicide and Its Controlled Release in Biodegradable Poly(vinyl alcohol)/Starch Film. AB - Commercial herbicide atrazine (AT) was first loaded into the lumen of halloysite nanotubes (HNTs) in the amount of 9 wt %, and then the AT-loaded HNTs (HNTs-AT) were further incorporated into poly(vinyl alcohol)/starch composites (PVA/ST, with the weight ratio of 80/20) to construct a dual drug delivery system. AT loaded in nanotubes displayed much slower release from PVA/ST film in water than free AT; for example, the total release amount of AT from PVA/ST film with loaded AT was only 61% after 96 h, while this value reached 97% in PVA/ST film with free AT. The release behavior of AT from PVA/ST film with HNTs-AT was first dominated by the mechanism of matrix erosion and then by the mechanism of Fickian diffusion. In addition, combining HNTs and PVA/ST blends together in the controlled release of herbicide also reduced its leaching through the soil layer, which would be useful for diminishing the environmental pollution caused by pesticide. PMID- 29131615 TI - Ir4(CO)12-Catalyzed Benzylic C(sp3)-H Silylation of 2-Alkylpyridines with Hydrosilanes Leading to 2-(1-Silylalkyl)pyridines. AB - The iridium-catalyzed C(sp3)-H silylation of 2-alkylpyridines with hydrosilanes at the benzylic position to afford 2-(1-silylalkyl)pyridines is described. The low product yield was markedly improved by adding 3,5-dimethylpyridine. Norbornene is also an essential additive for the reaction to proceed as a hydrogen scavenger. Carbon monoxide plays an important role in the catalytic cycle as a ligand. Other transition-metal carbonyls such as Rh4(CO)12 and Ru3(CO)12 can also be used as catalysts for this C-H silylation. PMID- 29131616 TI - Antiproliferative Dimeric Aporphinoid Alkaloids from the Roots of Thalictrum cultratum. AB - Inspired by the intriguing structures and bioactivities of dimeric alkaloids, 11 new thalifaberine-type aporphine-benzylisoquinoline alkaloids, thalicultratines A K, a tetrahydroprotoberberine-aporphine alkaloid, thalicultratine L, and five known ones were isolated from the roots of Thalictrum cultratum. Their structures were defined on the basis of NMR and HRESIMS data. The antiproliferative activities of compounds 1-17 were evaluated against human leukemia HL-60 and prostate cancer PC-3 cells. Most alkaloids showed potent cytotoxicity against selected cancer cells. Preliminary SARs are discussed. The most active new compound (3), with an IC50 value of 1.06 MUM against HL-60 cells, was selected for mechanism of action studies. The results revealed that compound 3 induced apoptosis and arrested the HL-60 cell cycle at the S phase with the loss of mitochondria membrane potential. The nuclear morphological Hoechst 33258 staining assay was also carried out, and the results confirmed apoptosis. PMID- 29131617 TI - Coupling Matched Molecular Pairs with Machine Learning for Virtual Compound Optimization. AB - Matched molecular pair (MMP) analyses are widely used in compound optimization projects to gain insights into structure-activity relationships (SAR). The analysis is traditionally done via statistical methods but can also be employed together with machine learning (ML) approaches to extrapolate to novel compounds. The here introduced MMP/ML method combines a fragment-based MMP implementation with different machine learning methods to obtain automated SAR decomposition and prediction. To test the prediction capabilities and model transferability, two different compound optimization scenarios were designed: (1) "new fragments" which occurs when exploring new fragments for a defined compound series and (2) "new static core and transformations" which resembles for instance the identification of a new compound series. Very good results were achieved by all employed machine learning methods especially for the new fragments case, but overall deep neural network models performed best, allowing reliable predictions also for the new static core and transformations scenario, where comprehensive SAR knowledge of the compound series is missing. Furthermore, we show that models trained on all available data have a higher generalizability compared to models trained on focused series and can extend beyond chemical space covered in the training data. Thus, coupling MMP with deep neural networks provides a promising approach to make high quality predictions on various data sets and in different compound optimization scenarios. PMID- 29131618 TI - NP-StructurePredictor: Prediction of Unknown Natural Products in Plant Mixtures. AB - Identification of the individual chemical constituents of a mixture, especially solutions extracted from medicinal plants, is a time-consuming task. The identification results are often limited by challenges such as the development of separation methods and the availability of known reference standards. A novel structure elucidation system, NP-StructurePredictor, is presented and used to accelerate the process of identifying chemical structures in a mixture based on a branch and bound algorithm combined with a large collection of natural product databases. NP-StructurePredictor requires only targeted molecular weights calculated from a list of m/z values from liquid chromatography-mass spectrometry (LC-MS) experiments as input information to predict the chemical structures of individual components matching the weights in a mixture. NP-StructurePredictor also provides the predicted structures with statistically calculated probabilities so that the most likely chemical structures of the natural products and their analogs can be proposed accordingly. Four data sets consisting of different Chinese herbs with mixtures containing known compounds were selected for validation studies, and all their components were correctly identified and highly predicted using NP-StructurePredictor. NP-StructurePredictor demonstrated its applicability for predicting the chemical structures of novel compounds by returning highly accurate results from four different validation case studies. PMID- 29131619 TI - Synthesis of 1,2-Dihydropyrimidine-2-carboxylates via Regioselective Addition of Rhodium(II) Carbenoids to 2H-Azirine-2-carbaldimines. AB - An efficient two-step procedure "imine formation/azirine-carbenoid coupling" has been developed for the preparation of 1,2-dihydropyrimidines from azirine-2 carbaldehydes, primary amines, and diazo carbonyl compounds under Rh(II) catalysis. The formation of 1,2-dihydropyrimidines involves 100% regioselective addition of the rhodium carbenoid to endocyclic nitrogen atom of the 2H-azirine-2 carbaldimine. According to the DFT calculations the reaction proceeds via dissociation of the metal-bound complex of the azirinium ylide to metal-free azirinium ylide, ring-opening of the latter to give a 1,5-diazahexa-1,3,5-triene, followed by 1,6-cyclization. The 1,2-dihydropyrimidines with two different electron-withdrawing substituents at the C2 position can undergo in solution inversion of configuration of the stereogenic center at C2 via "the N1-C2 bond cleavage/rotation around the N-C single bond/1,6-cyclization" sequence. PMID- 29131620 TI - Carbene-Catalyzed Indole 3-Methyl C(sp3)-H Bond Functionalization. AB - The metal-free catalytic functionalization of aromatic sp2-carbons and benzylic sp3-carbons remains challenging. Here we report a carbene-catalyzed functionalization of the 3-methyl sp3-carbon attached to 2-formyl-indoles. The reaction proceeds through an NHC-bound o-quinodimethane as the key intermediate generated from 2-formyl-3-methylindoles under oxidative conditions. Reactive ketones are found to be effective substrates to produce substituted hydropyrano[3,4-b]indoles in good to excellent yields. PMID- 29131621 TI - Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity. AB - Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or "warhead"). Structural changes that increase or decrease warhead reactivity, guided by methods to predict the effect of those changes, have the potential to tune warhead reactivity and negate issues related to potency and/or toxicity. The half-life to adduct formation with glutathione (GSH t1/2) is a useful assay for measuring the reactivity of cysteine-targeting covalent warheads but is limited to synthesized molecules. In this manuscript we assess the ability of several experimental and computational approaches to predict GSH t1/2 for a range of cysteine targeting warheads, including a novel method based on pKa. Furthermore, matched molecular pairs analysis has been performed against our internal compound collection, revealing structure-activity relationships between a selection of different covalent warheads. These observations and methods of prediction will be valuable in the design of new covalent inhibitors with desired levels of reactivity. PMID- 29131622 TI - Computational Study of Engineered Cytochrome P450-Catalyzed C-H Amination: The Origin of the Regio- and Stereoselectivity. AB - Cytochrome P450 enzymes were recently engineered to catalyze the C-H amination reaction of aryl sulfonyl azides with excellent regio- and stereoselectivity (Arnold and co-workers J. Am. Chem. Soc. 2014 , 136 , 15505 ). The mechanism of this reaction was studied by quantum mechanical (QM)/molecular mechanical (MM) calculations in this work. The C-H activation is found to be a stepwise process consisting of hydrogen abstraction (H-abstraction) of the reactive C-H bond by an iron nitrenoid cofactor to produce the biradical intermediate and subsequent radical rebinding to form the final product. The rate of rotation of the carbon radical center was estimated to be much faster than that of radical rebinding, which implies that the H-abstraction does not determine the stereoselectivity. For mutant A, the H-abstraction step has a barrier of 16.7 kcal/mol, which is 3.0 kcal/mol higher than that of the following radical rebinding step. The H abstraction step determines the regioselectivity, but the radical rebinding step determines the stereoselectivity. Barriers of these two steps are 16.1 and 27.5 kcal/mol, respectively, for mutant B. It is different from mutant A in that the radical rebinding step has the higher barrier and determines both the regio- and stereoselectivity. The initial distances between the hydrogens of reactive C-H bonds and the iron nitrenoid were found to not correlate with their reactivities. The calculated barriers are qualitatively consistent with the experimentally observed regio- and stereoselectivity with the exception of the stereoselectivity of mutant B. The lower barriers of mutant A presumably come from the stabilization effect of the H-bond between G265 and the sulfone O. This H-bond does not exist in mutant B. The conformation of the protein backbone, with the exception of the active site, does not change much (RMSD < 0.05) along the reaction pathway. PMID- 29131624 TI - One-Pot Trifluoromethylative Functionalization of Amides: Synthesis of Trifluoromethylated Bis(indolyl)arylmethanes and Triarylmethanes. AB - Efficient and general one-pot trifluoromethylative functionalization of amides has been accomplished for the synthesis of various trifluoromethylated bis(indolyl)arylmethane, utilizing trifluoromethyltrimethylsilane and substituted indoles as nucleophiles. The developed reaction involves the in situ generation and trapping of a trifluoromethylated iminium ion, derived from the trifluoromethylated hemiaminal of amide, with various substituted indoles. This method has been successfully extended to the synthesis of diverse trifluoromethylated triarylmethanes employing phenols as nucleophiles. Furthermore, the potential of the method was demonstrated via the two-step synthesis of a trifluoromethylated analog of a hypolipidemic and anti-obesity agent. PMID- 29131623 TI - Iodide Binding in Sodium-Coupled Cotransporters. AB - Several apical iodide translocation pathways have been proposed for iodide efflux out of thyroid follicular cells, including a pathway mediated by the sodium coupled monocarboxylate transporter 1 (SMCT1), which remains controversial. Herein, we evaluate structural and functional similarities between SMCT1 and the well-studied sodium-iodide symporter (NIS) that mediates the first step of iodide entry into the thyroid. Free-energy calculations using a force field with electronic polarizability verify the presence of a conserved iodide-binding pocket between the TM2, TM3, and TM7 segments in hNIS, where iodide is coordinated by Phe67, Gln72, Cys91, and Gln94. We demonstrate the mutation of residue Gly93 of hNIS to a larger amino acid expels the side chain of a critical tryptophan residue (Trp255) into the interior of the binding pocket, partially occluding the iodide binding site and reducing iodide affinity, which is consistent with previous reports associating mutation of this residue with iodide uptake deficiency and hypothyroidism. Furthermore, we find that the position of Trp255 in this hNIS mutant mirrors that of Trp253 in wild-type hSMCT1, where a threonine (Thr91) occupies the position homologous to that occupied by glycine in wild-type hNIS (Gly93). Correspondingly, mutation of Thr91 to glycine in hSMCT1 makes the pocket structure more like that of wild-type hNIS, increasing its iodide affinity. These results suggest that wild-type hSMCT1 in the inward-facing conformation may bind iodide only very weakly, which may have implications for its ability to transport iodide. PMID- 29131625 TI - Effects of Planting and Processing Modes on the Degradation of Dithianon and Pyraclostrobin in Chinese Yam (Dioscorea spp.). AB - The yam (Dioscorea spp.) is widely cultivated in China. The degradation of dithianon and pyraclostrobin in yams with different planting and processing treatments was investigated in this article. An analytical method for two pesticides in yam and yam plant was developed, and recoveries were between 77% and 93%, with relative standard deviations from 0.8% to 7.4%, respectively. On the basis of this method, half-lives for plants grown on stakes versus plants grown without stakes were compared. The results indicated that the half-life for pesticide residues for plants grown on stakes versus plants grown without stakes differed as 6.7 versus 3.1 days for dithianon and 5.4 versus 5.2 days for pyraclostrobin. Dithianon was significantly influenced by planting mode because of its low stability under sunlight. The processing factors of various processing treatments (hot air-drying, vacuum freeze-drying, microwave vacuum-drying, infrared-drying, steaming, and boiling) were all <1, indicating that those processes can reduce residues of two pesticides at different levels. Significant amounts of residues were removed during the boiling treatment, whereas the others showed less effect. PMID- 29131626 TI - TfOH-Catalyzed One-Pot Domino Reaction for Diastereoselective Synthesis of Polysubstituted Tetrahydrospiro[carbazole-1,3'-indoline]s. AB - TfOH-catalyzed one-pot sequential reaction of indoles, acetophenones (cyclic ketones), and various 3-methyleneoxindolines in toluene afforded polysubstituted tetrahydrospiro[carbazole-1,3'-indoline]s in satisfactory yields. 1H NMR spectra and single-crystal structures indicated that the obtained tetrahydrospiro[carbazole-1,3'-indoline]s existing in an unusual trans configuration. The reaction mechanism was believed to proceed with domino acid catalyzed 3-alkenylation of indoles with acetophenones, Diels-Alder reaction of 3 alkyenylindoles with 3-methyleneoxindolines, and an acid-catalyzed diastereoisomerization process. PMID- 29131627 TI - Enhancement of 9alpha-Hydroxy-4-androstene-3,17-dione Production from Soybean Phytosterols by Deficiency of a Regulated Intramembrane Proteolysis Metalloprotease in Mycobacterium neoaurum. AB - Modification of the sterol catabolism pathway in mycobacteria may result in the accumulation of some valuable steroid pharmaceutical intermediates, such as 9alpha-hydroxy-4-androstene-3,17-dione (9-OHAD). In previous work, sigma factor D (SigD) was identified as a negative factor of the 9-OHAD production in Mycobacterium neoaurum. Here, the deficiency of rip1 putatively coding for a regulated intramembrane proteolysis metalloprotease (Rip1), which could cleave the negative regulator of SigD (anti-SigD), enhanced the transcription of some key genes (choM1, kshA, and hsd4A) in the sterol catabolic pathway. Furthermore, the deletion of rip1 increased the consumption of phytosterols by 37.8% after 96 h of growth in M. neoaurum. The production of 9-OHAD in the engineered M. neoaurumDeltakstD1DeltakstD2DeltakstD3Deltarip1 (MnDeltak123Deltarip1) strain was ultimately increased by 27.3% compared to that in its parental strain M. neoaurumDeltakstD1DeltakstD2DeltakstD3 (MnDeltak123). This study further confirms the important role of SigD-related factors in the catabolism of sterols. PMID- 29131628 TI - Synthesis of [1,3,4]Thiadiazolo[3',2':1,2]imidazo[4,5-c]quinolines including Pictet-Spengler Reaction and Exploration of Their C-2 Reactivity through SNAr. AB - This work reports the design of [1,3,4]thiadiazolo[3',2':1,2]imidazo[4,5 c]quinolines using a Pictet-Spengler reaction. The scope of the reaction was achieved from 6-(2-aminophenyl)imidazo[2,1-b][1,3,4]thiadiazole derivatives and available aldehydes. A wide range of aldehydes were employed to examine the scope of the cyclization. In parallel, a mechanism investigation was realized and showed a hydride transfer which led to a dismutation of the intermediate species. To complete this methodological study, a "sequential" oxidation/SNAr procedure was performed to achieve C-2 nucleophilic substitution using several amine types. PMID- 29131629 TI - Enzymatic Synthesis and Structural Characterization of Theanderose through Transfructosylation Reaction Catalyzed by Levansucrase from Bacillus subtilis CECT 39. AB - This work addresses the high-yield and fast enzymatic production of theanderose, a naturally occurring carbohydrate, also known as isomaltosucrose, whose chemical structure determined by NMR is alpha-d-glucopyranosyl-(1 -> 6)-alpha-d glucopyranosyl-(1 -> 2)-beta-d-fructofuranose. The ability of isomaltose to act as an acceptor in the Bacillus subtilis CECT 39 levansucrase-catalyzed transfructosylation reaction to efficiently produce theanderose in the presence of sucrose as a donor is described by using four different sucrose:isomaltose concentration ratios. The maximum theanderose concentration ranged from 122.4 to 130.4 g L-1, was obtained after only 1 h and at a moderate temperature (37 degrees C), leading to high productivity (109.7-130.4 g L-1h-1) and yield (up to 37.3%) values. The enzymatic synthesis was highly regiospecific, since no other detectable acceptor reaction products were formed. The development of efficient and cost-effective procedures for the biosynthesis of unexplored but appealing oligosaccharides as potential sweeteners, such as theanderose, could help to expand its potential applications which are currently limited by their low availability. PMID- 29131630 TI - Role of Regioisomeric Bicyclo[3.3.0]octa-2,5-diene Ligands in Rh Catalysis: Synthesis, Structural Analysis, Theoretical Study, and Application in Asymmetric 1,2- and 1,4-Additions. AB - In order to study the impact of regioisomeric diene ligands on the formation and catalytic activity of Rh complexes, a series of C2- and CS-symmetric 2,5 disubstituted bicyclo[3.3.0]octa-2,5-dienes C2-L and CS-L, respectively, were synthesized from Weiss diketone by simultaneous deprotonation/electrophilic trapping of both oxo functions, and the catalytic behavior was studied in the presence of [RhCl(C2H4)2]2. Complexes [RhCl(C2-L)]2 bearing C2-symmetric ligands catalyzed effectively the asymmetric arylation of N-tosylaldimines to (S) diarylamines with yields and ee values up to 99%. In Hayashi-Miyaura reactions, however, the complexes showed poor catalytic activity. When complexes [RhCl(CS L)]2 with CS-symmetric ligand or mixtures of [RhCl(C2-L)]2 and [RhCl(CS-L)]2 were employed in 1,2-additions, racemic addition products were observed, suggesting a C?C isomerization of the diene ligands. X-ray crystal structure analysis of both Rh complexes formed from the [RhCl(C2H4)2]2 precursor and ligands C2-L and CS-L revealed that only the C2-symmetric ligand C2-L coordinated to the Rh, whereas CS L underwent a Rh-catalyzed C?C isomerization to rac-C2-L, which then gave the racemic [RhCl(rac-C2-L)]2 complex. DFT calculations of the relative stabilities of the Rh complexes and the proposed intermediates provided a mechanistic rationale via Rh-mediated hydride transfer. PMID- 29131631 TI - Cytotoxicity, Hemolytic Toxicity, and Mechanism of Action of Pulsatilla Saponin D and Its Synthetic Derivatives. AB - The strong hemolytic toxicity of pulsatilla saponin D (1, HD50 6.3 MUM) has hampered its clinical development as an injectable anticancer agent. To combat this challenge, 17 new derivatives of 1 with ring C, C-28, or C-3 modifications were synthesized and evaluated for cytotoxicity against several selected human tumor lines, as well as for hemolytic toxicity against rabbit erythrocytes. Structure-activity relationship (SAR) and structure-toxicity relationship (STR) correlations were also elucidated. Compared to the lead compound 1, the hemolytic activity of all 17 derivatives dropped dramatically. Notably, compound 14 exhibited significant cytotoxicity toward A549 human lung cancer cells (IC50 2.8 MUM) in a dose-dependent manner without hemolytic toxicity (HD50 > 500 MUM). Molecular studies indicated that 14 induced typical G1 cell cycle arrest and apoptosis in A549 cells, and Western blot assays suggested that both intrinsic and extrinsic apoptosis pathways were activated by 14. Collectively, compound 14 may merit further development as a potential anti-lung cancer agent. PMID- 29131632 TI - Spontaneous Microstructure Formation at Water/Paraffin Oil Interfaces. AB - An experimental investigation of spontaneous emulsification is proposed with a water drop pendant in a paraffin oil (PO) solution loaded with a surfactant (SPAN80). Optical microscopy in a transmission mode is employed for high-spatial resolution image recording. The kinetics of spontaneous emulsification is studied. It is shown to generate a darkening of the drops because of interface modification with a characteristic time that depends upon the SPAN80 concentration. For low concentrations, spontaneous emulsification is slow and produces micrometer-sized droplets, whereas for large concentrations, it is fast and bush-like microstructures are observed. These microstructures increase in size and progressively invade the complete water/PO interfaces, detach, and finally migrate into the PO phase. This transport phenomenon withdraws water from the drops and leads to a gradual shrinking of their volume. At the end of this process, they appear as deformed objects surrounded by a loose membrane. PMID- 29131633 TI - Effect of the Helix-Coil Transition in Bovine Skin Gelatin on Its Associative Phase Separation with Lysozyme. AB - It is known that the formation of electrostatic polyelectrolyte complexes can induce conformational changes in the interacting macromolecules. However, the opposite effect, namely, that of the helix-coil transition of one of the interacting polyelectrolytes on its associative phase separation with another polyelectrolyte and the possible phase transitions in such systems, has not been determined. Atomic force and confocal laser scanning microscopy, phase analysis, dynamic and electrophoretic light scattering, turbidimetry, absorption, and fluorescence measurements as well as differential scanning calorimetry and rheology were used to study the effect of the helix-coil transition in bovine skin gelatin (Gel) on its associative phase separation with hen egg white lysozyme (Lys) at different temperatures (18-40 degrees C) and various Lys/Gel weight ratios (0.01-100) at low ionic strength (0.01) and pH 7.0. The effects of the main variables on the phase state, the phase diagram, and the main complexation and binding parameters as well as the temperature and enthalpy of the helix-coil transition of Gel within the complexes were investigated. Associative phase separation is observed only for the system with Gel in the helix state. Effective charge and structure and the solution and rheological behavior of the formed complexes proved to be dependent on the [An-]/[Cat+] charge ratio. The localization of Lys within the complex particles has irregular character without the formation of a single center of binding. The binding of Lys with Gel does not lead to the disruption of its tertiary structure or to an appreciable change in the thermodynamic parameters of the thermal transitions of Lys. Gel in the coil state interacts only weakly with Lys, forming water-soluble complex associates. It is suggested that the Voorn-Overbeek model could potentially describe the stronger binding and phase separation in the case of Gel in the helix state. PMID- 29131634 TI - General Oriented Synthesis of Precise Carbon-Confined Nanostructures by Low Pressure Vapor Superassembly and Controlled Pyrolysis. AB - Earth-abundant metal-based nanostructured materials have been widely studied for potential energy conversion and storage. However, controlled synthesis of functional nanostructures with high electron conductivity, high reaction activity, and structural stability is still a formidable challenge for further practical applications. Herein, for the first time, we develop a facile, efficient, and general method for the oriented synthesis of precise carbon confined nanostructures by low-pressure vapor superassembly of a thin metal organic framework (MOF) shell and subsequent controlled pyrolysis. The selected nanostructured metal oxide precursors not only act as metal ion sources but also orient the superassembly of gaseous organic ligands through the coordination reactions under the low-pressure condition, resulting in the formation of a tunable MOF shell on their surfaces. This strategy is further successfully extended to obtain various precise carbon-confined nanostructures with diverse compositions and delicate morphologies. Notably, these as-prepared carbon confined architectures exhibit outstanding electrochemical performances in water splitting and lithium storage. The remarkable performances are mainly attributed to the synergistic effect from appropriate chemical compositions and stable carbon-confined structures. This synthetic approach and proposed mechanism open new avenues for the development of functional nanostructured materials in many frontier fields. PMID- 29131635 TI - Temperature-Dependent Coercive Field Measured by a Quantum Dot Strain Gauge. AB - Coercive fields of piezoelectric materials can be strongly influenced by environmental temperature. We investigate this influence using a heterostructure consisting of a single crystal piezoelectric film and a quantum dots containing membrane. Applying electric field leads to a physical deformation of the piezoelectric film, thereby inducing strain in the quantum dots and thus modifying their optical properties. The wavelength of the quantum dot emission shows butterfly-like loops, from which the coercive fields are directly derived. The results suggest that coercive fields at cryogenic temperatures are strongly increased, yielding values several tens of times larger than those at room temperature. We adapt a theoretical model to fit the measured data with very high agreement. Our work provides an efficient framework for predicting the properties of ferroelectric materials and advocating their practical applications, especially at low temperatures. PMID- 29131636 TI - Template-Guided Assembly of Silk Fibroin on Cellulose Nanofibers for Robust Nanostructures with Ultrafast Water Transport. AB - The construction of multilength scaled hierarchical nanostructures from diverse natural components is critical in the progress toward all-natural nanocomposites with structural robustness and versatile added functionalities. Here, we report a spontaneous formation of peculiar "shish kebab" nanostructures with the periodic arrangement of silk fibroin domains along straight segments of cellulose nanofibers. We suggest that the formation of these shish kebab nanostructures is facilitated by the preferential organization of heterogeneous (beta-sheets and amorphous silk) domains along the cellulose nanofiber driven by modulated axial distribution of crystalline planes, hydrogen bonding, and hydrophobic interactions as suggested by all-atom molecular dynamic simulations. Such shish kebab nanostructures enable the ultrathin membrane to possess open, transparent, mechanically robust interlocked networks with high mechanical performance with up to 30 GPa in stiffness and 260 MPa in strength. These nanoporous robust membranes allow for the extremely high water flux, up to 3.5 * 104 L h-1 m-2 bar-1 combined with high rejection rate for various organic molecules, capability of capturing heavy metal ions and their further reduction into metal nanoparticles for added SERS detection capability and catalytic functionalities. PMID- 29131637 TI - Copper-Catalyzed Enantioselective Synthesis of beta-Boron beta-Amino Esters. AB - In this report, the enantioselective, copper-catalyzed borylation of beta amidoacrylates is disclosed. A broad variety of biologically important alpha aminoboronates has been prepared with consistently high levels of enantiocontrol using an inexpensive copper catalyst and a commercially available chiral ligand. The method can be applied to the synthesis of novel boron-containing dipeptides and hemiboronates. PMID- 29131638 TI - Lipid Pore-Filled Silica Thin-Film Membranes for Biomimetic Recovery of Dilute Carbohydrates. AB - Selectively permeable biological membranes containing lipophilic barriers inspire the design of biomimetic carrier-mediated membranes for aqueous solute separation. The recovery of glucose, which can reversibly bind to boronic acid (BA) carriers, is examined in lipid pore-filled silica thin-film composite membranes with accessible mesopores. The successful incorporation of lipids (1,2 dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) and BA carriers (4-((N-Boc amino)methyl)phenylboronic acid, BAMP-BA) in the pores of mesoporous silica (~10 nm pore diameter) through evaporation deposition is verified by confocal microscopy and differential scanning calorimetry. In the absence of BA carriers, lipids confined inside the pores of silica thin films (~200 nm thick) provide a factor of 14 increase in diffusive transport resistance to glucose, relative to traditional supported lipid bilayers formed by vesicle fusion on the porous surface. The addition of lipid-immobilized BAMP-BA (59 mol % in DPPC) facilitates the transport of glucose through the membrane; glucose flux increases from 45 * 10-8 to 225 * 10-8 mol/m2/s in the presence of BAMP-BA. Furthermore, the transport can be improved by environmental factors including pH gradient (to control the binding and release of glucose) and temperature (to adjust lipid bilayer fluidity). The successful development of biomimetic nanocomposite membranes demonstrated here is an important step toward the efficient dilute aqueous solute upgrading or separations, such as the processing of carbohydrates from lignocellulose hydrolysates, using engineered carrier/catalyst/support systems. PMID- 29131639 TI - Proteomic Characterization of Transcription and Splicing Factors Associated with a Metastatic Phenotype in Colorectal Cancer. AB - We investigated new transcription and splicing factors associated with the metastatic phenotype in colorectal cancer. A concatenated tandem array of consensus transcription factor (TF)-response elements was used to pull down nuclear extracts in two different pairs of colorectal cancer cells, KM12SM/KM12C and SW620/480, genetically related but differing in metastatic ability. Proteins were analyzed by label-free LC-MS and quantified with MaxLFQ. We found 240 proteins showing a significant dysregulation in highly metastatic KM12SM cells relative to nonmetastatic KM12C cells and 257 proteins in metastatic SW620 versus SW480. In both cell lines there were similar alterations in genuine TFs and components of the splicing machinery like UPF1, TCF7L2/TCF-4, YBX1, or SRSF3. However, a significant number of alterations were cell-line specific. Functional silencing of MAFG, TFE3, TCF7L2/TCF-4, and SRSF3 in KM12 cells caused alterations in adhesion, survival, proliferation, migration, and liver homing, supporting their role in metastasis. Finally, we investigated the prognostic value of the altered TFs and splicing factors in cancer patients. SRSF3 and SFPQ showed significant prognostic value. We observed that SRSF3 displayed a gradual loss of expression associated with cancer progression. Loss of SRSF3 expression was significantly associated with poor survival and shorter disease-free survival, particularly in early stages, in colorectal cancer. PMID- 29131640 TI - Photoluminescence by Intercalation of a Fluorescent beta-Diketone Dye into a Layered Silicate. AB - A beta-diketone dye was packed into the two-dimensional nanospace of a synthetic smectite (Sumecton SA), which is a cation-exchangeable layered silicate, to induce strong emission owing to molecular packing of the dye. An emissive dye, 1 (4-methoxyphenyl)-3-(4-pyridyl)-1,3-propandione, was prepared through a Claisen condensation reaction; the dye exhibited aggregation-induced emission, which is enhanced emission owing to clustering of molecules to form aggregates in poor solvents or in the solid state. The dye was nonemissive in solution. However, strong green emission was observed because of the restriction of molecular motion when the protonated dye was accommodated into the interlayer nanospace of the silicate layers through cation-exchange reactions. The restricted motion was confirmed by the smaller nonradiative relaxation rate constant obtained by time resolved luminescence and quantum yield measurements. A moderate dye packing (0.11 mmol/g) in the interlayer space is important to obtain enhanced emission, whereas the intercalation of a large amount of dye (0.27 mmol/g) resulted in concentration quenching. Therefore, the interlayer space of the layered silicate used here was responsible for the strong emission because of moderate packing of the accommodated beta-diketones. PMID- 29131641 TI - QCM-D Investigation of Swelling Behavior of Layer-by-Layer Thin Films upon Exposure to Monovalent Ions. AB - Polyelectrolyte multilayers and layer-by-layer assemblies are susceptible to structural changes in response to ionic environment. By altering the salt type and ionic strength, structural changes can be induced by disruption of intrinsically bound ion pairs within the multilayer network via electrostatic screening. Notably, high salt concentrations have been used for the purposes of salt-annealing and self-healing of LbL assemblies with KBr, in particular, yielding a remarkably rapid response. However, to date, the structural and swelling effects of various monovalent ion species on the behavior of LbL assemblies remain unclear, including a quantitative view of ion content in the LbL assembly and thickness changes over a wide concentration window. Here, we investigate the effects of various concentrations of KBr (0 to 1.6 M) on the swelling and de-swelling of LbL assemblies formed from poly(diallyldimethylammonium) polycation (PDADMA) and poly(styrene sulfonate) polyanion (PSS) in 0.5 M NaCl using quartz-crystal microbalance with dissipation (QCM-D) monitoring as compared to KCl, NaBr, and NaCl. The ion content after salt exchange is quantified using neutron activation analysis (NAA). Our results demonstrate that Br- ions have a much greater effect on the structure of as prepared thin films than Cl- at ionic strengths above assembly conditions, which is possibly caused by the more chaotropic nature of Br-. It is also found that the anion in general dominates the swelling response as compared to the cation because of the excess PDADMA in the multilayer. Four response regimes are identified that delineate swelling due to electrostatic repulsion, slight contraction, swelling due to doping, and film destruction as ionic strength increases. This understanding is critical if such materials are to be used in applications requiring submersion in chemically dynamic environments such as sensors, coatings on biomedical implants, and filtration membranes. PMID- 29131642 TI - Single Layer Surface-Grafted PMMA as a Negative-Tone e-Beam Resist. AB - One of the important challenges in electron beam lithography is nanofabrication on nonflat or irregular surfaces. Although spin coating is the most popular technique for resist coating, it is not suitable for nonflat, irregular substrates because a uniform film cannot be achieved on those surfaces. Here, it is demonstrated that single layer surface-grafted PMMA can be used as a negative tone e-beam resist, and it can be applied to nonflat, irregular surfaces as well as flat, conventional surfaces. Although it is well known that heavily exposed PMMA undergoes cross-linking and works as a negative-tone e-beam resist when developed by solvent, solvent does not work as a developer for negative-tone single-layer surface-grafted PMMA. Instead, thermal treatment at 360 degrees C for 1 min is used to develop PMMA. PMID- 29131643 TI - Electrophysiology of Epithelial Sodium Channel (ENaC) Embedded in Supported Lipid Bilayer Using a Single Nanopore Chip. AB - Nanopore-based technologies are highly adaptable supports for developing label free sensor chips to characterize lipid bilayers, membrane proteins, and nucleotides. We utilized a single nanopore chip to study the electrophysiology of the epithelial Na+ channel (ENaC) incorporated in supported lipid membrane (SLM). An isolated nanopore was developed inside the silicon cavity followed by fusing large unilamellar vesicles (LUVs) of DPPS (1,2-dipalmitoyl-sn-glycero-3 phosphoserine) and DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine) to produce a solvent-free SLM with giga-ohm (GOmega) sealed impedance. The presence and thickness of SLM on the nanopore chip were confirmed using atomic force spectroscopy. The functionality of SLM with and without ENaC was verified in terms of electrical impedance and capacitance by sweeping the frequency from 0.01 Hz to 100 kHz using electrochemical impedance spectroscopy. The nanopore chip exhibits long-term stability for the lipid bilayer before (144 h) and after (16 h) incorporation of ENaC. Amiloride, an inhibitor of ENaC, was utilized at different concentrations to test the integrity of fused ENaC in the lipid bilayer supported on a single nanopore chip. The developed model presents excellent electrical properties and improved mechanical stability of SLM, making this technology a reliable platform to study ion channel electrophysiology. PMID- 29131644 TI - Simultaneous Introduction of Two Nitroxides in the Reaction: A New Approach to the Synthesis of Heterospin Complexes. AB - A new approach to the synthesis of multispin compounds has been developed, namely, the simultaneous introduction of two different stable nitroxides (nitronyl nitroxide and imino nitroxide) in a reaction with a metal ion. An important characteristic of the new method is that nitronyl nitroxide and imino nitroxide introduced in the reaction with the metal are the products of different series; i.e., the nitronyl nitroxide molecule differs from the imino nitroxide molecule not only in one additional oxygen molecule per molecule but also in another substituent in the side chain of the organic paramagnet. This possibility was demonstrated on the synthesis of multispin compounds [Ni2(A1)(L2)2(Piv)(MeOH)], [Ni2(L1)(A2)2(Piv)(H2O)], [Co2(A1)(L2)2(Piv)(MeOH)], and [Co3(L1)2(A2)2(Piv)2], in which Ln and An differ in the substituent in the phenyl ring. The number of multispin compounds that can be synthesized by the proposed method is almost unlimited. The heterospin complexes of transition metals with coordinated nitronyl nitroxide and imino nitroxide in one molecule contain energy-different exchange interaction channels that differ in both magnitude and sign, as confirmed by the quantum-chemical analysis of exchange channels in [Ni(B1)(B2)2](NO3)2. The series of mixed-radical complexes may include compounds with nontrivial magnetic properties such as [Co2(A1)(L2)2(Piv)(MeOH)], which experiences bulk magnetic ordering below 3.5 K. PMID- 29131645 TI - High Resolution Monitoring Above and Below the Groundwater Table Uncovers Small Scale Hydrochemical Gradients. AB - Hydrochemical solute concentrations in the shallow subsurface can be spatially highly variable within small scales, particularly at interfaces. However, most monitoring systems fail to capture these small scale variations. Within this study, we developed a high resolution multilevel well (HR-MLW) with which we monitored water across the interface of the unsaturated and saturated zone with a vertical resolution of 0.05-0.5 m. We installed three of these 4 m deep HR-MLWs in the riparian zone of a third-order river and analyzed for hydrochemical parameters and stable water isotopes. The results showed three distinct vertical zones (unsaturated zone, upper saturated zone, lower saturated zone) within the alluvial aquifer. A 2 m thick layer influenced by river water (upper saturated zone) was not captured by existing monitoring wells with higher screen length. Hydrochemical data (isotopes, total ions) were consistent in all HR-MLWs and showed similar variation over time emphasizing the reliability of the installed monitoring system. Further, the depths zones were also reflected in the NO3-N concentrations; with high spatial variabilities between the three wells. The zonation was constant over time, with seasonal variability in the upper saturated zone due to the influence of river water. This study highlights the use of high resolution monitoring for identifying the spatial and temporal variability of hydrochemical parameters present in many aquifer systems. Possible applications range from riparian zones, agricultural field sites to contaminated site studies, wherever an improved understanding of biogeochemical turnover processes is necessary. PMID- 29131646 TI - Multifunctional Material with Efficient Optoelectronic Integrated Molecular Switches Based on a Flexible Thin Film/Crystal. AB - Switchable materials, due to their potential applications in the fields of sensors, photonic devices, digital processing, etc., have been developed drastically. However, they still face great challenges in effectively inducing multiple molecular switching. Herein organic-inorganic hybrid compounds, an emerging class of hydrosoluble optoelectronic-active materials, welcome a new member with smart unique optical/electrical (fluorescence/dielectric) dual switches (switching ON/OFF), that is, [C5H13NBr][Cd3Br7] (1) in the form of both a bulk crystal and an ultraflexible monodirectional thin film, which simultaneously exhibits fast dielectric/fluorescent dual switching triggered by an optical/thermal/electric signal with a high signal-to-noise ratio of 35 (the highest one in the known optical/dielectric dual molecular switches). Additionally, the exceptional stability/fatigue resistance as well as the fantastic extensibility/compactness of thin films (more than 10000 times folding over 90 degrees ), makes 1 an ideal candidate for single-molecule intelligent wearable devices and seamlessly integrated optoelectronic multiswitchable devices. This opens up a new route toward advanced light/electric high performance switches/memories based on organic-inorganic hybrid compounds. PMID- 29131647 TI - Efficient Construction of Free Energy Profiles of Breathing Metal-Organic Frameworks Using Advanced Molecular Dynamics Simulations. AB - In order to reliably predict and understand the breathing behavior of highly flexible metal-organic frameworks from thermodynamic considerations, an accurate estimation of the free energy difference between their different metastable states is a prerequisite. Herein, a variety of free energy estimation methods are thoroughly tested for their ability to construct the free energy profile as a function of the unit cell volume of MIL-53(Al). The methods comprise free energy perturbation, thermodynamic integration, umbrella sampling, metadynamics, and variationally enhanced sampling. A series of molecular dynamics simulations have been performed in the frame of each of the five methods to describe structural transformations in flexible materials with the volume as the collective variable, which offers a unique opportunity to assess their computational efficiency. Subsequently, the most efficient method, umbrella sampling, is used to construct an accurate free energy profile at different temperatures for MIL-53(Al) from first principles at the PBE+D3(BJ) level of theory. This study yields insight into the importance of the different aspects such as entropy contributions and anharmonic contributions on the resulting free energy profile. As such, this thorough study provides unparalleled insight in the thermodynamics of the large structural deformations of flexible materials. PMID- 29131648 TI - Treatment of Vinca minor Leaves with Methyl Jasmonate Extensively Alters the Pattern and Composition of Indole Alkaloids. AB - Alkaloids extracted from mature Vinca minor leaves were fractionated by preparative HPLC. By means of HRMS and NMR data, the main alkaloids were identified as vincamine, strictamine, 10-hydroxycathofoline, and vincadifformine. Upon treatment with methyl jasmonate (MeJA), the pattern and composition of the indole alkaloids changed extensively. While 10-hydroxycathofoline and strictamine concentrations remained unaltered, vincamine and vincadifformine levels showed a dramatic reduction. Upon MeJA treatment, four other indole alkaloids were detected in high quantities. Three of these alkaloids have been identified as minovincinine, minovincine, and 9-methoxyvincamine. Whereas minovincinine and minovincine are known to occur in trace amounts in V. minor, 9-methoxyvincamine represents a novel natural product. Based on the high similarities of vincamine and 9-methoxyvincamine and their inverse changes in concentrations, it is postulated that vincamine is a precursor of 9-methoxyvincamine. Similarly, vincadifformine seems to be converted first to minovincinine and finally to minovincine. Because MeJA treatment greatly altered the alkaloidal composition of V. minor, it could be used as a potential elicitor of alkaloids that are not produced under normal conditions. PMID- 29131649 TI - Characterization of Proteomes Extracted through Collagen-based Stable Isotope and Radiocarbon Dating Methods. AB - Isotope analyses on "collagen" extracted from ancient bone have been routinely used for dietary and chronological inferences worldwide for decades. These methods involve the decalcification of biomineralized tissues with acid, often followed by processes to remove exogenous contaminants, and then gelatinization of what is often described as the "collagen" fraction. However, little is known about the relative content of collagen to the many other noncollagenous proteins (NCPs) potentially present. Some of these NCPs have great longevity in ancient bone, and some, for example, fetuin-A, are useful for obtaining better taxonomic information than collagen. This study uses Orbitrap Elite LC-MS/MS to characterize the proteomes of the acid-soluble and base-soluble fractions, which are usually discarded, and the gelatinized "collagen" fraction obtained from both stable isotope and radiocarbon methods applied to several ancient bovine bones. The results showed that all fractions tested contain numerous NCPs, but the base soluble fraction for both methods contains the greatest number of NCPs with the highest relative abundances. This study confirms that not only do the waste fractions obtained from the "collagen" extraction procedure of stable isotope or radiocarbon dating methods yield a plentiful resource of NCPs that is currently being overlooked but that they also provide proteomes as complex as those obtained from standard proteomics methods. PMID- 29131650 TI - Revealing the Solvation Structure and Dynamics of Carbonate Electrolytes in Lithium-Ion Batteries by Two-Dimensional Infrared Spectrum Modeling. AB - Carbonate electrolytes in lithium-ion batteries play a crucial role in conducting lithium ions between two electrodes. Mixed solvent electrolytes consisting of linear and cyclic carbonates are commonly used in commercial lithium-ion batteries. To understand how the linear and cyclic carbonates introduce different solvation structures and dynamics, we performed molecular dynamics simulations of two representative electrolyte systems containing either linear or cyclic carbonate solvents. We then modeled their two-dimensional infrared (2DIR) spectra of the carbonyl stretching mode of these carbonate molecules. We found that the chemical exchange process involving formation and dissociation of lithium ion/carbonate complexes is responsible for the growth of 2DIR cross peaks with increasing waiting time. In addition, we also found that cyclic carbonates introduce faster dynamics of dissociation and formation of lithium-ion/carbonate complexes than linear carbonates. These findings provide new insights into understanding the lithium-ion mobility and its interplay with solvation structure and ultrafast dynamics in carbonate electrolytes used in lithium-ion batteries. PMID- 29131651 TI - Increased Echocardiographic Pulmonary Pressure in HIV-infected and -uninfected Individuals in the Veterans Aging Cohort Study. AB - RATIONALE: The epidemiology and prognostic impact of increased pulmonary pressure among HIV-infected individuals in the antiretroviral therapy era is not well described. OBJECTIVES: To examine the prevalence, clinical features, and outcomes of increased echocardiographic pulmonary pressure in HIV-infected and -uninfected individuals. METHODS: This study evaluated 8,296 veterans referred for echocardiography with reported pulmonary artery systolic pressure (PASP) estimates from the Veterans Aging Cohort study, an observational cohort of HIV infected and -uninfected veterans matched by age, sex, race/ethnicity, and clinical site. The primary outcome was adjusted mortality by HIV status. MEASUREMENTS AND MAIN RESULTS: PASP was reported in 2,831 HIV-infected and 5,465 HIV-uninfected veterans (follow-up [mean +/- SD], 3.8 +/- 2.6 yr). As compared with uninfected veterans, HIV-infected veterans with HIV viral load greater than 500 copies/ml (odds ratio, 1.27; 95% confidence interval [CI], 1.05-1.54) and those with CD4 cell count less than 200 cells/MUl (odds ratio, 1.28; 95% CI, 1.02 1.60) had a higher prevalence of PASP greater than or equal to 40 mm Hg. As compared with uninfected veterans with a PASP less than 40 mm Hg, HIV-infected veterans with a PASP greater than or equal to 40 mm Hg had an increased risk of death (adjusted hazard ratio, 1.78; 95% CI, 1.57-2.01). This risk persisted even among participants without prevalent comorbidities (adjusted hazard ratio, 3.61; 95% CI, 2.17-6.01). The adjusted risk of mortality in HIV-infected veterans was higher at all PASP values than in uninfected veterans, including at values currently considered to be normal. CONCLUSIONS: HIV-infected people with high HIV viral loads or low CD4 cell counts have a higher prevalence of increased PASP than uninfected people. Mortality risk in HIV-infected veterans increases at lower values of PASP than previously recognized and is present even among those without prevalent comorbidities. These findings may inform clinical decision making regarding screening and surveillance of pulmonary hypertension in HIV infected individuals. PMID- 29131652 TI - Novel Homozygous LRP5 Mutations in Mexican Patients with Osteoporosis Pseudoglioma Syndrome. AB - AIMS: Osteoporosis-pseudoglioma syndrome (OPPG) is an uncommon autosomal recessive disorder characterized by the rare association of early-onset osteoporosis and severe ocular abnormalities such as persistent fetal vasculature and microphthalmia. Biallelic mutations in the low-density lipoprotein receptor related protein-5 gene (LRP5) have been associated with OPPG. We present clinical and genetic data from three Mexican OPPG patients, a pair of sibs, and a sporadic case. MATERIALS AND METHODS: Three patients underwent clinical examination, including a complete ophthalmic evaluation. Based on the clinical diagnosis of OPPG, the entire coding sequence of LRP5 was polymerase chain reaction-amplified and directly Sanger-sequenced. Genetic testing was extended to the parents of the affected patients. RESULTS: Phenotypic variability was observed in the familial case and molecular analysis identified a novel homozygous c.1145C>T, p.(Pro382Leu) variant in both sibs. As expected, their parents were heterozygous carriers. The sporadic patient exhibited a severe osseous phenotype, microphthalmia, and neurological symptoms. In this patient, homozygosity for the c.442C>T, p.(Gln148*) variant was demonstrated, whereas her parents were heterozygous carriers. The p.(Pro382Leu) pathogenic mutation has been previously reported only in a compound heterozygous state in OPPG patients. CONCLUSIONS: Two novel homozygous missense and nonsense variants were demonstrated in three OPPG cases from Mexico. Our results expand the spectrum of disease-causing LRP5 mutations. This is the first report of OPPG in our population and our findings may potentially add to a genotype-phenotype correlation. PMID- 29131653 TI - The Incidence of Venous Thromboembolism After Achilles Tendon Surgery in Patients Receiving Thromboprophlaxis. AB - BACKGROUND: METHODS: RESULTS: CONCLUSIONS. PMID- 29131654 TI - Association Between Nonmedical Use of Prescription Drugs and Sleep Quality in a Large College Student Sample. AB - OBJECTIVE/BACKGROUND: Poor sleep and nonmedical use (NMU) of prescription drugs (NMUPD) are both common among college students. Since lack of sleep adversely influences academic performance, this study examined the association between NMUPD and subjective sleep quality among college students. PARTICIPANTS: Students who completed the American College Health Association-National College Health Assessment data (Fall 2010, Spring 2011; N = 135,874). METHODS: Associations were examined between NMUPD in four classes over the past 12 months (antidepressant, painkillers, sedatives, and stimulants), and five aspects of sleep quality (Enough Sleep, Early Awakening, Daytime Sleepiness, Difficulty Falling Asleep, and Problem With Daytime Sleepiness) in the past seven days. RESULTS: Any NMUPD (at least one class), NMU of stimulants specifically, and NMU of painkillers specifically were associated with getting fewer days of Enough Sleep (OR: 0.86, 0.93, and 0.84 respectively), more days of Early Awakening (OR: 1.28, 1.10, and 1.28 respectively), Daytime Sleepiness (OR: 1.23, 1.13, and 1.16 respectively), and Difficulty Falling Asleep (OR:1.32, 1.10, and 1.27 respectively; p < .0001, each). NMU of sedatives was significantly associated with having Problem With Daytime Sleepiness (OR: 1.10), more days of Early Awakening (OR: 1.12), and Difficulty Falling Asleep (OR: 1.17; p < .0001). CONCLUSIONS: NMUPD is associated with poor sleep among college students. Therefore, behavioral medicine screening and treatment of this vulnerable population should consider sleep health, NMUPD, and the potential that these problems may be comorbid. PMID- 29131655 TI - Psychotropic Drug Prescription in Adolescents: A Retrospective Study in a Swiss Psychiatric University Hospital. AB - OBJECTIVES: This retrospective study aims to evaluate off-label prescriptions and administrations of psychotropic medications in adolescents in a university psychiatric hospital in Switzerland. METHODS: Data were collected during the entire stays from the electronic database for 76 inpatients in 2008 and 76 inpatients in 2014. Data collected included gender, age, psychiatric diagnosis, duration of hospitalization, and psychotropic drug prescriptions and administrations. RESULTS: A total of 224 psychotropic drugs (mean 2.9 drugs/patient) were prescribed in 2008 and 268 (mean 3.5 drugs/patient) in 2014. Due to the prescriptions of some drugs as required, only 76% of the prescriptions were actually administered in 2008 (mean 2.3 drugs/patient) and 55% in 2014 (mean 1.9 drugs/patient). Antipsychotics were the most frequently prescribed drugs in 2008 (74% of patients) and 2014 (86% of patients). Anxiolytics were also highly prescribed in 2008 (54% of patients) and 2014 (66% of patients), as well as antidepressants in 2008 (30% of patients), but less in 2014 (13% of patients). Overall, 69% of prescriptions were found to be off label in 2008 and 68% in 2014, according to age, diagnosis, dose, or formulation as approved by Swissmedic. The medication classes with the highest rate of off-label prescriptions were antidepressants (100% for both years), antipsychotics (94% in 2008 and 92% in 2014), and hypnotics (67% in 2008 and 100% in 2014). For both study periods, at least one off-label psychotropic drug prescription and administration was recorded in 96% and 79% of the patients, respectively. CONCLUSION: The high rate of off-label psychotropic drug use strengthens the need for clinical trials to better evaluate the efficacy and safety of these treatments in adolescents. PMID- 29131656 TI - Mechanical behavior of a total chest wall prosthesis with rib-like features. AB - The Department of Thoracic Surgery of the National Institute of Cancer in Milan developed a new rib-cage prosthesis which tries to combine flexibility, protection and bio-compatibility. This new replacement concept has been implanted in many patients, showing cheering results in term of reconstructions simplicity, postoperative complications reduction and patients comfort. This paper investigates and discusses in detail the mechanical behavior of the innovative rib cage prosthesis. Mechanical strength and stiffness are numerically evaluated in order to asses its limits and if it is fully compatible with patients 'normal' life. PMID- 29131657 TI - Variability of the dynamic stiffness of foot joints. Effect of gait velocity variation. AB - BACKGROUND: Comparison of dynamic stiffness of foot joints was previously proposed to investigate pathological situations with changes in the properties of muscle and passive structures. Samples must be controlled to reduce the variability within groups being compared, which may arise from different sources, such as gait speed or foot posture index (FPI). METHODS: In this work, variability in the measurement of the dynamic stiffness of ankle, midtarsal and metatarsophalangeal joints was studied in a controlled sample of healthy adult male subjects with normal FPI, and the effect of gait speed was analyzed. In Experiment I, dynamic stiffnesses were obtained in three sessions, five trials per session, for each subject, taking the mean value across trials as representative of each session. In Experiment II, five trials were considered at slow, comfortable, and fast velocities RESULTS: Results showed similar inter- and intra-session errors and intra-subject errors within sessions, indicating the goodness of using five trials per session for averaging. Intra- and inter-subject variability data provided can be used to select the sample size in future comparative analyses. Significant differences with gait speed were observed in most dynamic stiffnesses considered, with a general rise when gait speed increased, especially at the midtarsal joint, this being attributed to an active modulation produced by the central nervous system. CONCLUSIONS: Differences from gait speed were higher than intra- and inter-session repeatability errors for the propulsion phases at the ankle and midtarsal joints, comparative analyses at these phases needing a more exhaustive control of gait speed to reduce the required sample size. s. PMID- 29131658 TI - Measuring Male-to-Male Differences in Fertility or Effects of Semen Treatments. AB - Fertility is a convenient but meaningless term unless the outcome measure is stipulated and accounts for dependence of male fertility on the female population. We describe outcome measures and detail the impacts of the physiological status of each female and her external environment, as well as management imposed by humans. We explain the dominant role of the female reproductive tract as a series of hurdles for sperm seeking an ovum. Each spermatozoon in an ejaculate is unique, although usually most are morphologically similar. Semen seemingly contains three subpopulations of sperm, based on fate within a female and role in hampering the success of the ultimate winning spermatozoon; we define these subpopulations. The numerical size of each subpopulation placed into a female determines the shape of the dose-response curve leading to possible live young. Heterospermic artificial insemination provides far greater sensitivity to detect differences, partly because the female environment is identical for each comparison. PMID- 29131659 TI - Stress Outcomes of Four Types of Perceived Interruptions. AB - Objective We sought to define and measure four types of perceived interruptions and to examine their relationships with stress outcomes. Background Interruptions have been defined and measured in a variety of inconsistent ways. No study has simultaneously examined the subjective experience of all types of interruptions. Method First, we provide a synthesized definition and model of interruptions that aligns interruptions along two qualities: origin and degree of multitasking. Second, we create and validate a self-report measure of these four types of perceived interruptions within two samples (working undergraduate students and working engineers). Last, we correlate this measure with self-reported psychological and physical stress outcomes. Results Our results support the four factor model of interruptions. Results further support the link between each of the four types of interruptions (intrusions, breaks, distractions, and a specific type of ruminations, discrepancies) and stress outcomes. Specifically, results suggest that distractions explain a unique portion of variance in stress outcomes above and beyond the shared variance explained by intrusions, breaks, and discrepancies. Conclusion The synthesized four-factor model of interruptions is an adequate representation of the overall construct of interruptions. Further, perceived interruptions can be measured and are significantly related to stress outcomes. Application Measuring interruptions by observation can be intrusive and resource intensive. Additionally, some types of interruptions may be internal and therefore unobservable. Our survey measure offers a practical alternative method for practitioners and researchers interested in the outcomes of interruptions, especially stress outcomes. PMID- 29131660 TI - Biomechanical and Morphometric Properties of Long Flexor Tendons of the Toes: A Cadaver Study. AB - BACKGROUND: METHODS: RESULTS: CONCLUSIONS. PMID- 29131661 TI - Validation of Essential Acoustic Parameters for Highly Urgent In-Vehicle Collision Warnings. AB - Objective The aim of this study was to validate the importance of key acoustic criteria for use as in-vehicle forward collision warning (FCW) systems. Background Despite recent advances in vehicle safety, automobile crashes remain one of the leading causes of death. As automation allows for more control of noncritical functions by the vehicle, the potential for disengagement and distraction from the driving task also increases. It is, therefore, as important as ever that in-vehicle safety-critical interfaces are intuitive and unambiguous, promoting effective collision avoidance responses upon first exposure even under divided-attention conditions. Method The current study used a driving simulator to assess the effectiveness of two warnings, one that met all essential acoustic parameters, one that met only some essential parameters, and a no-warning control in the context of a lead vehicle-following task in conjunction with a cognitive distractor task and collision event. Results Participants receiving an FCW comprising five essential acoustic components had improved collision avoidance responses relative to a no-warning condition and an FCW missing essential elements on their first exposure. Responses to a consistently good warning (GMU Prime) improved with subsequent exposures, whereas continued exposure to the less optimal FCW (GMU Sub-Prime) resulted in poorer performance even relative to receiving no warning at all. Conclusions This study provides support for previous warning design studies and for the validity of five key acoustic parameters essential for the design of effective in-vehicle FCWs. Application Results from this study have implications for the design of auditory FCWs and in-vehicle display design. PMID- 29131662 TI - Isoniazid Monoresistance and Rate of Culture Conversion among Patients in the State of Georgia with Confirmed Tuberculosis, 2009-2014. AB - RATIONALE: Isoniazid-monoresistant tuberculosis (INH-monoresistant TB) is the most common drug-resistant TB type in the United States; however, its impact on TB treatment outcomes is not clear. OBJECTIVES: This study aims to understand 1) factors associated with INH-monoresistant TB and 2) the association between INH monoresistance and response to TB treatment. METHODS: We studied all patients with TB (age, >=15 yr) reported to the Georgia State Electronic Notifiable Disease Surveillance System (SENDSS) from 2009 to 2014. INH-monoresistant TB was defined as a Mycobacterium tuberculosis isolate resistant to isoniazid only. Time to sputum culture conversion was defined as the time (measured in days) from TB treatment initiation to the date of the first consistently negative culture result reported to the SENDSS. Logistic regression and Cox proportional hazard models were used to estimate the odds and hazard rate of sputum culture conversion, all-cause mortality, and poor TB outcome among patients with INH monoresistant TB. RESULTS: Among 1,141 culture-confirmed patients with available drug susceptibility testing results, 998 (87.5%) were susceptible to TB first line drugs, and 143 (12.5%) were patients with INH-monoresistant TB. In multivariable analysis, male sex (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.01-2.67) and homelessness (aOR, 5.55; 95% CI, 3.38-9.17) were associated with higher odds of INH-monoresistant TB. In the same multivariable model, older age (>=65 yr old) (aOR, 0.21; 95% CI, 0.07-0.55) and miliary disease (aOR, 0.19; 95% CI, 0.01-0.96) were associated with lower odds of INH monoresistant TB. Among 1,116 patients with pulmonary TB, the median time to sputum culture conversion was 30 days (interquartile range, 13-58). The rate of culture conversion was similar among patients with and without INH monoresistance (adjusted cause-specific hazard ratio, 1.15; 95% CI, 0.95-1.40). INH monoresistant TB was not significantly associated with poor TB treatment outcomes (aOR, 1.61; 95% CI, 0.67-3.70) or mortality during TB treatment (aOR, 1.72; 95% CI, 0.58-4.94). CONCLUSIONS: Our findings suggest that compared with drug susceptible TB, patients in Georgia with INH-monoresistant TB have a similar response to TB treatment including culture conversion rate, final TB treatment outcome, and all-cause mortality. PMID- 29131664 TI - Tissue repair after selective alveolar corticotomy in orthodontic patients: A preliminary study. AB - OBJECTIVES: To analyze histologic findings of bone remodeling at the time of surgery and 90 days later at corticotomized and noncorticotomized sites. MATERIALS AND METHODS: Eight adult patients with bilaterally inclined mandibular molars were included in this split-mouth study. Corticotomy was performed on the test side, and bone was harvested on both mandibular hemi-arches. Bone blocks were shipped to Forsyth Institute lab (Boston, Mass). After surgery, cantilevers were activated to upright inclined mandibular molars on both sides. Approximately 90 days after surgery, new mandibular bone blocks were harvested from test and control sites. Histologic analyses were performed on both groups (test and control sides) at two time points: baseline (T0) and 90 days after surgery (T90). Bone blocks were stained with hematoxylin and eosin, and Masson's trichrome. The protocols enabled screening of new bone formation and collagen in mineralized and nonmineralized connective tissue. Outcomes were compared using a clustered generalized estimating equations model Results: The test group at T90 exhibited an increase of 16% of primary bone ( P < .05), an increase of 6.6 in osteocytes quantity ( P = .039), and an increase of 4.06 in reversal lines quantity ( P = .924). Both groups exhibited a decrease in the inorganic proportion. CONCLUSIONS: The intentional bone injury performed in adult patients undergoing orthodontic treatment can be considered temporary and reversible. Evidence indicates that baseline bone characteristics are unaltered. PMID- 29131668 TI - Nasal Bleeding Probably Associated with Methylphenidate. PMID- 29131663 TI - Factors associated with long-term vertical skeletal changes induced by facemask therapy in patients with Class III malocclusion. AB - OBJECTIVES: This study investigated the long-term vertical skeletal changes induced by facemask therapy in patients with Class III malocclusion and different vertical skeletal patterns. MATERIALS AND METHODS: A total of 54 patients (20 boys and 34 girls; mean age, 7.7 +/- 2.0 years) with Class III malocclusion who were successfully treated with facemask therapy were included in this study. Vertical skeletal changes (overbite depth indicator, angle between the Sella Nasion (SN) plane and Gonion-Gnathion (GoGn) line, angle between the Frankfort horizontal (FH) plane and mandibular plane, gonial angle, and angle between the SN plane and palatal plane) were measured on lateral cephalograms from before treatment (T0) to after facemask therapy (T1) and from T0 to after retention (T2). Multivariate linear regression analysis was used to study the associations of the patients' skeletal patterns with the short-term (T0-T1) and long-term (T0 T2) vertical skeletal changes as a result of facemask therapy. RESULTS: The mean treatment period of facemask therapy (T0-T1) was 1.4 +/- 0.6 years, and the mean retention period (T1-T2) was 6.9 +/- 2.6 years. Age at T0 was significantly correlated with vertical skeletal changes from T0 to T1. Differences in the treatment results between sexes were not significant. The angle between point A point B line and mandibular plane to mandibular plane angle at T0 and the angle between the FH plane and mandibular plane at T0 were significant predictors for short-term and long-term changes. Changes in the Sella-Nasion-point A from T0 to T1 and from T1 to T2 significantly affected vertical changes in the short term and long term, respectively. CONCLUSIONS: Vertical skeletal changes as a result of facemask therapy are significantly associated with severity of the skeletal Class III malocclusion and mandibular plane angulation before treatment and the amount of forward maxillary growth during the treatment and retention periods. PMID- 29131669 TI - Research in High-Altitude and Mountain Emergency Medicine: Is Methodology Key? PMID- 29131670 TI - Canine Hepatitis Associated with Intrahepatic Bacteria in Three Dogs. AB - This case report describes the detection of intrahepatic bacteria in formalin fixed paraffin-embedded histopathological sections from three dogs with neutrophilic, pyogranulomatous, or lymphoplasmacytic hepatitis and cholangiohepatitis. In each of these cases, eubacterial fluorescence in situ hybridization enabled colocalization of intrahepatic bacteria with neutrophilic and granulomatous inflammation in samples that were negative for bacteria when evaluated by routine hematoxylin and eosin histopathology augmented with histochemical stains. Positive responses to antimicrobial therapy were observed in of 2 out of 2 patients that were treated with antimicrobials. These findings suggest that eubacterial fluorescence in situ hybridization analysis of formalin fixed paraffin-embedded histopathological sections is more sensitive than conventional histochemical stains for the diagnosis of bacteria-associated canine hepatitis. PMID- 29131671 TI - In Vitro Evaluation of Evacuated Blood Collection Tubes as a Closed-Suction Surgical Drain Reservoir. AB - The initial negative pressures of evacuated blood collection tubes (EBCT) and their in vitro performance as a rigid closed-suction surgical drain (CSSD) reservoir has not been evaluated in the scientific literature despite being described in both human and veterinary texts and journals. The initial negative pressures of EBCT sized 3, 6, 10, and 15 mL were measured and the stability of the system monitored. The pressure-to-volume curve as either air or water was added and maximal filling volumes were measured. Evacuated blood collection tubes beyond the manufacture's expiration date were evaluated for initial negative pressures and maximal filling volumes. Initial negative pressure ranged from -214 mm Hg to -528 mm Hg for EBCT within the manufacturer's expiration date. Different pressure-to-volume curves were found for air versus water. Optimal negative pressures of CSSD are debated in the literature. Drain purpose and type of exudates are factors that should be considered when deciding which EBCT size to implement. Evacuated blood collection tubes have a range of negative pressures and pressure-to-volume curves similar to previously evaluated CSSD rigid reservoirs. Proper drain management and using EBCT within labeled expiration date are important to ensure that expected negative pressures are generated. PMID- 29131672 TI - Urethral Sphincter Mechanism Incompetence in Dogs: An Update. AB - Urethral sphincter mechanism incompetence (USMI) is the most common cause of acquired urinary incontinence in dogs. The pathogenesis of USMI is multifactorial and complex. Studies have shown variable results regarding the effects and timing of sterilization on the incidence of USMI. Diagnosis of USMI is often based on history, physical examination, and elimination of other differentials. Treatment options for USMI include medications, such as alpha-adrenergic agents and estrogen products, minimally-invasive urethral bulking procedures, surgical procedures (e.g., indwelling urethral occluders), or combination therapy. The overall prognosis for USMI is typically fair to good with long-term therapy. PMID- 29131673 TI - Evaluation of Parasite Egg and Cyst Recovery Using Devices Designed for Centrifugal or Stationary Flotation. AB - Two new devices (OT, ST), were recently introduced for the recovery of parasite eggs and cysts for microscopic examination. These devices, two stationary flotation devices, and a standard double-centrifugal sugar-flotation were compared using common flotation solutions and methods recommended by the manufacturers for the recovery of hookworm, ascaridoid, and whipworm eggs from companion animal fecal samples. Additionally, the recovery of Giardia cysts in the OT device using a zinc sulfate versus sodium nitrate solution was evaluated. Double-centrifugal sugar-flotation (1.30 specific gravity) was the most sensitive method for the recovery of the nematode eggs from feces of companion animals. Overall, centrifugation increased the recovery of eggs as compared with standing flotation methods, with the ST performing equivalently to the OT. Although these more recently introduced tests have good sensitivities for the nematodes tested, egg recovery was routinely markedly less than that achieved by standard double centrifugal sugar-flotation, and false-negatives did occur. Still, the OT and ST generally have increased recoveries over the two standing flotation devices, and are significantly better than these for the recovery of ascaridoid and whipworm eggs from dog and cat samples. Zinc sulfate (1.18 specific gravity) is recommended for the recovery of Giardia cysts when using the OT device. PMID- 29131674 TI - Congenital Malformations Resembling VACTERL Association in a Golden Retriever. AB - A 2 mo old golden retriever presented with malformation of the left thoracic limb and a small circular indentation of the skin in the cranial thoracic spine. Radiographs showed a cleft between the second and fifth metacarpal bones of the left thoracic limb compatible with ectrodactyly and spina bifida affecting T4 and T5 vertebrae. Magnetic resonance imaging of the thoracic spine showed dorsal reposition of the spinal cord and a tract connecting from the dura mater to the skin. No other malformations were detected. Surgical excision of the tract was performed and histopathological examination diagnosed a dermoid sinus type IV. Dermoid sinus and spina bifida are well-recognized congenital spinal and spinal cord defects, yet association with other congenital malformation are rarely reported in dogs. The here-reported dog had spinal and spinal cord abnormalities with concurrent limb malformation, which are two components of a nonrandom association of birth defects described as VACTERL in people. To the authors' knowledge, this is the first report describing concurrent dermoid sinus type IV, spina bifida, and ectrodactyly in a dog, and highlights the importance of patient examination for occurrence of multiple malformations to provide an appropriate prognosis for an owner. PMID- 29131675 TI - Dedifferentiated Chondrosarcoma in the Dog and Cat: A Case Series and Review of the Literature. AB - This retrospective case series describes seven dogs and one cat diagnosed with dedifferentiated chondrosarcoma, an uncommon, aggressive variant of chondrosarcoma. The purpose of the study is to describe clinical, imaging, and histopathological findings of this tumor. Medical records and the diagnostic laboratory database at Colorado State University from 2000 to 2015 were reviewed and complete medical records were available for the eight animals in this report. Similar to what has been reported in people, poor long-term survival and high metastatic rate, particularly to the lungs, was observed in our case series. A bimorphic pattern on imaging (radiographs, computed tomography, and MRI) consisting of mineralized and nonmineralized areas was seen mirroring the high grade sarcomatous component adjacent to a low-grade chondroid component seen histopathologically. A review of the human literature including suspected etiology, imaging findings, histopathology, and survival times with various treatment options is presented. This article describes the first reported cases of dedifferentiated chondrosarcoma in the veterinary literature. Early accurate recognition could lead to treatment plans tailored to this variant. PMID- 29131676 TI - Incidence of Postoperative Neurologic Complications in Pugs Following Portosystemic Shunt Attenuation Surgery. AB - Postoperative seizures occur in 5-12% of dogs following surgical attenuation of congenital extrahepatic portosystemic shunts (CEPSS) and are often refractory to treatment. Because pugs are predisposed to necrotizing meningoencephalitis, they may be at higher risk of developing neurologic complications after CEPSS attenuation. We hypothesized that pugs have a higher prevalence of postoperative neurologic complications and that pugs who died due to neurologic complications would have evidence of encephalitis at necropsy. Records were searched for pugs that had undergone surgical correction of a single extrahepatic CEPSS. Fourteen pugs met the inclusion criteria and were compared with a control group of 30 dogs of varying breeds who also underwent surgical attenuation for a single CEPSS. Four of 14 pugs (28.6%) died or were euthanized within 1 mo after surgery for neurologic complications, compared with only 1 of 30 dogs in the control group (P < .029). No evidence of necrotizing meningoencephalitis was seen on necropsy. Pugs may be at an increased risk of developing fatal neurologic complications following surgical attenuation for CEPSS. Further studies are indicated to investigate reasons for this increased risk, as well as to determine any factors that may indicate which pugs are at higher risk. PMID- 29131677 TI - Methylphenidate Has Superior Efficacy Over Parent-Child Interaction Therapy for Preschool Children with Disruptive Behaviors. AB - OBJECTIVE: To compare the effectiveness between parent-child interaction therapy (PCIT) and methylphenidate in preschool children with attention deficit/hyperactivity disorder (ADHD) symptoms and disruptive behaviors who had remaining significant behavior problems after previous behavioral parent training. METHODS: We included 35 preschool children, ranging in age between 3.4 and 6.0 years. Participants were randomized to PCIT (n = 18) or methylphenidate (n = 17). Outcome measures were maternal ratings of the intensity and number of behavior problems and severity of ADHD symptoms. Changes from pretreatment to directly posttreatment were compared between groups using two-way mixed analysis of variance. We also made comparisons of both treatments to a nonrandomized care as usual (CAU) group (n = 17) regarding intensity and number of behavior problems. All children who started one of the treatments were included in the analyses. RESULTS: Mothers reported a significantly more decreased intensity of behavior problems after methylphenidate (pre-post effect size d = 1.50) compared with PCIT (d = 0.64). ADHD symptoms reduced significantly over time only after methylphenidate treatment (d = 0.48) and not after PCIT. Changes over time of children in the CAU treatment were nonsignificant. CONCLUSIONS: Although methylphenidate was more effective than PCIT, both interventions may be effective in the treatment of preschool children with disruptive behaviors. Our findings are preliminary as our sample size was small and the use of methylphenidate in preschool children lacks profound safety data as reflected by its off-label status. More empirical support is needed from studies with larger sample sizes. PMID- 29131678 TI - Exergames Designed for Older Adults: A Pilot Evaluation on Psychosocial Well Being. AB - OBJECTIVE: Exergames are increasingly been used in the primary healthcare domain for older adults who are 65 years and above. However, most of the exergames on current market are not designed for the aging population. The current study introduced five new exergames developed for elderly and evaluated their benefits. METHODS: Five new exergames were developed by researchers from Finland, Singapore, and Japan, in which the game topics, difficulties, and user interface were designed particularly for older adults. A between-group pilot study was further conducted to evaluate their psychosocial effects by comparing to traditional exercise and care-as-usual program, with a sample of 30 community dwelling older adults in Singapore. RESULTS: Results showed that exergame group had significantly higher exercise enjoyment over other two groups. Exergame group has lower self-efficacy than other two groups, although it was not statistically significant. Significant subgroup difference was detected in neither life satisfaction nor loneliness across the three groups. CONCLUSION: The study highlighted the effect of fun and entertainment elements on the psychosocial effect of exergames and called for simpler interactive systems and easier exergame tasks for the older adults. PMID- 29131680 TI - From the Editor-in-Chief's Desk. PMID- 29131679 TI - Knowledge and Opinions of Postpartum Mothers About the Lactational Amenorrhea Method: The Turkish Experience. AB - OBJECTIVE: This study was performed to investigate mothers' opinions and knowledge about the contraceptive feature of breastfeeding. BACKGROUND: Breastfeeding is quite beneficial in terms of mother, baby, and public health. Although it has long been known to have a contraceptive effect and although it is common in many countries, women usually do not use it as a contraceptive method. MATERIALS AND METHODS: This is a descriptive study and included 400 mothers in their early postpartum period. Data were collected with a questionnaire at face to-face interviews within 3 days of giving birth. Obtained data were analyzed with descriptive statistics. RESULTS: One third of the mothers were primiparous and 66.5% of the mothers had breastfeeding experience. Of these, 38.9% of the mothers said that they received knowledge about the contraceptive effect of breastfeeding and 68.9% of these mothers received this knowledge from a nurse. Seventeen percent of the mothers receiving this knowledge reported that breastfeeding was a contraceptive and 1.8% of the mothers reported that it was sometimes contraceptive. Around 41.3% of the mothers thought that they would be able to use breastfeeding as a contraceptive method. Almost all the mothers wanted to get information about the contraceptive feature of breastfeeding. CONCLUSIONS: As our research shows, four of every five mothers in their early postpartum period turned out to believe that breastfeeding was not contraceptive, although the mothers are very eager and ready for this information. Therefore, it is important that health professionals providing antenatal and postnatal counseling about breastfeeding and contraception should offer women accurate information about this method. PMID- 29131681 TI - Biotechnological Approach To Preserve Fresh Pasta Quality. AB - Fresh pasta is highly susceptible to microbial contamination because of its high water activity and nutrient content. In this study, a new biopreservation system was examined that consists of an active sodium alginate solution containing Lactobacillus reuteri and glycerol, which was added during the production process of pasta. Our aim was to extend the fresh pasta shelf life by the in situ production of reuterin, thereby avoiding the use of thermal treatments that generally compromise food sensory characteristics. Two experimental studies were carried out with the product packaged under either ordinary or modified atmospheric conditions. Microbiological and sensory quality indices were monitored to determine the effectiveness of biopreservation on product quality during storage. The use of the active solution with L. reuteri and glycerol during the production process of pasta improved both microbial and sensory quality, particularly when combined with modified atmosphere. PMID- 29131682 TI - Analysis of Nutritional Traits and Aflatoxin Contamination in Selected Maize Varieties from Pakistan. AB - Recently, cultivation of high-yielding hybrid maize varieties has revolutionized maize production in Pakistan. Analyses of nutritional traits and aflatoxin (AF) contamination in these varieties can aid in the identification of susceptible and resistant varieties, particularly for cultivation in the Pakistani agro-climatic environment. Five spring maize varieties-Pioneer, Neelam, DK-919, Desi, and Hi maize-were selected for analyses of their nutritional, tocopherol, and AF contents. Protein, carbohydrate, oil, ash, fiber, and moisture contents ranged between 8.7 and 10.8%, 68 and 71%, 3.72 and 5.56%, 1.09 and 1.81%, 1.1 and 3.1%, and 11.7 and 14.2%, respectively. Tocopherol levels in selected varieties were in the range of 461 to 1,430 MUg/g. Hi-maize exhibited significantly higher protein and tocopherol contents than the other varieties, indicating its better suitability for feed and silage applications. The highest mean level of total AFs, 14.5 +/- 0.12 MUg/kg, was found in Desi, and results showed that the most dominant AF found in the maize varieties was AFB1. Furthermore, the results showed that the higher the level of tocopherol, the lower the concentration of total AFs and vice versa in maize varieties. The results can be used to investigate additional susceptible maize varieties that are resistant to fungal attack. PMID- 29131683 TI - Persistence of Non-O157 Shiga Toxin-Producing Escherichia coli in Dairy Compost during Storage. AB - Dairy compost with 20, 30, or 40% moisture content (MC) was inoculated with a mixture of six non-O157 Shiga toxin-producing Escherichia coli (STEC) serovars at a final concentration of 5.1 log CFU/g and then stored at 22 and 4 degrees C for 125 days. Six storage conditions-4 degrees C and 20% MC, 4 degrees C and 30% MC, 4 degrees C and 40% MC, 22 degrees C and 20% MC, 22 degrees C and 30% MC, and 22 degrees C and 40% MC-were investigated for the persistence of non-O157 STEC in the dairy compost. During the entire storage, fluctuations in indigenous mesophilic bacterial levels were observed within the first 28 days of storage. After inoculation, the non-O157 STEC population increased 0.69 and 0.79 log CFU/g in the dairy compost with 30 and 40% MC at 22 degrees C within the first day, respectively; for all other storage conditions, the pathogen population decreased rapidly. After the 125-day storage, the reductions of non-O157 STEC for 4 degrees C and 20% MC, 4 degrees C and 30% MC, 4 degrees C and 40% MC, 22 degrees C and 20% MC, 22 degrees C and 30% MC, and 22 degrees C and 40% MC storage conditions were >4.52, >4.55, 3.89, >4.61, 3.60, and 3.17 log CFU/g, respectively. All the survival curves showed an extensive tail, indicating non-O157 STEC can survive at least for 125 days in the dairy compost. The survival data were analyzed with log linear with tailing and Weibull models. Compared with the log-linear with tailing model, the Weibull model was found to be a better choice for predicting the survival of non-O157 STEC in dairy compost owing to a high overall R2 value (0.8738 to 0.9909). The decay rate of non-O157 STEC was higher in dairy compost stored at 4 degrees C compared with at 22 degrees C, and the same trend was found for the compost with 40% MC versus 20% MC. In addition, two non-O157 STEC serotypes (STEC O145 and O45) were detected on the last day of the longitudinal study and may deserve special attention in the Big 6 STEC group. Our results have provided scientific data for risk assessment of the microbiological safety of dairy compost to control non-O157 STEC during subsequent storage of dairy compost. PMID- 29131684 TI - Robust Evaluations of Intensive Care Unit Length of Stay Using Observational Data. PMID- 29131685 TI - Hospice Reflection. PMID- 29131686 TI - The estimation of the economic burden of measles in terms of direct and indirect costs per case. PMID- 29131688 TI - Carl June Speaks of His Pioneering Efforts That Led to the First Food and Drug Administration-Approved Gene Therapy Product. PMID- 29131687 TI - The Questionnaire of Cognitive and Affective Empathy: A Comparison Between Paper and-Pencil Versus Online Formats in Italian Samples. AB - The most recent conceptualizations of empathy recognize affective empathy as distinct from cognitive empathy. Consequently, instruments that assess these 2 types of empathy have been developed. Among them, the Questionnaire of Cognitive and Affective Empathy (QCAE) is a particularly promising, relatively new, self report measure consisting of 31 items. To examine the cross-cultural adaptability of the QCAE, we investigated the psychometric properties of an Italian version in 2 samples and with 2 different formats of administration. Study 1 (n = 407) used archival data collected via paper and pencil; Study 2 (n = 285) used newly collected data, obtained with an online format. In these studies, in addition to the QCAE, 6 other instruments measuring empathy-related constructs (i.e., interpersonal competence, well-being, personality traits, emotion regulation, alexithymia, and emotion recognition) were administered, too. Data analysis focused on factor structure, internal consistency, and convergent validity. The findings of both studies provide support for the cross-cultural applicability of the QCAE, and reveal interesting associations between empathy and the other constructs under examination. PMID- 29131689 TI - Do pedometers with or without education on exercise increase functional walking capacity and physical activity level in adolescents with juvenile idiopathic arthritis? AB - To evaluate the impact of pedometer use on the physical activity (PA) and functional walking capacity (FWC) of adolescents with juvenile idiopathic arthritis (JIA) and lower extremity (LE) involvement. Twenty-seven adolescents, aged 11-19 years with JIA and LE involvement, participated in the three-phase pedometer study that introduced the use of a pedometer and an education seminar at 6 weeks. Measurements were taken at the baseline first visit and at weeks 6, 12, and 20. The primary outcome measure was the 6-minute walk test (6MWT). Thirteen completed the study. Six-minute walk distance (6MWD) significantly increased from baseline (458.0 +/- 70.8 m) to the end of phase 1 (501.4 +/- 59.8 m) (p = 0.035), prior to receiving the pedometer; and from baseline to the end of study (p = 0.0037). No significant changes in 6MWD were found between weeks 6 and 12 (intervention) (p = 0.77) or between weeks 12 and 20 (follow through phase) (p = 0.27). In adolescents with LE JIA, consistent guidance and support by rheumatology professionals appears to positively influence PA and measures of FWC as seen through improved 6MWD. There was insufficient evidence to show that pedometers further increased FWC or PA. PMID- 29131690 TI - Investigating ioflupane I123 injection and single photon emission tomography as an imaging biomarker for long-term sequelae following mild traumatic brain injury. AB - OBJECTIVE: To determine whether there were differences in clinical outcomes for ioflupane I123 injection (DaTscan) and single photon emission tomography consistent with early Parkinson's disease (PD) among individuals with a history of mild traumatic brain injury (mTBI). METHODS: We performed a case-control study among patients presenting to the Emergency Room (ER) during 2006-2013 with mTBI (cases, n = 34) or without mTBI (controls, n = 33). We performed clinical and imaging measurements in cases and controls at least 1-year post-presentation to the ER (average three years four months). RESULTS: All DaTscans obtained were qualitatively normal. There were no qualitative DaTscan differences between cases and controls. There was, however, a significant increase in caudate asymmetry in controls versus cases (p = 0.02), but this finding was no longer significant after correction for multiple comparisons. There was a suggestion of a trend of poorer clinical score test measures among those with mTBI, although the overall mean score difference between cases and controls was not clinically significant. CONCLUSION: Our small study does not provide support for DaTscan changes suggestive of PD in the one to seven years following mTBI. A trend towards poorer clinical measures was seen but was not clinically relevant in our small sample. Further work in a large population is necessary to support these findings. PMID- 29131692 TI - Stigma and Counter-Stigma Frames, Cues, and Exemplification: Comparing News Coverage of Depression in the English- and Spanish-Language Media in the U.S. AB - A content analysis was conducted to compare news coverage of depression in the English- and Spanish-language media in the United States (N = 355). The study revealed that the English-language media reported stereotypes more frequently than the Spanish-language news media. The presence of all four types of stereotypes (i.e., the mentally ill as violent, suicidal, incompetent, and weak) was associated with the increased use of the stigma frame in the English-language news media, while only the violence stereotype was associated with the increased use of the stigma frame in the Spanish-language news media. The presence of recovery information and positive emotions was associated with the increased use of the counter-stigma frame in both English- and Spanish-language news media. Furthermore, the study found that the use of exemplars was generally correlated with an increase in stereotypical coverage, particularly in English-language news media, but a decrease in educational information in both news media. PMID- 29131691 TI - A new mutation of the CDH1 gene in a patient with an aggressive signet-ring cell carcinoma of the stomach. AB - Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segregation study in the family detected the same mutation in his healthy 31-year-old brother. The mutation affects one of the extracellular repeat (CAD repeats) domains which is essential for the homophilic binding specificity that directs "E-cadherin" to bind with itself each others. In this case, immunohistochemical analysis showed no expression of E-cadherin in the tumor sample and was a useful prescreening tool to genetic testing. This finding was associated with a poor response to trastuzumab-based treatment. PMID- 29131693 TI - Perceived Risk Associated with MDMA (Ecstasy/Molly) Use among African Americans: What Prevention and Treatment Providers Should Know. AB - The research literature on MDMA (ecstasy/molly) use has largely relied on samples of ravers/club-goers, gay men, and international populations (e.g., United Kingdom, Australia). As a result, very little is known about MDMA use among African Americans. This study aimed to address this gap by adding to the limited amount of research with this population. The goal of this study was to identify and characterize the perceived risks that African Americans associate with using MDMA. Surveys (n = 100) and in-depth interviews (n = 15) were conducted with African American young adults in Southwest Florida between August 2014 and November 2015. Almost the entire sample (91%) associated risks with their MDMA use. The most prevalent types of perceived risks associated with MDMA use were physical harm (e.g., dehydration, fatal overdose, and cardiac damage). Qualitative interview data are also presented to better contextualize these perceived risks. These data provide insight into the risks most salient on the minds of African Americans, and can be used to begin developing and tailoring interventions that target MDMA use among this population. While more research is needed on this topic, these results represent a step forward in our understanding of MDMA use among African Americans. PMID- 29131694 TI - Role of Neuron-Glial Interaction Mediated by IL-1beta in Ectopic Tooth Pain. AB - Although many reports have demonstrated that ectopic pain develops in the orofacial region following tooth pulp inflammation, which often causes misdiagnosis and inappropriate treatment for patients with pulpitis, the precise mechanism remains unknown. In the present study, we hypothesized that the functional interaction between satellite glial cells and neurons mediated by interleukin 1beta (IL-1beta) in the trigeminal ganglion (TG) is involved in ectopic orofacial pain associated with tooth pulp inflammation. The digastric muscle electromyogram (D-EMG) activity elicited by capsaicin administration into the maxillary second molar tooth pulp was analyzed to evaluate the noxious reflex and was significantly increased in rats with inflammation of the maxillary first molar (M1) versus rats injected with saline. A significant increase in the expression of connexin43 (Cx43), a gap junction containing protein, was observed in activated satellite glial cells surrounding second molar-innervating neurons in the TG after M1 pulpitis. Daily administration of Gap26, a Cx43 mimetic peptide and inhibitor, in the TG significantly suppressed the enhancement of capsaicin-induced D-EMG activity and the percentage of Fluoro-Gold (FG)-labeled cells encircled by glial fibrillary acid protein-immunoreactive (IR) + Cx43-IR cells after M1 pulp inflammation ( P < 0.01). The percentage of FG-labeled cells encircled by glial fibrillary acid protein-IR + IL-1beta-IR cells, IL-1 type I receptor-IR cells labeled with FG, and TRPV1-IR cells labeled with FG significantly increased after M1 pulp inflammation ( P < 0.01). Daily administration of IL-1ra, an IL-1 receptor antagonist, into the TG significantly reduced the enhancement of capsaicin-induced D-EMG activity and the percentage of TRPV1-IR neurons labeled with FG after M1 pulp inflammation ( P < 0.01). The present findings suggest that satellite glial cell is activated in the TG via activated gap junctions composed of Cx43 following tooth pulp inflammation, which leads to the hyperactivation of remote neurons via IL-1beta mechanisms and results in ectopic tooth pulp pain in the adjacent tooth. PMID- 29131696 TI - Risk Factors for Discontinuation of Treatment for Neovascular Age-Related Macular Degeneration. AB - PURPOSE: To investigate risk factors for treatment discontinuation for neovascular age-related macular degeneration (nAMD). METHODS: Data from the Swedish Macula Register and the Skane Healthcare Register are reported on the treatment received by 932 nAMD patients diagnosed 2013-2015. Treatment discontinuation is defined as having a termination visit or lacking a control or treatment visit during the period of 10-14 months after the diagnostic visit. The risk of treatment discontinuation during the first year is estimated using a Poisson model and a classification tree. RESULTS: 503 eyes (50.9%) discontinued the treatment within the first year. Patients with visual acuity below 60 ETDRS letters (20/60 Snellen) at baseline, serious comorbidities, or treated at the university hospital have a 42% (95% CI 25-61%, P < 0.001), 27% (95% CI 13-43%, P = 0.001) and 30% (95% CI 15-46%, P < 0.001) increased risk to discontinue treatment compared with similar patients. Patients on ranibizumab therapy have a 45% (95% CI 28-63%, P < 0.001) increased risk for treatment discontinuation during year 1 compared with patients on aflibercept therapy. The classification tree also shows that patients on ranibizumab therapy and those with low VA at baseline are at a higher risk of terminating treatment. CONCLUSIONS: Almost half of the patients starting anti-VEGF therapy discontinue treatment during the first year. Patients with risk factors may require additional support to continue with the treatment. Aflibercept therapy could be an alternative to patients at risk of treatment discontinuation. PMID- 29131695 TI - Time Since First Acting on Same-Sex Attraction and Recreational Drug Use among Men Who Have Sex With Men (MSM): Is There an Effect of "Gay Age"? AB - BACKGROUND: Men who have sex with men (MSM) have higher rates of substance use compared to men who have sex with women. Among MSM, drug use is linked to higher risk sexual behavior and acquisition of HIV and other sexually transmitted infections. OBJECTIVES: We hypothesize that time since first acting on one's same sex attraction, or one's "gay age", could be predictive of drug using behavior. METHODS: We examined this question among 176 MSM, aged 18-35, presenting at a public sexual health clinic. Behavioral data were captured using interviewer- and self-administered surveys and clinical data were extracted from medical records. We used modified Poisson regression to examine associations between gay age and recent recreational drug use, and separately, between gay age and recent marijuana use. RESULTS: In total, 43% of participants reported recent marijuana use and 26% of participants reported recent use of other drugs. The associations between gay age and marijuana use and other drug use varied by HIV status. After adjustment for biological age, race, and education, a one-year increase in gay age was associated with significantly increased drug use among HIV-negative men (adjusted prevalence ratio (aPR): 1.08; 95% confidence interval (CI): 1.03-1.14), but we observed no association between gay age and drug use among HIV-positive men (aPR: 0.96, 95% CI: 0.86-1.07). Gay age was not associated with marijuana use in HIV-negative (aPR: 1.00, 95% CI: 0.95-1.04) or HIV-positive (aPR: 1.06, 95% CI: 0.98-1.14) men. CONCLUSIONS: In summary, HIV-negative MSM who had experienced more time since first same-sex experience had significantly increased prevalence of recent drug use. PMID- 29131697 TI - Teamwork, collaboration, coordination, and networking: Why we need to distinguish between different types of interprofessional practice. PMID- 29131698 TI - The Anti-Inflammatory and Antioxidant Effects of Salvia officinalis on Lipopolysaccharide-Induced Inflammation in Rats. AB - Salvia officinalis, which has a high phenolic acid and flavonoid content, is a powerful antioxidant and anti-inflammatory herb. Inflammation plays an important role in the pathophysiology of many diseases and could cause damage by means of oxidative stress. The aim of this study was to investigate the anti-inflammatory and antioxidant activity of S. officinalis formed lipopolysaccharide (LPS) induced experimental inflammation model. Four- to five-month-old 42 female Wistar albino rats were divided into six groups. Three groups were administered intraperitoneally 1 mg/kg LPS. Twenty-four hours after injection of LPS, 10 and 30 mg/kg S. officinalis extract were given orally to treatment groups. Pulmonary and hepatic 18F-fluoro-deoxy-D-glucose (18F-FDG) uptake was calculated to determine the status of inflammation by 18F-fluoro-deoxy-D-glucose-positron emission tomography (18FDG-PET) scan. Antioxidant enzyme activities and nitric oxide (NO) and malondialdehyde (MDA) levels were determined. Nuclear factor-kappa B (NF-kappaB) and tumor necrosis factor-alpha (TNF-alpha) levels were also detected in serum. As a result, lung and liver 18F-FDG uptake was found to be higher in the inflammation group than control group. MDA levels in erythrocyte and all tissue samples (liver, lung, and kidney) were found to be significantly higher compared to treatment groups. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities of the inflammation group in the liver, lung, kidney tissues, and erythrocyte SOD and CAT activities were determined to significantly lower than groups treated with S. officinalis. Increased NO, NF kappaB, and TNF-alpha levels were found in the inflammation group. S. officinalis has been observed to have useful effects on LPS-induced inflammation and oxidative stress in rats. PMID- 29131699 TI - Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia. AB - Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different ( P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype-specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse. PMID- 29131700 TI - Integrated Risk Stratification Using Minimal Residual Disease and Sentinel Genetic Alterations in Pediatric Acute Lymphoblastic Leukemia. PMID- 29131701 TI - Are the Level of Knowledge and Practices of Pregnant Women Regarding Folic Acid Supplementation Still Inadequate? A Cross-Sectional Study in a Middle Eastern Urban Setting. AB - This observational cross-sectional study aimed to examine the knowledge and practices of pregnant women in North Lebanon regarding periconceptional folic acid (FA) supplementation. A convenience sample of pregnant women attending gynecology clinics in North Lebanon was recruited between May and September 2013. Data were collected from a face-to-face interview performed by a trained local dietician as well as from review of obstetric charts. A total of 465 women were included in the study. Only 37 (7.9%) were aware of the role of FA in preventing birth defects, while 129 (27.7%) were able to identify one food item rich in FA or folate. Only 125 (26.9%) were taking FA supplementation before pregnancy. While 440 (94.6%) participants were taking FA supplements during pregnancy, 158 (34%) were receiving an inadequate dose. Adequate preconceptional supplementation of FA was significantly associated with the women's level of education (p =.008), planned pregnancy (p <.0001), and gynecologic visit before pregnancy (p <.0001). Moreover, young age (p =.003) and small number of children (p =.019) were significant predictors of adequate supplementation during pregnancy. Our study revealed deficient knowledge and inadequate intake of FA supplements before and during pregnancy. PMID- 29131702 TI - Postoperative Refractive Errors Following Pediatric Cataract Extraction with Intraocular Lens Implantation. AB - PURPOSE: Advances in surgical techniques allow implantation of intraocular lenses (IOL) with cataract extraction, even in young children. However, there are several challenges unique to the pediatric population that result in greater degrees of postoperative refractive error compared to adults. METHODS: Literature review of the techniques and outcomes of pediatric cataract surgery with IOL implantation. RESULTS: Pediatric cataract surgery is associated with several sources of postoperative refractive error. These include planned refractive error based on age or fellow eye status, loss of accommodation, and unexpected refractive errors due to inaccuracies in biometry technique, use of IOL power formulas based on adult normative values, and late refractive changes due to unpredictable eye growth. CONCLUSIONS: Several factors can preclude the achievement of optimal refractive status following pediatric cataract extraction with IOL implantation. There is a need for new technology to reduce postoperative refractive surprises and address refractive adjustment in a growing eye. PMID- 29131703 TI - Expectant inner-city women: attitudes about contraception given infant feeding choice. AB - PURPOSE: We sought to examine whether low-income inner-city expectant women who intend to breastfeed make different contraceptive choices than those who intend to formula feed. MATERIALS AND METHODS: This cross-sectional pilot study surveyed expectant women age 14 years and older receiving prenatal care at MacDonald Women's Hospital, Cleveland Ohio (01 November 2016-15 January 2017). Questions assessed knowledge and attitudes regarding infant feeding and contraception options, and postpartum feeding and contraceptive intentions. RESULTS: We enrolled 223 expectant women, mean age 25.6 years at a median of 30 weeks gestation; 192 (86.5%) were African-American and 171 (75%) were multiparous. Women intending to breastfeed had 0.44 times the odds of intending to use birth control after delivery (95% CI [0.19-1.05], p = .06), while women intending to feed formula had 2.26 times the odds of intending to use birth control after delivery (95% CI [0.95-5.40]). Contraceptive attitudes significantly impacted intent to use contraception (p = .007), with every point higher on the contraception attitudes scale equating to a 7% increase in odds of postpartum contraception use. CONCLUSIONS: Postpartum contraceptive intentions do not differ significantly between women intending to breastfeed and those intending formula feeding. Contraception attitudes do not significantly change this association, but were significantly related to contraceptive intent. Findings highlight the importance of providing comprehensive birth control education to all expectant mothers, regardless of feeding intention. Our study is unique in addressing interactions between maternal contraceptive and feeding intentions among expectant women at high risk for both not breastfeeding and unintended short interval pregnancy. PMID- 29131704 TI - Impact of team composition on student perceptions of interprofessional teamwork: A 6-year cohort study. AB - Interprofessional education (IPE) provides students with opportunities to learn about the roles and responsibilities of other professions and develop communication and teamwork skills. As different health professions have recognised the importance of IPE, the number of disciplines participating in IPE events is increasing. Consequently, it is important to examine the effect group structure has on the learning environment and student knowledge acquisition during IPE events. The purpose of this study was to determine the effect of group composition on student perceptions of interprofessional teamwork and collaboration when participating in a case-based IPE forum. To examine this construct, six cohorts of students were divided into two groups: Group-one (2010 2012) included students from five professions. Group-two (2013-2015) included students from 10 professions. The only other change for group-two was broadening the case scenarios to ensure a role for each profession. At the conclusion of the case-based IPE forums, both groups demonstrated a statistically significant increase in 'readiness for interprofessional learning' and 'interdisciplinary education perceptions'. However, participants in group-one (2010-2012) demonstrated a greater change in scores when compared to group-two (2013-2015). It was concluded a case-based IPE forum with students from numerous health professions participating in a discussion about broad case scenarios was moderately effective at introducing students to other health professions and increasing their knowledge of others' identities. However, a smaller grouping of professions with targeted cases was more effective at influencing student perceptions of the need for teamwork. When planning an IPE event, faculty should focus on intentional groupings of professions to reflect the social context of healthcare teams so all students can fully participate and experience shared learning. PMID- 29131705 TI - Early Education and Employment Outcomes After Cancer in Adolescents and Young Adults. AB - PURPOSE: This study describes the early educational and vocational outcomes of Australian adolescents and young adults (AYAs) after cancer diagnosis and examines factors associated with these outcomes. METHODS: Within this cross sectional national Australian study, 196 AYAs aged 15-25 years at cancer diagnosis and within 6-24 months of diagnosis were recruited from 18 sites. Participants completed a survey that included questions about school and work outcomes, support received regarding necessary changes to education and vocation, and validated measures of anxiety, depression, and post-traumatic stress. RESULTS: Almost half of the sample (43%) was not fully "back on track" with their previous educational and vocational plans. Post-traumatic stress and emotional symptoms were associated with poorer school/work functioning (beta = -0.95, p = 0.009 and beta = -1.27, p = 0.001, respectively). Higher PedsQL school/work functioning was associated with a slightly greater likelihood of being "back on track" with education and work plans (OR 1.03, p = 0.001). AYAs who felt well supported regarding changes to education and work plans more frequently reported receiving support from formal sources and from more sources than those who felt less supported. Unmet need of accessing an educational or vocational advisor was significantly more frequent in adult than in pediatric settings (42% vs. 17%; p = 0.024). Parents were the most common source of educational or vocational support for AYAs rather than professionals. CONCLUSION: This study highlights the connection between school and work participation and mental health in a national sample of AYAs with cancer. It suggests distinct benefits of educational and vocational support. PMID- 29131706 TI - Alzheimer's Disease-Current Status and Future Directions. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder of the brain. The presence of amyloid-beta (Abeta) plaques, neurofibrillary tangles (NFTs), loss of neurons, synapses, and altered sensory perceptions, including memory loss, delineate AD. However, the cause of AD is not clearly known. Several genetic and nongenetic factors have been implicated in the disease. Of the genes, the E4 allele of apolipoprotein E is the largest known genetic risk factor of AD. This review article focuses on the various genetic and other predisposing factors that account for AD, pathophysiology of the disease, and the mechanisms by which Abeta plaques and NFTs are formed and could affect AD brain. In addition, recent advances and current diagnostics available for AD patients are detailed. As oxidative stress has been implicated in the etiology of the disease, special emphasis is given for nutrition based antioxidant therapies and interventional strategies for reducing/treating AD. PMID- 29131707 TI - Plasma Neutrophil Gelatinase-Associated Lipocalin Measured Immediately After Restoration of Spontaneous Circulation Predicts Acute Kidney Injury in Cardiac Arrest Survivors Who Underwent Therapeutic Hypothermia. AB - Early diagnosis of acute kidney injury (AKI) after cardiac arrest (CA) is challenging. We aimed to identify the diagnostic and prognostic performance of neutrophil gelatinase-associated lipocalin (NGAL) for AKI and its clinical outcomes. A retrospective observational study, involving adult comatose CA survivors treated with therapeutic hypothermia between May 2013 and December 2016, was conducted. AKI was classified according to the guidelines of Kidney Disease Improving Global Outcomes. NGAL levels were measured after return of spontaneous circulation (ROSC). The primary outcome was development of AKI within 7 days after CA, and the secondary outcome was inhospital mortality. The study included 279 patients, of which 111 (39.8%) developed AKI and 61 (21.9%) died. Thirty-seven (33.3%) of patients in the AKI group had stage 3 AKI, and 45 (40.5%) patients received renal replacement therapy. The area under the curve of NGAL levels for diagnosing AKI was 0.725 (95% confidence interval [CI] 0.668-0.776), and NGAL levels were independently associated with the development of AKI (odds ratio [OR] 1.004; 95% CI 1.002-1.006). Nonsurvivors had significantly higher NGAL levels (221.0 ng/mL [154.0-355.5] vs. 148.5 ng/mL [97.0-232.9]; p < 0.001). The development of AKI was independently associated with mortality (OR 4.926; 95% CI 2.353-10.311); however, NGAL level was not associated with mortality (OR 1.000; 95% CI 0.999-1.001). Plasma NGAL level measured after ROSC can be an early predictor for the development of AKI after CA. The presence of AKI was associated with increased inhospital mortality. PMID- 29131708 TI - Processes in Increasing Participation of African American Women in Cancer Prevention Trials: Development and Pretesting of an Audio-Card. AB - The enrollment of African American women into cancer prevention trials (CPTs) continues to be low despite their higher cancer mortality rates. Clinical trials are vital to the discovery of new prevention, diagnostic, and treatment methods that improve cancer outcomes. This study addressed attitudes and beliefs associated with the sub optimal participation of African American women in CPTs through the development and pretesting of an educational tool. The use of community-engaged research (CER) in the formative phase of this study was the basis for developing an audio-card. Cultural and linguistic elements were incorporated into the tool's audio and written messages, and visual images highlighted the importance of CPT participation among African American women. The CPT beliefs and behavioral intent of 30 African American women who received information from the audio-card were compared with 30 controls. Findings indicated statistically significant differences at posttest between the control and treatment groups in personal value (p = .03), social influence (p = .03), and personal barriers (p = .0001); personal barriers in the pretest group also demonstrated significant differences (p = .009). Consideration of cultural context and language needs of populations are vital to the development and design of effective health promoting tools. PMID- 29131709 TI - An exploration of motor learning concepts relevant to use of speech-generating devices. AB - For individuals who rely on speech-generating devices (SGDs) to complement and substitute for spoken language, speed, and accuracy of access to the device are paramount for effective communication. There is some evidence that application of motor memory principles may improve effectiveness of SGD-based communication. This article reviews motor learning models and principles, including learning stages, types of practice, and environmental factors that affect learning, and highlights the potential applications of these principles in dynamic display SGD design, intervention, and research. PMID- 29131710 TI - Fluorescence Spectroscopy as a Tool for the Assessment of Liver Samples with Several Stages of Fibrosis. AB - BACKGROUND: During the last years, fluorescence spectroscopy has been used as a potential tool for the evaluation and characterization of tissues with different disease conditions due to its low cost, high sensitivity, and minimally or noninvasive character. OBJECTIVE: In this study, fluorescence spectroscopy was used to study 19 paraffin blocks containing human liver tissue from biopsies. METHODS AND RESULTS: All samples were previously analyzed by two senior pathologists in a single-blind trial. After their evaluation, four liver samples were classified as nonfibrosis (F0), four as initial fibrosis (F1-F2), four as advanced fibrosis (F3), and six as cirrhosis (F4). The fluorescence was induced at different wavelengths as follows: 330, 365, and 405 nm using a portable fiber optic system. The fluorescence spectra were recorded in the range of 400-750 nm. A distinctive correlation between the shape of each spectrum and the level of fibrosis in the liver sample was detected. A multi-variate statistical analysis based on principal component analysis followed by linear discrimination analysis was applied to develop algorithms able to distinguish different stages of fibrosis based on the characteristics of fluorescence spectra. Pairwise comparisons were performed: F0 versus F1-F2, F1-F2 versus F3, F3 versus F4, and F1-F2 versus F4. The algorithms applied to each set of data yielded values of sensitivity and specificity that were higher than 90% and 95%, respectively, in all the analyzed cases. CONCLUSIONS: With this study, it is concluded that fluorescence spectroscopy can be used as a complementary tool for the assessment of liver fibrosis in liver tissue samples, which sets the stage for subsequent clinical trials. PMID- 29131711 TI - Aerobic treatment of swine manure to enhance anaerobic digestion and microalgal cultivation. AB - Aerobic treatment of swine manure was coupled with anaerobic digestion and microalgal cultivation. A 14-day aerobic treatment reduced the total solid content of swine manure by >15%. Ammonia and carbon dioxide were stripped by the air supplied, and this off-gas was further used to aerate the culture of Chlorella vulgaris. The microalgal growth rates in Bristol medium and the wastewater with the off-gas increased from 0.08 to 0.22 g/L/d and from 0.15 to 0.24 g/L/d, respectively. Meanwhile, the aerobically treated swine manure showed a higher methane yield during anaerobic digestion. The experimental results were used to establish a demonstration unit consisting of a 100 L composter, a 200 L anaerobic digester, a 60 L tubular photobioreactor, and a 300 L micro-open raceway pond. PMID- 29131712 TI - How rice Glycogen Synthase Kinase-like 5 (OsGSK5) integrates salinity stress response to source-sink adaptation: A proposed model. AB - We have previously shown that overexpression of GSK3-like kinase 5 in rice (OsGSK5) was associated with higher starch accumulation and better growth under severe salinity stress. Short-term 14CO2 feeding experiments suggested that OsGSK5 promoted higher flux to starch accumulation in the roots under this condition and that this mechanism may help to underscore the better growth characteristics observed. Here, we expand upon this hypothesis and consider (1) how OsGSK5 action could fit into a signaling model that integrates salinity stress to changes in starch metabolism, and (2) how this would facilitate whole plant physiological adaptations in source-to-sink partitioning. We also discuss additional functions of OsGSK5, necessary to support this adaptive mechanism. PMID- 29131713 TI - Vaccines We Need But Don't Have. AB - Vaccinations have had tremendous success in the 20th century. However, in the 21st century, we are facing complex immunological issues in relation to controlling underlying infectious diseases. Therefore, new technologies are needed to develop vaccines against infectious diseases like respiratory syncytial virus, human immunodeficiency virus, and cytomegalovirus. In addition, recent emerging infections have taught us that we must prepare preventative measures in advance using our scientific abilities. PMID- 29131714 TI - Understanding variations in secondary findings reporting practices across U.S. genome sequencing laboratories. AB - BACKGROUND: Increasingly used for clinical purposes, genome and exome sequencing can generate clinically relevant information that is not directly related to the reason for testing (incidental or secondary findings). Debates about the ethical implications of secondary findings were sparked by the American College of Medical Genetics (ACMG) 2013 policy statement, which recommended that laboratories report pathogenic alterations in 56 genes. Although wide variation in laboratories' secondary findings policies has been reported, little is known about its causes. METHODS: We interviewed 18 laboratory directors and genetic counselors at 10 U.S. laboratories to investigate the motivations and interests shaping secondary findings reporting policies for clinical exome sequencing. Analysis of interview transcripts and laboratory documents was informed by sociological theories of standardization. RESULTS: Laboratories varied widely in terms of the types of secondary findings reported, consent-form language, and choices offered to patients. In explaining their adaptation of the ACMG report, our participants weighed genetic information's clinical, moral, professional, and commercial value in an attempt to maximize benefits for patients and families, minimize the costs of sequencing and analysis, adhere to professional norms, attract customers, and contend with the uncertain clinical implications of much of the genetic information generated. CONCLUSIONS: Nearly all laboratories in our study voluntarily adopted ACMG's recommendations, but their actual practices varied considerably and were informed by laboratory-specific judgments about clinical utility and patient benefit. Our findings offer a compelling example of standardization as a complex process that rarely leads simply to uniformity of practice. As laboratories take on a more prominent role in decisions about the return of genetic information, strategies are needed to inform patients, families, and clinicians about the differences between laboratories' practices and ensure that the consent process prompts a discussion of the value of additional genetic information for patients and their families. PMID- 29131715 TI - Microplastic potentiates triclosan toxicity to the marine copepod Acartia tonsa (Dana). AB - Microplastics (MP) are contaminants of environmental concern partly due to plastics ability to sorb and transport hydrophobic organic contaminants (HOC). The importance of this "vector effect" is currently being debated in the scientific community. This debate largely ignores that the co-exposures of MP and HOC are mixtures of hazardous agents, which can be addressed from a mixture toxicity perspective. In this study, mixture effects of polyethylene microbeads (MP) and triclosan (TCS) (a commonly used antibacterial agent in cosmetics) were assessed on the marine copepod Acartia tonsa. Data indicated that MP potentiate the toxicity of TCS, illustrating the importance of understanding the mixture interaction between plastics and HOC when addressing the environmental importance of the vector effect. PMID- 29131716 TI - Compassion-Focused Therapy as an Intervention for Adult Survivors of Sexual Abuse. AB - Child sexual abuse can have long-term negative impacts across psychological, physical, and interpersonal domains. Some of the common issues for survivors of sexual abuse include shame and self-blame, attachment-based difficulties, avoidant coping strategies, and reduced capacity for self-compassion. Compassion focused therapy is a transdiagnostic intervention that specifically responds to these concerns. Compassion-focused therapy was originally developed for clients who experience high levels of shame and self-criticism and aims to strengthen the soothing and affiliative system through the cultivation of compassion. This article will highlight the theoretical alignment between some of the common issues and impacts associated with experiences of sexual abuse, with the core underlying principles of compassion-focused therapy. This includes (a) the capacity of the therapy's evolutionary framework to reduce perceptions of self blame, (b) the cultivation of compassion to respond to feelings of shame, (c) acknowledgment of the role of early attachment experiences and facilitation of corrective affiliative experiences, (d) regulation of the threat-based system following trauma, and (e) provision of an alternative to avoidant-based coping by responding to distress with compassion. It is proposed that the theoretical framework and core focus and aims of compassion-focused therapy are highly applicable for survivors of sexual abuse and therefore holds significant promise as a treatment option for this client group. PMID- 29131717 TI - In Vitro Effects of High-Intensity Laser Photobiomodulation on Equine Bone Marrow Derived Mesenchymal Stem Cell Viability and Cytokine Expression. AB - OBJECTIVE: This study aimed to examine the influence of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation on equine bone marrow-derived mesenchymal stem cell (MSC) viability, proliferation, and cytokine expression in vitro. BACKGROUND: Photobiomodulation of cells using monochromatic light is a technique designed to influence cellular processes. Previous studies have shown dose-dependent effects of low-level laser irradiation on cell proliferation and cytokine expression in a range of cell types and species. Evidence for the influence of 1064 nm wavelength near-infrared irradiation on MSCs is sparse, and high-energy doses have shown inhibitory effects. METHODS: MSC cultures from six horses were exposed to 1064 nm irradiation with an energy density of 9.77 J/cm2 and a mean output power of 13.0 W for 10 sec. MSC viability and proliferation were evaluated through flow cytometry and real-time live cell analysis. Gene expression and cytokine production in the first 24 h after irradiation were analyzed through polymerase chain reaction (PCR), multiplex assay, and enzyme linked immunosorbent assay. RESULTS: No difference in viability was detected between irradiated and control MSCs. Irradiated cells demonstrated slightly lower proliferation rates, but remained within 3.5% confluence of control cells. Twenty four hours after irradiation, irradiated MSCs demonstrated a significant increase in expression of interleukin (IL)-10 and vascular endothelial growth factor (VEGF) compared with control MSCs. CONCLUSIONS: Under these irradiation parameters, equine MSCs remained viable and expressed increased concentrations of IL-10 and VEGF. IL-10 has an anti-inflammatory action by inhibiting the synthesis of proinflammatory cytokines at the transcriptional level. This response to 1064 nm irradiation shows promise in the photobiomodulation of MSCs to enhance their therapeutic properties. PMID- 29131718 TI - Is abstinence really the best option? Exploring the role of exercise in the treatment and management of eating disorders. AB - Exercise prescription is suggested to help manage exercise abuse and improve overall eating disorder (ED) prognosis. This study explored emerging perceptions of ED health professionals concerning the role of exercise as a supportive treatment for EDs. Semi-structured interviews were conducted with international health professionals (n=13) with expertise in ED treatment. Verbatim transcripts were analyzed through thematic analysis. Four themes were revealed and titled 1) understanding the current state; 2) gaining perspectives; 3) barriers and benefits; 4) one size does not fit all. Within these themes, participants described the current state of exercise in ED treatment and suggested there exists a gap in research knowledge and practice. Participants also identified the implications of incorporating exercise into treatment and how an exercise protocol may be designed. Results enhance the understanding of the role of exercise in ED treatment and how it may further benefit individuals with EDs. PMID- 29131719 TI - Does Smile Intensity in Photographs Really Predict Longevity? A Replication and Extension of Abel and Kruger (2010). AB - Abel and Kruger (2010) found that the smile intensity of professional baseball players who were active in 1952, as coded from photographs, predicted these players' longevity. In the current investigation, we sought to replicate this result and to extend the initial analyses. We analyzed (a) a sample that was almost identical to the one from Abel and Kruger's study using the same database and inclusion criteria ( N = 224), (b) a considerably larger nonoverlapping sample consisting of other players from the same cohort ( N = 527), and (c) all players in the database ( N = 13,530 valid cases). Like Abel and Kruger, we relied on categorical smile codings as indicators of positive affectivity, yet we supplemented these codings with subjective ratings of joy intensity and automatic codings of positive affectivity made by computer programs. In both samples and for all three indicators, we found that positive affectivity did not predict mortality once birth year was controlled as a covariate. PMID- 29131720 TI - Dimensions of Experience: Exploring the Heterogeneity of the Wandering Mind. AB - The tendency for the mind to wander to concerns other than the task at hand is a fundamental feature of human cognition, yet the consequences of variations in its experiential content for psychological functioning are not well understood. Here, we adopted multivariate pattern analysis to simultaneously decompose experience sampling data and neural functional-connectivity data, which revealed dimensions that simultaneously describe individual variation in self-reported experience and default-mode-network connectivity. We identified dimensions corresponding to traits of positive-habitual thoughts and spontaneous task-unrelated thoughts. These dimensions were uniquely related to aspects of cognition, such as executive control and the ability to generate information in a creative fashion, and independently distinguished well-being measures. These data provide the most convincing evidence to date for an ontological view of the mind-wandering state as encompassing a broad range of different experiences and show that this heterogeneity underlies mind wandering's complex relationship to psychological functioning. PMID- 29131721 TI - Postural Stability in Healthy Child and Youth Athletes: The Effect of Age, Sex, and Concussion-Related Factors on Performance. AB - BACKGROUND: Postural stability plays a key role in sport performance, especially after concussion. Specific to healthy child and youth athletes, little is known about the influence development and sex may have on postural stability while considering other subjective clinical measures used in baseline/preinjury concussion assessment. This study aims to describe age- and sex-based trends in postural stability in uninjured child and youth athletes at baseline while accounting for concussion-related factors. HYPOTHESES: (1) Postural stability performance will improve with age, (2) females will display better postural stability compared to males, and (3) concussion-like symptoms will affect postural stability performance in healthy children and youth. STUDY DESIGN: Cross sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: This study comprised 889 healthy/uninjured child and youth athletes (54% female, 46% male) between the ages of 9 and 18 years old. Participants completed preseason baseline testing, which included demographic information (age, sex, concussion history), self report of concussion-like symptoms (Post-Concussion Symptom Inventory [PCSI] Child and PCSI-Youth), and measures of postural stability (BioSway; Biodex Medical Systems). Two versions of the PCSI were used (PCSI-C, 9- to 12-year-olds; PCSI-Y, 13- to 18-year-olds). Postural stability was assessed via sway index under 4 sway conditions of increasing difficulty by removing visual and proprioceptive cues. RESULTS: In children aged 9 to 12 years old, there were significant age- ( P < 0.05) and sex-based effects ( P < 0.05) on postural stability. Performance improved with age, and girls performed better than boys. For youth ages 13 to 18 years old, postural stability also improved with age ( P < 0.05). In both child and youth subgroups, postural stability worsened with increasing concussion-like symptoms ( P < 0.05). CONCLUSION: There are developmental and baseline symptom trends regarding postural stability performance. CLINICAL RELEVANCE: These findings provide a preliminary foundation for postconcussion comparisons and highlight the need for a multimodal approach in assessing and understanding physical measures such as postural stability. PMID- 29131722 TI - When Is Congruency Helpful? Interactive Effects of Frame, Motivational Orientation, and Perceived Message Quality on Fruit and Vegetable Consumption. AB - Health messages framed to be congruent with people's motivational orientation have been shown to be generally effective in promoting health behavior change, but some inconsistencies have been found. This study tested whether the perceived quality of a health message moderated the congruency effect in the domain of fruit and vegetable (FV) consumption. Undergraduate participants (N = 109) read a health message promoting FV intake in which the frame (gain vs. loss) was either congruent or incongruent with their approach/avoidance motivational orientation. Perceived message quality and intention to increase FV intake were assessed after message exposure, and self-reported FV intake was assessed one week later. A significant interaction between congruency and perceived message quality was found on both intention and FV intake. When messages were congruent, higher intentions and FV intake were observed when perceived message quality was high, but the reverse pattern was observed when perceived message quality was low. The findings support the potential utility of using congruently-framed messages to promote fruit and vegetable consumption, while also underscoring the necessity of using high-quality messages in order for congruency to influence health-related behaviors. PMID- 29131723 TI - Comment on "Mesothelioma from asbestos exposures: Epidemiologic patterns and impact in the United States" by R A Lemen, Journal of Toxicology and Environmental Health, Part B 2016;19:250-265. PMID- 29131724 TI - The Latest Laser Innovations in Dentistry. PMID- 29131725 TI - Contraceptive knowledge, use and intentions of Malawian women undergoing obstetric fistula repair. AB - OBJECTIVES: Unintended pregnancy contributes to morbidities, such as obstetric fistula. Furthermore, after fistula repair, women should avoid pregnancy for a year to prevent its breakdown. Our study objective was to evaluate the contraceptive knowledge, practices and intentions of women undergoing obstetric fistula repair at a centre in Malawi. METHODS: This cross-sectional study used a standardised survey to examine the contraceptive knowledge, practices and intentions of women undergoing obstetric fistula repair in Lilongwe, Malawi, between September 2011 and November 2014. Log binomial models were used to examine correlates of prior and planned contraceptive use. RESULTS: The analysis included 569 women, of whom 61.3% had heard of, and 38.7% had used a modern method of contraception. Women aged 20-49 years, married, with secondary education or higher and with living children were significantly more likely to report prior use of a modern contraceptive method. Of the 354 women who still had reproductive potential (premenopausal women who had not undergone sterilisation) and answered questions on future contraceptive use, less than half (41.6%) planned to use a modern method of contraception after fistula repair. Planned modern contraceptive use was significantly associated with being currently married and having secondary education or higher. CONCLUSIONS: Contraceptive knowledge, prior use and planned future use were low in our study population. To increase contraceptive use among women undergoing obstetric fistula repair, interventions in the postoperative period must seek to increase their family planning knowledge and access to contraceptive methods. PMID- 29131726 TI - The Psychology of Yoga Practitioners: A Cluster Analysis. AB - Yoga practitioners (N = 261) completed the revised Expression of Spirituality Inventory (ESI) and the Multidimensional Body-Self Relations Questionnaire. Cluster analysis revealed three clusters: Cluster A scored high on all four spiritual constructs. They had high positive evaluations of their appearance, but a lower orientation towards their appearance. They tended to have a high evaluation of their fitness and health, and higher body satisfaction. Cluster B showed lower scores on the spiritual constructs. Like Cluster A, members of Cluster B tended to show high positive evaluations of appearance and fitness. They also had higher body satisfaction. Members of Cluster B had a higher fitness orientation and a higher appearance orientation than members of Cluster A. Members of Cluster C had low scores for all spiritual constructs. They had a low evaluation of, and unhappiness with, their appearance. They were unhappy with the size and appearance of their bodies. They tended to see themselves as overweight. There was a significant difference in years of practice between the three groups (Kruskall -Wallis, p = .0041). Members of Cluster A have the most years of yoga experience and members of Cluster B have more yoga experience than members of Cluster C. These results suggest the possible existence of a developmental trajectory for yoga practitioners. Such a developmental sequence may have important implications for yoga practice and instruction. PMID- 29131727 TI - Guidelines for teaching yoga to women with breast cancer-related lymphoedema: an evidence-based approach. AB - Breast cancer-related lymphoedema (BCRL) is a chronic condition that requires lifelong management to prevent the condition worsening and to reduce the threat of infection. Women are affected in all domains of their life. As a holistic practice, yoga may be of benefit by reducing both the physical and psychosocial effects of lymphoedema. Women with BCRL are attending yoga classes in increasing numbers, so it is essential that yoga be based on principles that ensure lymphoedema is controlled and not exacerbated. Two Randomised Controlled Trials with a yoga intervention have had positive results after an 8-week intervention (n=28) and 6-months after a 4-week intervention (n=18). The first study had several significant results and women reported increased biopsychosocial improvements. Both studies showed trends to improved lymphoedema status. The yoga interventions compromised breathing, physical postures, meditation and relaxation practices based on Satyananda Yoga(r), with modifications to promote lymphatic drainage and following principles of best current care for those with BCRL. Individual needs were considered. The yoga protocol that was used in the 8-week trial is presented. Our aim is to provide principles for yoga teachers/therapists working with this clientele that can be adapted to other yoga styles. Further, these principles may provide a basis for the development of yoga programs for people with secondary lymphoedema in other areas of their body as the population requiring cancer treatment continues to increase. Whilst the style of yoga presented here has had positive outcomes, further application and research is needed to fully demonstrate its effectiveness. PMID- 29131728 TI - Yoga practice is associated with superior motor imagery performance. AB - Yoga is an activity that aims to integrate physical, mental and spiritual elements and is an increasingly popular approach to enhancing physical fitness. The integration of imagery within yoga practice is considered an important component and may be critical in contributing to the benefits of yoga that have been reported. In this study, we tested whether individuals who practice yoga demonstrate superior performance on an objective measure of implicit motor imagery. Thirty-six participants (18 yoga, 18 non-yoga) matched for age, sex and handedness, undertook the hand laterality recognition task; an objective measure of implicit motor imagery performance. Accuracy and response times were gathered and analysed to determine any group differences as well as any differences relating to the typical hallmarks of imagery (i.e. dominance and awkwardness effects) on the task. Response Times (RTs) in the yoga group were significantly faster than controls (p < 0.05) and there was also a trend towards greater accuracy for the Yoga group (p = 0.073). Dominance effects (faster responses to images corresponding with the dominant limb) and Awkwardness effects (faster responses to images corresponding with natural compared with awkward postures) were evident across groups, supporting the participants' use of motor imagery in undertaking the task. Additionally, a Group * Awkwardness interaction (p < 0.05) revealed that the enhanced imagery performance for the yoga group was most pronounced for awkward postures. This is the first study to show that yoga practice is associated with superior motor imagery performance; an association that may be important in explaining the established rehabilitative value of yoga for chronic pain. PMID- 29131729 TI - Yoga Communities and Eating Disorders: Creating Safe Space for Positive Embodiment. AB - With adequate education and guidance, yoga communities, as part of the therapeutic landscape in the 21st century, can play a significant role promoting positive embodiment for those with, and at-risk for, eating disorders (EDs). To do this, yoga teachers need to know how to create a body-positive community and be able to recognize and respond to those at risk and struggling with EDs in their communities. In order to address yoga teaching methods associated with EDs and ED risk, broader conceptual approaches and specific practices associated with positive embodiment are offered. These include the broader conceptual approaches of: intentional inclusion and acceptance, experiential emphasis, supporting positive embodiment and inquiry. Studio pragmatics are also detailed as related to the body, breath, emotions, and community. Assessment, referral, and community engagement are also addressed. PMID- 29131730 TI - Psychological Benefits of Yoga for Female Inmates. AB - Female inmates involved in the Yoga Prison Project at two correctional facilities in South Carolina served as subjects. Inmates were selected from those who applied to participate in a ten-week trauma-focused yoga program. To create control and experimental groups, inmates who requested to participate were randomly assigned to be in the class (Treatment Group, n = 33) or a waitlist (Control Group, n = 17). Inmates on the waitlist subsequently joined the next class, so all who applied and were eligible participated in a yoga class. Measures of stress, depression, self control, anxiety, self awareness and rumination were used and data was collected from both groups before the initial yoga class began and again at the end, ten weeks later. To assess the changes from pre-intervention to post-intervention, mixed design ANOVA tests were conducted. Inmates in the yoga group reported significant decreases in depression and stress and improved self-awareness. No significant changes were found on measures of anxiety, rumination and self-control in the yoga groups. Although not statistically significant, anxiety scores did decrease and self-control scores improved for the yoga group, while inmates in the control group reported a worsening or no change on these two measures. No changes were found in rumination levels. The results suggest that Yoga is a relatively inexpensive intervention that could benefit both inmates and prison staff by reducing some negative behaviors and possibly mental health problems. PMID- 29131731 TI - Editorial. PMID- 29131732 TI - Yoga and Healthcare in the United Kingdom. AB - The emergence of yoga therapy in the United Kingdom began about 45 years ago with the emergence of yoga therapy organizations that offered both treatment and training. The integration of yoga into the National Health Service (NHS) is gradually happening Because: (a) yoga research supports its efficacy as a cost effective, preventive and complementary treatment for a host of non-communicable diseases; and (b) the escalating economic burden of long-term conditions is overwhelming the NHS. The NHS is actively developing 'sustainability and transformation plans' that include yoga. Chief among these is 'social prescribing,' which empowers patients with complex health needs through activities groups. These activities reduce sedentary habits and social isolation, while helping patients to be more self-reliant. The NHS has allocated L450 million in funding to implement a variety of programs for its own staff, in which staff yoga classes were expressly mentioned. The yoga community is mobilizing forces and applying for funding to pilot relevant NHS staff yoga courses that can support the service in achieving its vision. Research shows that integrating yoga therapy for the treatment of low back pain (LBP) into the NHS would result in significant cost savings as compared with usual care. The National Institute for Health and Care Excellence (NICE) Guidelines on LBP and sciatica include yoga as one of the recommended treatments for these conditions. Three groups of yoga teachers, using different yoga practices, have gained traction with the NHS for the application of yoga therapy to LBP. Many regional hospitals in England have yoga classes. The NHS Choices website, which conveys information to the public regarding treatment options, has a page dedicated to the health benefits of yoga. Several institutions offer comprehensive training programs in yoga therapy and yoga therapy is recognized as an official profession. The Yoga in Healthcare Alliance has been established to help integrate yoga therapy into the NHS. This consists of parliamentarians, leaders in the NHS, yoga researchers, health professionals, and representatives from leading yoga organizations. PMID- 29131733 TI - The importance of research literacy for yoga therapists. AB - Evidence-Informed Practice (EIP) utilizes the three components of expert opinion, research evidence, and client values. It is a recommended training competency for integrative health practitioners in diverse fields, such as acupuncture and massage therapy. Research Literacy (RL) is a necessary pre-requisite to EIP. Many yoga therapists have limited training in these skills, which negatively impacts inter-professional communication and collaboration, as well as further advancement of yoga therapy research and practice. In this article, we propose inclusion of RL and EIP in the training of yoga therapists. Benefits for client care, collaborative care, and the field of yoga therapy are discussed. PMID- 29131734 TI - Yoga Therapy in Japan. AB - This perspective piece gives an overview of the current situation of yoga therapy in Japan today. Traditional yoga in Japan suffered a serious setback in 1995 with a nerve gas terrorist attack on the Tokyo subway, which was carried out by a cult that recruited members through yoga classes. But with the increase in popularity with modern forms of yoga such as Iyengar yoga, Ashtanga yoga and hot yoga in the West, the general public in Japan today is forgetting its aversion to yoga and considers it to be something that can contribute to good health. In 2012, the Japan Yoga Therapy Society (JYTS) conducted a study on adverse events in yoga classes throughout Japan with the University of Kyushu School of Medicine, with support from the Ministry of Health, Labour and Welfare. This study indicated that more than half of people attending yoga classes have some form of chronic illness, with 42.3% receiving outpatient care. This survey was the beginning of growing interest from both the government and universities in yoga therapy. JYTS is beginning to make inroads into bringing yoga therapy into cancer and palliative care, senior citizen homes, alcohol and drug addiction rehabilitation, cardiovascular rehabilitation, and research on trauma and schizophrenia. While there are still limited opportunities for yoga therapists to work in mainstream healthcare services, there is growing interest among medical professionals in both physical and mental health. JYTS is beginning to make inroads into bringing yoga therapy into cancer and palliative care, senior citizen homes, alcohol and drug addiction rehabilitation, cardiovascular rehabilitation, and research on trauma and schizophrenia. While there are still limited opportunities for yoga therapists to work in mainstream healthcare services, there is growing interest among medical professionals in both physical and mental health. This perspective piece introduces some of the developments in yoga therapy research and practice in Japan. PMID- 29131735 TI - Implementation of Yoga Therapy into U.S. Healthcare Systems. PMID- 29131736 TI - Interpretive phenomenological analysis of a lawsuit contending that school-based yoga is religion: A study of school personnel. AB - This study focused on the perspectives of school personnel affiliated with the Encinitas Union School District in California following a lawsuit arguing that their yoga-based program included religion and therefore was unsuitable for implementation in public schools and was unconstitutional. Participants (N = 32) were interviewed using a semistructured interview, and data were analyzed according to Interpretative Phenomenological Analysis. Five super-ordinate themes (including sub-themes) were identified in an iterative process, including: participants' perspectives on the roots of yoga and the type of yoga taught in their district; the process of introducing a yoga-in-the-schools program in light of this contention (including challenges and obstacles, and how these were met); perspectives on the lawsuit and how the process unfolded; effects of the lawsuit on school climate and beyond; and perspectives on yoga as, and as not, religious. The study attempts to shed light on the impact of an ongoing lawsuit on a school district at the time of implementation of a program for students' well being. PMID- 29131737 TI - The Use of Yoga by Physical Therapists in the United States. AB - How physical therapists (PTs) in the United States currently use yoga in their clinical practices is unknown. The purpose of this study was to determine how PTs in the United States view yoga as a physical therapy (PT) tool and how PTs use yoga therapeutically. The authors conducted a 24-item survey via electronic communications of the Geriatric, Orthopedic, Pediatric, and Women's Health Sections of the American Physical Therapy Association. Participants (n = 333) from 47 states and the District of Columbia replied. Reported use of therapeutic yoga among participants was high (70.6%). Of those participants, nearly a third use asana and pranayama only. Most participants using therapeutic yoga also include additional mindfulness-related elements such as sensory awareness, concentration/focus, and/or meditation. Most participants learned about yoga through personal experiences, with many participants citing lack of familiarity in using yoga in PT practice. Safety is the primary concern of participants when recommending yoga to patients as an independent health and wellness activity. Interdisciplinary communication between PTs, yoga therapists, and yoga teachers is warranted to address the post-discharge needs of clients. Healthcare changes have required PTs to adapt to a biopsychosocial-spiritual model (BPSS) for improved patient outcomes. Therapeutic yoga may provide an opportunity for PTs to expand their role in health and wellness and chronic disease management. There is opportunity for continuing education in therapeutic yoga for PTs. PMID- 29131738 TI - Experiences of women who participated in a beta-test for an online-streamed yoga intervention after a stillbirth. AB - BACKGROUND: Little is known about how to best care for mothers after stillbirth. As such, this paper will report the satisfaction and perceptions of an online yoga intervention (12-week beta test) in women after stillbirth. METHODS: Participants (n=74) had a stillbirth within the last 24-months (M time since loss 9.65 +/- 6.9 months). Post-intervention satisfaction surveys and interviews and dropout surveys were conducted. Descriptive statistics were used to analyze survey responses and demographic information. A phenomenological approach was used to explore and understand unique experiences of participant interviews. Data were analyzed using NVivo10. RESULTS: Twenty-six women (M age 33.73 +/- 4.38) were completers (> 3 wks of yoga), 26 (M age 31.82 +/- 4.13) were non-completers (< 3 wks of yoga), and 22 (M age 32.94 +/- 2.93) dropped out. Twenty completers participated in a post-intervention satisfaction survey with 75% (n=15) reporting being very satisfied or satisfied with the online yoga intervention, found it to be very enjoyable or enjoyable, and very helpful or helpful to cope with grief. Satisfaction and perceptions of the intervention in those who completed an interview (n=12) were clustered around the following themes: benefits, barriers, dislikes, satisfaction, and preferences. Of the 22 dropouts, 14 completed a dropout survey. Women withdrew from the study due to pregnancy (n=3, 21%), burden (n=3, 21%), stress (n=2, 14%), lack of time (n=2, 14%), did not enjoy (n=1, 7%), and other (n=3, 21%). CONCLUSION: Findings here may be used to help design future research. PMID- 29131739 TI - Yoga as Sanctuary: A Valuable Mind-Body Intervention for the Lesbian Community. AB - Poetic autoethnography provides a research methodology to explore yoga as a mind body intervention that creates sanctuary. Using this qualitative method and retrieving data from my personal journals, daily workout journals, experiences as a lesbian-identified participant in yoga classes, and yoga instructor, I turn the research lens on myself in order to examine my sociological life story. At a critical time in my life when I was struggling with the fragmentation, anxiety, and despair resulting from dealing with homophobia in a heteronormative world, yoga provided sanctuary for me. My yoga practice increased my self-efficacy, providing transferable techniques for finding refuge within myself, irrespective of the adversity I was facing in my life. Places of sanctuary are critical for members of minority groups who often face marginalization and oppression, which compromise their well-being. PMID- 29131740 TI - The Impact of Prenatal Yoga on Exercise Attitudes and Behavior: Teachable moments from a Randomized Controlled Trial. AB - OBJECTIVE: Pregnancy serves as an opportune time for "teachable moments" to elicit positive behavior change. We evaluated change in exercise perception, behavior and gestational weight gain in participants engaged in a one-hour educational experience. METHODS: Women between 28 0/7 to 36 6/7 weeks with no prior yoga experience carrying a non-anomalous singleton fetus participated in a randomized controlled trial on prenatal yoga. The yoga group engaged in a one hour yoga class; the attention control educational group, in a one-hour presentation on exercise, nutrition and obesity in pregnancy. Maternal perception of yoga, exercise effects and current health status was conducted before and after the intervention. Gestational weight gain (GWG) and body mass index (BMI) were assessed. A postpartum survey was performed to determine self-reported behavioral changes during and after pregnancy. RESULTS: Over 6 months, 52 women were randomized and 46 (88%) completed the study. Women reported a more positive attitude towards exercise and yoga after the yoga intervention. Total GWG was similar (yoga 32.9 versus education 32.8 pounds, p = 0.98). Stratified by pre pregnancy BMI, 13% gained within and 61% gained above the Institute of Medicine guidelines in each group. Of 29 inactive women prior to the intervention, 60% of the yoga group and 75% of the education group began prenatal exercises after the intervention and 50% of each group continued to exercise after delivery. There were no significant differences between groups. CONCLUSION: A one-time, one-hour intervention teaching a new exercise or educating women during pregnancy can positively impact pregnancy behaviors and perception with the potential to improve maternal and neonatal outcomes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov , NCT02063711. PMID- 29131741 TI - Editorial Board Page EOV. PMID- 29131742 TI - The Structure and Acquisition of Sensorimotor Maps. AB - One of the puzzles of learning to talk or play a musical instrument is how we learn which movement produces a particular sound: an audiomotor map. Existing research has used mappings that are already well learned such as controlling a cursor using a computer mouse. By contrast, the acquisition of novel sensorimotor maps was studied by having participants learn arm movements to auditory targets. These sounds did not come from different directions but, like speech, were only distinguished by their frequencies. It is shown that learning involves forming not one but two maps: a point map connecting sensory targets with motor commands and an error map linking sensory errors to motor corrections. Learning a point map is possible even when targets never repeat. Thus, although participants make errors, there is no opportunity to correct them because the target is different on every trial, and therefore learning cannot be driven by error correction. Furthermore, when the opportunity for error correction is provided, it is seen that acquiring error correction is itself a learning process that changes over time and results in an error map. In principle, the error map could be derived from the point map, but instead, these two maps are independently acquired and jointly enable sensorimotor control and learning. A computational model shows that this dual encoding is optimal and simulations based on this architecture predict that learning the two maps results in performance improvements comparable with those observed empirically. PMID- 29131743 TI - Integration and Temporal Processing of Asynchronous Audiovisual Speech. AB - Multisensory integration of visual mouth movements with auditory speech is known to offer substantial perceptual benefits, particularly under challenging (i.e., noisy) acoustic conditions. Previous work characterizing this process has found that ERPs to auditory speech are of shorter latency and smaller magnitude in the presence of visual speech. We sought to determine the dependency of these effects on the temporal relationship between the auditory and visual speech streams using EEG. We found that reductions in ERP latency and suppression of ERP amplitude are maximal when the visual signal precedes the auditory signal by a small interval and that increasing amounts of asynchrony reduce these effects in a continuous manner. Time-frequency analysis revealed that these effects are found primarily in the theta (4-8 Hz) and alpha (8-12 Hz) bands, with a central topography consistent with auditory generators. Theta effects also persisted in the lower portion of the band (3.5-5 Hz), and this late activity was more frontally distributed. Importantly, the magnitude of these late theta oscillations not only differed with the temporal characteristics of the stimuli but also served to predict participants' task performance. Our analysis thus reveals that suppression of single-trial brain responses by visual speech depends strongly on the temporal concordance of the auditory and visual inputs. It further illustrates that processes in the lower theta band, which we suggest as an index of incongruity processing, might serve to reflect the neural correlates of individual differences in multisensory temporal perception. PMID- 29131744 TI - Not Doomed to Repeat: Enhanced Medial Prefrontal Cortex Tracking of Errors Promotes Adaptive Behavior during Adolescence. AB - Feedback information is one of the most powerful forces that promotes learning, providing guidance for changes to ongoing behavioral patterns. Previous examinations of feedback learning have largely relied on explicit feedback based on task performance. However, learning is not restricted to explicit feedback and likely involves other forms of more subtle feedback cues. One potential form of this kind of learning may involve internally generated feedback in response to error commission. Whether this error-related response prompts neural and behavioral adaptation that overlaps with, or is distinct from, those evoked by external feedback is largely unknown. To explore this gap, 55 adolescents completed a difficult behavioral inhibition task designed to elicit relatively high rates of error commission during an fMRI session. We examined neural adaptation after accumulating errors (i.e., internally generated negative feedback events) at the group level, as well as the impact of individual differences in error tracking on overall task performance. Group effects show that medial PFC (mPFC) activation tracks accumulating errors; however, reduced tracking of errors is associated with greater total false alarms. These findings suggest that increased mPFC integration of error-related feedback is beneficial for task performance and, in concert with previous findings, suggests a domain general role for mPFC integration of negative feedback. PMID- 29131745 TI - Ventrolateral Prefrontal Cortex Updates Chosen Value According to Choice Set Size. AB - Having chosen an item typically increases the subjective value of the chosen item, and people generally enjoy making choices from larger choice sets. However, having too many items to choose from can reduce the value of chosen items-for example, because of conflict or choice difficulty. In this study, we investigated the effects of choice set size on behavioral and neural value updating (revaluation) of the chosen item. In the scanner, participants selected items from choice sets of various sizes (one, two, four, or eight items). After they chose an item, participants rerated the chosen item, and we quantified revaluation by taking the difference of postchoice minus prechoice ratings. Revaluation of chosen items increased up to choice sets of four alternatives but then decreased again for items chosen from choice sets of eight alternatives, revealing both a linear and a quadratic effect of choice set size. At the time of postchoice rating, activation of the ventrolateral pFC (VLPFC) reflected the influence of choice set size on parametric revaluation, without significant relation to either prechoice or postchoice ratings tested separately. Additional analyses revealed relations of choice set size to anterior cingulate and insula activity during actual choice and increased coupling of both regions to revaluation-related VLPFC during postchoice rating. These data suggest that the VLPFC plays a central role in a network that relates choice set size to updating the value of chosen items and integrates choice overload with value-enhancing effects of larger choice sets. PMID- 29131746 TI - Topical oxygen therapy promotes the healing of chronic diabetic foot ulcers: a pilot study. AB - OBJECTIVE: Interventions that can heal or reduce diabetic foot ulcer (DFU) size may reduce the incidence of infection and amputation, and reduce associated social and economic costs. Many chronic wounds exhibit a degree of hypoxia and this leads to a reduction in healing processes including cell division and differentiation, angiogenesis, infection prevention, and collagen production. The aim of this pilot study was to assess the effects of a device supplying continuous oxygen ambulatory therapy on healing in chronic DFUs. METHOD: Patients with chronic DFUs from two tertiary referral hospitals in the UK received treatment with the device. Data were prospectively obtained on wound size using standardised digital images measured by a clinician blinded to the study. Data on device satisfaction and pain were also obtained. RESULTS: We recruited 10 patients, with a mean ulcer duration of 43 weeks (median: 43 weeks) before treatment. By week eight, mean ulcer size had decreased by 51% (median: 53%). Seven of the 10 ulcers were in a healing trajectory, one ulcer present for 56 weeks healed completely, a two-year old ulcer was reduced by more than 50%, and a third, present for 88 weeks, was down to 10% of its original size by the end of the eight-week study. There was also a non-significant trend towards reduction in pain and the device was extremely well tolerated. CONCLUSION: The ambulatory topical oxygen delivery device showed a significant beneficial effect on wound size. This poses practical advantages over currently existing oxygen-based wound therapies such as hyperbaric oxygen therapy due to its continuous oxygen delivery, ease of use, safety and lower cost. The results of this study warrant further review of the device in comparison to standard wound therapies. PMID- 29131747 TI - Linking challenges in wound healing: key highlights from the Hartmann congress. AB - With a special focus on advanced wound healing (wound bed preparation, epithelialisation and hydration) and negative pressure wound therapy, the Hartmann LINK for Wound Healing Congress took place in Belfast, Northern Ireland, on 19 September. The event aimed to promote the latest advances in wound care and highlight the main challenges that clinicians face when treating different types of wounds. Annabel De Coster, editor of the British Journal of Community Nursing, gives an overview of selected talks from the congress. PMID- 29131748 TI - A multicentre, clinical evaluation of a hydro-responsive wound dressing: the Glasgow experience. AB - OBJECTIVE: Our aim was to assess the effectiveness of hydro-responsive wound dressing (HRWD) in debridement and wound bed preparation of a variety of acute and chronic wounds that presented with devitalised tissue needing removal so that healing may proceed. METHOD: This was a non-comparative evaluation of acute and chronic wounds that required debridement as part of their normal treatment regimen. Clinicians recorded wound changes including a subjective assessment level of devitalised tissue and wound bed preparation, presence of pain, wound status (e.g., wound size) and periwound skin condition. Data was also collected from clinicians and patients to provide information on clinical performance of the dressing. RESULTS: We recruited 100 patients with a variety of wound types into the study. Over 90% of the clinicians reported removal of devitalised tissue to enable a healing response in both chronic and acute wounds. Specifically, over the course of the evaluation period, levels of devitalised tissue (necrosis and slough) reduced from 85.5% to 26.3%, and this was accompanied by an increase in wound bed granulation from 12.0% to 33.7%. Correspondingly, there was a 40% reduction in wound area, hence a clinically relevant healing response was seen upon treatment with HRWD. It is also noteworthy that this patient population included a significant proportion of chronic wounds (51.4%) that showed no signs of wound progression within <4 weeks before study inclusion. Of these chronic wounds, 93% demonstrated wound progression upon treatment with HRWD. Despite reported pain levels being low pre- and post-dressing change, overall wound pain improved (reduced) in 48% of patients. Periwound skin condition showed a tendency towards improvement, and the fluid management capabilities of the HRWD was reported as good to excellent in the majority of cases. Wound infections were reduced by at least 60% over the evaluation period. A simple cost-effective analysis demonstrated significant savings using HRWD (L6.33) over current standard practice regimens of a four-step debridement process (L8.05), larval therapy (L306.39) and mechanical pad debridement (L11.46). CONCLUSION: HRWD was well tolerated and was demonstrated to be an efficient debridement tool providing rapid, effective and pain free debridement in a variety of wound types. PMID- 29131750 TI - A holistic approach to examining the evidence. PMID- 29131749 TI - Patient-centred care: a call to action for wound management. PMID- 29131751 TI - A diabetic foot ulcer treated with hydrogel and hyperbaric oxygen therapy: a case study. AB - This study reports on the case of an elderly patient, with diabetes, and a bullous wound on the left big toe that led to an amputation of the first and second left toes. The amputation was because of deep injury as it was not able to heal with a conventional treatment. After completing the normal treatment and the removal of a bacterial infection in the lesion, the patient underwent a treatment that was based on a hydrogel gel (0.9% saline solution) and hyperbaric oxygen therapy (HBOT). After 60 sessions of the therapy, almost complete closure of the wound was observed. There were no reports of discomfort or infection during the treatment. After seven months of treatment almost complete healing was observed with no infection. This treatment appears to be effective and should be recommended for the treatment of DFUs. PMID- 29131752 TI - Surfactants and their role in wound cleansing and biofilm management. AB - Surfactants are widely used as detergents, emulsifiers, wetting agents, foaming agents and dispersants in the cosmetics, hygiene, food and oil industries. Their use in a clinical setting is also common, particularly within the field of wound care. Many wound cleansers contain surfactants and subsequently there is available data that shows the growing potential of these wound cleansers in the enhancement of wound closure. The presence of microorganisms in wounds has been recognised as a significant factor that delay healing. In complex or chronic wounds that are complicated by biofilms, persistent inflammation or the production of non-viable tissue and slough, the use of surfactants has been shown to aid in the removal of these barriers to wound healing. The use of concentrated surfactant(poloxamer) based wound dressings represent an important component of wound management. Consequently, this article will discuss the effect of clinically used surfactants, with specific focus on a concentrated poloxamer for use against wound biofilm. PMID- 29131753 TI - Effectiveness of compression bandaging education for wound care nurses. AB - OBJECTIVE: Compression bandaging is an essential component in the treatment of venous leg ulcers (VLUs). An adequate pressure and stiffness is needed in order for the treatment to be successful. The aim of this study was to evaluate the effectiveness of a training workshop on compression bandaging among wound care nurses who had no previous experience in application of compression bandages, immediately post-training and six months after training. METHOD: A quasi experimental design, conducted at Maccabi Healthcare Services, in which nurses underwent a four-hour educational session, including practising with a device that measures sub-bandage pressure. RESULTS: We assessed 37 nurses. Before training, 5.4% of nurses bandaged in the optimal range; after training, 58% bandaged in optimal range, and six months post-training, 37% bandaged in optimal range. At post- and six months post-training, no nurse bandaged 'too low' (<=20mmHg). Stiffness of the bandage was achieved in only 5.4% of nurses before training; 62% immediately after, and 75% six months after training. CONCLUSION: We conclude that the proposed educational session using a device that measures the pressure applied is an effective way to teach wound care nurses how to use compression bandages. However, more practise is needed to achieve an optimal range of pressure over time. PMID- 29131754 TI - Perioperative, local and systemic warming in surgical site infection: a systematic review and meta-analysis. AB - OBJECTIVE: Surgical site infection (SSI) is a common cause of postoperative morbidity. Perioperative hypothermia may contribute to surgical complications including increased risk of SSI. In this systematic review and meta-analysis, the effectiveness of active and passive perioperative warming interventions to prevent SSI was compared with standard (non-warming) care. METHOD: Ovid MEDLINE; Ovid EMBASE; EBSCO CINAHL Plus; The Cochrane Wounds Specialised Register, and The Cochrane Central Register of Controlled Trials were searched, with no restrictions on language, publication date or study setting for randomised controlled trials (RCTs) and cluster RCTs. Adult patients undergoing elective or emergency surgery under general anaesthesia, receiving any active or passive warming intervention perioperatively were included. Selection, risk of bias assessment and data extraction were performed by two review authors, independently. Outcomes studied were SSI (primary outcome), inpatient mortality, hospital length of stay and pain (secondary outcomes). RESULTS: We identified four studies, including 769 patients. The risk ratio (RR) for SSI in warming groups was 0.36 [95% confidence interval (CI): 0.23, 0.56; p<0. 001]. Length of hospitalisation was 1.13 days less in warming groups [95% CI: -3.07, 5.33; p=0.600]. The RR for mortality in the warming groups was 0.77 [95% CI: 0.17, 3.43; p=0.730]. A meta-analysis for pain outcome could not be conducted. CONCLUSION: This review provides evidence in favour of active warming to prevent SSI, but insufficient evidence of active warming to reduce length of hospital stay and mortality. Benefits of passive warming remain unclear and warrant further research. PMID- 29131755 TI - Letters. PMID- 29131756 TI - Combined use of modulated ultrasound and electric current stimulation for diabetic foot ulcers: a case series. AB - OBJECTIVE: Diabetic foot ulcers (DFUs) are a significant challenge in wound care practice. Our aim was to evaluate the combined use of of two therapies, ultrasound and electrostimulation, in the treatment of DFUs. METHOD: This study employed a prospective, non-comparative, case series design, undertaken in a podiatry-led diabetic foot clinic, in an acute hospital setting, in an urban location in Ireland. We recruited patinets with hard-to-heal DFUs who were treated twice a week with combined modulated ultrasound and electric current stimulation. RESULTS: We recruited seven patients with eight chronic DFUs. A mean wound size reduction of 71% was achieved and there were no adverse reactions to the therapy. CONCLUSION: The results of this small case series indicate that combined modulated ultrasound and electric current stimulation offers promise as an adjunct therapy for DFUs. Further large scale trials are now warranted. PMID- 29131757 TI - Explaining the forest plot in meta-analyses. PMID- 29131758 TI - Titin Gene and Protein Functions in Passive and Active Muscle. AB - The thin and thick filaments of muscle sarcomeres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platform, and provider of passive tension and elasticity in myocytes. This review summarizes recent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and cardiac myocytes. A main theme is the evolving role of titin as a modulator of contraction. Topics include strain-sensing via titin in the sarcomeric A-band as the basis for length-dependent activation, titin elastic recoil and refolding of titin domains as an energy source, and Ca2+-dependent stiffening of titin stretched during eccentric muscle contractions. Findings suggest that titin stiffness is a principal regulator of the contractile behavior of striated muscle. Physiological or pathological changes to titin stiffness therefore affect contractility. Taken together, titin emerges as a linker element between passive and active myocyte properties. PMID- 29131759 TI - Cultural and ethical considerations in late-life polyvictimization. AB - This article examines the cultural and ethical considerations for professionals working with older adults who experience polyvictimization. Drawing from the Department of Justice training program, Polyvictimization in Later Life (OVC/TTAC, 2017), topics include cultural competencies, ethical standards, personal and professional ethics, and ethical considerations when working in teams. Also described are specific suggestions and recommendations to ensure sensitive and ethical responses when working with cases involving polyvictimization. PMID- 29131760 TI - Deep Learning: A Primer for Radiologists. AB - Deep learning is a class of machine learning methods that are gaining success and attracting interest in many domains, including computer vision, speech recognition, natural language processing, and playing games. Deep learning methods produce a mapping from raw inputs to desired outputs (eg, image classes). Unlike traditional machine learning methods, which require hand-engineered feature extraction from inputs, deep learning methods learn these features directly from data. With the advent of large datasets and increased computing power, these methods can produce models with exceptional performance. These models are multilayer artificial neural networks, loosely inspired by biologic neural systems. Weighted connections between nodes (neurons) in the network are iteratively adjusted based on example pairs of inputs and target outputs by back propagating a corrective error signal through the network. For computer vision tasks, convolutional neural networks (CNNs) have proven to be effective. Recently, several clinical applications of CNNs have been proposed and studied in radiology for classification, detection, and segmentation tasks. This article reviews the key concepts of deep learning for clinical radiologists, discusses technical requirements, describes emerging applications in clinical radiology, and outlines limitations and future directions in this field. Radiologists should become familiar with the principles and potential applications of deep learning in medical imaging. (c)RSNA, 2017. PMID- 29131761 TI - 2017 Version of LI-RADS for CT and MR Imaging: An Update. AB - The Liver Imaging Reporting and Data System (LI-RADS) is a reporting system created for the standardized interpretation of liver imaging findings in patients who are at risk for hepatocellular carcinoma (HCC). This system was developed with the cooperative and ongoing efforts of an American College of Radiology supported committee of diagnostic radiologists with expertise in liver imaging and valuable input from hepatobiliary surgeons, hepatologists, hepatopathologists, and interventional radiologists. In this article, the 2017 version of LI-RADS for computed tomography and magnetic resonance imaging is reviewed. Specific topics include the appropriate population for application of LI-RADS; technical recommendations for image optimization, including definitions of dynamic enhancement phases; diagnostic and treatment response categories; definitions of major and ancillary imaging features; criteria for distinguishing definite HCC from a malignancy that might be non-HCC; management options following LI-RADS categorization; and reporting. (c)RSNA, 2017. PMID- 29131762 TI - Strengths and Weaknesses of Synthetic Mammography in Screening. AB - Synthetic mammography (SM) consists of two-dimensional images reconstructed from digital breast tomosynthesis (DBT) data. Unlike standard full-field digital mammography (FFDM), SM does not require additional radiation exposure. SM is being introduced in breast imaging centers because early clinical data demonstrate that synthetic images are comparable to FFDM in cancer detection, positive predictive values, and recall rates. SM has completely replaced FFDM in some practices. Thus, an understanding of SM and its strengths and weaknesses compared with those of FFDM is essential. The artifacts of SM include blurring subcutaneous tissue, loss of resolution in the axilla on mediolateral oblique views, pseudocalcifications, and decreased resolution near foreign bodies (eg, biopsy markers). SM's strengths include a reduced radiation dose, shorter acquisition time compared with a combined FFDM/DBT screening examination (with potentially less motion artifact), and increased conspicuity of calcifications, spiculated margins, and architectural distortion. The weaknesses of SM include the potential for false positives due to pseudocalcifications and the difficulty in assessing for motion artifact. This article reviews SM and its role in screening and presents clinical cases to highlight SM's strengths, weaknesses, and artifacts. (c)RSNA, 2017. PMID- 29131763 TI - Immune Checkpoint Inhibitor Cancer Therapy: Spectrum of Imaging Findings. AB - Immune checkpoint inhibitors are a new class of cancer therapeutics that have demonstrated striking successes in a rapid series of clinical trials. Consequently, these drugs have dramatically increased in clinical use since being first approved for advanced melanoma in 2011. Current indications in addition to melanoma are non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, urothelial carcinoma, and classical Hodgkin lymphoma. A small subset of patients treated with immune checkpoint inhibitors undergoes an atypical treatment response pattern termed pseudoprogression: New or enlarging lesions appear after initiation of therapy, thereby mimicking tumor progression, followed by an eventual decrease in total tumor burden. Traditional response standards applied at the time of initial increase in tumor burden can falsely designate this as treatment failure and could lead to inappropriate termination of therapy. Currently, when new or enlarging lesions are observed with immune checkpoint inhibitors, only follow-up imaging can help distinguish patients with pseudoprogression from the large majority in whom this observation represents true treatment failure. Furthermore, the unique mechanism of immune checkpoint inhibitors can cause a distinct set of adverse events related to autoimmunity, which can be severe or life threatening. Given the central role of imaging in cancer care, radiologists must be knowledgeable about immune checkpoint inhibitors to correctly assess treatment response and expeditiously diagnose treatment-related complications. The authors review the molecular mechanisms and clinical applications of immune checkpoint inhibitors, the current strategy to distinguish pseudoprogression from progression, and the imaging appearances of common immune-related adverse events. (c)RSNA, 2017. PMID- 29131765 TI - Comprehensive Cross-sectional Imaging of the Pulmonary Veins. AB - The pulmonary veins carry oxygenated blood from the lungs to the heart, but their importance to the radiologist extends far beyond this seemingly straightforward function. The anatomy of the pulmonary veins is variable among patients, with several noteworthy variant and anomalous patterns, including supernumerary pulmonary veins, a common ostium, anomalous pulmonary venous return, and levoatriocardinal veins. Differences in pulmonary vein anatomy and the presence of variant or anomalous anatomy can be of critical importance, especially for preoperative planning of pulmonary and cardiac surgery. The enhancement or lack of enhancement of the pulmonary veins can be a clue to clinically important disease, and the relationship of masses to the pulmonary veins can herald cardiac invasion. The pulmonary veins are also an integral part of thoracic interventions, including lung transplantation, pneumonectomy, and radiofrequency ablation for atrial fibrillation. This fact creates a requirement for radiologists to have knowledge of the pre- and postoperative imaging appearances of the pulmonary veins. Many of these procedures are associated with important potential complications involving the pulmonary veins, for which diagnostic imaging plays a critical role. A thorough knowledge of the pulmonary veins and a proper radiologic approach to their evaluation is critical for the busy radiologist who must incorporate the pulmonary veins into a routine "search pattern" at computed tomography (CT) and magnetic resonance imaging. This article is a comprehensive CT-based imaging review of the pulmonary veins, including their embryology, anatomy (typical and anomalous), surgical implications, pulmonary vein thrombosis, pulmonary vein stenosis, pulmonary vein pseudostenosis, and the relationship of tumors to the pulmonary veins. Online supplemental material is available for this article. (c)RSNA, 2017. PMID- 29131764 TI - Nongynecologic Findings Seen at Pelvic US. AB - Ultrasonography (US) is frequently the first imaging modality used to examine women with symptoms involving the pelvis. It is widely available and involves no exposure to ionizing radiation. Images can be acquired with a transabdominal, endovaginal, or translabial approach, and the use of video clips and three dimensional reconstructions can be helpful. US is excellent for assessment of the uterus, ovaries, and adnexa. Occasionally, nongynecologic pelvic diseases arising from the gastrointestinal, genitourinary, and musculoskeletal systems and the pelvic peritoneal and extraperitoneal spaces may be detected and can be a source of diagnostic dilemma. US can be helpful not only in the detection but also occasionally in the characterization of such entities. Computed tomography and magnetic resonance imaging are useful in complicated cases. In this article, the normal US appearance of the bowel and US signs of bowel disease and specific entities, including appendicitis, diverticular disease, bowel obstruction, appendiceal mucocele, and intestinal tumors, are reviewed. The lower urinary tract is included in the field of view in every pelvic US examination; commonly encountered entities related to the urinary bladder, distal ureter, and urethra are illustrated. In addition to arising in the gastrointestinal and genitourinary tracts, pathologic conditions in the pelvis can arise in the peritoneal or extraperitoneal space. Although conditions of the pelvic peritoneal and extraperitoneal spaces are rare, it is important to recognize these entities and distinguish them from the more common gynecologic diseases. Owing to the implications for diagnosis and management, radiologists and other physicians who perform pelvic US should be aware of the spectrum of nongynecologic pathologic entities that can be detected. (c)RSNA, 2017. PMID- 29131767 TI - Invited Commentary on "Differentiation of Solid Renal Tumors with Multiparametric MR Imaging". PMID- 29131766 TI - Mimics of Malignancy in Abdominal Imaging: Multisystem Radiology. PMID- 29131768 TI - From Inguinal Hernias to Spermatic Cord Lipomas: Pearls, Pitfalls, and Mimics of Abdominal and Pelvic Hernias. AB - Abdominal and pelvic hernias may be indolent and detected incidentally, manifest acutely with pain and distress, or cause chronic discomfort. Physical examination findings are often ambiguous and insufficient for optimal triage. Therefore, accurate anatomic delineation and identification of complications are critical for effective treatment planning. Imaging, particularly computed tomography, provides a vital understanding of the hernia's location and size, involved viscera, and severity of associated complications. Reader familiarity with the imaging appearances and anatomic landmarks of hernias is important for correct diagnosis, which may impact preoperative planning and reduce morbidity. This article reviews the appearance of anatomic structures in the abdominal wall and pelvis that are important for diagnosing common and uncommon abdominal and pelvic hernias, and it highlights key imaging features that are helpful for differentiating hernias, mimics, and their complications. Online DICOM image stacks are available for this article . (c)RSNA, 2017. PMID- 29131769 TI - Imaging of the Endometrium: Physiologic Changes and Diseases: Women's Imaging. PMID- 29131770 TI - Differentiation of Solid Renal Tumors with Multiparametric MR Imaging. AB - Characterization of renal tumors is critical to determine the best therapeutic approach and improve overall patient survival. Because of increased use of high resolution cross-sectional imaging in clinical practice, renal masses are being discovered with increased frequency. As a result, accurate imaging characterization of these lesions is more important than ever. However, because of the wide array of imaging features encountered as well as overlapping characteristics, identifying reliable imaging criteria for differentiating malignant from benign renal masses remains a challenge. Multiparametric magnetic resonance (MR) imaging based on various anatomic and functional parameters has an important role and adds diagnostic value in detection and characterization of renal masses. MR imaging may allow distinction of benign solid renal masses from several renal cell carcinoma (RCC) subtypes, potentially suggest the histologic grade of a neoplasm, and play an important role in ensuring appropriate patient management to avoid unnecessary surgery or other interventions. It is also a useful noninvasive imaging tool for patients who undergo active surveillance of renal masses and for follow-up after treatment of a renal mass. The purpose of this article is to review the characteristic MR imaging features of RCC and common benign renal masses and propose a diagnostic imaging approach to evaluation of solid renal masses using multiparametric MR imaging. (c)RSNA, 2017. PMID- 29131772 TI - Congratulations to the 2017 RSNA Outstanding Educator: Dorothy Bulas, MD. PMID- 29131773 TI - Update on Cardiovascular Applications of Multienergy CT. AB - Advances in scanner technology enabling shorter scan times, improvements in spatial and temporal resolution, and more dose-efficient data reconstruction coupled with rapidly growing evidence from clinical trials have established computed tomography (CT) as an important imaging modality in the evaluation of cardiovascular disorders. Multienergy (or spectral or dual-energy) CT is a relatively recent advance in which attenuation data from different energies are used to characterize materials beyond what is possible at conventional CT. Current technologies for multienergy CT are either source based (ie, dual source, rapid kilovoltage switching, dual spin, and split beam) or detector based (ie, dual layer and photon counting), and material-based decomposition occurs in either image or projection space. In addition to conventional diagnostic images, multienergy CT provides image sets such as iodine maps, virtual nonenhanced, effective atomic number, and virtual monoenergy (VM) images as well as data at the elemental level (CT fingerprinting), which can complement and in some areas overcome the limitations posed by conventional CT methods. In myocardial perfusion imaging, iodine maps improve the sensitivity of perfusion defects, and VM images improve the specificity by decreasing artifacts. Iodine maps are also useful in improving the performance of CT in delayed-enhancement imaging. In pulmonary perfusion imaging, iodine maps enhance the sensitivity of detection of both acute and chronic pulmonary emboli. Low-energy (as measured in kiloelectron volts) VM images allow enhancement of vascular contrast, which can either be used to lower contrast dose or salvage a suboptimal contrast-enhanced study. High energy VM images can be used to decrease or eliminate artifacts such as beam hardening and metallic artifacts. Virtual nonenhanced images have similar attenuation as true nonenhanced images and help in reducing radiation dose by eliminating the need for the latter in multiphasic vascular studies. Other potential applications of multienergy CT include calcium scoring from virtual nonenhanced images created from coronary CT angiograms and myocardial iron quantification. Online supplemental material is available for this article. (c)RSNA, 2017. PMID- 29131774 TI - Imaging of Juvenile Hip Conditions Predisposing to Premature Osteoarthritis: Pediatric Imaging. PMID- 29131775 TI - Traumatic Hip Dislocation: What the Orthopedic Surgeon Wants to Know. AB - Hip dislocation is an important orthopedic emergency usually seen in young patients who have experienced high-energy trauma, often resulting in significant long-term morbidity. Rapid identification and reduction is critical, as prolonged dislocation increases the risk of developing avascular necrosis of the femoral head, and posttraumatic osteoarthritis is a common complication, even in the absence of associated fractures. Identification and timely management of hip dislocation are highly dependent on imaging, both at presentation and after attempted reduction. It is imperative for the radiologist to understand imaging features that guide management of hip dislocation to ensure timely identification, characterization, and communication of clinically relevant results. Although the importance of prompt identification of hip dislocation is universally recognized, the significance of imaging features that guide correct management and are thought to prevent complications is less emphasized in the radiology literature. In this article, the authors review the anatomy of the hip, common injury mechanisms for various types of dislocations, and imaging findings for associated injuries. They review the most commonly used classification systems and propose a simplified checklist approach to hip dislocation to aid rapid interpretation and communication of the most clinically relevant imaging features to the treating orthopedic surgeon. (c)RSNA, 2017. PMID- 29131776 TI - Clinical PET Imaging in Prostate Cancer-Erratum. PMID- 29131777 TI - Malignant Solitary Fibrous Tumor of the Liver: AIRP Best Cases in Radiologic Pathologic Correlation. AB - Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP). PMID- 29131778 TI - Adventures and Misadventures in Plastic Surgery and Soft-Tissue Implants. AB - Soft-tissue augmentation and implants are increasingly seen by the radiologist as more techniques emerge for a variety of indications and locations. Some surgical and implant procedures are performed for purely cosmetic reasons in otherwise healthy patients seeking to improve their body image, and some are performed for reconstruction after cancer or other chronic illnesses. Abdominoplasty, liposuction, and autologous fat grafting can be performed for abdominal and gluteal contouring. Injection of liquid injectable silicone has historically been fraught with legal issues, although it continues to be used for augmentation in a variety of anatomic locations. Newer solid silicone implants have revolutionized cosmetic and reconstructive muscular contouring. Subdermal implants placed by nonmedical professionals are relatively new and unrecognized within the medical establishment, although such implants have been described in the popular culture. Perhaps the most rapidly increasing segment of cosmetic procedures, however, is minimally invasive cosmesis in the form of soft-tissue fillers in the hands and face. Finally, the major principles of breast augmentation and penile implants are also reviewed. Regardless of the location and the type of implant, complications of plastic surgery and soft-tissue implants can generally be classified into the following categories: seroma, hematoma, infection, migration, vascular or nerve compression, fibrosis, foreign-body reaction, and rupture or breakdown. Key concepts include knowing the appropriate anatomic location and the normal postoperative appearance so that complications can be properly detected. A broad range of approved, off-label, and illicit plastic surgical and implant procedures are described and their complications illustrated with cases with classic imaging findings. (c)RSNA, 2017. PMID- 29131780 TI - Ceftriaxone-Resistant Neisseria gonorrhoeae, Canada, 2017. AB - We identified a ceftriaxone-resistant Neisseria gonorrhoeae isolate in a patient in Canada. This isolate carried the penA-60 allele, which differs substantially from its closest relative, mosaic penA XXVII (80% nucleotide identity). Epidemiologic and genomic data suggest spread from Asia. Antimicrobial susceptibility surveillance helps prevent spread of highly resistant N. gonorrhoeae strains. PMID- 29131781 TI - Cholera: ending a 50-year pandemic. PMID- 29131783 TI - Systemic sclerosis: advances and prospects. PMID- 29131782 TI - A new milestone for STIs in the USA. PMID- 29131779 TI - Sport Sampling Is Associated With Improved Landing Technique in Youth Athletes. AB - BACKGROUND: Sport sampling is recommended to promote fundamental movement skill acquisition and physical activity. In contrast, sport specialization is associated with musculoskeletal injury risk, burnout, and attrition from sport. There is limited evidence to support the influence of sport sampling on neuromuscular control, which is associated with injury risk, in youth athletes. HYPOTHESIS: Athletes who participated in only 1 sport during the previous year would demonstrate higher Landing Error Scoring System (LESS) scores than their counterparts. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 355 youth athletes (age range, 8-14 years) completed a test session with a jump-landing task, which was evaluated using the LESS. Participants were categorized as single sport (SS) or multisport (MS) based on their self-reported sport participation in the past year. Their duration of sport sampling (low, moderate, high) was determined based on their sport participation history. Participants were dichotomized into good (LESS <5) or poor (LESS >=5) categories. Chi-square tests were performed to evaluate for the association between control category (good, poor) and participation (MS, SS), as well as sport-sampling duration (low, moderate, high). RESULTS: The MS group was 2.5 times (95% CI, 1.9-3.1) as likely to be categorized as having good control compared with the SS group (chi2(355) = 10.10, P < 0.01). Recreational participants in the "high" sport-sampling duration group were 5.8 times (95% CI, 3.1-8.5) and 5.4 times (95% CI, 4.0-6.8) as likely to be categorized as having good control compared with the moderate and low groups (chi2(216) = 11.20, P < 0.01). CONCLUSION: Sport sampling at a young age is associated with improved neuromuscular control, which may reduce injury risk in youth athletes. CLINICAL RELEVANCE: Youth athletes should be encouraged to try participating in multiple sports to enhance their neuromuscular control and promote long-term physical activity. PMID- 29131784 TI - In search of global governance for research in epidemics. PMID- 29131785 TI - Offline: America-the Fourth World. PMID- 29131786 TI - Lupus research centre fosters collaboration. PMID- 29131787 TI - Mary Crow: leader in research on systemic lupus erythematosus. PMID- 29131789 TI - What's missing in climate change discussions? PMID- 29131790 TI - Right Care Series gets it wrong. PMID- 29131791 TI - Data sharing: experience from a tropical medicine research unit. PMID- 29131792 TI - Abdominal aortic aneurysms in women. PMID- 29131794 TI - Department of Error. PMID- 29131793 TI - Abdominal aortic aneurysms in women - Authors' reply. PMID- 29131795 TI - FreeStyle Libre: contact irritation versus contact allergy. PMID- 29131796 TI - Department of Error. PMID- 29131797 TI - Jaundice, abdominal pain, and fever in a young woman. PMID- 29131800 TI - Qualitative and quantitative evaluation of dynamic changes in non-culprit coronary atherosclerotic lesion morphology: a longitudinal OCT study. AB - AIMS: There is limited in vivo evidence regarding the temporal evolution of non culprit coronary plaque morphology. We aimed to evaluate changes in non-culprit plaque morphology over time by optical coherence tomography (OCT). METHODS AND RESULTS: Seventy-two (72) patients with 257 non-culprit segments with serial OCT studies were analysed. Non-culprit 5 mm-long coronary segments from the same imaged region were matched between baseline and follow-up. OCT plaque characterisation including automated attenuation analysis was performed, and changes over a median follow-up of 6.2 months were evaluated. On segment level, lumen area decreased from baseline to follow-up, whereas fibrous cap thickness increased. Similarly, plaque attenuation indices at follow-up were significantly decreased. Minimal cap thickness per patient did not change. In 68.5% of segments, plaque morphology did not change. Favourable change was observed in 18.4% of segments and unfavourable in 12.9%. There were no robust clinical predictors of change in plaque morphology. Attenuation analysis supported the qualitative characterisation, showing significantly different attenuation between different plaque types. CONCLUSIONS: In non-culprit coronary segments of patients with coronary artery disease under standard medical therapy, segment-level but not patient-level minimum fibrous cap thickness increases over time, with observations of both favourable and unfavourable changes in individual segments. PMID- 29131798 TI - Puerto Rico's health system after Hurricane Maria. PMID- 29131799 TI - Multislice computed tomography assessment of everolimus-eluting Absorb bioresorbable scaffolds in comparison with metallic drug-eluting stents from the ABSORB Japan randomised trial. AB - AIMS: Blooming artefacts limit accurate coronary assessment by multislice computed tomography (MSCT) in metallic stents. We sought to investigate whether bioresorbable vascular scaffolds (BVS) could be better assessed by MSCT. METHODS AND RESULTS: Among 400 patients in the randomised ABSORB Japan trial, a pre specified MSCT substudy was performed in 98 patients (103 lesions) in the BVS arm and 49 patients (49 lesions) in the cobalt-chromium everolimus-eluting stent (CoCr-EES) arm at 13 months prior to follow-up angiography. The assessability of BVS by MSCT was superior to that of CoCr-EES (94% versus 67%, p<0.001). Blooming artefacts were the main reason CoCr-EES could not be analysed (29%), while marker artefacts precluded analysis in 1.1% of BVS. In the CoCr-EES arm, non-assessable lesions were more prevalent in segments with 2.5 mm stents compared to 3.0 or 3.5 mm stents (75.0% versus 23.5%, p=0.01), while in the BVS arm image quality was good regardless of the diameter. The in-device minimal lumen diameter by MSCT was smaller than that by QCA with a difference of 0.61 mm in the CoCr-EES arm, vs. only 0.026 mm in the BVS arm. CONCLUSIONS: The feasibility of MSCT assessment of BVS-treated lesions was greater than that for lesions with CoCr-EES. PMID- 29131801 TI - Real-world experience using the ACURATE neo prosthesis: 30-day outcomes of 1,000 patients enrolled in the SAVI TF registry. AB - AIMS: The aim of the SAVI TF registry was to assess the safety and performance of the self-expanding ACURATE neo transfemoral transcatheter heart valve in a large patient population with severe aortic stenosis and to investigate whether the outcomes obtained in the CE-mark cohort can be replicated in an unselected all comers population. METHODS AND RESULTS: From October 2014 until April 2016, 1,000 patients were enrolled in this prospective, European multicentre registry. Patients were 81.1+/-5.2 years and had a logistic EuroSCORE II and STS score of 6.6+/-7.5% and 6.0+/-5.6%, respectively. Predilatation was performed in 96.1% of patients and postdilatation in 44.8%. Procedural and device success were both obtained in 98.7%; failure comprised nine valve-in-valve procedures, three conversions to surgery, and one aborted procedure. The primary endpoint was 30 day mortality, which was observed in 14 patients (1.4% [95% CI: 0.7-2.1]). Disabling stroke was seen in 1.2% (95% CI: 0.5-1.9) and new pacemaker implantation in 8.3% (95% CI: 6.6-10.0). At discharge, mean effective orifice area was 1.77+/-0.46 cm2 and mean gradient 8.4+/-4.0 mmHg; 4.1% of patients had a more than mild paravalvular leak. CONCLUSIONS: In this initial experience, treatment with the ACURATE neo prosthesis resulted in good clinical outcomes with very low complication rates. PMID- 29131802 TI - Acute and one-year clinical outcomes following implantation of bioresorbable vascular scaffolds: the ABSORB UK Registry. AB - AIMS: The aim of this registry was to monitor practice patterns and outcomes in patients treated with Absorb bioresorbable vascular scaffolds (BVS) during the early phase of usage in the UK. METHODS AND RESULTS: A total of 1,005 patients with de novo coronary lesions were treated using careful implantation techniques at 24 centres. Follow-up at one year was obtained in 99%. An independent clinical events committee and angiographic core lab adjudicated all events. Patient age was 52 years and 46% presented with acute coronary syndromes. Lesion complexity was B2/C in 47.4%, with an average of 1.4+/-0.6 BVS implanted and a BVS length of 28+/-14.3 mm. A single BVS was implanted in 71.3%. High pressure post-dilatation was performed in 94.9%, with 50% using intravascular imaging. Device success was achieved in 98.7% and procedure success in 97.3% of patients. At one year, the device-oriented endpoint target lesion failure was 3.2%, and the patient-oriented endpoint major adverse cardiac events was 3.4%. Definite ST occurred in 1.4%. By multivariable analysis, scaffold size of 2.5 mm predicted ST at one year (OR 3.27, 95% CI: 1.28-8.37; p=0.014). CONCLUSIONS: With careful patient selection and technique, TLF rates following BVS implantation in real-world practice are comparable with contemporary drug-eluting stents. ST rates remain high, with small vessel size identified as a contributory factor. PMID- 29131804 TI - Assessing the performance of the PRECISE-DAPT and PARIS risk scores for predicting one-year out-of-hospital bleeding in acute coronary syndrome patients. AB - AIMS: The PRECISE-DAPT and PARIS risk scores (RSs) were recently developed for bleeding risk assessment in percutaneous coronary intervention (PCI) patients treated with dual antiplatelet therapy (DAPT). We aimed to assess the performance of these RSs for predicting out-of-hospital bleeding in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: Retrospectively, we studied 1,926 consecutive ACS patients treated with PCI and DAPT. The performance of RSs for predicting one-year BARC type 2, 3 or 5 bleeding and BARC type 3 or 5 bleeding was assessed and compared. Both RSs were effective for the prediction of bleeding events. For BARC type 2, 3 or 5 bleeding, the c-statistic values for PRECISE-DAPT and PARIS were 0.61 and 0.63 (p=0.29), respectively. The two scores displayed equal c-statistics of 0.73 for predicting BARC type 3 or 5 bleeding. PARIS significantly outperformed PRECISE-DAPT in terms of indices of categoryless net reclassification improvement and integrated discrimination. Decision curve analyses also favoured PARIS. CONCLUSIONS: Within our cohort, PARIS and PRECISE DAPT were fairly to moderately effective for the prediction of bleeding. Their predictiveness varies according to the bleeding severity. PARIS-derived bleeding risk assessment was associated with a higher net benefit compared to PRECISE-DAPT based bleeding risk assessment. PMID- 29131803 TI - Bench testing and coronary artery bifurcations: a consensus document from the European Bifurcation Club. AB - This is a consensus document from the European Bifurcation Club concerning bench testing in coronary artery bifurcations. It is intended to provide guidelines for bench assessment of stents and other strategies in coronary bifurcation treatment where the United States Food and Drug Administration (FDA) or International Organization for Standardization (ISO) guidelines are limited or absent. These recommendations provide guidelines rather than a step-by-step manual. We provide data on the anatomy of bifurcations and elastic response of coronary arteries to aid model construction. We discuss testing apparatus, bench testing endpoints and bifurcation nomenclature. PMID- 29131805 TI - Management of radiation-induced valvular heart disease due to Hodgkin's Lymphoma in the modern era. PMID- 29131806 TI - Impact of guidewire recrossing point into stent jailed side branch for optimal kissing balloon dilatation: core lab 3D optical coherence tomography analysis. AB - AIMS: We aimed to investigate the influence of the guidewire recrossing point on the incidence of incomplete stent apposition (ISA) after kissing balloon dilatation (KBD), and also clinical and angiographic outcome at nine months in a prospective multicentre registry. METHODS AND RESULTS: One hundred and five patients underwent single crossover stenting across the side branch (SB) and subsequent KBD. The jailing configuration of the SB orifice and the guidewire recrossing position were assessed by off-line 3D-OCT in the core lab. We defined the cases that achieved both link-free carina configuration and distal recrossing as the LFD group (54 cases), and the other cases as the non-LFD group (51 cases). ISA in the LFD group was significantly smaller than that in the non-LFD group (6.7+/-5.9% vs. 17.0+/-10.5%, p<0.0001). The distal recrossing rate was 83%. Proximal recrossing increased ISA compared with distal recrossing, particularly in parallel bifurcations (17.1+/-10.1% vs. 6.3+/-6.0%, p<0.0001). At follow-up, though event rates did not differ, SB restenosis in the non-LFD group tended to be higher than in the LFD group (20.5% vs. 8.3%, p=0.1254). CONCLUSIONS: The guidewire recrossing point and the location of a stent link at the SB orifice had an influence on the ISA. KBD with optimal conditions under 3D-OCT guidance may reduce SB restenosis. PMID- 29131807 TI - Towards frameless maskless SRS through real-time 6DoF robotic motion compensation. AB - Stereotactic radiosurgery (SRS) uses precise dose placement to treat conditions of the CNS. Frame-based SRS uses a metal head ring fixed to the patient's skull to provide high treatment accuracy, but patient comfort and clinical workflow may suffer. Frameless SRS, while potentially more convenient, may increase uncertainty of treatment accuracy and be physiologically confining to some patients. By incorporating highly precise robotics and advanced software algorithms into frameless treatments, we present a novel frameless and maskless SRS system where a robot provides real-time 6DoF head motion stabilization allowing positional accuracies to match or exceed those of traditional frame based SRS. A 6DoF parallel kinematics robot was developed and integrated with a real-time infrared camera in a closed loop configuration. A novel compensation algorithm was developed based on an iterative closest-path correction approach. The robotic SRS system was tested on six volunteers, whose motion was monitored and compensated for in real-time over 15 min simulated treatments. The system's effectiveness in maintaining the target's 6DoF position within preset thresholds was determined by comparing volunteer head motion with and without compensation. Comparing corrected and uncorrected motion, the 6DoF robotic system showed an overall improvement factor of 21 in terms of maintaining target position within 0.5 mm and 0.5 degree thresholds. Although the system's effectiveness varied among the volunteers examined, for all volunteers tested the target position remained within the preset tolerances 99.0% of the time when robotic stabilization was used, compared to 4.7% without robotic stabilization. The pre clinical robotic SRS compensation system was found to be effective at responding to sub-millimeter and sub-degree cranial motions for all volunteers examined. The system's success with volunteers has demonstrated its capability for implementation with frameless and maskless SRS treatments, potentially able to achieve the same or better treatment accuracies compared to traditional frame based approaches. PMID- 29131808 TI - Linear energy transfer incorporated intensity modulated proton therapy optimization. AB - The purpose of this study was to investigate the feasibility of incorporating linear energy transfer (LET) into the optimization of intensity modulated proton therapy (IMPT) plans. Because increased LET correlates with increased biological effectiveness of protons, high LETs in target volumes and low LETs in critical structures and normal tissues are preferred in an IMPT plan. However, if not explicitly incorporated into the optimization criteria, different IMPT plans may yield similar physical dose distributions but greatly different LET, specifically dose-averaged LET, distributions. Conventionally, the IMPT optimization criteria (or cost function) only includes dose-based objectives in which the relative biological effectiveness (RBE) is assumed to have a constant value of 1.1. In this study, we added LET-based objectives for maximizing LET in target volumes and minimizing LET in critical structures and normal tissues. Due to the fractional programming nature of the resulting model, we used a variable reformulation approach so that the optimization process is computationally equivalent to conventional IMPT optimization. In this study, five brain tumor patients who had been treated with proton therapy at our institution were selected. Two plans were created for each patient based on the proposed LET incorporated optimization (LETOpt) and the conventional dose-based optimization (DoseOpt). The optimized plans were compared in terms of both dose (assuming a constant RBE of 1.1 as adopted in clinical practice) and LET. Both optimization approaches were able to generate comparable dose distributions. The LET incorporated optimization achieved not only pronounced reduction of LET values in critical organs, such as brainstem and optic chiasm, but also increased LET in target volumes, compared to the conventional dose-based optimization. However, on occasion, there was a need to tradeoff the acceptability of dose and LET distributions. Our conclusion is that the inclusion of LET-dependent criteria in the IMPT optimization could lead to similar dose distributions as the conventional optimization but superior LET distributions in target volumes and normal tissues. This may have substantial advantages in improving tumor control and reducing normal tissue toxicities. PMID- 29131809 TI - Positioning true coincidences that undergo inter-and intra-crystal scatter for a sub-mm resolution cadmium zinc telluride-based PET system. AB - The kinematics of Compton scatter can be used to estimate the interaction sequence of inter-crystal scatter interactions in 3D position-sensitive cadmium zinc telluride (CZT) detectors. However, in the case of intra-crystal scatter in a 'cross-strip' CZT detector slab, multiple anode and cathode strips may be triggered, creating position ambiguity due to uncertainty in possible combinations of anode-cathode pairings. As a consequence, methods such as energy weighted centroid are not applicable to position the interactions. In practice, since the event position is uncertain, these intra-crystal scatters events are discarded. In this work, we studied using Compton kinematics and a 'direction difference angle' to provide a method to correctly identify the anode-cathode pair corresponding to the first interaction position in an intra-crystal scatter event. GATE simulation studies of a NEMA NU4 image quality phantom in a small animal positron emission tomography under development composed of 192, [Formula: see text] mm CZT crystals shows that 47% of total numbers of multiple-interaction photon events (MIPEs) are intra-crystal scatter with a 100 keV lower energy threshold per interaction. The sensitivity of the system increases from 0.6 to 4.10 (using 10 keV as system lower energy threshold) by including rather than discarding inter- and intra-crystal scatter. The contrast-to-noise ratio (CNR) also increases from [Formula: see text] to [Formula: see text]. It was shown that a higher energy threshold limits the capability of the system to detect MIPEs and reduces CNR. Results indicate a sensitivity increase (4.1 to 5.88) when raising the lower energy threshold (10 keV to 100 keV) for the case of only two interaction events. In order to detect MIPEs accurately, a low noise system capable of a low energy threshold (10 keV) per interaction is desired. PMID- 29131810 TI - The role of trapped bubbles in kidney stone detection with the color Doppler ultrasound twinkling artifact. AB - The color Doppler ultrasound twinkling artifact, which highlights kidney stones with rapidly changing color, has the potential to improve stone detection; however, its inconsistent appearance has limited its clinical utility. Recently, it was proposed stable crevice bubbles on the kidney stone surface cause twinkling; however, the hypothesis is not fully accepted because the bubbles have not been directly observed. In this paper, the micron or submicron-sized bubbles predicted by the crevice bubble hypothesis are enlarged in kidney stones of five primary compositions by exposure to acoustic rarefaction pulses or hypobaric static pressures in order to simultaneously capture their appearance by high speed photography and ultrasound imaging. On filming stones that twinkle, consecutive rarefaction pulses from a lithotripter caused some bubbles to reproducibly grow from specific locations on the stone surface, suggesting the presence of pre-existing crevice bubbles. Hyperbaric and hypobaric static pressures were found to modify the twinkling artifact; however, the simple expectation that hyperbaric exposures reduce and hypobaric pressures increase twinkling by shrinking and enlarging bubbles, respectively, largely held for rough-surfaced stones but was inadequate for smoother stones. Twinkling was found to increase or decrease in response to elevated static pressure on smooth stones, perhaps because of the compression of internal voids. These results support the crevice bubble hypothesis of twinkling and suggest the kidney stone crevices that give rise to the twinkling phenomenon may be internal as well as external. PMID- 29131811 TI - Two-dimensional materials and one-dimensional carbon nanotube composites for microwave absorption. AB - In this work, hierarchical architecture MoS2/CNT nanohybrids synthesized by the hydrothermal method, with different CNT proportions are systematically investigated for their microwave absorption. MoS2 nanoflowers are anchored uniformly on the surface of a CNT when the proportion of the MoS2/CNT nanohybrids was 10:2, and the reflection loss can attain -20 dB in the range of 3.4-13.9 GHz with multiple thicknesses from 1.5-5.0 mm, while an optimal consequence of -46 dB can be reached at 6.6 GHz at 2.9 mm. The excellent performance indicates that the MoS2/CNT = 10:2 nanohybrids have the potential for use as microwave absorbing materials. PMID- 29131812 TI - An improved distance-to-dose correlation for predicting bladder and rectum dose volumes in knowledge-based VMAT planning for prostate cancer. AB - The overlap volume histogram (OVH) is an anatomical metric commonly used to quantify the geometric relationship between an organ at risk (OAR) and target volume when predicting expected dose-volumes in knowledge-based planning (KBP). This work investigated the influence of additional variables contributing to variations in the assumed linear DVH-OVH correlation for the bladder and rectum in VMAT plans of prostate patients, with the goal of increasing prediction accuracy and achievability of knowledge-based planning methods. VMAT plans were retrospectively generated for 124 prostate patients using multi-criteria optimization. DVHs quantified patient dosimetric data while OVHs quantified patient anatomical information. The DVH-OVH correlations were calculated for fractional bladder and rectum volumes of 30, 50, 65, and 80%. Correlations between potential influencing factors and dose were quantified using the Pearson product-moment correlation coefficient (R). Factors analyzed included the derivative of the OVH, prescribed dose, PTV volume, bladder volume, rectum volume, and in-field OAR volume. Out of the selected factors, only the in-field bladder volume (mean R = 0.86) showed a strong correlation with bladder doses. Similarly, only the in-field rectal volume (mean R = 0.76) showed a strong correlation with rectal doses. Therefore, an OVH formalism accounting for in field OAR volumes was developed to determine the extent to which it improved the DVH-OVH correlation. Including the in-field factor improved the DVH-OVH correlation, with the mean R values over the fractional volumes studied improving from -0.79 to -0.85 and -0.82 to -0.86 for the bladder and rectum, respectively. A re-planning study was performed on 31 randomly selected database patients to verify the increased accuracy of KBP dose predictions by accounting for bladder and rectum volume within treatment fields. The in-field OVH led to significantly more precise and fewer unachievable KBP predictions, especially for lower bladder and rectum dose-volumes. PMID- 29131813 TI - Mechanical fatigue resistance of an implantable branched lead system for a distributed set of longitudinal intrafascicular electrodes. AB - OBJECTIVE: A neural interface system has been developed that consists of an implantable stimulator/recorder can with a 15-electrode lead that trifurcates into three bundles of five individual wire longitudinal intrafascicular electrodes. This work evaluated the mechanical fatigue resistance of the branched lead and distributed electrode system under conditions designed to mimic anticipated strain profiles that would be observed after implantation in the human upper arm. APPROACH: Custom test setups and procedures were developed to apply linear or angular strain at four critical stress riser points on the lead and electrode system. Each test was performed to evaluate fatigue under a high repetition/low amplitude paradigm designed to test the effects of arm movement on the leads during activities such as walking, or under a low repetition/high amplitude paradigm designed to test the effects of more strenuous upper arm activities. The tests were performed on representative samples of the implantable lead system for human use. The specimens were fabricated using procedures equivalent to those that will be used during production of human-use implants. Electrical and visual inspections of all test specimens were performed before and after the testing procedures to assess lead integrity. MAIN RESULTS: Measurements obtained before and after applying repetitive strain indicated that all test specimens retained electrical continuity and that electrical impedance remained well below pre-specified thresholds for detection of breakage. Visual inspection under a microscope at 10* magnification did not reveal any signs of damage to the wires or silicone sheathing at the stress riser points. SIGNIFICANCE: These results demonstrate that the branched lead of this implantable neural interface system has sufficient mechanical fatigue resistance to withstand strain profiles anticipated when the system is implanted in an arm. The novel test setups and paradigms may be useful in testing other lead systems. PMID- 29131814 TI - Effects of an Exercise Protocol for Improving Handgrip Strength and Walking Speed on Cognitive Function in Patients with Chronic Stroke. AB - BACKGROUND Handgrip strength and walking speed predict and influence cognitive function. We aimed to investigate an exercise protocol for improving handgrip strength and walking speed, applied to patients with chronic stroke who had cognitive function disorder. MATERIAL AND METHODS Twenty-nine patients with cognitive function disorder participated in this study, and were randomly divided into one of two groups: exercise group (n=14) and control group (n=15). Both groups underwent conventional physical therapy for 60 minutes per day. Additionally, the exercise group followed an exercise protocol for handgrip using the hand exerciser, power web exerciser, Digi-Flex (15 minutes); and treadmill based weight loading training on their less-affected leg (15 minutes) using a sandbag for 30 minutes, three times per day, for six weeks. Outcomes, including cognitive function and gait ability, were measured before and after the training. RESULTS The Korean version of Montreal Cognitive Assessment (K-MoCA), Stroop test (both simple and interference), Trail Making-B, Timed Up and Go, and 10-Meter Walk tests (p<0.05) yielded improved results for the exercise group compared with the control group. Importantly, the K-MoCA, Timed Up and Go, and 10-Meter Walk test results were significantly different between the two groups (p<0.05). CONCLUSIONS The exercise protocol for improving handgrip strength and walking speed had positive effects on cognitive function in patients with chronic stroke. PMID- 29131815 TI - The karrikin receptor KAI2 promotes drought resistance in Arabidopsis thaliana. AB - Drought causes substantial reductions in crop yields worldwide. Therefore, we set out to identify new chemical and genetic factors that regulate drought resistance in Arabidopsis thaliana. Karrikins (KARs) are a class of butenolide compounds found in smoke that promote seed germination, and have been reported to improve seedling vigor under stressful growth conditions. Here, we discovered that mutations in KARRIKIN INSENSITIVE2 (KAI2), encoding the proposed karrikin receptor, result in hypersensitivity to water deprivation. We performed transcriptomic, physiological and biochemical analyses of kai2 plants to understand the basis for KAI2-regulated drought resistance. We found that kai2 mutants have increased rates of water loss and drought-induced cell membrane damage, enlarged stomatal apertures, and higher cuticular permeability. In addition, kai2 plants have reduced anthocyanin biosynthesis during drought, and are hyposensitive to abscisic acid (ABA) in stomatal closure and cotyledon opening assays. We identified genes that are likely associated with the observed physiological and biochemical changes through a genome-wide transcriptome analysis of kai2 under both well-watered and dehydration conditions. These data provide evidence for crosstalk between ABA- and KAI2-dependent signaling pathways in regulating plant responses to drought. A comparison of the strigolactone receptor mutant d14 (DWARF14) to kai2 indicated that strigolactones also contributes to plant drought adaptation, although not by affecting cuticle development. Our findings suggest that chemical or genetic manipulation of KAI2 and D14 signaling may provide novel ways to improve drought resistance. PMID- 29131816 TI - Automated visualization of rule-based models. AB - Frameworks such as BioNetGen, Kappa and Simmune use "reaction rules" to specify biochemical interactions compactly, where each rule specifies a mechanism such as binding or phosphorylation and its structural requirements. Current rule-based models of signaling pathways have tens to hundreds of rules, and these numbers are expected to increase as more molecule types and pathways are added. Visual representations are critical for conveying rule-based models, but current approaches to show rules and interactions between rules scale poorly with model size. Also, inferring design motifs that emerge from biochemical interactions is an open problem, so current approaches to visualize model architecture rely on manual interpretation of the model. Here, we present three new visualization tools that constitute an automated visualization framework for rule-based models: (i) a compact rule visualization that efficiently displays each rule, (ii) the atom-rule graph that conveys regulatory interactions in the model as a bipartite network, and (iii) a tunable compression pipeline that incorporates expert knowledge and produces compact diagrams of model architecture when applied to the atom-rule graph. The compressed graphs convey network motifs and architectural features useful for understanding both small and large rule-based models, as we show by application to specific examples. Our tools also produce more readable diagrams than current approaches, as we show by comparing visualizations of 27 published models using standard graph metrics. We provide an implementation in the open source and freely available BioNetGen framework, but the underlying methods are general and can be applied to rule-based models from the Kappa and Simmune frameworks also. We expect that these tools will promote communication and analysis of rule-based models and their eventual integration into comprehensive whole-cell models. PMID- 29131817 TI - Characterizing steady states of genome-scale metabolic networks in continuous cell cultures. AB - In the continuous mode of cell culture, a constant flow carrying fresh media replaces culture fluid, cells, nutrients and secreted metabolites. Here we present a model for continuous cell culture coupling intra-cellular metabolism to extracellular variables describing the state of the bioreactor, taking into account the growth capacity of the cell and the impact of toxic byproduct accumulation. We provide a method to determine the steady states of this system that is tractable for metabolic networks of arbitrary complexity. We demonstrate our approach in a toy model first, and then in a genome-scale metabolic network of the Chinese hamster ovary cell line, obtaining results that are in qualitative agreement with experimental observations. We derive a number of consequences from the model that are independent of parameter values. The ratio between cell density and dilution rate is an ideal control parameter to fix a steady state with desired metabolic properties. This conclusion is robust even in the presence of multi-stability, which is explained in our model by a negative feedback loop due to toxic byproduct accumulation. A complex landscape of steady states emerges from our simulations, including multiple metabolic switches, which also explain why cell-line and media benchmarks carried out in batch culture cannot be extrapolated to perfusion. On the other hand, we predict invariance laws between continuous cell cultures with different parameters. A practical consequence is that the chemostat is an ideal experimental model for large-scale high-density perfusion cultures, where the complex landscape of metabolic transitions is faithfully reproduced. PMID- 29131819 TI - Correction: Unmet needs for analyzing biological big data: A survey of 704 NSF principal investigators. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005755.]. PMID- 29131818 TI - Electrical stimulus artifact cancellation and neural spike detection on large multi-electrode arrays. AB - Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these measurements is challenging because the spike sorting process (identifying and segregating action potentials arising from different neurons) is greatly complicated by electrical stimulation artifacts across the array, which can exhibit complex and nonlinear waveforms, and overlap temporarily with evoked spikes. Here we develop a scalable algorithm based on a structured Gaussian Process model to estimate the artifact and identify evoked spikes. The effectiveness of our methods is demonstrated in both real and simulated 512-electrode recordings in the peripheral primate retina with single-electrode and several types of multi-electrode stimulation. We establish small error rates in the identification of evoked spikes, with a computational complexity that is compatible with real-time data analysis. This technology may be helpful in the design of future high-resolution sensory prostheses based on tailored stimulation (e.g., retinal prostheses), and for closed-loop neural stimulation at a much larger scale than currently possible. PMID- 29131820 TI - Rapid clearance of Schistosoma mansoni circulating cathodic antigen after treatment shown by urine strip tests in a Ugandan fishing community - Relevance for monitoring treatment efficacy and re-infection. AB - : Schistosomiasis control and elimination has priority in public health agendas in several sub-Saharan countries. However, achieving these goals remains a substantial challenge. In order to assess progress of interventions and treatment efficacy it is pertinent to have accurate, feasible and affordable diagnostic tools. Detection of Schistosoma mansoni infection by circulating cathodic antigen (CCA) in urine is an attractive option as this measure describes live worm infection noninvasively. In order to interpret treatment efficacy and re infection levels, knowledge about clearance of this antigen is necessary. The current study aims to investigate, whether antigen clearance as a proxy for decreasing worm numbers is reflected in decreasing CCA levels in urine shortly after praziquantel treatment. Here CCA levels are measured 24 hours post treatment in response to both a single and two treatments. The study was designed as a series of cross-sectional urine and stool sample collections from 446 individuals nested in a two-arm randomised single blinded longitudinal clinical trial cohort matched by gender and age (ClinicalTrials.gov Identifier: NCT00215267) receiving one or two praziquantel treatments. CCA levels in urine were determined by carbon-conjugated monoclonal antibody lateral flow strip assay and eggs per gram faeces for S. mansoni and soil-transmitted helminths by Kato Katz. Significant correlations between CCA levels and S. mansoni egg count at every measured time point were found and confirmed the added beneficial effect of a second treatment at two weeks after baseline. Furthermore, presence of hookworm was found not to be a confounder for CCA test specificity. Twenty-four hours post treatment measures of mean CCA scores showed significant reductions. In conclusion, removal of CCA in response to treatment is detectable as a decline in CCA in urine already after 24 hours. This has relevance for use and interpretation of laboratory based and point-of-care CCA tests in terms of treatment efficacy and re-infection proportions as this measure provides information on the presence of all actively feeding stages of S. mansoni, which conventional faecal microscopy methods do not accurately reflect. TRIAL REGISTRATION: ClinicalTrials.gov NCT00215267. PMID- 29131821 TI - Improving virtual screening of G protein-coupled receptors via ligand-directed modeling. AB - G protein-coupled receptors (GPCRs) play crucial roles in cell physiology and pathophysiology. There is increasing interest in using structural information for virtual screening (VS) of libraries and for structure-based drug design to identify novel agonist or antagonist leads. However, the sparse availability of experimentally determined GPCR/ligand complex structures with diverse ligands impedes the application of structure-based drug design (SBDD) programs directed to identifying new molecules with a select pharmacology. In this study, we apply ligand-directed modeling (LDM) to available GPCR X-ray structures to improve VS performance and selectivity towards molecules of specific pharmacological profile. The described method refines a GPCR binding pocket conformation using a single known ligand for that GPCR. The LDM method is a computationally efficient, iterative workflow consisting of protein sampling and ligand docking. We developed an extensive benchmark comparing LDM-refined binding pockets to GPCR X ray crystal structures across seven different GPCRs bound to a range of ligands of different chemotypes and pharmacological profiles. LDM-refined models showed improvement in VS performance over origin X-ray crystal structures in 21 out of 24 cases. In all cases, the LDM-refined models had superior performance in enriching for the chemotype of the refinement ligand. This likely contributes to the LDM success in all cases of inhibitor-bound to agonist-bound binding pocket refinement, a key task for GPCR SBDD programs. Indeed, agonist ligands are required for a plethora of GPCRs for therapeutic intervention, however GPCR X-ray structures are mostly restricted to their inactive inhibitor-bound state. PMID- 29131822 TI - Impact of the Ebola outbreak on Trypanosoma brucei gambiense infection medical activities in coastal Guinea, 2014-2015: A retrospective analysis from the Guinean national Human African Trypanosomiasis control program. AB - BACKGROUND: The 2014-2015 Ebola outbreak massively hit Guinea. The coastal districts of Boffa, Dubreka and Forecariah, three major foci of Human African Trypanosomiasis (HAT), were particularly affected. We aimed to assess the impact of this epidemic on sleeping sickness screening and caring activities. METHODOLOGY/PRINCIPAL FINDINGS: We used preexisting data from the Guinean sleeping sickness control program, collected between 2012 and 2015. We described monthly: the number of persons (i) screened actively; (ii) or passively; (iii) treated for HAT; (iv) attending post-treatment follow-up visits. We compared clinical data, treatment characteristics and Disability Adjusted Life-Years (DALYs) before (February 2012 to December 2013) and during (January 2014 to October 2015) the Ebola outbreak period according to available data. Whereas 32,221 persons were actively screened from February 2012 to December 2013, before the official declaration of the first Ebola case in Guinea, no active screening campaigns could be performed during the Ebola outbreak. Following the reinforcement and extension of HAT passive surveillance system early in 2014, the number of persons tested passively by month increased from 7 to 286 between April and September 2014 and then abruptly decreased to 180 until January 2015 and to none after March 2015. 213 patients initiated HAT treatment, 154 (72%) before Ebola and 59 (28%) during the Ebola outbreak. Those initiating HAT therapy during Ebola outbreak were recruited through passive screening and diagnosed at a later stage 2 of the disease (96% vs. 55% before Ebola, p<0.0001). The proportion of patients attending the 3 months and 6 months post-treatment follow-up visits decreased from 44% to 10% (p <0.0001) and from 16% to 3% (p = 0.017) respectively. The DALYs generated before the Ebola outbreak were estimated to 48.7 (46.7-51.5) and increased up to 168.7 (162.7-174.7), 284.9 (277.1-292.8) and 466.3 (455.7-477.0) during Ebola assuming case fatality rates of 2%, 5% and 10% respectively among under-reported HAT cases. CONCLUSIONS/SIGNIFICANCE: The 2014 2015 Ebola outbreak deeply impacted HAT screening activities in Guinea. Active screening campaigns were stopped. Passive screening dramatically decreased during the Ebola period, but trends could not be compared with pre-Ebola period (data not available). Few patients were diagnosed with more advanced HAT during the Ebola period and retention rates in follow-up were lowered. The drop in newly diagnosed HAT cases during Ebola epidemic is unlikely due to a fall in HAT incidence. Even if we were unable to demonstrate it directly, it is much more probably the consequence of hampered screening activities and of the fear of the population on subsequent confirmation and linkage to care. Reinforced program monitoring, alternative control strategies and sustainable financial and human resources allocation are mandatory during post Ebola period to reduce HAT burden in Guinea. PMID- 29131823 TI - Prevalence of extracranial carotid artery aneurysms in patients with an intracranial aneurysm. AB - BACKGROUND AND PURPOSE: Aneurysms in various arterial beds have common risk- and genetic factors. Data on the correlation of extracranial carotid artery aneurysms (ECAA) with aneurysms in other vascular territories are lacking. We aimed to investigate the prevalence of ECAA in patients with an intracranial aneurysm (IA). METHODS: We used prospectively collected databases of consecutive patients registered at the University Medical Center Utrecht with an unruptured intracranial aneurysm (UIA) or aneurysmal Subarachnoid hemorrhage (SAH). The medical files of patients included in both databases were screened for availability of radiological reports, imaging of the brain and of the cervical carotid arteries. All available radiological images were then reviewed primarily for the presence of an ECAA and secondarily for an extradural/cavernous carotid or vertebral artery aneurysm. An ECAA was defined as a fusiform dilation >=150% of the normal internal or common carotid artery or a saccular distention of any size. RESULTS: We screened 4465 patient records (SAH database n = 3416, UIA database n = 1049), of which 2931 had radiological images of the carotid arteries available. An ECAA was identified in 12/638 patients (1.9%; 95% CI 1.1-3.3) with completely imaged carotid arteries and in 15/2293 patients (0.7%; 95% CI 0.4-1.1) with partially depicted carotid arteries. Seven out of 27 patients had an additional extradural (cavernous or vertebral artery) aneurysm. CONCLUSIONS: This comprehensive study suggests a prevalence for ECAA of approximately 2% of patients with an IA. The rarity of the disease makes screening unnecessary so far. Future registry studies should study the factors associated with IA and ECAA to estimate the prevalence of ECAA in these young patients more accurately. PMID- 29131824 TI - Predictive model identifies key network regulators of cardiomyocyte mechano signaling. AB - Mechanical strain is a potent stimulus for growth and remodeling in cells. Although many pathways have been implicated in stretch-induced remodeling, the control structures by which signals from distinct mechano-sensors are integrated to modulate hypertrophy and gene expression in cardiomyocytes remain unclear. Here, we constructed and validated a predictive computational model of the cardiac mechano-signaling network in order to elucidate the mechanisms underlying signal integration. The model identifies calcium, actin, Ras, Raf1, PI3K, and JAK as key regulators of cardiac mechano-signaling and characterizes crosstalk logic imparting differential control of transcription by AT1R, integrins, and calcium channels. We find that while these regulators maintain mostly independent control over distinct groups of transcription factors, synergy between multiple pathways is necessary to activate all the transcription factors necessary for gene transcription and hypertrophy. We also identify a PKG-dependent mechanism by which valsartan/sacubitril, a combination drug recently approved for treating heart failure, inhibits stretch-induced hypertrophy, and predict further efficacious pairs of drug targets in the network through a network-wide combinatorial search. PMID- 29131825 TI - A model-based clustering method to detect infectious disease transmission outbreaks from sequence variation. AB - Clustering infections by genetic similarity is a popular technique for identifying potential outbreaks of infectious disease, in part because sequences are now routinely collected for clinical management of many infections. A diverse number of nonparametric clustering methods have been developed for this purpose. These methods are generally intuitive, rapid to compute, and readily scale with large data sets. However, we have found that nonparametric clustering methods can be biased towards identifying clusters of diagnosis-where individuals are sampled sooner post-infection-rather than the clusters of rapid transmission that are meant to be potential foci for public health efforts. We develop a fundamentally new approach to genetic clustering based on fitting a Markov-modulated Poisson process (MMPP), which represents the evolution of transmission rates along the tree relating different infections. We evaluated this model-based method alongside five nonparametric clustering methods using both simulated and actual HIV sequence data sets. For simulated clusters of rapid transmission, the MMPP clustering method obtained higher mean sensitivity (85%) and specificity (91%) than the nonparametric methods. When we applied these clustering methods to published sequences from a study of HIV-1 genetic clusters in Seattle, USA, we found that the MMPP method categorized about half (46%) as many individuals to clusters compared to the other methods. Furthermore, the mean internal branch lengths that approximate transmission rates were significantly shorter in clusters extracted using MMPP, but not by other methods. We determined that the computing time for the MMPP method scaled linearly with the size of trees, requiring about 30 seconds for a tree of 1,000 tips and about 20 minutes for 50,000 tips on a single computer. This new approach to genetic clustering has significant implications for the application of pathogen sequence analysis to public health, where it is critical to robustly and accurately identify clusters for the most cost-effective deployment of outbreak management and prevention resources. PMID- 29131826 TI - An interactive sports video game as an intervention for rehabilitation of community-living patients with schizophrenia: A controlled, single-blind, crossover study. AB - Hypofrontality is a state of decreased cerebral blood flow in the prefrontal cortex during executive function performance; it is commonly observed in patients with schizophrenia. Cognitive dysfunction, as well as the psychological symptoms of schizophrenia, influences the ability of patients to reintegrate into society. The current study investigated the effects of an interactive sports video game (IVG; Nintendo WiiTM Sports Resort) on frontal lobe function of patients with schizophrenia. A sample of eight patients (6 male and 2 female; mean age = 46.7 years, standard deviation (SD) = 13.7) engaged in an IVG every week for 3 months in a controlled, single-blind, crossover study. Before and after the intervention we examined frontal lobe blood-flow volume using functional near-infrared spectroscopy (fNIRS), and assessed functional changes using the Frontal Assessment Battery, Health-Related Quality of Life scale, and behaviorally assessed physical function tests. fNIRS revealed that prefrontal activity during IVG performance significantly increased in the IVG period compared with the control period. Furthermore, significant correlations between cerebral blood flow changes in different channels were observed during IVG performance. In addition, we observed intervention-related improvement in health-related quality of life following IVG. IVG intervention was associated with increased prefrontal cortex activation and improved health-related quality of life performance in patients with schizophrenia. Patients with chronic schizophrenia are characterized by withdrawal and a lack of social responsiveness or interest in others. Interventions using IVG may provide a useful low-cost rehabilitation method for such patients, without the need for specialized equipment. PMID- 29131827 TI - The interplay of various sources of noise on reliability of species distribution models hinges on ecological specialisation. AB - Digitized species occurrence data provide an unprecedented source of information for ecologists and conservationists. Species distribution model (SDM) has become a popular method to utilise these data for understanding the spatial and temporal distribution of species, and for modelling biodiversity patterns. Our objective is to study the impact of noise in species occurrence data (namely sample size and positional accuracy) on the performance and reliability of SDM, considering the multiplicative impact of SDM algorithms, species specialisation, and grid resolution. We created a set of four 'virtual' species characterized by different specialisation levels. For each of these species, we built the suitable habitat models using five algorithms at two grid resolutions, with varying sample sizes and different levels of positional accuracy. We assessed the performance and reliability of the SDM according to classic model evaluation metrics (Area Under the Curve and True Skill Statistic) and model agreement metrics (Overall Concordance Correlation Coefficient and geographic niche overlap) respectively. Our study revealed that species specialisation had by far the most dominant impact on the SDM. In contrast to previous studies, we found that for widespread species, low sample size and low positional accuracy were acceptable, and useful distribution ranges could be predicted with as few as 10 species occurrences. Range predictions for narrow-ranged species, however, were sensitive to sample size and positional accuracy, such that useful distribution ranges required at least 20 species occurrences. Against expectations, the MAXENT algorithm poorly predicted the distribution of specialist species at low sample size. PMID- 29131829 TI - A non-linear data mining parameter selection algorithm for continuous variables. AB - In this article, we propose a new data mining algorithm, by which one can both capture the non-linearity in data and also find the best subset model. To produce an enhanced subset of the original variables, a preferred selection method should have the potential of adding a supplementary level of regression analysis that would capture complex relationships in the data via mathematical transformation of the predictors and exploration of synergistic effects of combined variables. The method that we present here has the potential to produce an optimal subset of variables, rendering the overall process of model selection more efficient. This algorithm introduces interpretable parameters by transforming the original inputs and also a faithful fit to the data. The core objective of this paper is to introduce a new estimation technique for the classical least square regression framework. This new automatic variable transformation and model selection method could offer an optimal and stable model that minimizes the mean square error and variability, while combining all possible subset selection methodology with the inclusion variable transformations and interactions. Moreover, this method controls multicollinearity, leading to an optimal set of explanatory variables. PMID- 29131828 TI - Inhibition of HEWL fibril formation by taxifolin: Mechanism of action. AB - Among therapeutic approaches for amyloid-related diseases, attention has recently turned to the use of natural products as effective anti-aggregation compounds. Although a wealth of in vitro and in vivo evidence indicates some common inhibitory activity of these compounds, they don't generally suggest the same mechanism of action. Here, we show that taxifolin, a ubiquitous bioactive constituent of foods and herbs, inhibits formation of HEWL amyloid fibrils and their related toxicity by causing formation of very large globular, chain-like aggregates. A range of amyloid-specific techniques were employed to characterize this process. We found that taxifolin exerts its effect by binding to HEWL prefibrillar species, rather than by stabilizing the molecule in its native-like state. Furthermore, it's binding results in diverting the amyloid pathway toward formation of very large globular, chain-like aggregates with low beta-sheet content and reduced solvent-exposed hydrophobic patches. ThT fluorescence measurements show that the binding capacity of taxifolin is significantly reduced, upon generation of large protofibrillar aggregates at the end of growth phase. We believe these results may help design promising inhibitors of protein aggregation for amyloid-related diseases. PMID- 29131830 TI - Transcriptome profiling and digital gene expression analysis of sweet potato for the identification of putative genes involved in the defense response against Fusarium oxysporum f. sp. batatas. AB - Sweet potato production is constrained by Fusarium wilt, which is caused by Fusarium oxysporum f. sp. batatas (Fob). The identification of genes related to disease resistance and the underlying mechanisms will contribute to improving disease resistance via sweet potato breeding programs. In the present study, we performed de novo transcriptome assembly and digital gene expression (DGE) profiling of sweet potato challenged with Fob using Illumina HiSeq technology. In total, 89,944,188 clean reads were generated from 12 samples and assembled into 101,988 unigenes with an average length of 666 bp; of these unigenes, 62,605 (61.38%) were functionally annotated in the NCBI non-redundant protein database by BLASTX with a cutoff E-value of 10-5. Clusters of Orthologous Groups (COG), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations were examined to explore the unigenes' functions. We constructed four DGE libraries for the sweet potato cultivars JinShan57 (JS57, highly resistant) and XinZhongHua (XZH, highly susceptible), which were challenged with pathogenic Fob. Genes that were differentially expressed in the four libraries were identified by comparing the transcriptomes. Various genes that were differentially expressed during defense, including chitin elicitor receptor kinase 1 (CERK), mitogen activated protein kinase (MAPK), WRKY, NAC, MYB, and ethylene-responsive transcription factor (ERF), as well as resistance genes, pathogenesis-related genes, and genes involved in salicylic acid (SA) and jasmonic acid (JA) signaling pathways, were identified. These data represent a sequence resource for genetic and genomic studies of sweet potato that will enhance the understanding of the mechanism of disease resistance. PMID- 29131831 TI - Substrate specificity of human metallocarboxypeptidase D: Comparison of the two active carboxypeptidase domains. AB - Metallocarboxypeptidase D (CPD) is a membrane-bound component of the trans-Golgi network that cycles to the cell surface through exocytic and endocytic pathways. Unlike other members of the metallocarboxypeptidase family, CPD is a multicatalytic enzyme with three carboxypeptidase-like domains, although only the first two domains are predicted to be enzymatically active. To investigate the enzymatic properties of each domain in human CPD, a critical active site Glu in domain I and/or II was mutated to Gln and the protein expressed, purified, and assayed with a wide variety of peptide substrates. CPD with all three domains intact displays >50% activity from pH 5.0 to 7.5 with a maximum at pH 6.5, as does CPD with mutation of domain I. In contrast, the domain II mutant displayed >50% activity from pH 6.5-7.5. CPD with mutations in both domains I and II was completely inactive towards all substrates and at all pH values. A quantitative peptidomics approach was used to compare the activities of CPD domains I and II towards a large number of peptides. CPD cleaved C-terminal Lys or Arg from a subset of the peptides. Most of the identified substrates of domain I contained C terminal Arg, whereas comparable numbers of Lys- and Arg-containing peptides were substrates of domain II. We also report that some peptides with C-terminal basic residues were not cleaved by either domain I or II, showing the importance of the P1 position for CPD activity. Finally, the preference of domain I for C-terminal Arg was validated through molecular docking experiments. Together with the differences in pH optima, the different substrate specificities of CPD domains I and II allow the enzyme to perform distinct functions in the various locations within the cell. PMID- 29131832 TI - Ecosystem carbon stocks of mangroves across broad environmental gradients in West Central Africa: Global and regional comparisons. AB - Globally, it is recognized that blue carbon ecosystems, especially mangroves, often sequester large quantities of carbon and are of interest for inclusion in climate change mitigation strategies. While 19% of the world's mangroves are in Africa, they are among the least investigated of all blue carbon ecosystems. We quantified total ecosystem carbon stocks in 33 different mangrove stands along the Atlantic coast of West-Central Africa from Senegal to Southern Gabon spanning large gradients of latitude, soil properties, porewater salinity, and precipitation. Mangrove structure ranged from low and dense stands that were <1m in height and >35,000 trees ha-1 to tall and open stands >40m in height and <100 ha-1. Tremendous variation in ecosystem carbon (C) stocks was measured ranging from 154 to 1,484 Mg C ha-1. The mean total ecosystem carbon stock for all mangroves of West-Central Africa was 799 Mg C ha-1. Soils comprised an average of 86% of the total carbon stock. The greatest carbon stocks were found in the tall mangroves of Liberia and Gabon North with a mean >1,000 Mg C ha-1. The lowest carbon stocks were found in the low mangroves of the semiarid region of Senegal (463 Mg C ha-1) and in mangroves on coarse-textured soils in Gabon South (541 Mg C ha-1). At the scale of the entirety of West-Central Africa, total ecosystem carbon stocks were poorly correlated to aboveground ecosystem carbon pools, precipitation, latitude and soil salinity (r2 = <=0.07 for all parameters). Based upon a sample of 158 sites from Africa, Asia and Latin America that were sampled in a similar manner to this study, the global mean of carbon stocks for mangroves is 885 Mg C ha-1. The ecosystem carbon stocks of mangroves for West-Central Africa are slightly lower than those of Latin America (940 Mg C ha-1) and Asia (1049 Mg C ha-1) but substantially higher than the default Intergovernmental Panel on Climate Change (IPCC) values for mangroves (511 Mg C ha-1). This study provides an improved estimation of default estimates (Tier 1 values) of mangroves for Asia, Latin America, and West Central Africa. PMID- 29131833 TI - MEK inhibitors enhance therapeutic response towards ATRA in NF1 associated malignant peripheral nerve sheath tumors (MPNST) in-vitro. AB - OBJECTIVE: Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by an increased risk of malignant peripheral nerve sheath tumors (MPNST). Chemotherapy of MPNST is still insufficient. In this study, we investigated whether human tumor Schwann cells derived from NF1 associated MPNST respond to all-trans retinoic acid (ATRA). We analyzed effects of ATRA and MEK inhibitor (MEKi) combination therapy. METHODS: MPNST cell lines S462, T265, NSF1 were treated with ATRA and MEKi U0126 and PD0325901. We assessed cell viability, proliferation, migration, apoptosis and differentiation as well as mRNA expression of RAR and RXR subtypes and ATRA target genes such as CRABP2, CYP26A1, RARB and PDK1. We also analyzed CRABP2 methylation in cell lines and performed immunohistochemistry of human MPNST specimens. RESULTS: ATRA therapy reduced viability and proliferation in S462 and T265 cells, accompanied by differentiation, apoptosis and reduced migration. NSF1 cells which lacked RXRG expression did not respond to ATRA. We furthermore demonstrated that ATRA signaling was functional for common targets, and that mRNA expression of CRABP2 and its targets was raised by ATRA therapy, whereas alternative pathways via FABP5 were not induced. Finally, combination of ATRA and MEKi demonstrated additively reduced viability of T265 and S462 cells. CONCLUSIONS: We observed therapeutic effects in two of three MPNST cell lines pronounced by combination therapy. These data point to a potentially successful treatment of MPNST by combined application of ATRA and MEK inhibitors such as U0126 or PD0325901. PMID- 29131835 TI - No evidence of critical slowing down in two endangered Hawaiian honeycreepers. AB - There is debate about the current population trends and predicted short-term fates of the endangered forest birds, Hawai'i Creeper (Loxops mana) and Hawai'i 'Akepa (L. coccineus). Using long-term population size estimates, some studies report forest bird populations as stable or increasing, while other studies report signs of population decline or impending extinction associated with introduced Japanese White-eye (Zosterops japonicus) increase. Reliable predictors of impending population collapse, well before the collapse begins, have been reported in simulations and microcosm experiments. In these studies, statistical indicators of critical slowing down, a phenomenon characterized by longer recovery rates after population size perturbation, are reported to be early warning signals of an impending regime shift observable prior to the tipping point. While the conservation applications of these metrics are commonly discussed, early warning signal detection methods are rarely applied to population size data from natural populations, so their efficacy and utility in species management remain unclear. We evaluated two time series of state-space abundance estimates (1987-2012) from Hakalau Forest National Wildlife Refuge, Hawai'i to test for evidence of early warning signals of impending population collapse for the Hawai'i Creeper and Hawai'i 'Akepa. We looked for signals throughout the time series, and prior to 2000, when white-eye abundance began increasing. We found no evidence for either species of increasing variance, autocorrelation, or skewness, which are commonly reported early warning signals. We calculated linear rather than ordinary skewness because the latter is biased, particularly for small sample sizes. Furthermore, we identified break-points in trends over time for both endangered species, indicating shifts in slopes away from strongly increasing trends, but they were only weakly supported by Bayesian change-point analyses (i.e., no step-wise changes in abundance). The break-point and change-point test results, in addition to the early warning signal analyses, support that the two populations do not appear to show signs of critical slowing down or decline. PMID- 29131834 TI - Plasma microRNA profiling: Exploring better biomarkers for lymphoma surveillance. AB - Early detection of relapsed lymphoma improves response and survival. Current tools lack power for detection of early relapse, while being cumbersome and expensive. We searched for sensitive biomarkers that precede clinical relapse, and serve for further studies on therapy response and relapse. We recruited 20 healthy adults, 14 diffuse large B-cell lymphoma (DLBCL) patients and 11 Hodgkin lymphoma (HL) patients at diagnosis. Using small-RNA sequencing we identified in DLBCL patients increased plasma levels of miR-124 and miR-532-5p, and decreased levels of miR-425, miR-141, miR-145, miR-197, miR-345, miR-424, miR-128 and miR 122. In the HL group, we identified miR-25, miR-30a/d, miR-26b, miR-182, miR-186, miR-140* and miR-125a to be up-regulated, while miR-23a, miR-122, miR-93 and miR 144 were down-regulated. Pathway analysis of potential mRNAs targets of these miRNA revealed in the DLBCL group potential up-regulation of STAT3, IL8, p13k/AKT and TGF-B signaling, and potential down-regulation of the PTEN and p53 pathways; while in the HL group we have found the cAMP-mediated pathway and p53 pathway to be potentially down-regulated. Survival analyses revealed that plasma levels of miR-20a/b, miR-93 and miR-106a/b were associated with higher mortality. In conclusion, we identified sets of dysregulated circulating miRNA that might serve as reliable biomarkers for relapsed lymphoma. PMID- 29131836 TI - Opportunistic screening for atrial fibrillation in a real-life setting in general practice in Denmark-The Atrial Fibrillation Found On Routine Detection (AFFORD) non-interventional study. AB - Atrial fibrillation (AF) is a chronic disease with an incidence increasing steeply by age and affecting more than 11 million patients in Europe and the United States. Diagnosing AF is essential for the prevention of stroke by oral anticoagulation. Opportunistic screening for AF in patients >=65 years of age is recommended by the European and Danish Societies of Cardiology. The study aim was to examine the detection rate of AF in consecutively screened patients in the primary care setting in Denmark. In an open, non-interventional, cluster, multicenter, cross-sectional, observational study patients >=65 years of age entering consecutively into general practice clinics were invited to nurse assisted opportunistic screening for AF. The General Practice (GP) clinics participating were randomized to patient inclusion in three age groups: 65-74, 75 84, and >=85 years respectively. All patients underwent pulse palpation followed by 12-led electrocardiogram in case of irregular pulse. Two cardiologists validated all electrocardiogram examinations. Forty-nine general practice clinics recruited in total 970 patients split into three age groups; 480 patients (65-74 years), 372 (75-84 years), and 118 patients >=85 years of age. Co-morbidities increased by age with hypertension being most frequent. Eighty-seven patients (9%) were detected with an irregular pulse, representing 4.4%, 10.5% and 22.9%, respectively in the three age groups. Assessment of electrocardiograms by the GP showed suspicion of AF in 13 patients with final verification of electrocardiograms by cardiologists revealing 10 AF-patients. The highest detection rate of AF was found in the >=85 age group (3.39%) followed by the 65 74 age group (0.83%) and the 75-84 age group (0.54%). Opportunistic screening of AF in primary care is feasible and do result in the detection of new AF-patients. Close collaboration with cardiologists is advisable to avoid false positive screening results. PMID- 29131837 TI - Evidence for congruent impairment in micro and macrovascular function in type 1 diabetes. AB - Diabetes affects large and small vessels through mechanisms only partially known. In the present study, we evaluated the function of capillaries and large arteries in subjects with type 1 diabetes mellitus (T1DM) to study the effect of chronic hyperglycemia in the absence of other cardiovascular risk factors. Twenty-five subjects with T1DM and 12 healthy age-matched controls were enrolled. Nine patients had mild or moderate retinopathy. Contrast enhanced ultrasound was used to measure perfusion of the deep forearm flexor muscle of the non-dominant arm at rest (baseline) and after an ischemic stimulus (reactive hyperemia). Perfusion was expressed as Video Intensity (VI) in arbitrary unit (a.u.)/mm2. The time to reach peak VI after ischemia was also recorded. The function of large arteries was evaluated using flow-mediated vasodilation (FMD). VI was significantly lower in T1DM compared to control subjects both at baseline (0.22+/-0.16 vs 0.44+/-0.35 a.u./mm2, p<0.05), and after ischemia (0.33+/-0.24 vs 0.68+/-0.46 a.u./mm2, p<0.05). The time to reach peak VI after ischemia was markedly longer in T1DM (5.6+/-2.2 vs 4.0+/-1.7 seconds, p<0.02). These differences were more marked in T1DM subjects with retinopathy. FMD was lower in TIDM patients compared to controls (5.4+/-6.4 vs 10.7+/-4.5%, p<0.01). The present findings demonstrate that T1DM patients have defective peripheral skeletal muscle perfusion both at rest and after ischemia compared with control subjects. Low muscle perfusion associates with low FMD of the brachial artery. Furthermore, T1DM subjects with retinopathy have the least muscle perfusion and blunted response to hyperemia compared to T1DM without retinopathy. PMID- 29131838 TI - Expanded repertoire of kinetoplast associated proteins and unique mitochondrial DNA arrangement of symbiont-bearing trypanosomatids. AB - In trypanosomatids, the kinetoplast is the portion of the single mitochondrion that is connected to the basal body and contains the kDNA, a network composed by circular and interlocked DNA. The kDNA packing is conducted by Kinetoplast Associated Proteins (KAPs), which are similar to eukaryotic histone H1. In symbiont-harboring trypanosomatids (SHTs) such as Angomonas deanei and Strigomonas culicis, a beta-proteobacterium co-evolves with the host in a mutualistic relationship. The prokaryote confers nutritional benefits to the host and affects its cell structure. Atomic force microscopy showed that the topology of isolated kDNA networks is quite similar in the two SHT species. Ultrastructural analysis using high-resolution microscopy techniques revealed that the DNA fibrils are more compact in the kinetoplast region that faces the basal body and that the presence of the symbiotic bacterium does not interfere with kDNA topology. However, RT-PCR data revealed differences in the expression of KAPs in wild-type protozoa as compared to aposymbiotic cells. Immunolocalization showed that different KAPs present distinct distributions that are coincident in symbiont-bearing and in symbiont-free cells. Although KAP4 and KAP7 are shared by all trypanosomatid species, the expanded repertoire of KAPs in SHTs can be used as phylogenetic markers to distinguish different genera. PMID- 29131839 TI - Diversity and feeding strategies of soil microfauna along elevation gradients in Himalayan cold deserts. AB - High-elevation cold deserts in Tibet and Himalaya are one of the most extreme environments. One consequence is that the diversity of macrofauna in this environment is often limited, and soil microorganisms have a more influential role in governing key surface and subsurface bioprocesses. High-elevation soil microfauna represent important components of cold ecosystems and dominant consumers of microbial communities. Still little is known about their diversity and distribution on the edge of their reproductive and metabolic abilities. In this study, we disentangle the impact of elevation and soil chemistry on diversity and distribution of rotifers, nematodes and tardigrades and their most frequent feeding strategies (microbial filter-feeders, bacterivores, fungivores, root-fungal feeders, omnivores) along two contrasting altitudinal gradients in Indian NW Himalaya (Zanskar transect from 3805 to 4714 m a.s.l.) and southwestern Tibet (Tso Moriri transect from 4477 to 6176 m a.s.l.), using a combination of multivariate analysis, variation partitioning and generalized additive models. Zanskar transect had higher precipitation, soil moisture, organic matter and available nutrients than dry Tso Moriri transect. In total, 40 species of nematodes, 19 rotifers and 1 tardigrade were discovered. Species richness and total abundance of rotifers and nematodes showed mid-elevation peaks in both investigated transects. The optimum for rotifers was found at higher elevation than for nematodes. Diversity and distribution of soil microfauna was best explained by soil nitrogen, phosphorus and organic matter. More fertile soils hosted more diverse and abundant faunal communities. In Tso Moriri, bacterivores represented 60% of all nematodes, fungivores 35%, root-fungal feeders 1% and omnivores 3%. For Zanskar the respective proportions were 21%, 13%, 56% and 9%. Elevational optima of different feeding strategies occurred in Zanskar in one elevation zone (4400-4500 m), while in Tso Moriri each feeding strategy had their unique optima with fungivores at 5300 m (steppes), bacterivores at 5500 m (alpine grassland), filter-feeders at 5600 m and predators and omnivores above 5700 m (subnival zone). Our results shed light on the diversity of microfauna in the high-elevation cold deserts and disentangle the role of different ecological filters in structuring microfaunal communities in the rapidly-warming Himalayas. PMID- 29131840 TI - Comparative study of the 7th and 8th AJCC editions for gastric cancer patients after curative surgery. AB - OBJECTIVES: The classification of pathological tumor-node-metastasis (pTNM) staging of gastric cancer was revised in the 8th American Joint Committee on Cancer (AJCC) edition. The major revision was the separation of pN3a and pN3b in the pTNM staging. The current study evaluated the prognostic impact of this change. METHODS: A total of 1,517 patients who underwent curative surgery for gastric cancer with a retrieved lymph node number >=15 at our institution from January 1995 to December 2011 were enrolled. Survival was compared for the disease classified according to both the 7th and 8th editions. RESULTS: After separation of pN3a and pN3b in the pTNM stage definition, the 8th edition still provides significant survival differences between each stage. The multivariate analysis demonstrated that the pTNM stage in both the 7th and 8th editions was an independent prognostic factors of overall survival and disease-free survival. The 8th edition has a better homogeneity than the 7th edition with a significantly higher likelihood ratio chi-square test. Regarding the OS and DFS, the time dependent receiver operating characteristic (ROC) curves of the two staging systems are almost overlapping, indicating that the prognostic performance is comparable between the two staging systems. CONCLUSIONS: Both the 7th and 8th edition-based stages are independent prognostic factors for gastric cancer. The 8th edition has a better homogeneity than the 7th edition; the 8th edition provides discriminant survival differences among each pTNM stage that are comparable to those in the 7th edition. PMID- 29131841 TI - Determining the effectiveness of a video-based contact intervention in improving attitudes of Penang primary care nurses towards people with mental illness. AB - BACKGROUND: Mental illness-related stigma is common, and is associated with poorer outcomes in people with mental illness. This study evaluated the attitudes of primary care nurses towards people with mental illness and its associated factors; and the effectiveness of a short video-based contact intervention (VBCI) in improving these attitudes using a Malay version of the 15-item Opening Minds Stigma Scale for Healthcare Providers (OMS-HC-15-M). METHODS: A 5-minute VBCI was developed comprising elements of psychoeducation and interviews of people with mental illness and the people they interact with, relating to experience of mental illness and recovery. A pre-post cross-sectional study was conducted on 206 randomly selected primary care nurses in Penang, Malaysia. The OMS-HC-15-M questionnaire was administered before and immediately after participants viewed the VBCI. The difference in mean pre-post VBCI scores using paired t-tests, effect size and standardised response mean (SRM) were obtained. Factors correlating to attitudes were obtained using univariate and multivariate regression analyses. RESULTS: Differences in pre-post VBCI score were statistically significant (p<0.001) with a 14% score reduction, a moderate effect size and SRM at 0.97 (0.85-0.11) and 1.1 (0.97-1.2) respectively. By factoring in the Minimal Detectable Change statistic of 7.76, the VBCI produced a significant improvement of attitudes in 30% of the participants. Factors associated with less stigmatising attitudes at baseline were previous psychiatry-related training, desiring psychiatric training, and positive contact with people with mental illness. CONCLUSIONS: This is the first study in Malaysia to show that a brief VBCI is effective in improving attitudes of primary care nurses towards people with mental illness in the immediate term. Further studies are needed to determine if these results can be sustained in the longer term and generalizable to other health care professionals. Qualitative studies are warranted to provide insight to the factors correlating to these attitudes. (300 words). PMID- 29131842 TI - Positive selection and comparative molecular evolution of reproductive proteins from New Zealand tree weta (Orthoptera, Hemideina). AB - Animal reproductive proteins, especially those in the seminal fluid, have been shown to have higher levels of divergence than non-reproductive proteins and are often evolving adaptively. Seminal fluid proteins have been implicated in the formation of reproductive barriers between diverging lineages, and hence represent interesting candidates underlying speciation. RNA-seq was used to generate the first male reproductive transcriptome for the New Zealand tree weta species Hemideina thoracica and H. crassidens. We identified 865 putative reproductive associated proteins across both species, encompassing a diverse range of functional classes. Candidate gene sequencing of nine genes across three Hemideina, and two Deinacrida species suggests that H. thoracica has the highest levels of intraspecific genetic diversity. Non-monophyly was observed in the majority of sequenced genes indicating that either gene flow may be occurring between the species, or that reciprocal monophyly at these loci has yet to be attained. Evidence for positive selection was found for one lectin-related reproductive protein, with an overall omega of 7.65 and one site in particular being under strong positive selection. This candidate gene represents the first step in the identification of proteins underlying the evolutionary basis of weta reproduction and speciation. PMID- 29131844 TI - Excessive aggregation of membrane proteins in the Martini model. AB - The coarse-grained Martini model is employed extensively to study membrane protein oligomerization. While this approach is exceptionally promising given its computational efficiency, it is alarming that a significant fraction of these studies demonstrate unrealistic protein clusters, whose formation is essentially an irreversible process. This suggests that the protein-protein interactions are exaggerated in the Martini model. If this held true, then it would limit the applicability of Martini to study multi-protein complexes, as the rapidly clustering proteins would not be able to properly sample the correct dimerization conformations. In this work we first demonstrate the excessive protein aggregation by comparing the dimerization free energies of helical transmembrane peptides obtained with the Martini model to those determined from FRET experiments. Second, we show that the predictions provided by the Martini model for the structures of transmembrane domain dimers are in poor agreement with the corresponding structures resolved using NMR. Next, we demonstrate that the first issue can be overcome by slightly scaling down the Martini protein-protein interactions in a manner, which does not interfere with the other Martini interaction parameters. By preventing excessive, irreversible, and non-selective aggregation of membrane proteins, this approach renders the consideration of lateral dynamics and protein-lipid interactions in crowded membranes by the Martini model more realistic. However, this adjusted model does not lead to an improvement in the predicted dimer structures. This implicates that the poor agreement between the Martini model and NMR structures cannot be cured by simply uniformly reducing the interactions between all protein beads. Instead, a careful amino-acid specific adjustment of the protein-protein interactions is likely required. PMID- 29131843 TI - Vertigo and dizziness in adolescents: Risk factors and their population attributable risk. AB - OBJECTIVES: To assess potential risk factors for vertigo and dizziness in adolescents and to evaluate their variability by different vertigo types. The role of possible risk factors for vertigo and dizziness in adolescents and their population relevance needs to be addressed in order to design preventive strategies. STUDY DESIGN: The study population consisted of 1482 school-children between the age of 12 and 19 years, who were instructed to fill out a questionnaire on different vertigo types and related potential risk factors. The questionnaire specifically asked for any vertigo, spinning vertigo, swaying vertigo, orthostatic dizziness, and unspecified dizziness. Further a wide range of potential risk factors were addressed including gender, stress, muscular pain in the neck and shoulder region, sleep duration, migraine, coffee and alcohol consumption, physical activity and smoking. RESULTS: Gender, stress, muscular pain in the neck and shoulder region, sleep duration and migraine were identified as independent risk factors following mutual adjustment: The relative risk was 1.17 [1.10-1.25] for female sex, 1.07 [1.02-1.13] for stress, 1.24 [1.17-1.32] for muscular pain, and 1.09 [1.03-1.14] for migraine. The population attributable risk explained by these risk factors was 26%, with muscular pain, stress, and migraine accounting for 11%, 4%, and 3% respectively. CONCLUSION: Several established risk factors in adults were also identified in adolescents. Risk factors amenable to prevention accounted for 17% of the total population risk. Therefore, interventions targeting these risk factors may be warranted. PMID- 29131845 TI - Validity and reliability of Chinese version of Adult Carer Quality of Life questionnaire (AC-QoL) in family caregivers of stroke survivors. AB - The Adult Carer Quality of Life questionnaire (AC-QoL) is a reliable and valid instrument used to assess the quality of life (QoL) of adult family caregivers. We explored the psychometric properties and tested the reliability and validity of a Chinese version of the AC-QoL with reliability and validity testing in 409 Chinese stroke caregivers. We used item-total correlation and extreme group comparison to do item analysis. To evaluate its reliability, we used a test retest reliability approach, intraclass correlation coefficient (ICC), together with Cronbach's alpha and model-based internal consistency index; to evaluate its validity, we used scale content validity, confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) via principal component analysis with varimax rotation. We found that the CFA did not in fact confirm the original factor model and our EFA yielded a 31-item measure with a five-factor model. In conclusions, although some items performed differently in our analysis of the original English language version and our Chinese language version, our translated AC-QoL is a reliable and valid tool which can be used to assess the quality of life of stroke caregivers in mainland China. Chinese version AC-QoL is a comprehensive and good measurement to understand caregivers and has the potential to be a screening tool to assess QoL of caregiver. PMID- 29131846 TI - How many species and under what names? Using DNA barcoding and GenBank data for west Central African amphibian conservation. AB - Development projects in west Central Africa are proceeding at an unprecedented rate, often with little concern for their effects on biodiversity. In an attempt to better understand potential impacts of a road development project on the anuran amphibian community, we conducted a biodiversity assessment employing multiple methodologies (visual encounter transects, auditory surveys, leaf litter plots and pitfall traps) to inventory species prior to construction of a new road within the buffer zone of Moukalaba-Doudou National Park, Gabon. Because of difficulties in morphological identification and taxonomic uncertainty of amphibian species observed in the area, we integrated a DNA barcoding analysis into the project to improve the overall quality and accuracy of the species inventory. Based on morphology alone, 48 species were recognized in the field and voucher specimens of each were collected. We used tissue samples from specimens collected at our field site, material available from amphibians collected in other parts of Gabon and the Republic of Congo to initiate a DNA barcode library for west Central African amphibians. We then compared our sequences with material in GenBank for the genera recorded at the study site to assist in identifications. The resulting COI and 16S barcode library allowed us to update the number of species documented at the study site to 28, thereby providing a more accurate assessment of diversity and distributions. We caution that because sequence data maintained in GenBank are often poorly curated by the original submitters and cannot be amended by third-parties, these data have limited utility for identification purposes. Nevertheless, the use of DNA barcoding is likely to benefit biodiversity inventories and long-term monitoring, particularly for taxa that can be difficult to identify based on morphology alone; likewise, inventory and monitoring programs can contribute invaluable data to the DNA barcode library and the taxonomy of complex groups. Our methods provide an example of how non-taxonomists and parataxonomists working in understudied parts of the world with limited geographic sampling and comparative morphological material can use DNA barcoding and publicly available sequence data (GenBank) to rapidly identify the number of species and assign tentative names to aid in urgent conservation management actions and contribute to taxonomic resolution. PMID- 29131847 TI - Evolutionary history of callose synthases in terrestrial plants with emphasis on proteins involved in male gametophyte development. AB - Callose is a plant-specific polysaccharide (beta-1,3-glucan) playing an important role in angiosperms in many developmental processes and responses to biotic and abiotic stresses. Callose is synthesised at the plasma membrane of plant cells by callose synthase (CalS) and, among others, represents the main polysaccharide in the callose wall surrounding the tetrads of developing microspores and in the growing pollen tube wall. CalS proteins involvement in spore development is a plesiomorphic feature of terrestrial plants, but very little is known about their evolutionary origin and relationships amongst the members of this protein family. We performed thorough comparative analyses of callose synthase family proteins from major plant lineages to determine their evolutionary history across the plant kingdom. A total of 1211 candidate CalS sequences were identified and compared amongst diverse taxonomic groups of plants, from bryophytes to angiosperms. Phylogenetic analyses identified six main clades of CalS proteins and suggested duplications during the evolution of specialised functions. Twelve family members had previously been identified in Arabidopsis thaliana. We focused on five CalS subfamilies directly linked to pollen function and found that proteins expressed in pollen evolved twice. CalS9/10 and CalS11/12 formed well defined clades, whereas pollen-specific CalS5 was found within subfamilies that mostly did not express in mature pollen vegetative cell, although were found in sperm cells. Expression of five out of seven mature pollen-expressed CalS genes was affected by mutations in bzip transcription factors. Only three subfamilies, CalS5, CalS10, and CalS11, however, formed monophyletic, mostly conserved clades. The pairs CalS9/CalS10, CalS11/CalS12 and CalS3 may have diverged after angiosperms diversified from lycophytes and bryophytes. Our analysis of fully sequenced plant proteins identified new evolutionary lineages of callose synthase subfamilies and has established a basis for understanding their functional evolution in terrestrial plants. PMID- 29131848 TI - High-throughput m6A-seq reveals RNA m6A methylation patterns in the chloroplast and mitochondria transcriptomes of Arabidopsis thaliana. AB - This study is the first to comprehensively characterize m6A patterns in the Arabidopsis chloroplast and mitochondria transcriptomes based on our open accessible data deposited in NCBI's Gene Expression Omnibus with GEO Series accession number of GSE72706. Over 86% of the transcripts were methylated by m6A in the two organelles. Over 550 and 350 m6A sites were mapped, with ~5.6 to ~5.8 and ~4.6 to ~4.9 m6A sites per transcript, to the chloroplast and mitochondria genome, respectively. The overall m6A methylation extent in the two organelles was greatly higher than that in the nucleus. The m6A motif sequences in the transcriptome of two organelles were similar to the nuclear motifs, suggesting that selection of the m6A motifs for RNA methylation was conserved between the nucleus and organelle transcriptomes. The m6A patterns of rRNAs and tRNAs in the organelle were similar to those in the nucleus. However, the m6A patterns in coding RNAs were distinct between the nucleus and the organelle, suggesting that that regulation of the m6A methylation patterns may be different between the nuclei and the organelles. The extensively methylated transcripts in the two organelles were mainly associated with rRNA, ribosomal proteins, photosystem reaction proteins, tRNA, NADH dehydrogenase and redox. On average, 64% and 79% of the transcripts in the two organelles showed differential m6A methylation across three organs of the leaves, flowers and roots. The m6A methylation extent in the chloroplast was higher than that in the mitochondria. This study provides deep insights into the m6A methylation topology and differentiation in the plant organelle transcriptomes. PMID- 29131849 TI - Modelling the cost-effectiveness of HIV care shows a clear benefit when transmission risk is considered in the calculations - A message for Central and Eastern Europe. AB - BACKGROUND: HIV epidemic remains a major global health issue. Data from cost effectiveness analyses base on CD4+ count and morbidity in patients with symptomatic and asymptomatic HIV infection. The approach adopted in these analyses includes many other factors, previously not investigated. Additionally, we evaluate the impact of sexual HIV transmission due to delayed cART on the cost effectiveness of care. METHODS: A lifetime Markov model (1-month cycle) was developed to estimate the cost per quality adjusted life years (QALY) for a 1- and 3-year delay in starting cART (as compared to starting immediately at linkage to care) lifetime costs, clinical outcomes and cost-effectiveness. Patients were categorized into having asymptomatic HIV, AIDS, Hodgkin's Lymphoma, and non-AIDS defining condition. Mortality rates and utility values were obtained from published literature. The number of new infected persons was estimated on the basis of sexual orientation, the number of sexual partners per year, the number of sex acts per month, frequency of condom use and use of cART. For the input Test and Keep in Care (TAK) project cohort data were used. Costs of care, cART and potential life-years lost were based on estimated total costs and the difference in expected QALY gained between an HIV-positive and an average person in Polish population. Costs were based on real expenditures of the Ministry of Health, National Health Fund, available studies and experts' opinion. Costs and effects were discounted at rates of 5% and 3.5%, respectively. RESULTS: Input data were available for 141 patients form TAK cohort. The estimated number of new HIV infections in low, medium and high risk transmission groups were 0.28, 0.61, 2.07 with 1 and 0.82, 1.80, 6.11 with a 3-year delay, respectively. This reflected QALY loss due to cART delay of 0.52, 1.13, 3.84 and 2.02, 4.43, 15.03 for a 1- and 3-year delay, respectively. If additional costs of treatment and potential life-years lost due to new HIV infections were not taken into account, initiating cART immediately at linkage to care was not cost-saving irrespective of cART delay. Otherwise, when additional costs and QALY lost due to new HIV infections were included, immediate cART initiation was cost-saving regardless of the chosen scenarios. CONCLUSIONS: If new HIV infections are not taken into account, then starting cART immediately does not dominate comparing to delaying cART. When taking into account HIV transmission in cost-effectiveness analysis, immediate initiation of HIV treatment is a profitable decision from the public payer's perspective. PMID- 29131850 TI - Extension of biomass estimates to pre-assessment periods using density dependent surplus production approach. AB - Biomass reconstructions to pre-assessment periods for commercially important and exploitable fish species are important tools for understanding long-term processes and fluctuation on stock and ecosystem level. For some stocks only fisheries statistics and fishery dependent data are available, for periods before surveys were conducted. The methods for the backward extension of the analytical assessment of biomass for years for which only total catch volumes are available were developed and tested in this paper. Two of the approaches developed apply the concept of the surplus production rate (SPR), which is shown to be stock density dependent if stock dynamics is governed by classical stock-production models. The other approach used a modified form of the Schaefer production model that allows for backward biomass estimation. The performance of the methods was tested on the Arctic cod and North Sea herring stocks, for which analytical biomass estimates extend back to the late 1940s. Next, the methods were applied to extend biomass estimates of the North-east Atlantic mackerel from the 1970s (analytical biomass estimates available) to the 1950s, for which only total catch volumes were available. For comparison with other methods which employs a constant SPR estimated as an average of the observed values, was also applied. The analyses showed that the performance of the methods is stock and data specific; the methods that work well for one stock may fail for the others. The constant SPR method is not recommended in those cases when the SPR is relatively high and the catch volumes in the reconstructed period are low. PMID- 29131851 TI - GDSL lipases modulate immunity through lipid homeostasis in rice. AB - Lipids and lipid metabolites play important roles in plant-microbe interactions. Despite the extensive studies of lipases in lipid homeostasis and seed oil biosynthesis, the involvement of lipases in plant immunity remains largely unknown. In particular, GDSL esterases/lipases, characterized by the conserved GDSL motif, are a subfamily of lipolytic enzymes with broad substrate specificity. Here, we functionally identified two GDSL lipases, OsGLIP1 and OsGLIP2, in rice immune responses. Expression of OsGLIP1 and OsGLIP2 was suppressed by pathogen infection and salicylic acid (SA) treatment. OsGLIP1 was mainly expressed in leaf and leaf sheath, while OsGLIP2 showed high expression in elongating internodes. Biochemical assay demonstrated that OsGLIP1 and OsGLIP2 are functional lipases that could hydrolyze lipid substrates. Simultaneous down regulation of OsGLIP1 and OsGLIP2 increased plant resistance to both bacterial and fungal pathogens, whereas disease resistance in OsGLIP1 and OsGLIP2 overexpression plants was significantly compromised, suggesting that both genes act as negative regulators of disease resistance. OsGLIP1 and OsGLIP2 proteins mainly localize to lipid droplets and the endoplasmic reticulum (ER) membrane. The proper cellular localization of OsGLIP proteins is indispensable for their functions in immunity. Comprehensive lipid profiling analysis indicated that the alteration of OsGLIP gene expression was associated with substantial changes of the levels of lipid species including monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG). We show that MGDG and DGDG feeding could attenuate disease resistance. Taken together, our study indicates that OsGLIP1 and OsGLIP2 negatively regulate rice defense by modulating lipid metabolism, thus providing new insights into the function of lipids in plant immunity. PMID- 29131852 TI - Unraveling the key to the resistance of canids to prion diseases. AB - One of the characteristics of prions is their ability to infect some species but not others and prion resistant species have been of special interest because of their potential in deciphering the determinants for susceptibility. Previously, we developed different in vitro and in vivo models to assess the susceptibility of species that were erroneously considered resistant to prion infection, such as members of the Leporidae and Equidae families. Here we undertake in vitro and in vivo approaches to understand the unresolved low prion susceptibility of canids. Studies based on the amino acid sequence of the canine prion protein (PrP), together with a structural analysis in silico, identified unique key amino acids whose characteristics could orchestrate its high resistance to prion disease. Cell- and brain-based PMCA studies were performed highlighting the relevance of the D163 amino acid in proneness to protein misfolding. This was also investigated by the generation of a novel transgenic mouse model carrying this substitution and these mice showed complete resistance to disease despite intracerebral challenge with three different mouse prion strains (RML, 22L and 301C) known to cause disease in wild-type mice. These findings suggest that dog D163 amino acid is primarily, if not totally, responsible for the prion resistance of canids. PMID- 29131853 TI - Transcriptome analysis of Crossostephium chinensis provides insight into the molecular basis of salinity stress responses. AB - Soil salinization is becoming a limitation to the utilization of ornamental plants worldwide. Crossostephium chinensis (Linnaeus) Makino is often cultivated along the southeast coast of China for its desirable ornamental qualities and high salt tolerance. However, little is known about the genomic background of the salt tolerance mechanism in C. chinensis. In the present study, we used Illumina paired-end sequencing to systematically investigate leaf transcriptomes derived from C. chinensis seedlings grown under normal conditions and under salt stress. A total of 105,473,004 bp of reads were assembled into 163,046 unigenes, of which 65,839 (40.38% of the total) and 54,342 (33.32% of the total) were aligned in Swiss-Prot and Nr protein, respectively. A total of 11,331 (6.95%) differentially expressed genes (DEGs) were identified among three comparisons, including 2,239 in 'ST3 vs ST0', 5,880 in 'ST9 vs ST3' and 9,718 in 'ST9 vs ST0', and they were generally classified into 26 Gene Ontology terms and 58 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway terms. Many genes encoding important transcription factors (e.g., WRKY, MYB, and AP2/EREBP) and proteins involved in starch and sucrose metabolism, arginine and proline metabolism, plant hormone signal transduction, amino acid biosynthesis, plant-pathogen interactions and carbohydrate metabolism, among others, were substantially up-regulated under salt stress. These genes represent important candidates for studying the salt-response mechanism and molecular biology of C. chinensis and its relatives. Our findings provide a genomic sequence resource for functional genetic assignments in C. chinensis. These transcriptome datasets will help elucidate the molecular mechanisms responsible for salt-stress tolerance in C. chinensis and facilitate the breeding of new stress-tolerant cultivars for high-saline areas using this valuable genetic resource. PMID- 29131854 TI - Pre-harvest sprouting resistance and haplotype variation of ThVp-1 gene in the collection of wheat-wheatgrass hybrids. AB - The germplasm collection of 87 wheat-wheatgrass hybrids developed in Tsitisin Main Botanical Garden (Russia, Moscow) was evaluated for resistance to pre harvest sprouting (PHS) by spike sprouting (SS) and germination index (GI) assays as well as for spike and grain features. The PHS resistance variation and haplotype polymorphism of the wheatgrass ThVp-1 and wheat TaVp-1B genes orthologues of Vp-1 was revealed in the studied collection. Four haplotypes of ThVp-1 were revealed: ThVp-1a (41% of the entries), ThVp-1b (13%), ThVp-1c (29%), and ThVp-1d (15%). The association between the allelic state of ThVp-1 and PHS resistance in the wheat-wheatgrass hybrids was shown: haplotype ThVp-1d of the wheatgrass Vp-1 gene is significantly associated with reduced PHS in the wheat wheatgrass hybrids (mean SS 0.33, mean GI 0.64). The resistant entries may be perspective as a source of PHS resistance in the development of commercial cultivars of perennial wheat. PMID- 29131855 TI - Phytyl fatty acid esters in vegetables pose a risk for patients suffering from Refsum's disease. AB - Patients suffering from Refsum's disease show mutations in the enzyme necessary for the degradation of phytanic acid. Accumulation of this tetramethyl-branched fatty acid in inner organs leads to severe neurological and cardiac dysfunctions which can even result in death. Thus, patients with Refsum's disease have to follow a specific diet resigning foods with high levels of phytanic acid and trans-phytol like products from ruminant animals with a tolerable daily intake (TDI) of <= 10 mg/d. We recently reported the occurrence of phytyl fatty acid esters (PFAE, trans-phytol esterified with a fatty acid) in bell pepper with trans-phytol amounts of up to 5.4 mg/100 g fresh weight (FW). In this study we carried out in vitro-digestion experiments of PFAE with artificial digestion fluids. Our results demonstrate that PFAE actually are a source for bioavailable trans-phytol and thus add to the TDI. Eating only one portion of bell pepper (~150 g) could therefore lead to exploitation of the TDI of up to 81%. Analysis of additional vegetable matrices showed that also rocket salad with up to 4.2 mg/100 g FW trans-phytol bound in PFAE represents a risk-relevant food for patients with Refsum's disease and should therefore be taken into account. PMID- 29131856 TI - Examination of Sarcocystis spp. of giant snakes from Australia and Southeast Asia confirms presence of a known pathogen - Sarcocystis nesbitti. AB - We examined Sarcocystis spp. in giant snakes from the Indo-Australian Archipelago and Australia using a combination of morphological (size of sporocyst) and molecular analyses. We amplified by PCR nuclear 18S rDNA from single sporocysts in order to detect mixed infections and unequivocally assign the retrieved sequences to the corresponding parasite stage. Sarcocystis infection was generally high across the study area, with 78 (68%) of 115 examined pythons being infected by one or more Sarcocystis spp. Among 18 randomly chosen, sporocyst positive samples (11 from Southeast Asia, 7 from Northern Australia) the only Sarcocystis species detected in Southeast Asian snakes was S. singaporensis (in reticulated pythons), which was absent from all Australian samples. We distinguished three different Sarcocystis spp. in the Australian sample set; two were excreted by scrub pythons and one by the spotted python. The sequence of the latter is an undescribed species phylogenetically related to S. lacertae. Of the two Sarcocystis species found in scrub pythons, one showed an 18S rRNA gene sequence similar to S. zamani, which is described from Australia for the first time. The second sequence was identical/similar to that of S. nesbitti, a known human pathogen that was held responsible for outbreaks of disease among tourists in Malaysia. The potential presence of S. nesbitti in Australia challenges the current hypothesis of a snake-primate life cycle, and would have implications for human health in the region. Further molecular and biological characterizations are required to confirm species identity and determine whether or not the Australian isolate has the same zoonotic potential as its Malaysian counterpart. Finally, the absence of S. nesbitti in samples from reticulated pythons (which were reported to be definitive hosts), coupled with our phylogenetic analyses, suggest that alternative snake hosts may be responsible for transmitting this parasite in Malaysia. PMID- 29131857 TI - Internal tissue references for 18Fluorodeoxyglucose vascular inflammation imaging: Implications for cardiovascular risk stratification and clinical trials. AB - INTRODUCTION: 18Fluorodeoxyglucose (FDG) positron emission tomography (PET) uptake in the artery wall correlates with active inflammation. However, in part due to the low spatial resolution of PET, variation in the apparent arterial wall signal may be influenced by variation in blood FDG activity that cannot be fully corrected for using typical normalization strategies. The purpose of this study was to evaluate the ability of the current common methods to normalize for blood activity and to investigate alternative methods for more accurate quantification of vascular inflammation. MATERIALS AND METHODS: The relationship between maximum FDG aorta wall activity and mean blood activity was evaluated in 37 prospectively enrolled subjects aged 55 years or more, treated for hyperlipidemia. Target maximum aorta standardized uptake value (SUV) and mean background reference tissue activity (blood, spleen, liver) were recorded. Target-to-background ratios (TBR) and arterial maximum activity minus blood activity were calculated. Multivariable regression was conducted, predicting uptake values based on variation in background reference and target tissue FDG uptake; adjusting for gender, age, lean body mass (LBM), blood glucose, blood pool activity, and glomerular filtration rate (GFR), where appropriate. RESULTS: Blood pool activity was positively associated with maximum artery wall SUV (beta = 5.61, P<0.0001) as well as mean liver (beta = 6.23, P<0.0001) and spleen SUV (beta = 5.20, P<0.0001). Artery wall activity divided by blood activity (TBRBlood) or subtraction of blood activity did not remove the statistically significant relationship to blood activity. Blood pool activity was not related to TBRliver and TBRspleen (beta = -0.36, P = NS and beta = -0.58, P = NS, respectively). CONCLUSIONS: In otherwise healthy individuals treated for hyperlipidemia, blood FDG activity is associated with artery wall activity. However, variation in blood activity may mask artery wall signal reflective of inflammation, which requires normalization. Blood-based TBR and subtraction do not sufficiently adjust for blood activity. Warranting further investigation, background reference tissues with cellular uptake such as the liver and spleen may better adjust for variation in blood activity to improve assessment of vascular activity. PMID- 29131858 TI - The composition and initial evaluation of a grimace scale in ferrets after surgical implantation of a telemetry probe. AB - Reliable recognition of pain is difficult in ferrets as many currently available parameters are non-specific, inconsistent and/or impractical. Grimace scales have successfully been applied to assess pain in different animal species and might also be applicable to ferrets. To compose a Ferret Grimace Scale (FGS), we studied the facial musculature of ferrets and compared lateral photographs of 19 ferret faces at six time points before and after intraperitoneal telemetry probe implantation. We identified the Action Units (AUs) orbital tightening, nose bulging, cheek bulging, ear changes and whisker retraction as potential indicators of pain in ferrets. To evaluate whether these AUs could reliably be used to identify photographs taken before and after surgery, the photographs were scored 0, 1 or 2 (not, moderately or obviously present) by 11 observers that were blinded to the treatment and timing of the photographs. All AU-scores assigned to the photographs taken five hours after surgery were significantly higher compared to their time-matched baseline scores. Further analysis using the weights that were obtained using a Linear Discriminant Analysis revealed that scoring orbital tightening alone was sufficient to make this distinction with high sensitivity, specificity and accuracy. Including weighted scores for nose bulging, cheek bulging and ear change did not change this. As these AUs had more missing values than orbital tightening, their descriptions should be re-evaluated. Including whisker retraction, which had a negative weight, resulted in lower accuracy and should therefore in its current form be left out of the FGS. Overall, the results of this study suggest that the FGS and the AU orbital tightening in particular could be useful in a multifactorial pain assessment protocol for ferrets. However, before applying the FGS in practice, it should be further validated by incorporating more time points before and after applying (different) painful stimuli, and different levels of analgesia. PMID- 29131859 TI - Development and validation of an immunoperoxidase antigen detection test for improved diagnosis of rabies in Indonesia. AB - Rabies continues to pose a significant threat to human and animal health in regions of Indonesia. Indonesia has an extensive network of veterinary diagnostic laboratories and the 8 National laboratories are equipped to undertake diagnostic testing for rabies using the commercially-procured direct fluorescent antibody test (FAT), which is considered the reference (gold standard) test. However, many of the Indonesian Provincial diagnostic laboratories do not have a fluorescence microscope required to undertake the FAT. Instead, certain Provincial laboratories continue to screen samples using a chemical stain-based test (Seller's stain test, SST). This test has low diagnostic sensitivity, with negative SST-tested samples being forwarded to the nearest National laboratory resulting in significant delays for completion of testing and considerable additional costs. This study sought to develop a cost-effective and diagnostically-accurate immunoperoxidase antigen detection (RIAD) test for rabies that can be readily and quickly performed by the resource-constrained Provincial laboratories. This would reduce the burden on the National laboratories and allow more rapid diagnoses and implementation of post-exposure prophylaxis. The RIAD test was evaluated using brain smears fixed with acetone or formalin and its performance was validated by comparison with established rabies diagnostic tests used in Indonesia, including the SST and FAT. A proficiency testing panel was distributed between Provincial laboratories to assess the reproducibility of the test. The performance of the RIAD test was improved by using acetone fixation of brain smears rather than formalin fixation such that it was of equivalent accuracy to that of the World Organisation for Animal Health (OIE)-recommended FAT, with both tests returning median diagnostic sensitivity and specificity values of 0.989 and 0.993, respectively. The RIAD test and FAT had higher diagnostic sensitivity than the SST (median = 0.562). Proficiency testing using a panel of 6 coded samples distributed to 16 laboratories showed that the RIAD test had good reproducibility with an overall agreement of 97%. This study describes the successful development, characterisation and use of a novel RIAD test and its fitness for purpose as a screening test for use in provincial Indonesian veterinary laboratories. PMID- 29131860 TI - Does proximity of women to facilities with better choice of contraceptives affect their contraceptive utilization in rural Ethiopia? AB - BACKGROUND: There is limited evidence of the linkage between contraceptive use, the range of methods available and level of contraceptive stocks at health facilities and distance to facility in developing countries. The present analysis aims at examining the influence of contraceptive method availability and distance to the nearby facilities on modern contraceptive utilization among married women in rural areas in Ethiopia using geo-referenced data. METHODS: We used data from the first round of surveys of the Performance Monitoring & Accountability 2020 project in Ethiopia (PMA2020/Ethiopia-2014). The survey was conducted in a sample of 200 enumeration areas (EAs) where for each EA, 35 households and up to 3 public or private health service delivery points (SDPs) were selected. The main outcome variable was individual use of a contraceptive method for married women in rural Ethiopia. Correlates of interest include distance to nearby health facilities, range of contraceptives available in facilities, household wealth index, and the woman's educational status, age, and parity and whether she recently visited a health facility. This analysis primarily focuses on stock provision at public SDPs. RESULTS: Overall complete information was collected from 1763 married rural women ages 15-49 years and 198 SDPs in rural areas (97.1% public). Most rural women (93.9%) live within 5 kilometers of their nearest health post while a much lower proportion (52.2%) live within the same distance to the nearest health centers and hospital (0.8%), respectively. The main sources of modern contraceptive methods for married rural women were health posts (48.8%) and health centers (39.0%). The mean number of the types of contraceptive methods offered by hospitals, health centers and health posts was 6.2, 5.4 and 3.7 respectively. Modern contraceptive use (mCPR) among rural married women was 27.3% (95% CI: 25.3, 29.5). The percentage of rural married women who use modern contraceptives decreased as distance from the nearest SDP increased; 41.2%, 27.5%, 22.0%, and 22.6% of women living less than 2 kilometers, 2 to 3.9kilometers, 4 to 5.9 kilometers and 6 or more kilometers, respectively (p value<0.01). Additionally, women who live close to facilities that offer a wider range of contraceptive methods were significantly more likely to use modern contraceptives. The mCPR ranged from 42.3% among women who live within 2 kilometers of facilities offering 3 or more methods to 22.5% among women living more than 6 kilometers away from the nearest facility with the same number (3 or more methods) available after adjusting for observed covariates. CONCLUSIONS: Although the majority of the Ethiopian population lives within a relatively close distance to lower level facilities (health posts), the number and range of methods available (method choice) and proximity are independently associated with contraceptive utilization. By demonstrating the extent to which objective measures of distance (of relatively small magnitude) explain variation in contraceptive use among rural women, the study fills an important planning gap for family planning programs operating in resource limited settings. PMID- 29131861 TI - Delivery of epirubicin via slow infusion as a strategy to mitigate chemotherapy induced cardiotoxicity. AB - BACKGROUND: Continuous infusion of doxorubicin has been a strategy to reduce cardiotoxicity. Epirubicin is another anthracycline in common clinical use. However, evidence is lacking regarding whether this strategy can reduce cardiotoxicity of epirubicin without compromising antineoplastic efficacy. DESIGN AND METHODS: Healthy rats were randomized into groups: epirubicin (8 mg/kg) delivered intraperitoneally via micro osmotic pumps (MOP), epirubicin (8 mg/kg) by intraperitoneal (IP) bolus injection, and placebo control. Blood samples were collected for analyzing biomarkers of myocardial injury and pharmacokinetics. At chosen times, sub-groups of animals were sacrificed for histopathology. A mouse breast cancer cell line (4T1), stably transfected with luciferase, was orthotopically allografted in female mice, and treated in three groups as described above for the rats. Tumor growth was monitored by measuring tumor size as well as bioluminescence. RESULTS: Delivery by IP bolus and by MOP achieved essentially the same area under the curve of epirubicin plasma concentration time profile. Blood biomarkers showed that the degree of myocardial injury in MOP group was lower than that of IP group. Histopathology showed that there was less eosinophilic enhancement, interstitial hemorrhage and necrotizing muscle atrophy in MOP group than IP group. In the orthotopic breast cancer allograft mouse model, the antineoplastic effect of epirubicin by MOP was not different from that by IP as measured by tumor weights or by in vivo bioluminescence. CONCLUSION: Slow delivery of epirubicin by MOP reduced cardiotoxicity without compromising the antineoplastic effect compared to IP bolus delivery. These in vivo data support our previous clinical data that continuous intravenous infusion of epirubicin using micro infusion pumps over 48-96 hours had less cardiotoxicity than intravenous bolus injections. However, whether multiple doses of epirubicin given by MOP result in a lower magnitude of long term cardiomyopathy remains to be further investigated. PMID- 29131862 TI - Optimized approach for the identification of highly efficient correctors of nonsense mutations in human diseases. AB - About 10% of patients with a genetic disease carry a nonsense mutation causing their pathology. A strategy for correcting nonsense mutations is premature termination codon (PTC) readthrough, i.e. incorporation of an amino acid at the PTC position during translation. PTC-readthrough-activating molecules appear as promising therapeutic tools for these patients. Unfortunately, the molecules shown to induce PTC readthrough show low efficacy, probably because the mRNAs carrying a nonsense mutation are scarce, as they are also substrates of the quality control mechanism called nonsense-mediated mRNA decay (NMD). The screening systems previously developed to identify readthrough-promoting molecules used cDNA constructs encoding mRNAs immune to NMD. As the molecules identified were not selected for the ability to correct nonsense mutations on NMD prone PTC-mRNAs, they could be unsuitable for the context of nonsense-mutation linked human pathologies. Here, a screening system based on an NMD-prone mRNA is described. It should be suitable for identifying molecules capable of efficiently rescuing the expression of human genes harboring a nonsense mutation. This system should favor the discovery of candidate drugs for treating genetic diseases caused by nonsense mutations. One hit selected with this screening system is presented and validated on cells from three cystic fibrosis patients. PMID- 29131863 TI - Long-term retinal cone rescue using a capsid mutant AAV8 vector in a mouse model of CNGA3-achromatopsia. AB - Adeno-associated virus (AAV) vectors are important gene delivery tools for the treatment of many recessively inherited retinal diseases. For example, a wild type (WT) AAV5 vector can deliver a full-length Cnga3 (cyclic nucleotide-gated channel alpha-3) cDNA to target cells of the cone photoreceptor function loss 5 (cpfl5) mouse, a spontaneous animal model of achromatopsia with a Cnga3 mutation. Gene therapy restores cone-mediated function and blocks cone degeneration in the mice. However, since transgene expression delivered by an AAV vector shows relatively short-term effectiveness, this cannot be regarded as a very successful therapy. AAV2 and AAV8 vectors with capsid mutations have significantly enhanced transduction efficiency in retinas compared to WT AAV controls. In this study, AAV8 (Y447, 733F+T494V)-treated cpfl5 retinas showed greater preservation of short-term cone electroretinogram (ERG) responses than AAV8 (Y447, 733F)- or AAV2 (Y272, 444, 500, 730F+T491V)-mediated treatments. To explore the long-term rescue effect, AAV8 (Y447, 733F+T494V)-treated cpfl5 retinas were evaluated at 9 months following postnatal day 14 (P14) treatment. Rescued ERG responses in the cones of treated cpfl5 eyes decreased with increasing age, but still maintained more than 60% of the WT mouse responses at the oldest time point examined. Expression of CNGA3 and M/S-opsins was maintained in cone outer segments of the treated cpfl5 eyes and was equal to expression in age-matched WT retinas. Near-normal cone mediated water maze behavior was observed in the treated cpfl5 mice. As these are the longest follow-up data reported thus far, AAV8 with capsid Y-F and T-V mutations may be one of the most effective AAV vectors for long-term treatment in a naturally occurring mouse model of CNGA3 achromatopsia. PMID- 29131864 TI - Comparison of histone-like HU protein DNA-binding properties and HU/IHF protein sequence alignment. AB - BACKGROUND: The structure and function of bacterial nucleoid are controlled by histone-like proteins of HU/IHF family, omnipresent in bacteria and also founding archaea and some eukaryotes.HU protein binds dsDNA without sequence specificity and avidly binds DNA structures with propensity to be inclined such as forks, three/four-way junctions, nicks, overhangs and DNA bulges. Sequence comparison of thousands of known histone-like proteins from diverse bacteria phyla reveals relation between HU/IHF sequence, DNA-binding properties and other protein features. METHODOLOGY AND PRINCIPAL FINDINGS: Performed alignment and clusterization of the protein sequences show that HU/IHF family proteins can be unambiguously divided into three groups, HU proteins, IHF_A and IHF_B proteins. HU proteins, IHF_A and IHF_B proteins are further partitioned into several clades for IHF and HU; such a subdivision is in good agreement with bacterial taxonomy. We also analyzed a hundred of 3D fold comparative models built for HU sequences from all revealed HU clades. It appears that HU fold remains similar in spite of the HU sequence variations. We studied DNA-binding properties of HU from N. gonorrhoeae, which sequence is similar to one of E.coli HU, and HU from M. gallisepticum and S. melliferum which sequences are distant from E.coli protein. We found that in respect to dsDNA binding, only S. melliferum HU essentially differs from E.coli HU. In respect to binding of distorted DNA structures, S. melliferum HU and E.coli HU have similar properties but essentially different from M. gallisepticum HU and N. gonorrhea HU. We found that in respect to dsDNA binding, only S. melliferum HU binds DNA in non-cooperative manner and both mycoplasma HU bend dsDNA stronger than E.coli and N. gonorrhoeae. In respect to binding to distorted DNA structures, each HU protein has its individual profile of affinities to various DNA-structures with the increased specificity to DNA junction. CONCLUSIONS AND SIGNIFICANCE: HU/IHF family proteins sequence alignment and classification are updated. Comparative modeling demonstrates that HU protein 3D folding's even more conservative than HU sequence. For the first time, DNA binding characteristics of HU from N. gonorrhoeae, M. gallisepticum and S. melliferum are studied. Here we provide detailed analysis of the similarity and variability of DNA-recognizing and bending of four HU proteins from closely and distantly related HU clades. PMID- 29131865 TI - Associations between RET tagSNPs and their haplotypes and susceptibility, clinical severity, and thyroid function in patients with differentiated thyroid cancer. AB - BACKGROUND: It is unclear whether common genetic variants of the RET proto oncogene contribute to disease susceptibility, clinical severity, and thyroid function in differentiated thyroid cancer (DTC). METHODS: A total of 300 DTC patients and 252 healthy controls were enrolled in this study. Seven RET tagging single nucleotide polymorphisms were genotyped using the KASPar platform. RESULTS: Subgroup analysis showed that concomitant thyroid benign diseases were less likely to occur in DTC subjects with the rs1799939 AG or AG plus AA genotypes (odds ratio (OR) = 1.93 and 1.88, P = 0.009 and 0.011, respectively). A rare haplotype, CGGATAA, was associated statistically with a reduced risk of DTC (OR = 0.18, P = 0.001). Concerning the aggressive features of DTC, higher level of N stage was more likely to occur in subjects carrying the wild-type genotypes at rs1800860 site (for dominant model: OR = 0.48, P = 0.008). Another rare haplotype, CAAGCGT, conferred increased risk for the occurrence of distant metastasis (OR = 7.57, P = 0.009). Notably, higher thyroid stimulating hormone levels and lower parathyroid hormone levels were found in patients with rs2075912, rs2565200, and rs2742240 heterozygotes and rare homozygotes; similar results were observed between PTH levels and rs1800858. CONCLUSION: This study provided useful information on RET variants that should be subjected to further study. PMID- 29131866 TI - Association between mental health status and bone mineral density: Analysis of the 2008-2010 Korea national health and nutrition examination survey. AB - The current study aimed to investigate the association between mental health status and bone mineral density (BMD) using data from the Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2010. We enrolled 15,876 South Korean participants (4,010 postmenopausal females, 4,836 premenopausal females, and 7,016 males, all aged 20 years or older). BMD was measured using dual-energy radiography absorptiometry at the femoral neck (NK), lumbar spine (LSP), and total femur (TFM). Mental health status data were obtained from a self-report questionnaire that assessed psychological stress, depressed mood, and suicidal ideation. Psychological stress was negatively correlated with BMD in the LSP, NK, and TFM for the male group. Depressed mood was associated with lower BMD in the LSP, NK and TFM for the premenopausal female group, and in the LSP for the male group. Suicidal ideation was associated with lower BMD in the NK and TFM for the male group. Mental health problems were associated with lower BMD, especially in premenopausal females and males. Future investigations should focus on the shared pathophysiology between mental health problems and BMD, and the interrelationship between increased BMD and recovery from mental health problems. PMID- 29131868 TI - Design of the smart home system based on the optimal routing algorithm and ZigBee network. AB - To improve the traditional smart home system, its electric wiring, networking technology, information transmission and facility control are studied. In this paper, we study the electric wiring, networking technology, information transmission and facility control to improve the traditional smart home system. First, ZigBee is used to replace the traditional electric wiring. Second, a network is built to connect lots of wireless sensors and facilities, thanks to the capability of ZigBee self-organized network and Genetic Algorithm-Particle Swarm Optimization Algorithm (GA-PSOA) to search for the optimal route. Finally, when the smart home system is connected to the internet based on the remote server technology, home environment and facilities could be remote real-time controlled. The experiments show that the GA-PSOA reduce the system delay and decrease the energy consumption of the wireless system. PMID- 29131867 TI - Differential transcriptome analysis reveals genes related to cold tolerance in seabuckthorn carpenter moth, Eogystia hippophaecolus. AB - Seabuckthorn carpenter moth, Eogystia hippophaecolus (Lepidoptera: Cossidae), is an important pest of sea buckthorn (Hippophae rhamnoides), which is a shrub that has significant ecological and economic value in China. E. hippophaecolus is highly cold tolerant, but limited studies have been conducted to elucidate the molecular mechanisms underlying its cold resistance. Here we sequenced the E. hippophaecolus transcriptome using RNA-Seq technology and performed de novo assembly from the short paired-end reads. We investigated the larval response to cold stress by comparing gene expression profiles between treatments. We obtained 118,034 unigenes, of which 22,161 were annotated with gene descriptions, conserved domains, gene ontology terms, and metabolic pathways. These resulted in 57 GO terms and 193 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. By comparing transcriptome profiles for differential gene expression, we identified many differentially expressed proteins and genes, including heat shock proteins and cuticular proteins which have previously been reported to be involved in cold resistance of insects. This study provides a global transcriptome analysis and an assessment of differential gene expression in E. hippophaecolus under cold stress. We found seven differential expressed genes in common between developmental stages, which were verified with qPCR. Our findings facilitate future genomic studies aimed at improving our understanding of the molecular mechanisms underlying the response of insects to low temperatures. PMID- 29131870 TI - "Low platelet usage" haematology laboratories: To store or not to store? AB - In the UK, hospitals with annual platelet use of less than 500 pools, like our institution, usually do not store platelets on-site and these are only ordered from the national blood service (NBS) when a transfusion is required. In 2016, we piloted routine on-site storage of one pool of A RhD negative PLT. Data were collected retrospectively on units of PLTs ordered from NBS, units transfused to patients, wastage, requirements for emergency deliveries from NBS and overall cost. These were compared to corresponding data from the four preceding years (2012-2015). There was a 39% reduction in the PLT ordered from NBS in 2016 compared to previous years and a 50% reduction in transfused PLT. Annual wastage for 2016 increased by 23% even though the absolute number of wasted PLT did not alter significantly. Annual cost reduced by 36% in 2016 resulting from reduction in the total amount of PLTs ordered as well as reduction in emergency deliveries. PMID- 29131869 TI - Assessing current temporal and space-time anomalies of disease incidence. AB - Approaches used to early and accurately characterize epidemiologic patterns of disease incidence in a temporal and spatial series are becoming increasingly important. Cluster tests are generally designed for retrospective detection of epidemiologic anomalies in a temporal or space-time series. Timely identification of anomalies of disease or poisoning incidence during ongoing surveillance or an outbreak requires the use of sensitive statistical methods that recognize an incidence pattern at the time of occurrence. This report describes 2 novel analytical methods that focus on detecting anomalies of incidence at the time of occurrence in a temporal and space-time series. The first method describes the paucity of incidence at the time of occurrence in an ongoing surveillance and is designed to evaluate whether a decline in incidence occurs on the single current day or during the most recent few days. The second method provides an overall assessment of current clustering or paucity of incidence in a space-time series, allowing for several space regions. We illustrate the application of these methods using a subsample of a temporal series of data on the largest dengue outbreak in Taiwan in 2015 since World War II and demonstrate that they are useful to efficiently monitor incoming data for current clustering and paucity of incidence in a temporal and space-time series. In light of the recent global emergence and resurgence of Zika, dengue, and chikungunya infection, these approaching for detecting current anomalies of incidence in the ongoing surveillance of disease are particularly desired and needed. PMID- 29131871 TI - Associations between facial emotion recognition and young adolescents' behaviors in bullying. AB - This study investigated whether different behaviors young adolescents can act during bullying episodes were associated with their ability to recognize morphed facial expressions of the six basic emotions, expressed at high and low intensity. The sample included 117 middle-school students (45.3% girls; mean age = 12.4 years) who filled in a peer nomination questionnaire and individually performed a computerized emotion recognition task. Bayesian generalized mixed effects models showed a complex picture, in which type and intensity of emotions, students' behavior and gender interacted in explaining recognition accuracy. Results were discussed with a particular focus on negative emotions and suggesting a "neutral" nature of emotion recognition ability, which does not necessarily lead to moral behavior but can also be used for pursuing immoral goals. PMID- 29131873 TI - Longitudinal trajectories of mental health in Australian children aged 4-5 to 14 15 years. AB - Mental health can affect young people's sense of wellbeing and life satisfaction, their ability to participate in employment and education, and their onward opportunities in life. This paper offers a rare opportunity to longitudinally examine mental health in a population-representative study of children aged 4-5 years to 14-15 years. Using data from the Longitudinal Study of Australian Children (LSAC), this study examined maternally-reported child mental health over a 10 year period, in order to understand their initial mental health status early in life and its change over time, as measured by the Strengths and Difficulties Questionnaire. Longitudinal models were fitted from ages 4-5 to 14-15 years. Results showed that child sex, maternal mental health, socio-economic status (family income, maternal education, neighbourhood disadvantage), maternal hostility, and child temperament (persistence, sociability, reactivity) are all independent contributors to child mental health at age 4. These effects largely persist over time, with the effects of maternal mental health increasing slightly over time. Persistence of these effects suggests the need for early intervention and supports. The independent contribution of these factors to child mental health suggests that multi-faceted approaches to child and maternal mental health are needed. PMID- 29131872 TI - Genetic diversity of pneumococcal surface protein A in invasive pneumococcal isolates from Korean children, 1991-2016. AB - Pneumococcal surface protein A (PspA) is an important virulence factor of pneumococci and has been investigated as a primary component of a capsular serotype-independent pneumococcal vaccine. Thus, we sought to determine the genetic diversity of PspA to explore its potential as a vaccine candidate. Among the 190 invasive pneumococcal isolates collected from Korean children between 1991 and 2016, two (1.1%) isolates were found to have no pspA by multiple polymerase chain reactions. The full length pspA genes from 185 pneumococcal isolates were sequenced. The length of pspA varied, ranging from 1,719 to 2,301 base pairs with 55.7-100% nucleotide identity. Based on the sequences of the clade-defining regions, 68.7% and 49.7% were in PspA family 2 and clade 3/family 2, respectively. PspA clade types were correlated with genotypes using multilocus sequence typing and divided into several subclades based on diversity analysis of the N-terminal alpha-helical regions, which showed nucleotide sequence identities of 45.7-100% and amino acid sequence identities of 23.1-100%. Putative antigenicity plots were also diverse among individual clades and subclades. The differences in antigenicity patterns were concentrated within the N-terminal 120 amino acids. In conclusion, the N-terminal alpha-helical domain, which is known to be the major immunogenic portion of PspA, is genetically variable and should be further evaluated for antigenic differences and cross-reactivity between various PspA types from pneumococcal isolates. PMID- 29131874 TI - Association Between Inhaled Corticosteroid Use and Bone Fracture in Children With Asthma. AB - Importance: Daily use of inhaled corticosteroids is a widely recommended treatment for mild persistent asthma in children. There is concern that, similar to systemic corticosteroids, inhaled corticosteroids may have adverse effects on bone health. Objective: To determine whether there is an increased risk of bone fracture associated with inhaled corticosteroid use in children with asthma. Design, Setting, and Participants: In this population-based nested case-control study, we used health administrative databases to identify a cohort of children aged 2 to 18 years with a physician diagnosis of asthma between April 1, 2003, and March 31, 2014, who were eligible for public drug coverage through the Ontario Drug Benefit Program (Ontario, Canada). We matched cases of first fracture after asthma diagnosis to fracture-free controls (ratio of 1 to 4) based on date of birth (within 1 year), sex, and age at asthma diagnosis (within 2 years). We used a 1-year lookback period to ascertain history of inhaled corticosteroid use. Multivariable conditional logistic regression was used to obtain an odds ratio (OR) with 95% confidence interval for fracture, comparing no inhaled corticosteroid use vs current, recent, and past use. Exposures: Inhaled corticosteroid use during the child's 1-year lookback period, measured as current user if the prescription was filled less than 90 days prior to the index date, recent user (91-180 days), past user (181-365 days), or no use. Main Outcomes and Measures: First emergency department visit for fracture after asthma diagnosis, identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes. Results: This study included 19 420 children (61.0% male; largest proportion of children, 31.5%, were aged 6-9 years at their index date). The multivariable regression results did not show a significant association between first fracture after asthma diagnosis and current use (OR, 1.07; 95% CI, 0.97-1.17), recent use (OR, 0.96; 95% CI, 0.86-1.07), or past use (OR, 1.00; 95% CI, 0.91-1.11) of inhaled corticosteroids, compared with no use, while adjusting for sociodemographic factors and other medication use. However, use of systemic corticosteroids in the 1-year lookback period resulted in greater odds of fracture (OR, 1.17; 95% CI, 1.04-1.33). Conclusions and Relevance: Systemic corticosteroids, but not inhaled corticosteroids, were significantly associated with increased odds of fracture in the pediatric asthma population. PMID- 29131875 TI - Association of LRRK2 Haplotype With Age at Onset in Parkinson Disease. PMID- 29131876 TI - Errors in Data Input in Meta-analysis on Association Between Initial Use of e Cigarettes and Subsequent Cigarette Smoking Among Adolescents and Young Adults. PMID- 29131877 TI - Time to Appendectomy and Risk of Complicated Appendicitis and Adverse Outcomes in Children. PMID- 29131879 TI - Time to Appendectomy and Risk of Complicated Appendicitis and Adverse Outcomes in Children-Reply. PMID- 29131878 TI - Association of Brain Structure Changes and Cognitive Function With Combination Antiretroviral Therapy in HIV-Positive Individuals. AB - Importance: Despite the introduction of combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders continue to be a problem for treated HIV-positive individuals. The cause of this impairment remains unclear. Objective: To determine if detectable brain changes occur during a 2-year period in HIV-positive individuals who were aviremic and treated with cART. Design, Setting, and Participants: In this longitudinal case-control study, participants underwent neuroimaging and neuropsychological assessment approximately 2 years apart. Data were collected from October 26, 2011, to March 1, 2016. Data from 92 HIV-positive individuals were acquired at Washington University in St Louis from ongoing studies conducted in the infectious disease clinic and AIDS Clinical Trial Unit. A total of 55 HIV-negative control participants were recruited from the St Louis community and a research participant registry. A total of 48 HIV positive individuals who were aviremic and treated with cART and 31 demographically similar HIV-negative controls met the study requirements and were included in the analyses. Main Outcomes and Measures: Brain volumes were extracted with tensor-based and voxel-based morphometry and cortical modeling. Raw scores from neuropsychological tests quantified cognitive performance. Multivariable mixed-effects models assessed the effect of HIV serostatus on brain volumes and cognitive performance, and determined if HIV serostatus affected how these measures changed over time. With HIV-positive participants, linear regression models tested whether brain volumes and cognitive performance were associated with measures of infection severity and duration of infection. Results: The 2 groups were demographically similar (HIV-positive group: 23 women and 25 men; mean [SD] age, 47.7 [13.2] years; mean [SD] educational level, 13.3 [3.4] years; and HIV-negative group, 16 women and 15 men; mean [SD] age, 51.2 [12.9] years; mean [SD] educational level, 14.5 [2.1] years). The HIV-positive participants had poorer neuropsychological test scores compared with controls on the Trail Making Test Part A (5.9 seconds; 95% CI, 1.5-10.3; P = .01), Trail Making Test Part B (27.3 seconds; 95% CI, 15.0-39.6; P < .001), Digit Symbol Substitution Task (-12.5 marks; 95% CI, -18.9 to -6.0; P < .001), Letter-Number Sequencing (-2.5 marks; 95% CI, -3.7 to -1.3; P < .001), Letter Fluency (-6.6 words; 95% CI, -11.5 to -1.6; P = .01), and Hopkins Verbal Learning Test-Revised immediate recall (-2.4 words; 95% CI, -4.4 to -0.4; P = .05), after adjusting for age, sex, and educational level. Only changes in Trail Making Test Part A significantly differed between the groups. Cortical thickness and subcortical volumes were smaller in HIV-positive individuals compared with controls. However, changes in brain volume over time were similar between the groups. Conclusions and Relevance: These findings are consistent with the idea that cognitive and structural brain changes may occur early after seroconversion, and argue that maintaining aviremia with cART can prevent or minimize progressive brain injury. PMID- 29131880 TI - The Parkinson Pandemic-A Call to Action. PMID- 29131881 TI - Incorrect Affiliation. PMID- 29131882 TI - Time Course Response of the Heart and Circulatory System to Active Postural Changes. AB - Rotary blood pumps (RBPs) used for mechanical circulatory support of heart failure patients cannot passively change pump flow sufficiently in response to frequent variations in preload induced by active postural changes. A physiological control system that mimics the response of the healthy heart is needed to adjust pump flow according to patient demand. Thus, baseline data are required on how the healthy heart and circulatory system (i.e., heart rate (HR) and cardiac output (CO)) respond. This study investigated the response times of the healthy heart during active postural changes (supine-standing-supine) in 50 healthy subjects (27 male/23 female). Early response times (te) and settling times (ts) were calculated for HR and CO from data continuously collected with impedance cardiography. The initial circulatory response of HR and CO resulted in te of 9.0-11.7 s when standing up and te of 4.7-5.7 s when lying back down. Heart rate and CO settled in ts of 50.0-53.6 s and 46.3-58.2 s when standing up and lying down, respectively. In conclusion, when compared to active stand up, HR and CO responded significant faster initially when subjects were lying down (p < 0.05); there were no significant differences in response times between male and female subjects. These data will be used during evaluation of physiological control systems for RBPs, which may improve patient outcomes for end-stage heart failure patients. PMID- 29131883 TI - Errors in Data Input in Results, Figure, and Table. PMID- 29131885 TI - Median Time to Antiretroviral Therapy Initiation in a Cohort of Chinese Infants Born With HIV. PMID- 29131884 TI - Seizures and Encephalitis in Myelin Oligodendrocyte Glycoprotein IgG Disease vs Aquaporin 4 IgG Disease. AB - Importance: Antibodies to myelin oligodendrocyte glycoprotein IgG (MOG-IgG) are increasingly detected in patients with non-multiple sclerosis-related demyelination, some of whom manifest a neuromyelitis optica (NMO) phenotype. Cortical involvement, encephalopathy, and seizures are rare in aquaporin 4 antibody (AQP4-IgG)-related NMO in the white European population. However, the authors encountered several patients with seizures associated with MOG-IgG disease. Objective: To compare incidence of seizures and encephalitis-like presentation, or both between AQP4-IgG-positive and MOG-IgG-positive patients. Design, Setting, and Participants: Retrospective case series of all patients who were seropositive for MOG-IgG (n = 34) and the last 100 patients with AQP4-IgG disease (NMO spectrum disorder) seen in the NMO service between January 2013 and December 2016, and analysis was completed January 4, 2017. All patients were seen in a tertiary neurological center, The Walton Centre NHS Foundation Trust in Liverpool, England. Main Outcomes and Measures: The difference in seizure frequency between the AQP4-IgG-positive and MOG-IgG-positive patient groups was determined. Results: Thirty-four patients with MOG-IgG disease (20 female) with a median age at analysis of 30.5 years (interquartile range [IQR], 15-69 years), and 100 AQP4-IgG-positive patients (86 female) with a median age at analysis of 54 years (IQR, 12-91 years) were studied. Most patients were of white race. Five of the 34 patients with MOG-IgG (14.7%) had seizures compared with 1 patient with AQP4-IgG (2-sided P < .008, Fisher test). On magnetic resonance imaging, all 5 MOG-IgG-positive patients had inflammatory cortical brain lesions associated with the seizures. In 3 of the 5 MOG-IgG-positive patients, seizures occurred as part of the index event. Four of the 5 presented with encephalopathy and seizures, and disease relapsed in all 5 patients. Four of these patients were receiving immunosuppressant medication at last follow-up, and 3 continued to take antiepileptic medication. In contrast, the only AQP4-IgG-positive patient with seizures had a diagnosis of complex partial epilepsy preceding the onset of NMO by several years and experienced no encephalitic illness; her magnetic resonance imaging results demonstrated no cortical, subcortical, or basal ganglia involvement. Conclusions and Relevance: Patients with MOG-IgG-associated disease were more likely to have seizures and encephalitis-like presentation than patients with AQP4-IgG-associated disease. PMID- 29131886 TI - Determinant Factors for Arterial Hemodynamics in Hypertension: Theoretical Insights From a Computational Model-Based Study. AB - Hypertension is a well-documented predictive factor for cardiovascular events. Clinical studies have extensively demonstrated the differential hemodynamic consequences of various antihypertensive drugs, but failed to clearly elucidate the underlying mechanisms due to the difficulty in performing a quantitative deterministic analysis based on clinical data that carry confounding information stemming from interpatient differences and the nonlinearity of cardiovascular hemodynamics. In the present study, a multiscale model of the cardiovascular system was developed to quantitatively investigate the relationships between hemodynamic variables and cardiovascular properties under hypertensive conditions, aiming to establish a theoretical basis for assisting in the interpretation of clinical observations or optimization of therapy. Results demonstrated that heart period, central arterial stiffness, and arteriolar radius were the major determinant factors for blood pressures and flow pulsatility indices both in large arteries and in the microcirculation. These factors differed in the degree and the way in which they affect hemodynamic variables due to their differential effects on wave reflections in the vascular system. In particular, it was found that the hemodynamic effects of varying arteriolar radius were considerably influenced by the state of central arterial stiffness, and vice versa, which implied the potential of optimizing antihypertensive treatment by selecting proper drugs based on patient-specific cardiovascular conditions. When analyzed in relation to clinical observations, the simulated results provided mechanistic explanations for the beneficial pressure-lowering effects of vasodilators as compared to beta-blockers, and highlighted the significance of monitoring and normalizing arterial stiffness in the treatment of hypertension. PMID- 29131887 TI - Effect of an Intervention to Promote Breastfeeding on Asthma, Lung Function, and Atopic Eczema at Age 16 Years: Follow-up of the PROBIT Randomized Trial. AB - Importance: Atopic diseases, including asthma and atopic eczema, are the most common chronic conditions of childhood. Objective: To investigate whether an intervention to promote prolonged and exclusive breastfeeding protects against asthma, atopic eczema, and low lung function in adolescence. Design, Setting, and Participants: Follow-up of the Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster randomized trial in 30 Belarusian maternity hospitals and affiliated polyclinics; recruitment of 17 046 healthy term infants took place from June 15, 1996, to December 31, 1997. Data analysis was conducted from May 9, 2016, to April 21, 2017. The primary analytic approach was by modified intention to-treat analysis. Interventions: Randomization to receive a breastfeeding promotion intervention vs usual care. Main Outcomes and Measures: Spirometry and flexural eczema on standardized skin examination by study pediatricians were the primary outcomes; secondary outcomes were self-reported asthma diagnosis ever, and wheezing and flexural eczema symptoms in the previous year. Results: A total of 13 557 (79.5%) participants were followed up from September 15, 2012 to July 15, 2015. The intervention (7064 [79.7%]) and control (6493 [79.4%]) groups were similar at follow-up (3590 [50.8%] and 3391 [52.2%] male; mean [SD] age, 16.2 [0.6] and 16.1 [0.5] years, respectively). In the intervention group, 0.3% (21 of 7064) had flexural eczema on skin examination and mean (SD) forced expiratory volume in the first second of expiration/forced vital capacity (FEV1/FVC) ratio z score was -0.10 (1.82), compared with 0.7% (43 of 6493) and 0.35 (1.34), respectively, in the control group. In modified intention-to-treat analysis, accounting for clustering by polyclinic, a 54% lower risk of flexural eczema on skin examination was observed in the intervention compared with the control group (odds ratio [OR], 0.46; 95% CI, 0.25 to 0.86). Self-reported flexural eczema symptoms in the past year (OR, 0.57; 95% CI, 0.27 to 1.18), asthma (OR, 0.76; 95% CI, 0.47 to 1.23), and wheezing in the past year (OR, 0.66; 95% CI, 0.37 to 1.18) were less frequently reported in the intervention compared with the control group, but 95% CIs were wide and included the null. There was no significant difference in the FEV1/FVC ratio z score (beta -0.15; 95% CI, -0.76 to 0.45). All results were similar with additional adjustment for baseline characteristics, on instrumental variable analysis, and with multiple imputation among all 17 046 randomized participants. Conclusions and Relevance: A breastfeeding promotion intervention reduced flexural dermatitis risk but had no detectable effect on lung function or questionnaire-derived measures of atopic eczema or asthma in adolescence in a setting where atopic eczema and allergies are rare. Trial Registration: clinicaltrials.gov Identifier: NCT01561612. PMID- 29131888 TI - Exemplar Variability Facilitates Retention of Word Learning by Children With Specific Language Impairment. AB - Purpose: Variability in the input plays an important role in language learning. The current study examined the role of object variability for new word learning by preschoolers with specific language impairment (SLI). Method: Eighteen 4- and 5-year-old children with SLI were taught 8 new words in 3 short activities over the course of 3 sessions. Half of the children saw 3 identical objects corresponding to each new word during training (No Variability group); the other half of the children saw 3 different objects corresponding to each new word during training (High Variability group). Children completed vocabulary learning tests for objects seen during training and for new within-category objects that were never seen during training as a test of category generalization. Learning was assessed the day after each training activity, and retention was assessed 3 weeks after the last training session. Results: There were no group differences on trained or generalization items immediately following training sessions. However, children in the High Variability group demonstrated significantly better retention 3 weeks after experimental training. Conclusion: These findings demonstrate that object variability facilitates retention of new word learning by children with SLI. Supplemental Material: https://doi.org/10.23641/asha.5583979. PMID- 29131890 TI - Modeling Inspiratory Flow in a Porcine Lung Airway. AB - Inspiratory flow in a multigeneration pig lung airways was numerically studied at a steady inlet flow rate of 3.2 * 10-4 m3/s corresponding to a Reynolds number of 1150 in the trachea. The model was validated by comparing velocity distributions with previous measurements and simulations in simplified airway geometries. Simulation results provided detailed maps of the axial and secondary flow patterns at different cross sections of the airway tree. The vortex core regions in the airways were visualized using absolute helicity values and suggested the presence of secondary flow vortices where two counter-rotating vortices were observed at the main bifurcation and in many other bifurcations. Both laminar and turbulent flows were considered. Results showed that axial and secondary flows were comparable in the laminar and turbulent cases. Turbulent kinetic energy (TKE) vanished in the more distal airways, which indicates that the flow in these airways approaches laminar flow conditions. The simulation results suggested viscous pressure drop values comparable to earlier studies. The monopodial asymmetric nature of airway branching in pigs resulted in airflow patterns that are different from the less asymmetric human airways. The major daughters of the pig airways tended to have high airflow ratios, which may lead to different particle distribution and sound generation patterns. These differences need to be taken into consideration when interpreting the results of animal studies involving pigs before generalizing these results to humans. PMID- 29131889 TI - Poisson's Contraction and Fiber Kinematics in Tissue: Insight From Collagen Network Simulations. AB - Connective tissue mechanics is highly nonlinear, exhibits a strong Poisson's effect, and is associated with significant collagen fiber re-arrangement. Although the general features of the stress-strain behavior have been discussed extensively, the Poisson's effect received less attention. In general, the relationship between the microscopic fiber network mechanics and the macroscopic experimental observations remains poorly defined. The objective of the present work is to provide additional insight into this relationship. To this end, results from models of random collagen networks are compared with experimental data on reconstructed collagen gels, mouse skin dermis, and the human amnion. Attention is devoted to the mechanism leading to the large Poisson's effect observed in experiments. The results indicate that the incremental Poisson's contraction is directly related to preferential collagen orientation. The experimentally observed downturn of the incremental Poisson's ratio at larger strains is associated with the confining effect of fibers transverse to the loading direction and contributing little to load bearing. The rate of collagen orientation increases at small strains, reaches a maximum, and decreases at larger strains. The peak in this curve is associated with the transition of the network deformation from bending dominated, at small strains, to axially dominated, at larger strains. The effect of fiber tortuosity on network mechanics is also discussed, and a comparison of biaxial and uniaxial loading responses is performed. PMID- 29131891 TI - Missing Author Contributions. PMID- 29131893 TI - Omitted Disclosures or Potential Conflicts of Interest. PMID- 29131892 TI - The Costs and Benefits of Hospital Care by Primary Physicians: Continuity Counts. PMID- 29131894 TI - Evaluation of Polycythemia: A Teachable Moment. PMID- 29131896 TI - Association of Coded Severity With Readmission Reduction After the Hospital Readmissions Reduction Program. PMID- 29131895 TI - Association of Blood Pressure Lowering With Mortality and Cardiovascular Disease Across Blood Pressure Levels: A Systematic Review and Meta-analysis. AB - Importance: High blood pressure (BP) is the most important risk factor for death and cardiovascular disease (CVD) worldwide. The optimal cutoff for treatment of high BP is debated. Objective: To assess the association between BP lowering treatment and death and CVD at different BP levels. Data Sources: Previous systematic reviews were identified from PubMed, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effect. Reference lists of these reviews were searched for randomized clinical trials. Randomized clinical trials published after November 1, 2015, were also searched for in PubMed and the Cochrane Central Register for Controlled Trials during February 2017. Study Selection: Randomized clinical trials with at least 1000 patient years of follow-up, comparing BP-lowering drugs vs placebo or different BP goals were included. Data Extraction and Synthesis: Data were extracted from original publications. Risk of bias was assessed using the Cochrane Collaborations assessment tool. Relative risks (RRs) were pooled in random-effects meta-analyses with Knapp-Hartung modification. Results are reported according to PRISMA guidelines. Main Outcomes and Measures: Prespecified outcomes of interest were all-cause mortality, cardiovascular mortality, major cardiovascular events, coronary heart disease (CHD), stroke, heart failure, and end-stage renal disease. Results: Seventy-four unique trials, representing 306 273 unique participants (39.9% women and 60.1% men; mean age, 63.6 years) and 1.2 million person-years, were included in the meta-analyses. In primary prevention, the association of BP lowering treatment with major cardiovascular events was dependent on baseline systolic BP (SBP). In trials with baseline SBP 160 mm Hg or above, treatment was associated with reduced risk for death (RR, 0.93; 95% CI, 0.87-1.00) and a substantial reduction of major cardiovascular events (RR, 0.78; 95% CI, 0.70 0.87). If baseline SBP ranged from 140 to 159 mm Hg, the association of treatment with mortality was similar (RR, 0.87; 95% CI, 0.75-1.00), but the association with major cardiovascular events was less pronounced (RR, 0.88; 95% CI, 0.80 0.96). In trials with baseline SBP below 140 mm Hg, treatment was not associated with mortality (RR, 0.98; 95% CI, 0.90-1.06) and major cardiovascular events (RR, 0.97; 95% CI, 0.90-1.04). In trials including people with previous CHD and mean baseline SBP of 138 mm Hg, treatment was associated with reduced risk for major cardiovascular events (RR, 0.90; 95% CI, 0.84-0.97), but was not associated with survival (RR, 0.98; 95% CI, 0.89-1.07). Conclusions and Relevance: Primary preventive BP lowering is associated with reduced risk for death and CVD if baseline SBP is 140 mm Hg or higher. At lower BP levels, treatment is not associated with any benefit in primary prevention but might offer additional protection in patients with CHD. PMID- 29131897 TI - Comparison of Hospital Resource Use and Outcomes Among Hospitalists, Primary Care Physicians, and Other Generalists. AB - Importance: A physician's prior experience caring for a patient may be associated with patient outcomes and care patterns during and after hospitalization. Objective: To examine differences in the use of health care resources and outcomes among hospitalized patients cared for by hospitalists, their own primary care physicians (PCPs), or other generalists. Design, Setting, and participants: This retrospective study analyzed admissions for the 20 most common medical diagnoses among elderly fee-for-service Medicare patients from January 1 through December 31, 2013. Patients had at least 1 previous encounter with an outpatient clinician within the 365 days before admission, and diagnoses were restricted to the 20 most common diagnosis related groups. Data were collected from Medicare Parts A and B claims data, and outcomes were analyzed from January 1, 2013, through January 31, 2014. Exposures: Physician types included hospitalists, PCPs (ie, the physicians who provided a plurality of ambulatory visits in the year preceding admission), or generalists (not the patients' PCPs). Main Outcomes and Measures: Number of in-hospital specialist consultations, length of stay, discharge site, all-cause 7- and 30-day readmission rates, and 30-day mortality. Results: A total of 560 651 admissions were analyzed (41.9% men and 59.1% women; mean [SD] age, 80 [8] years). Patients' physicians were hospitalists in 59.7% of admissions; PCPs, in 14.2%; and other generalists, in 26.1%. Primary care physicians used consultations 3% more (relative risk, 1.03; 95% CI, 1.02-1.05) and other generalists used consultations 6% more (relative risk, 1.06; 95% CI, 1.05-1.07) than hospitalists. Lengths of stay were 12% longer among patients cared for by PCPs (adjusted incidence rate ratio, 1.12; 95% CI, 1.11-1.13) and 6% longer among those cared for by other generalists (adjusted incidence rate ratio, 1.06; 95% CI, 1.05-1.07) compared with patients cared for by hospitalists. However, PCPs were more likely to discharge patients home (adjusted odds ratio [AOR], 1.14; 95% CI, 1.11-1.17), whereas other generalists were less likely to do so (AOR, 0.94; 95% CI, 0.92-0.96). Relative to hospitalists, patients cared for by PCPs had similar readmission rates at 7 days (AOR, 0.98; 95% CI, 0.96-1.01) and 30 days (AOR, 1.02; 95% CI, 0.99-1.04), whereas other generalists' readmission rates were greater than hospitalists' rates at 7 (AOR, 1.05; 95% CI, 1.02-1.07) and 30 (AOR, 1.04; 95% CI, 1.03-1.06) days. Patients cared for by PCPs had lower 30-day mortality than patients of hospitalists (AOR, 0.94; 95% CI, 0.91 0.97), whereas the mortality rate of patients of other generalists was higher (AOR, 1.09; 95% CI, 1.07-1.12). Conclusions and Relevance: A PCP's prior experience with a patient may be associated with inpatient use of resources and patient outcomes. Patients cared for by their own PCP had slightly longer lengths of stay and were more likely to be discharged home but also were less likely to die within 30 days compared with those cared for by hospitalists or other generalists. PMID- 29131898 TI - Association of Maternal Obesity With Longitudinal Ultrasonographic Measures of Fetal Growth: Findings From the NICHD Fetal Growth Studies-Singletons. AB - Importance: Despite the increasing prevalence of pregravid obesity, systematic evaluation of the association of maternal obesity with fetal growth trajectories is lacking. Objective: To characterize differences in fetal growth trajectories between obese and nonobese pregnant women, and to identify the timing of any observed differences. Design, Setting, and Participants: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons study enrolled cohorts of pregnant women at 12 US health care institutions. Obese women (with prepregnancy body mass index > 30) and nonobese women (prepregnancy body mass indexes, 19-29.9) without major chronic diseases were recruited between 8 weeks and 0 days' gestation and 13 weeks and 6 days' gestation. A mixed longitudinal randomization scheme randomized participants into 1 of 4 schedules for 2-dimensional and 3-dimensional ultrasonograms to capture weekly fetal growth data throughout the remainder of their pregnancies. Main Outcomes and Measures: On each ultrasonogram, fetal humerus length, femur length, biparietal diameter, head circumference, and abdominal circumference were measured. Fetal growth curves were estimated using linear mixed models with cubic splines. Median differences in the fetal measures at each gestational week of the obese and nonobese participants were examined using the likelihood ratio and Wald tests after adjustment for maternal characteristics. Results: The study enrolled 468 obese and 2334 nonobese women between 8 weeks and 0 days' gestation and 13 weeks and 6 days' gestation. After a priori exclusion criteria, 443 obese and 2320 nonobese women composed the final cohort. Commencing at 21 weeks' gestation, femur length and humerus length were significantly longer for fetuses of obese woman than those of nonobese women. Differences persisted in obese and nonobese groups through 38 weeks' gestation (median femur length, 71.0 vs 70.2 mm; P = .01; median humerus length, 62.2 vs 61.6 mm; P = .03). Averaged across gestation, head circumference was significantly larger in fetuses of obese women than those of nonobese women (P = .02). Fetal abdominal circumference was not greater in the obese cohort than in the nonobese cohort but was significantly larger than in fetuses of normal-weight women (with body mass indexes between 19.0-24.9) commencing at 32 weeks (median, 282.1 vs 280.2 mm; P = .04). Starting from 30 weeks' gestation, estimated fetal weight was significantly larger for the fetuses of obese women (median, 1512 g [95% CI, 1494-1530 g] vs 1492 g [95% CI, 1484-1499 g]) and the difference grew as gestational age increased. Birth weight was higher by almost 100 g in neonates born to obese women than to nonobese women (mean, 3373.2 vs 3279.5 g). Conclusions and Relevance: As early as 32 weeks' gestation, fetuses of obese women had higher weights than fetuses of nonobese women. The mechanisms and long-term health implications of these findings are not yet established. PMID- 29131899 TI - A Comparison of Laboratory Testing in Teaching vs Nonteaching Hospitals for 2 Common Medical Conditions. AB - Importance: Robust laboratory use data are lacking to support the general assumption that teaching hospitals with trainees routinely order more laboratory tests for inpatients than do nonteaching hospitals. Objective: To quantify differences in the use of laboratory tests between teaching and nonteaching hospitals. Design, Setting, and Participants: A cross-sectional study was performed using a statewide database to identify hospitalizations with a primary diagnosis of bacterial pneumonia or cellulitis from January 1, 2014, to June 30, 2015, at teaching and nonteaching hospitals with 100 or more hospitalizations of each condition. Patients included were adult inpatients with a primary diagnosis of bacterial pneumonia (n = 24 118) or cellulitis (n = 19 211); patients excluded were those with an intensive care unit stay, transfer from another hospital, or a length of stay that was 2 SDs or more of the condition's mean length of stay. Main Outcomes and Measures: Mean laboratory tests per day stratified by illness severity, as well as factors associated with laboratory use rates. Results: A total of 43 329 hospitalized patients (20493 women and 22836 men) had a principal diagnosis of bacterial pneumonia or cellulitis across 11 major teaching hospitals, 12 minor teaching hospitals, and 73 nonteaching hospitals in Texas. Mean number of laboratory tests per day varied significantly by hospital type and was highest for major teaching hospitals for both conditions (bacterial pneumonia: major teaching hospitals, 13.21; 95% CI, 12.91-13.51; nonteaching hospitals, 8.92; 95% CI, 8.84-9.00; P < .001; cellulitis: major teaching hospitals, 10.43; 95% CI, 10.16-10.70; nonteaching hospitals, 7.29; 95% CI, 7.22 7.36; P < .001). This association held for all levels of illness severity for both conditions, except for patients with cellulitis with the highest illness severity level. In generalized mixed linear regression models, controlling for additional patient and encounter covariates, there was a significant difference in the marginal effect of hospital teaching status on mean number of laboratory tests per day between major teaching and nonteaching hospitals (difference in marginal mean laboratory tests per day for bacterial pneumonia, 3.58; 95% CI, 2.61-4.55; P < .001; for cellulitis, 2.61; 95% CI, 1.76-3.47; P < .001). Conclusions and Relevance: Compared with nonteaching hospitals, patients in Texas admitted to major teaching hospitals with bacterial pneumonia or cellulitis received significantly more laboratory tests after controlling for illness severity, length of stay, and patient demographics. These results support the need to examine how the culture of training environments may contribute to increased use of laboratory tests. PMID- 29131900 TI - Improving the Study of New Medicines for Children With Rare Diseases. PMID- 29131901 TI - Comparison of Foveal, Macular, and Peripapillary Intraretinal Thicknesses Between Autism Spectrum Disorder and Neurotypical Subjects. AB - Purpose: To compare thicknesses of intraretinal layers segmented by spectral domain optical coherence tomography (SD-OCT) between autism spectrum disorder (ASD) and neurotypical (NT) individuals. Methods: We performed 2 scans on 108 eyes from 54 participants (27 high-functioning ASD and 27 age- and sex-matched NT subjects): macular fast volume and peripapillary retinal nerve fiber layer (pRNFL). Macula was automatically segmented. The mean foveal and macular thickness of nine different layers and the thickness of nine pRNFL sectors were considered. Data from the right and left eyes were averaged for each participant. The results were compared between the ASD and NT groups. Associations between the Kaufman brief intelligence test (K-BIT), head circumference and SD-OCT results were also investigated in ASD individuals. Results: ASD subjects showed greater foveal thickness at total retina, total inner retina, inner plexiform and inner nuclear layers, and greater macular thickness at total retina and total inner retina. Inferior, nasal inferior and temporal inferior sectors of pRNFL were also thicker in the ASD participants than in the controls (P < 0.05, unpaired t-test). Significant correlations were found between some K-BIT results and temporal inferior and inferior pRNFL thicknesses in the ASD group (P < 0.05, Spearman's rank correlation). No associations were seen between head circumference and OCT parameters. Conclusions: There are intraretinal thickenings at different locations in ASD subjects when compared to NT controls. This fact should be taken into account when interpreting SD-OCT examinations in ASD individuals. Plus, some pRNFL thicknesses present positive correlations with scores of cognitive status in ASD. PMID- 29131902 TI - Choroidal Thickness In and Outside of Vascular Arcade in Healthy Eyes Using Spectral-Domain Optical Coherence Tomography. AB - Purpose: To study the distribution of choroidal thickness (CT) in and outside of the vascular arcade, as well as at the fovea in healthy eyes using spectral domain optical coherence tomography (OCT). Methods: Seventy healthy eyes were examined with OCT to obtain nine horizontal lines in and outside of the vascular arcade. Nine points including the central point of the line were chosen in 0.5-mm intervals to calculate CT. CT was measured at a total of 81 points in each patient to construct a map of CT distribution. Results: Average subfoveal CT showed a significant relationship with age (P < 0.001) and axial length (P = 0.001). In all nine horizontal lines, CT showed a rough trend of being thickest at a particular point and decreasing thereafter. The aspect of CT distribution was different among the nine horizontal lines (P < 0.001), and the near superotemporal line displayed the thickest choroid among the lines. The difference of the trend between temporal vertical lines was significant as well (P < 0.001). Conclusions: The CT generally decreased with age, but it decreased much faster in old age than in relatively younger people. CT displayed large variations among different points in and outside of the vascular arcade. The thickest choroid was located at the point superior to the fovea, not the fovea itself. Such physiological variations should be considered when interpreting pathologic changes of the choroid. PMID- 29131904 TI - Declining Medicaid Fees and Primary Care Appointment Availability for New Medicaid Patients. PMID- 29131903 TI - Slow Reading in Glaucoma: Is it due to the Shrinking Visual Span in Central Vision? AB - Purpose: Glaucoma is a leading cause of blindness worldwide, characterized by progressive loss of retinal ganglion cells. Patients with bilateral glaucoma read slower than normal cohorts. Here we examined the factors that may underlie slow reading in glaucoma and determined the best predictor of reading speed in glaucoma. Methods: A total of 38 subjects participated in this study: 17 patients with primary open-angle glaucoma (mean age = 64.71 years) and 21 age-similar normal controls (58.24 years). For each subject, we measured binocular visual acuity (BVA); binocular contrast sensitivity (BCS); stereoacuity; visual field mean deviation (MD); and the visual span (i.e., the number of letters recognizable at one glance) known to limit reading speed. The visual span was measured with a trigram letter-recognition task in which subjects identify trigrams flashed at varying letter positions left and right of the fixation. Oral reading speed was measured with short blocks of text. Results: Even after controlling for age, glaucoma patients showed significantly slower reading speed (by 19%, P < 0.05) and smaller visual span (by 11 bits, P < 0.001) compared to normal controls. While their BVA was relatively normal (20/20 Snellen equivalent), their BCS (P < 0.001); stereoacuity (P < 0.001); and visual field MD (P < 0.001) showed pronounced deficits. Multiple regression analysis further revealed that reading speed in glaucoma was best predicted by the visual span. Conclusions: Our results showed that slower reading speed in glaucoma was closely related to the shrinkage of the visual span. Our findings further support the view that the visual span plays a limiting role in reading speed. PMID- 29131905 TI - High Costs of FDA Approval for Formerly Unapproved Marketed Drugs. PMID- 29131908 TI - The Supreme Court Ruling in Sandoz v Amgen: A Victory for Follow-on Biologics. PMID- 29131909 TI - ST Elevations in the Setting of Hyperkalemia. PMID- 29131910 TI - Resistant Infantile Bacterial Conjunctivitis in Egypt: A Microbiology Study. AB - PURPOSE: To study the microbiological aspects of infantile bacterial conjunctivitis resistant to empirical topical antibiotic therapy in Egypt. METHODS: Ninety-two eyes of 86 infants with bacterial conjunctivitis were included in this prospective study. They all failed to show evidence of clinical improvement after 2 weeks of empirical topical antibiotic therapy. Conjunctival swabs were obtained from all patients for bacterial culture and antibiotic sensitivity testing. RESULTS: The age of the participants ranged from 4 to 6 months. Culture results revealed infection with a solitary organism in 48.9% of eyes. Mixed bacterial growth was reported in 47.8% of eyes, whereas 3.3% of eyes showed no bacterial growth. The most commonly isolated organisms were Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa. These organisms were highly sensitive to fluoroquinolones (levofloxacin, ciprofloxacin, ofloxacin, and norfloxacin), followed by chloramphenicol, vancomycin, and amikacin, and were resistant to carbapenems (imipenem and meropenem), fusidic acid, and pipracellin. CONCLUSIONS: Bacterial culture and antibiotic sensitivity testing provides beneficial diagnostic and therapeutic information when dealing with infantile resistant bacterial conjunctivitis. [J Pediatr Ophthalmol Strabismus. 2018;55(2):135-139.]. PMID- 29131911 TI - Time and Factors Affecting the Direction of Re-drift in Essential Infantile Esotropia. AB - PURPOSE: To investigate the development pattern and related factors of postoperative re-drift in infantile esotropia. METHODS: A total of 112 patients with infantile esotropia who underwent surgery before 3 years of age were included. Surgical outcomes were divided into (1) consecutive exotropia: more than 8 prism diopters (PD) of exodeviation; (2) recurrent esotropia: more than 8 PD of esodeviation; and (3) monofixation syndrome: maintenance of deviations within 8 PD. The occurrence rate, time of onset, and associated factors of the re drift were evaluated. RESULTS: At a mean follow-up of 9.5 years, consecutive exotropia developed in 37 patients (33.0%) and recurrent esotropia in 43 patients (38.4%). Whereas 76.7% of total recurrent esotropia cases were identified within postoperative 1 year, consecutive exotropia occurred constantly over 10 years postoperatively. The mean time to consecutive exotropia development from surgery was 78.6 months, greater than that of recurrent esotropia development (8.9 months) (P < 0.001). In multinomial logistic regression using monofixation syndrome as the reference category, fixation preference before surgery (odds ratio [OR]: 6.64, 95% confidence interval [CI]: 2.07 to 21.32) and the rate of myopic progression (OR: 15.07 per -1.00 D/year, 95% CI: 1.23 to 184.86) were associated with consecutive exotropia, whereas increase in the angle of esodeviation on postoperative day 1 (OR: 1.15, 95% CI: 1.04 to 1.26) was correlated with recurrent esotropia. CONCLUSIONS: This study demonstrates a difference between the development pattern of exotropic and esotropic drift after infantile esotropia surgery. Detailed preoperative assessment and close postoperative observation of deviations and refractive status will help to determine surgical outcomes of infantile esotropia. [J Pediatr Ophthalmol Strabismus. 2018;55(2):128-134.]. PMID- 29131912 TI - Practice Patterns in the Management of Amblyopia: A Survey Study. AB - PURPOSE: To characterize current practice preferences of pediatric ophthalmologists in the management of amblyopia and whether these are influenced by demographic variables. METHODS: A 10-question survey was distributed to all pediatric ophthalmologists and fellows attending the Annual Joseph H. Calhoun Pediatric Ophthalmology Forum at Wills Eye Hospital in 2016. The questionnaire consisted of demographic information and clinical management of amblyopia using clinical scenarios commonly encountered in pediatric ophthalmology practice. RESULTS: Of the 133 pediatric ophthalmologists who attended, 74 completed the survey, all of which were included in the data analysis. Seventy-six percent of respondents prescribed refractive correction to a 3 year old with untreated anisometropic amblyopia prior to initiating occlusion therapy. For a child with coexisting exotropia, 57% recommended refractive and occlusion therapy until significant visual improvement, then surgery; however, 30% would perform surgery earlier. Fifty-seven percent stopped occlusion therapy at 10 years of age or older. Sixty-four percent estimated a patient patching compliance rate of 50% to 75%. There was no significant relationship (P < .05) between any of the demographic variables, indicating that no group was more or less likely to respond to the question in any way. CONCLUSIONS: This study highlights the lack of a unified approach to certain aspects of amblyopia management. Physician related demographic variables did not significantly affect clinical decision making; however, variation did exist among respondents, a finding that warrants further investigation. [J Pediatr Ophthalmol Strabismus. 2018;55(2):100-106.]. PMID- 29131913 TI - Unilateral Congenital Cataract: Clinical Profile and Presentation. AB - PURPOSE: To study the clinical profile and presentation of children with unilateral cataract. METHODS: In this hospital-based, observational, cross sectional study, patients 15 years of age or younger who presented with unilateral cataract were recruited. Cases of cataract secondary to causes such as trauma or uveitis were excluded. Age at detection and presentation, distance from the treatment center, presenting complaints, cataract morphology, and biometry were noted for each case. RESULTS: A total of 76 patients were recruited. Most patients presented with complaints of leukocoria. Persistent fetal vasculature accounted for 27.6% of cases and was the most common identifiable cause of cataract in this study. Subsequently, patients were divided into two groups: no persistent fetal vasculature (control) and persistent fetal vasculature. A male predominance was noted in both groups. The mean age at detection was 27.58 +/- 37.02 and 6.17 +/- 8.42 months and the mean age at presentation was 55.613 +/- 45.21 and 14.83 +/- 17.75 months in the control and persistent fetal vasculature groups, respectively. In the persistent fetal vasculature group, a significant difference was noted in the axial length, keratometry, and corneal diameter between the affected and normal eyes (P = .027, .00176, and .0114, respectively). In the control group, this difference was observed only in keratometry readings (P = .0464). The mean distance traveled by patients to reach the treatment center was 211 km. CONCLUSIONS: Persistent fetal vasculature is an important and less identified cause of unilateral cataract. A significant delay is noted in the detection and presentation of unilateral cataract. [J Pediatr Ophthalmol Strabismus. 2018;55(2):107-112.]. PMID- 29131914 TI - Pediatric Orbital Primitive Neuroectodermal Tumors. AB - PURPOSE: To present the clinical, radiological, histopathological, immunohistochemical features and the follow-up of orbital primitive neuroectodermal tumors (PNETs) in pediatric patients along with a review of the literature. METHODS: A retrospective analysis of all diagnosed cases of orbital PNET was done. Patients' ophthalmic findings, imaging, immunohistochemistry, metastatic work-up, treatment, globe salvation, and survival were documented and a mini literature review of orbital PNET was performed. RESULTS: Four diagnosed cases of orbital PNET presented with proptosis and visual impairment were treated during the study period. The radiological imaging showed primary orbital involvement. There were three males and one female with a mean age of 63.75 months (range: 3 to 244 months). Histopathology of all studied patients showed round malignant cells with hyperchromatic nuclei, increased nuclear cytoplasmic ratio, and positive test results for CD99 and FLI-1. The studied patients underwent orbital surgery for excision of tumors followed by chemotherapy. One of the patients also had external radiation in addition to chemotherapy after a second recurrence. The follow-up period of these patients varied from 1 to 5 years. Only one child who had recurrence twice was followed up to 5 years, but was lost to follow-up after that. CONCLUSIONS: The authors believe that most orbital peripheral PNET tumors present as well-defined masses on both imaging and perioperatively and are easily removed surgically. The apparently disguised "benign profile" of orbital PNET may prove deceptive and the shorter duration of symptoms remains a strong reminder of the malignant nature of the lesion. [J Pediatr Ophthalmol Strabismus. 2018;55(2):93-99.]. PMID- 29131916 TI - Relevant Neonatal Topics of Interest. PMID- 29131915 TI - Visual and Refractive Outcomes of Children After Early Secondary Cataract Extraction Following Wound Repair for Penetrating Ocular Trauma. AB - PURPOSE: To evaluate the visual and refractive outcomes in children 8 years of age or younger with corneal laceration and cataract following penetrating ocular injuries who underwent primary corneal tear repair followed within 1 to 8 weeks by early secondary cataract extraction. METHODS: This retrospective, non comparative case series reviewed the admission and operative charts of children 8 years of age or younger (range: 3 to 8 years) who underwent corneal wound repair as the primary surgical procedure followed within 1 to 8 weeks by cataract extraction with intraocular lens implantation, with a minimum follow-up period of 6 months. The main outcome measures were best corrected visual acuity (BCVA) and refractive error as the spherical equivalent at the final follow-up visit. RESULTS: A total of 47 children (33 boys, 14 girls) were included. The mean age at the time of injury was 5.9 +/- 2.2 years (range: 3 to 8 years). Follow-up periods ranged from 6 months to 3 years (median: 18 months). The mean time gap between the wound repair and cataract extraction was 5 weeks (range: 1 to 8 weeks). Approximately 36 (77%) eyes obtained BCVA better than 6/18. All but one eye achieved BCVA better than 6/60. The deviation from emmetropia was less than 1.00 diopter (D) in 23 (54%) eyes, 1.00 to 3.00 D in 15 (35%) eyes, and more than 3.00 D in 5 (12%) eyes. CONCLUSIONS: Early removal of cataract with intraocular lens implantation 1 to 8 weeks after the primary wound repair in young children with penetrating corneal injuries can result in excellent visual and refractive outcomes with early intervention and aggressive amblyopia treatment. [J Pediatr Ophthalmol Strabismus. 2018;55(2):122-127.]. PMID- 29131917 TI - A Pediatrician's Take on a Few Common Infant Urologic and Gynecologic Issues. AB - Urologic and gynecologic issues are common in a pediatric primary care office. This article focuses on the evaluation and management of a few common diagnoses in infants and young children: fetal hydronephrosis, labial adhesions, physiologic phimosis, and hydrocele. This article can help pediatricians decide when these common issues can be managed in the primary care office and when they need subspecialty guidance. [Pediatr Ann. 2017;46(11):e397-e399.]. PMID- 29131918 TI - Neonatology: A Variety of Presentations, Diagnoses, and Treatments. PMID- 29131919 TI - Breast-Feeding Friendly, but Not Formula Averse. AB - Breast-feeding is the optimal source of newborn nutrition in term infants and is associated with multiple short- and long-term health benefits. Establishment of breast-feeding may be difficult in a small subset of mothers, which can lead to adverse consequences in the newborn. Some of the consequences of suboptimal nutritional provision to the newborn, such as severe hyperbilirubinemia and breast-feeding-associated hypernatremic dehydration, can have devastating and long-lasting sequelae. Timely identification of mothers and newborns at risk for developing these complications is necessary to avoid significant morbidity and mortality. In these cases, the judicious use of formula supplementation may be considered. However, more studies are necessary to develop comprehensive formula supplementation criteria and guidelines for pediatric medical providers. [Pediatr Ann. 2017;46(11):e402-e408.]. PMID- 29131920 TI - Congenital Hyperinsulinism. AB - Congenital hyperinsulinism is a rare disorder that commonly presents in the immediate postnatal period as persistent hypoglycemia. The condition is frequently resistant to medical therapies, and the genetic mutations implicated in the disorder can be predictive of response to therapy. Evaluation of hypoglycemia in the illustrative case presented in this article led to genetic testing identifying recessive mutations in the potassium channel subunits of the beta-islet pancreatic cells. Potassium channel defects are often refractory to medical therapies, so near-total pancreatectomy is usually indicated; however, genetic mutations leading to metabolic dysregulation within the beta-islet pancreatic cells are usually responsive to medical therapy. Aggressive treatment of hypoglycemia in the setting of congenital hyperinsulinism is important to prevent long-term neurologic sequelae secondary to hypoglycemia-induced brain injury. [Pediatr Ann. 2017;46(11):e409-e414.]. PMID- 29131921 TI - Hot Topics in Retinopathy of Prematurity. AB - Retinopathy of prematurity (ROP) is a condition seen in premature infants that is characterized by abnormal retinal blood vessel growth incited by relative hyperoxia and followed by hypoxia. It can have severe consequences ranging from high myopia to blindness. This article reviews recent "hot" topics related to ROP, specifically the changing incidence of ROP worldwide, the advent of predictive algorithms for screening for ROP, the emerging data behind efficacy of anti-vascular endothelial growth factor treatments for ROP, and advanced retinal imaging in children who were born premature. [Pediatr Ann. 2017;46(11):e415 e422.]. PMID- 29131922 TI - Prenatal and Postnatal Genetic Testing: Why, How, and When? AB - There have been major advances in genetic testing especially over the last 10 years. We have advanced from looking at simple chromosomes under a microscope to more sophisticated analysis of the DNA makeup of chromosomes and from testing a single gene to sequencing almost all of our genetic material. Similarly, in the field of prenatal testing we have made great strides in screening and diagnostic testing in the hope of detecting significant abnormalities in the fetus while decreasing the risk to the pregnancy. In this article the major types of genetic screening and diagnostic testing, both prenatal and postnatal, will be reviewed. [Pediatr Ann. 2017;46(11):e423-e427.]. PMID- 29131923 TI - Zika Virus: A Review for Pediatricians. AB - For the past several years, the Zika virus has been a topic of conversation among pediatric health care providers in many settings. This article provides current answers to many questions that may be posed to pediatricians, including inquiries about clinical presentation, testing, and prevention. Although infants born with congenital Zika syndrome often have microcephaly, there are other characteristic features, such as eye abnormalities, that one should recognize. Additionally, testing for the syndrome must be considered in all infants at risk for infection, including those who are asymptomatic at birth. Maternal travel to an endemic region or sexual intercourse with an exposed person shortly before or during pregnancy may put an infant at risk for infection. [Pediatr Ann. 2017;46(11):e428 e432.]. PMID- 29131925 TI - Erratum for "Pediatric Obstructive Sleep Apnea in High-Risk Populations: Clinical Implications". PMID- 29131924 TI - When an Orbital Infection Isn't Infectious at All: A Review of Orbital Inflammatory Syndrome. AB - Orbital inflammatory syndrome (OIS) includes a wide range of clinical manifestations and may initially be misdiagnosed as orbital cellulitis due similar symptoms of fever, periorbital swelling, and pain with eye movements. A diagnosis of OIS requires evaluation for underlying systemic disorders including autoimmune disorders and thyroid disease. Symptoms typically improve rapidly after initiation of steroid therapy, although recurrence can occur. This article presents an illustrative case of a 13-year-old girl with OIS. [Pediatr Ann. 2017;46(11):e433-e436.]. PMID- 29131926 TI - Erratum for "Pediatric Obstructive Sleep Apnea and Asthma: Clinical Implications". PMID- 29131928 TI - N and O isotope (delta15 Nalpha , delta15 Nbeta , delta18 O, delta17 O) analyses of dissolved NO3- and NO2- by the Cd-azide reduction method and N2 O laser spectrometry. AB - RATIONALE: The nitrogen and oxygen (delta15 N, delta18 O, delta17 O) isotopic compositions of NO3- and NO2- are important tracers of nutrient dynamics in soil, rain, groundwater and oceans. The Cd-azide method was used to convert NO3- or NO2 to N2 O for N and triple-O isotopic analyses by N2 O laser spectrometry. A protocol for laser-based headspace isotope analyses was compared with isotope ratio mass spectrometry. Lasers provide the ability to directly measure 17 O anomalies which can help discern atmospheric N sources. METHODS: delta15 N, delta18 O and delta17 O values were measured on N/O stable isotopic reference materials (IAEA, USGS) by conversion to N2 O using the Cd-azide method and headspace N2 O laser spectrometry. A 15 N tracer test assessed the position specific routing of N to the alpha or beta positions in the N2 O molecule. A data processing algorithm was used to correct for isotopic dependencies on N2 O concentration, cavity pressure and water content. RESULTS: NO3- /NO2- nitrogen is routed to the 15 Nalpha position of N2 O in the azide reaction; hence the delta15 Nalpha value should be used for N2 O laser spectrometry results. With corrections for cavity pressure, N2 O concentration and water content, the delta15 NalphaAIR , delta18 OVSMOW and delta17 OVSMOW values (0/00) of international reference materials were +4.8 +/- 0.1, +25.9 +/- 0.3, +12.7 +/- 0.2 (IAEA NO3 ), -1.7 +/- 0.1, -26.8 +/- 0.8, -14.4 +/- 1.1 (USGS34) and +2.6 +/- 0.1, +57.6 +/- 1.2, +51.2 +/- 2.0 (USGS35), in agreement with their values and with the isotope ratio mass spectrometry results. The 17 O excess for USGS35 was +21.2 +/- 90/00, in good agreement with previous results. CONCLUSIONS: The Cd-azide method yielded excellent results for routine determination of delta15 N, delta18 O and delta17 O values (and the 17 O excess) of nitrate or nitrite by laser spectrometry. Disadvantages are the toxicity of Cd-azide chemicals and the lack of automated sampling devices for N2 O laser spectrometers. The 15 N-enriched tracer test revealed potential for position-specific experimentation of aqueous nutrient dynamics at high 15 N enrichments by laser spectrometry, but exposed the need for memory corrections and improved spectral deconvolution of 17 O. PMID- 29131927 TI - Direct Evidence for the Origin of Bis-Gold Intermediates: Probing Gold Catalysis with Mass Spectrometry. AB - Gold-catalyzed alkyne hydration was studied by using in situ reacting mass spectrometry (MS) technology. By monitoring the reaction process in solution under different conditions (regular and very diluted catalyst concentrations, different pH values) and examining the reaction occurrence in the early reaction stage (1-2 ms after mixing) with MS, we collected a series of experimental evidence to support that the bis-gold complex is a potential key reaction intermediate. Furthermore, both experimental and computational studies confirmed that the sigma,pi-bis-gold complexes are not active intermediates toward nucleophilic addition. Instead, formation of geminally diaurated complex C is crucial for this catalytic process. PMID- 29131930 TI - Imprinted Naked Pt Nanoparticles on N-Doped Carbon Supports: A Synergistic Effect between Catalyst and Support. AB - A synergistic effect resulting from the interaction of small (2.4-3.1 nm) naked Pt nanoparticles (NPs) imprinted on N-doped carbon supports is evidenced by structural, electronic and electrochemical characterization. The size and distribution of the sputtered Pt NPs are found to be related to the nature of the support because Pt NPs are preferentially located at Ngraphitic sites. In addition, Rutherford backscattering shows that a deeper penetration of the Pt NPs is obtained in the N-doped carbon support with larger pore diameters. The ligand effect of the N-doped carbon supports is found to occur by electron donation from Npyrrolic and Ngraphitic sites to the Pt NPs and the electron acceptor behavior of the C=Npyridinic sites. The carbon matrix acquires a basic characteristic (electron-richer, metallic behavior) capable of interacting with metallic NPs akin to a bimetallic-like system. The imprinted Pt NPs are active catalysts for oxidation, although displaying poor catalytic activity for reduction reactions. The catalyst N-doped carbon supports play an important role in the overall catalytic process, rather than only acting as a simple active phase carrier. PMID- 29131929 TI - Insights on the Structure, Molecular Weight and Activity of an Antibacterial Protein-Polymer Hybrid. AB - Protein-polymer conjugates are attractive biomaterials which combine the functions of both proteins and polymers. The bioactivity of these hybrid materials, however, is often reduced upon conjugation. It is important to determine and monitor the protein structure and active site availability in order to optimize the polymer composition, attachment point, and abundance. The challenges in probing these insights are the large size and high complexity in the conjugates. Herein, we overcome the challenges by combining electron paramagnetic resonance (EPR) spectroscopy and atomic force microscopy (AFM) and characterize the structure of antibacterial hybrids formed by polyethylene glycol (PEG) and an antibacterial protein. We discovered that the primary reasons for activity loss were PEG blocking the substrate access pathway and/or altering protein surface charges. Our data indicated that the polymers tended to stay away from the protein surface and form a coiled conformation. The structural insights are meaningful for and applicable to the rational design of future hybrids. PMID- 29131932 TI - Redox-Dependent Metal-Metal Bonding in Trinuclear Metal Chains: Probing the Transition from Covalent Bonding to Exchange Coupling. AB - The synthesis and physical properties of two new cationic tri-metallic chains, [(PEt3 )3 RuCl3 M'Cl3 Ru(PEt3 )3 ]1+ , M'=Rh and Ir are reported. These are isostructural with a previously reported 17-electron all-ruthenium analogue, but replacing a d5 RuIII ion in the central position with d6 RhIII /IrIII has a significant impact on the nature of the metal-metal interactions. All three materials have been characterized electrochemically at the 18-, 17- and 16 electron levels. X-ray crystallography and spectroelectrochemistry, complemented by electronic structure analysis at the DFT and CASPT2 levels, indicate that whilst the presence of a RuIII ion in the center of the chain allows multi-center covalent bonding to develop, a closed-shell RhIII /IrIII ion pushes the system towards the exchange-coupled limit, where the outer Ru centers are only weakly interacting. This family of three isostructural compounds reveals how changes in metal composition can have subtle effects on physical properties of systems that lie close to the localized/delocalized borderline. PMID- 29131931 TI - Covariate-adjusted Spearman's rank correlation with probability-scale residuals. AB - It is desirable to adjust Spearman's rank correlation for covariates, yet existing approaches have limitations. For example, the traditionally defined partial Spearman's correlation does not have a sensible population parameter, and the conditional Spearman's correlation defined with copulas cannot be easily generalized to discrete variables. We define population parameters for both partial and conditional Spearman's correlation through concordance-discordance probabilities. The definitions are natural extensions of Spearman's rank correlation in the presence of covariates and are general for any orderable random variables. We show that they can be neatly expressed using probability scale residuals (PSRs). This connection allows us to derive simple estimators. Our partial estimator for Spearman's correlation between X and Y adjusted for Z is the correlation of PSRs from models of X on Z and of Y on Z, which is analogous to the partial Pearson's correlation derived as the correlation of observed-minus-expected residuals. Our conditional estimator is the conditional correlation of PSRs. We describe estimation and inference, and highlight the use of semiparametric cumulative probability models, which allow preservation of the rank-based nature of Spearman's correlation. We conduct simulations to evaluate the performance of our estimators and compare them with other popular measures of association, demonstrating their robustness and efficiency. We illustrate our method in two applications, a biomarker study and a large survey. PMID- 29131933 TI - The post-DANISH era in clinical cardiology: Need of a better selection of patients for implantable cardioverter-defibrillator in dilated cardiomyopathy. PMID- 29131935 TI - X-ray Structure of Catenated Lytic Transglycosylase SltB1. AB - Formation of catenanes by proteins is rare, with few known examples. We report herein the X-ray structure of a catenane dimer of lytic transglycosylase SltB1 of Pseudomonas aeruginosa. The enzyme is soluble and exists in the periplasmic space, where it modifies the bacterial cell wall. The catenane dimer exhibits the protein monomers in a noncovalent chain-link arrangement, whereby a stretch of 51 amino acids (to become a loop and three helices) from one monomer threads through the central opening of the structure of the partner monomer. The protein folds after threading in a manner that leaves two helices (alpha1 and alpha2) as stoppers to impart stability to the dimer structure. The symmetric embrace by the two SltB1 molecules occludes both active sites entirely, an arrangement that is sustained by six electrostatic interactions between the two monomers. In light of the observation of these structural motifs in all members of Family 3 lytic transglycosylases, catenanes might be present for those enzymes, as well. The dimeric catenane might represent a regulated form of SltB1. PMID- 29131934 TI - Methyl DNA Phosphate Adduct Formation in Rats Treated Chronically with 4 (Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4 (Methylnitrosamino)-1-(3-pyridyl)-1-butanol. AB - The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a powerful lung carcinogen in animal models and is considered a causative factor for lung cancer in tobacco users. NNK is stereoselectively and reversibly metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is also a lung carcinogen. Both NNK and NNAL undergo metabolic activation by alpha-hydroxylation on their methyl groups to form pyridyloxobutyl and pyridylhydroxybutyl DNA base and phosphate adducts, respectively. alpha Hydroxylation also occurs on the alpha-methylene carbons of NNK and NNAL to produce methane diazohydroxide, which reacts with DNA to form methyl DNA base adducts. DNA adducts of NNK and NNAL are important in their mechanisms of carcinogenesis. In this study, we characterized and quantified methyl DNA phosphate adducts in the lung of rats treated with 5 ppm of NNK, (S)-NNAL, or (R) NNAL in drinking water for 10, 30, 50, and 70 weeks, by using a novel liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method. A total of 23, 21, and 22 out of 32 possible methyl DNA phosphate adducts were detected in the lung tissues of rats treated with NNK, (S) NNAL, and (R)-NNAL, respectively. Levels of the methyl DNA phosphate adducts were 2290-4510, 872-1120, and 763-1430 fmol/mg DNA, accounting for 15-38%, 8%, and 5 9% of the total measured DNA adducts in rats treated with NNK, (S)-NNAL, and (R) NNAL, respectively. The methyl DNA phosphate adducts characterized in this study further enriched the diversity of DNA adducts formed by NNK and NNAL. These results provide important new data regarding NNK- and NNAL-derived DNA damage and new insights pertinent to future mechanistic and biomonitoring studies of NNK, NNAL, and other chemical methylating agents. PMID- 29131936 TI - Nanomechanical Force Mapping of Restricted Cell-To-Cell Collisions Oscillating between Contraction and Relaxation. AB - Contact-mediated cell migration strongly determines the invasiveness of the corresponding cells, collective migration, and morphogenesis. The quantitative study of cellular response upon contact relies on cell-to-cell collision, which rarely occurs in conventional cell culture. Herein, we developed a strategy to activate a robust cell-to-cell collision within smooth muscle cell pairs. Nanomechanical traction force mapping reveals that the collision process is promoted by the oscillatory modulations between contraction and relaxation and orientated by the filopodial bridge composed of nanosized contractile machinery. This strategy can enhance the occurrence of cell-to-cell collision, which renders it advantageous over traditional methods that utilize micropatterned coating to confine cell pairs. Furthermore, modulation of the balance between cell tugging force and traction force can determine the repolarization of cells and thus the direction of cell migration. Overall, our approach could help to reveal the mechanistic contribution in cell motility and provide insights in tissue engineering. PMID- 29131937 TI - Innovative in Situ Ball Mill for X-ray Diffraction. AB - The renewed interest of mechanochemistry as an ecofriendly synthetic route has inspired original methodologies to probe reactions, with the aim to rationalize unknown mechanisms. Recently, Friscic et al. ( Nat. Chem. 2013 , 5 , 66 - 73 , DOI: 10.1038/nchem.1505 ) monitored the progress of milling reactions by synchrotron X-ray powder diffraction (XRPD). For the first time, it was possible to acquire directly information during a mechanochemical process. This new methodology is still in its early stages, and its development will definitively transform the fundamental understanding of mechanochemistry. A new type of in situ ball mill setup has been developed at the Materials Science beamline (Swiss Light Source, Paul Scherrer Institute, Switzerland). Its particular geometry, described here in detail, results in XRPD data displaying significantly lower background and much sharper Bragg peaks, which in turn allow more sophisticated analysis of mechanochemical processes, extending the limits of the technique. PMID- 29131938 TI - A Crash Course in Calcium Channels. AB - Much progress has been made in understanding the molecular physiology and pharmacology of calcium channels. Recently, there have been tremendous advances in learning about calcium channel structure and function through crystallography and cryo-electron microscopy studies. Here, I will give an overview of our knowledge about calcium channels, and highlight two recent studies that give important insights into calcium channel structure. PMID- 29131939 TI - Concentration-Directed Polymorphic Surface Covalent Organic Frameworks: Rhombus, Parallelogram, and Kagome. AB - Polymorphic single-layered covalent organic frameworks (sCOFs) via on-surface synthesis have been investigated by employing the tetradentate monomer 1,3,6,8 tetrakis(p-formylphenyl)pyrene with D2h symmetry and ditopic linear diamine building blocks. Three kinds of well-ordered sCOFs, including rhombus, parallelogram, and Kagome networks, are observed on the graphite surface by scanning tunnel microscopy. The pore size and periodicity of sCOFs are tunable by employing diamine monomers with different lengths. Statistical analysis reveals that two types of quadrate networks are preferred at high concentration, whereas the occupancy of Kagome networks increases at low concentration. This trend can be understood by the differences in the network density of three kinds of networks. The reversibility and the self-sorting ability of the dynamic covalent reaction make it possible to control the polymorphic distribution similar to the principle demonstrated in supramolecular self-assembly. PMID- 29131940 TI - Fe-Cluster Compounds of Chalcogenides: Candidates for Rare-Earth-Free Permanent Magnet and Magnetic Nodal-Line Topological Material. AB - Fe-cluster-based crystal structures are predicted for chalcogenides Fe3X4 (X = S, Se, Te) using an adaptive genetic algorithm. Topologically different from the well-studied layered structures of iron chalcogenides, the newly predicted structures consist of Fe clusters that are either separated by the chalcogen atoms or connected via sharing of the vertex Fe atoms. Using first-principles calculations, we demonstrate that these structures have competitive or even lower formation energies than the experimentally synthesized Fe3X4 compounds and exhibit interesting magnetic and electronic properties. In particular, we show that Fe3Te4 can be a good candidate as a rare-earth-free permanent magnet and Fe3S4 can be a magnetic nodal-line topological material. PMID- 29131941 TI - A Molecular Level Understanding of Template Effects in Ionic Liquids. AB - The structure-directing or template effect has been invoked several times for ionic liquids to explain the different outcome in material synthesis, namely, different scaffolds or geometrical arrangements with varying ionic liquids. It is obvious to assume that such an effect can originate from the most likely complex microstructure, being present within the ionic liquid itself. In that regard, ionic liquids have already been shown to undergo a nanosegregation into polar and nonpolar phases, which is commonly known and denoted as microheterogeneity. In order to provide detailed insight on the molecular level and to understand the effects rising from this structuring, we performed molecular dynamics simulations on selected very simple model systems composed of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, considering ethyl, butyl, hexyl, and octyl side chains attached to the cations, mixed with either n-dodecanol or n-butanol. By analyzing snapshots of the simulation boxes and calculating spatial distribution functions, we can visualize that with increasing side chains, the systems show considerable nanosegregation into polar and nonpolar domains. Combined angular and distance distribution functions show that in case of the nanosegregating systems the side chains of the cations are preferentially arranged in a parallel fashion, which indicates a micelle-like structure for the ionic liquids. The alcohol molecules participate in and are, therefore, influenced by this microheterogeneity. It can be shown that in the case of the short IL alkyl side chains, the self-aggregation of the nonpolar units of the alcohols is much stronger, while for the long chain cations, the nonpolar entities of the alcohols are most often connected to the nonpolar units of the ionic liquids. Using our domain analysis tool, we can quantify these observations by tracking the number, size, and shape of the polar and nonpolar entities present in the different investigated systems. The aforementioned combined angular-distance distribution functions reveal a structure-directing effect of the ionic liquids on the alcohol molecules within our simple model systems. The ionic liquids act as template and order the alcohol molecules according to their own structure, resulting in a parallel alignment of the alkyl side chains of the alcohols and ionic liquid cations, with both polar groups being at the same side. These observations show that the microheterogeneous structure of ionic liquids can indeed be applied to order substrates with respect to each other or, for example, to catalysts in a predetermined fashion, opening new possibilities for explaining or enhancing selectivities of chemical reactions in ionic liquids. PMID- 29131942 TI - Molar Masses and Molar Mass Distributions of Chitin and Acid-Hydrolyzed Chitin. AB - Never-dried and dried crab shell chitin and squid pen chitin samples were acid hydrolyzed in 1 M HCl at 85 degrees C for up to 2 h. The crystallinities, crystal sizes, and degrees of N-acetylation of the acid-hydrolyzed chitin samples are almost unchanged the same before and after acid hydrolysis. The original and acid-hydrolyzed chitin samples were dissolved in 8% (w/w) lithium chloride/N,N, dimethylacetamide, and the solutions were subjected to size-exclusion chromatography with multiangle laser-light scattering analysis to determine their molar masses and molar mass distributions. The molar mass of each chitin sample decreases with increasing acid hydrolysis time, and the weight-average degree of polymerization (DPw) becomes constant after acid hydrolysis for 0.5 to 2 h. However, the DPw values of the chitin samples after acid hydrolysis for 2 h (DPw 2h) are different: Never-dried squid pen chitin has the highest DPw-2h of 1530, whereas the DPw-2h values of other chitin samples are in the range 220-410. PMID- 29131943 TI - Drift Tube Ion Mobility: How to Reconstruct Collision Cross Section Distributions from Arrival Time Distributions? AB - Ion mobility spectrometry allows one to determine ion collision cross sections, which are related to ion size and shape. Collision cross sections (CCS) are usually discussed based on the peak center, yet the width of each peak contains further information on the distribution of collision cross sections of each conformational ensemble. Here, we analyze how to convert arrival time distributions (ATD) to CCS distributions (CCSD). With a calibration curve taking into account the CCS dependence of the time spent outside the mobility region, one can reconstruct CCS distributions with correct peak center values. However, the peak widths are incorrectly rendered because ion diffusion, which affects the peak width in the time domain, is irrelevant to collision cross sections. For drift tube ion mobility, we describe a new method, coined "FWHMstep", using a step-field experiment and processing the peak's full width at half-maximum to reconstruct CCSDs. The width of the CCS distribution helps to characterize the analyte's structural heterogeneity, and/or its flexibility (i.e., the variety of ways the analyte ions can rearrange following electrospray into kinetically stable gas-phase conformations). PMID- 29131944 TI - Double Replication of Silica Colloidal Crystal Films. AB - Inverse opals made by polymerizing vinyl monomers inside a colloidal crystal have lattice dimensions that are contracted relative to the original hard template. This effect was studied in order to investigate the possibility of making double replicas of varying pore sizes from different materials, and to gain a better understanding of the polymer contraction behavior during replication. The degree of lattice contraction was measured using colloidal crystal films formed from silica spheres with diameters in the range 33-225 nm, and polymers pEDMA [poly(1,2-ethanediol dimethacrylate)], pDVB [poly(divinylbenzene)], pHDMA [poly(1,6-hexanediol dimethacrylate)], pBDMA [poly(1,4-butanediol dimethacrylate)], and a 5:4 copolymer mixture of pEDMA/pDVB. The degree of lattice contraction depended on the alkyl chain length of the monomer, as well as the degree of cross-linking, with up to 32% contraction observed for pEDMA when the silica template was removed. However, filling the polymer inverse opals with silica or titania returned the lattice spacing closer to its original size, an effect that can be rationalized in terms of the driving forces for contraction. Double replication of both single-component and binary silica colloidal crystals therefore generated silica and titania replicas of the original lattice. Thus, double replication provides a pathway for accessing periodic structures that are difficult to synthesize directly from materials such as titania. PMID- 29131946 TI - Impact of Linker Length and Composition on Fragment Binding and Cell Permeation: Story of a Bisbenzimidazole Dye Fragment. AB - Small molecules that modulate biological functions are targets of modern day drug discovery efforts. In a common platform fragment-based drug discovery, two fragments that bind to adjacent sites on a target are identified and are then linked together using different linkers to identify the linkage for optimum activity. What are not known from these studies are the effects these linkers, which typically contain C, H, and O atoms, have on the properties of the individual fragment. Herein, we investigate such effects in a bisbenzimidazole fragment whose derivatives have a wide range of therapeutic applications in nucleic acid recognition, sensing, and photodynamic therapy and as cellular probes. We report a dramatic effect of linker length and composition of alkynyl (clickable) Hoechst 33258 derivatives in target binding and cell uptake. We show that the binding of Hoechst 33258-modeled bisbenzimidazoles (1-9) that contain linkers of varying lengths (3-21 atoms) display length- and composition-dependent variation in B-DNA stabilization using a variety of spectroscopic methods. For a dodecamer DNA duplex, the thermal stabilization varied from 0.3 to 9.0 degrees C as the linker length increased from 3 to 21 atoms, respectively. Compounds with linker lengths of <=11 atoms (such as compounds 1 and 5) are localized in the nucleus, while compounds with long linkers (such as compounds 8 and 9) are distributed in the extranuclear space, as well, with possible interactions with extranuclear targets. These findings provide insights into future drug design by revealing how linkers can influence the biophysical and cellular properties of individual drug fragments. PMID- 29131947 TI - Online Differential Thermal Isotope Analysis of Hydration Water in Minerals by Cavity Ringdown Laser Spectroscopy. AB - We have developed a new method for measuring the isotopic composition (delta18O and deltaD) of different types of bonded water (e.g., molecular water, hydroxyl) contained in hydrated minerals by coupling a thermal gravimeter (TG) and a cavity ringdown laser spectrometer (CRDS). The method involves precisely step-heating a mineral sample, allowing the separation of the different types of waters that are released at different temperatures. Simultaneously, the water vapor evolved from the mineral sample is analyzed for oxygen and hydrogen isotopes by CRDS. Isotopic values for the separate peaks are calculated by integrating the product of the water amounts and its isotopic values, after correcting for background. We provide examples of the application of the differential thermal isotope analysis (DTIA) method to a variety of hydrous minerals and mineraloids including gypsum, clays, and amorphous silica (opal). The isotopic compositions of the total water evolved from a set of natural gypsum samples by DTIA are compared with the results of a conventional offline water extraction method followed by CRDS analysis. The results from both methods are in excellent agreement, and precisions (1sigma) for delta18O (+/-0.120/00) and deltaD (+/-0.80/00) of the total gypsum hydration water from the DTIA method are comparable to that obtained by the offline method. A range of analytical challenges and solutions (e.g., spectroscopic interferences produced by VOCs in natural samples, isotopic exchange with structural oxygen, etc.) are discussed. The DTIA method has wide ranging applications for addressing fundamental problems across many disciplines in earth and planetary sciences, including paleoclimatology, sedimentology, volcanology, water exchange between the solid earth and hydrosphere, and water on Mars and other planetary bodies. PMID- 29131945 TI - Enantioselectivity of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks. AB - Nineteen ortho-substituted PCBs are chiral and found enantioselectively enriched in ecosystems. Their differential actions on biological targets are not understood. PCB 95 (2,2',3,5',6-pentachlorobiphenyl), a chiral PCB of current environmental relevance, is among the most potent toward modifying ryanodine receptors (RyR) function and Ca2+ signaling. PCB 95 enantiomers are separated and assigned aR- and aS-PCB 95 using three chiral-column HPLC and circular dichroism spectroscopy. Studies of RyR1-enriched microsomes show aR-PCB 95 with >4* greater potency (EC50 = 0.20 +/- 0.05 MUM), ~ 1.3* higher efficacy (Bmax = 3.74 +/- 0.07 MUM) in [3H]Ryanodine-binding and >3* greater rates (R = 7.72 +/- 0.31 nmol/sec/mg) of Ca2+ efflux compared with aS-PCB 95, whereas racemate has intermediate activity. aR-PCB 95 has modest selectivity for RyR2, and lower potency than racemate toward the RyR isoform mixture in brain membranes. Chronic exposure of hippocampal neuronal networks to nanomolar PCB 95 during a critical developmental period shows divergent influences on synchronous Ca2+ oscillation (SCO): rac-PCB 95 increasing and aR-PCB 95 decreasing SCO frequency at 50 nM, although the latter's effects are nonmonotonic at higher concentration. aS-PCB95 shows the greatest influence on inhibiting responses to 20 Hz electrical pulse trains. Considering persistence of PCB 95 in the environment, stereoselectivity toward RyRs and developing neuronal networks may clarify health risks associated with enantioisomeric enrichment of PCBs. PMID- 29131948 TI - Stable Wettability Control of Nanoporous Microstructures by iCVD Coating of Carbon Nanotubes. AB - Scalable manufacturing of structured materials with engineered nanoporosity is critical for applications in energy storage devices (i.e., batteries and supercapacitors) and in the wettability control of surfaces (i.e., superhydrophobic and superomniphobic surfaces). Patterns formed in arrays of vertically aligned carbon nanotubes (VA-CNTs) have been extensively studied for these applications. However, the as-deposited features are often undesirably altered upon liquid infiltration and evaporation because of capillarity-driven aggregation of low density CNT forests. Here, it is shown that an ultrathin, conformal, and low-surface-energy layer of poly perfluorodecyl acrylate, poly(1H,1H,2H,2H-perfluorodecyl acrylate) (pPFDA), makes the VA-CNTs robust against surface-tension-driven aggregation and densification. This single vapor deposition step allows the fidelity of the as-deposited VA-CNT patterns to be retained during wet processing, such as inking, and subsequent drying. It is demonstrated how to establish omniphobicity or liquid infiltration by controlling the surface morphology. Retaining a crust of entangled CNTs and pPFDA aggregates on top of the patterned VA-CNTs produces micropillars with re-entrant features that prevent the infiltration of low-surface-tension liquids and thus gives rise to stable omniphobicity. Plasma treatments before and after polymer deposition remove the crust of entangled CNTs and pPFDA aggregates and attach hydroxyl groups to the CNT tips, enabling liquid infiltration yet preventing densification of the highly porous CNTs. The latter observation demonstrates the protective character of the pPFDA coating with the potential application of these surfaces for direct contact printing of microelectronic features. PMID- 29131949 TI - Crystalline Coordination Networks of Zero-Valent Metal Centers: Formation of a 3 Dimensional Ni(0) Framework with m-Terphenyl Diisocyanides. AB - A permanently porous, three-dimensional metal-organic material formed from zero valent metal nodes is presented. Combination of ditopic m-terphenyl diisocyanide, [CNArMes2]2, and the d10 Ni(0) precursor Ni(COD)2, produces a porous metal organic material featuring tetrahedral [Ni(CNArMes2)4]n structural sites. X-ray absorption spectroscopy provides firm evidence for the presence of Ni(0) centers, whereas gas-sorption and thermogravimetric analysis reveal the characteristics of a robust network with a microdomain N2-adsorption profile. PMID- 29131950 TI - Cooperative Bond Scission in a Soft Porous Crystal Enables Discriminatory Gate Opening for Ethylene over Ethane. AB - Here we report a soft porous crystal possessing hemilabile cross-links in its framework that exhibits exclusive gate opening for ethylene, enabling the discriminatory adsorption of ethylene over ethane. A Co-based porous coordination polymer (PCP) bearing vinylogous tetrathiafulvalene (VTTF) ligands, [Co(VTTF)], forms Co-S bonds as intermolecular cross-links in its framework in the evacuated closed state. The PCP recognizes ethylene via d-pi complexation on the accessible metal site that displaces and cleaves the Co-S bond to "unlock" the closed structure. This ethylene-triggered unlocking event facilitates remarkable nonporous-to-porous transformations that open up accessible void space. This structural transformation follows a two-step gate-opening process. Each phase, including the intermediate structure, was successfully characterized by single crystal X-ray diffraction analysis, which revealed an intriguing "half-open" structure suggestive of a disproportionate gate-opening phenomenon. The gate opening mechanism was also investigated theoretically; density functional theory and Monte Carlo calculations revealed that the unique "half-open" phase corresponds to a substantially stable intermediate over the possible transformation trajectories. While ethylene opens the gate, ethane does not because it is unable to coordinate to the Co center. This feature is maintained even at pressures above 1 MPa and at a temperature of 303 K, demonstrating the potential of the "gate-locking/unlocking" mechanism that exploits the hemilabile cross-linking in soft porous crystals. PMID- 29131951 TI - Nanoscopic Approach to Quantification of Equilibrium and Rate Constants of Complex Formation at Single-Molecule Level. AB - Equilibrium and rate constants are key descriptors of complex-formation processes in a variety of chemical and biological reactions. However, these parameters are difficult to quantify, especially in the locally confined, heterogeneous, and dynamically changing living matter. Herein, we address this challenge by combining stimulated emission depletion (STED) nanoscopy with fluorescence correlation spectroscopy (FCS). STED reduces the length-scale of observation to tens of nanometres (2D)/attoliters (3D) and the time-scale to microseconds, with direct, gradual control. This allows one to distinguish diffusional and binding processes of complex-formation, even at reaction rates higher by an order of magnitude than in confocal FCS. We provide analytical autocorrelation formulas for probes undergoing diffusion-reaction processes under STED condition. We support the theoretical analysis of experimental STED-FCS data on a model system of dye-micelle, where we retrieve the equilibrium and rates constants. Our work paves a promising way toward quantitative characterization of molecular interactions in vivo. PMID- 29131952 TI - Mesoscopic Diffusion of Poly(ethylene oxide) in Pure and Mixed Solvents. AB - We present results from an experimental dynamic light-scattering study of poly(ethylene oxide) (PEO) in both a pure solvent (water) and a mixed solvent (tert-butanol + water). The concentration dependence of the diffusive relaxation of the PEO molecules is found to be typical of polymers in a good solvent. However, the mesoscopic diffusive behavior of PEO in the mixed solvent is very different, indicating an initial collapse and subsequent reswelling of PEO caused by co-nonsolvency. Furthermore, in the solutions of PEO with very large molecular weights, we found additional hydrodynamic modes indicating the presence of PEO clusters and aggregates similar to those found by some other investigators. PMID- 29131953 TI - Electric Dipole-Magnetic Dipole Polarizability and Anapole Magnetizability of Hydrogen Peroxide as Functions of the HOOH Dihedral Angle. AB - The trace of tensors that account for chiroptical response of the H2O2 molecule is a function of the HO-OH dihedral angle. It vanishes at 0 degrees and 180 degrees , due to the presence of molecular symmetry planes, but also for values in the range 90-100 degrees of this angle, in which the molecule is unquestionably chiral. Such an atypical effect is caused by counterbalancing contributions of diagonal tensor components with nearly maximal magnitude but opposite sign, determined by electron flow in open or closed helical paths, and associated with induced electric and magnetic dipole moments and anapole moments. For values of dihedral angle external to the 90-100 degrees interval, the helical paths become smaller in size, thus reducing the amount of cancellation among diagonal components. Shrinking of helical paths determines the appearance of extremum values of tensor traces approximately at 50 degrees and 140 degrees dihedral angles. PMID- 29131954 TI - Ultrafast Wiggling and Jiggling: Ir2(1,8-diisocyanomenthane)42. AB - Binuclear complexes of d8 metals (PtII, IrI, RhI,) exhibit diverse photonic behavior, including dual emission from relatively long-lived singlet and triplet excited states, as well as photochemical energy, electron, and atom transfer. Time-resolved optical spectroscopic and X-ray studies have revealed the behavior of the dimetallic core, confirming that M-M bonding is strengthened upon dsigma* > psigma excitation. We report the bridging ligand dynamics of Ir2(1,8 diisocyanomenthane)42+ (Ir(dimen)), investigated by fs-ns time-resolved IR spectroscopy (TRIR) in the region of C=N stretching vibrations, nu(C=N), 2000 2300 cm-1. The nu(C=N) IR band of the singlet and triplet dsigma*psigma excited states is shifted by -22 and -16 cm-1 relative to the ground state due to delocalization of the psigma LUMO over the bridging ligands. Ultrafast relaxation dynamics of the 1dsigma*psigma state depend on the initially excited Franck Condon molecular geometry, whereby the same relaxed singlet excited state is populated by two different pathways depending on the starting point at the excited-state potential energy surface. Exciting the long/eclipsed isomer triggers two-stage structural relaxation: 0.5 ps large-scale Ir-Ir contraction and 5 ps Ir-Ir contraction/intramolecular rotation. Exciting the short/twisted isomer induces a ~5 ps bond shortening combined with vibrational cooling. Intersystem crossing (70 ps) follows, populating a 3dsigma*psigma state that lives for hundreds of nanoseconds. During the first 2 ps, the nu(C=N) IR bandwidth oscillates with the frequency of the nu(Ir-Ir) wave packet, ca. 80 cm 1, indicating that the dephasing time of the high-frequency (16 fs)-1 C=N stretch responds to much slower (~400 fs)-1 Ir-Ir coherent oscillations. We conclude that the bonding and dynamics of bridging di-isocyanide ligands are coupled to the dynamics of the metal-metal unit and that the coherent Ir-Ir motion induced by ultrafast excitation drives vibrational dephasing processes over the entire binuclear cation. PMID- 29131955 TI - Interaction between Water and Alkali Metal Ions and Its Temperature Dependence Revealed by Oxygen K-Edge X-ray Absorption Spectroscopy. AB - Interaction between water molecules and alkali metal ions in aqueous salt solutions has been studied by the oxygen K-edge soft X-ray absorption spectroscopy (XAS) in transmission mode. In the measurement of several alkali halide aqueous solutions with different alkali chlorides (Li, Na, and K) and different sodium halides (Cl, Br, and I), the pre-edge component arising from the hydration water molecules shows a blue shift in peak energy as strongly depending on cations but not on anions. In the temperature dependent measurement, the pre edge component arising from water molecules beyond the first hydration shell shows the same behavior as that of pure liquid water. On the other hand, the pre edge component arising from water molecules in the first hydration shell of Li+ ions is not evidently dependent on the temperature, indicating that the hydration water molecules are more strongly bound with Li+ ions than the other water molecules. These experimental results are supported by the results of radial distribution functions of the first hydration shell and their temperature dependence, evaluated by molecular dynamics simulations. PMID- 29131956 TI - Site-Specific Deuteration of Polyunsaturated Alkenes. AB - Selective deuteration of drugs and biologically relevant molecules is becoming increasingly important in the pharmaceutical industry. Site-selective isotopic reinforcement of polyunsaturated fatty acids (PUFAs) at their bis-allylic sites has been identified as a unique approach in preventing oxidative damage in these molecules, which had been linked to neuronal and retinal diseases, atherosclerosis, and aging. Typical methods for preparation of site-selectively deuterated PUFAs require rather long, laborious, and expensive syntheses. In this report, we disclose a very efficient catalytic protocol for site-specific deuteration of PUFAs and analogous poly-alkenes under exceptional kinetic control. Deuterium oxide (D2O) has been identified not only as a deuterium source but also as a crucial component in the overall reaction mechanism responsible for averting the formation of thermodynamically favored side-products. PMID- 29131957 TI - Excimer Formation Dynamics of Dipyrenyldecane in Structurally Different Ionic Liquids. AB - Ionic liquids, being composed of ions alone, may offer alternative pathways for molecular aggregation. These pathways could be controlled by the chemical structure of the cation and the anion of the ionic liquids. Intramolecular excimer formation dynamics of a bifluorophoric probe, 1,3-bis(1-pyrenyl)decane [1Py(10)1Py], where the fluorophoric pyrene moieties are separated by a long decyl chain, is investigated in seven different ionic liquids in 10-90 degrees C temperature range. The long alkyl separator allows for ample interaction with the solubilizing milieu prior to the formation of the excimer. The ionic liquids are composed of two sets, one having four ionic liquids of 1-butyl-3 methylimidazolium cation ([bmim+]) with different anions and the other having four ionic liquids of bis(trifluoromethylsulfonyl)imide anion ([Tf2N-]) with different cations. The excimer-to-monomer emission intensity ratio (IE/IM) is found to increase with increasing temperature in sigmoidal fashion. Chemical structure of the ionic liquid controls the excimer formation efficiency, as IE/IM values within ionic liquids with the same viscosities are found to be significantly different. The excited-state intensity decay kinetics of 1Py(10)1Py in ionic liquids do not adhere to a simplistic Birk's scheme, where only one excimer conformer forms after excitation. The apparent rate constants of excimer formation (ka) in highly viscous ionic liquids are an order of magnitude lower than those reported in organic solvents. In general, the higher the viscosity of the ionic liquid, the more sensitive is the ka to the temperature with higher activation energy, Ea. The trend in Ea is found to be similar to that for activation energy of the viscous flow (Ea,eta). Stokes-Einstein relationship is not followed in [bmim+] ionic liquids; however, with the exception of [choline][Tf2N], it is found to be followed in [Tf2N-] ionic liquids suggesting the cyclization dynamics of 1Py(10)1Py to be diffusion-controlled and to depend on the viscosity of the ionic liquid irrespective of the identity of the cation. The dependence of ionic liquid structure on cyclization dynamics to form intramolecular excimer is amply highlighted. PMID- 29131958 TI - Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics. AB - Benzotriazepin-2-ones were designed to mimic the suggested bioactive gamma-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system. PMID- 29131959 TI - Computational and Experimental Study of Thermodynamics of the Reaction of Titania and Water at High Temperatures. AB - Gaseous titanium hydroxide and oxyhydroxide species were studied with quantum chemical methods. The results are used in conjunction with an experimental transpiration study of titanium dioxide (TiO2) in water vapor-containing environments at elevated temperatures to provide a thermodynamic description of the Ti(OH)4(g) and TiO(OH)2(g) species. The geometry and harmonic vibrational frequencies of these species were computed using the coupled-cluster singles and doubles method with a perturbative correction for connected triple substitutions [CCSD(T)]. For the OH bending and rotation, the B3LYP density functional theory was used to compute corrections to the harmonic approximations. These results were combined to determine the enthalpy of formation. Experimentally, the transpiration method was used with water contents from 0 to 76 mol % in oxygen or argon carrier gases for 20-250 h exposure times at 1473-1673 K. Results indicate that oxygen is not a key contributor to volatilization, and the primary reaction for volatilization in this temperature range is TiO2(s) + H2O(g) = TiO(OH)2(g). Data were analyzed with both the second and third law methods using the thermal functions derived from the theoretical calculations. The third law enthalpy of formation at 298.15 K for TiO(OH)2(g) at 298 K was -838.9 +/- 6.5 kJ/mol, which compares favorably to the theoretical calculation of -838.7 +/- 25 kJ/mol. We recommend the experimentally derived third law enthalpy of formation at 298.15 K for TiO(OH)2, the computed entropy of 320.67 J/mol.K, and the computed heat capacity [149.192 + (-0.02539)T + (8.28697 * 10-6)T2 + (-15614.05)/T + (-5.2182 * 10-11)/T2] J/mol-K, where T is the temperature in K. PMID- 29131961 TI - Mechanistic Studies of the Deslongchamps Annulation. AB - The Cs2CO3-mediated annulations ("Deslongchamps annulations") of three spirocyclic benzoquinone monoketals 5b-d with an ester or acyl substituent at C-2 to two tert-butyl esters of gamma,delta-unsaturated beta-ketocarboxyl acids ("Nazarov reagents"; 2a,b) were monitored 1H NMR spectroscopically. This revealed that a primary product, by all likelihood the Michael adduct, forms fast and prior to the appearance of the Deslongchamps adduct. These primary products form reversibly. This was proved by two crossover and four scavenging experiments. Therein, components already incorporated in one of the mentioned primary products ended up in Deslongchamps adducts different from the one, which would have resulted if the respective primary product had reacted alone. However, these experiments leave open whether our primary products are intermediates en route to Deslongchamps products or whether they represent dead ends. PMID- 29131960 TI - Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition. AB - The enzyme SpnF, involved in the biosynthesis of spinosyn A, catalyzes a formal [4+2] cycloaddition of a 22-membered macrolactone, which may proceed as a concerted [4+2] Diels-Alder reaction or a stepwise [6+4] cycloaddition followed by a Cope rearrangement. Quantum mechanics/molecular mechanics (QM/MM) calculations combined with free energy simulations show that the Diels-Alder pathway is favored in the enzyme environment. OM2/CHARMM free energy simulations for the SpnF-catalyzed reaction predict a free energy barrier of 22 kcal/mol for the concerted Diels-Alder process and provide no evidence of a competitive stepwise pathway. Compared with the gas phase, the enzyme lowers the Diels-Alder barrier significantly, consistent with experimental observations. Inspection of the optimized geometries indicates that the enzyme may prearrange the substrate within the active site to accelerate the [4+2] cycloaddition and impede the [6+4] cycloaddition through interactions with active-site residues. Judging from partial charge analysis, we find that the hydrogen bond between the Thr196 residue of SpnF and the substrate C15 carbonyl group contributes to the enhancement of the rate of the Diels-Alder reaction. QM/MM simulations show that the substrate can easily adopt a reactive conformation in the active site of SpnF because interconversion between the C5-C6 s-trans and s-cis conformers is facile. Our QM/MM study suggests that the enzyme SpnF does behave as a Diels-Alderase. PMID- 29131962 TI - Intercalation and Deintercalation of Lithium at the Ionic Liquid-Graphite(0001) Interface. AB - The intercalation and deintercalation of lithium (Li) into / out of graphite(0001), which is a highly important process in Li-ion batteries, was investigated under ultrahigh vacuum conditions as a function of temperature, employing X-ray and ultraviolet photoelectron spectroscopy. Both the up-shifts of the core-level binding energy and the lowering of the work function DeltaPhi reveal that heating of a monolayer of the battery-relevant ionic liquid (IL) 1 butyl-1-methyl-pyrrolidinium bis(trifluoromethylsulfonyl)imide ([BMP]+[TFSI]-) adsorbed on lithiated graphite at 80 K to >230 K facilitates an accumulation of partially charged Lidelta+ atoms at the IL-graphite(0001) interface. This is accompanied by a partial IL decomposition, which is associated with the initial stages of the chemical formation of the solid-electrolyte interphase. PMID- 29131963 TI - Hybrid Integration of Solid-State Quantum Emitters on a Silicon Photonic Chip. AB - Scalable quantum photonic systems require efficient single photon sources coupled to integrated photonic devices. Solid-state quantum emitters can generate single photons with high efficiency, while silicon photonic circuits can manipulate them in an integrated device structure. Combining these two material platforms could, therefore, significantly increase the complexity of integrated quantum photonic devices. Here, we demonstrate hybrid integration of solid-state quantum emitters to a silicon photonic device. We develop a pick-and-place technique that can position epitaxially grown InAs/InP quantum dots emitting at telecom wavelengths on a silicon photonic chip deterministically with nanoscale precision. We employ an adiabatic tapering approach to transfer the emission from the quantum dots to the waveguide with high efficiency. We also incorporate an on-chip silicon photonic beamsplitter to perform a Hanbury-Brown and Twiss measurement. Our approach could enable integration of precharacterized III-V quantum photonic devices into large-scale photonic structures to enable complex devices composed of many emitters and photons. PMID- 29131964 TI - Electrostatic Origins of the Positive and Negative Charging Difference in the Contact Charge Electrophoresis of a Water Droplet. AB - The positive and negative charging difference in the contact charge electrophoresis of a water droplet suspended in oil was investigated to find out the origin of this charging difference. Through numerous experiments and numerical analysis, the charging difference has been found to be mainly originated from electrostatic sources. Two electrostatic sources were found in the present experimental setup, and by excluding those two sources the charging difference was successfully diminished. The present findings well explain previous experimental results and also provide design guidelines for consistent droplet movement control in contact charge electrophoresis-based digital microfluidic systems. Finally, further discussions on the obtained results, its implications, and future work are discussed. PMID- 29131965 TI - In Situ Visualization of Fast Surface Ion Diffusion in Vanadium Dioxide Nanowires. AB - We investigate in situ ion diffusion in vanadium dioxide (VO2) nanowires (NWs) by using photocurrent imaging. Alkali metal ions are injected into a NW segment via ionic liquid gating and are shown to diffuse along the NW axis. The visualization of ion diffusion is realized by spatially resolved photocurrent measurements, which detect the charge carrier density change associated with the ion incorporation. Diffusion constants are determined to be on the order of 10-10 cm2/s for both Li+ and Na+ ions at room temperature, while H+ diffuses much slower. The ion diffusion is also found to occur mainly at the surface of the NWs, as metal contacts can effectively block the ion diffusion. This novel method of visualizing ion distribution is expected to be applied to study ion diffusion in a broad range of materials, providing key insights on phase transition electronics and energy storage applications. PMID- 29131966 TI - Activation of the central melanocortin system in rats persistently reduces body and fat mass independently of caloric reduction. AB - Recent evidence indicate that melanotan II (MTII) reduces body mass independently of caloric reduction. Because MTII induces a transient hypophagia, caloric reduction is still considered a primary mechanism for MTII-mediated body mass loss. To examine the contribution of caloric reduction to long-term body mass loss in response to MTII, we centrally infused MTII or vehicle in ad libitum fed (MTII and Control) animals in comparison with a group of animals that were pair fed (PF) to the MTII group. Food intake and body mass were recorded daily, and body composition was assessed biweekly. The present study demonstrates that central MTII-mediated body mass loss is only partially mediated by caloric restriction, and the long-term body mass loss is independent of the initial hypophagia. More importantly, central MTII administration induced a rapid but sustained fat mass loss, independently of caloric reduction. MTII-treated animals preserved their lean/fat mass ratio throughout the study, whereas PF animals underwent a transient reduction of lean/fat mass ratio that was only normalized when food intake returned to Control level. In summary, it can be concluded that activation of the central melanocortin system in rats persistently reduces body and fat mass independently of caloric reduction. PMID- 29131967 TI - Prognostic role of neutrophil-to-lymphocyte ratio (NLR) in patients with operable ampullary carcinoma. AB - Ampullary carcinoma or cancer of the ampulla of Vater is a rare malignancy with a high recurrence rate. Although cost-effective biomarkers, such as neutrophil-to lymphocyte ratio (NLR), have been investigated in other cancers for predicting postoperative prognosis in patients, studies on the role of NLR in ampullary cancer are scarce. Here we aimed to evaluate the prognostic significance of preoperative NLR in patients with operable ampullary carcinoma. We retrospectively reviewed 87 patients who underwent pancreaticoduodenectomy for the treatment of ampullary carcinoma between December 1999 and April 2014. The association between NLR and prognosis (overall survival [OS] and disease-free survival [DFS]) was evaluated. Possible correlations between NLR and clinicopathological features were also assessed. The 5-year DFS and OS rates after surgery in patients with ampullary carcinoma were 51% and 63%, respectively. A high NLR (>=3.0) was found in 40 patients. The NLR was a significant prognostic factor for both OS and DFS. Multivariate analysis revealed a significantly worse OS in patients with positive surgical margins and NLR >=3 (p = 0.001). Patients with T3-T4 stage (p = 0.029) and NLR >=3 (p = 0.043) had a lower DFS. Patients with a high NLR had a significantly worse Eastern Cooperative Oncology Group performance score. Preoperative NLR is an independent and significant predictive factor of prognosis in patients with ampullary carcinoma. An elevated pretreatment NLR (e.g., NLR >=3) may be considered as a biomarker for poor prognosis in patients with ampullary carcinoma. PMID- 29131969 TI - Maternal communicative functions and mind-mindedness at 16 months as predictors of children's internal and non-internal language at 20 months. AB - The effects of Communicative functions and Mind-Mindedness on children's language development have been typically investigated in separate studies. The present longitudinal research was therefore designed to yield new insight into the simultaneous impact of these two dimensions of maternal responsiveness on the acquisition of expressive language skills in a sample of 25 mother-child dyads. The frequencies of five communicative functions (Tutorial, Didactic, Conversational, Control and Asynchronous) and two types of mind-related comments (attuned vs. non-attuned) were assessed from a 15-min play session at 16 months. Children's expressive language was examined at both 16 months (number of word types and tokens produced, and number of words attributed to the child in the Questionnaire for Communication and Early Language development) and 20 months (number of internal and non-internal words attributed to the child in the Italian version of the Mac Arthur-Bates Communicative Development Inventory). The main finding was that mothers' use of attuned mind-related comments at 16 months predicted internal state language at 20 months, above and beyond the effects of CFs and children's linguistic ability at 16 months; in addition, mothers' Tutorial function at 16 months marginally predicted non-internal state language at 20 months, after controlling for MM and children's linguistic ability at 16 months. These results suggest that different expressions of maternal responsiveness influence distinct aspects of children's expressive language in the second year of life, although the effects of MM appear to be more robust. PMID- 29131968 TI - Development of body emotion perception in infancy: From discrimination to recognition. AB - Research suggests that infants progress from discrimination to recognition of emotions in faces during the first half year of life. It is unknown whether the perception of emotions from bodies develops in a similar manner. In the current study, when presented with happy and angry body videos and voices, 5-month-olds looked longer at the matching video when they were presented upright but not when they were inverted. In contrast, 3.5-month-olds failed to match even with upright videos. Thus, 5-month-olds but not 3.5-month-olds exhibited evidence of recognition of emotions from bodies by demonstrating intermodal matching. In a subsequent experiment, younger infants did discriminate between body emotion videos but failed to exhibit an inversion effect, suggesting that discrimination may be based on low-level stimulus features. These results document a developmental change from discrimination based on non-emotional information at 3.5 months to recognition of body emotions at 5 months. This pattern of development is similar to face emotion knowledge development and suggests that both the face and body emotion perception systems develop rapidly during the first half year of life. PMID- 29131971 TI - In Reply. PMID- 29131970 TI - Aloe barbadensis miller versus silver sulfadiazine creams for wound healing by secondary intention in dogs and cats: A randomized controlled study. AB - The objective of this study was to compare the effectiveness of the topical application of Aloe barbadensis Miller (juice and fresh gel) to skin wounds, in dogs and cats, with that of topically applied silver sulfadiazine cream. The sample included 16 patients with cutaneous wounds (13 dogs and three cats) that were divided into three groups. Aloe vera "juice" and "fresh gel" were applied for groups I and II, respectively, while silver sulfadiazine was applied for the control group III. In order to evaluate the healing of wounds, the following parameters were taken into consideration: the percentage of wound shrinkage, the healing time and the macroscopic appearance of the scarring process. The interpretation of the data relating to the percentage of wound shrinkage showed a faster rate for groups I and II compared to that of group III. However, the wound shrinkage rates between "juice" and "fresh gel" protocols were not significantly different. Aloe vera was more effective than silver sulfadiazine, in accelerating wound shrinkage, reducing healing time and decreasing the severity of the associated injuries. PMID- 29131972 TI - Efficient adsorption of Selenium(IV) from water by hematite modified magnetic nanoparticles. AB - Selenium (Se) could enter the environment through different anthropogenic sources, posing potential health risk. The removal of trace Se(IV) from water by hematite coated magnetic nanoparticle (MNP@hematite) under different solution conditions was investigated through batch experiments. The adsorption capacity of Se(IV) by MNP@hematite was 25.0 mg/g.100 MUg/L of Se(IV) could be rapidly decreased to below 10 MUg/L by 0.1 g/L of MNP@hematite in 10 min. MNP@hematite could effectively remove Se(IV) in a wide pH range from 4 to 9. Se(IV) could form inner-sphere complex with MNP@hematite. Thus, the presence of chloride, nitrate, and sulfate (concentration of each anions <10 mM) did not affect the removal of Se(IV); whereas, carbonate (10 mM), silicate (1 mM), and phosphate (0.1 mM) yet reduced the adsorption efficiency by competing adsorption sites. Humic acid and alginate (up to 6 mg/L) did not have obviously influence on the removal of Se(IV). MNP@hematite particles were able to simultaneously remove Se(IV) and Sb(III) at trace level very efficiently in 10 min. The magnetic adsorbent can be easily recycled and regenerated in 10 mM NaOH for 15 min. In five consecutive cycles, the adsorption and desorption efficiencies were over 97% and 82%, respectively. MNP@hematite could be employed as effective adsorbent for Se(IV) removal from water. PMID- 29131973 TI - Investigation of the photocatalytic transformation of acesulfame K in the presence of different TiO2-based materials. AB - The photocatalytic transformation of acesulfame K - an artificial sweetener that has gained popularity over the last decades for being a calorie-free additive in food, beverages and several pharmaceutical products - was studied using three different photocatalysts, the benchmark TiO2-P25 and two other forms of synthetized titanium oxides named TiO2-SG1 and TiO2-SG2. The two latter materials were synthesized by a sol gel process in which the hydrolysis rate of titanium n butoxide was controlled by the water formed in situ through an esterification reaction between ethanol and acetic acid. The investigation included monitoring the sweetener disappearance, identifying its intermediate compounds, assessing mineralization and evaluating toxicity. The analyses were carried out using high performance liquid chromatography (HPLC) coupled with a LTQ-Orbitrap analyzer via an electrospray ionization (ESI) in the negative ion mode. This is a powerful tool for the identification, characterization and measurement of the transformation products (TPs); overall 13 species were identified. The use of several semiconductors has pointed out differences in terms of both photocatalytic efficiency and mechanism: the assessment of the evolution kinetics of each species (TPs, total organic carbon and inorganic ions) has brought to the elaboration of a general transformation pathway of acesulfame K. TiO2-SG2 proved to be the most efficient material in degrading the artificial sweetener and leads to the complete mineralization within 6 h of irradiation, while up to 16 h are required for TiO2-P25. PMID- 29131974 TI - Synthetic hospital wastewater treatment by coupling submerged membrane bioreactor and electrochemical advanced oxidation process: Kinetic study and toxicity assessment. AB - In this work, the combination of membrane bioreactor (MBR) and electro-oxidation (EO) process was studied for the treatment of a synthetic hospital wastewater fortified with four pharmaceutical pollutants namely carbamazepine (CBZ), ibuprofen (IBU), estradiol (E-E) at a concentration of 10 MUg L-1 venlafaxine (VEN) at 0.2 MUg L-1. Two treatment configurations were studied: EO process as pre-treatment and post-treatment. Wastewater treatment with MBR alone shows high removal percentages of IBU and E-E (~90%). Unlikely for CBZ and VEN, a low elimination percentage (~10%) was observed. The hydraulic and the solid retention times (HRT and SRT) were 18 h and 140 d respectively, while the biomass concentration in the MBR was 16.5 g L-1. To enhance pharmaceuticals elimination, an EO pretreatment was conducted during 40 min at 2 A. This configuration allowed a 92% removal for VEN, which was far greater than both treatments alone, with lower than 30% and 50% for MBR and EO, respectively. The MBR-EO coupling (EO as post-treatment) allows high removal percentages (~97%) of the four pharmaceutical pollutants after 40 min of treatment at a current intensity of 0.5 A with Nb/BDD as electrodes. This configuration appears to be very effective compared to the first configuration (EO-MBR) where EO process is used as a pre-treatment. Toxicity assessment showed that the treated effluent of this configuration is not toxic to Daphnia magna except at 100% v/v. The MBR-EO coupling appears to be a promising treatment for contaminated hospital effluents. PMID- 29131975 TI - Identification of urinary biomarkers of exposure to di-(2-propylheptyl) phthalate using high-resolution mass spectrometry and two data-screening approaches. AB - Di-(2-propylheptyl) phthalate (DPHP) is a plasticizer used in polyvinyl chloride and vinyl chloride copolymer that has been suggested to be a toxicant in rats and may affect human health. Because the use of DPHP is increasing, the general German population is being exposed to DPHP. Toxicant metabolism is important for human toxicant exposure assessments. To date, the knowledge regarding DPHP metabolism has been limited, and only four metabolites have been identified in human urine. Ultra-performance liquid chromatography was coupled with Orbitrap high-resolution mass spectrometry (MS) and two data-screening approaches-the signal mining algorithm with isotope tracing (SMAIT) and the mass defect filter (MDF)-for DPHP metabolite candidate discovery. In total, 13 and 104 metabolite candidates were identified by the two approaches, respectively, in in vitro DPHP incubation samples. Of these candidates, 17 were validated as tentative exposure biomarkers using a rat model, 13 of which have not been reported in the literature. The two approaches generated rather different tentative DPHP exposure biomarkers, indicating that these approaches are complementary for discovering exposure biomarkers. Compared with the four previously reported DPHP metabolites, the three tentative novel biomarkers had higher peak intensity ratios, and two were confirmed as DPHP hydroxyl metabolites based on their MS/MS product ion profiles. These three tentative novel biomarkers should be further investigated for potential application in human exposure assessment. PMID- 29131976 TI - Purification of eutrophic water containing chlorpyrifos by aquatic plants and its effects on planktonic bacteria. AB - In this study, the removal of nutrients and chlorpyrifos as well as shifts of planktonic bacterial communities in constructed microcosms were investigated to evaluate the influence of Phragmites australis, Nymphaea alba, and Myriophyllum verticillatum, and their combination, on the restoration of eutrophic water containing chlorpyrifos. Plant-treated groups showed a higher pollutant removal rate than did no-remediation controls, indicating that treatment with plants is effective at remediation of eutrophic water containing chlorpyrifos. Different plants showed different performance on the remediation of eutrophic water, e.g., P. australis manifested stronger capacity for removal of sediment chlorpyrifos. This finding indicated that an appropriate plant combination is needed to deal with complex wastewater. During the treatments, the planktonic bacterial communities were influenced by the concentrations of nutrients and pollutants. The changes of composition of bacterial communities indicated a strong correlation between the bacterial communities and the concentrations of pollutants. The plants also influenced the planktonic bacterial communities, especially at the early phase of treatments. For example, P. australis increased the abundance of Limnohabitans and Nevskia significantly and decreased the abundance of Devosia, Luteolibacter, Methylibium, and Caulobacter significantly. The abundance of Hydrocarboniphaga significantly increased in N. alba-treated microcosms, whereas in M. verticillatum-treated microcosms, the abundance of Limnohabitans and Bdellovibrio significantly increased. Our results suggest that the planktonic bacterial communities may be altered during phytoremediation, and the functions of the affected bacteria should be concerned. PMID- 29131977 TI - Source apportionment of heavy metals in agricultural soil based on PMF: A case study in Hexi Corridor, northwest China. AB - Hexi Corridor is the most important base of commodity grain and producing area for cash crops. However, the rapid development of agriculture and industry has inevitably led to heavy metal contamination in the soils. Multivariate statistical analysis, GIS-based geostatistical methods and Positive Matrix Factorization (PMF) receptor modeling techniques were used to understand the levels of heavy metals and their source apportionment for agricultural soil in Hexi Corridor. The results showed that the average concentrations of Cr, Cu, Ni, Pb and Zn were lower than the secondary standard of soil environmental quality; however, the concentrations of eight metals (Cr, Cu, Mn, Ni, Pb, Ti, V and Zn) were higher than background values, and their corresponding enrichment factor values were significantly greater than 1. Different degrees of heavy metal pollution occurred in the agricultural soils; specifically, Ni had the most potential for impacting human health. The results from the multivariate statistical analysis and GIS-based geostatistical methods indicated both natural sources (Co and W) and anthropogenic sources (Cr, Cu, Mn, Ni, Pb, Ti, V and Zn). To better identify pollution sources of heavy metals in the agricultural soils, the PMF model was applied. Further source apportionment revealed that enrichments of Pb and Zn were attributed to traffic sources; Cr and Ni were closely related to industrial activities, including mining, smelting, coal combustion, iron and steel production and metal processing; Zn and Cu originated from agricultural activities; and V, Ti and Mn were derived from oil- and coal-related activities. PMID- 29131978 TI - Simultaneous photodegradation of VOC mixture by TiO2 powders. AB - Volatile and semi volatile organic compounds' concentration have dramatically increased in indoor environments in recent years. UV light promotes titanium dioxide, which oxidises various molecules; however, most of the studies report the degradation of a single VOC. Here, we investigate the photo-oxidation of 17 molecules in mixture to have a realistic test of TiO2 efficacy. We compare P25, a nanometric catalyst, and 1077, a micrometric sample, that poses less health concerns. A proton-transfer-reaction mass spectrometer measured online the concentration of all the pollutants simultaneously. Aldehydes compete for the adsorption on both the catalyst's active sites and thus they degrade 70% and 55% with P25 and 1077 respectively. Considering the single pollutant oxidation, instead, aldehydes fully oxidize. Even though benzene is recalcitrant to degradation, P25 and 1077 reduced toluene's concentration to 97% and 96% in 55 min, respectively. Acetonitrile is refractory to photocatalysis. PMID- 29131979 TI - Non-methane hydrocarbons in a controlled ecological life support system. AB - Non-methane hydrocarbons (NMHCs) are vital to people's health and plants' growth, especially inside a controlled ecological life support system (CELSS) built for long-term space explorations. In this study, we measured 54 kinds of NMHCs to study their changing trends in concentration levels during a 4-person-180-day integrated experiment inside a CELSS with four cabins for plants growing and other two cabins for human daily activities and resources management. During the experiment, the total mixing ratio of measured NMHCs was 423 +/- 283 ppbv at the first day and it approached 2961 +/- 323 ppbv ultimately. Ethane and propane were the most abundant alkanes and their mixing ratios kept growing from 27.5 +/- 19.4 and 31.0 +/- 33.6 ppbv to 2423 +/- 449 ppbv and 290 +/- 10 ppbv in the end. For alkenes, ethylene and isoprene presented continuously fluctuating states during the experimental period with average mixing ratios of 30.4 +/- 19.3 ppbv, 7.4 +/- 5.8 ppbv. For aromatic hydrocarbons, the total mixing ratios of benzene, toluene, ethylbenzene and xylenes declined from 48.0 +/- 44 ppbv initially to 3.8 +/- 1.1 ppbv ultimately. Biomass burning, sewage treatment, construction materials and plants all contributed to NMHCs inside CELSS. In conclusion, the results demonstrate the changing trends of NMHCs in a long-term closed ecological environment's atmosphere which provides valuable information for both the atmosphere management of CELSS and the exploration of interactions between humans and the total environment. PMID- 29131980 TI - Pedestrians' perception and response towards vehicles during road-crossing at nighttime. AB - Pedestrian being involved in road traffic accidents (RTA) is about 22% of all road traffic related deaths. In this study, we have estimated the pedestrian's response towards an approaching vehicle and the time taken to correctly recognize it while they crossed the road in dim-light nighttime conditions. This is also extendable to cycles and other low powered vehicles. Thirty volunteers participated in this study. A collection of six videos, which comprised of different vehicle scenarios were shown to each of the participants. It was observed that correct identification and time to recognize the vehicle was fastest when light emitting diode (LED) strip was fixed between headlights of a four-wheeler. Average time to recognize a low beam car and a high beam car with an LED strip was 7.62+/-2.39s and 11.23+/-2.94s respectively, whereas correct identification rates of the said low beam and high beam cars with LED strips were 93.33% and 86.67% respectively. Earlier when no LED was used, time to recognize low beam car and high beam car without LED strip were 20.55+/-3.50s and 25.57+/ 4.14s respectively whereas correct identification of low beam car without LED strip and high beam car without LED strip were 90.00% and 56.67% respectively. Pedestrians are therefore less confused and can take right decision while crossing the road - particularly in a poor lighting environment - when there is a demarcating illumination between headlights of vehicle. PMID- 29131981 TI - Disturbances in the control of capillary flow in an aged APPswe/PS1DeltaE9 model of Alzheimer's disease. AB - Vascular changes are thought to contribute to the development of Alzheimer's disease, and both cerebral blood flow and its responses during neural activation are reduced before Alzheimer's disease symptoms onset. One hypothetical explanation is that capillary dysfunction reduces oxygen extraction efficacy. This study compares the morphology and hemodynamics of the microvasculature in the somatosensory cortex of 18-month-old APPSWE/PS1DeltaE9 (transgenic [Tg]) mice and wild-type (WT) littermates. In particular, the extent to which their capillary transit times homogenize during functional activation was measured and compared. Capillary length density was similar in both groups but capillary blood flow during rest was lower in the Tg mice, indicating that cortical oxygen availability is reduced. The capillary hemodynamic response to functional activation was larger, and lasted longer in Tg mice than in WT mice. The homogenization of capillary transit times during functional activation, which we previously demonstrated in young mice, was absent in the Tg mice. This study demonstrates that both neurovascular coupling and capillary function are profoundly disturbed in aged Tg and WT mice. PMID- 29131982 TI - Multimodal MRI quantification of the common neurostructural bases within the FTD ALS continuum. AB - The continuum hypothesis linking the behavioral variant of frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS) is supported by clinical, pathological, genetic, and neuroimaging evidence. In the present multimodal magnetic resonance study, we characterized the site and extent of shared neurostructural changes in gray and white matter in 20 bvFTD and 19 ALS patients without dementia. We found an overlap of macrostructural and microstructural damage in both patient groups compared with healthy controls, involving the right orbital and the bilateral anterior cingulate cortices, the corticospinal tract and corpus callosum. The quantification of gray and white matter damage within the areas of shared alterations highlighted a higher degree of atrophy in orbitofrontal and frontomedial regions in patients with more severe executive and/or behavioral symptoms, and a higher degree of degeneration in the motor pathway in patients with more severe motor neuron disorders. Our finding provides additional evidence confirming the FTD-ALS continuum hypothesis and supports the notion of a bimodal but convergent pattern of neurostructural changes characterizing bvFTD and ALS. PMID- 29131983 TI - Editorial Comment. PMID- 29131984 TI - Editorial Comment. PMID- 29131985 TI - Analysis of contaminated nuclear plant steel by laser-induced breakdown spectroscopy. AB - Laser Induced Breakdown Spectroscopy (LIBS) has the potential to allow direct, standoff measurement of contaminants on nuclear plant. Here, LIBS is evaluated as an analytical tool for measurement of Sr and Cs contamination on type 304 stainless steel surfaces. Samples were reacted in model acidic (PUREX reprocessing) and alkaline (spent fuel ponds) Sr and Cs bearing liquors, with LIBS multi-pulse ablation also explored to measure contaminant penetration. The Sr II (407.77nm) and Cs I (894.35nm) emission lines could be separated from the bulk emission spectra, though only Sr could be reliably detected at surface loadings >0.5mgcm-2. Depth profiling showed decay of the Sr signal with time, but importantly, elemental analysis indicated that material expelled from LIBS craters is redistributed and may interfere in later laser shot analyses. PMID- 29131986 TI - Field-scale multi-phase LNAPL remediation: Validating a new computational framework against sequential field pilot trials. AB - Remediation of subsurface systems, including groundwater, soil and soil gas, contaminated with light non-aqueous phase liquids (LNAPLs) is challenging. Field scale pilot trials of multi-phase remediation were undertaken at a site to determine the effectiveness of recovery options. Sequential LNAPL skimming and vacuum-enhanced skimming, with and without water table drawdown were trialled over 78days; in total extracting over 5m3 of LNAPL. For the first time, a multi component simulation framework (including the multi-phase multi-component code TMVOC-MP and processing codes) was developed and applied to simulate the broad range of multi-phase remediation and recovery methods used in the field trials. This framework was validated against the sequential pilot trials by comparing predicted and measured LNAPL mass removal rates and compositional changes. The framework was tested on both a Cray supercomputer and a cluster. Simulations mimicked trends in LNAPL recovery rates (from 0.14 to 3mL/s) across all remediation techniques each operating over periods of 4-14days over the 78day trial. The code also approximated order of magnitude compositional changes of hazardous chemical concentrations in extracted gas during vacuum-enhanced recovery. The verified framework enables longer term prediction of the effectiveness of remediation approaches allowing better determination of remediation endpoints and long-term risks. PMID- 29131987 TI - Quantifying the interactions among metal mixtures in toxicodynamic process with generalized linear model. AB - Predicting the toxicity of chemical mixtures is difficult because of the additive, antagonistic, or synergistic interactions among the mixture components. Antagonistic and synergistic interactions are dominant in metal mixtures, and their distributions may correlate with exposure concentrations. However, whether the interaction types of metal mixtures change at different time points during toxicodynamic (TD) processes is undetermined because of insufficient appropriate models and metal bioaccumulation data at different time points. In the present study, the generalized linear model (GLM) was used to illustrate the combined toxicities of binary metal mixtures, such as Cu-Zn, Cu-Cd, and Cd-Pb, to zebrafish larvae (Danio rerio). GLM was also used to identify possible interaction types among these method for the traditional concentration addition (CA) and independent action (IA) models. Then the GLM were applied to quantify the different possible interaction types for metal mixture toxicity (Cu-Zn, Cu Cd, and Cd-Pb to D. rerio and Ni-Co to Oligochaeta Enchytraeus crypticus) during the TD process at different exposure times. We found different metal interaction responses in the TD process and interactive coefficients significantly changed at different exposure times (p<0.05), which indicated that the interaction types among Cu-Zn, Cu-Cd, Cd-Pb and Ni-Co were time dependent. Our analysis highlighted the importance of considering joint actions in the TD process to understand and predict metal mixture toxicology on organisms. Moreover, care should be taken when evaluating interactions in toxicity prediction because results may vary at different time points. The GLM could be an alternative or complementary approach for BLM to analyze and predict metal mixture toxicity. PMID- 29131988 TI - Treatment adoption and relative effectiveness of aromatase inhibitors compared to tamoxifen in early breast cancer: A multi-institutional observational study. AB - BACKGROUND: Since 2005, aromatase inhibitors (AIs) have been the adjuvant treatment of choice for postmenopausal women with early breast cancer (BC). In this study we characterize the adoption of AIs in Portugal, variables associated with treatment administration, and compare its effectiveness (either in monotherapy or sequential therapy) to tamoxifen monotherapy (TAM). PATIENTS AND METHODS: This was a retrospective cohort study that included postmenopausal women with stage I-III hormone receptor (HR) positive BC diagnosed from 2006 to 2008 and treated with adjuvant endocrine therapy in four participating institutions. RESULTS: Of the 1283 eligible patients, 527 (41%) received an AI (16% as monotherapy, 25% as sequential therapy) and 756 (59%) TAM. Patients treated with AI had less differentiated tumors, with higher TNM stage, and were more frequently HER2-positive. Use of AI also differed by center (use range from 33% to 75%, p < 0.001). With a median follow-up of 6.3 years and controlling for clinicopathological and treatment characteristics, treatment with AI had a better overall survival (OS) when compared with TAM (adjusted-HR 0.55, 95% CI 0.37 0.81). CONCLUSION: AIs were successfully introduced as adjuvant treatment for HR positive BC in Portuguese hospitals. Its use was influenced by tumor and patient characteristics, but also center of care. In this large cohort, AI use was associated with an OS benefit. PMID- 29131989 TI - Microwave-assisted photocatalysis of neurotoxin compounds using metal oxides quantum dots/nanosheets composites: Photocorrosion inhibition, reusability and antibacterial activity studies. AB - Water pollution caused by different pollutants is one of the challenging tasks for the scientific community. We have prepared and characterized a material for removal of pollutant compounds. ZnO quantum dots decorated CuO nanosheets and TiO2 quantum dots decorated WO3 nanosheets composites have been prepared using a hydrothermal method. The as synthesized catalysts were characterized by various techniques. The crystallite sizes of CuO NSs and WO3 NSs were to be obtained 12.5 and 13.25nm and when dopped with ZnO and TiO2 size reduces to 3.2 and 3.9nm, respectively. The energy band gap of the CuO NSs, WO3 NSs, ZnO QDs/CuO NSs and TiO2 QDs/WO3 NSs composite are calculated to be 2.01, 2.61, 1.86 and 2.32eV, respectively. The prepared catalysts are efficiently utilized for the photocatalytic degradation of two neurotoxin compounds under UV and UV coupled with microwave irradiation. The prepared catalyst composites reveal excellent photocatalytic degradation of neurotoxin compound by degrading it up to 75% under UV and UV/microwave irradiation. The photocalysis efficiency in UV/microwave system is higher than UV system. The result shows that the ZnO QDs/CuO NSs and TiO2 QDs/WO3 NSs composites have excellent photocorrosion inhibition and reusability properties. Thus, prepared samples with positive surface potential upon interaction with negative surface potential of Enterococcus faecalis and Micrococcus luteus. PMID- 29131990 TI - Non-thermal near-infrared exposure photobiomodulates cellular responses to ionizing radiation in human full thickness skin models. AB - Ionizing and near-infrared radiation are both part of the therapeutic spectrum in cancer treatment. During cancer therapy ionizing radiation is typically used for non-invasive reduction of malignant tissue, while near-infrared photobiomodulation is utilized in palliative medical approaches, e.g. for pain reduction or impairment of wound healing. Furthermore, near-infrared is part of the solar wavelength spectrum. A combined exposure of these two irradiation qualities - either intentionally during medical treatment or unintentionally due to solar exposure - is therefore presumable for cancer patients. Several studies in different model organisms and cell cultures show a strong impact of near infrared pretreatment on ionizing radiation-induced stress response. To investigate the risks of non-thermal near-infrared (NIR) pretreatment in patients, a human in vitro full thickness skin models (FTSM) was evaluated for radiation research. FTSM were pretreated with therapy-relevant doses of NIR followed by X-radiation, and then examined for DNA-double-strand break (DSB) repair, cell proliferation and apoptosis. Double-treated FTSM revealed a clear influence of NIR on X-radiation-induced stress responses in cells in their typical tissue environment. Furthermore, over a 24h time period, double-treated FTSM presented a significant persistence of DSBs, as compared to samples exclusively irradiated by X-rays. In addition, NIR pretreatment inhibited apoptosis induction of integrated fibroblasts, and counteracted the radiation induced proliferation inhibition of basal keratinocytes. Our work suggests that cancer patients treated with X-rays should be prevented from uncontrolled NIR irradiation. On the other hand, controlled double-treatment could provide an alternative therapy approach, exposing the patient to less radiation. PMID- 29131991 TI - Enhanced mental imagery and intact perceptual organization in schizotypal personality disorder. AB - According to a widely held view, psychotic disorders such as schizophrenia are characterized by a vague boundary between the perception of the external world and the inner imagery of persons, objects, and events. In this study, we addressed the perception-imagery debate in schizotypal personality disorder (SPD). Thirty individuals with SPD and 30 matched healthy subjects completed a lateral masking task. Participants were asked to detect a low-contrast Gabor patch flanked by two collinear Gabor masks. In the perceptual task, the masks were physically present, whereas in the imagery task, participants only imagined the masks. By applying a binocular rivalry paradigm, we also measured the imagery priming effect. Results revealed that, in the perceptual task, collinear masks similarly decreased contrast threshold in SPD and controls. In the imagery task, contrast threshold reduction (facilitation by the imagined masks) was more pronounced in SPD relative to the controls. In the binocular rivalry paradigm, individuals with SPD showed higher imagery priming effects as compared to healthy controls. Enhanced imagery was not related to schizotypal traits. These results indicate intact early visual perception and heightened imagery in SPD, which may be a trait marker of unusual experiences without psychotic disorganization. PMID- 29131992 TI - Cross-validation of the Personality Assessment Inventory "Chronic Suicide Risk Index: S_Chron" in a large sample of offenders. AB - Recently, Sinclair et al. (2016) reported on the development of a new Personality Assessment Inventory (PAI) index designed to identify individuals with histories of multiple suicide attempts (Chronic Suicide Risk Index: S_Chron). We evaluated this new index in a sample of over 1000 criminal offenders who had been administered the PAI as part of a more extensive research project. The S_Chron meaningfully discriminated between those with multiple prior suicide attempts and those with 0-1 attempts, similar to what Sinclair et al. reported. However, it did not demonstrate incremental validity beyond the PAI's Suicidal Ideation scale. PMID- 29131993 TI - The structure of co-occurring PTSD and depression symptoms in a cohort of Marines pre- and post-deployment. AB - Symptoms of posttraumatic stress disorder (PTSD) and major depressive disorder are the most frequently co-occurring problems following potentially traumatic events. It is unclear whether these comorbidities represent two correlated but distinct disorders or a common post-event response. We sought to inform this question by examining the distinctiveness of PTSD and depression symptoms at four cross-sectional time points, using data from a parent prospective longitudinal study of 858 Marines evaluated before deployment and approximately 1, 5, and 8 months after returning from the Afghanistan war. We conducted a series of cross sectional confirmatory factor analyses of PTSD and depression symptoms at each time point, using the Posttraumatic Stress Disorder Checklist IV and the Beck Depression Inventory II. Analyses indicated that across all four assessments, self-reported symptoms on the measures were best explained by distinct but correlated subclusters of symptoms within each measure. This structure was supported by the data both before and after deployment, even with increases in average PTSD symptoms after deployment. These findings suggest that despite shared method variance and some symptom overlap, self-reports of PTSD and depression symptoms across a stressful combat deployment show distinct symptom subclusters rather than a general common trauma reaction in this sample of Marines. PMID- 29131994 TI - pH-dependent KOW provides new insights in understanding the adsorption mechanism of ionizable organic chemicals on carbonaceous materials. AB - The dominant adsorption mechanism of ionizable organic chemicals (IOCs) on carbonaceous materials is still unclear. This study used benzoic acid (BA), o chlorobenzoic acid (2-CBA) and p-chlorobenzoic acid (4-CBA) as representatives of IOCs to investigate the dominant adsorption mechanism on graphene oxide (GO) and graphite (GP), with a specific emphasis on the impact of pH-dependent KOW. The order of apparent adsorption of the investigated chemicals changed with pH, which could not be explained by their constant KOW. According to our measurement, KOW varied greatly with pH. The pH-dependent adsorption of BA, 2-CBA and 4-CBA were significantly correlated with pH-dependent KOW for both GO and GP. Our observations indicated that the hydrophobic effects may dominate the apparent adsorption of BA, 2-CBA and 4-CBA on GO and GP. Electrostatic repulsion played a minor role in their reduced adsorption at high pH. Negative charge-assisted H bond and pi-pi interactions may explain the adsorption of negatively charged BA, 2-CBA and 4-CBA on negatively charged GO. This study implied that pH-dependent KOW rather than constant KOW should be incorporated to understand IOC adsorption as affected by pH. PMID- 29131995 TI - Thermal air oxidation changes surface and adsorptive properties of black carbon (char/biochar). AB - In this study, we systematically investigated the effects of thermal air oxidation on the properties of biomass-derived black carbon (BC) made at carbonization temperatures (HTTs) of 300-700 degrees C. BC produced by including air in the carbonization step was found to have a low surface area and underdeveloped pore structure. Substantial changes of BC were observed after post pyrolysis thermal air oxidation (PPAO). Well-carbonized BC samples made anoxically at relatively high HTTs (600 and 700 degrees C) showed, after PPAO, significant increases in N2 BET surface area (SA) (up to 700 times), porosity (<60A) (up to 95 times), and adsorptivity (up to 120 times) of neutral organic species including two triazine herbicides and one natural estrogen. Partially carbonized BC made at a lower HTT (300 or 400 degrees C) showed moderate increases in these properties after PPAO, but a large increase in the intensity of Fourier transform infrared spectroscopy bands corresponding to various oxygen containing functional groups. Well-carbonized BC samples, on the other hand, were deficient in surface oxygen functionality even after the PPAO treatment. Adsorption of the test organic compounds on BC generally trended with BET SA when it was less than 300m2/g, but BET SA was poorly predictive of adsorption when it was greater than 300m2/g. Overall, our results suggest that thermal reactions between molecular oxygen and BC 1) increase surface oxygen functionality more effectively for low-HTT than for high-HTT BC samples; 2) increase SA and porosity (<60A) especially for high-HTT BC samples; and 3) create new adsorption sites and/or relieve steric restriction of organic molecules to micropores, thereby enhancing the adsorptivity of BC. These results will prove useful not only for understanding the fate of environmental BC but also in devising strategies for improving the practical performance of the engineered form of BC (i.e., biochar). PMID- 29131996 TI - Development and application of the diffusive gradients in thin films technique for simultaneous measurement of methcathinone and ephedrine in surface river water. AB - In this study, a passive sampling technique, diffusive gradients in thin films (DGT) was developed to simultaneously measure two drugs, methcathinone (MC) and ephedrine (EPH) in surface water. Four types of binding gels and four types of filter membranes were tested for the optimal configuration. XAD18 agarose binding gel and agarose diffusive gel, together with polyethersulfone filter membrane were used for measuring MC and EPH in the DGT device. 5% NH3 in acetonitrile was used as the elution solvent, with the elution efficiency for MC and EPH higher than 71%. At 25 degrees C, the diffusion coefficients of MC and EPH in the diffusive gel were 7.60*10-6cm2s-1 and 6.62*10-6cm2s-1, respectively. The DGT was effective in a wide range of pH (4-11) and ionic strength (NaCl: 0.001-0.5M). The DGT device was deployed in Beijing urban surface water for successive 7days to measure the time-weighted concentrations of MC and EPH. Results showed that EPH was detected in all samples, while MC was below its detection limit. DGT concentrations were comparable to the concentrations determined by SPE. This study demonstrated that the developed DGT method was effective to monitor the two drugs in surface water in situ. PMID- 29131997 TI - Organochlorine pesticides across the tributaries of River Ravi, Pakistan: Human health risk assessment through dermal exposure, ecological risks, source fingerprints and spatio-temporal distribution. AB - This study monitored the human health risks through dermal exposure, hazardous risks to ecological integrity, contamination levels, spatio-temporal distribution, and congener specific analysis of organochlorine pesticides (OCPs) across River Ravi and its three northern tributaries (Nullah Bein, Nullah Basanter and Nullah Deg). The residual levels of OCPs isomers were screened for water (n=54) and surface sediment (n=54) samples from twenty seven sampling sites in two alternate seasons (pre-monsoon and post-monsoon). The ?OCPs concentrations ranged from 13.61 to 1992.18ng/g dry weight and 12.89 to 128.16ng/L with predominance of beta-endosulfan and p,p'-DDT in sediment and water matrixes, respectively. Distribution pattern revealed significantly higher concentrations in upstream and midstream, suggesting considerable transboundary OCPs pollution. Calculated ratios of alpha-HCH/gamma-HCH, o,p'-DDT/p,p'-DDT, (DDE+DDD)/?DDTs and cis/trans-chlordane for water and sediments identified the fresh addition of lindane, technical DDTs and chlordane in the study area. Risk quotient (RQ) based ecological risk was found to be >1 at all studied streams during both seasons and elucidates higher risks for endosulfan (alpha-endosulfan) and endrin. Human health risk assessment indicated absence of hazardous (non-carcinogenic) risk through bathing in studied streams; as the hazard index values ranged from 1.09E 05 to 2.48E-02 (acceptable limit; <1). However, the calculated carcinogenic risk possessed by OCPs through dermal exposure ranged from 1.39E-10 to 1.98E-05 that highlighted the considerable carcinogenic risk associated to aldrin, dieldrin, p,p'-DDT and beta-endosulfan at certain studied sites. Therefore, the high levels of ecological risk and carcinogenic human health risk had emphasized an immediate elimination of ongoing OCPs addition in the studied area. PMID- 29131998 TI - Differential effects of copper nanoparticles/microparticles in agronomic and physiological parameters of oregano (Origanum vulgare). AB - The effects of metallic copper nanoparticles (nCu) in plants are not well understood. In this study, soil grown oregano (Origanum vulgare) was exposed for 60days to nCu and Cu microparticles (MUCu) at 0-200mgCu/kg. At harvest, Cu accumulation, biomass production, nutrient composition, and Cu fractions in soil were measured. Except for MUCu at 50mg/kg, both nCu and MUCu increased root Cu (28.4-116.0%) and shoot Cu (83.0-163.0% and 225.4-652.5%, respectively), compared with control. Copper accumulation from MUCu increased as the external MUCu increased. nCu and MUCu did not affect shoot length, malondialdehyde, or chlorophyll, but increased water content (6.9-12.5%) and reduced shoot biomass (21.6-58.5%), compared with control. In addition, at 50mg/kg, MUCu decreased root biomass and length (48.6% and 20.5%, respectively) and water content (1.8% and 3.9% at 100 and 200mg/kg, respectively). All treatments modified root and shoot Ca, Fe, Mg, and Mn (p<=0.05). Additionally, all Cu treatments decreased starch (33.9-58.5%), total sugar (39.5-55.7%), and reducing sugar (13.6-33.9%) in leaves. Results showed that metallic Cu nanoparticles/microparticles affected agronomical and physiological parameters in oregano, which could impact human nutrition. However, smaller size particles do not necessarily imply greater toxicity. PMID- 29131999 TI - Hydropower impacts on reservoir fish populations are modified by environmental variation. AB - Global transition towards renewable energy production has increased the demand for new and more flexible hydropower operations. Before management and stakeholders can make informed choices on potential mitigations, it is essential to understand how the hydropower reservoir ecosystems respond to water level regulation (WLR) impacts that are likely modified by the reservoirs' abiotic and biotic characteristics. Yet, most reservoir studies have been case-specific, which hampers large-scale planning, evaluation and mitigation actions across various reservoir ecosystems. Here, we investigated how the effect of the magnitude, frequency and duration of WLR on fish populations varies along environmental gradients. We used biomass, density, size, condition and maturation of brown trout (Salmo trutta L.) in Norwegian hydropower reservoirs as a measure of ecosystem response, and tested for interacting effects of WLR and lake morphometry, climatic conditions and fish community structure. Our results showed that environmental drivers modified the responses of brown trout populations to different WLR patterns. Specifically, brown trout biomass and density increased with WLR magnitude particularly in large and complex-shaped reservoirs, but the positive relationships were only evident in reservoirs with no other fish species. Moreover, increasing WLR frequency was associated with increased brown trout density but decreased condition of individuals within the populations. WLR duration had no significant impacts on brown trout, and the mean weight and maturation length of brown trout showed no significant response to any WLR metrics. Our study demonstrates that local environmental characteristics and the biotic community strongly modify the hydropower-induced WLR impacts on reservoir fishes and ecosystems, and that there are no one-size-fits-all solutions to mitigate environmental impacts. This knowledge is vital for sustainable planning, management and mitigation of hydropower operations that need to meet the increasing worldwide demand for both renewable energy and ecosystem services delivered by freshwaters. PMID- 29132000 TI - Reconciling monitoring and modeling: An appraisal of river monitoring networks based on a spatial autocorrelation approach - emerging pollutants in the Danube River as a case study. AB - Rivers extend in space and time under the influence of their catchment area. Our perception largely relies on discrete spatial and temporal observations carried out at certain sites located throughout the catchment (monitoring networks, MN). However, MNs are constrained by (a) the distribution of sampling sites, (b) the dynamics of the variable considered and (c) the river hydrological conditions. In this study, all three aspects were captured and quantified by applying a spatial autocorrelation modeling approach. We exemplarily studied its application to 235 emerging contaminants (pesticides, pharmaceuticals, and personal care products [PPCP], industrial and miscellaneous) measured at 55 sampling sites in the Danube River. 22 out of the 235 compounds monitored were present at all sites and 125 were found in at least 50%.We first calculated the Moran Index (MI) to characterize the spatial autocorrelation of the compound set. 59 compounds showed MI<=0, which can be interpreted as 'no spatial correlation'. Next, spatial autocorrelation models were set for each compound. From the autocorrelation parameter rho, catchment average correlation lengths were derived for each compound. MN optimality was examined and compounds were classified into three groups: (a) those with rho<=0 [25%]; (b) those with rho>0 and correl. length0 and correl. length>average distance between consecutive sites [73%]. The MN was considered optimal only for the latter class. Networks with the larger average distance between consecutive sites resulted in a decreasing number of optimally monitored compounds. Furthermore, neighbors vs. local relative contributions were quantified based on the spatial autocorrelation model for all the measured compounds. The results of this study show how autocorrelation models can aid water managers to improve the design of river MNs, which are a key aspect of the Water Framework Directive. PMID- 29132001 TI - Comparative effects of simulated acid rain of different ratios of SO42- to NO3- on fine root in subtropical plantation of China. AB - The influence of acid rain on forest trees includes direct effects on foliage as well as indirect soil-mediated effects that cause a reduction in fine-root growth. In addition, the concentration of NO3- in acid rain increases with the rapidly growing of nitrogen deposition. In this study, we investigated the impact of simulated acid rain with different SO42-/NO3- (S/N) ratios, which were 5:1 (S), 1:1 (SN) and 1:5 (N), on fine-root growth from March 2015 to February 2016. Results showed that fine roots were more sensitive to the effects of acid rain than soils in the short-term. Both soil pH and fine root biomass (FRB) significantly decreased as acid rain pH decreased, and also decreased with the percentage of NO3- increased in acid rain. Acid rain pH significantly influenced soil total carbon and available potassium in summer. Higher acidity level (pH=2.5), especially of the N treatments, had the strongest inhibitory impact on soil microbial activity after summer. The structural equation modelling results showed that acid rain S/N ratio and pH had stronger direct effects on FRB than indirect effects via changed soil and fine root properties. Fine-root element contents and antioxidant enzymes activities were significantly affected by acid rain S/N ratio and pH during most seasons. Fine-root Al ion content, Ca/Al, Mg/Al ratios and catalase activity were used as better indicators than soil parameters for evaluating the effects of different acid rain S/N ratios and pH on forests. Our results suggest that the ratio of SO42- to NO3- in acid rain is an important factor which could affect fine-root growth in subtropical forests of China. PMID- 29132002 TI - Brassica napus has a key role in the recovery of the health of soils contaminated with metals and diesel by rhizoremediation. AB - Contaminated soils are frequently characterized by the simultaneous presence of organic and inorganic contaminants, as well as a poor biological and nutritional status. Rhizoremediation, the combined use of phytoremediation and bioremediation, has been proposed as a Gentle Remediation Option to rehabilitate multi-contaminated soils. Recently, newer techniques, such as the application of metallic nanoparticles, are being deployed in an attempt to improve traditional remediation options. In order to implement a phytomanagement strategy on calcareous alkaline peri-urban soils simultaneously contaminated with several metals and diesel, we evaluated the effectiveness of Brassica napus L., a profitable crop species, assisted with organic amendment and zero-valent iron nanoparticles (nZVI). A two-month phytotron experiment was carried out using two soils, i.e. amended and unamended with organic matter. Soils were artificially contaminated with Zn, Cu and Cd (1500, 500 and 50mgkg-1, respectively) and diesel (6000mgkg-1). After one month of stabilization, soils were treated with nZVI and/or planted with B. napus. The experiment was conducted with 16 treatments resulting from the combination of the following factors: amended/unamended, contaminated/non-contaminated, planted/unplanted and nZVI/no-nZVI. Soil physicochemical characteristics and biological indicators (plant performance and soil microbial properties) were determined at several time points along the experiment. Carbonate content of soils was the crucial factor for metal immobilization and, concomitantly, reduction of metal toxicity. Organic amendment was essential to promote diesel degradation and to improve the health and biomass of B. napus. Soil microorganisms degraded preferably diesel hydrocarbons of biological origin (biodiesel). Plants had a remarkable positive impact on the activity and functional diversity of soil microbial communities. The nZVI were ineffective as soil remediation tools, but did not cause any toxicity. We concluded that rhizoremediation with B. napus combined with an organic amendment is promising for the phytomanagement of calcareous soils with mixed (metals and diesel) contamination. PMID- 29132004 TI - How are perceptions associated with water consumption in Canadian Inuit? A cross sectional survey in Rigolet, Labrador. AB - Concerns regarding the safety and aesthetic qualities of one's municipal drinking water supply are important factors influencing drinking water perceptions and consumption patterns (i.e. sources used and daily volume of consumption). In northern Canada, Inuit communities face challenges with drinking water quality, and many Inuit have reported concerns regarding the safety of their drinking water. The objectives of this research were to describe perceptions of municipal tap water, examine use of water sources and changes following the installation of a potable water dispensing unit (PWDU) in 2014, and identify factors associated with water consumption in the Inuit community of Rigolet. This study used data from three cross-sectional census surveys conducted between 2012 and 2014. Principal component analysis (PCA) was used to aggregate data from multiple variables related to perceptions of water, and logistic regressions were used to identify variables associated with water consumption patterns. Three quarters of residents reported using the PWDU after its installation, with concomitant declines reported in consumption of bottled, tap, and brook water. Negative perceptions of tap water were associated with lower odds of consuming tap water (ORPCAcomponent1=0.73, 95% CI 0.56-0.94; ORPCAcomponent2=0.67, 95% CI 0.49-0.93); women had higher odds of drinking purchased water compared to men (OR=1.90, 95% CI 1.11-3.26). The median amount of water consumed per day was 1L. Using brook water (OR=2.60, 95% CI 1.22-5.56) and living in a household where no one had full time employment (OR=2.94, 95% CI 1.35-6.39) were associated with consuming >2L of water per day. Results of this study may inform drinking water interventions, risk assessments, and public health messaging in Rigolet and other Indigenous communities. PMID- 29132005 TI - Discriminant analysis as a decision-making tool for geochemically fingerprinting sources of groundwater salinity. AB - Concern over contamination of groundwater resources in areas impacted by anthropogenic activities has led to an increasing number of baseline groundwater quality surveys intended to provide context for interpreting water quality data. Flexible screening tools that can parse through these large, regional datasets to identify spatial or temporal changes in water quality are becoming more important to groundwater scientists. One such tool, developed from previous work by the authors, makes use of linear discriminant analysis (LDA) to identify the most probable source of chloride salinity in groundwater samples based on their geochemical fingerprints. Here, we applied the model to a dataset of shallow groundwater with known sources of contamination compiled from two studies of groundwater quality in Illinois: Panno et al. (2005) and Hwang et al. (2015). By predicting the source of salinity in groundwater samples for which the sources of contamination are known, we validated model prediction-accuracy. Results show high classification accuracy for groundwater samples impacted by basin brines (e.g. deep saline groundwater) and road salt (>80%), with diminishing success for those impacted by organic sources of chloride, such as septic effluent and animal waste. Posterior probabilities, a statistic inherent to LDA, provide a proxy for prediction confidence that enables the model to be used for assessment and accountability measures, such as identifying parties responsible for contamination. LDA is complementary to fingerprinting using halogen ratios (e.g. Cl/Br) because it implicitly relies on halogen ratios for classification decisions while providing a clearer, more quantitative classification of contamination sources. Our model is ideal for regional assessment or initial screening of salinity sources in groundwater because it makes use of commonly measured solute concentrations in publicly available water quality databases. PMID- 29132003 TI - Treatment impacts on temporal microbial community dynamics during phytostabilization of acid-generating mine tailings in semiarid regions. AB - Direct revegetation, or phytostabilization, is a containment strategy for contaminant metals associated with mine tailings in semiarid regions. The weathering of sulfide ore-derived tailings frequently drives acidification that inhibits plant establishment resulting in materials prone to wind and water dispersal. The specific objective of this study was to associate pyritic mine waste acidification, characterized through pore-water chemistry analysis, with dynamic changes in microbial community diversity and phylogenetic composition, and to evaluate the influence of different treatment strategies on the control of acidification dynamics. Samples were collected from a highly instrumented one year mesocosm study that included the following treatments: 1) unamended tailings control; 2) tailings amended with 15% compost; and 3) the 15% compost-amended tailings planted with Atriplex lentiformis. Tailings samples were collected at 0, 3, 6 and 12months and pore water chemistry was monitored as an indicator of acidification and weathering processes. Results confirmed that the acidification process for pyritic mine tailings is associated with a temporal progression of bacterial and archaeal phylotypes from pH sensitive Thiobacillus and Thiomonas to communities dominated by Leptospirillum and Ferroplasma. Pore-water chemistry indicated that weathering rates were highest when Leptospirillum was most abundant. The planted treatment was most successful in disrupting the successional evolution of the Fe/S-oxidizing community. Plant establishment stimulated growth of plant-growth-promoting heterotrophic phylotypes and controlled the proliferation of lithoautotrophic Fe/S-oxidizers. The results suggest the potential for eco-engineering a microbial inoculum to stimulate plant establishment and inhibit proliferation of the most efficient Fe/S-oxidizing phylotypes. PMID- 29132006 TI - Ocean acidification dampens physiological stress response to warming and contamination in a commercially-important fish (Argyrosomus regius). AB - Increases in carbon dioxide (CO2) and other greenhouse gases emissions are changing ocean temperature and carbonate chemistry (warming and acidification, respectively). Moreover, the simultaneous occurrence of highly toxic and persistent contaminants, such as methylmercury, will play a key role in further shaping the ecophysiology of marine organisms. Despite recent studies reporting mostly additive interactions between contaminant and climate change effects, the consequences of multi-stressor exposure are still largely unknown. Here we disentangled how Argyrosomus regius physiology will be affected by future stressors, by analysing organ-dependent mercury (Hg) accumulation (gills, liver and muscle) within isolated/combined warming (DeltaT=4 degrees C) and acidification (DeltapCO2=1100MUatm) scenarios, as well as direct deleterious effects and phenotypic stress response over multi-stressor contexts. After 30days of exposure, although no mortalities were observed in any treatments, Hg concentration was enhanced under warming conditions, especially in the liver. On the other hand, elevated CO2 decreased Hg accumulation and consistently elicited a dampening effect on warming and contamination-elicited oxidative stress (catalase, superoxide dismutase and glutathione-S-transferase activities) and heat shock responses. Thus, potentially unpinned on CO2-promoted protein removal and ionic equilibrium between hydrogen and reactive oxygen species, we found that co-occurring acidification decreased heavy metal accumulation and contributed to physiological homeostasis. Although this indicates that fish can be physiologically capable of withstanding future ocean conditions, additional experiments are needed to fully understand the biochemical repercussions of interactive stressors (additive, synergistic or antagonistic). PMID- 29132007 TI - ASTA - A method for multi-criteria evaluation of water supply technologies to Assess the most SusTainable Alternative for Copenhagen. AB - Utilities in larger cities have to make complex decisions planning future investments in urban water infrastructure. Changes are driven by physical water stress or political targets for environmental water flows e.g. through the implementation of the European water framework directive. To include these environmental, economic and social sustainability dimensions we introduce a novel multi-criteria assessment method for evaluation of water supply technologies. The method is presented and demonstrated for four alternatives for water supply based on groundwater, rain- & stormwater or seawater developed for augmenting Copenhagen's current groundwater based water supply. To identify the most sustainable technology, we applied rank order distribution weights to a multi criteria decision analysis to combine the impact assessments of environment, economy and society. The three dimensions were assessed using 1) life-cycle assessment, 2) cost calculations taking operation and maintenance into account and 3) the multi-criteria decision analysis method Analytical hierarchy process. Specialists conducted the life-cycle assessment and cost calculations and the multi-criteria decision analyses were based on a stakeholder workshop gathering stakeholders relevant for the specific case. The workshop reached consensus on three sets of ranked criteria. Each set represented stakeholder perspectives with first priority given to one of the three sustainability dimensions or categories. The workshop reached consensus and when the highest weight was assigned to the environmental dimension of sustainability then the alternative of 'Rain- & stormwater harvesting' was the most sustainable water supply technology; when the highest weight was assigned to the economy or society dimensions then an alternative with 'Groundwater abstraction extended with compensating actions' was considered the most sustainable water supply technology. Across all three sets of ranked weights, the establishment of new well fields is considered the least sustainable alternative. PMID- 29132008 TI - Characterization of antibiotics in a large-scale river system of China: Occurrence pattern, spatiotemporal distribution and environmental risks. AB - Antibiotics and antibiotic resistance genes in the river system have received growing attention in recent years due to their potential threat to aquatic ecosystems and public health. Recognizing the occurrence and distribution of antibiotics in river environment and assessing their ecological risks are of important precondition for proposing effective strategies to protect basin safety. In this study, a comprehensive investigation was conducted to identify the contamination and risk characteristics of antibiotics in the aquatic environment of Hai River system (HRS) which is the largest water system in northern China. To attain this objective, several tools and methods were considered on the data set of water and sediment samples collected in the past ten years. The occurrence pattern, concentration levels and spatiotemporal distribution of antibiotics in the HRS were characterized utilizing statistical and comparative analysis. Risk quotients were employed to assess the adverse ecology effects caused by single antibiotic or their mixtures. Screening tool with priority factor and accumulation growth factor was used auxiliarily to prioritize antibiotics that should be of highly concern. Results indicated that the occurrence frequencies and concentration levels of 16 representative antibiotics in HRS were generally higher than those reported in global waters. Most antibiotics showed significant seasonal and spatial variations. Comparatively speaking, sulfamethoxazole, norfloxacin, erythromycin and roxithromycin posed higher risks to aquatic organisms in the HRS individually, and the combination of tetracycline and enrofloxacin indicated synergistical actions. Overall, due to their potential risks, considerable levels or quick increasing trends, 13 antibiotics were identified as priority contaminants in the HRS and should be paid special attention to be strictly regulated in the future. PMID- 29132009 TI - Temperature and metal exposure affect membrane fatty acid composition and transcription of desaturases and elongases in fathead minnow muscle and brain. AB - In this study, we tested the hypothesis that metal exposure affected the normal thermal response of cell membrane FA composition and of elongase and desaturase gene transcription levels. To this end, muscle and brain membrane FA composition and FA desaturase (fads2, degs2 and scd2) and elongase (elovl2, elovl5 and elovl6) gene transcription levels were analyzed in fathead minnows (Pimephales promelas) acclimated for eight weeks to 15, 25 or 30 degrees C exposed or not to cadmium (Cd, 6MUg/l) or nickel (Ni, 450 6MUg/l). The response of membrane FA composition to temperature variations or metal exposure differed between muscle and brain. In muscle, an increase of temperature induced a decrease of polyunsaturated FA (PUFA) and an increase of saturated FA (SFA) in agreement with the current paradigm. Although a similar response was observed in brain between 15 and 25 degrees C, at 30 degrees C, brain membrane unsaturation was higher than predicted. In both tissues, metal exposure affected the normal thermal response of membrane FA composition. The transcription of desaturases and elongases was higher in the brain and varied with acclimation temperature and metal exposure but these variations did not generally reflect changes in membrane FA composition. The mismatch between gene transcription and membrane composition highlights that several levels of control other than gene transcription are involved in adjusting membrane FA composition, including post-transcriptional regulation of elongases and desaturases and de novo phospholipid biosynthesis. Our study also reveals that metal exposure affects the mechanisms involved in adjusting cell membrane FA composition in ectotherms. PMID- 29132010 TI - Inhibition of sonic hedgehog signaling blocks cell migration and growth but induces apoptosis via suppression of FOXQ1 in natural killer/T-cell lymphoma. AB - The present study explored the effects of Forkhead box Q1 (FOXQ1) on cell proliferation, cell cycle and apoptosis via the Sonic hedgehog (Shh) pathway in Natural killer/T-cell lymphoma (NKTCL). Quantitative real time-polymerase chain reaction (qRT-PCR) was performed to detect FOXQ1 expression in 117 NKTCL patients and 120 healthy controls. Additionally, FOXQ1 expression in NKTCL cell lines (HANK-1, NK-92, SNK-6, SNT-8 and YT) was determined by western blotting and qRT PCR. SNK-6 cells were transfected with FOXQ1-shRNA or Shh pathway inhibitor Cyclopamine/recombinant protein Shh. Cell counting kit-8 (CCK-8) and 5-bromo-2 deoxy-uridine (BrdU) incorporation assays were conducted to detect cell proliferation, flow cytometry was used to determine the cell cycle and cell apoptosis, and western blotting was used to detect protein expression. FOXQ1 expression was higher in NKTCL patients than in healthy controls, which was related to Ann Arbor stage, bone marrow involvement and the 5year survival rate in NKTCL patients. Moreover, FOXQ1 expression, pathological type, Ann Arbor stage, B symptom and bone marrow involvement were independent risk factors in NKTCL. Shh pathway-related proteins were down-regulated after transfection of SNK 6 cells with FOXQ1-shRNA. Additionally, SNK-6 cell proliferation was greatly reduced, the cell cycle was blocked at the G0/G1 phase, and the expression of CyclinD1 and CyclinE was markedly decreased, while an increase in cell apoptosis with elevated Bcl-2-associated X protein (Bax) and Caspase-3 and reduced B-cell lymphoma/leukemia-2 (Bcl-2) were also observed. However, no significant alterations were observed between the FOXQ1-shRNA+Shh and Blank groups. The inhibition of FOXQ1 restricted NKTCL cell proliferation and growth but induced apoptosis via blocking the Shh signaling pathway. PMID- 29132011 TI - Effect of anode polarization on biofilm formation and electron transfer in Shewanella oneidensis/graphite felt microbial fuel cells. AB - In microbial fuel cells, electricity generation is assumed by bacterial degradation of low-grade organics generating electrons that are transferred to an electrode. The nature and efficiency of the electron transfer from the bacteria to the electrodes are determined by several chemical, physical and biological parameters. Specifically, the application of a specific potential at the bioanode has been shown to stimulate the formation of an electro-active biofilm, but the underlying mechanisms remain poorly understood. In this study, we have investigated the effect of an applied potential on the formation and electroactivity of biofilms established by Shewanella oneidensis bacteria on graphite felt electrodes in single- and double-chamber reactor configurations in oxic conditions. Using amperometry, cyclic voltammetry, and OCP/Power/Polarization curves techniques, we showed that a potential ranging between -0.3V and +0.5V (vs. Ag/AgCl/KCl sat.) and its converse application to a couple of electrodes leads to different electrochemical behaviors, anodic currents and biofilm architectures. For example, when the bacteria were confined in the anodic compartment of a double-chamber cell, a negative applied potential (-0.3V) at the bioanode favors a mediated electron transfer correlated with the progressive formation of a biofilm that fills the felt porosity and bridges the graphite fibers. In contrast, a positive applied potential (+0.3V) at the bioanode stimulates a direct electron transfer resulting in the fast-bacterial colonization of the fibers only. These results provide significant insight for the understanding of the complex bacteria-electrode interactions in microbial fuel cells. PMID- 29132012 TI - Distinct Ezrin Truncations Differentiate Metastases in Sentinel Lymph Nodes from Unaffected Lymph Node Tissues, from Primary Breast Tumors, and from Healthy Glandular Breast Tissues. AB - BACKGROUND: Lymph node metastasis status is a prognostic factor for further lymph node involvement and for patient survival in breast cancer patients. Frozen section analysis of lymph nodes is a reliable method for detection of macro metastases. However, this method is far less effective in detecting micro metastases, requesting improved diagnostic procedures. METHODS: We investigated expression and truncation of ezrin in (i) sentinel lymph node metastases, (ii) unaffected axillary lymph nodes, (iii) primary breast tumors, and (iv) healthy glandular breast tissues using 2D gel electrophoresis, SDS-PAGE, and mass spectrometry in addition to Western blotting. RESULTS: Full-length ezrin (E1; amino acids 1-586) is present in all four investigated tissues. Two truncated ezrin forms, one missing about the first hundred amino acids (E2a) and the other lacking about 150 C-terminal amino acids (E2b) were detectable in primary tumor tissues and in sentinel lymph node metastases but not in glandular tissues. Strikingly, an ezrin truncation (E3) which consists approximately of amino acids 238-586 was found strongly expressed in all sentinel lymph node metastases. Moreover, an N-terminal ezrin fragment (E4) that consists approximately of amino acids 1-273 was identified in sentinel lymph node metastases as well. CONCLUSIONS: We show for the first time the existence of tissue-dependent specific ezrin truncations. The distinguished strong Western blot staining of ezrin E3 in sentinel lymph node metastases underlines its capability to substantiate the occurrence of lymph node (micro)metastases in breast cancer patients. PMID- 29132013 TI - Chimeric Antigen Receptor-Modified T Cells Redirected to EphA2 for the Immunotherapy of Non-Small Cell Lung Cancer. AB - Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) is overexpressed in more than 90% of non-small cell lung cancer (NSCLC) but not significantly in normal lung tissue. It is therefore an important tumor antigen target for chimeric antigen receptors (CAR)-T-based therapy in NSCLC. Here, we developed a specific CAR targeted to EphA2, and the anti-tumor effects of this CAR were investigated. A second generation CAR with co-stimulatory receptor 4-1BB targeted to EphA2 was developed. The functionality of EphA2-specific T cells in vitro was tested with flow cytometry and real-time cell electronic sensing system assays. The effect in vivo was evaluated in xenograft SCID Beige mouse model of EphA2 positive NSCLC. These EphA2-specifc T cells can cause tumor cell lysis by producing the cytokines IFN-gamma when cocultured with EphA2-positive targets, and the cytotoxicity effects was specific in vitro. In vivo, the tumor signals of mice treated with EphA2-specifc T cells presented the tendency of decrease, and was much lower than the mice treated with non-transduced T cells. The anti-tumor effects of this CAR-T technology in vivo and vitro had been confirmed. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive NSCLC. PMID- 29132014 TI - A genetic algorithm for simulating correlated binary data from biomedical research. AB - Correlated binary data arise in a large variety of biomedical research. In order to evaluate methods for their analysis, computer simulations of such data are often required. Existing methods can often not cover the full range of possible correlations between the variables or are not available as implemented software. We propose a genetic algorithm that approaches the desired correlation structure under a given marginal distribution. The procedure generates a large representative matrix from which the probabilities of individual observations can be derived or from which samples can be drawn directly. Our genetic algorithm is evaluated under different specified marginal frequencies and correlation structures, and is compared against two existing approaches. The evaluation checks the speed and precision of the approach as well as its suitability for generating also high-dimensional data. In an example of high-throughput glycan array data, we demonstrate the usability of our approach to simulate the power of global test procedures. An implementation of our own and two other methods were added to the R-package 'RepeatedHighDim'. The presented algorithm is not restricted to certain correlation structures. In contrast to existing methods it is also evaluated for high-dimensional data. PMID- 29132015 TI - Statistical content-adapted sampling (SCAS) for 3D Computed Tomography. AB - In this paper, a framework to create a statistical content-adapted sampling (SCAS) for 3D X-ray Computed Tomography (CT) is introduced. SCAS aims at providing an accurate but light reconstruction volume. Based on decision theory, the 3D reconstruction space is sampled from the raw projection data in three steps to directly fit the sample. To do so, the structural information is first extracted from the projections by edge detection. This information is then merged in the reconstruction space, providing a pointcloud which accurately delineates the 3D interfaces of the specimen. From this pointcloud, a 3D mesh, closely fitting the shape of the studied object, is finally built via constrained Delaunay tetrahedralization. To assess the potential of the proposed SCAS for CT imaging, an iterative reconstruction was performed by classical Ordered Subset Simultaneous Algebraic Reconstruction Technique (OS-SART) - with fitting projection operator. The SCAS was evaluated on both numerical and experimental data. Results show that the use of statistical testing enabled the design of a robust, automated and fast method to build accurate pointclouds from a limited number of projections. The 3D meshes generated from these pointclouds are composed of few cells when compared to the regular voxel representation, leading to a downsize in computational cost and achieving up to 90% of memory footprint reduction. Simulations showed that performed reconstruction on such meshes provide accurate description of the object due to the finer sampling at interfaces. PMID- 29132016 TI - Children's representation of abstract relations in relational/array match-to sample tasks. AB - Five experiments compared preschool children's performance to that of adults and of non-human animals on match to sample tasks involving 2-item or 16-item arrays that varied according to their composition of same or different items (Array Match-to-Sample, AMTS). They establish that, like non-human animals in most studies, 3- and 4-year-olds fail 2-item AMTS (the classic relational match to sample task introduced into the literature by Premack, 1983), and that robust success is not observed until age 6. They also establish that 3-year-olds, like non-human animal species, succeed only when they are able to encode stimuli in terms of entropy, a property of an array (namely its internal variability), rather than relations among the individuals in the array (same vs. different), whereas adults solve both 2-item and 16-item AMTS on the basis of the relations same and different. As in the case of non-human animals, the acuity of 3- and 4 year-olds' representation of entropy is insufficient to solve the 2-item same different AMTS task. At age 4, behavior begins to contrast with that of non-human species. On 16-item AMTS, a subgroup of 4-year-olds induce a categorical rule matching all-same arrays to all-same arrays, while matching other arrays (mixed arrays of same and different items) to all-different arrays. These children tend to justify their choices using the words "same" and "different." By age 4 a number of our participants succeed at 2-item AMTS, also justifying their choices by explicit verbal appeals using words for same and different. Taken together these results suggest that the recruitment of the relational representations corresponding to the meaning of these words contributes to the better performance over the preschool years at solving array match-to-sample tasks. PMID- 29132017 TI - Antibiotic stewardship: The role of clinical nurses and nurse educators. PMID- 29132018 TI - The provision of accredited higher education on dementia in six European countries: An exploratory study. AB - BACKGROUND: The World Health Organization has identified developing the knowledge and skills of healthcare professionals who are involved in dementia care as a priority. Most healthcare professionals lack the necessary knowledge, skills and understanding to provide high quality dementia care. While dementia education amongst most UK university health and social care programmes is inconsistent, we know little about the provision of dementia education in European universities. OBJECTIVES: To examine the provision of accredited higher education on dementia in European countries, to illustrate that it is highly variable despite universities being the major provider of education for healthcare professionals internationally. DESIGN: An exploratory research design was used. SETTINGS: The providers of higher education undergraduate and postgraduate programmes in the Czech Republic, Portugal, Scotland, Slovenia, Spain, Sweden. PARTICIPANTS: Higher Education Institutions who provide undergraduate and postgraduate education in the fields of nursing, medicine, psychology, social work, physiotherapy, occupational therapy, and gerontology in six European countries. METHODS: The data was collected using a structured questionnaire. Researchers in each country conducted an internet-based search using the websites of Higher Education Institutions to identify existing accredited dementia education. RESULTS: These searches revealed a lack of dementia education in undergraduate health and social care study programmes. Three of the six countries offered postgraduate study programmes on dementia. There was a significant variation amongst the countries in relation to the provision of dementia education at undergraduate, postgraduate and doctoral levels. CONCLUSIONS: Dementia is a global challenge and educating and upskilling the workforce is a policy imperative. To deliver the best dementia care, investment in interprofessional evidence-based education is required if we are to respond effectively and compassionately to the needs of people living with dementia and their families. Higher Education Institutions have an important role to play in equipping health and social care professionals with the knowledge, skills and understanding to respond to this imperative. PMID- 29132019 TI - Molecular modeling on HIF-2alpha-ARNT dimer destabilization caused by R171A and/or V192D mutations in HIF-2alpha. AB - Oxygen homeostasis in normal and tumor cells is mediated by hypoxia-inducible factors (HIFs), which are active as heterodimer complexes, such as HIF-2alpha aryl hydrocarbon receptor nuclear translocator (ARNT) and HIF-1alpha-ARNT. A series of mutations on the interfaces between HIF-2alpha and ARNT and on the domain-domain interface within HIF-2alpha has been reported to exert varying effects on HIF-2alpha-ARNT dimerization. In the present study, molecular dynamic simulations were conducted to evaluate HIF-2alpha mutations, namely R171A, V192D, and R171A/V192D, which are not involved in the interaction with ARNT but impede HIF-2alpha-ARNT dimerization. Our results indicate that these mutations induct local conformation leading to a shortened (by V192D) or widened (by R171A and R171A/V192D) Y91-E346 separation distance, where E346 and Y91 are located on the HIF-2alpha and interact with ARNT according to electrostatic and geometrical shape complementarity, respectively. PMID- 29132020 TI - Separation of aflatoxin B1 from synthetic physiological fluids using talc and diatomite: Kinetic and isotherm aspects. AB - The objective of the study was to examine adsorption of the aflatoxin B1 from synthetic gastric fluid and synthetic intestinal fluid by talc, raw and calcined diatomite. The kinetic and equilibrium adsorption processes were studied in the batch adsorption experiments applying high performance liquid chromatography for the aflatoxin B1 determination. The kinetic study showed a very fast adsorption of the aflatoxin B1 onto the selected adsorbents from the both physiological fluids with reaching equilibrium within 1-15min. The aflatoxin B1 was almost completely adsorbed in initial linear step of the kinetic process that can be described well by the zero-order kinetics model. The experimental data of the equilibrium adsorption were characterized using the Langmuir and Freundlich isotherm models. The high adsorption effectiveness was found in a range of 90% 100% and 60%-100% for the diatomite samples and the talc respectively at the initial concentrations of the aflatoxin B1 as 31-300ng/mL. The possible mechanisms of the aflatoxin adsorption onto the used mineral adsorbents are also discussed in the work. PMID- 29132021 TI - Fibroin/dodecanol floating solidification microextraction for the preconcentration of trace levels of flavonoids in complex matrix samples. AB - A new fibroin/dodecanol floating solidification microextraction, coupled with high performance liquid chromatography, was developed and applied for enrichment and quantification of the trace flavonoids in traditional Chinese medicine and biological samples. Also, fibroin sensibilization mechanism was described, and influence of sample matrix to enrichment factor was investigated. In this method, a homogeneous fibroin/dodecanol of dispersed solution was employed as microextraction phase to flavonoids (myricetin, quercetin, isorhamnetin, chrysin, kaempferide), the several critical parameters affecting the performance, such as organic extractant, amount of fibroin in organic extractant, volume of extraction phase, dispersant, salt concentration, pH of sample phase, stirring rate, extraction time, and volume of sample phase were tested and optimized. Under the optimized conditions, enrichment factor of flavonoids ranged from 42.4 to 238.1 in different samples, excellent linearities with r2>= 0.9968 for all analytes were achieved, limits of detection were less than or equal to 5.0ng/mL, average recoveries were 92.5% to 115.0% in different samples. The new procedure is simple, fast, low cost, environmentally friendly and high EF, it can also be applied to the concentration and enrichment of the trace flavonoids in other complex matrixes. PMID- 29132022 TI - Determination of perfluoroalkyl acid isomers in biosolids, biosolids-amended soils and plants using ultra-high performance liquid chromatography tandem mass spectrometry. AB - Isomer-specific analysis of perfluoroalkyl acids (PFAAs) is important to accurately assess their environmental source, fate, and human risks. In this study, a method was developed for the determination of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) isomers in biosolids, biosolids-amended soils and plants using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The separation efficiencies of two chromatographic columns and extraction capacities of different methods were tested. Compared with the C18 column (ACQUITY UPLC BEH Shield RP18 column), the column with an alkyl perfluorinated C8 stationary phase (Epic FO LB column), in combination with the distinct MS/MS transitions of analytes, allowed better separation of most isomers. The ion-pair extraction method showed more effective matrix separation than that of the alkaline digestion method, with recoveries ranging from 79.6-105% for biosolids, 80.4-116% for soils, and 68.0-114% for plant tissues. The method detection limits ranged from 10 to 55, 3-13, and 8-58pg/g dry weight for biosolids, soil, and plants, respectively. This method was applied successfully to quantify individual isomers in biosolids, biosolids-amended soils and plants. Six PFOA, eight PFOS, and two PFHxS isomers were found in the samples, with linear isomers being the dominant species. Further analysis revealed that the translocation potentials of branched isomers within plants were higher than those of linear isomers. PMID- 29132023 TI - Quantification of fluorescent dyes in organ tissue samples via HPLC analysis. AB - The determination of regional blood flow via the accumulation of fluorescent microspheres is a concept regularly used in medical research. Typically, the microbeads get extracted from the tissue of interest and are then quantified by measuring the absorption or fluorescence of the incorporated dyes without further separation from the medium. However, in that case the absorption spectra of different dyes can overlap when used simultaneously, leading to an overestimation of the concentration. Additionally, background absorption from the medium can be problematic. Therefore, a high performance liquid chromatography method for the simultaneous detection of four dyes (orange, crimson, yellow-green and red) incorporated in different microbeads in samples from biological media such as organ tissue (brain, heart and kidneys) was developed. Since for biological samples often a large sample size is required for sufficient statistics, the method was optimized to yield very short run times. With this method it was possible to detect very low concentrations of only one microsphere per gram of organ tissue. By applying this sensitive quantification technique, it was demonstrated that the application of microbeads for perfusion measurements might not be reliable due to different organ distributions in each animal. PMID- 29132024 TI - A HILIC-UHPLC-MS/MS untargeted urinary metabonomics combined with quantitative analysis of five polar biomarkers on osteoporosis rats after oral administration of Gushudan. AB - A HILIC-UHPLC-MS/MS untargeted urinary metabonomic method combined with quantitative analysis of five potential polar biomarkers in rat urine was developed and validated, to further understand the anti-osteoporosis effect of Gushudan(GSD) and its mechanism on prednisolone-induced osteoporosis(OP) rats in this study. The metabolites were separated and identified on Waters BEH HILIC (2.1mm*100mm, 1.7MUm) column using the Waters ACQUITYTM ultra performance liquid chromatography system (Waters Corporation, Milford, USA) coupled with a Micromass Quattro MicroTM API mass spectrometer (Waters Corp, Milford, MA, USA). Principal component analysis (PCA) was used to identify potential biomarkers. Primary potential polar biomarkers including creatinine, taurine, betaine, hypoxanthine and cytosine, which were related to energy metabolism, lipid metabolism and amino acid metabolism, were found in the untargeted metabonomic research. Moreover, these targeted biomarkers were further separated and quantified in multiple reaction monitoring (MRM) with positive ionization mode, using tinidazole as internal standard (I.S.). Good linearities (r>0.99) were obtained for all the analytes with the low limit of quantification from 1.00 to 12.8MUg/mL. The relative standard deviation (RSD) of the intra-day and inter-day precisions were within 15.0% and the accuracy ranged from -14.3% to 13.5%. The recovery was more than 85.0%. And the validated method was successfully applied to investigate the urine samples of the control group, prednisolone-induced osteoporosis model group and Gushudan-treatment group in rats. Compared to the control group, the level of creatinine, taurine, betaine, hypoxanthine and cytosine in the model group revealed a significant decrease trend (p<0.05), while the Gushudan-treatment group showed no statistically differences by an independent sample t-test. This paper provided a better understanding of the therapeutic effect and mechanism of GSD on prednisolone-induced osteoporosis rats. PMID- 29132025 TI - Micro-QuEChERS extraction coupled to GC-MS for a fast determination of Bisphenol A in human urine. AB - Bisphenol A (BPA) is considered an endocrine disruptor and public concern over BPA exposure has been raised. Several studies have assessed human exposure to this plasticizer, confirming its ubiquitous presence and highlighting children as a public of special concern. A simple, efficient, cheap and green analytical procedure is reported within this paper. This paper reports, for the first time, the development of a modified Micro-QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method coupled to gas chromatography-mass spectrometry (GC-MS) as a new strategy for the efficient extraction and determination of Bisphenol A in human urine samples. Several parameters that are known to influence extraction were optimized. Good linearity was achieved at the studied concentration range (1 50MUg/L), with a correlation coefficient (R2) of 0.998. The optimized method proved to be accurate (>=74% recovery), reproducible (<11% relative standard deviation) and sensitive for BPA determination (detection limit of 0.13MUg/L and quantification limit of 0.43MUg/L). The analytical procedure was applied to the analyses of 12 urine samples collected from children living in the North/Center region of Portugal. BPA was detected in all the analyzed samples in concentrations ranging from 1.5MUg/L to 48.9MUg/L. The proposed methodology is suitable for the determination of BPA in urine samples in the framework of biomonitoring studies and bioanalytical analyses, applying GC-MS detection. PMID- 29132026 TI - Integrated omics analysis of root-preferred genes across diverse rice varieties including Japonica and indica cultivars. AB - Plant root systems play essential roles in developmental processes, such as the absorption of water and inorganic nutrients, and structural support. Gene expression is affected by growth conditions and the genetic background of plants. To identify highly conserved root-preferred genes in rice across diverse growth conditions and varieties, we used two independent meta-anatomical expression profiles based on a large collection of Affymetrix and Agilent 44K microarray data sets available for public use. We then identified 684 loci with root preferred expression, which were validated with in silico analysis using both meta-expression profiles. The expression patterns of four candidate genes were confirmed in vivo by monitoring expression of beta-glucuronidase under control of the candidate-gene promoters, providing new tools to manipulate agronomic traits associated with roots. We also utilized real-time PCR to examine the root preferential expression of 14 genes across four rice varieties, including japonica and indica cultivars. Using a database of rice genes with known functions, we identified the reported functions of 39 out of the 684 candidate genes. Sixteen genes are directly involved in root development, while the remaining are involved in processes indirectly related to root development (i.e., soil-stress tolerance or growth retardation). This indicates the importance of our candidate genes for studies on root development and function. Gene ontology enrichment analysis in the 'biological processes' category revealed that root preferred genes in rice are closely associated with nutrient transport-related genes, indicating that the primary role of roots is the uptake of nutrients from soil. In addition, predicted protein-protein interaction analysis suggested a molecular network for root development composed of 215 interactions associated with 44 root-preferred or root development-related genes. Taken together, our data provide an important foundation for future research on root development in rice. PMID- 29132027 TI - Evaluation of interference fit and bone damage of an uncemented femoral knee implant. AB - BACKGROUND: During implantation of an uncemented femoral knee implant, press-fit interference fit provides the primary stability. It is assumed that during implantation a combination of elastic and plastic deformation and abrasion of the bone will occur, but little is known about what happens at the bone-implant interface and how much press-fit interference fit is eventually achieved. METHODS: Five cadaveric femora were prepared and implantation was performed by an experienced surgeon. Micro-CT- and conventional CT-scans were obtained pre- and post-implantation for geometrical measurements and to measure bone mineral density. Additionally, the position of the implant with respect to the bone was determined by optical scanning of the reconstructions. By measuring the differences in surface geometry, assessments were made of the cutting error, the actual interference fit, the amount of bone damage, and the effective interference fit. FINDINGS: Our analysis showed an average cutting error of 0.67mm (SD 0.17mm), which pointed mostly towards bone under-resections. We found an average actual AP interference fit of 1.48mm (SD 0.27mm), which was close to the nominal value of 1.5mm. INTERPRETATION: We observed combinations of bone damage and elastic deformation in all bone specimens, which showed a trend to be related with bone density. Higher bone density tended to lead to lower bone damage and higher elastic deformation. The results of the current study indicate different factors that interact while implanting an uncemented femoral knee component. This knowledge can be used to fine-tune design criteria of femoral components to achieve adequate primary stability for all patients. PMID- 29132028 TI - DNA methylation and genetic variation of the angiotensin converting enzyme (ACE) in depression. AB - BACKGROUND: Depression is one of the most prevalent psychiatric disorders, and in older persons is associated with high levels of comorbidity and under-treatment. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis is consistently observed in the older population as well as depressed patients, with the angiotensin converting enzyme (ACE) a key regulator of the stress response. Epigenetic regulation of ACE may play an important role in HPA axis (dys)regulation. OBJECTIVE: To investigate ACE promoter methylation as a biomarker of late-life depression, and its association with genetic variation and cortisol secretion. METHOD: The longitudinal general population ESPRIT study is aimed at investigating psychiatric disorders in older persons (n=1863, average age=73). Depression was assessed using the Mini International Neuropsychiatric Interview according to DSM-IV criteria and the Centre for Epidemiologic Studies Depression Scale (CES-D). Genotype information for seven polymorphisms across the ACE gene was also available. Blood and saliva samples collected at baseline and used to extract DNA and measure cortisol, respectively. Sequenom MassARRAY was used to measure promoter DNA methylation of the ACE gene (n=552). RESULTS: There was no evidence of an association between ACE promoter methylation and depression. However, there was evidence that ACE genetic variants influenced methylation, and modified the association between depression and methylation (Delta at various sites; -2.05% to 1.74%; p=0.019 to 0.039). Multivariate analyses were adjusted for participants' lifestyle, health and medical history. Independent of depression status, ACE methylation was inversely correlated with cortisol levels (r=-0.336, p=0.042). CONCLUSION: This study provides evidence that associations between ACE methylation and depression are genotype-dependent, suggesting that the development of reliable depression biomarkers may need to consider methylation levels in combination with underlying genetic variation. ACE methylation may also be a suitable biomarker of cortisol and/or HPA axis activity. PMID- 29132029 TI - Reconstruction of atomic force microscopy image using compressed sensing. AB - Atomic Force Microscopy (AFM) is one of the most popular and advanced tools for ultra high-resolution imaging and nanomanipulation of nano-scale matter. But AFM imaging typically takes a long time. High-speed and high-precision AFM measurement has attracted wide attention in recent several years. In traditional AFM, simple reduction in the number of measurement points may lose essential sample topography information. To resolve such problems, an AFM image reconstruction method based on Compressed Sensing (CS) theory is applied to reduce image acquisition time without cutting down the image quality. The benefit of using CS approach in AFM is shortening the imaging time, minimizing the interaction with the sample, and finally avoiding sample damage in AFM. Three kinds of testing samples with high and low frequency components were examined by a scanning electron microscope (SEM) and by AFM. An orthogonal Matching Pursuit (OMP) algorithm is employed to reconstruct an AFM image with different sampling rates. Subsequently the reconstruction results of sample topography images are analyzed and evaluated. Using the CS approach in AFM can greatly improve the AFM imaging process. Experimental results show that the obtained reconstructed images have different resolution and quality, depending on the surface morphology of the sample and sampling rates. PMID- 29132030 TI - Capture and detection of Staphylococcus aureus with dual labeled aptamers to cell surface components. AB - In the present study, a high throughput whole cell SELEX method has been applied successfully in selecting specific aptamers against whole cells of Staphylococcus aureus, a potent food poisoning bacterium. A total ten rounds of SELEX and three rounds of intermittent counter SELEX, was performed to obtain specific aptamers. Obtained oligonucleotide pool were cloned, sequenced and then grouped into different families based on their primary sequence homology and secondary structure similarity. FITC labeled sequences from different families were selected for further characterization via flow cytometry analysis. The dissociation constant (Kd) values of specific and higher binders ranged from 34 to 128nM. Binding assays to assess the selectivity of aptamer RAB10, RAB 20, RAB 28 and RAB 35 demonstrated high affinity against S. aureus and low binding affinity for other bacteria. To demonstrate the potential use of the aptamer a sensitive dual labeled sandwich detection system was developed using aptamer RAB10 and RAB 35 with a detection limit of 102CFU/mL. Furthermore detection from mixed cell population and spiked sample emphasized the robustness as well as applicability of the developed method. Altogether, the established assay could be a reliable detection tool for the routine investigation of Staphylococcus aureus in samples from food and clinical sources. PMID- 29132031 TI - Effects of Microcystis on development of early life stage Japanese medaka (Oryzias latipes): Comparative toxicity of natural blooms, cultured Microcystis and microcystin-LR. AB - Freshwater cyanobacterial harmful algal blooms (CyanoHABs) caused by algae in the genus Microcystis have been increasing in frequency and severity in recent decades. Microcystis blooms threaten aquatic organisms through effects associated with the rapid increase of biomass and the production of the hepatotoxin microcystin (MC) by toxic strains. Among fish, effects of blooms are likely to be more severe for early life stages, and physiological impacts on this life stage could significantly impact recruitment and fish populations. This study explores the effects of Microcystis blooms on the development of fish using the model organism, the Japanese medaka (Oryzias latipes), under realistic exposure conditions. Medaka embryos were exposed to natural blooms collected from New York City (USA) lakes, lab cultures of Microcystis, and MC-LR solutions. Field collected samples were more toxic than lab cultures (even when compared at the same algal density or MC concentration), causing decreased survival, premature time to hatch, reduced body length, yolk sac edema, and decreased heart rate, while lab culture exposures only resulted in bradycardia. Heart rate was the most sensitive endpoint measured, being depressed in embryos exposed to both lab cultures and field collected blooms. Generalized linear model analysis indicated bradycardia was statistically associated with both cell densities of blooms and MC concentrations, while single factor analysis indicated that MC concentrations had a stronger correlation compared to cell densities. However, MC exposure could not fully explain the effects observed, as exposures to MC-LR solutions alone were not able to reduce heart rate as severely as algal exposures. Collectively, these experiments indicate that factors beyond exposure to MC or even isolated Microcystis strains influence heart rate of fish exposed to Microcystis blooms. Enhanced mortality, depressed heart rate, and abnormal development observed in response to environmentally realistic exposures of Microcystis blooms could affect success of fish at both individual or population levels. PMID- 29132032 TI - Influence of body size, metabolic rate and life history stage on the uptake and excretion of the lampricide 3-trifluoromethyl-4-nitrophenol (TFM) by invasive sea lampreys (Petromyzon marinus). AB - Invasive sea lamprey (Petromyzon marinus) are controlled in the Great Lakes using the lampricide 3-trifluoromethyl-4-nitrophenol (TFM), which is applied to streams infested with larval lamprey. However, lamprey that survive treatments (residuals) remain a challenge because they may subsequently undergo metamorphosis into parasitic juvenile animals that migrate downstream to the Great Lakes, where they feed on important sport and commercial fishes. The goal of this study was to determine if body size and life stage could potentially influence sea lamprey tolerance to TFM by influencing patterns of TFM uptake and elimination. Because mass specific rates of oxygen consumption (MO2) are lower in larger compared to smaller lamprey, we predicted that TFM uptake would be negatively correlated to body size, suggesting that large larvae would be more tolerant to TFM exposure. Accordingly, TFM uptake and MO2 were measured in larvae ranging in size from 0.2-4.2g using radio-labelled TFM (14C-TFM) and static respirometry. Both were inversely proportional to wet mass (M), and could be described usingthe allometric power relationship: Y=aMb, in which MO2=1.86M0.53 and TFM Uptake=7.24M0.34. We also predicted that body size would extend to rates of TFM elimination, which was measured following the administration of 14C-TFM (via intraperitoneal injection). However, there were no differences in the half lives of elimination of TFM (T 1/2-TFM). There were also no differences in MO2 or TFM uptake amongst size-matched larval, metamorphosing (stages 6-7), or post metamorphic (juvenile) sea lamprey. However, the T1/2-TFM was significantly lower in larval than post-metamorphic lamprey (juvenile), indicating the larval lamprey cleared TFM more efficiently than juvenile lamprey. We conclude that larger larval sea lamprey are more likely to survive TFM treatments suggesting that body size might be an important variable to consider when treating streams with TFM to control these invasive species. PMID- 29132033 TI - Radon and NO2 levels and related environmental factors in 100 underground subway platforms over two-year period. AB - In this study, the environmental factors that affect radon (Rn) and nitrogen dioxide (NO2) levels in subway-station underground platforms are evaluated, and the outdoor NO2 levels are compared with those obtained for the underground platforms. The Rn and NO2 levels from May 2013 to September 2015 are determined for lines 1-4 of the Seoul Metro, via calculation of the arithmetic means of the Rn and NO2 levels with their standard deviations (SDs). The underground Rn levels in 2013 are found to be significantly higher than those recorded in 2015 for the Seoul Metro. In addition, the Rn levels are related to the station depth and construction year. Further, the underground NO2 levels are shown to be significantly higher than the outdoor levels for all four Seoul Metro subway lines. The Rn levels are also found to vary significantly between months, and are shown to increase gradually with depth from 8 to 20 m. The Rn levels are also higher for stations constructed in the 1980s. Therefore, stricter monitoring of Rn level may be required for stations constructed in the 1980s and/or having platform depths within the 8-20 m range. Island-type platform stations based on granite areas may also require careful attention. PMID- 29132034 TI - Impact of flow-mediated dilatation and coronary calcification in providing complementary information on the severity of coronary artery disease. AB - BACKGROUND AND AIMS: Endothelial dysfunction and coronary artery calcification (CAC) may represent two distinct and separate processes in the development of coronary atherosclerosis. However, the interaction between these factors in determining the development of coronary artery disease (CAD) is uncertain. METHODS: Brachial artery flow-mediated dilatation (FMD) was measured by high resolution ultrasound before coronary angiography, in 156 patients undergoing coronary CT angiography on suspicion of CAD (M/F 100/56, age 67 +/- 11yrs). CAC score was measured with the Agatston method. RESULTS: The discriminative performance of FMD and CAC score in predicting the presence of type C lesion, multivessel disease, and high SYNTAX score (>22) was determined by ROC curve analysis. The optimal cutoff values for type C lesion were FMD <=3.70% (AUC 0.663, p = 0.037) and log(CACscore+1)>= 6.452 (AUC 0.735, p = 0.006). The combination of these cutoff values identified the lesion with the highest predictive accuracy of 82%. In addition, the optimal cutoff values for multivessel disease were FMD <=5.40% (AUC 0.689, p = 0.001) and log(CACscore+1)>= 5.914 (AUC 0.731, p = 0.001), while those for high SYNTAX score were FMD <=4.10% (AUC 0.664, p = 0.020) and log(CACscore+1) >=6.693 (AUC 0.817, p = 0.001). The combined measurement of each cutoff value identified multivessel disease and high SYNTAX score with predictive accuracy of 77% and 83%, respectively, which were significantly higher than each parameter alone, with the exception of the predictive accuracy of log(CACscore+1) for high SYNTAX score (p = 0.083). CONCLUSIONS: Endothelial dysfunction and CAC may provide complementary information in predicting the extent and severity of coronary artery disease. PMID- 29132035 TI - Brain volume in early MS patients with and without IgG oligoclonal bands in CSF. AB - BACKGROUND: Oligoclonal bands of IgG (OB) are proposed as an early prognostic factor of the disease. Growing attention is directed towards brain volume evaluation as a possible marker of the severity of MS. Previous studies found that MS patients lacking OB have less brain atrophy. AIM: to evaluate a possible relationship between OB and cerebral volume in a cohort of early MS patients. METHODS: Inclusion criteria were: diagnosis of relapsing-remitting MS; CSF analysis and MRI acquired simultaneously and within 12 months from clinical onset. A total of 15 healthy controls underwent MRI. RESULTS: In 20 MS patients, CSF analysis did not show OB synthesis (OB negative group). A control group of 25 MS patients in whom OB was detected was also randomly recruited (OB positive group). T test showed a significant difference in NWV between the OB positive and OB negative groups (P value = 0.01), and between the OB positive group and the healthy controls (P value = 0.001). No differences were detected between OB negative group and healthy controls. Multivariable linear regression showed a relationship between NWV and OB synthesis (P value = 0.02) controlling for age, gender, and EDSS. CONCLUSIONS: Our preliminary results suggest that OB positive patients show more atrophy of white matter since early phases of the disease, supporting the role of CSF analysis as a prognostic factor in MS. PMID- 29132036 TI - Holding immature bovine oocytes in a commercial embryo holding medium: High developmental competence for up to 10 h at room temperature. AB - Bovine in vitro embryo production (IVP) following Ovum Pick Up (OPU) is all too often hampered by a large time gap between the harvest of oocytes of the first and last OPU session of the day. Immediately after retrieval, oocyte maturation is initiated, resulting in oocytes maturing at different time points which necessitates laborious scheduling of the IVP process. In this study, the potential of a commercial embryo holding medium (EHM; Syngro, Bioniche Inc.) to hold immature bovine oocytes was validated. We assessed the effect of holding time and temperature on (1) oocytes' maturation; (2) blastocyst development and quality at day 8 post insemination; and (3) blastocyst yield in small groups of oocytes/zygotes simulating OPU settings. Oocytes, harvested from slaughterhouse ovaries, were held for 6 h (either at 4 degrees C, room temperature [RT; 22-25 degrees C], or 38.5 degrees C), for 10 h (at 4 degrees C or RT), and for 14 h (only at RT) in 1 mL sterile glass osmometer tubes filled with EHM prior to standard maturation (22 h at 38.5 degrees C) and subsequent IVP. Results were compared with controls in which no prior holding was applied. Differences between the treated and control groups were assessed by generalized mixed-effects models and considered significant at P < 0.05. Generally, oocytes held up to 14 h in EHM at different temperatures remained at the germinal vesicle stage. Holding immature oocytes in EHM for 6 h at 38.5 degrees C and for 10 h at 4 degrees C significantly decreased maturation (57.1 +/- 4.1% VS 80.9 +/- 3.2% and 68.6 +/- 3.5% VS 80.7 +/- 2.9%; respectively), and development (11.0 +/- 1.8% VS 36.2 +/- 2.8% and 20.1 +/- 3.3% VS 40.6 +/- 4.6%) (P < 0.05). However, holding in EHM for both 6 and 10 h at RT, did not affect the maturation rates (83.2 +/- 2.9% and 78.9 +/- 3.2%) nor day 8 blastocyst rates (35.2 +/- 2.7% and 40.2 +/- 4.5%). Prolonging holding time to 14 h in RT decreased maturation and day 8 blastocyst yield (71.9 +/- 3.5% VS 84.5 +/- 2.7% and 25.7 +/- 2.5% VS 39.5 +/- 2.8%, respectively) (P < 0.05). Holding oocytes in EHM did not significantly affect embryonic quality as assessed by differential apoptotic staining in any of the time points. To simulate OPU-settings, small groups of 10 oocytes were held in EHM for 6 or 10 h at RT. When subsequently matured, fertilized and cultured per 8 zygotes, day 8 blastocyst rate was not affected (19.8 +/- 3.5% VS 20.6 +/- 3.6% and 18.8 +/- 3.6% VS 18.3 +/- 3.4%). In conclusion, immature bovine oocytes can be successfully conserved in EHM at RT for up to 10 h without compromising their embryonic developmental competence nor quality. PMID- 29132037 TI - Flunixin meglumine improves pregnancy rate in embryo recipient beef cows with an excitable temperament. AB - Objectives were to determine effects of: 1) handling temperament and administration of flunixin meglumine, an inhibitor of prostaglandin F2a (PGF2a) synthesis, given at the time of embryo transfer, on pregnancy rates in beef cattle embryo transfer recipients; 2) handling temperament and flunixin meglumine on peripheral concentrations of progesterone, cortisol, substance-P, prostaglandin F metabolites (PGFM, (13,14-dihydro-15-keto-PGF2a) and isoprostane 8-epi PGF2a; and 3) flunixin meglumine treatment on proportion of non-pregnant recipient cows returning to estrus within an expected interval. Angus cross beef cows (n = 710) at 7 locations were assigned a body condition score (BCS: 1, emaciated; 9, obese) and a temperament score [0, calm, slow chute exit; walk (n = 352), 1, excited, fast chute exit; jump, trot or run (n = 358)] and were synchronized with Select-Synch with a controlled internal drug release (CIDR) protocol. Estrus detection aids were applied at CIDR removal and cows were observed thrice daily for estrus until 72 h. Recipient cows that expressed estrus and had a corpus luteum received a frozen-thawed embryo on Day 7 after estrus. At the time of transfer, recipient cows were randomly allocated to receive 10 mL of flunixin meglumine im, immediately after transfer (n = 365) or served as an untreated control (n = 345). In a subset of cows (n = 80), ovarian ultrasonography was performed on the day of embryo transfer to determine corpus luteum volume and blood samples were collected twice, at the time of embryo transfer and 7 d later. All cows received estrus detection aids again on Day 14 (7 d after embryo transfer) and were observed for estrus twice daily until Day 24. Accounting for treatment (P > 0.1), embryo transfer difficulty score (P < 0.1), temperament by treatment interaction (P < 0.05), recipient cows with calm temperament had a higher pregnancy rate compared to those with an excited temperament [59.4 (209/352) vs 51.7% (185/358)]. The pregnancy rate for excitable cows without flunixin meglumine was lower (46.3% 81/175) compared to excitable cows that did received flunixin meglumine [56.8% (104/183)], and calm cows that did [59.3% (108/182)] or did not [59.4% (104/170)] receive flunixin meglumine. Proportions of non-pregnant recipient cows returning to estrus on Days 18-24 were not different between flunixin meglumine and control groups, 87.6% (134/153) and 84.0% (137/163), respectively (P > 0.1). At the time of embryo transfer and 7 d later, there were moderate to strong correlations among circulating concentrations of progesterone, cortisol, substance-P, PGFM and isoprostane 8-epi PGF2a. Among excitable cows, progesterone concentrations were lower and cortisol, substance-P, PGFM and isoprostane 8-epi PGF2a concentrations were greater for cows in the control group compared to cows that received flunixin meglumine. In conclusion, administration of flunixin meglumine improved pregnancy rates in excitable recipient cows following embryo transfer without affecting the proportion of non-pregnant cows returning to estrus. PMID- 29132038 TI - Hemodynamics of the corpus luteum in mares during experimentally impaired luteogenesis and partial luteolysis. AB - The aim of the current project was to characterize the luteal vascularity and the plasma concentrations of progesterone (P4), prolactin (PRL) and 13,14-dihydro-15 keto-PGF2alpha (PGFM) in mares with luteal disturbances during early and mid diestrus. In Experiment 1, twenty-one mares were treated with 2 mL of 0.9% NaCl, or 1 mg Dinoprost, or 10 mg Dinoprost on day two after ovulation (Control-D2, 1/10PGF-D2 and PGF-D2 groups, respectively; n = 7 mares/group). In Experiment 2, similar treatments were performed eight days post-ovulation using a different cohort of 21 mares (Control-D8, 1/10PGF-D8 and PGF-D8 groups, respectively; n = 7 mares/group). Blood samples were collected hourly and power-Doppler examinations of the corpus luteum (CL) were performed every 6 h from H0 (moment immediately before treatment) to H48. Data collection was also done once a day from D0 (day of ovulation) to D20. In Experiment 1, the PGF-D2 and 1/10PGF-D2 groups had lower increase of plasma concentration of P4 until H48 and reduced maximum P4 concentrations on D8-D11 than mares from the Control-D2 group. However, no differences among groups were detected for luteal vascularity during early and mid-diestrus. In Experiment 2, complete and partial luteolysis were detected in mares from the PGF-D8 and 1/10PGF-D8 groups, respectively. Luteal vascularity and plasma P4 concentrations differed among Control-D8, PGF-D8 and 1/10PGF-D8 groups on H48. Partially regressed CLs (1/10PGF-D8 group) generated more Doppler signals than completed regressed CLs (PGF-D8 group) between D10 and D13. In both experiments, a transient increase in PRL activity was observed in parallel to the PGFM pulse in mares receiving 1 or 10 mg Dinoprost. The use of prostaglandin on D2 at conventional or 1/10 of the dose impaired the luteal development in mares. Moreover, the low dose of prostaglandin lead to partial regression of mature CLs. The blood supply was reduced in partially regressed CLs, but not in CLs undergoing impaired luteogenesis. PMID- 29132039 TI - The CXCL12-CXCR4 signaling promotes oocyte maturation by regulating cumulus expansion in sheep. AB - Gonadotropins and growth factors synergistically regulate folliculogenesis and oocyte development. C-X-C motif chemokine 12 (CXCL12) and its receptor CXCR4 are expressed in ovaries of sheep, cattle and other species, however, roles of this multifunctional signal axis in oocyte maturation are not defined. Using sheep as a model, we examined the expression patterns and functions of the CXCL12-CXCR4 axis during oocyte maturation. CXCL12 and CXCR4 mRNA and protein were present in oocytes and granulosa cells. Relative abundance of CXCR4 transcript was controlled by epidermal growth factor (EGF). Transient inhibition of CXCR4 suppressed oocyte nuclear maturation while supplementing recombination CXCL12 significantly increased percent of oocyte undergone metaphase I phase. Inhibition of CXCR4 function decreased cumulus expansion growth rate. Furthermore, granulosa cell migration was impaired and expression of hyaluronan synthase 2 (HAS2) and hyaluronan binding protein tumor necrosis factor-alpha-induced protein 6 (TNFAIP6) were downregulated by CXCR4 inhibition. These findings revealed a novel role of the CXCL12-CXCR4 signaling in oocyte development in sheep. PMID- 29132040 TI - Inclusion complexes between cisplatin and oxidized carbon nanostructures: A theoretical approach. AB - The toxicity of inclusion compounds formed by carbon nanostructures depends on its functionalized surface, use of solvents, dosage and other properties. Molecular modeling has potentially contributed to the understanding of the chemical nature of the formation of these systems and allows advancement in studies of the mechanism of transport, release of drugs and their biological implications. This work reports a quantum chemical investigation of the inclusion complexes formation between oxidized carbon nanotube (CNTox)/nanocone (CNCox) structure and cisplatin molecule, using the density functional theory (DFT) with the B3LYP functional and 6-31G(d,p)/LanL2DZ standard basis sets. Our results indicate that the cDDP@CNTox (inclusion complex - cisplatin into oxidized carbon nanotube) and cDDP@CNCox (inclusion complex - cisplatin into oxidized carbon nanocone) systems form stable molecular complexes that can be used as drug delivery devices. Our theoretical simulation of molecular spectra (IR, Raman and 1H NMR) reveals substantial changes due to complex formation that can be easily experimentally observed. PMID- 29132041 TI - Preparation of a beta-tricalcium phosphate nanocoating and its protein adsorption behaviour by quartz crystal microbalance with dissipation technique. AB - Beta-tricalcium phosphate (beta-TCP) nanocoatings, which can be analysed using a quartz crystal microbalance with dissipation technique (QCM-D), were fabricated on a gold surface by electrophoretic deposition. The influences of electric field intensity and electrophoresis time were investigated. The adsorption behaviours of bovine serum albumin (BSA) and lysozyme (LSZ) on Au and beta-TCP surfaces were observed in real time by QCM-D. The homogeneous beta-TCP nanocoating with moderately sized particles on gold surface was fabricated at 25V/cm for 5min, and it met the requirements for the QCM-D experiment. The adsorption behaviour of BSA was different from that of LSZ, which was caused by the differences of protein properties. The adsorption quantity of BSA on a beta-TCP surface was higher than that on a gold surface. However, the adsorption amount of LSZ on a beta-TCP surface was lower than that on a gold surface. The electrostatic force was the major factor affecting the adsorption quantities of BSA and LSZ on Au and beta TCP surfaces based on the investigation of various factors. The findings reported here will be useful for understanding the mechanism of the interaction between biomaterials and proteins. PMID- 29132042 TI - Long-range interactions keep bacterial cells from liquid-solid interfaces: Evidence of a bacteria exclusion zone near Nafion surfaces and possible implications for bacterial attachment. AB - Hydrophilic surfaces of both abiotic and biological origin have been shown to bear particle-exclusion zones as large as hundreds of micrometers at liquid-solid interfaces. Here we present the first systematic investigation and evidence for bacteria-free exclusion zones for several bacterial strains, including pathogens associated with hospital infections and/or foodborne outbreaks: Staphylococcus aureus, Escherichia coli O157:H7, and Listeria monocytogenes. Tests were carried out both in a phosphate buffer, as well as triptic soy broth (TSB) of high ionic strength. Bacterial cell density distribution at the Nafion-liquid interface was visualized using confocal laser scanning microscopy. A robust image analysis method was developed to generate a profile of cell concentration near the interface and quantify EZ size. Results revealed an exclusion zone (EZ) of 40 60MUm and a transition zone (TZ) of 40-80MUm for bacterial cells suspended in tryptic soy broth. There were no statistical differences in the size of EZ and TZ for the bacterial strains tested with the same substrate, but differences existed for different substrates tested, implying a physicochemical underpinning for EZ. In a test conducted with E. coli, cells progressively penetrated EZ over 2days. Furthermore, EZ-bearing Nafion had 80% less biomass accumulation of E. coli over 2days compared to an EZ-less, hydrophilic, smooth aluminum oxide surface. This suggests that EZ may represent the first line of defense, spatially and temporally, against bacteria approaching certain hydrophilic surfaces. These findings could have important implications in developing biofouling-resistant material surfaces for applications sensitive to bacterial attachment and biofilm formation. PMID- 29132043 TI - The effect of diethylene glycol monoethyl ether on skin penetration ability of diclofenac acid nanosuspensions. AB - : The poor ability of many drugs to cross skin layers is the main limiting factor for the exploitation of the transdermal route for drug delivery. As a consequence, several approaches have been proposed to overcome the skin barrier, such as the inclusion of penetration enhancers in the topically applied drug solutions and emulsions. In this work, the penetration enhancer diethylene glycol monoethyl ether was included in novel diclofenac acid nanocrystal formulations, developed using the wet media milling technique and Poloxamer 188 as stabilizer. The nanosuspensions were characterized by different techniques such as scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, Fourier-transform infrared spectroscopy and photon correlation spectroscopy. The influence of diethylene glycol monoethyl ether on (trans)dermal delivery of diclofenac nanosuspensions was evaluated by in vitro studies using Franz diffusion cells and pig skin. RESULTS: demonstrated that the presence of diethylene glycol monoethyl ether influences the Poloxamer 188 ability to stabilize the nanocrystals during the milling process, leading to larger particles as compared to penetration enhancer-free nanosuspensions. As previously reported, the in vitro permeation studies indicate the nanosizing as a key factor in the dermal penetration of topically applied diclofenac. Surprisingly enough, the inclusion of increasing amounts of the penetration enhancer in the formulation decreased the diclofenac accumulation in the stratum corneum, while showing no significant effect on the drug delivered to the epidermis. Overall, the present results exclude a synergistic effect of the nanosizing approach and the addition of diethylene glycol monoethyl ether in regard to the skin penetration of diclofenac applied as a nanosuspension. PMID- 29132044 TI - Exposure to thin-ideal media affect most, but not all, women: Results from the Perceived Effects of Media Exposure Scale and open-ended responses. AB - Findings conflict as to whether thin-ideal media affect women's body satisfaction. Meta-analyses of experimental studies reveal small or null effects, but many women endorse appearance-related media pressure in surveys. Using a novel approach, two samples of women (Ns=656, 770) were exposed to bikini models, fashion models, or control conditions and reported the effects of the images their body image. Many women reported the fashion/bikini models made them feel worse about their stomachs (57%, 64%), weight (50%, 56%), waist (50%, 56%), overall appearance (50%, 56%), muscle tone (46%, 52%), legs (45%, 48%), thighs (40%, 49%), buttocks (40%, 43%), and hips (40%, 46%). In contrast, few women (1 6%) reported negative effects of control images. In open-ended responses, approximately one-third of women explicitly described negative media effects on their body image. Findings revealed that many women perceive negative effects of thin-ideal media in the immediate aftermath of exposures in experimental settings. PMID- 29132045 TI - Bullying and Social Anxiety in Chinese Children: Moderating Roles of Trait Resilience and Psychological Suzhi. AB - Research examining the relationship between bullying victimization and social anxiety has mainly been conducted in Western countries, and little is known about the mechanisms underlying this relationship. This study explores the correlation between bullying victimization and social anxiety in a Chinese context and determines the moderating roles of psychological suzhi (a mental quality characterized by being steady, essential and implicit that affects adaptive, developmental, and creative behavior) and trait resilience among victims of bullying. Data were obtained from a stratified sample of 1903 children in the fourth, fifth, and sixth grades. All participants completed measures of bullying victimization, social anxiety, trait resilience, and psychological suzhi. The results indicated that, after controlling for grade, residential area, and parental marital status, bullying victimization positively predicted children's social anxiety. In addition, multi-group analysis suggested that the association in girls was stronger relative to that observed in boys. Regarding underlying processes, trait resilience moderated the effect of bullying victimization on social anxiety only in girls. Further assessment of the latent interaction effects indicated that the protective effect of trait resilience was stronger for girls experiencing high, relative to low, levels of bullying victimization, and psychological suzhi buffered against the detrimental effects of bullying on children's social anxiety. Most notably, unlike the moderating effect of resilience, the buffering effect of psychological suzhi against social anxiety was most prominent when bullying victimization was low. Findings underscore the importance of enhancing trait resilience and psychological suzhi in interventions designed to reduce children's social anxiety. PMID- 29132046 TI - Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture. AB - The physical and architectural cues of the extracellular matrix (ECM) play a critical role in regulating important cellular functions such as spreading, migration, proliferation, and differentiation. Natural ECM is a complex viscoelastic scaffold composed of various distinct components that are often organized into a fibrillar microstructure. Hydrogels are frequently used as synthetic ECMs for 3D cell culture, but are typically elastic, due to covalent crosslinking, and non-fibrillar. Recent work has revealed the importance of stress relaxation in viscoelastic hydrogels in regulating biological processes such as spreading and differentiation, but these studies all utilize synthetic ECM hydrogels that are non-fibrillar. Key mechanotransduction events, such as focal adhesion formation, have only been observed in fibrillar networks in 3D culture to date. Here we present an interpenetrating network (IPN) hydrogel system based on HA crosslinked with dynamic covalent bonds and collagen I that captures the viscoelasticity and fibrillarity of ECM in tissues. The IPN hydrogels exhibit two distinct processes in stress relaxation, one from collagen and the other from HA crosslinking dynamics. Stress relaxation in the IPN hydrogels can be tuned by modulating HA crosslinker affinity, molecular weight of the HA, or HA concentration. Faster relaxation in the IPN hydrogels promotes cell spreading, fiber remodeling, and focal adhesion (FA) formation - behaviors often inhibited in other hydrogel-based materials in 3D culture. This study presents a new, broadly adaptable materials platform for mimicking key ECM features of viscoelasticity and fibrillarity in hydrogels for 3D cell culture and sheds light on how these mechanical and structural cues regulate cell behavior. PMID- 29132047 TI - In situ label-free monitoring of human adipose-derived mesenchymal stem cell differentiation into multiple lineages. AB - Precise characterizations of stem cell differentiation into specific lineages, especially in non-destructive and non-invasive manner, are extremely important for generating patient-specific cells without mass loss of differentiated cells. Here, we report a new method capable of in situ label-free quantification of stem cell differentiation into multiple lineages, even at a single cell level. The human adipose-derived mesenchymal stem cells (hADMSCs) were first differentiated into two different types of cells (osteoblasts and adipocytes) and these differentiated cells were then intensively analyzed by micro-Raman spectroscopy. Interestingly, the Raman peaks assigned to lipid droplets and hydroxyapatite were found to be highly specific to the adipocyte (fat cell) and osteoblast (bone cell) and were thus found to be useful for generating label-free single cell Raman images in combination with CH3 (2935 cm-1) peaks for visualizing cell shape. Remarkably, based on these Raman images, we found that the osteogenesis of hADMSCs could be determined and quantified after 9 days of differentiation, which is a week earlier than with the typical alizarin red staining method. In the case of adipogenesis, the increase of lipid droplets in the cytoplasm at the single cell level could be clearly visualized and detected during the entire period of adipogenesis, which is impossible using any other currently available methods such as Oil Red O and immunostaining. Hence, the new method reported in this study is highly promising as an analytical tool for precise in-situ monitoring of stem cell differentiation, and could facilitate the use of stem cell-based materials for the regenerative therapies. PMID- 29132048 TI - Brain white matter structure and language ability in preschool-aged children. AB - Brain alterations are associated with reading and language difficulties in older children, but little research has investigated relationships between early language skills and brain white matter structure during the preschool period. We studied 68 children aged 3.0-5.6 years who underwent diffusion tensor imaging and participated in assessments of Phonological Processing and Speeded Naming. Tract based spatial statistics and tractography revealed relationships between Phonological Processing and diffusion parameters in bilateral ventral white matter pathways and the corpus callosum. Phonological Processing was positively correlated with fractional anisotropy and negatively correlated with mean diffusivity. The relationships observed in left ventral pathways are consistent with studies in older children, and demonstrate that structural markers for language performance are apparent as young as 3 years of age. Our findings in right hemisphere areas that are not as commonly found in adult studies suggest that young children rely on a widespread network for language processing that becomes more specialized with age. PMID- 29132049 TI - Male Syrian hamsters are more susceptible to intravenous infection with species C human adenoviruses than are females. AB - Recently, increasing attention has been focused on the influence of sex on the course of infectious diseases. Thus far, the best-documented examples point toward an immune-mediated mechanism: the generally stronger immune response in females can result in a faster clearance of the pathogen or, conversely, a more severe immune-mediated pathology. Here, we report that human species C adenoviruses replicate more and cause more pathology in male Syrian hamsters than in females. We also show that this sex disparity is not caused by a stronger immune response to the infection by the female hamsters. Rather, the liver of male hamsters is more susceptible to adenovirus infection: after intravenous injection, more hepatocytes become infected in male animals than in females. We hypothesize that Kupffer cells (hepatic tissue macrophages) of female animals are more active in sequestering circulating virions, and thus protect hepatocytes more efficiently than those of males. PMID- 29132051 TI - High-purity capture of CTCs based on micro-beads enhanced isolation by size of epithelial tumor cells (ISET) method. AB - In this paper, we develop a low-cost size-based microfluidic chip using conventional polycarbonate membrane to isolate CTCs from blood, and propose a strategy to increase the capture efficiency before cell filtration by a size enlargement method utilizing modified microbeads specifically binding to CTCs. Up to 91% of target cells were isolated from whole blood samples using our microfluidic capture system at a flow rate of 1mL/min. Moreover, a WBC depletion process is introduced which greatly decreases the WBC retaining on the filter membrane. The tests of immunofluorescence analysis of cells captured on the membrane were performed, which demonstrates that the device could provide a dependable CTC identification and CTC count in whole blood samples. Finally, the device was further validated in the detection of CTCs from blood samples of cancer patients, and it indicates a promising capability to detect CTC response to treatment. PMID- 29132050 TI - Cannabinoid hyperemesis syndrome: Review of the literature and of cases reported to the French addictovigilance network. AB - BACKGROUND: Cannabinoid hyperemesis syndrome is a variant of cyclical vomiting syndrome in a context of chronic cannabis usage. Our aim was to compare French cases to those identified in the international literature in order to further our knowledge of the clinical criteria, pathophysiology and treatments for cannabinoid hyperemesis syndrome. METHODS: We analysed cases reported in the international literature up to 30 June 2017, obtained from the MEDLINE, PsycINFO and The Cochrane Library databases; we selected relevant articles based on title and abstract. We also analysed cases of cannabinoid hyperemesis syndrome reported to the French addictovigilance network. RESULTS: A systematic search through the three databases enabled us to identify 137 articles. Finally, 55 articles were selected as they involved reported cases. In total, 113 cases were reported in these 55 articles. We were thus able to analyse 29 reported French cases of cannabinoid hyperemesis syndrome. Cannabinoid hyperemesis syndrome mainly affects young male subjects who have been smoking cannabis daily for several years. Taking hot baths or showers is the most effective means of relieving the symptoms, while antiemetics and dopamine antagonists do not appear to effective for relieving nausea and vomiting. CONCLUSIONS: French cases display the same characteristics as the cases identified in the international literature. The pathophysiology of cannabinoid hyperemesis syndrome is unclear and several hypotheses have been put forward in the literature. We have only begun to characterise the syndrome, though there is an outbreak of cannabinoid hyperemesis syndrome in France. PMID- 29132052 TI - Aptamer-functionalized capacitance sensors for real-time monitoring of bacterial growth and antibiotic susceptibility. AB - To prevent spread of infection and antibiotic resistance, fast and accurate diagnosis of bacterial infection and subsequent administration of antimicrobial agents are important. However, conventional methods for bacterial detection and antibiotic susceptibility testing (AST) require more than two days, leading to delays that have contributed to an increase in antibiotic-resistant bacteria. Here, we report an aptamer-functionalized capacitance sensor array that can monitor bacterial growth and antibiotic susceptibility in real-time. While E. coli and S. aureus were cultured, the capacitance increased over time, and apparent bacterial growth curves were observed even when 10 CFU/mL bacteria was inoculated. Furthermore, because of the selectivity of aptamers, bacteria could be identified within 1h using the capacitance sensor array functionalized with aptamers. In addition to bacterial growth, antibiotic susceptibility could be monitored in real-time. When bacteria were treated with antibiotics above the minimum inhibitory concentration (MIC), the capacitance decreased because the bacterial growth was inhibited. These results demonstrate that the aptamer functionalized capacitance sensor array might be applied for rapid ASTs. PMID- 29132053 TI - TDDFT study on excited state intramolecular proton transfer mechanism in 2-amino 3-(2'-benzazolyl)-quinolines. AB - The intramolecular proton transfer reaction of the 2-amino-3-(2'-benzoxazolyl) quinoline (ABO) and 2-amino-3-(2'-benzothiazolyl)-quinoline (ABT) molecules in both S0 and S1 states at B3LYP/6-311++G(d,p) level in ethanol solvent have been studied to reveal the deactivation mechanism of the tautomers of the two molecules from the S1 state to the S0 state. The results show that the tautomers of ABO and ABT molecules may return to the S0 state by emitting fluorescence. In addition, the bond lengths, angles and infrared spectra are analyzed to confirm the hydrogen bonds strengthened upon photoexcitation, which can facilitate the proton transfer process. The frontier molecular orbitals (MOs) and natural bond orbital (NBO) are also calculated to indicate the intramolecular charge transfer which can be used to explore the tendency of ESIPT reaction. The potential energy surfaces of the ABO and ABT molecules in the S0 and S1 states have been constructed. According to the energy potential barrier of 9.12kcal/mol for ABO molecule and 5.96kcal/mol for ABT molecule, it can be indicated that the proton transfer may occur in the S1 state. PMID- 29132054 TI - Contrast-enhanced imaging features and differentiation of benign and malignant focal splenic lesions. AB - To assess the value of imaging features for differentiating malignant from benign focal splenic lesions, 79 pathologically proved cases with contrast-enhanced CT or MRI were retrospectively studied. The morphological characteristics were assessed and the enhancement patterns were classified into five categories. After multivariate logistic analysis, the lesion margin and enhancement patterns were significantly different between benign and malignant lesions. The combination of ill-defined margin and hypovascular enhancement for suggesting malignant lesions had a good specificity (94.9%) and accuracy (89.9%). Morphological and enhancement characteristics on CT/MRI may be valuable in differentiating malignant from benign focal splenic lesions. PMID- 29132056 TI - Central venous pressure and ultrasonographic measurement correlation and their associations with intradialytic adverse events in hospitalized patients: A prospective observational study. AB - PURPOSE: To investigate correlation of central venous pressure (CVP) with ultrasonographic measurement of central veins, along with association between these variables and occurrence of intradialytic adverse events in hospitalized patients. MATERIALS AND METHODS: Patients requiring hemodialysis via dialysis catheter were prospectively enrolled. CVP measurements through catheter, internal jugular vein aspect ratio, subclavian vein collapsibility, inferior vena cava (IVC) maximal diameter, and IVC collapsibility were recorded before and after hemodialysis. Predictive accuracy of ultrasonographic measurements in discriminating high versus low CVP and their association with intradialytic adverse events were evaluated. Area under receiver operating characteristic curves (AUCs) were calculated. RESULTS: Fifty-nine patients were enrolled. Median (interquartile range) pre- and post-dialysis CVPs were 8 (4-13)mmHg and 6 (3 10)mmHg, respectively (P<0.01). In pre-dialysis, IVC collapsibility had the highest AUC (0.79, P<0.01) to predict CVP >8mmHg. In post-dialysis, IVC maximal diameter had the highest AUC (0.86, P<0.01) to predict CVP <=4mmHg. Fifteen patients (25%) had adverse events. Neither pre-dialytic CVP nor ultrasonographic variables were associated with occurrence of adverse events. CONCLUSIONS: Highest accuracy in predicting low and high CVP was observed with ultrasonographic assessment of IVC diameter and collapsibility. Adverse events were not predicted by pre-dialytic CVP or ultrasonographic measurements. PMID- 29132055 TI - Benefit and clinical significance of retrospectively obtained spectral data with a novel detector-based spectral computed tomography - Initial experiences and results. AB - OBJECTIVES: To evaluate the benefits and clinical significance of retrospectively generated spectral image-datasets with the novel detector-based Spectral CT (SDCT). METHODS: A total of 118 body CTs from the SDCT prototype were included. Based on the clinical indication, two radiologists were asked if they would have opted for a dual-energy mode/scan if the patient was scanned in one of the other commercially-available dual-energy scanners, which need prospective selection of dual energy mode. They also reviewed the scans, identified cases that would benefit from spectral images and evaluated these images for clinical utility and significance on a five-point scale, with 1 being the least and 5 being the highest. RESULTS: Dual-energy mode would have been prospectively selected in 20 cases (17%) for Reader 1 and 25 cases (21%) for Reader 2. Additional spectral images were requested for 94 cases (80%) and 96 cases (81%) respectively. A total of 196 and 206 spectral image-sets were utilized respectively with 97% and 96% of these image-sets useful retrospectively. The distribution of scores on the five point scale for Readers 1 and 2 were, 1-7% & 6%; 2-26% & 30%; 3-36% & 36%; 4-27% & 21% and; 5-4% & 7%. Clinically significant score (>=4) was noted in 31% and 28% respectively. CONCLUSIONS: Additional spectral datasets retrospectively reconstructed from SDCT enhanced the diagnostic capabilities by reducing artifacts, improving contrast and allowing lesion characterization. PMID- 29132057 TI - Predictors of hemodynamic derangement during intubation in the critically ill: A nested case-control study of hemodynamic management-Part II. AB - PURPOSE: Our primary aim was to identify predictors of immediate hemodynamic decompensation during the peri-intubation period. METHODS: We conducted a nested case-control study of a previously identified cohort of adult patients needing intubation admitted to a medical-surgical ICU during 2013-2014. Hemodynamic derangement was defined as cardiac arrest and/or the development of systolic blood pressure <90mmHg and/or mean arterial pressure <65mmHg 30min following intubation. Data during the peri-intubation period was analyzed. RESULTS: The final cohort included 420 patients. Immediate hemodynamic derangement occurred in 170 (40%) patients. On multivariate modeling, age/10year increase (OR 1.20, 95% CI 1.03-1.39, p=0.02), pre-intubation non-invasive ventilation (OR 1.71, 95% CI 1.04-2.80, p=0.03), pre-intubation shock index/1 unit (OR 5.37 95% CI 2.31-12.46, p<=0.01), and pre-intubation modified shock index/1 unit (OR 2.73 95% CI 1.48 5.06, p<=0.01) were significantly associated with hemodynamic derangement. Those experiencing hemodynamic derangement had higher ICU [47 (28%) vs. 33 (13%); p<=0.001] and hospital [69 (41%) vs. 51 (20%); p<=0.001] mortality. CONCLUSIONS: Hemodynamic derangement occurred at a rate of 40% and was associated with increased mortality. Increasing age, use of non-invasive ventilation before intubation, and increased pre-intubation shock and modified shock index values were significantly associated with hemodynamic derangement post-intubation. PMID- 29132058 TI - Clinical significance of the coexistence of carotid artery plaque and white matter disease in patients with symptomatic cerebral infarction. AB - OBJECTIVES: Symptomatic cerebral infarction (CI) can occur in patients without main cerebral artery stenosis or occlusion. This study investigated the unique features of carotid artery plaque and white matter disease (WMD) in patients with symptomatic CI and transient ischemic attack (TIA) but without stenosis or occlusion of a main cerebral artery. PATIENTS AND METHODS: We studied 647 patients who underwent both carotid ultrasound examination and brain magnetic resonance images. Plaque score (PS), plaque number, maximal plaque intima-media thickness and grades of WMD were examined. Subjects were divided into four groups, the CI group, TIA group, myocardial infarction (MI) group and risk factor (RF) group. Plaque and WMD were analyzed in cerebral ischemia group (CI and TIA), compared to non-cerebral ischemia groups and to a high PS group and a high WMD grade group from the RF group. RESULTS: Both of each value of plaque and grades of WMD in the cerebral ischemia group were significantly higher than those in other groups. Grades of WMD in the cerebral ischemia group were significantly higher than those in the high PS group, although there was no significant difference of the each value of plaque between the two groups. The each value of plaque in the cerebral ischemia group was also significantly higher than those in the high WMD grade group, although there was no significant difference of grade of WMD between the two groups. CONCLUSION: Simultaneous increases in carotid artery plaque and WMD are associated with symptomatic CI, which is not caused by stenosis or occlusion of a main cerebral artery. PMID- 29132059 TI - Lumbar vertebra surgery performed with a bilateral intramuscular iliocostal muscle block. PMID- 29132060 TI - Traditional beliefs and practices in pregnancy, childbirth and postpartum: A review of the evidence from Asian countries. AB - INTRODUCTION: Asian women suffer the largest proportion of the world's maternal deaths. To reduce this, policymakers and healthcare providers must encourage women with traditionally low rates of maternal health care utilization to access services. OBJECTIVE: The purpose of this study is to provide a comprehensive review of the most common traditional practices in Asia relating to pregnancy, childbirth and the postpartum period. DESIGN: We conducted a literature search of articles: a) focusing on Asia; b) relating to pregnancy, childbirth or postpartum, c) relating to traditional beliefs and/or cultural practices; and 4) published in English in the year 2000 or more recently. FINDINGS: A total of 74 articles are included in this review; 20 articles related to pregnancy, 44 to childbirth, and 45 to postpartum. More than one-half (38) of the articles focused on South Asia and 13 related to China. In the pregnancy category, the majority of the studies focused on dietary recommendations and behavioral taboos. For the childbirth category, many articles examined beliefs and practices that helped to explain women's aversion to institutional births, such as preference for traditional birth positions, and fear of medical interventions. In the postpartum period, confinement was common because postpartum women were perceived to be weak, fragile and vulnerable to illness. Other prevalent beliefs and practices across Asian countries included massage, the state of pollution after childbirth, the use of traditional healers and traditional medicine and herbs, beliefs relating to hot/cold imbalance, behavioral taboos, magic, and superstition. KEY CONCLUSIONS: Many Asian women continue to practice a wide range of traditional beliefs and practices during pregnancy, childbirth, and the postpartum period. More information is needed on the benefits of formal maternal healthcare services; such educational programs should be geared towards not only women but also husbands, parents, and in-laws. By recognizing and appreciating common local beliefs, providers can be better positioned to provide culturally competent care. Instead of reducing the choices available to women during the birth experience, providers should understand, respect, and integrate cultural interpretations of childbirth and the needs of women and their families. PMID- 29132061 TI - Synchronous peritoneal metastases of small bowel adenocarcinoma: Insights into an underexposed clinical phenomenon. AB - BACKGROUND: The aim of this population-based study was to provide insight into the incidence, risk factors and treatment-related survival of patients with peritoneal metastases (PM) of small bowel adenocarcinoma (SBA). METHODS: Data from the Netherlands Cancer Registry were used. All patients diagnosed with SBA between 2005 and 2014 were included. The influence of patient and tumour characteristics on the odds of developing PM was analysed. Subsequently, for all further analyses, patients without synchronous PM of SBA were excluded. The log rank test and Kaplan-Meier analyses were conducted to estimate survival, and the Cox proportional hazards model was used to evaluate the risk of death. RESULTS: Of the 1428 included patients diagnosed with SBA, 181 (13%) presented with synchronous PM. Synchronous PM was found in 9% of the duodenal tumours and in 17% of the more distal tumours. Median overall survival of all patients with PM was 5.9 months, whereas survival of both 11 months was observed in patients treated with primary tumour resection or palliative chemotherapy and 32 months after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC). Poor prognostic factors for survival were age >=70 years (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.1-2.2), systemic metastases other than PM (HR 2.0, 95% CI 1.4-2.9) and an advanced (HR 1.9, 95% CI 1.3-3.0) or unknown T-stage (HR 2.1, 95% CI 1.2-3.5). CONCLUSIONS: Synchronous PM was frequently encountered in SBA. Without treatment, prognosis was extremely poor. Survival was higher after primary tumour resection, palliative chemotherapy and CRS+HIPEC, but selection bias probably played a significant role calling for further clinical research. PMID- 29132063 TI - Right thalamic bleed resulting in hypersexuality successfully treated with Selective Serotonin reuptake inhibitor Sertraline - A case report. PMID- 29132062 TI - Risk of early-onset prostate cancer associated with occupation in the Nordic countries. AB - BACKGROUND: Early-onset prostate cancer is often more aggressive and may have a different aetiology than later-onset prostate cancer, but has been relatively little studied to date. We evaluated occupation in relation to early- and later onset prostate cancer in a large pooled study. METHODS: We used occupational information from census data in five Nordic countries from 1960 to 1990. We identified prostate cancer cases diagnosed from 1961 to 2005 by linkage of census information to national cancer registries and calculated standardised incidence ratios (SIRs) separately for men aged 30-49 and those aged 50 or older. We also conducted separate analyses by period of follow-up, 1961-1985 and 1986-2005, corresponding to pre- and post-prostate-specific antigen (PSA) screening. RESULTS: For early-onset prostate cancer (n = 1521), we observed the highest SIRs for public safety workers (e.g. firefighters) (SIR = 1.71, 95% confidence interval [CI]: 1.23-2.31) and military personnel (SIR = 1.97, 95% CI: 1.31-2.85). These SIRs were significantly higher than the SIRs for later-onset disease (for public safety workers, SIR = 1.10, 95% CI: 1.07-1.14 and for military personnel, SIR = 1.09, 95% CI: 1.05-1.13; pheterogeneity = 0.005 and 0.002, respectively). Administrators and technical workers also demonstrated significantly increased risks for early-onset prostate cancer, but the SIRs did not differ from those of later-onset disease (pheterogeneity >0.05). While our early-onset finding for public safety workers was restricted to the post-PSA period, that for military personnel was restricted to the pre-PSA period. CONCLUSION: Our results suggest that occupational exposures, particularly for military personnel, may be associated with early-onset prostate cancer. Further evaluation is needed to explain these findings. PMID- 29132064 TI - Patients' and caregivers' contributions for differentiating epileptic from psychogenic nonepileptic seizures. Value and limitations of self-reporting questionnaires: A pilot study. AB - PURPOSE: Questionnaires investigating semiology and comorbidities of psychogenic non-epileptic seizures (PNES) have been used mainly to help physicians expedite referrals to epilepsy centres for confirmation of diagnosis rather than as alternative diagnostic tool when video-EEG monitoring (VEM), the current gold standard, is not available or is inconclusive. METHODS: We developed one structured questionnaire for patients, exploring subjective experiences and vulnerabilities and one for eyewitnesses, focused on features observable during typical events to study prospectively 50 consecutive adult patients with PNES or epileptic seizures (ES) admitted for VEM. A list of variables representing specific signs, symptoms and risk factors was obtained from each question. Specificity (SP) and sensitivity (SE) of each variable were calculated analyzing patient's and witness' responses against the final diagnosis. Statistical significance was assessed using the Fisher's exact test. RESULTS: Twenty-eight patients' questionnaires (17 PNES, 11 ES) were eligible for analysis. Seven variables with high SE and SP, of which 5 statistically significant, emerged as diagnostic predictors. They comprised three historical items: head injury, physical abuse and chronic fatigue; two warning signs: heart racing and tingling or numbness; one triggering sign: headache; one postictal symptom: physical pain. Sixteen witness questionnaires (6 PNES, 10 ES) were available. Side-to-side head movements and eyes closed were the statistically significant variables. CONCLUSION: Pending further refinements, ad hoc questionnaires specifically designed for patients and eyewitnesses, may represent a practical tool for distinguishing ES from PNES in settings without sophisticated facilities or when VEM is inconclusive. PMID- 29132065 TI - Common components analysis: An adapted approach for evaluating programs. AB - Common Components Analysis (CCA) summarizes the results of program evaluations that utilize randomized control trials and have demonstrated effectiveness in improving their intended outcome(s) into their key elements. This area of research has integrated and modified the existing CCA approach to provide a means of evaluating components of programs without a solid evidence-base, across a variety of target outcomes. This adapted CCA approach (a) captures a variety of similar program characteristics to increase the quality of the comparison within components; (b) identifies components from four primary areas (i.e., content, process, barrier reduction, and sustainability) within specific programming domains (e.g., vocation, social); and (c) proposes future directions to test the extent to which the common components are associated with changes in intended program outcomes (e.g., employment, job retention). The purpose of this paper is to discuss the feasibility of this adapted CCA approach. To illustrate the utility of this technique, researchers used CCA with two popular employment programs that target successful Veteran reintegration but have limited program evaluation - Hire Heroes USA and Hire Our Heroes. This adapted CCA could be applied to longitudinal research designs to identify all utilized programs and the most promising components of these programs as they relate to changes in outcomes. PMID- 29132067 TI - Limited generalization with varied, as compared to specific, practice in short term motor learning. AB - The schema theory of learning predicts that varied training in motor learning should give rise to better transfer than specific training. For example, throwing beanbags during practice to targets 5 and 9ft away should better generalize to targets 7 and 11ft away, as compared to only throwing to a target 7ft away. In this study, we tested this prediction in a throwing task, when the pretest, practice, and posttest were all completed within an hour. Participants in the varied group practiced throwing at 5 and 9ft targets, while participants in the specific group practiced throwing at 7ft only. All participants reliably reduced errors from pretest to posttest. The varied group never outperformed the specific group at the 7ft target (the trained target for the specific group). They did not reliably outperform the specific group at 11ft, either. The numerically better performance at 11ft by the varied group was due, as it turned out in a subsequent experiment, to the fact that 11ft was closer to 9ft (one of the two training targets for the varied group) than to 7ft (the training target for the specific group). We conclude that varied training played a very limited role in short-term motor learning. PMID- 29132066 TI - Fungal interactions with the human host: exploring the spectrum of symbiosis. AB - Fungi are ubiquitous transient or persistent human colonisers, and form the mycobiome with shifts in niche specific mycobiomes (dysbiosis) being associated with various diseases. These complex interactions of fungal species with the human host can be viewed as a spectrum of symbiotic relationships (i.e. commensal, parasitic, mutualistic, amensalistic). The host relevant outcome of the relationship is the damage to benefit ratio, elegantly described in the damage response framework. This review focuses on Candida albicans, which is the most well studied human fungal symbiont clinically and experimentally, its transition from commensalism to parasitism within the human host, and the factors that influence this relationship. PMID- 29132068 TI - Secretoneurin and PE-11 immunoreactivity in the human dental pulp. AB - OBJECTIVE: To explore whether there are differences in the concentration of the secretogranin II-derived peptide secretoneurin and the chromogranin B-derived peptide PE-11 between the healthy and inflamed human dental pulps. Furthermore, colocalization studies with calcitonin gene-related peptide were performed to confirm the sensory origin of the peptidergic nerves in the dental pulp. DESIGN: The concentrations of secretoneurin and PE-11 were determined by highly sensitive radioimmunoassays in extracts of dental pulps, the molecular form of secretoneurin immunoreactivities by RP-HPLC with subsequent radioimmunoassay and colocalization studies with calcitonin gene-related peptide were performed by double immunofluorescence. RESULTS: Only secretoneurin but not PE-11 was detectable by radioimmunoassays whereas nerve fibers could be made visible for both secretoneurin and PE-11. Furthermore, there was a full colocalization of secretoneurin and PE-11 with calcitonin gene-related peptide in immunohistochemical experiments. There were no differences in the concentration of secretoneurin between the healthy and inflamed human dental pulp and moreover, the characterization of the secretoneurin immunoreactivities revealed that only authentic secretoneurin was detected with the secretoneurin antibody. CONCLUSIONS: There is unequivocal evidence that secretoneurin and PE-11 are constituents of the sensory innervation of the human dental pulp and although not exclusively but are yet present in unmyelinated C-fibers which transmit predominantly nociceptive impulses. Secretoneurin might be involved in local effector functions as well, particularly in neurogenic inflammation, given that this is the case despite of unaltered levels in inflamed tissue. PMID- 29132069 TI - Risk factors for tooth loss in middle and older age after up to 10 years: An observational cohort study. AB - OBJECTIVE: The objective of this research was to identify risk factors for tooth loss in two birth cohorts, quinquagenarians and septuagenarians, after up to 10 years of clinical observation. DESIGN: One hundred and twenty-three participants were recruited from the Interdisciplinary Study of Adult Development (ILSE) and examined at baseline and up to 10 years after. Thirty-nine and 84 participants belonged to the older (OC; born in 1930/32) cohort and younger (YC; born in 1950/52) cohort, respectively. Each participant underwent a dental examination comprising evaluation of the dental status (number of teeth, prosthetic restorations), Plaque Index (PI), Gingival Index (GI), DMF-S, periodontal probing depths (PD) and tooth mobility (TM). Incidence of tooth loss over the study period was calculated for both cohorts as well as for the grouped dental target variables. A logistic regression model for tooth loss (0=tooth present/1=tooth lost) was compiled with possible binary confounders. RESULTS: During the study period (eight years in mean), 1.2 (1.9) and 2.6 (2.6) teeth were lost in YC and OC, respectively, reflecting correspondent loss rates of 5% and 14% (p<0.001). However, primarily TM >1 merged into substantial tooth loss (60% lost). The regression analysis confirmed the bivariate findings. Older age and worse oral health issues were identified as risk factors for tooth loss(p<0.05). CONCLUSIONS: Both quinquagenarians and septuagenarians show relevant tooth loss over a period of up to 10 years but more in septuagenarians. The predominant predictor for tooth loss seems to be greater tooth mobility. With the rising challenges due to aging in several societies, knowing the risks might help clinicians when weighing treatment strategies and should encourage refining preventive measures for older patients. PMID- 29132070 TI - Sixteen-year history of rituximab therapy for 1085 pemphigus vulgaris patients: A systematic review. AB - Pemphigus vulgaris (PV) is a rare autoimmune disease due to the production of pathogenic autoantibodies directed against desmoglein 1 and 3, usually affecting both skin and mucous membranes. Recently, rituximab, a chimeric IgG1 monoclonal antibody which targets the CD20 molecules have been regarded as a promising treatment for PV. In this study, a systematic review was conducted to conclude on how and which PV patients could benefit from rituximab infusion. Search in PubMed results in 114 relevant studies, which met the criteria. Total of 1085 PV patients with different conditions, including unresponsive childhood/juvenile or adult PV patients, women of childbearing age, those with chronic infections with the risk of reactivation have been evaluated. Although the majority of these patients well responded to rituximab, some of them did not respond, and the paucity of patients experienced exacerbation of disease. In addition to the rituximab monotherapy or its combination with conventional therapies, different novel combination therapies of rituximab with immunoadsorption and/or IVIg have shown promising results. Moreover, using rituximab as the first-line treatment has emerged recently. Pneumocystis carinii pneumonia and septicemia were found as the two fatal and serious adverse events associated with rituximab. Moreover, development or reactivation of herpes simplex and herpes zoster and cytomegalovirus should be warned. Similar to the adults, those with childhood and juvenile PV could be successfully treated with rituximab. Although rituximab seems to trigger reactivation of chronic infections, such as viral hepatitis and HIV infection, no related report was found. Administration of rituximab in approximately ten months before conception also was found safe and effective for a successful pregnancy. In conclusion, rituximab is very effective in adult and childhood/juvenile PV. However, there is a risk of not responding, exacerbation of disease and development of fatal infections. Moreover, it seems to be a promising first-line treatment for refractory PV. PMID- 29132071 TI - Reliability of clinically feasible dual-task tests: Expanded timed get up and go test as a motor task on young healthy individuals. AB - Dual-Task testing has been reported to have a higher sensitivity to deficits associated with concussion; however, the feasibility as a clinical or field test is questionable due to the requirements of laboratory-based equipment. With an overarching goal of exploration of clinically feasible Dual-Task testing options, the specific aims of this study were 1) to evaluate the reliability of Dual-Task testing methods using the Expanded Timed Get-Up-and-Go (ETGUG) paired with Backward Digit Recall (BDR), Serial Seven (SS), and Auditory Pure Switch Task (APST), and 2) to determine the effects of Dual-Task testing on motor and cognitive performance in healthy college-aged individuals. Fifty-four healthy young adults completed two separate testing sessions, which consisted of Single Task tests in a randomized order followed by 3 pairs of Dual-Task tests in a randomized order. Test-retest reliability for ETGUG time to completion was excellent for all Single- and Dual-Task conditions (ICC 0.89-0.92); however, ETGUGBDR and ETGUGSS were associated with learning effects (p=0.002 and 0.007, respectively). Test-retest reliability for Response Rate of the cognitive tasks was lower than those of motor task and all outcomes were associated with learning effects. The completion time of the ETGUGAPST pair indicated excellent reliability with no learning effect. Performance level declined in all tasks under Dual-Task conditions compared to Single-Task; however, motor tasks showed larger deficits indicating the prioritization of the cognitive task compared to the motor task. PMID- 29132072 TI - Peripheral brain-derived neurotrophic factor in attention-deficit/hyperactivity disorder: A comprehensive systematic review and meta-analysis. AB - BACKGROUND: Studies suggest that dysfunction of BDNF is a possible contributor to the pathology and symptoms of attention-deficit/hyperactivity disorder (ADHD). Several studies have found changes of peripheral BDNF levels in ADHD, but findings are not always consistent. The aim of our study was to assess the association between peripheral BDNF levels and ADHD by using a meta-analysis. METHODS: A systematic search of Pubmed, Web of Science and China National Knowledge Infrastructure identified 10 articles encompassing a sample of 1183 individuals for the meta-analysis. Meta-analysis was performed in a fixed/random effect model by using the software Review Manager 5.2. RESULTS: Our meta-analysis suggests that peripheral BDNF levels did not differ significantly between ADHD and controls with the standardized mean difference (SMD) of 0.62 (95% CI -0.12 to 1.35, p = 0.10). However, it is intriguing that BDNF levels were significantly higher in males with ADHD compared with controls (SMD = 0.49, 95% CI = 0.14-0.84, p = 0.006), whereas there was no difference in BDNF levels between ADHD female patients and control groups (SMD = 0.21,95% CI = -0.44 to 0.86, p = 0.53). LIMITATIONS: High heterogeneity was noted across sampled studies, which may be a function of sample size, participants sampled, variations in study design, or other factors. CONCLUSIONS: We found that though there was no significantly difference in peripheral BDNF levels between ADHD patients and control groups overall, BDNF levels were significantly higher in males with ADHD compared with controls. Our results suggested a sex-specific association between peripheral blood BDNF levels and ADHD male patients. PMID- 29132073 TI - Evaluation of a text-message-based maintenance intervention for Major Depressive Disorder after inpatient cognitive behavioral therapy. AB - INTRODUCTION: High relapse rates in Major Depressive Disorder (MDD) indicate the need for interventions enhancing the sustainability of treatment outcomes. Primary aim of the present study was to evaluate the effectiveness of a text message-based maintenance intervention for depression (TMMI-D). Additionally, we aimed to clarify whether the use of individualized messages would lead to better outcome than the use of standardized messages which focused upon adaptive ways of regulating undesired emotions. METHODS: In this RCT, 226 individuals who had completed inpatient treatment for MDD were randomly allocated to a condition in which participants received TMMI-D with standardized messages targeting emotion regulation, or to a condition with individualized messages, or to a waitlist control condition. Primary outcome was depressive symptom severity assessed with the BDI-II. RESULTS: Multilevel analyses suggest that participants receiving TIMMI-D with standardized messages reported a significantly smaller increase of depressive symptoms during the post-treatment and follow-up interval than did patients in the waitlist control condition. Contrastingly, there was no such effect for patients who had used TIMMI-D with individualized messages. LIMITATIONS: Limitations include proportions of missing data, thus, generalizing the findings of the present study might be an overestimation. CONCLUSION: Text message-based interventions may help increase the sustainability of outcome after treatment for MDD. The unexpected superiority of the standardized over the individualized version is in line with research that points to the efficacy of interventions fostering adaptive emotion regulation as a means to treat depression (and other mental disorders). PMID- 29132075 TI - Alcohol-induced disinhibition is associated with impulsivity, depression, and suicide attempt: A nationwide community sample of Korean adults. AB - BACKGROUND: Alcohol-induced disinhibition (AID) is defined as a "loss of restraint over some form of behavior after drinking alcohol regardless of its amount". Although many previous studies have investigated on alcohol use disorder and suicide attempt, few studies have focused on AID and suicide. METHODS: A total of 9461 adults who had a history of drinking completed a face-to-face interview using the Korean version of Composite International Diagnostic Interview (K-CIDI) with the Suicide Module, and Barratt Impulsiveness Scale 11 (BIS-11). In this study, we defined the AID group as those who had been involved with the two antisocial behaviors, including fights, being arrested or dangerous driving, according to the K-CIDI. RESULTS: Among 9461 subjects, 564 were classified as the AID group (5.96%). The AID group had a significantly higher number of lifetime suicidal ideation, plan, attempt, and multiple attempts, and higher BIS-11 scores than non-AID group. The total scores of BIS-11 of the AID group reported the highest score compared with other psychiatric disorders. The AID group experienced more frequently three types of alcohol withdrawal symptoms, including nervousness, heart beating fast, and feeling weak. Compared with subjects without both AID and MDD, subjects with both AID and MDD showed significant association with a lifetime suicide attempt (AOR = 6.86, p < 0.001) and showed stronger association with multiple attempts (AOR = 10.38, p < 0.001). CONCLUSION: AID was associated with suicide attempt and impulsivity, and the both AID and MDD showed much stronger association with lifetime suicide attempt and multiple attempts. PMID- 29132076 TI - Kinematic analysis of direct pointing in projection-based stereoscopic environments. AB - This work investigated the effects of visual information, parallax, and target positions on movement performances in projection-based stereoscopic displays (PSDs). Fifteen (26.5 +/- 3.83 years) self-declared right-handed individuals, with normal or corrected to normal visual acuity, completed pointing tasks in stereoscopic and real environments (RE). Three-dimensional spatial data, recorded by a motion system composed of six infrared cameras, was used to compute kinematics of reaching a real/virtual object at a combination of three parallax and nine frontal planar positions. The results indicated that movement in the PSD was slower and needed longer confirmation time than that in the RE. This might be because of the difficulty and misperception of distance associated with PSD. The motions were initiated faster but took longer to complete in vision-based conditions. The overall kinematic parameters were better as targets were presented closer to participants and around the center of displays. However, during pointing at a target that was continuously visible or presented briefly and disappeared, participants applied similar movement strategies to approach the visual objects. The comparable kinematics and movement behaviors in stereoscopic displays encourage the use of direct pointing that would enhance reaching and grasping tasks - which are important in applications such as rehabilitation, surgical training, and other programs that employ upper limbs. In addition, the more natural interaction by direct pointing minimizes the effort of learning new skills to use other devices. PMID- 29132074 TI - Robust symptom networks in recurrent major depression across different levels of genetic and environmental risk. AB - BACKGROUND: Genetic risk and environmental adversity-both important risk factors for major depression (MD)-are thought to differentially impact on depressive symptom types and associations. Does heterogeneity in these risk factors result in different depressive symptom networks in patients with MD? METHODS: A clinical sample of 5784 Han Chinese women with recurrent MD were interviewed about their depressive symptoms during their lifetime worst episode of MD. The cases were classified into subgroups based on their genetic risk for MD (family history, polygenic risk score, early age at onset) and severe adversity (childhood sexual abuse, stressful life events). Differences in MD symptom network structure were statistically examined for these subgroups using permutation-based network comparison tests. RESULTS: Although significant differences in symptom endorsement rates were seen in 18.8% of group comparisons, associations between depressive symptoms were similar across the different subgroups of genetic and environmental risk. Network comparison tests showed no significant differences in network strength, structure, or specific edges (P-value > 0.05) and correlations between edges were strong (0.60-0.71). LIMITATIONS: This study analyzed depressive symptoms retrospectively reported by severely depressed women using novel statistical methods. Future studies are warranted to investigate whether similar findings hold in prospective longitudinal data, less severely depressed patients, and men. CONCLUSIONS: Similar depressive symptom networks for MD patients with a higher or lower genetic or environmental risk suggest that differences in these etiological influences may produce similar symptom networks downstream for severely depressed women. PMID- 29132077 TI - Lovastatin analogues and other metabolites from soil-derived Aspergillus terreus YIM PH30711. AB - Eight previously undescribed metabolites including of lovastatin analogues, a pair of diastereoisomers, a cyclopentenone dimer, and three polyketides were isolated from the culture of Aspergillus terreus YIM PH30711. Two types of unprecedented skeletons, benzene-cyclopentanone complex and linear polyketide, and an unusual dimer structure were determined by spectral analysis. Compound, 3alpha-hydroxy-3,5-dihydromonacolin L showed moderate activity against HMG-CoA reductase, with an inhibition ratio of 34% at the concentration of 50 MUM, while lovastatin and dihydromonacolin K ethyl ester presented much stronger activity against HMGR with inhibition rates of 85% and 90% at the concentration of 50 MUM, respectively. Aspereusin A was active against AChE with a ratio of 62% at the concentration of 50 MUM, while its stereomers did not showed obvious inhibition (<10%). The configuration at C-4 of these three diastereoisomers was crucial in the inhibition against AChE, and the beta-orientation of substituted methoxyl acrylic acid should be beneficial to the combining with AChE. PMID- 29132078 TI - Rubipodanones A-D, naphthohydroquinone dimers from the roots and rhizomes of Rubia podantha. AB - Four previously undescribed naphthohydroquinone dimers named rubipodanones A-D, together with 19 known quinones containing three known napthohydroquinone dimers named rubioncolin C, methyl 5-hydroxy-dinaphtho[1,2-2',3']furan-7,12-dione-6 carboxylate and rubialatin B, were isolated from the roots and rhizomes of Rubia podantha. Their structures and absolute configurations were determined mainly by NMR, X-ray diffraction, and computational methods. Rubipodanones C and D, the glycosides of rubipodanone A and a pair of C-3 epimer, are the first identified dimeric napthohydroquinone glycosides from the Rubia plants. All naphthohydroquinone dimers were evaluated for their cytotoxicities against ten tumor cell lines and effects on the tumor-associated NF-kappaB signaling pathway, and rubioncolin C showed the best cytotoxicity with IC50 value of 1.53 MUM and NF kappaB inhibitory activity with IC50 value of 2.97 MUM. These results also demonstrated that the key roles of C-3 configuration and sugar group for biological activities of rubipodanone C. PMID- 29132079 TI - Absence of delay in spontaneous use of gestures in spoken narratives among children with Autism Spectrum Disorders. AB - BACKGROUND: Gestures are spontaneous hand movements produced when speaking. Despite gestures being of communicative significance, little is known about the gestural production in spoken narratives in six- to 12-year-old children with Autism Spectrum Disorders (ASD). AIMS: The present study examined whether six- to 12-year-old children with ASD have a delay in gestural production in a spoken narrative task, in comparison to their typically-developing (TD) peers. METHODS AND PROCEDURES: Six- to-12-year-old children with ASD (N=14) and their age- and IQ-matched TD peers (N=12) narrated a story, which could elicit spontaneous speech and gestures. Their speech and gestures were then transcribed and coded. OUTCOMES AND RESULTS: Both groups of children had comparable expressive language skills. Children with ASD produced a similar number of pointing and marker gestures to TD children and significantly more iconic gestures in their spoken narratives. While children with ASD produced more reinforcing gestures than their TD counterparts, both groups of children produced comparable numbers of disambiguating and supplementary gestures. CONCLUSIONS: Our findings indicate that children with ASD may be as capable as TD children in gestural production when they engage in spoken narratives, which gives them spontaneity in producing gestures. PMID- 29132080 TI - New approaches for computing ligand-receptor binding kinetics. AB - The recent and growing evidence that the efficacy of a drug can be correlated to target binding kinetics has seeded the development of a multitude of novel methods aimed at computing rate constants for receptor-ligand binding processes, as well as gaining an understanding of the binding and unbinding pathways and the determinants of structure-kinetic relationships. These new approaches include various types of enhanced sampling molecular dynamics simulations and the combination of energy-based models with chemometric analysis. We assess these approaches in the light of the varying levels of complexity of protein-ligand binding processes. PMID- 29132081 TI - The relationship between physical and mental health: A mediation analysis. AB - There is a strong link between mental health and physical health, but little is known about the pathways from one to the other. We analyse the direct and indirect effects of past mental health on present physical health and past physical health on present mental health using lifestyle choices and social capital in a mediation framework. We use data on 10,693 individuals aged 50 years and over from six waves (2002-2012) of the English Longitudinal Study of Ageing. Mental health is measured by the Centre for Epidemiological Studies Depression Scale (CES) and physical health by the Activities of Daily Living (ADL). We find significant direct and indirect effects for both forms of health, with indirect effects explaining 10% of the effect of past mental health on physical health and 8% of the effect of past physical health on mental health. Physical activity is the largest contributor to the indirect effects. There are stronger indirect effects for males in mental health (9.9%) and for older age groups in mental health (13.6%) and in physical health (12.6%). Health policies aiming at changing physical and mental health need to consider not only the direct cross-effects but also the indirect cross-effects between mental health and physical health. PMID- 29132082 TI - Increased suppression of methane production by humic substances in response to warming in anoxic environments. AB - Humic substances (HS) are redox-active and can function as organic terminal electron acceptors in anaerobic microbial respiration, which plays a relevant role on suppressing the emissions of methane (CH4) in anoxic systems. However, it is unclear whether or not there is an inherent link between suppression of CH4 emissions by HS and warming temperature. In this study, we assess the effects of HS additions on CH4 production in paddy and wetland soils and their responses to increasing temperature by incubation experiments. We show that the intensity of HS to suppress CH4 production under anoxic condition is positively associated with the temperature, which may be due to the fact that the activities of enzymes involved in methanogenesis have lower temperature sensitivity than those involved in microbial HS reduction, and that the methanogenesis process is less susceptible to increasing temperature compared to the microbial HS reduction process. The hypothetical increase in the effectiveness of pH alteration and HS toxicity caused by warming may be also responsible for the increased inhibition of CH4 production by HS addition in response to increasing temperature. Our findings highlight the increasingly important role of HS in suppressing CH4 production in anoxic ecosystems in a future warmer world. PMID- 29132083 TI - Fly ash classification efficiency of electrostatic precipitators in fluidized bed combustion of peat, wood, and forest residues. AB - The increasing use of biomasses in the production of electricity and heat results in an increased amount of burning residue, fly ash which disposal is becoming more and more restricted and expensive. Therefore, there is a great interest in utilizing fly ashes instead of just disposing of it. This study aimed to establish whether the utilization of fly ash from the fluidized bed combustion of peat, wood, and forest residues can be improved by electrostatic precipitator separation of sulfate, chloride, and some detrimental metals. Classification selectivity calculations of electrostatic precipitators for three different fuel mixtures from two different power plants were performed by using Nelson's and Karnis's selectivity indices. Results showed that all fly ashes behaved similarly in the electrostatic separation process SiO2 resulted in coarse fractions with Nelson's selectivity of 0.2 or more, while sulfate, chloride, and the studied detrimental metals (arsenic, cadmium, and lead) enriched into fine fractions with varying selectivity from 0.2 to 0.65. Overall, the results of this study suggest that it is possible to improve the utilization potential of fly ashes from fluidized bed combustion in concrete, fertilizer, and earth construction applications by using electrostatic precipitators for the fractionating of fly ashes in addition to their initial function of collecting fly ash particles from flue gases. The separation of the finer fractions (ESP 2 and 3) from ESP 1 field fly ash is recommended. PMID- 29132084 TI - Integrated and ecosystemic approaches for bridging the gap between environmental management and port management. AB - The rapid exploitation of coastal and marine ecosystemic capital is on course to reach a critical point. The difficulty of implementing Integrated and ecosystem based management models, taking into the account the great complexity of the marine socio-ecological systems, has resulted in a significant gap between theory and practice. The majority of authors emphasize difficulties in engaging and convincing private stakeholders and a number of economic sectors involved in these processes. This reticence is traditionally more pronounced in the port sector, despite their important role in the transformation of coastal and marine areas. This paper seeks to establish bridges between the Environmental Management systems and Tools (EMT) of economic sectors and the Integrated and Ecosystem Based Management models (IEBM). To achieve this goal, an effort has been made to rethink concepts and principles traditionally used in EMT to bring them into line with those of IEBM. A DPSIR adapted framework is proposed and applied in a conceptual model, where the necessary elements for environmental management tools and ecosystemic models coexist. The logic of ecosystem services has been included, with special attention to the variable of human behaviour. How the proposals fit into the reality of the maritime-port sector was analysed in a transversal way, seeking Socio-Ecological Port System (SEPS) perspectives. This made it possible to move from Environmental Management Systems to an Integrated and Ecosystem Based Port Environmental Management System (PEMS-IEB). From a managerial perspective, it was also suggested that an additional DPSIR framework should be applied to the "response" component, the management system itself, understood as a system with its own elements, processes and interrelations. PMID- 29132085 TI - How clear-cutting affects fire severity and soil properties in a Mediterranean ecosystem. AB - Forest management practices in Mediterranean ecosystems are frequently employed to reduce both the risk and severity of wildfires. However, these pre-fire treatments may influence the effects of wildfire events on soil properties. The aim of this study is to examine the short-term effects of a wildfire that broke out in 2015 on the soil properties of three sites: two exposed to management practices in different years - 2005 (site M05B) and 2015 (site M15B) - and one that did not undergo any management (NMB) and to compare their properties with those recorded in a plot (Control) unaffected by the 2015 wildfire. We analyzed aggregate stability (AS), soil organic matter (SOM) content, total nitrogen (TN), carbon/nitrogen ratio (C/N), inorganic carbon (IC), pH, electrical conductivity (EC), extractable calcium (Ca), magnesium (Mg), sodium (Na), and potassium (K), microbial biomass carbon (Cmic) and basal soil respiration (BSR). In the managed plots, a clear-cutting operation was conducted, whereby part of the vegetation was cut and left covering the soil surface. The AS values recorded at the Control site were significantly higher than those recorded at M05B, whereas the TN and SOM values at NMB were significantly higher than those recorded at M05B. IC was significantly higher at M05B than at the other plots. There were no significant differences in C/N ratio between the analyzed sites. Soil pH at M05B was significantly higher than the value recorded at the Control plot. Extractable Ca was significantly higher at NMB than at both M05B and the Control, while extractable Mg was significantly lower at M05B than at NMB. Extractable K was significantly lower at the Control than at the three fire-affected plots. Cmic was significantly higher at NMB than at the Control. BSR, BSR/C and BSR/Cmic values at the fire-affected sites were significantly lower than those recorded at the Control. No significant differences were identified in Cmic/C. Overall, a comparison of the pre-fire treatments showed that NMB was the practice that had the least negative effects on the soil properties studied, followed by M15B, and that fire severity was highest at M05B due to the accumulation of dead plant fuel. PMID- 29132086 TI - Strengthening detoxication impacts of Coprinus comatus on nickel and fluoranthene co-contaminated soil by bacterial inoculation. AB - To develop an efficient and environmental-friendly approach to detoxicate nickel (Ni) and fluoranthene co-contaminated soil, the combined application of Coprinus comatus (C. comatus) with Serratia sp. FFC5 and/or Enterobacter sp. E2 was investigated. The pot experiment tested the influences of bacterial inoculation on the growth of C. comatus, content of Ni in C. comatus, Ni speciation in soil, fluoranthene dissipation, soil enzymatic activities, bacterial population and community structure. With the inoculation of bacteria, the fresh weights of C. comatus, concentration of Ni in C. comatus and the dissipation rates of fluoranthene were increased by 17.73-29.38%, 68.97-204.97% and 34.84-60.90%, respectively. Notably, results illustrated that the co-inoculation of FFC5 and E2 showed better effect in biomass enhancement, Ni accumulation and fluoranthene dissipation than solitary inoculation. Simultaneously, higher soil enzymatic and microbiological activities suggested that the integrated detoxication method of bacteria and C. comatus could improve soil quality. Therefore, we can infer that bacterial inoculation strengthened detoxication effect of C. comatus in Ni fluoranthene co-contaminated soil, indicating that the combined application of C. comatus and bacteria can be an efficient alternative for detoxicating Ni and fluoranthene co-contaminated soil. PMID- 29132087 TI - Traditional cattle vs. introduced deer management in Chaco Serrano woodlands (Argentina): Analysis of environmental sustainability at increasing densities. AB - Wild ungulate populations have increased and expanded considerably in many regions, including austral woodlands and forests where deer (Cervus elaphus) have been introduced as an alternative management to traditional cattle grazing. In this study, we compared traditional cattle with introduced deer management at increasing deer densities in the "Chaco Serrano" woodlands of Argentina to assess their ecological sustainability. We used three ecological indicators (abundance of tree regeneration, woody plant diversity and browsing damage) as proxies for environmental sustainability in woody systems. Our results indicate that traditional cattle management, at stocking rates of ~10 ind km-2, was the most ecologically sustainable management since it allowed greater tree regeneration abundance, higher richness of woody species and lower browsing damage. Importantly, cattle management and deer management at low densities (10 ind km-2) showed no significant differences in species richness and abundance of seedlings, although deer caused greater browsing damage on saplings and juveniles. However, management regimes involving high deer densities (~35 deer km2) was highly unsustainable in comparison to low (~10 deer km-2) and medium (~20 deer km-2) densities, with 40% probability of unsustainable browsing as opposed to less than 5% probability at low and medium densities. In addition, high deer densities caused a strong reduction in tree regeneration, with a 19-30% reduction in the abundance of seedlings and young trees when compared to low deer densities. These results showed that the effect of increasing deer densities on woody plant conservation was not linear, with high deer densities causing a disproportional deleterious effect on tree regeneration and sustainable browsing. Our results suggest that traditional management at low densities or the use of introduced ungulates (deer breeding areas) at low-medium densities (<20 deer km-2) are compatible with woody vegetation conservation. However, further research is needed on plant palatability, animal habitat use (spatial heterogeneity) and species turnover and extinction (comparison to areas of low-null historical browsing) to better estimate environmental sustainability of Neotropical ungulate dominated woodlands. PMID- 29132088 TI - Analysing the impacts of air quality policies on ecosystem services; a case study for Telemark, Norway. AB - There is an increasing interest in considering the effects of air pollution on ecosystem services supply in order to enhance cost-benefit analyses of air pollution policies. This paper presents a generic, conceptual approach that can be used to link atmospheric deposition of air pollutants to ecosystem services supply and societal benefits. The approach is applied in a case study in the Telemark county of Norway. First, we examine the potential effects of four European air quality policy scenarios on N deposition in the ecosystems of this county. Second, we analyse the subsequent impacts on the supply of three ecosystem services: carbon sequestration, timber production and biodiversity. Changes in the supply of the first two services are analysed in both physical and monetary units, biodiversity effects are only analysed in physical terms. The scenarios derive from work conducted in the context of the European National Emissions Ceilings Directive. In the 2010 base case the benefits of carbon sequestration are estimated at 13 million euro per year and the value of timber harvesting at 2.9 million euro per year. Under the examined policy scenarios aiming to reduce nitrogen emissions the societal benefits resulting from these two ecosystem services in Telemark are found to be reduced; the scenarios have little effect on terrestrial biodiversity. Such results cannot be scaled up, individual ecosystem services respond differently to changes in air pollution depending upon type of pollutant, type of ecosystem, type of service, and the magnitude of change. The paper further presents an analysis of the uncertainties that need to be considered in linking air pollution and ecosystem services including those in deposition rates, ecosystem responses, human responses and in the values of ecosystem services. Our conceptual approach is also useful for larger scale analysis of air pollution effects on ecosystem services, for example at national or potentially European scale. PMID- 29132089 TI - Neural effects of environmental advertising: An fMRI analysis of voice age and temporal framing. AB - Ecological information offered to society through advertising enhances awareness of environmental issues, encourages development of sustainable attitudes and intentions, and can even alter behavior. This paper, by means of functional Magnetic Resonance Imaging (fMRI) and self-reports, explores the underlying mechanisms of processing ecological messages. The study specifically examines brain and behavioral responses to persuasive ecological messages that differ in temporal framing and in the age of the voice pronouncing them. The findings reveal that attitudes are more positive toward future-framed messages presented by young voices. The whole-brain analysis reveals that future-framed (FF) ecological messages trigger activation in brain areas related to imagery, prospective memories and episodic events, thus reflecting the involvement of past behaviors in future ecological actions. Past-framed messages (PF), in turn, elicit brain activations within the episodic system. Young voices (YV), in addition to triggering stronger activation in areas involved with the processing of high-timbre, high-pitched and high-intensity voices, are perceived as more emotional and motivational than old voices (OV) as activations in anterior cingulate cortex and amygdala. Messages expressed by older voices, in turn, exhibit stronger activation in areas formerly linked to low-pitched voices and voice gender perception. Interestingly, a link is identified between neural and self-report responses indicating that certain brain activations in response to future-framed messages and young voices predicted higher attitudes toward future framed and young voice advertisements, respectively. The results of this study provide invaluable insight into the unconscious origin of attitudes toward environmental messages and indicate which voice and temporal frame of a message generate the greatest subconscious value. PMID- 29132090 TI - The potential use of transdermal drug delivery for the prophylaxis and management of stroke and coronary artery disease. AB - In 2013, cardiovascular disease was responsible for 30.8% (800,937) of all 2,596,993 deaths, or approximately 1 of every 3 deaths while stroke caused about 1 of every 20 deaths in the United States [1]. To put it in context, about 795,000 people continue to have a new or recurrent stroke (ischemic or hemorrhagic) [1] in the USA. Mechanical vascular recanalization and thrombolysis with tissue plasminogen activator are the only clinically useful approaches available now for the management of ischemic stroke [2]. Antiplatelet therapy with aspirin and/or clopidogrel is also a common practice utilized for the management of stroke, acute myocardial infarction and coronary artery disease [3]. There are two different but closely related approaches to improve therapy- to develop new disease-modifying agents or to find alternative drug administration routes for existing drugs. Transdermal drug delivery leverages the advantages of injections and tablets- painlessness, minimal invasiveness and the avoidance of presystemic metabolism and can potentially be applied to medications used for the prevention and/or management of coronary artery disease and stroke. PMID- 29132091 TI - Effect of anti-diabetic drugs on bone metabolism: Evidence from preclinical and clinical studies. AB - Diabetes mellitus is associated with abnormal bone health and an increased risk of fracture even though patients have normal or higher BMD. The mechanisms behind diabetes mellitus- induced various skeletal disorders remain unclear. Anti diabetic drugs may have negative or positive impact on bone metabolism. For instance, thiazolidinediones increases the bone loss and risk of fracture possibly through PPARgamma activation in bone marrow cells and hamper osteoblastogenesis via decreasing Runx2 transcription factor, IGF-1 and Wnt signalling pathways. In contrast, metformin and sulfonylureas have a neutral or positive effect on bone health and reduced risk of fracture. Results from the preclinical and clinical studies convey conflicting findings over insulin safety profile on bone health. Incretin-based therapy (GLP-1 receptor agonist and DPP-4 inhibitors) and SGLT2 inhibitors are currently marketed anti- diabetic drugs. While evidence from animal studies suggest that incretin-based therapy have anabolic effect on bone, limited clinical data of DPP-4 inhibitors and GLP-1 receptor agonist indicated a neutral effect on the bone health and risk of fracture. SGLT2 inhibitors may cause bone loss or increase fracture risk due to altered calcium, phosphate and sodium concentration. Therefore, safety concerns of anti-diabetic drugs are crucial for the management of diabetes mellitus. In this review, analysis of the available evidence for effect of anti-diabetic drugs on the bone metabolism and fracture risk in diabetes mellitus is described. PMID- 29132092 TI - Berberine attenuates cognitive impairment and ameliorates tau hyperphosphorylation by limiting the self-perpetuating pathogenic cycle between NF-kappaB signaling, oxidative stress and neuroinflammation. AB - BACKGROUND: Berberine (BBR) plays an important role in the prevention and treatment of Alzheimer's disease (AD). The present work was to explore whether BBR ameliorates cognitive deficits in AD and to investigate whether its underlying mechanism involves inhibiting hyperphosphorylated tau protein. METHODS: The cognitive function was measured by the Morris water maze (MWM) test. The levels of hyperphosphorylated tau proteins were determined by Western blot. The biomarkers of NF-kappaB signaling pathway and oxidative stress were detected by Western blot and biochemical assays. The biomarkers of neuroinflammation were determined by Western blot and immunohistochemistry. RESULTS: BBR improved learning and memory in APP/PS1 mice. BBR decreased the hyperphosphorylated tau protein in the hippocampus of APP/PS1 mice. BBR lowered the activity of NF-kappaB signaling in the hippocampus of AD mice. BBR-administration promoted the activity of glutathione (GSH) and inhibited lipid peroxidation in the hippocampus of AD mice. CONCLUSION: BBR attenuated cognitive deficits and limited hyperphosphorylation of tau via inhibiting the activation of NF-kappaB signaling pathway, and by retarding oxidative stress and neuro-inflammation. PMID- 29132093 TI - A benzothiazole/piperazine derivative with acetylcholinesterase inhibitory activity: Improvement in streptozotocin-induced cognitive deficits in rats. AB - BACKGROUND: Acetylcholinesterase (AChE) inhibitors are frequently prescribed to mitigate the cognitive decline in Alzheimer's disease. Thus, we investigated the possible efficacy of the AChE inhibitor 2-[(6-Nitro-2-benzothiazolyl)amino]-2 oxoethyl4-[2-(N,N-dimethylamino)ethyl] piperazine-1 carbodithioate (BPCT) in a streptozotocin (STZ)-induced Alzheimer's disease model (SADM). METHODS: First, we analyzed the molecular interaction of BPCT with AChE via a docking study. Then, the cognitive effects of BPCT (10 and 20mg/kg) were evaluated in intracerebroventricular STZ- and vehicle-administered rats with the elevated plus maze (EPM), Morris water maze (MWM), and active avoidance (AA) tests. Locomotor activity was also assessed. RESULTS: Docking analysis indicated significant binding of BPCT to the AChE active site. In behavioral tests, STZ administration impaired cognitive performance in SADM rats versus control rats. Treatment with donepezil or BPCT significantly decreased the prolonged 2nd retention transfer latency and 2nd retention latency time values of the SADM group in the EPM and MWM tests, respectively. Further, prolonged latency times were decreased and reduced frequency of avoidance events were increased in the AA test. Locomotor activity between groups was not different. CONCLUSION: BPCT appears to function as a central AChE inhibitor, and its improvement of deficits in SADM rats suggests that it has therapeutic potential in Alzheimer's disease. PMID- 29132094 TI - Antidepressants for irritable bowel syndrome-A systematic review. AB - BACKGROUND: According to the multifactorial etiology of Irritable bowel syndrome (IBS), psychological factors play an important role. It is possible that antidepressant therapy may be more effective for patients with IBS. The aim of this study was a systematic review of the best available antidepressant therapies for IBS. METHODS: The databases Medline, PubMed, EMBASE, and the Cochrane Controlled Trials Register for randomized controlled trials were searched for studies published before September 2016. Meta-analyses, randomized controlled trials, controlled trials, uncontrolled trials, cohort studies, and open-label studies were analyzed. RESULTS: Of 513 articles, 29 fulfilled the inclusion criteria: 6 meta-analyses, 18 randomized controlled trials, and 5 studies without randomization. In these studies, the efficacy of tricyclics, selective serotonin reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors, were analyzed in IBS. Different interventions were used, though in most studies their effect on global symptom relief in IBS as a primary outcome was investigated. Generally, patients' tolerance of the therapies was good. Only severe adverse events were observed as a result of the nature of the drug. CONCLUSIONS: Generally, antidepressants improved IBS symptoms. In comparison with placebo, tricyclic therapy for IBS was more effective than selective serotonin reuptake inhibitors. Antidepressants might be an alternative therapy for patients suffering from IBS, especially diarrhea-predominant IBS. PMID- 29132095 TI - Inhibition of TNF reduces mechanical orofacial hyperalgesia induced by Complete Freund's Adjuvant by a TRPV1-dependent mechanism in mice. AB - BACKGROUND: Inflammation in the orofacial region results in pain and is associated with many pathological states, including migraine, neuralgias and temporomandibular disorder. Although extensively studied, the mechanisms responsible for these conditions are not known and effective treatments are lacking. We reported earlier that the proinflammatory cytokine tumor necrosis factor (TNF) plays an important role in regulation of trigeminal ganglion (TG) neuron function in vitro. In the present study we investigated the role of TNF in mechanical hypersensitivity in mice. METHODS: We employed the Complete Freund's Adjuvant (CFA)-induced model of orofacial pain and evaluated the effect of blocking of soluble TNF activity by peripheral administration of the novel dominant negative TNF biologic, XPro1595. RESULTS: We show that CFA administration into the lower lip causes hyperalgesia and an increase in both expression of transient receptor potential vanilloid subfamily member 1 (TRPV1) mRNA and in the average intensity of TRPV1 protein immunoreactivity in TG neurons. We also show that intraperitoneal administration of XPro1595 prevents both CFA-induced mechanical hypersensitivity and, as shown in immunohistochemical staining - upregulation of TRPV1 protein expression in TG neurons. CONCLUSIONS: We conclude that one of the possible regulatory mechanisms of TNF in pain involves upregulation of the nociceptor TRPV1, and that peripheral treatment with a selective anti-soluble TNF biologic can prevent hyperalgesia caused by inflammation in the orofacial region. Therefore, these new findings suggest that XPro1595 may serve as a novel treatment for orofacial pain disorders. PMID- 29132096 TI - Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1. AB - BACKGROUND: Increased CYP2E1 protein and activity levels can be the main cause of stress-mediated liver damage in diabetes. In this work we investigated the quercetin properties to prevent diabetic oxidative liver injury through inhibition of CYP2E1. METHODS: Animals were randomly divided into three groups (n=5 for each group): non-diabetic control, STZ-diabetic rats and STZ-diabetic rats administered with quercetin (50mg/kg bw, per day, during 30days). Markers of oxidative stress and liver injury, hepatocyte ultrastructure and levels of CYP2E1 protein and activity were examined using biochemical, electron microscopy and molecular biological methods. RESULTS: It was shown that symptoms of diabetes (hyperglycemia, bodyweight loss, damaged hepatocyte ultrastructure), signs of oxidative stress in liver (2-fold intensification of peroxide process and 2-fold depletion of antioxidants) and serum markers of liver damage (3.5-, 1.5- and 5 fold increase in levels of ALT, AST and GGT, respectively) were present in STZ diabetic rats. We found 3- and 2.5-fold increase in levels of protein and activity of CYP2E1 in the liver of STZ-diabetic rats. We demonstrated that the administration of quercetin leads to significant decrease in CYP2E1 activity (5- and 2-times compared to STZ-diabetic and control group, respectively). That was accompanied by normalization of pro-oxidant-antioxidant balance, improving the ultrastructure of hepatocytes and rates of serum markers of liver injury. CONCLUSIONS: CYP2E1 can play a crucial role in stress-induced pathological processes in the liver in diabetes, and the inhibition of the enzyme by quercetin during the development of diabetes mainly prevents the oxidative damage in liver. PMID- 29132097 TI - The development of a new artificial model of a finger for assessing transmitted vibrations. AB - Prolonged exposure of the hand to tool-induced vibrations is associated with the occurrence of conditions such as vibration white finger. This study involves the development of a new artificial model that approximates both loading and vibration behaviour of the human finger. The layered system uses polypropylene "bones", encased in a cylinder of low modulus, room-temperature curing silicone gel (to replicate subcutaneous tissues), with an outer layer of latex (to replicate the dermis and epidermis). A protocol for manufacture was developed and dynamic mechanical analysis was carried out on a range of gels in order to choose a range close to the mechanical properties of the human finger. The load deflection behaviour under quasi-static loading was obtained using an indenter. The indentation measurements were then compared with a set of validation data obtained from human participant testing under the same conditions. A 2-D FE model of the finger was also used to assess vibration responses using existing parameters for a human finger and those obtained from the tested materials. Vibration analysis was conducted under swept sinusoidal excitations ranging from 10 to 400Hz whilst the FE finger model was pressed 6mm toward the handle. Results were found to compare well. This synthetic test-bed and protocol can now be used in future experiments for assessing finger-transmitted vibrations. For instance, it can aid in assessing anti-vibration glove materials without the need for human subjects and provide consistent control of test parameters such as grip force. PMID- 29132098 TI - Understanding the mechanism for the mechanical property degradation of a lithium disilicate glass-ceramic by annealing. AB - Post-crystallization annealing above the Tg was applied to a lithium disilicate glass-ceramic with microstructure consisting of glassy matrix and rod-like lithium disilicate crystals, effect of the annealing on the mechanical behavior was investigated. Flexural strength and VIF toughness of the glass-ceramic unexpectedly decreased after the annealing. The mechanical behavior variation was understood based on residual micro-stress analysis. Coefficient of thermal expansion for the glassy matrix presented a tendency to increase after the annealing, which would enlarge the thermal expansion mismatch between the glassy matrix and the lithium disilicate crystals. As a result, the residual micro stresses in the glass-ceramic abnormally increased with increasing the annealing time. The mechanical property degradation was attributed to the annealing-induced increase of the residual micro-stresses. PMID- 29132099 TI - Tribological properties of PVA/PVP blend hydrogels against articular cartilage. AB - This research investigated in-vitro tribological performance of the articulation of cartilage-on- polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) blend hydrogels using a custom-designed multi-directional wear rig. The hydrogels were prepared by repeated freezing-thawing cycles at different concentrations and PVA to PVP fractions at a given concentration. PVA/PVP blend hydrogels showed low coefficient of friction (COF) values (between 0.12 +/- 0.01 and 0.14 +/- 0.02) which were closer to the cartilage-on-cartilage articulation (0.03 +/- 0.01) compared to the cartilage-on-stainless steel articulation (0.46 +/- 0.06). The COF increased with increasing hydrogel concentration (p = 0.03) and decreasing PVP content at a given concentration (p < 0.05). The cartilage-on-hydrogel tests showed only the surface layers of the cartilage being removed (average volume loss of the condyles was 12.5 +/- 4.2mm3). However, the hydrogels were found to be worn/deformed. The hydrogels prepared at a higher concentration showed lower apparent volume loss. A strong correlation (R2 = 0.94) was found between the COF and compressive moduli of the hydrogel groups, resulting from decreasing contact congruency. It was concluded that the hydrogels were promising as hemiarthroplasty materials, but that improved mechanical behaviour was required for clinical use. PMID- 29132100 TI - Comparison of microsphere penetration with LC Bead LUMITM versus other commercial microspheres. AB - The purpose of this study was to evaluate LC Bead LUMITM (40-90um and 70-150um) in order to determine if their increased resistance to compression influences microsphere penetration and distribution compared to more compressible commercial microspheres. LC Bead LUMITM 40-90um and 70-150um, LC BeadM1(r) 70-150um, EmbozeneTM 40um and EmbozeneTM 100um size and distributions were measured using optical microscopy. Penetration in vitro was evaluated using an established 'plate model', consisting of a calibrated tapered gap between a glass plate and plastic housing to allow visual observation of microsphere penetration depth. Behaviour in vivo was assessed using a rabbit renal embolization model with histopathologic confirmation of vessel penetration depth. Penetration behaviour in vitro was reproducible and commensurate with the measured microsphere size, the smaller the microsphere the deeper the penetration. Comparison of the microsphere diameter measured on the 2D plate model versus the corresponding average microsphere size measured by histopathology in the kidney showed no significant differences (p = > 0.05 Mann-Whitney, demonstrating good in vitro - in vivo predictive capabilities of the plate model) confirming predictable performance for LC Bead LUMITM (40-90um and 70-150um) based on microsphere size, their increased rigidity having no bearing on their depth of penetration and distribution. An assessment of a LC Bead LUMITM (40-90um and 70-150um) has shown that despite having greater resistance to compression, these microspheres behave in a predictable manner within in vitro and in vivo models comparable with more compressible microspheres of similar sizes. PMID- 29132101 TI - Contributions of the layer topology and mineral content to the elastic modulus and strength of fish scales. AB - Fish scales are an interesting natural structural material and their functionality requires both flexibility and toughness. Our previous studies identified that there are spatial variations in the elastic properties of fish scales corresponding to the anatomical regions, and that they appear to be attributed to changes in the microstructure. In the present study, a model is proposed that describes the elastic behavior of elasmoid fish scales in terms of the relative contributions of the limiting layer and both the internal and external elasmodine. The mechanical properties of scales from the Megalops atlanticus (i.e. tarpon) were characterized in tension and compared with predictions from the model. The average error between the predicted and the experimental properties was 7%. It was found that the gradient in mineral content and aspect ratio of the apatite crystals in the limiting layer played the most important roles on the elastic modulus of the scales. Furthermore, misalignment of plies in the external elasmodine from the longitudinal direction was shown to reduce the elastic modulus significantly. This is one approach for modulating the fish scale flexibility for a high mineral content that is required to increase the resistance to puncture. PMID- 29132102 TI - Atomic-scale investigation of physical adsorption of water molecules and aggressive ions to ettringite's surfaces. AB - The strength and durability of cementitious composite materials are adversely affected by the ingress of water molecules and aggressive ions into their intrinsic meso- and nano-pore spaces. Among various phases of hydrated cement paste (HCP), aluminum-rich phases play an important role in controlling the diffusivity of aqueous solutions, which can contain aggressive ions. To this date, however, there has been no systematic study to understand the adsorption mechanisms and chloride binding capacity of the aluminum-rich phases of HCP. This research gap has been the motivation of the current study to investigate the physical adsorption characteristics of ettringite as the main aluminum-rich phase of HCP and the primary hydrated product of calcium sulfoaluminate cement. Through a set of Molecular Dynamics simulations supported by macro-scale experimental tests, a fundamental insight into the molecular origins of the diffusion of water molecules, as well as sodium and chloride ions, in contact with ettringite is provided. As the primary objective of this study is to evaluate the transport properties at and near solution/solid interfaces, the molecular adsorption mechanisms are characterized for inner- and outer-sphere distances from the solid substrate. With an in-depth understanding of the structure and dynamics of water molecules and aggressive ions in contact with ettringite's surfaces, the outcome of this study provides reliable measures of physical adsorption, binding capacity, and self-diffusion coefficient, which can be further employed to introduce strategies to avoid the degradation of a wide variety of cementitious materials exposed to harsh environmental conditions. PMID- 29132103 TI - Fixed-bed column studies of total organic carbon removal from industrial wastewater by use of diatomite decorated with polyethylenimine-functionalized pyroxene nanoparticles. AB - In this study, a fixed-bed column adsorption process was employed to remove organic pollutants from a real industrial wastewater effluent using polyethylenimine-functionalized pyroxene nanoparticles (PEI-PY) embedded into Diatomite at very low mass percentage. Various dynamic parameters (e.g., inlet concentration, inlet flow rate, bed height, and PEI-nanoparticle concentration in Diatomite, (%nps)) were investigated to determine the breakthrough behavior. The obtained breakthrough curves were fit with a convection-dispersion model to determine the characteristic parameters based on mass transfer phenomena. The axial dispersion coefficient (DL) and group of dimensionless numbers; including Renold number (Re), Schmidt number (Sc), and Sherwood number (Sh) were all determined and correlated by Wilson-Geankoplis correlation that was used to estimate the external film diffusion coefficients (Kc) at 0.0015 < Re<55. PMID- 29132104 TI - Hollow polydopamine colloidal composite particles: Structure tuning, functionalization and applications. AB - Engineering hollow particles with high complexity in their morphology or composition is highly desirable for both fundamental studies and practical applications. Here, we combine mussel-inspired polydopamine (PDA) chemistry with template-assisted and hydrothermal approaches to explore a general approach for engineering hollow PDA colloidal composite particles with tunable complexities in terms of particle geometry, shell architecture and chemical composition. PDA coating and hydrothermal treatment are carried out sequentially in the same environment, which not only simplifies the experimental procedure but also avoids the use of hazardous core-removers. This approach is generally applicable to a wide variety of colloidal templates irrespective of their shape, material and structure, allowing the void structure and geometry (spherical void, yolk-shell, multi-shells and non-spherical cavity) to be controlled. The surface of the PDA shell provides a versatile platform for a number of secondary reactions (e.g., electroless metallization, superhydrophobic modification, Michael addition and nanoparticle decoration). Consequently, tuning the exterior or interior of the hollow PDA shell with various functional materials offers a range of potential uses in superhydrophobic surfaces, catalysis, photocatalysis and surface-enhanced Raman spectrum sensing. PMID- 29132105 TI - Viscoelastic drops moving on hydrophilic and superhydrophobic surfaces. AB - So-called "superhydrophobic" surfaces are strongly non-wetting such that fluid droplets very easily roll off when the surface is tilted. Our interest here is in understanding if this is also true, all else held equal, for viscoelastic fluid drops. We study the movement of Newtonian and well-characterised constant viscosity elastic liquids when various surfaces, including hydrophilic (smooth glass), weakly hydrophobic (embossed polycarbonate) and superhydrophobic surfaces (embossed PTFE), are impulsively tilted. Digital imaging is used to record the motion and extract drop velocity. Optical and SEM imaging is used to probe the surfaces. In comparison with "equivalent" Newtonian fluids (same viscosity, density surface tension and contact angles), profound differences for the elastic fluids are only observed on the superhydrophobic surfaces: the elastic drops slide at a significantly reduced rate and complex branch-like patterns are left on the surface by the drop's wake including, on various scales, beads-on-a-string like phenomena. The strong viscoelastic effect is caused by stretching filaments of fluid from isolated islands, residing at pinning sites on the surface pillars, of order ~30 um in size. On this scale, the local strain rates are sufficient to extend the polymer chains, locally increasing the extensional viscosity of the solution, retarding the drop. PMID- 29132106 TI - Silver oxide nanoparticles embedded silk fibroin spuns: Microwave mediated preparation, characterization and their synergistic wound healing and anti bacterial activity. AB - The synergistic wound healing and antibacterial activity of silver oxide nanoparticles embedded silk fibroin (Ag2O-SF) spuns is reported here. UV-Vis spectro photometric analysis of these spuns showed the surface plasmon resonance (SPR) confirming the formation of the silver oxide nanoparticles (Ag2O NPs) on the surface of the silk fibroin (SF). Scanning electron microscope (SEM) and Differential scanning calorimetry (DSC) also confirmed the presence of Ag2O NPs on surface of SF. X-ray diffraction (XRD) analysis revealed the crystalline nature of both SF and Ag2O-SF. Fourier transform infrared spectroscopy (FT-IR) results showed the different forms of silk (I and II) and their corresponding protein (amide I, II, III) confirmations. Biodegradation study revealed insignificant changes in the morphology of Ag2O-SF spuns even after 14 days of immersion in phosphate buffered saline (PBS). Ag2O-SF spuns showed excellent antibacterial activity against both pathogen (S. aureus and M. tuberculosis) and non-pathogen (E. coli) bacteria. More importantly, In vitro wound healing (scratch assay) assay revealed fast migration of the T3T fibroblast cells through the scratch area treated with extract of Ag2O-SF spuns and the area was completely covered within 24 h. Cytotoxicity assay confirmed the biocompatible nature of the Ag2O-SF spuns, thus suggesting an ideal material for wound healing and anti-bacterial applications. PMID- 29132107 TI - Removal of phosphate from water by lanthanum-modified zeolites obtained from fly ash. AB - The possibility and effectiveness of removal of phosphate from aqueous solutions with the use of new low-cost synthetic zeolites obtained from fly ash and modified with lanthanum, was studied. Physicochemical properties of the zeolites were characterized by different techniques such as X-ray diffraction, low temperature nitrogen sorption and scanning electron microscopy. It has been established that lanthanum is preferentially located in the zeolites channels and cages, which is related to the ion-exchange method of modification. Introduction of lanthanum cations leads to a reduction in BET surface area, mainly due to a decrease in the area of micropores and reduction in the pore volume. The key element of the study was a series of tests of phosphate adsorption from aqueous solutions. The efficiency of adsorption process was found to depend on the concentration of adsorbate, pH of its solution and temperature. The sorption capacity of zeolites obtained from fly ashes (La-P1, La-A) towards phosphate was compared with that of a natural zeolite - clinoptilolite, modified with lanthanum (La-CLP). The sorption capacities of the particular samples were as follows: La P1 - 58.2 mg/g, La-A - 44.0 mg/g and La-CLP - 24.6 mg/g. The experimental data were well fitted by the Langmuir isotherm model. The sorption capacities of all samples towards phosphate increased with temperature increasing from 25 to 60 degrees C. The values of the thermodynamic parameters DeltaH0 and DeltaG0 revealed that the adsorption was spontaneous and endothermic. PMID- 29132108 TI - Facile formation of metallic bismuth/bismuth oxide heterojunction on porous carbon with enhanced photocatalytic activity. AB - Bismuth/bismuth oxide heterojunction on porous carbon (Bi0/Bi2O3@C) was successfully prepared by a surfactant-assisted sol-gel method. This composite photocatalyst was fabricated by depositing Bi2O3 and metallic bismuth nanoparticles (NPs) on porous carbon sheets. Bi NPs were created by in-situ reduction of Bi2O3 with amorphous carbon. During the synthesis, bismuth and carbon precursors were mixed in different ratios, resulting in distinct amounts of metallic bismuth in the composites. The composites showed large specific surface area and pore volume as well as strong light absorption ability due to the existing carbon. In addition, the plasmonic bismuth NPs were found to behave as a noble metal, which is able to generate hot charge carriers under visible light irradiation. Photocatalytic performance of the Bi0/Bi2O3@C composites was investigated by degradation of methylene blue. It turned out that the composites showed much higher efficiency as compared to bare Bi2O3, which may be attributed to the synergistic effects of porous structures, improved optical absorption, and surface plasmon resonance. PMID- 29132109 TI - Highly enhanced adsorption performance of U(VI) by non-thermal plasma modified magnetic Fe3O4 nanoparticles. AB - In this study, magnetic Fe3O4 nanoparticles (MNP) modified with O phosphorylethanolamine (O-PEA) were successfully prepared by non-thermal plasma induced method with different treatment times. The raw and modified MNP were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectrophotometer (FT-IR), and vibration sample magnetometer (VSM). The modified MNP samples show higher adsorption capacity for U(VI) removal and longer treatment time results in higher adsorption capacity and efficiency. The experimental parameters were optimized by means of the response surface methodology to improve the removal efficiency of U(VI) by the modified adsorbents from aqueous solutions. The O-PEA modified MNP with 120 min treatment time shows the highest adsorption capacity with 228.17 mg?g-1 among the five samples at 293.15 K. Thermodynamic studies reveal that the adsorption process of U(VI) onto O-PEA modified MNP is endothermic and spontaneous. XPS studies indicate that the U(VI) removal is fulfilled through the binding interactions between U(VI) and NH2, OH and phosphate groups on the modified MNP surface. This work not only provides a simple, convenient and cost-effective way for water treatment by plasma modification, but also provides a new insight into preparing promising adsorbents to achieve magnetic separation from aqueous solution. PMID- 29132110 TI - Comprehensive phospholipid and sphingomyelin profiling of different brain regions in mouse model of anxiety disorder using online two-dimensional (HILIC/RP)-LC/MS method. AB - A novel online system including two-dimensional liquid chromatography coupled to high-resolution mass spectrometry (2D-LC/MS) was developed and applied for comprehensive phospholipid (PL) and sphingomyelin (SM) profiling of dorsal hippocampus (DHPC), ventral (VHPC) and prefrontal cortex (PFC) brain regions in a mouse model of anxiety disorder. In the first dimension, lipid classes were distinguished by hydrophilic interaction liquid chromatography (HILIC), while the second dimensional separation of individual PL and SM species was achieved by reversed-phase (RP) chromatography. For the enrichment of lipid species in diluted HILIC effluent, two RP trapping columns were used separately. The developed fully-automated 2D method allowed the quantitative analysis of over 150 endogenous PL and SM species in mouse brain regions within 40min. The developed method was applied in a pilot study, which aimed to find alteration of PL and SM composition in a mouse model of anxiety disorder. In the case of 37 PL and SM species, significant differences were observed between high anxiety-related behavior (AX) and low anxiety-related behavior (nAX) mice. In mice having elevated anxiety, the most typical trend was the downregulation of PL species, in particular, in VHPC. PMID- 29132111 TI - Characterization of global metabolic profile of Rhodiola crenulata after oral administration in rat plasma, urine, bile and feces based on UHPLC-FT-ICR MS. AB - Rhodiola crenulata has been widely used as a health food, antifatigue and antidepressant in China and many other countries for centuries. However, to date the metabolism of it in vivo still remains unclear. In this study, UHPLC-FT-ICR MS was used to analyze the major components and their metabolites in rats after oral administration of Rhodiola crenulata for the first time. A total of 179 constituents, including 37 prototype compounds and 142 metabolites (89 phase I metabolites and 53 phase II metabolites) were tentatively identified. The metabolic pathways included hydroxylation, deglycosylation, dehydrogenation, glucuronidation and sulphate conjugation. In summary, this study showed an insight into the metabolism of Rhodiola crenulata in vivo, which may provide helpful chemical information for better understanding the multiple functions of it. And also, the developed method could be used as a reliable strategy to study the metabolic profile for other traditional chinese medicines. PMID- 29132112 TI - Raman spectroscopy as a PAT for pharmaceutical blending: Advantages and disadvantages. AB - Raman spectroscopy has been positively evaluated as a tool for the in-line and real-time monitoring of powder blending processes and it has been proved to be effective in the determination of the endpoint of the mixing, showing its potential role as process analytical technology (PAT). The aim of this study is to show advantages and disadvantages of Raman spectroscopy with respect to the most traditional HPLC analysis. The spectroscopic results, obtained directly on raw powders, sampled from a two-axis blender in real case conditions, were compared with the chromatographic data obtained on the same samples. The formulation blend used for the experiment consists of active pharmaceutical ingredient (API, concentrations 6.0% and 0.5%), lactose and magnesium stearate (as excipients). The first step of the monitoring process was selecting the appropriate wavenumber region where the Raman signal of API is maximal and interference from the spectral features of excipients is minimal. Blend profiles were created by plotting the area ratios of the Raman peak of API (AAPI) at 1598cm-1 and the Raman bands of excipients (AEXC), in the spectral range between 1560 and 1630cm-1, as a function of mixing time: the API content can be considered homogeneous when the time-dependent dispersion of the area ratio is minimized. In order to achieve a representative sampling with Raman spectroscopy, each sample was mapped in a motorized XY stage by a defocused laser beam of a micro-Raman apparatus. Good correlation between the two techniques has been found only for the composition at 6.0% (w/w). However, standard deviation analysis, applied to both HPLC and Raman data, showed that Raman results are more substantial than HPLC ones, since Raman spectroscopy enables generating data rich blend profiles. In addition, the relative standard deviation calculated from a single map (30 points) turned out to be representative of the degree of homogeneity for that blend time. PMID- 29132113 TI - Fluorometric detection of protein-ligand engagement: The case of phosphodiesterase5. AB - Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP. The great clinical success of the PDE5 inhibitors, Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) has led to an increasing interest for this class of enzymes. Recent studies have shown a correlation between tumor growth and PDE5 overexpression, making PDE5-selective inhibitors promising candidates for cancer treatment. The search for such inhibitors rests today on radioactive assays. In this work, we exploit the conserved catalytic domain of the enzyme and propose a faster and safer method for detecting the binding of ligands and evaluate their affinities. The new approach takes advantage of Forster Resonance Energy Transfer (FRET) between, as the donor, a fluorescein-like diarsenical probe able to covalently bind a tetracysteine motif fused to the recombinant PDE5 catalytic domain and, as the acceptor, a rhodamine probe covalently bound to the pseudosubstrate cGMPS. The FRET efficiency decreases when a competitive ligand binds the PDE5 catalytic site and displaces the cGMPS-rhodamine conjugate. We have structurally investigated the PDE5/cGMPS-rhodamine complex by molecular modelling and have used the FRET signal to quantitatively characterize its binding equilibrium. Competitive displacement experiments were carried out with tadalafil and cGMPS. An adaptation of the competitive-displacement equilibrium model yielded the affinities for PDE5 of the incoming ligands, nano- and micromolar, respectively. PMID- 29132114 TI - Drug-eluting silicone hydrogel for therapeutic contact lenses: Impact of sterilization methods on the system performance. AB - Although contact lenses are promising platforms for ocular drug delivery and have been extensively studied for that purpose, the influence of sterilization methods on these systems remains barely investigated. In this work, a silicone-based hydrogel was produced and loaded with different ophthalmic drugs: levofloxacin, chlorhexidine, diclofenac and timolol. The drug release profiles, along with several material properties, were evaluated before and after sterilization by three different methods steam heat, gamma-irradiation and ozone gas. Independently of the sterilization method used, the results of the swelling and mechanical properties tests strongly indicate the occurrence of specific drug polymer interactions promoted by the sterilization. In general, these interactions led to a decrease on the amount of drug released. It is shown that gamma-irradiation and ozone led to significant degradation of all of the drugs used in this study. Thus, it was concluded that steam heat is the sterilization method with less impact on the devices. More importantly, the present work shows that the development of efficient and functional drug delivery devices for ophthalmic purposes cannot be done independently of a careful analysis of the influence of the sterilization procedures and methods on the degradation of these polymeric systems as a whole. PMID- 29132115 TI - Comparative interfacial in vitro digestion of protein and polysaccharide oil/water films. AB - The behaviour of proteins (beta-lactoglobulin (betalg) and soy protein isolate (SPI)) and a surface active polysaccharide (hydroxypropylmethylcellulose, HPMC) o/w interfacial films under simulated gastrointestinal conditions using the interfacial tensiometer Octopus were compared and related to the performance of the emulsions (using the same emulsifiers) under in vitro digestion. The evolution of interfacial tension (gamma) was used to investigate the effect of gastrointestinal fluids on o/w interfacial films. Clear differences were observed among these emulsifiers. During the gastric phase, HPMC showed the lowest change in gamma values as compared to protein films. The most important changes occurred during the intestinal stage where it was observed an important decrease of gamma associated with the rapid penetration of BS, followed by a lower rate of decrease attributable to the accumulation of FFA at the interface. In the last stage, the subphase was exchanged by buffer alone, to remove the reversibly adsorbed digestion products. SPI formed the most resistant interface to the remotion of digestion products, followed by HPMC and finally by betalg. The results agree with the degree of lipolysis reported for the emulsions stabilized by these emulsifiers, which suggest that lipid digestion could be modulated by the ability of emulsifiers to prevent the BS activity (to adsorb at the O/W interface or remove the inhibitory digestion products from the interface). Thus, emulsifiers BS interactions appears as a key factor in controlling the lipolysis. PMID- 29132116 TI - The outcome of laparoscopic subtotal cholecystectomy in difficult cases - A case series. AB - INTRODUCTION: Laparoscopic subtotal cholecystectomy (LSC) is a widely used technique for managing cholelithiasis with severe cholecystitis. The increasing popularity its utilization is due to the good safety profile and acceptable results. This case series evaluates the short- and long-term results of Indonesian patients who underwent LSC with an objective to determine whether the procedure can be a standard approach for difficult cholecystectomy in our institution. PRESENTATION OF CASE: Thirty-four Indonesian patients (26 men, 8 women) with the mean age of 54.6 years (median 54 years, range 30-84 years) who underwent LSC were retrospectively analyzed. Nineteen patients are suffering from type II diabetes mellitus and fourteen patients with suspected choledocoholithiasis underwent ERCP prior to LSC. The major postoperative diagnosis was acute cholecystitis (16 patients), followed by gallbladder empyema (10 patients), chronic cholecystitis (5 patients), history of cholangitis (1 patient), Mirizzi's syndrome (1 patient) and stone retention post-ERCP (1 patient). DISCUSSION: The mean operating time was 158minutes (median 150minutes, range 60-240minutes), mean length of hospital stay of 4.6days (median 3days, range 2-33days) and drain usage for 3.6days (median 3.0days, range 1-19days). Postoperatively there was one case of bilioenteric fistula, one case of stone retention and two cases of prolonged upper gastrointestinal symptoms. There is no case of biliary leakage, peritonitis or wound infection. CONCLUSION: The outcome of LSC in this case series is comparable with other publications showing a general favorability of LSC. Further studies are needed to elucidate the clinical benefits of several LSC technical points such as stump closure, posterior wall diathermy and drain usage. Based on this preliminary finding, LSC can be applied as a standard procedure for difficult cases in our institution. PMID- 29132117 TI - An extrapulmonary manifestation of lymphangioleiomyomatosis: A rare case report. AB - Lymphangioleiomyomatosis (LAM) is a rare and fatal disease which occurs almost exclusively in young women. The disease often affects lungs and most of the patients die from respiratory failure. It is often initially misdiagnosed as asthma or chronic obstructive pulmonary disease. The most common presentations of pulmonary LAM (P-LAM) include dyspnea and coughing. Chylothorax and spontaneous pneumothorax may be seen in advanced cases. Although rare, it may present with extrapulmonary LAM (E-LAM). Renal angiomyolipomas and abdominal lymphadenopathies (LAPs) are common in E-LAM cases. Pelvic retroperitoneal masses are very rare and often require exploratory laparotomy. Herein, we report a 36-year-old female case of a rare extrapulmonary manifestation of LAM who was treated with abdominal and thoracic surgery, radiotherapy and finally sirolimus. PMID- 29132118 TI - Primary malignant melanoma of the female urethra: Report of a rare neoplasm of the urinary tract. AB - INTRODUCTION: Melanoma is a malignant tumor that can affect any area of the anatomical economy. Its occurance in the female urethra is extremely rare. We report a case of primary malignant urethral melanoma developed in an elderly female patient. PRESENTATION OF CASE: A 70 years old female presented with dysuria, poor stream, gross haematuria, intermittent blood spots, and a painful mass. On physical examination, there were no suspicious lesions on the skin. On external genital examination, a lesion at the level of the urethral meatus was observed. The mass was removed by wide local excision under spinal anaesthesia. The pathological diagnosis was malignant melanoma of the urethra. DISCUSSION: The common presentations include bleeding and/or discharge per urethra, voiding dysfunction and the presence of tumor mass. Survival depends on the stage, location and size of the neoplasm at the time of diagnosis. Despite major surgery, radiotherapy or immunotherapy; malignant melanoma usually has a poor prognosis. CONCLUSION: Melanoma of the female urethra is an extremely uncommon pathology leading to paucity of literature and any definite recommendations regarding management. The histological and immunohistochemical findings can be helpful in making an early and accurate diagnosis of malignant melanoma in the urogenital region. PMID- 29132119 TI - How tall buildings affect turbulent air flows and dispersion of pollution within a neighbourhood. AB - The city of London, UK, has seen in recent years an increase in the number of high-rise/multi-storey buildings ("skyscrapers") with roof heights reaching 150 m and more, with the Shard being a prime example with a height of ~310 m. This changing cityscape together with recent plans of local authorities of introducing Combined Heat and Power Plant (CHP) led to a detailed study in which CFD and wind tunnel studies were carried out to assess the effect of such high-rise buildings on the dispersion of air pollution in their vicinity. A new, open-source simulator, FLUIDITY, which incorporates the Large Eddy Simulation (LES) method, was implemented; the simulated results were subsequently validated against experimental measurements from the EnFlo wind tunnel. The novelty of the LES methodology within FLUIDITY is based on the combination of an adaptive, unstructured, mesh with an eddy-viscosity tensor (for the sub-grid scales) that is anisotropic. The simulated normalised mean concentrations results were compared to the corresponding wind tunnel measurements, showing for most detector locations good correlations, with differences ranging from 3% to 37%. The validation procedure was followed by the simulation of two further hypothetical scenarios, in which the heights of buildings surrounding the source building were increased. The results showed clearly how the high-rise buildings affected the surrounding air flows and dispersion patterns, with the generation of "dead zones" and high-concentration "hotspots" in areas where these did not previously exist. The work clearly showed that complex CFD modelling can provide useful information to urban planners when changes to cityscapes are considered, so that design options can be tested against environmental quality criteria. PMID- 29132120 TI - RNA-based dynamic genetic controllers: development strategies and applications. AB - Dynamic regulation of gene expression in response to various molecules is crucial for both basic science and practical applications. RNA is considered an attractive material for creating dynamic genetic controllers because of its specific binding to ligands, structural flexibility, programmability, and small size. Here, we review recent advances in strategies for developing RNA-based dynamic controllers and applications. First, we describe studies that re engineered natural riboswitches to generate new dynamic controllers. Next, we summarize RNA-based regulatory mechanisms that have been exploited to build novel artificial dynamic controllers. We also discuss computational methods and high throughput selection approaches for de novo design of dynamic RNA controllers. Finally, we explain applications of dynamic RNA controllers for metabolic engineering and synthetic biology. PMID- 29132122 TI - Modelling the long-term effect of wastewater compositions on maximum sulfide and methane production rates of sewer biofilm. AB - Reliable modelling of sulfide and methane production in sewer systems is required for efficient sewer emission management. Wastewater compositions affect sulfide and methane production kinetics through both its short-term variation influencing the substrate availability to sewer biofilms, and its long-term variation affecting the sewer biofilm structure. While the short-term effect is well considered in existing sewer models with the use of Monod or half-order equations, the long-term effect has not been explicitly considered in current sewer models suitable for network modelling. In this study, the long-term effect of wastewater compositions on sulfide and methane production activities in rising main sewers was investigated. A detailed biofilm model was firstly developed, and then calibrated and validated using experimental data measured during the entire biofilm development period of a laboratory sewer reactor. Based on scenario simulations using the detailed biofilm model, empirical equations describing the long-term effect of sulfate and sCOD (soluble chemical oxygen demand) concentrations on kH2S (the maximum sulfide production rate of sewer biofilm) and kCH4 (the maximum methane production rate of sewer biofilm) were proposed. These equations require further verification in future studies before their potential integration into network-wide sewer models. PMID- 29132121 TI - The therapeutic potential of CFTR modulators for COPD and other airway diseases. AB - Airways diseases, especially chronic obstructive pulmonary disease (COPD) and asthma, are common causes of morbidity and mortality worldwide. There is an ongoing unmet need for novel and effective therapies. There is an established pathophysiological link and phenotypic similarity between the chronic bronchitis phenotype of COPD and cystic fibrosis (CF). New evidence suggests that CFTR dysfunction may play a role in other common airways diseases such as COPD, non atopic asthma and non-CF bronchiectasis. Newly approved and investigational drugs that target both mutant and wild-type CFTR channels have provided a new treatment opportunity addressing the mucus defect in pulmonary diseases that share the same pathophysiology with CF. PMID- 29132123 TI - A comparative study of electro-dewatering process performance for activated and digested wastewater sludge. AB - Electro-dewatering (EDW) is an alternative emerging and energy-efficient technology that provides improved liquid/solids separations in the dewatering of wastewater sludge. The EDW technology is not only an innovative dewatering method for significantly reducing the volume of wastewater sludge before re-utilization or disposal, but is also a promising emerging method which may potentially be used for decontamination purposes. In this study, the influence of the sludge properties (e.g. electrical conductivity, zeta potential, specific cake resistance, among others) on their mechanical and electrical behaviour in terms of dewaterability and electro-dewaterability, the applied current (current density from 20 to 80 A/m2), and filter cloth position relative to the electrode was investigated. A two-sided filter press at lab-scale with moving anode was used, and the treatment performance of the EDW process on two different types of wastewater sludge (activated and digested) was thoroughly assessed from both an electrochemical viewpoint and in terms of the dewatering rate. The results showed that the conditioned digested sludge was more easily dewatered by mechanical dewatering (MDW) with 34-35% (w%) of dry solids content compared to 19-20% (w%) for the activated sludge, thanks to the lower content of both the microbial extracellular polymeric substances (EPS) and the volatile suspended solids fraction. For the EDW results, the electrical conductivity of the sludge was pivotal to the dryness of the final solids and therefore also to the dewatering kinetics. The results demonstrated that the activated sludge arrived at an equilibrium much faster (after approximately 3600 s) compared with digested sludge, thanks to its lower electrical conductivity (0.8 mS/cm) providing a greater voltage drop across the cathode and therefore more repulsion of the solids from the cathode leading to continuously high filtrate flowrate. Also the EDW performance was analysed by comparing the ratio of the filtrate volume collected at the anode to the volume collected at the cathode side. For digested sludge at 5 bar, 40 A/m2 different positions of the filter cloth were tested but these configurations barely impacted the EDW performance, despite having a significant impact on the energy requirements. At industrial scale, it would be useful to position the filter cloths at some distance from the electrodes, but this study shows that this benefit may be quickly outweighed by the loss in EDW energy efficiency. PMID- 29132124 TI - Variations of moisture and organics in activated sludge during Fe0/S2O82- conditioning-horizontal electro-dewatering process. AB - The feasibility of using Fe0/S2O82- conditioning (zero valence iron (ZVI)/persulfate (ps)) integrated with horizontal electro-dewatering (HED) to improve the dewaterability of activated sludge (AS) was evaluated. The removal and migration of free and bound water in the ZVI/ps-HED process were determined, along with the organic matter migration between the solid and liquid phases of AS biosolids. Results showed that the optimum conditioning dosages were determined as 0.35 g ZVI/g dry solids (DS) and 0.15 g ps/g DS on the basis of capillary suction time variation. The lowest final water content (WC) of 83.67% in AS occurred after the HED treatment at 40 V and 120 min as determined using the response surface methodology. Despite the disruption of AS flocs and microbial cells through SO4-. oxidation during the ZVI/ps conditioning, the particle size and mass fractal dimension of the AS flocs remained relatively stable as the zeta potential increased from -8.5 mV to -4.6 mV. The coagulation of Fe3+ from the oxidation of Fe2+ by ps contributed to the relatively stable condition, which favored the subsequent momentum of the electroosmotic flow. Moreover, the ZVI/ps conditioning decreased the bound water content (BWC, from 1.83 g/g DS to 1.38 g/g DS) and increased the free water content (FWC, from 60.27 g/g DS to 60.91 g/g DS), indicating a transformation from free water to bound water. After the ZVI/ps HED process, the FWC and BWC were removed significantly with ratios of 96.32% and 79.78%, respectively. Along with water removal through the ZVI/ps-HED process, the organic matter in the supernatant/filtrate initially increased and further rose at the HED stage. The analysis of the extracellular polymeric substance (EPS) content showed that the proteins (PNs) and polysaccharides (PSs) at the liquid and solid phases decreased due to oxidative degradation. Furthermore, the ZVI/ps stage significantly reduced the PNs content of slime to 57.22%, the PSs content of EPS to 68.50%, and the PN-like substances in the slime and tightly bound EPS to 74.90% and 52.47%, respectively. In addition, the WC of AS correlated with the contents of PN and microbial by-product-like material in slime, as well as tryptophan in TB-EPS, and the low EPS content in AS indicated good dewaterability. Thus, ZVI/ps should be selected as a pretreatment prior to HED. PMID- 29132125 TI - Simulation of photoreactive transients and of photochemical transformation of organic pollutants in sunlit boreal lakes across 14 degrees of latitude: A photochemical mapping of Sweden. AB - Lake water constituents, such as chromophoric dissolved organic matter (CDOM) and nitrate, absorb sunlight which induces an array of photochemical reactions. Although these reactions are a substantial driver of pollutant degradation in lakes they are insufficiently understood, in particular on large scales. Here, we provide for the first time comprehensive photochemical maps covering a large geographic region. Using photochemical kinetics modeling for 1048 lakes across Sweden we simulated the steady-state concentrations of four photoreactive transient species, which are continuously produced and consumed in sunlit lake waters. We then simulated the transient-induced photochemical transformation of organic pollutants, to gain insight into the relevance of the different photoreaction pathways. We found that boreal lakes were often unfavorable environments for photoreactions mediated by hydroxyl radicals (OH) and carbonate radical anions (CO3-), while photoreactions mediated by CDOM triplet states (3CDOM*) and, to a lesser extent, singlet oxygen (1O2) were the most prevalent. These conditions promote the photodegradation of phenols, which are used as plastic, medical drug and herbicide precursors. When CDOM concentrations increase, as is currently commonly the case in boreal areas such as Sweden, 3CDOM* will also increase, promoting its importance in photochemical pathways even more. PMID- 29132126 TI - Improved analysis of ground vibrations produced by man-made sources. AB - Man-made sources of ground vibration must be carefully monitored in urban areas in order to ensure that structural damage and discomfort to residents is prevented or minimised. The research presented in this paper provides a comparative evaluation of various methods used to analyse a series of tri-axial ground vibration measurements generated by rail, road, and explosive blasting. The first part of the study is focused on comparing various techniques to estimate the dominant frequency, including time-frequency analysis. The comparative evaluation of the various methods to estimate the dominant frequency revealed that, depending on the method used, there can be significant variation in the estimates obtained. A new and improved analysis approach using the continuous wavelet transform was also presented, using the time-frequency distribution to estimate the localised dominant frequency and peak particle velocity. The technique can be used to accurately identify the level and frequency content of a ground vibration signal as it varies with time, and identify the number of times the threshold limits of damage are exceeded. PMID- 29132127 TI - A functional connection between dyskerin and energy metabolism. AB - The human DKC1 gene encodes dyskerin, an evolutionarily conserved nuclear protein whose overexpression represents a common trait of many types of aggressive sporadic cancers. As a crucial component of the nuclear H/ACA snoRNP complexes, dyskerin is involved in a variety of essential processes, including telomere maintenance, splicing efficiency, ribosome biogenesis, snoRNAs stabilization and stress response. Although multiple minor dyskerin splicing isoforms have been identified, their functions remain to be defined. Considering that low-abundance splice variants could contribute to the wide functional repertoire attributed to dyskerin, possibly having more specialized tasks or playing significant roles in changing cell status, we investigated in more detail the biological roles of a truncated dyskerin isoform that lacks the C-terminal nuclear localization signal and shows a prevalent cytoplasmic localization. Here we show that this dyskerin variant can boost energy metabolism and improve respiration, ultimately conferring a ROS adaptive response and a growth advantage to cells. These results reveal an unexpected involvement of DKC1 in energy metabolism, highlighting a previously underscored role in the regulation of metabolic cell homeostasis. PMID- 29132129 TI - Administration of Curcumin Protects Kidney Tubules Against Renal Ischemia Reperfusion Injury (RIRI) by Modulating Nitric Oxide (NO) Signaling Pathway. AB - BACKGROUND/AIMS: To explore the protective effect of curcumin on renal ischemia reperfusion injury (RIRI) in rats, and its influence on nephridial tissue's NO and cGMP levels as well as downstream signaling pathway, to elucidate the possible mechanism of curcumin on RIRI. METHODS: 36 Sprague Dawley rats (SD rats) were randomly divided into Sham group, Model group, curcumin (CUR +) Model group, 12 rats per group. They were all given RIRI model preparation by unilateral artery occlusion method. All groups' beta2-MG in urine in 24h, serum Cr and BUN were compared, and UAER were calculated. Nitric oxide synthase (NOS), cGMP dependent protein kinase (PKG), Caspase-3 expression were all determined by western blot. Nitric oxide (NO), NOS and cGMP levels were also examined by using ELISA. All groups' nephridial histomorphology and kidney tubules score were evaluated and compared. RESULTS: beta2-MG and UAER in urine, serum Cr and BUN, in renal tissue were all elevated in Model of RIRI, indicating the success of animal model of RIRI establishment, and above index in CUR + Model group were all lower than those in Model group. Furthermore, iNOS, NO, cGMP, PKG and Caspase-3 in renal tissue were all increased in Model of RIRI, indicating the NO signaling pathway was activated, which is one of the pathogenesis of RIRI, and above index in CUR + Model group were all lower than those in Model group, suggesting that inactivation of iNOS/NO/cGMP/PKG signaling pathway is one of the reasons that explain the protective effect of curcumin in RIRI. CONCLUSION: The activation of iNOS/NO/cGMP/PKG signaling pathway and the consequent promoted apoptosis of renal tubules are significantly involved in the pathogenesis of development of RIRI, and curcumin treatment could protect renal tubules against RIRI, at least partially, by suppressing the activated iNOS/NO/cGMP/PKG signaling pathway. PMID- 29132128 TI - A single cysteine post-translational oxidation suffices to compromise globular proteins kinetic stability and promote amyloid formation. AB - Oxidatively modified forms of proteins accumulate during aging. Oxidized protein conformers might act as intermediates in the formation of amyloids in age-related disorders. However, it is not known whether this amyloidogenic conversion requires an extensive protein oxidative damage or it can be promoted just by a discrete, localized post-translational modification of certain residues. Here, we demonstrate that the irreversible oxidation of a single free Cys suffices to severely perturb the folding energy landscape of a stable globular protein, compromise its kinetic stability, and lead to the formation of amyloids under physiological conditions. Experiments and simulations converge to indicate that this specific oxidation-promoted protein aggregation requires only local unfolding. Indeed, a large scale analysis indicates that many cellular proteins are at risk of undergoing this kind of deleterious transition; explaining how oxidative stress can impact cell proteostasis and subsequently lead to the onset of pathological states. PMID- 29132130 TI - Effect of Huagantongluofang, a Chinese Traditional Medicine, in Hepatic Fibrogenesis in a Mouse Model of Biliary Cirrhosis. AB - BACKGROUND: Biliary cirrhosis (BC) is a chronic cholestatic liver disease, in which hepatic fibrosis is an early symptom. This study aimed to identify the biological function and the therapeutic effect of a Chinese traditional medicine, HuaGanTongLuoFang (HGTLF), in a mouse model of BC. METHODS: The mice (n = 72) were randomly divided into a sham group (n =12) and BC group (n = 60). The animals in the BC group were then randomly divided into five groups (n = 12 in each) and treated with three different doses of HGTLF, ureodeoxycholic acid (UDCA), or normal saline (the model group). Four weeks later, serum and liver tissues were obtained from all the animals for analyses. Hematoxylin and eosin (H&E) staining was used to quantify the hepatic morphology, while real-time PCR and Enzyme-linked immunosorbent assay (ELISA) were used to determine the level of hepatic fibrosis-related genes. RESULTS: Compared with the model group, all three doses of HGTLF improved hepatic function, as well as reducing inflammation and fibrogenesis. The best therapeutic effect was observed in the high-dose HGTLF group. Furthermore, HGTLF contributed to down-regulation of hepatic fibrosis related genes (platelet-derived growth factor [PDGF], transforming growth factor beta [TGF-beta], p38, nuclear factor-kappaB [NF-kB], intercellular adhesion molecular-1 [ICAM-1], and tissue inhibitor of metalloproteinase-1 [TIMP-1]). CONCLUSION: The data suggested that HGTLF effectively improved liver function and the morphology of the liver tissue in a mouse model of BC, possibly via suppression of hepatic fibrosis-related signals. PMID- 29132131 TI - IL-6 Promotes FSH-Induced VEGF Expression Through JAK/STAT3 Signaling Pathway in Bovine Granulosa Cells. AB - BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) has been demonstrated to play a pivotal role in the regulation of angiogenesis in ovarian follicular development, particularly during the preovulatory period. Although numerous studies have shown that interleukin-6 (IL-6) is one of the major inducing factors that regulate the expression of VEGF in non-ovarian cells, whether it involved in regulating the expression of VEGF in normal ovarian granulosa cells is still unknown. The aim of this study was to elucidate the mechanisms underlying the effect of IL-6 on FSH-induced VEGF expression in bovine granulosa cells derived from large follicles. METHODS: VEGF mRNA expression in granulosa cells after IL-6 with/without inhibitors treatment was analyzed by RT-qPCR. Phosphorylation levels of ERK1/2 and STAT3 proteins induced by IL-6 were analyzed by western blotting. The protein levels produced by granulosa cells were detected by ELISA. RESULTS: High concentration of IL-6 (10ng/ml) can significantly up-regulate FSH-induced VEGF gene and protein expression levels in granulosa cells, and also promote the VEGF upstream regulators HIF-1alpha and COX2 mRNA expression. VEGF expression levels were significantly decreased after specifically blocking HIF-1alpha and COX2 by using inhibitors. The up-regulation effect of IL-6 on FSH-induced VEGF expression in granulosa cells mainly through activating the JAK/STAT3 signaling pathway, which can be impaired by JAK inhibitors. CONCLUSION: IL-6 can promote FSH-induced VEGF expression in granulosa cells, which is mainly achieved by increasing the expression of HIF-1alpha and COX2.This promoting effect is mediated by activating the JAK/STAT3 pathway. Moreover, there may be a synergistic relationship between FSH and IL-6 in the regulation of VEGF expression. PMID- 29132132 TI - Care of the Acute Kidney Injury Survivor. AB - While the short-term implications of acute kidney injury (AKI) have been known for many years, far less attention has been paid to the health of AKI survivors. This was perhaps fueled by a prevailing wisdom that if a patient was fortunate enough to survive the primary illness associated with AKI, the prognosis for future health was auspicious. More recently, this dogma was challenged by data suggesting that after an episode of AKI, patients remain at risk of experiencing multiple adverse health outcomes. Greater recognition and appreciation of the risks faced by AKI survivors have led to the development of quality improvement initiatives that are supposed to enrich this vulnerable population. PMID- 29132133 TI - Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics. AB - Endomorphin-1 (EM1) and endomorphin-2 (EM2) are two endogenous ligands that belong to the opioid peptide family and have the highest affinity and selectivity for the u-opioid receptor (MOR). The neuroanatomical distribution, ultrastructural features and neural circuitry of EM-containing neuronal structures have been morphologically demonstrated. In addition, the modulation effects of the EMs in different areas reflect their potential endogenous roles in many major physiological processes, including their remarkable roles in the transmission and modulation of noxious information. The distinguished antinociceptive property of the EMs in acute and chronic pain, including neuropathic pain, cancer pain and inflammatory pain, has been revealed and investigated for therapeutic purposes. However, EMs exert adverse effects in the gastrointestinal, urinary, cardiovascular, and respiratory systems, which impede the development of EMs as new analgesics. Numerous studies have synthesized and investigated EM analogues and demonstrated that these EM derivatives had improved pharmacological properties, supporting their therapeutic perspectives. In the present review, the results of previous studies, particularly morphological and pharmacological studies, were summarized. Finally, EM modifications and their potential clinical implications were described. Applying this knowledge about EMs may provide information for further investigations in clinical application. PMID- 29132134 TI - Xia-Yu-Xue Decoction Inhibits Intestinal Epithelial Cell Apoptosis in CCl4 Induced Liver Fibrosis. AB - BACKGROUND/AIMS: Intestine-derived endotoxin is thought to play a role in the development of liver fibrosis. However, the pathological change in the intestine during liver fibrosis is still poorly understood. Here, we investigated the effects of Xia-yu-xue decoction (XYXD) on intestinal inflammation, apoptosis, and tight junction integrity in the carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Murine liver fibrosis was developed by CCI4 treatment three times per week over a 6-week period. The CCl4-treated mice were divided into two groups: the CCl4-water group (n=8, CCl4) and the CCl4-XYXD group (n=8, CCl4+XYXD). The CCl4+XYXD mice were treated with XYXD from the beginning of the first week. The expression of inflammatory cytokines and apoptotic molecules were examined using immunohistochemistry, real-time PCR, and western blot. The intestinal epithelial cell apoptosis was examined by TUNEL staining. The tight junction-related molecules, such as ZO-1, claudin, and occludin in the gut were measured by real-time PCR. RESULTS: In CCl4-treated mice damage of the intestinal epithelia and infiltration of inflammatory cells into the lamina propria and muscular layer were observed. Proinflammatory markers MCP-1, TNF-alpha, CXCL11, IL-6, and CD68 were significantly increased in the intestinal epithelia in CCI4 treated mice. The expression of pro-apoptotic molecules including Fas and Bax was increased in the intestinal epithelia in CCI4-treated mice compared with that in control. The number of TUNEL-positive intestinal epithelial cells was also markedly increased in CCl4-treated mice. The expression of the tight junction proteins including ZO-1, claudin, and occludin was significantly decreased in CCI4-treated mice compared with that in control mice. Notably, XYXD treatment ameliorated increased inflammatory markers and apoptosis-related molecules and decreased tight-junction proteins in CCl4-treated mice. CONCLUSION: CCl4 treatment increased expression of proinflammatory cytokines and pro-apoptotic molecules and disrupted tight junction integrity in the intestine. XYXD treatment ameliorated intestinal inflammation, cell death, and tight junction disintegrity induced by CCl4 treatment, suggesting that XYXD inhibits CCl4-mediated liver fibrosis at least in part by ameliorating the intestinal epithelial damage. PMID- 29132135 TI - Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration. AB - BACKGROUND/AIMS: Age-related macular degeneration (AMD) is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. METHODS: We examined the CD4+ T cell compartments and their functions in AMD patients. RESULTS: AMD patients presented significantly higher frequencies of interferon (IFN)-gamma-expressing and interleukin (IL)-17-expressing CD4+ T cells than healthy controls. The levels of IFN-gamma and IL-17 expression by CD4+ T cells were significantly higher in AMD patients. These IFN-gamma-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3+ and CCR4+CCR6+ expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE)-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-gamma and IL-17. CONCLUSIONS: This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN gamma- and IL-17-dependent fashion, and could potentially serve as therapeutic targets. PMID- 29132136 TI - MEG3 Suppresses Human Pancreatic Neuroendocrine Tumor Cells Growth and Metastasis by Down-Regulation of Mir-183. AB - BACKGROUND/AIMS: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms which arise from pancreatic islet cells. Recently, lncRNA MEG3 has been reported as a tumor suppressor in variety cancers. This study aimed to reveal the functional effects of MEG3 on pNETs which has not been uncovered previously. METHODS: The expression of MEG3, miR-183, and BRI3 in BON1 cells were altered by transfection with their specific vectors/shRNA, or mimic/inhibitor. Thereafter, cell viability, apoptosis, the protein expressions of cell cycle related factors, and apoptosis associated factors, as well as cell migration and invasion were respectively assessed by typan blue staining, flow cytometry, western blotting, and transwell assay. RESULTS: MEG3 was low expressed in BON1 and QGP-1 cells, when compared to three normal cell lines (HEK293, CCL-153, and EC-304). MEG3 overexpression decreased BON1 cells viability, invasion, migration, but significantly induced apoptosis. miR-183 was a direct target of MEG3, and miR-183 up-regulation abolished the anti-growth and anti-metastasis effects of MEG3 overexpression on BON1 cells. Moreover, BRI3 was a target of miR-183, and BRI3 exhibited a tumor-promoting role possibly via activation of p38/ERK/AKT and Wnt/beta-Catenin signaling in BON1 cells. CONCLUSION: This study demonstrated a tumor suppressive effect of MEG3 in BON1 cells that suppresses tumor cells growth and metastasis. A novel regulatory mechanism has been revealed that modulation of MEG3/miR-183/BRI3 axis may be pivotal in pNET. PMID- 29132137 TI - Altered Circular RNA Expression in Patients with Repeated Implantation Failure. AB - BACKGROUND/AIMS: CircRNAs play an important role in regulating gene expression and the specific role of circRNAs in the pathogenesis of repeated implantation failure remains unclear. The aim of this study is to assess the differentially expressed circRNAs in patients with repeated implantation failure. METHODS: We screened circRNA expression profiles in endometrial biopsies taken from six women with repeated implantation failure and control group using circRNA microarray. Bioinformatic analyses were applied to study these differentially expressed circRNAs. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm these results. RESULTS: The data from circRNA microarrays clearly revealed that 856 unique circRNAs were significantly altered (p<0.05). The up-regulated expression of hsa_circRNA_070616, hsa_circRNA_103716, hsa_circRNA_104001, hsa_circRNA_104854 and the down-regulated expression of hsa_circRNA_004183, hsa_circRNA_044353, hsa_circRNA_404686 were further validated by qRT-PCR. CONCLUSION: this study demonstrates that a number of circRNAs were differentially expressed in patients with repeated implantation failure compared with normal controls and may offer novel molecular candidates for diagnosis and clinical treatment of embryo implantation failures. PMID- 29132138 TI - Acute Effects of Vitamin C Exposure On Colonic Crypts: Direct Modulation of pH Regulation. AB - BACKGROUND/AIM: Colorectal cancer is still considered a leading cause of death in the United States and worldwide. One potential way to improve survival besides detection is to look to new therapeutic agents that can be taken prophylactically to reduce the risk of tumor formation. For cancer cells to grow and invade, a higher (more alkaline) intracellular pH must occur. We chose to examine a specific nutraceutical agent, which is Vitamin C. The acute effect of Vitamin C exposure on normal colonic crypts has been studied, providing some insight into how Vitamin C achieve its effect. METHODS: Distal colon was excised from rats. Following enzymatic digestion single colonic crypts were isolated. Colonic crypts were loaded with pH sensitive dye to measure the intracellular pH changes. Crypts were exposed to solutions +/- Vitamin C. RESULTS: 10 mM Vitamin C decreased Na+ dependent intracellular pH recovery. Vitamin C modulates SVCT leading to changes in proton extrusion. Vitamin C entry occurs via either SVCT2 on the basolateral membrane or by transcellular passive diffusion through tight junctions to the apical membrane and then active transport via SVCT1. CONCLUSION: Acute addition of Vitamin C to the basolateral membrane maintains low intracellular pH for a longer period which could halt and/or prevent tumor formation. PMID- 29132139 TI - Study of HSPB6: Insights into the Properties of the Multifunctional Protective Agent. AB - HSPB6(Heat shock protein B6), is also referred to as P20/HSP20. Unlike other many other members of sHSP(small Heat shock protein) family, which tend to form high molecular-mass oligomers, in solution, human HSPB6 only forms dimers. However, it still exhibits chaperon-like activity comparable with that of HSPB5. It is expressed ubiquitously, with high and constitutive expression in muscular tissues. sHSPs characteristically function as molecular chaperones and HSPB6 also has a molecular chaperone activity. HSPB6 is up-regulated in response to diverse cellular stress or damage and protect cells from otherwise lethal conditions. HSPB6 is widely recognized as a principle mediator of cardioprotective signaling and recent studies have unraveled the protective role of HSPB6 in disease or injury to the central nervous system. Moreover, accumulating evidence has implicated HSPB6 as a key mediator of diverse vital physiological processes, such as smooth muscle relaxation, platelet aggregation. The versatility of HSPB6 can be explained by its direct involvement in regulating different client proteins and its ability to form heterooligomer with other sHSPs, which seems to be dependent on HSPB6 phosphorylation. This review focuses on the properties including expression and regulation pattern, phosphorylation, chaperon activity, multiple cellular targets of HSPB6, as well as its possible role in physical and pathological conditions. PMID- 29132140 TI - Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury. AB - BACKGROUND/AIMS: Spinal cord injury (SCI) is a common and devastating disease, which results in systemic inflammatory response syndrome and secondary lung injury. Mitochondrial dysfunction and inflammation are closely related to lung injury in diverse disease models. No studies have demonstrated the effects of mitochondrial targeted peptide SS-31 in a mouse model of SCI-induced lung injury. METHODS: Immediately after injury, mice in the treatment groups received a daily, single-dose intraperitoneal injection of SS-31 and for the next 2 days. The sham and SCI groups also received a daily single dose of vehicle (DMSO and 0.9% NaCl, 1: 3). The lung tissue of mice was examined after SCI, and tissue damage, apoptosis, inflammation, and mitochondrial dysfunction were recorded. RESULTS: SS 31 treatment attenuated lung edema and tissue damage. Furthermore, SS-31 treatment reduced apoptosis of alveolar type II cells, the number of total macrophages and M1 macrophages, and neutrophil infiltration. Moreover, SS-31 treatment attenuated reactive oxygen species levels, reversed mitochondrial dysfunction and inhibited NLRP3 inflammasome activation. CONCLUSIONS: Collectively, our results demonstrate that SS-31 attenuates mitochondrial dysfunction, controls inflammatory responses, and alleviates the severity of lung damage in a mouse model of SCI-induced lung injury. PMID- 29132141 TI - Shoulder giant schwannoma - a diagnosis to be considered in painless shoulder masses. AB - Tumours formed from peripheral nerve sheaths are rare in the shoulder. We present the case of a 80-year-old female referred to an orthopaedic surgery clinic because of a large painless mass of the right shoulder, with one year of evolution. There was no history of trauma, involvement of any other joint or systemic complaints. Given the clinical and imagiological suspicion of a giant synovial cyst, the patient underwent complete surgical resection of the mass, which took place without any complications or functional impairment. Histological diagnosis - schwannoma - was unexpected given the lesion characteristics and the low incidence of these benign tumours. They usually present as a slow growth mass, where pain and neurological deficits are uncommon. Among the complementary tests available, MRI is the gold standard. Still, the diagnosis is made preoperatively only in a minority of cases. We emphasize the need to consider this rare clinical entity in the differential diagnosis of slow evolution tumourations of the shoulder, in order to avoid unnecessary surgery and to minimize the risk of iatrogenic injury of the involved nerve. PMID- 29132143 TI - A Jurassic gliding euharamiyidan mammal with an ear of five auditory bones. AB - Gliding is a distinctive locomotion type that has been identified in only three mammal species from the Mesozoic era. Here we describe another Jurassic glider that belongs to the euharamiyidan mammals and shows hair details on its gliding membrane that are highly similar to those of extant gliding mammals. This species possesses a five-boned auditory apparatus consisting of the stapes, incus, malleus, ectotympanic and surangular, representing, to our knowledge, the earliest known definitive mammalian middle ear. The surangular has not been previously identified in any mammalian middle ear, and the morphology of each auditory bone differs from those of known mammals and their kin. We conclude that gliding locomotion was probably common in euharamiyidans, which lends support to idea that there was a major adaptive radiation of mammals in the mid-Jurassic period. The acquisition of the auditory bones in euharamiyidans was related to the formation of the dentary-squamosal jaw joint, which allows a posterior chewing movement, and must have evolved independently from the middle ear structures of monotremes and therian mammals. PMID- 29132145 TI - Gene therapy: Transgenic stem cells replace skin. PMID- 29132142 TI - Solar abundance ratios of the iron-peak elements in the Perseus cluster. AB - The metal abundance of the hot plasma that permeates galaxy clusters represents the accumulation of heavy elements produced by billions of supernovae. Therefore, X-ray spectroscopy of the intracluster medium provides an opportunity to investigate the nature of supernova explosions integrated over cosmic time. In particular, the abundance of the iron-peak elements (chromium, manganese, iron and nickel) is key to understanding how the progenitors of typical type Ia supernovae evolve and explode. Recent X-ray studies of the intracluster medium found that the abundance ratios of these elements differ substantially from those seen in the Sun, suggesting differences between the nature of type Ia supernovae in the clusters and in the Milky Way. However, because the K-shell transition lines of chromium and manganese are weak and those of iron and nickel are very close in photon energy, high-resolution spectroscopy is required for an accurate determination of the abundances of these elements. Here we report observations of the Perseus cluster, with statistically significant detections of the resonance emission from chromium, manganese and nickel. Our measurements, combined with the latest atomic models, reveal that these elements have near-solar abundance ratios with respect to iron, in contrast to previous claims. Comparison between our results and modern nucleosynthesis calculations disfavours the hypothesis that type Ia supernova progenitors are exclusively white dwarfs with masses well below the Chandrasekhar limit (about 1.4 times the mass of the Sun). The observed abundance pattern of the iron-peak elements can be explained by taking into account a combination of near- and sub-Chandrasekhar-mass type Ia supernova systems, adding to the mounting evidence that both progenitor types make a substantial contribution to cosmic chemical enrichment. PMID- 29132144 TI - A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. AB - Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. We estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, we evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Our model predicts survival in anti-CTLA-4-treated patients with melanoma and anti-PD-1 treated patients with lung cancer. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumours and rapidly evolving pathogens. PMID- 29132147 TI - Corrigendum: Widespread movement of meltwater onto and across Antarctic ice shelves. AB - This corrects the article DOI: 10.1038/nature22049. PMID- 29132151 TI - Should You Screen for and Manage Depression in Patients With a Recent Acute Coronary Syndrome? PMID- 29132150 TI - Functional Impairment and Decline in Middle Age: A Cohort Study. AB - Background: Difficulties with daily functioning are common in middle-aged adults. However, little is known about the epidemiology or clinical course of these problems, including the extent to which they share common features with functional impairment in older adults. Objective: To determine the epidemiology and clinical course of functional impairment and decline in middle age. Design: Cohort study. Setting: The Health and Retirement Study. Participants: 6874 community-dwelling adults aged 50 to 56 years who did not have functional impairment at enrollment. Measurements: Impairment in activities of daily living (ADLs), defined as self-reported difficulty performing 1 or more ADLs, assessed every 2 years for a maximum follow-up of 20 years, and impairment in instrumental ADLs (IADLs), defined similarly. Data were analyzed by using multistate models that estimate probabilities of different outcomes. Results: Impairment in ADLs developed in 22% of participants aged 50 to 64 years, in whom further functional transitions were common. Two years after the initial impairment, 4% (95% CI, 3% to 5%) of participants had died, 9% (CI, 8% to 11%) had further ADL decline, 50% (CI, 48% to 52%) had persistent impairment, and 37% (CI, 35% to 39%) had recovered independence. In the 10 years after the initial impairment, 16% (CI, 14% to 18%) had 1 or more episodes of functional decline and 28% (CI, 26% to 30%) recovered from their initial impairment and remained independent throughout this period. The pattern of findings was similar for IADLs. Limitation: Functional status was self-reported. Conclusion: Functional impairment and decline are common in middle age, as are transitions from impairment to independence and back again. Because functional decline in older adults has similar features, current interventions used for prevention in older adults may hold promise for those in middle age. Primary Funding Source: National Institute on Aging and National Center for Advancing Translational Sciences through the University of California, San Francisco, Clinical and Translational Sciences Institute. PMID- 29132152 TI - Diagnostic Accuracy of Screening Tests and Treatment for Post-Acute Coronary Syndrome Depression: A Systematic Review. AB - Background: Patients who have had an acute coronary syndrome (ACS) event have an increased risk for depression. Purpose: To evaluate the diagnostic accuracy of depression screening instruments and to compare safety and effectiveness of depression treatments in adults within 3 months of an ACS event. Data Sources: MEDLINE, EMBASE, PsycINFO, CINAHL, and Cochrane Database of Systematic Reviews from January 2003 to August 2017, and a manual search of citations from key primary and review articles. Study Selection: English-language studies of post ACS patients that evaluated the diagnostic accuracy of depression screening tools or compared the safety and effectiveness of a broad range of pharmacologic and nonpharmacologic depression treatments. Data Extraction: 2 investigators independently screened each article for inclusion; abstracted the data; and rated the quality, applicability, and strength of evidence. Data Synthesis: Evidence from 6 of the 10 included studies showed that a range of depression screening instruments produces acceptable levels of diagnostic sensitivity, specificity, and negative predictive values (70% to 100%) but low positive predictive values (below 50%). The Beck Depression Inventory-II was the most studied tool. A large study found that a combination of cognitive behavioral therapy (CBT) and antidepressant medication improved depression symptoms, mental health-related function, and overall life satisfaction more than usual care. Limitation: Few studies, no evaluation of the influence of screening on clinical outcomes, and no studies addressing several clinical interventions of interest. Conclusion: Depression screening instruments produce diagnostic accuracy metrics that are similar in post-ACS patients and other clinical populations. Depression interventions have an uncertain effect on cardiovascular outcomes, but CBT combined with antidepressant medication produces modest improvement in psychosocial outcomes. Primary Funding Source: Agency for Healthcare Research and Quality (PROSPERO: CRD42016047032). PMID- 29132154 TI - Patients Contributing to Their Doctors' Notes: Insights From Expert Interviews. PMID- 29132153 TI - Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study. AB - Background: Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. Objective: To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice. Design: Retrospective cohort. Setting: National U.S. Food and Drug Administration Sentinel network. Patients: Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014. Measurements: Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score-matched patients starting treatment with dabigatran or warfarin. Results: Among 25 289 patients starting dabigatran therapy and 25 289 propensity score-matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran. Limitation: Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values). Conclusion: In matched adults with atrial fibrillation treated in practice, the incidences of stroke and bleeding with dabigatran versus warfarin were consistent with those seen in trials. The possible relationship between dabigatran and myocardial infarction warrants further investigation. Primary Funding Source: U.S. Food and Drug Administration. PMID- 29132146 TI - Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies. PMID- 29132155 TI - Functional Impairment and Decline in Middle Age. PMID- 29132156 TI - Low-Dose Aspirin to Reduce the Risk for Myocardial Infarction Among Patients With Coronary Stents Undergoing Noncardiac Surgery. PMID- 29132157 TI - Bringing Data to Life: Interactive Visualizations of Complex Data. PMID- 29132158 TI - Do the Tenets of Late-Life Disability Apply to Middle Age? PMID- 29132160 TI - A New Chapter in Patient-Centered Care: Sharing the Medical Note? PMID- 29132159 TI - Aspirin in Patients With Previous Percutaneous Coronary Intervention Undergoing Noncardiac Surgery. AB - Background: Uncertainty remains about the effects of aspirin in patients with prior percutaneous coronary intervention (PCI) having noncardiac surgery. Objective: To evaluate benefits and harms of perioperative aspirin in patients with prior PCI. Design: Nonprespecified subgroup analysis of a multicenter factorial trial. Computerized Internet randomization was done between 2010 and 2013. Patients, clinicians, data collectors, and outcome adjudicators were blinded to treatment assignment. (ClinicalTrials.gov: NCT01082874). Setting: 135 centers in 23 countries. Patients: Adults aged 45 years or older who had or were at risk for atherosclerotic disease and were having noncardiac surgery. Exclusions were placement of a bare-metal stent within 6 weeks, placement of a drug-eluting stent within 1 year, or receipt of nonstudy aspirin within 72 hours before surgery. Intervention: Aspirin therapy (overall trial, n = 4998; subgroup, n = 234) or placebo (overall trial, n = 5012; subgroup, n = 236) initiated within 4 hours before surgery and continued throughout the perioperative period. Of the 470 subgroup patients, 99.9% completed follow-up. Measurements: The 30-day primary outcome was death or nonfatal myocardial infarction; bleeding was a secondary outcome. Results: In patients with prior PCI, aspirin reduced the risk for the primary outcome (absolute risk reduction, 5.5% [95% CI, 0.4% to 10.5%]; hazard ratio [HR], 0.50 [CI, 0.26 to 0.95]; P for interaction = 0.036) and for myocardial infarction (absolute risk reduction, 5.9% [CI, 1.0% to 10.8%]; HR, 0.44 [CI, 0.22 to 0.87]; P for interaction = 0.021). The effect on the composite of major and life-threatening bleeding in patients with prior PCI was uncertain (absolute risk increase, 1.3% [CI, -2.6% to 5.2%]). In the overall population, aspirin increased the risk for major bleeding (absolute risk increase, 0.8% [CI, 0.1% to 1.6%]; HR, 1.22 [CI, 1.01 to 1.48]; P for interaction = 0.50). Limitation: Nonprespecified subgroup analysis with small sample. Conclusion: Perioperative aspirin may be more likely to benefit rather than harm patients with prior PCI. Primary Funding Source: Canadian Institutes of Health Research. PMID- 29132161 TI - A Research Agenda for High-Value Palliative Care. PMID- 29132163 TI - Optimized care in Patients with Rare Diseases: TSC at the Center for Rare Diseases (ZSEUKS) at Saarland University Medical Center, Germany. AB - Providing comprehensive medical care for patients with rare diseases is both challenging and rewarding. We will give a short summary of the most relevant medical issues pertinent to this subject, and will illustrate some of these issues by sharing our experience in the care of patients with TSC disease. PMID- 29132166 TI - Congenital Transcobalamin II Deficiency: A Rare Entity with a Broad Differential. PMID- 29132164 TI - Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms. AB - Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in RUNX1 and genes of the RAS pathway appeared more instrumental in the pathogenesis of FA myeloid malignancies. RUNX1 mutations were associated with more advanced disease. Interestingly, one patient with refractory anemia with ring sideroblasts harbored the SF3B1 p.K700E mutation highlighting the mutation's causative role in MDS with ring sideroblasts even in the context of FA. On the whole, our findings implicate a different genetic architecture of FA MDS/AML from adult sporadic MDS. Notably, the genetic events resemble those described in pediatric MDS. PMID- 29132165 TI - IVH in VLBW Preterm Babies - Therapy with Recombinant Activated F VII? AB - Backround Intraventricular hemorrhage (IVH) remains a dangerous and frequent complication in very low birth weight (VLBW) infants. Activated factor VII (aFVII) activates the coagulation cascade and is a potential tool for stopping active bleeding, including limiting the extent of an IVH. This retrospective treatment observation compared data for infants with IVH progression treated with fresh frozen plasma (FFP) alone or with a combination of FFP and aFVII. Methods/Intervention All infants were subject to cranial ultrasonography at least twice daily. When an IVH was detected, treatment with FFP (5-20 ml/kg every 4-6 h) was commenced and the parents were informed. If the parents endorsed aFVII treatment and the IVH showed progress, aFVII (30-50 ug/kg body weight 4-6 times within 16-24 h) was given. Otherwise, infants were treated with FFP only. We compared the course of IVH between the aFVII+FFP treated infants and a control group (FFP only). Results 35 patients throughout were included in the analysis (17 control and 18 aFVII group). Demographic data was not different between groups. The progress of IVH was significantly less in the aFVII group (p<0.01). During the hospital stay, 2 of the infants in the aFVII group died compared to 4 in the control group. A posthemorrhagic hydrocephalus developed in 3 aFVII and 6 control infants. All other outcome parameters and follow-up-results 2 years after treatment did not differ significantly. Conclusion These data show that in the case of a progressing IVH, aFVII may be a candidate for limiting its extent. A prospective randomized trial is warranted. PMID- 29132162 TI - What Recent History Has Taught Us About Responding to Emerging Infectious Disease Threats. AB - Presidential administrations face any number of unexpected crises during their tenure, and global pandemics are among the most challenging. As of January 2017, one of the authors had served under 5 presidents as the director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. During each administration, the government faced unexpected pandemics, ranging from the HIV/AIDS pandemic, which began during the Reagan administration, to the recent Zika outbreak in the Americas, which started during the Obama administration. These experiences underscored the need to optimize preparation for and response to these threats whenever and wherever they emerge. This article recounts selected outbreaks occurring during this period and highlights lessons that were learned that can be applied to the infectious disease threats that will inevitably be faced in the current presidential administration and beyond. PMID- 29132167 TI - Smoldering Development of Acute Megakaryoblastic Leukemia with Clonal Evolution in an Infant without Down Syndrome. PMID- 29132168 TI - Nachruf fur Prof. Dr. Enno Kleihauer. PMID- 29132170 TI - Thyroid Dysfunction States and Incident Cardiovascular Events: The Tehran Thyroid Study. AB - The objective of the study was to investigate the relation of different thyroid function states with the incidence of cardiovascular disease (CVD)/coronary heart disease (CHD) among a Middle-Eastern population with a high incidence of CVD/CHD. A total of 3975 participants entered the study (43.6% men). According to their thyroid stimulating hormone (TSH) and free thyroxin (FT4) levels, the participants were categorized into 5 groups: euthyroid, subclinical hypothyroidism, overt hypothyroidism, subclinical hyperthyroidism, and overt hyperthyroidism. Multivariable Cox proportional hazard models were used to assess the relation of different thyroid function states with incident CVD/CHD, with euthyroid state as reference. The mean age (SD) of the participants was 46.5 (12.0) years. At baseline, no significant difference was observed in the frequency of prevalent CVD cases (n=201) between all groups. No significant interaction was found between prevalent CVD and different thyroid function states with outcomes, hence, we did not exclude participants with prevalent CVD from data analysis. A total of 400 CVD events (358 CHD cases) during a median follow up of 11.2 years (inter-quartile range: 1.96) occurred. During the follow-up, even in the age and sex adjusted model, no association was observed between different states of thyroid dysfunction and incidence of CVD/CHD. The multivariable hazard ratios (95% CI) of subclinical hypothyroidism, hypothyroidism, subclinical hyperthyroidism, and hyperthyroidism for CVD events were 1.21 (0.77-1.88), 0.76 (0.33-1.69), 0.81 (0.46-1.41) and 1.48 (0.70-3.16), respectively. Both at baseline and during follow-up, no relation was observed between different states of thyroid function with prevalence and incidence of CVD/CHD. PMID- 29132169 TI - Anterior Cervical Decompression and Fusion or Posterior Foraminotomy for Cervical Radiculopathy: Results of a Single-Center Series. AB - BACKGROUND: Anterior cervical diskectomy and fusion (ACDF) or posterior foraminotomy (PF) are standard treatment options for cervical radiculopathy due to disk prolapse. Which method produces superior results has not yet been established. One reason for the dilemma, among others, is a lack of detailed outcome analysis in previous studies. We quantified outcome to compare both methods in our retrospective single-center series. METHOD: We conducted a retrospective analysis of 107 patients with cervical radiculopathy who were operated on via ACDF or via PF. Demographic data, symptoms, neurologic status, and pathology were recorded and correlated to outcome parameters such as Odom's criteria, visual analog scale values of radicular pain, Neck Disability Index values, and subjective satisfaction, which were also compared between both treatment groups. Intraoperative data, early and late complications, and reoperations were recorded and compared between both surgical groups. RESULTS: None of the recorded preoperative data were predictive for postoperative outcome parameters. Patients in the PF group reported better overall outcome (Odom's criteria) and greater relief of radicular and neck pain. Operative time and blood loss were less in the PF group. Both groups showed comparable early complication rates, but PF patients tended to have more late reoperations. CONCLUSION: Due to a better overall outcome as well as greater relief of radicular and neck pain in our cohort, we consider PF the first-line treatment if morphology of the pathology is suitable. PMID- 29132171 TI - Metabolic Endotoxemia-Activated Macrophages Promote Pancreatic beta Cell Death via IFNbeta-Xaf1 Pathway. AB - Metabolic endotoxemia has been implicated in the pathogenesis of type 2 diabetes. In addition to adipose tissue inflammation, inflammatory cell infiltration is also observed in islets, although its effect on islets is largely unknown. We hypothesized that macrophage infiltration into islets leads to impairment of alpha or beta cell function, which ultimately act to exacerbate the pathophysiology of diabetes. Gene expression in a murine alpha cell line, alphaTC1, and beta cell line, betaTC6, was investigated by DNA microarray after co-culturing the cells with a murine macrophage cell line, RAW 264.7, in the presence or absence of bacterial endotoxin. Among the genes showing highly upregulated expression, genes specifically upregulated only in beta cells were evaluated to determine the roles of the gene products on the cellular function of beta cells. In both alpha and beta cells, expression of type I interferon responsive genes was highly upregulated upon endotoxin stimulation. Among these genes, expression of the X-linked inhibitor of apoptosis (Xiap)-associated factor 1 (Xaf1) gene, which is associated with the induction of apoptosis, was specifically enhanced in beta cells by endotoxin stimulation. This upregulation appeared to be mediated by macrophage-derived interferon beta (IFNbeta), as endotoxin-stimulated macrophages produced higher amounts of IFNbeta, and exogenous addition of IFNbeta into betaTC6 cultures resulted in increased Xaf1 protein production and cleaved caspase 3, which accelerated beta-cell apoptosis. Macrophages activated by metabolic endotoxemia infiltrated into islets and produced IFNbeta, which induced beta-cell apoptosis by increasing the expression of Xaf1. PMID- 29132172 TI - Can Screening and Confirmatory Testing in the Management of Patients with Primary Aldosteronism be Improved? AB - Widespread application of the plasma aldosterone/renin ratio (ARR) as a screening test has led to the recognition that primary aldosteronism (PA) is the most common specifically treatable and potentially curable form of hypertension, accounting for 5-10% of patients. Maximal detection requires accurate diagnostic approaches and awareness and control of factors that confound results, including most antihypertensives, posture, time of day, dietary salt, and plasma potassium. Recent studies have revealed potential for false positives in patients on beta adrenoceptor blockers, and, when direct renin concentration (but not plasma renin activity) is used to measure renin, in women during the luteal phase of the menstrual cycle or receiving estrogen-containing contraceptives or hormonal replacement therapy. In addition to verapamil slow release, hydralazine and prazosin, moxonidine has minimal effects on the ARR and can be used to control hypertension during work-up. Fludrocortisone suppression testing, while probably the most reliable means of definitively confirming or excluding PA, is time consuming and expensive, requiring a five day inpatient stay. A novel approach, upright (seated) saline infusion suppression testing (SST), has shown excellent reliability with much greater sensitivity than conventional recumbent SST in a recent pilot study, and requires only a day visit. Accurate measurement of aldosterone is essential for each step of PA workup: introduction of new, highly reliable high-throughput mass spectrometric methods into clinical practice has represented a major advance. In response to concerns raised about accuracy of renin assays, new mass spectrometric methods for measuring angiotensin II are currently being assessed in the clinical setting. PMID- 29132173 TI - Premenstrual Syndrome Diagnosis: A Comparative Study between the Daily Record of Severity of Problems (DRSP) and the Premenstrual Symptoms Screening Tool (PSST). AB - OBJECTIVE: To validate the premenstrual symptoms screening tool (PSST) in relation to the daily record of severity of problems (DRSP) for premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) diagnoses. METHODS: A cross-sectional study with 127 women (20-45 years) with PMS complaints. The women were evaluated in terms of weight, height and body mass index (BMI). After using the primary care evaluation of mental disorders (PRIME-MD) questionnaire to exclude the diagnosis of depression, the PSST was completed and the women were instructed to fill out the DRSP for two consecutive menstrual cycles. The agreement between the two questionnaires was assessed by the Kappa (k) and the prevalence-adjusted, bias-adjusted kappa (PABAK) values. RESULTS: Two-hundred and eighty-two women met the eligibility criteria and answered the PSST. The DRSP was completed for two cycles by 127 women. The percentages of women with PMS and PMDD diagnoses by the DRSP were 74.8% and 3.9% respectively; by PSST, the percentages were41.7% and 34.6% respectively. The number of patients considered "normal" (with symptoms below the threshold for the diagnosis of PMS) was similar in both questionnaires. There was no agreement (Kappa = 0.12) in the results of PMS/ PMDD diagnosis (the PABAK coefficient confirmed this result = 0.39). The PSST had a high sensitivity (79%) and a low specificity (33.3%) for PMS/PMDD diagnosis. CONCLUSION: The PSST should be considered a diagnostic screening tool. Positive PMS/PMDD cases by PSST should be further evaluated by DRSP to confirm the diagnosis. PMID- 29132174 TI - Feasibility, safety, and diagnostic yield of the Extra Wide Angle View (EWAVE) colonoscope for the detection of colorectal lesions. AB - BACKGROUND AND STUDY AIMS: The adenoma detection rate (ADR) of conventional colonoscopy can still be improved. We conducted a prospective multicenter cohort study to assess the feasibility, safety, and diagnostic yield of the Extra Wide Angle View (EWAVE) colonoscope, which offers a 235 degrees view obtained from a forward-viewing and two lateral backward-viewing lenses incorporated into one image. PATIENTS AND METHODS: The study was performed between November 2015 and June 2016. EWAVE colonoscopy was performed in patients with an increased risk of colorectal cancer by experienced and EWAVE-trained endoscopists (>= 500 colonoscopies, >= 10 with the EWAVE system). RESULTS: A total of 193 patients underwent EWAVE colonoscopy. The cecal intubation rate was 97.4 %. EWAVE colonoscopy had a polyp detection rate (PDR) of 61.1 % (118 /193), ADR of 39.9 % (77 /193), and advanced ADR of 13.5 % (26 /193). No adverse events occurred. CONCLUSIONS: EWAVE colonoscopy is feasible and safe. The ADR appears comparable to those achieved with conventional colonoscopes in similar patient populations. To further elucidate the additional benefits of wide-angle-view colonoscopes, randomized trials would be required. PMID- 29132175 TI - Simethicone improves bowel cleansing with low-volume polyethylene glycol: a multicenter randomized trial. AB - BACKGROUND AND STUDY AIMS: For bowel preparation, using a reduced volume of polyethylene glycol (PEG) solution without influencing its effectiveness would be preferable. While simethicone shows great potential as an adjunctive agent, data on its use are limited. We aimed to clarify whether simethicone added to low volume PEG solution improved bowel cleansing. PATIENTS AND METHODS : Consecutive adult patients registered for colonoscopy were recruited from seven medical centers in South China between 15 April and 15 July 2015 and prospectively randomized into two groups: 2 L PEG (conventional group) and 2 L PEG plus simethicone (simethicone group). The primary endpoint was the effectiveness of bowel cleansing according to the Boston Bowel Preparation Scale (BBPS). Secondary endpoints included cecal intubation time, adenoma detection rate (ADR), patient safety and compliance, and adverse events. RESULTS : We included 290 and 289 patients in the conventional and simethicone groups, respectively, for analysis. The proportion with acceptable bowel cleansing (BBPS >= 6) was significantly higher in the simethicone group than in the conventional group (88.2 % vs. 76.6 %; P < 0.001). The mean (SD) BBPS score was significantly lower in the conventional group (6.5 [1.8] vs. 7.3 [1.7]; P < 0.001), as was the bubble score (2.5 [0.7] vs. 2.8 [0.5]; P < 0.001). The average cecal intubation time was significantly shorter in the simethicone group (6.3 [3.1] vs. 7.5 [5.1] minutes; P < 0.001). The ADR in the right colon was higher in the simethicone group than in the conventional group (16.6 % vs. 10.3 %; P = 0.03). Safety and compliance, including the taste, smell, and dosage of PEG, were similar for both groups. CONCLUSIONS: Simethicone added to low-volume PEG solution improves bowel cleansing efficacy, with similar safety and compliance, shorter cecal intubation time, and higher ADR. PMID- 29132176 TI - Verapamil (VER) Enhances the Cytotoxic Effects of Docetaxel and Vinblastine Combined Therapy Against Non-Small Cell Lung Cancer Cell Lines. AB - Lung cancer is one of the foremost tumor-associated cause of death in the world. Most of the patients with NSCLC possesses an advanced disease at diagnosis, and are thus probable subject for systemic therapy. This study aims to evaluate the cytotoxicity of vinblastine and docetaxel combined therapy for the treatment of NSCLC, as well as verapamil (VER) enhancement of the combined therapy. We conducted P-glycoprotein (P-gp) gene expression, protein expression with RT-PCR and western blot respectively, apoptotic response of the combined therapy with VER is also determined using DAPI staining (%). Result of DAPI staining confirmed combination therapy promotes cell apoptosis to greater extent as compared to each drug alone. Real-time RT-PCR analysis revealed that mdr-1 expression level increased 6 fold with docetaxel (40 nM) and 2 fold with vinblastine (30 nM) after 24 h (p<0.001). Consequently, combination therapy reduced drug-induced up regulation of mdr-1 significantly (p<0.05). VER with the drug combination increased P-gp expression (p<0.05). These data provide evidence showing combined therapy is a better approach to improve the efficacy of chemotherapy and decreasing drug resistance. PMID- 29132177 TI - An Insight on Silk Protein Sericin: From Processing to Biomedical Application. AB - Silks are naturally occurring polymers that have been used clinically as sutures for hundreds of years. It's so for obtained from insects or worms, silk consists of a filament core protein, termed fibroin, and a glue-like coating made up of sericin proteins. An important component of silk has an extended history of being discarded as a waste in the course of silk processing. The cost of sericin for tissue engineering is underestimated and its capability in using as regenerative remedy has simply began to be explored. Its variable amino acid composition and various functional groups confer upon it attractive bioactive proteins, which are particularly interesting for biomedical programs. Because of its antioxidant properties, moisturizing ability, and mitogenic effect on mammalian cells, sericin is beneficial in cell regeneration and tissue engineering. Research shows that keratinocytes and fibroblasts have brought about the improvement of sericin primarily based biomaterials for skin tissue repair, in particular as wound dressings. Moreover, sericin may be used for bone tissue engineering due to its ability to set off nucleation of bone-like hydroxyapatite. Stable silk sericin biomaterials, as films, sponges, and hydrogels, are obtained by means of cross linking, ethanol precipitation, or mixing with different polymers. Now a day, sericin may also be used for delivery of drugs due to its chemical reactivity and pH-responsiveness which facilitate the fabrication of nano and microparticles, hydrogels, and conjugated molecules, enhancing the bioactivity of drugs. In this review, we outlined the current headways from extraction of sericin till its physical properties and biomedical applications. PMID- 29132178 TI - Patterns of Systemic and Cervicovaginal Fluid Inflammatory Cytokines throughout Pregnancy. AB - OBJECTIVE: This study describes the normal variations in serum and cervicovaginal fluid (CVF) cytokine levels throughout pregnancy. STUDY DESIGN: This multicenter, prospective study examined trimester-specific maternal serum and CVF cytokines (interleukin [IL]-1alpha, IL-1beta, IL-6, IL-8, IL-10, tumor necrosis factor-alpha, and C-reactive protein [CRP]). A two-factor linear mixed modeling approach compared cytokine distribution, while pairwise comparisons evaluated differences over time. RESULTS: Trimester-specific serum cytokine data were available for 288, 243, and 221 patients, whereas CVF cytokine data were available for 273, 229, and 198 patients. CVF had significantly higher concentrations of IL-1alpha, IL-1beta, IL-6, IL-8, and matrix metalloproteinase-8 (p < 0.001), irrespective of the trimester. At all time points, IL-10 and CRP concentrations were higher in serum than CVF (p < 0.001). Serum IL-10 increased significantly throughout pregnancy (p < 0.001). CONCLUSION: Differences in cytokine distribution across different biological fluids are evident throughout pregnancy. These findings provide a framework for examining patterns of changes in cytokines throughout pregnancy. PMID- 29132179 TI - Comparative Study of the Effects of Continuous Positive Airway Pressure and Nasal High-Flow Therapy on Diaphragmatic Dimensions in Preterm Infants. AB - OBJECTIVE: Nasal continuous positive airway pressure (nCPAP) and nasal high-flow therapy (nHFT) are the most common forms of noninvasive respiratory support in preterm infants. We conducted this study to compare effects of nCPAP and nHFT on diaphragmatic dimensions as assessed by bedside ultrasonography in preterm infants. STUDY DESIGN: A prospective, randomized crossover study comprised 24 preterm infants. Group 1 (n = 12): started on nCPAP for 60 minutes and then switched to nHFT for 60 minutes. Group 2 (n = 12): started on nHFT for 60 minutes then switched to nCPAP for 60 minutes. Ultrasonographic assessment of diaphragmatic dimensions was performed at the end of each epoch. RESULTS: There were no statistically significant differences in diaphragmatic dimensions at the end of each epoch of nCPAP or nHFT. The diaphragm thickening fraction (DTF) was not significantly different with either nCPAP or nHFT [23.4 (13.7-28.0) versus 23.4 (11.2-31.6), p = 0.57]. No significant differences were found regarding heart rate, respiratory rate, Silverman-Anderson scores, and SpO2 on nCPAP and nHFT. All infants enrolled tolerated the crossover maneuver. CONCLUSION: Stable preterm infants (30.3 +/- 2.2 weeks' gestation) with mild respiratory dysfunction show comparable effects on diaphragm thickness and excursion during relatively brief periods of support on nCPAP or nHFT. CLINICAL TRIAL REGISTRATION: Registry name: Clinical Trials.gov. Registration number: NCT02421328. Web link to study on registry: https://clinicaltrials.gov/ct2/show/NCT02421328. PMID- 29132181 TI - Protective Effects of Quercetin on Necrotizing Enterocolitis in a Neonatal Rat Model. AB - INTRODUCTION: Necrotizing enterocolitis (NEC) is one of the major health problems of newborn period. To date, a large amount of chemicals have been tested for NEC and some showed limited beneficial effects. The research for better results still continues. This study aims to investigate the effects of quercetin (QE) on NEC treatment in rats. METHODS: Newborn rats were divided into control, NEC, and NEC + QE groups. In NEC and NEC + QE groups, experimental NEC was induced. NEC + QE group animals were also given QE. Weight changes of the animals were recorded, and serum total antioxidant status (TAS), total oxidant status (TOS), malondialdehyde (MDA), and glutathione (GSH) levels were measured. Histologic evaluation of the distal ileum and the terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. RESULTS: A significant increase in the TAS levels was observed in NEC + QE group. Only NEC group exhibited significantly higher TOS and MDA levels and lower GSH levels. Rats in the NEC + QE group had better histopathology and less apoptosis than NEC group. CONCLUSION: QE is effective in enhancing antioxidant defense mechanism, limiting oxidative stress, reducing intestinal damage, and preventing NEC development. PMID- 29132180 TI - Health Care Utilization after NICU Discharge and Neurodevelopmental Outcome in the First 2 Years of Life in Preterm Infants. AB - OBJECTIVE: The objective of this study was to determine predictors of health care utilization and its association with neurodevelopmental outcome in a recent cohort of preterm infants. STUDY DESIGN: A total of 405 infants (born 2008-2011) seen in neonatal intensive care unit (NICU) follow-up were compared for use of hospitalizations (hosps), emergency room (ER), subspecialties (SS), and results of the Bayley-III. High rate of use was defined as having >1 hosp, ER, or SS. Multiple regression adjusted for the effect of risk factors on high health care use. RESULTS: High hosp rate was associated with public health insurance (PHI; p = 0.021), severely abnormal head ultrasound (SAHUS; p = 0.04) at 1 year, and PHI (p = 0.011), younger gestational age (GA) (p = 0.029) at 2 years. High ER use was associated with PHI, younger GA at 1 year (p = 0.007 and 0.012) and 2 years (p = 0.010 and 0.005). High SS was associated with NICU morbidities including small for GA (p = 0.005), retinopathy of prematurity (p = 0.001), necrotizing enterocolitis (p = 0.03), and SAHUS (p = 0.045). At 20 months, infants with high hosp and SS had higher rates of cerebral palsy and significantly lower mean cognitive, language, and motor scores. CONCLUSION: Health care utilization is high among preterm infants in recent years and significantly associated with worse neurodevelopmental outcome. Further research is needed to determine if health care utilization after NICU discharge is an independent predictor of poor outcome. PMID- 29132182 TI - [Rare case of a blunt cervical sports-related trauma in a young patient]. PMID- 29132183 TI - [Editor's Comment]. PMID- 29132184 TI - [Not Available]. PMID- 29132185 TI - [Not Available]. PMID- 29132186 TI - [Not Available]. PMID- 29132187 TI - ? PMID- 29132188 TI - [Hearing Loss and Speech Recognition in the Elderly]. AB - Elderly people often complain about poor speech understanding in noisy environments. In clinical practice, speech tests under noise conditions are used to examine hearing ability. The HORSTAT study, conducted on a population-based random sample consisting of 1903 adults, used the Goettingen Sentence Test (GOSA) under noise conditions along with pure-tone audiometry. Hearing impairment was defined as pure-tone average at 0.5, 1, 2 and 4 kHz (PTA-4) greater than 25 dB HL in the better ear (WHO criterion). As expected, pure-tone thresholds and speech recognition thresholds (SRT) in GOSA worsened steadily with age. For a comparison of PTA-4, SRTGOSA and self-reported hearing, analysis was limited to 553 adults aged 60-85 years with PTA-4 below 50 dB HL and SRTs measured with a constant 65 dB SPL noise level. The percentage of hearing-impaired increased from 13 % in the 60-65 year-old people to 60 % in those aged 80-85 years. Overall, 68 % of the 60 85 years adults showed normal hearing in terms of unimpaired hearing according to the WHO criterion. The SRTGOSA of 66 % of the elderly adults with normal hearing, however, did not lie within the reference range established with young normal hearing subjects in the HORSTAT study (4.8 +/- 1.8 dB SNR, mean+/-2 * standard deviation). Among the 553 elderly, only 24 % reached this reference range. PTA-4 and SRTGOSA results showed moderate to good correlations (Pearson r = 0.562, within 5-years bands: 0.372-0.514). From PTA-4 >= 30 dB HL and SRTGOSA >=- 2 dB SNR, respectively, more than half of the subjects reported hearing difficulties. Despite the continuous decline of PTA-4 and SRTGOSA with age, the proportion of self-reported hearing difficulties as well as the self-rated hearing ability score stagnated. From the age of 70 years onwards, the elderly in the HORSTAT sample tend to overestimate their hearing abilities and to underestimate their difficulties. PMID- 29132189 TI - [From the Expert's Office: Examination of Bell's palsy in consideration of the Austrian private accident insurance]. PMID- 29132191 TI - ? PMID- 29132190 TI - [Not Available]. PMID- 29132192 TI - ? PMID- 29132193 TI - Impact of supervised student optometry consultations on the patient experience. AB - BACKGROUND: Understanding patient perceptions of having students involved in their clinical care is important as we strive to develop optimal models of care that integrate teaching with the best possible experience for the patient. The aim was to ascertain the impact of supervised optometry student consultations on the patient experience. METHODS: A survey comprising 45 questions was mailed to consecutive adult patients who had undergone a comprehensive eye examination at the Australian College of Optometry over a four-week period. RESULTS: Responses were received from 193 patients who had a student involved in their care (44 per cent response rate; 156 completed correctly) and 177 who did not have a student involved (32 per cent response rate; 105 completed correctly). There was no significant difference in overall patient satisfaction between the teaching and non-teaching clinics (p = 0.18). Over 87 per cent of patients in the teaching clinic felt completely comfortable with a student examining them, 44 per cent felt their care was better because a student was involved and 97 per cent rated the overall performance of the student as very good or good. Although 12 per cent would rather have seen only the optometrist and three per cent would not be happy to have a student involved in their eye care again, 100 per cent believed it is important for students to work with patients. The most common reason for student acceptance was the importance of students needing opportunities to learn. The main reasons for unwillingness to have a student involved in future were the additional time taken and prolonged testing. CONCLUSIONS: The findings of this study suggest that most patients view supervised student involvement in their optometric care as an important and highly positive experience. However, efforts should be made to avoid excessively long consultations and prolonged testing. Concerns about patient satisfaction and acceptance are largely unwarranted and should not prevent optometry students being involved in patient care. PMID- 29132194 TI - Development of a surgical trainer assessment questionnaire. AB - BACKGROUND: The assessment of surgical trainees has become well-established in practice; however, this is not yet the case for surgical trainers. The aim of this study was to develop a trainer assessment questionnaire (OxTrAQ) based on the 12 key trainer attributes identified by a previous systematic review, to then explore this questionnaire's potential domains and test its reliability. METHODS: The OxTrAQ was piloted at two surgical training centres in two surgical sub specialities. At each centre, every trainee assessed every trainer while under their clinical supervision. RESULTS: Internal consistency (Cronbach's alpha) was calculated for this 12-item questionnaire as 0.958. Factor analysis revealed two domains which accounted for 77.997% of the variance; these were the general domain (nine items) and the independence domain (three items). Inter-observer reliability was shown by the intraclass correlation coefficients (ICCs) (average measures) for the overall OxTrAQ score, general domain score and independence domain score which were 0.951, 0.945 and 0.955 for centre 1 and 0.857, 0.819 and 0.883 for centre 2, respectively. Intra-observer reliability was shown by the ICCs (average measures) for the overall OxTrAQ score, general domain score and independence domain score which were 0.925, 0.913 and 0.940, respectively. Construct validity was demonstrated by a high correlation (Spearman rho = 0.886, P = 0.019) between trainer scores and the scores predicted by the trainers themselves. CONCLUSIONS: The OxTrAQ is a simple trainer assessment questionnaire which has demonstrated both high inter- and intra-observer reliability. PMID- 29132195 TI - Current evidence for the use of N-acetylcysteine following liver resection. AB - BACKGROUND: N-acetylcysteine (NAC) has many uses in medicine; notable in the management of paracetamol toxicity, acute liver failure and liver surgery. The aim of this review was to critically appraise the published literature for the routine use of NAC in liver resection surgery. METHODS: An electronic search was performed of EBSCOhost (Medline and CINAHL database), PubMed and the Cochrane Library for the period 1990-2016. MeSH headings: 'acetyl-cysteine', 'liver resection' and 'hepatectomy' were used to identify all relevant articles published in English. RESULTS: Following the search criteria used, three articles were included. Two of these studies were randomized controlled trials. All the studies collated data on morbidity and mortality. All three studies did not show a significant difference in overall complications rates in patients that underwent hepatic resection that had NAC infusion compared with patients that did not. In one study, NAC administration was associated with a higher frequency of grade A post-hepatectomy liver failure. In another study, a significantly higher incidence of delirium was observed in the NAC group, which led to the trial to be terminated early. CONCLUSION: The current published data do not support the routine use of NAC following liver resection. PMID- 29132196 TI - Carotid endarterectomy: the change in practice over 11 years in a stroke centre. AB - BACKGROUND: Recent research evidence has impacted the practice of carotid endarterectomy (CEA). We aim to characterize changes in the practice and outcome of CEA over time in a single large-volume stroke centre. METHODS: All patients who underwent CEA from 2004 to 2014 and carotid angioplasty and stenting (CAS) from 2003 to 2008 at an Australian metropolitan tertiary stroke centre hospital were included. Clinical data were analysed to identify time trends in choice of intervention, patient selection, preoperative imaging utilization, surgical timing and outcome. RESULTS: There were 510 CEAs performed during 2004-2014 and 95 CASs during 2003-2008. The proportion of patients undergoing CEA compared to CAS increased from 60% to 90% from 2004 to 2008 (P < 0.001). CAS patients were more likely to have cardiac co-morbidities. From 2004 to 2014, the proportion of CEA patients aged >=80 years increased (P = 0.001) and the proportion of asymptomatic patients decreased (P = 0.003) over time. Median time from symptom onset to surgery decreased from 52 days (Q1: 25, Q3: 74) in 2004 to 8 days (Q1: 5, Q3: 37) in 2014 (P < 0.001). Use of preoperative ultrasonography decreased whilst CT angiography and the number of imaging modalities applied to each patient increased over time (P < 0.001). Overall, 5.9% of CEAs were complicated by death, stroke or acute myocardial infarction with no significant change over time. CONCLUSION: The trends in CEA practice at our centre align with international trends and guidelines. This study provides a representative indicator of Australian hospital practice, and illustrates how evidence from research is translated into clinical care. PMID- 29132201 TI - Malignant intercostal psammomatous melanotic schwannoma in a patient with Carney complex. PMID- 29132203 TI - Coexistence of metastatic thyroid cancer and tuberculosis in a single neck lymph node: a rare association. PMID- 29132199 TI - Non-fasting triglyceride levels in the Korean population with and without ischemic heart disease and cerebrovascular disease. AB - Background/Aims: Associations between non-fasting triglyceride (TG) levels and a risk of ischemic heart disease (IHD) and cerebrovascular accident (CVA) have been suggested in Caucasians. We aimed to investigate whether non-fasting TG levels reflect the risk of IHD/CVA in Koreans. Methods: We conducted an analysis of patients aged >= 30 years from the nationwide survey database. Fasting TG was defined as a measurement taken >= 12 hours since the last meal. Non-fasting TG was categorized by fasting duration of 0 to 3, 4 to 7, and 8 to 11 hours. Results: In subjects without history of IHD/CVA, diabetes, or lipid-lowering medication, the TG level was significantly elevated for 7 hours in men compared to fasting TG levels (p = 0.011); the mean TG levels were 154.9 mg/dL (standard error [SE], 13.0), 177.0 mg/dL (SE, 12.1), 148.8 mg/dL (SE, 2.8), and 141.5 mg/dL (SE, 1.4) for 0 to 3, 4 to 7, 8 to 11, and >=12 hours' fasting, respectively. In women, there was no difference in TG level according to fasting duration after adjustment for confounders. In men without diabetes, the TG level from 4 to 7 hours' fasting showed a significant difference between subjects with or without IHD/CVA even after adjustments for age, body mass index, lipid medication, exercise, and dietary factors (215.1 mg/dL vs. 177.3 mg/dL, p < 0.001). Conclusions: In men, non-fasting TG levels from 4 to 7 hours' fasting were significantly associated with IHD/CVA, and were superior to fasting TG levels level in the significant association with the history of IHD or CVA. PMID- 29132202 TI - Acute gastric dilatation and ischemia associated with portal vein gas caused by binge eating. PMID- 29132206 TI - Study Break: Streptokinase for Treatment of Thrombotic Disorders: The End? Or the End of the Beginning? PMID- 29132200 TI - Expression and prognostic significance of microRNAs in Korean patients with myelodysplastic syndrome. AB - Background/Aims: Various alterations of microRNA (miRNA) expression have been reported in myelodysplastic syndrome (MDS). We aimed to investigate the unique patterns and prognostic significance of miRNA expression in Korean patients with MDS. Methods: Bone marrow mononuclear cells were collected from eight healthy controls and 26 patients with MDS, and miRNAs were isolated and assessed via quantitative real-time polymerase chain reaction for selected miRNAs, including miR-21, miR-124a, miR-126, miR-146b-5p, miR-155, miR-182, miR-200c, miR-342-5p, miR-708, and Let-7a. Results: MiR-124a, miR-155, miR-182, miR-200c, miR-342-5p, and Let-7a were significantly underexpressed in patients with MDS, compared to healthy controls. MiR-21, miR-126, 146b-5p, and miR-155 transcript levels were significantly lower in international prognostic scoring system lower (low and intermediate-1) risk MDS than in higher (intermediate-2 and high) risk MDS. Higher expression levels of miR-126 and miR-155 correlated with significantly shorter overall survival and leukemia-free survival. Higher miR-124a expression also tended to be related to shorter survivals. Conclusions: Although our study was limited by the relatively small number of patients included, we identified several miRNAs associated with pathogenesis, leukemic transformation, and prognosis in MDS. PMID- 29132198 TI - Clinical features of snoring patients during sedative endoscopy. AB - Background/Aims: Snoring is the sound of turbulence and vibration of the upper respiratory tissues and has been identified as a risk factor of obstructive sleep apnea (OSA) and cardiovascular disease. The aim of this study was to identify associated clinical factors in snoring patients undergoing sedative endoscopy. Methods: A total of 49 patients who snored during standard sedative endoscopy and 127 controls were prospectively enrolled from June 2015 to June 2016. The Korean version of the Berlin Questionnaire was used to identify risk factors of OSA. Clinical information, including comorbidities, was collected from electronic medical records. Results: The snoring group showed a higher risk of OSA (42.9% vs. 26.8%, p = 0.039), and a higher prevalence of coronary artery disease (10.2% vs. 0.8%, p = 0.007) and advanced gastric cancer (12.2% vs. 2.4%, p = 0.015) compared with the control group. Multivariate analysis showed that coronary artery disease (odds ratio [OR], 13.93; 95% confidence interval [CI], 1.24 to 155.90; p = 0.033) and advanced gastric cancer (OR, 5.21; 95% CI, 1.01 to 26.98; p = 0.049) were significantly associated with snoring. However, a history of gastrectomy showed only a marginally significant association with snoring (OR, 2.16; 95% CI, 0.91 to 5.11; p = 0.079). Conclusions: Patients who snore during sedative endoscopy may need to be evaluated for possible coronary artery disease. PMID- 29132204 TI - Complete cure of advanced hepatocellular carcinoma with right adrenal gland metastasis and portal vein thrombosis by multiple applications of an interdisciplinary therapy: case report with 8-year follow up. AB - Hepatocellular carcinoma (HCC) is the sixth most common cause of death worldwide and the main cause of primary liver cancer. The principle problem of HCC is the poor prognosis, since advanced HCC reportedly has a median survival of only 9 months. The standard therapies are sorafenib and regorafenib, but the outcomes remain unclear. We report a 60-year-old man with advanced HCC with right adrenal gland metastasis and portal vein tumor thrombosis, who showed a complete response to multiple applications of an interdisciplinary therapy. PMID- 29132197 TI - Humanized Mice for the Evaluation of Francisella tularensis Vaccine Candidates. AB - Francisella tularensis (FT), a highly infectious pathogen, is considered to be a potential biological weapon owing to the current lack of a human vaccine against it. Tul4 and FopA, both outer membrane proteins of FT, play an important role in the bacterium's immunogenicity. In the present study, we evaluated the immune response of mice-humanized with human CD34+ cells (hu-mice)-to a cocktail of recombinant Tul4 and FopA (rTul4 and rFopA), which were codon-optimized and expressed in Escherichia coli. Not only did the cocktail-immunized hu-mice produce a significant human immunoglobulin response, they also exhibited prolonged survival against an attenuated live vaccine strain as well as human T cells in the spleen. These results suggest that the cocktail of rTul4 and rFopA had successfully induced an immune response in the hu-mice, demonstrating the potential of this mouse model for use in the evaluation of FT vaccine candidates. PMID- 29132207 TI - Ultraflat, Pristine, and Robust Carbon Electrode for Fast Electron-Transfer Kinetics. AB - Electron-beam (e-beam) deposition of carbon on a gold substrate yields a very flat (0.43 nm of root-mean-square roughness), amorphous carbon film consisting of a mixture of sp2- and sp3-hybridized carbon with sufficient conductivity to avoid ohmic potential error. E-beam carbon (eC) has attractive properties for conventional electrochemistry, including low background current and sufficient transparency for optical spectroscopy. A layer of KCl deposited by e-beam to the eC surface without breaking vacuum protects the surface from the environment after fabrication until dissolved by an ultrapure electrolyte solution. Nanogap voltammetry using scanning electrochemical microscopy (SECM) permits measurement of heterogeneous standard electron-transfer rate constants (k degrees ) in a clean environment without exposure of the electrode surface to ambient air. The ultraflat eC surface permitted nanogap voltammetry with very thin electrode-to substrate gaps, thus increasing the diffusion limit for k degrees measurement to >14 cm/s for a gap of 44 nm. Ferrocene trimethylammonium as the redox mediator exhibited a diffusion-limited k degrees for the previously KCl-protected eC surface, while k degrees was 1.45 cm/s for unprotected eC. The k degrees for Ru(NH3)63+/2+ increased from 1.7 cm/s for unprotected eC to above the measurable limit of 6.9 cm/s for a KCl-protected eC electrode. PMID- 29132205 TI - Secretome of Aggregated Embryonic Stem Cell-Derived Mesenchymal Stem Cell Modulates the Release of Inflammatory Factors in Lipopolysaccharide-Induced Peripheral Blood Mononuclear Cells AB - Background: Bone marrow mesenchymal stem cells (BM-MSCs) have emerged as a potential therapy for various inflammatory diseases. Because of some limitations, several recent studies have suggested the use of embryonic stem cell-derived MSCs (ESC-MSCs) as an alternative for BM-MSCs. Some of the therapeutic effects of the ESC-MSCs are related to the secretion of a broad array of cytokines and growth factors, known as secretome. Harnessing this secretome for therapeutic applications requires the optimization of production of secretary molecules. It has been shown that aggregation of MSCs into 3D spheroids, as a preconditioning strategy, can enhance immunomodulatory potential of such cells. In this study, we investigated the effect of secretome derived from human ESC-MSCs (hESC-MSCs) spheroids on secretion of IL-1beta, IL-10, and tumor necrosis factor alpha (TNF alpha) from lipopolysaccharide (LPS)-induced peripheral blood mononuclear cells (PBMCs). Methods: In the present study, after immunophenotyping and considering mesodermal differentiation of hESC-MSCs, the cells were non-adherently grown to prepare 3D aggregates, and then conditioned medium or secretome was extracted from the cultures. Afterwards, the anti-inflammatory effects of the secretome were assessed in an in vitro model of inflammation. Results: Results from this study showed that aggregate-prepared secretome from hESC-MSCs was able to significantly decrease the secretion of TNF-alpha (301.7 +/- 5.906, p < 0.0001) and IL-1beta (485.2 +/- 48.38, p < 0.001) from LPS-induced PBMCs as the indicators of inflammation, in comparison with adherent culture-prepared secretome (TNF-alpha: 166.6 +/- 8.04, IL-1beta: 125.2 +/- 2.73). Conclusion: Our study indicated that cell aggregation can be an appropriate strategy to increase immunomodulatory characteristics of hESC-MSCs. PMID- 29132208 TI - Organic Chemical Characterization and Mass Balance of a Hydraulically Fractured Well: From Fracturing Fluid to Produced Water over 405 Days. AB - A long-term field study (405 days) of a hydraulically fractured well from the Niobrara Formation in the Denver-Julesburg Basin was completed. Characterization of organic chemicals used in hydraulic fracturing and their changes through time, from the preinjected fracturing fluid to the produced water, was conducted. The characterization consisted of a mass balance by dissolved organic carbon (DOC), volatile organic analysis by gas chromatography/mass spectrometry, and nonvolatile organic analysis by liquid chromatography/mass spectrometry. DOC decreased from 1500 mg/L in initial flowback to 200 mg/L in the final produced water. Only ~11% of the injected DOC returned by the end of the study, with this 11% representing a maximum fraction returned since the formation itself contributes DOC. Furthermore, the majority of returning DOC was of the hydrophilic fraction (60-85%). Volatile organic compound analysis revealed substantial concentrations of individual BTEX compounds (0.1-11 mg/L) over the 405-day study. Nonvolatile organic compounds identified were polyethylene glycols (PEGs), polypropylene glycols (PPG), linear alkyl-ethoxylates, and triisopropanolamine (TIPA). The distribution of PEGs, PPGs, and TIPA and their ubiquitous presence in our samples and the literature illustrate their potential as organic tracers for treatment operations or in the event of an environmental spill. PMID- 29132209 TI - Carbon, Nitrogen, and Mercury Isotope Evidence for the Biogeochemical History of Mercury in Hawaiian Marine Bottomfish. AB - The complex biogeochemical cycle of Hg makes identifying primary sources of fish tissue Hg problematic. To identify sources and provide insight into this cycle, we combined carbon (delta13C), nitrogen amino acid (delta15NPhe), and Hg isotope (Delta199Hg, Delta201Hg, delta202Hg) data for six species of Hawaiian marine bottomfish. Results from these isotopic systems identified individuals within species that likely fed from separate food webs. Terrestrial freshwater inputs to coastal sediments were identified as the primary source of tissue Hg in the jack species, Caranx ignobilis, which inhabit shallow marine ecosystems. Thus, coastal C. ignobilis were a biological vector transporting Hg from freshwater environments into marine ecosystems. Depth profiles of Hg isotopic compositions for bottomfish (excludung C. ignobilis) were similar, but not identical, to profiles for open-ocean pelagic fishes, suggesting that in both settings inorganic Hg, which was ultimately transformed to monomethylmercury (MeHg) and bioaccumulated, was dominantly from a single source. However, differences between pelagic fish and bottomfish profiles were attributable to mass-dependent fractionation in the benthos prior to incorporation into the food web. Results also confirmed that bottomfish relied, at least in part, on a benthic food web and identified the incorporation of deeper water oceanic MeHg sources into deeper water sediments prior to food web uptake and transfer. PMID- 29132210 TI - Organocatalytic Visible Light Enabled SNAr of Heterocyclic Thiols: A Metal-Free Approach to 2-Aminobenzoxazoles and 4-Aminoquinazolines. AB - The direct amination reaction of heterocyclic thiols has been developed in the presence of the nonhazardous photocatalyst Rose Bengal under irradiation of visible light. The reaction provides a straightforward approach to pharmaceutically and synthetically useful 2-aminobenzoxazole and 4 aminoquinazoline derivatives from the corresponding heterocyclic thiols with amines in good to excellent yields. Our photochemical reaction can be successfully adapted into a continuous flow reactor which is applicable for large scale chemical industry. The key benefits of this reaction include the use of metal-free, low-cost Rose Bengal catalyst and practical operation (ambient temperature, open flask, and undried solvents). PMID- 29132211 TI - Aggregation Behavior of Dissolved Black Carbon: Implications for Vertical Mass Flux and Fractionation in Aquatic Systems. AB - The fluvial export of dissolved black carbon (DBC) is a major land-ocean flux in the global black carbon cycle, affecting the size of refractory carbon pool in the oceans. The aggregation behavior of DBC is a significant determinant of its transport and vertical mass flux. In this study, the aggregation kinetics and interaction energy of DBC leached from biochar were investigated. DBC was mainly stabilized by hydration force and underwent structural compacting in divalent cation solutions. Na+ and Mg2+ had limited impact on the colloidal stability of DBC due to the strong hydration of these cations. Ca2+ and Ba2+ readily destabilized DBC by forming inner-sphere complexes, reducing its hydrophilicity. Consistently, charge reversal of DBC was observed with high concentrations of Ca2+ and Ba2+. Simulated sunlight exposure led to photo-oxidation of DBC, increasing its colloidal stability. DBC behaved nonconservatively in laboratory mixing experiments using estuary water samples due to aggregation/sedimentation; while model aquatic humic acid behaved conservatively. Our results infer that there is a vertical mass flux of DBC and possible fractionation from the dissolved organic matter pool in the fluvial and estuarine systems, which have been overlooked in efforts to determine global carbon budgets and associated climate change implications. PMID- 29132212 TI - Oil Exposure Impairs In Situ Cardiac Function in Response to beta-Adrenergic Stimulation in Cobia (Rachycentron canadum). AB - Aqueous crude oil spills expose fish to varying concentrations of dissolved polycyclic aromatic hydrocarbons (PAHs), which can have lethal and sublethal effects. The heart is particularly vulnerable in early life stages, as PAH toxicity causes developmental cardiac abnormalities and impaired cardiovascular function. However, cardiac responses of juvenile and adult fish to acute oil exposure remain poorly understood. We sought to assess cardiac function in a pelagic fish species, the cobia (Rachycentron canadum), following acute (24 h) exposure to two ecologically relevant levels of dissolved PAHs. Cardiac power output (CPO) was used to quantify cardiovascular performance using an in situ heart preparation. Cardiovascular performance was varied using multiple concentrations of the beta-adrenoceptor agonist isoproterenol (ISO) and by varying afterload pressures. Oil exposure adversely affected CPO with control fish achieving maximum CPO's (4 mW g-1 Mv) greater than that of oil-exposed fish (1 mW g-1 Mv) at ISO concentrations of 1 * 10-6 M. However, the highest concentration of ISO (1 * 10-5 M) rescued cardiac function. This indicates an interactive effect between oil-exposure and beta-adrenergic stimulation and suggests if animals achieve very large increases in beta-adrenergic stimulation it could play a compensatory role that may mitigate some adverse effects of oil exposure in vivo. PMID- 29132213 TI - A novel xanthone dimer derivative with antibacterial activity isolated from the bark of Garcinia mangostana. AB - A novel xanthone dimer derivative, garmoxanthone (1), together with 10 known compounds (2-11), were isolated from bark of Garcinia mangostana. Their structures were established through spectroscopic methods. Garmoxanthone exhibited strong inhibitory activities against MRSA ATCC 43300 and MRSA CGMCC 1.12409 (with MIC values of both 3.9 MUg/mL) and moderate activities against tested strains of Vibrio (with MIC values ranging from 15.6 to 31.2 MUg/mL). Garmoxanthone is a unique xanthone dimer with linkage of a fused 5/6 ring system and its absolute configuration was elucidated on the basis of experimental and calculated electronic circular dichroism. Garmoxanthone exhibited strong antibacterial activity which partially validated the ethnobotanical use of G. mangostana in the treatment of infections. PMID- 29132214 TI - Chemical Probes for Redox Signaling and Oxidative Stress. AB - SIGNIFICANCE: Cellular reactive oxygen species (ROS) mediate redox signaling cascades that are critical to numerous physiological and pathological processes. Analytical methods to monitor cellular ROS levels and proteomic platforms to identify oxidative post-translational modifications (PTMs) of proteins are critical to understanding the triggers and consequences of redox signaling. Recent Advances: The prevalence and significance of redox signaling has recently been illuminated through the use of chemical probes that allow for sensitive detection of cellular ROS levels and proteomic dissection of oxidative PTMs directly in living cells. CRITICAL ISSUES: In this review, we provide a comprehensive overview of chemical probes that are available for monitoring ROS and oxidative PTMs, and we highlight the advantages and limitations of these methods. FUTURE DIRECTIONS: Despite significant advances in chemical probes, the low levels of cellular ROS and low stoichiometry of oxidative PTMs present challenges for accurately measuring the extent and dynamics of ROS generation and redox signaling. Further improvements in sensitivity and ability to spatially and temporally control readouts are essential to fully illuminate cellular redox signaling. Antioxid. Redox Signal. 00, 000-000. PMID- 29132216 TI - Curcumin Decreases Hyperphosphorylation of Tau by Down-Regulating Caveolin-1/GSK 3beta in N2a/APP695swe Cells and APP/PS1 Double Transgenic Alzheimer's Disease Mice. AB - Caveolin-1, the marker protein of membranal caveolae, is not only involved in cholesterol regulation, but also participates in the cleavage of amyloid [Formula: see text]-protein precursor (APP) and the generation of [Formula: see text]-amyloid peptide. It has been reported to be tightly related with Tau. In our previous studies, curcumin has been confirmed to play a neuroprotective role in Alzheimer's disease (AD), but its effects on Caveolin-1, Tau and their correlation, and the mechanism is still unknown. As such, in the present study, N2a/WT cells, N2a/APP695swe cell and six-month-old APP/PS1 double transgenic mice were enrolled. After curcumin treatment, the expression of Caveolin-1, Tau and their relationship was detected, and the potential mechanisms were explored. The results showed that in the N2a/APP695swe cells, curcumin not only decreased the number of caveolae, but also made their membrane to be thinner; and curcumin could decreased the expression of phosphorylated Tau (P-Tau(ser404)/Tau) and Caveolin-1 ([Formula: see text]), but the expression of phosphorylated GSK 3[Formula: see text] (P-GSK-3[Formula: see text]/GSK-3[Formula: see text] was increased ([Formula: see text]). In APP/PS1 transgenic mice, the same results were observed. Taken together, our data suggest that curcumin may play an important role in AD via reducing Caveolin-1, inactivating GSK-3[Formula: see text] and inhibiting the abnormal excessive phosphorylation of Tau, which will provide a new theory for AD treatment with curcumin. PMID- 29132215 TI - In Vivo Molecular Electron Paramagnetic Resonance-Based Spectroscopy and Imaging of Tumor Microenvironment and Redox Using Functional Paramagnetic Probes. AB - SIGNIFICANCE: A key role of the tumor microenvironment (TME) in cancer progression, treatment resistance, and as a target for therapeutic intervention is increasingly appreciated. Among important physiological components of the TME are tissue hypoxia, acidosis, high reducing capacity, elevated concentrations of intracellular glutathione (GSH), and interstitial inorganic phosphate (Pi). Noninvasive in vivo pO2, pH, GSH, Pi, and redox assessment provide unique insights into biological processes in the TME, and may serve as a tool for preclinical screening of anticancer drugs and optimizing TME-targeted therapeutic strategies. Recent Advances: A reasonable radiofrequency penetration depth in living tissues and progress in development of functional paramagnetic probes make low-field electron paramagnetic resonance (EPR)-based spectroscopy and imaging the most appropriate approaches for noninvasive assessment of the TME parameters. CRITICAL ISSUES: Here we overview the current status of EPR approaches used in combination with functional paramagnetic probes that provide quantitative information on chemical TME and redox (pO2, pH, redox status, Pi, and GSH). In particular, an application of a recently developed dual-function pH and redox nitroxide probe and multifunctional trityl probe provides unsurpassed opportunity for in vivo concurrent measurements of several TME parameters in preclinical studies. The measurements of several parameters using a single probe allow for their correlation analyses independent of probe distribution and time of measurements. FUTURE DIRECTIONS: The recent progress in clinical EPR instrumentation and development of biocompatible paramagnetic probes for in vivo multifunctional TME profiling eventually will make possible translation of these EPR techniques into clinical settings to improve prediction power of early diagnostics for the malignant transition and for future rational design of TME targeted anticancer therapeutics. Antioxid. Redox Signal. 28, 1365-1377. PMID- 29132218 TI - Infant Reflux in the Primary Care Setting: A Brief Educational Intervention and Management Changes. AB - There has been a significant increase in prescription of acid suppression therapy to infants despite limited support for efficacy and safety. Prior studies have shown that educational interventions can improve clinician practices. Our aim is to implement an educational module with high-yield evidence to decrease the rate of prescribing these medications. Chart review of infants seen by residents after completing module was performed. Twelve clinic sessions before and after intervention were examined. 28 residents completed the intervention and required clinics. Before implementation, 1.8% of infants seen were prescribed acid suppression with none receiving proton pump inhibitors (PPIs). After completion, 0.8% of infants were prescribed acid suppression and 1 patient received PPI. This was not a significant change. The study was unsuccessful in effecting changes in provider prescribing practices. Although, this is not the outcome expected, it is encouraging to have a low initial rate of PPI therapy prescribed patients. PMID- 29132217 TI - Update on pulmonary arterial hypertension research: proceedings from a meeting of experts. AB - BACKGROUND: While pulmonary arterial hypertension (PAH) remains a progressive, symptomatic condition characterized by increased pulmonary vascular resistance, ultimately leading to right heart failure, great strides have been made in its understanding and treatment over the past two decades. REVIEW: Continued research in pre-clinical, clinical, and health economic areas of research, in addition to registry analyses and technology advances, is critical for understanding the pathophysiology of the disease and devising the best ways to monitor and manage patients. On December 3, 2016, the latest pre-clinical, clinical, health economic outcome, and registry data on PAH was presented in a symposium sponsored by Actelion. This paper reviews the published research and insight into upcoming research that was presented at this interactive meeting. PMID- 29132219 TI - Achieving positive outcomes in complex cases: The Admiral Nurse Dementia Helpline (Innovative Practice). AB - Carer distress is an all too common factor in caring for someone with dementia, whether living with the person with dementia, or trying to maintain their independence when they are living alone. Providing support for families on many day-to-day issues with immediacy as and when they arise can be very difficult to achieve for services on the ground as carer need can be difficult to anticipate as well as the changing status of the person with dementia. This paper discusses the innovative role of managing complexity on a dementia telephone helpline manned by Admiral Nurses, specialist dementia nurses, in expertly supporting a family over a weekend where there were health concerns of a family member with dementia and a high level of carer distress. PMID- 29132220 TI - Catheter-Directed Thrombolysis Versus Standard Anticoagulation for Acute Lower Extremity Deep Vein Thrombosis: A Meta-Analysis of Clinical Trials. AB - Standard anticoagulant treatment alone for acute lower extremity deep vein thrombosis (DVT) is ineffective in eliminating thrombus from the deep venous system, with many patients developing postthrombotic syndrome (PTS). Because catheter-directed thrombolysis (CDT) can dissolve the clot, reducing the development of PTS in iliofemoral or femoropopliteal DVT. This meta-analysis compares CDT plus anticoagulation versus standard anticoagulation for acute iliofemoral or femoropopliteal DVT. Ten trials were included in the meta analysis. Compared with anticoagulant alone, CDT was shown to significantly increase the percentage patency of the iliofemoral vein ( P < .00001; I2 = 44%) and reduce the risk of PTS ( P = .0002; I2 = 79%). In subgroup analysis of randomized controlled trials, CDT was not shown to prevent PTS ( P = .2; I2 = 59%). A reduced PTS risk was shown, however, in nonrandomized trials ( P < .00001; I2 = 47%). Meta-analysis showed that CDT can reduce severe PTS risk ( P = .002; I2 = 0%). However, CDT was not indicated to prevent mild PTS ( P = .91; I2 = 79%). A significant increase in bleeding events ( P < .00001; I2 = 33%) and pulmonary embolism (PE) ( P < .00001; I2 = 14%) were also demonstrated. However, for the CDT group, the duration of stay in the hospital was significantly prolonged compared to the anticoagulant group ( P < .00001; I2 = 0%). There was no significant difference in death ( P = .09; I2 = 0%) or recurrent venous thromboembolism events ( P = .52; I2 = 58%). This meta-analysis showed that CDT may improve patency of the iliofemoral vein or severe PTS compared with anticoagulation therapy alone, but measuring PTS risk remains controversial. However, CDT could increase the risk of bleeding events, PE events, and duration of hospital stay. PMID- 29132221 TI - 2009 IOM guidelines for gestational weight gain: how well do they predict outcomes across ethnic groups? AB - OBJECTIVE: To determine whether the Institute Of Medicine's (IOM) 2009 guidelines for weight-gain during pregnancy are predictive of maternal and infant outcomes in ethnic minority populations. METHODS: We designed a population-based study using administrative data on 181,948 women who delivered live singleton births in Washington State between 2006-2008. We examined risks of gestational hypertension, preeclampsia/eclampsia, cesarean delivery, and extended hospital stay in White, Black, Native-American, East-Asian, Hispanic, South-Asian and Hawaiian/Pacific islander women according to whether they gained more or less weight during pregnancy than recommended by IOM guidelines. We also examined risks of neonatal outcomes including Apgar score <7 at 5 min, admission to NICU, requirement for ventilation, and a diagnosis of small or large for gestational age at birth. RESULTS: Gaining too much weight was associated with increased odds for gestational hypertension (adjusted OR (aOR) ranged between 1.53-2.22), preeclampsia/eclampsia (aOR 1.44-1.81), cesarean delivery (aOR 1.07-1.38) and extended hospital stay (aOR 1.06-1.28) in all ethnic groups. Gaining too little weight was associated with decreased odds for gestational hypertension and delivery by cesarean section in Whites, Blacks and Hispanics. Gaining less weight or more weight than recommended was associated with increased odds for small for gestational age and large for gestational age infants respectively, in all ethnic groups. CONCLUSIONS: Adherence to the 2009 IOM guidelines for weight gain during pregnancy reduces risk for various adverse maternal outcomes in all ethnic groups studied. However, the guidelines were less predictive of infant outcomes with the exception of small and large for gestational age. ABBREVIATIONS: GWG: Gestational weight gain; IOM/NRC; Institute of Medicine and National Research Council; NICU: Neonatal intensive care need for ventilation; SGA: Small for gestational age; LGA: Large for gestational age; BERD: Birth Events Records Database; CHARS: Comprehensive Hospital Discharge Abstract Reporting System; ICD: International Classification of Disease; LMP: Last menstrual period; OR: Odds ratio. PMID- 29132222 TI - Abandoned to the strains of daily life: a qualitative study of the long-term experiences in partners to persons after a mild to moderate stroke. AB - PURPOSE: To describe the experiences of everyday life over 6 years after stroke, from the perspectives of partners to persons after stroke. MATERIALS AND METHODS: Semi structured individual interviews were conducted with seven partners to persons who had had stroke. The interviews were recorded and then transcribed verbatim. The participants comprised two men and five women aged 60-82 years. The data were collected and analysed using a grounded theory approach. RESULTS: One core category Living in strained everyday circumstances and three categories Feelings of anxiety, Living a demanding day to day life, and Adjusting to a changed role emerged from the analysis. The participants had developed strategies and new ways to boost their energy level in order to find the strength needed for their everyday life. CONCLUSION: This study shows that the everyday lives of partners to people who have had a stroke are characterised by feelings of strain and anxiety and that they need possibilities for different kinds of long-term support. Our findings may contribute to increased knowledge among health workers and increased readiness to offer support or referral to other meeting places such as peer support groups. Implications for rehabilitation The everyday lives of partners to people who have had a stroke are characterised by feelings of strain and anxiety. Partners to people who have had a stroke need possibilities for different kinds of long-term support. Possibilities for relief among partners to persons after stroke may be organised for example within the municipality or by patient organisations and other voluntary networks such as peer support groups. PMID- 29132223 TI - Comparison of the relative stability of pharmaceutical cocrystals consisting of paracetamol and dicarboxylic acids. AB - OBJECTIVE: The aim of this study is to evaluate the relative stability of pharmaceutical cocrystals consisting of paracetamol (APAP) and oxalic acid (OXA) or maleic acid (MLA). SIGNIFICANCE: These observations of cocrystal stability under various conditions are useful coformer criteria when cocrystals are selected as the active pharmaceutical ingredient in drug development. METHOD: The relative stability was determined from the preferentially formed cocrystals under various conditions. RESULT: Cocrystal of APAP-OXA was more stable than that of APAP-MLA in a ternary cogrinding system and possessed thermodynamical stability. On the other hand, when grinding with moisture or maintaining at high temperatures and relative humidity conditions, APAP-MLA was more stable, and OXA converted to OXA dihydrate. In the slurry method, APAP-OXA was more stable in aprotic solvents because the APAP-OXA with low-solubility product precipitated. CONCLUSIONS: The relative stability order was affected by preparing conditions of presence of moisture. This order might attribute to the small difference of crystal structure in the extension of the hydrogen bond network. PMID- 29132224 TI - Incidence and costs of cardiac device infections: retrospective analysis using German health claims data. AB - AIM: Estimate incidence and costs of cardiac device infections (CDIs) in Germany. MATERIALS & METHODS: Patients had an implantable cardioverter defibrillator implanted over 2010-2013 and were followed to December 2014 using German health insurance claims data. A case-controlled analysis was performed using propensity score matching methods. RESULTS: Risk of CDI 12 months post-implant was 3.4% overall, either 2.9% for de novo procedures versus 4.4% for replacement procedures. Mean 3-year incremental expenditure per patient for patients with CDI compared with controls was ?31,493 for de novo implant patients and ?33,777 for replacement patients. Mean incremental expenditure was ?59,419 per patient with a major infection. CONCLUSION: CDIs are highly expensive to manage, reinforcing the need for strategies to reduce their occurrence. PMID- 29132225 TI - How can the health belief model and self-determination theory predict both influenza vaccination and vaccination intention ? A longitudinal study among university students. AB - Background and objective Seasonal influenza is frequent among students and often responsible for impaired academic performance and lower levels of general health. However, the vaccination rate in this population is very low. As the seasonal influenza vaccine is not compulsory in France, it is important to improve the vaccination uptake by identifying predictors of both intention and behaviour. This study investigated the effect of decisional balance, motivation and self efficacy on vaccination acceptance using the Extended Health Belief Model (HBM) and Self-Determination Theory (SDT). Design and Main Outcome Measures University students were invited to fill in an online survey to answer questions about their influenza vaccination intention, and HBM and SDT constructs. A one-year longitudinal follow-up study investigated vaccination behaviour. Results Autonomous motivation and self-efficacy significantly influenced the intention to have the influenza vaccine, and vaccine behaviour at one-year follow-up. Intention predicted a significant proportion of variation (51%) in behaviour, and mediated the effect of these predictors on vaccination behaviour. Conclusion These results suggest that motivation concepts of the Self-Determination Theory can be adequately combined with the Health Belief Model to understand vaccination behaviour. PMID- 29132226 TI - Investigating the relationship between language and picture understanding in children with autism spectrum disorder. AB - Previous studies report that minimally verbal children with autism spectrum disorder show impaired picture comprehension when matched to typically developing controls on language comprehension. Here, we compare both picture comprehension and picture production abilities in linguistically delayed children with autism spectrum disorder and typically developing controls matched on language comprehension and language production. Participants were 20 children with autism spectrum disorder ( M age: 11.2 years) and 20 typically developing children ( M age: 4.4 years) matched on age equivalents for receptive language (autism spectrum disorder, M: 4.6 years; typically developing, M: 4.5 years) and expressive language (autism spectrum disorder, M: 4.4 years; typically developing, M: 4.5 years). Picture comprehension was assessed by asking children to identify the three-dimensional referents of line drawings. Picture production was assessed by asking children to create representational drawings of unfamiliar objects and having raters identify their referents. The results of both picture tasks revealed statistically equivalent performance for typically developing children and children with autism spectrum disorder, and identical patterns of performance across trial types. These findings suggest that early deficits in pictorial understanding displayed by minimally verbal individuals may diminish as their expressive language skills develop. Theoretically, our study indicates that development in linguistic and pictorial domains may be inter-related for children with autism spectrum disorder (as is the case for typical development). PMID- 29132228 TI - Editorial: Innovative Practice. PMID- 29132229 TI - Hyperbaric Oxygen Therapy in the Treatment of Acute Severe Traumatic Brain Injury: A Systematic Review. AB - There has been no major advancement in a quarter of a century for the treatment of acute severe traumatic brain injury (TBI). This review summarizes 40 years of clinical and pre-clinical research on the treatment of acute TBI with hyperbaric oxygen therapy (HBO2) in the context of an impending National Institute of Neurologic Disorders and Stroke-funded, multi-center, randomized, adaptive Phase II clinical trial -the Hyperbaric Oxygen Brain Injury Treatment (HOBIT) trial. Thirty studies (eight clinical and 22 pre-clinical) that administered HBO2 within 30 days of a TBI were identified from PubMed searches. The pre-clinical studies consistently reported positive treatment effects across a variety of outcome measures with almost no safety concerns, thus providing strong proof-of-concept evidence for treating severe TBI in the acute setting. Of the eight clinical studies reviewed, four were based on the senior author's (GR) investigation of HBO2 as a treatment for acute severe TBI. These studies provided evidence that HBO2 significantly improves physiologic measures without causing cerebral or pulmonary toxicity and can potentially improve clinical outcome. These results were consistent across the other four reviewed clinical studies, thus providing preliminary clinical data supporting the HOBIT trial. This comprehensive review demonstrates that HBO2 has the potential to be the first significant treatment in the acute phase of severe TBI. PMID- 29132227 TI - Oxidative Stress in HIV Infection and Alcohol Use: Role of Redox Signals in Modulation of Lipid Rafts and ATP-Binding Cassette Transporters. AB - AIMS: Human immunodeficiency virus (HIV) infection induces oxidative stress and alcohol use accelerates disease progression, subsequently causing immune dysfunction. However, HIV and alcohol impact on lipid rafts-mediated immune dysfunction remains unknown. In this study, we investigate the modulation by which oxidative stress induces reactive oxygen species (ROS) affecting redox expression, lipid rafts caveiloin-1, ATP-binding cassette (ABC) transporters, and transcriptional sterol regulatory element-binding protein (SREBP) gene and protein modification and how these mechanisms are associated with arachidonic acid (AA) metabolites in HIV positive alcohol users, and how they escalate immune dysfunction. RESULTS: In both alcohol using HIV-positive human subjects and in vitro studies of alcohol with HIV-1 gp120 protein in peripheral blood mononuclear cells, increased ROS production significantly affected redox expression in glutathione synthetase (GSS), super oxide dismutase (SOD), and glutathione peroxidase (GPx), and subsequently impacted lipid rafts Cav-1, ABC transporters ABCA1, ABCG1, ABCB1, and ABCG4, and SREBP transcription. The increased level of rate-limiting enzyme 3-hydroxy-3-methylglutaryl HMG-CoA reductase (HMGCR), subsequently, inhibited 7-dehydrocholesterol reductase (DHCR-7). Moreover, the expression of cyclooxygenase-2 (COX-2) and lipoxygenase-5 (5-LOX) mRNA and protein modification tentatively increased the levels of prostaglandin E2 synthases (PGE2) in plasma when compared with either HIV or alcohol alone. INNOVATION: This article suggests for the first time that the redox inhibition affects lipid rafts, ABC-transporter, and SREBP transcription and modulates AA metabolites, serving as an important intermediate signaling network during immune cell dysfunction in HIV-positive alcohol users. CONCLUSION: These findings indicate that HIV infection induces oxidative stress and redox inhibition, affecting lipid rafts and ABC transports, subsequently upregulating AA metabolites and leading to immune toxicity, and further exacerbation with alcohol use. Antioxid. Redox Signal. 28, 324-337. PMID- 29132231 TI - The use of desflurane for neurosurgical procedures in rhesus macaque ( Macaca mulatta). AB - Volatile agents are widely used to anaesthetise laboratory non-human primates as they allow a rapid induction and recovery as well as an easy adjustment of the anaesthesia plan. Desflurane is currently the volatile agent with the lowest solubility in blood, and hence enables the most rapid onset of anaesthesia and most rapid recovery. This study aimed to investigate the suitability of desflurane for maintenance of general anaesthesia in rhesus macaques undergoing elective experimental neurosurgery. Fourteen primates (five males and nine females) were sedated with ketamine (10 mg kg-1) and anaesthesia was induced with propofol (usually 8 mg kg-1 IV). Anaesthesia was maintained with desflurane (5.9 +/- 0.8 %) and alfentanil (0.2-0.5 ug kg-1 min-1 IV). Animals were mechanically ventilated. Meloxicam (0.3 mg kg-1) and methylprednisolone infusion (5.4 mg kg-1 h-1) were also administered. All the primates were successfully anaesthetised and no severe complications related to the procedure or the anaesthesia regimen occurred. No major differences in physiological parameters and recovery times between the male and female groups were found. Emergence from anaesthesia was rapid (male 5.2 +/- 2.4 min; female 4.1 +/- 1.7 min) but its quality was assessed as equivalent to two other volatile anaesthetics, isoflurane and sevoflurane. These had previously been assessed for neuroanaesthesia in rhesus macaques. In conclusion, this study demonstrated that desflurane was suitable for maintenance of general anaesthesia for elective experimental neurosurgical procedures in rhesus macaque. However the vasodilatory action of the desflurane may limit its use in cases of severe intracranial hypertension or systemic hypotension. PMID- 29132230 TI - Combination therapy for obesity. AB - Obesity is a chronic disease with serious consequences and although lifestyle modification is considered first line treatment, it is often ineffective, especially in the long term. Relatively few people with obesity will undergo the most effective currently available treatment of bariatric surgery. Pharmacotherapy can bridge the gap between lifestyle modification and surgery, but many monotherapies have only modest efficacy or require high doses with unacceptable side effects. As with many other areas of medicine, combination therapy is now becoming accepted as a way of optimising efficacy for weight management, whilst minimising adverse effects. Combinations may use different medications with complementary modes of action. Currently available combination therapies are low-dose phentermine and sustained release topiramate and naltrexone/bupropion. Many other possibilities exist and promising options include combination of phentermine with a sodium glucose co-transporter 2 inhibitor or combination of a glucagon-like peptide 1 agonist with other gut hormones or with a sodium glucose co-transporter 2 inhibitor. The ultimate aim is to match the efficacy of bariatric surgery with a combination of medicines, but this remains an elusive goal. PMID- 29132233 TI - Prospects for modulating the CD40/CD40L pathway in the therapy of the hyper-IgM syndrome. AB - The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described extensively in previous literature. Interruption of the CD40/CD40L signal causes hyper-IgM (HIGM) syndrome, which has been classified and recognized as a group of rare inherited immune deficiency disorders. Defects in CD40 and CD40L interactions or in downstream signaling molecules, including activation-induced cytidine deaminase, uracyl-DNA-glycosylase, NF-kappaB and DNA repair enzymes, result in an increased level of serum IgM and a significantly decreased or absent level of IgA, IgG and IgE that is accompanied by severe recurrent infections and autoimmune diseases. Many genetic defects in HIGM have been identified and, as a result, it is possible for patients to be definitively diagnosed by gene sequencing and to delineate the immunological features of the patients. Modifying the CD40/CD40L signaling pathway may offer the possibility of restoring the normal serum Ab production and curing the immunodeficiency. Hematopoietic stem cell transplantation has achieved a high rate of success using a sibling donor. In addition, successful examples of treating other immunodeficiencies using gene therapy indicated that there was a possibility of eradicating HIGM with this approach. In this review, we summarize the current drugs and a variety of therapeutic approaches for the treatment of the HIGM syndrome by interfering with the defective CD40/CD40L pathway. PMID- 29132232 TI - Embedded Multimaterial Extrusion Bioprinting. AB - Embedded extrusion bioprinting allows for the generation of complex structures that otherwise cannot be achieved with conventional layer-by-layer deposition from the bottom, by overcoming the limits imposed by gravitational force. By taking advantage of a hydrogel bath, serving as a sacrificial printing environment, it is feasible to extrude a bioink in freeform until the entire structure is deposited and crosslinked. The bioprinted structure can be subsequently released from the supporting hydrogel and used for further applications. Combining this advanced three-dimensional (3D) bioprinting technique with a multimaterial extrusion printhead setup enables the fabrication of complex volumetric structures built from multiple bioinks. The work described in this paper focuses on the optimization of the experimental setup and proposes a workflow to automate the bioprinting process, resulting in a fast and efficient conversion of a virtual 3D model into a physical, extruded structure in freeform using the multimaterial embedded bioprinting system. It is anticipated that further development of this technology will likely lead to widespread applications in areas such as tissue engineering, pharmaceutical testing, and organs-on-chips. PMID- 29132234 TI - Upcycling umbilical cords: bridging regenerative medicine with neonatology. AB - Preterm birth is a major health concern that affects 10% of all worldwide deliveries. Many preterm infants are discharged from the hospital with morbidities that lead to an increased risk for neurodevelopmental impairment, recurrent hospitalizations, and life-long conditions. Unfortunately, the treatment of these conditions is palliative rather than curative, which calls for novel and innovative strategies. Progress in regenerative medicine has offered therapeutic options for many of these conditions. Specifically, human umbilical cord mesenchymal stem cells (MSCs) and cord blood (UCB) cells have shown promise in treating adult-onset diseases. Unlike bone-marrow and embryonic derived stem cells, umbilical cord-derived cells are easily and humanely obtained, have low immunogenicity, and offer the potential of autologous therapy. While there are several studies to uphold the efficacy of umbilical cord MSCs in adult therapies, there remains an unmet need for the investigation of its use in treating neonates. The purpose of this review is to provide a summary of current information on the potential therapeutic benefits and clinical applicability of umbilical cord MSCs and UCB cells. Promising preclinical studies have now led to a research movement that is focusing on cell-based therapies for preterm infants. PMID- 29132235 TI - A Cell-Based Assay to Investigate Hypolipidemic Effects of Nonalcoholic Fatty Liver Disease Therapeutics. AB - In the recent past, there has been a growing interest in developing nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) therapeutics. As a result, a need for in vitro cell models of human hepatic steatosis and high throughput assays to measure intracellular lipid levels has arisen. To address this growing need, we optimized the conditions based on the current literature to fatten HepG2 hepatocytes by adding a mixture of saturated and unsaturated fatty acids (oleate/palmitate, 2:1 molar ratio) without inducing any overt cytotoxicity. Our results indicate that hepatocytes fatten in a concentration- (0.75-1.5 mM of fatty acids) and time-dependent manner, with a substantial increase in intracellular lipid levels seen within 6 h. Additionally, a method to quantify lipid levels in cells using a fluorescent reagent that is more sensitive than that in conventional assays and adaptable for high-throughput screening is presented. Lastly, the utility of the in vitro cell model and an assay based on AdipoRed to measure hypolipidemic effects of therapeutic drugs is demonstrated using fenofibrate, a molecule that was previously shown to lower lipid levels in the liver. PMID- 29132236 TI - Neuroimaging findings using transfontanellar ultrasound in newborns with microcephaly and Zika virus infection: a comment. PMID- 29132237 TI - Neural circuits of eating behaviour: Opportunities for therapeutic development. AB - Understanding of the neural and physiological substrates of hunger and satiety has increased rapidly over the last three decades, and pharmacological targets have already been identified for the treatment of obesity that has moved from pre clinical screening to therapies approved by regulatory authorities. Initially, this review describes the way in which physiological signals of energy availability interact with hedonic and rewarding properties of food to modulate the neural circuitry that supports eating behaviour. This is followed by a brief account of current and promising targets for drug development and a review of the wide range of preclinical paradigms that model important influences on human eating behaviour, and can be used to guide early stages of the drug development process. PMID- 29132238 TI - Nanomicelle drug with acid-triggered doxorubicin release and enhanced cellular uptake ability based on mPEG-graft-poly(N-(2-aminoethyl)-L-aspartamide) hexahydrophthalic acid copolymers. AB - In order to achieve the passive tumor targeting and acid-triggered drugs release in lysosomes, optimized delivery system for doxorubicin based on pH-sensitive complex nanomicelles with suitable particle size was developed in this research. Particularly, poly(L-succinimide) was thoroughly ring-opened by ethylenediamine to give the poly(N-(2-aminoethyl)-L-aspartamide). Then, graft copolymer mPEG graft-poly(N-(2-aminoethyl)-L-aspartamide)-hexahydrophthalic acid (mPEG-g-P(ae Asp)-Hap) was synthesized by grafting mPEG-2000 and hexahydrophthalic anhydride onto poly(N-(2-aminoethyl)-L-aspartamide). In vitro studies revealed that mPEG-g P(ae-Asp)-Hap copolymer was stable in neutral solutions but tend to be hydrolyzed under acidic condition, which was attributed to the acid-sensitive properties of hexahydrophthalic amides (beta-carboxylic amides). MPEG-g-P(ae-Asp)-Hap copolymer with critical aggregation concentration of 0.166 mg.mL-1 could self-assemble into stable blank nanomicelles with an average particle hydrodynamic diameter of 98.1 nm, but the hydrodynamic diameter of doxorubicin-loaded nanomicelles (mPEG-g-P(ae Asp)-Hap.Dox) was smaller and approximately 77.5 nm. MPEG-g-P(ae-Asp)-Hap.Dox nanomicelles showed sustained drug release profiles over 34 h, and the cumulative drug release showed a tendency to increase from 25% to 62% with the pH value decreasing from 7.4 to 5.0 due to the acid-triggered disassembly of nanomicelles. The cytotoxicity of mPEG-g-P(ae-Asp)-Hap.Dox nanomicelles against A549 treated with 40 mM NH4Cl (lysosomotropic weak bases) was decreased significantly than that without NH4Cl treatment, further confirmed the drug release from the nanomicelles was triggered by the low pH value of lysosome (pH 5.0). Compared with doxorubicin HCl, mPEG-g-P(ae-Asp)-Hap.Dox nanomicelle drug showed enhanced cellular uptake ability during 2 or 4 h of incubation due to the endocytosis mechanism of nanomicelle drug. In summary, the cleavage of pH-sensitive beta carboxylic amides bonds on the hydrophobic branch of mPEG-g-P(ae-Asp)-Hap copolymer triggered the disassembly of the nanomicelles and release of doxorubicin in the acidic lysosomal compartments of cancer cells. These nanomicelles exhibited excellent potential for drug delivery due to their smart properties-PEGylation, suitable size, and acid-triggered drug release. PMID- 29132239 TI - Lunate fractures and associated radiocarpal and midcarpal instabilities: a systematic review. AB - The aim of this study was to analyse lunate fractures and any associated osseo ligamentous injuries. A systematic review identified 34 cases. We identified carpal instabilities at the radiocarpal and midcarpal joints in volar and dorsal directions. Radiocarpal instabilities (10/34) were usually dorsoradial (8/10), with a transverse lunate fracture, best seen on a coronal image. Midcarpal instabilities (24/34) were usually volar (14/18), with a volar lunate shear fracture, best seen on a sagittal image. Instabilities were sub-classified into non-displaced, subluxated and dislocated. Associated fractures of the scaphoid and the radial and ulnar styloid processes were common. Lunate fractures without subluxation or dislocation had good outcomes with cast immobilization or fixation of associated fractures. Lunate fracture-subluxations are unstable injuries that are best managed with fixation of the carpal fractures. Lunate fracture dislocations are complex injuries, requiring stabilization of the lunate, associated fractures and ligament injuries; complications are common and acute or delayed salvage procedures may be required. PMID- 29132240 TI - Can surgical guidelines minimize complications after Maia(r) trapeziometacarpal joint arthroplasty with unconstrained cups? AB - : The most important complications of trapeziometacarpal arthroplasty are dislocation and component loosening. Incorrect cup position is often a contributing factor. Intra-operative guidelines to optimize cup orientation have recently been described. We evaluated the functional and radiological outcome of 50 Maia(r) trapeziometacarpal prostheses that were implanted according to these guidelines. The minimum follow-up was 56 months. No constrained cups were used. Functional outcome was good to excellent. No spontaneous dislocations occurred. No radiological signs of loosening were observed. There was one case of premature wear. The survival rate was 96% (95% confidence interval 85 to 99%) at a mean of 65 months, with two prosthesie removed for posttraumatic trapezial fractures. This study shows that correct implant position can lead to reliable medium-term results after trapeziometacarpal joint arthroplasty. LEVEL OF EVIDENCE: IV. PMID- 29132241 TI - Rectovaginal fistula following surgery for deep infiltrating endometriosis: Does lesion size matter? AB - Objective This study was performed to identify risk factors for postoperative rectovaginal fistula (PRF) in patients with deep infiltrating endometriosis (DIE). Methods Data were retrospectively obtained from the medical records of 104 patients with DIE, and statistical analysis was used to detect risk factors for PRF. Results Five of 104 (4.8%) patients developed PRF from 5 to 16 days postoperatively. The operative procedures included 84 (80.8%) superficial excisions, 6 (5.8%) full-thickness disc excisions, and 14 (13.5%) bowel resections. Most lesions were located in the cul-de-sac, and the mean lesion size was 2.6 cm (range, 0.5-7.0 cm). The univariate analysis showed that lesion location, larger lesion size, and surgical technique were statistically significant risk factors for PRF. Conclusion Surgical procedures should be very carefully executed in patients with DIE lesions of >=4 cm. PMID- 29132242 TI - Relationship between thyroid hormone levels and transient tachypnea of the newborn in late-preterm, early-term, and term infants. AB - PURPOSE: We aimed to investigate the association between thyroid hormone levels and transient tachypnea of the newborn (TTN) among late-preterm, early-term, and term infants admitted to neonatal intensive care unit (NICU). MATERIALS AND METHOD: In the current retrospective study, neonates admitted to the NICU due to TTN were assigned to the TTN group (n = 404). Healthy neonates who were followed up in the well-baby nursery comprised the control group (n = 7335). Infants were grouped by gestational age into late-preterm (34-366 weeks), early-term (37-386 weeks), and term subgroups (39-416 weeks). Serum levels of thyroid-stimulating hormone (TSH) and thyroxin (T4) were determined from venipuncture samples taken at least 48 hours after birth. The relationship between thyroid hormone levels and the need for NICU admission for TTN was compared between groups. RESULTS: Compared to control infants, term neonates with TTN had significantly higher TSH levels, whereas late-preterm and early-term neonates with TTN had significantly lower T4 levels. Birth weight and mode of delivery had no effect on NICU admission for TTN. CONCLUSIONS: Infants admitted to NICU due to TTN had significantly different thyroid hormone levels with differences depending on gestational age. PMID- 29132244 TI - Adipocytokines and ghrelin level of bipolar patients from manic episode to euthymic episode. AB - PURPOSE: Obesity and metabolic syndrome (MeS) are more frequently observed in bipolar patients than the general population. This may result from the differences of adipocytokines and ghrelin levels in bipolar disorder. MATERIAL AND METHODS: We evaluated the leptin, adiponectin, resistin and ghrelin levels in bipolar patients (n = 30) in manic episode and in a control group (n = 30). After treatment, the same patients were evaluated again during the euthymic episode. We also measured the insulin, glucose, insulin resistance (HOMA), trygliceride (TG), total cholesterol (TCHOL), high density lipoprotein cholesterol (HDL) and low density lipoprotein cholesterol (LDL) in relation to the (MeS). RESULTS: When controlling for age, BMI and glucose, leptin levels were higher in the bipolar disorder manic episode group (BD-ME) and bipolar euthymic episode group (BD-EE) than the control group; resistin levels were higher in the BD-ME compared to the control group and it had a positive correlation with Young Mania Rating Scale (YMRS). After treatment, ghrelin levels were higher in the BD-EE compared to the BD-ME group. There was no difference among the groups with respect to adiponectin. CONCLUSIONS: The present results point that high leptin, resistin and ghrelin levels may be involved in the early pathophysiological process which can lead to later obesity and MeS in patients with bipolar disorder. PMID- 29132245 TI - Radial vs coccygeal artery Doppler blood pressure measurement in conscious cats. AB - Objectives The aims of the study were to compare the results of systolic blood pressure (SBP) measurements at the radial and coccygeal artery by Doppler ultrasonography and to assess the impact of gender, age, body weight, body condition score (BCS) and stress score on disagreements. Methods Eighty cats were included in this prospective, block randomised crossover trial. Blood pressure measurements were performed at home, during hospitalisation or in a local animal shelter by a single trained observer according to the latest ISFM consensus guidelines. Statistical analysis included Spearman's correlation and ANOVA. Results Measurement or site order had no effect on blood pressure measurements ( P = 0.157, P = 0.965). Correlation of radial and coccygeal SBP was moderate (rsp = 0.519, P <0.001) and measurements at the tail were by mean 18.7 +/- 37 mmHg higher. The differences between the measuring sites were neither correlated with age (rsp = 0.044, P = 0.710) nor with body weight (rsp = 0.122, P = 0.337). A significant effect of BCS ( P = 0.016), but not gender ( P = 0.246) or stress score ( P = 0.424) was identified. Of the 25 cats with a coccygeal SBP ?170 mmHg, 14 (56%) were categorised as mildly hypertensive or normotensive when measurements were performed at the forelimb. Conclusions and relevance Choice of the measuring site, coccygeal vs radial artery, has a significant impact on Doppler ultrasonographic SBP results. In many cats, these discrepancies are huge and would certainly affect treatment decisions. Possible explanations include cone-shaped tails, especially in obese cats, leading to distal gapping or slippage of cylindrical cuffs and peripheral pulse pressure amplification. Further studies are urgently needed to clarify whether the discordances are artefacts or have a pathological background. PMID- 29132246 TI - Phage-derived protein-mediated targeted chemotherapy of pancreatic cancer. AB - Pancreatic cancer has been a life-threatening illness associated with high incidence and mortality rates. Paclitaxel (PCT) that causes mitotic arrest in cancer cells disrupting microtubule function is used for pancreatic cancer treatment. Nausea, anorexia and abdominal pain are some of the typical dose limiting toxicity associated gastrointestinal side effects of the drug. Here, we present the use of polymeric mixed micelles to enable a targeted delivery of PCT and to provide additional advantages such as enhanced drug solubility, bioavailability and minimal dose-limiting toxicity. Also, these micelles self assemble with pancreatic cancer cells-specific phage proteins P38, L1 and with the hydrophobic drug PCT resolving the issue of complex chemistry efforts normally needed for any conjugation. Our cytotoxicity and binding experiment results in vitro in 2 D and 3 D models suggested that the phage protein-targeted drug-loaded micelles bind and exhibit higher cell killing over the non-targeted ones. PMID- 29132243 TI - Protective Effects of Estradiol and Dihydrotestosterone following Spinal Cord Injury. AB - Spinal cord injury (SCI) results in lesions that destroy tissue and disrupt spinal tracts, producing deficits in locomotor and autonomic function. We previously demonstrated that motoneurons and the muscles they innervate show pronounced atrophy after SCI, and these changes are prevented by treatment with testosterone. Here, we assessed whether the testosterone active metabolites estradiol and dihydrotestosterone have similar protective effects after SCI. Young adult female rats received either sham or T9 spinal cord contusion injuries and were treated with estradiol, dihydrotestosterone, both, or nothing via Silastic capsules. Basso-Beattie-Bresnahan locomotor testing was performed weekly and voiding behavior was assessed at 3 weeks post-injury. Four weeks after SCI, lesion volume and tissue sparing, quadriceps muscle fiber cross-sectional area, and motoneuron dendritic morphology were assessed. Spontaneous locomotor behavior improved after SCI, but hormone treatments had no effect. Voiding behavior was disrupted after SCI, but was significantly improved by treatment with either estradiol or dihydrotestosterone; combined treatment was maximally effective. Treatment with estradiol reduced lesion volume, but dihydrotestosterone alone and estradiol combined with dihydrotestosterone were ineffective. SCI-induced decreases in motoneuron dendritic length were attenuated by all hormone treatments. SCI-induced reductions in muscle fiber cross-sectional areas were prevented by treatment with either dihydrotestosterone or estradiol combined with dihydrotestosterone, but estradiol treatment was ineffective. These findings suggest that deficits in micturition and regressive changes in motoneuron and muscle morphology seen after SCI are ameliorated by treatment with estradiol or dihydrotestosterone, further supporting a role for steroid hormones as neurotherapeutic agents in the injured nervous system. PMID- 29132247 TI - Management of a Rare Case With Severe Hydrofluoric Acid Burns: Important Roles of Neutralizers and Continuous Renal Replacement Therapy. AB - Hydrofluoric acid (HF), a dangerous inorganic acid, is widely used in various industries and in daily life. Chemical burns caused by HF exposure occur more frequently in some regions worldwide. It has been reported that some cases with HF burns can be lethal due to the hypertoxicity of HF. In this article, we present a case of a 24-year-old worker who suffered HF burns by 53% HF solution to his face, neck, and nasal cavity. This patient quickly developed electrolyte disturbance, that is, hypocalcemia, and hypopotassemia, and myocardial injury after exposure. Multiple measures had been taken to treat this patient, including fluid resuscitation, electrolyte replacement, timely wound treatment with neutralizers, and respiratory tract care. Moreover, continuous renal replacement therapy was also employed to remove fluoride in the circulatory system and rectify the electrolyte disturbance and acid-base imbalance. The patient smoothly pulled though and survived. High fluoride levels in the dialysate solution were confirmed, indicating that continuous renal replacement therapy is an effective and potentially lifesaving treatment for acute HF poisoning. PMID- 29132248 TI - Gene delivery system of pDNA using the blood glycoprotein fetuin. AB - Fetuin is a biocompatible plasma protein and strongly enhances phagocytosis of bacteria, DNA and apoptotic cells by peripheral blood cells such as monocytes, macrophages and dendritic cells. We developed a novel gene delivery system: ternary complexes constructed with pDNA, polyethylenimine (PEI) and fetuin. Without covalent binding, fetuin was able to coat pDNA-PEI complexes, and stable anionic nanoparticles formed at a weight ratio greater than 30. Optimised pDNA PEI-fetuin complexes significantly decreased the cytotoxicity of pDNA-PEI complexes in the melanoma cell line B16F10. Furthermore, the pDNA-PEI-fetuin complexes had higher transgene efficiency compared to that of commercial lipofectin previously reported in B16F10 cells despite an anionic surface. The pDNA-PEI-fetuin complexes did not agglutinate with erythrocytes. The pDNA-PEI fetuin complexes had high gene expression in the spleen after intravenous administration in mice. Thus, the pDNA-PEI-fetuin complexes were a useful in vivo gene delivery system with tropism for the spleen. PMID- 29132249 TI - Re: "Low-Dose Childhood Radiation Effects to the Thyroid Follow a Linear Dose Response Trend and Persist Even 45+ Years After Exposure" (Clin Thyroidol 2017;29:235-236). PMID- 29132250 TI - The influence of Pilates exercises on body balance in the standing position of hearing impaired people. AB - PURPOSE: Hearing impairment may affect the body posture maintenance. The aim of the study was to evaluate the effect of modified Pilates exercise program on the body posture maintenance in hearing impaired people. METHODS: Eighty students (aged 13-24) were enrolled and randomly allocated into two groups: test group (n = 41) which attended an original program based on modified Pilates exercises and control group (n = 39) which attended standard physical education classes. Stabilographic tests were conducted at baseline and after 6-week training program. RESULTS: Both groups showed improved control of body balance in a standing position manifested in reductions of the length of path, surface area, and speed of deflection. Modified Pilates program was significantly more effective in improving body balance control in relaxed posture and with feet together than standard physical education classes. The greater efficiency of the modified Pilates program was expressed in a significant improvement in balance control parameters, i.e., path length, surface area, and speed of deflection. CONCLUSIONS: The modified Pilates program was more effective in improving body balance control in the hearing impaired people than standard physical education classes. Modification of physical activity recommendations for hearing impaired students may be considered; however, further research is required. Implications for Rehabilitation Hearing impairment impacts the mental, social and, physical spheres of life as well as deteriorates equivalent reactions and the way body posture is maintained. In hearing impaired people, control of body balance and muscle coordination is often disturbed, thus more attention should be paid to exercises associated with balance which may improve the ability to learn and develop motor skills. Modified Pilates program was significantly more effective in improving body balance control than standard physical education classes in hearing impaired people. PMID- 29132252 TI - Association between fetal myocardial performance index and fetal heart rate monitoring: a prospective observational cohort study. AB - OBJECTIVE: To evaluate whether the left myocardial performance index (MPI) changes in association with the fetal heart rate (FHR) tracing during labor. STUDY DESIGN: Women with term, singleton pregnancies, in labor were recruited to this prospective cohort study. PRIMARY OUTCOME: difference in left MPI between Category of fetal heart rate tracings. SECONDARY OUTCOMES: differences in left MPI by FHR characteristics. Participants underwent ultrasound examination, during which fetal MPI was measured. RESULTS: Twenty-four laboring patients were recruited. There were 13 patients with Category I FHR, 11 patients with Category II FHR, and 0 patients with Category III FHR. Demographics were similar between the groups. MPI was not significantly different between fetuses with Category I or Category II FHR (0.67 versus 0.65, p = .385). MPI was significantly higher in fetuses with accelerations versus those without (0.71 versus 0.59, p = .045). MPI was not significantly different for fetuses with or without decelerations (0.65 versus 0.68, p = .350), between deceleration type (0.50 versus 0.64 versus, 0.75, p = .421), or between variability type (0.56 versus 0.68, p = .113). CONCLUSIONS: MPI of fetuses in term, laboring patients did not vary with differing FHR characteristics except for the presence or absence of accelerations. PMID- 29132251 TI - Hearing impairment is common among Saami adults in Northern Finland. AB - : The Saami are the only indigenous population in Europe and their traditional living area is northern Scandinavia. Hearing impairment (HI) among Saami has not been studied before. The objective was to investigate the presence and type of HI among Saami adults, aged 49-77 years (median age 61 years), living in northern Finland. In addition, the presence of self-reported hearing difficulties, difficulties to hear in background noise and tinnitus were studied. An epidemiological, cross-sectional study encompassing a structured interview, otological examination and audiometry was performed. Bilateral HI was present in 42.9% of men and 29.4% of women, when HI was defined as a pure tone average (PTA) of at least 20 dB hearing level (HL) or more at the frequencies of 0.5, 1, 2 and 4 kHz. In one or both ears (worse ear hearing level, WEHL0.5,1,2,4>=20 dB HL) HI was present in 61.8% of men and 42.2% of women. Sensorineural high frequency hearing impairment was found to be most common. Nearly half (46.9%) of the study subjects reported hearing problems and more than half (55.6%) reported difficulties in following conversation in background noise. Measured HI and subjective hearing difficulties are common among the Saami adults. The healthcare personnel working in this area should be aware of the hearing problems of the Saami population. ABBREVIATIONS: ARHI, Age-related hearing impairment; PTA, Pure tone average; HI, Hearing impairment; HL, Hearing level; BEHL, Better ear hearing level; WEHL, Worse ear hearing level; CI, Confidence interval. PMID- 29132253 TI - New binary copper(II) complexes containing intercalating ligands: DNA interactions, an unusual static quenching mechanism of BSA and cytotoxic activities. AB - New binary copper(II) complexes - [Cu(4-mphen)2(NO3)]NO3.H2O (1), [Cu(5-mphen)2 (NO3)]NO3.H2O (2), the known complex [Cu(dmphen)2(NO3)]NO3 (3) and [Cu(tmphen)2 (NO3)]NO3.H2O (4) - (4-mphen: 4-methyl-1,10-phenanthroline, 5-mphen: 5-methyl 1,10-phenanthroline, dmphen: 4,7-dimethyl-1,10-phenanthroline, tmphen: 3,4,7,8 tetramethyl-1,10-phenanthroline), have been synthesized and characterized by CHN analysis, ESI-MS, FTIR and single-crystal X-ray diffraction techniques. Interaction of these complexes with calf thymus DNA (CT-DNA) has been investigated by absorption spectral titration, ethidium bromide (EB) and Hoechst 33,258 displacement assay and thermal denaturation measurement. These complexes cleaved pUC19 plasmid DNA in the absence and presence of an external agent. Notably, in the presence of H2O2 as an activator, the cleavage abilities of these complexes are obviously enhanced at low concentration. Addition of hydroxyl radical scavengers like DMSO shows significant inhibition of the DNA cleavage activity of these complexes. BSA quenching mechanism was investigated with regard to the type of quenching, binding constant, number of binding locations and the thermodynamic parameters. The experimental results suggested that the probable quenching mechanism was an unusual static process and hydrophobic forces play a dominant role. The CT-DNA and BSA binding efficiencies of these complexes follow the order: 4 > 3 > 1 > 2. Furthermore, in vitro cytotoxicities of these complexes on tumor cells lines (Caco-2, MCF-7 and A549) and healthy cell line (BEAS-2B) showed that these complexes exhibited anticancer activity with low IC50 values. The effect of hydrophobicity of the methyl-substituted phenanthrolines on DNA and protein binding activities of these complexes is discussed. PMID- 29132254 TI - Reverse-Flow Intrinsic Fasciocutaneous Island Flaps in Foot Reconstruction. AB - Reconstruction of soft tissue defects in the foot remains a challenge due to its specialized tissue for weightbearing and ambulation. Considering the principle of replacing "like with like," adjacent soft tissues would be a best option for a donor site. Although several kinds of reverse-flow island flaps for the lower leg have been well described, intrinsic foot reverse flow flaps have been rarely reported. We describe 3 kinds of reverse-flow intrinsic fasciocutaneous flaps (RIFFs) for foot reconstruction. From September 2012 to August 2015, a retrospective study was done on case notes of all patients who had a RIFF for coverage of soft tissue defects within the foot following trauma or tumor ablation. A total of 7 patients were included in this study, with an average of 5 * 3.5 cm sized defects in the forefoot, second and third web space, and sole, which were reconstructed with RIFF. All flaps were well perfused and recovered excellent function of the foot with satisfactory aesthetics and minimal limitations in range of motion. However, one case showed a complication of venous congestion, due to remnant scar tissues, which resolved after medical leech application. Donor defects healed completely with split thickness skin grafting in all cases. Soft tissue defects within the foot were repaired successfully by RIFF. In spite of its technical challenges, it is a reliable one-stage procedure requiring no microsurgical anastomosis. Precise vascular evaluation of the reverse inflow has to be preceded for satisfactory outcome of RIFF. PMID- 29132255 TI - Selected Radiation Safety Aspects Including Transportation and Lodging After Outpatient 131I Therapy for Differentiated Thyroid Cancer. AB - BACKGROUND: Whether radioactive iodine (131I) treatments for differentiated thyroid cancer should be performed as an outpatient or inpatient remains controversial. The objective of this study was to survey selected aspects of radiation safety of patients treated with 131I for differentiated thyroid cancer as an outpatient. METHODS: An e-mail invitation was sent to over 15,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc. to complete a web-based survey on selected aspects of radiation safety regarding their last outpatient 131I treatment. RESULTS: A total of 1549 patients completed the survey. Forty five percent (699/1541) of the respondents reported no discussion on the choice of an inpatient or outpatient treatment. Moreover, 5% (79/1541) of the respondents reported that their insurance company made the decision. Survey respondents recalled receiving oral and written radiation safety instructions 97% (1459/1504) and 93% (1351/1447) of the time, respectively. Nuclear medicine physicians delivered oral and written instructions to 54% (807/1504) and 41% (602/1462) of the respondents, respectively. Eighty-eight percent (1208/1370) of the respondents were discharged within 1 hour after receiving their 131I treatment, and 97% (1334/1373) traveled in their own car after being released from the treating facility. Immediately post-therapy, 94% (1398/1488) of the respondents stayed at their own home or a relative's home, while 5% (76/1488) resided in a public lodging. The specific recommendations received by patients about radiation precautions varied widely among the respondents. Ninety-nine percent (1451/1467) of the respondents believed they were compliant with the instructions. CONCLUSION: This is the largest, patient-based survey published regarding selected radiation safety aspects of outpatient 131I treatment. This survey suggests several concerns about radiation safety, such as the decision process regarding inpatient versus outpatient treatment, instructions about radiation safety, transportation, and lodging after radioiodine therapy. These concerns warrant further discussion, guidelines, and/or policies. PMID- 29132256 TI - MCP-1 produced by keratinocytes is associated with leucocyte recruitment during elicitation of nickel-induced occupational allergic contact dermatitis. AB - To investigate the expression profile of monocyte chemoattractant peptide-1 (MCP 1) by keratinocytes after nickel exposure and to identify its role for leucocyte migration during nickel-induced occupational allergic contact dermatitis (OACD), 26 workers diagnosed with nickel-induced OACD were enrolled. Skin biopsies from the positive nickel-challenged sites at different time points were assessed by immunohistochemistry (IHC) for MCP-1, CD68, CD45RO, and in situ hybridization (ISH) for MCP-1, using chronic periumbilical dermititis as controls. The expressions of MCP-1 in HaCaT cell culture after nickel treatment were quantified by enzyme-linked immunosorbent assay. The results showed that at positive nickel challenged sites, strong expressions of MCP-1, both messenger RNA (mRNA) and protein, were detected in the basal keratinocytes during the early phase (24-48 h after nickel application), paralleled by the recruitment of CD68+ and CD45RO+ cells to the skin compartments. The expressions of MCP-1 declined gradually in the late phase (72-96 h after nickel application). Treatment with nickel sulfate at noncytotoxic concentrations (0.01-100 uM) induced a concentration-related elevation of MCP-1 expression by HaCaT cells compared to the untreated cells. The data indicated that a temporal expression pattern of MCP-1 produced by keratinocytes after nickel exposure was involved in the complex process of mononuclear cell infiltration during elicitation of nickel-induced OACD. Targeting MCP-1 might be a potential therapeutic strategy for OACD. PMID- 29132257 TI - Risk factors for non-fatal occupational injuries among construction workers: A case-control study. AB - BACKGROUND: Substance abuse is a serious problem, because it affects both workers and young people. Prevalence and consequences of cannabis abuse among construction workers in particular are not well studied in Egypt. OBJECTIVES: To determine the association between non-fatal occupational injuries among construction workers and their demographic and occupational factors and to assess the frequency of cannabis abuse and its relationship to injury severity and workdays lost. SUBJECTS AND METHODS: A case-control study was conducted at Mansoura Emergency Hospital. Cases were 100 acutely injured male workers. A control group of 90 healthy age-matched workers was selected from 8 construction sites. Workers were interviewed, and a questionnaire was completed that included socio-demographic data, full occupational history, and causes and type of injury. Injury outcome measures included lost workdays and the injury severity score (ISS). Cannabis abuse in injured workers was monitored by preliminary testing of urine and confirmatory testing of blood. RESULTS: Logistic regression analysis revealed that the independent predictors of occupational injuries were rural residence, being a carpenter or painter and past history of injuries. The most common accidents were slipping falls (62%). Confirmed cannabis test was positive in 51.1% of the injured workers. Median days away from work were greater among cannabis users than non-users. The ISS was significantly higher among users compared to non-users ( p < 0.05). CONCLUSION: Cannabis abuse can increase injury severity and prolong workdays lost. Drug testing is recommended for at-risk construction workers with inadequate safety measures. PMID- 29132258 TI - Effect of three pretreatment techniques on the chemical composition and on the methane yields of Opuntia ficus-indica (prickly pear) biomass. AB - Opuntia ficus-indica (OFI) is an emerging biomass that has the potential to be used as substrate in anaerobic digestion. The goal of this work was to investigate the effect of three pretreatment techniques (thermal, alkaline, acidic) on the chemical composition and the methane yield of OFI biomass. A composite experimental design with three factors and two to three levels was implemented, and regression modelling was employed using a total of 10 biochemical methane potential (BMP) tests. The measured methane yields ranged from 289 to 604 NmL/gVSadded; according to the results, only the acidic pretreatment (HCl) was found to significantly increase methane generation. However, as the experimental values were quite high with regards to the theoretical methane yield of the substrate, this effect still needs to be confirmed via further research. The alkaline pretreatment (NaOH) did not noticeably affect methane yields (an average reduction of 8% was recorded), despite the fact that it did significantly reduce the lignin content. Thermal pretreatment had no effect on the methane yields or the chemical composition. Scanning electron microscopy images revealed changes in the chemical structure after the addition of NaOH and HCl. Modelling of the cumulated methane production by the Gompertz modified equation was successful and aided in understanding kinetic advantages linked to some of the pretreatments. For example, the alkaline treatment (at the 20% dosage) at room temperature resulted to a MUmax (maximum specific methane production rate [NmLCH4/(gVSadded.d)]) equal to 36.3 against 18.6 for the control. PMID- 29132259 TI - Costs associated with the management of waste from healthcare facilities: An analysis at national and site level. AB - Given rising spend on the provision of healthcare services, the sustainable management of waste from healthcare facilities is increasingly becoming a focus as a means of reducing public health risks and financial costs. Using data on per capita healthcare spend at the national level, as well as a case study of a hospital in Italy, this study examined the relationship between trends in waste generation and the associated costs of managing the waste. At the national level, healthcare spend as a percentage of gross domestic product positively correlated with waste arisings. At the site level, waste generation and type were linked to department type and clinical performance, with the top three highest generating departments of hazardous healthcare waste being anaesthetics (5.96 kg day-1 bed 1), paediatric and intensive care (3.37 kg day-1 bed-1) and gastroenterology digestive endoscopy (3.09 kg day-1 bed-1). Annual overall waste management costs were $US5,079,191, or approximately $US2.36 kg-1, with the management of the hazardous fraction of the waste being highest at $US3,707,939. In Italy, reduction in both waste arisings and the associated costs could be realised through various means, including improved waste segregation, and linking the TARI tax to waste generation. PMID- 29132260 TI - The psychological and social consequences of single-sided deafness in adulthood. AB - OBJECTIVES: This study examined the subjective psychological and social effects of highly asymmetric hearing loss (single-sided deafness [SSD]) in adults. DESIGN: Three group interviews were conducted using the critical incident technique and analysed using an inductive thematic analysis. STUDY SAMPLE: Eight adults with a clinical diagnosis of a moderately severe hearing loss or greater in one ear and normal or near-normal hearing in the other ear. RESULTS: A range of functional hearing difficulties associated with SSD including impaired speech in background noise and reduced spatial awareness were reported to affect social and psychological well-being. Social consequences of SSD resulted from activity limitations and participation restrictions including withdrawal from and within situations. Participants reported psychological effects including worrying about losing the hearing in their other ear, embarrassment related to the social stigma attached to hearing loss and reduced confidence and belief in their abilities to participate. CONCLUSIONS: Single-sided deafness can be associated with many negative consequences. Counselling may help overcome the psychological consequences of hearing loss regardless of whether technological support such as a hearing aid is prescribed. The audiological management of these individuals should support the development of listening strategies and set appropriate expectations for participation in everyday listening situations. PMID- 29132261 TI - Computational analyses of interactions between ALK-5 and bioactive ligands: insights for the design of potential anticancer agents. AB - Activin Receptor-Like Kinase 5 (ALK-5) is related to some types of cancer, such as breast, lung, and pancreas. In this study, we have used molecular docking, molecular dynamics simulations, and free energy calculations in order to explore key interactions between ALK-5 and six bioactive ligands with different ranges of biological activity. The motivation of this work is the lack of crystal structure for inhibitor-protein complexes for this set of ligands. The understanding of the molecular structure and the protein-ligand interaction could give support for the development of new drugs against cancer. The results show that the calculated binding free energy using MM-GBSA, MM-PBSA, and SIE is correlated with experimental data with r2 = 0.88, 0.80, and 0.94, respectively, which indicates that the calculated binding free energy is in excellent agreement with experimental data. In addition, the results demonstrate that H bonds with Lys232, Glu245, Tyr249, His283, Asp351, and one structural water molecule play an important role for the inhibition of ALK-5. Overall, we discussed the main interactions between ALK-5 and six inhibitors that may be used as starting points for designing new molecules to the treatment of cancer. PMID- 29132262 TI - Diastolic Dysfunction is Common in Survivors of Pediatric Differentiated Thyroid Carcinoma. AB - INTRODUCTION: Whether pediatric patients with differentiated thyroid carcinoma (DTC) are at risk of developing treatment-related adverse effects on cardiac function is unknown. We therefore studied in long-term survivors of pediatric DTC the prevalence of cardiac dysfunction and atrial fibrillation in relation to treatment variables, and the association between cardiac dysfunction and plasma biomarkers. METHODS: In this nationwide prospective multicenter study, cardiac assessments were performed in 66 adult survivors of pediatric DTC (age at diagnosis <=18 years and follow-up >=5 years after diagnosis) treated in the Netherlands between 1970 and 2009. Assessment included echocardiography, plasma biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive troponin-T, galectin-3), and 24-hour Holter electrocardiography. Echocardiographic measurements were compared with retrospective data of 66 sex- and age-matched unaffected Dutch controls. Diastolic dysfunction was defined as an early diastolic septal and/or lateral tissue velocity (e') less than 2 SD of mean age adjusted reference data. RESULTS: The survivors (86.4% women) had at DTC diagnosis a median age of 16 years. Median follow-up was 17 years. Left ventricular ejection fraction <50% was found in one survivor, and median global longitudinal systolic strain was near normal. Diastolic dysfunction was present in 14 asymptomatic survivors (21.2%). Overall, diastolic function of survivors was lower compared with controls (e'mean 14.5 versus 15.8 cm/s, P = 0.006). Older attained age and higher waist circumference were associated with decreased diastolic function, whereas thyrotropin levels and cumulative administered radioiodine dose were not. In survivors, biomarkers were not associated with diastolic dysfunction; atrial fibrillation was not observed. CONCLUSION: While systolic function is unaffected, diastolic dysfunction is frequently observed in asymptomatic long-term survivors of pediatric DTC, which may suggest early cardiac aging. PMID- 29132263 TI - Movement pattern and physiological response in recreational small-sided football effect of number of players with a fixed pitch size. AB - Recreational soccer is an effective health-promoting activity, but it is unclear how different game formats influence internal and external load. Thus, to be able to advise how to maximise the outcome of recreational football, we examined movement pattern and physiological response in 11 untrained men (32.6 +/- 6.7 yrs, 23.3 +/- 4.9 fat%, 43.4 +/- 5.3 ml.min-1.kg-1) during three football sessions comprising 4 * 12 min of 3v3, 5v5 or 7v7 with a constant pitch size of 20 * 40 m. Movement pattern, heart rate (HR), blood lactate and RPE were measured during and after the 12-min periods. Greater (P < 0.05) total distance and high speed distance was covered during 3v3 than 5v5 (14 and 30%) and 7v7 (15 and 75%). Mean HR was higher in 3v3 (85.7 +/- 5.7%HRmax) and 5v5 (84.2 +/- 5.1%HRmax) than in 7v7 (80.7 +/- 4.6%HRmax, P < 0.05) and percentage time >90%HR was higher in 3v3 (43 +/- 18%, P < 0.05) than in 5v5 (28 +/- 21%) and 7v7 (18 +/- 14%). Blood lactate was higher in 3v3 (7.4 +/- 2.7 mmol.l-1) than in 7v7 (4.5 +/- 2.2 mmol.l 1, P < 0.001) but not in 5v5 (6.1 +/- 2.1 mmol.l-1, P = 0.061). RPE was higher in 3v3 (6.7 +/- 2.3, P < 0.01) than in 5v5 (5.2 +/- 2.2) and 7v7 (4.3 +/- 2.3). In conclusion, higher external and internal load was found with fewer players, when the pitch size is fixed. PMID- 29132264 TI - Leg amputation side determines performance in curve sprinting: a case study on a Paralympic medalist. AB - The lower limb kinetics of curve sprinting in amputees are not well described in the literature, particularly with respect to the effect of the side of amputation. This is an issue due to the importance of the knowledge for prosthetic design and classification of athletes. Thus, the aim of this study was to investigate the influence of side of amputation on curve sprinting performance in athletes with a unilateral leg amputation. A three-dimensional motion analysis system (Vicon), four force plates (Kistler) and a modified mathematical human model (ALASKA) were used to compare clockwise and counter clockwise curve sprinting lower limb kinematics and kinetics of a Paralympic medalist with a left sided knee exarticular amputation. Results reveal that vertical ground reaction force application and total vertical impulse were lower when the affected limb was at the inside of the curve. The unaffected limb showed joint mechanics different to those established for non-amputee athletes and might contribute better to propulsion when being the inside limb. Curve sprinting biomechanics and the ability to attain high radial velocities are directly dependent on the side of amputation relative to the curve direction in a unilateral amputee athlete of highest performance level. PMID- 29132265 TI - Time-based prospective memory in children and adolescents with 22q11.2 deletion syndrome. AB - OBJECTIVE: 22q11.2 deletion syndrome, also known as velo-cardio-facial syndrome (VCFS) is a genetic disorder caused by a microdeletion on chromosome 22q11.2 and characterized by marked impairment in visual attention and executive function. The present study examined if this cognitive deficit extends to prospective memory (the type of memory involved in remembering to perform actions in the future). METHOD: 20 participants with 22q11.2DS aged between 6 and 14 were included in the study as well as 22 typically developing individuals (TDC) aged 6 12. To measure prospective memory, participants were asked to play a driving game (the Dresden Cruiser). This time-based prospective memory task required children to remember to refuel their car when the fuel level was low by pressing a refuel button while driving. RESULTS AND DISCUSSION: Participants with 22q11.2DS remembered less often to refuel the car. Furthermore, participants with 22q11.2DS checked the fuel gage significantly less often than the controls. CONCLUSIONS: Participants with 22q11.2DS therefore demonstrate difficulties completing a time based prospective memory task. This can be explained by a generally less frequent time checking behavior in comparison to TDC. PMID- 29132266 TI - In-Silico molecular docking and simulation studies on novel chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage as vital inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. AB - The structural motifs of chalcones, flavones, and triazoles with varied substitutions have been studied for the antimalarial activity. In this study, 25 novel derivatives of chalcone and flavone hybrid derivatives with 1, 2, 3 triazole linkage are docked with Plasmodium falciparum dihydroorotate dehydrogenase to establish their inhibitory activity against Plasmodium falciparum. The best binding conformation of the ligands at the catalytic site of dihydroorotate dehydrogenase are selected to characterize the best bound ligand using the best consensus score and the number of hydrogen bond interactions. The ligand namely (2E)-3-(4-{[1-(3-chloro-4-fluorophenyl)-1H-1, 2, 3-triazol-4 yl]methoxy}-3-methoxyphenyl-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one, is one the among the five best docked ligands, which interacts with the protein through nine hydrogen bonds and with a consensus score of five. To refine and confirm the docking study results, the stability of complexes is verified using Molecular Dynamics Simulations, Molecular Mechanics /Poisson-Boltzmann Surface Area free binding energy analysis, and per residue contribution for the binding energy. The study implies that the best docked Plasmodium falciparum dihydroorotate dehydrogenase-ligand complex is having high negative binding energy, most stable, compact, and rigid with nine hydrogen bonds. The study provides insight for the optimization of chalcone and flavone hybrids with 1, 2, 3-triazole linkage as potent inhibitors. PMID- 29132267 TI - Spatial Bias Induced by Simple Addition and Subtraction: From Eye Movement Evidence. AB - The associations between number and space have been intensively investigated. Recent studies indicated that this association could extend to more complex tasks, such as mental arithmetic. However, the mechanism of arithmetic-space associations in mental arithmetic was still a topic of debate. Thus, in the current study, we adopted an eye-tracking technology to investigate whether spatial bias induced by mental arithmetic was related with spatial attention shifts on the mental number line or with semantic link between the operator and space. In Experiment 1, participants moved their eyes to the corresponding response area according to the cues after solving addition and subtraction problems. The results showed that the participants moved their eyes faster to the leftward space after solving subtraction problems and faster to the right after solving addition problems. However, there was no spatial bias observed when the second operand was zero in the same time window, which indicated that the emergence of spatial bias may be associated with spatial attention shifts on the mental number line. In Experiment 2, participants responded to the operator (operation plus and operation minus) with their eyes. The results showed that mere presentation of operator did not cause spatial bias. Therefore, the arithmetic-space associations might be related with the movement along the mental number line. PMID- 29132268 TI - Simplifying Logistics and Avoiding the Unnecessary in Patients With Breast Cancer Undergoing Sentinel Node Biopsy. A Prospective Feasibility Trial of the Preoperative Injection of Super Paramagnetic Iron Oxide Nanoparticles. AB - PURPOSE: Sentinel node is routinely localized with the intraoperative use of a radioactive tracer, involving challenging logistics. Super paramagnetic iron oxide nanoparticle is a non-radioactive tracer with comparable performance that could allow for preoperative localization, would simplify the procedure, and possibly be of value in axillary mapping before neoadjuvant treatment. The current trial aimed to determine the a priori hypothesis that the injection of super paramagnetic iron oxide nanoparticles in the preoperative period for the localization of the sentinel node is feasible. METHODS: This is a prospective feasibility trial, conducted from 9 September 2014 to 22 October 2014 at Uppsala University Hospital. In all, 12 consecutive patients with primary breast cancer planned for resection of the primary and sentinel node biopsy were recruited. Super paramagnetic iron oxide nanoparticles were injected in the preoperative visit in the outpatient clinic. The radioactive tracer (99mTc) and the blue dye were injected perioperatively in standard fashion. A volunteer was injected with super paramagnetic iron oxide nanoparticles to follow the decline in the magnetic signal in the sentinel node over time. The primary outcome was successful sentinel node detection. RESULTS: Super paramagnetic iron oxide nanoparticles' detection after preoperative injection (3-15 days) was successful in all cases (100%). In the volunteer, axillary signal was presented for 4 weeks. No adverse effects were noted. Conclusion and relevance: Preoperative super paramagnetic iron oxide nanoparticles' injection is feasible and leads to successful detection of the sentinel node. That may lead to simplified logistics as well as the identification, sampling, and marking of the sentinel node in patients planned for neoadjuvant treatment. PMID- 29132269 TI - Correlation of Concussion Symptom Profile with Head Impact Biomechanics: A Case for Individual-Specific Injury Tolerance. AB - Concussion is a brain injury induced by biomechanical forces that is broadly defined as a complex pathophysiological process affecting the brain. The intricate link between biomechanical input and concussion injury response is poorly understood. We aimed to test the hypothesis that greater biomechanical forces would result in the presentation of more concussion-related symptoms that would take longer to resolve. The objective of this study was to investigate the relationship between an array of biomechanical parameters measured for concussive impacts and the presentation and resolution of concussion symptoms. A total of 319 collegiate football players from six universities were recruited to participate in this study. Certified athletic trainers and/or team physicians at each site diagnosed and treated concussions sustained by subjects through participation in football. The subjects' helmets were instrumented with accelerometer arrays that measured linear and rotational head accelerations for each impact experienced during games and practices. Correlations between biomechanical measurements associated with concussion symptom presentation and recovery were quantified. A total of 22 subjects collectively sustained 25 concussions, with three subjects sustaining two concussions each. Biomechanical measures associated with injury were not found to be correlated with number of symptoms, Sport Concussion Assessment Tool 3 Symptom Severity Score, or time to symptom resolution. Linear and rotational accelerations associated with injury were not correlated with symptom severity for any of the 22 individual symptoms evaluated. Further, we found no association between impact location and presence of any individual symptom when ignoring severity grade. While concussive impacts did not stand out relative to impacts that did not result in injury, concussive impacts were among the most severe for each individual player. This suggests tolerance to head acceleration might be individual-specific, meaning similar biomechanical inputs can produce different injury presentations between individuals. Future investigations should consider individual-specific analyses of tolerance to head acceleration and injury response. PMID- 29132270 TI - Occupational exposure, attitude to HIV-positive patients and uptake of HIV counselling and testing among health care workers in a tertiary hospital in Nigeria. AB - Health care workers (HCWs) are at risk of occupational exposure to HIV. Their attitude to HIV-positive patients influences patients' willingness and ability to access quality care. HIV counselling and testing (HCT) services are available to inform HCWs and patients about their status. There is little information about HCT uptake and attitude to HIV-positive patients among HCWs in tertiary health facilities in Nigeria. The aim of this study was to determine occupational exposure and attitude to HIV-positive patients and level of uptake of HCT services among HCWs in a tertiary hospital in Nigeria. A cross-sectional design was utilized. A total of 977 HCWs were surveyed using semi-structured, self administered questionnaires. Nurses and doctors comprised 78.2% of the respondents. Their mean age was 35 +/- 8.4 years. Almost half, 47.0%, reported accidental exposure to blood and body fluids (BBFs) in the preceding year. The main predictor of accidental exposure to BBFs in the last year was working in a surgical department, OR = 1.7, 95% CI (1.1-2.6). HCWs aged <40 years, OR = 5.5, 95% CI (1.9-15.9), who had worked for >5 years, OR = 3.6, 95% CI (1.4-9.3) and who work in nursing department, OR = 6.8, 95% CI (1.7-27.1) were more likely to be exposed to BBFs. Almost half, 52.9%, had accessed HCT services. Predictors for HCT uptake were age <40 years OR = 1.6, 95% CI (1.1-2.4), having worked for >5 years OR = 1.5, 95% CI (1.03-2.2) and working in medical department OR = 1.7, 95% CI (1.1-2.8). Respondents in nursing departments were more likely to require routine HIV test for all patients, OR = 3.9, 95% CI (2.4-6.2). HCWs in the laboratory departments were more likely to believe that HIV patients should be on separate wards, OR = 3.6, 95% CI (1.9-7.0). HCWs should be protected and encouraged to access HCT services in order to be effective role models in the prevention of HIV/AIDS. PMID- 29132271 TI - Capgras Syndrome in Advanced Parkinson's Disease. AB - Psychosis is common in Parkinson's disease (PD), especially in advanced disease, and can lead to a number of psychotic symptoms, including delusions. One uncommon delusion is Capgras syndrome (CS). The authors report on three PD patients with a history of deep brain stimulation (DBS) who developed this delusion. The anatomic targets in these three patients were the subthalamic nuclei in two patients and the globus pallidus interna in one patient. The length of time between surgery and development of CS varied but was greater than 6 months. Additionally, all three patients showed evidence of impaired cognition prior to development of CS. Therefore, due to the length of time between DBS and CS in all three cases and the fact that one patient developed CS months after DBS explanation, DBS does not appear to be associated with CS. Given the distressing nature of this condition, patients with advanced PD who undergo DBS should be regularly screened for symptoms of psychosis with awareness of CS as a potential form. PMID- 29132272 TI - Traumatic Brain Injury and Posttraumatic Stress Disorder: Conceptual, Diagnostic, and Therapeutic Considerations in the Context of Co-Occurrence. AB - The events leading to traumatic brain injury (TBI) are often psychologically traumatic (e.g., motor vehicle accidents) or occur within a broader context of psychological trauma, such as military combat or recurrent interpersonal violence. In such cases, posttraumatic stress disorder (PTSD) may develop and serve to complicate TBI recovery. Likewise, brain trauma may impede emotional resolution following psychological trauma exposure. This article addresses comorbid PTSD and TBI, including the epidemiology of PTSD following TBI; the clinical presentation of the comorbidity; potential mechanisms that complicate recovery from psychological trauma and TBI when they co-occur; and considerations for the clinical management of PTSD in the context of TBI, including implications for both psychosocial and psychopharmacological PTSD treatments. Although the authors address the full spectrum of TBI severity, because PTSD more commonly co occurs with mild TBI, compared with moderate and severe TBI, the authors focus in particular on mild TBI. PMID- 29132273 TI - Neuropsychiatric Factors Linked to Adherence and Short-Term Outcome in a U.S. Functional Neurological Disorders Clinic: A Retrospective Cohort Study. AB - Despite advancements in the assessment and management of functional neurological disorder (FND), the feasibility of implementing a new standard of care remains unclear. Chart reviews were performed for 100 patients with motor FND to investigate factors related to treatment adherence and clinical improvement over an average follow-up of 7 months. Of 81 patients who returned for follow-up, a history of chronic pain disorder inversely correlated with improvement. Of the 50 individuals newly referred for treatment, adherence correlated with improvement, while having abnormal neuroimaging inversely correlated with improvement. This study supports the feasibility of applying a new standard of care for FND. PMID- 29132274 TI - Olanzapine Improved Symptoms and Olfactory Function in an Olfactory Reference Syndrome Patient. PMID- 29132276 TI - Atlantic Crossings. PMID- 29132275 TI - Evidence of Biased Advertising in the Case of Social Egg Freezing. AB - Oocyte cryopreservation, or 'egg freezing,' is the practice of preserving unfertilised oocytes for later fertilisation. This practice allows women to extend their reproductive years. In 2014, Facebook and Apple announced that they would subsidise their female employees' elective - or 'social' - use of egg freezing so that these women can more easily reconcile the demands of career and family life. This announcement engendered controversy and moral debate. Given that social egg freezing (SEF) is becoming more popular, ethical and empirical analyses are warranted. Here, I utilise content analysis to examine media messages in advertising for SEF. I conclude that many fertility clinics engage in biased advertising - i.e. they advertise the service persuasively, not informatively, emphasising indirect benefits while minimising risks and the low chance of successfully bringing a child to term. As advertising for medical services has been shown to influence the use of those services, advertising for SEF should emphasise clear and easily interpretable statistics about success rate, usage rate, cost, and risk. PMID- 29132277 TI - Legal responses to HIV and AIDS: lessons from Swaziland. AB - Since 1999, the HIV and AIDS epidemic in Swaziland has been declared a national disaster, and today HIV and AIDS still pose a great threat to the survival and development of Swaziland and its people. The impact of the pandemic necessitated a multi-faceted response from the government. This paper critically evaluates the Swaziland legal response to HIV and AIDS. The objective is to assess whether and to what extent Swazi law addresses human rights issues related to HIV and AIDS. Through the application of a human rights based theory, the paper analyses the domestication of Swaziland's treaty commitments, and the constitutional and the statutory frameworks. The paper advances the importance of "law" as a tool that can create an enabling environment for a national response to HIV and AIDS. It analyses how the government has successfully crafted the normative framework so as to make it responsive to the fight against HIV and AIDS, and the shortcomings of the Swaziland legal system in this fight. The paper argues that even though a credible legal and policy environment is in place, some laws still need to be supplemented, reviewed and amended so that the legal system adequately addresses the human rights issues related to HIV and AIDS. The paper suggests improvements to the legal system which mainly relate to aligning the legal framework with the Constitution of Swaziland and international conventions to which Swaziland is party. PMID- 29132278 TI - Gendered childcare norms - evidence from rural Swaziland to inform innovative structural HIV prevention approaches for young women. AB - Addressing discriminatory gender norms is a prerequisite for preventing HIV in women, including young women. However, the gendered expectation that women will perform unpaid childcare-related labour is rarely conceptualised as influencing their HIV risk. Our aim was to learn from members of a rural Swazi community about how gendered childcare norms. We performed sequential, interpretive analysis of focus group discussion and demographic survey data, generated through participatory action research. The results showed that gendered childcare norms were firmly entrenched and intertwined with discriminatory norms regarding sexual behaviour. Participants perceived that caring for children constrained young women's educational opportunities and providing for children's material needs increased their economic requirements. Some young women were perceived to engage in "transactional sex" and depend financially on men, including "sugar daddies", to provide basic necessities like food for the children they cared for. Our results suggested that men were no longer fulfilling their traditional role of caring for children's material needs, despite women's traditional role of caring for their physical and emotional needs remaining firmly entrenched. The results indicate that innovative approaches to prevent HIV in young women should incorporate structural approaches that aim to transform gendered norms, economically empower women and implement policies guaranteeing women equal rights. PMID- 29132279 TI - "I will take ARVs once my body deteriorates": an analysis of Swazi men's perceptions and acceptability of Test and Start. AB - Swaziland has the highest HIV prevalence in the world. To mitigate the spread and devastation caused by HIV and to improve the wellbeing of people living with HIV, the country has adopted the latest available HIV prevention campaigns, including "Test and Start". Because evidence from randomised controlled trials has demonstrated a significant risk reduction in HIV transmission when HIV-positive people start antiretroviral therapy (ART) early, Swaziland aims to find these people and link them to treatment. This study presents findings regarding the perceptions of this promising HIV-prevention intervention among men aged 17-69 years. A combination of qualitative methods including focus group discussions (12), in-depth interviews (17), informal conversations and participant observation (21) were used to collect data in two peri-urban communities in 2013 2014. Findings illustrate that men still fear taking an HIV test because of a relatively high probability of a positive test which some still interpret as a death sentence. Other potential barriers to the effectiveness of Test and Start programmes include lack of hospitality in hospitals, fear of starting treatment early related to side effects of ART, poverty, and lack of trust in the financial stability of the Swazi government. We argue that several social factors need to be considered for the Test and Start programme to be more effective. PMID- 29132280 TI - Mixed results: the protective role of schooling in the HIV epidemic in Swaziland. AB - Swaziland has the highest HIV prevalence in the world. It is recognised that young women, especially adolescents, are particularly vulnerable to HIV infection and bear a disproportionate burden of HIV incidence. The HIV data from Swaziland show the location of the epidemic, which is particularly high among adolescent girls and young women. This paper is based on research in Swaziland, commissioned because of the perception that large numbers of children were dropping out of the school. It was assumed that these "dropouts" had increased risk of HIV exposure. This study carried out a detailed analysis using the Annual Education Census Reports from 2012 to 2014 produced by the Ministry of Education. In addition, this topic was explored, during fieldwork with key informants in the country. While HIV prevalence rises rapidly among young women in Swaziland, as is the case across most of Southern Africa, the data showed there were few dropouts. This was the case at all levels of education - primary, junior secondary and senior secondary. The major reason for dropping out of primary school was family reasons; and in junior and senior secondary, pregnancy was the leading cause. Swaziland is doing well in terms of getting its children into school, and, for the most part, keeping them there. This paper identifies the students who face increased vulnerability: the limited number of dropouts; repeaters who consequently were "out-of-age for grade"; and orphans and vulnerable children (OVC). The learners who were classified as repeaters and OVC greatly outnumbered the dropouts. We argue, on the basis of these data, for re-focussed attention and the need to develop a method for tracking children as they move across the vulnerable groups. We acknowledge schooling is protective in reducing children's vulnerability to HIV, and Swaziland is on the right track in education, although there are challenges. PMID- 29132282 TI - HIV research impact: the quest for a helix. PMID- 29132281 TI - Constrained relationship agency as the risk factor for intimate partner violence in different models of transactional sex. AB - Women who engage in transactional sex are more likely to experience intimate partner violence (IPV) and are at higher risk of HIV. However, women engage in transactional sex for a variety of reasons and the precise mechanism linking transactional sex and IPV is not fully understood. We conducted a behavioural survey with a cross-sectional sample of 401 women attending 1 rural and 1 urban public antenatal clinic in Swaziland between February and June 2014. We used structural equation modelling to identify and measure constrained relationship agency (CRA) as a latent variable, and then tested the hypothesis that CRA plays a significant role in the pathway between IPV and transactional sex. After controlling for CRA, receiving more material goods from a sexual partner was not associated with higher levels of physical or sexual IPV and was protective against emotional IPV. CRA was the single largest predictor of IPV, and more education was associated with decreased levels of constrained relationship agency. Policies and interventions that target transactional sex as a driver of IPV and HIV may be more successful if they instead target the broader social landscape that constrains women's agency and drives the harmful aspects of transactional sex. PMID- 29132283 TI - Predictors of survival among HIV-positive children on ART in Swaziland. AB - The objective of the study was to determine predictors of survival among HIV positive children (<15 years) in Swaziland. A retrospective cohort analysis of medical records for 4 167 children living with HIV who were initiated on antiretroviral therapy (ART) between 2004 and 2008, and followed up until 2014 was conducted in clinical settings at 36 health facilities. The Kaplan Meier Estimator, signed-ranks test, and the Cox proportional hazards regression model were applied to determine survival probabilities, significant difference among stratified survival functions and adjusted hazard ratios respectively. The results reveal that the median survival time for children was 78 months (95% CI: 77-79). Children who were initiated early on ART had higher survival probability over time (HR: 0.35 [95% CI: 0.21-0.57], p < 0.001) compared to those whose ART initiation was delayed. Children within the age group of <1 years had higher hazard (HR = 1.55 [95% CI: 1.16-2.08], p < 0.001) of death than children within the age group of 1-14 years. Children who were nourished had 88% lower hazard of death (HR: 0.12 [95% CI: 0.07-0.19], p < 0.001) than severely malnourished children. The study demonstrates that ART paediatric services are effective in increasing survival among HIV infected children and early initiated children have high survival probability. Active tuberculosis (TB), malnutrition, and delayed ART initiation remain predictors of poor survival among children living with HIV. PMID- 29132284 TI - Love matters: exploring conceptions of love in Rwanda and Swaziland and relationship to HIV and intimate partner violence. AB - Health risks such as intimate partner violence (IPV) and HIV infection often occur within intimate sexual relationships, yet the study of love and intimacy is largely absent from health research on African populations. This study explores how women and men in Rwanda and Swaziland understand and represent love in their intimate sexual partnerships. In Rwanda, 58 in-depth interviews with 15 couples, 12 interviews with activists, and 24 focus group discussions were carried out during formative and evaluative research of the Indashyikirwa programme, which aims to reduce IPV and support healthy couple relationships. In Swaziland, 117 in depth, life-course interviews with 14 women and 14 men focused on understanding intimate sexual partnerships. We analysed these qualitative data thematically using a Grounded Theory approach. Participants described love as being foundational to their intimate sexual partnerships. Women and men emphasised that love is seen and expressed through actions and tangible evidence such as gifts and material support, acts of service, showing intentions for marriage, sexual faithfulness, and spending time together. Some participants expressed ambivalent narratives regarding love, gifts, and money, acknowledging that they desired partners who demonstrated love through material support while implying that true love should be untainted by desires for wealth. IPV characterised many relationships and was perceived as a threat to love, even as love was seen as a potential antidote to IPV. Careful scholarship of love is critical to better understand protective and risk factors for HIV and IPV and for interventions that seek to ameliorate these risks. PMID- 29132285 TI - Empowering caregivers of orphans and vulnerable children in Swaziland. AB - This paper reports on the health and psychosocial impacts of a programme designed to economically empower female caregivers of orphans and vulnerable children (OVC). The results presented are from a cohort of 492 female caregivers who participated in savings groups and were responsible for 887 OVC. The data showed that the caregivers had increased earnings, borrowed more, repaid their loans, and expanded their businesses. Important health impacts were found for both the caregivers and the OVC. Access to health care increased and the proportion of OVC and caregivers who reported being too ill to take part in daily activities decreased. Results showed that WORTH savings group members increased their financial resources and used them to improve the wellbeing of OVC in their care. The economic and social empowerment had a positive impact on child protection, child wellbeing and health. PMID- 29132286 TI - The gendered experiences of children in child-headed households in Swaziland. AB - This study investigated the gender dynamics of living in child-headed households (CHHs) in a rural area in Swaziland that experiences high levels of drought, poverty and HIV and AIDS. Using a qualitative research methodology, the study examined ways in which children in CHHs meet their daily family needs and address their vulnerabilities according to their gender, focusing on the experiences of the children. The study sample consisted of 10 households, with 5 boy and 5 girl headed households from the chiefdoms within the area. A semi-structured interview guide was used to conduct interviews in the respondents' own homes. The study focused on the gendered coping strategies used by the children to sustain their household welfare. Three factors were examined: leadership, food provision and education. The findings show that birth order conferred headship or leadership to the eldest sibling irrespective of their gender. Variations in the performance of the three factors, which were influenced by the gender of the household head, were observed. Generally, the children acted in accordance with their socio cultural norms demanded in fulfilling the role of leadership and food provision. Boy-headed households become disadvantaged because of the boys' reluctance to take tasks which would contravene traditional Swazi notions of masculinity. This was exacerbated by societal expectations of the independence of boys. Hegemonic masculinity puts boys at a disadvantage when societal expectations require them to enact their masculinity through independence, rather than by drawing on the support of their neighbours/family/social networks. However, girls conformed to traditional Swazi norms. Societal compassion with the vulnerability of girls produced sustainable social arrangements and fostered resilience in girl-headed households. PMID- 29132290 TI - History of the HIV epidemic and response in Swaziland. PMID- 29132287 TI - A qualitative analysis of the barriers to antiretroviral therapy initiation among children 2 to 18 months of age in Swaziland. AB - HIV/AIDS remains one of the leading causes of death among children under 5 years old in Swaziland. Although studies have shown that early initiation of infants and children diagnosed with HIV on antiretroviral therapy (ART) significantly reduces mortality, many children do not initiate ART until the later stages of disease. This study was designed to collect qualitative data from mothers and caregivers of HIV-positive children to identify the barriers to ART initiation. Focus group discussion (FGD) sessions were conducted in siSwati between July and September 2014 among caregivers of aged children 2-18 months in Swaziland who did or did not initiate ART between January 2011 and December 2012 after HIV DNA PCR positive diagnosis of the infants. Denial, guilt, lack of knowledge, tuberculosis (TB)/HIV co-infection, HIV-related stigma, lack of money, and distance to clinics were reported by the participants as barriers to ART initiation. The findings further revealed that non-initiation on ART was not linked to a negative perception of the treatment. Findings suggest a need to improve sensitivity among healthcare workers as well as education and counselling services that will facilitate the ART initiation process. PMID- 29132291 TI - HIV prevention needs for men who have sex with men in Swaziland. AB - Men who have sex with men (MSM) have a high HIV burden and also often face multiple other challenges accessing HIV services, including legal and social issues. Although Swaziland recently started responding with interventions for MSM, significant gaps still exist both in information and programming. This study aimed to explore the HIV prevention needs of MSM in Swaziland, including factors elevating their risks and vulnerabilities to HIV infection; to find out what HIV prevention strategies exist; and to determine how best to meet the prevention needs of MSM. A total of 50 men who reported anal sex with other men in the past 12 months were recruited through simple respondent driven sampling. They completed either a structured quantitative survey (n = 35) or participated in a semi-structured qualitative interview (n = 15). Both quantitative and qualitative findings indicated perceived and experienced stigma among MSM. This predominantly manifested as internalised stigma, which may lead to alcohol abuse and sexual risky behaviours. At least 83% (29/35) of the quantitative sample had been labelled with derogatory terms because of their sexual orientation, while 66% (23/35) had experienced being avoided. There was limited knowledge of risk practices: When asked, 54% (19/35) of quantitative respondents reported that vaginal and anal sex carry an equal risk of HIV infection. Participants also had little knowledge on new HIV prevention methods such as pre-exposure prophylaxis (PrEP) and rectal microbicides. MSM needs included safe spaces in form of drop-in centres and non-hostile HIV services. Although Swaziland recently started interventions for key populations, including MSM, there is still a general lack on information to inform managers and implementers on the HIV prevention needs of MSM in Swaziland. Such information is crucial for designers of official and HIV programmes. Research is needed to increase knowledge on the HIV prevention needs for key populations, including MSM. PMID- 29132292 TI - fLPS: Fast discovery of compositional biases for the protein universe. AB - BACKGROUND: Proteins often contain regions that are compositionally biased (CB), i.e., they are made from a small subset of amino-acid residue types. These CB regions can be functionally important, e.g., the prion-forming and prion-like regions that are rich in asparagine and glutamine residues. RESULTS: Here I report a new program fLPS that can rapidly annotate CB regions. It discovers both single-residue and multiple-residue biases. It works through a process of probability minimization. First, contigs are constructed for each amino-acid type out of sequence windows with a low degree of bias; second, these contigs are searched exhaustively for low-probability subsequences (LPSs); third, such LPSs are iteratively assessed for merger into possible multiple-residue biases. At each of these stages, efficiency measures are taken to avoid or delay probability calculations unless/until they are necessary. On a current desktop workstation, the fLPS algorithm can annotate the biased regions of the yeast proteome (>5700 sequences) in <1 s, and of the whole current TrEMBL database (>65 million sequences) in as little as ~1 h, which is >2 times faster than the commonly used program SEG, using default parameters. fLPS discovers both shorter CB regions (of the sort that are often termed 'low-complexity sequence'), and milder biases that may only be detectable over long tracts of sequence. CONCLUSIONS: fLPS can readily handle very large protein data sets, such as might come from metagenomics projects. It is useful in searching for proteins with similar CB regions, and for making functional inferences about CB regions for a protein of interest. The fLPS package is available from: http://biology.mcgill.ca/faculty/harrison/flps.html , or https://github.com/pmharrison/flps , or is a supplement to this article. PMID- 29132293 TI - Genomic regions associated with host response to porcine reproductive and respiratory syndrome vaccination and co-infection in nursery pigs. AB - BACKGROUND: The WUR1000125 (WUR) single nucleotide polymorphism (SNP) can be used as a genetic marker for host response to porcine reproductive and respiratory syndrome (PRRS), PRRS vaccination, and co-infection with porcine circovirus type 2b (PCV2b). Objectives of this study were to identify genomic regions other than WUR associated with host response to PRRS vaccination and PRRSV/PCV2b co infection and regions with a different effect on host response to co-infection, depending on previous vaccination for PRRS. METHODS: Commercial crossbred nursery pigs were pre-selected for WUR genotype (n = 171 AA and 198 AB pigs) where B is the dominant and favorable allele. Half of the pigs were vaccinated for PRRS and 4 weeks later, all pigs were co-infected with PRRS virus and PCV2b. Average daily gain (ADG) and viral load (VL) were quantified post vaccination (Post Vx) and post co-infection (Post Co-X). Single-SNP genome-wide association analyses were then conducted to identify genomic regions associated with response to vaccination and co-infection. RESULTS: Multiple SNPs near the major histocompatibility complex were significantly associated with PCV2b VL (-log 10 P >= 5.5), regardless of prior vaccination for PRRS. Several SNPs were also significantly associated with ADG Post Vx and Post Co-X. SNPs with a different effect on ADG, depending on prior vaccination for PRRS, were identified Post Vx ( log 10 P = 5.6) and Post Co-X (-log 10 P = 5.5). No SNPs were significantly associated with vaccination VL (-log10 P <= 4.7) or PRRS VL (-log10 P <= 4.3). Genes near SNPs associated with vaccination VL, PRRS VL, and PCV2b VL were enriched (P <= 0.01) for immune-related pathways and genes near SNPs associated with ADG were enriched for metabolism pathways (P <= 0.04). SNPs associated with vaccination VL, PRRS VL, and PCV2b VL showed overrepresentation of health QTL identified in previous studies and SNPs associated with ADG Post Vx of Non-Vx pigs showed overrepresentation of growth QTL. CONCLUSIONS: Multiple genomic regions were associated with PCV2b VL and ADG Post Vx and Post Co-X. Different SNPs were associated with ADG, depending on previous vaccination for PRRS. Results of functional annotation analyses and novel approaches of using previously-reported QTL support the identified regions. PMID- 29132295 TI - Correction to: Dual transcriptome of the immediate neutrophil and Candida albicans interplay. PMID- 29132294 TI - Artificial selection for odor-guided behavior in Drosophila reveals changes in food consumption. AB - BACKGROUND: The olfactory system enables organisms to detect chemical cues in the environment and can signal the availability of food or the presence of a predator. Appropriate behavioral responses to these chemical cues are therefore important for organismal survival and can influence traits such as organismal life span and food consumption. However, understanding the genetic mechanisms underlying odor-guided behavior, correlated responses in other traits, and how these constrain or promote their evolution, remain an important challenge. Here, we performed artificial selection for attractive and aversive behavioral responses to four chemical compounds, two aromatics (4-ethylguaiacol and 4 methylphenol) and two esters (methyl hexanoate and ethyl acetate), for thirty generations. RESULTS: Artificial selection for odor-guided behavior revealed symmetrical responses to selection for each of the four chemical compounds. We then investigated whether selection for odor-guided behavior resulted in correlated responses in life history traits and/or food consumption. We found changes in food consumption upon selection for behavioral responses to aromatics. In many cases, lines selected for increased attraction to aromatics showed an increase in food consumption. We then performed RNA sequencing of lines selected for responses to 4-ethylguaiacol to identify candidate genes associated with odor guided behavior and its impact on food consumption. We identified 91 genes that were differentially expressed among lines, many of which were associated with metabolic processes. RNAi-mediated knockdown of select candidate genes further supports their role in odor-guided behavior and/or food consumption. CONCLUSIONS: This study identifies novel genes underlying variation in odor-guided behavior and further elucidates the genetic mechanisms underlying the interrelationship between olfaction and feeding. PMID- 29132296 TI - A fragment based method for modeling of protein segments into cryo-EM density maps. AB - BACKGROUND: Single-particle analysis of electron cryo-microscopy (cryo-EM) is a key technology for elucidation of macromolecular structures. Recent technical advances in hardware and software developments significantly enhanced the resolution of cryo-EM density maps and broadened the applicability and the circle of users. To facilitate modeling of macromolecules into cryo-EM density maps, fast and easy to use methods for modeling are now demanded. RESULTS: Here we investigated and benchmarked the suitability of a classical and well established fragment-based approach for modeling of segments into cryo-EM density maps (termed FragFit). FragFit uses a hierarchical strategy to select fragments from a pre-calculated set of billions of fragments derived from structures deposited in the Protein Data Bank, based on sequence similarly, fit of stem atoms and fit to a cryo-EM density map. The user only has to specify the sequence of the segment and the number of the N- and C-terminal stem-residues in the protein. Using a representative data set of protein structures, we show that protein segments can be accurately modeled into cryo-EM density maps of different resolution by FragFit. Prediction quality depends on segment length, the type of secondary structure of the segment and local quality of the map. CONCLUSION: Fast and automated calculation of FragFit renders it applicable for implementation of interactive web-applications e.g. to model missing segments, flexible protein parts or hinge-regions into cryo-EM density maps. PMID- 29132297 TI - Association between beta2-adrenergic receptor gene polymorphisms and adverse events of ritodrine in the treatment of preterm labor: a prospective observational study. AB - BACKGROUND: Ritodrine, a tocolytic beta2-agonist, has been used extensively in Europe and Asia despite its safety concerns. This study was designed to identify associations between beta2-adrenergic receptor (ADRB2) polymorphisms and adverse drug events (ADEs) in patients with preterm labor treated with ritodrine. RESULTS: This follow-up study was prospectively conducted at Ewha Womans University Mokdong Hospital in Korea. Five single nucleotide polymorphisms (SNPs) of the ADRB2 gene (rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719) were analyzed in 186 pregnant women with preterm labor. Patients with the AA genotype of rs1042717 had significantly lower incidence of ADEs compared to those with the G allele (p = 0.009). In multivariate analysis, one of the predictors of ADEs was the maximum infusion rate of ritodrine (AOR 4.47, 95% CI 1.31-15.25). Rs1042719 was also a significant factor for ritodrine-induced ADEs. The CC genotype carriers had 78% decreased risk of ADEs compared to those with other genotypes. CONCLUSIONS: This study demonstrates that ADEs induced by ritodrine are associated with ADRB2 gene polymorphisms, as well as the infusion rate of ritodrine in pregnant women with preterm labor. PMID- 29132298 TI - Population genetic structure is shaped by historical, geographic, and environmental factors in the leguminous shrub Caragana microphylla on the Inner Mongolia Plateau of China. AB - BACKGROUND: Understanding how landscape factors, including suites of geographic and environmental variables, and both historical and contemporary ecological and evolutionary processes shape the distribution of genetic diversity is a primary goal of landscape and conservation genetics and may be particularly consequential for species involved in ecological restoration. In this study, we examine the factors that shape the distribution of genetic variation in a leguminous shrub (Caragana microphylla) important for restoration efforts on the Mongolian Plateau in China. This region houses several major bioclimatic gradients, and C. microphylla is an important restoration species because it stabilizes soils and prevents advancing desertification on the Inner Mongolia Plateau caused by ongoing climate change. RESULTS: We assembled an expansive genomic dataset, consisting of 22 microsatellite loci, four cpDNA regions, and 5788 genome-wide SNPs from ten populations of C. microphylla. We then applied ecological niche modelling and linear and non-linear regression techniques to investigate the historical and contemporary forces that explain patterns of genetic diversity and population structure in C. microphylla on the Inner Mongolia Plateau. We found strong evidence that both geographic and environmental heterogeneity contribute to genetic differentiation and that the spatial distribution of genetic diversity in C. microphylla appears to result partly from the presence of a glacial refugium at the southwestern edge of its current range. CONCLUSIONS: These results suggest that geographic, environmental, and historical factors have all contributed to spatial genetic variation in this ecologically important species. These results should guide restoration plans to sustain genetic diversity during plant translocations. PMID- 29132299 TI - Chronic administration of parecoxib exerts anxiolytic-like and memory enhancing effects and modulates synaptophysin expression in mice. AB - BACKGROUND: Previous studies have shown that cyclooxygenase-2, a key enzyme that converts arachidonic acid to prostaglandins, is involved in anxiety and cognitive processes, but few studies have investigated the effects of chronic administration of cyclooxygenase-2 inhibitors on anxiety, learning and memory under normal physiological conditions. The aim of the study was to investigate the effects of chronic administration of parecoxib, a cyclooxygenase-2 inhibitor, on anxiety behavior and memory performance under normal physiological conditions and to explore the possible neural mechanism underlying parecoxib-mediated effects. METHODS: Adult male ICR mice were randomly divided into four groups: the control group and three parecoxib groups. Mice received normal saline or parecoxib (2.5, 5.0 or 10 mg/kg) intraperitoneal injection once a day for 21 days, respectively. Elevated plus-maze, novel object recognition and Y maze tests were conducted on day 23, 24 and 26, respectively. Four additional groups that received same drug treatment were used to measure synaptophysin protein levels by western blot and prostaglandin E2 (PGE2) levels by ELISA in the amygdala and hippocampus on day 26. RESULTS: Chronic parecoxib exerted an anxiolytic-like effect in the plus-maze test test, and enhanced memory performance in the novel object recognition and Y maze tests. Western blot analysis showed that chronic parecoxib down-regulated synaptophysin levels in the amygdala and up-regulated synaptophysin levels in the hippocampus. ELISA assay showed that chronic parecoxib inhibited PGE2 in the hippocampus but not amygdala. CONCLUSIONS: Chronic parecoxib exerts anxiolytic-like and memory enhancing effects, which might be mediated through differential modulation of synaptophysin and PGE2 in the amygdala and hippocampus. PMID- 29132300 TI - Plant-mediated RNAi silences midgut-expressed genes in congeneric lepidopteran insects in nature. AB - BACKGROUND: Plant-mediated RNAi (PMRi) silencing of insect genes has enormous potential for crop protection, but whether it works robustly under field conditions, particularly with lepidopteran pests, remains controversial. Wild tobacco Nicotiana attenuata and cultivated tobacco (N. tabacum) (Solanaceae) is attacked by two closely related specialist herbivores Manduca sexta and M. quinquemaculata (Lepidoptera, Sphingidae). When M. sexta larvae attack transgenic N. attenuata plants expressing double-stranded RNA(dsRNA) targeting M. sexta's midgut-expressed genes, the nicotine-ingestion induced cytochrome P450 monooxygenase (invert repeat (ir)CYP6B46-plants) and the lyciumoside-IV-ingestion induced beta-glucosidase1 (irBG1-plants), these larval genes which are important for the larvae's response to ingested host toxins, are strongly silenced. RESULTS: Here we show that the PMRi procedure also silences the homologous genes in native M. quinquemaculata larvae feeding on irCYP6B46 and irBG1-transgenic N. attenuata plants in nature. The PMRi lines shared 98 and 96% sequence similarity with M. quinquemaculata homologous coding sequences, and CYP6B46 and BG1 transcripts were reduced by ca. 90 and 80%, without reducing the transcripts of the larvae's most similar, potential off-target genes. CONCLUSIONS: We conclude that the PMRi procedure can robustly and specifically silence genes in native congeneric insects that share sufficient sequence similarity and with the careful selection of targets, might protect crops from attack by congeneric-groups of insect pests. PMID- 29132301 TI - Measuring frailty in clinical practice: a comparison of physical frailty assessment methods in a geriatric out-patient clinic. AB - BACKGROUND: The objectives of this study were to determine: 1) the prevalence of frailty using Fried's phenotype method and the Short Performance Physical Battery (SPPB), 2) agreement between frailty assessment methods, 3) the feasibility of assessing frailty using Fried's phenotype method and the SPPB. METHODS: This cross-sectional study was conducted at a geriatric out-patient clinic in Hamilton, Canada. A research assistant conducted all frailty assessments. Patients were classified as non-frail, pre-frail or frail according to Fried's phenotype method and the SPPB. Agreement among methods is reported using the Cohen kappa statistic (standard error). Feasibility data included the percent of eligible participants agreeing to attempt the frailty assessments (criterion for feasibility: >=90% of patients agreeing to the frailty assessment), equipment required, and safety considerations. A p-value of <0.05 is considered significant. RESULTS: A total of 110 participants (92%) and 109 participants (91%) agreed to attempt Fried's phenotype method and SPPB, respectively. No adverse events occurred during any assessments. According to Fried's phenotype method, the prevalence of frailty and pre-frailty was 35% and 56%, respectively, and according to the SPPB, the prevalence of frailty and pre-frailty was 50% and 35%, respectively. There was fair to moderate agreement between methods for determining which participants were frail (0.488 [0.082], p < 0.001) and pre frail (0.272 [0.084], p = 0.002). CONCLUSIONS: Frailty and pre-frailty are common in this geriatric outpatient population, and there is fair to moderate agreement between Fried's phenotype method and the SPPB. Over 90% of the patients who were eligible for the study agreed to attempt the frailty assessments, demonstrating that according to our feasibility criteria, frailty can be assessed in this patient population. Assessing frailty may help clinicians identify high-risk patients and tailor interventions based on baseline frailty characteristics. PMID- 29132302 TI - Immunomodulatory role for membrane vesicles released by THP-1 macrophages and respiratory pathogens during macrophage infection. AB - BACKGROUND: During infection, inflammation is partially driven by the release of mediators which facilitate intercellular communication. Amongst these mediators are small membrane vesicles (MVs) that can be released by both host cells and Gram-negative and -positive bacteria. Bacterial membrane vesicles are known to exert immuno-modulatory and -stimulatory actions. Moreover, it has been proposed that host cell-derived vesicles, released during infection, also have immunostimulatory properties. In this study, we assessed the release and activity of host cell-derived and bacterial MVs during the first hours following infection of THP-1 macrophages with the common respiratory pathogens non-typeable Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa. RESULTS: Using a combination of flow cytometry, tunable resistive pulse sensing (TRPS)-based analysis and electron microscopy, we demonstrated that the release of MVs occurs by both host cells and bacteria during infection. MVs released during infection and bacterial culture were found to induce a strong pro-inflammatory response by naive THP-1 macrophages. Yet, these MVs were also found to induce tolerance of host cells to secondary immunogenic stimuli and to enhance bacterial adherence and the number of intracellular bacteria. CONCLUSIONS: Bacterial MVs may play a dual role during infection, as they can both trigger and dampen immune responses thereby contributing to immune defence and bacterial survival. PMID- 29132303 TI - Prevalence of naturally occurring NS5A resistance-associated substitutions in patients infected with hepatitis C virus subtype 1a, 1b, and 3a, co-infected or not with HIV in Brazil. AB - BACKGROUND: Non-structural 5A protein (NS5A) resistance-associated substitutions (RASs) have been identified in patients infected with hepatitis C virus (HCV), even prior to exposure to direct-acting antiviral agents (DAAs). Selection for these variants occurs rapidly during treatment and, in some cases, leads to antiviral treatment failure. DAAs are currently the standard of care for hepatitis C treatment in many parts of the world. Nevertheless, in Brazil, the prevalence of pre-existing NS5A RASs is largely unknown. In this study, we evaluated the frequency of naturally occurring NS5A RASs in Brazilian patients infected with HCV as either a monoinfection or coinfection with human immunodeficiency virus (HIV). METHODS: Direct Sanger sequencing of the NS5A region was performed in 257 DAA-naive patients chronically infected with HCV (156 monoinfected with HCV and 101 coinfected with HIV/HCV). RESULTS: The frequencies of specific RASs in monoinfected patients were 14.6% for HCV GT-1a (M28 V and Q30H/R), 6.0% for GT-1b (L31F/V and Y93H), and 22.6% for GT-3a (A30K and Y93H). For HIV/HCV-coinfected patients, the frequencies of RAS were 3.9% for GT-1a (M28 T and Q30H/R), and 11.1% for GT-1b (Y93H); no RASs were found in GT-3a sequences. CONCLUSIONS: Substitutions that may confer resistance to NS5A inhibitors exist at baseline in Brazilian DAA-naive patients infected with HCV GT-1a, -1b, and -3a. Standardization of RAS definitions is needed to improve resistance analyses and to facilitate comparisons of substitutions reported across studies worldwide. Therapeutic strategies should be optimized to efficiently prevent DAA treatment failure due to selection for RASs, especially in difficult-to-cure patients. PMID- 29132304 TI - The three CYBA variants (rs4673, rs1049254 and rs1049255) are benign: new evidence from a patient with CGD. AB - BACKGROUND: Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease caused by the defect of NADPH oxidase. Mutations in CYBB or CYBA gene may result in membrane subunits, gp91phox or p22phox, expression failure respectively and NADPH oxidase deficiency. Previous study showed that three variants, c.214 T > C (rs4673), c.521 T > C (rs1049254) and c.*24G > A (rs1049255), in CYBA gene form a haplotype, which are associated with decreased reactive oxygen species generation. The study aims to confirm the three above mentioned variants are benign and report a novel mutation in CYBB gene. METHODS: A patient with CGD and his family members were enrolled in the study. NADPH oxidase activity and gp91phox protein expression of neutrophils were analyzed by flow cytometry. Direct sequencing was used to detect CYBB and CYBA gene mutations. RESULTS: The patient was diagnosed with CGD according to clinical and immune phenotype. The case has a novel homozygous mutation in CYBB gene and the above mentioned three variants in CYBA gene. The mutation in CYBB gene was confirmed to be pathogenic, and the three variants in CYBA gene to be benign. CONCLUSIONS: The study not only reported a novel mutation in CYBB, which results in CGD, but also confirmed the above mentioned three variants in CYBA are benign. PMID- 29132305 TI - Associations between skin barrier characteristics, skin conditions and health of aged nursing home residents: a multi-center prevalence and correlational study. AB - BACKGROUND: Geriatric patients are affected by a range of skin conditions and dermatological diseases, functional limitations and chronic diseases. Skin problems are highly prevalent in elderly populations. Aim of this study was to investigate possible associations between health, functional and cutaneous variables in aged long-term care residents. METHODS: This observational, cross sectional, descriptive prevalence study was conducted in a random sample of 10 institutional long-term care facilities in Berlin. In total, n = 223 residents were included. Demographic and functional characteristics, xerosis cutis, incontinence associated dermatitis, pressure ulcers and skin tears were assessed. Stratum corneum hydration, transepidermal water loss, skin surface pH and skin temperature were measured. Data analysis was descriptive and explorative. To explore possible bivariate associations, a correlation matrix was created. The correlation matrix was also used to detect possible collinearity in the subsequent regression analyses. RESULTS: Mean age (n = 223) was 83.6 years, 67.7% were female. Most residents were affected by xerosis cutis (99.1%; 95% CI: 97.7% 100.0%). The prevalence of pressure ulcers was 9.0% (95% CI: 5.0% - 13.0%), of incontinence associated dermatitis 35.4% (95% CI: 29.9% - 42.2%) and of skin tears 6.3% (95% CI: 3.2% - 9.5%). Biophysical skin parameters were not associated with overall care dependency, but with age and skin dryness. In general, skin dryness and measured skin barrier parameters were associated between arms and legs indicating similar overall skin characteristics of the residents. CONCLUSION: Prevalence of xerosis cutis, pressure ulcers and skin tears were high, indicating the load of these adverse skin conditions in this population. Only few associations of demographic characteristics, skin barrier impairments and the occurrence of dry skin, pressure ulcers, skin tears and incontinence associated dermatitis have been detected, that might limit the diagnostic value of skin barrier parameters in this population. Overall, the measured skin barrier parameters seem to have limited diagnostic value for the reported skin conditions except xerosis cutis. TRIAL REGISTRATION: This study is registered at https://clinicaltrials.gov/ct2/show/NCT02216526 . Registration date: 8th November 2014. PMID- 29132306 TI - RNA-Seq analysis of resistant and susceptible sub-tropical maize lines reveals a role for kauralexins in resistance to grey leaf spot disease, caused by Cercospora zeina. AB - BACKGROUND: Cercospora zeina is a foliar pathogen responsible for maize grey leaf spot in southern Africa that negatively impacts maize production. Plants use a variety of chemical and structural mechanisms to defend themselves against invading pathogens such as C. zeina, including the production of secondary metabolites with antimicrobial properties. In maize, a variety of biotic and abiotic stressors induce the accumulation of the terpenoid phytoalexins, zealexins and kauralexins. RESULTS: C. zeina-susceptible line displayed pervasive rectangular grey leaf spot lesions, running parallel with the leaf veins in contrast to C. zeina-resistant line that had restricted disease symptoms. Analysis of the transcriptome of both lines indicated that genes involved in primary and secondary metabolism were up-regualted, and although different pathways were prioritized in each line, production of terpenoid compounds were common to both. Targeted phytoalexin analysis revealed that C. zeina-inoculated leaves accumulated zealexins and kauralexins. The resistant line shows a propensity toward accumulation of the kauralexin B series metabolites in response to infection, which contrasts with the susceptible line that preferentially accumulates the kauralexin A series. Kauralexin accumulation was correlated to expression of the kauralexin biosynthetic gene, ZmAn2 and a candidate biosynthetic gene, ZmKSL2. We report the expression of a putative copalyl diphosphate synthase gene that is induced by C. zeina in the resistant line exclusively. DISCUSSION: This study shows that zealexins and kauralexins, and expression of their biosynthetic genes, are induced by C. zeina in both resistant and susceptible germplasm adapted to the southern African climate. The data presented here indicates that different forms of kauralexins accumulate in the resistant and susceptible maize lines in response to C. zeina, with the accumulation of kauralexin B compounds in a resistant maize line and kauralexin A compounds accumulating in the susceptible line. PMID- 29132307 TI - Involvement of LeMDR, an ATP-binding cassette protein gene, in shikonin transport and biosynthesis in Lithospermum erythrorhizon. AB - BACKGROUND: Shikonin is a naphthoquinone secondary metabolite with important medicinal value and is found in Lithospermum erythrorhizon. Considering the limited knowledge on the membrane transport mechanism of shikonin, this study investigated such molecular mechanism. RESULTS: We successfully isolated an ATP binding cassette protein gene, LeMDR, from L. erythrorhizon. LeMDR is predominantly expressed in L. erythrorhizon roots, where shikonin accumulated. Functional analysis of LeMDR by using the yeast cell expression system revealed that LeMDR is possibly involved in the shikonin efflux transport. The accumulation of shikonin is lower in yeast cells transformed with LeMDR overexpressing vector than that with empty vector. The transgenic hairy roots of L. erythrorhizon overexpressing LeMDR (MDRO) significantly enhanced shikonin production, whereas the RNA interference of LeMDR (MDRi) displayed a reverse trend. Moreover, the mRNA expression level of LeMDR was up-regulated by treatment with shikonin and shikonin-positive regulators, methyl jasmonate and indole-3 acetic acid. There might be a relationship of mutual regulation between the expression level of LeMDR and shikonin biosynthesis. CONCLUSIONS: Our findings demonstrated the important role of LeMDR in transmembrane transport and biosynthesis of shikonin. PMID- 29132308 TI - Effect of two non-synonymous ecto-5'-nucleotidase variants on the genetic architecture of inosine 5'-monophosphate (IMP) and its degradation products in Japanese Black beef. AB - BACKGROUND: Umami is a Japanese term for the fifth basic taste and is an important sensory property of beef palatability. Inosine 5'-monophosphate (IMP) contributes to umami taste in beef. Thus, the overall change in concentration of IMP and its degradation products can potentially affect the beef palatability. In this study, we investigated the genetic architecture of IMP and its degradation products in Japanese Black beef. First, we performed genome-wide association study (GWAS), candidate gene analysis, and functional analysis to detect the causal variants that affect IMP, inosine, and hypoxanthine. Second, we evaluated the allele frequencies in the different breeds, the contribution of genetic variance, and the effect on other economical traits using the detected variants. RESULTS: A total of 574 Japanese Black cattle were genotyped using the Illumina BovineSNP50 BeadChip and were then used for GWAS. The results of GWAS showed that the genome-wide significant single nucleotide polymorphisms (SNPs) on BTA9 were detected for IMP, inosine, and hypoxanthine. The ecto-5'-nucleotidase (NT5E) gene, which encodes the enzyme NT5E for the extracellular degradation of IMP to inosine, was located near the significant region on BTA9. The results of candidate gene analysis and functional analysis showed that two non-synonymous SNPs (c.1318C > T and c.1475 T > A) in NT5E affected the amount of IMP and its degradation products in beef by regulating the enzymatic activity of NT5E. The Q haplotype showed a positive effect on IMP and a negative effect on the enzymatic activity of NT5E in IMP degradation. The two SNPs were under perfect linkage disequilibrium in five different breeds, and different haplotype frequencies were seen among breeds. The two SNPs contribute to about half of the total genetic variance in IMP, and the results of genetic relationship between IMP and its degradation products showed that NT5E affected the overall concentration balance of IMP and its degradation products. In addition, the SNPs in NT5E did not have an unfavorable effect on the other economical traits. CONCLUSION: Based on all the above findings taken together, two non-synonymous SNPs in NT5E would be useful for improving IMP and its degradation products by marker-assisted selection in Japanese Black cattle. PMID- 29132309 TI - Significant differences in terms of codon usage bias between bacteriophage early and late genes: a comparative genomics analysis. AB - BACKGROUND: Viruses undergo extensive evolutionary selection for efficient replication which effects, among others, their codon distribution. In the current study, we aimed at understanding the way evolution shapes the codon distribution in early vs. late viral genes in terms of their expression during different stages in the viral replication cycle. To this end we analyzed 14 bacteriophages and 11 human viruses with available information about the expression phases of their genes. RESULTS: We demonstrated evidence of selection for distinct composition of synonymous codons in early and late viral genes in 50% of the analyzed bacteriophages. Among others, this phenomenon may be related to the time specific adaptation of the viral genes to the translation efficiency factors involved at different bacteriophage developmental stages. Specifically, we showed that the differences in codon composition in different temporal gene groups cannot be explained only by phylogenetic proximities between the analyzed bacteriophages, and can be partially explained by differences in the adaptation to the host tRNA pool, nucleotide bias, GC content and more. In contrast, no difference in temporal regulation of synonymous codon usage was observed in human viruses, possibly because of a stronger selection pressure due to a larger effective population size in bacteriophages and their bacterial hosts. CONCLUSIONS: The codon distribution in large fractions of bacteriophage genomes tend to be different in early and late genes. This phenomenon seems to be related to various aspects of the viral life cycle, and to various intracellular processes. We believe that the reported results should contribute towards better understanding of viral evolution and may promote the development of relevant procedures in synthetic virology. PMID- 29132310 TI - Rapid evolutionary divergence of diploid and allotetraploid Gossypium mitochondrial genomes. AB - BACKGROUND: Cotton (Gossypium spp.) is commonly grouped into eight diploid genomic groups and an allotetraploid genomic group, AD. The mitochondrial genomes supply new information to understand both the evolution process and the mechanism of cytoplasmic male sterility. Based on previously released mitochondrial genomes of G. hirsutum (AD1), G. barbadense (AD2), G. raimondii (D5) and G. arboreum (A2), together with data of six other mitochondrial genomes, to elucidate the evolution and diversity of mitochondrial genomes within Gossypium. RESULTS: Six Gossypium mitochondrial genomes, including three diploid species from D and three allotetraploid species from AD genome groups (G. thurberi D1, G. davidsonii D3-d and G. trilobum D8; G. tomentosum AD3, G. mustelinum AD4 and G. darwinii AD5), were assembled as the single circular molecules of lengths about 644 kb in diploid species and 677 kb in allotetraploid species, respectively. The genomic structures of mitochondrial in D group species were identical but differed from the mitogenome of G. arboreum (A2), as well as from the mitogenomes of five species of the AD group. There mainly existed four or six large repeats in the mitogenomes of the A + AD or D group species, respectively. These variations in repeat sequences caused the major inversions and translocations within the mitochondrial genome. The mitochondrial genome complexity in Gossypium presented eight unique segments in D group species, three specific fragments in A + AD group species and a large segment (more than 11 kb) in diploid species. These insertions or deletions were most probably generated from crossovers between repetitive or homologous regions. Unlike the highly variable genome structure, evolutionary distance of mitochondrial genes was 1/6th the frequency of that in chloroplast genes of Gossypium. RNA editing events were conserved in cotton mitochondrial genes. We confirmed two near full length of the integration of the mitochondrial genome into chromosome 1 of G. raimondii and chromosome A03 of G. hirsutum, respectively, with insertion time less than 1.03 MYA. CONCLUSION: Ten Gossypium mitochondrial sequences highlight the insights to the evolution of cotton mitogenomes. PMID- 29132311 TI - Weighted gene co-expression network analysis of expression data of monozygotic twins identifies specific modules and hub genes related to BMI. AB - BACKGROUND: The therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins. RESULTS: In the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings. Categories of positive regulation of nitric-oxide synthase biosynthetic process, positive regulation of NF-kappa B import into nucleus, and peroxidase activity were significantly enriched within GO database and NF-kappa B signaling pathway within KEGG database. DEGs of NAMPT, TLR9, PTGS2, HBD, and PCSK1N might be associated with obesity. In the WGCNA, among the total 20 distinct co-expression modules identified, coral1 module (68 genes) had the strongest positive correlation with BMI (r = 0.56, P = 0.04) and disease status (r = 0.56, P = 0.04). Categories of positive regulation of phospholipase activity, high-density lipoprotein particle clearance, chylomicron remnant clearance, reverse cholesterol transport, intermediate-density lipoprotein particle, chylomicron, low-density lipoprotein particle, very-low-density lipoprotein particle, voltage-gated potassium channel complex, cholesterol transporter activity, and neuropeptide hormone activity were significantly enriched within GO database for this module. And alcoholism and cell adhesion molecules pathways were significantly enriched within KEGG database. Several hub genes, such as GAL, ASB9, NPPB, TBX2, IL17C, APOE, ABCG4, and APOC2 were also identified. The module eigengene of saddlebrown module (212 genes) was also significantly correlated with BMI (r = 0.56, P = 0.04), and hub genes of KCNN1 and AQP10 were differentially expressed. CONCLUSION: We identified significant genes and specific modules potentially related to BMI based on the gene expression profile data of monozygotic twins. The findings may help further elucidate the underlying mechanisms of obesity development and provide novel insights to research potential gene biomarkers and signaling pathways for obesity treatment. Further analysis and validation of the findings reported here are important and necessary when more sample size is acquired. PMID- 29132312 TI - Genomic analysis of endemic clones of toxigenic and non-toxigenic Corynebacterium diphtheriae in Belarus during and after the major epidemic in 1990s. AB - BACKGROUND: Diphtheria remains a major public health concern with multiple recent outbreaks around the world. Moreover, invasive non-toxigenic strains have emerged globally causing severe infections. A diphtheria epidemic in the former Soviet Union in the 1990s resulted in ~5000 deaths. In this study, we analysed the genome sequences of a collection of 93 C. diphtheriae strains collected during and after this outbreak (1996 - 2014) in a former Soviet State, Belarus to understand the evolutionary dynamics and virulence capacities of these strains. RESULTS: C. diphtheriae strains from Belarus belong to ten sequence types (STs). Two major clones, non-toxigenic ST5 and toxigenic ST8, encompassed 76% of the isolates that are associated with sore throat and diphtheria in patients, respectively. Core genomic diversity is limited within outbreak-associated ST8 with relatively higher mutation rates (8.9 * 10-7 substitutions per strain per year) than ST5 (5.6 * 10-7 substitutions per strain per year) where most of the diversity was introduced by recombination. A variation in the virulence gene repertoire including the presence of tox gene is likely responsible for pathogenic differences between different strains. However, strains with similar virulence potential can cause disease in some individuals and remain asymptomatic in others. Eight synonymous single nucleotide polymorphisms were observed between the tox genes of the vaccine strain PW8 and other toxigenic strains of ST8, ST25, ST28, ST41 and non-toxigenic tox gene-bearing (NTTB) ST40 strains. A single nucleotide deletion at position 52 in the tox gene resulted in the frameshift in ST40 isolates, converting them into NTTB strains. CONCLUSIONS: Non-toxigenic C. diphtheriae ST5 and toxigenic ST8 strains have been endemic in Belarus both during and after the epidemic in 1990s. A high vaccine coverage has effectively controlled diphtheria in Belarus; however, non-toxigenic strains continue to circulate in the population. Recombination is an important evolutionary force in shaping the genomic diversity in C. diphtheriae. However, the relative role of recombination and mutations in diversification varies between different clones. PMID- 29132313 TI - Comparative transcriptome analysis of a lowly virulent strain of Erwinia amylovora in shoots of two apple cultivars - susceptible and resistant to fire blight. AB - BACKGROUND: Erwinia amylovora is generally considered to be a homogeneous species in terms of phenotypic and genetic features. However, strains show variation in their virulence, particularly on hosts with different susceptibility to fire blight. We applied the RNA-seq technique to elucidate transcriptome-level changes of the lowly virulent E. amylovora 650 strain during infection of shoots of susceptible (Idared) and resistant (Free Redstar) apple cultivars. RESULTS: The highest number of differentially expressed E. amylovora genes between the two apple genotypes was observed at 24 h after inoculation. Six days after inoculation, only a few bacterial genes were differentially expressed in the susceptible and resistant apple cultivars. The analysis of differentially expressed gene functions showed that generally, higher expression of genes related to stress response and defence against toxic compounds was observed in Free Redstar. Also in this cultivar, higher expression of flagellar genes (FlaI), which are recognized as PAMP (pathogen-associated molecular pattern) by the innate immune systems of plants, was noted. Additionally, several genes that have not yet been proven to play a role in the pathogenic abilities of E. amylovora were found to be differentially expressed in the two apple cultivars. CONCLUSIONS: This RNA-seq analysis generated a novel dataset describing the transcriptional response of the lowly virulent strain of E. amylovora in susceptible and resistant apple cultivar. Most genes were regulated in the same way in both apple cultivars, but there were also some cultivar-specific responses suggesting that the environment in Free Redstar is more stressful for bacteria what can be the reason of their inability to infect of this cultivar. Among genes with the highest fold change in expression between experimental combinations or with the highest transcript abundance, there are many genes without ascribed functions, which have never been tested for their role in pathogenicity. Overall, this study provides the first transcriptional profile by RNA-seq of E. amylovora during infection of a host plant and insights into the transcriptional response of this pathogen in the environments of susceptible and resistant apple plants. PMID- 29132314 TI - Proteomics in non-human primates: utilizing RNA-Seq data to improve protein identification by mass spectrometry in vervet monkeys. AB - BACKGROUND: Shotgun proteomics utilizes a database search strategy to compare detected mass spectra to a library of theoretical spectra derived from reference genome information. As such, the robustness of proteomics results is contingent upon the completeness and accuracy of the gene annotation in the reference genome. For animal models of disease where genomic annotation is incomplete, such as non-human primates, proteogenomic methods can improve the detection of proteins by incorporating transcriptional data from RNA-Seq to improve proteomics search databases used for peptide spectral matching. Customized search databases derived from RNA-Seq data are capable of identifying unannotated genetic and splice variants while simultaneously reducing the number of comparisons to only those transcripts actively expressed in the tissue. RESULTS: We collected RNA-Seq and proteomic data from 10 vervet monkey liver samples and used the RNA-Seq data to curate sample-specific search databases which were analyzed in the program Morpheus. We compared these results against those from a search database generated from the reference vervet genome. A total of 284 previously unannotated splice junctions were predicted by the RNA-Seq data, 92 of which were confirmed by peptide spectral matches. More than half (53/92) of these unannotated splice variants had orthologs in other non-human primates, suggesting that failure to match these peptides in the reference analyses likely arose from incomplete gene model information. The sample-specific databases also identified 101 unique peptides containing single amino acid substitutions which were missed by the reference database. Because the sample-specific searches were restricted to actively expressed transcripts, the search databases were smaller, more computationally efficient, and identified more peptides at the empirically derived 1 % false discovery rate. CONCLUSION: Proteogenomic approaches are ideally suited to facilitate the discovery and annotation of proteins in less widely studies animal models such as non-human primates. We expect that these approaches will help to improve existing genome annotations of non-human primate species such as vervet. PMID- 29132315 TI - Comprehensive genomic analysis of the CNGC gene family in Brassica oleracea: novel insights into synteny, structures, and transcript profiles. AB - BACKGROUND: The cyclic nucleotide-gated ion channel (CNGC) family affects the uptake of cations, growth, pathogen defence, and thermotolerance in plants. However, the systematic identification, origin and function of this gene family has not been performed in Brassica oleracea, an important vegetable crop and genomic model organism. RESULTS: In present study, we identified 26 CNGC genes in B. oleracea genome, which are non-randomly localized on eight chromosomes, and classified into four major (I-IV) and two sub-groups (i.e., IV-a and IV-b). The BoCNGC family is asymmetrically fractioned into the following three sub-genomes: least fractionated (14 genes), most fractionated-I (10), and most fractionated-II (2). The syntenic map of BoCNGC genes exhibited strong relationships with the model Arabidopsis thaliana and B. rapa CNGC genes and provided markers for defining the regions of conserved synteny among the three genomes. Both whole genome triplication along with segmental and tandem duplications contributed to the expansion of this gene family. We predicted the characteristics of BoCNGCs regarding exon-intron organisations, motif compositions and post-translational modifications, which diversified their structures and functions. Using orthologous Arabidopsis CNGCs as a reference, we found that most CNGCs were associated with various protein-protein interaction networks involving CNGCs and other signalling and stress related proteins. We revealed that five microRNAs (i.e., bol-miR5021, bol-miR838d, bol-miR414b, bol-miR4234, and bol-miR_new2) have target sites in nine BoCNGC genes. The BoCNGC genes were differentially expressed in seven B. oleracea tissues including leaf, stem, callus, silique, bud, root and flower. The transcript abundance levels quantified by qRT-PCR assays revealed that BoCNGC genes from phylogenetic Groups I and IV were particularly sensitive to cold stress and infections with bacterial pathogen Xanthomonas campestris pv. campestris, suggesting their importance in abiotic and biotic stress responses. CONCLUSION: Our comprehensive genome-wide analysis represents a rich data resource for studying new plant gene families. Our data may also be useful for breeding new B. oleracea cultivars with improved productivity, quality, and stress resistance. PMID- 29132316 TI - Genome-wide analysis and transcriptomic profiling of the auxin biosynthesis, transport and signaling family genes in moso bamboo (Phyllostachys heterocycla). AB - BACKGROUND: Auxin is essential for plant growth and development. Although substantial progress has been made in understanding auxin pathways in model plants such as Arabidopsis and rice, little is known in moso bamboo which is famous for its fast growth resulting from the rapid cell elongation and division. RESULTS: Here we showed that exogenous auxin has strong effects on crown and primary roots. Genes involved in auxin action, including 13 YUCCA (YUC) genes involved in auxin synthesis, 14 PIN-FORMED/PIN-like (PIN/PILS) and 7 AUXIN1/LIKE AUX1 (AUX1/LAX) members involved in auxin transport, 10 auxin receptors (AFB) involved in auxin perception, 43 auxin/indole-3-aceticacid (AUX/IAA) genes, and 41 auxin response factors (ARF) involved in auxin signaling were identified through genome-wide analysis. Phylogenetic analysis of these genes from Arabidopsis, Oryza sativa and bamboo revealed that auxin biosynthesis, transport, and signaling pathways are conserved in these species. A comprehensive study of auxin-responsive genes using RNA sequencing technology was performed, and the results also supported that moso bamboo shared a conserved regulatory mechanism for the expression of auxin pathway genes; meanwhile it harbors its own specific properties. CONCLUSIONS: In summary, we generated an overview of the auxin pathway in bamboo, which provides information for uncovering the precise roles of auxin pathway in this important species in the future. PMID- 29132317 TI - Development of amplicon deep sequencing markers and data analysis pipeline for genotyping multi-clonal malaria infections. AB - BACKGROUND: Amplicon deep sequencing permits sensitive detection of minority clones and improves discriminatory power for genotyping multi-clone Plasmodium falciparum infections. New amplicon sequencing and data analysis protocols are needed for genotyping in epidemiological studies and drug efficacy trials of P. falciparum. METHODS: Targeted sequencing of molecular marker csp and novel marker cpmp was conducted in duplicate on mixtures of parasite culture strains and 37 field samples. A protocol allowing to multiplex up to 384 samples in a single sequencing run was applied. Software "HaplotypR" was developed for data analysis. RESULTS: Cpmp was highly diverse (He = 0.96) in contrast to csp (He = 0.57). Minority clones were robustly detected if their frequency was >1%. False haplotype calls owing to sequencing errors were observed below that threshold. CONCLUSIONS: To reliably detect haplotypes at very low frequencies, experiments are best performed in duplicate and should aim for coverage of >10'000 reads/amplicon. When compared to length polymorphic marker msp2, highly multiplexed amplicon sequencing displayed greater sensitivity in detecting minority clones. PMID- 29132318 TI - BugMat and FindNeighbour: command line and server applications for investigating bacterial relatedness. AB - BACKGROUND: Large scale bacterial sequencing has made the determination of genetic relationships within large sequence collections of bacterial genomes derived from the same microbial species an increasingly common task. Solutions to the problem have application to public health (for example, in the detection of possible disease transmission), and as part of divide-and-conquer strategies selecting groups of similar isolates for computationally intensive methods of phylogenetic inference using (for example) maximal likelihood methods. However, the generation and maintenance of distance matrices is computationally intensive, and rapid methods of doing so are needed to allow translation of microbial genomics into public health actions. RESULTS: We developed, tested and deployed three solutions. BugMat is a fast C++ application which generates one-off in memory distance matrices. FindNeighbour and FindNeighbour2 are server-side applications which build, maintain, and persist either complete (for FindNeighbour) or sparse (for FindNeighbour2) distance matrices given a set of sequences. FindNeighbour and BugMat use a variation model to accelerate computation, while FindNeighbour2 uses reference-based compression. Performance metrics show scalability into tens of thousands of sequences, with options for scaling further. CONCLUSION: Three applications, each with distinct strengths and weaknesses, are available for distance-matrix based analysis of large bacterial collections. Deployed as part of the Public Health England solution for M. tuberculosis genomic processing, they will have wide applicability. PMID- 29132319 TI - Association of NOS3 gene polymorphisms with essential hypertension in Sudanese patients: a case control study. AB - BACKGROUND: Essential hypertension (EH) is influenced by various environmental and genetic factors. Nitric oxide is important for the functional integrity of the vascular endothelium and is produced in endothelial cells by the enzyme endothelial nitric oxide synthase (eNOS). EH has a strong genetic component, and the NOS3 gene, which encodes eNOS, represents an interesting candidate for contribution to the phenotype. The most clinically relevant polymorphisms in the NOS3 gene are rs1799983 in exon 7 (encoding Glu298Asp), a variable number tandem repeat (VNTR) in intron 4, and rs2070744 (T-786C) in the promoter region. This study aims to investigate the association between these three polymorphisms in the NOS3 gene and EH in Sudanese patients. METHODS: Hypertensive patients (n = 157) > 18 years of age with established hypertension from various hospitals in Khartoum, and controls (n = 85) > 18 years of age and with blood pressure measurements <140/90, were included in this case control study. Genotypes at the NOS3 variants were determined using TaqMan and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analyses. Genotype and allele frequencies were compared between the two groups by chi2 analysis, and differences were expressed as odds ratios with 95% confidence intervals (CIs). P values <0.05 were considered statistically significant. RESULTS: The rs2070744 polymorphism in NOS3 was found to be associated with EH in the Sudanese population as the patients group had higher frequency of CC genotype compared with the controls (6.6% vs 6.1%, p = 0.02). Considering a dominant inheritance model, the frequency of TC + CC genotypes in patients was significantly higher than that in the control subjects (52.6% vs 34.1%, respectively; p < 0.01), with an odds ratio (95% CI) of 2.14 (1.23-3.74). In addition, the C allele was more frequent in the patients than the control group (29.6% vs 20%, p = 0.03, OR = 1.84 (1.15-2.93)). The c allele of intron 4 VNTR was reported in >1% of the Sudanese population under study. CONCLUSION: The results of this study indicated that the rs2070744 polymorphism in NOS3 may be a genetic susceptibility factor for EH in the Sudanese population. The c allele of intron 4 VNTR is not rare in the Sudanese population. PMID- 29132320 TI - Histologic chorioamnionitis does not modulate the oxidative stress and antioxidant status in pregnancies complicated by spontaneous preterm delivery. AB - BACKGROUND: Infection induced-inflammation and other risk factors for spontaneous preterm birth (PTB) and preterm premature rupture of membranes (pPROM) may cause a redox imbalance, increasing the release of free radicals and consuming antioxidant defenses. Oxidative stress, in turn, can initiate intracellular signaling cascades that increase the production of pro-inflammatory mediators. The objective of this study was to evaluate the oxidative damage to proteins and antioxidant capacity profiles in amniochorion membranes from preterm birth (PTB) and preterm premature rupture of membranes (pPROM) and to determine the role of histologic chorioamnionitis in this scenario. METHODS: We included 27 pregnant women with PTB, 27 pPROM and 30 at term. Protein oxidative damage was assayed by 3-nitrotyrosine (3-NT) and carbonyl levels, using enzyme-linked immunosorbent assay (ELISA) and modified dinitrophenylhydrazine assay (DNPH), respectively. Total antioxidant capacity (TAC) was measured by ELISA. RESULTS: Protein oxidative damage determined by carbonyl levels was lower in PTB group than pPROM and term groups (p < 0.001). PTB group presented higher TAC compared with pPROM and term groups (p = 0.002). Histologic chorioamnionitis did not change either protein oxidative damage or TAC regardless of gestational outcome. CONCLUSION: These results corroborates previous reports that pPROM and term birth exhibit similarities in oxidative stress- induced senescence and histologic chorioamnionitis does not modulate oxidative stress or antioxidant status. PMID- 29132321 TI - The role of the specialized team in the operation of continuous renal replacement therapy: a single-center experience. AB - BACKGROUND: The requirement of continuous renal replacement therapy (CRRT) is increasing with the growing incidence of acute kidney injury (AKI). The decision to initiate CRRT is not difficult if an adequate medical history is obtained. However, the handling and maintenance of CRRT constitute a labor-intensive intervention that requires specialized skills. For these reasons, our center organized a specialized CRRT team in March 2013. The aim of this study is to report on the role of a specialized CRRT team and to evaluate the team's outcome. METHODS: This retrospective single-center study evaluated AKI patients who underwent CRRT in the intensive care unit (ICU) from March 2011 to February 2015. Patients were divided into two groups based on whether they received specialized CRRT team intervention. We collected information on demographic characteristics, laboratory parameters, SOFA score, CRRT initiation time, actual delivered dose and CRRT down-time. In-hospital mortality was defined by medical chart review. Binary logistic regression analysis was used to define factors associated with in hospital mortality. RESULTS: A total of 1104 patients were included in this study. The mean patient age was 63.85 +/- 14.39 years old, and 62.8% of the patients were male. After the specialized CRRT team intervention, there was a significant reduction in CRRT initiation time (5.30 +/- 13.86 vs. 3.60 +/- 11.59 days, p = 0.027) and CRRT down-time (1.78 +/- 2.23 vs. 1.38 +/- 2.08 h/day, p = 0.002). The rate of in-hospital mortality decreased after the specialized CRRT team intervention (57.5 vs. 49.2%, p = 0.007). When the multivariable analysis was adjusted, delayed CRRT initiation (HR 1.054(1.036-1.072), p < 0.001) was a significant factor in predicting in-hospital mortality, along with an increased SOFA score, lower serum albumin and prolonged prothrombin time. CONCLUSIONS: Our study shows that specialized CRRT team intervention reduced CRRT initiation time, down-time and in-hospital mortality. This study could serve as a logical basis for implementing specialized CRRT teams hospital-wide. PMID- 29132322 TI - Stillbirth is associated with perceived alterations in fetal activity - findings from an international case control study. AB - BACKGROUND: Stillbirth after 28 weeks gestation affects between 1.3-8.8 per 1000 births in high-income countries. The majority of stillbirths in this setting occur in women without established risk factors. Identification of risk factors which could be identified and managed in pregnancy is a priority in stillbirth prevention research. This study aimed to evaluate women's experiences of fetal movements and how these relate to stillbirth. METHODS: An international internet based case-control study of women who had a stillbirth >=28 weeks' gestation within 30 days prior to completing the survey (n = 153) and women with an ongoing pregnancy or a live born child (n = 480). The online questionnaire was developed with parent stakeholder organizations using a mixture of categorical and open ended responses and Likert scales. Univariate and multiple logistic regression was used to determine crude (unadjusted) and adjusted odds ratios (aOR) with 95% confidence intervals (CI). Summative content analysis was used to analyse free text responses. RESULTS: Women whose pregnancy ended in stillbirth were less likely to check fetal movements (aOR 0.54, 95% CI 0.35-0.83) and were less likely to be told to do so by a health professional (aOR 0.55, 95% CI 0.36-0.86). Pregnancies ending in stillbirth were more frequently associated with significant abnormalities in fetal movements in the preceding two weeks; this included a significant reduction in fetal activity (aOR 14.1, 95% CI 7.27-27.45) or sudden single episode of excessive fetal activity (aOR 4.30, 95% CI 2.25-8.24). Cases described their perception of changes in fetal activity differently to healthy controls e.g. vigorous activity was described as "frantic", "wild" or "crazy" compared to "powerful" or "strong". CONCLUSIONS: Alterations in fetal activity are associated with increased risk of stillbirth. Pregnant women should be educated about awareness of fetal activity and reporting abnormal activity to health professionals. PMID- 29132323 TI - Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma. AB - BACKGROUND: Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells. METHODS: Using more sensitive and specific transcriptome deep sequencing, we compared previously published small miRNA and long mRNA of a set of GC B cells and eBL tumors. MiRWalk2.0 was used to identify the validated target genes for the deregulated miRNAs, which would be important for understanding the regulatory networks associated with eBL development. RESULTS: We found 211 differentially expressed (DE) genes (79 upregulated and 132 downregulated) and 49 DE miRNAs (22 up-regulated and 27 down-regulated). Gene Set enrichment analysis identified the enrichment of a set of MYC regulated genes. Network propagation-based method and correlated miRNA-mRNA expression analysis identified dysregulated miRNAs, including miR-17~95 cluster members and their target genes, which have diverse oncogenic properties to be critical to eBL lymphomagenesis. Central to all these findings, we observed the downregulation of ATM and NLK genes, which represent important regulators in response to DNA damage in eBL tumor cells. These tumor suppressors were targeted by multiple upregulated miRNAs (miR-19b-3p, miR-26a-5p, miR-30b-5p, miR-92a-5p and miR-27b-3p) which could account for their aberrant expression in eBL. CONCLUSION: Combined loss of p53 induction and function due to miRNA-mediated regulation of ATM and NLK, together with the upregulation of TFAP4, may be a central role for human miRNAs in eBL oncogenesis. This facilitates survival of eBL tumor cells with the IGH/MYC chromosomal translocation and promotes MYC-induced cell cycle progression, initiating eBL lymphomagenesis. This characterization of miRNA-mRNA interactions in eBL relative to GC B cells provides new insights on miRNA-mediated transcript regulation in eBL, which are potentially useful for new improved therapeutic strategies. PMID- 29132324 TI - CAISMOV24, a new human low-grade serous ovarian carcinoma cell line. AB - BACKGROUND: The spontaneous immortalization of primary malignant cells is frequently assigned to their genetic instability during in vitro culturing. In this study, the new epithelial ovarian cancer cell line CAISMOV24 was described and compared with its original low-grade serous ovarian carcinoma. METHODS: The in vitro culture was established with cells isolated from ascites of a 60-year old female patient with recurrent ovarian cancer. The CAISMOV24 line was assessed for cell growth, production of soluble biomarkers, expression of surface molecules and screened for typical mutations found in serous ovarian carcinoma. Additionally, comparative genomic hybridization was employed to compare genomic alterations between the CAISMOV24 cell line and its primary malignant cells. RESULTS: CAISMOV24 has been in continuous culture for more than 30 months and more than 100 in vitro passages. The cell surface molecules EpCAM, PVR and CD73 are overexpressed on CAISMOV24 cells compared to the primary malignant cells. CAISMOV24 continues to produce CA125 and HE4 in vitro. Although the cell line had developed alongside the accumulation of genomic alterations (28 CNV in primary cells and 37 CNV in CAISMOV24), most of them were related to CNVs already present in primary malignant cells. CAISMOV24 cell line harbored KRAS mutation with wild type TP53, therefore it is characterized as low-grade serous carcinoma. CONCLUSION: Our results corroborate with the idea that genomic alterations, depicted by CNVs, can be used for subtyping epithelial ovarian carcinomas. Additionally, CAISMOV24 cell line was characterized as a low-grade serous ovarian carcinoma, which still resembles its primary malignant cells. PMID- 29132325 TI - Level, causes, and risk factors of stillbirth: a population-based case control study from Chandigarh, India. AB - BACKGROUND: Globally, India ranks first in the absolute number of stillbirths. Hence, the level, causes, and risk factors of stillbirths were estimated to facilitate designing of prevention strategy. METHODS: Capture and recapture method was used to identify 301 stillbirths from 1st July 2013 to 31st August 2014 in Chandigarh Union Territory of India. Verbal autopsies (n = 181) were done at household level to identify causes of stillbirths. Risk factors were determined using case-control approach. Women who had a stillbirth in the past 3 months were enrolled as cases (n = 181) and those who had live-birth in same neighbourhood were included as controls (n = 181). Statistical differences in the distribution of characteristics of cases and controls were tested by t test and chi square test respectively for quantitative and categorical variables. In logistic regression models adjusted odds ratios (aOR) and 95% confidence intervals (CIs) were estimated for various risk factors. RESULTS: Stillbirth rate was estimated to be 16/1000 birth. Antepartum causes were more common (68%) than intrapartum causes (32%). Among maternal conditions, hypertension (18.2%) and chorio-amnionitis (13.8%), and among foetal conditions, growth restriction (19.9%) and congenital anomalies (18.8%) were the leading causes. In about half of the stillbirths foetal (48%) and maternal (44.7%) causes were unidentifiable. Risk factors of stillbirths were: higher maternal age (aOR 1.1, 95%CI 1.0-1.2), vaginal delivery (aOR 8.1, 95%CI 2.6-26), induced labour (aOR 2.6, 95%CI 1.5 4.5), green or light brown liquor (aOR 2.0, 95%CI 1.1-3.8), preterm delivery (aOR 6.4, 95%CI 3.7-11) and smaller household size (aOR 1.2, 95% CI 1.1-1.3). CONCLUSIONS: Stillbirth rate was high in Chandigarh Union Territory of India. Major causes and risk factors amenable to interventions were infections, hypertension, congenital malformations, foetal growth restriction, pre-maturity and household size. Therefore, better maternity ante-natal and intra-natal care is required to achieve a single digit stillbirth rate. PMID- 29132326 TI - Association between gene expression profile of the primary tumor and chemotherapy response of metastatic breast cancer. AB - BACKGROUND: To better predict the likelihood of response to chemotherapy, we have conducted a study comparing the gene expression patterns of primary tumours with their corresponding response to systemic chemotherapy in the metastatic setting. METHODS: mRNA expression profiles of breast carcinomas of patients that later developed distant metastases were analyzed using supervised and non-supervised classification techniques to identify predictors of response to chemotherapy. The top differentially expressed genes between the responders and non-responders were identified and further explored. An independent dataset which was generated to predict response to neo-adjuvant CT was utilized for the purpose of validation. Response to chemotherapy was also correlated to the clinicopathologic characteristics, molecular subtypes, metastatic behavior and survival outcomes. RESULTS: Anthracycline containing regimens were the most common first line treatment (58.4%), followed by non-anthracycline/non-taxane containing (25.8%) and taxane containing (15.7%) regimens. Response was achieved in 41.6% of the patients to the first line CT and in 21.8% to second line CT. Response was not found to be significantly correlated to tumour type, grade, lymph node status, ER and PR status. Patients with HER2+ tumours showed better response to anthracycline containing therapy (p: 0.002). Response to first and second line chemotherapy did not differ among gene expression based molecular subtypes (p: 0.236 and p: 0.20). Using supervised classification, a 14 gene response classifier was identified. This 14-gene predictor could successfully predict the likelihood of better response to first and second line CT (p: <.0001 and p: 0.761, respectively) in the training set. However, the predictive value of this gene set in data of response to neoadjuvant chemotherapy could not be validated. CONCLUSIONS: To our knowledge, this is the first study revealing the relation between gene expression profiles of the primary tumours and their chemotherapy responsiveness in the metastatic setting. In contrast to the findings for neoadjuvant chemotherapy treatment, there was no association of molecular subtype with response to chemotherapy in the metastatic setting. Using supervised classification, we identified a classifier of chemotherapy response; however, we could not validate this classifier using neoadjuvant response data. TRIAL REGISTRATION: Non applicable. Subjects were retrospectively registered. PMID- 29132327 TI - Explaining variance in self-directed learning readiness of first year students in health professional programs. AB - BACKGROUND: Self-directed learning (SDL) is expected of health science graduates; it is thus a learning outcome in many pre-certification programs. Previous research identified age, gender, discipline and prior education as associated with variations in students' self-directed learning readiness (SDLR). Studies in other fields also propose personality as influential. METHOD: This study investigated relationships between SDLR and age, gender, discipline, previous education, and personality traits. The Self-Directed Learning Readiness Scale and the 50-item 'big five' personality trait inventory were administered to 584 first year undergraduate students (n = 312 female) enrolled in a first-session undergraduate interprofessional health sciences subject. RESULTS: Students were from health promotion, health services management, therapeutic recreation, sports and exercise science, occupational therapy, physiotherapy, and podiatry. Four hundred and seven responses (n = 230 females) were complete. SDLR was significantly higher in females and students in occupational therapy and physiotherapy. SDLR increased with age and higher levels of previous education. It was also significantly associated with 'big five' personality trait scores. Regression analysis revealed 52.9% of variance was accounted for by personality factors, discipline and prior experience of tertiary education. CONCLUSION: Demographic, discipline and personality factors are associated with SDLR in the first year of study. Teachers need to be alert to individual student variation in SDLR. PMID- 29132328 TI - Posterior shoulder dislocation with associated reverse Hill-Sachs lesion: treatment options and functional outcome after a 5-year follow up. AB - BACKGROUND: The current study describes several surgical techniques for the treatment of the reverse Hill - Sachs lesion after posterior shoulder dislocation; we also aimed to present long term results followed for a minimum of five years. METHODS: This study is a prospective case series of 17 patients who were treated in our clinic between 2008 and 2011. Patients with a defect size smaller than 25% of the articular surface were treated conservatively. An endoprosthesis of the glenohumeral joint was implanted in patients with a defect size bigger than 40%. All remaining patients were treated by a variety of operative techniques, depending on the quality of the bone and size of the defect. RESULTS: Twelve of seventeen patients had a defect size of the humeral articular surface between 25% and 40% with a mean age of 39 years. Depending on the defect size these patients were treated with retrograde chondral elevation, antegrade cylindrical graft or a graft of the iliac bone crest with an open approach. All the procedures showed fair results, e.g. the open approach with a graft of the iliac bone crest (2010: Dash 3.89, Constant 90.33, Rowe 86.67; 2015: Dash 2.22, Constant 92.00, Rowe 93.33). CONCLUSION: The open approach is not a disadvantage for the functional outcome. The treatment algorithm should involve the superficial size of the defect as well as the depth of the defect and the time interval between the dislocation and the surgical treatment. TRIAL REGISTRATION: 223/2012BO2 , 02 August 2010. PMID- 29132329 TI - Determinants of patterns of maternal and child health service utilization in a rural community in south eastern Nigeria. AB - BACKGROUND: Women and children constitute a large proportion of any population. They are the most vulnerable to morbidity and mortality especially in developing countries. In many situations the problem of poor maternal and child health stems from the poor use of available services even when they are not of optimum quality. This study seeks to describe the patterns of utilization of Maternal and Child health (MCH) services in a rural area of Enugu State, and identify factors that are associated with and responsible for determining them. METHODS: The study used a cross sectional analytic design. Pretested semi structured questionnaires were administered by interviewers to 602 women from a rural community in Enugu state, South east Nigeria. Two focus group discussions (FGDs) involving 8-10 men/ women each were conducted to identify factors affecting service utilization. Chi square analysis was done to identify factors associated with Maternal and Child Health services utilization. Logistic regression was used to identify determinants of utilization patterns. N vivo software was used to analyze findings of the FGDs. RESULTS: The study revealed that increasing age, educational level, monthly income, number of children and occupation of both women and their husbands were associated with increased MCH service utilization. Average monthly income (OR: 1.317, p = 0.048, CI: 0.073-0.986) and number of children (OR: 1.196, p < 0.01,CI: 1.563-7.000) were determinants of increased use of child care services while educational level (OR: 0.495, p < 0.001, CI: 1.244 2.164) and age (OR: 0.115, p < 0.001, CI: 0.838-0.948) determined better use of delivery and family planning services respectively. CONCLUSIONS: Improved use of MCH services is related to socio economic challenges women face such as illiteracy and low income. Furthermore, the way health facilities and their staff are perceived by rural women affect how they use some of these services and should be considered in programs which seek to reduce maternal and child mortality. Behavioral change programs with high local content need to be implemented within rural areas especially among younger, illiterate women . PMID- 29132330 TI - The association of polymorphic markers Arg399Gln of XRCC1 gene, Arg72Pro of TP53 gene and T309G of MDM2 gene with breast cancer in Kyrgyz females. AB - BACKGROUND: The association of genes XRCC1, TP53 and MDM2 with breast cancer (BC) has never been tested in Kyrgyz population. We, therefore, aimed to identify an association of alleles and genotypes of polymorphic markers Arg399Gln of gene XRCC1, Arg72Pro of gene TP53, and T309G of gene MDM2 with the risk of BC in Kyrgyz women. METHODS: This was a case-control study of 219 women of Kyrgyz origin with morphologically verified BC (N = 117) and 102 controls, age-matched with BC cases. The mean age of subjects in this study was 52.2 +/- 10.8 years. We extracted DNA from the venous blood and genotyped polymorphic markers Arg399Gln of gene XRCC1, Arg72Pro of gene TP53 and T309G of gene MDM2 using polymerase chain reaction and the method of restriction fragment polymorphism. RESULTS: Allele 399Gln (OR 1.57; 95% CI 1.05-2.35), Arg399Gln of gene XRCC1 heterozygous genotype (OR 2.77; 95% CI 1.60-4.80), the combination of Arg399Gln/Arg72Pro of genes XRCC1/TP53 heterozygous genotype (OR 3.98; 95% CI 1.57-10.09), Arg399Gln/T309G of genes XRCC1/MDM2 (OR 3.0; 95% CI 1.18-7.56), as well as Arg399Gln/Arg72Pro/T309G of genes XRCC1/TP53/MDM2 (OR 6.40; 95% CI 1.18-34.63) were associated with BC in Kyrgyz women. CONCLUSIONS: This is the first study to identify the inter-loci interaction and to find molecular markers of individual risk of BC in Kyrgyz women. PMID- 29132332 TI - First and second year medical students identify and self-stereotype more as doctors than as students: a questionnaire study. AB - BACKGROUND: The emergence of medical students' professional identity is important. This paper considers this in a snapshot of the early years of undergraduate medical education. From the perspective of social identity theory, it also considers self-stereotyping, the extent to which individuals associate with attributes identified as typical of groups. METHOD: Paper questionnaires were completed by first and second year medical students following teaching sessions at the beginning (October) and end (April) of the academic year. Questionnaires consisted of scales measuring the strength and importance of identity and self-stereotyping, referent to 'doctors' and 'students'. Linear mixed effects regression considered longitudinal and cross-sectional effects of progress through the course, and differences in responses to 'doctor' and 'student' measures. RESULTS: In October, responses were received from 99% (n = 102) and 75% (n = 58) of first and second year cohorts respectively, and in April from 81% (n = 83) and 73% (n = 56). Response rates were over 95% of those present. Linear mixed effects regression found that all 'doctor'-referent measures were higher than 'student' measures. Strength of identity and self stereotyping decreased between beginning and end of the year (across both groups). Men indicated lower importance of identity than women, also across both groups. There were no differences between year groups. Self-stereotyping was predicted more by importance of identification with a group than by strength of identification. CONCLUSIONS: Findings reinforce observations that medical students identify strongly as doctors from early in their studies, and that this identification is greater than as students. Decreases over time are surprising, but may be explained by changing group salience towards the end of the academic year. The lack of a gender effect on strength of identification contrasts with the literature, but may reflect students' lack of 'performance' of professional identity, while the effect on importance is speculated to be linked to social identity complexity. Identification with professional group may have implications for how medical schools treat students. The findings on self-stereotyping have relevance to recruitment if applicant populations are limited to those already internalising a stereotype. There may be consequences for the wellbeing of those who feel they cannot fulfil stereotypes when in training. PMID- 29132331 TI - Adaptation of the GoldenBraid modular cloning system and creation of a toolkit for the expression of heterologous proteins in yeast mitochondria. AB - BACKGROUND: There is a need for the development of synthetic biology methods and tools to facilitate rapid and efficient engineering of yeast that accommodates the needs of specific biotechnology projects. In particular, the manipulation of the mitochondrial proteome has interesting potential applications due to its compartmentalized nature. One of these advantages resides in the fact that metalation occurs after protein import into mitochondria, which contains pools of iron, zinc, copper and manganese ions that can be utilized in recombinant metalloprotein metalation reactions. Another advantage is that mitochondria are suitable organelles to host oxygen sensitive proteins as a low oxygen environment is created within the matrix during cellular respiration. RESULTS: Here we describe the adaptation of a modular cloning system, GoldenBraid2.0, for the integration of assembled transcriptional units into two different sites of the yeast genome, yielding a high expression level. We have also generated a toolkit comprising various promoters, terminators and selection markers that facilitate the generation of multigenic constructs and allow the reconstruction of biosynthetic pathways within Saccharomyces cerevisiae. To facilitate the specific expression of recombinant proteins within the mitochondrial matrix, we have also included in the toolkit an array of mitochondrial targeting signals and tested their efficiency at different growth conditions. As a proof of concept, we show here the integration and expression of 14 bacterial nitrogen fixation (nif) genes, some of which are known to require specific metallocluster cofactors that contribute to their stability yet make these proteins highly sensitive to oxygen. For one of these genes, nifU, we show that optimal production of this protein is achieved through the use of the Su9 mitochondrial targeting pre-sequence and glycerol as a carbon source to sustain aerobic respiration. CONCLUSIONS: We present here an adapted GoldenBraid2.0 system for modular cloning, genome integration and expression of recombinant proteins in yeast. We have produced a toolkit that includes inducible and constitutive promoters, mitochondrial targeting signals, terminators and selection markers to guarantee versatility in the design of recombinant transcriptional units. By testing the efficiency of the system with nitrogenase Nif proteins and different mitochondrial targeting pre sequences and growth conditions, we have paved the way for future studies addressing the expression of heterologous proteins in yeast mitochondria. PMID- 29132333 TI - Oestrogen receptor beta isoform expression in sporadic colorectal cancer, familial adenomatous polyposis and progressive stages of colorectal cancer. AB - BACKGROUND: Among the sex hormones, oestrogen may play a role in colorectal cancer, particularly in conjunction with oestrogen receptor-beta (ERbeta). The expression of ERbeta isoform variants and their correlations with familial adenomatous polyposis (FAP) syndrome and sporadic colorectal carcinomas are poorly described. METHODS: This study aimed to investigate the expression levels of the ERbeta1, ERbeta2, ERbeta4 and ERbeta5 isoform variants using quantitative RT-PCR (921 analyses) in FAP, normal mucosa, adenomatous polyps and sporadic colorectal carcinomas. RESULTS: Decreased expression of ERbeta isoforms was identified in sporadic polyps and in sporadic colorectal cancer as well as in polyps from FAP syndrome patients compared with normal tissues (p < 0.001). In FAP patients, ERbeta1 and ERbeta5 isoforms showed significant down-expression in polyps (p < 0.001) compared with matched normal tissues. However, no differences were observed when sporadic colorectal carcinomas were compared to normal mucosa tissues. These findings suggest an association of the ERbeta isoform variants in individuals affected by germline mutations of the APC gene. Progressively decreased expression of ERbeta was found in polyps at early stages of low-grade dysplasia, followed by T1-T2 and T3-T4 tumours (p < 0.05). In sporadic colorectal cancer, the loss of expression was an independent predictor of recurrence, and ERbeta1 and ERbeta5 expression levels were associated with better disease-free survival (p = 0.002). CONCLUSION: These findings may provide a better understanding of oestrogens and their potential preventive and therapeutic effects on sporadic colorectal cancer and cancers associated with FAP syndrome. PMID- 29132334 TI - Is perfect good? - Dimensions of perfectionism in newly admitted medical students. AB - BACKGROUND: Society expects physicians to perform perfectly but high levels of perfectionism are associated with symptoms of distress in medical students. This study investigated whether medical students admitted to medical school by different selection criteria differ in the occurrence of perfectionism. METHODS: Newly enrolled undergraduate medical students (n = 358) filled out the following instruments: Multidimensional Perfectionism Scale (MPS-H), Multidimensional Perfectionism Scale (MPS-F), Big Five Inventory (BFI-10), General Self-Efficacy Scale (GSE), Patient Health Questionnaire 9 (PHQ-9), and Generalized Anxiety Disorder 7 (GAD-7). Sociodemographic data such as age, gender, high school degrees, and the way of admission to medical school were also included in the questionnaire. RESULTS: The 298 participating students had significantly lower scores in Socially-Prescribed Perfectionism than the general population independently of their way of admission to medical school. Students who were selected for medical school by their high school degree showed the highest score for Adaptive Perfectionism. Maladaptive Perfectionism was the strongest predictor for the occurrence symptoms of depression and anxiety regardless of the way of admission. CONCLUSIONS: Students from all admission groups should be observed longitudinally for performance and to assess whether perfectionism questionnaires might be an additional useful instrument for medical school admission processes. PMID- 29132335 TI - Topical zoledronic acid decreases micromotion induced bone resorption in a sheep arthroplasty model. AB - BACKGROUND: Initial micromotion of a total hip replacement is associated with aseptic loosening. The use of bisphosphonates could be one way to reduce peri implant bone resorption induced by micromotion. Bisphosphonates compounds are inhibitors of bone resorption. The aim of this study was to investigate whether local treatment with bisphosphonate would reduce bone resorption and fibrous tissue around an experimental implant subjected to micromotion. METHODS: One micromotion implant were inserted into each medial femoral condyle in ten sheep. During each gait cycle the implant axially piston 0.5 mm. During surgery one of the femoral condyles were locally treated with 0.8 mg zoledronate. The other condyle served as control. Observation period was 12 weeks. RESULTS: Histological evaluation showed a fibrous capsule around both the control and bisphosphonate implants. Histomorphometrical analysis showed that 97% of the surface on both control and bisphosphonate implants were covered by fibrous tissue. However, the bisphosphonate was able to preserve bone in a 1 mm zone around the implants. CONCLUSION: This study indicates that local treatment with bisphosphonate cannot prevent the formation of a fibrous capsule around an implant subjected to micromotion, but bisphosphonate is able to reduce resorption of peri-prosthetic bone. PMID- 29132336 TI - Study protocol: the Labor Progression Study, LAPS - does the use of a dynamic progression guideline in labor reduce the rate of intrapartum cesarean sections in nulliparous women? A multicenter, cluster randomized trial in Norway. AB - BACKGROUND: The increasing rate of intrapartum cesarean sections is subject of attention and concern as it is associated with adverse outcomes. Labor dystocia is one of the most frequent indications for cesarean sections even though there is no consensus on criteria for labor dystocia. Traditionally the progression of labor follows guidelines based on Friedman's curve from the mid 1950s. In 2010 Zhang presented a new labor curve and a dynamic guideline for labor progression based on contemporary research. The main aim of this trial is to evaluate whether adhering to Zhang's guideline for labor progression, changes the intrapartum cesarean section rate in nulliparous women without jeopardising maternal and neonatal outcomes compared to a traditional guide line called the 4-h action line based on Friedman's curve. METHODS/DESIGN: A multicenter cluster randomized trial including 14 birth care units in Norway is conducted. Seven units are randomized to use the 4-h action line guideline for labor progression and seven units are randomized to use Zhang's new dynamic guideline for labor progression, for all nulliparous women with a singleton fetus in a cephalic presentation and spontaneous onset of labor at term. Clinical outcomes are compared between the groups. The determination of the sample size (number of clusters and individuals) is based on a power calculation of intrapartum cesarean section, which is 9.2% in the study population (p1). Further, we expect that the intrapartum cesarean section rate will be 6.7% (p2) which is a 25% reduction, when using the new guideline. With a chosen significance level of 0.05, a power of 80% and p1 = 9.2% and p2 = 6.9%, we should include at least 14 clusters and 6582 individuals. DISCUSSION: Clinical consequences when using the guideline by Zhang have, to the best of our knowledge, not been investigated earlier. The results will provide a strong basis to make a qualified decision on whether it is beneficial to introduce a dynamic labor progression curve in contemporary obstetrics both nationally and internationally. TRIAL REGISTRATION: Clinicaltrials, NCT02221427. PMID- 29132337 TI - Gene expression signatures of neuroendocrine prostate cancer and primary small cell prostatic carcinoma. AB - BACKGROUND: Neuroendocrine prostate cancer (NEPC) may be rising in prevalence as patients with advanced prostate cancer potentially develop resistance to contemporary anti-androgen treatment through a neuroendocrine phenotype. While prior studies comparing NEPC and prostatic adenocarcinoma have identified important candidates for targeted therapy, most have relied on few NEPC patients due to disease rarity, resulting in thousands of differentially expressed genes collectively and offering an opportunity for meta-analysis. Moreover, past studies have focused on prototypical NEPC samples with classic immunohistochemistry profiles, whereas there is increasing recognition of atypical phenotypes. In the primary setting, small cell prostatic carcinoma (SCPC) is frequently admixed with adenocarcinomas that may be clonally related, and a minority of SCPCs express markers typical of prostatic adenocarcinoma while rare cases do not express neuroendocrine markers. We derived a meta-signature of prototypical high-grade NEPC, then applied it to develop a classifier of primary SCPC incorporating disease heterogeneity. METHODS: Prototypical NEPC samples from 15 patients across 6 frozen tissue microarray datasets were assessed for genes with consistent outlier expression relative to adenocarcinomas. Resulting genes were used to determine subgroups of primary SCPCs (N=16) and high-grade adenocarcinomas (N=16) profiled by exon arrays using formalin-fixed paraffin embedded (FFPE) material from our institutional archives. A subgroup classifier was developed using differential expression for feature selection, and applied to radical prostatectomy cohorts. RESULTS: Sixty nine and 375 genes demonstrated consistent outlier expression in at least 80% and 60% of NEPC patients, with close resemblance in expression between NEPC and small cell lung cancer. Clustering by these genes generated 3 subgroups among primary samples from our institution. Nearest centroid classification based on the predominant phenotype from each subgroup (9 prototypical SCPCs, 9 prototypical adenocarcinomas, and 4 atypical SCPCs) achieved a 4.5% error rate by leave-one-out cross-validation. The classifier identified SCPC-like expression in 40% (2/5) of mixed adenocarcinomas and 0.3-0.6% of adenocarcinomas from prospective (4/2293) and retrospective (2/355) radical prostatectomy cohorts, where both SCPC-like retrospective cases subsequently developed metastases. CONCLUSIONS: Meta-analysis generates a robust signature of prototypical high-grade NEPC, and may facilitate development of a primary SCPC classifier based on FFPE material with potential prognostic implications. PMID- 29132338 TI - Determinants of stillbirth among women deliveries at Amhara region, Ethiopia. AB - BACKGROUND: Stillbirth is one of general medical issues that could contribute significantly to creating nations like Ethiopia. This study aimed to determine the prevalence and related factors of stillbirth among deliveries at Amhara region, Ethiopia. METHODS: The study used the Ethiopian Mini Demographic and Health Survey (EMDHS) data collected from 2555 eligible Amhara region women in 2014. Bi-variable and multi-variable binary logistic regression analysis was used. RESULTS: The prevalence of stillbirth outcomes became 85 per 1000 (total live birth). Besides, majority of women did not attend any formal education and had no antenatal care follow up. Women whose age at first birth below 18 years were 1859(72.8%) and the mean preceding birth interval were 33.6 months. Even women who attended primary and above education were about 50% and they were less likely to have had stillbirth outcomes than those who had no education (AOR: 0.505, 95% CI 0.311-0.820) and women having higher household wealth index were less likely to have had stillbirth outcomes as it is compared to the reference category. Moreover, women having preceding birth interval above 36 months were about 89% of less likely to end up stillbirth outcomes as compared to women having preceding birth interval below 24 months (AOR: 0.109, 95% CI 0.071 8.0.168). CONCLUSIONS: It could be inferred that a stillbirth result is one of the general medical issues in Amhara Region. Among different factors considered in this study, age, age at first birth, wealth index, birth order number and preceding birth interval in months were found to be significantly associated factors for stillbirth. Therefore, more awareness of early birth, widening birth interval, enhancing maternal care (for aged women) and early birth order number could be recommended. PMID- 29132339 TI - Sequential E2 levels not ovarian maximal diameter estimates were correlated with outcome of cetrotide therapy for management of women at high-risk of ovarian hyperstimulation syndrome: a randomized controlled study. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an important condition with considerable morbidity and a small risk of mortality and most commonly results as an iatrogenic condition following follicular stimulation of the ovaries. We aimed to evaluate safety and efficacy of 3-day cetrotide therapy started on day of oocyte retrieval (Day-0) in women at high-risk for development of ovarian hyperstimulation syndrome (OHSS) after GnRH agonist induction protocol. METHODS: Forty-eight women fulfilling inclusion criteria underwent ultrasound scanning for maximal ovarian diameter (MOD) estimation and ascites grading. Patients underwent embryo freezing, but the study group received 3-day Cetrotide sc injection (0.25 mg/day) started on Day-0. Serum E2, pain scores and MOD were checked daily. Hematocrite value (Ht%), total leucocytic count (TLC), gastrointestinal (GI) manifestations and ascites grading were re-evaluated on Day 3, 6 and 8. RESULTS: Sequential serum E2 levels decreased significantly in both groups with significantly lower levels in the study group. Sequential MOD estimates showed non-significant difference between the two groups and versus Day 0 estimates. On Day-2, pain scores showed progressive significant decrease compared to Day-0 scores in both groups with significantly lower scores in the study group. On Day-3; four control patients still had vomiting and by Day-6, 6 of the control patients still had GI manifestations with significant difference versus the study group. Compared to Day-0 estimates, Ht% and TLC were significantly lower on Day-3, 6 and 8 in the study group, but only on Day-8 in the control group. Day-3 and Day-8 ascites grading in both groups was significantly lower compared to respective Day-0 grading with significant difference in favor of the study group. Six patients required hospitalization, but without mortalities. Day-3 E2 levels in the study group showed positive significant correlation with clinical and other laboratory data and ascites grading, while the correlation was non-significant with MOD. CONCLUSION: The 3 day cetrotide therapy starting after oocyte retrieval with embryo transfer freezing could be an appropriate management policy for women received GnHR agonist induction protocol and were at high-risk for OHSS. Sequential E2 serum levels could predict outcome more perfectly than sequential MOD estimates. TRIAL REGISTRATION: Trial registration ( clinicaltrial.gov registration) NCT02823080 (retrospective) Initial Release 21-6-2016 Last Release 3-1-2017 Unique Protocol ID: Benha U Secondary IDs: kmsalama. PMID- 29132340 TI - What do Japanese residents learn from treating dying patients? The implications for training in end-of-life care. AB - BACKGROUND: How medical residents' experiences with care for dying patients affect their emotional well-being, their learning outcomes, and the formation of their professional identities is not fully understood. We examine residents' emotional states and learning occurring during the provision of care to dying patients and specifically discuss the impact of providing end-of-life (EOL) care on professional identity formation. METHODS: Semi-structured interviews were conducted with 13 residents who had graduated in the last 3 to 5 years. Thematic theoretical analysis was applied, and key themes were developed based on Kolb's experiential learning cycle. RESULTS: Eight key themes emerged from the analysis. The residents experienced dilemmas in confronting the reality of medical uncertainty as well as a disruption of emotional state and self-efficacy. Although the residents felt a sense of helplessness and guilt, they were able to reflect on strategies for handling medical care that focused on patients and that required a truly sincere attitude. They also contemplated the importance of palliative care and communication with patients, patients' family members and medical staff. Building on these experiences, the residents rebuilt a sense of awareness that allowed them to directly engage with the type of medical care that they are likely to be called upon to perform in the future as the population continues to age. CONCLUSIONS: This study revealed Japanese residents' perceptions, emotions and learning processes in caring for dying patients by applying Kolb's experiential learning theory. The findings of this study may illuminate valuable pieces of knowledge for future education in EOL care. PMID- 29132341 TI - Can hybrid hyaluronic acid represent a valid approach to treat rizoarthrosis? A retrospective comparative study. AB - BACKGROUND: Osteoarthritis (OA) of the trapeziometacarpal joint (TMJ) is a disabling condition with a significant impact on quality of life. The optimal management of hand OA requires a combination of non-pharmacological and pharmacological treatments that include intra-articular (i.a.) therapy. EULAR experts recommend corticosteroid injections in TMJ OA and underline the usefulness of hyaluronic acid (HA). The aim of this study was the assessment of the efficacy and tolerability of i.a. injections of a hybrid formulation of HA (Sinovial H-L(r)) in comparison to triamcinolone in patients with TMJ OA. METHODS: This 6-months observational comparative study, retrospective analyzed the medical records of 100 patients with monolateral or bilateral TMJ OA, treated with two injections of Sinovial H-L(r) (Sinovial H-L Group) or of triamcinolone acetonide (Triamcinolone Group). Clinical assessments were recorded at the time of the first and second injection and after one, 3 and 6 months. The primary outcomes were the change in global pain on a Visual Analogue Scale (VAS) and in hand function evaluated by the Functional Index for Hand OA (FIHOA) from baseline to month 6. Secondary outcomes were the improvement of the duration of morning stiffness, Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study 36-Item Short Form (SF-36). The comparison between the two groups of treatment were performed with the Wilcoxon rank-sum test for continuous variables and with chi-square or Fisher exact test for categorical variables. Statistical significance was set at p < 0.05. RESULTS: Both therapies provided effective pain relief and joint function improvement, but the benefits achieved were statistically significantly superior in the Sinovial H-L Group than the Triamcinolone Group after one month (p < 0.01) from the beginning of the therapy and during the 6-months follow-up (p < 0.001). Furthermore, Sinovial H-L(r) was associated with a significant decrease in the duration of morning stiffness and with a significant improvement in the HAQ score and physical component summary (PCS)-SF-36. CONCLUSIONS: Our results suggested that the hybrid formulation of HA may be more effective than triamcinolone in pain relief and joint function improvement with a rapid and persistent effect, resulting a valid alternative to steroid in the management of TMJ OA. TRIAL REGISTRATION: ClinicalTrials.gov, date of registration: June 14, 2017, NCT03200886 . The present trial was retrospectively registered. PMID- 29132342 TI - A low-cost uterine balloon tamponade for management of postpartum hemorrhage: modeling the potential impact on maternal mortality and morbidity in sub-Saharan Africa. AB - BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal deaths worldwide. This study sought to quantify the potential health impact (morbidity and mortality reductions) that a low-cost uterine balloon tamponade (UBT) could have on women suffering from uncontrolled PPH due to uterine atony in sub-Saharan Africa. METHODS: The Maternal and Neonatal Directed Assessment of Technology (MANDATE) model was used to estimate maternal deaths, surgeries averted, and cases of severe anemia prevented through UBT use among women with PPH who receive a uterotonic drug but fail this therapy in a health facility. Estimates were generated for the year 2018. The main outcome measures were lives saved, surgeries averted, and severe anemia prevented. RESULTS: The base case model estimated that widespread use of a low-cost UBT in clinics and hospitals could save 6547 lives (an 11% reduction in maternal deaths), avert 10,823 surgeries, and prevent 634 severe anemia cases in sub-Saharan Africa annually. CONCLUSIONS: A low-cost UBT has a strong potential to save lives and reduce morbidity. It can also potentially reduce costly downstream interventions for women who give birth in a health care facility. This technology may be especially useful for meeting global targets for reducing maternal mortality as identified in Sustainable Development Goal 3. PMID- 29132343 TI - Diet and endometrial cancer: a focus on the role of fruit and vegetable intake, Mediterranean diet and dietary inflammatory index in the endometrial cancer risk. AB - BACKGROUND: Endometrial cancer is the fourth most common cancer in European women. The major risk factors for endometrial cancer are related to the exposure of endometrium to estrogens not opposed to progestogens, that can lead to a chronic endometrial inflammation. Diet may play a role in cancer risk by modulating chronic inflammation. METHODS: In the framework of a case-control study, we recruited 297 women with newly diagnosed endometrial cancer and 307 controls from Northern Italy. Using logistic regression, we investigated the role of fruit and vegetable intake, adherence to the Mediterranean diet (MD), and the dietary inflammatory index (DII) in endometrial cancer risk. RESULTS: Women in the highest quintile of vegetable intake had a statistically significantly lower endometrial cancer risk (adjusted OR 5th quintile vs 1st quintile: 0.34, 95% CI 0.17-0.68). Women with high adherence to the MD had a risk of endometrial cancer that was about half that of women with low adherence to the MD (adjusted OR: 0.51, 95% CI 0.39-0.86). A protective effect was detected for all the lower quintiles of DII, with the highest protective effect seen for the lowest quintile (adjusted OR 5th quintile vs 1st quintile: 3.28, 95% CI 1.30-8.26). CONCLUSIONS: These results suggest that high vegetable intake, adherence to the MD, and a low DII are related to a lower endometrial cancer risk, with several putative connected biological mechanisms that strengthen the biological plausibility of this association. PMID- 29132344 TI - Tubeless versus standard percutaneous nephrolithotomy: an update meta-analysis. AB - BACKGROUND: To update a previously published systematic review and meta-analysis on the efficacy and safety of tubeless percutaneous nephrolithotomy (PCNL). METHODS: A systematic literature search of EMBASE, PubMed, Web of Science, and the Cochrane Library was performed to confirm relevant studies. The scientific literature was screened in accordance with the predetermined inclusion and exclusion criteria. After quality assessment and data extraction from the eligible studies, a meta-analysis was conducted using Stata SE 12.0. RESULTS: Fourteen randomized controlled trials (RCTs) involving 1148 patients were included. Combined results demonstrated that tubeless PCNL was significantly associated with shorter operative time (weighted mean difference [WMD], -3.79 min; 95% confidence interval [CI], -6.73 to -0.85; P = 0.012; I2 = 53.8%), shorter hospital stay (WMD, -1.27 days; 95% CI, -1.65 to -0.90; P < 0.001; I2 = 98.7%), faster time to return to normal activity (WMD, -4.24 days; 95% CI, -5.76 to -2.71; P < 0.001; I2 = 97.5%), lower postoperative pain scores (WMD, -16.55 mm; 95% CI, -21.60 to -11.50; P < 0.001; I2 = 95.7%), less postoperative analgesia requirements (standard mean difference, -1.09 mg; 95% CI, -1.35 to 0.84; P < 0.001; I2 = 46.8%), and lower urine leakage (Relative risk [RR], 0.30; 95% CI 0.15 to 0.59; P = 0.001; I2 = 41.2%). There were no significant differences in postoperative hemoglobin reduction (WMD, -0.02 g/dL; 95% CI, -0.04 to 0.01; P = 0.172; I2 = 41.5%), stone-free rate (RR, 1.01; 95% CI, 0.97 to 1.05; P = 0.776; I2 = 0.0%), postoperative fever rate (RR, 1.05; 95% CI, 0.57 to 1.93; P = 0.867; I2 = 0.0%), or blood transfusion rate (RR, 0.79; 95% CI, 0.36 to 1.70; P = 0.538; I2 = 0.0%). The results of subgroup analysis were consistent with the overall findings. The sensitivity analysis indicated that most results remained constant when total tubeless or partial tubeless or mini-PCNL studies were excluded respectively. CONCLUSIONS: Tubeless PCNL is an available and safe option in carefully evaluated and selected patients. It is significantly associated with the advantages of shorter hospital stay, shorter time to return to normal activity, lower postoperative pain scores, less analgesia requirement, and reduced urine leakage. PMID- 29132345 TI - The role of controllable lifestyle in the choice of specialisation among Hungarian medical doctors. AB - BACKGROUND: Hungary has been serious facing human resources crisis in health care, as a result of a massive emigration of health workers. The resulting shortage is unevenly distributed among medical specialisations. The findings of research studies are consistent in that the most important motivating factor of the choice of the medical career and of medical specialisations is professional interest. Beyond this, it is important to examine other reasons of why students do or do not choose certain specialisations. The lifestyle determined by the chosen speciality is one such factor described in the literature. METHODS: Using convenient sampling, first year resident medical doctors from each of the four Hungarian universities with a medical faculty were asked to participate in the study in 2008. In total 391 first year resident medical doctors completed the self-administered questionnaire indicating a 57.3% response rate. On the basis of the work of Schwartz et al. (Acad Med 65(3):207-210, 1990), the specialisation fields were divided into the two main categories of non-controllable (NCL) or controllable lifestyles (CL). We carried out a factor analysis on motivating factors and set up an explanatory model regarding the choice of CL and NCL specialisations. RESULTS: Two maximum likelihood factors were extracted from the motivational questions: "lifestyle and income" and "professional interest and consciousness". The explanatory model on specialisation choice shows that the "professional interest and consciousness" factor increases the likelihood of choosing NCL specialisations. In contrast the "lifestyle and income" factor has no significant impact on the choice of CL/NCL specialisations in the model. CONCLUSIONS: Our results confirm the important role of professional interest in the choice of medical specializations in Hungary. On the other hand, it seems surprising that we found no significant difference in the "lifestyle and income" related motivation among those medical residents, who opted for CL as opposed to those, who opted for NCL specialisations. This does not necessarily mean that lifestyle is not an important motivating factor, but that it is equally important for both groups of medical residents. PMID- 29132346 TI - Less healthy breakfast cereals are promoted more frequently in large supermarket chains in Canada. AB - BACKGROUND: The majority of food expenditures are made in supermarkets and this environment influences our purchasing and food intake. Breakfast cereals are frequently marketed as healthy food choices. The objective of this study was to examine the frequency of in-store promotions for cold breakfast cereals in Canadian supermarkets and to determine whether healthier or less healthy breakfast cereals are promoted more frequently. METHODS: Data was collected once per week over a four-week period from a convenience sample of the five largest Canadian supermarkets in the Ottawa/Gatineau area. Data collection included the number of shelf facings, promotional displays, and the cost of cereals/100 g. The UK Nutrient Profiling Model was used to determine the healthfulness of each breakfast cereal. RESULTS: 29.8% (n = 67) of the 225 unique cereals were classified as healthier and 70.2% (n = 158) were classified as less healthy. Less healthy cereals were displayed at eye level, in the profitable middle shelves, 2.9 times more frequently than healthier cereals. There were 5.3 times more breakfast cereal shelf facings, 4.2 more end cap displays, 1.7 more mid-aisle displays and 3.3 more special pricing signage for less healthy cereals compared to healthier cereals. Less healthy cereals had a significantly higher average total number of shelf facings compared to healthier cereals (t = -4.28 (280.8), p < .001). CONCLUSIONS: Breakfast cereal manufacturers need to consider reformulation of their breakfast cereals to improve their healthfulness and supermarkets need to increase the marketing of healthy breakfast cereals within their stores. PMID- 29132347 TI - Knee arthrodesis versus above-the-knee amputation after septic failure of revision total knee arthroplasty: comparison of functional outcome and complication rates. AB - BACKGROUND: After septic failure of total knee arthroplasty (TKA) and multiple revision operations resulting in impaired function, bone and/or soft-tissue damage a reconstruction with a revision arthroplasty might be impossible. Salvage procedures to regain mobility and quality of life are an above-the-knee amputation or knee arthrodesis. The decision process for the patient and surgeon is difficult and data comparing arthrodesis versus amputation in terms of function and quality of life are scarce. The purpose of this study was to analyse and compare the specific complications, functional outcome and quality of life of above-the-knee amputation (AKA) and modular knee-arthrodesis (MKA) after septic failure of total knee arthroplasty. METHODS: Eighty-one patients treated with MKA and 32 patients treated with AKA after septic failure of TKA between 2003 and 2012 were included in this cohort study. Demographic data, comorbidities, pathogens and complications such as re-infection, implant-failure or revision surgeries were recorded in 55MKA and 20AKA patients. Functional outcome with use of the Lower-Extremity-Functional-Score (LEFS) and the patients reported general health status (SF-12-questionnaire) was recorded after a mean interval of 55 months. RESULTS: A major complication occurred in more than one-third of the cases after MKA and AKA, whereas recurrence of infection was with 22% after MKA and 35% after AKA the most common complication. Patients with AKA and MKA showed a comparable functional outcome with a mean LEFS score of 37 and 28 respectively (p = 0.181). Correspondingly, a comparable physical quality of life with a mean physical SF-12 of 36 for AKA patients and a mean score of 30 for MKA patients was observed (p = 0.080). Notably, ten AKA patients that could be fitted with a microprocessor-controlled-knee-joint demonstrated with a mean LEFS of 56 a significantly better functional outcome than other amputee patients (p < 0.01) or MKA patients (p < 0.01). CONCLUSION: Naturally, the decision process for the treatment of desolate situations of septic failures following revision knee arthroplasty is depending on various factors. Nevertheless, the amputation should be considered as an option in patients with a good physical and mental condition. PMID- 29132348 TI - Extraperitoneal laparoscopic resection for retroperitoneal lymphatic cysts: initial experience. AB - BACKGROUND: To assess the safety and efficacy of laparoscopic retroperitoneal resection for retroperitoneal lymphatic cysts. METHODS: A retrospective analysis was conducted based on clinical data from eight patients with hydronephrosis caused by retroperitoneal lymphatic cysts. All patients underwent laparoscopic retroperitoneal lymphatic cyst resection and received postoperative follow-up. A follow-up ultrasound was performed postoperatively every 6-12 months to evaluate the recovery of the hydronephrosis. RESULTS: All operations were successful, and their postoperative pathological results revealed lymphatic cyst walls. The operation time ranged from 43 to 88 min (mean: 62 min), with a blood loss of 20 to 130 mL (mean: 76 mL), and the length of hospital stay was 3 to 6 days (mean: 4.5 days). Within the follow-up of 12 to 36 months (mean: 28.5 months), great relief was detected in all eight cases, and no recurrence was found. Moreover, complications such as renal pedicle or renal pelvis injury were not observed. CONCLUSIONS: Laparoscopic retroperitoneal lymphatic cyst resection is an effective treatment for retroperitoneal lymphatic cysts and has the advantages of being minimally invasive, producing less intraoperative blood loss and leading to a quick recovery. This treatment thus deserves further studies. PMID- 29132349 TI - Measurement properties of comorbidity indices in maternal health research: a systematic review. AB - BACKGROUND: Maternal critical illness occurs in 1.2 to 4.7 of every 1000 live births in the United States and approximately 1 in 100 women who become critically ill will die. Patient characteristics and comorbid conditions are commonly summarized as an index or score for the purpose of predicting the likelihood of dying; however, most such indices have arisen from non-pregnant patient populations. We sought to systematically review comorbidity indices used in health administrative datasets of pregnant women, in order to critically appraise their measurement properties and recommend optimal tools for clinicians and maternal health researchers. METHODS: We conducted a systematic search of MEDLINE and EMBASE to identify studies published from 1946 and 1947, respectively, to May 2017 that describe predictive validity of comorbidity indices using health administrative datasets in the field of maternal health research. We applied a methodological PubMed search filter to identify all studies of measurement properties for each index. RESULTS: Our initial search retrieved 8944 citations. The full text of 61 articles were identified and assessed for final eligibility. Finally, two eligible articles, describing three comorbidity indices appropriate for health administrative data remained: The Maternal comorbidity index, the Charlson comorbidity index and the Elixhauser Comorbidity Index. These studies of identified indices had a low risk of bias. The lack of an established consensus-building methodology in generating each index resulted in marginal sensibility for all indices. Only the Maternal Comorbidity Index was derived and validated specifically from a cohort of pregnant and postpartum women, using an administrative dataset, and had an associated c-statistic of 0.675 (95% Confidence Interval 0.647-0.666) in predicting mortality. CONCLUSIONS: Only the Maternal Comorbidity Index directly evaluated measurement properties relevant to pregnant women in health administrative datasets; however, it has only modest predictive ability for mortality among development and validation studies. Further research to investigate the feasibility of applying this index in clinical research, and its reliability across a variety of health administrative datasets would be incrementally helpful. Evolution of this and other tools for risk prediction and risk adjustment in pregnant and post-partum patients is an important area for ongoing study. PMID- 29132350 TI - Avian infectious bronchitis virus disrupts the melanoma differentiation associated gene 5 (MDA5) signaling pathway by cleavage of the adaptor protein MAVS. AB - BACKGROUND: Melanoma differentiation associated gene 5 (MDA5) and retinoic acid inducible gene-I (RIG-I) selectively sense cytoplasmic viral RNA to induce an antiviral immune response. Infectious bronchitis virus (IBV) is one of the most important infectious agents in chickens, and in chicken cells, it can be recognized by MDA5 to activate interferon production. RIG-I is considered to be absent in chickens. However, the absence of RIG-I in chickens raises the question of whether this protein influences the antiviral immune response against IBV infection. RESULTS: Here, we showed that chicken cells transfected with domestic goose RIG-I (dgRIG-I) exhibited increased IFN-beta activity after IBV infection. We also found that IBV can cleave MAVS, an adaptor protein downstream of RIG-I and MDA5 that acts as a platform for antiviral innate immunity at an early stage of infection. CONCLUSIONS: Although chicken MDA5 (chMDA5) is functionally active during IBV infection, the absence of RIG-I may increase the susceptibility of chickens to IBV infection, and IBV may disrupt the activation of the host antiviral response through the cleavage of MAVS. PMID- 29132351 TI - Therapeutic efficacy of pentoxifylline on proteinuria and renal progression: an update. AB - Blood pressure control with renin-angiotensin system (RAS) blockade has remained the gold standard for treating patients with proteinuric chronic kidney disease (CKD) up to date. Nevertheless, RAS blockade slows but does not halt the progression of kidney disease, thus highlighting the need to search for additional therapeutic approaches. The nonselective phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) is an old drug that exhibits prominent anti inflammatory, anti-proliferative and anti-fibrotic activities both in vitro and in vivo. Studies in human subjects have shown that PTX monotherapy decreases urinary protein excretion, and add-on therapy of PTX to background RAS blockade additively reduces proteinuria in patients with CKD of various etiology. More recent studies find that PTX combined with RAS blockade delays the decline of glomerular filtration rate in diabetic patients with mild to moderate CKD, and reduces the risk of end-stage renal disease in diabetic and non-diabetic patients in late stage of CKD with high proteinuria levels. In this review, we update the clinical trial results of PTX as monotherapy, or in conjunction or in comparison with RAS blockade on patients with proteinuria and CKD, and propose a mechanistic scheme explaining the renoprotective activities of this drug. PMID- 29132352 TI - Intensive care antibiotic consumption and resistance patterns: a cross correlation analysis. AB - BACKGROUND: Over recent decades, a dramatic increase in infections caused by multidrug-resistant pathogens has been observed worldwide. The aim of the present study was to investigate the relationship between local resistance bacterial patterns and antibiotic consumption in an intensive care unit in a Romanian university hospital. METHODS: A prospective study was conducted between 1st January 2012 and 31st December 2013. Data covering the consumption of antibacterial drugs and the incidence density for the main resistance phenotypes was collected on a monthly basis, and this data was aggregated quarterly. The relationship between the antibiotic consumption and resistance was investigated using cross-correlation, and four regression models were constructed, using the SPSS version 20.0 (IBM, Chicago, IL) and the R version 3.2.3 packages. RESULTS: During the period studied, the incidence of combined-resistant and carbapenem resistant P. aeruginosa strains increased significantly [(gradient = 0.78, R2 = 0.707, p = 0.009) (gradient = 0.74, R2 = 0.666, p = 0.013) respectively], mirroring the increase in consumption of beta-lactam antibiotics with beta lactamase inhibitors (piperacillin/tazobactam) and carbapenems (meropenem) [(gradient = 10.91, R2 = 0.698, p = 0.010) and (gradient = 14.63, R2 = 0.753, p = 0.005) respectively]. The highest cross-correlation coefficients for zero time lags were found between combined-resistant vs. penicillins consumption and carbapenem-resistant P. aeruginosa strains vs. carbapenems consumption (0.876 and 0.928, respectively). The best model describing the relation between combined resistant P. aeruginosa strains and penicillins consumption during a given quarter incorporates both the consumption and the incidence of combined-resistant strains in the hospital department during the previous quarter (multiple R2 = 0.953, p = 0.017). The best model for explaining the carbapenem resistance of P. aeruginosa strains based on meropenem consumption during a given quarter proved to be the adjusted model which takes into consideration both previous consumption and incidence density of strains during the previous quarter (Multiple R2 = 0.921, p = 0.037). CONCLUSIONS: The cross-correlation coefficients and the fitted regression models provide additional evidence that resistance during the a given quarter depends not only on the consumption of antibacterial chemotherapeutic drugs in both that quarter and the previous one, but also on the incidence of resistant strains circulating during the previous quarter. PMID- 29132353 TI - The effectiveness of community-based coordinating interventions in dementia care: a meta-analysis and subgroup analysis of intervention components. AB - BACKGROUND: Interventions aiming to coordinate services for the community-based dementia population vary in components, organisation and implementation. In this review we aimed to evaluate the effectiveness of community-based care coordinating interventions on health outcomes and investigate whether specific components of interventions influence their effects. METHODS: We searched four databases from inception to April 2017: Medline, The Cochrane Library, EMBASE and PsycINFO. This was aided by a search of four grey literature databases, and backward and forward citation tracking of included papers. Title and abstract screening was followed by a full text screen by two independent reviewers, and quality was assessed using the CASP appraisal tool. We then conducted meta analyses and subgroup analyses. RESULTS: A total of 14 randomised controlled trials (RCTs) involving 10,372 participants were included in the review. Altogether we carried out 12 meta-analyses and 19 subgroup analyses. Meta analyses found coordinating interventions showed a statistically significant improvement in both patient behaviour measured using the Neuropsychiatric Inventory (NPI) (mean difference (MD) = -9.5; 95% confidence interval (CI): -18.1 to -1.0; p = 0.03; number of studies (n) = 4; I2 = 88%) and caregiver burden (standardised mean difference (SMD) = -0.54; 95% CI: -1.01 to -0.07; p = 0.02; n = 5, I2 = 92%) compared to the control group. Subgroup analyses found interventions using a case manager with a nursing background showed a greater positive effect on caregiver quality of life than those that used case managers from other professional backgrounds (SMD = 0.94 versus 0.03, respectively; p < 0.001). Interventions that did not provide supervision for the case managers showed greater effectiveness for reducing the percentage of patients that are institutionalised compared to those that provided supervision (odds ratio (OR) = 0.27 versus 0.96 respectively; p = 0.02). There was little evidence of effects on other outcomes, or that other intervention components modify the intervention effects. CONCLUSION: Results show that coordinating interventions in dementia care has a positive impact on some outcomes, namely patient behaviour and caregiver burden, but the evidence is inconsistent and results were not strong enough to draw definitive conclusions on general effectiveness. With the rising prevalence of dementia, effective complex interventions will be necessary to provide high quality and effective care for patients, and facilitate collaboration of health, social and third sector services. PMID- 29132354 TI - Correction to: Dapagliflozin decreases small dense low-density lipoprotein cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin. AB - Following publication of the original article [1], the authors identified a number of errors. In Result (P.3), Table 1 (P.4), Table 5 (P.9) and Supplementary Table 1, the correct unit for adiponectin was MUg/mL. In Table 1 (P.4), the correct value for the post treatment body weight in dapagliflozin was 76.2+/ 14.8. In Table 6 (P.10), the correct value for the pre treatment sd LDL/LDL-C in decreased LDL-C group was 0.38+/-0.10. PMID- 29132355 TI - Criteria for prioritization of HIV programs in Viet Nam: a discrete choice experiment. AB - BACKGROUND: With the decline in funding for Viet Nam's response to the HIV epidemic, there is a need for evidence on the criteria to guide the prioritization of HIV programs. There is a gap in the research on the relative importance of multiple criteria for prioritizing a package of interventions. This study elicits preferences and the trade-offs made between different HIV programs by relevant stakeholders and decision-makers in Viet Nam. It also pays attention to how differences in social and professional characteristics of stakeholders and their agency affiliations shape preferences for HIV program criteria in Viet Nam. METHODS: This study uses self-explicated ranking and discrete choice experiments to determine the relative importance of five criteria - effectiveness, feasibility, cost-effectiveness, rate of investment and prevention/treatment investment ratio - to stakeholders when they evaluate and select hypothetical HIV programs. The study includes 69 participants from government, civil society, and international development partners. RESULTS: Results of the discrete choice experiment show that overall the feasibility criterion is ranked highest in importance to the participants when choosing a hypothetical HIV program, followed by sustainability, treatment to prevention spending ratio, and effectiveness. The participant's work in management, programming, or decision-making has a significant effect on the importance of some criteria to the participant. In the self-explicated ranking effectiveness is the most important criterion and the cost-effectiveness criterion ranks low in importance across all groups. CONCLUSIONS: This study has shown that the preferred HIV program in Viet Nam is feasible, front-loaded for sustainability, has a higher proportion of investment on prevention, saves more lives and prevents more infections. Similarities in government and civil society rankings of criteria can create common grounds for future policy dialogues between stakeholders. Innovative models of planning should be utilized to allow inputs of informed stakeholders at relevant stages of the HIV program planning process. PMID- 29132356 TI - Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases? AB - Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require anticoagulation therapy. Although more and more replaced by direct oral anticoagulants, vitamin K antagonists (VKAs) are still widely used. VKAs induce profound deficiency of vitamin K, a key activator in the coagulation pathway. It is recognized however that vitamin K is also an essential cofactor in the activation of other extrahepatic proteins, such as matrix Gla protein (MGP), a potent inhibitor of arterial calcification. No or insufficient MGP activation by the use of VKAs is associated with a rapid progression of vascular calcification, which may enhance the risk for overt cardiovascular disease. Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients. PMID- 29132357 TI - Mapping multiple components of malaria risk for improved targeting of elimination interventions. AB - There is a long history of considering the constituent components of malaria risk and the malaria transmission cycle via the use of mathematical models, yet strategic planning in endemic countries tends not to take full advantage of available disease intelligence to tailor interventions. National malaria programmes typically make operational decisions about where to implement vector control and surveillance activities based upon simple categorizations of annual parasite incidence. With technological advances, an enormous opportunity exists to better target specific malaria interventions to the places where they will have greatest impact by mapping and evaluating metrics related to a variety of risk components, each of which describes a different facet of the transmission cycle. Here, these components and their implications for operational decision making are reviewed. For each component, related mappable malaria metrics are also described which may be measured and evaluated by malaria programmes seeking to better understand the determinants of malaria risk. Implementing tailored programmes based on knowledge of the heterogeneous distribution of the drivers of malaria transmission rather than only consideration of traditional metrics such as case incidence has the potential to result in substantial improvements in decision-making. As programmes improve their ability to prioritize their available tools to the places where evidence suggests they will be most effective, elimination aspirations may become increasingly feasible. PMID- 29132358 TI - FTIR spectroscopy as a unified method for simultaneous analysis of intra- and extracellular metabolites in high-throughput screening of microbial bioprocesses. AB - BACKGROUND: Analyses of substrate and metabolites are often bottleneck activities in high-throughput screening of microbial bioprocesses. We have assessed Fourier transform infrared spectroscopy (FTIR), in combination with high throughput micro bioreactors and multivariate statistical analyses, for analysis of metabolites in high-throughput screening of microbial bioprocesses. In our previous study, we have demonstrated that high-throughput (HTS) FTIR can be used for estimating content and composition of intracellular metabolites, namely triglyceride accumulation in oleaginous filamentous fungi. As a continuation of that research, in the present study HTS FTIR was evaluated as a unified method for simultaneous quantification of intra- and extracellular metabolites and substrate consumption. As a proof of concept, a high-throughput microcultivation of oleaginous filamentous fungi was conducted in order to monitor production of citric acid (extracellular metabolite) and triglyceride lipids (intracellular metabolites), as well as consumption of glucose in the cultivation medium. RESULTS: HTS FTIR analyses of supernatant samples was compared with an attenuated total reflection (ATR) FTIR, which is an established method for bioprocess monitoring. Glucose and citric acid content of growth media was quantified by high performance liquid chromatography (HPLC). Partial least square regression (PLSR) between HPLC glucose and citric acid data and the corresponding FTIR spectral data was used to set up calibration models. PLSR results for HTS measurements were very similar to the results obtained with ATR methodology, with high coefficients of determination (0.91-0.98) and low error values (4.9-8.6%) for both glucose and citric acid estimates. CONCLUSIONS: The study has demonstrated that intra- and extracellular metabolites, as well as nutrients in the cultivation medium, can be monitored by a unified approach by HTS FTIR. The proof-of-concept study has validated that HTS FTIR, in combination with Duetz microtiter plate system and chemometrics, can be used for high throughput screening of microbial bioprocesses. It can be anticipated that the approach, demonstrated here on single-cell oil production by filamentous fungi, can find general application in screening studies of microbial bioprocesses, such as production of single-cell proteins, biopolymers, polysaccharides, carboxylic acids, and other type of metabolites. PMID- 29132359 TI - Portable wireless neurofeedback system of EEG alpha rhythm enhances memory. AB - BACKGROUND: Effect of neurofeedback training (NFT) on enhancement of cognitive function or amelioration of clinical symptoms is inconclusive. The trainability of brain rhythm using a neurofeedback system is uncertainty because various experimental designs are used in previous studies. The current study aimed to develop a portable wireless NFT system for alpha rhythm and to validate effect of the NFT system on memory with a sham-controlled group. METHODS: The proposed system contained an EEG signal analysis device and a smartphone with wireless Bluetooth low-energy technology. Instantaneous 1-s EEG power and contiguous 5-min EEG power throughout the training were developed as feedback information. The training performance and its progression were kept to boost usability of our device. Participants were blinded and randomly assigned into either the control group receiving random 4-Hz power or Alpha group receiving 8-12-Hz power. Working memory and episodic memory were assessed by the backward digital span task and word-pair task, respectively. RESULTS: The portable neurofeedback system had advantages of a tiny size and long-term recording and demonstrated trainability of alpha rhythm in terms of significant increase of power and duration of 8-12 Hz. Moreover, accuracies of the backward digital span task and word-pair task showed significant enhancement in the Alpha group after training compared to the control group. CONCLUSIONS: Our tiny portable device demonstrated success trainability of alpha rhythm and enhanced two kinds of memories. The present study suggest that the portable neurofeedback system provides an alternative intervention for memory enhancement. PMID- 29132360 TI - NeoAnalysis: a Python-based toolbox for quick electrophysiological data processing and analysis. AB - BACKGROUND: In a typical electrophysiological experiment, especially one that includes studying animal behavior, the data collected normally contain spikes, local field potentials, behavioral responses and other associated data. In order to obtain informative results, the data must be analyzed simultaneously with the experimental settings. However, most open-source toolboxes currently available for data analysis were developed to handle only a portion of the data and did not take into account the sorting of experimental conditions. Additionally, these toolboxes require that the input data be in a specific format, which can be inconvenient to users. Therefore, the development of a highly integrated toolbox that can process multiple types of data regardless of input data format and perform basic analysis for general electrophysiological experiments is incredibly useful. RESULTS: Here, we report the development of a Python based open-source toolbox, referred to as NeoAnalysis, to be used for quick electrophysiological data processing and analysis. The toolbox can import data from different data acquisition systems regardless of their formats and automatically combine different types of data into a single file with a standardized format. In cases where additional spike sorting is needed, NeoAnalysis provides a module to perform efficient offline sorting with a user-friendly interface. Then, NeoAnalysis can perform regular analog signal processing, spike train, and local field potentials analysis, behavioral response (e.g. saccade) detection and extraction, with several options available for data plotting and statistics. Particularly, it can automatically generate sorted results without requiring users to manually sort data beforehand. In addition, NeoAnalysis can organize all of the relevant data into an informative table on a trial-by-trial basis for data visualization. Finally, NeoAnalysis supports analysis at the population level. CONCLUSIONS: With the multitude of general-purpose functions provided by NeoAnalysis, users can easily obtain publication-quality figures without writing complex codes. NeoAnalysis is a powerful and valuable toolbox for users doing electrophysiological experiments. PMID- 29132361 TI - The impacts of implementation of National Essential Medicines Policies on primary healthcare institutions: a cross-sectional study in China. AB - BACKGROUND: In 2009, China implemented the National Essential Medicines Policies (NEMPs) as part of a new round of medical system reforms. This study aims to evaluate the impacts of the NEMPs on primary healthcare institutions and discuss the roles of the policies in the new healthcare reforms of China. METHODS: The study selected a total of six representative provinces of China, generating a sample of 261 primary healthcare institutions from August to December in 2010. A questionnaire survey developed by the study team was distributed to all of the primary healthcare institutions. Nine indicators from three dimensions as the outcome variables were used and calculated to evaluate the impacts of implementation of policies. All of the outcome variables were tested using independent-samples T test between the treatment group (with the NEMPs implemented) and the control group (without the NEMPs implemented). RESULTS: The ratio of drug sales and institution revenues at primary healthcare institutions was 42.99% in the treatment group, which was significantly lower than the control group (53.90%, p < 0.01), while the ratio of financial subsidies of the treatment group was shown to be higher (30.78% VS 20.82%, p < 0.01). The rate of healthcare workers income growth was greater in the treatment group (15.35% VS 5.79%, p = 0.006). The treatment group exhibited higher outpatient and emergency visits per month in urban areas (2720 VS 1763 visits per month) and rural areas (3830 VS 3633), and higher prescriptions per month in urban areas (2048 VS 1025, p = 0.005) and rural areas (3806 VS 3251). The treatment group used more essential medicines and received greater income from essential medicines while the drug price markup rate was lower. CONCLUSIONS: The NEMPs appear to affect the transformation of the operation mechanisms of primary healthcare institutions, the improvement of the mechanisms for government investment, and the healthcare pricing system. Meanwhile, the gaps between urban and rural areas need to be addressed. In conclusion, the NEMPs of China are instrumental to the aim of providing basic healthcare services to every citizen. PMID- 29132363 TI - Women's autonomy and maternal healthcare service utilization in Ethiopia. AB - BACKGROUND: Most previous studies on healthcare service utilization in low-income countries have not used a multilevel study design to address the importance of community-level women's autonomy. We assessed whether women's autonomy, measured at both individual and community levels, is associated with maternal healthcare service utilization in Ethiopia. METHODS: We analyzed data from the 2005 and 2011 Ethiopia Demographic and Health Surveys (N = 6058 and 7043, respectively) for measuring women's decision-making power and permissive gender norms associated with wife beating. We used Spearman's correlation and the chi-squared test for bivariate analyses and constructed generalized estimating equation logistic regression models to analyze the associations between women's autonomy indicators and maternal healthcare service utilization with control for other socioeconomic characteristics. RESULTS: Our multivariate analysis showed that women living in communities with a higher percentage of opposing attitudes toward wife beating were more likely to use all three types of maternal healthcare services in 2011 (adjusted odds ratios = 1.21, 1.23, and 1.18 for four or more antenatal care visits, health facility delivery, and postnatal care visits, respectively). In 2005, the adjusted odds ratios were 1.16 and 1.17 for four or more antenatal care visits and health facility delivery, respectively. In 2011, the percentage of women in the community with high decision-making power was positively associated with the likelihood of four or more antenatal care visits (adjusted odds ratio = 1.14). The association of individual-level autonomy on maternal healthcare service utilization was less profound after we controlled for other individual level and community-level characteristics. CONCLUSIONS: Our study shows that women's autonomy was positively associated with maternal healthcare service utilization in Ethiopia. We suggest addressing woman empowerment in national policies and programs would be the optimal solution. PMID- 29132362 TI - Knockdown of SOX2OT inhibits the malignant biological behaviors of glioblastoma stem cells via up-regulating the expression of miR-194-5p and miR-122. AB - BACKGROUND: Accumulating evidence has highlighted the potential role of long non coding RNAs (lncRNAs) in the biological behaviors of glioblastoma stem cells (GSCs). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-SOX2OT on the biological behaviors of GSCs. RESULTS: Real-time PCR demonstrated that SOX2OT expression was up-regulated in glioma tissues and GSCs. Knockdown of SOX2OT inhibited the proliferation, migration and invasion of GSCs, and promoted GSCs apoptosis. MiR-194-5p and miR-122 were down-regulated in human glioma tissues and GSCs, and miR-194-5p and miR-122 respectively exerted tumor-suppressive functions by inhibiting the proliferation, migration and invasion of GSCs, while promoting GSCs apoptosis. Knockdown of SOX2OT significantly increased the expression of miR-194-5p and miR-122 in GSCs. Dual luciferase reporter assay revealed that SOX2OT bound to both miR-194-5p and miR 122. SOX3 and TDGF-1 were up-regulated in human glioma tissues and GSCs. Knockdown of SOX3 inhibited the proliferation, migration and invasion of GSCs, promoted GSCs apoptosis, and decreased TDGF-1 mRNA and protein expression through direct binding to the TDGF-1 promoter. Over-expression of miR-194-5p and miR-122 decreased the mRNA and protein expression of SOX3 by targeting its 3'UTR. Knockdown of TDGF-1 inhibited the proliferation, migration and invasion of GSCs, promoted GSCs apoptosis, and inhibited the JAK/STAT signaling pathway. Furthermore, SOX3 knockdown also inhibited the SOX2OT expression through direct binding to the SOX2OT promoter and formed a positive feedback loop. CONCLUSION: This study is the first to demonstrate that the SOX2OT-miR-194-5p/miR-122-SOX3 TDGF-1 pathway forms a positive feedback loop and regulates the biological behaviors of GSCs, and these findings might provide a novel strategy for glioma treatment. PMID- 29132364 TI - "I'm not strong enough; I'm not good enough. I can't do this, I'm failing"- A qualitative study of low-socioeconomic status smokers' experiences with accesssing cessation support and the role for alternative technology-based support. AB - BACKGROUND: The social gradient in smoking rates persist with an overrepresentation of smoking and its associated harms concentrated within lower socioeconomic status (SES) populations. Low-SES smokers are motivated to quit but face multiple barriers when engaging a quit attempt. An understanding of the current treatment service model from the perspectives of treatment-seeking low SES smokers is needed to inform the design of alternative smoking cessation support services tailored to the needs of low-SES populations. This qualitative study aimed to: i) explore low-SES smokers' recent quitting experiences; ii) assess factors that impact treatment engagement; and iii) determine the acceptability and feasibility of alternative approaches to smoking cessation. METHOD: Low-SES participants (n = 24) previously enrolled in a smoking cessation RCT participated in either a semi-structured focus group or in-depth telephone interview. Data was obtained and analysed using thematic analysis from October 2015 to June 2016. Analysis was deductive from the interview guide and supplemented inductively. RESULTS: Participants expressed feelings of guilt and shame around their smoking behaviour and experienced stigmatisation for their smoking. Guilt, shame, and stigmatisation negatively impacted treatment seeking behaviours with most avoiding current quit services. Costs of pharmacotherapy and treatment adherence were commonly cited barriers to treatment success. Electronic cigarettes were perceived to be unsafe due to uncertainty on their legal status and regulatory restrictions. Technology-based text-messaging quit support was endorsed as a more favourable alternative compared to existing behavioural treatment services. CONCLUSION: Stigmatisation was commonly endorsed and acted as an impediment to current treatment utilisation. Electronic-cigarettes may present a viable harm reduction alternative, but their likely uptake in socioeconomically disadvantaged groups in Australia is limited by smokers' uncertainty about their regulation and legality. Mobile phone based cessation support may provide an alternative to telephone counselling and overcome the stigmatisation low-SES smokers face while trying to quit. PMID- 29132365 TI - Socioeconomic inequalities in under-five mortality in rural Bangladesh: evidence from seven national surveys spreading over 20 years. AB - BACKGROUND: Socioeconomic inequality in health and mortality remains a disturbing reality across nations including Bangladesh. Inequality drew renewed attention globally. Bangladesh though made impressive progress in health, it makes an interesting case for learning. This paper examined the trends and changing pattern of socioeconomic inequalities in under-five mortality in rural Bangladesh. It also examined whether mother's education had any effect in reducing socioeconomic inequalities. METHODS: Data from rural samples of seven Bangladesh Demographic Health Surveys, carried out so far, were used. Children born alive during 5 years preceding the surveys were included in the analysis. Univariate, bivariate and multivariate analyses were carried out. RESULTS: Under five mortality rate steadily declined over the years from 128/1000 in 1994 to 48 in 2014. Females had 8% lower mortality rates than males. Children of mothers with no schooling had 1.88 times higher mortality than those whose mother had six or more years of schooling. Similarly, children from low asset category households had on an average 1.17 times higher mortality rate than those from high asset category households. Inequality by mother's education disappeared in the recent years, and inequality by household socioeconomic condition persisted all through. The pattern of inequality by sex, mother's education, and household socioeconomic status was not changed statistically significantly over the years, and mothers' education did not reduce socioeconomic inequalities. DISCUSSION: The reduction in mortality was consistent with changes in the proximate determinants of child survival in the country. Proximate determinants included maternal factors, environmental contamination, nutrient deficiency, personal illness control, and injury. Health and population programmes have been effective in increasing immunization coverage, use of ORS for managing diarrhoeal diseases, and increasing contraceptive use. Development activities on the other hand raised the literacy, especially among females, demand for modern health services, and reduction of poverty. However, socioeconomic inequality still exists in both under-five mortality and proximate determinants of child survival. CONCLUSIONS: The socioeconomic inequality in under-five mortality is showing resistance against further reduction. An assessment of the adequacy of the existing programmes taking the proximate determinants of child survival into consideration will be useful for further improvement. PMID- 29132366 TI - Prokaryotic expression and characterization of the heterodimeric construction of ZnT8 and its application for autoantibodies detection in diabetes mellitus. AB - BACKGROUND: In the present work we described the recombinant production and characterization of heterodimeric construction ZnT8-Arg-Trp325 fused to thioredoxin using a high-performance expression system such as Escherichia coli. In addition, we apply this novel recombinant antigen in a non-radiometric method, with high sensitivity, low operational complexity and lower costs. RESULTS: ZnT8 was expressed in E. coli as a fusion protein with thioredoxin (TrxZnT8). After 3 h for induction, recombinant protein was obtained from the intracellular soluble fraction and from inclusion bodies and purified by affinity chromatography. The expression and purification steps, analyzed by SDS-PAGE and western blot, revealed a band compatible with TrxZnT8 expected theoretical molecular weight (~ 36.8 kDa). The immunochemical ability of TrxZnT8 to compete with [35S]ZnT8 (synthesized with rabbit reticulocyte lysate system) was assessed qualitatively by incubating ZnT8A positive patient sera in the presence of 0.2-0.3 MUM TrxZnT8. Results were expressed as standard deviation scores (SDs). All sera became virtually negative under antigen excess (19.26-1.29 for TrxZnT8). Also, radiometric quantitative competition assays with ZnT8A positive patient sera were performed by adding TrxZnT8 (37.0 pM-2.2 uM), using [35S]ZnT8. All dose-response curves showed similar protein concentration that caused 50% inhibition (14.9-0.15 nM for TrxZnT8). On the other hand, preincubated bridge ELISA for ZnT8A detection was developed. This assay showed 51.7% of sensitivity and 97.1% of specificity. CONCLUSIONS: It was possible to obtain with high-yield purified heterodimeric construction of ZnT8 in E. coli and it was applied in cost-effective immunoassay for ZnT8A detection. PMID- 29132367 TI - Proposal for coordinated health research in PFAS-contaminated communities in the United States. AB - The drinking water of more than six million Americans in numerous communities has been found to contain highly fluorinated chemicals at concentrations of concern. Certain of these chemicals, including perfluorooctanoic acid and perfluorooctane sulfonic acid, are known to be persistent, bioaccumulative, and associated with adverse health outcomes in humans and animal models. The possible health impacts of exposure to highly fluorinated chemicals are of great concern to communities whose water has been impacted. Community members want information, and are asking for biomonitoring, exposure pathway analysis, and health studies. Governmental agencies are striving to deal with these multiple concerns in the face of information and resource constraints. We propose the development of a high-level research strategy to maximize what can be learned about health effects of highly fluorinated chemicals and methods to reduce or eliminate exposure. We suggest coordinating the research across multiple communities for greater statistical power. If implemented, such a strategy could help to generate information and evidence integration to enable regulatory decision making and contribute to reducing future exposures. PMID- 29132368 TI - Frequency of canine nt230(del4) MDR1 mutation in prone pure breeds, their crosses and mongrels in Israel - insights from a worldwide comparative perspective. AB - BACKGROUND: Sensitivity to macrocyclic lactones, which are commonly used in veterinary clinics, was first found in Rough Collies, and was attributed in 2001 to a 4 bp deletion in the MDR1 gene. The list of affected breeds currently includes 13 breeds. Researchers from different countries and continents examined the allelic frequencies of the nt230(del4) MDR1 mutation, emphasizing the clinical importance of this test not only to mutation-prone dogs, but also to their crosses and mongrels, since treatment of a deletion carrier with these compounds may lead to its death. In this study, the allelic frequencies of nt230(del4) MDR1 mutation in affected breeds, their crosses, unrelated pure breeds and mongrels are reported for the state of Israel (n = 1416 dogs). The Israeli data were compared with reports from the US, Europe, UK, Australia and Japan. RESULTS: The allelic frequencies of nt230(del4) MDR1 mutation in Israel for Australian, Swiss and German Shepherds (31%, 17% and 2.4%, respectively) are similar to the corresponding frequencies worldwide, much higher for Border Collies (4.8%), twice lower for Rough Collies (28%, compared to 55% or more elsewhere), and ~1% for mongrels. The frequencies for crosses of Australian Shepherd and Border Collies in Israel are 4 and 1.6 times lower, respectively, compared to the frequencies for the respective pure breeds. CONCLUSIONS: This work, that for the first time presents the frequency of nt230(del4) MDR1 mutation in Israel, along with a worldwide survey, has implications for clinicians, owners and breeders of sheepdogs and their crosses and supports the need for extra care in treatment and in future breeding. Of note, the relative proportion of affected breeds, in the overall tested dogs, might be higher than their actual proportion in Israel due to directed samples collection by veterinarians for clinical purposes, as these are mainly limited to certain affected breeds or dogs that resemble them. PMID- 29132369 TI - Impact of pharmacist-led medication management in care transitions. AB - BACKGROUND: When patients are discharged from hospital to home, it is a highlighted vulnerable period for which medication - related problems are prevalent. Researchers have proposed a telephone follow-up intervention as a means to reduce hospital readmissions. However, the outcome of the intervention with the engagement of pharmacists in managing patients' medicines after discharge has not been well explored. The objectives of this study were (1) to determine whether a pharmacist telephone follow-up intervention focusing on patients' medicines management support is associated with a reduction in 30-day readmission rates and (2) to describe the number and types of pharmacist interventions in care transitions. METHODS: This was a case-cohort study conducted in two acute hospitals in the UK. Pharmacists performed a telephone follow-up intervention to discharged patients to provide medicines management support. Patients who received pharmacist telephone follow-up calls within 14 days of discharge formed the intervention group. A subset of medical patient population discharged in the month of May 2013 formed the comparison group. During a series of two-telephone follow-up, pharmacists identified post-discharge pharmaceutical problems and provided patient-tailored interventions accordingly. The impact of pharmacist interventions was assessed using a risk assessment matrix tool by two senior pharmacists. Overall 30-day readmission rates in the intervention group were measured and compared with the comparison group using a chi-square test. RESULTS: Between 5th and 25th June 2013, a total of 62 medical patients participated in the study. Pharmacists provided 192 interventions as a result of pharmacist telephone follow-up intervention. The most prevalent type of interventions was the provision of drug information (n=40), followed by screening patient adherence (n=30) and advising on adverse drug reactions (n=27). The impact of interventions was assessed, and 49.3% of the identified risks intervened by pharmacists were associated with moderate risk. The 30-day readmission rates in the intervention group were 11.3% compared to 9.0% in the control group (p = 0.376); this was not statistically significant. CONCLUSIONS: A pharmacist TFU intervention did not show a benefit in 30-day hospital readmissions. However, a pharmacist TFU intervention was an effective method to solve or avoid critical pharmaceutical problems. A future study using a larger scale trial is warranted. PMID- 29132370 TI - Expanding malaria diagnosis and treatment in Lao PDR: lessons learned from a public-private mix initiative. AB - BACKGROUND: As in other countries of the Greater Mekong Sub-region (GMS), the private health sector constitutes a significant avenue where malaria services are provided and presents a unique opportunity for public-private collaboration. In September 2008, a public-private mix (PPM) strategy was launched initially in four northern and southern provinces in Lao PDR to increase access to rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT), improve quality of care, and collect routine malaria data from the private sector. Throughout the process, key stakeholders were involved in the planning, monitoring and supervision of project sites. Following an initial assessment in 2009, the PPM initiative expanded to an additional 14 district sites to a total of 245 private pharmacies and 16 clinics covering 8 provinces and 22 districts. By June 2016, a total of 317 pharmacies, 30 clinics in 32 districts of the 8 provinces were participating in the PPM network and reported monthly malaria case data. METHODS: This descriptive study documented the process of initiating and maintaining the PPM network in Lao PDR. Epidemiological data reported through the routine surveillance system from January 2009 to June 2016 were analyzed to illustrate the contribution of case reporting from the private sector. RESULTS: A total of 2,301,676 malaria tests were performed in the PPM districts, which included all the PPM pharmacies and clinics (176,224, 7.7%), proportion of patients tested from 14,102 (4.6%) in 2009 to 29,554 (10.4%) in 2015. Over the same period of 90 months, a total of 246,091 positive cases (10.7%) were detected in PPM pharmacies and clinics (33,565; 13.6%), in the same districts as the PPM sites. The results suggest that the PPM sites contributed to a significant increasing proportion of patients positive for malaria from 1687 (7.4%) in 2009 to 5697 (15.8%) in 2015. CONCLUSIONS: Ensuring adequate and timely supplies of RDTs and ACT to PPM sites is critical. Frequent refresher training is necessary to maintain data quality, motivation and feedback. In the context of malaria elimination, the PPM initiative should be expanded further to ensure that all febrile cases seen through the private sector in malaria transmission areas are tested for malaria and treated appropriately. Results from the PPM must be integrated into a centralized registry of malaria cases that should prompt required case and foci investigations and responses to be conducted as part of elimination efforts. PMID- 29132371 TI - Survey of vector-borne agents in feral cats and first report of Babesia gibsoni in cats on St Kitts, West Indies. AB - BACKGROUND: As there is little data on vector-borne diseases of cats in the Caribbean region and even around the world, we tested feral cats from St Kitts by PCR to detect infections with Babesia, Ehrlichia and spotted fever group Rickettsia (SFGR) and surveyed them for antibodies to Rickettsia rickettsii and Ehrlichia canis. RESULTS: Whole blood was collected from apparently healthy feral cats during spay/ neuter campaigns on St Kitts in 2011 (N = 68) and 2014 (N = 52). Sera from the 52 cats from 2014 were used to detect antibodies to Ehrlichia canis and Rickettsia rickettsii using indirect fluorescent antibody tests and DNA extracted from whole blood of a total of 119 cats (68 from 2011, and 51 from 2014) was used for PCRs for Babesia, Ehrlichia and Rickettsia. We could not amplify DNA of SFG Rickettsia in any of the samples but found DNA of E. canis in 5% (6/119), Babesia vogeli in 13% (15/119), Babesia gibsoni in 4% (5/119), mixed infections with B. gibsoni and B. vogeli in 3% (3/119), and a poorly characterized Babesia sp. in 1% (1/119). Overall, 10% of the 52 cats we tested by IFA for E. canis were positive while 42% we tested by indirect fluorescent antibody (IFA) for R. rickettsii antigens were positive. CONCLUSIONS: Our study provides the first evidence that cats can be infected with B. gibsoni and also indicates that cats in the Caribbean may be commonly exposed to other vector borne agents including SFGR, E. canis and B. vogeli. Animal health workers should be alerted to the possibility of clinical infections in their patients while public health workers should be alerted to the possibility that zoonotic SFGR are likely circulating in the region. PMID- 29132372 TI - Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3. AB - BACKGROUND: Hepatitis B virus (HBV) infection in the body can damage liver cells and cause disorders in blood lipid metabolism. Apolipoprotein C3 (ApoC3) plays an important role in the regulation of lipid metabolism, but no study on the HBV regulation of ApoC3 has been reported. This purpose of this study was to investigate the effect of HBV on ApoC3 expression and its regulatory mechanism. METHODS: The expression levels of ApoC3 mRNA and protein in the human hepatoma cell lines HepG2 and HepG2.2.15 were determined using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The HepG2 cells were co-transfected with the ApoC3 gene promoter and either HBV infected clone pHBV1.3 or its individual genes. The changes in luciferase activity were assayed. The expression levels of ApoC3 mRNA and protein were determined using RT-qPCR and Western blot. The content of ApoC3 in the supernatant of the cultured cells was determined using an enzyme-linked immunosorbent assay (ELISA). The sera were collected from 149 patients with HBV infection and 102 healthy subjects at physical examination as the normal controls. The serological levels of ApoC3 in the HBV group and the normal control group were determined using ELISA. The contents of serum triglyceride (TG) and very-low-density lipoprotein (VLDL) in the HBV patients and the normal control were determined using an automatic biochemical analyser. RESULTS: The expression levels of ApoC3 mRNA and protein were lower in the HepG2.2.15 cells than in the HepG2 cells. pHBV1.3 and its X gene could inhibit the activity of the ApoC3 promoter and its mRNA and protein expression. The serum levels of ApoC3, VLDL and TG were 65.39 +/- 7.48 MUg/ml, 1.24 +/- 0.49 mmol/L, and 0.46 +/- 0.10 mmol/L in the HBV patients and 41.02 +/- 6.88 MUg/ml, 0.76 +/- 0.21 mmol/L, 0.29 +/- 0.05 mmol/L in the normal controls, respectively, statistical analysis revealed significantly lower serum levels of ApoC3, VLDL and TG in HBV patients than in the normal controls (P < 0.05). CONCLUSION: HBV can inhibit the in vivo and in vitro synthesis and secretion of ApoC3. PMID- 29132373 TI - Understanding malaria treatment-seeking preferences within the public sector amongst mobile/migrant workers in a malaria elimination scenario: a mixed-methods study. AB - BACKGROUND: Migration flows and the emerging resistance to artemisinin-based combination therapy in the Greater Mekong Sub-region (GMS) create programmatic challenges to meeting the AD 2030 malaria elimination target in Myanmar. The National Malaria Control Programme (NMCP) targeted migrant workers based mainly on the stability of their worksites (categories 1: permanent work-setting; categories 2 and 3: less stable work-settings). This study aims to assess the migration patterns, malaria treatment-seeking preferences, and challenges encountered by mobile/migrant workers at remote sites in a malaria-elimination setting. METHODS: A mixed-methods explanatory sequential study retrospectively analysed the secondary data acquired through migrant mapping surveys (2013-2015) in six endemic regions (n = 9603). A multivariate logistic regression model was used to ascertain the contributing factors. A qualitative strand (2016-2017) was added by conducting five focus-group discussions (n = 50) and five in-depth interviews with migrant workers from less stable worksites in Shwegyin Township, Bago Region. The contiguous approach was used to integrate quantitative and qualitative findings. RESULTS: Among others, migrant workers from Bago Region were significantly more likely to report the duration of stay >= 12 months (63% vs. 49%) and high seasonal mobility (40% vs. 35%). Particularly in less stable settings, a very low proportion of migrant workers (17%) preferred to seek malaria treatment from the public sector and was significantly influenced by the worksite stability (adjusted OR = 1.4 and 2.3, respectively for categories 2 and 1); longer duration of stay (adjusted OR = 3.5); and adjusted OR < 2 for received malaria messages, knowledge of malaria symptoms and awareness of means of malaria diagnosis. Qualitative data further elucidated their preference for the informal healthcare sector, due to convenience, trust and good relations, and put migrant workers at risk of substandard care. Moreover, the availability of cheap anti malarial in unregistered small groceries encouraged self-medication. Infrequent or no contact with rural health centres and voluntary health workers worsened the situation. CONCLUSIONS: Mitigating key drivers that favour poor utilization of public-sector services among highly mobile migrant workers in less stable work settings should be given priority in a malaria-elimination setting. These issues are challenging for the NMCP in Myanmar and might be generalized to other countries in the GMS to achieve malaria-elimination goals. Further innovative out reach programmes designed and implemented specific to the nature of mobile/migrant workers is crucial. PMID- 29132374 TI - Yeast interfering RNA larvicides targeting neural genes induce high rates of Anopheles larval mortality. AB - BACKGROUND: Although larviciding can reduce the number of outdoor biting malaria vector mosquitoes, which may help to prevent residual malaria transmission, the current larvicide repertoire is faced with great challenges to sustainability. The identification of new effective, economical, and biorational larvicides could facilitate maintenance and expansion of the practice of larviciding in integrated malaria vector mosquito control programmes. Interfering RNA molecules represent a novel class of larvicides with untapped potential for sustainable mosquito control. This investigation tested the hypothesis that short interfering RNA molecules can be used as mosquito larvicides. RESULTS: A small interfering RNA (siRNA) screen for larval lethal genes identified siRNAs corresponding to the Anopheles gambiae suppressor of actin (Sac1), leukocyte receptor complex member (lrc), and offtrack (otk) genes. Saccharomyces cerevisiae (baker's yeast) was engineered to produce short hairpin RNAs (shRNAs) for silencing of these genes. Feeding larvae with the engineered yeasts resulted in silenced target gene expression, a severe loss of neural synapses in the larval brain, and high levels of larval mortality. The larvicidal activities of yeast interfering RNA larvicides were retained following heat inactivation and drying of the yeast into user-friendly tablet formulations that induced up to 100% larval mortality in laboratory trials. CONCLUSIONS: Ready-to-use dried inactivated yeast interfering RNA larvicide tablets may someday be an effective and inexpensive addition to malaria mosquito control programmes and a valuable, biorational tool for addressing residual malaria transmission. PMID- 29132375 TI - Comparative transcriptome analysis of soybean response to bean pyralid larvae. AB - BACKGROUND: Soybean is one of most important oilseed crop worldwide, however, its production is often limited by many insect pests. Bean pyralid is one of the major soybean leaf-feeding insects in China. To explore the defense mechanisms of soybean resistance to bean pyralid, the comparative transcriptome sequencing was completed between the leaves infested with bean pyralid larvae and no worm of soybean (Gantai-2-2 and Wan82-178) on the Illumina HiSeqTM 2000 platform. RESULTS: In total, we identified 1744 differentially expressed genes (DEGs) in the leaves of Gantai-2-2 (1064) and Wan82-178 (680) fed by bean pyralid for 48 h, compared to 0 h. Interestingly, 315 DEGs were shared by Gantai-2-2 and Wan82-178, while 749 and 365 DEGs specifically identified in Gantai-2-2 and Wan82-178, respectively. When comparing Gantai-2-2 with Wan82-178, 605 DEGs were identified at 0 h feeding, and 468 DEGs were identified at 48 h feeding. Gene Ontology (GO) annotation analysis revealed that the DEGs were mainly involved in the metabolic process, single-organism process, cellular process, responses to stimulus, catalytic activities and binding. Pathway analysis showed that most of the DEGs were associated with the plant-pathogen interaction, phenylpropanoid biosynthesis, phenylalanine metabolism, flavonoid biosynthesis, peroxisome, plant hormone signal transduction, terpenoid backbone biosynthesis, and so on. Finally, we used qRT-PCR to validate the expression patterns of several genes and the results showed an excellent agreement with deep sequencing. CONCLUSIONS: According to the comparative transcriptome analysis results and related literature reports, we concluded that the response to bean pyralid feeding might be related to the disturbed functions and metabolism pathways of some key DEGs, such as DEGs involved in the ROS removal system, plant hormone metabolism, intracellular signal transduction pathways, secondary metabolism, transcription factors, biotic and abiotic stresses. We speculated that these genes may have played an important role in synthesizing substances to resist insect attacks in soybean. Our results provide a valuable resource of soybean defense genes that will benefit other studies in this field. PMID- 29132376 TI - EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment. AB - BACKGROUND: Glioblastoma multiforme (GBM) induces tumor immunosuppression through interacting with tumor-infiltrating microglia or macrophages (TAMs) with an unclear pathogenesis. Enhancer of zeste homolog 2 (EZH2) is abundant in GBM samples and cell lines and is involved in GBM proliferation, cell cycle, and invasion, whereas its association with innate immune response is not yet reported. Herein, the aim of this study was to investigate the role of EZH2 in GBM immune. METHODS: Co-culturing models of human/murine GBM cells with PBMC derived macrophages/primary microglia were employed. EZH2 mRNAs and function were suppressed by siEZH2 and DZNep. Real-time PCR and flow cytometry were used to determine levels of microglia/macrophages markers. The fluorescence-labeled latex beads and flow cytometry were utilized to evaluate phagocytic abilities of microglia. CCK8 assay was performed to assess microglia proliferation. RESULTS: EZH2 inhibition led to significant reduction of TGFbeta1-3 and IL10 and elevation of IL1beta and IL6 in human and murine GBM cells. More importantly, EZH2 suppression in GBM cells resulted in significant increase of M1 markers (TNFalpha and iNOS) and decrease of a pool of M2 markers in murine microglia. The proportion of CD206+ cells was decreased in PBMC-derived macrophages as co incubated with EZH2-inhibited GBM cells. Functional researches showed that phagocytic capacities of microglia were significantly ameliorated after EZH2 inhibition in co-culturing GBM cells and microglia proliferation was declined after addition of TGFbeta2 antibodies to co-incubated GBM cells with EZH2 inhibition. Besides, we found that EZH2 suppression in GBM cells enhanced co culturing microglia engulfment through activation of iNOS. CONCLUSIONS: Our data demonstrates that EZH2 participates in GBM-induced immune deficient and EZH2 suppression in GBM can remodel microglia immune functions, which is beneficial for understanding GBM pathogenesis and suggests potential targets for therapeutic approaches. PMID- 29132378 TI - Protocol for the study of self-perceived psychological and emotional well-being of young Paralympic athletes. AB - BACKGROUND: We present the detailed protocol set up to investigate how agonistic sport affects the self-perceived psychological and emotional well-being of disabled young people. METHODS: The study will be carried out on a number of subjects as large as 800-1200, using well-established indices that give a quantitative measure of such well-being, namely SF-12 and PGWBI. The related questionnaires will be administered to the participants to a forthcoming international event, the European Para-Youth Games, 9-15 October 2017, Liguria, Italy, as well as to a reference population of a similar number of subjects, made up of young disabled people that do not practice agonistic sport. DISCUSSION: We expect that the outcomes of the study may strongly impact not only the socio sanitary field but also society in general, as disabled people can be considered an extreme situation in the issue of balancing individual needs and environment to pursue psychological well-being. TRIAL REGISTRATION: ISRCTN14389453 (29 June 2017). PMID- 29132377 TI - The development and psychometric properties of the Arabic version of the child oral health impact profile-short form (COHIP- SF 19). AB - BACKGROUND: This study aims to cross-culturally adapt the original English language COHIP-SF 19 to Arabic culture and to test its psychometric properties in a community sample. METHODS: The Arabic COHIP-SF 19 was developed and its psychometric properties were examined in a population-based sample of 876 schoolchildren who were aged 12 years of age, in Benghazi, Libya. The Arabic COHIP-SF 19 was tested for its internal consistency, reproducibility, construct validity, factorial validity and floor as well as ceiling effects. A Mann-Whitney U test was used to compare the mean scores of COHIP-SF 19 by participants' caries status and self-reported oral health rating, satisfaction and treatment need. RESULTS: The Arabic COHIP-SF 19 was successfully and smoothly developed. It showed an acceptable level of equivalence to the original version. Overall, the internal consistency and reproducibility were acceptable to excellent, with a Cronbach's alpha of 0.84 and an intra-class correlation coefficient (ICC) of 0.76. All hypotheses predefined to test construct validity were confirmed. That is, children who had active dental caries, and who rated their oral health as poor, were not satisfied with their oral health or indicated the need of treatment had lower COHIP-SF 19 scores (P < 0.05). Floor or ceiling effects were not observed. The exploratory Factorial analysis suggested a 4-component solution and deletion of one item. CONCLUSION: The Arabic COHIP-SF 19 was successfully developed. The measure demonstrated satisfactory reliability and validity to estimate OHRQoL in a representative sample of 12-year-old schoolchildren. PMID- 29132379 TI - Effects of somatosensory electrical stimulation on motor function and cortical oscillations. AB - BACKGROUND: Few patients recover full hand dexterity after an acquired brain injury such as stroke. Repetitive somatosensory electrical stimulation (SES) is a promising method to promote recovery of hand function. However, studies using SES have largely focused on gross motor function; it remains unclear if it can modulate distal hand functions such as finger individuation. OBJECTIVE: The specific goal of this study was to monitor the effects of SES on individuation as well as on cortical oscillations measured using EEG, with the additional goal of identifying neurophysiological biomarkers. METHODS: Eight participants with a history of acquired brain injury and distal upper limb motor impairments received a single two-hour session of SES using transcutaneous electrical nerve stimulation. Pre- and post-intervention assessments consisted of the Action Research Arm Test (ARAT), finger fractionation, pinch force, and the modified Ashworth scale (MAS), along with resting-state EEG monitoring. RESULTS: SES was associated with significant improvements in ARAT, MAS and finger fractionation. Moreover, SES was associated with a decrease in low frequency (0.9-4 Hz delta) ipsilesional parietomotor EEG power. Interestingly, changes in ipsilesional motor theta (4.8-7.9 Hz) and alpha (8.8-11.7 Hz) power were significantly correlated with finger fractionation improvements when using a multivariate model. CONCLUSIONS: We show the positive effects of SES on finger individuation and identify cortical oscillations that may be important electrophysiological biomarkers of individual responsiveness to SES. These biomarkers can be potential targets when customizing SES parameters to individuals with hand dexterity deficits. TRIAL REGISTRATION: NCT03176550; retrospectively registered. PMID- 29132380 TI - Addressing challenges in scaling up TB and HIV treatment integration in rural primary healthcare clinics in South Africa (SUTHI): a cluster randomized controlled trial protocol. AB - BACKGROUND: A large and compelling clinical evidence base has shown that integrated TB and HIV services leads to reduction in human immunodeficiency virus (HIV)- and tuberculosis (TB)-associated mortality and morbidity. Despite official policies and guidelines recommending TB and HIV care integration, its poor implementation has resulted in TB and HIV remaining the commonest causes of death in several countries in sub-Saharan Africa, including South Africa. This study aims to reduce mortality due to TB-HIV co-infection through a quality improvement strategy for scaling up of TB and HIV treatment integration in rural primary healthcare clinics in South Africa. METHODS: The study is designed as an open label cluster randomized controlled trial. Sixteen clinic supervisors who oversee 40 primary health care (PHC) clinics in two rural districts of KwaZulu-Natal, South Africa will be randomized to either the control group (provision of standard government guidance for TB-HIV integration) or the intervention group (provision of standard government guidance with active enhancement of TB-HIV care integration through a quality improvement approach). The primary outcome is all cause mortality among TB-HIV patients. Secondary outcomes include time to antiretroviral therapy (ART) initiation among TB-HIV co-infected patients, as well as TB and HIV treatment outcomes at 12 months. In addition, factors that may affect the intervention, such as conditions in the clinic and staff availability, will be closely monitored and documented. DISCUSSION: This study has the potential to address the gap between the establishment of TB-HIV care integration policies and guidelines and their implementation in the provision of integrated care in PHC clinics. If successful, an evidence-based intervention comprising change ideas, tools, and approaches for quality improvement could inform the future rapid scale up, implementation, and sustainability of improved TB-HIV integration across sub-Sahara Africa and other resource-constrained settings. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02654613 . Registered 01 June 2015. PMID- 29132381 TI - Patients with juvenile idiopathic arthritis in clinical remission with positive power Doppler signal in joint ultrasonography have an increased rate of clinical flare: a prospective study. AB - BACKGROUND: Ultrasonography (US) studies carried out on joints of juvenile idiopathic arthritis (JIA) patients in clinical remission demonstrate the presence of subclinical synovitis. The significance of subclinical synovitis and the positive power Doppler (PD) signal on US in JIA in clinical remission is not well understood. The objectives of this study were to assess whether the changes detected by US in patients with JIA in clinical remission can predict disease flare and to evaluate factors associated with flare and joint damage over 30 months of follow-up. METHODS: A prospective study was performed with clinical and ultrasound evaluation in 34 joints of JIA patients in clinical remission. Clinical evaluation including physical exam, functional capacity and inflammatory markers was performed at baseline and every six months thereafter, for a total period of 30 months. US evaluation included presence of synovitis, PD signal and erosion at baseline and every 12 months thereafter. Subclinical synovitis was defined when there was synovitis with or without positive PD signal in US joints of patients in clinical remission. Flare was defined as any joint presenting clinical arthritis requiring therapy modification. RESULTS: We evaluated a total of 35 patients, 28 (80%) girls, 14 (40%) persistent oligoarticular subtype, 12 (34.3%) oligoarticular extended and 9 (25.7%) polyarticular and 26 (74.3%) in remission on medication. Twenty (57.1%) patients flared. The risk of flare was five times higher in patients with positive PD signal and 14 times higher in patients in remission on medication. Regarding the assessment of joints after 6 months and 12 months of US evaluation, 70/3162 (2.2%) joints and 80/2108 (3.8%) joints flared, respectively. Joints with subclinical synovitis with positive PD signal flared more after 6 and 12 months. Twenty five of 2108 (1.2%) joints showed erosion over time. Joints with subclinical synovitis with or without positive PD signal showed more erosion. CONCLUSIONS: Patients in remission on medication with subclinical synovitis with positive PD signal on US have a higher risk of flare, therefore they should be monitored closely during treatment. In the same way, joints with subclinical synovitis with or without positive PD signal should be monitored due to the risk of flare and joint damage. PMID- 29132382 TI - Early motor function after local treatment of brain metastases in the motor cortex region with stereotactic radiotherapy/radiosurgery or microsurgical resection: a retrospective study of two consecutive cohorts. AB - BACKGROUND: We compared the functional outcome and influential factors of two standard treatment modalities for central cerebral metastases: electrophysiological-controlled microsurgical resection (MSR) and stereotactic radiotherapy/stereotactic radiosurgery (SRT/SRS). METHODS: We performed a database search for central metastasis treatments during the period from January 2008 to September 2012 in two clinical registers: 1) register for intraoperative neuromonitoring (Department of Neurosurgery), and 2) prospective database for SRT/SRS (Department of Radiotherapy). Neurological status before and after treatment, Karnofsky performance index (KPI), histology, tumor localization and volume, and oncological status were standardized and pooled together for analysis. Muscle strength was graded on a scale of 0-5. RESULTS: We identified 27 MSR and 41 SRT/SRS cases from 68 treatments. The MSR-treated patients had significant less muscle strength in the upper and lower extremities before and after the treatment as compared to the patients receiving SRT/SRS. Muscle strength of the extremities did not change for patients receiving SRT/SRS, while MSR patients had significant improvement in lower extremity muscle strength (p = 0.05) and a non-significant improvement in the upper extremities. MSR showed significant improvement in hemiparesis as compared to radiotherapy, but this was accompanied with a significant deterioration of extremity muscle strength after surgery, as compared to SRT/SRS (improvement p = 0.04, deterioration p = 0.10). CONCLUSION: Electrophysiologically guided microsurgery of central metastases had a significantly better functional outcome regarding hemiparesis. However, there was also a trend for less secondary neurological deterioration after SRT/SRS. TRIAL REGISTRATION: ISRCTN81776764. Retrospectively Registered 27 July 2017. PMID- 29132383 TI - An unusually large osteochondroma of the mandibular angle: a case report. AB - BACKGROUND: Osteochondroma is a benign bone tumor that can occur in both the mesenchymal and craniofacial bones. However, craniofacial osteochondromas are extremely rare, because the mandible develops by intramembranous ossification rather than by endochondral ossification. CASE PRESENTATION: The most common site of craniofacial osteochondroma is the mandibular condyle, followed by the coronoid process. In the present study, we have described the case of a 64-year old Japanese man with an unusually large osteochondroma located on the internal angle of the mandibular body. Clinical, radiological, pathological, and treatment related aspects are discussed with respect to the tumor origins. CONCLUSIONS: In the medical literature, there have been few reports of large osteochondromas of the mandibular angle with no clinical symptoms. PMID- 29132384 TI - MiR-361-5p inhibits glycolytic metabolism, proliferation and invasion of breast cancer by targeting FGFR1 and MMP-1. AB - BACKGROUND: MicroRNAs function as key regulators in various human cancers, including breast cancer (BC). MiR-361-5p has been proved to be a tumor suppressor in colorectal cancer and gastric cancer in our previous study. In this study, we aim to find out the function of miR-361-5p in breast cancer progression and elaborate the mechanism that miR-361-5p acts its function in breast cancer. METHODS AND RESULTS: Here we reported that miR-361-5p was down-regulated in breast cancer tissue compared with normal breast tissue and the expression of miR 361-5p was positively associated with prognosis in BC patients. Functional studies showed that overexpression of miR-361-5p suppressed the proliferation, invasion and metastasis of breast cancer cells both in vivo and in vitro. Mechanistically, we found that miR-361-5p inhibited the proliferation of BC cells by suppressing glycolysis. FGFR1, a promoter of glycolysis-related enzyme, was identified as the target of miR-361-5p that promoted glycolysis and repressed oxidative phosphorylation. Furthermore, we demonstrated that miR-361-5p inhibited breast cancer cells invasion and metastasis by targeting MMP-1. An inverse expression pattern was also found between miR-361-5p and FGFR1 or MMP-1 in a cohort of 60 BC tissues. CONCLUSION: Our results indicate that miR-361-5p inhibits breast cancer cells glycolysis and invasion by respectively repressing FGFR1 and MMP-1, suggesting that miR-361-5p and its targets may serve as therapeutic targets in breast cancer treatment. PMID- 29132386 TI - Primary single suture anchor re-fixation of anterior cruciate ligament proximal avulsion tears leads to good functional mid-term results: a preliminary study in 12 patients. AB - BACKGROUND: Current studies demonstrate encouraging short-term results after primary anterior cruciate ligament (ACL) suture anchor repair. However, earlier studies reported deterioration of knee function at 5-year follow-up following good clinical short-term recovery. Therefore, the aim of this study was to evaluate clinical long-term results after primary ACL repair at a minimum 5-year follow-up. METHODS: In a retrospective study, 13 patients were included between 2009 and 2012. Inclusion criteria were an acute proximal, femoral avulsion tear of the ACL with good tissue quality and sagittal instability in a healthy, demanding patient. Patients suffering proximal tibial fractures, arthrosis, or multiligamentous injuries of the knee were excluded. The ACL was anchored to the footprint by a single 2.9-mm push lock anchor, followed by additional microfracturing. For follow-up, patients were evaluated according to Lysholm score, modified Cincinnati score, and Tegner activity score. Clinical examination was performed using Lachman and pivot-shift testing and range of motion and sagittal stability measurement, using a Rolimeter. RESULTS: Mean follow-up was 79 (range 60 to 98) months. One patient was lost to follow-up, and 11 out of 12 patients were examined clinically. Eight patients achieved good subjective and clinical outcome. One patient suffered an early re-tear, and one patient with additional patellar tendon tear and one patient with polyarthritis demonstrated poor subjective and clinical results due to lasting instability. Seven out of 12 patients reached preoperative Tegner activity score postoperatively again. The mean Lysholm score was 85.3 points, mean subjective IKDC score was 87.3 points, and mean modified Cincinnati score was 83.8 points. Rolimeter measurements demonstrated a mean side-to-side difference of 2 (range 1-5) mm. CONCLUSION: In the current study, primary surgical re-fixation of proximal, femoral ACL avulsion tears using single suture anchor repair resulted in good to excellent clinical mid-term outcomes. However, in cases of additional serious damage to extensor structures or systemic rheumatic disease, loss of function and unsatisfying clinical results occurred. Further prospective randomized controlled trials are necessary to confirm the encouraging long-term results of this study. TRIAL REGISTRATION: Bavarian National Medical Chamber of Physicians, file number 2016 095. German Clinical Trials ( DRKS00013059 ). PMID- 29132385 TI - Aptamer selection and applications for breast cancer diagnostics and therapy. AB - Aptamers are short non-coding, single-stranded oligonucleotides (RNA or DNA) developed through Systematic Evolution of Ligands by Exponential enrichment (SELEX) in vitro. Similar to antibodies, aptamers can bind to specific targets with high affinity, and are considered promising therapeutic agents as they have several advantages over antibodies, including high specificity, stability, and non-immunogenicity. Furthermore, aptamers can be produced at a low cost and easily modified, and are, therefore, called "chemical antibodies". In the past years, a variety of aptamers specifically bound to both breast cancer biomarkers and cells had been selected. Besides, taking advantage of nanomaterials, there were a number of aptamer-nanomaterial conjugates been developed and widely investigated for diagnostics and targeted therapy of breast cancer. In this short review, we first present a systematical review of various aptamer selection methods. Then, various aptamer-based diagnostic and therapeutic strategies of breast cancer were provided. Finally, the current problems, challenges, and future perspectives in the field were thoroughly discussed. PMID- 29132387 TI - Theoretically proposed optimal frequency for ultrasound induced cartilage restoration. AB - BACKGROUND: Matching the frequency of the driving force to that of the system's natural frequency of vibration results in greater amplitude response. Thus we hypothesize that applying ultrasound at the chondrocyte's resonant frequency will result in greater deformation than applying similar ultrasound power at a frequency outside of the resonant bandwidth. Based on this resonant hypothesis, our group previously confirmed theoretically and experimentally that ultrasound stimulation of suspended chondrocytes at resonance (5 MHz) maximized gene expression of load inducible genes. However, this study was based on suspended chondrocytes. The resonant frequency of a chondrocyte does not only depend on the cell mass and intracellular stiffness, but also on the mechanical properties of the surrounding medium. An in vivo chondrocyte's environment differs whether it be a blood clot (following microfracture), a hydrogel or the pericellular and extracellular matrices of the natural cartilage. All have distinct structures and compositions leading to different resonant frequencies. In this study, we present two theoretical models, the first model to understand the effects of the resonant frequency on the cellular deformation and the second to identify the optimal frequency range for clinical applications of ultrasound to enhance cartilage restoration. RESULTS: We showed that applying low-intensity ultrasound at the resonant frequency induced deformation equivalent to that experimentally calculated in previous studies at higher intensities and a 1 MHz frequency. Additionally, the resonant frequency of an in vivo chondrocyte in healthy conditions, osteoarthritic conditions, embedded in a blood clot and embedded in fibrin ranges from 3.5 - 4.8 MHz. CONCLUSION: The main finding of this study is the theoretically proposed optimal frequency for clinical applications of therapeutic ultrasound induced cartilage restoration is 3.5 - 4.8 MHz (the resonant frequencies of in vivo chondrocytes). Application of ultrasound in this frequency range will maximize desired bioeffects. PMID- 29132388 TI - A composite robotic-based measure of upper limb proprioception. AB - BACKGROUND: Proprioception is the sense of the position and movement of our limbs, and is vital for executing coordinated movements. Proprioceptive disorders are common following stroke, but clinical tests for measuring impairments in proprioception are simple ordinal scales that are unreliable and relatively crude. We developed and validated specific kinematic parameters to quantify proprioception and compared two common metrics, Euclidean and Mahalanobis distances, to combine these parameters into an overall summary score of proprioception. METHODS: We used the KINARM robotic exoskeleton to assess proprioception of the upper limb in subjects with stroke (N = 285. Mean days post stroke = 12 +/- 15). Two aspects of proprioception (position sense and kinesthetic sense) were tested using two mirror-matching tasks without vision. The tasks produced 12 parameters to quantify position sense and eight to quantify kinesthesia. The Euclidean and Mahalanobis distances of the z-scores for these parameters were computed each for position sense, kinesthetic sense, and overall proprioceptive function (average score of position and kinesthetic sense). RESULTS: A high proportion of stroke subjects were impaired on position matching (57%), kinesthetic matching (65%), and overall proprioception (62%). Robotic tasks were significantly correlated with clinical measures of upper extremity proprioception, motor impairment, and overall functional independence. Composite scores derived from the Euclidean distance and Mahalanobis distance showed strong content validity as they were highly correlated (r = 0.97-0.99). CONCLUSIONS: We have outlined a composite measure of upper extremity proprioception to provide a single continuous outcome measure of proprioceptive function for use in clinical trials of rehabilitation. Multiple aspects of proprioception including sense of position, direction, speed, and amplitude of movement were incorporated into this measure. Despite similarities in the scores obtained with these two distance metrics, the Mahalanobis distance was preferred. PMID- 29132390 TI - A transwell assay that excludes exosomes for assessment of tunneling nanotube mediated intercellular communication. AB - BACKGROUND: Tunneling nanotubes (TNTs) are naturally-occurring filamentous actin based membranous extensions that form across a wide spectrum of mammalian cell types to facilitate long-range intercellular communication. Valid assays are needed to accurately assess the downstream effects of TNT-mediated transfer of cellular signals in vitro. We recently reported a modified transwell assay system designed to test the effects of intercellular transfer of a therapeutic oncolytic virus, and viral-activated drugs, between cells via TNTs. The objective of the current study was to demonstrate validation of this in vitro approach as a new method for effectively excluding diffusible forms of long- and close-range intercellular transfer of intracytoplasmic cargo, including exosomes/microvesicles and gap junctions in order to isolate TNT-selective cell communication. METHODS: We designed several steps to effectively reduce or eliminate diffusion and long-range transfer via these extracellular vesicles, and used Nanoparticle Tracking Analysis to quantify exosomes following implementation of these steps. RESULTS: The experimental approach outlined here effectively reduced exosome trafficking by >95%; further use of heparin to block exosome uptake by putative recipient cells further impeded transfer of these extracellular vesicles. CONCLUSIONS: This validated assay incorporates several steps that can be taken to quantifiably control for extracellular vesicles in order to perform studies focused on TNT-selective communication. PMID- 29132389 TI - Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3-5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed. PMID- 29132392 TI - False-negative BRAF V600E mutation results on fine-needle aspiration cytology of papillary thyroid carcinoma. AB - BACKGROUND: The BRAF V600E mutation is highly specific for papillary thyroid carcinoma (PTC). A test for this mutation can increase the diagnostic accuracy of fine-needle aspiration cytology (FNAC), but a considerably high false-negative rate for the BRAF V600E mutation on FNAC has been reported. In this study, we investigated the risk factors associated with false-negative BRAF V600E mutation results on FNAC. METHODS: BRAF V600E mutation results of 221 PTC nodules between December 2011 and June 2013 were retrospectively reviewed. BRAF V600E mutation results on both preoperative FNAC and postoperative formalin-fixed, paraffin embedded (FFPE) samples were compared. We investigated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of BRAF V600E mutation results on FNAC. And, we identified the risk factors associated with false-negative results. RESULTS: Of 221 PTC nodules, 150 (67.9%) on FNAC and 185 (83.7%) on FFPE samples were BRAF V600E mutation positive. The sensitivity, specificity, PPV, and NPV for BRAF V600E mutation testing with FNAC were 80.5, 97.2, 99.3, and 49.3%, respectively. Thirty-six (16.3%) BRAF V600E mutation-negative nodules on FNAC were mutation positive on FFPE sample analysis. Risk factors for these false-negative results were age, indeterminate FNAC results (nondiagnostic, atypia of undetermined significance (AUS), and findings suspicious for PTC), and PTC subtype. CONCLUSION: False-negative rate of BRAF mutation testing with FNAC for thyroid nodules is increased in cases of old age, indeterminate FNAC pathology results, and certain PTC subtypes. Therapeutic surgery can be considered for these cases. A well-designed prospective study with informed consent of patients will be essential for more informative results. PMID- 29132391 TI - NADPH oxidases in Parkinson's disease: a systematic review. AB - Parkinson's disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients. Furthermore, knockout or genetic inactivation of NADPH oxidases exert a neuroprotective effect and reduce detrimental aspects of pathology in experimental models of the disease. However, the connections between NADPH oxidases and the biological processes believed to contribute to neuronal death are not well known. This review provides a comprehensive summary of our current understanding about expression and physiological function of NADPH oxidases in neurons, microglia and astrocytes and their pathophysiological roles in PD. It summarizes the findings supporting the role of both microglial and neuronal NADPH oxidases in cellular disturbances associated with PD such as neuroinflammation, alpha-synuclein accumulation, mitochondrial and synaptic dysfunction or disruption of the autophagy-lysosome system. Furthermore, this review highlights different steps that are essential for NADPH oxidases enzymatic activity and pinpoints major obstacles to overcome for the development of effective NADPH oxidases inhibitors for PD. PMID- 29132393 TI - Interferon-gamma-inducible protein 16 (IFI16) is required for the maintenance of Epstein-Barr virus latency. AB - BACKGROUND: Epstein-Barr virus (EBV) exhibits both lytic and latent (Lat. I, II, and III) phases in an infected individual. It's during the latent phase of EBV that all EBV-associated cancers, including Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease arise. Interferon-gamma-inducible protein 16 (IFI16) is a well-established innate immune sensor and viral transcriptional regulator involved in response to invading DNA viruses. During latency, IFI16 remains in the nucleus, in part bound to the EBV genome; however, neither its role in EBV lytic cycle or latency has been established. METHODS: Short interfering RNA against IFI16 and IFI16 overexpression were used to identify the role of IFI16 in the maintenance of EBV latency I. We also studied how induction of the lytic cycle affected IFI16 using the EBV positive, latently infected Akata or MUTU-1 cell lines. Akata cells were induced with TPA and MUTU-1 cells with TGF-beta up to 96 h and changes in IFI16 protein were analyzed by Western blotting and immunofluorescence microscopy. To assess the mechanism of IFI16 decrease, EBV DNA replication and late lytic transcripts were blocked using the viral DNA polymerase inhibitor phosphonoacetic acid. RESULTS: Knockdown of IFI16 mRNA by siRNA resulted in enhanced levels of EBV lytic gene expression from all temporal gene classes, as well as an increase in the total EBV genome abundance, whereas overexpression of exogenous IFI16 reversed these effects. Furthermore, 96 h after induction of the lytic cycle with either TPA (Akata) or TGF-beta (MUTU-1), IFI16 protein levels decreased up to 80% as compared to the EBV-negative cell line BJAB. Reduction in IFI16 was observed in cells expressing EBV lytic envelope glycoprotein. The decreased levels of IFI16 protein do not appear to be dependent on late lytic transcripts of EBV but suggest involvement of the immediate early, early, or a combination of both gene classes. CONCLUSIONS: Reduction of IFI16 protein levels following lytic cycle induction, as well as reactivation from latency after IFI16 mRNA knockdown suggests that IFI16 is crucial for the maintenance of EBV latency. More importantly, these results identify IFI16 as a unique host factor protein involved in the EBV lifecycle, making it a potential therapeutic target to combat EBV-related malignancies. PMID- 29132394 TI - Comparative epidemiology of porcine circovirus type 3 in pigs with different clinical presentations. AB - BACKGROUND: Porcine circovirus type 3 (PCV3), as an emerging circovirus species, was reported to be widely circulating in the United States, China, South Korea and Poland. Previous studies revealed that PCV3 was mainly concentrated in sick animals with respiratory disease, skin disease, reproductive disorders and so on. However, the circulating status of PCV3 in pigs with other clinical presentations (especilly asymptomatic or diarrhea) was not well established. FINDINGS: In this study, to conduct a comparative epidemiological survey of PCV3, 80 weaned pig serum samples with severe respiratory disease (SRD), 175 weaned pig serum samples with mild respiratory disease (MRD), 216 asymptomatic weaned pig serum samples, 35 diarrheal weaned pig samples and 35 non-diarrheal weaned pig samples were collected from eight provinces of China. Via qPCR testing, PCV3 was circulating in all sampling provinces, with total positive rates varying from 1.04% to 100%. Interestingly, the PCV3-positive rate was significantly higher in weaned pigs with SRD (63.75%, 51/80) than in those weaned pigs with MRD (13.14%, 23/175) and asymptomatic pigs (1.85%, 4/216) (P < 0.01). Similarly, the PCV3-positive rate was significantly higher in diarrheal weaned pigs (17.14%, 6/35) than in non diarrheal weaned pigs (2.86%, 1/35) (P < 0.05). Moreover, the lower Ct values of qPCR were frequently found in those weaned pigs or fattening pigs with respiratory disease and diarrhea rather than that in asymptomatic pigs. Sequence analysis showed that low genetic diversity existed among those PCV3 sequences collected from pigs with different clinical presentations. CONCLUSIONS: The present study further extends evidence that newly described PCV3 widely circulates in six additional provinces of Southern and Northern China and has high similarity to previously reported isolates. As an emerging virus of swine, although the present case-control study reveals that PCV3 has a potential association with swine respiratory disease and diarrhea, further investigations into the pathogenesis are needed to ascertain the role of PCV3 in swine health. PMID- 29132395 TI - Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure. AB - BACKGROUND: One of the most common side effects of the immunosuppressive drug tacrolimus (FK506) is the increased risk of new-onset diabetes mellitus. However, the molecular mechanisms underlying this association have not been fully clarified. METHODS: We studied the effects of the therapeutic dose of tacrolimus on mitochondrial fitness in beta-cells. RESULTS: We demonstrate that tacrolimus impairs glucose-stimulated insulin secretion (GSIS) in beta-cells through a previously unidentified mechanism. Indeed, tacrolimus causes a decrease in mitochondrial Ca2+ uptake, accompanied by altered mitochondrial respiration and reduced ATP production, eventually leading to impaired GSIS. CONCLUSION: Our observations individuate a new fundamental mechanism responsible for the augmented incidence of diabetes following tacrolimus treatment. Indeed, this drug alters Ca2+ fluxes in mitochondria, thereby compromising metabolism-secretion coupling in beta-cells. PMID- 29132397 TI - Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets. AB - BACKGROUND: Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. METHODS: Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial. RESULTS: Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model. CONCLUSIONS: Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor. PMID- 29132396 TI - Circulating cell-free DNA and circulating tumor cells, the "liquid biopsies" in ovarian cancer. AB - Limited understanding of ovarian cancer (OC) genome portrait has hindered the therapeutic advances. The serial monitoring of tumor genotypes is becoming increasingly attainable with circulating cell-free DNA (cf-DNA) and circulating tumor cells (CTCs) emerging as "liquid biopsies". They represent non-invasive biomarkers and are viable, as they can be isolated from human plasma, serum and other body fluids. Molecular characterization of circulating tumor DNA (ct-DNA) and CTCs offer unique potentials to better understand the biology of metastasis and resistance to therapies. The liquid biopsies may also give innovative insights into the process of rapid and accurate identification, resistant genetic alterations and a real time monitoring of treatment responses. In addition, liquid biopsies are shedding light on elucidating signal pathways involved in invasiveness and metastasis competence; but the detection and molecular characterization of ct-DNA and CTCs are still challenging, since they are rare, and the amount of available samples are very limited. This review will focus on the clinical potential of ct-DNA and CTCs in both the early and advanced diagnosis, prognosis, and in the identification of resistance mutations in OC. PMID- 29132398 TI - Traditions, beliefs and indigenous technologies in connection with the edible longhorn grasshopper Ruspolia differens (Serville 1838) in Tanzania. AB - BACKGROUND: Edible insects are an important source of food to many African populations. The longhorn grasshopper, Ruspolia differens (Serville 1838), commonly known as senene in Tanzania is one of the most appreciated edible insects by societies around Lake Victoria crescent. Senene is primarily an essential treat for the tribes around the lake, e.g., the Haya of Tanzania, Luo of Kenya and Baganda of Uganda. Despite its importance as a food item and appreciation as a delicacy, there are few studies dealing with culture, beliefs and indigenous technology in connection with the senene. The main objective of this study was to survey indigenous technologies, processing methods and traditions in relation to senene consumption among the Haya tribe in Kagera region of Tanzania. METHODS: Our ethnographic study was conducted through semi structured interviews. A total of 51 locals, 26 females and 25 males aged 21 to 60 years were interviewed (with 3 female and 7 male key informants among them). Questions focused on cultures, beliefs and traditions towards senene consumption. Processing, preservation and shelf-life as well as nutritional knowledge were also investigated. RESULTS: Harvesting for household consumption was mainly done through wild collection. Traditionally made traps were mostly used for commercial harvesting. Deep frying was the most preferred processing method while smoking was the most preferred preservation method, with shelf-life of up to 12 months. Interesting traditions and taboos associated with senene consumption were identified, with men monopolising the insects as food by declaring the insects taboo for women and children. Deep fried senene in locally packed containers were mostly sold by street vendors, but also available from a variety of stores and supermarkets. CONCLUSION: Beyond being just an important traditional delicacy, senene is becoming increasingly popular, providing opportunity for local businesses. Indigenous technologies for harvesting, processing and preserving senene exist, but must be improved to meet food processing standards, thereby promoting commercialization. This carries economic potential essential for improving incomes and livelihoods of women and smallholder farmers, improving household level food security. PMID- 29132399 TI - Automated quantification of steatosis: agreement with stereological point counting. AB - BACKGROUND: Steatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, we have evaluated different analysis methods in terms of their agreement with stereological point counting (SPC) performed by a hepatologist. METHODS: The evaluation was based on a large and representative data set of 970 histological images from human patients with different liver diseases. Three of the evaluated methods were built on previously published approaches. One method incorporated a new approach to improve the robustness to image variability. RESULTS: The new method showed the strongest agreement with the expert. At 20* resolution, it reproduced steatosis area fractions with a mean absolute error of 0.011 for absent or mild steatosis and 0.036 for moderate or severe steatosis. At 10* resolution, it was more accurate than and twice as fast as all other methods at 20* resolution. When compared with SPC performed by two additional human observers, its error was substantially lower than one and only slightly above the other observer. CONCLUSIONS: The results suggest that the new method can be a suitable automated replacement for SPC. Before further improvements can be verified, it is necessary to thoroughly assess the variability of SPC between human observers. PMID- 29132400 TI - Hospitalization causes and outcomes in HIV patients in the late antiretroviral era in Colombia. AB - BACKGROUND: Antiretroviral therapy (ART) has modified the natural history of HIV infection: the incidence of opportunistic infections (OIs) has decreased and mortality associated to HIV has improved dramatically. The reasons for hospitalization have changed; OIs are no longer the most common reason for admission. This study describes the patient population, admission diagnosis and hospital course of HIV patients in Colombia in the ART era. METHODS: Patients admitted with HIV/AIDS at six hospitals in Medellin, Colombia between August 1, 2014 and July 31, 2015 were included. Demographic, laboratory, and clinical data were prospectively collected. RESULTS: 551 HIV-infected patients were admitted: 76.0% were male, the median age was 37 (30-49). A new diagnosis of HIV was made in 22.0% of patients during the index admission. 56.0% of patients of the entire cohort had been diagnosed with HIV for more than 1 year and 68.9% were diagnosed in an advanced stage of the disease. More than 50.0% of patients had CD4 counts less than 200 CD4 cells/MUL and viral loads greater than 100,000 copies. The main reasons for hospital admissions were OIs, tuberculosis, esophageal candidiasis and Toxoplasma encephalitis. The median hospital stay was 14 days (IQR 8-23). Admission to the intensive care unit (ICU) was required in 10.3% of patients and 14.3% were readmitted to the hospital; mortality was 5.4%. CONCLUSIONS: Similar to other countries in the developing world, in Colombia, the leading cause of hospitalization among HIV-infected patients remain opportunistic infections. However, in-hospital mortality was low, similar to those described for high income countries. Strategies to monitor and optimize the adherence and retention in HIV programs are fundamental to maximize the benefit of ART. PMID- 29132401 TI - Meta-analysis comparing laparoscopic versus open resection for gastric gastrointestinal stromal tumors larger than 5 cm. AB - BACKGROUND: Data on the safety and feasibility of laparoscopic versus open resection for gastric gastrointestinal stromal tumors (GISTs) larger than 5 cm are limited. Therefore, the aim of this meta-analysis was to compared laparoscopic and open resection for gastric GISTs larger than 5 cm. METHODS: We perform a literature search on PubMed, the Cochrane Library, and Embase. Review Manage version 5.1 (RevMan 5.1) was used for data analysis. The GRADE profiler software (version 3.6) was used to estimate the level of evidence. RESULTS: A total of 6 observational studies and one unpublished retrospective cohort study met the inclusion criteria for the meta-analysis: 203 patients in LAP and 214 patients in OPEN group. The pooled result revealed that laparoscopic resection was associated with a same operative time (WMD = -0.87 min; 95% CI: -47.50 to 47.75; P = 0.97), intraoperative blood loss (WMD = -34.38 ml; 95% CI: -79.60 to 10.84; P = 0.14), overall complications (RR = 0.65; 95% CI: 0.38 to 1.12; P = 0.12), better 5-year disease-free survival (HR = 0.40; 95% CI: 0.17 to 0.91; P = 0.03) and overall survival (HR = 0.09; 95% CI: 0.02 to 0.40; P = 0.002) compared with open resection. CONCLUSION: Laparoscopic resection is a technically and oncologically safe and feasible approach for large-sized gastric GISTs (>= 5 cm) compared to open resection. PMID- 29132402 TI - Efficient high-throughput molecular method to detect Ehrlichia ruminantium in ticks. AB - BACKGROUND: Ehrlichia ruminantium is the causal agent of heartwater, a fatal tropical disease affecting ruminants with important economic impacts. This bacterium is transmitted by Amblyomma ticks and is present in sub-Saharan Africa, islands in the Indian Ocean and the Caribbean, where it represents a threat to the American mainland. METHODS: An automated DNA extraction method was adapted for Amblyomma ticks and a new qPCR targeting the pCS20 region was developed to improve E. ruminantium screening capacity and diagnosis. The first step in the preparation of tick samples, before extraction, was not automated but was considerably improved by using a Tissue Lyser. The new pCS20 Sol1 qPCR and a previously published pCS20 Cow qPCR were evaluated with the OIE standard pCS20 nested PCR. RESULTS: pCS20 Sol1 qPCR was found to be more specific than the nested PCR, with a 5-fold increase in sensitivity (3 copies/reaction vs 15 copies/reaction), was less prone to contamination and less time-consuming. As pCS20 Sol1 qPCR did not detect Rickettsia, Anasplasma and Babesia species or closely related species such as Panola Mountain Ehrlichia, E. chaffeensis and E. canis, its specificity was also better than Cow qPCR. In parallel, a tick 16S qPCR was developed for the quality control of DNA extraction that confirmed the good reproducibility of the automated extraction. The whole method, including the automated DNA extraction and pCS20 Sol1 qPCR, was shown to be sensitive, specific and highly reproducible with the same limit of detection as the combined manual DNA extraction and nested PCR, i.e. 6 copies/reaction. Finally, 96 samples can be tested in one day compared to the four days required for manual DNA extraction and nested PCR. CONCLUSIONS: The adaptation of an automated DNA extraction using a DNA/RNA viral extraction kit for tick samples and the development of a new qPCR increased the accuracy of E. ruminantium epidemiological studies, as well as the diagnostic capabilities and turn-over time for surveillance of heartwater. This new method paves the way for large-scale screening of other bacteria and viruses in ticks as well as genetic characterization of ticks and tick-pathogen coevolution studies. PMID- 29132403 TI - The interplay of demography and selection during maize domestication and expansion. AB - BACKGROUND: The history of maize has been characterized by major demographic events, including population size changes associated with domestication and range expansion, and gene flow with wild relatives. The interplay between demographic history and selection has shaped diversity across maize populations and genomes. RESULTS: We investigate these processes using high-depth resequencing data from 31 maize landraces spanning the pre-Columbian distribution of maize, and four wild teosinte individuals (Zea mays ssp. parviglumis). Genome-wide demographic analyses reveal that maize experienced pronounced declines in effective population size due to both a protracted domestication bottleneck and serial founder effects during post-domestication spread, while parviglumis in the Balsas River Valley experienced population growth. The domestication bottleneck and subsequent spread led to an increase in deleterious alleles in the domesticate compared to the wild progenitor. This cost is particularly pronounced in Andean maize, which has experienced a more dramatic founder event compared to other maize populations. Additionally, we detect introgression from the wild teosinte Zea mays ssp. mexicana into maize in the highlands of Mexico, Guatemala, and the southwestern USA, which reduces the prevalence of deleterious alleles likely due to the higher long-term effective population size of teosinte. CONCLUSIONS: These findings underscore the strong interaction between historical demography and the efficiency of selection and illustrate how domesticated species are particularly useful for understanding these processes. The landscape of deleterious alleles and therefore evolutionary potential is clearly influenced by recent demography, a factor that could bear importantly on many species that have experienced recent demographic shifts. PMID- 29132404 TI - Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) results in vascular leakage, inflammation and respiratory failure. There are currently no approved pharmacological treatments for ARDS and standard of care involves treatment of the underlying cause, and supportive care. The vascular leakage may be related to reduced concentrations of local adenosine, which is involved in maintaining endothelial barrier function. Interferon (IFN) beta-1a up-regulates the cell surface ecto-5'-nucleotidase cluster of differentiation 73 (CD73), which increases adenosine levels, and IFN beta-1 may, therefore, be a potential treatment for ARDS. In a phase I/II, open-label study in 37 patients with acute lung injury (ALI)/ARDS, recombinant human IFN beta-1a was well tolerated and mortality rates were significantly lower in treated than in control patients. METHODS/DESIGN: In this phase III, double-blind, randomized, parallel-group trial, the efficacy and safety of recombinant human IFN beta-1a (FP-1201-lyo) will be compared with placebo in adult patients with ARDS. Patients will be randomly assigned to receive 10 MUg FP-1201-lyo or placebo administered intravenously once daily for 6 days and will be monitored for 28 days or until discharged from the intensive care unit. Follow-up visits will then take place at days 90, 180 and 360. The primary endpoint is a composite endpoint including any cause of death at 28 days and days free of mechanical ventilation within 28 days among survivors. Secondary endpoints include: all-cause mortality at 28, 90, 180 and 360 days; organ failure-free days; length of hospital stay; pharmacodynamic assessment including measurement of myxovirus resistance protein A concentrations; and measures of quality of life, respiratory and neurological function at 180 and 360 days. The estimated sample size to demonstrate a reduction in the primary outcome between groups from 30% to 15% is 300 patients, and the study will be conducted in 70-80 centers in nine countries across Europe. DISCUSSION: There are no effective specific treatments for patients with ARDS and mortality rates remain high. The results from this study will provide evidence regarding the efficacy of a potential new therapeutic agent, FP-1201-lyo, in improving the clinical course and outcome for patients with moderate/severe ARDS. TRIAL REGISTRATION: European Union Clinical Trials Register, no: 2014-005260-15 . Registered on 15 July 2017. PMID- 29132405 TI - Identifying predictive features of Clostridium difficile infection recurrence before, during, and after primary antibiotic treatment. AB - BACKGROUND: Colonization by the pathogen Clostridium difficile often occurs in the background of a disrupted microbial community. Identifying specific organisms conferring resistance to invasion by C. difficile is desirable because diagnostic and therapeutic strategies based on the human microbiota have the potential to provide more precision to the management and treatment of Clostridium difficile infection (CDI) and its recurrence. METHODS: We conducted a longitudinal study of adult patients diagnosed with their first CDI. We investigated the dynamics of the gut microbiota during antibiotic treatment, and we used microbial or demographic features at the time of diagnosis, or after treatment, to predict CDI recurrence. To check the validity of the predictions, a meta-analysis using a previously published dataset was performed. RESULTS: We observed that patients' microbiota "before" antibiotic treatment was predictive of disease relapse, but surprisingly, post-antibiotic microbial community is indistinguishable between patients that recur or not. At the individual OTU level, we identified Veillonella dispar as a candidate organism for preventing CDI recurrence; however, we did not detect a corresponding signal in the conducted meta-analysis. CONCLUSION: Although in our patient population, a candidate organism was identified for negatively predicting CDI recurrence, results suggest the need for larger cohort studies that include patients with diverse demographic characteristics to generalize species that robustly confer colonization resistance against C. difficile and accurately predict disease relapse. PMID- 29132406 TI - SjCRT, a recombinant Schistosoma japonicum calreticulin, induces maturation of dendritic cells and a Th1-polarized immune response in mice. AB - BACKGROUND: It is well known that immunization of radiation-attenuated (RA) schistosoma cercariae or schistosomula can induce high levels of protective immunity against schistosoma cercariae reinfection in many animals. Many studies have shown that the Th1 cellular immune response is crucial for the protective effect elicited by RA schistosomula. However, the molecular mechanism of this strong protective immunity remains unclear. METHODS: The expression profiles of Schistosoma japonicum calreticulin (SjCRT) in RA and normal schistosoma-derived cells were investigated by flow cytometry. The effect of recombinant SjCRT (rSjCRT) on mouse dendritic cells (DCs) was determined by FACS, ELISA and RT-PCR analysis. We also analyzed the effects of SjCRT on the activation of spleen cells from mice immunized with rSjCRT by detecting lymphocyte proliferation and the cytokine profiles of splenocytes. RESULTS: We found that the expression level of SjCRT in the cells from RA larvae was significantly higher than that in cells from normal schistosomula at early stages of development (day 4). The results of effect of rSjCRT on mouse DCs showed that rSjCRT could induce phenotypic and functional maturation of DCs, and SjCRT bound to the surface of DCs through the CD91 receptor and could be engulfed by DCs. The results of activation of splenocytes from mice immunized with rSjCRT also demonstrate that rSjCRT can effectively stimulate the proliferative response of splenic lymphocytes, elicit splenocytes from immunized mice to secrete high levels of IFN-gamma, TNF-alpha and IL-4, and activate CD4+ T cells to produce high levels of IFN-gamma. CONCLUSION: SjCRT is one of the immunostimulatory molecules released from RA schistosomula cells, might play a crucial role in conferring a Th1-polarized immune response induced by RA cercariae/schistosomula in mice, and is a candidate molecule responsible for the high levels of protective immunity induced by RA schistosomula. PMID- 29132407 TI - Frequency and determinants for hemorrhagic transformation of posterior cerebral stroke : Posterior ischemic stroke and hemorrhagic transformation. AB - BACKGROUND: hemorrhagic transformation is a threatening ischemic stroke complication. Frequency of hemorrhagic transformation differs greatly among studies, and its risk factors have been usually studied in patients with anterior ischemic stroke who received thrombolytic therapy. We evaluated, in a hospital based series of patients with posterior ischemic stroke not treated with thrombolysis, frequency and risk factors of hemorrhagic transformation. Patients with posterior circulation stroke were seen in our Department during the period January 2004 to December 2009. Demographic and clinical information were collected. We estimated risk for spontaneous hemorrhagic transformation by means of uni- and multivariate logistic regression analyses. RESULTS: 119 consecutive patients were included (73 males, 61.3%). Hemorrhagic transformation was observed in 7 patients (5.9%). Only clinical worsening was significantly associated with hemorrhagic transformation (OR 6.8, 95% CI 1.3-34.5). CONCLUSIONS: Our findings indicate that patients with posterior have a low risk of spontaneous hemorrhagic transformation, suggesting that these patients might have greater advantage from intravenous thrombolysis. PMID- 29132408 TI - Using semantics for representing experimental protocols. AB - BACKGROUND: An experimental protocol is a sequence of tasks and operations executed to perform experimental research in biological and biomedical areas, e.g. biology, genetics, immunology, neurosciences, virology. Protocols often include references to equipment, reagents, descriptions of critical steps, troubleshooting and tips, as well as any other information that researchers deem important for facilitating the reusability of the protocol. Although experimental protocols are central to reproducibility, the descriptions are often cursory. There is the need for a unified framework with respect to the syntactic structure and the semantics for representing experimental protocols. RESULTS: In this paper we present "SMART Protocols ontology", an ontology for representing experimental protocols. Our ontology represents the protocol as a workflow with domain specific knowledge embedded within a document. We also present the S ample I nstrument R eagent O bjective (SIRO) model, which represents the minimal common information shared across experimental protocols. SIRO was conceived in the same realm as the Patient Intervention Comparison Outcome (PICO) model that supports search, retrieval and classification purposes in evidence based medicine. We evaluate our approach against a set of competency questions modeled as SPARQL queries and processed against a set of published and unpublished protocols modeled with the SP Ontology and the SIRO model. Our approach makes it possible to answer queries such as Which protocols use tumor tissue as a sample. CONCLUSION: Improving reporting structures for experimental protocols requires collective efforts from authors, peer reviewers, editors and funding bodies. The SP Ontology is a contribution towards this goal. We build upon previous experiences and bringing together the view of researchers managing protocols in their laboratory work. Website: https://smartprotocols.github.io/ . PMID- 29132409 TI - Insight into the genetic diversity of Anaplasma marginale in cattle from ten provinces of China. AB - BACKGROUND: Anaplasma marginale is an important tick-transmitted rickettsial pathogen of cattle, with worldwide distribution and an important economic impact. The genetic diversity of A. marginale strains has been extensively characterized in different geographical regions throughout the world, while information is limited on studies in China. This study was carried out to determine the prevalence and genetic diversity of A. marginale strains in cattle from ten provinces of China. METHODS: A total of 557 blood samples from cattle were collected and screened for the occurrence of A. marginale by PCR based on the msp4 gene. The partial msp1a gene containing tandem repeat sequences was further amplified from msp4 positive samples. The Msp1a amino acid repeats were identified, and genetic variation of A. marginale strains was characterized based on the variation in the repeated portion of Msp1a. RESULTS: Our results showed that 31.6% of 557 cattle were positive for A. marginale. The infection rates of A. marginale varied considerably from 0 to 96.9% in different sampling regions. Sequence analysis revealed that two msp4 sequence variants of A. marginale exist in cattle. One hundred and three msp1a sequences were obtained and permitted to identify 42 Msp1a tandem repeats, 21 of which were not previously published for A. marginale. Moreover, 61 A. marginale genotypes were identified based on the structure of Msp1a tandem repeats. CONCLUSIONS: Anaplasma marginale is widely distributed in China and a high prevalence of infection was observed in cattle. The geographical strains of A. marginale were molecularly characterized based on the structure of Msp1a tandem repeats. Forty-two Msp1a tandem repeats and 61 genotypes of A. marginale were identified. This study, for the first time, revealed the genetic diversity of A. marginale strains in cattle in China. PMID- 29132410 TI - Application of latent class analysis in assessing the competency of physicians in China. AB - BACKGROUND: The physicians' competency is an important public health issue around the world. Several international organizations have taken the lead in examining the competencies required to be a physician. The purpose of this study is to identify subgroups of physicians' competency based upon the importance results of competency evaluation and provide a scientific basis for the qualitative research of the competency of physicians. METHODS: A cross-sectional study was conducted on a large population-based sample in 31 provinces, autonomous regions and municipalities directly under the central government in China. The latent class analysis was performed to identify patterns of physicians' competency using M plus software. RESULTS: In this study, the latent class analysis was adopted to identify the appropriate number of distinct latent classes of physicians' competency based on eight competency dimensions, and a four-class model best fit the data, which are excellent competency group, lack of professionalism competency group, individual competency driven group, and lack of competency cognitive group. Therefore, 6247 physicians can be divided into four latent classes based on the importance results of competency evaluation, and the number of each class is 5684, 284, 215 and 64, respectively. CONCLUSION: These findings suggested that latent class analysis can be used to study the competency of physicians, and four distinct subgroups were identified. Therefore, we can effectively understand the patterns of physicians' competency, and the health administrative departments could utilize more specific measures according to their different competency subgroups, and providing individualized training schemes in the future training and management of physicians. PMID- 29132412 TI - Prospects for using risk scores in polygenic medicine. AB - Genome-wide association studies have made strides in identifying common variation associated with disease. The modest effect sizes preclude risk prediction based on single genetic variants, but polygenic risk scores that combine thousands of variants show some predictive ability across a range of complex traits and diseases, including neuropsychiatric disorders. Here, we consider the potential for translation to clinical use. PMID- 29132411 TI - An isolated elevation in blood urea level is not 'uraemia' and not an indication for renal replacement therapy in the ICU. AB - The decision to initiate renal replacement therapy (RRT) and the optimal timing for commencement is a difficult decision faced by clinicians when treating acute kidney injury (AKI) in the intensive care setting. Without clinically significant ureamic symptoms or emergent indications (electrolyte abnormalities, volume overload) the timing of RRT initiation remains contentious and inconsistent across health providers. Current trends of initiating RRT in the ICU are often based on isolated blood urea levels without clear guidelines demonstrating an upper limit for treatment. Although the appropriate upper limit remains unclear, it is reasonable to conclude that a blood urea level less than 40 mmol/L is not in itself an indication for RRT, especially in the absence of supporting evidence of kidney impairment (anuria, elevated serum creatinine), presenting a welcome reminder to treat the patient and not a number. PMID- 29132413 TI - Germacranolide-type sesquiterpene lactones from Smallanthus sonchifolius with promising activity against Leishmania mexicana and Trypanosoma cruzi. AB - BACKGROUND: Leishmaniasis and Chagas disease are life-threatening illnesses caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively. They are known as "neglected diseases" due to the lack of effective drug treatments and the scarcity of research work devoted to them. Therefore, the development of novel and effective drugs is an important and urgent need. Natural products are an important source of bioactive molecules for the development of new drugs. In this study, we evaluated the activity of enhydrin, uvedalin and polymatin B, three sesquiterpene lactones (STLs) isolated from Smallanthus sonchifolius, on Leishmania mexicana (MNYC/BZ/62/M) and Trypanosoma cruzi (Dm28c). In addition, the in vivo trypanocidal activity of enhydrin and uvedalin and the effects of these STLs on parasites' ultrastructure were evaluated. METHODS: The inhibitory effect of the three STLs on the growth of L. mexicana amastigotes and promastigotes as well as T. cruzi epimastigotes was evaluated in vitro. The changes produced by the STLs on the ultrastructure of parasites were examined by transmission electron microscopy (TEM). Enhydrin and uvedalin were also studied in a murine model of acute T. cruzi infection (RA strain). Serum activities of the hepatic enzymes alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase were used as biochemical markers of hepatotoxicity. RESULTS: The three compounds exhibited leishmanicidal activity on both parasite forms with IC50 values of 0.42-0.54 MUg/ml for promastigotes and 0.85-1.64 MUg/ml for intracellular amastigotes. Similar results were observed on T. cruzi epimastigotes (IC50 0.35-0.60 MUg/ml). The TEM evaluation showed marked ultrastructural alterations, such as an intense vacuolization and mitochondrial swelling in both L. mexicana promastigotes and T. cruzi epimastigotes exposed to the STLs. In the in vivo study, enhydrin and uvedalin displayed a significant decrease in circulating parasites (50-71%) and no signs of hepatotoxicity were detected. CONCLUSIONS: Enhydrin, uvedalin and polymatin B possess significant leishmanicidal and trypanocidal activity on different parasite stages. These results show that these compounds may provide valuable leads for the development of new drugs against these neglected parasitic diseases. PMID- 29132414 TI - Effect of frenotomy on breastfeeding variables in infants with ankyloglossia (tongue-tie): a prospective before and after cohort study. AB - BACKGROUND: Controversy exists regarding ankyloglossia (tongue-tie) and its clinical impact on breastfeeding, including the benefits, or otherwise, of tongue tie release (frenotomy). As exclusive breastfeeding rates in Ireland are already considerably low (46% on discharge home from the maternity unit following birth in 2014), it is imperative to protect and support breastfeeding, including identifying the associated effects that frenotomy might have on breastfeeding variables. OBJECTIVE: To determine the associated effects of frenotomy on breastfeeding variables in infants with ankyloglossia. METHODS: A prospective before and after cohort study was conducted. Following ethical approval, two self reported questionnaires were administered to women whose infants were undergoing frenotomy at seven healthcare clinics in the Republic of Ireland. Data on breastfeeding variables prior to the frenotomy procedure and at 1-month post frenotomy were collected and compared. Descriptive statistics (frequencies and proportions) were used to analyse, separately, the pre- and post-frenotomy data. Inferential statistics (z-test scores for differences between proportions (alpha <0.05) and mean differences (MD) with 95% confidence intervals (CI)) were used for pre- and post-frenotomy comparative analyses. RESULTS: Ninety-eight women returned the baseline questionnaire, and, of these, 89 returned the follow-up questionnaire. The most common reason for seeking a frenotomy was difficulty with latch (38%). Private lactation consultants were the main person recommending a frenotomy (31%). Rates of exclusive breastfeeding remained similar pre- and post frenotomy (58% versus 58%), although rates of formula feeding increased two-fold at follow-up. Infants' ability to extend their tongues to the lower lip after frenotomy was significantly increased (p < 0.0001). Almost all participants (91%) reported an overall improvement in breastfeeding post-frenotomy. Pain on breastfeeding was significantly reduced post-frenotomy (MD 2.90, 95% CI 3.75 to 2.05) and overall LATCH scale scores were significantly increased (MD -0.50, 95% CI -0.67 to -0.33). CONCLUSIONS: This study supports the hypothesis that frenotomy has a positive effect on breastfeeding variables in infants with ankyloglossia. These findings, however, are based on a relatively small number of participants from one country only where breastfeeding rates are low. Further, larger studies are required to substantiate these findings. PMID- 29132415 TI - Acupuncture for postprandial distress syndrome (APDS): study protocol for a randomized controlled trial. AB - BACKGROUND: Postprandial distress syndrome (PDS) is referred to as meal-related functional dyspepsia (FD) and causes a reduced quality of life (QoL) for patients. Several randomized controlled trials (RCTs) have suggested that acupuncture is an effective treatment for FD, but few studies were particularly for PDS. This pilot study was designed to determine the feasibility and efficacy of acupuncture in patients with PDS characterized by postprandial fullness and early satiation according to the Rome III criteria. METHODS: This is a multi center, two-arm, blinded (participants), pilot RCT. Forty-two participants who meet the inclusion criteria will be randomly assigned to the verum acupuncture group or minimal acupuncture group in a 1:1 ratio. Both treatments consist of 12 sessions of 20 min duration over four weeks (three sessions per week). The primary outcome measurement is the proportion of persons who improve as assessed using the global outcome by the overall treatment effect (OTE) at end-of treatment (EOT) (four weeks after randomization). Global assessment at weeks 8 and 16 after randomization is one of the secondary outcomes. The other secondary outcomes including symptoms, disease-specific QoL, and depression and anxiety will be assessed at weeks 4, 8, and 16 after randomization. DISCUSSION: This pilot study will help determine the feasibility and efficacy of acupuncture in patients with PDS. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN18135146 . Registered on 7 July 2016. PMID- 29132416 TI - Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders. AB - Endothelin-converting enzyme-like 1 (ECEL1, also termed DINE in rodents), a membrane-bound metalloprotease, has been identified as a gene responsible for distal arthrogryposis (DA). ECEL1-mutated DA is generally characterized by ocular phenotypes in addition to the congenital limb contractures that are common to all DA subtypes. Until now, the consequences of the identified pathogenic mutations have remained incompletely understood because of a lack of detailed phenotypic analyses in relevant mouse models. In this study, we generated a new knock-in mouse strain that carries an ECEL1/DINE pathogenic G607S missense mutation, based on a previous study reporting atypical DA hindlimb phenotypes in two siblings with the mutation. We compared the morphological phenotypes of G607S knock-in mice with C760R knock-in mice that we previously established. Both C760R and G607S knock-in mouse embryos showed similar axonal arborization defects with normal trajectory patterns from the spinal cord to the target hindlimb muscles, as well as axon guidance defects of the abducens nerves. Intriguingly, distinct phenotypes in DINE protein localization and mRNA expression were identified in these knock-in mouse lines. For G607S, DINE mRNA and protein expression was decreased or almost absent in motor neurons. In the C760R mutant mice DINE was expressed and localized in the somata of motor neurons but not in axons. Our mutant mouse data suggest that ECEL1/DINE G607S and C760R mutations both lead to motor innervation defects as primary causes in ECEL1-mutated congenital contracture disorders. However, the functional consequences of the two mutations are distinct, with loss of axonal transport of ECEL1/DINE in C760R mutants and mRNA expression deficits in G607S mutants. PMID- 29132417 TI - Quantifying mitochondrial DNA copy number using robust regression to interpret real time PCR results. AB - BACKGROUND: Real time PCR (rtPCR) is a quantitative assay to determine the relative DNA copy number in a sample versus a reference. The [Formula: see text] method is the standard for the analysis of the output data generated by an rtPCR experiment. We developed an alternative based on fitting a robust regression to the rtPCR signal. This new data analysis tool reduces potential biases and does not require all of the compared DNA fragments to have the same PCR efficiency. RESULTS: Comparing the two methods when analysing 96 identical PCR preparations showed similar distributions of the estimated copy numbers. Estimating the efficiency with the [Formula: see text] method, however, required a dilution series, which is not necessary for the robust regression method. We used rtPCR to quantify mitochondrial DNA (mtDNA) copy numbers in three different tissues types: breast, colon and prostate. For each type, normal tissue and a tumor from the same three patients were analysed. This gives a total of six samples. The mitochondrial copy number is estimated to lie between 200 and 300 copies per cell. Similar results are obtained when using the robust regression or the [Formula: see text] method. Confidence ratios were slightly narrower for the robust regression. The new data analysis method has been implemented as an R package. PMID- 29132418 TI - Indoor air pollution from secondhand tobacco smoke, solid fuels, and kerosene in homes with active tuberculosis disease in South Africa. AB - OBJECTIVES: Secondhand tobacco smoke (SHS), use of solid fuels, and kerosene may play an important role in perpetuating the tuberculosis (TB) epidemic. The purpose of this study was to explore the prevalence of household air pollution (HAP) from these sources in homes of someone with TB in a high HIV-prevalence setting. A convenience sample of homes and household members participating in an ongoing active case-finding study in Matlosana district townships surrounding Klerksdorp, South Africa were included. RESULTS: We found a high prevalence of air pollution from SHS, solid fuels, and kerosene among individuals in homes with a case of prevalent active TB disease in Klerksdorp, South Africa. Adults in 40% of homes reported a daily smoker in the home, and 70% of homes had detectable air nicotine. In homes with a history of previous TB (prior to but not including the index case) as compared to those without previous TB, both SHS (83% vs. 65%, respectively) and solid/kerosene fuel use for more than 1 h/day (27% vs. 21%, respectively) were more prevalent. Larger studies are needed to estimate the risk of TB from these types of air pollution in HIV infected individuals and settings with high HIV prevalence. PMID- 29132419 TI - Success of anti-CD20 monoclonal antibody treatment for severe autoimmune hemolytic anemia caused by warm-reactive immunoglobulin A, immunoglobulin G, and immunoglobulin M autoantibodies in a child: a case report. AB - BACKGROUND: Autoimmune hemolytic anemia is rare in children. First-line therapies for this disease consist of corticosteroids and intravenously administered immunoglobulin that are effective in most patients. However, a small proportion of cases (5 to 10%) is refractory to these therapies and may represent a medical emergency, especially when hemolysis is due to warm immunoglobulin M. Recently, reports of the use of rituximab in adult autoimmune diseases have shown promising results. In children, there are few studies on the use of rituximab in the treatment for autoimmune hemolytic anemia, especially on its long-term efficacy and adverse effects. CASE PRESENTATION: Here, we report the case of a 10-year-old Tunisian girl with refractory acute autoimmune hemolytic anemia caused by warm reactive immunoglobulin A, immunoglobulin G, immunoglobulin M, and C3d autoantibodies. First-line treatments using corticosteroids and intravenously administered immunoglobulin were ineffective in controlling her severe disease. On the other hand, she was successfully treated with rituximab. In fact, her hemolytic anemia improved rapidly and no adverse effects were observed. CONCLUSIONS: The case that we report in this paper shows that rituximab could be an alternative therapeutic option in severe acute autoimmune hemolytic anemia with profound hemolysis refractory to conventional treatment. Moreover, it may preclude the use of plasmapheresis in such an urgent situation with a sustained remission. PMID- 29132420 TI - Substance P and patterned silk biomaterial stimulate periodontal ligament stem cells to form corneal stroma in a bioengineered three-dimensional model. AB - BACKGROUND: We aimed to generate a bioengineered multi-lamellar human corneal stroma tissue in vitro by differentiating periodontal ligament stem cells (PDLSCs) towards keratocytes on an aligned silk membrane. METHODS: Human PDLSCs were isolated and identified. The neuropeptide substance P (SP) was added in keratocyte differentiation medium (KDM) to evaluate its effect on keratocyte differentiation of PDLSCs. PDLSCs were then seeded on patterned silk membrane and cultured with KDM and SP. Cell alignment was evaluated and the expression of extracellular matrix (ECM) components of corneal stroma was detected. Finally, multi-lamellar tissue was constructed in vitro by PDLSCs seeded on patterned silk membranes, which were stacked orthogonally and stimulated by KDM supplemented with SP for 18 days. Sections were prepared and subsequently stained with hematoxylin and eosin or antibodies for immunofluorescence observation of human corneal stroma-related proteins. RESULTS: SP promoted the expression of corneal stroma-related collagens (collagen types I, III, V, and VI) during the differentiation induced by KDM. Patterned silk membrane guided cell alignment of PDLSCs, and important ECM components of the corneal stroma were shown to be deposited by the cells. The constructed multi-lamellar tissue was found to support cells growing between every two layers and expressing the main type of collagens (collagen types I and V) and proteoglycans (lumican and keratocan) of normal human corneal stroma. CONCLUSIONS: Multi-lamellar human corneal stroma like tissue can be constructed successfully in vitro by PDLSCs seeded on orthogonally aligned, multi-layered silk membranes with SP supplementation, which shows potential for future corneal tissue engineering. PMID- 29132421 TI - Durability monitoring of long-lasting insecticidal (mosquito) nets (LLINs) in Madagascar: physical integrity and insecticidal activity. AB - BACKGROUND: Long-lasting insecticidal mosquito nets (LLINs) are highly effective for malaria prevention. However, it is also clear that durability monitoring is essential to predict when, post-distribution, a net population, no longer meets minimum WHO standards and needs to be replaced. Following a national distribution campaign in 2013, we tracked two durability indicators, physical integrity and bio-efficacy at six and 12 months post-distribution. While the loss of net integrity during this period was in line with expectations for a one-year net life, bio-efficacy results suggested that nets were losing insecticidal effect faster than expected. The rate of bio-efficacy loss varied significantly between different net brands. METHODS: We tested 600 randomly selected LLINs, 200 from each of three net brands. Each brand came from different eco-epidemiological zones reflecting the original distribution scheme. Fabric integrity (size and number of holes) was quantified using the proportional hole index (pHI). A subsample of the nets, 134 new nets, 150 at six months and 124 at 12 months, were then tested for bio-efficacy using the World Health Organization (WHO) recommended method. RESULTS: Three net types, Netprotect(r), Royalsentry(r) and Yorkool(r), were followed. After six months, 54%, 39% and 45%, respectively, showed visible loss of integrity. The median pHI by type was estimated to be one, zero and one respectively. The percentage of damaged nets increased after 12 months such that 83.5%, 74% and 68.5%, had holes. The median pHI for each brand of nets was 47.5, 47 and 23. No significant difference in the estimated pHI at either six or 12 months was observed. There was a statistically significant difference in the proportion of hole size category between the three brands (chi 2 = 15.761, df = 4, P = 0.003). In cone bio-assays, mortality of new Yorkool(r) nets was surprisingly low (48.6%), mortality was 90.2% and 91.3% for Netprotect(r) and Royalsentry(r) (F (2, 131) = 81.59, P < 0.0001), respectively. At 12 month use, all tested nets were below the WHO threshold for replacement. CONCLUSION: These findings suggest that there is a need for better net quality control before distribution. More frequent replacement of LLINs is probably not an option programmatically. Regardless of prior approval, LLIN durability monitoring for quality assessment as well as net loss following distribution is necessary to improve malaria control efforts. PMID- 29132422 TI - Cellular origin of the viral capsid-like bacterial microcompartments. AB - : ?: Bacterial microcompartments (BMC) are proteinaceous organelles that structurally resemble viral capsids, but encapsulate enzymes that perform various specialized biochemical reactions in the cell cytoplasm. The BMC are constructed from two major shell proteins, BMC-H and BMC-P, which form the facets and vertices of the icosahedral assembly, and are functionally equivalent to the major and minor capsid proteins of viruses, respectively. This equivalence notwithstanding, neither of the BMC proteins displays structural similarity to known capsid proteins, rendering the origins of the BMC enigmatic. Here, using structural and sequence comparisons, we show that both BMC-H and BMC-P, most likely, were exapted from bona fide cellular proteins, namely, PII signaling protein and OB-fold domain-containing protein, respectively. This finding is in line with the hypothesis that many major viral structural proteins have been recruited from cellular proteomes. REVIEWERS: This article was reviewed by Igor Zhulin, Jeremy Selengut and Narayanaswamy Srinivasan. For complete reviews, see the Reviewers' reports section. PMID- 29132423 TI - Effect of having private health insurance on the use of health care services: the case of Spain. AB - BACKGROUND: Several stakeholders have undertaken initiatives to propose solutions towards a more sustainable health system and Spain, as an example of a European country affected by austerity measures, is looking for ways to cut healthcare budgets. METHODS: The aim of this paper is to study the effect of private health insurance on health care utilization using the latest micro-data from the European Community Household Panel (ECHP), the Spanish National Health Survey (SNHS) and the European Union Statistics on Income and Living Conditions (EU SILC). We use matching techniques based on propensity score methods: single match, four matches, bias-adjustment and allowing for heteroskedasticity. RESULTS: The results demonstrate that people with a private health insurance, use the public health system less than individuals without double health insurance coverage. CONCLUSIONS: Our conclusions are useful when policy makers design public-private partnership policies. PMID- 29132424 TI - Novel insights in cough and breathing patterns of patients with idiopathic pulmonary fibrosis performing repeated 24-hour-respiratory polygraphies. AB - BACKGROUND: The main symptoms of patients with idiopathic pulmonary fibrosis (IPF) are cough and dyspnea. IPF leads to a restrictive lung disorder impacting daytime and nocturnal breathing patterns. In this pilot study we assessed the course of day- and nighttime respiration, oxygenation, and cough over a period of 8 months as well as differences between wakefulness and sleep in IPF patients. METHODS: Repetitive 24-h respiratory polygraphies (RP) and pulmonary function tests were performed at baseline and after 3, 4, 7 and 8 months. Cough-index, oxygenation parameters (SpO2, time with SpO2 < 90%, desaturation index), respiratory rate and heart rate were assessed for differences between wakefulness and sleep. The first and the last RP were compared to identify changes of these parameters over time. Statistical analyses were performed with Wilcoxon signed rank tests. RESULTS: Nine IPF patients (8 male, median age 67 years (IQR 60, 77) with 37 valid 24-h RPs were included. Eight patients (88.9%) received antifibrotic treatment. Cough was more prevalent during wakefulness with a median cough-index of 14.8/h (IQR 10.9, 16.8) and 1.6/h (IQR 1.3-2.8) during sleep, p = 0.0039. Oxygenation parameters showed no difference, while respiratory- and heart rate were significantly higher during wakefulness. Despite stable pulmonary function tests over 8 months, the initially elevated respiratory rate increased further during wakefulness (baseline RR median 25.7/min (IQR 19.8, 26.6) vs. RR median 32.2/min (IQR 26.5, 40.9) at follow-up, p = 0.0273). The other respiratory parameters remained stable over time. CONCLUSION: Cough in IPF patients is more prevalent during wakefulness than during sleep. Further studies with a larger sample size and longer a follow-up period are needed to evaluate the role of the respiratory rate during wakefulness as a potential clinical follow up parameter in IPF. PMID- 29132425 TI - Establishment of a medium-scale mosquito facility: optimization of the larval mass-rearing unit for Aedes albopictus (Diptera: Culicidae). AB - BACKGROUND: Standardized larval rearing units for mosquito production are essential for the establishment of a mass-rearing facility. Two larval rearing units, developed respectively by the Guangzhou Wolbaki Biotech Co. Ltd. (Wolbaki) and Insect Pest Control Laboratory, Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture (FAO/IAEA-IPCL), are tested to assess their potential uses to mass-rear the larval stages of Aedes albopictus in support of the establishment of a medium-scale mosquito facility for the application of mosquito genetic control strategies. METHODS: The triple Wolbachia-infected Ae. albopictus strain (HC strain) was used in this study. The effects of larval densities of two larval rearing trays (corresponding to 2.4, 3.0 and 3.6 larvae/cm2) and tray size/position (top, middle and bottom layers) on the pupae production and larval survival were assessed when trays were stacked within the larval rearing units. The male pupae production, female pupae contamination after sex separation, and male mating competitiveness were also studied by using both larval rearing units in their entirety. RESULTS: The optimal larval rearing density for Wolbaki-tray (Wol-tray) was 6,600 larvae (equal to 3.0 larvae/cm2) and 18,000 larvae (3.6 larvae/cm2) for the FAO/IAEA-IPCL tray (IAEA-tray). No significant difference in pupae production was observed when trays were stacked within top, middle or bottom layers for both units. At thirty-four hours after the first pupation, the average male pupae production was (0.89 * 105) for the Wol-unit and (3.16 * 105) for the IAEA-unit. No significant difference was observed in female pupae contamination between these two units. The HC males showed equal male mating competitiveness to wild type males for mating with wild type females in large cages, regardless of whether they were reared in the Wol-unit or IAEA-unit. CONCLUSIONS: The current study has indicated that both the Wol-unit and IAEA-unit are suitable for larvae mass-rearing for Ae. albopictus. However, the IAEA-unit, with higher male production and less space required compared to the Wol-unit, is recommended to be used in support of the establishment of a medium-sized mosquito facility. PMID- 29132426 TI - Comment on "A re-assessment of the safety of silver in household water treatment: rapid systematic review of mammalian in vivo genotoxicity studies". AB - We wish to thank Fewtrell, Majuru, and Hunter for their article highlighting genotoxic risks associated with the use of particulate silver for primary drinking water treatment. The recent promotion of colloidal silver products for household water treatment in developing countries is problematic due to previously identified concerns regarding manufacturing quality and questionable advertising practices, as well as the low efficiency of silver nanoparticles to treat bacteria, viruses, and protozoa in source waters. However, in the conclusion statement of the manuscript, Fewtrell et al. state, "Before colloidal Ag or AgNP are used in filter matrices for drinking water treatment, consideration needs to be given to how much silver is likely to be released from the matrix during the life of the filter." Unfortunately, it appears Fewtrell et al. were unaware that studies of silver nanoparticle and silver ion elution from ceramic filters manufactured and used in developing countries have already been completed. These existing studies have found that: 1) silver ions, not silver nanoparticles, are eluted from ceramic filters treated with silver nanoparticles or silver nitrate; and, 2) silver ions have not been shown to be genotoxic. Thus, the existing recommendation of applying silver nanoparticles to ceramic filters to prevent biofilm formation within the filter and improve microbiological efficacy should still be adhered to, as there is no identified risk to people who drink water from ceramic filters treated with silver nanoparticles or silver nitrate. We note that efforts should continue to minimize exposure to silver nanoparticles (and silica) to employees in ceramic filter factories in collaboration with the organizations that provide technical assistance to ceramic filter factories. PMID- 29132427 TI - Risk of falling among hospitalized patients with high modified Morse scores could be further Stratified. AB - BACKGROUND: Falls during hospitalization harbor both clinical and financial outcomes. The modified Morse fall scale [MMFS] is widely used for an in-hospital risk-of-fall assessment. Nevertheless, the majority of patients at risk of falling, i.e. with high MMFS, do not fall. The aim of this study was to ascertain our study hypothesis that certain patients' characteristics (e.g. serum electrolytes, usage of a walking device etc.) could further stratify the risk of falls among hospitalized patients with MMFS. METHODS: This was a retrospective cohort analysis of adult patients hospitalized in Internal Medicine departments. RESULTS: The final cohort included 428 patients aged 76.8+/-14.0 years. All patients had high (9 or more) MMFS upon admission, and their mean MMFS was 16.2+/ 6.1. A group of 139 (32.5%) patients who fell during their hospitalization was compared with a control group of 289 (67.5%) patients who did not fall. The fallers had higher MMFS, a higher prevalence of mild dependence, and a greater use of a cane or no walking device. Regression analysis showed the following patients' characteristics to be independently associated with an increased risk of falling: mild dependence (OR=3.99, 95% CI 1.97-8.08; p<0.0001), treatment by anti-epileptics (OR=3.9, 95% CI 1.36-11.18; p=0.011), treatment by hypoglycemic agents (OR=2.64, 95% CI 1.08-6.45; p= 0.033), and hypothyroidism (OR=3.66, 05%CI 1.62-8.30; p=0.002). In contrast to their role in the MMFS, the use of a walker or a wheelchair was found to decrease the risk of falling (OR=0.3, 95% CI 0.13 0.69; p=0.005 and OR=0.25, 95% CI 0.11-0.59; p= 0.002). CONCLUSIONS: Further risk stratification of hospitalized patients, already known to have a high MMFS, which would take into account the characteristics pointed out in this study, should be attained. PMID- 29132428 TI - Characterization of Pb51 in Plasmodium berghei as a malaria vaccine candidate targeting both asexual erythrocytic proliferation and transmission. AB - BACKGROUND: A vaccine that targets multiple developmental stages of malaria parasites would be an effective tool for malaria control and elimination. METHODS: A conserved gene in Plasmodium, the Plasmodium berghei gene (PBANKA_020570) encoding a 51 kDa protein (pb51 gene), was identified through search of the PlasmoDB database using a combination of expression and protein localization criteria. A partial domain of the Pb51 protein was expressed in a prokaryotic expression system (rPb51) and used for immunization in mice. The protein expression profile and localization were studied by Western blot and indirect immunofluorescence assay (IFA), respectively. The inhibitory effect of the anti-rPb51 antibodies on parasite proliferation was evaluated in erythrocytes in vivo. The transmission-blocking activity of the immune sera was determined by in vitro ookinete conversion assay and by direct mosquito feeding assay (DFA). RESULTS: The rPb51 elicited specific antibodies in mice. Western blot confirmed Pb51 expression in schizonts, gametocytes and ookinetes. IFA showed localization of Pb51 on the outer membranes of schizonts, gametocytes, zygotes, retorts, ookinetes and sporozoites of P. berghei. Mice immunized with the rPb51 protein significantly reduced parasite proliferation and gametocyte conversion in vivo. Moreover, the rPb51 antisera also significantly reduced the in vitro ookinete conversion when added into the ookinete culture medium. In DFA, mice immunized with the rPb51 reduced the prevalence of mosquito infection by 21.3% and oocyst density by 54.8%. CONCLUSIONS: In P. berghei, P51 was expressed in both asexual erythrocytic and sexual stages and localized on the surface of these stages with the exception of the ring stage. The anti-rPb51 antibodies inhibited both P. berghei proliferation in mice and transmission of the parasite to mosquitoes. PMID- 29132429 TI - Characterization of skin function associated with obesity and specific correlation to local/systemic parameters in American women. AB - BACKGROUND: Obesity is considered problematic not only as a major cause of diabetes, hypertension, and dyslipidemia, but also as a risk of intractable dermatosis; however influence of obesity on skin function has not been clarified. To clarify the mechanism of obesity-associated skin disorders, we aimed to characterize the skin function of subjects with obesity, and identify possible influencing factors. METHODS: Complex analyses including instrumental measurement, biochemical and lipidomics were performed for facial skin and physical evaluation in 93 Caucasian women with obesity (OB) and non-obesity (NOB). RESULTS: In OB, imbalance in metabolism of carbohydrate and lipid, autonomic nerve activity, and secreted factors were confirmed. In the skin properties in OB, surface roughness was higher by 70%, the water content was lower by 12%, and changes in the lipid profile of stratum corneum ceramide were observed; in particular, a 7% reduction of [NP]-type ceramide, compared with NOB. Moreover, significant redness accompanied by a 34% increase in skin blood flow was observed in OB. Correlation analysis elucidated that the water content was strongly correlated with local skin indices, such as the ceramide composition, redness, blood flow, and TNFalpha in the stratum corneum, whereas roughness was correlated with the systemic indices, such as serum insulin, leptin, and IL-6. CONCLUSIONS: Characteristics of obesity-associated skin were (A) reduction of the barrier and moisturizing function accompanied by intercellular lipid imbalance, (B) increased redness accompanied by hemodynamic changes, and (C) surface roughness. It was suggested that each symptom is due to different causes in local and/or systemic physiological impairment related to the autonomic nerve-vascular system, inflammation and insulin resistance. PMID- 29132430 TI - Hospital choice in Germany from the patient's perspective: a cross-sectional study. AB - BACKGROUND: In many countries health policy encourages patients to choose their hospital, preferably by considering information of performance reports. Previous studies on hospital choice mainly have focused on patients undergoing elective surgery. This study examined a representative sample of hospital inpatients across disciplines and treatment interventions in Germany. Its research questions were: How many patients decide where to go for hospital treatment? How much time do patients have before admission? Which sources of information do they use, and which criteria are relevant to their decision? METHODS: Cross-sectional observational study covering 1925 inpatients of 46 departments at 17 hospitals in 2012. The stratified survey comprised 11 medical disciplines (internal medicine, gynaecology, obstetrics, paediatrics, psychiatry, orthopaedics, neurology, urology, ENT and geriatrics) on 3 hospital care levels representing 91.9% of all hospital admissions to inpatient care in Germany in 2012. The statistical analysis calculated the frequency distributions and 95% confidence intervals of characteristics related to the hospital choice. RESULTS: 63.0% [60.9-65.2] of patients in Germany chose the hospital themselves, but only 21.1% [19.3-22.9] had more than one week to decide prior to admission. Major sources of information were personal knowledge of hospitals, relatives, outpatient health professionals and the Internet. Main criteria for the decision were personal experience with a hospital, recommendations from relatives and providers of outpatient services, a hospital's reputation and distance from home. Specific quality information as provided by performance reports were of secondary importance. CONCLUSIONS: A majority of patients in the German health system choose their hospital freely. Providers of outpatient health care can have an important "agent" function in the quality-oriented hospital choice especially for patients with little time prior to admission and those who do not decide themselves. Hospitals have an impact on patients' future hospital choices by the treatment experience they provide to patients. PMID- 29132431 TI - Obstetric care navigation: a new approach to promote respectful maternity care and overcome barriers to safe motherhood. AB - BACKGROUND: Disrespectful and abusive maternity care is a common and pervasive problem that disproportionately impacts marginalized women. By making mothers less likely to agree to facility-based delivery, it contributes to the unacceptably high rates of maternal mortality in low- and middle-income countries. Few programmatic approaches have been proposed to address disrespectful and abusive maternity care. OBSTETRIC CARE NAVIGATION: Care navigation was pioneered by the field of oncology to improve health outcomes of vulnerable populations and promote patient autonomy by providing linkages across a fragmented care continuum. Here we describe the novel application of the care navigation model to emergency obstetric referrals to hospitals for complicated home births in rural Guatemala. Care navigators offer women accompaniment and labor support intended to improve the care experience-for both patients and providers-and to decrease opposition to hospital-level obstetric care. Specific roles include deflecting mistreatment from hospital staff, improving provider communication through language and cultural interpretation, advocating for patients' right to informed consent, and protecting patients' dignity during the birthing process. Care navigators are specifically chosen and trained to gain the trust and respect of patients, traditional midwives, and biomedical providers. We describe an ongoing obstetric care navigator pilot program employing rapid-cycle quality improvement methods to quickly identify implementation successes and failures. This approach empowers frontline health workers to problem solve in real time and ensures the program is highly adaptable to local needs. CONCLUSION: Care navigation is a promising strategy to overcome the "humanistic barrier" to hospital delivery by mitigating disrespectful and abusive care. It offers a demand-side approach to undignified obstetric care that empowers the communities most impacted by the problem to lead the response. Results from an ongoing pilot program of obstetric care navigation will provide valuable feedback from patients on the impact of this approach and implementation lessons to facilitate replication in other settings. PMID- 29132432 TI - AC-93253 iodide, a novel Src inhibitor, suppresses NSCLC progression by modulating multiple Src-related signaling pathways. AB - BACKGROUND: The tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds. METHODS: Human non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment. Src and Src-related protein expression in AC-93253 iodide-treated PC9, PC9/gef, and A549 cells were assessed by western blotting. The effects of AC-93253 iodide on cancer cell colony formation, invasion, and migration were assessed in PC9 and PC9/gef cells. The synergistic effects of gefitinib and AC-93253 iodide were evaluated by combination index (CI)-isobologram analysis in gefitinib-resistant cell lines. The efficacy of AC-93253 iodide in vivo was determined using nude mice treated with either the compound or the vehicle. RESULTS: Among the compounds, AC-93253 iodide exhibited the most potent dose-independent inhibitory effects on the activity of Src as well as on that of the Src-related proteins EGFR, STAT3, and FAK. Furthermore, AC-93253 iodide significantly suppressed cancer cell proliferation, colony formation, invasion, and migration in vitro and tumor growth in vivo. AC-93253 iodide sensitized tumor cells to gefitinib treatment regardless of whether the cells were gefitinib-sensitive (PC9) or resistant (H1975 and PC9/gef), indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our findings also suggested that the inhibitory effects of AC-93253 iodide on lung cancer progression may be attributable to its ability to modulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, MEK, ERK, and EGFR. CONCLUSIONS: Our data suggest that AC 93253 iodide inhibits NSCLC cell growth and motility by regulating multiple Src related pathways. Our findings may facilitate the development of therapeutic strategies and anti-tumor drugs that may be useful for treating lung cancer in the future. PMID- 29132433 TI - Impaired Ciliogenesis in differentiating human bronchial epithelia exposed to non Cytotoxic doses of multi-walled carbon Nanotubes. AB - BACKGROUND: Multi-walled carbon nanotubes (MWCNTs) are engineered nanomaterials used for a variety of industrial and consumer products. Their high tensile strength, hydrophobicity, and semi-conductive properties have enabled many novel applications, increasing the possibility of accidental nanotube inhalation by either consumers or factory workers. While MWCNT inhalation has been previously shown to cause inflammation and pulmonary fibrosis at high doses, the susceptibility of differentiating bronchial epithelia to MWCNT exposure remains unexplored. In this study, we investigate the effect of MWCNT exposure on cilia development in a differentiating air-liquid interface (ALI) model. Primary bronchial epithelial cells (BECs) were isolated from human donors via bronchoscopy and treated with non-cytotoxic doses of MWCNTs in submerged culture for 24 h. Cultures were then allowed to differentiate in ALI for 28 days in the absence of further MWCNT exposure. At 28 days, mucociliary differentiation endpoints were assessed, including whole-mount immunofluorescent staining, histological, immunohistochemical and ultrastructural analysis, gene expression, and cilia beating analysis. RESULTS: We found a reduction in the prevalence and beating of ciliated cells in MWCNT-treated cultures, which appeared to be caused by a disruption of cellular microtubules and cytoskeleton during ciliogenesis and basal body docking. Expression of gene markers of mucociliary differentiation, such as FOXJ1 and MUC5AC/B, were not affected by treatment. Colocalization of basal body marker CEP164 with gamma-tubulin during days 1-3 of ciliogenesis, as well as abundance of basal bodies up to day 14, were attenuated by treatment with MWCNTs. CONCLUSIONS: Our results suggest that a single exposure of bronchial cells to MWCNT during a vulnerable period before differentiation may impair their ability to develop into fully functional ciliated cells. PMID- 29132434 TI - An acetabular-preserving procedure for pelvic giant cell tumor involving partial acetabulum. AB - BACKGROUND: The management of pelvic giant cell tumors (GCTs) involving the acetabulum remains a challenge for surgeons on how to balance the relative benefits of minimizing recurrence and maintaining postoperative hip function. The present study was to present and evaluate the clinical indications, operative technique, and outcomes of pelvic GCTs involving partial acetabulum treated with multiplanar osteotomy and reconstruction of autogenous femoral head bone grafts combined with cementless total hip arthroplasty (THA). METHODS: We retrospectively reviewed seven patients with pelvic GCTs involving partial acetabulum who underwent multiplanar osteotomy and reconstruction of autogenous femoral head bone grafts combined with cementless THA from January 2010 to October 2014. We assess the outcome including the bone graft healing, nonunion, hardware failure, infection, tumor recurrence, and metastasis. And the functional outcome was evaluated by the Musculoskeletal Tumor Society (MSTS)93 score. RESULTS: All patients were followed up for a mean of 38.1 months (range 26-61 months). All bone grafts are union. No failure of acetabular components, wound healing problem, or deep infection was suspected. No patient experienced metastasis. Recurrence was observed in one out of seven patients, treated by extended resection and implanting iodine ions in the surgical area. The mean MSTS93 score was 29.4 (range 28-30). All patients were disease-free and resumed activities of daily living at the most recent follow-up. CONCLUSIONS: As long as one of the two columns is retained and the resulting defect does not exceed the supra-acetabular line, multiplanar osteotomy and reconstruction of autogenous femoral head bone grafts combined with cementless THA is a viable strategy for the treatment of pelvic GCTs involving partial acetabulum. However, a large-scale prospective clinical study is still needed to verify these procedures. PMID- 29132435 TI - Vasculotide reduces pulmonary hyperpermeability in experimental pneumococcal pneumonia. AB - BACKGROUND: Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality worldwide. Despite effective antimicrobial therapy, CAP can induce pulmonary endothelial hyperpermeability resulting in life-threatening lung failure due to an exaggerated host-pathogen interaction. Treatment of acute lung injury is mainly supportive because key elements of inflammation-induced barrier disruption remain undetermined. Angiopoietin-1 (Ang-1)-mediated Tie2 activation reduces, and the Ang-1 antagonist Ang-2 increases, inflammation and endothelial permeability in sepsis. Vasculotide (VT) is a polyethylene glycol clustered Tie2-binding peptide that mimics the actions of Ang-1. The aim of our study was to experimentally test whether VT is capable of diminishing pneumonia induced lung injury. METHODS: VT binding and phosphorylation of Tie2 were analyzed using tryptophan fluorescence spectroscopy and phospho-Tie-2 enzyme linked immunosorbent assay. Human and murine lung endothelial cells were investigated by immunofluorescence staining and electric cell-substrate impedance sensing. Pulmonary hyperpermeability was quantified in VT-pretreated, isolated, perfused, and ventilated mouse lungs stimulated with the pneumococcal exotoxin pneumolysin (PLY). Furthermore, Streptococcus pneumoniae-infected mice were therapeutically treated with VT. RESULTS: VT showed dose-dependent binding and phosphorylation of Tie2. Pretreatment with VT protected lung endothelial cell monolayers from PLY-induced disruption. In isolated mouse lungs, VT decreased PLY induced pulmonary permeability. Likewise, therapeutic treatment with VT of S. pneumoniae-infected mice significantly reduced pneumonia-induced hyperpermeability. However, effects by VT on the pulmonary or systemic inflammatory response were not observed. CONCLUSIONS: VT promoted pulmonary endothelial stability and reduced lung permeability in different models of pneumococcal pneumonia. Thus, VT may provide a novel therapeutic perspective for reduction of permeability in pneumococcal pneumonia-induced lung injury. PMID- 29132436 TI - Towards fair and effective North-South collaboration: realising a programme for demand-driven and locally led research. AB - BACKGROUND: At the turn of the 90s, studies showed that health research contributed little to health and development in low- and middle-income countries because it was oriented towards international priorities and dominated by researchers from the North. A new approach to North-South collaboration was required that would support demand-driven and locally led research in the South. The aim of this study was to analyse the development and functioning of a programme for demand-driven and locally led research in Ghana that was supported by a North-South collaboration. METHODS: For this mixed-method case study, we combined document analysis, key informant interviews and observation of programme events. RESULTS: The development of the research programme started with constructing a sponsorship constellation in the Netherlands. After highlighting the problems with traditional research collaboration, an advisory council formulated a vision for a more equal and effective approach to North-South collaboration. Together with Ghanaian partners, this vision was turned into a proposal for a Ghanaian-led programme for demand-driven and locally led research, which was funded by the Netherlands government. Research priority setting showed that the Ghanaian research needs were very different from the priorities of foreign funders and researchers. After a slow start, the number of locally submitted proposals increased from 13 in 2001 to 94 in 2005, revealing the existence of a substantial, but partly latent reservoir of research capacity. In total, 79 studies were funded. An impact evaluation showed that the results of the majority of the studies were used to contribute to action. Despite its success, the research programme came to an end in 2008 after the sponsorship constellation in the Netherlands fell apart. CONCLUSION: Our study shows that realising a programme for demand-driven and locally led research in the South provides an effective approach to North-South collaboration in which results are used and local capacities and institutions are strengthened. PMID- 29132437 TI - Hap2, a novel gene in Babesia bigemina is expressed in tick stages, and specific antibodies block zygote formation. AB - BACKGROUND: Bovine babesiosis is a tick-borne disease caused by the protozoan parasites of the genus Babesia. In their host vector, Babesia spp. undergo sexual reproduction. Therefore, the development of sexual stages and the subsequent formation of the zygote are essential for the parasite to invade the intestinal cells of the vector tick and continue its life-cycle. HAP2/GCS1 is a protein identified in plants, protozoan parasites and other organisms that has an important role during membrane fusion in fertilization processes. The identification and characterization of HAP-2 protein in Babesia would be very significant to understand the biology of the parasite and to develop a transmission-blocking vaccine in the future. RESULTS: To isolate and sequence the hap2 gene DNA from an infected bovine with Babesia bigemina was purified. The hap2 gene was amplified, cloned and sequenced. The sequences of hap2 from four geographically different strains showed high conservation at the amino acid level, including the typical structure with a signal peptide and the HAP2/GSC domain. Antisera anti-HAP2 against the conserved extracellular region of the HAP2 amino acid sequence were obtained from rabbits. The expression of hap2 in the host and vector tissues was analyzed by using semi-quantitative RT-PCR, and the protein was examined by western blot and immunofluorescence. Based on the RT-PCR and WB results, HAP2 is expressed in both, sexual stages induced in vitro, and in infected ticks as well. We did not detect any expression in asexual erythrocytic stages of B. bigemina, relevantly anti-HAP2 specific antibodies were able to block zygotes formation in vitro. CONCLUSION: Babesia bigemina HAP2 is expressed only in tick-infecting stages, and specific antibodies block zygote formation. Further studies regarding the function of HAP2 during tick infection may provide new insights into the molecular mechanisms of sexual reproduction of the parasite. PMID- 29132438 TI - Framingham risk score for estimation of 10-years of cardiovascular diseases risk in patients with metabolic syndrome. AB - BACKGROUND: There are a few studies evaluating the predictive value of Framingham risk score (FRS) for cardiovascular disease (CVD) risk assessment in patients with metabolic syndrome in Iran. Because of the emerging high prevalence of CVD among Iranian population, it is important to predict its risk among populations with potential predictive tools. Therefore, the aim of the current study is to evaluate the FRS and its determinants in patients with metabolic syndrome. METHODS: In the current cross-sectional study, 160 patients with metabolic syndrome diagnosed according to the National Cholesterol Education Adult Treatment Panel (ATP) III criteria were enrolled. The FRS was calculated using a computer program by a previously suggested algorithm. RESULTS: Totally, 77.5, 16.3, and 6.3% of patients with metabolic syndrome were at low, intermediate, and high risk of CVD according to FRS categorization. The highest prevalence of all of metabolic syndrome components were in low CVD risk according to the FRS grouping (P < 0.05), while the lowest prevalence of these components was in high CVD risk group (P < 0.05). According to multiple logistic regression analysis, high systolic blood pressure (SBP) and fasting serum glucose (FSG) were potent determinants of intermediate and high risk CVD risk of FRS scoring compared with low risk group (P < 0.05). CONCLUSION: In the current study, significant associations between components of metabolic syndrome and different FRS categorization among patients with metabolic syndrome were identified. High SBP and FSG were associated with meaningfully increased risk of CVD compared with other parameters. TRIAL REGISTRATIONS: The study is not a trial; the registration number is not applicable. PMID- 29132439 TI - The proportion of the population of England that self-identifies as lesbian, gay or bisexual: producing modelled estimates based on national social surveys. AB - OBJECTIVES: There is currently no widely accepted estimate of the proportion of people in England that self-identifies as lesbian, gay or bisexual (LGB), which is needed if we are to compare health inequality between different population groups. Using systematic review methods, this study identified all national social surveys with a question on sexual orientation and pooled those which represented the overall population of England. LGB proportions were synthesized into an aggregated mean estimate using weights based on sample size, response rate and missing data. The modelled estimate was stratified by socio-demographic and geographical variables. RESULTS: Twenty-two national surveys were identified of which 15 were suitable for pooling. Synthesis resulted in a weighted mean estimate of 2.50% of the adult population of England identifying as LGB or 'other'. The proportion was highest in men, people below 45 years of age and the London region. The (theoretical) upper limit was 5.89% if all non-responders were assumed to identify as LGB. The reported 2.50% presents a minimum and may be influenced by respondents' perceptions of confidentiality and social acceptance. It is however the most robust estimate currently available and can be used as baseline to understand health and wellbeing needs of different groups. PMID- 29132440 TI - INfluence of Successful Periodontal Intervention in REnal Disease (INSPIRED): study protocol for a randomised controlled pilot clinical trial. AB - BACKGROUND: Patients with chronic kidney disease (CKD) exhibit increased morbidity and mortality which is associated with an increased systemic inflammatory burden. Identifying and managing comorbid diseases that contribute to this load may inform novel care pathways that could have a beneficial impact on the morbidity/mortality associated with CKD. Periodontitis, a highly prevalent, chronic inflammatory disease affecting the supporting structures of teeth, is associated with an increased systemic inflammatory and oxidative stress burden and the successful treatment of periodontitis has been shown to reduce both. This pilot study aims to gather data to inform a definitive study into the impact of successful periodontal treatment on the cardio-renal health of patients with CKD. METHODS/DESIGN: This pilot study will employ a randomised, controlled, parallel-group design. Sixty adult patients, with CKD with a high risk of progression and with periodontitis, from the Queen Elizabeth Hospital, Birmingham, will be randomised to receive either immediate, intensive periodontal treatment (n = 30) or treatment at a delay of 12 months (n = 30). Patients will be excluded if they have reached end-stage renal disease or have received specialist periodontal treatment in the previous year. Periodontal treatment will be delivered under local anaesthetic, on an outpatient basis, over several visits by a qualified dental hygienist at the Birmingham Dental Hospital, UK. Patients in the delayed-treatment arm will continue to receive the standard community level of periodontal care for a period of 12 months followed by the intensive periodontal treatment. Randomization will occur using a centralised telephone randomisation service, following baseline assessments. The assessor of periodontal health will be blinded to the patients' treatment allocation. Patients in either arm will be followed up at 3-monthly intervals for 18 months. Aside from the pilot outcomes to inform the practicalities of a larger trial later, data on cardio-renal function, periodontal health and patient-reported outcomes will be collected at each time point. DISCUSSION: This pilot randomised controlled trial will investigate the viability of undertaking a larger-scale study investigating the effect of treating periodontitis and maintaining periodontal health on cardio-renal outcomes in patients with CKD. TRIAL REGISTRATION: National Institute of Health Research (NIHR) Clinical Research Network (UKCRN ID: 18458), ID: ISRCTN10227738 . Registered retrospectively to both registers on 23 April 2015. PMID- 29132442 TI - From the Editors. PMID- 29132443 TI - Ethnic Differences in Mental Health and Race-Based Data Collection. AB - There is strong evidence of ethnic disparities in chronic medical conditions, such as diabetes and cardiovascular diseases; however, less is known about ethnic differences in mental illness and health service utilization. Previous studies have shown that Asians are more likely to avoid or delay seeking help for their mental illness. We conducted a population-based study using Ontario health administrative data to examine ethnic differences in mental illness severity at hospital presentation. We found that Chinese and South Asian psychiatric patients were significantly more likely to be involuntarily admitted and exhibited more aggressive behaviours and psychotic symptoms compared to the general population. Our study highlights the need to better understand how individual, family and health-system factors contribute to the observed ethnic disparities. This paper also describes the current status of ethnicity and race-based data collection in Ontario and the benefits of routinely collecting more ethnicity data in our healthcare system to ensure equitable healthcare access and outcomes for all Ontarians. PMID- 29132441 TI - Early screening for Chlamydia trachomatis in young women for primary prevention of pelvic inflammatory disease (i-Predict): study protocol for a randomised controlled trial. AB - BACKGROUND: Genital infection with Chlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection, especially among young women. Mostly asymptomatic, it can lead, if untreated, to pelvic inflammatory disease (PID), tubal factor infertility and ectopic pregnancy. Recent data suggest that Ct infections are not controlled in France and in Europe. The effectiveness of a systematic strategy for Ct screening in under-25 women remains controversial. The main objective of the i-Predict trial (Prevention of Diseases Induced by Chlamydia trachomatis) is to determine whether early screening and treatment of 18- to-24-year-old women for genital Ct infection reduces the incidence of PID over 24 months. METHODS/DESIGN: This is a randomised prevention trial including 4000 eighteen- to twenty-four-year-old sexually active female students enrolled at five universities. The participants will provide a self-collected vaginal swab sample and fill in an electronic questionnaire at baseline and at 6, 12 and 18 months after recruitment. Vaginal swabs in the intervention arm will be analysed immediately for Ct positivity, and participants will be referred for treatment if they have a positive test result. Vaginal swabs from the control arm will be analysed at the end of the study. All visits to general practitioners, gynaecologists or gynaecology emergency departments for pelvic pain or other gynaecological symptoms will be recorded to evaluate the incidence of PID, and all participants will attend a final visit in a hospital gynaecology department. The primary endpoint measure will be the incidence of PID over 24 months. The outcome status (confirmed, probable or no PID) will be assessed by two independent experts blinded to group assignment and Ct status. DISCUSSION: This trial is expected to largely contribute to the development of recommendations for Ct screening in young women in France to prevent PID and related complications. It is part of a comprehensive approach to gathering data to facilitate decision making regarding optimal strategies for Ct infection control. The control group of this randomised trial, following current recommendations, will allow better documentation of the natural history of Ct infection, a prerequisite to evaluating the impact of Ct screening. Characterisation of host immunogenetics will also allow identification of women at risk for complications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02904811 . Registered on September 14, 2016. World Health Organisation International Clinical Trials Registry, NCT02904811. AOM, 15-0063 and P150950. Registered on September 26, 2016. A completed Standard Protocol Items : Recommendations for International Trials (SPIRIT) Checklist is available in additional file 1. PMID- 29132444 TI - Unnecessary Care in Canada. PMID- 29132445 TI - Physician Remuneration for Remote Consults: An Overview of Approaches across Canada. AB - While lengthy waits for medical specialists remains a persistent problem across Canada, remote consult presents a strategy to address this issue. Connecting primary healthcare providers to specialists via electronic (eConsult) or telephone consult enables care providers to deliver appropriate, speciality informed care for their patients in the primary care setting, reducing the time spent waiting for specialists and potentially preventing unnecessary referrals to specialty care. These remote consult models are the focus of a new pan-Canadian quality improvement collaborative delivered by the Canadian Foundation for Healthcare Improvement in partnership with Canada Health Infoway, the College of Family Physicians of Canada and the Royal College of Physicians and Surgeons of Canada. Successful implementation of remote consult services requires alignment of remuneration for physicians. This article presents an overview of compensation arrangements across Canada for remote (telephone or electronic) and select in person consults. It also shares key messages for payers and providers to inform future direction in this area. PMID- 29132446 TI - A Model for Developing Clinical Analytics Capacity: Closing the Loops on Outcomes to Optimize Quality. AB - Closed Loop Analytics(c) is receiving growing interest in healthcare as a term referring to information technology, local data and clinical analytics working together to generate evidence for improvement. The Closed Loop Analytics model consists of three loops corresponding to the decision-making levels of an organization and the associated data within each loop - Patients, Protocols, and Populations. The authors propose that each of these levels should utilize the same ecosystem of electronic health record (EHR) and enterprise data warehouse (EDW) enabled data, in a closed-loop fashion, with that data being repackaged and delivered to suit the analytic and decision support needs of each level, in support of better outcomes. PMID- 29132447 TI - Clinical Documentation in an Era of Increasing Transparency: The Impact of Electronic Portals on Care. AB - Electronic health records (EHRs) and consumer health portals have implications for improving the quality and cost-effectiveness of healthcare and make it much easier for patients and families to access health information in a timely and convenient manner. However, the accessibility of information afforded by EHRs and health portals changes the dynamic of control over health information in very significant ways. Institutions and their clinicians have typically been the caretakers of these documents; therefore, the introduction of portals represents a major cultural shift in healthcare. The efforts of both clinicians and patients are needed to effectively make this shift, as the implementation of new technology is uniquely challenging within a healthcare setting. An interactive workshop was facilitated to understand clinicians' perceived challenges of this shift with a specific focus on the implications of increased transparency and patients' increased access to health information. PMID- 29132448 TI - Partnering with Patients: The Toronto Central LHIN Telehomecare Experience. AB - Chronic obstructive pulmonary disease (COPD) and heart failure are responsible for significant healthcare costs in Ontario. One program developed to improve the management of these conditions is Telehomecare, which provides six months of health status monitoring and patient self-management education at no cost to participating COPD and heart failure patients. The Toronto Central Local Health Integration Network (LHIN; formerly the Toronto Central Community Care Access Centre), an early participant, enrolled over 3,000 Telehomecare patients between 2012 and 2016. Research shows that the program reduces emergency department visits and hospital admissions, improves patient confidence and self-management skills and is associated with high patient satisfaction. Program improvements and expansion are ongoing. PMID- 29132449 TI - Using Mobile Apps to Communicate Vaccination Records: A City-wide Evaluation with a National Immunization App, Maternal Child Registry and Public Health Authorities. AB - Medicine is experiencing a paradigm shift, where patients are increasingly involved in the management of their health data. We created a mobile app which permitted parental reporting of immunization status to public health authorities. We describe app use as a proxy for feasibility and acceptability as well as data utility for public health surveillance. The evaluation period ran from April 27, 2015, to April 18, 2017, during which time 2,653 unique children's records were transmitted, containing 36,105 vaccinations. Our findings suggest that mobile immunization reporting is feasible and may be an acceptable complement to existing reporting methods. Measures of data utility suggest that mobile reporting could enable more accurate assessments of vaccine coverage. PMID- 29132450 TI - Monitoring Receptivity to Online Health Messages by Tracking Daily Web Traffic Engagement Patterns: A Review of More than 13 Million US Web Exposures over 1,235 Days. AB - Reaching the recipient of online health messages is necessary to Web-based health promotion applications. To measure willingness to adhere to a health-related Web message, we explored the frequency with which more than 13 million Web users ignored or opted to receive a random inbound message. The findings suggest declining curiosity among Web users about online messages, and that certain days may be more propitious than others for communicating with users. This approach can be modified to gather more granular insights into how messages, including timing and design features, can be tailored to promote improved public health messaging. PMID- 29132451 TI - Interprofessional Education for Internationally Educated Health Professionals: Pathways to Licensure. AB - In response to the shortage of healthcare professionals, the Canadian government has supported two innovative health workforce planning strategies: interprofessional education for interprofessional collaboration and recruiting internationally educated health professionals (IEHPs). Interprofessional collaboration is increasingly expected by Canadian-educated healthcare professionals; IEHPs must also be oriented to this practice model. An environmental scan and iterative assessments and evaluations informed the development of an online interprofessional competency toolkit aimed at training and assessing interprofessional collaboration for IEHPs. This paper outlines the complex licensure pathways for seven healthcare professions and confirms "collaboration" is a required competency, further validating the need for the toolkit. PMID- 29132452 TI - Improving Care Experiences, Efficiencies and Quality of Care for Seniors in Alberta. AB - Improving Care Experiences, Efficiencies and Quality of Care for Seniors in Alberta Forum was held to explore the current challenges and opportunities in seniors' care. A diverse group of 53 attendees, representing a cross section of healthcare organizations, front-line healthcare providers, researchers and patients, participated in facilitative, small group discussions to share and propose solutions to barriers to coordinating and integrating care for the senior population across the continuum within the Edmonton zone, to comment on a standardized assessment that may inform integrated care and support planning and to outline steps towards health information continuity. PMID- 29132453 TI - Code Grey: Stained Surgical Instruments and Their Impact on One Canadian Health Authority. AB - In 2016, NL's largest RHA was faced with serious challenges stemming from the discovery of stained surgical instruments at its two largest hospitals. This discovery prompted a series of postponed surgeries, an extensive internal mobilization of labour and the purchase of millions of dollars of new equipment. In tackling these challenges, the organization not only acquired a better understanding of its surgical tools, but it also gained renewed appreciation for the resilience of its human resources. By describing this incident and the lessons learned, we hope to offer insight to providers in similar circumstances. PMID- 29132454 TI - Coding Accuracy for Outpatient Ophthalmic Surgery: St. Joseph's Healthcare Hamilton. AB - Coding accuracy is an important factor in ensuring hospitals receive adequate reimbursement from the government for healthcare services rendered. A retrospective review of 100 charts, the purpose of this study was to determine the degree of coding accuracy from the surgeon perspective, for outpatient procedures performed for ophthalmic services at St. Joseph's Healthcare Hamilton from July to December 2016. Using ICD-10-CA, Canadian Classification of Health Interventions, Quality-Based Procedures criteria where applicable, and the 3M Coding and Reimbursement system, this paper reveals three primary sources of coding errors and presents recommendations to increase accuracy of reimbursement for the benefit of both the Ministry of Health and hospital organizations. PMID- 29132455 TI - Going Beyond the 9-1-1 Call - What BC Emergency Health Services is Doing to Improve Timely Access to Emergency Care. AB - British Columbia Emergency Health Services (BCEHS) uses an internationally recognized Medical Priority Dispatch System to assign appropriate responses to 9 1-1 calls based on patients' clinical acuity. In 2015, 71% of Omega calls (classified as calls involving low acuity injuries) were assigned an ambulance. To better meet patients' needs, BCEHS collaborated with HealthLink BC's Nursing Services (HLBC NS) to audit over 2,000 calls. Based on the results, three Plan, Do, Study, Act (PDSA) cycles were implemented, yielding a 35% decrease in ambulances assigned and a 173% increase in referrals to HLBC NS to provide more suitable support. Ultimately, the interventions allowed these ambulances to be reallocated to more critical patients. PMID- 29132456 TI - [Incidence of late-onset sepsis in very low birth weight and extremely low birth weight infants and risk factors for late-onset sepsis]. AB - OBJECTIVE: To investigate the incidence of late-onset sepsis (LOS) in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants in the neonatal intensive care unit (NICU) and the risk factors for LOS. METHODS: A retrospective analysis was performed for the clinical data of all VLBW and ELBW infants who were hospitalized in the NICU between January 2011 and December 2013. According to the presence or absence of LOS, these infants were divided into LOS group and non-LOS group. The incidence and mortality rates of LOS, common pathogenic bacteria, and risk factors for LOS were analyzed. RESULTS: Of the 226 VLBW and ELBW infants, 117 (51.8%) developed LOS, among whom 45 had a confirmed diagnosis of LOS and 72 had a clinical diagnosis of LOS. The LOS group had a significantly higher mortality rate than the non-LOS group [13.7% (16/117) vs 4.6% (5/109); P<0.05]. Bacterial culture found 51 strains of pathogenic bacteria, among which 32 (63%) were Gram-negative bacteria, 16 (31%) were Gram-positive bacteria, and 3 (6%) were fungi. The multivariate logistic regression analysis showed that gestational age, small for gestational age (SGA), duration of parenteral nutrition, peripherally inserted central catheter (PICC) placement, and mechanical ventilation were independent risk factors for LOS in VLBW and ELBW infants (OR=0.84, 1.59, 1.34, 3.11, and 4.55 respectively; P<0.05). CONCLUSIONS: LOS has high incidence and mortality rates in VLBW and ELBW infants. Common pathogenic bacteria of LOS are Gram-negative bacteria. Low gestational age, long duration of parenteral nutrition, SGA, PICC placement, and mechanical ventilation may increase the risk of LOS in VLBW and ELBW infants. PMID- 29132457 TI - [Relationship between serum 25(OH)D levels at birth and respiratory distress syndrome in preterm infants]. AB - OBJECTIVE: To investigate the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels at birth and respiratory distress syndrome (RDS) in preterm infants. METHODS: This retrospective study recruited preterm infants with gestational age of below 34 weeks who were born between January 2014 and December 2016. These preterm infants were divided into two groups: RDS (n=72) and control (n=40). Clinical data of the two groups were collected, including gestational age, birth weight, gender, delivery mode, Apgar scores at 1 minute and 5 minutes, incidence of maternal gestational diabetes mellitus, and use of prenatal steroid hormone. Peripheral blood samples were collected and 25(OH)D levels were measured by chemiluminescence immunoassay. The association between serum 25(OH)D levels at birth and RDS was analyzed by multivariate logistic regression. RESULTS: Apgar scores at 1 minute and 5 minutes and serum 25(OH)D levels in the RDS group were significantly lower than those in the control group (P<0.05), while the rates of neonatal asphyxia and vitamin D deficiency were significantly higher than those in the control group (P<0.05). Multivariate logistic regression analysis showed that neonatal asphyxia (OR=2.633, 95%CI: 1.139-6.085) and vitamin D deficiency (OR=4.064, 95%CI: 1.625-10.165) were risk factors for RDS in preterm infants. CONCLUSIONS: Vitamin D deficiency might be associated with increased risk of RDS in preterm infants. Reasonable vitamin D supplementation during pregnancy might reduce the incidence of RDS in preterm infants. PMID- 29132458 TI - [Efficacy of analgesic and sedative treatments in children with mechanical ventilation in the pediatric intensive care unit]. AB - OBJECTIVE: To compare the efficacy and safety of different analgesic and sedative treatments in children with mechanical ventilation in the pediatric intensive care unit (PICU). METHODS: Eighty children with mechanical ventilation in the PICU who needed analgesic and sedative treatments were equally and randomly divided into midazolam group and remifentanil+midazolam group. The sedative and analgesic effects were assessed using the Ramsay Scale and the Face, Legs, Activity, Cry and Consolability (FLACC) Scale. The following indices were recorded for the two groups: vital signs, ventilator parameters, organ function, total doses of remifentanil and midazolam, duration of mechanical ventilation, length of PICU stay, PICU cost, and incidence of adverse events. RESULTS: Satisfactory sedation was achieved in the two groups, but the remifentanil+midazolam group had a significantly shorter time to analgesia and sedation than the midazolam group. The remifentanil+midazolam group had a significantly higher percentage of patients with grade 3-4 on the Ramsay Scale and a significantly lower dose of midazolam than the midazolam group (P<0.05). Both groups showed decreases in heart rate (HR), mean arterial pressure (MAP), and spontaneous breathing frequency (RRs) after treatment. However, the remifentanil+midazolam group had significantly greater decreases in HR at 3-24 hours after treatment and MAP and RRs at 3-12 hours after treatment than the midazolam group (P<0.05). Compared with the midazolam group, the remifentanil+midazolam group had significantly higher ventilator tidal volume and transcutaneous oxygen saturation at 6 and 12 hours after treatment and significantly lower end-tidal carbon dioxide partial pressure at 6 and 12 hours after treatment (P<0.05). The remifentanil+midazolam group had significantly shorter time to awake, extubation time, duration of mechanical ventilation, and length of PICU stay than the midazolam group (P<0.05). There were no significant differences in PICU cost, incidence of adverse events, and hepatic and renal functions before and after treatment between the two groups (P>0.05). Both groups showed a significant decrease in fasting blood glucose level after treatment (P<0.05). CONCLUSIONS: For children with mechanical ventilation in the PICU, remifentanil+midazolam treatment can rapidly achieve analgesia and sedation, improve the effect of mechanical ventilation, and reduce the dose of sedative compared with midazolam alone, and is well tolerated. PMID- 29132459 TI - [Short-term clinical outcomes of neonates of secundiparous mothers: a single center cohort study]. AB - OBJECTIVE: To investigate the short-term clinical outcomes of neonates of secundiparous mothers, and to provide a reference for the clinical practice after the change in birth policy. METHODS: A cohort study was performed for the parturients and their neonates born in Yongkang Maternal and Child Health Care Hospital in Zhejiang, China between June 2015 and April 2016. According to the parity of the mother, the neonates were divided into primiparous group and secundiparous group. The short-term clinical outcomes of neonates were compared between the two groups. RESULTS: A total of 4 091 neonates who met the inclusion criteria were enrolled, and there were 2 023 neonates in the primiparous group and 2 068 in the secundiparous group. In the secundiparous group, most mothers (57.16%) were aged 26-34 years, and 16.49% were aged above 35 years. Compared with the primiparous group, the secundiparous group had a significantly higher rate of births by cesarean section (42.55% vs 25.06%; P<0.05). The percentages of neonatal respiratory distress syndrome (NRDS; 8.6% vs 3.4%) and transient tachypnea of the newborn (TTN; 7.2% vs 2.6%; P<0.05) in hospitalized neonates from the secundiparous group were significantly higher than in those from the primiparous group. CONCLUSIONS: Elderly parturient women are not the major population of secundiparous parturients. The neonates of secundiparous mothers have a higher rate of births by cesarean section, which might be associated with increased percentages of NRDS and TTN in hospitalized neonates from the secundiparous mothers. PMID- 29132460 TI - [Genetic diagnosis of 10 neonates with primary carnitine deficiency]. AB - OBJECTIVE: To study the gene mutation profile of primary carnitine deficiency (PCD) in neonates, and to provide a theoretical basis for early diagnosis and treatment, genetic counseling, and prenatal diagnosis of PCD. METHODS: Acylcarnitine profile analysis was performed by tandem mass spectrometry using 34 167 dry blood spots on filter paper. The SLC22A5 gene was sequenced and analyzed in neonates with free carnitine (C0) levels lower than 10 MUmol/L as well as their parents. RESULTS: In the acylcarnitine profile analysis, a C0 level lower than 10 MUmol/L was found in 10 neonates, but C0 level was not reduced in their mothers. The 10 neonates had 10 types of mutations at 20 different sites in the SLC22A5 gene, which included 4 previously unreported mutations: c.976C>T, c.919delG, c.517delC, and c.338G>A. Bioinformatics analysis showed that the four new mutations were associated with a risk of high pathogenicity. CONCLUSIONS: Tandem mass spectrometry combined with SLC22A5 gene sequencing may be useful for the early diagnosis of PCD. Identification of new mutations enriches the SLC22A5 gene mutation profile. PMID- 29132461 TI - [Clinical features of Rubinstein-Taybi syndrome and novel mutation in the CREBBP gene: an analysis of one case]. AB - The patient was a girl aged 3 years and 8 months with normal body length and body weight at birth. The girl had feeding difficulty after birth. Her height, body weight, and head circumference were below the 3rd percentile. She had intellectual disability and an unusual facies manifesting as arched shaggy eyebrows, down-slanting palpebral fissures, and broad nasal bridge, but had no a beaked nose, broad thumbs, or big toes. These clinical manifestations were basically consistent with Rubinstein-Taybi syndrome (RSTS). Gene sequencing identified a heterozygous splice site mutation, c.3779T+1G>T, in the CREBBP gene, which did not exist in her parents. Therefore, a definite diagnosis of RSTS was made. The mutation c.3779T+1G>T had not been reported in the Human Gene Mutation Database and was identified as a novel pathogenic mutation. Then the girl was given rehabilitation training for delayed language and motor development. The girl has been followed up for 3 months in the outpatient department, but the effect of rehabilitation treatment has not been evaluated. PMID- 29132462 TI - [Familial male-limited precocious puberty due to Asp578His mutations in the LHCGR gene: clinical characteristics and gene analysis in an infant]. AB - The aim of the study was to provide a descriptive analysis of familial male limited precocious puberty (FMPP), which is a rare inherited disease caused by heterozygous constitutively activating mutations of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR). The patient was a ten-month-old boy, presenting with penile enlargement, pubic hair formation, and spontaneous erections. Based on the clinical manifestations and laboratory data, including sexual characteristics, serum testosterone levels, GnRH stimulation test, and bone age, this boy was diagnosed with peripheral precocious puberty. Subsequently the precocious puberty-related genes were analyzed by direct DNA sequencing of amplified PCR products from the patient and his parents. Genetic analysis revealed a novel heterozygous missense mutation c.1732G>C (Asp578His) of the LHCGR gene exon11 in the patient, which had never been reported. His parents had no mutations. After combined treatment with aromatase inhibitor letrozole and anti-androgen spironolactone for six months, the patient's symptoms were controlled. The findings in this study expand the mutation spectrum of the LHCGR gene, and provide molecular evidence for the etiologic diagnosis as well as for the genetic counseling and prenatal diagnosis in the family. PMID- 29132463 TI - [Serum levels of 25-hydroxyvitamin D in children with tic disorders]. AB - OBJECTIVE: To examine serum 25-hydroxyvitamin D levels in children with tic disorders (TD) and to explore the relationship between vitamin D level and TD. METHODS: One hundred and thirty-two children who were diagnosed with TD between November 2016 and May 2017 were enrolled as the TD group, including 8 cases of Tourette syndrome, 32 cases of chronic TD, and 92 cases of transient TD. One hundred and forty-four healthy children served as the control group. Peripheral venous blood samples were collected from each child. Serum levels of 25 hydroxyvitamin D were measured using HPLC-MS/MS. The categories of vitamin D status based on serum 25-hydroxyvitamin D level included: normal (>30 ng/mL), insufficiency (10-30 ng/mL) and deficiency (<10 ng/mL). RESULTS: Mean serum level of 25-hydroxyvitamin D in the TD group was significantly lower than that in the control group (P<0.01). The rate of vitamin D insufficiency or deficiency in the TD group was significantly higher than in the control group (P<0.01). Mean serum level of 25-hydroxyvitamin D in the transient tic group was higher than in the TS group (P<0.05). CONCLUSIONS: Vitamin D insufficiency or deficiency might be associated with the development of TD, and the level of serum 25-hydroxyvitamin D might be related to the classification of TD. PMID- 29132464 TI - [Clinical manifestations and genetic diagnosis of paroxysmal kinesigenic dyskinesia]. AB - The clinical manifestations of five children with paroxysmal kinesigenic dyskinesia (PKD) were retrospectively analyzed and their gene mutations were analyzed by high-throughput sequencing and chromosome microarray. The 5 patients consisted of 4 males and 1 female and the age of onset was 6-9 years. Dyskinesia was induced by sudden turn movement, scare, mental stress, or other factors. These patients were conscious and had abnormal posture of unilateral or bilateral extremities, athetosis, facial muscle twitching, and abnormal body posture. The frequency of onset ranged from 3-5 times a month to 2-7 times a day, with a duration of <30 seconds every time. Electroencephalography showed no abnormality in these patients. Three patients had a family history of similar disease. The high-throughput sequencing results showed that a heterozygous mutation in the PRRT2 gene, c.649_650insC (p.R217PfsX8), was found in two patients; the mutation c.436C>T (p.P146S) was found in one patient; a splice site mutation, IVS2-1G>A, was found in one patient. The two mutations c.436C>T and IVS2-1G>A had not been reported previously. The chromosome microarray analysis was performed in one patient with negative results of gene detection, and the chromosome 16p11.2 deletion (0.55 Mb) was observed. Low-dose carbamazepine was effective for treatment of the 5 patients. PKD is a rare neurological disease. The detection of the PRRT2 gene by multiple genetic analysis can help the early diagnosis of PKD. PMID- 29132465 TI - [Application of flexible bronchoscopy in children with respiratory diseases]. AB - OBJECTIVE: To investigate the significance of flexible bronchoscopy in children with respiratory diseases. METHODS: A retrospective analysis was performed for the clinical data of 80 children who were hospitalized due to respiratory diseases (including severe pneumonia, Mycoplasma pneumoniae pneumonia with atelectasis/lung consolidation/local emphysema, protracted pneumonia, coughing and wheezing of unknown cause, chronic cough of unknown cause, and laryngeal stridor) and who underwent flexible bronchoscopy/alveolar lavage. RESULTS: Bronchoscopy found that all the 80 children had endobronchial inflammation, among whom 28 children had severe airway obstruction by secretion. Twenty-four children had congenital airway dysplasia besides endobronchial inflammation, and three children had bronchial foreign bodies. In the children with coughing and wheezing of unknown cause and laryngeal stridor, some had congenital airway dysplasia or bronchial foreign bodies. Among the 27 children with Mycoplasma pneumoniae pneumonia, 26 had severe airway obstruction/embolization by secretion; 25 children (93%) underwent chest imaging again at 2 weeks after alveolar lavage, and the results showed complete or partial lung recruitment. Among the 80 children who underwent bronchoscopy, 3 had severe hypoxemia during surgery, 1 had epistaxis, 1 had minor bleeding during alveolar lavage, 3 had transient bronchospasm, and 5 had postoperative fever; these children were all improved after symptomatic treatment. CONCLUSIONS: Flexible bronchoscopy is safe and reliable in children with respiratory diseases. Early alveolar lavage under a flexible bronchoscope is recommended for children with severe/refractory Mycoplasma pneumoniae pneumonia to improve prognosis. Flexible bronchoscopy is recommended for children with recurrent coughing and wheezing and persistent laryngeal stridor, in order to directly observe the throat and airway under an endoscope. PMID- 29132466 TI - [Association of drug resistance of Mycoplasma pneumoniae with DNA load and genotypes in children with Mycoplasma pneumoniae pneumonia]. AB - OBJECTIVE: To investigate the association of drug resistance of Mycoplasma pneumoniae (MP) with DNA load and genotypes in children with MP pneumonia. METHODS: A total of 230 children who were hospitalized and diagnosed with MP pneumonia between January 2012 and December 2016 were enrolled. Throat swabs were collected from the 230 children, and a rapid drug sensitivity assay was used to determine the sensitivity of clinical isolates of MP to nine commonly used antibacterial agents. Quantitative real-time PCR was used to measure MP-DNA load in throat swabs. PCR sequencing was used to determine the genotype of 2063 locus of the MP 23S rRNA V domain. RESULTS: Of the 230 children, 86 (37.4%) had genotype A in 2063 locus, 134 (58.3%) had genotype G, 8 (3.5%) had genotype C, and 2 (0.9%) had genotype T. Mutant strains (genotype G+C+T) had a significantly higher MP-DNA load than wild-type strains (genotype A) (P<0.05). The strains resistant to erythromycin, azithromycin, clarithromycin, and clindamycin had a significantly higher MP-DNA load than non-resistant strains (P<0.05). MP had a high drug resistance rate to macrolide antibiotics. More than 60% of the cases with resistance to macrolides were found to have A2063G mutations. MP was rarely resistant to quinolones (less than 2%). CONCLUSIONS: Mutations in 2063 locus of the MP 23S rRNA V domain may result in the resistance of MP to macrolides and the change in DNA load and can be used as a basis for selecting drugs for MP. PMID- 29132467 TI - [Distribution characteristics of serum specific IgE for inhaled allergens in children with different airway allergic diseases]. AB - OBJECTIVE: To investigate the distribution characteristics of serum specific IgE (sIgE) for inhaled allergens in children with different airway allergic diseases. METHODS: Fluorescent enzyme-linked immunosorbent assay on the UniCAP250 system was performed to measure serum sIgE for 9 common inhaled allergens in 256 children aged 3-14 years with different airway allergic diseases. According to the clinical diagnosis, these children were divided into rhinitis group (37 children with allergic rhinitis), asthma group (82 children with bronchial asthma), and rhinitis-asthma group (137 children with allergic rhinitis complicated by bronchial asthma). The three groups were compared in terms of the detection rates of 9 inhaled allergens, sensitization level, and number of allergens. RESULTS: The detection rate of serum sIgE for inhaled allergens was 57.3% (47/82) in the asthma group, 86.5% (32/37) in the rhinitis group, and 82.5% (113/137) in the rhinitis-asthma group (P<0.05). The most common allergen in the asthma, rhinitis, and the rhinitis-asthma groups was mould fungi (32.9%, 54.1%, and 48.9% respectively), followed by dust mites (30.5%, 45.9%, and 46.0% respectively), pollen (26.8%, 35.1%, and 32.8% respectively), pets (12.2%, 27.0%, and 18.2% respectively), and cockroach (9.8%, 5.4%, and 5.8% respectively). The rhinitis group and the rhinitis-asthma group had a significantly higher detection rate of mould fungi (mx2) than the asthma group (P<0.0166). There were no significant differences in the sensitization level of 9 allergens and number of allergens between the three groups. CONCLUSIONS: In children with either bronchial asthma, allergic rhinitis, or bronchial asthma complicated by allergic rhinitis, the three most common inhaled allergens are mould fungi, dust mites, and pollens. Compared with bronchial asthma, allergic rhinitis may be more closely associated with sensitization by mould fungi. The three common airway allergic diseases have similar distribution characteristics of inhaled allergens. PMID- 29132468 TI - [Benign infantile convulsions associated with mild gastroenteritis: a clinical analysis and follow-up study]. AB - OBJECTIVE: To study the clinical features and prognosis of benign infantile convulsions associated with mild gastroenteritis (BICE). METHODS: A retrospective analysis was performed for the clinical data of 436 children with BICE, and among these children, 206 were followed up for 1.5 to 7 years. Some parents were invited to complete the Weiss Functional Defect Scale to evaluate the long-term social function. RESULTS: The peak age of onset of BICE was 13-24 months, and BICE had a higher prevalence rate in September to February of the following year. Convulsions mainly manifested as generalized tonic-clonic seizures, which often occurred within 24 hours after disease onset and lasted for less than 5 minutes each time. Sometimes they occurred in clusters. During the follow-up of 206 children, only one had epileptiform discharge, and the other children had normal electroencephalographic results. The parents of all the 206 children thought their children had normal intelligence and had no marked changes in character. Based on the Weiss Functional Defect Scale completed by the parents of some BICE children, there was no significant difference in the long-term social function between BICE children and healthy children matched by age and sex. CONCLUSIONS: BICE mainly occurs in children aged 1-2 years, with the manifestation of transient generalized seizures in most children and cluster seizures in some children. BICE seldom progresses to epilepsy and has good prognosis. PMID- 29132469 TI - [Clinical characteristics and prognostic analysis of children with congenital heart disease complicated by postoperative acute kidney injury]. AB - OBJECTIVE: To analyze the perioperative clinical data of children with congenital heart disease complicated by acute kidney injury (AKI) after cardiopulmonary bypass (CPB) surgery, and to explore potential factors influencing the prognosis. METHODS: A retrospective analysis was performed among 118 children with congenital heart disease who developed AKI within 48 hours after CPB surgery. RESULTS: In the 118 patients, 18 died after 48 hours of surgery. Compared with the survivors, the dead children had significantly higher incidence of cyanotic disease and Risk Adjustment for Congenital Heart Surgery-1 (RACHS-1) scores before surgery; during surgery, the dead children had significantly longer CPB time and aortic cross-clamping time, a significantly higher proportion of patients receiving crystalloid solution for myocardial protection, and a significantly higher mean blood glucose level. Within 48 hours after surgery, the dead children had significantly higher positive inotropic drug scores, significantly higher creatinine values, a significantly higher incidence of stage 3 AKI, a significantly higher proportion of patients receiving renal replacement the, and significantly higher usage of blood products (P<0.05). The mortality rate of the patients increased with increased intraoperative blood glucose levels (P<0.05). Patients with intraoperative blood glucose levels >8.3 mmol/L had a significantly lower postoperative cumulative survival rate and a significantly shorter mean survival time than those with blood glucose levels <= 8.3 mmol/L (P<0.05). CONCLUSIONS: Intraoperative blood glucose levels are associated with the prognosis in children with congenital heart disease complicated by AKI after CPB surgery. Maintaining good intraoperative blood glucose control can improve the prognosis of the children. PMID- 29132470 TI - [Effects of bone marrow mesenchymal stem cell transplantation on retinal neovascularization in neonatal rats with oxygen-induced retinopathy]. AB - OBJECTIVE: To explore the effects of rat bone mesenchymal stem cell (BMSC) transplantation on retinal neovascularization, and to observe the changes of hypoxia-inducible factor-1 alpha (HIF-1alpha) and vascular endothelial growth factors (VEGF) in rats with oxygen-induced retinopathy (OIR). METHODS: Seventy two seven-day-old Sprague-Dawley rats were randomly divided into three groups: normal control (CON), model (OIR) and BMSC transplantation. In the BMSC transplantation group, BMSCs were transplanted 5 days after oxygen conditioning. The phosphate buffered saline of the same volume was injected in the CON and OIR groups. The OIR model was prerpared according to the classic hyperoxygen method. At seven days after transplantation, retinal neovascularization was examined by retinal flat-mount staining and hematoxylin eosin (HE) staining. The expression of HIF-1alpha and VEGF proteins was examined by immunohistochemistry staining and Western blot analysis. RESULTS: The retinal flat-mount staining results showed that the vessels were well organized in the CON group, but the vessels were irregularly organized, and lots of nonperfusion areas were observed in the OIR group. The large vessels were a bit circuitous, the retinal vessels were relatively organized, and less nonperfusion areas were noted in the BMSC transplantation group. The HE staining results showed that many neovessels and preretinal neovascular (pre-RNC) cells were observed on the internal limiting membrane in the OIR group. There were less pre-RNC cells in the BMSC transplantation group compared with the OIR group (P<0.01). The immunohistochemistry analysis showed that more HIF-1alpha+ and VEGF+ cells were observed in the OIR group compared with the CON group, and less HIF-1alpha+ and VEGF+ cells were observed in the BMSC transplantation group compared with OIR group (P<0.05). The Western blot analysis showed the expression of HIF-1alpha and VEGF proteins in the OIR group was significantly higher than that in the CON group. The expression of HIF-1alpha and VEGF proteins in the BMSC transplantation group was lower than that in the OIR group (P<0.01). CONCLUSIONS: BMSC transplantation therapy could alleviate retinal neovascularization in OIR rats, and its mechanisms might be associated with the inhibition of the expression of HIF-1alpha and VEGF proteins. PMID- 29132471 TI - [Oridonin inhibits proliferation of Jurkat cells via the down-regulation of Brg1]. AB - OBJECTIVE: To investigate the effect of oridonin on the human acute lymphocytic leukemia cell line Jurkat and its mechanism. METHODS: Jurkat cells were cultured in vitro and treated with various concentrations (0, 1.25, 2.5, 5, and 10 MUmol/L) of oridonin for different lengths of time (24, 48, and 72 hours). The proliferation of Jurkat cells was analyzed by MTT assay. The changes in nuclear morphology were evaluated by fluorescence microscopy at 12 hours after treatment with various concentrations of oridonin. The expression levels of Brg1, P53, and C-myc were determined by semi-quantitative Western blot in Jurkat cells treated with various concentrations of oridonin for 24 hours or 5 MUmol/L oridonin for various lengths of time (0, 2, 6, 12, and 24 hours). The expression levels of P53 and C-myc and proliferation of Jurkat cells were evaluated after Brg1 expression was knocked down by Brg1-specific siRNA. RESULTS: Compared with the control group, the proliferation of oridonin-treated Jurkat cells was significantly inhibited in a concentration- and time-dependent manner (P<0.05). According to the florescence microscopic analysis, oridonin treatment led to nuclear pyknosis in Jurkat cells. Compared with the control group, Jurkat cells treated with 5 MUmol/L oridonin had reduced expression of Brg1 and C-myc but elevated expression of P53. Brg1 knock-down led to a significant reduction in proliferation of Jurkat cells (P<0.05), up-regulated expression of P53, and down-regulated expression of C-myc. CONCLUSIONS: Oridonin can inhibit the proliferation of Jurkat cells, probably via the Brg1 signaling pathway. PMID- 29132472 TI - [Research progress in Ph-like childhood acute lymphoblastic leukemia]. AB - Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subtype of B-lineage ALL (B-ALL) that displays a gene expression profile (GEP) similar to Philadelphia chromosome-positive ALL (Ph+ ALL). It has a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, frequently accompanied by abnormal transcription factors related to lymphatic development. Children with Ph-like ALL account for 15% of children with high-risk B-ALL. It has adverse clinical features and a poor prognosis. Tyrosine kinase inhibitors combined with chemotherapy can significantly improve the prognosis of children with Ph+ ALL, suggesting that targeted therapy based on the molecular cytogenetic abnormalities of Ph-like ALL has good research prospects. This paper expounds the genetic alterations, pathogenesis, clinical features, diagnostic measures, and potential therapeutic approaches of Ph-like childhood ALL based on recent research progress in Ph-like ALL. PMID- 29132473 TI - [Progress in clinical studies of chimeric antigen receptor engineered T cells for treatment of childhood cancer]. AB - Nowadays, the 5-year survival rate of childhood cancer patients can be more than 80%, but some patients with relapse and refractory cancers have shown no good response to traditional strategies. Chimeric antigen receptor engineered T (CAR T) cell therapy is promising for these patients. CAR-T cells recognize the tumor associated antigens in a non-major histocompatibility complex-restricted manner, so their anti-tumor ability is enhanced. There are four generations of CAR-T cells now. The complete remission rate of pediatric patients with relapse and refractory acute lymphoblastic leukemia can be as high as 90% when treated with CD19-targeting CAR-T cells. Furthermore, CAR-T cell therapy can also be used to bridge to transplantation and donor CAR-T cell infusion can be a strategy to prevent relapse after hematopoietic stem cell transplantation. As to solid tumors, only patients with neuroblastoma present good response to the GD2 targeting CAR-T cell therapy. The toxic or side effects of CAR-T cell therapy include cytokine release syndrome, off-tumor effect, tumor lysis syndrome, and insertion mutation. Although the CD19-targeting CAR-T cell therapy for childhood cancer can result in a high remission rate, the relapse rate is high, including CD19+ and CD19- relapse. The mechanisms for relapse merit further investigatio. PMID- 29132474 TI - Growing Disease Burden in Pakistan: Status, Challenges, and Opportunities. PMID- 29132475 TI - Relation of Muscle Indices with Metabolic Parameters and C-Peptide in Type 2 Diabetes Mellitus. AB - OBJECTIVE: To assess the relation between bioimpedance measurements and metabolic parameters and C-peptide in patient with type 2 diabetes mellitus (DM). STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Kartal Dr Lutfi Kirdar Training and Research Hospital, Pendik Kaynarca Diabetes Center, Exercise and Metabolism Unit, between January and March 2015. METHODOLOGY: Patients with DM, aged less than 65 years, were assessed for bioimpedance analysis, fasting plasma glucose (FPG), HbA1c, C-peptide levels, triglyceride levels, LDL cholesterol, and HDL-cholesterol levels. Skeletal muscle index, total muscle index, skeletal muscle percentage, and total muscle percentage were used for muscle-related analyses. Mann-Whitney U-test or independent t-test were used to compare differences between two independent groups. Pearson correlation test or Spearman correlation test were used to find out correlation between variables. RESULTS: Atotal of 359 DM patients were enrolled in the study. Mean age was 51.6 +/-8.0 years, and 278 (77.7%) of the participants were females. After adjusting age and gender variables, there was no relation between muscle-related measurements and FPG, triglyceride, LDL-cholesterol (p>0.05). However, there was muscle-related indexes (MRI) positively correlation with C-peptide and inversely associated with HDL-cholesterol (p<0.05). CONCLUSION: Muscle-related indices positively correlated with C-peptide, which showed endogenous insulin reserve. PMID- 29132476 TI - Helicobacter PyloriAssociation with Expression of CDX2 in Intestinal Metaplasia. AB - OBJECTIVE: To assess whether helicobacter pylori was associated with CDX2 expression in intestinal metaplasia, atrophic gastritis, dysplasia and gastric cancer. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Department of Pathology, The First Hospital of Jilin University, Changchun, China, from August 2016 to January 2017. METHODOLOGY: CDX2 expression was evaluated in 62 gastric antral biopsies; including 32 cases of intestinal metaplasia (IM) and 10 cases each of atrophic gastritis (AG), dysplasia and gastric cancer. Hematoxylin and Eosin staining was used to detect H.pyloriand immunohistochemistry was performed to observe CDX2 in the samples. RESULTS: Of the 62 patients inducted in the study, CDX2 expression was observed in 53 (85.5%). Mean age of these patients was 59 years (s.d.:11.3; range: 38-87) and included 32 males (60.38%) and 21 females (39.62%). However, age and gender were not found to be significantly associated with expression of CDX2 (p >0.05). CDX2 was very frequently expressed in individuals with IM (90.6%). Most of the patients with IM were males (17/29) as compared to females (12/29). However, the difference was not statistically significant (p=0.568). Only 4 out of 29 IM CDX2 positive specimens tested positive for H.pylori(p=1.0). CONCLUSION: CDX2 is highly expressed along the atrophic gastritis-metaplasia-dysplasia-cancer sequential. Though CDX2 expression is quite dominant in IM, but its expression is not associated with H.pyloriinfection. PMID- 29132477 TI - Elective Division of Ilioinguinal Nerve in Inguinal Hernioplasty: Remedy for the Morbid Postoperative Inguinal Pain. AB - OBJECTIVE: To compare the postoperative pain in inguinal hernioplasty, by preserving versus wide elective division of ilioinguinal nerve. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Surgical Department, Civil Hospital, Karachi, from January till August 2015. METHODOLOGY: All patients of either gender above 15 years of age, undergoing mesh repair for unilateral, reducible inguinal hernia, were included. Patients with recurrent inguinal hernia, bilateral inguinal hernia, and those who will require emergency hernia surgeries like irreducible, obstructed, and strangulated hernia, were excluded. They were randomly assigned 42 into inguinal nerve preservation group (group A) and 42 in division (group B). Postoperative pain was assessed at first day, at discharge and after one month using visual analogue scale. RESULTS: There were a total of 84 patients. Group Apatients had median (IQR) pain scores of 5 (1) and 3 (2) as compared to group B pain scores of 4 (2) and 2 (1) at 24 hours of surgery and at discharge, respectively (p <0.05). Median (IQR) postoperative pain score one month after inguinal hernioplasty was 2.5 (1) in group A, while 0.5 (1) in group B (p <0.05). Asignificant decline in the pain scores were observed in group B from the first day of surgery till one month afterwards (p <0.05). CONCLUSION: Wide resection of ilioinguinal nerve has a lower frequency of postoperative pain in comparison to the ilioinguinal nerve preservation, in inguinal hernioplasty. PMID- 29132478 TI - Treatment for Symptomatic Bacterial Vaginosis: ARandomized Controlled Trial. AB - OBJECTIVE: To compare the efficacy of multiple doses of vaginal clindamycin with a single oral dose of secnidazole for the treatment of bacterial vaginosis. STUDY DESIGN: Double-blinded randomized controlled trial. PLACE AND DURATION OF STUDY: Shifa Foundation Community Health Center, from March 2012 till February 2015. METHODOLOGY: After obtaining written informed consent, a pelvic examination was performed for the confirmation of symptoms of milky white vaginal discharge on speculum examination, positive Amine test and presence of clue cells on microscopy. Pregnant women, known diabetes or any immunocompromised condition, were excluded. Blinding of the patient, doctor, and the pharmacist was done. Study cohort was then divided into two groups, Group Areceived medicine pack Awhich contained active clindamycin and placebo oral preparation, whereas group B was given pack B which contained active 2-gm secnidazole with placebo vaginal cream. Primary outcome and therapeutic success were defined by correction of two out of three (normal Nugent score, negative Amine test, and no milky white discharge) on day 15. RESULTS: At 15th day of treatment, 96.6% participants in vaginal clindamycin group (Group A), recovered from the bacterial vaginosis; whereas, (group B) 23% patients were cured in oral secnidazole group. CONCLUSION: Multiple doses of vaginal clindamycin are superior to single dose of oral secnidazole for the treatment of bacterial vaginosis. PMID- 29132479 TI - Current Trends of Antimicrobial Susceptibility of Typhoidal Salmonellae Isolated at Tertiary Care Hospital. AB - OBJECTIVE: To determine the current trend of antimicrobial susceptibility of typhoidal Salmonellae. STUDY DESIGN: Descriptive cross-sectional study. PLACE AND DURATION OF STUDY: The study was carried out in the Department of Microbiology, PNS Shifa Hospital, Karachi, from January 2014 to December 2015. METHODOLOGY: Blood culture samples received from the wards and outpatient departments were included. Isolates of Salmonella were dealt with standard microbiological procedures. The antimicrobial sensitivity against the typhoidal Salmonellaewas determined using Kirby-Bauer disc diffusion method as per the guidelines of Clinical and Laboratory Standards Institute (2013). RESULTS: Atotal of 460 typhoidal Salmonellaewere isolated; out of which 270 were Salmonella typhiand 190 were Salmonella paratyphiA. The percentage of MDR isolates of S. typhiwas 57% and that of S. paratyphiAwas 42%. None of the isolates were resistant to ceftriaxone, while sensitivity to ciprofloxacin (07% and 0% for S. typhiand S. paratyphiA, respectively) was very low. CONCLUSION: There is high percentage of MDR isolates of typhoidal Salmonellaein our region. The antimicrobial sensitivity of typhoidal Salmonellaeto conventional agent has not improved enough to recommend their empirical use. There is almost complete resistance to fluoroquinolones as well, leaving very limited available treatment options. PMID- 29132480 TI - The Relation of Health-Related Practices of Pregnant Women, Fatigue and Prenatal Attachment. AB - OBJECTIVE: To examine the relation of the health-related practices of expectant mothers during pregnancy and fatigue in mother and prenatal attachment. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Sakarya Training and Research Hospital, Turkey, between February and April 2016. METHODOLOGY: The study sample consisted of pregnant women (at least 20-week gestation) aged 18 years or above (n=211) who applied to prenatal care services and agreed to participate in the study. The data were collected through a Personal Information Form, Brief Fatigue Inventory (BFI) and the Prenatal Attachment Inventory (PAI). RESULTS: The PAI medians of the participants were 55 [42-64], and the BFI medians were 30 [23-42], and a negative, statistically significant relationship was found between BFI and PAI (r= -0.184, p=0.007). CONCLUSION: Expectant mothers who develop positive health behaviors during pregnancy feel less fatigue and positively affect the prenatal attachment. It is important to evaluate prenatal attachment and identify the mother with low attachment scores. PMID- 29132481 TI - Inhibitory Effect of AG490 on STAT3 Signal Transduction Pathway in Nasopharyngeal Carcinoma Cells. AB - OBJECTIVE: To determine the effect of JAK kinase inhibitor AG490 on proliferation and apoptosis of nasopharyngeal carcinoma cell line C666-1 and explore the inhibitory effect of AG490 on STAT3 signal transduction pathway. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Xi'an Ninth Hospital, Xi'an, China, from May 2015 to December 2016. METHODOLOGY: AG490 was applied to C666-1 cells. Cell proliferation was detected by MTTassay. Cell cycle and apoptosis were detected by flow cytometry. The expression of STAT3 and p-STAT3 protein was detected by immobilized Western blot. RESULTS: AG490 could effectively inhibit proliferation of C666-1 cellsin vitro, and the inhibitory effect was characterized by time and concentration dependence. AG490 induced apoptosis of nasopharyngeal carcinoma cells, and apoptosis rate increased with prolongation of the time. AG490 could inhibit expression of STAT3 and p-STAT3 protein in C666-1 cells. CONCLUSION: AG490 can down-regulate expression of STAT3 and p-STAT3 protein in C666-1 cells, inhibit proliferation of nasopharyngeal carcinoma cells and promote apoptosis of nasopharyngeal carcinoma cells. PMID- 29132482 TI - Effectiveness of Functional Electrical Stimulation (FES) versus Conventional Electrical Stimulation in Gait Rehabilitation of Patients with Stroke. AB - OBJECTIVE: To compare the effectiveness of functional electrical stimulation (FES) versus conventional electrical stimulation in gait rehabilitation of patients with stroke for finding the most appropriate problem-oriented treatment for foot drop patients in a shorter time period. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, from July to December 2016. METHODOLOGY: Subjects with foot drop due to stroke were allotted randomly into 1 of 2 groups receiving standard rehabilitation with Functional Electrical Stimulation (FES) or Electrical Muscle Stimulation (EMS). FES was applied on tibialis anterior 30 minutes/day, five days/week for six weeks. EMS was also applied on the tibialis anterior five days/week for six weeks. Outcome measures included Fugl-Meyer Assessment Scale, Modified Ashworth Scale, Berg Balance Scale (BBS), Time Up and Go Test (TUG) and Gait Dynamic Index (GDI). They were recorded at baseline, after 3 and 6 weeks. Pre- and post-treatment scores were analyzed between two groups on SPSS-20. RESULTS: After six weeks of intervention, significant improvement was recorded in Fugl-Meyer Assessment score (p<0.001), modified Ashworth Scale score (p=0.027), Berg Balance Scale score (p<0.001), Time Up and Go Test (p<0.001) and Gait Dynamic Index (p=0.012) of the group subjected to FES. CONCLUSION: Gait training with FES is more effective than EMS in improving mobility, balance, gait performance and reducing spasticity in stroke patients. The research will help clinicians to select appropriate treatment of foot drop in stroke patients. PMID- 29132483 TI - Glanular Hypospadias Management with Modified Circumcision and Firlit Procedure. AB - OBJECTIVE: To document the results of using simple technique of Firlit procedure with modified circumcision for treatment of glanular hypospadias. STUDY DESIGN: Descriptive case series. PLACE AND DURATION OF STUDY: Department of Urology, Shifa International Hospital, Islamabad, from January 2011 till May 2017. METHODOLOGY: The subjects included pediatric patients who underwent repair of glanular hypospadias by using modified circumcision and Firlit procedure. Patients were analyzed for operative time, age, hospital stay, and peroperative and postoperative complications. Chart review was done for collection of data on specified proforma. RESULTS: There were 73 patients with mean age of 1.81 +/-0.92 years. Children were discharged on the same day. None of them needed catheterization and dressing. Temporary dressing was used for mild bleeding immediate post op in 13 (17.80%) cases only. Postoperative complication such as urinary retention, fever, severe pain, or urinary tract infection were not seen in children. Meatal stenosis was not seen on a 2-24 months' follow-up. Satisfactory urine stream and good cosmesis was noted by the parents. CONCLUSION: The Firlit technique for the repair of glanular hypospadias was simple and satisfactory in terms of urine stream and cosmesis with minimal complications. PMID- 29132484 TI - Abdominal CT Findings in Patients with Primary Lymphoma Causing Small Bowel Obstruction. AB - The purpose of this study was to investigate retrospectively CTfindings in patients with primary lymphoma causing small bowel obstruction. CTscans of 11 patients with small bowel lymphoma were separately analysed in terms of affected section of the small bowel, focality, wall thickness, pattern and degree of contrast enhancement, lymphadenopathy, organ involvement, perforation, and the presence of intraabdominal fluid. Eight patients had diffuse large B-cell lymphoma, and one patient each had marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT), T-cell lymphoma, and anaplastic T-cell lymphoma. Affected sections of the bowels involved were jejunum (n=5, 45.4%), ileum (n=2, 18.1%), and one case (9%) each of distal ileum, distal jejunum, distal jejunum and ileum, and distal jejunum and colon. Primary gastrointestinal (GI) lymphoma is an uncommon disease, that may lead to small bowel obstruction sometimes. PMID- 29132485 TI - Prognostic Role of Acellular Mucin Pools in Patients with Rectal Cancer after Pathological Complete Response to Preoperative Chemoradiation: Systematic Review and Meta-Analysis. AB - The prognostic implication of acellular mucin pools (AMP) in rectal cancer is controversial. There is no Level-I evidence regarding their prognostic impact. This systematic review was performed to determine the impact of AMPon survival in patients with rectal cancer, who demonstrate pathological complete response (PCR) to preoperative chemoradiation (CRT). Asystematic literature review was performed by searching MEDLINE and EMBASE database. For overall survival, the overall random effect model favored mucin negative tumors (HR=2, 95% CI=0.8-4.8) with heterogeneity (I-squared=0, p=0.6). However, the pooled analysis was not significant due to small sample. For disease-free survival, four studies showed HR >1; however, the pooled random effect model indicated little difference in risk (HR=1.06, 95% CI=0.4-2.4) with heterogeneity (I-squared=49.5%, p=0.07). No definite prognostic role of AMPin rectal cancer patients with PCR was found. These results, however, should be interpreted with caution. PMID- 29132486 TI - OptiCard: An Inexpensive and Portable Method of Bedside Direct Fundoscopy. AB - The use of fundoscopy to observe and grade retinal changes in diabetes and hypertension is well known. Fundus screening is recommended prior to discharge of every neonate from the neonatal unit to rule out congenital cataract. However, the traditional direct fundoscopes are expensive and, therefore, not available in majority of the hospitals in developing countries. Also, fundoscopy needs special expertise to use the device. OptiCard is an inexpensive new method of direct fundoscopy that allows visualization of retina and optic disc with or without the use of cell phone. The affordability and ease of use of this device can result in better patient care in hospital setups with limited resources. PMID- 29132487 TI - Delta-Beta Thalassaemia in a Pathan Family. AB - Delta-beta-thalassaemia (deltabeta-thalassaemia) is a rare type of thalassaemia which mostly results from deletion of delta and beta genes with preservation of gamma genes. deltabeta-thalassaemia is classified into (deltabeta)+ and (deltabeta)0 types. The (deltabeta)0-thalassemia is further divided into GgammaAgamma(deltabeta)0-thalassaemia and Ggamma(Agammadeltabeta)0-thalassaemia. In heterozygous state, (deltabeta)0mutations give rise to phenotype resembling beta-thalassaemia trait but with raised Hb-F, ranging from 5 to 20%, without a rise in Hb-A2. In homozygotes, the clinical picture is usually that of thalassaemia intermedia and the patients have 100% Hb-F. Workup of a 1-year child suffering from pallor, chronic ill health, and splenomegaly referred to our laboratory with the suspicion of beta-thalassaemia, ultimately resulted in a diagnosis on polymerase chain reaction as having homozygous inversion/deletion Ggamma(Agammadeltabeta)0-thalassaemia. Her family members were also investigated. PMID- 29132488 TI - Optic Disc Pit Maculopathy Triggered by Childbirth. AB - We describe a case of a healthy lady with a known optic disc pit who developed serous maculopathy a few hours after childbirth. We believe this is the first published description of a trigger factor responsible for serous macular detachment in eyes known to have a disc pit. She was successfully treated by means of pars plana vitrectomy and gas injection, resulting in slight visual improvement. PMID- 29132489 TI - Auto-Amputated Ovary Presenting as Abdominal Mass in an Infant. AB - Among female infants, a mass in the abdomen carries a large number of differential diagnoses. Arelatively uncommon condition is ovarian cyst, which may be encountered among such patients. Even more rare condition is auto-amputation of ovary. We herein, present a case of a female infant who presented as abdominal mass and turned out to be autoamputation of right ovary attached to mesentery of intestine. It was excised successfully and the patient is doing well at 3 years follow-up. PMID- 29132490 TI - Rehabilitation of a Complex Oro-Facial Defect by Modified Prosthetic Approach. AB - Loss of part of the face is associated with physical disability, social isolation and immense psychological trauma. Proper rehabilitation of such a patient is a challenging yet satisfying task for a maxillofacial prosthodontist. Facial prostheses are commonly fabricated of silicone because of many favorable properties, though it predisposes to fungal growth.This report is of a patient with history of uncontrolled diabetes and associated invasive fungal infection, leading to a complex oro-facial defect, which was rehabilitated successfully with a silicone facial prosthesis lined by a material more resistant to fungal growth along with a cast partial obturator. Other design and procedural modifications were also made to suit the needs of the case. Wise selection of materials, keeping in mind the properties of materials, is important in successful rehabilitation. PMID- 29132491 TI - Sacubitril/Valsartan: Practice Changing Guideline in the Management of Congestive Heart Failure. PMID- 29132492 TI - Regenerative Therapy by Replacement of Stem Cells in Females. PMID- 29132493 TI - Hepatitis C Transmission among Intravenous Drug Users in Pakistan: Time to Intervene. PMID- 29132494 TI - Seminoma in Undescended Testis Presenting as Metastatic Enlarged Cervical Lymph Nodes. PMID- 29132495 TI - Solitary Neurofibroma of Gingiva - An Immunohistochemical Interpretation Using S 100. PMID- 29132496 TI - Relationship Issues and High Divorce Rate among Surgeons. PMID- 29132497 TI - From micro to macro: assessing implementation of integrated care in Australia. AB - Many countries and health systems are pursuing integrated care as a means of achieving better outcomes. However, no standard approaches exist for comparing integration approaches across models or settings, and for evaluating whether the key components of integrated care are present in different initiatives. This study sheds light on how integrated care is being implemented in Australia, using a new tool to characterise and compare integration strategies at micro, meso and macro levels. In total, 114 staff from a purposive sample of 38 integrated care projects completed a survey based on the Rainbow Model of Integrated Care. Ten key informants gave follow-up interviews. Participating projects reported using multiple strategies to implement integrated care, but descriptions of implementation were often inconsistent. Micro-level strategies, including clinical-professional service coordination and person-centred care, were most commonly reported. A common vision was often described as an essential foundation for joint work. However, performance feedback appeared under-utilised, as did strategies requiring macro-level action such as data linkages or payment reform. The results suggest that current integrated care efforts are unevenly weighted towards micro-level strategies. Increased attention to macro-level strategies may be warranted in order to accelerate progress and sustain integrated care in Australia. PMID- 29132498 TI - Perspectives from practice: complexities of personal care workers. AB - Personal care workers (PCWs) make up the bulk of the workforce in residential and community care services. The knowledge and skill set needed for safe and effective practice in care settings is extensive. A diverse range of registered training organisations (RTOs) offering Certificate III and IV in Individual Support (aging, home and community) are tasked with producing job-ready PCWs. However, the curricula of these programs vary. Additionally, a national code of conduct for healthcare workers became effective in October 2015 as a governance framework for PCWs. The language of the code statements is ambiguous making it unclear how this framework should be translated by RTOs and applied in the preservice practice preparation of PCWs. Employers of PCWs need to feel confident that the content of the preservice education of PCWs satisfactorily prepares them for the diverse contexts of their practice. Likewise, the health professionals who supervise PCWs must be assured about the knowledge and skills of the PCW if they are to safely delegate care activities. The perspectives presented in this discussion make it clear that investigation into the nebulous nature of PCW education, regulation and practice is needed to identify the shortcomings and enable improved practice. PMID- 29132499 TI - Use of medical emergency call data as a marker of quality of emergency department care in the post-National Emergency Access Target era. AB - Objectives Any new model of care should always be accompanied by rigorous monitoring to ensure that there are no negative consequences, especially any that impact upon patient safety. In 2013, 'THERMoSTAT' (Two- Hour Evaluation and Referral Model for Shorter Turnaround Times), an emergency department model of care developed by Royal Brisbane and Women's Hospital staff was launched to gain efficiencies and improve hospital National Emergency Access Target (NEAT) compliance. The aim of this study was to trial the use of medical emergency call data as a novel marker of the quality of care delivered by our emergency department.Methods Incidence of medical emergency calls for hospital emergency admission patients for the 2 years pre- and 1 year post-THERMoSTAT were compared after standardising for overall hospital activity.Results During the study period, hospital activity increased 10%, and the emergency department experienced a total of 222645 presentations, 68000 (30.5%) of which converted into an admission. THERMoSTAT improved NEAT compliance by 17% (from 57.7% to 74.9%) with no change in any patient-safety indicators. A total of 8432 medical emergency calls were made on 5930 patients, 2831 of whom were emergency admissions. After adjusting for hospital activity, there was no change in the average number of patients per week who triggered a medical emergency call after the introduction of THERMoSTAT. These results were reproduced when data was analysed for: total number of inpatients triggering calls; emergency admission patients; and emergency admission patients within the first 24h or first 4h of admission.Conclusions This is the first report to investigate the correlation between inpatient medical emergency call incidence and emergency department model of care. Medical emergency call data showed significant promise as a measure of morbidity and as a more direct, objective, simple, quantitative and meaningful measure of patient safety.What is known about the topic? It is well established that extended emergency department lengths of stay are associated with poorer patient outcomes. The corollary of this is not always true however; shorter emergency department length of stay does not automatically translate into better care. Although the underlying philosophy of NEAT is to enhance patient care, there is a risk of negative consequences if NEAT is seen as an end in itself. Many of the commonly used emergency department key performance indicators focus on the timeliness of care and there is a scarcity of easily quantifiable markers that reliably reflect the quality of that care.What does this paper add? This study builds on the concept of medical emergency call incidence as a marker of safety and quality. It explores the utility of using the number of medical emergency calls made in the first few hours of an emergency admission as an indicator of the quality of care delivered by the emergency department. This is significant because it introduces a measure that has a focus that embraces more than the timeliness of care only.What are the implications for practitioners? If medical emergency call incidence in early emergency admissions can be proven to accurately reflect emergency department quality of care then it would provide an easily monitored, objective, quantitative and prompt measure that evaluates dimensions other than timeliness. PMID- 29132500 TI - 'Falls not a priority': insights on discharging older people, admitted to hospital for a fall, back to the community. AB - Falls are common among older people and a leading cause of injury-related hospitalisation. The immediate post-hospitalisation period is a risky time for further falls. This paper explores discharge strategies from the perspectives of older people hospitalised for a fall and liaison nurses assisting people to return home. Exploratory mixed methods were used. Semi-structured interviews with older people were conducted regarding their experience of the fall and discharge strategies. Quality of life, falls risk and functional capacity were measured by questionnaire. Liaison nurses were also interviewed. Interviews were audio recorded, transcribed and thematically analysed. Mixed-method synthesis occurred using role-ordered matrix analysis. Older people (n=13) and liaison nurses (n=6) participated. Older persons' quality of life was average and falls risk high. Thematic analysis revealed three key themes: 'falls are not a priority', 'information not given, or given and not retained' and 'reduction in confidence and independence'. Role-ordered matrix analysis identified differences between acute and rehabilitative hospital stays. Older people hospitalised for a fall present a unique opportunity for implementation of falls prevention strategies. However, hospitalisation is often a time of crisis with competing priorities. Timing and relevance are crucial for optimal uptake of falls prevention strategies, with the primary care setting well-placed for their implementation. PMID- 29132501 TI - Low education levels are associated with early age of sexual debut, drug use and risky sexual behaviours among young Indigenous Australians. AB - : Background Earlier age at sexual debut is associated with drug and alcohol use, risky sexual behaviours and sexually transmissible infections (STI). METHODS: In the present study, 2320 young Indigenous Australians were surveyed. RESULTS: Most study participants had sex for the first time when they were 14 years or younger (79% and 67% for males and females respectively). More than 80% of participants were categorised as being in the high-risk category for the combined sexual risk factors (i.e. not using condoms, drunk or high at last sexual act, or three or more sexual partners in the past year). There was a linear decreasing trend between the proportion of males and females who had less than high school education and age at first sex (Ptrend<0.001). Compared with the highest quintile of age at first sexual debut (>=18 years), those in the bottom quintile (<15 years) were less likely to have completed high school (63% vs 32% respectively for males; 68% vs 26% respectively for females; Ptrend<0.001 for both). CONCLUSIONS: The findings of the present study suggest that sex education and STI prevention should start early when targeting Indigenous young people, with age appropriate messages. Sex education should be comprehensive and address individual risk behaviours, sexual agency and societal vulnerability to not only delay sexual debut, but also to emphasise the importance of STI prevention through condom use, which clearly already works to a certain extent with this group. PMID- 29132502 TI - Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals. AB - Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative analyses of mitochondrial proteomes, cellular transcriptomes and targeted metabolomics of five knockout mouse strains deficient in essential factors required for mitochondrial DNA gene expression, leading to OXPHOS dysfunction. Moreover, we describe sequential protein changes during post-natal development and progressive OXPHOS dysfunction in time course analyses in control mice and a middle lifespan knockout, respectively. Very unexpectedly, we identify a new response pathway to OXPHOS dysfunction in which the intra-mitochondrial synthesis of coenzyme Q (ubiquinone, Q) and Q levels are profoundly decreased, pointing towards novel possibilities for therapy. Our extensive omics analyses provide a high-quality resource of altered gene expression patterns under severe OXPHOS deficiency comparing several mouse models, that will deepen our understanding, open avenues for research and provide an important reference for diagnosis and treatment. PMID- 29132503 TI - Gyrification of the cerebral cortex requires FGF signaling in the mammalian brain. AB - Although it has been believed that the evolution of cortical folds was a milestone, allowing for an increase in the number of neurons in the cerebral cortex, the mechanisms underlying the formation of cortical folds are largely unknown. Here we show regional differences in the expression of fibroblast growth factor receptors (FGFRs) in the developing cerebral cortex of ferrets even before cortical folds are formed. By taking the advantage of our in utero electroporation technique for ferrets, we found that cortical folding was impaired in the ferret cerebral cortex when FGF signaling was inhibited. We also found that FGF signaling was crucial for producing Pax6-positive neural progenitors in the outer subventricular zone (OSVZ) of the developing cerebral cortex. Furthermore, we found that upper layers of the cerebral cortex were preferentially reduced by inhibiting FGF signaling. Our results shed light on the mechanisms of cortical folding in gyrencephalic mammalian brains. PMID- 29132505 TI - The Mobility and Impact of Frailty in the Intensive Care Unit. AB - Prevalence of pre-existing frailty in patients admitted to the intensive care unit (ICU) is increasing. Critical illness leads to a catabolic state that further diminishes body reserves and contributes to frailty independent of age and prehospital functional status. Because early mobilization of patients in the ICU results in accelerated recovery and improvement in functional status and quality of life, frailty can severely affect the mobility of patients in ICU ultimately prolonging recovery. Understanding the concept of frailty and the association of frailty and its impact on mobility in the ICU, identifying patients, and timely resource allocation helps in optimum care and improves clinical outcomes. PMID- 29132504 TI - A transatlantic perspective on 20 emerging issues in biological engineering. AB - Advances in biological engineering are likely to have substantial impacts on global society. To explore these potential impacts we ran a horizon scanning exercise to capture a range of perspectives on the opportunities and risks presented by biological engineering. We first identified 70 potential issues, and then used an iterative process to prioritise 20 issues that we considered to be emerging, to have potential global impact, and to be relatively unknown outside the field of biological engineering. The issues identified may be of interest to researchers, businesses and policy makers in sectors such as health, energy, agriculture and the environment. PMID- 29132507 TI - Management of Traumatic Brain Injury. AB - Traumatic brain injury remains a serious public health problem, causing death and disability for millions. In order to maximize outcomes in the face of a complex injury to a complex organ, a variety of advanced neuromonitoring techniques may be used to guide surgical and medical decision-making. Because of the heterogeneity of injury types and the plethora of treatment confounders present in this patient population, the scientific study of specific interventions is challenging. This challenge highlights the need for a firm understanding of the anatomy and pathophysiology of brain injuries when making clinical decisions in the intensive care unit. PMID- 29132508 TI - Brain Death. AB - Death determined by neurologic criteria, commonly referred to as "brain death," occurs when function of the entire brain ceases, including the brain stem. Diagnostic criteria for brain death are explicit but controversy exists regarding nuances of the evaluation and potential confounders of the examination. Hospitals and ICU teams should carefully consider which clinicians will perform brain death testing and should use standard processes, including checklists to prevent diagnostic errors. Proper diagnosis is essential because misdiagnosis can be catastrophic. Timely, accurate brain death determination and aggressive physiologic support are cornerstones of both good end-of-life care and successful organ donation. PMID- 29132506 TI - Intensive Care Unit Delirium and Intensive Care Unit-Related Posttraumatic Stress Disorder. AB - Delirium is one of the most common behavioral manifestations of acute brain dysfunction in the intensive care unit (ICU) and is a strong predictor of worse outcome. Routine monitoring for delirium is recommended for all ICU patients using validated tools. In delirious patients, a search for all reversible precipitants is the first line of action and pharmacologic treatment should be considered when all causes have been ruled out, and it is not contraindicated. Long-term morbidity has significant consequences for survivors of critical illness and for their caregivers. ICU patients may develop posttraumatic stress disorder related to their critical illness experience. PMID- 29132509 TI - Goals of Care and End of Life in the ICU. AB - Despite advances in surgical critical care, critical illness remains traumatic and has long-term adverse sequelae. Unrealistic expectations and erroneous assumptions about outcomes acceptable to patients have been identified as drivers of goal-discordant treatment. Goal setting in the ICU begins with compassionately delivered, accurate, and honest prognostic information. Through skilled communication and shared decision making, clinicians forge a mutual understanding of patient values and priorities and the role of therapeutic options in achieving patient goals. Ensuring that treatment is goal-concordant and meets physical, psychosocial, existential, and spiritual needs is crucial for attaining optimal patient and caregiver outcomes, independent of survival. PMID- 29132510 TI - Indications and Methods of Anticoagulation Reversal. AB - The use of anticoagulation in the prevention of strokes due to atrial fibrillation or the treatment of venous thromboembolic disease has been on the rise. With the advent and proliferation of direct oral anticoagulation medications, the management of anticoagulation reversal has become increasingly complex, especially when urgent or emergent reversal is required. This review details the commonly used parenteral and oral anticoagulants, the treatment strategies necessary for their reversal, and therapies still in development. PMID- 29132511 TI - Resuscitation for Hypovolemic Shock. AB - Hemorrhage is the leading cause of preventable deaths in trauma patients. After presenting a brief history of hemorrhagic shock resuscitation, this article discusses damage control resuscitation and its adjuncts. Massively bleeding patients in hypovolemic shock should be treated with damage control resuscitation principles including limited crystalloid, whole blood or balance blood component transfusion to permissive hypotension, preventing hypothermia, and stopping bleeding as quickly as possible. PMID- 29132512 TI - Ultrasound and Other Innovations for Fluid Management in the ICU. AB - Ultrasound is a user-dependent tool that can help guide therapy. The use of ultrasound to guide central line placement decreases complication rates. Cardiac ultrasound can help with the diagnosis of cases of hypotension. Lung and pleura ultrasound is a useful adjunct for diagnosis causes of desaturation. Abdominal ultrasound can help in rapid visitation of fluid and intra-abdominal structures. PMID- 29132513 TI - Sepsis and Septic Shock Strategies. AB - Three therapeutic principles most substantially improve organ dysfunction and survival in sepsis: early, appropriate antimicrobial therapy; restoration of adequate cellular perfusion; timely source control. The new definitions of sepsis and septic shock reflect the inadequate sensitivity, specify, and lack of prognostication of systemic inflammatory response syndrome criteria. Sequential (sepsis-related) organ failure assessment more effectively prognosticates in sepsis and critical illness. Inadequate cellular perfusion accelerates injury and reestablishing perfusion limits injury. Multiple organ systems are affected by sepsis and septic shock and an evidence-based multipronged approach to systems based therapy in critical illness results in improve outcomes. PMID- 29132514 TI - Ventilator Strategies for Chronic Obstructive Pulmonary Disease and Acute Respiratory Distress Syndrome. AB - The management of the ventilator in patients with chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS) has a dramatic effect on the overall outcome. The incidence of COPD is increasing as the US population grows older. The most effective means to deal with pulmonary complications is to avoid them, but both COPD and ARDS have evidence-based interventions that have been shown to improve outcomes. Pulmonary complications affect up to 40% of patients, and their occurrence is associated with an increased duration of hospital stay, and an increased mortality. PMID- 29132515 TI - Acute Kidney Injury in the Critically Ill. AB - Acute kidney injury (AKI) occurs frequently in the surgical intensive care unit and results in significant morbidity and mortality. AKI needs to be identified early and underlying causes treated or eliminated. Sepsis, major surgery such as coronary artery bypass, and hypovolemia are the most common causes and patients with underlying comorbidities have increased susceptibility. Treatment should begin by ensuring that patients are adequately resuscitated and all contributing causes are replaced or eliminated. After stabilization of hemodynamic status and elimination of contributing causes, treatment becomes largely supportive and may require the use of a renal replacement therapy. PMID- 29132516 TI - Decompensated Cirrhosis and Fluid Resuscitation. AB - The critically ill patient with decompensated cirrhosis has a unique physiology and alterations in albumin that need to be understood to properly resuscitate them and minimize morbidity and mortality. Little data exist on specific resuscitation of the patient with cirrhosis compared with those patients without liver disease. The effectiveness of albumin administration compared with saline administration in common settings, such as large-volume paracentesis, can be extrapolated to the care of the general surgical patient but further studies in this area are warranted. This article enhances the understanding of unique physiology of the patient with decompensated cirrhosis to guide their needs in fluid resuscitation in critical illness. PMID- 29132517 TI - Surgical Critical Care: Gastrointestinal Complications. AB - Critical illness and injury affect the gastrointestinal tract almost uniformly. Complications include the sequelae of direct intestinal injury and repair, impaired motility, intra-abdominal hypertension, and ulceration, among others. Contemporary clinical practice has incorporated many advances in the prevention and treatment of gastrointestinal complications during critical illness. This article discusses the epidemiology, risk factors, means of diagnosis, treatment, and prevention of some of these compilations. PMID- 29132518 TI - Foreword. PMID- 29132519 TI - What's New in Surgery Critical Care? PMID- 29132520 TI - Gastroesophageal Reflux Disease. AB - Gastroesophageal reflux disease (GERD) is a gastrointestinal motility disorder that results from the reflux of stomach contents into the esophagus or oral cavity resulting in symptoms or complications. The typical symptoms of GERD are heartburn and regurgitation of gastric contents into the oropharynx. GERD affects quality of life and may cause erosive esophagitis, esophageal strictures, and Barrett esophagus, a precursor to esophageal adenocarcinoma. GERD is a clinical diagnosis and is most effectively treated with proton-pump inhibitors (PPIs). Long-term use of PPIs is associated with bone fractures, chronic renal disease, acute renal disease, community-acquired pneumonia, and Clostridium difficile intestinal infection. PMID- 29132521 TI - Gallbladder Dysfunction: Cholecystitis, Choledocholithiasis, Cholangitis, and Biliary Dyskinesia. AB - The prevalence of gallstones is 10% to 15% in adults. Individuals with acute cholecystitis present with right upper quadrant pain, fever, and leukocytosis. Management includes supportive care and cholecystectomy. The prevalence of choledocholithiasis is 10% to 20%, and serious complications include cholangitis and gallstone pancreatitis. The goal of management in individuals with choledocholithiasis consists of clearing common bile duct stones. Acute ascending cholangitis is a life-threatening condition involving acute inflammation and infection of the common bile duct. Treatment includes intravenous fluids, analgesia, intravenous antibiotics, and biliary drainage and decompression. Biliary dyskinesia includes motility disorders resulting in biliary colic in the absence of gallstones. PMID- 29132522 TI - Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) defines a condition of hepatic steatosis with or without hepatic injury. NAFLD is increasing in prevalence worldwide and presents a public health burden. Most patients are asymptomatic, although some present with fatigue and right upper quadrant pain. NAFLD is discovered incidentally when patients have elevated liver enzymes or fatty liver is seen on imaging modalities. Imaging studies can confirm fatty deposits in the liver, but needle biopsy is needed to determine degree of inflammation. The mainstay of treatment is weight loss and controlling diabetes and hyperlipidemia. Liver transplantation is considered when disease progresses to cirrhosis. PMID- 29132523 TI - Pancreatitis and Pancreatic Cancer. AB - Most cases of acute pancreatitis are related to gallstones. More than 80% resolve within a few days. The diagnosis is based on upper abdominal pain, elevated lipase and/or amylase, and transabdominal ultrasound findings. Management requires early aggressive hydration, pain control, nutritional support, and monitoring for progression. Patients who develop hypovolemia, systemic inflammatory response, pancreatic necrosis, and organ failure have high mortality, risk of recurrence, and progression to chronic pancreatitis (CP). Genetic predisposition and repeated injury may be necessary for CP. Management requires control of pain and exocrine and endocrine symptoms, plus reduction of risk factors, especially alcohol intake. PMID- 29132524 TI - Hepatitis A and B Infections. AB - Hepatitis A virus causes acute viral hepatitis, presenting with jaundice, nausea, and vomiting. Symptoms are self-limited and treated symptomatically. Routine vaccination of infants has greatly reduced the incidence in the United States. Vaccination is recommended for all infants and adults at increased risk. Hepatitis B virus can cause acute and chronic viral hepatitis. Acute hepatitis B is usually self-limited, but can develop into a chronic infection. Patients are at highest risk for developing chronic disease if they are infected at a younger age. Routine vaccination and universal screening of pregnant women has decreased the transmission of hepatitis B virus. PMID- 29132525 TI - Hepatitis C: A New Era. AB - More than 2 million Americans are infected with hepatitis C virus (HCV), and only about half are aware that they are infected. Primarily blood-borne, risk factors for the virus include injection or intranasal drug use, unregulated tattoos, incarceration, and blood transfusion before 1992. In addition, 75% of those with the virus were born between 1945 and 1965, thus making the baby-boomer cohort a population of screening interest. Because acute and early chronic HCV are often asymptomatic, screening of at-risk individuals is of utmost importance. Left untreated, HCV can go on to produce significant hepatic and extrahepatic manifestations. PMID- 29132526 TI - Diverticular Disease of the Gastrointestinal Tract. AB - Almost all gastrointestinal tract diverticula require no intervention if they are asymptomatic. There is no clear diagnostic modality of choice for diagnosis and surveillance of diverticulum. Medical treatment should be attempted before surgical intervention because significant morbidity is may be associated with resection. PMID- 29132527 TI - Irritable Bowel Syndrome: Epidemiology, Pathophysiology, Diagnosis, and Treatment. AB - Irritable bowel syndrome is a common medical condition that significantly alters patient quality of life and presents a series of diagnostic and treatment challenges to the treating provider. This article provides an updated and straightforward overview of the disease, its pathophysiology, diagnosis, and treatment options. PMID- 29132528 TI - An Update on Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) includes 2 chronic idiopathic inflammatory diseases: ulcerative colitis and Crohn disease. The incidence and prevalence of IBD is increasing worldwide. It can affect people of all ages, including children and geriatric populations, and can impact all aspects of life. In this article, diagnosis and treatment of IBD in adults, pediatric, pregnant, and elderly populations are explored from the perspective of a primary care physician. PMID- 29132529 TI - Celiac Disease and Gluten Sensitivity. AB - Celiac disease is an immune-mediated enteropathy triggered by gluten that affects genetically predisposed individuals, typically causing intestinal symptoms and malabsorption. Diagnosis requires stepwise evaluation with anti-tissue transglutaminase IgA and histologic analysis of the small bowel. Strict adherence to a gluten-free diet is the primary treatment. Patients with symptoms thought to be related to gluten but without evidence of celiac disease are difficult to diagnose and treat. Consider first advising general nutritional improvements. If symptoms persist, involve a trained dietitian for restrictive diets and consider evaluation for small intestinal bacterial overgrowth or other treatments for irritable bowel syndrome. PMID- 29132530 TI - Diagnosis and Management of Anorectal Disorders in the Primary Care Setting. AB - Anorectal disorders are very common among a wide population of patients. Because patients may be embarrassed about the anatomic location of their symptoms, they may present to care late in the course of their illness. Care should be taken to validate patient concerns and normalize fears. This article discusses the diagnoses and management of common anorectal disorders among patients presenting to a primary care physician. PMID- 29132531 TI - Gastrointestinal Malignancies. AB - This article reviews esophageal, gastric, and colon cancers for the primary care physician. Risk factors, demographics, and screening are discussed. The rise of Western lifestyle has been a mixed blessing for these cancers. Our modern world has led to the decline of gastric cancer from the leading cause of cancer death before the 1930s to the 13th leading cause of cancer death now. Conversely, esophageal cancer is increasing faster than any other cancer. Screening for esophageal and gastric cancer is not practical in the West, but screening for colon cancer is gratifying for the patient and physician. PMID- 29132532 TI - Emerging Topics in Gastroenterology. AB - The bacteria and fungi in the human gut make up a community of microorganisms that lives in symbiosis with humans, engaging in numerous diverse interactions that influence health. This article outlines the current knowledge on emerging topics in gastroenterology, including microbiome and probiotics, fecal microbiota transplantation, cyclic vomiting syndrome, eosinophilic esophagitis, and microscopic colitis. PMID- 29132533 TI - Erratum. PMID- 29132534 TI - Bugs, Drugs, and the Unknown. PMID- 29132535 TI - Gastroenterology. PMID- 29132536 TI - Effects of acute hyperinsulinemia on skeletal muscle mitochondrial function, reactive oxygen species production, and metabolism in premenopausal women. AB - BACKGROUND: Acute metabolic demands that promote excessive and/or prolonged reactive oxygen species production may stimulate changes in mitochondrial oxidative capacity. PURPOSE: To assess changes in skeletal muscle H2O2 production, mitochondrial function, and expression of genes at the mRNA and protein levels regulating energy metabolism and mitochondrial dynamics following a hyperinsulinemic-euglycemic clamp in a cohort of 11 healthy premenopausal women. METHODS: Skeletal muscle biopsies of the vastus lateralis were taken at baseline and immediately following the conclusion of a hyperinsulinemic euglycemic clamp. Mitochondrial production of H2O2 was quantified fluorometrically and mitochondrial oxidation supported by pyruvate, malate, and succinate (PMS) or palmitoyl carnitine and malate (PCM) was measured by high resolution respirometry in permeabilized muscle fiber bundles. mRNA and protein levels were assessed by real time PCR and Western blotting. RESULTS: H2O2 emission increased following the clamp (P<0.05). Coupled respiration (State 3) supported by PMS and the respiratory control ratio (index of mitochondrial coupling) for both PMS and PCM were lower following the clamp (P<0.05). IRS1 mRNA decreased, whereas PGC1alpha and GLUT4 mRNA increased following the clamp (P<=0.05). PGC1alpha, IRS1, and phosphorylated AKT protein levels were higher after the clamp compared to baseline (P<0.05). CONCLUSIONS: This study demonstrated that acute hyperinsulinemia induced H2O2 production and a concurrent decrease in coupling of mitochondrial respiration with ATP production in a cohort of healthy premenopausal women. Future studies should determine if this uncoupling ameliorates peripheral oxidative damage, and if this mechanism is impaired in diseases associated with chronic oxidative stress. PMID- 29132537 TI - NFIL3 is a negative regulator of hepatic gluconeogenesis. AB - OBJECTIVE: Nuclear factor interleukin-3 regulated (NFIL3) has been known as an important transcriptional regulator of the development and the differentiation of immune cells. Although expression of NFIL3 is regulated by nutritional cues in the liver, the role of NFIL3 in the glucose metabolism has not been extensively studied. Thus, we wanted to explore the potential role of NFIL3 in the control of hepatic glucose metabolism. MATERIALS/METHODS: Mouse primary hepatocytes were cultured to perform western blot analysis, Q-PCR and chromatin immunoprecipitation assay. 293T cells were cultured to perform luciferase assay. Male C57BL/6 mice (fed a normal chow diet or high fat diet for 27weeks) as well as ob/ob mice were used for experiments with adenoviral delivery. RESULTS: We observed that NFIL3 reduced glucose production in hepatocytes by reducing expression of gluconeogenic gene transcription. The repression by NFIL3 required its basic leucine zipper DNA binding domain, and it competed with CREB onto the binding of cAMP response element in the gluconeogenic promoters. The protein levels of hepatic NFIL3 were decreased in the mouse models of genetic- and diet induced obesity and insulin resistance, and ectopic expression of NFIL3 in the livers of insulin resistant mice ameliorated hyperglycemia and glucose intolerance, with concomitant reduction in expression of hepatic gluconeogenic genes. Finally, we witnessed that knockdown of NFIL3 in the livers of normal chow fed mice promoted elevations in the glucose levels and expression of hepatic gluconeogenic genes. CONCLUSIONS: In this study, we showed that NFIL3 functions as an important regulator of glucose homeostasis in the liver by limiting CREB mediated hepatic gluconeogenesis. Thus, enhancement of hepatic NFIL3 activity in insulin resistant state could be potentially beneficial in relieving glycemic symptoms in the metabolic diseases. PMID- 29132538 TI - Immunometabolic profiling of T cells from patients with relapsing-remitting multiple sclerosis reveals an impairment in glycolysis and mitochondrial respiration. AB - BACKGROUND: Metabolic reprogramming is shaped to support specific cell functions since cellular metabolism controls the final outcome of immune response. Multiple sclerosis (MS) is an autoimmune disease resulting from loss of immune tolerance against central nervous system (CNS) myelin. Metabolic alterations of T cells occurring during MS are not yet well understood and their studies could have relevance in the comprehension of the pathogenetic events leading to loss of immune tolerance to self and to develop novel therapeutic strategies aimed at limiting MS progression. METHODS AND RESULTS: In this report, we observed that extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), indicators of glycolysis and oxidative phosphorylation, respectively, were impaired during T cell activation in naive-to-treatment relapsing remitting (RR)MS patients when compared with healthy controls. These results were also corroborated at biochemical level by a reduced expression of the glycolitic enzymes aldolase, enolase 1, hexokinase I, and by reduction of Krebs cycle enzymes dihydrolipoamide-S-acetyl transferase (DLAT) and dihydrolipoamide-S succinyl transferase (DLST). Treatment of RRMS patients with interferon beta-1a (IFN beta-1a) was able to restore T cell glycolysis and mitochondrial respiration as well as the amount of the metabolic enzymes to a level comparable to that of healthy controls. These changes associated with an up-regulation of the glucose transporter-1 (GLUT-1), a key element in intracellular transport of glucose. CONCLUSIONS: Our data suggest that T cells from RRMS patients display a reduced engagement of glycolysis and mitochondrial respiration, reversible upon IFN beta 1a treatment, thus suggesting an involvement of an altered metabolism in the pathogenesis of MS. PMID- 29132540 TI - Current Strategies for the Delivery of Therapeutic Proteins and Enzymes to Treat Brain Disorders. AB - Brain diseases and injuries are growing to be one of the most deadly and costly medical conditions in the world. Unfortunately, current treatments are incapable of ameliorating the symptoms let alone curing the diseases. Many brain diseases have been linked to a loss of function in a protein or enzyme, increasing research for improving their delivery. This is no easy task due to the delicate nature of proteins and enzymes in biological conditions, as well as the many barriers that exist in the body ranging from those in circulation to the more specific barriers to enter the brain. Several main techniques are being used (physical delivery, protein/enzyme conjugates, and nanoparticle delivery) to overcome these barriers and create new therapeutics. This review will cover recently published data and highlights the benefits and deficits of possible new protein or enzyme therapeutics for brain diseases. PMID- 29132539 TI - The diabetic heart utilizes ketone bodies as an energy source. AB - BACKGROUND: Diabetic heart is characterized by failure of insulin to increase glucose uptake and increasingly relies on free fatty acids (FFAs) as a source of fuel in animal models. However, it is not well known how cardiac energy metabolism is altered in diabetic hearts in humans. We examined cardiac fuel metabolism in the diabetics as compared to non-diabetics who underwent cardiac catheterization for heart diseases. MATERIAL AND METHODS: The study subjects comprised 81 patients (male 55, female 26, average age 63.0+/-10.0years) who underwent the cardiac catheterization for heart diseases. Thirty-six patients were diagnosed as diabetics (diabetic group) and 45 as non-diabetics (non diabetic group). Blood samplings were done in both the aortic root (Ao) and coronary sinus (CS) simultaneously and the plasma levels of FFAs, glucose, lactate, pyruvate, total ketone bodies and beta-hydroxybutyrate were measured and compared between the two groups. RESULTS: The myocardial uptake of glucose, lactate and pyruvate were decreased, whereas those of total ketone bodies, beta hydroxybutyrate and acetoacetate were increased in the diabetics as compared to the non-diabetics. However, the myocardial uptakes of FFAs were not significantly increased in the diabetics as compared to the non-diabetics. CONCLUSIONS: Cardiac uptakes of carbohydrate (glucose, lactate and pyruvate) were decreased, whereas those of total ketone bodies and beta-hydroxybutyrate were increased in the diabetics as compared to the non-diabetics in humans. Ketone bodies therefore are utilized as an energy source partially replacing glucose in the human diabetic heart. PMID- 29132542 TI - Impact of Inflammation on the Blood-Neural Barrier and Blood-Nerve Interface: From Review to Therapeutic Preview. AB - A number of nervous system disorders are characterized by a state of inflammation (neuroinflammation) in which members of the innate immune system, most notably mast cells and microglia-acting as single entities and in unison-produce inflammatory molecules that play major roles. A neuroinflammatory environment can weaken not only blood-nerve and blood-brain barrier (BBB) integrity but also that of the blood-spinal cord barrier. Mast cells, with their distribution in peripheral nerves and the central nervous system, are positioned to influence blood-nerve barrier characteristics. Being close also to the perivasculature and on the brain side of the BBB, the mast cell is well positioned to disrupt BBB function. Interestingly, tissue damage and/or stress activates homeostatic mechanisms/molecules expressed by mast cells and microglia, and includes N acylethanolamines. Among the latter, N-palmitoylethanolamine has distinguished itself as a key component in supporting homeostasis of the organism against external stressors capable of provoking inflammation. This review will discuss the pathobiology of neuroinflammation with emphasis on mast cells and microglia, their roles in BBB health, and novel therapeutic opportunities, including nanoscale delivery for targeting these immune cells with a view to maintain the BBB. PMID- 29132541 TI - Novel Treatment Strategies Using TiO2-Nanowired Delivery of Histaminergic Drugs and Antibodies to Tau With Cerebrolysin for Superior Neuroprotection in the Pathophysiology of Alzheimer's Disease. AB - More than 5.5 million Americans of all ages are suffering from Alzheimer's disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (AbetaP) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated AbetaP deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation. PMID- 29132544 TI - Histaminergic Receptors Modulate Spinal Cord Injury-Induced Neuronal Nitric Oxide Synthase Upregulation and Cord Pathology: New Roles of Nanowired Drug Delivery for Neuroprotection. AB - The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a rat model. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flow at 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO2-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCI-induced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist alpha-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous system thwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors. PMID- 29132543 TI - Intravenous Administration of Functionalized Magnetic Iron Oxide Nanoparticles Does Not Induce CNS Injury in the Rat: Influence of Spinal Cord Trauma and Cerebrolysin Treatment. AB - Influence of iron oxide magnetic nanoparticles (IOMNPs, 10nm in diameter, 0.25 or 0.50mg/mL in 100MUL, i.v.) on the blood-brain barrier (BBB) permeability, edema formation, and neuronal or glial changes within 4-24h after administration was examined in normal rats and after a focal spinal cord injury (SCI). Furthermore, effect of cerebrolysin, a balanced composition of several neurotrophic factors, and active peptide fragments was also evaluated on IOMNP-induced changes in central nervous system (CNS) pathology. The SCI was inflicted in rats by making a longitudinal incision into the right dorsal horn of the T10-11 segments and allowed to survive 4 or 24h after trauma. Cerebrolysin (2.5mL/kg, i.v.) was given either 30min before IOMNP injection in the 4-h SCI group or 4h after injury in the 24-h survival groups. Control group received cerebrolysin in identical situation following IOMNP administration. In all groups, leakage of serum albumin in the CNS as a marker of BBB breakdown and activation of astrocytes using glial fibrillary acidic protein was evaluated by immunohistochemistry. The neuronal injury was examined by Nissl staining. The IOMNPs alone in either low or high doses did not induce CNS pathology either following 4 or 24h after administration. However, administration of IOMNPs in SCI group slightly enhanced the pathological changes in the CNS after 24h but not 4h after trauma. Cerebrolysin treatment markedly attenuated IOMNP-induced aggravation of SCI induced cord pathology and induced significant neuroprotection. These observations are the first to show that IOMNPs are safe for the CNS and cerebrolysin treatment prevented CNS pathology following a combination of trauma and IOMNP injection. This indicated that cerebrolysin might be used as adjunct therapy during IOMNP administration in disease conditions, not reported earlier. PMID- 29132545 TI - Nanoformulation: A Useful Therapeutic Strategy for Improving Neuroprotection and the Neurorestorative Potential in Experimental Models of Parkinson's Disease. AB - Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, but current therapies are only symptomatic. Experimental models are necessary to go deeper in the comprehension of pathophysiological mechanism and to assess new therapeutic strategies. The unilateral 6-hydroxydopamine (6-OHDA) lesion either in medial forebrain bundle (MFB) or into the striatum in rats affords to study various stages of PD depending on the evolution time lapsed. A promising alternative to address the neurodegenerative process is the use of neurotrophic factors; but its clinical use has been limited due to its short half-life and rapid degradation after in vivo administration, along with difficulties for crossing the blood-brain barrier (BBB). Tyrosine hydroxylase (TH) immunostaining revealed a significant decrease of the TH-immunopositive striatal volume in 6 OHDA group from rostral to caudal one. The loss of TH-ir neurons and axodendritic network (ADN) was higher in caudal sections showing a selective vulnerability of the topological distributed dopaminergic system. In addition to a remarkable depletion of dopamine in the nigrostriatal system, the administration of 6-OHDA into MFB induces some other neuropathological changes such as an increase of glial fibrillary acidic protein (GFAP) positive cells in substantia nigra (SN) as well as in striatum. Intrastriatal implantation of micro- or nanosystems delivering neurotrophic factor in parkinsonized rats for bypassing BBB leads to a significative functional and morphological recovery. Neurorestorative morphological changes (preservation of the TH-ir cells and ADN) along the rostrocaudal axis of caudoputamen complex and SN have been probed supporting a selective recovering after the treatment as well. Others innovative therapeutic strategies, such as the intranasal delivery, have been recently assessed in order to search the NTF effects. In addition some others methodological key points are reviewed. PMID- 29132546 TI - Preface. PMID- 29132547 TI - Distribution of genes encoding resistance to aminoglycoside modifying enzymes in methicillin-resistant Staphylococcus aureus (MRSA) strains. AB - Today Methicillin-Resistant Staphylococcus aureus (MRSA) have acquired multiple resistance to a wide range of antibiotics including aminoglycosides. So, this study was aimed to investigate the rate of aminoglycoside resistance and the frequency of aminoglycoside resistance mediated genes of aac(Ia)-2, aph(3)-IIIa and ant(4')-Ia among MRSA strains. A total of 467 staphylococci isolates were collected from various clinical samples. S. aureus strains were identified by standard culture and identification criteria and investigating of presence of 16S rRNA and nuc genes. Cefoxitin disk diffusion, and oxacillin-salt agar screening methods were used to detect the MRSA strains with subsequent molecular identification for the presence of mecA gene. Antibiotic susceptibility of MRSA strains against aminoglycoside antibiotics was evaluated by using agar disk diffusion method. Multiplex PCR for the presence of aac(Ia)-2, aph(3)-IIIa and ant(4')-Ia encoding genes for aminoglycosides were performed for MRSA strains. From total staphylococci tested isolates, 262 (56.1%) were identified as S. aureus, of which 161 (61.45%) were detected as MRSA and all comprised mecA gene. The resistance pattern of MRSA strains to aminoglycoside antibiotics were: gentamicin 136 (84.5%); amikacin 125 (77.6%); kanamycin 139 (86.3%); tobramycin 132 (82%); and neomycin 155 (96.3%). The frequency of aac(Ia)-2, aph(3)-IIIa, and ant(4')-Ia genes among MRSA strains, were 64%, 42% and 11.8% respectively. In conclusion, as MRSA strains are of great concern in human infections, the results of present study could provide a useful resource for health sectors for choosing appropriate antibiotics for the effective treatment of infections due to MRSA strains. PMID- 29132548 TI - Excretory/secretory proteases and mechanical movement of Anisakis pegreffii infective larvae in the penetration of BALB/c mice gastrointestine. AB - Anisakiasis is a human parasitic disease caused by infection with the infective larvae of Anisakis. Accidental infection in humans causes the gastrointestinal pathophysiological effects of mechanical tissue damage by migrating larvae. The mechanism of the infective larval invasion and migration is suspected to involve larval excretory/secretory proteases and motility. This study demonstrates the penetration rate of the infective larvae of Anisakis pegreffii in mouse gastrointestine depends on the time after infection, and that only 15% of larvae remain in the gastrointestinal tract 3 h after infection. Strong activities of matrix metalloproteinases (MMPs) and serine proteases, especially plasmin, were found in the excretory/secretory products of A. pegreffii; these can be inhibited by ONO-4817 and phenylmethylsulfonyl fluoride, respectively. The protease activity was also significantly decreased in another 1 h of cultivation of larvae in fresh 0.9% normal saline (NS) after previous cultivation for 48 h in NS. The motility scores of larvae were significantly lower after 48 h of cultivation in NS. The penetration rate of A. pegreffii larvae in the gastrointestine of infected mice sequentially were 90% in the freshly prepared, 68% in serine protease inhibited, 55% in MMPs inhibited larvae, and 16% in larvae cultivated in NS for 48 h. Therefore, this study demonstrates that MMPs and serine proteases excreted and secreted by A. pegreffii and the mechanical movement of infective larvae participate in the penetration of the gastrointestine of mice after infection. PMID- 29132549 TI - Association of copy number variations in complement factor H-Related genes among age-related macular degenerative subjects. AB - Age-related macular degeneration (AMD) is the most widely recognised cause of irreversible vision loss and previous studies have suggested that the advancement of wet AMD is influenced by both modifiable and non-modifiable elements. Single nucleotide polymorphism (SNPs) and copy number of variations (CNVs) have been associated with AMD in various populations, however the results are conflicting. Our aim is to determine the CNVs of Complement Factor H-Related genes among Malaysian subjects with wet AMD. 130 patients with wet AMD and 120 healthy controls were included in this research. DNA was extracted from all subjects and CNVs of CFH, CFHR1 and CFHR3 genes; determined using quantitative real-time PCR and were compared between the two groups. A consistent association was observed between CFH gene and wet AMD susceptibility (P < 0.05). The age-adjusted data suggests a possible increased risk of AMD disease (P < 0.05). No correlation was detected between CNVs and wet AMD for the remaining genes after we compared the frequencies of mean for that gene. An association was observed between CFH CNVs and wet AMD in the Malaysian population, however, strong evidence of a link with wet AMD was not found. Further investigative studies are needed using larger sample sizes to elucidate the role of CNVs in AMD pathogenesis. PMID- 29132550 TI - Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis. AB - The current study is a retrospective analysis of 49 patients with bone metastatic prostate cancer: 26 receiving androgen deprivation therapy (ADT) alone versus 23 receiving cytoreductive cryosurgery of the primary tumor plus ADT treatment. Progression-free survival (PFS) was the primary outcome variable, and Cox proportional hazards regression analysis was used to identify predictors for PFS. The baseline characteristics were generally comparable between the 2 groups. Median follow-up time was 41 months (range 24-56) and 37 months (range 19-53) in ADT alone group and cryosurgery groups, respectively. Patients receiving cryosurgery had significantly longer PFS (35 vs 25 months, P = 0.0027) and time to castration resistance (36 vs 25 months, P = 0.0011). Cox multivariate analysis associated longer PFS with the following factors: cryosurgery (HR0.207, 95% CI 0.094-0.456), lower prostate specific antigen at diagnosis (<=100 ng/ml, HR0.235, 95% CI 0.072-0.763) and lower Gleason score (<=7, HR0.195, 95% CI 0.077-0.496). Cryosurgery reduced the risk of progression by 79.3%. In conclusion, cytoreductive cryosurgery of the primary tumor in patients with bone metastatic prostate cancer could reduce the risk of progression and delay time to castration resistant prostate cancer. PMID- 29132551 TI - Vonoprazan treatment improves gastrointestinal symptoms in patients with gastroesophageal reflux disease. AB - The effects of vonoprazan, a new potassium-competitive acid blocker, on gastroesophageal reflux disease (GERD) symptom are not fully elucidated. The aim of this study is to determine the effect of vonoprazan on GERD and associated gastrointestinal symptoms. We retrospectively reviewed 88 Helicobacter pylori negative patients with GERD treated with vonoprazan 10 mg daily. Symptoms were evaluated using the Izumo scale, which reflects quality of life related to various abdominal symptoms. The rates of improvement and resolution of GERD symptoms were 86% (76/88) and 57% (50/88), respectively. Improvement and resolution in patients with erosive esophagitis was higher than in those with non erosive reflux disease (91% vs 83%, p = 0.260 and 71% vs 47%, p = 0.025, respectively). We attempted to identify factors which predict the effects of vonoprazan. Multivariate analysis identified advanced age (>=60-year-old) (odds ratio [OR] 7.281, 95% confidence interval [CI] 2.056-25.776, p = 0.002), obesity (BMI >= 24) (OR 3.342, 95%CI 1.124-9.940, p = 0.030) and erosive esophagitis (OR 4.368, 95%CI 1.281-14.895, p = 0.018) as positive predictors of resolution of GERD symptoms. Alcohol use (OR 0.131, 95%CI 0.027-0.632, p = 0.011) and history of H. pylori eradication (OR 0.171, 95%CI 0.041-0.718, p = 0.015) were identified as negative predictors. Vonoprazan also improved epigastric pain (73%), postprandial distress (60%), constipation (58%) and diarrhea (52%) in patients with GERD. In conclusion, vonoprazan 10 mg daily is effective in improving GERD symptoms. Advanced age, obesity, erosive esophagitis, alcohol use and history of H. pylori eradication influence the resolution of GERD symptoms. Treatment with vonoprazan favorably affects gastrointestinal symptoms in patients with GERD. PMID- 29132552 TI - Intravenous drug abuse is a risk factor in the failure of two-stage treatment for infected total hip arthroplasty. AB - Reinfection after two-stage revision hip arthroplasty (RHA) is still a complex issue. Only few studies revealed the factors affecting the success rate in the treatment of periprosthetic hip infection (PHI), especially risk factors. A retrospective study was conducted using records of 30 patients underwent two stage RHA for infected total hip arthroplasty (THA). Treatment was defined as successful if a patient did not need any reoperation or invasive procedure such as image-guided drainage during the two years after reimplantation. Treatment was defined as failure if any surgery or invasive procedure or long-term antibiotic suppression was considered necessary to control infection. Four patients had infection recurrence defined as failed and three of them had intravenous drug abuse. Twenty-six patients had no infection recurrence at the end of follow-up and one of them had intravenous drug abuse but quitting after surgery. We suggest that once adequate cleaning up achieved, risk of reinfection may be little even in immunocompromised patients with RHA because of relative less old age than those with revisional total knee arthroplasty. Patients of the reinfection group were younger and non-obese with adequate nutritional status. We may consider intravenous drug abuse could take a great toll on health and lead to reinfection. Finally, we suggest performing the gold-standard two-stage reimplantation technique to manage cases with infection, educating drug abusers regarding the risk of surgical failure, and implementing a quitting program at least 1 year before the index surgery. PMID- 29132553 TI - Dysregulation of glucose metabolism since young adulthood increases the risk of cardiovascular diseases in patients with bipolar disorder. AB - Aging patients with bipolar disorder (BD) are at a high risk of cardiovascular diseases (CVDs). However, few studies have directly examined the association between metabolic risks and CVDs in patients with BD across the lifespan. Therefore, the aim of this study was to determine lifetime metabolic risk factors for CVDs in patients with BD. We recruited BD-I patients who were more than 50 years old and had had at least one psychiatric hospitalization. Patients who had a cardiologist-confirmed CVD diagnosis (ICD-9 code 401-414) were assigned to the case group. Fifty-five cases were matched with 55 control patient without CVDs based on age and sex. Clinical data were obtained by retrospectively reviewing 30 years of hospital records. Compared to control subjects, a significantly higher proportion of cases had impaired fasting glucose between ages 31 and 40 (44.0% versus 17.4%, p = 0.046), diabetes mellitus between ages 41 and 50 (25.6% versus 8.6%, p = 0.054), and diabetes mellitus after age 51 (36.3% versus 12.7%, p = 0.005). No significant difference was found in overweight, obesity, or dyslipidemia. After adjusting for years of education, first episode as mania, and second generation antipsychotic use, lifetime diabetes mellitus remained a risk factor for CVDs (OR = 4.45, 95% CI = 1.89-10.66, p = 0.001). The findings suggest that glucose dysregulation across the adult age span is probably the major metabolic risk contributing to CVDs in patients with BD. Clinicians therefore have to notice the serum fasting glucose levels of BD patients since young adulthood. PMID- 29132554 TI - Early development of saphenous vein graft infected pseudoaneurysm caused by perioperative Enterobacter cloacae bacteremia. PMID- 29132555 TI - Considerations in Testing for Inherited Breast Cancer Predisposition in the Era of Personalized Medicine. AB - Technological advances realized through next-generation sequencing technologies coupled with the loss of the ability to patent genes have led to reduction in costs for genetic testing. As a result, more people are being identified with inherited breast cancer syndromes that may affect recommendations for surveillance and risk reduction. Surgeons, at the forefront for patients newly diagnosed with breast cancer, must keep current with the changing landscape of genetics to continue to provide appropriate counsel and care. This article provides an overview of individuals at risk for inherited cancer predisposition and recommendations for surveillance and management. PMID- 29132556 TI - Neoadjuvant Endocrine Therapy: Who Benefits Most? AB - Neoadjuvant endocrine therapy (NET) can be effective at downstaging patients with estrogen receptor-positive tumors and identifying those tumors that are endocrine sensitive and resistant. The optimal prognostic markers for stratification are under investigation. Use of NET will allow the identification of patients with estrogen receptor-positive tumors who might benefit from additional treatment and allow better understanding of endocrine resistance. PMID- 29132557 TI - Triple-Negative Breast Cancer: Who Should Receive Neoadjuvant Chemotherapy? AB - Progress in the treatment of triple-negative breast cancer remains an important challenge. Given the aggressive biology and high risk of distant recurrence, systemic chemotherapy is warranted in most patients. Neaodjuvant chemotherapy benefits patients with locally advanced disease by downsizing the tumor and increasing the probability of breast-conserving surgery. Clinical and pathologic responses provide important prognostic information, which makes neoadjuvant therapy an attractive approach for all patients with triple-negative breast cancer. Clinical research in the neoadjuvant setting is focused on improvement in pathologic complete response rates and outcomes of patients with residual disease. PMID- 29132558 TI - Intraoperative Margin Assessment in Breast Cancer Management. AB - The goal of breast-conserving surgery is to excise the tumor with negative margins while achieving a successful cosmetic result. Although it is not feasible to have re-excision rates of zero, several techniques have been described to reduce the need for a return to the operating room. When rates of re-excision are high, consideration should be given to using 1 or more of these techniques. It is critical that re-excision rates are tracked when new techniques are implemented to ensure progress. In addition, attention must be paid to ensuring that cosmetic outcomes remain optimal. PMID- 29132559 TI - Oncoplastic Breast Reconstruction: Should All Patients be Considered? AB - Oncoplastic surgery of the tissue defect from partial mastectomy should be considered for all patients. It can result in in significant asymmetries from scar contraction, skin tethering, and alterations in the nipple areolar complex location. Indications, risks, and benefits are discussed. Optimal procedures are described, considering resected specimen volume, primary tumor location, tumor to breast size ratio, and the impact on the nipple areolar complex. Indications for plastic surgery consultation and joint surgery are discussed. Surgical management includes incision planning, preservation of the nipple areolar complex pedicle and position, patient positioning, incision location, and recovery. PMID- 29132560 TI - Alternatives to Standard Fractionation Radiation Therapy After Lumpectomy: Hypofractionated Whole-Breast Irradiation and Accelerated Partial-Breast Irradiation. AB - Adjuvant whole-breast irradiation (WBI) after lumpectomy has been an established standard of care for decades. Standard-fractionation WBI delivered over 5 to 7 weeks can achieve durable tumor control with low toxicity but can be inconvenient for patients and cost ineffective. Hypofractionated WBI can be completed in 3 to 4 weeks and, based on long-term randomized data, is the preferred standard of care in select patients. Accelerated partial-breast irradiation can be delivered using even shorter treatment regimens. Although the available data on accelerated partial-breast irradiation is more limited, early results suggest it is an effective alternative to WBI in select patients. PMID- 29132561 TI - Surgical Intervention for Lymphedema. AB - Lymphedema is a chronic, progressive disease with no curative treatment. Breast cancer therapy is the most common cause of secondary lymphedema in the developed world. Treatment includes nonsurgical and surgical strategies. Conservative measures are reserved for subclinical lymphedema. Surgical options are divided into physiologic (to restore function) and reductive (to remove diseased tissue). Early stage disease is managed with physiologic procedures. Reductive treatment is reserved for moderate to severe staged disease owing to high morbidity. Surgical options effectively decrease edema and improve quality of life. However, further research is necessary to best establish management of lymphedema. PMID- 29132562 TI - Breast Cancer Disparities: How Can We Leverage Genomics to Improve Outcomes? AB - Breast cancer mortality rates are higher in African American compared with white American women. Disproportionately rising incidence rates, coupled with higher rates of biologically aggressive disease among African Americans is resulting in a widening of the mortality disparity. Higher rates of triple-negative breast cancer among African American women, as well as women from western sub-Saharan Africa, has prompted questions regarding the role of African ancestry as a marker of hereditary susceptibility for specific disease phenotypes. Advances in germline genetics, as well as somatic tumor genomic research, hold great promise in the effort to understand the biology of breast cancer variations between different population subsets. PMID- 29132563 TI - When Does Atypical Ductal Hyperplasia Require Surgical Excision? AB - Atypical ductal hyperplasia (ADH) is a proliferative, nonobligate precursor breast lesion and a marker of increased risk for breast carcinoma. Surgical excision remains the standard recommendation following a core needle biopsy result consistent with ADH. Recent research suggests that women with no mass lesion or discordance, removal of greater than or equal to 90% of calcifications at the time of core needle biopsy, involvement of less than or equal to 2 terminal duct lobular units, and absence of cytologic atypia or necrosis are likely to have a less than 5% chance of a missed cancer. PMID- 29132564 TI - Tomosynthesis in Breast Cancer Imaging: How Does It Fit into Preoperative Evaluation and Surveillance? AB - An important limitation of conventional two-dimensional mammography is the overlap of dense breast tissue obscuring masses. Digital breast tomosynthesis (DBT) has emerged as a mammographic technology that overcomes this limitation and is considered an overall better mammogram. DBT has been shown to detect significantly more breast cancer than conventional two-dimensional mammography, and to decrease the number of callbacks for diagnostic evaluation from screening mammography. Usually the callback evaluation is deemed to be overlap of tissue requiring no further management. DBT is used in the screening and diagnostic setting, and for guidance of wire localization or core biopsy, performing more accurately in the dense breast. PMID- 29132566 TI - Are There Alternative Strategies for the Local Management of Ductal Carcinoma in Situ? AB - The management of ductal carcinoma in situ (DCIS) has traditionally followed the evidence base for invasive breast cancer using surgery, radiation therapy, and drug therapy to remove the DCIS from the breast and reduce the risk of recurrence for both DCIS and invasive breast cancer. Because of concerns regarding the overtreatment of DCIS, randomized controlled trials have been established to test the outcomes (invasive breast cancer outcomes and patient-reported outcome measures) of active surveillance compared with guideline-concordant care for low risk (for progression) DCIS. These strategies are undergoing rigorous evaluation to evaluate alternatives to the current management of DCIS. PMID- 29132565 TI - Anatomy and Breast Cancer Staging: Is It Still Relevant? AB - Breast cancer staging concisely summarizes disease status, creating a framework for assessing and relaying prognostic information. The fundamental concepts and components of breast cancer staging are reviewed. The AJCC Cancer Staging Manual, which includes traditional anatomic factors, now includes additional tumor characteristics: tumor grade, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and (when available) multigene panel testing from the primary tumor. With these updates, staging provides the most reliable system for accurately predicting patient outcome. When the AJCC 8th edition guidelines are adopted, they will more closely reflect tumor biology. PMID- 29132567 TI - Lobular Breast Cancer: Different Disease, Different Algorithms? AB - Invasive lobular carcinoma (ILC) is the second most common type of breast cancer, with a unique pathogenesis and distinct clinical biology. ILCs display a characteristic loss of E-cadherin, are largely estrogen receptor positive, HER2 negative, and low to intermediate grade. These features portend a favorable prognosis, but there is a tendency for late recurrences and atypical metastases. ILCs tend to be insidious and infiltrative, which can pose a challenge for diagnosis, and emerging data suggest they may have a propensity for a differing response to standard therapies. PMID- 29132569 TI - Innovation in the Diagnosis and Management of Breast Cancer. PMID- 29132570 TI - Integrating New Knowledge and Surgical Innovation into the Diagnosis and Management of Breast Cancer. PMID- 29132571 TI - The Human Factor: Optimizing Trauma Team Performance in Dynamic Clinical Environments. AB - Resilience is built, not born, and there is no single strategy that reliably manufactures resilient performance in all circumstances. Optimizing team performance in dynamic environments involves the complex interplay of strategies that target individual preparation, team interaction, environmental optimization, and systems-level resilience engineering. To accomplish this, health care can draw influence from human factors research to inform tangible, practical, and measurable improvements in performance and outcomes, modified to suit local and domain-specific needs. PMID- 29132568 TI - Molecular Subtypes and Local-Regional Control of Breast Cancer. AB - In the era of personalized medicine, there has been significant progress regarding the molecular analysis of breast cancer subtypes. Research efforts have focused on how classification of subtypes could provide information on prognosis and influence treatment planning. Although much is known about the impact of different molecular subtypes on disease-specific survival, more recent studies have investigated the role of the different molecular subtypes on local-regional recurrence. This is an area of active study, and in recent years there has been significant progress. This article describes outcomes among disease subtypes to aid in optimal surgical decision-making to improve local-regional control. PMID- 29132572 TI - Secondary Gains: Advances in Neurotrauma Management. AB - Neurotrauma is a leading cause of death and is associated with many secondary injuries. A balance of mean arterial pressure (MAP) and intracranial pressure (ICP) is required to ensure adequate cerebral blood flow and cerebral perfusion pressure. Evaluation and management in the emergency department entails initial stabilization and resuscitation while assessing neurologic status. ICP management follows a tiered approach. Intubation requires consideration of preoxygenation, head of bed elevation, first pass success, and adequate analgesia and sedation. Early consultation with neurosurgery is needed for definitive therapy. Focused evaluation and management play a significant role in optimizing patient outcomes. PMID- 29132573 TI - Critical Decisions in the Management of Thoracic Trauma. AB - Traumatic injuries to the thorax are common after both blunt and penetrating trauma. Emergency medicine physicians must be able to manage the initial resuscitation and diagnostic workup of these patients. This involves familiarity with a range of radiologic investigations and invasive bedside procedures, including resuscitative thoracotomy. This knowledge is critical to allow for rapid decision making when life-threatening injuries are encountered. This article explores the initial resuscitation and assessment of patients after thoracic trauma, discusses available imaging modalities, reviews frequently performed procedures, and provides an overview of the indications for operative intervention, while emphasizing the critical decision making throughout. PMID- 29132574 TI - Major Abdominal Trauma: Critical Decisions and New Frontiers in Management. AB - A standardized approach should be used with a patient with abdominal trauma, including primary and secondary surveys, followed by additional diagnostic testing as indicated. Specific factors can make the diagnosis of serious abdominal trauma challenging, particularly in the face of multiple and severe injuries, unknown mechanism of injury, altered mental status, and impending or complete cardiac arrest. Advances in technology in diagnosis and/or treatment with ultrasound, helical computed tomography, and resuscitative endovascular balloon occlusion of the aorta (REBOA) have significantly advanced trauma care, and are still the focus of current and ongoing investigations. PMID- 29132575 TI - Acute Management of the Traumatically Injured Pelvis. AB - Severe pelvic trauma is a challenging condition. The pelvis can create multifocal hemorrhage that is not easily compressible nor managed by traditional surgical methods such as tying off a blood vessel or removing an organ. Its treatment often requires reapproximation of bony structures, damage control resuscitation, assessment for associated injuries, and triage of investigations, as well as multimodality hemorrhage control (external fixation, preperitoneal packing, angioembolization, REBOA [resuscitative endovascular balloon occlusion of the aorta]) by multidisciplinary trauma specialists (general surgeons, orthopedic surgeons, endovascular surgeons/interventional radiologists). This article explores this complex clinical problem and provides a practical approach to its management. PMID- 29132576 TI - Management of Major Vascular Injuries: Neck, Extremities, and Other Things that Bleed. AB - Vascular injuries represent a significant burden of mortality and disability. Blunt injuries to the neck vessels can present with signs of stroke either immediately or in a delayed fashion. Most injuries are detected with computed tomography angiography and managed with either antiplatelet medications or anticoagulation. In contrast, patients with penetrating injuries to the neck vessels require airway management, hemorrhage control, and damage control resuscitation before surgical repair. The keys to diagnosis and management of peripheral vascular injury include early recognition of the injury; hemorrhage control with direct pressure, packing, or tourniquets; and urgent surgical consultation. PMID- 29132577 TI - Reanimating Patients After Traumatic Cardiac Arrest: A Practical Approach Informed by Best Evidence. AB - Resuscitation of traumatic cardiac arrest is typically considered futile. Recent evidence suggests that traumatic cardiac arrest is survivable. In this article key principles in managing traumatic cardiac arrest are discussed, including the importance of rapidly seeking prognostic information, such as signs of life and point-of-care ultrasonography evidence of cardiac contractility, to inform the decision to proceed with resuscitative efforts. In addition, a rationale for deprioritizing chest compressions, steps to quickly reverse dysfunctional ventilation, techniques for temporary control of hemorrhage, and the importance of blood resuscitation are discussed. The best available evidence and the authors' collective experience inform this article. PMID- 29132578 TI - Major Trauma Outside a Trauma Center: Prehospital, Emergency Department, and Retrieval Considerations. AB - Care of the critically injured begins well before the patient arrives at a large academic trauma center. It is important to understand the continuum of care from the point of injury in the prehospital environment, through the local hospital and retrieval, until arrival at a trauma center capable of definitive care. This article highlights the important aspects of trauma assessment and management outside of tertiary or quaternary care hospitals. Key elements of each phase of care are reviewed, including management pearls and institutional strategies to facilitate effective and efficient treatment of trauma patients from the point of injury forward. PMID- 29132579 TI - The Tragically Hip: Trauma in Elderly Patients. AB - Old age is a risk factor for poor outcome in trauma patients, as a result of undertriage and the presence of occult life-threatening injuries. The mechanisms of injury for geriatric trauma differ from those in younger patients, with a much higher incidence of low-impact trauma, especially falls from a low height. Frailty is a risk factor for severe injury after minor trauma, and caring for these patients require a multidisciplinary team with both trauma and geriatric expertise. With early recognition and aggressive management, severe injuries can still be associated with good outcomes, even in very elderly patients. PMID- 29132580 TI - The Kids Are Alright: Pediatric Trauma Pearls. AB - Pediatric patients with trauma pose unique challenges, both practical and cognitive, to front-line care providers. The combination of anatomic, physiologic, and metabolic factors leads to unique injury patterns with different approaches and responses to treatment compared with adults. A similar traumatic mechanism can lead to slightly different internal injuries with unique management and treatment strategies between the two groups. This article is intended for community, nonpediatric trauma centers, and emergency physicians who are frequently required to assess, resuscitate, and stabilize injured children before they can be safely transferred to a pediatric trauma center for ongoing definitive care and rehabilitation. PMID- 29132581 TI - Resuscitation Resequenced: A Rational Approach to Patients with Trauma in Shock. AB - Trauma resuscitation is a complex and dynamic process that requires a high performing team to optimize patient outcomes. More than 30 years ago, Advanced Trauma Life Support was developed to formalize and standardize trauma care; however, the sequential nature of the algorithm that is used can lead to ineffective prioritization. An improved understanding of shock mandates an updated approach to trauma resuscitation. This article proposes a resequenced approach that (1) addresses immediate threats to life and (2) targets strategies for the diagnosis and management of shock causes. This updated approach emphasizes evidence-based resuscitation principles that align with physiologic priorities. PMID- 29132582 TI - Airway Management in Trauma. AB - Airway management in the trauma patient presents numerous unique challenges beyond placement of an endotracheal tube and outcomes are dependent on the provider's ability to anticipate difficulty. Airway management strategies for the care of the polytrauma patient are reviewed, with specific considerations for those presenting with traumatic brain injury, suspected c-spine injury, the contaminated airway, the agitated trauma patient, maxillofacial trauma, and the traumatized airway. An approach to airway management that considers the potential anatomic and physiologic challenges in caring for these complicated trauma patients is presented. PMID- 29132583 TI - The Evolving Science of Trauma Resuscitation. AB - This review summarizes the evolution of trauma resuscitation from a one-size-fits all approach to one tailored to patient physiology. The most dramatic change is in the management of actively bleeding patients, with a balanced blood product based resuscitation approach (avoiding crystalloids) and surgery focused on hemorrhage control, not definitive care. When hemostasis has been achieved, definitive resuscitation to restore organ perfusion is initiated. This approach is associated with decreased mortality, reduced duration of stay, improved coagulation profile, and reduced crystalloid/vasopressor use. This article focuses on the tools and methods used for trauma resuscitation in the acute phase of trauma care. PMID- 29132584 TI - Damage Control: Advances in Trauma Resuscitation. PMID- 29132585 TI - Seismology and Advances in Trauma Resuscitation. PMID- 29132588 TI - Reporting Abuse. PMID- 29132587 TI - Teaching: A Newer Face. PMID- 29132591 TI - Just Another Day. PMID- 29132592 TI - Paramedic Clinical Ladder: Development and Implementation at 1 Institution. PMID- 29132593 TI - The Impact of Helicopter Emergency Medical Service Night Operations in South East England. AB - OBJECTIVE: This study sought to assess the impact of a helicopter emergency medical service (HEMS) capable of night operations. METHODS: This is a retrospective case review of all night HEMS missions attended by a charity air ambulance service in South East England over a 2-year period (October 1, 2013, to October 1, 2015). RESULTS: During the 2-year trial period, the HEMS service undertook a total of 5,004 missions and attended to 3,728 patients. Of these, 1,373 missions, or 27.4% of the total HEMS activity, were night missions. Night missions increased from year 1 (n = 617) to year 2 (n = 756). A mean of 1.9 missions per night were conducted, resulting in the treatment of 1.3 patients per night. A higher proportion of patients were transported to a major trauma center at night (64% vs. 51%, chi2 = 41.8, P < .0001). Weather conditions prevented HEMS from responding at night via air for 15% of the night operational hours. CONCLUSION: A 2-year trial period of a night HEMS service in South East England showed the predicted activation rate, with a mean of 1.3 patients attended to per night. Patients transported to a major trauma center had a mean Injury Severity Score of 23. Further research is warranted to determine if the night HEMS service conveys a patient outcome benefit. PMID- 29132594 TI - Ketamine Sedation for Patients With Acute Behavioral Disturbance During Aeromedical Retrieval: A Retrospective Chart Review. AB - OBJECTIVE: The aim of this study was to determine the prevalence, safety (as measured by the incidence of adverse events), and effectiveness (as measured by the incidence of intubations) of ketamine sedation in patients with acute behavioral disturbance (ABD) during air medical retrieval. METHODS: This was a retrospective observational study. Eligible patients were identified by searching the electronic databases of 2 air medical retrieval services in Queensland, Australia, for adult patients with ABD transported between January 1, 2015, and June 30, 2016. Data abstraction was performed as per standard chart review criteria. The incidences of intubations and adverse reactions were the main outcomes. RESULTS: One hundred twenty-two patients met the inclusion criteria. Thirty-one (25.4%) patients were intubated, 21 (17.2%) for airway protection/respiratory depression and 10 (8.1%) for persistent ABD. Twenty-one (17.2%) patients received ketamine, 3 of whom (14.3%) were intubated for persistent ABD. Nine (42.9%) patients developed hypertension after ketamine, 2 of whom needed intervention. One patient developed hypoxia after ketamine that resolved without intervention, and 1 patient developed increased secretions. No patients developed nausea, vomiting, emergence phenomena, apnea, or laryngospasm. CONCLUSION: Our study suggests that ketamine is a safe and effective agent for sedating patients with ABD during air medical retrieval. PMID- 29132595 TI - Remote ECLS-Implantation and Transport for Retrieval of Cardiogenic Shock Patients. AB - OBJECTIVE: Extracorporeal life support (ECLS) emerges as a salvage option in therapy refractory cardiogenic shock but is limited to highly specialized tertiary care centers. Critically ill patients are often too unstable for conventional transport. Mobile ECLS programs for remote implantation and subsequent air or ground-based transport for patient retrieval could solve this dilemma and make full-spectrum advanced cardiac care available to patients in remote hospitals in whom shock otherwise might be fatal. METHODS: From December 2012 to March 2016, 40 patients underwent venoarterial ECLS implantation in remote hospitals with subsequent transport to our center and were retrospectively analyzed. The mobile ECLS team was available 24/7, implantation was performed percutaneously bedside, and compact support systems designed for transport were used. RESULTS: Twenty percent of the patients were female; the mean age was 55 +/ 10 years, and the mean Interagency Registry for Mechanically Assisted Circulatory Support score was 1.3 +/- 0.5. Patient retrieval was accomplished via ground-based (n = 29, 72.5%, mean distance = 27.9 +/- 29.7 km [range, 5.6-107.1 km]) or air (n = 11, mean distance = 62.4 +/- 27.2 km [range, 38.9-116.4 km]) transport. No ECLS-related complications occurred during transport. The ECLS system could be explanted in 65.0% (n = 26) of patients, and the 30-day survival rate was 52.5% (n = 21). CONCLUSION: Remote ECLS implantation and interfacility transport on ECLS are feasible and effective. Interdisciplinary teams and full spectrum cardiac care are essential to achieve optimal outcomes. Rapid-response ECLS networks have the potential to substantially increase the survival of cardiogenic shock patients. PMID- 29132596 TI - Air Medical-Evacuated Battle Injuries: French Army 2001 to 2014 in Afghanistan. AB - OBJECTIVE: The purpose of strategic air medical evacuation (STRAT AE) is to enable the continuity of care and repatriation of wounded soldiers. Between 2001 and 2014, STRAT AEs have been implemented many times over the course of the military engagement in Afghanistan. The purpose of this work was to study the nature of the pathologies and the medicalization of patients most seriously wounded during the PAMIR Operation (Afghanistan). METHODS: This was an epidemiological study conducted retrospectively from January 1, 2001, to December 31, 2014, of the STRAT AEs with the air medical team from the Afghan operating room to France. Data were collected from air evacuation medical records. RESULTS: Between 2001 and 2014, 109 patients underwent STRAT AEs for a traumatic pathology originating from a battle injury. According to the categorization of Standardization Agreement 3204, 57% of the wounded were priority 1, whereas 43% were priority 2 and 80% showed high dependency (level 1 or 2). Seventy-two percent of evacuations were individual, and 28% were performed in groups. The air medical team was enhanced by a critical care anesthesiologist in 85% of the cases. No deaths occurred in-flight. CONCLUSION: The French experience in Afghanistan was marked by performing mostly individual STRAT AEs among wounded warriors requiring extensive medicalization. PMID- 29132597 TI - Retrospective Review of Pediatric Transport: Where Do Our Patients Go After Transport? AB - OBJECTIVE: This review describes disposition of transported children and identifies contributing factors affecting optimal patient placement. The study describes timing and patient placement indicators in transport patients to identify areas of improvement, re-education, and training. METHODS: A retrospective chart review for transports via our pediatric specialty transport team from January 1, 2012, to December 31, 2014, was performed. Patients were identified by the transport quality assurance performance improvement database, hospital electronic medical records, and transport medical records. RESULTS: Three thousand two hundred fifty-six pediatric patient transports were reviewed. One hundred forty-three records were excluded. Of the remaining 3,113 patients, admission disposition was: 1,487 (47%) pediatric intensive care unit, 120 (4%) pediatric cardiovascular intensive care unit, 835 (27%) step-down critical care unit, 438 (14%) emergency department, 194 (6%) general floor, 29 (1%) neonatal intensive care unit, and 10 (< 1%) operating room. Of the 22% transported to a lower-acuity unit, several subsequently required critical care. Children transported for traumatic injuries had a shorter emergency department length of stay than medical patients. CONCLUSION: Our study validates the efficient use of pediatric specialty transport team resources. Many transported patients are critically ill, require specialized pediatric services, or require definitive pediatric emergency department care. PMID- 29132599 TI - Concern Network. PMID- 29132598 TI - A 6-Year-Old Male Cold Water Near Drowning Where You Might Least Expect It. PMID- 29132600 TI - An overview of peer tutor training strategies at German medical schools. AB - BACKGROUND: An increased popularity of peer-assisted learning in medical schools all over the globe has caused a growing interest in taking a closer look into how student tutors are trained to handle the task. This article provides an overview of the tutor training strategies at five medical faculties in Germany. METHODS: Nine German medical faculties with an evident tutor training strategy were contacted by phone or e-mail. Ultimately, five of the nine contacted faculties responded and provided a detailed overview of their individual tutor training. RESULTS: In many cases, tutors receive a mandatory didactic training in preparation of the tutorials and also an additional technical or specialized training. Frequently, tutor training is provided within the framework of an organized, faculty-based tutor training program. There is a trend towards a needs adapted training strategy. CONCLUSION: There is a broad variety of peer teaching and tutor training strategies at the various faculties surveyed. Their individual characteristics are determined by factors such as the nature of tutorials and the number of students. PMID- 29132601 TI - First virtual special issue (VSI) in Clinical Neurophysiology: A novel way of enhancing accessibility and visibility of published research. PMID- 29132602 TI - Fighting antimicrobial resistance on all fronts. PMID- 29132603 TI - Estimates are not enough: scaling-up interventions to improve the health of people who inject drugs. PMID- 29132604 TI - Shigella infection in children and adults: a formidable foe. PMID- 29132605 TI - Population-level linear growth faltering in low-income and middle-income countries. PMID- 29132606 TI - Global infection prevention and control priorities 2018-22: a call for action. PMID- 29132607 TI - Maternal mortality: direct or indirect has become irrelevant. PMID- 29132608 TI - The costs of reaching the health-related SDGs. PMID- 29132609 TI - The costs of reaching the health-related SDGs. PMID- 29132610 TI - Gender myths in global health-a response to the response. PMID- 29132611 TI - Developing an antimicrobial resistance reference laboratory and surveillance programme in Vietnam. PMID- 29132612 TI - Severe malnutrition in infants displaced from Mosul, Iraq. PMID- 29132613 TI - Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis. AB - BACKGROUND: Shigella infections are a leading cause of diarrhoeal death among children in low-income and middle-income countries. WHO guidelines reserve antibiotics for treating children with dysentery. Reliance on dysentery for identification and management of Shigella infection might miss an opportunity to reduce Shigella-associated morbidity and mortality. We aimed to systematically review and evaluate Shigella-associated and dysentery-associated mortality, the diagnostic value of dysentery for the identification of Shigella infection, and the efficacy of antibiotics for children with Shigella or dysentery, or both. METHODS: We did three systematic reviews (for mortality, diagnostic value, and antibiotic treatment of Shigella and dysentery), and meta-analyses where appropriate, of studies in resource-limited settings. We searched MEDLINE, Embase, and LILACS database for studies published before Jan 1, 2017, in English, French, and Spanish. We included studies of human beings with diarrhoea and accepted all study-specific definitions of dysentery. For the mortality and diagnostic value searches, we excluded studies that did not include an effect estimate or data necessary to calculate this estimate. The search for treatment included only randomised controlled trials that were done after Jan 1, 1980, and assessed antibiotics in children (aged <18 years) with dysentery or laboratory confirmed Shigella. We extracted or calculated odds ratios (ORs) and 95% CIs for relative mortality and did random-effects meta-analysis to arrive at pooled ORs. We calculated 95% CIs assuming a binomial distribution and did random-effects meta-regression of log-transformed sensitivity and specificity estimates for diagnostic value. We assessed the heterogeneity of papers included in these meta analyses using the I2 statistic and evaluated publication bias using funnel plots. This review is registered with PROSPERO (CRD42017063896). FINDINGS: 3649 papers were identified and 60 studies were included for analyses: 13 for mortality, 27 for diagnostic value, and 20 for treatment. Shigella infection was associated with mortality (pooled OR 2.8, 95% CI 1.6-4.8; p=0.000) whereas dysentery was not associated with mortality (1.3, 0.7-2.3; p=0.37). Between 1977 and 2016, dysentery identified 1.9-85.9% of confirmed Shigella infections, with sensitivity decreasing over time (p=0.04). Ten (50%) of 20 included antibiotic trials were among children with dysentery, none were placebo-controlled, and two (10%) evaluated antibiotics no longer recommended for acute infectious diarrhoea. Ciprofloxacin showed superior microbiological, but not clinical, effectiveness compared with pivmecillinam, and no superior microbiological and clinical effectiveness compared with gatifloxacin. Substantial heterogeneity was reported for meta-analyses of the Shigella-associated mortality studies (I2=78.3%) and dysentery-associated mortality studies (I2=73.2%). Too few mortality studies were identified to meaningfully test for publication bias. No evidence of publication bias was found in this analysis of studies of diagnostic value. INTERPRETATION: Current WHO guidelines appear to manage dysentery effectively, but might miss opportunities to reduce mortality among children infected with Shigella who present without bloody stool. Further studies should quantify potential decreases in mortality and morbidity associated with antibiotic therapy for children with non-dysenteric Shigella infection. FUNDING: Bill & Melinda Gates Foundation and the Center for AIDS Research International Core. PMID- 29132614 TI - Early childhood linear growth faltering in low-income and middle-income countries as a whole-population condition: analysis of 179 Demographic and Health Surveys from 64 countries (1993-2015). AB - BACKGROUND: The causes of early childhood linear growth faltering (known as stunting) in low-income and middle-income countries remain inadequately understood. We aimed to determine if the progressive postnatal decline in mean height-for-age Z score (HAZ) in low-income and middle-income countries is driven by relatively slow growth of certain high-risk children versus faltering of the entire population. METHODS: Distributions of HAZ (based on WHO growth standards) were analysed in 3-month age intervals from 0 to 36 months of age in 179 Demographic and Health Surveys from 64 low-income and middle-income countries (1993-2015). Mean, standard deviation (SD), fifth percentiles, and 95th percentiles of the HAZ distribution were estimated for each age interval in each survey. Associations between mean HAZ and SD, fifth percentile, and 95th percentile were estimated using multilevel linear models. Stratified analyses were performed in consideration of potential modifiers (world region, national income, sample size, year, or mean HAZ in the 0-3 month age band). We also used Monte Carlo simulations to model the effects of subgroup versus whole-population faltering on the HAZ distribution. FINDINGS: Declines in mean HAZ from birth to 3 years of age were accompanied by declines in both the fifth and 95th percentiles, leading to nearly symmetrical narrowing of the HAZ distributions. Thus, children with relatively low HAZ were not more likely to have faltered than taller same age peers. Inferences were unchanged in surveys regardless of world region, national income, sample size, year, or mean HAZ in the 0-3 month age band. Simulations showed that the narrowing of the HAZ distribution as mean HAZ declined could not be explained by faltering limited to a growth-restricted subgroup of children. INTERPRETATION: In low-income and middle-income countries, declines in mean HAZ with age are due to a downward shift in the entire HAZ distribution, revealing that children across the HAZ spectrum experience slower growth compared to the international standard. Efforts to mitigate postnatal linear growth faltering in low-income and middle-income countries should prioritise action on community-level determinants of childhood HAZ trajectories. FUNDING: Bill & Melinda Gates Foundation. PMID- 29132615 TI - Prediction of lung cancer patient survival via supervised machine learning classification techniques. AB - Outcomes for cancer patients have been previously estimated by applying various machine learning techniques to large datasets such as the Surveillance, Epidemiology, and End Results (SEER) program database. In particular for lung cancer, it is not well understood which types of techniques would yield more predictive information, and which data attributes should be used in order to determine this information. In this study, a number of supervised learning techniques is applied to the SEER database to classify lung cancer patients in terms of survival, including linear regression, Decision Trees, Gradient Boosting Machines (GBM), Support Vector Machines (SVM), and a custom ensemble. Key data attributes in applying these methods include tumor grade, tumor size, gender, age, stage, and number of primaries, with the goal to enable comparison of predictive power between the various methods The prediction is treated like a continuous target, rather than a classification into categories, as a first step towards improving survival prediction. The results show that the predicted values agree with actual values for low to moderate survival times, which constitute the majority of the data. The best performing technique was the custom ensemble with a Root Mean Square Error (RMSE) value of 15.05. The most influential model within the custom ensemble was GBM, while Decision Trees may be inapplicable as it had too few discrete outputs. The results further show that among the five individual models generated, the most accurate was GBM with an RMSE value of 15.32. Although SVM underperformed with an RMSE value of 15.82, statistical analysis singles the SVM as the only model that generated a distinctive output. The results of the models are consistent with a classical Cox proportional hazards model used as a reference technique. We conclude that application of these supervised learning techniques to lung cancer data in the SEER database may be of use to estimate patient survival time with the ultimate goal to inform patient care decisions, and that the performance of these techniques with this particular dataset may be on par with that of classical methods. PMID- 29132616 TI - Imperceptible watermarking for security of fundus images in tele-ophthalmology applications and computer-aided diagnosis of retina diseases. AB - BACKGROUND AND OBJECTIVES: The authentication and integrity verification of medical images is a critical and growing issue for patients in e-health services. Accurate identification of medical images and patient verification is an essential requirement to prevent error in medical diagnosis. The proposed work presents an imperceptible watermarking system to address the security issue of medical fundus images for tele-ophthalmology applications and computer aided automated diagnosis of retinal diseases. METHODS: In the proposed work, patient identity is embedded in fundus image in singular value decomposition domain with adaptive quantization parameter to maintain perceptual transparency for variety of fundus images like healthy fundus or disease affected image. In the proposed method insertion of watermark in fundus image does not affect the automatic image processing diagnosis of retinal objects & pathologies which ensure uncompromised computer-based diagnosis associated with fundus image. Patient ID is correctly recovered from watermarked fundus image for integrity verification of fundus image at the diagnosis centre. RESULTS: The proposed watermarking system is tested in a comprehensive database of fundus images and results are convincing. EXPERIMENTAL: results indicate that proposed watermarking method is imperceptible and it does not affect computer vision based automated diagnosis of retinal diseases. CONCLUSIONS: Correct recovery of patient ID from watermarked fundus image makes the proposed watermarking system applicable for authentication of fundus images for computer aided diagnosis and Tele-ophthalmology applications. PMID- 29132617 TI - Pilot study of a smartphone-based intervention to promote cancer prevention behaviours. AB - BACKGROUND: Estimates predict that more than half of all cancers are due to inadequate lifestyle choices. Smartphones can be successfully used to support the behaviour change needed to prevent cancer. OBJECTIVE: The purpose of this study was to field-test Happy, a smartphone app designed to promote cancer prevention behaviours, based on tailored-messages. METHODS: Thirty-two participants downloaded and used the app for 28 consecutive days (4 weeks). At the end of this period, they all answered an online questionnaire and ten of them were interviewed. Usability, feasibility, message receptivity, and perceived impact of the app were assessed. RESULTS: Compliance with cancer prevention guidelines was lower than expected. Happy was considered simple, intuitive and easy to use. Messages sent by the app were considered easy to understand, providing good advice and meaningful information that catch reader's attention. Participants also considered that Happy might be an effective way to promote cancer prevention. Collected data showed an increased frequency in several cancer prevention related behaviours and an increase in the overall putative cancer prevention level. CONCLUSIONS: This study showed the viability of designing and implementing smartphone-based interventions to promote cancer prevention behaviours. The results suggest that Happy is usable and might help users change their behaviour towards healthier choices and thus reduce their personal cancer risk. PMID- 29132618 TI - Telehealth attitudes and use among medical professionals, medical students and patients in China: A cross-sectional survey. AB - BACKGROUND: Telehealth aims to revolutionize health care by migrating health care from hospitals and satellite clinics directly into the home and onto mobile devices. Telehealth has the potential to increase public access to healthcare in China, where large segments of the population remain underserved, yet little is known about current attitudes and use of telehealth in the country. OBJECTIVE: Our aim was to determine attitudes and use of telehealth in China among medical professionals and patients, as well as identify factors that may affect its use. METHODS: Using a custom-designed questionnaire, we performed a cross-sectional survey of medical professionals, medical students and patients at three large hospitals in Chengdu, Sichuan, China. We used a structural model to analyze the influence of factors that may affect use of telehealth. RESULTS: Of 600 questionnaires that were distributed, 550 (96.49%) were analyzed. Most respondents (63.28%) were familiar with using telehealth to "schedule medical appointments/pay medical fees online", but relatively few (28.55%) used this feature. Nearly half of respondents were familiar with the concept of a "virtual visit" (46.18%), but only 12.18% had ever engaged in such visits. Medical professionals and students generally showed higher awareness and greater use of telehealth than patients. The strongest concern about telehealth among respondents was "authenticity and reliability of data from remote monitoring of patients" (75.17%). The proportion of respondents concerned about the potential disadvantages of telehealth was highest among students and lowest among patients. Awareness and use of telehealth were associated with previous experience with health-related use of the Internet and experience with traditional forms of telehealth, but not with social status or attitude toward telehealth. CONCLUSIONS: Medical professionals and patients alike in China have a high awareness of telehealth, primarily traditional forms of telehealth, but only a small percentage actually use it. Patients have much lower awareness and use of telehealth than medical professionals and medical students, though they have generally positive attitudes towards telehealth. Telehealth is still in its infancy in China, and the environment for its development is largely favorable among current and future medical professionals. PMID- 29132619 TI - A statistical analysis based recommender model for heart disease patients. AB - OBJECTIVES: An intelligent information technology based system could have a positive impact on the life-style of patients suffering from chronic diseases by providing useful health recommendations. In this paper, we have proposed a hybrid model that provides disease prediction and medical recommendations to cardiac patients. The first part aims at implementing a prediction model, that can identify the disease of a patient and classify it into one of the four output classes i.e., non-cardiac chest pain, silent ischemia, angina, and myocardial infarction. Following the disease prediction, the second part of the model provides general medical recommendations to patients. METHODS: The recommendations are generated by assessing the severity of clinical features of patients, estimating the risk associated with clinical features and disease, and calculating the probability of occurrence of disease. The purpose of this model is to build an intelligent and adaptive recommender system for heart disease patients. The experiments for the proposed recommender system are conducted on a clinical data set collected and labelled in consultation with medical experts from a known hospital. RESULTS: The performance of the proposed prediction model is evaluated using accuracy and kappa statistics as evaluation measures. The medical recommendations are generated based on information collected from a knowledge base created with the help of physicians. The results of the recommendation model are evaluated using confusion matrix and gives an accuracy of 97.8%. CONCLUSION: The proposed system exhibits good prediction and recommendation accuracies and promises to be a useful contribution in the field of e-health and medical informatics. PMID- 29132620 TI - Identifying and prioritizing the tools/techniques of knowledge management based on the Asian Productivity Organization Model (APO) to use in hospitals. AB - INTRODUCTION: Appropriate knowledge, correct information, and relevant data are vital in medical diagnosis and treatment systems. Knowledge Management (KM) through its tools/techniques provides a pertinent framework for decision-making in healthcare systems. The objective of this study was to identify and prioritize the KM tools/techniques that apply to hospital setting. METHODS: This is a descriptive-survey study. Data were collected using a -researcher-made questionnaire that was developed based on experts' opinions to select the appropriate tools/techniques from 26 tools/techniques of the Asian Productivity Organization (APO) model. Questions were categorized into five steps of KM (identifying, creating, storing, sharing, and applying the knowledge) according to this model. The study population consisted of middle and senior managers of hospitals and managing directors of Vice-Chancellor for Curative Affairs in Kerman University of Medical Sciences in Kerman, Iran. The data were analyzed in SPSS v.19 using one-sample t-test. RESULTS: Twelve out of 26 tools/techniques of the APO model were identified as the tools applicable in hospitals. "Knowledge cafe" and "APO knowledge management assessment tool" with respective means of 4.23 and 3.7 were the most and the least applicable tools in the knowledge identification step. "Mentor-mentee scheme", as well as "voice and Voice over Internet Protocol (VOIP)" with respective means of 4.20 and 3.52 were the most and the least applicable tools/techniques in the knowledge creation step. "Knowledge cafe" and "voice and VOIP" with respective means of 3.85 and 3.42 were the most and the least applicable tools/techniques in the knowledge storage step. "Peer assist and 'voice and VOIP' with respective means of 4.14 and 3.38 were the most and the least applicable tools/techniques in the knowledge sharing step. Finally, "knowledge worker competency plan" and "knowledge portal" with respective means of 4.38 and 3.85 were the most and the least applicable tools/techniques in the knowledge application step. CONCLUSION: The results showed that 12 out of 26 tools in the APO model are appropriate for hospitals of which 11 are significantly applicable, and "storytelling" is marginally applicable. In this study, the preferred tools/techniques for implementation of each of the five KM steps in hospitals are introduced. PMID- 29132621 TI - Effect of computer use on physician-patient communication using a validated instrument: Patient perspective. AB - BACKGROUND: Physician-patient communication is essential in the physician-patient relationship. Concerns were raised about the impact of the computer on this relationship with the increase in use of electronic medical records (EMR). Most studies addressed the physician's perspective and only few explored the patient's perspective. AIM: This study aims to assess the patient's perspective of the effect of the physician's computer use during the clinical encounter on the interpersonal and communication skills of the physician using a validated communication assessment tool (CAT). DESIGN AND SETTINGS: This is a cross sectional survey of three hundred eighty-two patients who visited the family medicine clinics (FMC) at the American University of Beirut Medical Center (AUBMC). MATERIAL AND METHODS: At the end of the visit with the physician, the patients were approached by the clinical assistant to fill a paper-based questionnaire privately in the waiting room to measure communication skills of physicians using CAT. RESULTS: Nearly two-thirds of the patients (62%) did not consider that using the computer by their physician during the visit would negatively affect the patient-doctor communication. Patients rated their physician with a higher communication score when there was an ongoing relationship between the physician and the patient. Higher communication scores were reported for extensive use of the computer by the physician to check results (p<0.001), to retrieve patient record information (p<0.001) and to educate patients (p<0.001) as compared to less use. CONCLUSIONS: Physician-patient communication was not negatively affected by the physician use of the computer as rated by patients. An ongoing relationship with the physician remains a significant predictor of better physician-patient communication even in the presence of the computer. PMID- 29132623 TI - Corrigendum to "Ensemble Risk Model of Emergency Admissions (ERMER)"[Int. J. Med. Inf. 103 (2017) 65-77]. PMID- 29132622 TI - Know thy eHealth user: Development of biopsychosocial personas from a study of older adults with heart failure. AB - BACKGROUND: Personas are a canonical user-centered design method increasingly used in health informatics research. Personas-empirically-derived user archetypes can be used by eHealth designers to gain a robust understanding of their target end users such as patients. OBJECTIVE: To develop biopsychosocial personas of older patients with heart failure using quantitative analysis of survey data. METHOD: Data were collected using standardized surveys and medical record abstraction from 32 older adults with heart failure recently hospitalized for acute heart failure exacerbation. Hierarchical cluster analysis was performed on a final dataset of n=30. Nonparametric analyses were used to identify differences between clusters on 30 clustering variables and seven outcome variables. RESULTS: Six clusters were produced, ranging in size from two to eight patients per cluster. Clusters differed significantly on these biopsychosocial domains and subdomains: demographics (age, sex); medical status (comorbid diabetes); functional status (exhaustion, household work ability, hygiene care ability, physical ability); psychological status (depression, health literacy, numeracy); technology (Internet availability); healthcare system (visit by home healthcare, trust in providers); social context (informal caregiver support, cohabitation, marital status); and economic context (employment status). Tabular and narrative persona descriptions provide an easy reference guide for informatics designers. DISCUSSION: Personas development using approaches such as clustering of structured survey data is an important tool for health informatics professionals. We describe insights from our study of patients with heart failure, then recommend a generic ten-step personas development process. Methods strengths and limitations of the study and of personas development generally are discussed. PMID- 29132624 TI - The value of EHR-based assessment of physician competency: An investigative effort with internal medicine physicians. AB - OBJECTIVE: The purpose of this study was to investigate the potential of developing an EHR-based model of physician competency, named the Skill Deficiency Evaluation Toolkit for Eliminating Competency-loss Trends (Skill-DETECT), which presents the opportunity to use EHR-based models to inform selection of Continued Medical Education (CME) opportunities specifically targeted at maintaining proficiency. METHODS: The IBM Explorys platform provided outpatient Electronic Health Records (EHRs) representing 76 physicians with over 5000 patients combined. These data were used to develop the Skill-DETECT model, a predictive hybrid model composed of a rule-based model, logistic regression model, and a thresholding model, which predicts cognitive clinical skill deficiencies in internal medicine physicians. A three-phase approach was then used to statistically validate the model performance. RESULTS: Subject Matter Expert (SME) panel reviews resulted in a 100% overall approval rate of the rule based model. Area under the receiver-operating characteristic curves calculated for each logistic regression curve resulted in values between 0.76 and 0.92, which indicated exceptional performance. Normality, skewness, and kurtosis were determined and confirmed that the distribution of values output from the thresholding model were unimodal and peaked, which confirmed effectiveness and generalizability. CONCLUSIONS: The validation has confirmed that the Skill-DETECT model has a strong ability to evaluate EHR data and support the identification of internal medicine cognitive clinical skills that are deficient or are of higher likelihood of becoming deficient and thus require remediation, which will allow both physician and medical organizations to fine tune training efforts. PMID- 29132625 TI - Variation in interoperability across clinical laboratories nationwide. AB - OBJECTIVE: To characterize nationwide variation and factors associated with clinical laboratories': (1) capabilities to send structured test results electronically to ordering practitioners' EHR systems; and (2) their levels of exchange activity, as measured by whether they sent more than three-quarters of their test results as structured data to ordering practitioners' EHR systems. MATERIALS AND METHODS: A national survey of all independent and hospital laboratories was conducted in 2013. Using an analytic weighted sample of 9382 clinical laboratories, a series of logistic regression analyses were conducted to identify organizational and area characteristics associated with clinical laboratories' exchange capability and activity. RESULTS: Hospital-based clinical laboratories (71%) and larger clinical laboratories (80%) had significantly higher levels of capability compared to independent (58%) and smaller laboratories (48%), respectively; though all had similar levels of exchange activity, with 30% of clinical laboratories sending 75% or more of their test results electronically. In multivariate analyses, hospital and the largest laboratories had 1.87 and 4.40 higher odds, respectively, of possessing the capability to send results electronically compared to independent laboratories (p<0.001). Laboratories located in areas with a higher share of potential exchange partners had a small but significantly greater capability to send results electronically and higher levels of exchange activity(p<0.05). CONCLUSION: Clinical laboratories' capability to exchange varied by size and type; however, all clinical laboratories had relatively low levels of exchange activity. The role of exchange partners potentially played a small but significant role in driving exchange capability and activity. PMID- 29132626 TI - Early hospital mortality prediction of intensive care unit patients using an ensemble learning approach. AB - BACKGROUND: Mortality prediction of hospitalized patients is an important problem. Over the past few decades, several severity scoring systems and machine learning mortality prediction models have been developed for predicting hospital mortality. By contrast, early mortality prediction for intensive care unit patients remains an open challenge. Most research has focused on severity of illness scoring systems or data mining (DM) models designed for risk estimation at least 24 or 48h after ICU admission. OBJECTIVES: This study highlights the main data challenges in early mortality prediction in ICU patients and introduces a new machine learning based framework for Early Mortality Prediction for Intensive Care Unit patients (EMPICU). MATERIALS AND METHODS: The proposed method is evaluated on the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II) database. Mortality prediction models are developed for patients at the age of 16 or above in Medical ICU (MICU), Surgical ICU (SICU) or Cardiac Surgery Recovery Unit (CSRU). We employ the ensemble learning Random Forest (RF), the predictive Decision Trees (DT), the probabilistic Naive Bayes (NB) and the rule-based Projective Adaptive Resonance Theory (PART) models. The primary outcome was hospital mortality. The explanatory variables included demographic, physiological, vital signs and laboratory test variables. Performance measures were calculated using cross-validated area under the receiver operating characteristic curve (AUROC) to minimize bias. 11,722 patients with single ICU stays are considered. Only patients at the age of 16 years old and above in Medical ICU (MICU), Surgical ICU (SICU) or Cardiac Surgery Recovery Unit (CSRU) are considered in this study. RESULTS: The proposed EMPICU framework outperformed standard scoring systems (SOFA, SAPS-I, APACHE-II, NEWS and qSOFA) in terms of AUROC and time (i.e. at 6h compared to 48h or more after admission). DISCUSSION AND CONCLUSION: The results show that although there are many values missing in the first few hour of ICU admission, there is enough signal to effectively predict mortality during the first 6h of admission. The proposed framework, in particular the one that uses the ensemble learning approach - EMPICU Random Forest (EMPICU-RF) offers a base to construct an effective and novel mortality prediction model in the early hours of an ICU patient admission, with an improved performance profile. PMID- 29132627 TI - Examining health disparities by gender: A multimorbidity network analysis of electronic medical record. AB - PROBLEM: Multimorbidity health disparities have not been well examined by gender. Co-occurring diseases may be mutually deleterious, co-occurring independently, or co-occurring from a common antecedent. Diseases linked by a common antecedent may be caused by biological, behavioral, social, or environmental factors. This paper aims to address the co-occurrences of diseases using network analysis. METHODS: In this study, we identify these multi-morbidities from a large electronic medical record (EMR) containing diagnoses, symptoms and treatment data on more than 22.1 million patients. We create multimorbidity networks from males and females medical records and compare their structural properties. RESULTS: Our macro analysis at the organ-level indicates that females have a stronger multimorbidity network than males. For example, the female multimorbidity network includes six linkages to mental health, wherein the male multimorbidity network includes only two linkages to mental health. The strength of some disease associations between lipid metabolism and chronic heart disorders is stronger in males than females. CONCLUSION: Our multimorbidity network analysis by gender identifies specific differences in disease diagnosis by gender, and presents questions for biological, behavioral, clinical, and policy research. PMID- 29132628 TI - The use of computerized physician order entry with clinical decision support reduces practice variance in ordering preoperative investigations: A retrospective cohort study. AB - BACKGROUND AND GOAL OF STUDY: Over-ordering of routine preoperative investigations is prevalent. Adherence to institutional guidelines differs among physicians. Our institution integrated a Clinical Decision Support (CDS) model into our hospital's Computerized Physician Ordering Entry (CPOE) system to guide physician orders. We investigate if the implementation of CDS into CPOE increases physician adherence to our institutional guidelines. METHODS: A retrospective cohort study in a tertiary academic hospital over 18 months. The CDS model incorporated into the hospital's CPOE system prompts preoperative investigations based on the patient's age, gender, American Society of Anesthesiologists (ASA) score and complexity of the surgery when physicians use the Electronic Admission Form (EAF). These investigations include: Full Blood Count (FBC), Chest Radiography (CXR), Coagulation Panel (CP), Renal Panel (RP) and Electrocardiogram (ECG). Orders are 'concordant' if they followed guidelines; 'over' if they were not required by guidelines, and 'under' if they were required by guidelines but not ordered. RESULTS AND DISCUSSION: 11,792 patients - 7977 patients in the pre implementation group, and 3815 patients in the post-implementation group. After implementation of CDS, overall guideline-concordant ordering rate increased by 3.9%, over orders decreased by 0.6% and under-orders decreased by 3.3% (P<0.001). CP showed the greatest increase in concordant orders by 12.0% and greatest decrease in under-orders by 11.1%. RP, ECG and CXR also showed modest increases in concordance rate. No significant change in ordering of FBC was found, due to the high pre-implementation concordance frequency of 96.3%. ECG and CXR have the lowest rates of concordant orders and highest rates of 'over' orders in both groups. Concordant orders were lowest in ASA 1 patients, and better in patients with higher ASA. Concordant orders across all ASA scores improved significantly after CDS was implemented. CONCLUSION: Implementation of CDS model into the CPOE system has improved physician adherence to guidelines for certain preoperative investigations. PMID- 29132629 TI - To share or not to share: The role of epistemic belief in online health rumors. AB - OBJECTIVES: This paper investigates the role of epistemic belief in affecting Internet users' decision to share online health rumors. To delve deeper, it examines how the characteristics of rumors-true or false, textual or pictorial, dread or wish-shape the decision-making among epistemologically naive and robust users separately. METHODS: An experiment was conducted. Responses were obtained from 110 participants, who were exposed to eight rumors. This yielded 880 cases (110 participants*8 rumors) for statistical analyses. RESULTS: Epistemologically naive participants were more likely to share online health rumors than epistemologically robust individuals. Epistemologically robust participants were more likely to share textual rumors than pictorial ones. However, there were no differences between true and false rumors or between dread and wish rumors for either epistemologically naive or robust participants. CONCLUSIONS: This paper contributes to the understanding of users' health information sharing behavior. It encourages users to cultivate robust epistemic belief in order to improve their online health information processing skills. PMID- 29132630 TI - Evaluating e-consultation implementations based on use and time-line across various specialties. AB - BACKGROUND: Electronic Consultation (e-consults) can provide improved access, enhance patient and provider satisfaction, and reduce beneficiary travel expenses. We explored how e-consults were implemented across three specialty areas, diabetes (Diab), gastroenterology (GI), and neurosurgery (Neuro), at two Veterans Affairs hospitals in terms of strategies for use and time-lines. METHODS: We conducted observations and electronically shadowed patient e consultations submitted to a specialty care service by primary care provider(s) at the two sites during a thirteen-month period. We divided the e-consult process in each specialty into three broad milestones; Request (from primary to specialty), Response (from specialty back to primary), and Follow up (from primary to patient), and recorded the flow and time in each category. An overall hierarchy of e-consults was developed to illustrate the many ways an e-consult was used. The Kolmogorov-Smirnov test was used to compare the distribution of time across specialties. RESULTS: A total of 394 consults submitted between April 14, 2012 and May 2, 2013 were reviewed (Diab=152, GI=169, Neuro=73). Of the 152 diabetes specialty clinic e-consults, 35% required some sort of direct contact with the patient by the specialty clinic before a recommendation was provided. Overall, 58% of the e-consults were completed within 20days, while 68% were completed within 30days. The Response times between Diab and GI were significantly different (median=0 vs. 3days; p<0.0001) and so were Follow up times (median=0 vs. 4days; p<0.0001). All three stages were statistically different between Diab and Neuro; however, there was not enough evidence to suggest any differences between GI and Neuro. CONCLUSIONS: The use of an e consult is likely to vary based on the specialty, but the often significant variations in time may continue to hinder prompt access to care. E-consult design, implementation, documentation, training, self-learning, and monitoring should be tailored to get the most benefit out of this system. PMID- 29132631 TI - Success or failure of hospital information systems of public hospitals affiliated with Zahedan University of Medical Sciences: A cross sectional study in the Southeast of Iran. AB - INTRODUCTION: After implementation, evaluation of hospital information systems (HISs) is critical to ensure the fulfillment of the system goals. This study aimed to assess the success or failure of HISs in public hospitals affiliated with Zahedan University of Medical Sciences. MATERIALS AND METHODS: A cross sectional descriptive and analytic study was performed in 2016. The study population comprised IT and HIS authorities and hospital information system users. The sample consisted of 468 participants. The data were collected using two questionnaires and analyzed with the SPSS software using descriptive and analytical statistics. RESULTS: The mean score of functional, behavioral, ethical, organizational, cultural and educational factors from the users' perspective was 3.14+/-0.66, 2.97+/- 0.60, 3.39+/-0.70, 2.96+/-0.642, 3.09+/ 0.63, and 2.95+/-0.74, respectively. The mean score of organizational, behavioral, cultural, technological, educational and legal factors from IT and HIS authorities' perspective was 3.51+/-0.54, 3.35+/-0.45, 2.75+/-0.61, 3.58+/ 0.32, and 3.96+/-0.59, respectively. CONCLUSIONS: The evaluated hospital information systems were considered relatively successful in terms of functional, ethical, and cultural factors but were considered as a relative failure in terms of behavioral, organizational, and educational factors form the users' perspective. Only the legal factor showed success, while organizational, behavioral, technical and educational factors showed relative success and the cultural factor showed relative failure from HIS and IT authorities' perspective. Therefore, assessing the users' needs before implementing the system, involving them in various stages of implementation, training them, and improving their computer skills seem to be necessary to achieve a better level of system success. PMID- 29132632 TI - Improved detection of congestive heart failure via probabilistic symbolic pattern recognition and heart rate variability metrics. AB - OBJECTIVE: A timely diagnosis of congestive heart failure (CHF) is crucial to evade a life-threatening event. This paper presents a novel probabilistic symbol pattern recognition (PSPR) approach to detect CHF in subjects from their cardiac interbeat (R-R) intervals. METHOD: PSPR discretizes each continuous R-R interval time series by mapping them onto an eight-symbol alphabet and then models the pattern transition behavior in the symbolic representation of the series. The PSPR-based analysis of the discretized series from 107 subjects (69 normal and 38 CHF subjects) yielded discernible features to distinguish normal subjects and subjects with CHF. In addition to PSPR features, we also extracted features using the time-domain heart rate variability measures such as average and standard deviation of R-R intervals. RESULTS: An ensemble of bagged decision trees was used to classify two groups resulting in a five-fold cross-validation accuracy, specificity, and sensitivity of 98.1%, 100%, and 94.7%, respectively. However, a 20% holdout validation yielded an accuracy, specificity, and sensitivity of 99.5%, 100%, and 98.57%, respectively. Results from this study suggest that features obtained with the combination of PSPR and long-term heart rate variability measures can be used in developing automated CHF diagnosis tools. PMID- 29132633 TI - The use of online forums by people living with HIV for help in understanding personal health information. AB - PURPOSE: Effective self-management of the human immunodeficiency virus/acquired immune deficiency virus (HIV/AIDS) requires constant vigilance over personal health information. Little is known about the contribution of online communities to this endeavour. This paper reports a study to investigate how people living with HIV/AIDS use an online community to try to understand their personal health information by analysing how health information is shared and asked about, and how the community responds to questions. METHODS: A webscraper was used to gather all messages in the 200 most recently active threads in an online forum for people living with HIV/AIDS, resulting in a total of 2455 messages. These were filtered for all instances of individuals sharing their personal health information and asking the community for help in understanding it. Thematic analysis was used to determine the types of questions asked, the personal health information shared and the information that was asked about. Messages from the community aiming to address the questions were analysed using a framework of social support. RESULTS: Approximately 10% of the 2455 messages were found to be involved in this activity: 60 messages contained questions, and 192 messages responded to address the questions. The most frequent type of question was about causation. While users shared a wide variety of information about their health, they most commonly asked about reactions, lab results, and other conditions. Nearly all the messages from the community that aimed to answer the questions provided informational support, which is a type of social support, and the community shared their own personal experiences in these responses. CONCLUSIONS: This study demonstrates that online forums are used by people living with HIV to ask specific questions as a means of understanding their personal health information. The analysis provides a better understanding of the questions that people living with HIV have about their health information, and the types of support they receive from the community. The results provide a basis for further research into community support and self-management and will enable improved tools to support self-management. PMID- 29132634 TI - A model to determine payments associated with radiology procedures. AB - OBJECTIVE: Across the United States, there is a growing number of patients in Accountable Care Organizations and under risk contracts with commercial insurance. This is due to proliferation of new value-based payment models and care delivery reform efforts. In this context, the business model of radiology within a hospital or health system context is shifting from a primary profit center to a cost-center with a goal of cost savings. Radiology departments need to increasingly understand how the transactional nature of the business relates to financial rewards. The main challenge with current reporting systems is that the information is presented only at an aggregated level, and often not broken down further, for instance, by type of exam. As such, the primary objective of this research is to provide better visibility into payments associated with individual radiology procedures in order to better calibrate expense/capital structure of the imaging enterprise to the actual revenue or value-add to the organization it belongs to. MATERIALS AND METHODS: We propose a methodology that can be used to determine technical payments at a procedure level. We use a proportion based model to allocate payments to individual radiology procedures based on total charges (which also includes non-radiology related charges). RESULTS: Using a production dataset containing 424,250 radiology exams we calculated the overall average technical charge for Radiology to be $873.08 per procedure and the corresponding average payment to be $326.43 (range: $48.27 for XR and $2750.11 for PET/CT) resulting in an average payment percentage of 37.39% across all exams. DISCUSSION: We describe how charges associated with a procedure can be used to approximate technical payments at a more granular level with a focus on Radiology. The methodology is generalizable to approximate payment for other services as well. Understanding payments associated with each procedure can be useful during strategic practice planning. CONCLUSIONS: Charge-to-total charge ratio can be used to approximate radiology payments at a procedure level. PMID- 29132635 TI - Need of informatics in designing interoperable clinical registries. AB - Clinical registries are designed to collect information relating to a particular condition for research or quality improvement. Intuitively, informatics in the area of data management and extraction plays a central role in clinical registries. Due to various reasons such as lack of informatics awareness or expertise, there may be little informatics involvement in designing clinical registries. In this paper, we studied a clinical registry from two critical perspectives, data quality and interoperability, where informatics can play a role. We evaluated these two aspects of an existing registry, Gynecology Surgery Registry, by mapping data elements and value sets, used in the registry, to a standardized terminology, SNOMED-CT. The results showed that majority of the values are ad-hoc and only 6 of 91 procedures in the registry could be mapped to the SNOMED-CT. To tackle this issue, we assessed the feasibility of automated data abstraction process, by training machine learning classifiers, based on existing manually extracted data. These classifiers achieved a reasonable average F-measure of 0.94. We concluded that more informatics engagement is needed to improve the interoperability, reusability, and quality of the registry. PMID- 29132636 TI - Systematic data ingratiation of clinical trial recruitment locations for geographic-based query and visualization. AB - BACKGROUND: Prior studies of clinical trial planning indicate that it is crucial to search and screen recruitment sites before starting to enroll participants. However, currently there is no systematic method developed to support clinical investigators to search candidate recruitment sites according to their interested clinical trial factors. OBJECTIVE: In this study, we aim at developing a new approach to integrating the location data of over one million heterogeneous recruitment sites that are stored in clinical trial documents. The integrated recruitment location data can be searched and visualized using a map-based information retrieval method. The method enables systematic search and analysis of recruitment sites across a large amount of clinical trials. METHODS: The location data of more than 1.4 million recruitment sites of over 183,000 clinical trials was normalized and integrated using a geocoding method. The integrated data can be used to support geographic information retrieval of recruitment sites. Additionally, the information of over 6000 clinical trial target disease conditions and close to 4000 interventions was also integrated into the system and linked to the recruitment locations. Such data integration enabled the construction of a novel map-based query system. The system will allow clinical investigators to search and visualize candidate recruitment sites for clinical trials based on target conditions and interventions. RESULTS: The evaluation results showed that the coverage of the geographic location mapping for the 1.4 million recruitment sites was 99.8%. The evaluation of 200 randomly retrieved recruitment sites showed that the correctness of geographic information mapping was 96.5%. The recruitment intensities of the top 30 countries were also retrieved and analyzed. The data analysis results indicated that the recruitment intensity varied significantly across different countries and geographic areas. CONCLUSION: This study contributed a new data processing framework to extract and integrate the location data of heterogeneous recruitment sites from clinical trial documents. The developed system can support effective retrieval and analysis of potential recruitment sites using target clinical trial factors. PMID- 29132638 TI - Impact of an integrated electronic handover tool on pediatric junior medical staff (JMS) handover. AB - BACKGROUND: Clinical medical handover between doctors forms a critical part of the patient care process. However, with the evolution of junior medical staff (JMS) working conditions, time pressure and increasing clinical and administrative loads mean that quality clinical handover is increasingly important yet more challenging to achieve. This study evaluated the impact of a newly integrated electronic handover tool on JMS adoption and usage of the tool, as well as impacts on the quality (accuracy and redundancy) of handover data, JMS perceived workflow (time management and communication) and JMS satisfaction. FINDINGS: The majority of JMS surveyed used the tool at 1 (87.0%) and 3 (67.4%) months post implementation. After the introduction of the electronic handover tool, 67.5% of users spent less than 15min updating handover data in the electronic handover tool, compared to just 6.7% prior to the introduction. 28.3% of respondents noted that there was >25% redundant data, compared to more than half (52.2%) prior to introduction of the electronic tool. Overall JMS satisfaction with their handover process was significantly higher post implementation of the integrated electronic handover report (17.4% pre, 80.4% at 1 month, 67.4% at 3 months). CONCLUSION: A newly introduced integrated electronic medical record handover tool had a high uptake amongst JMS, and resulted in improvement in perceived handover efficiency, a reduction in redundant data entry and improved JMS handover satisfaction. PMID- 29132637 TI - Coding acute stroke care and telestroke with the International Classification of Health Interventions (ICHI). AB - BACKGROUND: and purpose: Acute stroke care is to detect, diagnose, and treat patients in the shortest amount of time. Access to acute stroke care may however be limited in some areas and telemedicine has been thus used to increase its access. Coding acute stroke care as a health intervention had limited attention in the past. METHODS: The International Classification of Health Interventions (ICHI) currently under development was used to identify existing codes relevant for coding acute stroke care interventions, including telestroke. A review of the ICHI was conducted to identify codes relevant for acute stroke care by two independent reviewers. RESULTS: A matching ICHI code was found for each of the steps in the acute stroke care process but no ICHI codes were available to specifically capture telestroke. CONCLUSION: As telemedicine intervention is likely to become more common in the future, it will be imperative that the ICHI is able to code such interventions. PMID- 29132639 TI - Technical attributes, health attribute, consumer attributes and their roles in adoption intention of healthcare wearable technology. AB - PURPOSE: This paper aims to explore factors influencing the healthcare wearable technology adoption intention from perspectives of technical attributes (perceived convenience, perceived irreplaceability, perceived credibility and perceived usefulness), health attribute (health belief) and consumer attributes (consumer innovativeness, conspicuous consumption, informational reference group influence and gender difference). DESIGN/METHODOLOGY/APPROACH: By integrating technology acceptance model, health belief model, snob effect and conformity and reference group theory, hypotheses and research model are proposed. The empirical investigation (N=436) collects research data through questionnaire. FINDINGS: Results show that the adoption intention of healthcare wearable technology is influenced by technical attributes, health attribute and consumer attributes simultaneously. For technical attributes, perceived convenience and perceived credibility both positively affect perceived usefulness, and perceived usefulness influences adoption intention. The relation between perceived irreplaceability and perceived usefulness is only supported by males. For health attribute, health belief affects perceived usefulness for females. For consumer attributes, conspicuous consumption and informational reference group influence can significantly moderate the relation between perceived usefulness and adoption intention and the relation between consumer innovativeness and adoption intention respectively. What's more, consumer innovativeness significantly affects adoption intention for males. ORIGINALITY/VALUE: This paper aims to discuss technical attributes, health attribute and consumer attributes and their roles in the adoption intention of healthcare wearable technology. Findings may provide enlightenment to differentiate product developing and marketing strategies and provide some implications for clinical medicine. PMID- 29132640 TI - Fluorescence enhancement for noble metal nanoclusters. AB - Noble metal nanoclusters have attracted great attentions in the area of fluorescence related applications due to their special properties such as low toxicity, excellent photostability and bio-compatibility. However, they still describe disadvantages for low quantum yield compared to quantum dots and organic dyes though the brightness of the fluorescence play an important role for the efficiency of the applications. Attentions have been attracted for exploring strategies to enhance the fluorescence based on the optical fundamentals through various protocols. Some methods have already been successfully proposed for obtaining relative highly fluorescent nanoclusters, which will potentially describe advantages for the application. In this review, we summarize the approach for enhancement of the fluorescence of the nanoclusters based on the modification of the properties, improvement of the synthesis process and optimization of the environment. The limitation and directions for future development of the fabrication of highly fluorescent metal nanoclusters are demonstrated. PMID- 29132641 TI - Force Spectroscopy with 9-MUs Resolution and Sub-pN Stability by Tailoring AFM Cantilever Geometry. AB - Atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) is a powerful yet accessible means to characterize the unfolding/refolding dynamics of individual molecules and resolve closely spaced, transiently occupied folding intermediates. On a modern commercial AFM, these applications and others are now limited by the mechanical properties of the cantilever. Specifically, AFM-based SMFS data quality is degraded by a commercial cantilever's limited combination of temporal resolution, force precision, and force stability. Recently, we modified commercial cantilevers with a focused ion beam to optimize their properties for SMFS. Here, we extend this capability by modifying a 40 * 18 MUm2 cantilever into one terminated with a gold-coated, 4 * 4 MUm2 reflective region connected to an uncoated 2-MUm-wide central shaft. This "Warhammer" geometry achieved 8.5-MUs resolution coupled with improved force precision and sub-pN stability over 100 s when measured on a commercial AFM. We highlighted this cantilever's biological utility by first resolving a calmodulin unfolding intermediate previously undetected by AFM and then measuring the stabilization of calmodulin by myosin light chain kinase at dramatically higher unfolding velocities than in previous AFM studies. More generally, enhancing data quality via an improved combination of time resolution, force precision, and force stability will broadly benefit biological applications of AFM. PMID- 29132642 TI - Validity of Arabic version of the two-question Quick Inventory of Depression (QID 2-Ar): Screening for multiple sclerosis in an Arab environment and during the Syrian war. AB - PURPOSE: This study aimed to validate the Arabic version of the two-question Quick Inventory of Depression (QID-2-Ar) in multiple sclerosis (MS) patients living in Syria during the war. METHODS: A total of 100 Syrian MS patients, aged 18-60 years, were recruited at Damascus Hospital and Ibn Al-Nafees Hospital to validate the QID-2-Ar, including analyses of its screening test parameters and its construct validity. RESULTS: The QID-2-Ar screening parameters for depression tested very positively, and its construct validity was also favorable (P<0.01). CONCLUSION: The QID-2-Ar is a good screening test for detecting depression. Using a threshold score of >=1 rather than 2 resulted in more depressed patients being correctly identified. The Arabic version of the QID-2-Ar also has highly favorable psychometric properties. It is valid for assessing depression, especially the two main depressive symptoms (depressive mood and anhedonia) listed in DSM-V. This is a useful tool for researchers and practitioners, and a threshold score of 2 on the QID-2-Ar is recommended to be more certain that all those with depression are detected without having to use a complete depression questionnaire such as the Beck Depression Inventory (BDI)-II. PMID- 29132643 TI - Guillain-Barre syndrome due to hepatitis E. PMID- 29132644 TI - Delineating sites of failure following post-prostatectomy radiation treatment using 68Ga-PSMA-PET. AB - PURPOSE: To identify sites of failure with 68Ga-PSMA-PET (PSMA-PET) imaging in patients who have Biochemical Failure (BF) following post-prostatectomy radiotherapy. MATERIAL AND METHODS: Between June 2006 and January 2016, 409 men received post prostatectomy intensity modulated radiation treatment (IMRT) with protocolised planning. 310 patients received radiation treatment (RT) to the Prostate Fossa (PF) alone and 99 patients received RT to PF and pelvic lymphatics (PF + LN) usually in combination with androgen deprivation (AD) therapy. Any failure not detected on conventional imaging was delineated with PSMA-PET scanning. Sites of failure were characterised as in-field (PF +/- LN), or out of field (nodal alone, distant metastatic alone (visceral or bone) or multi-site failure). Nodal failure was further divided into pelvic failure and/or distant failure. RESULTS: 119 men developed BF, defined as a PSA rise of >0.2 or greater, above post-RT nadir. Freedom from BF was 71% in the PF group and 70% in the PF + LN group, with median follow up of 52 and 44 months respectively. AD was used concomitantly in 13% of the PF group and 92% of the PF + LN group. 81 patients with BF (68%) had PSMA-PET imaging performed as per study intent, 67 (80%) of whom had PSMA avid disease identified. PSMA-PET delineated in-field failure occurred in 2/50 (4%) of the PF group and 1/17 (6%) in the PF + LN group. Nodal failure alone was 33/50 (66%) for the PF group vs 7/17 (41%) for the PF + LN group. For the nodal only failure patients, 18/33 (55%) had pelvic-only nodal failure in the PF group compared to 1/7 (14%) in the PF + LN group (p = 0.03). 16 (32%) of the PSMA avid failures in the PF group would have been encompassed by standard pelvic lymphatic radiotherapy volumes. CONCLUSION: Post-prostatectomy radiation treatment resulted in excellent in-field control rates. Isolated pelvic nodal failure was rare in those receiving radiotherapy to the prostatic fossa and pelvic nodes but accounted for one third of failures in those receiving PF alone treatment. PMID- 29132645 TI - Assessing the 16 hour intern shift limit: Results of a multi-center, mixed methods study of residents and faculty in general surgery. AB - BACKGROUND: The study explores how residents and faculty assess the ACGME's 16-h limit on intern shifts. METHODS: Questionnaire response rates were 76% for residents (N = 291) and 71% for faculty (N = 279) in 13 general surgery residency programs. Results include means, percentage in agreement, and statistical tests for 15 questionnaire items. Semi-structured interviews conducted with 39 residents and 43 faculty were analyzed for main themes. RESULTS: Few view the intern shift limit as a positive change. Views differ (P < 0.01) for residents and faculty on 12 of 15 item means and across PGY levels on all 15 items. Interviews indicate concerns about losses with respect to education and professional development, difficulties when interns transition to their second year, and how intern shifts may be more fatiguing than expected. CONCLUSIONS: The 16-h limit on intern shifts has remained a source of concern and an educational challenge for residents and faculty. PMID- 29132646 TI - Should they stay or should they go now? Exploring the impact of team familiarity on interprofessional team training outcomes. AB - INTRODUCTION: Although simulation is an effective method for enhancing team competencies, it is unclear how team familiarity impacts this process. We examined how team familiarity impacted team competencies. METHODS: Trainees were assigned to stable or dynamic teams to participate in three simulated cases. Situation awareness (SA) data was collected through in-scenario freezes. The recorded performances were assessed for clinical effectiveness (ClinEff) and teamwork. All data are reported on a 1-100% (100% = perfect performance) scale. RESULTS: Forty-six trainees (23 General Surgery; 23 Emergency Medicine) were randomized by specialty into stable (N = 8) or dynamic (N = 7) groups. Overall changes from Sim 1 to Sim3 were 12.2% (p < 0.01), -1.1% (ns), and 7.1% (p < 0.01) for SA, ClinEff, and Teamwork, respectively. However, improvements differed by condition, with stable teams reflecting improvements in ClinEff (15.2%; p < 0.05), whereas dynamic team ClinEff improvement (8.7%) was not significant. Both groups demonstrated improvements in teamwork (stable = 9%, p < 0.05; dynamic = 4.9%, p < 0.05). CONCLUSIONS: Teams who continued to work together demonstrated increased improvements in clinical effectiveness and teamwork, while dynamic teams only demonstrated improvements in teamwork. PMID- 29132647 TI - Normative data for the Patient-Rated Wrist Evaluation questionnaire. AB - STUDY DESIGN: Cross-sectional study. INTRODUCTION: The Patient-Rated Wrist Evaluation (PRWE) questionnaire is used to evaluate functional outcomes after treatment of wrist and hand injuries and nontraumatic conditions. Since patients commonly present with an injury, it is impossible to assess preinjury physical functioning. Therefore, it is important to be aware of the population-based normative data. PURPOSE OF THE STUDY: The aim of this study was to determine the normative data for the PRWE questionnaire. Secondary, we aimed to determine if there were factors influencing these normative data. METHODS: Visitors and employees of 4 hospitals were requested to participate. Excluded were all participants who were scheduled for surgery or were in treatment or after treatment for an injury of the wrist or hand within 1 year after trauma. All participants were asked to complete the PRWE questionnaire and were asked for their age, sex, history of wrist or hand fracture or surgery, daily activities, and the type of employment. The socioeconomic status was determined based on the zip code. RESULTS: The median PRWE score was 0 (interquartile range: 0-8.5) and the mean score 7.7 (standard deviation: 15.0). Women had significantly higher scores compared to men, and younger individuals had significantly lower scores. Participants with a history of wrist or hand fracture or surgery, and participants who were unfit for work had significantly higher scores. Socioeconomic status was not correlated with the PRWE score. DISCUSSION: The purpose was to provide an representative overview of the normative data for the normal population. We did not want to present the data of an unnatural healthy population, which is not representative of the normal population. Deleting patients with chronic wrist or hand complaints, would have resulted in normative values which are not representable for the normal, average population. CONCLUSION: Low scores are observed for the PRWE in the general population. These scores are age and sex dependent and are higher in individuals with a history of wrist or hand fracture or surgery or who are unfit for work. PMID- 29132648 TI - Leisure-Time, Domestic, and Work-Related Physical Activity and Their Prospective Associations With All-Cause Mortality in Patients With Cardiovascular Disease. AB - This study aimed to examine the prospective associations between total physical activity, leisure-time physical activity (LTPA), and domestic and work-related physical activity (DWPA) involving heavy physical labor, with all-cause mortality in patients with cardiovascular disease (CVD). A 7-year follow-up cohort design was used based on the data from the Taiwan 2005 National Health Interview Survey, which was linked to the 2005 to 2012 Taiwan National Health Insurance claims data. Multivariable Cox proportional hazard models were utilized to assess the associations between physical activity and all-cause mortality in 2,370 patients with CVD. Participants who achieved a volume of all physical activities of >=1,000 kcal/week experienced lower risks of all-cause mortality than those who achieved less. Additionally, an inverse relation between LTPA and all-cause mortality was observed. Furthermore, participants who reported exertions (1 to 999 kcal/week) in DWPA had the lowest risk of all-cause mortality. This study provides evidence that patients with CVD who achieve at least a moderate volume of physical activity reduce their mortality risk. It also reveals that both LTPA and DWPA may be important contributors to the reduced risk of premature death among this clinical population. PMID- 29132650 TI - Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and End-Stage Renal Disease. AB - Over the past decade, there have been tremendous advancements in anticoagulation therapies for stroke prevention in patients with atrial fibrillation (AF). Although the non-vitamin K antagonist oral anticoagulants (NOACs) demonstrated favorable clinical outcomes compared with warfarin overall, the decision to anticoagulate and the choice of appropriate agent in patients with AF and concomitant chronic kidney disease (CKD) or end-stage renal disease (ESRD) are a particularly complex issue. CKD and ESRD increase both the risk of stroke and bleeding, and since all of the NOACs undergo various levels of renal clearance, renal dysfunction inevitably affects the pharmacokinetics of the drug in each patient. Furthermore, the randomized controlled clinical trials of each NOAC versus warfarin often did not include patients with advanced CKD or ESRD. In this focused review, we describe the available evidence supporting the use of NOACs for prevention of stroke in patients with AF with concomitant advanced CKD or ESRD. Although questions of safety and appropriate use of these new agents in CKD and ESRD remain, NOACs offer a significant step forward in the anticoagulation management of at-risk patients with AF. PMID- 29132651 TI - Wide-QRS Complex Tachycardia. AB - In a man with a wide-QRS complex tachycardia, a history of an inferior left ventricular scar, atrioventricular dissociation during the tachycardia, and a QRS morphology inconsistent with right or left bundle branch block exclude a diagnosis of supraventricular tachycardia with aberrant ventricular conduction due to bundle branch block or ventricular preexcitation and establish a diagnosis of ventricular tachycardia. PMID- 29132649 TI - Doppler Versus Thermodilution-Derived Coronary Microvascular Resistance to Predict Coronary Microvascular Dysfunction in Patients With Acute Myocardial Infarction or Stable Angina Pectoris. AB - Coronary microvascular resistance is increasingly measured as a predictor of clinical outcomes, but there is no accepted gold-standard measurement. We compared the diagnostic accuracy of 2 invasive indices of microvascular resistance, Doppler-derived hyperemic microvascular resistance (hMR) and thermodilution-derived index of microcirculatory resistance (IMR), at predicting microvascular dysfunction. A total of 54 patients (61 +/- 10 years) who underwent cardiac catheterization for stable coronary artery disease (n = 10) or acute myocardial infarction (n = 44) had simultaneous intracoronary pressure, Doppler flow velocity and thermodilution flow data acquired from 74 unobstructed vessels, at rest and during hyperemia. Three independent measurements of microvascular function were assessed, using predefined dichotomous thresholds: (1) coronary flow reserve (CFR), the average value of Doppler- and thermodilution-derived CFR; (2) cardiovascular magnetic resonance (CMR) derived myocardial perfusion reserve index; and (3) CMR-derived microvascular obstruction. hMR correlated with IMR (rho = 0.41, p <0.0001). hMR had better diagnostic accuracy than IMR to predict CFR (area under curve [AUC] 0.82 vs 0.58, p <0.001, sensitivity and specificity 77% and 77% vs 51% and 71%) and myocardial perfusion reserve index (AUC 0.85 vs 0.72, p = 0.19, sensitivity and specificity 82% and 80% vs 64% and 75%). In patients with acute myocardial infarction, the AUCs of hMR and IMR at predicting extensive microvascular obstruction were 0.83 and 0.72, respectively (p = 0.22, sensitivity and specificity 78% and 74% vs 44% and 91%). We conclude that these 2 invasive indices of coronary microvascular resistance only correlate modestly and so cannot be considered equivalent. In our study, the correlation between independent invasive and noninvasive measurements of microvascular function was better with hMR than with IMR. PMID- 29132652 TI - It Is Time to Look for New Treatments for Posttraumatic Stress Disorder: Can Sympathetic System Modulation Be an Answer? PMID- 29132654 TI - Reply to: It Is Time to Look for New Treatments for Posttraumatic Stress Disorder: Can Sympathetic System Modulation Be an Answer? PMID- 29132653 TI - Prefrontal and Striatal Gamma-Aminobutyric Acid Levels and the Effect of Antipsychotic Treatment in First-Episode Psychosis Patients. AB - BACKGROUND: Abnormally elevated levels of gamma-aminobutyric acid (GABA) in the medial prefrontal cortex (mPFC) have been reported in antipsychotic-free patients with schizophrenia. Whether such GABA elevations are also present in other brain regions and persist after antipsychotic treatment has not been previously investigated. METHODS: Twenty-eight antipsychotic-naive patients with first episode psychosis (FEP) and 18 healthy control subjects completed the study. Following baseline proton magnetic resonance spectroscopy scans targeting the mPFC and a second region, the dorsal caudate, patients with FEP were treated with oral risperidone for 4 weeks at an initial dose of 1 mg/day that was titrated as necessary based on clinical judgment. After the 4-week treatment period, both groups were brought back to undergo outcome magnetic resonance spectroscopy scans, which were identical to the scans conducted at baseline. RESULTS: At baseline, higher GABA levels were found both in the mPFC and in the dorsal caudate of patients with FEP compared with healthy control subjects. Following 4 weeks of antipsychotic treatment, GABA levels in patients with FEP decreased relative to baseline in the mPFC, but decreased only at the trend level relative to baseline in the dorsal caudate. For either brain region, GABA levels at 4 weeks or posttreatment did not differ between patients with FEP and healthy control subjects. CONCLUSIONS: The results of the present study documented elevations of GABA levels both in the mPFC and, for the first time, in the dorsal caudate of antipsychotic-naive patients with FEP, which normalized in both regions following 4 weeks of antipsychotic treatment. PMID- 29132655 TI - ? PMID- 29132656 TI - ? PMID- 29132657 TI - [Assessment to carry out with a patient who has suffered a fall]. AB - A fall in an elderly person can lead to severe complications. It is a serious event which must not be minimised in any way and which must serve as a warning signal for the caregiver. The exploration of the factors involved requires a detailed and comprehensive evaluation of the patient. A complete assessment coordinated by a geriatric doctor is recommended. PMID- 29132658 TI - [Elderly hospitalised people and walking capacities]. AB - Falls in the elderly are frequent. A study carried out over 6 months in a university hospital's acute geriatric unit highlighted the real walking capacities of hospitalised elderly people. It also changed the perception of caregivers, doctors and nurses with regard to the real physical aptitudes of these patients enabling the risk of falls to be reduced in preparation for their return home or to a residential care home. PMID- 29132659 TI - [Assessment of walking problems in the elderly person]. AB - Walking problems represent a major public health issue in the geriatric population due to their frequency and the dramatic consequences they cause. They also mark a starting point of the physical frailty of elderly people. Their early detection should result in adapted functional rehabilitation in order to reduce the associated complications. Overview of walking problems in the elderly and the clinical means for assessing them. PMID- 29132660 TI - [Remote assistance in the home for fall detection]. AB - Remote assistance first appeared in the 1970s and the equipment has since evolved. Today, 20% of falls in elderly people aged 80 or over are detected by a remote assistance call. There are obstacles to the development of this system, notably the stigmatisation of old age and frailty. There is also the coexistence of the fear of disturbing neighbours, a feeling of an invasion of freedom and a certain fatality. Above all, remote assistance must remain an individual choice. PMID- 29132661 TI - [The occupational therapist and the assessment of the elderly person's home]. AB - The falls of elderly people in their home are frequently related to the environment. Plans and photographs of the home provided by the patient's relatives are useful and constitute relevant assessment tools. The home visit is even more effective as it helps to identify areas which pose a high risk of falling which cannot be picked up by the other tools. PMID- 29132662 TI - [Delirium in a nursing home: a survey of general practitioners]. AB - Delirium is all the more frequent and serious when it occurs in a nursing home. A study was carried out to assess the current practices of general practitioners in the management of delirium in a nursing home in order to identify the issues involved and to suggest areas for improvement. The doctors identified three main difficulties: the management of behavioural disorders, the conditions of practice of a private practitioner in a healthcare institution and the relations with the different caregivers of the nursing home. PMID- 29132663 TI - [The management of risks related to deaths in geriatrics]. AB - Caregivers are inevitably exposed to the death of the people they care for as almost all deaths occur in a health or medical-social facility. This generates emotional situations which naturally impact on caregivers in their everyday work. The healthcare manager must take into account this reality in the management of risks related to the issue of death. PMID- 29132664 TI - ? PMID- 29132665 TI - ? PMID- 29132666 TI - Prevention of Food Allergies. AB - This review summarizes the current state of play with regard to food allergy prevention. Food allergy prevention strategies focused on promoting timely introduction of allergenic foods (predominantly peanut) into the infant diet have recently been introduced in several countries. Additional prevention strategies currently under investigation include optimizing infant vitamin D levels, modulating the gut microbiota through use of probiotics, and preventing eczema to reduce the risk of food sensitization through a damaged skin barrier. PMID- 29132667 TI - Complementary and Alternative Medicine for Treatment of Food Allergy. AB - The prevalence of food allergy is increasing. Food allergy can be life threatening and there is no approved treatment available. Allergen avoidance and rescue medication remain the sole management tools. Complementary and alternative medicine (CAM) use is common in the United States. However, research into safety and efficacy for food allergy is limited. Continued scientific research into food allergy herbal formula 2 (FAHF-2), refined methods of formulation, purified compounds, and other modalities are needed. Traditional Chinese medicine is the main component of CAM in the United States. Conventional doctors, CAM practitioners, and patients' families must collaborate to comanage these patients. PMID- 29132669 TI - Epidemiology of Food Allergy. AB - Understanding the epidemiology of food allergy is complicated by the difficulty of identifying it on a large scale. The prevalence of food allergy is higher in younger age groups and decreases with age. Allergy to peanut and egg seems to be more common in Northern Europe, the United States, Canada and Australia compared with Southern Europe, Eastern Europe and Asia, whereas shellfish and fish allergies may be more common in Asia. The rate of transient unrecognized food allergy may be high and variable recognition of food allergy may explain some of the differences seen in food allergy prevalence. PMID- 29132668 TI - Diagnosis and Management of Eosinophilic Esophagitis. AB - Unlike traditional food allergies, immunoglobulin E (IgE) is not a key mediator of eosinophilic esophagitis (EoE). Nonetheless, foods antigens are important triggers of EoE, and allergists play an important role in management of this chronic disease. This review addresses insights into the diagnosis and management as it relates to our evolving understanding about the pathogenesis of EoE. PMID- 29132670 TI - Food Protein-Induced Enterocolitis Syndrome. AB - Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that usually presents in infancy. Cow's milk, soy, and grains are the most common food triggers. FPIES can present as a medical emergency with symptoms including delayed persistent emesis or diarrhea that can lead to severe dehydration and hemodynamic instability with abnormal laboratory markers. Diagnosis can often be made based on clinical history and noted improvement in symptoms once the suspected triggers have been removed from the diet, with oral food challenge as the gold standard for confirmation of diagnosis in unclear cases. PMID- 29132671 TI - Unproven Diagnostic Tests for Food Allergy. AB - The gold standard for diagnosis of immunoglobulin E (IgE)-mediated food allergy remains the oral food challenge, with serum IgE testing and skin prick testing serving as acceptable alternatives. However, the increase in prevalence of food allergy (both physician diagnosed and patient suspected) has led patients to pursue a variety of other alternative diagnostic procedures for suspected food allergy, which are reviewed in this article. These procedures (IgG testing, electrodermal testing, cytotoxic testing, provocation/neutralization, and applied kinesiology) have largely been unproven and may lead to unnecessary elimination diets. PMID- 29132673 TI - Diagnosis of Food Allergy. AB - Food allergy diagnosis remains challenging. Most standard methods are unable to differentiate sensitization from clinical allergy. Recognizing food allergy is of utmost importance to prevent life-threatening reactions. On the other hand, faulty interpretation of tests leads to overdiagnosis and unnecessary food avoidances. Highly predictive models have been established for major food allergens based on skin prick testing and food-specific immunoglobulin E but are lacking for most other foods. Although many newer diagnostic techniques are improving the accuracy of food allergy diagnostics, an oral food challenge remains the only definitive method of confirming a food allergy. PMID- 29132672 TI - Oral Tolerance Development and Maintenance. AB - The gastrointestinal tract has an abundant mucosal immune system to develop and maintain oral tolerance. The oral route of administration takes advantage of the unique set of immune cells and pathways involved in the induction of oral tolerance. Food allergy results from a loss of oral tolerance toward ingested antigens. Oral immunotherapy is thought to initiate desensitization through interaction of an allergen with mucosal dendritic cells that initiate downstream immune system modulation through regulatory T cells and effector T cells. PMID- 29132675 TI - The Role of Baked Egg and Milk in the Diets of Allergic Children. AB - Baked egg and baked milk are tolerated by most children who are allergic to hen's egg and cow's milk. Incorporating baked goods into the diets of allergic children may help them outgrow their primary allergy more quickly, with changes observed akin to immunotherapy. Benefits may also include increased quality of life and improved nutritional status. The search for a reliable biomarker to predict tolerance to baked goods is ongoing. Most children with a milk or egg allergy who are not previously tolerating egg or milk in baked goods should be offered an observed oral food challenge. PMID- 29132674 TI - Food Allergy Management. AB - The management of food allergies requires the cooperation of the food allergic person, physician, family, and social contacts. For children, school management of food allergies is a key component of the overall approach. Recognition of the signs and symptoms of allergic reactions and preparation to administer the appropriate treatment of mild and severe symptoms in the event of accidental exposure is necessary. Avoidance of food allergens is facilitated by label reading and dietary guidance is extremely important to minimize nutritional deficiencies. Medications and vaccines with food-derived excipients generally do not need to be avoided because, in most cases, they contain little food protein. PMID- 29132676 TI - Interventional Therapies for the Treatment of Food Allergy. AB - Treatment of IgE-mediated food allergies is limited to allergen avoidance and emergency treatment on accidental ingestion, which is not uncommon. In recent years, interest in interventional therapies to treat food allergy has increased significantly. Although oral, sublingual, and epicutaneous immunotherapy have shown promise in studies, none is approved as therapy for food allergy to date and questions remain regarding efficacy, safety, dosing, and duration of therapy. PMID- 29132677 TI - Adjuvant Therapies in Food Immunotherapy. AB - Finding an effective curative treatment for food allergy is a research priority. Although oral immunotherapy (OIT) is effective at inducing desensitization, the temporary nature of this effect and high rates of adverse reactions have highlighted a need for novel strategies to improve tolerance induction and safety. One such strategy is the use of an adjuvant together with food immunotherapy to either suppress allergic reactions and/or modulate the underlying allergic immune response. In particular, the use of bacterial adjuvants seems to be a promising means of enhancing OIT-induced sustained unresponsiveness and warrants further investigation. PMID- 29132678 TI - The Quest for Food Allergy Treatments: On Course and Gaining Steam...Finally. PMID- 29132679 TI - Food Allergy. PMID- 29132681 TI - [DNA repair as a therapeutic target]. AB - The transmission of an intact and stable genetic code at each cell division relies on different DNA repair systems. Germline mutations of some of these genes cause cancer predisposition, whereas somatic mutations are frequently found in various cancer types, generating genomic instability. As a consequence, cancer cell becomes more susceptible to additional DNA damage. Pharmacological inhibition of DNA repair pathways exploits this frailty: it triggers more damages than cancer cell can tolerate, finally leading to apoptosis. The success of PARP (poly-ADP-ribose polymerase) inhibitors in BRCA1/2-mutated ovarian cancer shows the clinical relevance of this strategy. Herein, we explain the functioning of different DNA-repair pathways, describe the implicated proteins, and their close relation with cell-cycle checkpoints. We focus on novel therapeutic agents targeting DNA repair, their clinical results, and discuss challenges of combination therapies. PMID- 29132682 TI - [Biomarkers of radiation-induced DNA repair processes]. AB - The identification of DNA repair biomarkers is of paramount importance. Indeed, it is the first step in the process of modulating radiosensitivity and radioresistance. Unlike tools of detection and measurement of DNA damage, DNA repair biomarkers highlight the variations of DNA damage responses, depending on the dose and the dose rate. The aim of the present review is to describe the main biomarkers of radiation-induced DNA repair. We will focus on double strand breaks (DSB), because of their major role in radiation-induced cell death. The most important DNA repair biomarkers are DNA damage signaling proteins, with ATM, DNA PKcs, 53BP1 and gamma-H2AX. They can be analyzed either using immunostaining, or using lived cell imaging. However, to date, these techniques are still time and money consuming. The development of "omics" technologies should lead the way to new (and usable in daily routine) DNA repair biomarkers. PMID- 29132683 TI - [Impairment of DNA damage response and cancer]. AB - Maintaining the genetic integrity is a key process in cell viability and is enabled by a wide network of repair pathways. When this system is defective, it generates genomic instability and results in an accumulation of chromosomal aberrations and mutations that may be responsible for various clinical phenotypes, including susceptibility to develop cancer. Indeed, these defects can promote not only the initiation of cancer, but also allow the tumor cells to rapidly acquire mutations during their evolution. Several genes are involved in these damage repair systems and particular polymorphisms are predictive of the onset of cancer, the best described of them being BRCA. In addition to its impact on carcinogenesis, the DNA damage repair system is now considered as a therapeutic target of choice for cancer treatment, as monotherapy or in combination with other cytotoxic therapies, such as chemotherapies or radiotherapy. PARP inhibitors are nowadays the best known, but other agents are emerging in the field of clinical research. The enthusiasm in this area is coupled with promising results and a successful collaboration between clinicians and biologists would allow to optimize treatment plans in order to take full advantage of the DNA repair system modulation. PMID- 29132684 TI - Interactions between lactobacilli and chicken macrophages induce antiviral responses against avian influenza virus. AB - Macrophages are an important cell type of the innate immune system that upon activation, can exert antiviral functions and also can induce virus-specific adaptive immune responses. Macrophage interaction with certain probiotic bacteria such as lactobacilli can enhance antiviral functions of these cells. We have previously shown that administration of lactobacilli to chickens can effectively augment immune response to vaccine antigens. Here, we investigated the effects of representative strains of three Lactobacillus species, L. acidophilus, L. reuteri and L. salivarius used alone or in combination, in enhancing antiviral activity of chicken macrophages against avian influenza virus in an in vitro model using MQ-NCSU cells. Treatment of macrophages with probiotic lactobacilli significantly enhanced the antiviral functions, as determined by the virus titration assay. We also found that lactobacilli stimulation of macrophages induced significantly higher expression of interleukin (IL)-1beta, interferon (IFN)- gamma and IFN alpha cytokine genes as well as interferon regulatory factor-7 (IRF7), 2',5' oligoadenylate synthetase (OAS) and interferon-inducible transmembrane protein M3 (IFITM3) genes. Furthermore, macrophages that were treated with lactobacilli had significantly enhanced production of nitric oxide (NO) and IFN-gamma protein as well as surface expression of the costimulatory molecule CD40. However, the antiviral and immunostimulatory effects of probiotic lactobacilli largely depended on the Lactobacillus species studied. Collectively, the results from our study using an in vitro model showed that certain Lactobacillus species can effectively augment antiviral responses in chicken macrophages. PMID- 29132685 TI - First report on the isolation of Trueperella abortisuis from companion animals. AB - The present study gives a detailed phenotypic and genotypic characterization of three Trueperella abortisuis strains isolated from a ten year old male Hovawart dog with an abscess of anal sac, from urine of an eight year old European shorthair cat with urolithiasis and nephrolithiasis and from a 14year old Maine Coon cat with a perianal abscess, respectively. All three strains could be identified phenotypically, by MALDI-TOF MS analysis and genotypically by sequencing the 16S rDNA and the molecular target genes gap and tuf. The present study gives a first description of T. abortisuis of this origin. PMID- 29132686 TI - An infrequent case of anaphylaxis. PMID- 29132687 TI - Pliocene crocodiles from Kanapoi, Turkana Basin, Kenya. AB - Three crocodylid species are known from the Pliocene Kanapoi locality in the western Turkana Basin. One of these, Crocodylus thorbjarnarsoni, includes material previously referred to Crocodylus niloticus (the modern Nile crocodile currently living in Lake Turkana) and Rimasuchus lloydi. C. thorbjarnarsoni was a gigantic horned crocodile similar in overall shape to most other generalized crocodylids, but its closest known relative is another extinct species, Crocodylus anthropophagus from the Pleistocene of Olduvai Gorge in Tanzania. It is not closely related to C. niloticus. The second is an extinct form of sharp nosed crocodile (Mecistops), a group of slender-snouted crocodylids currently restricted to western and central Africa. The third is Euthecodon, a crocodylid with an extremely long, slender, and distinctively notched snout. Euthecodon and C. thorbjarnarsoni are known from substantial numbers of specimens, but only one Mecistops specimen has been identified from the locality. The crocodylian fauna at Kanapoi is taxonomically similar to that of most other Plio-Pleistocene fluviolacustrine deposits in the Turkana Basin. Crocodylian diversity in the Turkana region contracted from a peak of five co-existing species in the late Miocene to one today; this contraction was underway by the early Pliocene, but crocodylian diversity remained stable at three species until well into the Quaternary. PMID- 29132688 TI - Temporal trends in outpatient management of incident pulmonary embolism and associated mortality. AB - INTRODUCTION: In clinical trial settings, outpatient management of pulmonary embolism (PE) is feasible and safe, but less is known on its use in routine care. We determined trends in outpatient management of PE and associated mortality in a large non-select patient population. METHODS: All residents of Quebec, Canada with a first-ever work-up for suspected PE in the emergency department (ED) over 10years were included. Patients could transition to outpatient management and from unconfirmed to confirmed PE in a time-varying fashion. Comparing the years 2005-9 with 2000-4, we assessed the odds ratio (OR) for outpatient management, and relative risk (RR) for all-cause mortality, readmissions for PE, and major bleeding in 30days. We adjusted the RR for a mortality risk score. RESULTS: Of 15,217 patients included, 7583 were outpatients (7.5% confirmed PE) and 7634 were inpatients (60.6% confirmed PE). In all, 10.9% of patients with confirmed PE were outpatients, but outpatient management of confirmed PE was more likely in the latter study period (OR 1.73, 95%CI 1.44-2.09). Among outpatients with confirmed PE, mortality (RR 0.84, 95%CI 0.15-4.61) and readmission (RR 1.25, 95%CI 0.45 3.48) rates were stable, and only 3 major bleeding events were noted. Inpatients with confirmed PE had stable mortality rates (RR 0.95, 95%CI 0.72-1.24). CONCLUSION: Outpatient PE management increased over 10years while remaining fairly uncommon. Nevertheless, stable mortality and readmission rates indicate this practice is safe in routine care, and add to the growing evidence in support of outpatient PE management. PMID- 29132689 TI - Raw Genomic Data: Storage, Access, and Sharing. AB - Patients are increasingly being encouraged and supported to access and control their own medical and genomic data. We argue that well-established and transparent raw genomic data retention and returning policies are imperative to enable patients to practice their rights to access and control raw data. PMID- 29132690 TI - Cyclin-dependent kinase 5 regulates MAPK/ERK signaling in the skin of mice. AB - Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase that has been shown to play important roles in many tissues except the nervous system. We previously reported that CDK5 showed differential expression in the transcriptome profiles of the skin of alpacas with different hair colors. To understand the functional role of CDK5 in hair color determination, we constructed CDK5-knockdown mice and identified the effect on the mitogen activated protein kinase (MAPK) pathway in the mouse skin. Quantitative real-time polymerase chain reaction, co-immunoprecipitation, and western blotting were performed to analyze the effects of CDK5-knockdown on the MAPK pathway in mice. The results showed that MAP3K6 was inhibited by phosphorylated CDK5 through its activator CDK7. The decrease in MAP3K6 levels caused down-regulation of MEK1 and ERK expression, leading to the up-regulation of miR-143-3p, which targets MAP3K6 via Dicer. Taken together, our findings indicate that CDK5 functions in regulating the MAPK pathway. Given that MAP3K6 was inhibited in two directions, this mechanism can provide insight into the contributions of the MAPK/ERK pathway to the inhibition of melanin production. PMID- 29132691 TI - [Practical assessment of DSAEK in the management of endothelial decompensation following penetrating keratoplasty]. AB - PURPOSE: To report our anatomical and functional results as well as possible complications of the first six Descemet's stripping endothelial keratoplasties (DSAEK) performed in our department for endothelial decompensation after penetrating keratoplasty (PK) METHODS: This was a retrospective and observational monocentric study of six patients with DSAEK after prior PK between January 2015 and July 2016. The data collected were: demographic characteristics (age, sex), ophthalmological comorbidities, initial indication for PK, delay between PK and DSAEK. Best corrected visual acuity (BCVA) preoperatively and at 1, 3 and 6 months postoperatively were collected in Monoyer's and Parinaud scale and converted to log MAR for statistical analysis. The central cornea and graft thickness measured on OCT as well as postoperative complications were also collected. RESULTS: Mean follow-up duration was 7.2 months [3-10]. The average time after PK was 7.7 years. The mean age of the patients was 67.5 years [32-87]. The initial indication for PK was Fuchs dystrophy (3/6), pseudophakic bullous keratopathy (1/6), corneal laceration (1/6) and other corneal dystrophy (1/6). The authors report one case a combined phaco-DSAEK surgery. The complications observed were: an early graft detachment treated by an additional air bubble injection (1/6) and cystoid macular edema in one other case. The average central corneal thickness decreased from 780MUm at day 7 postoperatively to 656MUm at 6 months. The average thickness of the graft decreased from 154MUm at day 7 to 122MUm at 6 months. The mean preoperative BCVA was 1.52 log MAR [1.0-1.7], compared to the mean postoperative BCVA which was 1.5 log MAR [1.1-2.3] at 1 month, 1.15 log MAR [0.5-1.7] at 3 months and 1.1 log MAR [0.7-1.7] at 6 months (data available for 4 patients at 6 months). The recovery of visual acuity was limited in 2 cases, despite corneal clarity restored in all our patients. DISCUSSION: Our results can be compared to those described in literature. As more penetrating keratoplasty grafts reach the end of their lives, this will allow for more powerful studies. CONCLUSION: DSAEK on eyes previously treated with PK is a good alternative to a new PK in the case of endothelial decompensation of the graft. The possibility of a posterior lamellar graft allows for faster visual recovery, with preservation of the anterior corneal power and a lower rate of complications. PMID- 29132692 TI - [Inner nuclear layer microcysts associated with tobacco-alcohol optic neuropathy]. PMID- 29132693 TI - Relationship between visual outcomes and retinal fluid resorption in patients with diabetic macular edema treated with ranibizumab. AB - PURPOSE: We assessed the relationship between visual acuity (VA) recovery and a qualitative criterion - complete retinal fluid resorption (CRFR) - among patients treated with ranibizumab for diabetic macular edema (DME) METHODS: All consecutive diabetic patients with central DME received a loading dose of 3 monthly injections of ranibizumab 0.5mg, followed by retreatments on an as-needed basis as determined by monthly follow-up. Patients were divided into 3 groups: CRFR (defined as a CRT <300MUm and restoration of the foveolar pit) with BCVA<=70 letters (group 1: G1), CRFR with BCVA>70 letters (20/40) (G2), and persistent retinal fluid throughout the follow-up (G3). RESULTS: Forty eyes were included. Mean baseline VA was 48.7 letters and no patient had VA>70 letters. Twenty-four (60%) eyes achieved CRFR: 12 (30%) in G1 and 12 (30%) in G2. In 16 patients (40%), the efficacy of the treatment was partial without CRFR (G3). At the time of the initial CRFR, VA was 57.4 letters in G1 (min-max: 30-65) and 77.5 letters in G2 (71-85). In G3, maximal VA during follow-up was 55 letters (25-70) and no patient achieved a VA >70 letters. CONCLUSIONS: In this study, CRFR was required but not sufficient to achieve a VA>70 letters. PMID- 29132695 TI - Thai clinicians' attitudes toward antimicrobial stewardship programs. AB - BACKGROUND: Effective hospital-wide antimicrobial stewardship (AMS) programs need multidisciplinary engagement; however, clinicians' attitudes have not been investigated in Thailand where AMS is in early development. The aim of this study was to explore Thai clinicians' (doctors, nurses, and pharmacists) perceptions and attitudes toward AMS. METHODS: A paper-based survey was distributed in a 1,000-bed university hospital in Bangkok, Thailand, between November 9, 2015, and December 21, 2015. A total of 1,087 clinicians participated: 392 doctors, 613 nurses, and 82 pharmacists. RESULTS: Most participants agreed that improving antimicrobial prescribing would decrease antimicrobial resistance (AMR) and should be a priority of hospital policy. Doctors were less likely to agree with policies that limit antimicrobial prescribing (P < .001) than nurses or pharmacists, and were less likely to be interested in participating in AMS education than other clinicians (P < .001). Pharmacists indicated higher agreement with the statement, recommending that a specialist team provide individualized antimicrobial prescribing advice (P < .01) and that feedback improves antimicrobial selection (P < .001). Nurses were less likely to agree that community antibiotic use (P < .001) or patient pressure for antibiotics contribute to AMR (P < .001). CONCLUSIONS: AMS programs are vital to improving antimicrobial use by clinicians. Understanding clinicians' attitudes and perceptions related to AMS is important to ensure that AMS programs developed address areas relevant to local clinical needs. PMID- 29132694 TI - Unrelated immunodeficiency states may impact outcomes and immune checkpoint molecule expression in patients with mycosis fungoides: A clinicopathologic case control study. AB - BACKGROUND: Immunodeficiency (ID) correlates with worse outcomes and decreased immune checkpoint molecule expression in melanoma. The impact of ID in mycosis fungoides (MF) is unknown. OBJECTIVE: Our goal was to evaluate the impact of ID in MF. METHODS: We conducted a case-control study of 17 patients with MF and ID versus age-, stage-, and race-matched controls as a subset of a comparative analysis of 23 patients with MF with ID (prior lymphoma, recent/current pregnancy, HIV, hypogammaglobulinemia, and prior chemotherapy) versus without ID. Programmed cell death 1 (PD1), programmed death ligand 1 (PDL1), forkhead box p3, and interleukin 17 immunohistochemistry was performed on 12 patients with ID and 10 controls. RESULTS: Patients with ID had more treatment failure (14 of 23 vs 5 of 17 [P = .028]), more treatment failure within 3 years of diagnosis (12 of 23 vs 4 of 17 [P = .050]), more angiocentrism (6 of 12 vs 0 of 10 [P = .005]), larger cells (1.92 +/- 0.51 out of 3 vs 1.30 +/- 0.48 out of 3 [P = .009]), more cases with at least 10% PD1 positivity (9 of 11 vs 4 of 10 [P = .031]) and at least 10% PDL1 positivity (7 of 12 vs 2 of 10 [P = .042]), and a higher average percentage of PD1+ cells (43.27 +/- 40.22 vs 11.2 +/- 13.62 [P = .028]). No differences in survival, forkhead box p3 expression, interleukin 17 expression, histologic depth, ulceration, granulomatous changes, or syringotropism were seen. LIMITATIONS: This was a small single-center study with heterogeneous immunodeficiencies. CONCLUSION: ID correlated with worse outcomes and increased PD1 and PDL1 expression in MF. Patients with MF and ID may be candidates for immune checkpoint inhibitor therapy, pending further investigation. PMID- 29132696 TI - Development and validation of an automated ventilator-associated event electronic surveillance system: A report of a successful implementation. AB - BACKGROUND: Surveillance is an important tool for infection control; however, this task can often be time-consuming and take away from infection prevention activities. With the increasing availability of comprehensive electronic health records, there is an opportunity to automate these surveillance activities. The objective of this article is to describe the implementation of an electronic algorithm for ventilator-associated events (VAEs) at a large academic medical center METHODS: This article reports on a 6-month manual validation of a dashboard for VAEs. We developed a computerized algorithm for automatically detecting VAEs and compared the output of this algorithm to the traditional, manual method of VAE surveillance. RESULTS: Manual surveillance by the infection preventionists identified 13 possible and 11 probable ventilator-associated pneumonias (VAPs), and the VAE dashboard identified 16 possible and 13 probable VAPs. The dashboard had 100% sensitivity and 100% accuracy when compared with manual surveillance for possible and probable VAP. We report on the successfully implemented VAE dashboard. Workflow of the infection preventionists was simplified after implementation of the dashboard with subjective time-savings reported. CONCLUSIONS: Implementing a computerized dashboard for VAE surveillance at a medical center with a comprehensive electronic health record is feasible; however, this required significant initial and ongoing work on the part of data analysts and infection preventionists. PMID- 29132697 TI - Treatment of Postsurgical Chylothorax. AB - BACKGROUND: Postoperative chylothorax can be managed by any or all of observation, parenteral nutrition, surgical duct ligation, pleurodesis, or thoracic duct embolization. The objective of this study was to determine the efficacy of standard therapies, such as surgical duct ligation and observation, compared with newer treatment methods (thoracic duct embolization). METHODS: A prospectively maintained database at a single institution was used to identify and review patients with postoperative chylothorax from 2008 to 2015. RESULTS: Postoperative chylothorax occurred in 97 patients, including 54 men (56%). The median age was 61 years (range, 24 to 87 years). Thoracic duct leak followed esophagectomy in 46 patients (47%), pulmonary resection in 30 (31%), mediastinal mass resection in 7 (8%), and after other procedures in 15. Of 28 medically observed patients achieving resolution without intervention, the median peak chest tube output in 24 hours was 725 mL compared with 1,910 mL in the group that required intervention (p = 0.0001). Thoracic duct ligation was successful in 44 of 52 patients that proceeded to the operating room (85%). Of the 40 patients undergoing diagnostic lymphangiography, a leak was identified in 34 (85%), but the cisterna chyli could only be cannulated in 19 (48%) and was subsequently successful in 15 (38%). CONCLUSIONS: Patients with chylous chest tube outputs of 1,100 mL or more in 24 hours postoperatively should be considered for intervention. Intention-to-treat analysis shows surgical duct ligation is more effective than thoracic duct embolization, with the ability to cannulate the cisterna chyli being the limiting factor. Lymphangiography may help determine which patients are better treated with ligation or embolization. PMID- 29132698 TI - Risk Factor Analysis for Intraoperative Extracorporeal Membrane Oxygenation Weaning Failure After Lung Transplantation. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been widely used for hemodynamic support during lung transplantation (LTx). We evaluated the risk factors associated with failure of weaning from ECMO in the operating room during LTx. METHODS: We retrospectively reviewed 74 consecutive patients who had undergone LTx from March 2013 to February 2016. Patients who underwent single LTx, multiorgan transplantation, and LTx for pulmonary hypertension were excluded. All operations were performed under ECMO support. Clinical data of donor, recipient, and intraoperative parameters were reviewed. RESULTS: Younger donors (40 +/- 11 versus 45 +/- 10 years, p = 0.047), donors with shorter mechanical ventilation (125 +/- 74 versus 160 +/- 80 minutes, p = 0.066) and donors with higher Pao2 at 100% oxygen (455 +/- 87 mm Hg versus 399 +/- 88 mm Hg, p = 0.008) were significantly different in the ECMO weaning group than in the weaning failure group. Of the recipients, the number of patients who had preoperative ECMO support were significantly fewer in the successful weaning group than in the weaning failure group (11.9% versus 34.4%, p = 0.061). The operation time was significantly shorter in the weaning group than in the weaning failure group (392 +/- 66 versus 435 +/- 82 minutes, p = 0.014). In multivariate logistic regression analysis, the independent risk factors for ECMO weaning were donor age (odds ratio 1.101, 95% confidence interval: 1.030 to 1.177, p = 0.005), donor Pao2 (odds ratio 0.992, 95% confidence interval: 0.984 to 0.999, p = 0.034), and operation time (odds ratio 1.010, 95% confidence interval: 1.000 to 1.019, p = 0.043). CONCLUSIONS: Our results showed that younger donor age, high Pao2, and shorter operation time were factors related to successful ECMO weaning in the operating room after LTx. PMID- 29132699 TI - Is Endocan a Diagnostic Marker for Pneumonia After Cardiac Surgery? The ENDOLUNG Study. AB - BACKGROUND: Postoperative pneumonia is frequent after cardiac surgery and is associated with increased morbidity and mortality. We tested the hypothesis that endocan is an early biomarker for the detection of pneumonia after cardiac surgery. METHODS: Between January and May 2016, 155 patients scheduled to undergo elective cardiac surgery with cardiopulmonary bypass were prospectively included in the study. Serum level of endocan was measured at five timepoints (preoperative, and at 6, 24, 48, and 72 hours after the end of surgery). Procalcitonin and C-reactive protein were measured at 24 and 72 hours. The preoperative and postoperative characteristics of the patients were recorded. Independent predictors of postoperative pneumonia were identified by logistic regression. Threshold values of endocan predictive of postoperative pneumonia were determined using receiver-operating characteristics curve analysis. RESULTS: Seventeen patients (11%) had pneumonia after surgery. Endocan greater than 3.7 ng/mL before induction of anesthesia, or greater than 12.1 ng/mL at 6 hours after surgery, as well body mass index higher than 27 kg/m2 and duration of surgery were independent predictors of postoperative pneumonia. At induction of anesthesia, an endocan cutoff value of 3.7 ng/mL had 65% sensitivity and 72% specificity for the prediction of postoperative pneumonia; whereas at 6 hours, with a cutoff value of 12.1 ng/mL, these values were 71% and 75%, respectively. The time saved by endocan dosage compared with clinical diagnosis of postoperative pneumonia was 96 hours. CONCLUSIONS: This study shows that endocan is an early marker of postoperative pneumonia in patients after cardiac surgery. PMID- 29132700 TI - Early Operation in Patients With Mitral Valve Infective Endocarditis and Acute Stroke Is Safe. AB - BACKGROUND: To determine if preoperative embolic stroke is associated with an increased risk of postoperative stroke among patients undergoing early operation for mitral valve (MV) infective endocarditis (IE), we compared outcomes among patients presenting with and without acute stroke. METHODS: From 2003 to 2015, 243 consecutive patients underwent surgery for active MV IE. Patients were categorized into 2 groups: 72% (174 of 243 patients) with no preoperative acute stroke (clinical, radiographic or both) and 28% (69 of 243 patients) with stroke. Both preoperative and postoperative strokes were confirmed in all patients with brain computed tomography or magnetic resonance imaging and comprehensive examination by a neurologist. RESULTS: Among patients presenting with stroke, 33% (23 of 69 patients) were asymptomatic and had only positive imaging findings. The median time from admission to operation was 5 days. The overall rate of new postoperative stroke was 4% (10 of 243 patients). The rate of postoperative stroke was not different between the 2 groups: 4% (7 of 174 patients) among patients with no preoperative stroke and 4% (3 of 69 patients) with stroke (p = 0.9). One patient developed a hemorrhagic conversion of an acute infarct. Operative mortality was 7% (13 of 174 patients) among patients with no preoperative stroke and 7% (5 of 69 patients) among patients with stroke (p = 0.9). CONCLUSIONS: MV surgery for IE and acute stroke can be performed early with a low risk of postoperative neurologic complications. When indicated, surgical intervention for MV IE complicated by acute stroke should not be delayed. PMID- 29132701 TI - Postoperative Outcome After Pulmonary Surgery for Non-Small Cell Lung Cancer in Elderly Patients. AB - BACKGROUND: Lung cancer is the main cause of cancer-related death in the Netherlands. Surgery offers the best potential cure, but lower rates of surgery are recorded for octogenarians because of concerns regarding morbidity and mortality. METHODS: We analyzed the Dutch Lung Surgery Audit database to determine the postoperative outcome of lung cancer resections for patients aged 60 years or more between January 2013 and December 2014. Three groups were compared: patients aged 80 years or more, patients aged 70 to 79 years, and patients aged 60 to 69 years. Multivariable analysis was done of postoperative complications and operative mortality. RESULTS: In all, 2,133 lung cancer resections were performed, of which 70.5% by video-assisted thoracic surgery. Postoperative complications were observed in 637 patients (29.9%), without any difference among the three age groups (p = 0.278). Factors associated with complications were sex, percentage predicted forced expiratory volume in 1 second, percentage predicted diffusion capacity of lung for carbon monoxide, coronary artery bypass graft, chronic obstructive pulmonary disease, and resection more extensive than limited. The mean operative mortality was 2.1% (44 patients), 6.0% (10 patients) among octogenarians (p < 0.001). Age 80 years or more, percentage predicted forced expiratory volume in 1 second, performance status, and congestive heart failure independently predicted operative mortality. CONCLUSIONS: A higher operative mortality rate was observed among octogenarians, but the incidence of complications was similar in all age groups. PMID- 29132702 TI - Neutrophil-Lymphocyte Ratio: Prognostic Impact in Heart Surgery. Early Outcomes and Late Survival. AB - BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a recognized marker of inflammation associated with poor outcomes in various clinical situations. We analyzed the prognostic significance of preoperative elevated NLR in patients undergoing cardiac surgery. METHODS: We performed a retrospective review of 3,027 consecutive patients undergoing cardiac surgery. Receiver-operating characteristic was used to determine the cutoff value for elevated NLR. Multivariate regression was used to determine the predictive value of preoperative NLR on clinical outcomes. Cox proportional hazards functions were used to determine predictors of late events. Late survival data to 16 years was obtained from the Ministry of Interior. RESULTS: The cutoff value for elevated NLR was 2.6. Patients with elevated NLR were older (p < 0.0001), had a higher incidence of cardiac comorbidity (p < 0.0001), and higher European System for Cardiac Operative Risk Evaluation score (p < 0.0001). An elevated NLR emerged as an independent predictor of operative mortality (hazard ratio [HR] 2.15, 95% confidence interval [CI]: 1.51 to 3.08, p < 0.0001); pleural effusion (HR 1.42, 95% CI: 1.13 to 1.80, p = 0.003); low output syndrome (HR 1.54, 95% CI: 1.23 to 1.93, p = 0.0002); prolonged ventilation (HR 1.49, 95% CI: 1.23 to 1.82, p = 0.0001); or composite outcomes (HR 1.61, 95% CI: 1.36 to 1.91, p < 0.0001). The NLR emerged as an independent predictor of late mortality (HR 1.19, 95% CI: 1.11 to 1.28; p < 0.0001). CONCLUSIONS: Elevated NLR is associated with a higher incidence of adverse outcomes after cardiac surgery. It is a predictor of operative as well as late mortality. Further studies are warranted to determine whether prophylactic treatment with antiinflammatory agents can prevent such outcomes. It may be warranted to include the baseline NLR as another variable in risk stratification of patients about to undergo cardiac surgery. PMID- 29132703 TI - Rapid Deployment Aortic Valve Replacement: Excellent Results and Increased Effective Orifice Areas. AB - BACKGROUND: The aim of this study was to evaluate the effects of rapid deployment aortic valve replacement (RDAVR) on surgical outcome and hemodynamics compared with standard aortic valve replacement (AVR). METHODS: One hundred sixty-three RDAVR patients (isolated, n = 67; combined with coronary artery bypass graft surgery [CABG], n = 96) were compared with a propensity matched control group (n = 163). Primary endpoints included association between valve type and procedure times, prosthesis size, transvalvular gradient, and indexed effective orifice area. Secondary endpoints were postoperative mortality and morbidity. RESULTS: Aortic cross-clamp and cardiopulmonary bypass times in the RDAVR group were 55 +/ 23 and 88 +/- 38 minutes, respectively, compared with 77 +/- 22 and 105 +/- 38 minutes in the control group (p < 0.001). In the subgroup of patients undergoing isolated RDAVR (n = 67 of 163), the aortic cross-clamp and cardiopulmonary bypass times were 38 +/- 13 and 66 +/- 22 minutes, respectively, compared with 55 +/- 14 and 81 +/- 18 minutes in the control group (n = 67 of 163; p < 0.001). The RDAVR patients received larger prostheses (23.3 +/- 1.8 mm) compared with standard AVR (22.8 +/- 1.5 mm; p = 0.002). Mean transvalvular gradients and indexed effective orifice areas were 9 +/- 5 mm Hg and 1.11 +/- 0.11, respectively, in the RDVAR group compared with 13 +/- 5 mm Hg and 0.95 +/- 0.08 in the control group (p < 0.001). Hospital mortality was similar in both groups (1.8%, n = 3 of 163; p = 1.000). Postoperative pacemaker rates were 3.5% (n = 3 of 67) for isolated RDAVR versus 3.0% (n = 2 of 67; p = 0.649) for isolated AVR and 12.5% (n = 12 of 96) for RDAVR/CABG versus 4.2% (n = 4 of 96; p = 0.032) for AVR/CABG. CONCLUSIONS: RDAVR facilitates reduced aortic cross-clamp and cardiopulmonary bypass times compared with standard AVR, particularly in patients undergoing concomitant procedures, allowing the use of larger prostheses and resulting in lower transvalvular gradients and higher indexed effective orifice area compared with standard AVR. Therefore, RDAVR may help to overcome patient-prosthesis mismatch in some patients. PMID- 29132704 TI - Extent of Resection and Lymph Node Assessment for Clinical Stage T1aN0M0 Typical Carcinoid Tumors. AB - BACKGROUND: The optimal extent of lung resection and lymph node (LN) assessment for surgical treatment of clinical stage T1aN0M0 typical carcinoid tumors is unclear. Using a cohort including only these patients, we aimed to determine the impact of extent of lung resection and LN assessment on overall survival. METHODS: Patients undergoing lobectomy or sublobar resection for clinical stage T1aN0M0 intraparenchymal typical carcinoid tumor were identified in the National Cancer Data Base from 1998 to 2012. Kaplan-Meier analysis was used to determine overall survival. A multivariable Cox proportional hazards model was used to determine independent predictors of mortality. RESULTS: Of 1,495 patients, 536 (35.9%) had sublobar resection (wedge resection, n = 429; segmentectomy, n = 91) and 959 (64.2%) had lobectomy. There were 366 patients (24.5%) with no LN assessment. As tumor size increased, sublobar resection decreased and LN assessment increased. Overall, 60 patients (4.0%) were upstaged. Fifty-two patients were upstaged because of LN metastases (40 pN1, 11 pN2, and 1 pN3). The 5-year overall survival rate was 87%. It was 88% for lobectomy versus 87% for sublobar resection (p = 0.3), 65% for LN upstaging versus 89% for patients without LN upstaging, and 86% for patients with no LN assessment (p = 0.002). Independent predictors of mortality included LN upstaging, age, male sex, and Charlson comorbidity index. CONCLUSIONS: For patients with clinical stage T1aN0M0 typical carcinoid, sublobar resection results in similar overall survival compared with lobectomy. However, regardless of resection type, LN assessment is important to identify LN upstaging, the strongest independent predictor of overall mortality. PMID- 29132705 TI - IL-17A improves the efficacy of mesenchymal stem cells in ischemic-reperfusion renal injury by increasing Treg percentages by the COX-2/PGE2 pathway. AB - Mesenchymal stem cells (MSCs) are effective for the management of experimental ischemia-reperfusion acute kidney injury (IRI-AKI). Immune modulation is one of the important mechanisms of MSCs treatment. Interleukin-17A (IL-17A) pretreated MSCs are more immunosuppressive with minimal changes in immunogenicity in vitro. Here, we demonstrated that administration of IL-17A-pretreated MSCs resulted in significantly lower acute tubular necrosis scores, serum creatinine, and BUN of mice with IRI-AKI, compared with the administration of MSCs. Of the co-cultured splenocytes, IL-17A-pretreated MSCs significantly increased the percentages of CD4+Foxp3+ Tregs and decreased concanavalin A-induced T cell proliferation. Furthermore, mice with IRI-AKI that underwent IL-17A-pretreated MSC therapy had significantly lower serum IL-6, TNF-alpha, and IFN-gamma levels, a higher serum IL-10 level, and higher spleen and kidney Treg percentages than the mice that underwent MSCs treatment. Additionally, the depletion of Tregs by PC61 (anti-CD25 antibody) reversed the enhanced treatment efficacy of the IL-17A-pretreatedMSCs on mice with IRI-AKI. Additionally, IL-17A upregulated COX-2 expression and increased PGE2 production. The blockage of COX-2 by celecoxib reversed the benefit of IL-pretreated 17A-MSCs on the serum PGE2 concentration, spleen and kidney Tregs percentages, serum creatinine and BUN levels, renal acute tubular necrosis scores, and serum IL-6, TNF-alpha, IFN-gamma, and IL-10 levels of IRI pretreated mice with AKI, compared with MSCs. Thus, our results suggest that IL 17A pretreatment enhances the efficacy of MSCs on mice with IRI-AKI by increasing the Treg percentages through the COX-2/PGE2 pathway. PMID- 29132706 TI - Putting proton pump inhibitors into perspective. PMID- 29132707 TI - Non-invasive cardiac output monitoring (NICOM(r)) can predict the evolution of uteroplacental disease-Results of the prospective HANDLE study. Letter to the Editor. PMID- 29132708 TI - Unfair discrimination in prenatal aneuploidy screening using cell-free DNA? PMID- 29132709 TI - Letter to the editor, re: Lynch et al., 2017. PMID- 29132710 TI - Re: A novel technique of NexoBridTM application to burns on the hands by L.R. Springford, H. Creasy, T. Cubison, B. Dheansa [Burns 2017;43:1129-39]. PMID- 29132711 TI - Orient Expression: Solving the Mystery of Asian Prostate Cancer? PMID- 29132712 TI - Re: Rita Faria, Marta O. Soares, Eldon Spackman, et al. Optimising the Diagnosis of Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging: A Cost-effectiveness Analysis Based on the Prostate MR Imaging Study (PROMIS). Eur Urol 2018;73:23-30. PMID- 29132713 TI - Perioperative Morbidity of Lymph Node Dissection for Renal Cell Carcinoma: A Propensity Score-based Analysis. AB - BACKGROUND: There are little data regarding the morbidity of lymph node dissection (LND) for renal cell carcinoma (RCC) to assess its risk-benefit ratio. OBJECTIVE: To evaluate the association of LND with 30-d complications among patients undergoing radical nephrectomy (RN) for RCC. DESIGN, SETTING, AND PARTICIPANTS: A total of 2066 patients underwent RN for M0 or M1 RCC between 1990 and 2010, of whom 774 (37%) underwent LND. INTERVENTION: RN with or without LND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations of LND with 30-d complications were examined using logistic regression with several propensity score techniques. Extended LND, defined as removal of >=13 lymph nodes, was examined in a sensitivity analysis. RESULTS AND LIMITATIONS: A total of 184 (9%) patients were pN1 and 302 (15%) were M1. Thirty-day complications occurred in 194 (9%) patients, including Clavien grade >=3 complications in 81 (4%) patients. Clinicopathologic features were well balanced after propensity score adjustment. In the overall cohort, LND was not statistically significantly associated with Clavien grade >=3 complications, although there was an approximately 40% increased risk of any Clavien grade complication that did not reach statistical significance. Likewise, LND was not significantly associated with any Clavien grade or Clavien grade >=3 complications when separately evaluated among M0 or M1 patients. Extended LND was not significantly associated with any Clavien grade or Clavien grade >=3 complications. LND was not associated with length of stay or estimated blood loss. Limitations include a retrospective design. CONCLUSIONS: LND is not significantly associated with an increased risk of Clavien grade >=3 complications, although it may be associated with a modestly increased risk of minor complications. In the absence of increased morbidity, LND may be justified in a predominantly staging role in the management of RCC. PATIENT SUMMARY: Lymph node dissection for renal cell carcinoma is not associated with increased rates of major complications. PMID- 29132714 TI - PSMA-RADS Version 1.0: A Step Towards Standardizing the Interpretation and Reporting of PSMA-targeted PET Imaging Studies. AB - The use of [18F]- and [68Ga]-labeled inhibitors of prostate-specific membrane antigen (PSMA) for positron emission tomography (PET) imaging of prostate cancer is now widespread. We have proposed a reporting and data system called PSMA-RADS version 1.0, which is a framework for classifying PSMA-targeted PET scans and individual findings into categories that reflect the likelihood of the presence of prostate cancer. PMID- 29132715 TI - Scanning electron microscopic observations of early stages of interaction of Trichoderma harzianum, Gliocladium virens and Bacillus subtilis with Acaulospora colombiana. PMID- 29132716 TI - A 14-20kDa protein binds to the upstream region of the phtM operon involved in the synthesis of phaseolotoxin in Pseudomonas syringae pv. phaseolicola NPS3121. AB - Pseudomonas syringae pv. phaseolicola is a phytopathogenic bacterium in beans that produces a phytotoxin called phaseolotoxin, in whose synthesis a group of genes that belong to the "Pht cluster" are involved. This cluster comprises 23 genes arranged in 5 transcriptional units, two monocistronic (argK, phtL) and three polycistronic (phtA, phtD, phtM) operons, whose expression is increased at 18 degrees C, correlating with the production of phaseolotoxin by the bacterium. So far, the regulatory mechanisms involved in phaseolotoxin synthesis are poorly understood and only the requirement of low temperatures for its synthesis has been demonstrated. Therefore, in this study we searched for regulatory proteins that could be involved in the phaseolotoxin synthesis, focusing on the regulation of the phtM operon. Gel shift assays showed that the promoter region of the phtM operon contains binding sites for putative regulatory proteins, which are encoded outside the Pht cluster and are independent of the GacS-GacA two-component system. Deletion assays with the promoter region of the phtM operon show that the binding site for a putative transcription factor is located within a 58bp region. The putative transcription factor of the phtM operon has an apparent molecular mass in the 14-20kDa range. Furthermore, the results demonstrate that the transcription factor recognizes and binds the upstream phtM region as monomer o multimer of a single polypeptide. Our findings provide new insights into the regulatory mechanisms involved in phaseolotoxin production, and suggest that the Pht cluster was integrated into the global regulatory mechanism of P. syringae pv. phaseolicola. PMID- 29132717 TI - Effects of the ENSO on rainfall erosivity in the Fujian Province of southeast China. AB - Rainfall erosivity is one important factor that controls soil erosion. The interannual variability of rainfall erosivity in southeast China connected to the ENSO (El Nino-Southern Oscillation). Rainfall erosivity across southeast China was assessed using daily rainfall data from 60 meteorological stations during the period from 1980 to 2013. We determined that models of erosivity based on daily rainfall can accurately predict annual rainfall erosivity. This paper presents a study of the effects of Nino3.4 SST (Sea Surface Temperatures) anomalies, the SOI (Southern Oscillation Index) and the MEI (Multivariate El Nino-Southern Oscillation Index) on rainfall erosivity in the southeast of China. Results indicated that average rainfall erosivity is stronger during El Nino events and weaker during La Nina events. Correlation analyses were applied to rainfall erosivity and Nino3.4 SST anomalies, SOI, and MEI. The effects of Nino3.4 SST and SOI on rainfall erosivity are evident, as demonstrated by a statistically significant correlation (>95% confidence level). MEI was the best indicator (P<0.01) for representing the state of the ENSO. Results further indicated that 45, 31, and 40 of the 60 meteorological stations showed a significant correlation (P<0.05) between rainfall erosivity and SST anomalies, SOI, and MEI, respectively. Most of these stations were located in western Fujian Province. The ENSO was determined to exert the strongest influence on rainfall erosivity. This information would be useful in the implementation of new soil conservation strategies. PMID- 29132718 TI - Bioturbation effects on bioaccumulation of cadmium in the wetland plant Typha latifolia: A nature-based experiment. AB - The development of efficient bioremediation techniques to reduce aquatic pollutant load in natural sediment is one of the current challenges in ecological engineering. A nature-based solution for metal bioremediation is proposed through a combination of bioturbation and phytoremediation processes in experimental indoor microcosms. The invertebrates Tubifex tubifex (Oligochaeta Tubificidae) was used as an active ecological engineer for bioturbation enhancement. The riparian plant species Typha latifolia was selected for its efficiency in phyto accumulating pollutants from sediment. Phytoremediation efficiency was estimated by using cadmium as a conservative pollutant known to bio-accumulate in plants, and initially introduced in the overlying water (20MUg Cd/L of cadmium nitrate - Cd(NO3)2.4H2O). Biological sediment reworking by invertebrates' activity was quantified using luminophores (inert particulates). Our results showed that bioturbation caused by tubificid worms' activity followed the bio-conveying transport model with a downward vertical velocity (V) of luminophores ranging from 16.7+/-4.5 to 18.5+/-3.9cm.year-1. The biotransport changed the granulometric properties of the surface sediments, and this natural process was still efficient under cadmium contamination. The highest value of Cd enrichment coefficient for plant roots was observed in subsurface sediment layer (below 1cm to 5cm depth) with tubificids addition. We demonstrated that biotransport changed the distribution of cadmium across the sediment column as well as it enhanced the pumping of this metal from the surface to the anoxic sediment layers, thereby increasing the bioaccumulation of cadmium in the root system of Typha latifolia. This therefore highlights the potential of bioturbation as a tool to be considered in future as integrated bioremediation strategies of metallic polluted sediment in aquatic ecosystems. PMID- 29132719 TI - A multidimensional comparison between MODIS and VIIRS AOD in estimating ground level PM2.5 concentrations over a heavily polluted region in China. AB - Satellite-derived aerosol optical depth (AOD) has been proven effective for estimating ground-level particles with an aerodynamic diameter <2.5MUm (PM2.5) concentrations. Using a time fixed effects regression model, we compared the capacity of two AOD sources, Moderate Resolution Imaging Spectroradiometer (MODIS) and Visible Infrared Imaging Radiometer Suite (VIIRS), to estimate ground level PM2.5 concentrations over a heavily polluted region in China. Regarding high-quality AOD data, the results show that the VIIRS model performs better than the MODIS model with respect to all model accuracy evaluation indexes (e.g., the coefficient of determination, R2, of the VIIRS and MODIS models are 0.76 and 0.71 during model fitting and 0.72 and 0.66 in cross validation, respectively), the potential for capturing high PM2.5 concentrations, and the precision of annual and seasonal PM2.5 estimates. However, the spatiotemporal coverage of the high quality VIIRS AOD is inferior to that of the MODIS AOD. We attempted to include medium-quality VIIRS AOD data to eliminate this, while exploring its influence on the performance of the VIIRS model. The results show that it improves the spatiotemporal coverage of the VIIRS AOD dramatically especially in winter, although a decline in model accuracy occurred. Compared to the MODIS model, the VIIRS model with both high-quality and medium-quality AOD data performs comparably or even better with respect to some model accuracy evaluation indexes (e.g., the model overfitting degree of the VIIRS and MODIS models are 7.46% and 5.82%, respectively), the potential for capturing high PM2.5 concentrations, and the precision of annual and seasonal PM2.5 estimates. Nevertheless, the VIIRS models did not perform as well as the MODIS model in summer. This study reveals the advantages and disadvantages of the MODIS and VIIRS AOD in simulating ground level PM2.5 concentrations, promoting research on satellite-based PM2.5 estimates. PMID- 29132720 TI - Intensify production, transform biomass to energy and novel goods and protect soils in Europe-A vision how to mobilize marginal lands. AB - The rapid increase of the world population constantly demands more food production from agricultural soils. This causes conflicts, since at the same time strong interest arises on novel bio-based products from agriculture, and new perspectives for rural landscapes with their valuable ecosystem services. Agriculture is in transition to fulfill these demands. In many countries, conventional farming, influenced by post-war food requirements, has largely been transformed into integrated and sustainable farming. However, since it is estimated that agricultural production systems will have to produce food for a global population that might amount to 9.1 billion by 2050 and over 10 billion by the end of the century, we will require an even smarter use of the available land, including fallow and derelict sites. One of the biggest challenges is to reverse non-sustainable management and land degradation. Innovative technologies and principles have to be applied to characterize marginal lands, explore options for remediation and re-establish productivity. With view to the heterogeneity of agricultural lands, it is more than logical to apply specific crop management and production practices according to soil conditions. Cross-fertilizing with conservation agriculture, such a novel approach will provide (1) increased resource use efficiency by producing more with less (ensuring food security), (2) improved product quality, (3) ameliorated nutritional status in food and feed products, (4) increased sustainability, (5) product traceability and (6) minimized negative environmental impacts notably on biodiversity and ecological functions. A sustainable strategy for future agriculture should concentrate on production of food and fodder, before utilizing bulk fractions for emerging bio based products and convert residual stage products to compost, biochar and bioenergy. The present position paper discusses recent developments to indicate how to unlock the potentials of marginal land. PMID- 29132721 TI - Endocrine pathology: past, present and future. AB - Endocrine pathology is the subspecialty of diagnostic pathology which deals with the diagnosis and characterisation of neoplastic and non-neoplastic diseases of the endocrine system. This relatively young subspecialty was initially focused mainly on thyroid and parathyroid pathology, with some participants also involved in studies of the pituitary, the endocrine pancreas, and the adrenal glands. However, the endocrine system involves much more than these traditional endocrine organs and the discipline has grown to encompass lesions of the dispersed neuroendocrine cells, including neuroendocrine tumours (NETs) of the lungs, gastrointestinal tract, thymus, breast and prostate, as well as paraganglia throughout the body, not just in the adrenals. Indeed, the production of hormones is the hallmark of the endocrine system, and some aspects of gynecological/testicular, bone and liver pathology also fall into the realm of this specialty. Many of the lesions that are the focus of this discipline are increasing in incidence and their pathology is becoming more complex with increased understanding of molecular pathology and a high incidence of familial disease. The future of endocrine pathology will demand a depth of understanding of structure, function, prognosis and prediction as pathologists play a key role in the multidisciplinary care team of patients with endocrine diseases. It is anticipated that new technologies will allow increased subspecialisation in pathology and growth of this important area of expertise. PMID- 29132723 TI - Ovarian sex cord-stromal tumours and their mimics. AB - Sex cord-stromal tumours of the ovary include many of the most morphologically intriguing ovarian neoplasms and albeit many of them are rare, they factor into the differential diagnosis more often than their frequency might suggest. The most common malignant form, the adult granulosa cell tumour, may grossly simulate various surface epithelial neoplasms. Microscopically, confusion with endometrioid carcinoma may occur because the cords and microfollicles of the granulosa cell tumour may be mimicked by endometrioid carcinoma and the latter may have pale nuclei with nuclear grooves. Thorough sampling generally resolves this differential and if not immunohistochemistry aids. Although the adult granulosa cell tumour typically has cells with scant cytoplasm in some cases the tumour cells are luteinised and others have cells with abundant pale cytoplasm. A reticulum stain may be of great aid in indicating whether cells of the type just noted are of granulosa or theca nature. Variations in the morphology of the juvenile variant of granulosa cell tumour that can be diagnostically challenging include those that have a macronodular pattern with scant follicular differentiation, those with marked sclerosis, and those that are unusually pleomorphic. The uncommon but histologically varied Sertoli-Leydig cell tumour is considered, emphasis being placed on the most recently described variant, the retiform pattern, with its potential to mimic surface epithelial neoplasms and even mixed mesodermal tumours. Considering the usual young age of the patient may be paramount in making this tumour come to the mind of the pathologist. The rare pure Sertoli cell tumour is briefly noted as is the sex cord tumour with annular tubules, well known because of its association in some cases with Peutz-Jeghers syndrome. Most do not have that association, however, but have their own interesting features including a greater than average risk, among sex cord stromal tumours, of nodal metastasis and progesterone production, and an occasional development from them of an otherwise typical Sertoli cell tumour. The stromal family includes the common fibroma which is challenging when it is cellular with some mitotic activity and the approach to such neoplasms is reviewed. Emphasis in the consideration of thecoma is placed on its typical cytological features and the overlap with what may be seen in some adult granulosa cell tumours. The review concludes with three fascinating pure stromal tumours all described within the last several decades: the sclerosing stromal tumour, the unusual luteinised thecoma associated with sclerosing peritonitis and the microcystic stromal tumour. The first is sometimes misdiagnosed when pure stromal neoplasms of other types are vascular and may have pseudolobules and it is essential that the pseudolobules of the sclerosing stromal tumour contain a haphazard admixture of fibroblasts and weakly luteinised cells. The remarkable tumours associated with peritonitis exhibit brisk mitotic activity but appear not to have a metastatic potential; they can cause significant problems because of the sclerosing peritonitis. The microcystic stromal tumour may mimic a steroid cell tumour or thecoma but unlike them is inhibin and calretinin negative, and stains for CD10 and beta-catenin. It often shows bizarre nuclei atypia but limited mitotic activity and appears to be clinically benign on the basis of still limited experience. PMID- 29132722 TI - Trajectories of premalignancy during the journey from melanocyte to melanoma. AB - A stepwise progression from melanocytic precursors to cutaneous melanoma is a well-established model, based on decades of careful observation and morphological analysis. The steps identified are benign melanocytic naevus, dysplastic naevus, 'radial growth phase' melanoma (including melanoma in situ) and 'vertical growth phase' melanoma (also termed tumourigenic melanoma). Recent genomic data have refined the understanding of the steps of melanoma development and their relationship to one another. These data support the existence of dysplastic naevi as distinct lesions; suggest the importance of clonal dynamics in the precursor steps of melanoma; and confirm the carcinogenic role of ultraviolet radiation throughout early melanoma development and progression. In this review, the steps of melanoma development and progression are summarised and discussed in the context of recent genomic studies. This new understanding of melanoma pathogenesis that has been facilitated through careful correlation of morphological and molecular features will allow the identification and development of robust biomarkers to assist in more accurate diagnosis and prognostication of melanocytic tumours. PMID- 29132724 TI - Emerging entities in renal cell neoplasia: thyroid-like follicular renal cell carcinoma and multifocal oncocytoma-like tumours associated with oncocytosis. AB - The list of accepted entities of renal cell neoplasia has burgeoned since the turn of the century through recognition of rare tumour types and the discovery of genetic mutations driving renal neoplasia syndromes. This growth has not finished and in this report we present examples of each of these types which were not included in the 2016 World Health Organization classification of renal neoplasia, but are candidates for inclusion in the next edition of the classification. Thyroid-like follicular renal cell carcinoma is a rare tumour type with a distinctive microscopic appearance resembling follicles of the thyroid gland. Thirty-nine cases have been described and the findings have been reasonably consistent. Oncocytoma-like tumours associated with oncocytosis arise as a result of somatic mutations in the mitochondrial genome. The differential diagnosis is mainly with the renal lesions of the Birt-Hogg-Dube syndrome, which is the result of germline mutations in the folliculin gene. Patients with oncocytoma-like tumours associated with oncocytosis are at great risk of developing renal failure as the proliferating lesions replace the renal parenchyma. Oncocytoma-like tumours have never been found to metastasise. PMID- 29132725 TI - Computational study of the role of fluid content and flow on the lumbar disc response in cyclic compression: Replication of in vitro and in vivo conditions. AB - The intervertebral disc viscoelastic response is governed primarily by its fluid content and flow. Invivo measurements demonstrate that the disc volume, fluid content, height and nucleus pressure completely recover during resting even after diurnal loading with twice longer duration (16 vs. 8 h). In view of much longer periods required for the recovery of disc height and pressure in vitro, concerns have been raised on the fluid inflow through the endplates that might be hampered by clogged blood vessels post mortem. This in silico study aimed to identify fluid-flow dependent response of discs and conditions essential to replicate in vitro and in vivo observations. An osmo-poroelastic finite element model of the human lumbar L4-L5 disc-bone unit was used. Simulating earlier in vitro experiments on bovine discs, the loading protocol started with 8 h preload at 0.06 MPa followed by 30 high/low compression loading cycles each lasting 7.5min at 0.5/0.06 MPa, respectively. Three different endplate configurations were investigated: free in- and outflow, no inflow and closed endplates with no flow. Additionally, the preload magnitude was increased from 0.06 MPa to 0.28 MPa and 0.50 MPa, or the initial nucleus hydration was reduced from 83% to 50%. For 0.06 MPa preload, the model with no inflow best matched in vitro trends. The model with free inflow increased segment height and nucleus pressure while the model with no fluid inflow resulted in a relatively small recovery in segment height and a rather constant nucleus pressure during unloading periods. Results highlight an excessive mobile fluid content as well as a restricted fluid inflow through endplates as likely causes of the discrepancies between in vivo and in vitro studies. To replicate in vivo conditions in vitro and in silico, disc hydration level should be controlled by adequate selection of preload magnitude/period and/or mobile fluid porosity. PMID- 29132726 TI - A procedure for determining parameters of a simplified ligament model. AB - A previous mathematical model of ligament force-generation treated their behavior as a population of collagen fibres arranged in parallel. When damage was ignored in this model, an expression for ligament force in terms of the deflection, x, effective stiffness, k, mean collagen slack length, MU, and the standard deviation of slack lengths, sigma, was obtained. We present a simple three-step method for determining the three model parameters (k, MU, and sigma) from force deflection data: (1) determine the equation of the line in the linear region of this curve, its slope is k and its x -intercept is -MU; (2) interpolate the force deflection data when x is -MU to obtain F0; (3) calculate sigma with the equation sigma=2piF0/k. Results from this method were in good agreement to those obtained from a least-squares procedure on experimental data - all falling within 6%. Therefore, parameters obtained using the proposed method provide a systematic way of reporting ligament parameters, or for obtaining an initial guess for nonlinear least-squares. PMID- 29132727 TI - Speed profiles in wheelchair court sports; comparison of two methods for measuring wheelchair mobility performance. AB - Wheelchair mobility performance is an important aspect in most wheelchair court sports, commonly measured with an indoor tracking system or wheelchair bound inertial sensors. Both methods provide key wheelchair mobility performance outcomes regarding speed. In this study, we compared speed profiles of both methods to gain insight into the level of agreement, for recommendations regarding future performance measurement. Data were obtained from 5 male highly trained wheelchair basketball players during match play. Players were equipped simultaneously with a tag on the footplate for the indoor tracking system (~8 Hz) and inertial sensors on both wheels and frame (199.8 Hz). Being part of a larger study on 3 vs 3 player game formats, data were collected in several matches with varying field sizes, but activity profiles closely resembled regular match play. Both systems provide similar outcomes regarding distance covered and average speed. Due to differences in sampling frequency and sensor location (reference point) on the wheelchair (for speed calculation), minor differences were revealed at low speeds (<2.5 m/s). Since both systems provide complementary features, a hybrid solution as proved feasible in this study, could possibly serve as the new gold standard for mobility performance measurement in wheelchair basketball or wheelchair court sports in general. PMID- 29132728 TI - Expanded access program with Nusinersen in SMA type I in Italy: Strengths and pitfalls of a successful experience. PMID- 29132729 TI - Wnt and Hedgehog: Secretion of Lipid-Modified Morphogens. AB - Morphogens are signaling molecules produced by a localized source, specifying cell fate in a graded manner. The source secretes morphogens into the extracellular milieu to activate various target genes in an autocrine or paracrine manner. Here we describe various secreted forms of two canonical morphogens, the lipid-anchored Hedgehog (Hh) and Wnts, indicating the involvement of multiple carriers in the transport of these morphogens. These different extracellular secreted forms are likely to have distinct functions. Here we evaluate newly identified mechanisms that morphogens use to traverse the required distance to activate discrete paracrine signaling. PMID- 29132730 TI - It is vital to identify the underlying cause of chronic laryngopharyngeal neuropathy. PMID- 29132731 TI - Adenoidectomy and chronic nasal obstruction developing after failure of nasal steroid therapy. PMID- 29132732 TI - The role of artificial and natural sweeteners in reducing the consumption of table sugar: A narrative review. AB - The rapid increase in the prevalence of obesity worldwide has been partially attributed to the overconsumption of added sugars. Recent guidelines call for limiting the consumption of simple sugars to less than 10% of daily caloric consumption. High intensity sweeteners are regulated as food additives and include aspartame, acesulfame-k, neotame, saccharin, sucralose, cyclamate and alitame. Steviol glycosides and Luo Han Guo fruit extracts are high intensity sweeteners that are designated as generally recognized as safe (GRAS). Commonly used non-caloric artificial sweeteners may have unfavorable effect on health including glucose intolerance and failure to cause weight reduction. The nutritive sweeteners include sugar alcohols such as sorbitol, xylitol, lactitol, mannitol, erythritol, trehalose and maltitol. Naturally occurring rare sugars have recently emerged as an alternative category of sweeteners. These monosaccharides and their derivatives are found in nature in small quantities and lack significant calories. This category includes d-allulose (d-psicose), d tagatose, d-sorbose and d-allose. Limiting consumption of any sweetener may well be the best health advice. Identifying natural sweeteners that have favorable effects on body weight and metabolism may help achieving the current recommendations of restricting simple sugar consumption. PMID- 29132733 TI - Enhanced nutrient supply to very low birth weight infants is associated with higher blood amino acid concentrations and improved growth. AB - BACKGROUND & AIMS: Customized nutrient supply is vital to ensure optimal growth among very low birth weight infants (birth weight < 1500 g). The supply of amino acids is especially important due to their impact on protein synthesis and growth. The objectives of this study were to evaluate the impact of enhanced nutrition on growth, blood concentrations of amino acids, and explore possible associations between amino acid concentrations and common neonatal morbidities. We hypothesized higher amino acids levels and growth velocity among infants on enhanced nutrient supply. METHODS: This randomized controlled trial was performed in three university neonatal intensive care units in Oslo, Norway. Fifty very low birth weight infants were randomized to a control or intervention group. Within 24 h after birth, infants in the intervention group received enhanced supply of energy, amino acids, lipids, long-chain polyunsaturated fatty acids and vitamin A, whereas the control group received a standard nutrient supply. The intervention continued until 52 weeks postmenstrual age or until a body weight of 5.5 kg was reached. Amino acid analyses were performed at birth, day 3, 5 weeks of age and 5 months corrected age. Detailed information about nutrient intake, morbidities, blood amino acid concentrations and growth velocity were collected from 44 infants (6 infants excluded). High-performance liquid chromatography was used for amino acid analysis. RESULTS: The intervention group (n = 23) received higher supply of proteins, with higher blood concentrations of amino acids measured at 5 weeks of age, and improved growth velocity (mean 17.4 vs 14.3 g/kg/day, p < 0.001) at 36 weeks postmenstrual age, compared to the control group (n = 21). The correlation between concentrations of branched chain amino acids (leucine, isoleucine and valine) and growth was stronger and more positive among infants: a) in the control group (correlation coefficient >= 0.68, p <= 0.004); b) born with birth weight appropriate for gestational age (correlation coefficient >= 0.53, p <= 0.009) and c) not diagnosed with septicemia (correlation coefficient >= 0.63, p <= 0.005). CONCLUSION: Enhanced nutrient supply to very low birth weight infants led to higher blood amino acid concentrations and improved growth. The correlations between amino acid concentrations and growth velocity were weaker in the intervention group as compared to the control group. This could reflect an upper threshold for protein synthesis and growth with our intervention, whereas a potential for further growth with increasing amino acid supply was possible for the control group. CLINICAL TRIAL REGISTRATION NO: NCT01103219. PMID- 29132734 TI - Role of vitamin E and D3 supplementation in Intra-Cytoplasmic Sperm Injection outcomes of women with polycystic ovarian syndrome: A double blinded randomized placebo-controlled trial. AB - BACKGROUND & AIMS: Ovulation induction has been proven to impose oxidative stress during ICSI treatment cycle. Also, data indicates that PCOS women show higher oxidative markers. Available data are not convincing about which antioxidant supplements have the potential to overcome oxidative stress in PCOS subjects. The aim of this trial was to investigate the possible role of combined vitamin E and D supplementation in the ICSI outcomes (oocyte number and quality, embryo number and quality, pregnancy rate) of PCOS subjects. METHODS: A total of 105 PCOS infertile women scheduled for ICSI were enrolled in a double-blinded RCT to treatment group (vitamin E, 400 mg/day - and vitamin D3, 50,000 IU/one in two weeks, n = 52) or placebo group (n = 53) for 8 weeks. The primary outcomes were implantation rate, pregnancy and clinical pregnancy rate. Secondary outcomes included oocyte quality, embryo quality, fertilization rate, alteration in serum MDA, TAC and vitamin D3 after treatment. Further, association between serum and follicular fluid Malondialdehyde (MDA), Total Antioxidant Capacity (TAC), and serum vitamin D3 level were assessed. RESULTS: Pregnancy, clinical pregnancy and implantation rate were significantly higher in treatment group (P < 0.001). Data analysis in both groups revealed a significant increase in serum MDA compared to baseline and a significant decrease in serum TAC compared to baseline after treatment. Further analysis showed that there is a positive weak association between vitamin D level, implantation rate (P = 0.015) and increased clinical pregnancy (P = 0.037). No significant association was detected between either follicular fluid or serum MDA and TAC and ICSI outcomes. CONCLUSIONS: In conclusion, the findings of this trial do not add clinical support to the evidence that vitamins E and D3 may play a role in the success rate of IVF via an antioxidant mechanism. REGISTRY CODE: IRCT2014081018662N1. PMID- 29132735 TI - Adherence to Mediterranean diet in HIV infected patients: Relation with nutritional status and cardiovascular risk. AB - BACKGROUND & AIMS: The Mediterranean diet (MedDiet) has been associated to a lower prevalence of metabolic syndrome (MS) and a lower cardiovascular risk (CVR). Our aim was to assess HIV infected individual's adherence to the MedDiet and its relationship with nutritional status and CVR. METHODS: Clinical and anthropometric data were collected and a nutritional assessment was performed. Adherence to the MedDiet was assessed using the questionnaire MedDietScore, ranging from 0 to 55, where higher scores indicated a higher adherence. CVR was estimated for each patient using the Framingham Risk Score (FRSs-CVD). RESULTS: We included 571 individuals, mostly males (67.1%; n = 383). MedDiet adherence score was 27.5 +/- 5.5 points. The proportion of overweight/obese individuals was 40.3% (n = 230) and MS 33.9% (n = 179); CVD estimation showed that 53.2% (n = 304), 30.1% (n = 172) and 16.6% (n = 95) of patients had a low, moderate and very high CVR, respectively. The group with BMI below 25 kg/m2 presented lower adherence to MedDiet and patients within moderate CVR category and with MS presented a higher adherence to MedDiet. CONCLUSIONS: Overall we found a moderate adherence to the Mediterranean diet. A higher adherence was associated to individuals with a BMI >= 25 kg/m2, those with MS and to patients with moderate to high cardiovascular risk, suggesting the adoption of this food pattern in the presence of comorbidities. PMID- 29132736 TI - Clinical effects of probiotics in cystic fibrosis patients: A systematic review. AB - Cystic fibrosis (CF) is characterised by a build-up of thick, intransient mucus linings of the digestive and respiratory mucosa, which disrupts digestive system functioning and microbiota composition. In view of the potential for probiotics to enhance microbiota composition in other contexts, this study investigated the current evidence for probiotics as an adjunct to usual therapy for CF. Electronic clinical databases were interrogated for human randomised, controlled, intervention trials (1985-2015) testing the effects of probiotics on clinical endpoints in CF were reviewed. From 191 articles identified in initial searches, six studies met the critical inclusion criteria, and were reviewed in detail. These studies varied in size (n = 22 to 61) but were generally small and showed substantial diversity in protocol, specific probiotic species used and range of clinical outcomes measured. Probiotic administration showed beneficial effects on fecal calprotectin levels, pulmonary exacerbation risk, and quality of life indicators. In one study, such changes were associated with variations in gut microbiota composition. Despite encouraging preliminary results, the limited number of small and highly varied studies to date do not justify the addition of probiotics as an adjunct to current CF treatment protocols. Importantly, very minimal adverse effects of probiotics have been reported. PMID- 29132737 TI - Discordance between bioelectrical impedance vector analysis and the new ESPEN definition of malnutrition for the diagnosis of hospital malnutrition. AB - BACKGROUND & AIMS: No universally accepted diagnostic criteria for malnutrition are available to date. The aim was to assess the concordance for the diagnosis of hospital malnutrition between the bioelectrical impedance vector analysis (BIVA) and the new definition of malnutrition proposed by the European Society for Clinical Nutrition and Metabolism (ESPEN). METHODS: A total of 140 adult hospitalized patients were included. The malnutrition risk was assessed by the Nutritional Risk Screening. The ESPEN malnutrition criteria (body mass index (BMI) <18.5 kg/m2, weight loss (WL) + low BMI, and WL + low fat free mass index (FFMI) were applied to each patient. The bioelectrical impedance of each patient was measured, and malnutrition was diagnosed using the BIVA method. Diagnostic concordance between the BIVA and the new ESPEN definition was assessed with the Kappa coefficient. RESULTS: The malnutrition prevalence was higher with the BIVA vs ESPEN definition (22.1% vs 13.6%) in the global population and was similar (12.8% vs 12.1%) in the population at risk of malnutrition. The diagnostic performance of the BIVA was acceptable, with higher sensitivity in patients with fluid overload (FO) and more specificity in euvolemic patients. Diagnostic concordance between the BIVA and the ESPEN definition was poor for the global population (kappa = 0.56) and the population at risk of malnutrition (kappa = 0.67) but was acceptable in patients with FO (kappa = 0.78). However, the discordant BIVA+/ESPEN- patients classified as false positives for BIVA showed clinical and body composition data (low FFMI, low phase angle) consistent with malnutrition. CONCLUSIONS: According to the clinical and bioelectrical characteristics of the discordant BIVA+/ESPEN- patients, the BIVA could perform better that the new ESPEN definition for the diagnosis of hospital malnutrition, which should be confirmed with other studies. PMID- 29132738 TI - Impact of implant-supported prostheses on nutritional status and oral health perception in edentulous patients. AB - BACKGROUND & AIMS: Improvement of nutritional status and perception of oral health are supposed to be different with complete conventional denture or implant supported fixed or removable prostheses. Since no study has been conducted in Lebanon, the aim of our study was to assess the nutritional status and oral heath related quality of life (OHRQoL) in totally edentulous patients after treatment with complete denture or implant supported-prostheses. MATERIAL AND METHODS: This was an observational clinical prospective study. A convenient sample of Lebanese people aged 60 years or more was selected between September 2013 and July 2015 from the Departments of removable and fixed prosthesis at Saint-Joseph University of Beirut. The treatment options included complete denture, implant-supported complete denture and implant-supported fixed prostheses. Nutritional status and OHRQoL were assessed with the Mini-Nutritional Assessment Index (MNA) and the Geriatric Oral Health Assessment Index (GOHAI) respectively at Baseline (first visit before treatment), 2-3 weeks after treatment (t1), 3 months (t2) and 6 months (t3) after treatment. RESULTS: Fifty-one participants (mean age: 69.39 +/- 7.164 years) were included. The results have shown an improvement over time in nutritional status and OHRQoL for all treatment groups. However, 2-3 weeks after treatment the number of participants at risk of malnutrition was higher with complete removable denture, intermediate with implant-supported complete denture and lower with implant-supported fixed prostheses (p-value = 0.049). Moreover, the mean GOHAI score was significantly lower over time with complete removable denture compared to implant-supported prostheses (p-value <0.05). CONCLUSION: Our study has shown an enhancement in the quality of life and the nutritional status for implant supported-prostheses compared to conventional removable dentures. Therefore, it is fundamental that dentists communicate with their patients about implant treatment to understand their expectations, to explain the outcomes and achieve the desired clinical result. PMID- 29132739 TI - Validity and reliability of the english version of the sick, control, one stone, fat, food (SCOFF) in Malaysia. AB - BACKGROUND & AIMS: Several questionnaires to screen for eating disorders have been validated in Malaysia. However, these tools are lengthy, and require specialist interpretation. The sick, control, one stone, fat, food (SCOFF) is easy to administer by non-specialists, but has not been validated in Malaysia. Therefore, the aim of our study was to validate the SCOFF on a non-clinical sample of tertiary students to determine if it could identify individuals with an eating disorder. METHODS: We recruited second year tertiary students from five faculties in a university in Malaysia, from June-November 2014, who could understand English. The SCOFF and the EAT-26 were administered at baseline. Two weeks later, the SCOFF was re-administered to assess for reliability. RESULTS: A total of 292 students were approached, and all agreed to participate (response rate = 100%). There was moderate correlation between the total SCOFF score with the EAT-26's dieting domain (spearman's rho = 0.504, p < 0.001), bulimia and food preoccupation domain (spearman's rho = 0.438, p < 0.001), and total score (spearman's rho = 0.483, p < 0.001). The internal consistency of the SCOFF was low (Cronbach alpha = 0.470). At retest, kappa scores ranged from 0.211 to 0.591. The sensitivity of the SCOFF was 77.4%, and its specificity was 60.5%. The positive predictive value was 18.9%, and its negative predictive value was 95.8%. CONCLUSIONS: The SCOFF was found to have adequate convergent validity and stable reliability. However, its internal consistency was low. The SCOFF can still be used in clinical practice. However, its positive results should be interpreted with caution due to its low positive predictive value. PMID- 29132741 TI - Model predictive controller-based multi-model control system for longitudinal stability of distributed drive electric vehicle. AB - Distributed drive electric vehicle(DDEV) has been widely researched recently, its longitudinal stability is a very important research topic. Conventional wheel slip ratio control strategies are usually designed for one special operating mode and the optimal performance cannot be obtained as DDEV works under various operating modes. In this paper, a novel model predictive controller-based multi model control system (MPC-MMCS) is proposed to solve the longitudinal stability problem of DDEV. Firstly, the operation state of DDEV is summarized as three kinds of typical operating modes. A submodel set is established to accurately represent the state value of the corresponding operating mode. Secondly, the matching degree between the state of actual DDEV and each submodel is analyzed. The matching degree is expressed as the weight coefficient and calculated by a modified recursive Bayes theorem. Thirdly, a nonlinear MPC is designed to achieve the optimal wheel slip ratio for each submodel. The optimal design of MPC is realized by parallel chaos optimization algorithm(PCOA)with computational accuracy and efficiency. Finally, the control output of MPC-MMCS is computed by the weighted output of each MPC to achieve smooth switching between operating modes. The proposed MPC-MMCS is evaluated on eight degrees of freedom(8DOF)DDEV model simulation platform and simulation results of different condition show the benefits of the proposed control system. PMID- 29132740 TI - Effects of using symbiotics in the clinical nutritional evolution of patients with chronic pancreatitis: Study prospective, randomized, controlled, double blind. AB - : Patients with chronic pancreatitis (CP) present malabsorption and changes in nutritional status. In this prospective, randomized, controlled, double-blinded, intervention study, developed at the Clinic of Pancreas, we aimed to assess whether the use of symbiotics changes the nutritional status, the biochemical data and the intestinal rate of these patients. The intervention consisted of administering 12 g/day of symbiotics composed of Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium bifidum and fructooligosaccharides to the intervention group and 12 g/day of medium absorption complex carbohydrate to the control group. The project was approved by the Ethics Committee of College of Technology and Science - FTC under the number process 0528-2008; reg. 498 e was registered under ClinicalTrials.gov. We evaluated 60 patients and the intervention lasted for 3 months, with monthly monitoring. A statistically significant reduction was observed in the results by day in relation to the initial frequency (x = 2.3) and the use of symbiotics in the second (x = 1.47) and third (x = 1.37) months (p = 0.001). In the control group, there was no significant change in this frequency (p = 0.157). The results showed an increase in the levels of hemoglobin (p < 0.001), hematocrit (p = 0.001), red blood cells (p < 0.001), total lymphocyte count (p < 0.002), serum magnesium (p < 0.001), albumin (0.001) and total serum cholesterol reduction (p < 0.001) with the use of symbiotics. The changes were not observed in the nutritional status of both groups. CONCLUSION: The use of symbiotics improved the clinical and laboratory profiles of the evaluated patients with CP, favoring the best clinical outcome, and may be a therapeutic option because of the low cost and therapeutic effectiveness in this population. PMID- 29132742 TI - [Statement in favor of the foundation of the Iberoamerican Society for Medical Mycology]. PMID- 29132743 TI - Nuclear sirtuins and inflammatory signaling pathways. AB - The regulation of chronic inflammation has received considerable research attention in recent years because of its contribution to the pathogenesis of chronic diseases such as arthritis, diabetes, metabolic syndrome and obesity. Thus, strategies that inhibit the inflammatory state may be beneficial in improving the pathophysiology of several inflammation-related disorders. Sirtuins are a family of histone deacetylases that contain seven enzymatic activities in mammals (SIRT1-SIRT7) and function to suppress gene transcription by epigenetic mechanisms. Nuclear sirtuins (SIRT 1, 2, 6 and 7) in particular may play an important role in the regulation of inflammatory responses. In the present review, we assessed the roles of nuclear sirtuins in inflammatory reactions: SIRT1 has been shown to suppress NF-kappab activity, the master regulator of cellular inflammatory response, decrease COX-2 and iNOS production, and increase antioxidant gene expression that suppressed inflammation. SIRT2 activity included the deacetylation of p65 subunit of NF-kappabeta and RIP-1, while SIRT6 has been shown to interact with p65/RelA bound to the NF-kappabeta promoter region and repress transcriptional activity. Furthermore, recent studies have shown that the absence of SIRT7 produced an increase in inflammation, illustrating that SIRT7 also functioned to decrease inflammation. Given their significant roles in the regulation of chronic inflammation, nuclear sirtuins represent potential therapeutic targets in the control of chronic inflammatory diseases. PMID- 29132744 TI - [Morphometry of pulmonary tissue: From manual to high throughput automation]. AB - Weibel's research has shown that any alteration of the pulmonary structure has effects on function. This demonstration required a quantitative analysis of lung structures called morphometry. This is possible thanks to stereology, a set of methods based on principles of geometry and statistics. His work has helped to better understand the morphological harmony of the lung, which is essential for its proper functioning. An imbalance leads to pathophysiology such as chronic obstructive pulmonary disease in adults and bronchopulmonary dysplasia in neonates. It is by studying this imbalance that new therapeutic approaches can be developed. These advances are achievable only through morphometric analytical methods, which are increasingly precise and focused, in particular thanks to the high-throughput automation of these methods. This review makes a comparison between an automated method that we developed in the laboratory and semi-manual methods of morphometric analyzes. The automation of morphometric measurements is a fundamental asset in the study of pulmonary pathophysiology because it is an assurance of robustness, reproducibility and speed. This tool will thus contribute significantly to the acceleration of the race for the development of new drugs. PMID- 29132745 TI - [Membranous microparticles and respiratory disease]. AB - Microparticles (MP) are plasmic membrane fragments released from cells after physiological stimulation or stress conditions like inflammation or infection. Their production is correlated to the rate of cell apoptosis. All types of cells can produce MP but they are produced mainly by platelets, endothelial cells, and leukocytes. They carry many bio-active molecules on their surface, specific to the parental cell, giving them the ability to be biomarkers and bio-effectors. MP are present in circulating blood, tissues and many biological fluids. Circulating MP levels can change during the course of many diseases. They have been the subject of many studies in the fields of cardiovascular disease and oncology. In the lungs, they are present in circulating blood and in the airways. They seem to have a role in pulmonary homeostasis in physiological situations and also in the expression of several disease processes. In this review of the literature, we were interested in the quantitative and qualitative variations in MP and their impact in airway diseases like chronic obstructive pulmonary disease (COPD) and asthma, pulmonary fibrosis and pulmonary hypertension. PMID- 29132746 TI - Diabetes mellitus as a poor mobilizer condition. AB - Hematopoietic stem cell (HSC) transplantation in an effective and curative therapy for numerous hematological malignancies. Mobilization of HSCs from bone marrow (BM) to peripheral blood (PB) followed by apheresis is the gold standard for obtaining HSCs for both autologous and allogeneic stem cell transplantation. After administration of granulocyte-colony stimulating factor (G-CSF), up to 30% of patients fail to mobilize "optimal" numbers of HSCs required for engraftment. This review summarizes the current experimental and clinical evidence that diabetes mellitus is a risk factor for poor mobilization. Diabetes causes a profound remodeling of the HSC niche, resulting in impaired release of HSCs. Experimental studies indicate that hyperglycemia hampers regulation of CXCL12 and clinical studies suggest that diabetes impairs HSC mobilization especially in response to G-CSF, but less to plerixafor. Understanding further the biochemical alterations in the diabetic BM will provide insights into future therapeutic strategies to reverse the so-called "diabetic stem cell mobilopathy". PMID- 29132747 TI - Cat Scratch Disease During Adalimumab Therapy: A Case Report. PMID- 29132748 TI - Status of Rheumatology in Spain in 2017: 2.0 Rheumatologists per 100,000 Population. PMID- 29132749 TI - Use of Immunomodulatory Drugs at a Uveitis Clinic. AB - OBJECTIVE: The treatment of noninfectious uveitis includes steroids and immunomodulatory drugs, the use of which has increased in the last few years, and the options have been enriched with the development of new treatments. However, clear therapeutic guidelines and protocols have not been developed. The purpose is to analyze the response to the drugs used and the characteristics of the patients treated at a multidisciplinary uveitis clinic. MATERIAL AND METHODS: Observational and retrospective study of the patients attended to from January 2012 to December 2015. Infectious, posttraumatic and postoperative uveitis, as well as masquerade syndrome, were excluded. RESULTS: Two hundred six patients were included. Overall, 58.80% had uveitis without association of systemic disease, mostly idiopathic uveitis, and 35.65% had uveitis with systemic involvement, mainly related to spondyloarthritis. Uveitis without systemic association and anterior uveitis achieved disease control with local treatment more frequently than others (p=.002 and p <.001, respectively). In all, 49.76% of the patients required systemic treatment. Among those treated with immunomodulators, 53.26% needed a second drug and 31.52% needed a third drug. Women required immunomodulators more often than men (P=.042). Methotrexate was the most widely used immunomodulator. Posterior uveitis responded less favorably to the second immunomodulator than anterior uveitis (p=.006). CONCLUSIONS: Almost half of the patients needed an immunomodulatory drug and some of them required successive drug changes. Intermediate uveitis was the most treatment-refractory uveitis. PMID- 29132750 TI - Study of Apoptosis and Intercellular Adhesion in Oral Mucosa of Patients With Osteonecrosis Induced by Biphosphonates. PMID- 29132751 TI - Synthesis, biological activities and SAR studies of new 3-substitutedphenyl-4 substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors. AB - A series of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases were synthesized through Mannich reaction with high yields. Their structures were confirmed by means of IR, 1H NMR, 13C NMR and elemental analysis. The preliminary bioassay indicated that compounds 7g, 7h and 7l exhibited potent in vitro inhibitory activities against ketol-acid reductoisomerase (KARI) with Ki value of (0.38 +/- 0.25), (6.59 +/- 2.75) and (8.46 +/- 3.99) MUmol/L, respectively, and were comparable with IpOHA. They could be new KARI inhibitors for follow-up research. Some of the title compounds also exhibited obvious herbicidal activities against Echinochloa crusgalli and remarkable in vitro fungicidal activities against Physalospora piricola and Rhizoctonia cerealis. The SAR of the compounds were analyzed, in which the molecular docking revealed the binding mode of 7g with the KARI, and the 3D-QSAR results provided useful information for guiding further optimization of this kind of structures to discover new fungicidal agents towards Rhizoctonia cerealis. PMID- 29132752 TI - Drug-target interactions that involve the replacement or displacement of magnesium ions. AB - Metal ions play important roles in protein and RNA structure and function and the construction of ligands frequently focuses on the exploitation of functionality designed to engage a metal. However, there are circumstances where functionality can be incorporated into a ligand to emulate the metal ion, allowing target engagement by displacing or replacing the metal and directly interacting with the metal-binding elements in the target. In this Digest, we illustrate protein and RNA modulators that exploit this design principle, with all of the examples based on the displacement or replacement of a magnesium ion, and which can confer a potency advantage. Moreover, this approach relies upon an inversion of the physical chemical properties of a more conventional metal-binding ligand. PMID- 29132753 TI - Multi-Product Microalgae Biorefineries: From Concept Towards Reality. AB - Although microalgae are a promising biobased feedstock, industrial scale production is still far off. To enhance the economic viability of large-scale microalgae processes, all biomass components need to be valorized, requiring a multi-product biorefinery. However, this concept is still too expensive. Typically, downstream processing of industrial biotechnological bulk products accounts for 20-40% of the total production costs, while for a microalgae multi product biorefinery the costs are substantially higher (50-60%). These costs are high due to the lack of appropriate and mild technologies to access the different product fractions such as proteins, carbohydrates, and lipids. To reduce the costs, simplified processes need to be developed for the main unit operations including harvesting, cell disruption, extraction, and possibly fractionation. PMID- 29132754 TI - The Engineering Potential of Rhodosporidium toruloides as a Workhorse for Biotechnological Applications. AB - Moving our society towards a bioeconomy requires efficient and sustainable microbial production of chemicals and fuels. Rhodotorula (Rhodosporidium) toruloides is a yeast that naturally synthesizes substantial amounts of specialty chemicals and has been recently engineered to (i) enhance its natural production of lipids and carotenoids, and (ii) produce novel industrially relevant compounds. The use of R. toruloides by companies and research groups has exponentially increased in recent years as a result of recent improvements in genetic engineering techniques and the availability of multiomics information on its genome and metabolism. This review focuses on recent engineering approaches in R. toruloides for bioproduction and explores its potential as a biotechnological chassis. PMID- 29132755 TI - [Non-invasive mechanical ventilation after the successful weaning: a comparision with the venturi mask]. PMID- 29132756 TI - Alcoholic hepatitis: calling time on an unhelpful diagnosis. PMID- 29132759 TI - Hepatitis B in sub-Saharan Africa: strategies to achieve the 2030 elimination targets. AB - The WHO global health sector strategy on viral hepatitis, created in May, 2016, aims to achieve a 90% reduction in new cases of chronic hepatitis B and C and a 65% reduction in mortality due to hepatitis B and C by 2030. Hepatitis B virus (HBV) is endemic in sub-Saharan Africa, and despite the introduction of universal hepatitis B vaccination and effective antiviral therapy, the estimated overall seroprevalence of hepatitis B surface antigen remains high at 6.1% (95% uncertainty interval 4.6-8.5). In this Series paper, we have reviewed the literature to examine the epidemiology, burden of liver disease, and elimination strategies of hepatitis B in sub-Saharan Africa. This paper reflects a supranational perspective of sub-Saharan Africa, and recommends several priority elimination strategies that address the need both to prevent new infections and to diagnose and treat chronic infections. The key to achieving these elimination goals in sub-Saharan Africa is the effective prevention of new infections via universal implementation of the HBV birth-dose vaccine, full vaccine coverage, access to affordable diagnostics to identify HBV-infected individuals, and to enable linkage to care and antiviral therapy. PMID- 29132760 TI - Hepatitis C in sub-Saharan Africa: the current status and recommendations for achieving elimination by 2030. AB - In 2016, WHO adopted a strategy for the elimination of viral hepatitis by 2030. Africa, and more specifically, sub-Saharan Africa, carries a substantial portion of the global burden of viral hepatitis, especially chronic hepatitis B and hepatitis C virus infections. The task that lies ahead for sub-Saharan Africa to achieve elimination is substantial, but not insurmountable. Major developments in the management of hepatitis C have put elimination within reach, but several difficulties will need to be navigated on the path to elimination. Many of the challenges faced are unique to sub-Saharan Africa and the development of strategies is complicated by a scarcity of good data from countries and regions within sub-Saharan Africa. However, this hindrance should not act as a barrier to delay interventions in screening, detection, and linkage to care. Moreover, by sharing experiences from across sub-Saharan Africa, countries can create supranational synergies to develop their programmes and work together in a more cohesive manner to tackle the burden of hepatitis C in sub-Saharan Africa. In this Series paper, several issues related to hepatitis C in sub-Saharan Africa are addressed, including prevalence, risk factors, and fibrosis assessment, and recommendations are given by experts from across the region. Simplified diagnostic algorithms and treatment regimens for both HIV co-infected and hepatitis C mono-infected patients are suggested. The recommendations are consensus based and provided to guide the development of programmes in sub Saharan Africa. Political will and appropriate funding will be required to provide impetus to implement these recommendations. PMID- 29132761 TI - Syphilitic hepatitis. PMID- 29132762 TI - The Ottawa Hospital RADiologist Activity Reporting (RADAR) Productivity Metric: Effects on Radiologist Productivity. PMID- 29132763 TI - Spontaneous Bilateral Pneumothoraces in Erdheim-Chester Disease. PMID- 29132764 TI - Muscle Involvement in Long-term Malignant Pleural Mesothelioma. PMID- 29132765 TI - Cortical thinning correlates of changes in visuospatial and visuoperceptual performance in Parkinson's disease: A 4-year follow-up. AB - BACKGROUND: Growing evidence highlights the relevance of posterior cortically based cognitive deficits in Parkinson's disease (PD) as possible biomarkers of the evolution to dementia. Cross-sectional correlational studies have established a relationship between the degree of atrophy in posterior brain regions and visuospatial and visuoperceptual (VS/VP) impairment. The aim of this study is to address the progressive cortical thinning correlates of VS/VP performance in PD. METHODS: Forty-four PD patients and 20 matched healthy subjects were included in this study and followed for 4 years. Tests used to assess VS/VP functions included were: Benton's Judgement of Line Orientation (JLOT), Facial Recognition (FRT), and Visual Form Discrimination (VFDT) Tests; Symbol Digit Modalities Test (SDMT); and the Pentagon Copying Test (PCT). Structural magnetic resonance imaging data and FreeSurfer were used to evaluate cortical thinning evolution. RESULTS: PD patients with normal cognition (PD-NC) and PD patients with mild cognitive impairment (PD-MCI) differed significantly in the progression of cortical thinning in posterior regions. In PD-MCI patients, the change in VS/VP functions assessed by PCT, JLOT, FRT, and SMDT correlated with the symmetrized percent change of cortical thinning of occipital, parietal, and temporal regions. In PD-NC patients, we also observed a correlation between changes in FRT and thinning in parieto-occipital regions. CONCLUSION: In this study, we establish the neuroanatomical substrate of progressive changes in VS/VP performance in PD patients with and without MCI. In agreement with cross-sectional data, VS/VP changes over time are related to cortical thinning in posterior regions. PMID- 29132766 TI - Neutrophil to lymphocyte ratio predict mortality and major adverse cardiac events in acute coronary syndrome: A systematic review and meta-analysis. AB - OBJECTIVES: Neutrophil to lymphocyte ratio (NLR) might be associated with the mortality or major adverse cardiac events (MACEs) in acute coronary syndrome (ACS) patients. We performed a meta-analysis to evaluate the correlation between NLR and mortality/MACEs in ACS. METHODS: We assessed clinical trials through Pubmed, EMBASE, the Cochrane Library and Web of science in investigating the association between NLR and mortality/MACEs in ACS patients up to August 15, 2017. The primary outcome was mortality or recurrent MACEs. RESULTS: In total, 8 studies of 9406 patients were included in the systematic and meta-analysis. Our analysis indicated that elevated pretreatment NLR was a poor prognostic marker for patients with recent ACS in predicting medium to long-term mortality/MACEs (OR 1.26, 95%CI 1.13-1.41). And the analysis indicated that higher pretreatment NLR value was associated with higher in-hospital mortality in ACS patients (OR 6.39, 95%CI 1.49-27.38, p<0.001). The NLR value of 5.0 maybe a cut-off value for ACS risk. CONCLUSIONS: In patients with a recent ACS, an elevated pretreatment NLR value is effective in predicting the risk of mortality/MACEs. PMID- 29132767 TI - [Management of pregnant women with first episode of genital herpes. Guidelines for clinical practice from the French college of gynecologists and obstetricians (CNGOF)]. AB - OBJECTIVE: To provide guidelines for the management of first episode genital herpes during pregnancy and in the immediate postpartum period. METHODS: MedLine and Cochrane Library databases search and review of the main foreign guidelines. RESULTS: In case of first episode genital herpes during pregnancy, antiviral treatment with acyclovir (200mg 5 times daily) or valacyclovir (1000mg twice daily) for 5 to 10 days is recommended (grade C). The patient should be tested for HIV if not previously done (grade B). Daily suppressive antiviral treatment with acyclovir (400mg 3 times daily) or valacyclovir (500mg twice daily) is recommended from 36 weeks for women who have had a first episode genital herpes during pregnancy (grade B). A cesarean section should be performed in case of suspicion of first episode genital herpes at the onset of labor (grade B) or premature rupture of the membranes at term (professional consensus), or in case of first episode genital herpes less than 6 weeks before delivery (professional consensus). In the event of first episode genital herpes highlighted in the postpartum period, the neonatologist should be informed (professional consensus). The patient may be treated according the scheme described above. CONCLUSION: A cesarean section should be performed in case of first episode genital herpes less than 6 weeks before delivery. PMID- 29132768 TI - ? AB - OBJECTIVE: Identify measures to diagnose, prevent and treat genital herpes infection during pregnancy and childbirth and neonatal infection. METHODS: Bibliographic search from Medline, Cochrane Library databases and research of international clinical practice guidelines. RESULTS: Genital herpes lesion is most often due to HSV2 (LE2). The risk of HSV seroconversion during pregnancy is 1 to 5% (LE2). Genital herpes ulceration during pregnancy in a woman with history of genital herpes corresponds with a recurrence. In this situation, there is no need for virologic confirmation (grade B). In case of genital lesions in a pregnant woman that do not report any genital herpes before, it is recommended to perform a virological confirmation by PCR and HSV type specific IgG (Professional consensus). In case of first episode genital herpes during pregnancy, antiviral treatment with acyclovir (200mg 5 times daily) or valacyclovir (1000mg twice daily) for 5 to 10 days is recommended (grade C). In case of recurrent herpes during pregnancy, antiviral therapy with acyclovir (200mg 5 times daily) or valacyclovir (500mg twice daily) can be administered (grade C). The risk of neonatal herpes is estimated between 25% and 44% in case of initial episode (LE2) and 1% in case of recurrence (LE3) at the time of delivery. Antiviral prophylaxis should be offered for women with first episode genital herpes or recurrent genital herpes during pregnancy from 36 weeks of gestation and until delivery (grade B). In case of a history of genital herpes without episode of recurrence during pregnancy, it is not recommended routinely offer a prophylactic treatment (professional consensus). A cesarean section should be performed if there is a suspicion of first episode genital herpes at the onset of labor (grade B), in the event of premature rupture of the membranes at term (professional consensus), or in case of first episode genital herpes less than 6 weeks before delivery (professional consensus). In case of recurrent genital herpes at the onset of labor, cesarean delivery will be all the more considered if the membranes are intact and vaginal delivery will be all the more considered in case of prolonged rupture of membranes (professional consensus). Neonatal herpes is rare and mainly due to HSV-1 (LE3). In most of the case of neonatal herpes, the mothers have no history of genital herpes (LE 3). In case of suspicion of neonatal herpes, different samples (blood and cerebrospinal fluid) for HSV PCR must be carried out to confirm the diagnosis (professional consensus). Any newborn suspected of neonatal herpes should be treated with intravenous acyclovir (60mg/kgs/day 3 times daily) (grade A) prior to the results of HSV PCR (professional consensus). The duration of the treatment depends on the clinical form (professional consensus) CONCLUSION: There is no formal evidence that it is possible to reduce the risk of neonatal herpes in genital herpes during pregnancy. However, appropriate care can reduce the symptoms associated with herpes, the risk of recurrence term and the cesarean rate performed to decrease the risk of neonatal herpes. PMID- 29132769 TI - [Genital herpes and pregnancy: Serological and molecular diagnostic tools. Guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF)]. AB - OBJECTIVES: To describe serological and molecular tools available for genital and neonatal herpes, and their use in different clinical situations. METHODS: Bibliographic investigations from MedLine database and consultation of international clinical practice guidelines. RESULTS: Virological confirmation of genital herpes during pregnancy or neonatal herpes must rely on PCR (Professional consensus). HSV type-specific serology (IgG) will allow determining the immune status of a patient (in the absence of clinical lesions). However, there is currently no evidence to justify universal HSV serological testing during pregnancy (Professional consensus). In case of genital lesions in a pregnant woman that do not report any genital herpes before, it is recommended to perform a virological confirmation by PCR and HSV type-specific IgG in order to distinguish a true primary infection, a non-primary infection associated with first genital manifestation, from a recurrence (Grade C). HSV IgM is useless for diagnosis of genital herpes (Grade C). If a pregnant woman has personal history of genital herpes but no lesions, whatever the gestational age, it is not recommended to perform genital sampling nor serology (Professional consensus). In case of recurrence, if the lesion is characteristic of herpes, virological confirmation is not necessary (Professional Agreement). However, if the lesion is not characteristic, virological confirmation by PCR should be performed (Professional consensus). At birth, HSV PCR samples should be collected as soon as neonatal herpes is suspected (symptomatic neonate) (best before beginning antiviral treatment but must not delay the treatment), or after 24hours of life in case of asymptomatic neonate born to a mother with herpes lesions at delivery (Professional consensus). Clinical samples for virological confirmation should include at least blood and a peripheral location. In case of clinical manifestations of herpes in the neonate, first samples PCR positive, preterm birth, or maternal primary infection or non-primary infection associated with first genital manifestation at delivery, CSF should also be collected as well as samples of lesions in the neonate if present (Professional consensus). Sampling should be repeated in case of PCR negative but strong evidence of neonatal herpes (Professional consensus). HSV serology is useless for diagnosis of neonatal herpes (Grade C). CONCLUSIONS: Virological confirmation for diagnosis of genital herpes during pregnancy or neonatal herpes must rely on PCR. PCR assays available in France are very reliable. Specific IgG are dedicated to restricted indications. PMID- 29132770 TI - [Management of pregnant women with recurrent herpes. Guidelines for clinical practice from the French College of Gynecologists, Obstetricians (CNGOF)]. AB - OBJECTIVE: To provide guidelines for the management of woman with genital herpes during pregnancy or labor and with known history of genital herpes. METHODS: MedLine and Cochrane Library databases search and review of the main foreign guidelines. RESULTS: Genital herpes ulceration during pregnancy in a woman with history of genital herpes correspond to a recurrence. In this situation, there is no need for virologic confirmation (Grade B). In case of recurrent herpes during pregnancy, antiviral therapy with acyclovir or valacyclovir can be administered but provide low efficiency on duration and severity of symptoms (Grade C). Antiviral treatment proposed is acyclovir (200mg 5 times daily) or valacyclovir (500mg twice daily) for 5 to 10 days (Grade C). Recurrent herpes is associated with a risk of neonatal herpes around 1% (LE3). Antiviral prophylaxis should be offered for women with recurrent genital herpes during pregnancy from 36 weeks of gestation and until delivery (Grade B). There is no evidence of the benefit of prophylaxis in case or recurrence only before the pregnancy. There is no recommendation for systematic prophylaxis for women with history of recurrent genital herpes and no recurrence during the pregnancy. At the onset of labor, virologic testing is indicated only in case of genital ulceration (Professional consensus). In case of recurrent genital herpes at the onset of labor, cesarean delivery will be all the more considered if the membranes are intact and/or in case of prematurity and/or in case of HIV positive woman and vaginal delivery will be all the more considered in case of prolonged rupture of membranes after 37 weeks of gestation in an HIV negative woman (Professional consensus). CONCLUSION: In case of recurrent genital herpes at the onset of labor and intact membranes, cesarean delivery should be considered. In case of recurrent genital herpes and prolonged rupture of membranes at term, the benefit of cesarean delivery is more questionable and vaginal delivery should be considered. PMID- 29132771 TI - [Neonatal herpes: Epidemiology, clinical manifestations and management. Guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF)]. AB - OBJECTIVES: To describe the epidemiology of neonatal herpes and its risk factors, clinical and paraclinic manifestations, propose guidelines for a newborn at risk of neonatal herpes, describe treatment modalities, describe post-natal transmission and its prevention. METHODS: Bibliographic search from Medline, Cochrane Library databases and research of international clinical practice guidelines. RESULTS: Neonatal herpes is rare (about 20 cases per year in France) and mainly due to HSV 1 (level of evidence LE3). The main risk factors for mother to-child transmission are maternal primary episode of genital herpes close to delivery and serotype HSV 1 (LE3). There are three clinical forms of neonatal herpes : SEM infection for skin, eyes and mucosa, central nervous system (CNS) associated infection, and the disseminated infection. Neurological mortality and morbidity depend on the clinical form and the HSV serotype (LE3). In most of the case of neonatal herpes, the mothers have no history of genital herpes (LE3). Fever and vesicular rash may be absent at the time of diagnosis (LE3). In case of suspicion of neonatal herpes, different samples (blood and cerebrospinal fluid) for HSV PCR must be carried out to confirm the diagnosis (Professional consensus). Any newborn suspected of neonatal herpes should be treated with intravenous aciclovir (Grade A) prior to the results of HSV PCR (Professional consensus). In case of maternal genital herpes at delivery, the management of an asymptomatic newborn depends on the evaluation of the risk of transmission. In case of maternal reactivation (low risk of transmission), HSV PCR samples are taken at 24hours of life and the newborn must be follow closely until results. In the case of maternal primary episode or non-primary infection first episode (high risk of transmission), the samples are taken at 24hours of life and intravenous treatment with aciclovir is started (Professional consensus). The treatment of neonatal herpes is based on intravenous aciclovir (60mg/kg/day divided into 3 injections) (Grade C). The duration of the treatment depends on the clinical form (14 days for the SEM infection, 21 days for the other forms) (Professional consensus). A relay with aciclovir per os (300mg/m2/day) for 6 months is recommended to improve the neurological outcome and reduce the risk of reactivation (grade B). Post-natal transmission is mainly due to HSV 1. The rules for the prevention of post-natal transmission must be known by parents and family, but also by nursing staff (Professional consensus). Breastfeeding is not contraindicated in cases of maternal herpes, except if there is herpetic lesion on the nipple (Professional consensus). Parents of newborns at risk for neonatal herpes should receive information on the clinical signs to be monitored at home after hospital discharge (Professional consensus). CONCLUSIONS: Neonatal herpes is a rare disease with a high morbidity and mortality. The management of a newborn at risk requires good coordination between the obstetric and pediatric teams and parent's information. PMID- 29132772 TI - [Primary management of endometrial carcinoma. Joint recommendations of the French society of gynecologic oncology (SFOG) and of the French college of obstetricians and gynecologists (CNGOF)]. AB - OBJECTIVES: The management of endometrial carcinoma is constantly evolving. The SFOG and the CNGOF decided to jointly update the previous French recommendations (Institut national du cancer 2011) and to adapt to the French practice the 2015 recommendations elaborated at the time of joint European consensus conference with the participation of the three concerned European societies (ESGO, ESTRO, ESMO). MATERIAL AND METHODS: A strict methodology was used. A steering committee was put together. A systematic review of the literature since 2011 has been carried out. A first draft of the recommendations has been elaborated, with emphasis on high level of evidence. An external review by users representing all the concerned discipines and all kinds of practice was completed. Three hundred and four comments were sent by 54 reviewers. RESULTS: The management of endometrial carcinoma requires a precise preoperative workup. A provisional estimate of the final stage is provided. This estimation impact the level of surgical staging. Surgery should use a minimal invasive approach. The final pathology is the key of the decision concerning adjuvant therapy, which involves surveillance, radiation therapy, brachytherapy, or chemotherapy. CONCLUSION: The management algorithms allow a fast, state of the art based, answer to the clinical questions raised by the management of endometrial cancer. They must be used only in the setting of a multidisciplinary team at all stages of the management. PMID- 29132773 TI - [Maternal deaths due to sudden death. Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Sudden death is defined as unexpected cardiac arrest occurring less than one hour after the onset of the first symptoms. Between 2010 and 2012, 23 maternal deaths were considered as unexplained sudden deaths and three of them were not evaluated due to a lack of clinical data. In addition, 13 maternal deaths with an identified cause occurred in a clinical context of sudden death (7 cases of pulmonary embolism, 2 cases of epilepsy, and 2 cases of cardiomyopathy). The first maneuvers of resuscitation in the presence of bystanders were attempted in 8 of 22 cases (36%). This emphasizes the importance of teaching the non-medical resuscitation modalities of cardiac arrest in pregnant women. Pregnant women must receive accurate resuscitation as the whole population. An autopsy was performed in 10 of 33 cases (30%) and was considered incomplete in 3 patients. This result emphasizes the necessity to perform a systematic and specialized autopsy in the context of sudden maternal death, which is mostly unexplained. PMID- 29132774 TI - [Herpes and pregnancy: Guidelines for clinical practice - introduction]. PMID- 29132776 TI - Predicting Predator Recognition in a Changing World. AB - Through natural as well as anthropogenic processes, prey can lose historically important predators and gain novel ones. Both predator gain and loss frequently have deleterious consequences. While numerous hypotheses explain the response of individuals to novel and familiar predators, we lack a unifying conceptual model that predicts the fate of prey following the introduction of a novel or a familiar (reintroduced) predator. Using the concept of eco-evolutionary experience, we create a new framework that allows us to predict whether prey will recognize and be able to discriminate predator cues from non-predator cues and, moreover, the likely persistence outcomes for 11 different predator-prey interaction scenarios. This framework generates useful and testable predictions for ecologists, conservation scientists, and decision-makers. PMID- 29132775 TI - [Maternal deaths due to cardiovascular disease. Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Between 2010 and 2012, 29 maternal deaths were caused by cardiovascular disease, i.e. an overall maternal mortality ratio of 1.2 per 100,000 live births. Deaths occurred in pre-existing heart disease (n=19), peripartum cardiomyopathy (n=5), or arterial rupture (n=5). Care was considered non-optimal in three of five patients with congenital heart disease and due to delayed management by specialized teams. Pregnant patients with heart disease should be considered to be at high risk of mortality or severe cardiovascular complications and therefore reoriented as soon as possible to a perinatal center with the expertise of these pathologies. A delay in the management related to incorrect diagnosis was reported in three patients with peripartum cardiomyopathy. Peripartum cardiomyopathy should be considered in patients with severe left ventricular failure on cardiac ultrasound and particularly in women without pre-existing cardiac disease. A diagnosis of myocardial infarction was never suspected despite suggestive clinical and paraclinical criteria. A suggestive symptomatology of myocardial infarction reported in any pregnant woman and during the immediate postpartum period, and regardless of cardiovascular risk factors, should be promptly investigated and managed. PMID- 29132777 TI - A comparison between biostimulation and bioaugmentation in a solid treatment of anaerobic sludge: Drug content and microbial evaluation. AB - Emerging pollutants can reach the environment through the sludge of Wastewater Treatment Plants. In this work, the use of Trametes versicolor in biopiles at lab scale was studied, evaluating its capacity to remove the most hydrophobic Pharmaceuticals and assessing the evolution of the biopiles microbial communities. The total removal of drugs at real concentrations from sewage sludge was assessed for non-inoculated and fungal inoculated biopiles, testing if the re inoculation of the biopiles after 22 days of treatment would improve the removal yields. It was found that 2 out of the 15 initially detected pharmaceuticals were totally degraded after 22 days, and re-inoculated fungal biopiles achieved higher removal rates than non-re-inoculated fungal biopiles for single compounds and for all the drugs simultaneously: 66.45% and 49.18% re-inoculated and non-re inoculated biopiles, respectively. Finally, the study of the bacterial and fungal communities revealed that fungal inoculated and non-inoculated biopiles evolved to similar communities adapted to the presence of those drugs. PMID- 29132778 TI - Discourse coalitions in Swiss waste management: gridlock or winds of change? AB - As a complex socio-technical system, waste management is crucially important for the sustainable management of material and energy flows. Transition to better performing waste management systems requires not only determining what needs to be changed but also finding out how this change can be realized. Without understanding the political context, insights from decision support tools such as life cycle assessment (LCA) are likely to be lost in translation to decision and policy making. This study strives to provide a first insight into the political context and address the opportunities and barriers pertinent to initiating a change in Swiss waste management. For this purpose, the discourses around a major policy process are analysed to uncover the policy beliefs and preferences of actors. Discourse coalitions are delineated by referring to the Advocacy Coalition Framework (Sabatier, 1998) and using the Discourse Network Analysis (Leifeld and Haunss, 2012) method. The results display an incoherent regime (Fuenfschilling and Truffer, 2014) with divergent belief clusters on core issues in waste management. Yet, some actors holding different beliefs appear to have overlapping interests on secondary issues such as the treatment of biogenic waste or plastics. Although the current political context hinders a system-wide disruptive change, transitions can be initiated at local or regional scale by utilizing the shared interest across different discourse coalitions. PMID- 29132779 TI - Reliability assessment of bioreactor landfills using Monte Carlo simulation and coupled hydro-bio-mechanical model. AB - The performance of a bioreactor landfill is highly influenced by the simultaneous interactions of several coupled processes that occur within the landfill. In addition, the high uncertainty and spatial variability in the geotechnical properties of municipal solid waste (MSW) poses significant challenge in accurately predicting the performance of bioreactor landfills. In this study, a 2D coupled hydro-bio-mechanical (CHBM) model was employed to predict the behavior of MSW in bioreactor landfills. The numerical model integrated a two-phase flow hydraulic model, a plane-strain formulation of Mohr-Coulomb constitutive model, and a first order decay biodegradation model. The statistical ranges (mean and standard deviation) of some of the major influential MSW properties were derived from the published studies. Random fields of spatially variable MSW properties were generated following the log-normal distribution. Reliability-based analysis was carried out by performing several realizations of Monte-Carlo simulations and the statistical response of the output results including the moisture distribution, pore fluid pressures, landfill settlement, and interface shear response of the composite liner system were quantified. The results clearly indicate the importance of considering spatial variability of the geotechnical MSW properties and its influence on the performance of bioreactor landfills during leachate injection operations. A comparison of the results with the deterministic analysis was performed to evaluate the relative benefits and to emphasize the need for reliability-based analysis for effective design of bioreactor landfills. PMID- 29132780 TI - Sustainable wineries through waste valorisation: A review of grape marc utilisation for value-added products. AB - Grapes are one of the most cultivated fruits worldwide, with one third of total production used in winemaking. Both red and white winemaking processes result in substantial quantities of solid organic waste, such as grape marc (pomace) and stalks, which requires suitable disposal. Grape marc accounts for approximately 10-30% of the mass of grapes crushed and contains unfermented sugars, alcohol, polyphenols, tannins, pigments, and other valuable products. Being a natural plant product rich in lignocellulosic compounds, grape marc is also a promising feedstock for renewable energy production. However, despite grape marc having such potential, advanced technologies to exploit this have not been widely adopted in wineries and allied industries. This review covers opportunities beyond traditional composting and animal feed, and examines value-added uses via the extraction of useful components from grape marc, as well as thermochemical and biological treatments for energy recovery, fuel or beverage alcohol production, and specialty novel products and applications such as biosurfactants and environmental remediation. New advances in relevant technology for each of these processes are discussed, and future directions proposed at both individual producer and regional facility scales, including advanced processing techniques for integrated ethanol production followed by bioenergy generation from the spent marc. PMID- 29132781 TI - Optimisation of surfactant decontamination and pre-treatment of waste chicken feathers by using response surface methodology. AB - Commercially processed, untreated chicken feathers are biologically hazardous due to the presence of blood-borne pathogens. Prior to valorisation, it is crucial that they are decontaminated to remove the microbial contamination. The present study focuses on evaluating the best technologies to decontaminate and pre-treat chicken feathers in order to make them suitable for valorisation. Waste chicken feathers were washed with three surfactants (sodium dodecyl sulphate) dimethyl dioctadecyl ammonium chloride, and polyoxyethylene (40) stearate) using statistically designed experiments. Process conditions were optimised using response surface methodology with a Box-Behnken experimental design. The data were compared with decontamination using an autoclave. Under optimised conditions, the microbial counts of the decontaminated and pre-treated chicken feathers were significantly reduced making them safe for handling and use for valorisation applications. PMID- 29132782 TI - Midterm outcomes after postoperative delirium on cognition and mood in patients after cardiac surgery. AB - OBJECTIVE: Delirium is a common neurologic complication after cardiac surgery. Our primary objective was to determine the impact of delirium on self-reported problems with midterm cognitive functioning and mood postcardiac surgery. METHODS: A single-center, prospective cohort study was conducted, enrolling 197 patients undergoing coronary artery bypass grafting or valve replacement. Baseline cognition and mood were assessed preoperatively in elective patients as a part of routine care using the Montreal Cognitive Assessment and Patient Health Questionnaire 9, respectively. During hospitalization, delirium was diagnosed using the Confusion Assessment Method (Confusion Assessment Method/Confusion Assessment Method Intensive Care Unit). Follow-up assessments were carried out via telephone interview at 6 to 9 months after cardiac surgery using the EuroQoL 5D, Patient Health Questionnaire 9, Alcohol Use Disorders Identification Test Consumption, Memory Impairment Screen, and Category Fluency Test assessments. We examined resultant scores in the domains of cognition and mood among delirious and nondelirious cohorts, controlling for confounders deemed clinically relevant. RESULTS: A total of 197 patients were enrolled in the study, of whom 44 (22%) developed postoperative delirium. After adjustment, no differences were observed in cognitive functioning between the delirious and nondelirious subjects after 6 to 9 months. However, delirious patients were more likely to experience self reported problems in affective (depression and anxiety) functioning as measured by the EuroQoL-5D (odds ratio, 4.41; 95% confidence interval, 1.51-12.92; P < .01). CONCLUSIONS: Postoperative delirium is associated with increased anxiety and depression at 6 to 9 months postcardiac surgery. Future investigation should seek to evaluate the utility of screening programs for affective disorders in those individuals who develop delirium in the postoperative period. PMID- 29132783 TI - Neuroendocrine tumors of the lung: Has the stage been set? PMID- 29132784 TI - The elusive mass in the right atrium: A liver in the heart. PMID- 29132785 TI - Nonrheumatoid Arthritis of the Hand. AB - Arthropathy of the hand is commonly encountered. Contributing factors such as aging, trauma, and systemic illness all may have a role in the evolution of this pathology. Besides rheumatoid arthritis, other diseases affect the small joints of the hand. A review of nonrheumatoid hand arthropathies is beneficial for clinicians to recognize these problems. PMID- 29132786 TI - Outcomes Following Acute Metacarpophalangeal Joint Arthroplasty Dislocation: An Analysis of 37 Cases. AB - PURPOSE: There remains a paucity of information regarding the treatment outcomes of dislocation after metacarpophalangeal (MCP) joint arthroplasty. The purpose of this study was to assess the outcomes of surgical and nonsurgical treatment modalities of MCP arthroplasty dislocations. METHODS: Of 816 MCP joint arthroplasties over a 14-year period, there were 37 (4%) acute MCP joint dislocations that required intervention by a health care professional. Implants involved included 28 nonconstrained implants including pyrocarbon (n = 17) and surface replacement arthroplasty (n = 11), and 9 silicone implants. The analysis included the treatment of dislocations after primary (n = 30) and revision (n = 7) MCP joint arthroplasty. Dislocation was defined as clinical and radiographic evidence of MCP joint prosthetic acute dislocation diagnosed and treated by a fellowship trained hand surgeon. RESULTS: Etiologies underlying the dislocations included implant fracture (n = 6), component loosening (n = 2), and soft tissue deficiency (n = 29). Of the 37 dislocations, treatments included 14 nonsurgical (closed reduction, orthosis fabrication) all of which ultimately failed. Surgically, including some of the failed prior procedures, 18 soft tissue stabilization procedures and 21 revision arthroplasties were performed, with 6 that had failed soft tissue stabilization. The soft tissue stabilization procedures had a 28% success rate in achieving a stable MCP joint. Revision arthroplasty had a 71% success rate. Subgroup analysis showed an 86% success rate for silicone revisions and a 43% success rate with nonconstrained revisions, with 80% and 36% 5-year survival free of instability, for the 2 types of implants, respectively. CONCLUSIONS: The treatment of MCP joint arthroplasty dislocation with revision to silicone implant appears to hold the most promise in achieving a stable MCP joint after an acute prosthetic dislocation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29132787 TI - Distal Biceps Brachii Tendon Transfer for Re-establishing Extrinsic Finger Function: Feasibility Study in Cadavers. AB - PURPOSE: To determine the anatomic feasibility of transferring the biceps brachii tendon into either the extensor digitorum communis (EDC) or flexor digitorum profundus (FDP), determine the excursion imparted to EDC and FDP tendons after transfer, and compare the work capacity of the cadaver biceps to previously published data on the biceps as well as the recipient muscles by calculating the physiologic cross-sectional area (PCSA). METHODS: Four fresh-frozen cadaver shoulder-elbow-wrist specimens were used to measure tendon excursion that can be obtained with transfer of the distal biceps tendon into either the EDC or FDP. Two cadavers had distal biceps-to-EDC transfer performed, and the other 2 had distal biceps-to-FDP performed. Passive ranging of each elbow from flexion to extension and active loading at 90 degrees of elbow flexion were then performed on each specimen to determine tendon excursion. An analysis of the PCSA of the biceps muscle was performed on each specimen. RESULTS: Distal biceps-to-EDC transfer resulted in an average of 24 mm of tendon excursion with passive loading, and 24 mm of tendon excursion with active loading. Distal biceps-to-FDP transfer resulted in an average of 24 mm of tendon excursion with passive loading, and 24 mm of tendon excursion with active loading. The average PCSA was 3.6 cm2. CONCLUSIONS: Transfer of the distal biceps tendon into the EDC or FDP is anatomically feasible and provides roughly 24 mm of tendon excursion to the tendon units. The PCSA in the specimens used is slightly lower than other published data; it closely approximates the PCSA of the EDC, but is only half of the PCSA of the FDP in previously published data. CLINICAL RELEVANCE: The findings suggest potentially novel transfer options for restoring finger flexion and extension in patients lacking FDP or EDC function. PMID- 29132788 TI - Arthroscopic Partial Trapeziectomy With Soft Tissue Interposition for Symptomatic Trapeziometacarpal Arthritis: 6-Month and 5-Year Minimum Follow-Up. AB - PURPOSE: To determine if arthroscopic partial trapeziectomy (APT) and soft tissue interposition arthroplasty is an effective treatment for symptomatic trapeziometacarpal arthritis. METHODS: We retrospectively evaluated 30 consecutive patients with symptomatic isolated trapeziometacarpal arthritis, Eaton-Littler stages II and III. Treatment consisted of an APT with soft tissue interposition utilizing an acellular dermal matrix as the interposition material. At a minimum of 6 months and 5 years after surgery, Numeric Pain Rating Scale (NPRS), Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), grip strength, oppositional and appositional pinch strengths, arthroplasty space, and thumb range of motion (ROM) were evaluated. RESULTS: At 6-month minimum follow up, 30 of 30 patients reported a significant reduction in pain; preoperative NPRS averaged 8.2 and decreased to 1.3. Average QuickDASH score was 17.5. Twenty-nine of 30 thumbs could adduct fully in the plane of the palm. Twenty-four patients were available for 5-year minimum follow-up. Average QuickDASH score measured 8.9, whereas pain (mean NPRS, 0.8), grip, and pinch strengths were not significantly different from the 6-month assessment. There was a small reduction in arthroplasty space at 5-year follow-up that did not affect clinical outcome measures. Thumb ROM did not change between the 6-month and the 5-year follow-up. Complications were rare. CONCLUSIONS: An APT with interposition arthroplasty utilizing an acellular dermal matrix as the interposition material is a safe and reliable procedure with satisfactory outcomes at short- and long-term follow-up. Pain, strength, QuickDASH, and ROM do not significantly change between the 6 month and the 5-year follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29132789 TI - Scaphoid Fracture Fixation in a Nonunion Model: A Biomechanical Study Comparing 3 Types of Fixation. AB - PURPOSE: Union of a scaphoid fracture after fixation is influenced by various factors, one of which is fracture stability. This study aims to compare the biomechanical stability of 3 different types of scaphoid fracture fixation in a scaphoid nonunion model. METHODS: Thirty cadaveric scaphoid specimens were assigned to one of 3 different fixation groups: (1) single 3.0-mm compression screw, (2) two 2.2-mm screws, and (3) scaphoid plate. A 3-mm volar wedge osteotomy was created at the scaphoid waist to simulate a nonunion model. The primary outcome measure was load to failure, whereas secondary outcome measures were load to 2-mm displacement, energy absorbed, stiffness, and mode of failure, recorded by video and retrieval analysis. RESULTS: There was a significantly lower load to failure in the single screw construct compared with that in the double screw (mean difference 187.2 N) and plate fixation constructs (mean difference 150.7 N). The mean load to 2-mm displacement in the single screw construct (91.5 N) was also significantly lower than that in the double screw (181.8 N) and plate fixation constructs (197.2 N). There was a significantly lower stiffness with the single screw fixation compared with that of the double screws (mean difference 85.4 N/mm), and lower energy absorbed with single screws when compared with that of double screws (mean difference 386.5 mJ) and when compared with plate fixation (mean difference 270.8 mJ). CONCLUSIONS: In this biomechanical study comparing fixation methods using a model of scaphoid nonunion with bone loss, we found that double screws or plate fixation demonstrated significantly greater stability, stiffness, and energy absorption when compared with a single compression screw. We found no discernible differences between double screw fixation and the plate groups. CLINICAL RELEVANCE: The use of double screws or plate fixation in a nonunion setting may allow accelerated rehabilitation without compromise to fracture stability. PMID- 29132790 TI - Ulnar Thumb Pulp Reconstruction Using the Anterograde Homodigital Neurovascular Island Flap. AB - The thumb ulnar pulp is a critical component of key pinch and precision manipulation. Injuries to this area should be reconstructed with robust, sensate tissue that restores bulk and contour. The existing reconstructive options, however, have substantial risks and drawbacks. We describe an anterograde homodigital neurovascular island flap that provides both sensate and durable coverage of the ulnar thumb pulp. The flap uses innervated glabrous tissue, limits donor site morbidity to the thumb and first web space, and does not require microvascular anastomoses or nerve coaptation. The flap has been previously described for nonthumb fingertip injuries, but it has not been applied to the thumb. We discuss several important technical modifications that are essential to raising and insetting this flap in the thumb, review potential pitfalls, and highlight key steps to ensuring judicious intraoperative decision making and success. PMID- 29132791 TI - In Vitro Kinematic Assessment of a Hinged Elbow Orthosis Following Lateral Collateral Ligament Injury. AB - PURPOSE: Elbow lateral collateral ligament injuries (LCLI) are often managed with protected mobilization using a hinged elbow orthosis (HEO). The objective of this investigation was to determine the effectiveness of an HEO in stabilizing the elbow following LCLI. METHODS: Seven fresh-frozen cadaveric upper extremity specimens were studied using a custom simulator that enabled elbow motion via computer-controlled actuators and servomotors attached to relevant tendons. Specimens were examined in 4 arm positions (dependent, overhead, horizontal, and varus) and 2 forearm positions (pronation and supination) during both passive and simulated active elbow extension. Specimens were examined before and after simulated LCLI, and then with the addition of an HEO. The lateral collateral ligament, common extensor origin, and lateral elbow capsule were sectioned in the injury model. An electromagnetic tracking system measured ulnohumeral kinematics. RESULTS: The orthosis did not change elbow stability in any arm position during active motion. Muscle activation and forearm pronation enhanced stability in the dependent, horizontal, and varus positions while the HEO was applied. CONCLUSIONS: This HEO does not improve the in vitro stability of the elbow following simulated LCLI. CLINICAL RELEVANCE: An HEO may be safe to use during active motion, but when a patient is not activating the muscles normally (ie, owing to fatigue or cognitive impairment) and the arm is in positions in which the weight of the orthosis might increase joint distraction, an HEO may be harmful. If an HEO is used, the forearm should be braced in pronation following LCLI. PMID- 29132792 TI - [Neuromeningeal cryptococcosis in patients infected with HIV at Agadir regional hospital, (Souss-Massa, Morocco)]. AB - INTRODUCTION: Neuromeningeal cryptococcosis (NMC) is a severe and fatal opportunistic infection. Lethality is frequent in the absence of treatment, especially in the presence of HIV co-infection. OBJECTIVE: To determine the prevalence, epidemiological, clinical, biological and therapeutic aspects as well as the evolution of NMC for patients infected with HIV. PATIENTS AND METHODS: This is a retrospective study of 40 cases of neuromeningeal cryptococcosis diagnosed in HIV-infected patients. Data are collected for 7 years (from January 2010 to December 2016) in the registers of the parasitology laboratory and the infectious diseases department at the regional hospital center in Agadir. RESULTS: A reduction in the prevalence of neuromeningeal cryptococcosis in HIV infected patients was noted from 2010 to 2016 (3.66% to 0.83%). The overall prevalence of NMC was 1.53%. The mean age was 37+/-10 years old, with 90% of patients aged less than 45 years. The main clinical symptomatology was headache (75%). The main cytochemical abnormalities of cerebrospinal fluid analysis were hyperproteinorachy (60%), hypoglycorachy (63%) and lymphocytosis (50%). The mean CD4 cell count was 47/mm3. Patients were initially treated with amphotericin B, relayed with fluconazole. The overall lethality was 35%. CONCLUSION: Neuromeningeal cryptococcosis is a serious opportunistic infection in patients HIV-infected, and the lethality rate remains unacceptable. Fighting NMC in HIV+ patients requires early diagnosis, increased access to antiretrovirals, rapid introduction of appropriate treatment and the prescription of effective systemic antifungals. PMID- 29132794 TI - Saccharomyces cerevisiae fungemia after probiotic treatment in an intensive care unit patient. AB - Saccharomyces cerevisiae is a common colonizer of the human gastrointestinal system as a benign organism. Enteral supplementation of this yeast as a probiotic product is effective in the treatment of antibiotic associated diarrhae. In rare occasions it can cause invasive infections. We present two fungemia cases in an intensive care unit following probiotic treatment containing S. boulardii. We are warning the safety of probiotic treatment in critically ill patients. PMID- 29132793 TI - [French recommendations on control measures to reduce the infectious risk in immunocompromised patients]. AB - The increase use of immunosuppressive treatments in patients with solid cancer and/or inflammatory diseases requires revisiting our practices for the prevention of infectious risk in the care setting. A review of the literature by a multidisciplinary working group at the beginning of 2014 wished to answer the following 4 questions to improve healthcare immunocompromised patients: (I) How can we define immunocompromised patients with high, intermediate and low infectious risk, (II) which air treatment should be recommended for this specific population? (III) What additional precautions should be recommended for immunocompromised patients at risk for infection? (IV) Which global environmental control should be recommended? Based on data from the literature and using the GRADE method, we propose 15 recommendations that could help to reduce the risk of infection in these exposed populations. PMID- 29132795 TI - [Interdigital tinea pedis resulting from Fusarium spp. in Dakar, Senegal]. AB - INTRODUCTION: Fungal interdigital tinea pedis (ITP) is a common pathology mainly due to dermatophytes and yeasts. Fusarium sp. is rarely incriminated in the genesis of intertrigo. In Dakar, a recent study conducted in 2016 on fungal ITP showed that Fusarium were more involved in the etiology of ITP than dermatophytes, coming just after yeasts dominated by Candida. Following this, we wanted to draw attention to the increasing incidence of ITP resulting from Fusarium spp., in Dakar, Senegal, and to analyze the epidemiological and mycological particularities of these ITP due to Fusarium spp. PATIENTS AND METHODS: A retrospective study including all patients received at the laboratory for suspicion of ITP between January 1st, 2014 and June 30th, 2017 was conducted. Diagnosis was based on mycological examination, including direct examination and culture. Mycological analysis was considered positive when direct examination and culture were positive after at least one repeat. RESULTS: Twenty-nine cases of Fusarium ITP accounting for 44.6% of all ITP in the study period were diagnosed in 15 men and 14 women. The mean age of the patients was 48.4 years. Fusarium ITP were diagnosed in immunocompetent patients except in two diabetics. The mean duration of the lesions was 6.83 years. The most frequent species isolated belonged to the Fusarium solani complex with 19 cases. CONCLUSION: Fusarium ITP in a healthy subject requires regular monitoring because any subsequent decrease in immune defenses could lead to fatal hematogenous spread. PMID- 29132796 TI - Old drug, new indication: Olsalazine sodium reduced serum uric acid levels in mice via inhibiting xanthine oxidoreductase activity. AB - Hyperuricemia, a long-term purine metabolic disorder, is a well-known risk factor for gout, hypertension and diabetes. In maintaining normal whole-body purine levels, xanthine oxidase (XOD) is a key enzyme in the purine metabolic pathway, as it catalyzes the oxidation of hypoxanthine to xanthine and finally to uric acid. Here we used the protein-ligand docking software idock to virtually screen potential XOD inhibitors from 3167 approved small compounds/drugs. The inhibitory activities of the ten compounds with the highest scores were tested on XOD in vitro. Interestingly, all the ten compounds inhibited the activity of XOD at certain degrees. Particularly, the anti-ulcerative-colitis drug olsalazine sodium demonstrated a great inhibitory activity for XOD (IC50 = 3.4 mg/L). Enzymatic kinetic studies revealed that the drug was a hybrid-type inhibitor of xanthine oxidase. Furthermore, the drug strikingly decreased serum urate levels, serum/hepatic activities of XOD at a dose-dependent manner in vivo. Thus, we demonstrated a successful hunting process of compounds/drugs for hyperuricemia through virtual screening, supporting a potential usage of olsalazine sodium in the treatment of hyperuricemia. PMID- 29132797 TI - Cloaca reconstruction: a new algorithm which considers the role of urethral length in determining surgical planning. AB - BACKGROUND: Cloacal malformations represent a uniquely complex challenge for surgeons. The surgical approach to date has been based on the common channel (CC) length with two patient groups considered: less than or greater than 3cm, which we believe is an oversimplification. We reviewed 19 patients, referred after surgery done elsewhere. Eight had postoperative urinary complications, 3 had constant urinary leakage and had been left after surgery with a urethra <1cm, .5 with an original 3 to 5cm common channel, who had undergone total urogenital mobilization (TUM), experienced peri-operative urethral loss needing a vesicostomy, and later, a Mitrofanoff. These patients together with a review of the cloacal and urological literature led us to design a new algorithm where urethral length is a key determinant for care. METHODS: We prospectively collected data on 31 consecutive cloaca patients referred to our team (2014 to 2016) and managed according to this new protocol. The CC length, urethral length, surgical technique employed, and initial outcomes were recorded. RESULTS: Of 31 primary cases, CC length was 1 to 3cm in 20, 3 to 5cm in 9, and greater than 5cm in 2. In the 1 to 3cm and the 3 to 5cm groups, a urethra less than 1.5cm led us to perform an urogenital separation. We only performed a TUM if the urethra was greater than 1.5cm. Using this protocol, we performed a urogenital separation in 1 of 20 in the 1 to 3cm CC group, 6 of 9 in the 3 to 5cm CC group, and 2 of 2 in the greater than 5cm CC group. Seven patients underwent separation, who with the previous approach, would have had a TUM. Thus far, no urinary leakage or urethral loss has occurred in any patient, but follow-up is less than 3years. CONCLUSION: Urethral length appears to be a vitally important component in cloacal reconstruction. A short urethra left after repair can lead to urinary leakage. A TUM done under the wrong circumstances can lead to urethral loss. We describe a new technical approach to cloacal repair which considers urethral length but recognize that long term urological outcomes will need to be carefully documented. TYPE OF STUDY: Clinical cohort study with no comparative group. LEVEL OF EVIDENCE: Level 4. PMID- 29132798 TI - The impact of racial/ethnic disparities on survival for children and adolescents with extremity sarcomas: A population-based study. AB - PURPOSE: The purpose of this study was to determine whether racial/ethnic disparities exist in disease presentation, treatment, and survival among children and adolescents with extremity sarcoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) data were analyzed for patients <20years old with soft tissue extremity sarcomas from 1973 to 2013. Multivariate logistic regression was performed to determine the association between race/ethnicity and disease stage at presentation and likelihood of surgical resection. Overall survival (OS) was evaluated using hazard ratios with 95% confidence intervals. RESULTS: 1261 cases were identified: 650 (52%) non-Hispanic whites (NHW), 313 (25%) Hispanics, 182 (14%) non-Hispanic blacks (NHB), and 116 (9%) other race/ethnicity. Logistic regression results showed that Hispanics and NHB were 51% and 44%, respectively, less likely to undergo surgical resection compared to NHW (OR=0.49, 95% CI: 0.30 0.80; OR=0.56, 95% CI: 0.32-0.98, respectively). Factors associated with failure to undergo surgical resection included histology, lower extremity site, tumor size, and distant metastases. OS based on race/ethnicity significantly differed using the log-rank test, with NHB having the worst survival (p<0.05). CONCLUSIONS: We conclude that NHB, Hispanics, and other race/ethnicity were less likely to undergo surgical resection for extremity sarcoma. Further work is needed to better characterize and eliminate disparities in the management and outcomes of children with extremity sarcomas. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: IV. PMID- 29132799 TI - Surgical exploration for impalpable testis: Which should be first, inguinal exploration or laparoscopic abdominal exploration? AB - PURPOSE: To discuss an optimal surgical approach for impalpable testis in children, our own treatment results and those reported in the literature were reviewed. MATERIALS AND METHODS: Seventy-two impalpable testes were diagnosed in 68 patients: unilateral in 64 patients and bilateral in 4 patients. All patients underwent surgical exploration at the ages of 6 to 140months (median, 15months). The inguinal canal was initially explored, and abdominal exploration was performed with laparoscopy when an extra-abdominal testis was not identified. In addition, articles regarding surgical exploration for impalpable testis, published over the last 20years, were retrieved and the results were examined. RESULTS: Testes were detected by inguinal exploration in 28 of 72 (39%) impalpable testes: intracanalicular in 22 testes and at the internal inguinal ring (peeping or low abdominal testis) in 6 testes. All these testes were treated by conventional inguinal orchidopexy. Laparoscopic exploration was performed in 44 (61%) impalpable testes, and 4 (5.6%) high abdominal testes were detected and treated by two-stage Fowler-Stephens orchidopexy. Vanishing or absent testis was the final diagnosis in the remaining 40 testes (55.6%). The literature review showed that the ratios of intra- and extra-abdominal testes were lower in the articles that reported the results of inguinal or scrotal exploration than in those of laparoscopic exploration, although the difference was not significant. CONCLUSIONS: Considering the relatively low incidence of high abdominal testis, we recommend to start with inguinal exploration for impalpable testis. When an extra-abdominal testis is not detected, transinguinal laparoscopic exploration should be indicated. LEVEL OF EVIDENCE: Treatment study, Level IV. PMID- 29132800 TI - Fetal bone marrow homing of donor mesenchymal stem cells after transamniotic stem cell therapy (TRASCET). AB - PURPOSE: Donor cell engraftment patterns following transamniotic stem cell therapy (TRASCET) with amniotic fluid mesenchymal stem cells (afMSCs) are incompatible with solely direct amniotic seeding. We sought to determine whether fetal bone marrow is a component of such engraftment and to examine the chronology of afMSC placental trafficking. METHODS: Two groups of Sprague-Dawley rat fetuses received volume-matched intraamniotic injections on gestational day 17 (E17; term E22): either afMSCs labeled with a luciferase reporter gene or luciferase protein alone. Placental samples were procured at daily time points thereafter until term. Fetal bone marrow was obtained at term only owing to size constraints. Specimens were screened for luminescence via microplate luminometry. RESULTS: Donor afMSCs were identified in the bone marrow and placenta of fetuses receiving labeled afMSCs, but not in those receiving luciferase alone (P<0.001). Luminescence was significantly higher in placentas at E18 compared to E19 (P<0.001), E20 (P=0.007), and E21 (P=0.004), with no difference with E22/term (P=0.97). CONCLUSIONS: Donor mesenchymal stem cells home to the fetal bone marrow after intraamniotic injection. The chronology of placental trafficking is suggestive of controlled cell routing rather than plain cell clearance. Fetal bone marrow engraftment of donor cells significantly expands potential applications of transamniotic stem cell therapy. PMID- 29132801 TI - Robotic stereotactic treatment for malignant metastasis of solid tumour in the pancreas: A multiple case report and review of literature. AB - Metastatic involvement of the pancreas occurs in 5% of patients affected by advanced malignancies. Surgical resection has been reported by number of authors as a valuable option to improve disease control, in particular in patients with limited disease burden and favourable histotypes; however, the benefit of this procedure has been questioned due to patient selection, technical challenges and relevant risk of perioperative mortality and severe complications. In the present study, a cohort of surgically unfit patients affected by a solitary metastasis in the pancreas from various primary tumours received stereotactic radiotherapy with an ablative dose schedule, obtaining promising local and distant disease progression-free delay with minor toxicity. This is the first report to our knowledge on the use of ablative stereotactic radiotherapy of metastasis in the pancreatic gland. PMID- 29132802 TI - [Prophylactic radiotherapy in a single fraction of 10Gy at intervention pleural site in patient with malignant pleural mesothelioma: A retrospective monocentric cohort study]. AB - PURPOSE: Prophylactic radiotherapy to prevent procedure-tracts metastases from malignant pleural mesothelioma remains controversial and clinical practice varies. The purpose was to assess the efficacy of local radiotherapy in a single fraction of 10Gy in preventing malignant seeding at intervention pleural site in patients with malignant pleural mesothelioma. MATERIAL AND METHODS: This is a retrospective cohort study, including patients with histological confirmed malignant pleural mesothelioma treated by prophylactic irradiation to prevent interventional site metastases with a unique fraction of 10Gy with 6 to 18MeV, from January 1990 to December 2013 in the institut de cancerologie de Lorraine (Nancy, France). RESULTS: Ninety-one patients were treated by irradiation in intervention site, involving 120 intervention pleural sites, 91 thoracoscopies, 17 thoracotomies with chest drain and 12 CT or ultrasound guided needle biopsies. The median follow-up was 7 months (interquartile between 3 and 15 months). The overall survival was 43.5% at 12 months. The local progression free survival was 43.7% at 12 month. The incidence of local recurrence was 8% at 12 months. The median interval from radiotherapy to local recurrence was 4 months (2; 32). No grade II or higher toxicity was observed. CONCLUSION: Irradiation of pleural intervention sites with a single fraction of 10Gy is effective, well tolerated, simple, fast and cost effective. PMID- 29132803 TI - High dose irradiation after pleurectomy/decortication or biopsy for pleural mesothelioma treatment. AB - PURPOSE: The role played by radiation therapy after pleurectomy/decortication or surgical biopsy in malignant pleural mesothelioma is uncertain. We treated patients with accelerated hypofractionated radiotherapy using helical tomotherapy and intensity-modulated arc therapy in an attempt to keep lung toxicity to a minimum. The present study reports the feasibility and toxicity of this approach. MATERIAL AND METHODS: Between 2008 and 2012, 36 patients with malignant pleural mesothelioma underwent accelerated hypofractionated radiotherapy to the hemithorax after pleurectomy/decortication (19 patients) or biopsy (17 patients). The prescription dose was 25Gy in five fractions over 5 consecutive days. RESULTS: We observed three patients with G3 pneumonitis, five cases of grade 2 dyspnea and six cases of grade 2 cough. The median follow-up was 37 months (range: 3-54 months). The median overall survival for patients who underwent pleurectomy/decortication followed by radiotherapy was 21.6 months [95% confidence interval (95% CI): 15.5-24.1] compared to 19.4 months for patients not submitted to surgery. CONCLUSION: Treatment of intact lung with pleural intensity modulated arc irradiation in malignant pleural mesothelioma patients with malignant pleural mesothelioma proved safe and feasible, with an acceptable rate of pneumonitis. Survival rates were encouraging for both biopsy-only and pleurectomy/decortication groups. We are currently conducting a phase II dose escalation trial in a similar patient setting to prospectively evaluate the impact of radiotherapy on toxicity, disease-free survival and overall survival. PMID- 29132804 TI - A Randomized Controlled Trial Comparing the Utility of Lighted Stylet and GlideScope for Double-Lumen Endobronchial Intubation. AB - OBJECTIVE: To compare GlideScope and lighted stylet for double-lumen endobronchial tube (DLT) intubation in terms of intubation time, success rate of first attempt at intubation, difficulty in DLT advancement toward the glottis, and postoperative sore throat and hoarseness. DESIGN: A prospective, randomized study. SETTING: Medical center governed by a university hostpial. PARTICIPANTS: Sixty-two adult patients undergoing thoracic surgery using DLT intubation. INTERVENTION: After the induction of anesthesia, DLT intubation was performed using GlideScope (n = 32) or lighted stylet (n = 32). MEASUREMENTS AND MAIN RESULTS: Number of intubation attempts, difficulty of DLT advancement toward the glottis, time taken for DLT intubation, and the incidence and severity of postoperative sore throat and hoarseness at 1 and 24 hours after surgery were evaluated. Time taken for DLT intubation was shorter in the lighted stylet group compared with the GlideScope group (30 [28-32] s v 45 [38-53] s, median [interquartile range], respectively; p < 0.001). DLT advancement toward the glottis was easier in the lighted stylet group than in the GlideScope group (p = 0.016). The success rate of DLT intubation in the first attempt (96.9% v 90.6% for lighted stylet and GlideScope, respectively), and the incidence and severity of postoperative sore throat and hoarseness were not different between the two groups. CONCLUSIONS: The use of lighted stylet allowed easier advancement of the DLT toward the glottis in the oropharyngeal space and reduced time for achieving DLT intubation compared with GlideScope. PMID- 29132805 TI - Feasibility of the Use of Transesophageal Echocardiography as a Surface Probe for Puncturing and Catheterization of the Internal Jugular Vein: A Randomized Controlled Pilot Study. AB - OBJECTIVE: To compare the transesophageal echocardiography (TEE) probe as a surface probe with the vascular probe for guiding internal jugular vein (IJV) catheterization. DESIGN: Prospective, randomized, controlled pilot study. SETTING: University hospital. PARTICIPANTS: One hundred cardiac surgery patients, including 50 adult and 50 pediatric patients. INTERVENTIONS: Patients in the TEE probe group received right IJV catheterization using the TEE probe, while the vascular probe group used the vascular probe for catheterization. MEASUREMENTS AND MAIN RESULTS: The puncture time, first-attempt success rate, quality of the imaging with needle tip positioning, wire positioning, and catheter positioning were recorded. The incidence of complication or any adverse event also was observed. Adult patients: In the vascular probe group, the success rate for first attempt IJV catheterization was 24/25 (96%), while in the TEE probe group, the success rate for first attempt IJV catheterization was 25/25 (100%). There was no statistical difference in the puncture time, image quality, needle tip positioning, wire positioning, and catheter positioning between groups (p > 0.05). Pediatric patients: The success rate for first-attempt IJV catheterization was 100% in both groups, and there were no statistical differences in the puncture time, image quality, and positioning between the 2 groups (p > 0.05). No complications or adverse events were observed in either group. CONCLUSION: The TEE probe, used as a surface probe, can be used to guide IJV puncturing and catheterization in cardiac surgery patients with favorable feasibility and safety. PMID- 29132806 TI - Heart Transplantation in an Era of Mechanical Circulatory Support. PMID- 29132807 TI - Development and Validation of the Voice Catastrophization Index. AB - INTRODUCTION: Catastrophization is a cognitive distortion that has been studied in pain patients and found to be a significant factor in their disability and response to treatment. Dysphonia patients may demonstrate a similar behavior, suggesting the existence of voice catastrophization. OBJECTIVE: To establish the validity of the Voice Catastrophization Index (VCI), a new instrument estimating voice symptoms catastrophization. METHODS: A prospective study. Patients with and without voice conditions were administered with the VCI, Voice-Related Quality of Life (V-RQOL), and the Generalized Anxiety Disorder-7 (GAD-7)questionnaires. Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) rating was determined for patients with voice conditions. RESULTS: Ninety-one patients participated, 65 with voice conditions and 26 without. 61.5% were females; mean age was 49.8 +/- 15.7 years. The VCI score for patients with voice conditions was significantly higher, 22.46 +/- 16.56, compared with 3.96 +/- 10.79, respectively (P value < 0.0001). The VCI demonstrated moderate correlation with both V-RQOL and GAD-7 scores: -0.562 and 0.560, respectively (P value < 0.000001); however, it showed no correlation with the CAPE-V. The VCI's internal consistency with each of its three dimensions and 13 items was acceptable to strong. The reproducibility and stability was demonstrated in a subgroup of 26 patients; 81% of these patients had a difference of 10 or less points between the two evaluations. CONCLUSIONS: The VCI accomplished the requirements of a scale's validity for estimation of voice symptoms catastrophization in voice patients. The potential role of voice catastrophization as a predictor of treatment response and tailoring can now be investigated using the VCI. PMID- 29132808 TI - Bilateral Vocal Fold Medialization: A Treatment for Abductor Spasmodic Dysphonia. AB - INTRODUCTION: Abductor spasmodic dysphonia, a difficult-to-treat laryngologic condition, is characterized by spasms causing the vocal folds to remain abducted despite efforts to adduct them during phonation. Traditional treatment for abductor spasmodic dysphonia-botulinum toxin injection into the posterior cricoarytenoid muscle-can be both technically challenging and uncomfortable. Due to the difficulty of needle placement, it is often unsuccessful. The purpose of this investigation is to present a previously undescribed treatment for abductor spasmodic dysphonia-bilateral vocal fold medialization. METHODS: A retrospective case review of all cases of abductor spasmodic dysphonia treated in a tertiary care laryngology practice with bilateral vocal fold medialization over a 10-year period was performed. The Voice Handicap Index and the Voice-Related Quality of Life surveys were utilized to assess patient satisfaction with voice outcome. RESULTS: Six patients with abductor spasmodic dysphonia treated with bilateral vocal fold medialization were identified. Disease severity ranged from mild to severe. All six patients reported statistically significant improvement in nearly all Voice Handicap Index and Voice-Related Quality of Life parameters. They reported fewer voice breaks and greater ease of communication. Results were noted immediately and symptoms continue to be well controlled for many years following medialization. CONCLUSIONS: Bilateral vocal fold medialization is a safe and effective treatment for abductor spasmodic dysphonia. It is performed under local anesthesia and provides phonation improvement in the short and long term. PMID- 29132809 TI - Reframing the issue of direct social perception: Comment on "Seeing mental states: An experimental strategy for measuring the observability of other minds" by Cristina Becchio et al. PMID- 29132810 TI - Medium-retaining Petri dish insert to grow and image cultured cells. AB - BACKGROUND: Microscope chambers that accept glass coverslips with cultured cells are often used to monitor intracellular Ca2+ concentration ([Ca2+]i) during cell superfusion. Unfortunately, the experimental maneuvers associated with the coverslip installation in these chambers (medium removal and re-application) trigger unintended [Ca2+]i elevations. NEW METHOD: To prevent these [Ca2+]i elevations, a Petri dish insert has been constructed. The insert features a superfusion-optimized well to grow cell cultures. After this insert is removed from the Petri dish, the well retains the medium. This feature allows the inserts to be installed in microscope chambers while keeping the cells submerged at all times. RESULTS: These inserts were used to test the impact of a transient medium removal from the well (an equivalent of a coverslip removal from the medium) on [Ca2+]i in primary murine cortical neurons and astrocytes, and in HEK-293 cells. In all of these models, the medium removal/re-application caused a micromolar [Ca2+]i spike. While in neurons this spike was caused by a Ca2+ influx, in astrocytes and HEK-293 cells, it was caused by a Ca2+ release from intracellular stores. After the spike, a subpopulation of neurons failed to restore low [Ca2+]i; in 24% of the astrocytes, the spike triggered [Ca2+]i oscillations. However, prior to the spike, [Ca2+]i was low and uniform in all these cells. COMPARISON WITH EXISTING METHOD(S): The new method avoids the artificially induced [Ca2+]i elevations that take place during the handling of glass coverslips with cultured cells. CONCLUSIONS: The new method allows monitoring [Ca2+]i without disturbing the basal [Ca2+]i levels. PMID- 29132811 TI - Requirements of a new allergen regulation. PMID- 29132812 TI - The antitumor effect of folic acid conjugated-Auricularia auricular polysaccharide-cisplatin complex on cervical carcinoma cells in nude mice. AB - A tumor-targeted, folic acid (FA) conjugated-Auricularia auricular polysaccharide (AAP) -cis-diaminedichloroplatinum (CDDP) complex (FA-AAP-CDDP) was used for cervical carcinoma chemotherapy. The drug delivery system was able to enhance the antitumor potency of CDDP, and to reduce the toxic side effects of CDDP. The kidney of mice treated by FA-AAP-CDDP complex had higher superoxide dismutase, catalase, and glutathione peroxidase activities, and lower malondialdehyde. FA AAP-CDDP complex could induce more interleukin-2, interleukin-4, and interferon gamma in mice. In addition, the FA-AAP-CDDP complex significantly promoted the expression of Bax and caspase-3 protein, but inhibited the expression of Bcl-2 protein, which activated the mitochondrial apoptotic pathway of tumor cells in nude mice. Moreover, the FA-AAP-CDDP complex had a higher intratumoral accumulation, was lower in the kidneys. This study may provide a new direction for folate receptor targeted polymers to improve anti-tumor activity, but reduce side effects of CDDP. PMID- 29132813 TI - Mismatch negativity: A simple and useful biomarker of N-methyl-d-aspartate receptor (NMDAR)-type glutamate dysfunction in schizophrenia. PMID- 29132814 TI - Incidence of child and adolescent mental disorders in children aged 0-17 with familial high risk for severe mental illness - A Danish register study. AB - BACKGROUND: Offspring of parents with severe mental illness (SMI: schizophrenia, bipolar disorder or major depressive disorder) have an increased risk of developing mental disorder themselves. In childhood they may have neurodevelopmental delays, cognitive deficits and social adversities. We aimed to investigate if these individuals are more at risk of being diagnosed with a mental disorder during childhood/adolescence in a national sample. METHODS: By linking Danish registers we established a cohort consisting of all persons born to parents with SMI with those born to parents without SMI serving as a reference group. Incidence rate ratios (IRRs) for offspring diagnosed with a mental disorder by parental mental disorder were calculated. RESULTS: Offspring of parents with SMI showed increased IRR for all diagnoses of child and adolescent mental disorders compared to the reference group. Offspring of mothers with schizophrenia had IRR of 2.60 (CI: 2.50-2.70, N=2550) of having any diagnoses, for children of fathers with schizophrenia IRR was 2.06 (CI: 1.97-2.16, N=1901) and for offspring of two parents with schizophrenia IRR was 4.57 (CI: 3.94-5.31, N=175). For individuals with a mother with bipolar disorder the IRR was 2.29 (CI: 2.09-2.50, N=502), with a father 1.77 (CI: 1.74-1.87, N=320), whereas the IRR was 2.96 (CI: 2.63-3.34, N=264) if both parents had unipolar depression. DISCUSSION: Offspring of parents with a SMI have a higher risk of being diagnosed with any child and adolescent mental disorder. The IRRs for all diagnoses during childhood were increased by a factor 2-4. Having two ill parents increased the IRR. PMID- 29132815 TI - Impaired mismatch negativity to frequency deviants in individuals at ultra-high risk for psychosis, and preliminary evidence for further impairment with transition to psychosis. AB - BACKGROUND: There is evidence to suggest that people with established psychotic disorders show impairments in the mismatch negativity induced by a frequency deviant sound (fMMN), and that these impairments worsen with the deterioration of psychotic symptoms. This study aimed to test whether individuals at ultra-high risk (UHR) for psychosis show pre-morbid impairments in fMMN, and if so, whether fMMN continues to deteriorate with transition to psychosis. METHOD: fMMN was recorded in a cohort of UHR individuals (n=42) and compared to healthy controls (n=29). Of the 27 UHR participants who returned for a second EEG session, six participants had transitioned to psychosis by 12-month follow-up (UHR-T) and were compared to the 21 participants who did not transition (UHR-NT). RESULTS: fMMN amplitude was significantly reduced, relative to healthy controls, in the UHR cohort. Furthermore, UHR-T individuals showed a significant decrease in fMMN amplitude over the period from baseline to post-transition; this reduction was not observed in UHR-NT. CONCLUSIONS: These results suggest that fMMN is abnormal in UHR individuals, as has repeatedly been found previously in people with established psychotic disorders. The finding that fMMN impairment worsens with transition to psychosis is consistent with the staging model of psychosis; however, caution must be taken in interpreting these findings, given the extremely small sample size of the UHR-T group. PMID- 29132816 TI - Deferiprone inhibits iron overload-induced tissue factor bearing endothelial microparticle generation by inhibition oxidative stress induced mitochondrial injury, and apoptosis. AB - Iron overload-induced cardiovascular toxicity is one of the most common causes of morbidity and mortality in beta-thalassemia major patients. We have previously shown that iron overload-induced systemic arterial changes characterized by endothelial dysfunction are associated with increased endothelial microparticle (EMP) release. In this study, we further demonstrate how EMP release is associated with iron-induced mitochondrial injury and apoptosis of endothelial cells. Iron increased the production of reactive oxygen species (ROS) and calcium influx into mitochondria [Ca2+]m. Iron also disturbed mitochondrial respiration function and eventually led to loss of mitochondrial membrane potential (DeltaPsim). A significant increase in apoptotic cells and EMPs were found under iron treatment. EMPs contained tissue factor (TF), which has potential clinical impact on thromboembolic phenomenon. Then, we investigated the salvaging effect of deferiprone (L1) on endothelial cell damage and EMP release. We found that L1 could inhibit iron-induced ROS generation, and decrease mitochondrial damage with the resultant effect of less endothelial cell apoptosis and EMP release. L1 could protect endothelial cells from iron-induced toxic effects and minimize EMP release, which could be potentially helpful in a subgroup of thalassemia patients who have increased thromboembolic complications. PMID- 29132817 TI - A National Description of Treatment among United States Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: To characterize lifetime and current rates of attention deficit/hyperactivity disorder (ADHD) treatments among US children and adolescents with current ADHD and describe the association of these treatments with demographic and clinical factors. STUDY DESIGN: Data are from the 2014 National Survey of the Diagnosis and Treatment of ADHD and Tourette Syndrome, a follow-back survey of parents from the 2011-2012 National Survey of Children's Health. Weighted analyses focused on receipt of ADHD treatment among children aged 4-17 years with current ADHD (n = 2495) by 4 treatment types: medication, school supports, psychosocial interventions, and alternative treatments. RESULTS: Medication and school supports were the most common treatments received, with two thirds of children and adolescents with ADHD currently receiving each treatment. Social skills training was the most common psychosocial treatment ever received (39%), followed by parent training (31%), peer intervention (30%), and cognitive behavioral therapy (20%). Among alternative treatments, 9% were currently taking dietary supplements, and 11% had ever received neurofeedback. Most children (67%) had received at least 2 of the following: current medication treatment, current school supports, or lifetime psychosocial treatment; 7% had received none of these 3 treatment types. CONCLUSIONS: A majority of school-aged children and adolescents with ADHD received medication treatment and school supports, whereas fewer received recommended psychosocial interventions. Efforts to increase access to psychosocial treatments may help close gaps in service use by groups currently less likely to receive treatment, which is important to ensure that the millions of school-aged US children diagnosed with ADHD receive quality treatment. PMID- 29132818 TI - Bilirubin Albumin Binding and Unbound Unconjugated Hyperbilirubinemia in Premature Infants. AB - OBJECTIVE: To evaluate the associations between unbound bilirubin (UB) and total serum bilirubin (TSB), bilirubin:albumin molar ratio (BAMR), and bilirubin albumin binding affinity (Ka) as a function of gestational age (GA) in infants born at 24-33 weeks GA. STUDY DESIGN: In a prospective observational study, TSB and UB were measured twice daily at least 8 hours apart during the first postnatal week. Serum albumin was measured to calculate BAMR on each day. The highest UB on each day, corresponding TSB, and serum albumin were used to calculate the Ka on each day. RESULTS: For the 166 infants studied, peak UB significantly correlated with concomitant Ka (r = -0.44, P = .001) but not with concomitant TSB or BAMR after adjusting for GA. On multiple regression analyses, there was a significant association of concomitant Ka (-0.06, 95% CI -0.08 to 0.04, P = .0001), but not concomitant TSB or BAMR with peak UB after controlling for GA, birth weight, race, and sex. GA group was a significant effect modifier for the association between Ka and peak UB (0.03, 95% CI 0.02-0.04, P < .001). Interaction analyses showed the association between concomitant Ka and peak UB was significant for the 24-30 weeks GA group infants, but not for the 301/7-33 weeks GA group infants. CONCLUSIONS: Peak UB was primarily associated with a decrease in binding affinity in infants <=30 weeks GA. Interventions aimed at improving binding affinity may be important in decreasing the risk of bilirubin induced neurotoxicity. PMID- 29132819 TI - Quorum-Sensing Systems as Targets for Antivirulence Therapy. AB - The development of novel therapies to control diseases caused by antibiotic resistant pathogens is one of the major challenges we are currently facing. Many important plant, animal, and human pathogens regulate virulence by quorum sensing, bacterial cell-to-cell communication with small signal molecules. Consequently, a significant research effort is being undertaken to identify and use quorum-sensing-interfering agents in order to control diseases caused by these pathogens. In this review, an overview of our current knowledge of quorum sensing systems of Gram-negative model pathogens is presented as well as the link with virulence of these pathogens, and recent advances and challenges in the development of quorum-sensing-interfering therapies are discussed. PMID- 29132820 TI - Optimization and application of fabric phase sorptive extraction coupled to ultra high performance liquid chromatography tandem mass spectrometry for the determination of cytostatic drug residues in environmental waters. AB - Every year, hundreds of tons of organic pollutants reach the environment through effluents released from wastewater treatment plants worldwide, and many of these compounds have harmful effects on the aquatic ecosystem. A new class of emerging pollutants of high concern is cytostatic drugs, which are designed to treat different types of cancers by attacking cells. Environmental concentrations of cytostatic drugs are known to be in the range of ngL-1, and for this reason, it is imperative to develop analytical methods of extraction and preconcentration to allow for subsequent instrumental analysis of these drugs. In this work, a rapid, simple and green method for the analysis of seven cytostatic drug compounds that are commonly used in anti-cancer therapies was developed using a novel extraction process based on a powerful miniaturized technique, fabric phase sorptive extraction (FPSE) coupled to ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The major parameters that affect the extraction process were optimized. The new method shows good linearity, with a relative standard deviation (RSD) of less than 12%. Relative recoveries higher than 40% were obtained for the studied compounds, and the detection limit of the method was within the values at which these compounds are usually found in environmental water (0.20ngL-1 to 80ngL-1). The Limit of Quantification ranged from 0.68 to 267ngL-1. Significant suppression of the signal due to the matrix effect, a common shortcoming attributed to interference from the extraction process as well as the use of ionization mode, was not observed. Subsequently, the method was applied to real wastewater samples from an effluent obtained from a hospital area and three wastewater treatment plants located in Gran Canaria Island, Spain. PMID- 29132821 TI - Determination of the content of alkyl ketene dimer in its latex by an ionic liquid assisted headspace gas chromatography. AB - This paper reports on an ionic-liquid assisted headspace gas chromatographic (HS GC) for the determination of the content of alkyl ketene dimer (AKD) in its latex samples, in which the GC system was equipped with a thermal conductivity detector (TCD). The method was based on the AKD hydrolysis conducted in 1-butyl-3 methylimidazolium chloride (ionic-liquid) added medium at 100 degrees C for 10min in a closed headspace sample vial, and the measured CO2 (the resulting product of the hydrolysis) by HS-GC. The results showed that the present method has a good measurement precision (RSD <2.3%) and accuracy (recoveries from 96 - 105%), and the limit of quantitation (LOQ) is 0.9%. The present method is very suitable to be used for the routine check of AKD content in its latex sample in mill applications. The study also showed that the content of AKD in the tested commercial latex samples were in the range of 3.5-12%. PMID- 29132822 TI - Bifunctionalized ordered mesoporous organosilica synthesized in deep eutectic solvent for extraction of triazine herbicides from watermelon. AB - A C8-and-amino-bifunctionalized ordered mesoporous organosilica (C8-AMS) was prepared in a deep eutectic solvent-a green solvent-that was used as the reaction medium for this procedure instead of organic solvents or other catalyst for the first time. This method provided a nontoxic way for C8 grafting and obtaining an ordered mesoporous organosilica material with both hydrophilic and hydrophobic groups. Besides advantages such as its large surface area, regular and uniform pore size, and hydrothermal stability, the obtained bifunctionalized C8-AMS also have two main functional groups in the obtained structure, C8 and amino, which enriched the adsorption mechanism of the material and as a result improved the adsorption selectivity of C8-AMS. Its performance as an adsorbent was estimated in extracting trace triazine herbicides from watermelon using solid-phase extraction (SPE) followed by high-performance liquid chromatography (HPLC). The proposed method provided satisfactory features in terms of linearity (0.01 2.00MUgg-1), limits of detection (2.9-5.1ngg-1), accuracy (recovery: 85.7 101.7%), and precision (intra-day and inter-day RSDs: 1.68-2.60% and 3.05-4.01%). PMID- 29132823 TI - Comprehensive profiling of minor tyrosinase inhibitors from Gastrodia elata using an off-line hyphenation of ultrafiltration, high-speed countercurrent chromatography, and high-performance liquid chromatography. AB - In the present study, a novel hyphenation of ultrafiltration (UF), high-speed countercurrent chromatography (HSCCC), and high-performance liquid chromatography (HPLC) was developed for comprehensive profiling and characterization of the minor tyrosinase inhibitors from Gastrodia elata (GE). A small quantity of GE extract was first fractionated by HSCCC, using elution solvents with a wide range of polarities to enrich minor compounds; then, the fractions were profiled by UF HPLC to generate a comprehensive 2D chromatogram of the distribution of bioactive components. To determine the binding affinities of these bioactive components, the binding degree (BD%) was calculated by peak area reduction, in which a higher BD% indicates a higher binding affinity to tyrosinase. Among the 212 metabolites, 49 were identified as tyrosinase ligands, 17 of which showed high binding affinity. According to the 2D chromatogram, these 17 candidates were isolated by semiprep-HPLC for characterization of their structure using off-line hyphenated ultraviolet (UV), electron ionized mass spectrometry (EIMS), proton nuclear magnetic resonance (1H NMR). Their activities were further validated by functional assays. In conclusion, the approach developed here can comprehensively identify both major and minor bioactive constituents from natural products, and provide meaningful suggestions to direct further research. Compared to conventional approaches, this approach, developed by hyphenating several techniques, is a highly efficient means for comprehensive profiling of potent minor compounds extracted from natural products. PMID- 29132824 TI - Power partial-discard strategy to obtain improved performance for simulated moving bed chromatography. AB - A novel power partial-discard (PPD) strategy was developed as a variant of the partial-discard (PD) operation to further improve the separation performance of the simulated moving bed (SMB) process. The PPD operation varied the flow rates of discard streams by introducing a new variable, the discard amount (DA) as well as varying the reported variable, discard length (DL), while the conventional PD used fixed discard flow rates. The PPD operations showed significantly improved purities in spite of losses in recoveries. Remarkably, the PPD operation could provide more enhanced purity for a given recovery or more enhanced recovery for a given purity than the PD operation. The two variables, DA and DL, in the PPD operation played a key role in achieving the desired purity and recovery. The PPD operations will be useful for attaining high-purity products with reasonable recoveries. PMID- 29132825 TI - Preconcentration and partial separation of nitroaromatic vapors using a methyltrimethoxysilane-based sol-gel. AB - Typical trace vapor analysis involves sorbent trapping, followed by desorption and chromatographic separation. This communication describes a method for streamlining this process by combining sorbent sampling/preconcentration with partial separation achieved through temperature-programmed thermal desorption. A novel sorbent trap was formulated in which tubular glass liners for a programmable-temperature gas chromatograph inlet were coated with a sol-gel based polymer stationary phase synthesized from methyltrimethoxysilane precursor and installed into the inlet, which was directly connected to a mass-selective detector by a fused silica capillary transfer line. This method is shown to achieve partial separation of two nitroaromatic vapors in a total 3-5min analysis time, which represents a tenfold improvement in speed in terms of the overall cycle time compared to an analogous conventional vapor analysis method. Both analytes proved to have a high dynamic range and loading capacity, with nitrobenzene achieving both high and low sampling extremes (0.32ng-4MUg sampling concentration) with only a slight compromise in peak broadening. The multivariate curve resolution by alternating least squares algorithm (MCR-ALS) was shown to successfully resolve the overlapped elution profiles of the two nitroaromatic test vapors examined in this study. PMID- 29132826 TI - Use of chromatographic and electrophoretic tools for assaying elastase, collagenase, hyaluronidase, and tyrosinase activity. AB - Elastase, collagenase, hyaluronidase and tyrosinase, are very interesting enzymes due to their direct implication in skin aging and as therapeutic hits. Different techniques can be used to study these enzymes and to evaluate the influence of effectors on their kinetics. Nowadays, analytical techniques have become frequently used tools for miniaturizing enzyme assays. The main intention of this article is to review chromatographic and electrophoretic tools that study the four enzymes above mentioned. More specifically, the use of high-performance liquid chromatography and capillary electrophoresis and their derivative techniques for monitoring these enzymes will be investigated. The advantages and limitations of these assays will also be discussed. The original use of microscale thermophoresis and thin layer chromatography in this domain will also be covered. PMID- 29132827 TI - High-performance thin-layer chromatographic methods in the evaluation of the antioxidant and anti-hyperglycemic activity of Myrmecodia platytyrea as a promising opportunity in diabetes treatment. AB - The steady increase of diabetes is becoming a major burden on health care systems. As diabetic complications arise from oxidative stress, an antioxidant therapy along with anti-diabetic drugs is recommended. Myrmecodia or ant plant is highly valued as a traditional medicine in West Papua. It is used as an alternative treatment for diabetes, as the substances produced by ants can reduce blood sugar levels. The aim of this study was to develop and establish high performance thin-layer chromatographic (HPTLC)-bioautographic methods to measure the antioxidant and hypoglycemic effects in different extracts from Myrmecodia platytyrea and to compare them with sterol content. Antioxidant activity in methanol, ethanol, dichloromethane (DCM) and ethyl acetate (EA) extracts were measured with a direct HPTLC-2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) assay, while hypoglycemic effects were assessed using a newly developed alpha amylase inhibitory activity assay. Stigmasterol is observed, after derivatization with anisaldehyde, as purple colored zones under visible light at hRF values of 0.66. The highest antioxidant activity was observed in the ethanol extract which is rich in polyphenols and flavonoids, while the DCM extract did not show antioxidant activity, but had significant alpha-amylase inhibitory activity. The highest alpha-amylase inhibitory activity was observed in the EA and DCM extracts and was related to their stigmasterol content. PMID- 29132829 TI - The lipolytic degradation of highly structured cubic micellar nanoparticles of soy phosphatidylcholine and glycerol dioleate by phospholipase A2 and triacylglycerol lipase. AB - The effects of different lipolytic enzymes on the structure of lipid liquid crystalline nano-particles (LCNP) have been investigated by cryogenic transmission electron microscopy (cryo-TEM) and synchrotron small angle X-ray diffraction (SAXD). Here we used highly structured cubic micellar (Fd3m) nanoparticles of 50/50 (wt%/wt%) soy phosphatidyl choline (SPC)/glycerol dioleate (GDO) as substrate. Two types of lipolytic enzymes were used, phospholipase A2 (PLA2) that catalyses degradation of the phospholipid component, SPC, and porcine pancreatic triacylglycerol lipase (TGL) that facilitate the hydrolysis of the diglyceride, GDO. Evolution of the structure was found to be very different and linked to specificity of the two types of enzymes. PLA2, which hydrolyses the lamellar forming component, SPC, induces a reversed micellar lipid phase, while TGL which hydrolysis the reverse phase forming compound, GDO, induces a lamellar phase. PMID- 29132828 TI - Lactoferrin, chitosan and Melaleuca alternifolia-natural products that show promise in candidiasis treatment. AB - The evolution of microorganisms resistant to many medicines has become a major challenge for the scientific community around the world. Motivated by the gravity of such a situation, the World Health Organization released a report in 2014 with the aim of providing updated information on this critical scenario. Among the most worrying microorganisms, species from the genus Candida have exhibited a high rate of resistance to antifungal drugs. Therefore, the objective of this review is to show that the use of natural products (extracts or isolated biomolecules), along with conventional antifungal therapy, can be a very promising strategy to overcome microbial multiresistance. Some promising alternatives are essential oils of Melaleuca alternifolia (mainly composed of terpinen-4-ol, a type of monoterpene), lactoferrin (a peptide isolated from milk) and chitosan (a copolymer from chitin). Such products have great potential to increase antifungal therapy efficacy, mitigate side effects and provide a wide range of action in antifungal therapy. PMID- 29132830 TI - Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations. AB - INTRODUCTION: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. RESULTS: In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. CONCLUSIONS: We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed. PMID- 29132831 TI - Association between increased EEG signal complexity and cannabis dependence. AB - Both acute and regular cannabis use affects the functioning of the brain. While several studies have demonstrated that regular cannabis use can impair the capacity to synchronize neural assemblies during specific tasks, less is known about spontaneous brain activity. This can be explored by measuring EEG complexity, which reflects the spontaneous variability of human brain activity. A recent study has shown that acute cannabis use can affect that complexity. Since the characteristics of cannabis use can affect the impact on brain functioning, this study sets out to measure EEG complexity in regular cannabis users with or without dependence, in comparison with healthy controls. We recruited 26 healthy controls, 25 cannabis users without cannabis dependence and 14 cannabis users with cannabis dependence, based on DSM IV TR criteria. The EEG signal was extracted from at least 250 epochs of the 500ms pre-stimulation phase during a visual evoked potential paradigm. Brain complexity was estimated using Lempel-Ziv Complexity (LZC), which was compared across groups by non-parametric Kruskall Wallis ANOVA. The analysis revealed a significant difference between the groups, with higher LZC in participants with cannabis dependence than in non-dependent cannabis users. There was no specific localization of this effect across electrodes. We showed that cannabis dependence is associated to an increased spontaneous brain complexity in regular users. This result is in line with previous results in acute cannabis users. It may reflect increased randomness of neural activity in cannabis dependence. Future studies should explore whether this effect is permanent or diminishes with cannabis cessation. PMID- 29132832 TI - The proposed 'concordance-statistic for benefit' provided a useful metric when modeling heterogeneous treatment effects. AB - OBJECTIVES: Clinical prediction models that support treatment decisions are usually evaluated for their ability to predict the risk of an outcome rather than treatment benefit-the difference between outcome risk with vs. without therapy. We aimed to define performance metrics for a model's ability to predict treatment benefit. STUDY DESIGN AND SETTING: We analyzed data of the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) trial and of three recombinant tissue plasminogen activator trials. We assessed alternative prediction models with a conventional risk concordance-statistic (c statistic) and a novel c-statistic for benefit. We defined observed treatment benefit by the outcomes in pairs of patients matched on predicted benefit but discordant for treatment assignment. The 'c-for-benefit' represents the probability that from two randomly chosen matched patient pairs with unequal observed benefit, the pair with greater observed benefit also has a higher predicted benefit. RESULTS: Compared to a model without treatment interactions, the SYNTAX score II had improved ability to discriminate treatment benefit (c-for benefit 0.590 vs. 0.552), despite having similar risk discrimination (c-statistic 0.725 vs. 0.719). However, for the simplified stroke-thrombolytic predictive instrument (TPI) vs. the original stroke-TPI, the c-for-benefit (0.584 vs. 0.578) was similar. CONCLUSION: The proposed methodology has the potential to measure a model's ability to predict treatment benefit not captured with conventional performance metrics. PMID- 29132833 TI - Trial registry searches for randomized controlled trials of new drugs required registry-specific adaptation to achieve adequate sensitivity. AB - OBJECTIVES: To analyze the availability of randomized controlled trials (RCTs) of new drugs in trial registries and to develop and test different search strategies in ClinicalTrials.gov (CT.gov), the EU Clinical Trials Register (EU-CTR), and the International Clinical Trials Registry Platform (ICTRP). STUDY DESIGN AND SETTING: Information from dossiers submitted by pharmaceutical companies was analyzed regarding the registration of the included RCTs in CT.gov, EU-CTR and ICTRP; different search strategies were developed and tested to determine performance. RESULTS: A total of 192 (95%) of 203 RCTs on newly approved drugs were registered in CT.gov; the 11 nonregistered trials were completed before 2005 or represented non-RCTs. Simple searches for RCTs on 18 new drugs using the generic drug name yielded a sensitivity of 94% in CT.gov (EU-CTR: 71%; ICTRP: 60%). The main reason for study nondetection was the sole use of the drug code in the registry entries. Simple searches for RCTs on 13 conditions using reasonably inferred search terms yielded a sensitivity of 100% in CT.gov. CONCLUSION: Almost all relevant RCTs on newly approved drugs will probably be identified in CT.gov alone. A sensitive search in CT.gov can be conducted using single search terms. The searches in ICTRP and EU-CTR should include several search terms (e.g., derived via text analysis). PMID- 29132834 TI - Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis. AB - BACKGROUND & AIMS: To evaluate the controversies among the studies assessing the association between folic acid intake or folate status and colorectal cancer risk. METHODS: PubMed, Cochrane library and references of related articles were searched from January 2000 to September 2016. Studies on folic acid intake or folate status and colorectal cancer or adenoma risk were included. Full text review was conducted for potentially eligible studies. Quality assessment was performed. Random-effects meta-analysis was used to estimate risk ratio and 95% Confidence Intervals. Analysis was conducted by Comprehensive Meta-Analysis software. RESULTS: Folic acid supplement intake showed no significant effect on colorectal cancer risk in meta-analysis of randomized controlled trials, RR: 1.07 (95% CI: 0.86-1.43). The effect on risk was not significant in cohort studies either; RR = 0.96 (95% CI: 0.76-1.21). However, there was significant reduced colorectal cancer risk in total folate intake in cohort studies; 0.71 (95% CI: 0.59-0.86). Odds Ratio was also significantly reduced in case control studies; 0.77 (95% CI: 0.62-0.95). Nevertheless once folate status was measured as Red Blood Cell folate content, no significant effect on colorectal cancer risk was observed; 1.05 (95% CI: 0.85-1.30). CONCLUSION: The differences in bioavailability and metabolism of synthetic folic acid and natural dietary folate as well as variation in the baseline characteristics of subjects and various methods of folate status assessment might be the main reasons for these controversies. Findings of present study highlight the importance of individualized folic acid supplement intake given the fact that the beneficiary effects of long term folic acid supplementation is not confirmed. PMID- 29132835 TI - A history that goes hand in hand: Reflections on the development of health economics and the role played by Social Science & Medicine, 1967-2017. PMID- 29132837 TI - Prepubertal chrysin exposure upregulates either AR in male ventral prostate or AR and ERalpha in Skene's paraurethral gland of pubertal and adult gerbils. AB - Chrysin is a plant-derived polyphenol that has the potential to increase endogenous testosterone levels both by inhibiting the aromatase enzyme and by stimulating testicular steroidogenesis. The effects of chrysin on the prostate are unknown, especially during its development and functional maturation. Thus, the aim of this study was to evaluate the effects of chrysin prepubertal exposure on the male and female prostates of both pubertal and adult gerbils. To evaluate the possible androgenic responses of chrysin, gerbils were also exposed to testosterone. Male and female gerbils were exposed to chrysin or to testosterone cypionate from postnatal day 15 to 42. Male and female gerbils were euthanized at either 43days or 90days age. The prostates were collected for biometrical, morphological and immunohistochemical analysis. The results showed that prepubertal exposure to chrysin had differential effects on the prostate of both pubertal and adult animals. The prostates of male and female pubertal gerbils showed no histological alterations, although there was increased frequency of androgen receptor (AR) in males and females, and estrogen receptor alpha (ERalpha) in females. Adult males and females presented developed prostate glands, with higher cell proliferative rate. In addition, AR and ERalpha frequency remained high in the prostate of adult animals. These results demonstrated that prepubertal exposure to chrysin disrupts steroid receptors regulation in the prostate, potentiating the response of this gland to the biological effects of endogenous steroids. In this context, excessive consumption of phytoestrogens during the critical stages of development should be considered with caution. PMID- 29132838 TI - Therapeutic effects of diosgenin in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system. Currently, there is no drug available to cure this kind of disease. Diosgenin is a plant-derived steroid saponin. A previous study in our lab revealed that diosgenin can promote oligodendrocyte progenitor cell differentiation and accelerate remyelination. In the present study, we found that diosgenin dose-dependently alleviated the progression of experimental autoimmune encephalomyelitis with reduced central nervous system inflammation and demyelination. We also found that diosgenin treatment can significantly inhibit the activation of microglia and macrophages, suppress CD4+ T cell proliferation and hinder Th1/Th17 cell differentiation. Therefore, we suggested that diosgenin may be a potential therapeutic drug for inflammatory demyelinating diseases, such as MS. PMID- 29132836 TI - Prevalence of Fabry Disease in Young Patients with Stroke in Argentina. AB - BACKGROUND: Fabry disease (FD) is an underdiagnosed cause of stroke in young adults, but the frequency of this association is largely unknown. We estimated the prevalence of FD in a nationwide cohort of young adults who had stroke and transient ischemic attack (TIA) in Argentina. METHODS: This was a prospective, multicenter study of stroke and FD in young adults (18-55 years) conducted in Argentina between 2011 and 2015. Patients were enrolled if they had had a TIA or an ischemic or hemorrhagic stroke within the previous 180 days. FD was diagnosed by measuring alpha-galactosidase A activity (males) and through genetic studies (females). RESULTS: We enrolled 311 patients (54% men, mean age: 41 years). Ischemic events occurred in 89% of patients (80% infarcts, 9% TIA) and hemorrhagic strokes in 11%. One female (.3% of the total group, 1% of the cryptogenic ischemic strokes) had the pathogenic mutation c.888G>A/p.Met296Ile /Exon 6 on the GAL gene. Her only other manifestation of FD was angiokeratoma. Eighteen females had nonpathogenic intronic variations: c.-10C>T, c.-12G>A, or both. Two patients had the nonpathogenic mutation D313Y, while a third had the likely benign mutation S126G. CONCLUSIONS: FD was identified in 1 patient (.3%) in this first Latin American study. The patient presented with a late-onset oligo symptomatic form of the disease. A large number of nonpathogenic mutations were present in our cohort, and it is essential that they not be mistaken for pathogenic mutations to avoid unnecessary enzyme replacement treatment. PMID- 29132839 TI - Inferior Vena Cava Filters in Patients with Acute Pulmonary Embolism and Cancer. AB - BACKGROUND: Administrative data have shown a lower mortality in hospitalized patients with pulmonary embolism and cancer who receive a vena cava filter. In the absence of a randomized controlled trial of vena cava filters in such patients, further investigation is necessary. Therefore, we performed this investigation using administrative data from a different database than used previously, and we investigate patients hospitalized in more recent years. METHODS: We analyzed administrative data from the Premier Healthcare Database, 2010-2014, in patients hospitalized with pulmonary embolism and solid malignant tumors. Patients were identified on the basis of International Classification of Disease, Ninth Revision, Clinical Modification codes. RESULTS: Patients aged >60 years had a lower in-hospital all-cause mortality with vena cava filters than those who did not have filters, 346 of 4648 (7.4%) compared with 2216 of 19,847 (11.2%) (P < .0001) (relative risk 0.67). Among patients aged >60 years who received an inferior vena cava, all-cause mortality within 3 months was 704 of 4648 (15.1%), compared with 3444 of 19,847 (17.4%) among those who did not receive a filter (P < .0001) (relative risk 0.86). CONCLUSION: Elderly patients with pulmonary embolism and cancer may be a special population in whom inferior vena cava filters reduce in-hospital and 3-month all-cause mortality. Further investigation is needed, particularly in younger patients. PMID- 29132840 TI - d-Peptides as inhibitors of PR3-membrane interactions. AB - Proteinase 3 (PR3) is a neutrophil serine protease present in cytoplasmic granules but also expressed at the neutrophil surface where it mediates proinflammatory effects. Studies of the underlying molecular mechanisms have been hampered by the lack of inhibitors of the PR3 membrane anchorage. Indeed while there exist inhibitors of the catalytic activity of PR3, its membrane interfacial binding site (IBS) is distinct from its catalytic site. The IBS has been characterized both by mutagenesis experiments and molecular modeling. Through docking and molecular dynamics simulations we have designed d-peptides targeting the PR3 IBS. We used surface plasmon resonance to evaluate their effect on the binding of PR3 to phospholipid bilayers. Next, we verified their ability of binding to PR3 via fluorescence spectroscopy and isothermal titration calorimetry. The designed peptides did not affect the catalytic activity of PR3. A few peptides bound to PR3 hydrophobic pockets and inhibited PR3 binding to lipids. While the (KFF)3K d-peptide inconveniently showed a significant affinity for the lipids, another d-peptide (SAKEAFFKLLAS) did not and it inhibited the PR3 membrane binding site with IC50 of about 40MUM. Our work puts forward d-peptides as promising inhibitors of peripheral protein-membrane interactions, which remain high-hanging fruits in drug design. PMID- 29132842 TI - [A comparison of post-surgical plasma glucose levels in patients on fluids with different glucose concentrations]. AB - OBJECTIVE: To compare plasma glucose levels and incidence of hyperglycaemia in the post-operative period after general surgery using fluids with different glucose. METHODOLOGY: A randomised, open-label, non-blind, clinical trial was conducted on patients admitted to Paediatric Intensive Care Unit after elective surgery. The inclusion criteria were from 6 months to 14 years of age, with a weight greater than 6kg, onset glucose level >60mg/dL, and a signed informed consent, with no oral intake and maintenance intravenous fluid therapy using fluids with 3.3% or 5% glucose. Plasma glucose levels were measured before surgery, on admission, and 8, 24, and 48h, with the mean glucose levels and incidence of hyperglycaemia (glucose level >150mg/dL) in both groups being compared. RESULTS: A total of 60 patients received glucose/saline 1/3 (51mEq/L sodium and 33g/L glucose), and 70 glucose/saline 5/0.9% (154mEq/L sodium and 50g/L glucose). Mean glucose levels were higher in the group receiving glucose 5%, with no statistical difference. There was no significant difference in the incidence of hyperglycaemia; 8h: 26% in the 3.3% group vs. 21.3% in the 5% group (P=.63); 24h: 20% vs. 22.7% (P=.8); and 48h: 19% vs. 23.1% (P=.78). CONCLUSIONS: The use of fluids with 3.3% glucose in the post-operative period of general surgery maintains mean glucose levels in a similar range to that of patients receiving fluids with 5% glucose, with no difference in the incidence of hyperglycaemia. PMID- 29132841 TI - Pelargonidin-3-O-glucoside and its metabolites have modest anti-inflammatory effects in human whole blood cultures. AB - This study hypothesized that the predominant strawberry anthocyanin, pelargonidin 3-O-glucoside (Pg-3-glc), and 3 of its plasma metabolites (4-hydroxybenzoic acid, protocatechuic acid, and phloroglucinaldehyde [PGA]) would affect phagocytosis, oxidative burst, and the production of selected pro- and anti-inflammatory cytokines in a whole blood culture model. For the assessment of phagocytosis and oxidative burst activity of monocytes and neutrophils, whole blood was preincubated in the presence or absence of the test compounds at concentrations up to 5 MUmol/L, followed by analysis of phagocytic and oxidative burst activity using commercially available test kits. For the cytokine analysis, diluted whole blood was stimulated with lipopolysaccharide in the presence or absence of the test compounds at concentrations up to 5 MUmol/L. Concentrations of selected cytokines (tumor necrosis factor-alpha, interleukin [IL]-1beta, IL-6, IL-8, and IL-10) were determined using a cytometric bead array kit. There were no effects of any of the test compounds on phagocytosis of opsonized or nonopsonized Escherichia coli or on oxidative burst activity. Pg-3-glc and PGA at 0.08 MUmol/L increased the concentration of IL-10 (P<.01 and P<.001, respectively), but there was no effect on tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-8, and there were no effects of the other compounds. In conclusion, this study demonstrated a lack of effect of these compounds on the opsonization, engulfment, and subsequent destruction of bacteria. Pg-3-glc and PGA, at physiologically relevant concentrations, had anti-inflammatory properties; however, effects were modest, only observed at the lowest dose tested and limited to IL-10. PMID- 29132843 TI - [Validation study of an acute bronchiolitis severity scale to determine admission to a Paediatric Intensive Care Unit]. AB - INTRODUCTION: At present, there are few validated scoring tests for assessing acute bronchiolitis (AB) severity, and limited information on their test power. The aim of the present study is to evaluate the validity of an acute bronchiolitis severity score (ABSS) to help in deciding PICU admission. PATIENTS AND METHOD: Prospective, descriptive, observational study of previously healthy infants under 1 year of age with AB, where the ABSS was used to compare severity as regards the need for PICU admission. The sample size was estimated as at least 175 patients. The research team was trained in the use of ABSS. All patients in the study were evaluated with ABSS daily, as well as in the case of clinical deterioration. The initial and maximum ABSS scores were contrasted to the need for PICU admission. A receiver operative curve was constructed, and the area under the curve was calculated, and the optimum point of sensitivity / specificity was estimated. RESULTS: The study included a total of 190 patients (male / female: 58% / 42%). PICU was required in 11 (6%). The mean+/- SD ABSS maximal score for patients who required and did not require PICU was 10.55+/- 1.12 and 6.35+/- 2.3, respectively (P<.001). The AUC for ABSS-maximal was 0.94 (P<.001, 95% CI: 0.90-0.98). The optimal cut-off point was set at >=10 points for a sensitivity of 82% and a specificity of 91%. CONCLUSIONS: ABSS estimates the severity of AB regarding the need for PICU admission, with a sensitivity and specificity of clinical usefulness. PMID- 29132844 TI - [Skin infection due to Mycobacterium marinum]. PMID- 29132845 TI - [Appropriateness of the therapeutic effort in the case of Charlie Gard]. PMID- 29132846 TI - Development of the Chinese-version of the exercise self-regulatory efficacy scale for patients with chronic obstructive pulmonary disease. AB - BACKGROUND: A valid and reliable instrument for assessing exercise self regulatory efficacy (Ex-SRE) is lacking in Taiwan. OBJECTIVE: To develop and validate a Chinese-version of the Ex-SRE scale (Ex-SRES-Chinese). METHODS: Published guidelines were followed for cross-cultural adaptation of Ex-SRES Chinese. Psychometric testing was conducted in 76 subjects with chronic obstructive pulmonary diseases (COPD). RESULTS: Ex-SRES-Chinese achieved clarity, culture appropriateness, and functional equivalence for measuring Ex-SRE. The scale-level content validity index of the Ex-SRES-Chinese was 0.99. The internal consistency reliability (Cronbach's alpha) was 0.925. Factor analysis identified a single factor with a high eigenvalue of 7.6 accounting for 47.5% of the total variance. The construct validity of Ex-SRES-Chinese was supported by higher Ex SRE in subjects who exercise regularly in the past than those who did not (p = 0.033). In addition, Ex-SRE was positively associated with weekly exercise time (r = 0.58; p < 0.0001). CONCLUSIONS: Ex-SRES-Chinese is a useful cross-culturally adapted instrument with good psychometric properties for measuring Ex-SRE in COPD patients in Taiwan. PMID- 29132847 TI - A scoping review on interventions to promote physical activity among adults with disabilities. AB - BACKGROUND: Despite the strong evidence that physical activity (PA) is a key determinant of health, there is limited knowledge on the content and outcomes of PA promotion interventions among individuals with disabilities. OBJECTIVE: To conduct a scoping review in order to examine the published literature on PA promotion interventions among adults with disabilities. METHODS: A scoping review following the methodological framework provided by Arksey and O'Malley used electronic databases (MEDLINE, PsycINFO, and CINAHL), reference lists, and journals to locate studies. Inclusion criteria were based on study aim, outcome measures, and a disability definition by the WHO International Classification of Functioning, Disability and Health. The Behavior Change Techniques Taxonomy version 1 and Furlan and collaborators' risk of bias assessment were utilized during the data charting stage. RESULTS: Thirty-eight articles met the inclusion criteria. Most of the studies (70%) reported a significant increase in PA behavior immediately following intervention. However, less than half of the studies (46%) examined the maintenance of pre-/post-test differences. The number of identified behavior change techniques was significantly higher for successful PA promotion interventions than for interventions with no effects on PA. Approximately one-third of studies (32%) were rated as having a high risk of bias. CONCLUSIONS: Although findings support the idea that PA promotion interventions produce positive changes in PA behavior for a variety of disability conditions, risk of bias assessment calls for prudence. There are opportunities for continued development of the area of PA promotion among individuals with disabilities through systematic reviews and meta-analyses. PMID- 29132848 TI - Lymphedema: Pathophysiology and clinical manifestations. AB - Lymphedema is a localized form of tissue swelling resulting from excessive retention of lymphatic fluid in the interstitial compartment and caused by impaired lymphatic drainage. Lymphedema is classified as primary or secondary. Primary lymphedema is caused by developmental lymphatic vascular anomalies. Secondary lymphedema is acquired and arises as a result of an underlying systemic disease, trauma, or surgery. We performed PubMed and Google Scholar searches of the English-language literature (1966-2017) using the terms lymphedema, cancer related lymphedema, and lymphatic complications. Relevant publications were manually reviewed for additional resources. This progressive chronic disease has serious implications on patients' quality of life. It is often misdiagnosed because it mimics other conditions of extremity swelling. There is no definitive cure for lymphedema. However, with proper diagnosis and management, its progression and potential complications may be limited. PMID- 29132849 TI - Treatment of vismodegib-associated muscle cramps with cyclobenzaprine: A retrospective review. PMID- 29132850 TI - Inpatient dermatology consultations: Motivation and practice of requesting providers. PMID- 29132851 TI - Association between pemphigus and psoriasis: A population-based large-scale study. PMID- 29132852 TI - Topical 15% resorcinol for hidradenitis suppurativa: An uncontrolled prospective trial with clinical and ultrasonographic follow-up. PMID- 29132853 TI - Assessing clinical response and defining minimal disease activity in plaque psoriasis with the Physician Global Assessment and body surface area (PGA * BSA) composite tool: An analysis of apremilast phase 3 ESTEEM data. PMID- 29132854 TI - Price discrepancies among mobile medication applications for common dermatologic prescriptions: Observational cost analysis. PMID- 29132855 TI - Willingness to pay and quality of life in alopecia areata. PMID- 29132856 TI - Circumventing iPLEDGE: Circumventing ethical responsibility? PMID- 29132857 TI - Declining care to unvaccinated patients: Ethical and legal considerations. PMID- 29132858 TI - Doctors' mental health, burnout, and suicidality: Professional and ethical issues in the workplace. PMID- 29132859 TI - Lymphedema: Diagnostic workup and management. AB - Lymphedema is a localized form of tissue swelling resulting from excessive retention of lymphatic fluid in the interstitial compartment. It is caused by impaired lymphatic drainage. Lymphedema is a chronic progressive disease with serious physical and psychosocial implications. It can be challenging to diagnose, especially in obese patients and in those with coexisting venous disease. We performed PubMed and Google Scholar searches of the English-language literature (1966-2017) using the terms lymphedema, lymphedema management, and lymphatic complications. Relevant publications were manually reviewed for additional resources. There are currently no standard guidelines for the diagnosis of lymphedema. There is no cure yet for lymphedema, and the objective for management is to limit disease progression and prevent complications. PMID- 29132860 TI - A novel clinical sign to aid in the diagnosis of superficial basal cell carcinoma. PMID- 29132861 TI - The water-drop test for the diagnosis of koilonychia. PMID- 29132862 TI - Correction of vermilion lip retraction after mucosal advancement flap: A countertraction technique. PMID- 29132863 TI - The hungry caterpillar flap: A variant of the V-to-Y island pedicle flap. PMID- 29132864 TI - Injection of filler for volume replacement of the whole face using a single-entry method. PMID- 29132865 TI - Traction taping: An effective adjunct for excising tumors in skin folds. PMID- 29132866 TI - Comment on "Efficacy and safety of etanercept and adalimumab with and without a loading dose for psoriasis: A systematic review". PMID- 29132867 TI - Reply to: Comment on "Efficacy and safety of etanercept and adalimumab with and without a loading dose for psoriasis: A systematic review". PMID- 29132868 TI - High-risk category for early annual ophthalmology screening of patients receiving hydroxychloroquine. PMID- 29132869 TI - Reply to: "High risk category for early annual ophthalmology screening on hydroxychloroquine". PMID- 29132870 TI - mTOR inhibitor rapamycin induce polymorphonuclear myeloid-derived suppressor cells mobilization and function in protecting against acute graft-versus-host disease after bone marrow transplantation. AB - The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) has been shown to be an effective immunosuppressor in the management of acute graft-versus host disease (aGVHD) after bone marrow transplantation. Myeloid-derived suppressor cells (MDSCs) also have a protective effect in aGVHD regulation. However, the relationship between RAPA and MDSCs in aGVHD models is unclear. Meanwhile, the effect of RAPA on different subgroups of MDSCs is also less well described. In this study, we demonstrate that in vivo administration of RAPA results in the expansion and functional enhancement of polymorphonuclear MDSCs (PMN-MDSCs) in a murine model of aGVHD. RAPA treatment can enhance the suppressive function of PMN-MDSCs via up-regulation of arginase1 (Arg1) and induced nitric oxide synthase (iNOS) at later time points. Moreover, RAPA can also induce a strong immunosuppressive function in PMN-MDSCs from murine bone marrow in vitro, but has a contrary effect on monocytic MDSCs (M-MDSCs). We found that RAPA-treated PMN-MDSCs can restrain the differentiation of Th1/Th2 cells and promote induction of regulatory T cells in in vitro studies. PMID- 29132871 TI - The role of TGFbeta in wound healing pathologies. AB - Wound healing is one of the most complex processes in multicellular organisms, involving numerous intra- and intercellular signalling pathways in various cell types. It involves extensive communication between the cellular constituents of diverse skin compartments and its extracellular matrix. Miscommunication during healing may have two distinct damaging consequences: the development of a chronic wound or the formation of a hypertrophic scar/keloid. Chronic wounds are defined as barrier defects that have not proceeded through orderly and timely reparation to regain structural and functional integrity. Several growth factors are involved in wound healing, of which transforming growth factor beta (TGFbeta) is of particular importance for all phases of this procedure. It exerts pleiotropic effects on wound healing by regulating cell proliferation, differentiation, extracellular matrix production, and modulating the immune response. In this review we are presenting the role of TGFbeta in physiological and pathological wound healing. We show that the context-dependent nature of the TGFbeta signaling pathways on wound healing is the biggest challenge in order to gain a therapeutically applicable comprehensive knowledge of their specific involvement in chronic wounds. PMID- 29132873 TI - HPV genotype profile in a Norwegian cohort with ASC-US and LSIL cytology with three year cumulative risk of high grade cervical neoplasia. AB - OBJECTIVE: To explore the HPVgenotype profile in Norwegian women with ASC-US/LSIL cytology and the subsequent risk of high-grade cervical neoplasia (CIN 3+). METHODS: In this observational study delayed triage of ASC-US/LSIL of 6058 women were included from 2005 to 2010. High-risk HPV detection with Hybrid Capture 2 (HC2) was used and the HC2+ cases were genotyped with in-house nmPCR. Women were followed-up for histologically confirmed CIN3+ within three years of index HPV test by linkage to the screening databases at the Cancer Registry of Norway. RESULTS: HC2 was positive in 45% (2756/6058) of the women. Within 3years CIN3+ was diagnosed in 26% of women<34year and in 15%>=34year. HC2 was positive at index in 94% of CIN3+ cases and negative in 64 cases including three women with cervical carcinomas. Women<34years with single infections of HPV 16, 35, 58 or 33 or multiple infections including HPV 16, 52, 33 or 31 were associated with highest proportions of CIN 3+. Older women with single infection with HPV 16, 33, 31 or 35 or multiple infections including HPV 16, 33, 31 or 18/39 were more likely to develop CIN 3+. CONCLUSIONS: HPV 16 and HPV 33 at baseline both as single or multiple infections, were associated with the highest risk for CIN3+. Among older women, all 13 high-risk genotypes as single infection were associated with >20% risk of CIN3+. Further studies are necessary to risk stratify the individual genotypes to reduce the number of colposcopies in Norway. PMID- 29132872 TI - An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer. AB - OBJECTIVES: The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. METHODS: Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. RESULTS: Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53-3.49) and cancer specific survival (HR 3.95; 95%CI 2.10-7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04-4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. CONCLUSIONS: A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system. PMID- 29132874 TI - Combining serum microRNA and CA-125 as prognostic indicators of preoperative surgical outcome in women with high-grade serous ovarian cancer. AB - OBJECTIVES: The most widely used approach for the clinical management of women with high-grade serous ovarian cancer (HGSOC) is surgery, followed by platinum and taxane based chemotherapy. The degree of macroscopic disease remaining at the conclusion of surgery is a key prognostic factor determining progression free and overall survival. We sought to develop a non-invasive test to assist surgeons to determine the likelihood of achieving complete surgical resection. This knowledge could be used to plan surgical approaches for optimal clinical management. METHODS: We profiled 170 serum microRNAs (miRNAs) using the Serum/Plasma Focus miRNA PCR panel containing locked nucleic acid (LNA) primers (Exiqon) in women with HGSOC (N=56) and age-matched healthy volunteers (N=30). Additionally, we measured serum CA-125 levels in the same samples. The HGSOC cohort was further classified based on the degree of macroscopic disease at the conclusion of surgery. Stepwise logistic regression was used to identify predictive markers. RESULTS: We identified a combination of miR-375 and CA-125 as the strongest discriminator of healthy versus HGSOC serum, with an area under the curve (AUC) of 0.956. The inclusion of miR-210 increased the AUC to 0.984; however, miR-210 was affected by hemolysis. The combination of miR-34a-5p and CA-125 was the strongest predictor of completeness of surgical resection with an AUC of 0.818. CONCLUSION: A molecular test incorporating circulating miRNA to predict completeness of surgical resection for women with HGSOC has the potential to contribute to planning for optimal patient management, ultimately improving patient outcome. PMID- 29132875 TI - Aspirin use and endometrial cancer risk and survival. AB - The role of acetylsalicylic acid (aspirin) as a chemo-preventive and adjuvant therapeutic agent for cancers is generating attention. Mounting evidence indicates that aspirin reduces the incidence and mortality of certain obesity related cancers, particularly colorectal cancer. In endometrial cancer, previous studies examining the effect of aspirin remain inconsistent as to the reduction in the risk of endometrial cancer. While some evidence indicates protective effects in obese women, other studies have showed a potential deleterious effect of these medications on endometrial cancer outcomes. However, exposure measurement across studies has been inconsistent in recording dose, duration, and frequency of use; thus making comparisons difficult. In this article, we review the evidence for the association between endometrial cancer and obesity, the pharmacological differences between regular- and low-dose aspirin, as well as the potential anti-tumor mechanism of aspirin, supporting a possible therapeutic effect on endometrial cancer. A proposed mechanism behind decreased cancer mortality in endometrial cancer may be a result of inhibition of metastasis via platelet inactivation and possible prostaglandin E2 suppression by aspirin. Additionally, aspirin use in particular may have a secondary benefit for obesity related comorbidities including cardiovascular disease in women with endometrial cancer. Although aspirin-related bleeding needs to be considered as a possible adverse effect, the benefits of aspirin therapy may exceed the potential risk in women with endometrial cancer. The current evidence reviewed herein has resulted in conflicting findings regarding the potential effect on endometrial cancer outcomes, thus indicating that future studies in this area are needed to resolve the effects of aspirin on endometrial cancer survival, particularly to identify specific populations that might benefit from aspirin use. PMID- 29132876 TI - The Distraction in Action Tool(c): Feasibility and Usability in Clinical Settings. AB - PURPOSE: Distraction is a relatively simple, evidence-based intervention to minimize child distress during medical procedures. Timely on-site interventions that instruct parents on distraction coaching are needed. The purpose of this study was to test the feasibility and usability of the Distraction in Action Tool(c) (DAT(c)), which 1) predicts child risk for distress with a needle stick and 2) provides individualized instructions for parents on how to be a distraction coach for their child in clinical settings. DESIGN AND METHODS: A mixed-methods descriptive design was used to test feasibility and usability of DAT in the Emergency Department and a Phlebotomy Lab at a large Midwest Academic Medical Center. Twenty parents of children ages 4-10years requiring venipuncture and clinicians performing 13 of those procedures participated. Participants completed an evaluation and participated in a brief interview. RESULTS: The average age of the children was 6.8years, and 80% of parent participants were mothers. Most parents reported the DAT was not difficult to use (84.2%), understandable (100%), and they had a positive experience (89.5%). Clinicians thought DAT was helpful (100%) and did not cause a meaningful delay in workflow (92%). CONCLUSION: DAT can be used by parents and clinicians to assess their children's risk for procedure related distress and learn distraction techniques to help their children during needle stick procedures. PRACTICE IMPLICATIONS: DAT for parents is being disseminated via social media and an open-access website. Further research is needed to disseminate and implement DAT in community healthcare settings. PMID- 29132877 TI - Antithrombotic therapy in peripheral artery disease. PMID- 29132878 TI - Secondary prevention shifts into second gear. PMID- 29132882 TI - Validation of the "V". PMID- 29132881 TI - Valve-sparing root repair: V-shaped remodeling can be performed in all sinuses. PMID- 29132883 TI - Simplest solutions are not always the cleverest: Can we stitch in an infected annulus? Should we rethink the current guidelines? PMID- 29132884 TI - Allografts remain a cornerstone of surgical treatment of invasive and destructive aortic valve infective endocarditis: Surgeon and technique do matter! PMID- 29132885 TI - Weak evidence, strong opinions, and high expectations. PMID- 29132886 TI - Sutureless aortic valve replacement: Progress for the sake of progress? PMID- 29132887 TI - The Edwards Intuity Elite valve: Not to repeal nor replace, but rather additive to surgical aortic valve replacement options. PMID- 29132889 TI - Echocardiographic correlates to right ventricular dysfunction and failure. PMID- 29132888 TI - The Cardiothoracic Surgical Trials Network: Implications for clinical practice. PMID- 29132891 TI - Contract with the patient with injection drug use and infective endocarditis: Surgeons perspective. PMID- 29132890 TI - "Right ventricle looks bad." "no, it doesn't." "yes, it does." PMID- 29132892 TI - Contracts with people who inject drugs following valve surgery: Unrealistic and misguided expectations. PMID- 29132893 TI - Is rigid sternal fixation really better? Was the correct control group used? PMID- 29132894 TI - The right wiring configuration for sternal closure: Science or mythology? PMID- 29132895 TI - Is more always better in sternal closure? PMID- 29132896 TI - Ground glass opacity of the lung: The veil that needs lifting. PMID- 29132897 TI - Blocking the double-lumen orifice versus apneic oxygenation during 1-lung ventilation. PMID- 29132898 TI - Understanding the efficacy of apneic oxygen insufflation during thoracoscopic lobectomy. PMID- 29132899 TI - The merit of oxygen insufflation during one-lung ventilation. PMID- 29132900 TI - Experience from the Thoracic Surgery Residents Association traveling fellowship: Adult and pediatric lung transplantation in Toronto. PMID- 29132901 TI - An implication of Klotho-related molecules in different smoking-related health outcomes between men and women. AB - BACKGROUND: Men and women react differently to some disease states, and women are reported to be more sensitive than men to the toxic effects of smoking. We examined the serum concentration of Klotho-related molecules, alpha-Klotho (alphaKl) and fibroblast growth factor (FGF)-21, and the influence of smoking on these molecules in both sexes. METHODS: Subjects included 90 men and 140 women in good health who underwent a health examination. RESULTS: Among male subjects, serum concentrations of FGF-21, soluble salphaKl, and inflammation-related cytokine interleukin (IL)-6 were significantly higher in smokers than in never smokers. In females, serum concentrations of FGF-21 and IL-6 were significantly higher in smokers than in never-smokers; however, salphaKl concentrations were slightly lower in smokers than in never-smokers. Serum concentrations of salphaKl were correlated with smoking status and IL-6 only in male subjects, suggesting an anti-inflammatory effect of salphaKl only in men. Serum concentrations of FGF-21 were correlated with the concentrations of total cholesterol, triglycerides, and HbA1c, which are important factors of metabolic disorders in females, suggesting that metabolic disorders in female smokers may be more serious than that in male smokers. CONCLUSIONS: Klotho-related molecules showed a differential association and response to smoking between men and women. PMID- 29132903 TI - Progressive multifocal leukoencephalopathy in patients receiving rituximab and cyclophosphamide after haplo-identical T-cell replete transplantation and review of the literature. AB - John Cunningham virus (JCV) reactivation, occurring mainly in immunocompromised patients, leads to progressive multifocal leukoencephalopathy, an uncommon but lethal disease. JCV reactivation after T-cell replete haploidentical stem cell transplantation, in the pre-cyclophosphamide era, is poorly represented in the literature. We therefore describe two cases of acute myeloid leukemia who developed JCV reactivation after receiving cyclophosphamide and rituximab post haploidentical stem cell transplantation, and review the literature, aiming to a better understanding of the disease course and its risk factors. PMID- 29132902 TI - Histopathological assessment of primary osteoarthritic knees in large patient cohort reveal the possibility of several potential patterns of osteoarthritis initiation. AB - OBJECTIVE: The two main objectives of the study include (1) Test the hypothesis that the lateral femoral condyle (LFC) in patients with primary OA and varus knees undergoing total knee arthroplasty (TKA) can be used as a model to better characterize varying histological features of human OA, (2) Correlate characteristic OA features using the established histopathological scoring systems (HHGS and OARSI) to understand potential histopathological patterns of OA initiation. DESIGN: Two osteochondral specimens (4*4*8mm) were collected from fifty patient's LFC at the time of TKA (total 100 specimens), who presented preserved lateral knee compartment with joint space width>2mm. Three independent readers graded the sections on three different occasions using HHGS and OARSI systems. The correlation between individual parameters of the two scoring systems and their inter- and intra-reader variability, reliability and reproducibility were estimated. RESULTS: All samples in this cohort showed abnormal histopathological features. Total histopathological scores of the LFC ranged from HHGS median=4.6 (range=0 to 11), and OARSI median=5.2 (range=0 to 19.5). The four individual sub-items of HHGS scoring system (structure, cells, safraninO staining, tidemark) were weakly correlated, with the correlation between structure and cellularity being the strongest (r=0.40). Both the scoring systems had similar repeatability and reproducibility coefficients of<21%. CONCLUSIONS: OA changes in the LFC are not confined to any one region, and maybe seen in different regions of cartilage, tidemark, subchondral bone, and/or the marrow space vascularity. These variations may point to the possibility of several potential patterns of initiation in OA. PMID- 29132879 TI - Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease. METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2.5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0.74, 95% CI 0.65-0.86, p<0.0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0.89, 95% CI 0.78-1.02, p=0.094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1.66, 95% CI 1.37-2.03, p<0.0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1.51, 95% CI 1.23-1.84, p<0.0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0.77, 95% CI 0.65-0.90, p=0.0012). INTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide. FUNDING: Bayer AG. PMID- 29132904 TI - Straight leg elevation to rule out pelvic injury. AB - OBJECTIVE: Pelvic x-ray is frequently used as a screening tool during initial assessment of injured patients. However routine use in the awake and alert blunt trauma patient may be questioned due to low yield. We propose a clinical tool that may avoid unnecessary imaging by examining whether the ability to straight leg raise, without pain, can rule out pelvic injury. METHODS: We conducted a prospective cohort study with the exposure variables of ability to straight leg raise and presence of pain on doing so, and presence of pelvic fracture on x-ray as the primary outcome variable. RESULTS: Of the 328 participants, 35 had pelvic fractures, and of these 32 were either unable to straight leg raise, or had pain on doing so, with a sensitivity of 91.43% (95% CI: 76.94-98.2%) and a negative predictive value of 98.57% (95% CI: 95.88-99.70%). The 3 participants with a pelvic fracture who could straight leg raise with no pain, all had a GCS of less than 15, and therefore, among the sub-group of patients with GCS15, a 100% sensitivity and 100% negative predictive value for straight leg raise with no pain to rule out pelvic fracture was demonstrated. CONCLUSION: Among awake, alert patients, painless straight leg raise can exclude pelvic fractures and be incorporated into initial examination during reception and resuscitation of injured patients. PMID- 29132905 TI - Purification and biochemical characterization of a 22-kDa stable cysteine- like protease from the excretory-secretory product of the liver fluke Fasciola hepatica by using conventional techniques. AB - This study describes the purification and characterization of a stable protease activity isolated from Fasciola hepatica adult worms maintained in vitro by employing acetone precipitation (40-60%) followed by a gel filtration through Sephadex G-100 and DEAE- cellulose ion exchange column. Through this three-step purification, the enzyme was purified 11-fold with a specific activity of 1893.9U/mg and 31.5% recovery. After the final ultrafiltration step, the purification fold was increased up to 13.1 and the overall activity yield reached a rate of 18.8%. The MW of the purified protease was estimated by reducing SDS PAGE to be 22kDa while the proteolytic activity detection was carried out by zymography on non-denaturing SDS-PAGE containing the casein as substrate. Using this substrate, the protease showed extreme proteolytic activity at pH 5.5 and temperature 35-40 degrees C and was highly stable over a wide range of pH, from 5.0 to 10.0. In addition to its preference for the Z-Phe-Arg-AMC fluorogenic substrate resulting in maximum proteolytic activity (99.7%) at pH 7.0, the pure protease exhibited highest cleavage activity against hemoglobin and casein substrates at pH 5.5 (85.6% and 82.8%, respectively). The Km values obtained for this protease were 5.4, 13, 160 and approximately 1000MUM using respectively the fluorogenic substrate Z-Phe-Arg-AMC, hemoglobin, casein and albumin. The protease activity was completely inhibited either by E-64 inhibitor (5mM) or iodoacetamide (10mM), indicating its cysteine nature. The usefulness of the purified protease as an antigen was studied by immunoblotting. Thus, sera from sheep experimentally infected with F. hepatica recognized the protease band at 2 weeks post-infection (WPI) and strongly at 7 WPI. The early detection of antibodies anti- F. hepatica suggests the application of this molecule as a specific epitope for the serodiagnosis of fascioliasis disease. PMID- 29132906 TI - A selective knockout method for discovery of minor active components from plant extracts: Feasibility and challenges as illustrated by an application to Salvia miltiorrhiza. AB - Natural products have been recognized to play an invaluable role in drug discovery. However, efficient discovery of minor active constituents from natural sources is challenging due to the low abundance and complex matrices. In this study, we developed a selective knockout method to discover minor bioactive components from complex phytochemical mixtures, using a Chinese medicine as an example. Based on the chromatographic fingerprint, six major components in the ethyl acetate extract of the root of Salvia miltiorrhiza (EASM) were selectively knocked out via high-resolution peak fraction (HRPF) approach. The remaining extract was automatically enriched and fractionated to generate a chemical library consisting of 62 minor components with contents less than 30/00. Simultaneously, a parallel mass-spectrometry (MS) analysis was performed to ensure purity and to characterize the structure of the compound in each fraction. Via an antioxidant response element (ARE)-driven luciferase reporter system, 33 minor components were screened out as nuclear factor erythroid 2-related factor 2 (Nrf2) activators and 30 components were identified. Here, the Nrf2 activation activities of 21 components have been reported for the first time. Different from the existing methods for discovery of active compounds from natural products, in the developed method of this manuscript, the major components are selectively removed, and the fractions of the minor components are prepared after several times of preparative HPLC enrichment by high-resolution peak fraction approach. It improves the prospective discovery of minor active components from complex medicinal herbs. PMID- 29132908 TI - Editorial: Special Section: RemiTB Infection, Genetics and Evolution. PMID- 29132907 TI - Determination of 3,5 - dimethylpyrazolium glyceroborate nitrification inhibitor in nitrogen fertilizer samples: HPLC-DAD method development and validation for 3,5 - dimethylpyrazole. AB - 3,5 - Dimethylpyrazolium glyceroborate is a nitrification inhibitor (a member of pyrazole derivatives) used for the fixation of nitrogen into the soil. In this study, an HPLC-DAD method was developed and validated for determination of 3,5 - dimethylpyrazole in order to determine 3,5 - dimethylpyrazolium glyceroborate in fertilizer samples. For method development, analytical parameters like type of eluent solution and column filling material and device parameters like eluent flow rate, column oven temperature and measurement wavelength were all optimized. For method validation, implementations were performed for linearity, limit of detection (LOD), limit of quantification (LOQ), specificity, stability, intra- and inter-day precision and accuracy. The developed and validated method was used for inhibitor detection in nitrogenous fertilizers. Sample analyses were performed with 95.6-103.3% recovery rates and 0-4.61% relative errors. PMID- 29132880 TI - Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0.90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0.72, 95% CI 0.57-0.90, p=0.0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0.54 95% CI 0.35-0.82, p=0.0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0.86, 95% CI 0.69-1.08, p=0.19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0.67, 95% CI 0.45-1.00, p=0.05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1.61, 95% CI 1.12-2.31, p=0.0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1.68, 95% CI 1.17-2.40; p=0.0043). INTERPRETATION: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. FUNDING: Bayer AG. PMID- 29132909 TI - A comprehensive systematic review of pharmacy perspectives on interprofessional education and collaborative practice. AB - INTRODUCTION: Pharmacists are key professionals in the collaborative working process and are integral members of the healthcare team. However, there is paucity of information regarding their perspectives towards interprofessional education (IPE) and collaborative practice. AIMS: The aim of this systematic review is to synthesise, summarise and evaluate the quality of the quantitative and qualitative literature related to the perspectives of pharmacy students, pharmacy faculty and practising pharmacists toward IPE and collaborative practice. The perspectives included their views, experiences and attitudes with a special focus on their perceived benefits and challenges in relation to IPE and collaborative practice. METHODS: An integrated mixed method systematic review was conducted. Four electronic databases were searched for articles published in English between 2000 and 2015. The Mixed Methods Appraisal Tool (MMAT) was used to assess the quality of the studies. RESULTS: Twenty-nine articles were identified meeting the selection criteria from the first initial search of 8512 articles. Seventeen articles (59%) targeted pharmacy students, 11 articles (38%) focused on practising pharmacists and 1 study (3%) was related to pharmacy faculty. The majority of studies were conducted in the United States (n = 13), were published in the last five years (83%, n = 24) and employed quantitative methods (52%, n = 15). The two commonly used survey instruments to measure the perspectives were: different versions of the RIPLS (35%, n = 6) and the IEPS scale (35%, n = 6). Fourteen of the 29 studies were rated as low quality (MMAT = 25%), eight studies were rated as average quality (MMAT = 50%), four were rated as high quality (MMAT 75%) and three were rated as very poor quality (MMAT 0%). No studies were rated with 100% MMAT quality. Overall, the findings suggest that pharmacy students, practicing pharmacists and faculty valued interprofessional education and collaborative practice and had positive attitudes towards it. Five main findings have been identified from this review: heterogeneity in reporting IPE research, traditional professional image of the pharmacist, lack of longitudinal follow-up, lack of IPE research on faculty and paucity in mixed method studies in terms of quality and numbers. CONCLUSIONS: These findings will provide an opportunity to stakeholders and policy makers to develop and implement IPE activities that are meaningful, comprehensive and unique. Sustained efforts are required not just in undergraduate curricula but also in healthcare settings to improve and promote an interprofessional culture at individual and organisational level. PMID- 29132910 TI - Pharmacy practice in Pakistan: The Catch-22 continues. PMID- 29132911 TI - Antioxidant, anti-inflammatory and gastroprotective activity of Filipendula ulmaria (L.) Maxim. and Filipendula vulgaris Moench. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Meadowsweet (Filipendula ulmaria (L.) Maxim.) and dropwort (Filipendula vulgaris Moench) are herbaceous perennials employed in folk medicine for their antirheumatic, antipyretic and anti-ulcer properties. AIM OF THE STUDY: To assess ethnomedicinal claims through investigation of antioxidant, anti-inflammatory and gastroprotective effects of F. ulmaria and F. vulgaris lyophilized flower infusions (LFIs) as well as the F. vulgaris isolated flavonoids spiraeoside, kaempferol 4'-O-glucoside, astragalin 2'-O-gallate, mixture of hyperoside 2'-O-gallate and isoquercitrin 2'-O-gallate, and a tannin tellimagrandin II. MATERIALS AND METHODS: Free radical scavenging activity of the tested samples was determined by examining their ability to neutralize DPPH and OH radicals in vitro, whereas reducing properties were assessed in Ferric Reducing Antioxidant Power (FRAP) assay. Anti-inflammatory activity was studied ex vivo in human platelets by monitoring the effect on eicosanoid biosynthesis. Gastroprotective action was estimated in animal model of acute gastric injury induced by ethanol. RESULTS: LFIs and spiraeoside exerted activities comparable to those of positive control in DPPH-radical scavenging and FRAP antioxidant assays, whereas notable hydroxyl radical scavenging ability was demonstrated only for spiraeoside (IC50 = 5.1MUg/mL). Among tested samples, astragalin 2"-O-gallate (IC50 = 141.1MUg/mL) and spiraeoside (IC50 = 4.69MUg/mL) the most markedly inhibited production of pro-inflammatory prostaglandin E2 and 12(S)-hydroxy (5Z,8Z,10E,14Z)-eicosatetraenoic acid in human platelets, respectively. Examination of LFIs (100-300mg/kg, p.o.) gastroprotective action in rats revealed their capacity to preserve mucosal integrity. In addition, spiraeoside (50mg/kg, p.o.) and tellimagrandin II (40mg/kg, p.o.) showed ulcer preventive ability. CONCLUSION: Current study supports documented traditional use of investigated herbs and indicates that flavonoid and tannin components are partially responsible for the demonstrated pharmacological activities. PMID- 29132912 TI - Humanization in healthcare arises from the need for a holistic approach to illness. AB - Suffering is not only exclusive to patients or their relatives, but also to the health professionals, who feel to be at the center of the depersonalization process. Over-technification and the fact that the disease process is sometimes the only focal point of our activities, together with the ever-increasing influence of institutional power seen in recent times, all cause the health professional to be the first in demanding a change in health institution dynamics. Following initial reflection from one of the most technified medical specialties (Intensive Care Medicine), classically isolated from the rest of the Hospital and from the community, we implemented a project aimed at securing integration and empathy in our approach to patients and their relatives in the Intensive Care Unit (ICU) of Infanta Margarita Hospital. The project was designed to incorporate tools for working on the most important elements of a humanization plan, i.e., the patients, their relatives, the health professionals and the community, attempting to disclose the work done in the ICU over a period of 12 months. This project is referred to as the Project ICU Infanta Margarita: 1 year: 12 months for 12 commitments. PMID- 29132915 TI - Human recombinant erythropoietin reduces sensorimotor dysfunction and cognitive impairment in rat models of chronic kidney disease. AB - INTRODUCTION: Chronic kidney disease (CKD) can cause anaemia and neurological disorders. Recombinant human erythropoietin (rHuEPO) is used to manage anaemia in CKD. However, there is little evidence on the effects of rHuEPO on behaviour and cognitive function in CKD. This study aimed to evaluate the impact of rHuEPO in sensorimotor and cognitive functions in a CKD model. METHODS: Male Wistar rats were randomly assigned to 4 groups: control and CKD, with and without rHuEPO treatment (1050 IU per kg body weight, once weekly for 4 weeks). The Morris water maze, open field, and adhesive removal tests were performed simultaneously to kidney damage induction and treatment. Markers of anaemia and renal function were measured at the end of the study. RESULTS: Treatment with rHuEPO reduced kidney damage and corrected anaemia in rats with CKD. We observed reduced sensorimotor dysfunction in animals with CKD and treated with rHuEPO. These rats also completed the water maze test in a shorter time than the control groups. CONCLUSIONS: rHuEPO reduces kidney damage, corrects anemia, and reduces sensorimotor and cognitive dysfunction in animals with CKD. PMID- 29132914 TI - Comparison of cyclopentolate versus tropicamide cycloplegia: A systematic review and meta-analysis. AB - PURPOSE: The aim of the present meta-analysis is to compare the efficacy of cyclopentolate and tropicamide in controlling accommodation during refraction. METHODS: A comprehensive literature search was performed in PubMed, Scopus, Science direct and Ovid databases by the key words: "tropicamide"; "cyclopentolate"; "cycloplegia" and "cycloplegic" from inception to April 2016. Methodological quality of the literature was evaluated according to the Oxford Center for Evidence Based Medicine and modified Newcastle-Ottawa scale. Statistical analyses were performed using Comprehensive Meta-Analysis (version 2; Biostat Inc., USA). RESULTS: The present meta-analysis included six studies (three randomized controlled trials and three case-control studies). Pooled standardized difference in the mean changes in the refractive error was 0.175 D [lower and upper limits: -0.089; 0.438] more plus in the cyclopentolate group compared to the tropicamide group; however, this difference was not statistically significant (p=0.194; Cochrane Q value=171.72 (p<0.05); I2=95.34%). Egger's regression intercept was -5.33 (p=0.170). Considering type of refractive errors; refractive assessment procedure and age group; although cycloplegic effect of cyclopentolate was stronger than tropicamide; however, this effect was only statistically significant in children; hyperopic patients and with retinoscopy. CONCLUSION: We suggest that tropicamide may be considered as a viable substitute for cyclopentolate due to its rapid onset of action. Although these results should be used cautiously in infants and in patients with high hyperopia or strabismus when using tropicamide as the sole cycloplegic agent especially in situations that the findings are variable or there is no consistency between the examination results and clinical manifestations of the visual problems. PMID- 29132913 TI - Beta2 adrenergic receptor silencing change intraocular pressure in New Zealand rabbits. AB - PURPOSE/AIM: Glaucoma consists of a group of progressive optic neuropathies that are characterized by degeneration of the optic nerve and irreversible visual filed loss. Elevated intraocular pressure is the only proven treatable risk factor and commercial products used for glaucoma treatment are focused in lowering intraocular pressure. These drugs can have various undesirable side effects and this invites to look for new strategies. The purpose of this work is to study the use of a siRNA (small interfering RNA) to selectively silence beta2 adrenergic receptors and to see whether it reduces IOP (intraocular pressure). MATERIAL AND METHODS: Topical instillation of beta2 adrenergic receptors small interfering RNA (siRNA, 25-250MUg) was applied and IOP was measured with a Tonopen XL up to 9 consecutive days. The effect of such siRNA was compared to commercial compounds such as Timoftlol, Trusopt and Xalatan, and it was also analyzed if some anatomical changes occurred by microscopy. RESULTS: siRNA designed for beta2 adrenergic receptor induced a reduction of intraocular pressure (IOP) of 30+/-5%, compared to a control (scrambled siRNA). The results in terms of IOP decrease were similar to that found with commercial compounds but a long-lasting hypotensive action was shown by beta2 adrenergic receptor siRNA treatment as compared to commercial drugs. No apparent side effects were observed in the ocular structures. CONCLUSION: The use of siRNA against the beta2 adrenergic receptors could provide an interesting therapeutic strategy for glaucoma treatment. PMID- 29132916 TI - Insulin-Degrading Enzyme in the Fight against Alzheimer's Disease. AB - After decades of research and clinical trials there is still no cure for Alzheimer's disease (AD). While impaired clearance of amyloid beta (Abeta) peptides is considered as one of the major causes of AD, it was recently complemented by a potential role of other toxic amyloidogenic species. Insulin degrading enzyme (IDE) is the proteolytic culprit of various beta-forming peptides, both extracellular and intracellular. On the basis of demonstrated allosteric activation of IDE against Abeta, it is possible to propose a new strategy for the targeted IDE-based cleansing of different toxic aggregation prone peptides. Consequently, specific allosteric activation of IDE coupled with state-of-the-art compound delivery and CRISP-Cas9 technique of transgene insertion can be instrumental in the fight against AD and related neurodegenerative maladies. PMID- 29132917 TI - NanoBRET Approaches to Study Ligand Binding to GPCRs and RTKs. AB - Recent advances in the development of fluorescent ligands for G-protein-coupled receptors (GPCRs) and receptor tyrosine kinase receptors (RTKs) have facilitated the study of these receptors in living cells. A limitation of these ligands is potential uptake into cells and increased nonspecific binding. However, this can largely be overcome by using proximity approaches, such as bioluminescence resonance energy transfer (BRET), which localise the signal (within 10nm) to the specific receptor target. The recent engineering of NanoLuc has resulted in a luciferase variant that is smaller and significantly brighter (up to tenfold) than existing variants. Here, we review the use of BRET from N-terminal NanoLuc tagged GPCRs or a RTK to a receptor-bound fluorescent ligand to provide quantitative pharmacology of ligand-receptor interactions in living cells in real time. PMID- 29132918 TI - The first-in-human experience with a minimally invasive, ambulatory, counterpulsation heart assist system for advanced congestive heart failure. AB - BACKGROUND: The intravascular ventricular assist system (iVAS) is a new, minimally invasive, ambulatory counterpulsation heart assist system delivered via the subclavian artery and powered by a portable driver. It is designed for recovery, bridge to transplantation (BTT) or for prolonging medical therapy. We report the first-in-human (FIH) experience with iVAS. METHODS: This is a prospective, non-randomized single arm, U.S. Food and Drug Administration (FDA) approved early feasibility trial in patients listed for cardiac transplantation. The primary end-point was survival to transplant or stroke-free survival at 30 days. RESULTS: Fourteen patients were enrolled and 13 (92.8%) were treated with iVAS. At time of implant, the average age was 58 +/- 6.7 years; 85% were male; 28% had ischemic cardiomyopathy; and 3 were Interagency Registry for Mechanically Assisted Devices (INTERMACS) Level 2, 9 were Level 3, and 1 was Level 4. The mean left ventricular ejection fraction was 22%, left ventricular internal diameter diastole was 7.13 mm, and 69% had moderate or severe mitral regurgitation. There were no intra-operative complications. Intensive care unit stay after implant was 6 +/- 6 days. All patients were transplanted after 32 +/- 21 days. There were no deaths or thromboembolic events: 1 patient required escalation of mechanical support, and post-implant complications included pleuritis/pericarditis (n = 1) and neuropathy (n = 2). No intra-operative blood transfusions were required. CONCLUSIONS: This study demonstrates a high rate of successful outcomes with an excellent risk-to-benefit profile. This FIH experience reveals that the iVAS can be successfully inserted in a standardized approach, provide hemodynamic support, can be interrupted for short periods, and allows for ambulation. A multicenter trial to investigate effectiveness and safety is warranted. PMID- 29132919 TI - Clonal replacement and expansion among invasive meningococcal isolates of serogroup W in France. AB - BACKGROUND: Neisseria meningitidis group W (NmW) belonging to the clonal complex ST-11 (NmW/cc11) spread in Europe and in France in 2000 and declined thereafter. In France, invasive meningococcal disease (IMD) due to NmW increased again in 2012 and thereafter since 2015. Several sub-lineages of NmW/cc11 are circulating worldwide with successive epidemic waves. We aimed to describe recent epidemiological trends of NmW in France and to explore the microbiological and epidemiological characteristics associated with different NmW/cc11 sub-lineages. METHODS: The epidemiology of NmW was described based on data collected through mandatory notification of IMD and strain typing data for culture-confirmed and PCR-confirmed cases for the period 2000-2016. All culture-confirmed cases due to NmW from the period 2010-2016 were characterised by whole genome sequencing (WGS). A detailed epidemiological analysis was performed for culture-confirmed cases on the basis of WGS data. FINDINGS: During the period 2010-2016, genotyping was obtained for 148 cases including all the 132 culture-confirmed cases, among which 127 were matched with epidemiological data, and 16 PCR-confirmed cases (out of a total of 47 PCR-confirmed cases). An increase in IMD was observed in 2012 and was linked to isolates belonging to the "Anglo-French-Hajj" sub-lineage. These isolates have decreased significantly since 2013 and have been replaced by NmW/cc11 isolates related to the "South American - UK" sub-lineage which caused a marked increase in the number of cases of NmW in 2016. In this sub-lineage, the "original UK strain" was first detected in 2012 and increased thereafter, followed by the recently described "UK 2013-strain". Isolates related to the "South American-UK" sub-lineage represented 45% of all NmW cultured isolates from the whole period 2010-2016 but were the most frequent isolates in 2016, representing 76% of the total NmW typed isolates and 94% of the typed NmW/cc11 isolates. A changing pattern in the epidemiology of NmW has been observed in 2015 2016 in relation to the spread of the "UK 2013-strain" with a sharp increase in the number of cases among persons aged 15 years and over and a high case fatality rate (CFR). Among cases due to the "UK 2013-strain", 94% of cases were aged 15 years and over and the CFR was 28%. INTERPRETATION: Our data suggest a recent clonal replacement among NmW/cc11 isolates with the expansion of the "South American-UK" sub-lineage in France and particularly the "UK 2013-strain" which was predominant in 2015 and 2016. A shift in the age-distribution of IMD due to NmW to older ages and the high CFR are consistent with the expansion of a new virulent clone in a naive population. These data may have an impact on tailoring vaccination strategies against NmW. PMID- 29132920 TI - Environmental heterogeneity associated with European perch (Perca fluviatilis) predation on invasive round goby (Neogobius melanostomus). AB - Spatiotemporal environmental variation affects fish feeding behaviour and capacity for piscivorous control of prey populations, which is important for management when prey include invasive species causing ecosystem impacts. We assessed gut-contents of an important piscivore (European perch Perca fluviatilis) over two years, and analysed variables affecting initiation and amounts of feeding, focusing on an important invasive prey species, round goby (Neogobius melanostomus). We show that predation is primarily controlled by variation of physical and habitat characteristics surrounding perch. Fish prey began being incorporated in diets of perch that were >150 mm, with temperature conditions controlling initiation of their feeding. Total amounts of fish in perch diets, and amounts of round goby individually, were strongly affected by macrophyte cover; seldom were fish present in perch stomachs when macrophyte cover was >40%. Environmental densities of round goby were related to multivariate diet composition in ways that suggest predation of some native species may be relaxed in areas of dense round goby populations. There was evidence that perch predation is unlikely to limit populations of the invader, as there was only a weak relationship between round goby densities and amounts in gut contents. The results have ecosystem management implications, because some variables found to be important could be manipulated to control round goby or other similar invaders e.g. fisheries management of native piscivore stock density and body-size, or modification of benthic environment structure. PMID- 29132921 TI - Empirical data demonstrates risk-tradeoffs between landscapes for herbivorous fish may promote reef resilience. AB - Herbivores balance resource requirements with predation risk, which can differ among landscapes; hence, landscape can shape these trade-offs, influencing herbivore distribution and behavior. While this paradigm has been well established on coral-dominated reefs, tropical reefs worldwide are shifting to algal dominance. If herbivores avoid algae due to higher risk and forage in coral, these algal states may be stabilized. However, if herbivores forage more in resource-rich algal states, this may promote coral recovery. We assessed the distribution and behavior of herbivorous fishes in Moorea, French Polynesia in coral and algal turf-dominated fringing reef sites. Acanthuridae were more abundant in coral states and Labridae, tribe Scarinae, in algal turf states, though total fish abundances were equivalent in the two states. Fish in both families spent more time feeding in algal states and hiding/swimming in coral states. Thus, behavior reflects the trade-off between resource acquisition and refuge in these two landscapes and may promote recovery to coral. PMID- 29132922 TI - Physical and chemical properties of model composites containing quaternary ammonium methacrylates. AB - OBJECTIVE: Investigate physical and chemical properties of model composites formulated with quaternary ammonium salt monomers (QAS) at different concentrations and alkyl chains lengths METHODS: QAS with 12 dimethylaminododecyl methacrylate (DMADDM) and 16 dimethylaminohexadecyl methacrylate (DMAHDM) chains lengths were synthesized and incorporated at 5 and 10% in model composites, resulting in four groups: G12.5 (DMADDM 5%), G12.10 (DMADDM 10%), G16.5 (DMAHDM 5%), G16.10 (DMAHDM 10%). One group was used as control group (CG 0%). Degree of conversion (DC); water sorption (WS) and solubility (SL); hygroscopic expansion (HE); degradation temperature (DT); glass transition temperature (Tg) and polymerization shrinkage (PS) were determined. Knoop hardness (KNH), flexural strength (FS) and elastic modulus (EM) were measured before and after storage Data were submitted to ANOVA and Tukey's test (p<=0.05). RESULTS: DC ranged between 76.1 (G12.10) and 70.7 (G16.5) %; CG had the lowest WS, SL and HE. There was no statistical difference for PS and FS. KHN values ranged between 30.2 (GC) and 25 (G16.10) and after storage the performance was depended on QAS concentration and chain length. For EM, CG had the highest values before and after storage and no difference was observed in the QAS groups before storage. After storage, the results were dependent on QAS concentration (3.5-4.3GPa). SIGNIFICANCE: In general, the addition of QAS increased composite's degradation compared with the CG. In the tested QAS, the addition of DMADDM at 5% concentration resulted in a less degradable material. PMID- 29132923 TI - On the joint distribution of tree height and tree length under the coalescent. AB - Many statistics that examine genetic variation depend on the underlying shapes of genealogical trees. Under the coalescent model, we investigate the joint distribution of two quantities that describe genealogical tree shape: tree height and tree length. We derive a recursive formula for their exact joint distribution under a demographic model of a constant-sized population. We obtain approximations for the mean and variance of the ratio of tree height to tree length, using them to show that this ratio converges in probability to 0 as the sample size increases. We find that as the sample size increases, the correlation coefficient for tree height and length approaches (pi2-6)/[pi2pi2-18]~0.9340. Using simulations, we examine the joint distribution of height and length under demographic models with population growth and population subdivision. We interpret the joint distribution in relation to problems of interest in data analysis, including inference of the time to the most recent common ancestor. The results assist in understanding the influences of demographic histories on two fundamental features of tree shape. PMID- 29132924 TI - Impact of capsaicin, an active component of chili pepper, on pathogenic chlamydial growth (Chlamydia trachomatis and Chlamydia pneumoniae) in immortal human epithelial HeLa cells. AB - Chlamydia trachomatis is the leading cause of sexually transmitted infections worldwide. Capsaicin, a component of chili pepper, which can stimulate actin remodeling via capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) and anti-inflammatory effects via PPARgamma (peroxisome proliferator-activated receptor-gamma) and LXRalpha (liver X receptor alpha), is a potential candidate to control chlamydial growth in host cells. We examined whether capsaicin could inhibit C. trachomatis growth in immortal human epithelial HeLa cells. Inclusion forming unit and quantitative PCR assays showed that capsaicin significantly inhibited bacterial growth in cells in a dose-dependent manner, even in the presence of cycloheximide, a eukaryotic protein synthesis inhibitor. Confocal microscopic and transmission electron microscopic observations revealed an obvious decrease in bacterial numbers to inclusions bodies formed in the cells. Although capsaicin can stimulate the apoptosis of cells, no increase in cleaved PARP (poly (ADP-ribose) polymerase), an apoptotic indicator, was observed at a working concentration. All of the drugs tested (capsazepine, a TRPV1 antagonist; 5CPPSS-50, an LXRalpha inhibitor; and T0070907, a PPARgamma inhibitor) had no effect on chlamydial inhibition in the presence of capsaicin. In addition, we also confirmed that capsaicin inhibited Chlamydia pneumoniae growth, indicating a phenomena not specific to C. trachomatis. Thus, we conclude that capsaicin can block chlamydial growth without the requirement of host cell protein synthesis, but by another, yet to be defined, mechanism. PMID- 29132925 TI - Successful transcatheter arterial antimicrobial and steroid therapy for refractory liver abscess in chronic granulomatous disease: A case report and review of literature. AB - Hepatic abscess in chronic granulomatous disease (CGD) is very refractory and frequently requires multiple surgeries with frequent morbidities. Although surgical interventions are often required, patients are often not able to have surgery for various reasons. We present the case of a 21-year-old man with recurrent hepatic abscess in CGD. We could not provide surgical interventions due to the lack of a fluid cavity and the patient's refusal, and therefore we administered transcatheter arterial antimicrobial and steroid therapy. He did not have any exacerbation for more than 18 months after the final transcatheter treatment. This is the first reported case of successful transcatheter arterial antimicrobial and steroid therapy for refractory hepatic abscess in CGD. Although the patient's burden and medical cost were not inconsequential, this case shows that the transcatheter arterial antimicrobial and steroid therapy may be a treatment option for patients who are not candidates for surgical interventions. PMID- 29132926 TI - Molecular epidemiology of beta-lactamase production in penicillin-susceptible Staphylococcus aureus under high-susceptibility conditions. AB - Little is known about the prevalence of beta-lactamase production in penicillin susceptible Staphylococcus aureus isolates under high-susceptibility conditions. We analyzed S. aureus isolates with penicillin G minimum inhibitory concentration (MIC) <= 0.12 MUg/ml that were recovered from in-/outpatients (n = 108) between 2016 and 2017 in Japan. beta-Lactamase production was detected by nitrocefin based and Clinical and Laboratory Standards Institute penicillin zone edge testing and blaZ PCR. All isolates were categorized as having penicillin G MIC <=0.03 MUg/ml using an automated system; MICs determined based on the microdilution method were 0.016 MUg/ml (2%), 0.03 MUg/ml (44%), and 0.06 MUg/ml (54%). Notably, no isolates harbored the blaZ gene. The results from the nitrocefin-based and zone edge tests were consistent with those obtained by PCR. S. aureus isolates with penicillin G MIC <=0.03 MUg/ml exhibited a low frequency of beta-lactamase production. Thus, screening for beta-lactamase production may be unnecessary for isolates showing such high susceptibility. PMID- 29132928 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 29132927 TI - Whole exome sequencing identified a pathogenic mutation in RYR2 in a Chinese family with unexplained sudden death. AB - OBJECTIVE: This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope. MATERIALS AND METHODS: Whole exome sequencing and target capture sequencing were respectively conducted for two related patients. The genetic data was screened using the 1000 genomes project and SNP database (PubMed), and the identified mutations were assessed for predicted pathogenicity using the SIFT and Polyphen-2 algorithms. RESULTS: We identified a heterozygous mutation in the RYR2 gene at c.490C>T (p.P164S), highly conserved across all species, in three family members of USD, syncope and malignant ventricular tachycardias induced by treadmill exercise test, while another heterozygous de novo mutation in SCN5A at c.5576G>A p.R1859H was detected in one family member. Both variants were verified by Sanger sequencing. Importantly, RYR2 p.P164S is associated with the risk of sudden cardiac death, such as in catecholaminergic polymorphic ventricular tachycardia. CONCLUSIONS: A pathogenic mutation in RYR2 (p.P164S) is the likely cause of USD in a Chinese family associated with malignant ventricular arrhythmias. Whole exome and target capture sequencing can be useful for discovering the genetic causes of USD. PMID- 29132929 TI - A New Scope and a New Editorial Team for The American Journal of Pathology. AB - This Editorial describes new enhanced scope of The American Journal of Pathology and introduces its new editorial team. PMID- 29132930 TI - A novel algorithm increases the delivery of effective cardiac resynchronization therapy during atrial fibrillation: The CRTee randomized crossover trial. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) requires a high percentage of ventricular pacing (%Vp) to maximize its clinical benefits. Atrial fibrillation (AF) has been shown to reduce %Vp in CRT due to competition with irregular intrinsic atrioventricular (AV) conduction. We report the results of a prospective randomized crossover trial evaluating the amount of effective CRT delivered during AF with a novel algorithm (eCRTAF). OBJECTIVE: The purpose of this study was to determine whether eCRTAF increases the amount of effective CRT delivered during AF compared to a currently available rate regularization algorithm. METHODS: Patients previously implanted with a cardiac resynchronization therapy-defibrillator and with a history of AF and intact AV conduction received up to 4 weeks of control (Conducted AF Response) and up to 4 weeks of eCRTAF in a randomized sequence. The percent effective CRT (%eCRT) pacing, which excludes beats without left ventricular capture, %Vp, and mean heart rate (HR) were recorded during AF and sinus rhythm. RESULTS: The eCRTAF algorithm resulted in a significantly higher %eCRT during AF than control (87.8% +/- 7.8% vs 80.8% +/- 14.3%; P <.001) and %Vp during AF than control (90.0% +/- 5.9% vs 83.2% +/- 11.9%; P <.001), with a small but statistically significant increase in mean HR of 2.5 bpm (79.5 +/- 9.7 bpm vs 77.0 +/- 9.9 bpm; P <.001). CONCLUSION: In a cohort of CRT patients with a history of AF, eCRTAF significantly increased %eCRT pacing and %Vp during AF with a small increase in mean HR. This algorithm may represent a novel noninvasive method of significantly increasing effective CRT delivery during AF, potentially improving CRT response. PMID- 29132931 TI - Hybrid surgical vs percutaneous access epicardial ventricular tachycardia ablation. AB - BACKGROUND: There is limited experience of surgical epicardial access in the contemporary era of ventricular tachycardia ablation after cardiac surgery. OBJECTIVES: The purpose of this study was to describe our institutional experience with surgical epicardial access and the influence of surgical approach and compare outcomes with those of a propensity-matched percutaneous epicardial access control group. METHODS: We performed a retrospective study of consecutive surgical epicardial ventricular tachycardia (VT) ablation cases from a single center. Surgical cases were propensity-matched to percutaneous epicardial ablation controls and short-term and long-term outcomes were compared. RESULTS: Between 2004 and 2016, 38 patients underwent 40 surgical epicardial access procedures (subxiphoid, n = 22; thoracotomy, n = 18). The commonest indication was prior coronary artery bypass grafting (45%), valve surgery (22%), or ventricular assist device (VAD) (10%). The mean procedure time was 444 minutes (standard deviation, 107 minutes). Mapped epicardial geometry area was 149 cm2 (interquartile range 182 cm2), which comprised 36% of the mapped epicardial geometric area of a percutaneous control group. Subxiphoid access gave preferential access to the inferior and inferolateral left ventricular segments and was less frequently able to access the anterior, anterolateral, and apical segments compared with a thoracotomy approach. When compared with results from a propensity-matched percutaneous-access group, short-term outcomes, complication rates, and 1-year survival free from a combined end point of VT recurrence, death, or transplantation were not statistically different. CONCLUSIONS: Surgical epicardial access after cardiac surgery for ablation of VT in patients with careful preprocedure evaluation can be performed with acceptable safety with no statistical difference in long-term outcomes compared with a propensity-matched percutaneous epicardial cohort. The region of left ventricular epicardium that can be mapped is limited compared with that of percutaneous cases and is determined by the surgical approach. PMID- 29132932 TI - Apoptotic effect as biomarker of disease, severity and follow-up in interstitial cystitis. AB - OBJECTIVE: To determine whether the apoptotic effect test could serve as a biomarker of severity in bladder pain syndrome/interstitial cystitis. MATERIAL AND METHODS: A prospective study was conducted between January 2010 and January 2015, which included 57 patients diagnosed with interstitial cystitis and 49 diagnosed with chronic pelvic pain of gynaecological origin. The urine was exposed to cell cultures, and the urine's capacity for inducing apoptosis in the cultures was analysed. A statistical analysis was then conducted to assess whether the apoptotic effect was associated with the symptoms. RESULTS: After performing an analysis of the association between the degree of apoptotic effect and the symptoms of patients with interstitial cystitis, we observed a significant increase in the mean percentages of apoptosis as the degree of symptom severity increased. After analysing the association between the apoptotic effect and symptoms, we obtained a positive correlation in the patients with interstitial cystitis and a lack of correlation in the patients with chronic pelvic pain of gynaecological origin. The rates of apoptosis increased progressively in the patients with interstitial cystitis as the symptoms increased, while the patients with chronic pelvic pain of gynaecological origin remained stable. CONCLUSIONS: The apoptotic effect of the urine of patients with interstitial cystitis could be a marker of disease, thus differentiating patients with interstitial cystitis from patients with chronic pelvic pain. The effect could also provide an objective measure of symptom severity. PMID- 29132933 TI - Long-term follow-up of the AdVance(r)/AdVanceXP(r) sling. What are the surgeons' impressions? What are the patients'? AB - OBJECTIVES: To analyse the safety, efficacy and quality of life of patients with male stress urinary incontinence after radical prostatectomy treated with the AdVance(r) and AdvanceXP(r) slings. PATIENTS AND METHOD: The study included 92 patients with stress urinary incontinence after radical prostatectomy treated with the AdVance(r) and AdVanceXP(r) sling between May 2008 and December 2015. A perineal repositioning test was performed in all cases with sphincter coaptation of>=1.5cm. Mild stress urinary incontinence was defined as the use of 1-2 absorbers/24h; moderate was defined as 3-5 absorbers/24h; and severe was defined as more than 5 absorbers/24h. Healing was defined as the total absence of using pads; improvement was defined as a reduction>50% in the number of pads; and failure was defined as a reduction<50, no improvement or worsened incontinence. Check-ups were conducted at 3, 12 and 36 months after the surgery. We employed the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) for the quality of life index. The complications are listed according to the Clavien-Dindo classification. RESULTS: The degree of preoperative incontinence was mild in 23.9%, moderate in 67.4% and severe in 8.7% of the patients. The mean use of preoperative pads was 3.1 (range 1-6, 95% CI). The mean preoperative ICIQ SF score was 16.5 (15-20). Sphincter coaptation>=1.5cm using the perineal repositioning test was present in 87 patients (94.6%). The mean follow-up from insertion of the sling was 42.1 months. Some 89.1% of the patients were healed at 3 months, 70.7% were healed at 12 months, and 70.4% were healed at 36 months. The ICIQ-SF score at 3, 12 and 36 months showed significant improvement (P<.001) compared with the preoperative score. CONCLUSIONS: The Advance(r) and AdvanceXP(r) system are effective over time in terms of urinary continence and patient satisfaction. PMID- 29132934 TI - The evolution of pathogen virulence: Effects of transitions between host types. AB - Much of evolutionary epidemiology theory is derived from a perspective in which all hosts, and all parasites, are epidemiologically equivalent. This stands in contrast to the well-documented existence of the numerous processes generating heterogeneity among hosts and parasites that can profoundly influence evolutionary/epidemiological dynamics. Age-related immunological changes, inequities in nutritional status, and interactions between parasites via coinfection are just a few of the many factors that generate heterogeneity among hosts in the ways they express susceptibility to, and respond to infection by, a focal pathogen. Moreover, organisms age, nutritional states improve or worsen, and co-infections can be cleared or acquired, implying that transitions between these different disease states are the rule, rather than the exception, in natural disease systems. Here we develop the theoretical framework for modeling the implications of such transitions in these multi-type host settings for the evolution of virulence. Results show that ignoring these common sources of host heterogeneities in disease characteristics can lead to both quantitatively and qualitatively mischaracterized evolutionary predictions. PMID- 29132935 TI - Risk factors and outcomes of candidemia caused by Candida parapsilosis complex in a medical center in northern Taiwan. AB - To investigate the risk factors and outcomes associated with Candida parapsilosis candidemia, a retrospective study was conducted at a tertiary medical center in northern Taiwan. Patients with C. parapsilosis candidemia and corresponding controls with C. albicans candidemia were chosen and their demographics, comorbidities, risk factors, and clinical outcomes were reviewed. Antifungal susceptibility tests were performed using the Sensititre YeastOne colorimetric system. Matrix-assisted laser desorption ionization-time of flight mass spectrometry was used to classify the genomic species. Of the 270 candidemias found in 253 patients, C. albicans was the most common Candida species isolated (43.0%), followed by C. parapsilosis (22.6%), C. tropicalis (17.4%), and C. glabrata (10.0%). The 30-day mortality of C. parapsilosis candidemia was significantly lower than that of C. albicans candidemia (21.7% vs. 53.9%, P<0.001). C. parapsilosis was positively associated with antifungal agent exposure [OR 7.261 (95% CI, 1.603-32.879), P=0.010], but negatively associated with Candida colonization [OR 0.303 (95% CI, 0.123-0.745), P=0.009], and immunosuppressant use [OR 0.264 (95% CI, 0.099-0.705), P=0.008]. In-hospital mortality was associated with the Sequential Organ Failure Assessment Score [OR 1.255 (95% CI, 1.002-1.573), P=0.048]. The clinical outcomes did not differ across genomic species and in the minimum inhibitory concentrations of fluconazole. PMID- 29132936 TI - Evaluation of an in-house developed multiplex real-time PCR for the detection of IMP, OXA-23, GES carbapenemases and the transmissible colistin-resistant mcr gene on the BD MAXTM open system. PMID- 29132938 TI - Endovascular management of extracranial occlusions at the hyperacute phase of stroke with tandem occlusions. AB - BACKGROUND AND PURPOSE: The management of cervical artery occlusions in hyperacute stroke with tandem cervical/intracranial occlusions has not yet become standardized, especially when the circle of Willis is effective. METHODS: We retrospectively analyzed the safety and accuracy of current approaches to manage the cervical occlusion in consecutive patients with tandem occlusions addressed for intracranial mechanical thrombectomy (MT) in our department from January 2012 to May 2017. The different approaches that could be performed in a same patient during the same procedure or hospitalization were analyzed separately. RESULTS: We reported 64 approaches to manage the cervical occlusion in 49 patients with tandem occlusion (14% of MT): medical treatment alone in 16/64 (25%), stenting/angioplasty in 16/64 (25%), occlusion with coils in 12/64 (19%), angioplasty alone in 9/64 (14%), stent-retriever in 8/64 (12%), and/or thromboaspiration in 3/64 (5%). Early ipsilateral embolic recurrence occurred after 9/64 (14%) of them. It was strongly associated with the presence of a cervical intraluminal thrombus (P=0.001) and was then lower after occlusion with coils and stent-retriever compared to medical treatment alone and thromboaspiration (P=0.002). Occlusion with coils had a lower rate of radiological intracranial hemorrhage at 48-hour compared to other approaches (P=0.009). The 3-month rates of favorable outcome (P=0.806) and mortality (P=0.878) were similar. One delayed stroke was imputable to an occlusion with coils, for a median (Q1-Q3) follow-up of 10 (3-20) months. CONCLUSIONS: Cervical occlusion with coils and thrombectomy with stent-retrievers may be relevant to prevent early embolic recurrence in cervical occlusions with intraluminal thrombus. Stent-retrievers should be further assessed as a first-line approach, since delayed stroke may occur following occlusion with coils. Medical treatment alone may be sufficient when no cervical intraluminal thrombus is present, the Willis polygon is effective, and the cervical occlusion can be crossed easily to perform the intracranial thrombectomy. PMID- 29132937 TI - Arsenic exposure during embryonic development alters the expression of the long noncoding RNA growth arrest specific-5 (Gas5) in a sex-dependent manner. AB - Our previous studies suggest that prenatal arsenic exposure (50ppb) modifies epigenetic control of the programming of the glucocorticoid receptor (GR) signaling system in the developing mouse brain. These deficits may lead to long lasting consequences, including deficits in learning and memory, increased depressive-like behaviors, and an altered set-point of GR feedback throughout life. To understand the arsenic-induced changes within the GR system, we assessed the impact of in utero arsenic exposure on the levels of the GR and growth arrest specific-5 (Gas5), a noncoding RNA, across a key gestational period for GR programming (gestational days, GD 14-18) in mice. Gas5 contains a glucocorticoid response element (GRE)-like sequence that binds the GR, thereby decreasing GR-GRE dependent gene transcription and potentially altering GR programming. Prenatal arsenic exposure resulted in sex-dependent and age-dependent shifts in the levels of GR and Gas5 expression in fetal telencephalon. Nuclear GR levels were reduced in males, but unchanged in females, at all gestational time points tested. Total cellular Gas5 levels were lower in arsenic-exposed males with no changes seen in arsenic-exposed females at GD16 and 18. An increase in total cellular Gas-5 along with increased nuclear levels in GD14 arsenic-exposed females, suggests a differential regulation of cellular compartmentalization of Gas5. RIP assays revealed reduced Gas5 associated with the GR on GD14 in the nuclear fraction prepared from arsenic-exposed males and females. This decrease in levels of GR Gas5 binding continued only in the females at GD18. Thus, nuclear GR signaling potential is decreased in prenatal arsenic-exposed males, while it is increased or maintained at levels approaching normal in prenatal arsenic-exposed females. These findings suggest that females, but not males, exposed to arsenic are able to regulate the levels of nuclear free GR by altering Gas5 levels, thereby keeping GR nuclear signaling closer to control (unexposed) levels. PMID- 29132939 TI - Automated brain tissue and myelin volumetry based on quantitative MR imaging with various in-plane resolutions. AB - BACKGROUND AND PURPOSE: Segmented brain tissue and myelin volumes can now be automatically calculated using dedicated software (SyMRI), which is based on quantification of R1 and R2 relaxation rates and proton density. The aim of this study was to determine the validity of SyMRI brain tissue and myelin volumetry using various in-plane resolutions. METHODS: We scanned 10 healthy subjects on a 1.5T MR scanner with in-plane resolutions of 0.8, 2.0 and 3.0mm. Two scans were performed for each resolution. The acquisition time was 7-min and 24-sec for 0.8mm, 3-min and 9-sec for 2.0mm and 1-min and 56-sec for 3.0mm resolutions. The volumes of white matter (WM), gray matter (GM), cerebrospinal fluid (CSF), non WM/GM/CSF (NoN), brain parenchymal volume (BPV), intracranial volume (ICV) and myelin were compared between in-plane resolutions. Repeatability for each resolution was then analyzed. RESULTS: No significant differences in volumes measured were found between the different in-plane resolutions, except for NoN between 0.8mm and 2.0mm and between 2.0mm and 3.0mm. The repeatability error value for the WM, GM, CSF, NoN, BPV and myelin volumes relative to ICV was 0.97%, 1.01%, 0.65%, 0.86%, 1.06% and 0.25% in 0.8mm; 1.22%, 1.36%, 0.73%, 0.37%, 1.18% and 0.35% in 2.0mm and 1.18%, 1.02%, 0.96%, 0.45%, 1.36%, and 0.28% in 3.0mm resolutions. CONCLUSION: SyMRI brain tissue and myelin volumetry with low in plane resolution and short acquisition times is robust and has a good repeatability so could be useful for follow-up studies. PMID- 29132941 TI - Screening test of HIV in Emergency Departments: How? When? Who? PMID- 29132940 TI - Bullseye's representation of cerebral white matter hyperintensities. AB - BACKGROUND AND PURPOSE: Visual rating scales have limited capacities to depict the regional distribution of cerebral white matter hyperintensities (WMH). We present a regional-zonal volumetric analysis alongside a visualization tool to compare and deconstruct visual rating scales. MATERIALS AND METHODS: 3D T1 weighted, T2-weighted spin-echo and FLAIR images were acquired on a 3T system, from 82 elderly participants in a population-based study. Images were automatically segmented for WMH. Lobar boundaries and distance to ventricular surface were used to define white matter regions. Regional-zonal WMH loads were displayed using bullseye plots. Four raters assessed all images applying three scales. Correlations between visual scales and regional WMH as well as inter and intra-rater variability were assessed. A multinomial ordinal regression model was used to predict scores based on regional volumes and global WMH burdens. RESULTS: On average, the bullseye plot depicted a right-left symmetry in the distribution and concentration of damage in the periventricular zone, especially in frontal regions. WMH loads correlated well with the average visual rating scores (e.g. Kendall's tau [Volume, Scheltens]=0.59 CI=[0.53 0.62]). Local correlations allowed comparison of loading patterns between scales and between raters. Regional measurements had more predictive power than global WMH burden (e.g. frontal caps prediction with local features: ICC=0.67 CI=[0.53 0.77], global volume=0.50 CI=[0.32 0.65], intra-rater=0.44 CI=[0.23 0.60]). CONCLUSION: Regional-zonal representation of WMH burden highlights similarities and differences between visual rating scales and raters. The bullseye infographic tool provides a simple visual representation of regional lesion load that can be used for rater calibration and training. PMID- 29132942 TI - Treatment with dalbavancin in a patient with septic thrombophlebitis of the internal jugular vein due to Staphylococcus aureus after insertion of an implantable cardioverter defibrillator. PMID- 29132943 TI - Breast abscess due to Actinomyces turicensis in a non-puerperal woman. PMID- 29132944 TI - Necrotic lesion in an immunosuppressed patient. PMID- 29132945 TI - Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD. AB - BACKGROUND: Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown. STUDY DESIGN: Prospective observational cohort study. SETTINGS & PARTICIPANTS: 3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013. PREDICTOR: Baseline uric acid concentrations. OUTCOMES: Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality. RESULTS: During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) >= 45mL/min/1.73m2 (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m2. There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007). LIMITATIONS: Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time. CONCLUSIONS: Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD. PMID- 29132946 TI - An Interview Study of Patient and Caregiver Perspectives on Advance Care Planning in ESRD. AB - BACKGROUND: Advance care planning (ACP) empowers patients to consider and communicate their current and future treatment goals. However, it can be an emotionally charged process for patients with kidney disease and their caregivers. This study aimed to describe the perspectives and attitudes of patients with end-stage renal disease (ESRD) and their caregivers toward ACP. STUDY DESIGN: Qualitative study. SETTING & PARTICIPANTS: Patients with ESRD (n=24) and their caregivers (n=15) aged 36 to 91 years at various stages of ACP ("not commenced," "in progress," or "completed") from 3 renal services. METHODOLOGY: Semistructured interviews. ANALYTICAL APPROACH: Transcripts were analyzed using thematic analysis. RESULTS: 5 major themes were identified: articulating core values (avoiding futile and undignified treatment, reevaluating terms of dialysis, framing a life worth living, and refusing to be a burden), confronting conversations (signifying death and defeat, accepting inevitable death, and alleviating existential tension), negotiating mutual understanding (broaching taboos and assisting conflicted caregivers), challenging patient autonomy (family pressures to continue dialysis, grief diminishing caregivers' capacity, and leveraging support), and decisional disempowerment (lacking medical transparency and disappointment with clinical disinterest). LIMITATIONS: Only English-speaking patients/caregivers participated in the interview. CONCLUSIONS: ACP provides patients with ESRD and their caregivers a conduit for accepting and planning for impending death and to express treatment preferences based on self dignity and value of living. However, ACP can be considered taboo, may require caregivers to overcome personal and decisional conflict, and may be complex if patients and caregivers are unable to accept the reality of the patient's illness. We suggest that ACP facilitators and clinicians make ACP more acceptable and less confrontational to patients and caregivers and that strategies be put in place to support caregivers who may be experiencing overwhelming grief or who have conflicting goals, particularly when they are called on to make end-of-life decisions. PMID- 29132948 TI - Extending the Structural View of Class B GPCRs. AB - The secretin-like class B family of G protein-coupled receptors (GPCRs) are key players in hormonal homeostasis. Recent structures of various receptors in complex with a variety of orthosteric and allosteric ligands provide fundamental new insights into the function and mechanism of class B GPCRs, including: (i) ligand-induced changes in the relative orientation of the extracellular and transmembrane receptor domains; (ii) intramolecular interaction networks that stabilize conformational changes to accommodate intracellular G protein binding; and (iii) allosteric modulation of receptor activation. This review provides a comprehensive analysis of the structural, biochemical, and pharmacological data on class B GPCRs for understanding ligand-receptor interaction and modulation mechanisms and assessing the potential implications for drug discovery for the secretin-like GPCR family. PMID- 29132947 TI - Associations Between Weight Loss, Kidney Function Decline, and Risk of ESRD in the Chronic Kidney Disease in Children (CKiD) Cohort Study. AB - BACKGROUND: Anorexia and malnutrition are associated with poor outcomes in children with chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: We assessed changes in body mass index (BMI) as kidney function declines and its association with risk for end-stage renal disease (ESRD) among 854 participants followed between 2005 to 2013 in the CKD in Children (CKiD) Study. PREDICTORS: Repeated measurements of estimated glomerular filtration rate (eGFR) by serum creatinine concentration in our trajectory analysis using mixed models; change in BMI z score (per year) after eGFR decreased to <35mL/min/1.73m2 in logistic regression models. OUTCOMES: Repeated measurements of BMI z score (as a reflection of weight status) in our trajectory analysis; ESRD in logistic regression models. RESULTS: During a mean longitudinal follow-up of 3.4 years, BMI z scores remained stable until eGFR decreased to <35mL/min/1.73m2. When eGFR decreased to <35mL/min/1.73m2, a mean decline in BMI z score of 0.13 (95% CI, 0.09-0.17) was noted with each 10-mL/min/1.73m2 further decline in eGFR. This was statistically significantly different from the weight trajectory when eGFR was >=35mL/min/1.73 m2 (P<0.001). Among children and adolescents with significant weight loss (defined as decline in BMI z score > 0.2 per year) after eGFR decreased to <35mL/min/1.73m2, the odds of ESRD was 3.28 (95% CI, 1.53-7.05) times greater compared with participants with stable BMI z scores (BMI z score change per year of 0-0.1). LIMITATIONS: Observational nature of our study, lack of longitudinal assessments of inflammatory markers. CONCLUSIONS: In children and adolescents with CKD, weight loss mostly occurs when eGFR decreases to <35mL/min/1.73m2, and this weight loss was associated with higher risk for ESRD. Further studies are needed to define the reasons for the association between weight loss and more rapid progression to ESRD in children and adolescents. PMID- 29132949 TI - Redefining neuroendocrinology: Epigenetics of brain-body communication over the life course. AB - The brain is the central organ of stress and adaptation to stress that perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor, and it does so somewhat differently in males and females. The expression of steroid hormone receptors throughout the brain has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the entire brain and body via hormonal and neural pathways. Mediated in part via systemic hormonal influences, the adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neuronal replacement, dendritic remodeling, and synapse turnover. This article is both an account of an emerging field elucidating brain-body interactions at multiple levels, from molecules to social organization, as well as a personal account of my laboratory's role and, most importantly, the roles of trainees and colleagues, along with my involvement in interdisciplinary groups working on this topic. PMID- 29132951 TI - School-Based Health Centers, Depression, and Suicide Risk Among Adolescents. AB - INTRODUCTION: This study examined whether increasing availability of mental health services at school-based health centers in Oregon public schools would be associated with a decrease in the likelihood of depressive episodes and suicide risk among adolescents. METHODS: The study included 168 Oregon public schools that participated in the Oregon Healthy Teens Survey in 2013 and 2015. Twenty five schools had a school-based health center, and 14 of those schools increased the availability of mental health services from 2013 to 2015. The Oregon Healthy Teens Survey included questions about having a depressive episode, suicidal ideation, and attempting suicide in the past year. Multilevel logistic regression analyses were conducted in 2017 to examine associations between increasing mental health services and the likelihood of past year depressive episodes, suicidal ideation, and suicide attempts. Analyses also compared student subgroups defined by demographic characteristics (e.g., gender). RESULTS: Students at school-based health center schools that increased availability of mental health services were less likely to report depressive episodes (OR=0.88, p<0.01), suicidal ideation (OR=0.84, p<0.01), and suicide attempts (OR=0.82, p<0.01) from 2013 to 2015 compared with all other schools. Significant risk reductions in past year depressive episodes and suicidal ideation were also observed in school-based health center schools that increased availability of mental health services relative to other schools with school-based health centers. No significant differences were observed for student demographic subgroups. CONCLUSIONS: This study suggests that increasing availability of school-based mental health services can help to reduce depressive episodes and suicide risk among adolescents. PMID- 29132950 TI - Fifteen-year Weight and Disordered Eating Patterns Among Community-based Adolescents. AB - INTRODUCTION: The current study aims to characterize weight-change trajectories and their concomitant associations with prospectively measured dieting and other disordered eating behaviors among initially nonoverweight adolescents during the transition to adulthood. METHODS: A population-based sample (n=1,091) self reported their height/weight, dieting, unhealthy weight-control behaviors, and binge eating at 5-year intervals between 1998/1999 and 2013/2014, spanning early/middle adolescence through middle/late young adulthood. Data were analyzed in 2016/2017. RESULTS: Groups were categorized as those who were never overweight (n=562), were overweight during at least one measurement point and gained weight more rapidly (n=246) or gradually (n=238) than their peers, or were overweight during at least one measurement point but returned to nonoverweight status by middle/late young adulthood (n=45). Thus, nearly half of adolescents became overweight during the transition to adulthood. Those who were never overweight had the lowest rates of dieting (males: F[9, 1,314]=2.54, p=0.0069, females: F[9, 1,927]=3.02, p=0.0014) and unhealthy weight-control behaviors (males: F[9, 1,313]=3.30, p=0.0005, females: F[9, 1,927]=3.02, p=0.0014), whereas some of these behaviors tended to track with weight gain in rapid and gradual weight gainers. CONCLUSIONS: Although adolescents who are already overweight are most frequently targeted for weight-gain prevention and early intervention programs, results suggest that healthy lifestyle interventions could also benefit individuals who may be perceived as low risk for overweight in adulthood by nature of being nonoverweight in adolescence. Dieting and unhealthy weight control behaviors tended to be associated with weight gain, suggesting that they are ineffective in addition to being potentially harmful. PMID- 29132952 TI - Use of Welcome to Medicare Visits Among Older Adults Following the Affordable Care Act. AB - INTRODUCTION: To encourage greater utilization of preventive services among Medicare beneficiaries, the 2010 Affordable Care Act waived coinsurance for the Welcome to Medicare visit, making this benefit free starting in 2011. The objective of this study was to determine the impact of the Affordable Care Act on Welcome to Medicare visit utilization. METHODS: A 5% sample of newly enrolled fee for-service Medicare beneficiaries for 2005-2016 was used to estimate changes in Welcome to Medicare visit use over time. An interrupted time series model examined whether Welcome to Medicare visits increased significantly after 2011, controlling for pre-intervention trends and other autocorrelation. RESULTS: Annual Welcome to Medicare visit rates began at 1.4% in 2005 and increased to 12.3% by 2016. The quarterly Welcome to Medicare visit rate, which was almost 1% at baseline, was increasing by 0.06% before the 2011 Affordable Care Act provision (p<0.001). Immediately following the 2011 Affordable Care Act provision, the rate increased by about 1% in the first quarter of 2011 (intercept, p<0.001), followed by an increase of 0.13% every subsequent quarter (slope, p<0.001). This general trend was observed in subgroup analyses, although this trend varied by subgroups where the pre-Affordable Care Act trends of lower utilization persisted over time for non-whites and improved less quickly for men, regions other than Northeast, and beneficiaries without any supplemental insurance. CONCLUSIONS: The Affordable Care Act, and perhaps the removal of cost sharing, was associated with increased use of the Welcome to Medicare visit; however, even with the increased use, there is room for improvement. PMID- 29132953 TI - Emergency Department Visits Involving Opioid Overdoses, U.S., 2010-2014. PMID- 29132954 TI - Weight Status and Cigarette and Electronic Cigarette Use in Adolescents. AB - INTRODUCTION: Research shows that adolescents who are overweight or obese may be at greater risk of cigarette smoking, and that this relationship may vary by gender. However, this relationship is understudied for electronic cigarettes (e cigarettes). Given the high rate of adolescent obesity and the rise in e cigarette use in adolescents, this relationship should be investigated. METHODS: Data are from the third wave (collected October 2015-January 2016) of the Texas Adolescent Tobacco and Marketing Surveillance system. Students were in the seventh, ninth, and 11th grades (n=2,733) from five counties surrounding four major Texas metropolitan areas (Houston, Austin, San Antonio, Dallas). Weighted logistic regression was used to determine if weight status (healthy weight, overweight, or obese) was correlated with ever and past 30-day cigarette or e cigarette use, controlling for sociodemographics. Models were stratified by gender. Data analyses were conducted in March 2017. RESULTS: Compared with healthy-weight boys, obese boys had higher odds of past 30-day e-cigarette use (AOR=3.45, 95% CI=1.34, 8.33) and cigarette smoking (AOR=4.52, 95% CI=1.32, 15.51). There was no significant relationship between weight status and cigarette or e-cigarette use in girls. CONCLUSIONS: This study supports that there is a positive relationship between weight status and past 30-day cigarette and e cigarette use for boys, but that there is no association for girls. PMID- 29132956 TI - The XTEND-CIU study: Long-term use of omalizumab in chronic idiopathic urticaria. PMID- 29132955 TI - Injuries From Physical Abuse: National Survey of Children's Exposure to Violence I-III. AB - INTRODUCTION: Official data sources do not provide researchers, practitioners, and policy makers with complete information on physical injury from child abuse. This analysis provides a national estimate of the percentage of children who were injured during their most recent incident of physical abuse. METHODS: Pooled data from three cross-sectional national telephone survey samples (N=13,052 children) included in the National Survey of Children's Exposure to Violence completed in 2008, 2011, and 2014 were used. RESULTS: Analyses completed in 2016 indicate that 8.4% of children experienced physical abuse by a caregiver. Among those with injury data, 42.6% were injured in the most recent incident. No differences in injury were observed by sex, age, race/ethnicity, or disability status. Victims living with two parents were less likely to be injured (27.1%) than those living in other family structures (53.8%-59%, p<0.001). Incidents involving an object were more likely to result in injury (59.3% vs 38.5%, p<0.05). Injured victims were significantly more likely to experience substantial fear (57.3%) than other victims (34.4%, p<0.001). CONCLUSIONS: A substantial percentage of physical abuse victims are physically hurt to the point that they still feel pain the next day, are bruised, cut, or have a broken bone. Self-report data indicate this is a more common problem than official data sources suggest. The lack of an object in an incident of physical abuse does not protect a child from injury. The results underscore the impact of childhood physical abuse and the importance of early prevention activities. PMID- 29132957 TI - Allergy terminology: Toward a common language and shared understanding. PMID- 29132958 TI - Transforming growth factor-beta1 decreases epithelial tight junction integrity in chronic rhinosinusitis with nasal polyps. PMID- 29132959 TI - Breast-feeding and risk of asthma, hay fever, and eczema. PMID- 29132960 TI - Influenza-derived peptides cross-react with allergens and provide asthma protection. AB - BACKGROUND: The hygiene hypothesis is the leading concept to explain the current asthma epidemic, which is built on the observation that a lack of bacterial contact early in life induces allergic TH2 immune responses. OBJECTIVE: Because little is known about the contribution of respiratory tract viruses in this context, we evaluated the effect of prior influenza infection on the development of allergic asthma. METHODS: Mice were infected with influenza and, once recovered, subjected to an ovalbumin- or house dust mite-induced experimental asthma protocol. Influenza-polarized effector memory T (Tem) cells were transferred adoptively to allergen-sensitized animals before allergen challenge. A comprehensive in silico analysis assessed homologies between virus- and allergen-derived proteins. Influenza-polarized Tem cells were stimulated ex vivo with candidate peptides. Mice were immunized with a pool of virus-derived T-cell epitopes. RESULTS: In 2 murine models we found a long-lasting preventive effect against experimental asthma features. Protection could be attributed about equally to CD4+ and CD8+ Tem cells from influenza-infected mice. An in silico bioinformatic analysis identified 4 influenza- and 3 allergen-derived MHC class I and MHC class II candidate T-cell epitopes with potential antigen-specific cross reactivity between influenza and allergens. Lymphocytes from influenza-infected mice produced IFN-gamma and IL-2 but not IL-5 on stimulation with the aforementioned peptides. Immunization with a mixture of the influenza peptides conferred asthma protection, and peptide-immunized mice transferred protection through CD4+ and CD8+ Tem cells. CONCLUSION: For the first time, our results illustrate heterologous immunity of virus-infected animals toward allergens. This finding extends the original hygiene hypothesis. PMID- 29132962 TI - Autoinflammatory phenotypes in Aicardi-Goutieres syndrome with interferon upregulation and serological autoimmune features. PMID- 29132961 TI - Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations. AB - BACKGROUND: IL-33 plays an important role in the development of experimental asthma. OBJECTIVE: We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of asthma in a mouse model. METHODS: We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. RESULTS: Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of experimental asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL 9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13+ CD4 T cells, forkhead box P3-positive regulatory T cells, and IL-5+ ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45+lin-CD25+ cells) and IL-13+ ILC2s, emergence of a TSLP receptor-positive IL-9+ ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9+ and IL-13+ ILC2 numbers in the lung. CONCLUSIONS: Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9+ and IL-13+ ILC2s and mast cells and leads to development of chronic experimental asthma. An anti-TSLP antibody abrogates all pathologic features of asthma in this model. PMID- 29132963 TI - Screening for viral extraneous agents in live-attenuated avian vaccines by using a microbial microarray and sequencing. AB - The absence of extraneous agents (EA) in the raw material used for production and in finished products is one of the principal safety elements related to all medicinal products of biological origin, such as live-attenuated vaccines. The aim of this study was to investigate the applicability of the Lawrence Livermore Microbial detection array version 2 (LLMDAv2) combined with whole genome amplification and sequencing for screening for viral EAs in live-attenuated vaccines and specific pathogen-free (SPF) eggs. We detected positive microarray signals for avian endogenous retrovirus EAV-HP and several viruses belonging to the Alpharetrovirus genus in all analyzed vaccines and SPF eggs. We used a microarray probe mapping approach to evaluate the presence of intact retroviral genomes, which in addition to PCR analysis revealed that several of the positive microarray signals were most likely due to cross hybridization with the EAV HPDeltapol and ALV-E ev1, ev3 and ev6 loci sequences originating from the chicken genome. Sequencing of the vaccines on a MiSeq instrument verified the microarray findings and showed similar cross hybridization. Our results suggest that genomic microarrays and sequencing of avian attenuated vaccines may be applied in tests for EA. PMID- 29132964 TI - Premenstrual Dysphoric Disorder: Contemporary Diagnosis and Management. AB - Most ovulatory women experience premenstrual symptoms (premenstrual syndrome, molimina) which indicate impending menstruation and are of little clinical relevance because they do not affect quality of life. A few women, however, experience significant physical and/or psychological symptoms before menstruation that, if left untreated, would result in deterioration in functioning and relationships. The precise etiology remains elusive, although new theories are gaining support in pre-clinical and early clinical trials. Refined diagnostic criteria allow better discrimination of this condition from other psychiatric diagnoses and the selection of symptom appropriate therapies that afford relief for most women. Pharmacotherapies (particularly selective serotonin reuptake inhibitors and SNRIs) represent the first-line treatment for premenstrual dysphoric disorder and severe, mood-related premenstrual syndrome. Continuous combined oral contraceptives have limited evidence for usefulness in premenstrual dysphoric disorder, whereas medical ovarian suppression is often recommended for patients who fail to respond or cannot tolerate first-line treatments (e.g., selective serotonin reuptake inhibitors). The use of cognitive behavioural therapies is promising, but it remains limited by sparse data and restricted access to trained professionals. A proper diagnosis (particularly the distinction from other underlying psychiatric conditions) is crucial for the implementation of effective therapy and alleviation of this impairing condition. PMID- 29132965 TI - Letter: Modelling in Down Syndrome Screening. PMID- 29132966 TI - Effect of Maternal and Pregnancy Risk Factors on Early Neonatal Death in Planned Home Births Delivering at Home. AB - OBJECTIVE: The prevalence of home birth in the United States is increasing, although its safety is undetermined. The objective of this study was to investigate the effects of obstetrical risk factors on early neonatal death in planned home births delivering at home. METHODS: The authors conducted a retrospective 3-year cohort study consisting of planned home births that delivered at home in the United States between 2011 and 2013. The study excluded infants with congenital and chromosomal anomalies and infants born at <=34 weeks' gestation. Multivariate logistic regression models were used to estimate the adjusted effects of individual obstetrical variables on early neonatal deaths within 7 days of delivery. RESULTS: During the study period, there were 71 704 planned and delivered home births. The overall early neonatal death rate was 1.5 deaths per 1000 planned home births. The risks of early neonatal death were significantly higher in nulliparous births (OR 2.71; 95% CI 1.71-4.31), women with a previous CS (OR 2.62, 95% CI 1.25-5.52), non-vertex presentations (OR 4.27; 95% CI 1.33-13.75), plural births (OR 9.79; 95% CI 4.25-22.57), preterm births (OR 4.68; 95% CI 2.30-9.51), and births at >=41 weeks of gestation (OR 1.76; 95% CI 1.09-2.84). CONCLUSION: Early neonatal deaths occur more commonly in certain obstetrical contexts. Patient selection may reduce adverse neonatal outcomes among planned home births. PMID- 29132967 TI - Unexplained Infertility and Undiagnosed Celiac Disease: Study of a Multiethnic Canadian Population. AB - OBJECTIVE: The aims of this study were to examine the prevalence of Celiac disease (CD) in Canadian women with unexplained infertility versus women with an identifiable cause of infertility and to assess the sensitivity of the point-of care Biocard Celiac Test Kit versus standard serum serologic testing. METHODS: In this prospective cohort study, women aged 18 to 44 who were evaluated for infertility between February 2010 and May 2012 at a tertiary academic care fertility clinic in Toronto, ON, were invited to participate. They were categorized as having unexplained infertility (Cases) or infertility secondary to a known cause (Controls). Women on a gluten-free diet or previously diagnosed with CD were excluded. Outcome measures were the Celiac Questionnaire, serum testing for tissue transglutaminase IgA antibody (anti-tTG IgA), serum IgA levels, and Biocard Celiac Test Kit. RESULTS: Of 685 women approached, 1.2% (4/326) with unexplained infertility and 1.1% (4/359) with an identifiable infertility cause were newly found to have CD. Biocard testing revealed the same results as standard serologic IgA and anti-tTG IgA testing. CONCLUSION: CD was not more common in women with unexplained infertility than those with an identifiable cause of infertility. These results do not support the routine screening of Canadian women with infertility for CD. PMID- 29132968 TI - Canaliculitis due to Gemella haemolysans in a single isolate. AB - CASE REPORT: An 84 year-old woman was referred for evaluation of a painless swelling with small purulent discharge in her left upper canaliculus, and an associated epiphora of one-month duration. The patient was diagnosed with acute primary canaliculitis. She was treated with topical and oral antibiotics, as well as topical corticoids for three months, with little response. Surgical treatment with left upper canaliculotomy and curettage was then performed, and Gemella haemolysans was identified from the curetted material. The patient had no recurrence of the disease two months after the surgery. DISCUSSION: This is the first time that Gemella haemolysans is described as unique agent causing primary canaliculitis. PMID- 29132969 TI - [Multiple morbidity patterns, level of control and haemorrhagic risk in patients with vitamin K antagonists]. PMID- 29132970 TI - At-home and in-group delivery of constraint-induced movement therapy in children with hemiparesis: A systematic review. AB - BACKGROUND: Constraint-induced movement therapy (CIMT) is increasingly recognized as an effective therapy for children with hemiparesis. However, the effectiveness of CIMT outside the standard rehabilitation protocol in clinical settings is less known. The aim of this systematic review was to investigate the effectiveness of CIMT conducted at home or in a group. METHODS: We searched CINAHL, PubMed and ScienceDirect in August 2017 to select articles of studies investigating the impact of CIMT performed at home and in a group on affected upper-limb ability, occupational performance, and quality of life of children. Quality was evaluated with the PEDro scale. RESULTS: Among 374 reports of studies, 30 met the criteria; 15 examined CIMT at home and 15 in a group. CIMT with the 2 delivery models, at home or in a group, had a positive effect on the affected upper-limb ability and occupational performance. The quality of evidence was high for both these outcomes. However, the evidence was weaker and the results too limited to conclude on the impact on quality of life. The data also suggested that the glove may not be the best type of constraint. CONCLUSIONS: CIMT performed at home or in a group may be a promising intervention for rehabilitation for children with hemiparesis, but more studies on the impact on quality of life are warranted. PMID- 29132971 TI - Physical therapy improves lower limb muscle strength but not function in individuals with amyotrophic lateral sclerosis: A case series study. PMID- 29132972 TI - Pathways back to driving after acquired brain injury: Patients do not always follow medical advice! PMID- 29132973 TI - Mutual influence of sleep and circadian clocks on physiology and cognition. AB - The 24-h sleep-wake cycle is one of the most prominent outputs of the circadian clock system. At the same time, changes in sleep-wake behavior feedback on behavioral and physiological circadian rhythms, thus altering the coordination of the body's clock network. Sleep and circadian rhythm disruption have similar physiological endpoints including metabolic, cognitive, and immunologic impairments. This raises the question to which extent these phenomena are causally linked. In this review, we summarize different physiologic outcomes of sleep deprivation and mistimed sleep and discuss the experimental evidence for a mediating role of the circadian clock machinery in this context. PMID- 29132975 TI - A novel temporal pattern of childhood cerebral X-linked adrenoleukodystrophy. AB - We report a 9-year-old boy, with childhood cerebral X-linked adrenoleukodystrophy (CCALD), presenting with an episode of loss of consciousness, fixed gaze, hypotonia and vomit with spontaneous resolution and post-ictal sleep. Behavioural impairment has been observed since the previous five months. Magnetic Resonance Images (MRI) revealed isolated bilateral, symmetric, confluent temporal white matter lesions involving also corticospinal tracts, with sparing of the parieto occipital and frontal white matter. This report outlines an atypical neuroradiological localization of X-linked adrenoleukodystrophy and neuropsychological findings not specifically related to the brain involvement seen at the MRI. PMID- 29132974 TI - Topical electrophilic nitro-fatty acids potentiate cutaneous inflammation. AB - Endogenous electrophilic fatty acids mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction and gene expression. Nitro-fatty acids and other electrophilic fatty acids may thus be useful for the prevention and treatment of immune-mediated diseases, including inflammatory skin disorders. In this regard, subcutaneous (SC) injections of nitro oleic acid (OA NO2), an exemplary nitro-fatty acid, inhibit skin inflammation in a model of allergic contact dermatitis (ACD). Given the nitration of unsaturated fatty acids during metabolic and inflammatory processes and the growing use of fatty acids in topical formulations, we sought to further study the effect of nitro-fatty acids on cutaneous inflammation. To accomplish this, the effect of topically applied OA NO2 on skin inflammation was evaluated using established murine models of contact hypersensitivity (CHS). In contrast to the effects of subcutaneously injected OA NO2, topical OA-NO2 potentiated hapten-dependent inflammation inducing a sustained neutrophil-dependent inflammatory response characterized by psoriasiform histological features, increased angiogenesis, and an inflammatory infiltrate that included neutrophils, inflammatory monocytes, and gammadelta T cells. Consistent with these results, HPLC-MS/MS analysis of skin from psoriasis patients displayed a 56% increase in nitro-conjugated linoleic acid (CLA-NO2) levels in lesional skin compared to non-lesional skin. These results suggest that nitro-fatty acids in the skin microenvironment are products of cutaneous inflammatory responses and, in high local concentrations, may exacerbate inflammatory skin diseases. PMID- 29132976 TI - Investigations into the carbonic anhydrase inhibition of COS-releasing donor core motifs. AB - Carbonyl sulfide (COS) releasing scaffolds are gaining popularity as hydrogen sulfide (H2S) donors through exploitation of the carbonic anhydrase (CA)-mediated hydrolysis of COS to H2S. The majority of compounds in this emerging class of donors undergo triggerable decomposition (often referred to as self-immolation) to release COS, and a handful of different COS-releasing structures have been reported. One benefit of this donation strategy is that numerous caged COS containing core motifs are possible and are poised for development into self immolative COS/H2S donors. Because the intermediate release of COS en route to H2S donation requires CA, it is important that the COS donor motifs do not inhibit CA directly. In this work, we investigate the cytotoxicity and CA inhibition properties of different caged COS donor cores, as well as caged CO2 and CS2 motifs and non-self-immolative control compounds. None of the compounds investigated exhibited significant cytotoxicity or enhanced cell proliferation at concentrations up to 100 MUM in A549 cells, but we identified four core structures that function as CA inhibitors, thus providing a roadmap for the future development of self-immolative COS/H2S donor motifs. PMID- 29132977 TI - Hajj - Beyond traveller's diarrhea. PMID- 29132978 TI - Intensive care in severe malaria: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. AB - Severe malaria is common in tropical countries in Africa, Asia, Oceania and South and Central America. It may also occur in travelers returning from endemic areas. Plasmodium falciparum accounts for most cases, although P vivax is increasingly found to cause severe malaria in Asia. Cerebral malaria is common in children in Africa, manifests as coma and seizures, and has a high morbidity and mortality. In other regions, adults may also develop cerebral malaria but neurological sequelae in survivors are rare. Acute kidney injury, liver dysfunction, thrombocytopenia, disseminated intravascular coagulopathy (DIC) and acute respiratory distress syndrome (ARDS) are also common in severe malaria. Metabolic abnormalities include hypoglycemia, hyponatremia and lactic acidosis. Bacterial infection may coexist in patients presenting with shock or ARDS and this along with a high parasite load has a high mortality. Intravenous artesunate has replaced quinine as the antimalarial agent of choice. Critical care management as per severe sepsis is also applicable to severe malaria. Aggressive fluid boluses may not be appropriate in children. Blood transfusions may be required and treatment of seizures and raised intracranial pressure is important in cerebral malaria in children. Mortality in severe disease ranges from 8 to 30% despite treatment. PMID- 29132979 TI - Hemodynamic effect of bolus versus slower infusion of intravenous crystalloid. PMID- 29132980 TI - Disparities in hemodynamic resuscitation of the obese critically ill septic shock patient. PMID- 29132981 TI - Improvement of in-situ gamma spectrometry methods by Monte-Carlo simulations. AB - Performing in-situ measurements of gamma radiation originating from soil requires adequate detection efficiency curves, which can be obtained by Monte-Carlo simulations. In simulations, soil density of 1.046 g/cm3 was used, with the following elemental composition of soil in which gamma radiation was generated: O - 47%, Si -35%, Al - 8%, Fe - 3.9%, C - 2.1%, Ca - 1.4%, K - 1.3%, N - 0.6%, Mg - 0.6%, N - 0.1%. Soil matrix was represented by cylindrical volume of 1.5 m diameter and 0.5m thickness, while germanium detector was placed at 1 m height above the soil. The simulated gamma spectrum, originated from K-40, as well as from members of Th-232 chain, and daughters of Ra-226, was obtained. Homogeneous distribution of various radionuclides (Ra-226, Th-232, K-40) in soil matrix is considered in this work. Gamma spectra obtained in simulations were analyzed, and together with simulated detection efficiency data they provide comparison with real experimental measurements and practical application of results derived by Monte-Carlo simulations. As a result of this work, the corresponding detection efficiency curve for HPGe detector was obtained, which can be applied for in-situ measurements of radionuclide concentration in soil, assuming uniform radionuclide distribution. In order to validate our simulation results regarding detection efficiency, we performed in-situ measurements of soil radioactivity and compared the obtained activity concentrations with laboratory measurements. We found a good agreement, within activity concentration uncertainty, between in-situ measurement results and average values of activity concentrations obtained by laboratory measurements. PMID- 29132982 TI - Longitudinal Study of Bladder Continence in Patients with Spina Bifida in the National Spina Bifida Patient Registry. AB - PURPOSE: Achieving bladder continence in individuals with spina bifida is a lifetime management goal. We investigated bladder continence status through time and factors associated with this status in patients with spina bifida. MATERIALS AND METHODS: We used National Spina Bifida Patient Registry data collected from 2009 through 2015 and applied generalized estimating equation models to analyze factors associated with bladder continence status. RESULTS: This analysis included 5,250 participants with spina bifida in a large, multi-institutional patient registry who accounted for 12,740 annual clinic visit records during the study period. At last followup mean age was 16.6 years, 22.4% of participants had undergone bladder continence surgery, 92.6% used some form of bladder management and 45.8% reported bladder continence. In a multivariable regression model the likelihood of bladder continence was significantly greater in those who were older, were female, were nonHispanic white, had a nonmyelomeningocele diagnosis, had a lower level of lesion, had a higher mobility level and had private insurance. Continence surgery history and current management were also associated with continence independent of all other factors (adjusted OR and 95% CI 1.9, 1.7 2.1 and 3.8, 3.2-4.6, respectively). The association between bladder management and continence was stronger for those with a myelomeningocele diagnosis (adjusted OR 4.6) than with nonmyelomeningocele (adjusted OR 2.8). CONCLUSIONS: In addition to demographic, social and clinical factors, surgical intervention and bladder management are significantly and independently associated with bladder continence status in individuals with spina bifida. The association between bladder management and continence is stronger in those with myelomeningocele. PMID- 29132983 TI - Relative Supersaturation of 24-Hour Urine and Likelihood of Kidney Stones. AB - PURPOSE: The relative supersaturation of calcium oxalate, calcium phosphate and uric acid is used clinically in kidney stone prevention. The magnitude of the association between relative supersaturation and stone risk requires further quantification. MATERIALS AND METHODS: We performed a cross-sectional study using 24-hour urine collections from the NHS (Nurses' Health Study) I and II, and HPFS (Health Professionals Follow-up Study) cohorts to quantify the association between the relative supersaturation of calcium oxalate, calcium phosphate and uric acid, and the likelihood of stone formation. RESULTS: The OR of being a stone former was 5.85 (95% CI 3.40-10.04) in NHS I, 6.38 (95% CI 3.72-11.0) in NHS II and 6.95 (95% CI 3.56-13.6) in HPFS for the highest category of calcium oxalate relative supersaturation compared with less than 1.0. The OR of being a stone former was 1.86 (95% CI 0.94-3.71) in NHS I, 4.37 (95% CI 2.68-7.10) in NHS II and 3.59 (95% CI 2.04-6.31) in HPFS for the highest category of calcium phosphate relative supersaturation compared with less than 1.0. For uric acid relative supersaturation the OR of being a stone former was 4.30 (95% CI 2.34 7.90) in NHS I and 2.74 (95% CI 1.71-4.40) in NHS II for the highest relative supersaturation category compared with less than 1.0. In HPFS the uric acid relative supersaturation was not significantly associated with the likelihood of stone formation. CONCLUSIONS: The likelihood of being a stone former increases with higher relative supersaturation of calcium oxalate and calcium phosphate in men and women, and with higher relative supersaturation of uric acid in women. PMID- 29132984 TI - Penile Sparing Surgery for Penile Cancer: A Multicenter International Retrospective Cohort. AB - PURPOSE: We evaluated recurrence outcomes of penile sparing surgery in what is to our knowledge the largest multicenter cohort of patients to date. MATERIALS AND METHODS: We retrospectively identified patients treated with penile sparing surgery from May 1990 to July 2016 at 5 tertiary referral institutions. Treatments consisted of circumcision, wide local excision, laser therapy with or without local excision, partial or total glansectomy and glans resurfacing. The study primary end point was local recurrence-free survival, defined from initial treatment to time of local recurrence and estimated with the Kaplan-Meier method. RESULTS: After applying study exclusion criteria 1,188 patients were included in analysis. During the median followup of 43.0 months there were 252 local recurrences (21.2%), of which 99 (39.3%) developed in year 1. Median time to local recurrence was 16.3 months and the 5-year local recurrence-free survival incidence was 73.6%. When stratified by stage, the 5-year local recurrence-free survival rate was 75.0%, 71.4% and 75.9% in Ta/Tis, T1 and T2 cases, respectively (log rank p = 0.748). Of the recurrences 58.3% were treated with repeat organ sparing procedures and the secondary partial (total) penectomy rate was 19.0%. Only margin status was significantly associated with local recurrence on multivariate analysis (p = 0.001). Study limitations included the retrospective design and the heterogeneous clinical approach. CONCLUSIONS: Penile sparing surgery can provide excellent local control for superficial penile tumors as well as for appropriately selected invasive lesions. Strict followup in the early postoperative period is highly recommended. PMID- 29132985 TI - Validation of KDRI/KDPI for the selection of expanded criteria kidney donors. AB - INTRODUCTION: KDRI / KDPI are tools use in kidney donor evaluation. It has been proposed as a substitute of, or complementary to preimplantation renal biopsy. These scores has not been validated in Spain. OBJECTIVE: 1) To investigate the concordance between KDPI and histological scores (preimplantation renal biopsy) and 2) To assess the relationship between KDRI, KDPI and histological score on graft survival in the expanded criteria donors group. METHODOLOGY: Retrospective cohort study from 1 January 1998 until 31 December 2010. RESULTS: During the study 120 donors were recruited, that resulted in 220 preimplantation renal biopsies. 144 (65%) grafts were considered suitable for kidney transplantation. 76 (34.5%) were discarded. Median follow up has been 6.4 years (sd 3.9). Median age 63.1 years (sd 8.2), males (145; 65.9%), non-diabetic (191; 86.8%) and without another cardiovascular risk factors (173; 78.6%). 153 (69.5%) donors died of cerebrovascular disease. There were significant differences in KDRI/KDPI score in both groups 1.56/89 (sd 0.22) vs 1.66/93 (sd 0.15), p<0.01). The KDPI showed moderate concordance and correlation with the histological score (AUC 0.64 / correlation coefficient 0.24, p <0.01). KDPI (HR 24.3, p<0.01) and KDRI (HR 23.3, p<0.01) scores were associated with graft survival in multivariate analysis. CONCLUSION: 1) KPDI and histological scores show moderate concordance. The utility of both scores as combined tools it has to be determined. 2) KDPI score, and especially KDRI score, are valid for estimating graft survival and combined with the biopsy can help to individualized decision making in the expanded criteria donors pool. PMID- 29132986 TI - Acute hepatitis secondary to high-dose intravenous methylprednisolone. PMID- 29132987 TI - Effectiveness of Dextromethorphan/Quinidine in Frontotemporal Dementia. PMID- 29132988 TI - Safety and immunogenicity of a novel multiple antigen pneumococcal vaccine in adults: A Phase 1 randomised clinical trial. AB - BACKGROUND: Pneumococcal vaccines, combining multiple protein antigens, provide an alternative approach to currently marketed vaccines and may provide broader protection against pneumococcal disease. This trial evaluated the safety and immunogenicity of a novel vaccine candidate PnuBioVax in healthy young adults. METHODS: In a Phase 1 double-blind study, 36 subjects (18-40 years) were randomised to receive 3 doses of PnuBioVax, 28 days apart, at one of three dose levels (50, 200, 500 ug) or placebo. Safety assessments included rates of emergent adverse events (AEs), injection site and systemic reactions. Immunogenicity endpoints included antibody titre against PnuBioVax and selected pneumococcal antigens. RESULTS: In the placebo (n=9) and PnuBioVax (n=27) vaccinated subjects, there were 15 and 72, reported TEAEs, respectively. The majority of TEAEs were classified as common vaccine related AEs. There were no serious AEs. Common vaccine-related AEs occurred in 13 PnuBioVax (48%) and 2 placebo (22%) subjects and were all headaches (mild and moderate). Injection site reactions, mostly pain and tenderness (graded mild or moderate) were reported, in particular in the 200 ug and 500 ug PnuBioVax groups. There were no clinically significant changes in vital signs, ECG or blood chemistries. Subjects receiving the higher dose (200 and 500 MUg) demonstrated a greater fold increase in IgG titre compared with the starting dose (50 MUg) or the placebo group. The fold increase was statistically significantly higher for 200 and 500ug PnuBioVax vs 50ug PnuBioVax and placebo at each timepoint post-immunisation. Most subjects receiving 200 and 500 ug PnuBioVax demonstrated a >=2-fold increase in antibody against pneumolysin (Ply), Pneumococcal surface antigen (PsaA), PiaA (Pneumococcal iron acquisition), PspA (Pneumococcal surface protein A) and pilus proteins (RrgB and RrgA). CONCLUSIONS: All dose levels were considered safe and well tolerated. There was a statistically significant increase in anti-PnuBioVax IgG titres at the 200 and 500 ug dose levels compared to 50 ug and placebo. TRIAL REGISTRATION NUMBER: NCT02572635https://www.clinicaltrials.gov. PMID- 29132990 TI - Beneficiary characteristics and vaccinations in the end-stage renal disease Medicare beneficiary population, an analysis of claims data 2006-2015. AB - BACKGROUND: The Advisory Committee on Immunization Practices (ACIP) routinely recommends three vaccines - influenza, hepatitis B, and pneumococcal vaccines - for End-Stage Renal Disease (ESRD) dialysis patients. METHODS: We sought to assess vaccination coverage among fee-for-service (FFS) Medicare beneficiaries with ESRD who received Part B dialysis services at any point from January 1, 2006 through December 31, 2015 (through June 30, 2016 for influenza). To assess influenza vaccination rates in a given influenza season, we restricted the population to beneficiaries who were continuously enrolled in Medicare Parts A and B throughout all twelve months of that season. To assess hepatitis B and pneumococcal vaccine coverage following dialysis initiation, we developed a Kaplan-Meier curve for all patients who began dialysis between 2006 and 2015. RESULTS: For influenza vaccination, we identified an average of approximately 325,000 ESRD dialysis beneficiaries enrolled through each influenza season from 2006-2015. Seasonal influenza vaccination rates steadily increased during the 10 year period, from 52% in 2006-2007 to 71% in 2015-2016. The greatest increases in influenza vaccination appear in non-white beneficiaries with overall utilization in non-whites higher than in whites (p < .001). For the hepatitis B and pneumococcal vaccinations, we identified over 350,000 ESRD dialysis beneficiaries who began dialysis over the 10-year study window. The probability of receiving a hepatitis B vaccine within the first three years of entering into the ESRD program was higher (77%) than the probability of receiving any pneumococcal vaccine (53%). 45% of ESRD patients completed at least one dose of the two hepatitis B series (three-dose or four-dose) at any time during the study period. CONCLUSIONS: Opportunities exist at regional and facility levels to improve vaccination coverage. Compliance to ACIP recommendations may directly affect risk for ESRD dialysis patients for complications from diseases that can be mitigated by vaccination. PMID- 29132989 TI - Differential gene expression elicited by children in response to the 2015-16 live attenuated versus inactivated influenza vaccine. AB - BACKGROUND: In recent influenza seasons, the live attenuated influenza vaccine (LAIV) has not demonstrated the same level of vaccine effectiveness as that observed among children who received the inactivated influenza vaccine (IIV). To better understand this difference, this study compared the mRNA sequencing transcription profile (RNA seq) in children who received either IIV or LAIV. METHODS: Children 3-17years of age receiving quadrivalent influenza vaccine were enrolled. Blood samples were collected on Day 0 prior to vaccination and again on Day 7 (range 6-10days) following vaccination. Total RNA was isolated from PAXgene tubes and sequenced for a custom panel of 89 transcripts using the TruSeq Targeted RNA Expression method. Fold differences in normalized RNA seq counts from Day 0 to Day 7 were calculated, log2 transformed and compared between the two vaccine groups. RESULTS: Of 72 children, 46 received IIV and 26 received LAIV. Following IIV vaccination, 7 genes demonstrated significant differential expression at Day 7 (down-regulated). In contrast, following LAIV vaccination, 8 genes demonstrated significant differential expression at Day 7 (5 up-regulated and 3 down-regulated). Only two genes demonstrated similar patterns of regulation in both groups. CONCLUSIONS: Differential regulation of genes was observed between 2015-16 LAIV and IIV recipients. These results help to elucidate the immune response to influenza vaccines and may be related to the difference in vaccine effectiveness observed in recent years between LAIV and IIV. PMID- 29132991 TI - Attitudes about adult vaccines and reminder/recall in a safety net population. AB - Little is known about adult patients' attitudes toward vaccination and preferences for reminder/recall. The objective of this study was to determine patient perspectives on adult vaccines generally; attitudes about Tdap, pneumococcal polysaccharide (PPSV-23), and seasonal influenza vaccines specifically; and preferences for adult reminder/recall delivery. Twelve focus groups were conducted with 68 patients in a safety net health system. The sample was stratified by preferred language (English or Spanish), age (18-64 or 65+), and health status (with or without chronic conditions). Participants expressed positive attitudes toward vaccines generally, but had little knowledge of specific vaccines other than influenza, about which they expressed concerns. Although none reported previous experience receiving reminder/recall notices for adult vaccines, all were in favor of receiving them. These results suggest potential patient interest in greater adoption of evidence-based methods to improve immunization rates, and highlight the need for improved communication between providers and patients about adult vaccines. PMID- 29132993 TI - Re-evaluating the effect of Favipiravir treatment on rabies virus infection. AB - There is no antiviral treatment available once clinical disease following rabies virus infection has initiated. Considered a neglected tropical disease, >60,000 human rabies deaths are estimated each year despite the availability of pre- and post-exposure prophylaxis for pre-immunisation or administration following a potential exposure before the onset of clinical disease. Such post-exposure treatments include administration of rabies immunoglobulin (RIG) and vaccination at a distant site to prime a humoral immune response. However, current therapeutic options are limited. Regardless there is a need for molecules that target virus infection following the onset of clinical disease where the outcome of infection is invariably fatal. Numerous molecules have been assessed as potential antivirals against rabies virus (RABV) but with little promise. Favipiravir (T-705) is a broad-spectrum RNA polymerase inhibitor, which has been shown to have antiviral activity against a range of RNA viruses including some against RABV. In the present study, the utility of T-705 has been reassessed in vitro as well as in vivo in a murine model using intraperitoneal administration to investigate any immune protective effect of the molecule. In vitro T-705 effectively reduces RABV replication. However, in vivo, following assessment of various applications of the molecule in both pre- and post-exposure scenarios, the effect was limited. T-705 treatment delayed the onset of clinical signs when virus was delivered intramuscularly at a higher dose (106.8 TCID50/ml) and reduced the number of mice that developed clinical signs when virus was delivered at a lower dose (105.8 TCID50/ml) during the observation period. The day at which treatment commenced did not appear to have a statistically significant effect on the results in either experiment. The use of T-705 as a single biological entity may be limited, however, further work is required to assess the synergistic effect of T-705 as a component of a multi-drug therapy for treating human rabies infections. PMID- 29132992 TI - Measuring the timeliness of childhood vaccinations: Using cohort data and routine health records to evaluate quality of immunisation services. AB - BACKGROUND: To achieve full benefits of vaccination programmes, high uptake and timely receipt of vaccinations are required. OBJECTIVES: To examine uptake and timeliness of infant and pre-school booster vaccines using cohort study data linked to health records. METHODS: We included 1782 children, born between 2000 and 2001, participating in the Millennium Cohort Study and resident in Wales, whose parents gave consent for linkage to National Community Child Health Database records at the age seven year contact. We examined age at receipt, timeliness of vaccination (early, on-time, delayed, or never), and intervals between vaccine doses, based on the recommended schedule for children at that time, of the following vaccines: primary (diphtheria, tetanus, pertussis (DTP), polio, Meningococcal C (Men C), Haemophilus influenzae type b (Hib)); first dose of measles, mumps and rubella (MMR); and pre-school childhood vaccinations (DTP, polio, MMR). We compared parental report with child health recorded MMR vaccination status at age three years. RESULTS: While 94% of children received the first dose of primary vaccines early or on time, this was lower for subsequent doses (82%, 65% and 88% for second and third doses and pre-school booster respectively). Median intervals between doses exceeded the recommended schedule for all but the first dose with marked variation between children. There was high concordance (97%) between parental reported and child health recorded MMR status. CONCLUSIONS: Routine immunisation records provide useful information on timely receipt of vaccines and can be used to assess the quality of childhood vaccination programmes. Parental report of MMR vaccine status is reliable. PMID- 29132994 TI - Countries' interest in a hepatitis B vaccine licensed for the controlled temperature chain; survey results from African and Western Pacific regions. AB - Chronic hepatitis B infection can be prevented by hepatitis B vaccine birth dose (hepB-BD) given within 24 h after birth, followed by two hepatitis B vaccinations within the first year of life. Yet nearly half of World Health Organization (WHO) Member States do not provide a hepB-BD. Barriers are primarily attributed to vaccine storage and transportation, as well as high rates of home births. Delivering the vaccine outside the cold chain could potentially increase coverage. To do this, WHO recommends vaccines be licensed for use in a "controlled temperature chain" (CTC), which requires a given product to tolerate temperature excursions up to at least 40 degrees C for a minimum of three days. To date, no hepB vaccine is labelled for CTC. To inform dialogue with manufacturers, WHO conducted a survey among countries in the African and Western Pacific Regions (AFR and WPR) to assess demand for a hepatitis B product licensed for use in a CTC. Twenty-five (44%) countries responded, with 8 of 11 (73%) from the WPR and 17 of 46 (37%) from the AFR. Of these responding countries, 5 in AFR and all 8 in WPR have introduced universal hepB-BD. Seventy-two percent indicated that CTC would facilitate the provision of hepB-BD. While no overall difference in responses was detected between countries either providing or not providing hepB-BD, countries that already introduced hepB-BD but had low hepB-BD coverage were particularly interested in CTC. Irrespective of hepB-BD policy, responding countries suggested that a CTC-licenced product would be beneficial, though the price of such a vaccine would influence procurement decisions. This survey was beneficial to inform the CTC agenda. However, countries' lack of experience with HepB-BD as well as with CTC and the fact that countries were commenting on a product that is not yet on the market should be acknowledged. PMID- 29132996 TI - Q-Vax Q fever vaccine failures, Victoria, Australia 1994-2013. AB - Q-Vax(r), a whole cell formalin inactivated vaccine, is currently the only licensed Q fever vaccine for humans world-wide. Efficacy is high, although vaccine failures have been described for those vaccinated within the incubation of a naturally acquired infection. In Australia, it is widely used to prevent occupational acquisition of Q fever and is the mainstay for outbreak control. A retrospective review of all notified cases of acute Q fever to the Victorian department of health, 1993-2013, revealed 34 of 659 cases were previously vaccinated and 10 cases were positive on pre-vaccination screening, precluding vaccination. Twenty-one cases described high-risk exposures for C. burnetii prior to and within 15 days post vaccination and are likely to have been vaccinated within the incubation period of a natural infection. Thirteen cases described symptom onset more than 15 days post vaccination and thus may represent the first described series of Q-Vax vaccine failures following appropriate vaccination. PMID- 29132995 TI - Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques. AB - Antibodies recognizing conformational epitopes in Pfs48/45, an antigen expressed on the surface of Plasmodium falciparum gametes and zygotes, have firmly established Pfs48/45 as a promising transmission blocking vaccine (TBV) candidate. However, it has been difficult to reproducibly express Pfs48/45 in a variety of recombinant expression systems. The goal of our studies was to evaluate functional immunogenicity of Pfs48/45 using DNA vaccine format in rhesus macaques. An additional goal was to ensure that when used in combination with another malarial antigen, specific immunity to both antigens was not compromised. For testing combination vaccines, we employed Pfs25 DNA plasmids that have previously undergone evaluations in rodents and nonhuman primates. Pfs25 is expressed on the surface of parasites after fertilization and is also a lead TBV candidate. DNA plasmids based on codon-optimized sequences of Pfs48/45 and Pfs25 were administered by in vivo electroporation, followed by a final recombinant protein boost. Our studies demonstrate that Pfs48/45 encoded by DNA plasmids is capable of inducing potent transmission blocking antibody responses, and such transmission blocking immune potency of Pfs48/45 was not compromised when tested in combination with Pfs25, These findings provide the evidence in favor of further studies on Pfs48/45 and Pfs25, either alone or in combination with other known malaria vaccine candidates for developing effective vaccines capable of interrupting malaria transmission. PMID- 29132997 TI - Thyroid hormone improves insulin signaling and reduces the activation of neurodegenerative pathway in the hippocampus of diabetic adult male rats. AB - AIMS: Diabetes mellitus (DM) and impairments of glucose metabolism and insulin resistance in the brain have been suggested as a likely etiology of Alzheimer's disease (AD). Studies have shown that thyroid hormones (THs) improve insulin sensitivity in DM rats and act as mediators of the plasticity of the nervous system altering behavior and cognitive function. Based on these findings, this study aimed to evaluate the effects of diabetes and triiodothyronine (T3) treatment upon proteins associated with DM and AD in the central nervous system. MAIN METHODS: Euglycemic and Diabetic (alloxan-induced) male Wistar rats were daily treated with T3 (1.5MUg/100g body weight) or vehicle (saline) for a 4-week period and subdivided into the following groups: euglycemic treated with saline (Control=C); diabetic treated with saline (Diabetic=D); euglycemic treated with T3 (T3); diabetic treated with T3 (DT3). The expression of insulin signaling, neurodegenerative and neuron survival markers was evaluated in the hippocampus by immunoblotting, ELISA, and RT-PCR. KEY FINDINGS: T3 treatment decreased glycemia, restored the insulin signaling and reduced the activation of glycogen synthase kinase 3 (GSK3) and tau proteins content in the hippocampus of diabetic rats. SIGNIFICANCE: The present data provide evidence that T3 treatment of diabetic rats is able to improve insulin sensitivity and reduce the activation of the neurodegenerative pathway in the brain, which might provide neuroprotection in this experimental model. PMID- 29132998 TI - Waiting for Radiology Test Results: Patient Expectations and Emotional Disutility. AB - PURPOSE: To measure patient willingness to wait and emotional disutility of waiting for outpatient imaging test results. METHODS: A prospective HIPAA compliant multicenter outpatient quality improvement survey was administered by a trained interviewer to 218 outpatients from November 1, 2016, to February 1, 2017. The survey was vetted by patient- and family-centered care advocates with experience in survey design and underwent precognitive testing for readability. Six clinical scenarios were tested. Descriptive statistics were calculated. RESULTS: The response (93% [202 of 218]) and completion (93% [188 of 202]) rates were excellent. Anxiety (28% [57 of 202]), depression (26% [53 of 202]), and cancer (23% [46 of 202]) histories were common. Median stated expectations for imaging test results receipt were 3 days after a screening examination (interquartile range [IQR] 5 days); 2 days after chest x-ray for chest pain (IQR 3) or MRI or CT for back pain (IQR 2); and 1 day after chest x-ray for pneumonia (IQR 2), MRI or CT for brain tumor (IQR 2), or CT for cancer treatment (IQR 3). If imaging results are not received, the median time patients stated they would wait to call their provider was 1 to 5 days (varied by indication). Waiting for imaging results exerts an emotional change in 45% (91 of 202) of individuals, with the majority (85% [77 of 91]) experiencing anxiety (minimal 28%, mild 45%, moderate 22%, severe 4%, extreme 1%). CONCLUSIONS: Patients expect outpatient imaging results within 1 to 3 days and will call providers by 1 to 5 days. Waiting for test results commonly induces anxiety. PMID- 29132999 TI - Radiologists and Social Media: Do Not Forget About Facebook. AB - PURPOSE: Facebook (Facebook, Inc, Menlo Park, California, USA) is the most popular social networking platform worldwide. Facebook groups are virtual communities of people who share a common interest. Breast Imaging Radiologists is a Facebook group for radiologists with an interest in breast imaging. The purpose of this study was to analyze the membership and activity of the Breast Imaging Radiologists Facebook group (BIRFG) for 2 years since its inception. METHODS: Using both the Grytics (www.grytics.com) and Sociograph (www.sociograph.io) analytic engines, the activity of the BIRFG was analyzed retrospectively from its inception on February 11, 2015, through February 12, 2017. Activity data were exported for further qualitative and quantitative analysis using Excel (Microsoft, Redmond, Washington, USA). Member demographic data were obtained by querying public Facebook profiles, US News Doctor Finder (US News & World Report, Washington, DC, USA), Doximity (Doximity, San Francisco, California, USA), and Google (Google Inc, Mountain View, California, USA). RESULTS: Membership grew from 1 to 774 over the study period, and 84% of the members were female. There were 493 posts, 3,253 comments, and 1,732 reactions; 92% of posts received either comments or reactions. Each post received an average of 6.6 comments, and 55% of members were active over the study period. There was an increase in all measures of activity from year 1 to year 2. CONCLUSIONS: Our findings indicate that radiologists find value in using Facebook groups as a forum to network and exchange information about breast imaging. This may be generalizable to other radiology subspecialties. Given the popularity and accessibility of Facebook for personal use, it may prove a more comfortable social medium for radiologists to interact professionally. PMID- 29133000 TI - Effectiveness of a Decision-Making Protocol for the Surgical Treatment of Lumbar Stenosis with Grade 1 Degenerative Spondylolisthesis. AB - BACKGROUND: Addition of fusion to decompression for stenosis with grade 1 degenerative spondylolisthesis is a controversial topic, and the question remains if fusion provides any benefit to the patient that warrants the increased health care utilization and perioperative morbidity. There is no consensus on indications for use of fusion over decompression alone. METHODS: Patients received fusion or decompression according to a decision-making protocol based on their pattern of complaints, location of the compression, and facet angles and effusion as proven predictors of postoperative instability. Propensity score matching of patients was done for baseline data. RESULTS: The study comprised 102 patients in 2 equally sized groups. No intergroup differences in numeric rating scale and Oswestry Disability Index were detected at any follow-up point (all P > 0.05). Duration of surgery, length of stay, estimated blood loss, and radiation doses were higher in the fusion group (all P < 0.001). Cumulative reoperation rate was similar with 6% for fusion and 8% for decompression (P > 0.05), as was the complication rate (8% vs. 6%, P > 0.05). Postoperative iatrogenic progression of spondylolisthesis requiring fusion surgery was seen in only 2% in the decompression group. CONCLUSIONS: Use of a decision-making protocol led to a low rate of iatrogenically increased spondylolisthesis after decompression, while retaining outcomes. These data suggest that a decision-making protocol based on clinical history, location of nerve root compression, and proven radiologic predictors of postoperative instability assigns patients to fusion or decompression in a safe and effective manner. PMID- 29133001 TI - Effects of Low Bone Mineral Status on Biomechanical Characteristics in Idiopathic Scoliotic Spinal Deformity. AB - BACKGROUND: Low bone mass in patients with adolescent idiopathic scoliosis has been well reported. Poor bone quality was regarded as a new and unique prognostic factor in aggravating curve progression. However, the potential biomechanical correlation between them remains unclear. METHODS: Three-dimensional finite element models of idiopathic scoliotic spine with different bone mineral status were created for axial loading simulation. An axial load of 3 different body weights was applied on different bone mineral mass models. The mechanical responses of the vertebral cortical and cancellous bone, facet joints, end plate, and intervertebral disc were analyzed. RESULTS: Accompanied with the low bone mineral status, thoracic scoliosis produced asymmetric and higher stress in the cortical bone, lumbar facet joints, and end plate at the concave side of the thoracic structure curve. Stress increased in the disc at the apex of the scoliosis, whereas it mildly decreased in the L4-5 and L5-S1 disc. Body weight gain increased the stress in scoliotic spine structures in all bone mineral statues. CONCLUSIONS: Biomechanical simulations indicated that low bone mineral mass might aggravate curve progression and induce more serious lumbar compensatory scoliosis in patients with adolescent idiopathic scoliosis. Weight gain was also a risk factor for curve progression. PMID- 29133002 TI - Clinical Characteristics of Lumbosacral Spinal Dural Arteriovenous Fistula (DAVF) Comparison with Thoracic DAVF. AB - OBJECTIVE: Spinal dural arteriovenous fistula (DAVF) occurs at any spinal level, but the clinical characteristics of lumbosacral DAVF have not been well documented. The purpose of this study was to evaluate clinical characteristics of lumbosacral DAVF and compare these features with those in thoracic DAVF. METHODS: Twenty-five consecutive patients with 16 thoracic and 9 lumbosacral DAVFs were included (mean age, 63.9 years; 20 men). All patients presented with progressive myelopathy. Preoperative and postoperative neurologic deficits were compared between thoracic and lumbosacral DAVF groups. Using magnetic resonance imaging, the extent of T2 high-intensity areas and signal flow voids were documented. Follow-up after surgical interventions ranged from 6 to 96 months (mean, 38.1 months). RESULTS: Preoperatively, patients suffering lumbosacral DAVF tended to be more severely disabled compared with thoracic DAVF patients. Lumbosacral DAVF patients exhibited diminished patellar (P = 0.04) and Achilles tendon reflexes (P < 0.01), while most thoracic DAVF patients exhibited hyperreflexia. In magnetic resonance imaging, signal flow voids around the spinal cord were evident in only 4 of 9 lumbosacral DAVF patients (P = 0.012). Rather, a serpentine signal flow void of the filum terminale was a hallmark of lumbosacral DAVFs to distinguish them from thoracic DAVFs. In the lumbosacral DAVF group, postoperative improvements were significantly better in micturition function (P = 0.02). CONCLUSIONS: In lumbosacral DAVF, postoperative micturition function recovery was superior to thoracic DAVF. Intradural lumbar signal flow void is indicative of lumbosacral DAVF. For appropriate management, it is important to recognize these differences between lumbosacral and thoracic DAVF. PMID- 29133003 TI - Atlanto-Occipital Rotatory Dislocation: A Case Report and Systematic Review. AB - BACKGROUND: Atlanto-occipital rotatory dislocation (AORD) has rarely been reported in the literature; for this reason, the clinicoradiologic characteristics of this injury are not well described. METHODS: We describe the case of a 67-year-old man who sustained a cervical spine trauma. He reported only neck pain and was neurologically intact. A computed tomography scan showed a rotatory displacement of the atlanto-occipital joints associated with a widened condylar-C1 interval; in addition, magnetic resonance imaging showed injuries to the stabilizing ligaments of this area. A systematic literature review was also performed to identify previous cases of patients with AORD. RESULTS: The patient was treated with craniocervical fixation from occipital to C1, achieving a good outcome. The literature review yielded 9 cases of patients with AORD. Compared with patients with atlanto-occipital dislocation, patients with rotatory dislocations have a less severe degree of displacement of the atlanto-occipital joints and better clinical outcome. CONCLUSIONS: Compared with previously classified atlanto-occipital dislocations, AORD is an independent and unique variation. AORD presents with different biomechanical, clinicoradiologic, and prognostic characteristics and represents an important addition to the spectrum of atlanto-occipital dislocation injuries. PMID- 29133004 TI - Neuroendoscopic Treatment of Cystic Craniopharyngiomas: A Case Series with Systematic Review of the Literature. AB - BACKGROUND: Total removal of craniopharyngiomas is burdened by high morbidity. In cases of a cystic or mixed craniopharyngioma, when the symptoms are caused by the cystic component of the tumor, a less invasive surgical approach aiming at cyst drainage may be recommended. Here, we report our experience with intraventricular neuroendoscopy, describe our clear-cut surgical technique, and analyze results in the context of literature data. METHODS: We reviewed the clinical data of 8 consecutive adult patients affected by cystic or mixed craniopharyngioma who were treated with intraventricular neuroendoscopy at our institution in the last decade. At surgery, wide opening and emptying of the cyst was performed; a ventricular catheter with adjunctive holes was then placed to maintain a continuous cerebrospinal fluid (CSF) washout. A systematic review of the pertinent literature was performed and a pooled analysis of individual data from selected studies was made. RESULTS: Ten neuroendoscopic procedures were performed. The treatment determined immediate neurologic and radiologic improvement without significant complications in all patients. No chemical meningitis was observed. Recurrence rate was 20%, in line with literature data. Median progression-free survival was 57 months. The systematic review of the literature showed that neuroendoscopy carries a lower recurrence rate than stereotaxy (P = 0.0390). Moreover, the creation of a cyst-CSF communication is a protective factor against recurrences. Finally, adjuvant radiotherapy determined no significant differences in terms of cyst recurrence rate. CONCLUSIONS: We describe a neuroendoscopic treatment of cystic craniopharyngiomas that, without adjuvant radiotherapy, is safe and effective and ensures long-term recurrence free survival. PMID- 29133005 TI - Correlation Between Contrast Time-Density Time on Digital Subtraction Angiography and Flow: An in Vitro Study. AB - BACKGROUND AND PURPOSE: Digital subtraction angiography (DSA) provides an excellent anatomic characterization of cerebral vasculature, but hemodynamic assessment is often qualitative and subjective. Various clinical algorithms have been produced to semiquantify flow from the data obtained from DSA, but few have tested them against reliable flow values. METHODS: An arched flow model was created and injected with contrast material. Seventeen injections were acquired in anterior-posterior and lateral DSA projections, and 4 injections were acquired in oblique projection. Image intensity change over the angiogram cycle of each DSA run was analyzed through a custom MATLAB code. Time-density plots obtained were divided into 3 components (time-density times, TDTs): TDT10%-100% (time needed for contrast material to change image intensity from 10% to 100%), TDT100% 10% (time needed for contrast material to change image intensity from 100% to 10%), and TDT25%-25% (time needed for contrast material to change from 25% image intensity to 25%). Time-density index (TDI) was defined as model cross-sectional area to TDT ratio, and it was measured against different flow rates. RESULTS: TDI10%-100%, TDI100%-10%, and TDI25%-25% all correlated significantly with flow (P < 0.001). TDI10%-100%, TDI100%-10%, and TDI25%-25% showed, respectively, a correlation coefficient of 0.91, 0.91, and 0.97 in the anterior-posterior DSA projections (P < 0.001). In the lateral DSA projection, TDI100%-10% showed a weaker correlation (r = 0.57; P = 0.03). Also in the oblique DSA projection, TDIs correlated significantly with flow. CONCLUSIONS: TDI on DSA correlates significantly with flow. Although in vitro studies might overlook conditions that occur in patients, this method appears to correlate with the flow and could offer a semiquantitative method to evaluate the cerebral blood flow. PMID- 29133006 TI - Anterior Transdiscal Axial Screw Fixation for Subaxial Cervical Spine: A Biomechanical Study. AB - OBJECTIVE: To evaluate stability of anterior transdiscal axial screw (ATAS) fixation for anterior instrumentation and to compare with standard anterior cervical decompression and fusion and plate (ACDFP) fixation in human subaxial cervical spine. METHODS: Flexibility tests were conducted on 7 cadaveric specimens (C5-T1) in an intact and injured state and instrumented with ACDFP fixation, ATAS fixation, and ACDFP plus ATAS fixation at the C6-7 segment after section of the anterior and posterior longitudinal ligaments and discectomy. A pure moment of +/-2.0 N-m was applied to the specimen in flexion-extension, lateral bending, and axial rotation. Range of motion (ROM) and neutral zone were calculated for the C6-7 segment. RESULTS: ROM was reduced significantly compared with the intact or injured condition for 3 configurations under all motions. ATAS fixation resulted in similar ROM in C6-7 compared with ACDFP fixation in flexion (2.7 degrees vs. 2.6 degrees , P = 0.419), extension (2.7 degrees vs. 2.1 degrees , P = 0.152), and lateral bending (4.6 degrees vs. 4.2 degrees , P = 0.295) but larger ROM in axial rotation (6.1 degrees vs. 5.3 degrees , P = 0.014). When combined with an anterior plate, ATAS fixation reduced ROM to 1.2 degrees in flexion, 1.1 degrees in extension, 3.3 degrees in lateral bending, and 3.8 degrees in axial rotation, which were significantly smaller than ACDFP or ATAS fixation alone. CONCLUSIONS: ATAS fixation is a biomechanically effective alternative or supplemental method of anterior fixation in subaxial cervical spine. PMID- 29133007 TI - Comparison of Clinical and Radiographic Outcomes for Posterior Fossa Decompression with and without Duraplasty for Treatment of Pediatric Chiari I Malformation: A Prospective Study. AB - OBJECTIVE: The aim of this study was to prospectively compare the radiographic and clinical outcomes between the posterior fossa decompression (PFD) and PFD with duraplasty (PFDD) procedures in adolescent patients with Chiari malformation type I (CMI). METHODS: Ninety adolescent patients with CMI were randomly assigned to undergo either PFDD or PFD. In both groups, a dissection from the occipital bone was performed. The dura was not opened in the PFD group, and the outer layer of dura was resected. However, in the PFDD group, the dura mater was opened and expanded. Data were analyzed for clinical outcome, complications, and syrinx resolution. RESULTS: The age, gender, and preoperative neurologic status were similar between the 2 groups. Compared with the PFD group, patients undergoing PFDD had significantly longer operation time, longer postoperative drainage time, and higher drainage volume. At the latest follow-up, no statistically significant difference was found between the 2 groups in terms of syrinx resolution. The clinical outcomes were similar in the PFDD and PFD group. Compared with the PFD group, patients in the PFDD group had a higher incidence of cerebrospinal fluid leak. CONCLUSIONS: Compared with the more aggressive decompression with duraplasty, PFD without duraplasty produces comparable radiologic and clinical outcomes and is associated with a lower risk of complications. PMID- 29133008 TI - Biotechnological potential of novel glycoside hydrolase family 70 enzymes synthesizing alpha-glucans from starch and sucrose. AB - Transglucosidases belonging to the glycoside hydrolase (GH) family 70 are promising enzymatic tools for the synthesis of alpha-glucans with defined structures from renewable sucrose and starch substrates. Depending on the GH70 enzyme specificity, alpha-glucans with different structures and physicochemical properties are produced, which have found diverse (potential) commercial applications, e.g. in food, health and as biomaterials. Originally, the GH70 family was established only for glucansucrase enzymes of lactic acid bacteria that catalyze the synthesis of alpha-glucan polymers from sucrose. In recent years, we have identified 3 novel subfamilies of GH70 enzymes (designated GtfB, GtfC and GtfD), inactive on sucrose but converting starch/maltodextrin substrates into novel alpha-glucans. These novel starch-acting enzymes considerably enlarge the panel of alpha-glucans that can be produced. They also represent very interesting evolutionary intermediates between sucrose-acting GH70 glucansucrases and starch-acting GH13 alpha-amylases. Here we provide an overview of the repertoire of GH70 enzymes currently available with focus on these novel starch acting GH70 enzymes and their biotechnological potential. Moreover, we discuss key developments in the understanding of structure-function relationships of GH70 enzymes in the light of available three-dimensional structures, and the protein engineering strategies that were recently applied to expand their natural product specificities. PMID- 29133009 TI - Periconceptional maternal fever, folic acid intake, and the risk for neural tube defects. AB - PURPOSE: Previous studies have shown an association between maternal fever in early pregnancy and neural tube defects (NTDs) such as spina bifida. Periconceptional folic acid intake has been shown to reduce the risk of these outcomes. METHODS: Using data from the Slone Epidemiology Center Birth Defects Study (1998-2015), we examined the impact of folic acid on the relationship between maternal fever in the periconceptional period (28 days before and after the last menstrual period) and NTDs. Logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Mothers of 375 cases and 8247 nonmalformed controls were included. We observed an elevated risk for NTDs for fever in the periconceptional period (OR: 2.4; 95% CI: 1.5-4.0). This association was weaker for mothers who reported consuming the recommended amount of folic acid (>=400 MUg per day; OR: 1.8; 95% CI: 0.8-4.0) than mothers with low folic acid intake (<400 MUg per day; OR: 4.2; 95% CI: 2.2 8.2). CONCLUSIONS: Our data support an association between maternal periconceptional fever and an increased risk for NTDs and also provide evidence that this association was attenuated for mothers who reported consuming folic acid at recommended levels in the periconceptional period. PMID- 29133010 TI - Three fatalities associated with the synthetic cannabinoids 5F-ADB, 5F-PB-22, and AB-CHMINACA. AB - The use of synthetic cannabinoids (SC) has been widespread in certain groups of drug users for many years. In the scientific literature many intoxication cases and a number of fatalities after the use of synthetic cannabinoids were reported. In this paper three death cases are described with involvement of the synthetic cannabinoids 5F-PB-22, AB-CHMINACA, and 5F-ADB. The three cases occurred in the eastern region of Germany, which is known as a region of high methamphetamine abuse. All decedents were male, between 25 and 41 years old, and had a known history of drug use. Femoral blood concentrations of the synthetic cannabinoids were measured using a validated LC-MS/MS method. The concentration of 5F-PB-22 in the first case was 0.37ng/mL, the concentration of AB-CHMINACA in the second case was approximately 4.1ng/mL (extrapolated) and the 5F-ADB concentration in the third case was 0.38ng/mL. Compared to other published cases the concentrations in the here presented cases seem to be in the lower range. However, taking into account the scene of death, the results of the forensic autopsy and the full toxicological analysis, the deaths can be explained as a direct consequence of consumption of synthetic cannabinoids, although in case one and two relevant amounts of ethanol were found, and in case three trimipramine and olanzapine were present in non-toxic concentrations. It has to be noted that concentrations of synthetic cannabinoids in femoral blood cannot directly be judged as toxic or lethal due to the possibility of postmortem redistribution and the development of tolerance after frequent use. Therefore, all available information has to be considered carefully before stating SC use as the cause of death. PMID- 29133011 TI - Aging affects the response of female rats to a hypercaloric diet. AB - Metabolic syndrome is a major risk factor for the development of cardiovascular diseases and diabetes, among other conditions. Studies have shown that aging and metabolic syndrome share several metabolic alterations, and that aged individuals, in particular females, are at an increased risk of developing metabolic disorders. Although several studies have investigated the effects of hypercaloric diets in the development of obesity and metabolic syndrome in young animals, few studies have investigated these parameters in aged animals, especially in females. Therefore, the aim of this study was to investigate the effects of a hypercaloric diet in metabolic parameters of young and aged female rats, including its effects on lipid and glycemic profile and on liver lipid content. When compared to young animals, the aged rats presented increased serum levels of triglycerides and decreased serum levels of HDL cholesterol and glycemia, as well as increased hepatic levels of triglycerides and total cholesterol. The hypercaloric diet increased food intake, body weight gain and adiposity index, leading both young and aged animals to a dyslipidemia, represented by increased serum levels of triglycerides. The hypercaloric diet increased the glycemia and the HOMA index only in the young animals. On the other hand, the diet increased the frequency of hepatocellular microvacuolar degeneration only in the aged animals. In summary, it was observed that the females from different ages respond differently to hypercaloric diet intake: while the aged animals were more resistant to the changes in the glycemic profile, they were more susceptible to the hepatic damage caused by this diet. PMID- 29133012 TI - Tinnitus-related fear: Mediating the effects of a cognitive behavioural specialised tinnitus treatment. AB - OBJECTIVE: Cognitive behavioural treatments (CBT) for the reduction of tinnitus complaints have been shown to be effective; however the specific mechanisms of change are yet to be unveiled. Reductions in tinnitus-related fear have been indicated to be an important factor in alleviating tinnitus suffering. The role of tinnitus-related fear has been proposed as a mediator explaining the cognitive behavioural treatment effects on tinnitus severity, tinnitus-related impairment and general quality of life of tinnitus patients. METHODS: A two-group, single centre RCT was carried out with adult tinnitus patients (n = 492), with 3 follow up assessments up to 12 months after randomization. Patients were randomly assigned to Usual Care (UC) or Specialised cognitive behavioral stepped Care (SC). A repeated-measures design, with group as a between subjects factor, and time as the within-subject factor, was used in an intention-to-treat analysis. Mixed regressions for assessing mediation effects were performed with general health, tinnitus distress, tinnitus related impairment as the dependent variables and tinnitus related fear as the mediator variable. RESULTS: Tinnitus-related fear appears to mediate part of the treatment benefits of specialized CBT for Tinnitus, as compared to usual care, with respect to increased quality of life ratings, and decreased tinnitus severity and tinnitus related impairments. CONCLUSIONS: The effectiveness of specialized cognitive behavioural treatment approaches for tinnitus might be partly explained by significant reductions in tinnitus-related fear. These results are relevant in that currently, though CBT approaches in tinnitus management have been proven to lead to decreased suffering of tinnitus patients, the psychological mechanisms causing these benefits are still to be discovered. PMID- 29133013 TI - The Optimal inter-implant interval in pediatric sequential bilateral implantation. AB - An increasing number of children receive bilateral cochlear implants (CIs) sequentially. Outcomes of bilateral implantation show high variability. This retrospective analysis investigates the optimal inter-implant interval. For this purpose, speech comprehension results of 250 children who underwent sequential bilateral cochlear implantation were evaluated. All individuals underwent periodic speech perception testing in quiet and noise. The most recent unilateral data for each side were statistically analyzed. Speech test outcomes were evaluated with reference to age at first implantation and interval between implantations. A statistically significant difference for speech test performance was obtained between the first-implanted ear and the second-implanted ear for all children (expressed as a mean). These outcomes were dependent on the inter implant interval. There was a significant correlation (r = - 0.497; p = 0.000) between speech test results and the inter-implant interval. Nevertheless, one subgroup of 27 children had the same or better results for the second side as compared with the first. In conclusion, the evaluation of the inter-implant interval and age groups at first implantation showed a preferred interval of up to four years in children under the age of 4 at first implantation. The older the children were at first implantation, the shorter the inter-implant interval had to be. It is as a direct consequence of this interval that children for whom it was longer were also older. PMID- 29133015 TI - Brentuximab vedotin for advanced Hodgkin's lymphoma. PMID- 29133014 TI - Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. AB - BACKGROUND: A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy. METHODS: We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18-60 years) with newly diagnosed, advanced, classical Hodgkin's lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1.8 mg/kg on day 1, etoposide 200 mg/m2 on days 2-4, doxorubicin 35 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, procarbazine 100 mg/m2 on days 2-8, and prednisone 40 mg/m2 on days 2-15) or BrECADD (brentuximab vedotin 1.8 mg/kg on day 1, etoposide 150 mg/m2 on days 2 4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13.2-21.5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204. FINDINGS: Between Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73-94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83-99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77-96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3-4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3-4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1-2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period. INTERPRETATION: Both eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkin's lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity. FUNDING: Takeda Pharmaceuticals. PMID- 29133016 TI - Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing based approaches. AB - MicroRNAs are important components of the post-transcriptional fine-tuning of macrophage gene expression in physiological and pathological conditions. However, the mechanistic underpinnings and the cis-acting genomic factors of how macrophage polarizing signals induce miRNA expression changes are not well characterized. Therefore, we systematically evaluated the transcriptional basis underlying the inflammation-mediated regulation of macrophage microRNome using the combination of different next generation sequencing datasets. We investigated the LPS-induced expression changes at mature miRNA and pri-miRNA levels in mouse macrophages utilizing a small RNA-seq method and publicly available GRO-seq dataset, respectively. Next, we identified an enhancer set associated with LPS responsive pri-miRNAs based on publicly available H3K4 mono-methylation-specific ChIP-seq and GRO-seq datasets. This enhancer set was further characterized by the combination of publicly available ChIP and ATAC-seq datasets. Finally, direct interactions between the miR-155-coding genomic region and its distal regulatory elements were identified using a 3C-seq approach. Our analysis revealed 15 robustly LPS-regulated miRNAs at the transcriptional level. In addition, we found that these miRNA genes are associated with an inflammation-responsive enhancer network. Based on NFkappaB-p65 and JunB transcription factor binding, we showed two distinct enhancer subsets associated with LPS-activated miRNAs that possess distinct epigenetic characteristics and LPS-responsiveness. Finally, our 3C-seq analysis revealed the LPS-induced extensive reorganization of the pri-miR-155 associated functional chromatin domain as well as chromatin loop formation between LPS-responsive enhancers and the promoter region. Our genomic approach successfully combines various genome-wide datasets and allows the identification of the putative regulatory elements controlling miRNA expression in classically activated macrophages. PMID- 29133018 TI - The Pathophysiology of Frailty: Why Sex Is So Important. PMID- 29133017 TI - Rpb5 modulates the RNA polymerase II transition from initiation to elongation by influencing Spt5 association and backtracking. AB - Rpb5 is a subunit shared by the three eukaryotic RNA polymerases although its role in transcription remains unclear. It has been proposed that it makes contact with the promoter DNA and to participate in the coordination of the opening/closing of the RNA polymerase II DNA cleft. Here, we report the specific role of Rpb5 in the function of the yeast RNA polymerase II. The rpb5-P151T mutation specifically impairs transcription elongation by RNA polymerase II but does not influence the functions of RNA polymerases I or III. The comparison of RNA polymerase II ChIP and run-on signals indicates a higher tendency to backtrack by this mutant, in agreement with its lower elongation rate and its genetic interactions with dst1Delta mutant. This phenotype is particularly striking shortly after transcription initiation and is linked to differences in the phosphorylation state of the RNA polymerase II and reduced recruitment of Spt5 to transcribe chromatin, thus influencing its anti-backtracking activity. All together, our results reveal an important role of Rpb5 in the transition from initiation to elongation mediated by the RNA polymerase II, by modulating the Spt5 association, and the backtracking activity of the enzyme. PMID- 29133019 TI - Frequency and significance of qSOFA criteria during adult rapid response team reviews: A prospective cohort study. AB - AIM: A new definition of sepsis released by an international task-force has introduced the concept of quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA). This study aimed to measure the proportion of patients who fulfilled qSOFA criteria during a Rapid Response Team (RRT) review and to assess their associated outcomes. METHODS: We conducted a prospective study of adult RRT reviews over a one month period between 6th June and 10th July 2016 in a large tertiary hospital in Melbourne Australia RESULTS: Over a one-month period, there were 282 RRT reviews, 258 of which were included. One hundred out of 258 (38.8%) RRT review patients fulfilled qSOFA criteria. qSOFA positive patients were more likely to be admitted to the intensive care unit (29% vs 18%, P=0.04), to have repeat RRT reviews (27% vs 13%; p=0.007) and die in hospital (31% vs 10%, P<0.001). qSOFA positive patients with suspected infection were more likely to be admitted to the intensive care unit compared to patients with infection alone (37% vs 15%, P=0.002). Eleven of 42 patients (26%) who had infection and qSOFA died whilst in hospital, compared to 8/55 (15%) of patients with infection alone (P=0.2). CONCLUSION: Adult patients who are qSOFA positive at the time of their RRT review are at increased risk of in-hospital mortality. The assessment of qSOFA may be a useful triage tool during a RRT review. PMID- 29133020 TI - [The fight against smoking. The need to consider behavioral dependence]. AB - The prevalence of smoking in France remains very high compared to other developed Western countries. The management of smoking in smokers is often limited to nicotinic substitution, whether medicated or linked to the use of electronic cigarettes or varenicline and advices more or less reliable or helpful. This strategy of aiding smoking cessation, if isolated, leads to a high number of failures. It is therefore necessary to consider behavioral dependence, in the broad sense in three aspects, "behavioral" (the motor Gestures), cognitive (thoughts) and emotional (emotions). Behaviorists distinguish open (motor) and closed behaviors (cognitions and emotions), the latter two, emotions and cognitions, being quite often related. Practical examples of action in this direction are proposed. PMID- 29133021 TI - [A chest radiography not compatible with life, but...]. PMID- 29133022 TI - Modelling piglet growth and mortality on commercial hog farms using variables describing individual animals, litters, sows and management factors. AB - Increases in sow prolificacy have reduced piglet vitality, growth capacity and weight at weaning and even pig weight at slaughter. The aim of this study was to develop a model that predicts likelihood of mortality and weight at weaning. A database containing 3214 records of birth weight, weight gain at 24h, rectal temperature at 24h, litter size, age at weaning, fostering status, manual assistance of birth and oxytocin use as well as the corresponding 227 records of sow parity and feed intake was analysed using logit functions for mortality and linear functions for weaning weight. The best model of mortality predicted increased likelihood as birth weight, rectal temperature and 0-24h weight gain decreased and sow parity and time between births increased (P<0.01, chi2=2910). The best model of weaning weight predicted increases with increasing birth weight, 0-24h body weight gain, age at weaning and sow parity and decreases with increasing litter size at 24h (P<0.01; AICC=4324; RMSE=0.82). This study confirmed that birth weight and weight gain during the first 24h are the principal factors influencing piglet growth and pre-weaning mortality. PMID- 29133023 TI - In Search of the Right Time and Right Place: Screening Adolescents and Youth for Human Immunodeficiency Virus in the United States. PMID- 29133024 TI - Determination of the knowledge level, attitudes, and behaviors of islamic religious officials toward blood donation. AB - The aim of the present study was to determine knowledge level, attitudes, and behaviors of Islamic religious officials toward blood donation. This study included 334 religious officials rendering service in the province of Kahramanmaras, located in the Mediterranean region of Turkey. A questionnaire was administered to gather sociodemographic data of the participants and their knowledge levels, attitudes, and behaviors toward blood donation. The questionnaire consisted of 11 questions that yielded a total of 11 points. The religious officials in the study included 206 imams (61.7%, males) and 128 Quran course instructors (38.3%, females). Of study participants, 134 (40.1%) reported a previous experience of blood donation and 200 (59.9%) denied previous experience of blood donation. The mean knowledge score was 7.09+/-2.54 points for males and 6.89+/-2.18 points for females. Male and female participants achieved comparable scores (p=0.476). Of the participants, 291 (87.1%) agreed and nine (2.7%) disagreed with the expression, "Blood donation is permissible in Islam;" 34 (10.2%) participants had no idea. The present study revealed considerable deficiencies in knowledge about blood donation among religious officials. In addition, the rate of blood donation and willingness to donate blood were low among religious officials. Although the level of knowledge about blood donation was similar in males and females, it was an interesting finding that the blood donation rate was significantly higher in males than in females. PMID- 29133025 TI - Perivalvular Mitral Abscess Fistulised to the Pericardial Cavity Revealing Staphylococcal Endocarditis. AB - BACKGROUND: Fistula to the pericardial cavity is a very rare complication of perivalvular abscess during infective endocarditis, with Staphylococcus aureus being the most commonly associated microorganism. METHODS: We report a fatal septic shock due to a mitral endocarditis revealed by a myocardial abscess fistulised toward the pericardial cavity. RESULTS: A 66-year-old female without previous valvular disease was admitted to intensive care for severe sepsis. A few hours after admission, an unexpected cardiac arrest occurred. Chest computed tomographic-scan and transoesophageal echocardiography revealed a pericardial effusion due to a perivalvular mitral abscess fistulised toward the pericardial cavity. Despite prompt management including surgical debridement and appropriate antibiotics, death occurred 36hours after intensive care admission. All blood cultures as well as native mitral valve and pericardial fluid grew methicillin sensitive Staphylococcus aureus. CONCLUSIONS: Intensivists should consider this rare complication in patients with staphylococcal infective endocarditis and perivalvular abscess. PMID- 29133026 TI - Levels of adhesion molecules in peripheral blood correlat with stages of diabetic retinopathy and may serve as bio markers for microvascular complications. AB - BACKGROUND: Proliferative diabetic retinopathy is a devastating complication of diabetes mellitus, developing within 15 years in 50% of patients with type 1 diabetes mellitus (DM) and in 10% of patients with type 2 DM. The correlation between levels of inflammatory markers in the peripheral blood and retinopathy staging has not been studied yet, and the purpose of this prospective study was to find a possible association between inflammation and staging of diabetic retinopathy. METHODS: A prospective (pilot) study that measured level of adhesion molecules in the peripheral blood of 10 healthy subjects and 30 patients with type 2 diabetes mellitus. Patients were grouped by the degree of retinopathy: 10 without retinopathy, 10 with non-proliferative retinopathy [NPDR] and 10 with proliferative retinopathy [PDR]. After signing the consent form, an ophthalmologic examination was performed, and 10 mL of blood was drawn. In order to assess adhesion molecules' level serum samples were collected, frozen, and stored at a temperature of -80 degrees C until analysis was performed as one batch. RESULTS: 10 healthy volunteers and 30 patients were enrolled. Healthy volunteers were younger (36.6 +/- 7.9 years) compared to patients (no retinopathy 64.5 +/- 10.8 years, NPDR 71.4 +/- 8.9 years, and PDR 63.3 +/- 11.6 years) (p = .0003 for all groups of patients in comparison with the healthy subjects). VCAM-1 levels were increased by retinopathy staging - starting from 81.86 +/- 3.80 ng/ml (healthy), 105.55 +/- 1.37 ng/ml (no retinopathy), 111.78 +/- 4.14 ng/ml (NPDR), and 123.45 +/- 3.99 ng/ml (PDR), with a significant difference between healthy and patients without retinopathy (p = .03), between no retinopathy and NPDR (p = .001), and between NPDR and PDR (p < .0001). E selectin was increased in correlation with severity of the retinopathy, with a significant difference between groups of patients (p = .03 between healthy subjects and T2DM patients without retinopathy, p = .001 between patients with T2DM no retinopathy and NPDR, p < .0001 between NPDR and PDR). CONCLUSIONS: We found a significant increase in levels of adhesion molecules (VCAM-1) and selectins (E-selectin) in parallel with increased severity of diabetic retinopathy, with a significant difference of inflammatory markers between stages of retinopathy. PMID- 29133027 TI - Nutrient analysis of Kunapa jala and Pancha gavya and their evaluation on germination of Ashwagandha and Kalamegha seeds: A comparative study. AB - BACKGROUND: Vrikshayurveda, an ancient science of plant life described by Surapala, deals with healthy growth and productivity of plants, which has clearly outlined a systematized agricultural practice that insisted the use of Kunapa jala (KJ) and Pancha gavya (PG). OBJECTIVE: An experiment was conducted to validate KJ and PG by nutrient analysis and their effect on the germination parameters of Ashwagandha and Kalamegha seeds in comparison with other treatment groups. MATERIALS AND METHODS: KJ and PG were prepared according to the classical references. The nutrient contents and germination parameters of KJ and PG were compared with other groups namely control (Contr), farmyard manure (FYM), humic acid (HA) and NPK. RESULTS: The pH and EC were 5.793, 2.653 dS/m and 5.584, 2.216 dS/m for KJ and PG respectively. KJ possess highest nutrient contents followed by PG. The germination parameters revealed the better activity of NPK followed by KJ, PG, HA, FYM and Contr. CONCLUSION: KJ and PG were found to be good in nutrient contents and were found to be effective on studied germination parameters of Ashwagandha and Kalamegha seeds. PMID- 29133028 TI - Evolution and postglacial colonization of Seewis hantavirus with Sorex araneus in Finland. AB - Hantaviruses have co-existed with their hosts for millions of years. Seewis virus (SWSV), a soricomorph-borne hantavirus, is widespread in Eurasia, ranging from Central Siberia to Western Europe. To gain insight into the phylogeography and evolutionary history of SWSV in Finland, lung tissue samples of 225 common shrews (Sorex araneus) trapped from different parts of Finland were screened for the presence of SWSV RNA. Forty-two of the samples were positive. Partial small (S), medium (M) and large (L) segments of the virus were sequenced, and analyzed together with all SWSV sequences available in Genbank. The phylogenetic analysis of the partial S-segment sequences suggested that all Finnish SWSV strains shared their most recent common ancestor with the Eastern European strains, while the L segment suggested multiple introductions. The difference between the L- and S segment phylogenies implied that reassortment events play a role in the evolution of SWSV. Of the Finnish strains, variants from Eastern Finland occupied the root position in the phylogeny, and had the highest genetic diversity, supporting the hypothesis that SWSV reached Finland first form the east. During the spread in Finland, the virus has formed three separate lineages, identified here by correlation analysis of genetic versus geographic distance combined with median joining network analysis. These results support the hypothesis that Finnish SWSV recolonized Finland with its host, the common shrew, from east after the last ice age 12,000-8000years ago, and then subsequently spread along emerging land bridges towards west or north with the migration and population expansion of its host. PMID- 29133029 TI - Host genetics and dengue fever. AB - Dengue is a major worldwide problem in tropical and subtropical areas; it is caused by four different viral serotypes, and it can manifest as asymptomatic, mild, or severe. Many factors interact to determine the severity of the disease, including the genetic profile of the infected patient. However, the mechanisms that lead to severe disease and eventually death have not been determined, and a great challenge is the early identification of patients who are more likely to progress to a worse health condition. Studies performed in regions with cyclic outbreaks such as Cuba, Brazil, and Colombia have demonstrated that African ancestry confers protection against severe dengue. Highlighting the host genetics as an important factor in infectious diseases, a large number of association studies between genetic polymorphisms and dengue outcomes have been published in the last two decades. The most widely used approach involves case-control studies with candidate genes, such as the HLA locus and genes for receptors, cytokines, and other immune mediators. Additionally, a Genome-Wide Association Study (GWAS) identified SNPs associated with African ethnicity that had not previously been identified in case-control studies. Despite the increasing number of publications in America, Africa, and Asia, the results are quite controversial, and a meta analysis is needed to assess the consensus among the studies. SNPs in the MICB, TNF, CD209, FcgammaRIIA, TPSAB1, CLEC5A, IL10 and PLCE1 genes are associated with the risk or protection of severe dengue, and the findings have been replicated in different populations. A thorough understanding of the viral, human genetic, and immunological mechanisms of dengue and how they interact is essential for effectively preventing dengue, but also managing and treating patients. PMID- 29133030 TI - 20(S)-protopanaxadiol (PPD) alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of Egr-1, c-Fos and c-Jun in mice. AB - 20(S)-protopanaxadiol (PPD) possesses various biological properties, including anti-inflammatory, antitumor and anti-fatigue properties. Recent studies found that PPD functioned as a neurotrophic agent to ameliorate the sensory deficit caused by glutamate-induced excitotoxicity through its antioxidant effects and exhibited strong antidepressant-like effects in vivo. The objective of the present study was first to investigate the effect of PPD in scopolamine (SCOP) induced memory deficit in mice and the potential mechanisms involved. In this study, mice were pretreated with PPD (20 and 40 MUmol/kg) and donepezil (1.6 mg/kg) intraperitoneally (i.p) for 14 days. Then, open field test was used to assess the effect of PPD on the locomotor activity and mice were daily injected with SCOP (0.75 mg/kg) to induce cognitive deficits and then subjected to behavioral tests by object location recognition (OLR) experiment and Morris water maze (MWM) task. The cholinergic system function, oxidative stress biomarkers and protein expression of Egr-1, c-Fos, and c-Jun in mouse hippocampus were examined. PPD was found to significantly improve the performance of amnesia mice in OLR and MWM tests. PPD regulated cholinergic function by inhibiting SCOP-induced elevation of acetylcholinesterase (AChE) activity, decline of choline acetyltransferase (ChAT) activity and decrease of acetylcholine (Ach) level. PPD suppressed oxidative stress by increasing activities of antioxidant enzymes such as superoxide dismutase (SOD) and lowering maleic diadehyde (MDA) level. Additionally, PPD significantly elevated the expression of Egr-1, c-Fos, and c Jun in hippocampus at protein level. Taken together, all these results suggested that 20(S)-protopanaxadiol (PPD) may be a candidate compound for the prevention against memory loss in some neurodegenerative diseases such as Alzheimer's disease (AD). PMID- 29133031 TI - Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti tumor activity in thioacetamide-induced hepatocellular carcinoma model. AB - Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase 3, BCL-2 and TGF-beta1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect. PMID- 29133032 TI - Measurements of neuronal color tuning: Procedures, pitfalls, and alternatives. AB - Measuring the color tuning of visual neurons is important for understanding the neural basis of vision, but it is challenging because of the inherently three dimensional nature of color. Color tuning cannot be represented by a one dimensional curve, and measuring three-dimensional tuning curves is difficult. One approach to addressing this challenge is to analyze neuronal color tuning data through the lens of mathematical models that make assumptions about the shapes of tuning curves. In this paper, we discuss the linear-nonlinear cascade model as a platform for measuring neuronal color tuning. We compare fitting this model by three techniques: two using response-weighted averaging and one using numerical optimization of likelihood. We highlight the advantages and disadvantages of each technique and emphasize the effects of the stimulus distribution on color tuning measurements. PMID- 29133033 TI - Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant. AB - A series of A-ring-modified lamellarin N analogues were designed, synthesized, and evaluated as potential noncovalent inhibitors of the EGFR T790M/L858R mutant, a causal factor in the drug-resistant non-small cell lung cancer. Several water soluble ammonium- or guanidinium-tethered analogues exhibited good kinase inhibitory activities. The most promising analogue, 14f, displayed an excellent inhibitory profile against the T790M/L858R mutant [IC50 (WT) = 31.8 nM; IC50 (T790M/L858R) = 8.9 nM]. The effects of A-ring-substituents on activity were rationalized by docking studies. PMID- 29133034 TI - CPAP treatment for children with pneumonia in low-resource settings. PMID- 29133035 TI - Design and synthesis of novel thiobarbituric acid derivatives targeting both wild type and BRAF-mutated melanoma cells. AB - A series of novel thio- and seleno-barbituric acid derivatives were synthesized by varying the substituents at N1 and N3 (ethyl, methyl, allyl, and phenyl), and C5 tethered with dienyl and trienyl moieties attached to substituents such as phenyl, 2-furanyl, 2-thiophenyl, 1-naphthyl, and 3-pyridyl. The cytotoxic potential of these derivatives was evaluated by using MTT assay against melanoma cell lines expressing either wild-type (CHL-1) or mutant (UACC 903) BRAF gene. Among all, 2b and 8b were identified as the most potent compounds. Both 2b and 8b inhibited viability of various melanoma cells and induced cell death as evidenced by Live and Dead assay. Western blot analysis showed that they induce PARP cleavage and inhibit anti-apoptotic Bcl-2, Bcl-xL and Survivin in a dose dependent manner within 24 h of the treatment. Novel thiobarbituric acid analogs also inhibited viability of various other solid tumor cell lines, such as pancreatic, breast, and colon. Overall, 2b, 2d, and 8b emerged as the most effective compounds and make good leads for the development of future therapeutic agents. PMID- 29133036 TI - 1,2,4-Thiadiazolidin-3,5-diones as novel hydrogen sulfide donors. AB - Hydrogen sulfide (H2S) is an endogenous modulator that plays significant physio pathological roles in several biological systems. In this research field there is a large interest in developing selective CBS and CSE inhibitors and H2S releasing moieties, that could be either used as therapeutic agents or linked to known drugs. One of the major problem is the limited availability of chemicals that ensure a controlled release of H2S in vitro as well in vivo. Aiming to obtain novel H2S donors, whose release properties could be appropriately modulated, we have synthesized a series of 1,2,4-thiadiazolidine-3,5-diones (THIA 1-10) as innovative donors that could release H2S in controlled manner. All the synthesized compounds were evaluated for their H2S releasing properties by an amperometric approach and for their vasorelaxant ability on aorta rings. In order to rationalize the obtained results, a detailed study on the release mechanism has been performed using the most efficient H2S donor, THIA 3 (Cmax 65.4 MUM and EC50 1.7 MUM). PMID- 29133037 TI - The Novel 4-Phenyl-2-Phenoxyacetamide Thiazoles modulates the tumor hypoxia leading to the crackdown of neoangiogenesis and evoking the cell death. AB - Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8a-ab were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC50 value of ~ 13 MUM. The mechanism of cytotoxicity assessed for anti-tumor studies both in ascites and solid tumor models in-vivo inferred the regressed tumor activity. This is due to changes in the cause of tumor microenvironment with crackdown of neovascularization and evoking apoptosis process as assessed by CAM, corneal vascularization and apoptotic hallmarks in 8f treated cells. The molecular gene studies inferred involvement of HIF-1upregulation and stabilization of p53 which are interlinked in signaling as conferred by immunoblot analysis. PMID- 29133038 TI - New metalo-therapeutics of NSAIDs against human breast cancer cells. AB - The non steroidal anti-inflammatory drugs (NSAID's)-silver(I) metallodrugs of aspirin (aspH), salicylic acid (salH2), naproxen (napH) acid or p-hydrobenzoic acid (pHbzaH) and the mitochondriotropic triphenylarsine (tpAs) with the formulae [Ag(asp)(tpAs)3] (1), [Ag(salH)(tpAs)3] (2), [Ag(nap)(tpAs)3] (3) and {[Ag(pHbza)(tpAs)3]?(dmf)} (4) and [Ag(tpAs)3(NO3)] (5) have been synthesized and characterized by m.p., FT-IR, UV-vis and 1H NMR, spectroscopic techniques and X ray crystallography. The in vitro cytotoxic activity of 1-5 against human breast adenocarcinoma cancer cells: MCF-7 (positive to estrogen receptors (ERs)) and MDA MB-231 (negative to estrogen receptors (ERs)) was evaluated. Compound 4 exhibits the stronger activity against MCF-7 (2.5 +/- 0.1 MUMU), while 1 the strongest one against MDA-MB-231 (3.2 +/- 0.3 MUMU). The IC50 values against normal human fetal lung fibroblast cells lie between 3.0 and 3.7 MUMU. The toxic effect of 1-5 was evaluated against normal human fetal lung fibroblast cells (MRC-5 cells). The IC50 values of 1-5 lie between 2.9 and 3.7 MUMU. The genotoxicity or not of 1-5 against MRC-5 cells was detected from the presence or absence of micronucleus using fluorescence microscopy. The presence of micronucleus in MRC-5 cells (3.0 3.7% in contrast to 1% of the untreated cells) confirms the in vitro toxic behaviour of the compounds. The apoptotic pathway, though the mitochondrion, was confirmed by cell cycle arrest (increasing of the apoptotic cells, in sub-G1 phase (3.5 (5) - 13.3% (4)) in contrast of 1.8% in the control group) and permeabilization of the mitochondrial membrane test (MMP assay). Moreover, the ability of 1-5 to interact with Calf Thymus (CT)-DNA was also studied. Compound 4 exhibits the highest DNA binding constant (Kb= (25.0 +/- 9.7) * 104 M-1). The inhibitory activity of 1-5 against the enzyme lipoxygenase (LOX) is also investigated. The activity order is 1 > 4 > 3 > 2,5. PMID- 29133039 TI - Biological activity of dihydropyrimidinone (DHPM) derivatives: A systematic review. AB - Dihydropyrimidinones are heterocycles with a pyrimidine moiety in the ring nucleus, which, in recent decades, have aroused interest in medicinal chemistry due to alleged versatile biological activity. In this systematic review, we describe the currently published activities of dihydropyrimidinone derivatives. Between 1990 and December 31st, 2016, 115 articles outlined biological activities or toxicity of DHPM derivatives, 12 of those involved in vivo experiments. The main activities associated with this class of compounds are antitumoral (43 articles), anti-inflammatory (12 articles), antibacterial (20 articles) and calcium channel antagonism/inhibition (14 articles). Antitumoral activity is the main biological property evaluated, since the main representative compound of this class (monastrol) is a known Eg5 kinesin inhibitor. This review depicts a variety of other pharmacological activities associated with DHPM derivatives, but the main findings are essentially in vitro characteristics of the substances. This review presents the current state of the art of DHPM biological activities and demonstrates that there is still a need for further in vivo studies to better delineate the pharmacological potential of this class of substances. PMID- 29133040 TI - Synthesis and biological evaluation of novel alkylated polyamine analogues as potential anticancer agents. AB - A new class of polyamine analogues modified by alkylation at the terminal of the polyamine chain has been synthesized and their structures were determined by 1H NMR, 13C NMR, ESI-MS and elemental analysis. As the representative compound, 3f displayed a broad spectrum of anti-cancer effects by MTT assays. Tumor xenograft model and pulmonary metastasis model showed that compound 3f significantly suppressed tumor growth and metastasis in vivo, which was more stronger than the reference drug amonafide. Molecular mechanisms indicated that compound 3f exhibited antiproliferative activities and induced the generation of reactive oxygen species (ROS), which resulted in the occurrence of autophagy. The downregulated expression of MMP-9 and beta-catenin by compound 3f accounted for the inhibition of migration. Taken altogether, the in vitro and in vivo biological evaluations corroborated compound 3f to be an effective anticancer agent. PMID- 29133041 TI - Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains. AB - Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains. Rational modifications of analogues by introduction of hydrophobic substituents on the aromatic ring has led to more than tenfold increase in antibacterial activity against multidrug resistant Gram positive strains. To elucidate a potential mechanism of action for this potentially novel class of antimicrobials, several bacterial enzymes were identified as putative targets according to literature data and pharmacophoric similarity searches for potent ADK analogues. Among the seven bacterial targets chosen, the strongest favorable binding interactions were observed between most active analogue and S. aureus dehydrosqualene synthase and DNA gyrase. Furthermore, the docking results in combination with literature data suggest that these novel molecules could also target several other bacterial enzymes, including prenyl-transferases and methionine aminopeptidase. These results and our statistically significant 3D QSAR model could be used to guide the further design of more potent derivatives as well as in virtual screening for novel antibacterial agents. PMID- 29133042 TI - Synthesis of bis-indolylmethanes as new potential inhibitors of beta glucuronidase and their molecular docking studies. AB - Thirty-two (32) bis-indolylmethane-hydrazone hybrids 1-32 were synthesized and characterized by 1HNMR, 13CNNMR and HREI-MS. All compounds were evaluated in vitro for beta-glucuronidase inhibitory potential. All analogs showed varying degree of beta-glucuronidase inhibitory potential ranging from 0.10 +/- 0.01 to 48.50 +/- 1.10 MUM when compared with the standard drug d-saccharic acid-1,4 lactone (IC50 value 48.30 +/- 1.20 MUM). Derivatives 1-32 showed the highest beta glucuronidase inhibitory potentials which is many folds better than the standard drug d-saccharic acid-1,4-lactone. Further molecular docking study validated the experimental results. It was proposed that bis-indolylmethane may interact with some amino acid residues located within the active site of beta-glucuronidase enzyme. This study has culminated in the identification of a new class of potent beta-glucuronidase inhibitors. PMID- 29133043 TI - 1,4-Naphthoquinones potently inhibiting P2X7 receptor activity. AB - P2X7 receptor (P2X7R) is an ATP-gated ion-channel with potential therapeutic applications. In this study, we prepared and searched a series of 1,4 naphthoquinones derivatives to evaluate their antagonistic effect on both human and murine P2X7 receptors. We explored the structure-activity relationship and binding mode of the most active compounds using a molecular modeling approach. Biological analysis of this series (eight analogues and two compounds) revealed significant in vitro inhibition against both human and murine P2X7R. Further characterization revealed that AN-03 and AN-04 had greater potency than BBG and A740003 in inhibiting dye uptake, IL-1beta release, and carrageenan-induced paw edema in vivo. Moreover, we used electrophysiology and molecular docking analysis for characterizing AN-03 and AN-04 action mechanism. These results suggest 1,4 napthoquinones, mainly AN-04, as potential leads to design new P2X7R blockers and anti-inflammatory drugs. PMID- 29133044 TI - Molecular docking, design, synthesis and antifungal activity study of novel triazole derivatives. AB - The incidence of life-threatening fungal infections has dramatically increased for decades. In order to develop novel antifungal agents, two series of (2R,3R)-1 (1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-substitutied)-2-butanols (3a o, 5a-f, 8a-u), which were analogues of voriconazole, were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS. The MIC80 values showed that the target compounds 3a-o indicated better activities than fluconazole on three important fungal pathogens except for 3i. Significant activity of compounds 3d, 3k, 3n, 3m and 3o was observed on the Aspergillus fumigatus strain (MIC80 range: 1-0.125 MUg/ml). Especially, compound 3k had strong activity to inhibit the growth of ten fungal pathogens. But it didn't exhibit good activity in in vivo value. Molecular docking experiments demonstrated that 3k possessed superior affinity with target enzyme by strong hydrogen bond from morpholine ring. PMID- 29133045 TI - Synthesis, characterization, and antileishmanial activity of neutral N heterocyclic carbenes gold(I) complexes. AB - A series of five new mononuclear neutral gold(I) complexes containing N heterocyclic carbenes (NHCs) was synthesized and fully characterized by spectroscopic methods. The X-ray structures of four complexes are presented. These gold(I) complexes together with four other neutral gold(I)-NHC complexes previously described were evaluated in vitro against Leishmania infantum promastigotes and axenic amastigotes. Moreover, their cytotoxicity was assessed on the murine macrophages J774A.1. Except one complex (10), eight gold(I)-NHC-Cl complexes show potent activity against the pathological relevant form of L. infantum amastigote with IC50 in the low micromolar and submicromolar range and five of them exhibit a SI close to 10. The lead-complex 11 displays a very high and selective activity (IC50 = 190 nM, SI = 40.29) and constitutes the best promising gold(I)-based drug of this series. PMID- 29133046 TI - Design, synthesis and biological evaluation of novel benzimidazole amidines as potent multi-target inhibitors for the treatment of non-small cell lung cancer. AB - A series of novel amidino 2-substituted benzimidazoles linked to 1,4 disubstituted 1,2,3-triazoles were synthesized by implementation of microwave and ultrasound irradiation in click reaction and subsequent condensation of thus obtained 4-(1,2,3-triazol-1-yl)benzaldehyde with o-phenylenediamines. In vitro antiproliferative screening of compounds performed on human cancer cell lines revealed that p-chlorophenyl-substituted 1,2,3-triazolyl N-isopropylamidine 10c and benzyl-substituted 1,2,3-triazolyl imidazoline 11f benzimidazoles had selective and potent cytostatic activities in the low nM range against non-small cell lung cancer cell line A549, which could be attributed to induction of apoptosis and primary necrosis. Additional Western blot analyses showed different mechanisms of cytostatic activity between compounds 10c and 11f that could be associated with the nature of aromatic substituent at 1-(1,2,3-triazolyl) and amidino moiety at C-5 position of benzimidazole ring. Specifically, compound 11f abrogated the activity of several protein kinases including TGM2, CDK9, SK1 and p38 MAPK, whereas compound 10c did not have profound effect on the activities of CDK9 and TGM2, but instead showed moderate downregulation of SK1 activity concomitant with a significant reduction in p38 MAPK. Further in silico structural analysis demonstrated that compound 11f bound slightly better to the ATP binding site of p38 MAPK compared to 10c, which correlated well with observed stronger decrement in the expression level of phospho-p38 MAPK elicited by 11f in comparison with 10c. PMID- 29133047 TI - Discovery of new potent molecular entities able to inhibit mPGES-1. AB - mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE2 production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE2 levels induced by inflammatory stimuli, with neither affecting PGE2 constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE2 related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug-like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities. PMID- 29133048 TI - Structural optimization and structure-activity relationship studies of N-phenyl 7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants. AB - The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4 b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9 tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC50 (half maximal inhibitory concentration) values of 0.010 MUM, 0.015 MUM, and 0.009 MUM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation. PMID- 29133049 TI - Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti cancer activity. AB - Tetrandrine is a dibenzyltetrahydroisoquinoline alkaloid, isolated from traditional Chinese medicinal plant Stephania tetrandra, with anti-tumor activity. Our previous study identified several derivatives of tetrandrine showing better activities than parental compound against human hepatocellular carcinoma cells. To increase diversity and cytotoxic activities of the original compound, a series of novel 14-urea-tetrandrine derivatives were synthesized through structural modification of tetrandrine. These derivaties demonstrated a moderate to strong anti-proliferative activities against human cell lines HEL and K562 (Leukemia), prostate (PC3), breast (MDA-MB-231) and melanoma (WM9). Compound 4g showed strongest cytotoxic effect against PC3 cells with IC50 value of 0.64 MUM, which was 12-fold, 31-fold and 26-fold lower than the parental tetrandrine, 5-fluorouracil and cisplatin, respectively. Preliminary structure-activity relationship study indicated that urea subsititution was the key pharmacophore for the enhancement of their antitumor activities. Induction of apoprosis by 4g was associated with the activation of pro-apoptotic protein BAX and inhibition of antiapoptosis proteins survivin as well as Bcl-2. Moreover, activation of caspases led to increase cleavage of PARP, which further accelerates apoptotic cell death. These results reveal that the compound 4g may be used as a potential anticancer drug candidate. PMID- 29133050 TI - Newly designed organotin(IV) carboxylates with peptide linkage: Synthesis, structural elucidation, physicochemical characterizations and pharmacological investigations. AB - Fourteen new organotin(IV) carboxylate complexes with peptide linkage of (2-(4 methoxy-2-nitrophenylcarbamoyl)benzoic acid) were successfully synthesized and characterized by elemental analyses, FT-IR, NMR (1H, 13C and 119Sn) and single crystal X-ray techniques. FT-IR results of the sodium salt of 2-(4-methoxy-2 nitrophenylcarbamoyl)benzoic acid and complexes showed that the coordination took place via oxygen atoms of the carboxylate group. 1J(119Sn-13C), 2J(119Sn-1H) and theta values calculated from 1H and 13C NMR data using Lockhart's equation reveal a trigonal bipyramidal geometry for triorganotin(IV) derivatives and an octahedral geometry for diorganotin(IV) derivatives. Crystallographic data for three triorganotin(IV) complexes (1-3) showed the tin has distorted trigonal bipyramidal geometry. In vitro anticancer activity against lung carcinoma (H-157) and kidney fibroblast (BHK-21) cell lines as well as antileishmanial activity against the promastigote forms of leishmania major of the synthesized compounds were also studied and the complexes were found biologically active. The in vitro antibacterial activity of most of the synthesized organotin(IV) derivatives against the studied bacterial pathogens is higher than those of the standard 3rd generation antibiotics such as Tetracycline, Penicillin G, Ampicillin, Amoxicillin. This suggest the use of these newly designed organotin(IV) derivatives as potent antibiotics. The synthesized compounds interact with DNA via intercalative mode of interaction. Viscosity measurement results also support the intercalative mode of interaction for the compounds with DNA. PMID- 29133051 TI - Design, synthesis and preliminary biological evaluation of 5,8-dihydropteridine 6,7-diones that induce apoptosis and suppress cell migration. AB - Pteridines are an important class of fused heterocycles found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives were designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum antiproliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest that the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells. PMID- 29133052 TI - Design and synthesis of short amphiphilic cationic peptidomimetics based on biphenyl backbone as antibacterial agents. AB - Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3'-amino-[1,1'-biphenyl]-3 carboxylic acid backbone to mimic the essential properties of natural AMPs. By altering hydrophobicity and charge, we identified the most potent analogue 25g that was active against both Gram-positive Staphylococcus aureus (MIC = 15.6 MUM) and Gram-negative Escherichia coli (MIC = 7.8 MUM) bacteria. Cytoplasmic permeability assay results revealed that 25g acts primarily by depolarization of lipids in cytoplasmic membranes. The active compounds were also investigated for their cytotoxicity to human cells, lysis of lipid bilayers using tethered bilayer lipid membranes (tBLMs) and their activity against established biofilms of S. aureus and E. coli. PMID- 29133053 TI - Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1. AB - To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-gamma-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-gamma-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation. PMID- 29133054 TI - Synthesis, crystal structure and biological evaluation of a new dasatinib copper(II) complex as telomerase inhibitor. AB - A new copper(II) complex of dasatinib (DAS) was synthesized and characterized via ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction analysis, 1H and 13C NMR spectroscopy, and elemental analysis. The composition of the new complex (1) was found to be [Cu(DAS + H)(NO3)2(H2O)]NO3.(H2O).(CH3OH). Through MTT assay, it was found that 1 had high cytotoxicity towards A549, HeLa, BEL-7402, Hep-G2, NCI H460, and MGC80-3 tumor cell lines, with IC50 values in 4.04-13.04 MUM. The Hep G2 cells were the most sensitive to 1. It is worth noting that compared with DAS and cisplatin, 1 not only had higher in vitro anticancer activity but also exhibited greater selective toxicity towards Hep-G2 cells than for normal HL-7702 cells. Experimental results from cell apoptosis analysis, cellular uptake, TRAP silver staining assay, RT-PCR, western blot, and transfection assays showed that 1 was most likely a telomerase inhibitor that targeted c-myc G-quadruplex DNA. The high cytotoxicity and biological behaviors of 1 could be correlated with the central copper(II) atom in the coordinated mode with DAS. PMID- 29133055 TI - Green, unexpected synthesis of bis-coumarin derivatives as potent anti-bacterial and anti-inflammatory agents. AB - A green and efficient protocol has been developed and a series of coumarin based pyrano[3,2-c]chromene derivatives (2) have been synthesized using multi-component reaction (MCR) approach. Unexpected 3-coumarinyl-3-pyrazolylpropanoic acids (3) and C4-C4 chromenes (5) have been isolated instead of expected product 4 by the reaction of compound (2) in formic acid at 90 degrees C for about 4-5 h and at 130 degrees C for about 8-10 h respectively. Further, C4-C4chromenes (5) formation was confirmed by intramolecular cyclization of compounds (3). These compounds were screened for their biological activities and most of them exhibited promising antibacterial activity. The anti-inflammatory assay was evaluated against HRBC membrane stabilization method and the compounds exhibit excellent anti-inflammatory activity. Molecular docking study has been performed for all the synthesized compounds with Klebsiella pneumoni aeacetolactate synthase and results obtained are quite promising. PMID- 29133056 TI - Therapeutic potential of songorine, a diterpenoid alkaloid of the genus Aconitum. AB - Alkaloids are well-studied secondary metabolites, with recent preclinical studies evidencing that many of them exhibit anti-cancer, anti-depressant, anti nociceptive, anti-inflammatory, anti-pyretic, anti-platelet, anti-oxidant, and anti-bacterial properties. Aconitum is a genus rich of diverse alkaloids. More than 450 alkaloids have been identified in a variety of species. Songorine is a C20 diterpenoid alkaloid and 12-keto analog of napelline, isolated from Aconitum soongaricum and was associated with a heterogeneous panel of biological functions. However, the bioactivity profile of this natural product has not been reviewed up to now. The present manuscript aims to summarize the most important biological activities associated with songorine administration in preclinical models. The most significant data found in the scientific literature were evaluated in order to summarize the potential clinical utility of songorine in a diverse spectrum of pathologies and conditions. Songorine and its derivatives have many pharmacological effects including anti-arrhythmic, anti-cardiac fibrillation, excitation of synaptic transmission, anxiolytic effects, anti nociceptive, anti-inflammatory, anti-arthritis effects, and a regenerative effect in a skin excision wound animal model. Despite its outstanding pharmacotherapeutic potential, songorine has never been tested in clinical trials. Therefore, further evaluation is required to better evaluate its clinical utility. PMID- 29133057 TI - Development of 11C-Labeled omega-sulfhydryl fatty acid tracer for myocardial imaging with PET. AB - [11C]-S-methyl-16-thiopalmitic acid (a) was developed with excellent heart-to background uptake ratios and higher retention in heart. Myocardial uptake and metabolism of the tracer is markedly higher CPT I dependent. When compared to [11C]-S-methyl-14-thiomyristic acid (b), [11C]-S-methyl-12-thiododecanoic acid (c) and [11C]-palmitate, a showed an early high uptake and a significantly slower late clearance in heart and a prolonged myocardial elimination half-life (30 min). Analysis of heart tissue and urine samples showed that a was metabolized via beta-oxidation in myocardium. Small animal PET images of the accumulation of a in the rat myocardium were clearly superior to [11C]-palmitate. These initial studies suggest that a could be a potentially useful clinical PET tracer to assess myocardial fatty acid metabolism. PMID- 29133058 TI - Design and synthesis of thienopyrimidine urea derivatives with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7. AB - A series of novel tetrahydrobenzothieno[2,3-d]pyrimidine urea derivatives was synthesized according to fragment-based design strategy. They were evaluated for their anticancer activity against MCF-7 cell line. Three compounds 9c, 9d and 11b showed 1.5-1.03 folds more potent anticancer activity than doxorubicin. In this study, a promising multi-sited enzyme small molecule inhibitor 9c, which showed the most potent anti-proliferative activity, was identified. The anti proliferative activity of this compound appears to correlate well with its ability to inhibit topoisomerase II (IC50 = 9.29 MUM). Moreover, compound 9c showed excellent VEGFR-2 inhibitory activity, at the sub-micromolar level with IC50 value 0.2 MUM, which is 2.1 folds more potent than sorafenib. Moreover, activation of damage response pathway of the DNA leads to cell cycle arrest at G2/M phase, accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining, indicating that cell death proceeds through an apoptotic mechanism. Compound 9c showed potent pro-apoptotic effect through induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was confirmed by a significant increase in the expression of the tumor suppressor gene p53, elevation in Bax/BCL-2 ratio and a significant increase in the level of active caspase-3. Quantitative structure-activity relationship (QSAR) studies delivered equations of five 3D descriptors with R2 = 0.814. This QSAR model provides an effective technique for understanding the observed antitumor properties and thus could be adopted for developing effective lead structures. PMID- 29133059 TI - Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma. AB - The products of 5-lipoxygenase are synthesized and released in the airway when an asthmatic reaction occurs. 5-lipoxygenase via arachidonic acid metabolism produces leukotrienes that mediate bronchoconstriction and inflammatory modifications essential in the pathophysiology of asthma. Until to now, only one approved 5-LO inhibitor, zileuton, can be found as a potential therapy for asthma. With the increasing number of indications for anti-leukotriene (anti-LT) drugs, the development of 5-LO inhibitor agents becomes increasingly important. The present MiniReview reports an update on 5-LO inhibitors currently under clinical investigation. In addition, the latest advances focused on the development of new 5-lipoxygenase inhibitors as asthma anti-inflammatory agents are also discussed. PMID- 29133060 TI - Recent advances in the discovery of potent and selective HDAC6 inhibitors. AB - Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including alpha-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized. PMID- 29133061 TI - Design, synthesis and cytotoxic activity of N-Modified oleanolic saponins bearing A glucosamine. AB - A series of N-acyl, N-alkoxycarbonyl, and N-alkylcarbamoyl derivatives of 2' deoxy-glucosyl bearing oleanolic saponins were synthesized and evaluated against HL-60, PC-3, and HT29 tumor cancer cells. The SAR studies revealed that the activity increased in order of conjugation of 2' -amino group with carbamate > amide > urea derivatives. Lengthening the alkyl chain increased the cytotoxicity, the peak activity was found to around heptyl to nonyl substitutions. 2'-N heptoxycarbonyl derivative 56 was found to be the most cytotoxic (IC50 = 0.76 MUM) against HL-60 cells. Due to the interesting SARs of alkyl substitutions, we hypothesized that their location in the cell was different, and pursued a location study using 2'-(4"-pentynoylamino) 2'-deoxy-glucosyl OA, which suggested that these compounds distributed mainly in the cytosol. PMID- 29133062 TI - Anatomical and physiological basis of continuous spike-wave of sleep syndrome after early thalamic lesions. AB - OBJECTIVE: Early neonatal thalamic lesions account for about 14% of continuous spike-wave of sleep (CSWS) syndrome, representing the most common etiology in this epileptic encephalopathy in children, and promise useful insights into the pathophysiology of the disease. METHODS: We describe nine patients with unilateral neonatal thalamic lesions which progressed to CSWS. Longitudinal whole night and high-density electroencephalograms (EEGs) were performed, as well as detailed imaging and clinical evaluation. Visual evoked potentials were used to probe cortical excitability. RESULTS: Thalamic volume loss ranged from 19% to 94%, predominantly on medial and dorsal nuclei and sparing the ventral thalamus. Lesions produced white matter loss and ventricle enlargement on the same hemisphere, which in four patients was associated with selective loss of thalamic cortical fibers. Cortical thickness quantification failed to reveal hemispheric asymmetries. Impact on EEG rhythms was mild, with a volume-loss-related decrease in alpha power and preservation of sleep spindles. The sleep continuous spiking was lateralized to the hemisphere with the lesion. Visual cortex stimulation in five patients with posterior cortex spiking revealed an abnormal frequency dependent excitability at 10-20Hz on the side of the lesion. SIGNIFICANCE: Unilateral selective thalamic-cortical disconnection is a common feature in our patients and is associated with both a focal pattern of CSWS and a pathological type of frequency-dependent excitability (peak: 10-20Hz). We propose that this excitability represents an abnormal synaptic plasticity previously described as the augmenting response. This synaptic plasticity has been described as absent in the corticocortical interactions in healthy experimental animals, emerging after ablation of the thalamus and producing a frequency-dependent potentiation with a peak at 10-20Hz. Because this response is potentiated by sleep states of reduced brainstem activation and by appropriate stimulating rhythms, such as sleep spindles, the simultaneous occurrence of these two factors in nonrapid-eye movement sleep is proposed as an explanation for CSWS in our patients. PMID- 29133063 TI - Octopamine enhances the immune responses of freshwater giant prawn, Macrobrachium rosenbergii, via octopamine receptors. AB - Octopamine (OA) is known to play an important role in regulating insect immune responses. In Macrobrachium rosenbergii (18.0 +/- 1.7 g), OA at 25.0 and 250.0 pmol/prawn significantly increased THC, semigranular cells (SGCs) and PO activity in hemocytes per 50 MUL hemolymph, hyaline cells, granular cells (GCs) and RBs in hemocytes per 10 MUL hemolymph, and RBs per hemocyte, and however, significantly decreased PO activity per granulocyte (GC + SGC), which returned to control levels after 4 h of injection. The significantly increased phagocytic activity and clearance efficiency of prawn received OA for 8 h returned to control levels after 16 h of injection. In addition, the significantly increased glucose and decreased lactate were observed within 1 h of OA injection. In the susceptibility test, prawn received OA at 25.0 or 250.0 pmol/prawn for 2 h then challenged with Lactococcus garvieae at 105 colony-forming units/prawn significantly increased the resistance of prawns by 23.3% and 30.0%, respectively, compared to the saline challenged control after 144 h of challenge. In addition, the changes on immunocompetence induced by OA were observed to be blocked by adrenoceptors antagonists. These results suggest that OA administration at 250.0 pmol/prawn or less causes the mediate a transient up-regulation in immune and physiologic responses to promote the resistance of M. rosenbergii to L. garvieae, which are thought to be mediated by alpha- and beta-adrenergic-like octopamine receptors. PMID- 29133064 TI - Evaluation of Abortion Stigma in the Workforce: Development of the Revised Abortion Providers Stigma Scale. AB - OBJECTIVES: We report on the development of a scale measuring abortion providers' experiences of stigma. STUDY DESIGN: Using previous measures, qualitative data, and expert review, we created a 49-item question pool. We administered questions to 315 abortion providers before participation in the Providers Share Workshop. We explored the factor structure and item quality using exploratory factor analysis. We assessed reliability using Cronbach's alpha. To test construct validity, we calculated Pearson's correlation coefficients between the stigma scales, the Maslach Burnout Inventory, and the K10 measure of psychological distress. We used Stata SE/12.0 for analyses. RESULTS: Factor analysis revealed a 35-item, five-factor model: worries about disclosure, internalized states, social judgment, social isolation, and discrimination (Cronbach's alphas 0.79-0.94). Our stigma measure was correlated with psychological distress (r = 0.40; p < .001), and with Maslach Burnout Inventory's emotional exhaustion (r = 0.27; p < .001), and depersonalization (0.23; p < .001) subscales, and was inversely correlated with Maslach Burnout Inventory's personal accomplishment subscale (r = -0.15; p < .05). CONCLUSIONS: Psychometric analysis of this scale reveals that it is a reliable and valid tool for measuring stigma in abortion providers, and may be helpful in evaluating stigma reduction programs. PMID- 29133065 TI - [Functional tricuspid regurgitation and apical hypertrophic cardiomyopathy. Diagnostic and therapeutic strategy regarding a clinical case]. PMID- 29133066 TI - [QTc interval in the neonatal period in a Mexican population. A pilot study]. AB - INTRODUCTION: QT interval prolongation is associated with ventricular arrhythmias and sudden death syndrome. OBJECTIVE: To determine the value of QTc interval in healthy newborns in a general hospital in Jalisco, Mexico, and their outcome during their first months of life. METHODS: The study included healthy newborns from March to November 2016, in the Hospital General of Occidente in Jalisco, Mexico. A 12-lead electrocardiogram was performed at a speed of 25mm/s during the first 48h of life. The QT interval was measured in lead DII, and the QTc interval was calculated using the Bazett formula. Patients detected with QTc prolongation were assessed monthly with an ECG and echocardiogram. If they persisted with prolonged QTc interval, they were re-evaluated at 6 months with an ECG, 24h Holter, and electrocardiography study on parents and siblings. Those who persisted with prolonged QTc interval were evaluated with an ECG at 9 months. RESULTS: The study included 548 patients. The mean QTc interval at birth was 459 ms; during this period 33 patients has a QTc greated that 470 ms; which were evaluated monthly with a new electrocardiographic study, obtaining a mean QTc interal of 446 ms. At 6 months 16 patients were evaluated, with a mean QTc interval of 434ms. At 9 months, 6 patients were found to have a mean QTc interval of 438ms, and only 4 patients persisted with a prolonged QTc interval. CONCLUSIONS: The QTc interval in our population is prolonged compared to other populations and with a gradual return to normal. PMID- 29133067 TI - [Subacute myocardial perforation related to a pacemaker lead. Case report and literature review]. AB - Myocardial perforation related to cardiac electronic devices leads is a rare, but unfortunate complication, since its clinical implications are potentially lethal. The fluoroscopic outcome of case of subacute right ventricular perforation is presented, together with an analysis based on a literature review. PMID- 29133068 TI - Reply to "Stimulus, response and excitability - What is new?" PMID- 29133069 TI - Relaxin-2 connecting peptide (pro-RLX2) levels in second trimester serum samples to predict preeclampsia. AB - OBJECTIVES: Preeclampsia is a serious complication of pregnancy, threatening fetal and maternal health. The aim of our study is to examine the association between preeclampsia and the connecting peptide of the pregnancy hormone relaxin (pro-RLX2) as a potential new biochemical marker. STUDY DESIGN: This is a nested case/control study derived from the cohort of pregnancies delivering at Women & Infants Hospital. Cases were identified at a clinic or by hospital codes, and individually confirmed by record review. Stored samples were available from 'integrated' Down syndrome screening. Results were expressed as multiples of the median (MoM). MAIN OUTCOME MEASURES: Preeclampsia was classified as early/severe, late/severe, or mild based on professional guidelines. RESULTS: Fifty-one cases were each matched with five control pregnancies. Population distribution parameters were derived for cases and controls. As shown previously, discrimination between cases and controls (applying MoM analysis) was possible for PlGF (0.576, p < .05), inhibin A (1.45, p < .05) and endoglin (1.278, p < .05). No association with preeclampsia was found for pro-RLX2. However, pro-RLX2 correlates with Inhibin A and Endoglin. CONCLUSIONS: Endoglin, Inhibin A and PlGF are highly predictive of preeclampsia. Quantification of pro-RLX2 is not able to predict preeclampsia. Nevertheless, the potential involvement of relaxin 2/pro RLX2 in the pathophysiology of preeclampsia requires further study. PMID- 29133070 TI - Percutaneous Treatment for Native Mitral Regurgitation. AB - Severe mitral regurgitation (MR) confers an adverse prognosis, frequently with debilitating symptoms of heart failure. While open surgical correction has been the standard of care for decades, novel catheter-based technologies have emerged that are highly effective in the treatment of MR. These percutaneous technologies, which include methods for both repair as well as valve replacement, have the potential to address unmet clinical needs in patients with MR, and serve as a viable alternative to surgery. PMID- 29133071 TI - Red blood cell distribution width is associated with mortality in elderly patients with sepsis. AB - INTRODUCTION: RDW is a prognostic biomarker and associated with mortality in cardiovascular disease, stroke and metabolic syndrome. For elderly patients, malnutrition and multiple comorbidities exist, which could affect the discrimination ability of RDW in sepsis. The main purpose of our study was to evaluate the prognostic value of RDW in sepsis among elderly patients. METHODS: This was a retrospective cohort study conducted in emergency department intensive care units (ED-ICU) between April 2015 and November 2015. Elderly patients (>=65years old) who were admitted to the ED-ICU with a diagnosis of severe sepsis and/or septic shock were included. The demographic data, biochemistry data, qSOFA, and APACHE II score were compared between survivors and nonsurvivors. RESULTS: A total of 117 patients was included with mean age 81.5+/-8.3years old. The mean APACHE II score was 21.9+/-7.1. In the multivariate Cox proportional hazards model, RDW level was an independent variable for mortality (hazard ratio: 1.18 [1.03-1.35] for each 1% increase in RDW, p=0.019), after adjusting for CCI, any diagnosed malignancy, and eGFR. The AUC of RDW in predicting mortality was 0.63 (95% confidence interval [CI]: 0.52-0.74, p=0.025). In subgroup analysis, for qSOFA <2, nonsurvivors had higher RDW levels than survivors (17.0+/-3.3 vs. 15.3+/-1.4%, p=0.044). CONCLUSIONS: In our study, RDW was an independent predictor of in-hospital mortality in elderly patients with sepsis. For qSOFA scores <2, higher RDW levels were associated with poor prognosis. RDW could be a potential parameter used alongside the clinical prediction rules. PMID- 29133072 TI - Treatment of pediatric black widow spider envenomation: A national poison center's experience. AB - BACKGROUND: Black widow species (Latrodectus species) envenomation can produce a syndrome characterized by painful muscle rigidity and autonomic disturbances. Symptoms tend to be more severe in young children and adults. We describe black widow spider exposures and treatment in the pediatric age group, and investigate reasons for not using antivenom in severe cases. METHODS: All black widow exposures reported to the Rocky Mountain Poison Center between January 1, 2012, and December 31, 2015, were reviewed. Demographic data were recorded. Patients were divided into 2 groups. Group 1: contact through families from their place of residence, public schools and/or cases where patients were not referred to healthcare facilities. Group 2: patient contact through healthcare facilities. RESULTS: 93 patients were included. Forty (43%) calls were in Group 1 and 53 (57%) in Group 2. Symptoms were evident in all victims; 43 (46.2%) were grade 1, 16 (17.2%) grade 2 and 34 (36.5%) grade 3, but only 14 patients (41.1%) of this group received antivenom. Antivenom use was associated with improvement of symptoms within minutes, and all treated patients were discharged within hours, without an analgesic requirement or any complications. Reasons for not receiving antivenom included: skin test positive (2/20), strong history of asthma or allergies (2/20), physician preference (2/20), non-availability of the antivenom at the health care facility (14/20). CONCLUSION: In our study, most symptomatic black widow envenomations were minor. Relatively few patients received antivenom, but antivenom use was associated with shorter symptom duration among moderate and major outcome groups. PMID- 29133073 TI - Comparing daily shoulder motion and frequency after anatomic and reverse shoulder arthroplasty. AB - BACKGROUND: Both anatomic (TSA) and reverse total shoulder arthroplasty (RTSA) are common interventions for glenohumeral arthrosis, with the goal of relieving pain and restoring mobility. Understanding shoulder arthroplasty motion and frequency is of interest in evaluating effectiveness and in predicting bearing wear for implant development and optimization. The purpose of this study was to measure and compare the total daily shoulder motion of patients after TSA and RTSA. METHODS: Thirty-six human subjects who had undergone shoulder arthroplasty wore a custom instrumented garment that tracked upper extremity motion for the waking hours of 1 day. The 3-dimensional orientation of each humeral sensor was transformed with respect to the torso to calculate total joint motion and frequency, with comparison of TSA to RTSA. In addition, the yearly motion of the shoulder was extrapolated. RESULTS: The majority of shoulder motion occurred below 80 degrees of elevation (P < .001), totaling on average 821 +/- 45 and 783 +/- 27 motions per hour for TSA and RTSA, respectively. Conversely, elevations >80 degrees were significantly less frequent, totaling only 52 +/- 44 (P < .001) and 38 +/- 27 (P < .001) motions per hour for TSA and RTSA, respectively. No significant differences were detected between TSA and RTSA shoulders (P = .22) or their respective contralateral asymptomatic sides (P = .64, P = .62). When extrapolated, it was estimated that each TSA and RTSA shoulder elevated above 60 degrees approximately 1 million and 0.75 million cycles per year, respectively. DISCUSSION: Mean shoulder motions after TSA or RTSA were not significantly different from the contralateral asymptomatic side. In addition, no significant differences were detected in shoulder motion or frequency between TSA and RTSA. PMID- 29133074 TI - Epidemiology of glenohumeral dislocation and subsequent instability in an urban population. AB - BACKGROUND: Glenohumeral dislocation is the most commonly encountered adult joint instability. The epidemiology in the United Kingdom and worldwide is unclear and often limited to young, active groups that are not representative of general populations. Information regarding epidemiology and outcome from a first dislocation is useful for trauma service planning and patient counseling. We calculated the incidence of shoulder instability after a first dislocation in our urban population and investigated predictors of recurrent instability. METHODS: A prospectively collected trauma database was retrospectively examined to identify patients with a first-time dislocation. Demographics, subsequent dislocation, and instability details were collected from electronic patient records. RESULTS: In a 38-month study period, 329 first dislocations occurred in a population of 475,147 with mean follow-up 28.5 months (range, 10-50 months). The overall incidence for first-time dislocations in this population was 21.9 per 100,000 population, of which 7.9% sustained a redislocation and 6.1% had further symptomatic instability. There were 18.8% with associated greater tuberosity fractures, 8.8% sustained a nerve injury, and 2.7% were posterior dislocations. A bimodal distribution was observed for males (peak incidence per 100,000 of 42.1 and 50.9 in 15-24 and >=85 age groups, respectively), and unimodal for females (peak 45.7 in the 65-74 age group). CONCLUSION: We demonstrate a previously unreported burden of dislocation in older age groups and suggest a rate of recurrence lower than previously reported in the United Kingdom. The group aged 15 to 19 years was at the highest risk of recurrent dislocation and instability. Gender was not a significant predictor of instability. PMID- 29133075 TI - Spinal cord self-repair during tail regeneration in Polypedates maculatus and putative role of FGF1 as a neurotrophic factor. AB - Spinal cord injury could be fatal in man and often results in irreversible medical conditions affecting mobility. However, anuran amphibians win over such pathological condition by the virtue of regeneration abilities. The tail of anuran tadpoles therefore allures researchers to study spinal cord injury and self- repair process. In the present study, we inflicted injury to the spinal cord by means of surgical transection of the tail and investigated the self repair activity in the tadpoles of the Indian tree frog Polypedates maculatus. We also demonstrate for the first time by immunofluorescence localization the expression pattern of Fibroblast Growth Factor1 (FGF1) during spinal cord regeneration which has not been documented earlier in anurans. FGF1, bearer of the mitogenic and neurotrophic properties seems to be expressed by progenitor cells that facilitate regeneration. Spinal cord during tail regeneration in P. maculatus attains functional recovery within a span of 2 weeks thus enabling the organism to survive in an aquatic medium till metamorphosis. Moreover, during the course of spinal cord regeneration in the regenerating tail, melanocytes showed an interesting behaviour as these neural crest derivatives were missing near the early regenerates until their reappearance where they were positioned in close proximity with the regenerated spinal cord as in the normal tail. PMID- 29133076 TI - Comparison of the hemodynamic tolerance and the biological parameters of four acetate-free hemodialysis methods. AB - PURPOSE: Acetate in hemodialysis solutions exerts inflammatory, vasodilatatory and cardio-depressive effects. Citrate has been proposed as an optimal substitute. The aim of the present trial was the comparison of the hemodynamic and biological parameters on a group of patients dialysed consecutively with 4 acetate-free haemodialysis techniques. METHODS: In a prospective crossover manner, we measured the hemodynamic and biological effects of four acetate-free hemodialysis methods: he acetate-free biofiltration with variable potassium (AFBK) and three methods with a citrate buffer: onventional hemodialysis (HD), on line hemodiafiltration (HDF) and on-line hemofiltration (HF). Fourteen chronic hemodialysis patients (9 males mean age 72.21+/-11.21 years old) underwent 6 four hour dialysis sessions for 2 weeks on each of the 4 studied techniques. RESULTS: The AFBK technique presented less intradialytic hypotensive episodes (1 in 84 sessions) compared to the other techniques (HD: 29/84, HDF 22/82 and HF: 14/78; P<0.001). The blood pressure after one, two, three hours of dialysis and at the end of the hemodialysis session was significantly higher in the AFBK technique. On AFBK the net ultrafiltration (UF) (P<0.001) and the UF as a percentage of the dry weight (P=0.005) were significantly higher. A significant correlation between the prevalence of hypotensive episodes and the change of serum potassium levels (P=0.002) during the first hour of dialysis was detected. CONCLUSIONS: AFBK is associated with a better intradialytic hemodynamic tolerance and could be an optimal method for frail hypotension-prone hemodialysis patients. PMID- 29133077 TI - [Chronic kidney failure and biotin: A combination inducing unusual results in thyroid and parathyroid investigations, report of 2 cases]. AB - In clinical chemistry, many immunoassays apply biotin and streptavidin in the assay principle. Presence of high levels of biotin in patient samples can produce negative or positive interference depending on the assay format. In this study, we describe 2 clinical cases with chronic kidney failure and with unusual thyroid and parathyroid function test results due to biotin interference. We studied the impact of biotin levels on thyroid stimulating hormone (TSH), free thyroxine (T4L) and parathormone (PTH) results with a pool of sera loaded with several concentrations of biotin. In sandwich assays (TSH and PTH), excess biotin displaces biotinylated antibodies resulting in apparently low concentration of the analyte. With competitive immunoassays (T4L), excess biotin competes with biotinylated analog for the binding sites on streptavidin resulting in low signal and falsely high concentration of the analyte. In conclusion, chronic kidney failure combined to therapeutic biotin is in favour of high levels of biotin which causes seriously misleading results in assays using biotin-streptavidin mechanisms. PMID- 29133079 TI - Baicalein attenuates monocrotaline-induced pulmonary arterial hypertension by inhibiting vascular remodeling in rats. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder characterized by elevated pulmonary arterial pressure (PAP) and right ventricular hypertrophy (RVH) driven by progressive vascular remodeling. Reversing adverse vascular remodeling is an important concept in the treatment of PAH. Endothelial injury, inflammation, and oxidative stress are three main contributors to pulmonary vascular remodeling. Baicalein is a natural flavonoid that has been shown to possess anti-proliferative, anti-inflammatory, anti-oxidative, and cardioprotective properties. We hypothesized that baicalein may prevent the progression of PAH and preserve the right heart function by inhibiting pulmonary arterial remodeling. METHODS: Male Sprague-Dawley rats were distributed randomly into 4 groups: control, monocrotaline (MCT)-exposed, and MCT exposed plus baicalein treated rats (50 and 100 mg/kg/day for 2 weeks). Hemodynamic changes, RVH, and lung morphological features were examined on day 28. Apoptosis was determined by TUNEL staining, and the mRNA levels of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 were detected by qRT-PCR. The changes in oxidative indicators, including malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH Px) were measured using corresponding commercial kits. The levels of Bax, Bcl-2, and cleaved caspase-3, and the activation of mitogen-activated protein kinase (MAPK) and NF-kappaB were assessed by western blotting. RESULTS: MCT induced an increase in hemodynamic parameters and RVH, which were attenuated by baicalein treatment. Baicalein also blocked MCT-induced pulmonary arterial remodeling. The levels of apoptotic (Bax/Bcl-2 ratio and cleaved caspase-3) and inflammatory (IL 6, TNF-alpha, and IL-1beta) biomarkers in lung tissue were lower in baicalein treated groups. Baicalein also decreased MDA level, and increased SOD and GSH-Px activity in rat pulmonary tissue. Furthermore, baicalein inhibited MCT-induced activation of the MAPK and NF-kappaB pathways. CONCLUSION: Baicalein ameliorates MCT-induced PAH by inhibiting pulmonary arterial remodeling at least partially via the MAPK and NF-kappaB pathways in rats. PMID- 29133078 TI - Enteric Delivery of Regenerating Family Member 3 alpha Alters the Intestinal Microbiota and Controls Inflammation in Mice With Colitis. AB - BACKGROUND & AIMS: Paneth cell dysfunction causes deficiencies in intestinal C type lectins and antimicrobial peptides, which leads to dysbiosis of the intestinal microbiota, alters the mucosal barrier, and promotes development of inflammatory bowel diseases. We investigated whether transgenic (TG) expression of the human regenerating family member 3 alpha gene (REG3A) alters the fecal microbiota and affects development of colitis in mice. METHODS: We performed studies with C57BL/6 mice that express human regenerating family member 3 alpha (hREG3A) in hepatocytes, via the albumin gene promoter. In these mice, hREG3A travels via the bile to the intestinal lumen. Some mice were given dextran sodium sulfate (DSS) to induce colitis. Feces were collected from mice and the composition of the microbiota was analyzed by 16S ribosomal RNA sequencing. The fecal microbiome was also analyzed from mice that express only 1 copy of human REG3A transgene but were fed feces from control mice (not expressing hREG3A) as newborns. Mice expressing hREG3A were monitored for DSS-induced colitis after cohousing or feeding feces from control mice. Colitis was induced in another set of control and hREG3A-TG mice by administration of trinitrobenzene sulfonic acid; some mice were given intrarectal injections of the hREG3A protein. Colon tissues were collected from mice and analyzed by histology and immunohistochemistry to detect mucin 2, as well as by 16S ribosomal RNA fluorescence in situ hybridization, transcriptional analyses, and quantitative polymerase chain reaction. We measured levels of reactive oxygen species (ROS) in bacterial cultures and fecal microbiota using 2',7'-dichlorofluorescein diacetate and flow cytometry. RESULTS: The fecal microbiota of mice that express hREG3A had a significant shift in composition, compared with control mice, with enrichment of Clostridiales (Ruminococcaceae, Lachnospiraceae) and depletion of Bacteroidetes (Prevotellaceae); the TG mice developed less-severe colitis following administration of DSS than control mice, associated with preserved gut barrier integrity and reduced bacterial translocation, epithelial inflammation, and oxidative damage. A similar shift in the composition of the fecal microbiota occurred after a few months in TG mice heterozygous for REG3A that harbored a wild-type maternal microbiota at birth; these mice developed less-severe forms of colitis following DSS administration. Cohoused and germ-free mice fed feces from REG3A-TG mice and given DSS developed less-severe forms of colitis and had reduced lipopolysaccharide activation of the toll-like receptor 4 and increased survival times compared with mice not fed feces from REG3A-TG mice. REG3A TG mice developed only mild colonic inflammation after exposure to 2,4,6-trinitrobenzene sulfonic acid, compared with control mice. Control mice given intrarectal hREG3A and exposed to 2,4,6-trinitrobenzene sulfonic acid showed less colon damage and inflammation than mice not given intrarectal hREG3A. Fecal samples from REG3A-TG mice had lower levels of ROS than feces from control mice during DSS administration. Addition of hREG3A to bacterial cultures reduced levels of ROS and increased survival of oxygen-sensitive commensal bacteria (Faecalibacterium prausnitzii and Roseburia intestinalis). CONCLUSIONS: Mice with hepatocytes that express hREG3A, which travels to the intestinal lumen, are less sensitive to colitis than control mice. We found hREG3A to alter the colonic microbiota by decreasing levels of ROS. Fecal microbiota from REG3A-TG mice protect non-TG mice from induction of colitis. These findings indicate a role for reduction of oxidative stress in preserving the gut microbiota and its ability to prevent inflammation. PMID- 29133080 TI - Population pharmacokinetics of nintedanib in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Nintedanib is a potent intracellular inhibitor of tyrosine kinases, including the receptor kinases vascular endothelial growth factor, platelet derived growth factor and fibroblast growth factor. A previous model assessed the population pharmacokinetics of nintedanib and its main metabolite BIBF 1202 in patients with non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). The objective of this analysis was to further characterise the population pharmacokinetics of nintedanib in patients with IPF by including data from the Phase III trials. METHODS: We pooled data from 933 patients with IPF participating in the Phase II TOMORROW trial and the two Phase III INPULSIS trials. Plasma concentrations of nintedanib (n = 3501) were analysed using nonlinear mixed-effects modelling. RESULTS: Pharmacokinetics of nintedanib was described by a one-compartment model with linear elimination, first-order absorption and an absorption lag time. The population estimates of absorption rate, lag time, apparent total clearance and apparent volume of distribution at steady state for a typical IPF patient were 0.0814 h-1, 0.689 h, 994 L/h, and 265 L. The model confirmed age, body weight, smoking and Asian race (with different effect sizes in different Asian subpopulations) as statistically significant covariates influencing nintedanib exposure. Serum lactate dehydrogenase levels were identified as another factor significantly influencing nintedanib plasma concentrations. No individual covariate at extreme values (5th and 95th percentiles of baseline for continuous covariates) resulted in changes in exposure of more than 50% relative to a typical patient. CONCLUSIONS: The developed model provides further details about the pharmacokinetics of nintedanib in patients with IPF and can be used for simulations exploring covariate effects and exposure-response analyses in this patient population. PMID- 29133081 TI - [Medical treatment of endometriosis: Hormonal treatment of pain, impact on evolution and future perspectives]. AB - CONTEXT: Endometriosis is a chronic painful disease, for which hormone therapy is usually offered as a first line option to women not willing to conceive. OBJECTIVES: To analyse and synthesize the literature, from 2006 onwards, on pain control, and disease evolution in oemn using combined hormonal contraceptives, progestins and GnRH analogs. Data on other current and future treatment perspectives is included as well. SOURCES: Medline (Pubmed), the Cochrane Library, and endometriosis treatment recommendations published by European Society of Human Reproduction and Embryology (ESHRE), National Institute for health and Care Excellence (NICE), American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG) and Societe des Obstetriciens et Gynecologues du Canada (SOGC). STUDY SELECTION: Meta-analysis and clinical trials are included. RESULTS: Study quality is heterogeneous in general. Hormone therapy inconstantly allows pain relief and prevention of endometrioma and rectovaginal wall nodules recurrence. Available molecules and routes of administration as well as risk benefit balance are evaluated. Data on future perspectives are limited to date and do not allow use in routine. CONCLUSION: Hormonal treatment of endometriosis relies on combined hormonal contraceptives (using different routes of administration), progestins and particularly the levonorgestrel-releasing IUS, and GnRH analogs as a last option, in combination with an add-back therapy. Promising alternatives are currently under preclinical and clinical evaluation. PMID- 29133082 TI - [Impact of residents arrival on requests for secondary medicalized inter-hospital transfers]. PMID- 29133083 TI - Jejunal diverticulitis. Review and treatment algorithm. AB - Diverticulitis is much less common in the jejunum than in colonic diverticula probably because of diverticulum larger size, better intra-luminal flow and relatively sterile jejunal content. Complications of jejunal diverticulitis are acute intestinal obstruction, diverticular bleeding and mainly perforation with mesenteric abscess, localized or generalized peritonitis. The Multi-detector row computed tomography is now the best diagnostic imaging for small bowel diverticulitis as well as its complications. Magnetic resonance enterography is also quite useful but it is still impractical to resort to such an imaging in an abdominal emergency. Non-surgical treatment is usually sufficient for jejunal diverticulitis without peritonitis but it does not prevent recurrence of diverticulitis. Surgery is mandatory in case of generalized peritonitis or voluminous local abscess complicating small bowel diverticulitis. In case of extensive small bowel diverticulosis, resection should be limited to the intestinal loop with complicated diverticulum (local abscess, peritonitis or bleeding) to avoid short bowel syndrome. Poor prognostic factors are advanced age, associated comorbidities, delayed diagnosis and mainly the time interval between perforation and surgery. PMID- 29133084 TI - MRI for the measurement of liver iron content, and for the diagnosis and follow up of iron overload disorders. AB - MRI is now the reference method for detecting and quantifying hepatic and extrahepatic iron overload, regardless of its cause. The decrease of the hepatic signal is proportional to the amount of iron in the tissues. It is more pronounced with T2*-weighted gradient echo sequences. It increases proportionally with the strength of the magnetic field. Thus a 3-T MRI is be more sensitive and probably more accurate to detect a slight iron overload, as seen in dysmetabolic hepatosiderosis. Conversely, a 1.5-T MRI better estimates a high overload. Quantification can be done with the calculation of T2* (or R2*) or by using the liver to muscle signal intensity ratio (SIR). Today with a single multi-echo gradient-echo sequence, obtained in a unique apnea, the two methods can be used simultaneously. An associated quantification of steatosis is also obtained. This same type of sequence is proposed for quantification of iron in other tissues and in particular for the myocardium. PMID- 29133085 TI - Corrigendum to "One step fabrication of hydrogel microcapsules with hollow core for assembly and cultivation of hepatocyte spheroids" [Acta Biomater. 50 (2017) 428-436]. PMID- 29133086 TI - Role of entanglement concentration in dynamic viscoelasticity and film-forming property of cereal starches. AB - Entanglement concentration (ce, w/v) means the onset of overlap and interpenetration of random-coil chains in a macromolecule solution. The effects of ce on the dynamic viscoelasticity and film-forming property of cereal starches were investigated. The results showed that ce affected significantly the ratio of crystalline to amorphous regions of normal rice starch, waxy rice starch, normal maize starch and wheat starch because the absorbance ratio (1047cm-1/1022cm-1) increased more obviously at concentrations increasing from 0.1% to ce. Storage modulus increased faster than loss modulus with increasing frequency. The presence of lower entanglement density and stronger mobility of the chain segments in normal rice starch due to the highest crossover, whereas the contrary is the case for waxy rice starch. But, no crossover point occurred in four cereal starch dispersions at concentrations =ce. Comparatively, wheat and normal rice starches had good filming properties. PMID- 29133087 TI - Preparation and characterization of a novel biocomposite based on duck feet gelatin as alternative to bovine gelatin. AB - Edible duck feet gelatin (DFG)-based biocomposites with different glycerol (GLY) contents (15%, 25%, and 35% of dried DFG) were prepared. Physicochemical, mechanical, barrier, and heat seal properties of DFG films were characterized and compared as an alternative to bovine gelatin film. Increasing glycerol from 15 to 35% decreased the TS and YM and EB and HS increased, in value of 42.54-7.27 and 1240-157.10MPa and 22.82-50.33% and 42.06-347.15N/m respectively. The water vapor permeability (WVP) and oxygen permeability (OP) of films were increased from 4.78 to 5.6*10-11gm-1Pa-1s-1 and from 3.97 to 33.99cm3mMU/m2 d kPa respectively. GAB model estimations showed monolayer water content of films increased with the increase of plasticizer content. Moisture sorption isotherm modelling exhibited a type II BET classification. Fourier transform infrared (FTIR) spectra showed shifted peak at approximately 1024cm-1, which was related to glycerol. The results show that the properties of DFG film are suitable for use as an alternative material to bovine gelatin film. PMID- 29133088 TI - Fructose-human serum albumin interaction undergoes numerous biophysical and biochemical changes before forming AGEs and aggregates. AB - Fructose is a reducing and highly lipogenic sugar that has unique metabolic effects in the liver. Non-enzymatic fructosylation of proteins generates advanced glycation end products (AGEs). Human serum albumin (HSA) may undergo fructosylation vis-a-vis AGEs formation. High fructose consumption may lead to structurally altered and functionally compromised fructosylated-HSA-AGEs, which can cause damage to hepatocytes resulting in hepatic macro- and microvesicular steatosis. In this study, HSA was incubated with varying concentrations of fructose for 10days and the induced changes were studied. Fructosylated-HSA exhibited hyperchromicity, increased AGE-specific fluorescence, quenching of tryptophan fluorescence and increased melting temperature. Nepsilon [carboxymethyl]-lysine (CML), was detected by liquid chromatography mass spectrometry (LC-MS). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) results showed decreased mobility in fructosylated-HSA. Perturbations in secondary and tertiary structure were revealed by fourier transform-infrared spectroscopy (FT-IR), supported by far- and near-UV circular dichroism (CD). Dynamic light scattering (DLS) and Matrix-Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) mass spectrometry studies suggested increase in molecular mass of fructosylated-HSA. Amyloidogenic aggregates were confirmed from Congo red, Thioflavin T assay and Scanning electron microscope (SEM). These investigations confirmed the structural alterations in fructosylated-HSA and warrants further study to probe the role of fructosylated-HSA-AGEs in hepatopathy vis-a-vis fatty liver diseases. PMID- 29133089 TI - Cellulose gum and copper nanoparticles based hydrogel as antimicrobial agents against urinary tract infection (UTI) pathogens. AB - In the present study, stable copper nanoparticles (CuNPs) were successfully prepared in the hydrogel matrix. The prepared nanocomposite (HCuNPs) was characterized via x-ray diffraction (XRD), electron microscopy (TEM), and energy dispersive (EDX) and x-ray photoelectron spectroscopic (XPS) studies. The wide scan XPS spectra support the presence of C, N and O in neat hydrogel; while, the XPS spectra of HCuNPs demonstrate the presence of Cu along with C, N, and O elements. TEM studies show the formation of spherical shaped CuNPs in the size range from 7 to 12nm. The rheology results reveal that the storage modulus (G') of the HCuNPs was found to be higher than the loss modulus (G"). Additionally, the antibacterial activities and cytotoxic were carried out against urinary tract infection (UTI) microbes and HeLa (cervical) cells respectively. The antibacterial results reveal that HCuNPs composites show higher zone of inhibition against these pathogens then that of corresponding hydrogel matrix. The cytotoxic effects suggest that the prepared nanocomposite could be used as promising candidates for biomedical applications. PMID- 29133090 TI - Characterization of a novel exopolysaccharide produced by Lactobacillus gasseri FR4 and demonstration of its in vitro biological properties. AB - In this study, hetero-exopolysaccharide of Lactobacillus gasseri FR4 isolated from native chicken was produced and purified. The molecular weight of LgEPS was found to be 1.86*105Da. The gas chromatographic analysis revealed that the LgEPS was majorly composed of glucose (65.31%), mannose (16.51%), galactose (8.45%), rhamnose (6.55%) and a small fraction of fucose (3.18%). The functional groups of LgEPS were confirmed by FT-IR analysis. The 1D (1H and 13C) and 2D NMR (COSY and HSQC) analysis showed the presence of 1,6 linked-alpha-d-Glcp, 1,4 linked-alpha-d Galp, 1,3,4 linked-alpha-d-Manp, 1,3 linked-alpha-l-Rhap, 1,4 linked-alpha-l Fucp, 1,4 linked-beta-d-Glcp, and beta-d-Galp-1 residues. SEM and AFM micrographs revealed the fibrous and porous nature of LgEPS. Moreover, LgEPS exhibited in vitro antioxidant, antibacterial and antibiofilm activity against various food borne pathogens, which proved that this LgEPS might be used in food industries as an antioxidant agent, viscosifying agent and antimicrobial agent etc. PMID- 29133091 TI - Synthesis and characterization of cotton fiber-based nanocellulose. AB - Nanocellulose prepared from the natural material has a promising wide range of opportunities to obtain the superior material properties towards various end products. In this research, commercially available natural cotton was treated with aqueous sodium hydroxide solution to eliminate the hemicellulose and lignin, then cellulose was collected. The collected cellulose was subjected to acid hydrolysis using sulfuric acid to obtain nanocellulose. The prepared nanocellulose was further characterized with the aid of Fourier transform infrared spectroscopy, X-ray diffraction and Scanning Electron Microscopy to elucidate the chemical structure, crystallinity and the morphology. PMID- 29133092 TI - Cloning and biochemical characterization of a novel kappa-carrageenase from newly isolated marine bacterium Pedobacter hainanensis NJ-02. AB - Enzymatic preparation of carrageenan oligosaccharides has drawn increasing attention due to its advantages of mild reaction conditions and excellent product specificity. A novel gene (CgkA) encoding a new kappa-carrageenase was cloned, heterogeneously expressed and characterized from a newly isolated marine bacterium Pedobacter hainanensis NJ-02. It consisted of 1539bp and encoded 512 amino acid residues with a molecular weight of 57.12kDa. Multiple alignment analysis indicated that CgkA belongs to glycoside hydrolase (GH) family 16 and was most homologous to kappa-carrageenase of Zobellia sp. M-2 with identity of 50%. The recombinant enzyme showed maximal activity of 3659.72U/mg at 40 degrees C and pH 7.0. Additionally, it could retain more than 80% of its maximal activity after being incubated at pH of 5.0-9.0 below 40 degrees C.K+ and Na+ with a wide range of concentration can activate the enzyme, while other divalent ions such as Cu2+, Zn2+ showed inhibitory effect on the enzyme. The ESI-MS analysis of hydrolysates indicated that the enzyme can endolytically depolymerize the carrageenan into tetrasaccharides and hexasaccharides. The results suggest that it is an endo-type carrageenase and could be a valuable enzyme tool to produce carrageenan oligosaccharides with higher Dps. PMID- 29133093 TI - Purification, molecular properties, structural characterization, and immunomodulatory activities of water soluble polysaccharides from Sargassum angustifolium. AB - Sulfated polysaccharides isolated from Sargassum angustifolium and purified to determine their structural characteristics and biological activities. Crude polysaccharides and fractions (F1 and F2) were chiefly composed of neutral sugars (49.4-68.5%) and sulfates (12.5-23.0%) along with small amounts of uronic acids (1.3-13.6%) and proteins (4.1-4.7%). Polysaccharides were mainly constructed of different levels of fucose (23.9-69.9%) and galactose (22.5-29.8%) sugars. Subfractions with molecular weights ranging from 157.2 to 790.8*103g/mol were identified for isolated polysaccharides. Polysaccharides induced RAW264.7 macrophage cells to release noticeable amounts of nitric oxide and cytokines including IL-1beta, TNF-alpha, IL-6, IL-10 and IL-12 through NF-kappaB and MAPKs signaling pathways. Sulfate esters of fraction F2 were necessary to its bioactivity and they were located on carbons 2, 4 and 6 of the major sugars. Fraction F2 was formed of (1->4)- and (1->3)-linked fucose residues branched at C 2 and C-4 as well as (1->6)-linked galactose residues branched at C-3. PMID- 29133094 TI - The rheological behavior of polysaccharides sequential extracted from Polygonatum cyrtonema Hua. AB - The present study investigated the rheological properties of polysaccharides (HBSS, CHSS, DASS, CASS) sequentially extracted from Polygonatum cyrtonema Hua. The monosaccharide, uronic acid, total carbohydrate, protein content of four polysaccharides were analyzed. The total carbohydrate content of PCHPs (HBSS, CHSS, DASS, and CASS) were 78.39, 71.86, 69.99 and 73.73% respectively, containing Rha, Ara, Man, Gal besides uronic acid and protein. The non-Newtonian fluidic nature of PCHPs was affected by the types of polysaccharides, concentration, temperature, pH, types and concentration of salt ions. Specifically, the apparent viscosity of four PCHPs solutions at 1%(w/w) concentration were shown as CHSS>HBSS>CHSS>CASS with increased concentration and shear thinning phenomenon and decreased system temperature. Subsequently, the apparent viscosity of four PCHPs at pH 10 or pH 4 were lower than that at pH 7. The Na+ increased the apparent viscosity of HBSS at increasing concentrations, while, decreased for remaining fractions with increasing Na+ concentration. Moreover, higher Ca2+ concentration was inversely proportional to apparent viscosity of four PCHPs. The oscillatory rheological properties showed that linear viscoelastic region of PCHPs was 1-4% which resulted into viscoelastic material. HBSS, DASS and CASS at 0.1%(w/w) showed more viscous behavior at low frequency and enhanced elastic property with the increasing oscillation frequency. PMID- 29133095 TI - Carboxymethyl dextran-based hypoxia-responsive nanoparticles for doxorubicin delivery. AB - In an attempt to develop the hypoxia-responsive nanoparticles for cancer therapy, a polymer conjugate, consisting of carboxymethyl dextran (CMD) and black hole quencher 3 (BHQ3), was prepared. The polymer conjugate can self-assemble into nanoparticles (CMD-BHQ3 NPs) under aqueous conditions. The anticancer drug, doxorubicin (DOX), was loaded in CMD-BHQ3 NPs to prepare DOX@CMD-BHQ3 NPs. The CMD-BHQ3 NPs released DOX in a sustained manner under physiological conditions, whereas the release rate of DOX remarkably increased under hypoxic conditions throughout the cleavage of the azo bond in BHQ3. In vitro cytotoxicity study revealed that DOX@CMD-BHQ3 NPs showed higher toxicity under hypoxic conditions than normoxic conditions. Confocal microscopic images indicated oxygen-dependent intracellular release of DOX from DOX@CMD-BHQ3. In vivo biodistribution study demonstrated that CMD-BHQ3 NPs were preferentially accumulated in the tumor after systemic administration into tumor-bearing mice. Overall, CMD-BHQ3 might be a promising carrier for selective drug release in the hypoxic tumor. PMID- 29133096 TI - Modification of structure and physicochemical properties of buckwheat and oat starch by gamma-irradiation. AB - Effects of gamma irradiation on the physicochemical, rheological and thermal properties of the buckwheat and oat starch were studied. Results revealed that the transition temperature and enthalpy of gelatinization of starch decreased with increase in irradiation dose. Pasting properties (peak, trough, setback, pasting temperature and final viscosity) of both the starches were decreased by gamma irradiation. Gamma irradiation also resulted in the reduction in the per cent crystallinity of the starches. Apparent amylose content and swelling index decreased with increase in dose. However, solubility index was increased by gamma irradiation. No surface fissures were seen in irradiated starches. FTIR spectra pattern did not change by gamma irradiation. PMID- 29133097 TI - Biological and textural properties of underutilized exudate gums of Jammu and Kashmir, India. AB - Three different exudate gums were studied for their in-vitro antioxidant activity, functional and textural properties. In-vitro antioxidant activity of the gum exudates was evaluated in terms of DPPH radical scavenging, hydroxyl radical scavenging, reducing power and phenolic content assays. Among the gum exudates, almond gum exhibited maximum DPPH inhibition of 35.52+/-1.125% followed by apricot gum and gum arabic at the concentration of 1mg/mL. Gum arabic had significantly higher reducing power than the other exudate gums. For OH (hydroxyl radical) scavenging assay apricot gum gave the highest scavenging activity (58.31%+/-0.25) compared to other gum exudates at the concentration of 10mg/mL The total phenolic content of the gums followed the order gum arabic>almond gum>apricot gum. All the three exudate gums didn't inhibit the growth of B. subtilis and S. aureus at the concentration of 4mg/mL. Apricot gum was more efficient against Candida albicans, with an inhibition zone of 19.66mm, in comparison to gum arabic and almond gum. Solubility of gum exudates varied significantly (p<0.05) in the range of 23.00+/-3.53-85.75+/-0.35%. Almond gum with the least foaming capacity formed highly stabilized foams when compared to rest of the exudate gums. The antioxidant potential of the gums may appreciate their inclusion in wide variety of food systems as functional additives. PMID- 29133098 TI - Chemical modification of citrus pectin: Structural, physical and rheologial implications. AB - The present study aimed to investigate the physical, structural and rheological modifications caused by the chemical modification process of citrus pectin. Therefore, three commercial citrus pectins with different degree of esterification were chemically modified by sequential alkali and acidic hydrolytic process to produce modified citrus pectins (MCP) with special properties. The molar mass (Mw), degree of esterification (DE), monosaccharide composition, 13C NMR spectra, homogeneity, morphology (SEM) and rheological behavior of both native and modified citrus pectins (MCP) were investigated. The chemical modification reduced the acid uronic content (up to 28.3%) and molar mass (up to 29.98%), however, showed little influence on the degree of esterification of native pectins. Modified citrus pectins presented higher amounts of neutral monosaccharides, mainly galactose, arabinose and rhamnose, typical of the Ramnogalacturonana-I (RG-I) region. Rheological tests indicated that the native and modified citrus pectins presented pseudoplastic behavior, however, the MCP samples were less viscous, compared to the native ones. Modified samples presented better dissolution in water and less strong gels, with good stability during oscillatory shearing at 25 degrees C. This study aims to better understand the implications that chemical modifications may impose on the structure of citrus pectins. PMID- 29133099 TI - Coupled adsorption-photocatalytic degradation of crystal violet under sunlight using chemically synthesized grafted sodium alginate/ZnO/graphene oxide composite. AB - This research aimed to synthesize natural polymer nanocomposite and employ it for coupled adsorption- photocatalytic degradation of crystal violet. Sodium alginate g-poly (acrylic acid-co-cinnamic acid) and its composites with ZnO nanorods and graphene oxide sheets were synthesized and characterized using FT-IR, XRD, SEM, HR-TEM and DR/UV-vis spectroscopy. The adsorption efficiency of samples for crystal violet has been studied in the dark. The effect of different parameters as pH, initial dye concentration, contact time and temperature on the adsorption efficiency of the synthesized sample has been examined. Kinetics studies showed that the adsorption of all samples was well described by the pseudo-second-order model and the equilibrium adsorption results fitted Freundlich model. The maximum adsorption capacity achieved at pH 5.0 was 13.85 mg g-1. Thermodynamic studies exhibited that the adsorption is spontaneous, endothermic in nature and leads to higher entropy. Coupled adsorption-photocatalytic degradation studies under sunlight showed an enhancement in the removal efficiency by 10%. In the case of sodium alginate-g-poly (acrylic acid-co-cinnamic acid)/ZnO/graphene oxide composite, the removal efficiency after 5 h under sunlight was 94% versus 84% in the dark. PMID- 29133100 TI - Physicochemical properties of a high molecular weight levan from Brenneria sp. EniD312. AB - A high molecular weight levan was produced by a novel levansucrase and some properties of this polymer were investigated. The levan exhibited a poroid microstructure as well as series of individual ellipsoidal or spheroidal particles. The weight-average molecular weight (M-w) of the levan was determined to be 1.41*108Da. In a 0.1% solution, the levan showed a mean diameter of 176nm, while in a 1% solution the diameter was 182nm. The decomposition temperature was determined to be 216.67 degrees C, with an endothermic peak at 147.41 degrees C and a melting enthalpy of 76.9J/g. The small angle X-ray diffraction pattern showed a distinctive peak pattern between 15 degrees and 40 degrees (2q). The levan solution showed a shear-thinning behaviour. These results suggest this levan could be a good additive in the food processing industry, as well as an important bio-based material in the medicinal or chemical industry. PMID- 29133101 TI - Antioxidant, antiproliferative, and immunostimulatory effects of cell wall alpha d-mannan fractions from Kluyveromyces marxianus. AB - This study evaluated the antioxidant, antiproliferative, and immunostimulatory properties of cell wall alpha-d-mannan fractions from yeast Kluyveromyces marxianus CCT7735. Filter centrifugation was used to obtain four fractions (KMM 1, KMM-2, KMM-3, and KMM-4) with molecular weight ranging from 7.6 to 75.1kDa. KMM-1 and KMM-2 comprised D-mannose with traces of D-glucose, whereas other fractions contained only D-mannose. Total sugar found in samples ranged from 85.9% to 96.1%, while protein and phenolic contents were 1.21% and 0.41%, respectively. Although only KMM-1 was able to scavenge superoxide radicals, all fractions presented total antioxidant capacity as well as reducing power, hydroxyl-radical scavenging, and copper- and iron-chelating activities. No fraction was cytotoxic to HeLa cells. However, all samples inhibited the proliferation of the tumor cell Hep-G2 and presented minor cytotoxicity against normal 3T3 cells. All fractions showed mitogenic activity in macrophages and all, except KMM-4, induced nitric oxide production in macrophages, suggestive of their immunostimulatory effects. PMID- 29133102 TI - Development of bioactive cellulose nanocrystals derived from dominant cellulose polymorphs I and II from Capsosiphon Fulvescens for biomedical applications. AB - Cellulose I and II polymorphs were isolated from Capsosiphon fulvescens (CF) using the conventional method of extraction and direct mercerization of raw sample, respectively. The morphological and structural differences between the isolated polymorphs were studied by FTIR, FESEM and XRD. Direct mercerization of raw CF yielded the transformation of highly crystalline cellulose I (81.3%) to II (63.7%) as observed in the shifting of XRD patterns. The derived cellulose I and II were hydrolyzed (60% w/w H2SO4, 55 degrees C, 1h, 10mL/g) to obtain the spindle-shaped cellulose nanocrystals. Cellulose nanocrystal I was observed to have a mean thickness and length of 12.67+/-2.69 and 92.31+/-21.31nm, respectively; while cellulose nanocrystal II has a mean thickness and length of 15.58+/-2.85 and 78.09+/-18.22nm, respectively. Furthermore, a fiber-like mat assembly, which could be used as supplement support structure for tissue engineering, was obtained after subjecting the aqueous cellulose nanocrystal suspensions to freeze-drying. A possible application of this material can be as a biocompatible and biodegradable composite for tissue engineering and other biomedical applications. PMID- 29133103 TI - Health-related effects and improving extractability of cereal arabinoxylans. AB - Arabinoxylans (AXs) are major dietary fibers. They are composed of backbone chains of beta-(1-4)-linked xylose residues to which alpha-l-arabinose are linked in the second and/or third carbon positions. Recently, AXs have attracted a great deal of attention because of their biological activities such as their immunomodulatory potential. Extraction of AXs has some difficulties; therefore, various methods have been used to increase the extractability of AXs with varying degrees of success, such as alkaline, enzymatic, mechanical extraction. However, some of these treatments have been reported to be either expensive, such as enzymatic treatments, or produce hazardous wastes and are non-environmentally friendly, such as alkaline treatments. On the other hand, mechanical assisted extraction, especially extrusion cooking, is an innovative pre-treatment that has been used to increase the solubility of AXs. The aim of the current review article is to point out the health-related effects and to discuss the current research on the extraction methods of AXs. PMID- 29133104 TI - Imparting functionality viz color, antioxidant and antibacterial properties to develop multifunctional wool with Tectona grandis leaves extract using reflectance spectroscopy. AB - In recent years, considerable attention has been given to plant colorants for use in dyeing applications because of their newly discovered properties such as insect repellency, deodorizing, antioxidant, sun protection, and antibacterial activity. In view of their better biocompatibility, biodegradability, less toxicity, natural colorants are gaining worldwide interest for producing elegant hues and highly functional value-added textiles. In the present work, we investigated the coloring and functional finishing of wool with Tectona grandis L. leaves extract with the emphasis on effect of metallic salt mordants on colorimetric potential, fastness, radical scavenging potential, and antibacterial activity in an attempt to develop bioactive fibres for use in health care applications. The pretreatment of wool with ferrous sulfate, potassium aluminium sulfate and stannous chloride provided a significant enhancement in CIELa*b* parameters and fastness properties. Antioxidant tests showed that the control dyed wool had excellent radical scavenging activity than mordanted samples. In addition, metal mordants particularly ferrous sulfate enhanced the durability of antibacterial efficacy to several laundering cycles. It can be concluded that the extract of Tectona grandis may be developed as multifunctional finishing agent to impart simultaneous color, antioxidant and antibacterial properties to wool based fabrics. PMID- 29133105 TI - Four cases of spinal epidural angiolipoma. PMID- 29133106 TI - Considerations for general anaesthesia in Parkinson's disease. AB - Parkinson's disease is a common neurodegenerative disorder in the elderly which when present has a significant influence on surgical management. These patients necessitate additional perioperative and anaesthetic considerations across disease specific domains as well as in relation to the respiratory and cardiovascular systems. This brief review focuses on the factors which contribute to perioperative morbidity, including the use of medications that may exacerbate symptoms or adversely interact with treatments for Parkinson's disease. Recommended dosing practices to reduce complications during hospitalisation are covered. In addition, recent concerns regarding anaesthetic exposure in early childhood as a risk factor for the development of Parkinson's disease are discussed in light of data from animal models of anaesthetic neurotoxicity and epidemiological studies. PMID- 29133107 TI - Paraneoplastic neuromyelitis optica spectrum disorder: A case report and review of the literature. AB - Neuromyelitis optica spectrum disorders (NMOSD) are demyelinating, autoimmune diseases affecting the central nervous system. Typically, recurrent optic neuritis and longitudinal extensive transverse myelitis dominates the clinical picture. In most cases NMOSD are associated with autoantibodies targeting the water channel aquaporin-4 (AQP-4). NMOSD usually present in young adults. Clinical findings suggestive of NMOSD in elderly patients should raise the suspicion of a paraneoplastic etiology. To our knowledge, we report the first case of a 66 year-old female patient with paraneoplastic NMOSD that is associated with squamous cell lung carcinoma. Anti-AQP-4 was present in both the serum and cerebrospinal fluid of the patient. However, immunhistological staining of the malignant tissue did not show presence of AQP-4 on the surface of tumour cells. PMID- 29133108 TI - A role for consolidation in cross-modal category learning. AB - The ability to categorize objects and events is a fundamental human skill that depends upon the representation of multimodal conceptual knowledge. This study investigated the acquisition and consolidation of categorical information that required participants to integrate information across visual and auditory dimensions. The impact of wake- and sleep-dependent consolidation was investigated using a paradigm in which training and testing were separated by a delay spanning either an evening of sleep or daytime wakefulness, with a paired associate episodic memory task used as a measure of classic sleep-dependent consolidation. Participants displayed good evidence of category learning, but did not show any wake- or sleep-dependent changes in memory for category information immediately following the delay. This is in contrast to paired-associate learning, where a sleep-dependent benefit was observed in memory recall. To replicate real-world concept learning, in which knowledge is acquired across multiple distinct episodes, participants were given a second opportunity for category learning following the consolidation delay. Here we found an interaction between consolidation and learning; with greater improvements in category knowledge as a result of the second learning session for those participants who had a sleep-filled delay. These results suggest a role for sleep in the consolidation of recently acquired categorical knowledge; however this benefit does not emerge as an immediate benefit in memory recall, but by enhancing the effectiveness of future learning. This study therefore provides insights into the processes responsible for the formation and development of conceptual representations. PMID- 29133110 TI - Provision of medical abortion by midlevel healthcare providers in Kyrgyzstan: testing an intervention to expand safe abortion services to underserved rural and periurban areas. AB - OBJECTIVE: To demonstrate the feasibility and safety of training midlevel healthcare providers (midwives and family nurses) to provide medical abortion and postabortion contraception in underserved areas in Kyrgyzstan. STUDY DESIGN: This was an implementation study at four referral facilities and 28 Felsher Obstetric Points in two districts to train their midwives and family nurses to deliver safe and effective abortion care with co-packaged mifepristone-misoprostol and provide contraceptives postabortion. The outcome of abortion - complete abortion, incomplete abortion or o-going pregnancy - was the primary end point measured. An international consultant trained 18 midwives and 14 family nurses (with midwifery diplomas) to provide medical abortion care. Supervising gynecologists based in the referral centers and study investigators based in Bishkek provided monthly monitoring of services and collection of patient management forms. A voluntary self-administered questionnaire at the follow-up visit documented women's acceptability of medical abortion services. All study data were cross-checked and entered into an online data management system for descriptive analysis. RESULTS: Between August 2014 and September 2015, midwives provided medical abortion to 554 women with a complete abortion rate of 97.8%, of whom 62% chose to use misoprostol at home. No women were lost to follow-up. Nearly all women (99.5%) chose a contraceptive method postabortion; 61% of women receiving services completed the acceptability form, of whom more than 99% indicated a high level of satisfaction with the service and would recommend it to a friend. CONCLUSION: This study demonstrates that trained Kyrgyz midwives and nurses can provide medical abortion safely and effectively. This locally generated evidence can be used by the Kyrgyz Ministry of Health to reduce unintended pregnancy and expand safe abortion care to women in underserved periurban and rural settings. IMPLICATIONS: Success in scaling up midwife/nurse provision of medical abortion in Kyrgyzstan will require registration of mifepristone-misoprostol, regulations permanently allowing midwife/nurse provision, strengthened procurement and distribution systems to prevent stockouts of supplies, preservice training of midwives/nurses and their involvement in district level supervision, monitoring and reporting, and support from supervisors. PMID- 29133109 TI - Temporal gradient during famous face naming is associated with lower cerebral blood flow and gray matter volume in aging. AB - OBJECTIVE: Evidence suggests that famous face naming may be a cognitive ability especially sensitive to the early pathological processes of Alzheimer's disease (AD) and that those at risk for AD may demonstrate a Ribot temporal gradient (RTG), characterized by better performance for naming remote famous faces than for naming recent famous faces. Reductions in cerebral blood flow (CBF) and gray matter volume (GMV) have been implicated in the neuropathological cascade of AD and show utility as biomarkers of AD risk. We examined whether a RTG during famous face naming was associated with lower CBF and/or GMV among a group of cognitively normal older adults. METHODS: Voxel-wise independent samples t-tests were employed to contrast resting CBF values between those who exhibited a RTG (RTG+) during a famous face naming task and those who did not (RTG-) among a sample of 52 cognitively normal older adults (25 RTG-, 27 RTG+; mean age = 73). Groups were also compared on GMV using a voxel-wise general linear model. RESULTS: Significant group differences in CBF and GMV were found, whereby the RTG+ group demonstrated reduced CBF and GMV within medial temporal lobe regions (hippocampus, parahippocampal gyrus), relative to the RTG- group. CONCLUSIONS: This represents the first study to show that cognitively intact older adults who demonstrate a RTG during famous face naming exhibit vascular dysregulation and structural changes similar to that seen in AD risk. Findings suggest that famous face naming ability may be particularly sensitive to the very early brain changes associated with AD. PMID- 29133111 TI - Effect of oral contraception on anemia in 12 low- and middle-income countries. AB - CONTEXT: In low- and middle-income countries, anemia is a major public health issue in women of reproductive age for a series of factors including iron deficiency. OBJECTIVE: To estimate prevalence of anemia and to assess the association of low level of hemoglobin versus duration of use of oral contraceptives (OC). METHODS: Demographic and Health Surveys of 12 countries, conducted between 2005 and 2012, were analyzed. The status of anemia was separately evaluated for nonpregnant women using OC for at least 6 months, 1 year and 2 years, and for women using no method of contraception and/or using nonhormonal contraception. RESULTS: The total study population comprised 201,720 women, with 40% diagnosed with anemia; around 1 out of 25 women was using oral contraception. The current and continuous use of oral contraception was of benefit against anemia, with the risk for anemia decreasing from odds ratio (OR) 0.68 [95% confidence interval (CI) 0.64-0.73] for use of at least 6 months to OR 0.56 (95% CI 0.52-0.61) for use of at least 1 year and to OR 0.50 (95% CI 0.46 0.54) for use of at least 2 years. CONCLUSIONS: Findings reinforce evidence of the noncontraceptive benefit of long-term use of OC and provide valuable information for policy makers, family planning staff and clinicians working in low- and middle-income countries in efforts to control anemia. PMID- 29133112 TI - Persistent abdominal pain after laparoscopic cholecystectomy is associated with increased healthcare consumption and sick leave. AB - BACKGROUND: Although, 33% to 40% of symptomatic gallstone patients reported persistent abdominal pain after laparoscopic cholecystectomy, there is no data on the burden of this pain to the healthcare system and society at large. This study determined healthcare consumption, sick leave, and costs in patients with persistent abdominal pain after laparoscopic cholecystectomy. Secondly, predictive factors for healthcare consumption were assessed. METHODS: This cross sectional study included all 146 patients with persistent abdominal pain (patient reported on Gastro-Intestinal Quality of Life Index (score 0-3) 24 weeks after laparoscopic cholecystectomy, derived from a previous prospective cohort. Healthcare consumption was assessed using Medical Consumption Questionnaire and medical records, and sick leave using Productivity Cost Questionnaire. Costs were calculated according "Guideline for performing economic evaluations in healthcare." Predictors of healthcare consumption were assessed using logistic regression analysis. RESULTS: In the study, 124/146 patients (85%) responded after mean follow-up of 31.0 months (standard deviation 6.5); 104 were female, mean age of responders was 52 years. Sixty-nine patients needed additional healthcare; 30.6% primary care; 37.1% secondary care; 16% emergency department admission; 8.9% hospital admission; 33.9% diagnostic procedures; 17.7% medication; 5.6% other interventions. Medical costs were $555 (BCa 95% confidence interval, $329-$852) and costs of sick leave were $361 (Bias-corrected and accelerated (BCa) 95% confidence interval, $189-$566) per year per patient. Younger age (odds ratio 0.95, 95% confidence interval, 0.92-0.98) and higher postoperative pain score (odds ratio 1.02, 95% confidence interval, 1.01-1.04) were associated with increased healthcare consumption. CONCLUSION: Persistent abdominal pain after laparoscopic cholecystectomy is associated with additional healthcare in 56% of patients. Yearly, medical costs and costs of sick leave are 20% of the initial costs of laparoscopic cholecystectomy. PMID- 29133113 TI - Postmastectomy purpura: as benign as it looks? PMID- 29133114 TI - Neurocognitive performance profile postparathyroidectomy: a pilot study of computerized assessment. AB - BACKGROUND: Neurocognitive symptoms attributable to primary hyperparathyroidism are important diagnostic criteria, yet the basic characterization and assessment of neurocognitive deficits in primary hyperparathyroidism are not defined fully. METHODS: In this prospective pilot study, patients with unequivocal biochemical diagnosis of primary hyperparathyroidism were evaluated for neurocognitive performance preoperatively and postparathyroidectomy (2 weeks, 6 months) using a battery of computerized modular tests designed by LUMOSITY. The individual test scores and aggregate scores representing a subject's total neurocognitive performance profile were calculated. Statistical comparisons between groups were performed using univariate analysis and repeated measures of analysis of variance. RESULTS: In the study, 34 participants were assessed preoperatively; 18 completed all 3 assessments, 2 completed pretest and 6-month assessments, and 30 completed preoperative and 2-week postparathyroidectomy assessments. Primary hyperparathyroidism patients demonstrated significant deficits in memory, attention, mental flexibility, and speed of processing when compared with controls. Total neurocognitive performance profile score was significantly lower at the preoperative (P = .0001) and 2-week postparathyroidectomy (P = .0004) time points when compared with controls; this difference was bridged by 6 months postparathyroidectomy. CONCLUSION: Computerized neurocognitive performance profile assessment validated the neurocognitive benefits of parathyroidectomy. Additional study is needed to determine if this novel method provides long-term, objective, quantifiable, and accessible neurocognitive performance profile assessment in primary hyperparathyroidism patients and can serve as a valuable diagnostic and prognostic tool. PMID- 29133115 TI - Structural features of the interaction of the 3'-untranslated region of mRNA containing exosomal RNA-specific motifs with YB-1, a potential mediator of mRNA sorting. AB - We have previously shown that YB-1 is the only protein of the HEK293 cell cytoplasmic (S100) extract that specifically interacts with RNA hairpins each containing one of the motifs ACCAGCCU (1), CAGUGAGC (2) and UAAUCCCA (3), which had been identified as often found in exosomal RNA and proposed as potential cis acting elements targeting RNAs into exosomes. Here we explored the interactions of YB-1 with a fragment of the 3'-untranslated region (UTR) of septin 14 mRNA (SEPT14 RNA), which contains all three motifs. We demonstrated the occurrence of YB-1 among proteins pulled down from the HEK293 S100 extract using biotinylated SEPT14 RNA. With recombinant YB-1, it was found that SEPT14 RNA can bind up to 5 moles of protein per mole of RNA in a cooperative manner, which was shown to be mainly facilitated by the presence of the above motifs. RNA hairpins with motifs 1 and 2 competed with SEPT14 RNA for binding to the protein, whereas that with motif 3 was less competitive, in accordance with the affinity of YB-1 for these RNA hairpins. With YB-1-bound RNA, nucleotides protected from attack by hydroxyl radicals were revealed in all three motifs, although hairpins with motif 2 and especially with motif 1 contained many protected nucleotides outside the motifs, suggesting that the specific environments of these motifs contribute significantly to the YB-1 binding. An analysis of the environments of motifs 1-3 in the HEK293 cell mRNA 3' UTRs gained from RNA-seq data led us to conclude that the primary binding sites of YB-1 in the 3' UTRs are hairpins containing some part of the motif along with its specific surroundings; the consensus sequences of these hairpins were derived. Thus, our findings provide a new understanding of the structural basis of the interactions between YB-1 and mRNAs carrying the aforementioned motifs. PMID- 29133116 TI - Physiology and biochemistry of type 2 diabetes: A tribute to Dr Alain Ktorza. PMID- 29133117 TI - Application of mixed peptide arrays to study combinatorial readout of chromatin modifications. AB - The N-terminal tails of histone proteins are massively decorated with post translational modifications (PTMs), which play important roles in the regulation of gene expression. Several highly conserved chromatin interacting proteins can bind to histone modifications in a sequence and modification specific manner employing specific reading domains. These proteins often contain several reading domains, which can cooperate in the readout of different PTMs. To gain a better insight into the combinatorial readout of PTMs, we developed a method to study the binding of double reading domains to mixed peptide arrays containing two different peptides in each spot. For that, differently modified and unmodified peptides were prepared by SPOT synthesis and solubilized. Then, two peptides were mixed and spotted onto a glass slide creating peptide spots presenting two modifications on two different peptides. Different combinations of mixed spots containing modified and unmodified peptides were generated and incubated with recombinant double reading domains to study their synergistic binding. For validation of the method, we used the well-studied BPTF subunit of the NURF chromatin-remodeling complex. BPTF contains a plant homeodomain finger (PHD) and a Bromodomain recognizing H3K4me3 and H4K16ac, respectively. We first confirmed with peptide arrays and Fluorescence Anisotropy (FA) measurements that the BPTF PHD-Bromo (PB) domain interacts specifically with the expected modifications. Using our novel tool, we observed a strong and synergistic binding only to peptide spots containing both modifications, which was lost if one of the domains was inactivated by a mutation. These data indicate that BPTF-PB simultaneously interacts with both target modifications using its PHD and Bromodomain. In agreement with the synergistic peptide interaction on mixed peptide arrays, we also show that chromatin pulldown by BPTF-PB depends on the activity of both reading domains. We conclude that mixed peptide spot arrays are a powerful, cheap and novel method for screening the combinatorial interaction space of multidomain reading proteins. Using this approach hundreds of mixed peptide spots can be prepared and tested for binding in principle allowing for an unbiased medium throughput investigation. PMID- 29133118 TI - Functional characterization of a serine protease inhibitor modulated in the infection of the Aedes aegypti with dengue virus. AB - During feeding with blood meal, female Aedes aegypti can transmit infectious agents, such as dengue, yellow fever, chikungunya and Zika viruses. Dengue virus causes human mortality in tropical regions of the world, and there is no specific treatment or vaccine with maximum efficiency being used for these infections. In the vector-virus interaction, the production of several molecules is modulated by both mosquitoes and invading agents. However, little information is available about these molecules in the Ae. aegypti mosquito during dengue infection. Inhibitors of the pacifastin family have been described to participate in the immune response of insects and Pac2 is the only gene of this family present in Ae. aegypti being then chosen for investigation. Pac2 was expressed in E. coli, purified and analyzed by mass spectrometry and SDS-PAGE. The Pac2 transcript was detected by qPCR, and its protein levels were assessed by Western blotting. The inhibitory activity of Pac2 was measured using its Ki, IC50 and zymography. Mosquito infections with DENV were introduced with the Brazilian ACS-46 DENV-2 strain propagated in C6/36 cells. In the present work, we showed that it is possibly involved in the interaction of the mosquitoes with the dengue virus. The Pac2 transcript was detected in larvae and in both the salivary gland and midgut of Ae. aegypti females, while the native protein was identified in females 3 h post-blood meal. Pac2 is a strong inhibitor of trypsin-like and thrombin-like proteases, which are present in 4th instar larvae midgut and females 24 h after blood meal. During DENV infection, up regulation of Pac2 expression occurs in the salivary gland and midgut. Pac2 is the first Pacifastin inhibitor member described in mosquitoes. Our results suggest that Pac2 acts on mosquito serine proteases, mainly the trypsin-like type, and is under transcriptional control by virus infection signals to allow its survival in the vector or by the mosquito as a defense mechanism against virus infection. PMID- 29133119 TI - Towards topical microRNA-directed therapy for epidermal disorders. AB - There remains an unmet dermatological need for innovative topical agents that achieve better longterm outcomes with fewer side effects. Modulation of the expression and activity of microRNA (miRNAs) represents an emerging translational framework for the development of such innovative therapies because changes in the expression of one miRNA can have wide-ranging effects on diverse cellular processes associated with disease. In this short review, the roles of miRNA in epidermal development, psoriasis, cutaneous squamous cell carcinoma and re epithelisation are highlighted. Consideration is given to the delivery of oligonucleotides that mimic or inhibit miRNA function using vehicles such as cell penetrating peptides, spherical nucleic acids, deformable liposomes and liquid crystalline nanodispersions. Formulation of miRNA-directed oligonucleotides with such skin-penetrating epidermal agents will drive the development of RNA-based cutaneous therapeutics for deployment as primary or adjuvant therapies for epidermal disorders. PMID- 29133120 TI - Enhanced oral absorption and anticancer efficacy of cabazitaxel by overcoming intestinal mucus and epithelium barriers using surface polyethylene oxide (PEO) decorated positively charged polymer-lipid hybrid nanoparticles. AB - Polymer-lipid hybrid nanoparticles, PMONPs, were developed to improve the oral absorption of cabazitaxel (CTX), a semi-synthetic taxane derivative, by overcoming multiple gastrointestinal barriers. The nano-carrier is comprised of a poly(epsilon-caprolactone) (PCL) and chain triglyceride (MCT) hybrid core for drug loading, and a positively charged surface while slightly concealed with a polyethylene oxide (PEO) shell by insertion of poloxamer 188, with the aim of improving the intestinal mucus permeation and epithelial cell uptake. The CTX loaded PMONPs (CTX-PMONPs) were optimized with 10% MCT content in the core, and characterization showed they were on the nanoscale with a size of 170.2+/-5.7nm, zeta potential of +40.90+/-3.05mV, drug loading of 11.5%, and sustained release property. Enhanced mucus permeation of PMONPs were confirmed in a bulk permeation test, in situ SPIP and intestinal distribution study, and is likely attributed to the combined effect of positive charge and hydrophilic PEO layer on the surface. Meanwhile, promoted cellular uptake was found in mucus-secreting cells evaluation, in which potential adsorptive transcytosis, caused by positively charged surface, played a key role. Furthermore, lymphatic transport was positively demonstrated, contributing to the high oral absorption of CTX-PMONPs. The oral bioavailability of CTX was elevated from 7.7% (CTX solution (CTX-Sol)) to 56.6% after oral administration of CTX-PMONPs, approximately 7.3 times higher than that of CTX-Sol. An in vivo anticancer efficiency study showed that CTX PMONPs orally exhibited a good tumor inhibition effect, and reduced the CTX caused systemic toxicity compared with intravenous CTX-Sol. In conclusion, PMONPs are able to efficiently orally deliver the anticancer drug, CTX, into systemic circulation, and can achieve the desired oral anticancer effect. This surface modified polymer-lipid hybrid nanoparticle is likely to be a promising carrier for oral delivery of small molecule anticancer drugs. PMID- 29133121 TI - Analysis of Early Death in Japanese Patients With Advanced Non-small-cell Lung Cancer Treated With Nivolumab. AB - BACKGROUND: The increased risk for early death owing to anti-programmed cell death 1 inhibitors is a major disadvantage that requires special management. We evaluated the frequency, causes, and risk factors of early death during nivolumab treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting. PATIENTS AND METHODS: The medical records of patients with NSCLC who started receiving nivolumab between December 17, 2015 and July 31, 2016 in 3 Japanese institutes were collected. Early death was defined as any death within 3 months from the start of nivolumab treatment, irrespective of its cause. Treatment response was evaluated using the Response Evaluation Criteria In Solid Tumors criteria, version 1.1. RESULTS: A total of 201 patients with NSCLC were enrolled, and 38 (18.9%) died within the first 3 months. Thirty-one (81.6%) patients who experienced early death developed progressive disease, whereas 14 (36.8%) patients who experienced early death demonstrated nivolumab-induced immune related adverse events, which required corticosteroid intervention, including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic regression demonstrated that an Eastern Cooperative Oncology Group performance status score >= 2 (odds ratio [OR], 5.66; 95% confidence interval [CI], 2.01-15.61; P < .001), C-reactive protein-to-albumin ratio > 0.3 (OR, 10.56; 95% CI, 3.61-30.86; P < .001), and the response to prior treatment (OR, 2.07; 95% CI, 1.03-4.14; P = .041) were independent predictors for early death. CONCLUSION: Disease progression and immune-related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology Group performance status score >= 2, pretreatment C-reactive protein-to-albumin ratio > 0.3, and poor response to prior treatment were associated with early death. PMID- 29133122 TI - Involvement of cannabinoid receptor type 2 in light-induced degeneration of cells from mouse retinal cell line in vitro and mouse photoreceptors in vivo. AB - Earlier studies showed that the expressions of the agonists of the cannabinoid receptors are reduced in the vitreous humor of patients with age-related macular degeneration (AMD), and the cannabinoid type 2 receptor is present in the retinas of rats and monkeys. The purpose of this study was to determine whether the cannabinoid type 2 receptor is involved in the light-induced death of cultured 661W cells, an immortalized murine retinal cell line, and in the light-induced retinal degeneration in mice. Time-dependent changes in the expression and location of retinal cannabinoid type 2 receptor were determined by Western blot and immunostaining. The cannabinoid type 2 receptor was down-regulated in murine retinae and cone cells. In the in vitro studies, HU-308, a cannabinoid type 2 receptor agonist, had a protective effect on the light-induced death of 661W cells, and this effect was attenuated by SR144528, a cannabinoid type 2 receptor antagonist. Because the cannabinoid type 2 receptor is a G-protein coupled receptor and is coupled with Gi/o protein, we investigated the effects of the cAMP-dependent protein kinase (PKA). HU-308 and H89, a PKA inhibitor, deactivated PKA in retinal cone cells, and H89 also suppressed light-induced cell death. For the in vivo studies, a cannabinoid type 2 receptor agonist, HU-308, or an antagonist, SR144528, was injected intravitreally into mouse eyes before the light exposure. Electroretinography was used to determine the physiological status of the retinas. Injection of HU-308 improved the a- and b-waves of the ERGs and also the thickness of the outer nuclear layer of the murine retina after light exposure. These findings indicate that the cannabinoid type 2 receptor is involved in the light-induced retinal damage through PKA signaling. Thus, activation of cannabinoid type 2 receptor may be a therapeutic approach for light associated retinal diseases. PMID- 29133123 TI - A proteometabolomic study of Actinidia deliciosa fruit development. PMID- 29133124 TI - Proteomic approaches to uncover the flooding and drought stress response mechanisms in soybean. AB - : Soybean is the important crop with abundant protein, vegetable oil, and several phytochemicals. With such predominant values, soybean is cultivated with a long history. However, flooding and drought stresses exert deleterious effects on soybean growth. The present review summarizes the morphological changes and affected events in soybean exposed to such extreme-water conditions. Sensitive organ in stressed soybean at different-developmental stages is presented based on protein profiles. Protein quality control and calcium homeostasis in the endoplasmic reticulum are discussed in soybean under both stresses. In addition, the way of calcium homeostasis in mediating protein folding and energy metabolism is addressed. Finally, stress response to flooding and drought is systematically demonstrated. This review concludes the recent findings of plant response to flooding and drought stresses in soybean employed proteomic approaches. BIOLOGICAL SIGNIFICANCE: Soybean is considered as traditional-health food because of nutritional elements and pharmacological values. Flooding and drought exert deleterious effects to soybean growth. Proteomic approaches have been employed to elucidate stress response in soybean exposed to flooding and drought stresses. In this review, stress response is presented on organ-specific manner in the early stage plant and soybean seedling exposed to combined stresses. The endoplasmic reticulum (ER) stress is induced by both stresses; and stress-response in the ER is addressed in the root tip of early-stage soybean. Moreover, calcium-response processes in stressed plant are described in the ER and in the cytosol. Additionally, stress-dependent response was discussed in flooded and drought stressed plant. This review depicts stress response in the sensitive organ of stressed soybean and forms the basis to develop molecular markers related to plant defense under flooding and drought stresses. PMID- 29133125 TI - Very low doses of muscimol and baclofen ameliorate cognitive deficits and regulate protein expression in the brain of a rat model of streptozocin-induced Alzheimer's disease. AB - Recent studies devoted to neuroprotection have focused on the role of the gamma aminobutyric acid (GABA) system in regulating neuroinflammatory processes which play a key role in the neurodegenerative processes observed in Alzheimer's disease (AD) by inducing glial cell overactivation and impairing neurotransmission. Data on the efficacy of classical GABA-A and GABA-B receptor agonists (muscimol and baclofen, respectively) in animal models of AD are not available. Moreover, no published studies have examined the ability of optimal doses of these compounds to prevent neuroinflammation, the alterations in neurotransmission and cognitive deficits. In the present study, we used a non transgenic rat model of AD obtained by intracerebroventricular streptozocin (STZ) injection and assessed the effects of muscimol and baclofen at very low doses (0.01-0.05mg/kg) on spatial memory and the expression of cortical and hippocampal proteins related to neuroinflammation, namely proteins involved in astroglial functions (glial fibrillary acidic protein, GFAP), GABA synthesis (GABA synthesizing enzyme, glutamic acid decarboxylase 67, GAD67) and acetylcholine degradation (acetylcholine esterase). The presented study demonstrated that in a rat model of STZ-induced AD both muscimol and baclofen at the tested doses exerted memory-enhancing and anti-inflammatory effects, as well as normalization of acetylcholine esterase and GABA expression. We suggested that the function of very low doses of GABA receptor agonists differs from typical GABA-related inhibition and may be mediated by the allosteric sites of GABA receptors or other non-specific cell regulatory pathways. PMID- 29133126 TI - The role of urotensin-II and its receptors in sepsis-induced lung injury under diabetic conditions. AB - This study aimed to investigate the potential role of urotensin-II receptors in sepsis-induced lung injury in diabetic mice using urotensin-II receptor agonists and antagonists. A total of 110 male CD1 mice were used in this study. Diabetes was induced by 200mg/kg streptozotocin. One month after diabetes induction, the cecal ligation and puncture-induced polymicrobial sepsis model was applied in the diabetic and non-diabetic mice. Low and high doses of human urotensin-II agonist (HU-II) and antagonist (palosuran) were administered one hour after sepsis induction. HU-II administration was repeated in two-hour intervals. Blood and tissue samples were collected at 6 and 12H after sepsis induction for biochemical, molecular, and histopathologic examinations. Regarding to the lungs mRNA expression and immunohistochemistry results of TNF-alpha, IL1 beta, IL6, and NF-kappaB, it was observed that cytokine levels significantly increased in the diabetes group and the sepsis groups compared to the healthy group; this increase was significantly higher in the diabetes-sepsis groups. Our biochemical (superoxide dismutase, glutathione, and malondialdehyde) and histopathological findings in the lungs also supported these results. All increased parameters were significantly reduced dose-dependently by the administration of palosuran, an urotensin receptor antagonist. mRNA expression of urotensin-II and its receptor were examined in the lung tissue. Palosuran administration significantly reduced the urotensin-II and urotensin-II receptor levels that increased in the damaged tissue. This study has shown that urotensin-II and urotensin-II receptors contribute to the aggravation of sepsis-induced lung injury in diabetic mice; palosuran prevents this damage by antagonizing urotensin-II receptors. PMID- 29133127 TI - Knockdown of LncRNA PVT1 inhibits tumorigenesis in non-small-cell lung cancer by regulating miR-497 expression. AB - Plasmacytoma variant translocation1 (PVT1) was reported to be upregulated in non small-cell lung cancer (NSCLC) tissues, serve as a promising biomarker for diagnosis and prognosis of NSCLC, and promoted NSCLC cell proliferation. However, the detailed molecular mechanism of PVT1 involved in the pathogenesis and development of NSCLC remains largely unknown. In this study, the expression levels of PVT1 and miR-497 in NSCLC cells were determined by qRT-PCR. Cell viability, invasion and apoptosis were detected by MTT assay, cell invasion assay and flow cytometry analysis, respectively. RNA immunoprecipitation (RIP) and luciferase reporter assay were performed to confirm whether PVT1 directly interacts with miR-497. A xenograft mouse model was established to confirm the effect of PVT1 on tumor growth in vivo and the underlying molecular mechanism. Our findings indicated that PVT1 was significantly upregulated and miR-497 was markedly downregulated in NSCLC cell lines. si-PVT1 effectively decreased the expression of PVT1 and increased the expression of miR-497. PVT1 knockdown remarkably inhibited cell viability, invasion and promoted apoptosis in NSCLC cells. RIP and luciferase reporter assay demonstrated that PVT1 could directly interact with miR-497. Moreover, PVT1 overexpression reversed the inhibitory effect of miR-497 on cell viability, invasion and promotion effect on apoptosis of NSCLC cells. Furthermore, in vivo experiment showed that knockdown of PVT1 inhibited tumor growth in vivo and promoted miR-497 expression. In conclusion, knockdown of PVT1 inhibited cell viability, invasion and induced apoptosis in NSCLC by regulating miR-497 expression, elucidating the molecular mechanism of the oncogenic role of PVT1 in NSCLC and providing an lncRNA-directed target for NSCLC. PMID- 29133128 TI - BCA3 contributes to the malignant progression of hepatocellular carcinoma through AKT activation and NF-kappaB translocation. AB - Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide with elusive molecular mechanisms. The aim of this study is to investigate the clinical significance and biological roles of breast cancer-associated protein 3 (BCA3) in HCC. Our investigation demonstrated that BCA3 expression was up regulated in primary HCC tissues, and BCA3 levels were positively correlated with tumor size, TNM stage, microvascular invasion and poor prognosis. BCA3 promoted tumor growth, metastasis and angiogenesis of HCC in vitro and in vivo. Moreover, we found that BCA3 induced aggressive behaviors were mediated by AKT activation, which in turn activated mTOR signalling pathway and induced cytoplasm-nuclear translocation of NF-kappaB p65. Blockage of AKT signalling pathway by a specific AKT inhibitor LY294002 impaired BCA3 mediated phenotypes. Collectively, our current study indicated the pleiotropic effects of BCA3 in HCC progression, and blockage of BCA3-AKT pathway might contribute to development of therapeutic measures for HCC. PMID- 29133130 TI - Far-ultraviolet spectral changes of titanium dioxide with gold nanoparticles by ultraviolet and visible light. AB - Attenuated total reflectance spectra including the far-ultraviolet (FUV, <=200nm) region of titanium dioxide (TiO2) with and without gold (Au) nanoparticles were measured. A newly developed external light-irradiation system enabled to observe spectral changes of TiO2 with Au nanoparticles upon light irradiations. Absorption in the FUV region decreased and increased by the irradiation with ultraviolet and visible light, respectively. These spectral changes may reflect photo-induced electron transfer from TiO2 to Au nanoparticles under ultraviolet light and from Au nanoparticles to TiO2 under visible light, respectively. PMID- 29133129 TI - HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element. AB - In pursuit of novel therapeutics targeting the hepatitis B virus (HBV) infection, we evaluated a dihydroquinolizinone compound (DHQ-1) that in the nanomolar range reduced the production of virion and surface protein (HBsAg) in tissue culture. This compound also showed broad HBV genotype coverage, but was inactive against a panel of DNA and RNA viruses of other species. Oral administration of DHQ-1 in the AAV-HBV mouse model resulted in a significant reduction of serum HBsAg as soon as 4 days following the commencement of treatment. Reduction of HBV markers in both in vitro and in vivo experiments was related to the reduced amount of viral RNA including pre-genomic RNA (pgRNA) and 2.4/2.1 kb HBsAg mRNA. Nuclear run-on and subcellular fractionation experiments indicated that DHQ-1 mediated HBV RNA reduction was the result of accelerated viral RNA degradation in the nucleus, rather than the consequence of inhibition of transcription initiation. Through mutagenesis of HBsAg gene sequences, we found induction of HBsAg mRNA decay by DHQ-1 required the presence of the HBV posttranscriptional regulatory element (HPRE), with a 109 nucleotides sequence within the central region of the HPRE alpha sub-element being the most critical. Taken together, the current study shows that a small molecule can reduce the overall levels of HBV RNA, especially the HBsAg mRNA, and viral surface proteins. This may shed light on the development of a new class of HBV therapeutics. PMID- 29133131 TI - Influence of the hydrogen bond quantum nature in liquid water and heavy water on stimulated Raman scattering. AB - Stimulated Raman scattering (SRS) of liquid water and heavy water have been investigated using Nd:YAG laser. The SRS spectra of liquid heavy water indicate that ice-VII and ice-VIII structures are formed by shock-induced compression (SIC) in forward and backward directions, respectively. Simultaneously, the SRS spectra reveal of liquid water that only ice-VII structure is formed in the backward direction. The difference in ice structures formed by SIC in liquid water and heavy water could be attributed to the effect of the hydrogen bond quantum nature with H+. SRS spectra of 2M NaOH water solution with ice-VII and ice-VIII structures have been successfully obtained in forward and backward, respectively, as OH- greatly reduce the quantum nature of hydrogen bonds by neutralizing H+ in water. The hydrogen bond quantum nature is important for understanding isotope calibration test structure and isotopic effect. PMID- 29133132 TI - Application of dyes extracted from Alternanthera dentata leaves and Musa acuminata bracts as natural sensitizers for dye-sensitized solar cells. AB - The natural dyes anthocyanin and chlorophyll were extracted from Musa acuminata bracts and Alternanthera dentata leaves, respectively. The dyes were then applied as sensitizers in TiO2-based dye-sensitized solar cells (DSSCs). The ethanol extracts of the dyes had maximum absorbance. High dye yields were obtained under extraction temperatures of 70 to 80 degrees C, and the optimal extraction temperature was approximately 80 degrees C. Moreover, dye concentration sharply decreased under extraction temperatures that exceeded 80 degrees C. High dye concentrations were obtained using acidic extraction solutions, particularly those with a pH value of 4. The DSSC fabricated with anthocyanin from M. acuminata bracts had a conversion efficiency of 0.31%, short-circuit current (Isc) of 0.9mA/cm2, open-circuit voltage (Voc) of 0.58V, and fill factor (FF) of 62.22%. The DSSC sensitized with chlorophyll from A. dentata leaves had a conversion efficiency of 0.13%, Isc of 0.4mA/cm-2,Voc of 0.54V, and FF of 67.5%. The DSSC sensitized with anthocyanin from M. acuminata bracts had a maximum incident photon-to-current conversion efficiency of 42%, which was higher than that of the DSSC sensitized with chlorophyll from A. dentata leaves (23%). Anthocyanin from M. acuminata bracts exhibited the best photosensitization effects. PMID- 29133133 TI - Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective. AB - Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy. PMID- 29133134 TI - Sensing the Breaks: Cytosolic Chromatin in Senescence and Cancer. AB - Cellular senescence constitutes a stable growth arrest characterized by DNA damage response (DDR) activation and by the senescence-associated secretory phenotype (SASP). SASP, through its paracrine effects, stimulates the immune system for senescence eradication. Similarly, chemotherapy-treated cancers activate an interferon-mediated response to induce anti-tumor immunity. Recent studies now uncover a new role for the innate DNA sensing pathway in the recognition of cytosolic chromatin in senescence and cancer. PMID- 29133135 TI - Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer. AB - Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance. It is therefore crucial to develop assays for accurate HRD detection and to broaden the patient population who can avail of novel treatment options. PMID- 29133136 TI - Comparison of the near field/far field model and the advanced reach tool (ART) model V1.5: exposure estimates to benzene during parts washing with mineral spirits. AB - The Advanced Reach Tool V1.5 (ART) is a mathematical model for occupational exposures conceptually based on, but implemented differently than, the "classic" Near Field/Far Field (NF/FF) exposure model. The NF/FF model conceptualizes two distinct exposure "zones"; the near field, within approximately 1m of the breathing zone, and the far field, consisting of the rest of the room in which the exposure occurs. ART has been reported to provide "realistic and reasonable worst case" estimates of the exposure distribution. In this study, benzene exposure during the use of a metal parts washer was modeled using ART V1.5, and compared to actual measured workers samples and to NF/FF model results from three previous studies. Next, the exposure concentrations expected to be exceeded 25%, 10% and 5% of the time for the exposure scenario were calculated using ART. Lastly, ART exposure estimates were compared with and without Bayesian adjustment. The modeled parts washing benzene exposure scenario included distinct tasks, e.g. spraying, brushing, rinsing and soaking/drying. Because ART can directly incorporate specific types of tasks that are part of the exposure scenario, the present analysis identified each task's determinants of exposure and performance time, thus extending the work of the previous three studies where the process of parts washing was modeled as one event. The ART 50th percentile exposure estimate for benzene (0.425ppm) more closely approximated the reported measured mean value of 0.50ppm than the NF/FF model estimates of 0.33ppm, 0.070ppm or 0.2ppm obtained from other modeling studies of this exposure scenario. The ART model with the Bayesian analysis provided the closest estimate to the measured value (0.50ppm). ART (with Bayesian adjustment) was then used to assess the 75th, the 90th and 95th percentile exposures, predicting that on randomly selected days during this parts washing exposure scenario, 25% of the benzene exposures would be above 0.70ppm; 10% above 0.95ppm; and 5% above 1.15ppm. These exposure estimates at the three different percentiles of the ART exposure distribution refer to the modeled exposure scenario not a specific workplace or worker. This study provides a detailed comparison of modeling tools currently available to occupational hygienists and other exposure assessors. Possible applications are considered. PMID- 29133137 TI - A systematic review of the public health risks of bioaerosols from intensive farming. AB - BACKGROUND: Population growth, increasing food demands, and economic efficiency have been major driving forces behind farming intensification over recent decades. However, biological emissions (bioaerosols) from intensified livestock farming may have the potential to impact human health. Bioaerosols from intensive livestock farming have been reported to cause symptoms and/or illnesses in occupational-settings and there is concern about the potential health effects on people who live near the intensive farms. As well as adverse health effects, some potential beneficial effects have been attributed to farm exposures in early life. The aim of the study was to undertake a systematic review to evaluate potential for adverse health outcomes in populations living near intensive livestock farms. MATERIAL AND METHODS: Two electronic databases (PubMed and Scopus) and bibliographies were searched for studies reporting associations between health outcomes and bioaerosol emissions related to intensive farming published between January 1960 and April 2017, including both occupational and community studies. Two authors independently assessed studies for inclusion and extracted data. Risk of bias was assessed using a customized score. RESULTS: 38 health studies met the inclusion criteria (21 occupational and 1 community study measured bioaerosol concentrations, 16 community studies using a proxy measure for exposure). The majority of occupational studies found a negative impact on respiratory health outcomes and increases in inflammatory biomarkers among farm workers exposed to bioaerosols. Studies investigating the health of communities living near intensive farms had mixed findings. All four studies of asthma in children found increased reported asthma prevalence among children living or attending schools near an intensive farm. Papers principally investigated respiratory and immune system outcomes. CONCLUSIONS: The review indicated a potential impact of intensive farming on childhood respiratory health, based on a small number of studies using self-reported outcomes, but supported by findings from occupational studies. Further research is needed to measure and monitor exposure in community settings and relate this to objectively measured health outcomes. PMID- 29133138 TI - Contextual factors and motivations affecting rural community sanitation in low- and middle-income countries: A systematic review. AB - BACKGROUND: Unsafe management of human faecal waste represents a major risk for public health, particularly in low- and middle-income countries. Efforts to improve sanitation conditions are considerably sensitive to contextual specifics of natural and social environments. This review operationalises, analyses, and synthesises evidence of how contextual factors and motivations affect different sanitation outcomes with a specific focus on community approaches to rural sanitation. METHODS AND FINDINGS: We operationalised contextual factors and motivations as determinants that influence sanitation conditions independently of the examined intervention. We conducted a systematic search of both peer-reviewed and grey literature with no restriction on the methods After screening the titles and abstracts of 19,198 records obtained through initial searches, we scrutinised the full content of 621 studies for relevance. While 102 of these studies qualified to be assessed for risk of bias and information content, ultimately, just 40 studies met our eligibility criteria. Of these 40 studies from 16 countries, 26 analysed specific interventions and 14 were non-interventional. None of the experimental studies reported the effects of contextual factors or motivations as operationalised in this study and only observational evidence was thus used in our review. We found that sanitation interventions are typically seen as the principal vehicles of change, the main instruments to fix 'deviant' behaviour or ensure access to infrastructure. The programmatic focus of this study on sanitation determinants that act independently of specific interventions questions this narrow understanding of sanitation dynamics. We identified 613 unique observations of quantitatively or qualitatively established relationships between certain contextual factors or motivations and 12 different types of sanitation outcomes. The sanitation determinants were classified into 77 typologically similar groups clustered into 12 broader types and descriptively characterised. We developed a graphical synthesis of evidence in the form of a network model referred to as the sanitation nexus. The sanitation nexus depicts how different groups of determinants interlink different sanitation outcomes. It provides an empirically derived conceptual model of sanitation with an aggregate structure indicating similarities and dissimilarities between sanitation outcomes with respect to how their sets of underlying determinants overlap. CONCLUSION: This study challenged the understanding of context as merely something that should be controlled for. Factors that affect targeted outcomes independently of the analysed interventions should be scrutinised and reported. This particularly applies to interventions involving complex human-environment interactions where generalisability is necessarily indirect. We presented a novel approach to comprehending the contextual factors and motivations which influence sanitation outcomes. Our approach can be analogously applied when mapping and organising underlying drivers in other areas of public and environmental health. The sanitation nexus derived in this study is designed to inform practitioners and researchers about sanitation determinants and the outcomes they influence. PMID- 29133139 TI - Methemoglobin reductase activity in intact fish red blood cells. AB - Red blood cells (RBCs) possess methemoglobin reductase activity that counters the ongoing oxidation of hemoglobin (Hb) to methemoglobin (metHb), which in circulating blood is caused by Hb autoxidation or reactions with nitrite. We describe an assay for determining metHb reductase activity in intact RBCs in physiological saline at normal Pco2 and pH. After initial loading of oxygenated RBCs with nitrite (partly oxidizing Hb to metHb), the nitrite is removed by three washes of the RBCs in nitrite-free physiological saline to enable the detection of RBC metHb reductase activity in the absence of counteracting oxidation. This assay was used to compare metHb reduction in rainbow trout and carp RBCs under both oxygenated and deoxygenated conditions. Washing resulted in effective wash out of nitrite to low and safe values (~2MUM). The subsequent decline in [metHb] with time followed first-order kinetics, allowing characterization of metHb reductase activity through the first order rate constant k. In oxygenated RBCs at 25 degrees C, the k values for rainbow trout and carp were slightly below or above 0.01min-1, respectively; which is double the value reported for mammals at 37 degrees C. We conclude the higher metHb reductase activity in fish offsets their higher Hb autoxidation and higher likelihood of encountering elevated nitrite. Deoxygenation significantly raised the rates of RBC metHb reduction, and more so in rainbow trout than in carp. The temperature sensitivity of metHb reduction in rainbow trout RBCs was high (Q10 ~2.8) and instrumental in handling increased Hb autoxidation with temperature. PMID- 29133140 TI - The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer. AB - The histone methyltransferase G9a (EHMT2) is a key enzyme for dimethylation of lysine 9 at histone 3 (H3K9me2), a suppressive epigenetic mark. G9a is over expressed in tumor cells and contributes to cancer aggressiveness. Biliary tract cancer (BTC) is a rare cancer with dismal prognosis due to a lack of effective therapies. Currently, there are no data on the role of G9a in BTC carcinogenesis. We analyzed G9a expression in n=68 BTC patient specimens and correlated the data with clinicopathological and survival data. Moreover, we measured G9a expression in a panel of BTC cell lines and evaluated the cytotoxic effect of G9a inhibition in BTC cells using established small-molecule G9a inhibitors. G9a was considerably expressed in about half of BTC cases and was significantly associated with grading and tumor size. Additionally, we observed significant differences of G9a expression between growth type and tumor localization groups. G9a expression diametrically correlated with Vimentin (positive) and E-Cadherin (negative) expression. Importantly, survival analysis revealed G9a as a significant prognostic factor of poor survival in patients with BTC. In BTC cells, G9a and H3K9me2 were detectable in a cell line-dependent manner on mRNA and/or protein level, respectively. Treatment of BTC cells with established small molecule G9a inhibitors resulted in reduction of cell viability as well as reduced G9a and H3K9me2 protein levels. The present study strongly suggests that G9a contributes to BTC carcinogenesis and may represent a potential prognostic factor as well as a therapeutic target. PMID- 29133141 TI - Abdominal fat pad excisional biopsy for the diagnosis and typing of systemic amyloidosis. AB - In the past, the diagnosis and typing of amyloidosis often required an invasive biopsy of an internal organ, such as the heart or kidneys. Abdominal fat pad excisional biopsy (FPEB) offers a less invasive approach, but the sensitivity of this technique has been unclear. To determine the sensitivity of FPEB for immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, we performed a retrospective clinicopathologic analysis of 97 patients who had undergone FPEB, of which 16 were positive for amyloid. The most significant pretest feature predicting a positive FPEB was a serum free light chain kappa/lambda ratio less than .5, and in this group of patients the probability of a positive biopsy was dependent on the size of the biopsy (P=.004). In FPEBs, the amyloid was present in multiple distinct patterns: pericellular, septal, medium sized vessel, small vessel, and nodular. For patients with AL amyloidosis for which direct typing was attempted using the FPEB tissue, the amyloid was successfully typed in the FPEB in 90% of cases. The overall sensitivity of FPEB was 79% for AL amyloidosis and 12% for ATTR amyloidosis (P=.0003). In patients with AL amyloidosis, the sensitivity of FPEB was dependent on biopsy size, with small biopsies (<=700 mm3) having a sensitivity of ~50%, and large biopsies (>700 mm3) having a sensitivity of ~100%. This study demonstrates that FPEB has high sensitivity for AL amyloidosis, and can be routinely used to type the amyloid. However, FPEB has low sensitivity for ATTR amyloidosis in our patient population. PMID- 29133142 TI - Dedifferentiated endometrial carcinomas with neuroendocrine features: a clinicopathologic, immunohistochemical, and molecular genetic study. AB - Undifferentiated endometrial carcinoma is an aggressive type of uterine cancer, which is occasionally associated with a low-grade endometrioid carcinoma component. This combination is referred to as "dedifferentiated endometrioid endometrial carcinoma." Neuroendocrine expression may occur in undifferentiated endometrial carcinoma, but its significance in dedifferentiated endometrial carcinomas is unknown. To gain insight into the pathogenesis of these tumors we have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, beta catenin, SMARCB1, synaptophysin, chromogranin A, and CD56) and mutational status (PTEN, KRAS, PIK3CA, TP53 and POLE) of 4 dedifferentiated endometrial carcinomas with strong and diffuse neuroendocrine expression. All tumors demonstrated neuroendocrine expression in >=70% of the cells in the undifferentiated carcinoma areas. Loss of expression of at least 1 DNA mismatch repair protein was observed in 2 cases, and p53 immunoreaction was aberrant (mutated/inactivated) in one case. All carcinomas were negative for beta-catenin and maintained nuclear SMARCB1 (INI1) and ARID1A expression. Three tumors shared identical endometrioid molecular profile (PTEN and/or PIK3CA mutations) in both components. One tumor had POLE exonuclease domain mutation in the undifferentiated component. In one case, TP53 mutation was found exclusively in the undifferentiated component. Two patients died with peritoneal carcinomatosis and abdominal metastases, respectively; one patient died of a renal failure without evidence of disease, and the last patient is alive and free of disease at 3.3 years. Dedifferentiated endometrial carcinomas with neuroendocrine features are clinically and molecularly heterogeneous tumors. Probably, these carcinomas might acquire undifferentiated phenotype through mutations in TP53 and POLE. PMID- 29133143 TI - Pathologic and clinical characteristics of early onset renal cell carcinoma. AB - The majority of renal cell carcinomas (RCCs) occur within the 7th decade of life, uncommonly arising in adults <=46 years. We reviewed the clinicopathologic features of early onset RCC and evaluated the role of immunohistochemistry (IHC) in potentially identifying diagnoses of newly recognized RCC subtypes that may have been previously misclassified. A retrospective review was performed from 2011-2016 for cases of RCC. Early onset RCC was defined as <=46 years of age. Clinicopathologic findings and hematoxylin and eosin (H&E) slides were reviewed on early onset RCC patients. IHC was performed on all cases previously diagnosed as unclassified or papillary. Clinicopathologic findings were compared to a control group of RCC patients >46 years over the same time period. We identified 98/598 (16.4%) early onset RCCs. The median age in the early onset RCC and control group was 38.4 and 62.8 years, respectively. The early onset RCC group contained 33/96 (34.3%) females and 63/96 (65.6%) males, including 52/96 (54.2%) whites, 39/96 (40.6%) African Americans, 4/96 (4.2%) Hispanics, and 1/96 (1%) Asian. Nonwhites were significantly more likely to develop early onset RCC (P=.004). Early onset RCCs included 52% clear cell, 28.6% papillary, 8.2% unclassified, 5.1% chromophobe, 3.1% clear cell papillary(CCP), and 3 other rare tumors. Six unclassified and 26 papillary RCCs had tissue available for IHC. Two of 6 (33.3%) unclassified RCCs were reclassified (1 CCP, 1 Xp11 translocation). One of 26 (3.8%) papillary RCCs was reclassified as CCP. Early onset RCCs were more likely to occur in nonwhites (P=.004), be lower stage (P=.03), and undergo partial nephrectomy (P=.002). Few unclassified and papillary tumors were reclassified with IHC. PMID- 29133144 TI - Influence of lighting color temperature on effort-related cardiac response. AB - Higher color temperature refers to a higher proportion of blue spectral components of light, that are known to be associated with higher alertness state in humans. Based on motivational intensity theory (Brehm & Self, 1989), here we predicted that this lighting-induced alertness state should inform about the readiness to perform and this way influence subjective task demand and thus mental effort. To test this, study participants spent 15min under one of four lighting color temperature conditions and then performed a cognitive task. As predicted, effort-related cardiac response, indexed by a shortened cardiac pre ejection period, decreased with increasing color temperature of light, as indicated by a significant single planned linear contrast. These results demonstrate that spectral properties of light can influence mental effort mobilization. PMID- 29133145 TI - EGFR and Ras regulate DDX59 during lung cancer development. AB - Oncogenes EGFR and ras are frequently mutated and activated in human lung cancers. In this report, we found that both EGFR and Ras signaling can upregulate RNA helicase DDX59 in lung cancer cells. DDX59 can be induced through the mitogen activated protein kinase (MAPK) pathway after EGFR or Ras activation. Inhibitors for Ras/Raf/MAP pathway significantly decreased DDX59 expression at both protein and mRNA levels. Through immunohistochemistry, we found that DDX59 protein expression correlated with Ras and EGFR mutation status in human lung adenocarcinoma. Finally, through a xenograft nude mice model, we demonstrated that DDX59 is pivotal for EGFR mutated lung cancer cell growth in vivo. Our study identified a novel protein downstream of Ras and EGFR, which may serve as a potential therapeutic drug target for lung cancer patients. PMID- 29133146 TI - Association of genetic polymorphisms with erythrocyte traits: Verification of SNPs reported in a previous GWAS in a Japanese population. AB - Erythrocyte count and volume are the commonly used hematological indices for anemia that change in various diseases. To date, however, only one study ever exists that addressed erythrocyte trait-associated single nucleotide polymorphisms (SNPs) in a Japanese population. Because that study was performed in patients with various diseases, we confirmed the reported associations in a general population. Participants in the current study were from the Shizuoka component of the Japan Multi-Institutional Collaborative Cohort Study, which included 4971 men and women aged 35 to 69years who were recruited between 2006 and 2007. We analyzed the association of seven selected SNPs with the following erythrocyte traits: red blood cell count, hemoglobin (Hb) and hematocrit (Ht) levels, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. The erythrocyte traits were regressed on a number of minor alleles of selected SNPs. Then we compared our findings with those from a genome-wide association study performed in a Japanese population. We replicated the association of ABO rs495828, PDGFRA-KIT rs218237, USP49-MED20-BSYL CCND3 rs3218097, C6orf182-CD164 rs11966072, TERT rs2736100, and TMPRSS6 rs5756504 with erythrocyte traits in our independent Japanese population. In addition, we found a significant interaction between TERT rs2736100 and smoking habit that affected Hb and Ht levels. PMID- 29133147 TI - cDNA sequences of GHF9 endo-beta-1,4-glucanases in terrestrial Crustacea. AB - This study aimed to sequence and identify a glycosyl hydrolase family 9 (GHF9) endo-beta-1,4-glucanase expressed in the midgut gland of the herbivorous gecarcinid land crab, Gecarcoidea natalis. Hence this would explain the gene responsible for the production of previously purified and characterised endo-beta 1,4-glucanases. Three different transcripts, two complete and one partial were sequenced from cDNA and an open reading frame of 1383bp was produced. Translated, this would produce a putative protein of 460 amino acid residues, including a 16 amino acid residue signal peptide. The mature protein (without signal peptide) is predicted to have a molecular mass of 47.6-47.7kDa; this closely matches the molecular mass (47.4kDa) of one of the three endo-beta-1,4-glucanase/lichenase enzymes purified previously from G. natalis. It is therefore proposed that the gene described here encodes one of the previously characterised enzymes. The presence of multiple transcripts suggests gene duplication. To confirm that the gene is widely expressed within the Crustacea, cDNA encoding a GHF9 endo-beta-1,4 glucanase was also sequenced in diverse crustaceans, the deposit feeding soldier crab, Mictyris platycheles and the terrestrial hermit crabs, Coenobita purlatus and C. brevimanus. An open reading frame of 1356bp was sequence from M. platycheles, while an incomplete open reading frames of 1384 and 1523bp were respectively sequenced from Coenobita brevimanus and C. perlatus. The midgut gland of M. platycheles contained activity (0.704+/-0.218MUmol reducing sugars produced. min-1.mg-1 tissue wet weight) of a 26.3+/-0.3(5) endo-beta-1,4 glucanase isozyme (determined from activity staining). These species, particularly M. platycheles does not consume and digest significant amounts of plant cellulose. This implies that the ancestral enzyme is not a cellulase, but rather it may be involved in hydrolysing cellulose like polysaccharides within other organisms such as algae. PMID- 29133149 TI - Spontaneous eye blink rate: An index of dopaminergic component of sustained attention and fatigue. AB - Blink rate is a behavioral index highly correlated with frontostriatal dopaminergic activity. The present research was aimed at studying the modulation of spontaneous blink rate in function of the increasing attentional load induced by the Mackworth Clock Test. Since blinking interferes with sensory processing, we expected a decreasing blink rate with increasing attentional demand. Three tasks of 7-min each and different difficulties were administered: the Mackworth had a red dot moving in a circle with intervals varying from 500ms, 350ms to 200ms, corresponding to increasing task difficulty. Participant had to detect the rare jumps of one position by the red dot (targets). The blink rate was recorded from thirty-three female students starting from vertical oculogram recording of the right eye. The time course of blink rate across the 7-min task was also analyzed to test the hypothesis that fatigue arises also during brief tasks depending on the difficulty level. Results showed that the Hard task (200ms dot intervals) was associated with greater percentage of missed targets, faster response times and smaller blink rates with respect to the Medium and Easy ones. Analysis of the time course within the task revealed an increase of blink rate, indexing larger fatigue, starting in the 4th minute, independent from the difficulty level. In addition, trial-by-trial analysis showed that under strong attentional demand dopamine-related blink activity was inhibited throughout the whole task. Results point to the use of blink rate as an ecological index of dopaminergic component of attentional load and fatigue and revealed how human attention drops after relatively brief intervals of about 4min. PMID- 29133151 TI - Laparoscopic Management of a Rudimentary Uterine Horn. AB - STUDY OBJECTIVE: To demonstrate a technique of laparoscopic management of a rudimentary horn in a 12-year-old girl. DESIGN: A step-by-step explanation of the surgery using a video (instructive video) approved by the local institutional review board. SETTING: A university hospital (University Hospital of Strasbourg, Strasbourg, France). PATIENT: A 12-year-old girl with a uterine rudimentary horn. INTERVENTION: We describe a case of a 12-year-old girl who had no medical history. She had her first menstruation at 11 years old with major left pelvic pain occurring each month. Ultrasonography showed a duplication of the uterus with a liquid collection on the left side; this type of malformation is called an accessory and cavitated uterine mass. Medical treatment was initiated with progestin. Magnetic resonance imaging showed a left noncommunicating rudimentary horn with a unicornuate uterus. No other malformation was present, particularly in the kidneys. A primary vaginal endoscopy was performed showing a single cervix without vaginal malformation. It was decided to perform a laparoscopic excision of the left rudimentary horn. We placed a 10-mm optical port into the umbilicus and 3 accessory 5-mm trocars. Evaluation of the abdominal cavity showed 2 normal adnexas with normal ovaries. We decided to start with a left salpingectomy using the Ligasure device (Medtronic, Minneapolis, MN), staying close to the tube to preserve ovarian vascularization. The remnant fimbria must be removed to avoid cancerization. Then, the vesicouterine septum was divided until we reached the cervix to dissect the bladder from the rudimentary horn. The broad ligament was fenestrated in order to push the left ureter laterally .The utero-ovarian pedicle was transected with the Ligasure device; the left ovary was preserved and vascularized by the left infundibulopelvic ligament. We then dissected the left uterine artery. The posterior peritoneum was opened. The resection of the rudimentary horn was performed by means of a monopolar hook. The dissection was performed slowly with selective coagulation until we reached the cavity of the horn, with old blood flowing out. The entire cavity was removed, and we confirmed the absence of communication with the other part of the uterus. Uterine reconstruction was performed with inverted separated stiches of a 2-0 braided suture, and, finally, an antiadhesion barrier was placed. CONCLUSIONS: Laparoscopic management of a uterine rudimentary horn is feasible with satisfactory uterine reconstruction. This is not the first case of this surgery performed by laparoscopy. A similar case has been published in 2015 [1], and recently another video [2] has been published describing 2 other cases. PMID- 29133150 TI - Structure and function of Per-ARNT-Sim domains and their possible role in the life-cycle biology of Trypanosoma cruzi. AB - Per-ARNT-Sim (PAS) domains of proteins play important roles as modules for signalling and cellular regulation processes in widely diverse organisms such as Archaea, Bacteria, protists, plants, yeasts, insects and vertebrates. These domains are present in many proteins where they are used as sensors of stimuli and modules for protein interactions. Characteristically, they can bind a broad spectrum of molecules. Such binding causes the domain to trigger a specific cellular response or to make the protein containing the domain susceptible to responding to additional physical or chemical signals. Different PAS proteins have the ability to sense redox potential, light, oxygen, energy levels, carboxylic acids, fatty acids and several other stimuli. Such proteins have been found to be involved in cellular processes such as development, virulence, sporulation, adaptation to hypoxia, circadian cycle, metabolism and gene regulation and expression. Our analysis of the genome of different kinetoplastid species revealed the presence of PAS domains also in different predicted kinases from these protists. Open-reading frames coding for these PAS-kinases are unusually large. In addition, the products of these genes appear to contain in their structure combinations of domains uncommon in other eukaryotes. The physiological significance of PAS domains in these parasites, specifically in Trypanosoma cruzi, is discussed. PMID- 29133148 TI - Adventitious viruses in insect cell lines used for recombinant protein expression. AB - Insect cells are widely used for recombinant protein expression, typically as hosts for recombinant baculovirus vectors, but also for plasmid-mediated transient transfection or stable genetic transformation. Insect cells are used to express proteins for research, as well as to manufacture biologicals for human and veterinary medicine. Recently, several insect cell lines used for recombinant protein expression were found to be persistently infected with adventitious viruses. This has raised questions about how these infections might affect research performed using those cell lines. Furthermore, these findings raised serious concerns about the safety of biologicals produced using those cell lines. In response, new insect cell lines lacking adventitious viruses have been isolated for use as improved research tools and safer biological manufacturing platforms. Here, we review the scientific and patent literature on adventitious viruses found in insect cell lines, affected cell lines, and new virus-free cell lines. PMID- 29133152 TI - Laparoscopic-Assisted Uterus Retrieval From Live Organ Donors for Uterine Transplant. AB - STUDY OBJECTIVE: The authors present the first ever laparoscopic-assisted uterus retrieval in a live donor for uterus transplant. DESIGN: A step-by-step surgical demonstration. SETTING: Galaxy CARE Laparoscopy Institute, Pune, India. PATIENTS: Two patients, ages 21 and 26 years, with Mayer-Rokitansky-Kuster-Hauser syndrome and Asherman syndrome, respectively, with their mothers as donors. INTERVENTIONS: A 12-member team was formed. After a review of the available literature on uterine transplant, a protocol was formulated and submitted to the Institutional Review Board (IRB). Approval from the Institutional Review Board was obtained. Thorough screening of the candidates was done. Two consecutive uterine transplants were done on 2 successive days. Vessels were harvested laparoscopically in both donors. Uterus was retrieved through a small abdominal incision, to prevent any injury to the uterus and harvested vessels. Uterus was transplanted in the recipients by end-to-side anastomosis of the harvested vessels to the external iliac vessels, followed by anchoring of supports of the donor uterus to those of the recipients. MEASUREMENTS AND MAIN RESULTS: Surgical intra- and postoperative parameters, postoperative investigations, and follow-up data of 4 months. The operative time for laparoscopic donor surgery was 4 hours. Bench surgery took 45 minutes. The recipient surgery was completed in 4 hours. There were no intraoperative or immediate postoperative complications. Both recipients started menstruating after 34 days and 48 days, respectively, and have had 3 cycles of menses at regular intervals to date. After discharge, follow-up cervical biopsies at 3 weekly intervals showed no signs of rejection. Uterine artery Doppler ultrasound showed good flow in both patients. CONCLUSION: Laparoscopic-assisted donor retrieval is feasible and affords all advantages of a minimally invasive technique. It helps in better dissection of vessels, shortens the operative time, and helps minimize tissue handling, thereby reducing the morbidity of the procedure. PMID- 29133153 TI - Nitroxoline in geriatric patients with lower urinary tract infection fails to achieve microbiologic eradication: a noncomparative, prospective observational study. PMID- 29133155 TI - A prospective study of travellers' diarrhoea: analysis of pathogen findings by destination in various (sub)tropical regions. AB - OBJECTIVES: Eighty million travellers visiting (sub)tropical regions contract travellers' diarrhoea (TD) each year, yet prospective data comparing the prevalence of TD pathogens in various geographical regions are scarce. Our recent study using modern molecular methods found enteropathogenic (EPEC) and enteroaggregative (EAEC) Escherichia coli to be the most frequent pathogens, followed by enterotoxigenic E. coli (ETEC) and Campylobacter. We revisited our data to compare the findings by geographical region. METHODS: A total of 459 prospectively recruited travellers provided stool samples and completed questionnaires before and after visiting destinations in various geographical regions. A multiplex quantitative real-time PCR assay was used to analyse Salmonella, Yersinia, Campylobacter jejuni/Campylobacter coli, Shigella, Vibrio cholerae, EPEC, EAEC, ETEC, enterohaemorrhagic E. coli and enteroinvasive E. coli. RESULTS: TD was contracted by 69% (316/459) of the subjects; EPEC and EAEC outnumbered ETEC and Campylobacter in all regions. Multiple pathogens were detected in 42% (133/316) of the samples. The proportions of all pathogens varied by region. The greatest differences were seen for Campylobacter: while relatively frequent in South Asia (n = 11; 20% of the 55 with TD during travel) and Southeast Asia (15/84, 15%), it was less common in East and West Africa (5/71, 7% and 1/57, 2%) and absent in South America and the Caribbean (0/40). CONCLUSIONS: EPEC and EAEC outnumbered ETEC and Campylobacter everywhere, yet the proportions of pathogen findings varied by region, with ETEC and Campylobacter rates showing the greatest differences. The high frequency of multibacterial findings in many regions indicates a need for further investigation of the clinical role of each pathogen. PMID- 29133154 TI - Adverse birth outcomes associated with Zika virus exposure during pregnancy in Sao Jose do Rio Preto, Brazil. AB - OBJECTIVES: We aimed to report the first 54 cases of pregnant women infected by Zika virus (ZIKV) and their virologic and clinical outcomes, as well as their newborns' outcomes, in 2016, after the emergence of ZIKV in dengue-endemic areas of Sao Paulo, Brazil. METHODS: This descriptive study was performed from February to October 2016 on 54 quantitative real-time PCR ZIKV-positive pregnant women identified by the public health authority of Sao Jose do Rio Preto, Sao Paulo, Brazil. The women were followed and had clinical and epidemiologic data collected before and after birth. Adverse outcomes in newborns were analysed and reported. Urine or blood samples from newborns were collected to identify ZIKV infection by reverse transcription PCR (RT-PCR). RESULTS: A total of 216 acute Zika-suspected pregnant women were identified, and 54 had the diagnosis confirmed by RT-PCR. None of the 54 women miscarried. Among the 54 newborns, 15 exhibited adverse outcomes at birth. The highest number of ZIKV infections occurred during the second and third trimesters. No cases of microcephaly were reported, though a broad clinical spectrum of outcomes, including lenticulostriate vasculopathy, subependymal cysts, and auditory and ophthalmologic disorders, were identified. ZIKV RNA was detected in 18 of 51 newborns tested and in eight of 15 newborns with adverse outcomes. CONCLUSIONS: Although other studies have associated many newborn outcomes to ZIKV infection during pregnancy, these same adverse outcomes were rare or nonexistent in this study. The clinical presentation the newborns we studied was mild compared to other reports, suggesting that there is significant heterogeneity in congenital Zika infection. PMID- 29133156 TI - Current status of spurt of chikungunya in Pakistan. PMID- 29133157 TI - Microbiologic and clinical characteristics of biofilm-forming Candida parapsilosis isolates associated with fungaemia and their impact on mortality. AB - OBJECTIVES: Biofilm formation (BF) by fungal isolates may dramatically complicate infection. We determined the ability of Candida parapsilosis isolates from single fungaemia episodes to form biofilms and we analysed biofilm subgroups for antifungal susceptibility and pathogenic potential. We then correlated BF with clinical characteristics and outcomes of the episodes. METHODS: BF was measured using the crystal violet biomass assay. Antifungal susceptibility of preformed biofilms was assessed, and virulence was studied using the Galleria mellonella model. A retrospective analysis of patients' clinical records was performed. RESULTS: Of 190 patient-unique isolates, 84, 38 and 68 were identified as having high BF (HBF), moderate BF (MBF) or low BF (LBF), respectively. Among 30 randomly selected isolates, nine (eight HBF and one MBF), six (all HBF) and one (HBF) isolates had elevated sessile minimum inhibitory concentrations to fluconazole, anidulafungin or amphotericin B; all HBF and MBF isolates had elevated voriconazole sessile minimum inhibitory concentrations. G. mellonella killing rates of HBF isolates were significantly greater than MBF (or LBF) isolates (50% vs. 20%, 2 days from infection). By comparing HBF/MBF (106 patients) and LBF (84 patients) groups, we found that HBF/MBF patients had more central venous catheter related fungaemias (62/106 (58.5%) vs. 29/84 (34.5%), p 0.001) and were more likely to die at 30 days from fungaemia onset (61/106 (57.5%) vs. 28/84 (33.3%), p 0.01). In the HBF/MBF group, azole antifungal therapy and central venous catheter removal were significantly associated with a higher and lower 30-day mortality rate, respectively. CONCLUSIONS: C. parapsilosis BF influences the clinical outcome in patients with fungaemia. PMID- 29133158 TI - CMI policy on antimicrobial stewardship research. PMID- 29133159 TI - Highly conserved exposed immunogenic peptides of Omp34 against Acinetobacter baumannii: An innovative approach. AB - Omp34, also known as Omp34kDa or Omp33-36 is a virulence factor associated with A. baumannii metabolic fitness or its adherence and invasion to human epithelial cells. This protein is also introduced as a specific antigen which could induce strong antibody responses. In the present in silico study, recent vaccine design strategies such as 'antigen minimization' and 'high epitope density' were invoked to design a soluble immunogen with higher antigenicity. As an advantage, the tools employed in the current study are easily available. Exposed peptides in linear B-cell epitopes were predicted and their conservancy and immunogenicity were evaluated. In this regard, constructs were designed by removal of inappropriate regions. Based on the obtained results the external loops (L1-L7) were exclusively considered of which L3, L6 and L7 were the most appropriate of which the most appropriate were in L3>L6>L7 order while L2 was assigned as an inappropriate peptide. The final construct, named Omp34-4, encompasses three copies of L3, two copies of L6 and L7 and one copy of L1, L4 and L5. The designed construct is predicted to be a soluble antigen with enhanced epitope density and antigenicity. Omp34 is present in >1600 strains of A. baumannii with >=98% identity. So, it could be applicable in diagnostic kits and an immunotherapy choice against A. baumannii. It could be presumed that co-administration of Omp34 4 and a recently designed OmpA-derived antigen could confer sufficient protection against A. baumannii-associated infections. In vitro and in vivo experiments are needed to confirm all these data. The innovative approach could be generalized to vaccine designs focused on OMPs. PMID- 29133160 TI - The changes of red blood cell viscoelasticity and sports anemia in male 24-hr ultra-marathoners. AB - BACKGROUND: In endurance sports, stress, dehydration and release of chemical factors have been associated with red blood cell (RBC) alterations of structure and function, which may contribute to sports anemia, a well-observed phenomenon during long-distance running. Until now, the investigation of the changes of viscoelastic properties of RBC membrane, a decisive factor of RBC deformability to avoid hemolysis, is lacking, especially in an Oriental population. METHODS: nineteen runners were prospectively recruited into our study. Hematological parameters were analyzed before and immediately after the 2015 Taipei 24H Ultra Marathon Festival, Taiwan. Video particle tracking microrheology was used to determine viscoelastic properties of each RBC sample by calculating the dynamic elastic modulus G'(f) and the viscous modulus G"(f) at frequency f = 20 Hz. RESULTS: Haptoglobin, RBC count, hemoglobin, hematocrit, mean cell hemoglobin, plasma free hemoglobin and unsaturated iron-binding capacity values of the recruited runners showed a statistically significant drop in the post-race values. Blood concentration of reticulocyte and ferritin were significantly higher at post-race compared with pre-race. 15 out of the 19 runners had a concurrent change in the elastic and the viscous moduli of their RBCs. Changes in the elastic and the viscous moduli were correlated with changes in the RBC count, hemoglobin and hematocrit. CONCLUSION: Viscoelasticity properties, the elastic modulus G'(f) and the viscous modulus G"(f) of RBCs are associated with endurance exercise-induced anemia. PMID- 29133161 TI - The efficacy of high volume of local infiltration analgesia for postoperative pain relief after total hip arthroplasty under general anaesthesia - A randomised controlled trial. AB - BACKGROUND AND AIM: Research regarding patients undergoing total hip arthroplasty (THA) has shown no significant difference in postoperative pain with or without the use of local infiltration analgesia (LIA). The aim was to evaluate whether intra-operative LIA with Ropivacaine in patients undergoing THA under general anaesthesia reduces postoperative pain. METHOD: A randomised, placebo-controlled trial. Forty patients undergoing elective primary THA under general anaesthesia were allocated to an intervention group (RG) who received 150 ml of LIA or a placebo group (CG) who received 150 ml of saline solution. RESULTS: There were no differences in demographic data or duration of anesthesia. The total mean dose of morphine given was 16 +/- 12 mg (RG) and 13 +/- 9 mg (CG) (p=0.238). Pain scores (Numeric rating scale, NRS) on arrival at the PACU (time 0) were Md 1 in the RG groupvs Md 5 in the CG group (p = 0.026). During the first 2 h the Md NRS values in the RG group were <=3 whereas the Md values in the CG were >=3. No significant differences in NRS were found at 1-6 h after arrival at the PACU. CONCLUSION: Our study suggests that there is a positive effect of LIA on pain scores within the first hour postoperatively in patients undergoing elective primary THA under general anaesthesia. PMID- 29133162 TI - ? PMID- 29133164 TI - Pre-incision urethral plate width does not impact short-term Tubularized Incised Plate urethroplasty outcomes. AB - INTRODUCTION: Two reports have found that urethral plate (UP) widths <8 mm before tubularized incised plate (TIP) incision increased urethroplasty complications. The present study measured pre-incision UP width in consecutive boys undergoing TIP to determine if it affected outcomes. METHODS: The present study followed the method previously used by Holland and Smith, and Sarhan et al. to measure UP width before creating glans wings or performing midline plate incision in consecutive patients with primary hypospadias and ventral curvature <30 degrees , who all underwent TIP repair (Summary Fig.). Glans width at its widest point was also measured. Multiple logistic regression assessed urethroplasty complications (fistula, glans dehiscence, meatal stenosis/urethral stricture, diverticulum) based on pre-incision UP width, glans width, patient age, and meatal location. RESULTS: The UP widths were determined in 224 consecutive primary TIP repairs during 2012-2015: 200 distal, 11 midshaft, and 13 proximal. The UP width was <8 mm in 192/224 (86%) patients. Mean pre-incision width was 6.1 mm (SD 1.5, range 2 11), without difference in UP widths according to meatal location (P = 0.06). Mean post-incision UP width was 12 mm (SD 2.2, range 10-16). Mean change in width after incision (delta/original UP width) was 116% (SD 63, range 20-250). There was follow-up in 186 patients for a mean of 6 months. Urethroplasty complications (five fistulas, six glans dehiscence) were diagnosed in 11 (6%): 9/165 distal, 1/9 midshaft, and 1/12 proximal repairs. There was no difference in those <8 vs >=8 mm (11/160 vs 0/26, P = 0.17). Similarly, UP width was not different between patients with and without urethroplasty complications. Multiple logistic regression in these 186 patients - including meatal location, UP width, glans width, and age - found only glans width <14 mm was associated with increased odds of urethroplasty complications (OR 19.2, 95% CI 3.5-106, AUC = 0.799). DISCUSSION: The data show that pre-incision UP width is not an independent risk factor for urethroplasty complications. However, it is possible that technical factors, such as how deeply the dorsal incision is made or size of the urethral stent, might contribute to this finding by other authors. After watching the TIP repair, Smith stated that the plate incision was deeper than he made. Sarhan et al. reported a mean change of 57% in UP width after incision, whereas the present one was double at 116% (i.e. from 6 mm pre-incision to 12 mm post incision), and they used an 8-Fr catheter. While they stated that they incised the plate deeply, the lower percentage increase in width suggests that it was not as deep as was recommended. CONCLUSIONS: The UP width before incision did not increase urethroplasty complications. Surgeons do not need to measure or categorize the UP to determine suitability for TIP repair, as long as the plate incision is made deeply to the corpora. PMID- 29133165 TI - Infant crossed renal ectopia with UPJ obstruction repaired via robot-assisted laparoscopic pyeloplasty. AB - INTRODUCTION: We present a robot-assisted approach to surgical treatment of UPJ obstruction associated with crossed renal ectopia in a male infant. METHODS: A 31 year-old woman presented at 37 weeks gestation for prenatal hydronephrosis and delivered at 39 weeks. Renal ultrasound identified the bladder and right kidney in a crossed ectopic position in the left pelvis, and MRI showed the cystic lesion to be hydronephrosis associated with a ureteropelvic junction obstruction of the crossed ectopic right kidney. At three months of age, a robot-assisted laparoscopic dismembered pyeloplasty was performed. Post-operative renal ultrasounds at one, two, and 7 months showed persistent but decreasing hydronephrosis. He remains asymptomatic. DISCUSSION: Crossed renal ectopia with associated ureteropelvic junction obstruction has been reported in the literature and managed using both open and minimally invasive approaches. To our knowledge, this is the first reported robot-assisted pyeloplasty performed for this condition in an infant. CONCLUSIONS: With careful patient selection, the robot assisted laparoscopic approach can be applied to infants that require pyeloplasty for kidneys with anomalous development that have evidence of ureteropelvic junction obstruction. PMID- 29133166 TI - Determination of threshold value for follow-up of isolated antenatal hydronephrosis detected in the second trimester. AB - INTRODUCTION: Isolated antenatal hydronephrosis (ANH), defined as a dilation of the renal pelvis (>=5 mm), is one of the most common abnormalities detected on prenatal ultrasound. However, established cut-off values for postnatal follow-up differ between countries and are based on little evidence. The current protocol in the Netherlands for follow-up might be too conservative. OBJECTIVE: To assess the applicability of a higher threshold for follow-up of isolated antenatal hydronephrosis (ANH) than the current practice, without the risk of missing significant postnatal urinary tract obstruction. STUDY DESIGN: Retrospective case series on all fetuses with isolated ANH (anteroposterior pelvic diameter (APPD) >=5 mm) at the second trimester anomaly scan, and diagnosed between 2000 and 2009, in relationship to renal outcome. RESULTS: A total of 279 infants with second trimester isolated ANH were included. In 201/279 (72%) fetuses, ANH had normalized (APPD <10 mm) before the third trimester scans. Hydronephrosis persisted postnatally in a minority of 56/279 (20.1%). Postnatal assessment showed signs of obstruction in 41/279 (14.7%) infants, duplicated collecting system or vesicoureteral reflux (VUR). Surgery was performed in 18/279 (6.5%) infants. A non-functioning kidney was shown in 6/279 (2.2%) infants with ANH. Mild ANH (APPD <7 mm) during the second trimester (172/279 (61.6%)) never resulted in surgery for renal anomalies or non-functioning kidney. Infants with an APPD >=10 mm in the second trimester were far more likely to develop renal anomalies or undergo surgery compared with infants with an APPD 7-10 mm. The number of non-functioning kidneys was too low to be conclusive. CONCLUSIONS: Follow-up ultrasounds for isolated ANH >=7 mm instead of >=5 mm at the second trimester scan would have saved 62% of third trimester scans, without missing any infant with a non-functioning kidney, significant obstruction or symptomatic VUR. In view of the results, it is reasonable that referral for follow-up of second trimester ANH is not strictly indicated in cases with an APPD <7 mm. PMID- 29133163 TI - Non-visual arrestins regulate the focal adhesion formation via small GTPases RhoA and Rac1 independently of GPCRs. AB - Arrestins recruit a variety of signaling proteins to active phosphorylated G protein-coupled receptors in the plasma membrane and to the cytoskeleton. Loss of arrestins leads to decreased cell migration, altered cell shape, and an increase in focal adhesions. Small GTPases of the Rho family are molecular switches that regulate actin cytoskeleton and affect a variety of dynamic cellular functions including cell migration and cell morphology. Here we show that non-visual arrestins differentially regulate RhoA and Rac1 activity to promote cell spreading via actin reorganization, and focal adhesion formation via two distinct mechanisms. Arrestins regulate these small GTPases independently of G-protein coupled receptor activation. PMID- 29133168 TI - Autologous granulation tissue tubes for replacement of urethral defects: An experimental study in male rabbits. AB - INTRODUCTION: Tubularized urethroplasty is commonly performed in clinical practice using genital skin flaps, bladder mucosa, and buccal mucosa. However, the long-term effects are not satisfying, and donor site morbidities remain a problem. Besides, those grafts are unavailable with malignant conditions of the urinary tract, a history of lichen sclerosis, or oral disease. OBJECTIVE: An autologous granulation tissue tube of any required length and diameter can be produced by implanting foreign objects subcutaneously (Summary Fig.). The current study aimed to investigate to what extent of length this fully autologous tissue could be used for tubularized urethroplasty, satisfying urethral patency and tissue regeneration, in male rabbits. STUDY DESIGN: Twenty-seven New Zealand male rabbits were randomly divided into three groups. Silastic tubes were implanted subcutaneously in Group 1 and Group 2. By 2 weeks the granulation tissue encapsulating the tubes was harvested. In Group 1, pendulous urethral segments of 1 cm were excised, and urethroplasty was performed with the granulation tissue tube in an end-to-end fashion. In Group 2, a pendulous urethral segment of 1.5 cm was replaced with the tissue tube. In Group 3, a pendulous urethral defect of 1 cm was repaired by re-anastomosis as control. Serial urethrograms were performed at 1, 2 and 6 months postoperatively. Meanwhile, the neo-urethra were harvested and analyzed grossly and histologically. RESULTS: The urethrograms showed that all animals in Group 1 maintained a wide urethral caliber. In contrast, animals in Group 2 and Group 3 developed progressive strictures. Histologically, an intact urothelium with one to two cell layers lined the graft by 1 month, which was surrounded by increasing organized smooth muscle in Group 1. By 6 months, the grafts were completely integrated into native urethra. Nevertheless, extensive fibrosis occurred in Group 2 and Group 3. DISCUSSION: The tissue successfully maintained patency and guided urethral regeneration across a distance of 1 cm. As an epithelium-free graft, the tissue showed better results than acellular matrix for tubularized urethroplasty compared with previous studies. Nevertheless, several limitations existed: (1) the urethral defect was created in healthy urethra, which could not fully simulate the clinical situation; (2) as a small animal model, rabbit was less informative for clinical problems; (3) the tissue was inadequate for long segmental urethral replacement. Further study is needed before the procedure is used clinically. CONCLUSION: An autologous granulation tissue tube grown subcutaneously could be successfully used to repair urethral defects of 1 cm in male rabbits. PMID- 29133167 TI - Patterns of lymph node sampling and the impact of lymph node density in favorable histology Wilms tumor: An analysis of the national cancer database. AB - INTRODUCTION: There is controversy about the role of lymph node (LN) sampling or dissection in the management of favorable histology (FH) Wilms tumor (WT), specifically how it performed and how it may impact survival. OBJECTIVE: The objective of this study was to analyze factors affecting LN sampling patterns and the impact of LN yield and density (number of positive LNs/LNs examined) on overall survival (OS) in patients with advanced-stage favorable histology Wilms tumor (FHWT). METHODS: The National Cancer Database (NCDB) was queried for patients with FHWT during 2004-2013. Demographic, clinical and OS data were abstracted for those who underwent surgical resection. Poisson regression was performed to analyze how factors influenced LN yield. Patients with positive LNs had LN density calculated and were further analyzed. RESULTS: A total of 2340 patients met criteria, with a median age at diagnosis of 3 years (range 0-78 years). The median number of LNs examined was three (range 0-87). Lymph node yield was affected by age, race, insurance, tumor size, laterality, advanced stage, LN positivity, and institutional volume. A total of 390 (16.6%) patients had LN-positive disease. Median LN density for these LN-positive patients was 0.38 (range 0.02-1) (Summary Figure). Estimated 5-year OS was significantly improved for those with LN density <=0.38 vs. >0.38 (94% vs. 84.6%, P = 0.012). In this population, on multivariate analysis, age and LN density were significant predictors of OS. DISCUSSION: It is difficult to compile large numbers of cases in rare diseases like WT, and fortunately a large administrative database such as the NCDB can serve as a great resource. However, administrative data come with inherent limitations such as missing data and inability to account for a variety of factors that may influence LN yield and/or OS (specimen designation, pathologist experience, surgeon experience/volume, institutional Children's Oncology Group (COG) association, etc.). In this specific disease, the American Joint Committee on Cancer staging (captured by the NCDB) is different than the COG WT staging system that is used clinically, and the NCDB does not capture oncologic outcomes beyond OS. CONCLUSIONS: In a review of the NCDB, various factors associated with LN yield and observed LN density were identified to be significantly associated with OS in patients with LN-positive FHWT. This reinforces the need for adequate LN sampling at the time of WT surgery, to maximize surgical disease control. It was proposed that LN density as a metric may allow for improved risk-stratification, and possibly allow for therapeutic reduction in a sub-set of patients with low LN density. PMID- 29133169 TI - Ureteroscopy for paediatric calculi: The twin-surgeon model. AB - We describe our 'Tips and tricks' of ureteroscopy and lasertripsy (URSL) for paediatric ureteric calculi. All regional referrals directed to the paediatric urologist are discussed in a formal stone multidisciplinary team (MDT) meeting with urologists, radiologists, and biochemical pathologist. A paediatric urologist (SG) and an experienced adult endourologist (BS) do these stone procedures jointly as a twin-surgeon team approach for each patient. PMID- 29133170 TI - Hydronephrosis and crossing vessels in children: Optimization of diagnostic therapeutic pathway and analysis of color Doppler ultrasound and magnetic resonance urography diagnostic accuracy. AB - INTRODUCTION: Ureteropelvic junction obstruction (UPJO) is one of the most frequent urological diseases affecting the pediatric population. It can be due to both intrinsic stenosis of the junction and extrinsic causes such as the presence of crossing vessels (CVs), which can be detected by color Doppler ultrasound (CD US). Magnetic resonance urography (MRU) is a good alternative, but sedation and infusion of a contrast agent are required. OBJECTIVE: The aim of this study was to analyze the diagnostic accuracy of CD-US and MRU in visualizing CVs in pediatric hydronephrosis, in order to decide the correct diagnostic pathway in the pre-operative phase. MATERIAL AND METHODS: A retrospective review was performed of medical records for all patients who underwent surgical treatment for hydronephrosis from August 2006 to February 2016. Ultrasound and scintigraphy had been performed on all patients. Data about CD-US and MRU were collected. A high-level technology ultrasound scanner and a 1.5 T MR scanner were used. The presence of CVs at surgery was considered the gold standard. Sensitivity, specificity, positive and negative predictive values (NPV) were calculated and reported for both of the imaging techniques. RESULTS: A total of 220 clinical charts were reviewed. Seventy-three CVs were identified at surgery (33.2% of UPJO). The median age was statistically higher in the group with CVs compared to the group without CVs (P < 0.001). The sensitivity and NPV of CD-US in detecting CVs were higher than MRU (sensitivity 93.3% vs. 71.7%, NPV 95.7% vs. 77.6%, respectively). DISCUSSION: According to the data, CD-US had higher sensitivity and NPV than MRU, resulting in superior detection of CVs. It is important for a surgeon to know that a child has a CV, especially in older children in which the incidence of extrinsic UPJO is higher. The main limitation of this study was the presence of incomplete data, due to the retrospectivity. CONCLUSIONS: In the pre operative phase, the CD-US should be considered as the investigation of choice to detect CVs in children with hydronephrosis (Summary Fig). Moreover, CD-US has lower costs than MRU, and sedation with infusion of contrast agent is unnecessary. For the future, it could be useful to lead a prospective comparison between the two imaging techniques. PMID- 29133171 TI - Addressing antimicrobial resistance in the UK and Europe. PMID- 29133172 TI - Measuring the emulsification dynamics and stability of self-emulsifying drug delivery systems. AB - Self-emulsifying drug delivery systems (SEDDS) are one of the most promising technologies in the drug delivery field, particularly for addressing solubility and bioavailability issues of drugs. The development of these drug carriers excessively relies in visual observations and indirect determinations. The present manuscript intended to describe a method able to measure the emulsification of SEDDS, both micro and nano-emulsions, able to measure the droplet size and to evaluate the physical stability of these formulations. Additionally, a new process to evaluate the physical stability of SEDDS after emulsification was also proposed, based on a cycle of mechanical stress followed by a resting period. The use of a multiparameter continuous evaluation during the emulsification process and stability was of upmost value to understand SEDDS emulsification process. Based on this method, SEDDS were classified as fast and slow emulsifiers. Moreover, emulsification process and stabilization of emulsion was subject of several considerations regarding the composition of SEDDS as major factor that affects stability to physical stress and the use of multicomponent with different properties to develop a stable and robust SEDDS formulation. Drug loading level is herein suggested to impact droplets size of SEDDS after dispersion and SEDDS stability to stress conditions. The proposed protocol allows an online measurement of SEDDS droplet size during emulsification and a rationale selection of excipients based on its emulsification and stabilization performance. PMID- 29133173 TI - Effects of norquetiapine, the active metabolite of quetiapine, on cloned hERG potassium channels. AB - Quetiapine is an atypical antipsychotic drug that is widely used for the treatment of schizophrenia. It is mainly metabolized by a cytochrome P450 system in the liver. Norquetiapine is a major active metabolite in humans with a pharmacological profile that differs distinctly from that of quetiapine. We used the whole-cell patch-clamp technique to investigate the effects of norquetiapine on hERG channels that are stably expressed in HEK cells. Quetiapine and norquetiapine inhibited the hERG tail currents at -50mV in a concentration dependent manner with IC50 values of 8.3 and 10.8MUM, respectively, which suggested equal potency. The block of hERG currents by norquetiapine was voltage dependent with a steep increase over a range of voltages for channel activation. However, at more depolarized potentials where the channels were fully activated, the block by norquetiapine was voltage-independent. The steady-state inactivation curve of the hERG currents was shifted to the hyperpolarizing direction in the presence of norquetiapine. Norquetiapine did not produce a use-dependent block. A fast application of norquetiapine inhibited the hERG current elicited by a 5s depolarizing pulse to +60mV, which fully inactivated the hERG currents, suggesting an inactivated-state block. During a repolarizing pulse wherein the hERG current was slowly deactivated, albeit remaining in an open state, a fast application of norquetiapine rapidly and reversibly inhibited the open state of the hERG current. Our results indicated that quetiapine and norquetiapine had equal potency in inhibiting hERG tail currents. Norquetiapine inhibited the hERG current by preferentially interacting with the open and/or inactivated states of the channels. PMID- 29133174 TI - ABCA1 rs2230805 and rs2230806 common gene variants are associated with Alzheimer's disease. AB - The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a relevant positional and functional candidate gene for Alzheimer's disease (AD). A case control association study of genetic variations covering the ABCA1 locus was performed in relation to AD risk in a Hungarian sample. Five single nucleotide polymorphisms (rs2422493: C-477T, rs2740483: G-17C, rs2230805: G474A/L158L, rs2230806: G656A/R219K and rs2066718: G2311A/V771M) were genotyped in 431 AD patients and 302 cognitively healthy, elderly controls. In single marker analysis, significant associations were found in the case of rs2230805 and rs2230806 polymorphisms: the minor A allele containing genotypes for both polymorphisms were more frequent in the control compared to the AD group. Haplotype analysis revealed that rs2230805, rs2230806 and rs2066718 polymorphisms created a linkage disequilibrium (LD) block with a strong LD between rs2230805 and rs2230806 polymorphisms. In the haplotype risk association tests, A-A-G haplotype of the rs2230805-rs2230806-rs2066718 polymorphisms was found to be nominally significantly more frequent in the control group. After correcting p values for multiple testing, only the effects of the rs2230805 and rs2230806 polymorphisms remained significant in the recessive model suggesting a modest protective effect of their minor alleles in AD, which should be interpreted with considerable caution, until further studies elucidate their role in AD pathology. PMID- 29133175 TI - Role of KCNQ2 channels in orofacial cold sensitivity: KCNQ2 upregulation in trigeminal ganglion neurons after infraorbital nerve chronic constrictive injury. AB - Sensitivity to cooling temperatures often becomes heightened in orofacial regions leading to orofacial cold allodynia/hyperalgesia after chronic trigeminal nerve injury. KCNQ2 channels are involved in controlling excitability of primary afferent neurons and thereby regulate sensory functions under both physiological and pathological conditions. In the present study, we sought to determine whether KCNQ2 channels in trigeminal nerves are involved in regulating orofacial operant behavioral responses to cooling stimulation. We also sought to examine whether chronic trigeminal nerve injury may alter KCNQ2 channel expression in trigeminal ganglions. Using the orofacial operant tests, animals show cold allodynia/hyperalgesia in orofacial regions following infraorbital nerve chronic constrictive injury (ION-CCI), which could be alleviated by subcutaneous administration of retigabine, a KCNQ2 activator. In contrast, subcutaneous administration of the KCNQ2 inhibitor XE991 directly elicits cold allodynia/hyperalgesia in sham animals. Using immunostaining, we show that KCNQ2 channels are primarily expressed in small-sized TG neurons. Interestingly, KCNQ2 channel expression becomes significantly upregulated in TG neurons following the ION-CCI. Our results suggest that KCNQ2 channels are involved in regulating orofacial cold sensitivity. Upregulation of KCNQ2 channels may be a compensatory change in attempting to limit injury-induced trigeminal hyperexcitability. PMID- 29133176 TI - Effect of zonisamide on refractory epilepsy during pregnancy in lamotrigine resistant kindled rats. AB - Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the art medical treatment continues to be a major clinical problem. Pregnancy is a state where drug pharmacokinetic changes are more pronounced and more rapid than any other period of life. The current study investigated the effect of zonisamide (ZNS) on refractory epilepsy during pregnancy in lamotrigine-resistant kindled rats. Fifty-six lamotrigine (LTG)-resistant kindled Wistar rats were divided into five experimental (four pregnant and one non-pregnant) and 2 positive controls (pregnant and non-pregnant) groups and eight intact Wistar rats were put in the negative pregnant control group. Experimental groups received daily ZNS 50mg/kg by oral gavage and 30min later, pentylenetetrazol (PTZ) (30mg/kg) was injected intraperitoneal (i.p) on Gestational Days 10-15 (in rats with or without ZNS or methanol and ethyl acetate as a ZNS solvent challenge in days -5 to 0) or Days 15 20 and for six days in the non-pregnant group. The positive control groups received the ZNS solvent for the same number of days, but the negative pregnant control group did not receive any treatment. Epilepsy was significantly controlled by ZNS in the experimental groups compared to the positive control groups. It was concluded that ZNS can control refractory epilepsy during pregnancy and increase pregnancy survival in refractory epileptic rats. PMID- 29133177 TI - Region-specific alterations in astrocyte and microglia morphology following exposure to blasts in the mouse hippocampus. AB - Traumatic brain injury (TBI) is a serious public health concern, especially injuries from repetitive insults. The main objective of this study was to immunocytochemically examine morphological alterations in astrocytes and microglia in the hippocampus 48h following a single blast versus multiple blasts in adult C57BL/6 mice. The effects of ketamine and xylazine (KX), two common anesthetic agents used in TBI research, were also evaluated due to the confounding effect of anesthetics on injury outcome. Results showed a significant increase in hypertrophic microglia that was limited to the outer molecular layer of the dentate gyrus, but only in the absence of KX. Although the presence or absence of KX had no effect on astrocytes following a single blast, a significant decrease in astrocytic immunoreactivity was observed in the stratum lacunosum moleculare following multiple blasts in the absence of KX. The morphological changes in astrocytes and microglia reported in this study reveal region-specific differences in the absence of KX that could have significant implications for our interpretation of glial alterations in animal models of injury. PMID- 29133178 TI - Lymphatic vasculature in human dural superior sagittal sinus: Implications for neurodegenerative proteinopathies. AB - Recent reports have characterized functional lymphatic vessels, which drain both fluid and immune cells from the CSF to the deep cervical lymph nodes, lining the dural sinuses in mice. If conserved in the human brain these vessels could have profound implications for neuroinflammatory and neurodegenerative diseases. We provide evidence of the presence of lymphatic vessels in human dura obtained at autopsy, at the level of the superior sagittal sinus, in 4 individuals. Immunohistochemistry for the lymphatic vessel endothelial cell marker podoplanin revealed the widespread presence of multiple structures with a distinct lumen distributed throughout the superior sagittal sinus. These vessels provide a putative infrastructure for drainage of macromolecules from the brain parenchyma and represent an exciting avenue of exploration for involvement in the pathogenesis of neurodegenerative proteinopathies including Parkinson's disease. PMID- 29133179 TI - Stage-related central corneal epithelial transformation in congenital aniridia associated keratopathy. AB - PURPOSE: To relate central corneal epithelial phenotype to degree of keratopathy in a limbal stem cell deficient population. METHODS: 37 patients (67 eyes) with aniridia-associated keratopathy (AAK) underwent corneal examination including slit lamp biomicroscopy to determine the Grade of AAK, Cochet-Bonnet esthesiometry, and in vivo confocal microscopy (IVCM) to assess morphology of the central corneal epithelium and subepithelial region. RESULTS: AAK Grade ranged from 1 (limbal involvement only) to 4 (total conjunctivalization), with progression from Grade 1 occurring after the age of 20. 30% of subjects had an asymmetric Grade between eyes. In early-stage AAK (Grades 1-2), central epithelial cells had mixed corneal-conjunctival phenotype, touch sensitivity and subbasal nerves diminished, and mature dendritic cells, inflammatory leukocytes, and blood vessels were present despite central transparency in the slit lamp. In later stages (Grades 3-4) of the LSCD, neural deficit and nerve function worsened, immune cell invasion increased, and lymphatic vessels were detected in several cases. Goblet cells and epithelial cysts were observed to varying degrees in all stages, but without clear association to AAK severity. The clinical grade and progression of AAK was strongly associated with the central corneal epithelial phenotype. CONCLUSIONS: AAK is associated with degradation of epithelial phenotype, a neural deficit, and immune compromised status even in the clear central cornea in the earliest stages. IVCM can aid in assessing whether the conditions for limbal stem cell maintenance are likely to exist, based on morphology of the central epithelial microenvironment. PMID- 29133180 TI - Exposure to perfluoroalkyl substances during pregnancy and child behaviour at 5 to 9years of age. AB - We examined associations between prenatal exposure to perfluorohexane sulfonic acid (PFHxS), perfluoroheptanoic acid (PFHpA), perfluorononanoic acid (PFNA), and perfluorodecanic acid (PFDA) - and child behaviour (SDQ-total) and hyperactivity (sub-scale) at 5-9years of age in birth cohorts from Greenland and Ukraine. Pregnancy serum samples (N=1023) were analysed for perfluoroalkyl substances (PFASs) and categorised into tertiles and also used as continuous exposure variables. Problem behaviour and hyperactivity were assessed, using the Strength and Difficulties Questionnaire (SDQ) and categorised as normal/borderline and abnormal. Associations were analysed using multiple logistic and linear regression. High compared to low prenatal PFHxS exposure was associated with 1.16 (95% confidence interval (CI): 0.08; 2.25) point higher SDQ-total (more problem behaviour) in Greenland and 0.80 (CI: 0.06; 1.54) point higher SDQ-total in the combined analyses, whereas no association was present in Ukraine alone. One natural log-unit increase in prenatal PFNA exposure was associated with 0.90 (CI: 0.10; 1.71) points higher SDQ-total in Greenland and 0.72 (CI: 0.13; 1.31) points higher in the combined analysis and no association in Ukraine. Prenatal PFAS exposure was unrelated to problem behaviour (abnormal SDQ-total). In the combined analysis, odds ratio (OR) (CI) for hyperactivity was 1.8 (1.0; 3.2) for one natural log-unit increase in prenatal PFNA and 1.7 (1.0; 3.1) for one natural log unit increase in prenatal PFDA exposure. Findings are compatible with weak effects on child behaviour of prenatal exposure to some PFASs although spurious results are not entirely unlikely. The associations were strongest in Greenland. PMID- 29133181 TI - National trends in admission for cardiac rehabilitation after a myocardial infarction in France from 2010 to 2014. AB - BACKGROUND: Follow-up care and rehabilitation services [soins de suite et readaptation (SSR)], especially cardiac rehabilitation (CR), constitute a key stage for patients who have had an acute myocardial infarction (AMI). AIMS: To study admission to SSR, especially for CR, among patients hospitalized for AMI in France in 2014, and its temporal trend between 2010 and 2014. METHODS: We used the French National Hospital Database to select patients hospitalized with a main diagnosis of AMI (identified by ICD-10 codes I21 to I23) in the first semester of each year from 2010 to 2014. We then searched for rehabilitation admission in the 6 months after the index hospitalization. We calculated age-standardized rates of admission for CR and for other rehabilitation purposes. The average annual percentage change in admission rates was analysed by Poisson regression. RESULTS: In 2014, among the 29,424 patients hospitalized for an AMI in the first 6 months of the year, 10,873 (36.9%) were subsequently admitted to SSR units. More specifically, the age-standardized rate of patients hospitalized in CR units reached 28.4% (n=8380), and was greater among men (29.6%, n=6707) than among women (24.9%, n=1673). Between 2010 and 2014, rates of admission for CR increased by 5.0% per year in men and 6.6% per year in women. We found a great increase in ambulatory CR management, which accounted for half of the admissions for CR in 2014. CONCLUSIONS: Favourable trends in rates of admission for CR were reported in both sexes and at all ages, except the oldest. The increase in ambulatory management contributed to these changes. Despite these trends, rates of admission for CR after AMI remain low. PMID- 29133182 TI - A novel method for localization and ablation of conduction gaps after wide antral circumferential ablation of pulmonary veins. AB - BACKGROUND: Atrial fibrillation ablation is often performed by achieving pulmonary vein isolation using the "wide antral circumferential ablation" (WACA) technique, but many pulmonary veins remain connected because of conduction gaps in the ablation line. AIM: To analyse the efficacy of a novel technique based on pacing manoeuvres to detect gaps in an initial WACA lesion. METHODS: Patients referred for radiofrequency atrial fibrillation ablation were enrolled prospectively. A WACA lesion set was performed, isolating ipsilateral pulmonary veins together. If pulmonary vein isolation was not achieved, the atria were paced using an ablation catheter. For each pacing site, "activation delay" and "activation sequence" were analysed using a circular mapping catheter positioned at the pulmonary vein ostium. RESULTS: Twenty-one patients were included. A total of 25 non-isolated WACA lesion sets were studied. Three patterns were identified: (1) the activation delays converged towards one point with the shortest delay; no modification of the activation sequence (indicating one gap); (2) the activation delays converged towards at least two close locations; no change in the activation sequence (indicating at least two close gaps); (3) the activation delays converged towards at least two remote locations; modification of the activation sequence (indicating at least two remote gaps). Pacing manoeuvres and effect of ablation allowed precise localization of gaps, ultimately leading to pulmonary vein isolation in all patients. CONCLUSION: This simple pacing method accurately detected the location of residual connections after WACA lesion sets performed for atrial fibrillation ablation, allowing pulmonary vein isolation to be achieved. PMID- 29133183 TI - Fragments generated upon extracellular matrix remodeling: Biological regulators and potential drugs. AB - The remodeling of the extracellular matrix (ECM) by several protease families releases a number of bioactive fragments, which regulate numerous biological processes such as autophagy, angiogenesis, adipogenesis, fibrosis, tumor growth, metastasis and wound healing. We review here the proteases which generate bioactive ECM fragments, their ECM substrates, the major bioactive ECM fragments, together with their biological properties and their receptors. The translation of ECM fragments into drugs is challenging and would take advantage of an integrative approach to optimize the design of pre-clinical and clinical studies. This could be done by building the contextualized interaction network of the ECM fragment repertoire including their parent proteins, remodeling proteinases, and their receptors, and by using mathematical disease models. PMID- 29133185 TI - Squatting Re-education With Lumbo-Pelvic-Thigh Muscle Cocontraction Improves Functional Performance in Patellofemoral Pain Syndrome: A Case Presentation. AB - Anterior knee pain, with or without joint crepitus during squatting, is the common clinical feature in the individuals with patellofemoral pain syndrome (PFPS). Altered lower extremity alignment and lumbo-pelvic-thigh muscles motor control is often associated with PFPS. Although current interventions recommend individual muscle activation and strength training exercises, the reported benefits of cocontraction-based exercises in PFPS is limited. This might be due to the long-standing hypothesis that exercise-induced cocontraction of thigh muscles may induce a negative effect by increasing the joint contact forces in individuals with knee osteoarthritis. This case report demonstrates that neuromuscular re-education performed with lumbo-pelvic-thigh muscle cocontraction may improve functional performance and reduce patellofemoral joint crepitus in PFPS. Further controlled trials are necessary to generalize these results LEVEL OF EVIDENCE: V. PMID- 29133186 TI - A Novel Protocol for Contact Isolation for Multidrug-Resistant Organisms in Children on Inpatient Rehabilitation and Effects on Functional Outcomes: A Noninferiority Study. AB - BACKGROUND: The incidence of contact isolation for multidrug-resistant organisms is increasing in acute hospitals and inpatient rehabilitation units alike. There is limited evidence on the effect of contact isolation on functional outcomes during inpatient rehabilitation. OBJECTIVE: To determine whether the use of a modified contact isolation protocol (MCI) resulted in noninferior functional outcomes compared with children without contact isolation (NCI) on inpatient rehabilitation. DESIGN: This is a retrospective noninferiority study. SETTING: One academically affiliated pediatric inpatient rehabilitation unit located in a children's hospital. PATIENTS: All children with any diagnosis admitted to inpatient rehabilitation from January 1, 2007, to December 31, 2014. METHODS OR INTERVENTIONS: We compared functional outcomes for 2 groups of children. MAIN OUTCOME MEASUREMENTS: Primary outcome measures included the Functional Independence Measure for Children (WeeFIM) efficiency and the change in the Developmental Functional Quotient (DFQ) for the WeeFIM. Noninferiority margins of 0.63 for the WeeFIM efficiency and 0.092 for the change in DFQ for the WeeFIM were used. RESULTS: There were a total of 949 patients of whom 899 were NCI, 48 MCI, and 2 excluded due to missing information. Patients with MCI had functional outcomes that were noninferior to those with NCI including the WeeFIM efficiency (mean difference 0.002, 95% CI -0.38 to 0.404) and the change in DFQ for the WeeFIM (mean difference -0.05, 95% CI -0.058 to 0.003). CONCLUSIONS: The modified contact isolation protocol, having resulted in noninferior functional outcomes in inpatient rehabilitation may provide adequate contact isolation while allowing for noninferior functional outcomes. This may be a guide in the face of an ever increasing need for contact isolation. LEVEL OF EVIDENCE: III. PMID- 29133184 TI - JNK is antagonized to ensure the correct number of interommatidial cells pattern the Drosophila retina. AB - Apoptosis is crucial during the morphogenesis of most organs and tissues, and is utilized for tissues to achieve their proper size, shape and patterning. Many signaling pathways contribute to the precise regulation of apoptosis. Here we show that Jun N-terminal Kinase (JNK) activity contributes to the coordinated removal of interommatidial cells via apoptosis in the Drosophila pupal retina. This is consistent with previous findings that JNK activity promotes apoptosis in other epithelia. However, we found that JNK activity is repressed by Cindr (the CIN85 and CD2AP ortholog) in order to promote cell survival. Reducing the amount of Cindr resulted in ectopic cell death. Increased expression of the Drosophila JNK basket in the setting of reduced cindr expression was found to result in even more severe apoptosis, whilst ectopic death was found to be reduced if retinas were heterozygous for basket. Hence Cindr is required to properly restrict JNK mediated apoptosis in the pupal eye, resulting in the correct number of interommatidial cells. A lack of precise control over developmental apoptosis can lead to improper tissue morphogenesis. PMID- 29133187 TI - Duddingtonia flagrans formulated in rice bran in the control of Oesophagostomum spp. intestinal parasite of swine. AB - Three experimental assays with Duddingtonia flagrans (isolated AC001) were carried out. The growth of the genus Duddingtonia present in formulation of rice bran, its predatory capability on Oesophagostomum spp. infective larvae (L3) in petri dishes (assay 1), its action in faecal cultures with eggs of that parasite (assay 2) and isolate's capability of predation after passing through gastrointestinal tract of swine (assay 3) was evaluated. At assay 3, feces were collected at time intervals of 12, 24, 36, 48, and 60 h after feed animals with the formulation. Assays 1 and 2 showed a statistical difference (p < 0.01) by the F test when comparing the treated group with the control group. At the both assays, was observed in the treated group a reduction percentage of 74.18% and 88.38%, respectively. In assay 3, there was a statistical difference between the treated group and the control group at all collection times (p < 0.01). Regarding the collection periods, there was no statistical difference over time in the treatment group (p > 0.05). The results demonstrate that the fungal isolate AC001 formulated in rice bran can prey on L3 of Oesophagostomum spp., in vitro and after passing through the gastrointestinal tract, without loss of viability. This isolate may be an alternative in the control of Oesophagostomum spp. in swine. PMID- 29133188 TI - Coronary Angiography and Interventions in Patients With Hereditary Hemorrhagic Telangiectasia. PMID- 29133189 TI - Correction in article by Gonzalez-Vilchez et al. "Spanish Heart Transplantation Registry. 27th Official Report of the Spanish Society of Cardiology Working Group on Heart Failure and Heart Transplantation (1984-2015)", Rev Esp Cardiol. 2016;69:1071-1082. PMID- 29133190 TI - Integrating geriatric assessment in the first line chemotherapy treatment in older patients with metastatic colorectal cancer: Results of a prospective observational cohort study (AVAPLUS). AB - OBJECTIVES: This study aims to investigate the use of chemotherapy with or without bevacizumab in older patients with metastatic colorectal cancer (mCRC) in current daily practice and to identify predictive parameters for treatment related outcomes. PATIENTS AND METHODS: This is a Belgian multi-centre, observational cohort study. Patients>=70years old with mCRC considered suitable for first-line chemotherapy were eligible for inclusion. At baseline geriatric screening and assessment was performed. Treatment choice was at the discretion of the investigator. Treatment duration, Progression Free Survival (PFS) and safety were recorded. RESULTS: Between August 2011 and July 2013, 252 patients with mCRC were included of which 50.8% were treated with bevacizumab. Median treatment duration was 5.5months and median PFS was 8.9months. Approximately 50% of patients experienced severe adverse events, most frequently diarrhea. In multivariate analysis, baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was predictive for treatment duration (p=0.0047), PFS (p<0.0001) and severe toxicity and baseline nutritional status for PFS (p=0.0007). In patients with a good ECOG-PS, nutritional status was predictive for PFS. CONCLUSIONS: In current daily practice in Belgium, half of older patients with colorectal cancer treated with chemotherapy also receive bevacizumab. Nearly half of older patients presented with severe toxicity during treatment. Baseline nutritional status is a predictive marker for PFS. Patients with a baseline ECOG-PS>=2 have shorter PFS and higher risk of severe toxicity and should therefore be treated with caution. PMID- 29133191 TI - Galectin-3: mediator of microglia responses in injured brain. AB - Galectin-3 is a pleiotropic protein involved in cell activation, proliferation and migration and plays a pivotal part as an inflammatory mediator in neurodegeneration. Galectin-3 is associated with microglial activation and proliferation after ischemia. Given its putative role as a dynamic fine-tuner of microglia, activation of Galectin-3 provides molecular cues in design of new immunomodulatory strategies for stroke management. This review summarizes recent evidence on the role of Galectin-3 as a mediator of immune responses in damaged brain and mechanisms employed by Galectin-3 to affect microglial function. PMID- 29133192 TI - Maternal Micronutrients, Omega-3 Fatty Acids and Gene Expression of Angiogenic and Inflammatory Markers in Pregnancy Induced Hypertension Rats. AB - BACKGROUND AND AIMS: Preeclampsia is a disorder of pregnancy and is associated with inflammation and altered angiogenesis. The present study examines the effect of micronutrient and omega-3 fatty acid supplementation (individual, as well as combined) on genes involved in inflammation and angiogenesis, as well as global DNA methylation levels in a pregnancy induced hypertension (PIH) rat model. METHODS: Pregnant Wistar rats were randomly assigned to six dietary groups: control, PIH (Pregnancy induced hypertension) Induced; PIH Induced with micronutrient supplements with vitamin B12 (PIHB), folate (PIHF), omega-3 fatty acid (PIHO), and combined supplementation (PIHC) (micronutrients and omega-3 fatty acids). Half the dams were dissected on 20 d of gestation to collect placental tissue, and half were allowed to deliver normally on 22 d of gestation and were assigned to a postnatal control diet. The offspring were dissected at 3 month of age. RESULTS: PIH induction increased the mRNA levels of the pro inflammatory cytokine IL-6 (p <0.01), while lowering the placental anti inflammatory cytokine IL-10 (p <0.05) at d20 of gestation. It also increased the expression of TNF-alpha (p <0.05) in the liver of 3 month old offspring. The combined supplementation of folic acid, vitamin B12 and omega-3 fatty acids improved placental IL-10 levels and decreased TNF-alpha levels in offspring livers. CONCLUSION: Our data indicate that a combined supplementation of vitamin B12, folic acid and omega-3 fatty acid was useful for the better management of preeclampsia in an animal model. PMID- 29133193 TI - Prognostic Value of microRNA-224 in Various Cancers: A Meta-analysis. AB - BACKGROUND: During previous studies, microRNA-224 (miR-224) was frequently investigated and discovered to be of vital significance to prognosis of patients with various cancers. However, its accurate prognostic value has not been estimated worldwide. Herein, we performed meta-analysis to assess its potential predictive value in a variety of human tumors. METHODS: Qualified researches were identified up to March 1, 2017 through performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews. Overall survival (OS), disease-free survival (DFS) or progression-free survival (PFS) as a prognosis for various cancers were extracted and calculated, if available. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Stata version 13.0 (StataCorp, College Station, Texas, USA). RESULTS: 22 eligible studies with 3000 patients were ultimately brought into the current meta analysis. It suggested that high miR-224 expression was significantly associated with poor OS in tissue (HR = 1.43, 95% CI = 1.00-2.03). During multivariate analysis, high miR-224 expression was more significantly associated with OS in tissue (HR = 2.81, 95% CI = 1.91-4.13). Likewise, there were significant associations between tissue miR-224 expression and colorectal cancer (CRC), diffuse large B-cell lymphoma (DLBCL) and gastric cancer (GC) patients (p <0.05). Nevertheless, there were not significant associations between high tissue miR-224 expression and DFS (HR = 2.15, 95% CI = 0.97-4.79) or PFS (HR = 0.92, 95% CI = 0.53-1.59). CONCLUSION: As far as the present researches are concerned, tissue miR-224 has a significantly prognostic value in various cancers, especially in CRC, DLBCL and GC. Due to the complicated pathogenesis of cancers, more large scale and standard researches are requisite. PMID- 29133194 TI - Effect of Native and Minimally Modified Low-density Lipoprotein on the Activation of Monocyte Subsets. AB - BACKGROUND: In atherosclerosis, monocytes are essential and secrete pro inflammatory cytokines in response to modified low-density lipoprotein (LDL). Human CD14++CD16-, CD14++CD16+ and CD14+CD16++ monocytes produce different cytokines. The objective of this research was to determine the number of monocyte subsets positives to cytokines in response to native (nLDL) and minimally modified LDL (mmLDL). METHODS: Human monocytes from healthy individuals were purified by negative selection and were stimulated with nLDL, mmLDL or LPS. Subsequently, human total monocytes were incubated with monoclonal antibodies specific for CD14 or both CD14 and CD16 to characterize total monocytes and monocyte subsets and with antibodies specific to anti-tumor necrosis factor (TNF) alpha, anti-interleukin (IL)-6 and anti-IL-10. The number of cells positive for cytokines was determined and cells cultured with nLDL, mmLDL and LPS were compared with cells cultured only with culture medium. RESULTS: We found that nLDL does not induce in the total monocyte population or in the three monocyte subsets positives to cytokines. MmLDL induced in total monocytes positives to TNF alpha and IL-6 as well as in both CD14++CD16+ and CD14+CD16++ and in CD14++CD16+ monocytes, respectively. Moreover, total monocytes and the three monocyte subsets expressed few amounts of cells positives to IL-10 in response to mmLDL. CONCLUSION: Our study demonstrated that nLDL did not induce cells positives to cytokines and that the CD14++CD16+ and CD14+CD16++ monocyte subsets could be the main sources of TNF-alpha and IL-6, respectively, in response to mmLDL, which promotes the development and progression of atherosclerotic plaque. PMID- 29133195 TI - A self-administered questionnaire to measure the painful symptoms of endometriosis: Results of a modified DELPHI survey of patients and physicians. AB - PURPOSE: To develop a questionnaire based on patients' verbal descriptors, to measure the painful symptoms of endometriosis. METHODS: We performed a two-round modified DELPHI procedure mixing endometriosis patients and physicians to select a set of statements to describe the painful symptoms of endometriosis. Each panelist rated each statement based on diagnosis validity and clarity. The clinicians were experts in endometriosis management selected from various geographic regions in France. Patients were women with surgically confirmed endometriosis who volunteered from a patient association and from the recruitment of the participating physicians. The first round questions were derived from words and phrases in narratives of pain by endometriosis patients. RESULTS: Overall, 76 experts were invited, and of these 56 (74%), comprising 33 patients and 23 gynecologists, responded to the first round questionnaire, and 40 (71.4%) to the second round. Among the 48 statements assessed in the first-round questionnaire, 11 were selected after completion of the two round DELPHI procedure. After discussion and rewording of some items, a total of 21 questions were selected during a final face-to-face meeting. The content of the final questionnaire is organized according to four dimensions: (i) spontaneous pelvic pain and dysmenorrhea, (ii) dyspareunia, (iii) painful bowel symptoms, (iv) and other symptoms. We also provide an English (UK) version produced using several steps of translation and back-translation. CONCLUSIONS: The questionnaire has content validity to measure the subjective experiences of patients with painful endometriosis and can provide a solid basis on which to develop an efficient patient-centered outcome to measure the painful symptoms in therapeutic or in diagnostic studies of endometriosis. PMID- 29133196 TI - Cold EMR of large sessile serrated polyps at colonoscopy (with video). AB - BACKGROUND AND AIMS: The optimal technique for the resection of sessile serrated polyps (SSPs) is unknown, with established limitations and risks with conventional polypectomy. Although cold snare polypectomy is safe, the efficacy of piecemeal resection for large lesions is untested. In this study we evaluate the safety and efficacy of cold EMR for large SSPs. METHODS: Patients presenting for elective colonoscopy at an academic endoscopy center with 1 or more SSPs >=10 mm in size were enrolled, excluding those on anticoagulant or antiplatelet therapy other than aspirin. Lesions were resected with a cold EMR technique comprising submucosal injection of succinylated gelatin and dilute methylene blue before piecemeal cold snare resection of all visible polyp with a margin of normal tissue. Outcomes were the presence of residual serrated neoplasia in biopsy specimens from the defect margin and findings on surveillance colonoscopy. RESULTS: Cold EMR was performed on 163 SSPs during 105 procedures in 99 patients (97% women; median age, 57 years). The mean size was 17.5 mm: 61 SSPs were >=20 mm and 13 SSPs >=30 mm, and 97.5% were in the proximal colon. Cytologic dysplasia was present in 2 (1.2%). Margin biopsy specimens were positive in 2 lesions (1.2%). Surveillance colonoscopy for 82% of lesions (median, 5 months) showed residual serrated tissue in 1, treated with cold snare, but no evidence of recurrence in the remainder. Minor adverse events were seen in 3 patients; no delayed bleeding was observed. CONCLUSIONS: Cold EMR is a safe and effective method for the removal of large SSPs. PMID- 29133197 TI - Inhibition of leukotriene B4 synthesis protects against early brain injury possibly via reducing the neutrophil-generated inflammatory response and oxidative stress after subarachnoid hemorrhage in rats. AB - Leukotriene B4 (LTB4) is a highly potent neutrophil chemoattractant and neutrophils induces inflammatory response and oxidative stress when they recruit to and infiltrate in the injuried/inflamed site, such as the brain parenchyma after aneurysmal subarachnoid hemorrhage (SAH). This study is to investigate the potential effects of inhibition of LTB4 synthesis on neutrophil recruitment, inflammatory response and oxidative stress, as well as early brain injury (EBI) in rats after SAH. A pre-chiasmatic cistern SAH model of rats was used in this experiment. SC 57461A was used to inhibit LTB4 synthesis via intracerebroventricular injection. The brain tissues of temporal lobe after SAH were analyzed. Neuronal injury, brain edema and neurological function were evaluated to investigate the development of EBI. We found that inhibition of LTB4 synthesis after SAH could reduce the level of myeloperoxidase, alleviate the inflammatory response and oxidative stress, and reduce neuronal death in the brain parenchyma, and ameliorate brain edema and neurological behavior impairment at 24h after SAH. These results suggest that inhibition of LTB4 synthesis might alleviate EBI after SAH possibly via reducing the neutrophil-generated inflammatory response and oxidative stress. PMID- 29133198 TI - Study of the mechanical reliability of an S-shaped adjustable osteosynthesis plate for bilateral sagittal split osteotomies. Study on 15 consecutive cases. AB - INTRODUCTION: The main challenge during the osteosynthesis of a bilateral sagittal split osteotomy (BSSO) is to take into account the correct position of the condyle. Adjustable plates can be used to fine-tune the final occlusion without changing the osteosynthesis. A new type of adjustable plate is presented in this article. The aim is to assess the mechanical reliability of this system during the surgery and during the healing period, thanks to a preliminary prospective on 15 consecutive cases. MATERIAL AND METHODS: The bridge of the plate studied here has an "S"-shape and can be bent in two different planes. Fifteen patients presenting a maxilla-mandibular disharmony have been operated on with this device. Clinical results were evaluated three months postoperatively and the mechanical reliability of the device was studied prospectively from teleradiographies of 15 patients operated on in our department. RESULTS: This study shows good results, with respect to the mechanical reliability of this S shaped adjustable plate, three months postoperatively corresponding to the bone healing period. Radiographic observations did not show any significant displacement at the osteosynthesis site. DISCUSSION: This preliminary study shows the mechanical reliability of this new S-shaped adjustable plate. Its semi-rigid character may allow for certain condyle position adaptability. No plate fracture was reported for this 15 patient series. These encouraging results have to be confirmed on a larger series. PMID- 29133199 TI - Isolation and characterization of a novel tyrosinase produced by Sahara soil actinobacteria and immobilization on nylon nanofiber membranes. AB - In the present study different actinomycete strains were collected and isolated from Algerian Sahara soil with the aim to select novel enzymes with promising features for biotechnological applications. The Ms1 strain was selected, amongst the others, for its capability to produce melanin in different solid media. Ms1 chromosomal DNA was sequenced and the strain assigned to Streptomyces cyaneofuscatus sp. A tyrosinase (MW~30kD) encoding sequence was identified and the corresponding enzyme was isolated and biochemically characterized. The tyrosinase showed the highest activity and stability at neutral and alkaline pH and it was able to oxidize l-DOPA at T=55 degrees C and pH 7. The enzyme showed variable stability in presence of various water-miscible organic solvents, while it was inactivated by reducing agents. The tyrosinase activity was unaffected by NaCl and enhanced by different cations. Furthermore, the enzyme showed a higher specificity for diphenols than monophenols showing a higher diphenolase than monophenolase activity. Finally, tyrosinase was stabilized by immobilization on nylon nanofiber membranes with a payload of 82% when 1% glutaraldeyde was used. Taken all together, these results show that the enzyme displays interesting properties for biotechnological purposes. PMID- 29133200 TI - Histologic and Hemodynamic Correlates of Right Ventricular Function in a Pressure Overload Model: a Study Using Three-Dimensional Speckle Tracking Echocardiography. AB - The aim of our study was to assess the characterization of right ventricular (RV) deformation using three-dimensional (3D) speckle tracking echocardiography (STE) and association of 3D-STE indices with histologic and hemodynamic parameters in a chronic RV pressure overload animal model. Pulmonary artery banding (PAB) was used to induce RV pressure overload in seven beagles. 3D-STE, histologic and hemodynamic measurements were performed in PAB and sham-operated beagles 3 mo after PAB. RV longitudinal, radial and circumferential strain was measured from 3D-STE. Three mo after PAB, RV longitudinal strain was decreased; whereas radial and circumferential strain remained unchanged in PAB group. RV longitudinal strain was associated with interstitial fibrosis (r = -0.733) in the endocardial layer of the RV free wall. RV circumferential strain was related to dp/dtmax (r = 0.718). The significant correlations of RV 3D-STE indices with histologic and hemodynamic parameters indicate that 3D-STE may be a valuable tool for assessment of ventricular function in RV pressure overload. PMID- 29133201 TI - Diabetes-related amputations create considerable public health burden in the UK. AB - AIMS: The main aim of this study was to assess the cost of diabetic amputation (both direct and indirect) to the National Health Service from the point of amputation onwards. METHODS: This systematic review involved searches of published literature between January 2007 and March 2017 mainly using the bibliographic databases, the Cochrane Library, EMBASE via Ovid(r), MEDLINE via Ovid(r), as well as grey literature, both in print and in electronic formats published through non-commercial publications, which reported the cost of amputation due to diabetic foot ulcers. RESULTS: The studies included in this review varied considerably in estimating the cost including cost elements and how those costs were categorised. The cost estimates for inpatient care associated with amputation involving admissions or procedures on amputation stumps in people with diabetes was L43.8 million. The annual expenditure for post-amputation care involving prosthetic care, physiotherapy, transport and wheelchair use was L20.8 million. CONCLUSIONS: There is a considerable public health and economic burden caused by diabetes-related amputations in England. More focussed research is needed with improved methods of estimating costs that would account for direct and indirect costs associated with diabetic amputation. PMID- 29133202 TI - Glycated haemoglobin is increased in critically ill patients with stress hyperglycaemia: Implications for risk of diabetes in survivors of critical illness. AB - It remains uncertain if stress hyperglycaemia (SH) indicates a long-term predisposition to the development of type 2 diabetes. We conducted a retrospective observational study in critically ill patients and found SH to be associated with an increased HbA1c, which may indicate an increased risk of type 2 diabetes. PMID- 29133203 TI - Expression and functional characterization of tachykinin-related peptides in the blood-feeding bug, Rhodnius prolixus. AB - Tachykinins (tachykinin-related peptides, TRPs) are multifunctional neuropeptides that have widespread distribution in the central nervous system (CNS) and in the gastrointestinal tract of many insects, and most have been shown to stimulate contractions of visceral muscles. Invertebrate TRPs carry a characteristic conserved C-terminal pentapeptide (FXGXR-amide) and most of them share some amino acid sequence similarities (approx. 45%) with the vertebrate and mammalian tachykinin family. We have functionally characterized the tachykinins in R. prolixus (Rhopr-TKs) and partially cloned the transcript that encodes for the peptide precursor. The transcript encodes 8 Rhopr-TKs, 7 of which are unique with Rhopr-TK 5 having 2 copies. The spatial distribution analysis of the Rhopr-TK transcript indicates that the highest expression levels are in the CNS, but transcript expression is also associated with salivary glands, fat body, dorsal vessel, and the various gut compartments. Rhopr-TK 1, 2 and 5 significantly increase the frequency and amplitude of peristaltic contractions of the salivary glands. Hindgut muscle also displayed a dose-dependent increase in basal tonus in response to Rhopr-TK1, 2 and 5. TK-like immunoreactivity was seen in a small group of processes that are situated on the lateral margins of the hindgut. Interestingly, kinin-like immunoreactivity is seen in immunoreactive processes on the lateral margin of the hindgut as well as fine processes covering the entire hindgut. Co-localization studies show that TK-like staining is always co localized with kinin-like immunoreactivity, whereas kinin-like staining is seen in the fine processes that are devoid of TK-like immunoreactivity indicating that TKs are most likely released together with kinins to act on the hindgut. Rhopr Kinin 2 is a potent stimulator of hindgut muscle contraction in R. prolixus. Addition of Rhopr-Kinin 2 and Rhopr-TK 2 to the hindgut leads to a contraction that was additive of the effects of Rhopr-Kinin 2 and Rhopr-TK 2 alone. PMID- 29133204 TI - Investigating phase separation in amorphous solid dispersions via Raman mapping. AB - The bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs) can be significantly improved by so-called amorphous solid dispersions (ASDs). However, the long-term stability of ASDs might be impaired by API recrystallization and/or amorphous phase separation (APS). So far, no methods have been reported to quantify APS in ASDs. In this work, phase-separation kinetics as well as the compositions of the two amorphous phases evolving due to APS were quantitatively determined for the first time using confocal Raman spectroscopy. Raman spectra were evaluated via non-linear multivariate Indirect Hard Modeling and verified by differential scanning calorimetry and hot-stage microscopy. APS in water-free ASDs of ibuprofen and poly (DL-lactic-co-glycolic acid) was investigated considering the influence of temperature and polymer architecture (linear vs. star-shaped). Water absorbed at 40 degrees C and 75% relative humidity (RH) promotes APS which was quantified for formulations of felodipine/poly(vinyl pyrrolidone) and ibuprofen/poly(vinyl pyrrolidone). PMID- 29133205 TI - HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study. AB - We have developed a tumor environment-responsive polymeric anticancer prodrug containing pirarubicin (THP) conjugated to N-(2-hydroxypropyl) methacrylamide copolymer (PHPMA), [P-THP], through a spacer containing pH-sensitive hydrazone bond, that showed remarkable therapeutic effect against various tumor models and in a human pilot study. Toward clinical development, here we report THP release profile from its HPMA copolymer conjugate, the conjugate stability, protein and cell-binding and solubility of P-THP. Size exclusion chromatography of P-THP (molecular weight 38 kDa) showed similar hydrodynamic volume as bovine serum albumin (BSA) in aqueous solution, with no apparent interactions with BSA, nor aggregation by itself. pH-responsive release of free THP was reconfirmed at pHs 6.5 and lower. The drug release was significantly affected by a type of used buffer. Phosphate buffer seems to facilitate faster hydrazone bond cleavage at pH 7.4 whereas higher stability was achieved in L-arginine solution which yielded only little cleavage and THP release, approx. 15% within 2 weeks at the same pH at 25 degrees C. Furthermore, ex vivo study using sera of different animal species showed very high stability of P-THP. Incubation with blood showed high stability of P-THP during circulation, without binding to blood cells. These findings revealed that L-arginine solution provides appropriate media for formulation of P-THP infusion solution as tumor-targeted polymeric anticancer drug based on EPR effect. PMID- 29133206 TI - Relationship between polarities of antibiotic and polymer matrix on nanoparticle formulations based on aliphatic polyesters. AB - In the field of nanomedicine, nanoparticles are developed to target antibiotics to sites of bacterial infection thus enabling adequate drug exposure and decrease development of resistant bacteria. In the present study, we investigated the encapsulation of two antibiotics with different polarity into different PEGylated polymeric nanoparticles based on aliphatic polyesters, to obtain a better understanding of critical factors determining encapsulation and release. The nanoparticles were prepared from diblock copolymers comprising of a poly(ethylene glycol) block attached to an aliphatic polyester block of varying polarity: poly(lactic-co-glycolic acid) (mPEG-PLGA), poly(lactic-co-hydroxymethyl glycolic acid) (mPEG-PLHMGA) and poly(lactic-co-benzyloxymethyl glycolic acid) (mPEG PLBMGA). Hydrophobic bedaquiline and hydrophilic vancomycin were encapsulated via single and double-emulsion solvent evaporation techniques, respectively. Encapsulation, degradation and release studies at physiological simulating conditions were performed. Drug polarity and preparation techniques influenced encapsulation efficiency into polymer nanoparticles, giving almost complete encapsulation of bedaquiline and approx. 30% for vancomycin independent of the polymer type. The nonpolar bedaquiline showed a predominantly diffusion controlled release independent of polymer composition. However, polar vancomycin was released by a combination of diffusion and polymer degradation, which was significantly affected by polymer composition, the most hydrophilic polymer displaying the fastest release. PMID- 29133207 TI - Oral hepatitis B vaccine: chitosan or glucan based delivery systems for efficient HBsAg immunization following subcutaneous priming. AB - The World Health Organization encourages "the development of oral formulations to simplify their transport, storage and administration in poor countries", and to "facilitate an effective immunization program to prevent sexually transmitted hepatitis B". Thus, two distinct and promising delivery systems were developed: recombinant hepatitis B surface antigen (HBsAg) encapsulated into alginate-coated chitosan particles (AlgChiPs) and into glucan particles (GPs) mainly composed of beta-1,3-d-glucan. In vitro preliminary studies showed that both could be internalized by peripheral blood mononuclear cells and murine Peyer's patches, an imperative aspect regarding oral immunization. Chitosan particles (ChiPs) have shown interesting immunostimulating properties as mast cells activators. Vaccination studies reveal that three oral immunizations induced serum anti-HBsAg Immunoglobulin G (IgG) in 60 % of the animals and anti-HBsAg secretory IgA in faeces for both formulations. When subcutaneous (SC) priming was done, followed by two oral boosts, all mice were responder and much higher serum anti-HBsAg IgG titers were observed, besides mucosal protective immunity. PMID- 29133208 TI - Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients. AB - BACKGROUND: Fanconi Anemia (FA) is a rare and heterogeneous genetic syndrome. It is associated with short stature, bone marrow failure, high predisposition to cancer, microcephaly and congenital malformation. Many genes have been associated with FA. Previously, two adult patients with biallelic pathogenic variant in Breast Cancer 1 gene (BRCA1) had been identified in Fanconi Anemia-like condition. CLINICAL REPORT: The proband was a 2.5 year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features. Her parents were third degree cousins. Routine screening tests for short stature was normal. METHODS: We conducted whole exome sequencing (WES) of the proband and used an analysis pipeline to identify rare nonsynonymous genetic variants that cause short stature. RESULTS: We identified a homozygous loss-of-function BRCA1 mutation (c.2709T > A; p. Cys903*), which promotes the loss of critical domains of the protein. Cytogenetic study with DEB showed an increased chromosomal breakage. We screened heterozygous parents of the index case for cancer and we detected, in her mother, a metastatic adenocarcinoma in an axillar lymph node with probable primary site in the breast. CONCLUSION: It is possible to consolidate the FA-like phenotype associated with biallelic loss-of function BRCA1, characterized by microcephaly, short stature, developmental delay, dysmorphic face features and cancer predisposition. In our case, the WES allowed to establish the genetic cause of short stature in the context of a chromosome instability syndrome. An identification of BRCA1 mutations in our patient allowed precise genetic counseling and also triggered cancer screening for the patient and her family members. PMID- 29133209 TI - Genome-wide sequencing expands the phenotypic spectrum of EP300 variants. AB - Many disease genes are defined by their role in causing specific clinically recognizable syndromes. Heterozygous loss of function of the gene EP300 is responsible for a minority of cases of Rubinstein-Taybi syndrome (RSTS). With the application of whole-exome sequencing and whole-genome sequencing, there is the potential to discover new genotype-phenotype correlations. The purpose of this case series is to describe three unrelated females without classic manifestations of RSTS who were unexpectedly found on genome-wide sequencing to have likely pathogenic variants in EP300. These individuals expand our knowledge of the disease spectrum by virtue of their very rare or novel clinical features. Results are placed within the context of all prior published EP300 cases not ascertained by targeted testing, which are disproportionately female compared with a cohort identified because of a clinical suspicion of RSTS (p = 0.01). There are implications for diagnosis, management, and genetic counselling of individuals with EP300-related disease. PMID- 29133210 TI - High speed flow cytometry allows the detection of circulating endothelial cells in hemangioblastoma patients. AB - Circulating endothelial cells (CECs) detach from the intima monolayer after endothelial damages. Their circulating endothelial progenitors (CEPs) represent less than 0.01% of nucleated blood cells. Increased levels of CECs and CEPs have been detected in patients with several types of cancer, suggesting that they could be a useful blood-based marker for detecting a tumor, or for monitoring its clinical course. However, their routine monitoring is time consuming and technically challenging. Here, we present a flow cytometry method for quantifying such cells in a cohort of patients with hemangioblastoma (HB). HB is a rare benign tumor, responsible for 1-2.5% of primary intracranial tumors and up to 10% of spinal cord tumors, and for which no tools are available to predict the onset or recurrence in patients undergoing surgical removal of tumor mass. This method allowed us to accurately quantifying CEC and CEP before and after surgery. CEPs are present at high levels in HB patients than control before intervention, and decrease after tumor removal, suggesting that their percentage could represent a valid tool to monitor the disease onset and recurrence. PMID- 29133211 TI - Beta-lactam resistance among Enterobacteriaceae in Cambodia: The four-year itch. AB - Although antibiotics are too often used inappropriately in Cambodia, published data on antimicrobial resistance in this country are scarce. Epidemic dissemination and the transfer of resistance genes to other bacterial species put the population at risk. The aim of this study was to evaluate the frequency and characteristics of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) isolated in consecutive samples tested at Institut Pasteur du Cambodge over a 4-year period (2012-2015). Antimicrobial susceptibility testing was performed by disk diffusion on agar technique and the results were read automatically using an OSIRIS system. The Etest was used to determine minimum inhibitory concentrations (MIC) for some resistance phenotypes. The strain most commonly identified was Escherichia coli (63.9%). The proportion of ESBL-E increased gradually over the study period, from 23.8% to 38.4%. ESBL was detected in 42.7% of the E. coli strains and 33.7% of all Klebsiella pneumoniae isolated. The proportion of ESBL-producing E. coli increased significantly from 28.9% in 2012 to 48.2% in 2015, while the increase for K. pneumoniae remained non-significant. Multidrug resistance was high in this Cambodian series, with some strains displaying resistance to all antibiotics available in the country. There is currently no established system for the surveillance of antimicrobial resistance in Cambodia. Collecting samples from clinical settings throughout the country is critical to assess the impact of antimicrobial drug use in patients in Cambodia and in the Mekong Region. PMID- 29133212 TI - Quantitative and systems pharmacology 2. In silico polypharmacology of G protein coupled receptor ligands via network-based approaches. AB - G protein-coupled receptors (GPCRs) are the largest super family with more than 800 membrane receptors. Currently, over 30% of the approved drugs target human GPCRs. However, only approximately 30 human GPCRs have been resolved three dimensional crystal structures, which limits traditional structure-based drug discovery. Recent advances in network-based systems pharmacology approaches have demonstrated powerful strategies for identifying new targets of GPCR ligands. In this study, we proposed a network-based systems pharmacology framework for comprehensive identification of new drug-target interactions on GPCRs. Specifically, we reconstructed both global and local drug-target interaction networks for human GPCRs. Network analysis on the known drug-target networks showed rational strategies for designing new GPCR ligands and evaluating side effects of the approved GPCR drugs. We further built global and local network based models for predicting new targets of the known GPCR ligands. The area under the receiver operating characteristic curve of more than 0.96 was obtained for the best network-based models in cross validation. In case studies, we identified that several network-predicted GPCR off-targets (e.g. ADRA2A, ADRA2C and CHRM2) were associated with cardiovascular complications (e.g. bradycardia and palpitations) of the approved GPCR drugs via an integrative analysis of drug target and off-target-adverse drug event networks. Importantly, we experimentally validated that two newly predicted compounds, AM966 and Ki16425, showed high binding affinities on prostaglandin E2 receptor EP4 subtype with IC50=2.67MUM and 6.34MUM, respectively. In summary, this study offers powerful network-based tools for identifying polypharmacology of GPCR ligands in drug discovery and development. PMID- 29133213 TI - Long noncoding RNAs act as regulators of autophagy in cancer. AB - Long noncoding RNAs (lncRNAs) have emerged as critical regulators in various cellular processes. Studies have disclosed an important function of lncRNAs in the regulation of autophagy, a crucial cellular homeostatic mechanism that plays a pro-survival or pro-death role in cancer. Deregulation of lncRNAs can contribute to tumorigenesis and cancer progression, wherein lncRNAs can act as oncogenes or tumor suppressors. In this review, we highlight the recent advances in understanding the relationship between lncRNAs and autophagy regulation in cancer. Exploiting the newly emerging knowledge of the lncRNA-autophagy-cancer axis may provide novel targets for cancer therapy. PMID- 29133214 TI - Antibacterial activity and pharmacokinetic profile of a promising antibacterial agent: 14-O-[(4-Amino-6-hydroxy-pyrimidine-2-yl)thioacetyl] mutilin. AB - A new pleuromutilin derivative, 14-O-[(4-Amino-6-hydroxy-pyrimidine-2 yl)thioacetyl] mutilin (APTM), has been synthesized and proved most potent antibacterial agent in in vitro assays, suggesting that further development of this compound may lead to a promising antibacterial drug. In this study, we further evaluated the cytotoxicity, antibacterial efficacy and the pharmacokinetic profile of APTM. In BRL 3A cells, 50% of viability was obtained when 363MUg/mL of APTM was used, while retapamulin and tiamulin fumarate needed 49 and 28MUg/mL, respectively, to reach this viability. Compared to tiamulin fumarate, APTM showed higher inhibition efficacy and faster bactericidal activity against S. aureus and lower 50% effective dose (ED50) in mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA). Docking experiment for APTM showed a similar binding pattern with tiamulin. Furthermore, a simple, accurate and sensitive HPLC method for the determination of APTM in rabbit plasma was developed and successfully applied to pharmacokinetic study, in which the half life (t1/2), clearance rate (Cl) and the area under the plasma concentration-time curve (AUC0->infinity) were 3.37h, 0.35L/h/kg and 70.68MUg.h/m, respectively. PMID- 29133215 TI - Myocardial infarction and gut microbiota: An incidental connection. AB - Myocardial infarction (MI) is the main cause of cardiovascular crises that entails serious concerns in mortality, morbidity, and cost to the society. The main therapeutic goal of modern cardiology is to develop novel approaches to minimize inflammation, myocardial necrosis/apoptosis, and enhance cardiac repair after MI. Though MI can be affected by genetic and environmental factors, the search for targeting lifestyle factors has been of greater interest. One such potential factor is the microbiota, the human intestinal microbial community. Although the fundamental data on the role of microbiome on MI is more limited, the disruption of intestinal flora structure provokes MI and poor prognosis. Since gut microbiota is readily modifiable through a variety of interventions, it can be targeted to modulate the host signaling pathways involved in inflammation and MI pathogenesis. Symbiosis bacteria can reduce ischemia/reperfusion injury and inflammation; moreover, they can regulate lipid metabolism, blood pressure, apoptosis, MI size, and overall cardiac survival. In this review, we provide an overview of the development of MI following the dysbiosis microbiota and give an update on a microbiota-based therapeutic strategy to delay or prevent MI. PMID- 29133216 TI - Anti-cancer effects of naturally derived compounds targeting histone deacetylase 6-related pathways. AB - Alterations of the epigenetic machinery, affecting multiple biological functions, represent a major hallmark enabling the development of tumors. Among epigenetic regulatory proteins, histone deacetylase (HDAC)6 has emerged as an interesting potential therapeutic target towards a variety of diseases including cancer. Accordingly, this isoenzyme regulates many vital cellular regulatory processes and pathways essential to physiological homeostasis, as well as tumor multistep transformation involving initiation, promotion, progression and metastasis. In this review, we will consequently discuss the critical implications of HDAC6 in distinct mechanisms relevant to physiological and cancerous conditions, as well as the anticancer properties of synthetic, natural and natural-derived compounds through the modulation of HDAC6-related pathways. PMID- 29133217 TI - Association between sleep disturbance and new-onset subjective knee pain in Great East Japan Earthquake survivors: A prospective cohort study in the Miyagi prefecture. AB - BACKGROUND: The Great East Japan Earthquake (GEJE) and Tsunami devastated the northeastern coast of Japan on March 11, 2011. This study aimed to determine whether sociopsychological factors, such as sleep disturbance and psychological distress, influenced new-onset subjective knee pain in survivors during the post disaster phase of the GEJE. METHODS: From November 2012 to February 2013 (2 years after the GEJE) and from November 2013 to February 2014 (3 years after the GEJE), survivors (>=18 years) completed self-reported questionnaires. A total of 1470 survivors responded to the questionnaires and were included in this study. New onset subjective knee pain was defined as knee pain by encircled response absent at 2 years but present at 3 years after the GEJE. Two years after the GEJE, >=10/24 points on the Kessler Psychological Distress Scale, and >=6/24 points on the Athens Insomnia Scale defined the presence of psychological distress and sleep disturbance, respectively. Multiple logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of the association between new-onset subjective knee pain and psychological distress or sleep disturbance. RESULTS: Among the participants, 10.9% (160/1470) reported experiencing new-onset subjective knee pain. Sleep disturbance was significantly associated with new-onset subjective knee pain (OR, 1.57, 95% CI, 1.08-2.29, P = 0.017); however, psychological distress was not (OR, 1.07, 95% CI, 0.65-1.78, P = 0.80). CONCLUSIONS: This is the first study to indicate an association between sleep disturbance and new-onset subjective knee pain among survivors of the GEJE. 247/300. PMID- 29133218 TI - Cluster Analysis Identifies 3 Phenotypes within Allergic Asthma. AB - BACKGROUND: Asthma is a heterogeneous chronic disease with different clinical expressions and responses to treatment. In recent years, several unbiased approaches based on clinical, physiological, and molecular features have described several phenotypes of asthma. Some phenotypes are allergic, but little is known about whether these phenotypes can be further subdivided. OBJECTIVE: We aimed to phenotype patients with allergic asthma using an unbiased approach based on multivariate classification techniques (unsupervised hierarchical cluster analysis). METHODS: From a total of 54 variables of 225 patients with well characterized allergic asthma diagnosed following American Thoracic Society (ATS) recommendation, positive skin prick test to aeroallergens, and concordant symptoms, we finally selected 19 variables by multiple correspondence analyses. Then a cluster analysis was performed. RESULTS: Three groups were identified. Cluster 1 was constituted by patients with intermittent or mild persistent asthma, without family antecedents of atopy, asthma, or rhinitis. This group showed the lowest total IgE levels. Cluster 2 was constituted by patients with mild asthma with a family history of atopy, asthma, or rhinitis. Total IgE levels were intermediate. Cluster 3 included patients with moderate or severe persistent asthma that needed treatment with corticosteroids and long-acting beta-agonists. This group showed the highest total IgE levels. CONCLUSIONS: We identified 3 phenotypes of allergic asthma in our population. Furthermore, we described 2 phenotypes of mild atopic asthma mainly differentiated by a family history of allergy. PMID- 29133219 TI - Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial. AB - BACKGROUND: The high levels of eicosanoid production and the clinical efficacy of leukotriene-modifying pharmacotherapies for patients with aspirin-exacerbated respiratory disease (AERD) suggest that other interventions targeting arachidonic acid dysregulation may also improve disease control. OBJECTIVE: To assess the utility of a high omega-3/low omega-6 diet for the treatment of AERD. METHODS: Prospective, nonblinded dietary intervention in 10 adult patients with AERD at Brigham and Women's Hospital in Boston, MA. The primary objective was for subjects to reduce dietary omega-6 fatty acid consumption to less than 4 g/d and increase omega-3 intake to more than 3 g/d. The primary outcome was change in urinary leukotriene E4, with changes in other eicosanoids, platelet activation, lung function, and patient-reported questionnaires also assessed. RESULTS: Of the 10 subjects who screened for the study, all 10 completed the dietary intervention. Urinary leukotriene E4 decreased by 0.17 ng/mg (95% CI, -0.29 to 0.04; P = .02) and tetranor prostaglandin D-M decreased by 0.66 ng/mg creatinine (95% CI, -1.21 to -0.11; P = .02). There was a 15.1-point reduction in the 22 item Sino-Nasal Outcome Test score (95% CI, -24.3 to -6.0; P = .01), a 0.27-point reduction in the 7-item Asthma Control Questionnaire score (95% CI, -0.52 to 0.03; P = .03), and no change in FEV1 % predicted (P = .92) or forced vital capacity % predicted (P = .74). All patients lost some weight over the 2-week intervention period, and there were no diet-associated adverse events. CONCLUSIONS: A high omega-3/low omega-6 diet may be an appropriate adjunct treatment option for patients with AERD. PMID- 29133220 TI - Effects of Exercise and Diet in Nonobese Asthma Patients-A Randomized Controlled Trial. AB - BACKGROUND: Behavioral interventions focusing on exercise and healthy diet improve asthma control in obese patients with asthma, but whether these interventions can lead to improvements in nonobese patients remains unclear. OBJECTIVES: In a randomized, controlled parallel-group design, we studied the effects of an 8-week intervention of either exercise (high-intensity interval training), diet (high protein/low glycemic index), or a combination of the 2, on asthma control and clinical outcomes in nonobese patients with asthma. METHODS: Nonobese adult patients with asthma (n = 149) were randomized to 1 of 4 groups: an exercise group, a diet group, an exercise + diet group, or a control group. Outcomes included Asthma Control Questionnaire (ACQ) score, asthma-related quality-of-life (Asthma-Related Quality-of-Life Questionnaire [AQLQ]) score, inflammatory cell counts in induced sputum, FEV1, fractional exhaled nitric oxide, and airway hyperresponsiveness (AHR). RESULTS: A total of 125 patients completed the study and were included in the data analysis. Patients in the exercise + diet group improved the ACQ score from 1.9 +/- 0.7 to 1.0 +/- 0.7 and the AQLQ score from 5.2 +/- 0.8 to 6.2 +/- 0.7, which was statistically significant when compared with changes in the control group (P < .05 and <.01, respectively). The exercise group and the diet group did not improve either the ACQ score or the AQLQ score significantly compared with the control group and there were no significant changes in sputum cell counts, FEV1, fractional exhaled nitric oxide, or AHR within any groups following the intervention period. CONCLUSIONS: The combination of exercise and diet improves asthma control in nonobese patients, but does not affect AHR or airway inflammation. PMID- 29133221 TI - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome successfully treated with mepolizumab. PMID- 29133222 TI - Physical Activity and Exercise Capacity in Severe Asthma: Key Clinical Associations. AB - BACKGROUND: Physical inactivity and sedentary time are distinct behaviors that may be more prevalent in severe asthma, contributing to poor disease outcomes. Physical activity and sedentary time in severe asthma however have not been extensively examined. OBJECTIVE: We aimed to objectively measure physical activity and sedentary time in people with severe asthma compared with age matched control participants, describing the associations of these behaviors with clinical and biological outcomes. We hypothesized that people with severe asthma would be less active and more sedentary. In addition, more activity and less sedentary time would be associated with better clinical outcomes and markers of systemic and airway inflammation in people with severe asthma. METHODS: Adults with severe asthma (n = 61) and sex- and age-matched controls (n = 61) underwent measurement of lung function, exercise capacity, asthma control, health status, and airway and systemic inflammation. Physical activity and sedentary time were measured using an accelerometer. RESULTS: The severe asthma and control groups were matched in terms of age and sex (32 [53%] females in each group). Individuals with severe asthma accumulated less minutes per day in moderate and higher intensity activity, median (IQR) 21.9 (12.9-36.0) versus 41.7 (29.5-65.2) (P < .0001) and accumulated 2,232 fewer steps per day (P = .0002). However, they engaged in more light-intensity physical activity. No differences were found for sedentary time. In a multivariate regression model, steps per day were strongly and independently associated with better exercise capacity in participants with severe asthma (coefficient, 0.0169; 95% CI, 0.008-0.025; P < .001). CONCLUSIONS: People with severe asthma perform less moderate and vigorous activity than do controls. Higher levels of activity and lower levels of sedentary time are associated with better exercise capacity, asthma control, and lower levels of systemic inflammation. PMID- 29133223 TI - Phenotypical Differences of Childhood- and Adult-Onset Atopic Dermatitis. AB - BACKGROUND: Little is known about adult-onset atopic dermatitis (AD). OBJECTIVE: To determine the associations and clinical characteristics of adult-onset AD. METHODS: A prospective study of 356 adults with AD (age >=18 years) was performed using standardized questionnaires and examination. AD severity was assessed using the Patient-Oriented Eczema Measure, Eczema Area and Severity Index, Scoring Atopic Dermatitis, body surface area, and numeric rating scale for itch and sleeplessness. Latent class analysis was used to determine dominant clinical phenotypes. Multivariate logistic regression was used to determine the relationship between adult-onset AD and distinct phenotypes. RESULTS: One hundred forty-nine adults (41.9%) reported onset of AD during adulthood, with 87 (24.4%) after the age of 50 years. Adult- versus childhood-onset AD was associated with birthplace outside the United States (chi2, P = .0008), but not sex, race/ethnicity, current smoking status, or alcohol consumption (P >= .11); and decreased personal history of asthma, hay fever, and food allergy and family history of asthma and food allergy (P <= .0001 for all). There was no significant difference in the Eczema Area and Severity Index, Scoring Atopic Dermatitis, body surface area, numeric rating scale for itch and sleeplessness, or Patient Oriented Eczema Measure between adult- and childhood-onset AD (Mann-Whitney U test, P >= .10). Latent class analysis identified 3 classes: (1) high probability of flexural dermatitis and xerosis with intermediate to high probabilities of head, neck, and hand dermatitis; (2) high probability of flexural dermatitis and xerosis, but low probabilities of head, neck, and hand dermatitis; and (3) lower probability of flexural dermatitis, but the highest probabilities of virtually all other signs and symptoms. Adult-onset AD was significantly associated with class 1 (multivariate logistic regression; adjusted odds ratio, 5.54; 95% CI, 1.59-19.28) and class 3 (adjusted odds ratio, 14.03; 95% CI, 2.33-85.50). CONCLUSIONS: Self-reported adult-onset AD is common and has distinct phenotypes with lesional predilection for the hands and/or head/neck. PMID- 29133224 TI - FeNO and Exercise Testing in Children at Risk of Asthma. AB - BACKGROUND: Exercise testing is the gold standard for diagnosing exercise-induced bronchoconstriction in children, but requires considerable cooperation and medical resources. Therefore, fraction of exhaled nitric oxide (FeNO) has been proposed as a tool to predict the need for exercise testing. OBJECTIVE: The objective of this study was to investigate the relationship between FeNO, exercise test results, and a history of respiratory symptoms during exercise in children at risk of asthma. METHODS: FeNO measurement, exercise testing, and interview about respiratory symptoms during exercise were completed in 224 seven year-old children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood2000 birth cohort. The associations between FeNO, exercise test results, and reported respiratory symptoms during exercise were analyzed adjusting for gender, respiratory infections, and inhaled corticosteroid treatment. The associations were also analyzed stratified by asthma and atopic status. RESULTS: Of the 224 children, 28 (13%) had an established asthma diagnosis and 58 (26%) had a positive exercise test (>=15% drop in forced expiratory volume in 1 second [FEV1] from baseline). FeNO and bronchial obstruction after exercise were linearly associated with a doubling of FeNO corresponding to a 2.4% drop in FEV1 (95% confidence interval, 0.8-4.1; P < .01). However, a receiver operating characteristic curve analysis showed that the best cutoff of FeNO for predicting exercise test outcome among children who reported respiratory symptoms during exercise was 17 ppb, which only had 74% negative predictive value. There was no association between FeNO and reported respiratory symptoms during exercise (odds ratio = 1.3 [0.8-1.9]; P = .29) or reported symptoms during exercise and exercise test results (odds ratio = 1.0 [1.0-1.1]; P = .12). CONCLUSIONS: A history of respiratory symptoms during exercise was not associated with either elevated FeNO or a positive exercise test in children at risk of asthma. FeNO and exercise test results were linearly associated traits, but FeNO could not reliably be used dichotomized to predict the need of exercise testing. PMID- 29133225 TI - Longitudinal Evaluation of Chronic Rhinosinusitis Symptoms in a Population-Based Sample. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent and disabling condition of the nose and sinuses. The natural history of CRS symptoms in a general population sample has not been previously studied. OBJECTIVE: In a general population-based sample from Pennsylvania, we used 2 questionnaires mailed 6 months apart to estimate the prevalence of, and identify predictors for, stability or change in symptoms over time. METHODS: We mailed the baseline and 6 month follow-up questionnaires to 23,700 primary care patients and 7,801 baseline responders, respectively. We categorized nasal and sinus symptoms using European Position Paper on Rhinosinusitis (EPOS) epidemiologic criteria. We defined 6 symptom groups over time on the basis of the presence of CRS symptoms at baseline and follow-up. We performed multivariable survey logistic regression controlling for confounding variables comparing persistent versus nonpersistent, recurrent versus stable past, and incident versus never. RESULTS: There were 4,966 responders at follow-up: 558 had persistent symptoms, 190 recurrent symptoms, and 83 new symptoms meeting EPOS criteria for CRS. The prevalence of persistent symptoms was 4.8% (95% CI, 3.8-5.8), whereas the annual cumulative incidence of new symptoms was 1.9% and of recurrent symptoms was 3.2%. More severe symptoms at baseline were associated with persistence, whereas minor symptoms, allergies, and multiple treatments were associated with the development of new symptoms. CONCLUSIONS: Less than half with nasal and sinus symptoms meeting CRS EPOS criteria in our general, regional population had symptom persistence over time, with symptom profiles at baseline and age of onset being strongly associated with stability of symptoms. PMID- 29133226 TI - The effect of dietary neonicotinoid pesticides on non-flight thermogenesis in worker bumble bees (Bombus terrestris). AB - For bumble bees (genus Bombus), the capacity for non-flight thermogenesis is essential for two fundamental processes undertaken by adult workers, namely recovery from torpor after chilling and brood incubation. Farmland bees can be widely exposed to dietary residues of neurotoxic neonicotinoid insecticides that appear in the nectar and pollen of treated bee-attractive crops, which may harm them. An earlier study shows that dietary neonicotinoids cause complex alterations to thermoregulation in honey bees, but their effect on the thermogenic capabilities of individual bumble bees has been untested previously. We therefore conducted laboratory trials involving separate dietary exposures of bumble bees to two neonicotinoids, imidacloprid and thiamethoxam, and we measured their effects on the thoracic temperatures of bees during recovery from chilling. Specifically, we used thermal imaging to measure the rates of rewarming by individual bees after chill-induced torpor and to quantify their equilibrated thoracic temperatures post-recovery. We found that both toxicants caused dose dependent decreases in the rates of rewarming and in the equilibrated thoracic temperatures. As previously found in honey bees, the dose-response relationship for imidacloprid exhibited a biphasic hormesis with low-dose stimulation and high dose inhibition, for which we propose a mechanism. Our present study is among the first to detect ecologically relevant effects on bees in neonicotinoid exposures involving dietary concentrations below 5 ppb. If the effects on thoracic temperatures that we observed over a short period were sustained, they could have ecologically significant impacts on farmland bumble bees. PMID- 29133227 TI - Chilling effect on termination of reproductive diapause in Listronotus maculicollis (Coleoptera: Curculionidae). AB - Diapausing adults of the annual bluegrass weevil, Listronotus maculicollis, were collected from their hibernating sites at different times in autumn and winter, and subjected to different conditions to observe diapause termination by dissecting and measuring the reproductive organs. When diapausing weevils were maintained under laboratory cold conditions (10 h light at 6 degrees C:14 h dark at 4 degrees C) from early December to late March, the sizes of reproductive organs of both sexes increased or fluctuated slightly, and very few females had developing oocytes, suggesting that most adults did not resume development during the chilling period. When diapausing weevils (chilled for 40-83 days) were transferred to warm conditions (LD 14:10 and 21 degrees C) for different lengths of time, reproductive organ sizes in both sexes increased as chilling period prolonged, implying that chilling played an important role in diapause termination. Under field conditions, an apparent peak of reproductive development was observed on January 07 when 80% of males and 53% of females had resumed growth of reproductive organs. Diapausing weevils collected in September without chilling did not develop successfully despite exposure to warm conditions. In contrast, 87% of males and 93% of females collected from the field on January 21 had initiated reproductive development after 5 days of exposure to warm conditions, indicating the necessity of chilling for diapause termination. Male and female reproductive organ sizes increased faster and to a greater final size the longer the preceding chilling period was. The prolonged chilling period in the field resulted in more synchronized and advanced development in L. maculicollis when exposed to warm conditions. PMID- 29133228 TI - Effects of cold acclimation on rectal macromorphology, ultrastructure, and cytoskeletal stability in Gryllus pennsylvanicus crickets. AB - Cold-acclimated insects maintain ion and water balance in the cold, potentially by reducing permeability or increasing diffusion distance across ionoregulatory epithelia such as the rectum. We explored whether cold acclimation induces structural modifications that minimize water and ion diffusion across the rectum and maintain rectal cell integrity. We investigated rectal structure and cytoskeletal stability in chill-susceptible adult Gryllus pennsylvanicus crickets acclimated for one week to either warm (25 degrees C) or cold (12 degrees C) conditions. After acclimation, we used light and transmission electron microscopy to examine rectal macromorphology and rectal pad paracellular ultrastructure. We also used fluorescence microscopy and a filamentous-actin (F-actin) specific phalloidin stain to compare the polymerization state of the actin cytoskeleton for each of the acclimation groups before and after a cold shock (1 h at -4 degrees C). Cold acclimation did not alter rectal pad cell density, or the thickness of the rectal pads, muscle, or cuticle. The tortuosity and width of the rectal pad paracellular channels also did not differ between warm- and cold acclimated crickets. Rectal pad cells had clear basal and apical regions with differing densities of F-actin. Cold shock reduced the density of F-actin in warm acclimated crickets, whereas cold-acclimated crickets appeared to have unchanged (basal) or enhanced (apical) F-actin density after cold shock. This suggests that while cold acclimation does not modify rectal permeability through structural modifications to increase diffusion distance for water and ions, cold-acclimated crickets have a modified cytoskeleton that resists the depolymerising effects of cold shock. PMID- 29133229 TI - Use of electrical penetration graphs (EPG) and quantitative PCR to evaluate the relationship between feeding behaviour and Pandora neoaphidis infection levels in green peach aphid, Myzus persicae. AB - A real-time qPCR method was developed, validated, and used to quantity the fungal pathogen, P. neoaphidis, within aphids at different times during infection; colonization rate fitted the Gompertz model well (R2 = 0.9356). Feeding behaviour of P. neoaphidis-infected and uninfected M. persicae were investigated, for the first time, using DC-electrical penetration graphs (DC-EPG) that characterized the waveforms made during different aphid stylet probing periods corresponding to epidermis penetration, salivation and ingestion. In the 6 h following the 12-h incubation period (to achieve infection), there were significant differences in the number of events of Np (non-probing) and C (stylet pathway) between infected and uninfected aphids. However, the difference between total duration of Np and C were not significantly different between infected and uninfected aphids. There were no significant differences in the number of events or total duration of E1 (phloem salivation) or E2 (phloem ingestion) between infected and uninfected aphids. There were significant differences in mean number of events and total duration of the pd waveform (intracellular punctures) in infected and uninfected aphids. In the 16 h prior to death, the same differences in behaviour were observed but they were even more obvious. Furthermore, the total duration time of E2 was significantly greater in uninfected aphids than infected aphids, a change that had not been observed in the first 6 h observation period. In conclusion, qPCR quantification demonstrated 'molecular' colonization levels throughout infection, and EPG data analysis during the two periods (during early infection and then during late infection just prior to death) demonstrated the actual physical effects of fungal infection on feeding behaviour of M. persicae; this has the potential to decrease the aphid's capacity of transmission and dispersal. These studies increase our understanding of the interaction between P. neoaphidis and its host aphid. PMID- 29133230 TI - Birth, coming of age and death: The intriguing life of long noncoding RNAs. AB - Mammalian genomes are pervasively transcribed, with long noncoding RNAs being the most abundant fraction. Recent studies have highlighted the central role played by these transcripts in several physiological and pathological processes. Despite several metabolic features shared between coding and noncoding transcripts, these two classes of RNAs exhibit multiple differences regarding their biogenesis and processing. Here we review such distinctions, focusing on the unique features of specific long noncoding RNAs. PMID- 29133232 TI - Embryological and comparative description of the cephalic vein joining the external jugular vein: A case report. AB - The cephalic vein arises from the radial end of the dorsal venous arch. It turns around the radial border of the forearm and passes proximally along the arm to the shoulder, where it enters the axillary vein by penetrating the clavipectoral triangle. The cephalic vein is prone to vary at the antecubital fossa, where it forms numerous anastomoses. A male cadaver fixated with a 10% formalin solution was dissected during regular anatomy lessons. It was found that the cephalic vein crossed the upper third of the arm between two fasciculi of the deltoid muscle and reached the shoulder, where it passed above the acromion and crossed the posterior border of the clavicle in order to join the external jugular vein. The cephalic vein is one of the most used veins for innumerous activities, such as venipunctures and arteriovenous fistula creation. Furthermore, it is an anatomical landmark known for its consistent anatomy, as it possesses low rates of variability. Despite that, its anatomical variations are clinically and surgically significant and healthcare professionals must be aware of the variations of this vessel. We aim to report a rarely described variation of the cephalic vein and discuss its embryological, phylogenetic and clinical features. PMID- 29133231 TI - Distinct inflammatory response patterns are evident among men and women with higher depressive symptoms. AB - Extensive research links depression and inflammation, with emerging evidence suggesting some differences between males and females in these associations. However, relatively few studies have examined stimulated inflammatory responses (ex vivo) in depression. The present research investigated the associations between depressive symptoms, basal inflammation, and LPS-stimulated production of pro- (IL-1beta, IL-6, IL-8, TNF-alpha) and an anti-inflammatory cytokine (IL-10), with a focus on the extent to which gender moderates these relationships. As part of a larger study, 162 socio-economically and racially diverse subjects (ages 25 65, 67% women) completed extensive self-report measures, including depressive symptoms. Whole blood was quantified for basal inflammation, or incubated with 1MUg/mL lipopolysaccharide (LPS) for 2h (at 37 degrees C, 5% CO2) to quantify inflammatory responses to bacterial challenge. We examined the associations between depression and inflammatory markers in regression analyses, controlling for age, BMI, race/ethnicity, income, education, and use of medications. No main effects were observed between depressive symptoms and basal or stimulated levels of inflammation. Moderation analyses revealed a significant interaction between depressive symptoms and gender for stimulated TNF-alpha, stimulated IL-6 (p<0.05), and a marginally significant interaction for stimulated IL-10 (p=0.07). For men, higher depressive symptoms were associated with significantly higher production of TNF-alpha (p<0.05) and marginally higher IL-6 (p=0.07), but not with the anti-inflammatory cytokine IL-10. For women, higher depressive symptoms were associated with significantly lower production of TNF-alpha and IL-10 (ps<0.05), and marginally lower IL-6 (p=0.06). These findings provide evidence for gender differences in the association of depressive symptoms with inflammatory response patterns, and highlight the utility of assessing ex vivo immune responses in blood. Implications for health are discussed. PMID- 29133234 TI - Editorial. PMID- 29133233 TI - Freeze-Drying From Organic Cosolvent Systems, Part 1: Thermal Analysis of Cosolvent-Based Placebo Formulations in the Frozen State. AB - The use of cosolvent systems has been demonstrated to shorten lengthy freeze drying processes and improve the solubility and stability of certain active pharmaceutical ingredients. The goal of the present study was to evaluate the suitability of 2 thermal characterization techniques, differential scanning calorimetry and freeze-dry microscopy, and to identify an optimal cosolvent system. Binary mixtures of a cosolvent (tert-butanol, dimethyl sulfoxide, 1,4 dioxane, acetone, or ethanol) and water were investigated. Ternary mixtures of frequently used excipients (50 mg/g mannitol, sucrose, glycine, or polyvinylpyrrolidone [PVP]) and a solvent-water system were then analyzed for their thermal properties. PVP presented a particularly high glass transition temperature (Tg') in 70% tert-butanol at -17.9 degrees C. Large needle-shaped crystals that have been shown to be associated with improved processability were observed with mannitol and PVP in 40% 1,4-dioxane. A heterogeneous sublimation rate of the solvent and water whose impact on product stability remained unclear was observed with PVP in 40% 1,4-dioxane. Freeze-dry microscopy analysis demonstrated a possible extension of the process time for PVP in 99% dimethyl sulfoxide due to a slowly moving sublimation front. Conceivable negative consequences and the need for special treatment for low-melting cosolvents, such as ethanol and acetone, were predicted and discussed. PMID- 29133235 TI - Can the Cellular Internalization of Cargo Proteins Be Enhanced by Fusing a Tat Peptide in the Center of Proteins? A Fluorescence Study. AB - The aim of this study was to investigate whether the cellular uptake of cargo proteins can be enhanced by fusing a Tat peptide in the center of proteins; glutathione-S-transferase (GST)-Tat-green fluorescent protein (GFP) and GST-GFP Tat proteins were first constructed and expressed. The cellular internalization of both proteins was then evaluated and compared in HeLa cells using fluorescent microscopy and flow cytometry, as well as the transdermal delivery in human skin using confocal microscopy. Results from in vitro cell experiments showed that GST Tat-GFP protein efficiently internalized into HeLa cells when a Tat peptide was fused in the center of proteins, whereas its efficiency is lower than that of GST GFP-Tat protein with a Tat peptide terminal fused. Ex vivo transdermal delivery data also demonstrated that the lower efficiency of GST-Tat-GFP penetrating through human stratum corneum layer when compared with GST-GFP-Tat. Furthermore, both GST-GFP-Tat and GST-Tat-GFP presented a various degree of a mixture of cytoplasmic diffuse staining and punctate surface staining, and the pattern of distribution varied considerably in HeLa cell experiments depending on the concentration of protein used. Therefore, an improved mechanism for Tat conjugated proteins was proposed, in which Tat-conjugated proteins were first associated with cell membrane, then accumulated on the cell surface, and finally internalized into cells by pore formation mechanism. PMID- 29133236 TI - Prediction of Apparent Oral Clearance of Small-Molecule Inhibitors in Pediatric Patients. AB - The purpose of this study was to build regression models for the prediction of apparent oral clearance (CL/F) for small-molecule inhibitors in the pediatric population using data obtained from adults. Two approaches were taken; a simple allometric regression model which considers no interdrug or interindividual variability and an allometric regression model with mixed-effects modeling where some variability parameters are included in the model. Average CL/F values were obtained for 15 drugs at various dosages from 31 literatures (a total of 139 data sets) conducted in adults and for 15 drugs from 26 literatures (62 data sets) conducted in children. Data were randomly separated into the "modeling" or "validation" data set, and the 2 allometric regression models were applied to the modeling data set. The predictive ability of the models was examined by comparing the observed and model-predicted CL/F in children using the validation data set. The percentage root mean square error was 17.2% and 26.3% in the simple allometric regression model and the allometric regression model with mixed effects modeling, respectively. The predictive ability of the 2 models seems acceptable, suggesting that they could be useful for predicting the CL/F of new small-molecule inhibitors and for determining adequate doses in clinical pharmacotherapy for children. PMID- 29133237 TI - Dermatology and its unique diagnostic heuristics. PMID- 29133238 TI - miR-146a targets c-met and abolishes colorectal cancer liver metastasis. AB - A major complication of colorectal cancer (CRC), one of the most frequent and deadly types of cancer, is disease progression via liver metastases. At this stage, very few treatment options are available for patients, and the disease remains incurable. Herein, we used a well-established mouse model of CRC liver metastasis (CLM) to identify new regulators of this process. Using serial transplantation of murine MC38 adenocarcinoma cells, we obtained liver metastatic variants that displayed extremely strong colonization abilities. Using these newly established cell lines, we performed gene expression arrays and microRNA (miR) profiling. Comparative and predictive analyses between the two arrays showed higher expression of c-met and concomitant reduction of miR-146a in the mestastatic variants. In CRC patients, expression levels of both c-met and miR 146a were similar between primary tumors and liver metastases. Interestingly, we identified c-met as a new target for miR-146a, as miR-146a was able to impede c met translation. Of relevance, overexpression of miR-146a in metastatic clones showed reduced in vitro malignancy and abolished the development of primary tumor and liver metastases. Our results document a new mechanism for c-met regulation in CLM and highlight the crucial role of miR-146a in suppressing tumorigenesis. PMID- 29133239 TI - Emerging role of plexins signaling in glioma progression and therapy. AB - Gliomas are highly invasive brain tumors with increased resistance to chemotherapy and high recurrence rate. Neoplastic cells commonly infiltrate into the surrounding tissue even at low grade tumors. Cell migration is often ceased at white and grey matter junctions indicating the involvement of tropic and axon guidance molecules in glioma growth and invasion. Emerging evidence implicates plexin-semaphorin signaling in the pathobiology of gliomas. Plexins are transmembrane receptors divided into four subfamilies (Plexins-A to -D) with differential specificity and functionality. They are involved in cell adhesion and motility, vascular growth and organogenesis, as well as tumor progression. In gliomas, plexins-A serve as coreceptors of neuropilins and transduce signals of class 3 semaphorins to PI3K/Akt pathway promoting cell growth, migration and invasion. Plexins-B1 and -B2 bind class 4 semaphorins to regulate RhoGTPases and induce glioma invasiveness and angiogenesis while, plexins-B3 interact with class 5 semaphorins to inhibit cell invasion and promote astrocytic cell differentiation via glial fibrillary acidic protein (GFAP) regulation. This review focuses on the biological roles of plexin-semaphorin signaling in glioma pathogenesis and discusses their potential as prognostic biomarkers and therapeutic targets. PMID- 29133240 TI - Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach. AB - Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin). The human CNS PBPK model could successfully predict their concentration-time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6-fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target-site concentrations in humans, which are essential for drug development and patient treatment. PMID- 29133241 TI - In silico comparisons between natural inhibitors of ABCB1/P-glycoprotein to overcome doxorubicin-resistance in the NCI/ADR-RES cell line. AB - To investigate compound-protein binding mode and molecular dynamic simulation of P-glycoprotein (P-gp), in silico studies were performed to compare 12 naturally occurring compounds using two softwares. The net results showed that piperine (PIP) had the best binding affinity. In vitro studies on doxorubicin (DOX) resistant NCI/ADR-RES cells, known to express P-gp, showed that, dose dependently, PIP significantly increased intracellular accumulation of rhodamine 123 and had cytotoxic effects accessed by MTT assay. In addition, PIP at 25 and 50MUM significantly potentiated DOX-induced cytotoxicity on the same cell line. P gp ATPase assay showed that both DOX and PIP had dose-dependent inhibition of orthovandate-sensitive ATPase activity, indicating they are both P-gp inhibitors, with IC50 of 84+/-1 and 37+/-2MUM, respectively. PIP did not show any activation of ATPase activity, while DOX did, indicating that P-gp does not accept PIP as a substrate. Using DOX at concentration 33.33MUM together with PIP (100MUM), DOX mediated P-gp ATPase activity was decreased to levels 4-folds lower than DOX alone. In conclusion, both in silico and in vitro studies confirm that PIP is an inhibitor of P-gp mediated DOX efflux, suggesting PIP as a promising adjuvant to DOX cancer chemotherapy. PMID- 29133242 TI - Revisiting in vitro release test for topical gel formulations: The effect of osmotic pressure explored for better bio-relevance. AB - Release test methods for topical dosage forms including pharmacopeial tests require a large volume of release media, with limited application for high throughput screening. In the present study, we evaluated Transwell assay to miniaturize the release test method for optimization of thermoreversible topical gel formulations. We also explored the osmotic effect on the in vitro release rates from gel formulations to understand the bio-relevance of release media. An extreme vertices type of mixture design in Minitab(r)16 generated eleven formulations composed of poloxamer 407, poloxamer 188, and phosphate buffered saline (PBS). A quadratic equation adequately described the composition dependence of gelation temperature. Epidermal growth factor (EGF) and trypan blue were used as model drugs for proteins and small molecules, respectively. Cumulative release in PBS containing 30% sucrose exhibited linear correlation with respect to the gel compositions, while PBS without sucrose did not differentiate various compositions. Higher release rates in PBS than in sucrose media are attributable to the osmotic water flow from PBS into the donor phase, and subsequent increase in diffusivity. The time course of in vivo near-infrared fluorescence imaging of topical EGF gels on the wound sites were consistent with the in vitro release profiles measured with PBS as the release media. To the best of our knowledge, this is the first study to propose a release test method suitable for high throughput screening of topical formulations with emphasis on the osmotic pressure effect. Bio-relevant release media composition for a topical formulation would vary depending on its clinical application because the osmotic water flow through the normal skin would be negligible compared to compromised skin. PMID- 29133243 TI - Peptides as a strategy against biofilm-forming microorganisms: Structure-activity relationship perspectives. AB - Biofilm forming microorganisms substantially enhance their virulence and drug resistance causing and alternatives are need to combat this health problem. In this context, peptides are an exceptional strategy in drug design and pharmaceutical innovation due to their diverse chemical features, biological activity and biotechnological relevance. Therefore, this study proposes a comprehensive assessment of a wide range of peptides, targeting biofilms. It provides chemical and molecular information and a Structural Activity Relationship perspective in order to delineate minimal requirements for antibiofilm activity and contributing to the development of new antibiofilm agents. In light of this, it was possible to propose a peptide design model (X1 X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20) to be tested in the war against resistant microorganisms. PMID- 29133244 TI - Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C. AB - BACKGROUND & AIMS: Ledipasvir/sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study, 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the Summary of Product Characteristics (SmPC), 8-week treatment may be considered in naive non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of an 8 week regimen of LDV/SOF under real-world conditions. The aim of the present study was to characterise patients receiving 8 weeks of LDV/SOF compared to those receiving 12 weeks of LDV/SOF, and to describe therapeutic outcomes in routine clinical practice. METHODS: The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. RESULTS: Overall, 84.6% (2,034/2,404) of the safety population (intention-to treat-1 [ITT1]) and 98.2% (2,029/2,066) of the per protocol (PP) population achieved sustained virological response at week 12 (SVR12). In the 8-week group, 85.1% (824/968) of ITT1 and 98.3% (821/835) of PP patients achieved SVR12, while in the 12-week group, 85.5% (1,210/1,415) of ITT1, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). CONCLUSIONS: Under real-world conditions a high proportion of eligible patients receiving 8-week LDV/SOF treatment achieved SVR12. Relapse occurred more frequently in patients who did not meet the selection criteria according to the SmPC. LAY SUMMARY: In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8-week) resulted in equivalent cure rates to 12 week treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Clinical Trial number: DRKS00009717 (German Clinical Trials Register, DRKS). PMID- 29133245 TI - Acute liver failure: Do the EASL guidelines address the whole spectrum? PMID- 29133246 TI - Potentially inappropriate liver transplantation in the era of the "sickest first" policy - A search for the upper limits. AB - Liver transplantation has emerged as a highly efficient treatment for a variety of acute and chronic liver diseases. However, organ shortage is becoming an increasing problem globally, limiting the applicability of liver transplantation. In addition, potential recipients are becoming sicker, thereby increasing the risk of losing the graft during transplantation or in the initial postoperative period after liver transplantation (three months). This trend is challenging the model for end-stage liver disease allocation system, where the sickest candidates are prioritised and no delisting criteria are given. The weighting of the deontological demand for "equity", trying to save every patient, regardless of the overall utility; and "efficiency", rooted in utilitarianism, trying to save as many patients as possible and increase the overall quality of life of patients facing the same problem, has to be reconsidered. In this article we are aiming to overcome the widespread concept of futility in liver transplantation, providing a definition of potentially inappropriate liver transplantation and giving guidance on situations where it is best not to proceed with liver transplantation, to decrease the mortality rate in the first three months after transplantation. We propose "absolute" and "relative" conditions, where early post-transplant mortality is highly probable, which are not usually captured in risk scores predicting post-transplant survival. Withholding liver transplantation for listed patients in cases where liver transplant is not deemed clearly futile, but is potentially inappropriate, is a far-reaching decision. Until now, this decision had to be discussed extensively on an individual basis, applying explicit communication and conflict resolution processes, since the model for end-stage liver disease score and most international allocation systems do not include explicit delisting criteria to support a fair delisting process. More work is needed to better identify cases where transplantation is potentially inappropriate and to integrate and discuss these delisting criteria in allocation systems, following a societal debate on what we owe to all liver transplant candidates. PMID- 29133247 TI - Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1,006 nodules. AB - BACKGROUND & AIMS: The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned because of the risk of a false positive diagnosis in cases of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS Liver Imaging Reporting and Data System [LI-RADS(r)]) to classify lesions at risk of HCC investigated by CEUS. The aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. METHODS: A total of 1,006 nodules from 848 patients with chronic liver disease at risk of HCC were collected in five Italian centers and retrospectively analyzed. Nodules were classified as LR-5, (HCC) if >=1 cm with arterial phase hyperenhancement, and late washout (onset >=60 s after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (n = 506) or histology (n = 500). RESULTS: The median nodule size was 2 cm. Of 1,006 nodules, 820 (81%) were HCC, 40 (4%) were cholangiocarcinoma, 116 (11%) regenerative nodules (+/-dysplastic). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96 [47%]) and the LR-4 202 (HCC 173 [87%]). CONCLUSIONS: The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non-invasive diagnosis. LAY SUMMARY: This is a retrospective study of approximately 1,000 focal lesions at risk for hepatocellular carcinoma (HCC). Herein, we demonstrate that the refined definition of the typical contrast enhanced ultrasound pattern of HCC introduced by the Liver Imaging Reporting and Data System (LI-RADS(r)) practically abolishes the risk of misdiagnosis of other malignant entities (e.g. cholangiocarcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose HCC in cirrhosis. PMID- 29133248 TI - Evolution of the hygiene hypothesis into biota alteration theory: what are the paradigms and where are the clinical applications? AB - For thousands of years, changes in human cultures have altered the biota associated with the human body, and those alterations have strongly influenced human health. The hygiene hypothesis has evolved over the past 30 years into a nuanced biota alteration theory, but modern medical priorities and regulatory policies have resulted in tragic underutilization of the acquired knowledge. PMID- 29133249 TI - Immunomodulation of dual specificity phosphatase 4 during visceral leishmaniasis. AB - DUSP4, an inducible protein has a substrate specificity toward ERK1/2, a component of MAP kinase which is enhanced during Leishmania infection. The DUSP4 /- mice show increased susceptibility towards the infection caused by Toxoplasma gondii and Leishmania mexicana. These observations emphatically established the fact that unlike DUSP1, DUSP4 has host protective role. In our study, it has been Leishmania donovani, the causative agent of visceral leishmaniasis (VL) significantly reduced the expression of DUSP4 during infection. In order to find out the host protective role of DUSP4 in macrophages during VL, we silenced DUSP4 prior to infection and the parasite number within macrophage was counted. Under DUSP4 knock-down condition, phosphorylation of p38 MAPK and generation of pro inflammatory response like IL-12, TNF-alpha, and iNOS was decreased significantly. Silencing DUSP4 promoted the phosphorylation of ERK1/2 and the generation of anti-inflammatory response like- IL-10, TGF-beta with increased Arginase-1 and Cox-2 activity. Glycyrrhizic Acid (GA), an immunomodulator, already known to suppress L. donovani infection, found to up-regulate DUSP4 expression during L. donovani infection. On the other hand, GA failed to increase Th1 cytokine production and decrease Th2 response during DUSP4 knock-down condition suggesting the key role of DUSP4 while providing protection during L. donovani infection. PMID- 29133250 TI - Success of Immunosuppressive Treatments in Patients with Chronic Graft-versus Host Disease. AB - Moderate to severe chronic graft-versus-host disease (GVHD) is treated with potent immunosuppressive therapy (IST) to modulate the allo-immune response, control symptoms, and prevent further organ damage. We sought to understand the types of treatments used in clinical practice and the likelihood of successful treatment associated with each. A chart review was performed for 250 adult patients at Fred Hutchinson Cancer Research Center enrolled in a prospective observational study. After a median follow-up of 5.6 years for survivors, approximately one-third were still on IST (of whom half were on fourth or greater line of therapy), one-third were alive and off IST, and one-third had relapsed or died. Approximately half of survivors stopped all IST at least once, although half of these restarted IST after a median of 3.4 months (interquartile range, 2.3 to 8.0) off therapy. Successful discontinuation of IST for at least 9 months was associated with myeloablative conditioning (P = .04), more years since transplant (P = .009), and lack of oral (P < .001) and skin (P = .049) involvement compared with those who had to restart IST. We conclude that patients with chronic GVHD usually receive multiple lines and years of IST, with only a third off IST, alive, and free of malignancy at 5 years after chronic GVHD diagnosis. Patients stopping IST should be cautioned to self-monitor and continue close medical follow-up, especially for 3 to 6 months after stopping IST. PMID- 29133251 TI - Immune response of interferon-gamma-inducible lysosomal thiol reductase (GILT) from Chinese sturgeon (Acipenser sinensis) to microbial invasion and its antioxdative activity in lipopolysaccharides-treated mammalian dentritic cells. AB - Interferon-gamma-inducible lysosomal thiol reductase (GILT) plays an important role in the major histocompatibility complex-restricted antigen processing of endocytosed proteins via catalyzing the disulfide bond reduction in the endocytic pathway. Here, the cDNA of Chinese sturgeon (Acipenser sinensis) GILT (CsGILT) was cloned. It contained an open reading frame of 762 nucleotides encoding a protein of 254 amino acids with an estimated molecular weight of 28.1 kDa. The characteristic structural features, including a signature sequence CQHGX2ECX2NX4C, a CXXC motif, two potential N-glycosylation sites, and eight conserved cysteines were detected in the deduced amino acid sequence of CsGILT. CsGILT was widely expressed in Chinese sturgeon with the highest expression in the spleen, and CsGILT mRNA expression was significantly up-regulated when Chinese sturgeons were challenged with polyinosinic polycytidylic acid or Vibrio anguillarum. The recombinant CsGILT displayed obvious thiol reductase activity demonstrated by catalyzing the reduction of mouse IgG(H+L) by dithiothreitol into heavy chain and light chain. CsGILT also displayed significant antioxidant activity in mouse dentritic cells as indicated by its increasing GSH level and GSH/GSSG ratio, decreasing intracellular reactive oxygen species and nitric oxide levels and lipid peroxidation, as well as enhancing the activities of the antioxidative redox enzymes including catalase and superoxide dismutase. Our results suggested an important role for CsGILT in the immune response in Chinese sturgeon to pathogen invasion possibly via a conserved functional mechanism throughout vertebrate evolution, contributing to our understanding the immune biology and protection of Chinese sturgeon. PMID- 29133252 TI - l-rhamnose-binding lectins (RBLs) in Nile tilapia, Oreochromis niloticus: Characterization and expression profiling in mucosal tissues. AB - Rhamnose-binding lectins (RBLs) are crucial elements associated with innate immune responses to infections and have been characterized from a variety of teleost fishes. Given the importance of RBL in teleost fishes, we sought to study the diversity and expression profiles of RBLs in an important cultured fish, Nile tilapia (Oreochromis niloticus) following experimental infection with Streptococcus agalactiae, a major cause of streptococcosis in farmed tilapia. In this study, four predicted RBL genes were identified from Nile tilapia and were designated as OnRBL3a, OnRBL3b, OnRBL3c, and OnRBL3d. These OnRBLs were composed of two tandem-repeated type five carbohydrate recognition domains (CRDs), classified as type IIIc, and all clustered together phylogenetically. OnRBL-CRDs shared conserved topology of eight cysteine residues, characteristic peptide motifs of -YGR- and -DPC- (or -FGR- and -DTC-), and similar exon/intron organization. OnRBLs had the highest expression in immune-related tissues, gills, intestine or liver. However, the changes of OnRBL expression in the gills and intestine at 2 h, 4 h and 24 h post S. agalactiae challenge were modest, suggesting that tilapia may not mediate the entry or confront the infection of S. agalactiae through induction of RBL genes. The observed expression pattern may be related to the RBL type and CRD composition, S. agalactiae pathogenesis, the accessibility of ligands on the bacterial surface, and/or the species of fish. OnRBLs characterized in this study were the first RBL members identified in Nile tilapia and their characterization will expand our knowledge of RBLs in immunity. PMID- 29133253 TI - The oxidative stress and antioxidant responses of Litopenaeus vannamei to low temperature and air exposure. AB - Low temperature and air exposure were the key attributes for waterless transportation of fish and shrimp. In order to investigate the oxidative stress and antioxidant responses of the live shrimp Litopenaeus vannamei in the mimic waterless transportation, live shrimp were cooled at 13 degrees C for 3 min, stored in oxygen at 15 degrees C for 12 h, and then revived in water at 25 degrees C. The survival rate of shrimp under this waterless transportation system was over 86.67%. The ultrastructure of hepatopancreas cells were observed while activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), glutathione peroxidase (GSH-Px), antisuperoxide anion free radicals (ASAFR), total antioxidant capacity (TAOC), reactive oxygen species (ROS) production, content of malondialdehyde (MDA) and relative mRNA expressions of CAT and GSH-Px in the hemolymph and hepatopancreas were determined. Slight distortions of some organelles in hepatopancreas cells was reversible upon the shrimp revived from the cold shock. The activities of SOD, POD, CAT, GSH-Px, TAOC, ROS production and relative mRNA expressions of CAT and GSH-Px increased following the cold shock and reached peak levels after 3 or 6 h of storage, and then decreased gradually. There was no significant difference between the fresh and the revived shrimp in SOD, POD, GSH-Px, TAOC, ROS, MDA and relative mRNA expressions of CAT and GSH-Px. The oxidative stress and antioxidant responses were tissue-specific because hepatopancreas seemed to have a greater ability to defend against organelle damage and was more sensitive to stress than hemolymph based on the results of SOD activity, MDA content and GSH-Px mRNA expression. These results revealed that low temperature and air exposure caused significant oxidative and antioxidant responses, but did not lead to irreversible damages in this waterless system. PMID- 29133254 TI - Characteristics and Progression of Preclinical Inflammatory Bowel Disease. AB - BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a chronic disease usually diagnosed after the appearance of gastrointestinal symptoms. Little is known about IBD progression during its early and even preclinical phases. We aimed to determine the number of new incidental diagnoses of IBD in an older population, and evaluate disease progression from its early stages. METHODS: We performed a retrospective analysis of 31,005 colonoscopies performed during colorectal cancer screening of patients with positive results from fecal immunochemical tests, at 11 centers in the Basque Country (Spain) from 2009 through 2014. We collected clinical and laboratory data from all asymptomatic individuals suspected to have IBD during screening colonoscopies, with histologic confirmation. RESULTS: Colonoscopy screening led to 79 new diagnoses of ulcerative colitis, 24 of Crohn's disease, and 7 of unclassified colitis (average patient age, 57 y; interquartile range, 52-62 y; 57% male). Eleven patients had symptoms before colonoscopy and were excluded from the analysis. Among those patients who were asymptomatic at diagnosis, 36% developed symptoms after a follow-up period of 25 months (interquartile range, 10.5-42 mo), mostly rectal bleeding and diarrhea. Treatment was prescribed for 81 patients (88%), and 2 cases required surgery. CONCLUSIONS: We analyzed data from a large cohort of patients with IBD diagnosed at early or even preclinical stages, from an older population. New incidental diagnoses of IBD were made in 0.35% of individuals undergoing a population-based screening colonoscopy-most were classified as ulcerative colitis. Approximately one third of patients developed symptoms during the follow-up period. PMID- 29133255 TI - High Prevalence of Barrett's Esophagus and Esophageal Squamous Cell Carcinoma After Repair of Esophageal Atresia. AB - BACKGROUND & AIMS: Esophageal atresia is rare, but improved surgical and intensive care techniques have increased rates of survival in children, so there are now many adults with this disorder. Many patients with esophageal atresia develop gastroesophageal reflux (GER), raising concerns about increased risk of Barrett's esophagus (BE; prevalence of 1.3%-1.6% in general population) and esophageal carcinoma. We assessed the prevalence of BE and esophageal carcinoma in this population. METHODS: We performed a prospective study of 289 patients with esophageal atresia at the Department of Gastroenterology and Hepatology at Erasmus MC University Medical Center in The Netherlands, from May 2012 through March 2017. A total of 151 (median age, 25.4 y; age range, 16.8-68.6 y) underwent upper endoscopies as part of a surveillance program for (pre)malignant esophageal lesions. Biopsies were collected and analyzed by histology. We collected data on patients' use of medications, tobacco, and alcohol; gastrointestinal symptoms; ability to swallow; complaints of GER; and type of atresia and surgeries. Prevalence of esophageal squamous cell carcinoma (ESCC) was determined using data from The Netherlands Cancer Registry. The number of persons alive on January 1, 2016, in the esophageal atresia cohort and in the general Dutch population were used to calculate the 10-year prevalence of ESCC per 100,000 persons in both populations. RESULTS: Forty-seven percent of patients with esophageal atresia had a history of GER and 20.5% had undergone fundoplication surgery. Endoscopy revealed normal esophagus in 68.2% of patients, esophagitis in 7.3%, and columnar lined esophagus in 24.5%. Histology revealed normal mucosa in 50.3% of patients, esophagitis in 23.2%, gastric metaplasia in 17.2%, and BE in 6.6% (at a median age of 31.6 years). A history of fundoplication surgery was associated with BE (P = .03). Three ESCCs developed, in 2 men, at ages 42, 44, and 60 years. This corresponded to a prevalence of 0.7% in patients with esophageal atresia-a value 108-fold higher than in the same age group in the general population. CONCLUSIONS: The prevalence of BE is 4-fold higher in young adults with esophageal atresia, and the prevalence of ESCC is 108-fold higher than in the general population. This finding could have important implications for transition of young adults from pediatric care to adult gastroenterology departments to receive life-long endoscopic follow-up evaluation to facilitate early diagnosis of relevant lesions. PMID- 29133256 TI - When Should Screening Stop for Elderly Individuals at Average and Increased Risk for Colorectal Cancer? PMID- 29133257 TI - Comparative Efficacy of Colonoscope Distal Attachment Devices in Increasing Rates of Adenoma Detection: A Network Meta-analysis. AB - BACKGROUND & AIMS: Several add-on devices have been developed to increase rates of colon adenoma detection (ADR). We assessed their overall and comparative efficacy, and estimated absolute magnitude of benefit through a network meta analysis. METHODS: We searched the PubMed/Medline and Embase database through March 2017 and identified 25 randomized controlled trials (comprising 16,103 patients) that compared the efficacy of add-on devices (cap; Endocuff; Arc Medical Design Ltd, Leeds, UK, and Endorings; Us Endoscopy, Mentor, OH) with each other or with standard colonoscopy. The primary outcome was ADR; secondary outcomes included rate of polyp detection, and rate of and time to cecal intubation. We performed pairwise and network meta-analyses, and appraised quality of evidence using Grading of Recommendations Assessment, Development and Evaluation. We estimated the magnitude of increase in ADR by low-performing endoscopists (baseline ADR, 10%) and high-performing endoscopists (baseline ADR, 40%) with use of these devices. RESULTS: Overall, distal attachment devices increased ADR compared with standard colonoscopy (relative risk [RR], 1.13; 95% CI, 1.03-1.23; low-quality evidence), with potential absolute increases in ADR to 11.3% for low-performing endoscopists and to 45.2% for high-performing endoscopists. In a comparative evaluation, we found low-quality evidence that Endocuff increases ADR compared with standard colonoscopy (RR, 1.21; 95% CI, 1.03 1.41), with anticipated increases in ADR to 12% for low-performing endoscopists and to 48% for high-performing endoscopists. We found very low quality evidence to support the use of Endorings (RR, 1.70; 95% CI, 0.86-3.36) or caps (RR, 1.07; 95% CI, 0.96-1.19) vs standard colonoscopy for increasing ADR. The benefit of one distal attachment device over another was uncertain due to very low quality evidence. CONCLUSIONS: Based on network meta-analysis, we anticipate only modest improvement in ADRs with use of distal attachment devices, especially in low performing endoscopists. PMID- 29133258 TI - When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes? PMID- 29133259 TI - Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice. AB - Normal bone mineralization requires phosphate oversaturation in bone matrix vesicles, as well as normal regulation of phosphate metabolism via the interplay among bone, intestine, and kidney. In turn, derangement of phosphate metabolism greatly affects bone function and structure. The type III sodium-dependent phosphate transporters, PiT-1 and PiT-2, are believed to be important in tissue phosphate metabolism and physiological bone formation, but their requirement and molecular roles in bone remain poorly investigated. In order to decipher the role of PiT-2 in bone, we examined normal bone development, growth, and mineralization in global PiT-2 homozygous knockout mice. PiT-2 deficiency resulted in reduced vertebral column, femur, and tibia length as well as mandibular dimensions. Micro computed tomography analysis revealed that bone mineral density in the mandible, femur, and tibia were decreased, indicating that maintenance of bone function and structure is impaired in both craniofacial and long bones of PiT-2 deficient mice. Both cortical and trabecular thickness and mineral density were reduced in PiT-2 homozygous knockout mice compared with wild-type mice. These results suggest that PiT-2 is involved in normal bone development and growth and plays roles in cortical and trabecular bone metabolism feasibly by regulating local phosphate transport and mineralization processes in the bone. Further studies that evaluate bone cell-specific loss of PiT-2 are now warranted and may yield insight into complex mechanisms of bone development and growth, leading to identification of new therapeutic options for patients with bone diseases. PMID- 29133260 TI - Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes. AB - OBJECTIVE: Chondrocytes express many kinds of hormone receptors. The function of Follicle stimulating hormone (FSH) in the ovary is mediated by FSH receptor (FSHR). FSH receptor (FSHR) is found in many non-ovarian tissues, however it has been unclear if chondrocytes express FSHR. The purpose of this study is to determine it. METHODS: Mouse primary chondrocytes and human articular cartilage tissues were examined. The expression and sequence of FSHR mRNA by reverse transcription polymerase chain reaction (RT-PCR) and sequenced, respectively, and its protein expression was tested using western blotting and location was observed under immunofluorescence microscopy. Ovarian tissue was as a positive control. After FSH stimulated mouse chondrocytes, intracellular cAMP levels were assessed by ELISA, and gene expression relative to Mouse WNT Signaling Pathway was tested by RT2 Profiler PCR Arrays. RESULTS: FSHR was detected at the transcriptional level and confirmed to have the same sequence as that of ovary derived mRNA of FSHR. FSHR proteins presented at the same line as the positive proteins of ovary, in mouse chondrocytes and human cartilage tissue, respectively. FSHR proteins were located at the cell membrane. Intracellular cAMP contents were significantly elevated up to 7-fold in mouse chondrocytes by forskolin (100 mM) (P < 0.001); however, different doses of FSH did not change the cAMP contents in mouse primary chondrocytes. RT2 Profiler PCR Arrays demonstrated that FSH could cause changes in gene expression among the 84 preordained genes, such as Fosl1, Rhou, and Dkk1, in mouse chondrocytes relative to the control. CONCLUSION: Mouse chondrocytes and human articular cartilage express functional FSHR. Moreover, FSH can act on chondrocytes and cause genetic changes. PMID- 29133261 TI - Dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo. AB - Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non cytotoxic to the prostate epithelial cells. At the molecular level, SF2523 downregulated BRD4-regulated genes (cyclin D1, c-Myc and androgen receptor) and almost blocked AKT-S6K1 activation in prostate cancer cells. In vivo, SF2523 intraperitoneal administration at the well-tolerated dose inhibited human prostate cancer xenograft growth in severe combined immunodeficient (SCID) mice. BRD4-regulated genes (cyclin D1, c-Myc and androgen receptor) and AKT-S6K1 activation were inhibited in SF2523-treated tumors. Together, dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo. PMID- 29133262 TI - 911 Emergency Medical Services and Re-Triage to Level I Trauma Centers. AB - BACKGROUND: Interfacility transfer of undertriaged patients to higher-level trauma centers has been found to result in a delay of appropriate care and an increase in mortality. To address this, for the last 10 years our region has used 911 emergency medical services (EMS) paramedics for rapid re-triage of undertriaged patients to our institution's Level I trauma center. We sought to determine whether using 911 EMS for re-triage to our institution was associated with worse outcomes-with mortality as the primary end point-compared with direct EMS transport from point of injury. STUDY DESIGN: We retrospectively reviewed all trauma activations to our institution during a 16-month period; 3,394 active traumas were analyzed. RESULTS: Two hundred and seventy patients (8%) arrived via 911 EMS re-triage and 3,124 (92%) arrived via direct EMS transport. Total EMS transport time was significantly longer (122.5 minutes vs 33.7 minutes; p < 0.001) between the 2 groups, but there was no significant difference in mortality rates (4.1% vs 3.6%; p = 0.67). CONCLUSIONS: These data show that although using 911 EMS for re-triage is associated with an increase in total transport time, it does not result in an increase in mortality compared with direct EMS transport. We conclude that the use of 911 EMS can be considered a safe method to re-triage patients to higher-level trauma centers. PMID- 29133263 TI - Prospective Evaluation of Pasireotide in Patients Undergoing Pancreaticoduodenectomy: The Washington University Experience. AB - BACKGROUND: Pasireotide is a newer generation somatostatin analogue that led to a significant reduction in pancreatic fistula after pancreatectomy in a single center randomized controlled trial. We sought to determine if pasireotide reduces the incidence of pancreatic fistula and other complications after pancreaticoduodenectomy at our high volume center. STUDY DESIGN: All patients undergoing pancreaticoduodenectomy between April 2011 and January 2017 were prospectively followed, and their complications were graded using the Modified Accordion Grading System (MAGS) in our institutional complications database. For 18 months, 5 pancreatic surgeons used pasireotide routinely in patients undergoing pancreaticoduodenectomy. Patients receiving pasireotide were then propensity score-matched to patients who did not receive pasireotide, and their outcomes were compared. RESULTS: There were 459 patients who underwent pancreaticoduodenectomy, and 127 patients (28%) received pasireotide. Patients who received pasireotide were significantly more likely to have dilated pancreatic ducts and have a drain left at the time of surgery. Patients who received pasireotide had no difference in pancreatic fistula, overall complications, 90-day readmission, or 90-day mortality. However, patients who received pasireotide had a significantly reduced rate of postoperative bleeding/anemia (8.7% vs 16.9%, p = 0.03). Among 112 propensity score-matched pairs, patients who received pasireotide did not have significantly different rates of pancreatic fistula, and the rates of severe (MAGS grades 3 to 6) pancreatic fistula were identical between the 2 groups (7.1% vs 7.1%, p = 1.00). Matched patients who received pasireotide had significantly decreased postoperative bleeding/anemia (9.8% vs 19.6%, p = 0.04). CONCLUSIONS: Pasireotide did not reduce the incidence or severity of pancreatic fistulas after pancreaticoduodenectomy, but was associated with a decrease in postoperative bleeding/anemia. A multicenter randomized trial is needed to accurately define the role of pasireotide in the postoperative management of pancreaticoduodenectomy patients. PMID- 29133264 TI - Comparative Analysis of Clinical, Treatment, and Survival Characteristics of Basaloid and Squamous Cell Carcinoma of the Esophagus. AB - BACKGROUND: Basaloid squamous cell carcinoma (BSC) is a rare variant of squamous cell carcinoma (SqCC) of the esophagus. Even though pathologically thought to be more aggressive than SqCC, there is discrepancy in the literature regarding the outcomes of BSC compared with those of SqCC. STUDY DESIGN: We conducted a retrospective cohort study using the Surveillance Epidemiology and End Results (SEER) database. All patients with a histologic diagnosis of BSC and SqCC between 2004 and 2013 were included. We compared treatment and survival characteristics of patients with BSC and SqCC. RESULTS: There were 16,158 patients included in this study; 173 patients (1.1%) had BSC. There were no significant differences between the 2 groups based on age, sex, marital status, insurance, or geographic region of diagnosis, but patients with BSC were more likely to be Caucasian (73.4% vs 64.7%; p = 0.017). Among staged patients, baseline tumor stage was similar in both groups. However, BSC tumors were more likely to be of high pathologic grade (56.8% vs 38.2%; p < 0.001). Patients with SqCC were more likely to receive radiation therapy (36.9% vs 53.9%; p < 0.001), while patients with BSC were more likely to undergo resection (32.4% vs 17.0%; p < 0.001). Median overall survival was similar in both groups (14 vs 9 months; log rank = 0.144), and this relationship persisted after stratification by treatment. CONCLUSIONS: Even though more likely to be poorly differentiated at presentation, BSC of the esophagus seems to have similar clinical features and survival outcomes when compared with SqCC. Patients with BSC and SqCC should undergo stage-specific treatment to achieve optimal outcomes. PMID- 29133265 TI - Critical Under-Reporting of Hernia Mesh Properties and Development of a Novel Package Label. AB - BACKGROUND: With an array of hernia meshes with varying properties, intraoperative decision making for the optimal mesh is critical. Although meshes are subjected to regulatory review through the Food and Drug Administration, it is unknown whether mesh properties are visually accessible. To facilitate greater knowledge for the surgeon on mesh choice, we aimed to comprehensively analyze hernia mesh packaging and regulations. STUDY DESIGN: Labeling guidelines and 510(k) requirements across Food and Drug Administration-regulated products were analyzed and compared with mesh packaging. Packages and Instructions for Use were analyzed for commonly available hernia meshes. Literature review was conducted to understand recommended guidelines for mesh products. A novel hernia mesh packaging label was designed to rectify under-reporting. RESULTS: We found that food labels undergo critical scrutiny and detailed specifications, yet medical devices are not subjected to similar guidelines. The highest reported property on packages was the presence of a barrier (80%), and the lowest reported property was barrier composition (33%). For Instructions for Use, the lowest reported properties were mechanics (31%) and thickness (11%), both of which were not reported on packaging. Descriptive terms for pore size and mechanics were reported inconsistently. To overcome this under-reporting of properties, we propose a novel packaging label with properties chosen from regulatory guidelines, packaging analysis, and literature review. CONCLUSIONS: Although standardized terminology has been proposed in literature, property knowledge has not adequately permeated surgery, industry, or regulatory guidelines. There is extreme under-reporting and lack of consistency of clinically important mesh properties. Standardized packaging labels will provide accessibility of these properties and aim to bring standardized terminology into practice. With an increase in access to important properties, this can facilitate intraoperative decision making on a case-by-case basis. PMID- 29133266 TI - Mapping suicide mortality in Ohio: A spatial epidemiological analysis of suicide clusters and area level correlates. AB - Previous studies have investigated spatial patterning and associations of area characteristics with suicide rates in Western and Asian countries, but few have been conducted in the United States. This ecological study aims to identify high risk clusters of suicide in Ohio and assess area level correlates of these clusters. We estimated spatially smoothed standardized mortality ratios (SMR) using Bayesian conditional autoregressive models (CAR) for the period 2004 to 2013. Spatial and spatio-temporal scan statistics were used to detect high-risk clusters of suicide at the census tract level (N=2952). Logistic regression models were used to examine the association between area level correlates and suicide clusters. Nine statistically significant (p<0.05) high-risk spatial clusters and two space-time clusters were identified. We also identified several significant spatial clusters by method of suicide. The risk of suicide was up to 2.1 times higher in high-risk clusters than in areas outside of the clusters (relative risks ranged from 1.22 to 2.14 (p<0.01)). In the multivariate model, factors strongly associated with area suicide rates were socio-economic deprivation and lower provider densities. Efforts to reduce poverty and improve access to health and mental health medical services on the community level represent potentially important suicide prevention strategies. PMID- 29133267 TI - Comparing McGrath(r) MAC video laryngoscope with Macintosh direct laryngoscopy for novice laryngoscopists in children. Reply. PMID- 29133268 TI - Initial training of French residents in obstetric anaesthesia: A national survey. PMID- 29133269 TI - Austral influenza outbreak and its impact on an intensive care unit. PMID- 29133270 TI - Comparing McGrath(r) MAC video laryngoscope with Macintosh direct laryngoscopy for novice laryngoscopists in children. PMID- 29133271 TI - Rescue transtracheal jet ventilation during difficult intubation in patients with upper airway cancer. AB - INTRODUCTION: The failure rates of intubation and/or mask ventilation are higher in patients with neck or upper airway disease. To ensure oxygenation, rescue trans-tracheal jet ventilation (RTTJV) may be used. In this critical situation, a high rate of complications has been reported. The aim of this study was to report RTTJV performed by a jet ventilator with an end-expiratory pressure control in an experienced institution. PATIENTS AND METHODS: From a computerised database of 63,905 anaesthesia cases, the anaesthetic reports of patients who underwent emergency RTTJV during intubation were studied retrospectively. The following information were analysed: anaesthetic procedures, data from the monitoring: lowest SpO2, duration of SpO2<90%, and complications. Success of emergency RTTJV was defined when SpO2 was>90% under jet ventilation. RESULTS: RTTJV was used in 31 patients, of whom 26 had upper airway cancer, (pre-treatment, n=9, post treatment, n=17). Difficult intubation was anticipated in 15 out of 31 cases including six fiber-optic-aided intubations under spontaneous ventilation. RTTJV was effective in all cases with quick restoration of oxygenation (SpO2>90%). During jet ventilation, final airway control was performed either by oral intubation (n=25) or tracheotomy (n=1) in a short delay (mean: 8.1+/-1.7min). Subcutaneous emphysema was observed in one case without pneumothorax. CONCLUSION: RTTJV with end-expiratory pressure control allowed oxygenation during difficult intubation, with a low rate of complications. PMID- 29133272 TI - A new national quality indicator reflecting pain relief in the PACU has been launched and initial results show the positive performance of French teams. PMID- 29133273 TI - Plasma free thyroxine in the upper quartile is associated with an increased incidence of major cardiovascular events in older men that do not have thyroid dysfunction according to conventional criteria. AB - BACKGROUND: The aim of this study was to assess the association of plasma free thyroxine (FT4) and serum thyroid stimulating hormone (TSH) concentrations with the past diagnosis of cardiovascular disease and incidence of new cardiovascular events in older men with no known thyroid disease. METHODS: This study involved a cohort of community-recruited older men without known thyroid disease. Plasma FT4 and serum TSH were measured by immunoassay. Past cardiovascular disease diagnosis was defined through questionnaire data. The incidence of major cardiovascular events were assessed using the Western Australian Data Linkage System. The associations of plasma FT4 and serum TSH with the past diagnosis of cardiovascular disease and the incidence of new major cardiovascular events (cardiovascular death, myocardial infarction or stroke) were examined using logistic regression and Cox proportional hazard analyses. RESULTS: 3712 men were followed for a mean of 9.5years. Men with plasma FT4 in the upper quartile, compared to other men, were more likely to have been previously diagnosed with cardiovascular disease but this association did not persist after adjustment for other risk factors. Men with plasma FT4 in the upper quartile, compared to other men, had an increased incidence of major cardiovascular events (adjusted hazard ratio, HR, 1.15, 95% CI 1.00-1.31) and myocardial infarction alone (adjusted HR 1.29, 95% CI 1.06-1.54). CONCLUSION: This study suggests that older men with higher levels of plasma FT4 not meeting current criteria for the diagnosis of hyperthyroidism are at increased risk of major cardiovascular events. PMID- 29133274 TI - Gender differences in the impact of anemia on subclinical myocardial damage and cardiovascular mortality in the general population: The Yamagata (Takahata) study. AB - BACKGROUND: Anemia has been shown to worsen cardiovascular diseases. However, it is unclear whether there is a gender difference in the impact of anemia on subclinical myocardial damage and cardiovascular mortality in the general population. METHODS: A prospective cohort study was conducted in a community based on annual health checks. Serum heart-type fatty acid binding protein (H FABP) levels, which is a marker for myocardial damage, and blood counts were measured at baseline in subjects without previous cardiovascular diseases (n=3111). RESULTS: There were 343 subjects (11.0%) with anemia at baseline. H FABP levels were inversely correlated with hemoglobin concentrations in male subjects, whereas there was no such correlation in female subjects, irrespective of the status of menopause. Prevalence of myocardial damage (H-FABP >=4.3ng/ml) was significantly higher in male subjects with anemia than those without, irrespective of the type of anemia (microcytic, normocytic, and macrocytic). Multivariate logistic regression analysis revealed that anemia was an independent predictor of myocardial damage after adjusting for confounders. During 10years of follow-up, there were 204 all-cause deaths including 57 cardiovascular deaths. Kaplan-Meier analysis demonstrated that cardiovascular mortality was higher in male subjects with anemia than in those without. However, anemia was not associated with cardiovascular mortality in female subjects. Multivariate Cox proportional hazard analysis revealed that anemia was an independent predictor of all-cause and cardiovascular mortalities after adjusting for confounders. CONCLUSION: Anemia was an independent predictor of all-cause and cardiovascular mortalities, and subclinical myocardial damage in male subjects, but not in female subjects. PMID- 29133275 TI - Normal values for myocardial deformation within the right heart measured by feature-tracking cardiovascular magnetic resonance imaging. AB - BACKGROUND: Reproducible and repeatable assessment of right heart function is vital for monitoring congenital and acquired heart disease. There is increasing evidence for the additional value of myocardial deformation (strain and strain rate) in determining prognosis. This study aims to determine the reproducibility of deformation analyses in the right heart using cardiovascular magnetic resonance feature tracking (FT-CMR); and to establish normal ranges within an adult population. METHODS: A cohort of 100 healthy subjects containing 10 males and 10 females from each decade of life between the ages of 20 and 70 without known congenital or acquired cardiovascular disease, hypertension, diabetes, dyslipidaemia or renal, hepatic, haematologic and systemic inflammatory disorders underwent FT-CMR assessment of right ventricular (RV) and right atrial (RA) myocardial strain and strain rate. RESULTS: RV longitudinal strain (Ell) was 21.9+/-3.24% (FW+S Ell) and -24.2+/-3.59% (FW-Ell). Peak systolic strain rate (S') was -1.45+/-0.39s-1 (FW+S) and -1.54+/-0.41s-1 (FW). Early diastolic strain rate (E') was 1.04+/-0.26s-1 (FW+S) and 1.04+/-0.33s-1 (FW). Late diastolic strain rate (A') was 0.94+/-0.33s-1 (FW+S) and 1.08+/-0.33s-1 (FW). RA peak strain was -21.1+/-3.76%. The intra- and inter-observer ICC for RV Ell (FW+S) was 0.92 and 0.80 respectively, while for RA peak strain was 0.92 and 0.89 respectively. CONCLUSIONS: Normal values of RV & RA deformation for healthy individuals using FT-CMR are provided with good RV Ell and RA peak strain reproducibility. Strain rate suffered from sub-optimal reproducibility and may not be satisfactory for clinical use. PMID- 29133276 TI - De novo assembly and annotation of the whole genomic analysis of Vibrio campbellii RT-1 strain, from infected shrimp: Litopenaeus vannamei. AB - OBJECTIVES: This study aimed to sequence the whole genome of Vibrio campbellii RT 1 strain. METHODS: V. campbellii strain was isolated from an infected shrimp, Litopenaeus vannamei collected from aquaculture ponds, India (12.1899 degrees N, 79.9249 degrees E). The whole genome sequencing (WGS) was performed using the Illumina Hiseq 2500 platform and assembled de novo using SPAdes and Velvet optimiser. Furthermore, the gene prediction and annotation were performed by a rapid prokaryotic genome tool-Prokka. RESULTS: The genome of V. campbellii RT-1 strain has one circular chromosome with 6327218 bp long. V. campbellii RT-1 strain contains 5787 predicted genes with an average of 45% GC content. A total of 86 known genes associated with pathogenicity were identified and 28 genes were found to be responsible for virulence factors. Furthermore, 1112 unigenes were subjected to Gene Ontology (GO) terms, and 4895 predicted proteins were annotated with Clusters of orthologous (COGs) functional groups. CONCLUSIONS: The phylogenetic position of V. campbellii RT-1 strain was established through whole genome sequencing and genomic tools which provides a strong platform to further study on genomic alterations and phenotype of V. campbellii. PMID- 29133277 TI - OrthoGNC: A Software for Accurate Identification of Orthologs Based on Gene Neighborhood Conservation. AB - Orthology relations can be used to transfer annotations from one gene (or protein) to another. Hence, detecting orthology relations has become an important task in the post-genomic era. Various genomic events, such as duplication and horizontal gene transfer, can cause erroneous assignment of orthology relations. In closely-related species, gene neighborhood information can be used to resolve many ambiguities in orthology inference. Here we present OrthoGNC, a software for accurately predicting pairwise orthology relations based on gene neighborhood conservation. Analyses on simulated and real data reveal the high accuracy of OrthoGNC. In addition to orthology detection, OrthoGNC can be employed to investigate the conservation of genomic context among potential orthologs detected by other methods. OrthoGNC is freely available online at http://bs.ipm.ir/softwares/orthognc and http://tinyurl.com/orthoGNC. PMID- 29133278 TI - Imaging for the Detection of Locoregional Recurrences in Biochemical Progression After Radical Prostatectomy-A Systematic Review. AB - CONTEXT: Local and regional recurrence after radical prostatectomy (RP) can be treated using salvage radiotherapy (SRT). If the recurrence can be delineated on diagnostic imaging, this could allow for increasingly individualized SRT. OBJECTIVE: This systematic review aimed at evaluating the evidence regarding the usefulness of positron emission tomography (PET) and magnetic resonance imaging (MRI) in identifying local and regional recurrences, with the aim to further individualize the SRT treatment. EVIDENCE ACQUISITION: A systematic PubMed/Medline search was conducted in December 2015. Studies included were imaging studies of post-RP patients focusing on local and/or regional recurrence where sensitivity and specificity of MRI or PET were the primary end points. Only studies using biopsy, other histological analysis, and/or treatment follow-up as reference standard were included. Quality Assessment of Diagnostic Accuracy Studies-2 was used to score the study quality. Twenty-five articles were deemed of sufficient quality and included in the review. EVIDENCE SYNTHESIS: [11C]Acetate had the highest pooled sensitivity (92%), while [11C]choline and [18F]choline had pooled sensitivities of 71% and 84%, respectively. The PET tracer with highest pooled specificity was [11C]choline (86%). Regarding MRI, MR spectroscopy combined with dynamic contrast enhanced (DCE) MRI showed the highest pooled sensitivity (89%). High pooled sensitivities were also seen using multiparametric MRI (84%), diffusion-weighted MRI combined with T2-weigthed (T2w) imaging (82%), and DCE MRI combined with T2w imaging (82%). These also showed high pooled specificities (85%, 89%, and 92%, respectively). CONCLUSIONS: Both MRI and PET have adequate sensitivity and specificity for the detection of prostate cancer recurrences post-RP. Multiparametric MRI, using diffusion weighted and/or DCE imaging, and the choline-labeled tracers showed high pooled sensitivity and specificity, although their ranges were broad. PATIENT SUMMARY: After reviewing imaging studies of recurrent prostate cancer after prostatectomy, we concluded that choline positron emission tomography and diffusion-weighted magnetic resonance imaging can be proposed as the current standard, with high sensitivity and specificity. PMID- 29133279 TI - Effect of 17beta-estradiol on estrogen receptor negative breast cancer cells in an osteolytic mouse model. AB - 17beta-Estradiol (E2) promotes metastasis of triple negative breast cancer cells to bone. Recent studies show many triple negative breast cancer cell lines lacking the 66 kDa estrogen receptor (ER) alpha (ERalpha66) or its splice variant ERalpha46, express another splice variant, ERalpha36 associated with membrane mediated rapid actions of the hormone. qPCR and western blot confirmed that MCF7 cells possessed ERalpha splice variants ERalpha66, ERalpha46 and ERalpha36, while ER-negative breast cancer cells MDA-MB-231 possessed only ERalpha36. MDA-MB-231 breast cancer cells were implanted into medullary canals of ovariectomized female athymic nude mice femurs (N = 8 mice/treatment). To examine the effect of E2 on osteolysis, mice were treated with 0.72 mg E2 or placebo via 60 day release osmotic pumps implanted subcutaneously. Legs were examined by Faxitron through the course of the study, and by microCT and histology after 8 weeks. Greater occurrence of osteolysis and pathologic fracture was observed in E2-treated animals compared to placebo, and microCT demonstrated less bone volume remaining in MDA-MB-231 treated legs compared to contralateral control legs, as well as E2 treated animals compared to placebo. E2-treated animals had significantly greater tumor volume compared to placebo. Large nests of anaplastic tumor cells with eroded cortical margin were observed in E2-treated animals compared to placebo. MDA MB 231 breast cancer cells positive for ERalpha36 but negative for ERalpha46/66 had enhanced osteolysis, pathologic fractures, and tumor volume in an in vivo osteolytic mouse model when treated with 17beta-estradiol compared to placebo, demonstrating a role for ERalpha36 in bone tumor progression. PMID- 29133280 TI - MAT2A promotes porcine adipogenesis by mediating H3K27me3 at Wnt10b locus and repressing Wnt/beta-catenin signaling. AB - Methionine adenosyltransferase (MAT) is a critical biological enzyme and that can catalyze L-met and ATP to form S-adenosylmethionine (SAM), which is acted as a biological methyl donor in transmethylation reactions involving histone methylation. However, the regulatory effect of methionine adenosyltransferase2A (MAT2A) and its associated methyltransferase activity on adipogenesis is still unclear. In this study, we investigate the effect of MAT2A on adipogenesis and its potential mechanism on histone methylation during porcine preadipocyte differentiation. We demonstrated that overexpression of MAT2A promoted lipid accumulation and significantly up-regulated the levels of adipogenic marker genes including PPARgamma, SREBP-1c, and aP2. Whereas, knockdown of MAT2A or inhibition MATII enzyme activity inhibited lipid accumulation and down-regulated the expression of the above-mentioned genes. Mechanistic studies revealed that MAT2A interacted with histone-lysine N-methyltransferase Ezh2 and was recruited to Wnt10b promoter to repress its expression by promoting H3K27 methylation. Additionally, MAT2A interacted with MafK protein and was recruited to MARE element at Wnt10b gene. The catalytic activity of MAT2A as well as its interacting factor-MAT2B, was required for Wnt10b repression and supplying SAM for methyltransferases. Moreover, MAT2A suppressed Wnt10b expression and further inhibited Wnt/beta-catenin signaling to promote adipogenesis. PMID- 29133281 TI - Should Medical Assistance in Dying Be Extended to Incompetent Patients With Dementia? Research Protocol of a Survey Among Four Groups of Stakeholders From Quebec, Canada. AB - BACKGROUND: Alzheimer's disease and related disorders affect a growing number of people worldwide. Quality of life is generally good in the early stages of these diseases. However, many individuals fear living through the advanced stages. Such fears are triggering requests for medical assistance in dying (MAiD) by patients with dementia. Legislation was recently passed in Canada and the province of Quebec allowing MAiD at the explicit request of a patient who meets a set of eligibility criteria, including competence. Some commentators have argued that MAiD should be accessible to incompetent patients as well, provided appropriate safeguards are in place. Governments of both Quebec and Canada are currently considering whether MAiD should be accessible through written requests made in advance of loss of capacity. OBJECTIVE: Aimed at informing the societal debate on this sensitive issue, this study will compare stakeholders' attitudes towards expanding MAiD to incompetent patients with dementia, the beliefs underlying stakeholders' attitudes on this issue, and the value they attach to proposed safeguards. This paper describes the study protocol. METHODS: Data will be collected via a questionnaire mailed to random samples of community-dwelling seniors, relatives of persons with dementia, physicians, and nurses, all residing in Quebec (targeted sample size of 385 per group). Participants will be recruited through the provincial health insurance database, Alzheimer Societies, and professional associations. Attitudes towards MAiD for incompetent patients with dementia will be elicited through clinical vignettes featuring a patient with Alzheimer's disease for whom MAiD is considered towards the end of the disease trajectory. Vignettes specify the source of the request (from the patient through an advance request or from the patient's substitute decision-maker), manifestations of suffering, and how close the patient is to death. Arguments for or against MAiD are used to elicit the beliefs underlying respondents' attitudes. RESULTS: The survey was launched in September 2016 and is still ongoing. At the time of submission, over 850 respondents have returned the questionnaire, mostly via mail. CONCLUSIONS: This study will be the first in Canada to directly compare views on MAiD for incompetent patients with dementia across key stakeholder groups. Our findings will contribute valuable data upon which to base further debate about whether MAiD should be accessible to incompetent patients with dementia, and if so, under what conditions. PMID- 29133282 TI - Effectiveness of a Web 2.0 Intervention to Increase Physical Activity in Real World Settings: Randomized Ecological Trial. AB - BACKGROUND: The translation of Web-based physical activity intervention research into the real world is lacking and becoming increasingly important. OBJECTIVE: To compare usage and effectiveness, in real-world settings, of a traditional Web 1.0 Web-based physical activity intervention, providing limited interactivity, to a Web 2.0 Web-based physical activity intervention that includes interactive features, such as social networking (ie, status updates, online "friends," and personalized profile pages), blogs, and Google Maps mash-ups. METHODS: Adults spontaneously signing up for the freely available 10,000 Steps website were randomized to the 10,000 Steps website (Web 1.0) or the newly developed WALK 2.0 website (Web 2.0). Physical activity (Active Australia Survey), quality of life (RAND 36), and body mass index (BMI) were assessed at baseline, 3 months, and 12 months. Website usage was measured continuously. Analyses of covariance were used to assess change over time in continuous outcome measures. Multiple imputation was used to deal with missing data. RESULTS: A total of 1328 participants completed baseline assessments. Only 3-month outcomes (224 completers) were analyzed due to high attrition at 12 months (77 completers). Web 2.0 group participants increased physical activity by 92.8 minutes per week more than those in the Web 1.0 group (95% CI 28.8-156.8; P=.005); their BMI values also decreased more (-1.03 kg/m2, 95% CI -1.65 to -0.41; P=.001). For quality of life, only the physical functioning domain score significantly improved more in the Web 2.0 group (3.6, 95% CI 1.7-5.5; P<.001). The time between the first and last visit to the website (3.57 vs 2.22 weeks; P<.001) and the mean number of days the website was visited (9.02 vs 5.71 days; P=.002) were significantly greater in the Web 2.0 group compared to the Web 1.0 group. The difference in time-to-nonusage attrition was not statistically significant between groups (Hazard Ratio=0.97, 95% CI 0.86 1.09; P=.59). Only 21.99% (292/1328) of participants (n=292 summed for both groups) were still using either website after 2 weeks and 6.55% (87/1328) were using either website after 10 weeks. CONCLUSIONS: The website that provided more interactive and social features was more effective in improving physical activity in real-world conditions. While the Web 2.0 website was visited significantly more, both groups nevertheless displayed high nonusage attrition and low intervention engagement. More research is needed to examine the external validity and generalizability of Web-based physical activity interventions. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12611000253909; https://anzctr.org.au /Trial/Registration/TrialReview.aspx?id=336588&isReview=true (Archived by WebCite at http://www.webcitation.org/6ufzw 2HxD). PMID- 29133283 TI - Open-Source Electronic Health Record Systems for Low-Resource Settings: Systematic Review. AB - BACKGROUND: Despite the great impact of information and communication technologies on clinical practice and on the quality of health services, this trend has been almost exclusive to developed countries, whereas countries with poor resources suffer from many economic and social issues that have hindered the real benefits of electronic health (eHealth) tools. As a component of eHealth systems, electronic health records (EHRs) play a fundamental role in patient management and effective medical care services. Thus, the adoption of EHRs in regions with a lack of infrastructure, untrained staff, and ill-equipped health care providers is an important task. However, the main barrier to adopting EHR software in low- and middle-income countries is the cost of its purchase and maintenance, which highlights the open-source approach as a good solution for these underserved areas. OBJECTIVE: The aim of this study was to conduct a systematic review of open-source EHR systems based on the requirements and limitations of low-resource settings. METHODS: First, we reviewed existing literature on the comparison of available open-source solutions. In close collaboration with the University of Gondar Hospital, Ethiopia, we identified common limitations in poor resource environments and also the main requirements that EHRs should support. Then, we extensively evaluated the current open-source EHR solutions, discussing their strengths and weaknesses, and their appropriateness to fulfill a predefined set of features relevant for low-resource settings. RESULTS: The evaluation methodology allowed assessment of several key aspects of available solutions that are as follows: (1) integrated applications, (2) configurable reports, (3) custom reports, (4) custom forms, (5) interoperability, (6) coding systems, (7) authentication methods, (8) patient portal, (9) access control model, (10) cryptographic features, (11) flexible data model, (12) offline support, (13) native client, (14) Web client,(15) other clients, (16) code-based language, (17) development activity, (18) modularity, (19) user interface, (20) community support, and (21) customization. The quality of each feature is discussed for each of the evaluated solutions and a final comparison is presented. CONCLUSIONS: There is a clear demand for open-source, reliable, and flexible EHR systems in low-resource settings. In this study, we have evaluated and compared five open-source EHR systems following a multidimensional methodology that can provide informed recommendations to other implementers, developers, and health care professionals. We hope that the results of this comparison can guide decision making when needing to adopt, install, and maintain an open-source EHR solution in low-resource settings. PMID- 29133285 TI - Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. PMID- 29133284 TI - The Association of Health Literacy and Electronic Health Literacy With Self Efficacy, Coping, and Caregiving Perceptions Among Carers of People With Dementia: Research Protocol for a Descriptive Correlational Study. AB - BACKGROUND: In the last decade, electronic health (eHealth) literacy has attracted the attention of the scientific community, as it is associated with the self-management of patients with chronic diseases and the quality and cost of care. It is estimated that 80% of people with chronic diseases are cared for at home by a family member, friend, or relative. Informal carers are susceptible to physical and mental health problems, as well as social and financial hardships. Nevertheless, there seems to be a research gap in terms of carers' needs, skills, and available resources in the age of new technologies, with the vital role of eHealth literacy of the carers remaining unexplored. OBJECTIVE: The aim of this study was to investigate the level of eHealth literacy and health literacy of primary and secondary carers of people with dementia, to explore the association between health and eHealth literacy, as well as their association with the caregiving variables: self-efficacy, coping, and caring perceptions. METHODS: A sample of 200 primary carers (the carer who supports the people with dementia in everyday living) and 200 secondary carers (family member, friend, or other person in the social network assisting the primary carer in their role) will be recruited from dementia day care centers and Alzheimer's associations in Greece and Cyprus. The study will be a cross-sectional correlational descriptive study. Tools to be used include the eHealth Literacy Scale adapted for carers to measure eHealth literacy, European Health Literacy Survey Questionnaire 16 (HLS-EU-Q16), Single Item Literacy Screener, Revised Scale for Caregiving Self-Efficacy, Carers of Older People in Europe (COPE) index for caregiving perceptions, and COPE brief to measure selected coping strategies. Descriptive statistics will be reported, and correlations between different variables will be explored with parametric and nonparametric measures. RESULTS: As a preliminary study, the HLS-EU-Q16 has been validated in 107 older people. The internal consistency of the scale as estimated using Cronbach alpha coefficient was .77, somewhat lower than other validation studies. Recruitment of pilot study participants started in May 2017. CONCLUSIONS: Carers' eHealth literacy is a new field. Whereas previous studies have focused on the role and impact of low eHealth literacy and health literacy among older adults, the eHealth literacy of carers, and in fact carers of people with dementia, has not been explored. We hypothesize an association between eHealth literacy and health literacy level with carers' perceptions about caregiving role, self-efficacy, and coping strategies. A possible moderator in these associations is the secondary carers' eHealth and health literacy level, which will also be explored. By confirming the above hypotheses, tailored eHealth literacy interventions for carers of people with dementia and their families will be developed as a direct outcome of this research. PMID- 29133286 TI - Eosinophilic esophagitis: update on management and controversies. AB - Eosinophilic esophagitis is a chronic allergen driven immune mediated disease that is increasingly recognized as a leading cause of dysphagia and foregut symptoms in children and adults. Much knowledge has been gained in recent years on the genetic and environmental risk factors for this disease, the associated inflammatory milieu, and the long term complications from esophageal remodeling. In this review we will highlight recent progress made in research into this disease, focusing on adults. We will discuss ongoing efforts to develop a minimally invasive technique that may obviate the need for repeated endoscopic assessment of disease activity. Moreover, we will review studies using novel tools such as mucosal impedance and functional lumen imaging as potential surrogate markers for mucosal integrity and esophageal remodeling. With regard to the treatment of eosinophilic inflammation, we will discuss the controversies surrounding responsiveness to proton pump inhibitors in some patients. Therapeutic trials continue to support the use of topical glucocorticoids and empiric food elimination diets as first line treatments. We will discuss ongoing efforts to optimize the elimination diet protocol to decrease the level and duration of food restrictions. Looking ahead, our growing knowledge on the pathogenesis of eosinophilic esophagitis has enabled further advancement of promising targeted biologic therapies. PMID- 29133287 TI - Basket Study Yields Approval for Rare Cancer. AB - The FDA, in a regulatory first, approved a targeted therapy based on a basket study. The move, which expanded the indications for the BRAF inhibitor vemurafenib to include Erdheim-Chester disease, points to a new approval pathway for drugs that treat rare cancers. PMID- 29133288 TI - Father is banned from visiting brain damaged son as High Court battle continues. PMID- 29133289 TI - Winter crisis? What crisis? PMID- 29133290 TI - CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8+ T Cell-Relevant Genes. AB - CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors. CD96, HHLA2, CCR5, CXCR5, and CCL5 were among the immune-related genes regulated by differential DNA methylation, leading to changes in mRNA and protein expression. These genes are also differentially methylated in naive versus antigen-experienced CD8+ T cells. The transcription factor TCF1 and the microRNA miR-21 were regulated by DNA methylation upon CD137 costimulation. Such gene-expression regulatory factors can, in turn, broaden the effects of DNA methylation by controlling expression of their target genes. Overall, chromatin remodeling is postulated to leave CD137-costimulated T lymphocytes poised to differentially respond upon subsequent antigen recognition. Accordingly, CD137 connects costimulation during priming to genome-wide DNA methylation and chromatin reprogramming. Cancer Immunol Res; 6(1); 69-78. (c)2017 AACR. PMID- 29133291 TI - Watcher Initiative Associated With Decrease in Failure to Rescue Events in Pediatric Population. AB - BACKGROUND AND OBJECTIVES: Improved situation awareness may prevent unplanned ICU transfers. Transfers with serious safety issues may be classified as unrecognized situation awareness failure events (UNSAFE) and are associated with intubation, vasopressors, or >3 fluid boluses within 1 hour before or after ICU arrival. Our aim was to decrease the proportion of unplanned ICU transfers that met UNSAFE criteria by 50% in 1 year. METHODS: We adapted a previously described huddle based intervention. In May 2015, we started a daily safety brief with hospital wide representation; concurrently, nurses and residents separately identified watcher patients (ie, patients at risk for UNSAFE transfers) to be reported in the daily safety brief. Watcher patients frequently differed between the groups, so in July 2015, we started twice-daily watcher huddles on a pilot floor. During these huddles, nurses and residents jointly identified watcher patients on the basis of defined criteria and deployed mitigation plans. By March 2016, we implemented these huddles hospital-wide. We reviewed the electronic medical record to categorize all unplanned ICU transfers as safe or UNSAFE. Our outcome was the proportion of unplanned ICU transfers that met UNSAFE criteria. RESULTS: In the 16-month pre-intervention period, 49 of the 322 unplanned ICU transfers were UNSAFE (median 15.5%); in the 12-month post-intervention period, 13 of the 329 unplanned ICU transfers were UNSAFE (median 3%). These findings represent an 81% reduction in the proportion of UNSAFE transfers. CONCLUSIONS: Watcher huddles incorporated into the daily inpatient routine can significantly decrease UNSAFE transfers. PMID- 29133292 TI - Intracellular hepatitis B virus increases hepatic cholesterol deposition in alcoholic fatty liver via hepatitis B core protein. AB - Hepatitis B virus (HBV) infection is a prevalent infectious disease with serious outcomes like chronic and acute hepatitis, cirrhosis, and hepatocellular carcinoma. However, the metabolic alteration by HBV is rarely taken into consideration. With the high prevalence of alcohol consumption and chronic HBV infection, their overlap is assumed to be an increasing latent hazard; although the extent has not been calculated. Moreover, the impact of chronic alcohol consumption combined with HBV on cholesterol metabolism is unknown. Six-week-old male FVB/Ncrl mice were hydrodynamically injected with a pGEM-4Z-1.3HBV vector and then fed an ethanol diet for 6 weeks. Serum biomarkers and liver histology, liver cholesterol levels, and cholesterol metabolism-related molecules were measured. In vitro assays with HBx, hepatitis B surface (HBs), or hepatitis B core (HBc) protein expression in HepG2 cells costimulated with ethanol were conducted to assess the cholesterol metabolism. HBV expression synergistically increased cholesterol deposition in the setting of alcoholic fatty liver. The increase of intrahepatic cholesterol was due to metabolic alteration in cholesterol metabolism, including increased cholesterol synthesis, decreased cholesterol degradation, and impaired cholesterol uptake. Overexpression of HBV component HBc, but not HBs or HBx, selectively promoted the hepatocellular cholesterol level. PMID- 29133293 TI - IL-33-Responsive Group 2 Innate Lymphoid Cells Are Regulated by Female Sex Hormones in the Uterus. AB - Group 2 innate lymphoid cells (ILC2s) reside in multiple organs in the body, where they play roles in immunity, tissue homeostasis, and metabolic regulation. However, little is known about the regulatory mechanisms of ILC2s in different organs. Here, we identified ILC2s in the mouse uterus and found that they express cell surface molecules, including the IL-33 receptor, ST2, that are roughly comparable to those expressed by lung ILC2s. Both in vivo and in vitro treatment with IL-33 induced type 2 cytokine production in uterine ILC2s, suggesting that they respond to IL-33 in a manner similar to ILC2s in other organs. Importantly, uterine ILC2s were nearly absent in ovariectomized mice and were increased in wild-type mice by estrogen administration, whereas lung ILC2s were unaffected by both ovariectomy and estrogen administration. Likewise, a marked reduction in uterine ILC2s was observed in mice deficient in estrogen receptor alpha or estrogen receptor beta. Furthermore, uterine ILC2s highly expressed estrogen receptor alpha, and in vitro culture of isolated uterine ILC2s with 17beta estradiol modified expression of a number of genes. Finally, an increased prevalence in neonatal mortality was observed in litters from dams lacking the IL 33 receptor, ST2. Taken together, our findings indicate that unlike lung IL2Cs, uterine ILC2s are regulated by female sex hormones, which may specialize them for specific physiological functions. PMID- 29133294 TI - Proinflammatory T Cell Status Associated with Early Life Adversity. AB - Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA (n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69+CD8+ T cells (p = 0.022), increased numbers of HLA-DR+ CD4 and HLA-DR+ CD8 T cells (p < 0.001), as well as increased numbers of CD25+CD8+ T cells (p = 0.036). ELA also showed a trend toward higher numbers of CCR4+CXCR3-CCR6+ CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health risk behaviors, but rather a primary effect of early life programming on immune cells. PMID- 29133295 TI - Head injury mechanisms in FIS World Cup alpine and freestyle skiers and snowboarders. AB - INTRODUCTION: Head injuries represent a concern in skiing and snowboarding, with traumatic brain injuries being the most common cause of death. AIM: To describe the mechanisms of head and face injuries among World Cup alpine and freestyle skiers and snowboarders. METHODS: We performed a qualitative analysis of videos obtained of head and face injuries reported through the International Ski Federation Injury Surveillance System during 10 World Cup seasons (2006-2016). We analysed 57 head impact injury videos (alpine n=29, snowboard n=13, freestyle n=15), first independently and subsequently in a consensus meeting. RESULTS: During the crash sequence, most athletes (84%) impacted the snow with the skis or board first, followed by the upper or lower extremities, buttocks/pelvis, back and, finally, the head. Alpine skiers had sideways (45%) and backwards pitching falls (35%), with impacts to the rear (38%) and side (35%) of the helmet. Freestyle skiers and snowboarders had backwards pitching falls (snowboard 77%, freestyle 53%), mainly with impacts to the rear of the helmet (snowboard 69%, freestyle 40%). There were three helmet ejections among alpine skiers (10% of cases), and 41% of alpine skiing injuries occurred due to inappropriate gate contact prior to falling. Athletes had one (47%) or two (28%) head impacts, and the first impact was the most severe (71%). Head impacts were mainly on snow (83%) on a downward slope (63%). CONCLUSION: This study has identified several characteristics of the mechanisms of head injuries, which may be addressed to reduce risk. PMID- 29133296 TI - Comparison of preservation and transportation protocols for preloaded Descemet membrane endothelial keratoplasty. AB - BACKGROUND/AIMS: Descemet membrane endothelial keratoplasty (DMEK) preparation is technically demanding and is a limiting factor for uptake of this kind of surgery. Supply methods that simplify the procedure for surgeons are key to increasing uptake. This study compares two different shipping protocols for DMEK. METHODS: An 8.5 mm DMEK graft was punched, marked and loaded for transportation in two different conditions: (A) endothelium trifolded inwards in organ culture conditions (n=7) and (B) endothelium rolled outwards in hypothermic conditions (n=7). Tissues were shipped from Italy to the UK, then analysed for orientation, endothelial cell density, denuded areas, cell mortality, triple viability staining (Hoechst/ethidium homodimer/calcein AM (HEC)), immunolocalisation of ZO 1 and Na/K-ATPase proteins, visualisation of actin filaments using phalloidin and histological analysis using H&E on paraffin-embedded sections. RESULTS: All tissues clearly showed the mark used for graft orientation. After shipping in condition A, there was an increase in cell mortality of 8.1% and in denuded areas of 22.4%, whereas for condition B there was an increase in cell mortality of 14.2% and in denuded areas of 34.3% after shipping. HEC staining revealed areas of viable cells and apoptotic cells, with large denuded areas found in the periphery for condition B and within folds for condition A. CONCLUSIONS: Prestripped preloaded DMEK grafts retained sufficient viable cells for transplantation, with condition A (endothelium-in) offering the advantage of greater flexibility of use due to a longer shelf-life. HEC analysis provides further detailed information as to the status of DMEK grafts and should be used in future similar studies. PMID- 29133297 TI - Evaluating the triplet hypothesis during rhythmic mastication in primates. AB - Mammalian mastication involves precise jaw movements including transverse movement of the mandible during the power stroke. Jaw elevation and transverse movement are driven by asymmetrical jaw elevator muscle activity, which is thought to include a phylogenetically primitive and conserved triplet motor pattern consisting of: triplet I (balancing side: superficial masseter and medial pterygoid; working side: posterior temporalis), which reaches onset, peak and offset first; and triplet II (working side: superficial masseter and medial pterygoid; balancing side: posterior temporalis), which is active second. Although the presence of a triplet motor pattern has been confirmed in several primate species, the prevalence of this motor pattern - i.e. the proportion of masticatory cycles that display it - has not been evaluated in primates. The present study quantifies the presence and prevalence of the triplet motor pattern in five different primate species, Eulemur fulvus, Propithecus verreauxi, Papio anubis, Macacafuscata and Pan troglodytes, using mean onset, peak and offset time relative to working superficial masseter. In all five of the species studied, the mean triplet motor pattern was observed at peak muscle activation, and in four out of the five species the triplet motor pattern occurred more frequently than expected at random at peak muscle activation and offset. Non-triplet motor patterns were observed in varying proportions at different time points in the masticatory cycle, suggesting that the presence or absence of the triplet motor pattern is not a binomial trait. Instead, the primate masticatory motor pattern is malleable within individual cycles, within individual animals and therefore within species. PMID- 29133299 TI - Fatigue and risk: are train drivers safer than doctors? PMID- 29133300 TI - The Importance of Satellite Sequence Repression for Genome Stability. AB - Up to two-thirds of eukaryotic genomes consist of repetitive sequences, which include both transposable elements and tandemly arranged simple or satellite repeats. Whereas extensive progress has been made toward understanding the danger of and control over transposon expression, only recently has it been recognized that DNA damage can arise from satellite sequence transcription. Although the structural role of satellite repeats in kinetochore function and end protection has long been appreciated, it has now become clear that it is not only these functions that are compromised by elevated levels of transcription. RNA from simple repeat sequences can compromise replication fork stability and genome integrity, thus compromising germline viability. Here we summarize recent discoveries on how cells control the transcription of repeat sequence and the dangers that arise from their expression. We propose that the link between the DNA damage response and the transcriptional silencing machinery may help a cell or organism recognize foreign DNA insertions into an evolving genome. PMID- 29133301 TI - Taming the Beast: Control of APC/CCdc20-Dependent Destruction. AB - The anaphase-promoting complex/cyclosome (APC/C) is a large multisubunit ubiquitin ligase that triggers the metaphase-to-anaphase transition in the cell cycle by targeting the substrates cyclin B and securin for destruction. APC/C activity toward these two key substrates requires the coactivator Cdc20. To ensure that cells enter mitosis and partition their duplicated genome with high accuracy, APC/CCdc20 activity must be tightly controlled. Here, we discuss the mechanisms that regulate APC/CCdc20 activity both before and during mitosis. We focus our discussion primarily on the chromosomal pathways that both accelerate and delay APC/C activation by targeting Cdc20 to opposing fates. The findings discussed provide an overview of how cells control the activation of this major cell cycle regulator to ensure both accurate and timely cell division. PMID- 29133298 TI - Functional Redundancy of Variant and Canonical Histone H3 Lysine 9 Modification in Drosophila. AB - Histone post-translational modifications (PTMs) and differential incorporation of variant and canonical histones into chromatin are central modes of epigenetic regulation. Despite similar protein sequences, histone variants are enriched for different suites of PTMs compared to their canonical counterparts. For example, variant histone H3.3 occurs primarily in transcribed regions and is enriched for "active" histone PTMs like Lys9 acetylation (H3.3K9ac), whereas the canonical histone H3 is enriched for Lys9 methylation (H3K9me), which is found in transcriptionally silent heterochromatin. To determine the functions of K9 modification on variant vs. canonical H3, we compared the phenotypes caused by engineering H3.3K9R and H3K9R mutant genotypes in Drosophila melanogaster Whereas most H3.3K9R , and a small number of H3K9R , mutant animals are capable of completing development and do not have substantially altered protein-coding transcriptomes, all H3.3K9R H3K9R combined mutants die soon after embryogenesis and display decreased expression of genes enriched for K9ac. These data suggest that the role of K9ac in gene activation during development can be provided by either H3 or H3.3. Conversely, we found that H3.3K9 is methylated at telomeric transposons and that this mark contributes to repressive chromatin architecture, supporting a role for H3.3 in heterochromatin that is distinct from that of H3. Thus, our genetic and molecular analyses demonstrate that K9 modification of variant and canonical H3 have overlapping roles in development and transcriptional regulation, though to differing extents in euchromatin and heterochromatin. PMID- 29133302 TI - Don't put off until tomorrow what you can do today: Early cholecystectomy is cost effective in symptomatic cholelithiasis requiring hospitalization. PMID- 29133303 TI - Supplementary antimicrobials for patients with HIV and <100 CD4 cells/uL are associated with improved survival. PMID- 29133304 TI - Stem cells, in vitro gametogenesis and male fertility. AB - Reconstitution in culture of biological processes, such as differentiation and organization, is a key challenge in regenerative medicine, and one in which stem cell technology plays a central role. Pluripotent stem cells and spermatogonial stem cells are useful materials for reconstitution of germ cell development in vitro, as they are capable of differentiating into gametes. Reconstitution of germ cell development, termed in vitro gametogenesis, will provide an experimental platform for a better understanding of germ cell development, as well as an alternative source of gametes for reproduction, with the potential to cure infertility. Since germ cells are the cells for 'the next generation', both the culture system and its products must be carefully evaluated. In this issue, we summarize the progress in in vitro gametogenesis, most of which has been made using mouse models, as well as the future challenges in this field. PMID- 29133305 TI - Organ transplantation rates in the UK. PMID- 29133306 TI - Quaking Inhibits Doxorubicin-Mediated Cardiotoxicity Through Regulation of Cardiac Circular RNA Expression. AB - RATIONALE: RBPs (RNA-binding proteins) have been described to be expressed and regulated in various organs including the heart. Little is known about the role of RBPs in heart failure induced by the chemotherapy drug doxorubicin and their interaction with circular RNAs. OBJECTIVE: We aimed to identify key RBPs involved in doxorubicin-mediated heart failure and to elucidate their function. METHODS AND RESULTS: Global transcriptome profiling from murine myocardium exposed to doxorubicin identified 5 differentially expressed RBPs. Expression of the RBP QKI (Quaking) in response to doxorubicin was strongly downregulated in rodent cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes in vitro and in vivo in mice. Knockdown of Qki in primary cardiomyocytes increased apoptosis and atrophy after treatment with doxorubicin, whereas lentiviral mediated overexpression of Qki5 inhibited the doxorubicin-induced apoptosis in cardiomyocytes. In vivo, AAV9 (adeno-associated virus serotype 9)-mediated cardiac overexpression of Qki5 prevented cardiac apoptosis and cardiac atrophy induced by doxorubicin and improved cardiac function. Mechanistically, by lentiviral-based overexpression and CRISPR/Cas9-mediated silencing of Qki5, we identified regulated expression of specific circular RNAs derived from Ttn (Titin), Fhod3 (Formin homology 2 domain containing 3), and Strn3 (Striatin, calmodulin-binding protein 3). Moreover, inhibition of Ttn-derived circular RNA increased the susceptibility of cardiomyocytes to doxorubicin. CONCLUSIONS: We here show that overexpression of Qki5 strongly attenuates the toxic effect of doxorubicin via regulating a set of circular RNAs. Qki5 is, thus, an interesting target molecule to combat doxorubicin-induced cardiotoxicity. PMID- 29133308 TI - GPs call for end to "local rationing" of prescribing. PMID- 29133309 TI - Correction: Dietary intake of fibre and risk of knee osteoarthritis in two US prospective cohorts. PMID- 29133307 TI - The Anti-inflammatory Effect of Personalized Omega-3 Fatty Acid Dosing for Reducing Prostaglandin E2 in the Colonic Mucosa Is Attenuated in Obesity. AB - This clinical trial developed a personalized dosing model for reducing prostaglandin E2 (PGE2) in colonic mucosa using omega-3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, omega 3):arachidonic acid (AA, omega-6) ratios as biomarkers of colonic mucosal PGE2 concentration. Normal human volunteers were given low and high omega-3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE2 reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE2 Mean colonic mucosal PGE2 concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE2 were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12 hydroxyicosatetraenoic acids, and PGE3 increased substantially. Future biomarker driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. Cancer Prev Res; 10(12); 729-37. (c)2017 AACR. PMID- 29133311 TI - Quantifying research output on poverty and non-communicable disease behavioural risk factors in low-income and lower middle-income countries: a bibliometric analysis. AB - OBJECTIVES: Low-income and lower middle-income countries (LLMICs) bear a disproportionate burden of non-communicable diseases (NCDs). WHO has repeatedly called for more research on poverty and NCDs in these settings, but the current situation remains unquantified. We aimed to assess research output on poverty and NCD risk factors from these countries in relation to upper middle-income and high income countries. DESIGN: Bibliometric analysis of primary research published between 1 January 1990 and 4 May 2017. We searched 13 databases, combining terms for poverty and NCD behavioural risk factors (tobacco, alcohol, diet and physical activity). Independent dual review was used to screen titles, abstracts and full papers. Two-tailed t-testing and multiple linear regression analyses were used to compare differences in means. OUTCOMES: (1) Proportion of lead authors affiliated with institutions based in high and upper middle-income countries vs LLMICs. (2) Mean number of citations for publications from each region. (3) Mean journal impact factor for studies from each region. RESULTS: Ninety-one (67%) of the 136 included studies were led by scientists affiliated with LLMIC-based institutions. These authors represented 17/83 LLMICs (20%), and their studies garnered 4.8 fewer citations per paper than studies led by high-income and upper middle-income affiliated authors; however, this finding was non-significant (P=0.67). Papers led by authors based in high-income and upper middle-income countries were published in journals with a mean impact factor 3.1 points higher than those from LLMICs (4.9 vs 1.7) adjusting for year of publication and number of citations (P<0.001). CONCLUSIONS: Most poverty and NCD risk factor research is led by authors from a small number of LLMICs. These studies are being published in relatively low-impact journals, and the vast majority of LLMICs are not producing any research in this area that is vital to their social and economic development. The paucity of domestic evidence must be addressed to inform global policy. PMID- 29133312 TI - Exploring perceptions and experiences of patients who have chronic pain as state prescription opioid policies change: a qualitative study in Indiana. AB - OBJECTIVES: The misuse and abuse of prescription opioids (POs) is an epidemic in the USA today. Many states have implemented legislation to curb the use of POs resulting from inappropriate prescribing. Indiana legislated opioid prescribing rules that went into effect in December 2013. The rules changed how chronic pain is managed by healthcare providers. This qualitative study aims to evaluate the impact of Indiana's opioid prescription legislation on the patient experiences around pain management. SETTING: This is a qualitative study using interviews of patient and primary care providers to obtain triangulated data sources. The patients were recruited from an integrated pain clinic to which chronic pain patients were referred from federally qualified health clinics (FQHCs). The primacy care providers were recruited from the same FQHCs. The study used inductive, emergent thematic analysis. PARTICIPANTS: Nine patient participants and five primary care providers were included in the study. RESULTS: Living with chronic pain is disruptive to patients' lives on multiple dimensions. The established pain management practices were disrupted by the change in prescription rules. Patient-provider relationships, which involve power dynamics and decision making, shifted significantly in parallel to the rule change. CONCLUSIONS: As a result of the changes in pain management practice, some patients experienced significant challenges. Further studies into the magnitude of this change are necessary. In addition, exploring methods for regulating prescribing while assuring adequate access to pain management is crucial. PMID- 29133310 TI - Convergent origination of a Drosophila-like dosage compensation mechanism in a reptile lineage. AB - Sex chromosomes differentiated from different ancestral autosomes in various vertebrate lineages. Here, we trace the functional evolution of the XY Chromosomes of the green anole lizard (Anolis carolinensis), on the basis of extensive high-throughput genome, transcriptome and histone modification sequencing data and revisit dosage compensation evolution in representative mammals and birds with substantial new expression data. Our analyses show that Anolis sex chromosomes represent an ancient XY system that originated at least ~160 million years ago in the ancestor of Iguania lizards, shortly after the separation from the snake lineage. The age of this system approximately coincides with the ages of the avian and two mammalian sex chromosomes systems. To compensate for the almost complete Y Chromosome degeneration, X-linked genes have become twofold up-regulated, restoring ancestral expression levels. The highly efficient dosage compensation mechanism of Anolis represents the only vertebrate case identified so far to fully support Ohno's original dosage compensation hypothesis. Further analyses reveal that X up-regulation occurs only in males and is mediated by a male-specific chromatin machinery that leads to global hyperacetylation of histone H4 at lysine 16 specifically on the X Chromosome. The green anole dosage compensation mechanism is highly reminiscent of that of the fruit fly, Drosophila melanogaster Altogether, our work unveils the convergent emergence of a Drosophila-like dosage compensation mechanism in an ancient reptilian sex chromosome system and highlights that the evolutionary pressures imposed by sex chromosome dosage reductions in different amniotes were resolved in fundamentally different ways. PMID- 29133313 TI - Site-specific cancer mortality inequalities by employment and occupational groups: a cohort study among Belgian adults, 2001-2011. AB - OBJECTIVE: This study probes into site-specific cancer mortality inequalities by employment and occupational group among Belgians, adjusted for other indicators of socioeconomic (SE) position. DESIGN: This cohort study is based on record linkage between the Belgian censuses of 1991 and 2001 and register data on emigration and mortality for 01/10/2001 to 31/12/2011. SETTING: Belgium. PARTICIPANTS: The study population contains all Belgians within the economically active age (25-65 years) at the census of 1991. OUTCOME MEASURES: Both absolute and relative measures were calculated. First, age-standardised mortality rates have been calculated, directly standardised to the Belgian population. Second, mortality rate ratios were calculated using Poisson's regression, adjusted for education, housing conditions, attained age, region and migrant background. RESULTS: This study highlights inequalities in site-specific cancer mortality, both related to being employed or not and to the occupational group of the employed population. Unemployed men and women show consistently higher overall and site-specific cancer mortality compared with the employed group. Also within the employed group, inequalities are observed by occupational group. Generally manual workers and service and sales workers have higher site-specific cancer mortality rates compared with white-collar workers and agricultural and fishery workers. These inequalities are manifest for almost all preventable cancer sites, especially those cancer sites related to alcohol and smoking such as cancers of the lung, oesophagus and head and neck. Overall, occupational inequalities were less pronounced among women compared with men. CONCLUSIONS: Important SE inequalities in site-specific cancer mortality were observed by employment and occupational group. Ensuring financial security for the unemployed is a key issue in this regard. Future studies could also take a look at other working regimes, for instance temporary employment or part-time employment and their relation to health. PMID- 29133315 TI - Testosterone in advance age: a New Zealand longitudinal cohort study: Life and Living in Advanced Age (Te Puawaitanga o Nga Tapuwae Kia Ora Tonu). AB - OBJECTIVES: Serum testosterone (T) levels in men decline with age. Low T levels are associated with sarcopenia and frailty in men aged >80 years. T levels have not previously been directly associated with disability in older men. We explored associations between T levels, frailty and disability in a cohort of octogenarian men. SETTING: Data from all men from Life and Living in Advanced Age Cohort Study in New Zealand, a longitudinal cohort study in community-dwelling older adults. PARTICIPANTS: Community-dwelling (>80 years) adult men excluding those receiving T treatment or with prostatic carcinoma. OUTCOMES MEASURES: Associations between baseline total testosterone (TT) and calculated free testosterone (fT), frailty (Fried scale) and disability (Nottingham Extended Activities of Daily Living scale (NEADL)) (baseline and 24 months) were examined using multivariate regression and Wald's chi2 techniques. Subjects with the lowest quartile of baseline TT and fT values were compared with those in the upper three quartiles. RESULTS: Participants: 243 men, mean (SD) age 83.7 (2.0) years. Mean (SD) TT=17.6 (6.8) nmol/L and fT=225.3 (85.4) pmol/L. On multivariate analyses, lower TT levels were associated with frailty: beta=0.41, p=0.017, coefficient of determination (R2)=0.10 and disability (NEADL) (beta=-1.27, p=0.017, R2=0.11), low haemoglobin (beta=-7.38, p=0.0016, R2=0.05), high fasting glucose (beta=0.38, p=0.038, R2=0.04) and high C reactive protein (CRP) (beta=3.57, p=0.01, R2=0.06). Low fT levels were associated with frailty (beta=0.39, p=0.024, R2=0.09) but not baseline NEADL (beta=-1.29, p=0.09, R2=0.09). Low fT was associated with low haemoglobin (beta=-7.83, p=0.0008, R2=0.05) and high CRP (beta=2.86, p=0.04, R2=0.05). Relationships between baseline TT and fT, and 24-month outcomes of disability and frailty were not significant. CONCLUSIONS: In men over 80 years, we confirm an association between T levels and baseline frailty scores. The new finding of association between T levels and disability is potentially relevant to debates on T supplementation in older men, though, as associations were not present at 24 months, further work is needed. PMID- 29133314 TI - Decisional needs assessment of patients with complex care needs in primary care: a participatory systematic mixed studies review protocol. AB - INTRODUCTION: Patients with complex care needs (PCCNs) often suffer from combinations of multiple chronic conditions, mental health problems, drug interactions and social vulnerability, which can lead to healthcare services overuse, underuse or misuse. Typically, PCCNs face interactional issues and unmet decisional needs regarding possible options in a cascade of interrelated decisions involving different stakeholders (themselves, their families, their caregivers, their healthcare practitioners). Gaps in knowledge, values clarification and social support in situations where options need to be deliberated hamper effective decision support interventions. This review aims to (1) assess decisional needs of PCCNs from the perspective of stakeholders, (2) build a taxonomy of these decisional needs and (3) prioritise decisional needs with knowledge users (clinicians, patients and managers). METHODS AND ANALYSIS: This review will be based on the interprofessional shared decision making (IP SDM) model and the Ottawa Decision Support Framework. Applying a participatory research approach, we will identify potentially relevant studies through a comprehensive literature search; select relevant ones using eligibility criteria inspired from our previous scoping review on PCCNs; appraise quality using the Mixed Methods Appraisal Tool; conduct a three-step synthesis (sequential exploratory mixed methods design) to build taxonomy of key decisional needs; and integrate these results with those of a parallel PCCNs' qualitative decisional need assessment (semistructured interviews and focus group with stakeholders). ETHICS AND DISSEMINATION: This systematic review, together with the qualitative study (approved by the Centre Integre Universitaire de Sante et Service Sociaux du Saguenay-Lac-Saint-Jean ethical committee), will produce a working taxonomy of key decisional needs (ontological contribution), to inform the subsequent user centred design of a support tool for addressing PCCNs' decisional needs (practical contribution). We will adapt the IP-SDM model, normally dealing with a single decision, for PCCNs who experience cascade of decisions involving different stakeholders (theoretical contribution). Knowledge users will facilitate dissemination of the results in the Canadian primary care network. PROSPERO REGISTRATION NUMBER: CRD42015020558. PMID- 29133316 TI - Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types. AB - INTRODUCTION: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3zeta signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. METHODS AND ANALYSIS: This open label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3*108, 1*109 and 3*109 NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. ETHICS APPROVAL AND DISSEMINATION: Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT03018405, EudraCT 2016-003312-12; Pre-result. PMID- 29133317 TI - Association between visceral obesity and hepatitis C infection stratified by gender: a cross-sectional study in Taiwan. AB - OBJECTIVES: The global prevalence of hepatitis C virus (HCV) is approximately 2% 3%, and the prevalence of the positive anti-HCV antibody has been increasing. Several studies have evaluated regional adipose tissue distribution and metabolism over the past decades. However, no study has focused on the gender difference in visceral obesity among patients with HCV infection. DESIGN: Retrospective cross-sectional study. SETTING: We reviewed the medical records of patients who visited a hospital in Southern Taiwan for health check-up from 2013 to 2015. PARTICIPANTS: A total of 1267 medical records were collected. We compared patient characteristics, variables related to metabolic risk and body composition measured using bioelectrical impedance analysis between the groups. Regression models were built to adjust for possible confounding factors. RESULTS: The prevalence rate of the positive anti-HCV antibody was 8.8% in the study population, 8.5% in men and 9.2% in women. Men with HCV infection tended to be older and have lower total cholesterol levels and higher alanine aminotransferase (ALT) levels (p<0.001). Women with HCV infection tended to be older and have higher levels of fasting glucose and ALT (p<0.001). After adjusting for confounding factors, body fat percentage, fat-free mass/body weight (BW) and muscle mass/BW were found to be the independent determinants of visceral obesity in patients without HCV infection (p<0.001). However, the trend was not such obvious in patients with HCV infection, though still statistically significant (p<0.05). Furthermore, the trend was less significant in men with HCV infection. CONCLUSIONS: The findings suggested that HCV modulates host lipid metabolism and distribution to some extent, and a gender difference was also noted. PMID- 29133318 TI - Examining the association between maternal atopy and birth outcomes using a retrospective cohort in the southeastern region of the USA. AB - OBJECTIVE: To assess birth outcomes in primiparous women with diagnosis of non asthmatic atopy (NAA). Researchers hypothesised that women with NAA would have reduced the risk of adverse birth outcomes compared with women without NAA. NAA is defined as having allergic rhinitis and/or atopic dermatitis. SETTING: Women were mostly treated in primary care settings in South Carolina, USA. PARTICIPANTS: This is a retrospective cohort study in which participants were identified using a Medicaid database. Participants were primiparous women aged 19 to 25. Births occurring between 2004 and 2014 were identified using the South Carolina's Vital Statistics (VS) records of live births. Incomplete records (ie, information on plural birth, gestational age at birth or birth weight missing), plural births or infants born before completing 24 weeks of gestation were excluded. This provided 65 650 complete maternal-infant dyads, representing 97.6% of the maternal records and 96.9% of the VS records. Women previously diagnosed with NAA were frequency matched 1:4 to non-atopic controls for a total of 9965 maternal-infant dyads used in the statistical analysis. PRIMARY OUTCOME MEASURES: Low birth weight, small for gestational age and preterm birth. RESULTS: Linear tests for trend were statistically significant (p<0.001), indicating that NAA was associated with improved birth weight and gestational age at birth. After controlling for potential confounders, mothers with NAA had equal risk for each outcome when compared with mothers with no diagnosis of NAA. CONCLUSION: A diagnosis of NAA among women living in the southeastern region of the USA does not reduce the risk of adverse birth outcomes nor does it elevate the risk of same. Additional studies with more rigorous designs are warranted to confirm the findings in this study. PMID- 29133319 TI - Identification of factors associated with resilience in medical students through a cross-sectional census. AB - OBJECTIVES: Research on resilience has been gaining momentum, and it has already been shown that increased resilience creates positive changes at the individual and collective levels. Understanding of the factors associated with resilience may guide specific actions directed towards different populations. The objective of this study was to investigate these associated factors within a population of medical students. DESIGN: Cross-sectional census. SETTING: A public medical school in the state of Rio de Janeiro, Brazil. PARTICIPANTS: Out of a total of 551 medical students, five students were excluded due to inactive registrations, and four transferred students were also excluded, resulting in a total of 542 remaining participants. MEASURES: Adopting an anonymous questionnaire that included the Resilience Scale, in addition to questions related to sociodemographic, behavioural health-related and academic variables, the association between these variables and resilience was investigated. RESULTS: The high rate of answers to each item constitutes a indication of students' interest in participating, whereas the lowest percentile was 97.1%. The mean resilience score obtained was considered moderate. Factors such as gender, race, previous schools attended, financial independence, living situation, parents' education level, religion, quota-based admission, smoking, alcohol abuse and use of illegal drugs were not associated with resilience. In a multivariate analysis using ordinal logistic regression, associations were maintained only between the highest resilience score and the non-use of habit-forming prescription drugs (OR: 0.58; 95% CI 0.41 to 0.80), having a better perception of one's own health (OR: 0.57; 95% CI 0.41 to 0.81) and being older (OR: 1.37; 95% CI 1.12 to 1.67). CONCLUSION: The census performed with the medical students showed, with the multivariate analysis, that besides age, the variables most closely tied with resilience were health and medicalisation, and the variables connected with income and religion showed no association. PMID- 29133320 TI - Effect of an intensive 3-week preoperative home rehabilitation programme in patients with chronic obstructive pulmonary disease eligible for lung cancer surgery: a multicentre randomised controlled trial. AB - INTRODUCTION: Surgery is the standard curative treatment for lung cancer but is only possible in patients with local tumour and preserved exercise capacity. Improving fitness before surgery can reduce postoperative complications and mortality. However, preoperative rehabilitation remains difficult to implement for several reasons. We aim to investigate the effectiveness of an intensive 3 week home-based preoperative exercise training programme on hospital discharge ability, postoperative complications and physical performance in patients with chronic obstructive pulmonary disease (COPD) who are eligible for lung cancer surgery. METHODS AND ANALYSIS: We designed a multicentre randomised controlled trial. The randomisation sequence will be generated and managed electronically by a research manager independent of assessments or interventions. We will recruit 90 patients with COPD and a diagnosis of lung cancer from four university hospitals. The rehabilitation group (R group) will receive a standardised preoperative home exercise programme for 3 weeks, combining both high-intensity training and usual physical therapy. The R group will perform 15 training sessions over 3 weeks on a cycloergometer. A physical therapist experienced in pulmonary rehabilitation will visit the patient at home and supervise one session a week. The R group will be compared with a control group receiving preoperative usual physical therapy only. The primary outcome will be hospital discharge ability assessed with a 10-item list. Secondary outcomes will be postoperative course (complication rate and mortality) as well as pulmonary function, exercise capacity and quality of life assessed 1 month before and the day before surgery. ETHICS AND DISSEMINATION: This protocol has been approved by the French health authority for research (2016-A00622-49) and the research ethics committee/institutional review board (AU1267). Adverse events that occur during the protocol will be reported to the principal investigator. The results will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03020251. PMID- 29133321 TI - Can physical assessment techniques aid diagnosis in people with chronic fatigue syndrome/myalgic encephalomyelitis? A diagnostic accuracy study. AB - OBJECTIVE: To assess five physical signs to see whether they can assist in the screening of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and potentially lead to quicker treatment. METHODS: This was a diagnostic accuracy study with inter-rater agreement assessment. Participants recruited from two National Health Service hospitals, local CFS/ME support groups and the community were examined by three practitioners on the same day in a randomised order. Two allied health professionals (AHPs) performed independent examinations of physical signs including: postural/mechanical disturbances of the thoracic spine, breast varicosities, tender Perrin's point, tender coeliac plexus and dampened cranial flow. A physician conducted a standard clinical neurological and rheumatological assessment while looking for patterns of illness behaviour. Each examination lasted approximately 20 min. RESULTS: Ninety-four participants were assessed, 52 patients with CFS/ME and 42 non-CFS/ME controls, aged 18-60. Cohen's kappa revealed that agreement between the AHPs was substantial for presence of the tender coeliac plexus (kappa=0.65, p<0.001) and moderate for postural/mechanical disturbance of the thoracic spine (kappa=0.57, p<0.001) and Perrin's point (kappa=0.56, p<0.001). A McNemar's test found no statistically significant bias in the diagnosis by the experienced AHP relative to actual diagnosis (p=1.0) and a marginally non-significant bias by the newly trained AHP (p=0.052). There was, however, a significant bias in the diagnosis made by the physician relative to actual diagnosis (p<0.001), indicating poor diagnostic utility of the clinical neurological and rheumatological assessment. CONCLUSIONS: Using the physical signs appears to improve the accuracy of identifying people with CFS/ME and shows agreement with current diagnostic techniques. However, the present study concludes that only two of these may be needed. Examining for physical signs is both quick and simple for the AHP and may be used as an efficient screening tool for CFS/ME. This is a small single-centre study, and therefore, further validation in other centres and larger populations is needed. PMID- 29133322 TI - Factors contributing to medicine-related problems in adult patients with diabetes and/or cardiovascular diseases in Saudi Arabia: a qualitative study. AB - OBJECTIVES: To investigate the factors contributing to medicine-related problems (MRPs) among patients with cardiovascular diseases (CVDs) and/or diabetes in Saudi Arabia. DESIGN: Qualitative semistructured interviews were conducted. Interviews were audio recorded then transcribed into Microsoft Word. The transcribed interviews were then imported into the qualitative analysis software NVivo where thematic analysis was applied. Thematic synthesis was achieved by coding and developing subthemes/themes from the findings of the interviews. SETTING: Five healthcare centres in Najran, Saudi Arabia. PARTICIPANTS: 25 adult patients with diabetes and/or CVDs. RESULTS: The study cohort included 16 men and 9 women with a median age of 61.8 years (40-85 years). Diabetes was the main condition encountered among 23 patients and CVDs were reported among 18 patients. Perceived factors leading to MRPs were of four types and related to: patient-, healthcare system-, clinical (condition-) and medicine-related factors. Patient related factors were related to living situation, religious practices, diet/exercise and patients' behaviour towards the condition and medicines. Healthcare system-related factors comprised sources and availability of medicines, ease of access to healthcare system and patient satisfaction with healthcare providers. Clinical (condition-) related factors associated with both the knowledge and control over condition, and effects of the condition among medicines intake. Medicine-related factors included lack of knowledge about medicines and medicine use. CONCLUSIONS: The results of this study uncovered many factors associated with MRPs among patients with CVDs and diabetes in Saudi Arabia, especially in reference to lifestyle and medicine use. Improving communication with healthcare professional alongside the introduction of national clinical guidance would mitigate the unwanted health complications related to medicine use. PMID- 29133323 TI - Characteristics and healthcare utilisation patterns of high-cost beneficiaries in the Netherlands: a cross-sectional claims database study. AB - OBJECTIVE: To determine medical needs, demographic characteristics and healthcare utilisation patterns of the top 1% and top 2%-5% high-cost beneficiaries in the Netherlands. DESIGN: Cross-sectional study using 1 year claims data. We broke down high-cost beneficiaries by demographics, the most cost-incurring condition per beneficiary and expensive treatment use. SETTING: Dutch curative health system, a health system with universal coverage. PARTICIPANTS: 4.5 million beneficiaries of one health insurer. MEASURES: Annual total costs through hospital, intensive care unit use, expensive drugs, other pharmaceuticals, mental care and others; demographics; most cost-incurring and secondary conditions; inpatient stay; number of morbidities; costs per ICD10-chapter (International Statistical Classification of Diseases, 10th revision); and expensive treatment use (including dialysis, transplant surgery, expensive drugs, intensive care unit and diagnosis-related groups >?30 000). RESULTS: The top 1% and top 2%-5% beneficiaries accounted for 23% and 26% of total expenditures, respectively. Among top 1% beneficiaries, hospital care represented 76% of spending, of which, respectively, 9.0% and 9.1% were spent on expensive drugs and ICU care. We found that 54% of top 1% beneficiaries were aged 65 years or younger and that average costs sharply decreased with higher age within the top 1% group. Expensive treatments contributed to high costs in one-third of top 1% beneficiaries and in less than 10% of top 2%-5% beneficiaries. The average number of conditions was 5.5 and 4.0 for top 1% and top 2%-5% beneficiaries, respectively. 53% of top 1% beneficiaries were treated for circulatory disorders but for only 22% of top 1% beneficiaries this was their most cost-incurring condition. CONCLUSIONS: Expensive treatments, most cost-incurring condition and age proved to be informative variables for studying this heterogeneous population. Expensive treatments play a substantial role in high-costs beneficiaries. Interventions need to be aimed at beneficiaries of all ages; a sole focus on the elderly would leave many high-cost beneficiaries unaddressed. Tailored interventions are needed to meet the needs of high-cost beneficiaries and to avoid waste of scarce resources. PMID- 29133324 TI - Effects of falls prevention interventions on falls outcomes for hospitalised adults: protocol for a systematic review with meta-analysis. AB - INTRODUCTION: Falls are a major global public health problem and leading cause of accidental or unintentional injury and hospitalisation. Falls in hospital are associated with longer length of stay, readmissions and poor outcomes. Falls prevention is informed by knowledge of reversible falls risk factors and accurate risk identification. The extent to which hospital falls are prevented by evidence based practice, patient self-management initiatives, environmental modifications and optimisation of falls prevention systems awaits confirmation. Published reviews have mainly evaluated community settings and residential care facilities. A better understanding of hospital falls and the most effective strategies to prevent them is vital to keeping people safe. OBJECTIVES: To evaluate the effectiveness of falls prevention interventions on reducing falls in hospitalised adults (acute and subacute wards, rehabilitation, mental health, operating theatre and emergency departments). We also summarise components of effective falls prevention interventions. METHODS AND ANALYSIS: This protocol has been registered. The systematic review will be informed by Cochrane guidelines and reported according to the Preferred Reporting Items for Systematic review and Meta-Analysis statement. INCLUSION CRITERIA: randomised controlled trials, quasi randomised trials or controlled clinical trials that evaluate falls prevention interventions for use by hospitalised adults or employees. Electronic databases will be searched using key terms including falls, accidental falls, prevention, hospital, rehabilitation, emergency, mental health, acute and subacute. Pairs of independent reviewers will conduct all review steps. Included studies will be evaluated for risk of bias. Data for variables such as age, participant characteristics, settings and interventions will be extracted and analysed with descriptive statistics and meta-analysis where possible. The results will be presented textually, with flow charts, summary tables, statistical analysis (and meta-analysis where possible) and narrative summaries. ETHICS AND DISSEMINATION: Ethical approval is not required. The systematic review will be published in a peer-reviewed journal and disseminated electronically, in print and at conferences. Updates will guide healthcare translation into practice. TRAIL REGISTRATION NUMBER: PROSPERO 2017: CRD 42017058887. Available from https://www.crd.york.ac.uk/prospero. PMID- 29133325 TI - Minimally invasive surgery versus open surgery in the treatment of lumbar spondylolisthesis: study protocol of a multicentre, randomised controlled trial (MISOS trial). AB - INTRODUCTION: Patients with symptomatic spondylolisthesis are frequently treated with nerve root decompression, in addition to pedicle screw fixation and interbody fusion. Minimally invasive approaches are gaining attention in recent years, although there is no clear evidence supporting the proclamation of minimally invasive spine surgery (MISS) being better than open surgery. We present the design of the MISOS (Minimal Invasive Surgery versus Open Surgery) trial on the effectiveness of MISS versus open surgery in patients with degenerative or spondylolytic spondylolisthesis. METHODS AND ANALYSIS: All patients (age 18-75 years) with neurogenic claudication or radicular leg pain based on low-grade degenerative or spondylolytic spondylolisthesis with persistent complaints for at least 3 months are eligible. Patients will be randomised into mini-open decompression with bilateral interbody fusion with percutaneous pedicle screw fixation (MISS), or conventional surgery with decompression and instrumented fusion with pedicle screws and bilateral interbody fusion (open). The primary outcome measure is Visual Analogue Scale of self reported low back pain. Secondary outcome measures include improvement of leg pain, Oswestry Disability Index, patients' perceived recovery, quality of life, resumption of work, complications, blood loss, length of hospital stay, incidence of reoperations and documentation of fusion. This study is designed as a multicentre, randomised controlled trial in which two surgical techniques are compared in a parallel group design. Based on a 20 mm difference of low back pain score at 6 weeks (power of 90%, assuming 8% loss to follow-up), a total of 184 patients will be needed. All analyses will be performed according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethical Review Board Southwest Holland in August 2014 (registration number NL 49044.098.14) and subsequently approved by the board of all participating hospitals. Dissemination will include peer-reviewed publications and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NTR 4532, pre-results. PMID- 29133326 TI - Risks for comorbidity in children with atopic disorders: an observational study in Dutch general practices. AB - OBJECTIVE: This study aimed to investigate both atopic and non-atopic comorbid symptoms and diseases in children with physician-diagnosed atopic disorders (atopic eczema, asthma and allergic rhinitis). METHODS: All children aged 0-18 years listed in a nationwide primary care database (the Netherlands Institute for Health Services Research-Primary Care Database) with routinely collected healthcare data in 2014 were selected. Children with atopic disorders were matched on age and gender with non-atopic controls within the same general practice. A total of 404 International Classification of Primary Care codes were examined. Logistic regression analyses were performed to examine the associations between the presence of atopic disorders and (non-)atopic symptoms and diseases by calculating ORs. RESULTS: Having one of the atopic disorders significantly increased the risk of having other atopic-related symptoms, even if the child was not registered as having the related atopic disorder. Regarding non-atopic comorbidity, children with atopic eczema (n=15 530) were at significantly increased risk for (infectious) skin diseases (OR: 1.2-3.4). Airway symptoms or (infectious) diseases (OR: 2.1-10.3) were observed significantly more frequently in children with asthma (n=7887). Children with allergic rhinitis (n=6835) had a significantly distinctive risk of ear-nose-throat-related symptoms and diseases (OR: 1.5-3.9). Neither age nor gender explained these increased risks. CONCLUSION: General practitioners are not always fully aware of relevant atopic and non-atopic comorbidity. In children known to have at least one atopic disorder, specific attention is required to avoid possible insufficient treatment and unnecessary loss of quality of life. PMID- 29133327 TI - Easier said than done: a qualitative study conducted in the USA exploring Latino family child care home providers as role models for healthy eating and physical activity behaviours. AB - OBJECTIVE: Latinos are the largest and most rapidly growing minority population group in the USA and are disproportionally affected by obesity and related chronic diseases. Child care providers likely influence the eating and physical activity behaviours of children in their care, and therefore are important targets for interventions designed to prevent childhood obesity. Nonetheless, there is a paucity of research examining the behaviours of family child care home (FCCH) providers and whether they model healthy eating and physical activity behaviours. Therefore, this study explored Latino FCCH providers' beliefs and practices related to healthy eating, physical activity and sedentary behaviours, and how they view their ability to serve as role models for these behaviours for young children in their care. METHODS: This is a qualitative study consisting of six focus groups conducted in Spanish with a sample of 44 state-licensed Latino FCCH providers in the state of Massachusetts. Translated transcripts were analysed using thematic analyses to identify meaningful patterns. RESULTS: Analyses revealed that Latino FCCH providers have positive beliefs and attitudes about the importance of healthy eating and physical activity for children in their care, but personally struggle with these same behaviours and with maintaining a healthy weight status. The ability of Latino FCCH providers to model healthy eating and physical activity may be limited by their low self efficacy in their ability to be physically active, eat a healthy diet and maintain a healthy weight. CONCLUSIONS: Interventions designed to improve healthy eating and physical activity behaviours of children enrolled in FCCHs should address providers' own health behaviours as well as their modelling of these health behaviours. Future research can build on the findings of this qualitative study by quantifying Latino FCCH providers' eating and physical activity behaviours, and determining how these behaviours influence behaviours and health outcomes of children in their care. PMID- 29133328 TI - Associations of time of day with cardiovascular disease risk factors measured in older men: results from the British Regional Heart Study. AB - OBJECTIVE: We estimated associations of time of day with cardiovascular disease (CVD) risk factors measured in older men. METHODS: CVD risk factors (markers of inflammation and haemostasis, and cardiac markers) were measured on one occasion between 08:00 and 19:00 hours in 4252 men aged 60-79 years from the British Regional Heart Study. Linear models were used to estimate associations between time of day and risk factors. When an association was found, we examined whether the relationship between risk factors and cardiovascular mortality was affected by the adjustment for time of day using survival analyses. RESULTS: N-terminal pro-brain natriuretic peptide (NT-proBNP) levels increased by 3.3% per hour (95% CI 1.9% to 4.8%), interleukin-6 (IL-6) increased by 2.6% per hour (95% CI 1.8% to 3.4%), while tissue plasminogen activator (t-PA) decreased by 3.3% per hour (95% CI 3.7% to 2.9%); these associations were unaffected by adjustment for possible confounding factors. The percentages of variation in these risk factors attributable to time of day were less than 2%. In survival analyses, the association of IL-6, NT-proBNP and t-PA with cardiovascular mortality was not affected by the adjustment for time of day. C reactive protein, fibrinogen, D dimer, von Willebrand factor and cardiac troponin T showed no associations with time of day. CONCLUSIONS: In older men, markers of inflammation (IL-6), haemostasis (t-PA) and a cardiac marker (NT-proBNP) varied by time of day. The contribution of time of day to variations in these markers was small and did not appear to be relevant for the CVD risk prediction. PMID- 29133329 TI - Involvement of people with dementia in making decisions about their lives: a qualitative study that appraises shared decision-making concerning daycare. AB - OBJECTIVE: To explore how people with dementia, their informal caregivers and their professionals participate in decision making about daycare and to develop a typology of participation trajectories. DESIGN: A qualitative study with a prospective, multiperspective design, based on 244 semistructured interviews, conducted during three interview rounds over the course of a year. Analysis was by means of content analysis and typology construction. SETTING: Community settings and nursing homes in the Netherlands. PARTICIPANTS: 19 people with dementia, 36 of their informal caregivers and 38 of their professionals (including nurses, daycare employees and case managers). RESULTS: The participants' responses related to three critical points in the decision-making trajectory about daycare: (1) the initial positive or negative expectations of daycare; (2) negotiation about trying out daycare by promoting, resisting or attuning to others; and (3) trying daycare, which resulted in positive or negative reactions from people with dementia and led to a decision. The ways in which care networks proceeded through these three critical points resulted in a typology of participation trajectories, including (1) working together positively toward daycare, (2) bringing conflicting perspectives together toward trying daycare and (3) not reaching commitment to try daycare. CONCLUSION: Shared decision making with people with dementia is possible and requires and adapted process of decision making. Our results show that initial preferences based on information alone may change when people with dementia experience daycare. It is important to have a try-out period so that people with dementia can experience daycare without having to decide whether to continue it. Whereas shared decision making in general aims at moving from initial preferences to informed preferences, professionals should focus more on moving from initial preferences to experienced preferences for people with dementia. Professionals can play a crucial role in facilitating the possibilities for a try-out period. PMID- 29133330 TI - Improving best practise for patients receiving hospital discharge letters: a realist review protocol. AB - INTRODUCTION: Discharge documents are important for transferring information from hospitals to the referring clinician; in the UK and many countries, this is often the patient's general practitioner or family physician. However, patients may or may not receive their discharge letters, and whether patients should routinely receive discharge letters remains unclear. METHODS AND ANALYSIS: The review will consolidate evidence on patients receiving discharge letters through the theory driven approach of a realist review.The review will be conducted systematically and seek to explain how, why, for whom and in what contexts does this practice 'work'. The review will specifically explore whether there are benefits of this practice and if so what are the important contexts for triggering the mechanisms associated with these outcome benefits. Negative effects will also be considered.Several steps will occur: devising initial rough programme theory, searching the evidence, selecting relevant documents, extracting data, synthesising and finally programme theory refinement. As the process is viewed as iterative, this cycle of steps may be repeated as many times as is necessary to reach theoretical saturation and may not be linear.The initial programme theory will be tested and refined throughout the review process and by stakeholder involvement of National Health Service (NHS) policy makers, practitioners and service users. ETHICS AND DISSEMINATION: Formal ethical review is not required. The resulting programme theory is anticipated to explain how the intervention of patients receiving written discharge communication may work in practice, for whom and in what contexts; this will inform best practice of patients receiving discharge communication. The review findings will be disseminated in a peer reviewed journal and presentations and discussions with relevant organisations and stakeholders. While the review will be from the perspective of the UK NHS, its findings should be relevant to other healthcare systems. PROSPERO REGISTRATION NUMBER: CRD42017069863. PMID- 29133331 TI - Malnutrition and its association with readmission and death within 7 days and 8 180 days postdischarge in older patients: a prospective observational study. AB - OBJECTIVE: The relationship between admission nutritional status and clinical outcomes following hospital discharge is not well established. This study investigated whether older patients' nutritional status at admission predicts unplanned readmission or death in the very early or late periods following hospital discharge. DESIGN, SETTING AND PARTICIPANTS: The study prospectively recruited 297 patients >=60 years old who were presenting to the General Medicine Department of a tertiary care hospital in Australia. Nutritional status was assessed at admission by using the Patient-Generated Subjective Global Assessment (PG-SGA) tool, and patients were classified as either nourished (PG-SGA class A) or malnourished (PG-SGA classes B and C). A multivariate logistic regression model was used to adjust for other covariates known to influence clinical outcomes and to determine whether malnutrition is a predictor for early (0-7 days) or late (8-180 days) readmission or death following discharge. OUTCOME MEASURES: The impact of nutritional status was measured on a combined endpoint of any readmission or death within 0-7 days and between 8 and 180 days following hospital discharge. RESULTS: Within 7 days following discharge, 29 (10.5%) patients had an unplanned readmission or death whereas an additional 124 (50.0%) patients reached this combined endpoint within 8-180 days postdischarge. Malnutrition was associated with a significantly higher risk of combined endpoint of readmissions or death both within 7 days (OR 4.57, 95% CI 1.69 to 12.37, P<0.001) and within 8-180 days (OR 1.98, 95% CI 1.19 to 3.28, P=0.007) following discharge and this risk remained significant even after adjustment for other covariates. CONCLUSIONS: Malnutrition in older patients at the time of hospital admission is a significant predictor of readmission or death both in the very early and in the late periods following hospital discharge. Nutritional state should be included in future risk prediction models. TRIAL REGISTRATION NUMBER: ACTRN No. 12614000833662; Post-results. PMID- 29133332 TI - Built to last? The sustainability of health system improvements, interventions and change strategies: a study protocol for a systematic review. AB - INTRODUCTION: The sustainability of healthcare interventions and change programmes is of increasing importance to researchers and healthcare stakeholders interested in creating sustainable health systems to cope with mounting stressors. The aim of this protocol is to extend earlier work and describe a systematic review to identify, synthesise and draw meaning from studies published within the last 5 years that measure the sustainability of interventions, improvement efforts and change strategies in the health system. METHODS AND ANALYSIS: The protocol outlines a method by which to execute a rigorous systematic review. The design includes applying primary and secondary data collection techniques, consisting of a comprehensive database search complemented by contact with experts, and searching secondary databases and reference lists, using snowballing techniques. The review and analysis process will occur via an abstract review followed by a full-text screening process. The inclusion criteria include English-language, peer-reviewed, primary, empirical research articles published after 2011 in scholarly journals, for which the full text is available. No restrictions on location will be applied. The review that results from this protocol will synthesise and compare characteristics of the included studies. Ultimately, it is intended that this will help make it easier to identify and design sustainable interventions, improvement efforts and change strategies. ETHICS AND DISSEMINATION: As no primary data were collected, ethical approval was not required. Results will be disseminated in conference presentations, peer reviewed publications and among policymaker bodies interested in creating sustainable health systems. PMID- 29133333 TI - Barriers and facilitators to orthopaedic surgeons' uptake of decision aids for total knee arthroplasty: a qualitative study. AB - OBJECTIVES: The demand for total knee arthroplasty (TKA) is increasing. Differentiating who will derive a clinically meaningful improvement from TKA from others is a key challenge for orthopaedic surgeons. Decision aids can help surgeons select appropriate candidates for surgery, but their uptake has been low. The aim of this study was to explore the barriers and facilitators to decision aid uptake among orthopaedic surgeons. DESIGN: A qualitative study involving face-to-face interviews. Questions were constructed on the Theoretical Domains Framework to systematically explore barriers and facilitators. SETTING: One tertiary hospital in Australia. PARTICIPANTS: Twenty orthopaedic surgeons performing TKA. OUTCOME MEASURES: Beliefs underlying similar interview responses were identified and grouped together as themes describing relevant barriers and facilitators to uptake of decision aids. RESULTS: While prioritising their clinical acumen, surgeons believed a decision aid could enhance communication and patient informed consent. Barriers identified included the perception that one's patient outcomes were already optimal; a perceived lack of non-operative alternatives for the management of end-stage osteoarthritis, concerns about mandatory cut-offs for patient-centred care and concerns about the medicolegal implications of using a decision aid. CONCLUSIONS: Multifaceted implementation interventions are required to ensure that orthopaedic surgeons are ready, willing and able to use a TKA decision aid. Audit/feedback to address current decision making biases such as overconfidence may enhance readiness to uptake. Policy changes and/or incentives may enhance willingness to uptake. Finally, the design/implementation of effective non-operative treatments may enhance ability to uptake by ensuring that surgeons have the resources they need to carry out decisions. PMID- 29133334 TI - National citation patterns of NEJM, The Lancet, JAMA and The BMJ in the lay press: a quantitative content analysis. AB - OBJECTIVES: To analyse the total number of newspaper articles citing the four leading general medical journals and to describe national citation patterns. DESIGN: Quantitative content analysis. SETTING/SAMPLE: Full text of 22 general newspapers in 14 countries over the period 2008-2015, collected from LexisNexis. The 14 countries have been categorised into four regions: the USA, the UK, Western World (European countries other than the UK, and Australia, New Zealand and Canada) and Rest of the World (other countries). MAIN OUTCOME MEASURE: Press citations of four medical journals (two American: NEJM and JAMA; and two British: The Lancet and The BMJ) in 22 newspapers. RESULTS: British and American newspapers cited some of the four analysed medical journals about three times a week in 2008-2015 (weekly mean 3.2 and 2.7 citations, respectively); the newspapers from other Western countries did so about once a week (weekly mean 1.1), and those from the Rest of the World cited them about once a month (monthly mean 1.1). The New York Times cited above all other newspapers (weekly mean 4.7). The analysis showed the existence of three national citation patterns in the daily press: American newspapers cited mostly American journals (70.0% of citations), British newspapers cited mostly British journals (86.5%) and the rest of the analysed press cited more British journals than American ones. The Lancet was the most cited journal in the press of almost all Western countries outside the USA and the UK. Multivariate correspondence analysis confirmed the national patterns and showed that over 85% of the citation data variability is retained in just one single new variable: the national dimension. CONCLUSION: British and American newspapers are the ones that cite the four analysed medical journals more often, showing a domestic preference for their respective national journals; non-British and non-American newspapers show a common international citation pattern. PMID- 29133335 TI - Barriers and facilitators to learn and improve through morbidity and mortality conferences: a qualitative study. AB - OBJECTIVES: To explore barriers and facilitators to successful morbidity and mortality conferences (M&M), driving learning and improvement. DESIGN: This is a qualitative study with semistructured interviews. Inductive, thematic content analysis was used to identify barriers and facilitators, which were structured across a pre-existing framework for change in healthcare. SETTING: Dutch academic surgical department with a long tradition of M&M. PARTICIPANTS: An interview sample of surgeons, residents and physician assistants (n=12). RESULTS: A total of 57 barriers and facilitators to successful M&M, covering 18 themes, varying from 'case type' to 'leadership', were perceived by surgical staff. While some factors related to M&M organisation, others concerned individual or social aspects. Eight factors, of which four were at the social level, had simultaneous positive and negative effects (eg, 'hierarchy' and 'team spirit'). Mediating pathways for M&M success were found to relate to available information, staff motivation and realisation processes. CONCLUSIONS: This study provides leads for improvement of M&M practice, as well as for further research on key elements of successful M&M. Various factors were perceived to affect M&M success, of which many were individual and social rather than organisational factors, affecting information and realisation processes but also staff motivation. Based on these findings, practical recommendations were formulated to guide efforts towards best practices for M&M. PMID- 29133336 TI - Psychological, behavioural and physiological effects of three long-acting reversible contraception (LARC) methods: protocol for an ancillary study of the ECHO randomised trial. AB - INTRODUCTION: This is the protocol for an ancillary study to the multicentre Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial, a three-arm randomised trial comparing the effects of depot medroxyprogesterone acetate (DMPA), the levonorgestrel (LNG) implant and the copper intrauterine device (IUD) on HIV incidence (NCT02550067 pre-results). The ancillary study will compare other non-contraceptive effects of these three long-acting, reversible contraceptions about which there is little existing comparative evidence. METHODS AND ANALYSIS: Women randomised to IUD, DMPA and LNG implant (1:1:1) at one of the ECHO trial sites will be asked to participate in the ancillary study at the 1 month follow-up visit. Research staff will interview women that consent to participate at the 3-month follow-up visit. Primary outcomes are depression, sexual dysfunction and menstrual disturbances. The Beck Depression Inventory will be used to assess depression and the Arizona Sexual Experiences Scale to assess sexual dysfunction. Participants will also be asked to prospectively complete a 28-day symptom diary. The required sample size is 522 participants. Depression scores will be analysed as continuous and categorical variables. Analysis will be by intention to treat. ETHICS AND DISSEMINATION: The ancillary study protocol received ethical approval from the University of the Witwatersrand Committee for Research on Human Subjects on 17 February 2016 (reference no. 14112). The results will be disseminated in a peer-reviewed open-access journal. TRIAL REGISTRATION NUMBER: PACTR201706001651380. PMID- 29133337 TI - Identification of myocardial infarction type from electronic hospital data in England and Australia: a comparative data linkage study. AB - OBJECTIVE: To determine the utility of International Classification of Diseases (ICD) codes in investigating trends in ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) using person linked electronic hospitalisation data in England and Western Australia (WA). METHODS: All hospital admissions with myocardial infarction (MI) as the principal diagnosis were identified from 2000 to 2013 from both jurisdictions. Fourth-digit ICD-10 codes were used to delineate all MI types-STEMI, NSTEMI, unspecified and subsequent MI. The annual frequency of each MI type was calculated as a proportion of all MI admissions. For all MI and each MI type, age-standardised rates were calculated and age-adjusted Poisson regression models used to estimate annual percentage changes in rates. RESULTS: In 2000, STEMI accounted for 49% of all MI admissions in England and 59% in WA, decreasing to 35% and 25% respectively by 2013. Less than 10% of admissions were recorded as NSTEMI in England throughout the study period, whereas by 2013, 70% of admissions were NSTEMI in WA. Unspecified MI comprised 60% of all MI admissions in England by 2013, compared with <1% in WA. Trends in age-standardised rates differed for all MI (England, -2.7%/year; WA, +1.7%/year), underpinned by differing age-adjusted trends in NSTEMI (England, -6.1%/year; WA, +10.2%/year). CONCLUSION: Differences between the proportion and trends for MI types in English and WA data were observed. These were consistent with the coding standards in each country. This has important implications for using electronic hospital data for monitoring MI and identifying MI types for outcome studies. PMID- 29133338 TI - Social work's scope of practice in the provision of primary mental health care: protocol for a scoping review. AB - INTRODUCTION: Social work is a key member of interprofessional primary healthcare teams and foundational to primary healthcare reforms that aim to improve the provision of mental healthcare. Little is known, however, about social work's scope of practice within primary healthcare settings, particularly in the provision of mental healthcare. The objective of this study is to identify and describe social work's scope of practice as it relates to mental healthcare in primary healthcare settings. METHODS AND ANALYSIS: A scoping review will be conducted using the methodology established by Arksey and O'Malley. We will search electronic databases (MEDLINE, Embase, PsycINFO, CINAHL, Social Services Abstracts and Social Work Abstracts) to identify studies appropriate for inclusion. One reviewer will independently screen all abstracts and full-text studies for inclusion, with supervision by lead investigator. We will include any study that focuses on social work and mental healthcare within primary healthcare settings. All bibliographic data, study characteristics and range of social work practice activities will be collected and analysed using a tool developed by the research team. ETHICS AND DISSEMINATION: The scoping review will synthesise social work's scope of practice in the provision of mental healthcare within primary healthcare settings. This review will be the first step to formally develop guidelines for social work practice in primary healthcare. The results will be disseminated through a peer-reviewed publication and conference presentations. PMID- 29133340 TI - Effects of hawthorn ( Crataegus pentagyna) leaf extract on electrophysiologic properties of cardiomyocytes derived from human cardiac arrhythmia-specific induced pluripotent stem cells. AB - Cardiac arrhythmias are major life-threatening conditions. The landmark discovery of induced pluripotent stem cells has provided a promising in vitro system for modeling hereditary cardiac arrhythmias as well as drug development and toxicity testing. Nowadays, nutraceuticals are frequently used as supplements for cardiovascular therapy. Here we studied the cardiac effects of hawthorn ( Crataegus pentagyna) leaf extract using cardiomyocytes (CMs) differentiated from healthy human embryonic stem cells, long QT syndrome type 2 (LQTS2), and catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) patient specific induced pluripotent stem cells. The hydroalcoholic extract resulted in a dose-dependent negative chronotropic effect in all CM preparations leading to a significant reduction at 1000 ug/ml. This was accompanied by prolongation of field potential durations, although with different magnitudes in CMs from different human embryonic stem cell and iPSC lines. Hawthorn further prolonged field potential durations in LQTS2 CMs but reduced the beating frequencies and occurrence of immature field potentials triggered by beta1-adrenergic stimulation in CPVT1 CMs at 300 and 1000 ug/ml. Furthermore, isoquercetin and vitexin flavonoids significantly slowed down isoproterenol (5 uM)-induced beating frequencies at 3 and 10 ug/ml. Therefore, C. pentagyna leaf extract and its isoquercetin and vitexin flavonoids may be introduced as a novel nutraceutical with antiarrhythmic potential for CPVT1 patients.-Pahlavan, S., Tousi, M. S., Ayyari, M., Alirezalu, A., Ansari, H., Saric, T., Baharvand, H. Effects of hawthorn ( Crataegus pentagyna) leaf extract on electrophysiologic properties of cardiomyocytes derived from human cardiac arrhythmia-specific induced pluripotent stem cells. PMID- 29133341 TI - The trafficking protein, EHD2, positively regulates cardiac sarcolemmal KATP channel surface expression: role in cardioprotection. AB - ATP-sensitive K+ (KATP) channels uniquely link cellular energy metabolism to membrane excitability and are expressed in diverse cell types that range from the endocrine pancreas to neurons and smooth, skeletal, and cardiac muscle. A decrease in the surface expression of KATP channels has been linked to various disorders, including dysregulated insulin secretion, abnormal blood pressure, and impaired resistance to cardiac injury. In contrast, up-regulation of KATP channel surface expression may be protective, for example, by mediating the beneficial effect of ischemic preconditioning. Molecular mechanisms that regulate KATP channel trafficking are poorly understood. Here, we used cellular assays with immunofluorescence, surface biotinylation, and patch clamping to demonstrate that Eps15 homology domain-containing protein 2 (EHD2) is a novel positive regulator of KATP channel trafficking to increase surface KATP channel density. EHD2 had no effect on cardiac Na+ channels (Nav1.5). The effect is specific to EHD2 as other members of the EHD family-EHD1, EHD3, and EHD4-had no effect on KATP channel surface expression. EHD2 did not directly affect KATP channel properties as unitary conductance and ATP sensitivity were unchanged. Instead, we observed that the mechanism by which EHD2 increases surface expression is by stabilizing KATP channel-containing caveolar structures, which results in a reduced rate of endocytosis. EHD2 also regulated KATP channel trafficking in isolated cardiomyocytes, which validated the physiologic relevance of these observations. Pathophysiologically, EHD2 may be cardioprotective as a dominant-negative EHD2 mutant sensitized cardiomyocytes to ischemic damage. Our findings highlight EHD2 as a potential pharmacologic target in the treatment of diseases with KATP channel trafficking defects.-Yang, H. Q., Jana, K., Rindler, M. J., Coetzee, W. A. The trafficking protein, EHD2, positively regulates cardiac sarcolemmal KATP channel surface expression: role in cardioprotection. PMID- 29133339 TI - Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F. AB - Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurologic disorder, but its molecular mechanisms remain unclear. One variant of CMT, 2F, is characterized by mutations in heat shock protein 27 (Hsp27). As bioactive sphingolipids have been implicated in neurodegenerative diseases, we sought to determine if their dysregulation is involved in CMT. Here, we show that Hsp27 knockout mice demonstrated decreases in ceramide in peripheral nerve tissue and that the disease-associated Hsp27 S135F mutant demonstrated decreases in mitochondrial ceramide. Given that Hsp27 is a chaperone protein, we examined its role in regulating ceramide synthases (CerSs), an enzyme family responsible for catalyzing generation of the sphingolipid ceramide. We determined that CerSs colocalized with Hsp27, and upon the presence of S135F mutants, CerS1 lost its colocalization with mitochondria suggesting that decreased mitochondrial ceramides result from reduced mitochondrial CerS localization rather than decreased CerS activity. Mitochondria in mutant cells appeared larger with increased interconnectivity. Furthermore, mutant cell lines demonstrated decreased mitochondrial respiratory function and increased autophagic flux. Mitochondrial structural and functional changes were recapitulated by blocking ceramide generation pharmacologically. These results suggest that mutant Hsp27 decreases mitochondrial ceramide levels, producing structural and functional changes in mitochondria leading to neuronal degeneration.-Schwartz, N. U., Linzer, R. W., Truman, J.-P., Gurevich, M., Hannun, Y. A., Senkal, C. E., Obeid, L. M. Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie Tooth 2F. PMID- 29133342 TI - Exercise training protects human and rodent beta cells against endoplasmic reticulum stress and apoptosis. AB - Prolonged exercise has positive metabolic effects in obese or diabetic individuals. These effects are usually ascribed to improvements in insulin sensitivity. We evaluated whether exercise also generates circulating signals that protect human and rodent beta cells against endoplasmic reticulum (ER) stress and apoptosis. For this purpose, we obtained serum from humans or mice before and after an 8 wk training period. Exposure of human islets or mouse or rat beta cells to human or rodent sera, respectively, obtained from trained individuals reduced cytokine (IL-1beta+IFN-gamma)- or chemical ER stressor induced beta-cell ER stress and apoptosis, at least in part via activation of the transcription factor STAT3. These findings indicate that exercise training improves human and rodent beta-cell survival under diabetogenic conditions and support lifestyle interventions as a protective approach for both type 1 and 2 diabetes.-Paula, F. M. M., Leite, N. C., Borck, P. C., Freitas-Dias, R., Cnop, M., Chacon-Mikahil, M. P. T., Cavaglieri, C. R., Marchetti, P., Boschero, A. C., Zoppi, C. C., Eizirik, D. L. Exercise training protects human and rodent beta cells against endoplasmic reticulum stress and apoptosis. PMID- 29133343 TI - Clinical and Histologic Characterization of Nonalcoholic Steatohepatitis in African American Patients. AB - OBJECTIVE: There has been a widespread misconception among physicians that African Americans are protected from developing nonalcoholic steatohepatitis (NASH). However, a formal histologic and metabolic comparison against well matched Caucasians has never been performed. RESEARCH DESIGN AND METHODS: Sixty seven African American patients were matched 2:1 to Caucasians (n = 134) for age, sex, BMI, hemoglobin A1c, and prevalence of type 2 diabetes mellitus (T2DM). Screening for NASH included measurement of intrahepatic triglyceride content by proton MRS (1H-MRS), followed by a liver biopsy if patients had hepatic steatosis. Insulin resistance was estimated during an oral glucose tolerance test using the Matsuda Index. RESULTS: Compared with Caucasians, African American patients had a lower intrahepatic triglyceride content (mean +/- SD 6.1 +/- 6.8% vs. 9.4 +/- 7.5%, P = 0.007) and the presence of nonalcoholic fatty liver disease (NAFLD) was less common (25.0% vs. 51.9%, P = 0.003). However, prevalence of NASH was not different between ethnicities in patients with NAFLD (57.1% vs. 73.3%, P = 0.12). Moreover, they showed similar severity in each of the individual histologic parameters (inflammation, ballooning, and fibrosis). Among patients with NAFLD, insulin resistance was similar between both ethnic groups (Matsuda Index: 3.3 +/- 1.8 vs. 3.1 +/- 1.9, P = 0.61; adipose tissue insulin resistance [Adipo-IR] index: 5.7 +/- 4.6 vs. 6.4 +/- 4.7 mmol/L ? uU/mL, P = 0.53) but appeared to be worse in African American versus Caucasian patients without NAFLD (Matsuda Index: 4.9 +/- 3.6 vs. 7.0 +/- 4.9, P = 0.11; Adipo-IR: 3.9 +/- 2.8 vs. 2.7 +/- 2.3 mmol/L ? uU/mL, P = 0.06). African American patients also had lower plasma triglycerides and higher HDL cholesterol, independent of the severity of intrahepatic triglyceride. CONCLUSIONS: Although African Americans have lower intrahepatic triglyceride accumulation, once NAFLD develops, NASH occurs as frequently, and as severe, as in Caucasian patients. Therefore, African Americans with NAFLD should be screened for NASH with the same degree of clinical resolve as in Caucasian patients. PMID- 29133344 TI - Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial. PMID- 29133345 TI - Small RNA teg49 Is Derived from a sarA Transcript and Regulates Virulence Genes Independent of SarA in Staphylococcus aureus. AB - Expression of virulence factors in Staphylococcus aureus is regulated by a wide range of transcriptional regulators, including proteins and small RNAs (sRNAs), at the level of transcription and/or translation. The sarA locus consists of three overlapping transcripts generated from three distinct promoters, all containing the sarA open reading frame (ORF). The 5' untranslated regions (UTRs) of these transcripts contain three separate regions ~711, 409, and 146 nucleotides (nt) upstream of the sarA translation start, the functions of which remain unknown. Recent transcriptome-sequencing (RNA-Seq) analysis and subsequent characterization indicated that two sRNAs, teg49 and teg48, are processed and likely produced from the sarA P3 and sarA P1 transcripts of the sarA locus, respectively. In this report, we utilized a variety of sarA promoter mutants and cshA and rnc mutants to ascertain the contributions of these factors to the generation of teg49. We also defined the transcriptional regulon of teg49, including virulence genes not regulated by SarA. Phenotypically, teg49 did not impact biofilm formation or affect overall SarA expression significantly. Comparative analyses of RNA-Seq data between the wild-type, teg49 mutant, and sarA mutant strains indicated that ~133 genes are significantly upregulated while 97 are downregulated in a teg49 deletion mutant in a sarA-independent manner. An abscess model of skin infection indicated that the teg49 mutant exhibited a reduced bacterial load compared to the wild-type S. aureus Overall, these results suggest that teg49 sRNA has a regulatory role in target gene regulation independent of SarA. The exact mechanism of this regulation is yet to be dissected. PMID- 29133346 TI - Mycobacterium tuberculosis GroEL2 Modulates Dendritic Cell Responses. AB - Mycobacterium tuberculosis successfully subverts the host immune response to promote disease progression. In addition to its known intracellular niche in macrophages, M. tuberculosis interferes with the functions of dendritic cells (DCs), which are the primary antigen-presenting cells of the immune system. We previously showed that M. tuberculosis dampens proinflammatory responses and impairs DC functions through the cell envelope-associated serine protease Hip1. Here we present data showing that M. tuberculosis GroEL2, a substrate of Hip1, modulates DC functions. The full-length GroEL2 protein elicited robust proinflammatory responses from DCs and promoted DC maturation and antigen presentation to T cells. In contrast, the cleaved form of GroEL2, which predominates in M. tuberculosis, was poorly immunostimulatory and was unable to promote DC maturation and antigen presentation. Moreover, DCs exposed to full length, but not cleaved, GroEL2 induced strong antigen-specific gamma interferon (IFN-gamma), interleukin-2 (IL-2), and IL-17A cytokine responses from CD4+ T cells. Moreover, the expression of cleaved GroEL2 in the hip1 mutant restored the robust T cell responses to wild-type levels, suggesting that proteolytic cleavage of GroEL2 allows M. tuberculosis to prevent optimal DC-T cell cross talk during M. tuberculosis infection. PMID- 29133347 TI - Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways. AB - To better understand the innate immune response to Vibrio cholerae infection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-kappaB, mitogen activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor gene TLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signaling in vivo, our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases in DUOX2 and TLR8 expression were also modeled in vitro when Caco-2 or THP-1 cells, respectively, were stimulated with live V. cholerae but not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response to V. cholerae extend our understanding of the mucosal immune signaling pathways and effectors activated in vivo following cholera. PMID- 29133348 TI - Nonpathogenic Colonization with Chlamydia in the Gastrointestinal Tract as Oral Vaccination for Inducing Transmucosal Protection. AB - Chlamydia has been detected in the gastrointestinal tracts of humans and animals. We now report that gastrointestinal Chlamydia muridarum is able to induce robust transmucosal protection in mice. C. muridarum colonization in the gastrointestinal tract correlated with both a shortened course of C. muridarum genital tract infection and stronger protection against subsequent genital tract challenge infection. Mice preinoculated intragastrically with C. muridarum became highly resistant to subsequent C. muridarum infection in the genital tract, resulting in prevention of pathology in the upper genital tract. The transmucosal protection in the genital tract was rapidly induced, durable, and dependent on major histocompatibility complex (MHC) class II antigen presentation but not MHC class I antigen presentation. Although a deficiency in CD4+ T cells only partially reduced the transmucosal protection, depletion of CD4+ T cells from B cell-deficient mice completely abolished the protection, suggesting a synergistic role of both CD4+ T and B cells in the gastrointestinal C. muridarum-induced transmucosal immunity. However, the same protective immunity did not significantly affect C. muridarum colonization in the gastrointestinal tract. The long-lasting colonization with C. muridarum was restricted to the gastrointestinal tract and was nonpathogenic to either gastrointestinal or extragastrointestinal tissues. Furthermore, gastrointestinal C. muridarum did not alter the gut microbiota or the development of gut mucosal resident memory T cell responses to a nonchlamydial infection. Thus, Chlamydia may be developed into a safe and orally deliverable replicating vaccine for inducing transmucosal protection. PMID- 29133349 TI - The role of calprotectin in withholding zinc and copper from Candida albicans. AB - The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans was poorly understood and here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with sub-picomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitation are temporally distinct. The Cu response progresses throughout 72 hours, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the host-pathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans. PMID- 29133350 TI - Extracellular histones induce erythrocyte fragility and anemia. AB - Extracellular histones have been shown to play an important pathogenic role in many diseases, primarily through their cytotoxicity toward nucleated cells and their ability to promote platelet activation with resultant thrombosis and thrombocytopenia. In contrast, little is known about the effect of extracellular histones on erythrocyte function. We demonstrate in this study that histones promote erythrocyte aggregation, sedimentation, and using a novel in vitro shear stress model, we show that histones induce erythrocyte fragility and lysis in a concentration-dependent manner. Furthermore, histones impair erythrocyte deformability based on reduced passage of erythrocytes through an artificial spleen. These in vitro results were mirrored in vivo with the injection of histones inducing anemia within minutes of administration, with a concomitant increase in splenic hemoglobin content. Thrombocytopenia and leukopenia were also observed. These findings suggest that histones binding to erythrocytes may contribute to the elevated erythrocyte sedimentation rates observed in inflammatory conditions. Furthermore, histone-induced increases in red blood cell lysis and splenic clearance may be a significant factor in the unexplained anemias seen in critically ill patients. PMID- 29133351 TI - Efficacy and safety outcomes of recanalisation procedures in patients with acute symptomatic pulmonary embolism: systematic review and network meta-analysis. AB - BACKGROUND: We aimed to review the efficacy and safety of recanalisation procedures for the treatment of PE. METHODS: We searched PubMed, the Cochrane Library, EMBASE, EBSCO, Web of Science and CINAHL databases from inception through 31 July 2015 and included randomised clinical trials that compared the effect of a recanalisation procedure versus each other or anticoagulant therapy in patients diagnosed with PE. We used network meta-analysis and multivariate random-effects meta-regression to estimate pooled differences between each intervention and meta-regression to assess the association between trial characteristics and the reported effects of recanalisation procedures versus anticoagulation. RESULTS: For all-cause mortality, there were no significant differences in event rates between any of the recanalisation procedures and anticoagulant treatment (full-dose thrombolysis: OR 0.60; 95% CI0.36 to 1.01; low dose thrombolysis: 0.47; 95% CI 0.14 to 1.59; and catheter-associated thrombolysis: 0.31; 95% CI 0.01 to 7.96). Full-dose thrombolysis increased the risk of major bleeding (2.00; 95% CI 1.06 to 3.78) compared with anticoagulation. Catheter-directed thrombolysis was associated with the lowest probability of dying (surface under the cumulative ranking curve (SUCRA), 0.67), followed by low dose thrombolysis (SUCRA, 0.66) and full-dose thrombolysis (SUCRA, 0.55). Similarly, low-dose thrombolysis was associated with the lowest probability of major bleeding (SUCRA, 0.61), followed by catheter-directed thrombolysis (SUCRA, 0.54) and full-dose thrombolysis (SUCRA, 0.17). The results were similar in sensitivity analyses based on restricting only to studies in haemodynamically stable patients with PE. CONCLUSIONS: In the treatment of PE, recanalisation procedures do not seem to offer a clear advantage compared with standard anticoagulation. Low-dose thrombolysis was associated with the lowest probability of dying and bleeding. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015024670. PMID- 29133352 TI - Primary ciliary dyskinesia: keep it on your radar. PMID- 29133353 TI - Hypertension Editors Welcome Comments From Regional Hypertension Societies. PMID- 29133354 TI - 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. PMID- 29133355 TI - Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. AB - OBJECTIVE: To review the literature systematically and perform meta-analyses to address these questions: 1) Is there evidence that self-measured blood pressure (BP) without other augmentation is superior to office-based measurement of BP for achieving better BP control or for preventing adverse clinical outcomes that are related to elevated BP? 2) What is the optimal target for BP lowering during antihypertensive therapy in adults? 3) In adults with hypertension, how do various antihypertensive drug classes differ in their benefits and harms compared with each other as first-line therapy? METHODS: Electronic literature searches were performed by Doctor Evidence, a global medical evidence software and services company, across PubMed and EMBASE from 1966 to 2015 using key words and relevant subject headings for randomized controlled trials that met eligibility criteria defined for each question. We performed analyses using traditional frequentist statistical and Bayesian approaches, including random-effects Bayesian network meta-analyses. RESULTS: Our results suggest that: 1) There is a modest but significant improvement in systolic BP in randomized controlled trials of self-measured BP versus usual care at 6 but not 12 months, and for selected patients and their providers self-measured BP may be a helpful adjunct to routine office care. 2) systolic BP lowering to a target of <130 mm Hg may reduce the risk of several important outcomes including risk of myocardial infarction, stroke, heart failure, and major cardiovascular events. No class of medications (ie, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers, or beta blockers) was significantly better than thiazides and thiazide-like diuretics as a first-line therapy for any outcome. PMID- 29133356 TI - 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. PMID- 29133357 TI - Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice. AB - The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA. PMID- 29133359 TI - Mesoscale Nanoparticles: An Unexpected Means for Selective Therapeutic Targeting of Kidney Diseases! PMID- 29133358 TI - Sex Differences in Mechanisms of Hypertension Associated With Obesity. PMID- 29133361 TI - Should 24-Hour Ambulatory Blood Pressure Monitoring Become Part of Regular Checkup in Women With Previous Preeclampsia? PMID- 29133360 TI - Selective Nanoparticle Targeting of the Renal Tubules. AB - Direct targeting to the kidneys is a promising strategy to improve drug therapeutic index for the treatment of kidney diseases. We sought to investigate the renal selectivity and safety of kidney-targeted mesoscale nanoparticle technology. We found that direct intravenous administration of these particles resulted in 26-fold renal selectivity and localized negligibly in the liver or other organs. The nanoparticles targeted the renal proximal tubular epithelial cells, as evidenced by intravital microscopy and ex vivo imaging. Mice treated with the nanoparticles exhibited no negative systemic consequences, immune reaction, liver impairment, or renal impairment. The localization of material selectively to the renal tubules is uncommon, and this work portends the development of renal-targeted drugs for the treatment of kidney diseases. PMID- 29133362 TI - Three-Month Endothelial Human Endothelin-1 Overexpression Causes Blood Pressure Elevation and Vascular and Kidney Injury. AB - Endothelium-derived endothelin (ET)-1 has been implicated in the development of hypertension and end-organ damage, but its exact role remains unclear. We have shown that tamoxifen-inducible endothelium-restricted human ET-1 overexpressing (ieET-1) mice exhibited blood pressure rise after a 3-week induction in an ET type A (ETA) receptor-dependent manner, in absence of vascular and renal injury. It is unknown whether long-term ET-1 overexpression results in sustained blood pressure elevation and vascular and renal injury. Adult male ieET-1 and control tamoxifen-inducible endothelium-restricted Cre recombinase (ieCre) mice were induced with tamoxifen and 2.5 months later, were treated with or without the ETA receptor blocker atrasentan for 2 weeks. Three-month induction of endothelial human ET-1 overexpression increased blood pressure (P<0.01), reduced renal artery flow (P<0.001), and caused mesenteric small artery stiffening (P<0.05) and endothelial dysfunction (P<0.01). These changes were accompanied by enhanced mesenteric small artery Col1A1 and Col3A1 expression, and perivascular adipose tissue oxidative stress (P<0.05) and monocyte/macrophage infiltration (P<0.05). Early renal injury was demonstrated by increased kidney injury molecule-1 expression in renal cortex tubules (P<0.05), with, however, undetectable lesions using histochemistry staining and unchanged urinary albumin. There was associated increased myeloid (CD11b+) and myeloid-derived suppressive cell (CD11b+Gr-1+) renal infiltration (P<0.01) and greater frequency of myeloid and renal cells expressing the proinflammatory marker CD36 (P<0.05). Atrasentan reversed or reduced all of the above changes (P<0.05) except the endothelial dysfunction and collagen expression and reduced renal artery flow. These results demonstrate that long-term exposure to endothelial human ET-1 overexpression causes sustained blood pressure elevation and vascular and renal injury via ETA receptors. PMID- 29133363 TI - Prevalence of Hypertensive Phenotypes After Preeclampsia: A Prospective Cohort Study. AB - : Preeclampsia is associated with increased cardiovascular and renal risk. The aim of this prospective cohort study was to characterize the early postpartum blood pressure (BP) profile after preeclampsia. We enrolled 115 women with preeclampsia and 41 women with a normal pregnancy in a prospective cohort study. At 6 to 12 week postpartum, we assessed the prevalence of different hypertensive phenotypes using 24-hour ambulatory BP monitoring (ABPM), as well as the risk of salt sensitivity and the variability of BP derived from ABPM parameters. Among patients with preeclampsia, 57.4% were still hypertensive at the office. Daytime ABP was significantly higher in the preeclampsia group (118.9+/-15.0/83.2+/-10.4 mm Hg) than in controls (104.8+/-7.9/71.6+/-5.3 mm Hg; P<0.01). Differences between groups were similar for nocturnal BP values. Fifty percent of preeclampsia women remained hypertensive on ABPM in the postpartum, of whom 24.3% were still under antihypertensive treatment; 17.9% displayed a white-coat hypertension and 11.6% had masked hypertension. In controls, 2.8% had white-coat hypertension; none had masked hypertension or needed hypertensive treatment. The prevalence of nondippers was similar 59.8% in the preeclampsia group versus 51.4% in controls. High-risk class of salt sensitivity of BP was increased in preeclampsia women (48.6%) compared with controls (17.1%); P<0.01. In conclusion, ABPM 6 to 12 weeks after delivery reveals a high rate of sustained ambulatory, nocturnal, and masked hypertension after preeclampsia. This finding may help identify women who should be included in a postpartum cardiovascular risk management program. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01095939. PMID- 29133364 TI - Day-by-Day Variability of Home Blood Pressure and Incident Cardiovascular Disease in Clinical Practice: The J-HOP Study (Japan Morning Surge-Home Blood Pressure). AB - We assessed the relationship between day-by-day home blood pressure (BP) variability and incident cardiovascular disease (CVD) in clinical practice. J-HOP study (Japan Morning Surge-Home Blood Pressure) participants underwent home BP monitoring in the morning and evening for a 14-day period, and their BP levels and BP variability independent of the mean (VIM) were assessed. Incident CVD events included coronary heart disease and stroke. Cox models were fitted to assess the home BP variability-CVD risk association. Among 4231 participants (mean+/-SD age, 64.9+/-10.9 years; 53.3% women; 79.1% taking antihypertensive medication), mean (SD) home systolic BP (SBP) levels over time and VIMSBP were 134.2 (14.3) and 6.8 (2.5) mm Hg, respectively. During a 4-year follow-up period (16 750.3 person-years), 148 CVD events occurred. VIMSBP was associated with CVD risk (hazard ratio per 1-SD increase, 1.32; 95% confidence interval [CI], 1.15 1.52), independently of mean home SBP levels over time and circulating B-type natriuretic peptide levels or urine albumin-to-creatinine ratio. Adding VIMSBP to the CVD prediction model improved the discrimination (C statistic, 0.785 versus 0.770; C statistic difference, 0.015; 95% CI, 0.003-0.028). Changes in continuous net reclassification improvement (0.259; 95% CI, 0.052-0.537), absolute integrated discrimination improvement (0.010; 95% CI, 0.003-0.016), and relative integrated discrimination improvement (0.104; 95% CI, 0.037-0.166) were also observed with the addition of VIMSBP to the CVD prediction models. In addition to the assessments of mean home SBP levels and cardiovascular end-organ damage, home BP variability measurements may provide a clinically useful distinction between high- and low-risk groups among Japanese outpatients. PMID- 29133365 TI - Prediagnostic Smoking Is Associated with Binary and Quantitative Measures of ER Protein and ESR1 mRNA Expression in Breast Tumors. AB - Background: Smoking is a possible risk factor for breast cancer and has been linked to increased risk of estrogen receptor-positive (ER+) disease in some epidemiologic studies. It is unknown whether smoking has quantitative effects on ER expression.Methods: We examined relationships between smoking and ER expression from tumors of 1,888 women diagnosed with invasive breast cancer from a population-based study in North Carolina. ER expression was characterized using binary (+/-) and continuous measures for ER protein, ESR1 mRNA, and a multigene luminal score (LS) that serves as a measure of estrogen signaling in breast tumors. We used logistic and linear regression models to estimate temporal and dose-dependent associations between smoking and ER measures.Results: The odds of ER+, ESR1+, and LS+ tumors among current smokers (at the time of diagnosis), those who smoked 20 or more years, and those who smoked within 5 years of diagnosis were nearly double those of nonsmokers. Quantitative levels of ESR1 were highest among current smokers compared with never smokers overall [mean (log2) = 9.2 vs. 8.7, P < 0.05] and among ER+ cases; however, we did not observe associations between smoking measures and continuous ER protein expression.Conclusions: In relationship to breast cancer diagnosis, recent smoking was associated with higher odds of the ER+, ESR1+, and LS+ subtype. Current smoking was associated with elevated ESR1 mRNA levels and an elevated LS, but not with altered ER protein.Impact: A multigene LS and single-gene ESR1 mRNA may capture tumor changes associated with smoking. Cancer Epidemiol Biomarkers Prev; 27(1); 67-74. (c)2017 AACR. PMID- 29133366 TI - Lifestyle and Reproductive Factors and Ovarian Cancer Risk by p53 and MAPK Expression. AB - Background: One model of ovarian cancer development model divides tumors into two types. Type I tumors are characterized by KRAS and BRAF mutations, which can activate mitogen-activated protein kinase (MAPK). Type II tumors are characterized by tubal precursor lesions with p53 mutations. We evaluated the association between lifestyle and reproductive factors and risk of ovarian cancer defined by p53 and MAPK expression.Methods: Epithelial ovarian cancer cases (n = 274) and controls (n = 1,907) were identified from the Nurses' Health Study and Nurses' Health Study II prospective cohorts, and the population-based New England Case-Control study. Reproductive and lifestyle exposures were assessed by questionnaire/interview. We performed immunohistochemical assays for p53 and MAPK expression. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using polytomous logistic regression.Results: Parity was associated with a decreased risk of p53 wild-type tumors (OR = 0.31; 95% CI, 0.18-0.55), but not p53-mutant tumors (OR = 0.92; 95% CI, 0.54-1.59)(Pheterogeneity < 0.01). Family history of breast or ovarian cancer was associated with risk of MAPK-negative (OR = 2.06; 95% CI, 1.39-3.06), but not MAPK-positive tumors (OR = 0.74; 95% CI, 0.43 1.27; Pheterogeneity< 0.01). In cross-classified analyses, family history of breast or ovarian cancer was most strongly associated with p53-mutant/MAPK negative tumors (OR = 2.33; 95% CI, 1.44-3.75). Differences by MAPK expression were also observed for estrogen plus progesterone hormone therapy use (Pheterogeneity = 0.03).Conclusions: These findings provide evidence that parity, family history, and estrogen plus progesterone hormone therapy use may be differentially associated with tumor subtypes defined by p53 and MAPK expression.Impact: In future studies, other immunohistochemical markers or gene expression profiles that more clearly define these subtypes should be considered. Cancer Epidemiol Biomarkers Prev; 27(1); 96-102. (c)2017 AACR. PMID- 29133367 TI - Regulatory T-cell Genes Drive Altered Immune Microenvironment in Adult Solid Cancers and Allow for Immune Contextual Patient Subtyping. AB - Background: The tumor microenvironment is an important factor in cancer immunotherapy response. To further understand how a tumor affects the local immune system, we analyzed immune gene expression differences between matching normal and tumor tissue.Methods: We analyzed public and new gene expression data from solid cancers and isolated immune cell populations. We also determined the correlation between CD8, FoxP3 IHC, and our gene signatures.Results: We observed that regulatory T cells (Tregs) were one of the main drivers of immune gene expression differences between normal and tumor tissue. A tumor-specific CD8 signature was slightly lower in tumor tissue compared with normal of most (12 of 16) cancers, whereas a Treg signature was higher in tumor tissue of all cancers except liver. Clustering by Treg signature found two groups in colorectal cancer datasets. The high Treg cluster had more samples that were consensus molecular subtype 1/4, right-sided, and microsatellite-instable, compared with the low Treg cluster. Finally, we found that the correlation between signature and IHC was low in our small dataset, but samples in the high Treg cluster had significantly more CD8+ and FoxP3+ cells compared with the low Treg cluster.Conclusions: Treg gene expression is highly indicative of the overall tumor immune environment.Impact: In comparison with the consensus molecular subtype and microsatellite status, the Treg signature identifies more colorectal tumors with high immune activation that may benefit from cancer immunotherapy. Cancer Epidemiol Biomarkers Prev; 27(1); 103-12. (c)2017 AACR. PMID- 29133368 TI - Transcription Factors VND1-VND3 Contribute to Cotyledon Xylem Vessel Formation. AB - Arabidopsis (Arabidopsis thaliana) VASCULAR-RELATED NAC-DOMAIN1 (VND1) to VND7 encode a group of NAC domain transcription factors that function as master regulators of xylem vessel element differentiation. These transcription factors activate the transcription of genes required for secondary cell wall formation and programmed cell death, key events in xylem vessel element differentiation. Because constitutive overexpression of VND6 and VND7 induces ectopic xylem vessel element differentiation, functional studies of VND proteins have largely focused on these two proteins. Here, we report the roles of VND1, VND2, and VND3 in xylem vessel formation in cotyledons. Using our newly established in vitro system in which excised Arabidopsis cotyledons are stimulated to undergo xylem cell differentiation by cytokinin, auxin, and brassinosteroid treatment, we found that ectopic xylem vessel element differentiation required VND1, VND2, and VND3 but not VND6 or VND7. The importance of VND1, VND2, and VND3 also was indicated in vivo; in the vnd1 vnd2 vnd3 seedlings, xylem vessel element differentiation of secondary veins in cotyledons was inhibited under dark conditions. Furthermore, the light responsiveness of VND gene expression was disturbed in the vnd1 vnd2 vnd3 mutant, and vnd1 vnd2 vnd3 failed to recover lateral root development in response to the change of light conditions. These findings suggest that VND1 to VND3 have specific molecular functions, possibly linking light conditions to xylem vessel formation, during seedling development. PMID- 29133369 TI - Transcription Factor WRKY75 Interacts with DELLA Proteins to Affect Flowering. AB - Flowering time is tightly controlled by both endogenous and exogenous signals. Although several lines of evidence have suggested the involvement of WRKY transcription factors in floral initiation, the underlying mechanisms and signaling pathways involved remain elusive. Here, we newly identified Arabidopsis (Arabidopsis thaliana) WRKY DNA binding protein75 (WRKY75) as a positive regulator of flowering initiation. Mutation of WRKY75 resulted in a delay in flowering, whereas overexpression of WRKY75 significantly accelerated flowering in Arabidopsis. Gene expression analysis showed that the transcript abundance of the flowering time integrator gene FLOWERING LOCUS T (FT) was lower in wrky75 mutants than in the wild type, but greater in WRKY75-overexpressing plants. Chromatin immunoprecipitation assays revealed that WRKY75 directly binds to the promoter of FT Both in vivo and in vitro biochemical analyses demonstrated that WRKY75 interacts with DELLA proteins. We found that both REPRESSOR OF ga1-3 (RGA) RGA-LIKE1 (RGL1) and GA INSENSITIVE (GAI) can repress the activation ability of WRKY75, thereby attenuating expression of its regulon. Genetic analyses indicated that WRKY75 positively regulates flowering in a FT-dependent manner and overexpression of RGL1 or gain-of-function of GAI could partially rescue the early flowering phenotype of WRKY75-overexpressing plants. Taken together, our results demonstrate that WRKY75 may function as a new component of the GA mediated signaling pathway to positively regulate flowering in Arabidopsis. PMID- 29133370 TI - A Mucin-Like Protein of Planthopper Is Required for Feeding and Induces Immunity Response in Plants. AB - The brown planthopper, Nilaparvata lugens, is a pest that threatens rice (Oryza sativa) production worldwide. While feeding on rice plants, planthoppers secrete saliva, which plays crucial roles in nutrient ingestion and modulating plant defense responses, although the specific functions of salivary proteins remain largely unknown. We identified an N. lugens-secreted mucin-like protein (NlMLP) by transcriptome and proteome analyses and characterized its function, both in brown planthopper and in plants. NlMLP is highly expressed in salivary glands and is secreted into rice during feeding. Inhibition of NlMLP expression in planthoppers disturbs the formation of salivary sheaths, thereby reducing their performance. In plants, NlMLP induces cell death, the expression of defense related genes, and callose deposition. These defense responses are related to Ca2+ mobilization and the MEK2 MAP kinase and jasmonic acid signaling pathways. The active region of NlMLP that elicits plant responses is located in its carboxyl terminus. Our work provides a detailed characterization of a salivary protein from a piercing-sucking insect other than aphids. Our finding that the protein functions in plant immune responses offers new insights into the mechanism underlying interactions between plants and herbivorous insects. PMID- 29133371 TI - Turnip Mosaic Virus Counteracts Selective Autophagy of the Viral Silencing Suppressor HCpro. AB - Autophagy is a conserved intracellular degradation pathway and has emerged as a key mechanism of antiviral immunity in metazoans, including the selective elimination of viral components. In turn, some animal viruses are able to escape and modulate autophagy for enhanced pathogenicity. Whether host autophagic responses and viral countermeasures play similar roles in plant-virus interactions is not well understood. Here, we have identified selective autophagy as antiviral pathway during plant infection with turnip mosaic virus (TuMV), a positive-stranded RNA potyvirus. We show that the autophagy cargo receptor NBR1 suppresses viral accumulation by targeting the viral RNA silencing suppressor helper-component proteinase (HCpro), presumably in association with virus-induced RNA granules. Intriguingly, TuMV seems to antagonize NBR1-dependent autophagy during infection by the activity of distinct viral proteins, thereby limiting its antiviral capacity. We also found that NBR1-independent bulk autophagy prevents premature plant death, thus extending the lifespan of virus reservoirs and particle production. Together, our study highlights a conserved role of selective autophagy in antiviral immunity and suggests the evolvement of viral protein functions to inhibit autophagy processes, despite a potential trade-off in host survival. PMID- 29133372 TI - Gradually Decreasing Starch Branching Enzyme Expression Is Responsible for the Formation of Heterogeneous Starch Granules. AB - Rice (Oryza sativa) endosperm is mainly occupied by homogeneous polygonal starch from inside to outside. However, morphologically different (heterogeneous) starches have been identified in some rice mutants. How these heterogeneous starches form remains unknown. A high-amylose rice line (TRS) generated through the antisense inhibition of starch branching synthase I (SBEI) and SBEIIb contains four heterogeneous starches: polygonal, aggregate, elongated, and hollow starch; these starches are regionally distributed in the endosperm from inside to outside. Here, we investigated the relationship between SBE dosage and the morphological architecture of heterogeneous starches in TRS endosperm from the view of the molecular structure of starch. The results indicated that their molecular structures underwent regular changes, including gradually increasing true amylose content but decreasing amylopectin content and gradually increasing the ratio of amylopectin long chain but decreasing the ratio of amylopectin short chain. Granule-bound starch synthase I (GBSSI) amounts in the four heterogeneous starches were not significantly different from each other, but SBEI, SBEIIa, and SBEIIb showed a gradually decreasing trend. Further immunostaining analysis revealed that the gradually decreasing SBEs acting on the formation of the four heterogeneous granules were mainly due to the spatial distribution of the three SBEs in the endosperm. It was suggested that the decreased amylopectin in starch might remove steric hindrance and provide extra space for abundant amylose accumulation when the GBSSI amount was not elevated. Furthermore, extra amylose coupled with altered amylopectin structure possibly led to morphological changes in heterogeneous granules. PMID- 29133373 TI - Arabidopsis ACTIN-DEPOLYMERIZING FACTOR3 Is Required for Controlling Aphid Feeding from the Phloem. AB - The actin cytoskeleton network has an important role in plant cell growth, division, and stress response. Actin-depolymerizing factors (ADFs) are a group of actin-binding proteins that contribute to reorganization of the actin network. Here, we show that the Arabidopsis (Arabidopsis thaliana) ADF3 is required in the phloem for controlling infestation by Myzus persicae Sulzer, commonly known as the green peach aphid (GPA), which is an important phloem sap-consuming pest of more than fifty plant families. In agreement with a role for the actin depolymerizing function of ADF3 in defense against the GPA, we show that resistance in adf3 was restored by overexpression of the related ADF4 and the actin cytoskeleton destabilizers, cytochalasin D and latrunculin B. Electrical monitoring of the GPA feeding behavior indicates that the GPA stylets found sieve elements faster when feeding on the adf3 mutant compared to the wild-type plant. In addition, once they found the sieve elements, the GPA fed for a more prolonged period from sieve elements of adf3 compared to the wild-type plant. The longer feeding period correlated with an increase in fecundity and population size of the GPA and a parallel reduction in callose deposition in the adf3 mutant. The adf3-conferred susceptibility to GPA was overcome by expression of the ADF3 coding sequence from the phloem-specific SUC2 promoter, thus confirming the importance of ADF3 function in the phloem. We further demonstrate that the ADF3 dependent defense mechanism is linked to the transcriptional up-regulation of PHYTOALEXIN-DEFICIENT4, which is an important regulator of defenses against the GPA. PMID- 29133374 TI - The RIN-MC Fusion of MADS-Box Transcription Factors Has Transcriptional Activity and Modulates Expression of Many Ripening Genes. AB - Fruit development and ripening is regulated by genetic and environmental factors and is of critical importance for seed dispersal, reproduction, and fruit quality. Tomato (Solanum lycopersicum) ripening inhibitor (rin) mutant fruit have a classic ripening-inhibited phenotype, which is attributed to a genomic DNA deletion resulting in the fusion of two truncated transcription factors, RIN and MC In wild-type fruit, RIN, a MADS-box transcription factor, is a key regulator of the ripening gene expression network, with hundreds of gene targets controlling changes in color, flavor, texture, and taste during tomato fruit ripening; MC, on the other hand, has low expression in fruit, and the potential functions of the RIN-MC fusion gene in ripening remain unclear. Here, overexpression of RIN-MC in transgenic wild-type cv Ailsa Craig tomato fruits impaired several ripening processes, and down-regulating RIN-MC expression in the rin mutant was found to stimulate the normal yellow mutant fruit to produce a weak red color, suggesting a distinct negative role for RIN-MC in tomato fruit ripening. By comparative transcriptome analysis of rin and rin 35S::RIN-MC RNA interference fruits, a total of 1,168 and 1,234 genes were identified as potential targets of RIN-MC activation and inhibition. Furthermore, the RIN-MC fusion gene was shown to be translated into a chimeric transcription factor that was localized to the nucleus and was capable of protein interactions with other MADS-box factors. These results indicated that tomato RIN-MC fusion plays a negative role in ripening and encodes a chimeric transcription factor that modulates the expression of many ripening genes, thereby contributing to the rin mutant phenotype. PMID- 29133375 TI - Spatial Control of Gene Expression by miR319-Regulated TCP Transcription Factors in Leaf Development. AB - The characteristic leaf shapes we see in all plants are in good part the outcome of the combined action of several transcription factor networks that translate into cell division activity during the early development of the organ. We show here that wild-type leaves have distinct transcriptomic profiles in center and marginal regions. Certain transcripts are enriched in margins, including those of CINCINNATA-like TCPs (TEOSINTE BRANCHED, CYCLOIDEA and PCF1/2) and members of the NGATHA and STYLISH gene families. We study in detail the contribution of microRNA319 (miR319)-regulated TCP transcription factors to the development of the center and marginal regions of Arabidopsis (Arabidopsis thaliana) leaves. We compare in molecular analyses the wild type, the tcp2 tcp4 mutant that has enlarged flat leaves, and the tcp2 tcp3 tcp4 tcp10 mutant with strongly crinkled leaves. The different leaf domains of the tcp mutants show changed expression patterns for many photosynthesis-related genes, indicating delayed differentiation, especially in the marginal parts of the organ. At the same time, we found an up-regulation of cyclin genes and other genes that are known to participate in cell division, specifically in the marginal regions of tcp2 tcp3 tcp4 tcp10 Using GUS reporter constructs, we confirmed extended mitotic activity in the tcp2 tcp3 tcp4 tcp10 leaf, which persisted in small defined foci in the margins when the mitotic activity had already ceased in wild-type leaves. Our results describe the role of miR319-regulated TCP transcription factors in the coordination of activities in different leaf domains during organ development. PMID- 29133377 TI - Information provided by diagnostic and screening tests: improving probabilities. AB - Uncertainty in clinical encounters is inevitable and despite this uncertainty clinicians must still work with patients to make diagnostic and treatment decisions. Explicit diagnostic reasoning based on probabilities will optimise information in relation to uncertainty. In clinical diagnostic encounters, there is often pre-existing information that reflects the probability any particular patient has a disease. Diagnostic testing provides extra information that refines diagnostic probabilities. However, in general diagnostic tests will be positive in most, but not all cases of disease (sensitivity) and may not be negative in all cases of disease absence (specificity). Bayes rule is an arithmetic method of using diagnostic testing information to refine diagnostic probabilities. In this method, when probabilities are converted to odds, multiplication of the odds of disease before diagnostic testing, by the positive likelihood ratio (LR+), the sensitivity of a test divided by 1 minus the specificity refines the probability of a particular diagnosis. Similar arithmetic applies to the probability of not having a disease, where the negative likelihood ratio is the specificity divided by 1 minus the sensitivity. A useful diagnostic test is one where the LR+ is greater than 5-10. This can be clarified by creating a contingency table for hypothetical groups of patients in relation to true disease prevalence and test performance predicted by sensitivity and specificity. Most screening tests in populations with a low prevalence of disease have a very high ratio of false positive results to true positive results, which can also be illustrated by contingency tables. PMID- 29133376 TI - Distinct Functions of STARCH SYNTHASE 4 Domains in Starch Granule Formation. AB - The formation of normal starch granules in Arabidopsis (Arabidopsis thaliana) leaf chloroplasts requires STARCH SYNTHASE 4 (SS4). In plants lacking SS4, chloroplasts typically produce only one round granule rather than multiple lenticular granules. The mechanisms by which SS4 determines granule number and morphology are not understood. The N-terminal region of SS4 is unique among SS isoforms and contains several long coiled-coil motifs, typically implicated in protein-protein interactions. The C-terminal region contains the catalytic glucosyltransferase domains, which are widely conserved in plant SS and bacterial glycogen synthase (GS) isoforms. We investigated the specific roles of the N- and C-terminal regions of SS4 by expressing truncated versions of SS4 and a fusion between the N-terminal region of SS4 and GS in the Arabidopsis ss4 mutant. Expression of the N-terminal region of SS4 alone did not alter the ss4 mutant phenotype. Expression of the C-terminal region of SS4 alone increased granule initiation but did not rescue their aberrant round morphology. Expression of a self-priming GS from Agrobacterium tumefaciens also increased the number of round granules. Remarkably, fusion of the N-terminal region of SS4 to A. tumefaciens GS restored the development of wild-type-like lenticular starch granules. Interestingly, the N-terminal region of SS4 alone or when fused to GS conferred a patchy subchloroplastic localization similar to that of the full-length SS4 protein. Considered together, these data suggest that, while the glucosyltransferase activity of SS4 is important for granule initiation, the N terminal part of SS4 serves to establish the correct granule morphology by properly localizing this activity. PMID- 29133378 TI - Grit and tidiness: could what we know help us achieve success? PMID- 29133379 TI - Ventricular Tachycardia in the Setting of Chagasic Cardiomyopathy: Use of Voltage Mapping to Characterize Endoepicardial Nonischemic Scar Distribution. AB - BACKGROUND: Chagasic cardiomyopathy (CC) is the most frequent nonischemic substrate causing left ventricular (LV) tachycardia in Latin America. Systematic characterization of the LV epicardial/endocardial scar distribution and density in CC has not been performed. Additionally, the usefulness of unipolar endocardial electroanatomic mapping to identify epicardial scar has not been assessed in this setting. METHODS AND RESULTS: Nineteen patients with CC undergoing detailed epicardial and endocardial LV tachycardia mapping and ablation were included. A total of 8494 epicardial and 6331 endocardial voltage signals and 314 epicardial/endocardial matched pairs of points were analyzed. Basal lateral LV scar involvement was observed in 18 of 19 patients. Bipolar voltage mapping demonstrated larger epicardial than endocardial scar and core dense (<=0.5 mV) scar areas (28 [20-36] versus 19 [15-26] and 21 [2-49] versus 4 [0-7] cm2; P=0.049 and P=0.004, respectively). Bipolar epicardial and endocardial voltages within scar were low (0.4 [0.2-0.55] and 0.54 [0.33-0.87] mV, respectively) and confluent, indicating a dense/transmural scarring process in CC. The endocardial unipolar voltage value (with a newly proposed <=4-mV cutoff) predicted the presence and extent of epicardial bipolar scar (P<0.001). CONCLUSIONS: CC causes a unique ventricular tachycardia substrate concentrated to the basal lateral LV, with marked epicardial predominance. The scar pattern is particularly dense and transmural as compared with the more erratic/patchy scar patterns seen in other nonischemic cardiomyopathies. Endocardial unipolar voltage mapping serves to characterize epicardial scar in this setting. PMID- 29133381 TI - Endocardial Unipolar Voltage Maps to Identify Epicardial Circuits During Ventricular Tachycardia Ablation in Chagasic Cardiomyopathy: When the Pot of Gold May Not Be at the Other End of the Rainbow. PMID- 29133380 TI - Atrial Substrate and Triggers of Paroxysmal Atrial Fibrillation in Patients With Obstructive Sleep Apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with atrial remodeling, atrial fibrillation (AF), and increased incidence of arrhythmia recurrence after pulmonary vein (PV) isolation. We aimed to characterize the atrial substrate, including AF triggers in patients with paroxysmal AF and OSA. METHODS AND RESULTS: In 86 patients with paroxysmal AF (43 with >=moderate OSA [apnea hypopnea index >=15] and 43 without OSA [apnea-hypopnea index <5]), right atrial and left atrial voltage distribution, conduction velocities, and electrogram characteristics were analyzed during atrial pacing. AF triggers were examined before and after PV isolation and targeted for ablation. Patients with OSA had lower atrial voltage amplitude (right atrial, P=0.0005; left atrial, P=0.0001), slower conduction velocities (right atrial, P=0.02; left atrial, P=0.0002), and higher prevalence of electrogram fractionation (P=0.0001). The areas of atrial abnormality were consistent among patients, most commonly involving the left atrial septum (32/43; 74.4%). At baseline, the PVs were the most frequent triggers for AF in both groups; however, after PV isolation patients with OSA had increased incidence of additional extra-PV triggers (41.8% versus 11.6%; P=0.003). The 1-year arrhythmia-free survival was similar between patients with and without OSA (83.7% and 81.4%, respectively; P=0.59). In comparison, control patients with paroxysmal AF and OSA who underwent PV isolation alone without ablation on extra-PV triggers had increased risk of arrhythmia recurrence (83.7% versus 64.0%; P=0.003). CONCLUSIONS: OSA is associated with structural and functional atrial remodeling and increased incidence of extra-PV triggers. Elimination of these triggers resulted in improved arrhythmia-free survival. PMID- 29133382 TI - Atrial Fibrillation and Obstructive Sleep Apnea: Beyond the Pulmonary Veins. PMID- 29133383 TI - Structured education programme for women with polycystic ovary syndrome: a randomised controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of a structured education programmes in women with polycystic ovary syndrome (PCOS). METHODS: Single-centre, randomised controlled trial, testing a single exposure to a group-based, face-to-face, structured education programme. Inclusion criteria were women with PCOS, aged 18 49 years inclusive and body mass index >=23 kg/m2 for black and minority ethnicities or >=25 kg/m2 for white Europeans. Primary outcome was step-count/day at 12 months. Secondary outcomes included indices of physical activity, cardiovascular risk factors, quality of life (QoL) and illness perception (IP). RESULTS: 161 women were included (78 control, 83 intervention); 69% white; mean age 33.4 (s.d. 7.6) years, of whom 100 (48 intervention; 52 control) attended their 12-month visit (38% attrition). 77% of the intervention arm attended the education programme. No significant change in step-count was observed at 12 months (mean difference: +351 steps/day (95% confidence interval -481, +1183); P = 0.40). No differences were found in biochemical or anthropometric outcomes. The education programme improved participants' IP in 2 dimensions: understanding their PCOS (P < 0.001) and sense of control (P < 0.01) and improved QoL in 3 dimensions: emotions (P < 0.05), fertility (P < 0.05), weight (P < 0.01) and general mental well-being (P < 0.01). DISCUSSION: A single exposure to structured education programme did not increase physical activity or improve biochemical markers in overweight and obese women with PCOS. However, providing a structured education in parallel to routine medical treatment can be beneficial for participants' understanding of their condition, reducing their anxiety and improving their QoL. PMID- 29133384 TI - Estrogen and high-fat diet induced alterations in C57BL/6 mice endometrial transcriptome profile. AB - Unopposed estrogen stimulation and insulin resistance are known to play important roles in endometrial cancer (EC), but the interaction between these two factors and how they contribute to endometrial lesions are not completely elucidated. To investigate the endometrial transcriptome profile and the associated molecular pathway alterations, we established an ovariectomized C57BL/6 mouse model treated with subcutaneous implantation of 17-beta estradiol (E2) pellet and/or high-fat diet (HFD) for 12 weeks to mimic sustained estrogen stimulation and insulin resistance. Histomorphologically, we found that both E2 and E2 + HFD groups showed markedly enlarged uterus and increased number of endometrial glands. The endometrium samples were collected for microarray assay. GO and KEGG analysis showed that genes regulated by E2 and/or HFD are mainly responsible for immune response, inflammatory response and metabolic pathways. Further IPA analysis demonstrated that the acute phase response signaling, NF-kappaB signaling, leukocyte extravasation signaling, PPAR signaling and LXR/RXR activation pathways are mainly involved in the pathways above. In addition, the genes modulated reciprocally by E2 and/or HFD were also analyzed, and their crosstalk mainly focuses on enhancing one another's activity. The combination analysis of microarray data and TCGA database provided potential diagnostic or therapeutic targets for EC. Further validation was performed in mice endometrium and human EC cell lines. In conclusion, this study unraveled the endometrial transcriptome profile alterations affected by E2 and/or HFD that may disturb endometrial homeostasis and contribute to the development of endometrial hyperplasia. PMID- 29133385 TI - Targeted next-generation sequencing of cancer genes in poorly differentiated thyroid cancer. AB - Poorly differentiated thyroid carcinoma (PDTC) is a rare malignancy with higher mortality than well-differentiated thyroid carcinoma. The histological diagnosis can be difficult as well as the therapy. Improved diagnosis and new targeted therapies require knowledge of DNA sequence changes in cancer-relevant genes. The TruSeq Amplicon Cancer Panel was used to screen cancer genomes from 25 PDTC patients for somatic single-nucleotide variants in 48 genes known to represent mutational hotspots. A total of 4490 variants were found in 23 tissue samples of PDTC. Ninety-eight percent (4392) of these variants did not meet the inclusion criteria, while 98 potentially pathogenic or pathogenic variants remained after filtering. These variants were distributed over 33 genes and were all present in a heterozygous state. Five tissue samples harboured not a single variant. Predominantly, variants in P53 (43% of tissue samples) were identified, while less frequently, variants in APC, ERBB4, FLT3, KIT, SMAD4 and BRAF (each in 17% of tissue samples) as well as ATM, EGFR and FBXW7 (each in 13% of tissue samples) were observed. This study identified new potential genetic targets for further research in PDTC. Of particular interest are four observed ERBB4 (alias HER4) variants, which have not been connected to this type of thyroid carcinoma so far. In addition, APC and SMAD4 mutations have not been reported in this subtype of cancer either. In contrast to other reports, we did not find CTNNB1 variants. PMID- 29133386 TI - Restoration of Rostral Ventrolateral Medulla Cystathionine-gamma Lyase Activity Underlies Moxonidine-Evoked Neuroprotection and Sympathoinhibition in Diabetic Rats. AB - We recently demonstrated a fundamental role for cystathionine-gamma lyase (CSE) derived hydrogen sulfide (H2S) in the cardioprotective effect of the centrally acting drug moxonidine in diabetic rats. Whether a downregulated CSE/H2S system in the rostral ventrolateral medulla (RVLM) underlies neuronal oxidative stress and sympathoexcitation in diabetes has not been investigated. Along with addressing this question, we tested the hypothesis that moxonidine prevents the diabetes-evoked neurochemical effects by restoring CSE/H2S function within its major site of action, the RVLM. Ex vivo studies were performed on RVLM tissues of streptozotocin (55 mg/kg, i.p.) diabetic rats treated daily for 3 weeks with moxonidine (2 or 6 mg/kg; gavage), H2S donor sodium hydrosulfide (NaHS) (3.4 mg/kg, i.p.), CSE inhibitor DL-propargylglycine (DLP) (37.5 mg/kg, i.p.), a combination of DLP with moxonidine, or their vehicle. Moxonidine alleviated RVLM oxidative stress, neuronal injury, and increased tyrosine hydroxylase immunoreactivity (sympathoexcitation) by restoring CSE expression/activity as well as heme oxygenase-1 (HO-1) expression. A pivotal role for H2S in moxonidine evoked neuroprotection is supported by the following: 1) NaHS replicated the moxonidine-evoked neuroprotection, and the restoration of RVLM HO-1 expression in diabetic rats; and 2) DLP abolished moxonidine-evoked neuroprotection in diabetic rats, and caused RVLM neurotoxicity, reminiscent of a diabetes-evoked neuronal phenotype, in healthy rats. These findings suggest a novel role for RVLM CSE/H2S/HO-1 in moxonidine-evoked neuroprotection and sympathoinhibition, and as a therapeutic target for developing new drugs for alleviating diabetes-evoked RVLM neurotoxicity and cardiovascular anomalies. PMID- 29133388 TI - Assessing the present and future probability of Hurricane Harvey's rainfall. AB - We estimate, for current and future climates, the annual probability of areally averaged hurricane rain of Hurricane Harvey's magnitude by downscaling large numbers of tropical cyclones from three climate reanalyses and six climate models. For the state of Texas, we estimate that the annual probability of 500 mm of area-integrated rainfall was about 1% in the period 1981-2000 and will increase to 18% over the period 2081-2100 under Intergovernmental Panel on Climate Change (IPCC) AR5 representative concentration pathway 8.5. If the frequency of such event is increasingly linearly between these two periods, then in 2017 the annual probability would be 6%, a sixfold increase since the late 20th century. PMID- 29133387 TI - Insights into functions of the H channel of cytochrome c oxidase from atomistic molecular dynamics simulations. AB - Proton pumping A-type cytochrome c oxidase (CcO) terminates the respiratory chains of mitochondria and many bacteria. Three possible proton transfer pathways (D, K, and H channels) have been identified based on structural, functional, and mutational data. Whereas the D channel provides the route for all pumped protons in bacterial A-type CcOs, studies of bovine mitochondrial CcO have led to suggestions that its H channel instead provides this route. Here, we have studied H-channel function by performing atomistic molecular dynamics simulations on the entire, as well as core, structure of bovine CcO in a lipid-solvent environment. The majority of residues in the H channel do not undergo large conformational fluctuations. Its upper and middle regions have adequate hydration and H-bonding residues to form potential proton-conducting channels, and Asp51 exhibits conformational fluctuations that have been observed crystallographically. In contrast, throughout the simulations, we do not observe transient water networks that could support proton transfer from the N phase toward heme a via neutral His413, regardless of a labile H bond between Ser382 and the hydroxyethylfarnesyl group of heme a In fact, the region around His413 only became sufficiently hydrated when His413 was fixed in its protonated imidazolium state, but its calculated pKa is too low for this to provide the means to create a proton transfer pathway. Our simulations show that the electric dipole moment of residues around heme a changes with the redox state, hence suggesting that the H channel could play a more general role as a dielectric well. PMID- 29133389 TI - Selective killing of Helicobacter pylori with pH-responsive helix-coil conformation transitionable antimicrobial polypeptides. AB - Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix-coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(gamma-6-N-(methyldihexylammonium)hexyl l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues. PMID- 29133390 TI - Recovery of taste organs and sensory function after severe loss from Hedgehog/Smoothened inhibition with cancer drug sonidegib. AB - Striking taste disturbances are reported in cancer patients treated with Hedgehog (HH)-pathway inhibitor drugs, including sonidegib (LDE225), which block the HH pathway effector Smoothened (SMO). We tested the potential for molecular, cellular, and functional recovery in mice from the severe disruption of taste organ biology and taste sensation that follows HH/SMO signaling inhibition. Sonidegib treatment led to rapid loss of taste buds (TB) in both fungiform and circumvallate papillae, including disruption of TB progenitor-cell proliferation and differentiation. Effects were selective, sparing nontaste papillae. To confirm that taste-organ effects of sonidegib treatment result from HH/SMO signaling inhibition, we studied mice with conditional global or epithelium specific Smo deletions and observed similar effects. During sonidegib treatment, chorda tympani nerve responses to lingual chemical stimulation were maintained at 10 d but were eliminated after 16 d, associated with nearly complete TB loss. Notably, responses to tactile or cold stimulus modalities were retained. Further, innervation, which was maintained in the papilla core throughout treatment, was not sufficient to sustain TB during HH/SMO inhibition. Importantly, treatment cessation led to rapid and complete restoration of taste responses within 14 d associated with morphologic recovery in about 55% of TB. However, although taste nerve responses were sustained, TB were not restored in all fungiform papillae even with prolonged recovery for several months. This study establishes a physiologic, selective requirement for HH/SMO signaling in taste homeostasis that includes potential for sensory restoration and can explain the temporal recovery after taste dysgeusia in patients treated with HH/SMO inhibitors. PMID- 29133391 TI - Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme. AB - Populations with large mutation supplies adapt via the "greedy" substitution of the fittest genotype available, leading to fast and repeatable short-term responses. At longer time scales, smaller mutation supplies may in theory lead to larger improvements when distant high-fitness genotypes more readily evolve from lower-fitness intermediates. Here we test for long-term adaptive benefits from small mutation supplies using in vitro evolution of an antibiotic-degrading enzyme in the presence of a novel antibiotic. Consistent with predictions, large mutant libraries cause rapid initial adaptation via the substitution of cohorts of mutations, but show later deceleration and convergence. Smaller libraries show on average smaller initial, but also more variable, improvements, with two lines yielding alleles with exceptionally high resistance levels. These two alleles share three mutations with the large-library alleles, which are known from previous work, but also have unique mutations. Replay evolution experiments and analyses of the adaptive landscape of the enzyme suggest that the benefit resulted from a combination of avoiding mutational cohorts leading to local peaks and chance. Our results demonstrate adaptive benefits from limited mutation supplies on a rugged fitness landscape, which has implications for artificial selection protocols in biotechnology and argues for a better understanding of mutation supplies in clinical settings. PMID- 29133392 TI - Closed-loop control of targeted ultrasound drug delivery across the blood brain/tumor barriers in a rat glioma model. AB - Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood-brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies. PMID- 29133393 TI - Sequential induction of Fur-regulated genes in response to iron limitation in Bacillus subtilis. AB - Bacterial cells modulate transcription in response to changes in iron availability. The ferric uptake regulator (Fur) senses intracellular iron availability and plays a central role in maintaining iron homeostasis in Bacillus subtilis Here we utilized FrvA, a high-affinity Fe2+ efflux transporter from Listeria monocytogenes, as an inducible genetic tool to deplete intracellular iron. We then characterized the responses of the Fur, FsrA, and PerR regulons as cells transition from iron sufficiency to deficiency. Our results indicate that the Fur regulon is derepressed in three distinct waves. First, uptake systems for elemental iron (efeUOB), ferric citrate (fecCDEF), and petrobactin (fpbNOPQ) are induced to prevent iron deficiency. Second, B. subtilis synthesizes its own siderophore bacillibactin (dhbACEBF) and turns on bacillibactin (feuABC) and hydroxamate siderophore (fhuBCGD) uptake systems to scavenge iron from the environment and flavodoxins (ykuNOP) to replace ferredoxins. Third, as iron levels decline further, an "iron-sparing" response (fsrA, fbpAB, and fbpC) is induced to block the translation of abundant iron-utilizing proteins and thereby permit the most essential iron-dependent enzymes access to the limited iron pools. ChIP experiments demonstrate that in vivo occupancy of Fur correlates with derepression of each operon, and the graded response observed here results, at least in part, from higher-affinity binding of Fur to the "late"-induced genes. PMID- 29133394 TI - Role of estrogen receptor beta in neural differentiation of mouse embryonic stem cells. AB - The ability to propagate mature cells and tissue from pluripotent stem cells offers enormous promise for treating many diseases, including neurodegenerative diseases. Before such cells can be used successfully in neurodegenerative diseases without causing unwanted cell growth and migration, genes regulating growth and migration of neural stem cells need to be well characterized. Estrogen receptor beta (ERbeta) is essential for migration of neurons and glial cells in the developing mouse brain. To examine whether ERbeta influences differentiation of mouse embryonic stem cells (mESC) into neural lineages, we compared control and ERbeta knockout (BERKO) mESCs at defined stages of neural development and examined the effects of an ERbeta-selective ligand (LY3201) with a combination of global and targeted gene-expression profiling and the expression of key pluripotency markers. We found that ERbeta was induced in embryoid bodies (EBs) and neural precursor cells (NPCs) during development. Proliferation was higher in BERKO NPCs and was inhibited by LY3201. Neurogenesis was reduced in BERKO ES cells, and oligodendrogliogenesis was enhanced. BERKO EBs expressed higher levels of key ectodermal and neural progenitor markers and lower levels of markers for mesoderm and endoderm lineages. ERbeta-regulated factors are involved in cell adhesion, axon guidance, and signaling of Notch and GABA receptor pathways, as well as factors important for the differentiation of neuronal precursors into dopaminergic neurons (Engrailed 1) and for the oligodendrocyte fate acquisition (Olig2). Our data suggest that ERbeta is an important component for differentiation into midbrain neurons as well as for preventing precocious oligodendrogliogenesis. PMID- 29133395 TI - RNA stem structure governs coupling of dicing and gene silencing in RNA interference. AB - PremicroRNAs (premiRNAs) possess secondary structures consisting of a loop and a stem with multiple mismatches. Despite the well-characterized RNAi pathway, how the structural features of premiRNA contribute to dicing and subsequent gene silencing efficiency remains unclear. Using single-molecule FISH, we demonstrate that cytoplasmic mRNA, but not nuclear mRNA, is reduced during RNAi. The dicing rate and silencing efficiency both increase in a correlated manner as a function of the loop length. In contrast, mismatches in the stem drastically diminish the silencing efficiency without impacting the dicing rate. We show that this decoupling effect is not due to the loading to the RNA-induced silencing complex, RNA uptake, or cellular dicing. We postulate that the stem mismatches perturb the handover of the cleaved miRNAs from Dicer to Argonaute, leading to poor strand selection. Our results imply that the stem structures prevalent in cellular miRNAs have suboptimal silencing efficiency. PMID- 29133397 TI - Skill networks and measures of complex human capital. AB - We propose a network-based method for measuring worker skills. We illustrate the method using data from an online freelance website. Using the tools of network analysis, we divide skills into endogenous categories based on their relationship with other skills in the market. Workers who specialize in these different areas earn dramatically different wages. We then show that, in this market, network based measures of human capital provide additional insight into wages beyond traditional measures. In particular, we show that workers with diverse skills earn higher wages than those with more specialized skills. Moreover, we can distinguish between two different types of workers benefiting from skill diversity: jacks-of-all-trades, whose skills can be applied independently on a wide range of jobs, and synergistic workers, whose skills are useful in combination and fill a hole in the labor market. On average, workers whose skills are synergistic earn more than jacks-of-all-trades. PMID- 29133396 TI - Repression of miR-31 by BCL6 stabilizes the helper function of human follicular helper T cells. AB - Follicular helper T cells (TFHs) are a key component of adaptive immune responses as they help antibody production by B cells. Differentiation and function of TFH cells are controlled by the master gene BCL6, but it is largely unclear how this transcription repressor specifies the TFH program. Here we asked whether BCL6 controlled helper function through down-regulation of specific microRNAs (miRNAs). We first assessed miRNA expression in TFH cells and defined a TFH specific miRNA signature. We report that hsa-miR-31-5p (miR-31) is down-regulated in TFH; we showed that BCL6 suppresses miR-31 expression by binding to its promoter; and we demonstrated that miR-31 inhibits the expression of molecules that control T-helper function, such as CD40L and SAP. These findings identify a BCL6-initiated inhibitory circuit that stabilizes the follicular helper T cell program at least in part through the control of miRNA transcription. Although BCL6 controls TFH activity in human and mouse, the role of miR-31 is restricted to human TFH cell differentiation, reflecting a species specificity of the miR-31 action. Our findings highlight miR-31 as a possible target to modulate human T cell dependent antibody responses in the settings of infection, vaccination, or immune dysregulation. PMID- 29133398 TI - Analysis of high-resolution 3D intrachromosomal interactions aided by Bayesian network modeling. AB - Long-range intrachromosomal interactions play an important role in 3D chromosome structure and function, but our understanding of how various factors contribute to the strength of these interactions remains poor. In this study we used a recently developed analysis framework for Bayesian network (BN) modeling to analyze publicly available datasets for intrachromosomal interactions. We investigated how 106 variables affect the pairwise interactions of over 10 million 5-kb DNA segments in the B-lymphocyte cell line GB12878. Strictly data driven BN modeling indicates that the strength of intrachromosomal interactions (hic_strength) is directly influenced by only four types of factors: distance between segments, Rad21 or SMC3 (cohesin components),transcription at transcription start sites (TSS), and the number of CCCTC-binding factor (CTCF) cohesin complexes between the interacting DNA segments. Subsequent studies confirmed that most high-intensity interactions have a CTCF-cohesin complex in at least one of the interacting segments. However, 46% have CTCF on only one side, and 32% are without CTCF. As expected, high-intensity interactions are strongly dependent on the orientation of the ctcf motif, and, moreover, we find that the interaction between enhancers and promoters is similarly dependent on ctcf motif orientation. Dependency relationships between transcription factors were also revealed, including known lineage-determining B-cell transcription factors (e.g., Ebf1) as well as potential novel relationships. Thus, BN analysis of large intrachromosomal interaction datasets is a useful tool for gaining insight into DNA-DNA, protein-DNA, and protein-protein interactions. PMID- 29133399 TI - Reply to Breuer et al.: Molecular dynamics simulations do not provide functionally relevant values of redox potential in MtrF. PMID- 29133400 TI - Redox potentials in the decaheme cytochrome MtrF: Poisson-Boltzmann vs. molecular dynamics simulations. PMID- 29133401 TI - Multiple Legionella pneumophila effector virulence phenotypes revealed through high-throughput analysis of targeted mutant libraries. AB - Legionella pneumophila is the causative agent of a severe pneumonia called Legionnaires' disease. A single strain of L. pneumophila encodes a repertoire of over 300 different effector proteins that are delivered into host cells by the Dot/Icm type IV secretion system during infection. The large number of L. pneumophila effectors has been a limiting factor in assessing the importance of individual effectors for virulence. Here, a transposon insertion sequencing technology called INSeq was used to analyze replication of a pool of effector mutants in parallel both in a mouse model of infection and in cultured host cells. Loss-of-function mutations in genes encoding effector proteins resulted in host-specific or broad virulence phenotypes. Screen results were validated for several effector mutants displaying different virulence phenotypes using genetic complementation studies and infection assays. Specifically, loss-of-function mutations in the gene encoding LegC4 resulted in enhanced L. pneumophila in the lungs of infected mice but not within cultured host cells, which indicates LegC4 augments bacterial clearance by the host immune system. The effector proteins RavY and Lpg2505 were important for efficient replication within both mammalian and protozoan hosts. Further analysis of Lpg2505 revealed that this protein functions as a metaeffector that counteracts host cytotoxicity displayed by the effector protein SidI. Thus, this study identified a large cohort of effectors that contribute to L. pneumophila virulence positively or negatively and has demonstrated regulation of effector protein activities by cognate metaeffectors as being critical for host pathogenesis. PMID- 29133402 TI - Assigning chemoreceptors to chemosensory pathways in Pseudomonas aeruginosa. AB - In contrast to Escherichia coli, a model organism for chemotaxis that has 5 chemoreceptors and a single chemosensory pathway, Pseudomonas aeruginosa PAO1 has a much more complex chemosensory network, which consists of 26 chemoreceptors feeding into four chemosensory pathways. While several chemoreceptors were rigorously linked to specific pathways in a series of experimental studies, for most of them this information is not available. Thus, we addressed the problem computationally. Protein-protein interaction network prediction, coexpression data mining, and phylogenetic profiling all produced incomplete and uncertain assignments of chemoreceptors to pathways. However, comparative sequence analysis specifically targeting chemoreceptor regions involved in pathway interactions revealed conserved sequence patterns that enabled us to unambiguously link all 26 chemoreceptors to four pathways. Placing computational evidence in the context of experimental data allowed us to conclude that three chemosensory pathways in P. aeruginosa utilize one chemoreceptor per pathway, whereas the fourth pathway, which is the main system controlling chemotaxis, utilizes the other 23 chemoreceptors. Our results show that while only a very few amino acid positions in receptors, kinases, and adaptors determine their pathway specificity, assigning receptors to pathways computationally is possible. This requires substantial knowledge about interacting partners on a molecular level and focusing comparative sequence analysis on the pathway-specific regions. This general principle should be applicable to resolving many other receptor-pathway interactions. PMID- 29133404 TI - Correction for Sansone et al., Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. PMID- 29133403 TI - Parochial trust and cooperation across 17 societies. AB - International challenges such as climate change, poverty, and intergroup conflict require countries to cooperate to solve these complex problems. However, the political tide in many countries has shifted inward, with skepticism and reluctance to cooperate with other countries. Thus, cross-societal investigations are needed to test theory about trust and cooperation within and between groups. We conducted an experimental study in 17 countries designed to test several theories that explain why, who, and where people trust and cooperate more with ingroup members, compared with outgroup members. The experiment involved several interactions in the trust game, either as a trustor or trustee. We manipulated partner group membership in the trust game (ingroup, outgroup, or unknown) and if their reputation was at stake during the interaction. In addition to the standard finding that participants trust and cooperate more with ingroup than outgroup members, we obtained findings that reputational concerns play a decisive role for promoting trust and cooperation universally across societies. Furthermore, men discriminated more in favor of their ingroup than women. Individual differences in cooperative preferences, as measured by social value orientation, predicted cooperation with both ingroup and outgroup members. Finally, we did not find support for three theories about the cross-societal conditions that influence the degree of ingroup favoritism observed across societies (e.g., material security, religiosity, and pathogen stress). We discuss the implications for promoting cooperation within and between countries. PMID- 29133405 TI - Parallel magnetic field suppresses dissipation in superconducting nanostrips. AB - The motion of Abrikosov vortices in type-II superconductors results in a finite resistance in the presence of an applied electric current. Elimination or reduction of the resistance via immobilization of vortices is the "holy grail" of superconductivity research. Common wisdom dictates that an increase in the magnetic field escalates the loss of energy since the number of vortices increases. Here we show that this is no longer true if the magnetic field and the current are applied parallel to each other. Our experimental studies on the resistive behavior of a superconducting Mo0.79Ge0.21 nanostrip reveal the emergence of a dissipative state with increasing magnetic field, followed by a pronounced resistance drop, signifying a reentrance to the superconducting state. Large-scale simulations of the 3D time-dependent Ginzburg-Landau model indicate that the intermediate resistive state is due to an unwinding of twisted vortices. When the magnetic field increases, this instability is suppressed due to a better accommodation of the vortex lattice to the pinning configuration. Our findings show that magnetic field and geometrical confinement can suppress the dissipation induced by vortex motion and thus radically improve the performance of superconducting materials. PMID- 29133407 TI - Correction for Danhart et al., Conformational and chemical selection by a trans acting editing domain. PMID- 29133406 TI - Proteome-wide modulation of degradation dynamics in response to growth arrest. AB - In dividing cells, cytoplasmic dilution is the dominant route of clearance for long-lived proteins whose inherent degradation is slower than the cellular growth rate. Thus, as cells transition from a dividing to a nondividing state, there is a propensity for long-lived proteins to become stabilized relative to short-lived proteins, leading to alterations in the abundance distribution of the proteome. However, it is not known if cells mount a compensatory response to counter this potentially deleterious proteostatic disruption. We used a proteomic approach to demonstrate that fibroblasts selectively increase degradation rates of long-lived proteins as they transition from a proliferating to a quiescent state. The selective degradation of long-lived proteins occurs by the concurrent activation of lysosomal biogenesis and up-regulation of macroautophagy. Through this mechanism, quiescent cells avoid the accumulation of aged long-lived proteins that would otherwise result from the absence of cytoplasmic dilution by cell division. PMID- 29133408 TI - Ecosystem management and land conservation can substantially contribute to California's climate mitigation goals. AB - Modeling efforts focused on future greenhouse gas (GHG) emissions from energy and other sectors in California have shown varying capacities to meet the emissions reduction targets established by the state. These efforts have not included potential reductions from changes in ecosystem management, restoration, and conservation. We examine the scale of contributions from selected activities in natural and agricultural lands and assess the degree to which these actions could help the state achieve its 2030 and 2050 climate mitigation goals under alternative implementation scenarios. By 2030, an Ambitious implementation scenario could contribute as much as 147 MMTCO2e or 17.4% of the cumulative reductions needed to meet the state's 2030 goal, greater than the individual projected contributions of four other economic sectors, including those from the industrial and agricultural sectors. On an annual basis, the Ambitious scenario could result in reductions as high as 17.9 MMTCO2e?y-1 or 13.4% of the state's 2030 reduction goal. Most reductions come from changes in forest management (61% of 2050 projected cumulative reductions under the Ambitious scenario), followed by reforestation (14%), avoided conversion (11%), compost amendments to grasslands (9%), and wetland and grassland restoration (5%). Implementation of a range of land-based emissions reduction activities can materially contribute to one of the most ambitious mitigation targets globally. This study provides a flexible, dynamic framework for estimating the reductions achievable through land conservation, ecological restoration, and changes in management regimes. PMID- 29133409 TI - Psychological targeting as an effective approach to digital mass persuasion. AB - People are exposed to persuasive communication across many different contexts: Governments, companies, and political parties use persuasive appeals to encourage people to eat healthier, purchase a particular product, or vote for a specific candidate. Laboratory studies show that such persuasive appeals are more effective in influencing behavior when they are tailored to individuals' unique psychological characteristics. However, the investigation of large-scale psychological persuasion in the real world has been hindered by the questionnaire based nature of psychological assessment. Recent research, however, shows that people's psychological characteristics can be accurately predicted from their digital footprints, such as their Facebook Likes or Tweets. Capitalizing on this form of psychological assessment from digital footprints, we test the effects of psychological persuasion on people's actual behavior in an ecologically valid setting. In three field experiments that reached over 3.5 million individuals with psychologically tailored advertising, we find that matching the content of persuasive appeals to individuals' psychological characteristics significantly altered their behavior as measured by clicks and purchases. Persuasive appeals that were matched to people's extraversion or openness-to-experience level resulted in up to 40% more clicks and up to 50% more purchases than their mismatching or unpersonalized counterparts. Our findings suggest that the application of psychological targeting makes it possible to influence the behavior of large groups of people by tailoring persuasive appeals to the psychological needs of the target audiences. We discuss both the potential benefits of this method for helping individuals make better decisions and the potential pitfalls related to manipulation and privacy. PMID- 29133410 TI - Unprecedented pathway of reducing equivalents in a diflavin-linked disulfide oxidoreductase. AB - Flavoproteins participate in a wide variety of physiologically relevant processes that typically involve redox reactions. Within this protein superfamily, there exists a group that is able to transfer reducing equivalents from FAD to a redox active disulfide bridge, which further reduces disulfide bridges in target proteins to regulate their structure and function. We have identified a previously undescribed type of flavin enzyme that is exclusive to oxygenic photosynthetic prokaryotes and that is based on the primary sequence that had been assigned as an NADPH-dependent thioredoxin reductase (NTR). However, our experimental data show that the protein does not transfer reducing equivalents from flavins to disulfides as in NTRs but functions in the opposite direction. High-resolution structures of the protein from Gloeobacter violaceus and Synechocystis sp. PCC6803 obtained by X-ray crystallography showed two juxtaposed FAD molecules per monomer in redox communication with an active disulfide bridge in a variant of the fold adopted by NTRs. We have tentatively named the flavoprotein "DDOR" (diflavin-linked disulfide oxidoreductase) and propose that its activity is linked to a thiol-based transfer of reducing equivalents in bacterial membranes. These findings expand the structural and mechanistic repertoire of flavoenzymes with oxidoreductase activity and pave the way to explore new protein engineering approaches aimed at designing redox-active proteins for diverse biotechnological applications. PMID- 29133411 TI - Specific inhibition of GPCR-independent G protein signaling by a rationally engineered protein. AB - Activation of heterotrimeric G proteins by cytoplasmic nonreceptor proteins is an alternative to the classical mechanism via G protein-coupled receptors (GPCRs). A subset of nonreceptor G protein activators is characterized by a conserved sequence named the Galpha-binding and activating (GBA) motif, which confers guanine nucleotide exchange factor (GEF) activity in vitro and promotes G protein dependent signaling in cells. GBA proteins have important roles in physiology and disease but remain greatly understudied. This is due, in part, to the lack of efficient tools that specifically disrupt GBA motif function in the context of the large multifunctional proteins in which they are embedded. This hindrance to the study of alternative mechanisms of G protein activation contrasts with the wealth of convenient chemical and genetic tools to manipulate GPCR-dependent activation. Here, we describe the rational design and implementation of a genetically encoded protein that specifically inhibits GBA motifs: GBA inhibitor (GBAi). GBAi was engineered by introducing modifications in Galphai that preclude coupling to every known major binding partner [GPCRs, Gbetagamma, effectors, guanine nucleotide dissociation inhibitors (GDIs), GTPase-activating proteins (GAPs), or the chaperone/GEF Ric-8A], while favoring high-affinity binding to all known GBA motifs. We demonstrate that GBAi does not interfere with canonical GPCR G protein signaling but blocks GBA-dependent signaling in cancer cells. Furthermore, by implementing GBAi in vivo, we show that GBA-dependent signaling modulates phenotypes during Xenopus laevis embryonic development. In summary, GBAi is a selective, efficient, and convenient tool to dissect the biological processes controlled by a GPCR-independent mechanism of G protein activation mediated by cytoplasmic factors. PMID- 29133412 TI - Cell-autonomous adiposity through increased cell surface GLUT4 due to ankyrin-B deficiency. AB - Obesity typically is linked to caloric imbalance as a result of overnutrition. Here we propose a cell-autonomous mechanism for adiposity as a result of persistent cell surface glucose transporter type 4 (GLUT4) in adipocytes resulting from impaired function of ankyrin-B (AnkB) in coupling GLUT4 to clathrin-mediated endocytosis. Adipose tissue-specific AnkB-KO mice develop obesity and progressive pancreatic islet dysfunction with age or high-fat diet (HFD). AnkB-deficient adipocytes exhibit increased lipid accumulation associated with increased glucose uptake and impaired endocytosis of GLUT4. AnkB binds directly to GLUT4 and clathrin and promotes their association in adipocytes. AnkB variants that fail to restore normal lipid accumulation and GLUT4 localization in adipocytes are present in 1.3% of European Americans and 8.4% of African Americans, and are candidates to contribute to obesity susceptibility in humans. PMID- 29133413 TI - Socioeconomic status and genetic influences on cognitive development. AB - Accurate understanding of environmental moderation of genetic influences is vital to advancing the science of cognitive development as well as for designing interventions. One widely reported idea is increasing genetic influence on cognition for children raised in higher socioeconomic status (SES) families, including recent proposals that the pattern is a particularly US phenomenon. We used matched birth and school records from Florida siblings and twins born in 1994-2002 to provide the largest, most population-diverse consideration of this hypothesis to date. We found no evidence of SES moderation of genetic influence on test scores, suggesting that articulating gene-environment interactions for cognition is more complex and elusive than previously supposed. PMID- 29133415 TI - Phenological shifts conserve thermal niches in North American birds and reshape expectations for climate-driven range shifts. AB - Species respond to climate change in two dominant ways: range shifts in latitude or elevation and phenological shifts of life-history events. Range shifts are widely viewed as the principal mechanism for thermal niche tracking, and phenological shifts in birds and other consumers are widely understood as the principal mechanism for tracking temporal peaks in biotic resources. However, phenological and range shifts each present simultaneous opportunities for temperature and resource tracking, although the possible role for phenological shifts in thermal niche tracking has been widely overlooked. Using a canonical dataset of Californian bird surveys and a detectability-based approach for quantifying phenological signal, we show that Californian bird communities advanced their breeding phenology by 5-12 d over the last century. This phenological shift might track shifting resource peaks, but it also reduces average temperatures during nesting by over 1 degrees C, approximately the same magnitude that average temperatures have warmed over the same period. We further show that early-summer temperature anomalies are correlated with nest success in a continental-scale database of bird nests, suggesting avian thermal niches might be broadly limited by temperatures during nesting. These findings outline an adaptation surface where geographic range and breeding phenology respond jointly to constraints imposed by temperature and resource phenology. By stabilizing temperatures during nesting, phenological shifts might mitigate the need for range shifts. Global change ecology will benefit from further exploring phenological adjustment as a potential mechanism for thermal niche tracking and vice versa. PMID- 29133414 TI - Correlating kinetic and structural data on ubiquinone binding and reduction by respiratory complex I. AB - Respiratory complex I (NADH:ubiquinone oxidoreductase), one of the largest membrane-bound enzymes in mammalian cells, powers ATP synthesis by using the energy from electron transfer from NADH to ubiquinone-10 to drive protons across the energy-transducing mitochondrial inner membrane. Ubiquinone-10 is extremely hydrophobic, but in complex I the binding site for its redox-active quinone headgroup is ~20 A above the membrane surface. Structural data suggest it accesses the site by a narrow channel, long enough to accommodate almost all of its ~50-A isoprenoid chain. However, how ubiquinone/ubiquinol exchange occurs on catalytically relevant timescales, and whether binding/dissociation events are involved in coupling electron transfer to proton translocation, are unknown. Here, we use proteoliposomes containing complex I, together with a quinol oxidase, to determine the kinetics of complex I catalysis with ubiquinones of varying isoprenoid chain length, from 1 to 10 units. We interpret our results using structural data, which show the hydrophobic channel is interrupted by a highly charged region at isoprenoids 4-7. We demonstrate that ubiquinol-10 dissociation is not rate determining and deduce that ubiquinone-10 has both the highest binding affinity and the fastest binding rate. We propose that the charged region and chain directionality assist product dissociation, and that isoprenoid stepping ensures short transit times. These properties of the channel do not benefit the exhange of short-chain quinones, for which product dissociation may become rate limiting. Thus, we discuss how the long channel does not hinder catalysis under physiological conditions and the possible roles of ubiquinone/ubiquinol binding/dissociation in energy conversion. PMID- 29133416 TI - RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth. AB - Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNgamma secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNgamma decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNgamma in the RSK2 KO mice compared with the WT mice. Since IFNgamma is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifngamma gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNgamma expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNgamma mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNgamma mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNgamma signaling. PMID- 29133417 TI - Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction. AB - Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (hRETNTg+) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS) induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of Nippostrongylus brasiliensis (Nb)-infected hRETNTg+ mice after a fatal LPS dose compared with naive mice or Nb-infected hRETNTg- mice. Employing immunoprecipitation assays, hRETNTg+Tlr4-/- mice, and human immune cell culture, we demonstrate that hRetn binds the LPS receptor Toll-like receptor 4 (TLR4) through its N terminal and modulates STAT3 and TBK1 signaling, triggering a switch from proinflammatory to anti-inflammatory responses. Further, we generate hRetn N-terminal peptides that are able to block LPS proinflammatory function. Together, our studies identify a critical role for hRetn in blocking LPS function with important clinical significance in helminth-induced immunomodulation and sepsis. PMID- 29133418 TI - Normalized value coding explains dynamic adaptation in the human valuation process. AB - The notion of subjective value is central to choice theories in ecology, economics, and psychology, serving as an integrated decision variable by which options are compared. Subjective value is often assumed to be an absolute quantity, determined in a static manner by the properties of an individual option. Recent neurobiological studies, however, have shown that neural value coding dynamically adapts to the statistics of the recent reward environment, introducing an intrinsic temporal context dependence into the neural representation of value. Whether valuation exhibits this kind of dynamic adaptation at the behavioral level is unknown. Here, we show that the valuation process in human subjects adapts to the history of previous values, with current valuations varying inversely with the average value of recently observed items. The dynamics of this adaptive valuation are captured by divisive normalization, linking these temporal context effects to spatial context effects in decision making as well as spatial and temporal context effects in perception. These findings suggest that adaptation is a universal feature of neural information processing and offer a unifying explanation for contextual phenomena in fields ranging from visual psychophysics to economic choice. PMID- 29133419 TI - Supercooled and glassy water: Metastable liquid(s), amorphous solid(s), and a no man's land. AB - We review the recent research on supercooled and glassy water, focusing on the possible origins of its complex behavior. We stress the central role played by the strong directionality of the water-water interaction and by the competition between local energy, local entropy, and local density. In this context we discuss the phenomenon of polyamorphism (i.e., the existence of more than one disordered solid state), emphasizing both the role of the preparation protocols and the transformation between the different disordered ices. Finally, we present the ongoing debate on the possibility of linking polyamorphism with a liquid liquid transition that could take place in the no-man's land, the temperature pressure window in which homogeneous nucleation prevents the investigation of water in its metastable liquid form. PMID- 29133420 TI - Resident macrophages of pancreatic islets have a seminal role in the initiation of autoimmune diabetes of NOD mice. AB - Treatment of C57BL/6 or NOD mice with a monoclonal antibody to the CSF-1 receptor resulted in depletion of the resident macrophages of pancreatic islets of Langerhans that lasted for several weeks. Depletion of macrophages in C57BL/6 mice did not affect multiple parameters of islet function, including glucose response, insulin content, and transcriptional profile. In NOD mice depleted of islet-resident macrophages starting at 3 wk of age, several changes occurred: (i) the early entrance of CD4 T cells and dendritic cells into pancreatic islets was reduced, (ii) presentation of insulin epitopes by dispersed islet cells to T cells was impaired, and (iii) the development of autoimmune diabetes was significantly reduced. Treatment of NOD mice starting at 10 wk of age, when the autoimmune process has progressed, also significantly reduced the incidence of diabetes. Despite the absence of diabetes, NOD mice treated with anti-CSF-1 receptor starting at 3 or 10 wk of age still contained variably elevated leukocytic infiltrates in their islets when examined at 20-40 wk of age. Diabetes occurred in the anti-CSF-1 receptor protected mice after treatment with a blocking antibody directed against PD-1. We conclude that treatment of NOD mice with an antibody against CSF-1 receptor reduced diabetes incidence and led to the development of a regulatory pathway that controlled autoimmune progression. PMID- 29133421 TI - Early Neolithic wine of Georgia in the South Caucasus. AB - Chemical analyses of ancient organic compounds absorbed into the pottery fabrics from sites in Georgia in the South Caucasus region, dating to the early Neolithic period (ca. 6,000-5,000 BC), provide the earliest biomolecular archaeological evidence for grape wine and viniculture from the Near East, at ca. 6,000-5,800 BC. The chemical findings are corroborated by climatic and environmental reconstruction, together with archaeobotanical evidence, including grape pollen, starch, and epidermal remains associated with a jar of similar type and date. The very large-capacity jars, some of the earliest pottery made in the Near East, probably served as combination fermentation, aging, and serving vessels. They are the most numerous pottery type at many sites comprising the so-called "Shulaveri Shomutepe Culture" of the Neolithic period, which extends into western Azerbaijan and northern Armenia. The discovery of early sixth millennium BC grape wine in this region is crucial to the later history of wine in Europe and the rest of the world. PMID- 29133422 TI - Nutritional and greenhouse gas impacts of removing animals from US agriculture. AB - As a major contributor to agricultural greenhouse gas (GHG) emissions, it has been suggested that reducing animal agriculture or consumption of animal-derived foods may reduce GHGs and enhance food security. Because the total removal of animals provides the extreme boundary to potential mitigation options and requires the fewest assumptions to model, the yearly nutritional and GHG impacts of eliminating animals from US agriculture were quantified. Animal-derived foods currently provide energy (24% of total), protein (48%), essential fatty acids (23 100%), and essential amino acids (34-67%) available for human consumption in the United States. The US livestock industry employs 1.6 * 106 people and accounts for $31.8 billion in exports. Livestock recycle more than 43.2 * 109 kg of human inedible food and fiber processing byproducts, converting them into human-edible food, pet food, industrial products, and 4 * 109 kg of N fertilizer. Although modeled plants-only agriculture produced 23% more food, it met fewer of the US population's requirements for essential nutrients. When nutritional adequacy was evaluated by using least-cost diets produced from foods available, more nutrient deficiencies, a greater excess of energy, and a need to consume a greater amount of food solids were encountered in plants-only diets. In the simulated system with no animals, estimated agricultural GHG decreased (28%), but did not fully counterbalance the animal contribution of GHG (49% in this model). This assessment suggests that removing animals from US agriculture would reduce agricultural GHG emissions, but would also create a food supply incapable of supporting the US population's nutritional requirements. PMID- 29133423 TI - Gap junctional coupling between retinal amacrine and ganglion cells underlies coherent activity integral to global object perception. AB - Coherent spike activity occurs between widely separated retinal ganglion cells (RGCs) in response to a large, contiguous object, but not to disjointed objects. Since the large spatial separation between the RGCs precludes common excitatory inputs from bipolar cells, the mechanism underlying this long-range coherence remains unclear. Here, we show that electrical coupling between RGCs and polyaxonal amacrine cells in mouse retina forms the synaptic mechanism responsible for long-range coherent activity in the retina. Pharmacological blockade of gap junctions or genetic ablation of connexin 36 (Cx36) subunits eliminates the long-range correlated spiking between RGCs. Moreover, we find that blockade of gap junctions or ablation of Cx36 significantly reduces the ability of mice to discriminate large, global objects from small, disjointed stimuli. Our results indicate that synchronous activity of RGCs, derived from electrical coupling with amacrine cells, encodes information critical to global object perception. PMID- 29133424 TI - Dopamine reward prediction error signal codes the temporal evaluation of a perceptual decision report. AB - Learning to associate unambiguous sensory cues with rewarded choices is known to be mediated by dopamine (DA) neurons. However, little is known about how these neurons behave when choices rely on uncertain reward-predicting stimuli. To study this issue we reanalyzed DA recordings from monkeys engaged in the detection of weak tactile stimuli delivered at random times and formulated a reinforcement learning model based on belief states. Specifically, we investigated how the firing activity of DA neurons should behave if they were coding the error in the prediction of the total future reward when animals made decisions relying on uncertain sensory and temporal information. Our results show that the same signal that codes for reward prediction errors also codes the animal's certainty about the presence of the stimulus and the temporal expectation of sensory cues. PMID- 29133425 TI - Matter wave speckle observed in an out-of-equilibrium quantum fluid. AB - We report the results of the direct comparison of a freely expanding turbulent Bose-Einstein condensate and a propagating optical speckle pattern. We found remarkably similar statistical properties underlying the spatial propagation of both phenomena. The calculated second-order correlation together with the typical correlation length of each system is used to compare and substantiate our observations. We believe that the close analogy existing between an expanding turbulent quantum gas and a traveling optical speckle might burgeon into an exciting research field investigating disordered quantum matter. PMID- 29133426 TI - Mechanism of SOA formation determines magnitude of radiative effects. AB - Secondary organic aerosol (SOA) nearly always exists as an internal mixture, and the distribution of this mixture depends on the formation mechanism of SOA. A model is developed to examine the influence of using an internal mixing state based on the mechanism of formation and to estimate the radiative forcing of SOA in the future. For the present day, 66% of SOA is internally mixed with sulfate, while 34% is internally mixed with primary soot. Compared with using an external mixture, the direct effect of SOA is decreased due to the decrease in total aerosol surface area and the increase of absorption efficiency. Aerosol number concentrations are sharply reduced, and this is responsible for a large decrease in the cloud albedo effect. Internal mixing decreases the radiative effect of SOA by a factor of >4 compared with treating SOA as an external mixture. The future SOA burden increases by 24% due to CO2 increases and climate change, leading to a total (direct plus cloud albedo) radiative forcing of -0.05 W m-2 When the combined effects of changes in climate, anthropogenic emissions, and land use are included, the SOA forcing is -0.07 W m-2, even though the SOA burden only increases by 6.8%. This is caused by the substantial increase of SOA associated with sulfate in the Aitken mode. The Aitken mode increase contributes to the enhancement of first indirect radiative forcing, which dominates the total radiative forcing. PMID- 29133427 TI - Phasic inhibition as a mechanism for generation of rapid respiratory rhythms. AB - Central neural networks operate continuously throughout life to control respiration, yet mechanisms regulating ventilatory frequency are poorly understood. Inspiration is generated by the pre-Botzinger complex of the ventrolateral medulla, where it is thought that excitation increases inspiratory frequency and inhibition causes apnea. To test this model, we used an in vitro optogenetic approach to stimulate select populations of hindbrain neurons and characterize how they modulate frequency. Unexpectedly, we found that inhibition was required for increases in frequency caused by stimulation of Phox2b-lineage, putative CO2-chemosensitive neurons. As a mechanistic explanation for inhibition dependent increases in frequency, we found that phasic stimulation of inhibitory neurons can increase inspiratory frequency via postinhibitory rebound. We present evidence that Phox2b-mediated increases in frequency are caused by rebound excitation following an inhibitory synaptic volley relayed by expiration. Thus, although it is widely thought that inhibition between inspiration and expiration simply prevents activity in the antagonistic phase, we instead propose a model whereby inhibitory coupling via postinhibitory rebound excitation actually generates fast modes of inspiration. PMID- 29133428 TI - Intact hemisphere and corpus callosum compensate for visuomotor functions after early visual cortex damage. AB - Unilateral damage to the primary visual cortex (V1) leads to clinical blindness in the opposite visual hemifield, yet nonconscious ability to transform unseen visual input into motor output can be retained, a condition known as "blindsight." Here we combined psychophysics, functional magnetic resonance imaging, and tractography to investigate the functional and structural properties that enable the developing brain to partly overcome the effects of early V1 lesion in one blindsight patient. Visual stimuli appeared in either the intact or blind hemifield and simple responses were given with either the left or right hand, thereby creating conditions where visual input and motor output involve the same or opposite hemisphere. When the V1-damaged hemisphere was challenged by incoming visual stimuli, or controlled manual responses to these unseen stimuli, the corpus callosum (CC) dynamically recruited areas in the visual dorsal stream and premotor cortex of the intact hemisphere to compensate for altered visuomotor functions. These compensatory changes in functional brain activity were paralleled by increased connections in posterior regions of the CC, where fibers connecting homologous areas of the parietal cortex course. PMID- 29133430 TI - The Dual Function of the Polybasic Juxtamembrane Region of Syntaxin 1A in Clamping Spontaneous Release and Stimulating Ca2+-Triggered Release in Neuroendocrine Cells. AB - The exact function of the polybasic juxtamembrane region (5RK) of the plasma membrane neuronal SNARE, syntaxin 1A (Syx), in vesicle exocytosis, although widely studied, is currently not clear. Here, we addressed the role of 5RK in Ca2+-triggered release, using our Syx-based intramolecular fluorescence resonance energy transfer (FRET) probe, which previously allowed us to resolve a depolarization-induced Ca2+-dependent close-to-open transition (CDO) of Syx that occurs concomitant with evoked release, both in PC12 cells and hippocampal neurons and was abolished upon charge neutralization of 5RK. First, using dynamic FRET analysis in PC12 cells, we show that CDO occurs following assembly of SNARE complexes that include the vesicular SNARE, synaptobrevin 2, and that the participation of 5RK in CDO goes beyond its participation in the final zippering of the complex, because mutations of residues adjacent to 5RK, believed to be crucial for final zippering, do not abolish this transition. In addition, we show that CDO is contingent on membrane phosphatidylinositol 4,5-bisphosphate (PIP2), which is fundamental for maintaining regulated exocytosis, as depletion of membranal PIP2 abolishes CDO. Prompted by these results, which underscore a potentially significant role of 5RK in exocytosis, we next amperometrically analyzed catecholamine release from PC12 cells, revealing that charge neutralization of 5RK promotes spontaneous and inhibits Ca2+-triggered release events. Namely, 5RK acts as a fusion clamp, making release dependent on stimulation by Ca2+SIGNIFICANCE STATEMENT Syntaxin 1A (Syx) is a central protein component of the SNARE complex, which underlies neurotransmitter release. Although widely studied in relation to its participation in SNARE complex formation and its interaction with phosphoinositides, the function of Syx's polybasic juxtamembrane region (5RK) remains unclear. Previously, we showed that a conformational transition of Syx, related to calcium-triggered release, reported by a Syx-based FRET probe, is abolished upon charge neutralization of 5RK (5RK/A). Here we show that this conformational transition is dependent on phosphatidylinositol 4,5-bisphosphate (PIP2) and is related to SNARE complex formation. Subsequently, we show that the 5RK/A mutation enhances spontaneous release and inhibits calcium-triggered release in neuroendocrine cells, indicating a previously unrecognized role of 5RK in neurotransmitter release. PMID- 29133429 TI - Microbial pathway for anaerobic 5'-methylthioadenosine metabolism coupled to ethylene formation. AB - Numerous cellular processes involving S-adenosyl-l-methionine result in the formation of the toxic by-product, 5'-methylthioadenosine (MTA). To prevent inhibitory MTA accumulation and retain biologically available sulfur, most organisms possess the "universal" methionine salvage pathway (MSP). However, the universal MSP is inherently aerobic due to a requirement of molecular oxygen for one of the key enzymes. Here, we report the presence of an exclusively anaerobic MSP that couples MTA metabolism to ethylene formation in the phototrophic bacteria Rhodospirillum rubrum and Rhodopseudomonas palustris In vivo metabolite analysis of gene deletion strains demonstrated that this anaerobic MSP functions via sequential action of MTA phosphorylase (MtnP), 5-(methylthio)ribose-1 phosphate isomerase (MtnA), and an annotated class II aldolase-like protein (Ald2) to form 2-(methylthio)acetaldehyde as an intermediate. 2 (Methylthio)acetaldehyde is reduced to 2-(methylthio)ethanol, which is further metabolized as a usable organic sulfur source, generating stoichiometric amounts of ethylene in the process. Ethylene induction experiments using 2 (methylthio)ethanol versus sulfate as sulfur sources further indicate anaerobic ethylene production from 2-(methylthio)ethanol requires protein synthesis and that this process is regulated. Finally, phylogenetic analysis reveals that the genes corresponding to these enzymes, and presumably the pathway, are widespread among anaerobic and facultatively anaerobic bacteria from soil and freshwater environments. These results not only establish the existence of a functional, exclusively anaerobic MSP, but they also suggest a possible route by which ethylene is produced by microbes in anoxic environments. PMID- 29133431 TI - Restoration of Dendritic Complexity, Functional Connectivity, and Diversity of Regenerated Retinal Bipolar Neurons in Adult Zebrafish. AB - Adult zebrafish (Danio rerio) are capable of regenerating retinal neurons that have been lost due to mechanical, chemical, or light damage. In the case of chemical damage, there is evidence that visually mediated behaviors are restored after regeneration, consistent with recovery of retinal function. However, the extent to which regenerated retinal neurons attain appropriate morphologies and circuitry after such tissue-disrupting lesions has not been investigated. Adult zebrafish of both sexes were subjected to intravitreal injections of ouabain, which destroys the inner retina. After retinal regeneration, cell-selective markers, confocal microscopy, morphometrics, and electrophysiology were used to examine dendritic and axonal morphologies, connectivities, and the diversities of each, as well as retinal function, for a subpopulation of regenerated bipolar neurons (BPs). Although regenerated BPs were reduced in numbers, BP dendritic spreads, dendritic tree morphologies, and cone-bipolar connectivity patterns were restored in regenerated retinas, suggesting that regenerated BPs recover accurate input pathways from surviving cone photoreceptors. Morphological measurements of bipolar axons found that numbers and types of stratifications were also restored; however, the thickness of the inner plexiform layer and one measure of axon branching were slightly reduced after regeneration, suggesting some minor differences in the recovery of output pathways to downstream partners. Furthermore, ERG traces from regenerated retinas displayed waveforms matching those of controls, but with reduced b-wave amplitudes. These results support the hypothesis that regenerated neurons of the adult zebrafish retina are capable of restoring complex morphologies and circuitry, suggesting that complex visual functions may also be restored.SIGNIFICANCE STATEMENT Adult zebrafish generate new retinal neurons after a tissue-disrupting lesion. Existing research does not address whether regenerated neurons of adults successfully reconnect with surrounding neurons and establish complex morphologies and functions. We report that, after a chemical lesion that ablates inner retinal neurons, regenerated retinal bipolar neurons (BPs), although reduced in numbers, reconnected to undamaged cone photoreceptors with correct wiring patterns. Regenerated BPs had complex morphologies similar to those within undamaged retina and a physiological measure of photoreceptor-BP connectivity, the ERG, was restored to a normal waveform. This new understanding of neural connectivity, morphology, and physiology suggests that complex functional processing is possible within regenerated adult retina and offers a system for the future study of synaptogenesis during adult retinal regeneration. PMID- 29133433 TI - Attention Priority Map of Face Images in Human Early Visual Cortex. AB - Attention priority maps are topographic representations that are used for attention selection and guidance of task-related behavior during visual processing. Previous studies have identified attention priority maps of simple artificial stimuli in multiple cortical and subcortical areas, but investigating neural correlates of priority maps of natural stimuli is complicated by the complexity of their spatial structure and the difficulty of behaviorally characterizing their priority map. To overcome these challenges, we reconstructed the topographic representations of upright/inverted face images from fMRI BOLD signals in human early visual areas primary visual cortex (V1) and the extrastriate cortex (V2 and V3) based on a voxelwise population receptive field model. We characterized the priority map behaviorally as the first saccadic eye movement pattern when subjects performed a face-matching task relative to the condition in which subjects performed a phase-scrambled face-matching task. We found that the differential first saccadic eye movement pattern between upright/inverted and scrambled faces could be predicted from the reconstructed topographic representations in V1-V3 in humans of either sex. The coupling between the reconstructed representation and the eye movement pattern increased from V1 to V2/3 for the upright faces, whereas no such effect was found for the inverted faces. Moreover, face inversion modulated the coupling in V2/3, but not in V1. Our findings provide new evidence for priority maps of natural stimuli in early visual areas and extend traditional attention priority map theories by revealing another critical factor that affects priority maps in extrastriate cortex in addition to physical salience and task goal relevance: image configuration.SIGNIFICANCE STATEMENT Prominent theories of attention posit that attention sampling of visual information is mediated by a series of interacting topographic representations of visual space known as attention priority maps. Until now, neural evidence of attention priority maps has been limited to studies involving simple artificial stimuli and much remains unknown about the neural correlates of priority maps of natural stimuli. Here, we show that attention priority maps of face stimuli could be found in primary visual cortex (V1) and the extrastriate cortex (V2 and V3). Moreover, representations in extrastriate visual areas are strongly modulated by image configuration. These findings extend our understanding of attention priority maps significantly by showing that they are modulated, not only by physical salience and task-goal relevance, but also by the configuration of stimuli images. PMID- 29133432 TI - Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice. AB - The brainstem locus coeruleus (LC) supplies norepinephrine to the forebrain and degenerates in Alzheimer's disease (AD). Loss of LC neurons is correlated with increased severity of other AD hallmarks, including beta-amyloid (Abeta) plaques, tau neurofibrillary tangles, and cognitive deficits, suggesting that it contributes to the disease progression. Lesions of the LC in amyloid-based transgenic mouse models of AD exacerbate Abeta pathology, neuroinflammation, and cognitive deficits, but it is unknown how the loss of LC neurons affects tau mediated pathology or behavioral abnormalities. Here we investigate the impact of LC degeneration in a mouse model of tauopathy by lesioning the LC of male and female P301S tau transgenic mice with the neurotoxin N-(2-chloroethyl)-N-ethyl bromobenzylamine (DSP-4) starting at 2 months of age. By 6 months, deficits in hippocampal-dependent spatial (Morris water maze) and associative (contextual fear conditioning) memory were observed in lesioned P301S mice while performance remained intact in all other genotype and treatment groups, indicating that tau and LC degeneration act synergistically to impair cognition. By 10 months, the hippocampal neuroinflammation and neurodegeneration typically observed in unlesioned P301S mice were exacerbated by DSP-4, and mortality was also accelerated. These DSP-4-induced changes were accompanied by only a mild aggravation of tau pathology, suggesting that increased tau burden cannot fully account for the effects of LC degeneration. Combined, these experiments demonstrate that loss of LC noradrenergic neurons exacerbates multiple phenotypes caused by pathogenic tau, and provides complementary data to highlight the dual role LC degeneration has on both tau and Abeta pathologies in AD.SIGNIFICANCE STATEMENT Elucidating the mechanisms underlying AD is crucial to developing effective diagnostics and therapeutics. The degeneration of the LC and loss of noradrenergic transmission have been recognized as ubiquitous events in AD pathology, and previous studies demonstrated that LC lesions exacerbate pathology and cognitive deficits in amyloid-based mouse models. Here, we reveal a complementary role of LC degeneration on tau-mediated aspects of the disease by using selective lesions of the LC and the noradrenergic system to demonstrate an exacerbation of cognitive deficits, neuroinflammation, neurodegeneration in a transgenic mouse model of tauopathy. Our data support an integral role for the LC in modulating the severity of both canonical AD-associated pathologies, as well as the detrimental consequences of LC degeneration during disease progression. PMID- 29133434 TI - PKD1 Promotes Functional Synapse Formation Coordinated with N-Cadherin in Hippocampus. AB - Functional synapse formation is critical for the wiring of neural circuits in the developing brain. The cell adhesion molecule N-cadherin plays important roles in target recognition and synaptogenesis. However, the molecular mechanisms that regulate the localization of N-cadherin and the subsequent effects remain poorly understood. Here, we show that protein kinase D1 (PKD1) directly binds to N cadherin at amino acid residues 836-871 and phosphorylates it at Ser 869, 871, and 872, thereby increasing the surface localization of N-cadherin and promoting functional synapse formation in primary cultured hippocampal neurons obtained from embryonic day 18 rat embryos of either sex. Intriguingly, neuronal activity enhances the interactions between N-cadherin and PKD1, which are critical for the activity-dependent growth of dendritic spines. Accordingly, either disruption the binding between N-cadherin and PKD1 or preventing the phosphorylation of N cadherin by PKD1 in the hippocampal CA1 region of male rat leads to the reduction in synapse number and impairment of LTP. Together, this study demonstrates a novel mechanism of PKD1 regulating the surface localization of N-cadherin and suggests that the PKD1-N-cadherin interaction is critical for synapse formation and function.SIGNIFICANCE STATEMENT Defects in synapse formation and function lead to various neurological diseases, although the mechanisms underlying the regulation of synapse development are far from clear. Our results suggest that protein kinase D1 (PKD1) functions upstream of N-cadherin, a classical synaptic adhesion molecule, to promote functional synapse formation. Notably, we identified a crucial binding fragment to PKD1 at C terminus of N-cadherin, and this fragment also contains PKD1 phosphorylation sites. Through this interaction, PKD1 enhances the stability of N-cadherin on cell membrane and promotes synapse morphogenesis and synaptic plasticity in an activity-dependent manner. Our study reveals the role of PKD1 and the potential downstream mechanism in synapse development, and contributes to the research for neurodevelopment and the therapy for neurological diseases. PMID- 29133436 TI - Ventral Midline Thalamus Is Necessary for Hippocampal Place Field Stability and Cell Firing Modulation. AB - The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are reciprocally connected with the hippocampus (Hip) and the medial prefrontal cortex (mPFC). Growing evidence suggests that these nuclei might play a crucial role in cognitive processes requiring Hip-mPFC interactions, including spatial navigation. Here, we tested the effect of ReRh lesions on the firing properties and spatial activity of dorsal hippocampal CA1 place cells as male rats explored a familiar or a novel environment. We found no change in the spatial characteristics of CA1 place cells in the familiar environment following ReRh lesions. Contrariwise, spatial coherence was decreased during the first session in a novel environment. We then investigated field stability of place cells recorded across 5 d both in the familiar and in a novel environment presented in a predefined sequence. While the remapping capacity of the place cells was not affected by the lesion, our results clearly demonstrated a disruption of the CA1 cellular representation of both environments in ReRh rats. More specifically, we found ReRh lesions to produce (1) a pronounced and long-lasting decrease of place field stability and (2) a strong alteration of overdispersion (i.e., firing variability). Thus, in ReRh rats, exploration of a novel environment appears to interfere with the representation of the familiar one, leading to decreased field stability in both environments. The present study shows the involvement of ReRh nuclei in the long-term spatial stability of CA1 place fields.SIGNIFICANCE STATEMENT Growing evidence suggest that the ventral midline thalamic nuclei (reuniens and rhomboid) might play a substantial role in various cognitive tasks including spatial memory. In the present article, we show that the lesions of these nuclei impair the spatial representations encoded by CA1 place cells of both familiar and novel environments. First, reduced variability of place cell firing appears to indicate an impairment of attentional processes. Second, impaired stability of place cell representations could explain the long-term memory deficits observed in previous behavioral studies. PMID- 29133435 TI - Coordinated Plasticity of Synapses and Astrocytes Underlies Practice-Driven Functional Vicariation in Peri-Infarct Motor Cortex. AB - Motor rehabilitative training after stroke can improve motor function and promote topographical reorganization of remaining motor cortical movement representations, but this reorganization follows behavioral improvements. A more detailed understanding of the neural bases of rehabilitation efficacy is needed to inform therapeutic efforts to improve it. Using a rat model of upper extremity impairments after ischemic stroke, we examined effects of motor rehabilitative training at the ultrastructural level in peri-infarct motor cortex. Extensive training in a skilled reaching task promoted improved performance and recovery of more normal movements. This was linked with greater axodendritic synapse density and ultrastructural characteristics of enhanced synaptic efficacy that were coordinated with changes in perisynaptic astrocytic processes in the border region between head and forelimb areas of peri-infarct motor cortex. Disrupting synapses and motor maps by infusions of anisomycin (ANI) into anatomically reorganized motor, but not posterior parietal, cortex eliminated behavioral gains from rehabilitative training. In contrast, ANI infusion in the equivalent cortical region of intact animals had no effect on reaching skills. These results suggest that rehabilitative training efficacy for improving manual skills is mediated by synaptic plasticity in a region of motor cortex that, before lesions, is not essential for manual skills, but becomes so as a result of the training. These findings support that experience-driven synaptic structural reorganization underlies functional vicariation in residual motor cortex after motor cortical infarcts.SIGNIFICANCE STATEMENT Stroke is a leading cause of long-term disability. Motor rehabilitation, the main treatment for physical disability, is of variable efficacy. A better understanding of neural mechanisms underlying effective motor rehabilitation would inform strategies for improving it. Here, we reveal synaptic underpinnings of effective motor rehabilitation. Rehabilitative training improved manual skill in the paretic forelimb and induced the formation of special synapse subtypes in coordination with structural changes in astrocytes, a glial cell that influences neural communication. These changes were found in a region that is nonessential for manual skill in intact animals, but came to mediate this skill due to training after stroke. Therefore, motor rehabilitation efficacy depends on synaptic changes that enable remaining brain regions to assume new functions. PMID- 29133437 TI - Abnormal Microglia and Enhanced Inflammation-Related Gene Transcription in Mice with Conditional Deletion of Ctcf in Camk2a-Cre-Expressing Neurons. AB - CCCTC-binding factor (CTCF) is an 11 zinc finger DNA-binding domain protein that regulates gene expression by modifying 3D chromatin structure. Human mutations in CTCF cause intellectual disability and autistic features. Knocking out Ctcf in mouse embryonic neurons is lethal by neonatal age, but the effects of CTCF deficiency in postnatal neurons are less well studied. We knocked out Ctcf postnatally in glutamatergic forebrain neurons under the control of Camk2a-Cre. CtcfloxP/loxP;Camk2a-Cre+ (Ctcf CKO) mice of both sexes were viable and exhibited profound deficits in spatial learning/memory, impaired motor coordination, and decreased sociability by 4 months of age. Ctcf CKO mice also had reduced dendritic spine density in the hippocampus and cerebral cortex. Microarray analysis of mRNA from Ctcf CKO mouse hippocampus identified increased transcription of inflammation-related genes linked to microglia. Separate microarray analysis of mRNA isolated specifically from Ctcf CKO mouse hippocampal neurons by ribosomal affinity purification identified upregulation of chemokine signaling genes, suggesting crosstalk between neurons and microglia in Ctcf CKO hippocampus. Finally, we found that microglia in Ctcf CKO mouse hippocampus had abnormal morphology by Sholl analysis and increased immunostaining for CD68, a marker of microglial activation. Our findings confirm that Ctcf KO in postnatal neurons causes a neurobehavioral phenotype in mice and provide novel evidence that CTCF depletion leads to overexpression of inflammation-related genes and microglial dysfunction.SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a DNA-binding protein that organizes nuclear chromatin topology. Mutations in CTCF cause intellectual disability and autistic features in humans. CTCF deficiency in embryonic neurons is lethal in mice, but mice with postnatal CTCF depletion are less well studied. We find that mice lacking Ctcf in Camk2a-expressing neurons (Ctcf CKO mice) have spatial learning/memory deficits, impaired fine motor skills, subtly altered social interactions, and decreased dendritic spine density. We demonstrate that Ctcf CKO mice overexpress inflammation-related genes in the brain and have microglia with abnormal morphology that label positive for CD68, a marker of microglial activation. Our findings suggest that inflammation and dysfunctional neuron-microglia interactions are factors in the pathology of CTCF deficiency. PMID- 29133438 TI - Normal Topography and Binocularity of the Superior Colliculus in Strabismus. AB - In subjects with alternating strabismus, either eye can be used to saccade to visual targets. The brain must calculate the correct vector for each saccade, which will depend on the eye chosen to make it. The superior colliculus, a major midbrain center for saccade generation, was examined to determine whether the maps serving each eye were shifted to compensate for strabismus. Alternating exotropia was induced in two male macaques at age 1 month by sectioning the tendons of the medial recti. Once the animals grew to maturity, they were trained to fixate targets with either eye. Receptive fields were mapped in the superior colliculus using a sparse noise stimulus while the monkeys alternated fixation. For some neurons, sparse noise was presented dichoptically to probe for anomalous retinal correspondence. After recordings, microstimulation was applied to compare sensory and motor maps. The data showed that receptive fields were offset in position by the ocular deviation, but otherwise remained aligned. In one animal, the left eye's coordinates were rotated ~20 degrees clockwise with respect to those of the right eye. This was explained by a corresponding cyclorotation of the ocular fundi, which produced an A-pattern deviation. Microstimulation drove the eyes accurately to the site of receptive fields, as in normal animals. Single cell recordings uncovered no evidence for anomalous retinal correspondence. Despite strabismus, neurons remained responsive to stimulation of either eye. Misalignment of the eyes early in life does not alter the organization of topographic maps or disrupt binocular convergence in the superior colliculus.SIGNIFICANCE STATEMENT Patients with strabismus are able to make rapid eye movements, known as saccades, toward visual targets almost as gracefully as subjects with normal binocular alignment. They can even exercise the option of using the right eye or the left eye. It is unknown how the brain measures the degree of ocular misalignment and uses it to compute the appropriate saccade for either eye. The obvious place to investigate is the superior colliculus, a midbrain oculomotor center responsible for the generation of saccades. Here, we report the first experiments in the superior colliculus of awake primates with strabismus using a combination of single-cell recordings and microstimulation to explore the organization of its topographic maps. PMID- 29133439 TI - Re-conceptualizing the origins of life. AB - Over the last several hundred years of scientific progress, we have arrived at a deep understanding of the non-living world. We have not yet achieved an analogous, deep understanding of the living world. The origins of life is our best chance at discovering scientific laws governing life, because it marks the point of departure from the predictable physical and chemical world to the novel, history-dependent living world. This theme issue aims to explore ways to build a deeper understanding of the nature of biology, by modelling the origins of life on a sufficiently abstract level, starting from prebiotic conditions on Earth and possibly on other planets and bridging quantitative frameworks approaching universal aspects of life. The aim of the editors is to stimulate new directions for solving the origins of life. The present introduction represents the point of view of the editors on some of the most promising future directions.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133440 TI - Coarse-graining as a downward causation mechanism. AB - Downward causation is the controversial idea that 'higher' levels of organization can causally influence behaviour at 'lower' levels of organization. Here I propose that we can gain traction on downward causation by being operational and examining how adaptive systems identify regularities in evolutionary or learning time and use these regularities to guide behaviour. I suggest that in many adaptive systems components collectively compute their macroscopic worlds through coarse-graining. I further suggest we move from simple feedback to downward causation when components tune behaviour in response to estimates of collectively computed macroscopic properties. I introduce a weak and strong notion of downward causation and discuss the role the strong form plays in the origins of new organizational levels. I illustrate these points with examples from the study of biological and social systems and deep neural networks.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133441 TI - Universal biology and the statistical mechanics of early life. AB - All known life on the Earth exhibits at least two non-trivial common features: the canonical genetic code and biological homochirality, both of which emerged prior to the Last Universal Common Ancestor state. This article describes recent efforts to provide a narrative of this epoch using tools from statistical mechanics. During the emergence of self-replicating life far from equilibrium in a period of chemical evolution, minimal models of autocatalysis show that homochirality would have necessarily co-evolved along with the efficiency of early-life self-replicators. Dynamical system models of the evolution of the genetic code must explain its universality and its highly refined error minimization properties. These have both been accounted for in a scenario where life arose from a collective, networked phase where there was no notion of species and perhaps even individuality itself. We show how this phase ultimately terminated during an event sometimes known as the Darwinian transition, leading to the present epoch of tree-like vertical descent of organismal lineages. These examples illustrate concrete examples of universal biology: the quest for a fundamental understanding of the basic properties of living systems, independent of precise instantiation in chemistry or other media.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133442 TI - A probabilistic framework for identifying biosignatures using Pathway Complexity. AB - One thing that discriminates living things from inanimate matter is their ability to generate similarly complex or non-random structures in a large abundance. From DNA sequences to folded protein structures, living cells, microbial communities and multicellular structures, the material configurations in biology can easily be distinguished from non-living material assemblies. Many complex artefacts, from ordinary bioproducts to human tools, though they are not living things, are ultimately produced by biological processes-whether those processes occur at the scale of cells or societies, they are the consequences of living systems. While these objects are not living, they cannot randomly form, as they are the product of a biological organism and hence are either technological or cultural biosignatures. A generalized approach that aims to evaluate complex objects as possible biosignatures could be useful to explore the cosmos for new life forms. However, it is not obvious how it might be possible to create such a self contained approach. This would require us to prove rigorously that a given artefact is too complex to have formed by chance. In this paper, we present a new type of complexity measure, which we call 'Pathway Complexity', that allows us not only to threshold the abiotic-biotic divide, but also to demonstrate a probabilistic approach based on object abundance and complexity which can be used to unambiguously assign complex objects as biosignatures. We hope that this approach will not only open up the search for biosignatures beyond the Earth, but also allow us to explore the Earth for new types of biology, and to determine when a complex chemical system discovered in the laboratory could be considered alive.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133443 TI - The thermodynamic efficiency of computations made in cells across the range of life. AB - Biological organisms must perform computation as they grow, reproduce and evolve. Moreover, ever since Landauer's bound was proposed, it has been known that all computation has some thermodynamic cost-and that the same computation can be achieved with greater or smaller thermodynamic cost depending on how it is implemented. Accordingly an important issue concerning the evolution of life is assessing the thermodynamic efficiency of the computations performed by organisms. This issue is interesting both from the perspective of how close life has come to maximally efficient computation (presumably under the pressure of natural selection), and from the practical perspective of what efficiencies we might hope that engineered biological computers might achieve, especially in comparison with current computational systems. Here we show that the computational efficiency of translation, defined as free energy expended per amino acid operation, outperforms the best supercomputers by several orders of magnitude, and is only about an order of magnitude worse than the Landauer bound. However, this efficiency depends strongly on the size and architecture of the cell in question. In particular, we show that the useful efficiency of an amino acid operation, defined as the bulk energy per amino acid polymerization, decreases for increasing bacterial size and converges to the polymerization cost of the ribosome. This cost of the largest bacteria does not change in cells as we progress through the major evolutionary shifts to both single- and multicellular eukaryotes. However, the rates of total computation per unit mass are non monotonic in bacteria with increasing cell size, and also change across different biological architectures, including the shift from unicellular to multicellular eukaryotes.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133444 TI - Exploring astrobiology using in silico molecular structure generation. AB - The origin of life is typically understood as a transition from inanimate or disorganized matter to self-organized, 'animate' matter. This transition probably took place largely in the context of organic compounds, and most approaches, to date, have focused on using the organic chemical composition of modern organisms as the main guide for understanding this process. However, it has gradually come to be appreciated that biochemistry, as we know it, occupies a minute volume of the possible organic 'chemical space'. As the majority of abiotic syntheses appear to make a large set of compounds not found in biochemistry, as well as an incomplete subset of those that are, it is possible that life began with a significantly different set of components. Chemical graph-based structure generation methods allow for exhaustive in silico enumeration of different compound types and different types of 'chemical spaces' beyond those used by biochemistry, which can be explored to help understand the types of compounds biology uses, as well as to understand the nature of abiotic synthesis, and potentially design novel types of living systems.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133445 TI - Conceptualizing the origin of life in terms of evolution. AB - In this opinion piece, we discuss how to place evolution in the context of origin of-life research. Our discussion starts with a popular definition: 'life is a self-sustained chemical system capable of undergoing Darwinian evolution'. According to this definition, the origin of life is the same as the origin of evolution: evolution is the 'end' of the origin of life. This perspective, however, has a limitation, in that the ability of evolution in and of itself is insufficient to explain the origin of life as we know it, as indicated by Spiegelman's and Lincoln and Joyce's experiments. This limitation provokes a crucial question: What conditions are required for replicating systems to evolve into life? From this perspective, the origin of life includes the emergence of life through evolution: evolution is a 'means' of the origin of life. After reviewing Eigen's pioneering work on this question, we mention our ongoing work suggesting that a key condition might be conflicting multi-level evolution. Taken together, there are thus two questions regarding the origin of life: how evolution gets started, and how evolution produces life. Evolution is, therefore, at the centre of the origin of life, where the two lines of enquiry must meet.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133446 TI - Bulk measurements of messy chemistries are needed for a theory of the origins of life. AB - A feature of many of the chemical systems plausibly involved in the origins of terrestrial life is that they are complex and messy-producing a wide range of compounds via a wide range of mechanisms. However, the fundamental behaviour of such systems is currently not well understood; we do not have the tools to make statistical predictions about such complex chemical networks. This is, in part, due to a lack of quantitative data from which such a theory could be built; specifically, functional measurements of messy chemical systems. Here, we propose that the pantheon of experimental approaches to the origins of life should be expanded to include the study of 'functional measurements'-the direct study of bulk properties of chemical systems and their interactions with other compounds, the formation of structures and other behaviours, even in cases where the precise composition and mechanisms are unknown.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133447 TI - Subsumed complexity: abiogenesis as a by-product of complex energy transduction. AB - The origins of life bring into stark relief the inadequacy of our current synthesis of thermodynamic, chemical, physical and information theory to predict the conditions under which complex, living states of organic matter can arise. Origins research has traditionally proceeded under an array of implicit or explicit guiding principles in lieu of a universal formalism for abiogenesis. Within the framework of a new guiding principle for prebiotic chemistry called subsumed complexity, organic compounds are viewed as by-products of energy transduction phenomena at different scales (subatomic, atomic, molecular and polymeric) that retain energy in the form of bonds that inhibit energy from reaching the ground state. There is evidence for an emergent level of complexity that is overlooked in most conceptualizations of abiogenesis that arises from populations of compounds formed from atomic energy input. We posit that different forms of energy input can exhibit different degrees of dissipation complexity within an identical chemical medium. By extension, the maximum capacity for organic chemical complexification across molecular and macromolecular scales subsumes, rather than emerges from, the underlying complexity of energy transduction processes that drive their production and modification.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133448 TI - Origin of life in a digital microcosm. AB - While all organisms on Earth share a common descent, there is no consensus on whether the origin of the ancestral self-replicator was a one-off event or whether it only represented the final survivor of multiple origins. Here, we use the digital evolution system Avida to study the origin of self-replicating computer programs. By using a computational system, we avoid many of the uncertainties inherent in any biochemical system of self-replicators (while running the risk of ignoring a fundamental aspect of biochemistry). We generated the exhaustive set of minimal-genome self-replicators and analysed the network structure of this fitness landscape. We further examined the evolvability of these self-replicators and found that the evolvability of a self-replicator is dependent on its genomic architecture. We also studied the differential ability of replicators to take over the population when competed against each other, akin to a primordial-soup model of biogenesis, and found that the probability of a self-replicator outcompeting the others is not uniform. Instead, progenitor (most recent common ancestor) genotypes are clustered in a small region of the replicator space. Our results demonstrate how computational systems can be used as test systems for hypotheses concerning the origin of life.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133449 TI - Life as an emergent phenomenon: studies from a large-scale boid simulation and web data. AB - A large group with a special structure can become the mother of emergence. We discuss this hypothesis in relation to large-scale boid simulations and web data. In the boid swarm simulations, the nucleation, organization and collapse dynamics were found to be more diverse in larger flocks than in smaller flocks. In the second analysis, large web data, consisting of shared photos with descriptive tags, tended to group together users with similar tendencies, allowing the network to develop a core-periphery structure. We show that the generation rate of novel tags and their usage frequencies are high in the higher-order cliques. In this case, novelty is not considered to arise randomly; rather, it is generated as a result of a large and structured network. We contextualize these results in terms of adjacent possible theory and as a new way to understand collective intelligence. We argue that excessive information and material flow can become a source of innovation.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133451 TI - Chance, necessity and the origins of life: a physical sciences perspective. AB - Earth's 4.5-billion-year history has witnessed a complex sequence of high probability chemical and physical processes, as well as 'frozen accidents'. Most models of life's origins similarly invoke a sequence of chemical reactions and molecular self-assemblies in which both necessity and chance play important roles. Recent research adds two important insights into this discussion. First, in the context of chemical reactions, chance versus necessity is an inherently false dichotomy-a range of probabilities exists for many natural events. Second, given the combinatorial richness of early Earth's chemical and physical environments, events in molecular evolution that are unlikely at limited laboratory scales of space and time may, nevertheless, be inevitable on an Earth like planet at time scales of a billion years.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133450 TI - Resurrecting ancestral genes in bacteria to interpret ancient biosignatures. AB - Two datasets, the geologic record and the genetic content of extant organisms, provide complementary insights into the history of how key molecular components have shaped or driven global environmental and macroevolutionary trends. Changes in global physico-chemical modes over time are thought to be a consistent feature of this relationship between Earth and life, as life is thought to have been optimizing protein functions for the entirety of its approximately 3.8 billion years of history on the Earth. Organismal survival depends on how well critical genetic and metabolic components can adapt to their environments, reflecting an ability to optimize efficiently to changing conditions. The geologic record provides an array of biologically independent indicators of macroscale atmospheric and oceanic composition, but provides little in the way of the exact behaviour of the molecular components that influenced the compositions of these reservoirs. By reconstructing sequences of proteins that might have been present in ancient organisms, we can downselect to a subset of possible sequences that may have been optimized to these ancient environmental conditions. How can one use modern life to reconstruct ancestral behaviours? Configurations of ancient sequences can be inferred from the diversity of extant sequences, and then resurrected in the laboratory to ascertain their biochemical attributes. One way to augment sequence-based, single-gene methods to obtain a richer and more reliable picture of the deep past, is to resurrect inferred ancestral protein sequences in living organisms, where their phenotypes can be exposed in a complex molecular-systems context, and then to link consequences of those phenotypes to biosignatures that were preserved in the independent historical repository of the geological record. As a first step beyond single-molecule reconstruction to the study of functional molecular systems, we present here the ancestral sequence reconstruction of the beta-carbonic anhydrase protein. We assess how carbonic anhydrase proteins meet our selection criteria for reconstructing ancient biosignatures in the laboratory, which we term palaeophenotype reconstruction.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133452 TI - An intermediate level of abstraction for computational systems chemistry. AB - Computational techniques are required for narrowing down the vast space of possibilities to plausible prebiotic scenarios, because precise information on the molecular composition, the dominant reaction chemistry and the conditions for that era are scarce. The exploration of large chemical reaction networks is a central aspect in this endeavour. While quantum chemical methods can accurately predict the structures and reactivities of small molecules, they are not efficient enough to cope with large-scale reaction systems. The formalization of chemical reactions as graph grammars provides a generative system, well grounded in category theory, at the right level of abstraction for the analysis of large and complex reaction networks. An extension of the basic formalism into the realm of integer hyperflows allows for the identification of complex reaction patterns, such as autocatalysis, in large reaction networks using optimization techniques.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133453 TI - Expanding the informational chemistries of life: peptide/RNA networks. AB - The RNA world hypothesis simplifies the complex biopolymer networks underlining the informational and metabolic needs of living systems to a single biopolymer scaffold. This simplification requires abiotic reaction cascades for the construction of RNA, and this chemistry remains the subject of active research. Here, we explore a complementary approach involving the design of dynamic peptide networks capable of amplifying encoded chemical information and setting the stage for mutualistic associations with RNA. Peptide conformational networks are known to be capable of evolution in disease states and of co-opting metal ions, aromatic heterocycles and lipids to extend their emergent behaviours. The coexistence and association of dynamic peptide and RNA networks appear to have driven the emergence of higher-order informational systems in biology that are not available to either scaffold independently, and such mutualistic interdependence poses critical questions regarding the search for life across our Solar System and beyond.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133454 TI - Protoenzymes: the case of hyperbranched polyesters. AB - Enzymes are biopolymeric complexes that catalyse biochemical reactions and shape metabolic pathways. Enzymes usually work with small molecule cofactors that actively participate in reaction mechanisms and complex, usually globular, polymeric structures capable of specific substrate binding, encapsulation and orientation. Moreover, the globular structures of enzymes possess cavities with modulated microenvironments, facilitating the progression of reaction(s). The globular structure is ensured by long folded protein or RNA strands. Synthesis of such elaborate complexes has proven difficult under prebiotically plausible conditions. We explore here that catalysis may have been performed by alternative polymeric structures, namely hyperbranched polymers. Hyperbranched polymers are relatively complex structures that can be synthesized under prebiotically plausible conditions; their globular structure is ensured by virtue of their architecture rather than folding. In this study, we probe the ability of tertiary amine-bearing hyperbranched polyesters to form hydrophobic pockets as a reaction promoting medium for the Kemp elimination reaction. Our results show that polyesters formed upon reaction between glycerol, triethanolamine and organic acid containing hydrophobic groups, i.e. adipic and methylsuccinic acid, are capable of increasing the rate of Kemp elimination by a factor of up to 3 over monomeric triethanolamine.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133455 TI - How causal analysis can reveal autonomy in models of biological systems. AB - Standard techniques for studying biological systems largely focus on their dynamical or, more recently, their informational properties, usually taking either a reductionist or holistic perspective. Yet, studying only individual system elements or the dynamics of the system as a whole disregards the organizational structure of the system-whether there are subsets of elements with joint causes or effects, and whether the system is strongly integrated or composed of several loosely interacting components. Integrated information theory offers a theoretical framework to (1) investigate the compositional cause-effect structure of a system and to (2) identify causal borders of highly integrated elements comprising local maxima of intrinsic cause-effect power. Here we apply this comprehensive causal analysis to a Boolean network model of the fission yeast (Schizosaccharomyces pombe) cell cycle. We demonstrate that this biological model features a non-trivial causal architecture, whose discovery may provide insights about the real cell cycle that could not be gained from holistic or reductionist approaches. We also show how some specific properties of this underlying causal architecture relate to the biological notion of autonomy. Ultimately, we suggest that analysing the causal organization of a system, including key features like intrinsic control and stable causal borders, should prove relevant for distinguishing life from non-life, and thus could also illuminate the origin of life problem.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133457 TI - Listening: a neglected aspect of safe handover. PMID- 29133456 TI - The role of public goods in planetary evolution. AB - Biological public goods are broadly shared within an ecosystem and readily available. They appear to be widespread and may have played important roles in the history of life on Earth. Of particular importance to events in the early history of life are the roles of public goods in the merging of genomes, protein domains and even cells. We suggest that public goods facilitated the origin of the eukaryotic cell, a classic major evolutionary transition. The recognition of genomic public goods challenges advocates of a direct graph view of phylogeny, and those who deny that any useful phylogenetic signal persists in modern genomes. Ecological spillovers generate public goods that provide new ecological opportunities.This article is part of the themed issue 'Reconceptualizing the origins of life'. PMID- 29133458 TI - The responses to the "cancer drugs scandal" must fully involve patients-an essay by Tessa Richards. PMID- 29133459 TI - Pathophysiological changes in the cerebellum and brain stem in a rabbit model after superior petrosal vein sacrifice. AB - In certain surgical procedures, sacrificing the superior petrosal vein (SPV) is required. Previous studies have reported transient cerebellar edema, venous infarction, or hemorrhage that might occur after sectioning of the SPV. The present study investigated the pathophysiological changes in cerebellum and brain stem after SPV sacrifice. Rabbits were divided into the operation group where the SPV was sacrificed and the control group where the SPV remained intact. Each group was further subdivided into 4, 8, 12, 24, 48, and 72 h groups which represented the time period from sacrificing of the SPV to killing of the rabbits. The water content (WC), Na+ content, K+ content, and pathophysiological changes in cerebellum and brain stem tissue were measured. In comparison with the control, the WC and Na+ content of cerebellar tissue were increased in the 4, 8, 12, and 24 h operation subgroups (P<0.05), but only increased in the 4-h subgroup of the brain stem tissue (P<0.05). The K+ content of the cerebellar tissue decreased in the 4, 8, 12, and 24 h operation subgroups (P<0.05) but only decreased in the 4-h subgroup of brain stem tissue (P<0.05). Nissl staining and TEM demonstrated that cerebellar edema occurred in the 4, 8, 12, and 24 h operation subgroups but not in the 48- and 72-h subgroups. Brain stem edema occurred in the 4-h operation subgroup. In summary, cerebellum and brain stem edema can be observed at different time points after sacrificing of the SPV in the rabbit model. PMID- 29133461 TI - Ratings game: an analysis of Nursing Home Compare and Yelp ratings. AB - BACKGROUND: Two strategies for rating the quality of nursing homes (NHs) in the USA are exemplified by the Nursing Home Compare (NHC) website, launched by the federal Centers for Medicare and Medicaid Services in 1998, and Yelp.com, an online consumer review site that has grown in popularity since its founding in 2004. Both sites feature a 5-star rating system. While much is known about NHC ratings, little is known about NH Yelp ratings. This study examines Yelp ratings for NHs in California and compares these ratings with NHC ratings. Understanding how these ratings relate can inform efforts to empower consumers and enhance NH decision-making. METHODS: We collected NHC and Yelp ratings for all California NHs between September and November 2016. For each NH with a Yelp review, we recorded the star rating and the total number of reviews. We also recorded the NHC 5-star rating and NHC ratings for inspections, staffing and quality measures (QMs). We conducted descriptive statistics and frequencies for these variables. We conducted correlations and tested means to compare the ratings. RESULTS: A total of 675 NHs (68.1% of the total sample of 991 NHs) had both Yelp ratings and NHC ratings. Correlations between the Yelp and NHC ratings were relatively weak. The Yelp rating was significantly lower than the 5-star NHC rating and the NHC ratings for staffing and QMs. It was significantly higher than the NHC inspection rating. CONCLUSIONS: This study found that when consumers rate NHs on Yelp, their ratings differ considerably from NHC ratings, a finding in keeping with similar studies of NH quality measurement. Further research is needed to analyse the content of Yelp reviews and compare the themes and topics consumers identify with those reported on NHC. PMID- 29133460 TI - Elevated HuR in Pancreas Promotes a Pancreatitis-Like Inflammatory Microenvironment That Facilitates Tumor Development. AB - Human antigen R (ELAVL1; HuR) is perhaps the best-characterized RNA-binding protein. Through its overexpression in various tumor types, HuR promotes posttranscriptional regulation of target genes in multiple core signaling pathways associated with tumor progression. The role of HuR overexpression in pancreatic tumorigenesis is unknown and led us to explore the consequences of HuR overexpression using a novel transgenic mouse model that has a >2-fold elevation of pancreatic HuR expression. Histologically, HuR-overexpressing pancreas displays a fibroinflammatory response and other pathological features characteristic of chronic pancreatitis. This pathology is reflected in changes in the pancreatic gene expression profile due, in part, to genes whose expression changes as a consequence of direct binding of their respective mRNAs to HuR. Older mice develop pancreatic steatosis and severe glucose intolerance. Elevated HuR cooperated with mutant K-rasG12D to result in a 3.4-fold increase in pancreatic ductal adenocarcinoma (PDAC) incidence compared to PDAC presence in K rasG12D alone. These findings implicate HuR as a facilitator of pancreatic tumorigenesis, especially in the setting of inflammation, and a novel therapeutic target for pancreatitis treatment. PMID- 29133462 TI - Improving PICC use and outcomes in hospitalised patients: an interrupted time series study using MAGIC criteria. AB - BACKGROUND: Although important in clinical care, reports of inappropriate peripherally inserted central catheter (PICC) use are growing. OBJECTIVE: To test whether implementation of the Michigan Appropriateness Guide for Intravenous Catheters (MAGIC) can improve PICC use and patient outcomes. DESIGN: Quasi experimental, interrupted time series design at one study site with nine contemporaneous external controls. SETTING: Ten hospitals participating in a state-wide quality collaborative from 1 August 2014 to 31 July 2016. PATIENTS: 963 hospitalised patients who received a PICC at the study site vs 6613 patients at nine control sites. INTERVENTION: A multimodal intervention (tool, training, electronic changes, education) derived from MAGIC. MEASUREMENTS: Appropriateness of PICC use and rates of PICC-associated complications. Segmented Poisson regression was used for analyses. RESULTS: Absolute rates of inappropriate PICC use decreased substantially at the study site versus controls (91.3% to 65.3% ( 26.0%) vs 72.2% to 69.6% (-2.6%); P<0.001). After adjusting for underlying trends and patient characteristics, however, a marginally significant 13.8% decrease in inappropriate PICC use occurred at the study site (incidence rate ratio 0.86 (95% CI 0.74 to 0.99; P=0.048)); no change was observed at control sites. While the incidence of all PICC complications decreased to a greater extent at the study site, the absolute difference between controls and intervention was small (33.9% to 26.7% (-7.2%) vs 22.4% to 20.8% (-1.6%); P=0.036). LIMITATIONS: Non-randomised design limits inference; the most effective component of the multimodal intervention is unknown; effects following implementation were modest. CONCLUSIONS: In a multihospital quality improvement project, implementation of MAGIC improved PICC appropriateness and reduced complications to a modest extent. Given the size and resources required for this study, future work should consider cost-to-benefit ratio of similar approaches. PMID- 29133463 TI - This ICE/SCRM Melts in the Dark: Light-Dependent COP1-Mediated Protein Degradation in Stomatal Formation. PMID- 29133464 TI - Disarming the Assassins within: Plant Cells Use S-Nitrosylation to Deactivate the HopAI1 Effector. PMID- 29133465 TI - CORTICAL MICROTUBULE DISORDERING1 Is Required for Secondary Cell Wall Patterning in Xylem Vessels. AB - Proper patterning of the cell wall is essential for plant cell development. Cortical microtubule arrays direct the deposition patterns of cell walls at the plasma membrane. However, the precise mechanism underlying cortical microtubule organization is not well understood. Here, we show that a microtubule-associated protein, CORD1 (CORTICAL MICROTUBULE DISORDERING1), is required for the pitted secondary cell wall pattern of metaxylem vessels in Arabidopsis thaliana Loss of CORD1 and its paralog, CORD2, led to the formation of irregular secondary cell walls with small pits in metaxylem vessels, while overexpressing CORD1 led to the formation of abnormally enlarged secondary cell wall pits. Ectopic expression of CORD1 disturbed the parallel cortical microtubule array by promoting the detachment of microtubules from the plasma membrane. A reconstructive approach revealed that CORD1-induced disorganization of cortical microtubules impairs the boundaries of plasma membrane domains of active ROP11 GTPase, which govern pit formation. Our data suggest that CORD1 promotes cortical microtubule disorganization to regulate secondary cell wall pit formation. The Arabidopsis genome has six CORD1 paralogs that are expressed in various tissues during plant development, suggesting they are important for regulating cortical microtubules during plant development. PMID- 29133467 TI - In the Heat of the Moment: ZTL-Mediated Protein Quality Control at High Temperatures. PMID- 29133466 TI - Shine-Dalgarno Sequences Play an Essential Role in the Translation of Plastid mRNAs in Tobacco. AB - In prokaryotic systems, the translation initiation of many, though not all, mRNAs depends on interaction between a sequence element upstream of the start codon (the Shine-Dalgarno sequence [SD]) and a complementary sequence in the 3' end of the 16S rRNA (anti-Shine-Dalgarno sequence [aSD]). Although many chloroplast mRNAs harbor putative SDs in their 5' untranslated regions and the aSD displays strong conservation, the functional relevance of SD-aSD interactions in plastid translation is unclear. Here, by generating transplastomic tobacco (Nicotiana tabacum) mutants with point mutations in the aSD coupled with genome-wide analysis of translation by ribosome profiling, we provide a global picture of SD dependent translation in plastids. We observed a pronounced correlation between weakened predicted SD-aSD interactions and reduced translation efficiency. However, multiple lines of evidence suggest that the strength of the SD-aSD interaction is not the only determinant of the translational output of many plastid mRNAs. Finally, the translation efficiency of mRNAs with strong secondary structures around the start codon is more dependent on the SD-aSD interaction than weakly structured mRNAs. Thus, our data reveal the importance of the aSD in plastid translation initiation, uncover chloroplast genes whose translation is influenced by SD-aSD interactions, and provide insights into determinants of translation efficiency in plastids. PMID- 29133468 TI - Blue Light Perception via Chlorochrome? Give Us the Greens of Summer. PMID- 29133470 TI - Bridging the Global Digital Health Divide for Cardiovascular Disease. PMID- 29133471 TI - Rheumatic Heart Disease: Is Continuum of Care Achievable in Africa? PMID- 29133469 TI - An invisible ubiquitin conformation is required for efficient phosphorylation by PINK1. AB - The Ser/Thr protein kinase PINK1 phosphorylates the well-folded, globular protein ubiquitin (Ub) at a relatively protected site, Ser65. We previously showed that Ser65 phosphorylation results in a conformational change in which Ub adopts a dynamic equilibrium between the known, common Ub conformation and a distinct, second conformation wherein the last beta-strand is retracted to extend the Ser65 loop and shorten the C-terminal tail. We show using chemical exchange saturation transfer (CEST) nuclear magnetic resonance experiments that a similar, C terminally retracted (Ub-CR) conformation also exists at low population in wild type Ub. Point mutations in the moving beta5 and neighbouring beta-strands shift the Ub/Ub-CR equilibrium. This enabled functional studies of the two states, and we show that while the Ub-CR conformation is defective for conjugation, it demonstrates improved binding to PINK1 through its extended Ser65 loop, and is a superior PINK1 substrate. Together our data suggest that PINK1 utilises a lowly populated yet more suitable Ub-CR conformation of Ub for efficient phosphorylation. Our findings could be relevant for many kinases that phosphorylate residues in folded protein domains. PMID- 29133473 TI - Evaluating and Improving Cardiovascular Health System Management in Low- and Middle-Income Countries. PMID- 29133472 TI - Rheumatic Heart Disease Treatment Cascade in Uganda. AB - BACKGROUND: Rheumatic heart disease (RHD) is a leading cause of premature death and disability in low-income countries; however, few receive optimal benzathine penicillin G (BPG) therapy to prevent disease progression. We aimed to comprehensively describe the treatment cascade for RHD in Uganda to identify appropriate targets for intervention. METHODS AND RESULTS: Using data from the Uganda RHD Registry (n=1504), we identified the proportion of patients in the following care categories: (1) diagnosed and alive as of June 1, 2016; (2) retained in care; (3) appropriately prescribed BPG; and (4) optimally adherent to BPG (>80% of prescribed doses). We used logistic regression to investigate factors associated with retention and optimal adherence. Overall, median (interquartile range) age was 23 (15-38) years, 69% were women, and 82% had clinical RHD. Median follow-up time was 2.4 (0.9-4.0) years. Retention in care was the most significant barrier to achieving optimal BPG adherence with only 56.9% (95% confidence interval, 54.1%-59.7%) of living subjects having attended clinic in the prior 56 weeks. Among those retained in care, however, we observed high rates of BPG prescription (91.6%; 95% confidence interval, 89.1%-93.5%) and optimal adherence (91.4%; 95% confidence interval, 88.7-93.5). Younger age, latent disease status, and access to care at a regional center were the strongest independent predictors of retention and optimal adherence. CONCLUSIONS: Our study suggests that improving retention in care-possibly by decentralizing RHD services would have the greatest impact on uptake of antibiotic prophylaxis among patients with RHD in Uganda. PMID- 29133474 TI - How can we prepare better for influenza epidemics? PMID- 29133475 TI - Response to: Comment on l'Ami et al titled 'Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial' by den Broeder et al. PMID- 29133476 TI - Response to: 'Uric acid and incident dementia: a population-based cohort study' by Lee and Song. PMID- 29133477 TI - Reproducibility of Left Ventricular Dimension Versus Area Versus Volume Measurements in Pediatric Patients With Dilated Cardiomyopathy. AB - BACKGROUND: Multiple echocardiographic methods are used to measure left ventricular size and function. Clinical management is based on individual evaluations and longitudinal trends. The Pediatric Heart Network VVV study (Ventricular Volume Variability) in pediatric patients with dilated cardiomyopathy has reported reproducibility of several of these measures, and how disease state and number of beats impact their reproducibility. In this study, we investigated the impact of observer and sonographer variation on reproducibility of dimension, area, and volume methods to determine the best method for both individual and sequential evaluations. METHODS AND RESULTS: In 8 centers, echocardiograms were obtained on 169 patients prospectively. During the same visit, 2 different sonographers acquired the same imaging protocol on each patient. Each acquisition was analyzed by 2 different observers; first observer analyzed the first acquisition twice. Intraobserver, interobserver, interacquisition, and interobserver-acquisition (different observers and different acquisition) reproducibility were assessed on measurements of left ventricular end-diastolic dimension, area, and volume. Left ventricular shortening fraction, ejection fraction, mass, and fractional area change were calculated. Percent difference was calculated as (interobservation difference/mean)*100. Interobserver reproducibility for both acquisitions was better for both volume and dimension measurements (P<=0.002) compared with area measurements, whereas intraobserver, interacquisition (for both observers), and interobserver-acquisition reproducibilities (for both observer-acquisition sets) were best for volume measurements (P<=0.01). Overall, interobserver-acquisition percent differences were significantly higher than interobserver and interacquisition percent differences (P<0.001). CONCLUSIONS: In pediatric patients with dilated cardiomyopathy, compared with dimension and area methods, left ventricular measurements by volume method have the best reproducibility in settings where assessment is not performed by the same personnel. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00123071. PMID- 29133479 TI - Mother With Diabetes Mellitus and Infant With Hypertrophic Obstructive Cardiomyopathy: Milrinone Precluded Need for Extracorporeal Membrane Oxygenation. PMID- 29133478 TI - Clinical Relevance of 18F-Sodium Fluoride Positron-Emission Tomography in Noninvasive Identification of High-Risk Plaque in Patients With Coronary Artery Disease. AB - BACKGROUND: 18F-sodium fluoride (18F-NaF) positron-emission tomography has been introduced as a potential noninvasive imaging tool to identify plaques with high risk characteristics in patients with coronary artery disease. We sought to evaluate the clinical relevance of 18F-NaF uptake using optical coherence tomography (OCT), intravascular ultrasound (IVUS), and coronary computed tomography angiography in patients with coronary artery disease. METHODS AND RESULTS: The target population consisted of 51 prospectively enrolled patients (93 stenoses) who underwent 18F-NaF positron-emission tomography before invasive coronary angiography. 18F-NaF uptake was compared with IVUS- and OCT-derived plaque characteristics. In the coronary computed tomography angiography subgroup (46 lesions), qualitative lesion characteristics were compared between 18F-NaF positive and 18F-NaF-negative plaques using adverse plaque characteristics. The plaques with 18F-NaF uptake showed significantly higher plaque burden, more frequent posterior attenuation and positive remodeling in IVUS, and significantly higher maximum lipid arc and more frequent microvessels in OCT (all P<0.05). There were no differences in minimum lumen area and area of calcium between 18F NaF-positive and 18F-NaF-negative lesions. Among 51 lesions with 18F-NaF-positive uptake, 48 lesions (94.1%) had at least one of high-risk characteristics. The 18F NaF tissue-to-background ratio in plaques with high-risk characteristics was significantly higher than in those without (1.09 [95% confidence interval, 0.85 1.34] versus 0.62 [95% confidence interval, 0.42-0.82], P<0.001 for IVUS definition; 0.76 [95% confidence interval, 0.54-0.98] versus 0.42 [95% confidence interval, 0.21-0.62], P=0.014 for OCT definition). Among the 15 lesions that met both IVUS- and OCT-defined criteria for high-risk plaque, 14 (93.3%) showed 18F NaF-positive uptake. There was no difference in the prevalence of plaques with any adverse plaque characteristics between 18F-NaF-positive and 18F-NaF-negative plaques in the coronary computed tomography angiography subgroup (85.2% versus 78.9%; P=0.583). CONCLUSIONS: This study's results suggest that 18F-NaF positron emission tomography can be a useful noninvasive diagnostic tool to identify and localize plaque with high-risk characteristics. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02388412. PMID- 29133480 TI - Masking and Unmasking of Isolated Noncompaction of the Left Ventricle With Real Time Contrast Echocardiography. PMID- 29133481 TI - 18F-Fluoride Imaging and Other Plaque-Seeking Diagnostic Strategies: Understanding the Reality and Setting the Ground Rules.... PMID- 29133482 TI - Quantification of Left Ventricular Size and Function by 2-Dimensional Echocardiography: So Basic and So Difficult: How to Increase the Accuracy and Reproducibility in Children? PMID- 29133483 TI - cTAGE5 deletion in pancreatic beta cells impairs proinsulin trafficking and insulin biogenesis in mice. AB - Proinsulin is synthesized in the endoplasmic reticulum (ER) in pancreatic beta cells and transported to the Golgi apparatus for proper processing and secretion into plasma. Defects in insulin biogenesis may cause diabetes. However, the underlying mechanisms for proinsulin transport are still not fully understood. We show that beta cell-specific deletion of cTAGE5, also known as Mea6, leads to increased ER stress, reduced insulin biogenesis in the pancreas, and severe glucose intolerance in mice. We reveal that cTAGE5/MEA6 interacts with vesicle membrane soluble N-ethyl-maleimide sensitive factor attachment protein receptor Sec22b. Sec22b and its interaction with cTAGE5/MEA6 are essential for proinsulin processing. cTAGE5/MEA6 may coordinate with Sec22b to control the release of COPII vesicles from the ER, and thereby the ER-to-Golgi trafficking of proinsulin. Importantly, transgenic expression of human cTAGE5/MEA6 in beta cells can rescue not only the defect in islet structure, but also dysfunctional insulin biogenesis and glucose intolerance on cTAGE5/Mea6 conditional knockout background. Together our data provide more insight into the underlying mechanism of the proinsulin trafficking pathway. PMID- 29133484 TI - Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells. AB - Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells. Here, we show that cells have varied abilities to cluster extra centrosomes. Epithelial cells are innately inefficient at clustering even in the presence of HSET/KIFC1, which is essential but not sufficient to promote clustering. The presence of E-cadherin decreases cortical contractility during mitosis through a signaling cascade leading to multipolar divisions, and its knockout promotes clustering and survival of cells with multiple centrosomes. Cortical contractility restricts centrosome movement at a minimal distance required for HSET/KIFC1 to exert its function, highlighting a biphasic model for centrosome clustering. In breast cancer cell lines, increased levels of centrosome amplification are accompanied by efficient clustering and loss of E-cadherin, indicating that this is an important adaptation mechanism to centrosome amplification in cancer. PMID- 29133486 TI - CORRECTION. PMID- 29133485 TI - Pyk2 and FAK differentially regulate invadopodia formation and function in breast cancer cells. AB - The nonreceptor tyrosine kinase Pyk2 is highly expressed in invasive breast cancer, but the mechanism by which it potentiates tumor cell invasiveness is unclear at present. Using high-throughput protein array screening and bioinformatic analysis, we identified cortactin as a novel substrate and interactor of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 colocalizes with cortactin to invadopodia of invasive breast cancer cells, where it mediates epidermal growth factor-induced cortactin tyrosine phosphorylation both directly and indirectly via Src-mediated Abl-related gene (Arg) activation, leading to actin polymerization in invadopodia, extracellular matrix degradation, and tumor cell invasion. Both Pyk2 and the closely related focal adhesion kinase (FAK) regulate tumor cell invasion, albeit via distinct mechanisms. Although Pyk2 regulates tumor cell invasion by controlling invadopodium-mediated functions, FAK controls invasiveness of tumor cells by regulating focal adhesion-mediated motility. Collectively, our findings identify Pyk2 as a unique mediator of invadopodium formation and function and also provide a novel insight into the mechanisms by which Pyk2 mediates tumor cell invasion. PMID- 29133487 TI - Reflections From a Statistical Editor: Elements of Great Manuscripts. PMID- 29133488 TI - Randomized Controlled Trial of Text Message Reminders for Increasing Influenza Vaccination. AB - PURPOSE: Seasonal influenza vaccine is recommended and funded for groups at higher risk of serious infection, but uptake is suboptimal. We conducted a randomized controlled trial of short message service (SMS) reminders for influenza vaccination. METHODS: Six weeks after seasonal influenza vaccinations began, we identified high-risk patients who had a mobile telephone number on record at 10 practices in Western Australia. Thirty-two percent of the selected patients had already been vaccinated in the current year and were ineligible. Of the remaining 12,354 eligible patients at each practice one-half were randomly assigned to receive a vaccination reminder by SMS (intervention) and the rest received no SMS (control). Approximately 3 months after the SMS was sent (the study period), vaccination data were extracted from the patients' electronic medical records. Log-binomial regression models were used to calculate the relative risk (RR) of vaccination between the intervention and control group. RESULTS: Twelve-percent (769 of 6,177) of the intervention group and 9% (548 of 6,177) of the control group were vaccinated during the study period, a 39% relative increase attributable to the SMS (RR = 1.39; 95% CI, 1.26-1.54). For every 29 SMSs sent, costing $3.48, 1 additional high-risk patient was immunized. The greatest effect was observed for children younger than 5 years, whose parents were more than twice as likely to have their child vaccinated if they received a SMS reminder (RR = 2.43; 95% CI, 1.79-3.29). CONCLUSION: We found SMS reminders to be a modestly effective, low-cost means to increase seasonal influenza vaccine coverage among high-risk patients. PMID- 29133489 TI - Continuity of Primary Care and Emergency Hospital Admissions Among Older Patients in England. AB - PURPOSE: Secondary health care services have been under considerable pressure in England as attendance rates increase, resulting in longer waiting times and greater demands on staff. This study's aim was to examine the association between continuity of care and risk of emergency hospital admission among older adults. METHODS: We analyzed records from 10,000 patients aged 65 years and older in 2012 within 297 English general practices obtained from the Clinical Practice Research Datalink and linked with Hospital Episode Statistics. We used the Bice and Boxerman (BB) index and the appointed general practitioner index (last general practitioner consulted before hospitalization) to quantify patient-physician continuity. The BB index was used in a prospective cohort approach to assess impact of continuity on risk of admission. Both indices were used in a separate retrospective nested case-control approach to test the effect of changing physician on the odds of hospital admission in the following 30 days. RESULTS: In the prospective cohort analysis, the BB index showed a graded, non-significant inverse relationship of continuity of care with risk of emergency hospital admission, although the hazard ratio for patients experiencing least continuity was 2.27 (95% CI, 1.37-3.76) compared with those having complete continuity. In the retrospective nested case-control analysis, we found a graded inverse relationship between continuity of care and emergency hospital admission for both BB and appointed general practitioner indices: for the latter, the odds ratio for those experiencing least continuity was 2.32 (95% CI, 1.48-3.63) relative to those experiencing most continuity. CONCLUSIONS: Marked discontinuity of care might contribute to increased unplanned hospital admissions among patients aged 65 years and older. Schemes to enhance continuity of care have the potential to reduce hospital admissions. PMID- 29133490 TI - Auscultation While Standing: A Basic and Reliable Method to Rule Out a Pathologic Heart Murmur in Children. AB - PURPOSE: The distinction between physiologic (innocent) and pathologic (organic) heart murmurs is not always easy in routine practice, leading too often to unnecessary cardiology referrals and expensive investigations. We aimed to test the hypothesis that the complete disappearance of murmur on standing can exclude cardiac disease in children. METHODS: From January 2014 to January 2015, we prospectively included 194 consecutive children aged 2 to 18 years who were referred for heart murmur evaluation to pediatric cardiologists at 2 French medical centers. Heart murmur characteristics while supine and then while standing were recorded, and an echo-cardiogram was performed. RESULTS: Overall, 30 (15%) of the 194 children had a pathologic heart murmur as determined by an abnormal echocardiogram. Among the 100 children (51%) who had a murmur that was present while they were supine but completely disappeared when they stood up, only 2 had a pathologic murmur, and just 1 of them needed further evaluation. Complete disappearance of the heart murmur on standing therefore excluded a pathologic murmur with a high positive predictive value of 98% and specificity of 93%, albeit with a lower sensitivity of 60%. CONCLUSIONS: Disappearance of a heart murmur on standing is a reliable clinical tool for ruling out pathologic heart murmurs in children aged 2 years and older. This basic clinical assessment would avoid many unnecessary referrals to cardiologists. PMID- 29133491 TI - Exploring Attributes of High-Value Primary Care. AB - PURPOSE: Medicare's merit-based incentive payment system and narrowing of physician networks by health insurers will stoke clinicians' and policy makers' interest in care delivery attributes associated with value as defined by payers. METHODS: To help define these attributes, we analyzed 2009 to 2011 commercial health insurance claims data for more than 40 million preferred provider organization patients attributed to over 53,000 primary care practice sites. We identified sites ranking favorably on both quality and low total annual per capita health care spending ("high-value") and sites ranking near the median ("average-value"). Sites were selected for qualitative assessment from 64 high value sites and 102 average-value sites with more than 1 primary care physician who delivered adult primary care and provided services to enough enrollees to permit meaningful spending and quality ranking. Purposeful sampling ensured regional diversity. Physicians experienced in primary care assessment and blinded to site rankings visited 12 high-value sites and 4 average-value sites to identify tangible attributes of care delivery that could plausibly explain a high ranking on value. RESULTS: Thirteen attributes of care delivery distinguished sites in the high-value cohort. Six attributes attained statistical significance: decision support for evidence-based medicine, risk-stratified care management, careful selection of specialists, coordination of care, standing orders and protocols, and balanced physician compensation. CONCLUSIONS: Awareness of care delivery attributes that distinguish their high-value peers may help physicians respond successfully to incentives from Medicare and private payers to lower annual health care spending and improve quality of care. PMID- 29133492 TI - General Practitioner-Performed Compression Ultrasonography for Diagnosis of Deep Vein Thrombosis of the Leg: A Multicenter, Prospective Cohort Study. AB - BACKGROUND: Patients with suspected deep vein thrombosis (DVT) of the lower limb represent a diagnostic dilemma for general practitioners. Compression ultrasonography (US) is universally recognized as the best test of choice. We assessed the diagnostic accuracy of compression US performed by general practitioners given short training in the management of symptomatic proximal DVT. METHODS: From May 2014 to May 2016, we evaluated in a multicenter, prospective cohort study all consecutive outpatients with suspected DVT; bilateral proximal lower limb compression US was performed by general practitioners and by physicians expert in vascular US, each group blinded to the other's findings. In all examinations with a negative or nondiagnostic result, compression US was repeated by the same operator after 5 to 7 days. Inter-observer agreement and accuracy were calculated. RESULTS: We enrolled a total of 1,107 patients. The expert physicians diagnosed DVT in 200 patients, corresponding to an overall prevalence of 18.1% (95% CI, 15.8%-20.3%). The agreement between the trained general practitioners and the experts was excellent (Cohen kappa = 0.86; 95% CI, 0.84-0.88). Compression US performed by general practitioners had a sensitivity of 90.0% (95% CI, 88.2%-91.8%) and a specificity of 97.1% (95% CI, 96.2%-98.1%) with a diagnostic accuracy for DVT of 95.8% (95% CI, 94.7%-97.0%). CONCLUSIONS: Our results suggest that, even in hands of physicians not expert in vascular US, compression US can be a reliable tool in the diagnosis of DVT. We found that the sensitivity achieved by general practitioners appeared suboptimal, however, so future studies should evaluate the implementation of proper training strategies to maximize skill. PMID- 29133493 TI - An Autoethnographic Examination of Postpartum Depression. AB - PURPOSE: This article examines postpartum depression (PPD) using autoethnography to explore the stigmatization of depression and cultural expectations of motherhood. Because the personal experiences of living with PPD are often absent from primary care literature, this article uses first-person narrative and analysis of intensive mothering to explore the barriers to seeking PPD treatment, the need for increasing physician confidence and comfort using screening tools, and the impact PPD stigma has on patients and their health care. METHODS: Autoethnography, as a relatively unfamiliar methodology in primary care, is used to illuminate individual experiences of living with PPD. The author details a series of encounters as wife, mother, and patient by narrating what it means to live with the disease. A thematic analysis of the series of first-person narratives was employed to further understand the culture of motherhood and shed light on the stigmatization of PPD. RESULTS: Four themes emerged from the analysis revealing the pressures surrounding the cultural ideologies of intensive mothering and the stigma of mental illness: essentialism, failure, shame, and avoidance. DISCUSSION: There is a need to reframe cultural perceptions of motherhood and PPD to positively impact familial interactions and health care encounters for those who live with the illness. The article calls for providing broader diagnostic efforts, more comprehensive care, and engagement with patients in shared decision making around the diagnosis and treatment of PPD. PMID- 29133494 TI - Multimorbidity and Decision-Making Preferences Among Older Adults. AB - PURPOSE: Understanding individuals' preferences for participating in health care decisions is foundational to delivering person-centered care. We aimed to (1) explore preferences for health care decision making among older adults, and (2) identify multimorbidity profiles associated with preferring less active, ie, passive, participation among older US adults. METHOD: Ours was a cross-sectional, nationally representative study of 2,017 National Health and Aging Trends Study respondents. Passive decision-making preference was defined as preferring to leave decisions to physicians. Multimorbidity profiles, based on 13 prevalent chronic conditions, were examined as (1) presence of 2 or more conditions, (2) a simple conditions count, and (3) a condition clusters count. Multiple logistic regression was used with adjustment for age, sex, education, English proficiency, and mobility limitation. RESULTS: Most older adults preferred to participate actively in making health care decisions. Older adults with 4 or more conditions, however, and those with multiple condition clusters are relatively less likely to prefer active decision making. CONCLUSIONS: Primary care physicians should initiate a shared decision-making process with older adults with 4 or more conditions or multiple condition clusters. Physicians should anticipate variation in decision-making preferences among older adults and adapt a decision-making process that suits individuals' preferences for participation to ensure person centered care delivery. PMID- 29133495 TI - Trends in Patient-Perceived Shared Decision Making Among Adults in the United States, 2002-2014. AB - To ascertain changes in shared decision making (SDM), we analyzed data from the nationally representative Medical Expenditure Panel Survey. We aggregated responses to questions into a 7-point SDM composite score. Between 2002 and 2014, the mean SDM composite score increased from 4.4 to 5.0 (P <.01), indicating greater patient-perceived SDM. In multivariate modeling, SDM scores were higher for black vs white patients (+0.33 points) and those with a same-race/ethnicity usual source of care (+0.24 points; both P <.05). Scores were lower for patients with poor-perceived health (-0.41 points), Asian vs white race/ethnicity (-0.28 points), and no insurance (-0.17 points; all P <.05). Improvement efforts should target Americans without a same-race/ethnicity usual source of care and with poor perceived health. PMID- 29133496 TI - Factors Influencing Allopurinol Initiation in Primary Care. AB - Despite guidance on appropriate initiation, urate-lowering therapy is prescribed for only a minority of patients with gout. Electronic health records for 8,142 patients with gout were used to investigate the effect of age, sex, comorbidities, number of consultations, and meeting internationally agreed eligibility criteria on time to allopurinol initiation. Time to first prescription was modeled using multilevel Cox proportional hazards regression. Allopurinol initiation was positively associated with meeting eligibility criteria at diagnosis of gout, but negatively associated with becoming eligible after diagnosis. Managing gout as a chronic disease, with regular reviews to discuss allopurinol treatment, may reduce barriers to treatment. PMID- 29133497 TI - Comparative Associations Between Measures of Anti-cholinergic Burden and Adverse Clinical Outcomes. AB - PURPOSE: No consensus has been reached regarding which anticholinergic scoring system works most effectively in clinical settings. The aim of this population based cohort study was to examine the association between anticholinergic medication burden, as defined by different scales, and adverse clinical outcomes among older adults. METHODS: From Taiwan's Longitudinal Health Insurance Database, we retrieved data on monthly anticholinergic drug use measured by the Anticholinergic Risk Scale (ARS), the Anticholinergic Cognitive Burden Scale (ACB), and the Drug Burden Index - Anticholinergic component (DBI-Ach) for 116,043 people aged 65 years and older during a 10-year follow-up. For all 3 scales, a higher score indicates greater anticholinergic burden. We used generalized estimating equations to examine the association between anticholinergic burden (ARS and ACB: grouped from 0 to >=4; DBI-Ach: grouped as 0, 0-0.5, and 0.5-1) and adverse outcomes, and stratified individuals by age group (aged 65-74, 75-84, and >=85 years). RESULTS: Compared with the ARS and DBI Ach, the ACB showed the strongest, most consistent dose-response relationships with risks of all 4 adverse outcomes, particularly in people aged 65 to 84 years. For example, among those 65 to 74 years old, going from an ACB score of 1 to a score of 4 or greater, individuals' adjusted odds ratio increased from 1.41 to 2.25 for emergency department visits; from 1.32 to 1.92 for all-cause hospitalizations; from 1.10 to 1.71 for fracture-specific hospitalizations; and from 3.13 to 10.01 for incident dementia. CONCLUSIONS: Compared with the 2 other scales studied, the ACB shows good dose-response relationships between anticholinergic burden and a variety of adverse outcomes in older adults. For primary care and geriatrics clinicians, the ACB may be a helpful tool for identifying high-risk populations for interventions. PMID- 29133499 TI - Caring for the Tribe: From Addiction to Zen. AB - The culture of medicine is rapidly changing. The majority of primary care physicians are now employed, and the decisions that govern us are made farther and farther from the point of care. Our sense of well-being is threatened less by the demands of clinical practice than it is by the emptiness of our job: we have forgotten who we are working for, or working with, or why we are working at all. The solution lies in creating the kind of practice environment that we advocate for in each of our patients' lives. PMID- 29133498 TI - The Foundations Framework for Developing and Reporting New Models of Care for Multimorbidity. AB - PURPOSE: Multimorbidity challenges health systems globally. New models of care are urgently needed to better manage patients with multimorbidity; however, there is no agreed framework for designing and reporting models of care for multimorbidity and their evaluation. METHODS: Based on findings from a literature search to identify models of care for multimorbidity, we developed a framework to describe these models. We illustrate the application of the framework by identifying the focus and gaps in current models of care, and by describing the evolution of models over time. RESULTS: Our framework describes each model in terms of its theoretical basis and target population (the foundations of the model) and of the elements of care implemented to deliver the model. We categorized elements of care into 3 types: (1) clinical focus, (2) organization of care, (3) support for model delivery. Application of the framework identified a limited use of theory in model design and a strong focus on some patient groups (elderly, high users) more than others (younger patients, deprived populations). We found changes in elements with time, with a decrease in models implementing home care and an increase in models offering extended appointments. CONCLUSIONS: By encouragin greater clarity about the underpinning theory and target population, and by categorizing the wide range of potentially important elements of an intervention to improve care for patients with multimorbidity, the framework may be useful in designing and reporting models of care and help advance the currently limited evidence base. PMID- 29133500 TI - Hatpins. AB - Hatpins is a first-person narrative that delves into a physician's experience of a patient death during the early years of residency. The essay reflects on the conflicted physician-patient relationships that can develop even over the short tenure of residency. While residency seeks to create medically prepared and compassionate physicians, this piece speaks to the importance of the often subtle learning that comes from ethical, social, and cultural aspects of both the lives and deaths of our patients. PMID- 29133501 TI - How Health Systems Can Promote Healthier Eating. PMID- 29133502 TI - Huddling Up: Expanding Clinic Huddles. PMID- 29133510 TI - Single Cell Immuno-Laser Microdissection Coupled to Label-Free Proteomics to Reveal the Proteotypes of Human Brain Cells After Ischemia. AB - Cerebral ischemia entails rapid tissue damage in the affected brain area causing devastating neurological dysfunction. How each component of the neurovascular unit contributes or responds to the ischemic insult in the context of the human brain has not been solved yet. Thus, the analysis of the proteome is a straightforward approach to unraveling these cell proteotypes. In this study, post-mortem brain slices from ischemic stroke patients were obtained corresponding to infarcted (IC) and contralateral (CL) areas. By means of laser microdissection, neurons and blood brain barrier structures (BBB) were isolated and analyzed using label-free quantification. MS data are available via ProteomeXchange with identifier PXD003519. Ninety proteins were identified only in neurons, 260 proteins only in the BBB and 261 proteins in both cell types. Bioinformatics analyses revealed that repair processes, mainly related to synaptic plasticity, are outlined in microdissected neurons, with nonexclusive important functions found in the BBB. A total of 30 proteins showing p < 0.05 and fold-change> 2 between IC and CL areas were considered meaningful in this study: 13 in neurons, 14 in the BBB and 3 in both cell types. Twelve of these proteins were selected as candidates and analyzed by immunohistofluorescence in independent brains. The MS findings were completely verified for neuronal SAHH2 and SRSF1 whereas the presence in both cell types of GABT and EAA2 was only validated in neurons. In addition, SAHH2 showed its potential as a prognostic biomarker of neurological improvement when analyzed early in the plasma of ischemic stroke patients. Therefore, the quantitative proteomes of neurons and the BBB (or proteotypes) after human brain ischemia presented here contribute to increasing the knowledge regarding the molecular mechanisms of ischemic stroke pathology and highlight new proteins that might represent putative biomarkers of brain ischemia or therapeutic targets. PMID- 29133512 TI - Exosomes From Adipose-Derived Stem Cells Attenuate Adipose Inflammation and Obesity Through Polarizing M2 Macrophages and Beiging in White Adipose Tissue. AB - Adipose-derived stem cells (ADSCs) play critical roles in controlling obesity associated inflammation and metabolic disorders. Exosomes from ADSCs exert protective effects in several diseases, but their roles in obesity and related pathological conditions remain unclear. In this study, we showed that treatment of obese mice with ADSC-derived exosomes facilitated their metabolic homeostasis, including improved insulin sensitivity (27.8% improvement), reduced obesity, and alleviated hepatic steatosis. ADSC-derived exosomes drove alternatively activated M2 macrophage polarization, inflammation reduction, and beiging in white adipose tissue (WAT) of diet-induced obese mice. Mechanistically, exosomes from ADSCs transferred into macrophages to induce anti-inflammatory M2 phenotypes through the transactivation of arginase-1 by exosome-carried active STAT3. Moreover, M2 macrophages induced by ADSC-derived exosomes not only expressed high levels of tyrosine hydroxylase responsible for catecholamine release, but also promoted ADSC proliferation and lactate production, thereby favoring WAT beiging and homeostasis in response to high-fat challenge. These findings delineate a novel exosome-mediated mechanism for ADSC-macrophage cross talk that facilitates immune and metabolic homeostasis in WAT, thus providing potential therapy for obesity and diabetes. PMID- 29133511 TI - Which Individuals To Choose To Update the Reference Population? Minimizing the Loss of Genetic Diversity in Animal Genomic Selection Programs. AB - Genomic selection (GS) is commonly used in livestock and increasingly in plant breeding. Relying on phenotypes and genotypes of a reference population, GS allows performance prediction for young individuals having only genotypes. This is expected to achieve fast high genetic gain but with a potential loss of genetic diversity. Existing methods to conserve genetic diversity depend mostly on the choice of the breeding individuals. In this study, we propose a modification of the reference population composition to mitigate diversity loss. Since the high cost of phenotyping is the limiting factor for GS, our findings are of major economic interest. This study aims to answer the following questions: how would decisions on the reference population affect the breeding population, and how to best select individuals to update the reference population and balance maximizing genetic gain and minimizing loss of genetic diversity? We investigated three updating strategies for the reference population: random, truncation, and optimal contribution (OC) strategies. OC maximizes genetic merit for a fixed loss of genetic diversity. A French Montbeliarde dairy cattle population with 50K SNP chip genotypes and simulations over 10 generations were used to compare these different strategies using milk production as the trait of interest. Candidates were selected to update the reference population. Prediction bias and both genetic merit and diversity were measured. Changes in the reference population composition slightly affected the breeding population. Optimal contribution strategy appeared to be an acceptable compromise to maintain both genetic gain and diversity in the reference and the breeding populations. PMID- 29133513 TI - Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma. AB - LESSONS LEARNED: Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens. BACKGROUND: Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression-free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM. MATERIALS AND METHODS: In this phase II, single-center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28-day cycle. The primary endpoint was 6-month PFS (PFS6). RESULTS: Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%-44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6-12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment-related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified. CONCLUSION: Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy. PMID- 29133514 TI - First Prospective Multicenter Italian Study on the Impact of the 21-Gene Recurrence Score in Adjuvant Clinical Decisions for Patients with ER Positive/HER2 Negative Breast Cancer. AB - BACKGROUND: The Breast DX Italy prospective study evaluated the impact of the 21 gene recurrence score (RS) result on adjuvant treatment decisions for patients with early breast cancer. MATERIALS AND METHODS: Nine centers (two Hub and seven Spoke centers of the Veneto Oncology Network) participated. Consecutive patients with estrogen receptor positive, human epidermal growth receptor negative, T1-T3, N0-N1 early breast cancer were prospectively registered; only those meeting protocol-defined clinicopathological "intermediate risk" criteria were eligible for the RS test. Pre-RS and post-RS physicians' treatment recommendations and treatment actually received were collected. RESULTS: A total of n = 124 N0 and n = 126 N1 patients underwent the RS assay. The majority had Grade 2 tumors (71%); median age was 55 years, median tumor size was 16 mm, and median Ki67 expression was 20%. Patients enrolled at Hub centers presented higher-risk features. The distribution of RS results was <18 (60.8%), 18-30 (32.4%), and >30 (6.8%). The indication before RS was hormonal therapy (HT) alone in 52% of cases. An indication before RS of chemotherapy (CT)+HT was more frequent for patients with N1 versus N0 tumors (57% vs. 39%, p = .0035) and for patients enrolled at Hub versus Spoke centers (54% vs. 36%, p = .007).The overall rate of change in treatment decision was 16% (n = 40), mostly from CT+HT to HT (n = 30). According to nodal status, rate of change in treatment decision was 12% for the N0 cohort and 20% for the N1 cohort. The proportion of patients recommended to CT+HT was significantly reduced from before to after RS (48% to 40%, p < .0016), especially in the N1 cohort (57% to 45%, p = .0027) and at Hub centers (54% to 44%, p = .001). CONCLUSION: Despite frequent indication of HT before RS, the use of the RS assay further contributed to sparing CT, especially for patients with N1 tumors and at Hub centers. IMPLICATIONS FOR PRACTICE: This study shows that, although a high proportion of patients were recommended to receive endocrine treatment alone before knowing the recurrence score (RS) assay, the RS test further contributed in sparing chemotherapy for some of these patients, especially in case of the N1 stage or for patients enrolled at referral centers. These data highlight the need for further work in collaboration with health authorities and companies in order to define strategies for the implementation of the use of RS testing in clinical practice in the Italian setting. PMID- 29133515 TI - "Rather one more chemo than one less...": Oncologists and Oncology Nurses' Reasons for Aggressive Treatment of Young Adults with Advanced Cancer. AB - BACKGROUND: Empirical research demonstrates that there is a tendency to administer tumor-directed therapy to patients with advanced cancer close to death, especially if they are young. The aim of this qualitative study was to understand oncologists' treatment decisions and oncology nurses' perception of these decisions in young adult patients and to investigate the extent to which young age was a factor in cancer treatment decisions. MATERIALS AND METHODS: We conducted 29 face-to-face interviews with oncologists and oncology nurses at the Department of Hematology and Oncology at the University Hospital in Munich, Germany. The interviews were analyzed according to the grounded theory approach. RESULTS: Oncologists and nurses reported that decisions about limiting cancer treatment with young adult patients are the most challenging and stressful in clinical practice. Apart from using young age as a proxy for patient's medical fitness, oncologists' decisions in favor of more aggressive treatment of younger patients were mainly guided by ethical reasons such as patient preferences and the perceptions of injustice associated with dying at a young age, as well as by psychological reasons, such as identification and emotional entanglement. CONCLUSION: "Struggling" together with the patient against the injustice of dying young for a longer lifetime is an important factor driving aggressive treatment in young adult patients. However, oncologists might run a risk of neglecting other ethical aspects, such as a principle of nonmaleficence, that might even result in life-shortening adverse events. IMPLICATIONS FOR PRACTICE: This study identifies two ethical and one psychological reasons for patients' overtreatment: 1) patients' preference for further treatment; 2) oncologists' perception of un fairness of dying young; and 3) identification and emotional entanglement with patient. These findings emphasize the need for oncologists' awareness of the reasons guiding their treatment decisions - a sole focus on patients' preferences and on the fighting against the unfairness of dying young might lead to neglecting obligations of non-maleficence. Self-reflection, the balance of empathy and professional distance as well as timely end of life discussions and involvement of psycho-oncologists are needed in the care of young cancer patients. PMID- 29133516 TI - Quality of Randomized Controlled Trials Reporting in the Treatment of Adult Patients with High-Grade Gliomas. AB - BACKGROUND: The randomized controlled trial (RCT) is the gold standard to objectively assess the effect of treatments. To help improve the quality of RCTs, experts established a list of recommendations, the CONsolidated Standards of Reporting Trials (CONSORT) Statement. In this study, we evaluated the implementation of the CONSORT Statement in the field of high-grade gliomas in adult patients and looked for criteria associated with higher quality of RCTs. MATERIALS AND METHODS: We searched all high-grade gliomas RCTs published in PubMed between January 1990 and December 2016. The quality of these RCTs was assessed by completing a modified CONSORT Score (CS). RESULTS: Ninety-six published RCTs were identified. The median CS was 19.5 on a scale of 0-33. Items were not equally reported. Items regarding the method of randomization or the blinding were reported in less than 25% of RCTs. However, the CS has constantly improved over the years. Before the implementation of the CONSORT Statement in 1996, the median CS was 13, whereas it was 17 for the period 1996-2004 and 22 after 2005. A higher CS was observed when RCTs were published in a journal with an impact factor above 10 (p < .001) or after 2010 (p = .001), when the primary outcome was clearly defined (p < .001) and for RCTs that enrolled more than 200 patients (p = .004). CONCLUSION: Although there has been a steady improvement in the CS over the years in the field of high-grade gliomas, a major effort must be made in the reporting methods for randomization and blinding. IMPLICATIONS FOR PRACTICE: This study showed that the quality of reporting of randomized control trials (RCTs) concerning the treatment of high-grade gliomas is poor. Factors associated with a better quality of reports were identified and should be incorporated into the design of future RCTs. When clinicians read the results of RCTs, they should be aware of the possible inadequate reporting from these trials and take it into account for the management of their patients. This study identifies how RCTs can be improved in their reporting but also in their design, in order to advance care for patients with high-grade gliomas in the future. PMID- 29133517 TI - Clinical Trials in Oncology and Defining Benefit. PMID- 29133518 TI - In Reply. PMID- 29133519 TI - Deep RNA Sequencing Uncovers a Repertoire of Human Macrophage Long Intergenic Noncoding RNAs Modulated by Macrophage Activation and Associated With Cardiometabolic Diseases. AB - BACKGROUND: Sustained and dysfunctional macrophage activation promotes inflammatory cardiometabolic disorders, but the role of long intergenic noncoding RNA (lincRNA) in human macrophage activation and cardiometabolic disorders is poorly defined. Through transcriptomics, bioinformatics, and selective functional studies, we sought to elucidate the lincRNA landscape of human macrophages. METHODS AND RESULTS: We used deep RNA sequencing to assemble the lincRNA transcriptome of human monocyte-derived macrophages at rest and following stimulation with lipopolysaccharide and IFN-gamma (interferon gamma) for M1 activation and IL-4 (interleukin 4) for M2 activation. Through de novo assembly, we identified 2766 macrophage lincRNAs, including 861 that were previously unannotated. The majority (~85%) was nonsyntenic or was syntenic but not annotated as expressed in mouse. Many macrophage lincRNAs demonstrated tissue enriched transcription patterns (21.5%) and enhancer-like chromatin signatures (60.9%). Macrophage activation, particularly to the M1 phenotype, markedly altered the lincRNA expression profiles, revealing 96 lincRNAs differentially expressed, suggesting potential roles in regulating macrophage inflammatory functions. A subset of lincRNAs overlapped genomewide association study loci for cardiometabolic disorders. MacORIS (macrophage-enriched obesity-associated lincRNA serving as a repressor of IFN-gamma signaling), a macrophage-enriched lincRNA not expressed in mouse macrophages, harbors variants associated with central obesity. Knockdown of MacORIS, which is located in the cytoplasm, enhanced IFN-gamma-induced JAK2 (Janus kinase 2) and STAT1 (signal transducer and activator of transcription 1) phosphorylation in THP-1 macrophages, suggesting a potential role as a repressor of IFN-gamma signaling. Induced pluripotent stem cell-derived macrophages recapitulated the lincRNA transcriptome of human monocyte-derived macrophages and provided a high-fidelity model with which to study lincRNAs in human macrophage biology, particularly those not conserved in mouse. CONCLUSIONS: High-resolution transcriptomics identified lincRNAs that form part of the coordinated response during macrophage activation, including specific macrophage lincRNAs associated with human cardiometabolic disorders that modulate macrophage inflammatory functions. PMID- 29133520 TI - Harmonizing the Paradigm With the Data in Stable Coronary Artery Disease: A Review and Viewpoint. PMID- 29133521 TI - Circulating Total Bilirubin and Future Risk of Hypertension in the General Population: The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Prospective Study and a Mendelian Randomization Approach. AB - BACKGROUND: Circulating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association. METHODS AND RESULTS: Plasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New-onset hypertension was recorded in 1206 participants during a median follow-up of 10.7 years. Baseline total bilirubin was approximately log-linearly associated with hypertension risk. Age- and sex-adjusted hazard ratio for hypertension per 1-SD increase in loge total bilirubin was 0.86 (0.81-0.92; P<0.001), which was attenuated to 0.94 (0.88-0.99; P=0.040) after further adjustment for established risk factors and other potential confounders. The association was marginally significant on further adjustment for high-sensitivity C-reactive protein (0.94; 0.88-1.00; P=0.067). A genetic variant at the UGT1A1*28 locus consistently shown to be strongly associated with circulating bilirubin levels-rs6742078-was not significantly associated with blood pressure or hypertension (P>0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure. CONCLUSIONS: The weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted. PMID- 29133522 TI - Systolic Blood Pressure Response in SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD (Action to Control Cardiovascular Risk in Diabetes): A Possible Explanation for Discordant Trial Results. AB - BACKGROUND: SPRINT (Systolic Blood Pressure Intervention Trial) and the ACCORD (Action to Control Cardiovascular Risk in Diabetes) blood pressure trial used similar interventions but produced discordant results. We investigated whether differences in systolic blood pressure (SBP) response contributed to the discordant trial results. METHODS AND RESULTS: We evaluated the distributions of SBP response during the first year for the intensive and standard treatment groups of SPRINT and ACCORD using growth mixture models. We assessed whether significant differences existed between trials in the distributions of SBP achieved at 1 year and the treatment-independent relationships of achieved SBP with risks of primary outcomes defined in each trial, heart failure, stroke, and all-cause death. We examined whether visit-to-visit variability was associated with heterogeneous treatment effects. Among the included 9027 SPRINT and 4575 ACCORD participants, the difference in mean SBP achieved between treatment groups was 15.7 mm Hg in SPRINT and 14.2 mm Hg in ACCORD, but SPRINT had significantly less between-group overlap in the achieved SBP (standard deviations of intensive and standard groups, respectively: 6.7 and 5.9 mm Hg in SPRINT versus 8.8 and 8.2 mm Hg in ACCORD; P<0.001). The relationship between achieved SBP and outcomes was consistent across trials except for stroke and all-cause death. Higher visit-to visit variability was more common in SPRINT but without treatment-effect heterogeneity. CONCLUSIONS: SPRINT and ACCORD had different degrees of separation in achieved SBP between treatment groups, even as they had similar mean differences. The greater between-group overlap of achieved SBP may have contributed to the discordant trial results. PMID- 29133523 TI - Sampling technique and detection rates of oropharyngeal and anorectal gonorrhoea using nucleic acid amplification tests in men who have sex with men. AB - OBJECTIVES: The objective of this study was to examine the associations between clinicians' self-reported sampling technique and the detection rate of gonorrhoea at the oropharynx and anorectum using a highly sensitive nucleic acid amplification test (NAAT). METHODS: We analysed oropharyngeal and anorectal gonorrhoea swab results among men who have sex with men attending the Melbourne Sexual Health Centre (MSHC) between March 2015 and December 2016. Swabs were tested by NAAT using the Aptima Combo 2 transcription-mediated amplification assay due to its high sensitivity. Clinicians at MSHC were invited to complete a questionnaire on sampling techniques in November 2016. Univariable generalised estimating equations (GEE) logistic regressions were performed to determine the association between gonorrhoea detection rates and clinicians' sampling technique. Patients' epidemiological risk factors were included in the multivariable GEE logistic model. RESULTS: A total of 2605 oropharyngeal gonorrhoea and 2392 anorectal gonorrhoea swab results were analysed. There was no significant difference in the detection rates of gonorrhoea between the 23 clinicians at the oropharynx (range 3.6%-16.9%, median 8.2%, P=0.302) or and anorectum (range 2.4%-17.3%, median 10.5%, P=0.177). Variations in clinicians' self-reported sampling technique were not associated with oropharyngeal or anorectal gonorrhoea detection rates after adjusting for patients' epidemiological risk factors. CONCLUSIONS: This study shows that differences in clinicians' self-reported sampling technique did not result in measurable differences in the detection rate for oropharyngeal or anorectal gonorrhoea when using NAAT. PMID- 29133524 TI - HPV vaccination among men who have sex with men in Ireland: GPs' awareness and vaccination rates. PMID- 29133526 TI - Involvement of Gbetagamma subunits of Gi protein coupled with S1P receptor on multivesicular endosomes in F-actin formation and cargo sorting into exosomes. AB - Exosomes play a critical role in cell-to-cell communication by delivering cargo molecules to recipient cells. However, the mechanism underlying the generation of the exosomal multivesicular endosome (MVE) is one of the mysteries in the field of endosome research. Although sphingolipid metabolites such as ceramide and sphingosine 1-phosphate (S1P) are known to play important roles in MVE formation and maturation, the detailed molecular mechanisms are still unclear. Here, we show that Rho family GTPases, including Cdc42 and Rac1, are constitutively activated on exosomal MVEs and are regulated by S1P signaling as measured by fluorescence resonance energy transfer (FRET)-based conformational changes. Moreover, we detected S1P signaling-induced filamentous actin (F-actin) formation. A selective inhibitor of Gbetagamma subunits, M119, strongly inhibited both F-actin formation on MVEs and cargo sorting into exosomal intralumenal vesicles of MVEs, both of which were fully rescued by the simultaneous expression of constitutively active Cdc42 and Rac1. Our results shed light on the mechanism underlying exosomal MVE maturation and inform the understanding of the physiological relevance of continuous activation of the S1P receptor and subsequent downstream G protein signaling to Gbetagamma subunits/Rho family GTPases-regulated F-actin formation on MVEs for cargo sorting into exosomal intralumenal vesicles. PMID- 29133525 TI - Optineurin promotes autophagosome formation by recruiting the autophagy-related Atg12-5-16L1 complex to phagophores containing the Wipi2 protein. AB - Autophagy is a quality-control mechanism that helps to maintain cellular homeostasis by removing damaged proteins and organelles through lysosomal degradation. During autophagy, signaling events lead to the formation of a cup shaped structure called the phagophore that matures into the autophagosome. Recruitment of the autophagy-associated Atg12-5-16L1 complex to Wipi2-positive phagophores is crucial for producing microtubule-associated protein 1 light chain 3-II (LC3-II), which is required for autophagosome formation. Here, we explored the role of the autophagy receptor optineurin (Optn) in autophagosome formation. Fibroblasts from Optn knock-out mouse showed reduced LC3-II formation and a lower number of autophagosomes and autolysosomes during both basal and starvation induced autophagy. However, the number of Wipi2-positive phagophores was not decreased in Optn-deficient cells. We also found that the number of Atg12/16L1 positive puncta and recruitment of the Atg12-5-16L1 complex to Wipi2-positive puncta are reduced in Optn-deficient cells. Of note, Optn was recruited to Atg12 5-16L1-positive puncta, and interacted with Atg5 and also with Atg12-5 conjugate. A disease-associated Optn mutant, E478G, defective in ubiquitin binding, was also defective in autophagosome formation and recruitment to the Atg12-5-16L1-positive puncta. Moreover, we noted that Optn phosphorylation at Ser-177 was required for autophagosome formation but not for Optn recruitment to the phagophore. These results suggest that Optn potentiates LC3-II production and maturation of the phagophore into the autophagosome, by facilitating the recruitment of the Atg12-5 16L1 complex to Wipi2-positive phagophores. PMID- 29133529 TI - Closing the Remaining Evidence Gap: Randomized Controlled Trial Data to Support Statin Therapy for Low-Density Lipoprotein >=190 mg/dL. PMID- 29133527 TI - Interaction of the phosphorylated DNA-binding domain in nuclear receptor CAR with its ligand-binding domain regulates CAR activation. AB - The nuclear protein constitutive active/androstane receptor (CAR or NR1I3) regulates several liver functions such as drug and energy metabolism and cell growth or death, which are often involved in the development of diseases such as diabetes and hepatocellular carcinoma. CAR undergoes a conversion from inactive homodimers to active heterodimers with retinoid X receptor alpha (RXRalpha), and phosphorylation of the DNA-binding domain (DBD) at Thr-38 in CAR regulates this conversion. Here, we uncovered the molecular mechanism by which this phosphorylation regulates the intramolecular interaction between CAR's DBD and ligand-binding domain (LBD), enabling the homodimer-heterodimer conversion. Phosphomimetic substitution of Thr-38 with Asp increased co-immunoprecipitation of the CAR DBD with CAR LBD in Huh-7 cells. Isothermal titration calorimetry assays also revealed that recombinant CAR DBD-T38D, but not nonphosphorylated CAR DBD, bound the CAR LBD peptide. This DBD-LBD interaction masked CAR's dimer interface, preventing CAR homodimer formation. Of note, EGF signaling weakened the interaction of CAR DBD T38D with CAR LBD, converting CAR to the homodimer form. The DBD-T38D-LBD interaction also prevented CAR from forming a heterodimer with RXRalpha. However, this interaction opened up a CAR surface, allowing interaction with protein phosphatase 2A. Thr-38 dephosphorylation then dissociated the DBD-LBD interaction, allowing CAR heterodimer formation with RXRalpha. We conclude that the intramolecular interaction of phosphorylated DBD with the LBD enables CAR to adapt a transient monomer configuration that can be converted to either the inactive homodimer or the active heterodimer. PMID- 29133531 TI - Unusual ST-Segment Elevation in the Anterolateral Precordial Leads: Ischemia, Brugada Phenocopy, Brugada Syndrome, All, or None? PMID- 29133530 TI - Human Endogenous Retrovirus K and Pulmonary Arterial Hypertension: A New Take on a Retro Idea. PMID- 29133528 TI - SUMO chain formation relies on the amino-terminal region of SUMO-conjugating enzyme and has dedicated substrates in plants. AB - The small ubiquitin-related modifier (SUMO) conjugation apparatus usually attaches single SUMO moieties to its substrates, but SUMO chains have also been identified. To better define the biochemical requirements and characteristics of SUMO chain formation, mutations in surface-exposed Lys residues of Arabidopsis SUMO-conjugating enzyme (SCE) were tested for in vitro activity. Lys-to-Arg changes in the amino-terminal region of SCE allowed SUMO acceptance from SUMO activating enzyme and supported substrate mono-sumoylation, but these mutations had significant effects on SUMO chain assembly. We found no indication that SUMO modification of SCE promotes chain formation. A substrate was identified that is modified by SUMO chain addition, showing that SCE can distinguish substrates for either mono-sumoylation or SUMO chain attachment. It is also shown that SCE with active site Cys mutated to Ser can accept SUMO to form an oxyester, but cannot transfer this SUMO moiety onto substrates, explaining a previously known dominant negative effect of this mutation. PMID- 29133532 TI - Early Outcomes of Repair of Left Ventricular Apical Aneurysms in Patients With Hypertrophic Cardiomyopathy. PMID- 29133533 TI - Letter by Natale et al Regarding Article, "Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study)". PMID- 29133534 TI - Response by Perez de Isla et al to Letter Regarding Article, "Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study)". PMID- 29133535 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Impact of the Clinical Frailty Scale on Outcomes After Transcatheter Aortic Valve Replacement". PMID- 29133536 TI - Response by Yamamoto et al to Letter Regarding Article, "Impact of the Clinical Frailty Scale on Outcomes After Transcatheter Aortic Valve Replacement". PMID- 29133537 TI - Expression of Concern for Takano et al., "Vital Role of the Calpain-Calpastatin System for Placental-Integrity-Dependent Embryonic Survival". PMID- 29133538 TI - Delivering more equitable primary health care in Northern Canada. PMID- 29133539 TI - Validation of the Ottawa Subarachnoid Hemorrhage Rule in patients with acute headache. AB - BACKGROUND: We previously derived the Ottawa Subarachnoid Hemorrhage Rule to identify subarachnoid hemorrhage (SAH) in patients with acute headache. Our objective was to validate the rule in a new cohort of consecutive patients who visited an emergency department. METHODS: We conducted a multicentre prospective cohort study at 6 university-affiliated tertiary-care hospital emergency departments in Canada from January 2010 to January 2014. We included alert, neurologically intact adult patients with a headache peaking within 1 hour of onset. Treating physicians in the emergency department explicitly scored the rule before investigations were started. We defined subarachnoid hemorrhage as detection of any of the following: subarachnoid blood visible upon computed tomography of the head (from the final report by the local radiologist); xanthochromia in the cerebrospinal fluid (by visual inspection); or the presence of erythrocytes (> 1 * 106/L) in the final tube of cerebrospinal fluid, with an aneurysm or arteriovenous malformation visible upon cerebral angiography. We calculated sensitivity and specificity of the Ottawa SAH Rule for detecting or ruling out subarachnoid hemorrhage. RESULTS: Treating physicians enrolled 1153 of 1743 (66.2%) potentially eligible patients, including 67 with subarachnoid hemorrhage. The Ottawa SAH Rule had 100% sensitivity (95% confidence interval [CI] 94.6%-100%) with a specificity of 13.6% (95% CI 13.1%-15.8%), whereas neuroimaging rates remained similar (about 87%). INTERPRETATION: We found that the Ottawa SAH Rule was sensitive for identifying subarachnoid hemorrhage in otherwise alert and neurologically intact patients. We believe that the Ottawa SAH Rule can be used to rule out this serious diagnosis, thereby decreasing the number of cases missed while constraining rates of neuroimaging. PMID- 29133541 TI - Autosomal dominant polycystic kidney disease. PMID- 29133540 TI - Diagnosis and management of low-back pain in primary care. PMID- 29133542 TI - Dermal leishmaniasis in a 25-year-old Syrian refugee. PMID- 29133543 TI - Fish processing and human infection. PMID- 29133544 TI - Neurosyphilis is an easily missed cause of encephalopathy. PMID- 29133545 TI - Gairdner award winner recognized for sharing his techniques. PMID- 29133546 TI - Gairdner recipient improved stroke treatment globally. PMID- 29133547 TI - Electronic health records contributing to physician burnout. PMID- 29133548 TI - Uganda grapples with new Marburg disease outbreak. PMID- 29133549 TI - Pharmacokinetics and Exposure-Response Analysis of RG7667, a Combination of Two Anticytomegalovirus Monoclonal Antibodies, in a Phase 2a Randomized Trial To Prevent Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients. AB - RG7667, a novel combination of two anticytomegalovirus (anti-CMV) monoclonal IgG1 antibodies (MCMV5322A and MCMV3068A), was designed to block CMV entry into host cells. It was developed as a potential therapy for preventing CMV infection and disease in transplant recipients. RG7667 was assessed for preventing CMV infection in a phase 2a trial with CMV-seronegative recipients of kidney transplants from CMV-seropositive donors. The patients received 4 intravenous doses of RG7667 (10 mg/kg of body weight of each antibody, n = 60) or placebo (n = 60) at the time of the transplant and at 1, 4, and 8 weeks after the transplant. Serum samples were collected for pharmacokinetic (PK) analysis and antidrug antibody (ADA) evaluation. To guide future dose selection, the relationships between RG7667 exposure and pharmacological activity were evaluated. MCMV5322A and MCMV3068A exposures were confirmed in all RG7667-treated patients. Mean clearances for MCMV5322A and MCMV3068A were 2.97 and 2.65 ml/day/kg, respectively, and the terminal half-lives of MCMV5322A and MCMV3068A were 26.9 and 27.4 days, respectively. The ADA incidence was low and was not associated with lower drug exposure. Patients with RG7667 or component antibody exposures greater than the respective median values had a lower incidence of viremia at 12 weeks and 24 weeks after transplantation and a longer delayed time to detectable CMV viremia than patients with exposures less than the median values. MCMV5322A and MCMV3068A exhibited expected IgG1 PK profiles in high-risk kidney transplant recipients, consistent with the earlier PK behavior of RG7667 in healthy subjects. Higher drug exposure was associated with better anti-CMV pharmacological activity. (This study has been registered at ClinicalTrials.gov under identifier NCT01753167.). PMID- 29133550 TI - Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box. AB - Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. The drugs currently used against toxoplasmosis are few in number and show several limitations, such as drug intolerance, poor bioavailability, or drug resistance mechanism developed by the parasite. Thus, it is important to find new compounds able to inhibit parasite invasion or proliferation. In this study, the 400 compounds of the open-access Pathogen Box, provided by the Medicines for Malaria Venture (MMV) foundation, were screened for their anti-Toxoplasma gondii activity. A preliminary in vitro screening performed over 72 h by an enzyme-linked immunosorbent assay (ELISA) revealed 15 interesting compounds that were effective against T. gondii at 1 MUM. Their cytotoxicity was estimated on Vero cells, and their 50% inhibitory concentrations (IC50) were further calculated. As a result, eight anti-Toxoplasma gondii compounds with an IC50 of less than 2 MUM and a selectivity index (SI) value of greater than 4 were identified. The most active was MMV675968, showing an IC50 of 0.02 MUM and a selectivity index value equal to 275. Two other compounds, MMV689480 and MMV687807, also showed a good activity against T. gondii, with IC50s of 0.10 MUM (SI of 86.6) and 0.15 MUM (SI of 11.3), respectively. Structure-activity relationships for the eight selected compounds also were discussed on the basis of fingerprinting similarity measurements using the Tanimoto method. The anti-Toxoplasma gondii compounds highlighted here represent potential candidates for the development of new drugs that could be used against toxoplasmosis. PMID- 29133551 TI - Copper Ions and Coordination Complexes as Novel Carbapenem Adjuvants. AB - Carbapenem-resistant Enterobacteriaceae are urgent threats to global human health. These organisms produce beta-lactamases with carbapenemase activity, such as the metallo-beta-lactamase NDM-1, which is notable due to its association with mobile genetic elements and the lack of a clinically useful inhibitor. Here we examined the ability of copper to inhibit the activity of NDM-1 and explored the potential of a copper coordination complex as a mechanism to efficiently deliver copper as an adjuvant in clinical therapeutics. An NDM-positive Escherichia coli isolate, MS6192, was cultured from the urine of a patient with a urinary tract infection. MS6192 was resistant to antibiotics from multiple classes, including diverse beta-lactams (penicillins, cephalosporins, and carbapenems), aminoglycosides, and fluoroquinolones. In the presence of copper (range, 0 to 2 mM), however, the susceptibility of MS6192 to the carbapenems ertapenem and meropenem increased markedly. In standard checkerboard assays, copper decreased the MICs of ertapenem and meropenem against MS6192 in a dose-dependent manner, suggesting a synergistic mode of action. To examine the inhibitory effect of copper in the absence of other beta-lactamases, the blaNDM-1 gene from MS6192 was cloned and expressed in a recombinant E. coli K-12 strain. Analysis of cell extracts prepared from this strain revealed that copper directly inhibited NDM-1 activity, which was confirmed using purified recombinant NDM-1. Finally, delivery of copper at a low concentration of 10 MUM by using the FDA-approved coordination complex copper-pyrithione sensitized MS6192 to ertapenem and meropenem in a synergistic manner. Overall, this work demonstrates the potential use of copper coordination complexes as novel carbapenemase adjuvants. PMID- 29133552 TI - CD101, a Novel Echinocandin, Possesses Potent Antibiofilm Activity against Early and Mature Candida albicans Biofilms. AB - Currently available echinocandins are generally effective against Candida biofilms, but the recent emergence of resistance has underscored the importance of developing new antifungal agents that are effective against biofilms. CD101 is a long-acting novel echinocandin with distinctive pharmacokinetic properties and improved stability and safety relative to other drugs in the same class. CD101 is currently being evaluated as a once-weekly intravenous (i.v.) infusion for the treatment of candidemia and invasive candidiasis. In this study, we determined (i) the effect of CD101 against early and mature phase biofilms formed by C. albicansin vitro and (ii) the temporal effect of CD101 on the formation of biofilms using time-lapse microscopy (TLM). Early- or mature-phase biofilms were formed on silicone elastomer discs and were exposed to the test compounds for 24 h and quantified by measuring their metabolic activity. Separate batches were observed under a confocal microscope or used to capture TLM images from 0 to 16 h. Measurements of their metabolic activity showed that CD101 (0.25 or 1 MUg/ml) significantly prevented adhesion-phase cells from developing into mature biofilms (P = 0.0062 or 0.0064, respectively) and eradicated preformed mature biofilms (P = 0.04 or 0.01, respectively) compared to those of untreated controls. Confocal microscopy showed significant reductions in biofilm thicknesses for both early and mature phases (P < 0.05). TLM showed that CD101 stopped the growth of adhesion- and early-phase biofilms within minutes. CD101-treated hyphae failed to grow into mature biofilms. These results suggest that CD101 may be effective in the prevention and treatment of biofilm-associated nosocomial infections. PMID- 29133553 TI - Synthesis and Evaluation of Methyl 4-(7-Hydroxy-4,4,8-Trimethyl-3 Oxabicyclo[3.3.1]Nonan-2-yl)Benzoate as an Antileishmanial Agent and Its Synergistic Effect with Miltefosine. AB - In our interest in oxabicyclic compounds as potent antileishmanial agents, the present work deals with the chemical synthesis of a new oxabicyclic derivative, methyl 4-(7-hydroxy-4,4,8-trimethyl-3-oxabicyclo[3.3.1]nonan-2-yl)benzoate (PS 207). This oxabicyclic derivative showed a good antileishmanial effect on the parasite, on both the promastigote and the amastigote. The mode of parasitic death from PS-207 seemed to be apoptosis-like. Interestingly, the combination of PS-207 with a low dose of miltefosine showed a synergistic effect against the parasite. PMID- 29133555 TI - Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel beta-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii. AB - The novel diazabicyclooctenone ETX2514 is a potent, broad-spectrum serine beta lactamase inhibitor that restores sulbactam activity against resistant Acinetobacter baumannii The frequency of spontaneous resistance to sulbactam ETX2514 in clinical isolates was found to be 7.6 * 10-10 to <9.0 * 10-10 at 4* MIC and mapped to residues near the active site of penicillin binding protein 3 (PBP3). Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a sulbactam-sensitive isolate, resistance also mapped to stringent response genes associated with resistance to PBP2 inhibitors, suggesting that in addition to beta-lactamase inhibition, ETX2514 may enhance sulbactam activity in A. baumannii via inhibition of PBP2. PMID- 29133556 TI - Interspecies Transmission of the blaOXA-48 Gene from a Klebsiella pneumoniae High Risk Clone of Sequence Type 147 to Different Escherichia coli Clones in the Gut Microbiota. PMID- 29133554 TI - What Is Resistance? Impact of Phenotypic versus Molecular Drug Resistance Testing on Therapy for Multi- and Extensively Drug-Resistant Tuberculosis. AB - Rapid and accurate drug susceptibility testing (DST) is essential for the treatment of multi- and extensively drug-resistant tuberculosis (M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using Bactec 960 MGIT or Lowenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TB drugs. Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs; Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0) and whole-genome sequencing (WGS) were translated into individual algorithm-derived treatment regimens for each patient. We further analyzed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results. Compared with pDST, the average agreement in the number of drugs prescribed in genotypic regimens ranged from just 49% (95% confidence interval [CI], 39 to 59%) for Xpert and 63% (95% CI, 56 to 70%) for LPAs to 93% (95% CI, 88 to 98%) for WGS. Only the WGS regimens did not contain any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high. WGS can be used to rule in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be reexamined to avoid systematic false-susceptible results in low-level resistant isolates. PMID- 29133557 TI - A Novel Mechanism of Inactivating Antibacterial Nitro Compounds in the Human Pathogen Staphylococcus aureus by Overexpression of a NADH-Dependent Flavin Nitroreductase. AB - Recently, the nitro-substituted bisquaternary bisnaphthalimides were reported to have substantial anti-infective activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Here, we selected resistant S. aureus clones by cultivation in increasing concentrations of the most active compound, MT02. Interestingly, MT02-resistant variants induced a diffusible red color of the broth. Chromatographic and spectroscopic investigations revealed a stepwise reduction of the bisquaternary bisnaphthalimides' nitro groups to amino groups. The corresponding derivatives were completely inactive against staphylococci. RNA sequencing experiments revealed a strong overexpression of a novel oxidoreductase in MT02-resistant strains. Deletion mutants of this enzyme did not produce the red color and were not able to develop resistance against bisquaternary bisnaphthalimides. Biochemical reactions confirmed an NADH-dependent deactivation of the nitro substituted compounds. Thus, this is the first report of a nitroreductase-based antibiotic resistance mechanism in the human pathogen S. aureus. PMID- 29133558 TI - Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis. AB - Lopinavir-ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir-ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir-ritonavir and drugs routinely used for MDR-TB treatment in HIV-infected children. A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 with MDR-TB receiving treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin and 16 without TB) who were established on a lopinavir-ritonavir-containing antiretroviral regimen. One-compartment models with first-order absorption and elimination for both lopinavir and ritonavir were combined into an integrated model. The dynamic inhibitory effect of the ritonavir concentration on lopinavir clearance was described using a maximum inhibition model. Even after adjustment for the effect of body weight with allometric scaling, a large variability in lopinavir and ritonavir exposure, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir, was detected. MDR-TB treatment did not have a significant effect on the bioavailability, clearance, or absorption rate constants of lopinavir or ritonavir. Most children (81% of children with MDR-TB, 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was found to have no significant effect on the key pharmacokinetic parameters of lopinavir or ritonavir. These findings should be considered in the context of the large interpatient variability found in the present study and the study's modest sample size. PMID- 29133559 TI - Mutations in Gene fusA1 as a Novel Mechanism of Aminoglycoside Resistance in Clinical Strains of Pseudomonas aeruginosa. AB - Resistance of clinical strains of Pseudomonas aeruginosa to aminoglycosides can result from production of transferable aminoglycoside-modifying enzymes, of 16S rRNA methylases, and/or mutational derepression of intrinsic multidrug efflux pump MexXY(OprM). We report here the characterization of a new type of mutant that is 4- to 8-fold more resistant to 2-deoxystreptamine derivatives (e.g., gentamicin, amikacin, and tobramycin) than the wild-type strain PAO1. The genetic alterations of three in vitro mutants were mapped on fusA1 and found to result in single amino acid substitutions in domains II, III, and V of elongation factor G (EF-G1A), a key component of translational machinery. Transfer of the mutated fusA1 alleles into PAO1 reproduced the resistance phenotype. Interestingly, fusA1 mutants with other amino acid changes in domains G, IV, and V of EF-G1A were identified among clinical strains with decreased susceptibility to aminoglycosides. Allelic-exchange experiments confirmed the relevance of these latter mutations and of three other previously reported alterations located in domains G and IV. Pump MexXY(OprM) partly contributed to the resistance conferred by the mutated EF-G1A variants and had additive effects on aminoglycoside MICs when mutationally upregulated. Altogether, our data demonstrate that cystic fibrosis (CF) and non-CF strains of P. aeruginosa can acquire a therapeutically significant resistance to important aminoglycosides via a new mechanism involving mutations in elongation factor EF-G1A. PMID- 29133560 TI - Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis. AB - Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation. PMID- 29133561 TI - Outcomes of Vancomycin plus a beta-Lactam versus Vancomycin Only for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. AB - The objective of this retrospective study was to compare the rates of treatment failure, which was a composite of clinical and microbiologic failure, of patients receiving vancomycin and a beta-lactam to those receiving vancomycin only for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Patients 16 to 89 years of age with MRSA bacteremia admitted to a university-affiliated hospital from 1 January 2014 to 31 December 2016 were screened for study inclusion. Patients were eligible if they received >48 h of vancomycin and a beta-lactam (combination group) or vancomycin only (standard group) within 48 h after bacteremia onset. A total of 182 patients were screened: 47 were included in the standard group, and 63 were in the combination group. The combination group had a higher baseline body mass index (29.2 +/- 8.0 kg/m2 versus 25.8 +/- 7.1 kg/m2, P = 0.022), acute physiologic assessment and chronic health evaluation-II (APACHE II) score (median [interquartile range], 21 [15 to 26] versus 16 [10 to 22], P = 0.003), and incidence of septic shock (31.8% versus 14.9%, P = 0.047). Using multivariate analysis, combination therapy was the only variable that decreased treatment failures (odds ratio [95% confidence interval], 0.337 [0.142 to 0.997]), while vancomycin MIC > 1 mg/liter and male gender increased treatment failures (4.018 [1.297 to 12.444] and 2.971 [1.040 to 8.488], respectively). The 30-day mortality rates (15.0% versus 14.9%, P = 1.000) and the incidence of adverse drug events (19.1% versus 23.4%, P = 0.816) were not statistically different between the combination and standard groups. Combination therapy of vancomycin with a beta-lactam led to significantly fewer treatment failures than vancomycin monotherapy for MRSA bacteremia. PMID- 29133562 TI - Ritonavir-Boosted Protease Inhibitors but Not Cobicistat Appear Safe in HIV Positive Patients Ingesting Dabigatran. PMID- 29133564 TI - Fungal Prophylaxis with a Gastro-Resistant Posaconazole Tablet for Patients with Hematological Malignancies in the POSANANTES Study. AB - Posaconazole is an antifungal drug used in both prophylaxis and treatment of invasive fungal infections. Its oral formulation requires therapeutic drug monitoring. To overcome gastric acidity, a gastro-resistant posaconazole tablet has recently been developed. POSANANTES was a prospective noninterventional study that aimed to monitor plasma concentration trough level (Cmin) of posaconazole tablets used prophylactically in patients with hematological malignancies. Fifty patients were included. Group A (n = 31) included patients receiving induction chemotherapy for myeloid malignancies, and group B (n = 19) included patients treated for graft-versus-host disease after allogeneic hematopoietic stem cells transplantation. In multivariate analysis, female sex, group B assignment, and evaluation of Cmin at day 8 (versus any other day planned by the analysis) were associated with a higher Cmin, while diarrhea was associated with a lower Cmin (P < 0.05). Thirty-four percent (n = 17) of all included patients had to prematurely stop treatment, mainly in group A. In conclusion, this real-life prospective study showed good absorption of posaconazole tablets used for prophylaxis in patients with hematological malignancies, even though this strategy was somewhat limited due to the high number of patients in group A who had to stop their treatment in an untimely fashion. PMID- 29133563 TI - A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location. AB - The search for antiprion compounds has been encouraged by the fact that transmissible spongiform encephalopathies (TSEs) share molecular mechanisms with more prevalent neurodegenerative pathologies, such as Parkinson's and Alzheimer's diseases. Cellular prion protein (PrPC) conversion into protease-resistant forms (protease-resistant PrP [PrPRes] or the scrapie form of PrP [PrPSc]) is a critical step in the development of TSEs and is thus one of the main targets in the screening for antiprion compounds. In this work, three trimethoxychalcones (compounds J1, J8, and J20) and one oxadiazole (compound Y17), previously identified in vitro to be potential antiprion compounds, were evaluated through different approaches in order to gain inferences about their mechanisms of action. None of them changed PrPC mRNA levels in N2a cells, as shown by reverse transcription-quantitative real-time PCR. Among them, J8 and Y17 were effective in real-time quaking-induced conversion reactions using rodent recombinant PrP (rPrP) from residues 23 to 231 (rPrP23-231) as the substrate and PrPSc seeds from hamster and human brain. However, when rPrP from residues 90 to 231 (rPrP90-231), which lacks the N-terminal domain, was used as the substrate, only J8 remained effective, indicating that this region is important for Y17 activity, while J8 seems to interact with the PrPC globular domain. J8 also reduced the fibrillation of mouse rPrP23-231 seeded with in vitro-produced fibrils. Furthermore, most of the compounds decreased the amount of PrPC on the N2a cell surface by trapping this protein in the endoplasmic reticulum. On the basis of these results, we hypothesize that J8, a nontoxic compound previously shown to be a promising antiprion agent, may act by different mechanisms, since its efficacy is attributable not only to PrP conversion inhibition but also to a reduction of the PrPC content on the cell surface. PMID- 29133565 TI - Emergence of Chromosome-Borne Colistin Resistance Gene mcr-1 in Clinical Isolates of Klebsiella pneumoniae from India. PMID- 29133566 TI - Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens. AB - Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers for efficacy are area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24ss), AUC/MIC, and time above the MIC during the dosing interval (T > MIC), while QTc prolongation was associated with the maximal concentration at steady state (Cmaxss) in a thorough QTc phase 1 study. Using PK data collected from 470 patients from the previously conducted phase 3 complicated skin and skin structure infection (cSSSI) trials, population PK modeling and Monte Carlo simulation (MCS) were used to identify a fixed iclaprim dosage regimen for the ongoing phase 3 ABSSSI studies that maximizes AUC0-24ss, AUC/MIC, and T > MIC while minimizing the probability of a Cmaxss of >=800 ng/ml relative to the values for the previously employed cSSSI regimen of 0.8 mg/kg of body weight infused intravenously over 0.5 h every 12 h. The MCS analyses indicated that administration of 80 mg as a 2-h infusion every 12 h provides 28%, 28%, and 32% increases in AUC0-24ss, AUC/MIC, and T > MIC, respectively, compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the probability of a Cmaxss of >=800 ng/ml, by 9%. Based on PK/PD analyses, 80 mg iclaprim administered over 2 h every 12 h was selected as the dosing scheme for subsequent phase 3 clinical trials. PMID- 29133567 TI - Risk Factors and Outcomes Associated with Multidrug-Resistant Acinetobacter baumannii upon Intensive Care Unit Admission. AB - Multidrug-resistant (MDR) Acinetobacter baumannii, associated with broad-spectrum antibiotic use, is an important nosocomial pathogen associated with morbidity and mortality. This study aimed to investigate the prevalence of MDR A. baumannii perirectal colonization among adult patients upon admission to the intensive care unit (ICU) over a 5-year period and to identify risk factors and outcomes associated with colonization. A retrospective cohort analysis of patients admitted to the medical intensive care unit (MICU) and surgical intensive care unit (SICU) at the University of Maryland Medical Center from May 2005 to September 2009 was performed using perirectal surveillance cultures on admission. Poisson and logistic models were performed to identify associated risk factors and outcomes. Four percent of the cohort were positive for MDR A. baumannii at ICU admission. Among patients admitted to the MICU, those positive for MDR A. baumannii at admission were more likely to be older, to have received antibiotics before ICU admission, and to have shorter length of stay in the hospital prior to ICU admission. Among patients admitted to the SICU, those colonized were more likely to have at least one previous admission to our hospital. Patients positive for MDR A. baumannii at ICU admission were 15.2 times more likely to develop a subsequent positive clinical culture for A. baumannii and 1.4 times more likely to die during the current hospitalization. Risk factors associated with MDR A. baumannii colonization differ by ICU type. Colonization acts as a marker of disease severity and of risk of developing a subsequent Acinetobacter infection and of dying during hospitalization. Therefore, active surveillance could guide empirical antibiotic selection and inform infection control practices. PMID- 29133568 TI - Activity of Ceftolozane-Tazobactam against Carbapenem-Resistant, Non Carbapenemase-Producing Pseudomonas aeruginosa and Associated Resistance Mechanisms. AB - Although carbapenems are effective for treating serious multidrug-resistant Pseudomonas aeruginosa infections, carbapenem-resistant P. aeruginosa (CRPA) is now being reported worldwide. Ceftolozane-tazobactam (C/T) demonstrates activity against many multidrug-resistant isolates. We evaluated the activity of C/T and compared its activity to that of ceftazidime-avibactam (C/A) using a well characterized collection of non-carbapenemase-producing CRPA isolates. Forty-two non-carbapenemase-producing CRPA isolates from a previous study (J. Y. Lee and K. S. Ko, Int J Antimicrob Agents 40:168-172, 2012, https://doi.org/10.1016/j.ijantimicag.2012.04.004) were included. All had been previously shown to be negative for blaIMP, blaVIM, blaSPM, blaGIM, blaSIM, and blaKPC by PCR. In the prior study, expression of oprD, ampC, and several efflux pump genes had been defined by quantitative reverse transcription-PCR. Here, antimicrobial susceptibility was determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Time-kill curve assays were performed using three C/T- and C/A-susceptible CRPA isolates. Among 42 non-carbapenemase-producing CRPA isolates, overall susceptibility to C/T was 95.2%, compared to 71.4%, 42.9%, 23.8%, 21.4%, and 2.4% for C/A, ceftazidime, piperacillin-tazobactam, cefepime, and meropenem, respectively. The C/T resistance rate was significantly lower than that of C/A among isolates showing decreased oprD and increased mexB expression (5.1% versus 25.6%, P = 0.025, and 4.3% versus 34.8%, P = 0.022, respectively). In time-kill curve studies, C/T was less bactericidal than C/A against an isolate with decreased oprD and increased ampC expression. C/T was active against 95.2% of non-carbapenemase-producing CRPA clinical isolates. No apparent correlation of C/T MIC values with specific mutation-driven resistance mechanisms was noted. PMID- 29133570 TI - Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model. AB - The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC) producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ~550 mg . h/liter, versus 320 mg . h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae. PMID- 29133569 TI - Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection. AB - Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machine learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2- and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dose-dependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was ~2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD. PMID- 29133571 TI - Development of Protective Immunity in New Zealand White Rabbits Challenged with Bacillus anthracis Spores and Treated with Antibiotics and Obiltoxaximab, a Monoclonal Antibody against Protective Antigen. AB - The recommended management of inhalational anthrax, a high-priority bioterrorist threat, includes antibiotics and antitoxins. Obiltoxaximab, a chimeric monoclonal antibody against anthrax protective antigen (PA), is licensed under the U.S. Food and Drug Administration's (FDA's) Animal Rule for the treatment of inhalational anthrax. Because of spore latency, disease reemergence after treatment cessation is a concern, and there is a need to understand the development of endogenous protective immune responses following antitoxin-containing anthrax treatment regimens. Here, acquired protective immunity was examined in New Zealand White (NZW) rabbits challenged with a targeted lethal dose of Bacillus anthracis spores and treated with antibiotics, obiltoxaximab, or a combination of both. Survivors of the primary challenge were rechallenged 9 months later and monitored for survival. Survival rates after primary and rechallenge for controls and animals treated with obiltoxaximab, levofloxacin, or a combination of both were 0, 65, 100, and 95%, and 0, 100, 95, and 89%, respectively. All surviving immune animals had circulating antibodies to PA and serum toxin-neutralizing titers prior to rechallenge. Following rechallenge, systemic bacteremia and toxemia were not detected in most animals, and the levels of circulating anti-PA IgG titers increased starting at 5 days postrechallenge. We conclude that treatment with obiltoxaximab, alone or combined with antibiotics, significantly improves the survival of rabbits that received a lethal inhalation B. anthracis spore challenge dose and does not interfere with the development of immunity. Survivors of primary challenge are protected against reexposure, have rare incidents of systemic bacteremia and toxemia, and have evidence of an anamnestic response. PMID- 29133572 TI - Drug Repositioning Meets Precision in Glioblastoma. AB - Glioblastoma has a gigantic unmet medical need. Molecular knowledge has evolved substantially, including data on clonal selection with progression. Past trials for all-comers may have produced false negative results. Molecular precision at progression needs workup of new tissue, and revisiting drugs with a focus on brain tumor penetration may yield surprises. Clin Cancer Res; 24(2); 256-8. (c)2017 AACRSee related article by Byron et al., p. 295. PMID- 29133574 TI - Human Papillomavirus Immunity in Oropharyngeal Cancer: Time to Change the Game? AB - For the first time, human papillomavirus (HPV)-specific immunity has been linked directly to the beneficial prognosis of oropharyngeal squamous cell carcinoma (OPSCC). Those patients lacking HPV immunity fare much worse. These results harbor crucial implications for future management of HPV-driven OPSCC as well as for its definition. Clin Cancer Res; 24(3); 505-7. (c)2017 AACRSee related article by Welters et al., p. 634. PMID- 29133573 TI - The RARS-MAD1L1 Fusion Gene Induces Cancer Stem Cell-like Properties and Therapeutic Resistance in Nasopharyngeal Carcinoma. AB - Purpose: Nasopharyngeal carcinoma (NPC) is the most common head and neck cancer in Southeast Asia. Because local recurrence and distant metastasis are still the main causes of NPC treatment failure, it is urgent to identify new tumor markers and therapeutic targets for advanced NPC.Experimental Design: RNA sequencing (RNA seq) was applied to look for interchromosome translocation in NPC. PCR, FISH, and immunoprecipitation were used to examine the fusion gene expression at RNA, DNA, and protein levels in NPC biopsies. MTT assay, colony formation assay, sphere formation assay, co-immunoprecipitation, chromatin immunoprecipitation assay, and in vivo chemoresistance assay were applied to explore the function of RARS-MAD1L1 in NPC.Results: We demonstrated that RARS-MAD1L1 was present in 10.03% (35/349) primary NPC biopsies and 10.7% (9/84) in head and neck cancer (HNC) samples. RARS MAD1L1 overexpression increased cell proliferation, colony formation, and tumorigenicity in vitro, and the silencing of endogenous RARS-MAD1L1 reduced cancer cell growth and colony formation in vitro In addition, RARS-MAD1L1 increased the side population (SP) ratio and induced chemo- and radioresistance. Furthermore RARS-MAD1L1 interacted with AIMP2, which resulted in activation of FUBP1/c-Myc pathway. The silencing of FUBP1 or the administration of a c-Myc inhibitor abrogated the cancer stem cell (CSC)-like characteristics induced by RARS-MAD1L1. The expression of c-Myc and ABCG2 was higher in RARS-MAD1L1-positive HNC samples than in negative samples.Conclusions: Our findings indicate that RARS MAD1L1 might contribute to tumorigenesis, CSC-like properties, and therapeutic resistance, at least in part, through the FUBP1/c-Myc axis, implying that RARS MAD1L1 might serve as an attractive target for therapeutic intervention for NPC. Clin Cancer Res; 24(3); 659-73. (c)2017 AACR. PMID- 29133575 TI - Childhood Sports Participation and Adolescent Sport Profile. AB - OBJECTIVES: We aimed to increase understanding of the link between sport specialization during childhood and adolescent physical activity (PA). The objectives were as follows: (1) describe the natural course of sport participation over 5 years among children who are early sport samplers or early sport specializers and (2) determine if a sport participation profile in childhood predicts the sport profile in adolescence. METHODS: Participants (n = 756, ages 10-11 years at study inception) reported their participation in organized and unorganized PA during in-class questionnaires administered every 4 months over 5 years. They were categorized as early sport samplers, early sport specializers, or nonparticipants in year 1 and as recreational sport participants, performance sport participants, or nonparticipants in years 2 to 5. The likelihood that a childhood sport profile would predict the adolescent profile was computed as relative risks. Polynomial logistic regression was used to identify predictors of an adolescent sport profile. RESULTS: Compared with early sport specialization and nonparticipation, early sport sampling in childhood was associated with a higher likelihood of recreational participation (relative risk, 95% confidence interval: 1.55, 1.18-2.03) and a lower likelihood of nonparticipation (0.69, 0.51-0.93) in adolescence. Early sport specialization was associated with a higher likelihood of performance participation (1.65, 1.19 2.28) but not of nonparticipation (1.01, 0.70-1.47) in adolescence. Nonparticipation in childhood was associated with nearly doubling the likelihood of nonparticipation in adolescence (1.88, 1.36-2.62). CONCLUSIONS: Sport sampling should be promoted in childhood because it may be linked to higher PA levels during adolescence. PMID- 29133576 TI - Spillover Effects of Adult Medicaid Expansions on Children's Use of Preventive Services. AB - BACKGROUND: Since the passage of the Affordable Care Act, Medicaid enrollment has increased by ~17 million adults, including many low-income parents. One potentially important, but little studied, consequence of expanding health insurance for parents is its effect on children's receipt of preventive services. METHODS: By using state Medicaid eligibility thresholds linked to the 2001-2013 Medical Expenditure Panel Surveys, we assessed the relationship between changes in adult Medicaid eligibility and children's likelihood of receiving annual well child visits (WCVs). In instrumental variable analyses, we used these changes in Medicaid eligibility to estimate the relationship between parental enrollment in Medicaid and children's receipt of WCVs. RESULTS: Our analytic sample consisted of 50 622 parent-child dyads in families with incomes <200% of the federal poverty level, surveyed from 2001 to 2013. On average, a 10-point increase in a state's parental Medicaid eligibility (measured relative to the federal poverty level) was associated with a 0.27 percentage point higher probability that a child received an annual WCV (95% confidence interval: 0.058 to 0.48 percentage points, P = .012). Instrumental variable analyses revealed that parental enrollment in Medicaid was associated with a 29 percentage point higher probability that their child received an annual WCV (95% confidence interval: 11 to 47 percentage points, P = .002). CONCLUSIONS: In our study, we demonstrate that Medicaid expansions targeted at low-income adults are associated with increased receipt of recommended pediatric preventive care for their children. This finding reveals an important spillover effect of parental insurance coverage that should be considered in future policy decisions surrounding adult Medicaid eligibility. PMID- 29133577 TI - Evidence for a Uniform Medicaid Eligibility Threshold for Children and Parents. PMID- 29133578 TI - Orlistat-induced oxalate nephropathy: an under-recognised cause of chronic kidney disease. AB - Two patients developed kidney failure due to oxalate deposition in the kidney while taking orlistat. Cessation of orlistat was followed by partial recovery of kidney function. The mechanism by which orlistat causes hyperoxaluria and the management of orlistat-induced oxalate nephropathy is reviewed. We suggest that all patients taking orlistat are at risk of this condition, which may develop insidiously and is easily overlooked. Monitoring of kidney function of patients taking orlistat is warranted. PMID- 29133579 TI - Tubular sigmoid duplication in an adult man: an interesting incidental finding. AB - A 61-year-old man attended an outpatient colorectal clinic for a chronic, non specific abdominal pain, associated with rectal bleeding. He underwent a number of investigations including a CT pneumocolon, which revealed an incidental finding of 20 cm of additional sigmoid colon. This case is interesting because tubular sigmoid duplication is an extremely unusual condition, rarely diagnosed in adults; only a few cases have been reported of this condition in the adult population. Our team chose to treat this patient conservatively, in order to avoid putting the patient at risk of an unnecessary surgery. PMID- 29133580 TI - Successful downstaging of locally recurrent penile squamous cell carcinoma with neoadjuvant nanosomal docetaxel lipid suspension (NDLS) based regimen followed by curative surgery. AB - Penile squamous cell carcinoma (pSCC) is a relatively rare disease in Western world but is a significant health problem in developing countries like India. We report here a case of successful multimodality management of recurrent pSCC with pelvic lymphadenopathy in a 56-year-old male patient with poorly controlled diabetes. The patient presented with ulceroproliferative growth over the residual penile stump clinically involving root of penis and with right pelvic lymphadenopathy. The patient had a history of partial penectomy done elsewhere 20 months ago. In view of the comorbidities, locally recurrent disease and presence of right Iliac lymphadenopathy, the patient was treated with nanosomal docetaxel lipid suspension (NDLS), cisplatin and 5-fluorouracil (TPF regimen) in the neoadjuvant setting followed by staged surgical resection. This is the first case report showing successful treatment of recurrent pSCC with NDLS-based TPF regimen in the neoadjuvant setting followed by staged surgery in a patient with poorly controlled diabetes. PMID- 29133581 TI - Global aphasia in a case of bilateral frontal lobe infarcts involving both caudate nuclei. PMID- 29133582 TI - Use of ketamine for acute suicidal ideation in a patient with chronic pain on prescribed cannabinoids. AB - Ketamine is a standard anaesthetic drug that has been studied as a possible treatment for acute suicidal ideation. Aside to the potential psychotropic effects of ketamine, a Cochrane review reported that available studies suggest a modest effect of ketamine for chronic pain months to years after surgical intervention. We present a patient with acute suicidal ideation who required immediate inpatient psychiatric admission in the setting of concurrent chronic pain on cannabinoids which could not be prescribed within our inpatient hospital setting. This presented a clinical dilemma to rapidly reverse the patient's suicidality while substituting the patient's prescribed cannabinoid products with an alternative pain regimen. Since there is emerging support in the use of ketamine in suicidality and chronic pain, we administered ketamine while withholding cannabinoid products and found evidence to support its use in rapid reversal of suicidal ideation and temporary chronic pain relief. PMID- 29133583 TI - Urachal sinus leading to pyourachus presenting as recurrent periumbilical sepsis in an infant. PMID- 29133584 TI - Asymptomatic contrast medium extravasation. PMID- 29133585 TI - Post-traumatic untreated chronic osteomyelitis: an extreme presentation with severe complications. PMID- 29133586 TI - Prenatal diagnosis of left isomerism with normal heart. PMID- 29133587 TI - Single coronary artery with high aortic take-off-a rare coronary anomaly. PMID- 29133589 TI - Precision Oncology beyond Targeted Therapy: Combining Omics Data with Machine Learning Matches the Majority of Cancer Cells to Effective Therapeutics. AB - Precision oncology involves identifying drugs that will effectively treat a tumor and then prescribing an optimal clinical treatment regimen. However, most first line chemotherapy drugs do not have biomarkers to guide their application. For molecularly targeted drugs, using the genomic status of a drug target as a therapeutic indicator has limitations. In this study, machine learning methods (e.g., deep learning) were used to identify informative features from genome scale omics data and to train classifiers for predicting the effectiveness of drugs in cancer cell lines. The methodology introduced here can accurately predict the efficacy of drugs, regardless of whether they are molecularly targeted or nonspecific chemotherapy drugs. This approach, on a per-drug basis, can identify sensitive cancer cells with an average sensitivity of 0.82 and specificity of 0.82; on a per-cell line basis, it can identify effective drugs with an average sensitivity of 0.80 and specificity of 0.82. This report describes a data-driven precision medicine approach that is not only generalizable but also optimizes therapeutic efficacy. The framework detailed herein, when successfully translated to clinical environments, could significantly broaden the scope of precision oncology beyond targeted therapies, benefiting an expanded proportion of cancer patients. Mol Cancer Res; 16(2); 269 78. (c)2017 AACR. PMID- 29133588 TI - Quantitative analysis of multilayer organization of proteins and RNA in nuclear speckles at super resolution. AB - Nuclear speckles are self-assembled organelles composed of RNAs and proteins. They are proposed to act as structural domains that control distinct steps in gene expression, including transcription, splicing and mRNA export. Earlier studies identified differential localization of a few components within the speckles. It was speculated that the spatial organization of speckle components might contribute directly to the order of operations that coordinate distinct processes. Here, by performing multi-color structured illumination microscopy, we characterized the multilayer organization of speckles at a higher resolution. We found that SON and SC35 (also known as SRSF2) localize to the central region of the speckle, whereas MALAT1 and small nuclear (sn)RNAs are enriched at the speckle periphery. Coarse-grained simulations indicate that the non-random organization arises due to the interplay between favorable sequence-encoded intermolecular interactions of speckle-resident proteins and RNAs. Finally, we observe positive correlation between the total amount of RNA present within a speckle and the speckle size. These results imply that speckle size may be regulated to accommodate RNA accumulation and processing. Accumulation of RNA from various actively transcribed speckle-associated genes could contribute to the observed speckle size variations within a single cell. PMID- 29133590 TI - Genotoxic Damage Activates the AMPK-alpha1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival. AB - Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the alpha1 but not the alpha2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2+-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G1-phase cell-cycle arrest, and enhanced cell viability/survival after etoposide treatment, with both effects being abolished by knockout of AMPK-alpha1 and alpha2. The CDK4/6 inhibitor palbociclib also caused G1 arrest in G361 but not HeLa cells and, consistent with this, enhanced cell survival after etoposide treatment only in G361 cells. These results suggest that AMPK activation protects cells against etoposide by limiting entry into S phase, where cells would be more vulnerable to genotoxic stress.Implications: These results reveal that the alpha1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-alpha1 (but not -alpha2) is amplified in some human cancers. Furthermore, alpha1-selective inhibitors might enhance the anticancer effects of genotoxic-based therapies. Mol Cancer Res; 16(2); 345-57. (c)2017 AACR. PMID- 29133591 TI - Chemokine Signaling Facilitates Early-Stage Breast Cancer Survival and Invasion through Fibroblast-Dependent Mechanisms. AB - Ductal carcinoma in situ (DCIS) is the most common form of breast cancer, with 50,000 cases diagnosed every year in the United States. Overtreatment and undertreatment remain significant clinical challenges in patient care. Identifying key mechanisms associated with DCIS progression could uncover new biomarkers to better predict patient prognosis and improve guided treatment. Chemokines are small soluble molecules that regulate cellular homing through molecular gradients. CCL2-mediated recruitment of CCR2+ macrophages are a well established mechanism for metastatic progression. Although the CCL2/CCR2 pathway is a therapeutic target of interest, little is known about the role of CCR2 expression in breast cancer. Here, using a mammary intraductal injection (MIND) model to mimic DCIS formation, the role of CCR2 was explored in minimally invasive SUM225 and highly invasive DCIS.com breast cancer cells. CCR2 overexpression increased SUM225 breast cancer survival and invasion associated with accumulation of CCL2 expressing fibroblasts. CCR2-deficient DCIS.com breast cancer cells formed fewer invasive lesions with fewer CCL2+ fibroblasts. Cografting CCL2-deficient fibroblasts with DCIS.com breast cancer cells in the subrenal capsule model inhibited tumor invasion and survival associated with decreased expression of aldehyde dehydrogenase (ALDH1), a proinvasive factor, and decreased expression of HTRA2, a proapoptotic serine protease. Through data mining analysis, high expression of CCR2 and ALDH1 and low HTRA2 expression were correlated with poor prognosis of breast cancer patients.Implications: This study demonstrates that CCR2 overexpression in breast cancer drives early-stage breast cancer progression through stromal-dependent expression of CCL2 with important insight into prognosis and treatment of DCIS. Mol Cancer Res; 16(2); 296-308. (c)2017 AACR. PMID- 29133593 TI - Adipose-Derived VEGF-mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women. AB - Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.Implications: Adipocyte-derived VEGF-mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309-21. (c)2017 AACR. PMID- 29133592 TI - PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors. AB - KRAS mutations in non-small cell lung cancer (NSCLC) cause increased levels of DNA damage and replication stress, suggesting that inhibition of the DNA damage response (DDR) is a promising strategy for radiosensitization of NSCLC. This study investigates the ability of a WEE1 inhibitor (AZD1775) and a PARP inhibitor (olaparib) to radiosensitize KRAS-mutant NSCLC cells and tumors. In addition to inhibiting the DDR, these small-molecule inhibitors of WEE1 and PARP induce DNA replication stress via nucleotide exhaustion and PARP trapping, respectively. As monotherapy, AZD1775 or olaparib alone modestly radiosensitized a panel of KRAS mutant NSCLC lines. The combination of agents, however, significantly increased radiosensitization. Furthermore, AZD1775-mediated radiosensitization was rescued by nucleotide repletion, suggesting a mechanism involving AZD1775-mediated replication stress. In contrast, radiosensitization by the combination of AZD1775 and olaparib was not rescued by nucleosides. Whereas both veliparib, a PARP inhibitor that does not efficiently trap PARP1 to chromatin, and PARP1 depletion radiosensitized NSCLC cells as effectively as olaparib, which does efficiently trap PARP, only olaparib potentiated AZD1775-mediated radiosensitization. Taken together, these mechanistic data demonstrate that although nucleotide depletion is sufficient for radiosensitization by WEE1 inhibition alone, and inhibition of PARP catalytic activity is sufficient for radiosensitization by olaparib alone, PARP1 trapping is required for enhanced radiosensitization by the combination of WEE1 and PARP inhibitors.Implications: This study highlights DNA replication stress caused by nucleotide depletion and PARP1 trapping as an important mechanism of radiosensitization in KRAS-mutant tumors and supports further development of DNA replication as a therapeutic target. Mol Cancer Res; 16(2); 222-32. (c)2017 AACR. PMID- 29133594 TI - Competitive Kinase Enrichment Proteomics Reveals that Abemaciclib Inhibits GSK3beta and Activates WNT Signaling. AB - The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice. Several clinically active kinase inhibitors were profiled, including trametinib, BMS-777607, dasatinib, abemaciclib, and palbociclib. MIB/MS competition analyses of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib and palbociclib revealed overlapping and unique kinase targets. Competitive MIB/MS analysis of abemaciclib revealed 83 target kinases, and dose-response MIB/MS profiling revealed glycogen synthase kinase 3 alpha and beta (GSK3alpha and beta) and Ca2+/calmodulin-dependent protein kinase II delta and gamma (CAMKIIdelta and gamma) as the most potently inhibited. Cell-based and in vitro kinase assays show that in contrast to palbociclib, abemaciclib directly inhibits GSK3alpha/beta and CAMKIIgamma/delta kinase activity at low nanomolar concentrations. GSK3beta phosphorylates beta-catenin to suppress WNT signaling, while abemaciclib (but not palbociclib or ribociclib) potently activates beta-catenin-dependent WNT signaling. These data illustrate the power of competitive chemical proteomics to define kinase target specificities for kinase inhibitors, thus informing clinical efficacy, dose-limiting toxicities, and drug-repurposing efforts.Implications: This study uses a rapid and quantitative proteomics approach to define inhibitor target data for commonly administered therapeutics and provides a cell-based alternative to in vitro kinome profiling. Mol Cancer Res; 16(2); 333-44. (c)2017 AACR. PMID- 29133595 TI - Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia. AB - Mixed lineage leukemia (MLL) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPG) in many patients. Long distance inverse (LDI)-PCR, the "gold standard" technique that is used to characterize MLL breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next generation sequencing (NGS) approach that requires low RNA input was tested. Anchored multiplex PCR-based enrichment (AMP-E) was used to rapidly identify a broad range of MLL fusions in patient specimens. Libraries generated using Archer FusionPlex Heme and Myeloid panels were sequenced using the Illumina platform. Diagnostic specimens (n = 39) from pediatric leukemia patients were tested with AMP-E and validated by LDI-PCR. In concordance with LDI-PCR, the AMP-E method successfully identified TPGs without prior knowledge. AMP-E identified 10 different MLL fusions in the 39 samples. Only two specimens were discordant; AMP E successfully identified a MLL-MLLT1 fusion where LDI-PCR had failed to determine the breakpoint, whereas a MLL-MLLT3 fusion was not detected by AMP-E due to low expression of the fusion transcript. Sensitivity assays demonstrated that AMP-E can detect MLL-AFF1 in MV4-11 cell dilutions of 10-7 and transcripts down to 0.005 copies/ng.Implications: This study demonstrates a NGS methodology with improved sensitivity compared with current diagnostic methods for MLL rearranged leukemia. Furthermore, this assay rapidly and reliably identifies MLL partner genes and patient-specific fusion sequences that could be used for monitoring minimal residual disease. Mol Cancer Res; 16(2); 279-85. (c)2017 AACR. PMID- 29133596 TI - Exposure to ambient fine particulate matter and semen quality in Taiwan. AB - OBJECTIVES: Environmental exposure to chemicals has been considered a potential factor contributing to deteriorated semen quality. However, previous literature on exposure to air pollution and semen quality is inconsistent. We therefore investigated the health effects of short-term and long-term exposure to fine particulate matter (PM2.5) on semen quality in Taiwanese men from the general population. METHODS: A cross-sectional study was conducted among 6475 male participants aged 15-49 years who participated in a standard medical examination programme in Taiwan between 2001 and 2014. Semen quality was assessed according to the WHO 1999 guidelines, including sperm concentration, total motility, progressive motility and morphology. Three-month and 2-year average PM2.5 concentrations were estimated at each participant's address using a spatiotemporal model based on satellite-derived aerosol optical depth data. Multivariable linear and logistic regressions were used to examine the associations between PM2.5 and semen quality. RESULTS: A robust association was observed between exposure to PM2.5 and decreased normal morphology. Every increment of 5 ug/m3 in 2-year average PM2.5 was significantly associated with a decrease of 1.29% in sperm normal morphology and a 26% increased risk of having the bottom 10% of sperm normal morphology, after adjusting for a wide range of potential confounders (p<0.001). On the other hand, an increment of 5 ug/m3 in 2 year average PM2.5 was associated with an increase of 1.03*106/mL in sperm concentration and a 10% decreased risk of being the bottom 10% of sperm concentration (both p<0.001). Similar results were found for 3-month PM2.5. CONCLUSIONS: Exposure to ambient PM2.5 air pollution is associated with a lower level of sperm normal morphology and a higher level of sperm concentration. PMID- 29133597 TI - Occupational exposure to asbestos and risk of cholangiocarcinoma: a population based case-control study in four Nordic countries. AB - OBJECTIVES: To assess the association between occupational exposure to asbestos and the risk of cholangiocarcinoma (CC). METHODS: We conducted a case-control study nested in the Nordic Occupational Cancer (NOCCA) cohort. We studied 1458 intrahepatic CC (ICC) and 3972 extrahepatic CC (ECC) cases occurring among subjects born in 1920 or later in Finland, Iceland, Norway and Sweden. Each case was individually matched by birth year, gender and country to five population controls. The cumulative exposure to asbestos (measured in fibres (f)/ml * years) was assessed by applying the NOCCA job-exposure matrix to data on occupations collected during national population censuses (conducted in 1960, 1970, 1980/81 and 1990). Odds ratios (OR) and 95% CI were estimated using conditional logistic regression models adjusted by printing industry work. RESULTS: We observed an increasing risk of ICC with cumulative exposure to asbestos: never exposed, OR 1.0 (reference category); 0.1-4.9 f/mL * years, OR 1.1 (95% CI 0.9 to 1.3); 5.0 9.9 f/mL * years, OR 1.3 (95% CI 0.9 to 2.1); 10.0-14.9 f/mL * years, OR 1.6 (95% CI 1.0 to 2.5); >=15.0 f/mL * years, OR 1.7 (95% CI 1.1 to 2.6). We did not observe an association between cumulative asbestos exposure and ECC. CONCLUSIONS: Our study provides evidence that exposure to asbestos might be a risk factor for ICC. Our findings also suggest that the association between ECC and asbestos is null or weaker than that observed for ICC. Further studies based on large industrial cohorts of asbestos workers and possibly accounting for personal characteristics and clinical history are needed. PMID- 29133598 TI - Half-lives of PFOS, PFHxS and PFOA after end of exposure to contaminated drinking water. AB - BACKGROUND: Municipal drinking water contaminated with perfluorinated alkyl acids had been distributed to one-third of households in Ronneby, Sweden. The source was firefighting foam used in a nearby airfield since the mid-1980s. Clean water was provided from 16 December 2013. OBJECTIVE: To determine the rates of decline in serum perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), and their corresponding half-lives. METHODS: Up to seven blood samples were collected between June 2014 and September 2016 from 106 participants (age 4-84 years, 53% female). RESULTS: Median initial serum concentrations were PFHxS, 277 ng/mL (range 12-1660); PFOS, 345 ng/mL (range 24 1500); and PFOA, 18 ng/mL (range 2.4-92). The covariate-adjusted average rates of decrease in serum were PFHxS, 13% per year (95% CI 12% to 15%); PFOS, 20% per year (95% CI 19% to 22%); and PFOA, 26% per year (95% CI 24% to 28%). The observed data are consistent with a first-order elimination model. The mean estimated half-life was 5.3 years (95% CI 4.6 to 6.0) for PFHxS, 3.4 years (95% CI 3.1 to 3.7) for PFOS and 2.7 years (95% CI 2.5 to 2.9) for PFOA. The interindividual variation of half-life was around threefold when comparing the 5th and 95th percentiles. There was a marked sex difference with more rapid elimination in women for PFHxS and PFOS, but only marginally for PFOA. CONCLUSIONS: The estimated half-life for PFHxS was considerably longer than for PFOS and PFOA. For PFHxS and PFOS, the average half-life is shorter than the previously published estimates. For PFOA the half-life is in line with the range of published estimates. PMID- 29133599 TI - Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. AB - BACKGROUND: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults provides recommendations for the definition of hypertension, systolic and diastolic blood pressure (BP) thresholds for initiation of antihypertensive medication, and BP target goals. OBJECTIVES: This study sought to determine the prevalence of hypertension, implications of recommendations for antihypertensive medication, and prevalence of BP above the treatment goal among US adults using criteria from the 2017 ACC/AHA guideline and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7). METHODS: The authors analyzed data from the 2011 to 2014 National Health and Nutrition Examination Survey (N = 9 623). BP was measured 3 times following a standardized protocol and averaged. Results were weighted to produce US population estimates. RESULTS: According to the 2017 ACC/AHA and JNC7 guidelines, the crude prevalence of hypertension among US adults was 45.6% (95% confidence interval [CI]: 43.6% to 47.6%) and 31.9% (95% CI: 30.1% to 33.7%), respectively, and antihypertensive medication was recommended for 36.2% (95% CI: 34.2% to 38.2%) and 34.3% (95% CI: 32.5% to 36.2%) of US adults, respectively. Nonpharmacological intervention is advised for the 9.4% of US adults with hypertension who are not recommended for antihypertensive medication according to the 2017 ACC/AHA guideline. Among US adults taking antihypertensive medication, 53.4% (95% CI: 49.9% to 56.8%) and 39.0% (95% CI: 36.4% to 41.6%) had BP above the treatment goal according to the 2017 ACC/AHA and JNC7 guidelines, respectively. CONCLUSIONS: Compared with the JNC7 guideline, the 2017 ACC/AHA guideline results in a substantial increase in the prevalence of hypertension, a small increase in the percentage of US adults recommended for antihypertensive medication, and more intensive BP lowering for many adults taking antihypertensive medication. PMID- 29133600 TI - Availability and Use of Shared Data From Cardiometabolic Clinical Trials. AB - BACKGROUND: Sharing of patient-level clinical trial data has been widely endorsed. Little is known about how extensively these data have been used for cardiometabolic diseases. We sought to evaluate the availability and use of shared data from cardiometabolic clinical trials. METHODS: We extracted data from ClinicalStudyDataRequest.com, a large, multisponsor data-sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies. RESULTS: From January 2013 to May 2017, the platform had data from 3374 clinical trials, of which 537 (16%) evaluated cardiometabolic therapeutics (phase 1, 36%; phase 2, 17%; phase 2/3, 1%; phase 3, 42%; phase 4, 4%). They covered 74 therapies and 398 925 patients. Diabetes mellitus (60%) and hypertension (15%) were the most common study topics. Median time from study completion to data availability was 79 months. As of May 2017, ClinicalStudyDataRequest.com had received 318 submitted proposals, of which 163 had signed data-sharing agreements. Thirty of these proposals were related to cardiometabolic therapies and requested data from 79 unique studies (15% of all trials, 29% of phase 3/4 trials). Most (96%) data requesters of cardiometabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Most proposals were for secondary hypothesis-generating questions, with only 1 proposed reanalysis of the original study primary hypothesis. To date, 3 peer-reviewed articles have been published after a median of 19 months (9-32 months) from the data-sharing agreement. CONCLUSIONS: Despite availability of data from >500 cardiometabolic trials in a multisponsor data-sharing platform, only 15% of these trials and 29% of phase 3/4 trials have been accessed by investigators thus far, and a negligible minority of analyses have reached publication. PMID- 29133601 TI - Burden of Catastrophic Health Expenditures for Acute Myocardial Infarction and Stroke Among Uninsured in the United States. PMID- 29133602 TI - Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME. PMID- 29133603 TI - Canagliflozin: Cui Bono? PMID- 29133604 TI - Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). AB - BACKGROUND: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation. METHODS: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals >=50 years of age with >=2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals >=30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death). RESULTS: Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70 3.29; interaction P value=0.63). CONCLUSIONS: Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754. PMID- 29133605 TI - Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). AB - BACKGROUND: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. METHODS: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. RESULTS: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. CONCLUSIONS: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633. PMID- 29133606 TI - Effects of Bariatric Surgery in Obese Patients With Hypertension: The GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension). AB - BACKGROUND: Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution. Randomized trials designed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed. METHODS: In this randomized, single-center, nonblinded trial, we included patients with hypertension (using >=2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/m2. Patients were randomized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary end point was reduction of >=30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure <140 mm Hg and 90 mm Hg, respectively, at 12 months. RESULTS: We included 100 patients (70% female, mean age 43.8+/-9.2 years, mean body mass index 36.9+/-2.7 kg/m2), and 96% completed follow-up. Reduction of >=30% of the total number of antihypertensive medications while maintaining controlled blood pressure occurred in 41 of 49 patients from the gastric bypass group (83.7%) compared with 6 of 47 patients (12.8%) from the control group with a rate ratio of 6.6 (95% confidence interval, 3.1-14.0; P<0.001). Remission of hypertension was present in 25 of 49 (51%) and 22 of 48 (45.8%) patients randomized to gastric bypass, considering office and 24-hour ambulatory blood pressure monitoring, respectively, whereas no patient submitted to medical therapy was free of antihypertensive drugs at 12 months. A post hoc analysis for the primary end point considering the SPRINT (Systolic Blood Pressure Intervention Trial) target reached consistent results, with a rate ratio of 3.8 (95% confidence interval, 1.4-10.6; P=0.005). Eleven patients (22.4%) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives. Waist circumference, body mass index, fasting plasma glucose, glycohemoglobin, low-density lipoprotein cholesterol, triglycerides, high sensitivity C-reactive protein, and 10-year Framingham risk score were lower in the gastric bypass than in the control group. CONCLUSIONS: Bariatric surgery represents an effective strategy for blood pressure control in a broad population of patients with obesity and hypertension. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01784848. PMID- 29133607 TI - Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World). AB - BACKGROUND: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual end points or safety concerns. METHODS: We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on-treatment analyses were performed. RESULTS: After propensity matching, 25 258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50-0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60-0.75). SGLT2i initiation was also associated with an ~2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12-3.51). Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis. CONCLUSIONS: In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments. PMID- 29133608 TI - Systemic vasculitis with dermatomyositis, hearing loss, neuropathy, and multiorgan dysfunction. PMID- 29133609 TI - Editors' Note. PMID- 29133610 TI - Letter re: Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE. PMID- 29133611 TI - Author response: Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE. PMID- 29133612 TI - Letter re: Effects of orthostatic hypotension on cognition in Parkinson disease. PMID- 29133613 TI - Author response: Effects of orthostatic hypotension on cognition in Parkinson disease. PMID- 29133614 TI - Clinical Reasoning: Prognostication after cardiac arrest: What do we really know? PMID- 29133615 TI - Teaching Video NeuroImages: The pathologic deep abdominal reflex. PMID- 29133616 TI - Margaret McCartney: Doctors should care about cycling. PMID- 29133617 TI - Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo. AB - FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib resistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. Mol Cancer Ther; 17(1); 84-95. (c)2017 AACR. PMID- 29133619 TI - Clinical Application of Circulating Tumor DNA in the Genetic Analysis of Patients with Advanced GIST. AB - Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. Although, circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance, but the concordance was strong for patients with tumor size > 10 cm or Ki-67 > 5%. Tumor size, mitotic figure, Ki-67, and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type, were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients. Mol Cancer Ther; 17(1); 290-6. (c)2017 AACR. PMID- 29133618 TI - Therapeutic Impact of Nanoparticle Therapy Targeting Tumor-Associated Macrophages. AB - Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest antiangiogenic therapy-induced hypoxia can induce tumor "stemness" as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor-associated macrophages (TAM). As such, TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) nanoparticles deplete TAMs in both solid tumor and ascites models of ovarian cancer. As a therapeutic agent, these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to antiangiogenic therapy, (ii) prevent antiangiogenic therapy-induced increases in cancer stem-like cells in both murine and human tumor cell models, (iii) prevent antiangiogenic therapy-induced increases in VEGF C, and (iv) prevent antiangiogenic therapy-induced BRCA1 gene expression. Combined, this work strongly supports the development of TAM-targeted nanoparticle therapy. Mol Cancer Ther; 17(1); 96-106. (c)2017 AACR. PMID- 29133620 TI - Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response-Targeted Therapies in Breast Cancer. AB - Disruption of Cyclin-Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by IHC in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer-specific survival taking HER2 status into account; however, absent CDK12 protein expression significantly correlated with a triple-negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK, and gammaH2AX, suggesting a novel mechanism of CDK12 associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple-negative breast cancers. Mol Cancer Ther; 17(1); 306-15. (c)2017 AACR. PMID- 29133621 TI - The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA. AB - We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N = 55; 26%), appendiceal adenocarcinoma (N = 46; 22%), hepatocellular carcinoma (N = 31; 15%), and pancreatic ductal adenocarcinoma (N = 25; 12%). The majority of patients (58%) had >=1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0-13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had >=1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76%-8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall, concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (N = 105 patients) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of 123 patients with characterized alterations, >99% (122/123; 57% of entire population tested; 122/213) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and theoretically pharmacologically tractable ctDNA alterations that merit further studies in prospective trials. Mol Cancer Ther; 17(1); 297-305. (c)2017 AACR. PMID- 29133623 TI - IMMU-140, a Novel SN-38 Antibody-Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma. AB - HLA-DR is a member of the MHC class II antigen family expressed on hematologic and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti-HLA-DR antibody-drug conjugate composed of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors. IMMU-140 had dual therapeutic mechanisms, as evidenced by its retention of nonoverlapping anti-HLA DR nonclassical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models [acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and melanoma], IMMU 140 provided significant therapeutic efficacy compared with controls, in vitro, in 3D spheroid models, and in vivo Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared with parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU 140 therapy mediated >80% improvement in survival. Therapy was well tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU 140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development. Mol Cancer Ther; 17(1); 150-60. (c)2017 AACR. PMID- 29133622 TI - Ceritinib Enhances the Efficacy of Trametinib in BRAF/NRAS-Wild-Type Melanoma Cell Lines. AB - Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single-agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both three-dimensional spheroid culture and long-term colony formation experiments. Coadministration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS-WT melanoma model; this was not due to ALK inhibition by ceritinib. Mechanistic studies showed the ceritinib-trametinib combination to increase suppression of MAPK and TORC1 signaling. Similar results were seen when BRAF/NRAS WT melanoma cells were treated with a combination of trametinib and the TORC1/2 inhibitor INK128. We next used mass spectrometry-based chemical proteomics and identified known and new ceritinib targets, such as IGF1R and ACK1, respectively. Validation studies suggested that ceritinib could suppress mTORC1 signaling in the presence of trametinib through inhibition of IGF1R and/or ACK1 in a cell line dependent manner. Together, our studies demonstrated that combining a specific inhibitor (trametinib) with a more broadly targeted agent (ceritinib) has efficacy against tumors with heterogeneous mutational profiles. Mol Cancer Ther; 17(1); 73-83. (c)2017 AACR. PMID- 29133624 TI - Histopathological, histomorphometrical, and radiological evaluations of hydroxyapatite/bioactive glass and fluorapatite/bioactive glass nanocomposite foams as cell scaffolds in rat tibia: an in vivo study. AB - Bone defects are common and persistent problems in clinical orthopedics and dentistry. The development of synthetic reconstruction materials is essential owing to the restricted access to natural bone grafts, disease transmission risks, surgical costs, donor-site morbidity, infections, and immune response related complications. The present study was done to evaluate the histopathological, histomorphometrical, and radiological characteristics of composite foams containing hydroxyapatite/bioactive glass (HA/BG) and fluorapatite/bioactive glass (FA/BG) as cell scaffolds in rat tibia reconstruction. A total of 60 rats were divided into four equal groups, of which three groups were implanted with HA/BG, FA/BG, and CenoBone(r) biomaterials, and the fourth group served as the implant-free controls. Five rats from each group were sacrificed at 15, 30, or 60 days after implantation, and radiological, histopathological, and histomorphometrical assessments were carried out. Based on the findings, no foreign body reaction was present in the rats. Additionally, bone-biomaterial contact occurred directly without the involvement of connective tissues. The number of osteoblasts was reduced in the implant groups, whereas the trabecular thickness and rate of new bone formation were increased in all groups, where the increase in the FA/BG group was the most prominent. The mean percentage difference in bone density between the implant site and the host bone was greater in the FA/BG group at all three time points of the study. Based on the results of the present study and the positive characteristics of these nanocomposite foams, they can be suitable options for implantation in damaged tissues in tissue engineering. PMID- 29133625 TI - The interplay of peptide affinity and scaffold stiffness on neuronal differentiation of neural stem cells. AB - Cells are sensitive to physical cues in their environment, such as the stiffness of the substrate, peptide density, and peptide affinity. Understanding how neural stem cells (NSCs) sense and respond to these matrix cues has the potential to improve disease outcome, particularly if a regenerative response can be exploited. While the material properties are known to influence other stem cells, little is known about how NSC differentiation is altered by this interplay of mechanical, or bulk properties, with peptide concentration and affinity, or microscale properties. We are interested in the combined effect of bulk and microscale features in an in vitro hydrogel model and therefore we investigated NSC differentiation by focusing on integrin interactions via RGD peptide affinity and concentration. Our studies demonstrated that the peptide concentration affected adhesion as there were more cells on scaffolds with 1 mM RGD than 2.5 mM RGD. The hydrogel stiffness affected neurite length in differentiating NSCs, as 0.1-0.8 kPa substrates promoted greater neurite extension than 4.2-7.9 kPa substrates. The NSCs differentiated towards beta-IotaIotaIota tubulin positive cells on scaffolds with RGD after 7 days and those scaffolds containing 1 mM linear or cyclic RGD had longer neurite extensions than scaffolds containing 0.1 or 2.5 mM RGD. While peptide affinity had a lesser effect on the NSC response in our hydrogel system, blocking actin, myosin II, or integrin interactions resulted in changes to the cell morphology and focal adhesion assembly. Overall, these results demonstrated NSCs are more responsive to a change in tissue stiffness than peptide affinity in the range of gels tested, which may influence design of materials for neural tissue engineering. PMID- 29133626 TI - Pediatric ophthalmology, neuro-ophthalmology, uvea, and oculoplasty: Survival is the only option. PMID- 29133627 TI - Altered tear inflammatory profile in Indian keratoconus patients. PMID- 29133628 TI - How safe is safe, and where are we in the journey toward safest of safe? PMID- 29133629 TI - Pediatric ophthalmology and strabismus in India: Wake-up call and the way forward! PMID- 29133630 TI - Non-contact lens related Acanthamoeba keratitis. AB - The purpose of the study is to describe epidemiology, clinical features, diagnosis, and treatment of Acanthamoeba keratitis (AK) with special focus on the disease in nonusers of contact lenses (CLs). This study was a perspective based on authors' experience and review of published literature. AK accounts for 2% of microbiology-proven cases of keratitis. Trauma and exposure to contaminated water are the main predisposing factors for the disease. Association with CLs is seen only in small fraction of cases. Contrary to classical description experience in India suggests that out of proportion pain, ring infiltrate, and radial keratoneuritis are seen in less than a third of cases. Majority of cases present with diffuse infiltrate, mimicking herpes simplex or fungal keratitis. The diagnosis can be confirmed by microscopic examination of corneal scraping material and culture on nonnutrient agar with an overlay of Escherichia coli. Confocal microscopy can help diagnosis in patients with deep infiltrate; however, experience with technique and interpretation of images influences its true value. Primary treatment of the infection is biguanides with or without diamidines. Most patients respond to medical treatment. Corticosteroids play an important role in the management and can be used when indicated after due consideration to established protocols. Surgery is rarely needed in patients where definitive management is initiated within 3 weeks of onset of symptoms. Lamellar keratoplasty has been shown to have good outcome in cases needing surgery. Since the clinical features of AK in nonusers of CL are different, it will be important for ophthalmologists to be aware of the scenario wherein to suspect this infection. Medical treatment is successful if the disease is diagnosed early and management is initiated soon. PMID- 29133631 TI - Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy. AB - Leber's hereditary optic neuropathy (LHON) is a common inherited mitochondrial disorder that is characterized by the degeneration of the optic nerves, leading to vision loss. The major mutations in the mitochondrial genes ND1, ND4, and ND6 of LHON subjects are found to increase the oxidative stress experienced by the optic nerve cell, thereby leading to nerve cell damage. Accurate treatments are not available and drugs that are commercially available like Idebenone, EPI-743, and Bendavia with their antioxidant role help in reducing the oxidative stress experienced by the cell thereby preventing the progression of the disease. Genetic counseling plays an effective role in making the family members aware of the inheritance pattern of the disease. Gene therapy is an alternative for curing the disease but is still under study. This review focuses on the role of mitochondrial genes in causing LHON and therapeutics available for treating the disease. A systematic search has been adopted in various databases using the keywords "LHON," "mitochondria," "ND1," "ND4," "ND6," and "therapy" and the following review on mitochondrial genetics and therapeutics of LHON has been developed with obtained articles from 1988 to 2017. PMID- 29133632 TI - Uveal effusion syndrome in 104 eyes: Response to corticosteroids - The 2017 Axel C. Hansen lecture. AB - PURPOSE: The purpose of the study was to investigate the corticosteroids for uveal effusion syndrome (UES). METHODS: Retrospective series of 104 eyes with UES treated with oral corticosteroids (OCS), periocular corticosteroids (PCS), topical corticosteroids (TCS), or observation (OBS). Main outcome measure was UES resolution. RESULTS: Of 104 eyes, treatment included OCS (n = 27), PCS (n = 12), TCS (n = 11), and OBS (n = 54). A comparison of the four groups (OCS vs. PCS vs. TCS vs. OBS) revealed differences in those managed with OCS versus OBS as younger (66 vs. 72 years, P = 0.049), PCS versus OBS as male (100% vs. 54%, P = 0.002), PCS versus OBS with decreased visual acuity (VA)/visual field (91% vs. 51%, P = 0.018), and OBS versus OCS as asymptomatic (28% vs. 0%, P = 0.001). Of the 59 with follow-up information, management included OCS (n = 21), PCS (n = 12), TCS (n = 6), and OBS (n = 20). There were differences in initial VA <20/400 in PCS versus OBS (42% vs. 5%, P = 0.018), effusion thickness in TCS versus OCS (7 vs. 3 mm, P = 0.004), and serous retinal detachment in PCS versus OBS (100% vs. 30%, P < 0.001) and PCS versus OCS (100% vs. 57%, P = 0.012). Regarding outcomes, VA showed less worsening in OCS versus OBS (0% vs. 30%, P = 0.008) and OCS versus PCS (0% vs. 33%, P = 0.012). There was no difference in rate of effusion resolution or effusion recurrence. Overall, using combination of corticosteroid therapies, effusion resolution was achieved in 56/59 (95%) cases and the need for surgical management with scleral windows was necessary in only 3/59 (5%) cases. Complications included cataract (n = 9) and no instance of steroid-induced glaucoma. CONCLUSION: Management of UES is complex and depends on disease severity. Using various corticosteroid delivery routes, UES control was achieved in 95%, and scleral window surgery was required in only 5%. A trial of corticosteroids can benefit patients with UES. PMID- 29133633 TI - Altered tear inflammatory profile in Indian keratoconus patients - The 2015 Col Rangachari Award paper. AB - PURPOSE: Conventionally, keratoconus (KC) has been considered a noninflammatory corneal ectatic disorder. Recent evidence suggests a possible role of inflammation in the pathogenesis of KC. Hence, we analyzed the levels of inflammatory factors in the tear fluid of Indian KC patients. METHODS: Tear fluid samples were collected from age- and sex-matched healthy controls and KC patients (with different grades). The levels of the inflammatory factors in tears were analyzed using cytometric bead array (Human Soluble Protein Flex Set System, BD Biosciences) for levels of interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12p70, IL-23p40, IL-13, IL-17A, IL-17F, IL-21, interferon-alpha (IFNalpha), IFNgamma, tumor necrosis factor-alpha, CCL2/monocyte chemotactic protein-1, CCL4/macrophage inflammatory protein-1beta (MIP-1beta), MIP-1alpha, CCL5/RANTES, CXCL10/IP10, ICAM1, CD62E, vascular endothelial growth factor and transforming growth factor beta. RESULTS: An increase in Kmax and Kmean, and a decrease in central corneal thickness was observed with increasing grades of KC. Tear analysis showed that most of the tear soluble factors, including cytokines, chemokines, growth factors and cell adhesion molecules were significantly elevated in the KC patients compared to the controls. CONCLUSION: Our findings suggest that inflammatory factors associated with KC may play a role in its pathogenesis. This opens the potential to explore anti-inflammatory strategies to either halt or delay the progression of KC. PMID- 29133634 TI - Immunohistochemical expression of X-linked inhibitor of apoptosis in eyelid sebaceous gland carcinoma predicts a worse prognosis. AB - PURPOSE: Overexpression of the inhibitors of apoptosis proteins have been demonstrated in a variety and of solid tumors including melanomas and nonmelanomas skin cancers. X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of apoptosis which prevents apoptosis by inhibiting caspases 9, 7, and 3. The prognostic value of XIAP in sebaceous gland carcinoma (SGC) remains unexplored. METHODS: The immunohistochemical expression of XIAP was evaluated in 29 SGC cases. RESULTS: The cytoplasmic overexpression of XIAP was detected in 62% SGC cases. XIAP expression was found to be significantly associated with advanced age, large tumor size, and with reduced disease-free survival (P = 0.0174). XIAP expression and advance tumor Grade III emerged as significant risk factors on univariate analysis. On stepwise multivariate analysis, both increased cytoplasmic XIAP expression and high tumor grade were found to be significantly associated with recurrence. Patients with low XIAP immunoexpression had a longer disease-specific survival than those with high expression in the 5-year follow up. CONCLUSION: The present study demonstrates at the immunohistochemical level that XIAP is overexpressed in SGC and that high expression could be of biological significance in the development of eyelid SGC. Our finding suggests that up regulation of XIAP may aggravate tumor metastasis in SGC. PMID- 29133635 TI - Is the distance from punctum a factor in the anatomical and functional success of canalicular laceration repairs? AB - PURPOSE: The aim is to analyze the influence of the location of lacrimal canalicular laceration over the eventual anatomical and functional success after surgery. METHODS: Retrospective, observational study of proximal canalicular laceration (PCL) and distal canalicular laceration (DCL) repairs by a single surgeon (MS). The distance between lacrimal punctum and the lateral canalicular lacerated end was defined as proximal (<6 mm) and distal (>=6 mm). The operation theater setup, microscopic magnified view, local adrenaline, and pigtail probe were used to locate the medial canalicular lacerated end. All patients underwent lacrimal stenting and the stents were removed after 3 months (12th week visit). After stent removal, a fluorescein dye disappearance test and lacrimal irrigation were performed to assess the anatomical and functional success of the operation. RESULTS: Of 36 canalicular lacerations, 30 (83.33%) were monocanalicular lacerations which were repaired using monocanalicular stents. Of 6 (16.67%) bicanalicular lacerations, three were repaired using bicanalicular stents while in the remaining three, one monocanalicular stent was placed in each lacerated canaliculi. The medial cut end was identified by magnified visualization in 27 (75%), with adjunctive local adrenaline in four (11.11%) and pigtail probe in five (13.89%) patients. The mean post stent removal follow-up was 44 weeks. The DCL (n = 24, 66.67%) showed better functional and complete success as compared to PCL (75% vs. 33.33%, P = 0.03). Eight (22.22%) had spontaneous stent extrusion, two (5.56%) had loop prolapse, four (11.11%) had punctum granuloma, and three (8.33%) had medial canthus dystopia. CONCLUSION: The location of canalicular laceration may help to prognosticate the functional and qualified success rate. We experienced better-qualified success in the distal canalicular laceration group. PMID- 29133636 TI - Diagnosis of limbal stem cell deficiency based on corneal epithelial thickness measured on anterior segment optical coherence tomography. AB - PURPOSE: The purpose of this study is to investigate the epithelial thickness in the cornea and limbus in limbal stem cell deficiency (LSCD) using anterior segment optical coherence tomography (AS-OCT). METHODS: This was a cross sectional, comparative study. OCT images of 30 eyes of 19 patients with LSCD collected by AS-OCT were scanned. Corneal epithelial thickness was recorded at the central cornea and the superior, nasal, inferior, and temporal limbus. Measurment of the same region of 30 normal eyes served as control. Epithelial thickness in all locations was measured by 2 independent observers. RESULTS: The mean epithelial layer thickness was 61.3 +/- 2.9 MU in the central cornea and 62.7 +/- 4.3 MU in the limbus in the control. The epithelial thickness in LSCD patients was found to be 41.33 +/- 2.8 MU. An average reduction of 22.2% in the central cornea and 32.15% in the limbus was found in patients with LSCD (P < 0.05). Epithelial thinning correlated with the severity of LSCD in both cornea and limbus. In eyes with sectoral LSCD, a similar degree of epithelial thinning was also detected in the clinically unaffected limbal regions. CONCLUSION: Both corneal and limbal epithelia become progressively thinner in LSCD. Epithelial thickness assessment using AS-OCT as a noninvasive tool could be used as a diagnostic measure of LSCD. PMID- 29133637 TI - The inhibitory effect of different concentrations of KH902 eye drops on corneal neovascularization induced by alkali burn. AB - PURPOSE: The aim of this study was to evaluate the inhibitory effect of different concentrations of KH902 eye drops on rabbit corneal neovascularization (CNV) induced by alkali burn. METHODS: Forty-eight adult rabbits were randomized into four groups after alkali burning: Group A (2.5 mg/ml), Group B (5 mg/ml), and Group C (10 mg/ml) by different concentrations of KH902 eye drops and Group D by saline solution as control with three times a day for 2 weeks. At days 7, 14, and 28, the anterior segment photographs, confocal microscopy, and histopathology were performed to evaluate corneal opacity, neovascularization, inflammatory cell density, vessel size, and edema. Immunohistochemistry was applied to analyze the vascular endothelial growth factor (VEGF) level. RESULTS: (1) The CNV in the medicine-treated groups showed a reduction without obvious corneal side effects histologically. (2) Compared to the control group, the three medicine-treated groups showed a reduction in the VEGF levels and CNV areas on days 7, 14, and 28 and in the inflammatory cell density on days 14 and 28 (P < 0.01). The difference of inflammatory cell density between the three medicine-treated groups existed on day 14 (P < 0.01). There were differences in the VEGF levels between Groups A, B, and C on days 7, 14, and 28 (P < 0.01), not for Groups B and C on day 28 (P > 0.05). CONCLUSION: KH902 eye drops in lower concentration showed an obvious reduction of the CNV growing for rabbit corneal alkali burn without side effects. PMID- 29133638 TI - Comparison of the Endosaver with noninjector techniques in Descemet's stripping endothelial keratoplasty. AB - PURPOSE: Minimal loss of corneal endothelial cells during corneal transplantation is a major target but remains a point of controversy among specialists. Hence, the available method to best achieve this continues to stir progress in the field. The aim of this study is to evaluate the use of the Endosaver injector device for graft insertion in Descemet's stripping endothelial keratoplasty (DSEK) and compare the visual outcomes and endothelial cell survival between the Endosaver injector and Goosey grasping forceps insertion techniques. METHODS: This was a retrospective, interventional, consecutive case series undertaken at the University of Southampton Eye Department to assess outcomes of DSEK using the Endosaver injector device compared to noninjector DSEK insertion. Postoperative specular microscopy alongside manifest refraction at 6 and 12 months was evaluated and compared. Mann-Whitney U-test was employed for the statistical analysis of data. RESULTS: Both the Endosaver and Goosey forceps groups showed an improvement in best corrected visual acuity. No significant statistical difference was found in preoperative and postoperative best-corrected visual acuity between the Endosaver and non-Endosaver insertion groups. Mean preoperative endothelial cell count was 2660 (+/-130) for the Endosaver group and 2608 (+/-66) for the non-Endosaver group. Postoperative endothelial counts at 6 and 12 months showed a significant difference between the Endosaver: 2104 (+/ 199)-1896 (+/-226) and the non-Endosaver: 1492 (+/-207)-1314 (+/-224) (P < 0.005) groups, respectively. CONCLUSION: The Endosaver injection device is associated with less trauma to endothelium during graft insertion due to the minimal touch technique employed. A smaller insertion wound of 4.0 mm compared to noninjector cases enabled a more stable system during surgery with no or minimal anterior chamber shallowing. The combination of a stable host with minimal endothelial graft handling and subsequent trauma potentially leads to higher endothelial cell counts when the Endosaver injection device is used compared to forceps insertion. PMID- 29133639 TI - Comparison of seropositivity of human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and syphilis among Hospital Cornea Retrieval Programme-Donors versus voluntary cornea donors at a large eye bank in Eastern India. AB - PURPOSE: To compare the serology profile of donors from Hospital Cornea Retrieval Programme-donors (HCRP-D) and voluntary cornea donors (VC-D) from a large eye bank in Eastern India. METHODS: This is a retrospective analysis of donor details from January 2011 to December 2016. Donor demographics, cause of death, and serology reports were compiled. Postmortem blood was tested for human immunodeficiency virus 1 and 2 (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis using government-approved kits as per the National Programme for Control of Blindness Standards of Eye Banking. Donors for whom serology was not possible were excluded. RESULTS: A total of 4300 of 4353 donors were included of which 74.3% were hospital donors and 25.7% were voluntary donors. A total of 93 (2.2%) donors with 94 seropositive reports were noted: 79 (84.9%) from HCRP-D and 14 (15.1%) from VC-D which was statistically significantly higher (P = 0.02). Among seropositive reports, HIV, HBV, HCV, and syphilis accounted for 12 (12.8%), 38 (40.4%), 36 (38.3%), and eight (8.5%), respectively. There was no correlation between the cause of death and seropositivity. A statistically significant decreasing trend in seroprevalence among hospital donors was observed over the years (5.3% in 2011 to 1.4% in 2016; P = 0.004). Two (0.47%) of 421 hospital donors with prior negative serology were found to be seropositive. CONCLUSION: Seropositive rates are significantly higher among hospital donors in spite of medical prescreening compared to nonscreened voluntary donors. Serology should be repeated even when prior reports are available. PMID- 29133641 TI - Simultaneous use of amniotic membrane and Mitomycin C in trabeculectomy for primary glaucoma. AB - PURPOSE: This study aimed to propose the role of amniotic membrane transplantation (AMT) as an additional modulator in primary Mitomycin C (MMC) augmented trabeculectomy. METHODS: This was a randomized prospective interventional study. Forty eyes of 39 adult patients with uncontrolled primary glaucoma were randomly divided into two equal groups. Control group underwent trabeculectomy augmented with MMC while the study group underwent additional AMT. Patients were followed up for 12 months and outcomes measured were intraocular pressure (IOP), need for additional intervention, and bleb morphology. RESULTS: Complete success (defined as IOP <16 mmHg on no medication) could be achieved in 85% eyes in study group while it was 60% in control group (P = 0.04). IOP reduced by 71.1% in study group from 41.9 +/- 10.6 to 12.1 +/- 2.7 mmHg and from 40.5 +/- 8.5 to 12.8 +/- 4.5 mmHg in control group, a decline of 68.29%. Blebs in AMT group showed better bleb morphology in terms of significantly better extent (E3) on day 1 (P = 0.03) and better height (H2 and H3) (P = 0.04), according to the Indiana Bleb Appearance Grading Scale, at all follow-up visits along with normal vascularity. The study group required significantly lesser (P = 0.03) bleb needlings as compared to control group. CONCLUSION: Amnion enhanced the efficacy of MMC-modulated trabeculectomy in terms of eyes with complete success and lesser interventions such as bleb needling. This reiterates the role of amnion as a safe and effective bleb modulator. A diffusely elevated bleb with healthier conjunctiva can go a long way in predicting better health and longevity of the bleb. PMID- 29133640 TI - Evaluation of spectral domain optical coherence tomography parameters in ocular hypertension, preperimetric, and early glaucoma. AB - PURPOSE: The objective of this study is to evaluate the diagnostic ability of retinal nerve fiber layer (RNFL), macular, optic nerve head (ONH) parameters in healthy subjects, ocular hypertension (OHT), preperimetric glaucoma (PPG), and early glaucoma (EG) patients, to reveal factors affecting the diagnostic ability of spectral domain-optical coherence tomography (SD-OCT) parameters and risk factors for glaucoma. METHODS: Three hundred and twenty-six eyes (89 healthy, 77 OHT, 94 PPG, and 66 EG eyes) were analyzed. RNFL, macular, and ONH parameters were measured with SD-OCT. The area under the receiver operating characteristic curve (AUC) and sensitivity at 95% specificity was calculated. Logistic regression analysis was used to determine the glaucoma risk factors. Receiver operating characteristic regression analysis was used to evaluate the influence of covariates on the diagnostic ability of parameters. RESULTS: In PPG patients, parameters that had the largest AUC value were average RNFL thickness (0.83) and rim volume (0.83). In EG patients, parameter that had the largest AUC value was average RNFL thickness (0.98). The logistic regression analysis showed average RNFL thickness was a risk factor for both PPG and EG. Diagnostic ability of average RNFL and average ganglion cell complex thickness increased as disease severity increased. Signal strength index did not affect diagnostic abilities. Diagnostic ability of average RNFL and rim area increased as disc area increased. CONCLUSION: When evaluating patients with glaucoma, patients at risk for glaucoma, and healthy controls RNFL parameters deserve more attention in clinical practice. Further studies are needed to fully understand the influence of covariates on the diagnostic ability of OCT parameters. PMID- 29133642 TI - Frequency of primary mutations of Leber's hereditary optic neuropathy patients in North Indian population. AB - PURPOSE: Leber's hereditary optic neuropathy (LHON) is an inherited optic neuropathy characterized by subacute painless vision loss. The majority of LHON is caused due to one of the three primary mutations in the mitochondrial DNA (m.G3460A, m.G11778A, and m.T14484C). The frequency of these mutations differs in different populations. The purpose of this study is to observe the frequency of three common primary mutations in the North Indian population. METHODS: Forty LHON patients within the age group of 10-50 years underwent molecular testing for primary mutations. For two patients, testing for mother and other siblings was also carried out, using bidirectional sequencing. RESULTS: A total of 11 out of 40 (27.5%) patients were found to be carrying m.G11778A mutation. Siblings of two probands were also positive for the same mutation. In one family, two primary mutations (m.G11778A and m.T14484C) were found in the proband and in the mother as well. CONCLUSION: In this study, 27.5% mutation was detected in North Indian LHON families. These results suggest that m.G11778A mutation is more frequent in this population. The results of the present study are compatible with studies of an Asian population and Northern European population. PMID- 29133643 TI - Next-generation sequencing reveals a novel NDP gene mutation in a Chinese family with Norrie disease. AB - PURPOSE: Norrie disease (ND) is a rare X-linked genetic disorder, the main symptoms of which are congenital blindness and white pupils. It has been reported that ND is caused by mutations in the NDP gene. Although many mutations in NDP have been reported, the genetic cause for many patients remains unknown. In this study, the aim is to investigate the genetic defect in a five-generation family with typical symptoms of ND. METHODS: To identify the causative gene, next generation sequencing based target capture sequencing was performed. Segregation analysis of the candidate variant was performed in additional family members using Sanger sequencing. RESULTS: We identified a novel missense variant (c.314C>A) located within the NDP gene. The mutation cosegregated within all affected individuals in the family and was not found in unaffected members. By happenstance, in this family, we also detected a known pathogenic variant of retinitis pigmentosa in a healthy individual. CONCLUSION: c.314C>A mutation of NDP gene is a novel mutation and broadens the genetic spectrum of ND. PMID- 29133644 TI - Stenotrophomonas maltophilia: An emerging entity for cluster endophthalmitis. AB - PURPOSE: This was a study of acute cluster endophthalmitis along with clinical features, culture results, and visual outcomes of 10 eyes of 10 patients after intravitreal injection of Avastin (bevacizumab) in one sitting from a single vial. METHODS: Retrospective review of intravitreal injection of 1.25 mg/0.05 ml bevacizumab that was given to 10 eyes of 10 patients on the same day from a freshly opened vial. All patients manifested with endophthalmitis the next day. Vitreous tap for direct smear and culture was done. Intravitreal antibiotics and steroids were injected and appropriate treatment begun. The injection vial of the same batch was sent for VITEKTM identification and antimicrobial susceptibility of isolates. RESULTS: Endophthalmitis presented within 24 h of intravitreal injection. There was a remarkable absence of posterior pupillary synechia. Two cases were culture-positive (20%), showing pseudomonoid growth. The vial of the same batch revealed a pseudomonoid bacilli Stenotrophomonas maltophilia using VITEKTM, which was resistant to multiple drugs. Hence, the contaminated vial was identified as the source of infection in our case. Among 10 patients, two underwent pars plana vitrectomy. Visual acuity returned to preendophthalmitis levels in 9/10 eyes after 1 month. One patient was lost to follow-up. Late complications included retinal detachment in one case and neovascular glaucoma in another. CONCLUSION: Early recognition and treatment are key factors in improving outcomes. Causative etiology could be microbial contamination of the drug vial. S. maltophilia should be considered a pathogenic organism of postintravitreal endophthalmitis. PMID- 29133645 TI - Retinal shortening: Ultrasonic evaluation of proliferative vitreoretinopathy. AB - PURPOSE: To evaluate the effect of extraretinal proliferative vitreoretinopathy (PVR) on retinal shortening in eyes with rhegmatogenous retinal detachment (RD) using ultrasound (USG) and objectively prove the presence of intraretinal PVR (iPVR). METHODS: This is a double-masked pilot prospective controlled case series. Patients with total RD planned for vitreoretinal surgery were included in the study. USG was used to determine retinal-to-choroidal length ratios (RCRs) in all the quadrants. Group 1 included 10 patients with preoperative PVR more than Grade B while Group 2 had 14 with PVR of Grades A or B. Severe retinal shortening was defined as RCR < 0.8. Primary outcome measures were severe retinal shortening and an early unexplained recurrence of RD within 15 days of surgery. RESULTS: Mean RCRs were significantly low in all the four quadrants of Group 1 upon comparison with Group 2. The mean RCR had a good negative correlation with number of quadrants of PVR (R = -0.66, P <= 0.001). Overall, severe quadrantic retinal shortening was detected in nine patients. In these 9 patients, 11 of the 36 retinal quadrants had severe retinal shortening in the absence of extraretinal PVR (ePVR). Six patients developed early unexplained RD, and all of these belonged to Group 1. Severe quadrantic retinal shortening had the highest odds ratio of developing early unexplained RD (odds ratio = 58, P = 0.01). CONCLUSION: Retinal shortening occurs both due to ePVR and iPVR, and iPVR occurs independently at least in some cases. Severe quadrantic retinal shortening indicates poor primary anatomical prognoses. PMID- 29133646 TI - Efficacy of 1% atropine eye drops in retarding progressive axial myopia in Indian eyes. AB - PURPOSE: The aim of this study is to assess the efficacy of 1% atropine eye drops for the retardation of progressive axial myopia in Indian eyes. METHODS: This prospective interventional cohort study included children aged 5-16 years. Both the eyes of myopic children with progressive increase of >=-0.5D sphere/year with the best-corrected vision of >=6/6 were treated with once a day application of 1% atropine eye drops and progressive addition photogray lenses. The progression of myopia after 1-year follow-up was analyzed. RESULTS: Sixty eyes of thirty myopes were included in the study. The mean age was 10 years and 15 were girls. The mean baseline sphere was -5.2D (-2.5D--13D). Mean duration of follow-up was 23 months (12-36 months). The baseline rate of progression was reduced from -0.6D/year (range -0.5D/year to -3D/year) to -0.2D/year (range 0D/year to -1.5D/year) after atropine therapy. Seventeen patients (57%) had to use the atropine in the daytime to reach the target progression of P = 0.6). The efficacy of atropine drops did not have a correlation with the age of the patients or the magnitude of baseline myopia (Pearson's r = 0). CONCLUSION: 1% atropine eye drops was well tolerated and efficacious for the retardation of progressive myopia in Indian eyes. Effectiveness was better with daytime application. Further studies are necessary to assess the role of 1% atropine in the rapid progressors and patients poorly responding to low-dose atropine. PMID- 29133647 TI - Conquering myopia: Have we hit pay dirt? PMID- 29133648 TI - Modified adjustable suture hang-back recession: Description of technique and comparison with conventional adjustable hang-back recession. AB - PURPOSE: This study aims to describe and compare modified hang-back recession with the conventional hang-back recession in large angle comitant exotropia (XT). METHODS: A prospective, interventional, double-blinded, randomized study on adult patients (>18 years) undergoing single eye recession-resection for large angle (>30 prism diopters) constant comitant XT was conducted between January 2011 and December 2015. Patients in Group A underwent modified hang-back lateral rectus recession with adjustable knot while in Group B underwent conventional hang-back recession with an adjustable knot. Outcome parameters studied were readjustment rate, change in deviation at 6 weeks, complications and need for resurgery at 6 months. RESULTS: The groups were comparable in terms of age and preoperative deviation. The patients with the modified hang back (Group A) fared significantly better (P < 0.05) than those with conventional hang back (Group B) in terms of lesser need for adjustment, greater correction in deviation at 6 weeks and lesser need for resurgery at 6 months. CONCLUSION: This modification offers several advantages, significantly reduces resurgery requirement and has no added complications. PMID- 29133649 TI - Is pediatric ophthalmology a popular subspecialty in India: Present scenario and future remedies. AB - PURPOSE: The aim of the study was to assess the attitude and perceptions of residents regarding Pediatric Ophthalmology and Strabismus (POS) subspecialty training. We also explored the possible barriers and solutions to promoting POS in India. METHODS: A questionnaire consisting of 20 items, with a 5-point Likert scale, was provided to all postgraduate residents of Ophthalmology in the year 2013-2014. Semistructured interview of a selected panel of experts was carried out to understand the challenges, barriers, and opportunities for developing POS subspecialty in India. The data collected were coded and statistically analyzed using standard methods for quantitative and qualitative data. RESULTS: Out of 81 residents, 69 responded (85.2%). The mean age of the respondents was 27.5 +/- 1.23 years. Forty eight (69.0%) residents reported that there was no structured surgical teaching and systematic periodic posting in this subspecialty during their residency program. Residents who stated difficulty to understand the subject were 59%. Pursuing POS as a career choice was indicated by 21.0%. Major attracting attributes of POS fellowship were intellectual stimulation (69.7%) and independent operative skills (57.5%). Dissuading factors were difficulty to handle children (54.5%) and stress factor (48.4%). Expert views were grouped under four domains, such as doctor-patient ratio, infrastructure, training opportunities, utilization, and accessibility to POS services. CONCLUSION: The study has provided useful insights into the preferential behavior among trainee resident doctors and reasons for not choosing POS as a possible choice of future fellowships. PMID- 29133650 TI - Epidemiology, clinical profile and factors, predicting final visual outcome of pediatric ocular trauma in a tertiary eye care center of Central India. AB - PURPOSE: Ocular trauma constitutes an important cause of preventable visual morbidity worldwide. This study was done to study the incidence, sociodemographic pattern, and clinical profile of ocular trauma in pediatric age group. Also to evaluate the factors influencing final visual outcome in these patients. METHODS: This was a prospective interventional study concerning ocular trauma in pediatric patients up to 16 years of age of either sex. Various variables having an impact on final visual outcome were studied, and results were analyzed using statistical indices - relative risk, Chi-square test, P value, and linear regression analysis. RESULTS: A total of 220 cases of trauma were evaluated with the mean age being 8.74 +/- 3.93 years, males were predominantly affected and open globe injuries outnumbered blunt injuries. Penetrating injuries accounted for 67.79% cases of open globe injury, rupture being the least (2.54%). Stepwise multiple linear regression analysis executed, showed the best predictors in the descending order for final visual outcome were presenting visual acuity, size of corneal tear, type of injury, zone of injury, time period between injury and treatment with a variance of 35.9%, 6.3%, 5.3%, 3.7%, and 2.7%, respectively. All above variables were also found to be statistically significant (P < 0.05) on Chi square test. CONCLUSION: We report the first study on the epidemiology and clinical outcomes of pediatric ocular trauma in central India. Poor initial Visual Acuity and posterior segment involvement adversely affect the visual outcome. Early medical treatment and globe-salvaging repair should be done in all eyes suffering from trauma. PMID- 29133651 TI - Comparison of 30-2 Standard and Fast programs of Swedish Interactive Threshold Algorithm of Humphrey Field Analyzer for perimetry in patients with intracranial tumors. AB - PURPOSE: To find out whether 30-2 Swedish Interactive Threshold Algorithm (SITA) Fast is comparable to 30-2 SITA Standard as a tool for perimetry among the patients with intracranial tumors. METHODS: This was a prospective cross sectional study involving 80 patients aged >=18 years with imaging proven intracranial tumors and visual acuity better than 20/60. The patients underwent multiple visual field examinations using the two algorithms till consistent and repeatable results were obtained. RESULTS: A total of 140 eyes of 80 patients were analyzed. Almost 60% of patients undergoing perimetry with SITA Standard required two or more sessions to obtain consistent results, whereas the same could be obtained in 81.42% with SITA Fast in the first session itself. Of 140 eyes, 70 eyes had recordable field defects and the rest had no defects as detected by either of the two algorithms. Mean deviation (MD) (P = 0.56), pattern standard deviation (PSD) (P = 0.22), visual field index (P = 0.83) and number of depressed points at P < 5%, 2%, 1%, and 0.5% on MD and PSD probability plots showed no statistically significant difference between two algorithms. Bland Altman test showed that considerable variability existed between two algorithms. CONCLUSION: Perimetry performed by SITA Standard and SITA Fast algorithm of Humphrey Field Analyzer gives comparable results among the patients of intracranial tumors. Being more time efficient and with a shorter learning curve, SITA Fast my be recommended as a standard test for the purpose of perimetry among these patients. PMID- 29133652 TI - Hospital anxiety and depression scale assessment of 100 patients before and after using low vision care: A prospective study in a tertiary eye-care setting. AB - PURPOSE: Assessment of anxiety and depression in patients attending low vision care (LVC) using Hospital Anxiety and Depression Scale (HADS). METHODS: In this prospective, observational study, 100 patients with best-corrected visual acuity (BCVA) worse than 6/18 in the better eye or limitation of field of vision to <10 degrees from center of fixation were assessed on the depression and anxiety subscales of HADS questionnaire before and after LVC. HADS is a 14-item scale with seven items each for anxiety and depression subscales. Scoring for each item ranges from zero to three. A subscale score >8 denotes anxiety or depression. RESULTS: Mean age at presentation was 38.2 years. Mean duration of symptoms was 9.6 years. Underlying etiology of visual impairment included retinal dystrophy/degeneration (n = 35), disorders of the optic nerve (n = 17), glaucoma (n = 10), diabetic retinopathy (n = 9), age-related macular degeneration (n = 5), uncorrected refractive errors (n = 5), and miscellaneous diseases (n = 19). Mean presenting BCVA in the better eye was 0.83 (+/-0.64) which improved significantly to 0.78 (+/-0.63) after LVC (P < 0.001). The HADS-Depression subscale score was comparable for severity of visual impairment for both distance (P = 0.57) and near vision (P = 0.61). Similarly, HADS-Anxiety scores were also comparable for severity of distance (P = 0.34) and near-visual impairment (NVI; P = 0.50). At baseline, mean HADS-Depression and HADS-Anxiety scores were 8.4 (+/-3.7) and 9.6 (+/-4.3) points, which improved significantly to 6.0 (+/-3.4) and 6.7 (+/-3.7), respectively, after low-vision correction (P < 0.001). CONCLUSION: Low vision correction can significantly improve anxiety and depression indicators in visually impaired patients. PMID- 29133653 TI - Multimodal imaging features of resolving multiple evanescent white dot syndrome. PMID- 29133654 TI - "Dye front reciprocation" in combined central retinal vein occlusion with cilioretinal artery infarction. PMID- 29133655 TI - Polypoidal choroidopathy associated with choroidal nevus. PMID- 29133656 TI - An unusual intraocular foreign body: Intravitreal cilium following scleral buckling for retinal detachment repair. PMID- 29133657 TI - Revisiting the "Tram-Track" sign. PMID- 29133658 TI - Role of amniotic membrane and full-thickness skin graft in reconstruction of kissing nevus of eyelids. AB - A 20-year-old girl presented with a large pigmented lesion over the temporal aspect of left lateral canthus involving the lateral one-third of both eyelids, since birth. A slow increase in its size had been noticed for the past 2 years. On examination, a hairy nevus measuring 34 mm * 22 mm was noticed involving left eyelid skin, the mucocutaneous junction (MCJ), palpebral conjunctiva, and lateral canthus. The surface was irregularly thick and covered with long, thick, and pigmented hairs. A clinical diagnosis of kissing nevus of eyelids was kept and a surgical resection with reconstruction planned. A customized full-thickness skin graft (FTSG) and amniotic membrane grafts (AMGs) were used for the reconstruction of cutaneous and MCJ, respectively. Histopathology showed the features of junctional nevus. At 4 months of follow-up, a well taken FTSG and healthy/sharp MCJ were noticed with no recurrence. We advocate a possible role of AMG, particularly in the reconstruction of the conjunctival mucosa and MCJ. PMID- 29133659 TI - Congenital capillary hemangioma arising from palpebral conjunctiva of a neonate. AB - Capillary hemangioma is the most common benign vascular eyelid tumor in childhood. The periocular lesion appears within the first few weeks after birth and usually has superficial or deep components. Primary conjunctival capillary hemangiomas are rarely reported. We present the case of a 2-day-old child with a pedunculated capillary hemangioma arising from superior palpebral conjunctiva. A complete surgical excision was performed under general anesthesia, and the child was asymptomatic at follow-up of two months. PMID- 29133660 TI - Predescemetocele: A distinct clinical entity. AB - The case report incorporates a Fourier-domain optical coherence tomography (OCT) examination for demonstration of the existence of pre-Descemet's layer (PDL; Dua's layer) overlying a descemetocele and demonstrates predescemetocele as a separate clinical entity. The prospective analysis was done in two cases that had descemetocele, and OCT demonstrated the presence of PDL over an unruptured descemetocele that offers resilience and can be treated with an elective deep anterior lamellar keratoplasty or a penetrating keratoplasty. A descemetocele, when covered with PDL, should be correctly designated as a predescemetocele. Loss of PDL leads to baring of Descemet's membrane that eventually ruptures. PMID- 29133661 TI - The sting of a honey bee: An unusual subconjunctival foreign body. AB - Ocular foreign bodies (FBs) are often encountered in clinical practices. However, there are cases in which the presence of the FB is difficult to diagnose based on mere history taking and/or clinical examination. We herein present a case of unusual subconjunctival foreign body in the form of the sting of a honey bee in a 63-year-old farmer. This was removed from the superior forniceal subconjunctival space in toto with forceps under a microscope in the operation theater. This case emphasizes the need to elicit a complete history and a careful ocular examination with double eversion of the eyelid to avoid missing any foreign body lodged in the fornices and subconjunctival space in patients who complained of foreign body sensation. PMID- 29133662 TI - A tiny tick can cause a big health problem. AB - Ticks are tiny crawling bugs in the spider family that feed by sucking blood from animals. They are second only to mosquitoes as vectors of human disease, both infectious and toxic. Infected ticks spread over a hundred diseases, some of which are fatal if undetected. They spread the spirochete (which multiplies in the insect's gut) with a subsequent bite to the next host. We describe the only reported cases of peri ocular tick bite from India that presented to us within a span of 3 days and its management. Due suspicion and magnification of the lesions revealed the ticks which otherwise masqueraded as small skin tags/moles on gross examination. The ticks were firmly latched on to the skin and careful removal prevented incarceration of the mouth parts. Rickettsial diseases that were believed to have disappeared from India are reemerging and their presence has recently been documented in at least 11 states in the country. Among vector borne diseases, the most common, Lyme disease, also known as the great mimicker, can present with rheumatoid arthritis, fibromyalgia, depression, attention deficit hyperactivity disorder, multiple sclerosis, chronic fatigue syndrome, cardiac manifestations, encephalitis, and mental illness, to name some of the many associations. Common ocular symptoms and signs include conjunctivitis, keratitis, uveitis, and retinitis. Early detection and treatment of tick borne diseases is important to prevent multi system complications that can develop later in life. PMID- 29133663 TI - Combined central retinal artery and vein occlusion with optic perineuritis following herpes zoster dermatitis in an immunocompetent child. AB - A 15-year-old healthy boy developed acute, rapidly progressing visual loss in left eye following herpes zoster dermatitis, with a combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO), along with optic perineuritis. Laboratory tests were negative. Despite an empirical, intensive antiviral treatment with systemic corticosteroids, and vision could not be restored in the affected eye. Herpes zoster dermatitis, in an immunocompetent individual, may be associated with a combined CRAO and CRVO along with optic perineuritis, leading to profound visual loss. PMID- 29133664 TI - Optical coherence tomography angiography features of acute macular neuroretinopathy in dengue fever. AB - A 39-year-old female with dengue fever presented with decreased vision in both eyes. Visual acuity was 20/200 and 20/80 in the right eye (OD) and left eye (OS), respectively. Fundus showed granular, grayish-white lesions in the parafoveal region in OD. Multimodal imaging including optical coherence tomography angiography (OCTA), optical coherence tomography (OCT), and fluorescein angiography (FA) was performed. FA showed late hyperfluorescence with few microaneurysms in OS. OCT showed hyperreflectivity in various layers, suggestive of acute macular neuroretinopathy (AMN). OCTA showed disruption of retinal capillary plexuses. This case shows how OCTA provides newer insights into the pathogenesis of AMN lesions in dengue fever. PMID- 29133665 TI - A rare case of bilateral tractional retinal detachment following snakebite. AB - A 13-year-old female presented with diminution of vision in both eyes for 3 months following snakebite. Best-corrected visual acuities were hand movement in both eyes. Fundoscopy showed vitreous hemorrhage, and B-scan ultrasonography revealed an underlying tractional retinal detachment (TRD) involving the macula in both eyes. Patient underwent 25-gauge pars plana vitrectomy in conjunction with belt buckling, endolaser, and silicone oil tamponade in the left eye. At 6 weeks postoperatively, best-corrected visual acuity of the left eye was noted to be 20/200 with settled TRD and attached retina. Bilateral proliferative retinopathy with TRD is a hitherto unreported complication of snake bite. PMID- 29133666 TI - Blood flow pattern in a choroidal hemangioma imaged on swept-source-optical coherence tomography angiography. AB - This report demonstrates the blood flow pattern in a case of choroidal hemangioma (CH) using swept-source-optical coherence tomography angiography (SS-OCTA). Fluorescein angiography, SS-OCT, and SS-OCTA images of a patient with CH were obtained using a standard protocol. The internal vascular pattern of the tumor was identified on both OCT and OCTA. Dark areas were identified in the CH. These were interspersed between areas of visible blood flow, as imaged on SS-OCTA. Peripheral vascular arcades were also identified within the tumor. SS-OCTA should be evaluated as an imaging tool to study the blood flow within choroidal tumors. PMID- 29133667 TI - Methoxsalen-induced macular toxicity. AB - Psoralen compounds such as methoxsalen are photosensitizer agents used in conjunction with ultraviolet A (UVA) radiation exposure as photochemotherapy (Psoralens and ultraviolet-A therapy [PUVA therapy]) for certain epidermal skin disorders such as psoriasis and vitiligo. Methoxsalen has been shown to be associated with premature cataract formation by forming adducts with lens proteins following oral administration and subsequent UVA exposure. Hence, the use of UV-filtering glasses is recommended during PUVA therapy sessions. Ocular tissues can be exposed to its photosensitizing effect with subsequent UV radiation exposure through sunlight if the patient was to be without protective eye glasses, potentially causing macular toxicity. Till date, there have been no reports in the literature of any posterior segment ocular toxicity arising from methoxsalen use. Here, we describe a case of a bilateral macular toxicity in a middle-aged male treated with methoxsalen for vitiligo. PMID- 29133668 TI - Vitrectomy for full-thickness macular hole in adult-onset Coats' disease. AB - The occurrence of full thickness macular hole in Coats' disease is extremely rare. The purpose of this case report is to report pars plana vitrectomy for the treatment of full thickness macular hole in a patient with adult onset Coats disease. A young male presented with decreased vision in his right eye because of full thickness macular hole. The macular hole was found to be associated with adult onset Coats' disease that was evident on ultra-wide field imaging. The patient underwent laser photocoagulation to the vascular telangiectasia followed by pars plana vitrectomy, large internal limiting membrane peeling and gas tamponade. This resulted in regression of exudation, closure of macular hole and improvement in vision. Coats disease of adult onset can present with decreased vision because of full thickness macular hole. Vitrectomy with internal limiting membrane peeling can result in excellent visual outcome. PMID- 29133669 TI - Severe Gemella haemolysans endophthalmitis following ranibizumab intravitreal injection. AB - Gemella haemolysans is a commensal of the upper respiratory tract that is rarely involved in ocular pathology. We present a unique case of endophthalmitis with negative cultures and positive 16s ribosomal ribonucleic acid gene sequencing showing G. haemolysans infection after an intravitreal ranibizumab injection for wet age-related macular degeneration. PMID- 29133670 TI - Multicolor imaging in optic disc swelling. AB - Differentiating optic disc edema (ODE) from pseudo optic disc edema (PODE) continues to pose a diagnostic dilemma. Current report highlights the role of multicolor imaging (MC) in differentiating ODE from PODE. Composite multicolor images of the disc in ODE show greenish hyperreflectance that extends beyond the optic disc margins with irregular blurry margins and obscured disc vasculature whereas PODE shows a greenish hyperreflectance with clear and distinct margins and well delineated disc vasculature. MC imaging adds to the present armamentarium of imaging modalities obviating needless neurological evaluation mandatory in a case of true disc edema. PMID- 29133671 TI - Commentary: Multicolor imaging in optic disc swelling. PMID- 29133672 TI - Spontaneous anatomical and functional recovery of bilateral electric shock maculopathy. AB - A 12-year-old boy presented with best-corrected visual acuity (BCVA) of 6/9 in both eyes following an episode of electric shock. Optical coherence tomography (OCT) showed disruption of the ellipsoid zone as well as retinal pigment epithelium (RPE) layer. Fundus autofluorescence (FAF) showed increased central hypoautofluorescence in both eyes. At 3-month follow-up, BCVA improved to 6/6 with OCT showing spontaneous resolution of maculopathy in both eyes with reorganized RPE layer and ellipsoid zone. To the best of our knowledge, this is the first case of bilateral electric shock maculopathy (ESM) with spontaneous anatomical as well as functional recovery. Ophthalmologists must be aware of various forms of ESM. OCT and FAF must be done in patients presenting with defective vision and history of electric shock for the diagnostic as well as prognostic evaluation. PMID- 29133673 TI - Case of intraocular foreign body partly lodged in the ethmoid sinus. PMID- 29133674 TI - Modified Scharioth's technique of scleral fixation of intraocular lens. PMID- 29133675 TI - Conjunctival leiomyosarcoma: A case report and review of literature. PMID- 29133676 TI - Reply to Conjunctival leiomyosarcoma: A case report and review of literature. PMID- 29133677 TI - Pediatric optic neuritis: Points to ponder! PMID- 29133678 TI - Reply to Pediatric optic neuritis: Points to ponder. PMID- 29133679 TI - The cover page. PMID- 29133680 TI - Nurturing Neurosurgery with basics and compassion ...Some thoughts. PMID- 29133681 TI - Founders of Indian Neurosciences: Professor Bimal Kumar Bachhawat and Professor Bal Krishan Anand. PMID- 29133682 TI - "Against the tide, nothing to hide"- the saga of a community neurosurgeon. PMID- 29133683 TI - Small vessel CNS vasculitis-optimism and challenges in imaging diagnosis. PMID- 29133685 TI - Cardiomyopathy in acromegaly and the effect of trans-sphenoidal surgery. PMID- 29133684 TI - Central nervous system vasculitis imaging: Simplified. PMID- 29133687 TI - Demonstration of autonomic dysfunction in traumatic brachial plexus injury using quantitative sudomotor axon reflex test. PMID- 29133686 TI - Echocardiographic improvements following transsphenoidal surgery for acromegaly. PMID- 29133688 TI - Assessment of autonomic dysfunction in traumatic brachial plexus injury: A regional pain management strategy or merely a research tool? PMID- 29133689 TI - Neurological perspective of globus pallidus interna deep brain stimulation in dystonia. PMID- 29133690 TI - Pallidal deep brain stimulation in dystonia. PMID- 29133691 TI - Deep brain stimulation in dystonia: The current status. PMID- 29133692 TI - Meningiomas: Objective assessment of proliferative indices by immunohistochemistry and automated counting method. PMID- 29133693 TI - Proliferation in meningiomas: Introducing objectivity in assessment. PMID- 29133694 TI - Manganese in manganism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease: A narrative review. AB - The collective evidence to date suggests that environmental exposure to excessive amounts of manganese (Mn) can cause a neurodegenerative condition known as manganism. It is now also relatively clear that Mn is involved in the pathogenesis of Alzheimer's disease and at least some prion diseases. The potential involvement of Mn in a panel of other neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Batten disease has been suggested and investigated, but the results to date are somewhat inconclusive. Herein, previously reported experimental studies investigating the involvement of Mn in the pathogenesis of these conditions are narratively reviewed. PMID- 29133695 TI - Manganese, manganism and other neurodegenerative diseases: Is it a cause of concern? PMID- 29133696 TI - The influence of initial stroke severity on mortality, overall functional outcome and in-hospital placement at 90 days following acute ischemic stroke: A tertiary hospital stroke register study. AB - BACKGROUND AND PURPOSE: Epidemiological studies on the extent of the interaction and/or influence of stroke severity on clinical outcomes are important. The aim of the present study was to investigate the putative (and degree of) impact of initial stroke severity in predicting the overall functional outcome, in-hospital placement, and mortality in acute ischemic stroke (AIS) in comparison with age, admission to the stroke unit and thrombolytic treatment. MATERIALS AND METHODS: The John Hunter Hospital acute stroke register was used to collect a retrospective cohort of AIS patients being assessed for reperfusion therapy and admitted between January 2006 and December 2013. Univariate and multivariate logistic regression and receiver operating characteristics analyses were used to assess associations with functional outcome, in-hospital placement, and mortality at 90 days. RESULTS: 608 AIS patients with complete datasets were included in the study. On univariate analysis, initial stroke severity showed the strongest independent association to the risk of death within 90 days (Odds ratio (OR) =1.15; P < 0.001; 95% confidence interval (CI) = [1.11, 1.18]); age was a less significant independent influence (OR = 1.02; P = 0.049; 95% CI = [1.00, 1.03]). Multivariate logistic regression analysis demonstrated that initial stroke severity independently predicted the 90 day mortality (OR = 1.16; 95% CI = [1.12, 1.2]; P < 0.0001) and unfavorable outcome (OR = 1.16; 95% CI = [1.13, 1.2]; P < 0.0001). Higher National Institute of Health Stroke Scale at admission was significantly associated with longer in-hospital placement (P < 0.0001). CONCLUSIONS: In this acute stroke cohort, initial stroke severity had a major impact on the likelihood of death following an AIS and appears to be the dominant influence on the overall stroke outcome and in-hospital placement. PMID- 29133697 TI - Initial stroke severity and stroke outcome - the inseparable link. PMID- 29133698 TI - Predicting and explaining outcome after stroke. PMID- 29133699 TI - Referral practice, reporting standards, and the impact of dopamine transporter scans done in a tertiary hospital. AB - AIMS: We studied the referral practice, reporting standards, and the impact of 123 ioflupane single photon emission computed tomogram dopamine transporters (DAT SPECT) scans conducted for the diagnosis and clinical management of patients. SETTINGS AND DESIGNS: The present study was a retrospective, non-interventional study. MATERIALS AND METHODS: We assessed the DAT scan referral and the official reports available from the Nuclear Medicine Department of the Mater Misericordiae University Hospital over 1 year (2013). We also assessed the impact of the DAT scan result on the management of patients by analyzing patient records. The European Association of Nuclear Medicine Neuroimaging (EANM) 2010 and the Federal Drug Administration (FDA) 2012 guidelines were taken as the standard against which the quality of our DAT scans reporting was assessed. STATISTICAL METHODS: Microsoft Excel 2010 and graphpad software were used for statistical analysis. RESULTS: Twenty five (56.2%) out of a total of 48 DAT scans were performed to confirm early Parkinson's disease, 5 (8.9%) were done to exclude drug-induced parkinsonism, and 8 (14.3%) to distinguish essential tremor from parkinsonism; 2 scans were performed to distinguish Lewy body diseases from Alzheimer's dementia, and 4 indications were outside the recommended guidelines. Twelve out of the 26 (46%) abnormal scans had bilateral abnormalities. Twenty one out of the 25 DAT scans proved the clinical diagnosis of degenerative parkinsonism to be correct. CONCLUSION: The overall compliance of the DAT imaging with the existing standard guidelines was good. DAT scan can be very useful in clinical practice because it influences the clinical diagnosis and management in 23% of the patients. PMID- 29133700 TI - Wearing off: A complex phenomenon often poorly recognized in Parkinson's disease. A study with the WOQ-19 questionnaire. AB - BACKGROUND: 'Wearing off' refers to the phenomenology of movement disorders in Parkinson's disease (PD) that appears early and is much commoner than generally believed. It may be present in the form of either motor symptoms or non-motor symptoms. AIM: To investigate the utility of wearing-off questionnaire (WOQ-19, Italian version) in the outpatient clinical practice to assess the suitability of different combinations of treatment, in various stages of PD. METHODS: 73 consecutive patients (58% male and 42% female) suffering from PD were recruited through the Santorso Hospital and San Martino Hospital from September 2012 to March 2014. The patients were asked to indicate whether or not they experienced any of the 19 symptoms listed in the questionnaire during the day; if one or more of these referred symptoms relating to PD improved after taking an additional dose of levodopa; and, if these variations were present routinely. Furthermore, we also evaluated the possible correlation between the presence of motor and non motor symptoms that were listed in the WOQ 19 with the motor impairment assessed by the Hoehn and Yahr stage (HY) and the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor section, in the whole patient cohort as well as in different subgroups undergoing therapy. RESULTS: Among the 73 patients, 22% were receiving levodopa (a mean daily dose of 300 +/- 121.3 mg), 38.3% levodopa and dopamine agonists, 12.3% levodopa/rasagiline, 8.2% levodopa/selegiline, and 19.2% a combination of levodopa/dopamine agonists (DA)/monoamine oxidase inhibitors (MAOI). The most prevalent symptoms were the non-motor symptoms included in the WOQ-19. A significant correlation between the scores obtained on the different motor and non-motor items recorded by the WOQ-19 and the UPDRS motor section and HY scores was found. The therapeutic benefit was especially related to the motor symptoms. DISCUSSION: In clinical practice, this simple and easily administered questionnaire may be useful for the early detection of fluctuations in symptomatology in patients with PD. It will, therefore, help to improve the quality of the global care of patients with PD detected in various stages of the disease. PMID- 29133701 TI - Prevalence, burden, and risk factors of migraine: A community-based study from Eastern India. AB - BACKGROUND: Headache is common in communities; however, epidemiological research regarding its prevalence is infrequent in India. AIM: We planned to study the prevalence of migraine, its disease burden, and the associated risk factors. SETTING AND DESIGN: This is an urban community study conducted in Kolkata with a cross-sectional and nested case-control design. MATERIALS AND METHODS: The criteria to study headache among a representative sample (aged 20-50 years) was based on the International Classification of Headache Disorders-II. Sex- and age matched controls without headache were evaluated for putative risk factors. The disease burden was measured as disability adjusted life years (DALY). RESULTS: Screening of 2421 individuals revealed that the 1-year prevalence of migraine was 14.12%. Education, environmental exposure, travel, and oral contraceptives determine approximately 75% of the underlying risks. DALY showed maximum burden among women in the age range of between 30 and 34 years. CONCLUSION: The community-based prevalence of migraine in India is similar to that observed in other countries except Africa. The burden was maximum among women. The risk factors responsible for migraine should be addressed and institution of public health measures are warranted. PMID- 29133702 TI - Migraine: More than 'just a mere headache,' yet common. PMID- 29133703 TI - CNS small vessel vasculitis: Distinct MRI features and histopathological correlation. AB - BACKGROUND: Central nervous system (CNS) vasculitis is an uncommon disease, which is a diagnostic and therapeutic challenge for physicians. Large and medium vessel vasculitis is relatively easy to diagnose by angiogram compared to small vessel vasculitis, where angiograms are often normal; imaging features described till date are sensitive but not specific. PURPOSE: Here, we describe distinct magnetic resonance (MR) imaging features of CNS small vessel vasculitis. MATERIALS AND METHODS: Five histologically proven small vessel vasculitis cases were retrospectively reviewed from medical records between January 2008 to July 2012. Angiogram (magnetic resonance angiography in all and digital subtraction angiography in three patients) were normal, ruling out associated large and medium vessel vasculitis. The MR imaging findings were analyzed for T2/fluid attenuated inversion recovery (FLAIR) hyperintensities and blooming on susceptibility weighted imaging (SWI). RESULTS: Five patients (3 males) with a mean age of 34.2 years (range: 18 to 62 years) were included for analysis. Three patients with lymphocytic vasculitis had 43 discrete T2/FLAIR hyperintense lesions in brain parenchyma. All the brain lesions revealed central areas of SWI blooming in linear and/or lace-like pattern, surrounded by FLAIR hyperintensity. Corresponding T1-weighted contrast-enhanced images revealed subtle linear and lace-like enhancement. Coarse granular pattern of SWI blooming was seen in the patient with tuberculous vasculitis and no parenchymal abnormalities were seen in the patient with hypertrophic pachymeningitis. CONCLUSIONS: The linear SWI blooming along the course of small cerebral vessels and lace-like enhancement pattern in spin echo post-contrast T1-weighted sequences are suggestive MR imaging features for lymphocytic CNS small vessel vasculitis. PMID- 29133704 TI - Survival trends in glioma: Experience at a tertiary care centre. AB - BACKGROUND: Even after decades of research in the field of gliomas, the overall prognosis is still quite dismal. Several factors have been proposed that affect the outcome and survival length of patients with a glioma. Here, we present a series of 471 patients, who underwent surgical resection of their glioma at a tertiary level neurosurgical centre. MATERIALS AND METHODS: We noted retrospective data of patients' age, histological tumor grade, and whether or not intraoperative magnetic resonance imaging (MRI) was used, and assessed the survival length of these patients from the day of surgery. RESULTS: The overall survival in our series was approximately 14 months. Predictably, those with age less than 40 years and those with Karnofsky performance score (KPS) >=80 had longer survival than those with a higher age and KPS <80; those with World Health Organisation (WHO) grade IV lesions had the shortest survival length compared to all the other grades. However, while comparing survival among other tumor grades, we did not find significant difference. Further, use of intraoperative MRI did not offer any statistically significant difference in survival. CONCLUSION: In addition to the conventional prognostic factors we need more definate ways to accurately predict survival in patients harbouring a glioma. Probably, assessing molecular characteristics of the individual tumors, such as presence of isocitrate dehydrogenase (IDH) mutation versus wild-type IDH, would help us in predicting survival more accurately. PMID- 29133705 TI - Outcome assessment in gliomas - the way forward. PMID- 29133706 TI - A randomized placebo-controlled trial of progesterone with or without hypothermia in patients with acute severe traumatic brain injury. AB - OBJECTIVE: Among newer neuroprotectant modalities, hypothermia and progesterone have shown a beneficial role in preliminary studies enrolling patients with severe traumatic brain injury (sTBI). The primary objective of this study was to evaluate the efficacy of progesterone with or without prophylactic hypothermia in acute sTBI patients. MATERIALS AND METHODS: This is a prospective, outcome assessor, statistician blinded, randomized, and placebo-controlled phase II trial of progesterone with or without hypothermia (factorial design). All adult patients (18-65 years) with acute sTBI (Glasgow coma score of 4-8) and presenting to trauma center within 8 h after injury were included in the trial. Computer generated randomization was done after exclusion; sequentially numbered, opaque, sealed envelope technique was used for allocation concealment. The enrollment duration was from January 2012 to October 2014. The primary endpoint was dichotomized Glasgow outcome score (GOS) [poor recovery = GOS 1-3; good recovery = GOS 4-5], and secondary endpoints were functional independence measure (FIM) score and mortality rate at 6 and 12 months follow-up after recruitment. RESULTS: A total of 107 patients were randomized into four groups (placebo [n = 27], progesterone [n = 26], hypothermia alone [n = 27], and progesterone + hypothermia [n = 27]). The study groups were comparable in baseline parameters except for a higher incidence of decompressive craniectomy in the placebo group (P = 0.001). The analysis of GOS at 6 months revealed statistically significant better outcome in the hypothermia group (82%; P = 0.01) and a weaker evidence for progesterone group (74%; P = 0.07) as compared with the placebo group (44%). However, the outcome benefit was marginal at 1-year follow-up for the hypothermia group (82% vs. 58%, P = 0.17). The adjusted odds ratio of poor recovery at 6 months in the hypothermia group was 0.21 (confidence interval = 0.05-0.84, P = 0.03), as compared with the placebo group. Although mean FIM scores at 6 and 12 months respectively were marginally higher in the hypothermia and progesterone groups compared with the placebo group (P = 0.06 and 0.27), the proportion of functionally independent individuals were similar in all the groups (P = 0.79 and 0.51). The mortality rates were similar in all the groups at 6 and 12 months (P = 0.78 and 0.52 respectively). CONCLUSIONS: A strong evidence for prophylactic hypothermia and a weak evidence for progesterone therapy was observed for a better primary outcome at 6 months as compared to the placebo. A similar trend was observed at a 1-year follow-up. Contrary to our hypothesis, prophylactic hypothermia therapy suppressed the beneficial effects of progesterone therapy in sTBI patients. The complex cascades of factors responsible for such interactions are still unknown and need to be further determined. PMID- 29133707 TI - Impact of transsphenoidal surgery on asymptomatic cardiomyopathy in patients with acromegaly. A single-blinded study. AB - BACKGROUND: Patients with acromegaly have 2-3 times the expected mortality rates primarily due to cardiovascular risks. Echocardiographic studies showing improvement of cardiac function following transsphenoidal surgery (TSS) are limited. MATERIALS AND METHODS: All patients with acromegaly underwent preoperative echocardiography and tissue Doppler (Philips i33, 3D ECHO) for assessment of cardiac indices. In the prospective group of patients, echocardiography was repeated after 6 months of surgery. In the retrospective group of patients, echocardiography was performed for left ventricular diastolic dysfunction and ejection fraction. Biochemical cure was confirmed at least after 6 months by glucose-suppressed plasma growth hormone (GH) concentrations (GH OGTT) of less than 0.4 ng/ml, random GH of less than 1 ng/ml, and normal age corrected insulin-like growth factor (IGF-1) values. RESULTS: In the prospective group (38 patients), there was a significant decrease in the left ventricular mass (LVM) and LVM index (LVMI) in patients who were cured as well as in patients with postoperative growth hormone (GH) 1-5 ng/ml. In the prospective group, LVMI completely normalized in 2 and a new-onset deterioration was detected in 1 patient (who was not cured) and improved in 8 others. Left ventricular systolic function was abnormal at baseline in 18 (47.3%) patients, which normalized in 11 (61.1%) patients postoperatively, and in 7 patients, it improved significantly although it did not normalize completely. There was also a significant improvement in the left ventricular ejection fraction (P = 0.01). Post TSS, in patients with GH-OGTT >5 ng/ml, there was no significant decrease in the LVM, LVMI and ejection fraction (EF). In the retrospective group, 62 patients were analyzed for a change in the EF with a mean follow-up of 20.3 months. There was a significant improvement in the left ventricular EF in patients who were cured (P < 0.001). CONCLUSION: Reduction in growth hormone levels and insulin-like growth factor type 1 can decrease the LVM and LVMI, which directly or indirectly contributes to the improvement in diastolic as well as systolic function and probably mortality. PMID- 29133708 TI - Demonstration of autonomic dysfunction in traumatic brachial plexus injury using quantitative sudomotor axon reflex test: Preliminary results. AB - OBJECTIVE: To objectively document autonomic dysfunction in the affected arm with traumatic brachial plexus injury (TBPI) using quantitative sudomotor axon reflex test (QSART). MATERIALS AND METHODS: Patients with TBPI presenting to the neurosurgical outpatient department from August 2013 to November 2014 were included in the study. The QSART was administered to each patient with prior informed consent detailing the procedure. A total of 20 patients with TBPI were included in the study. The age, sex, mode of injury, date of injury, side of injury, and type of injury (pan brachial plexus vs preserved distal function) were recorded. The presence of any pain was also recorded. The injuries were also grouped as preganglionic and postganglionic injuries based on clinical, electroneuromyography (ENMG) and magnetic resonance imaging (MRI) findings. The results of the test for the affected and normal limb were recorded and analyzed with appropriate statistical tests to determine any significant differences. RESULTS: The study included 20 patients, with their age ranging from 15 to 50 years. Out of the 20 patients, one was female and the rest 19 were males. Seven (35%) of the injuries were complete (pan brachial plexus) and 13 (65%) were incomplete (preserved distal function). All patients had preganglionic TBPI. There was no evidence of any statistically significant difference between the affected and normal arm for total sweat volume (P = 0.20) and latency period (P = 0.42). However, the average mean values for the same were lower in the affected arm as compared to the normal. The baseline sweat output (P = 0.010), however, was significantly lower in the affected arm as compared to the normal arm. CONCLUSION: QSART has demonstrated reduced baseline sweat output in the affected arm in patients with TBPI. This indicates the presence of autonomic dysfunction in the injured arm. PMID- 29133709 TI - Experience of pallidal deep brain stimulation in dystonia at a tertiary care centre in India: An initial experience. AB - INTRODUCTION: Dystonia is one of the most prevalent forms of movement disorders and is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonia causes significant morbidity with an adverse impact on the quality of life. When dystonia is medically refractory, causing severe pain and impairment in activities of daily living, deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a potential option to reduce disability. MATERIALS AND METHODS: This is a chart review of patients who underwent DBS for dystonia (from 2009 to 2015) at our tertiary referral centre. A total of ten patients (7 males, 3 females) underwent DBS for non-parkinsonian conditions. The patients were selected after failure of adequate medical management. All the patients had a severe disability with normal cognitive (Mini-Mental State Examination) and psychiatric profile. They also had to have a suitable GPi for DBS based on magnetic resonance imaging. RESULTS: The mean baseline Burke-Fahn-Marsden dystonia movement score of the 10 patients selected for surgery was 60.3 +/- 27.3 (ranging from 19 to 104). On repeated-measures analysis of variance, there was significant difference in the different time points (pre-DBS, post-DBS at 3 months, 6 months, and 1 year) F (3, 5) = 7.68, P = 0.026. The data showed that there was a maximum improvement after 1 year of stimulation (pre-DBS vs. 3 months 12.9 +/- 1.9 vs 8.8 +/- 2.1, P = 0.01; pre-DBS vs. 6 months 12.9 +/- 1.9 vs 7.4 +/- 1.6, P = 0.04; pre-DBS vs. 1 year, 12.9 +/- 1.9 vs. 7 +/- 2.4. CONCLUSION: In medically refractory primary or secondary dystonia patients, bilateral GPi DBS can be considered as an option. Patients with disabling symptoms that significantly deteriorate activities of daily life may consider DBS before these symptoms become fixed. PMID- 29133710 TI - Role of preoperative imaging in the diagnosis of primary diffuse craniospinal leptomeningeal gliomatosis. AB - We present an unusual case of primary diffuse craniospinal leptomeningeal gliomatosis (PGDL), who was initially diagnosed on the basis of imaging, laboratory findings, and cranial meningeal biopsy as tuberculous meningitis and showed clinical deterioration while on anti-tuberculous treatment for 2 months. The patient was subsequently correctly diagnosed on diffusion weighted and post contrast T1-weighted imaging of the craniospinal axis along with whole body imaging. The radiological findings were confirmed on histopathology and immunohistochemistry performed from the previous block as well as biopsy from the nodular mass in the lumbosacral meninges. We conclude that peroperative imaging may help in pinpointing the correct diagnosis and assist in guiding the surgeon to the site of biopsy. PMID- 29133711 TI - An unusual case of acute encephalitic syndrome: Is it acute measles encephalitis or subacute sclerosing panencephalitis? AB - Subacute sclerosing panencephalitis is a late complication of measles infection and develops usually 6 to 15 years after the primary measles infection. Fulminant subacute sclerosing panencephalitis is an infrequently encountered form wherein the disease rapidly progresses to death. A six-year old male child presented with fever, abnormal movements of the left side of body followed by weakness of the left side of the body, and involuntary abnormal movements of right upper and lower limbs. On examination, he was drowsy and was unable to communicate. He had right-sided hemiballismus. He also had left-sided hemiparesis and the left plantar reflex was extensor. Cerebrospinal fluid examination revealed elevated protein and cells. In the serum and cerebrospinal fluid, anti-measles IgG antibodies were found to be positive. No other viral marker was noted in the cerebrospinal fluid. Magnetic resonance imaging of the brain showed extensive damage to the right temporal, parietal, and to a lesser extent, the frontal region as well as subcortical structures of these regions. Electroencephalography revealed generalized slowing of waves. Over a period of the next 3 days, the intensity and frequency of choreiform movements markedly reduced and the patient developed periodic generalized myoclonus, which was predominantly present on the right side. The patient succumbed to his illness and died after one month. Fulminant subacute sclerosing panencephalitis may have unusual clinical manifestations such as hemiballismus. In fulminant subacute sclerosing panencephalitis, neuroimaging may show extensive cortical damage. PMID- 29133712 TI - Meningiomas: Objective assessment of proliferative indices by immunohistochemistry and automated counting method. AB - BACKGROUND: The most reliable histological correlate of recurrence risk in meningiomas is increased mitotic activity. Proliferative index with Ki-67 immunostaining is a helpful adjunct to manual counting. However, both show considerable inter-observer variability. A new immunohistochemical method for counting mitotic figures, using antibody against the phosphohistone H3 (PHH3) protein was introduced. Similarly, a computer based automated counting for Ki-67 labelling index (LI) is available. AIMS AND OBJECTIVES: To study the use of these new techniques in the objective assessment of proliferation indices in meningiomas. MATERIALS AND METHODS: This was a retrospective study of intracranial meningiomas diagnosed during the year 2013.The hematoxylin and eosin (H and E) sections and immunohistochemistry (IHC) with Ki-67 were reviewed by two pathologists. Photomicrographs of the representative areas were subjected to Ki 67 analysis by Immunoratio (IR) software. Mean Ki-67 LI, both manual and by IR were calculated. IHC with PHH3 was performed. PHH3 positive nuclei were counted and mean values calculated. Data analysis was done using SPSS software. RESULTS: A total of 64 intracranial meningiomas were diagnosed. Evaluation on H and E, PHH3, Ki-67 LI (both manual and IR) were done in 32 cases (22 grade I and 10 grade II meningiomas). Statistically significant correlation was seen between the mitotic count in each grade and PHH3 values and also between the grade of the tumor and values of Ki-67 and PHH3. CONCLUSION: Both the techniques used in the study had advantage over, as well as, correlated well with the existing techniques and hence, can be applied to routine use. PMID- 29133713 TI - Three-dimensional model printing for surgery on arteriovenous malformations. AB - AIM: Surgery for intracranial complex vascular malformations can be quite exigent and involves considerable preoperative planning. Here, we present the advantages of using three-dimensional (3D) printed models as a preoperative investigational modality. MATERIAL AND METHODS: 3D printed models were made from thin-slice computed tomography (CT) angiography scans of 6 patients with arteriovenous malformations over an18-month period from August 2015 to December 2016. The locations of the arteriovenous malformations were in the Sylvian fissure in 1 patient, posterior frontal region in 2 patients, subfrontal region in 1 patient, and parietal region in 2 patients. The CT angiography was performed on a 64-slice CT scanner. Thin-slice axial CT sections were acquired and a volume file was created of the arteriovenous malformation and the required skull bones. The file was then transferred to the 3D printer for creating the model. RESULTS: The model depicted the precise nature of the compactness and location of the nidus in relationship to the skull. It was possible to clearly delineate the course, size, and number of feeding vessels and draining veins. The model made identification of the normal and abnormal vessels easier and assisted in the preparation and conduct of surgery. The model was made to scale and was placed beside the surgeon during the operation. The limitation of current technology was that the exact differentiation of arteries and veins by color coding was not possible. CONCLUSION: 3D printed models can be helpful in getting information regarding the architecture and character of the arteriovenous malformation. The models are cost effective and easy to build. PMID- 29133714 TI - Options for the management of brain arteriovenous malformations. PMID- 29133715 TI - Minimally invasive lateral foraminotomy with partial lateral facetectomy for lumbar radiculopathy-An evaluation of facet integrity and description of the procedure. AB - Foraminal stenosis causing nerve root compression and radiculopathy is a relatively common pathology in the lumbar spine. The treatment of choice, when surgery is indicated, is foraminal decompression at the affected level, usually through a conventional midline open foraminotomy. Minimally invasive lateral foraminotomy with partial lateral facetectomy is a potentially effective surgical alternative when such a surgery is warranted. The evaluation of the efficacy and benefits of this approach for treatment of radiculopathy; an assessment of facet integrity; and, a detailed description of the procedure are also provided. Patients with predominantly unilateral lower limb radiculopathy, who had persistent symptoms despite conservative therapy, underwent a minimally invasive lumbar lateral foraminotomy (through tubular retractors) with partial lateral facetectomy. The Oswestry disability index (ODI) and the visual analog scale (VAS) for back and leg pain were evaluated preoperatively, postoperatively, and at the latest follow-up. Facet integrity was evaluated with postoperative computed tomography (CT) scans. Between 2013 and 2014, in the 12 patients who underwent this procedure and were evaluted after a minimum follow up of 1 year, there was significant improvement in the ODI, VAS based back pain, and VAS based leg pain. A minimally invasive, lateral foraminotomy with partial lateral facetectomy is an effective alternative technique for treatment of radiculopathy due to foraminal stenosis in a carefully selected subgroup of patients. A larger study would possibly highlight the effectiveness of this procedure. PMID- 29133716 TI - The Department of Neurosurgery, G. B. Pant Hospital, New Delhi. AB - The history of the prestigious Department of Neurosurgery, Gobind Ballabh Pant Institute of Medical Education Institute and Research, New Delhi, a leading tertiary care centre, is presented. Its eminent faculty and outstanding patient care attracts patients and students from all over the country.The patients opt for this institution to get a standard of care that may be comparable with the highest standards prevalent; and, the students achieve their goal of getting excellent education in Neurosurgery at par with the best institutes of the world. The department has, therefore, over the years, established its place in the country as a premier training facility and an epitome of medical excellence. PMID- 29133717 TI - A summary of some of the recently published, seminal papers in neuroscience. PMID- 29133718 TI - Lessons learnt from accidental spillage of glue between nerve and artery during microvascular decompression. PMID- 29133719 TI - Enterococcus faecalis: An unusual etiology of lumbar spondylodiscitis in a patient with chronic kidney disease (undergoing hemodialysis) and sigmoid diverticulosis. PMID- 29133720 TI - Aortic dissection in the thrombolysis era: Rare but potentially fatal cause of stroke. PMID- 29133721 TI - Retroclival subdural hematoma after a lumbar puncture: An uncommon complication for a common procedure. PMID- 29133722 TI - A longitudinal study of retinal nerve fibre layer profile in patients with multiple sclerosis and its significance. PMID- 29133723 TI - Paroxysmal painful tonic spasm due to remote effect of old basal ganglia hemorrhage. PMID- 29133724 TI - An unusual mode of revelation of Wernicke's encephalopathy: Bilateral blindness with bilateral hypoacousia. PMID- 29133725 TI - Moyamoya syndrome in a child with methyl tetrahydrofolate reductase mutation. PMID- 29133726 TI - Therapeutic plasma exchange in a patient of myasthenic crisis, refractory to intravenous immunoglobulin and immunosuppressive therapy. PMID- 29133727 TI - Clinically amyopathic dermatomyositis associated with cerebral venous sinus thrombosis and macrophage activation syndrome. PMID- 29133728 TI - Upper limb monochorea in a patient with an acute pontine bleed. PMID- 29133729 TI - Spontaneous resolution of a spinal arachnoid cyst. PMID- 29133730 TI - Unexpected cause of leg pain in a patient with lower back pain. PMID- 29133731 TI - Nonconvulsive status in the trauma centre: Think of cerebral fat embolism. PMID- 29133733 TI - Intracranial melioidosis: First report in a human immunodeficiency virus positive individual manifesting as cranial osteomyelitis. PMID- 29133732 TI - Acute axonal polyneuropathy following resection of a glioblastoma multiforme. PMID- 29133734 TI - Advanced magnetic resonance imaging in the diagnosis of primary intracranial malignant melanoma. PMID- 29133736 TI - Giant bilateral cavernous segment internal carotid artery aneurysms. PMID- 29133735 TI - Sternberg's canal - A rare cause of spontaneous cerebrospinal fluid rhinorrhea. PMID- 29133737 TI - Spontaneous spinal epidural hematoma mimicking a cerebrovascular disease. PMID- 29133738 TI - Dorsolumbar fungal (aspergillus) epidural granuloma in an immunocompetent patient: Review of literature. PMID- 29133739 TI - MRI findings in methotrexate-induced acute toxic leukoencephalopathy. PMID- 29133740 TI - Marchiafava Bignami disease. PMID- 29133741 TI - MRI in a patient with sporadic Creutzfeldt-Jakob disease with over 72 months survival. PMID- 29133742 TI - Intraventricular vein thrombosis in a patient with cerebral venous thrombosis. PMID- 29133743 TI - Rachipagus parasitic twin. PMID- 29133744 TI - Patellar jerks in the 3-Tesla era: No knee-jerk excitement anymore! PMID- 29133745 TI - Two founders of Bombay Neurosciences: Additional facts. PMID- 29133746 TI - Spinal model for teaching and training. PMID- 29133747 TI - Glaucoma due to Valsalva manoeuvre. PMID- 29133748 TI - Books from my shelf. PMID- 29133749 TI - Prof. K V Mathai (1926 - 2017). PMID- 29133750 TI - What Are the Unanswered Questions and Unmet Needs in Inflammatory Bowel Disease Management in Asia? PMID- 29133751 TI - Shanghai Score: A Prognostic and Adjuvant Treatment-evaluating System Constructed for Chinese Patients with Hepatocellular Carcinoma after Curative Resection. AB - BACKGROUND: For Chinese patients with hepatocellular carcinoma (HCC), surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis after surgery is diverse. We aimed to construct a scoring system (Shanghai Score) for individualized prognosis estimation and adjuvant treatment evaluation. METHODS: A multivariate Cox proportional hazards model was constructed based on 4166 HCC patients undergoing resection during 2001-2008 at Zhongshan Hospital. Age, hepatitis B surface antigen, hepatitis B e antigen, partial thromboplastin time, total bilirubin, alkaline phosphatase, gamma-glutamyltransferase, alpha fetoprotein, tumor size, cirrhosis, vascular invasion, differentiation, encapsulation, and tumor number were finally retained by a backward step-down selection process with the Akaike information criterion. The Harrell's concordance index (C-index) was used to measure model performance. Shanghai Score is calculated by summing the products of the 14 variable values times each variable's corresponding regression coefficient. Totally 1978 patients from Zhongshan Hospital undergoing resection during 2009-2012, 808 patients from Eastern Hepatobiliary Surgery Hospital during 2008-2010, and 244 patients from Tianjin Medical University Cancer Hospital during 2010-2011 were enrolled as external validation cohorts. Shanghai Score was also implied in evaluating adjuvant treatment choices based on propensity score matching analysis. RESULTS: Shanghai Score showed good calibration and discrimination in postsurgical HCC patients. The bootstrap-corrected C-index (confidence interval [CI]) was 0.74 for overall survival (OS) and 0.68 for recurrence-free survival (RFS) in derivation cohort (4166 patients), and in the three independent validation cohorts, the CI s for OS ranged 0.70-0.72 and that for RFS ranged 0.63-0.68. Furthermore, Shanghai Score provided evaluation for adjuvant treatment choices (transcatheter arterial chemoembolization or interferon-alpha). The identified subset of patients at low risk could be ideal candidates for curative surgery, and subsets of patients at moderate or high risk could be recommended with possible adjuvant therapies after surgery. Finally, a web server with individualized outcome prediction and treatment recommendation was constructed. CONCLUSIONS: Based on the largest cohort up to date, we established Shanghai Score - an individualized outcome prediction system specifically designed for Chinese HCC patients after surgery. The Shanghai Score web server provides an easily accessible tool to stratify the prognosis of patients undergoing liver resection for HCC. PMID- 29133752 TI - Proportion of Uterine Malignant Tumors in Patients with Laparoscopic Myomectomy: A National Multicenter Study in China. AB - BACKGROUND: The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma; therefore, the use of morcellation is limited in the USA. A large sample study is necessary to assess the proportion of uterine malignant tumors found in patients with laparoscopic myomectomy. METHODS: A national multicenter study was performed in China. From 2002 to 2014, 33,723 cases were retrospectively selected. We calculated the prevalence and recorded the clinical characteristics of the patients with malignancy after morcellation application. A total of 62 cases were finally pathologically confirmed as malignant postoperatively. Additionally, the medical records of the 62 patients were analyzed in details. RESULTS: The proportion of postoperative malignancy after morcellation application was 0.18% (62/33,723) for patients who underwent laparoscopic myomectomy. Nearly 62.9% (39/62) of patients had demonstrated blood flow signals in the uterine fibroids before surgery. And, 23 (37.1%) patients showed rapid growth at the final preoperative ultrasound. With respect to the pathological types, 38 (61.3%) patients had detectable endometrial stromal sarcoma, 13 (21.0%) had detectable uterine leiomyosarcoma, only 3 (3.2%) had detectable carcinosarcoma, and 5 (8.1%) patients with leiomyoma had an undetermined malignant potential. CONCLUSIONS: The proportion of malignancy is low after using morcellation in patients who undergo laparoscopic myomectomy. Patients with fast growing uterine fibroids and abnormal ultrasonic tumor blood flow should be considered for malignant potential, and morcellation should be avoided. PMID- 29133753 TI - Transcatheter Arterial Chemoembolization Combined with Simultaneous Computed Tomography-guided Radiofrequency Ablation for Large Hepatocellular Carcinomas. AB - BACKGROUND: Currently, the treatment of large hepatocellular carcinoma (HCC) is still a challenging problem. Transcatheter arterial chemoembolization (TACE) is the main treatment for intermediate end-stage HCC, while it is only a palliative and not a curative treatment due to the existence of residual tumors, and radiofrequency ablation (RFA) has limitations in complete ablation of large HCC. We hypothesized that TACE combined with simultaneous RFA (herein referred to as TACE + RFA) could improve the efficacy and survival of large HCC. This study aimed to investigate the feasibility, efficacy, and safety of TACE + RFA on single large HCC. METHODS: A total of 66 patients with single large HCC (>=5 cm in diameter) were recruited between February 2010 and June 2016. TACE was first performed and computed tomography was performed immediately after TACE, and the lesions with poor lipiodol deposition were subjected to simultaneous RFA. The success rate, technique-related complications, liver and kidney functions, serum alpha-fetoprotein (AFP) levels, progression-free survival (PFS), median survival time (MST), focal control rate, and long-term survival rate were evaluated. RESULTS: TACE + RFA were performed smoothly in all the patients with the success rate of 100%. Intra- and post-operative severe complications were not observed. There were no marked differences in mean alanine transaminase or aspartate transaminase before TACE + RFA compared with 7 days after TACE + RFA (all P > 0.05). In 57 AFP-positive patients, the levels of serum AFP were reduced by 100.0%, 100.0%, and 94.7% at 1, 3, and 6 months after TACE + RFA, respectively; the tumor control rates (complete remission + partial remission) were 100.0% (66/66), 92.4% (61/66), 87.9% (58/66), and 70.1% (39/55) at 1, 3, 6, and 12 months after TACE + RFA, respectively. Patients were followed up for 7-82 months after TACE + RFA. The MST was 18.3 months, PFS was 14.2 +/- 6.2 months, and the 1 , 3-, and 5-year survival rates were 93.2% (55/59), 42.5% (17/40), and 27.2% (9/33), respectively. CONCLUSION: TACE + RFA is safe, feasible, and effective in enhancing the focal control rate and survival rate of patients with large HCC. PMID- 29133754 TI - Comparison of Clinical Features between Pyoderma Gangrenosum Concomitant by Inflammatory Bowel Disease and Idiopathic Pyoderma Gangrenosum. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that is highly associated with inflammatory bowel disease (IBD). Certain PG patients with no systemic disorders have been diagnosed with idiopathic PG. This study sought to clarify the difference between PG with IBD and idiopathic PG based on clinical features, laboratory tests, and medications. METHODS: Twelve patients with PG and IBD and 24 patients with idiopathic PG, who were hospitalized in Peking Union Medical College Hospital from 2000 to 2017, were retrospectively categorized into the IBD group and control group, respectively. Data of clinical features, laboratory tests, and medications were collected and compared between the two groups. RESULTS: Both groups were similar with respect to their clinical features. However, the IBD group had an increased occurrence of arthralgia or arthritis (58.3% vs. 12.5%, P = 0.007), anemia (83.3% and 29.2%, P = 0.004), and an increased percentage of antineutrophilic cytoplasmic antibody (ANCA)-positive patients (85.7% and 0.0%, P < 0.001), compared to the control group. CONCLUSION: PG patients with IBD had increased occurrence rates of arthralgia or arthritis, anemia, and ANCA-positive status compared to idiopathic PG patients. PMID- 29133755 TI - Analysis of the Relationship between Helicobacter pylori Infection and Diabetic Gastroparesis. AB - BACKGROUND: Whether Helicobacter pylori infection is associated with diabetic gastroparesis (DGP) is unclear. This study aimed to investigate the potential correlation between H. pylori infection and DGP. METHODS: In this study, 163 patients with type 2 diabetes mellitus and 175 nondiabetic patients who were treated in our department were divided into DGP, simple diabetes, non-DGP (NDG), and normal groups based on their conditions. The H. pylori infection rate in each group was calculated. H. pylori eradication therapy was performed for patients with H. pylori infection in each group. The eradication rates were compared between the groups, and the improvements in gastroparesis-associated symptoms were compared before and after treatment in patients with DGP. RESULTS: The H. pylori infection rate was 74.6% in the DGP group, which was significantly higher than that in the simple diabetes (51.1%, P < 0.01), NDG (57.7%, P < 0.05), and normal groups (48.0%, P < 0.01). With increased disease course, the incidence of DGP and the H. pylori infection rate gradually increased (P < 0.05). In the DGP group, the incidences of upper abdominal pain and distention, early satiety, and anorexia were 75.5%, 66.0%, and 67.9%, respectively, before eradication treatment; and 43.4%, 35.8%, and 39.6%, respectively, after eradication treatment, and the difference was statistically significant (P < 0.01). In patients with DGP with successful H. pylori eradication, the number of barium strips discharged after eradication was 5.9 +/- 1.0, which was significantly larger than that before treatment (4.1 +/- 0.7, P < 0.01). In addition, the number of barium strips discharged was significantly larger in patients with DGP with successful H. pylori eradication than those with failed H. pylori eradication (P < 0.01). CONCLUSIONS: DGP development might be associated with H. pylori infection. H. pylori eradication can effectively improve dyspepsia associated symptoms and delayed gastric emptying in patients with DGP. PMID- 29133756 TI - Signal Transducer and Activator of Transcription 3 for the Differentiation of Hepatocellular Carcinoma from Cirrhosis. AB - BACKGROUND: Overexpression and constitutive activation of signal transducer and activator of transcription (STAT) 3 have been suggested in the tumorigenesis of many human cancers, including multiple carcinomas, melanoma, and lymphoma. The diagnosis of hepatocellular carcinoma (HCC) in lobectomy specimens is usually straightforward, but distinguishing cirrhosis from well-differentiated HCC can be challenging in core biopsies. Our aims were to investigate the expression level of STAT3 and phosphorylated STAT3 (pSTAT3) in HCC and cirrhosis, and the application of STAT3 in the differential diagnosis of HCC and cirrhosis. METHODS: Sixty cases were divided into three groups: patients with HCC only (Group 1), HCC and cirrhosis (Group 2), and cirrhosis only (Group 3). Formalin-fixed and paraffin-embedded tissue sections were stained immunohistochemically for STAT3, pSTAT3, and CD163. The values obtained from the tissue sections of each group were compared in statistical analysis. RESULTS: STAT3 showed a high level in HCC and was a significant marker for differentiating HCC from cirrhosis (P < 0.0001). The odds ratio between HCC and cirrhosis increased 34.4 times when the intensity of STAT3 increased by 1 level. Spearman's correlation and Chi-square tests also demonstrated that expression level of STAT3 did not correlate with age, gender, or the presence of a cirrhotic background. CONCLUSIONS: STAT3 staining differs significantly in HCC and cirrhosis. The findings reinforce the role of STAT3 in the tumorigenesis of HCC and provide a useful marker to differentiate HCC from cirrhosis in challenging liver biopsies. PMID- 29133757 TI - Soluble Triggering Receptor Expressed on Myeloid Cells-1 and Inflammatory Markers in Colorectal Cancer Surgery: A Prospective Cohort Study. AB - BACKGROUND: Major abdominal surgery, including colorectal cancer (CRC) surgery, leads to systemic inflammatory response syndrome that can be detected and monitored with inflammatory markers testing. The aims of the study were to evaluate the usefulness of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) in following the inflammatory response in CRC surgery and postoperative period, as well as to determine if duration of the surgery and the time that the colon has been opened during the surgery (open colon time [OCT]) reflect a larger surgical stress through inflammatory markers rise. METHODS: The study included 20 patients who underwent CRC surgery and 19 healthy volunteers from June 2011 to September 2012. We determined inflammatory markers 1 day before surgery (T0), 24 h (T1), 48 h (T2), and 7 days after the surgery (T3). All statistical analyses were calculated using MedCalc Statistical Software version 14.8.1 (MedCalc Software bvba, Ostend, Belgium). RESULTS: Concentrations of CRP, PCT, and IL-6 in all measurement times were statistically different and sTREM-1 did not yield statistical significance. A weak positive correlation was found between IL-6 in T1 and T2 with the duration of the surgery (T1: r = 0.4060, P < 0.0001; T2: r = 0.3430, P < 0.0001) and OCT (T1: r = 0.3640, P < 0.0001, T2: r = 0.3430, P < 0.0001). A weak positive correlation between CRP in T2 and OCT (r = 0.4210, P < 0.0001) was also found. The interconnectivity of tested parameters showed a weak positive correlation between CRP and IL-6 in T1 (r = 0.3680; P < 0.0001), moderate positive correlation in T2 (r = 0.6770; P < 0.0001), and a strong positive correlation in T3 (r = 0.8651; P < 0.0001). CONCLUSIONS: CRP, IL-6, and PCT were shown to be reliable for postoperative monitoring. Simultaneous determination of CRP and IL-6 might not be useful as they follow similar kinetics. sTREM-1 might not be useful in CRC postoperative monitoring. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01244022;https://www.clinicaltrials.gov/ct2/show/NCT01244022?term=01244022&ran =1. PMID- 29133758 TI - Negative Correlation of Serum Hepatitis B Surface Antigen and Hepatitis B e Antigen Levels with the Severity of Liver Inflammation in Treatment-naive Patients with Chronic Hepatitis B Virus Infection. AB - BACKGROUND: Estimating the grades of liver inflammation is critical in the determination of antiviral therapy in patients chronically infected with hepatitis B virus (HBV). The aim of this study was to investigate the correlation of serum levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) with the liver inflammation grades in treatment-naive patients with chronic HBV infection. METHODS: We retrospectively enrolled 584 treatment-naive HBeAg-positive patients who underwent liver biopsy in Ditan Hospital from January 2008 to January 2016. Based on the severity of liver inflammation, the patients were divided into minimal, mild, and moderate groups. SPSS software was used for statistical analysis of all relevant data. RESULTS: The liver histological examinations showed that 324, 194, and 66 patients had minimal, mild, and moderate liver inflammation, respectively. The median age of the three groups was 30, 33, and 38 years, respectively (Chi2 = 26.00, P < 0.001). The median HBsAg levels in minimal, mild, and moderate inflammation groups were 4.40, 4.16, and 3.67 log U/ml, respectively, and the median HBeAg levels in the three groups were 3.12, 2.99, and 1.86 log sample/cutoff, respectively; both antigens tended to decrease as the grade of inflammation increased (Chi2 = 99.68 and Chi2 = 99.23, respectively; both P < 0.001). The cutoff values of receiver operating characteristic curve in the age, HBsAg and HBeAg levels were 36 years, 4.31 log U/ml, and 2.86 log S/CO, respectively, l to distinguish minimal grade and other grades of treatment-naive HBeAg-positive patients with chronic HBV infection. CONCLUSIONS: Serum HBsAg and HBeAg quantitation might gradually decrease with aggravated liver inflammation and the corresponding cutoff values might help us to distinguish minimal grades and other grades and detect those who do not need antiviral therapy in treatment-naive HBeAg-positive patients with chronic HBV infection. PMID- 29133759 TI - Factors Associated with Development of Vitiligo in Patients with Halo Nevus. AB - BACKGROUND: Halo nevus (HN) has been shown to be associated with vitiligo, but no standard signs are currently available to identify HN patients at risk of vitiligo, and the relevant data obtained in previous studies are somewhat conflicting. This study aimed to identify factors affecting the presence of vitiligo in HN patients. METHODS: We performed a retrospective study on consecutive patients with HN at the First Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2016. Detailed demographic and clinical data were collected to identify the factors associated with the presence of vitiligo in this cohort of patients using uni- and multi-variate logistic regression analyses. RESULTS: A total of 212 HN patients were included, 101 of whom had vitiligo-associated HN (HNV). Univariate analysis indicated that a personal history of thyroid diseases was positively associated with HNV (odds ratio [OR] = 10.761, P = 0.025), while the onset age of HN was negatively associated with HNV (OR = 0.537, P = 0.026). Multivariate analysis demonstrated that the Koebner phenomenon (KP; OR = 10.632, P < 0.0001), multiple HN (OR = 3.918, P < 0.0001), and a familial history of vitiligo (OR = 3.222, P = 0.014) were independent factors associated with HNV. CONCLUSIONS: HN without vitiligo has clinical features distinct from HN associated with vitiligo. HN patients with KP, multiple lesions, or familial history of vitiligo are more likely to develop vitiligo and therefore should be monitored for clinical signs of such accompanied conditions. PMID- 29133760 TI - A Gene Scan Study of RPE65 in Chinese Patients with Leber Congenital Amaurosis. AB - BACKGROUND: Leber congenital amaurosis (LCA) is a visual disease which is caused by RPE65 mutations and results in retinal degeneration and severe vision loss in early infancy. According to previous researches, mutations of the RPE65 gene account for 16% of all cases of LCA. This study aimed to identify RPE65 gene mutations in Chinese patients with LCA. METHODS: We recruited 52 sporadic patients from Peking University Third Hospital in 2016 and applied Sanger sequencing to identify variants among exons responsible for the disease. The genomic DNAs from blood leukocytes of these patients were isolated, and the entire coding region of the RPE65 gene was amplified by polymerase chain reaction. We then determined the sequence of RPE65 using ABI 3100 Genetic Analyzer. RESULTS: Our study identified that only 1 out of the 52 patients with LCA carried the previously unreported homozygosis missense mutation c1174A>C (T392P) of the RPE65 gene. However, the mutation was associated with the disease phenotype and not detected in 100 normal controls. CONCLUSIONS: Though we identified a novel missense mutation in the RPE65 gene that causes LCA, our result indicates that RPE65 mutations may not play a major role in the LCA patients in China since only 1 out of the 52 patients carried mutation in the RPE65 gene. PMID- 29133761 TI - Reduction on OFF-responses of Electroretinogram in Monkeys with Long-term High Intraocular Pressure. AB - BACKGROUND: There are ON- and OFF-pathways in the normal vertebrate retina. Short and long-flash electroretinogram (ERG) are suitable methods to observe the function of ON- and OFF-pathways in vivo, respectively. It is clear that high intraocular pressure (IOP) might cause dysfunction of cone-dominated photopic negative response (PhNR) in monkeys with high IOP in ON-pathway. However, whether cone-dominated OFF-responses are also affected is less known. The aim of this study was to observe photopic OFF-responses of ERG in monkeys with high IOP. METHODS: Nine monkeys were involved in the experiment from January 2006 to December 2016. High IOP was induced in the right eye by laser coagulation of the mid-trabecular meshwork in five monkeys. Six years after the laser coagulation, both short- and long-flash of the photopic ERG were recorded. Stimulus light was red flashes superimposed on a blue background. Four normal monkeys were examined under the same ERG protocols as controls. Paired t- test was used to compare the difference of each ERG parameter between the lasered eye and the fellow eye. Analysis of variance (ANOVA) with Tukey adjustment was adopted to calculate the differences among the lasered eye, the fellow eye, and the eyes of normal monkeys. RESULTS: The mean amplitude of a-wave (11.73 +/- 2.05) and PhNR (8.67 +/ 2.44) in lasered eyes was significantly lower than that of a-wave (21.47 +/- 3.15) and PhNR (22.05 +/- 3.42) in fellow eyes (P = 0.03 and P = 0.01, respectively) in response to short flash. The mean amplitude of d-wave (1.60 +/- 0.59) and i-wave (3.13 +/- 0.64) was significantly reduced in the lasered eyes than that of d-wave (4.01 +/- 0.56) and i-wave (8.79 +/- 1.75) in the fellow eyes (P = 0.02 and P = 0.02, respectively) in response to long flash. CONCLUSIONS: Reduced OFF-responses are recorded in monkeys with high IOP when dysfunction of photoreceptor is involved. The reduced OFF-responses to long-flash stimulus show evidence of anomalous retinal circuitry in glaucomatous retinopathy. PMID- 29133762 TI - Rare-earth Nanoparticle-induced Cytotoxicity on Spatial Cognition Memory of Mouse Brain. AB - BACKGROUND: Luminescent rare-earth-based nanoparticles have been increasingly used in nanomedicine due to their excellent physicochemical properties, such as biomedical imaging agents, drug carriers, and biomarkers. However, biological safety of the rare-earth-based nanomedicine is of great significance for future development in practical applications. In particular, biological effects of rare earth nanoparticles on human's central nervous system are still unclear. This study aimed to investigate the potential toxicity of rare-earth nanoparticles in nervous system function in the case of continuous exposure. METHODS: Adult ICR mice were randomly divided into seven groups, including control group (receiving 0.9% normal saline) and six experimental groups (10 mice in each group). Luminescent rare-earth-based nanoparticles were synthesized by a reported co precipitation method. Two different sizes of the nanoparticles were obtained, and then exposed to ICR mice through caudal vein injection at 0.5, 1.0, and 1.5 mg/kg body weight in each day for 7 days. Next, a Morris water maze test was employed to evaluate impaired behaviors of their spatial recognition memory. Finally, histopathological examination was implemented to study how the nanoparticles can affect the brain tissue of the ICR mice. RESULTS: Two different sizes of rare earth nanoparticles have been successfully obtained, and their physical properties including luminescence spectra and nanoparticle sizes have been characterized. In these experiments, the rare-earth nanoparticles were taken up in the mouse liver using the magnetic resonance imaging characterization. Most importantly, the experimental results of the Morris water maze tests and histopathological analysis clearly showed that rare-earth nanoparticles could induce toxicity on mouse brain and impair the behaviors of spatial recognition memory. Finally, the mechanism of adenosine triphosphate quenching by the rare earth nanoparticles was provided to illustrate the toxicity on the mouse brain. CONCLUSIONS: This study suggested that long-term exposure of high-dose bare rare earth nanoparticles caused an obvious damage on the spatial recognition memory in the mice. PMID- 29133763 TI - Effects of Melatonin Levels on Neurotoxicity of the Medial Prefrontal Cortex in a Rat Model of Parkinson's Disease. AB - BACKGROUND: Damage of the medial prefrontal cortex (mPFC) results in similar characteristics to the cognitive deficiency seen with the progress of Parkinson's disease (PD). Since the course of mPFC damage is still unclear, our study aimed to investigate the effects of melatonin (MT) on neurotoxicity in the mPFC of a rat model of PD. METHODS: One hundred and fifty-four normal, male Wistar rats were randomly divided into the following five groups: normal + normal saline (NS), normal + 6-hydroxydopamine (6-OHDA), sham pinealectomy (PX) + 6-OHDA, PX + 6-OHDA, and MT + 6-OHDA. 6-OHDA was injected into the right substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) of each group, except normal + NS, 60 days after the PX. In the MT treatment group, MT was administered immediately after the intraperitoneal injection at 4 p.m. every day, for 14 days. Neuronal apoptosis in the mPFC was examined using the TUNEL method, while the expression of tyrosine hydroxylase (TH), Bax,and Bcl-2 in this region was measured using immunohistochemistry. The concentration of malondialdehyde (MDA) in the mPFC was examined using the thiobarbituric acid method. RESULTS: Rats in the normal + 6-OHDA and sham PX + 6-OHDA groups were combined into one group (Group N + 6-OHDA) since there was no significant discrepancy between the groups for all the detected parameters. Apoptosis of cells in the NS, MT + 6-OHDA, N + 6 OHDA, and PX + 6-OHDA groups was successively significantly increased (Hc = 256.25, P < 0.001). The gray value of TH (+) fibers in the NS, MT + 6-OHDA, N + 6 OHDA, and PX + 6-OHDA groups was also successively significantly increased (F = 99.33, P < 0.001). The staining intensities of Bax and Bcl-2 were as follows: Group NS +/+, Group MT + 6-OHDA ++/+, Group N + 6-OHDA ++/+, and PX + 6-OHDA +++/+. The concentrations of MDA in the NS, MT + 6-OHDA, N + 6-OHDA, and PX + 6 OHDA groups were significantly increased in sequence (Hc = 296.309, P < 0.001). CONCLUSIONS: Neuronal damage of the VTA by 6-OHDA might induce VTA-mPFC nerve fibers to undergo anterograde nerve damage, in turn inducing transneuronal damage of the mPFC. PX significantly exacerbated the neurotoxicity in the mPFC, which was induced by the neuronal injury of the VTA. However, MT replacement therapy significantly alleviated the neurotoxicity in the mPFC. PMID- 29133764 TI - Advanced Role of Hippo Signaling in Endometrial Fibrosis: Implications for Intrauterine Adhesion. AB - OBJECTIVE: Intrauterine adhesion (IUA) is a major health problem that causes infertility, menstrual irregularities, and recurrent pregnancy losses in women. Unfortunately, treatments for IUA are limited, and there are currently no effective strategies for preventing IUA recurrence. In this review, we introduced the role of Hippo signaling in the normal endometrium and IUA and described the mechanisms by which the Hippo pathway integrates with the Wnt and transforming growth factor-beta (TGF-beta) signaling pathways to form an intricate network governing the development of fibrosis. DATA SOURCES: Original research articles in English that were published until July 2017 were collected from the PubMed database. STUDY SELECTION: Literature search was conducted using the search terms "endometrial fibrosis OR fibrosis AND or OR intrauterine adhesion OR Asherman syndrome OR IUA," "Hippo AND or OR Hippo/TAZ," "TGF-beta," and "Wnt." Related original research articles were included in the comprehensive analysis. RESULTS: Endometrial fibrosis is recognized as a key pathological event in the development of IUA, which is characterized by epithelial/fibroblast-myofibroblast transition. Myofibroblasts play crucial roles in the pathogenesis of fibrous scarring, and myofibroblast differentiation can be triggered by multiple signaling pathways. Hippo signaling is a critical regulator of the epithelial/fibroblast myofibroblast transition and alpha-smooth muscle actin, which exhibits a specific spatiotemporal expression in the endometrium. CONCLUSIONS: Hippo signaling plays a critical role in fibrous diseases and participates in cross talks with Wnt and TGF-beta signaling. Our findings not only contributed to knowledge on the pathogenesis of endometrial fibrosis, but can also serve as a useful resource for developing specific molecular inhibitors for IUA treatment and prevention. PMID- 29133765 TI - Geriatric Anesthesia-related Morbidity and Mortality in China: Current Status and Trend. AB - OBJECTIVE: The population of elderly patients and the amount of geriatric anesthesia have been growing rapidly in China. Thus, understanding the morbidity and mortality associated with geriatric anesthesia in China is critical to the improvement of anesthesia quality and outcome. The aim of the review was to discuss the geriatric anesthesia-related morbidity and mortality in China, as well as to point out the future trend. DATA SOURCES: Articles in this review were all searched from Wanfang, China National Knowledge Infrastructure (CNKI), VIP, PubMed, and Web of Science databases, based on the reports originated in China from January 2011 to December 2016. STUDY SELECTION: A total of 57 studies were selected for further study, including 12 retrospective studies, 35 prospective studies, 3 meta-analyses, 4 reviews, 1 viewpoint, and 2 case reports. Of the total studies, 42 studies were in Chinese while 15 were in English. RESULTS: The mortality and morbidity associated with geriatric anesthesia in China are not yet completely reported. Some factors have been recognized, while some are yet to be identified and confirmed. Several studies addressed postoperative cognitive dysfunction and postoperative delirium, whereas only a few studies can be found on renal complications. Thus, a nationwide registry is essential for geriatric anesthesia-associated adverse outcomes. The mortality associated with geriatric anesthesia in China should be reported promptly. In the future, the perspective of geriatric anesthesia needs to be expanded into perioperative geriatric medicine to improve the perioperative management strategy based on the postoperative outcome-directed concept transformation. CONCLUSIONS: Anesthesiologists should evaluate the physiological and medical status and focus on the prevention of potential complications in the perioperative setting with the goal to enhance elderly patients' long-term well-being and survival quality. PMID- 29133766 TI - Patient Education Improves Patient Knowledge and Acceptance on Antiviral Therapy of Hepatitis C in Rural China. PMID- 29133767 TI - Application of a Feedback Journal Club. PMID- 29133768 TI - Severe Pneumonitis after Nivolumab Treatment Accompanied by Acute Pulmonary Embolism in a Patient with Lung Adenocarcinoma. PMID- 29133769 TI - Wernicke Encephalopathy in a Patient with Pulmonary and Abdominal Tuberculosis. PMID- 29133770 TI - Posterior Mediastinal, Intraspinal, Intradural, Intramedullary Lipoma through a Kovalevsky Canal in the Thoracic Spine. PMID- 29133771 TI - Early Multiple Primary Lung Cancer without Fluorodeoxyglucose Uptake on Positron Emission Tomography-Computed Tomography and Displaying Different EGFR Molecular Profiles. PMID- 29133772 TI - Paraneoplastic Anti-N-Methyl-D-Aspartic Acid Receptor Encephalitis. PMID- 29133773 TI - A Rarely Concerned Magnetic Resonance Image Sign of Spinal Nerve Root Hypertrophy in Type 1A Charcot-Marie-Tooth Disease. PMID- 29133774 TI - Henna Tattoo: Temporary or Permanent? PMID- 29133775 TI - Pseudo-Bartter Syndrome in a Chinese Infant with Cystic Fibrosis Caused by c.532G>A Mutation in CFTR. PMID- 29133776 TI - Tacrolimus Levels Are Not Associated with Risk of Malignancy in Lung Transplant Recipients. AB - BACKGROUND Lung transplant (LTx) recipients suffer from high rates of malignancy. Exposure to immunosuppressive medication such as tacrolimus has been proposed as a risk factor for tumorigenesis. We hypothesized that chronically high levels of tacrolimus would be associated with risk of malignancy. MATERIAL AND METHODS The study was performed in a transplant center in Israel, with a nested case-control design. Cases were LTx recipients who were diagnosed with any solid or hematological malignancy except non-melanoma skin cancer. Controls were tumor free during their entire follow-up after LTx and had at least the same follow-up time as their matched case. Controls were matched to cases by age and type of transplant received (single/double). Tacrolimus levels were extracted and analyzed for median drug level and also integrated over time (area under the curve - AUC-tacrolimus). RESULTS We reviewed 412 LTx recipients in our registry. Thirty-nine cases of malignancy were diagnosed and 160 controls were matched, giving a crude tumor incidence rate of 26/100 000/year. Lung cancers were the commonest diagnosis. Cases and controls were well matched by age, smoking status, and LTx type. Median tacrolimus levels were 11.0 ng/ml and 11.3 ng/ml in cases and controls, respectively (p=0.88). The median log (AUC-tacrolimus) was 9.4 in the cases and 9.5 in the controls (p=0.59). CONCLUSIONS In this nested case control study, exposure to tacrolimus was similar in tumor cases and non-tumor controls. These data, based on a cohort with modest size, suggest either that tumorigenesis in LTx recipients is unrelated to tacrolimus exposure or that levels in these patients are above an unknown threshold at which the dose response effect is saturated. PMID- 29133777 TI - Acute Lymphoblastic Leukemia Patient with Variant ATF7IP/PDGFRB Fusion and Favorable Response to Tyrosine Kinase Inhibitor Treatment: A Case Report. AB - BACKGROUND Chromosomal translocations involving the PDGFRB gene have been reported in a broad spectrum of hematological malignancies. An ATF7IP/PDGFRB fusion was recently identified in a Philadelphia chromosome-like (Ph-like) B progenitor acute lymphoblastic leukemia (B-ALL) patient. Here we report on a special case of a Ph-like ALL patient who had a variant ATF7IP/PDGFRB fusion. CASE REPORT In this case, a variant fusion was created between ATF7IP exon 9 (instead of exon 13) and PDGFRB exon 11, resulting in the loss of 411 nucleotides and 137 amino acids in the ATF7IP/PDGFRB fusion cDNA and its encoded chimeric protein, respectively. Interestingly, ATF7IP has also been reported as a fusion partner of the JAK2 kinase gene in Ph-like ALL, but all of the genomic breakpoints in ATF7IP in this fusion reported thus far occurred in intron 13. Enforced expression of the variant ATF7IP/PDGFRB fusion induced cytokine independent growth and glucocorticoid resistance of BaF3 cells. Similar to the initially described ATF7IP/PDGFRB-bearing Ph-like ALL patient who was refractory to conventional chemotherapy but highly sensitive to tyrosine kinase inhibitor (TKI) monotherapy, our patient with a variant ATF7IP/PDGFRB fusion had a poor initial treatment response to chemotherapy but responded well to TKI-based therapy and is now doing well in continuous remission. CONCLUSIONS Ph-like ALL patient with an ATF7IP/PDGFRB fusion is rare, but can benefit from TKI therapy. PMID- 29133778 TI - Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Liraglutide Alters Bone Marrow Exosome-Mediated miRNA Signal Pathways in Ovariectomized Rats with Type 2 Diabetes. AB - BACKGROUND Compared with normal postmenopausal women, estrogen deficiency and hyperglycemia in postmenopausal women with type 2 diabetes (T2DM) lead to more severe bone property degradation. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been reported to improve bone condition among people with T2DM but the precise mechanisms remain unclear. Exosomes work as mediators in cell-to-cell communication, delivering functional miRNAs between cells. We aimed to explore the role of exosomes in T2DM-related bone metabolic disorders and the bone protective mechanisms of liraglutide. MATERIAL AND METHODS We made comparative analyses of bone marrow-derived exosomal miRNAs from ovariectomized (OVX) control rats, OVX + T2DM rats, and OVX + T2DM + liraglutide-treated rats. miRNA profiles were generated using high-throughput sequencing. Target gene prediction and pathway analysis were performed to investigate the signal pathway alterations. Three miRNAs were randomly chosen to validate their absolute expression levels by real-time quantitative PCR. RESULTS Bone marrow-derived exosomal miRNAs were different with respect to miRNA numbers, species, and expression levels. miRNA spectra varied under T2DM condition and after liraglutide treatment. By bioinformatics analysis, we found T2DM and liraglutide administration lead to significant changes in exosomal miRNAs which targeted to insulin secretion and insulin-signaling pathway. Wnt signaling pathway alteration was the critical point regarding bone metabolism. CONCLUSIONS Our findings show the selective packaging of functional miRNA cargoes into exosomes due to T2DM and liraglutide treatment. Bone marrow exosome-mediated Wnt signaling pathway alteration may play a part in the bone protective effect of liraglutide. PMID- 29133779 TI - Probing optical anisotropy of nanometer-thin van der waals microcrystals by near field imaging. AB - Most van der Waals crystals present highly anisotropic optical responses due to their strong in-plane covalent bonding and weak out-of-plane interactions. However, the determination of the polarization-dependent dielectric constants of van der Waals crystals remains a nontrivial task, since the size and dimension of the samples are often below or close to the diffraction limit of the probe light. In this work, we apply an optical nano-imaging technique to determine the anisotropic dielectric constants in representative van der Waals crystals. Through the study of both ordinary and extraordinary waveguide modes in real space, we are able to quantitatively determine the full dielectric tensors of nanometer-thin molybdenum disulfide and hexagonal boron nitride microcrystals, the most-promising van der Waals semiconductor and dielectric. Unlike traditional reflection-based methods, our measurements are reliable below the length scale of the free-space wavelength and reveal a universal route for characterizing low dimensional crystals with high anisotropies. PMID- 29133780 TI - O-GlcNAcylation of SIRT1 enhances its deacetylase activity and promotes cytoprotection under stress. AB - SIRT1 is the most evolutionarily conserved mammalian sirtuin, and it plays a vital role in the regulation of metabolism, stress responses, genome stability, and ageing. As a stress sensor, SIRT1 deacetylase activity is significantly increased during stresses, but the molecular mechanisms are not yet fully clear. Here, we show that SIRT1 is dynamically modified with O-GlcNAc at Ser 549 in its carboxy-terminal region, which directly increases its deacetylase activity both in vitro and in vivo. The O-GlcNAcylation of SIRT1 is elevated during genotoxic, oxidative, and metabolic stress stimuli in cellular and mouse models, thereby increasing SIRT1 deacetylase activity and protecting cells from stress-induced apoptosis. Our findings demonstrate a new mechanism for the activation of SIRT1 under stress conditions and suggest a novel potential therapeutic target for preventing age-related diseases and extending healthspan. PMID- 29133781 TI - Highly selective nickel-catalyzed gem-difluoropropargylation of unactivated alkylzinc reagents. AB - In spite of the important applications of difluoroalkylated molecules in medicinal chemistry, to date, the reaction of difluoroalkylating reagents with unactivated, aliphatic substrates through a controllable manner remains challenging and has not been reported. Here we describe an efficient nickel catalyzed cross-coupling of unactivated alkylzinc reagen?ts with gem difluoropropargyl bromides. The reaction proceeds under mild reaction conditions with high efficiency and excellent regiochemical selectivity. Transformations of the resulting difluoroalkylated alkanes lead to a variety of biologically active molecules, providing a facile route for applications in drug discovery and development. Preliminary mechanistic studies reveal that an alkyl nickel intermediate [Ni(tpy)alkyl] (tpy, terpyridine) is involved in the catalytic cycle. PMID- 29133782 TI - mTOR intersects antibody-inducing signals from TACI in marginal zone B cells. AB - Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-kappaB. Disruption of TACI-mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-kappaB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs. PMID- 29133783 TI - NOG1 increases grain production in rice. AB - During rice domestication and improvement, increasing grain yield to meet human needs was the primary objective. Rice grain yield is a quantitative trait determined by multiple genes, but the molecular basis for increased grain yield is still unclear. Here, we show that NUMBER OF GRAINS 1 (NOG1), which encodes an enoyl-CoA hydratase/isomerase, increases the grain yield of rice by enhancing grain number per panicle without a negative effect on the number of panicles per plant or grain weight. NOG1 can significantly increase the grain yield of commercial high-yield varieties: introduction of NOG1 increases the grain yield by 25.8% in the NOG1-deficient rice cultivar Zhonghua 17, and overexpression of NOG1 can further increase the grain yield by 19.5% in the NOG1-containing variety Teqing. Interestingly, NOG1 plays a prominent role in increasing grain number, but does not change heading date or seed-setting rate. Our findings suggest that NOG1 could be used to increase rice production. PMID- 29133784 TI - GyrI-like proteins catalyze cyclopropanoid hydrolysis to confer cellular protection. AB - GyrI-like proteins are widely distributed in prokaryotes and eukaryotes, and recognized as small-molecule binding proteins. Here, we identify a subfamily of these proteins as cyclopropanoid cyclopropyl hydrolases (CCHs) that can catalyze the hydrolysis of the potent DNA-alkylating agents yatakemycin (YTM) and CC-1065. Co-crystallography and molecular dynamics simulation analyses reveal that these CCHs share a conserved aromatic cage for the hydrolytic activity. Subsequent cytotoxic assays confirm that CCHs are able to protect cells against YTM. Therefore, our findings suggest that the evolutionarily conserved GyrI-like proteins confer cellular protection against diverse xenobiotics via not only binding, but also catalysis. PMID- 29133785 TI - Significance estimation for large scale metabolomics annotations by spectral matching. AB - The annotation of small molecules in untargeted mass spectrometry relies on the matching of fragment spectra to reference library spectra. While various spectrum spectrum match scores exist, the field lacks statistical methods for estimating the false discovery rates (FDR) of these annotations. We present empirical Bayes and target-decoy based methods to estimate the false discovery rate (FDR) for 70 public metabolomics data sets. We show that the spectral matching settings need to be adjusted for each project. By adjusting the scoring parameters and thresholds, the number of annotations rose, on average, by +139% (ranging from 92 up to +5705%) when compared with a default parameter set available at GNPS. The FDR estimation methods presented will enable a user to assess the scoring criteria for large scale analysis of mass spectrometry based metabolomics data that has been essential in the advancement of proteomics, transcriptomics, and genomics science. PMID- 29133786 TI - Heterogeneity in the Drosophila gustatory receptor complexes that detect aversive compounds. AB - Animals must detect aversive compounds to survive. Bitter taste neurons express heterogeneous combinations of bitter receptors that diversify their response profiles, but this remains poorly understood. Here we describe groups of taste neurons in Drosophila that detect the same bitter compounds using unique combinations of gustatory receptors (GRs). These distinct complexes also confer responsiveness to non-overlapping sets of additional compounds. While either GR32a/GR59c/GR66a or GR22e/GR32a/GR66a heteromultimers are sufficient for lobeline, berberine, and denatonium detection, only GR22e/GR32a/GR66a responds to strychnine. Thus, despite minimal sequence-similarity, Gr22e and Gr59c show considerable but incomplete functional overlap. Since the gain- or loss-of function of Gr22e or Gr59c alters bitter taste response profiles, we conclude a taste neuron's specific combination of Grs determines its response profile. We suspect the heterogeneity of Gr expression in Drosophila taste neurons diversifies bitter compound detection, improving animal fitness under changing environmental conditions that present a variety of aversive compounds. PMID- 29133787 TI - Virtual photons in the ground state of a dissipative system. AB - Much of the novel physics predicted to be observable in the ultrastrong light matter coupling regime rests on the hybridisation between states with different numbers of excitations, leading to a population of virtual photons in the system's ground state. In this article, exploiting an exact diagonalisation approach, we derive both analytical and numerical results for the population of virtual photons in presence of arbitrary losses. Specialising our results to the case of Lorentzian resonances we then show that the virtual photon population is only quantitatively affected by losses, even when those become the dominant energy scale. Our results demonstrate most of the ultrastrong-coupling phenomenology can be observed in loss-dominated systems which are not even in the standard strong coupling regime. We thus open the possibility to investigate ultrastrong-coupling physics to platforms that were previously considered unsuitable due to their large losses. PMID- 29133789 TI - Effect of Time-Delayed Feedback on the Interaction of a Dimer System with its Environment. AB - In this work, we report modeling of non-Markovian open quantum systems, consisting of an excitonic dimer that displays memory effect due to time delayed interaction with its environment. We, indeed investigate the effect of these time delays on quantum coherence and excitation dynamical behavior in the time domain generally considered for photosynthetic experiments (few hundred femtoseconds). In particular, we show that the coherence is maintained for periods proportional to time delays. Additionally, if delay is taken into account, coupling to the environment can be tuned to lower values, unlike in previous studies. This kind of intriguing effect can, therefore, when generalized to complete systems, permit more control on the experimental parameters, which may lead to more accurate description of the photosynthetic energy transfer functioning and subsequent applications in artificial photovoltaic research. PMID- 29133788 TI - Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells. AB - Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases. Moreover, CRISPR-Cas9-mediated deletion of candidate enhancers/SEs, targeting SEs with the bromodomain and extra-terminal domain inhibitor JQ1, or knockdown of overlapping long noncoding RNAs (lncRNAs) blocks AngII-induced genes associated with growth-factor signaling and atherosclerosis. Furthermore, JQ1 ameliorates AngII-induced hypertension, medial hypertrophy and inflammation in vivo in mice. These results demonstrate AngII-induced signals integrate enhancers/SEs and lncRNAs to increase expression of genes involved in VSMC dysfunction, and could uncover novel therapies. PMID- 29133790 TI - Climate change accelerates growth of urban trees in metropolises worldwide. AB - Despite the importance of urban trees, their growth reaction to climate change and to the urban heat island effect has not yet been investigated with an international scope. While we are well informed about forest growth under recent conditions, it is unclear if this knowledge can be simply transferred to urban environments. Based on tree ring analyses in ten metropolises worldwide, we show that, in general, urban trees have undergone accelerated growth since the 1960s. In addition, urban trees tend to grow more quickly than their counterparts in the rural surroundings. However, our analysis shows that climate change seems to enhance the growth of rural trees more than that of urban trees. The benefits of growing in an urban environment seem to outweigh known negative effects, however, accelerated growth may also mean more rapid ageing and shortened lifetime. Thus, city planners should adapt to the changed dynamics in order to secure the ecosystem services provided by urban trees. PMID- 29133792 TI - Controlled synthesis of conjugated polycarbazole polymers via structure tuning for gas storage and separation applications. AB - A series of conjugated microporous polymers (CMPs) based on 1,3,6,8 tetrabromocarbazole (N4CMP-1-5) is synthesized via Suzuki cross-coupling or Sonogashira polycondensation. The porosity properties and surface area of these polymer networks can be finely tuned by using a linker with different geometries or strut length. These polymers show the Brunauer-Emmett-Tellerthe (BET) surface areas ranging from 592 to 1426 m2 g-1. The dominant pore sizes of the polymers on the basis of the different linker are located between 0.36 and 0.61 nm. Gas uptake increases with BET surface area and micropore volume, N4CMP-3 polymer can capture CO2 with a capacity of 3.62 mmol g-1 (1.05 bar and 273 K) among the obtained polymers. All of the polymers show high isosteric heats of CO2 adsorption (25.5-35.1 kJ mol-1), and from single component adsorption isotherms, IAST-derived ideal CO2/N2 (28.7-53.8), CO2/CH4 (4.6-5.2) and CH4/N2 (5.7-10.5) selectivity. Furthermore, N4CMPs exhibit the high CO2 adsorption capacity of 542 800 mg g-1 at 318 K and 50 bar pressure. These data indicate that these materials are a promising potential for clean energy application and environmental field. PMID- 29133791 TI - Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection. AB - Although Danhong injection (DHI) is the most widely prescribed Chinese medicine for both stroke and coronary artery disease (CAD), its underlying common molecular mechanisms remain unclear. An integrated network pharmacology and experimental verification approach was used to decipher common pharmacological mechanisms of DHI on stroke and CAD treatment. A compound-target-disease & function-pathway network was constructed and analyzed, indicating that 37 ingredients derived from DH (Salvia miltiorrhiza Bge., Flos Carthami tinctorii and DHI) modulated 68 common targets shared by stroke and CAD. In-depth network analysis results of the top diseases, functions, pathways and upstream regulators implied that a common underlying mechanism linking DHI's role in stroke and CAD treatment was inflammatory response in the process of atherosclerosis. Experimentally, DHI exerted comprehensive anti-inflammatory effects on LPS, ox LDL or cholesterol crystal-induced NF-kappaB, c-jun and p38 activation, as well as IL-1beta, TNF-alpha, and IL-10 secretion in vascular endothelial cells. Ten of 14 predicted ingredients were verified to have significant anti-inflammatory activities on LPS-induced endothelial inflammation. DHI exerts pharmacological efficacies on both stroke and CAD through multi-ingredient, multi-target, multi function and multi-pathway mode. Anti-endothelial inflammation therapy serves as a common underlying mechanism. This study provides a new understanding of DHI in clinical application on cardiovascular and cerebrovascular diseases. PMID- 29133795 TI - Iced photochemical reduction to synthesize atomically dispersed metals by suppressing nanocrystal growth. AB - Photochemical solution-phase reactions have been widely applied for the syntheses of nanocrystals. In particular, tuning of the nucleation and growth of solids has been a major area of focus. Here we demonstrate a facile approach to generate atomically dispersed platinum via photochemical reduction of frozen chloroplatinic acid solution using ultraviolet light. Using this iced photochemical reduction, the aggregation of atoms is prevented, and single atoms are successfully stabilized. The platinum atoms are deposited on various substrates, including mesoporous carbon, graphene, carbon nanotubes, titanium dioxide nanoparticles, and zinc oxide nanowires. The atomically dispersed platinum on mesoporous carbon exhibits efficient catalytic activity for the electrochemical hydrogen evolution reaction, with an overpotential of only 65 mV at a current density of 100 mA cm-2 and long-time durability (>10 h), superior to state-of-the-art platinum/carbon. This iced-photochemical reduction may be extended to other single atoms, for example gold and silver, as demonstrated in this study. PMID- 29133794 TI - Unique phenotypes and clonal expansions of human CD4 effector memory T cells re expressing CD45RA. AB - The expression of CD45RA is generally associated with naive T cells. However, a subset of effector memory T cells re-expresses CD45RA (termed TEMRA) after antigenic stimulation with unknown molecular characteristics and functions. CD4 TEMRA cells have been implicated in protective immunity against pathogens such as dengue virus (DENV). Here we show that not only the frequency but also the phenotype of CD4 TEMRA cells are heterogeneous between individuals. These cells can be subdivided into two major subsets based on the expression of the adhesion G protein-coupled receptor GPR56, and GPR56+ TEMRA cells display a transcriptional and proteomic program with cytotoxic features that is distinct from effector memory T cells. Moreover, GPR56+ TEMRA cells have higher levels of clonal expansion and contain the majority of virus-specific TEMRA cells. Overall, this study reveals the heterogeneity of CD4 TEMRA cells and provides insights into T-cell responses against DENV and other viral pathogens. PMID- 29133793 TI - Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. AB - Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures. PMID- 29133796 TI - Pd supported on carbon containing nickel, nitrogen and sulfur for ethanol electrooxidation. AB - Carbon material containing nickel, nitrogen and sulfur (Ni-NSC) has been synthesized using metal-organic frameworks (MOFs) as precursor by annealing treatment with a size from 200 to 300 nm. Pd nanoparticles supported on the Ni NSC (Pd/Ni-NSC) are used as electrocatalysts for ethanol oxidation in alkaline media. Due to the synergistic effect between Pd and Ni, S, N, free OH radicals can form on the surface of Ni, N and S atoms at lower potentials, which react with CH3CO intermediate species on the Pd surface to produce CH3COO- and release the active sites. On the other hand, the stronger binding force between Pd and co doped N and S is responsible for enhancing dispersion and preventing agglomeration of the Pd nanoparticles. The Pd(20 wt%)/Ni-NSC shows better electrochemical performance of ethanol oxidation than the traditional commercial Pd(20 wt%)/C catalyst. Onset potential on the Pd(20 wt%)/Ni-NSC electrode is 36 mV more negative compared with that on the commercial Pd(20 wt%)/C electrode. The Pd(20 wt%)/Ni-NSC in this paper demonstrates to have excellent electrocatalytic properties and is considered as a promising catalyst in alkaline direct ethanol fuel cells. PMID- 29133797 TI - The deep conservation of the Lepidoptera Z chromosome suggests a non-canonical origin of the W. AB - Moths and butterflies (Lepidoptera) usually have a pair of differentiated WZ sex chromosomes. However, in most lineages outside of the division Ditrysia, as well as in the sister order Trichoptera, females lack a W chromosome. The W is therefore thought to have been acquired secondarily. Here we compare the genomes of three Lepidoptera species (one Dytrisia and two non-Dytrisia) to test three models accounting for the origin of the W: (1) a Z-autosome fusion; (2) a sex chromosome turnover; and (3) a non-canonical mechanism (e.g., through the recruitment of a B chromosome). We show that the gene content of the Z is highly conserved across Lepidoptera (rejecting a sex chromosome turnover) and that very few genes moved onto the Z in the common ancestor of the Ditrysia (arguing against a Z-autosome fusion). Our comparative genomics analysis therefore supports the secondary acquisition of the Lepidoptera W by a non-canonical mechanism, and it confirms the extreme stability of well-differentiated sex chromosomes. PMID- 29133798 TI - Motivational interviewing and urine cotinine feedback to stop passive smoke exposure in children predisposed to asthma: a randomised controlled trial. AB - We tested the effectiveness of a program consisting of motivational interviewing (MI) and feedback of urine cotinine to stop passive smoking (PS) in children at risk for asthma. Fifty-eight families with children 0-13 years with a high risk of asthma and PS exposure were randomised in a one-year follow-up study. The intervention group received the intervention program during 6 sessions (1/month) and the control group received measurements (questionnaires, urine cotinine, and lung function) only. The primary outcome measure was the percentage of families stopping PS (parental report verified and unverified with the child's urine cotinine concentration <10 MUg/l) in children during the intervention program. The analyses were performed with Mixed Logistic Regression. After 6 months, a significant group difference was observed for the unverified parental report of stopping PS in children: 27% of parents in the intervention group versus 7% in the control group. For the verified parental report, the difference was similar (23% versus 7%) but was not statistically significant. Despite a limited sample size, the results suggest that the intervention program is probably an effective strategy to stop PS in children. A program longer than 6 months might be necessary for a longer lasting intervention effect. PMID- 29133800 TI - Interfaces between hexagonal and cubic oxides and their structure alternatives. AB - Multi-layer structure of functional materials often involves the integration of different crystalline phases. The film growth orientation thus frequently exhibits a transformation, owing to multiple possibilities caused by incompatible in-plane structural symmetry. Nevertheless, the detailed mechanism of the transformation has not yet been fully explored. Here we thoroughly probe the heteroepitaxially grown hexagonal zinc oxide (ZnO) films on cubic (001)-magnesium oxide (MgO) substrates using advanced scanning transition electron microscopy, X ray diffraction and first principles calculations, revealing two distinct interface models of (001) ZnO/(001) MgO and (100) ZnO/(001) MgO. We have found that the structure alternatives are controlled thermodynamically by the nucleation, while kinetically by the enhanced Zn adsorption and O diffusion upon the phase transformation. This work not only provides a guideline for the interface fabrication with distinct crystalline phases but also shows how polar and non-polar hexagonal ZnO films might be manipulated on the same cubic substrate. PMID- 29133799 TI - Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors. AB - Aberrant promoter DNA hypermethylation is a hallmark of cancer; however, whether this is sufficient to drive cellular transformation is not clear. To investigate this question, we use a CRISPR-dCas9 epigenetic editing tool, where an inactive form of Cas9 is fused to DNA methyltransferase effectors. Using this system, here we show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2A, RASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest. Our data show that the key driver of this phenotype is repression of CDKN2A transcript p16 where myoepithelial cells harbour cancer-like gene expression but do not exhibit anchorage-independent growth. This work demonstrates that hit-and-run epigenetic events can prevent senescence entry, which may facilitate tumour initiation. PMID- 29133801 TI - Chromosome segregation occurs by microtubule pushing in oocytes. AB - During cell division, spindle microtubules ensure an equal repartition of chromosomes between the two daughter cells. While the kinetochore-dependent mechanisms that drive mitotic chromosome segregation are well understood, in oocytes of most species atypical spindles assembled in absence of centrosomes entail poorly understood mechanisms of chromosome segregation. In particular, the structure(s) responsible for force generation during meiotic chromosome separation in oocytes is unclear. Using quantitative light microscopy, electron tomography, laser-mediated ablation, and genetic perturbations in the Caenorhabditis elegans oocyte, we studied the mechanism of chromosome segregation in meiosis. We find spindle poles are largely dispensable, and in fact act as brakes for chromosome segregation. Instead, our results suggest that CLS-2 dependent microtubules of the meiotic central spindle, located between the segregating chromosomes and aligned along the axis of segregation, are essential. Our results support a model in which inter-chromosomal microtubules of the central spindle push chromosomes apart during meiotic anaphase in oocytes. PMID- 29133802 TI - A conformational switch in initiation factor 2 controls the fidelity of translation initiation in bacteria. AB - Initiation factor (IF) 2 controls the fidelity of translation initiation by selectively increasing the rate of 50S ribosomal subunit joining to 30S initiation complexes (ICs) that carry an N-formyl-methionyl-tRNA (fMet-tRNAfMet). Previous studies suggest that rapid 50S subunit joining involves a GTP- and fMet tRNAfMet-dependent "activation" of IF2, but a lack of data on the structure and conformational dynamics of 30S IC-bound IF2 has precluded a mechanistic understanding of this process. Here, using an IF2-tRNA single-molecule fluorescence resonance energy transfer signal, we directly observe the conformational switch that is associated with IF2 activation within 30S ICs that lack IF3. Based on these results, we propose a model of IF2 activation that reveals how GTP, fMet-tRNAfMet, and specific structural elements of IF2 drive and regulate this conformational switch. Notably, we find that domain III of IF2 plays a pivotal, allosteric, role in IF2 activation, suggesting that this domain can be targeted for the development of novel antibiotics. PMID- 29133803 TI - Microbial Diversity of Genital Ulcers of HSV-2 Seropositive Women. AB - We measured the microbial community structure of genital ulcers in women. Swabs from clinically detected ulcers were tested for HSV-2 and Treponema pallidum by polymerase chain reaction (PCR). HSV-2 and T. pallidum were detected by serum antibody testing. Microbial community structure was characterized by high throughput 16 s rRNA gene amplicon sequencing. Multiple group testing and Elastic net and Lasso regressions identified taxa associated with differences in factors of interest. Among 49 ulcer specimens from 49 HSV-2 seropositive women, by PCR HSV-2 was recovered from 28 (57%) specimens and T. pallidum from none; one woman showed serologic evidence of syphilis. Overall, 63% of women were HIV-positive and 49% had an uncircumcised male sex partner. By both multiple group testing and regression, Porphyromonas (FDR p-value = 0.02), Prevotella (FDR p-value = 0.03), Anaerococcus (FDR p-value = 0.07), and Dialister (FDR p-value = 0.09) were detected at higher relative abundance in HSV-2 PCR-positive than negative ulcers. The presence of HSV-2 in a lesion was associated with presumed bacterial agents of Bacterial vaginosis. Differences in bacterial communities may contribute to HSV-2 ulcer pathogenesis, severity, or prolonged healing. If these results are confirmed, future studies may consider the influence of BV treatment on women's GUD and HSV-2 incidence and recurrence. PMID- 29133804 TI - Antennal transcriptome analysis and expression profiles of olfactory genes in Anoplophora chinensis. AB - Olfaction in insects is essential for host identification, mating and oviposition, in which olfactory proteins are responsible for chemical signaling. Here, we determined the transcriptomes of male and female adult antennae of Anoplophora chinensis, the citrus longhorned beetle. Among 59,357 unigenes in the antennal assembly, we identified 46 odorant-binding proteins, 16 chemosensory proteins (CSPs), 44 odorant receptors, 19 gustatory receptors, 23 ionotropic receptors, and 3 sensory neuron membrane proteins. Among CSPs, AchiCSP10 was predominantly expressed in antennae (compared with legs or maxillary palps), at a significantly higher level in males than in females, suggesting that AchiCSP10 has a role in reception of female sex pheromones. Many highly expressed genes encoding CSPs are orthologue genes of A. chinensis and Anoplophora glabripennis. Notably, AchiPBP1 and AchiPBP2 showed 100% and 96% identity with AglaPBP1 and AglaPBP2 from A. glabripennis, with similar expression profiles in the two species; PBP2 was highly expressed in male antennae, whereas PBP1 was expressed in all three tissues in both males and females. These results provide a basis for further studies on the molecular chemoreception mechanisms of A. chinensis, and suggest novel targets for control of A. chinensis. PMID- 29133805 TI - Xanthine oxidoreductase activity is associated with serum uric acid and glycemic control in hemodialysis patients. AB - Xanthine oxidoreductase activity (XOR-a) plays an important role as a pivotal source of reactive oxygen species. In the present study, we investigated factors associated with plasma XOR-a in 163 hemodialysis patients (age 67.3 +/- 10.9 years; 89 males and 74 females), using a newly established, highly-sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Plasma glucose and serum uric acid levels correlated significantly and positively with plasma XOR-a. In multiple regression analyses, the presence of type 2 diabetes mellitus (T2DM) and plasma glucose were associated significantly, independently, and positively with plasma XOR-a. While serum uric acid correlated significantly and positively with plasma XOR-a in hemodialysis patients without T2DM, plasma glucose and serum glycated albumin, a new marker of glycemic control in diabetic hemodialysis patients, correlated significantly and positively with plasma XOR-a in those with T2DM. Multivariate analyses in those with T2DM revealed that plasma glucose and serum glycated albumin were associated significantly and independently with plasma XOR-a, and that serum uric acid was associated significantly and independently with XOR-a in those without T2DM. Our results suggested that glycemic control in hemodialysis patients may be important in regard to a decrease in ROS induced by XOR. PMID- 29133806 TI - Effect of Si on the Energy Band Gap Modulation and Performance of Silicon Indium Zinc Oxide Thin-Film Transistors. AB - The band gap properties of amorphous SiInZnO (a-SIZO) thin-film transistors (TFTs) with different Si concentrations have been studied. The electronic structures of the films, engineered by controlling the Si content, have been investigated through the changes of the band gap and band edge states. Carrier generation at oxygen vacancies can modify the band gap states of oxide thin films. Si suppresses the number of oxygen vacancies-which are carrier generation sites-so shifts the Fermi energy level away from the conduction band. It is difficult to derive the electronic structures of amorphous oxide semiconductors by electrical measurements. Thus, we used a combination of ultraviolet photoelectron spectroscopy, Kelvin probe measurements, and electron energy loss spectroscopy to measure the band gap and electrical performance variations of SIZO TFTs with Si doping. To verify the versatility of Si doping in modulating electronic properties, high-performance depletion-mode inverter circuits consisting of 0.1 to 0.3 wt% Si-doped a-SIZO TFTs were fabricated. These inverter models operate through the threshold voltage difference that arises from the different Si contents. High voltage gains of ~20.62 at a supply voltage of 15 V were obtained with the two TFTs, with a strong dependence on the subthreshold swing. PMID- 29133807 TI - Apelin conformational and binding equilibria upon micelle interaction primarily depend on membrane-mimetic headgroup. AB - Apelin is one of two peptide hormones that activate the apelin receptor (AR or APJ) to regulate the cardiovascular system, central nervous system, and adipoinsular axis. Here, we apply circular dichroism (CD) spectropolarimetry and nuclear magnetic resonance (NMR) spectroscopy to characterize the potential membrane binding by the two longest bioactive apelin isoforms, apelin-55 and -36, using membrane-mimetic dodecylphosphocholine (DPC), sodium dodecyl sulfate (SDS), and 1-palmitoyl-2-hydroxy-sn-glycero-3-[phospho-rac-(1-glycerol)] (LPPG) micelles. Pulsed field gradient diffusion NMR experiments demonstrated preferential interaction of both apelin-55 and -36 with anionic SDS and LPPG micelles over zwitterionic DPC micelles. Chemical shift perturbations and changes in ps-ns scale dynamics of apelin-55 in all micelles were similarly localized along the polypeptide backbone, demonstrating clear dependence upon detergent headgroup, while comparison of chemical shifts between apelin-55 and apelin-36 showed negligible differences indicative of highly similar modes of micelle interaction. Notably, the observed behaviour was consistent with an ensemble averaged pair of free and bound states in fast exchange on the NMR timescale proportional to the fraction of micelle-bound protein, implying a similar conformational equilibrium regardless of headgroup and tailgroup. Membrane catalysis of apelin-AR binding would thus give rise to analogous behaviour in the essential C-terminal region common to all apelin isoforms. PMID- 29133808 TI - Influence of polymerisation on the reversibility of low-energy proton exchange reactions by Para-Aminothiolphenol. AB - The reversibility of redox processes is an important function for sensing and molecular electronic devices such as pH reporters or molecular switches. Here we report the electrochemical behaviour and redox reversibility of para aminothiolphenol (PATP) after different polymerisation methods. We used electrochemical and photo-polymerisation in neutral buffers and plasma polymerisation in air to induce reversible redox states. The chemical stoichiometry and surface coverage of PATP in the polymerized layers were characterized by X-ray photoelectron spectroscopy (XPS), while cyclic voltammetry (CV) was used to measure the charge transfer, double layer capacitance and electrochemical rate of the layers during successive potential cycles. Our results show that the surface coverage of the redox active species is higher on electro-polymerised samples, however, after consecutive cycles all the methods converge to the same charge transfer, while the plasma polymerised samples achieve higher efficiency per molecule and UV polymerised samples have a higher electron transfer rate. PMID- 29133809 TI - Stromatolites on the rise in peat-bound karstic wetlands. AB - Stromatolites are the oldest evidence for life on Earth, but modern living examples are rare and predominantly occur in shallow marine or (hyper-) saline lacustrine environments, subject to exotic physico-chemical conditions. Here we report the discovery of living freshwater stromatolites in cool-temperate karstic wetlands in the Giblin River catchment of the UNESCO-listed Tasmanian Wilderness World Heritage Area, Australia. These stromatolites colonize the slopes of karstic spring mounds which create mildly alkaline (pH of 7.0-7.9) enclaves within an otherwise uniformly acidic organosol terrain. The freshwater emerging from the springs is Ca-HCO3 dominated and water temperatures show no evidence of geothermal heating. Using 16 S rRNA gene clone library analysis we revealed that the bacterial community is dominated by Cyanobacteria, Alphaproteobacteria and an unusually high proportion of Chloroflexi, followed by Armatimonadetes and Planctomycetes, and is therefore unique compared to other living examples. Macroinvertebrates are sparse and snails in particular are disadvantaged by the development of debilitating accumulations of carbonate on their shells, corroborating evidence that stromatolites flourish under conditions where predation by metazoans is suppressed. Our findings constitute a novel habitat for stromatolites because cool-temperate freshwater wetlands are not a conventional stromatolite niche, suggesting that stromatolites may be more common than previously thought. PMID- 29133810 TI - Selectivity and ligand-based molecular modeling of an odorant-binding protein from the leaf beetle Ambrostoma quadriimpressum (Coleoptera: Chrysomelidae) in relation to habitat-related volatiles. AB - In this study, the most abundant and antenna-specific odorant-binding protein (OBP) of the elm pest A. quadriimpressum, AquaOBP4, was expressed and purified. The selectivity of AquaOBP4 was investigated by screening against a panel of 40 habitat-relevant compounds. Based on the obtained results, a homologous model of AquaOBP4 was established. This model indicated that AquaOBP4 is highly homologous to DmelOBP LUSH and includes two main binding sites. A docking analysis showed that four of five active ligands bound at Site 1, whereas the other ligand was situated at Site 2. Furthermore, new ligands were docked in the model, and the results of fluorescence-based binding assays of these compounds were highly consistent with the binding conformation and binding affinity predicted by our model. Additionally, three binding odorants derived from elm leaves elicited a strong electroantennogram response and exerted a significant attractive effect on adult A. quadriimpressum. All of the results showed that AquaOBP4 is likely linked to the foraging behavior of A. quadriimpressum. This study provides a new reliable tool for future large-scale compound screenings and revealed several functional chemicals that might aid the development of a better pest management approach for A. quadriimpressum. PMID- 29133811 TI - Site-specific phosphorylation regulates the structure and function of an intrinsically disordered domain of the glucocorticoid receptor. AB - Intrinsically disordered (ID) regions of the transcription factor proteins have much larger frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. Consistent with this phenomenon, most of the functionally known phosphorylation sites in the steroid receptor family of transcription factors are located in the ID N-terminal domain that contains a powerful activation function (AF1) region. In this study, we determined the structural and functional consequences of functionally known phosphorylation residues (Ser203, 211, and 226) located in the human glucocorticoid receptor's (GR's) ID AF1 domain. We report the relative importance of each phosphorylation site in inducing a functionally active ordered conformation in GR's ID AF1 domain. Our data demonstrate a mechanism through which ID domain of the steroid receptors and other similar transcription factors may adopt a functionally active conformation under physiological conditions. PMID- 29133812 TI - Surge-type and surge-modified glaciers in the Karakoram. AB - Glaciers in the Karakoram exhibit irregular behavior. Terminus fluctuations of individual glaciers lack consistency and, unlike other parts of the Himalaya, total ice mass remained stable or slightly increased since the 1970s. These seeming anomalies are addressed through a comprehensive mapping of surge-type glaciers and surge-related impacts, based on satellite images (Landsat and ASTER), ground observations, and archival material since the 1840s. Some 221 surge-type and surge-like glaciers are identified in six main classes. Their basins cover 7,734 +/- 271 km2 or ~43% of the total Karakoram glacierised area. Active phases range from some months to over 15 years. Surge intervals are identified for 27 glaciers with two or more surges, including 9 not previously reported. Mini-surges and kinematic waves are documented and surface diagnostic features indicative of surging. Surge cycle timing, intervals and mass transfers are unique to each glacier and largely out-of-phase with climate. A broad class of surge-modified ice introduces indirect and post-surge effects that further complicate tracking of climate responses. Mass balance in surge-type and surge modified glaciers differs from conventional, climate-sensitive profiles. New approaches are required to account for such differing responses of individual glaciers, and effectively project the fate of Karakoram ice during a warming climate. PMID- 29133813 TI - RCS Diversity of Electromagnetic Wave Carrying Orbital Angular Momentum. AB - An electromagnetic (EM) wave with orbital angular momentum (OAM) has a helical wave front, which is different from that of the plane wave. The phase gradient can be found perpendicular to the direction of propagation and proportional to the number of OAM modes. Herein, we study the backscattering property of the EM wave with different OAM modes, i.e., the radar cross section (RCS) of the target is measured and evaluated with different OAM waves. As indicated by the experimental results, different OAM waves have the same RCS fluctuation for the simple target, e.g., a small metal ball as the target. However, for complicated targets, e.g., two transverse-deployed small metal balls, different RCSs can be identified from the same incident angle. This valuable fact helps to obtain RCS diversity, e.g., equal gain or selective combining of different OAM wave scattering. The majority of the targets are complicated targets or expanded targets; the RCS diversity can be utilized to detect a weak target traditionally measured by the plane wave, which is very helpful for anti-stealth radar to detect the traditional stealth target by increasing the RCS with OAM waves. PMID- 29133814 TI - Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species. AB - Antimicrobial peptides as part of the mammalian innate immune system target and remove major bacterial pathogens, often through irreversible damage of their cellular membranes. To explore the mechanism by which the important cathelicidin peptide LL-37 of the human innate immune system interacts with membranes, we performed biochemical, biophysical and structural studies. The crystal structure of LL-37 displays dimers of anti-parallel helices and the formation of amphipathic surfaces. Peptide-detergent interactions introduce remodeling of this structure after occupation of defined hydrophobic sites at the dimer interface. Furthermore, hydrophobic nests are shaped between dimer structures providing another scaffold enclosing detergents. Both scaffolds underline the potential of LL-37 to form defined peptide-lipid complexes in vivo. After adopting the activated peptide conformation LL-37 can polymerize and selectively extract bacterial lipids whereby the membrane is destabilized. The supramolecular fibril like architectures formed in crystals can be reproduced in a peptide-lipid system after nanogold-labelled LL-37 interacted with lipid vesicles as followed by electron microscopy. We suggest that these supramolecular structures represent the LL-37-membrane active state. Collectively, our study provides new insights into the fascinating plasticity of LL-37 demonstrated at atomic resolution and opens the venue for LL-37-based molecules as novel antibiotics. PMID- 29133815 TI - LC-MS guided isolation of three pairs of enantiomeric alkaloids from Macleaya cordata and their enantioseparations, antiproliferative activity, apoptosis inducing property. AB - (+/-)-Macleayins F-H (1-3), three pairs of new enantiomeric alkaloid dimers, along with four known alkaloids (4-7) as their plausible biogenetic precursors, were isolated from the aerial parts of Macleaya cordata. Compounds 1-3 were obtained under the guidance of LC-MS investigation, and their structures were elucidated by analysis of the 1D and 2D NMR spectroscopic data. The racemic mixtures were successfully separated by chiral HPLC, and the absolute configurations of enantiomers were determined by electronic circular dichroism (ECD) spectroscopy. Compounds 1-7 showed antiproliferative activity against HL-60 with IC50 values of 1.34-41.30 MUM, especially compounds 1-2 exhibited the best inhibitory activity against HL-60 cell lines. In addition, the preliminary mechanism investigation for compound 2 using Annexin V/7-AAD double-staining assay, DAPI staining assay and JC-1 staining method, indicated that 2 inhibited cancer cell proliferation potentially through inducing apoptosis via the mitochondria-related pathway and arrested cell cycle of HL-60 cells at S phase. PMID- 29133816 TI - Disruption of diphthamide synthesis genes and resulting toxin resistance as a robust technology for quantifying and optimizing CRISPR/Cas9-mediated gene editing. AB - We have devised an effective and robust method for the characterization of gene editing events. The efficacy of editing-mediated mono- and bi-allelic gene inactivation and integration events is quantified based on colony counts. The combination of diphtheria toxin (DT) and puromycin (PM) selection enables analyses of 10,000-100,000 individual cells, assessing hundreds of clones with inactivated genes per experiment. Mono- and bi-allelic gene inactivation is differentiated by DT resistance, which occurs only upon bi-allelic inactivation. PM resistance indicates integration. The robustness and generalizability of the method were demonstrated by quantifying the frequency of gene inactivation and cassette integration under different editing approaches: CRISPR/Cas9-mediated complete inactivation was ~30-50-fold more frequent than cassette integration. Mono-allelic inactivation without integration occurred >100-fold more frequently than integration. Assessment of gRNA length confirmed 20mers to be most effective length for inactivation, while 16-18mers provided the highest overall integration efficacy. The overall efficacy was ~2-fold higher for CRISPR/Cas9 than for zinc finger nuclease and was significantly increased upon modulation of non-homologous end joining or homology-directed repair. The frequencies and ratios of editing events were similar for two different DPH genes (independent of the target sequence or chromosomal location), which indicates that the optimization parameters identified with this method can be generalized. PMID- 29133817 TI - Transgenic Cavendish bananas with resistance to Fusarium wilt tropical race 4. AB - Banana (Musa spp.) is a staple food for more than 400 million people. Over 40% of world production and virtually all the export trade is based on Cavendish banana. However, Cavendish banana is under threat from a virulent fungus, Fusarium oxysporum f. sp. cubense tropical race 4 (TR4) for which no acceptable resistant replacement has been identified. Here we report the identification of transgenic Cavendish with resistance to TR4. In our 3-year field trial, two lines of transgenic Cavendish, one transformed with RGA2, a gene isolated from a TR4 resistant diploid banana, and the other with a nematode-derived gene, Ced9, remain disease free. Transgene expression in the RGA2 lines is strongly correlated with resistance. Endogenous RGA2 homologs are also present in Cavendish but are expressed tenfold lower than that in our most resistant transgenic line. The expression of these homologs can potentially be elevated through gene editing, to provide non-transgenic resistance. PMID- 29133818 TI - Searching for prostate cancer by fully automated magnetic resonance imaging classification: deep learning versus non-deep learning. AB - Prostate cancer (PCa) is a major cause of death since ancient time documented in Egyptian Ptolemaic mummy imaging. PCa detection is critical to personalized medicine and varies considerably under an MRI scan. 172 patients with 2,602 morphologic images (axial 2D T2-weighted imaging) of the prostate were obtained. A deep learning with deep convolutional neural network (DCNN) and a non-deep learning with SIFT image feature and bag-of-word (BoW), a representative method for image recognition and analysis, were used to distinguish pathologically confirmed PCa patients from prostate benign conditions (BCs) patients with prostatitis or prostate benign hyperplasia (BPH). In fully automated detection of PCa patients, deep learning had a statistically higher area under the receiver operating characteristics curve (AUC) than non-deep learning (P = 0.0007 < 0.001). The AUCs were 0.84 (95% CI 0.78-0.89) for deep learning method and 0.70 (95% CI 0.63-0.77) for non-deep learning method, respectively. Our results suggest that deep learning with DCNN is superior to non-deep learning with SIFT image feature and BoW model for fully automated PCa patients differentiation from prostate BCs patients. Our deep learning method is extensible to image modalities such as MR imaging, CT and PET of other organs. PMID- 29133819 TI - Low perceptual sensitivity to altered video speed in viewing a soccer match. AB - When watching videos, our sense of reality is continuously challenged. How much can a fundamental dimension of experience such as visual flow be modified before breaking the perception of real time? Here we found a remarkable indifference to speed manipulations applied to a popular video content, a soccer match. In a condition that mimicked real-life TV watching, none of 100 naive observers spontaneously noticed speed alterations up/down to 12%, even when asked to report motion anomalies, and showed very low sensitivity to video speed changes (Just Noticeable Difference, JND = 18%). When tested with a constant-stimuli speed discrimination task, JND was still high, though much reduced (9%). The presence of the original voice-over with compensation for pitch did not affect perceptual performance. Thus, our results document a rather broad tolerance to speed manipulations in video viewing, even under attentive scrutiny. This finding may have important implications. For example, it can validate video compression strategies based on sub-threshold temporal squeezing. This way, a soccer match can last only 80 min and still be perceived as natural. More generally, knowing the boundaries of natural speed perception may help to optimize the flow of artificial visual stimuli which increasingly surround us. PMID- 29133820 TI - Early Postnatal Cardiomyocyte Proliferation Requires High Oxidative Energy Metabolism. AB - Cardiac energy metabolism must cope with early postnatal changes in tissue oxygen tensions, hemodynamics, and cell proliferation to sustain development. Here, we tested the hypothesis that proliferating neonatal cardiomyocytes are dependent on high oxidative energy metabolism. We show that energy-related gene expression does not correlate with functional oxidative measurements in the developing heart. Gene expression analysis suggests a gradual overall upregulation of oxidative-related genes and pathways, whereas functional assessment in both cardiac tissue and cultured cardiomyocytes indicated that oxidative metabolism decreases between the first and seventh days after birth. Cardiomyocyte extracellular flux analysis indicated that the decrease in oxidative metabolism between the first and seventh days after birth was mostly related to lower rates of ATP-linked mitochondrial respiration, suggesting that overall energetic demands decrease during this period. In parallel, the proliferation rate was higher for early cardiomyocytes. Furthermore, in vitro nonlethal chemical inhibition of mitochondrial respiration reduced the proliferative capacity of early cardiomyocytes, indicating a high energy demand to sustain cardiomyocyte proliferation. Altogether, we provide evidence that early postnatal cardiomyocyte proliferative capacity correlates with high oxidative energy metabolism. The energy requirement decreases as the proliferation ceases in the following days, and both oxidative-dependent metabolism and anaerobic glycolysis subside. PMID- 29133821 TI - Incidence of asymptomatic neurosyphilis in serofast Chinese syphilis patients. AB - More new diagnosed syphilis cases were reported in china, the incidence and relevant factors of asymptomatic neurosyphilis (ANS) in serofast syphilis patients were unclear. Clinical and laboratory data of 402 Human Immunodeficiency Virus (HIV) negative, serofast syphilis patients, who underwent lumbar puncture at the Peking University Ditan Teaching Hospital between September 2008 and August 2016, were collected. Incidence of ANS was verified and the relevant factors were further analyzed. According to the ANS criteria, 139 (34.6%) patients had ANS. Of these, 40 (28.8%) had reactive cerebrospinal fluid (CSF), rapid plasma reagin (RPR) positive, 115 (82.7%) had CSF white blood cell (WBC) count > 5 * 106/L, 28 (20.1%) had CSF protein concentration > 45 mg/dL (without other neurological diseases). Patients aged 51-60 years, of non-Han ethnicity, with serum RPR titer 1:32 and >= 1:64 were 2.28-fold, 9.11-fold, 5.12-fold and 5.69-fold, respectively, more likely to have ANS. The incidence of ANS was 34.6% among Chinese serofast syphilis patients. Age, ethnicity and serum RPR titer were associated with high risk of ANS. PMID- 29133822 TI - A non-smooth tumor margin on preoperative imaging assesses microvascular invasion of hepatocellular carcinoma: A systematic review and meta-analysis. AB - Microvascular invasion (MVI) is rarely diagnosed preoperatively in hepatocellular carcinoma (HCC). The aim of this meta-analysis is to assess the diagnostic power of a non-smooth tumor margin on preoperative imaging for MVI. We performed a literature search using the PubMed, Embase and Cochrane Library databases, and 11 studies were included involving 618 MVI-positive cases and 1030 MVI-negative cases. Considerable heterogeneity was found, and was indicated to be attributable to the mean patient ages in the included studies. In subgroups of studies with a mean patient age older than 60 years and studies with computed tomography (CT) as the imaging method (as opposed to magnetic resonance imaging (MRI)), heterogeneity was low, and the diagnostic odds ratio (DOR) of the single two dimensional imaging feature for MVI was 21.30 (95% CI [12.52, 36.23]) and 28.78 (95% CI [13.92, 59.36]), respectively; this power was equivalent to or greater than that of certain multivariable-based scoring systems. In conclusion, a non smooth tumor margin on preoperative imaging is of great value for MVI assessment and should be considered for inclusion in future scoring systems. PMID- 29133823 TI - Identification of miRNA-mediated drought responsive multi-tiered regulatory network in drought tolerant rice, Nagina 22. AB - Comparative characterization of microRNA-mediated stress regulatory networks in contrasting rice cultivars is critical to decipher plant stress response. Consequently, a multi-level comparative analysis, using sRNA sequencing, degradome analysis, enzymatic and metabolite assays and metal ion analysis, in drought tolerant and sensitive rice cultivars was conducted. The study identified a group of miRNAs "Cultivar-specific drought responsive" (CSDR)-miRNAs (osa miR159f, osa-miR1871, osa-miR398b, osa-miR408-3p, osa-miR2878-5p, osa-miR528-5p and osa-miR397a) that were up-regulated in the flag-leaves of tolerant cultivar, Nagina 22 (N22) and Vandana, but down-regulated in the sensitive cultivar, Pusa Basmati 1 (PB1) and IR64, during drought. Interestingly, CSDR-miRNAs target several copper-protein coding transcripts like plantacyanins, laccases and Copper/Zinc superoxide dismutases (Cu/Zn SODs) and are themselves found to be similarly induced under simulated copper-starvation in both N22 and PB1. Transcription factor OsSPL9, implicated in Cu-homeostasis also interacted with osa-miR408-3p and osa-miR528-5p promoters. Further, N22 flag leaves showed lower SOD activity, accumulated ROS and had a higher stomata closure. Interestingly, compared to PB1, internal Cu levels significantly decreased in the N22 flag leaves, during drought. Thus, the study identifies the unique drought mediated dynamism and interplay of Cu and ROS homeostasis, in the flag leaves of drought tolerant rice, wherein CSDR-miRNAs play a pivotal role. PMID- 29133824 TI - Comparison and evaluation of two different methods to establish the cigarette smoke exposure mouse model of COPD. AB - Animal model of cigarette smoke (CS) -induced chronic obstructive pulmonary disease (COPD) is the primary testing methodology for drug therapies and studies on pathogenic mechanisms of disease. However, researchers have rarely run simultaneous or side-by-side tests of whole-body and nose-only CS exposure in building their mouse models of COPD. We compared and evaluated these two different methods of CS exposure, plus airway Lipopolysaccharides (LPS) inhalation, in building our COPD mouse model. Compared with the control group, CS exposed mice showed significant increased inspiratory resistance, functional residual capacity, right ventricular hypertrophy index, and total cell count in BALF. Moreover, histological staining exhibited goblet cell hyperplasia, lung inflammation, thickening of smooth muscle layer on bronchia, and lung angiogenesis in both methods of CS exposure. Our data indicated that a viable mouse model of COPD can be established by combining the results from whole-body CS exposure, nose-only CS exposure, and airway LPS inhalation testing. However, in our study, we also found that, given the same amount of particulate intake, changes in right ventricular pressure and intimal thickening of pulmonary small artery are a little more serious in nose-only CS exposure method than changes in the whole-body CS exposure method. PMID- 29133825 TI - Mixed Weyl semimetals and low-dissipation magnetization control in insulators by spin-orbit torques. AB - Reliable and energy-efficient magnetization switching by electrically induced spin-orbit torques is of crucial technological relevance for spintronic devices implementing memory and logic functionality. Here we predict that the strength of spin-orbit torques and the Dzyaloshinskii-Moriya interaction in topologically nontrivial magnetic insulators can exceed by far that of conventional metals. In analogy to the quantum anomalous Hall effect, we explain this extraordinary response in the absence of longitudinal currents as hallmark of monopoles in the electronic structure of systems that are interpreted most naturally within the framework of mixed Weyl semimetals. We thereby launch the effect of spin-orbit torque into the field of topology and reveal its crucial role in mediating the topological phase transitions arising from the complex interplay between magnetization direction and momentum-space topology. The presented concepts may be exploited to understand and utilize magnetoelectric coupling phenomena in insulating ferromagnets and antiferromagnets. PMID- 29133826 TI - Can 129I track 135Cs, 236U, 239Pu, and 240Pu apart from 131I in soil samples from Fukushima Prefecture, Japan? AB - In the present study, 129I activities and 129I/127I atom ratios were measured in 60 soil samples contaminated by the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. The 127I concentrations, 129I activities, and 129I/127I atom ratios in dry-weight were observed to be 0.121-23.6 mg kg-1, 0.962-275 mBq kg-1, and (0.215 79.3) * 10-7, respectively. The maximum values of both 129I activities and 129I/127I atom ratios in Japanese soil increased about three orders of magnitude due to this accident. The equation logy = 0.877logx + 0.173 (Pearson's r = 0.936; x, 129I concentration; y, 131I concentration; decay-corrected to March 11, 2011) instead of a simple constant may be a better way to express the relationship between 129I and 131I in Japanese soil affected by both global fallout and FDNPP accident fallout. In addition, a moderate correlation was observed between 129I and 135Cs (logy = 0.624logx + 1.01, Pearson's r = 0.627; x, 129I activity; y, 135Cs activity). However, 129I presented larger fractionations with less volatile radionuclides, such as 236U, 239Pu, and 240Pu. These findings indicated 135Cs could be roughly estimated from 129I or 131I; this is advantageous as fewer 135Cs data are available and 135Cs/137Cs is being considered a promising tracer during radiocesium source identification. PMID- 29133827 TI - Blastocyst Formation Rate and Transgene Expression are Associated with Gene Insertion into Safe and Non-Safe Harbors in the Cattle Genome. AB - Integration target site is the most important factor in successful production of transgenic animals. However, stable expression of transgene without disturbing the function of the host genome depends on promoter methylation, transgene copy number and transcriptional activity in integration regions. Recently, new genome editing tools have made much progress, however little attention has been paid to the identification of genomic safe harbors. The aim of the present study was to evaluate the effect of insertion site, promoter and copy number of transgene on the production of embryos from cattle fibroblast cells following somatic cell nuclear transfer (SCNT). So, three donor vectors were constructed with EGFP gene under control of different promoters. Each vector was integrated into safe and non-safe harbors in the genome using phiC31 integrase. Transgenic clones with a single copy of each vector were isolated. Each clone was analyzed to find site and frequency of integration, expression level and promoter methylation before SCNT, as well as transgene expression level and blastocyst formation rate after SCNT. The data obtained demonstrated that BF5, as a safe harbor, not only showed a stable expression, but also the rate of in vitro-produced embryos from BF5 clones are similar to that of non-transfected cells. PMID- 29133828 TI - Animal multicellularity and polarity without Wnt signaling. AB - Acquisition of multicellularity is a central event in the evolution of Eukaryota. Strikingly, animal multicellularity coincides with the emergence of three intercellular communication pathways - Notch, TGF-beta and Wnt - all considered as hallmarks of metazoan development. By investigating Oopsacas minuta and Aphrocallistes vastus, we show here that the emergence of a syncytium and plugged junctions in glass sponges coincides with the loss of essential components of the Wnt signaling (i.e. Wntless, Wnt ligands and Disheveled), whereas core components of the TGF-beta and Notch modules appear unaffected. This suggests that Wnt signaling is not essential for cell differentiation, polarity and morphogenesis in glass sponges. Beyond providing a comparative study of key developmental toolkits, we define here the first case of a metazoan phylum that maintained a level of complexity similar to its relatives despite molecular degeneration of Wnt pathways. PMID- 29133829 TI - Differential responses of body growth to artificial warming between parasitoids and hosts and the consequences for plant seed damage. AB - Temperature increase may disrupt trophic interactions by differentially changing body growth of the species involved. In this study, we tested whether the response of body growth to artificial warming (~2.2 degrees C) of a solitary koinobiont endo-parasitoid wasp (Pteromalus albipennis, Hymenoptera: Pteromalidae) differed from its main host tephritid fly (Tephritis femoralis, Diptera: Tephritidae; pre-dispersal seed predator), and whether the plant seed damage caused by wasp-parasitized and unparasitized maggots (larval flies) were altered by warming. In contrast to the significant and season-dependent effects of warming on body growth of the host tephritid fly reported in one of our previous studies, the effect of artificial warming on body growth was non significant on the studied wasp. Moreover, the warming effect on seed damage due to unparasitized maggots was significant and varied with season, but the damage by parasitized maggots was not altered by warming. Distinct responses of body growth to warming between parasitoids studied here and hosts assessed in a previous study indicate that temperature increase may differentially affect life history traits of animals along food chains, which is likely to affect trophic interactions. PMID- 29133830 TI - Non-destructive elemental analysis of a carbonaceous chondrite with direct current Muon beam at MuSIC. AB - Electron- or X-ray-induced characteristic X-ray analysis has been widely used to determine chemical compositions of materials in vast research fields. In recent years, analysis of characteristic X-rays from muonic atoms, in which a muon is captured, has attracted attention because both a muon beam and a muon-induced characteristic X-ray have high transmission abilities. Here we report the first non-destructive elemental analysis of a carbonaceous chondrite using one of the world-leading intense direct current muon beam source (MuSIC; MUon Science Innovative Channel). We successfully detected characteristic muonic X-rays of Mg, Si, Fe, O, S and C from Jbilet Winselwan CM chondrite, of which carbon content is about 2 wt%, and the obtained elemental abundance pattern was consistent with that of CM chondrites. Because of its high sensitivity to carbon, non-destructive elemental analysis with a muon beam can be a novel powerful tool to characterize future retuned samples from carbonaceous asteroids. PMID- 29133831 TI - Protein-Ligand Blind Docking Using QuickVina-W With Inter-Process Spatio-Temporal Integration. AB - "Virtual Screening" is a common step of in silico drug design, where researchers screen a large library of small molecules (ligands) for interesting hits, in a process known as "Docking". However, docking is a computationally intensive and time-consuming process, usually restricted to small size binding sites (pockets) and small number of interacting residues. When the target site is not known (blind docking), researchers split the docking box into multiple boxes, or repeat the search several times using different seeds, and then merge the results manually. Otherwise, the search time becomes impractically long. In this research, we studied the relation between the search progression and Average Sum of Proximity relative Frequencies (ASoF) of searching threads, which is closely related to the search speed and accuracy. A new inter-process spatio-temporal integration method is employed in Quick Vina 2, resulting in a new docking tool, QuickVina-W, a suitable tool for "blind docking", (not limited in search space size or number of residues). QuickVina-W is faster than Quick Vina 2, yet better than AutoDock Vina. It should allow researchers to screen huge ligand libraries virtually, in practically short time and with high accuracy without the need to define a target pocket beforehand. PMID- 29133832 TI - JMJD8 is a novel endoplasmic reticulum protein with a JmjC domain. AB - Jumonji C (JmjC) domain-containing proteins have been shown to regulate cellular processes by hydroxylating or demethylating histone and non-histone targets. JMJD8 belongs to the JmjC domain-only family that was recently shown to be involved in angiogenesis and TNF-induced NF-kappaB signaling. Here, we employed bioinformatic analysis and immunofluorescence microscopy to examine the physiological properties of JMJD8. We demonstrated that JMJD8 localizes to the lumen of endoplasmic reticulum and that JMJD8 forms dimers or oligomers in vivo. Furthermore, we identified potential JMJD8-interacting proteins that are known to regulate protein complex assembly and protein folding. Taken together, this work demonstrates that JMJD8 is the first JmjC domain-containing protein found in the lumen of the endoplasmic reticulum that may function in protein complex assembly and protein folding. PMID- 29133833 TI - Effect of soy on bone turn-over markers in men with type 2 diabetes and hypogonadism - a randomised controlled study. AB - Type 2 diabetes (T2DM) is associated with increased risk of fractures. Soy supplementation has been shown to have a beneficial effect on bone turnover markers (BTM) in postmenopausal women. However, the effect of soy supplementation on BTM in T2DM and particularly in men is unclear. We performed an analysis of a randomized double blind parallel study of 200 men with T2DM treated with soy, either with or without isoflavones. Outcome measures were type I collagen crosslinked beta C-telopeptide (betaCTX), and type 1 procollagen-N-propeptide (P1NP). The men, with a total testosterone <12 nmol/L, were treated with 15 g soy protein containing 66 mg of isoflavones (SPI) or 15 g soy protein alone without isoflavones (SP) daily for three months. There was a 15% reduction in betaCTX after three months of SPI compared to SP supplementation. There was no significant difference in P1NP with either SPI or SP supplementation. There was a significant linear correlation between the reduction in betaCTX in the SPI group with the reduction in HbA1c (r2 = 0.42; p = 0.04) and HOMA-IR (r2 = 0.54; p = 0.02). Our study indicates that there was a significant reduction in bone resorption following 3 months of SPI supplementation that correlated with an improvement of glycemic control in men with T2DM. PMID- 29133834 TI - Instability in CH3NH3PbI3 perovskite solar cells due to elemental migration and chemical composition changes. AB - Organic-inorganic halide perovskites have rapidly grown as favorable materials for photovoltaic applications, but accomplishing long-term stability is still a major research problem. This work demonstrates a new insight on instability and degradation factors in CH3NH3PbI3 perovskite solar cells aging with time in open air. X-ray photoelectron spectroscopy (XPS) has been used to investigate the compositional changes caused by device degradation over the period of 1000 hrs. XPS spectra confirm the migration of metallic ions from the bottom electrode (ITO) as a key factor causing the chemical composition change in the perovskite layer besides the diffusion of oxygen. XPS results are in good agreement with the crystallographic marks. Glow discharge optical emission spectrometry (GD-OES) has also been performed on the samples to correlate the XPS results. Based on the experimental results, fundamental features that account for the instability in the perovskite solar cell is discussed. PMID- 29133835 TI - Plug-and-play round-robin differential phase-shift quantum key distribution. AB - The round-robin differential-phase-shift quantum key distribution (RRDPS-QKD) protocol could provide an effective way to estimate the leakage information without monitoring the signal disturbance. Moreover, the self-compensating property of plug-and-play (P&P) setup can eliminate the variations of phase or polarization in QKD procedure. In the paper, we introduce the P&P concept into RRDPS-QKD, and propose a QKD protocol, named P&P RRDPS-QKD protocol, to make the RRDPS-QKD scheme more practical. We analyze the security, and discuss the key generation rate with infinite-intensity decoy state method. The results show that the proposed protocol is a good solution to RRDPS-QKD protocol with untrusted sources. It has a high security and its key generation rate could be as good as the protocol with trusted sources when the average input photon number N is greater than 106. In addition, the proposed protocol has a high noise tolerance in comparison with P&P BB84-QKD protocol. PMID- 29133836 TI - A Study on Image Quality in Polarization-Resolved Second Harmonic Generation Microscopy. AB - Second harmonic generation (SHG) microscopy represents a very powerful tool for tissue characterization. Polarization-resolved SHG (PSHG) microscopy extends the potential of SHG, by exploiting the dependence of SHG signals on the polarization state of the excitation beam. Among others, this dependence translates to the fact that SHG images collected under different polarization configurations exhibit distinct characteristics in terms of content and appearance. These characteristics hold deep implications over image quality, as perceived by human observers or by image analysis methods custom designed to automatically extract a quality factor from digital images. Our work addresses this subject, by investigating how basic image properties and the outputs of no-reference image quality assessment methods correlate to human expert opinion in the case of PSHG micrographs. Our evaluation framework is based on SHG imaging of collagen-based ocular tissues under different linear and elliptical polarization states of the incident light. PMID- 29133837 TI - Contrasting runoff trends between dry and wet parts of eastern Tibetan Plateau. AB - As the "Asian Water Tower", the Tibetan Plateau (TP) provides water resources for more than 1.4 billion people, but suffers from climatic and environmental changes, followed by the changes in water balance components. We used state-of the-art satellite-based products to estimate spatial and temporal variations and trends in annual precipitation, evapotranspiration and total water storage change across eastern TP, which were then used to reconstruct an annual runoff variability series for 2003-2014. The basin-scale reconstructed streamflow variability matched well with gauge observations for five large rivers. Annual runoff increased strongly in dry part because of increases in precipitation, but decreased in wet part because of decreases in precipitation, aggravated by noticeable increases in evapotranspiration in the north of wet part. Although precipitation primarily governed temporal-spatial pattern of runoff, total water storage change contributed greatly to runoff variation in regions with wide spread permanent snow/ice or permafrost. Our study indicates that the contrasting runoff trends between the dry and wet parts of eastern TP requires a change in water security strategy, and attention should be paid to the negative water resources impacts detected for southwestern part which has undergone vast glacier retreat and decreasing precipitation. PMID- 29133838 TI - Fungal networks serve as novel ecological routes for enrichment and dissemination of antibiotic resistance genes as exhibited by microcosm experiments. AB - Antibiotic resistance genes (ARGs) in the environment and their subsequent acquisition by clinically important microorganisms are a serious concern. However, the spread of environmental ARGs remain largely unknown. We report, for the first time, the involvement of soil fungi in the distribution of bacteria with ARGs via soil microcosms. qPCR assay detected unique ARGs specifically found in the mycosphere of different fungi. Interestingly, the taxonomically and ecologically different fungi exerted different selection pressures on ARGs originating from the same source. Test fungi supported different antibiotic resistance bacteria enriched in the mycosphere and even transported to distant places. The relative abundance of the tnpA gene decreased, for manure, along mycelial networks of all fungi. While the fungal strain NFC-5 enriched the intI1 gene more, opposite to two other fungi at the migration front compared with the inoculation point for both sources. Such data indicate the differential effect of different fungi to facilitate horizontal gene transfer potential under fungal selection pressure. Our study provides the evidence that fungi can contribute ARGs, host bacterial diversity and abundance, and such interactive microbial consortia have the potential to disseminate the resistance determinants from one place to another, thus increasing the ARGs exposure risk to humans. PMID- 29133839 TI - Genetic relationships and evolution of old Chinese garden roses based on SSRs and chromosome diversity. AB - Old Chinese garden roses are the foundation of the modern rose, which is one of the best-selling ornamental plants. However, the horticultural grouping and evolution of old Chinese garden roses are unclear. Simple sequence repeat (SSR) markers were employed to survey genetic diversity in old Chinese garden roses and genetic differentiation was estimated among different rose groups. Fluorescence in situ hybridization was used to study the physical localization of 5 S rDNA genes and a karyotype analysis was performed. The SSR data suggest that old Chinese garden roses could be divided into Old Blush group, Odorata group and Ancient hybrid China group. The Old Blush group had the most primitive karyotype. The Ancient hybrid China group and modern rose had the most evolved karyotypes and the highest genetic diversity. During the evolution of rose cultivars, 5 S rDNA increased in number, partially weakened in signal intensity and exhibited variation in distance from the centromere. In conclusion, rose cultivars evolved from the Old Blush Group to the Odorata group, the Ancient Hybrid China group and the modern rose. This work provides a basis for the collection, identification, conservation and innovation of rose germplasm resources. PMID- 29133840 TI - A rapid cosmic-ray increase in BC 3372-3371 from ancient buried tree rings in China. AB - Cosmic rays interact with the Earth's atmosphere to produce 14C, which can be absorbed by trees. Therefore, rapid increases of 14C in tree rings can be used to probe previous cosmic-ray events. By this method, three 14C rapidly increasing events have been found. Plausible causes of these events include large solar proton events, supernovae, or short gamma-ray bursts. However, due to the lack of measurements of 14C by year, the occurrence frequency of such 14C rapidly increasing events is poorly known. In addition, rapid increases may be hidden in the IntCal13 data with five-year resolution. Here we report the result of 14C measurements using an ancient buried tree during the period between BC 3388 and 3358. We found a rapid increase of about 90/00 in the 14C content from BC 3372 to BC 3371. We suggest that this event could originate from a large solar proton event. PMID- 29133841 TI - Nanopore electric snapshots of an RNA tertiary folding pathway. AB - The chemical properties and biological mechanisms of RNAs are determined by their tertiary structures. Exploring the tertiary structure folding processes of RNA enables us to understand and control its biological functions. Here, we report a nanopore snapshot approach combined with coarse-grained molecular dynamics simulation and master equation analysis to elucidate the folding of an RNA pseudoknot structure. In this approach, single RNA molecules captured by the nanopore can freely fold from the unstructured state without constraint and can be programmed to terminate their folding process at different intermediates. By identifying the nanopore signatures and measuring their time-dependent populations, we can "visualize" a series of kinetically important intermediates, track the kinetics of their inter-conversions, and derive the RNA pseudoknot folding pathway. This approach can potentially be developed into a single molecule toolbox to investigate the biophysical mechanisms of RNA folding and unfolding, its interactions with ligands, and its functions. PMID- 29133843 TI - Geometry and Evolution of the Cangdong Sag in the Bohai Bay Basin, China: Implications for Subduction of the Pacific Plate. AB - The Cangdong Sag is a complex Cenozoic rift basin at the center of the Bohai Bay Basin. Cenozoic structures in the Cangdong Sag can be subdivided into the Cangdong Fault System in the west and the Xuxi Fault System in the east. The geometry of the boundary faults varies along the axes of half-grabens. According to the cross-sectional strata geometry, unconformity and planar structural pattern, the Cenozoic structural evolution of the Cangdong Sag can be divided into four distinct stages: (1) major Paleocene initial rift, (2) latest Paleocene early Eocene intensive rift, (3) late Eocene-Oligocene strike-slip superimposed rift, and (4) Neogene to present-day post-rift depression. The extensional deformation was mainly derived from horizontal stress induced by the upwelling of asthenosphere. The strike-slip structure of the Cangdong Sag provides important information related to the subduction of the Western Pacific Plate. It was found that the strike-slip movement of the southern Xuxi Fault Zone was activated during the deposition of the third member of Shahejie Formation to the Dongying Formation; therefore, ~43 Ma probably marks the time when the Western Pacific Plate initially changed its subduction direction from northwest to nearly west. PMID- 29133844 TI - Utilization of Stainless-steel Furnace Dust as an Admixture for Synthesis of Cement-based Electromagnetic Interference Shielding Composites. AB - Electromagnetic interference (EMI) shielding receives attention due to the increasing abundance of electronics. The Cement based material can obtain EMI shielding properties through the use of appropriate "fillers" such as carbon, metal, and ferrite. As the most important by-product of stainless steelmaking operations, through the metal droplets and ferrite that it contains, stainless steel dust can be considered as a potential filler for EMI shielding applications. We have therefore utilized stainless-steel dust as an admixture for the synthesis of cement-based EMI shielding composites and show that it raises the EMI shielding effectiveness. In particular, a 45 mass pct of stainless-steel dust mixture of 5 mm thickness results in the enhancement of EMI shielding effectiveness to 6-9 dB as tested in the frequency range of 500 MHz-1.5 GHz. PMID- 29133842 TI - Serotonin regulates prostate growth through androgen receptor modulation. AB - Aging and testosterone almost inexorably cause benign prostatic hyperplasia (BPH) in Human males. However, etiology of BPH is largely unknown. Serotonin (5-HT) is produced by neuroendocrine prostatic cells and presents in high concentration in normal prostatic transition zone, but its function in prostate physiology is unknown. Previous evidence demonstrated that neuroendocrine cells and 5-HT are decreased in BPH compared to normal prostate. Here, we show that 5-HT is a strong negative regulator of prostate growth. In vitro, 5-HT inhibits rat prostate branching through down-regulation of androgen receptor (AR). This 5-HT's inhibitory mechanism is also present in human cells of normal prostate and BPH, namely in cell lines expressing AR when treated with testosterone. In both models, 5-HT's inhibitory mechanism was replicated by specific agonists of 5 Htr1a and 5-Htr1b. Since peripheral 5-HT production is specifically regulated by tryptophan hydroxylase 1(Tph1), we showed that Tph1 knockout mice present higher prostate mass and up-regulation of AR when compared to wild-type, whereas 5-HT treatment restored the prostate weight and AR levels. As 5-HT is decreased in BPH, we present here evidence that links 5-HT depletion to BPH etiology through modulation of AR. Serotoninergic prostate pathway should be explored as a new therapeutic target for BPH. PMID- 29133845 TI - The Prognostic Value of Platelet-to-Lymphocyte Ratio in Urological Cancers: A Meta-Analysis. AB - The relationship of platelet-to-lymphocyte ratio (PLR) and survival in urological cancers remained inconsistent in previous studies. Therefore, we performed a meta analysis to assess the prognostic significance of PLR in patients with urological cancers. A literature search was performed in the PubMed, Embase, and Web of Science up to July, 2017 and study quality was obtained using the Newcastle Ottawa Scale. To estimate the association of PLR and overall survival (OS) and other survival outcomes in urological cancers, we used pooled hazard ratios (HRs). Subgroup analyses were conducted on different ethnics, sample sizes and cut-off values. 20 high quality studies involving 7562 patients with urological cancers were included in this meta-analysis. High pretreatment PLR was significantly associated with poor OS in patients with urological cancers (pooled HR = 1.58). Elevated PLR was also correlated with other survival outcomes. However, we found that PLR was significantly relevant to the OS of patients with different types of urological cancers except bladder cancer (BCa, HR = 1.16, 95%CI: 0.96-1.41). In conclusion, elevated PLR was negatively related to the OS of patients with urological cancers, except in BCa. However, more large scale prospective studies with high quality are required in the future. PMID- 29133846 TI - Large scale matching of function to the genetic identity of retinal ganglion cells. AB - Understanding the role of neurons in encoding and transmitting information is a major goal in neuroscience. This requires insight on the data-rich neuronal spiking patterns combined, ideally, with morphology and genetic identity. Electrophysiologists have long experienced the trade-offs between anatomically accurate single-cell recording techniques and high-density multi-cellular recording methods with poor anatomical correlations. In this study, we present a novel technique that combines large-scale micro-electrode array recordings with genetic identification and the anatomical location of the retinal ganglion cell soma. This was obtained through optogenetic stimulation and subsequent confocal imaging of genetically targeted retinal ganglion cell sub-populations in the mouse. With the many molecular options available for optogenetic gene expression, we view this method as a versatile tool for matching function to genetic classifications, which can be extended to include morphological information if the density of labelled cells is at the correct level. PMID- 29133848 TI - Community effect of cardiomyocytes in beating rhythms is determined by stable cells. AB - The community effect of cardiomyocytes was investigated in silico by the change in number and features of cells, as well as configurations of networks. The theoretical model was based on experimental data and accurately reproduced recently published experimental results regarding coupled cultured cardiomyocytes. We showed that the synchronised beating of two coupled cells was tuned not to the cell with a faster beating rate, but to the cell with a more stable rhythm. In a network of cardiomyocytes, a cell with low fluctuation, but not a hight frequency, became a pacemaker and stabilised the beating rhythm. Fluctuation in beating rapidly decreased with an increase in the number of cells (N), almost irrespective of the configuration of the network, and a cell comes to have natural and stable beating rhythms, even for N of approximately 10. The universality of this community effect lies in the fluctuation-dissipation theorem in statistical mechanics. PMID- 29133847 TI - Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema. AB - Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis. PMID- 29133849 TI - Canonical germinant receptor is dispensable for spore germination in Clostridium botulinum group II strain NCTC 11219. AB - Clostridium botulinum is an anaerobic sporeforming bacterium that is notorious for producing a potent neurotoxin. Spores of C. botulinum can survive mild food processing treatments and subsequently germinate, multiply, produce toxin and cause botulism. Control of spore germination and outgrowth is therefore essential for the safety of mildly processed foods. However, little is known about the process of spore germination in group II C. botulinum (gIICb), which are a major concern in chilled foods because they are psychrotrophic. The classical model of spore germination states that germination is triggered by the binding of a germinant molecule to a cognate germinant receptor. Remarkably, unlike many other sporeformers, gIICb has only one predicted canonical germinant receptor although it responds to multiple germinants. Therefore, we deleted the gerBAC locus that encodes this germinant receptor to determine its role in germination. Surprisingly, the deletion did not affect germination by any of the nutrient germinants, nor by the non-nutrient dodecylamine. We conclude that one or more other, so far unidentified, germinant receptors must be responsible for nutrient induced germination in gIICb. Furthermore, the gerBAC locus was strongly conserved with intact open reading frames in 159 gIICb genomes, suggesting that it has nevertheless an important function. PMID- 29133850 TI - Astrocyte elevated gene-1 promotes tumour growth and invasion by inducing EMT in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is a common human malignancy with a high incidence rate and poor prognosis. Although astrocyte elevated gene 1 (AEG-1) expression is up-regulated in various human cancers and plays an important role in carcinogenesis and tumour progression, the impact of AEG-1 on the development and progression of OSCC remains unclear. Accordingly, this study aims to clarify the biological significance of AEG-1 in OSCC. We found AEG-1 to be overexpressed in OSCC tissues compared to normal oral mucosa. Knockdown or overexpression of AEG-1 in OSCC cell lines showed that AEG-1 is important for tumour growth, apoptosis, drug tolerance, and maintaining epithelial-mesenchymal transition (EMT)-mediated cell migration and invasion in vitro. Moreover, in a xenograft mouse model generated by AEG-1-overexpressing SCC15 cells, we found that higher expression of AEG-1 promoted tumour growth, angiogenesis, and EMT in vivo. These findings provide mechanistic insight into the role of AEG-1 in regulating OSCC tumour growth, apoptosis, drug tolerance, and invasion, as well as AEG-1-induced activation of p38 and NF-kappaB signalling, suggesting that AEG-1 is an important prognostic factor and therapeutic target for OSCC. PMID- 29133851 TI - The effects of sociability on exploratory tendency and innovation repertoires in wild Sumatran and Bornean orangutans. AB - It has been hypothesized that opportunities for social learning affect the size and complexity of the adult skill set of birds and mammals, their learning ability, and thus ultimately also their innovation frequency. To test these predictions we compared rates of social learning, rates of independent exploration (independent learning) and innovation repertoires between individuals of a highly sociable population of Pongo abelii at Suaq Balimbing and a less sociable population of Pongo pygmaeus wurmbii at Tuanan. Suaq immatures showed significantly higher rates of peering, even after controlling for differences in association time and diet complexity, implying that they make disproportionally greater use of their increased opportunities for social learning. As predicted, we found that immatures and adults at Suaq also showed significantly higher rates of exploratory behaviour. The difference between the individuals of the two popuations remained when controlling for association time, suggesting persistent developmental effects, intrinsic differences, or both. Accordingly, Suaq animals had a larger set of learned skills and a higher mean dietary complexity. Our findings show that population level sociability, individual rates of exploration and population-wide repertoires of innovations are positively linked, as predicted. PMID- 29133853 TI - Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins. AB - Burn wounds are one of the most important causes of mortality and especially morbidity around the world. Burn wound healing and skin tissue regeneration remain thus one of the most important challenges facing the mankind. In the present study we have addressed this challenge, applying a solution-stabilized dispersion TiO2 nanoparticles, hypothesizing that their ability to adsorb proteins will render them a strong capacity in inducing body fluid coagulation and create a protective hybrid material coating. The in vitro study of interaction between human blood and titania resulted at enhanced TiO2 concentrations in formation of rather dense gel composite materials and even at lower content revealed specific adsorption pattern initiating the cascade response, promising to facilitate the regrowth of the skin. The subsequent in vivo study of the healing of burn wounds in rats demonstrated formation of a strongly adherent crust of a nanocomposite, preventing infection and inflammation with quicker reduction of wound area compared to untreated control. The most important result in applying the TiO2 dispersion was the apparently improved regeneration of damaged tissues with appreciable decrease in scar formation and skin color anomalies. PMID- 29133852 TI - NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism. AB - Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c +/-(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention. PMID- 29133854 TI - Copper (II) binding of NAD(P)H- flavin oxidoreductase (NfoR) enhances its Cr (VI) reducing ability. AB - Microbes can reduce hexavalent chromium Cr (VI) to the less toxic and soluble trivalent Cr (III). Copper stimulates microbial reduction of Cr (VI) by the Bacillus, Ochrobactrum, and Gluconobacter species; however, the mechanism remains unclear. In our study, the rate of Cr (VI) reduction by Staphylococcus aureus LZ 01 was increased by 210 % when supplemented with 60 MUM Cu (II). A putative NAD(P)H-flavin oxidoreductase gene (nfoR) was upregulated under Cr (VI) stress. NfoR-knockout mutant displayed impaired reduction of Cr (VI) and Cu (II)-enhanced Cr (VI) reduction by nfoR isogenic mutant was attenuated in the presence of Cu (II). In vitro tests showed an increased V max value of 25.22 MUM min-1 mg-1 NfoR in the presence of Cu (II). Together, these results indicate that NfoR is responsible for Cu (II) enhancement. Isothermal titration calorimetry (ITC) assays confirmed the interaction of NfoR with Cu (II) at the dissociation constant of 85.5 MUM. Site-directed mutagenesis indicates that His100, His128, and Met165 residues may be important for Cu (II) binding, while Cys163 is necessary for the FMN binding of NfoR. These findings show that Cu (II)-enhanced NfoR belongs to a new branch of Cr (VI) reductases and profoundly influences Cr (VI) reduction. PMID- 29133855 TI - Effect of short-term exposure to ambient air particulate matter on incidence of delirium in a surgical population. AB - Delirium remains an independent risk factor for morbidity and mortality among older surgical adults. Recent research has shed light on the relationship between pollution and dementia, yet little is known about the health impacts of particulate matter (PM) on delirium. Therefore, we aim to further explore association of PM and delirium among surgical population. We conducted a time stratified case-crossover study. Electronic hospitalization summary reports derived from 26 major cities in China between 1 January 2014 and 31 December 2015 were used. Conditional logistic regression were applied to explore the association between perioperative PM exposure and delirium. A total of 559 surgical patients with delirium were identified. Both PM2.5 and SO2 on the day of surgery had a negative impact, with an interquartile range (IQR) increase in PM2.5 (47.5 MUg/m 3) and SO2 (22.2 MUg/m 3) significantly associated with an 8.79% (95% confidence interval [CI], 0.01-18.47%, P < 0.05) and 16.83% (95% CI, 0.10-36.35%, P < 0.05) increase in incidence of delirium, respectively. PM on other days during the perioperative period showed no significant impact. The present study showed that short-term exposure to ambient air PM on the day of surgery increased the incidence of delirium in a surgical population during hospitalization. PMID- 29133856 TI - Therapeutic targeting of extracellular DNA improves the outcome of intestinal ischemic reperfusion injury in neonatal rats. AB - Thrombosis and inflammation cooperate in the development of intestinal infarction. Recent studies suggest that extracellular DNA released by damaged cells or neutrophils in form of extracellular traps (NETs) contributes to organ damage in experimental models of ischemia-reperfusion injury. Here we compared the therapeutic effects of targeting fibrin or extracellular DNA in intestinal infarction after midgut volvulus in rats. Following iatrogenic midgut volvulus induction for 3 hours, we treated animals with a combination of tissue plasminogen activator (tPA) and low molecular weight heparin (LMWH) to target fibrin or with DNase1 to degrade extracellular DNA. The therapeutic effects of tPA/LMWH and DNase1 were analyzed after 7 days. We observed that both therapeutic interventions ameliorated tissue injury, apoptosis, and oxidative stress in the intestine. DNase1, but not tPA/LMWH, reduced intestinal neutrophil infiltration and histone-myeloperoxidase-complexes, a surrogate marker of NETs, in circulation. Importantly, tPA/LMWH, but not DNase1, interfered with hemostasis as evidenced by a prolonged tail bleeding time. In conclusion, our data suggest that the therapeutic targeting of fibrin and extracellular DNA improves the outcome of midgut volvulus in rats. DNase1 therapy reduces the inflammatory response including NETs without increasing the risk of bleeding. Thus, targeting of extracellular DNA may provide a safe therapy for patients with intestinal infarction in future. PMID- 29133857 TI - PDGFR-modulated miR-23b cluster and miR-125a-5p suppress lung tumorigenesis by targeting multiple components of KRAS and NF-kB pathways. AB - In NSCLC alterations in PDGF receptors are markers of worst prognosis and efficient targeting of these receptors is yet to be achieved. In this study, we explored PDGFR-regulated microRNAs demonstrating that miR-23b cluster and miR 125a-5p are downregulated by increased expression of PDGFR-alpha or PDGFR-beta in NSCLC cells. Mechanistically, the expression of these microRNAs is positively regulated by p53 and negatively modulated by NF-kB p65. Forced expression of miR 23b cluster or miR-125a-5p enhanced drug sensitivity and suppressed invasiveness of NSCLC cells by silencing several genes involved in oncogenic KRAS and NF-kB pathways, including SOS1, GRB2, IQGAP1, RALA, RAF-1, IKKbeta, AKT2, ERK2 and KRAS itself. Of note, an inverse correlation between miR-23b cluster, miR-125a-5p and respective target genes was also found in vivo in a large dataset of lung adenocarcinoma samples. Furthermore, in vivo delivery of miR-23b cluster or miR 125a-5p significantly repressed tumour growth in a highly aggressive NSCLC circulating tumour cell (CTC) patient derived explant (CDX) mouse model. In conclusion, our finding sheds light on the PDGFR signaling and endorses the possibility to employ miR-23b cluster and miR-125a-5p as therapeutic tools to silence simultaneously a range of redundant pathways and main effectors of tumorigenesis in NSCLC. PMID- 29133858 TI - Pumpless microfluidic system driven by hydrostatic pressure induces and maintains mouse spermatogenesis in vitro. AB - Three-dimensional aggregation and organ culture methods are critical for recreating in vivo cellular phenomena outside the body. Previously, we used the conventional gas liquid interphase organ culture method to induce complete mouse spermatogenesis. After incorporating microfluidic systems, we achieved a significant increase in efficiency and duration of spermatogenesis. One of the major drawbacks preventing the popularization of microfluidics, however, is the use of a power-pump to generate medium flow. In this study, we produced a pumpless microfluidic device using hydrostatic pressure and a resistance circuit to facilitate slow, longer lasting medium flow. During three months of culture, results in induction and maintenance of spermatogenesis showed no difference between pumpless and pump-driven devices. Correspondingly, the spermatogonial population was favorably maintained in the pumpless device compared to the conventional method. These results show the advantage of using microfluidic systems for organ culture experiments. Our pumpless device could be applied to a variety of other tissues and organs, and may revolutionize organ culture methods as a whole. PMID- 29133859 TI - Conformal transistor arrays based on solution-processed organic crystals. AB - Conformal transistor array based on solution-processed organic crystals, which can provide sensory and scanning features for monitoring, biofeedback, and tracking of physiological function, presents one of the most promising technologies for future large-scale low-cost wearable and implantable electronics. However, it is still a huge challenge for the integration of solution-processed organic crystals into conformal FETs owing to a generally existing swelling phenomenon of the elastic materials and the lack of the corresponding device fabrication technology. Here, we present a promising route to fabricate a conformal field-effect transistor (FET) array based on solution processed TIPS-pentacene single-crystal micro/nanowire array. By simply drop casting the organic solution on an anti-solvent photolithography-compatible electrode with bottom-contact coplanar configuration, the transistor array can be formed and can conform onto uneven objects. Excellent electrical properties with device yield as high as 100%, field-effect mobility up to 0.79 cm2V-1s-1, low threshold voltage, and good device uniformity are demonstrated. The results open up the capability of solution-processed organic crystals for conformal electronics, suggesting their substantial promise for next-generation wearable and implantable electronics. PMID- 29133860 TI - Trade-off between reproduction and lifespan of the rotifer Brachionus plicatilis under different food conditions. AB - Phaeocystis globosa, one of the most typical red tide-forming species, is usually mixed in the food composition of rotifers. To explore how rotifers respond by adjusting life history strategy when feeding on different quality foods, we exposed the rotifer Brachionus plicatilis to cultures with 100% Chlorella, a mixture of 50% P. globosa and 50% Chlorella, or 100% P. globosa. Results showed that rotifers exposed to 100% Chlorella or to mixed diets produced more total offspring and had higher age-specific fecundity than those exposed to 100% P. globosa. Food combination significantly affected the net reproduction rates of rotifers. By contrast, rotifers that fed on 100% P. globosa or on mixed diets had a longer lifespan than those fed on 100% Chlorella. The overall performances (combining reproduction and lifespan together) of rotifers cultured in 100% Chlorella or mixed diets were significantly higher than those cultured in 100% P. globosa. In general, Chlorella favors rotifers reproduction at the cost of shorter lifespan, whereas P. globosa tends to extend the lifespan of rotifers with lower fecundity, indicating that trade-off exists between reproduction and lifespan under different food conditions. The present study also suggests that rotifers may have the potential to control harmful P. globosa. PMID- 29133861 TI - Coupling of Oxy- and Deoxyhemoglobin concentrations with EEG rhythms during motor task. AB - A relationship between the brain rhythmic activity and the hemodynamic response was studied using the simultaneous measurement of electroencephalogram (EEG) and the functional near-infrared spectroscopy (fNIRS) during a motor task (self-paced right finger movements) for 10 subjects. An EEG recording with a 32-electrode (10 10) system was made and the hemodynamic response was obtained using 8 optodes placed over the sensorimotor cortex on both hemispheres. During the task an increase in oxyhemoglobine (HbO) was accompanied by a decrease in deoxyhemoglobine (HbR) concentration and a decrease in amplitudes (desynchronisation) of alpha (8-13 Hz) and beta (13-30 Hz) EEG rhythms. These phenomena were prominent in the hemisphere contralateral to the moving finger. The delays between the hemodynamic and electrophysiological variables were on average 2.8 s. Highly significant (p < 0.0001) negative Pearson correlations were found between HbO and alpha (r2 = -0.69) and HbO and beta (r2 = -0.54) rhythms. Positive correlations r2 = 0.5 between these rhythms and HbR were found. PMID- 29133862 TI - Off-centered Double-slit Metamaterial for Elastic Wave Polarization Anomaly. AB - The polarization anomaly refers to the polarization transition from longitudinal to shear modes along an equi-frequency contour of the same branch, which occurs only in some anisotropic elastic media, but the lack of natural materials exhibiting desired anisotropy makes its utilization impossible for potential novel applications. In this paper, we present a unique, non-resonant type elastic metamaterial made of off-centered, double-slit unit cells. We show that its wave polarization characteristics that determine the desired anomalous polarization for a certain application are tailorable. As an application, a mode converting wedge that transforms pure longitudinal into pure shear modes is designed by the proposed metamaterial. The physics involved in the mode conversion is investigated by simulations and experiments. PMID- 29133863 TI - A real-time Global Warming Index. AB - We propose a simple real-time index of global human-induced warming and assess its robustness to uncertainties in climate forcing and short-term climate fluctuations. This index provides improved scientific context for temperature stabilisation targets and has the potential to decrease the volatility of climate policy. We quantify uncertainties arising from temperature observations, climate radiative forcings, internal variability and the model response. Our index and the associated rate of human-induced warming is compatible with a range of other more sophisticated methods to estimate the human contribution to observed global temperature change. PMID- 29133864 TI - Effects of microgravity on osteoblast mitochondria: a proteomic and metabolomics profile. AB - The response of human primary osteoblasts exposed to simulated microgravity has been investigated and analysis of metabolomic and proteomic profiles demonstrated a prominent dysregulation of mitochondrion homeostasis. Gravitational unloading treatment induced a decrease in mitochondrial proteins, mainly affecting efficiency of the respiratory chain. Metabolomic analysis revealed that microgravity influenced several metabolic pathways; stimulating glycolysis and the pentose phosphate pathways, while the Krebs cycle was interrupted at succinate-fumarate transformation. Interestingly, proteomic analysis revealed that Complex II of the mitochondrial respiratory chain, which catalyses the biotransformation of this step, was under-represented by 50%. Accordingly, down regulation of quinones 9 and 10 was measured. Complex III resulted in up regulation by 60%, while Complex IV was down-regulated by 14%, accompanied by a reduction in proton transport synthesis of ATP. Finally, microgravity treatment induced an oxidative stress response, indicated by significant decreases in oxidised glutathione and antioxidant enzymes. Decrease in malate dehydrogenase induced a reverse in the malate-aspartate shuttle, contributing to dysregulation of ATP synthesis. Beta-oxidation of fatty acids was inhibited, promoting triglyceride production along with a reduction in the glycerol shuttle. Taken together, our findings suggest that microgravity may suppress bone cell functions, impairing mitochondrial energy potential and the energy state of the cell. PMID- 29133865 TI - Cold acclimation causes fiber type-specific responses in glucose and fat metabolism in rat skeletal muscles. AB - This study investigated fiber type-specific metabolic responses and the molecular mechanisms that regulate glucose and fat metabolism in oxidative and glycolytic muscles upon cold acclimation. Male Wistar rats were exposed to cold (4 degrees C) for 7 days, and then glycogen synthesis and content, glucose and palmitate oxidation, and the molecular mechanisms underlying these metabolic pathways were assessed in soleus (Sol), extensor digitorum longus (EDL), and epitrochlearis (Epit) muscles. Cold acclimation increased glycogen synthesis, glycogen content, glucose oxidation, and reduced glycogen synthase (GS) phosphorylation only in Sol muscles. Protein kinase B (AKT), glycogen synthase kinase 3 (GSK3), and AMP activated protein kinase (AMPK) phosphorylation increased in all three muscles upon cold acclimation. Cold acclimation increased palmitate oxidation, gene expression of the transcriptional co-activator Pgc-1alpha, lipoprotein lipase (Lpl), fatty acid transporter (Cd36), and Sarco/endoplasmic reticulum Ca2+-ATPase (Serca) in Sol, EDL, and Epit muscles. Sarcolipin was only detected and had its content increased in Sol muscles. In conclusion, cold-induced thermogenesis activated similar signaling pathways in oxidative and glycolytic muscles, but the metabolic fate of glucose differed in skeletal muscles with distinct fiber type composition. Furthermore, only muscles rich in type I fibers appeared to have the capacity for sarcolipin-mediated SERCA uncoupling. PMID- 29133866 TI - Gastric microbiome of Indian patients with Helicobacter pylori infection, and their interaction networks. AB - The gastric microbiome is suspected to have a role in the causation of diseases by Helicobacter pylori. Reports on their relative abundance vis-a-vis H. pylori are available from various ethnic and geographic groups, but little is known about their interaction patterns. Endoscopic mucosal biopsy samples from the gastric antrum and corpus of 39 patients with suspected H. pylori infection were collected and microbiomes were analyzed by 16S rDNA profiling. Four groups of samples were identified, which harbored Helicobacter as well as a diverse group of bacteria including Lactobacillus, Halomonas and Prevotella. There was a negative association between the microbiome diversity and Helicobacter abundance. Network analyses showed that Helicobacter had negative interactions with members of the gastric microbiome, while other microbes interacted positively with each other, showing a higher tendency towards intra-cluster co-occurrence/co operation. Cross-geographic comparisons suggested the presence of region-specific microbial abundance profiles. We report the microbial diversity, abundance variation and interaction patterns of the gastric microbiota of Indian patients with H. pylori infection and present a comparison of the same with the gastric microbial ecology in samples from different geographic regions. Such microbial abundance profiles and microbial interactions can help in understanding the pathophysiology of gastric ailments and can thus help in development of new strategies to curb it. PMID- 29133868 TI - From harmful Microcystis blooms to multi-functional core-double-shell microsphere bio-hydrochar materials. AB - Harmful algal blooms (HABs) induced by eutrophication is becoming a serious global environmental problem affecting public health and aquatic ecological sustainability. A novel strategy for the utilization of biomass from HABs was developed by converting the algae cells into hollow mesoporous bio-hydrochar microspheres via hydrothermal carbonization method. The hollow microspheres were used as microreactors and carriers for constructing CaO2 core-mesoporous shell CaO2 shell microspheres (OCRMs). The CaO2 shells could quickly increase dissolved oxygen to extremely anaerobic water in the initial 40 min until the CaO2 shells were consumed. The mesoporous shells continued to act as regulators restricting the release of oxygen from CaO2 cores. The oxygen-release time using OCRMs was 7 times longer than when directly using CaO2. More interestingly, OCRMs presented a high phosphate removal efficiency (95.6%) and prevented the pH of the solution from rising to high levels in comparison with directly adding CaO2 due to the OH- controlled-release effect of OCRMs. The distinct core-double-shell micro/nanostructure endowed the OCRMs with triple functions for oxygen controlled release, phosphorus removal and less impact on water pH. The study is to explore the possibility to prepare smarter bio-hydrochar materials by utilizing algal blooms. PMID- 29133867 TI - Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells. AB - Renal angiomyolipomas (AML) contain an admixture of clonal tumour cells with features of several different mesenchymal lineages, implying the existence of an unidentified AML neoplastic stem cell. Biallelic inactivation of TSC2 or TSC1 is believed to represent the driving event in these tumours. Here we show that TSC2 knockdown transforms senescence-resistant cultured mouse and human renal epithelial cells into neoplastic stem cells that serially propagate renal AML like tumours in mice. mTOR inhibitory therapy of mouse AML allografts mimics the clinical responses of human renal AMLs. Deletion of Tsc1 in mouse renal epithelia causes differentiation in vivo into cells expressing characteristic AML markers. Human renal AML and a renal AML cell line express proximal tubule markers. We describe the first mouse models of renal AML and provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells, uncovering an unexpected pathological differentiation plasticity of the proximal tubule. PMID- 29133869 TI - Erratum: Organocatalyzed synthesis of fluorinated poly(aryl thioethers). AB - A correction to this article has been published and is linked from the HTML version of this article. PMID- 29133870 TI - Oxygen Evolution Reaction at Microporous Pt Layers: Differentiated Electrochemical Activity between Acidic and Basic Media. AB - Nanoporous electrodes have received great attention because of their unique electrochemical properties. Here, the electrocatalytic oxygen evolution reaction (OER) activities at porous Pt layers with pore dimensions in the microporous range were examined. The OER activity of the porous Pt layers in acidic media increased as the porosity of the Pt layers increased, and the highest OER activity possessed an overpotential that was 270 mV lower than that of a bulk flat electrode. The porous Pt layers did not exhibit electrocatalytic enhancement for OER in basic media, wherein the surface area of the pores was not utilized for OER. The differentiated OER activity of the porous Pt layers demonstrated the different accessibility of reactants in OER: water and hydrated hydroxide ions. The roles of the pores in the Pt layers during OER were investigated using different Pt structures. The work will give insight into the electrochemistry of microporous electrode structures. PMID- 29133871 TI - Exploration of Antifungal and Immunomodulatory Potentials of a Furanone Derivative to Rescue Disseminated Cryptococosis in Mice. AB - Cryptococcus neoformans infection is quite complex with both host-pathogen interaction and host immune profile determining disease progress and therapeutic outcome. Hence in the present study, the potential utility of (E)-5 benzylidenedihydrofuran-2(3 H)-one (compound-6) was explored as an effective anticryptococcal compound with immunomodulatory potential. The efficacy of compound-6 in pulmonary cryptococosis model using H99 strain was investigated. The effective dose was found to provide 100% survival, with a significant reduction of yeast burden in lungs and brain. The biodistribution analysis provided evidence for the presence of higher concentration of compound-6 in major organs including lungs and brain. In addition, compound-6 treated mice had significantly higher expression of IL-6, IL-4 and IFN-gamma in lung and brain. Similarly, elevated expression of TNF-alpha, IL-beta1 and IL-12 were observed in lungs, suggesting the protective host response against C. neoformans. The reduction and clearance of fungal load in systemic organs and mouse survival are notable results to confirm the ability of compound-6 to treat cryptococcosis. In conclusion, the low molecular weight (174 Da), lipophilicity, its ability to cross blood brain barrier, and facilitating modulation of cytokine expression are the added advantages of compound-6 to combat against disseminated cryptococosis. PMID- 29133872 TI - The core-promoter factor TRF2 mediates a Fruitless action to masculinize neurobehavioral traits in Drosophila. AB - In fruit flies, the male-specific fruitless (fru) gene product FruBM plays a central role in establishing the neural circuitry for male courtship behavior by orchestrating the transcription of genes required for the male-type specification of individual neurons. We herein identify the core promoter recognition factor gene Trf2 as a dominant modifier of fru actions. Trf2 knockdown in the sexually dimorphic mAL neurons leads to the loss of a male-specific neurite and a reduction in male courtship vigor. TRF2 forms a repressor complex with FruBM, strongly enhancing the repressor activity of FruBM at the promoter region of the robo1 gene, whose function is required for inhibiting the male-specific neurite formation. In females that lack FruBM, TRF2 stimulates robo1 transcription. Our results suggest that TRF2 switches its own role from an activator to a repressor of transcription upon binding to FruBM, thereby enabling the ipsilateral neurite formation only in males. PMID- 29133873 TI - Coordinative Alignment of Chiral Molecules to Control over the Chirality Transfer in Spontaneous Resolution and Asymmetric Catalysis. AB - The production and availability of enantiomerically pure compounds that spurred the development of chiral technologies and materials are very important to the fine chemicals and pharmaceutical industries. By coordinative alignment of enantiopure guests in the metal-organic frameworks, we reported an approach to control over the chirality of homochiral crystallization and asymmetric transformation. Synthesized by achiral triphenylamine derivatives, the chirality of silver frameworks was determined by the encapsulated enantiopure azomethine ylides, from which clear interaction patterns were observed to explore the chiral induction principles. With the changing of addition sequence of substrates, the enantioselectivity of asymmetric cycloaddition was controlled to verify the determinant on the chirality of the bulky MOF materials. The economical chirality amplification that merges a series of complicated self-inductions, bulk homochiral crystallization and enantioselective catalysis opens new avenues for enantiopure chemical synthesis and provides a promising path for the directional design and development of homochiral materials. PMID- 29133874 TI - Distinct roles of NMB and GRP in itch transmission. AB - A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord. PMID- 29133875 TI - Heart function and thoracic aorta gene expression profiling studies of ginseng combined with different herbal medicines in eNOS knockout mice. AB - Ginseng, a popular herbal remedy, is often used in combination with other drugs to achieve the maximum therapeutic response. Shenfu (SFI) and Shenmai injection (SMI) have been widely used to treat cardiovascular disease in China. Our study explored the cardiovascular protection of SFI and SMI in eNOS knockout mice to investigate the differences and similarities of the two ginseng-combinations. Transthoracic echocardiography was performed to evaluate the left ventricular structure and function at baseline and 3, 7, and 14 days after drug administration. Agilent Gene Expression microarrays were used to demonstrate the gene expression profiling of the thoracic aorta. Ingenuity Pathway Analysis was performed to evaluate the mechanism improved by SFI and SMI in eNOS knockout mice. Both SFI and SMI could modulate Gadd45 Signaling from TOP15 canonical pathways. Moreover, SFI showed a better effect in the early treatment stage and improved myocardial function via GATA4, GATA6 and COL3A1. Meanwhile, SMI exerted better protective effects at the chronic stage, which may be related to endothelium protection by VEGFA and ACE. The advantage of multi-target by drug combination in progression of complex diseases should be noticed. The appropriate adjustment of drug combination could lead to a better accurate medical care in clinic. PMID- 29133876 TI - Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency. AB - Low rates of arteriovenous fistula (AVF) maturation prevent optimal fistula use for hemodialysis; however, the mechanism of venous remodeling in the fistula environment is not well understood. We hypothesized that the embryonic venous determinant Eph-B4 mediates AVF maturation. In human AVF and a mouse aortocaval fistula model, Eph-B4 protein expression increased in the fistula vein; expression of the arterial determinant Ephrin-B2 also increased. Stimulation of Eph-B-mediated signaling with Ephrin-B2/Fc showed improved fistula patency with less wall thickness. Mutagenesis studies showed that tyrosine-774 is critical for Eph-B4 signaling and administration of inactive Eph-B4-Y774F increased fistula wall thickness. Akt1 expression also increased in AVF; Akt1 knockout mice showed reduced fistula diameter and wall thickness. In Akt1 knockout mice, stimulation of Eph-B signaling with Ephrin-B2/Fc showed no effect on remodeling. These results show that AVF maturation is associated with acquisition of dual arteriovenous identity; increased Eph-B activity improves AVF patency. Inhibition of Akt1 function abolishes Eph-B-mediated venous remodeling suggesting that Eph B4 regulates AVF venous adaptation through an Akt1-mediated mechanism. PMID- 29133877 TI - Planar array with bidirectional elements for tunnel environments. AB - The growing demands for wireless communications in tunnel environments are driven by requests for maintaining uninterrupted internet access for users in tunnels as well as wireless connections for wireless sensors, security, and control networks. Nevertheless, wireless networks in tunnel environments are associated with technical challenges related to elongated wireless coverage in two opposite near-end-fire directions. Here, we introduce a low-profile bidirectional antenna that can be mounted on a large ground plane and that has a dual-magnetic-current mode exhibiting radiation patterns with 3-dB beamwidth coverage at near-end-fire angles. Furthermore, we realized a planar array with eight such bidirectional antennas that were configured as a sparse array in order to reduce the commonplace issues of mutual coupling and grating lobes. The radiation beams of the proposed antenna array can scan in the end-fire area (60 degrees < phi < 120 degrees , 45 degrees < theta < 80 degrees ), with scanning gains of 11~15 dB in the near-end-fire directions. In addition, we demonstrate that the proposed array can adaptively generate a directional single beam or multiple beams according to the positions of users, which is suitable for intelligent communication systems with low power consumptions and high communication bandwidths in tunnel environments. PMID- 29133878 TI - Past emergent phase of Shatsky Rise deep-marine igneous plateau. AB - The Cretaceous Period stands out in Earth's geologic history by ubiquitous and sustained massive eruption of lava, forming several enormous igneous plateaus in the ocean basins worldwide. It has been proposed that the subaerial phases of Cretaceous oceanic plateau formation spurred the global environmental deterioration, yet this view is supported by patchy fossil and/or rock evidence for uplifting of the plateau summits above the sea level. Reported here is by far the most comprehensive case of Cretaceous plateau emergence at northern Shatsky Rise, Northwest Pacific, based on the integration of unique micropalaeontological and seismic evidence. From just above the flat-topped igneous edifice, recent Integrated Ocean Drilling Program (at Site U1346) recovered early Cretaceous (Hauterivian) ostracod and foraminiferal assemblages showing marked shallow marine preferences. Most intriguing discovery is an ostracod taxon with well developed eye tubercles, which serves as compelling palaeobiological evidence for a very shallow, euphotic setting. By linking the nearshore biofacies (<20 m water depth) to the basement topography undoubtedly shaped by subaerial weathering and/or erosion, it is obvious that northern Shatsky Rise was remarkably emergent during its final emplacement phase. We suggest that early Cretaceous surface environments might have been affected, at least in part, by Shatsky Rise subaerial volcanism. PMID- 29133879 TI - Development of a genetic sensor that eliminates p53 deficient cells. AB - The TP53 gene fulfills a central role in protecting cells from genetic insult. Given this crucial role it might be surprising that p53 itself is not essential for cell survival. Indeed, TP53 is the single most mutated gene across different cancer types. Thus, both a theoretical and a question of significant practical applicability arise: can cells be programmed to make TP53 an essential gene? Here we present a genetic p53 sensor, in which the loss of p53 is coupled to the rise of HSV-TK expression. We show that the sensor can distinguish both p53 knockout and cells expressing a common TP53 cancer mutation from otherwise isogenic TP53 wild-type cells. Importantly, the system is sensitive enough to specifically target TP53 loss-of-function cells with the HSV-TK pro-drug Ganciclovir both in vitro and in vivo. Our work opens new ways to programming cell intrinsic transformation protection systems that rely on endogenous components. PMID- 29133880 TI - Dynamic tuning of optical absorbers for accelerated solar-thermal energy storage. AB - Currently, solar-thermal energy storage within phase-change materials relies on adding high thermal-conductivity fillers to improve the thermal-diffusion-based charging rate, which often leads to limited enhancement of charging speed and sacrificed energy storage capacity. Here we report the exploration of a magnetically enhanced photon-transport-based charging approach, which enables the dynamic tuning of the distribution of optical absorbers dispersed within phase change materials, to simultaneously achieve fast charging rates, large phase change enthalpy, and high solar-thermal energy conversion efficiency. Compared with conventional thermal charging, the optical charging strategy improves the charging rate by more than 270% and triples the amount of overall stored thermal energy. This superior performance results from the distinct step-by-step photon transport charging mechanism and the increased latent heat storage through magnetic manipulation of the dynamic distribution of optical absorbers. PMID- 29133881 TI - Author Correction: CLE peptide-encoding gene families in Medicago truncatula and Lotus japonicus, compared with those of soybean, common bean and Arabidopsis. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29133882 TI - Discovery of an expansive bacteriophage family that includes the most abundant viruses from the human gut. AB - Metagenomic sequence analysis is rapidly becoming the primary source of virus discovery 1-3 . A substantial majority of the currently available virus genomes come from metagenomics, and some of these represent extremely abundant viruses, even if never grown in the laboratory. A particularly striking case of a virus discovered via metagenomics is crAssphage, which is by far the most abundant human-associated virus known, comprising up to 90% of sequences in the gut virome 4 . Over 80% of the predicted proteins encoded in the approximately 100 kilobase crAssphage genome showed no significant similarity to available protein sequences, precluding classification of this virus and hampering further study. Here we combine a comprehensive search of genomic and metagenomic databases with sensitive methods for protein sequence analysis to identify an expansive, diverse group of bacteriophages related to crAssphage and predict the functions of the majority of phage proteins, in particular those that comprise the structural, replication and expression modules. Most, if not all, of the crAss-like phages appear to be associated with diverse bacteria from the phylum Bacteroidetes, which includes some of the most abundant bacteria in the human gut microbiome and that are also common in various other habitats. These findings provide for experimental characterization of the most abundant but poorly understood members of the human-associated virome. PMID- 29133883 TI - Pseudomonas aeruginosa defends against phages through type IV pilus glycosylation. AB - Since phages present a major challenge to survival in most environments, bacteria express a battery of anti-phage defences including CRISPR-Cas, restriction modification and abortive infection systems 1-4 . Such strategies are effective, but the phage genome-which encodes potentially inhibitory gene products-is still allowed to enter the cell. The safest way to preclude phage infection is to block initial phage adsorption to the cell. Here, we describe a cell-surface modification that blocks infection by certain phages. Strains of the opportunistic pathogen Pseudomonas aeruginosa express one of five different type IV pilins (T4P) 5 , two of which are glycosylated with O-antigen units 6 or polymers of D-arabinofuranose 7-9 . We propose that predation by bacteriophages that use T4P as receptors selects for strains that mask potential phage binding sites using glycosylation. Here, we show that both modifications protect P. aeruginosa from certain pilus-specific phages. Alterations to pilin sequence can also block phage infection, but glycosylation is considered less likely to create disadvantageous phenotypes. Through construction of chimeric phages, we show that specific phage tail proteins allow for infection of strains with glycosylated pili. These studies provide insight into first-line bacterial defences against predation and ways in which phages circumvent them, and provide a rationale for the prevalence of pilus glycosylation in nature. PMID- 29133884 TI - EphA2 is an epithelial cell pattern recognition receptor for fungal beta-glucans. AB - Oral epithelial cells discriminate between pathogenic and non-pathogenic stimuli, and only induce an inflammatory response when they are exposed to high levels of a potentially harmful microorganism. The pattern recognition receptors (PRRs) in epithelial cells that mediate this differential response are poorly understood. Here, we demonstrate that the ephrin type-A receptor 2 (EphA2) is an oral epithelial cell PRR that binds to exposed beta-glucans on the surface of the fungal pathogen Candida albicans. Binding of C. albicans to EphA2 on oral epithelial cells activates signal transducer and activator of transcription 3 and mitogen-activated protein kinase signalling in an inoculum-dependent manner, and is required for induction of a proinflammatory and antifungal response. EphA2 -/- mice have impaired inflammatory responses and reduced interleukin-17 signalling during oropharyngeal candidiasis, resulting in more severe disease. Our study reveals that EphA2 functions as a PRR for beta-glucans that senses epithelial cell fungal burden and is required for the maximal mucosal inflammatory response to C. albicans. PMID- 29133885 TI - A conserved stem of the Myxococcus xanthus sRNA Pxr controls sRNA accumulation and multicellular development. AB - The small RNA (sRNA) Pxr negatively controls multicellular fruiting body formation in the bacterium Myxococcus xanthus, inhibiting the transition from growth to development when nutrients are abundant. Like many other prokaryotic sRNAs, Pxr is predicted to fold into three stem loops (SL1-SL3). SL1 and SL2 are highly conserved across the myxobacteria, whereas SL3 is much more variable. SL1 is necessary for the regulatory function of Pxr but the importance of SL3 in this regard is unknown. To test for cis genetic elements required for Pxr function, we deleted the entire pxr gene from a developmentally defective strain that fails to remove Pxr-mediated blockage of development and reintroduced variably truncated fragments of the pxr region to test for their ability to block development. These truncations demonstrated that SL3 is necessary for Pxr function in the defective strain. We further show that a highly conserved eight-base-pair segment of SL3 is not only necessary for Pxr to block development in the defective strain under starvation conditions, but is also required for Pxr to prevent fruiting body development by a developmentally proficient wild-type strain under high-nutrient conditions. This conserved segment of SL3 is also necessary for detectable levels of Pxr to accumulate, suggesting that this segment either stabilizes Pxr against premature degradation during vegetative growth or positively regulates its transcription. PMID- 29133886 TI - Disentangling the co-structure of multilayer interaction networks: degree distribution and module composition in two-layer bipartite networks. AB - Species establish different interactions (e.g. antagonistic, mutualistic) with multiple species, forming multilayer ecological networks. Disentangling network co-structure in multilayer networks is crucial to predict how biodiversity loss may affect the persistence of multispecies assemblages. Existing methods to analyse multilayer networks often fail to consider network co-structure. We present a new method to evaluate the modular co-structure of multilayer networks through the assessment of species degree co-distribution and network module composition. We focus on modular structure because of its high prevalence among ecological networks. We apply our method to two Lepidoptera-plant networks, one describing caterpillar-plant herbivory interactions and one representing adult Lepidoptera nectaring on flowers, thereby possibly pollinating them. More than 50% of the species established either herbivory or visitation interactions, but not both. These species were over-represented among plants and lepidopterans, and were present in most modules in both networks. Similarity in module composition between networks was high but not different from random expectations. Our method clearly delineates the importance of interpreting multilayer module composition similarity in the light of the constraints imposed by network structure to predict the potential indirect effects of species loss through interconnected modular networks. PMID- 29133887 TI - A Complementary Scale of Biased Agonism for Agonists with Differing Maximal Responses. AB - Compelling data in the literature from the recent years leave no doubt about the pluridimensional nature of G protein-coupled receptor function and the fact that some ligands can couple with different efficacies to the multiple pathways that a receptor can signal through, a phenomenon most commonly known as functional selectivity or biased agonism. Nowadays, transduction coefficients (log(tau/KA)), based on the Black and Leff operational model of agonism, are widely used to calculate bias. Nevertheless, combining both affinity and efficacy in a single parameter can result in compounds showing a defined calculated bias of one pathway over other though displaying varying experimental bias preferences. In this paper, we present a novel scale (log(tau)), that attempts to give extra substance to different compound profiles in order to better classify compounds and quantify their bias. The efficacy-driven log(tau) scale is not proposed as an alternative to the affinity&efficacy-driven log(tau/KA) scale but as a complement in those situations where partial agonism is present. Both theoretical and practical approaches using MU-opioid receptor agonists are presented. PMID- 29133889 TI - Oral exposure to dibutyl phthalate exacerbates chronic lymphocytic thyroiditis through oxidative stress in female Wistar rats. AB - Chronic lymphocytic thyroiditis (CLT) is a common autoimmune disorder. The possible pathogenic role and mechanism of dibutyl phthalate (DBP) in CLT is still controversial. Experiments were conducted after 35-days of oral exposure to the three concentrations of DBP or saline, and three immunizations with thyroglobulin (TG). Healthy female Wistar rats were randomly divided into ten exposure groups (n = 8 each): (A) saline control, (B) 0.5 mg/kg/d DBP, (C) 5 mg/kg/d DBP, (D) 50 mg/kg/d DBP, (E) TG-immunized group, (F) TG- combined with 0.5 mg/kg/d DBP, (G) TG- combined with 5 mg/kg/d DBP, (H) TG- combined with 50 mg/kg/d DBP, (I) TG- combined with 50 mg/kg/d DBP plus 100 mg/kg/d vitamin C; (J) 100 mg/kg/d vitamin C. We showed that oral exposure DBP can aggravate CLT in rats. This deterioration was concomitant with increased thyroid auto antibodies, Th1/Th2 imbalance and Th17 immune response, activated pro-inflammatory and apoptosis pathways, and increased thyroid dysfunction in rats. Our results also suggested that DBP could promote oxidative damage. The study also found that vitamin C reduced the levels of oxidative stress and alleviated CLT. In short, the study showed that DBP exacerbated CLT through oxidative stress. PMID- 29133888 TI - Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology. AB - The epsilon4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers. PMID- 29133890 TI - Longrange PCR-based next-generation sequencing in pharmacokinetics and pharmacodynamics study of propofol among patients under general anaesthesia. AB - The individual response of patients to propofol results from the influence of genetic factors. However, the state of knowledge in this matter still remains insufficient. The aim of our study was to determine genetic predictors of variable pharmacokinetics and pharmacodynamics of propofol within selected 9 genes coding for propofol biotransformation enzymes, receptors and transporters. Our studies are the first extensive pharmaocgenetics research of propofol using high throughput sequencing technology. After the design and optimization of long range PCR-based next-generation sequencing experiment, we screened promoter and coding sequences of all genes analyzed among 87 Polish patients undergoing general anaesthesia with propofol. Initially we found that two variants, c.516 G > T in the CYP2B6 gene and c.2677 T > G in the ABCB1 gene, significantly correlate with propofol's metabolic profile, however after Bonferroni correction the P-values were not statistically significant. Our results suggest, that variants within the CYP2B6 and ABCB1 genes correlate stronger with propofol's metabolic profile compared to other 7 genes. CYP2B6 and ABCB1 variants can play a potentially important role in response to this anaesthetic and they are promising object for further studies. PMID- 29133891 TI - Decreased oxygen saturation levels in neonates with transposition of great arteries: Impact on appearance of cerebral veins in susceptibility-weighted imaging. AB - Purpose of this study was to investigate a potential correlation between the pattern of cerebral veins (CV) on susceptibility-weighted imaging (SWI) and blood oxygen saturation, as well as preoperative brain injury, in neonates with transposition of the great arteries (TGA). Eleven neonates with TGA underwent MRI preoperatively, including SWI, T1- and T2-weighted scans. Images were retrospectively evaluated and appearance of CV was graded from 0 (normal appearance) to 3 (severe prominent appearance). White matter injuries (WMI) and strokes were analysed. Results were correlated with preductal arterial oxygen saturation. As findings one subject showed a normal CV appearance (grade 0) whereas 10 showed pathological prominent CV (grades 1-3); median 2. Mean oxygen saturation ranged between 67.5% and 89.0% (median 81.0%). CV grade and mean oxygen saturation correlated significantly (p = 0.011). WMI were absent in 5 cases, mild in 4, and moderate in 2 cases. We conclude, that SWI has the potential to be used to estimate the current hypoxic burden on brain tissue in TGA newborns by assessing the prominence of the CV. PMID- 29133893 TI - Two-step process for disassembly mechanism of proteasome alpha7 homo-tetradecamer by alpha6 revealed by high-speed atomic force microscopy. AB - The 20S proteasome is a core particle of the eukaryotic proteasome responsible for proteolysis and is composed of layered alpha and beta hetero-heptameric rings. The alpha7 subunit, which is one of components of the alpha ring, is known to self-assemble into a double-ringed homo-tetradecamer composed of two layers of the alpha7 heptameric ring. The alpha7 tetradecamer is known to disassemble upon the addition of alpha6 subunit, producing a 1:7 hetero-octameric alpha6-alpha7 complex. However, the detailed disassembly mechanism remains unclear. Here, we applied high-speed atomic force microscopy (HS-AFM) to dissect the disassembly process of the alpha7 double ring caused by interaction with the alpha6. HS-AFM movies clearly demonstrated two different modes of interaction in which the alpha6 monomer initially cracks at the interface between the stacked two alpha7 single rings and the subsequent intercalation of the alpha6 monomer in the open pore of the alpha7 single ring blocks the re-association of the single rings into the double ring. This result provides a mechanistic insight about the disassembly process of non-native homo-oligomers formed by proteasome components which is crucial for the initial process for assembly of 20S proteasome. PMID- 29133894 TI - Microalbuminuria as a simple predictor of incident diabetes over 8 years in the Korean Genome and Epidemiology Study (KoGES). AB - Microalbuminuria (MAU) is a common subclinical disease and related with cardiovascular outcome both in diabetic and non-diabetic patients. However, there is rare data about the effect of MAU on the development of diabetes. Thus, we aimed to investigate whether MAU is associated with the development of incident diabetes. A total of 3385 subjects without diabetes (1503 men and 1882 women; mean age, 53 years) who participated in the Ansung-Ansan cohort study from 2001 2002 (baseline) to 2011-2012 (fifth follow-up visit) were followed for a mean of 8 years. The prevalence of MAU at baseline was 10.8% (365 patients), and the incidence of newly developed diabetes during the follow-up period was 15.3% (56 patients) in subjects with MAU. The hazard ratio (HR) for development of diabetes was 1.43 (95% confidence interval (CI) 1.07-1.91, p-value 0.016), independent of traditional risk factors for diabetes including pre-diabetes, age, obesity, and family history. The impact of MAU on diabetes was also significant in the non-pre diabetic population (HR 2.08, 95% CI 1.07-4.03, p-value 0.031). In conclusion, our results show that incident MAU is associated with future development of diabetes and could be an early marker for diabetes, even in the non-prediabetic population. PMID- 29133892 TI - ER-associated degradation regulates Alzheimer's amyloid pathology and memory function by modulating gamma-secretase activity. AB - Endoplasmic-reticulum-associated degradation (ERAD) is an important protein quality control system which maintains protein homeostasis. Constituents of the ERAD complex and its role in neurodegeneration are not yet fully understood. Here, using proteomic and FRET analyses, we demonstrate that the ER protein membralin is an ERAD component, which mediates degradation of ER luminal and membrane substrates. Interestingly, we identify nicastrin, a key component of the gamma-secretase complex, as a membralin binding protein and membralin-associated ERAD substrate. We demonstrate a reduction of membralin mRNA and protein levels in Alzheimer's disease (AD) brain, the latter of which inversely correlates with nicastrin abundance. Furthermore, membralin deficiency enhances gamma-secretase activity and neuronal degeneration. In a mouse AD model, downregulating membralin results in beta-amyloid pathology, neuronal death, and exacerbates synaptic/memory deficits. Our results identify membralin as an ERAD component and demonstrate a critical role for ERAD in AD pathogenesis. PMID- 29133895 TI - The safety and feasibility of laparoscopic common bile duct exploration for treatment patients with previous abdominal surgery. AB - The purpose of this study was to evaluate the safety and feasibility of laparoscopic common bile duct exploration (LCBDE) in patients with previous abdominal surgery (PAS). The outcomes were compared in 139 patients (103 upper and 36 lower abdominal surgeries) with PAS and 361 without PAS who underwent LCBDE. The operative time, hospital stay, rate of open conversion, postoperative complications, duct clearance, and blood loss were compared. Patients with PAS had longer operative times (P = 0.006), higher hospital costs (P = 0.043), and a higher incidence of wound complications (P = 0.011) than those without PAS. However, there were no statistically significant in the open conversion rate, blood loss, hospital stay, bile leakage, biliary strictures, residual stones, and mortality between patients with and without PAS (P > 0.05). Moreover, compared with those without PAS, patients with previous upper abdominal surgery (PUAS) had longer operative times (P = 0.005), higher hospital costs (P = 0.030), and a higher open conversion rate (P = 0.043), but patients with previous lower abdominal surgery (PLAS) had a higher incidence of wound complications (P = 0.022). LCBDE is considered safe and feasible for patients with PAS, including those with PUAS. PMID- 29133896 TI - The food-borne pathogen Campylobacter jejuni responds to the bile salt deoxycholate with countermeasures to reactive oxygen species. AB - Bile plays an important role in digestion, absorption of fats, and the excretion of waste products, while concurrently providing a critical barrier against colonization by harmful bacteria. Previous studies have demonstrated that gut pathogens react to bile by adapting their protein synthesis. The ability of pathogens to respond to bile is remarkably complex and still incompletely understood. Here we show that Campylobacter jejuni, a leading bacterial cause of human diarrheal illness worldwide, responds to deoxycholate, a component of bile, by altering global gene transcription in a manner consistent with a strategy to mitigate exposure to reactive oxygen stress. More specifically, continuous growth of C. jejuni in deoxycholate was found to: 1) induce the production of reactive oxygen species (ROS); 2) decrease succinate dehydrogenase activity (complex II of the electron transport chain); 3) increase catalase activity that is involved in H2O2 breakdown; and 4) result in DNA strand breaks. Congruently, the addition of 4-hydroxy-TEMPO (TEMPOL), a superoxide dismutase mimic that reacts with superoxide, rescued the growth of C. jejuni cultured in the presence of deoxycholate. We postulate that continuous exposure of a number of enteric pathogens to deoxycholate stimulates a conserved survival response to this stressor. PMID- 29133897 TI - WBSCR22 confers oxaliplatin resistance in human colorectal cancer. AB - Human WBSCR22 gene is involved in tumor metastasis, cell growth and invasion, however, its role in chemosensitivity to antitumor agents remains unknown. In this study, we analyzed the TCGA cohort and found the expression of WBSCR22 was significantly elevated in human colorectal cancer (CRC) tissue. WBSCR22 could be served as an independent risk predictor for overall survival (OS), and up regulated WBSCR22 could predict unfavorable OS for CRC patients. Knockdown of WBSCR22 significantly sensitized CRC cells to oxaliplatin in vitro and in vivo, while overexpression of WBSCR22 led to cellular resistance to oxaliplatin treatment. Although WBSCR22 knockdown did not change cell cycle, it increased the oxaliplatin-induced cellular apoptosis. WBSCR22 knockdown augmented the oxaliplatin-induced intracellular reactive oxygen species (ROS) production and ROS-induced 8-oxoguanine (8-oxoG) oxidative lesion accumulation, likely sensitizing oxaliplatin treatment. These results demonstrate that WBSCR22 is involved in CRC resistance to oxaliplatin, suggesting WBSCR22 may represent a novel oxaliplatin resistance biomarker as well as a potentail target for CRC therapeutics. PMID- 29133899 TI - Digitization of museum collections holds the potential to enhance researcher diversity. PMID- 29133898 TI - Intertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy. AB - Nanomedicines that co-deliver DNA, RNA, and peptide therapeutics are highly desirable yet remain underdeveloped for cancer theranostics. Herein, we report self-assembled intertwining DNA-RNA nanocapsules (iDR-NCs) that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as tumor-specific peptide neoantigens into antigen presenting cells (APCs) in lymph nodes for cancer immunotherapy. These nanovaccines were prepared by (1) producing tandem CpG and shRNA via concurrent rolling circle replication and rolling circle transcription, (2) self-assembling CpG and shRNA into DNA-RNA microflowers, (3) shrinking microflowers into iDR-NCs using PEG-grafted cationic polypeptides, and (4) physically loading neoantigen into iDR-NCs. CpG and shRNA in iDR-NCs synergistically activate APCs for sustained antigen presentation. Remarkably, iDR NC/neoantigen nanovaccines elicit 8-fold more frequent neoantigen-specific peripheral CD8+ T cells than CpG, induce T cell memory, and significantly inhibit the progression of neoantigen-specific colorectal tumors. Collectively, iDR-NCs represent potential DNA/RNA/peptide triple-co-delivery nanocarriers and synergistic tumor immunotherapeutic nanovaccines. PMID- 29133900 TI - 100 articles every ecologist should read. AB - Reading scientific articles is a valuable and major part of the activity of scientists. Yet, with the upsurge of currently available articles and the increasing specialization of scientists, it becomes difficult to identify, let alone read, important papers covering topics not directly related to one's own specific field of research, or that are older than a few years. Our objective was to propose a list of seminal papers deemed to be of major importance in ecology, thus providing a general 'must-read' list for any new ecologist, regardless of particular topic or expertise. We generated a list of 544 papers proposed by 147 ecology experts (journal editorial members) and subsequently ranked via random sample voting by 368 of 665 contacted ecology experts, covering 6 article types, 6 approaches and 17 fields. Most of the recommended papers were not published in the highest-ranking journals, nor did they have the highest number of mean annual citations. The articles proposed through the collective recommendation of several hundred experienced researchers probably do not represent an 'ultimate', invariant list, but they certainly contain many high-quality articles that are undoubtedly worth reading-regardless of the specific field of interest in ecology to foster the understanding, knowledge and inspiration of early-career scientists. PMID- 29133901 TI - A mesic maximum in biological water use demarcates biome sensitivity to aridity shifts. AB - Biome function is largely governed by how efficiently available resources can be used and yet for water, the ratio of direct biological resource use (transpiration, E T) to total supply (annual precipitation, P) at ecosystem scales remains poorly characterized. Here, we synthesize field, remote sensing and ecohydrological modelling estimates to show that the biological water use fraction (E T/P) reaches a maximum under mesic conditions; that is, when evaporative demand (potential evapotranspiration, E P) slightly exceeds supplied precipitation. We estimate that this mesic maximum in E T/P occurs at an aridity index (defined as E P/P) between 1.3 and 1.9. The observed global average aridity of 1.8 falls within this range, suggesting that the biosphere is, on average, configured to transpire the largest possible fraction of global precipitation for the current climate. A unimodal E T/P distribution indicates that both dry regions subjected to increasing aridity and humid regions subjected to decreasing aridity will suffer declines in the fraction of precipitation that plants transpire for growth and metabolism. Given the uncertainties in the prediction of future biogeography, this framework provides a clear and concise determination of ecosystems' sensitivity to climatic shifts, as well as expected patterns in the amount of precipitation that ecosystems can effectively use. PMID- 29133902 TI - A test of the hierarchical model of litter decomposition. AB - Our basic understanding of plant litter decomposition informs the assumptions underlying widely applied soil biogeochemical models, including those embedded in Earth system models. Confidence in projected carbon cycle-climate feedbacks therefore depends on accurate knowledge about the controls regulating the rate at which plant biomass is decomposed into products such as CO2. Here we test underlying assumptions of the dominant conceptual model of litter decomposition. The model posits that a primary control on the rate of decomposition at regional to global scales is climate (temperature and moisture), with the controlling effects of decomposers negligible at such broad spatial scales. Using a regional scale litter decomposition experiment at six sites spanning from northern Sweden to southern France-and capturing both within and among site variation in putative controls-we find that contrary to predictions from the hierarchical model, decomposer (microbial) biomass strongly regulates decomposition at regional scales. Furthermore, the size of the microbial biomass dictates the absolute change in decomposition rates with changing climate variables. Our findings suggest the need for revision of the hierarchical model, with decomposers acting as both local- and broad-scale controls on litter decomposition rates, necessitating their explicit consideration in global biogeochemical models. PMID- 29133904 TI - Ripening activator turned repressor. PMID- 29133903 TI - The winter pack-ice zone provides a sheltered but food-poor habitat for larval Antarctic krill. AB - A dominant Antarctic ecological paradigm suggests that winter sea ice is generally the main feeding ground for krill larvae. Observations from our winter cruise to the southwest Atlantic sector of the Southern Ocean contradict this view and present the first evidence that the pack-ice zone is a food-poor habitat for larval development. In contrast, the more open marginal ice zone provides a more favourable food environment for high larval krill growth rates. We found that complex under-ice habitats are, however, vital for larval krill when water column productivity is limited by light, by providing structures that offer protection from predators and to collect organic material released from the ice. The larvae feed on this sparse ice-associated food during the day. After sunset, they migrate into the water below the ice (upper 20 m) and drift away from the ice areas where they have previously fed. Model analyses indicate that this behaviour increases both food uptake in a patchy food environment and the likelihood of overwinter transport to areas where feeding conditions are more favourable in spring. PMID- 29133905 TI - Deglacial Tropical Atlantic subsurface warming links ocean circulation variability to the West African Monsoon. AB - Multiple lines of evidence show that cold stadials in the North Atlantic were accompanied by both reductions in Atlantic Meridional Overturning Circulation (AMOC) and collapses of the West African Monsoon (WAM). Although records of terrestrial change identify abrupt WAM variability across the deglaciation, few studies show how ocean temperatures evolved across the deglaciation. To identify the mechanism linking AMOC to the WAM, we generated a new record of subsurface temperature variability over the last 21 kyr based on Mg/Ca ratios in a sub thermocline dwelling planktonic foraminifera in an Eastern Equatorial Atlantic (EEA) sediment core from the Niger Delta. Our subsurface temperature record shows abrupt subsurface warming during both the Younger Dryas (YD) and Heinrich Event 1. We also conducted a new transient coupled ocean-atmosphere model simulation across the YD that better resolves the western boundary current dynamics and find a strong negative correlation between AMOC strength and EEA subsurface temperatures caused by changes in ocean circulation and rainfall responses that are consistent with the observed WAM change. Our combined proxy and modeling results provide the first evidence that an oceanic teleconnection between AMOC strength and subsurface temperature in the EEA impacted the intensity of the WAM on millennial time scales. PMID- 29133906 TI - Quantification of flexoelectricity in PbTiO3/SrTiO3 superlattice polar vortices using machine learning and phase-field modeling. AB - Flexoelectricity refers to electric polarization generated by heterogeneous mechanical strains, namely strain gradients, in materials of arbitrary crystal symmetries. Despite more than 50 years of work on this effect, an accurate identification of its coupling strength remains an experimental challenge for most materials, which impedes its wide recognition. Here, we show the presence of flexoelectricity in the recently discovered polar vortices in PbTiO3/SrTiO3 superlattices based on a combination of machine-learning analysis of the atomic scale electron microscopy imaging data and phenomenological phase-field modeling. By scrutinizing the influence of flexocoupling on the global vortex structure, we match theory and experiment using computer vision methodologies to determine the flexoelectric coefficients for PbTiO3 and SrTiO3. Our findings highlight the inherent, nontrivial role of flexoelectricity in the generation of emergent complex polarization morphologies and demonstrate a viable approach to delineating this effect, conducive to the deeper exploration of both topics. PMID- 29133907 TI - A primacy code for odor identity. AB - Humans can identify visual objects independently of view angle and lighting, words independently of volume and pitch, and smells independently of concentration. The computational principles underlying invariant object recognition remain mostly unknown. Here we propose that, in olfaction, a small and relatively stable set comprised of the earliest activated receptors forms a code for concentration-invariant odor identity. One prediction of this "primacy coding" scheme is that decisions based on odor identity can be made solely using early odor-evoked neural activity. Using an optogenetic masking paradigm, we define the sensory integration time necessary for odor identification and demonstrate that animals can use information occurring <100 ms after inhalation onset to identify odors. Using multi-electrode array recordings of odor responses in the olfactory bulb, we find that concentration-invariant units respond earliest and at latencies that are within this behaviorally-defined time window. We propose a computational model demonstrating how such a code can be read by neural circuits of the olfactory system. PMID- 29133908 TI - Optically-controlled long-term storage and release of thermal energy in phase change materials. AB - Thermal energy storage offers enormous potential for a wide range of energy technologies. Phase-change materials offer state-of-the-art thermal storage due to high latent heat. However, spontaneous heat loss from thermally charged phase change materials to cooler surroundings occurs due to the absence of a significant energy barrier for the liquid-solid transition. This prevents control over the thermal storage, and developing effective methods to address this problem has remained an elusive goal. Herein, we report a combination of photo switching dopants and organic phase-change materials as a way to introduce an activation energy barrier for phase-change materials solidification and to conserve thermal energy in the materials, allowing them to be triggered optically to release their stored latent heat. This approach enables the retention of thermal energy (about 200 J g-1) in the materials for at least 10 h at temperatures lower than the original crystallization point, unlocking opportunities for portable thermal energy storage systems. PMID- 29133909 TI - Tactile Frequency-Specific High-Gamma Activities in Human Primary and Secondary Somatosensory Cortices. AB - Humans can easily detect vibrotactile stimuli up to several hundred hertz, but underlying large-scale neuronal processing mechanisms in the cortex are largely unknown. Here, we investigated the macroscopic neural correlates of various vibrotactile stimuli including artificial and naturalistic ones in human primary and secondary somatosensory cortices (S1 and S2, respectively) using electrocorticography (ECoG). We found that tactile frequency-specific high-gamma (HG, 50-140 Hz) activities are seen in both S1 and S2 with different temporal dynamics during vibration (>100 Hz). Stimulus-evoked S1 HG power, which exhibited short-delayed peaks (50-100 ms), was attenuated more quickly in vibration than in flutter (<50 Hz), and their attenuation patterns were frequency-specific within vibration range. In contrast, S2 HG power, which was activated much later than that of S1 (150-250 ms), strikingly increased with increasing stimulus frequencies in vibration range, and their changes were much greater than those in S1. Furthermore, these S1-S2 HG patterns were preserved in naturalistic stimuli such as coarse/fine textures. Our results provide persuasive evidence that S2 is critically involved in neural processing for high-frequency vibrotaction. Therefore, we propose that S1-S2 neuronal co-operation is crucial for full-range, complex vibrotactile perception in human. PMID- 29133910 TI - Time-resolved diffraction of shock-released SiO2 and diaplectic glass formation. AB - Understanding how rock-forming minerals transform under shock loading is critical for modeling collisions between planetary bodies, interpreting the significance of shock features in minerals and for using them as diagnostic indicators of impact conditions, such as shock pressure. To date, our understanding of the formation processes experienced by shocked materials is based exclusively on ex situ analyses of recovered samples. Formation mechanisms and origins of commonly observed mesoscale material features, such as diaplectic (i.e., shocked) glass, remain therefore controversial and unresolvable. Here we show in situ pump-probe X-ray diffraction measurements on fused silica crystallizing to stishovite on shock compression and then converting to an amorphous phase on shock release in only 2.4 ns from 33.6 GPa. Recovered glass fragments suggest permanent densification. These observations of real-time diaplectic glass formation attest that it is a back-transformation product of stishovite with implications for revising traditional shock metamorphism stages. PMID- 29133911 TI - Species pool distributions along functional trade-offs shape plant productivity diversity relationships. AB - Grasslands deliver the resources for food production and are among the most biologically diverse ecosystems. These characteristics are often in conflict as increasing yield through fertilization can lead to biodiversity loss. Thus, the challenge in grassland management is to sustain both yield and diversity. Biodiversity-ecosystem functioning experiments typically reveal a positive relationship between manipulated species diversity and productivity. In contrast, observations of the effect of increasing productivity via fertilization suggest a negative association with biodiversity. Using a mathematical model simulating species co-existence along a resource gradient, we show that trade-offs and species pool structure (size and trait distribution) determines the shape of the productivity-diversity relationship. At a constant resource level, over-yielding drives a positive relationship between biodiversity and productivity. In contrast, along a resource gradient, the shape of the productivity-diversity relationship is determined by the distribution of species along trade-off axes and often resulted in a bell-shaped relationship. In accordance to this theoretical result, we then explain the general trend of plant biodiversity loss with fertilisation in the European flora, by showing empirical evidence that trait distribution of plant species pools throughout Europe is biased toward species preferring poorer soils. PMID- 29133912 TI - The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity. AB - The multiple antibiotic resistance (mar) operon of Escherichia coli is a paradigm for chromosomally encoded antibiotic resistance in enteric bacteria. The locus is recognised for its ability to modulate efflux pump and porin expression via two encoded transcription factors, MarR and MarA. Here we map binding of these regulators across the E. coli genome and identify an extensive mar regulon. Most notably, MarA activates expression of genes required for DNA repair and lipid trafficking. Consequently, the mar locus reduces quinolone-induced DNA damage and the ability of tetracyclines to traverse the outer membrane. These previously unrecognised mar pathways reside within a core regulon, shared by most enteric bacteria. Hence, we provide a framework for understanding multidrug resistance, mediated by analogous systems, across the Enterobacteriaceae. Transcription factors MarR and MarA confer multidrug resistance in enteric bacteria by modulating efflux pump and porin expression. Here, Sharma et al. show that MarA also upregulates genes required for lipid trafficking and DNA repair, thus reducing antibiotic entry and quinolone-induced DNA damage. PMID- 29133913 TI - Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration. AB - Myeloid derived suppressor cells (MDSC) produce nitric oxide (NO) and inhibit dendritic cell (DC) immune responses in cancer. DCs present cancer cell antigens to CD4+ T cells through Jak-STAT signal transduction. In this study, NO donors (SNAP and DETA-NONOate) inhibited DC antigen presentation. As expected, MDSC isolated from peripheral blood mononuclear cells (PBMC) from cancer patients produced high NO levels. We hypothesized that NO producing MDSC in tumor-bearing hosts would inhibit DC antigen presentation. Antigen presentation from DCs to CD4+ T cells (T cell receptor transgenic OT-II) was measured via a [3H]-thymidine incorporation proliferation assay. MDSC from melanoma tumor models decreased the levels of proliferation more than pancreatic cancer derived MDSC. T cell proliferation was restored when MDSC were treated with inhibitors of inducible nitric oxide synthase (L-NAME and NCX-4016). A NO donor inhibited OT II T cell receptor recognition of OT II specific tetramers, thus serving as a direct measure of NO inhibition of antigen presentation. Our group has previously demonstrated that STAT1 nitration also mediates MDSC inhibitory effects on immune cells. Therefore, a novel liquid chromatography-tandem mass spectrometry assay demonstrated that nitration of the STAT1-Tyr701 occurs in PBMC derived from both pancreatic cancer and melanoma patients. PMID- 29133914 TI - Carbon nanotubes as excitonic insulators. AB - Fifty years ago Walter Kohn speculated that a zero-gap semiconductor might be unstable against the spontaneous generation of excitons-electron-hole pairs bound together by Coulomb attraction. The reconstructed ground state would then open a gap breaking the symmetry of the underlying lattice, a genuine consequence of electronic correlations. Here we show that this excitonic insulator is realized in zero-gap carbon nanotubes by performing first-principles calculations through many-body perturbation theory as well as quantum Monte Carlo. The excitonic order modulates the charge between the two carbon sublattices opening an experimentally observable gap, which scales as the inverse of the tube radius and weakly depends on the axial magnetic field. Our findings call into question the Luttinger liquid paradigm for nanotubes and provide tests to experimentally discriminate between excitonic and Mott insulators. PMID- 29133915 TI - Impact of spatial characteristics in the left stenotic coronary artery on the hemodynamics and visualization of 3D replica models. AB - Cardiovascular disease has been the major cause of death worldwide. Although the initiation and progression mechanism of the atherosclerosis are similar, the stenotic characteristics and the corresponding medical decisions are different between individuals. In the present study, we performed anatomic and hemodynamic analysis on 8 left coronary arterial trees with 10 identified stenoses. A novel boundary condition method had been implemented for fast computational fluid dynamics simulations and patient-specific three-dimensional printed models had been built for visualizations. Our results suggested that the multiple spatial characteristics (curvature of the culprit vessel multiplied by an angle of the culprit's vessel to the upstream parent branch) could be an index of hemodynamics significance (r = -0.673, P-value = 0.033). and reduction of the maximum velocity from stenosis to downstream was found correlated to the FFRCT (r = 0.480, p = 0.160). In addition, 3D printed models could provide accurate replicas of the patient-specific left coronary arterial trees compare to virtual 3D models (r = 0.987, P-value < 0.001). Therefore, the visualization of the 3D printed models could help understand the spatial distribution of the stenoses and the hand-held experience could potentially benefit the educating and preparing of medical strategies. PMID- 29133917 TI - Validation of Self-reported Smoking with Urinary Cotinine Levels and Influence of Second-hand Smoke among Conscripts. AB - Accurate identification of smoking behaviour is crucial to monitor the smoking rate. This study used urinary cotinine (UC) as a biomarker to verify the effectiveness of self-reported smoking behaviour among conscripts during recruit training. The influence of second-hand smoke (SHS) on the UC concentration was also analysed. A cross-sectional study was conducted from July 2014 to December 2014. The participants comprised a total of 621 military service and basic military training conscripts. A self-administered questionnaire survey and a urine test were performed to verify the participants' smoking behaviour. The UC concentration of 100 ng/mL was adopted as the baseline to identify smokers. A high level of consistency was observed between the conscripts' self-reported results and the results validated by the UC concentrations (the overall kappa coefficient was 0.918). Moreover, the overall sensitivity and specificity were 92.9% and 98.1%, respectively. The sensitivity for the military service conscripts was significantly lower than that for the basic military training conscripts (86.1% vs. 97.5%, P-value = 0.002). For the self-reported nonsmokers among the military service conscripts, SHS exposure was related to their UC concentrations. The method of self-reporting through a questionnaire survey can serve as a tool to assess conscripts' smoking behaviour. PMID- 29133916 TI - BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability. AB - BRCA2-deficient cells exhibit gross genomic instability, but the underlying mechanisms are not fully understood. Here we report that inactivation of BRCA2 but not RAD51 destabilizes RPA-coated single-stranded DNA (ssDNA) structures at resected DNA double-strand breaks (DSBs) and greatly enhances the frequency of nuclear fragmentation following cell exposure to DNA damage. Importantly, these BRCA2-associated deficits are fueled by the aberrant activation of classical (c)- and alternative (alt)- nonhomologous end-joining (NHEJ), and rely on the well defined DNA damage signaling pathway involving the pro-c-NHEJ factor 53BP1 and its downstream effector RIF1. We further show that the 53BP1-RIF1 axis promotes toxic end-joining events via the retention of Artemis at DNA damage sites. Accordingly, loss of 53BP1, RIF1, or Artemis prolongs the stability of RPA-coated DSB intermediates in BRCA2-deficient cells and restores nuclear integrity. We propose that BRCA2 antagonizes 53BP1, RIF1, and Artemis-dependent c-NHEJ and alt NHEJ to prevent gross genomic instability in a RAD51-independent manner. PMID- 29133918 TI - Fast simultaneous assessment of renal and liver function using polymethine dyes in animal models of chronic and acute organ injury. AB - Simultaneous assessment of excretory liver and kidney function is still an unmet need in experimental stress models as well as in critical care. The aim of the study was to characterize two polymethine-dyes potentially suitable for this purpose in vivo. Plasma disappearance rate and elimination measurements of simultaneously injected fluorescent dyes DY-780 (hepato-biliary elimination) and DY-654(renal elimination) were conducted using catheter techniques and intravital microscopy in animals subjected to different organ injuries, i.e. polymicrobial sepsis by peritoneal contamination and infection, ischemia-reperfusion-injury and glycerol-induced acute kidney-injury. DY-780 and DY-654 showed organ specific and determined elimination routes in both healthy and diseased animals. They can be measured simultaneously using near-infrared imaging and spectrophotometry. Plasma disappearance rates of DY-780 and DY-654 are superior to conventional biomarkers in indicating hepatic or kidney dysfunction in different animal models. Greatest impact on liver function was found in animals with polymicrobial sepsis whereas glomerular damage due to glycerol-induced kidney-injury had strongest impact on DY-654 elimination. We therefore conclude that hepatic elimination and renal filtration can be assessed in rodents measuring plasma-disappearance rates of both dyes. Further, assessment of organ dysfunction by polymethine dyes correlates with, but outperforms conventional biomarkers regarding sensitivity and the option of spatial resolution if biophotonic strategies are applied. Polymethine-dye clearance thereby allows sensitive point-of-care assessment of both organ functions simultaneously. PMID- 29133919 TI - Integrating SANS and fluid-invasion methods to characterize pore structure of typical American shale oil reservoirs. AB - An integration of small-angle neutron scattering (SANS), low-pressure N2 physisorption (LPNP), and mercury injection capillary pressure (MICP) methods was employed to study the pore structure of four oil shale samples from leading Niobrara, Wolfcamp, Bakken, and Utica Formations in USA. Porosity values obtained from SANS are higher than those from two fluid-invasion methods, due to the ability of neutrons to probe pore spaces inaccessible to N2 and mercury. However, SANS and LPNP methods exhibit a similar pore-size distribution, and both methods (in measuring total pore volume) show different results of porosity and pore-size distribution obtained from the MICP method (quantifying pore throats). Multi scale (five pore-diameter intervals) inaccessible porosity to N2 was determined using SANS and LPNP data. Overall, a large value of inaccessible porosity occurs at pore diameters <10 nm, which we attribute to low connectivity of organic matter-hosted and clay-associated pores in these shales. While each method probes a unique aspect of complex pore structure of shale, the discrepancy between pore structure results from different methods is explained with respect to their difference in measurable ranges of pore diameter, pore space, pore type, sample size and associated pore connectivity, as well as theoretical base and interpretation. PMID- 29133920 TI - Energy neutral: the human foot and ankle subsections combine to produce near zero net mechanical work during walking. AB - The human foot and ankle system is equipped with structures that can produce mechanical work through elastic (e.g., Achilles tendon, plantar fascia) or viscoelastic (e.g., heel pad) mechanisms, or by active muscle contractions. Yet, quantifying the work distribution among various subsections of the foot and ankle can be difficult, in large part due to a lack of objective methods for partitioning the forces acting underneath the stance foot. In this study, we deconstructed the mechanical work production during barefoot walking in a segment by-segment manner (hallux, forefoot, hindfoot, and shank). This was accomplished by isolating the forces acting within each foot segment through controlling the placement of the participants' foot as it contacted a ground-mounted force platform. Combined with an analysis that incorporated non-rigid mechanics, we quantified the total work production distal to each of the four isolated segments. We found that various subsections within the foot and ankle showed disparate work distribution, particularly within structures distal to the hindfoot. When accounting for all sources of positive and negative work distal to the shank (i.e., ankle joint and all foot structures), these structures resembled an energy-neutral system that produced net mechanical work close to zero (-0.012 +/- 0.054 J/kg). PMID- 29133921 TI - Metabolomics identifies metabolite biomarkers associated with acute rejection after heart transplantation in rats. AB - The aim of this study was to identify metabolite biomarkers associated with acute rejection after heart transplantation in rats using a LC-MS-based metabolomics approach. A model of heterotopic cardiac xenotransplantation was established in rats, with Wistar rats as donors and SD rats as recipients. Blood and cardiac samples were collected from blank control rats (Group A), rats 5 (Group B) and 7 days (Group C) after heart transplantation, and pretreated rats 5 (Group D) and 7 days (Group E) post-transplantation for pathological and metabolomics analyses. We assessed International Society for Heart and Lung Transplantation (ISHLT) grades 0, 3B, 4, 1 and 1 rejection in groups A to E. There were 15 differential metabolites between groups A and B, 14 differential metabolites between groups A and C, and 10 differential metabolites between groups B and C. In addition, four common differential metabolites, including D-tagatose, choline, C16 sphinganine and D-glutamine, were identified between on days 5 and 7 post-transplantation. Our findings demonstrate that the panel of D-tagatose, choline, C16 sphinganine and D-glutamine exhibits a high sensitivity and specificity for the early diagnosis of acute rejection after heart transplantation, and LC-MS-based metabolomics approach has a potential value for screening post-transplantation biomarkers. PMID- 29133922 TI - Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress. AB - Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3Y705 contributes to its nucleic translocation, while phospho-Stat3S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well characterized signaling pathways interplaying with Stat3Y705, little is known about Stat3S727. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3Y705F, but not Stat3S727D, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38MAPK was involved and adding antioxidants, p38MAPK inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38MAPK-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy. PMID- 29133923 TI - Alignment of Multiple Electrospun Piezoelectric Fiber Bundles Across Serrated Gaps at an Incline: A Method to Generate Textile Strain Sensors. AB - In this paper, we report a new type of electrospinning collector that allows simultaneous collection and alignment of multiple poly(vinylidene fluoride trifluoroethylene) piezoelectric fiber bundles with a controlled separation. The key enabling feature is the serrated teeth along the edges across an inclined gap as a part of the conductive collector. As a result, the electrical field across the gap is shaped to direct the electrospun fibers to merge into multiple bundles. The sharp points on the serrated teeth provide favorable charge dissipation points and thus fibers are preferentially formed bridging two closest sharp points across the gap. To investigate the effectiveness of serrated teeth on the formation of multiple fiber bundles, three-dimensional finite element simulations are conducted. The corresponding collectors are implemented to experimentally study the resulting electrospun fibers. Both simulation and experimental results suggest that multiple fiber bundles can be formed under the condition of a low teeth pitch to gap distance ratio. Furthermore, a sharper tooth angle results in a higher preferential formation of fiber bundles. Finally, the total electrospinning time should be less than 60 seconds to maintain favorable electric field profile. We also demonstrate that these piezoelectric fiber bundles can serve as ultra-flexible textile sensors. PMID- 29133924 TI - Bio-detoxification of ricin in castor bean (Ricinus communis L.) seeds. AB - Ricin is a highly toxic ribosome-inactivating lectin occurring in the seeds of castor bean (Ricinus communis L.). Castor bean grows throughout tropical and sub tropical regions and is a very important crop due to its high seed content of ricinoleic acid, an unusual fatty acid, which has several industrial applications. However, due to the presence of the toxin, castor bean can cause death after the exposure of animals to low doses of ricin through skin contact, injection, inhalation or oral routes. Aiming to generate a detoxified genotype, we explored the RNAi concept in order to silence the ricin coding genes in the endosperm of castor bean seeds. Results indicated that ricin genes were effectively silenced in genetically modified (GM) plants, and ricin proteins were not detected by ELISA. Hemagglutination activity was not observed with proteins isolated from GM seeds. In addition, we demonstrated that seed proteins from GM plants were not toxic to rat intestine epithelial cells or to Swiss Webster mice. After oil extraction, bio-detoxified castor bean cake, which is very rich in valuable proteins, can be used for animal feeding. Gene silencing would make castor bean cultivation safer for farmers, industrial workers and society. PMID- 29133925 TI - Absorption and Extinction Cross Sections and Photon Streamlines in the Optical Near-field. AB - The optical interaction of light and matter is modeled as an oscillating dipole in a plane wave electromagnetic field. We analyze absorption, scattering and extinction for this system by the energy flow, visualized as streamlines of the Poynting vector. Depending on the dissipative damping of the oscillator, a part of the streamlines ends up in the dipole. Based on a graphical investigation of the streamlines, this represents the absorption cross section, and forms a far field absorption aperture. In the near-field of the oscillator, a modification of the aperture is observed. As in the case for a linear dipole, we model the energy flow and derive the effective absorption apertures for an oscillator with a circular dipole characteristics - such as an atom in free space. PMID- 29133926 TI - Genetic programs can be compressed and autonomously decompressed in live cells. AB - Fundamental computer science concepts have inspired novel information-processing molecular systems in test tubes 1-13 and genetically encoded circuits in live cells 14-21 . Recent research has shown that digital information storage in DNA, implemented using deep sequencing and conventional software, can approach the maximum Shannon information capacity 22 of two bits per nucleotide 23 . In nature, DNA is used to store genetic programs, but the information content of the encoding rarely approaches this maximum 24 . We hypothesize that the biological function of a genetic program can be preserved while reducing the length of its DNA encoding and increasing the information content per nucleotide. Here we support this hypothesis by describing an experimental procedure for compressing a genetic program and its subsequent autonomous decompression and execution in human cells. As a test-bed we choose an RNAi cell classifier circuit 25 that comprises redundant DNA sequences and is therefore amenable for compression, as are many other complex gene circuits 15,18,26-28 . In one example, we implement a compressed encoding of a ten-gene four-input AND gate circuit using only four genetic constructs. The compression principles applied to gene circuits can enable fitting complex genetic programs into DNA delivery vehicles with limited cargo capacity, and storing compressed and biologically inert programs in vivo for on-demand activation. PMID- 29133928 TI - The role of the cytoskeleton in biomineralisation in haptophyte algae. AB - The production of calcium carbonate by coccolithophores (haptophytes) contributes significantly to global biogeochemical cycling. The recent identification of a silicifying haptophyte, Prymnesium neolepis, has provided new insight into the evolution of biomineralisation in this lineage. However, the cellular mechanisms of biomineralisation in both calcifying and silicifying haptophytes remain poorly understood. To look for commonalities between these two biomineralisation systems in haptophytes, we have determined the role of actin and tubulin in the formation of intracellular biomineralised scales in the coccolithophore, Coccolithus braarudii and in P. neolepis. We find that disruption of the actin network interferes with secretion of the biomineralised elements in both C. braarudii and P. neolepis. In contrast, disruption of the microtubule network does not prevent secretion of the silica scales in P. neolepis but results in production of abnormally small silica scales and also results in the increased formation of malformed coccoliths in C. braarudii. We conclude that the cytoskeleton plays a crucial role in biomineralisation in both silicifying and calcifying haptophytes. There are some important similarities in the contribution of the cytoskeleton to these different forms of biomineralisation, suggesting that common cellular mechanisms may have been recruited to perform similar roles in both lineages. PMID- 29133927 TI - Random protein sequences can form defined secondary structures and are well tolerated in vivo. AB - The protein sequences found in nature represent a tiny fraction of the potential sequences that could be constructed from the 20-amino-acid alphabet. To help define the properties that shaped proteins to stand out from the space of possible alternatives, we conducted a systematic computational and experimental exploration of random (unevolved) sequences in comparison with biological proteins. In our study, combinations of secondary structure, disorder, and aggregation predictions are accompanied by experimental characterization of selected proteins. We found that the overall secondary structure and physicochemical properties of random and biological sequences are very similar. Moreover, random sequences can be well-tolerated by living cells. Contrary to early hypotheses about the toxicity of random and disordered proteins, we found that random sequences with high disorder have low aggregation propensity (unlike random sequences with high structural content) and were particularly well tolerated. This direct structure content/aggregation propensity dependence differentiates random and biological proteins. Our study indicates that while random sequences can be both structured and disordered, the properties of the latter make them better suited as progenitors (in both in vivo and in vitro settings) for further evolution of complex, soluble, three-dimensional scaffolds that can perform specific biochemical tasks. PMID- 29133929 TI - A necessary criterion for obtaining accurate lattice parameters by Rietveld method. AB - To obtain the lattice parameters accurately by the Rietveld method, the relationship between the lattice parameters and the peak-shift, which is the deviation in diffraction angle from the theoretical Bragg position, was studied. We show that the fitting accuracy of lattice parameters is related directly to the well reproducibility of the peak-shift. This study unveils that the peak shift consists of the experimental and the analytical ones. The analytical peak shift erroneously lowers a reliability factor R wp, which has, so far, been the conventional criterion of fit. The conventional Rietveld method obtains a unit cell which is a homothetic (proportional) unit-cell of the true one. We propose an additional criterion based on the peak-shift to obtain the true lattice parameters accurately. Our criterion can achieve reproducibility reasonably well for the experimental peak-shift, leading to highly improved accuracy of the lattice parameters. PMID- 29133931 TI - Design of dual-band cold mirrors. AB - Dual-band cold mirrors are designed based on third-order of 121.6 nm multilayers, and they are only composed of LaF3 and MgF2. The designed mirrors have a high reflectance at 121.6 nm and 280 nm, and a low reflectance in visible waveband; they also have a narrow bandwidth of 4 nm at 121.6 nm, and low sidelobe ripples of two stopbands. A broadband antireflection coating and an asymmetrically Gaussian-apodization of thickness-modulated design method are proposed to eliminate sidelobe ripples of the reflection zone. PMID- 29133930 TI - PLCgamma-dependent mTOR signalling controls IL-7-mediated early B cell development. AB - The precise molecular mechanism underlying the regulation of early B cell lymphopoiesis is unclear. The PLCgamma signaling pathway is critical for antigen receptor-mediated lymphocyte activation, but its function in cytokine signaling is unknown. Here we show that PLCgamma1/PLCgamma2 double deficiency in mice blocks early B cell development at the pre-pro-B cell stage and renders B cell progenitors unresponsive to IL-7. PLCgamma pathway inhibition blocks IL-7-induced activation of mTOR, but not Stat5. The PLCgamma pathway activates mTOR through the DAG/PKC signaling branch, independent of the conventional Akt/TSC/Rheb signaling axis. Inhibition of PLCgamma/PKC-induced mTOR activation impairs IL-7 mediated B cell development. PLCgamma1/PLCgamma2 double-deficient B cell progenitors have reduced expression of genes related to B cell lineage, IL-7 signaling, and cell cycle. Thus, IL-7 receptor controls early B lymphopoiesis through activation of mTOR via PLCgamma/DAG/PKC signaling, not via Akt/Rheb signaling. PMID- 29133932 TI - Post-earthquake Zika virus surge: Disaster and public health threat amid climatic conduciveness. AB - A recent major earthquake (M7.8), coupled with appropriate climatic conditions, led to significant destruction in Ecuador. Temperature variations, which may be induced by anthropogenic climate change, are often associated with changes in rainfall, humidity and pressure. Temperature and humidity are associated with ecological modifications that may favour mosquito breeding. We hypothesized that the disruptive ecological changes triggered by the earthquake, in the context of appropriate climatic conditions, led to an upsurge in Zika virus (ZIKV) infections. Here we show that, after controlling for climatic and socioeconomic conditions, earthquake severity was associated with incident ZIKV cases. Pre earthquake mean maximum monthly temperature and post-earthquake mean monthly pressure were negatively associated with ZIKV incidence rates. These results demonstrate the dynamics of post-disaster vector-borne disease transmission, in the context of conducive/favourable climatic conditions, which are relevant in a climate change-affected world where disasters may occur in largely populated areas. PMID- 29133933 TI - Photoacoustic and modulated reflectance studies of indirect and direct band gap in van der Waals crystals. AB - Photoacoustic (PA) and modulated reflectance (MR) spectroscopy have been applied to study the indirect and direct band gap for van der Waals (vdW) crystals: dichalcogenides (MoS2, MoSe2, MoTe2, HfS2, HfSe2, WS2, WSe2, ReS2, ReSe2, SnS2 and SnSe2) and monochalcogenides (GaS, GaSe, InSe, GeS, and GeSe). It is shown that the indirect band gap can be determined by PA technique while the direct band gap can be probed by MR spectroscopy which is not sensitive to indirect optical transitions. By measuring PA and MR spectra for a given compound and comparing them with each other it is easy to conclude about the band gap character in the investigated compound and the energy difference between indirect and direct band gap. In this work such measurements, comparisons, and analyses have been performed and chemical trends in variation of indirect and direct band gap with the change in atom sizes have been discussed for proper sets of vdW crystals. It is shown that both indirect and direct band gap in vdW crystals follow the well-known chemical trends in semiconductor compounds. PMID- 29133934 TI - Prostate cancer: Conserved lipid synthesis drives castration resistance. PMID- 29133935 TI - Sacral neuromodulation and alterations in brain activity - discussing discrepancies. PMID- 29133937 TI - Stones: Predicting stone episodes using cystine capacity. PMID- 29133938 TI - Prostate cancer: Response prediction with HSD3B1. PMID- 29133936 TI - The Rho GTPase signalling pathway in urothelial carcinoma. AB - Urothelial carcinoma remains a clinical challenge: non-muscle-invasive disease has a high rate of recurrence and risk of progression, and outcomes for patients with advanced disease are poor, owing to a lack of effective systemic therapies. The Rho GTPase family of enzymes was first identified >30 years ago and contains >20 members, which are divided into eight subfamilies: Cdc42, Rac, Rho, RhoUV, RhoBTB, RhoDF, RhoH, and Rnd. Rho GTPases are molecular on-off switches, which are increasingly being understood to have a critical role in a number of cellular processes, including cell migration, cell polarity, cell adhesion, cell cycle progression, and regulation of the cytoskeleton. This switch is an evolutionarily conserved system in which GTPases alternate between GDP-bound (inactive) and GTP bound (active) forms. The activities of these Rho GTPases are many, context dependent, and regulated by a number of proteins that are being progressively elucidated. Aberrations of the Rho GTPase signalling pathways have been implicated in various malignancies, including urothelial carcinoma, and understanding of the role of Rho GTPases in these diseases is increasing. This signalling pathway has the potential for therapeutic targeting in urothelial carcinoma. Research in this area is nascent, and much work is necessary before current laboratory-based research can be translated into the clinic. PMID- 29133941 TI - Bladder cancer: Context is key: dual roles of ANGPTL4. PMID- 29133939 TI - Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy. AB - Effective management of advanced urothelial bladder cancer is challenging. New discoveries that improve our understanding of molecular bladder cancer subtypes have revealed numerous potentially targetable genomic alterations and demonstrated the efficacy of treatments that harness the immune system. These findings have begun to change paradigms of bladder cancer therapy. For example, DNA repair pathway mutations in genes such as ERCC2, FANCC, ATM, RB1, and others can predict responses to neoadjuvant platinum-based chemotherapies and to targeted therapies on the basis of mutation status. Furthermore, an increasing number of pan-cancer clinical trials (commonly referred to as basket or umbrella trials) are enrolling patients on the basis of molecular and genetic predictors of response. These studies promise to provide improved insight into the true utility of personalized medicine in the treatment of bladder cancer and many other cancer types. Finally, therapies that modulate immune responses have shown great benefit in many cancer types. Several immune checkpoint inhibitors that target programmed cell death protein 1 (PD1), its ligand PDL1, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have already been approved for use in bladder cancer, representing the most important change to the urological oncologist's tool-kit in over a decade. These advances also provide opportunities for personalization of bladder cancer therapy. PMID- 29133942 TI - Canine Parvovirus ns1 gene and Chicken Anemia vp3 gene induce partial oncolysis of Canine Transmissible Venereal Tumor. AB - The oncolytic effect of Canine Parvovirus ns1 gene and Chicken Anemia vp3 gene in naturally occurring cases of Canine Transmissible Venereal Tumor (CTVT) is being reported. Dogs suffering from CTVT (N = 18) were systematically randomized into three groups viz. A, B, and C (n = 6). Animals of the groups A, B, and C received 100 ug of the ns1 gene, vp3 gene, and ns1 + vp3 gene combination, respectively, for three weeks intratumorally at weekly intervals; results were normalized against base values before commencement of therapy and after complete remission that were taken as negative and positive controls, respectively. Initiation of oncolytic gene therapy arrested the further progression of the tumor but most of the animals in the study underwent incomplete remission, indicating incomplete activity of ns1 and vp3 genes. The oncolytic effect of the treatments was in the order ns1 > vp3 > ns1 + vp3. Oncolysis was accompanied by decreased mitotic index and AgNOR count, and increased TUNEL positive cells and CD4+ lymphocyte counts. Our findings show that Canine Parvovirus ns1 may eventually find an important role as an oncolytic agent. PMID- 29133940 TI - Stimulators and activators of soluble guanylate cyclase for urogenital disorders. AB - Lower urinary tract symptoms (LUTS), comprising storage (such as urinary incontinence and urinary frequency), voiding, and postmicturition symptoms, are highly prevalent conditions that affect millions of people worldwide. LUTS have a profound effect on quality of life and are a considerable cost to health care systems. In men specifically, BPH commonly leads to LUTS. Clinical studies also show an association of LUTS with erectile dysfunction (ED). Nitric oxide (NO) has long been recognized as an important nonadrenergic, noncholinergic (NANC) transmitter in bladder, urethra, prostate, and corpus cavernosum smooth muscle. Data from clinical and basic research show that oxidation and degradation of soluble guanylate cyclase (sGC; also known as GCS) and reduced cyclic GMP (cGMP) levels are involved in the physiopathology of genitourinary diseases. The NO-sGC cGMP signalling pathway has a role in disease pathophysiology of the bladder, urethra, prostate, and corpus cavernosum in animal models and humans. Advances in targeting sGC directly to enhance cGMP production independently of endogenous NO have been made using NO-independent stimulators and activators of sGC. These molecules are potential therapeutics in the treatment of LUTS and ED. PMID- 29133943 TI - Randomly polarised beam produced by magnetooptically Q-switched laser. AB - Diode-pumped solid-state micro lasers are compact (centimetre-scale), highly stable, and efficient. Previously, we reported Q-switched lasers incorporating rare-earth substituted iron garnet (RIG) film. Here, the first demonstration of the magnetooptical (MO) Q-switch in an Nd:YAG laser cavity is performed. We fabricate a quasi-continuous-wave (QCW) diode-pumped Nd:YAG laser cavity, which is shortened to 10 mm in length and which contains an RIG film and a pair of small coils. This cavity yields a 1,064.58-nm-wavelength pulse with 25-ns duration and 1.1-kW peak power at a 1-kHz repetition ratio. Further, the polarisation state is random, due to the isotropic crystal structure of Nd:YAG and the fact that the MO Q-switch incorporating the RIG film does not require the presence of polarisers in the cavity. This is also the first report of an MO Q switch producing random polarisation. PMID- 29133945 TI - MicroRNA-7-5p mediates the signaling of hepatocyte growth factor to suppress oncogenes in the MCF-10A mammary epithelial cell. AB - MicroRNA-7 (miR-7) is a non-coding RNA of 23-nucleotides that has been shown to act as a tumor suppressor in various cancers including breast cancer. Although there have been copious studies on the action mechanisms of miR-7, little is known about how the miR is controlled in the mammary cell. In this study, we performed a genome-wide expression analysis in miR-7-transfected MCF-10A breast cell line to explore the upstream regulators of miR-7. Analysis of the dysregulated target gene pool predicted hepatocyte growth factor (HGF) as the most plausible upstream regulator of miR-7. MiR-7 was upregulated in MCF-10A cells by HGF, and subsequently downregulated upon treatment with siRNA against HGF. However, the expression of HGF did not significantly change through either an upregulation or downregulation of miR-7 expression, suggesting that HGF acts upstream of miR-7. In addition, the target genes of miR-7, such as EGFR, KLF4, FAK, PAK1 and SET8, which are all known oncogenes, were downregulated in HGF treated MCF-10A; in contrast, knocking down HGF recovered their expression. These results indicate that miR-7 mediates the activity of HGF to suppress oncogenic proteins, which inhibits the development of normal cells, at least MCF-10A, into cancerous cells. PMID- 29133944 TI - Region and cell-type resolved quantitative proteomic map of the human heart. AB - The heart is a central human organ and its diseases are the leading cause of death worldwide, but an in-depth knowledge of the identity and quantity of its constituent proteins is still lacking. Here, we determine the healthy human heart proteome by measuring 16 anatomical regions and three major cardiac cell types by high-resolution mass spectrometry-based proteomics. From low microgram sample amounts, we quantify over 10,700 proteins in this high dynamic range tissue. We combine copy numbers per cell with protein organellar assignments to build a model of the heart proteome at the subcellular level. Analysis of cardiac fibroblasts identifies cellular receptors as potential cell surface markers. Application of our heart map to atrial fibrillation reveals individually distinct mitochondrial dysfunctions. The heart map is available at maxqb.biochem.mpg.de as a resource for future analyses of normal heart function and disease. PMID- 29133946 TI - Whole genomic analysis of two potential recombinant strains within Human mastadenovirus species C previously found in Beijing, China. AB - Human mastadenovirus species C (HAdV-C) are the most common etiologic agents of respiratory disease in young children and are frequently detected worldwide including China. Two recombinant HAdV-C strains (BJ04 and BJ09) were isolated from infants with acute respiratory infection (ARI) in Beijing in 2012-2013. The whole genome sequences (WGS) of BJ04 and BJ09 were generated and compared to other 35 HAdV-C WGSs publicly available. Phylogenetic analyses showed that the BJ04 strain might be the result of three homologous recombination events involving the parental strains JX173086 (HAdV-1), NC_001405 (HAdV-2) and LC068718 (HAdV-6), whereas BJ09 viral genome might be made of genetic elements from JX173083 (HAdV-1), KF268199 (HAdV-5), and KR699642 (strain CBJ113). Despite intratypic recombination, amino acid analysis showed that the gene repertoire of BJ04 and BJ09 were similar to type 2 viruses. Finally, this analysis revealed that at least three lineages of HAdV-C have been identified in China, represented by BJ04 related to NC_001405, BJ09 related to CBJ113, and KF951595 (strain DD28) related to virus isolated in Japan. This study showed that the frequent recombination played an important driving force for complexity of the HAdV-C epidemic in Beijing, thereby demonstrating the necessity for epidemiological and virological surveillance for HAdV-C in China. PMID- 29133948 TI - Increased hippocampal tail volume predicts depression status and remission to anti-depressant medications in major depression. AB - Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD17) score ?16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD17 of ?7 following 8 weeks of randomized open label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment. PMID- 29133947 TI - Innate Cell-Mediated Cytotoxic Activity of European Sea Bass Leucocytes Against Nodavirus-Infected Cells: A Functional and RNA-seq Study. AB - Nervous necrosis virus (NNV) causes high mortalities in several marine species. We aimed to evaluate the innate cell-mediated cytotoxic (CMC) activity of head kidney leucocytes (HKLs) isolated from naive European sea bass (Dicentrarchus labrax) and gilthead seabream (Sparus aurata), a very susceptible and resistant fish species to NNV, respectively, against fish cell lines infected with NNV. Seabream HKLs showed significantly increased innate CMC activity against NNV infected cells, compared to those uninfected, while sea bass HKLs failed to do so. Thus, we performed a RNA-seq study to identify genes related to the CMC activity of sea bass leucocytes. Thus, we found that sea bass HKLs incubated with DLB-1 cells alone (CMC_DLB1) or with NNV-infected DLB-1 cells (CMC_DLB1-NNV) showed very similar transcriptomic profiles and the GO analysis revealed that most of the up-regulated genes were related to immunity. Strikingly, when the CMC samples with and without NNV were compared, GO analysis revealed that most of the up-regulated genes in CMC_DLB1-NNV samples were related to metabolism and very few to immunity. This is also in agreement with the functional data. These data point to the escape of CMC activity by NNV infection as an important factor involved in the high susceptibility to nodavirus infections of European sea bass. PMID- 29133949 TI - A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders. AB - The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD. PMID- 29133951 TI - mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors. AB - This corrects the article DOI: 10.1038/mp.2016.12. PMID- 29133952 TI - Engaging homeostatic plasticity to treat depression. AB - Major depressive disorder (MDD) is a complex and heterogeneous mood disorder, making it difficult to develop a generalized, pharmacological therapy that is effective for all who suffer from MDD. Through the fortuitous discovery of N methyl-D-aspartate receptor (NMDAR) antagonists as effective antidepressants, we have gained key insights into how antidepressant effects can be produced at the circuit and molecular levels. NMDAR antagonists act as rapid-acting antidepressants such that relief from depressive symptoms occurs within hours of a single injection. The mode of action of NMDAR antagonists seemingly relies on their ability to activate protein-synthesis-dependent homeostatic mechanisms that restore top-down excitatory connections. Recent evidence suggests that NMDAR antagonists relieve depressive symptoms by forming new synapses resulting in increased excitatory drive. This event requires the mammalian target of rapamycin complex 1 (mTORC1), a signaling pathway that regulates synaptic protein synthesis. Herein, we review critical studies that shed light on the action of NMDAR antagonists as rapid-acting antidepressants and how they engage a neuron's or neural network's homeostatic mechanisms to self-correct. Recent studies notably demonstrate that a shift in gamma-amino-butyric acid receptor B (GABABR) function, from inhibitory to excitatory, is required for mTORC1-dependent translation with NMDAR antagonists. Finally, we discuss how GABABR activation of mTORC1 helps resolve key discrepancies between rapid-acting antidepressants and local homeostatic mechanisms. PMID- 29133950 TI - Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. AB - Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We believe we report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild-type mice. Two factors contributed to this defect: (i) reduced GluN1 subunit levels in synaptic NMDA receptors and related currents, and (ii) impaired retrograde synaptic signaling by the endocannabinoid 2 arachidonoylglycerol (2-AG). Studies using a novel serial cue paradigm showed that episodic encoding is dependent on both the LPP and the endocannabinoid receptor CB1, and is strikingly impaired in Fmr1-KOs. Enhancing 2-AG signaling rescued both lppLTP and learning in the mutants. Thus, two consequences of the Fragile-X mutation converge on plasticity at one site in hippocampus to prevent encoding of a basic element of cognitive memory. Collectively, the results suggest a clinically plausible approach to treatment. PMID- 29133953 TI - Countering posttraumatic LHPA activation in refugee mothers and their infants. PMID- 29133954 TI - Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals. AB - Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg-1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97+/-10.65, P=0.04, Cohen's d=0.74). Participants were also significantly faster to initiate alcohol self administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder. PMID- 29133955 TI - Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis. AB - Inflammatory illness is associated with depression. Preclinical work has shown that chemokines are linked with peripheral-central crosstalk and may be important in mediating depressive behaviours. We sought to establish what evidence exists that differences in blood or cerebrospinal fluid chemokine concentration discriminate between individuals with depression and those without. Following PRISMA guidelines, we systematically searched Embase, PsycINFO and Medline databases. We included participants with physical illness for subgroup analysis, and excluded participants with comorbid psychiatric diagnoses. Seventy-three studies met the inclusion criteria for the meta-analysis. Individuals with depression had higher levels of blood CXCL4 and CXCL7 and lower levels of blood CCL4. Sensitivity analysis of studies with only physically healthy participants identified higher blood levels of CCL2, CCL3, CCL11, CXCL7 and CXCL8 and lower blood levels of CCL4. All other chemokines examined did not reveal significant differences (blood CCL5, CCL7, CXCL9, CXCL10 and cerebrospinal fluid CXCL8 and CXCL10). Analysis of the clinical utility of the effect size of plasma CXCL8 in healthy individuals found a negative predictive value 93.5%, given the population prevalence of depression of 10%. Overall, our meta-analysis finds evidence linking abnormalities of blood chemokines with depression in humans. Furthermore, we have demonstrated the possibility of classifying individuals with depression based on their inflammatory biomarker profile. Future research should explore putative mechanisms underlying this association, attempt to replicate existing findings in larger populations and aim to develop new diagnostic and therapeutic strategies. PMID- 29133957 TI - Hidden Magnetic States Emergent Under Electric Field, In A Room Temperature Composite Magnetoelectric Multiferroic. AB - The ability to control a magnetic phase with an electric field is of great current interest for a variety of low power electronics in which the magnetic state is used either for information storage or logic operations. Over the past several years, there has been a considerable amount of research on pathways to control the direction of magnetization with an electric field. More recently, an alternative pathway involving the change of the magnetic state (ferromagnet to antiferromagnet) has been proposed. In this paper, we demonstrate electric field control of the Anomalous Hall Transport in a metamagnetic FeRh thin film, accompanying an antiferromagnet (AFM) to ferromagnet (FM) phase transition. This approach provides us with a pathway to "hide" or "reveal" a given ferromagnetic region at zero magnetic field. By converting the AFM phase into the FM phase, the stray field, and hence sensitivity to external fields, is decreased or eliminated. Using detailed structural analyses of FeRh films of varying crystalline quality and chemical order, we relate the direct nanoscale origins of this memory effect to site disorder as well as variations of the net magnetic anisotropy of FM nuclei. Our work opens pathways toward a new generation of antiferromagnetic - ferromagnetic interactions for spintronics. PMID- 29133958 TI - Reductions in root hydraulic conductivity in response to clay soil and treated waste water are related to PIPs down-regulation in Citrus. AB - Citrus hydraulic physiology and PIP transcript levels were characterized in heavy (clay) and light (sandy loam) soils with and without treated waste water (TWW) irrigation after a summer irrigation season and at the end of a winter rainy season recovery period. Consistent reductions in clay soils compared to sandy loam were found for fresh water (FW) and TWW irrigation, respectively, in root water uptake, as well as in hydraulic conductivity of whole plant (Ks plant), stem (Ks stem) and root (Ks root). Transcript levels of most PIPs down-regulated following TWW irrigation in both soils, but relative gene expression of three PIPs was significantly higher in summer for sandy soil and FW than for clay soil and TWW; their mRNA levels was significantly correlated to Ks root. A pot experiment, which compared short term influences of saline and TWW found that both treatments, compared to FW, reduced root water uptake and PIPs mRNA levels by 2-fold after 20 days, and the decreases continued with time until the end of the experiment. These latter data indicated that salinity had an important influence. Our results suggest that plant hydraulic adjustment to soil texture and water quality occurs rapidly, i.e. within days, and is modulated by PIPs expression. PMID- 29133956 TI - Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway. AB - Immunoglobulin G (IgG) is a major effector molecule of the human immune response, and aberrations in IgG glycosylation are linked to various diseases. However, the molecular mechanisms underlying protein glycosylation are still poorly understood. We present a data-driven approach to infer reactions in the IgG glycosylation pathway using large-scale mass-spectrometry measurements. Gaussian graphical models are used to construct association networks from four cohorts. We find that glycan pairs with high partial correlations represent enzymatic reactions in the known glycosylation pathway, and then predict new biochemical reactions using a rule-based approach. Validation is performed using data from a GWAS and results from three in vitro experiments. We show that one predicted reaction is enzymatically feasible and that one rejected reaction does not occur in vitro. Moreover, in contrast to previous knowledge, enzymes involved in our predictions colocalize in the Golgi of two cell lines, further confirming the in silico predictions. PMID- 29133959 TI - A novel cytotherapy device for rapid screening, enriching and combining mesenchymal stem cells into a biomaterial for promoting bone regeneration. AB - Bone defects are a common challenge in clinic, usually warranting bone grafts. However, current strategies to obtain effective graft materials have many drawbacks. Mesenchymal stem cell (MSC)-based therapy is a promising alternative. We designed an innovative appliance named the stem cell screen-enrich-combine( biomaterials) circulating system (SECCS). In this study, 42 patients who required bone graft underwent SECCS-based treatment. Their bone marrow samples and beta tricalcium phosphate (beta-TCP) granules were processed in the SECCS for 10-15 minutes, to produce MSC/beta-TCP composites. These composites were grafted back into bone defect sites. The results showed 85.53% +/- 7.95% autologous MSCs were successfully screened, enriched, and seeded on the beta-TCP scaffolds synchronously. The cell viability remained unchanged after SECCS processing. Clinically, all patients obtained satisfactory bone healing. Thus, without in vitro culture, the SECCS can produce bioactive MSC/beta-TCP composites for bone regeneration during surgery. The SECCS represents a convenient, rapid, low-cost, and safe method for bone regeneration. PMID- 29133962 TI - Chronic periodontitis and the risk of erectile dysfunction: a systematic review and meta-analysis: methodological issues. PMID- 29133960 TI - Divergent roles for Clusterin in Lung Injury and Repair. AB - Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU-/-) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis. PMID- 29133961 TI - Triplex-quadruplex structural scaffold: a new binding structure of aptamer. AB - Apart from the canonical Watson-Crick duplex, nucleic acids can often form other structures, e.g. G-quadruplex and triplex. These structures give nucleic acid additional functions besides coding for genetic information. Aptamers are one type of functional nucleic acids that bind to specific targets with high selectivity and affinity by folding into special tertiary structures. Despite the fact that numerous aptamers have been reported, only a few different types of aptamer structures are identified. Here we report a novel triplex-quadruplex hybrid scaffold formed by a codeine binding aptamer (CBA). CBA and its derivatives are G-rich DNA sequences. Codeine binding can induce the formation of a complex structure for this aptamer containing a G-quadruplex and a G.GC triplex, while codeine is located at the junction of the triplex and quadruplex. When split CBA into two moieties, codeine does not bind either moieties individually, but can bind them together by inducing the formation of the triplex quadruplex scaffold. This structure formation induced by codeine binding is shown to inhibit polymerase reaction, which shows a potential application of the aptamer sequence in gene regulations. PMID- 29133963 TI - A Stroll Down Memory Lane. PMID- 29133964 TI - In vitro evaluation of repair bond strength of composite: Effect of surface treatments with bur and laser and application of universal adhesive. AB - Objectives: This study aimed to assess the effect of surface treatment by bur and laser and application of universal adhesive on repair bond strength of composite resin. Materials and Methods: A total of 120 composite blocks measuring 6*4*4 mm were fabricated of Filtek Z250 composite. All samples were subjected to 5,000 thermal cycles and divided into two groups for surface preparation by bur and by Er,Cr:YSGG laser (n = 60). The surfaces were then etched with orthophosphoric acid, rinsed with water and divided into three groups (silane, silane plus Single Bond and silane plus Single Bond Universal). Repair composite was then bonded to aged composite. Half of the samples in each group were stored in distilled water at 37 degrees C for 24 hours and the other half underwent 5000 thermal cycles. All samples were then subjected to shear bond strength testing using a universal testing machine at a crosshead speed of 1 mm/minute. The data were analyzed using one-way ANOVA and Tukey's HSD test. Mode of failure was determined using a stereomicroscope. Results: Bur preparation plus universal adhesive yielded the highest bond strength (30.16 u 2.26 MPa). Laser plus silane yielded the lowest bond strength (5.63 u 2.43 MPa). Bur preparation yielded significantly higher bond strength than laser (P < 0.001). Also, application of universal adhesive significantly improved bond strength compared to conventional adhesive and silane (P < 0.001). Bond strength after aging (5000 thermal cycles) had no significant difference with primary bond strength at 24 hours within each group (P = 0.182). Conclusion: Surface preparation of aged composite by bur and application of universal adhesive can improve the repair bond strength of composite. Application of silane (without adhesive) in the process of repair cannot provide adequately high repair bond strength. PMID- 29133965 TI - Evaluation of adjunctive effect of low-level laser Therapy on pain, swelling and trismus after surgical removal of impacted lower third molar: A double blind randomized clinical trial. AB - Background and Aim: Wisdom teeth remains impacted in the jaw due to several reasons and surgery of impacted wisdom teeth is one of the most common surgeries in dental clinics. Pain, swelling and trismus are the common complications after this surgery which affect quality of life. In articles, various methods are introduced to control immediate inflammatory-response associated with third-molar surgery. The aim of this study is to evaluate the adjunctive effect of low-level laser Therapy on pain, swelling and trismus after surgical removal of impacted lower third molar. Materials and Methods: This double-blind randomized controlled trial (RCT) was conducted on two groups of 24 patients (age range of 18-35) that had referred to surgical ward of Faculty of Dentistry, Tabriz University of Medical Sciences for surgery of their mandibular third molar(2015-16). All the subjects were systemically healthy and had at least one impacted mandibular third molar. After surgery, in experimental group, the laser was applied intraorally (inside the tooth socket) and extraorally (at the insertion point of the masseter muscle) immediately after surgery in contact with the target area for 25 seconds each. The laser energy was 2.5 J per area with an energy density of 5 J/ cm2 at the surface of the probe (spot size= 0.5 cm2). In the other group, as the control group, it was pretended to radiate. Trismus, pain, and swelling were evaluated on the first and seventh days after surgery. The obtained data were evaluated using SPSS 16 software and independent samples T-test. Findings: In the group where LLLT had been used, P> 0.05 was calculated for pain, swelling, and trismus on days 1 and 7 after surgery that was not statistically significant. Conclusion: Under limitations of this study, using low-power laser with mentioned parameters, clinically reduces pain, swelling and trismus after surgical removal of impacted mandibular wisdom, but not statistically significant. PMID- 29133966 TI - Effect of low-level laser therapy on fracture healing in rabbits. AB - Background and aims: The purpose of this study was to investigate the effect of low-level laser therapy (LLLT) on radial bone fracture gap healing in a rabbit model. Materials Subjects and Methods: Thirty male white New Zealand rabbits under general anesthesia had a 3mm slice of radial bone surgically removed. Fifteen rabbits were treated by 830 nm laser at 4 J/cm2 and 15 were used as non treated controls. Callus development was assessed by X-ray and radiographs every 7 days for 3 weeks. Results: Significant radiologic changes were observed in both groups against time (P > 0.001) or from week to week (P > 0.05). However, there was no statistical difference in radiologic scores after week 2 (P = 0.087) or week 3 (P = 0.077) between control and laser treated bone. Conclusions: Findings suggest that in this study, laser treatment did not enhance callus formation nor reduce repair time of complete fracture of the radius in rabbits. PMID- 29133967 TI - Comparison of marginal microleakage of flowable composite restorations in primary canine teeth prepared with high-speed diamond bur, Er:YAG laser and Er,Cr:YSGG laser. AB - Background and Objectives: Adhesive restorations have become highly popular in pediatric dentistry, and novel methods of cavity preparation with minimal patient discomfort including Er:YAG and Er,Cr:YSGG laser preparations have greatly advanced. This study aimed to compare the microleakage of composite restorations of class V cavities prepared in primary canine teeth with high-speed bur and Er:YAG and Er,Cr:YSGG lasers. Materials and Methods: This in vitro study was conducted on 30 class V cavities prepared on the buccal surfaces of primary canine teeth in three groups (n = 10) of bur preparation, Er:YAG laser and Er,Cr:YSGG laser. The cavities were etched, bonded and restored with Grandio flowable composite according to the manufacturer's instructions. After thermocycling, the teeth were immersed in 1% methylene blue dye for 24 hours to detect microleakage. The teeth were evaluated under a stereomicroscope at *32 magnification to assess the depth of penetration of methylene blue. The data were analyzed using SPSS version 19 and non-parametric Kruskal-Wallis and Mann Whitney tests. Results: Non-parametric Kruskal-Wallis test showed no significant difference in dye penetration among the three groups (P > 0.05). Pairwise comparisons of occlusal and gingival margins by nonparametric Mann Whitney test revealed no significant difference in microleakage either (P > 0.05). Conclusion: Use of Er:YAG and Er,Cr:YSGG lasers can decrease microleakage to the level of bur preparation. Bur and laser cavity preparations are not significantly different in terms of microleakage at the enamel or dentin margins. Thus, considering the advantages of laser, it may serve as a suitable alternative to bur preparation in pediatric dentistry. PMID- 29133968 TI - Effects of laser therapy and Grimaldi's muscle shortening manoeuvre on motor control of subjects with incomplete spinal cord injuries. AB - Background and Objectives: From year 2003 we treated positively 251 patients with Traumatic Spinal Cord Injuries (TSCI), using Non-Surgical Laser Therapy (NSLT). In order to increase muscle strength, we have also started using a physical therapy practice called Grimaldi's Muscle Shortening Manoeuvre (GMSM)The goal of our study is to obtain objective data suggesting the real effectiveness of the association of these two treatments. Study Design and Methods: In 2015, 10 patients with incomplete TSCI were enrolled. Further 10 subjects with similar features were included as control group. All patients have subtotal sensory loss and motor paralysis below the level of the lesion. Lasers used were 808, 10600, and 1064 nm, applied with a first cycle of four sessions per day for a total of 20 sessions. The patients participated in specific physical therapy training (GMSM) twice a day, for a total of eight sessions.Each cycle of laser and GMSM was replicated each month. Results: Results were considered positive if sensitivity increased at least two dermatomes per cycle under the level of the lesion. Results in muscle activity (on/off) were regarded as positive if sEMG showed modifications in CNS-muscle. Objective assessment of force displayed encouraging results. After each cycle, patients showed improvements in motor function and voluntary command. Follow-up is positive after 3 months. Conclusion: Associating laser treatment and Grimaldi's Muscle Shortening Manoeuvre (MSM) seems to be effective on muscle strength and motor control in patients affected by subtotal SCI compared to a control group. PMID- 29133969 TI - Treatment of Chronic Lower Extremity Ulcers with A New Er:Yag Laser Technology. AB - Chronic lower extremity ulcers (CLEUs) have a high prevalence and are difficult to treat due to their various aetiologies. The aim of this study is to evaluate the results achieved in treating CLEUs using an Erbium: YAG (Er:YAG) laser with RecoSMA technology. This laser emits thousands of microbeams of energy causing superficial epidermal ablation and a separation of dermal fibres due to a mechanical-acoustic and resonance effect. The evaluation of the results achieved was carried out by questionnaires completed by 18 patients enrolled in the study. Histological studies and photographs taken before each session (16 sessions in total) were analysed to visually monitor the clinical progress. The analyses were carried out with the help of computer software. The results after 16 treatment sessions showed the complete healing of ulcers or a decrease in their initial area of at least 55% in over 65% of the patients treated. The Student's t-test and Fisher's exact test were used for statistical analysis. The Er:YAG laser and RecoSMA technology ablates few epidermal cell layers, producing a mechanical acoustic effect with resonance action leading to tissue regeneration mechanisms. This technology offers an effective and safe alternative for treating CLEUs. PMID- 29133971 TI - The 12th Annual Meeting of the Japan Society for Laser Reproduction. PMID- 29133970 TI - Laser and Platelet-Rich Plasma to treat Medication-Related Osteonecrosis of the Jaws (MRONJ): a case report. AB - Aims: The appropriate management of Medication-Related OsteoNecrosis of the Jaw (MRONJ) is still a challenge for dentists and oral surgeons and in these last years high-technology instruments have been proposed at the different steps of interventions, also combined with promoters of tissue repair.The aim of this report is to show the advantages of a combined approach (laser and PRP) for the treatment of MRONJ. Methods: It is described the case of a patient positive for MRONJ observed at the Odontostomatology and Maxillo-Facial Surgery Unit of the Hospital of Piacenza where surgical approach was performed by using different devices: Er:YAG laser (2940 nm) to remove and vaporize necrotic hard tissue until bleeding bone; Platelet-Rich Plasma (PRP) to stimulate hard and soft tissue healing; diode laser (808 nm) to biostimulate the surgical site. Results: At the time of suture removal, wound closure was observed and the complete healing of the MRONJ site was observed for the 2 years follow up. Conclusion: This case may suggest that this kind of combined approach during all the steps of MRONJ treatment allows to perform a faster and less invasive surgery with a more comfortable postoperative healing process and it represents an innovative approach in this severe adverse event. PMID- 29133972 TI - The relationship between the physical cost index and knee extensor strength in children with hemiplegic cerebral palsy. AB - [Purpose] Lower extremity strength is a contributing factor to energy efficiency of gait. However, this contribution has not previously been evaluated in children with hemiplegic cerebral palsy (CP). The aim of this study was to evaluate the association between energy consumption, measured by the physical cost index (PCI), and strength of lower extremity, measured by the maximum knee extensor strength (MKES), in children with hemiplegic CP. [Subjects and Methods] Subjects were 10 children (4 males and 6 females; age, 7-17 years) with hemiplegic CP, but no history of orthopedic intervention or botulinum toxin treatment over the 1 year prior to the assessment. The PCI was measured during a 6-min walk test, and MKES using hand-held dynamometry, with the highest of two measures used for analysis. [Results] A negative correlation was identified between the PCI and MKES (R-value, -0.81 (affected) and -0.83 (unaffected) lower limb). [Conclusion] Higher lower extremity strength was associated with lower fatigability during a 6 min walk test in children with hemiplegic CP, providing evidence for the inclusion of strengthening exercises for both the affected and unaffected extremities in the rehabilitation of these children. PMID- 29133974 TI - Higher order optical aberrations and visual acuity in a randomized controlled trial comparing transepithelial versus epithelium-off corneal crosslinking for progressive keratoconus. AB - Purpose: The purpose of this study was to compare the effects of transepithelial crosslinking (trans-CXL) versus epithelium-off crosslinking (epi-off CXL) for progressive keratoconus with respect to the development of higher order aberrations (HOAs) and their effects on visual acuity. Materials and methods: A total of 61 patients were randomized and examined preoperatively and 1, 3, 6, and 12 months postoperatively in an academic referral center. Total corneal HOAs were compared between the two treatment groups using mixed linear modeling. Types of HOAs (coma, trefoil, and spherical aberration) that differed between groups were entered in a multivariable analysis to test their effect on uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA). Results: The epi-off CXL group had more flattening in maximal keratometry compared to the trans-CXL group (P=0.02). UDVA did not differ significantly between the groups (P=0.59); however, CDVA was significantly more improved in the trans-CXL group (P=0.02). Horizontal trefoil improved more in the epi-off group compared to the trans-CXL group (P=0.04), whereas the other HOAs were virtually unchanged in both groups. Differences in changes in HOAs between the two groups had no effect on either UCVA (P=0.76) or CDVA (P=0.96). Conclusion: Although HOAs are clinically relevant determinants of vision quality in keratoconus patients, the change in total HOAs post treatment did not differ between the trans-CXL and epi-off CXL groups. Only horizontal trefoil differed significantly post treatment between the trans-CXL and epi-off CXL groups. However, this difference did not independently affect either UDVA or CDVA. Trans-CXL provides no benefit over epi-off CXL regarding visual relevant HOAs. PMID- 29133973 TI - Duane retraction syndrome: causes, effects and management strategies. AB - Duane retraction syndrome (DRS) is a congenital eye movement anomaly characterized by variable horizontal duction deficits, with narrowing of the palpebral fissure and globe retraction on attempted adduction, occasionally accompanied by upshoot or down-shoot. The etiopathogenesis of this condition can be explained by a spectrum of mechanical, innervational, neurologic and genetic abnormalities occurring independently or which influence each other giving rise to patterns of clinical presentations along with a complex set of ocular and systemic anomalies. Huber type I DRS is the most common form of DRS with an earlier presentation, while Huber type II is the least common presentation. Usually, patients with unilateral type I Duane syndrome have esotropia more frequently than exotropia, those with type II have exotropia and those with type III have esotropia and exotropia occurring equally common. Cases of bilateral DRS may have variable presentation depending upon the type of presentation in each eye. As regards its management, DRS classification based on primary position deviation as esotropic, exotropic or orthotropic is more relevant than Huber's classification before planning surgery. Surgical approach to these patients is challenging and must be individualized based on the amount of ocular deviation, abnormal head position, associated globe retraction and overshoots. PMID- 29133975 TI - Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab. AB - Mepolizumab is an anti-interleukin-5 (IL-5) humanized monoclonal antibody that has been recently approved as an add-on biological treatment for severe eosinophilic asthma, by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Moreover, mepolizumab is also currently included within the step 5 of the Global Initiative for Asthma guidelines, as an add-on therapy for severe uncontrolled asthma. The relevant therapeutic benefits detectable in patients with refractory eosinophilic asthma receiving mepolizumab depend on the pivotal pathogenic role played by IL-5 in these subjects. Indeed, IL-5 is the key cytokine responsible for maturation, activation, proliferation, and survival of eosinophils. Therefore, IL-5 represents a strategic molecular target for anti-eosinophilic treatments. By selectively inhibiting the biological actions of IL-5, mepolizumab provides a valuable therapeutic option for patients with severe eosinophilic asthma, refractory to standard treatments including inhaled and even systemic corticosteroids. In particular, the very important advantages linked to the use of mepolizumab in these difficult-to-treat asthmatic individuals have been well documented by several different trials performed worldwide. PMID- 29133976 TI - Bisphosphonates, atherosclerosis and vascular calcification: update and systematic review of clinical studies. AB - Background: Epidemiologic and clinical data have suggested the existence of a biologic linkage between the bone system and the vascular system. Bisphosphonates (BPs) are effective inhibitors of bone resorption and are currently considered the drugs of choice for the prevention and treatment of osteoporosis and related fractures. Data from several publications have suggested that BPs may also be effective in reducing the atherosclerotic process and vascular calcification, but the results of these studies are contrasting. This review aimed to allow a better understanding of the relationships between BPs and atherosclerosis in humans. Materials and methods: Electronic databases of Pubmed-Medline, Cochrane Library and SCOPUS from inception to June 30, 2016 were searched. The full texts of the articles potentially eligible were carefully assessed and reviewed. Finally, 20 studies were found to be eligible and were included in the systematic review. All included studies were published between 2000 and 2014. Results: In several studies, etidronate limited the progression of aortic and coronary calcification in hemodialysis patients, whereas the nitrogen-containing-BPs given orally did not significantly reduce vascular calcifications in patients with chronic kidney disease, kidney trasplant or in those with osteoporosis. Nitrogen-containing-BPs present favorable effects both on vessel wall thickness and on arterial elasticity due to both a reduction in serum lipids and the interaction of BPs with the bone tissue, with the consequent release of bone turnover markers and cytokines into the bloodstream. Conclusion: To sum up, the BPs seem to have the potential of influencing atherosclerosis and calcium homeostasis at the level of vascular walls with several possible mechanisms which may differ according to the type, potency, dosage and administration route of BPs. Additional studies are needed to specifically address the mechanism by which BP use could influence cardiovascular morbidity and mortality. PMID- 29133977 TI - 5-Aza-2'-deoxycytidine protects against emphysema in mice via suppressing p16Ink4a expression in lung tissue. AB - Background: There is a growing realization that COPD, or at least emphysema, involves several processes presenting in aging and cellular senescence. Endothelial progenitor cells (EPCs) contribute to neovascularization and play an important role in the development of COPD. The gene for p16Ink4a is a major dominant senescence one. The aim of the present study was to observe changes in lung function, histomorphology of lung tissue, and expression of p16Ink4a in lung tissue and bone marrow-derived EPCs in emphysematous mice induced by cigarette smoke extract (CSE), and further to search for a potential candidate agent protecting against emphysema induced by CSE. Materials and methods: An animal emphysema model was induced by intraperitoneal injection of CSE. 5-Aza-2' deoxycytidine (5-Aza-CdR) was administered to the emphysematous mice. Lung function and histomorphology of lung tissue were measured. The p16Ink4a protein and mRNA in EPCs and lung tissues were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction, respectively. Results: CSE induced emphysema with increased p16Ink4a expression in lung tissue and bone marrow-derived EPCs. 5-Aza-CdR partly protected against emphysema, especially in the lung-morphology profile, and partly protest against the overexpression of p16Ink4a in EPCs and lung tissue induced by CSE. Conclusion: 5 Aza-CdR partly protected against emphysema in mice via suppressing p16Ink4a expression in EPCs and lung tissue. PMID- 29133978 TI - A nationwide structure for valid long-term oxygen therapy: 29-year prospective data in Sweden. AB - Background: Long-term oxygen therapy (LTOT) improves prognosis in COPD with severe hypoxemia. However, adherence to criteria for eligibility and quality of LTOT is often insufficient and varies between countries. The aim of this study was to evaluate a national structure for prescription and management of LTOT over three decades in Sweden. Methods: The study was a prospective, population-based study of 23,909 patients on LTOT from 1987 to 2015 in the Swedish National Register of Respiratory Failure (Swedevox). We assessed the prevalence, incidence, and structure of LTOT; completeness of registration in Swedevox; and validity of prescription and management of LTOT in Sweden according to seven published quality indicators. Results: LTOT was prescribed by 48 respiratory or medicine units and managed mainly by specialized oxygen nurses. Swedevox had a stable completeness of 85% of patients starting LTOT since 1987. The national incidence of LTOT increased from 3.9 to 14.7/100,000 inhabitants over the time period. In 2015, 2,596 patients had ongoing therapeutic LTOT in the registry, a national prevalence of 31.6/100,000. Adherence to prescription recommendations and fulfillment of quality criteria was stable or improved over time. Of patients starting LTOT in 2015, 88% had severe hypoxemia (partial pressure of arterial oxygen [PaO2] <7.4 kPa) and 97% had any degree of hypoxemia (PaO2 <8.0 kPa); 98% were prescribed oxygen >=15 hours/day or more; 76% had both stationary and mobile oxygen equipment; 75% had a mean PaO2 >8.0 kPa breathing oxygen; and 98% were non smokers. Conclusion: We present a structure for prescription, management, and follow-up of LTOT. The national registry effectively monitored adherence to prescription recommendations and most likely contributed to improved quality of care. PMID- 29133979 TI - Dietary nutrients associated with preservation of lung function in Hispanic and non-Hispanic white smokers from New Mexico. AB - Background: COPD is the third leading cause of death in the United States. Cigarette smoking accelerates the age-related forced expiratory volume in 1 s (FEV1) decline, an important determinant for the genesis of COPD. Hispanic smokers have lower COPD prevalence and FEV1 decline than non-Hispanic whites (NHWs). Patients and methods: A nutritional epidemiological study was conducted in the Lovelace Smokers cohort (LSC; n=1,829) and the Veterans Smokers cohort (n=508) to identify dietary nutrients (n=139) associated with average FEV1 and its decline and to assess whether nutrient intakes could explain ethnic disparity in FEV1 decline between Hispanics and NHW smokers. Results: Nutrients discovered and replicated to be significantly associated with better average FEV1 included magnesium, folate, niacin, vitamins A and D, eicosenoic fatty acid (20:1n9), eicosapentaenoic acid (20:5n3), docosapentaenoic acid (DPA; 22:5n3), docosahexaenoic acid (22:6n3), and fiber. In addition, greater intakes of eicosenoic fatty acid and DPA were associated with slower FEV1 decline in the LSC. Among omega 3 polyunsaturated fatty acids, DPA is the most potent nutrient associated with better average FEV1 and slower FEV1 decline. Adverse effect of continuous current smoking on FEV1 decline was completely negated in LSC members with high DPA intake (>20 mg/day). Slower FEV1 decline in Hispanics compared to NHWs may be due to the greater protection of eicosenoic fatty acid and DPA for FEV1 decline rather than greater intake of protective nutrients in this ethnic group. Conclusion: The protective nutrients for the preservation of FEV1 in ever smokers could lay foundation for designing individualized nutritional intervention targeting "optimal physiological levels" in human to improve lung function in ever smokers. Ethnic disparity in FEV1 decline may be explained by difference in magnitude of protection of dietary intakes of eicosenoic fatty acid and DPA between Hispanics and NHWs. PMID- 29133980 TI - Tailored nanostructured platforms for boosting transcorneal permeation: Box Behnken statistical optimization, comprehensive in vitro, ex vivo and in vivo characterization. AB - Ocular drug delivery systems suffer from rapid drainage, intractable corneal permeation and short dosing intervals. Transcorneal drug permeation could increase the drug availability and efficiency in the aqueous humor. The aim of this study was to develop and optimize nanostructured formulations to provide accurate doses, long contact time and enhanced drug permeation. Nanovesicles were designed based on Box-Behnken model and prepared using the thin film hydration technique. The formed nanodispersions were evaluated by measuring the particle size, polydispersity index, zeta potential, entrapment efficiency and gelation temperature. The obtained desirability values were utilized to develop an optimized nanostructured in situ gel and insert. The optimized formulations were imaged by transmission and scanning electron microscopes. In addition, rheological characters, in vitro drug diffusion, ex vivo and in vivo permeation and safety of the optimized formulation were investigated. The optimized insert formulation was found to have a relatively lower viscosity, higher diffusion, ex vivo and in vivo permeation, when compared to the optimized in situ gel. So, the lyophilized nanostructured insert could be considered as a promising carrier and transporter for drugs across the cornea with high biocompatibility and effectiveness. PMID- 29133982 TI - Combined aesthetic interventions for prevention of facial ageing, and restoration and beautification of face and body. AB - The Merz Institute of Advanced Aesthetics Expert Summit was held in Prague, Czech Republic, from 19-20 November 2016. The meeting had a distinct advisory board character and invited aesthetic practitioners from all over the world to hear an international faculty present a range of keynote lectures and conduct live injection sessions with an emphasis on recent developments in combination aesthetic interventions for face and body rejuvenation and beautification. Aging is associated with changes in bones, muscles, ligaments, adipose tissue, and skin and, moreover, involves interactions among these tissue types. To achieve the most natural and harmonious rejuvenation of the face, all changes that result from the aging process should be corrected, which generally involves treatment with more than a single agent or technology. Presentations described innovative treatment algorithms for the face and body and focused on patients' desires for natural-looking rejuvenation and how this requires a three-dimensional approach combining products that relax the musculature, volumize, and re-drape the skin. Besides treating the aging face, these procedures are increasingly used to enhance facial features as well as to delay facial aging in younger patients. The presentations covered patients from different ethnicities as well as the treatment of non-facial areas, with a particular focus on the use of Ultherapy(r) for skin lifting and tightening, and new aesthetic procedures such as Cellfina(r) and diluted Radiesse(r). The current report provides a summary of key presentations from the meeting. PMID- 29133981 TI - Electrostatic interactions between polyglutamic acid and polylysine yields stable polyion complex micelles for deoxypodophyllotoxin delivery. AB - To achieve enhanced physical stability of poly(ethylene glycol)-poly(d,l-lactide) polymeric micelles (PEG-PDLLA PMs), a mixture of methoxy PEG-PDLLA-polyglutamate (mPEG-PDLLA-PLG) and mPEG-PDLLA-poly(l-lysine) (mPEG-PDLLA-PLL) copolymers was applied to self-assembled stable micelles with polyion-stabilized cores. Prior to micelle preparation, the synthetic copolymers were characterized by 1H-nuclear magnetic resonance (NMR) and infrared spectroscopy (IR), and their molecular weights were calculated by 1H-NMR and gel permeation chromatography (GPC). Dialysis was used to prepare PMs with deoxypodophyllotoxin (DPT). Transmission electron microscopy (TEM) images showed that DPT polyion complex micelles (DPT PCMs) were spherical, with uniform distribution and particle sizes of 36.3+/-0.8 nm. In addition, compared with nonpeptide-modified DPT-PMs, the stability of DPT PCMs was significantly improved under various temperatures. In the meantime, the pH sensitivity induced by charged peptides allowed them to have a stronger antitumor effect and a pH-triggered release profile. As a result, the dynamic characteristic of DPT-PCM was retained, and high biocompatibility of DPT-PCM was observed in an in vivo study. These results indicated that the interaction of anionic and cationic charged polyionic segments could be an effective strategy to control drug release and to improve the stability of polymer-based nanocarriers. PMID- 29133983 TI - Concomitant psychiatric symptoms and impaired quality of life in women with cervical cancer: a critical review. AB - Our aim was to summarize the current relevant literature on concomitant psychiatric symptoms with a focus on anxiety/depression in a population with gynecologic cancer; to identify the predictors, associated factors, and prevention strategies of psychiatric disorders; to examine psychiatric disorders in a population with recurrent gynecologic cancer; and to describe the limitations of the literature and future research areas. Little is known about attending psychiatric disorders in patients with gynecologic and other malignant diseases like cervical or breast cancer. However, patients suffering from other types of gynecologic cancer (eg, genital/cervical cancer) may also have an increased risk of psychiatric symptoms. In this review, we identify the potential information deficits in this field. A two-rater independent literature search was conducted using the PubMed/Google Scholar search engines to systematically evaluate the literature on the research objectives, followed by a critical reflection on the results. Of the 77 screened studies, 15 met the criteria for inclusion in this review. Patients with gynecologic malignancies, especially cervical cancer, had a very high prevalence of psychiatric symptoms including depression (33%-52%). Additionally, the risk groups facing higher rates of concomitant reduced quality of life and increased psychiatric symptoms such as depression were identified. Specifically, low socioeconomic status, sexual inactivity, absence of a partner, and physical symptoms were correlated with an increased risk. Patients suffering from recurrent gynecologic cancer should receive particular attention because of their significantly increased risk of depressive symptoms. Screening programs are needed to detect psychiatric symptoms in cervical cancer patients and the associated high-risk groups. Regular screening should be implemented, and psychosocial care should be provided during follow-up. PMID- 29133984 TI - Are the timings and risk factors changing? Survival analysis of timing of first antenatal care visit among pregnant women in Nigeria (2003-2013). AB - Background: Child and maternal mortality and morbidity remain among the top global health challenges despite various efforts and multitude of resources directed to improving this situation over time. This study assessed trend of the timings of first antenatal care (ANC) visit in Nigeria and also identified the risk factors associated with it. Methods: The data obtained from three consecutive Nigerian Demographic and Health Surveys in 2003, 2008, and 2013 were pooled. We focused on the ANC attendance history during the current pregnancies or the last pregnancies within 5 years preceding the survey irrespective of how the pregnancy ended. The gestational age at time of first ANC visit was computed as the survival time, while others who did not attend ANC were censored. Basic descriptive statistics and survival analysis methods were used to analyze the data. Results: A total of 45,690 pregnancies were studied, of which 70% were from rural areas. Mothers were mostly (45%) aged 25-34 years and 47.1% had no formal education, while only 37.9% were involved in decisions on the use of health care facility. Prevalence of ANC use was 60.5% in 2008 and 65.8% in both 2003 and 2013. Less than one-third (32.3%) of the women accessed ANC within first 3 months of pregnancy, with highest rate (41.7%) among women with higher education and those from North Central Nigeria (42.7%). The hazard of the timing of first ANC visit was higher in years 2003 and 2013 than in 2008. Conclusion: Initiation of ANC visit in Nigeria is generally late with most women making first visit during second trimester, with significant variations across the years studied. The increase in coverage of ANC recorded in 2003 and 2013 was not accompanied by earlier commencement of ANC visit. Maternal health stakeholders should do more to ensure that all pregnant women start ANC visit earlier. PMID- 29133985 TI - Effects of immediate postpartum contraceptive counseling on long-acting reversible contraceptive use in adolescents. AB - Background: Adolescent pregnancy is a global public health problem, particularly repeated pregnancy. The best strategy to lower prevalence of adolescent pregnancy and repeated pregnancy is promoting highly effective long-acting contraceptive methods along with special counseling programs. Long-acting reversible contraception (LARC) is the ideal contraceptive of choice for adolescents. It is not known whether immediate postpartum contraceptive counseling increases postpartum LARC use in adolescents. Objective: To compare LARC use between immediate and conventional postpartum contraceptive counseling and discover predictive factors of postpartum LARC use. Materials and methods: This prospective, randomized controlled trial was conducted among postpartum adolescents at Department of Obstetrics and Gynecology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand, from 1 July 2016 to 31 March 2017. The participants were assigned to receive immediate postpartum contraceptive counseling or conventional postpartum contraceptive counseling. The primary outcome was postpartum LARC use. The secondary outcome was predictive factors for LARC use in postpartum adolescents. Results: Of the 233 postpartum adolescents, postpartum LARC use was 87 of 118 (73.7%) in the immediate postpartum counseling group and 49 of 115 (42.6%) in the conventional postpartum counseling group (odds ratio 3.780, 95% CI 2.18-6.57, p<0.001). A significant predictive factor for LARC use in postpartum adolescents was immediate postpartum counseling (odds ratio 3.67, 95% CI 2.10-6.41, p<0.001). Conclusion: Immediate postpartum contraceptive counseling led to a significant increase in postpartum use of LARC in adolescents, when compared with conventional (4-6 weeks) postpartum contraceptive counseling. Adolescent mothers who received immediate postpartum counseling were 3.67 times more likely to use LARC than those who received conventional postpartum counseling. PMID- 29133986 TI - Three new species of Pinelema from caves in Guangxi, China (Araneae, Telemidae). AB - Three new Pinelema species, P. cunfengensis Zhao & Li, sp. n. (??), P. podiensis Zhao & Li, sp. n. (??), and P. qingfengensis Zhao & Li, sp. n. (??), are described from the Guangxi Zhuang Autonomous Region of China, bringing the total number of Pinelema species to eight. All occur in Yunnan Province or the Guangxi Zhuang Autonomous Region. The male palp of Telemidae was studied for the first time using scanning electron microscope. PMID- 29133987 TI - A review of the land snail genus Alycaeus (Gastropoda, Alycaeidae) in Peninsular Malaysia. AB - A total of 11 species and 1 subspecies of Alycaeus were recognised in Peninsular Malaysia prior to this study. However, these taxonomic descriptions of Alycaeus taxa were based on limited numbers of examined materials, where a whole spectrum of morphological variations were not accounted for and diagnoses were often provided without sufficient comparison between congeners from across the peninsula. We reviewed Peninsular Malaysian Alycaeus through the examination of 5137 specimens in 522 collection lots from all major museum collections and literature sources. Based on these examined materials, we utilised a more comprehensive revised set of 39 shell and operculum characters, as well as living animal colour to describe all Alycaeus species in this paper. We also noted their habitat and ecology, as well as updated the distribution of each species. Of the 12 previously described taxa, 10 are reconfirmed as present on Peninsular Malaysia (Alycaeus balingensis, Alycaeus carinata, Alycaeus conformis, Alycaeus gibbosulus, Alycaeus kapayanensis, Alycaeus kelantanensis, Alycaeus liratulus, Alycaeus perakensis perakensis, Alycaeus perakensis altispirus and Alycaeus thieroti) and 2 are confirmed as absent from the peninsula (Alycaeus jagori and Alycaeus pyramidalis). A new record of Alycaeus robeleni is reported for Peninsular Malaysia. One species, Chamalycaeus jousseaumei is confirmed as present on the peninsula and is reassigned to Alycaeus. The subspecies Alycaeus perakensis altispirus Mollendorff, 1902, is elevated to species. Examined Peninsular Malaysian materials that do not fit previously recognised species are described as new species. A total of 11 new species are proposed (Alycaeus selangoriensissp. n., Alycaeus costacrassasp. n., Alycaeus ikanensissp. n., Alycaeus alticolasp. n., Alycaeus charasensissp. n., Alycaeus kurauensissp. n., Alycaeus regalissp. n., Alycaeus virgogravidasp. n., Alycaeus senyumensissp. n., Alycaeus expansussp. n., Alycaeus clementsisp. n.). Overall, 23 species of Alycaeus are now recognised in Peninsular Malaysia. PMID- 29133988 TI - Discovery of the genus Nipponodipogon Ishikawa in the Oriental region, with description of two new species from China (Hymenoptera, Pompilidae). AB - The genus Nipponodipogon Ishikawa, 1965 is newly recorded from China (Guangdong, Hainan, and Yunnan) and the Oriental Region. Two new species, N. orientalis Loktionov, Lelej & Xu, sp. n. (Guangdong, Hainan, Yunnan) and N. shimizui Loktionov, Lelej & Xu, sp. n. (Guangdong, Yunnan), are described and illustrated. The updated key to the species based on Shimizu et al. (2015) is given. PMID- 29133989 TI - A new species of wasp-mimicking clearwing moth from Peninsular Malaysia with DNA barcode and behavioural notes (Lepidoptera, Sesiidae). AB - A new species of clearwing moth, Pyrophleps ellawi Skowron Volponi, sp. n., is described from Peninsular Malaysia. Information on the habitat, time and conditions of occurrence, flight and mud-puddling behaviour, functional morphology, and DNA barcode are also provided. Photographs and a supplementary video from the wild demonstrate the postures and behaviour of this species of Pyrophleps, whose remaining members were described only on the basis of pinned specimens. This is the first record of this genus in Peninsular Malaysia. PMID- 29133990 TI - The acoustic repertoire of the Atlantic Forest Rocket Frog and its consequences for taxonomy and conservation (Allobates, Aromobatidae). AB - The use of acoustic signals is a common characteristic of most anuran species to mediate intraspecific communication. Besides many social purposes, one of the main functions of these signals is species recognition. For this reason, this phenotypic trait is normally applied to taxonomy or to construct evolutionary relationship hypotheses. Here the acoustic repertoire of five populations of the genus Allobates from the Brazilian Atlantic Forest are presented for the first time, on a vulnerable to extinction Neotropical taxon. The description of males' advertisement and aggressive calls and a female call emitted in a courtship context are presented. In addition, the advertisement calls of individuals from distinct geographical regions were compared. Differences in frequency range and note duration may imply in taxonomic rearrangements of these populations, once considered distinct species, and more recently, proposed as a single species, Allobates olfersioides. Calls of the male from the state of Rio de Janeiro do not overlap spectrally with calls of males from northern populations, while the shorter notes emitted by males from Alagoas also distinguishes this population from the remaining southern populations. Therefore, it is likely that at least two of the junior synonyms should be revalidated. Similarities among male advertisement and female calls are generally reported in other anuran species; these calls may have evolved from a preexisting vocalization common to both sexes. Male aggressive calls were different from both the male advertisement and female calls, since it was composed by a longer and multi-pulsed note. Aggressive and advertisement calls generally have similar dominant frequencies, but they have temporal distinctions. Such patterns were corroborated with the Atlantic Forest Rocket Frogs. These findings may support future research addressing the taxonomy of the group, behavioral evolution, and amphibian conservation. PMID- 29133992 TI - Five new species of the armored scale genus Andaspis MacGillivray (Hemiptera, Coccomorpha, Diaspididae) from New Caledonia. AB - New Caledonia is home to many endemic species of plants and animals. Here, we improve our grasp on that biota by describing five new species of armored scale insects in the genus Andaspis: Andaspis brevicornutasp. n, A. conicasp. n., A. nothofagisp. n., A. novaecaledoniaesp. n., and A. ornatasp. n. Each is known exclusively from collections on southern beeches (Nothofagus spp.) in New Caledonia. A key to the species of Andaspis of New Caledonia is provided. PMID- 29133991 TI - Nipponnemertes incainca sp. n. Adoption of the new taxonomic proposal for nemerteans (Nemertea, Cratenemertidae). AB - A new species Nipponemertes incainca is described from the intertidal zone of Santa Marta, Colombia. A new recent approach based on both morphological and molecular characters is applied for the description. The main characteristics of the species are: red color, head shield-shaped with a mid-dorsal cephalic ridge, furrows pre-cerebral inconspicuous with few faint ridges orthogonal to furrow axis, two irregular groups of eyespots situated at lateral margins in precerebral cephalic region, proboscis provided with papillae and 12 nerves, stylet smooth supported on an oval basis, and two pouches containing 3-4 accessory stylets each. The sequence of the COI gene was analyzed as an additional support for the new species. PMID- 29133993 TI - Lithobius (Chinobius) yuchernovi, a new lithobiid species from northeastern Siberia and the Kamchatka Peninsula, Russia (Chilopoda, Lithobiomorpha). AB - Lithobius yuchernovisp. n. is described, based on type material from the Ola Plateau, Magadan Region, Russia. The new species is widely distributed in northeastern Siberia, ranging from the Magadan Region, until the eastern Chukot Autonomous Region and the Kamchatka Peninsula in the southeast, whence non-type material is documented. This species belongs to the subgenus Chinobius Matic, 1973 based on the structure of the female gonopodal claw (more than two denticles on the internal ridge). It differs from all Palearctic species of the genus Lithobius by the following apomorphy: distoventral tubercle supporting a cluster of long and curved setae situated on the last male tibia. In addition, it shows dorsal and ventral sulci on the last legs. New replacement names are introduced: Lithobius zachiuinom. n. for Lithobius (Chinobius) orientalis (Matic, 1973) and Lithobius carlinom. n. for Lithobius (Alokobius) orientalis Attems, 1953. PMID- 29133994 TI - A commentary on the practice of using the so-called typeless species. AB - The fears expressed by Santos et al. (2016) that description of typeless species (new species described based on field photographs) can be fatal for the practice of taxonomy which will succumb to an uncontrollable stream of "species of questionable delimitation" are, in our opinion, exaggerated. The Code already protects taxonomic practice from subjectivity quite well by limiting opportunities for descriptions of new species based on field photos by rigid requirements, and only skilled taxonomists with extensive knowledge of a group are capable of fulfilling them. If a taxonomist has omitted to compare the new typeless species with the known species externally similar to it, the latter cannot be diagnosed and its name in that case becomes nomen nudum. Typeless species can coincide with species described earlier, but can represent a new species differing in internal features. To describe typeless species without infringement of Article 13.1 a taxonomist should compare this species to all related and similar species described earlier. PMID- 29133995 TI - Four new species of the genus Delia Robineau-Desvoidy in the Yunnan Province of China (Diptera, Anthomyiidae). AB - Four new species of the genus Delia from Yunnan Province are described: Delia dentiaedeagussp. n., Delia longiabdominasp. n., Delia nigerihalteressp. n., and Delia tuberisurstylasp. n. A catalogue of all Delia species recorded from Yunnan Province has also been included. PMID- 29133996 TI - Two new species and two new records of fungus-feeding Phlaeothripinae from China (Thysanoptera, Phlaeothripidae). AB - Two new species of fungivorous Phlaeothripinae, Mystrothrips levissp. n. and Urothrips lancangensissp. n., are described from China. Pentagonothrips antennalis Haga & Okajima and Plectrothrips bicolor Okajima are newly recorded in China. PMID- 29133997 TI - Eight new species of Batrisodes Reitter from China (Coleoptera, Staphylinidae, Pselaphinae). AB - Eight new species of the genus Batrisodes Reitter are described from continental China, seven of which were found in association with ants: B. abdominalissp. n. and B. tianmuensissp. n. with an Ectomomyrmex ant from Zhejiang; B. grossussp. n. with an Odontomachus ant from Guangxi; B. simianshanussp. n. with an Aphaenogaster ant from Chongqing; B. qiuluisp. n. with a Pheidole ant, B. xuhaoisp. n. with a Lasius ant, and B. zhouchaoisp. n. with Lasius and Nylanderia ants from Sichuan. Batrisodes zethussp. n. was collected from a leaf litter sample. PMID- 29133998 TI - A new species of the subgenus Scymnus from Pakistan (Coleoptera, Coccinellidae). AB - A new species, Scymnus (Scymnus) contortubus Rashid, Chen & Wang, sp. n., is described and illustrated from Pakistan. A diagnosis, remarks, illustrations, and a distribution map are provided of the new species and its most similar congener, S. (S..) nubilus Mulsant. PMID- 29133999 TI - A review of the occurrence and diversity of the sphragis in butterflies (Lepidoptera, Papilionoidea). AB - Males of many butterfly species secrete long-lasting mating plugs to prevent their mates from copulating with other males, thus ensuring their sperm will fertilize all future eggs laid. Certain species have further developed a greatly enlarged, often spectacular, externalized plug, termed a sphragis. This distinctive structure results from complex adaptations in both male and female genitalia and is qualitatively distinct from the amorphous, internal mating plugs of other species. Intermediate conditions between internal plug and external sphragis are rare. The term sphragis has often been misunderstood in recent years, hence we provide a formal definition based on accepted usage throughout most of the last century. Despite it being a highly apparent trait, neither the incidence nor diversity of the sphragis has been systematically documented. We record a sphragis or related structure in 273 butterfly species, representing 72 species of Papilionidae in 13 genera, and 201 species of Nymphalidae in 9 genera. These figures represent respectively, 13% of Papilionidae, 3% of Nymphalidae, and 1% of known butterfly species. A well-formed sphragis evolved independently in at least five butterfly subfamilies, with a rudimentary structure also occurring in an additional subfamily. The sphragis is probably the plesiomorphic condition in groups such as Parnassius (Papilionidae: Parnassiinae) and many Acraeini (Nymphalidae: Heliconiinae). Some butterflies, such as those belonging to the Parnassius simo group, have apparently lost the structure secondarily. The material cost of producing the sphragis is considerable. It is typically offset by production of a smaller spermatophore, thus reducing the amount of male derived nutrients donated to the female during mating for use in oogenesis and/or somatic maintenance. The sphragis potentially represents one of the clearest examples of mate conflict known. Investigating its biology should yield testable hypotheses to further our understanding of the selective processes at play in an 'arms race' between the sexes. This paper provides an overview, which will inform future study. PMID- 29134000 TI - A new species of the genus Kurixalus from Yunnan, China (Anura, Rhacophoridae). AB - A new species of the genus Kurixalus (Anura: Rhacophoridae) is described from Yunnan, China based on morphological and molecular evidence. The new species, Kurixalus lenquanensissp. n., is distinguished from other congeneric species by a combination of (1) smaller body size (SVL in males ranges from 25.0 to 28.9 mm), (2) obtusely pointed snout with no prominence on tip, (3) rough and brown dorsum with darker mark, (4) absence of large dark spots on ventral surface, (5) brownish clouded chin, (6) granular throat, chest, and belly, (7) presence of vomerine teeth, (8) serrated dermal fringes along outer edge of limbs, (9) slight nuptial pad, (10) golden brown iris, and (11) single internal vocal sac. The new species is known only from montane scrub vegetation at the type locality (Lenquan Village, Mengzi City, Yunnan Province) and Yangjiatian Village, Gejiu City, Yunnan Province. Genetically, the new species is nested within a clade of Taiwanese Kurixalus and recovered as the sister taxon to Kurixalus idiootocus with strong support values, indicating that the ancestor of this new species might have come from Taiwan Island or the ancestor of this new species may have been widespread in southern China and the descendent species in between Taiwan and Yunnan has become extinct. PMID- 29134001 TI - A new species of the genus Rana from Henan, central China (Anura, Ranidae). AB - A new species of brown frog Rana luanchuanensis Zhao & Yuan, sp. n. is described from Luanchuan County, western Henan, central China. The mitochondrial genealogy suggests that the new species is the sister taxon to the clade including R. amurensis and R. coreana, and is separated by uncorrected pairwise distances more than 12.5%. Morphologically, this new species differs from its congeners by a suite of characters. Analyses of partial sequences of cytochrome oxidase subunit I (COI) resolve the new species as a single matriline. PMID- 29134002 TI - Revision of Massylaea Mollendorff, 1898 (Stylommatophora, Helicidae). AB - In this paper some helicoid species from eastern Algeria are investigated using a morphological and molecular approach. The investigation of the genital organs of M. massylaea (Morelet, 1851), the type species of the genus Massylaea Mollendorff, 1898, showed the same autapomorphic character states as are considered typical for Eobania P. Hesse, 1913. These findings are fully supported by the genetic analysis using two mitochondrial and three nuclear markers. Thus, the latter genus has to be considered a synonym of the former. Currently, three species are known to comprise the genus, viz. M. massylaea, M. constantina (E. Forbes, 1838), and M. vermiculata (O. F. Muller, 1774). Several nominal taxa from northern Africa are synonymised with one of the species mentioned here under Massylaea. The generic position of the so-called "Massylaea" species from the High Atlas Mountains in southern Morocco remains unresolved. PMID- 29134003 TI - Notes on two crabs (Crustacea, Brachyura, Dynomenidae and Iphiculidae) collected from red coral beds in northern Taiwan, including a new species of Pariphiculus Alcock, 1896. AB - Two brachyuran species of the families Dynonemidae and Iphiculidae are reported from red coral beds in northern Taiwan. The dynonemid Acanthodromia margarita (Alcock, 1899) has hitherto been reported from the Andaman Sea, Japan, and Philippines and the species is here recorded for the first time from Taiwan. A new species of iphiculid, Pariphiculus stellatussp. n., is also described. The new Pariphiculus, which also occurs in the Philippines, is superficially similar to P. agariciferus Ihle, 1918, a species known from Indonesia, Japan, Philippines, South China Sea, Taiwan, and Vanuatu, but can be distinguished by distinct carapace, pleonal and male first gonopod features. PMID- 29134004 TI - Cirolana phuketensis, a new species of marine isopod (Crustacea, Isopoda, Cirolanidae) from the Andaman Sea coast of Thailand. AB - Cirolana phuketensissp. n. was collected from coral rubble from the Andaman sea coast of Thailand. C. phuketensissp. n. is described and fully illustrated; C. phuketensissp. n. can be recognized by the presence of transverse sutures on pereonites 2-4, pereonite 7 having three transverse sutures forming a nodulose ridge, antennula peduncle with articles 1 and 2 fully fused; pleotelson dorsal surface with 2 sub-median longitudinal carinae, each of which has one prominent tubercle, lateral margins weakly convex, and posterior margin narrow and rounded; 6 molariform robust setae pereopod 1 on inferior margin of merus and the penial openings are two low tubercles. A dichotomous key to species of Cirolana in Thailand is given. PMID- 29134005 TI - Taxonomic study of the genus Neocarpia Tsaur & Hsu, with descriptions of two new species from China (Hemiptera, Fulgoromorpha, Cixiidae). AB - The cixiid planthoppers genus Neocarpia Tsaur & Hsu, 2003 is reviewed. Two new species, N. acutata Zhi & Chen, sp. n. and N. reversa Zhi & Chen, sp. n., are described and illustrated from the southwest of China (Yunnan) to give the genus seven species in total. Female genitalia of four Chinese species are described and illustrated for the first time. A key to all known species of Neocarpia based on male genitalia, and a key to Chinese species (except for N. maai) based on female genitalia, are provided. The morphological characteristics of the posterior vagina, utilized to distinguish female species of Neocarpia, are also discussed. PMID- 29134006 TI - Cecidonius pampeanus, gen. et sp. n.: an overlooked and rare, new gall-inducing micromoth associated with Schinus in southern Brazil (Lepidoptera, Cecidosidae). AB - Galls induced by the larval stage of cecidosids (Lepidoptera: Cecidosidae) are complex, multi-trophic systems, still poorly studied. They may be associated with other insect feeding guilds, including inquilines, kleptoparasites, cecidophages, parasitoids, and predators. By causing death of the gall inducer early in life and altering the gall phenotype, inquilines may lead to misidentification of the true gall inducers. Here, we describe through light and scanning electron microscopy Cecidonius pampeanus, a new genus and species of cecidosid moth, from the Pampa biome, south Brazil. It induces unnoticed, small galls under swollen stems of Schinus weinmannifolius Mart. ex Engl. (Anacardiaceae). Such galls are severely attacked early in ontogeny either by unidentified parasitoids belonging to Lyrcus Walker (Pteromalidae) that feed upon the inducer, or by inquiline wasps of the genus Allorhogas Gahan (Braconidae). The inquilines modify the galls into large ones that last longer and promptly call attention. Free-living galls are rare and dehiscent, pupation of C. pampeanus occurring on the ground. Due to these reasons the true inducer has been overlooked in this case for more than a century. Additionally we inferred a phylogeny for Cecidosidae using sequences from mitochondrial and nuclear loci, and characterized genetic variation and gene flow across ten populations. Despite its natural history similarities with the African genus Scyrotis, Cecidonius is a much younger lineage, more closely related to the Neotropical cecidosids. C. pampeanus populations, which are now confined to a few mountain areas within its distribution range due to habitat destruction, are also genetically isolated, requiring conservation measures. PMID- 29134007 TI - Taxonomic notes on two sibling species of Metellina from Asia (Araneae, Tetragnathidae). AB - Two sibling species, Metellina orientalis (Spassky, 1932) and M. kirgisica (Bakhvalov, 1974), occurring in the Middle East and Central Asia are redescribed and their distributions mapped. The previously unknown male of M. kirgisica is described for the first time. Stridulatory files on male chelicera of Metellina are also documented for the first time. The occurrence of M. kirgisica in Azerbaijan and Tajikistan and the presence of M. orientalis in Turkey are confirmed. PMID- 29134008 TI - A genome-wide phylogeny of jumping spiders (Araneae, Salticidae), using anchored hybrid enrichment. AB - We present the first genome-wide molecular phylogeny of jumping spiders (Araneae: Salticidae), inferred from Anchored Hybrid Enrichment (AHE) sequence data. From 12 outgroups plus 34 salticid taxa representing all but one subfamily and most major groups recognized in previous work, we obtained 447 loci totalling 96,946 aligned nucleotide sites. Our analyses using concatenated likelihood, parsimony, and coalescent methods (ASTRAL and SVDQuartets) strongly confirm most previous results, resolving as monophyletic the Spartaeinae, Salticinae (with the hisponines sister), Salticoida, Amycoida, Saltafresia, and Simonida. The agoriines, previously difficult to place beyond subfamily, are finally placed confidently within the saltafresians as relatives of the chrysillines and hasariines. Relationships among the baviines, astioids, marpissoids, and saltafresians remain uncertain, though our analyses tentatively conclude the first three form a clade together. Deep relationships, among the seven subfamilies, appear to be largely resolved, with spartaeines, lyssomanines, and asemoneines forming a clade. In most analyses, Onomastus (representing the onomastines) is strongly supported as sister to the hisponines plus salticines. Overall, the much-improved resolution of many deep relationships despite a relatively sparse taxon sample suggests AHE is a promising technique for salticid phylogenetics. PMID- 29134009 TI - Occurrence and the ecological implication of a tropical anguillid eel Anguilla marmorata from peninsular Malaysia. AB - Recent studies suggested that accurate species identification in the tropical anguillid eels based on morphological examination requires confirmation by molecular genetic analysis. Previous studies found that two tropical anguillid eels, Anguilla bicolor bicolor and A. bengalensis bengalensis, were found in peninsular Malaysia (West Malaysia) based on morphological and molecular genetic analyses. This study is the first record of A. marmorata in peninsular Malaysia confirmed by both morphological and molecular genetic analyses. The present study also suggests that accurate tropical eel species identification is difficult by morphological identification alone; therefore, molecular genetic analysis is needed for precise species confirmation. PMID- 29134010 TI - Nornalup, a new genus of pselaphine beetle from southwestern Australia (Coleoptera, Staphylinidae, Pselaphinae, Faronitae). AB - A new genus and three new species of the southwestern Australian pselaphine beetles belonging to the supertribe Faronitae are described: Nornalup Park & Chandler, gen. n., based on Nornalup afoveatus Park & Chandler, sp. n., Nornalup quadratus Park & Chandler, sp. n., and Nornalup minusculus Park & Chandler, sp. n. Illustrations of their habitus and major diagnostic characters are provided, as well as distribution maps and a key to species. PMID- 29134011 TI - The larvae of Sericostoma bergeri Malicky, 1973 and Sericostoma herakles Malicky, 1999 (Trichoptera, Sericostomatidae). AB - This paper describes the previously unknown larvae of Sericostoma bergeri and S. herakles (Trichoptera: Sericostomatidae) restricted to European Ecoregion 6 (= Hellenic western Balkan). Information on the morphology of the larvae is given, and the most important diagnostic features are illustrated. Sericostoma bergeri and S. herakles can be easily separated from known sericostomatid larvae of Ecoregion 6 (Schizopelex huettingeri, Oecismus monedula, Sericostoma flavicorne and S. personatum) by the shape of the pronotum, presence or lack of a comma-like marking on the lateral protuberance, by the number of setae on abdominal dorsum IX, and by distribution patterns. With respect to the latter, S. bergeri is a micro-endemic of the Greek Islands of Euboea and Andros whereas S. herakles is an endemic of the Peloponnese. The species are integrated in a dichotomous key including the currently known Sericostomatidae larvae of the Hellenic western Balkan. In addition, ecological information on the two species is provided. PMID- 29134012 TI - Morphological analysis of Trichomycterus areolatus Valenciennes, 1846 from southern Chilean rivers using a truss-based system (Siluriformes, Trichomycteridae). AB - Trichomycterus areolatus Valenciennes, 1846 is a small endemic catfish inhabiting the Andean river basins of Chile. In this study, the morphological variability of three T. areolatus populations, collected in two river basins from southern Chile, was assessed with multivariate analyses, including principal component analysis (PCA) and discriminant function analysis (DFA). It is hypothesized that populations must segregate morphologically from each other based on the river basin that they were sampled from, since each basin presents relatively particular hydrological characteristics. Significant morphological differences among the three populations were found with PCA (ANOSIM test, r = 0.552, p < 0.0001) and DFA (Wilks's lambda = 0.036, p < 0.01). PCA accounted for a total variation of 56.16% by the first two principal components. The first Principal Component (PC1) and PC2 explained 34.72 and 21.44% of the total variation, respectively. The scatter-plot of the first two discriminant functions (DF1 on DF2) also validated the existence of three different populations. In group classification using DFA, 93.3% of the specimens were correctly-classified into their original populations. Of the total of 22 transformed truss measurements, 17 exhibited highly significant (p < 0.01) differences among populations. The data support the existence of T. areolatus morphological variation across different rivers in southern Chile, likely reflecting the geographic isolation underlying population structure of the species. PMID- 29134013 TI - Southern Ocean Echinoids database - An updated version of Antarctic, Sub Antarctic and cold temperate echinoid database. AB - This database includes over 7,100 georeferenced occurrence records of sea urchins (Echinodermata: Echinoidea) obtained from samples collected in the Southern Ocean (+180 degrees W/+180 degrees E; -35 degrees /-78 degrees S) during oceanographic cruises led over 150 years, from 1872 to 2015. Echinoids are common organisms of Southern Ocean benthic communities. A total of 201 species is recorded, which display contrasting depth ranges and distribution patterns across austral provinces and bioregions. Echinoid species show various ecological traits including different nutrition and reproductive strategies. Information on taxonomy, sampling sites, and sampling sources are also made available. Environmental descriptors that are relevant to echinoid ecology are also made available for the study area (-180 degrees W/+180 degrees E; -45 degrees /-78 degrees S) and for the following decades: 1955-1964, 1965-1974, 1975-1984, 1985 1994 and 1995-2012. They were compiled from different sources and transformed to the same grid cell resolution of 0.1 degrees per pixel. We also provide future projections for environmental descriptors established based on the Bio-Oracle database (Tyberghein et al. 2012). PMID- 29134014 TI - On the identity of Leptoxis taeniata - a misapplied name for the threatened Painted Rocksnail (Cerithioidea, Pleuroceridae). AB - The Painted Rocksnail, currently known as Leptoxis taeniata, is a federally threatened species native to the Mobile River basin in Alabama, USA. Presently restricted to four disjunct populations, the species is at considerable risk of extinction after a range decline of over 95% in the 20th century because of habitat alteration following impoundment of the Coosa River. Here, we reassess the identity and historical range of the Painted Rocksnail to improve communication and conservation efforts for the species. We determined that L. taeniata is a synonym of L. picta and that the name L. taeniata has been misapplied to the current concept of the Painted Rocksnail for which L. coosaensis is the oldest available name. Leptoxis coosaensis and L. picta are herein redescribed. After examination of historical material, we determined that records of the Painted Rocksnail outside the Coosa River drainage were misidentifications. Thus, we redefine the historical range of the Painted Rocksnail as restricted to the Coosa River and select tributaries above the Fall Line at Wetumpka, Alabama, rather than extending into the Alabama River as previously thought. Leptoxis coosaensis is in dire need of conservation, and management plans should take into consideration the revised historical range of the species. PMID- 29134015 TI - Biogeography and phylogenetic position of Enchodeloides signyensis (Loof, 1975), gen. n., comb. n. from Maritime Antarctic (Nematoda, Nordiidae). AB - The taxonomic position of the endemic Antarctic species Enchodeloides signyensis (Loof, 1975), gen. n., comb. n. (= Enchodelus signyensis Loof, 1975) is discussed on the basis of morphological study, including SEM, morphometric data, postembryonic observations, and sequence data of 18S rDNA and the D2-D3 expansion fragments of the large subunit rDNA. A number of characters such as the cuticle and stoma structures, including the presence of moderately developed cuticularised ring around the oral aperture, peculiarities of pharynx expansion, size and position of the posterior pair of pharyngeal nuclei, a less complex uterus, and the position of a posterior ventromedian supplement show that this species differs substantially from the other members of the genus Enchodelus. Furthermore, both the 18S and 28S rDNA-based phylogenetic trees of the Enchodelus sequences available in the GenBank formed two distinct clusters with E. signyensis being a part of a well-supported group with species of the genus Pungentus; therefore, it is proposed that its taxonomic position should be reconsidered. PMID- 29134016 TI - A new species of Notodiaptomus from the Ecuadorian Andes (Copepoda, Calanoida, Diaptomidae). AB - Notodiaptomus cannarensissp. n. is described from a reservoir on the Amazonian slope of the Ecuadorian Andes. The new species is unique among diaptomid calanoid copepods in the display of hypertrophied, symmetrical wing-like extensions at each side of the female composite genital somite. Furthermore, it displays a female urosome reduced to only two somites due to the incorporation of abdominal somites III and IV to the composite genital double-somite, and a male right fifth leg with the outer spine of second exopodal segment recurved and implanted proximally on margin. It differs from any other Notodiaptomus in the display of a large rectangular lamella on proximal segment of exopod of male right fifth leg. The species is currently known only from Mazar reservoir, a eutrophic water body placed above 2127 m a.s.l. on the River Paute (Canar Province; southern Ecuador), where it is the most common crustacean in the water column. PMID- 29134017 TI - New species of Rogmocrypta Simon, 1900 from New Caledonia, with remarks on relationships and distribution (Araneae, Salticidae). AB - Five new species of Rogmocrypta: R. karolinae (?), R. koniambo (?), R. patryki (?), R. raveni (?), and R. rollardae (?) are diagnosed, described, and illustrated. The definition of the genus is ammended and its distribution and relationships are discussed. PMID- 29134019 TI - The cockroach genus Sorineuchora Caudell, 1927 from China (Blattodea, Ectobiidae, Pseudophyllodromiinae). AB - In this paper, three new species (S. bimaculatasp. n., S. viridissp. n., and S. hispidasp. n.) and five known species, S. formosana (Matsumura, 1913), S. nigra (Shiraki, 1908), S. shanensis (Princis, 1950), S. bivitta (Bey-Bienko, 1969), and S. undulata (Bey-Bienko, 1958), are described and illustrated. Sorineuchora undulata was previously synonymized with S. nigra, and is now reinstated as a valid species. A key to the males of Sorineuchora from China is provided. PMID- 29134018 TI - A gene-tree test of the traditional taxonomy of American deer: the importance of voucher specimens, geographic data, and dense sampling. AB - The taxonomy of American deer has been established almost entirely on the basis of morphological data and without the use of explicit phylogenetic methods; hence, phylogenetic analyses including data for all of the currently recognized species, even if based on a single gene, might improve current understanding of their taxonomy. We tested the monophyly of the morphology-defined genera and species of New World deer (Odocoileini) with phylogenetic analyses of mitochondrial DNA sequences. This is the first such test conducted using extensive geographic and taxonomic sampling. Our results do not support the monophyly of Mazama, Odocoileus, Pudu, M. americana, M. nemorivaga, Od. hemionus, and Od. virginianus. Mazama contains species that belong to other genera. We found a novel sister-taxon relationship between "Mazama" pandora and a clade formed by Od. hemionus columbianus and Od. h. sitkensis, and transfer pandora to Odocoileus. The clade formed by Od. h. columbianus and Od. h. sitkensis may represent a valid species, whereas the remaining subspecies of Od. hemionus appear closer to Od. virginianus. Pudu (Pudu) puda was not found sister to Pudu (Pudella) mephistophiles. If confirmed, this result will prompt the recognition of the monotypic Pudella as a distinct genus. We provide evidence for the existence of an undescribed species now confused with Mazama americana, and identify other instances of cryptic, taxonomically unrecognized species-level diversity among populations here regarded as Mazama temama, "Mazama" nemorivaga, and Hippocamelus antisensis. Noteworthy records that substantially extend the known distributions of M. temama and "M." gouazoubira are provided, and we unveil a surprising ambiguity regarding the distribution of "M." nemorivaga, as it is described in the literature. The study of deer of the tribe Odocoileini has been hampered by the paucity of information regarding voucher specimens and the provenance of sequences deposited in GenBank. We pinpoint priorities for future systematic research on the tribe Odocoileini. PMID- 29134020 TI - Three new species of the Chinese planthopper genus Tetricodes Fennah (Hemiptera, Fulgoroidea, Issidae, Parahiraciini). AB - The diagnostic characters of the Chinese planthopper genus Tetricodes Fennah, 1956 are redefined. Three new species of this genus, T. ansatus Chang & Chen, sp. n. (China: Guangxi), T. parvispinus Chang & Chen, sp. n. (China: Guizhou) and T. similis Chang & Chen, sp. n. (China: Guizhou) are described and illustrated. The female genitalia of the genus is described and illustrated for the first time. A checklist and key to the species of Tetricodes are given. The synonymy of Tetricodes songae Zhang & Chen, 2009 with Tetricodes polyphemus Fennah, 1956, syn. n., is proposed. PMID- 29134021 TI - New species of Trigonalyidae (Hymenoptera) from NW China. AB - Four new species of Trigonalyidae are described and illustrated from Qinling Mts (Shaanxi, NW China): Bareogonalos xibeidai Tan & van Achterberg, sp. n., Jezonogonalos mandibularissp. n., J. shaanxiensissp. n., and Taeniogonalos paraclypeatasp. n.Orthogonalys hirasana Teranishi, 1929, is re-instated and reported from China. The female of Taeniogonalos alticola (Tsuneki, 1991) is described for the first time. In total, 18 species are known from Shaanxi province, 20 species for NW China, and eight described species are newly recorded for Shaanxi: Jezonogonalos luteata Chen et al., 2014, Orthogonalys hirasana Teranishi, 1929, O. elongata Teranishi, 1929, Pseudogonalos hahnii (Spinola, 1840), Taeniogonalos alticola (Tsuneki, 1991), T. formosana (Bischoff, 1913), T. taihorina (Bischoff, 1914), and Teranishia glabrata Chen et al., 2014. Poecilogonalos maga Teranishi, 1929, syn. n. and Taiwanogonalos claripennis Tsuneki, 1991, syn. n. are new synonyms of Taeniogonalos taihorina (Bischoff, 1914) and Taiwanogonalos alishana Tsuneki, 1991, syn. n. of Taeniogonalos alticola (Tsuneki, 1991). Revised keys to species of the genera Bareogonalos, Jezonogonalos, and Orthogonalys are included. PMID- 29134022 TI - Larva and pupa of Megatoma (s. str.) undata (Linnaeus, 1758) with remarks on biology and economic importance (Coleoptera, Dermestidae). AB - An updated description of the final larval instar and pupa of Megatoma (s. str.) undata (Linnaeus, 1758) (Coleoptera: Dermestidae) is presented. Several morphological characteristics of M. undata larvae are documented and discussed: antenna, epipharynx, mandibula, maxilla, ligula with labial palpi, hastisetae, terga, and condition of the antecostal suture. The paper is fully illustrated and includes some important additions to extend notes on this species available in the references. Summarised data about biology, economic importance, and distribution of M. undata are also provided. PMID- 29134023 TI - A new species of Oxyptilus Zeller from the southwestern United States (Lepidoptera, Pterophoridae). AB - Oxyptilus eleaneraesp. n., is described from New Mexico, Arizona, and Southwest Texas, and compared with the only other Oxyptilus occurring in the Nearctic Region, O. delawaricus Zeller. A redescription is provided for O. delawaricus. Adults and male and female genitalia are illustrated for both species. Key morphological characters, distributions, and relationships within the genus are discussed. PMID- 29134024 TI - Hidden in the urban parks of New York City: Themira lohmanus, a new species of Sepsidae described based on morphology, DNA sequences, mating behavior, and reproductive isolation (Sepsidae, Diptera). AB - New species from well-studied taxa such as Sepsidae (Diptera) are rarely described from localities that have been extensively explored and one may think that New York City belongs to this category. Yet, a new species of Themira (Diptera: Sepsidae) was recently discovered which is currently only known to reside in two of New York City's largest urban parks. Finding a new species of Themira in these parks was all the more surprising because the genus was revised in 1998 and is not particularly species-rich (13 species). Its status is confirmed as a new species based on morphology, DNA sequences, and reproductive isolation tests with a closely related species, and is described as Themira lohmanus Ang, sp. n. The species breeds on waterfowl dung and it is hypothesized that this makes the species rare in natural environments. However, it thrives in urban parks where the public feeds ducks and geese. The mating behavior of Themira lohmanus was recorded and is similar to the behavior of its closest relative T. biloba. PMID- 29134025 TI - Status of the new genera in Gistel's "Die Insecten-Doubletten aus der Sammlung des Herrn Grafen Rudolph von Jenison Walworth" issued in 1834. AB - All new genus-group names included in Gistel's list of Coleoptera from the collection of Count Rudolph von Jenison Walwort, published in 1834, are recorded. For each of these names, the originally included available species are listed and for those with at least one available species included, the type species and current status are provided. The following new synonymies are proposed [valid names in brackets]: Auxora [Nebria Latreille, 1806; Carabidae], Necrotroctes [Velleius Leach, 1819; Staphylinidae], Epimachus [Ochthephilum Stephens, 1829; Staphylinidae], Ocys [Anaulacaspis Ganglbauer, 1895; Staphylinidae], Hydatobia [Autalia Samouelle, 1819; Staphylinidae], Hedonius [Pyrophorus Billberg, 1820; Elateridae], Charmionus [Chalcolepidius Eschscholtz, 1829; Elateridae], Lamprias [Alaus Eschscholtz, 1829; Elateridae], Trypheus [Aeolus Eschscholtz, 1829; Elateridae], Antiphus [Cardiorhinus Eschscholtz, 1829; Elateridae], Phyletus [Lygistopterus Dejean, 1833; Lycidae], Phyllogaster [Lucidota Laporte, 1833; Lampyridae], Pyrrhigius [Phosphaenus Laporte, 1833; Lampyridae], Erota [Luciola Laporte, 1833; Lampyridae], Oxypterus [Aspisoma Laporte, 1833; Lampyridae], Phyllophagus [Chauliognathus Hentz, 1830; Cantharidae], Epaphius [Astylus Laporte, 1836; Melyridae], Isomerus [Choleva Latreille, 1797; Leiodidae], Berecyntha [Aulacochilus Chevrolat, 1836; Erotylidae], Geophilus [Psammodius Fallen, 1807; Scarabaeidae], Ceraunus [Golofa Hope, 1837; Scarabaeidae], Atrimedeus [Pentodon Hope, 1837; Scarabaeidae], Eupalus [Temnorhynchus Hope, 1837; Scarabaeidae], Polycarmes [Anoxia Laporte, 1832; Scarabaeidae], Acidota [Amphicoma Latreille, 1807; Glaphyridae], Cecrops [Mylaris Pallas, 1781; Tenebrionidae], Pythonissus [Zophobas Dejean, 1834; Tenebrionidae], Physignathus [Cymatothes Dejean, 1834; Tenebrionidae], Pelops [Prionychus Solier, 1835; Tenebrionidae], Accantosomus [Semiotus Eschscholtz, 1829; Elateridae]. The type species of the following genus-group taxa are proposed: Ocys [Aleochara nigra Gravenhorst, 1802; Staphylinidae], Hydatobia [Staphylinus impressus Olivier, 1795; Staphylinidae], Hedonius [Elater noctilucus Linnaeus, 1758; Elateridae], Charmionus [Elater porcatus Linnaeus, 1767; Elateridae], Epaphius [Dasytes variegatus Germar, 1823; Melyridae], Geophilus [Scarabeus asper Fabricius, 1775; Scarabaeidae], Atrimedeus [Scarabaeus punctatus Villers, 1789; Scarabaeidae], Polycarmes [Melolontha villosa Fabricius, 1781; Scarabaeidae], Cecrops [Tenebrio gigas Linnaeus, 1763; Tenebrionidae], Pythonissus [Helops morio Fabricius, 1777; Tenebrionidae], Ceratades [Cerambyx sutor Linnaeus, 1758; Cerambycidae]. The following genus-group names are declared nomina oblita [nomina protecta in square brackets]: Berecyntha [Aulacochilus Chevrolat, 1836; Erotylidae], Ceraunus [Golofa Hope, 1837; Scarabaeidae], Atrimedeus [Pentodon Hope, 1837; Scarabaeidae], Eupalus [Temnorhynchus Hope, 1837; Scarabaeidae], Pelops [Prionychus Solier, 1835; Tenebrionidae]. PMID- 29134027 TI - Salangathelphusa peractio, a new species of lowland freshwater crab from Pulau Langkawi, Peninsular Malaysia (Crustacea, Brachyura, Gecarcinucidae). AB - A new species of lowland freshwater crab of the family Gecarcinucidae, Salangathelphusa peractio, is described from Langkawi, an island off the northwestern coast of peninsular Malaysia. Salangathelphusa peractiosp. n. can be separated from S. brevicarinata (Hilgendorf, 1882) in having a proportionately broader external orbital tooth, a distinctly concave posterolateral margin, and the terminal segment of the male first gonopod is not distinctly bent laterally outwards; and from S. anophrys (Kemp, 1923) by its more quadrate carapace and the terminal segment of the male first gonopod possessing a relatively longer and less curved distal part. This is sixth wholly freshwater brachyuran species known from the island. PMID- 29134026 TI - Type material of Acanthocephala, Nematoda and other non-helminths phyla (Cnidaria, Annelida, and Arthropoda) housed in the Helminthological Collection of the Oswaldo Cruz Institute/ FIOCRUZ (CHIOC), Rio de Janeiro, Brazil, from 1979 to 2016. AB - The third part of the catalogue of type material in the Helminthological Collection of the Oswaldo Cruz Institute/FIOCRUZ (CHIOC), comprising types deposited between 1979 and 2016, is presented to complement the first list of all types that was published in 1979. This part encompasses Acanthocephala, Nematoda and the other non-helminth phyla Cnidaria, Annelida, and Arthropoda. Platyhelminthes was covered in the first (Monogenoidea) and second (Rhabditophora Trematoda and Cestoda) parts of the catalogue published in September 2016 and March 2017, respectively. The present catalogue comprises type material for 116 species distributed across five phyla, nine classes, 50 families, and 80 genera. Specific names are listed systematically, followed by type host, infection site, type locality, and specimens with their collection numbers and references. Species classification and nomenclature are updated. PMID- 29134028 TI - A new species of Physoctonus Mello-Leitao, 1934 from the 'Campos formations' of southern Amazonia (Scorpiones, Buthidae). AB - Further studies on new specimens of the rare genus Physoctonus Mello-Leitao, 1934, lead to the description of a third new species. Until now only Physoctonus debilis (C. L. Koch, 1840) and Physoctonus striatus Esposito et al., 2017, were known from sites located in the caatingas of the north-east region of Brazil. The new species of Physoctonus was collected by the French arachnologist J. Vellard in the Campos do Para during his field trips back to the 1920/1930, and entrusted to the author in the early 1980s. The populations of P. debilis and P. striatus from north-east Brazil and that of the new species certainly present disrupted distributions. Biogeographical comments on this pattern of distribution are also added. PMID- 29134029 TI - Five new species of the genus Euplocania Enderlein (Psocodea, 'Psocoptera', Psocomorpha, Ptiloneuridae) from Colombia. AB - Five new species of Euplocania from Colombia belonging in four species groups are here described and illustrated. They increase to 22 the number of species described in the genus, thirteen of which are endemic to Colombia, with one species shared with Brazil and Peru. Three new species groups of Euplocania are here diagnosed. A key to the identification of males of Colombian Euplocania is included. PMID- 29134030 TI - A new genus of protorhyssaline wasps in Raritan amber (Hymenoptera, Braconidae). AB - A second species of protorhyssaline wasps (Braconidae) is described and figured from inclusions in Upper Cretaceous (Turonian) amber of the Raritan Formation in New Jersey, USA. Rhetinorhyssalites emersoni, gen. n., sp. n., is distinguished from other protorhyssalines, particularly the contemporaneous Protorhyssalus goldmani. PMID- 29134031 TI - The dipteran family Celyphidae in the New World, with discussion of and key to world genera (Insecta, Diptera). AB - The family Celyphidae (Diptera, Lauxanioidea) is verified as part of the New World fauna, with a second specimen discovered of a species described from French Guiana in 1844 by P.J.M. Macquart. As this species possesses characteristics that clearly suggest a separate lineage from the Old World celyphids, a new genus is proposed, Atopocelyphusgen. n., with the type species, Celyphus ruficollis Macquart, in the new combination Atopocelyphus ruficollis (Macquart), comb. n. A key to world genera of Celyphidae is presented, along with discussion of generic concepts. Chamaecelyphus Frey is synonymized under Spaniocelyphus Hendel, syn. n., resulting in the following 10 new combinations: Spaniocelyphus africanus (Walker), comb. n.; S. dichrous (Bezzi), comb. n.; S. gutta (Speiser), comb. n.; S. halticinus (Frey), comb. n.; S. kalongensis (Vanschuytbroek), comb. n.; S. ruwenzoriensis (Vanschuytbroek), comb. n.; S. straeleni (Vanschuytbroek), comb. n.; S. upembaensis (Vanschuytbroek), comb. n.; S. violaceus (Vanschuytbroek), comb. n.; S. vrydaghi (Vanschuytbroek), comb. n. The subgenera of Celyphus Dalman are elevated to genus rank, as Paracelyphus Bigot, stat. rev., and Hemiglobus Frey, stat. rev., resulting in the following 17 new and revised combinations: Hemiglobus cheni (Shi), comb. n.; H. eos (Frey), comb. n.; H. lacunosus Frey, comb. rev.; H. pellucidus Frey, comb. rev.; H. planitarsalis (Shi), comb. n.; H. porosus (Tenorio), comb. n.; H. pulchmaculatus (Liu & Yang), comb. n.; H. quadrimaculatus (Tenorio), comb. n.; H. resplendens Frey, comb. rev.; H. rugosus (Tenorio), comb. n.; H. testaceus (Malloch), comb. n.; H. trichoporis (Shi), comb. n.; H. unicolor Frey, comb. rev.; H. violaceus Chen, comb. rev.; Paracelyphus hyacinthus Bigot, comb. rev.; P. medogis (Shi), comb. n.; P. vittalis (Shi), comb. n. PMID- 29134032 TI - The larva of Adicella syriaca, including a key to the European larvae of Adicella McLachlan, 1877 (Trichoptera, Leptoceridae). AB - Adicella syriaca is a leptocerid caddisfly distributed throughout the Balkan Peninsula, the Carpathians, the Hungarian Lowlands, the Pontic Province, and the Caucasus. This paper describes the previously unknown larva of this species, based on material from the Greek island of Corfu. Information on the morphology of the fifth larval instar is given, and the most important diagnostic features are illustrated. A key to the known larvae of the European species of Adicella McLachlan, 1877 is provided. In the context of existing identification keys, the larva of Adicella syriaca Ulmer, 1907 keys together with Adicella cremisa Malicky, 1972, but the species pair can be easily separated by the number of setae on the pro- and mesonotum, and setation patterns on abdominal dorsum IX. PMID- 29134033 TI - A New Cryptic Lactura from Texas (Lepidoptera, Zygaenoidea, Lacturidae). AB - A new species of Lactura is described from Texas: Lactura rubritegulasp. n. Identity of the new species can be reliably determined by both larval and adult characters, CO1 haplotypes, and its late-spring period of flight activity. Male genitalic features overlap with those of L. basistriga (Barnes & McDunnough, 1913), whereas female structures differ markedly between the pair. The new Sideroxylon-feeding species, rare in collections, is found principally in limestone areas in the vicinity San Antonio, Texas, westward through the southern Hill Country. We illustrate the adult and larval stages and male and female genitalia, review available DNA barcode data that support the recognition of the new Lactura, and briefly characterize its life history. PMID- 29134034 TI - At home at least: the taxonomic position of some north African Xerocrassa species (Pulmonata, ). AB - In order to clarify the systematic position of Helix latastei Letourneux in Letourneux & Bourguignat, 1887, and Helix latasteopsis Letourneux & Bourguignat, 1887, a comprehensive approach using morphological and molecular methods is presented. The investigation of the genital organs of both species showed that they belong to the genus Xerocrassa Monterosato, 1892 with two very small dart sacs and a few tubiform glandulae mucosae. In our phylogenetic analysis using the mitochondrial markers COI, 16S and the nuclear cluster 5.8-ITS2-28S, the results of the anatomical research were confirmed. Thus, the genus Ereminella Pallary, 1919, which is based on H. latastei, becomes a junior synonym of Xerocrassa. A review of the genus-level taxa Xerobarcana Brandt, 1959, and Xeroregima Brandt, 1959, showed that these should also be considered as synonyms of Xerocrassa. A third species, Helix lacertara Bourguignat, 1863 from Algeria was found to be closely related to X. latastei based on its shell morphology. A map showing the distribution of the three species treated is supplied. PMID- 29134035 TI - New Philippine species of Spilosmylus Kolbe (Neuroptera, Osmylidae). AB - New species of lance lacewings, Spilosmylus spilopteryxsp. n. and Spilosmylus tephrodestigmasp. n., are described from the Philippines and compared with congeners. Both species are characterised by a distinctive wing pattern, which in the case of Spilosmylus spilopteryxsp. n. is relatively spectacular among lacewings. An identification key to the species of Spilosmylus Kolbe known from the Philippines is also provided. PMID- 29134036 TI - Review of the tribe Chilocorini Mulsant from Iran (Coleoptera, Coccinellidae). AB - The Iranian checklist of the tribe Chilocorini Mulsant, 1846 (Coleoptera: Coccinellidae) is updated. In total, 13 species belonging to four genera (Brumoides Chapin, 1965, Chilocorus Leach, 1815, Exochomus Redtenbacher, 1843, and Parexochomus Barovsky, 1922) are listed from Iran. An identification key to all genera and species currently known from Iran is presented along with illustrations of adult specimens and male genitalia. PMID- 29134037 TI - Review of Perdita subgenus Procockerellia Timberlake (Hymenoptera, Andrenidae) and the first Perdita gynandromorph. AB - A systematic study of Perdita subgenus Procockerellia Timberlake and the related subgenus Allomacrotera Timberlake results in the synonymy of the latter with the former, and two specific synonymies: Perdita (Hexaperdita) glamis Timberlake is a junior synonym of Perdita (Procockerellia) stephanomeriae Timberlake, while Perdita (Procockerellia) brachyglossa Timberlake is a junior synonym of Perdita (Cockerellia) imbellis Timberlake. Perdita (Procockerellia) moldenkei Timberlake is moved to subgenus Cockerellia Ashmead. A revised subgeneric diagnosis and key to the three included species are provided. Diagnoses of species are updated with novel characters; distributions and biological data are expanded. A gynandromorph of P. (Procockerellia) moabensis Timberlake, the first known in the genus Perdita, is reported. PMID- 29134038 TI - The use of low cost compact cameras with focus stacking functionality in entomological digitization projects. AB - Digitization of specimen collections has become a key priority of many natural history museums. The camera systems built for this purpose are expensive, providing a barrier in institutes with limited funding, and therefore hampering progress. An assessment is made on whether a low cost compact camera with image stacking functionality can help expedite the digitization process in large museums or provide smaller institutes and amateur entomologists with the means to digitize their collections. Images of a professional setup were compared with the Olympus Stylus TG-4 Tough, a low-cost compact camera with internal focus stacking functions. Parameters considered include image quality, digitization speed, price, and ease-of-use. The compact camera's image quality, although inferior to the professional setup, is exceptional considering its fourfold lower price point. Producing the image slices in the compact camera is a matter of seconds and when optimal image quality is less of a priority, the internal stacking function omits the need for dedicated stacking software altogether, further decreasing the cost and speeding up the process. In general, it is found that, aware of its limitations, this compact camera is capable of digitizing entomological collections with sufficient quality. As technology advances, more institutes and amateur entomologists will be able to easily and affordably catalogue their specimens. PMID- 29134039 TI - Monogenea of fishes from the lagoon flats of Palmyra Atoll in the Central Pacific. AB - A survey of the monogeneans of fishes from the lagoon flats of Palmyra Atoll detected 16 species already reported from the Indo-West Pacific faunal region. A total of 653 individual fish from 44 species were collected from the sand flats bordering the lagoon of the atoll. Eighteen species of fish were infected with monogeneans. The monogenean species recovered were: Benedenia hawaiiensis on Acanthurus xanthopterus, Chaetodon auriga, Chaetodon lunula, Mulloidichthys flavolineatus, Pseudobalistes flavimarginatus and Rhinecanthus aculeatus; Ancyrocephalus ornatus on Arothron hispidus; Euryhaliotrema annulocirrus on Chaetodon auriga and Chaetodon lunula; Euryhaliotrema chrysotaeniae on Lutjanus fulvus; Euryhaliotrema grandis on Chaetodon auriga and Chaetodon lunula; Haliotrema acanthuri on Acanthurus triostegus; Haliotrema aurigae on Chaetodon auriga and Chaetodon lunula; Haliotrema dempsteri on Acanthurus xanthopterus; Haliotrema minutospirale on Mulloidichthys flavolineatus; Haliotrematoides patellacirrus on Lutjanus monostigma; Neohaliotrema bombini on Abudefduf septemfasciatus and Abudefduf sordidus; Acleotrema girellae and Acleotrema parastromatei on Kyphosus cinerascens; Cemocotylella elongata on Caranx ignobilis, Caranx melampygus and Caranx papuensis; Metamicrocotyla macracantha on Crenimugil crenilabris; and Pseudopterinotrema albulae on Albula glossodonta. All these monogenean-host combinations represent new geographical records. The monogenean species composition of the Palmyra Atoll is similar to that of the Hawaiian Islands. However, the number of species recovered was lower compared with other localities within the Indo-West Pacific, perhaps due to the geographical isolation of Palmyra Atoll. PMID- 29134040 TI - Revision of the West Palaearctic Polistes Latreille, with the descriptions of two species - an integrative approach using morphology and DNA barcodes (Hymenoptera, Vespidae). AB - The genus Polistes is revised for the West Palaearctic region based on morphology and DNA barcodes. The revision includes all known West Palaearctic species, raising the number of species in Europe to 14 and to 17 for the West Palaearctic realm. DNA barcodes were recovered from 15 species, 14 of which belong to the subgenus Polistes, and one, P. wattii, to the subgenus Gyrostoma. An integrative taxonomic approach combining morphology and molecular data (DNA barcoding) was employed to resolve longstanding taxonomic problems in this group. Two species, P. austroccidentalis van Achterberg & Neumeyer, sp. n. (= P. semenowi auctt.) from W and SW Europe and P. maroccanus Schmid-Egger, sp. n. from Morocco are described as new. Polistes bucharensis Erichson, 1849, and P. foederatus Kohl, 1898, were restored from synonymy. The following new synonyms are proposed: P. sulcifer Zimmermann, 1930, and Pseudopolistes sulcifer var. similator Zirngiebl, 1955, under P. semenowi Morawitz, 1889, syn. n.; Polistes iranus Guiglia, 1976, Polistes gallica var. ornata Weyrauch, 1938 and Polistes gallicus muchei Gusenleitner, 1976, under P. bucharensis Erichson, 1849, syn. n.; Polistes omissus var. ordubadensis Zirngiebl, 1955, and P. hellenicus Arens, 2011, under Polistes mongolicus du Buysson, 1911, syn. n. An illustrated key includes all species and additionally three species from the subgenera Aphanilopterus Meunier, 1888 and Gyrostoma Kirby, 1828 (including a Nearctic species recently introduced to Spain and two species occurring in Egypt, the Arabian Peninsula, and SW Asia). A phylogenetic analysis using Bayesian inference provides insights into phylogenetic relationships within the genus Polistes. PMID- 29134041 TI - A streamlined collecting and preparation protocol for DNA barcoding of Lepidoptera as part of large-scale rapid biodiversity assessment projects, exemplified by the Indonesian Biodiversity Discovery and Information System (IndoBioSys). AB - Here we present a general collecting and preparation protocol for DNA barcoding of Lepidoptera as part of large-scale rapid biodiversity assessment projects, and a comparison with alternative preserving and vouchering methods. About 98% of the sequenced specimens processed using the present collecting and preparation protocol yielded sequences with more than 500 base pairs. The study is based on the first outcomes of the Indonesian Biodiversity Discovery and Information System (IndoBioSys). IndoBioSys is a German-Indonesian research project that is conducted by the Museum fur Naturkunde in Berlin and the Zoologische Staatssammlung Munchen, in close cooperation with the Research Center for Biology - Indonesian Institute of Sciences (RCB-LIPI, Bogor). PMID- 29134042 TI - Direct Nerve Sutures in (Extended) Upper Obstetric Brachial Plexus Repair. AB - Background In rare, selected cases of severe (extended) upper obstetric brachial plexus palsy (OBPP), after supraclavicular exposure and distal mobilization of the traumatized trunks and careful neuroma excision, we decided to perform direct nerve coaptation with tolerable tension and immobilized the affected arm positioned in adduction and 90-degree elbow flexion for three weeks. Objectives We present our surgical technique and preliminary results in a prospective open patient series, including 22 patients (14 right and 8 left side affected) between 2009 and 2016, operated at a mean age of 8.4 months. Methods Analysis of functional results after a minimum of 18 months was conducted using the British Medical Research Council (BMRC) scale. Results All children reached 60-90 degrees of elbow flexion and 75 degrees of shoulder abduction at already six months after surgery. For those patients having already passed one year post surgery, the mean active shoulder abduction reached 92 degrees , and for those who past the 18 months 124 degrees . We discuss the actual knowledge about nerve coaptation under "reasonable" tension including its advantages and drawbacks. Conclusion This technique may be indicated in preoperatively selected cases of (extended) upper OBPP and may give good functional results. PMID- 29134043 TI - Foreword of the Special Issue on Motivation in Physical Education, Sport and Physical Activity and Health. PMID- 29134044 TI - The Effects of a Physical Education Intervention to Support the Satisfaction of Basic Psychological Needs on the Motivation and Intentions to be Physically Active. AB - The aim of the study was to investigate the effects of an intervention to support the basic psychological needs on the satisfaction of these needs, intrinsic motivation, intention to be physically active and some enjoyment-related outcomes in Physical Education. The present study incorporated strategies presented by Standage and Ryan (2012) in a previous study. A quasi-experimental study was conducted with two groups (nexperimental = 30; ncontrol = 23) of 2nd year Secondary Education students aged between 13 and 15 (M = 13.35, SD = .62) by delivering 24 physical education classes. The teacher in the experimental group underwent prior and continual training. The results revealed that the students from the experimental group showed a significant increase in the perception of autonomy and competence. Furthermore, the experimental group showed a greater perception than the control group in the enjoyment related to learning and contents. These results provide information about the efficacy of an intervention programme based on the strategies presented by Standage and Ryan (2012) to foster satisfaction of basic psychological needs and facilitate support for basic psychological needs to promote the development of positive learning-related outcomes. PMID- 29134045 TI - Teaching Games for Understanding: A Comprehensive Approach to Promote Student's Motivation in Physical Education. AB - It seems important to consider students' attitudes towards physical education (PE), and the way they learn sports. The present study examines students' perceptions of motivation and achievement in PE after experiencing three consecutive sport units. Two hundred and thirty seven students from the 1st, 2nd, 3rd, and 4th grade in a high school in Burgos (Spain) and two teachers agreed to participate. They were divided into two groups in order to compare two instructional approaches. The experimental group (A), 128 students, experienced Teaching Games for Understanding (TGfU), while the control group (B), 109 students, experienced a technical-traditional approach. Each group was taught by a different teacher. The study followed a mixed-method research design with quantitative (questionnaire) and qualitative (interview) data. Results revealed that group A showed greater motivation and achievement in PE than group B. Significant differences were found in achievement. Participants with better academic results in group A were more positive in sport participation. Meanwhile, students who practiced more extracurricular sports in group B were more actively involved in sport. Teachers disagreed greatly on the way sport should be taught in PE. PMID- 29134046 TI - Relationships between Physical Activity Levels, Self-Identity, Body Dissatisfaction and Motivation among Spanish High School Students. AB - The aim of this study was to examine the relationships between gender and the educational grade on the one hand, and physical activity levels, motivation, self identity, body dissatisfaction, the intention to be physically active and daily sitting time on the other, in a sample of Spanish high school adolescents. The sample consisted of 2087 Spanish students from the 3rd (n = 1141) and 4th grade (n = 946), both male (n = 1046) and female (n = 1041), ranging in age from 15 to 17 years old (M = 15.42; SD = .86). Students completed questionnaires to assess their levels of physical activity, self-identity, motivation, intention to be physically active and daily sitting time. The students' perceptions of their body height and mass were also tested. With the exception of walking MET values, the results showed gender differences in the variables tested. Male participants showed higher intrinsic motivation and lower amotivation than female participants. Furthermore, male students revealed higher levels of physical activity than female students. Finally, the research concluded with the importance of promoting intrinsic reasons for physical activity in order to encourage positive consequences in high school students. PMID- 29134047 TI - Middle and Elementary School Students' Changes in Self-Determined Motivation in a Basketball Unit Taught using the Tactical Games Model. AB - Studies examining student motivation levels suggest that this is a significant factor in students' engagement in physical education and may be positively affected when teachers employ alternative pedagogical models such as game centered approaches (GCAs). The aim of this study was to investigate changes in self-determined motivation of students as they participated in a GCA-basketball unit taught using the Tactical Games Model (TGM). Participants were 173 students (84 girls), 79 middle school (45 girls) and 94 (39 girls) elementary school students from four seventh and five fourth/fifth grade co-educational classes. Two teachers taught 32 (middle) and 33 (elementary) level one TGM basketball lessons. Need satisfaction and self-determined motivation data were collected using a previously validated instrument, while lesson context and teacher behavior data were recorded using systematic observation instruments. Repeated measures MANOVAs were employed to examine pre-posttest differences. Results revealed a significant main effect for time in need satisfaction for both middle (relatedness increased) and elementary school students (autonomy decreased) and a significant main effect in self-determined motivation for middle school students only (introjected regulation, external regulation, and amotivation all increased). Approximately 48%/42% (middle/elementary) of lesson time was game play, 22%/22% skill practice, 17%/17% management, and 13%/19% knowledge. The primary teacher behaviors used were instruction, management, specific observation, corrective feedback and modelling. Results indicate that it is important for future research to pay greater attention to the contextual factors associated with the application of the TGM, such as the students' previous exposure to TGM lessons, and the teachers' training and experience in utilizing the TGM. Indeed, results of the present study demonstrate that a longer-term commitment to the TGM is necessary to reduce controlling teacher behaviors, which will lead to positive changes in students' need satisfaction and self-determined motivation. Future research is therefore needed to embrace this challenge to provide an increased evidence-base for GCAs such as the TGM. PMID- 29134048 TI - The Cognitive and Motivation Intervention Program in Youth Female Volleyball Players. AB - This study, grounded in Self-Determination Theory (Deci and Ryan, 1985, 2002) was aimed to determine the influence of a cognitive-motivational intervention program, to improve the basic psychological need satisfaction of autonomy and competence, autonomous motivation, procedural knowledge, perceived performance and sport commitment, in youth volleyball players. Participants included 34 Under 19 female volleyball players. A quasi-experimental design was carried out with an experimental group (n = 16; M = 17.45; SD = .45) and a control group (n = 18; M = 16.64; SD = .70). The experimental group followed a multidimensional intervention program comprised of 24 sessions held over three months (two training sessions per week). It was based on two strategies: giving athletes the possibility of choice in specific training tasks (proposing training situations with several action alternatives) and questioning (cognitively involving players through tactical questions). A repeated-measures MANOVA 2 (group: experimental and control) x 2 (time: pre-test and post-test) was used to analyse the effect of Group x Time interaction. The results of the inter-group analysis showed significant differences in the post-test measurement between the experimental group and the control group (in favour of the experimental group) in the variables: basic psychological need satisfaction of autonomy and competence, autonomous motivation, procedural knowledge, perceived performance and sport commitment. Given the relevance of the cognitive-motivational processes, not only for performance but also for sport commitment, this intervention has important implications for sport coaching. PMID- 29134049 TI - The Prevalence and Covariates of Potential Doping Behavior in Kickboxing; Analysis among High-Level Athletes. AB - The official reports on doping behavior in kickboxing are alarming, but there have been no empirical studies that examined this problem directly. The aim of this study was to investigate the prevalence, gender differences and covariates of potential-doping-behavior, in kickboxing athletes. A total of 130 high-level kickboxing athletes (92 males, 21.37 +/- 4.83 years of age, 8.39 +/- 5.73 years of training experience; 38 women, 20.31 +/- 2.94 years of age; 9.84 +/- 4.74 years of training experience) completed questionnaires to study covariates and potential-doping behavior. The covariates were: sport factors (i.e. experience, success), doping-related factors (i.e. opinion about penalties for doping users, number of doping testing, potential-doping-behavior, etc.), sociodemographic variables, task- and ego-motivation, knowledge on sports nutrition, and knowledge on doping. Gender-based differences were established by independent t-tests, and the Mann-Whitney test. Multinomial logistic regression analyses were performed to define the relationships between covariates and a tendency toward potential doping behavior (positive tendency - neutral - negative tendency). The potential doping behavior was higher in those athletes who perceived kickboxing as doping contaminated sport. The more experienced kickboxers were associated with positive intention toward potential-doping behavior. Positive intention toward potential doping behavior was lower in those who had better knowledge on sports nutrition. The task- and ego-motivation were not associated to potential-doping behavior. Because of the high potential-doping-behavior (less than 50% of athletes showed a negative tendency toward doping), and similar prevalence of potential-doping behavior between genders, this study highlights the necessity of a systematic anti-doping campaign in kickboxing. Future studies should investigate motivational variables as being potentially related to doping behavior in younger kickboxers. PMID- 29134050 TI - Mental Strategies Predict Performance and Satisfaction with Performance among Soccer Players. AB - This study investigated the changes in mental strategies across the season and their effects on performance and satisfaction with individual performance. Data were collected three times: at the pre-season at Time 1 (T1; baseline), in the mid-season at Time 2 (T2; two-month follow-up), and at the end-of-season at Time 3 (T3; nine-month follow-up) among male soccer players (N = 97) aged 16-27. Athletes completed the questionnaires assessing the use of nine psychological strategies in competition and the level of satisfaction with individual performance. Endurance performance was measured objectively with a 300 m run. A high level of relaxation (T1) explained better 300 m run performance (T3) and a high level of self-talk explained a higher satisfaction with individual performance (T3). A rare use of distractibility and emotional control (T1) predicted a higher level of satisfaction with individual performance (T3). No predictive role of other psychological strategies was found. The use of emotional control, relaxation, and distractibility increased over the season, whereas the use of imagery and negative thinking declined. Besides the roles of self-talk, imagery, relaxation and goal-setting, the effects of distractibility and emotional control should be taken into account when considering athletes' mental training programs. PMID- 29134051 TI - Does Context, Practice or Competition affect Female Athletes' Achievement Goal Dominance, Goal Pursuit, Burnout and Motivation? AB - The goal of this study was to assess the effects of two different achievement sport contexts, practice and competition, on the motivational profile of professional/semi-professional athletes. Forty-eight Spanish national/international-level female athletes (basketball = 18; handball = 12; soccer = 11; volleyball = 7), mean age 25.14 +/- 3.43 years, agreed to participate in the study. They completed a questionnaire, prior and after training and competition, to assess achievement goals, achievement goal dominance, goal pursuit, motivational climate, motivation, burnout and perceived recovery-exertion. Data analyses revealed that, both in practice and competition, these team-sport athletes overwhelmingly showed a strong mastery-approach achievement goal in dominance as well as in pursuit. A significant finding was that this group of national/international-level, professional/semi-professional athletes not only adopted a mastery-approach achievement goal, but they also actively pursued it. It is also remarkable that this profile remained stable at post-tests, even after a painful defeat in competition, which produced a significant negative effect on the athletes' burnout (emotional and physical exhaustion and devaluation of sport participation) and self-determined motivation. As expected, the difference between total recovery and perceived exertion significantly increased after practice and competition. National/international-level team-sport professional/semi-professional female athletes held and pursue stable mastery-approach goal dominance. PMID- 29134052 TI - Effects of an Interpersonal Style Intervention for Coaches on Young Soccer Players' Motivational Processes. AB - The main goal of the study was to assess the effects of an intervention programme developed with soccer coaches, based on promoting strategies to optimise the satisfaction of the basic psychological needs of athletes. Eight soccer coaches, aged between 19 and 50 years (M = 32.5; SD = 14.34), participated in the study. They were selected intentionally (without academic or federative training) and divided equally into a control and an experimental group by random peer selection. Also, 109 soccer players, aged between 11 and 15 years (M = 13.78; SD = 1.38), divided into a control group (CG; n = 56) and an experimental group (EG; n = 53), participated in the experiment. The training programme (12 hours) was aimed to develop methodological and motivational strategies to promote autonomy, competence and relatedness need satisfaction among the players. The results showed that the participants in the EG decreased competence and relatedness control, while significantly increased (post-intervention) competence and relatedness needs satisfaction. Moreover, values for the EG did not decrease for autonomy, competence frustration and amotivation, while they increased for the sport commitment. Also, intrinsic motivation decreased in both groups (greater decrease in the CG). In conclusion, we can affirm the effectiveness of the training programme to create an environment of "bright side" motivation, and reduce thwarting styles, needs frustration and low self-determination levels. PMID- 29134053 TI - Motivational Antecedents of Well-Being and Health Related Behaviors in Adolescents. AB - Grounded in the Achievement Goal Theory framework of motivation and optimal functioning, there were two objectives of this study: (a) to test a model hypothesizing links between personal theories of school achievement, indices of the quality of academic engagement, wellbeing, and health-related behaviors, and (b) to explore whether the hypothesized model was invariant across gender groups. A multisection questionnaire pack tapping the targeted variables was administered to 967 teenagers (475 boys and 492 girls) aged between 11 to 16 years old. Structural equation modeling analysis revealed that Task theory of achievement predicted positively satisfaction in school and negatively boredom in school. An Ego theory of achievement was linked to higher levels of boredom in school. Satisfaction in school corresponded to higher life satisfaction, while boredom was negatively related. Higher life satisfaction was associated with lower tobacco, alcohol and marijuana consumption, more healthy food intake and greater levels of physical activity. The results revealed partial invariance of the model by gender. The quality of adolescents' involvement in the classroom holds important implications for adolescent's well-being and their health related behaviors. Interventions on the creation of a task-involving motivational climate in the school are proposed to promote healthy lifestyles among young people. PMID- 29134054 TI - Application of Two Intervention Programs in Order to Optimize Motivation and to Improve Eating Habits in Adult and Elderly Women. AB - The objective of this study was to analyse the effectiveness of two intervention programs: a physical exercise program with strategies to support the three basic psychological needs (autonomy, competence and relatedness); and a physical exercise program with nutritional education in order to improve the lifestyles of adult and elderly women who practiced functional maintenance. The Self Determination Theory was applied as the theoretical framework. A sample of 135 women aged between 40 and 88 years (59.66 +/- 10.76) who enrolled in a 12-week functional maintenance program and attended 24 exercise classes took part in the study. A quasi-experimental study was performed where strategies to support the three basic psychological needs were applied to one group and strategies for the improvement of eating habits were applied to the other group. No strategy was applied to the control group. The main results showed an improvement in experimental groups I and II when compared to the control group regarding the variables of autonomy, competence, intrinsic regulation, identified regulation, introjected regulation, external regulation and eating habits, after the application of the intervention programs. The conclusion is that both intervention programs were successful with this project's participants and that it is crucial to promote such intervention programs in functional maintenance classes, as they foster healthy lifestyles among participants. PMID- 29134055 TI - Influence of Goal Contents on Exercise Addiction: Analysing the Mediating Effect of Passion for Exercise. AB - Based on the self-determination theory (Deci and Ryan, 1985, 2000), the purpose of this study was to examine the effects of exercise goal contents on exercise addiction, taking into account the mediating effects of passion for exercise. A total of 384 university students (284 men and 100 women; Mage = 20.31, SD = 3.10) completed a questionnaire that measured exercise frequency and intensity, exercise goal contents (e.g. intrinsic: social affiliation, health management, skill development; extrinsic: image and social recognition), passion for exercise (e.g. harmonious and obsessive), and exercise addiction. After controlling the exercise frequency and intensity effects, results showed that goal contents did not directly predict exercise addiction. However, mediation analysis showed that goal contents predicted addiction through passion for exercise. These results support a motivational sequence in which extrinsic versus intrinsic goals influence exercise addiction because such goals are positively associated with obsessive passion for exercise and negatively associated with harmonious passion. PMID- 29134056 TI - Semicircular canals in Anolis lizards: ecomorphological convergence and ecomorph affinities of fossil species. AB - Anolis lizards are a model system for the study of adaptive radiation and convergent evolution. Greater Antillean anoles have repeatedly evolved six similar forms or ecomorphs: crown-giant, grass-bush, twig, trunk, trunk-crown and trunk-ground. Members of each ecomorph category possess a specific set of morphological, ecological and behavioural characteristics which have been acquired convergently. Here we test whether the semicircular canal system-the organ of balance during movement-is also convergent among ecomorphs, reflecting the shared sensory requirements of their ecological niches. As semicircular canal shape has been shown to reflect different locomotor strategies, we hypothesized that each Anolis ecomorph would have a unique canal morphology. Using three dimensional semilandmarks and geometric morphometrics, semicircular canal shape was characterized in 41 Anolis species from the Greater Antilles and the relationship between canal shape and ecomorph grouping, phylogenetic history, size, head dimensions, and perch characteristics was assessed. Further, canal morphology of modern species was used to predict the ecomorph affinity of five fossil anoles from the Miocene of the Dominican Republic. Of the covariates tested, our study recovered ecomorph as the single-most important covariate of canal morphology in modern taxa; although phylogenetic history, size, and head dimensions also showed a small, yet significant correlation with shape. Surprisingly, perch characteristics were not found to be significant covariates of canal shape, even though they are important habitat variables. Using posterior probabilities, we found that the fossil anoles have different semicircular canals shapes to modern ecomorph groupings implying extinct anoles may have been interacting with their Miocene environment in different ways to modern Anolis species. PMID- 29134057 TI - A 20-year investigation of declining leatherback hatching success: implications of climate variation. AB - Unprecedented increases in air temperature and erratic precipitation patterns are predicted throughout the twenty-first century as a result of climate change. A recent global analysis of leatherback turtle hatchling output predicts that the nesting site at Sandy Point National Wildlife Refuge (SPNWR) will experience the most significant regional climate alterations. We aimed to identify how local air temperatures and precipitation patterns influenced within-nest mortality and overall hatchling output at this site between 1990 and 2010. We show that while the greatest mortality occurred during the latest stages of development (stage three), the rate of embryo mortality was highest during the initial stages (stage zero) of development (approx. 3.8 embryos per day per clutch). Increased mortality at stage three was associated with decreased precipitation and increased temperature during this developmental period, whereas precipitation prior to, and during stage zero had the greatest influence on early mortality. There was a significant decline in overall hatching success (falling from 74% to 55%) and emergence rate (calculated from the number of hatchlings that emerged from the nest as a percentage of hatched eggs) which fell from 96% to 91%. However, there was no trend observed in local temperature or precipitation during this timeframe, and neither variable was related to hatching success or emergence rate. In conclusion, our findings suggest that despite influencing within-nest mortality, climatic variability does not account for the overall decline in hatchling output at SPNWR from 1990 to 2010. Further research is therefore needed to elicit the reasons for this decline. PMID- 29134058 TI - A test of four evolutionary hypotheses of pregnancy food cravings: evidence for the social bargaining model. AB - The onset of cravings for items not typically desired is often considered a hallmark of pregnancy. Given the ubiquity of cravings, this phenomenon remains surprisingly understudied. The current study tested four hypotheses of pregnancy food cravings: behavioural immune system, nutrient seeking, resource scarcity and social bargaining. The research took place in Tamil Nadu, South India, with pregnant women residing in rural villages (N = 94). Methods included structured interviews and anthropometric measures. Findings revealed that unripe mango and unripe tamarind were the two most frequently mentioned food cravings among this population, but were not sufficiently supported by the a priori models. Results confirmed that the social bargaining model was the best explanation for the etic category of toxic/pathogenic food items, suggesting that pregnant women crave dangerous foods when experiencing heightened social pressures. Finally, toxicity/pathogenicity was a confounding factor for the nutrient seeking and resource scarcity models, calling into question the validity of these models in adverse environments. Overall, these findings present important implications for research on pregnancy food cravings, such that in resource-scarce and pathogen dense environments, cravings might target teratogenic items that signal a need for increased social support. PMID- 29134059 TI - Speciation over the edge: gene flow among non-human primate species across a formidable biogeographic barrier. AB - Many genera of terrestrial vertebrates diversified exclusively on one or the other side of Wallace's Line, which lies between Borneo and Sulawesi islands in Southeast Asia, and demarcates one of the sharpest biogeographic transition zones in the world. Macaque monkeys are unusual among vertebrate genera in that they are distributed on both sides of Wallace's Line, raising the question of whether dispersal across this barrier was an evolutionary one-off or a more protracted exchange-and if the latter, what were the genomic consequences. To explore the nature of speciation over the edge of this biogeographic divide, we used genomic data to test for evidence of gene flow between macaque species across Wallace's Line after macaques colonized Sulawesi. We recovered evidence of post colonization gene flow, most prominently on the X chromosome. These results are consistent with the proposal that gene flow is a pervasive component of speciation-even when barriers to gene flow seem almost insurmountable. PMID- 29134060 TI - Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism. AB - Metabolism is the only biological system that can be fully modelled at genome scale. As a result, metabolic models have been increasingly used to study the molecular mechanisms of various diseases. Hypoxia, a low-oxygen tension, is a well-known characteristic of many cancer cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle and is a key enzyme in metabolic reprogramming in cancer metabolism. Here, we develop and manually curate a constraint-based metabolic model to investigate the mechanism of pyruvate dehydrogenase under hypoxia. Our results characterize the activity of pyruvate dehydrogenase and its decline during hypoxia. This results in lactate accumulation, consistent with recent hypoxia studies and a well-known feature in cancer metabolism. We apply machine-learning techniques on the flux datasets to identify reactions that drive these variations. We also identify distinct features on the structure of the variables and individual metabolic components in the switch from normoxia to hypoxia. Our results provide a framework for future studies by integrating multi-omics data to predict condition-specific metabolic phenotypes under hypoxia. PMID- 29134061 TI - The effect of leg-to-body ratio on male attractiveness depends on the ecological validity of the figures. AB - Leg-to-body ratio (LBR) predicts evolutionary fitness, and is therefore expected to influence bodily attractiveness. Previous investigations of LBR attractiveness have used a wide variety of stimuli, including line drawings, silhouettes, and computer-generated images based on anthropometric data. In two studies, community samples of heterosexual women from the USA rated the attractiveness of male figures presented as silhouettes and as detailed computer-generated images with three different skin tones (white, black, and an artificial grey). The effects of LBR depended on the image format. In particular, a curve-fitting analysis indicated that the optimally-attractive LBR for silhouettes was fractionally below the baseline, whereas the optima for more detailed computer-generated images was approximately 0.5 s.d. above the baseline and was similar for all three skin-tones. In addition, the participants' sensitivity to changes in the LBR was lowest for the silhouettes and highest for the grey figures. Our results add to evidence that the most attractive LBR is close to, but slightly above, the population mean, and caution that the effects of limb proportions on attractiveness depend on the ecological validity of the figures. PMID- 29134062 TI - Native freshwater species get out of the way: Prussian carp (Carassius gibelio) impacts both fish and benthic invertebrate communities in North America. AB - Prussian carp (Carassius gibelio) are one of the most noxious non-native species in Eurasia. Recently, Prussian carp, a non-native freshwater fish species, were genetically confirmed in Alberta, Canada and have been rapidly expanding their range in North America since establishment. Given their rapid range expansion, there is an increasing need to determine how Prussian carp may impact native species. We assessed the severity of the Prussian carp invasion by (i) determining their impact on fish communities, (ii) assessing their impact on benthic invertebrate communities, (iii) evaluating if Prussian carp alter abiotic conditions, and (iv) identifying where we find higher abundances of Prussian carp. When Prussian carp were established, we found significant changes to the fish community. Correspondingly, the degree of impact to benthic invertebrate communities was related to the stage of invasion (none, early or recent), where changes in fish communities were significantly concordant with changes in benthic invertebrate communities. Finally, we found that higher abundances of Prussian carp were significantly associated with lower abundances of a majority of native fish species. Altogether, using three lines of evidence, we determine that Prussian carp can have wide-ranging impacts on freshwater ecosystems in North America, pressing the need for management intervention. PMID- 29134063 TI - Diverse fen plant communities enhance carbon-related multifunctionality, but do not mitigate negative effects of drought. AB - Global change, like droughts, can destabilize the carbon sink function of peatlands, either directly or indirectly through changes in plant community composition. While the effects of drought and plant community composition on individual carbon (C) related processes are well understood, their effect on multiple C-related processes simultaneously-multifunctionality-is poorly known. We studied the effect of drought on four C-related processes (net and gross CO2 exchange, methane fluxes, and dissolved organic carbon content) in a plant removal experiment. Plant functional type (PFT) removal (graminoids, herbs, Polytrichum spp., incl. combinations) negatively affected multifunctionality; most markedly when all PFTs were removed. Our results corroborate a negative drought effect on C-related multifunctionality. Drought reduced multifunctionality, and this reduction was again largest when all PFTs were removed. Our data further indicate that much of these negative drought effects were carried over and maintained from the initial removal treatment. These results suggest that while a high diversity in plant functional types is associated to high C-related multifunctionality, plant community assembly does not drive the ability of peatlands to withstand the negative impacts of drought on multifunctionality. Hence, to safeguard the carbon cycling function in intact peatlands, the effects of climate change on the functional composition of the peatland plant community needs to be minimized. PMID- 29134064 TI - Cancer and intercellular cooperation. AB - The major transitions approach in evolutionary biology has shown that the intercellular cooperation that characterizes multicellular organisms would never have emerged without some kind of multilevel selection. Relying on this view, the Evolutionary Somatic view of cancer considers cancer as a breakdown of intercellular cooperation and as a loss of the balance between selection processes that take place at different levels of organization (particularly single cell and individual organism). This seems an elegant unifying framework for healthy organism, carcinogenesis, tumour proliferation, metastasis and other phenomena such as ageing. However, the gene-centric version of Darwinian evolution, which is often adopted in cancer research, runs into empirical problems: proto-tumoural and tumoural features in precancerous cells that would undergo 'natural selection' have proved hard to demonstrate; cells are radically context-dependent, and some stages of cancer are poorly related to genetic change. Recent perspectives propose that breakdown of intercellular cooperation could depend on 'fields' and other higher-level phenomena, and could be even mutations independent. Indeed, the field would be the context, allowing (or preventing) genetic mutations to undergo an intra-organism process analogous to natural selection. The complexities surrounding somatic evolution call for integration between multiple incomplete frameworks for interpreting intercellular cooperation and its pathologies. PMID- 29134065 TI - A bird-like skull in a Triassic diapsid reptile increases heterogeneity of the morphological and phylogenetic radiation of Diapsida. AB - The Triassic Period saw the first appearance of numerous amniote lineages (e.g. Lepidosauria, Archosauria, Mammalia) that defined Mesozoic ecosystems following the end Permian Mass Extinction, as well as the first major morphological diversification of crown-group reptiles. Unfortunately, much of our understanding of this event comes from the record of large-bodied reptiles (total body length > 1 m). Here we present a new species of drepanosaurid (small-bodied, chameleon like diapsids) from the Upper Triassic Chinle Formation of New Mexico. Using reconstructions of micro-computed tomography data, we reveal the three dimensional skull osteology of this clade for the first time. The skull presents many archaic anatomical traits unknown in Triassic crown-group reptiles (e.g. absence of bony support for the external ear), whereas other traits (e.g. toothless rostrum, anteriorly directed orbits, inflated endocranium) resemble derived avian theropods. A phylogenetic analysis of Permo-Triassic diapsids supports the hypothesis that drepanosaurs are an archaic lineage that originated in the Permian, far removed from crown-group Reptilia. The phylogenetic position of drepanosaurids indicates the presence of archaic Permian clades among Triassic small reptile assemblages and that morphological convergence produced a remarkably bird-like skull nearly 100 Myr before one is known to have emerged in Theropoda. PMID- 29134066 TI - The Electric Honeycomb; an investigation of the Rose window instability. AB - The Rose window instability is a little-explored electrohydrodynamic instability that manifests when a layer of low-conducting oil is placed in an electric field generated by corona discharge in a point-to-plane configuration. Above a critical voltage, the instability starts as a single dimple in the oil layer right below the point electrode and subsequently evolves into a characteristic pattern of polygonal cells. In this study, we experimentally explore governing parameters that guide the instability and document geometric attributes of the characteristic cellular pattern. The driving force for the instability has been attributed to the buildup of charged ions which in turn apply an electric pressure on the oil surface. We confirm the charged surface distribution using thermal imaging and demonstrate that the instability can be locally inhibited by preventing charge buildup under an ion shadow. PMID- 29134067 TI - Modelling the role of correctional services on gangs: insights through a mathematical model. AB - Research has shown that gang membership increases the chances of offending, antisocial behaviour and drug use. Gang membership should be acknowledged as part of crime prevention and policy designs, and when developing interventions and preventative programmes. Correctional services are designed to rehabilitate convicted offenders. We formulate a deterministic mathematical model using nonlinear ordinary differential equations to investigate the role of correctional services on the dynamics of gangs. The recruitment into gang membership is assumed to happen through an imitation process. An epidemic threshold value, [Formula: see text], termed the gang reproduction number, is proposed and defined herein in the gangs' context. The model is shown to exhibit the phenomenon of backward bifurcation. This means that gangs may persist in the population even if [Formula: see text] is less than one. Sensitivity analysis of [Formula: see text] was performed to determine the relative importance of different parameters in gang initiation. The critical efficacy epsilon* is evaluated and the implications of having functional correctional services are discussed. PMID- 29134068 TI - Living with own or husband's mother in the household is associated with lower number of children: a cross-cultural analysis. AB - It has been discussed in the literature that the presence of kin, particularly the presence of a women's own mother or her mother in law, may have fertility effects. We aimed to examine the effects of the presence of a woman's own or her husband's mother in the household on a woman's fertility in terms of number of children on a broad basis by analysing census data of over two million married women aged between 15 and 34 years from 14 countries worldwide. We find that with the exception of Iraq, across all countries, the majority of women live only with their spouse in the household. We further find that the presence of any mother in the household is invariably associated with a significantly lower number of children compared to women living only with their spouse. In addition, in most countries, a woman's number of children is lower if she lives with her own mother as compared to her husband's mother in the household. Number of children is nonlinearly associated with woman's age, the presence of any mother being related with an earlier start of childbearing but a shallower increase in number of children. We speculate that the presence of a mother in the household may slow down woman's reproduction, but also discuss alternative explanations. PMID- 29134069 TI - Engaging rural Australian communities in National Science Week helps increase visibility for women researchers. AB - During a week-long celebration of science, run under the federally supported National Science Week umbrella, the Catch a Rising Star: women in Queensland research (CaRS) programme flew scientists who identify as women to nine regional and remote communities in the Australian State of Queensland. The aim of the project was twofold: first, to bring science to remote and regional communities in a large, economically diverse state; and second, to determine whether media and public engagement provides career advancement opportunities for women scientists. This paper focuses on the latter goal. The data show: (i) a substantial majority (greater than 80%) of researchers thought the training and experience provided by the programme would help develop her career as a research scientist in the future, (ii) the majority (65%) thought the programme would help relate her research to end users, industry partners or stakeholders in the future, and (iii) analytics can help create a compelling narrative around engagement metrics and help to quantify influence. During the week-long project, scientists reached 600 000 impressions on one social media platform (Twitter) using a program hashtag. The breadth and depth of the project outcomes indicate funding bodies and employers could use similar data as an informative source of metrics to support hiring and promotion decisions. Although this project focused on researchers who identify as women, the lessons learned are applicable to researchers representing a diverse range of backgrounds. Future surveys will help determine whether the CaRS programme provided long-term career advantages to participating scientists and communities. PMID- 29134070 TI - Macrofouling communities and the degradation of plastic bags in the sea: an in situ experiment. AB - The increasing amount of plastic littered into the sea may provide a new substratum for benthic organisms. These marine fouling communities on plastic have not received much scientific attention. We present, to our knowledge, the first comprehensive analysis of their macroscopic community composition, their primary production and the polymer degradation comparing conventional polyethylene (PE) and a biodegradable starch-based plastic blend in coastal benthic and pelagic habitats in the Mediterranean Sea. The biomass of the fouling layer increased significantly over time and all samples became heavy enough to sink to the seafloor. The fouling communities, consisting of 21 families, were distinct between habitats, but not between polymer types. Positive primary production was measured in the pelagic, but not in the benthic habitat, suggesting that large accumulations of floating plastic could pose a source of oxygen for local ecosystems, as well as a carbon sink. Contrary to PE, the biodegradable plastic showed a significant loss of tensile strength and disintegrated over time in both habitats. These results indicate that in the marine environment, biodegradable polymers may disintegrate at higher rates than conventional polymers. This should be considered for the development of new materials, environmental risk assessment and waste management strategies. PMID- 29134071 TI - The scaling structure of the global road network. AB - Because of increasing global urbanization and its immediate consequences, including changes in patterns of food demand, circulation and land use, the next century will witness a major increase in the extent of paved roads built worldwide. To model the effects of this increase, it is crucial to understand whether possible self-organized patterns are inherent in the global road network structure. Here, we use the largest updated database comprising all major roads on the Earth, together with global urban and cropland inventories, to suggest that road length distributions within croplands are indistinguishable from urban ones, once rescaled to account for the difference in mean road length. Such similarity extends to road length distributions within urban or agricultural domains of a given area. We find two distinct regimes for the scaling of the mean road length with the associated area, holding in general at small and at large values of the latter. In suitably large urban and cropland domains, we find that mean and total road lengths increase linearly with their domain area, differently from earlier suggestions. Scaling regimes suggest that simple and universal mechanisms regulate urban and cropland road expansion at the global scale. As such, our findings bear implications for global road infrastructure growth based on land-use change and for planning policies sustaining urban expansions. PMID- 29134072 TI - Genetic signature of Last Glacial Maximum regional refugia in a circum-Antarctic sea spider. AB - The evolutionary history of Antarctic organisms is becoming increasingly important to understand and manage population trajectories under rapid environmental change. The Antarctic sea spider Nymphon australe, with an apparently large population size compared with other sea spider species, is an ideal target to look for molecular signatures of past climatic events. We analysed mitochondrial DNA of specimens collected from the Antarctic continent and two Antarctic islands (AI) to infer past population processes and understand current genetic structure. Demographic history analyses suggest populations survived in refugia during the Last Glacial Maximum. The high genetic diversity found in the Antarctic Peninsula and East Antarctic (EA) seems related to multiple demographic contraction-expansion events associated with deep-sea refugia, while the low genetic diversity in the Weddell Sea points to a more recent expansion from a shelf refugium. We suggest the genetic structure of N. australe from AI reflects recent colonization from the continent. At a local level, EA populations reveal generally low genetic differentiation, geographically and bathymetrically, suggesting limited restrictions to dispersal. Results highlight regional differences in demographic histories and how these relate to the variation in intensity of glaciation-deglaciation events around Antarctica, critical for the study of local evolutionary processes. These are valuable data for understanding the remarkable success of Antarctic pycnogonids, and how environmental changes have shaped the evolution and diversification of Southern Ocean benthic biodiversity. PMID- 29134073 TI - Why did the pheasant cross the road? Long-term road mortality patterns in relation to management changes. AB - Pheasants (Phasianus colchicus) are commonly killed on UK roads, presenting a threat to motorists and a loss to the game shooting industry. Pheasants may be inherently susceptible, or the recent increase in their artificial rearing and release may have exacerbated the situation, either through population increases or because artificial rearing has altered movement behaviour. We compared intra annual patterns of roadkill reported in the UK from the 1960s (prior to the onset of mass release programmes) with that from the 2010s (when pheasant release was well established and widespread), considering roadkill sex and locations and accounting for changes in traffic levels. Pheasants in the UK are disproportionately likely to be reported killed on roads. However, this likelihood has not changed notably over the past 50 years. Instead, the timing of roadkill has changed. Pheasants in the 2010s are no longer susceptible during their breeding season, unlike in the 1960s, perhaps because relatively few breed successfully. Instead, roadkill first peaks in September-November as pheasants disperse from release pens, females first. Roadkill declines over winter, but when supplementary feeding ceases in February, we see a second peak in roadkill. Roadkill rates are higher in regions of the UK where there is little arable farming and hence natural food supplies are scarce. PMID- 29134074 TI - Requirement of Pax6 for the integration of guidance cues in cell migration. AB - The intricate patterns of cell migration that are found throughout development are generated through a vast array of guidance cues. Responding integratively to distinct, often conflicting, migratory signals is probably crucial for cells to reach their correct destination. Pax6 is a master transcription factor with key roles in neural development that include the control of cell migration. In this study, we have investigated the ability of cells derived from cortical neurospheres from wild-type (WT) and Pax6-/- mouse embryos to integrate diverging guidance cues. We used two different cues, either separately or in combination: substratum nanogrooves to induce contact guidance, and electric fields (EFs) to induce electrotaxis. In the absence of an EF, both WT and Pax6-/- cells aligned and migrated parallel to grooves, and on a flat substrate both showed marked electrotaxis towards the cathode. When an EF was applied in a perpendicular orientation to grooves, WT cells responded significantly to both cues, migrating in highly oblique trajectories in the general direction of the cathode. However, Pax6-/- cells had an impaired response to both cues simultaneously. Our results demonstrate that these neurosphere derived cells have the capacity to integrate diverging guidance cues, which requires Pax6 function. PMID- 29134075 TI - Antifungal activity of water-stable copper-containing metal-organic frameworks. AB - Although metal-organic frameworks (MOFs) or porous coordination polymers have been widely studied, their antimicrobial activities have not yet been fully investigated. In this work, antifungal activity of copper-based benzene tricarboxylate MOF (Cu-BTC MOF), which is water stable and industrially interesting, is investigated against Candida albicans, Aspergillus niger, Aspergillus oryzae and Fusarium oxysporum. The Cu-BTC MOF can effectively inhibit the growth rate of C. albicans and remarkably inhibit the spore growth of A. niger, A. oryzae and F. oxysporum. This finding shows the potential of using Cu BTC MOF as a strong biocidal material against representative yeasts and moulds that are commonly found in the food and agricultural industries. PMID- 29134076 TI - 1-(2-aminophenyl)-1H-1,2,3-triazole-4-carboxylic acid: activity against Gram positive and Gram-negative pathogens including Vibrio cholerae. AB - We report a new synthetic aromatic epsilon-amino acid containing a triazole moiety with antimicrobial potential against Gram-positive, Gram-negative and pathogenic bacteria including Vibrio cholerae. Structure-property relationship studies revealed that all the functional groups are essential to enhance the antimicrobial activity. The 1-(2-aminophenyl)-1H-1,2,3-triazole-4-carboxylic acid was synthesized by click chemistry. From X-ray crystallography, the amino acid adopts a kink-like structure where the phenyl and triazole rings are perpendicular to each other and the amine and acid groups maintain an angle of 60 degrees . The agar diffusion test shows that the amino acid has significant antibacterial activity. The liquid culture test exhibits that the minimum inhibitory concentration (MIC) value for Bacillus subtilis and Vibrio cholerae is 59.5 ug ml-1. FE-SEM experiments were performed to study the morphological changes of bacterial shape after treatment with compound 1. The antimicrobial activity of the amino acid was further studied by DNA binding and degradation study, protein binding, dye-binding assay and morphological analysis. Moreover, the amino acid does not have any harmful effect on eukaryotes. PMID- 29134077 TI - Investigation of the acid/base behaviour of the opium alkaloid thebaine in LC-ESI MS mobile phase by NMR spectroscopy. AB - As part of a research programme to establish an analytical method for the simultaneous detection of the five major opium alkaloids in poppy seeds by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) it was discovered that the inclusion of thebaine produced two peaks for the same compound. This was in contrast to the effective simultaneous detection, by LC-ESI MS, of morphine, codeine, papaverine and noscapine. The presence of these two peaks for thebaine was investigated using nuclear magnetic resonance spectroscopy with deuterated solvents to emulate the mobile phase conditions experienced. It was found that the presence of 80%, or higher ratios of, water caused two epimeric forms of thebaine to be formed; this explained the presence of two peaks on the chromatogram. In contrast, when a lower water content was used with 1% acetic acid, one stable form of thebaine could be analysed and resulted in a single peak visible in the subsequent chromatography. PMID- 29134079 TI - Prediction for electronic, vibrational and thermoelectric properties of chalcopyrite AgX(X=In,Ga)Te2: PBE + U approach. AB - The electronic, vibrational and thermoelectric transport characteristics of AgInTe2 and AgGaTe2 with chalcopyrite structure have been investigated. The electronic structures are calculated using the density-functional theory within the generalized gradient approximation (GGA) of Perdew-Burke-Ernzerhof functional considering the Hubbard-U exchange correlation. The band-gaps of AgInTe2 and AgGaTe2 are much larger than previous standard GGA functional results and agree well with the existing experimental data. The effective mass of the hole and the shape of density of states near the edge of the valence band indicate AgInTe2 and AgGaTe2 are considerable p-type thermoelectric materials. An analysis of lattice dynamics shows the low thermal conductivities of AgInTe2 and AgGaTe2. The thermoelectric transport properties' dependence on carrier concentration for p type AgInTe2 and AgGaTe2 in a wide range of temperatures has been studied in detail. The results show that p-type AgInTe2 and AgGaTe2 at 800 K can achieve the merit values of 0.91 and 1.38 at about 2.12 * 1020 cm-3 and 1.97 * 1020 cm-3 carrier concentrations, respectively. This indicates p-type AgGaTe2 is a potential thermoelectric material at high temperature. PMID- 29134078 TI - Fe(OTf)3-catalysed Friedel-Crafts reaction of benzenoid arenes with alpha,beta unsaturated carbonyl compounds: easy access to 1,1-diarylalkanes. AB - A simple and efficient method for the synthesis of 1,1-diarylalkanes via the Friedel-Crafts-type alkylation reaction of electron-rich arenes with cinnamic acid ester derivatives or chalcones is reported. Iron triflate has been found to be the best catalyst for the Friedel-Crafts-type alkylation reaction with alpha,beta-unsaturated carbonyl compounds. This reaction afforded beta,beta diaryl carbonyl compounds in good yields (65-93%) and with excellent regioselectivities. Remarkably, this method is also compatible with a variety of indoles to provide 3-indolyl-aryl carbonyl compounds in excellent yields. Great efforts have been made to deduce a plausible reaction mechanism based on isotopic labelling experiments. PMID- 29134080 TI - Dichlorobenzene: an effective solvent for epoxy/graphene nanocomposites preparation. AB - It is generally recognized that dimethylformamide (DMF) and ethanol are good media to uniformly disperse graphene, and therefore have been used widely in the preparation of epoxy/graphene nanocomposites. However, as a solvent to disperse graphene, dichlorobenzene (DCB) has not been fully realized by the polymer community. Owing to high values of the dispersion component (deltad) of the Hildebrand solubility parameter, DCB is considered as a suitable solvent for homogeneous graphene dispersion. Therefore, epoxy/graphene nanocomposites have been prepared for the first time with DCB as a dispersant; DMF and ethanol have been chosen as the reference. The colloidal stability, mechanical properties, thermogravimetric analysis, dynamic mechanical analysis and scanning electron microscopic images of nanocomposites have been obtained. The results show that with the use of DCB, the tensile strength of graphene has been improved from 64.46 to 69.32 MPa, and its flexural strength has been increased from 97.17 to 104.77 MPa. DCB is found to be more effective than DMF and ethanol for making stable and homogeneous graphene dispersion and composites. PMID- 29134081 TI - Identification of the Beagle 2 lander on Mars. AB - The 2003 Beagle 2 Mars lander has been identified in Isidis Planitia at 90.43 degrees E, 11.53 degrees N, close to the predicted target of 90.50 degrees E, 11.53 degrees N. Beagle 2 was an exobiology lander designed to look for isotopic and compositional signs of life on Mars, as part of the European Space Agency Mars Express (MEX) mission. The 2004 recalculation of the original landing ellipse from a 3-sigma major axis from 174 km to 57 km, and the acquisition of Mars Reconnaissance Orbiter High Resolution Imaging Science Experiment (HiRISE) imagery at 30 cm per pixel across the target region, led to the initial identification of the lander in 2014. Following this, more HiRISE images, giving a total of 15, including red and blue-green colours, were obtained over the area of interest and searched, which allowed sub-pixel imaging using super high resolution techniques. The size (approx. 1.5 m), distinctive multilobed shape, high reflectivity relative to the local terrain, specular reflections, and location close to the centre of the planned landing ellipse led to the identification of the Beagle 2 lander. The shape of the imaged lander, although to some extent masked by the specular reflections in the various images, is consistent with deployment of the lander lid and then some or all solar panels. Failure to fully deploy the panels-which may have been caused by damage during landing-would have prohibited communication between the lander and MEX and commencement of science operations. This implies that the main part of the entry, descent and landing sequence, the ejection from MEX, atmospheric entry and parachute deployment, and landing worked as planned with perhaps only the final full panel deployment failing. PMID- 29134082 TI - Is the behavioural divergence between range-core and range-edge populations of cane toads (Rhinella marina) due to evolutionary change or developmental plasticity? AB - Individuals at the leading edge of expanding biological invasions often show distinctive phenotypic traits, in ways that enhance their ability to disperse rapidly and to function effectively in novel environments. Cane toads (Rhinella marina) at the invasion front in Australia exhibit shifts in morphology, physiology and behaviour (directionality of dispersal, boldness, risk-taking). We took a common-garden approach, raising toads from range-core and range-edge populations in captivity, to see if the behavioural divergences observed in wild caught toads are also evident in common-garden offspring. Captive-raised toads from the invasion vanguard population were more exploratory and bolder (more prone to 'risky' behaviours) than toads from the range core, which suggests that these are evolved, genetic traits. Our study highlights the importance of behaviour as being potentially adaptive in invasive populations and adds these behavioural traits to the increasing list of phenotypic traits that have evolved rapidly during the toads' 80-year spread through tropical Australia. PMID- 29134083 TI - Preparation of Surlyn films reinforced with cellulose nanofibres and feasibility of applying the transparent composite films for organic photovoltaic encapsulation. AB - This research concerns the development of Surlyn film reinforced with micro /nanofibrillated celluloses (MFC) for use as an encapsulant in organic photovoltaic (OPV) cells. The aim of this work was to investigate the effects of fibre types and the mixing methods on the structure-properties of the composite films. Three types of cellulose micro/nanofibrils were prepared: the as-received MFC, the dispersed MFC and the esterified MFC. The fibres were mixed with Surlyn via an extrusion process, using two different mixing methods. It was found that the extent of fibre disintegration and tensile modulus of the composite films prepared by the master-batching process was superior to that of the composite system prepared by the direct mixing method. Using the esterified MFC as a reinforcement, compatibility between polymer and the fibre increased, accompanied with the improvement of the percentage elongation of the Surlyn composite film. The percentage of light transmittance of the Surlyn/MFC films was above 88, regardless of the fibre types and fibre concentrations. The water vapour transmission rate of the Surlyn/esterified MFC film was 65% lower than that of the neat Surlyn film. This contributed to the longer lifetime of the OPV encapsulated with the Surlyn/esterified MFC film. PMID- 29134084 TI - Electrophoretic deposition of carbon nanotube on reticulated vitreous carbon for hexavalent chromium removal in a biocathode microbial fuel cell. AB - For Cr(VI)-removal microbial fuel cell (MFC), a more efficient biocathode in MFCs is required to improve the Cr(VI) removal and electricity generation. RVC-CNT electrode was prepared through the electrophoretic deposition of carbon nanotube (CNT) on reticulated vitreous carbon (RVC). The power density of MFC with an RVC CNT electrode increased to 132.1 +/- 2.8 mW m-2, and 80.9% removal of Cr(VI) was achieved within 48 h; compared to only 44.5% removal of Cr(VI) in unmodified RVC. Cyclic voltammetry, energy-dispersive spectrometry and X-ray photoelectron spectrometry showed that the RVC-CNT electrode enhanced the electrical conductivity and the electron transfer rate; and provided more reaction sites for Cr(VI) reduction. This approach provides process simplicity and a thickness control method for fabricating three-dimensional biocathodes to improve the performance of MFCs for Cr(VI) removal. PMID- 29134085 TI - Gene delivery ability of polyethylenimine and polyethylene glycol dual functionalized nanographene oxide in 11 different cell lines. AB - We recently developed a polyethylenimine (PEI) and polyethylene glycol (PEG) dual functionalized reduced graphene oxide (GO) (PEG-nrGO-PEI, RGPP) for high efficient gene delivery in HepG2 and Hela cell lines. To evaluate the feasibility and applicability of RGPP as a gene delivery carrier, we here assessed the transfection efficiency of RGPP on gene plasmids and siRNA in 11 different cell lines. Commercial polyalkyleneimine cation transfection reagent (TR) was used as comparison. In HepG2 cells, RGPP exhibited much stronger delivery ability for siRNA and large size plasmids than TR. For green fluorescent protein (GFP) plasmid, RGPP showed about 47.1% of transfection efficiency in primary rabbit articular chondrocytes, and about 27% of transfection efficiency in both SH-SY5Y and A549 cell lines. RGPP exhibited about 37.2% of GFP plasmid transfection efficiency in EMT6 cells and about 26.0% of GFP plasmid transfection efficiency in LO2 cells, but induced about 33% of cytotoxicity in both cell lines. In 4T1 and H9C2 cell lines, RGPP had less than 10% of GFP plasmid transfection efficiency. Collectively, RGPP is a potential nano-carrier for high-efficiency gene delivery, and needs to be further optimized for different cell lines. PMID- 29134086 TI - Multiple optimality criteria support Ornithoscelida. AB - A recent study of early dinosaur evolution using equal-weights parsimony recovered a scheme of dinosaur interrelationships and classification that differed from historical consensus in a single, but significant, respect; Ornithischia and Saurischia were not recovered as monophyletic sister-taxa, but rather Ornithischia and Theropoda formed a novel clade named Ornithoscelida. However, these analyses only used maximum parsimony, and numerous recent simulation studies have questioned the accuracy of parsimony under equal weights. Here, we provide additional support for this alternative hypothesis using Bayesian implementation of the Mkv model, as well as through number of additional parsimony analyses, including implied weighting. Using Bayesian inference and implied weighting, we recover the same fundamental topology for Dinosauria as the original study, with a monophyletic Ornithoscelida, demonstrating that the main suite of methods used in morphological phylogenetics recover this novel hypothesis. This result was further scrutinized through the systematic exclusion of different character sets. Novel characters from the original study (those not taken or adapted from previous phylogenetic studies) were found to be more important for resolving the relationships within Dinosauromorpha than the relationships within Dinosauria. Reanalysis of a modified version of the character matrix that supports the Ornithischia-Saurischia dichotomy under maximum parsimony also supports this hypothesis under implied weighting, but not under the Mkv model, with both Theropoda and Sauropodomorpha becoming paraphyletic with respect to Ornithischia. PMID- 29134087 TI - Do glucocorticoids predict fitness? Linking environmental conditions, corticosterone and reproductive success in the blue tit, Cyanistes caeruleus. AB - Glucocorticoids, including corticosterone (CORT), have been suggested to provide a physiological link between ecological conditions and fitness. Specifically, CORT, which is elevated in response to harsh conditions, is predicted to be correlated with reduced fitness. Yet, empirical studies show that CORT can be non significantly, positively and negatively linked with fitness. Divergent environmental conditions between years or study systems may influence whether CORT is linked to fitness. To test this, we monitored free-living blue tits (Cyanistes caeruleus) during breeding over 3 years. We quantified foraging conditions during brood rearing, and examined whether they were correlated with parental baseline CORT and reproductive success. We then tested whether CORT predicted fitness. Elevated parental CORT was associated with lower temperatures, greater rainfall and lower territory-scale oak density. Whereas asynchrony with the caterpillar food peak was correlated with reduced nestling mass and fledging success, but not parental CORT. Only low temperatures were associated with both reduced nestling mass and elevated parental CORT. Despite this, parents with elevated CORT had lighter offspring in all years. Contrarily, in 2009 parental CORT was positively correlated with the number fledged. The absence of a direct link between the foraging conditions that reduce nestling quality and elevate parental CORT suggests that parental CORT may provide a holistic measure of conditions where parents are working harder to meet the demands of developing young. As the positive correlation between parental CORT and fledging success differed between years, this suggests that contrasting conditions between years can influence correlations between parental CORT and fitness. Ultimately, as CORT concentrations are intrinsically variable and linked to the prevalent conditions, studies that incorporate environmental harshness will improve our understanding of evolutionary endocrinology. PMID- 29134088 TI - On the lack of a universal pattern associated with mammalian domestication: differences in skull growth trajectories across phylogeny. AB - As shown in a taxonomically broad study, domestication modifies postnatal growth. Skull shape across 1128 individuals was characterized by 14 linear measurements, comparing 13 pairs of wild versus domesticated forms. Among wild forms, the boar, the rabbit and the wolf have the highest proportion of allometric growth, explaining in part the great morphological diversity of the domesticated forms of these species. Wild forms exhibit more isometric growth than their domesticated counterparts. Multivariate comparisons show that dogs and llamas exhibit the greatest amount of differences in trajectories with their wild counterparts. The least amount is recorded in the pig-boar, and camel and horse pairs. Bivariate analyses reveal that most domesticated forms have growth trajectories different from their respective wild counterparts with regard to the slopes. In pigs and camels slopes are shared and intercepts are different. There is a trajectory extension in most domesticated herbivores and the contrary pattern in carnivorous forms. However, there is no single, universal and global pattern of paedomorphosis or any other kind of heterochrony behind the morphological diversification that accompanies domestication. PMID- 29134089 TI - MoO2 nanosheets embedded in amorphous carbon matrix for sodium-ion batteries. AB - MoO2 nanosheets embedded in the amorphous carbon matrix (MoO2/C) are successfully synthesized via a facile hydrothermal method and investigated as an anode for sodium-ion batteries. Because of the efficient ion transport channels and good volume change accommodation, MoO2/C delivers a discharge/charge capacity of 367.8/367.0 mAh g-1 with high coulombic efficiency (99.4%) after 100 cycles at a current density of 50 mA g-1. PMID- 29134090 TI - Assessment of dynamic material properties of intact rocks using seismic wave attenuation: an experimental study. AB - The mechanical properties of any substance are essential facts to understand its behaviour and make the maximum use of the particular substance. Rocks are indeed an important substance, as they are of significant use in the energy industry, specifically for fossil fuels and geothermal energy. Attenuation of seismic waves is a non-destructive technique to investigate mechanical properties of reservoir rocks under different conditions. The attenuation characteristics of five different rock types, siltstone, shale, Australian sandstone, Indian sandstone and granite, were investigated in the laboratory using ultrasonic and acoustic emission instruments in a frequency range of 0.1-1 MHz. The pulse transmission technique and spectral ratios were used to calculate the attenuation coefficient (alpha) and quality factor (Q) values for the five selected rock types for both primary (P) and secondary (S) waves, relative to the reference steel sample. For all the rock types, the attenuation coefficient was linearly proportional to the frequency of both the P and S waves. Interestingly, the attenuation coefficient of granite is more than 22% higher than that of siltstone, sandstone and shale for both P and S waves. The P and S wave velocities were calculated based on their recorded travel time, and these velocities were then used to calculate the dynamic mechanical properties including elastic modulus (E), bulk modulus (K), shear modulus (u) and Poisson's ratio (nu). The P and S wave velocities for the selected rock types varied in the ranges of 2.43-4.61 km s-1 and 1.43-2.41 km h 1, respectively. Furthermore, it was observed that the P wave velocity was always greater than the S wave velocity, and this confirmed the first arrival of P waves to the sensor. According to the experimental results, the dynamic E value is generally higher than the static E value obtained by unconfined compressive strength tests. PMID- 29134091 TI - Synthesis of zeolites Na-A and Na-X from tablet compressed and calcinated coal fly ash. AB - Zeolites Na-A and Na-X are important synthetic zeolites widely used for separation and adsorption in industry. It is of great significance to develop energy-efficient routines that can synthesize zeolites Na-A and Na-X from low cost raw materials. Coal fly ash (CFA) is the major residue from the combustion of coal and biomass containing more than 85% SiO2 and Al2O3, which can readily replace the conventionally used sodium silicate and aluminate for zeolite synthesis. We used Na2CO3 to replace the expensive NaOH used for the calcination of CFA and showed that tablet compression can enhance the contact with Na2CO3 for the activation of CFA through calcination for the synthesis of zeolites Na-A and Na-X under mild conditions. We optimized the control variables for zeolite synthesis and showed that phase-pure zeolite Na-A can be synthesized with CFA at reactant molar ratio, hydrothermal reaction temperature and reaction time of 1.3Na2O: 0.6Al2O3: 1SiO2: 38H2O at 80 degrees C for 6 h, respectively, while phase-pure zeolite Na-X can be synthesized at 2.2Na2O: 0.2Al2O3: 1SiO2: 88H2O at 100 degrees C for 8 h, respectively. The composition, morphology, specific surface area, vibration spectrum and thermogravimetry of synthesized Na-A and Na X were further characterized. PMID- 29134092 TI - Enhanced photovoltaic properties of perovskite solar cells by TiO2 homogeneous hybrid structure. AB - In this paper, we fabricated a TiO2 homogeneous hybrid structure for application in perovskite solar cells (PSCs) under ambient conditions. Under the standard air mass 1.5 global (AM 1.5G) illumination, PSCs based on homogeneous hybrid structure present a maximum power conversion efficiency of 5.39% which is higher than that of pure TiO2 nanosheets. The enhanced properties can be explained by the better contact of TiO2 nanosheets/nanoparticles with CH3NH3PbI3 and fewer pinholes in electron transport materials. The advent of such unique structure opens up new avenues for the future development of high-efficiency photovoltaic cells. PMID- 29134093 TI - Bringing ecology blogging into the scientific fold: measuring reach and impact of science community blogs. AB - The popularity of science blogging has increased in recent years, but the number of academic scientists who maintain regular blogs is limited. The role and impact of science communication blogs aimed at general audiences is often discussed, but the value of science community blogs aimed at the academic community has largely been overlooked. Here, we focus on our own experiences as bloggers to argue that science community blogs are valuable to the academic community. We use data from our own blogs (n = 7) to illustrate some of the factors influencing reach and impact of science community blogs. We then discuss the value of blogs as a standalone medium, where rapid communication of scholarly ideas, opinions and short observational notes can enhance scientific discourse, and discussion of personal experiences can provide indirect mentorship for junior researchers and scientists from underrepresented groups. Finally, we argue that science community blogs can be treated as a primary source and provide some key points to consider when citing blogs in peer-reviewed literature. PMID- 29134094 TI - The evolution of giant flightless birds and novel phylogenetic relationships for extinct fowl (Aves, Galloanseres). AB - The extinct dromornithids, gastornithids and phorusrhacids are among the most spectacular birds to have ever lived, with some giants exceeding 500 kg. The affinities and evolution of these and other related extinct birds remain contentious, with previous phylogenetic analyses being affected by widespread convergence and limited taxon sampling. We address these problems using both parsimony and tip-dated Bayesian approaches on an expansive taxon set that includes all key extinct flightless and flighted (e.g. Vegavis and lithornithids) forms, an extensive array of extant fowl (Galloanseres), representative Neoaves and palaeognaths. The Paleogene volant Lithornithidae are recovered as stem palaeognaths in the Bayesian analyses. The Galloanseres comprise four clades inferred to have diverged in the Late Cretaceous on Gondwana. In addition to Anseriformes and Galliformes, we recognize a robust new clade (Gastornithiformes) for the giant flightless Dromornithidae (Australia) and Gastornithidae (Eurasia, North America). This clade exhibits parallels to ratite palaeognaths in that flight presumably was lost and giant size attained multiple times. A fourth clade is represented by the Cretaceous Vegavis (Antarctica), which was strongly excluded from Anseriformes; thus, a crucial molecular calibration point needs to be reconsidered. The presbyornithids Wilaru (Australia) and Presbyornis (Northern Hemisphere) are robustly found to be the sister group to Anatoidea (Anseranatidae + Anatidae), a relatively more basal position than hitherto recognized. South America's largest bird, Brontornis, is not a galloansere, but a member of Neoaves related to Cariamiformes; therefore, giant Galloanseres remain unknown from this continent. Trait analyses showed that while gigantism and flightlessness evolved repeatedly in groups, diet is constrained by phylogeny: all giant Galloanseres and palaeognaths are herbivores or mainly herbivorous, and giant neoavians are zoophagous or omnivorous. PMID- 29134095 TI - The York Gospels: a 1000-year biological palimpsest. AB - Medieval manuscripts, carefully curated and conserved, represent not only an irreplaceable documentary record but also a remarkable reservoir of biological information. Palaeographic and codicological investigation can often locate and date these documents with remarkable precision. The York Gospels (York Minster Ms. Add. 1) is one such codex, one of only a small collection of pre-conquest Gospel books to have survived the Reformation. By extending the non-invasive triboelectric (eraser-based) sampling technique eZooMS, to include the analysis of DNA, we report a cost-effective and simple-to-use biomolecular sampling technique for parchment. We apply this combined methodology to document for the first time a rich palimpsest of biological information contained within the York Gospels, which has accumulated over the 1000-year lifespan of this cherished object that remains an active participant in the life of York Minster. These biological data provide insights into the decisions made in the selection of materials, the construction of the codex and the use history of the object. PMID- 29134096 TI - Co-infection does not predict disease signs in Gopherus tortoises. AB - In disease ecology, the host immune system interacts with environmental conditions and pathogen properties to affect the impact of disease on the host. Within the host, pathogens may interact to facilitate or inhibit each other's growth, and pathogens interact with different hosts differently. We investigated co-infection of two Mycoplasma and the association of infection with clinical signs of upper respiratory tract disease in four congeneric tortoise host species (Gopherus) in the United States to detect differences in infection risk and disease dynamics in these hosts. Mojave Desert tortoises had greater prevalence of Mycoplasma agassizii than Texas tortoises and gopher tortoises, while there were no differences in Mycoplasma testudineum prevalence among host species. In some host species, the presence of each pathogen influenced the infection intensity of the other; hence, these two mycoplasmas interact differently within different hosts, and our results may indicate facilitation of these bacteria. Neither infection nor co-infection was associated with clinical signs of disease, which tend to fluctuate across time. From M. agassizii DNA sequences, we detected no meaningful differentiation of haplotypes among hosts. Experimental inoculation studies and recurrent resampling of wild individuals could help to decipher the underlying mechanisms of disease dynamics in this system. PMID- 29134097 TI - The optimization of fermentation conditions for producing cellulase of Bacillus amyloliquefaciens and its application to goose feed. AB - The proper culture conditions for producing cellulase of Bacillus amyloliquefaciens S1, isolated from the cecum of goose was optimized by single factor experiment combined with orthogonal test. The properties of the cellulase were investigated by DNS method. The appropriate doses of B. amyloliquefaciens S1 were obtained by adding them to goose feed. It indicated that the suitable culture conditions of producing cellulase were the culture temperature of 37 degrees C, the initial pH of 7.0, the incubation time of 72 h and the loaded liquid volume of 75 ml per 250 ml. The effects of each factor on producing cellulase by B. amyloliquefaciens S1 were as follows: initial pH > incubation time = culture temperature > loaded liquid volume. The optimum reaction temperature and pH were 50 degrees C and 7.0, respectively. This enzyme is a kind of neutral cellulase that possesses resistance to heat and acidity. It showed high activity to absorbent cotton, soya bean meal and filter paper. By adding different doses of B. amyloliquefaciens S1 to the goose feed, it was found that the egg production, average egg weight, fertilization rate and the hatching rate were promoted both in experiment 1 (1.5 g kg-1) and experiment 2 (3 g kg-1). Also the difference of egg production, fertilization rate and hatching rate between experiment 1 and control group was obvious (p < 0.05), and the average egg weight was significantly increased in experiment 2 (p < 0.05). PMID- 29134098 TI - Progressive ontogenetic niche shift over the prolonged immaturity period of wandering albatrosses. AB - Very little is known about trophic ontogenetic changes over the prolonged immaturity period of long-lived, wide-ranging seabirds. By using blood and feather trophic tracers (delta13C and delta15N, and mercury, Hg), we studied age related changes in feeding ecology during the immature phase of wandering albatrosses Diomedea exulans when they gradually change from a pure oceanic life to visits to their future breeding grounds. Immatures fed in subtropical waters at high trophic positions during moult. Between- and within-individual variations in isotopic niche were very high, irrespective of age, highlighting wide-ranging exploratory behaviours. In summer, while acting as central-place foragers from their future breeding colony, individuals progressively relied on lower trophic level prey and/or southern latitudes as they aged, until occupying a similar isotopic niche to that of adults. Immatures had exceptionally high Hg burdens, with males having lower Hg concentrations than females, suggesting that they foraged more in subantarctic waters. Our findings suggest a progressive ontogenetic niche shift during central-place foraging of this long-lived species. PMID- 29134099 TI - Assessment of owner-directed aggressive behavioural tendencies of dogs in situations of possession and manipulation. AB - Excessive aggression is a common behaviour problem in dogs that can have various destructive effects on the affected people and the implicated dog. Aggressive behaviour directed towards the owner or other family members is one of the most frequently occurring aggressive phenotypes. Here, we examine the reliability of a short questionnaire assessing aggressive behaviours by two, contextually different behavioural tests: 'take away bone' and 'roll over'. Based on dogs' behaviour in the tests, we sorted dogs (N = 93) in two groups for each test, namely a less and a more disobedient/resistant group. The two principal components obtained in our questionnaire-'obedient' and 'aggressive towards owner'-showed significant differences between the behaviour groups. While dogs in the less disobedient/resistant groups had significantly higher 'obedient' and significantly lower 'aggressive towards owner' scores, dogs in the more disobedient/resistant groups had significantly higher 'aggressive towards owner' and significantly lower 'obedient' scores. Dogs' age, sex and neuter/spay status expressed their effect through interactions. Males, young dogs and intact dogs were less 'obedient' than older ones, while resistant spayed/neutered dogs were more aggressive towards the owner. The questionnaire used is a safe, easy to deploy and time-efficient tool to reliably assess certain owner-directed aggressive tendencies of family dogs. PMID- 29134100 TI - Three-dimensional innate mobility of the human foot bones under axial loading using biplane X-ray fluoroscopy. AB - The anatomical design of the human foot is considered to facilitate generation of bipedal walking. However, how the morphology and structure of the human foot actually contribute to generation of bipedal walking remains unclear. In the present study, we investigated the three-dimensional kinematics of the foot bones under a weight-bearing condition using cadaver specimens, to characterize the innate mobility of the human foot inherently prescribed in its morphology and structure. Five cadaver feet were axially loaded up to 588 N (60 kgf), and radiographic images were captured using a biplane X-ray fluoroscopy system. The present study demonstrated that the talus is medioinferiorly translated and internally rotated as the calcaneus is everted owing to axial loading, causing internal rotation of the tibia and flattening of the medial longitudinal arch in the foot. Furthermore, as the talus is internally rotated, the talar head moves medially with respect to the navicular, inducing external rotation of the navicular and metatarsals. Under axial loading, the cuboid is everted simultaneously with the calcaneus owing to the osseous locking mechanism in the calcaneocuboid joint. Such detailed descriptions about the innate mobility of the human foot will contribute to clarifying functional adaptation and pathogenic mechanisms of the human foot. PMID- 29134101 TI - Aligning evidence: concerns regarding multiple sequence alignments in estimating the phylogeny of the Nudibranchia suborder Doridina. AB - Molecular estimates of phylogenetic relationships rely heavily on multiple sequence alignment construction. There has been little consensus, however, on how to properly address issues pertaining to the alignment of variable regions. Here, we construct alignments from four commonly sequenced molecular markers (16S, 18S, 28S and cytochrome c oxidase subunit I) for the Nudibranchia using three different methodologies: (i) strict mathematical algorithm; (ii) exclusion of variable or divergent regions and (iii) manually curated, and examine how different alignment construction methods can affect phylogenetic signal and phylogenetic estimates for the suborder Doridina. Phylogenetic informativeness (PI) profiles suggest that the molecular markers tested lack the power to resolve relationships at the base of the Doridina, while being more robust at family level classifications. This supports the lack of consistent resolution between the 19 families within the Doridina across all three alignments. Most of the 19 families were recovered as monophyletic, and instances of non-monophyletic families were consistently recovered between analyses. We conclude that the alignment of variable regions has some effect on phylogenetic estimates of the Doridina, but these effects can vary depending on the size and scope of the phylogenetic query and PI of molecular markers. PMID- 29134102 TI - Imperial trophy or island relict? A new extinction paradigm for Pere David's deer: a Chinese conservation icon. AB - Determining the 'dynamic biogeography' of range collapse in threatened species is essential for effective conservation, but reconstruction of spatio-temporal patterns of population vulnerability and resilience can require use of non standard ecological data such as historical archives. Pere David's deer or milu, one of the few living mammal species that has become extinct in the wild, is historically known only from a small captive herd of unknown provenance that survived until 1900 in the Imperial Hunting Park near Beijing, from which all living individuals are descended. Using ancient DNA analysis, we demonstrate that two fawns collected in 1868 from Hainan Island, off the southern Chinese mainland, represent the only known wild milu specimens and were sampled from probably the last wild population. The Hainan milu population shows extremely low genetic differentiation from descendants of the Beijing herd, suggesting that this now-extinct population may have been the source of the captive herd. This revised extinction model refutes the supposed long-term survival of a captive milu herd for centuries or millennia after final extinction of wild populations, highlighting the vulnerability of remnant mammal populations in the absence of proactive management and the importance of historical museum collections for providing unique new insights on evolution, biogeography and conservation. Milu experienced a pattern of final population persistence on an island at the periphery of their former range, consistent with the 'range eclipse' or 'contagion' model of range collapse, and matching the spatial extinction dynamics of other extinct mammals such as the thylacine and woolly mammoth. PMID- 29134103 TI - Allometry of wing twist and camber in a flower chafer during free flight: How do wing deformations scale with body size? AB - Intraspecific variation in adult body mass can be particularly high in some insect species, mandating adjustment of the wing's structural properties to support the weight of the larger body mass in air. Insect wings elastically deform during flapping, dynamically changing the twist and camber of the relatively thin and flat aerofoil. We examined how wing deformations during free flight scale with body mass within a species of rose chafers (Coleoptera: Protaetia cuprea) in which individuals varied more than threefold in body mass (0.38-1.29 g). Beetles taking off voluntarily were filmed using three high-speed cameras and the instantaneous deformation of their wings during the flapping cycle was analysed. Flapping frequency decreased in larger beetles but, otherwise, flapping kinematics remained similar in both small and large beetles. Deflection of the wing chord-wise varied along the span, with average deflections at the proximal trailing edge higher by 0.2 and 0.197 wing lengths compared to the distal trailing edge in the downstroke and the upstroke, respectively. These deflections scaled with wing chord to the power of 1.0, implying a constant twist and camber despite the variations in wing and body size. This suggests that the allometric growth in wing size includes adjustment of the flexural stiffness of the wing structure to preserve wing twist and camber during flapping. PMID- 29134104 TI - King post truss as a motif for internal structure of (meta)material with controlled elastic properties. AB - One of the most interesting challenges in the modern theory of materials consists in the determination of those microstructures which produce, at the macro-level, a class of metamaterials whose elastic range is many orders of magnitude wider than the one exhibited by 'standard' materials. In dell'Isola et al. (2015 Zeitschrift fur angewandte Mathematik und Physik66, 3473-3498. (doi:10.1007/s00033-015-0556-4)), it was proved that, with a pantographic microstructure constituted by 'long' micro-beams it is possible to obtain metamaterials whose elastic range spans up to an elongation exceeding 30%. In this paper, we demonstrate that the same behaviour can be obtained by means of an internal microstructure based on a king post motif. This solution shows many advantages: it involves only microbeams; all constituting beams are undergoing only extension or compression; all internal constraints are terminal pivots. While the elastic deformation energy can be determined as easily as in the case of long-beam microstructure, the proposed design seems to have obvious remarkable advantages: it seems to be more damage resistant and therefore to be able to have a wider elastic range; it can be realized with the same three-dimensional printing technology; it seems to be less subject to compression buckling. The analysis which we present here includes: (i) the determination of Hencky-type discrete models for king post trusses, (ii) the application of an effective integration scheme to a class of relevant deformation tests for the proposed metamaterial and (iii) the numerical determination of an equivalent second gradient continuum model. The numerical tools which we have developed and which are presented here can be readily used to develop an extensive measurement campaign for the proposed metamaterial. PMID- 29134105 TI - Global network centrality of university rankings. AB - Universities and higher education institutions form an integral part of the national infrastructure and prestige. As academic research benefits increasingly from international exchange and cooperation, many universities have increased investment in improving and enabling their global connectivity. Yet, the relationship of university performance and its global physical connectedness has not been explored in detail. We conduct, to our knowledge, the first large-scale data-driven analysis into whether there is a correlation between university relative ranking performance and its global connectivity via the air transport network. The results show that local access to global hubs (as measured by air transport network betweenness) strongly and positively correlates with the ranking growth (statistical significance in different models ranges between 5% and 1% level). We also found that the local airport's aggregate flight paths (degree) and capacity (weighted degree) has no effect on university ranking, further showing that global connectivity distance is more important than the capacity of flight connections. We also examined the effect of local city economic development as a confounding variable and no effect was observed suggesting that access to global transportation hubs outweighs economic performance as a determinant of university ranking. The impact of this research is that we have determined the importance of the centrality of global connectivity and, hence, established initial evidence for further exploring potential connections between university ranking and regional investment policies on improving global connectivity. PMID- 29134106 TI - Robust clustering of languages across Wikipedia growth. AB - Wikipedia is the largest existing knowledge repository that is growing on a genuine crowdsourcing support. While the English Wikipedia is the most extensive and the most researched one with over 5 million articles, comparatively little is known about the behaviour and growth of the remaining 283 smaller Wikipedias, the smallest of which, Afar, has only one article. Here, we use a subset of these data, consisting of 14 962 different articles, each of which exists in 26 different languages, from Arabic to Ukrainian. We study the growth of Wikipedias in these languages over a time span of 15 years. We show that, while an average article follows a random path from one language to another, there exist six well defined clusters of Wikipedias that share common growth patterns. The make-up of these clusters is remarkably robust against the method used for their determination, as we verify via four different clustering methods. Interestingly, the identified Wikipedia clusters have little correlation with language families and groups. Rather, the growth of Wikipedia across different languages is governed by different factors, ranging from similarities in culture to information literacy. PMID- 29134107 TI - Correction to 'The role of climatic and geological events in generating diversity in Ethiopian grass frogs (genus Ptychadena)'. AB - [This corrects the article DOI: 10.1098/rsos.170021.]. PMID- 29134108 TI - Host and bacterial proteases influence biofilm formation and virulence in a murine model of enterococcal catheter-associated urinary tract infection. AB - Enterococcus faecalis is a leading causative agent of catheter-associated urinary tract infection (CAUTI), the most common hospital-acquired infection. Its ability to grow and form catheter biofilm is dependent upon host fibrinogen (Fg). Examined here are how bacterial and host proteases interact with Fg and contribute to virulence. Analysis of mutants affecting the two major secreted proteases of E. faecalis OG1RF (GelE, SprE) revealed that while the loss of either had no effect on virulence in a murine CAUTI model or for formation of Fg dependent biofilm in urine, the loss of both resulted in CAUTI attenuation and defective biofilm formation. GelE-, but not SprE- mutants, lost the ability to degrade Fg in medium, while paradoxically, both could degrade Fg in urine. The finding that SprE was activated independently of GelE in urine by a host trypsin like protease resolved this paradox. Treatment of catheter-implanted mice with inhibitors of both host-derived and bacterial-derived proteases dramatically reduced catheter-induced inflammation, significantly inhibited dissemination from bladder to kidney and revealed an essential role for a host cysteine protease in promoting pathogenesis. These data show that both bacterial and host proteases contribute to CAUTI, that host proteases promote dissemination and suggest new strategies for therapeutic intervention. PMID- 29134109 TI - Erratum: Author Correction: Norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant Staphylococcus aureus to beta lactam antibiotics. AB - [This corrects the article DOI: 10.1038/s41522-017-0026-1.]. PMID- 29134110 TI - Erratum: Ubiquitous overexpression of the DNA repair factor dPrp19 reduces DNA damage and extends Drosophila life span. AB - [This corrects the article DOI: 10.1038/s41514-017-0005-z.]. PMID- 29134111 TI - Periodontitis induced by bacterial infection exacerbates features of Alzheimer's disease in transgenic mice. AB - Periodontitis is a localized infectious disease caused by periodontopathic bacteria, such as Porphyromonas gingivalis. Recently, it has been suggested that bacterial infections may contribute to the onset and the progression of Alzheimer's disease (AD). However, we do not have any evidence about a causative relationship between periodontitis and AD. In this study, we investigated by using a transgenic mouse model of AD whether periodontitis evoked by P. gingivalis modulates the pathological features of AD. Cognitive function was significantly impaired in periodontitis-induced APP-Tg mice, compared to that in control APP-Tg mice. Levels of Amiloid beta (Abeta) deposition, Abeta40, and Abeta42 in both the hippocampus and cortex were higher in inoculated APP-Tg mice than in control APP-Tg mice. Furthermore, levels of IL-1beta and TNF-alpha in the brain were higher in inoculated mice than in control mice. The levels of LPS were increased in the serum and brain of P. gingivalis-inoculated mice. P. gingivalis LPS-induced production of Abeta40 and Abeta42 in neural cell cultures and strongly enhanced TNF-alpha and IL-1beta production in a culture of microglial cells primed with Abeta. Periodontitis evoked by P. gingivalis may exacerbate brain Abeta deposition, leading to enhanced cognitive impairments, by a mechanism that involves triggering brain inflammation. PMID- 29134112 TI - A review on ZnO-based electrical biosensors for cardiac biomarker detection. AB - Over the past few decades zinc oxide (ZnO)-based thin films and nanostructures have shown unprecedented performance in a wide range of applications. In particular, owing to high isoelectric point, biocompatibility and other multifunctional characteristics, ZnO has extensively been studied as a transduction material for biosensor development. The fascinating properties of ZnO help retain biological activity of the immobilized biomolecule and help in achieving enhanced sensing performance. As a consequence of recent advancements in this multidisciplinary field, diagnostic biosensors are expanding beyond traditional clinical labs to point-of-care and home settings. Label-free electrical detection of biomarkers has been demonstrated using ZnO-sensing platforms. In this review we highlight the characteristics of ZnO that enable realization of its use in development of point-of-care biosensors toward disease diagnosis, in particular cardiovascular diseases. PMID- 29134114 TI - A single center analysis of factors influencing study start-up timeline in clinical trials. AB - Aim: Efficient start-up phase in clinical trials is crucial to execution. The goal was to determine factors contributing to delays. Materials & methods: The start-up milestones were assessed for 38 studies and analyzed. Results: Total start-up time was shorter for following studies: device trials, no outsourcing, fewer ancillary services used and in interventional versus observational designs. The use of a centralized Institutional Review Board (IRB) versus a local IRB reduced time to approval. Studies that never enrolled took longer on average to finalize their budget/contract, and obtain IRB than ones that did enroll. Conclusion: Different features of clinical trials can affect timeline of start-up process. An understanding of the impact of each feature allows for optimization. PMID- 29134113 TI - Research advances in kinase enzymes and inhibitors for cardiovascular disease treatment. AB - The targeting of protein kinases has great future potential for the design of new drugs against cardiovascular diseases (CVDs). Enormous efforts have been made toward achieving this aim. Unfortunately, kinase inhibitors designed to treat CVDs have suffered from numerous limitations such as poor selectivity, bad permeability and toxicity. So, where are we now in terms of discovering effective kinase targeting drugs to treat CVDs? Various drug design techniques have been approached for this purpose since the discovery of the inhibitory activity of Staurosporine against protein kinase C in 1986. This review aims to provide context for the status of several emerging classes of direct kinase modulators to treat CVDs and discuss challenges that are preventing scientists from finding new kinase drugs to treat heart disease. PMID- 29134115 TI - Plant stem cells in cosmetics: current trends and future directions. AB - Plant regeneration at the cellular and tissue level is a unique process. Similar to animals, the stem cells in plants have properties that help stimulate and regenerate plants after injury. The unique properties of plant stem cells have been a recent area of interest and focus both in developing new cosmetics and studying how these extracts/phytohormones will influence animal skin. This special report focuses on the current evidence-based trends in plant stem cell based cosmetics and sheds light on the challenges that we need to overcome in order to see meaningful changes in human skin using topical cosmetics derived from plant stem cells. PMID- 29134117 TI - Identification of nonserotypeable Shigella spp. using genome sequencing: a step forward. AB - Aim: Sequencing technology has replaced conventional methods in identifying and characterizing bacterial pathogens. We characterized 23 nonserotypeable Shigella that biochemically resembled Shigella spp. using whole genome sequencing. Materials & methods: Genome sequences were analyzed using online tools based on 16S rRNA, k-mer, gyrB sequences and analysis of O-antigen arrangement was done using PATRIC database for species identification. Sequence types, plasmid types, antimicrobial resistance and virulence genes were also investigated. Results: The SpeciesFinder using 16S rRNA sequences identified only 74% of the isolates, whereas KmerFinder and gyrB sequence analysis identified 100% of the isolates to its species level. Antimicrobial resistance, virulence and plasmid incompatibility groups were identified in all the isolates. Sequence types were determined. Conclusion: This study shows that whole genome sequencing approach for Shigella O-antigen analysis has greater discriminative power than other methods using different bioinformatics pipeline for identification of nonserotypeable Shigella. PMID- 29134116 TI - Targeting subchondral bone mesenchymal stem cell activities for intrinsic joint repair in osteoarthritis. AB - Osteoarthritis (OA) is a common age-related disease with complex pathophysiology. It is characterized by wide-ranging tissue damage and ultimate biomechanical failure of the whole joint. However, signs of tissue adaptation and attempted repair responses are evident in OA-affected osteochondral tissues. Highlighted in this review article is the role of bone-resident mesenchymal stem cells (MSCs) in these bone remodeling responses, and a proposal that targeting MSC activities in OA subchondral bone could represent a novel approach for intrinsic joint regeneration in OA. The development of these therapies will require better understanding of MSC proliferation, migration and differentiation patterns in relation to OA tissue damage and further clarification of the molecular signaling events in these MSCs during disease progression. PMID- 29134118 TI - An overview of platelet products (PRP, PRGF, PRF, etc.) in the Iranian studies. AB - Aim: The aim of the study was to carry out a review of published studies on various platelet products in Iranian studies. Materials & methods: Electronic databases were searched for relevant articles. Two review authors independently extracted data via a tested extraction sheet, and disagreements were resolved by a meeting with a third review author. Results: Bone disorders (25%), wound and fistula (16%), dental and gingival disorders (14%) and osteoarthritis (11%) have more relative frequency based on different fields. Conclusion: The necessity of pursuing standard protocols in the preparation of platelet products, stating the precise content of platelets and growth factors, and long-term follow-up of study subjects were the most important points in Iranian studies. PMID- 29134120 TI - Biocompatible nickel-prussian blue@silver nanocomposites show potent antibacterial activities. AB - Aim: Silver nanoparticles have long been used as potent antibacterial agents. However, toxicity concerns of silver nanoparticles have limited their successful clinical applications. Hence, development of silver-based novel biocompatible nanomaterials for antibacterial applications is a challenging task. Materials & methods: Accordingly, in this work, we synthesized a biocompatible silver-based nanocomposite for antibacterial applications. The nanocompostie was characterized by several analytical techniques. The nanocomposite was further tested for its cytotoxicity in cells, chicken embryo and bacteria. Results & Conclusion: Herein, we report a simple and cost-effective method for the synthesis of nickel-prussian blue@silver nanocomposites. The nanocomposite is highly stable and shows biocompatibility observed by in vitro assay and by ex vivo chicken embryonic angiogenesis assay. The nanocomposite exhibits profound antibacterial activity toward Gram-negative (Escherichia coli) and Gram-positive (Bacillus subtillus) bacteria. The results altogether suggest the future potential applications of nickel-prussian blue@silver nanocomposite as an antibacterial agent. PMID- 29134119 TI - Identification of membrane proteome of Paracoccidioides lutzii and its regulation by zinc. AB - Aim: During infection development in the host, Paracoccidioides spp. faces the deprivation of micronutrients, a mechanism called nutritional immunity. This condition induces the remodeling of proteins present in different metabolic pathways. Therefore, we attempted to identify membrane proteins and their regulation by zinc in Paracoccidioides lutzii. Materials & methods: Membranes enriched fraction of yeast cells of P. lutzii were isolated, purified and identified by 2D LC-MS/MS detection and database search. Results & conclusion: Zinc deprivation suppressed the expression of membrane proteins such as glycoproteins, those involved in cell wall synthesis and those related to oxidative phosphorylation. This is the first study describing membrane proteins and the effect of zinc deficiency in their regulation in one member of the genus Paracoccidioides. PMID- 29134121 TI - Omega-3 fatty acids in atherosclerosis and coronary artery disease. AB - Omega-3 polyunsaturated fatty acids have emerged as possible protective factors associated with a decreased risk for myocardial infarction in populations with a high marine food intake, which may relate to effects on lipid metabolism, thrombosis and inflammation. Omega-3 fatty acids decrease triglyceride levels and also compete as substrates for enzymes involved in the biosynthesis of lipid mediators. The balance between omega-3-derived specialized proresolving mediators and pro-inflammatory lipid mediators from arachidonic acid metabolism can be measured as the resolvin-to-leukotriene ratio, which has been shown to predict subclinical atherosclerosis. The results of experimental, observational and randomized studies of omega-3 fatty acids are somewhat variable and should be interpreted in view of the models used and the populations studied. PMID- 29134123 TI - Green synthesis of capped gold nanoparticles and their effect on Gram-positive and Gram-negative bacteria. AB - Aim: We report synthesis of capped gold nanoparticles (C-AuNPs) of ~20-30 nm by reducing HAuCl4 with flower and leaf extracts of Ocimum tenuiflorum, leaves of Azadirachta indica and Mentha spicata and peel of Citrus sinensis plants. Methods: Atomic force microscopy (AFM) and transmission electron microscopy (TEM) determined their size, shape and topographical structures. The C-AuNPs with UV Vis spectrophotometer produced a maximum absorption within 530-535 nm wavelengths. Their Fourier transform IR stretching frequencies, from 450 to 4000 cm-1, have inferred HAuCl4 reduction to Au. Results: The 512 and 600 MUgml-1 C AuNP MICs were expressed on antimicrobial strains Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. Conclusion: The chosen plant extracts have reduced the Au3+ to Au0 with simultaneous in situ capping with bacteria inhibiting activities. Green routes for C-AuNP synthesis could be an asset for several other biomedical and bioengineering applications. PMID- 29134122 TI - Platelet phosphorylated TDP-43: an exploratory study for a peripheral surrogate biomarker development for Alzheimer's disease. AB - Aim: Alzheimer's disease (AD) and other forms of dementia create a noncurable disease population in world's societies. To develop a blood-based biomarker is important so that the remedial or disease-altering therapeutic intervention for AD patients would be available at the early stage. Materials & methods: TDP-43 levels were analyzed in postmortem brain tissue and platelets of AD and control subjects. Results: We observed an increased TDP-43 (<60%) in postmortem AD brain regions and similar trends were also observed in patient's platelets. Conclusion: Platelet TDP-43 could be used as a surrogate biomarker that is measurable, reproducible and sensitive for screening the patients with some early clinical signs of AD and can be used to monitor disease prognosis. PMID- 29134124 TI - The design and implementation of the software tracking cervical and lumbar vertebrae in spinal fluoroscopy images. AB - Aim: Manual analysis of neck kinematics is usually associated with measurement errors and it requires the use of software capabilities. Considering laboratory usage, software has been developed to solve the associated problems. Materials & methods: Fluoroscopic images taken from 78 women were used to design and evaluate the performance of the software. The software was implemented using C# language, according to the case-based reasoning technique. Results: The viewpoints of experts suggest accuracy of the software in tracking and calculations, which meets their information requirements. Conclusion: Using the software could help physiotherapists to accomplish their work in decreased time and with improved accuracy. PMID- 29134125 TI - How is the weather? Forecasting inpatient glycemic control. AB - Aim: Apply methods of damped trend analysis to forecast inpatient glycemic control. Method: Observed and calculated point-of-care blood glucose data trends were determined over 62 weeks. Mean absolute percent error was used to calculate differences between observed and forecasted values. Comparisons were drawn between model results and linear regression forecasting. Results: The forecasted mean glucose trends observed during the first 24 and 48 weeks of projections compared favorably to the results provided by linear regression forecasting. However, in some scenarios, the damped trend method changed inferences compared with linear regression. In all scenarios, mean absolute percent error values remained below the 10% accepted by demand industries. Conclusion: Results indicate that forecasting methods historically applied within demand industries can project future inpatient glycemic control. Additional study is needed to determine if forecasting is useful in the analyses of other glucometric parameters and, if so, how to apply the techniques to quality improvement. PMID- 29134126 TI - The urinary and serum levels of IL-32 in children with febrile urinary tract infections. AB - Aim: We assessed the urinary and serum levels of IL-32 in pediatric patients with acute pyelonephritis (APN) with and without renal scarring. Results: We enrolled children aged 2 months to 16 years with APN. Dimercaptosuccinic acid scans and ultrasonography studies were ordered for all patients, and a voiding. A total of 86 children (aged 57 +/- 39 months, 74 [86%] female) were enrolled in this study. Group 1 was composed of 19 (16 female) patients, group 2 of 38 (35 female) patients and group 3 of 29 (23 female) patients. There were no significant differences in the serum and absolute urinary levels of IL-32 (UIL-32) between groups, but the urinary IL-32/creatinine ratio (UIL-32/Cr) was significantly higher in children with pyelonephritis than controls. PMID- 29134127 TI - The characterization of human oral mucosal fibroblasts and their use as feeder cells in cultivated epithelial sheets. AB - Aim: To characterize human oral mucosa middle interstitial tissue fibroblasts (hOMFs) and their application in the cultivation of epithelial sheets. Methodology: hOMFs were cultured with methylcellulose to form cell clusters. hOMFs amplified in adhesive culture were analyzed by flow cytometry, and were found to differentiate into multiple cell types suitable for the cultivation of human corneal epithelial sheets. hOMFs were expanded from clusters to analyze CD56 and PDGFRalpha expression. Results: These cells showed similar differentiation patterns as keratocytes, and similar expression patterns as mesenchymal and neural cells. Furthermore, we established human corneal epithelial sheets using hOMFs. Conclusion: hOMFs may be of neural crest origin and possess multipotent differentiation capacity, and are suitable for use as an autologous cell source for corneal regeneration. PMID- 29134128 TI - A preliminary study for the assessment of PD-L1 and PD-L2 on circulating tumor cells by microfluidic-based chipcytometry. AB - Aim: Expression of PD-L1 in the tumor is associated with more favorable responses to anti-PD-1 therapy in multiple cancers. However, obtaining tumor biopsies for PD-L1 interrogation is an invasive procedure and challenging to assess repeatedly as the disease progresses. Materials & methods: Here we assess an alternative, minimally invasive approach to analyze blood samples for circulating tumor cells (CTCs) that have broken away from the tumor and entered the periphery. Our approach uses sized-based microfluidic CTC enrichment and subsequent characterization with microfluidic-based cytometry (chipcytometry). Conclusion: We demonstrate tumor-cell detection and characterization for PD-L1, and other markers, in both spiked and patient samples. This preliminary communication is the first report using chipcytometry for the characterization of CTCs. PMID- 29134129 TI - Comparison of Clinical & Laboratory Standards Institute standards in antimicrobial susceptibility among the carbapenemase producing Enterobacteriaceae. AB - Aim: Carbapenems are antibiotics reserved for treatment of severe infections. Carbapenem antimicrobial susceptibility testing profiles were determined in a population of Klebsiella pneumoniae, and their resistance assessed based on previous and current Clinical and Laboratory Standards Institute criteria. Materials & methods: Isolates were examined using an automated antimicrobial susceptibility testing method, and real time polymerase chain reaction to detect the resistance (blaKPC) gene. Results: The prevalence of blaKPC gene was 45/54 (83.3%). Five isolates that were susceptible under the previous criteria changed to nonsusceptible with the current standards. The overall difference in susceptibility between the standards was 8%. Conclusion: This study shows that the current Clinical and Laboratory Standards Institute criteria may not offer additional benefits in the fight against carbapenem-resistant Enterobacteriaceae. PMID- 29134130 TI - Recent progress in the research of cold-inducible RNA-binding protein. AB - Cold-inducible RNA-binding protein (CIRP) is a cold-shock protein which can be induced after exposure to a moderate cold-shock in different species ranging from amphibians to humans. Expression of CIRP can also be regulated by hypoxia, UV radiation, glucose deprivation, heat stress and H2O2, suggesting that CIRP is a general stress-response protein. In response to stress, CIRP can migrate from the nucleus to the cytoplasm and regulate mRNA stability through its binding site on the 3'-UTR of its targeted mRNAs. Through the regulation of its targets, CIRP has been implicated in multiple cellular process such as cell proliferation, cell survival, circadian modulation, telomere maintenance and tumor formation and progression. In addition, CIRP can also exert its functions by directly interacting with intracellular signaling proteins. Moreover, CIRP can be secreted out of cells. Extracellular CIRP functions as a damage-associated molecular pattern to promote inflammatory responses and plays an important role in both acute and chronic inflammatory diseases. Here, we summarize novel findings of CIRP investigation and hope to provide insights into the role of CIRP in cell biology and diseases. PMID- 29134132 TI - Abnormal subchondral bone remodeling and its association with articular cartilage degradation in knees of type 2 diabetes patients. AB - Type 2 diabetes (T2D) is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis (OA). Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic (n=70) and diabetes (n=51) groups. Tibial plateaus were also collected from cadaver donors (n=20) and used as controls. Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase (TRAP), osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International (OARSI) scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP+ osteoclasts and lower number of Osterix+ osteoprogenitors and Osteocalcin+ osteoblasts. T2D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2D-associated knee OA. PMID- 29134131 TI - Medicinally important aromatic plants with radioprotective activity. AB - Aromatic plants are often used as natural medicines because of their remedial and inherent pharmacological properties. Looking into natural resources, particularly products of plant origin, has become an exciting area of research in drug discovery and development. Aromatic plants are mainly exploited for essential oil extraction for applications in industries, for example, in cosmetics, flavoring and fragrance, spices, pesticides, repellents and herbal beverages. Although several medicinal plants have been studied to treat various conventional ailments only a handful studies are available on aromatic plants, especially for radioprotection. Many plant extracts have been reported to contain antioxidants that scavenge free radicals produced due to radiation exposure, thus imparting radioprotective efficacy. The present review focuses on a subset of medicinally important aromatic plants with radioprotective activity. PMID- 29134133 TI - Monitoring and Morphologic Classification of Pediatric Cataract Using Slit-Lamp Adapted Photography. AB - Purpose: To investigate the feasibility of pediatric cataract monitoring and morphologic classification using slit lamp-adapted anterior segmental photography in a large cohort that included uncooperative children. Methods: Patients registered in the Childhood Cataract Program of the Chinese Ministry of Health were prospectively selected. Eligible patients underwent slit-lamp adapted anterior segmental photography to record and monitor the morphology of their cataractous lenses. A set of assistance techniques for slit lamp-adapted photography was developed to instruct the parents of uncooperative children how to help maintain the child's head position and keep the eyes open after sleep aid administration. Results: Briefly, slit lamp-adapted photography was completed for all 438 children, including 260 (59.4%) uncooperative children with our assistance techniques. All 746 images of 438 patients successfully confirmed the diagnoses and classifications. Considering the lesion location, pediatric cataract morphologies could be objectively classified into the seven following types: total; nuclear; polar, including two subtypes (anterior and posterior); lamellar; nuclear combined with cortical, including three subtypes (coral-like, dust-like, and blue-dot); cortical; and Y suture. The top three types of unilateral cataracts were polar (55, 42.3%), total (42, 32.3%), and nuclear (23, 17.7%); and the top three types of bilateral cataracts were nuclear (110, 35.8%), total (102, 33.2%), and lamellar (34, 11.1%). Conclusions: Slit lamp-adapted anterior segmental photography is applicable for monitoring and classifying the morphologies of pediatric cataracts and is even safe and feasible for uncooperative children with assistance techniques and sleep aid administration. Translational Relevance: This study proposes a novel strategy for the preoperative evaluation and evidence-based management of pediatric ophthalmology (Clinical Trials.gov, NCT02748031). PMID- 29134134 TI - Predicting the Real-World Future of Glaucoma Patients? Cautions Are Required for Machine Learning. PMID- 29134135 TI - Polypoidal Choroidal Vasculopathy on Swept-Source Optical Coherence Tomography Angiography with Variable Interscan Time Analysis. AB - Purpose: To use a novel optical coherence tomography angiography (OCTA) algorithm termed variable interscan time analysis (VISTA) to evaluate relative blood flow speeds in polypoidal choroidal vasculopathy (PCV). Methods: Prospective cross sectional study enrolling patients with confirmed diagnosis of PCV. OCTA of the retina and choroid was obtained with a prototype swept-source OCT system. The acquired OCT volumes were centered on the branching vascular network (BVN) and polyps as determined by indocyanine-green angiography (ICGA). The relative blood flow speeds were characterized on VISTA-OCTA. Results: Seven eyes from seven patients were evaluated. Swept-source OCTA enabled detailed enface visualization of the BVN and polyps in six eyes. VISTA-OCTA revealed variable blood flow speeds in different PCV lesion components of the same eye, with faster flow in the periphery of polyps and slower flow in the center of each polyp, as well as relatively slow flow in BVN when compared with retinal vessels. BVNs demonstrated relatively faster blood flow speeds in the larger trunk vessels and relatively slower speeds in the smaller vessels. Conclusions: Swept-source OCTA identifies polyps in most, but not all, PCV lesions. This limitation that may be related to relatively slow blood flow within the polyp, which may be below the OCTA's sensitivity. VISTA-OCTA showed heterogeneous blood flow speeds within the polyps, which may indicate turbulent flow in the polyps. Translational Relevance: These results bring relevant insights into disease mechanisms that can account for the variable course of PCV, and can be relevant for diagnosis and management of patients with PCV. PMID- 29134136 TI - Creating a Full-thickness Choroidal Incision: An Ex Vivo Analysis of Human and Porcine Tissue Contraction Dynamics. AB - Purpose: We hypothesized that the elastic nature of the choroid leads to tissue contraction following a full-thickness, sharp incision. Furthermore, we sought to quantify, measure, and compare tissue contraction in ex vivo porcine globes and human globes of various ages using predetermined variables. Method: A full thickness, ex vivo choroidal incision was performed in either pig (n = 97) or human (n = 30) specimens. Variables included trephine diameter (1.5, 2.0, or 2.5 mm) versus a straight surgical blade, and temperature (1.7 degrees -4.4 degrees vs. 36.6 degrees F). Central centripetal and surround centrifugal tissue contractions were measured. Mean percentage tissue contraction was assessed as a ratio of trephine diameter to final tissue contraction measured immediately following each incision using a standardized device. Results: For trephination in pig specimens, centripetal contraction ranged from 38% to 50% with a mean of 44%. Centrifugal contraction was approximately 15%. Human choroidal contraction was 39% and 15%, respectively, with a statistically significant inverse relationship to age (R2 = 0.35, P <= 0.01). Asymmetric contraction was noted when incisions were closer to choroidal attachment sites to the sclera, such as near vortex ampullae. Linear incisions resulted in contraction that correlated with incision length (R2 = 0.35, P <= 0.001). Conclusions: A full-thickness choroidal incision results in significant tissue contraction. For circular incisions, the centripetal contraction approaches 50% of the original incision size. For linear incisions, the contraction corresponds directly with incision length. In human specimens, there is less contraction with advancing age. Translational Relevance: Our findings have clinical relevance for choroidal biopsy, traumatic injury, and choroidal translocation surgery. PMID- 29134137 TI - Pattern Electroretinography and Visual Evoked Potentials Provide Clinical Evidence of CNS Modulation of High- and Low-Contrast VEP Latency in Glaucoma. AB - Purpose: Both pattern electroretinography (PERG) and visual evoked potentials (VEP) can be performed using low- (15%; Lc) and high- (85%; Hc) contrast gratings that may preferentially stimulate the magno- and parvocellular pathways. We observed that among glaucomatous patients showing only one VEP latency deficit per eye, there appeared to be a very strong tendency for an Hc delay in one eye and an Lc delay in the other. Methods: Diopsys NOVA-LX system was used to measure VEP Hc and Lc latency among a clinical glaucoma population to find all individuals with either a single Hc or Lc latency abnormality in each eye (group 1), or with greater than 0 and less than 4 Hc or Lc VEP latency abnormalities in the two eyes (group 2) to determine whether a significant inverse correlation existed for these values in either group. Hc and Lc PERG data were also evaluated to assess associated retinal ganglion cell responses. Results: A strong inverse correlation (P = 0.0000003) was observed between the Hc and Lc VEP latency values among the 64 eyes in group 1. Group 2 provided a comparable result (n = 143; 286 eyes; P = 0.0005). PERG (n = 81; 162 eyes) also showed strong bilateral symmetry for magnitude values (P < 0.0001 for both Lc and Hc in groups 1 and 2). Conclusions: Bilateral retention of both low-resolution/high-speed and high resolution/low-speed function may persist with both eyes open despite symmetrically pathologic retinal ganglion cell PERG waveform asynchrony for Hc and Lc stimuli in the paired eyes. Translational Relevance: Clinical electrophysiology strongly suggests binocular compensation for dynamic dysfunction operates under central nervous system (CNS) control in glaucoma. PMID- 29134138 TI - Mobile acoustic transects miss rare bat species: implications of survey method and spatio-temporal sampling for monitoring bats. AB - Due to increasing threats facing bats, long-term monitoring protocols are needed to inform conservation strategies. Effective monitoring should be easily repeatable while capturing spatio-temporal variation. Mobile acoustic driving transect surveys ('mobile transects') have been touted as a robust, cost effective method to monitor bats; however, it is not clear how well mobile transects represent dynamic bat communities, especially when used as the sole survey approach. To assist biologists who must select a single survey method due to resource limitations, we assessed the effectiveness of three acoustic survey methods at detecting species richness in a vast protected area (Everglades National Park): (1) mobile transects, (2) stationary surveys that were strategically located by sources of open water and (3) stationary surveys that were replicated spatially across the landscape. We found that mobile transects underrepresented bat species richness compared to stationary surveys across all major vegetation communities and in two distinct seasons (dry/cool and wet/warm). Most critically, mobile transects failed to detect three rare bat species, one of which is federally endangered. Spatially replicated stationary surveys did not estimate higher species richness than strategically located stationary surveys, but increased the rate at which species were detected in one vegetation community. The survey strategy that detected maximum species richness and the highest mean nightly species richness with minimal effort was a strategically located stationary detector in each of two major vegetation communities during the wet/warm season. PMID- 29134139 TI - Male sex pheromone components in Heliconius butterflies released by the androconia affect female choice. AB - Sex-specific pheromones are known to play an important role in butterfly courtship, and may influence both individual reproductive success and reproductive isolation between species. Extensive ecological, behavioural and genetic studies of Heliconius butterflies have made a substantial contribution to our understanding of speciation. Male pheromones, although long suspected to play an important role, have received relatively little attention in this genus. Here, we combine morphological, chemical and behavioural analyses of male pheromones in the Neotropical butterfly Heliconius melpomene. First, we identify putative androconia that are specialized brush-like scales that lie within the shiny grey region of the male hindwing. We then describe putative male sex pheromone compounds, which are largely confined to the androconial region of the hindwing of mature males, but are absent in immature males and females. Finally, behavioural choice experiments reveal that females of H. melpomene, H. erato and H. timareta strongly discriminate against conspecific males which have their androconial region experimentally blocked. As well as demonstrating the importance of chemical signalling for female mate choice in Heliconius butterflies, the results describe structures involved in release of the pheromone and a list of potential male sex pheromone compounds. PMID- 29134140 TI - Genome-wide identification and characterization of GRAS transcription factors in tomato (Solanum lycopersicum). AB - Solanum lycopersicum, belonging to Solanaceae, is one of the commonly used model plants. The GRAS genes are transcriptional regulators, which play a significant role in plant growth and development, and the functions of several GRAS genes have been recognized, such as, axillary shoot meristem formation, radial root patterning, phytohormones (gibberellins) signal transduction, light signaling, and abiotic/biotic stress; however, only a few of these were identified and functionally characterized. In this study, a gene family was analyzed comprehensively with respect to phylogeny, gene structure, chromosomal localization, and expression pattern; the 54 GRAS members were screened from tomato by bioinformatics for the first time. The GRAS genes among tomato, Arabidopsis, rice, and grapevine were rebuilt to form a phylogenomic tree, which was divided into ten groups according to the previous classification of Arabidopsis and rice. A multiple sequence alignment exhibited the typical GRAS domain and conserved motifs similar to other gene families. Both the segmental and tandem duplications contributed significantly to the expansion and evolution of the GRAS gene family in tomato; the expression patterns across a variety of tissues and biotic conditions revealed potentially different functions of GRAS genes in tomato development and stress responses. Altogether, this study provides valuable information and robust candidate genes for future functional analysis for improving the resistance of tomato growth. PMID- 29134141 TI - Metabarcoding analysis of the stomach contents of the Antarctic Toothfish (Dissostichus mawsoni) collected in the Antarctic Ocean. AB - Stomach contents of the Antarctic toothfish, Dissostichus mawsoni, collected from subareas 58.4 and 88.3, were analyzed using next generation sequencing (NGS) technology. After processing the raw reads generated by the MiSeq platform, a total of 131,233 contigs (130 operational taxonomic units [OTUs]) were obtained from 163 individuals in subarea 58.4, and 75,961 contigs (105 OTUs) from 164 fish in subarea 88.3. At 98% sequence identity, species names were assigned to most OTUs in this study, indicating the quality of the DNA barcode database for the Antarctic Ocean was sufficient for molecular analysis, especially for fish species. A total of 19 species was identified from the stomach of D. mawsoni in this study, which included 14 fish species and five mollusks. More than 90% of contigs belonged to fish species, supporting the postulate that the major prey of D. mawsoni are fish. Two fish species, Macrourus whitsoni and Chionobathyscus dewitti, were the most important prey items (a finding similar to that of previous studies). We also obtained genotypes of prey items by NGS analysis, identifying an additional 17 representative haplotypes in this study. Comparison with three previous morphological studies and the NGS-based molecular identification in this study extended our knowledge regarding the prey of D. mawsoni, which previously was not possible. These results suggested that NGS based diet studies are possible, if several current technical limitations, including the quality of the barcode database or the development of precise molecular quantification techniques to link them with morphological values, are overcome. To achieve this, additional studies should be conducted on various marine organisms. PMID- 29134142 TI - Assemblage and functional categorization of dung beetles (Coleoptera: Scarabaeinae) from the Pantanal. AB - The Pantanal is one of the world's largest tropical wetland areas and harbors high mammal biomass. There is no formal list of dung beetle species, and studies on their functional roles have never being carried out in Pantanal. In this study, we identified dung beetle species occurring in the north Pantanal region (Pocone sub-region, Brazil) and studied their functional organization, by measuring morphological, behavioral and phenological traits. We collected 25,278 individuals belonging to 17 genera and 35 species. We identified eight functional groups in the habitat: Noturnal Telecoprids, Diurnal Telecoprids, Nesting Endocoprids, Small Nonrollers, Nocturnal Nester Paracoprids, Big Nesters Paracoprids, Non Nesters Paracoprids and Diurnal Nesters Paracoprids. The functional groups were defined mostly by two reproductive traits and two niche differentiation traits related to the use of fecal resources. This high diversification of both species and functional roles shows the importance of the group in a habitat with strong variation in availability of habitat and resources. PMID- 29134143 TI - EEG sensorimotor rhythms' variation and functional connectivity measures during motor imagery: linear relations and classification approaches. AB - Hands motor imagery (MI) has been reported to alter synchronization patterns amongst neurons, yielding variations in the mu and beta bands' power spectral density (PSD) of the electroencephalography (EEG) signal. These alterations have been used in the field of brain-computer interfaces (BCI), in an attempt to assign distinct MI tasks to commands of such a system. Recent studies have highlighted that information may be missing if knowledge about brain functional connectivity is not considered. In this work, we modeled the brain as a graph in which each EEG electrode represents a node. Our goal was to understand if there exists any linear correlation between variations in the synchronization patterns that is, variations in the PSD of mu and beta bands-induced by MI and alterations in the corresponding functional networks. Moreover, we (1) explored the feasibility of using functional connectivity parameters as features for a classifier in the context of an MI-BCI; (2) investigated three different types of feature selection (FS) techniques; and (3) compared our approach to a more traditional method using the signal PSD as classifier inputs. Ten healthy subjects participated in this study. We observed significant correlations (p < 0.05) with values ranging from 0.4 to 0.9 between PSD variations and functional network alterations for some electrodes, prominently in the beta band. The PSD method performed better for data classification, with mean accuracies of (90 +/- 8)% and (87 +/- 7)% for the mu and beta band, respectively, versus (83 +/- 8)% and (83 +/- 7)% for the same bands for the graph method. Moreover, the number of features for the graph method was considerably larger. However, results for both methods were relatively close, and even overlapped when the uncertainties of the accuracy rates were considered. Further investigation regarding a careful exploration of other graph metrics may provide better alternatives. PMID- 29134145 TI - Visual and acoustic components of courtship in the bird-of-paradise genus Astrapia (Aves: Paradisaeidae). AB - The distinctive and divergent courtship phenotypes of the birds-of-paradise make them an important group for gaining insights into the evolution of sexually selected phenotypic evolution. The genus Astrapia includes five long-tailed species that inhabit New Guinea's montane forests. The visual and acoustic components of courtship among Astrapia species are very poorly known. In this study, we use audiovisual data from a natural history collection of animal behavior to fill gaps in knowledge about the visual and acoustic components of Astrapia courtship. We report seven distinct male behaviors and two female specific behaviors along with distinct vocalizations and wing-produced sonations for all five species. These results provide the most complete assessment of courtship in the genus Astrapia to date and provide a valuable baseline for future research, including comparative and evolutionary studies among these and other bird-of-paradise species. PMID- 29134144 TI - Composition, diversity and function of intestinal microbiota in pacific white shrimp (Litopenaeus vannamei) at different culture stages. AB - Intestinal microbiota is an integral component of the host and plays important roles in host health. The pacific white shrimp is one of the most profitable aquaculture species commercialized in the world market with the largest production in shrimp consumption. Many studies revealed that the intestinal microbiota shifted significantly during host development in other aquaculture animals. In the present study, 22 shrimp samples were collected every 15 days from larval stage (15 day post-hatching, dph) to adult stage (75 dph) to investigate the intestinal microbiota at different culture stages by targeting the V4 region of 16S rRNA gene, and the microbial function prediction was conducted by PICRUSt. The operational taxonomic unit (OTU) was assigned at 97% sequence identity. A total of 2,496 OTUs were obtained, ranging from 585 to 1,239 in each sample. Forty-three phyla were identified due to the classifiable sequence. The most abundant phyla were Proteobacteria, Cyanobacteria, Tenericutes, Fusobacteria, Firmicutes, Verrucomicrobia, Bacteroidetes, Planctomycetes, Actinobacteria and Chloroflexi. OTUs belonged to 289 genera and the most abundant genera were Candidatus_Xiphinematobacter, Propionigenium, Synechococcus, Shewanella and Cetobacterium. Fifty-nine OTUs were detected in all samples, which were considered as the major microbes in intestine of shrimp. The intestinal microbiota was enriched with functional potentials that were related to transporters, ABC transporters, DNA repair and recombination proteins, two component system, secretion system, bacterial motility proteins, purine metabolism and ribosome. All the results showed that the intestinal microbial composition, diversity and functions varied significantly at different culture stages, which indicated that shrimp intestinal microbiota depended on culture stages. These findings provided new evidence on intestinal microorganism microecology and greatly enhanced our understanding of stage-specific community in the shrimp intestinal ecosystem. PMID- 29134146 TI - Indicators for the use of robotic labs in basic biomedical research: a literature analysis. AB - Robotic labs, in which experiments are carried out entirely by robots, have the potential to provide a reproducible and transparent foundation for performing basic biomedical laboratory experiments. In this article, we investigate whether these labs could be applicable in current experimental practice. We do this by text mining 1,628 papers for occurrences of methods that are supported by commercial robotic labs. Using two different concept recognition tools, we find that 86%-89% of the papers have at least one of these methods. This and our other results provide indications that robotic labs can serve as the foundation for performing many lab-based experiments. PMID- 29134147 TI - Anthropogenic water sources and the effects on Sonoran Desert small mammal communities. AB - Anthropogenic water sources (AWS) are developed water sources used as a management tool for desert wildlife species. Studies documenting the effects of AWS are often focused on game species; whereas, the effects on non-target wildlife are less understood. We used live trapping techniques to investigate rodent abundance, biomass, and diversity metrics near AWS and paired control sites; we sampled vegetation to determine rodent-habitat associations in the Sauceda Mountains of the Sonoran Desert in Arizona. A total of 370 individual mammals representing three genera and eight species were captured in 4,800 trap nights from winter 2011 to spring 2012. A multi-response permutation procedure was used to identify differences in small mammal community abundance and biomass by season and treatment. Rodent abundance, biomass, and richness were greater at AWS compared to control sites. Patterns of abundance and biomass were driven by the desert pocket mouse (Chaetodipus penicillatus) which was the most common capture and two times more numerous at AWS compared to controls. Vegetation characteristics, explored using principal components analysis, were similar between AWS and controls. Two species that prefer vegetation structure, Bailey's pocket mouse (C. baileyi) and white-throated woodrat (Neotoma albigula), had greater abundances and biomass near AWS and were associated with habitat having high cactus density. Although small mammals do not drink free-water, perhaps higher abundances of some species of desert rodents at AWS could be related to artificial structure associated with construction or other resources. Compared to the 30-year average of precipitation for the area, the period of our study occurred during a dry winter. During dry periods, perhaps AWS provide resources to rodents related to moisture. PMID- 29134148 TI - Transcriptome dynamics along axolotl regenerative development are consistent with an extensive reduction in gene expression heterogeneity in dedifferentiated cells. AB - Although in recent years the study of gene expression variation in the absence of genetic or environmental cues or gene expression heterogeneity has intensified considerably, many basic and applied biological fields still remain unaware of how useful the study of gene expression heterogeneity patterns might be for the characterization of biological systems and/or processes. Largely based on the modulator effect chromatin compaction has for gene expression heterogeneity and the extensive changes in chromatin compaction known to occur for specialized cells that are naturally or artificially induced to revert to less specialized states or dedifferentiate, I recently hypothesized that processes that concur with cell dedifferentiation would show an extensive reduction in gene expression heterogeneity. The confirmation of the existence of such trend could be of wide interest because of the biomedical and biotechnological relevance of cell dedifferentiation-based processes, i.e., regenerative development, cancer, human induced pluripotent stem cells, or plant somatic embryogenesis. Here, I report the first empirical evidence consistent with the existence of an extensive reduction in gene expression heterogeneity for processes that concur with cell dedifferentiation by analyzing transcriptome dynamics along forearm regenerative development in Ambystoma mexicanum or axolotl. Also, I briefly discuss on the utility of the study of gene expression heterogeneity dynamics might have for the characterization of cell dedifferentiation-based processes, and the engineering of tools that afforded better monitoring and modulating such processes. Finally, I reflect on how a transitional reduction in gene expression heterogeneity for dedifferentiated cells can promote a long-term increase in phenotypic heterogeneity following cell dedifferentiation with potential adverse effects for biomedical and biotechnological applications. PMID- 29134149 TI - The response of soil microbial communities to variation in annual precipitation depends on soil nutritional status in an oligotrophic desert. AB - Background: Soil microbial communities (SMC) play a central role in the structure and function of desert ecosystems. However, the high variability of annual precipitation could results in the alteration of SMC and related biological processes depending on soil water potential. The nature of the physiological adjustments made by SMC in order to obtain energy and nutrients remains unclear under different soil resource availabilities in desert ecosystems. In order to examine this dynamic, the present study examined the effects of variation in annual precipitation on physiological adjustments by the SMC across two vegetation-soil systems of different soil organic matter input in an oligotrophic desert ecosystem. Methods: We collected soil samples in the Cuatro Cienegas Basin (Mexico) under two vegetation covers: rosetophylous scrub (RS) and grassland (G), that differ in terms of quantity and quality of organic matter. Collections were conducted during the years 2011, 2012, 2013 and 2014, over which a noticeable variation in the annual precipitation occurred. The ecoenzymatic activity involved in the decomposition of organic matter, and the concentration of dissolved, available and microbial biomass nutrients, were determined and compared between sites and years. Results: In 2011, we observed differences in bacterial taxonomic composition between the two vegetation covers. The lowest values of dissolved, available and microbial nutrients in both cover types were found in 2012. The G soil showed higher values of dissolved and available nutrients in the wet years. Significant positive correlations were detected between precipitation and the ratios Cmic:Nmic and Cmic:Pmic in the RS soil and Cmic:Pmic and Nmic:Pmic in the G soil. The slopes of the regression with Cmic and Nmic were higher in the G soil and lower in the RS soil. Moreover, the SMC under each vegetation cover were co-limited by different nutrients and responded to the sum of water stress and nutrient limitation. Discussion: Soil community within both sites (RS and G) may be vulnerable to drought. However, the community of the site with lower resources (RS) is well adapted to acquire P resources by ecoenzyme upregulation during years with adequate precipitation, suggesting that this community is resilient after drought occurs. Under the Global Climate Change scenarios for desert ecosystems that predict reduced annual precipitation and an increased intensity and frequency of torrential rains and drought events, the soil microbial communities of both sites could be vulnerable to drought through C and P co-limitation and reallocation of resources to physiological acclimatization strategies in order to survive. PMID- 29134150 TI - HCV core antigen is an alternative marker to HCV RNA for evaluating active HCV infection: implications for improved diagnostic option in an era of affordable DAAs. AB - The core antigen of the hepatitis C virus (HCV Ag) presents an alternative marker to HCV RNA when screening patients for HCV viremia. This study sought to evaluate the utility of HCV Ag as a marker to assess active HCV infection in individuals residing in an HCV-endemic area. From 298 HCV-seropositive individuals evaluated for the presence of anti-HCV antibody, HCV Ag and HCV RNA, anti-HCV antibody was detected in 252 individuals (signal-to-cutoff ratios >=5), HCV RNA was detected in 222 individuals (88%), and HCV Ag was reactive (>=3 fmol/L) in 220 individuals (87%). HCV genotype 1, 3, and 6 were identified. HCV Ag significantly correlated with HCV RNA irrespective of HCV genotype and/or HBV co-infection (log HCV RNA = 2.67 + 0.95 [log HCV Ag], R2 = 0.890, p < 0.001). To predict HCV viremia (HCV Ag >= 3 fmol/L), the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 99%, 99%, 100%, 100% and 97%, respectively. We concluded that HCV Ag was a good surrogate marker for HCV RNA and could be used to diagnose active HCV infection in a resource-limited setting. As a result, a cost-effective strategy for screening and identifying active HCV carriers using HCV Ag detection would enable more patients access to efficacious and increasingly affordable direct-acting antivirals (DAAs) for the treatment of HCV infection. PMID- 29134151 TI - How can we reliably identify a taxon based on humeral morphology? Comparative morphology of desmostylian humeri. AB - Desmostylia is a clade of marine mammals belonging to either Tethytheria or Perissodactyla. Rich fossil records of Desmostylia were found in the Oligocene to Miocene strata of the Northern Pacific Rim, especially in the northwestern region, which includes the Japanese archipelago. Fossils in many shapes and forms, including whole or partial skeletons, skulls, teeth, and fragmentary bones have been discovered from this region. Despite the prevalent availability of fossil records, detailed taxonomic identification based on fragmentary postcranial materials has been difficult owing to to our limited knowledge of the postcranial diagnostic features of many desmostylian taxa. In this study, I propose the utilization of diagnostic characters found in the humerus to identify desmostylian genus. These characters can be used to identify isolated desmostylian humeri at the genus level, contributing to a better understanding of the stratigraphic and geographic distributions of each genus. PMID- 29134152 TI - The role of MEF2 transcription factors in dehydration and anoxia survival in Rana sylvatica skeletal muscle. AB - The wood frog (Rana sylvatica) can endure freezing of up to 65% of total body water during winter. When frozen, wood frogs enter a dormant state characterized by a cessation of vital functions (i.e., no heartbeat, blood circulation, breathing, brain activity, or movement). Wood frogs utilize various behavioural and biochemical adaptations to survive extreme freezing and component anoxia and dehydration stresses, including a global suppression of metabolic functions and gene expression. The stress-responsive myocyte enhancer factor-2 (MEF2) transcription factor family regulates the selective expression of genes involved in glucose transport, protein quality control, and phosphagen homeostasis. This study examined the role of MEF2A and MEF2C proteins as well as select downstream targets (glucose transporter-4, calreticulin, and muscle and brain creatine kinase isozymes) in 40% dehydration and 24 h anoxia exposure at the transcriptional, translational, and post-translational levels using qRT-PCR, immunoblotting, and subcellular localization. Mef2a/c transcript levels remained constant during dehydration and anoxia. Total, cytoplasmic, and nuclear MEF2A/C and phospho-MEF2A/C protein levels remained constant during dehydration, whereas a decrease in total MEF2C levels was observed during rehydration. Total and phospho-MEF2A levels remained constant during anoxia, whereas total MEF2C levels decreased during 24 h anoxia and P-MEF2C levels increased during 4 h anoxia. In contrast, cytoplasmic MEF2A levels and nuclear phospho-MEF2A/C levels were upregulated during anoxia. MEF2 downstream targets remained constant during dehydration and anoxia, with the exception of glut4 which was upregulated during anoxia. These results suggest that the upregulated MEF2 response reported in wood frogs during freezing may in part stem from their cellular responses to surviving prolonged anoxia, rather than dehydration, leading to an increase in GLUT4 expression which may have an important role during anoxia survival. PMID- 29134153 TI - HgtSIM: a simulator for horizontal gene transfer (HGT) in microbial communities. AB - The development and application of metagenomic approaches have provided an opportunity to study and define horizontal gene transfer (HGT) on the level of microbial communities. However, no current metagenomic data simulation tools offers the option to introduce defined HGT within a microbial community. Here, we present HgtSIM, a pipeline to simulate HGT event among microbial community members with user-defined mutation levels. It was developed for testing and benchmarking pipelines for recovering HGTs from complex microbial datasets. HgtSIM is implemented in Python3 and is freely available at: https://github.com/songweizhi/HgtSIM. PMID- 29134154 TI - A comparison of chloroplast genome sequences in Aconitum (Ranunculaceae): a traditional herbal medicinal genus. AB - The herbal medicinal genus Aconitum L., belonging to the Ranunculaceae family, represents the earliest diverging lineage within the eudicots. It currently comprises of two subgenera, A. subgenus Lycoctonum and A. subg. Aconitum. The complete chloroplast (cp) genome sequences were characterized in three species: A. angustius, A. finetianum, and A. sinomontanum in subg. Lycoctonum and compared to other Aconitum species to clarify their phylogenetic relationship and provide molecular information for utilization of Aconitum species particularly in Eastern Asia. The length of the chloroplast genome sequences were 156,109 bp in A. angustius, 155,625 bp in A. finetianum and 157,215 bp in A. sinomontanum, with each species possessing 126 genes with 84 protein coding genes (PCGs). While genomic rearrangements were absent, structural variation was detected in the LSC/IR/SSC boundaries. Five pseudogenes were identified, among which Psirps19 and Psiycf1 were in the LSC/IR/SSC boundaries, Psirps16 and PsiinfA in the LSC region, and Psiycf15 in the IRb region. The nucleotide variability (Pi) of Aconitum was estimated to be 0.00549, with comparably higher variations in the LSC and SSC than the IR regions. Eight intergenic regions were revealed to be highly variable and a total of 58-62 simple sequence repeats (SSRs) were detected in all three species. More than 80% of SSRs were present in the LSC region. Altogether, 64.41% and 46.81% of SSRs are mononucleotides in subg. Lycoctonum and subg. Aconitum, respectively, while a higher percentage of di-, tri-, tetra-, and penta- SSRs were present in subg. Aconitum. Most species of subg. Aconitum in Eastern Asia were first used for phylogenetic analyses. The availability of the complete cp genome sequences of these species in subg. Lycoctonum will benefit future phylogenetic analyses and aid in germplasm utilization in Aconitum species. PMID- 29134155 TI - Foliar microbiome transplants confer disease resistance in a critically endangered plant. AB - There has been very little effort to incorporate foliar microbiomes into plant conservation efforts even though foliar endophytes are critically important to the fitness and function of hosts. Many critically endangered plants that have been extirpated from the wild are dependent on regular fungicidal applications in greenhouses that cannot be maintained for remote out-planted populations, which quickly perish. These fungicides negatively impact potentially beneficial fungal symbionts, which may reduce plant defenses to pathogens once fungicide treatments are stopped. Using the host/parasite system of Phyllostegia kaalaensis and Neoerysiphe galeopsidis, we conducted experiments to test total foliar microbiome transplants from healthy wild relatives onto fungicide-dependent endangered plants in an attempt to mitigate disease and reduce dependency on fungicides. Plants were treated with total microbiome transplants or cultured subsets of this community and monitored for disease severity. High-throughput DNA screening of fungal ITS1 rDNA was used to track the leaf-associated fungal communities and evaluate the effectiveness of transplantation methods. Individuals receiving traditionally isolated fungal treatments showed no improvement, but those receiving applications of a simple leaf slurry containing an uncultured fungal community showed significant disease reduction, to which we partially attribute an increase in the mycoparasitic Pseudozyma aphidis. These results were replicated in two independent experimental rounds. Treated plants have since been moved to a native habitat and, as of this writing, remain disease-free. Our results demonstrate the effectiveness of a simple low-tech method for transferring beneficial microbes from healthy wild plants to greenhouse-raised plants with reduced symbiotic microbiota. This technique was effective at reducing disease, and in conferring increased survival to an out-planted population of critically endangered plants. It was not effective in a closely related plant. Plant conservation efforts should strive to include foliar microbes as part of comprehensive management plans. PMID- 29134156 TI - Preoperative cervical sagittal alignment parameters and their impacts on myelopathy in patients with cervical spondylotic myelopathy: a retrospective study. AB - Background: Cervical sagittal alignment plays an important role in the pathogenesis of cervical spondylotic myelopathy (CSM), but there are limited studies on the cervical sagittal parameters in CSM patients and their correlations with myelopathy. The aim of this study is to investigate the correlations among the preoperative cervical sagittal alignment parameters and their correlations with the development of myelopathy in patients with CSM. Methods: We retrospectively collected 212 patients with CSM who underwent surgical interventions. Gender, age, modified Japanese Orthopedic Association score (mJOA), cervical lordosis (CL), C2-C7 sagittal vertical axis (C2-C7 SVA), T1 slope (T1S), neck tilt (NT) and thoracic inlet angle (TIA) were collected before operation. Interobserver and intraobserver reliability were calculated for all measurements (intraclass correlation coefficient, ICC). Data were analyzed with Pearson and Spearman correlation tests and multiple linear regression analysis. Results: A total of 212 patients with CSM were included in this study (male: 136, female: 76) with an average age of 54.5 +/- 10.1 years old. Intraobserver and interobserver reliability for all included radiographic parameters presented good to excellent agreement (ICC > 0.7). No significant differences in demographic and radiological parameters have been observed between males and females (P > 0.05). We found statistically significant correlations among the following parameters: age with CL (r = 0.135, P = 0.049), age with T1S (r = 0.222, P = 0.001), CL with T1S (r = 0.291, P < 0.001), CL with C2-C7 SVA (r = - 0.395, P < 0.001), mJOA with age (r = - 0.274, P < 0.001), mJOA with C2-C7 SVA (r = - 0.219, P < 0.001) and mJOA with T1S(r = - 0.171, p = 0.013). Linear regression analysis showed that C2-C7 SVA was the predictor of CL (adjusted R2 = 0.152, P < 0.001) and multiple linear regression showed that age combined with C2 C7 SVA was a sensitive predictor of mJOA (adjusted R2 = 0.106, P < 0.001). Discussion: There were significant correlations among certain preoperative cervical sagittal parameters in CSM patients. CL was the only predictor of C2-C7 SVA. Age combined with C2-C7 SVA could predict the severity of myelopathy. PMID- 29134157 TI - Overland movement in African clawed frogs (Xenopus laevis): empirical dispersal data from within their native range. AB - Dispersal forms are an important component of the ecology of many animals, and reach particular importance for predicting ranges of invasive species. African clawed frogs (Xenopus laevis) move overland between water bodies, but all empirical studies are from invasive populations with none from their native southern Africa. Here we report on incidents of overland movement found through a capture-recapture study carried out over a three year period in Overstrand, South Africa. The maximum distance moved was 2.4 km with most of the 91 animals, representing 5% of the population, moving ~150 m. We found no differences in distances moved by males and females, despite the former being smaller. Fewer males moved overland, but this was no different from the sex bias found in the population. In laboratory performance trials, we found that males outperformed females, in both distance moved and time to exhaustion, when corrected for size. Overland movement occurred throughout the year, but reached peaks in spring and early summer when temporary water bodies were drying. Despite permanent impoundments being located within the study area, we found no evidence for migrations of animals between temporary and permanent water bodies. Our study provides the first dispersal kernel for X. laevis and suggests that it is similar to many non-pipid anurans with respect to dispersal. PMID- 29134158 TI - A Quick Evaluation of TRAM Flap Viability using Fingerstall-Type Tissue Oximetry. AB - Supplemental Digital Content is available in the text. PMID- 29134159 TI - Molecular characterization of Turnip mosaic potyvirus (TuMV)-infecting radish (Raphanus sativus L.) crop in India. AB - Nine isolates of Turnip mosaic potyvirus (TuMV)-infecting radish collected from different regions of Northern India were characterized. All isolates except for New Delhi and Rajasthan isolates resulted positive for TuMV in double antibody sandwich-enzyme linked immunosorbent assay (DAS-ELISA). RNA was isolated from leaves of infected plants and used in reverse transcriptase-polymerase chain reaction (RT-PCR) with TuMV coat protein (CP) gene-specific primers. Viral amplicons of expected 1000 bp size were obtained, which were further subjected to cloning and sequencing. CP gene of all the seven isolates was 867 bp long, encoding 288 amino acid residues. Percent homology of CP gene of all the Indian isolates among themselves and with other TuMV isolates retrieved from NCBI was in the range of 87-99 and 92-100% at nucleotide and amino acid levels, respectively. Phylogenetic analysis based upon CP gene nucleotide and amino acid sequences with other TuMV isolates reported from across the globe using unweighted pair group method with arithmetic mean (UPGMA) inferred classification of test isolates into basal-BR group due to their occurrence nearest to the TuMV isolates belonging to the basal-BR group. Information generated about the characteristic features of TuMV and geographical distribution of particular virus genotype-infecting radish crop will provide a platform for formulating disease resistance strategies. PMID- 29134160 TI - Optimized production and isolation of antibacterial agent from marine Aspergillus flavipes against Vibrio harveyi. AB - Statistical methodologies, including Plackett-Burman design and Box-Behnken design, were employed to optimize the fermentation conditions for the production of active substances against aquatic pathogen Vibrio harveyi by marine-derived Aspergillus flavipes strain HN4-13. The optimal crucial fermentation values for maximum production of active substances against V. harveyi were obtained as follows: X1 (peptone) = 0.3%, X2 (KCl) = 0.25%, and X3 (inoculum size) = 4.5%. The predicted diameter of inhibitory zone against V. harveyi was 23.39 mm, and the practical value reached 23.71 +/- 0.98 mm with a 62.3% increase. Bioassay guided fractionation resulted in the acquisition of two compounds whose structures were identified as questin (1) and emodin (2). Questin exhibited the same antibacterial activity against V. harveyi as streptomycin (MIC 31.25 ug/mL). This is the first time to report questin as a potential antibacterial agent against aquatic pathogen V. harveyi. PMID- 29134161 TI - Pneumatization Patterns of the Petrous Apex and Lateral Sphenoid Recess. AB - Introduction The petrous apex poses a challenge for surgical intervention due to poor access. As intraoperative image guidance and surgical instrumentation improve, newer endoscopic approaches are increasingly favored. This study aims to provide normative data on the anatomy of the lateral sphenoid sinus recess and petrous apex. These normative data could assist in determining the efficacy of a transnasal transsphenoidal approach to lesions of the anteroinferior petrous apex. Methods This is a retrospective study investigating normative data on all maxillofacial computed tomography (CT) scans performed at a level I trauma center over a 6-month period. All appropriate images had the pneumatization pattern of the petrous apex and lateral recess of the sphenoid sinus reviewed by a single otologist and graded bilaterally. These were then analyzed in SPSS; Pearson correlation analyses and chi 2 test were used. Results A total of 481 patients were identified, yielding a total of 962 temporal bones and sphenoid sinuses for analysis. Eighty-eight percent of sides analyzed had a nonpneumatized lateral recess. The petrous apex was nonpneumatized in 54% of sides analyzed. There was a correlation noted between the degree of pneumatization of the petrous apex and pneumatization of the lateral recess of the sphenoid. Conclusion This study is the first to provide normative data comparing pneumatization of the petrous apex and sphenoid sinus. These data may support future work evaluating the utility of an endonasal approach to the petrous apex. PMID- 29134162 TI - Lesions Mimicking Small Vestibular Schwannomas. AB - Objective Most tumors of the internal auditory canal and cerebellopontine angle (CPA) are vestibular schwannomas (VSs). Preoperative diagnosis is based on typical clinical symptoms and radiological findings. In rare cases, histopathology can, however, show different results. Design This is a retrospective chart and database review. Setting The study was conducted at a tertiary skull base referral center at a university hospital. Participants A total of 207 consecutive cases of VS surgery via the middle cranial fossa approach performed between December 2005 and January 2015 were reviewed. Main Outcome Measures The main outcome measures were definitive histologic findings in 198 specimens, analysis of preoperative magnetic resonance imaging (MRI) and computed tomography. Results Histopathology revealed three meningiomas and two cases of lipochoristomas. Clinical presentation was typical for VS in all five cases. In preoperative MRI, all tumors were suspected to be VSs. Retrospective analysis of the preoperative imaging did not lead to a modification of the diagnosis. Intraoperative findings showed increased adherence of the tumor to the adjacent tissue in two of the five cases. Conclusion CPA lesions other than VSs are unusual but have to be taken into account. In very small tumors, imaging still remains difficult. PMID- 29134163 TI - Prognostic Indices for Predicting Facial Nerve Outcome following the Resection of Large Acoustic Neuromas. AB - This study analyzes the simple ratio of anterior-to-posterior extension of large (>2.5 cm) acoustic neuromas relative to the internal auditory canal (ICA; anterior-posterior [A/P] index) as a tool for predicting risk of facial nerve (FN) injury. In total, 105 patients who underwent microsurgical resection for large acoustic neuromas were analyzed retrospectively. House-Brackmann (HB) scores were assessed immediately postoperatively, at 1 month, and at 1 year. Lateral-medial, inferior-superior, A/P, and maximum diameters were measured from preoperative magnetic resonance images. These measurements and the A/P index were analyzed using univariable and multivariable statistical models to assess relationship to FN outcomes. The retrosigmoid, translabyrinthine, and combined approaches were used, and the extent of resection was evaluated. For every 1 standard deviation increase in the A/P index, a patient was 3.87 times more likely have a higher postoperative HB score ( p < 0.0001). Accordingly, for every 1-mm increase anterior to the IAC, a patient was 16% more likely have a higher postoperative HB score ( p < 0.001). After controlling for tumor size, a patient was still 3.82 times more likely have a higher postoperative HB score for every 1 standard deviation increase in the A/P index ( p < 0.0001). While larger tumor size trended toward worse postoperative HB scores, it was not statistically significant. Our prognostic index may be useful to assess the risk of FN injury preoperatively for large acoustic neuromas, while also providing information about the tumor-nerve relationship. PMID- 29134164 TI - Visual Outcomes after Endoscopic Pituitary Surgery in Patients Presenting with Preoperative Visual Deficits. AB - Introduction Pituitary adenomas represent 15% of primary brain tumors. Visual disturbance is a common clinical manifestation of these neoplasms due, among other factors, to local mass effect on the optic system. Objective To evaluate changes of the visual fields in patients undergoing endoscopic endonasal approach (EEA) for pituitary adenomas and to find predictive factors for successful visual field outcome. Material and Methods This is a cross-sectional study. A review was conducted of medical records of consecutive patients with tumors of the sellar region undergoing EEA between January 2008 and December 2012 at the Skull Base Unit of Guillermo Grant Benavente Hospital, University of Concepcion, Concepcion, Chile, and who had undergone pre- and postoperative visual field evaluation. Results A total of 35 patients, with a mean age of 50.2 years, fulfilled the inclusion criteria. All patients had objective visual field disturbances before the surgery. Following surgery, 25 patients (71.4%) had favorable outcomes, whereas 8 (22.8%) had no change and 2 (5.8%) had an unfavorable outcome. Complete tumor removal was associated with a better visual outcome than those obtained after a subtotal removal. Discussion The EEA for pituitary tumors is particularly effective for visual field disturbances, with reported improvement rates ranging from 50 to 90%. Our series show similar results, with a 71.4% improvement of visual field disturbances. Conclusion This study adds further evidence to the current belief that EEA for pituitary adenomas is a safe and effective technique to improve visual field alterations. Complete removal of the tumor during surgery seems to be a predictive factor for a good visual outcome. PMID- 29134165 TI - An Innovate Robotic Endoscope Guidance System for Transnasal Sinus and Skull Base Surgery: Proof of Concept. AB - Objective Advanced transnasal sinus and skull base surgery remains a challenging discipline for head and neck surgeons. Restricted access and space for instrumentation can impede advanced interventions. Thus, we present the combination of an innovative robotic endoscope guidance system and a specific endoscope with adjustable viewing angle to facilitate transnasal surgery in a human cadaver model. Materials and Methods The applicability of the robotic endoscope guidance system with custom foot pedal controller was tested for advanced transnasal surgery on a fresh frozen human cadaver head. Visualization was enabled using a commercially available endoscope with adjustable viewing angle (15-90 degrees). Results Visualization and instrumentation of all paranasal sinuses, including the anterior and middle skull base, were feasible with the presented setup. Controlling the robotic endoscope guidance system was effectively precise, and the adjustable endoscope lens extended the view in the surgical field without the common change of fixed viewing angle endoscopes. Conclusion The combination of a robotic endoscope guidance system and an advanced endoscope with adjustable viewing angle enables bimanual surgery in transnasal interventions of the paranasal sinuses and the anterior skull base in a human cadaver model. The adjustable lens allows for the abandonment of fixed angle endoscopes, saving time and resources, without reducing the quality of imaging. PMID- 29134166 TI - Anterior Extension of Tumor is as Important as Tumor Size to Facial Nerve Outcome and Extent of Resection for Vestibular Schwannomas. AB - Objectives We examined vestibular schwannoma tumor dimension and direction of growth to determine whether these correlate with facial nerve outcome as well as extent of resection (EOR). Design Retrospective review of prospectively maintained databases. Participants 206 patients were a part of this study. Main Outcome Measures Tumor dimensions were measured using preoperative magnetic resonance imaging, and a series of ratios were then calculated to further characterize tumor dimension. Regression analyses were performed to investigate correlation with facial nerve outcome and EOR. Results Patients with tumor extending >1.5 cm anterior to the internal auditory canal (IAC) (AB measurement) were three times more likely to have postoperative House-Brackman grades of 3 or worse. We also found that an EB/BF ratio (representing elongated growth parallel to the IAC axis) >=1.1 was associated with half the risk of poor facial nerve outcome. Tumors with anterior-posterior diameter (AC measurement) >1.9 cm were five times less likely to undergo gross total resection (GTR). Furthermore, an increased degree of tumor extension into the IAC (DE measurement >2.4 cm) or an increased amount of brainstem compression (EB measurement >1.1 cm) were each associated with a nearly 3-fold decrease in the likelihood of GTR. Conclusion Our study demonstrates that anterior extent of the tumor is as important as tumor size to facial nerve outcome and degree of resection for vestibular schwannomas. PMID- 29134167 TI - Postoperative Imaging Findings Associated with Transpalpebral Craniotomy Approach to Anterior Cranial Fossa. AB - Background and Purpose The transpalpebral "eyelid" approach is a novel alternative to the traditional ciliary or supraciliary incision for supraorbital frontal craniotomy and access to the anterior cranial fossa. Though a prior publication from our institution has described the surgical approach in detail along with cosmetic and clinical outcomes, postoperative imaging findings have not yet been described. As this surgical technique becomes more widely practiced, it is essential for neuroradiologists, oculoplastic surgeons, and skull base neurosurgeons to be familiar with the expected postoperative imaging findings, especially those that prompt subsequent intervention. Materials and Methods A retrospective, institutional review board approved review was performed of 102 patients who underwent transpalpebral surgical approach at Allegheny General Hospital from June 2007 through May 2015. Operative reports, pathology reports, preoperative imaging, postoperative imaging, and postoperative clinical documentation were reviewed. Results Forty-nine percent of patients had solely benign expected postoperative imaging findings, 37% had various atypical findings not requiring further intervention (most commonly asymmetric globe protrusion and bone cement in a paranasal sinus), 6% had findings prompting minimally invasive bedside procedures (most commonly pseudomeningocele), and 8% had findings requiring surgical intervention. Conclusion The majority of imaging following the transpalpebral approach showed typical, benign findings, such as minimal pneumocephalus and asymmetric globe protrusion. Nonetheless, members of the clinical team should be aware of the small number of findings requiring intervention, especially pseudomeningocele. PMID- 29134168 TI - Anatomical Region Segmentation for Objective Surgical Skill Assessment with Operating Room Motion Data. AB - Background Most existing objective surgical motion analysis schemes are limited to structured surgical tasks or recognition of motion patterns for certain categories of surgeries. Analyzing instrument motion data with respect to anatomical structures can break the limit, and an anatomical region segmentation algorithm is required for the analysis. Methods An atlas was generated by manually segmenting the skull base into nine regions, including left/right anterior/posterior ethmoid sinuses, frontal sinus, left and right maxillary sinuses, nasal airway, and sphenoid sinus. These regions were selected based on anatomical and surgical significance in skull base and sinus surgery. Six features, including left and right eye center, nasofrontal beak, anterior tip of nasal spine, posterior edge of hard palate at midline, and clival body at foramen magnum, were used for alignment. The B-spline deformable registration was adapted to fine tune the registration, and bony boundaries were automatically extracted for final precision improvement. The resultant deformation field was applied to the atlas, and the motion data were clustered according to the deformed atlas. Results Eight maxillofacial computed tomography scans were used in experiments. One was manually segmented as the atlas. The others were segmented by the proposed method. Motion data were clustered into nine groups for every dataset and outliers were filtered. Conclusions The proposed algorithm improved the efficiency of motion data clustering and requires limited human interaction in the process. The anatomical region segmentations effectively filtered out the portion of motion data that are out of surgery sites and grouped them according to anatomical similarities. PMID- 29134169 TI - Age and Tumor Volume Predict Growth of Carotid and Vagal Body Paragangliomas. AB - Objective Treatment for head and neck paragangliomas (HNGPL) can be more harmful than the disease. After diagnosis, an initial period of surveillance is often indicated, and surgery or radiotherapy is reserved for progressive disease. With the aim to optimize this "wait and scan" strategy, we studied growth and possible predictors. Design A retrospective cohort study was conducted. Setting This study was conducted at a tertiary referral center for patients with HNGPL. Methods Tumor volume was estimated for 184 SDHD -related carotid and vagal body paragangliomas using sequential magnetic resonance imaging. Cox regression was used to study predictors of tumor growth. Results The estimated fraction of growing tumors ranged from 0.42 after 1 year of follow-up to 0.85 after 11 years. A median growth rate of 10.4 and 12.0% per year was observed for carotid and vagal body tumors, respectively. Tumor location, initial volume, and age ( p < 0.05) were included in our prediction model. The probability of growth decreased with increasing age and volume, indicating a decelerating growth pattern. Conclusions We created a prediction model (available online), enabling a more individualized "wait and scan" strategy. The favorable natural course of carotid and vagal body paragangliomas was confirmed; although with long follow-up growth will be observed in most cases. PMID- 29134170 TI - Effectiveness of Bilateral Inferior Petrosal Sinuses Sampling in Tumor Lateralization: Intraoperative Findings and Postoperative Results. AB - Object Diagnosis and treatment of Cushing's disease (CD) is a demanding endeavor. We evaluated the effectiveness of inferior petrosal sinus sampling (IPSS) in preoperative tumor lateralization and surgical outcomes. Methods Fifty two consecutive patients with CD and normal magnetic resonance imaging (MRI) were enrolled between 2009 and 2015. Selective catheterization of petrosal sinuses for IPSS was performed. All patients underwent microsurgical dissection, and if a lesion was found, underwent lesion resection. Demographic, biochemical, and intraoperative findings were prospectively collected and reviewed 6 and 12 months postoperatively. Results Forty-five patients (86.4%) had clear lateralization while seven patients had bilateral elevation. Twenty-two patients (42%) were found to have a macroscopic lesion, defined as an abnormal tissue during microsurgical dissection, which was thus resected. No patient had a lesion larger than 4 mm. Eighty-one percent of patients had the lesion where IPSS had been predicted. Hemi-hypophysectomy was performed on twenty-eight patients based on IPSS findings, since no lesion was found. Eighty-six percent of patients with lesion resection had biochemical remission by 12 months. Biochemical remission was documented in 78 and 71% of patients who underwent hemi-hypophysectomy by 6 and 12 months, respectively. Conclusion With careful microsurgical dissection, a macroscopic lesion could be found in a significant number of patients with normal MRI. When no lesion was found, we recommend performing a hemi-hypophysectomy based on IPSS findings, since prediction accuracy was high and remission rates were significant. PMID- 29134171 TI - Endoscopic Endonasal Repair of Internal Carotid Artery Injury during Endoscopic Endonasal Surgery. AB - Background Injury to the cavernous portion of the internal carotid artery (ICA) during endoscopic skull base surgery is a well-recognized rare complication that can be associated with high rates of morbidity and mortality. Many techniques have been suggested to manage ICA injury with varying degrees of success. Objectives We provide a detailed technical description of an operative technique for endoscopic management of carotid artery injury. Methods A case of ICA injury during endoscopic skull base surgery is presented. The immediate treatment measurements include: (1) early recognition of ICA injury, (2) briefing of the team and preparations, (3) packing, (4) harvesting of temporalis muscle patch, (5) placement of the muscle patch over the defect, and (6) gentle compression for 10 minutes. Results The technique facilitates quick repair and restores normal blood flow through the damaged artery. Exsanguination or the symptoms of stroke that may occur from prolonged occlusion of the ICA are therefore prevented. Conclusion The proposed protocol is useful for the management of a potentially life-threatening ICA injury. PMID- 29134172 TI - Posterior Nutcracker Phenomenon in a Patient with Left Atrial Isomerism. AB - Background Nutcracker phenomenon (NCP) can occur due to various anatomical anomalies. Anterior and posterior NCP are defined in the literature. Posterior NCP combined with left atrial isomerism is a rare condition. Case description We present a rare case of an asymptomatic posterior NCP involving the azygos vein in a patient with a complex cardiovascular pathology with left atrial isomerism, left ventricular outflow tract obstruction, interrupted inferior vena cava, and azygos continuation. Conclusion Detection of the NCP especially involving such a rare anatomical anomaly as an azygos continuation has a crucial importance for diagnostic and surgical procedures. PMID- 29134173 TI - Associations of lifetime walking and weight bearing exercise with accelerometer measured high impact physical activity in later life. AB - High impact physical activity (PA) is thought to benefit bone. We examined associations of lifetime walking and weight bearing exercise with accelerometer measured high impact and overall PA in later life. Data were from 848 participants (66.2% female, mean age = 72.4 years) from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Acceleration peaks from seven-day hip-worn accelerometer recordings were used to derive counts of high impact and overall PA. Walking and weight bearing exercise up to age 18, between 18-29, 30-49 and since age 50 were recalled using questionnaires. Responses in each age category were dichotomised and cumulative scores derived. Linear regression was used for analysis. Greater lifetime walking was related to higher overall, but not high impact PA, whereas greater lifetime weight bearing exercise was related to higher overall and high impact PA. For example, fully-adjusted differences in log-overall and log-high impact PA respectively for highest versus lowest lifetime scores were: walking [0.224 (0.087, 0.362) and 0.239 (- 0.058, 0.536)], and weight bearing exercise [0.754 (0.432, 1.076) and 0.587 (0.270, 0.904)]. For both walking and weight bearing exercise, associations were strongest in the 'since age 50' category. Those reporting the most walking and weight bearing exercise since age 50 had highest overall and high impact PA, e.g. fully-adjusted difference in log-high impact PA versus least walking and weight bearing exercise = 0.588 (0.226, 0.951). Promoting walking and weight bearing exercise from midlife may help increase potentially osteogenic PA levels in later life. PMID- 29134175 TI - Right retroperitoneal splenosis presenting as an adrenal mass. PMID- 29134176 TI - Recurrent hematuria in renal angio-venous malformation, delay diagnosis and endovascular treatment, a case report. PMID- 29134174 TI - Associations between mother's and children's moderate-to-vigorous physical activity and sedentary time in the family context. AB - The manner in which mothers' and children's moderate-to-vigorous physical activity (MVPA) and sedentary time (ST) are associated across different settings (i.e., at home versus outside of the home, on weekdays versus weekends) is not well understood. The purposes of this study were to: (Strong et al., 2005) describe associations between mothers' and children's levels of MVPA and ST, and (U.S. Department of Health and Human Services, 2008) determine how setting and mothers' and children's characteristics moderate the associations. We used baseline data from the University of Michigan Healthy Families baseline data (2013-2015) from 55 mothers who have children in two age groups (3-5.99 years [n = 25] and 10-12.99 years [n = 30]) for the analysis. MVPA and ST data were collected using accelerometry over a seven day period. Proportion of time spent in MVPA and ST between 08:00 am and 08:59 pm was calculated. Mixed-effects models were used to examine associations. After controlling for selected mother and child characteristics and setting variables, MVPA and ST levels were positively associated in mothers and their children (P < 0.001). The mother-child associations for MVPA and ST were 1.7 times (beta = 0.365 versus beta = 0.216) and 2.2 times (beta = 0.255 versus beta = 0.117) stronger, respectively, when both were at home together. The association did not differ by day of the week. The variations by setting underline the importance of developing home-based, family-centered interventions to increase PA and decrease ST. PMID- 29134177 TI - Endovesical leiomyoma of bladder treated by enucleation: A case report. PMID- 29134178 TI - Wheelchair services and use outcomes: A cross-sectional survey in Kenya and the Philippines. AB - Background: The World Health Organisation recommends that services accompany wheelchair distribution. This study examined the relationship of wheelchair service provision in Kenya and the Philippines and wheelchair-use-related outcomes. Method: We surveyed 852 adult basic manual wheelchair users. Participants who had received services and those who had not were sought in equal numbers from wheelchair-distribution entities. Outcomes assessed were daily wheelchair use, falls, unassisted outdoor use and performance of activities of daily living (ADL). Descriptive, bivariate and multivariable regression model results are presented. Results: Conditions that led to the need for a basic wheelchair were mainly spinal cord injury, polio/post-polio, and congenital conditions. Most Kenyans reported high daily wheelchair use (60%) and ADL performance (80%), while these practices were less frequent in the Philippine sample (42% and 74%, respectively). Having the wheelchair fit assessed while the user propelled the wheelchair was associated with greater odds of high ADL performance in Kenya (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.6, 5.1) and the Philippines (OR 2.8, 95% CI 1.8, 4.5). Wheelchair-related training was associated with high ADL performance in Kenya (OR 3.2, 95% CI 1.3, 8.4). In the Philippines, training was associated with greater odds of high versus no daily wheelchair use but also odds of serious versus no falls (OR 2.5, 95% CI 1.4, 4.5). Conclusion: Select services that were associated with some better wheelchair use outcomes and should be emphasised in service delivery. Service providers should be aware that increased mobility may lead to serious falls. PMID- 29134179 TI - Psychological well-being of adolescents with physical disabilities in Zimbabwean inclusive community settings: An exploratory study. AB - Background: The purpose of this study was to explore the psychological well-being of adolescents with physical disabilities living in inclusive community settings of Makonde Urban in Zimbabwe. An inclusive community is one that aims to remove exclusionary practices within the community and promote community systems that accept all people irrespective of their difference. Inclusive communities on their own are not uniquely designed for people with disabilities, but most developing countries have adopted them as a basic strategy to influence and enhance psychological well-being of people with disabilities. Methods: A constructivist lived experience perspective underpinned this research, in which multiple case studies were used to interact with the participants on inclusion and psychological well-being of adolescents with physical disabilities. Purposive sampling was used to select 14 participants (9 males and 5 females). Data were collected through face-to-face interviews and transcribed verbatim. Four themes emerged from the thematic analysis of data sources. Results: It was found that participants who were adolescents with physical disabilities living in inclusive community settings of Makonde Urban in Zimbabwe were having high levels of autonomy and choice, purpose in life, positive relations with others and good personal growth and self-acceptance. Conclusion: The findings of this study should enable inclusive communities' policy-makers and researchers to better understand the psychological well-being of adolescents with physical disabilities living in inclusive communities. PMID- 29134180 TI - Editorial. PMID- 29134181 TI - Pregnancy and live birth after follicle-stimulating hormone treatment for an infertile couple including a male affected by Sertoli cell-only syndrome. AB - In males with nonobstructive azoospermia, one of the main histopathologic patterns of the testis is Sertoli cell-only syndrome (SCOS), in which no germ cells are present and only Sertoli cells are contained in the seminiferous tubules. There is not any formal treatment for this pathological condition. However, several studies reported the possibility to perform testicular sperm extraction in patients with SCOS, although, according to some authors, sperm retrieval is possible only in the presence of focal spermatogenesis. We report the case of an infertile couple in whom the 30-year-old male was azoospermic. After the diagnosis, the patient underwent multiple bilateral testicular biopsies, which showed a histological pattern corresponding to SCOS. We administered a cycle of hormone stimulation followed by medically assisted procreation procedures to the male patient. Therefore, the male patient was treated with follicle-stimulating hormone gonadotropin for a total of 7 months (150 IU recombinant human follicle stimulating hormone three times per week). After carrying out a new multiple testicular sperm extraction, several spermatozoa were microscopically observed, and it was then possible to perform an intracytoplasmic sperm injection with subsequent embryo transfer of the blastocyst into the wife's uterus, and so pregnancy was established and developed. Subsequently, the pregnancy resulted in the live birth of a girl. PMID- 29134182 TI - High-Dose (2.5 mg) Intravitreal Bevacizumab as Rescue Therapy for Persistent Postradiation Cystoid Macular Edema. AB - Background/Aims: To investigate the efficacy of intravitreal high-dose (2.5 mg/0.1 mL) bevacizumab as rescue therapy for postradiation cystoid macular edema (CME) resistant to standard-dose (1.25 mg/0.05 mL) bevacizumab. Methods: Retrospective, interventional case series. Results: Fifteen eyes of 15 patients were included. Eyes were treated with a mean of 10 standard-dose (1.25 mg) bevacizumab injections but failed to show CME resolution. Following 3 monthly treatments of high-dose (2.5 mg) bevacizumab, mean central macular thickness (CMT) reduced significantly from 406 +/- 100 to 360 +/- 83 MUm (p = 0.01) and mean logMAR visual acuity improved from 0.55 +/- 0.17 (Snellen 20/71) to 0.48 +/- 0.21 (Snellen 20/60, p = 0.07). At the final follow-up of 9 months, CMT was 395 +/- 124 MUm (p = 0.67) and visual acuity was 0.51 +/- 0.23 (Snellen 20/65, p = 0.22). Five eyes (30%) had a >10% reduction in CMT at the final follow-up. In these eyes, the observed CMT reduction was statistically significant (p = 0.04) and logMAR visual acuity was significantly better (p <= 0.01) compared to the remainder of the cohort. Conclusions: Overall, the use of high-dose (2.5 mg) bevacizumab did not result in a sustained, significant improvement in CMT and visual acuity outcomes following incomplete response to standard-dose (1.25 mg) bevacizumab. However, a minority of eyes exhibited favorable response with significant CMT reduction. PMID- 29134183 TI - Pigmented Spindle Cell Nevus of Reed of the Eyelid. AB - Purpose: To report the clinical, pathological, and immunohistochemical features of the first pigmented spindle cell nevus (PSCN) of Reed documented to have appeared in the eyelid. Methods: The findings of clinical and histopathological examination are presented, along with differential diagnoses and a review of the pertinent literature. Case: A 3-year-old boy presented with a rapidly growing, heavily pigmented left lower lid papule raising the concern of malignancy, warranting excisional biopsy. Nests of predominantly junctional Mart-1-positive spindle cells were identified by histopathological examination. The cells were largely uniform in size, elongated, surrounded by granular and coarse melanin, with a Ki-67 proliferation index of 0-2%. Five-month follow-up did not evidence any recurrence or invasive behavior of this benign melanocytic tumor. Conclusion: This is the first documented case of PSCN of Reed, a distinct entity from Spitz nevus, presenting in the eyelid. The differential diagnoses include spindle cell and superficially spreading malignant melanoma as well as dysplastic nevus. Integration of clinical and histopathological findings with immunohistochemical and fluorescence in situ hybridization markers plays a central role in the diagnosis. PMID- 29134184 TI - Extranodal Marginal Zone Lymphoma of Ocular Adnexa: Outcomes following Radiation Therapy. AB - Aim: The aim of this study was to report outcomes following radiation therapy in patients with biopsy-proven extranodal marginal zone lymphoma of the ocular adnexa and uvea. Methods: Records from a single institution were retrospectively reviewed from January 1997 to December 2015. The mean follow-up duration was 38 months (range 0-194). Radiation therapy was administered to 77 eyes (60 patients); 57 of the 77 eyes (74%) were treated with radiation only (range 20-36 Gy, median 15 fractions). Radiation cataract, radiation retinopathy, and optic neuropathy assessments were performed on all eyes treated with radiation. Results: 100% of the 47 patients treated with radiation therapy only had local control with an average dose of 26.5 Gy (median 25.2 [range 20-36] Gy; 150-200 cGy per fraction). Four patients lost 2 lines or more of vision after radiation. The most common complication of radiation therapy was cataract formation/progression in 19 eyes (25%). Radiation retinopathy was observed only in 1 patient (1%). Conclusion: Our results confirm that radiation therapy (median 25 Gy) for extranodal marginal zone lymphoma of the ocular adnexa is associated with high local control and low risk of visually significant complications. PMID- 29134185 TI - Infiltrative Intraocular Conjunctival Squamous Cell Carcinoma after Local Resection and Brachytherapy: Clinical and Pathological Findings. AB - A pseudophakic 70-year-old man presented to the clinic with a slow-growing conjunctival mass in the left eye. He was diagnosed with a conjunctival exophytic lesion suspicious of invasive conjunctival squamous cell carcinoma (CSCC). Excisional biopsy showed a well-differentiated CSCC with positive margins and the patient underwent adjuvant brachytherapy. Six weeks later, examination of the anterior segment revealed cells in the anterior chamber and a neurotrophic corneal ulcer with corneal perforation. Considering the high suspicion of intraocular invasion of CSCC, the left eye was enucleated. Histopathologic findings showed scarring of the ciliary body with fibrosis temporally. Nasally, the sclera showed a lobular infiltration of well-differentiated squamous carcinoma. The central cornea exhibited a large ulcer with perforation and infiltrating squamous cells adhering to the posterior surface. To our knowledge, this is the first documented case of an intraocular diffuse recurrence of CSCC after resection and adjuvant brachytherapy, with clinicopathologic correlation of radiation effects on the ocular tissues. PMID- 29134186 TI - Cryptococcus Infection Network in Non-Human Immunodeficiency Virus Cohort (CINCH) Study: Initial Report of Treatment and Outcomes. PMID- 29134187 TI - Method for evaluation of human induced pluripotent stem cell quality using image analysis based on the biological morphology of cells. AB - We propose an image analysis method for quality evaluation of human pluripotent stem cells based on biologically interpretable features. It is important to maintain the undifferentiated state of induced pluripotent stem cells (iPSCs) while culturing the cells during propagation. Cell culture experts visually select good quality cells exhibiting the morphological features characteristic of undifferentiated cells. Experts have empirically determined that these features comprise prominent and abundant nucleoli, less intercellular spacing, and fewer differentiating cellular nuclei. We quantified these features based on experts' visual inspection of phase contrast images of iPSCs and found that these features are effective for evaluating iPSC quality. We then developed an iPSC quality evaluation method using an image analysis technique. The method allowed accurate classification, equivalent to visual inspection by experts, of three iPSC cell lines. PMID- 29134188 TI - Simulation study of quantitative precision of the PET/X dedicated breast PET scanner. AB - The goal for positron emission tomography (PET)/X is measuring changes in radiotracer uptake for early assessment of response to breast cancer therapy. Upper bounds for detecting such changes were investigated using simulation and two image reconstruction algorithms customized to the PET/X rectangular geometry. Analytical reconstruction was used to study spatial resolution, comparing results with the distance of the closest approach (DCA) resolution surrogate that is independent of the reconstruction method. An iterative reconstruction algorithm was used to characterize contrast recovery in small targets. Resolution averaged [Formula: see text] full width at half maximum when using depth-of-interaction (DOI) information. Without DOI, resolution ranged from [Formula: see text] to [Formula: see text] for scanner crystal thickness between 5 and 15 mm. The DCA resolution surrogate was highly correlated to image-based FWHM. Receiver operating characteristic analysis showed specificity and sensitivity over 95% for detecting contrast change from 5:1 to 4:1 (area under curve [Formula: see text]). For PET/X parameters modeled here, the ability to measure contrast changes benefited from higher photon absorption efficiency of thicker crystals while being largely unaffected by degraded resolution obtained with thicker crystals; DOI provided marginal improvements. These results assumed perfect data corrections and other idealizations, and thus represent an upper bound for detecting changes in small lesion radiotracer uptake of clinical interest using the PET/X system. PMID- 29134189 TI - Toward uniform implementation of parametric map Digital Imaging and Communication in Medicine standard in multisite quantitative diffusion imaging studies. AB - This paper reports on results of a multisite collaborative project launched by the MRI subgroup of Quantitative Imaging Network to assess current capability and provide future guidelines for generating a standard parametric diffusion map Digital Imaging and Communication in Medicine (DICOM) in clinical trials that utilize quantitative diffusion-weighted imaging (DWI). Participating sites used a multivendor DWI DICOM dataset of a single phantom to generate parametric maps (PMs) of the apparent diffusion coefficient (ADC) based on two models. The results were evaluated for numerical consistency among models and true phantom ADC values, as well as for consistency of metadata with attributes required by the DICOM standards. This analysis identified missing metadata descriptive of the sources for detected numerical discrepancies among ADC models. Instead of the DICOM PM object, all sites stored ADC maps as DICOM MR objects, generally lacking designated attributes and coded terms for quantitative DWI modeling. Source-image reference, model parameters, ADC units and scale, deemed important for numerical consistency, were either missing or stored using nonstandard conventions. Guided by the identified limitations, the DICOM PM standard has been amended to include coded terms for the relevant diffusion models. Open-source software has been developed to support conversion of site-specific formats into the standard representation. PMID- 29134190 TI - Locally adaptive magnetic resonance intensity models for unsupervised segmentation of multiple sclerosis lesions. AB - Multiple sclerosis (MS) is a neurological disease characterized by focal lesions and morphological changes in the brain captured on magnetic resonance (MR) images. However, extraction of the corresponding imaging markers requires accurate segmentation of normal-appearing brain structures (NABS) and the lesions in MR images. On MR images of healthy brains, the NABS can be accurately captured by MR intensity mixture models, which, in combination with regularization techniques, such as in Markov random field (MRF) models, are known to give reliable NABS segmentation. However, on MR images that also contain abnormalities such as MS lesions, obtaining an accurate and reliable estimate of NABS intensity models is a challenge. We propose a method for automated segmentation of normal appearing and abnormal structures in brain MR images that is based on a locally adaptive NABS model, a robust model parameters estimation method, and an MRF based segmentation framework. Experiments on multisequence brain MR images of 30 MS patients show that, compared to whole-brain MR intensity model and compared to four popular unsupervised lesion segmentation methods, the proposed method increases the accuracy of MS lesion segmentation. PMID- 29134191 TI - Assessing treatment response in triple-negative breast cancer from quantitative image analysis in perfusion magnetic resonance imaging. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is sensitive but not specific to determining treatment response in early stage triple-negative breast cancer (TNBC) patients. We propose an efficient computerized technique for assessing treatment response, specifically the residual tumor (RT) status and pathological complete response (pCR), in response to neoadjuvant chemotherapy. The proposed approach is based on Riesz wavelet analysis of pharmacokinetic maps derived from noninvasive DCE-MRI scans, obtained before and after treatment. We compared the performance of Riesz features with the traditional gray level co occurrence matrices and a comprehensive characterization of the lesion that includes a wide range of quantitative features (e.g., shape and boundary). We investigated a set of predictive models ([Formula: see text]) incorporating distinct combinations of quantitative characterizations and statistical models at different time points of the treatment and some area under the receiver operating characteristic curve (AUC) values we reported are above 0.8. The most efficient models are based on first-order statistics and Riesz wavelets, which predicted RT with an AUC value of 0.85 and pCR with an AUC value of 0.83, improving results reported in a previous study by [Formula: see text]. Our findings suggest that Riesz texture analysis of TNBC lesions can be considered a potential framework for optimizing TNBC patient care. PMID- 29134192 TI - Problems and Progress regarding Sex Bias and Omission in Neuroscience Research. AB - Neuroscience research has historically ignored female animals. This neglect comes in two general forms. The first is sex bias, defined as favoring one sex over another; in this case, male over female. The second is sex omission, which is the lack of reporting sex. The recognition of this phenomenon has generated fierce debate across the sciences. Here we test whether sex bias and omission are still present in the neuroscience literature, whether studies employing both males and females neglect sex as an experimental variable, and whether sex bias and omission differs between animal models and journals. To accomplish this, we analyzed the largest-ever number of neuroscience articles for sex bias and omission: 6636 articles using mice or rats in 6 journals published from 2010 to 2014. Sex omission is declining, as increasing numbers of articles report sex. Sex bias remains present, as increasing numbers of articles report the sole use of males. Articles using both males and females are also increasing, but few report assessing sex as an experimental variable. Sex bias and omission varies substantially by animal model and journal. These findings are essential for understanding the complex status of sex bias and omission in neuroscience research and may inform effective decisions regarding policy action. PMID- 29134194 TI - Biodiversity recovery following delta-wide measures for flood risk reduction. AB - Biodiversity declined markedly over the past 150 years, with the biodiversity loss in fluvial ecosystems exceeding the global average. River restoration now aims at flood safety while enhancing biodiversity and has had success locally. However, at the scale of large river distributaries, the recovery remained elusive. We quantify changes in biodiversity of protected and endangered species over 15 years of river restoration in the embanked floodplains of an entire river delta. We distinguish seven taxonomic groups and four functional groups in more than 2 million field observations of species presence. Of all 179 fluvial floodplain sections examined, 137 showed an increase in biodiversity, particularly for fast-spreading species. Birds and mammals showed the largest increase, that is, +13 and +3 percentage point saturation of their potential based on habitat. This shows that flood risk interventions were successfully combined with enhancement of biodiversity, whereas flood stage decreased (-24 cm). PMID- 29134195 TI - Ecological restoration success is higher for natural regeneration than for active restoration in tropical forests. AB - Is active restoration the best approach to achieve ecological restoration success (the return to a reference condition, that is, old-growth forest) when compared to natural regeneration in tropical forests? Our meta-analysis of 133 studies demonstrated that natural regeneration surpasses active restoration in achieving tropical forest restoration success for all three biodiversity groups (plants, birds, and invertebrates) and five measures of vegetation structure (cover, density, litter, biomass, and height) tested. Restoration success for biodiversity and vegetation structure was 34 to 56% and 19 to 56% higher in natural regeneration than in active restoration systems, respectively, after controlling for key biotic and abiotic factors (forest cover, precipitation, time elapsed since restoration started, and past disturbance). Biodiversity responses were based primarily on ecological metrics of abundance and species richness (74%), both of which take far less time to achieve restoration success than similarity and composition. This finding challenges the widely held notion that natural forest regeneration has limited conservation value and that active restoration should be the default ecological restoration strategy. The proposition that active restoration achieves greater restoration success than natural regeneration may have arisen because previous comparisons lacked controls for biotic and abiotic factors; we also did not find any difference between active restoration and natural regeneration outcomes for vegetation structure when we did not control for these factors. Future policy priorities should align the identified patterns of biophysical and ecological conditions where each or both restoration approaches are more successful, cost-effective, and compatible with socioeconomic incentives for tropical forest restoration. PMID- 29134193 TI - Snowball Earth climate dynamics and Cryogenian geology-geobiology. AB - Geological evidence indicates that grounded ice sheets reached sea level at all latitudes during two long-lived Cryogenian (58 and >=5 My) glaciations. Combined uranium-lead and rhenium-osmium dating suggests that the older (Sturtian) glacial onset and both terminations were globally synchronous. Geochemical data imply that CO2 was 102 PAL (present atmospheric level) at the younger termination, consistent with a global ice cover. Sturtian glaciation followed breakup of a tropical supercontinent, and its onset coincided with the equatorial emplacement of a large igneous province. Modeling shows that the small thermal inertia of a globally frozen surface reverses the annual mean tropical atmospheric circulation, producing an equatorial desert and net snow and frost accumulation elsewhere. Oceanic ice thickens, forming a sea glacier that flows gravitationally toward the equator, sustained by the hydrologic cycle and by basal freezing and melting. Tropical ice sheets flow faster as CO2 rises but lose mass and become sensitive to orbital changes. Equatorial dust accumulation engenders supraglacial oligotrophic meltwater ecosystems, favorable for cyanobacteria and certain eukaryotes. Meltwater flushing through cracks enables organic burial and submarine deposition of airborne volcanic ash. The subglacial ocean is turbulent and well mixed, in response to geothermal heating and heat loss through the ice cover, increasing with latitude. Terminal carbonate deposits, unique to Cryogenian glaciations, are products of intense weathering and ocean stratification. Whole-ocean warming and collapsing peripheral bulges allow marine coastal flooding to continue long after ice-sheet disappearance. The evolutionary legacy of Snowball Earth is perceptible in fossils and living organisms. PMID- 29134196 TI - Environmental controls on modern scleractinian coral and reef-scale calcification. AB - Modern reef-building corals sustain a wide range of ecosystem services because of their ability to build calcium carbonate reef systems. The influence of environmental variables on coral calcification rates has been extensively studied, but our understanding of their relative importance is limited by the absence of in situ observations and the ability to decouple the interactions between different properties. We show that temperature is the primary driver of coral colony (Porites astreoides and Diploria labyrinthiformis) and reef-scale calcification rates over a 2-year monitoring period from the Bermuda coral reef. On the basis of multimodel climate simulations (Coupled Model Intercomparison Project Phase 5) and assuming sufficient coral nutrition, our results suggest that P. astreoides and D. labyrinthiformis coral calcification rates in Bermuda could increase throughout the 21st century as a result of gradual warming predicted under a minimum CO2 emissions pathway [representative concentration pathway (RCP) 2.6] with positive 21st-century calcification rates potentially maintained under a reduced CO2 emissions pathway (RCP 4.5). These results highlight the potential benefits of rapid reductions in global anthropogenic CO2 emissions for 21st-century Bermuda coral reefs and the ecosystem services they provide. PMID- 29134197 TI - Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells. AB - The blood-brain barrier (BBB) is composed of specialized endothelial cells that are critical to neurological health. A key tool for understanding human BBB development and its role in neurological disease is a reliable and scalable source of functional brain microvascular endothelial cells (BMECs). Human pluripotent stem cells (hPSCs) can theoretically generate unlimited quantities of any cell lineage in vitro, including BMECs, for disease modeling, drug screening, and cell-based therapies. We demonstrate a facile, chemically defined method to differentiate hPSCs to BMECs in a developmentally relevant progression via small molecule activation of key signaling pathways. hPSCs are first induced to mesoderm commitment by activating canonical Wnt signaling. Next, these mesoderm precursors progress to endothelial progenitors, and treatment with retinoic acid leads to acquisition of BBB-specific markers and phenotypes. hPSC-derived BMECs generated via this protocol exhibit endothelial properties, including tube formation and low-density lipoprotein uptake, as well as efflux transporter activities characteristic of BMECs. Notably, these cells exhibit high transendothelial electrical resistance above 3000 ohm.cm2. These hPSC-derived BMECs serve as a robust human in vitro BBB model that can be used to study brain disease and inform therapeutic development. PMID- 29134199 TI - Rapid, directed transport of DC-SIGN clusters in the plasma membrane. AB - C-type lectins, including dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN), are all-purpose pathogen receptors that exist in nanoclusters in plasma membranes of dendritic cells. A small fraction of these clusters, obvious from the videos, can undergo rapid, directed transport in the plane of the plasma membrane at average speeds of more than 1 MUm/s in both dendritic cells and MX DC-SIGN murine fibroblasts ectopically expressing DC-SIGN. Surprisingly, instantaneous speeds can be considerably greater. In MX DC-SIGN cells, many cluster trajectories are colinear with microtubules that reside close to the ventral membrane, and the microtubule-depolymerizing drug, nocodazole, markedly reduced the areal density of directed movement trajectories, suggesting a microtubule motor-driven transport mechanism; by contrast, latrunculin A, which affects the actin network, did not depress this movement. Rapid, retrograde movement of DC-SIGN may be an efficient mechanism for bringing bound pathogen on the leading edge and projections of dendritic cells to the perinuclear region for internalization and processing. Dengue virus bound to DC-SIGN on dendritic projections was rapidly transported toward the cell center. The existence of this movement within the plasma membrane points to an unexpected lateral transport mechanism in mammalian cells and challenges our current concepts of cortex membrane interactions. PMID- 29134200 TI - Intraoceanic subduction spanned the Pacific in the Late Cretaceous-Paleocene. AB - The notorious ~60 degrees bend separating the Hawaiian and Emperor chains marked a prominent change in the motion of the Pacific plate at ~47 Ma (million years ago), but the origin of that change remains an outstanding controversy that bears on the nature of major plate reorganizations. Lesser known but equally significant is a conundrum posed by the pre-bend (~80 to 47 Ma) motion of the Pacific plate, which, according to conventional plate models, was directed toward a fast-spreading ridge, in contradiction to tectonic forcing expectations. Using constraints provided by seismic tomography, paleomagnetism, and continental margin geology, we demonstrate that two intraoceanic subduction zones spanned the width of the North Pacific Ocean in Late Cretaceous through Paleocene time, and we present a simple plate tectonic model that explains how those intraoceanic subduction zones shaped the ~80 to 47 Ma kinematic history of the Pacific realm and drove a major plate reorganization. PMID- 29134198 TI - omega-3 polyunsaturated fatty acids direct differentiation of the membrane phenotype in mesenchymal stem cells to potentiate osteogenesis. AB - Mammalian cells produce hundreds of dynamically regulated lipid species that are actively turned over and trafficked to produce functional membranes. These lipid repertoires are susceptible to perturbations from dietary sources, with potentially profound physiological consequences. However, neither the lipid repertoires of various cellular membranes, their modulation by dietary fats, nor their effects on cellular phenotypes have been widely explored. We report that differentiation of human mesenchymal stem cells (MSCs) into osteoblasts or adipocytes results in extensive remodeling of the plasma membrane (PM), producing cell-specific membrane compositions and biophysical properties. The distinct features of osteoblast PMs enabled rational engineering of membrane phenotypes to modulate differentiation in MSCs. Specifically, supplementation with docosahexaenoic acid (DHA), a lipid component characteristic of osteoblast membranes, induced broad lipidomic remodeling in MSCs that reproduced compositional and structural aspects of the osteoblastic PM phenotype. The PM changes induced by DHA supplementation potentiated osteogenic differentiation of MSCs concurrent with enhanced Akt activation at the PM. These observations prompt a model wherein the DHA-induced lipidome leads to more stable membrane microdomains, which serve to increase Akt activity and thereby enhance osteogenic differentiation. More broadly, our investigations suggest a general mechanism by which dietary fats affect cellular physiology through remodeling of membrane lipidomes, biophysical properties, and signaling. PMID- 29134201 TI - Pushing the limits of photoreception in twilight conditions: The rod-like cone retina of the deep-sea pearlsides. AB - Most vertebrates have a duplex retina comprising two photoreceptor types, rods for dim-light (scotopic) vision and cones for bright-light (photopic) and color vision. However, deep-sea fishes are only active in dim-light conditions; hence, most species have lost their cones in favor of a simplex retina composed exclusively of rods. Although the pearlsides, Maurolicus spp., have such a pure rod retina, their behavior is at odds with this simplex visual system. Contrary to other deep-sea fishes, pearlsides are mostly active during dusk and dawn close to the surface, where light levels are intermediate (twilight or mesopic) and require the use of both rod and cone photoreceptors. This study elucidates this paradox by demonstrating that the pearlside retina does not have rod photoreceptors only; instead, it is composed almost exclusively of transmuted cone photoreceptors. These transmuted cells combine the morphological characteristics of a rod photoreceptor with a cone opsin and a cone phototransduction cascade to form a unique photoreceptor type, a rod-like cone, specifically tuned to the light conditions of the pearlsides' habitat (blue shifted light at mesopic intensities). Combining properties of both rods and cones into a single cell type, instead of using two photoreceptor types that do not function at their full potential under mesopic conditions, is likely to be the most efficient and economical solution to optimize visual performance. These results challenge the standing paradigm of the function and evolution of the vertebrate duplex retina and emphasize the need for a more comprehensive evaluation of visual systems in general. PMID- 29134202 TI - A New Era of Minimally Invasive Surgery: Progress and Development of Major Technical Innovations in General Surgery Over the Last Decade. AB - Minimally invasive surgery (MIS) continues to play an important role in general surgery as an alternative to traditional open surgery as well as traditional laparoscopic techniques. Since the 1980s, technological advancement and innovation have seen surgical techniques in MIS rapidly grow as it is viewed as more desirable. MIS, which includes natural orifice transluminal endoscopic surgery (NOTES) and single-incision laparoscopic surgery (SILS), is less invasive and has better cosmetic results. The technological growth and adoption of NOTES and SILS by clinicians in the last decade has however not been uniform. We look at the differences in new developments and advancement in the different techniques in the last 10 years. We also aim to explain these differences as well as the implications in general surgery for the future. PMID- 29134203 TI - Use of Multiplex Quantitative PCR To Evaluate the Impact of Pneumococcal Conjugate Vaccine on Nasopharyngeal Pneumococcal Colonization in African Children. AB - Pneumococcal conjugate vaccine (PCV) immunization of children induces shifts in colonizing pneumococcal serotypes. This study evaluated the effect of infant vaccination with 7-valent PCV (PCV7) on vaccine serotype (VT) colonization and whether the increase in nonvaccine serotype (NVT) was due to either unmasking of previously low-density-colonizing serotypes or increase in acquisition of NVT. A multiplex quantitative PCR (qPCR) was used to evaluate VT and NVT nasopharyngeal colonization in archived swabs of PCV-vaccinated and PCV-unvaccinated African children at 9 and 15 to 16 months of age. Molecular qPCR clearly identified the vaccine effect typified by a decrease in VT colonization and an increase in NVT colonization. Serotype 19A was primarily responsible for the higher NVT carriage among PCV vaccinees at 9 months of age (53.4% difference; P = 0.021) and 16 months of age (70.7% difference; P < 0.001). Furthermore, the density of serotype 19A colonization was higher in PCV-vaccinated groups than in PCV-unvaccinated groups (3.76 versus 2.83 CFU/ml [P = 0.046], respectively, and 4.15 versus 3.04 CFU/ml [P = 0.013], respectively) at 9 and 16 months of age, respectively. Furthermore, serotype 19A was also more commonly reported as a primary isolate (by having the highest density among other cocolonizing serotypes identified in the sample) in PCV7-vaccinated children, while being equally a primary (46.2%) or nonprimary (53.8%) isolate in PCV-unvaccinated children. Molecular qPCR showed both serotype replacement and unmasking to be the cause for the increase in NVT colonization in PCV7-vaccinated children, as some serotypes were associated with an absolute increase in colonization (replacement), while others were associated with an increase in detection (unmasking). IMPORTANCE This study focused on evaluating the effect of infant vaccination with 7-valent pneumococcal conjugate vaccine (PCV7), using a multiplex qPCR method, on the density of serotype specific nasopharyngeal colonization in order to delineate the relative role of serotype replacement versus unmasking as the cause for the increase in nonvaccine serotype colonization in PCV7-vaccinated children. This is pertinent in the context of the ongoing deployment of PCV immunization in children, with surveillance of colonization considered an early proxy for disease that might arise from nonvaccine serotypes, as well as the success of childhood vaccination on indirect effect in the community through the interruption of pneumococcal transmission from vaccinated young children. PMID- 29134205 TI - Towards the electrochemical diagnostic of influenza virus: development of a graphene-Au hybrid nanocomposite modified influenza virus biosensor based on neuraminidase activity. AB - An effective electrochemical influenza A biosensor based on a graphene-gold (Au) hybrid nanocomposite modified Au-screen printed electrode has been developed. The working principle of the developed biosensor relies on the measurement of neuraminidase (N) activity. After the optimization of experimental parameters like the effect of bovine serum albumin addition and immobilization times of fetuin A and PNA lectin, the analytical characteristics of the influenza A biosensor were investigated. As a result, a linear range between 10-8 U mL-1 and 10-1 U mL-1 was found with a relative standard deviation value of 3.23% (for 10-5 U mL-1 of N, n:3) and a limit of detection value of 10-8 U mL-1 N. The developed biosensor was applied for real influenza virus A (H9N2) detection and very successful results were obtained. PMID- 29134204 TI - Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation. AB - Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that persistently infects humans, with nearly 95% seropositivity in adults. Infection in differentiating epithelia is permissive, but EBV-associated nasopharyngeal carcinoma (NPC) tumors harbor a clonal and nonproductive latent infection. However, in explanted NPC cultures and epithelial cell lines, episomal EBV genomes are frequently lost. The resulting unstable infection has hampered efforts to study the determinants of EBV persistence and latency in epithelial oncogenesis. The EBV nuclear antigen 1 (EBNA1) protein is required for tethering EBV episomes to cellular DNA and for mitotic segregation to daughter cells. Expression of EBNA1 does not ensure faithful partitioning of EBV episomes or replicons, suggesting that additional regulatory mechanisms have yet to be elucidated. The EBV latent membrane protein 1 (LMP1) is an oncogenic signaling protein expressed in latent and lytic cycles. This study identified that LMP1 contributes to the loss of EBV genomes in latently infected cells and promotes differentiation-induced lytic replication in a polarized air-liquid interface (ALI) culture model. Deletion of LMP1 in recombinantly infected 293 cells promoted the retention of EBV genomes in passaged cells, which was in part localized to a conserved PXQXT motif in the C-terminal signaling domain (CTAR1). Additionally, knockdown of LMP1 in the recombinantly infected NPC cell line HK1 resulted in decreased induction of lytic proteins and infectious EBV titers. These findings are consistent with the hypothesis that in epithelial infections, regulation of LMP1 mechanisms may be a determinant of infection outcome and a potential risk factor for EBV persistence in preneoplastic cells. IMPORTANCE Latent membrane protein 1 (LMP1) is a constitutively active oncogenic signaling protein encoded by Epstein-Barr virus (EBV). Despite monoclonal infection in cases of nasopharyngeal carcinoma (NPC), it has been difficult to reconcile the heterogeneous LMP1 protein levels detected in tumor cells. The LMP1 protein is a pleiotropic signaling protein with oncogenic potential. Findings from this study are consistent with the hypothesis that LMP1 has a role distinct from that of oncogenesis that facilitates the viral life cycle by promoting an unstable but productive infection in differentiating epithelia. PMID- 29134206 TI - Azulene-boronate esters: colorimetric indicators for fluoride in drinking water. AB - Low cost and in situ fluoride detection by non-experts is important for the determination of drinking water safety in developing countries. Colour reagents can provide results quickly without expensive equipment, but colorimetric fluoride indicators are often nonspecific, complex to use or do not work in water. Here we show that azulene-boronate indicators respond selectively to fluoride at concentrations relevant to the WHO limit of 1.5 mg L-1. PMID- 29134207 TI - Switchable bumps of a bead-embedded elastomer surface with variable adhesion. AB - An extremely simple structural design of a composite material composed of an elastomer sheet and hard beads embedded at the surface is proposed to realize a shape-tunable surface; it reversibly forms bumps/undulations in response to in plane tensile strain applied to the surface. Tribological properties such as adhesion therefore become switchable. PMID- 29134208 TI - Tunable plasmon resonance of molybdenum oxide nanoparticles synthesized in non aqueous media. AB - Plasmonic compound nanoparticles (NPs) have attracted great interest because they are prepared at lower cost and show unique optical properties. However, full replacement of the plasmonic noble metal NPs with the compound NPs has been difficult because most of the compound NPs exhibit plasmon resonance in the infrared range owing to low free carrier density and mobility. In order to overcome this limitation, we developed a new synthetic method for plasmonic MoO2 and MoO3-x NPs. Those NPs exhibit plasmon resonance at ~500 nm and 600-1000 nm, respectively, likely because of high carrier densities. The plasmonic properties of the NPs are tunable by changing the synthetic conditions or oxidizing and reducing the NPs. Their refractive index sensitivities are 115-260 nm RIU-1. Those molybdenum oxide NPs are expected to substitute for plasmonic noble metal NPs in optical, electronic, sensing and light harvesting devices and materials. PMID- 29134210 TI - General destabilization mechanism of pH-responsive Pickering emulsions. AB - The superior stability of Pickering emulsions can be detrimental in several applications. There is therefore growing interest in using stimuli responsive particle emulsifiers that can considerably reduce the cost of demulsification. Among the possible triggers for the remote control of emulsion stability, pH sensitive systems are advantageous because of the simplicity and ease of implementation. Herein, the destabilization mechanism of pH-switchable emulsions stabilized solely by particles of different shapes and surface properties - namely - hematite, silica and polystyrene - are discussed. The surface activity of all these particles can be tuned by controlling the surface charge density via dispersing them in aqueous solutions of different pH. Hematite particles of cuboidal, spherocylindrical, peanut and ellipsoidal shapes stabilized O/W emulsions at pH 6.5, but they were completely destabilized when the pH of the continuous phase was adjusted to either 2 or 12. Similarly, the O/W emulsions stabilized by silica rods and spheres at pH 2 were destabilized upon adjusting the pH to 6.5 and 12. The detachment of particles from the droplet surfaces resulted in partially covered drops that coalesced, leading to the destabilization of emulsions as confirmed by direct visualization via optical microscopy. The destabilization mechanism of the Pickering emulsions stabilized solely by pH responsive particles was observed to be general, and was mediated by the detachment of particles because of the pH induced wettability change. Furthermore, the pH responsive behaviour was found to be reversible. Since stable emulsions are formed in several particle-water-oil systems, the possibility of conveniently changing the pH of the continuous phase can be exploited to tune the particle wettability and thus the destabilization in applications that demand controlled demulsification. PMID- 29134211 TI - A theoretical study on the size-dependence of ground-state proton transfer in phenol-ammonia clusters. AB - Geometries and infrared (IR) spectra in the mid-IR region of phenol-(ammonia)n (PhOH-(NH3)n) (n = 0-10) clusters have been studied using density functional theory (DFT) to investigate the critical number of solvent molecules necessary to promote ground-state proton transfer (GSPT). For n <= 8 clusters, the most stable isomer is a non-proton-transferred (non-PT) structure, and all isomers found within 1.5 kcal mol-1 from it are also non-PT structures. For n = 9, the most stable isomer is also a non-PT structure; however, the second stable isomer is a PT structure, whose relative energy is within the experimental criterion of population (0.7 kcal mol-1). For n = 10, the PT structure is the most stable one. We can therefore estimate that the critical size of GSPT is n = 9. This is confirmed by the fact that these calculated IR spectra are in good accordance with our previous experimental results of mid-IR spectra. It is demonstrated that characteristic changes of the nu9a and nu12 bands in the skeletal vibrational region provide clear information that the GSPT reaction has occurred. It was also found that the shortest distance between the pi-ring and the solvent moiety is a good indicator of the PT reaction. PMID- 29134214 TI - Aggregation-induced emission assembled ultrathin films for white light-emitting diodes. AB - Avoiding the intractable aggregation-caused quenching in solid-state materials, two aggregation-induced emission molecules were first implemented to fabricate white-light emitting ultrathin films with boosted quantum yields via layer-by layer assembly. Such an ultrathin film-coated white light-emitting diode exhibits color purity. PMID- 29134215 TI - Li3Ge3Se6: the first ternary lithium germanium selenide with interesting infinity[Ge6Se12]n chains constructed by ethane-like [Ge2Se6]6- clusters. AB - Li3Ge3Se6, the first compound of the ternary Li/Ge/Se system, has been synthesized. Note that interesting 1D infinity[Ge6Se12]n chains constructed by ethane-like [Ge2Se6]6- clusters were discovered in its structure. Investigations on the structures of all the [Ge2Se6]6- cluster-containing compounds have shown that only in Li3Ge3Se6 are there 1D chains composed of [Ge2Se6]6- clusters, which result from the space limitation within the tunnels surrounded by LiSe6 octahedra. Raman spectrum was obtained to demonstrate the existence of Ge-Ge bonds. UV-visible-NIR diffuse reflection spectrum showed an optical bandgap of 2.08 eV. Theoretical calculations based on first principles have also been performed for its band structure and density of states to analyze its structure property relationship. PMID- 29134216 TI - Multiple interaction regulated phase transition behavior of thermo-responsive copolymers containing cationic poly(ionic liquid)s. AB - The effect of multiple interactions including anion-macromolecule interaction, water-mediated ion-macromolecule interaction and hydrophobic interaction on the phase transition behaviors of random copolymers P(OEGMA-co-BVIm[X]) comprising oligo(ethylene glycol)methacrylate (OEGMA) and imidazolium-based ionic liquids is investigated in the present study. Temperature-variable 1H NMR and FT-IR investigations demonstrated that the hydration of CH2 side chains in P(OEGMA-co BVIm[SCN]) was enhanced due to the anion-dipole interaction between a chaotropic anion SCN- and CH2 groups, and dehydration of C[double bond, length as m-dash]O groups served as the driving force of phase transition. In particular, the formation of C[double bond, length as m-dash]OD2O-PIL hydrogen bonds was preferred in P(OEGMA-co-BVIm[SCN]) during the phase transition process considering the interaction of IL-D2O associations and C[double bond, length as m dash]O groups. This water-mediated ion-macromolecule interaction acted as a "linkage" among polymers, resulting in the gradual dehydration of copolymers and the formation of stable small size micelles. As for P(OEGMA-co-BVIm[NTf2]), water molecules were sequentially squeezed out of the polymer chains upon heating and the self-aggregation of polymer chains was carried out through hydrophobic interaction between OEGMA side chains with IL segments wrapped in the aggregates. PMID- 29134217 TI - Dicationic phosphonium salts: Lewis acid initiators for the Mukaiyama-aldol reaction. AB - Two strategies were used to prepare dicationic phosphonium cations. The first method consists of the reaction of 1-chlorocyclopropenium salts with phosphines to obtain cyclopropenium-substituted phosphonium salts 10a-f[BF4]. Anion exchange was performed to access the corresponding [B(C6F5)4]- analogues 10a-f[B(C6F5)4], which showed much higher solubility in organic solvents. In addition, we developed a synthesis of dicationic phosphonium salts containing 2-, 3-, or 4 methylpyridinium substituents 11a-c[TfO], which were converted as well to their [B(C6F5)4]- analogues 11a-c[B(C6F5)4]. Finally, the phenoxy-substituted phosphonium salt 12[B(C6F5)4] was also prepared. All salts demonstrated remarkable stability in air as compared with their fluorinated analogues. The Lewis acidity of these salts was evaluated by means of theoretical calculations and finally, they were shown to be effective in initiating the Mukaiyama-aldol reaction. PMID- 29134218 TI - Antioxidant and anti-inflammatory properties of Ilex guayusa tea preparations: a comparison to Camellia sinensis teas. AB - Ilex guayusa tea preparations are now commercially available as Runa tea. Little is known regarding the antioxidant and anti-inflammatory bioactivities of this tea. The I. guayusa teas had a total polyphenolic content between 54.39 and 67.23 mg GAE per g dry mass and peroxyl radical scavenging capacities between 1773.41 and 2019 MUmol TE per g dry mass, nearly half of that for the Camellia sinensis teas. The I. guayusa teas afforded 60-80% protection from oxidative stress in the Caco-2 cellular antioxidant assay, comparable to the C. sinensis teas. The anti inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 cells of I. guayusa teas was similarly comparable to the C. sinensis teas with nitric oxide production reduced by 10-30%. Major compounds identified by mass spectrometry were the phenolic mono- and dicaffeoylquinic acid derivatives. I. guayusa teas are a good source of dietary phenolic compounds with cellular antioxidant and anti-inflammatory properties. PMID- 29134219 TI - Reaction kinetics of hydrogen abstraction from polycyclic aromatic hydrocarbons by H atoms. AB - Hydrogen abstraction reactions of polycyclic aromatic hydrocarbons (PAH) by H atoms play a very important role in both PAH and soot formation processes. However, large discrepancies up to a few orders of magnitude exist among the literature rate constant values. To increase the reliability of the computed rate constants, it is critical to obtain highly accurate potential energy surfaces. For this purpose, we have investigated the energetics of hydrogen abstraction from benzene and naphthalene using both high level-of-theory quantum chemistry methods and a series of density functional theory (DFT) methods, among which M06 2X/6-311g(d,p) has the best performance with a mean unsigned deviation from the CCSD(T)/CBS calculations of 1.0 kcal mol-1 for barrier heights and reaction energies. Thus, M06-2X/6-311g(d,p) has then been applied to compute the potential energy surfaces of the hydrogen abstraction reactions of a series of larger PAH. Based on the quantum chemistry calculations, rate constants are computed using the canonical transition state theory. The effects of the PAH size, structure, and reaction site on the energetics and rate constants are examined systematically. Finally, the hydrogen abstraction rate constants for application in PAH and soot surface chemistry models are recommended. PMID- 29134220 TI - Non-contact electric potential measurements of electrode components in an operating polymer electrolyte fuel cell by near ambient pressure XPS. AB - Photoelectron spectroscopy has the advantage of providing electric potentials by non-contact measurements based on the kinetic energy shift in component potential. We performed operando hard X-ray photoelectron spectroscopy (HAXPES) measurements with an 8 keV excitation source to measure the shift in electron kinetic energies as a function of the voltages of all the components at the anode and cathode electrodes of a polymer electrolyte fuel cell (PEFC). At the cathode electrode, when we increase the voltage between the cathode and anode from 0.2 to 1.2 V, the O 1s and F 1s peaks shift to a lower binding energy and the magnitude of the energy shift is equal to the voltage. The Pt 3d and C 1s peaks do not shift with the voltage since platinum nanoparticles and carbon supports at the cathode electrode have ground contact. In contrast to the cathode electrode, the peak shifts of all the components at the anode electrode show the same amount of shift as the voltages. It is clear that the change in the potential difference occurs only in an electrical double layer at the interface between the cathode electrode (Pt/C) and the electrolyte (Nafion and water), and that the anode electrode is in equilibrium as a pseudo-hydrogen electrode. Moreover, the electric potential variation of the cathode electrode in a PEFC under a power generation condition was also directly detected by operando HAXPES. PMID- 29134221 TI - An acyclic zincagermylene: rapid activation of dihydrogen at sub-ambient temperature. AB - The first example of a stable zincagermylene, :Ge(TBoN)(ZnL*) (TBoN = N(SiMe3){B(DipNCH)2}, Dip = C6H3Pri2-2,6; L* = -N{C6H2[C(H)Ph2]2Me 2,6,4}(SiPri3)) is prepared and shown to have unprecedented reactivity for a germylene, with respect to the activation of dihydrogen. Computational analyses point towards this being partially derived from the electron releasing nature of the amido-zinc fragment, which leads to a narrowing of the HOMO-LUMO gap in the compound. PMID- 29134222 TI - Water-soluble Au nanoclusters for multiplexed mass spectrometry imaging. AB - Homogeneous and water-soluble Au nanoclusters with high UV photon adsorption and high biocompatibility were utilized to enhance the detection sensitivity and lateral resolution of multiplexed mass spectrometry imaging based on laser desorption/ionization. PMID- 29134223 TI - Electric field effect on the magnetic properties of zigzag MoS2 nanoribbons with different edge passivation. AB - Electrical control of magnetic exchange coupling interactions is central to designing magnetic materials. In this study, we performed density functional theory calculations to investigate the magnetic spin configuration, magnetic moment, and magnetic coupling strength of zigzag MoS2 nanoribbons (zMoS2NRs) with different edge passivation, that is, pristine (Pristine), hydrogen termination (H tem), sulfur termination (S-term), and sulfhydryl termination (SH-term). Further, we investigated the influence of an external electric field (FExt) on the magnetic properties. Pristine and H-term showed an AFM ground configuration with considerably weak magnetic coupling strength while S-term and SH-term showed a single edge FM ground configuration in the absence of the electric field. When the external electric field was applied, the positive field intensified the original spin configuration, thus increasing the magnetic moment of the system while the negative field weakened the original spin configuration, thus decreasing the magnetic moment and further reversed the spin configuration from AFM to FM and vice versa in most systems. The magnetic coupling strength of the system increased for both Pristine and H-term regardless of the direction of the field. However, the extent of increase was much higher in Pristine due to the existence of relatively easily transferable dangling electrons compared with the constrained electrons of H-term restricted to chemical bonds. Our results demonstrate a possibility of reversible spin control from AFM to FM and vice versa by applying an electric field and the enhancement of the magnetic coupling strength of zMoS2NRs. PMID- 29134224 TI - Substitution of Re7+ into CaMnO3: an efficient free electron generation dopant for tuning of thermoelectric properties. AB - Highly dense CaMn1-xRexO3 (0 <= x <= 0.04) samples were prepared by solid-state synthesis. The effect of Re doping was assessed by the characterisation of crystal structure, oxygen content, and electrical and thermal transport properties. The oxidation state of the substituted Re was determined by X-ray absorption near edge spectra to be Re7+, and led to expansion of the lattice and an increase in electron carrier concentration due to the formation of Mn3+. The thermal behaviour of the electrical conductivity and the thermopower over a wide temperature range allowed identification of different conduction mechanisms: (1) below 110 K, 3D variable range hopping, (2) between 110 and 650 K, small polaron transport, and (3) above 650 K, activation of carriers over a mobility edge. Evaluation of the power factor expected for different dopant oxidation states as a function of dopant concentration shows that the doping strategy using a heavy heptavalent ion allows accessibility of the peak power factor at lower dopant concentrations, lowering the amount of non-ionised impurities, and therefore improves the electronic substitution efficiency, the ratio of activated carriers over the nominal doping concentration, compared to previously studied dopants. An increased power factor and a reduced lattice thermal conductivity are obtained with a peak figure of merit ZT = 0.16(3) at 947 K for CaMn0.98Re0.02O3. This is an approximately two-fold increase compared to undoped CaMnO3, and is comparable to the highest values reported for highly dense B-site doped CaMnO3. PMID- 29134225 TI - In situ TEM studies of the shape evolution of Pd nanocrystals under oxygen and hydrogen environments at atmospheric pressure. AB - We demonstrate an atomic scale TEM observation of shape evolutions of Pd nanocrystals under oxygen and hydrogen environments at atmospheric pressure. Combined with multi-scale structure reconstruction model calculations, the reshaping mechanism is fully understood. PMID- 29134226 TI - La2(Nb1-xYx)2O7-delta: discovery of a novel fluorite structure-based ionic conductor. AB - A novel fluorite structure-based compound of La2(Nb1-xYx)2O7-delta shows superior chemical stability and proton conduction. PMID- 29134228 TI - Author Correction: Novel six-week protocol for generating functional human connective tissue-type (MCTC) mast cells from buffy coats. AB - The online version of the original article can. PMID- 29134230 TI - Baicalin in flavocoxid may act against hepatitis B virus via a pro-inflammatory pathway. PMID- 29134229 TI - Decursin and decursinol angelate: molecular mechanism and therapeutic potential in inflammatory diseases. AB - Epidemiological studies have shown that inflammation plays a critical role in the development and progression of various chronic diseases, including cancers, neurological diseases, hepatic fibrosis, diabetic retinopathy, and vascular diseases. Decursin and decursinol angelate (DA) are pyranocoumarin compounds obtained from the roots of Angelica gigas. Several studies have described the anti-inflammatory effects of decursin and DA. Decursin and DA have shown potential anti-inflammatory activity by modulating growth factors such as vascular endothelial growth factor, transcription factors such as signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain enhancer of activated B cells, cellular enzymes including matrix metalloproteinases cyclooxygenase, and protein kinases such as extracellular receptor kinase, phosphatidylinositol-3-kinase, and protein kinase C. These compounds have the ability to induce apoptosis by activating pro-apoptotic proteins and the caspase cascade, and reduced the expression of anti-apoptotic proteins such as B-cell lymphoma 2 and B-cell lymphoma-extra-large. Interaction with multiple molecular targets and cytotoxic effects, these two compounds are favorable candidates for treating various chronic inflammatory diseases such as cancers (prostate, breast, leukemia, cervical, and myeloma), rheumatoid arthritis, diabetic retinopathy, hepatic fibrosis, osteoclastogenesis, allergy, and Alzheimer's disease. We have summarized the preliminary studies regarding the biological effects of decursin and DA. In this review, we will also highlight the functions of coumarin compounds that can be translated to a clinical practice for the treatment and prevention of various inflammatory ailments. PMID- 29134231 TI - Patterns of relapse as determined by 68Ga-PSMA ligand PET/CT after radical prostatectomy : Importance for tailoring and individualizing treatment. AB - PURPOSE: To evaluate the patterns of relapse and impact on the intended treatment when using 68Ga-prostate-specific membrane antigen (PSMA) ligand positron emission tomography/computed tomography (PET/CT) imaging for restaging of disease in patients with biochemical relapse after radical prostatectomy (RP) before salvage radiotherapy (sRT). METHODS: In all, 39 patients with biochemical recurrence after RP who had no primary indication for adjuvant RT due to the absence of biologically unfavorable disease (e.g., extracapsular extension, seminal vesicle invasion, positive margins, or lymph node involvement) underwent a 68Ga-PSMA ligand PET/CT for planning of sRT. RESULTS: PET/CT was positive in 84.6% (33/39) of patients. A total of 61 lesions were observed in these patients (on average 1.8 lesions per patient); 30.3% (10/33) of patients had locally recurrent disease in the prostatic bed. The clinical TNM stage (TNM: tumour-lymph nodes-metastasis-classification) was altered in 69.7% (23/33) of patients following PET, resulting in individualized treatment concepts. A prostate specific antigen (PSA) >1.0 ng/mL was significantly associated with an increased risk of extrapelvic metastatic disease (p = 0.048). The PSA level at the time of PSMA ligand PET/CT correlated with the peak standardized uptake value (SUVpeak; p = 0.002). According to current clinical guidelines, the remaining 15.4% (6/39) of patients without evidence of disease on PET received sRT with a dose of 66.0 Gy. CONCLUSION: Our results suggest that in patients with biochemical recurrence who did not receive early sRT, a 68Ga-PSMA ligand PET/CT for restaging of disease allows for tailoring and individualizing treatment. Particularly in patients with PSA levels above 1.0 ng/mL, a 68Ga-PSMA ligand PET/CT should be performed for therapy planning, since patients often have metastases not confined to the pelvis. PMID- 29134232 TI - Skeletally anchored mesialization of molars using digitized casts and two surface matching approaches : Analysis of treatment effects. AB - PURPOSE: To (1) quantify the three-dimensional treatment effect of a Mesialslider appliance using superimposed digital models, (2) to evaluate anchorage loss (measured by incisor displacement), and (3) to assess agreement between two different matching approaches, i.e., control point (CP)-based and iterative closest point (ICP) matching. METHODS: In a retrospective study, the effects of a skeletally anchored uni- and bilateral mesialization appliance (Mesialslider) as well as simultaneous mesialization and distalization appliance (Mesio Distalslider) were evaluated in 48 subjects (aged 11-53 years). Pre- and posttreatment casts were digitized and superimposed with two different approaches, i.e., using ten manually selected control points located at the anterior palate and by means of an automated ICP-matching approach using a standardized palatal reference area. The treatment effects were evaluated using control points on the maxillary central incisors and maxillary molar teeth, and the methods were compared through the application of linear regression analyses and computation of alignment errors. RESULTS: Average upper molar mesialization was 6.3 +/- 2.6 mm. Anchorage loss, designated as the mean amount of upper incisor displacement, was less than 0.5 mm in all dimensions investigated. Using the measurement method sufficient registration was possible using both approaches and corresponding tooth movements were significantly correlated (p < 0.01). CONCLUSIONS: Accurate measurements of tooth displacement can be performed using both CP- and ICP-based matching approaches. Within the limits of performing a retrospective study, a premolar width of molar mesialization appeared possible without clinically relevant anchorage loss. PMID- 29134234 TI - Light in the dark: 18F-FDG PET/CT in Staphylococcus aureus bacteremia of unknown origin. PMID- 29134235 TI - Correction to: The P/N (Positive-to-Negative Links) Ratio in Complex Networks-A Promising In Silico Biomarker for Detecting Changes Occurring in the Human Microbiome. AB - The original version of this article unfortunately contained a missing image. The flowchart was not captured in PDF version. The original article was corrected. PMID- 29134233 TI - [Genuine motor phenomena in schizophrenia : Neuronal correlates and pathomechanisms]. AB - Despite a growing body of evidence on motor dysfunction in schizophrenia spectrum disorders, the neuronal correlates of genuine motor abnormalities (GMA) are not fully elucidated at present. Moreover, the clinical relevance of a potential "motor intermediate phenotype" remains controversial. This systematic review aims at characterizing a "motor intermediate phenotype" in schizophrenia spectrum disorders. The second goal of this systematic review is to discuss GMA-associated brain alterations as potential biomarkers of psychosis risk syndrome and manifest motor symptoms against the background of current neuroimaging evidence. The detailed clinical assessment of GMA in the context of multimodal imaging could, in the future promote the early recognition of psychotic disorders and the initiation of disorder-oriented and individualized treatment. Taken as a whole the data provide initial evidence that motor dysfunction in schizophrenic spectrum disorders must be considered dimensionally. The predictive value of neurobiological results with respect to the transition to a life-threatening catatonia or the development of chronic dyskinesia, cannot currently be conclusively assessed. PMID- 29134236 TI - [Arthroscopic soft tissue stabilization of posttraumatic anterior shoulder instability : Techniques, limitations and long-term results]. AB - Arthroscopic soft tissue stabilization is a well-established and broadly accepted procedure to treat posttraumatic shoulder instability. Advantages in comparison to open stabilization procedures include improved visualization of the structural damage and a less invasive approach. Technical developments in recent years have led to further improvement of the arthroscopic technique for shoulder instability. This article presents a description of principles and new developments as it contains basic techniques including patient positioning, access portals, preparation of the glenoid bone, soft tissue handling and shuttle techniques. Modern suture anchor systems to achieve arthroscopic stabilization with the corresponding advantages and disadvantages are also presented. Furthermore, the limitations and long-term results of arthroscopic soft tissue stabilization are discussed. PMID- 29134237 TI - Neuronal Cell Adhesion Molecule 1 Regulates Leptin Sensitivity and Bone Mass. AB - The central nervous system is widely known to exert control over our systemic physiology via several mechanisms including the regulation of skeletal metabolism. Neuronal circuits within the hypothalamus have been shown to impact bone mass via leptin-dependent and independent mechanisms; however, the full extent to which the brain controls bone homeostasis is not known. We previously identified cell adhesion molecule1 (Cadm1) as a regulator of body weight and energy homeostasis via its expression in multiple regions of the brain. Here, we show that loss of Cadm1 expression in excitatory neurons results in increased leptin sensitivity in addition to a concomitant reduction in bone mass. Femoral length, bone mineral content, diaphyseal cross-sectional area, and bone strength were all lower in Cadm1-deficient animals. Conversely, inducing expression of Cadm1 in excitatory neurons decreased leptin sensitivity and increased femoral length, bone mineral content, and diaphyseal cross-sectional area. Together, these results illustrate an essential role for this synaptic protein in the neuronal regulation of skeletal bone metabolism. PMID- 29134238 TI - A Comparison of Anterograde Versus Retrograde Approaches for Neonatal Balloon Aortic Valvuloplasty. AB - In neonates requiring balloon aortic valvuloplasty, both anterograde and retrograde approaches are feasible. A recent comparison of these two approaches is lacking. A retrospective cohort study of neonates at a single center undergoing BAV from 9/00 to 7/14 was performed. Records were reviewed including pre- and post-intervention echocardiograms and catheterization data. Comparisons of acute efficacy and procedural safety were made based on type of approach utilized. Forty-two neonates underwent BAV. Eleven cases utilized exclusively an anterograde approach, while 31 included a retrograde approach (including 4 with both approaches used). There were no significant differences between groups in baseline demographic and clinical characteristics. Additionally, by both pre intervention echocardiogram and catheterization, there were no differences based on approach in aortic valve gradient, degree of aortic insufficiency (AI), or degree of mitral regurgitation (MR). Both approaches were equally efficacious in gradient reduction (45 +/- 17 vs. 44 +/- 21 mmHg, p = 0.97), and there was no difference in post-intervention AI as assessed by both catheterization and echocardiogram (52% vs. 64% none or trivial, p = 0.74). Additionally, there was no difference in the proportion of patients with an increased severity of MR after BAV (15% vs. 22%, p = 0.52). The retrograde approach required a larger arterial catheter and was associated with a higher rate of arterial thrombosis (61% vs. 18%, p = 0.014). Both anterograde and retrograde approaches to neonatal BAV appear to be equally efficacious in the short term. The anterograde approach avoids the need for a larger arterial catheter and may reduce the risk of arterial thrombosis. PMID- 29134239 TI - Temporomandibular joint atlas for detection and grading of juvenile idiopathic arthritis involvement by magnetic resonance imaging. AB - Contrast-enhanced magnetic resonance imaging (MRI) is considered the diagnostic standard for identifying involvement of the temporomandibular joint by juvenile idiopathic arthritis. Early or active arthritis is shown as bone marrow oedema, joint effusion, synovial thickening and increased joint enhancement. Subsequent joint damage includes characteristic deformity of the mandibular condyle, bone erosion, disk abnormalities and short mandibular ramus due to impaired growth. In this pictorial essay, we illustrate normal MRI findings and growth-related changes of the temporomandibular joint in children. The rationale and practical application of semiquantitative MRI assessment of joint inflammation and damage are discussed and presented. This atlas can serve as a reference for grading temporomandibular joint arthritis according to the scoring systems proposed by working groups of OMERACT (Outcome Measures in Rheumatology and Clinical Trials) and the EuroTMjoint research network. Systematic assessment of the level of inflammation, degree of osteochondral deformation, and growth of the mandibular ramus by MRI may aid in monitoring the course of temporomandibular joint arthritis and evaluating treatment options. PMID- 29134240 TI - Fine mapping of a male sterility gene ms-3 in a novel cucumber (Cucumis sativus L.) mutant. AB - KEY MESSAGE: The cucumber male sterility gene ms - 3 was fine mapped in a 76 kb region harboring an MMD1 -like gene Csa3M006660 that may be responsible for the male sterile in cucumber. A cucumber (Cucumis sativus L.) male sterile mutant (ms 3) in an advanced-generation inbred line was identified, and genetic analysis revealed that the male sterility trait was controlled by a recessive nuclear gene, ms-3, which was stably inherited. Histological studies suggested that the main cause of the male sterility was defective microsporogenesis, resulting in no tetrad or microspores being formed. Bulked segregant analysis (BSA) and genotyping of an F2 population of 2553 individuals were employed used to fine map ms-3, which was delimited to a 76 Kb region. In this region, a single non synonymous SNP was found in the Csa3M006660 gene locus, which was predicted to result in an amino acid change. Quantitative RT-PCR analysis of Csa3M006660 was consistent with the fact that it plays a role in the early development of cucumber pollen. The protein encoded by Csa3M006660 is predicted to be homeodomain (PHD) finger protein, and the high degree of sequence conservation with homologs from a range of plant species further suggested the importance of the ms-3 non-synonymous mutation. The data presented here provide support for Csa3M006660 as the most likely candidate gene for Ms-3. PMID- 29134241 TI - CT-based evaluation of volumetric bone density in fragility fractures of the pelvis-a matched case-control analysis. AB - : This matched case-control study compared the computed tomography (CT)-based regional bone density of patients with fragility fractures of the sacrum to a control without fracture. Patients with a sacral fracture demonstrated a significantly lower regional bone density of the sacrum, the sacral bone density not being correlated with the BMD by DXA of the spine. INTRODUCTION: The aim of this study is to compare the computed tomography-based regional bone density measured by Hounsfield units (HUs) in patients with and without fragility fractures of the sacrum. METHODS: Patients aged >= 50 years with a fragility fracture of the sacrum were compared to patients of similar age and gender who had a fall from standing height without fracture (n = 46). A matched case-control analysis was conducted by retrospective chart review and assessment of areal bone mineral density by lumbar DXA and by volumetric regional HU measurements in uncalibrated CT scans of the sacrum. RESULTS: Patients with a sacral fracture (age 74 +/- 11 years) showed a lower bone density in the body of S1 (HU 85 +/- 22) when compared to the matched control group without fracture (age 73 +/- 10 years, HU 125 +/- 37, p < 0.001). The CT-based bone density of S1 did not correlate with the DXA values of the lumbar spine (r = 0.223, p = 0.136), and lumbar spine T-scores did not differ between the groups (- 2.0 +/- 1.3 vs. - 1.9 +/- 1.2, p = 0.786). All measurements are based on uncalibrated scans, and absolute HU values are restricted to scans made on Siemens SOMATOM Force or SOMATOM Edge scanners. CONCLUSIONS: Patients with fragility fractures of the sacrum demonstrated a lower regional volumetric bone density of the sacrum when compared to a cohort without a fracture. Local sacral volumetric bone density as measured by CT seems to be independent from the areal BMD as measured by DXA of the lumbar spine. LEVEL OF EVIDENCE: level III. PMID- 29134242 TI - Serum parathyroid hormone is associated with increased cortical porosity of the inner transitional zone at the proximal femur in postmenopausal women: the Tromso Study. AB - : Serum parathyroid hormone (PTH) was associated with increased bone turnover markers and cortical porosity of the inner transitional zone at the proximal femur. These results suggest that PTH through increased intracortical bone turnover leads to trabecularisation of inner cortical bone in postmenopausal women. INTRODUCTION: Vitamin D deficiency leads to secondary hyperparathyroidism and increased risk for fractures, whereas its association with cortical porosity is less clear. We tested (i) whether serum 25-hydroxyvitamin D (25(OH)D) and PTH were associated with cortical porosity and (ii) whether the associations of 25(OH)D) and PTH with fracture risk are dependent on cortical porosity. METHODS: This case-control study included 211 postmenopausal women, 54-94 years old, with prevalent fractures and 232 controls from the Tromso Study. Serum 25(OH)D, PTH, and bone turnover markers (procollagen type I N-terminal propeptide [PINP] and C terminal cross-linking telopeptide of type I collagen [CTX]) were measured. Femoral subtrochanteric cortical and trabecular parameters were quantified using computed tomography, and femoral neck areal bone mineral density (FN aBMD) was quantified using dual-energy X-ray absorptiometry. RESULTS: Compared with controls, fracture cases exhibited reduced serum 25(OH)D and increased PTH, PINP, and CTX, increased femoral subtrochanteric cortical porosity, and reduced cortical thickness and FN aBMD (all, p < 0.05). Serum 25(OH)D was not associated with cortical parameters (all, p > 0.10). PTH was associated with increased PINP, CTX, and cortical porosity of the inner transitional zone and reduced trabecular bone volume/tissue volume and FN aBMD (p ranging from 0.003 to 0.054). Decreasing 25(OH)D and increasing PTH were associated with increased odds for fractures, independent of age, height, weight, calcium supplementation, serum calcium, cortical porosity, and thickness. CONCLUSIONS: These data suggest that serum PTH, not 25(OH)D, is associated with increased intracortical bone turnover resulting in trabecularisation of the inner cortical bone; nevertheless, decreasing 25(OH)D) and increasing PTH are associated with fracture risk, independent of cortical porosity and thickness. PMID- 29134243 TI - [Implants for genital prolapse : Pro mesh surgery]. AB - There has been an overall increase in pelvic organ prolapse due to demographic changes (increased life expectancy). Increasing sociocultural demands of women require treatments that are more effective with methods that are more successful. In the treatment of pelvic floor insufficiency and uterovaginal prolapse, pelvic floor reconstructions with mesh implants have proven to be superior to conventional methods such as the classic colporrhaphy, reconstructions with biomaterial, and native tissue repair in appropriately selected patients and when applying exact operation techniques, especially because of good long-term results and low recurrence rates. When making a systematic therapy plan, one should adhere to certain steps, for example, a pelvic floor reconstruction should be undertaken before performing the corrective procedure for incontinence. The approach, if vaginal, laparoscopic, or abdominal should be chosen wisely, taking into consideration the required space of action, in such a way that none or only minimal collateral damage related to the operation occurs. The use of instrumental suturing techniques and operation robots are advantageous in the case of difficult approaches and limited anatomical spaces. In principle, the surgeon who implants meshes should be able to explant them! The surgical concept of mesh-related interventions in the pelvis must meet established rules. "Implant as little mesh as possible and only as much suitable (!) mesh as absolutely necessary!" In the case of apical direct fixations, a therapeutically relevant target variable is the elevation angle of vagina (EAV). Established anatomical fixation points are preferable. A safe distance between implants and vulnerable tissue is to be maintained. Mesh-based prolapse repairs are indicated in recurrences, in primary situations, in combined defects of the anterior compartment, in central defects of multimorbid and elderly patients, and above all, when organ preservation is wanted. Native connective tissue structures are to be preserved, strengthened and reconstructed to restore altered functions. Practical skills for highly specialized mesh-based operations as well as effective techniques for complication management should be taught in interdisciplinary specialist courses. PMID- 29134244 TI - Modulation of CYP3A enzyme activity by diosmin and its consequence on carbamazepine pharmacokinetics in rats. AB - Diosmin is a widely used flavonoid for the treatment of varicose veins and hemorrhoids. Epileptic patients with hemorrhoids and varicose veins may use diosmin along with carbamazepine (CBZ) therapy, which leads to pharmacokinetic interaction between diosmin and CBZ. Therefore, the present study was performed to evaluate the effect of diosmin on the pharmacokinetics of CBZ in rats. Diosmin mediated altered CYP3A enzyme activity in human and rat liver microsomes was examined using CYP3A dependent erythromycin N-demethylase assay. Further, an in vivo pharmacokinetic study of oral administered CBZ in rats with and without diosmin pretreatment was performed. The CYP3A enzyme activity in human and rat liver microsomes was significantly (p < 0.05) decreased by diosmin when compared to control. Pretreatment with diosmin significantly (p < 0.05) enhanced maximum plasma concentration (C max), area under the curve (AUC), and half life (t 1/2), while significantly (p < 0.05) decreased elimination rate constant (k el) and apparent oral clearance (CL/F) of CBZ as compared to control rats. On the other hand, C max, AUC, and t 1/2 of carbamazepine 10, 11-epoxide (CBZE) were significantly (p < 0.05) decreased after diosmin pretreatment. Furthermore, diosmin pretreatment significantly (p < 0.05) decreased metabolic ratios of C max and AUC when compared to control, suggesting reduced formation of CBZ to CBZE. The results suggest that diosmin pretreatment might have inhibited CYP3A-mediated metabolism of CBZ. Accordingly, caution should be taken when diosmin is used in combination with therapeutic drugs metabolized by CYP3A enzyme in addition to CBZ. PMID- 29134245 TI - Esophageal pressure: research or clinical tool? AB - Esophageal manometry has traditionally been utilized for respiratory physiology research, but clinicians have recently found numerous applications within the intensive care unit. Esophageal pressure (PEs) is a surrogate for pleural pressures (PPl), and the difference between airway pressure (PAO) and PEs provides a good estimate for the pressure across the lung also known as the transpulmonary pressure (PL). Differentiating the effects of mechanical ventilation and spontaneous breathing on the respiratory system, chest wall, and across the lung allows for improved personalization in clinical decision making. Measuring PL in acute respiratory distress syndrome (ARDS) may help set positive end expiratory pressure (PEEP) to prevent derecruitment and atelectrauma, while assuring peak pressures do not cause over distension during tidal breathing and recruitment maneuvers. Monitoring PEs allows improved insight into patient ventilator interactions and may help in decisions to adjust sedation and paralytics to correct dyssynchrony. Intrinsic PEEP (auto-PEEP) may be monitored using esophageal manometry, which may also improve patient comfort and synchrony with the ventilator. Finally, during weaning, PEs may be used to better predict weaning success and allow for rapid intervention during failure. Improved consistency in definition and terminology and further outcomes research is needed to encourage more widespread adoption; however, with clear clinical benefit and increased ease of use, it appears time to reintroduce basic physiology into personalized ventilator management in the intensive care unit. PMID- 29134246 TI - Does high PEEP prevent alveolar cycling? AB - Acute respiratory distress syndrome (ARDS) patients need mechanical ventilation to sustain gas exchange. Animal experiments showed that mechanical ventilation with high volume/plateau pressure and no positive end-expiratory pressure (PEEP) damages healthy lungs, while low tidal volumes and the application of higher PEEP levels are protective. PEEP makes the lung homogeneous, reducing the pressure multiplication at the interface between lung units with different inflation statuses and keeps the lung open through the whole respiratory cycle, avoiding intratidal opening and closing. Four randomized clinical trials tested a higher PEEP strategy compared to a lower PEEP strategy but failed to show any survival benefit. These results, which apparently contradict preclinical data, may be explained by CT scanning, which investigates the behaviour of ARDS lung upon inflation and deflation demonstrating that: (1) 15 cmH2O PEEP is insufficient to overcome the closing pressures of the lung and keep it open through the whole respiratory cycle; (2) lung recruitment is continuous along the volume-pressure curve. The application of a PEEP level around 15 cmH2O does not abolish opening and closing, but the lung region undergoing opening and closing is simply shifted downward, i. e. becomes more vertebral in the supine patient. (3) Recruited lung tissue becomes poorly inflated and not well inflated; poorly inflated tissue is inhomogeneous: while increasing PEEP the reduction in lung inhomogeneity is small or non-existent. PMID- 29134248 TI - The ancient claudin Dni2 facilitates yeast cell fusion by compartmentalizing Dni1 into a membrane subdomain. AB - Dni1 and Dni2 facilitate cell fusion during mating. Here, we show that these proteins are interdependent for their localization in a plasma membrane subdomain, which we have termed the mating fusion domain. Dni1 compartmentation in the domain is required for cell fusion. The contribution of actin, sterol dependent membrane organization, and Dni2 to this compartmentation was analysed, and the results showed that Dni2 plays the most relevant role in the process. In turn, the Dni2 exit from the endoplasmic reticulum depends on Dni1. These proteins share the presence of a cysteine motif in their first extracellular loop related to the claudin GLWxxC(8-10 aa)C signature motif. Structure-function analyses show that mutating each Dni1 conserved cysteine has mild effects, and that only simultaneous elimination of several cysteines leads to a mating defect. On the contrary, eliminating each single cysteine and the C-terminal tail in Dni2 abrogates Dni1 compartmentation and cell fusion. Sequence alignments show that claudin trans-membrane helixes bear small-XXX-small motifs at conserved positions. The fourth Dni2 trans-membrane helix tends to form homo-oligomers in Escherichia plasma membrane, and two concatenated small-XXX-small motifs are required for efficient oligomerization and for Dni2 export from the yeast endoplasmic reticulum. Together, our results strongly suggest that Dni2 is an ancient claudin that blocks Dni1 diffusion from the intercellular region where two plasma membranes are in close proximity, and that this function is required for Dni1 to facilitate cell fusion. PMID- 29134247 TI - Epigenetic differences between naive and primed pluripotent stem cells. AB - It has been 8 years since the concept of naive and primed pluripotent stem cell states was first proposed. Both are states of pluripotency, but exhibit slightly different properties. The naive state represents the cellular state of the preimplantation mouse blastocyst inner cell mass, while the primed state is representative of the post-implantation epiblast cells. These two cell types exhibit clearly distinct developmental potential, as evidenced by the fact that naive cells are able to contribute to blastocyst chimeras, while primed cells cannot. However, the epigenetic differences that underlie the distinct developmental potential of these cell types remain unclear, which is rather surprising given the large amount of active investigation over the years. Elucidating such epigenetic differences should lead to a better understanding of the fundamental properties of these states of pluripotency and the means by which the naive-to-primed transition occurs, which may provide insights into the essence of stem cell commitment. PMID- 29134249 TI - Early SIV and HIV infection promotes the LILRB2/MHC-I inhibitory axis in cDCs. AB - Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response. PMID- 29134251 TI - Meniscal repair results in inferior short-term outcomes compared with meniscal resection: a cohort study of 6398 patients with primary anterior cruciate ligament reconstruction. AB - PURPOSE: To compare patient reported outcome measures (PROMs) during the first postoperative year between isolated anterior cruciate ligament (ACL) reconstruction and ACL reconstruction with concomitant meniscal intervention. METHODS: Patients who underwent primary ACL reconstruction at Capio Artro Clinic, Stockholm, Sweden, between 1st Jan 2001 and 31st Dec 2014 without concomitant injuries others than meniscal and/or cartilage lesions were included. Five groups of meniscal treatment simultaneously to ACL reconstruction were established; medial meniscal (MM) resection, MM repair, lateral meniscal (LM) resection, LM repair, and MM + LM resection. Patients treated with isolated ACL reconstruction formed a separate group. Preoperative, 6-month and 1-year Knee Injury and Osteoarthritis Outcome Score (KOOS), and Lysholm knee score and Tegner Activity scale were collected. Differences in the change over time were analyzed with an ANOVA for repeated measurements with age at surgery, gender, and cartilage injury as covariates. A univariate ANOVA was applied to analyze PROMs between groups at the final follow-up. RESULTS: A total of 6398 patients were included (56.8% males, mean age 28.5 +/- 10.2 years). The KOOS improved across all subscales for all treatment groups. The mean change over time differed significantly between groups for the subscales symptoms (p = 0.017) and activities in daily living (ADL) (p < 0.001). Symptoms was least improved in the MM repair group, while the MM + LM resection group showed the largest improvement. For the ADL subscale, the isolated ACL reconstruction group showed the least improvement and the MM + LM resection group showed the major improvement. At 1-year follow-up, a significant difference between the groups was found for the subscale symptoms (p = 0.019), where the MM repair group reported the lowest score [mean 78.4 (95% CI 76.3 80.5)]. No significant differences were found between groups in change of the Lysholm score over time; however, at 6 months, the difference between groups was significant (p = 0.006) with the meniscal repair groups reporting the lowest scores. CONCLUSION: Patients with concomitant meniscal resection are able to reach the same subjective knee function as isolated ACL reconstructions as early as 6 months postoperatively. However, patients with meniscal repair may have slightly worse subjective knee function at both 6- and 12-month follow-up. These findings could help clinicians to set realistic short-term expectations for patients undergoing ACL reconstruction with simultaneous meniscal intervention. LEVEL OF EVIDENCE: 3. PMID- 29134252 TI - Return to sports after the latarjet procedure: high return level of non-collision athletes. AB - PURPOSE: The purpose of this study was to compare the clinical outcomes, including the level of return to sport, of collision and non-collision athletes who had the Latarjet procedure. METHODS: A total of 56 shoulders of 29 collision and 27 non-collision athletes were retrospectively analyzed. All study participants underwent the Latarjet procedure between 2007 and 2014. Median age at the time of surgery was 26.5 years(18-43) and follow-up duration was 67.0 months(24-113). RESULTS: At the final follow-up, 54 (96.4%) patients returned to sports. Nine patients (16.1%) returned to the same level of sports. In a group of collision athletes, 1 patient (3.4%) returned to the same level, 16 (55.2%) returned to lower level, 10 (34.5%) changed sports, and 2 (6.9%) quit sports. In a group of noncollision athletes, 8 (29.6%) returned to same level, 11 (40.7%) returned at a lower level and 8 (29.6%) changed sports. The level of return to sports in collision group was statistically different from that in noncollision group (p = 0.046). The mean VAS, Rowe and UCLA scores improved significantly in both groups (p < 0.001) with no statistically significant difference between both groups. CONCLUSIONS: Although the clinical outcomes were not significantly different between collision and non-collision athletes, the level of return to sports was significantly higher in the non-collision group than in the collision group. The result suggests that the level of physical demand according to sport type is an important prognostic factor which predicts the level of return to sport after the Lartarjet procedure in athletes. LEVEL OF EVIDENCE: IV. PMID- 29134253 TI - The role of the neutrophil:lymphocyte ratio (NLR) and the CRP:albumin ratio (CAR) in predicting mortality following emergency laparotomy in the over 80 age group. AB - INTRODUCTION: Emergency laparotomy in the elderly is an increasingly common procedure which carries high morbidity and mortality. Risk prediction tools, although imperfect, can help guide management decisions. Novel markers of surgical outcomes may contribute to these scoring systems. The neutrophil:lymphocyte ratio (NLR) and CRP:albumin ratio (CAR) have been associated with outcomes in malignancy and sepsis. We assessed the use of ratio NLR and CAR as prognostic indicators in patients over the age of 80 undergoing emergency laparotomy. METHODS: A retrospective analysis of all patients over the age of 80 who underwent emergency laparotomy during a 3 year period was conducted. Pre and post-operative NLR and CAR were assessed in relation to outcome measures including inpatient, 30-day and 90-day mortality. Statistical analysis was conducted with Mann-Whitney U, receiver operating characteristics, Spearmans rank correlation coefficient and chi-squared tests. RESULTS: One hundred and thirty-six patients over the age of 80 underwent emergency laparotomy. Median age was 84 years (range 80-96 years). Overall inpatient mortality was 19.2%. Pre-operative and post-operative NLR and CAR were significantly raised in patients with sepsis v no sepsis (p < 0.05). Pre operative NLR was significantly associated with inpatient (p = 0.046), 30-day (p = 0.02) and 90-day mortality (p = 0.01) in patients with visceral perforation. A pre-operative NLR value of greater than 8 was associated with significantly increased mortality (p = 0.016, AUC:0.78). CAR was not associated with mortality. CONCLUSION: Pre-operative NLR is associated with mortality in patients with visceral perforation undergoing emergency laparotomy. NLR > 8 is associated with a poorer outcome in this group of patients. CAR was not associated with mortality in over-80s undergoing emergency laparotomy. PMID- 29134254 TI - Comparison of cardiovascular events among treatments for overactive bladder: a Danish nationwide cohort study. AB - PURPOSE: The purpose of this study is to explore the cardiovascular safety of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark. METHODS: This was a cohort study using data recorded in Danish registries from patients newly exposed to darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium in 2004-2012. We estimated crude and standardized incidence rates (IRs) for acute myocardial infarction (AMI); stroke; cardiovascular mortality; major adverse cardiac events (MACE, a combined endpoint of the previous three outcomes); and all-cause death for the individual and combined drugs. We also estimated crude, standardized, and propensity score-stratified incidence rate ratios (IRRs) comparing individual antimuscarinic drugs to tolterodine as the reference. RESULTS: Among 72,917 new users of OAB drugs (mean age, 66 years; 60% women), the standardized IR (95% confidence interval) per 1000 person-years for current use of any OAB drug was 2.7 (2.5-2.9) for AMI, 1.3 (1.2-1.5) for stroke, 7.8 (7.5-8.1) for MACE, 4.8 (4.5-5.0) for cardiovascular mortality, and 15.2 (14.8-15.6) for all-cause mortality. Propensity score-stratified IRRs for current use (reference, tolterodine) were close to the null for all drugs and endpoints. CONCLUSIONS: We did not identify differences in the risk of cardiovascular events or mortality among users of individual antimuscarinic OAB drugs. PMID- 29134256 TI - [Extragenital, disseminated infection with human papillomaviruses : Therapeutic response through vaccination with HPV]. AB - A 50-year-old man with widespread manifestation of warts and distinct pruritus for the last 5 years was diagnosed with a reactivated human papillomavirus (HPV) infection by three, genetically verified types (6, 16, 18), which are included in the vaccine Gardasil(r). Conventional treatment was not successful, but a rapid and significant reduction of the skin manifestation was observed after vaccination with Gardasil(r). To what extent therapy-resistant infections with HPV can be influenced through an active HPV vaccination should be investigated in future trials. PMID- 29134255 TI - Identification of generic and pathogen-specific cord blood monocyte transcriptomes reveals a largely conserved response in preterm and term newborn infants. AB - : Escherichia coli and Staphylococcus epidermidis are predominant causes of neonatal sepsis, particularly affecting preterm infants. Susceptibility to infection has been attributed to "immature" innate monocyte defences, but no studies have assessed global transcriptional responses of neonatal monocytes to these pathogens. Here, we aimed to identify and characterise the neonatal monocyte transcriptional responses to E. coli and S. epidermidis and the role of common modifiers such as gestational age (GA) and exposure to chorioamnionitis (a common complication of preterm birth) to better understand early life innate immune responses. RNA-sequencing was performed on purified cord blood monocytes from very preterm (< 32 weeks GA) and term infants (37-40 weeks GA) following standardised challenge with live S. epidermidis or E. coli. The major transcriptional changes induced by either pathogen were highly conserved between infant groups and stimuli, highlighting a common extant neonatal monocyte response to infection, largely mediated by TLR/NF-kappaB/TREM-1 signalling. In addition, we observed an activated interferon-centred immune response specific to stimulation with E. coli in both preterm and term infants. These data provide novel insights into the functionality of neonatal monocytes at birth and highlight potential pathways that could be targeted to reduce the harmful effects of bacterial-induced inflammation in sepsis. E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF-kappaB/TREM-1 signalling. IFN genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis. KEY MESSAGES: E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF kappaB/TREM-1 signalling. IFN-genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis. PMID- 29134257 TI - [Regional anesthesia: tradition and innovation]. PMID- 29134258 TI - Novel full-length major histocompatibility complex class I allele discovery and haplotype definition in pig-tailed macaques. AB - Pig-tailed macaques (Macaca nemestrina, Mane) are important models for human immunodeficiency virus (HIV) studies. Their infectability with minimally modified HIV makes them a uniquely valuable animal model to mimic human infection with HIV and progression to acquired immunodeficiency syndrome (AIDS). However, variation in the pig-tailed macaque major histocompatibility complex (MHC) and the impact of individual transcripts on the pathogenesis of HIV and other infectious diseases is understudied compared to that of rhesus and cynomolgus macaques. In this study, we used Pacific Biosciences single-molecule real-time circular consensus sequencing to describe full-length MHC class I (MHC-I) transcripts for 194 pig-tailed macaques from three breeding centers. We then used the full-length sequences to infer Mane-A and Mane-B haplotypes containing groups of MHC-I transcripts that co-segregate due to physical linkage. In total, we characterized full-length open reading frames (ORFs) for 313 Mane-A, Mane-B, and Mane-I sequences that defined 86 Mane-A and 106 Mane-B MHC-I haplotypes. Pacific Biosciences technology allows us to resolve these Mane-A and Mane-B haplotypes to the level of synonymous allelic variants. The newly defined haplotypes and transcript sequences containing full-length ORFs provide an important resource for infectious disease researchers as certain MHC haplotypes have been shown to provide exceptional control of simian immunodeficiency virus (SIV) replication and prevention of AIDS-like disease in nonhuman primates. The increased allelic resolution provided by Pacific Biosciences sequencing also benefits transplant research by allowing researchers to more specifically match haplotypes between donors and recipients to the level of nonsynonymous allelic variation, thus reducing the risk of graft-versus-host disease. PMID- 29134259 TI - Correction to: Cloning and characterization of a monoterpene synthase gene from flowers of Camelina sativa. AB - In the original publication, the order of figures and citations was incorrect. The corrections are listed below. PMID- 29134260 TI - More than black and white of scientific publishing. PMID- 29134261 TI - Drivers and challenges for implementing ISO 14001 environmental management systems in an emerging Gulf Arab country. AB - Worldwide, ISO 14001 certification for organizations has become the norm, but the Arab world accounts for an insignificant portion of all the certified organizations. There is a dearth of research on environmental management systems (EMS) in Arab and emerging countries and in public organizations. The objectives of this research are to: (1) examine the key drivers and challenges related to implementation of ISO 14001 certified EMS in the United Arab Emirates, an emerging Arab country and (2) compare and contrast these drivers and challenges between private and public organizations. We adopt an explorative, qualitative methodology, using semi-structured interviews with environmental managers in 11 organizations (6 private and 5 public) from different industrial sectors. Drivers of EMS certification were mostly similar between private and public organizations, with some differences. Compliance with regulations and standards, and increasing environmental performance were the main drivers for ISO 14001 certification in both private and public organizations. Commitment to sustainability was more important for public organizations. Cost reduction, competitors, leadership commitment and customers' demands were shared drivers, but more stressed by private organizations. Local community and employees' pressures were reported by private organizations only. The challenges to ISO 14001 implementation were similar for private and public organizations. They were: a lack of qualified human resources, practical challenges associated with implementation, a lack of regulations, a lack of support from management, and high costs. Our findings have implications for managers, academics, consultants, and policy makers in the UAE and other emerging markets. PMID- 29134262 TI - Evaluating Use of Environmental Flows to Aerate Streams by Modelling the Counterfactual Case. AB - This paper evaluates an experimental environmental flow manipulation by modeling the counterfactual case that no environmental flow was applied. This is an alternate approach to evaluating the effect of an environmental flow intervention when a before-after or control-impact comparison is not possible. In this case, the flow manipulation is a minimum flow designed to prevent hypoxia in a weir on the low-gradient Broken Creek in south-eastern Australia. At low flows, low reaeration rates and high respiration rates associated with elevated organic matter loading in the weir pool can lead to a decline in dissolved oxygen concentrations with adverse consequences both for water chemistry and aquatic biota. Using a one dimensional oxygen balance model fitted to field measurements, this paper demonstrates that increased flow leads to increases in reaeration rates, presumably because of enhanced turbulence and hence mixing in the surface layers. By comparing the observed dissolved oxygen levels with the modeled counterfactual case, we show that the environmental flow was effective in preventing hypoxia. PMID- 29134263 TI - Diminished Susceptibility of African-Americans to Non-tuberculous Mycobacterial Disease. AB - The incidence of three granulomatous response diseases-sarcoidosis, tuberculosis, and non-tuberculous mycobacterial pulmonary disease-differ markedly in African Americans versus Caucasians. In reviewing a large compendium of non-cystic fibrosis bronchiectasis, we noted that complicating infection with non tuberculous mycobacteria was relatively infrequent among individuals of African American descent, confirming previous observations of their inherent resistance. Disease-specific variance among African-Americans in the efficacy of their granulomatous response suggests a nexus, a mediating, immunological mechanism. Environmentally conditioned selection of SLC11A1 (Nramp1) alleles may account for this ethnic variance. PMID- 29134264 TI - Oxygen Desaturation in Daily Life and During a Laboratory-Based Protocol of Activities of Daily Living in COPD: Is There Relationship? AB - PURPOSE: To analyze the relationship between oxygen desaturation episodes during a laboratory-based ADL protocol and in real-life routine in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: Twenty patients with stable COPD (12 men, 70 +/- 7 years, FEV1% 54 +/- 15 predicted) with no indication for long-term oxygen therapy (LTOT) were submitted to assessments including ADL performance by the Londrina ADL Protocol (LAP) and level of physical activity in daily life, both while submitted to simultaneous activity and pulse oximeter monitoring. RESULTS: Episodes of desaturation >= 4% (ED >= 4%) during the LAP were correlated both with ED >= 4% in daily life (r = 0.45) and number of episodes of SpO2 under 88% (ED < 88%) in daily life (r = 0.59). ED < 88% during the LAP was also correlated with ED < 88% in daily life (r = 0.51), explaining 43% of its variance. CONCLUSION: In stable patients with COPD and no indication of LTOT, episodes of desaturation during a lab-based ADL protocol are moderately related to episodes of desaturation in daily (real) life, especially those episodes under 88%. PMID- 29134266 TI - Laryngopharyngeal reflux disease in the elderly. PMID- 29134265 TI - Deletion of the beta-Propeller Protein Gene Rv1057 Reduces ESAT-6 Secretion and Intracellular Growth of Mycobacterium tuberculosis. AB - Rv1057 is the only beta-propeller protein in Mycobacterium tuberculosis, but its biological function is still unclear. In this study, we generated a deletion mutant of Rv1057 (D1057) in the virulent M. tuberculosis strain H37Rv and examined the characteristics of the mutant in vitro and in macrophages. We found that deletion of Rv1057 reduces secretion of the major virulence factor ESAT-6 and ESAT-6 stops in the cell envelope fraction during secretion, although ESAT-6 levels were similar in lysates of the mutant and control strains. In infected macrophages, Rv1057 deletion significantly reduced the secretion levels of cytokines IL-1beta, IL-10, TNF-alpha, and INF-gamma, but did not affect IL-4 and IL-8. D1057-infected macrophages also release less LDH and produce more nitric oxide (NO) than H37Rv- and D1057com (Rv1057 complemented strain of D1057com) infected macrophages, indicating that D1057 has the decreased cytotoxicity compared to H37Rv or D1057com. In addition, the capacity of the Rv1057 deletion mutant to grow in macrophages was significantly lower than that of H37Rv and D1057com. Our findings support a role for Rv1057 in ESAT-6 secretion and in modulating the interactions between M. tuberculosis and macrophages. PMID- 29134267 TI - Complement in the pathogenesis of Alzheimer's disease. AB - The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimer's disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimer's disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain. PMID- 29134270 TI - Waclaw Blaise Orlowsky and his unacknowledged discovery in neurology. PMID- 29134268 TI - Clinical significance of transluminal attenuation gradient in 320-row area detector coronary CT angiography. AB - The clinical significance of the transluminal attenuation gradient (TAG) has not been established. We evaluated the incremental diagnostic value of TAG by 320-row area detector computed tomography (320-ADCT). Subjects were 65 patients who underwent one-rotation scanning by 320-ADCT and invasive coronary angiography (ICA) within 3 months. TAG values were obtained for the major epicardial vessels 2 mm or more each in RCA, LAD and LCX using automatic analysis software. Moreover, TAG values that excluded calcified lesions in calculation of the regression line were also evaluated (excluded-TAG). In LAD, 21 intermediate lesions underwent functional flow reserve (FFR), and the incremental diagnostic value for functional stenosis was evaluated. The TAG values in the normal vessels were - 8.3 +/- 5.0 (HU/cm) for the RCA (n = 32), - 23.3 +/- 4.3 for the LAD (n = 9) and - 20.6 +/- 10.0 for the LCX (n = 32). The RCA value was significantly higher (p < 0.001). The TAG values with stenosis degrees of <= 25%, 26-75%, >= 76% on ICA were - 8.3 +/- 5.0 (n = 32) vs - 10.3 +/- 7.2 (n = 25) vs - 10.0 +/- 5.4 (n = 4) in the RCA, - 23.3 +/- 4.3 (n = 9) vs - 21.0 +/- 11.5 (n = 35) vs - 23.5 +/- 15.3 (n = 10) in the LAD and - 21.1 +/- 15.1 (n = 32) vs - 21.1 +/- 15.1 (n = 16) vs - 17.7 +/- 15.7 (n = 6) in the LCX, with no significant difference among the three groups. The excluded-TAG values also showed no significant difference. The area under the curve in the diagnosis of FFR < 0.8 in 21 LAD cases was 0.542 for CT only, 0.694 for CT + TAG, and 0.694 for CT + excluded-TAG. In single time-phase scanning by 320-ADCT, TAG does not offer an incremental diagnostic value. PMID- 29134269 TI - Sclerosing mesenteritis as a presentation of myelodysplastic syndrome (MDS) with improvement following treatment targeted at MDS. PMID- 29134271 TI - Safety of pregnancy after cerebral venous thrombosis: systematic review update. PMID- 29134272 TI - CXCL13 as a diagnostic marker of neuroborreliosis and other neuroinflammatory disorders in an unselected group of patients. AB - BACKGROUND: The C-X-C motif chemokine ligand 13 (CXCL13) and its receptor CXCR5 play an important role in the homing of B-lymphocytes. As a biomarker in the cerebrospinal fluid (CSF), CXCL13 has increasingly been used for the diagnosis of neuroborreliosis (NB). We evaluated the diagnostic and prognostic potential of CXCL13 for NB and other neuroinflammatory diseases in an unselected cohort, paying attention to those patients particularly who might benefit from newly emerging CXCL13-directed therapies. METHODS: We report the CSF CXCL13 concentrations and other relevant baseline characteristics for an unselected cohort of 459 patients. We compare different diagnostic groups and analyse the sensitivity and specificity of CSF CXCL13 as a marker of NB. The course of the CXCL13 concentrations is reported in a subgroup of 19 patients. RESULTS: We confirm the high diagnostic yield of CXCL13 for NB in this unselected cohort. The optimal cut-off for the reliable diagnosis of NB was 93.83 pg/ml, resulting in a sensitivity and specificity of 95 and 97%, respectively (positive predictive value 55.9%, negative predictive value 99.8%), surpassing the sensitivity of both serological testing and PCR. CSF CXCL13 concentration showed a swift response to therapy. Non-NB patients with high CSF CXCL13 concentrations suffered from meningeosis neoplastica or infectious encephalitis. CONCLUSIONS: CXCL13 is a valuable tool for the diagnosis and assessment of therapeutic response in NB. Furthermore, our data point towards an emerging role of CXCL13 in the diagnosis and prognosis of viral encephalitis and meningeosis neoplastica. These results are of particular interest in the light of recently developed approaches to CXCL13-directed therapeutic interventions. PMID- 29134273 TI - O Cdc7 kinase where art thou? AB - Although Cdc7 protein kinase is important for regulating DNA replication in all eukaryotes and is a target for cancer therapy, it has never been localized in cells. Recently, a novel molecular genomic method used by our laboratory to localize Cdc7 to regions of chromosomes. Originally, mutations in the CDC7 gene were found in the classic cdc mutant collection of Hartwell et al. (Genetics 74:267-286, 1973). The CDC7 gene was found to encode a protein kinase called DDK that has been studied for many years, establishing its precise role in the initiation of DNA replication at origins. Recently, clinical studies are underway with DDK inhibitors against DDK in cancer patients. However, the conundrum is that Cdc7 has never been detected at origins of replication even though many studies have suggested it should be there. We used "Calling Card" system in which DNA binding proteins are localized to the genome via retrotransposon insertion and deep-sequencing methods. We have shown that Cdc7 localizes at many regions of the genome and was enriched at functional origins of replication. These results are consistent with DDK's role in many additional genomic processes including mutagenesis, chromatid cohesion, and meiotic recombination. Thus, the main conclusion from our studies is that Cdc7 kinase is found at many locations in the genome, but is enriched at functional origins of replication. Furthermore, we propose that application of the Calling Card system to other eukaryotes should be useful in identification of functional origins in other eukaryotic cells. PMID- 29134274 TI - Harvest of lymph nodes in colorectal cancer depends on demographic and clinical characteristics of the patients. AB - PURPOSE: This study aims to study the impact of clinical factors on the lymph node sampling in a large cohort of patients with colorectal cancer. METHODS: A colorectal cancer database of 2298 patients in Queensland, Australia, was established. Zero-inflated regression method was used to model positive lymph node counts given the number of lymph nodes examined, with patient's demographic and clinical factors as covariates in the model. Sensitivity and survival analyses were performed to illustrate the applicability of the recommendation of the minimum number of lymph nodes need to be pathologically examined. RESULTS: Younger patients with a larger sized tumour located at the left colon or rectum require fewer lymph nodes to be pathologically examined. Overall, 45.9% of the patients require eight or nine lymph nodes and 31.5% needs ten or 11 lymph nodes to be harvested for pathological examination. A simple formula could be used to obtain the minimum number of lymph node sampling required in patients with colorectal cancer based on patients' age as well as site and dimension of the cancer. CONCLUSIONS: The findings provide practical information about that the minimum number of lymph nodes that could be harvested at the time of collection of lymph nodes for pathological examination for patients with colorectal cancer. The minimum number of lymph nodes harvested depends on demographic (age) and clinical (location and dimension of cancer) characteristics of the patients with colorectal cancer. PMID- 29134275 TI - [Blepharitis component of dry eye syndrome]. AB - This review contains a compilation of long-standing and more recent relevant information on chronic blepharitis, especially in the context of dry eye disease regarding epidemiology, symptoms, clinical findings and pathophysiology. Chronic blepharitis often represents the underlying cause of dry eye disease but remains undetected and untreated in many cases; however, it can be a result of (hypovolemic) dry eye disease and leads to sometimes severe corneal complications, which are illustrated by material from our own patient archives. Recent findings regarding the lipid composition in the tear film in correlation with that of Meibomian gland secretions and the hypothesis of a biofilm as the basis of chronic blepharitis as a theoretical, not yet proven addition to the previously known pathophysiological factors, are discussed. PMID- 29134276 TI - [Novel current and future therapy options for treatment of dry eye disease]. AB - Dry eye disease was redefined by the dry eye workshop (DEWS II) in May 2017. According to the new definition "dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms". The current definition encompasses etiological factors, such as instability and hyperosmolarity of the tear film, ocular surface inflammation and damage as well as a new aspect compared to the former definition, neurosensory abnormalities. Recent and future therapeutic options for dry eye focus on treatment of the aforementioned pathogenetic events. New tear substitutes, medications and devices to stimulate tear production, innovative anti-inflammatory treatment, medications to influence corneal innervation and new methods for treatment of Meibomian gland dysfunction are already available or will be available in the near future. PMID- 29134277 TI - Should mini percutaneous nephrolithotomy (MiniPNL/Miniperc) be the ideal tract for medium-sized renal calculi (15-30 mm)? AB - INTRODUCTION: Reducing the percutaneous nephrolithotomy (PCNL) tract size reduces the morbidity associated with the procedure. Prolonged procedure time is a concern. Modification in technique required is to fragment the stone into smaller particles and remove them using the vacuum cleaner effect. This prospective study compares the efficacy and morbidity of reducing the tract size from the standard 24-16.5 Fr for stones sized from 16 to 30 mm. METHODS: 123 patients were enrolled in this prospective study and distributed into 2 groups based on the tract size used (group A 16.5/17.5 Fr Miniperc, N = 61 and group B: 22/24 Fr standard PCNL, N = 62). Critical factors assessed were procedure time, fluoroscopy time, blood loss, pain score, stone clearance status and complications. RESULTS: Both the groups were comparable with respect to age, creatinine and stone size. The blood loss (hemoglobin and PCV drop) was significantly less for group A (p < 0.001). Both the groups were comparable with regards to the pain score (p > 0.05). Nephrostomy was placed in 3 patients in group A and 14 patients in group B (p = 0.01). There was no significant difference in the procedure time amongst the 2 groups. A total of 9 patients (4 in group A and 5 in group B) had residual fragments greater than 3 mm. CONCLUSION: The 16.5 Fr Miniperc tract offers lower morbidity in terms of blood loss and maintains stone clearance comparable to larger 24 Fr tract size. It should be the ideal size used for medium sized renal stones. PMID- 29134278 TI - Management of biochemically recurrent prostate cancer: molecular imaging perspective. PMID- 29134279 TI - Dietary K+ and Cl- independently regulate basolateral conductance in principal and intercalated cells of the collecting duct. AB - The renal collecting duct contains two distinct cell types, principal and intercalated cells, expressing potassium Kir4.1/5.1 (KCNJ10/16) and chloride ClC K2 (ClC-Kb in humans) channels on their basolateral membrane, respectively. Both channels are thought to play important roles in controlling systemic water electrolyte balance and blood pressure. However, little is known about mechanisms regulating activity of Kir4.1/5.1 and ClC-K2/b. Here, we employed patch clamp analysis at the single channel and whole cell levels in freshly isolated mouse collecting ducts to investigate regulation of Kir4.1/5.1 and ClC-K2/b by dietary K+ and Cl- intake. Treatment of mice with high K+ and high Cl- diet (6% K+, 5% Cl ) for 1 week significantly increased basolateral K+-selective current, single channel Kir4.1/5.1 activity and induced hyperpolarization of basolateral membrane potential in principal cells when compared to values in mice on a regular diet (0.9% K+, 0.5% Cl-). In contrast, basolateral Cl--selective current and single channel ClC-K2/b activity was markedly decreased in intercalated cells under this condition. Substitution of dietary K+ to Na+ in the presence of high Cl- exerted a similar inhibiting action of ClC-K2/b suggesting that the channel is sensitive to variations in dietary Cl- per se. Cl--sensitive with-no-lysine kinase (WNK) cascade has been recently proposed to orchestrate electrolyte transport in the distal tubule during variations of dietary K+. However, co-expression of WNK1 or its major downstream effector Ste20-related proline-alanine-rich kinase (SPAK) had no effect on ClC-Kb over-expressed in Chinese hamster ovary (CHO) cells. Treatment of mice with high K+ diet without concomitant elevations in dietary Cl- (6% K+, 0.5% Cl-) elicited a comparable increase in basolateral K+-selective current, single channel Kir4.1/5.1 activity in principal cells, but had no significant effect on ClC-K2/b activity in intercalated cells. Furthermore, stimulation of aldosterone signaling by Deoxycorticosterone acetate (DOCA) recapitulated the stimulatory actions of high K+ intake on Kir4.1/5.1 channels in principal cells but was ineffective to alter ClC-K2/b activity and basolateral Cl conductance in intercalated cells. In summary, we report that variations of dietary K+ and Cl- independently regulate basolateral potassium and chloride conductance in principal and intercalated cells. We propose that such discrete mechanism might contribute to fine-tuning of urinary excretion of electrolytes depending on dietary intake. PMID- 29134281 TI - Anticipating cognitive effort: roles of perceived error-likelihood and time demands. AB - Why are some actions evaluated as effortful? In the present set of experiments we address this question by examining individuals' perception of effort when faced with a trade-off between two putative cognitive costs: how much time a task takes vs. how error-prone it is. Specifically, we were interested in whether individuals anticipate engaging in a small amount of hard work (i.e., low time requirement, but high error-likelihood) vs. a large amount of easy work (i.e., high time requirement, but low error-likelihood) as being more effortful. In between-subject designs, Experiments 1 through 3 demonstrated that individuals anticipate options that are high in perceived error-likelihood (yet less time consuming) as more effortful than options that are perceived to be more time consuming (yet low in error-likelihood). Further, when asked to evaluate which of the two tasks was (a) more effortful, (b) more error-prone, and (c) more time consuming, effort-based and error-based choices closely tracked one another, but this was not the case for time-based choices. Utilizing a within-subject design, Experiment 4 demonstrated overall similar pattern of judgments as Experiments 1 through 3. However, both judgments of error-likelihood and time demand similarly predicted effort judgments. Results are discussed within the context of extant accounts of cognitive control, with considerations of how error-likelihood and time demands may independently and conjunctively factor into judgments of cognitive effort. PMID- 29134280 TI - Delayed response after repeated 177Lu-PSMA-617 radioligand therapy in patients with metastatic castration resistant prostate cancer. AB - PURPOSE: Radioligand therapy (RLT) using Lutetium-177 labeled PSMA-617 (Lu-PSMA) ligand is a new therapeutic option for salvage therapy in heavily pretreated patients with metastatic castration resistant prostate cancer. The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu PSMA. METHODS: Seventy-one patients (median age: 72 years; range 44-87) received 3 cycles of RLT with Lu-PSMA (mean administered activity: 6.016 +/- 0.543 GBq) every 8 weeks. Response was evaluated using serum PSA levels and a PSA decline >=50% was considered as biochemical response. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle. RESULTS: A total of 213 cycles were performed in 71 patients. Data for response and adverse events were available for all patients. A PSA decline >=50% and some PSA decline occurred in 56% and 66% of the patients. Of 30 patients with a PSA response after the first cycle, 28 remained responders and 12/41 of non-responders responded to further therapy cycles. CONCLUSION: RLT with Lu-177-PSMA-617 shows respectable response rates. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy. PMID- 29134282 TI - ABA and IAA control microsporogenesis in Petunia hybrida L. AB - The formation of fertile male gametophyte is known to require timely degeneration of polyfunctional tapetum tissue. The last process caused by the programmed cell death (PCD) is a part of the anther program maturation which leads to sequential anther tissue destruction coordinated with pollen differentiation. In the present work, distribution of abscisic acid (ABA) and indole-3-acetic acid (IAA) in developing anthers of male-fertile and male-sterile lines of petunia (Petunia hybrida L.) was analyzed by using the immunohistochemical method. It was established that the development of fertile male gametophyte was accompanied by monotonous elevation of ABA and IAA levels in reproductive cells and, in contrast, their monotonous lowering in tapetum cells and the middle layers. Abortion of microsporocytes in the meiosis prophase in the sterile line caused by premature tapetum degeneration along with complete maintenance of the middle layers was accompanied by dramatic, twofold elevation in the levels of both the phytohormones in reproductive cells. The data obtained allowed us to conclude that at the meiosis stage ABA and IAA are involved in the PCD of microsporocytes. PMID- 29134283 TI - Investigation of the relation between bone mass density and serum preptin levels in pre- and postmenopausal women. AB - Preptin is a peptide hormone co-secreted with insulin and amylin from pancreatic beta cells. It has been demonstrated to have osteogenic effects both in vitro and in vivo. In the present study, serum preptin levels were measured in pre- and postmenopausal women with similar body mass indexes (BMIs) to elucidate its link with bone mineral density (BMD). Sixty women (30 premenopausal and 30 postmenopausal) with low bone mineral density were studied. The BMD scores, serum preptin levels and serum estradiol levels were measured. The correlation between serum preptin and estradiol levels with BMD was assessed. Serum preptin and estradiol levels were significantly lower in the postmenopausal women than the premenopausal subjects [2102.27 +/- 918.66 vs. 2667.30 +/- 940.41 ng/L (P < 0.05) and 39.32 +/- 31.74 vs. 99.24 +/- 49.24 pg/ml (P < 0.001), respectively]. The serum preptin levels had weak positive (albeit statistically significant) correlations with estradiol (r = 0.271, P = 0.036), femur neck BMD (r = 0.233, P = 0.035) and total hip BMD (r = 0.287, P = 0.031), but no correlation was observed between serum preptin levels and L1-4 lumbar spine BMD (r = 0.136, P = 0.474). The findings of the present study suggest that serum preptin levels in women decrease after menopause and have a positive correlation with estradiol, femoral and total hip BMDs. PMID- 29134284 TI - Comments on Sulimani et al.: A weekly 35,000 IU vitamin D supplementation improves bone turnover markers in vitamin D deficient Saudi adolescent females. PMID- 29134285 TI - Impact of variations in duodenal glucose load on insulin clearance in health and type 2 diabetes. PMID- 29134286 TI - Proteomic and metabolomic characterization of streptozotocin-induced diabetic nephropathy in TIMP3-deficient mice. AB - AIMS: The tissue inhibitor of metalloproteinase TIMP3 is a stromal protein that restrains the activity of both protease and receptor in the extracellular matrix and has been found to be down-regulated in diabetic nephropathy (DN), the leading cause of end-stage renal disease in developed countries. METHODS: In order to gain deeper insights on the association of loss of TIMP3 and DN, we performed differential proteomic analysis of kidney and blood metabolic profiling of wild type and Timp3-knockout mice before and after streptozotocin (STZ) treatment, widely used to induce insulin deficiency and hyperglycemia. RESULTS: Kidney proteomic data and blood metabolic profiles suggest significant alterations of peroxisomal and mitochondrial fatty acids beta-oxidation in Timp3-knockout mice compared to wild-type mice under basal condition. These alterations were exacerbated in response to STZ treatment. CONCLUSIONS: Proteomic and metabolomic approaches showed that loss of TIMP3 alone or in combination with STZ treatment results in significant alterations of kidney lipid metabolism and peripheral acylcarnitine levels, supporting the idea that loss of TIMP3 may generate a phenotype more prone to DN. PMID- 29134287 TI - Particulate matter levels in a South American megacity: the metropolitan area of Lima-Callao, Peru. AB - The temporal and spatial trends in the variability of PM10 and PM2.5 from 2010 to 2015 in the metropolitan area of Lima-Callao, Peru, are studied and interpreted in this work. The mean annual concentrations of PM10 and PM2.5 have ranges (averages) of 133-45 MUg m-3 (84 MUg m-3) and 35-16 MUg m-3 (26 MUg m-3) for the monitoring sites under study. In general, the highest annual concentrations are observed in the eastern part of the city, which is a result of the pattern of persistent local winds entering from the coast in a south-southwest direction. Seasonal fluctuations in the particulate matter (PM) concentrations are observed; these can be explained by subsidence thermal inversion. There is also a daytime pattern that corresponds to the peak traffic of a total of 9 million trips a day. The PM2.5 value is approximately 40% of the PM10 value. This proportion can be explained by PM10 re-suspension due to weather conditions. The long-term trends based on the Theil-Sen estimator reveal decreasing PM10 concentrations on the order of -4.3 and -5.3% year-1 at two stations. For the other stations, no significant trend is observed. The metropolitan area of Lima-Callao is ranked 12th and 16th in terms of PM10 and PM2.5, respectively, out of 39 megacities. The annual World Health Organization thresholds and national air quality standards are exceeded. A large fraction of the Lima population is exposed to PM concentrations that exceed protection thresholds. Hence, the development of pollution control and reduction measures is paramount. PMID- 29134290 TI - Re-emergence of Lilium callosum Sieb. et Zucc. in Taiwan after a fire allows propagation and renews the possibility of conservation. AB - BACKGROUND: Lilium callosum is native to Taiwan, but little is known about it since it has been considered extinct since 1915. After the rediscovery of this rare species after a fire in 2011 in Tunghsiao Township, intensive work has been conducted to count the number in the wild population, to develop a conservation strategy, and to understand its reproductive characteristics and even economic potential. RESULTS: To conserve the germplasm of this population, three scales from a wild L. callosum plant were collected to establish a mass propagation system. Flowers from two regenerated plants were crossed by hand-pollination, the ovules were rescued and cultured in vitro, and 10 offspring were obtained. The karyotype was determined to be 2n = 2x = 24 = 2m + 2m(sat) + 2sm + 8st + 10t. The phylogenetic analysis using ITS sequences revealed that the sample of L. callosum from Taiwan was not grouped with the other accessions of L. callosum from other regions. The native habitat is classified as grass-dominated vegetation at the early successional stage and a subtropical monsoon-type climate. To clarify the causes of population scarcity in the native environment, reproductive characteristics of regenerated plants were investigated. CONCLUSIONS: Based on the information from this study, it is possible that factors intrinsic to L. callosum could combine to limit pollination and seed formation. The L. callosum pollen only germinated at a temperature that was higher than the native environment, the plants are self-incompatibile, there was a and scarce population, scattered flowering time and dichogamy. Through the culture of these wild harvested parts, the diversity of the germplasm has been broadened and is now available to preserve this rare and valuable species for the future. PMID- 29134289 TI - Diversity of microbiota found in coffee processing wastewater treatment plant. AB - Cultivable microbiota presents in a coffee semi-dry processing wastewater treatment plant (WTP) was identified. Thirty-two operational taxonomic units (OTUs) were detected, these being 16 bacteria, 11 yeasts and 4 filamentous fungi. Bacteria dominated the microbial population (11.61 log CFU mL- 1), and presented the highest total diversity index when observed in the WTP aerobic stage (Shannon = 1.94 and Simpson = 0.81). The most frequent bacterial species were Enterobacter asburiae, Sphingobacterium griseoflavum, Chryseobacterium bovis, Serratia marcescens, Corynebacterium flavescens, Acetobacter orientalis and Acetobacter indonesiensis; these showed the largest total bacteria populations in the WTP, with approximately 10 log CFU mL- 1. Yeasts were present at 7 log CFU mL- 1 of viable cells, with Hanseniaspora uvarum, Wickerhamomyces anomalus, Torulaspora delbrueckii, Saturnispora gosingensis, and Kazachstania gamospora being the prevalent species. Filamentous fungi were found at 6 log CFU mL- 1, with Fusarium oxysporum the most populous species. The identified species have the potential to act as a biological treatment in the WTP, and the application of them for this purpose must be better studied. PMID- 29134288 TI - Task-relevant brain networks identified with simultaneous PET/MR imaging of metabolism and connectivity. AB - Except for task-specific functional MRI, the vast majority of imaging studies assessed human brain function at resting conditions. However, tracking task specific neuronal activity yields important insight how the brain responds to stimulation. We specifically investigated changes in glucose metabolism, functional connectivity and white matter microstructure during task performance using several recent methodological advancements. Opening the eyes and right finger tapping had elicited an increased glucose metabolism in primary visual and motor cortices, respectively. Furthermore, a decreased metabolism was observed in the regions of the default mode network, which allowed absolute quantification of commonly described deactivations during cognitive tasks. These brain regions showed widespread task-specific changes in functional connectivity, which stretched beyond their primary resting-state networks and presumably reflected the level of recruitment of certain brain regions for each task. Finally, the corresponding white matter fiber pathways exhibited changes in axial and radial diffusivity during the tasks, which were regionally distinctive for certain tract groups. These results highlight that even simple task performance leads to substantial changes of entire brain networks. Exploiting the complementary nature of the different imaging modalities may reveal novel insights how the brain processes external stimuli and which networks are involved in certain tasks. PMID- 29134291 TI - Local distribution of collagen fibers determines crack initiation site and its propagation direction during aortic rupture. AB - Although elucidation of the mechanism of aortic aneurysm rupture is important, the characteristics of crack initiation and propagation sites remain unknown. To determine the microscopic properties of these sites, the characteristics of local strains and constituents at crack initiation and propagation sites were investigated during biaxial stretching of porcine thoracic aortas (PTAs). PTAs were sliced into approximately 50-[Formula: see text]-thick sections, and the center of the sections was made especially thin using our previously developed technique. Alpha-elastin and cell nuclei were fluorescently labeled as indices of local elastin density and as a strain marker, respectively. Birefringence and second harmonic generation (SHG) light images were used to determine local collagen distributions. The specimens were then stretched biaxially with a laboratory-made tensile tester under a fluorescent microscope equipped with a birefringence imaging system. Local strains were calculated from the local displacement of the cell nuclei. The degree of alignment and density of local collagen fibers were measured from retardance and SHG images. The strain distributions, specifically the first and second principal, and maximum shear strains, fluorescent intensity of [Formula: see text]-elastin, and degree of alignment of collagen fibers, showed insignificant differences between the crack initiation sites and other sites. The retardance and intensity of SHG light at the crack initiation sites were significantly lower than those at other sites for all ([Formula: see text]) specimens. Cracks tended to propagate along the local direction of the collagen fibers. These results indicate that the local density and direction of collagen fibers play an important role in aorta rupture. PMID- 29134292 TI - Simultaneous determination of brazilin and protosappanin B in Caesalpinia sappan by ionic-liquid dispersive liquid-phase microextraction method combined with HPLC. AB - The conditions of heating, ionic liquid-based ultrasonic-assisted extraction combined with reverse-phase high performance liquid chromatography were optimized to simultaneously isolate and determinate brazilin and protosappanin B in Caesalpinia sappan. Ionic liquids, including [BMIM]Br, [BMIM]BF4, [BMIM]PF6 and [HMIM]PF6, were selected as extraction solvents while methanol, acetone, acetonitrile, ethanol and water were selected as dispersants. The chromatographic column was Purospher star RP-C18 (250 mm * 4.6 mm, 5 MUm), a mixture of methanol and 0.2% phosphoric acid-water was used as mobile phase at a flow rate 0.65 mL/min. The result displayed that the extraction yields of brazilin and protosappanin B were highest when the concentration of [BMIM]Br methanol solution as extraction solvent was 0.5 mol/L and the solid-liquid ratio was 1:50 (g/mL). Under the optimal extraction conditions, the contents of brazilin showed a good linearity (r = 1.0000) within the range of 1.25-7.50 MUg with the average recovery of 99.33%, the contents of protosappanin B also showed a good linearity (r = 0.9999) within the range of 0.50-3.00 MUg with the average recovery of 98.31%. This experiment, which adopted environmentally friendly reagent as extraction solvent, not only improved the extraction efficiency, but also avoided the environmental pollution caused by organic solvent. Moreover, it was simple and reliable, and can be of important significance in the study of Traditional Chinese Medicine active ingredient extraction methods. The antibacterial activities of the ionic liquids and methanol extracts were determined using the paper disc diffusion method. The ionic liquid extract was found to possess antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MIC value of 37.5 mg crude drug/mL), beta-Lactamase producing S. aureus (MIC values of 18.8 mg crude drug/mL), but not against E. coli, Extended spectrum beta-Lactamases E. coli and P. aeruginosa. Compared with the ionic liquid extract, the methanol extract was found to have antibacterial activity against S. aureus and methicillin-resistant S. aureus (MIC value of 75.0 mg crude drug/mL), beta-Lactamase producing S. aureus (MIC values of 150.0 mg crude drug/mL). However, the same, the methanol extract did not have antibacterial activity against E. coli, Extended spectrum beta-Lactamases E. coli and P. aeruginosa. PMID- 29134293 TI - Medicinal Foods for Functional GI Disorders. AB - PURPOSE OF REVIEW: Over the past 10 years, there has been a dramatic increase in basic and clinical research involving functional gastrointestinal disorders (FGIDs). New diagnostic and biomarker procedures are helping to identify physiologic disruptions associated with FGIDs on cellular and molecular levels. Simultaneously, clinicians are using new approaches to help manage patients with FGIDs. Among these, an important component of care has been the use of medical foods. These include probiotics, prebiotics, synbiotics, peppermint oil, caraway oil, curcumin, bovine immunoglobulin and many others. RECENT FINDINGS: The putative effects of different medical foods make these therapies attractive for the management of FGIDs. These include effects on several pathophysiological mechanisms such as anti-inflammatory, smooth muscle relaxation, analgesia, mitigation of gut barrier dysfunction, and stimulation or inhibition of gastrointestinal receptors. Recent research has also demonstrated the efficacy of medical food products such as peppermint oil and serum-derived bovine immunoglobulin for the management of irritable bowel syndrome. Older data supports the probiotic VSL#3 and Bifidobacterium species. For functional dyspepsia, positive effects have been observed with the combination of caraway seed oil and peppermint oil as well as with STW-5, a botanical combination preparation, although robust RCTs are lacking. With advancing knowledge regarding the pathogenesis of FGIDs, it is likely that the compounds available in the medical food category will increase dramatically, and they could play an important role in the management of several common and bothersome gastrointestinal conditions in the future. PMID- 29134294 TI - Destabilization of the Upright Posture Through Elevation of the Center of Mass. AB - The inverted pendulum model predicts that the major challenge for neural control of the upright posture is the inherent instability of the body due to the center of mass (COM) being above the base of support (BOS). If so, even slight elevation of the COM may substantially destabilize posture. The destabilizing effect of heavy load positioned above the COM has been demonstrated. We examined sensitivity of posture to light (1-5% of body weight) load by placing weights on the shoulders and assessing functional reach distance in the forward, right, and left directions and postural sway during quiet stance. At each load level, the quiet stance task was tested with and without vision. The 1% of body weight load significantly shortened reach distance in the forward direction. It also increased postural sway. Interestingly, additional weight did not result in further deficits. The results support high sensitivity of postural stability to COM elevation that increases the challenge for neural control of posture and that can potentially be used for early detection of declines in postural stability. PMID- 29134295 TI - Rod- versus cone-driven ERGs at different stimulus sizes in normal subjects and retinitis pigmentosa patients. AB - PURPOSE: To study how rod- and cone-driven responses depend on stimulus size in normal subjects and patients with retinitis pigmentosa (RP), and to show that comparisons between responses to full-field (FF) and smaller stimuli can be useful in diagnosing and monitoring disorders of the peripheral retina without the need for lengthy dark adaptation periods. METHOD: The triple silent substitution technique was used to isolate L-cone-, M-cone- and rod-driven ERGs with 19, 18 and 33% photoreceptor contrasts, respectively, under identical mean luminance conditions. Experiments were conducted on five normal subjects and three RP patients. ERGs on control subjects were recorded at nine different temporal frequencies (between 2 and 60 Hz) for five different stimulus sizes: FF, 70 degrees , 60 degrees , 50 degrees and 40 degrees diameter circular stimuli. Experiments on RP patients involved rod- and L-cone-driven ERG measurements with FF and 40 degrees stimuli at 8 and 48 Hz. Response amplitudes were defined as those of the first harmonic component after Fourier analysis. RESULTS: In normal subjects, rod-driven responses displayed a fundamentally different behavior than cone-driven responses, particularly at low temporal frequencies. At low and intermediate temporal frequencies (<= 12 Hz), rod-driven signals increased by a factor of about four when measured with smaller stimuli. In contrast, L- and M cone-driven responses in this frequency region did not change substantially with stimulus size. At high temporal frequencies (>= 24 Hz), both rod- and cone-driven response amplitudes decreased with decreasing stimulus size. Signals obtained from rod-isolating stimuli under these conditions are likely artefactual. Interestingly, in RP patients, both rod-driven and L-cone-driven ERGs were similar using 40 degrees and FF stimuli. CONCLUSION: The increased responses with smaller stimuli in normal subjects to rod-isolating stimuli indicate that a fundamentally different mechanism drives the ERGs in comparison with the cone driven responses. We propose that the increased responses are caused by stray light stimulating the peripheral retina, thereby allowing peripheral rod-driven function to be studied using the triple silent substitution technique at photopic luminances. The method is effective in studying impaired peripheral rod- and cone function in RP patients. PMID- 29134296 TI - P300-based acuity estimation in imitated amblyopia. AB - PURPOSE: A frequent approach to estimating visual acuity objectively is the recording of visual evoked potentials (VEPs) to patterns of different coarseness. This, however, overestimates acuity in patients with fragmented and distorted vision such as in amblyopia. This is likely due to VEP-based techniques using checkerboard or grating stimuli. We hypothesized that no overestimation would occur when the event-related potential P300 in response to optotype stimuli is used for acuity estimation. METHODS: In 29 visually normal participants, we recorded P300 responses to Landolt C optotypes of different sizes. Vision was artificially degraded by placing a patterned polymethyl methacrylate pane in front of the monitor, which resulted in fragmentation and distortion of the stimulus. As control, a frosted pane was used. Both panes were adjusted to yield the same reduction of acuity in a standard subjective acuity test. A difference of less than 0.1 log MAR was defined as criterion to judge the outcomes of the objective tests as equivalent for both types of artificial visual impairment. RESULTS: The average difference of P300-based objective acuity estimates between types of visual degradation was significantly smaller than 0.1 log MAR, indicating that the performance of the objective acuity test was equivalent for both types of visual degradation. CONCLUSION: Our data suggest that P300-based objective acuity testing with optotype stimuli is more akin to standard psychophysical acuity testing and thus a suitable approach in cases of visual impairment where VEP-based methods fail to yield reliable results. PMID- 29134297 TI - Community-Based Efforts to Prevent and Manage Diabetes in Women Living in Vulnerable Communities. AB - Social determinants of health likely play a significant role in the development of type 2 diabetes for women in vulnerable communities. Adult African American women diagnosed with or at-risk for diabetes in Inkster, Michigan (n = 113) and a group of demographically similar women in Flint, Michigan (n = 48) participated in programs aimed at increasing diabetes-related self-management behaviors through peer coaching, health literacy training, and social support. Participants completed surveys to measure changes in health, health behaviors, health literacy, and social support. We found that these diabetes programs with a focus on increasing women's capacity to practice health management behaviors, navigate the health care system, and connect with social support, led to an increase in healthy behaviors and a reported increase in both overall and diabetes-specific health over an 18 month period. Overall health, general diet and specific diet improved significantly (p < 0.05) from baseline to follow-up, when controlled for age, diabetes status and site. Exercise also improved, but the change was not statistically significant. Women who participated in the intervention changed health behaviors, and increased their sense of health literacy and social support. Improvement in women's access to and use of community preventive services, and the provision of outreach support using community health workers (CHWs) and peer mentorship was an integral part of creating these changes. Although this study found that a variety of diabetes prevention and management programs provided opportunities for positive health changes, findings also suggest that it is critical to address the burdens women from vulnerable communities face in order to participate in these programs. PMID- 29134298 TI - Case Report of Successful Medical Management of Progressive Gastric Band Penetration-to-Perforation After Band Insertion at Bariatric Surgery: Documentation by 12 Serial EGDs During 50 months of Observation. PMID- 29134299 TI - Fecal Transplantation for Treatment of Clostridium Difficile Infection in Elderly and Debilitated Patients. AB - BACKGROUND: Fecal microbiota transplantation (FMT) is a new technique recently introduced to treat recurrent Clostridium difficile infection (CDI). Little is known about the efficacy and risks of FMT in elderly and ill patients. AIM: To investigate FMT efficacy in ill and elderly patients compared to conventional treatment. METHODS: The study comprised two groups of patients between 2012 and 2016 with recurrent CDI at two medical centers in Israel. The study group received FMT and the controls conventional therapy. The primary end points were CDI recurrence, length of hospitalization, and short-term survival. RESULTS: Thirty-four patients altogether, (21 females, mean age 82 years) participated, 11 received FMT and 23 controls. Demographics and clinical characteristics were similar between the two groups. Comorbidity indexes, i.e., Charlson index was high in both groups. In the FMT group, 10/11 (90%) patients showed clinical improvement 3 days after initiating treatment compared to 9/23 (39%) in the control group, p = 0.02. Survival at 2 months did not differ between the groups (FMT 54%, Control 50%, p = 0.816), but mean survival in the FMT group was higher than in the control (12 vs. 4 months, respectively, p = 0.015). Two significant adverse events from the FMT group included suspected aspirations, both occurring during gastroscopy route of administration. CONCLUSIONS: FMT is effective for elderly and very ill patients. Safety is a concern, but is rare even in patients with much comorbidity. Colonoscopy may be the preferred route of FMT infusion. PMID- 29134300 TI - Freeze fracture: new avenues for the ultrastructural analysis of cells in vitro. AB - The ultrastructural analysis of biological membranes by freeze fracture has a 60 year tradition. In this review, we summarize the benefits of the freeze-fracture technique and review special structures analyzed by freeze fracture and by combined freeze-fracture replica immunogold labeling (FRIL) of cell cultures. In principle, every cellular membrane whether of cell suspensions, mono- or bilayers of cell cultures can be analyzed in freeze fracture. The combination of freeze fracture and immunogold labeling of the replica allows the ultrastructural identification of protein assemblies in combination with the molecular identification of their constituent proteins using specific antibodies. The analysis of fractured and labeled intramembrane particles enables determination of the arrangement and organization of proteins within the membrane due to the high resolution of the transmission electron microscope. Because of cell-specific ultrastructural features such as square arrays, identification of cell types can be performed in parallel. This review is aimed at presenting the possibilities of freeze fracture and FRIL in the high-resolution ultrastructural analysis of membrane proteins and their assembly in naive, transfected or otherwise treated cultured cells. At the interface of molecular approaches and morphology, the application of FRIL in genetically modified cells provides a novel and intriguing aspect for their analysis. PMID- 29134301 TI - Prostaglandin E2 receptor EP1 in healthy and diseased human endometrium. AB - Prostaglandin E2 (PGE2) is well described to be associated with both endometrial functions and disorders. The primary aim of this study was to explore the underlying mechanisms that affect the growth and function of endometrial epithelium and stroma by assessing the staining intensity of PGE2 receptors (EP) in healthy endometrium across the menstrual cycle and in pathological endometrium, such as ovarian endometriosis and endometrial cancer. We retrospectively analyzed the EPs staining intensity in human nonpregnant endometrium throughout the menstrual cycle by immunohistochemistry and further focused on EP1 (n = 42). The variation of EP1 was compared among healthy endometrium, ovarian endometriosis (n = 14), and endometrial cancer (n = 140) crosswise. EP1 presented cyclical changes with increased intensity in both epithelium and stroma during the proliferative phase. EP1 staining in the epithelium was increased in endometriotic tissue compared to healthy endometrium and tumor tissue, while in the stroma, the staining in the tumor was lower than that in both normal tissue and endometriosis. No significant differences in EP1 intensity were detected for histological, stage, grading, metastatic and recurrent subtypes in endometrial cancer. EP1 was also correlated with neither progression-free survival nor overall survival of patients with cancer. EP1 staining in progesterone receptor B (PRB)-positive tumor was stronger compared to PRB-negative tumor. EP1 may play a role in human endometrial physiology and pathology. Further studies on the effect of EP1 on human endometrium are needed. PMID- 29134303 TI - Comment on: Nomenclature in Ventral Hernia Repair. PMID- 29134302 TI - Nuclear organization during in vitro differentiation of porcine mesenchymal stem cells (MSCs) into adipocytes. AB - Differentiation of progenitor cells into adipocytes is accompanied by remarkable changes in cell morphology, cytoskeletal organization, and gene expression profile. Mature adipocytes are filled with a large lipid droplet and the nucleus tends to move to the cell periphery. It was hypothesized that the differentiation process is also associated with changes of nuclear organization. The aim of this study was to determine the number and distribution of selected components of nuclear architecture during porcine in vitro adipogenesis. The pig is an important animal model sharing many similarities to humans at the anatomical, physiological, and genetic levels and has been recognized as a good model for human obesity. Thus, understanding how cellular structures important for fundamental nuclear processes may be altered during adipocyte differentiation is of great importance. Mesenchymal stem cells (MSCs) were derived from bone marrow (BM-MSCs) and adipose tissue (AD-MSCs) and were cultured for 7 days in the adipogenic medium. A variable differentiation potential of these cell populations towards adipogenic lineage was observed, and for further study, a comparative characteristic of the nuclear organization in BM-MSCs and AD-MSCs was performed. Nuclear substructures were visualized by indirect immunofluorescence (nucleoli, nuclear speckles, PML bodies, lamins, and HP1alpha) or fluorescence in situ hybridization (telomeres) on fixed cells at 0, 3, 5, and 7 days of differentiation. Comprehensive characterization of these structures, in terms of their number, size, dynamics, and arrangement in three-dimensional space of the nucleus, was performed. It was found that during differentiation of porcine MSCs into adipocytes, changes of nuclear organization occurred and concerned: (1) the nuclear size and shape; (2) reduced lamin A/C expression; and (3) reorganization of chromocenters. Other elements of nuclear architecture such as nucleoli, SC-35 nuclear speckles, and telomeres showed no significant changes when compared to undifferentiated and mature fat cells. In addition, the presence of a low number of PML bodies was characteristic of the studied porcine mesenchymal stem cell adipogenesis system. It has been shown that the arrangement of selected components of nuclear architecture was very similar in MSCs derived from different sources, whereas adipocyte differentiation involves nuclear reorganization. This study adds new data on nuclear organization during adipogenesis using the pig as a model organism. PMID- 29134304 TI - Outcome of Thyroid Carcinoma Showing Thymus-Like Differentiation in Patients Undergoing Radical Resection. AB - BACKGROUND: Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignant tumor of the thyroid. It is difficult to diagnose, and there is no universally recognized therapeutic regimen. This study aims to define the clinicopathological features and discuss the optimal management of CASTLE. METHODS: We retrospectively analyzed six patients with CASTLE who accepted surgery at the First Hospital of China Medical University between January 2010 and December 2015. RESULTS: The six patients (three women and three men) had median age of 53 years (range 47-61 years). All patients presented with a slow growing, painless neck mass; three patients also had hoarseness. All tumors were located in middle-lower or lower lobe, and two tumors extended to the substernal region. All patients underwent radical surgery without postoperative radiotherapy or chemotherapy. Five patients had extrathyroidal extension and two had lymph node metastasis. All six tumors were positive for CD5 and negative for thyroglobulin (Tg) and thyroid transcription factor (TTF)-1. Median follow-up was 32 months (range 23-81 months). Lateral cervical lymph node metastasis occurred in one patient at 26 months after initial treatment. CONCLUSIONS: CASTLE is a rare, aggressive malignant tumor of the thyroid. Ultrasound, computed tomography, and fine-needle aspiration biopsy may not be sufficient to establish the diagnosis preoperatively; pathological examination and immunohistochemistry, particularly positive CD5 staining, are necessary to establish the diagnosis. Patients with CASTLE can yield a favorable outcome after radical surgery. PMID- 29134305 TI - Response to Letter to the Editor, Regarding Hardcastle TC, Muckart DJJ, Maier RV. Ventilation in Trauma Patients: The First 24 h is Different! World Journal of Surgery 2017;41(5):1153-1158. PMID- 29134306 TI - Suitable Ultrasonographic Approach to Assessing Vocal Cord Movement: Reply. PMID- 29134307 TI - Objective Evaluation of Gastroesophageal Reflux Disease in Patients with Paroxysmal Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Some evidence shows that gastroesophageal reflux disease (GERD) may be a trigger for paroxysmal AF (PAF). Most of the previous studies that correlated GERD and AF used questionnaires to diagnose GERD, not an objective evaluation. This study aims to evaluate in patients with PAF: (a) accuracy of symptoms to diagnose GERD; (b) prevalence of GERD; and (c) temporal correlation between cardiac arrhythmia and reflux. METHODS: Twenty-two patients (59% females, mean age 68 years) with PAF underwent esophageal manometry followed by ambulatory pH monitoring and concurrent Holter. Eight (36%) patients had GERD symptoms. Patients were grouped as GERD+ or GERD- based on the DeMeester score. Temporal correlation between arrhythmia and reflux was recorded. RESULTS: Six (27%) patients were GERD+. Symptoms had sensitivity and specificity of 50 and 70%, respectively, for the diagnosis of GERD. Episodic AF occurred in one patient only (GERD-). There were 23 episodes of AF during the test with 14% correlation with reflux. Persistent AF during the period of the test was found in five patients (60% GERD+). CONCLUSIONS: Our results show: (a) Symptoms have a low accuracy for the diagnosis of GERD; (b) the prevalence of GERD in patients with PAF is low; and PMID- 29134309 TI - The Physician Attrition Crisis: A Cross-Sectional Survey of the Risk Factors for Reduced Job Satisfaction among US Surgeons. PMID- 29134308 TI - Appendicitis: Rural Patient Status is Associated with Increased Duration of Prehospital Symptoms and Worse Outcomes in High- and Low-Middle-Income Countries. AB - INTRODUCTION: Appendicitis is a significant economic and healthcare burden in low , middle-, and high-income countries. We aimed to determine whether urban and rural patient status would affect outcomes in appendicitis in a combined population regardless of country of economic status. We hypothesize that patients from rural areas and both high- and low-middle-income countries would have disproportionate outcomes and duration of symptoms compared to their urban counterparts. METHODS: Adults (>=18 years) with appendicitis during 2010-2016 in South Africa and USA were reviewed using multi-institutional data. Baseline demographic, operative details, durations of stay, and complications (Clavien Dindo index) were collected. AAST grades were assigned by two independent reviewers based on operative findings. Summary, univariate, and multivariable analyses of rural and urban patients in both countries were performed. RESULTS: There were 2602 patients with a median interquartile range [IQR] of 26 [18-40] years; 45% were female. Initial management included McBurney incisions (n = 458, 18%), laparotomy (n = 915, 35%), laparoscopic appendectomy (n = 1185, 45%), and laparoscopy converted to laparotomy (n = 44, 2%). Comparing rural versus urban patient status, there were increased overall median [IQR] AAST grades (3 [1-5] vs. 2 [1-3], p = 0.001), prehospital duration of symptoms (2 [1-5] vs. 2 [1-3], p = 0.001), complications (44.3 vs. 23%, p = 0.001), and need for temporary abdominal closure (20.3 vs. 6.9%, p = 0.001). CONCLUSION: Despite socioeconomic status and country of origin, patients from more rural environments demonstrate poorer outcomes notwithstanding significant differences in overall disease severity. The AAST grading system may serve a potential benchmark to recognize areas with disparate disease burdens. This information could be used for strategic improvements for surgeon placement and availability. PMID- 29134311 TI - Important Research Elements in Aiding Training. PMID- 29134310 TI - Comparison of Surgical Outcomes Between Robotic and Laparoscopic Distal Gastrectomy for cT1 Gastric Cancer. AB - BACKGROUND: Increasing numbers of patients are treated by robotic distal gastrectomy (RDG); however, it remains unclear whether RDG is clinically comparable with conventional laparoscopic distal gastrectomy (LDG). This study aimed to clarify the feasibility of RDG from safety aspects. METHODS: The study included 109 cT1 gastric cancer patients who underwent RDG at Shizuoka Cancer Center from January 2012 to April 2015. Short-term outcomes were compared with 160 cT1 gastric cancer patients who underwent LDG during the same period. RESULTS: Patient characteristics were well matched. The RDG patients experienced longer operative times (323 min) than LDG patients (285 min; P < 0.001), although all other surgical outcomes were comparable between the groups. Drain amylase levels on POD 1 were significantly lower in the RDG group compared to LDG cases (median 452 U/L and 892 U/L; P < 0.001). The incidence of all complications was similar across the study patients, although intra-abdominal infectious complications tended to be lower in the RDG group than in the LDG group (2.8 and 8.1%; P = 0.112). CONCLUSIONS: RDG was comparable to LDG in terms of feasibility for cT1 gastric cancer. RDG has the potential to reduce pancreas damage and thus to decrease intra-abdominal infectious complications. PMID- 29134312 TI - Refining the Definitions of Biochemical and Clinical Cure for Primary Aldosteronism Using the Primary Aldosteronism Surgical Outcome (PASO) Classification System. AB - INTRODUCTION: Determination of outcomes after adrenalectomy for primary aldosteronism (PA) is limited by the lack of standardized definitions of cure. The Primary Aldosteronism Surgical Outcomes (PASO) group recently established new consensus definitions for biochemical and clinical cure of PA. We hypothesize that utilization of PASO definitions will better stratify patient outcomes after surgery compared to original and current criteria utilized to document cure. MATERIALS AND METHODS: Patients undergoing adrenalectomy for PA from 1996 to 2016 were studied. Clinical data were reviewed. Three different sets of criteria (original, current, and PASO) were evaluated for differences in documentation of cure. Demographic data were reported as median (range). Comparisons were made using the Mann-Whitney U test; p < 0.05 is significant. RESULTS: A total of 314 patients with PA were identified. Ninety patients (60 males) elected to proceed with surgery. In Group 1 (35 patients), 30 patients had clinical follow-up and 29 (97%) were cured using original criteria. In Group 2 (55 patients), cure was recorded in 98% when original criteria for cure were applied, 89% cured applying current criteria, and 6% had complete biochemical and clinical cure by PASO criteria. Aldosterone rose 3.6 ng/dL (0.1-34.8) in five patients during extended follow-up, with two patients changing from complete to partial or missing biochemical success. CONCLUSION: Significant heterogeneity exists in outcomes criteria utilized to document cure or clinical improvement after adrenalectomy for primary aldosteronism. Aldosterone levels change over time after adrenalectomy. PASO definitions of cure appear to allow for improved stratification of short- and long-term outcomes. PMID- 29134313 TI - Long-Term Outcome After Surgery for Medullary Thyroid Carcinoma: A Single-Center Experience. AB - BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare C cells-derived tumor, with a hardly predictable long-term prognosis. This study was aimed to evaluate the predictive factors of cure and survival after surgery for MTC in a monocentric series. METHODS: A retrospective analysis of the long-term outcomes was assessed in 255 MTC patients operated between 1980 and 2015 at Padua University hospital. RESULTS: Sporadic MTC occurred in 65.1% and hereditary MTC in 34.9% of patients. At a median follow-up of 93 months (range 7-430), the cure rate was 56.8%. The overall 10-year survival was 84.4%, and MTC-related death rate was 15.3%. Patients who died because of MTC had a median age of 61 years (range 21-84) and were at stages III-IV in all cases; deaths occurred in 18% of sporadic MTC, 6% of MEN2a and 66.7% of MEN2b patients. None of the patients at stages I-II died because of the disease, but 17.7% had persistent/recurrent disease. Based on univariate analysis, age, gender, genetic variant, extent and year of surgery, tumor size, lymph-nodal metastases and tumor stage significantly affected cure and survival rates. At multivariate analysis, only patient- and tumor-related features (age, lymph-nodal status and stage) remained significant independent prognostic factors. CONCLUSIONS: Radical surgery is the only chance of definitive cure in MTC, but it is possible only at early stage; in advanced stages, even extensive surgery could not grant cure and prolonged survival. Stage, nodal metastases and age remain the main predictive factors for cure and survival. PMID- 29134314 TI - Surgery for Primary Hyperparathyroidism with Normal Non-suppressed Parathyroid Hormone can be Both Challenging and Successful. AB - BACKGROUND: Criteria for diagnosing primary hyperparathyroidism (PHPT) include hypercalcemia in the presence of parathyroid hormone (PTH) levels that are either elevated (classic PHPT) or normal but non-suppressed. However, there is no standard definition of what constitutes normal non-suppressed levels, and data are lacking regarding the potential for surgical cure in these patients. METHODS: A retrospective review of patients undergoing parathyroidectomy for sporadic PHPT between 2012 and 2014 was performed. Patients with normal PTH were compared to classic PHPT patients to assess demographics, imaging, operative findings, and outcomes. RESULTS: In total, 332 patients met study criteria, and 60 (18%) had normal PTH levels. Negative sestamibi scans were seen more often with normal PTH levels (18.3 vs. 4.8%, p < 0.001). Patients with normal PTH were more likely to have >=2 glands removed (26.7 vs. 14.3%, p = 0.02), and the specimens were more likely to be classified as only mildly hypercellular or normocellular (20 vs. 2.9%, p < 0.001). Average follow-up was 24 months (range 6-55). Cure rate was 88% in the normal PTH group, compared to 96% in classic PHPT (p = 0.02). Among patients with normal PTH, those with PTH <= 55 pg/mL had an 83% cure rate, whereas those with PTH 56-65 had a 96% cure rate (p = 0.12). CONCLUSIONS: Parathyroidectomy can have a high cure rate in the context of normal PTH levels despite an increased likelihood of negative imaging and multigland resection. Operative success is equivalent to classic PHPT when PTH levels are > 55 pg/mL. PMID- 29134315 TI - Risk Factors for Early Postoperative Small Bowel Obstruction after Anterior Resection for Rectal Cancer: Methodological Issues. PMID- 29134316 TI - Long-Term Follow-Up of Retromuscular Incisional Hernia Repairs: Recurrence and Quality of Life. PMID- 29134317 TI - The impact of canal flare index on leg length discrepancy after total hip arthroplasty. AB - INTRODUCTION: The femoral stem should protrude from femur by an appropriate vertical distance to allow leg length equalization at hip arthroplasty; this distance depends on the size/shape of medullary canal and implant. The relationship between femoral morphology and achievability of leg length restoration is currently unclear. Our aim was to examine the impact of the femoral canal flare index (CFI) on the risk of leg length discrepancy (LLD) after total hip arthroplasty with different femoral stems. MATERIALS AND METHODS: The study cohort included 126 patients with unilateral primary total hip arthroplasty due to idiopathic osteoarthritis and three different types of implanted femoral stems. The impact of CFI on postoperative LLD was assessed with separate logistic regression model for each implant and covariables of age, gender, body mass index and femoral neck resection level. RESULTS: Higher CFI was an independent risk factor for postoperative LLD >= 5 mm with odds ratio 4.5 (p = 0.03) in 49 stems with cementless metaphyseal fixation Implantcast-EcoFit(r), regardless of the femoral neck resection level. CFI had no significant impact on LLD in 30 stems with cementless diaphyseal fixation EndoPlus-Zweymuller(r) or 47 cemented collared stems Link-SPII(r). No significant difference was observed between groups in pre/postoperative WOMAC scores, postoperative radiographic LLD, subjectively reported LLD, insole use or complications after mean 6.8 years of follow-up. CONCLUSIONS: Higher CFI increases the risk of clinically detectable postoperative LLD in single-wedge femoral stems with cementless metaphyseal fixation. CFI has no significant impact on LLD in femoral stems with cementless diaphyseal fixation or cemented fixation. PMID- 29134318 TI - The impact of different peripheral suture techniques on the biomechanical stability in flexor tendon repair. AB - PURPOSE: Flexor tendon repair consists of circumferential peripheral sutures in combination with core sutures to avoid fraying and reduces the exposure of suture material on tendon surface. The peripheral suture adds up to a tenfold increase of the biomechanical stability compared to the core suture alone. The purpose of our study was to determine the most favourable peripheral repair technique for tendon repair. METHODS: Seventy-two porcine flexor tendons underwent standardized tenotomy and repair using one of the following six methods (n = 12): simple running (SR), simple-locking (SL), Halsted-mattress (HM), lin-locking (LL), Lembert-mattress (LM), and Silfverskiold cross-stich (SCS) suture technique. The SL- suture was placed 2 mm; the HM, LM, SC, and LL suture were placed 5 mm from the tendon gap. The SR suture was placed 1, 2, and 3 mm from tendon ends; no additional core suture was applied. For cyclic testing (1000 cycles), elongation was calculated; for load to failure construct stiffness, yield load and maximum load were determined. RESULTS: The mean cyclic elongation for all tested suture techniques was less than 2 mm; there was no significant difference between the groups regarding elongation as well as yield load. The HM, LM, SCS, and LL suture techniques presented significantly higher maximum loads compared to the SR- and SL-sutures. The 3 mm SR showed significantly higher maximum loads compared to the 2 and 1 mm SR. CONCLUSIONS: Beside the distance from tendon gap, the type of linkage of the suture material across and beneath the epitendineum is important for biomechanical stability. Simple-running suture is easy to use, even with a slight increase of the distance from tendon gap significantly increases biomechanical strength. For future repairs of flexor tendon injuries, 3 mm stitch length is highly recommended for simple peripheral suture, while the Halsted mattress suture unites the most important qualities: biomechanically strong, most part of suture material placed epitendinous, and not too complicated to perform. PMID- 29134319 TI - Regional levels of physiological alpha-synuclein are directly associated with Lewy body pathology. PMID- 29134320 TI - Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no effective treatments. Numerous RNA-binding proteins (RBPs) have been shown to be altered in ALS, with mutations in 11 RBPs causing familial forms of the disease, and 6 more RBPs showing abnormal expression/distribution in ALS albeit without any known mutations. RBP dysregulation is widely accepted as a contributing factor in ALS pathobiology. There are at least 1542 RBPs in the human genome; therefore, other unidentified RBPs may also be linked to the pathogenesis of ALS. We used IBM Watson(r) to sieve through all RBPs in the genome and identify new RBPs linked to ALS (ALS-RBPs). IBM Watson extracted features from published literature to create semantic similarities and identify new connections between entities of interest. IBM Watson analyzed all published abstracts of previously known ALS-RBPs, and applied that text-based knowledge to all RBPs in the genome, ranking them by semantic similarity to the known set. We then validated the Watson top-ten-ranked RBPs at the protein and RNA levels in tissues from ALS and non-neurological disease controls, as well as in patient derived induced pluripotent stem cells. 5 RBPs previously unlinked to ALS, hnRNPU, Syncrip, RBMS3, Caprin-1 and NUPL2, showed significant alterations in ALS compared to controls. Overall, we successfully used IBM Watson to help identify additional RBPs altered in ALS, highlighting the use of artificial intelligence tools to accelerate scientific discovery in ALS and possibly other complex neurological disorders. PMID- 29134321 TI - Co-occurrence of mixed proteinopathies in late-stage Huntington's disease. AB - Accumulating evidence highlights the potential role of mixed proteinopathies (i.e., abnormal protein aggregation) in the development of clinical manifestations of neurodegenerative diseases (NDD). Huntington's disease (HD) is an inherited NDD caused by autosomal-dominant expanded CAG trinucleotide repeat mutation in the gene coding for Huntingtin (Htt). Previous studies have suggested the coexistence of phosphorylated-Tau, alpha-synuclein (alpha-Syn) and TAR DNA binding protein 43 (TDP-43) inclusions in HD. However, definite evidence that HD pathology in humans can be accompanied by other proteinopathies is still lacking. Using human post-mortem putamen samples from 31 controls and 56 HD individuals, we performed biochemical analyses of the expression, oligomerization and aggregation of Tau, alpha-Syn, TDP-43, and Amyloid precursor protein (APP)/Abeta. In HD brain, we observed reduced soluble protein (but not mRNA) levels of Htt, alpha-Syn, and Tau. Our results also support abnormal phosphorylation of Tau in more advanced stages of disease. Aberrant splicing of Tau exons 2, 3 (exclusion) and 10 (inclusion) was also detected in HD patients, leading to higher 0N4R and lower 1N3R isoforms. Finally, following formic acid extraction, we observed increased aggregation of TDP-43, alpha-Syn, and phosphorylated-Tau during HD progression. Notably, we observed that 88% of HD patients with Vonsattel grade 4 neuropathology displayed at least one non-Htt proteinopathy compared to 29% in controls. Interestingly, alpha-Syn aggregation correlated with Htt, TDP-43 and phosphorylated-Tau in HD but not in controls. The impact of this work is twofold: (1) it provides compelling evidences that Tau, alpha-Syn and TDP-43 proteinopathies are increased in HD, and (2) it suggests the involvement of common mechanisms leading to abnormal accumulation of aggregation-prone proteins in NDD. Further studies will be needed to decipher the impact of these proteinopathies on clinical manifestation of HD. PMID- 29134322 TI - Correlative factors' analysis of postural-related ocular cyclotorsion with image guided system. AB - PURPOSE: To explore the correlation between ocular cyclotorsion induced by sitting and supine positions as well as other selected factors, validated by an image-guided system. STUDY DESIGN: A cross-sectional study conducted in 73 inpatients (85 eyes) who received intraocular operations in China Medical University. METHODS: The ocular cyclotorsion degree was recorded using an image guided system (Verion Reference Unit, Alcon) by comparing images captured in sitting position, as well as pre- and post-different anesthesia methods in the supine position. Possible correlative factors including age, gender, eye axial length, best corrected visual acuity (BCVA), astigmatism degree, astigmatism axis, anesthesia, and comparison in laterality of eyes on ocular cyclotorsion were analyzed. RESULTS: The total cyclotorsion rate was 88.24% and the cyclotorsion degree ranged from - 14.0 degrees to + 12.0 degrees with an average of 4.6 degrees +/- 3.4 degrees . Excyclotorsion was predominant OD whereas incyclotorsion was predominant OS (p < 0.05). The effect of eye axial length, BCVA, astigmatism degree, astigmatism axis, anesthesia method, age and gender on cyclotorsion orientation was not statistically significant, neither did these factors show any significant differences in the ocular cyclotorsion degree (p > 0.05). Pre- and post-anesthesia, and different anesthetic methods, did not show any significant influence on the ocular cyclotorsion degree (p > 0.05). CONCLUSIONS: Cyclotorsion orientation seems to be correlated only with eye laterality. None of the other investigated factors, including age, gender, eye axial length, BCVA, astigmatism degree, astigmatism axis and anesthesia seems to affect cyclotorsion orientation or degree. PMID- 29134323 TI - Single-stage treatment of infected tibial non-unions and osteomyelitis with bone marrow granulocytes precursors protecting bone graft. AB - PURPOSE: Infected non-unions present a clinical challenge, especially with risk of recurrent infection. Bone marrow contains granulocyte precursors identified in vitro as colony forming units-granulocyte macrophage (CFU-GM) have a prophylactic action against infection. We therefore tested the hypothesis that bone marrow concentrated granulocytes precursors added to a standard bone graft could decrease the risk of recurrence of infection when single-stage treatment of infected tibial non-unions is performed with bone graft. METHODS: During a single stage procedure 40 patients with infected tibial non-union received a spongious bone graft supercharged with granulocytes precursors after debridement (study group). A control group (40 patients) was treated in a single stage with local debridement and standard bone graft obtained from the iliac crest. The antibiotic therapy protocol was the same (60 days) in the two groups. CFU-GM progenitors were harvested from bone marrow aspirated on the opposite iliac crest of the site where the cancellous bone was obtained. Union (radiographs and CT scan), a recurrence of clinical infection, and need for subsequent surgery were evaluated. RESULTS: Thirty-eight (95%) patients who received graft supercharged with granulocytes precursors achieved successful union without recurrence of infection during the seven-year follow-up versus 28 (70%) control patients; for the control group the mean graft resorption volume was 40%, while no bone graft resorption was found for the study group. CONCLUSION: Supercharging the cancellous bone graft with bone marrow granulocytes precursors protect the site of infected non union from recurrence of infection and bone resorption of the graft. PMID- 29134324 TI - Trend to Equilibrium for a Reaction-Diffusion System Modelling Reversible Enzyme Reaction. AB - A spatio-temporal evolution of chemicals appearing in a reversible enzyme reaction and modelled by a four-component reaction-diffusion system with the reaction terms obtained by the law of mass action is considered. The large time behaviour of the system is studied by means of entropy methods. PMID- 29134325 TI - Spatial Context and Health Inequity: Reconfiguring Race, Place, and Poverty. AB - Intimate connections among race, place, and poverty are increasingly featured in the health disparities literature. However, few models exist that can guide our understanding of these interconnections. We build on the Chicago School of Sociology's contributions in urban research and one of its contemporary elaborations, often described as the "neighborhood effects approach," to propose a three-axis model of health inequity. This model, in alignment with Chicago School theory, postulates a dynamic and adaptive relationship between spatial context and health inequity. Compositional axes of race and poverty form the foundation of the model. These compositional axes then intersect with a third axis of place to compose the built and social environment planes. We develop this model to provide conceptual guidance for clinical, policy, and public health researchers who aim to examine how these three features, taken together, have important implications for urban health. PMID- 29134326 TI - Inhibition of the Voltage-Dependent K+ Current by the Tricyclic Antidepressant Desipramine in Rabbit Coronary Arterial Smooth Muscle Cells. AB - We describe the effect of a tricyclic antidepressant drug desipramine on voltage dependent K+ (Kv) currents in freshly isolated rabbit coronary arterial smooth muscle cells using a conventional whole-cell patch clamp technique. Application of desipramine rapidly decreased the Kv current amplitude in a concentration dependent manner, with an IC50 value of 5.91 +/- 0.18 MUM and a Hill coefficient of 0.61 +/- 0.09. The steady-state inactivation curves of the Kv channels were not affected by desipramine. However, desipramine shifted the steady-state inactivation curves toward a more negative potential. Application of train pulses (1 or 2 Hz) slightly reduced the Kv current amplitude. Such reduction in the Kv current amplitude by train pulses increased in the presence of desipramine. Furthermore, the inactivation recovery time constant was also increased in the presence of desipramine, suggesting that desipramine-induced inhibition of the Kv current was use-dependent. Application of a Kv1.5 inhibitor (DPO-1) and/or a Kv2.1 inhibitor (guangxitoxin) did not change the inhibitory effect of desipramine on Kv currents. Based on these results, we concluded that desipramine directly inhibited the Kv channels in a dose- and state-dependent manner, but the effect was independent of norepinephrine/serotonin reuptake inhibition. PMID- 29134327 TI - Effects of land use types on dissolved trace metal concentrations in the Le'an River Basin, China. AB - Using land use types in multiple spatial scales (entire basin, buffer zones, and slopes) as well as statistical and spatial analysis, relationships between land use types and concentrations of dissolved trace metals were determined in the Le'an River Basin, China. The result showed that farmland and urban land were determined as the source of the pollutants, while forestland and grassland were identified as the sink of the pollutants. The temporal differences of relationships between land use types and concentrations of dissolved trace metals mainly due to the discrepancy of rainfall characteristics. Land use type close to river was a better indicator for the effectiveness of concentrations of trace metals, especially at scale of 0-200 m. Forestland and grassland on lower slopes greatly affected the water quality, and the former had no significant or weak influences on higher slopes. Urban land had the greater positive correlations with concentrations of dissolved trace metals on higher slopes, which are mainly due to frequent mining activity. Further analysis suggested that the buffer zones with low slope needed to be seriously taken into consideration for effective land use management in similar basin. PMID- 29134328 TI - Correction to: Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. AB - Unfortunately, in the original publication of this article, the copyright line was incorrectly published in PDF as "(c) The Author(s) 2017" instead of "(c)The Author(s) 2017 This article is an open access publication" and also the CC-BY description was not included. The description should be as follows. PMID- 29134330 TI - Is the incidence of esophageal adenocarcinoma increasing in Japan? Trends from the data of a hospital-based registration system in Akita Prefecture, Japan. AB - BACKGROUND: At present, squamous cell carcinoma accounts for most esophageal cancers in Japan; however, there is concern that the incidence of esophageal adenocarcinoma in Japan is increasing in comparison to Western countries. Akita Prefecture, with a population of 1 million, has the highest rate of esophageal cancer-associated mortality in Japan; the vast majority of these cases are squamous cell carcinoma. The aim of the present study was to investigate the latest trends in the incidence of esophageal adenocarcinoma in Akita Prefecture using a registration system. METHODS: We examined the data from a collaborative hospital-based registration system for cancer patients. Eleven of the main hospitals in Akita Prefecture participate in this system, which covers 90% of the cancer cases in the region and which provides near population-based data. Using this registration system, we examined the sequential trends in the percentage of adenocarcinoma cases in relation to total esophageal cancer cases in Akita Prefecture from 2007 to 2014. RESULTS: In 2007-2014, a total of 2527 esophageal cancer patients were registered in the system. Among these, only 43 (1.8%) had adenocarcinoma. However, the number of adenocarcinoma patients gradually increased from 1 case in 2007 to 14 cases in 2014. Consequently, the percentage of adenocarcinoma cases showed a significant increase from 0.66% in the first 4 years of the study period to 2.5% in the latter 4 years of the study period (P < 0.01). CONCLUSIONS: The latest hospital-based registration data for 2007-2014 suggest that the incidence of esophageal adenocarcinoma may have begun to increase in Akita Prefecture; this may reflect recent trends in other parts of Japan. PMID- 29134329 TI - Esophageal motility disorders: new perspectives from high-resolution manometry and histopathology. AB - High-resolution manometry (HRM) and peroral endoscopic myotomy (POEM) have contributed significantly to the field of esophageal motility disorders in recent years. The development of HRM has categorized various esophageal motility disorders with a focus on a diverse range of manometric anomalies. Additionally, the Chicago classification criteria is widely used for manometric diagnosis. Moreover, POEM was introduced as a minimally invasive radical therapy for achalasia and shows promise for other spastic esophageal motility disorders as well. POEM has also enabled a transluminal endoscopic approach for determining the histology of the esophageal muscle layer, which is expected to assist in elucidating the etiology of disorders associated with esophageal motility. The purpose of this review is to update the diagnosis, pathology, and treatment of esophageal motility disorders, with a focus on the recent advances in this field. PMID- 29134331 TI - Optimization and application of a DNA-launched infectious clone of equine arteritis virus. AB - Reverse genetics is one of the most powerful tools in modern virology. Equine arteritis virus (EAV) is the prototype member of the Equartevirus. In this study, a new reverse genetics system for the recovery of equine arteritis virus from a cDNA plasmid, which contains viral cDNA sequence flanked by hammerhead ribozyme (HamRz) and hepatitis delta virus ribozyme (HdvRz) sequences in both terminals of the viral genome, was developed by optimization of the promoter and terminator regions. Cellular RNA polymerase II drove the transcription of the viral genome. The results showed that the rescued virus (ic-EAV) shared similar morphological and growth characteristics with the wild-type (WT) virus, and could be distinguished from the WT virus via an engineered BspEI restriction site in the nsp3 gene. By using the reverse genetics method established in this study, a G-to C silent mutation at site 12642 resulted in a significant change in the plaque size of the rescued virus. Moreover, an eGFP-labeled EAV was constructed by introducing the eGFP gene into the infectious clone of EAV, which facilitated the observation of the infection of EAV in target cells. Hence, the newly reverse genetics method of EAV established in this study can be easily manipulated and would be helpful for studying the pathogenic mechanism of EAV. PMID- 29134332 TI - Type IV pilus biogenesis genes and their roles in biofilm formation in the biological control agent Lysobacter enzymogenes OH11. AB - Type IV pilus (T4P) is widespread in bacteria, yet its biogenesis mechanism and functionality is only partially elucidated in a limited number of bacterial species. Here, by using strain OH11 as the model organism, we reported the identification of 26 T4P structural or functional component (SFC) proteins in the Gram-negative Lysobacter enzymogenes, which is a biocontrol agent potentially exploiting T4P-mediated twitching motility for antifungal activity. Twenty such SFC coding genes were individually knocked-out in-frame to create a T4P SFC deletion library. By using combined phenotypic and genetic approaches, we found that 14 such SFCs, which were expressed from four operons, were essential for twitching motility. These SFCs included the minor pilins (PilEi, PilXi, PilVi, and FimTi), the anti-retraction protein PilY1i, the platform protein PilC, the extension/extraction ATPases (PilB, PilT, and PilU), and the PilMNOPQ complex. Among these, mutation of pilT or pilU caused a hyper piliation, while the remaining 12 SFCs were indispensable for pilus formation. Ten (FimTi, PilY1i, PilB, PilT, PilU, and the PilMNOPQ complex) of the 14 SFC proteins, as well as PilA, were further shown to play a key role in L. enzymogenes biofilm formation. Overall, our results provide the first report to dissect the genetic basis of T4P biogenesis and its role in biofilm formation in L. enzymogenes in detail, which can serve as an alternative platform for studying T4P biogenesis and its antifungal function. PMID- 29134333 TI - Whole-cell-dependent biosynthesis of sulfo-conjugate using human sulfotransferase expressing budding yeast. AB - Cytosolic sulfotransferases (SULTs), one of the predominant phase II drug metabolizing enzymes (DME), play important roles in metabolism of xeno- and endobiotics to generate their sulfo-conjugates. These sulfo-conjugates often have biological activities but are difficult to study, because even though only small amounts are required to evaluate their efficacy and safety, chemical or biological synthesis of sulfo-conjugatesis is often challenging. Previously, we constructed a DME expression system for cytochrome P450 and UGT, using yeast cells, and successfully produced xenobiotic metabolites in a whole-cell-dependent manner. In this study, we developed a yeast expression system for human SULTs, including SULT1A1, 1A3, 1B1, 1C4, 1E1, and 2A1, in Saccharomyces cerevisiae and examined its sulfo-conjugate productivity. The recombinant yeast cells expressing each of the SULTs successfully produced several hundred milligram per liter of xeno- or endobioticsulfo-conjugates within 6 h. This whole-cell-dependent biosynthesis enabled us to produce sulfo-conjugates without the use of 3' phosphoadenosine-5'-phosphosulfate, an expensive cofactor. Additionally, the production of regiospecific sulfo-conjugates of several polyphenols was possible with this method, making this novel yeast expression system a powerful tool for uncovering the metabolic pathways and biological actions of sulfo-conjugates. PMID- 29134334 TI - Effect on Completion of Clinical Pathway for Improving Clinical Indicator: Cases of Hospital Stay, Mortality Rate, and Comprehensive-Volume Ratio. AB - Many studies have analyzed the effects of clinical pathways, but most have considered only single diseases. The purpose of the present study was to exploratively analyze electronic medical records related to the use of clinical pathways, seeking trends that could usefully benefit clinical activity. From the data warehouse of University of Miyazaki Hospital, collected from April 2014 to March 2016, we retrospectively identified 6523 patients for whom a clinical pathway was applied. Other inclusion criteria were single hospitalization, the type of medical fee was comprehensive, and data were available so that all clinical indicators could be calculated. Two types of deviation from the clinical pathway were defined: cancellation (described in the clinical pathway but not implemented) and addition (not described in the clinical pathway but nevertheless implemented). If the code of International Classification of Diseases describing the clinical pathway differed from that describing where the medical resource was mostly spent, we considered this as indicating a complication. We compared principal clinical indicators (length of hospital stay, mortality rate, and comprehensive-volume ratio) by completion rate for the clinical pathway. Regardless of whether patients had complications, completing the clinical pathway was associated with a significant reduction in length of hospital stay. This finding indicated that length of hospital stay could be shortened if all medical treatments described in the clinical pathway were implemented. Our results demonstrated that it is possible to shorten the length of hospital stay by improving clinical pathways to include medical treatment for preventing complications. PMID- 29134335 TI - Quantitative analysis of senecavirus A in tissue samples from naturally infected newborn piglets. AB - In this study, we determined the distribution of senecavirus A (SVA) and viral RNA load in different organs and tissues of naturally infected piglets. A TaqMan based qRT-PCR assay was performed using RNA extracted from brainstem, cerebellum, cerebrum, heart, kidney, liver, lungs, small intestine, spleen, urinary bladder, and tonsils of seven newborn piglets. SVA was detected in 57 out of 70 tissue samples (81.4%). Viral loads ranged from 4.07 to 10.38 log10 genomic copies per g of tissue. The results show that SVA has tropism for various organs in naturally infected newborn piglets, especially for tonsils, spleen, lungs, and liver. Lymphoid organs had the highest viral loads and may be important sites for SVA replication. PMID- 29134336 TI - Complete genome sequence of a new member of the genus Badnavirus, Dioscorea bacilliform RT virus 3, reveals the first evidence of recombination in yam badnaviruses. AB - Yams (Dioscorea spp.) host a diverse range of badnaviruses (genus Badnavirus, family Caulimoviridae). The first complete genome sequence of Dioscorea bacilliform RT virus 3 (DBRTV3), which belongs to the monophyletic species group K5, is described. This virus is most closely related to Dioscorea bacilliform SN virus (DBSNV, group K4) based on a comparison of genome sequences. Recombination analysis identified a unique recombination event in DBRTV3, with DBSNV likely to be the major parent and Dioscorea bacilliform AL virus (DBALV) the minor parent, providing the first evidence for recombination in yam badnaviruses. This has important implications for yam breeding programmes globally. PMID- 29134337 TI - Recombination analysis of coxsackievirus B5 genogroup C. AB - Coxsackievirus B5 (CVB5) is a member of the species Enterovirus B of the genus Enterovirus, family Picornaviridae. Based on its VP1 sequence, CVB5 is divided into four genogroups: A, B, C, and D. From 2002 to 2012, CVB5 serotype genogroup C caused an outbreak of aseptic meningitis in China. In order to study the evolution of CVB5 genogroup C, phylogenetic and recombination analysis was performed using the 399 available enterovirus B genome sequences in the GenBank database. The results indicated that 10 strains of CVB5 serotype genogroup C resulted from recombination between members of genogroup B and echovirus serotype E6, and another 5 strains resulted from recombination between members of genogroup C and serotype CVB4. These recombination events were confirmed by phylogenetic analysis. PMID- 29134338 TI - Molecular characterization of a novel luteovirus infecting apple by next generation sequencing. AB - A new single-stranded positive-sense RNA virus, which shares the highest nucleotide (nt) sequence identity of 53.4% with the genome sequence of cherry associated luteovirus South Korean isolate (ChALV-SK, genus Luteovirus), was discovered in this work. It is provisionally named apple-associated luteovirus (AaLV). The complete genome sequence of AaLV comprises 5,890 nt and contains eight open reading frames (ORFs), in a very similar arrangement that is typical of members of the genus Luteovirus. When compared with other members of the family Luteoviridae, ORF1 of AaLV was found to encompass another ORF, ORF1a, which encodes a putative 32.9-kDa protein. The ORF1-ORF2 region (RNA-dependent RNA polymerase, RdRP) showed the greatest amino acid (aa) sequence identity (59.7%) to that of cherry-associated luteovirus Czech Republic isolate (ChALV-CZ, genus Luteovirus). The results of genome sequence comparisons and phylogenetic analysis, suggest that AaLV should be a member of a novel species in the genus Luteovirus. To our knowledge, it is the sixth member of the genus Luteovirus reported to naturally infect rosaceous plants. PMID- 29134339 TI - Feline immudeficiency virus subtypes B and A in cats from Sao Luis, Maranhao, Brazil. AB - Feline immunodeficiency virus (FIV) is a retrovirus of the genus Lentivirus that is distributed worldwide, with prevalence rates varying between 2.5% and 44%. FIV causes immunosuppression, with depletion of TCD4+ lymphocytes, with the majority of clinical signs caused by secondary and opportunistic infections. Blood samples were collected from nine domestic cats (Felis catus domesticus) from the city of Sao Luis, Maranhao State, Brazil. All samples were positive in a rapid immunochromatographic test (SNAP(r) Combo FeLV Ag/FIV Antibody Test) and in a polymerase chain reaction (PCR) assay. Phylogenetic analysis showed that six samples clustered within subtype B, one within subtype A, and two did not cluster with any known subtype. Five unique haplotypes (Hap-1, Hap-2, Hap-3, Hap-5 and Hap-6) and a shared haplotype (Hap-4) were found, this last one being the most frequent. This is the first report on the genetic diversity of FIV in the city of Sao Luis and the first report of subtype A in Brazil. New variations of the virus are also reported. PMID- 29134340 TI - Rapid visual detection of lily mottle virus using a loop-mediated isothermal amplification method. AB - Lily mottle virus (LMoV; genus Potyvirus, family Potyviridae) infects plants of the genus Lilium, causing a reduction in flower and bulb quality. A rapid and sensitive loop-mediated isothermal amplification (LAMP) assay was developed to detect the coat protein gene of LMoV. This LAMP method was highly specific for LMoV, with no cross-reaction with other lily viruses. The sensitivity of LMoV using the LAMP assay was 100 times more sensitive than that using conventional polymerase chain reaction. A reverse transcription LAMP (RT-LAMP) was then successfully applied to detect LMoV RNA. The newly established LAMP and one-step RT-LAMP provide an alternative method for detecting LMoV in lily plants. PMID- 29134341 TI - UniversitatsSpital Zurich: 80 years of neurosurgical patient care in Switzerland. AB - BACKGROUND: The predecessor of today's Department of Neurosurgery, UniversitatsSpital Zurich (USZ), was founded 80 years ago as the first independent Swiss clinic dedicated to neurosurgical patient care. On the occasion of this anniversary, we aimed to highlight the history of neurosurgery as a specialty at the USZ, and to put it into the historical context of Swiss and European Neurosurgery. METHOD: A literature review was conducted and we searched the archives of the USZ and the city of Zurich, as well as those of Swiss journals to extract relevant published articles, books, historical reports and pictures. The USZ Department of Medical History, the Museum of Medical History and the Swiss National Library were contacted to provide source material. To further verify the content, (emeritus) faculty from the USZ and external experts on the history of Swiss neurosurgery reviewed the manuscript. RESULTS: Surgeries of the head and spine had occasionally been conducted in Zurich by the general surgeons, Rudolf Ulrich Kronlein and Paul Clairmont, before an independent neurosurgical clinic was founded by Hugo Krayenbuhl on 6 July 1937. This was the first Swiss department dedicated to neurosurgical patient care. Besides providing high-quality medicine for both the local and wider population, the department was chaired by eminent leaders of neurosurgery, who influenced the scientific and clinical neurosurgery of their time. As such, it has long been regarded as one of the top teaching and research hospitals in Switzerland and in Europe. CONCLUSIONS: On the occasion of its 80th anniversary, we have performed an in depth review of its development, successes and challenges, with a special focus on the early decades. Reflecting on the past, we have identified common denominators of success in neurosurgery that remain valid today. PMID- 29134342 TI - An introduction and overview of machine learning in neurosurgical care. AB - BACKGROUND: Machine learning (ML) is a branch of artificial intelligence that allows computers to learn from large complex datasets without being explicitly programmed. Although ML is already widely manifest in our daily lives in various forms, the considerable potential of ML has yet to find its way into mainstream medical research and day-to-day clinical care. The complex diagnostic and therapeutic modalities used in neurosurgery provide a vast amount of data that is ideally suited for ML models. This systematic review explores ML's potential to assist and improve neurosurgical care. METHOD: A systematic literature search was performed in the PubMed and Embase databases to identify all potentially relevant studies up to January 1, 2017. All studies were included that evaluated ML models assisting neurosurgical treatment. RESULTS: Of the 6,402 citations identified, 221 studies were selected after subsequent title/abstract and full-text screening. In these studies, ML was used to assist surgical treatment of patients with epilepsy, brain tumors, spinal lesions, neurovascular pathology, Parkinson's disease, traumatic brain injury, and hydrocephalus. Across multiple paradigms, ML was found to be a valuable tool for presurgical planning, intraoperative guidance, neurophysiological monitoring, and neurosurgical outcome prediction. CONCLUSIONS: ML has started to find applications aimed at improving neurosurgical care by increasing the efficiency and precision of perioperative decision-making. A thorough validation of specific ML models is essential before implementation in clinical neurosurgical care. To bridge the gap between research and clinical care, practical and ethical issues should be considered parallel to the development of these techniques. PMID- 29134343 TI - Factors influencing cerebral aneurysm obliteration and reliability of indocyanine green video-angiography. AB - BACKGROUND: Indocyanine green video-angiography (ICG-V) is commonly used for intraoperative confirmation of aneurysm obliteration following clipping. However, direct puncture of the aneurysm wall occasionally results in blood leakage in patients for whom ICG-V has indicated complete closure. Therefore, the present study aimed to determine the reliability of ICG-V for confirming complete aneurysm closure, and to elucidate the factors underlying aneurysm obliteration and the occurrence of false-negative ICG-V findings. METHODS: Between June 2012 and June 2016, 89 patients (107 aneurysms total) undergoing aneurysm clipping were examined using ICG-V to confirm aneurysm closure. In ICG-V-negative cases, further confirmation of complete aneurysm closure was obtained via direct puncture of the aneurysm wall, except in cases where this procedure was deemed unsafe. To elucidate the possible causes of ICG-V inaccuracies, positive, negative, and false-negative ICG-V findings were compared in terms of aneurysm location (maximum height and length), neck width (parallel and orthogonal directions to the branching vessels), wall thickness around the neck, bifurcation angle, and direction of the clipping closure line. Statistical analyses were performed using the Welsh's t test and Chi-square test. RESULTS: Intraoperative ICG-V detected seven cases of incomplete aneurysm closure (6.5%), defined as positive ICG-V findings. Following direct aneurysm wall puncture, nine patients (8.4%) exhibited false-negative ICG-V findings. A Chi-square test revealed that false-negative ICG-V findings were significantly influenced by the presence of heterogeneous arteriosclerosis, and wall thickening at the clipping site, which were subjectively defined by the surgeon and confirmed by an independent observer, depending on the wall color and hardness, respectively. CONCLUSIONS: Although ICG-V is useful for intraoperative confirmation of aneurysm obliteration, our findings further highlight the risk of false-negative ICG-V findings. Acknowledgement of risk factors is crucial for efficient detection of false-negative ICG-V findings. PMID- 29134344 TI - A cross-sectional study of the relationship between blood lead levels and reported attention deficit disorder: an assessment of the economic impact on the United States. AB - Attention deficit disorder (ADD) is characterized by a pattern of inattention and/or impulsivity that is inconsistent with developmental level and interferes with normal functioning in at least two settings. A recent meta-analysis suggested a significant relationship between lead (Pb) exposure and attention deficit symptoms. This study evaluated the potential relationship between increasing blood Pb levels and the risk of a reported ADD diagnosis. This cross sectional study examined a sample of 2109 persons (32,762,158 weighted-persons) between 10 and 19 years-old from the 2003-2004 National Health and Nutritional Examination Survey (NHANES). This study analyzed demographic, socioeconomic, health related-questions, and laboratory tests using survey logistic and frequency modeling in SAS. On a microgram (MUg)/deciliter (dL) basis, a significant dose-response relationship between increasing blood Pb levels and the risk of a reported ADD outcome was confirmed (odds ratio (OR) = 1.237, p = 0.0227). The relationship between increasing blood Pb levels and the risk of a reported ADD remained consistent when examining covariates such as gender, race, and socioeconomic status (OR = 1.292, p = 0.0301). Control outcomes selected on an a priori basis to not be biologically plausibly linked to blood Pb levels showed no relationship with increasing blood Pb levels. This NHANES analysis revealed an estimated 380,000 persons born in the United States (US) from 1984 to 1993 were reported to have an ADD outcome as a consequence of elevated blood Pb levels and the excess lifetime costs of these persons would be about US $100 billion. Every effort should be made to eliminate childhood Pb exposure. PMID- 29134345 TI - Trends in mechanical circulatory support use and hospital mortality among patients with acute myocardial infarction and non-infarction related cardiogenic shock in the United States. AB - BACKGROUND: Recent trends on outcomes in cardiogenic shock (CS) complicating acute myocardial infarction (AMI) suggest improvements in early survival. However, with the ever-changing landscape in management of CS, we sought to identify age-based trends in these outcomes and mechanical circulatory support (MCS) use among patients with both AMI and non-AMI associated shock. METHODS: We queried the 2005-2014 Nationwide Inpatient Sample databases to identify patients with a diagnosis of cardiogenic shock. Trends in the incidence of hospital mortality, and use of MCS such as intra-aortic balloon pump (IABP), Impella/TandemHeart (IMP), and extra corporeal membrane oxygenation (ECMO) were analyzed within the overall population and among different age-categories (50 and under, 51-65, 66-80 and 81-99 years). We also made comparisons between patient groups admitted with CS complicating AMI and those with non-AMI associated CS. RESULTS: We studied 144,254 cases of CS, of which 55.4% cases were associated with an AMI. Between 2005 and 2014, an overall decline in IABP use (29.8-17.7%; ptrend < 0.01), and an uptrend in IMP use (0.1-2.6%; ptrend < 0.01), ECMO use (0.3-1.8%; ptrend < 0.01) and in-hospital mortality (44.1-52.5% AMI related, 49.6 53.5% non-AMI related; ptrend < 0.01) was seen. Patients aged 81-99 years had the lowest rate of MCS use (14.8%), whereas those aged 51-65 years had highest rate of MCS use (32.3%). Multivariable analysis revealed that patients aged 51-65 years (aOR 1.46, 95% CI 1.40-1.52; p<0.001), 66-80 years (aOR 2.51, 95% CI 2.39 2.63; p<0.01) and 81-99 years (aOR 5.04, 95% CI 4.78-5.32; p<0.01) had significantly higher hospital mortality compared to patients aged <= 50 years. Patients admitted with CS complicating AMI were older and had more comorbidities, but lower hospital mortality (45.0 vs. 48.2%; p < 0.001) when compared to non-AMI related CS. We also noted that the proportion of patients admitted with CS complicating AMI significantly decreased from 2005 to 2014 (65.3-45.6%; ptrend < 0.01) whereas those admitted without an associated AMI increased. CONCLUSIONS: IABP use has declined whereas IMP and ECMO use has increased over time among CS admissions. Older age was associated with an incrementally higher independent risk for hospital mortality. Recent trends indicate an increase in both proportion of patients admitted with CS without associated AMI and in-hospital mortality across all CS admissions irrespective of AMI status. PMID- 29134347 TI - Janus and the Great Men. PMID- 29134346 TI - Outcomes after percutaneous coronary intervention for chronic total occlusion according to baseline renal function. AB - BACKGROUND: Chronic kidney disease (CKD) adversely affects outcomes in patients with coronary artery disease. Data on the impact of renal impairment on prognosis of patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) are scarce. METHODS: A total of 2002 patients undergoing CTO PCI were stratified according to baseline renal function (group 1: estimated glomerular filtration rate [eGFR] >= 90 ml/min/1.73 m2, group 2: 60 to 89 ml/min/1.73 m2, group 3: 30 to 59 ml/min/1.73 m2, and group 4: <30 ml/min/1.73 m2). The primary outcome measure was all-cause mortality at a median follow-up of 2.6 (interquartile range 1.1-3.1) years. RESULTS: All-cause mortality increased with decreasing renal function (group 1: 5.0%, group 2: 9.5%, group 3: 26.4%, and group 4: 38.7%, log rank p < 0.001). Continuous eGFR values were significantly related with all-cause mortality (adjusted HR 0.98, 95% CI 0.98-0.99, p < 0.001). Procedural failure was associated with all-cause mortality both in patients with an eGFR < 60 ml/min/1.73 m2 (42.6 vs. 23.7%, adjusted HR 1.59, 95% CI 1.08-2.32, p = 0.02) and in those with an eGFR >= 60 ml/min/1.73 m2 (14.6 vs. 6.5%, adjusted HR 1.73, 95% CI 1.15-2.60, p = 0.009, interaction p = 0.47). CONCLUSIONS: Although renal impairment is associated with all-cause mortality in patients undergoing CTO PCI, successful CTO recanalization is related to improved survival irrespective of renal function. PMID- 29134348 TI - Machine learning-based quantitative texture analysis of CT images of small renal masses: Differentiation of angiomyolipoma without visible fat from renal cell carcinoma. AB - OBJECTIVE: To evaluate the diagnostic performance of machine-learning based quantitative texture analysis of CT images to differentiate small (<= 4 cm) angiomyolipoma without visible fat (AMLwvf) from renal cell carcinoma (RCC). METHODS: This single-institutional retrospective study included 58 patients with pathologically proven small renal mass (17 in AMLwvf and 41 in RCC groups). Texture features were extracted from the largest possible tumorous regions of interest (ROIs) by manual segmentation in preoperative three-phase CT images. Interobserver reliability and the Mann-Whitney U test were applied to select features preliminarily. Then support vector machine with recursive feature elimination (SVM-RFE) and synthetic minority oversampling technique (SMOTE) were adopted to establish discriminative classifiers, and the performance of classifiers was assessed. RESULTS: Of the 42 extracted features, 16 candidate features showed significant intergroup differences (P < 0.05) and had good interobserver agreement. An optimal feature subset including 11 features was further selected by the SVM-RFE method. The SVM-RFE+SMOTE classifier achieved the best performance in discriminating between small AMLwvf and RCC, with the highest accuracy, sensitivity, specificity and AUC of 93.9 %, 87.8 %, 100 % and 0.955, respectively. CONCLUSION: Machine learning analysis of CT texture features can facilitate the accurate differentiation of small AMLwvf from RCC. KEY POINTS: * Although conventional CT is useful for diagnosis of SRMs, it has limitations. * Machine-learning based CT texture analysis facilitate differentiation of small AMLwvf from RCC. * The highest accuracy of SVM-RFE+SMOTE classifier reached 93.9 %. * Texture analysis combined with machine-learning methods might spare unnecessary surgery for AMLwvf. PMID- 29134349 TI - The impact of MRI sequence on tumour staging and gross tumour volume delineation in squamous cell carcinoma of the anal canal. AB - OBJECTIVES: To compare maximum tumour diameter (MTD) and gross tumour volume (GTV) measurements between T2-weighted (T2-w) and diffusion-weighted (DWI) MRI in squamous cell carcinoma of the anal canal (SCCA) and assess sequence impact on tumour (T) staging. Second, to evaluate interobserver agreement and reader delineation confidence. METHODS: The staging MRI scans of 45 SCCA patients (25 females) were assessed retrospectively by two independent radiologists (0 and 5 years' experience of anal cancer MRI). MTD and GTV were delineated on both T2-w and high-b-value DWI images and compared between sequences; T staging was derived from MTD. Interobserver agreement was assessed and delineation confidence scored (1 to 5) by each observer. RESULTS: GTV and MTD were significantly and systematically lower on DWI versus T2-w sequences by 14.80%/9.98% (MTD) and 29.70%/12.25% (GTV) for each reader, respectively, causing T staging discordances in approximately a quarter of cases. Bland-Altman limits of agreement were narrower and intraclass correlation coefficients higher for DWI. Delineation confidence was greater on DWI: 40/42 cases were scored confidently (4 or 5) by each reader, respectively, versus 31/36 cases based on T2-w images. CONCLUSIONS: Sequence selection affects SCCA measurements and T stage. DWI yields higher interobserver agreement and greater tumour delineation confidence. KEY POINTS: * MTD and GTV measurements are significantly lower on DWI than on T 2 -w MRI. * Such differences cause T staging discordances in up to a quarter of cases. * DWI results in higher agreement between inexperienced and experienced observers. * DWI offers greater tumour delineation confidence to inexperienced readers. PMID- 29134350 TI - Subtraction multiphase CT angiography: A new technique for faster detection of intracranial arterial occlusions. AB - OBJECTIVE: To describe and evaluate a novel technical development to improve detection of intracranial vessel occlusions using multiphase CT angiography (MPCTA). MATERIALS AND METHODS: The institutional ethics committee approved the study. Fifty patients (30 consecutive distal (M2 or smaller) anterior circulation occlusions, ten M1 occlusions, ten cases without occlusion) presenting with suspected AIS who underwent MPCTA were included. Post-processing of MPCTA studies created "subtraction" and "delayed enhancement" (DE) datasets. Initially, non contrast CT and MPCTA studies for each patient were evaluated. Readers' confidence, speed and sensitivity of detection of intracranial vessel occlusions were recorded. After an interval of at least 4 weeks, readers were provided with post-processed images and studies were re-evaluated. RESULTS: While the sensitivity of detection of intracranial vessel occlusions was equal for both conventional MPCTA and subMPCTA, the mean time taken to identify a vessel occlusion decreased by 64 % using subMPCTA (16 s vs. 45 s with conventional MPCTA) (p<0.001). In addition, confidence in interpretation improved (from 4.4 to 4.9) using subMPCTA (p<0.001). CONCLUSION: SubMPCTA is a novel technique that aids in identifying small intracranial vessel occlusions in the suspected AIS patient. SubMPCTA increases confidence in interpretation and reduces the time taken to detect intracranial vessel occlusions. KEY POINTS: * SubMPCTA processes MPCTA data to better demonstrate intracranial arterial occlusions. * SubMPCTA increases confidence and speed of interpretation of MPCTA studies. * SubMPCTA may aid in rapidly differentiating acute ischaemic stroke from stroke mimics. PMID- 29134351 TI - 3D T2-weighted imaging to shorten multiparametric prostate MRI protocols. AB - OBJECTIVES: To determine whether 3D acquisitions provide equivalent image quality, lesion delineation quality and PI-RADS v2 performance compared to 2D acquisitions in T2-weighted imaging of the prostate at 3 T. METHODS: This IRB approved, prospective study included 150 consecutive patients (mean age 63.7 years, 35-84 years; mean PSA 7.2 ng/ml, 0.4-31.1 ng/ml). Two uroradiologists (R1, R2) independently rated image quality and lesion delineation quality using a five point ordinal scale and assigned a PI-RADS score for 2D and 3D T2-weighted image data sets. Data were compared using visual grading characteristics (VGC) and receiver operating characteristics (ROC)/area under the curve (AUC) analysis. RESULTS: Image quality was similarly good to excellent for 2D T2w (mean score R1, 4.3 +/- 0.81; R2, 4.7 +/- 0.83) and 3D T2w (mean score R1, 4.3 +/- 0.82; R2, 4.7 +/- 0.69), p = 0.269. Lesion delineation was rated good to excellent for 2D (mean score R1, 4.16 +/- 0.81; R2, 4.19 +/- 0.92) and 3D T2w (R1, 4.19 +/- 0.94; R2, 4.27 +/- 0.94) without significant differences (p = 0.785). ROC analysis showed an equivalent performance for 2D (AUC 0.580-0.623) and 3D (AUC 0.576-0.629) T2w (p > 0.05, respectively). CONCLUSIONS: Three-dimensional acquisitions demonstrated equivalent image and lesion delineation quality, and PI-RADS v2 performance, compared to 2D in T2-weighted imaging of the prostate. Three dimensional T2-weighted imaging could be used to considerably shorten prostate MRI protocols in clinical practice. KEY POINTS: * 3D shows equivalent image quality and lesion delineation compared to 2D T2w. * 3D T2w and 2D T2w image acquisition demonstrated comparable diagnostic performance. * Using a single 3D T2w acquisition may shorten the protocol by 40%. * Combined with short DCE, multiparametric protocols of 10 min are feasible. PMID- 29134352 TI - Accuracy of apparent diffusion coefficient in differentiating pancreatic neuroendocrine tumour from intrapancreatic accessory spleen. AB - OBJECTIVES: To evaluate and compare the accuracy of absolute apparent diffusion coefficient (ADC) and normalised ADC (lesion-to-spleen ADC ratio) in differentiating pancreatic neuroendocrine tumour (NET) from intrapancreatic accessory spleen (IPAS). METHODS: Study included 62 patients with the diagnosis of pancreatic NET (n=51) or IPAS (n=11). Two independent reviewers measured ADC on all lesions and spleen. Receiver operating characteristics (ROC) analysis to differentiate NET from IPAS was performed and compared for absolute and normalised ADC. Inter-reader reliability for the two methods was assessed. RESULTS: Pancreatic NET had significantly higher absolute ADC (1.431x10-3 vs 0.967x10-3 mm2/s; P<0.0001) and normalised ADC (1.59 vs 1.09; P<0.0001) compared to IPAS. An ADC value of >=1.206x10-3 mm2/s was 70.6% sensitive and 90.9% specific for the diagnosis of NET vs. IPAS. Lesion to spleen ADC ratio of >=1.25 was 80.4% sensitive, and 81.8% specific while ratio of >=1.29 was 74.5% sensitive and 100% specific in the differentiation. The area under the curve (AUCs) for two methods were similar (88.2% vs. 88.8%; P=0.899). Both methods demonstrated excellent inter-reader reliability with ICCs for absolute ADC and ADC ratio being 0.957 and 0.927, respectively. CONCLUSION: Both absolute and normalised ADC allow clinically relevant differentiation of pancreatic NET and IPAS. KEY POINTS: * Imaging overlaps between IPASs and pancreatic-NETs lead to unnecessary procedures including pancreatectomy. * Uniquely low ADC of spleen allows differentiating IPASs from pancreatic NETs. * Both absolute-ADC and normalised-ADC (lesion-to spleen ADC-ratio) demonstrate high accuracy in differentiating IPASs from NETs. * Both methods demonstrate excellent inter-reader reliability. PMID- 29134353 TI - Scan time reduction in diffusion-weighted imaging of the pancreas using a simultaneous multislice technique with different acceleration factors: How fast can we go? AB - OBJECTIVES: To investigate the feasibility of simultaneous multislice-accelerated diffusion-weighted imaging (sms-DWI) of the pancreas with different acceleration factors and its influence on image quality, acquisition time and apparent diffusion coefficients (ADCs) in comparison to conventional sequences. METHODS: DWI of the pancreas was performed at 1.5T in ten healthy volunteers and 20 patients with sms-accelerated echo-planar DWI using two different sms acceleration factors of 2 and 3 (sms2/3-DWI). These DWI sequences were compared to conventional DWI (c-DWI) in terms of image quality parameters (5-point Likert scale) and ADC measurements. RESULTS: c-DWI and sms2-DWI offered equivalently high overall image quality (4 [1; 5]) with scan time reduction to one-third (c DWI: 173 s, sms2-DWI: 56 s). Sms3-DWI showed significantly poorer overall image quality (3 [1; 5]; p < 0.0001). ADC values were significantly lower in sms3-DWI compared to c-DWI in the pancreatic body and tail (body: c-DWI 1.4 x 10-3 mm2/s, sms3-DWI 1.0 x 10-3 mm2/s, p = 0.028; tail: c-DWI 1.3 x 10-3 mm2/s and sms3-DWI 1.0 x 10-3 mm2/s, p = 0.014). CONCLUSIONS: Accelerated multislice DWI of the pancreas offers high image quality with a substantial reduction of acquisition time. Lower ADC values in multislice DWI should be considered in diagnostic reading. KEY POINTS: * Simultaneous multislice-accelerated diffusion-weighted imaging (sms-DWI) promises scan time minimisation. * Sms-DWI of the pancreas offers diagnostic image quality in volunteers and patients. * Sms-DWI with an acceleration factor of 2 offers high image quality. * Higher acceleration factors in sms-DWI do not provide sufficient diagnostic image quality. * ADC values may be lower in sms-DWI. PMID- 29134354 TI - Conventional and synthetic MRI in multiple sclerosis: a comparative study. AB - OBJECTIVES: To compare the assessment of patients with multiple sclerosis (MS) using synthetic and conventional MRI. MATERIALS AND METHODS: Synthetic and conventional axial images were prospectively acquired for 52 patients with diagnosed MS. Quantitative MRI (qMRI) was used for measuring proton density and relaxation times (T1, T2) and then, based on these parameters, synthetic T1W, T2W and FLAIR images were calculated. Image stacks were reviewed blindly, independently and in random order by two radiologists. The number and location for all lesions were documented and categorised. A combined report of lesion load and presence of contrast-enhancing lesions was compiled for each patient. Agreement was evaluated using kappa statistic. RESULTS: There was no significant difference in lesion detection using synthetic and conventional MRI in any anatomical region or for any of the three image types. Inter- and intra-observer agreements were mainly higher (p < 0.05) using conventional images but there was no significant difference in any specific region or for any image type. There was no significant difference in the outcome of the combined reports. CONCLUSION: Synthetic MR images show potential to be used in the assessment of MS dissemination in space (DIS) despite a slightly lower inter- and intra-observer agreement compared to conventional MRI. KEY POINTS: * Synthetic MR images may potentially be useful in the assessment of MS. * Examination times may be shortened. * Inter- and intra-observer agreement is generally higher using conventional MRI. PMID- 29134355 TI - Extracellular contrast agent-enhanced MRI: 15-min delayed phase may improve the diagnostic performance for hepatocellular carcinoma in patients with chronic liver disease. AB - OBJECTIVES: To determine the value of a 15-min delayed phase in extracellular contrast agent (ECA)-enhanced magnetic resonance imaging (MRI) for evaluation of hepatocellular carcinoma (HCC) in patients with chronic liver disease. METHODS: Between 2014 and 2015, 103 patients with chronic liver disease underwent ECA enhanced MRI; 133 lesions consisting of 107 HCCs, 23 benign lesions and three non HCC malignancies were identified with pathological or clinical diagnosis. MRI images were reviewed by two abdominal radiologists independently using the European Association for the Study of the Liver (EASL) and Liver Imaging Reporting and Data System (LI-RADS) criteria. Imaging features observed in the 15 min delayed phase were recorded. RESULTS: Of 107 HCCs, three or four additional HCCs were diagnosed according to the EASL criteria by adding the 15-min delayed phase, increasing sensitivity (Reviewer 1, from 69.2-72.0 % [P = 0.072]; Reviewer 2, from 75.7-79.4 % [P = 0.041]). Reviewers 1 and 2 upgraded one and four HCCs from LR-4 to LR-5 based on the LI-RADS, respectively. Among 23 benign lesions, no additional findings were observed in the 15-min delayed phase. CONCLUSIONS: Including the 15-min delayed phase in ECA-enhanced MRI may improve the diagnostic performance for HCC in patients with chronic liver disease. KEY POINTS: * Additional acquisition of 15-min delayed phase (FDP) requires approximately 20 s. * About 5 % of HCCs show washout or capsule appearance only in FDP. * Including FDP improves the sensitivity of extracellular contrast agent-enhanced MRI for HCC. * These results are applicable only to patients with chronic liver disease. PMID- 29134356 TI - Secretin-stimulated ultrasound estimation of pancreatic secretion in cystic fibrosis validated by magnetic resonance imaging. AB - OBJECTIVES: Secretin-stimulated magnetic resonance imaging (s-MRI) is the best validated radiological modality assessing pancreatic secretion. The purpose of this study was to compare volume output measures from secretin-stimulated transabdominal ultrasonography (s-US) to s-MRI for the diagnosis of exocrine pancreatic failure in cystic fibrosis (CF). METHODS: We performed transabdominal ultrasonography and MRI before and at timed intervals during 15 minutes after secretin stimulation in 21 CF patients and 13 healthy controls. To clearly identify the subjects with reduced exocrine pancreatic function, we classified CF patients as pancreas-sufficient or -insufficient by secretin-stimulated endoscopic short test and faecal elastase. RESULTS: Pancreas-insufficient CF patients had reduced pancreatic secretions compared to pancreas-sufficient subjects based on both imaging modalities (p < 0.001). Volume output estimates assessed by s-US correlated to that of s-MRI (r = 0.56-0.62; p < 0.001). Both s US (AUC: 0.88) and s-MRI (AUC: 0.99) demonstrated good diagnostic accuracy for exocrine pancreatic failure. CONCLUSIONS: Pancreatic volume-output estimated by s US corresponds well to exocrine pancreatic function in CF patients and yields comparable results to that of s-MRI. s-US provides a simple and feasible tool in the assessment of pancreatic secretion. KEY POINTS: * Cystic fibrosis patients with affected pancreas have reduced pancreatic secretions. * Secretin-stimulated sonography is a simple and feasible method to assess pancreatic output. * Secretin-simulated MRI is a more precise method to assess pancreatic secretions. * The sonographic and MRI methods yielded comparable pancreatic secretory output estimates. PMID- 29134357 TI - Apparent diffusion coefficient of vertebral haemangiomas allows differentiation from malignant focal deposits in whole-body diffusion-weighted MRI. AB - OBJECTIVES: The aim of this study was to identify apparent diffusion coefficient (ADC) values for typical haemangiomas in the spine and to compare them with active malignant focal deposits. METHODS: This was a retrospective single institution study. Whole-body magnetic resonance imaging (MRI) scans of 106 successive patients with active multiple myeloma, metastatic prostate or breast cancer were analysed. ADC values of typical vertebral haemangiomas and malignant focal deposits were recorded. RESULTS: The ADC of haemangiomas (72 ROIs, median ADC 1,085*10-6mm2s-1, interquartile range 927-1,295*10-6mm2s-1) was significantly higher than the ADC of malignant focal deposits (97 ROIs, median ADC 682*10-6mm2s 1, interquartile range 583-781*10-6mm2s-1) with a p-value < 10-6. Receiver operating characteristic (ROC) analysis produced an area under the curve of 0.93. An ADC threshold of 872*10-6mm2s-1 separated haemangiomas from malignant focal deposits with a sensitivity of 84.7 % and specificity of 91.8 %. CONCLUSIONS: ADC values of classical vertebral haemangiomas are significantly higher than malignant focal deposits. The high ADC of vertebral haemangiomas allows them to be distinguished visually and quantitatively from active sites of disease, which show restricted diffusion. KEY POINTS: * Whole-body diffusion-weighted MRI is becoming widely used in myeloma and bone metastases. * ADC values of vertebral haemangiomas are significantly higher than malignant focal deposits. * High ADCs of haemangiomas allows them to be distinguished from active disease. PMID- 29134358 TI - Abstracts from HSG 2017. PMID- 29134360 TI - Protein Kinase C in the Cerebellum: Its Significance and Remaining Conundrums. AB - Protein kinase C (PKC), a family of serine/threonine protein kinases, mediates a myriad of patho-physiological cellular events in various tissues. The originally discovered PKC (conventional) requires the binding of diacylglycerol and Ca2+ for full activation. The conventional PKC consists of four isoforms, PKCalpha, PKCbetaI/betaII, and PKCgamma. PKCalpha and PKCbetaI/betaII are expressed in the cells of various tissues including the brain, while PKCgamma is present specifically in neurons of the brain and spinal cord. The cerebellum expresses the largest amount of PKC with all its four isoforms. Purkinje cells express PKCalpha and PKCgamma. Previous studies have shown that PKCalpha is involved in the induction of long-term depression (LTD) at parallel fiber-Purkinje cell synapses. On the other hand, analysis of PKCgamma-deficient mice has revealed that PKCgamma plays a critical role in eliminating supernumerary climbing fiber synapses from developing Purkinje cells. Although why PKCalpha has no compensatory action in climbing fiber pruning in PKCgamma-deficient Purkinje cells had so far remained unclear, we have recently demonstrated that PKCalpha is also capable of pruning supernumerary climbing fiber synapses, but the expression levels of PKCalpha are too low to achieve pruning in PKCgamma-null Purkinje cells. Notably, although PKCgamma is most abundant in Purkinje cells, its physiological role in mature Purkinje cells remained totally unknown. In addition to a concise review of the physiological and pathological roles of conventional PKCs in Purkinje cells, this report postulates a contribution of PKCalpha in developing Purkinje cells and a possible involvement of PKCgamma in motor coordination in the mature cerebellum. PMID- 29134361 TI - Sonic Hedgehog Agonist Protects Against Complex Neonatal Cerebellar Injury. AB - The cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and postnatal glucocorticoid administration. We modeled chronic hypoxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of prednisolone as shown by greater volume loss and Purkinje cell death. In the setting of hypoxia and prednisolone, administration of a small molecule Smoothened-Hedgehog agonist (SAG) preserved cerebellar volume and protected against Purkinje cell death. Such protective effects were observed even when SAG was given as a one-time dose after dual insult. To model complex injury and determine cell type-specific roles for the hypoxia inducible factor (HIF) pathway, we performed conditional knockout of von Hippel Lindau (VHL) to hyperactivate HIF1alpha in cerebellar granule neuron precursors (CGNP) or Purkinje cells. Surprisingly, HIF activation in either cell type resulted in no cerebellar deficit. However, in mice administered prednisolone, HIF overactivation in CGNPs resulted in significant cerebellar hypoplasia, whereas HIF overactivation in Purkinje cells caused cell death. Together, these findings indicate that HIF primes both cell types for injury via glucocorticoids, and that hypoxia/HIF + postnatal glucocorticoid administration act on distinct cellular pathways to cause cerebellar injury. They further suggest that SAG is neuroprotective in the setting of complex neonatal cerebellar injury. PMID- 29134362 TI - Selecting patients for hyperthermia combined with preoperative chemoradiotherapy for locally advanced rectal cancer. AB - BACKGROUND: This study investigated the role of hyperthermia combined with preoperative concurrent chemoradiotherapy (CCRT) for locally advanced rectal cancer (LARC) according to hypoxic marker expression. METHODS: One hundred and nine LARC patients with tissue blocks available for immunohistochemical assessment of carbonic anhydrase 9 (CA9) expression were reviewed. CA9 expression was considered positive when the staining percentage of tumor cells was >25% (n = 31). Pelvic radiotherapy with a total dose of 39.6-45 Gy was delivered concurrently with fluorouracil-based chemotherapy. Hyperthermia was administered to 52 patients twice a week during CCRT. Treatment response and outcomes were compared between hyperthermochemoradiotherapy (HCRT) and CCRT groups. RESULTS: In patients with positive CA9 expression, the rates of downstaging (p = 0.060) and pathologic complete response (p = 0.064) tended to be higher in the HCRT group than in the CCRT group. Distant metastasis-free survival (p = 0.029) and cancer specific survival (p = 0.020) were significantly worse in tumors with both positive CA9 expression and poor tumor response. Negative CA9 expression, presence of major tumor response, and the use of hyperthermia were significant favorable prognostic factors for cancer-specific survival after the first recurrence in multivariate analysis. CONCLUSIONS: Hyperthermia might selectively enhance the preoperative treatment response in LARC with positive CA9 expression and offset the negative effect of hypoxia on prognosis. Pretreatment evaluation of hypoxia could aid in the selection of patients who might benefit from hyperthermia. PMID- 29134363 TI - Further augmentation of molecular responses with dasatinib therapy in chronic myeloid leukemia patients who gained major molecular response under imatinib. PMID- 29134364 TI - Correction to: Paternal lineage affinity of the Malay subethnic and Orang Asli populations in Peninsular Malaysia. AB - The original version of this article contains an error. The Author Abd Rashid Nur Haslindawaty has been added as to the above author group as third author. The original article was corrected. PMID- 29134365 TI - Correction to: Sex estimation of infants through geometric morphometric analysis of the ilium. AB - After publication of the original article, it was brought to authors' attention two errors that were included in the final publication. PMID- 29134359 TI - Anxiety, Depression, and the Microbiome: A Role for Gut Peptides. AB - The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses. PMID- 29134366 TI - Genetic characteristics of 19 STRs in Chinese Uzbek ethnic and its phylogenetic relationships with other 24 populations. AB - Allelic frequencies and genetic polymorphisms of 19 short tandem repeats loci were investigated so as to provide more genetic data for forensic applications in Chinese Uzbek group; besides, we evaluated phylogenetic relationships of Uzbek group with other populations. All loci were observed to conform to Hardy-Weinberg equilibrium after Bonferroni's correction. Two hundred and nine alleles were identified in 212 unrelated healthy Uzbek individuals and their allelic frequencies ranged from 0.0024 to 0.5259. The cumulative discrimination power and cumulative probability of exclusion were 0.999999999999999999999996501 and 0.999999998759, respectively. The results of population differentiation comparison, principal component analysis, and phylogenetic tree revealed that Uzbek group had close relationships with Uyghur and Kazakh groups. PMID- 29134368 TI - [Patellofemoral instability]. AB - Patellofemoral instability is an extremely limiting pathology in young and active patients. Anatomical reasons for patellar instability, such as high-riding patella, elevated distance from the tibial tuberosity to trochlear groove (TTTG), trochlear dysplasia, insufficient medial patellofemoral ligament (MPFL) and malpositioning of the axes and torsion can lead to chronic patellofemoral instability and must be thoroughly analyzed. The first dislocation can be treated conservatively, with the exception of an osteochondral defect. In the case of recurrent dislocation of the patella surgery is indicated, with good results regarding stability and less clear results regarding the influence on pain. The surgical approach is determined by the anatomical pathology. High-riding patella and elevated TTTG can be corrected by osteotomy of the tibial tuberosity and severe trochlear dysplasia by trochleoplasty. Insufficient MPFL can be reconstructed very successfully. The influence and correction of the axes and torsion are not yet fully understood and must be studied further. PMID- 29134369 TI - Evolution of the Contact Area with Normal Load for Rough Surfaces: from Atomic to Macroscopic Scales. AB - The evolution of the contact area with normal load for rough surfaces has great fundamental and practical importance, ranging from earthquake dynamics to machine wear. This work bridges the gap between the atomic scale and the macroscopic scale for normal contact behavior. The real contact area, which is formed by a large ensemble of discrete contacts (clusters), is proven to be much smaller than the apparent surface area. The distribution of the discrete contact clusters and the interaction between them are key to revealing the mechanism of the contacting solids. To this end, Green's function molecular dynamics (GFMD) is used to study both how the contact cluster evolves from the atomic scale to the macroscopic scale and the interaction between clusters. It is found that the interaction between clusters has a strong effect on their formation. The formation and distribution of the contact clusters is far more complicated than that predicted by the asperity model. Ignorance of the interaction between them leads to overestimating the contacting force. In real contact, contacting clusters are smaller and more discrete due to the interaction between the asperities. Understanding the exact nature of the contact area with the normal load is essential to the following research on friction. PMID- 29134371 TI - TiO2 Nanotube Arrays: Fabricated by Soft-Hard Template and the Grain Size Dependence of Field Emission Performance. AB - Highly ordered TiO2 nanotube (TNT) arrays were successfully synthesized by the combination of soft and hard templates. In the fabrication of them, anodic aluminum oxide membranes act as the hard template while the self-assembly of polystyrene-block-poly(ethylene oxide) (PS-b-PEO) complexed with titanium tetraisopropoxide (TTIP, the precursor of TiO2) provides the soft template to control the grain size of TiO2 nanotubes. Our results indicate that the field emission (FE) performance depends crucially on the grain size of the calcinated TiO2 which is dominated by the PS-b-PEO and its blending ratio with TTIP. The optimized sample (with the TTIP/PEO ratio of 3.87) exhibits excellent FE performances involving both a low turn-on field of 3.3 V/um and a high current density of 7.6 mA/cm2 at 12.7 V/MUm. The enhanced FE properties can be attributed to the low effective work function (1.2 eV) resulted from the smaller grain size of TiO2. PMID- 29134367 TI - Imaging of Cardiovascular Disease in Pregnancy and the Peripartum Period. AB - OPINION STATEMENT: Cardiovascular disease is an important cause of morbidity and mortality during pregnancy and the postpartum period. During pregnancy, the cardiovascular system undergoes extensive hemodynamic, hormonal, and microstructural changes which may exacerbate a preexisting underlying cardiovascular condition or predispose to cardiovascular complications not typically seen in young healthy women. Such conditions include spontaneous coronary artery dissection, atherosclerotic coronary artery disease, and peripartum cardiomyopathy. When evaluating this patient population, the diagnostic strategy should be tailored to specifically assess this distinct disease spectrum. The choice of imaging techniques must also consider potential risks to both the mother and child; a unique challenge of diagnostic imaging during pregnancy. The risk of radiation from radiography, computed tomography, and nuclear medicine imaging; iodinated and gadolinium-based contrast media for computed tomography and magnetic resonance imaging respectively; and heat deposition from sonography are of special importance during pregnancy. A thorough understanding of pregnancy-specific cardiovascular complications and the capabilities and risks of available diagnostic imaging modalities is crucial to appropriately manage the pregnant patient. PMID- 29134372 TI - Systematic Review of Cytoreductive Surgery and Bevacizumab-Containing Chemotherapy in Advanced Ovarian Cancer: Focus on Safety. AB - BACKGROUND: Initial experiences reported increased surgical morbidities in patients receiving cytoreductive surgery for colorectal cancer after bevacizumab containing chemotherapy; however, more recent literature suggests a favorable toxicity profile in patients with advanced ovarian cancer (AOC). With the aim of providing a more objective point of view on this controversial issue, we present here a systematic literature review. METHODS: Systematic revision of the available literature was conducted using the PubMed, MEDLINE, and EMBASE electronic databases. All studies reporting safety data regarding cytoreductive surgery performed before or after bevacizumab-containing chemotherapy have been analyzed for the purposes of this study. The study has been prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Forty-eight studies were retrieved from the electronic databases, with 23 (47.9%) being excluded due to an unsatisfactory study design. Among the remaining 25 manuscripts, 16 did not report data regarding surgical morbidities after cytoreductive surgery, therefore only 9 studies were included in the final analysis. Overall, 198 AOC patients received bevacizumab-containing neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in the context of five studies, among whom 21 women experienced grade 3/4 postoperative complications (10.6%), which appears to be in line with data reported in patients receiving IDS after carboplatin-paclitaxel NACT. Results from phase I-II clinical trials, and dataset analysis from GOG-0218, did not observe an increased incidence of complications in AOC patients receiving bevacizumab-containing adjuvant chemotherapy after cytoreductive surgery. CONCLUSIONS: The incorporation of bevacizumab into first-line chemotherapy was not associated with increased morbidities before and after cytoreductive surgery in women with AOC. PMID- 29134373 TI - Outcomes of Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients Older than 70 Years; Survival Benefit at Considerable Morbidity and Mortality: A Reply. PMID- 29134374 TI - Ultrasound-Guided Restaging and Localization of Axillary Lymph Nodes After Neoadjuvant Chemotherapy for Guidance of Axillary Surgery in Breast Cancer Patients: Experience with Activated Charcoal. AB - OBJECTIVE: The aim of this study was to review our experience with ultrasound (US)-guided localization of axillary lymph nodes using activated charcoal for the guidance of axillary surgery after neoadjuvant chemotherapy (NAC) in clinically node-positive breast cancer patients. METHODS: Between April 2016 and April 2017, US-guided localization of the most suspicious axillary lymph nodes at restaging US using activated charcoal (CharcotraceTM) was performed in 45 consecutive, clinically node-positive breast cancer patients who had less than two suspicious nodes after NAC and axillary surgery with sentinel node biopsy. Sentinel nodes were defined as radioactive nodes or nodes containing blue dye. The concordance between final pathological results for both the tattooed and sentinel nodes was analyzed. RESULTS: Sentinel node biopsy failed in five patients (11%) in whom axillary surgery was performed under the guidance of the tattooed node. The tattooed nodes were identified in the surgical field in 44 patients (98%). Of the 44 tattooed nodes, 25 (57%) were concordant with the sentinel nodes and 19 (43%) were non-sentinel nodes, including the five nodes with failed sentinel node biopsy. In the final pathological results, 18 patients (40%) had metastatic nodes. The sensitivities for detecting axillary metastasis of the sentinel node biopsy, tattooed node biopsy, and the sentinel and/or tattooed node biopsy were 61% (11/18), 67% (12/18), and 78% (14/18), respectively. CONCLUSION: US-guided localization of axillary lymph nodes using activated charcoal at restaging after NAC in clinically node-positive breast cancer patients is a useful technique to guide axillary surgery, with a high identification rate. PMID- 29134375 TI - In Reply: Centralization of Upper Gastrointestinal Cancer Care Should Be Dictated by Quality of Care. PMID- 29134376 TI - Treatment Patterns and Outcomes for Patients with Adrenocortical Carcinoma Associated with Hospital Case Volume in the United States: A Reply. PMID- 29134377 TI - Markers of Systemic Inflammatory Response are Prognostic Factors in Patients with Pancreatic Neuroendocrine Tumors (PNETs): A Prospective Analysis. AB - BACKGROUND: The prognosis and behavior of pancreatic neuroendocrine tumors (PNETs) vary and may be divergent even at the same stage or tumor grade. Markers of systemic inflammatory response are readily available and are inexpensive, and have been shown to be prognostic factors in several cancers. OBJECTIVE: The aim of this study was to evaluate the prognostic utility of markers of systemic inflammatory response in patients with PNETs. METHODS: A prospective study of 97 patients with PNETs was performed (median follow-up of 15 months, range 12-73 months). Neutrophil-to-lymphocyte ratios (NLRs) and lymphocyte-to-monocyte ratios (LMRs) were calculated at baseline and preoperatively. The primary outcome measures were progression-free survival (PFS) and recurrence-free survival (RFS) after curative resection. RESULTS: Among all patients, an NLR > 2.3 [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.05-6.08, p = 0.038] and the presence of distant metastases (HR 2.8, 95% CI 1.26-6.21, p = 0.012) were independent predictors of disease progression. Among patients who did not undergo surgery during the study period, both platelet-to-lymphocyte ratio (PLR) > 160.9 (HR 5.86, 95% CI 1.27-27.08, p = 0.023) and mean platelet volume > 10.75 fL (HR 6.63, 95% CI 1.6-27.48, p = 0.009) were independently associated with worse PFS on multivariable analysis. Among patients who underwent complete resection, an LMR < 3.46 was associated with a worse RFS (HR 9.72, 95% CI 1.19-79.42, p = 0.034). CONCLUSIONS: PLR > 160.9 and an MPV > 10.75 fL at baseline are independent predictors of disease progression, while an LMR < 3.46 is an independent predictor of tumor recurrence after complete resection in patients with PNETs. PMID- 29134378 TI - Organ Preservation in Rectal Cancer After Chemoradiation: Should We Extend the Observation Period in Patients with a Clinical Near-Complete Response? AB - BACKGROUND: To assess whether extending the observation period in patients with a near clinical complete response (near cCR) after chemoradiation (CRT) leads to an impaired oncological outcome. METHODS: Patients who had a clinical complete response (cCR) 8-10 weeks after CRT restaging with magnetic resonance imaging and endoscopy were offered a watch-and-wait strategy (W&W1), while patients with a near cCR were offered to undergo local excision or a second restaging 6-12 weeks later. Patients who achieved a cCR at the second restaging were also offered a watch-and-wait strategy (W&W2). RESULTS: Overall, 102 patients with a cCR at the first restaging immediately entered the W&W1, while the remaining 68 patients had a near cCR: 19 patients underwent transanal endoscopic microsurgery and 49 patients opted for a second restaging. Additionally, 44/49 (90%) patients showed a cCR at the second restaging and entered the W&W2. Patients in the W&W1 group had a 2-year local regrowth-free rate (LRFR) of 84% and 2-year overall survival (OS) of 99%, while patients in the W&W2 group had a 2-year LRFR of 73% and OS of 98% (p > 0.05). Multivariable Cox regression analyses showed that late inclusion was not a significant predictive factor for higher risk of LR or lower non regrowth disease-free survival. CONCLUSIONS: Overall, 90% of patients with a near cCR 8-10 weeks after CRT will proceed to a cCR 6-12 weeks later; therefore, it seems logical to extend the observation period rather than to proceed to surgery. Although there is a non-significant increase in local regrowth rate in these patients, it does not seem to impact the oncological outcome. PMID- 29134379 TI - How Low Can We Go-and Should We? Risk Reduction for Minimal-Volume DCIS. PMID- 29134380 TI - Radioactive Seed Localization Versus Wire Localization for Nonpalpable Breast Lesions: A Two-Year Initial Experience at a Large Community Hospital. AB - BACKGROUND: Radioactive seed localization (RSL) is a safe and effective alternative to wire localization (WL) for nonpalpable breast lesions. While several large academic institutions currently utilize RSL, few community hospitals have adopted this technique. OBJECTIVE: The aim of this study was to examine the experience of RSL versus WL at a large community hospital. METHODS: A retrospective chart review of patients who underwent RSL or WL for breast conserving surgery from 1 November 2013 to 31 November 2015. RESULTS: The total number of lesions examined was 382. RSL was utilized in 205 (54%) lesions, with 187 undergoing single RSL, while WL was used in 155 (40%) lesions, with 109 undergoing single WL; both techniques were used in 22 (6%) lesions. Pathology was benign in 142 (48%) lesions, with 93 RSLs and 49 WLs. For malignant lesions, mean specimen size was 36.3 g for single RSL and 35.9 g for single WL (p = 0.904). Re excision for margin clearance was required for 16 (17%) malignant lesions in the RSL group and 10 (17%) in the WL group (p = 0.954). For malignant lesions, mean operating room time was 86 min for single RSL versus 70 min for single WL (p = 0.014). CONCLUSIONS: The use of RSL is a viable option in the community setting, with several benefits over WL. While operative times were slightly longer with RSL, there was no difference in specimen size or re-excision rate for malignant lesions. PMID- 29134381 TI - Pre-SN Ultrasound-FNAC for Lymph Node Metastases in Melanoma Patients: A Reply. PMID- 29134382 TI - Comment on: Does Red Blood Cell Distribution Width Really Have a Prognostic Role in Upper Tract Urothelial Carcinoma? PMID- 29134383 TI - Spatial distribution and metal contamination in the coastal sediments of Al Khafji area, Arabian Gulf, Saudi Arabia. AB - To document the spatial distribution and metal contamination in the coastal sediments of the Al-Khafji area in the northern part of the Saudi Arabian Gulf, 27 samples were collected for Al, V, Cr, Mn, Cu, Zn, Cd, Pb, Hg, Sr, As, Fe, Co, and Ni analysis using inductively coupled plasma-mass spectrometer (ICP-MS). The results revealed the following descending order of the metal concentrations: Sr > Fe > Al > As > Mn > Ni > V > Zn > Cr > Cu > Pb > Co > Hg > Cd. Average levels of enrichment factor of Sr, As, Hg, Cd, Ni, V, Cu, Co, and Pb were higher than 2 (218.10, 128.50, 80.94, 41.50, 12.31, 5.66, 2.95, 2.90, and 2.85, respectively) and that means the anthropogenic sources of these metals, while Al, Zn, Cr and Mn have enrichment factor less than 2, which implies natural sources. Average values of Sr, Hg, Cd, Cr, Ni, and As in the coastal sediments of Al-Khafji area were mostly higher than the values recorded from the background shale and earth crust and from those results along coasts of the Caspian Sea and the Mediterranean Sea. The highest levels of Cu in the northern part of the studied coastline might be due to Al-Khafji desalination plant, while levels of Al, Ni, Cr, Fe, Mn, Pb, and Zn in the central part may be a result of landfilling and industrial sewage. The highest levels of As, Cd, Co, Cu, Hg, and V in the southern part seem to be due to oil pollutants from Khafji Joint Operations (KJO). The higher values of Sr in the studied sediments in general and particularly in locality 7 could relate to the hypersalinity and aragonitic composition of the scleractinian corals abundant in that area. PMID- 29134384 TI - Totally robotic single docking low anterior resection for rectal cancer: pearls and pitfalls. AB - Total robotic resection of mid- and low rectal cancers confers technical advantages within the confines of the pelvis and allows difficult rectal cancer cases to be performed efficiently with less risk of conversion to open. To maximize the advantage of robotic surgery, we utilize the technique of single docking totally robotic dissection for rectal cancer for both the Da Vinci Si and Xi Surgical Systems. All steps are performed robotically, with the surgery divided into two phases. The first phase consists of inferior mesenteric artery and vein ligation, sigmoid and descending colon mobilization and splenic flexure takedown. Phase two is rectal dissection and pelvic total mesorectal excision. In this article, which is complemented by a video, we describe in detail our surgical technique for totally robotic dissection for rectal cancer using a standardized 'medial to lateral' approach with emphasis on the pearls and pitfalls of this surgery. PMID- 29134385 TI - Robotic-assisted multivisceral resection for rectal cancer: short-term outcomes at a single center. AB - BACKGROUND: The safety and feasibility of robotic-assisted multivisceral resection for locally advanced rectal cancer remain unclear. The aim of this study was to assess the short-term outcomes of this procedure at our institution. METHODS: From December 2011 to December 2016, patients who underwent robotic assisted multivisceral resection for rectal cancer were investigated. Patient demographics, treatment characteristics, perioperative outcomes, and pathological results were evaluated retrospectively. RESULTS: There were 31 patients; 17 men (54.8%) and 14 women (45.2%), with a median age of 65 years (range 40-82 years). Twenty-one patients (67.7%) had a cT4 tumor, 9 patients (29.0%) had a pT4b tumor, and all patients except one (96.8%) underwent complete resection of the primary tumor with negative resection margins. Eleven patients (35.5%) received neoadjuvant chemoradiation. The most commonly resected organ was the vaginal wall (n = 12, 38.7%), followed by the prostate (n = 10, 32.3%). Lateral lymph node dissection was performed in 20 patients (64.5%). The median operative time was 394 min (range 189-549 min), and the median blood loss was 41 mL (range 0-502 mL). None of the patients received intraoperative blood transfusions or required conversion to open. Overall, postoperative complications occurred in 11 patients (35.5%). The most frequent complication was urinary retention (n = 5, 16.1%), and none of the patients developed serious complications classified as Clavien-Dindo grades III-V. CONCLUSIONS: Robotic-assisted multivisceral resection for rectal cancer is safe and technically feasible. PMID- 29134386 TI - Laparoscopic Deloyers procedure to facilitate primary anastomosis after extended resection for synchronous cancers of transverse colon and rectum: easy to preform with good functional outcome. PMID- 29134388 TI - Nicolaas Bloembergen: a pioneer in magnetic resonance and in maser and laser physics. PMID- 29134387 TI - Should the rectal defect be closed following transanal local excision of rectal tumors? A systematic review and meta-analysis. AB - BACKGROUND: Transanal local excision (TLE) has become the treatment of choice for benign and early-stage selected malignant tumors. However, closure of the rectal wall defect remains a controversial point and the available literature still remains unclear. Our aim was to determine through a systematic review of the literature and a meta-analysis of relevant studies whether or not the wall defect following TLE of rectal tumors should be closed. METHODS: Medline and the Cochrane Trials Register were searched for trials published up to December 2016 comparing open versus closed management of the surgical rectal defect after TLE of rectal tumors. Meta-analysis was performed using Review Manager 5.0. RESULTS: Four studies were analyzed, yielding 489 patients (317 in the closed group and 182 in the open group). Meta-analysis showed no significant difference between the closed and open groups regarding the overall morbidity rate (OR 1.26; 95% CI 0.32-4.91; p = 0.74), postoperative local infection rate (OR 0.62; 95% CI 0.23 1.62; p = 0.33), postoperative bleeding rate (OR 0.83; 95% CI 0.29-1.77; p = 0.63), and postoperative reintervention rate (OR 2.21; 95% CI 0.52-9.47; p = 0.29). CONCLUSIONS: This review and meta-analysis suggest that there is no difference between closure or non-closure of wall defects after TLE. PMID- 29134389 TI - Exploration, antifungal and antiaflatoxigenic activity of halophilic bacteria communities from saline soils of Howze-Soltan playa in Iran. AB - In the present study, halophilic bacteria communities were explored in saline soils of Howze-Soltan playa in Iran with special attention to their biological activity against an aflatoxigenic Aspergillus parasiticus NRRL 2999. Halophilic bacteria were isolated from a total of 20 saline soils using specific culture media and identified by 16S rRNA sequencing in neighbor-joining tree analysis. Antifungal and antiaflatoxigenic activities of the bacteria were screened by a nor-mutant A. parasiticus NRRL 2999 using visual agar plate assay and confirmed by high-performance liquid chromatography. Among a total of 177 halophilic bacteria belonging to 11 genera, 121 isolates (68.3%) inhibited A. parasiticus growth and/or aflatoxin production. The most potent inhibitory bacteria of the genera Bacillus, Paenibacillus and Staphylococcus were distributed in three main phylogenetic clusters as evidenced by 16S rRNA sequence analysis. A. parasiticus growth was inhibited by 0.7-92.7%, while AFB1 and AFG1 productions were suppressed by 15.1-98.9 and 57.0-99.6%, respectively. Taken together, halophilic bacteria identified in this study may be considered as potential sources of novel bioactive metabolites as well as promising candidates to develop new biocontrol agents for managing toxigenic fungi growth and subsequent aflatoxin contamination of food and feed in practice. PMID- 29134390 TI - Computational fluid dynamic modelling to determine the hemodynamic effects of implanting a transcatheter mitral valve within the left ventricle. PMID- 29134392 TI - Aidingibacillus halophilus gen. nov., sp. nov., a novel member of the family Bacillaceae. AB - A Gram-positive, non-motile, asporogenous and aerobic bacterium, designated YIM 98012T, was isolated from a salt lake in China. Strain YIM 98012T was found to be catalase and oxidase positive. Optimal growth of strain YIM 98012T was observed at 37 degrees C and pH 7.0 and it was found to grow in the presence of 5-20% (w/v) NaCl (optimum 10% NaCl). Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the novel strain is affiliated with the family Bacillaceae of the phylum Firmicutes and that it shares high (94.7%) sequence similarity with Alteribacillus persepolensis DSM 21632T and does not show sequence similarities of more than 94.0% to known members of other related genera. The major fatty acids (> 10%) were identified as anteiso-C15:0, anteiso C17:0, iso-C16:0 and C16:0. The genomic DNA G+C content was determined to be 41.0 mol% and the dominated respiratory quinone was identified as MK-7. The cell wall peptidoglycan of strain YIM 98012T was found to contain meso-diaminopimelic acid, while the polar lipids profile was found to include diphosphatidylglycerol, phosphatidylglycerol and phosphatidylcholine. Based on physiological and chemotaxonomic characteristics, strain YIM 98012T is concluded to be the type strain of the type species of a novel genus in the family Bacillaceae for which the name Aidingibacillus halophilus gen. nov., sp. nov. is proposed. The type strain is YIM 98012T (= KCTC 33868T = DSM 104332T). PMID- 29134393 TI - Metatranscriptomics reveals the hydrolytic potential of peat-inhabiting Planctomycetes. AB - Members of the phylum Planctomycetes are common inhabitants of northern Sphagnum dominated wetlands. Evidence is accumulating that, in these environments, some planctomycetes may be involved in degrading polymeric organic matter. The experimental data, however, remain scarce due to the low number of characterized representatives of this phylum. In a previous study, we used metatranscriptomics to assess the activity response of peat-inhabiting microorganisms to biopolymers abundantly present in native peat. The community responses to cellulose, xylan, pectin, and chitin availability were analysed relative to unamended controls. Here, we re-analysed these metatranscriptomes and retrieved a total of 1,602,783 rRNA and 35,522 mRNA sequences affiliated with the Planctomycetes. Each of the four polymers induced specific planctomycete responses. These were most pronounced on chitin. The two groups with increased 16S rRNA transcript pools were Gemmata- and Phycisphaera-like planctomycetes. Among uncultivated members of the Planctomycetaceae, two increased transcript pools were detected in pectin amended samples and belonged to Pirellula-like bacteria. The analysis of taxonomically assigned mRNA reads confirmed the specific response of Gemmata related planctomycetes to chitin amendment suggesting the presence of chitinolytic capabilities in these bacteria. PMID- 29134394 TI - Polyphasic taxonomic characterisation of a novel strain as Pararhizobium haloflavum sp. nov., isolated from soil samples near a sewage treatment tank. AB - A Gram-stain negative, aerobic, motile and ovoid- to rod-shaped bacteria strain, designated XC0140T, was isolated from soil samples near the sewage treatment tank of a chemical factory in Zhejiang Province, China, and subjected to polyphasic taxonomic investigation. Strain XC0140T grew at 10-37 degrees C and pH 6.0-9.0 (optimum, 35 degrees C and pH 7.5) and with 0-17% (w/v) NaCl (optimum, 1%). According to phylogenetic analysis based on 16S rRNA gene sequences, strain XC0140T was assigned to the genus Pararhizobium with high 16S rRNA gene sequence similarity of 95.97% to "Pararhizobium helanshanense CCNWQTX14T", followed by Pararhizobium sphaerophysae CCNWGS0238T (95.95%). Chemotaxonomic analysis showed that strain XC0140T contains ubiquinone-10 as the predominant respiratory quinone and possessed summed feature 8 (comprising C18: 1 omega7c and/or omega6c), 11 methyl C18:1 omega7c, C18: 0 and C16: 0 as predominant forms of fatty acids. The polar lipids of strain XC0140T consisted of seven phospholipids (PL), two aminolipids (AL), one glycolipid (GL) and three unidentified lipids (L1, L2 and L3). The DNA G+C content was 62.7 mol%. Based on the polyphasic taxonomic characterization, strain XC0140T is considered to represent a novel species of the genus Pararhizobium, for which the name Pararhizobium haloflavum sp. nov. is proposed. (type strain XC0140T = MCCC 1K03228T = KCTC 52582T). PMID- 29134395 TI - Choledochal malformation: terminology and aetiology. PMID- 29134396 TI - Comparing Perceived Adequacy of Help Received Among Different Classes of Individuals with Severe Mental Disorders at Five-Year Follow-Up: A Longitudinal Cluster Analysis. AB - This study developed a typology describing change in the perceived adequacy of help received among 204 individuals with severe mental disorders, 5 years after transfer to the community following a major mental health reform in Quebec (Canada). Participant typologies were constructed using a two-step cluster analysis. There were significant differences between T0 and T2 for perceived adequacy of help received and other independent variables, including seriousness of needs, help from services or relatives, and care continuity. Five classes emerged from the analysis. Perceived adequacy of help received at T2 increased for Class 1, mainly comprised of older women with mood disorders. Overall, greater care continuity and levels of help from services and relatives related to higher perceived AHR. Changes in perceived adequacy of help received resulting from several combinations of associated variables indicate that MH service delivery should respond to specific profiles and determinants. PMID- 29134397 TI - Increasing Rate of Psychological Distress in Urban Households: How Does Income Matter? AB - Numerous studies suggest 'social gradient' in health, but it is less clear whether every step up the socio-economic ladder improves health by the same degree. Based on 4326 households, the present study examines the relationship between household income and psychological distress while identifying specific risk factor in different income groups. Overall, 26.5% of sampled households were reported for being distressed. Work pressure (OR 2.0, p < 0.01) and reducing time for family/friends (OR 1.79, p < 0.01) in high-income group; overcrowding (OR 3.1, p < 0.001), lacking drinking water (OR 2.27, p < 0.001) and indoor noise pollution (OR 1.76, p < 0.001) in low income group and overcrowding (OR 3.1, p < 0.001), lacking affordable health care (OR 2.58, p < 0.001), and indoor noise pollution (OR 1.6, p < 0.001) in medium income group were significant predictors of psychological distress. People in lower income group are at greater risk of becoming distressed, but the higher income is not always the guarantor of psychological well-being. PMID- 29134399 TI - Influence of soil pathogens on early regeneration success of tropical trees varies between forest edge and interior. AB - Soil fungi are key mediators of negative density-dependent mortality in seeds and seedlings, and the ability to withstand pathogens in the shaded understory of closed-canopy forests could reinforce light gradient partitioning by tree species. For four species of tropical rainforest trees-two shade-tolerant and two shade-intolerant-we conducted a field experiment to examine the interactive effects of fungal pathogens, light, and seed density on germination and early seedling establishment. In a fully factorial design, seeds were sown into 1 m2 plots containing soil collected from underneath conspecific adult trees, with plots assigned to forest edge (high light) or shaded understory, high or low density, and fungicide or no fungicide application. We monitored total seed germination and final seedling survival over 15 weeks. Shade-intolerant species were strongly constrained by light; their seedlings survived only at the edge. Fungicide application significantly improved seedling emergence and/or survival for three of the four focal species. There were no significant interactions between fungicide and seed density, suggesting that pathogen spread with increased aggregation of seeds and seedlings did not contribute to pathogen mediated mortality. Two species experienced significant edge-fungicide interactions, but fungicide effects in edge vs. interior forest varied with species and recruitment stage. Our results suggest that changes to plant-pathogen interactions could affect plant recruitment in human-impacted forests subject to fragmentation and edge-effects. PMID- 29134398 TI - MicroRNAs and their role for T stage determination and lymph node metastasis in early colon carcinoma. AB - Worldwide, colon cancer is among the most common cancer entities. Understanding the molecular background is the key to enable accurate stage determination, which is crucial to assess optimal therapy options. The search for preoperative biomarkers is ongoing. In recent years, several studies have proposed a diagnostic and prognostic role for miRNAs in cancer. Aim of this study was to evaluate miRNA expression patterns correlating with tumor stage, especially lymph node metastasis, in primary colon carcinoma tissue. Screening was accomplished using GeneChip(r) miRNA v3.0 arrays (Thermo Fisher Scientific, Waltham, MA, USA) and validated via TaqMan(r) qPCR assays (Thermo Fisher Scientific, Waltham, MA, USA) to investigate miRNA expressions in 168 FFPE and 83 fresh frozen colon carcinoma samples. Regarding lymph node status, analyses displayed no significantly differential miRNA expression. Interestingly, divergent expression of miR-18a-5p, miR-20a-5p, miR-21-5p, miR-152-3p and miR-1973 was detected in stage pT1. Although miRNAs might not represent reliable biomarkers regarding lymph node metastasis status, they could support risk assessment in stage T1 tumors. PMID- 29134400 TI - Safe sites of pollen placement: a conflict of interest between plants and bees? AB - Plant stigmas and bee pollinators are competitors for pollen. Pollen placed on a pollinator's body can be picked up by conspecific stigmas or it can be collected by the pollinator as food. Hypothetically, one solution is for pollen to be placed on 'safe sites' on the pollinator's body, sites where the pollinator cannot easily remove it, leaving the pollen for stigmas. We compared 14 sites on the bumblebee body in terms of the ability of the bee to groom off fluorescent power, a dust that may be thought of as analogous to pollen. The safest sites were along the midline of the dorsal thorax, the dorsal abdomen, and the ventral abdomen. Next, we counted how much pollen is borne on the 14 sites by bees visiting one nectariferous and three nectarless Pedicularis species. In the four species, only 7, 26, 28, and 30% of pollen found on the bees were on safe sites. Finally, we observed that the 14 sites were contacted by stigmas of the four Pedicularis species; none of the most contacted sites were safe sites. Across all four Pedicularis species, pollen is mainly positioned on sites of the bee body that were beneficial for both the plant and the bee, not on sites detrimental to either of them. Our analysis showed that the conflict of interest between flowers and bees can be solved by cooperation. Pedicularis pollen is placed where it strengthens the mutualism between plants and pollinators. PMID- 29134401 TI - Duloxetine Protects Human Neuroblastoma Cells from Oxidative Stress-Induced Cell Death Through Akt/Nrf-2/HO-1 Pathway. AB - The contribution of oxidative stress to the pathophysiology of depression has been described in numerous studies. Particularly, an increased production of reactive oxygen species (ROS) caused by mitochondrial dysfunction can lead to neuronal cell death. Human neuroblastoma SH-SY5Y cells were used to investigate the neuroprotective effect of the antidepressant duloxetine against rotenone induced oxidative stress. SH-SY5Y cells were pretreated with duloxetine (1-5 uM) for 24 h followed by a 24-h rotenone exposure (10 uM). The phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) inhibitor LY294002 (10 uM) and the heme oxygenase 1 (HO-1) inhibitor zinc protoporphyrin IX-ZnPP (5 uM) were added to cultures 1 h prior duloxetine treatments. After treatments cell viability and ROS generation were assessed. NF-E2-related factor-2 (Nrf2) nuclear translocation was assessed by immunofluorescent staining after 4 and 8 h of duloxetine incubation. Furthermore, the Nrf2 and HO-1 mRNA expression was carried out after 4-48 h of duloxetine treatment by qRT-PCR. Duloxetine pretreatment antagonized rotenone induced overproduction of ROS and cell death in SH-SY5Y cells. In addition, a 1-h pretreatment with LY294002 abolished duloxetine's protective effect. Duloxetine also induced nuclear translocation of the Nrf2 and the expression of its target gene, HO-1. Finally, the HO-1 inhibitor, ZnPP, suppressed the duloxetine protective effect. Overall, these results indicate that the mechanism of duloxetine neuroprotective action against oxidative stress and cell death might rely on the Akt/Nrf2/HO-1 pathways. PMID- 29134402 TI - Modification in oxidative processes in muscle tissues exposed to laser- and light emitting diode radiation. AB - Exposure of living tissues to high-intensity red or near-infrared light can produce the oxidative stress effects both in the target zone and adjacent ones. The protein oxidative modification (POM) products can be used as reliable and early markers of oxidative stress. The contents of modified proteins in the investigated specimens can be evaluated by the 2,4-dinitrophenylhydrazine assay (the DNPH assay). Low-intensity red light is able to decrease the activity of oxidative processes and the DNPH assay data about the POM products in the biological tissues could show both an oxidative stress level and an efficiency of physical agent protection against the oxidative processes. Two control groups of white rats were irradiated by laser light, the first control group by red light and the second one by near-infrared radiation (NIR).Two experimental groups were consequently treated with laser and red low-level light-emitting diode radiation (LED). One of them was exposed to red laser light + LED and the other to NIR + LED. The fifth group was intact. Each group included ten animals. The effect of laser light was studied by methods of protein oxidative modifications. We measured levels of both induced and spontaneous POM products by the DNPH assay. The dramatic increase in levels of POM products in the control group samples when compared with the intact group data as well as the sharp decrease in the POM products in the experimental groups treated with LED low-level light were statistically significant (p <= 0.05). Exposure of skeletal muscles to high intensity red and near-infrared laser light causes oxidative stress that continues not less than 3 days. The method of measurement of POM product contents by the DNPH assay is a reliable test of an oxidative process rate. Red low intensity LED radiation can provide rehabilitation of skeletal muscle tissues treated with high-intensity laser light. PMID- 29134403 TI - Femtosecond lenticule extraction performed on a wrong meridian and effectively reversed by excimer laser ablation. PMID- 29134404 TI - Curcumin-mediated anti-microbial photodynamic therapy against Candida dubliniensis biofilms. AB - The purpose of this study was to evaluate the effectiveness of anti-microbial photodynamic therapy (aPDT) mediated by curcumin (Cur) associated with LED light against biofilms of Candida dubliniensis, and further, investigate cellular uptake and drug penetration through the biofilms under confocal laser scanning microscopy (CLSM). Four C. dubliniensis strains were tested: three clinical isolates from HIV-positive patients and one reference strain (CBS 7987). Biofilms were treated with three Cur concentrations (20.0, 30.0, and 40.0 MUM). All samples were incubated in the dark for 20 min and exposed to a 5.28 J/cm2 of LED light fluence. Additional samples of each strain were treated either with Cur or LED light only. Control samples had neither Cur nor light. After aPDT, results were read using the XTT salt reduction method. The data were statistically analyzed by two-way ANOVA followed by Games-Howell post-hoc test (alpha = 0.05). Confocal laser scanning microscopy was used to verify both the uptake of Cur by yeast cells and its penetration through the biofilm. The results showed that aPDT promoted significant reduction on the metabolism of the biofilm-organized cells of C. dubliniensis. Further, while Cur was rapidly taken up by C. dubliniensis cells, a longer time interval was required to allow Cur penetration into biofilm cells. Based on these results, aPDT associating LED and Cur presents promising potential on fungal control of biofilms of C. dubliniensis. PMID- 29134405 TI - Cell-type-specific gene expression patterns in the knee cartilage in an osteoarthritis rat model. AB - Osteoarthritis (OA) is a chronic degenerative disease that leads to joint failure, pain, and disability. Gene regulation is implicated as a driver of the imbalance between the expression of catabolic and anabolic factors that eventually leads to the degeneration of osteoarthritic cartilage. In our model, knee-joint OA was induced in male Wistar rats by intra-articular sodium monoiodoacetate (MIA) injections. Whole-genome microarrays were used to analyse the alterations in gene expression during the time-course of OA development (at 2, 14, and 28 days post-injection) in rat knee joints. The identified co expressed groups of genes were analysed for enriched regulatory mechanisms, functional classes, and cell-type-specific expression. This analysis revealed 272 regulated transcripts (ANOVA FDR < 0.1% and fold > 2). Functionally, the five major gene expression patterns (A-E) were connected to PPAR signalling and adipogenesis (in cluster A), WNT signalling (in cluster B), endochondral ossification (in cluster C), matrix metalloproteinases and the ACE/RAGE pathway (in cluster D), and the Toll-like receptor, and IL-1 signalling pathways (in cluster E). Moreover, the dynamic profiles of these transcriptional changes were assigned to cellular compartments of the knee joint. Classifying the molecular processes associated with the development of cartilage degeneration provides novel insight into the OA disease process. Our study identified groups of co regulated genes that share functional relationships and that may play an important role in the early and intermediate stages of OA. PMID- 29134406 TI - Chemical Interaction among Termite-Associated Microbes. AB - Bacteria and fungi in shared environments compete with one another for common substrates, and this competition typically involves microbially-produced small molecules. An investigation of one shared environmental niche, the carton material of the Formosan subterranean termite Coptotermes formosanus, identified the participants on one of these molecular exchanges. Molecular characterization of several termite-associated actinobacteria strains identified eleven known antimicrobial metabolites that may aid in protecting the C. formosanus colony from pathogenic fungal infections. One particular actinobacterial-derived small molecule, bafilomycin C1, elicited a strong chemical response from Trichoderma harzianum, a common soil saprophyte. Upon purification and structure elucidation, three major fungal metabolites were identified, t22-azaphilone, cryptenol, and homodimericin A. Both t22-azaphilone and homodimericin A are strongly upregulated, 123- and 38-fold, respectively, when exposed to bafilomycin C1, suggesting each play a role in defending T. harzianum from the toxic effect of bafilomycin C1. PMID- 29134407 TI - Epiphytic Bacteria Alter Floral Scent Emissions. AB - Floral scents are key mediators of biotic interactions between flowers and various organisms such as pollinators, antagonistic animals and bacteria. It has been shown that emissions of floral volatiles are influenced by interactions with other organisms at the levels of roots, leaves and flowers. However, it is largely unknown whether and how epiphytic bacteria associated with flowers affect the composition of floral scent. By comparing volatiles of sterile and inoculated plants we found that bacteria may add components, induce or reduce the emission of compounds, and potentially catabolize others. These mechanisms collectively altered the floral scent emission and led to clearly different compositions. Our results confirm that bacteria have the potential to interfere with flower-animal interactions with consequences for pollination and plant reproduction. PMID- 29134408 TI - Glucosamine reduces the inhibition of proteoglycan metabolism caused by local anaesthetic solution in human articular cartilage: an in vitro study. AB - BACKGROUND: We assessed whether local anaesthetics caused inhibition of proteoglycan metabolism in human articular cartilage and whether the addition of Glucosamine sulphate could prevent or allow recovery from this adverse effect on articular cartilage metabolism. METHODS: Cartilage explants obtained from 13 femoral heads from fracture neck of femur patients (average age 80 years, 10 female) were exposed to either 1% Lidocaine, 2% Lidocaine, 0.25% Bupivacaine, 0.5% Bupivacaine, 0.5% Levo-bupivacaine or a control solution (M199 culture medium). Glucosamine-6-Sulphate was added during or 1 h after exposure to 0.5% Bupivacaine to assess its protective and reparative effects. After exposure, the explants were incubated in culture medium containing radio labelled 35-sulphate and uptake was measured after 16 h to give an assessment of proteoglycan metabolism. RESULTS: The reduction in 35-S uptake compared to control was 65% for 1% Lidocaine (p < 0.001), 79% for 2% Lidocaine (p < 0.001), 61% for 0.25% Bupivacaine (p < 0.001), 85% for 0.5% Bupivacaine (p < 0.001) and 77% for 0.5% Levobupivacaine (p < 0.001). Glucosamine was able to protect the articular cartilage by reducing the inhibition of proteoglycan metabolism of 0.5% Bupivacaine from 85 to 30% (p < 0.001). When added after 0.5% Bupivacaine exposure, Glucosamine allowed some recovery with inhibition of metabolism to 70% (p = 0.004). CONCLUSION: Our results showed that all local anaesthetic solutions inhibited proteoglycan metabolism in articular cartilage and the addition of Glucosamine was able to reduce the inhibition of metabolism caused by 0.5% Bupivacaine. Intra-articular injection of local anaesthetics requires careful consideration of risks and benefits. PMID- 29134409 TI - A weekly 35,000 IU vitamin D supplementation improves bone turnover markers in vitamin D-deficient Saudi adolescent females: response to comments by Ribaldone et al. PMID- 29134410 TI - Extractive foraging of toxic caterpillars in wild northern pig-tailed macaques (Macaca leonina). AB - Extractive foraging in nonhuman primates may involve different levels of technical complexity in terms of the number of actions that must be performed and the manual dexterity involved. We describe the extractive foraging of caterpillars in wild northern pig-tailed macaques (Macaca leonina) at Khao Yai National Park, Thailand. The study group, observed from May to December 2016 (n = 146 days), comprised 60-70 habituated individuals, including 3-4 adult males, 20 23 adult females, and 36-47 immatures. Four adult males and five adult females, observed from September to November 2016 for a total of 24 days, were selected for focal animal sampling. Northern pig-tailed macaques were observed eating at least two families (Erebidae and Limacodidae) and three genera (Macrobrochis sp., Phlossa sp. and Scopelodes sp.) of caterpillars. While the monkeys ate short and small caterpillars with stinging setae and non-setae caterpillars without processing, they performed extensive caterpillar-rubbing behavior on large and long caterpillars with stinging setae. Based on 61 extractive foraging bouts, we found that caterpillar rubbing was hierarchically organized into five stages and 12 elements. Five stages of behavior sequence started with picking the caterpillar up, transporting it to a substrate, rubbing it to remove stinging setae, ingesting it, and then cleaning hands and mouth. Only adult macaques were observed using a leaf to rub stinging caterpillars. PMID- 29134411 TI - Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis. AB - Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) are cell surface located transmembrane ecto-enzymes of the CD39 superfamily which regulate inflammation and tissue repair by catalyzing the phosphohydrolysis of extracellular nucleotides and modulating purinergic signaling. In the liver, NTPDase2 is reportedly expressed on portal fibroblasts, but its functional role in regulating tissue regeneration and fibrosis is incompletely understood. Here, we studied the role of NTPDase2 in several models of liver injury using global knockout mice. Liver regeneration and severity of fibrosis were analyzed at different time points after exposure to carbon tetrachloride (CCl4) or 3,5 diethoxycarbonyl-1,4-dihydrocollidine (DDC) or partial hepatectomy in C57BL/6 wild-type and globally NTPDase2-deficient (Entpd2 null) mice. After chronic CCl4 intoxication, Entpd2 null mice exhibit significantly more severe liver fibrosis, as assessed by collagen content and histology. In contrast, deletion of NTPDase2 does not have a substantial effect on biliary-type fibrosis in the setting of DDC feeding. In injured livers, NTPDase2 expression extends from the portal areas to fibrotic septae in pan-lobular (CCl4-induced) liver fibrosis; the same pattern was observed, albeit to a lesser extent in biliary-type (DDC-induced) fibrosis. Liver regeneration after partial hepatectomy is not substantively impaired in global Entpd2 null mice. NTPDase2 protects from liver fibrosis resulting from hepatocellular injury induced by CCl4. In contrast, Entpd2 deletion does not significantly impact fibrosis secondary to DDC injury or liver regeneration after partial hepatectomy. Our observations highlight mechanisms relating to purinergic signaling in the liver and indicate possible therapeutic avenues and new cellular targets to test in the management of hepatic fibrosis. PMID- 29134412 TI - Engineered bone scaffolds with Dielectrophoresis-based patterning using 3D printing. AB - Patterning of cells into a specific pattern is an important procedure in tissue engineering to facilitate tissue culture and ingrowth. In this paper, a new type of 3D-printed scaffold utilizing dielectrophoresis (DEP) for active cell seeding and patterning was proposed. This scaffold adopted a concentric-ring design that is similar to native bone tissues. The scaffold was fabricated with a commercial three-dimensional (3D) printer. Polylactic Acid (PLA) was selected as the material for the printer and the fabricated scaffold was coated with gold to enhance the conductivity for DEP manipulation. Simulation from COMSOL confirmed that non-uniform electric fields were successfully generated under a voltage input. The properties of the scaffold were first characterized through a series of experiments. Then, preosteoblast MC3T3-E1 cells were seeded onto the coated scaffold and multiple cellular rings were observed under the microscope. The biocompatibility of the material was also examined and mineralized bone nodules were detected using Alizarin Red S Staining after 28 days of culture. The proposed scaffold design can enable formation of multiple ring patterns via DEP and the properties of the scaffold are suitable for bone tissue culture. This new type of 3D-printed scaffold with cell seeding mechanism offers a new and rapid approach for fabricating engineered scaffolds that can arrange cells into different patterns for various tissue engineering applications. PMID- 29134413 TI - Comparison of feature evaluation criteria for speech recognition based on electromyography. AB - In this paper, we present a performance comparison of 14 feature evaluation criteria and 4 classifiers for isolated Thai word classification based on electromyography signals (EMG) to find a near-optimal criterion and classifier. Ten subjects spoke 11 Thai number words in both audible and silent modes while the EMG signal from five positions of the facial and neck muscles were captured. After signal collection and preprocessing, 22 EMG features widely used in the EMG recognition field were computed and were then evaluated based on 14 evaluation criteria including both independent criteria (IC) and dependent criteria (DC) for feature evaluation and selection. Subsequently, the top nine features were selected for each criterion, and were used as inputs to classifiers. Four types of classifier were employed with 10-fold cross-validation to estimate classification performance. The results showed that features selected with a DC on a Fisher's least square linear discriminant classifier (D_FLDA) used with a linear Bayes normal classifier (LBN) gave the best average accuracies, of 93.25 and 80.12% in the audible and the silent modes, respectively. PMID- 29134415 TI - GSDME as an executioner of chemotherapy-induced cell death. PMID- 29134416 TI - Smart super rice. PMID- 29134414 TI - PAX3 Promotes Cell Migration and CXCR4 Gene Expression in Neural Crest Cells. AB - Neural crest (NC) cells are a multipotent cell population with powerful migration ability during development. C-X-C chemokine receptor type 4 (CXCR4) is a chemokine receptor implicated to mediate NC migration in various species, whereas the underlying mechanism is not well documented yet. PAX3 is a critical transcription factor for the formation of neural crest and the migration and differentiation of NCs. In this study, we retrieved a potential PAX3 binding element in the promoter of the CXCR4 gene, and we further found that PAX3 could promote the expression of CXCR4 and facilitate the migration of NCs. We finally demonstrated that PAX3 could bind the promoter region of CXCR4 and increase CXCR4 transcription by luciferase assay and electrophoretic mobility shift assay (EMSA). These findings suggested that PAX3 is a pivotal modulator of NC migration via regulating CXCR4 expression. PMID- 29134417 TI - Cross-neutralization of SARS coronavirus-specific antibodies against bat SARS like coronaviruses. PMID- 29134418 TI - Both structure and function of human monoclonal antibodies contribute to enhancement of Zika virus infectivity in vitro. PMID- 29134419 TI - Acute Administration of the Nonpathogenic, Saprophytic Bacterium, Mycobacterium vaccae, Induces Activation of Serotonergic Neurons in the Dorsal Raphe Nucleus and Antidepressant-Like Behavior in Association with Mild Hypothermia. AB - Peripheral immune activation can have profound physiologic and behavioral effects. One mechanism through which immune activation may affect physiology and behavior is through actions on brainstem neuromodulatory systems, such as serotonergic systems. To test this hypothesis, in Experiment 1, adult male BALB/c mice were implanted with telemetric recording devices and then immunized with Mycobacterium vaccae NCTC 11659 (0.1 mg, s.c.; Days - 28, - 14; N = 36). On Day 1, mice received an acute challenge with M. vaccae (0.1 mg, s.c.) or borate buffered saline vehicle. Core body temperature and locomotor activity recordings were conducted during a 36 h period beginning 24 h prior to challenge; 12 h following acute challenge, mice were either tested in a 6-min forced swim test, or served as home cage controls (n = 9 per group). In Experiment 2, the protocol was repeated, but with the aim of assessing c-Fos expression in brainstem serotonergic neurons, assessed 90 min following exposure to forced swim (N = 32; n = 8 per group). In Experiment 1, acute M. vaccae challenge in M. vaccae immunized mice, relative to vehicle-challenged controls, decreased locomotor activity and core body temperature measured 3 h following challenge, as measured by continuous telemetric recordings, and decreased immobility in the forced swim test measured 12 h following challenge. In Experiment 2, acute M. vaccae challenge in M. vaccae-immunized mice decreased home cage locomotion, in alignment with findings in Experiment 1, as measured by video-based behavioral analysis, and, among mice exposed to the forced swim test, increased c-Fos expression in subsets of serotonergic neurons within the dorsal raphe nucleus (DR) measured 13.5 h following challenge. Together, these data are consistent with the hypothesis that acute peripheral immune activation with a heat-killed preparation of M. vaccae transiently induces mild hypothermia in association with suppression of locomotor activity, activates subsets of serotonergic neurons in the DR, and induces antidepressant-like behavioral responses. PMID- 29134420 TI - Co-Localization and Interaction of Pax5 with Iba1 in Brain of Mice. AB - The Pax5, a B-cell-Specific Activator Protein (BSAP) and redox-sensitive transcription factor, is expressed in the immune-privileged brain, B-lymphocytes, lymph nodes and spleen. PAX5-mediated immune pathway has also been described in the progression of Glioblastoma multiforme. However, the status of Pax5 and its role in brain immunity are not yet elucidated. In silico analysis of Pax5 interacting proteins predicts its interaction with proteins of cell proliferation, differentiation of hematopoietic cells, neurogenesis and several cell signalling pathways. Promoter analysis shows multiple binding sites for Pax5 in promoter of ionized calcium-binding adapter molecule 1 (Iba1). Like Iba1, Pax5 is also associated with inflammatory and immune response, activation of leukocyte and remodelling of actin cytoskeleton. Therefore, localization and interaction of Pax5 with Iba1 in brain of mice were studied using Chromatin Immunoprecipitation (ChIP), Co-Immunoprecipitation (Co-IP) and Immuno-fluorescence assay. The Pax5- and Iba1-positive cells were observed in cerebral cortex, cerebellum, olfactory bulb, hippocampus, and ventricles of brain. The co-localization of Pax5 and Iba1 was evident in microglia in almost all evaluated regions of brain. In some regions, Pax5- and Iba1-positive were distinctly compartmentalized. The Pax5a/b interacts with Iba1 and binds to its regulatory sequences. Results indicate Pax5 associated activities of Iba1 in microglia in brain of mice. PMID- 29134421 TI - Relationship Between Childhood Sexual Abuse and HIV-Related Risks Among Men Who Have Sex with Men: Findings from Mainland China. AB - Men who have sex with men (MSM) carry the burden of HIV infection in China. Outside of China, a history of childhood sexual abuse (CSA) has been associated with HIV-related risks (behavioral, sexual, and mental health outcomes) among MSM. We therefore evaluated the relationship between CSA and these HIV-related risks among MSM in China. Cross-sectional data were collected via a survey from gay websites and social networking applications from MSM in 30 provinces in mainland China during a 3-month period in 2014 and 2015. Overall, 999 screened MSM who responded to questions on CSA were included. Multinomial logistic regression models-adjusted for sociodemographic confounders-showed that men who reported experiencing regular CSA and contact CSA, respectively, were more likely to use substances (adjusted odds ratio [AOR], 1.91; 95% confidence interval [CI] 1.39-2.62 and AOR, 1.70; 95% CI 1.25-2.31), had a history of sexually transmitted infections (AOR, 1.81; 95% CI 1.29-2.55 and AOR, 1.65; 95% CI 1.18-2.96), had more male sexual partners (AOR, 1.06; 95% CI 1.04-1.09 and AOR, 1.05; 95% CI 1.03 1.08), engaged in more condomless sex with men (AOR, 1.89; 95% CI 1.39-2.56 and AOR, 1.72; 95% CI 1.29-2.30), and experienced more psychological distress (AOR, 1.05; 95% CI 1.02-1.08 and AOR, 1.05; 95% CI 1.03-1.08). Both frequent and contact forms of CSA were positively associated with HIV-related risks among MSM, suggesting that general CSA prevention strategies and interventions are needed to support this population. PMID- 29134422 TI - HIV Prevention Among Young Women in South Africa: Understanding Multiple Layers of Risk. AB - Despite concerted prevention efforts, young South African women remain at the epicenter of the HIV epidemic. Although these women have grown up in a community powerfully affected by HIV, systematic investigation into how this "second generation" of HIV-affected youth navigates HIV risk is lacking. This study qualitatively explored a complex interplay of factors influencing HIV risk among young pregnant women in KwaZulu-Natal, South Africa. We conducted in-depth interviews with 35 pregnant women (22 HIV-uninfected and 13 HIV-infected) aged 18 21, 18 healthcare providers, and focus groups with 19 community stakeholders. Among the young women, HIV knowledge was high, and many reported taking some action to prevent pregnancy or HIV; however, these efforts were not routinely implemented. Themes related to HIV acquisition risk from all participants were organized using a socioecological framework and revolved around individual and developmental experiences (personal experience with HIV, perceived invincibility), family barriers (lack of adult supervision, pressure to leave school), relational barriers (lack of disclosure and partner communication, "burn out" around attempts to discuss condom use with partners, overdependence on partners), community-level barriers (township environment, lack of structured activities), and social barriers (poverty, HIV-related stigma). Some novel concepts emerged from the data, including an understanding of how overdependence on the romantic relationship may develop. Current HIV prevention efforts, including traditional HIV counseling and testing, condom distribution, and biomedical agents for HIV prevention, are unlikely to be effective without a broader, ecological up-to-date understanding of the evolving, intertwined, and complex constellation of factors that drive HIV risk behavior in this high-risk population. PMID- 29134423 TI - Perioperative respiratory complications: current evidence and strategy discussed in 2017 JA symposium. AB - Respiratory management during general anesthesia aims to safely secure the airway and maintain adequate ventilation to deliver oxygen to the vital organs, maintaining homeostasis even during surgery. Despite its clinical importance, anesthesiologists often encounter difficulties in properly managing respiration during the perioperative period, leading to severe respiratory complications. In this year's JA symposium, 5 editorial board members of Journal of Anesthesia (JA) who are experts in the field of respiratory management in anesthesia discussed the following topics: quitting smoking before surgery: exposure to passive smoke is damaging to children, ventilator-associated pneumonia, high inspiratory oxygen concentration and lung injury, aspiration pneumonia, and postoperative respiratory management strategy in patients with obstructive sleep apnea. We hope that this special article regarding this year's JA symposium may be useful for JA readers to manage clinical anesthesia on a daily basis. PMID- 29134424 TI - Anatomical basis for simultaneous block of greater and third occipital nerves, with an ultrasound-guided technique. AB - PURPOSE: In some headache disorders, for which the greater occipital nerve block is partly effective, the third occipital nerve is also suggested to be involved. We aimed to establish a simple technique for simultaneously blocking the greater and third occipital nerves. METHODS: We performed a detailed examination of dorsal neck anatomy in 33 formalin-fixed cadavers, and deduced two candidate target points for blocking both the greater and third occipital nerves. These target points were tested on three Thiel-fixed cadavers. We performed ultrasound guided dye injections into these points, examined the results by dissection, and selected the most suitable injection point. Finally, this target point was tested in three healthy volunteers. We injected 4 ml of local anesthetic and 1 ml of radiopaque material at the selected point, guided with a standard ultrasound system. Then, the pattern of local anesthetic distribution was imaged with computed tomography. RESULTS: We deduced that the most suitable injection point was the medial head of the semispinalis capitis muscle at the C1 level of the cervical vertebra. Both nerves entered this muscle, in close proximity, with little individual variation. In healthy volunteers, an anesthetic injected was confined to the muscle and induced anesthesia in the skin areas innervated by both nerves. CONCLUSIONS: The medial head of the semispinalis capitis muscle is a suitable landmark for blocking the greater and third occipital nerves simultaneously, by which occipital nerve involvement in various headache disorders may be rapidly examined and treated. PMID- 29134425 TI - Quick reference tidal volume cards reduce the incidence of large tidal volumes during surgery. AB - Ventilation with large tidal volumes (V T), greater than 10 ml/kg of predicted body weight (PBW), is associated with worse outcomes in critically ill and surgical patients. We hypothesized that the availability of quick reference cards with proposed V T ranges specific to gender and different heights would reduce the intraoperative use of large V T during prolonged abdominal surgery. We compared retrospectively the incidence of median V T used during prolonged (>=4-h long) abdominal surgery before ("before") and after ("after") the quick reference V T cards were made available in all anesthesia machines in operating rooms of a single academic US medical center. We evaluated the effect of the intervention on the primary outcome while adjusting for previously identified risk factors of large V T use: female gender, obesity (body mass index, BMI > 30), and short height (< 165 cm). The frequency of V T > 10 ml/kg PBW was 15.1% in the before group and 4.3% in the after group (p < 0.001). The frequency of large V T used during abdominal surgery was significantly decreased after the intervention even after adjusting for female gender, obesity or short height [adjOR 0.11 (95% CI 0.04-0.30)]. Our quick reference V T cards significantly reduced the frequency of large V T use during abdominal surgery. PMID- 29134426 TI - Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies. AB - INTRODUCTION: Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. METHODS: Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. RESULTS: Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUCinf) and C max. After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUCinf increased by about 90%. In the bioavailability study, AUCinf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. CONCLUSION: Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUCinf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated. FUNDING: Astellas Pharma. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003). PMID- 29134427 TI - Overall Survival of Patients with Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma Treated with Nimotuzumab in the Real World. AB - INTRODUCTION: Despite improvements in surgical techniques and treatments introduced into clinical practice, the overall survival of patients with esophageal squamous cell carcinoma remains low. Several epidermal growth factor receptor inhibitors are being evaluated in the context of clinical trials, but there is little evidence of effectiveness in real-world conditions. This study aimed at assessing the effectiveness of nimotuzumab combined with onco-specific treatment in Cuban real-life patients with locally advanced or metastatic esophageal squamous cell carcinoma. METHODS: A comparative and retrospective effectiveness study was performed. The 93 patients treated with nimotuzumab were matched, with use of propensity score matching, with patients who received a diagnosis of locally advanced or metastatic squamous cell carcinoma of the esophagus in three Cuban provinces reported between 2011 and 2015 to the National Cancer Registry. The Kaplan-Meier method was used to estimate event-time distributions. Log-rank statistics were used for comparisons of overall survival between groups. A two-component mixture model assuming a Weibull distribution was fitted to assess the effect of nimotuzumab on short-term and long-term survival populations. RESULTS: There was an increase in median overall survival in patients treated with nimotuzumab (11.9 months versus 6.5 months without treatment) and an increase in the 1-year survival rate (54.0% versus 21.9% without treatment). The 2-year survival rates were 21.1% for patients treated with nimotuzumab and 0% in the untreated cohort. There were statistically significant differences in survival between groups treated and not treated with nimotuzumab, both in the short-term survival population (6.0 months vs 4.0 months, p = 0.009) and in the long-term survival population (18.0 months vs 11.0 months, p = 0.001). CONCLUSIONS: Our study shows that nimotuzumab treatment concurrent with chemoradiotherapy increases the survival of real-world patients with locally advanced or metastatic esophageal squamous cell carcinoma. Further prospective studies are required to confirm the therapeutic effectiveness of nimotuzumab in esophageal cancer. PMID- 29134428 TI - The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single Dose, Parallel-Group Studies. AB - INTRODUCTION: Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir. METHODS: These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment. RESULTS: In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated. CONCLUSION: The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5-2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance FUNDING: Astellas Pharma. PMID- 29134429 TI - Self-Driving Cars and Engineering Ethics: The Need for a System Level Analysis. AB - The literature on self-driving cars and ethics continues to grow. Yet much of it focuses on ethical complexities emerging from an individual vehicle. That is an important but insufficient step towards determining how the technology will impact human lives and society more generally. What must complement ongoing discussions is a broader, system level of analysis that engages with the interactions and effects that these cars will have on one another and on the socio-technical systems in which they are embedded. To bring the conversation of self-driving cars to the system level, we make use of two traffic scenarios which highlight some of the complexities that designers, policymakers, and others should consider related to the technology. We then describe three approaches that could be used to address such complexities and their associated shortcomings. We conclude by bringing attention to the "Moral Responsibility for Computing Artifacts: The Rules", a framework that can provide insight into how to approach ethical issues related to self-driving cars. PMID- 29134430 TI - Modern drug design: the implication of using artificial neuronal networks and multiple molecular dynamic simulations. AB - We report the implementation of molecular modeling approaches developed as a part of the 2016 Grand Challenge 2, the blinded competition of computer aided drug design technologies held by the D3R Drug Design Data Resource ( https://drugdesigndata.org/ ). The challenge was focused on the ligands of the farnesoid X receptor (FXR), a highly flexible nuclear receptor of the cholesterol derivative chenodeoxycholic acid. FXR is considered an important therapeutic target for metabolic, inflammatory, bowel and obesity related diseases (Expert Opin Drug Metab Toxicol 4:523-532, 2015), but in the context of this competition it is also interesting due to the significant ligand-induced conformational changes displayed by the protein. To deal with these conformational changes we employed multiple simulations of molecular dynamics (MD). Our MD-based protocols were top-ranked in estimating the free energy of binding of the ligands and FXR protein. Our approach was ranked second in the prediction of the binding poses where we also combined MD with molecular docking and artificial neural networks. Our approach showed mediocre results for high-throughput scoring of interactions. PMID- 29134431 TI - Impact of domain knowledge on blinded predictions of binding energies by alchemical free energy calculations. AB - The Drug Design Data Resource (D3R) consortium organises blinded challenges to address the latest advances in computational methods for ligand pose prediction, affinity ranking, and free energy calculations. Within the context of the second D3R Grand Challenge several blinded binding free energies predictions were made for two congeneric series of Farsenoid X Receptor (FXR) inhibitors with a semi automated alchemical free energy calculation workflow featuring FESetup and SOMD software tools. Reasonable performance was observed in retrospective analyses of literature datasets. Nevertheless, blinded predictions on the full D3R datasets were poor due to difficulties encountered with the ranking of compounds that vary in their net-charge. Performance increased for predictions that were restricted to subsets of compounds carrying the same net-charge. Disclosure of X-ray crystallography derived binding modes maintained or improved the correlation with experiment in a subsequent rounds of predictions. The best performing protocols on D3R set1 and set2 were comparable or superior to predictions made on the basis of analysis of literature structure activity relationships (SAR)s only, and comparable or slightly inferior, to the best submissions from other groups. PMID- 29134432 TI - Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer. AB - Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 MUg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade >= 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade >= 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC. PMID- 29134433 TI - Practice makes perfect: relationship between hospital procedure volume and permanent pacemaker implantation after paroxysmal supraventricular tachycardia ablation. AB - PURPOSE: Paroxysmal supraventricular tachycardia (PSVT) ablation can result in injury to the atrioventricular (AV) node causing complete heart block requiring permanent pacemaker (PPM) implantation. Few studies have examined the impact of hospital PSVT ablation volume and PPM implantation rates post ablation. METHODS: We included adult patients from the Nationwide Inpatient Sample (NIS) database, from 1998 to 2011, using ICD-9 diagnoses codes 427.0 and 427.89 for PSVT and ICD 9 procedure code 37.34 for ablation. Patients with concomitant arrhythmias, prior pacemaker/defibrillator implants, or pre-existing sinus node dysfunction were excluded. Multivariate logistic regression analysis was performed to identify predictors of PPM implantation. RESULTS: There were 119,938 PSVT ablations from 1998 to 2011 with a mean age of 54.6 +/- 17.5 years and 64.1% females. The overall PPM implantation rate was 3.2%. PPM implantation rates in the first (1-14 ablations/year), second (15-32 ablations/year), and third (> 32/ablations/year) tertiles of annual PSVT ablation volume were respectively 4.4, 3.3, and 1.9% (p < 0.001). Increasing age, female gender, bifascicular, or trifascicular block and teaching hospital status were independent predictors of PPM implantation. The adjusted odds ratio for PPM implantation in hospitals performing > 32 PSVT ablations/year compared to hospitals performing <= 14 PSVT ablations/year was 0.54 (95% confidence interval 0.3-0.9, p = 0.026). CONCLUSIONS: PPM implantation rates are significantly lower in hospitals performing > 32 PSVT ablations/year, indicating that hospital experience is an important determinant of outcomes after PSVT ablation. PMID- 29134434 TI - Fluoroscopy-free AF ablation using transesophageal echocardiography and electroanatomical mapping technology. AB - PURPOSE: Guidelines recommend that radiation exposure during AF catheter ablation procedures should be 'as low as reasonably achievable' (ALARA), particularly since many patients may have multiple procedures. Consequently, avoiding radiation exposure altogether must, if safe to do so, be the ultimate goal. The primary objective was to determine the feasibility and efficacy of fluoroscopy free AF ablation compared to the fluoroscopy-assisted procedure. METHODS: Patients underwent AF ablation using commercially available technology with no routine pre-procedural imaging. The use of non-fluoroscopic imaging/mapping technologies permitted us to initially reduce x-ray exposure before eliminating its use altogether. This evolution of our practice proceeded in two stages: a 9 month period of optimising our fluoroscopy-free ablation protocol followed by a 9 month period during which we set out to complete the whole procedure routinely without fluoroscopy. We describe the protocol developed and report salient endpoints, such as complications, procedure times, patient experience, and procedural success rates. RESULTS: During the study period, fluoroscopy-free AF ablation was attempted in 69 patients: 24 in the 9-month 'development phase' and 45 in the 'implementation phase'. During the development phase, 13 of 24 patients (54%) were treated without the use of fluoroscopy. In the implementation phase, 45 patients underwent AF ablation of which 42 (93.3%) were fluoroscopy-free. A detailed description is given of the three cases in which fluoroscopy had to be used despite an intention not to. CONCLUSIONS: Fluoroscopy-free complex ablation procedures for the treatment of atrial fibrillation are safe and feasible in most patients. PMID- 29134435 TI - Plant Phenology Supports the Multi-emergence Hypothesis for Ebola Spillover Events. AB - Ebola virus disease outbreaks in animals (including humans and great apes) start with sporadic host switches from unknown reservoir species. The factors leading to such spillover events are little explored. Filoviridae viruses have a wide range of natural hosts and are unstable once outside hosts. Spillover events, which involve the physical transfer of viral particles across species, could therefore be directly promoted by conditions of host ecology and environment. In this report, we outline a proof of concept that temporal fluctuations of a set of ecological and environmental variables describing the dynamics of the host ecosystem are able to predict such events of Ebola virus spillover to humans and animals. We compiled a data set of climate and plant phenology variables and Ebola virus disease spillovers in humans and animals. We identified critical biotic and abiotic conditions for spillovers via multiple regression and neural network-based time series regression. Phenology variables proved to be overall better predictors than climate variables. African phenology variables are not yet available as a comprehensive online resource. Given the likely importance of phenology for forecasting the likelihood of future Ebola spillover events, our results highlight the need for cost-effective transect surveys to supply phenology data for predictive modelling efforts. PMID- 29134437 TI - A Qualitative Stakeholder Analysis of Avian Influenza Policy in Bangladesh. AB - Avian influenza is a major animal and public health concern in Bangladesh. A decade after development and implementation of the first national avian influenza and human pandemic influenza preparedness and response plan in Bangladesh, a two stage qualitative stakeholder analysis was performed in relation to the policy development process and the actual policy. This study specifically aimed to identify the future policy options to prevent and control avian influenza and other poultry-related zoonotic diseases in Bangladesh. It was recommended that the policy should be based on the One Health concept, be evidence-based, sustainable, reviewed and updated as necessary. The future policy environment that is suitable for developing and implementing these policies should take into account the following points: the need to formally engage multiple sectors, the need for clear and acceptable leadership, roles and responsibilities and the need for a common pool of resources and provision for transferring resources. Most of these recommendations are directed towards the Government of Bangladesh. However, other sectors, including research and poultry production stakeholders, also have a major role to play to inform policy making and actively participate in the multi-sectoral approach. PMID- 29134438 TI - A Concept Analysis of Spiritual Health. AB - Spiritual health is an important dimension of health and forms part of a comprehensive care. This study was conducted to redefine and clarify the components of spiritual health based on different worldviews through Walker and Avant's concept analysis method. Being given a life and a soul and having beliefs are the antecedents of spiritual health. The attributes of this concept include a morality-oriented intellectual connectedness with the self, others, and the universe guided by a connection with the Transcendent and Superior being in order to create meaning in life and find its purpose in the context of culture and religion; transcendence is ultimately the consequence of spiritual heath. Using the attributes appeared in this conceptual analysis, nurses can evaluate the spiritual health of their clients and help them create positive outcome by providing appropriate interventions. PMID- 29134436 TI - Common Cutaneous Bacteria Isolated from Snakes Inhibit Growth of Ophidiomyces ophiodiicola. AB - There is increasing concern regarding potential impacts of snake fungal disease (SFD), caused by Ophidiomyces ophiodiicola (Oo), on free-ranging snake populations in the eastern USA. The snake cutaneous microbiome likely serves as the first line of defense against Oo and other pathogens; however, little is known about microbial associations in snakes. The objective of this study was to better define the composition and immune function of the snake cutaneous microbiome. Eight timber rattlesnakes (Crotalus horridus) and four black racers (Coluber constrictor) were captured in Arkansas and Tennessee, with some snakes exhibiting signs of SFD. Oo was detected through real-time qPCR in five snakes. Additional histopathological techniques confirmed a diagnosis of SFD in one racer, the species' first confirmed case of SFD in Tennessee. Fifty-eight bacterial and five fungal strains were isolated from skin swabs and identified with Sanger sequencing. Non-metric multidimensional scaling and PERMANOVA analyses indicated that the culturable microbiome does not differ between snake species. Fifteen bacterial strains isolated from rattlesnakes and a single strain isolated from a racer inhibited growth of Oo in vitro. Results shed light on the culturable cutaneous microbiome of snakes and probiotic members that may play a role in fighting an emergent disease. PMID- 29134439 TI - Treatment-related survival associations of claudin-2 expression in fibroblasts of colorectal cancer. AB - Claudin-2 is a trans-membrane protein-component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU+/-irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients. PMID- 29134441 TI - Correction to: Abstracts : 29th European Congress of Pathology. AB - In Oral Free Paper Sessions, the first-author name was missing from the authorship group originally listed for Abstract OFP-04-012 (page S14), entitled "Differentiating primary pulmonary squamous cell carcinoma from squamous cell carcinoma of the cervix metastatic to the lung: Histological and immunohistochemistry study". PMID- 29134440 TI - Ki67 labeling index: assessment and prognostic role in gastroenteropancreatic neuroendocrine neoplasms. AB - In 1983, a monoclonal antibody, Ki67, was generated, that labeled the nuclei of proliferating non-neoplastic and neoplastic cells. The name Ki67 derived from the city of Kiel (Ki) where the antibody was produced in the university department of pathology and refers to the number of the original clone (67). Systematic assessment of the proliferative activity of tumors using Ki67 started in the 1990s, when Ki67, which only worked on frozen tissue, was complemented by the antibody MIB-1 that also worked in formalin-fixed tissues. Pancreatic neuroendocrine neoplasms (PanNENs) were the first endocrine tumors whose proliferative activity was assessed with Ki67. This approach was so successful that Ki67 was included as prognostic marker in the 2000 and 2004 WHO classifications of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In 2010, the WHO classification of GEP-NENs introduced a three-tiered grading, originally proposed by ENETS in 2006 that was mainly based on the Ki67 index. As it has subsequently been shown that the Ki67 index is the most reliable factor in the prognostic evaluation of GEP-NENs, especially of PanNENs, the 2017 WHO classification of PanNENs requires its use and strongly recommends exact assessment of the proportion Ki67-labeled cells as basis for the calculation of the Ki67 index. Problems in assessing the Ki67 index include intertumoral and intratumoral staining heterogeneity and counting methods. Despite such problems, the Ki67 index has emerged as indispensable for the prognostic and therapeutic stratification of the majority of GEP-NENs and can barely be replaced by counting mitoses. In future, however, it can be anticipated that the Ki67 cut-offs experience refinement in relation to the type of tumor, its location, and its response to therapy. It is also possible that the prognostic risk of an individual tumor is calculated for each Ki67 unit and not for an "a priori" fixed Ki67 class. PMID- 29134442 TI - Endothelial TNF-alpha induction by Hsp60 secreted from THP-1 monocytes exposed to hyperglycaemic conditions. AB - A non-resolving inflammation of the endothelium is recognised to be an important process leading to atherosclerosis. In diabetes, this process is thought to account for a significant number of cardiovascular disease-associated death and disability. However, the molecular mechanisms by which diabetes contributes to endothelial inflammation remain to be established. Whilst there is some evidence linking hyperglycaemia-induced reactive oxygen species (ROS) formation by the mitochondrial electron-transport chain to oxidative stress, cellular injury and apoptosis in the endothelium, a clear link to endothelium inflammation has not yet been established. The mitochondrial molecular stress protein Hsp60 is known to be secreted from mammalian cells and is capable of activating pro-inflammatory mediators on target cells expressing Toll-like receptors (TLRs). Hsp60 is also known to be elevated in serum of diabetes patients and has been shown to be upregulated by hyperglycaemic growth conditions in cultured human HeLa cells. This study shows that Hsp60 induced in human acute monocyte leukaemia cell line (THP-1) cells grown under hyperglycaemic conditions (25 mM glucose) was able to be secreted into growth media. Furthermore, the secretion of Hsp60 from THP-1 cells was able to be inhibited by 5,5-(N-N-dimethyl)-amiloride hydrochloride (DMA), an exosomal inhibitor. Interestingly, the conditioned media obtained from THP-1 cells grown in the presence of 25 mM glucose was able to induce the secretion of TNF-alpha in human vascular endothelium cell line (HUVEC). When conditioned media was immuno-depleted of Hsp60, there was a significant reduction in the release of TNF-alpha from the HUVEC cells. This suggests that a potential link may exist between hyperglycaemia-induced expression of Hsp60 in monocyte cells and vascular inflammation. Circulating levels of Hsp60 due to mitochondrial stress in diabetes patients could therefore be an important modulator of inflammation in endothelial cells and thus contribute to the increased incidences of atherosclerosis in diabetes mellitus. PMID- 29134443 TI - Circadian clock during plant development. AB - Plants have endogenous biological clocks that allow organisms to anticipate and prepare for daily and seasonal environmental changes and increase their fitness in changing environments. The circadian clock in plants, as in animals and insects, mainly consists of multiple interlocking transcriptional/translational feedback loops. The circadian clock can be entrained by environmental cues such as light, temperature and nutrient status to synchronize internal biological rhythms with surrounding environments. Output pathways link the circadian oscillator to various physiological, developmental, and reproductive processes for adjusting the timing of these biological processes to an appropriate time of day or a suitable season. Recent genomic studies have demonstrated that polymorphism in circadian clock genes may contribute to local adaptations over a wide range of latitudes in many plant species. In the present review, we summarize the circadian regulation of biological processes throughout the life cycle of plants, and describe the contribution of the circadian clock to local adaptation. PMID- 29134445 TI - Ptosis and bulbar onset: an unusual phenotype of familial ALS? AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neurons that usually spare the oculomotor nerves. Here, we describe a case of two siblings with a familial bulbar-onset ALS both with ptosis manifested at the onset of the disease. PMID- 29134444 TI - Association between restless legs syndrome and hypertension: a meta-analysis of nine population-based studies. AB - Previous population-based studies evaluating the association between restless legs syndrome (RLS) and cardiovascular risk factors have showed inconsistent results, especially for the relationship between RLS and hypertension. We, therefore, aimed to meta-analyze to assess the association between RLS and hypertension. PubMed and Embase databases were systematically searched to identify eligible studies. Nine population-based cross-sectional studies were selected for inclusion, involving 102,408 individuals. Overall, the prevalence of hypertension in RLS subjects was higher than those without RLS (OR = 1.36, 95% CI, 1.18-1.57, P = 0.043). Our findings indicate that RLS is associated with increased blood pressure. More large-scale and prospective studies are warranted to further clarify the relationship and its potential mechanism. PMID- 29134446 TI - Cleaner fish Labroides dimidiatus discriminate numbers but fail a mental number line test. AB - Several species of primates, including humans, possess a spontaneous spatial mental arrangement (i.e. mental number line MNL) of increasing numbers or continuous quantities from left to right. This cognitive process has recently been documented in domestic chicken in a spatial-numerical task, opening the possibility that MNL is a cognitive capacity that has been conserved across vertebrate taxa. In this scenario, fish might possess the MNL as well. Here we investigated whether cleaner fish Labroides dimidiatus show evidence for MNL in two experiments. In Experiment I, we tested fish's abilities in number discrimination, presenting simultaneously either small (2 vs 5) or large (5 vs 8) continuous quantities where one quantity was systematically rewarded. Experiment II used a protocol of an MNL task similar to the study on chickens. We trained cleaners with a target number (i.e. 5 elements), then we presented them with an identical pair of panels depicting either 2 elements or 8 elements, and we recorded their spontaneous choice for the left or right panel on each presentation. Cleaner fish showed high abilities in discriminating small and large numbers in Experiment I. Importantly, cleaners achieved this discrimination using numerical cues instead of non-numerical cues such as the cumulative surface area, density, and overall space. In contrast, cleaners did not allocate continuous quantities to space in Experiment II. Our findings suggest that cleaner fish possess numbering skills but they do not have an MNL. While similar studies on animals from various clades are needed to trace the evolution of MNL within vertebrates, our results suggest that this cognitive process might not be a capacity conserved across all vertebrate taxa. PMID- 29134447 TI - Should I fetch one or the other? A study on dogs on the object choice in the bimodal contrasting paradigm. AB - The present study assessed how dogs weigh gestural versus verbal information communicated to them by humans in transitive actions. The dogs were trained by their owners to fetch an object under three conditions: a bimodal congruent condition characterized by using gestures and voices simultaneously; a unimodal gestural condition characterized by using only gestures; and a unimodal verbal condition characterized by using only voices. An additional condition, defined as a bimodal incongruent condition, was later added, in which the gesture contrasted with the verbal command, that is, the owner indicated an object while pronouncing the name of the other object visible to dogs. In the incongruent condition, seven out of nine dogs choose to follow the gestural indication and performed above chance, two were at chance, whereas none of the dogs followed the verbal cues above chance. The dogs, as a group, performed above chance the gestural command in 73.6% of cases. The analysis of latencies in the above-mentioned four conditions exhibited significant differences. The unimodal verbal and the gestural conditions recorded a slower performance than both the bimodal incongruent and congruent conditions. No statistical differences were observed between the unimodal and bimodal conditions. Our results demonstrate that dogs, trained to respond equally well to gestural and verbal commands, choose to follow the indication provided by the gestural command than the verbal one to a significant extent in transitive actions. Furthermore, the responses to bimodal conditions were found to be quicker than the unimodal ones. PMID- 29134448 TI - Hyperammonemia associated with distal renal tubular acidosis or urinary tract infection: a systematic review. AB - BACKGROUND: Hyperammonemia usually results from an inborn error of metabolism or from an advanced liver disease. Individual case reports suggest that both distal renal tubular acidosis and urinary tract infection may also result in hyperammonemia. METHODS: A systematic review of the literature on hyperammonemia secondary to distal renal tubular acidosis and urinary tract infection was conducted. RESULTS: We identified 39 reports on distal renal tubular acidosis or urinary tract infections in association with hyperammonemia published between 1980 and 2017. Hyperammonemia was detected in 13 children with distal renal tubular acidosis and in one adult patient with distal renal tubular acidosis secondary to primary hyperparathyroidism. In these patients a negative relationship was observed between circulating ammonia and bicarbonate levels (P < 0.05). In 31 patients (19 children, 12 adults), an acute urinary tract infection was complicated by acute hyperammonemia and symptoms and signs of acute neuronal dysfunction, such as an altered level of consciousness, convulsions and asterixis, often associated with signs of brain edema, such as anorexia and vomiting. Urea-splitting bacteria were isolated in 28 of the 31 cases. The urinary tract was anatomically or functionally abnormal in 30 of these patients. CONCLUSIONS: This study reveals that both altered distal renal tubular acidification and urinary tract infection may be associated with relevant hyperammonemia in both children and adults. PMID- 29134449 TI - Iohexol plasma clearance in children: validation of multiple formulas and single point sampling times. AB - BACKGROUND: The non-ionic agent iohexol is increasingly used as the marker of choice for glomerular filtration rate (GFR) measurement. Estimates of GFR in children have low accuracy and limiting the number of blood-draws in this patient population is especially relevant. We have performed a study to evaluate different formulas for calculating measured GFR based on plasma iohexol clearance with blood sampling at only one time point (GFR1p) and to determine the optimal sampling time point. METHODS: Ninety-six children with chronic kidney disease (CKD) stage 1-5 (median age 9.2 years; range 3 months to 17.5 years) were examined in a cross-sectional study using iohexol clearance and blood sampling at seven time points within 5 h (GFR7p) as the reference method. Median GFR7p was 66 (range 6-153) mL/min/1.73 m2. The performances of six different single time-point formulas (Fleming, Ham and Piepsz, Groth and Aasted, Stake, Jacobsson- and Jacobsson-modified) were validated against the reference. The two-point GFR (GFR2p) was calculated according to the Jodal and Brochner-Mortensen formula. RESULTS: The GFR1p calculated according to Fleming with sampling at 3 h (GFR1p3h Fleming) had the best overall performance, with 82% of measures within 10% of the reference value (P10). In children with a GFR >= 30 mL/min/1.73 m2 (n = 78), the GFR1p3h-Fleming had a P10 of 92.3%, which is not significantly different (p = 0.29) from that of GFR2p (P10 = 96.2%). Considerable differences within and between the different formulas were found for different CKD stages and different time points for blood sampling. CONCLUSIONS: For determination of mGFR in children with CKD and an assumed GFR of >= 30 mL/min/1.73 m2 we recommend GFR1p3h Fleming as the preferred single-point method as an alternative to GFR2p. For children with a GFR < 30 mL/min/1.73 m2, we recommend the slope-GFR with at least two blood samples. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2. PMID- 29134452 TI - Invited comment to: European Hernia Society Guidelines on prevention and treatment of parastomal hernias. PMID- 29134450 TI - Comorbidity Burden of Dementia: A Hospital-Based Retrospective Study from 2003 to 2012 in Seven Cities in China. AB - Dementia is increasing dramatically and imposes a huge burden on society. To date, there is a lack of data on the health status of patients with dementia in China. In an attempt to investigate the comorbidity burden of dementia patients in China at the national level, we enrolled 2,938 patients with Alzheimer's disease (AD), vascular dementia (VaD), or other types of dementia, who were admitted to tertiary hospitals in seven regions of China from January 2003 to December 2012. The Charlson Comorbidity Index (CCI) was used to evaluate the comorbidity burden of the patients with dementia. Among these patients, 53.4% had AD, 26.3% had VaD, and 20.3% had other types of dementia. The CCI was 3.0 +/- 1.9 for all patients, 3.4 +/- 1.8 for those with VaD, and 3.0 +/- 2.1 for those with AD. The CCI increased with age in all patients, and the length of hospital stay and daily expenses rose with age and CCI. Males had a higher CCI and a longer stay than females. Moreover, patients admitted in the last 5 years of the study had a higher CCI than those admitted in the first 5 years. We found that the comorbidity burden of patients with dementia is heavy. These findings provide a better understanding of the overall health status of dementia patients, and help to increase the awareness of clinicians and policy-makers to improve medical care for patients. PMID- 29134451 TI - Seasonal variations in bacterioplankton community structures in two small rivers in the Himi region of central Japan and their relationships with environmental factors. AB - The aim of this study was to improve our understanding of seasonal variations and the effects of physicochemical conditions on the bacterioplankton communities in two small rivers, the Moo and Nakayachi Rivers in the Himi region of central Japan. These rivers are inhabited by unionid freshwater mussels, which are used for oviposition by the endangered Itasenpara bitterling (Acheilognathus longipinnis). Water samples were collected every month between March 2011 and February 2012. Changes in bacterioplankton community structures were analysed using an approach that did not require cultivating the bacteria and involved PCR and denaturing gradient gel electrophoresis. The bacterioplankton community structures in the two rivers were similar in all seasons except winter. The bacterial sequences identified were dominated by typical freshwater Actinobacteria, Bacteroidetes, Cyanobacteria, alpha-Proteobacteria, and beta Proteobacteria bacterioplankton. Many beta-Proteobacteria species were detected in all seasons, but Bacteroidetes species were dominant in the winter. The bacterioplankton community structures were affected by biochemical oxygen demand, chemical oxygen demand, chlorophyll-a concentration, water depth, and water temperature. These results provide a foundation for a more detailed understanding of the conditions that provide a suitable unionid habitat. PMID- 29134453 TI - Invited commentary on European Hernia Society Guidelines on prevention and treatment of parastomal hernias. PMID- 29134454 TI - Summary for patients: European Hernia Society guidelines on prevention and treatment of parastomal hernias. PMID- 29134455 TI - Invited comment to: European Hernia Society guidelines on prevention and treatment of parastomal hernias. PMID- 29134457 TI - Thinking about others and the future: Neural correlates of perspective taking relate to preferences for delayed rewards. AB - We infer the thoughts and feelings of others by taking their perspectives. Similar processes could be used to understand how we will be affected by future events, by allowing us to take the perspective of our future self. In this paper, we test this idea using a previously presented framework for guiding predictions. The framework proposes that a shared neural mechanism is involved in controlling egocentric bias, both while shifting our perspective away from self and towards others, and while shifting our perspective from immediate to future perspectives. To test this framework, 36 adults performed an intertemporal choice task. They were then scanned using 3T functional magnetic resonance imaging while completing a false-belief "localizer" task, which requires egocentric bias control. A positive correlation was observed between the right temporoparietal junction (rTPJ) response during the false-belief task, and preferences for delayed rewards in intertemporal choices. A subset of participants performed the intertemporal choice task again in the scanner, which revealed that the response of the same rTPJ cluster, individually localized during the false-belief task, was higher during delayed over immediate reward choices. In addition, functional connectivity between the rTPJ and ventromedial prefrontal cortex was found to differ between immediate and delayed choices. The current results indicate an overlap in processes of egocentric bias control and those that determine preferences in intertemporal choices, offering a social cognitive explanation for why rewards are devalued with delay in temporal discounting. PMID- 29134458 TI - Animal Cell Expression Systems. AB - The glycan profile of therapeutic recombinant proteins such as monoclonal antibodies is a critical quality attribute, which affects the efficacy of the final product. The cellular glycosylation process during protein expression is dependent upon a number of factors such as the availability of substrates in the media, the intracellular content of nucleotide sugars, and the enzyme repertoire of the host cells. In order to control the variability of glycosylation it is important to understand the critical process parameters and their acceptable range of values to enable reproducible production of proteins with a predetermined glycan profile providing the desired biological function or therapeutic effect. The depletion of critical nutrients such as glucose or galactose, which may occur toward the end of a culture process, can lead to truncated glycans. Terminal galactosylation and sialyation are particularly variable but may be controlled by the presence of some key media components. Ammonia accumulation, pH, and dissolved oxygen levels are also known to be key bioprocess parameters that affect the glycosylation of recombinant proteins. Specific enzyme inhibitors can be added to the media to drive the formation of selected and predetermined glycan profiles. Various attempts have been made to predict the glycan profiles of cellular expressed proteins and have led to metabolic models based upon knowledge of metabolic flux and the kinetics of individual glycosylation reactions.In contrast to single recombinant proteins, the glycan profiles of viral vaccines are far more complex and difficult to predict. The example of influenza A virus shows that hemagglutinin, the major antigenic determinant, has three to nine N-glycans, which may influence the antigenicity and efficacy of the vaccine. Glycosylation of the influenza A virus has been largely unmonitored in the past as production has been from eggs, where glycan profiles of antigens are difficult if not impossible to control. Over the past decade, however, there have been various commercial influenza vaccines made available from cell technology using animal host cells. Analysis of glycosylation control shows that the type of host cell has the greatest influence on the final analyzed glycan profile. Other factors such as the virus strain, the cultivation system, or various process parameters have been shown to have only a minor effect on the glycosylation pattern. We predict that the analysis of glycan profiles in viral vaccines will become increasingly important in the development and consistent manufacturing of safe and potent vaccines. Graphical Abstract. PMID- 29134456 TI - European Hernia Society guidelines on prevention and treatment of parastomal hernias. AB - BACKGROUND: International guidelines on the prevention and treatment of parastomal hernias are lacking. The European Hernia Society therefore implemented a Clinical Practice Guideline development project. METHODS: The guidelines development group consisted of general, hernia and colorectal surgeons, a biostatistician and a biologist, from 14 European countries. These guidelines conformed to the AGREE II standards and the GRADE methodology. The databases of MEDLINE, CINAHL, CENTRAL and the gray literature through OpenGrey were searched. Quality assessment was performed using Scottish Intercollegiate Guidelines Network checklists. The guidelines were presented at the 38th European Hernia Society Congress and each key question was evaluated in a consensus voting of congress participants. RESULTS: End colostomy is associated with a higher incidence of parastomal hernia, compared to other types of stomas. Clinical examination is necessary for the diagnosis of parastomal hernia, whereas computed tomography scan or ultrasonography may be performed in cases of diagnostic uncertainty. Currently available classifications are not validated; however, we suggest the use of the European Hernia Society classification for uniform research reporting. There is insufficient evidence on the policy of watchful waiting, the route and location of stoma construction, and the size of the aperture. The use of a prophylactic synthetic non-absorbable mesh upon construction of an end colostomy is strongly recommended. No such recommendation can be made for other types of stomas at present. It is strongly recommended to avoid performing a suture repair for elective parastomal hernia. So far, there is no sufficient comparative evidence on specific techniques, open or laparoscopic surgery and specific mesh types. However, a mesh without a hole is suggested in preference to a keyhole mesh when laparoscopic repair is performed. CONCLUSION: An evidence-based approach to the diagnosis and management of parastomal hernias reveals the lack of evidence on several topics, which need to be addressed by multicenter trials. Parastomal hernia prevention using a prophylactic mesh for end colostomies reduces parastomal herniation. Clinical outcomes should be audited and adverse events must be reported. PMID- 29134459 TI - Risk Mitigation in Preventing Adventitious Agent Contamination of Mammalian Cell Cultures. AB - Industrial-scale mammalian cell culture processes have been contaminated by viruses during the culturing phase. Although the historical frequency of such events has been quite low, the impact of contamination can be significant for the manufacturing company and for the supply of the product to patients. This chapter discusses sources of adventitious agent contamination risk in a cell culture process, provides a semiquantitative assessment of such risks, and describes potential process barriers that can be used to reduce contamination risk. High temperature, short-time (HTST) heat treatment is recommended as the process barrier of choice, when compatible with the process. A case study assessing the compatibility of HTST heat treatment with a cell culture medium is presented, and lessons learned are shared from our experiences over many years of developing and implementing virus barriers in mammalian cell culture processes. Graphical Abstract. PMID- 29134460 TI - Enzyme-Based Electrobiotechnological Synthesis. AB - Oxidoreductases are enzymes with a high potential for organic synthesis, as their selectivity often exceeds comparable chemical syntheses. The biochemical cofactors of these enzymes need regeneration during synthesis. Several regeneration methods are available but the electrochemical approach offers an efficient and quasi mass-free method for providing the required redox equivalents. Electron transfer systems involving direct regeneration of natural and artificial cofactors, indirect electrochemical regeneration via a mediator, and indirect electroenzymatic cofactor regeneration via enzyme and mediator have been investigated. This chapter gives an overview of electroenzymatic syntheses with oxidoreductases, structured by the enzyme subclass and their usage of cofactors for electron relay. Particular attention is given to the productivity of electroenzymatic biotransformation processes. Because most electroenzymatic syntheses suffer from low productivity, we discuss reaction engineering concepts to overcome the main limiting factors, with a focus on media conductivity optimization, approaches to prevent enzyme inactivation, and the application of advanced cell designs. Graphical Abstract. PMID- 29134461 TI - High-Throughput Process Development for Biopharmaceuticals. AB - The ability to conduct multiple experiments in parallel significantly reduces the time that it takes to develop a manufacturing process for a biopharmaceutical. This is particularly significant before clinical entry, because process development and manufacturing are on the "critical path" for a drug candidate to enter clinical development. High-throughput process development (HTPD) methodologies can be similarly impactful during late-stage development, both for developing the final commercial process as well as for process characterization and scale-down validation activities that form a key component of the licensure filing package. This review examines the current state of the art for HTPD methodologies as they apply to cell culture, downstream purification, and analytical techniques. In addition, we provide a vision of how HTPD activities across all of these spaces can integrate to create a rapid process development engine that can accelerate biopharmaceutical drug development. Graphical Abstract. PMID- 29134462 TI - Roles of Fibroblast Activation Protein and Hepatocyte Growth Factor Expressions in Angiogenesis and Metastasis of Gastric Cancer. AB - This study aims to explore the roles of fibroblast activation protein (FAP) and hepatocyte growth factor (HGF) expressions in the angiogenesis and metastasis of gastric cancer (GC). From May 2012 to December 2015, 110 GC patients who received surgical treatment in the First Hospital of Qinhuangdao were selected. The HGF and FAP expressions in 110 cases of GC, 130 cases of normal gastric mucosa and 115 cases of gastric ulcer were detected by streptavidin-perosidase (SP) method. Venous blood HGF level of GC patients was tested by enzyme-linked immunosorbent assay (ELISA). The micro-vessel number of the patients in the three groups were calculated and analyzed. In GC group, positive expression rates of FAP and HGF protein were 61.8% and 67.3% respectively, which were both higher than those in normal gastric mucosa and gastric ulcer groups. The micro-vessel numbers in patients of the normal gastric mucosa and gastric ulcer groups are far less than that in GC group. FAP, HGF and micro-vessel density (MVD) were significantly correlated with infiltration depth, tumor-node-metastasis (TNM) staging, lymph node metastasis (LNM) and distant metastasis. The results of ELISA showed that serum HGF level was related to tumor size, infiltration degree, TNM staging, LNM and distant metastasis. FAP and HGF expressions in GC were positively correlated with MVD, and the expressions of FAP and HGF in GC were in positive correlation. Our study provided evidence that high FAP and HGF expressions may be positively correlated with the angiogenesis and metastasis of GC. PMID- 29134463 TI - Stir-Frying of Chinese Cabbage and Pakchoi Retains Health-Promoting Glucosinolates. AB - Stir-frying is a cooking method, originating from Asia, in which food is fried in small amount of very hot oil. Nowadays in many other parts of the world stir frying is a very popular method to prepare vegetables, because it is fast and fried vegetables are tasty. However, the retention of phytochemicals like the health-beneficial glucosinolates in Brassica vegetables is less explored for stir frying in comparison to other cooking methods. This study investigates the retention of glucosinolates in Chinese cabbage (Brassica rapa ssp. pekinensis) and pakchoi (Brassica rapa ssp. chinensis) as affected by stir-frying at various cooking durations and temperatures. Stir-frying experiments were performed at set pan temperatures ranging from 160 to 250 degrees C for a duration of 1 to 8 min. Results showed that aliphatic glucobrassicanapin is the most abundant glucosinolate identified in fresh Chinese cabbage and pakchoi, contributing for 48 and 63% of the total glucosinolate content, respectively, followed by glucoiberin and gluconapin. Stir-frying retains the glucosinolates even at the highest temperature applied. Such retention is explained by the quick inactivation of the glucosinolate-hydrolytic enzyme myrosinase during the first minutes of frying, and by the thermal stability of the glucosinolates at those temperature/time conditions. Moreover, due to the absence of a separate water phase, leaching losses did not occur, in contrast to what is observed when boiling Brassica vegetables. These results show that stir-frying may be a suitable health-beneficial cooking option that prevents the loss of glucosinolates. PMID- 29134464 TI - Phytochemical Properties and Antioxidant Activities of Extracts from Wild Blueberries and Lingonberries. AB - Among Vaccinium species, blueberries (Vaccinium myrtillus L.) and lingonberries (Vaccinium vitis-idaea) are popular in the human diet. In this study, total phenolic, total flavonoid and total monomeric anthocyanin contents in the ethanol water extracts of blueberry and lingonberry fruits grown wild in the forests in the central region of Poland were assayed. Antioxidant activities of the extracts from each plant were also evaluated for scavenging ability on 1,1-diphenyl-2 picrylhydrazyl (DPPH) radicals and reducing power by cupric reducing antioxidant capacity (CUPRAC) method. Total phenolics in the blueberry extracts ranged from 4.58 to 5.28 mg GAE CE/g fw. The extracts from lingonberry fruits contained higher total contents of phenolic compounds (5.82-7.60 mg GAE/g fw) as well as total flavonoids (5.22-6.47 MUmol CE/g fw) than those from blueberries (3.74-4.18 MUmol CE/g fw). For the total monomeric anthocyanin contents, the blueberry extracts presented significantly higher values (3.01-3.93 mg cyanidin-3-glucoside (C3G) equivalent/g fw) in comparison to the lingonberry extracts (0.32-0.47). Blueberry extracts exhibited higher antioxidant activity measured by both assays in comparison to lingonberry extracts. Water extracts from fresh and dried fruits also exhibited significant antioxidant activities for both types of berries. Considering the health benefits that have been associated with polyphenolic consumption, these fruits could appear as a good source of this group of phytochemical compounds for their direct consumption or their use as ingredients for the design of new food products or food supplements. PMID- 29134465 TI - Current Role for Biomarkers in Clinical Diagnosis of Alzheimer Disease and Frontotemporal Dementia. AB - Purpose of review Alzheimer's disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance. Recent findings With the advent of 18F-labeled tracers that bind amyloid plaques, amyloid PET is now clinically available for the detection of amyloid pathology and to aid in a biomarker supported diagnosis of AD or mild cognitive impairment (MCI) due to AD. It is not yet possible to test for the specific FTD pathologies (tau or TDP-43); however, a diagnosis of FTD may be "imaging supported" based upon specific MRI or FDG-PET findings. Cerebrospinal fluid measures of amyloid-beta, total-tau, and phospho tau are clinically available and allow detection of both of the cardinal pathologies of AD: amyloid and tau pathology. Summary It is appropriate to pursue biomarker testing in cases of MCI and dementia when there remains diagnostic uncertainty and the result will impact diagnosis or treatment. Practically speaking, due to the rising prevalence of amyloid positivity with advancing age, measurement of biomarkers in cases of MCI and dementia is most helpful in early onset patients, patients with atypical clinical presentations, or when considering referral for AD clinical trials. PMID- 29134466 TI - Glycogen synthase kinase-3beta mediated regulation of matrix metalloproteinase-9 and its involvement in oral squamous cell carcinoma progression and invasion. AB - PURPOSE: Oral squamous cell carcinoma (OSCC)-related deaths mainly result from invasion of the tumor cells into local cervical lymph nodes. It has been reported that progressive basement membrane loss promotes the metastatic and invasive capacities of OSCCs. Matrix metalloproteinase-9 (MMP-9) is known to play a central role in tumor progression and invasion. However, the role of MMP-9 in OSCC invasion has so far remained paradoxical and little is known about its regulation. Here, we aimed to assess MMP-9 expression regulation and its activation by glycogen synthase kinase-3beta during human OSCC progression and invasion. METHODS: In the present study, 178 human OSCC samples, including 118 fresh samples (18 adjacent normal, 42 noninvasive and 58 invasive tumor samples) and 60 archival human tissue microarray (TMA) tongue cancer samples, were included. mRNA expression, protein expression, MMP-9/-2 activity, protein-protein interaction and Snail, c-Myc, beta-catenin and TIMP1 expression were assessed using RT-PCR, immunohistochemistry, Western blotting, co-immunoprecipitation and gelatin zymography analyses, respectively. Wnt5a and LPA mediated MMP-9 regulation was assessed in OCSCC-derived SCC-9 cells exogenously expressing GSK3beta (WT) or non phosphoryable GSK3beta (S9A). RESULTS: We observed a progressive up-regulation/activation of MMP-9 at various stages of oral tumor progression/invasion. Positive correlations were observed between MMP-9 and c-Myc expression, MMP-9 and MMP-2 activity, MMP-9 and TIMP1 expression and MMP-9 activity and TIMP1-MMP-9 interaction. In contrast, a negative correlation between phosphorylated beta-catenin and MMP-9 expression was observed. Conversely, we found that in oral tongue SCC MMP-9 expression was positively correlated with inactivation of GSK3 signaling. Finally, we found that Wnt5a and LPA mediated increased MMP-9 and decreased GSK3beta activities in tongue SCC-derived SCC-9 cells. MMP-9 regulation by GSK3beta was confirmed by using phosphoryable/regulatory GSK3beta (WT construct) and not by non-phosphoryable GSK3beta (S9A construct). CONCLUSIONS: Collectively, our results show that MMP-9 overexpression and activation are important events occurring during OSCC progression/invasion and that this overexpression/activation is regulated by c Myc, active MMP-2 and inactive GSK3beta mediated pathways. PMID- 29134469 TI - Erratum to: Mechanism of Phospholipid Hydrolysis for Oyster Crassostrea plicatula Phospholipids During Storage Using Shotgun Lipidomics. AB - Erratum to: Lipids https://doi.org/10.1007/s11745-017-4305-7. PMID- 29134470 TI - The effect of long-term confinement and the efficacy of exercise countermeasures on muscle strength during a simulated mission to Mars: data from the Mars500 study. AB - BACKGROUND: Isolation and long duration spaceflight are associated with musculoskeletal deconditioning. Mars500 was a unique, high-fidelity analogue of the psychological challenges of a 520-day manned mission to Mars. We aimed to explore the effect of musculoskeletal deconditioning on three outcome measures: (1) if lower limb muscle strength was reduced during the 520-day isolation; (2) if type I or II muscle fibres were differentially affected; and (3) whether any 70-day exercise interventions prevented any isolation-induced loss of strength. METHODS: Six healthy male subjects (mean +/- SEM) (34 +/- 3 years; 1.76 +/- 0.02 metres; 83.7 +/- 4.8 kg) provided written, informed consent to participate. The subjects' maximal voluntary contraction (MVC) was assessed isometrically in the calf (predominantly type I fibres), and maximal voluntary isokinetic force (MVIF) was assessed in the quadriceps/hamstrings (predominantly type II fibres) at 0.2 and 0.4 ms-1 using the Multifunctional Dynamometer for Space (MDS) at 35-day intervals throughout Mars500. Exercise interventions were completed 3-7 days/week throughout the 520-day isolation in a counterbalanced design excluding 142-177 days (rest period) and 251-284 days (simulated Mars landing). Exercise interventions included motorized treadmill running, non-motorized treadmill running, cycle ergometry, elastomer-based resistance exercise, whole-body vibration (WBV), and resistance exercise using MDS. RESULTS: Calf MVC did not reduce across the 520-day isolation and MDS increased strength by 18% compared to before that of 70-day exercise intervention. In contrast, there was a significant bilateral loss of MVIF across the 520 days at both 0.2 ms-1 (R 2 = 0.53; P = 0.001) and 0.4 ms-1 (0.4 ms-1; R 2 = 0.42; P = 0.007). WBV (+ 3.7 and 8.8%) and MDS (+ 4.9 and 5.2%) afforded the best protection against isolation-induced loss of MVIF, although MDS was the only intervention to prevent bilateral loss of calf MVC and leg MVIF at 0.2 and 0.4 ms-1. CONCLUSIONS: Mars500 induced significant loss of quadriceps/hamstrings MVIF but not calf MVC. Collectively, these data suggest that muscles with predominantly type I fibres were affected less by isolation compared to type II dominant muscles. MDS and WBV afforded the best protection against isolation-induced loss of strength and thus may have virtue in exploration class missions. PMID- 29134467 TI - Diterpenoid natural compound C4 (Crassin) exerts cytostatic effects on triple negative breast cancer cells via a pathway involving reactive oxygen species. AB - PURPOSE: Triple-negative breast cancers (TNBC) lack expression of three common cell surface receptors, i.e., estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Accordingly, TNBCs are associated with fewer treatment options and a relatively poor prognosis. Having screened a National Cancer Institute natural compound library, the purpose of this study was to investigate the bioactivity of compound C4 (Crassin) in TNBC cells. METHODS: Cell viability assays were performed in two TNBC cell lines, MDA MB-231 and 4T1, following C4 treatment in the presence or absence of the antioxidant N-acetyl-L-cysteine (NAC). Phosphorylation of Akt and ERK was assessed by Western blotting. Apoptosis, necrosis, autophagy, necroptosis, ferroptosis and cytostasis assays were performed to explain viability deficits resulting from C4 exposure. RESULTS: We found that the viability of the TNBC cells tested decreased in a concentration- and time-dependent fashion following C4 treatment. This decrease coincided with an unexpected increase in the expression of the cell survival effectors pAkt and pERK. In addition, we found that both the decreased cell viability and the increased pAkt/pERK levels could be rescued by the antioxidant NAC, suggesting a central role for reactive oxygen species (ROS) in the mechanism of action of C4. Necrosis, apoptosis, necroptosis and ferroptosis could be ruled out as cell death mechanisms. Instead, we found that C4 induced cytostasis downstream of ROS activation. Finally, we observed a synergistic effect between C4 and the chemotherapeutic drug doxorubicin in TNBC cells. CONCLUSIONS: From our in vitro data we conclude that C4 exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species. Its potential value in combination with cytotoxic therapies merits deeper investigation in pre-clinical models. PMID- 29134471 TI - The Impact of Heat Treatment on Porcine Heart Valve Leaflets. AB - The purpose of this study was to determine the impact of elevated temperature exposure in tissue banking on soft tissues. A secondary objective was to determine the relative ability of various assays to detect changes in soft tissues due to temperature deviations. Porcine pulmonary heart valve leaflets exposed to 37 degrees C were compared with those incubated at 52 and 67 degrees C for 10, 30 and 100 min. The analytical methods consisted of (1) viability assessment using the resazurin assay, (2) collagen content using the Sircol assay, and (3) permeability assessment using an electrical conductivity assay. Additionally, histology and two photon microscopy were used to reveal mechanisms of cell and tissue damage. Viability, collagen content, and permeability all decreased following heat treatment. In terms of statistical significance with respect to treatment temperature, cell viability was most affected (p < 0.0001), followed by permeability (p < 0.0001), and then collagen content (p = 0.13). After heat treatment, histology indicated increased apoptosis and two photon microscopy revealed a decrease in collagen fiber organization and an increase in elastin density. These results suggest that measures of cell viability would be best for assessing tissues where the cells are alive and that permeability may be best where cell viability is not intentionally maintained. PMID- 29134472 TI - Real-time wireless tumor tracking during breast conserving surgery. AB - PURPOSE: To evaluate a novel surgical navigation system for breast conserving surgery (BCS), based on real-time tumor tracking using the Calypso[Formula: see text] 4D Localization System (Varian Medical Systems Inc., USA). Navigation guided breast conserving surgery (Nav-BCS) was compared to conventional iodine seed-guided BCS ([Formula: see text]I-BCS). METHODS: Two breast phantom types were produced, containing spherical and complex tumors in which wireless transponders (Nav-BCS) or a iodine seed ([Formula: see text]I-BCS) were implanted. For navigation, orthogonal views and 3D volume renders of a CT of the phantom were shown, including a tumor segmentation and a predetermined resection margin. In the same views, a surgical pointer was tracked and visualized. [Formula: see text]I-BCS was performed according to standard protocol. Five surgical breast oncologists first performed a practice session with Nav-BCS, followed by two Nav-BCS and [Formula: see text]I-BCS sessions on spherical and complex tumors. Postoperative CT images of all resection specimens were registered to the preoperative CT. Main outcome measures were the minimum resection margin (in mm) and the excision times. RESULTS: The rate of incomplete tumor resections was 6.7% for Nav-BCS and 20% for [Formula: see text]I-BCS. The minimum resection margins on the spherical tumors were 3.0 +/- 1.4 mm for Nav-BCS and 2.5 +/- 1.6 mm for [Formula: see text]I-BCS (p = 0.63). For the complex tumors, these were 2.2 +/- 1.1 mm (Nav-BCS) and 0.9 +/- 2.4 mm ([Formula: see text]I-BCS) (p = 0.32). Mean excision times on spherical and complex tumors were 9.5 +/- 2.7 min and 9.4 +/- 2.6 min (Nav-BCS), compared to 5.8 +/- 2.2 min and 4.7 +/- 3.4 min ([Formula: see text]I-BCS, both (p < 0.05). CONCLUSIONS: The presented surgical navigation system improved the intra-operative awareness about tumor position and orientation, with the potential to improve surgical outcomes for non-palpable breast tumors. Results are positive, and participating surgeons were enthusiastic, but extended surgical experience on real breast tissue is required. PMID- 29134473 TI - Doctor Anonymous: Creating Contexts for Homosexuality as Mental Illness. AB - In this essay, the author describes how he faced institutionalized homophobia during his psychiatric training, and how he later wrote a play inspired by the life of a gay psychiatrist. Despite Freud's supportive stance, homosexuality aroused the antipathy of American organized psychiatry and psychoanalysis and came to be listed as an illness in the Diagnostic and Statistical Manual (DSM). Dr. John E. Fryer outed himself as "Dr. H Anonymous" at a 1972 meeting of the American Psychiatric Association, and the next year homosexuality was removed from the DSM. The 2014 play Doctor Anonymous offers a fictionalized account of this watershed moment in the history of the gay rights movement. The author discusses his own psychotherapeutic work with gay male patients, including those who had previously been treated with conversion therapy, and explores how the play mirrors his own life experience and the experience of his patients. PMID- 29134474 TI - Familial Limbal Stem Cell Deficiency: Clinical, Cytological and Genetic Characterization. PMID- 29134475 TI - Synchronized Spontaneous Otoacoustic Emissions Provide a Signal-to-Noise Ratio Advantage in Medial-Olivocochlear Reflex Assays. AB - Detection of medial olivocochlear-induced (MOC) changes to transient-evoked otoacoustic emissions (TEOAE) requires high signal-to-noise ratios (SNR). TEOAEs associated with synchronized spontaneous (SS) OAEs exhibit higher SNRs than TEOAEs in the absence of SSOAEs, potentially making the former well suited for MOC assays. Although SSOAEs may complicate interpretation of MOC-induced changes to TEOAE latency, recent work suggests SSOAEs are not a problem in non-latency dependent MOC assays. The current work examined the potential benefit of SSOAEs in TEOAE-based assays of the MOC efferents. It was hypothesized that the higher SNR afforded by SSOAEs would permit detection of smaller changes to the TEOAE upon activation of the MOC reflex. TEOAEs were measured in 24 female subjects in the presence and absence of contralateral broadband noise. Frequency bands with and without SSOAEs were identified for each subject. The prevalence of TEOAEs and statistically significant MOC effects were highest in frequency bands that also contained SSOAEs. The median TEOAE SNR in frequency bands with SSOAEs was approximately 8 dB higher than the SNR in frequency bands lacking SSOAEs. After normalizing by TEOAE amplitude, MOC-induced changes to the TEOAE were similar between frequency bands with and without SSOAEs. Smaller MOC effects were detectable across a subset of the frequency bands with SSOAEs, presumably due to a higher TEOAE SNR. These findings demonstrate that SSOAEs are advantageous in assays of the MOC reflex. PMID- 29134476 TI - Aminoglycoside Damage and Hair Cell Regeneration in the Chicken Utricle. AB - In this study, we present a systematic characterization of hair cell loss and regeneration in the chicken utricle in vivo. A single unilateral surgical delivery of streptomycin caused robust decline of hair cell numbers in striolar as well as extrastriolar regions, which in the striola was detected very early, 6 h post-insult. During the initial 12 h of damage response, we observed global repression of DNA replication, in contrast to the natural, mitotic hair cell production in undamaged control utricles. Regeneration of hair cells in striolar and extrastriolar regions occurred via high rates of asymmetric supporting cell divisions, accompanied by delayed replenishment by symmetric division. While asymmetric division of supporting cells is the main regenerative response to aminoglycoside damage, the detection of symmetric divisions supports the concept of direct transdifferentiation where supporting cells need to be replenished after their phenotypic conversion into new hair cells. Supporting cell divisions appear to be well coordinated because total supporting cell numbers throughout the regenerative process were invariant, despite the initial large-scale loss of hair cells. We conclude that a single ototoxic drug application provides an experimental framework to study the precise onset and timing of utricle hair cell regeneration in vivo. Our findings indicate that initial triggers and signaling events occur already within a few hours after aminoglycoside exposure. Direct transdifferentiation and asymmetric division of supporting cells to generate new hair cells subsequently happen largely in parallel and persist for several days. PMID- 29134477 TI - Difference in the size of the placenta and umbilical cord between women with natural pregnancy and those with IVF pregnancy. AB - PURPOSE: The purpose of this study was to compare the sizes of the placenta and umbilical cord in women with natural pregnancy versus those undergoing in vitro fertilization (IVF). METHODS: Overall, 1610 cases of uncomplicated single pregnancies with vaginal delivery at >= 37 weeks of gestation were included in this study. The patients were divided into two groups: natural pregnancy group (n = 1453) and IVF pregnancy not including intracytoplasmic sperm injection (ICSI) treatment (n = 157). The groups were compared in terms of gestational week, maternal age, parity, maternal weight gain, prepregnancy maternal BMI, infant weight at birth, infant head circumference, placental weight, cross section of the placenta, cross section of the umbilical cord, insertion site of the umbilical cord, and umbilical cord length. Stepwise selection and multivariate logistic regression were used for statistical analysis to correct the result as an independent factor. RESULTS: There was no difference in the size of the placenta and umbilical cord between women with natural pregnancy and with IVF, but the incidence of velamentous insertion of the cord was significantly increased in women with IVF pregnancy (adjusted odd ratio [AOR] 1.72, 95% confidence interval [CI] 1.08-2.72, p = 0.026). CONCLUSIONS: Although there is no difference in placental weight and cord size, velamentous insertion of the umbilical cord increases in IVF pregnancy and needs careful observation during the delivery process. PMID- 29134478 TI - Key factors enhancing sperm fertilizing ability are transferred from the epididymis to the spermatozoa via epididymosomes in the domestic cat model. AB - PURPOSE: Spermatozoa undergo critical changes in structure and function during the epididymal transit. Our previous studies in the domestic cat demonstrated that incidence of cenexin-a key protein involved in the centrosomal maturation progressively increases in sperm cells from caput to cauda epididymidis. The objectives of the study were to (1) characterize mechanisms involved in transferring key factors-using the cenexin as a marker-between the epididymis and maturing sperm cells and (2) demonstrate the impact of such mechanisms on the acquisition of functional properties by spermatozoa. METHODS: Epididymides were dissected from adult cat testes to assess the presence and localization of cenexin in testicular tissues and each epididymal segment (caput, corpus, and cauda) via immunofluorescence, Western blot, and mass spectrometry. RESULTS: Results showed that tissues, luminal fluid, and isolated epididymosomes from each segment contained cenexin. Co-incubation of immature sperm cells for 3 h with luminal fluid or epididymosomes followed by immunostaining revealed that percentages of sperm cells containing cenexin significantly increased in samples co-incubated with epididymosome suspensions. Additionally, epididymosome co incubation with immature spermatozoa resulted in sustained motility compared to untreated spermatozoa while there was no significant effect on acrosome integrity. CONCLUSIONS: Taken together, these results suggest that epididymosomes play a critical role in epididymal sperm maturation and could be ideal vehicles to assist in the enhancement or suppression of male fertility. PMID- 29134479 TI - Take Flight: the evolution of an Orton Gillingham-based curriculum. AB - Thirty years ago in this journal, Aylett Royall Cox reported on the development of Alphabetic Phonics, a revision of the existing Orton Gillingham treatment for children with dyslexia. This paper continues that discussion and reports on the evolution of that curriculum as it is represented in a comprehensive dyslexia treatment program informed by intervention research. The paper describes the curriculum and reports data from a hospital-based learning disabilities clinic that provides qualified support for treatment efficacy and the value of added comprehension instruction. The results are then discussed in the context of current and future issues in dyslexia intervention. PMID- 29134480 TI - False memory for orthographically versus semantically similar words in adolescents with dyslexia: a fuzzy-trace theory perspective. AB - The presented research was conducted in order to investigate the connections between developmental dyslexia and the functioning of verbatim and gist memory traces-assumed in the fuzzy-trace theory. The participants were 71 high school students (33 with dyslexia and 38 without learning difficulties). The modified procedure and multinomial model of Stahl and Klauer (simplified conjoint recognition model) was used to collect and analyze data. Results showed statistically significant differences in four of the model parameters: (a) the probability of verbatim trace recollection upon presentation of orthographically similar stimulus was higher in the control than dyslexia group, (b) the probability of verbatim trace recollection upon presentation of semantically similar stimulus was higher in the control than dyslexia group, (c) the probability of gist trace retrieval upon presentation of semantically similar stimulus was higher in the dyslexia than control group, and (d) the probability of gist trace retrieval upon target stimulus presentation (in the semantic condition) was higher in the control than dyslexia group. The obtained results suggest differences of memory functioning in terms of verbatim and gist trace retrieval between people with and without dyslexia on specific, elementary cognitive processes postulated by the fuzzy-trace theory. These can indicate new approaches in the education of persons with developmental dyslexia, focused on specific impairments and the strengths of their memory functioning. PMID- 29134481 TI - Inflectional morphology and dyslexia: Italian children's performance in a nonword pluralization task. AB - In this study, we present the results of an original experimental protocol designed to assess the performance in a pluralization task of 52 Italian children divided into two groups: 24 children with developmental dyslexia (mean age 10.0 years old) and 28 typically developing children (mean age 9.11 years old). Our task, inspired by Berko's Wug Test, had the aim of testing the subjects' ability to apply pluralization rules to nonwords in the morphologically complex context of Italian nominal inflection. Results demonstrate that dyslexics display poorer morphological skills in comparison to controls, showing lower accuracy in the task. Furthermore, the dissimilar performances reported by the subjects in the different conditions indicate that the ability to inflect nonwords depends on factors such as the rule's productivity, frequency, and opacity with respect to gender. Finally, the children's performance in this task was significantly related to their reading proficiency, and it could predict accuracy in word reading independently of phonological awareness and working memory. PMID- 29134482 TI - Potential or problem? An investigation of secondary school teachers' attributions of the educational outcomes of students with specific learning difficulties. AB - Despite strong support for inclusive education in principle, many teachers and administrators still demonstrate mixed responses to the inclusion of certain students in their classrooms. Students with specific learning difficulties (SpLD) form a large group of students in inclusive classrooms yet some provincial, state and national jurisdictions fail to acknowledge the existence of these students. Not acknowledging and understanding these students can deny them the recognition and resources necessary for their genuine participation in education and, in turn, society. The aim of this study was to examine British in-service secondary teachers' attributional responses to students with and without specific learning difficulties. The participants included 122 British secondary school teachers who were surveyed in response to vignettes of hypothetical male students who had failed a class test. The study found that while teachers attributed more positive causes towards students without SpLD, they exhibited more negative causes towards students with SpLD. Teachers' causal attributional outcomes of students' level of achievement can impact upon the students' own attributions, with teachers' responses for students with SpLD having the potential to, unintentionally, influence students' own sense of self-efficacy and motivation. The paper concludes with a consideration of the implications of the research and recommendations for practice. PMID- 29134483 TI - Evaluating the impact of dyslexia laws on the identification of specific learning disability and dyslexia. AB - Dyslexia is a specific learning disability that impacts word reading accuracy and/or reading fluency. Over half of the states in the USA have passed legislation intended to promote better identification of individuals with dyslexia. To date, no study has been conducted to investigate the potential impact of state laws on the identification of specific learning disability (SLD), and limited data has been presented on the rate at which students in public school settings are identified with dyslexia. The first aim of the current study was to determine if any detectable changes in the identification rates of SLD have occurred in states implementing dyslexia laws because most states do not report number of students identified as dyslexic but rather those students identified with an SLD. The second aim of the study was to characterize the rate of identifying dyslexia in the two states (Texas and Arkansas) that require public schools to report the number of students identified with dyslexia. The third aim was to characterize the identification rate across first to 12th grades. Current SLD rates range from 3.2 to 8.5% in all 50 states. Analysis of SLD prevalence rates did not vary between states with and without dyslexia laws in place. Moreover, there was no change in the identification of SLD once states had implemented these laws. Rates of dyslexia in Arkansas and Texas were less than 5%. Given the persistent levels indicating lack of reading proficiency, our review of data suggests that overall students with dyslexia are being underidentified. PMID- 29134484 TI - The role of feedback in implicit and explicit artificial grammar learning: a comparison between dyslexic and non-dyslexic adults. AB - The importance of feedback for learning has been firmly established over the past few decades. The question of whether feedback plays a significant role in the statistical learning abilities of adults with dyslexia, however, is currently unresolved. Here, we examined the role of feedback in grammaticality judgment, type of structural knowledge, and confidence rating in both typically developed and dyslexic adults. We implemented two artificial grammar learning experiments: implicit and explicit. The second experiment was directly analogous to the first experiment in all respects except training format: the standard memorization instruction was replaced with an explicit rule-search instruction. Each experiment was conducted with and without performance feedback. While both groups showed significantly improved learning in the feedback-based explicit artificial grammar learning task, only the typically developed adults demonstrated higher levels of conscious structural knowledge. The present study demonstrates that the basis for the grammaticality judgment of adults with dyslexia differs from that of typically developed adults, regardless of increase in the level of explicitness. PMID- 29134485 TI - Length effects in pseudo-word spelling: stronger in dyslexic than in non-dyslexic students. AB - It is often discussed whether dyslexics show a deviant pattern of reading and spelling development when compared to typically developing students, or whether they follow the same pattern as other students, only at markedly slower rate. The present cross-sectional study investigated phonological encoding skills in dyslexic Danish students. We compared dyslexic and non-dyslexic students from grades 3, 5, 7, and 9 and examined whether effects of item length were stronger in the dyslexic groups. Mixed between-within subjects analyses of variance revealed significant interactions between dyslexia status and item length as the dyslexics at all grade levels were more affected by item length than their non dyslexic peers. A marked developmental delay was apparent as the dyslexic group from grade 9 performed on approximately the same level as the non-dyslexic group from grade 3. Although the overall difference between these two groups was not significant, a significant interaction between dyslexia status and item length remained because the grade 9 dyslexics were more affected by item length than the younger non-dyslexic students. This difference in error profiles suggests a difference in the developmental patterns of dyslexic vs. non-dyslexic students. PMID- 29134486 TI - Proteasome-associated deubiquitinases and cancer. AB - Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS. PMID- 29134487 TI - Sildenafil citrate use in Addis Ababa: characteristics of users and pharmacists' dispensing practices. AB - Background Studies have reported misuse of sildenafil citrate for recreational purpose, not least by healthy young men. This is becoming a major concern, for medical and other reasons. Objective The aim of this study was to document the characteristics of sildenafil citrate users and to explore the dispensing practices of the medicine in selected community pharmacies in Addis Ababa, Ethiopia. Setting Data was collected in community pharmacies in Addis Ababa, Ethiopia. Method A survey, using a self-administrated questionnaire, was conducted among customers who purchased sildenafil citrate from community pharmacies. Simple descriptive statistics were used to analyse data. Also, semi structured interviews were conducted with community pharmacists. These were analysed thematically. Main outcome measures Socio-demographic characteristics (survey), themes (interviews). Results All survey respondents (n = 197) were men, 57.9% were below 40 years old, 53.8% had never been married and 58.4% had used sildenafil citrate before. A minority (16.2%) were diagnosed with erectile dysfunction. The main reason for buying sildenafil citrate was experimentation (45.7%). Pharmacists reported that sildenafil citrate was often dispensed without a prescription. The reason for this was, according to the interviewees, competition in the market. Also, the medicine was often dispensed without adequate information or counselling. Conclusions Selling and buying sildenafil citrate without a prescription seems to be common practice in pharmacies in Addis Ababa. It is crucial to strengthen the regulatory activity to protect customers from health risks. In addition pharmacy professionals should be supported to work in accordance with professional and legal standards. PMID- 29134488 TI - Impact of clinical pharmacists intervention on management of hyperglycemia in pregnancy in Jordan. AB - Background and objective Hyperglycemia in pregnancy is a risk factor for cardiovascular disease and postpartum (PP) diabetes. This study aimed to assess the impact of the clinical pharmacist-assisted program (CPAP) of optimizing drug therapy and intensive education on main management outcome measures of patient knowledge about diabetes, Quality of life (QoL) as measured by SF-36 including maternal complications, fasting plasma glucose (FPG) control, and HbA1c. Method This is a randomized controlled study. Pregnant (20-28 weeks) patients with hyperglycemia received CPAP (n = 51) as compared with conventional management (n = 34). Patients were then followed up for 6 weeks pp. Results A significant change was shown in the intervention group for diabetes knowledge (3.47% vs. control 2.03%, P < 0.05) and three aspects of health-related QoL. The need for caesarian delivery (58.8% vs. control 35.3%) and severe episodes of hypoglycemia (0% vs. control 8.8%) were significantly (P < 0.05) reduced in the intervention group. Six weeks PP reduction in HbA1c values was greater in the intervention group (- 0.54% vs. control - 0.08%, P = 0.04) with more FPG-controlled patients during pregnancy (94% vs. control 64.7%). Conclusion Clinical pharmacist assisted services in the management of pregnancy hyperglycemia fundamentally and significantly improve knowledge and disease control. PMID- 29134489 TI - The quick loss of carbapenem susceptibility in Pseudomonas aeruginosa at intensive care units. AB - Background Patients colonized with carbapenem-susceptible Pseudomonas aeruginosa (CSPA) strains upon admission to the intensive care unit (ICU) tend to be quickly followed by detected carbapenem-resistant P. aeruginosa strains after admission. Objective To assess the risk factors associated with the quick loss of carbapenem susceptibility and to identify time threshold of prior antimicrobial exposure for the loss during ICU stay. Setting A tertiary-care teaching hospital with 2560 beds located in the northwest region of China. Method A retrospective observational study was conducted between January 2013 and April 2016 at ICUs. Logistic regression analysis was used to assess risk factors, and receiver operating characteristic (ROC) analyses were constructed to identify the time threshold. Main outcome measure The time threshold and risk factors for the quick loss of carbapenem susceptibility. Results Among the 84 patients with CSPA initially, 32 (38.1%) patients were observed to have a loss of carbapenem susceptibility during ICU stay. Logistic regression analyses showed that previous carbapenem exposure was only independently associated with the loss of carbapenem susceptibility (odds ratio 13.16; 95% CI 3.13-55.24; p < 0.001). The optimal cut off was 3.5 days on ROC curve, indicating the high risk for loss of susceptibility. Conclusion In order to alleviate selective pressure caused by antipseudomonal carbapenems exposure, continued research is needed to determine the most appropriate carbapenems treatment strategies. PMID- 29134490 TI - Knot soliton in DNA and geometric structure of its free-energy density. AB - In general, the geometric structure of DNA is characterized using an elastic rod model. The Landau model provides us a new theory to study the geometric structure of DNA. By using the decomposition of the arc unit in the helical axis of DNA, we find that the free-energy density of DNA is similar to the free-energy density of a two-condensate superconductor. By using the phi-mapping topological current theory, the torus knot soliton hidden in DNA is demonstrated. We show the relation between the geometric structure and free-energy density of DNA and the Frenet equations in differential geometry theory are considered. Therefore, the free-energy density of DNA can be expressed by the curvature and torsion of the helical axis. PMID- 29134491 TI - DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer. AB - BACKGROUND: Significant inter-individual variation in the sensitivity to 5 fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5 fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients. METHODS: Colorectal cancer patients (n = 161) receiving 5-FU based chemotherapy were prospectively enrolled. DPYD and MTHFR polymorphisms were assessed in peripheral leukocytes. Multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity and efficacy. RESULTS: Multivariate analyses showed that DPYD*2A polymorphism was a predictive factor (P = 0.023) for grade 3 and grade 4 5-fluorouracil-related toxicities. Although MTHFR C677T polymorphism might act as forecasters for grade 3 or grade 4 neutropenia, diarrhea, and mucositis, this polymorphism was found to increase significantly (P = 0.006) the response of 5-FU. CONCLUSION: DPYD*2A and MTHFR C677T polymorphisms could explain 5-FU toxicity or clinical outcome in Bangladeshi colorectal patients. PMID- 29134492 TI - Cumulative improbability. PMID- 29134493 TI - Lethal and sub-lethal effects of select macrocyclic lactones insecticides on forager worker honey bees under laboratory experimental conditions. AB - Selective insecticide application is one important strategy for more precisely targeting harmful insects while avoiding or mitigating collateral damage to beneficial insects like honey bees. Recently, macrocyclic lactone-class insecticides have been introduced into the market place as selective bio insecticides for controlling many arthropod pests, but how to target this selectivity only to harmful insects has yet to be achieved. In this study, the authors investigated the acute toxicity of fourmacrocyclic lactone insecticides (commercialized as abamectin, emamectin benzoate, spinetoram, and spinosad) both topically and through feeding studies with adult forager honey bees. Results indicated emamectin benzoate as topically 133.3, 750.0, and 38.3-fold and orally 3.3, 7.6, and 31.7-fold more toxic, respectively than abamectin, spinetoram and spinosad. Using Hazard Quotients for estimates of field toxicity, abamectin was measured as the safest insecticide both topically and orally for honey bees. Moreover, a significant reduction of sugar solution consumption by treatment group honey bees for orally applied emamectin benzoate and spinetoram suggests that these insecticides may have repellent properties. PMID- 29134494 TI - Expression of Telomere-Associated Proteins is Interdependent to Stabilize Native Telomere Structure and Telomere Dysfunction by G-Quadruplex Ligand Causes TERRA Upregulation. AB - Telomere DNA can form specialized nucleoprotein structure with telomere associated proteins to hide free DNA ends or G-quadruplex structures under certain conditions especially in presence of G-quadruplex ligand. Telomere DNA is transcribed to form non-coding telomere repeat-containing RNA (TERRA) whose biogenesis and function is poorly understood. Our aim was to find the role of telomere-associated proteins and telomere structures in TERRA transcription. We silenced four [two shelterin (TRF1, TRF2) and two non-shelterin (PARP-1, SLX4)] telomere-associated genes using siRNA and verified depletion in protein level. Knocking down of one gene modulated expression of other telomere-associated genes and increased TERRA from 10q, 15q, XpYp and XqYq chromosomes in A549 cells. Telomere was destabilized or damaged by G-quadruplex ligand pyridostatin (PDS) and bleomycin. Telomere dysfunction-induced foci (TIFs) were observed for each case of depletion of proteins, treatment with PDS or bleomycin. TERRA level was elevated by PDS and bleomycin treatment alone or in combination with depletion of telomere-associated proteins. PMID- 29134495 TI - Apoptosis turns 21. PMID- 29134496 TI - An Analysis of Treatment-Seeking Behavior in Individuals with Gambling Disorder. AB - Gambling disorder affects approximately 1.1-3.5% of the population, with the rates being higher in young adults. Despite this high prevalence, little is known regarding which pathological gamblers decide to seek treatment. This study sought to examine the differences in three groups of pathological gamblers: those who did not seek treatment (n = 94), those who sought therapy (n = 106) and those who sought medication therapy (n = 680). All subjects were assessed on a variety of measures including demographics, family history, gambling history, comorbid psychiatric disorders and an assortment of clinical variables such as the Quality of Life Inventory, Hamilton Depression and Anxiety Rating Scales, Yale Brown Obsessive Compulsive Scale for Pathologic Gambling (PG-YBOCS), Barratt Impulsiveness Scale, Eysenck Impulsiveness Questionnaire and select cognitive tasks. Those seeking treatment were more likely to be Caucasian, have lost more money in the past year due to gambling, and were more likely to have legal and social problems as a result of their gambling. Those seeking therapy or medical treatment also scored significantly higher on the PG-YBOCS. This study suggests that pathologic gamblers seeking treatment were more likely to exhibit obsessive compulsive tendencies likely leading to the increased legal and social problems that exist in this group. PMID- 29134498 TI - Vasoplegic Shock Treated with Methylene Blue Complicated by Severe Serotonin Syndrome. AB - INTRODUCTION: Management of severe vasoplegic shock in overdose can be very challenging. We describe a case of severe refractory vasodilatory shock in poisoning where methylene blue (MB) was used with success. However, the patient subsequently developed severe Serotonin Syndrome (SS) as a result of an interaction between serotonergic drugs and MB. CASE REPORT: A 15-year-old male developed severe vasoplegic shock 1.5 hours after overdosing on several different medications including quetiapine slow release, quetiapine immediate release, desvenlafaxine slow release, venlafaxine, amlodipine, ramipril, fluoxetine, promethazine and lithium. His vasoplegic shock was resistant to high doses of noradrenaline and vasopressin. MB was administered 6.5 hours post ingestion and within 1 hour there was an improvement in his hemodynamic status and reduction of catecholamine requirements. Twelve hours post ingestion, he developed severe Serotonin Syndrome that lasted 5 days as a result of interaction between MB, a reversible monoamine oxidase inhibitor (MAO-I), and the antidepressants taken in overdose. MB had a calculated half-life of 38 hours. CONCLUSION: MB is a useful additional strategy for severe drug induced vasodilatory shock and may be potentially life-saving. Clinicians should be aware that it can interact with other drugs and cause life-threatening Serotonin Syndrome. Lower doses or shorter durations may be wise in patients at risk of this interaction. PMID- 29134497 TI - Italian Adult Gambling Behavior: At Risk and Problem Gambler Profiles. AB - The present study examined adult gambling behaviours from a local perspective in order to assess the adult at risk and problem gambler's profile stratified by genre and by different forms of game. 4773 Italian adults from 18 to 94 years old were administered a survey to assess socio-cultural information related to gambling behaviour and the SOGS to evaluate gambling behaviour severity. Logistic regression evidenced that both at risk and problem gamblers are associated with male gender, players that use to play to more than one game, gambling with strategy-based games. People with a gambler father or both parents who used to gamble were significantly more associated with problem gambling behaviour than participants with non-gambler parents. These results present adult profiles of at risk and problem providing a more clear understanding about the relationships between gambling behavior severity and type of gambling. PMID- 29134499 TI - Correction to: Trend of Changes in Serum Albumin and Its Relation with Sex, Age, and BMI Following Laparoscopic Mini-gastric Bypass Surgery in Morbid Obese Cases. AB - Due to a production error the bottom portion of Fig. 3 was missing in the version of this article originally published online. PMID- 29134500 TI - Systematic review of the feasibility and future of laparoscopic liver resection for difficult lesions. AB - Laparoscopic liver resection (LLR) is now performed widely, but is difficult to accomplish in some anatomical locations, such as the posterosuperior segments (S7 and S8) and caudate lobe (S1). An international survey revealed that lesions in these locations are less frequently indicated for LLR than those in other segments. Recent reports from experienced centers document several case series and present technical tips for treating such lesions. The lateral approach using intercostal (transdiaphragmatic) trocars was reported to be useful for lesions in the posterosuperior segments with a semi- to full-decubitus position. The thoracoscopic approach was also reported to be useful for lesions just under the diaphragm dome, but the tumor location and patient selection should be considered carefully because pneumoperitoneum pressure and Pringle's maneuver cannot be applied. Several case series have described the feasibility of LLR for caudate lobe lesions, with similar operative outcomes to lesions in the posterosuperior segments, but this demands technical expertise. The caudal view of laparoscopy is advantageous for approaching the caudate lobe. We conducted a systematic review to clarify the feasibility of LLR for difficult lesions and discuss its current and future status. PMID- 29134501 TI - Pharmacokinetic Properties of Saffron and its Active Components. AB - Saffron as a medicinal plant has many therapeutic effects. Phytochemical studies have reported that saffron is composed of at least four active ingredients which include crocin, crocetin, picrocrocin and safranal. The carotenoids of saffron are sensitive to oxygen, light, heat and enzymatic oxidization. However, regulation of these factors is required for saffron quality. Some pharmacologic effects of saffron and its active compounds include cardioprotective, neuroprotective, memory enhancer, antidepressant and anxiolytic. Among more than 150 chemicals of saffron, the most biologically active components are two carotenoids including crocin and crocetin. Most of the pharmacokinetic studies are related to these compounds. The pharmacokinetic studies have shown that crocin is not available after oral administration in blood circulation. Crocin is converted to crocetin in intestine but after intravenous injection, the level of crocetin in plasma is low. Crocetin can distribute in different tissues because of weak interaction between crocetin and albumin. Also it can penetrate blood brain barrier and reach CNS by passive transcellular diffusion; thus it can be effective in neurodegenerative disorders. The large portion of crocin is eliminated via feces. PMID- 29134503 TI - Short- and Long-Term Outcomes of Endoscope-Assisted Laparoscopic Wedge Resection for Gastric Submucosal Tumors Adjacent to Esophagogastric Junction. AB - BACKGROUND: Laparoscopic wedge resection (LWR) is used to treat gastric submucosal tumors (SMTs). However, LWR can injure the cardia if tumors are near the esophagogastric junction (EGJ), resulting in gastric stenosis. This study's purpose was to summarize our experience with endoscope-assisted LWR for gastric SMTs within 3 cm of the EGJ and to verify the procedure's feasibility and safety. METHODS: Data from 91 consecutive patients with gastric SMTs within 3 cm of the EGJ who underwent endoscope-assisted LWR at our hospital from 2007 to 2017 were obtained from a prospectively maintained database. The clinicopathological results, perioperative data, and long-term follow-up data were analyzed. RESULTS: All patients successfully underwent endoscope-assisted LWR. The mean distance from tumor to EGJ was 2.43 +/- 0.80 cm. Eighty-two patients underwent laparoscopic exogastric wedge resection (LEWR) and nine underwent laparoscopic transgastric wedge resection (LTWR). Mean operative time was 112.4 +/- 48.8 min; mean blood loss was 36.8 +/- 53.5 ml. Mean time to first flatus was 2.04 +/- 0.68 days. Mean time to liquid intake was 2.53 +/- 0.85 days. Mean postoperative hospital stay was 4.97 +/- 1.80 days. Three patients (3.3%) had postoperative complications, all Clavien-Dindo grade I. The mean maximum tumor diameter was 3.00 +/- 1.96 cm (range 0.5-10). LTWR was used more often than LEWR for SMTs in the posterior wall, those with intraluminal growth, and those closer to the EGJ. The mean follow-up time was 36.86 +/- 29.73 months (range 3-126). There was no stenosis of EGJ or tumor recurrence. Sixteen patients (17.6%) complained of upper gastrointestinal symptoms during the follow-up, which were all relieved by usage of acid suppressive medications. CONCLUSIONS: Endoscope-assisted LWR is safe, feasible, and effective for gastric SMTs near the EGJ. LTWR is preferable to LEWR for gastric SMTs in the posterior wall, those with intraluminal growth, and those closer to the EGJ. PMID- 29134504 TI - Ketorolac and Other NSAIDs Increase the Risk of Anastomotic Leakage After Surgery for GEJ Cancers: a Cohort Study of 557 Patients. AB - OBJECTIVE: The objective of this study is to investigate the impact of ketorolac and other nonsteroidal anti-inflammatory drugs on anastomotic leakage after surgery for gastro-esophageal-junction cancer. Within the last two decades, the incidence of gastro-esophageal-junction cancer has increased in the western world and surgery is the curative treatment modality of choice. Anastomotic leakage is a feared complication of gastro-esophageal surgery, as it increases recurrence, morbidity, and mortality. Nonsteroidal anti-inflammatory drugs are widely used for postoperative pain relief. Nonsteroidal anti-inflammatory drugs have, however, in colorectal surgery, been shown to increase the risk of anastomotic leakage. METHOD: In a historical cohort study, we investigated the impact of nonsteroidal anti-inflammatory drugs on anastomotic leakage in 557 patients undergoing surgery for gastro-esophageal-junction cancer. Data were collected from a prospective maintained database, the Danish National Patient Registry, and patient medical records. Data were analyzed using univariate and multivariate statistical models and were stratified for theoretical confounders. RESULTS: In univariate analysis, we did not observe any difference in age, gender, tobacco exposure, or comorbidity status between patients experiencing anastomotic leakage and those without. In multivariate analysis, gender, histology, and type of anastomosis proved to affect odds ratios for anastomotic leakage. After adjustment for possible confounders, we found an odds ratio of 6.05 (95% confidence interval 2.71; 13.5) for ketorolac use and of 5.24 (95% confidence interval 1.85; 14.8) for use of other nonsteroidal anti-inflammatory drugs for anastomotic leakage during the first seven postoperative days. CONCLUSION: In the present study, we found a strong association between the postoperative use of ketorolac and other nonsteroidal anti-inflammatory drugs and the risk for anastomotic leakage after surgery for gastro-esophageal-junction cancers. PMID- 29134502 TI - The Influence of Compatibility of Rhubarb and Radix Scutellariae on the Pharmacokinetics of Anthraquinones and Flavonoids in Rat Plasma. AB - BACKGROUND AND OBJECTIVES: Rhubarb-Radix scutellariae is a classic herb pair, which is commonly used to clear away heat and toxin in clinic. The aim of this study was to investigate the influence of compatibility of Rhubarb and Radix scutellariae on the pharmacokinetic behaviors of anthraquinones and flavonoids in rat plasma. METHODS: Eighteen rats were randomly divided into three groups, and were orally administered Rhubarb and/or Radix scutellariae extracts. A sensitive and rapid UPLC-MS/MS method was developed and validated to determine the concentrations of baicalin, baicalein, wogonside, wogonin, rhein, and emodin in rat plasma. The concentrations of phase II conjugates of flavonoid aglycones and anthraquinone aglycones were also determined after hydrolyzing the plasma with sulfatase. RESULTS: Compared with administration of Radix scutellariae alone, co administration of Rhubarb significantly decreased the first maximum plasma concentration (C max1) of baicalin, wogonside, and the phase II conjugates of baicalein, wogonin to 46.40, 61.27, 41.49, and 20.50%, respectively. The area under the plasma concentration-time curve from time zero to infinity (AUC0 infinity) was significantly decreased from 82.60 +/- 20.22 to 51.91 +/- 7.46 MUM.h for rhein and 276.83 +/- 98.02 to 175.42 +/- 86.82 MUM.h for the phase II conjugates of wogonin after compatibility. The time to reach the first maximum plasma concentration (T max1) of anthraquinones was shortened and the second peak of anthraquinones disappeared after compatibility. CONCLUSIONS: Compatibility of Rhubarb and Radix scutellariae can significantly affect the pharmacokinetic behaviors of characteristic constituents of the two herbs. The cause of these pharmacokinetic differences was further discussed combined with the in vivo ADME (absorption, disposition, metabolism, and excretion) processes of anthraquinones and flavonoids. PMID- 29134505 TI - Upregulated Sphingosine 1-Phosphate Receptor 1 Expression in Human and Murine Atherosclerotic Plaques. AB - PURPOSE: Dysregulation of sphingosine 1-phosphate receptor 1 (S1PR1) signaling contributes to inflammation-related pathophysiological changes in cardiovascular diseases including atherosclerosis (AS). S1PR1-targeting compounds significantly reduce lesion size in murine models of AS. Therefore, characterization of S1PR1 expression in vitro and in vivo in atherosclerotic plaque could enable mechanistic studies and inform S1PR1 targeted therapies. PROCEDURES: H&E staining and immunostaining studies were performed on variably diseased human femoral endarterectomy plaque specimens, as well as mouse aortic sections from ApoE-/- mice maintained on a high-fat diet (AS mice). In vitro autoradiography study in human femoral plaques was used to confirm the tracer specificity. Micro positron emission tomography (PET) and ex vivo autoradiography studies were conducted in AS mice and their controls using a S1PR1-specific radioligand [11C]TZ3321 for in vivo and ex vivo quantification of S1PR1 expression in mouse aortic plaques. RESULTS: Increased S1PR1 expression was observed in areas of human femoral endarterectomy plaque specimens with foam cell accumulation compared with control tissue; in vitro autoradiography study indicated that SEW2781, a S1PR1 compound was able to reduce the uptake of [11C]TZ3321 by 56 %. S1PR1 levels were also upregulated in AS mouse aortic plaques. MicroPET data showed the aorta-to-blood tracer uptake ratio in AS mice was approximately 20 % higher than that in controls. Autoradiographic study also revealed elevated tracer accumulation in AS mouse aorta. CONCLUSIONS: Upregulated S1PR1 expression in human and mouse atherosclerotic plaques was successfully identified by immunostaining and radioligand-based methods. This data demonstrates that [11C]TZ3321 PET provides great promise in imaging S1PR1 expression in atherosclerotic plaques. PMID- 29134506 TI - The risk of eating disorders and bone health in young adults: the mediating role of body composition and fitness. AB - PURPOSE: To analyze the independent relationship between the risk of eating disorders and bone health and to examine whether this relationship is mediated by body composition and cardiorespiratory fitness (CRF). METHODS: In this cross sectional study, bone-related variables, lean mass, fat mass (by DXA), risk of eating disorders (SCOFF questionnaire), height, weight, waist circumference and CRF were measured in 487 university students aged 18-30 years from the University of Castilla-La Mancha, Spain. ANCOVA models were estimated to test mean differences in bone mass categorized by body composition, CRF or risk of eating disorders. Subsequently, linear regression models were fitted according to Baron and Kenny's procedures for mediation analysis. RESULTS: The marginal estimated mean +/- SE values of total body bone mineral density for the categories "no risk of eating disorders" and "risk of eating disorders" were 1.239 +/- 0.126 < 1.305 +/- 0.089, P = 0.021. However, this relationship disappeared after adjustment for any of the parameters of body composition or CRF. Therefore, all body composition parameters (except for lean mass) and CRF turned out to be full mediators in the association between the risk of eating disorders and bone health in young adults. CONCLUSIONS: Body composition and CRF mediate the association between the risk of eating disorders and bone health. These findings highlight the importance of maintaining a healthy weight and good CRF for the prevention of the development of eating disorders and for the maintenance of good bone health in young adults. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study. PMID- 29134508 TI - Author Correction: Associated and Mediating Variables Related to Job Satisfaction among Professionals from Mental Health Teams. AB - The original version of this article unfortunately contained a mistake in the author group section. The family name of Dr. Francois should be "Chiocchio" not "Chiochio." PMID- 29134507 TI - Prevalence and characteristics of orthorexia nervosa in a sample of university students in Italy. AB - AIMS: Orthorexia nervosa (ON) has been recently defined as a pathological approach to feeding related to healthiness concerns and purity of food and/or feeding habits. This condition recently showed an increasing prevalence particularly among young adults. In order to investigate the prevalence of ON and its relationship with gender and nutritional style among young adults, we explored a sample of students from the University of Pisa, Italy. METHODS: Assessments included the ORTO-15 questionnaire and a socio-demographic and eating habits form. Subjects were dichotomized for eating habits (i.e. standard vs vegetarian/vegan diet), gender, parents' educational level, type of high school attended, BMI (low vs high vs normal BMI). Chi square tests were performed to compare rates of subjects with overthreshold ORTO-15 scores, and Student's unpaired t test to compare mean scores between groups. Two Classification tree analyses with CHAID growing method were employed to identify the variables best predicting ON and ORTO-15 total score. RESULTS: more than one-third of the sample showed ON symptoms (ORTO-15 >= 35), with higher rates among females. Tree analyses showed diet type to predict ON and ORTO-15 total score more than gender. CONCLUSIONS: Our results seem to corroborate recent data highlighting similarities between ON and anorexia nervosa (AN). We propose an interpretation of ON as a phenotype of AN in the broader context of Feeding and eating disorders (FEDs) spectrum. PMID- 29134509 TI - Selection of an Effective Indicator for Rapid Detection of Microorganisms Producing gamma-Polyglutamic Acid and Its Biosynthesis Under Submerged Fermentation Conditions Using Bacillus methylotrophicus. AB - gamma-Polyglutamic acid (gamma-PGA) is a biosynthetic outcome of glutamic acid polymerization by microbes. In the current study, we have isolated Bacillus methylotrophicus on solid differential media containing methylene blue. This is the first report mentioning the use of methylene blue to distinguish the monomeric and polymeric form of glutamic acid in the liquid medium using UV-Vis spectrophotometer. Our method can simplify the analytical process of gamma-PGA confirmation using the aforementioned studies. This screening protocol is sensitive to the detection of gamma-PGA quantities as low as 3 MUg/mL; thus, the potent producers can be effectively screened. Furthermore, we have carried out process optimization of the present strain for gamma-PGA production wherein we could obtain 1.4-fold improvement in the yield with respect to utilization of carbon source and 2.6-fold increase with respect to nitrogen source under submerged fermentation at a shake flask level. We have shown an increase in gamma PGA titer from 1.5 to 36 g/L using mannitol, monosodium glutamate, peptone, and tween 20. PMID- 29134510 TI - Drug Design for ALK-Positive NSCLC: an Integrated Pharmacophore-Based 3D QSAR and Virtual Screening Strategy. AB - The increasing death rates related to anaplastic lymphoma kinase (ALK)-positive lung cancer culminated in a significant interest in the discovery of novel inhibitors for ALK. In the present research work, pharmacophore-based 3D QSAR modeling and virtual screening strategy have been carried out to address these issues. Initially, a five-point pharmacophore model was developed using the biological data of 50 compounds which includes an FDA-approved ALK inhibitor, crizotinib. Using the generated pharmacophore, a 3D QSAR model was developed and used as a query to screen the DrugBank database. The model was found to be significant (R 2 = 0.9696) with an excellent predictive accuracy (Q 2 = 0.7652) as confirmed through validation of the both training and test molecule activities. Further, Glide docking score and absorption, distribution, metabolism and excretion properties were used to filter the screened candidates. Overall, our analysis results in three hits namely TR1, FAL, ZYW with higher docking scores, and good pharmaceutically relevant properties with increased CNS involvement. It is worth mentioning that FAL and ZYW were found to possess scaffolds with specific activity against ALK protein. We presume that the results obtained from this computational study are of immense importance in the rational designing of novel and more potent ALK inhibitors. PMID- 29134511 TI - Correction to: Rarely occurring mutation of ACVR1 gene in Moroccan patient with fibrodysplasia ossificans progressiva. AB - One of the author's name on this article was incorrectly spelled as "Renata Borcciadi". The correct spelling is "Renata Bocciardi" and is now presented correctly in this article. PMID- 29134512 TI - Artery compliance in patients with rheumatoid arthritis: results from a case control study. AB - Atherosclerosis is one of the most common complications of rheumatoid arthritis (RA). The objective of this study is to evaluate differences in large artery compliance (C1) and small artery compliance (C2) between RA and controls and evaluating factors associated with reduced compliance in the RA population. The profiling of large and small arterial compliance was analyzed in 185 RA patients and 88 healthy controls using Cardiovascular Profiling Instrument. The correlations of arterial compliance and the relevant clinical data were determined in these subjects. Then correlation analysis and regression analysis were performed to find whether rheumatoid arthritis patients have more risk factors than healthy controls in artery compliance and to explore the possible element involved in RA patients including traditional cardiovascular risk factors, RA disease-related factors, and the therapy. Compared with healthy controls, levels of C1 and C2 were significantly decreased in RA patients. Having adjusted the traditional risk factors associated with atherosclerosis, C1 and C2 decline was still a significant indicator in RA patients [odds ratio = 7.411(95%CI 3.275, 16.771) and 10.184(95%CI 4.546, 22.817)]. Using multi-factor regression analysis to adjust traditional risk factors for arterial compliance, we found that the levels of ESR was correlated with the abnormal large artery compliance [odds ratio = 1.021(95%CI 1.007, 1.035)]. The HAQ values and the current usage of leflunomide were correlated with the abnormal small artery compliance in RA patients [odds ratio = 1.161(95%CI 1.046, 1.289) and 6.170(95%CI 1.510, 25.215)]. The values of C1 and C2 are indicators of artery compliance in RA patients. ESR, HAQ values, and the usage of leflunomide might be possible risk factors of artery compliance. The evaluation of artery compliance could be an easy and reliable test that could help us to screen and predict cardiovascular disorders in RA patients. PMID- 29134513 TI - Current concepts and unmet needs in psoriatic arthritis. AB - Psoriatic arthritis is a chronic inflammatory arthritis that is part of the spondyloarthropathy group of rheumatic diseases and has associated co morbidities. It can present with various clinical manifestations making diagnosis and treatment challenging, resulting in significant disability and reduced quality of life for patients. Whilst there have been advances in understanding the pathogenic mechanisms of the disease which have resulted in targeted therapies, there is still the need for further studies as some patients fail or are intolerant of current therapies. Better identification of early disease and knowledge of prognostic markers would enable clinicians to initiate appropriate therapy with the expectation that early aggressive treatment will minimise joint damage progression. Improved knowledge of the condition would also enable clinicians to better tailor specific treatment strategies for each of the various clinical domains in psoriatic arthritis. PMID- 29134514 TI - Expression of BC1 Impairs Spatial Learning and Memory in Alzheimer's Disease Via APP Translation. AB - Aggregation of amyloid-beta (Abeta) peptides, which are the cleavage products of amyloid precursor protein (APP), is a major pathological hallmark in the brain of Alzheimer's disease (AD). Now, we know little about the roles of APP translation in the disease progression of AD. Here, we show that BC1, a long noncoding RNA (lncRNA), is expressed in the brain of AD mice. BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks aggregation of Abeta in the brain and protects against the spatial learning and memory deficits. Expression of exogenous BC1 in excitatory pyramidal neurons of mice induces Abeta peptides accumulation and the spatial learning and memory impairments. This study provides a novel mechanism underlying aggregation of Abeta peptides via BC1 induction of APP mRNA translation and hence warrants a promising target for AD therapy. PMID- 29134516 TI - Structural and biochemical insights into human zinc finger protein AEBP2 reveals interactions with RBBP4. PMID- 29134515 TI - Neuroprotective Potential and Paracrine Activity of Stromal Vs. Culture-Expanded hMSC Derived from Wharton Jelly under Co-Cultured with Hippocampal Organotypic Slices. AB - Regardless of enormous translational progress in stem cell clinical application, our knowledge about biological determinants of transplantation-related protection is still limited. In addition to adequate selection of the cell source well dedicated to a specific disease and optimal standardization of all other pre transplant procedures, we have decided to focus more attention to the impact of culture time and environment itself on molecular properties and regenerative capacity of cell cultured in vitro. The aim of this investigation was to determine neuroprotection-linked cell phenotypic and functional changes that could spontaneously take place when freshly isolated Wharton's jelly mesenchymal stem cell (WJ-MSC) undergo standard selection, growth, and spontaneous differentiation throughout passaging in vitro. For determining their neuroprotective potential, we used experimental model of human WJ-MSC co-culture with intact or oxygen-glucose-deprived (OGD) rat organotypic hippocampal culture (OHC). It has been shown that putative molecular mechanisms mediating regenerative interactions between WJ-MSC and OHC slices relies mainly on mesenchymal cell paracrine activity. Interestingly, it has been also found that the strongest protective effect is exerted by the co-culture with freshly isolated umbilical cord tissue fragments and by the first cohort of human mesenchymal stem cells (hMSCs) migrating out of these fragments (passage 0). Culturing of WJ-derived hMSC in well-controlled standard conditions under air atmosphere up to fourth passage caused unexpected decline of neuroprotective cell effectiveness toward OGD-OHC in the co-culture model. This further correlated with substantial changes in the WJ-MSC phenotype, profile of their paracrine activities as well as with the recipient tissue reaction evaluated by changes in the rat-specific neuroprotection-linked gene expression. PMID- 29134517 TI - Subcutaneous ketamine for postoperative pain relief in Rwanda: a randomized clinical trial. AB - PURPOSE: Postoperative pain control is often inadequate in low-income countries such as Rwanda, prompting the search for an inexpensive improvement. A randomized controlled trial was conducted to study the use of subcutaneous ketamine for the management of postoperative pain in patients undergoing major surgery in Kigali, Rwanda. METHODS: Fifty-nine patients undergoing major abdominal, head and neck, plastic, or gynecological surgeries were studied. In addition to standard care, patients received five subcutaneous injections of ketamine 1 mg.kg-1 (ketamine group, n = 30) or normal saline (placebo group, n = 29) during the postoperative period. The first injection was administered in the postanesthesia care unit and then every 12 hr thereafter starting at 20:00 on the day of surgery. Pain was assessed three times per day using an 11-point verbal response scale. Patients were also assessed for side effects, including nausea and vomiting, hallucinations, nightmares, sedation, hypertension, and seizures. RESULTS: The mean (SD) overall postoperative pain scale score was higher in the control group than in the ketamine group [4.8 (1.7) vs 3.7 (1.5), respectively; difference of means, 1.1; 95% confidence interval [CI], 0.3 to 1.9; P = 0.009]. Brief hallucinations (ketamine group, 11 patients; placebo group, 0 patients; risk difference, 0.37; 95% CI, 0.18 to 0.54; P < 0.001) were associated with ketamine administration. CONCLUSIONS: Results of this study in Kigali, Rwanda showed that subcutaneous administration of ketamine 1 mg.kg-1 twice daily, in addition to standard postoperative care, produced a small improvement in postoperative pain but resulted in more minor side effects TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02514122). Registered 31 July 2015. PMID- 29134518 TI - Erector spinae plane block for the management of chronic shoulder pain: a case report. AB - PURPOSE: The erector spinae plane (ESP) block has been described in the successful management of both thoracic and abdominal pain. Since the erector spinae muscle extends to the cervical spine, the ESP block may be potentially useful in painful conditions of the shoulder girdle. CLINICAL FEATURES: We performed a series of ESP blocks at the T2/T3 level in an elderly male patient with chronic shoulder pain. Immediate and profound analgesia with improved range of motion was consistently observed following the block. There was detectable sensory block in the congruent cervico-thoracic dermatomes with no motor block. Computed tomography imaging showed the spread of radiocontrast up to the C3 level in the vicinity of the neural foramina. Clinical analgesia generally outlasted the expected duration of conduction blockade and significantly contributed to overall improvement in the patient's symptoms. CONCLUSIONS: The ESP block may be a promising alternative to other interventional procedures in the management of chronic shoulder pain and deserves further study. PMID- 29134519 TI - Capability of Secale montanum trusted for phytoremediation of lead and cadmium in soils amended with nano-silica and municipal solid waste compost. AB - The purpose of this study is to evaluate the capability of Secale montanum trusted for phytoremediation of contaminated soils with lead (Pb) and cadmium (Cd). To conduct this study, soil samples were taken from contaminated rangelands soils around National Lead & Zinc Factory, Zanjan, Iran. In this study, which was performed in a greenhouse, after preparing the pot and treating soils with nano silica (NS) and municipal solid waste compost (MSWC) amendments, 20 Secale seeds were cultured in each pot. The translocation factor (TF), the bio-concentration factor (BCF), and remediation factor (RF) were calculated to determine the phytoremediation capability of Secale. Six months after establishment, plant organs were harvested and Pb and Cd concentrations were measured in shoot and roots of Secale. For statistical analysis and to compare the obtained means, ANOVA and Tukey's tests were performed, respectively. The pot experiment results showed that Pb uptake and accumulation by roots of S. montanum were highest in pots amended with NS500. In comparison, Pb concentration in shoots of Secale was highest in pots amended with MSWC 2%. In general, it seems that NS500 and MSWC 2% help phytoremediation capability of Secale in the Pb-contaminated soils. PMID- 29134520 TI - Benchmarking the scientific research on wastewater-energy nexus by using bibliometric analysis. AB - With an exponential increase in urbanization and industrialization, water pollution is an inevitable consequence of relatively lagging wastewater treatment facilities. The conventional activated sludge process for wastewater treatment primarily emphasizes the removal of harmful substances to maintain increasingly stringent effluent discharged standards, which is considered an energy-intensive technique. Therefore, innovative and sustainable wastewater treatment should pay more attention to energy and resource recovery in dealing with fossil fuel depletion, global-scale energy security, and climate change. A bibliometric analysis was applied to trace wastewater-energy nexus-related research during the period 1991 to 2015, with respect to the Science Citation Index EXPANDED (SCI EXPANDED) database. Journal of Hazardous Materials, ranking 1st in h-index (79), was the most productive journal (431, 4.5%) during the same time, followed by International Journal of Hydrogen Energy (422, 4.4%) and Water Research (393, 4.1%) journal, the latter owning a topmost journal impact factor. Though, China (2154, 22.5%) was the most productive country, while the USA with highest h-index (88) was the favorest collaborative country. The Chinese Academy of Sciences, China (241, 2.5%) produced the maximum publications. A novel method called "word cluster analysis" showed that the emerging sustainable processes and novel renewable energy application are applied in response to the desire for a net wastewater-energy nexus system. Based on different wastewater types, the emerging energy and sources recovery treatment processes of Anammox, anaerobic digestion, and microbial fuel cells gained extensive innovation. Evaluation indicators including sustainability, life cycle assessment, and environmental impact were appropriately used to dissert feasibility of the novel treatment methods in regard of renewable energy utilization, energy savings, and energy recovery. The transformation of the new concept of "broaden income source, economize on expenditures and exploit inner potential" should be generalized in order to achieve an environmentally sustainable development of wastewater-energy nexus system. PMID- 29134521 TI - Metals in Diplodus sargus cadenati and Sparisoma cretense-a risk assessment for consumers. AB - The increases in urbanization, demography and industrial activity, along with growing human needs which exploit the resources of the planet, have exponentially exacerbated pollution. In particular, the discharge of heavy metals into the marine ecosystem is a problem of global magnitude, as this may damage the diversity of marine species and ecosystems because of their toxicity, long persistence and bioaccumulation. Consequently, it is necessary to carry out an assessment of the risk of human exposure from the consumption of marine species potentially exposed to this type of pollutants. In the present study, the levels of toxic heavy metals (Cd, Pb and Al) as well as trace and essential metals (B, Ba, Co, Cu, Cr, Fe, Li, Mn, Mo, Ni, Sr, V and Zn) and macronutrients (Ca, K, Mg, Na) have been quantified in two species of fish for human consumption. In order to do this, a total of 80 muscle samples and 80 liver samples, belonging to two species of osteichthyes (bony fish), Diplodus sargus cadenati and Sparisoma cretense, were analyzed. The specimens studied were captured on the north coast of Gran Canaria (Canary Islands) using recreational fishing techniques. As they caught from the shore, the data obtained respond to the need to assess the toxic levels in two representative species of artisanal and recreational fishing in the area. The risk assessment indicated that these two fish species are safe for the average consumer; however, if the livers are frequently consumed, there may be potential risks because they exceed the Admissible Daily Intakes for Pb and Cd. PMID- 29134522 TI - Capacity of six shrub species to retain atmospheric particulates with different diameters. AB - Garden plants can absorb and retain atmospheric particles and are important for remediating environmental pollution. In this study, the dust retention characteristics of six typical shrub species were measured in the greenbelt of a road in the Chengyang District of Qingdao, China, and the maximum capacity for dust retention of each species was determined. The different diameters and areas occupied by particulate matter (PM) were analyzed on the leaf surfaces of the plants. Based on the results for the six shrub species, the rank order of average content of dust retention per unit leaf area was Euonymus japonicus > Pyracantha fortuneana > Ligustrum vicaryi > Amygdalus triloba > Ligustrum sinense > Forsythia suspensa, whereas the rank order of average content per unit volume was E. japonicus > A. triloba > P. fortuneana > L. vicaryi > L. sinense > F. suspensa. The maximum content of dust retention per unit leaf area was reached in approximately 24 days. Plants retained atmospheric PM primarily on the upper leaf surfaces. The primary portion of particles on the leaves was PM10 (over 80%), and PM2.5 was the principal component of PM10. Leaf surface structure significantly affected the abilities of plants to retain PM, and the plants with a thick wax layer or large and dense stomata adsorbed more PM, such as E. japonicus. This study provides a scientific basis for the capacity of landscape plants to retain different diameter particulates. PMID- 29134523 TI - Effect of water constituents on the degradation of sulfaclozine in the three systems: UV/TiO2, UV/K2S2O8, and UV/TiO2/K2S2O8. AB - Bicarbonate, phosphate, chloride ions, and humic substances are among the constituents most widely present in natural waters. These non-target constituents can greatly affect the efficiency of advanced oxidation processes used for water decontamination due to their capacity to interfere with the adsorption of the target compounds on the surface of TiO2, absorb photons, scavenge hydroxyl radicals (.OH), and generate photochemical reactive intermediates. In this work, the effect of these constituents on the degradation of sulfaclozine (SCL) was monitored in three different AOPs systems: UV/TiO2, UV/K2S2O8, and UV/TiO2/K2S2O8. It was shown that bicarbonate (HCO3-) and phosphate (HPO42-) ions enhanced the degradation of SCL in UV/TiO2 and UV/TiO2/K2S2O8 systems whereas the addition of humic substances influenced these rates with a much smaller extent. On the other hand, the degradation rate of SCL in the UV/K2S2O8 system was not affected by the presence of HCO3- and HPO42- but was inhibited in the presence of humic substances. In addition, the different mechanisms that can take place in the presence of these constituents were discussed and the degradation rate enhancement in presence of HCO3- and HPO42- was attributed to the formation of new reactive species such as carbonate (CO3.-) and hydroxyl (.OH) radicals activated by TiO2 holes (h+). In the presence of chloride (Cl-) and nitrate (NO3 ) ions, an enhancement of SCL adsorption on the surface of TiO2 was observed. Finally, a comparative study of the degradation of SCL in river water and ultrapure water was reported. PMID- 29134524 TI - Health risk assessment of arsenic and heavy metals (Cd, Cu, Co, Pb, and Sn) through consumption of caviar of Acipenser persicus from Southern Caspian Sea. AB - In the current study contents of As, Cd, Cu, Co, Pb, and Sn were determined in the caviar of Persian sturgeon collected from Southern Caspian Sea sampling site. After acid digestion of caviar specimens, the concentrations of elements determined using ICP-OES. The results showed that the mean concentrations (mg kg 1) of elements in caviar samples were 0.01 for As, 0.05 for Cd, 1.42 for Cu, 0.01 for Co, 0.01 for Pb, and 0.28 for Sn and for all the elements are significantly lower than the adverse level for the human consumption. Also, health risk index (HRI) values were within the safe limits (HRI < 1). Therefore, there is no potential health risk to adults and children via consumption of caviar. Due to the discharge of hazardous chemicals into the marine ecosystems especially the Caspian Sea, residue analysis of pollutants in the sea foods is recommended. PMID- 29134525 TI - Toxicities and risk assessment of heavy metals of the six most consumed fish from the Marmara Sea. AB - Bream, anchovy, horse mackerel, sea bass, sardine, and whiting that are commonly consumed by the Turkish community were collected from the Marmara Sea in September and March and were analyzed for trace elements and for fat content. The total concentrations of some metals in these fish were determined using ICP-MS in acid extracts obtained after microwave digestion. The seasonal fat contents of the fish samples were determined gravimetrically following a Soxhlet extraction method. Experimental results were evaluated statistically using t tests and principal component analyses. This enabled the comparison of the elements' contents in the fish samples in March and September and also led to an investigation into whether or not there is a relationship between the elements' contents and the fat amount. The results of this work showed that a significant temporal difference was observed. This difference was not related to the seasonal variation in fat concentrations. PMID- 29134526 TI - Mucociliary transport, differential white blood cells, and cyto-genotoxicity in peripheral erythrocytes in fish from a polluted urban pond. AB - The present study evaluated the water quality of a polluted pond through the analysis of in vitro mucociliary transport, hematological parameters, and biomarkers of cyto-genotoxicity in the Nile tilapia (Oreochromis niloticus). Blood and mucus samples were collected from ten specimens from the polluted pond and from ten specimens from a control area. The fish were anesthetized with 3% benzocaine, mucus was collected directly from the gills, and blood was drawn from the caudal artery. Blood smears were stained using the May-Grunwald Giemsa process for the differential leukocyte counts and to determine the frequency of leukocytes, thrombocytes, erythroblasts, micronuclei, and nuclear abnormalities. The results revealed low transportability in vitro, a high percentage of monocytes and eosinophils, and increased frequency of leukocytes and nuclear abnormalities in fish from the polluted pond. However, the frequency of thrombocytes and erythroblasts and the percentage of lymphocytes and neutrophils were significantly lower. It is possible to conclude that changes in fish are due to poor water quality and that these non-destructive biomarkers can be used for the biomonitoring of aquatic environments vulnerable to contamination. PMID- 29134527 TI - The removal of COD and NH3-N from atrazine production wastewater treatment using UV/O3: experimental investigation and kinetic modeling. AB - In this study, a UV/O3 hybrid advanced oxidation system was used to remove chemical oxygen demand (COD), ammonia nitrogen (NH3-N), and atrazine (ATZ) from ATZ production wastewater. The removal of COD and NH3-N, under different UV and O3 conditions, was found to follow pseudo-first-order kinetics with rate constants ranging from 0.0001-0.0048 and 0.0015-0.0056 min-1, respectively. The removal efficiency of ATZ was over 95% after 180 min treatment, regardless the level of UV power. A kinetic model was further proposed to simulate the removal processes and to quantify the individual roles and contributions of photolysis, direct O3 oxidation, and hydroxyl radical (OH.) induced oxidation. The experimental and kinetic modeling results agreed reasonably well with deviations of 12.2 and 13.1% for the removal of COD and NH3-N, respectively. Photolysis contributed appreciably to the degradation of ATZ, while OH. played a dominant role for the removal of both COD and NH3-N, especially in alkaline environments. This study provides insights into the treatment of ATZ containing wastewater using UV/O3 and broadens the knowledge of kinetics of ozone-based advanced oxidation processes. PMID- 29134528 TI - Potassium bromate as a food additive: a case study of Tunisian breads. AB - This study is the first investigation of potassium bromate as a food additive in Tunisian breads. In this study, levels of residual bromate were determined in 91 commercial breads from 31 bakeries randomly selected in two Tunisian cities. In total, 13 different types of bread were analyzed using a spectrophotometric method of bromate analysis. Bromate concentrations ranged from 5.95 to 49.31 MUg g-1, with an overall mean concentration of 19.92 MUg g-1. Significant differences were noticed between bromate levels in breads from bakeries of the two cities (P < 0.01). Based on the types of breads, Muffin contained the highest mean concentration of bromate residue (29.92 MUg g-1) as opposed to bread without salt, which had the lowest mean bromate level (13.53 MUg g-1). Compared to data available from other countries, our results showed relatively high bromate levels, which could potentially lead to long term toxic and carcinogenic effects in the Tunisian population. PMID- 29134529 TI - Transcriptional changes measured in rice roots after exposure to arsenite contaminated sediments. AB - Transcriptional analyses are discussed to provide a deeper understanding of the molecular mechanisms underlying toxic effects. Thus, they can complement classic ecotoxicological test methods and potentially allow the identification of biomarkers associated to the exposure of chemical stressors and or adverse biological effects. This feasibility study intended to identify a set of potential gene expression biomarkers for arsenite-exposure in rice roots that could complement the informative value of an existing sediment-contact test with rice. A sediment-contact test with Oryza sativa with the parameters inhibition of root and shoot elongation as phenotypic endpoints was used as basis. Rice plants were exposed to arsenite-spiked sediments. Transcriptomic changes in response to arsenite were observed by means of cDNA-microarray analysis regarding the whole transcriptome at two sublethal arsenite concentrations. In order to identify candidate biomarker genes, differentially expressed genes were identified. Arsenite-induced differentially expressed genes were significantly associated with gene ontology (GO)-terms that indicated a general stress response. Of the differentially expressed genes, five genes were selected and their expression was measured at seven arsenite concentrations by means of qPCR in order to obtain their expression profiles. Three candidate biomarker genes showed a dose dependent upregulation, while two showed no clear dose-dependent expression. The expression of all candidate biomarkers was also assessed in rice plants grown on two arsenic-contaminated natural sediments, but only one biomarker gene showed the expected upregulation. PMID- 29134530 TI - A review of heavy metal pollution levels and health risk assessment of urban soils in Chinese cities. AB - This study assessed literature-based data for the period 2006-2016 regarding heavy metal (As, Cd, Cr, Cu, Pb, Ni, Zn, and Hg) concentrations in soils from 32 Chinese cities and the associated human health risks. The mean concentrations of the eight metals were lower than the soil environmental quality standards in China, but were much higher than the background values for most cities. The enrichment factor (EF) and geoaccumulation index (I geo) values showed moderate pollution levels, possibly influenced by anthropogenic activity for Cd, Hg, Pb, and Zn. The pollution levels in eastern cities were much higher than those in western cities, and heavy metals concentrations in different types of cities followed the order: industrial based cities > more developed cities > metropoles > underdeveloped cities. The human health risk assessment for heavy metals in most cities indicated that non-carcinogenic risks were within threshold values (HI < 1). The total carcinogenic risk due to As, Cr, and Ni in most urban areas was in excess of 1 * 10-5, but was lower than 1 * 10-4. However, in some cities (e.g., Baoji City, Tiyuan City, and Xuzhou City), Ni and Cr have potential cancer risks for both adults and children. Compared to adults, children could be more seriously threatened by heavy metal contamination in soils. In general, we recommend that Cd, Hg, and Pb are selected as priority heavy metals pollutants that require control in Chinese cities. PMID- 29134531 TI - Enantioselective degradation of Myclobutanil and Famoxadone in grape. AB - The enantioselective degradation of myclobutanil and famoxadone enantiomers in grape under open field was investigated in this study. The absolute configuration of myclobutanil and famoxadone enantiomers was determined by the combination of experimental electronic circular dichroism (ECD) and calculated ECD spectra. The enantiomers residues of myclobutanil and famoxadone in grape were measured by sensitive high-performance liquid chromatography/tandem mass spectrometry (HPLC MS/MS). The linearity, precision, accuracy, matrix effect, and stability were assessed. And the limit of quantification (LOQ) for each enantiomer of myclobutanil and famoxadone in grape was evaluated to be 1.5 and 2 MUg kg-1. The myclobutanil and famoxadone showed the enantioselective degradation in grape, and the enantioselectivity of degradation for myclobutanil was more pronounced than that for famoxadone. The half-lives were 13.1 days and 25.7 days for S-(+) myclobutanil and R-(-)-myclobutanil in grape, separately. The half-life of S-(+) famoxadone was 31.5 days slightly shorter than that of R-(-)-famoxadone with half life being 38.5 days in grape. The probable reasons for the enantioselective degradation behavior of these two fungicides were also discussed. The results in the article might provide a reference to better assess the risks of myclobutanil and famoxadone enantiomers in grapes to human and environment. Graphical abstract The enantioselective analysis of myclobutanil and famoxadone in grape. PMID- 29134532 TI - A robust multi-objective bargaining methodology for inter-basin water resource allocation: a case study. AB - In this study, a new methodology is proposed to balance environmental and economic issues in water allocation under uncertainty. Two objective functions, including maximizing economic income (EI) and minimizing environmental pollution (EP), were considered as two groups of players to construct a deterministic multi objective bargaining methodology (DMOBM). In the next step, it is enhanced to a robust multi-objective bargaining methodology (RMOBM), which is capable of incorporating the main uncertainties exist in the problem. A large-scale inter basin water transfer case study was utilized to investigate the applicability of the developed model. The outputs of the models showed that Nash equilibrium provide a rather narrow range of solutions. According to the results, the required rounds to reach Nash equilibrium raised as the uncertainty level increased. In addition, higher levels of uncertainty lead to higher reduction in water allocating of receiving basin. Sensitivity analysis showed that economic income values are less sensitive to changes of uncertain parameters than the environmental objective function. The developed methodology could provide a framework to incorporate the behavior of different stakeholders. Furthermore, the proposed method can be reliable under the condition of facing water allocation uncertainties. PMID- 29134534 TI - Current status of cardiovascular surgery in Japan, 2013 and 2014: A report based on the Japan Cardiovascular Surgery Database (JCVSD). 1: Mission and history of JCVSD. AB - The Japan Cardiovascular Surgery Database (JCVSD) was created in 2000 with the support of the Society of Thoracic Surgeons (STS). The STS database content was translated to Japanese using the same disease criteria and in 2001, data entry for adult cardiac surgeries was initiated online using the University Hospital Medical Information Network (UMIN). In 2008, data entry for congenital heart surgeries was initiated in the congenital section of JCVSD and preoperative expected mortality (JapanSCORE) in adult cardiovascular surgeries was first calculated using the risk model of JCVSD. The Japan Surgical Board system merged with JCVSD in 2011, and all cardiovascular surgical data were registered in the JCVSD from 2012 onward. The reports resulting from the data analyses of the JCVSD will encourage further improvements in the quality of cardiovascular surgeries, patient safety, and medical care in Japan. PMID- 29134535 TI - Current status of cardiovascular surgery in Japan 2013 and 2014: A report based on the Japan Cardiovascular Surgery Database. 2: Congenital heart surgery. AB - OBJECTIVES: We analyzed the mortality and morbidity of congenital heart surgery in Japan using the Japan Cardiovascular Surgery Database (JCVSD). METHODS: Data regarding congenital heart surgery performed between January 2013 and December 2014 were obtained from JCVSD. The 20 most frequent procedures were selected and the mortality rates and major morbidities were analyzed. RESULTS: The mortality rates of atrial septal defect repair and ventricular septal defect repair were less than 1%, and the mortality rates of tetralogy of Fallot repair, complete atrioventricular septal defect repair, bidirectional Glenn, and total cavopulmonary connection were less than 2%. The mortality rates of the Norwood procedure and total anomalous pulmonary venous connection repair were more than 10%. The rates of unplanned reoperation, pacemaker implantation, chylothorax, deep sternal infection, phrenic nerve injury, and neurological deficit were shown for each procedure. CONCLUSION: Using JCVSD, the national data for congenital heart surgery, including postoperative complications, were analyzed. Further improvements of the database and feedback for clinical practice are required. PMID- 29134536 TI - Current status of cardiovascular surgery in Japan, 2013 and 2014: A report based on the Japan Cardiovascular Surgery Database 3. Coronary artery bypass surgery. AB - OBJECTIVE AND METHODS: Data on isolated coronary artery bypass grafting (CABG) performed in 2013 and 2014, and registered in the Japan Cardiovascular Surgery Database were reviewed for preoperative characteristics, postoperative outcomes, and choice of graft material for the left anterior descending artery (LAD). RESULTS: Isolated CABG was performed off-pump in 54.7% of cases, and graft material for the LAD was left internal thoracic artery in 74.3% and right internal thoracic artery in 15.6%. Operative mortality was 2.0% in elective cases, 8.2% in emergency cases, and 3.0% overall. In elective cases, operative mortality was 1.1% for off-pump CABG compared with 3.0% for on-pump CABG. CONCLUSIONS: Clinical results of our isolated CABG were reasonable and acceptable. PMID- 29134537 TI - Current status of cardiovascular surgery in Japan, 2013 and 2014: A report based on the Japan Cardiovascular Surgery Database. 4. Valvular heart surgery. AB - Data from the Japan cardiovascular surgery database from 2013 to 2014 were analyzed to demonstrate the mortality rate and choice of surgical procedures, especially concerning the selection of valve prosthesis for each valve position and patient age group, and the effects of preoperative complications on mortality and prosthetic valve selection. The proportion of each surgical procedure was compared for each patient age in the aortic, mitral, and tricuspid positions. The proportion of mechanical valve prostheses was 23.1, 40.5, and 11.4% in the aortic, mitral, and tricuspid positions, respectively, and was higher in hemodialysis than in non-hemodialysis patients. The operative mortality rate was 4.3, 11.7, 15.8, and 5.6% in all cases, hemodialysis patients, patients with liver dysfunction, and patients with atrial fibrillation and flutter, respectively, after Aaortic valve replacement, and 4.0, 14.4, 11.2, and 4.1%, respectively, in each group listed above after mitral valve surgery. These results clarify the current status of cardiac valvular surgery in Japan. PMID- 29134538 TI - Postoperative atrial fibrillation is less frequent in pulmonary segmentectomy compared with lobectomy. AB - OBJECTIVE: The aim of this study was to elucidate the characteristics and predictors of postoperative atrial fibrillation (POAF) from the standpoint of surgical mode. METHODS: Retrospective analysis was carried out on 607 patients who underwent lobectomy or segmentectomy for clinical stage IA lung cancer. We investigated the clinical factors to determine the predictors of the development of POAF. RESULTS: Of the 607 patients, 443 underwent lobectomy, and 164 underwent segmentectomy. POAF developed in 37 patients. Of these, 34 (7.7%) were in the lobectomy group, and 3 (1.8%) in the segmentectomy group. In the univariate analysis for predictors of POAF, age (p < 0.01), history of ischemic heart disease (p = 0.03), FEV1.0% (p < 0.01) and surgical mode (p = 0.01) showed significant differences between the groups. The multivariate analysis revealed that increasing age (p < 0.01, HR 1.059, CI 1.015-1.106), surgical mode (p = 0.02, HR 5.734, CI 1.350-24.361) and FEV1.0% < 70% (p = 0.03, HR 2.182, CI 1.067 4.461) were independent predictors of POAF. CONCLUSION: POAF was significantly less following segmentectomy compared with lobectomy. PMID- 29134539 TI - Germline variant in MSX1 identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma. AB - The vast majority of esophageal adenocarcinoma cases are sporadic and caused by somatic mutations. However, over the last decades several families have been identified with clustering of Barrett's esophagus and esophageal adenocarcinoma. This observation suggests that one or more hereditary factors may play a role in the initiation of Barrett's esophagus and esophageal adenocarcinoma in these families. A Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma was identified. Normal DNA obtained from the proband diagnosed with Barrett's esophagus was analyzed with SNP array and exome sequencing. A custom-made panel consisting of potential germline variants was verified in the normal DNA of the affected family members. In addition, the respective tumors were analyzed for somatic loss of the wild type allele or the presence of an inactivating somatic mutation in the wild type allele. Exome sequencing revealed 244 candidate variants in the normal DNA of the proband, of which 212 variants were verified successfully. After the normal DNA of the affected family members was analyzed for the presence of the 212 potential germline variants and subsequently the respective tumors, only one potential germline variant in MSX1 (chr4: 4861985 T > G, c.359T > G, p.V120G, NM_002448) showed loss of the wild type allele in the tumor DNAs of the affected family members. A germline variant in MSX1 was identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma. This finding indicates that the germline defect in MSX1 may be associated with Barrett's esophagus and cancer in this particular family. PMID- 29134540 TI - Acute connexin43 temporal and spatial expression in response to ischemic stroke. AB - Connexin43 (Cx43) gap junctions expressed in astrocytes can significantly impact neuronal survival in stroke. However, little is known regarding Cx43 spatial and temporal expression during the initial stages of brain ischemia. Using immunohistochemistry and Western blot analysis, we examined Cx43 spatial and temporal expression as a function of neuronal injury within the first 24 h after permanent middle cerebral artery occlusion (pMCAO). Western blot analysis showed a significant increase in Cx43 protein expression in the core ischemic area at 2 and 3 h after pMCAO. However, after 6 h of pMCAO Cx43 levels were significantly reduced. This reduction was due to cell death and concomitant Cx43 degradation in the expanding focal ischemic region, while the peri-infarct zone revealed intense Cx43 staining. The neuronal cell-death marker Fluoro-Jade C labeled injured neurons faintly at 1 h post-pMCAO with a time-dependent increase in both intensity and size of punctate staining. In addition, decreased microtubule associated protein 2 (MAP2) immunoreactivity and thionin staining similarly indicated cell damage beginning at 1 h after pMCAO. Taken together, Cx43 expression is sensitive to neuronal injury and can be detected as early as 2 h post-pMCAO. These findings underscore Cx43 gap junction as a potential early target for therapeutic intervention in ischemic stroke. PMID- 29134541 TI - Bovine herpesvirus-1 (BHV-1), bovine leukemia virus (BLV) and bovine viral diarrhea virus (BVDV) infections in Algerian dromedary camels (Camelus dromaderius). AB - This study was performed to investigate the presence of bovine herpesvirus-1 (BHV 1), bovine leukemia virus (BLV) and bovine viral diarrhea virus (BVDV) infections in dromedary camels (Camelus dromaderius) kept in mixed herds with sheep and goats in Algeria, since the prevalence of BHV-1, BVDV, and BLV infections among dromedary camels in Algeria is unknown. Totally, 111 camel sera were collected from two provinces (Laghouat and Ghardaia) in Algeria. The sera were analyzed for BHV-1 specific antibodies, BVDV specific antibodies and BVDV antigen using the ELISA, and BLV nucleic acid using PCR. The seropositivity rate was 9.0% for BVDV specific antibody, although 41.4% of camels tested were positive for BVDV antigen. Moreover, there was no evidence of BHV-1 and BLV infections. The results indicated that camels might represent an important source for BVDV infection in all ruminants, including cattle, sheep, and goats bred in mixed herds in Algeria, since they had a higher BVDV prevalence rates. Therefore, the prevention and control measures for BVDV infection should put in place in camel populations to limit the spread of BVDV infection to ruminant populations in Algeria. PMID- 29134542 TI - Influence of the menstrual cycle on compression-induced pain during mammography: correlation with the thickness and volume of the mammary gland. AB - In mammography, breast compression is necessary and an important factor influencing image quality. The purpose of this study was to determine the influence of the menstrual cycle on compression-induced pain during mammography and to evaluate the association between the thickness and volume of the mammary gland and pain. We examined basal body temperature and categorized the menstrual cycle into five phases. We executed breast compression in the craniocaudal view using a customized compression plate, to which we introduced an opening. We measured the thickness of the mammary gland under compression using echography. Immediately after releasing the compression, we evaluated pain using the visual analogue scale. We performed magnetic resonance imaging (MRI) on the same day and measured the volume of the mammary gland. The thickness of the mammary gland, pain, and the volume of the mammary gland were minimal in the late follicular phase and maximal in the late luteal and early follicular phases. It was shown that the changes in the thickness and volume of the mammary gland during the menstrual cycle accounted for the changes in compression-induced pain. On MRI examination of each breast quadrant, the same changes were observed in areas A and C. In area A, it was shown that both the anatomical characteristics and the increase in volume of the mammary gland were associated with pain. We concluded that the late follicular phase constitutes the optimal timing for mammography. PMID- 29134543 TI - Bayesian inference for psychology, part III: Parameter estimation in nonstandard models. AB - We demonstrate the use of three popular Bayesian software packages that enable researchers to estimate parameters in a broad class of models that are commonly used in psychological research. We focus on WinBUGS, JAGS, and Stan, and show how they can be interfaced from R and MATLAB. We illustrate the use of the packages through two fully worked examples; the examples involve a simple univariate linear regression and fitting a multinomial processing tree model to data from a classic false-memory experiment. We conclude with a comparison of the strengths and weaknesses of the packages. Our example code, data, and this text are available via https://osf.io/ucmaz/ . PMID- 29134544 TI - A broader phenotype of persistence emerges from individual differences in response to extinction. AB - The typical practice of averaging group performance during extinction gives the impression that responding declines gradually and homogeneously. However, previous studies of extinction in human infants have shown that some individuals persist in responding, whereas others abruptly cease responding. As predicted by theories of control, the infants who quickly resign typically display signs of sadness and despair when the expected reward is omitted. Using genetically diverse mice, here we observed a similar pattern of individual differences and the associated phenotypes. After learning to approach a food reward, upon extinction, some animals rapidly abandoned approach to the goal box, whereas other animals persisted in entering and searching the goal box. Interestingly, the persistent mice were slower to "give up" when confined to an inescapable pool of water (a test asserted to be indicative of susceptibility to depression) and exhibited a more extensive pattern of search for omitted rewards. Thus, extinction reveals a continuum in persistence, in which low values might reflect a susceptibility to the negative effects of stress and might predispose individuals to depression. PMID- 29134545 TI - Violence Exposure and Psychopathology in Latino Youth: The Moderating Role of Active and Avoidant Coping. AB - Despite high rates of exposure to community violence among Latino youth in urban communities, there is considerable variability in individual outcomes. This study examined (a) associations between coping and indices of Latino culture, (b) main effects of active/avoidant coping on psychopathology, and (c) whether coping moderates the impact of violence exposure on mental health in Latino youth. Participants included 168 Latino youth (56% female; ages 11-14) that took part in a short-term longitudinal study. Results indicate that youth acculturation was positively associated with active coping, but enculturation level and immigrant status were not associated with coping. Structural equation models suggested that active coping was negatively associated with internalizing problems (p = .046) while avoidant coping was positively associated with internalizing problems (p = .013) and posttraumatic stress symptoms (p = .024). Moderation analyses revealed that violence exposure was more strongly associated with internalizing problems as reliance on avoidance coping increased. However, at high levels of violence exposure, a greater reliance on active coping was related to increased posttraumatic stress problems. Findings suggest that consideration of the specific stressor, level of stress exposure, and mental health problem-type may be crucial in determining the effectiveness of a coping strategy. Implications for future research and intervention are discussed. PMID- 29134546 TI - Effect of hyperbaric air on endotoxin from Bacteroides fragilis strains. AB - The aim of the project was to determine any effect of hyperbaric air on Bacteroides fragilis strains cultivated under hyperbaric conditions. Previously, it was hypothesized that there was a correlation between the presence of Bacteroides bacteria in patients preferring a meaty diet and cancer of the small intestine, and particularly of the large intestine and rectum. With respect to the fact that Bacteroides fragilis (BAFR) group are important producers of endotoxins, measurement and statistical evaluation of endotoxin production by individual strains of isolated Bacteroides species were used to compare bacteria isolated from various clinical samples from patients with colon and rectum cancer in comparison with strains isolated from other non-cancer diagnoses. Endotoxin production was proven by quantitative detection using the limulus amebocyte lysate (LAL) test in EU/mL. Production of endotoxins in these bacteria cultured under hyperbaric air conditions was higher than those strains cultured under normobaric anaerobic conditions. But these differences in endotoxin production were not statistically significant (t test with log-transformed data, p value = 0.0910). Based on a two-tier t test for lognormal data, it is possible to cautiously conclude that a statistically significant difference was found between endotoxin production by Bacteroides fragilis strains isolated from non-carcinoma diagnoses (strains (1-6) and strains isolated from colorectal carcinoma diagnoses (strains 7-8; Wilcoxon non-parametric test p = 0.0132; t test = 0.1110; t test with log-transformed data, p value = 0.0294). PMID- 29134548 TI - A Didactic Course on "Philosophy of Psychiatry" for Psychiatry Residents. PMID- 29134547 TI - Detection of virulence-related genes in Lactococcus garvieae and their expression in response to different conditions. AB - Lactococcus garvieae has emerged as an important zoonotic pathogen. However, information regarding mechanisms and factors related to its pathogenicity is lacking. In the present study, we investigated the distribution and functionality of genes related to virulence factors in L. garvieae strains isolated from different niches (diseased fish, humans, meat and dairy products, vegetables), using both post-genomic and genotypic analysis. Putative genes encoding hemolysin, fibronectin-binding protein, and penicillin acylase were detected in all analyzed genomes/strains. Their expression was significantly induced by bile salt stress. Putative genes encoding bile salt hydrolase were found in a few strains from dairy and human sources, as well as the mobilizable tet genes. Finally, all genomes possessed a folate gene cluster, in which mutations in the dihydropteroate synthase gene (folP) could be related to sulfonamide resistance. To the best of our knowledge, this is the first study aimed to explore the pathogenic potential of L. garvieae through the analysis of numerous L. garvieae genomes/strains, coming from different sources. This approach allowed the detection of virulence-related genes not yet investigated in the species and the study of their expression after exposure to different environmental stresses. The results obtained suggest a virulence potential in some L. garvieae strains that can be exploited for survival in the human gastrointestinal tract. PMID- 29134549 TI - Time to Teach: Addressing the Pressure on Faculty Time for Education. PMID- 29134550 TI - The Transition to Precision Psychiatry and Pragmatic Inquiry Methods in Academic Psychiatry: The Example of Point-of-Care Clinical Trials. PMID- 29134551 TI - The Dangers of Direct-to-Consumer Genetic Testing for Alzheimer's Disease : Comment on "Personal Genomic Testing, Genetic Inheritance, and Uncertainty". AB - The overarching issue with this case study is poor regulation and quality control over direct-to-consumer genetic testing, delivered in the absence of any medical oversight. PMID- 29134552 TI - Intranasal delivery of alpha-asarone to the brain with lactoferrin-modified mPEG PLA nanoparticles prepared by premix membrane emulsification. AB - Alpha-asarone is a bioactive component of Acorus tatarincuii Schott with low bioavailability, which is often used for treatments of various brain diseases in clinical setting. This study was to formulate biodegradable methoxy polyethylene glycol-polylactic acid (mPEG-PLA) nanoparticles (NPs) surface-modified by lactoferrin (Lf), for delivering alpha-asarone into the brain following intranasal administration. Alpha-asarone NPs were prepared by premix membrane emulsification. The relative parameters were optimized by a Box-Behnken experimental design. The particle size, zeta potential, and dispersibility index of NPs and Lf-NPs were characterized. Their ex vivo permeation, pharmacokinetics, distribution in the brain and other tissue, brain targeting, and toxicity were investigated. Following intranasal administration, Lf-NPs had a better permeability and no significant poor bioavailability compared to NPs; the area under curve from 0 to 12 h of alpha-asarone in Lf-NPs of the olfactory bulb, hippocampus, olfactory bundles, and thalamus were 2.14-, 4.17-, 3.62-, and 1.96 fold of those in NP group, respectively. Lactoferrin could enhance the efficacy of brain targeting with NPs and reduce its liver accumulation. Toxicity of NPs on nasal mucosal cilia and epithelial cells was also decreased by Lf. To summarize, these results demonstrate that Lf-NPs of alpha-asarone have potential as a carrier for nose-to-brain delivery of alpha-asarone for brain diseases. PMID- 29134553 TI - Biological characterization of a novel hybrid copolymer carrier system based on glycogen. AB - The effective drug delivery systems for cancer treatment are currently on high demand. In this paper, biological behavior of the novel hybrid copolymers based on polysaccharide glycogen were characterized. The copolymers were modified by fluorescent dyes for flow cytometry, confocal microscopy, and in vivo fluorescence imaging. Moreover, the effect of oxazoline grafts on degradation rate was examined. Intracellular localization, cytotoxicity, and internalization route of the modified copolymers were examined on HepG2 cell line. Biodistribution of copolymers was addressed by in vivo fluorescence imaging in C57BL/6 mice. Our results indicate biocompatibility, biodegradability, and non toxicity of the glycogen-based hybrid copolymers. Copolymers were endocyted into the cytoplasm, most probably via caveolae-mediated endocytosis. Higher content of oxazoline in polymers slowed down cellular uptake. No strong colocalization of the glycogen-based probe with lysosomes was observed; thus, it seems that the modified externally administered glycogen is degraded in the same way as an endogenous glycogen. In vivo experiment showed relatively fast biodistribution and biodegradation. In conclusion, this novel nanoprobe offers unique chemical and biological attributes for its use as a novel drug delivery system that might serve as an efficient carrier for cancer therapeutics with multimodal imaging properties. PMID- 29134555 TI - Ciprofloxacin-loaded calcium alginate wafers prepared by freeze-drying technique for potential healing of chronic diabetic foot ulcers. AB - Calcium alginate (CA) wafer dressings were prepared by lyophilization of hydrogels to deliver ciprofloxacin (CIP) directly to the wound site of infected diabetic foot ulcers (DFUs). The dressings were physically characterized by scanning electron microscopy (SEM), texture analysis (for mechanical and in vitro adhesion properties), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Further, functional properties essential for wound healing, i.e., porosity, in vitro swelling index, water absorption (Aw), equilibrium water content (EWC), water vapor transmission rate (WVTR), evaporative water loss (EWL), moisture content, in vitro drug release and kinetics, antimicrobial activity, and cell viability (MTT assay) were investigated. The wafers were soft, of uniform texture and thickness, and pliable in nature. Wafers showed ideal wound dressing characteristics in terms of fluid handling properties due to high porosity (SEM). XRD confirmed crystalline nature of the dressings and FTIR showed hydrogen bond formation between CA and CIP. The dressings showed initial fast release followed by sustained drug release which can inhibit and prevent re infection caused by both Gram-positive and Gram-negative bacteria. The dressings also showed biocompatibility (> 85% cell viability over 72 h) with human adult keratinocytes. Therefore, it will be a potential medicated dressing for patients with DFUs infected with drug-resistant bacteria. PMID- 29134554 TI - Ex vivo rabbit cornea diffusion studies with a soluble insert of moxifloxacin. AB - The objective of this research was to develop and evaluate an ocular insert for the controlled drug delivery of moxifloxacin which could perhaps be used in the treatment of corneal keratitis or even bacterial endophthalmitis. We have evaluated the ex vivo ocular diffusion of moxifloxacin through rabbit cornea, both fresh and preserved under different conditions. Histological studies were also carried out. Subsequently, drug matrix inserts were prepared using bioadhesive polymers. The inserts were evaluated for their physicochemical parameters. Ophthalmic ex vivo permeation of moxifloxacin was carried out with the most promising insert. The formulate insert was thin and provided higher ocular diffusion than commercial formulations. Ocular diffusion studies revealed significant differences between fresh and frozen corneas. Histological examinations also showed differences in the thickness of stroma between fresh and frozen corneas. The ophthalmic insert we have developed allows a larger quantity of moxifloxacin to permeate through the cornea than existing commercial formulations of the drug. Ocular delivery of moxifloxacin with this insert could be a new approach for the treatment of eye diseases. PMID- 29134556 TI - Process optimization and particle engineering of micronized drug powders via milling. AB - Process control and optimization is a critical aspect of process analytical technology (PAT), quality by design (QbD), and the implementation of continuous manufacturing procedures. While process control and optimization techniques have been utilized in other manufacturing industries for decades, the pharmaceutical industry has only recently begun to adopt these procedures. Micronization, particularly milling, is a generally low-yield, high-energy consumption process that is well suited for a process optimization mindset. This review discusses optimization of the pharmaceutical milling process through design space development, theoretical and empirical modeling, and monitoring of critical quality attributes. PMID- 29134557 TI - Advancing Care Within an Adult Mental Health Day Hospital: Program Re-Design and Evaluation. AB - Day hospital mental health programs provide alternate care to individuals of high acuity that do not require an inpatient psychiatric stay. Ensuring provision of best practice within these programs is essential for patient stabilization and recovery. However, there is scant literature to review when creating such a program. This paper provides an overview of the steps an acute care hospital took when designing and implementing new programming within a day hospital program. Qualitative data was collected following initial program rollout. This data helped to inform the ongoing modification of groups offered, group scheduling and content, as well as ensuring patient satisfaction and adequate skill delivery during the rollout period and beyond. The goal of this paper is to inform health service delivery for other programs when attempting to build or re-design a day hospital program. PMID- 29134559 TI - List of referees. PMID- 29134558 TI - Development of hyperkalemia following treatment with dapagliflozin (DAPA) in a patient with type 2 diabetes after bilateral adrenalectomy. AB - Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is known to have a beneficial diuretic effect, in addition to a glucose-lowering effect. Although SGLT2 inhibitor has been reported, the increase of hyperkalemia in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors, their mechanism of action is unclear. We report the first case of a type 2 diabetes (T2DM) patient with potential mineralocorticoid deficiency who developed hyperkalemia after administration of DAPA. A 79-year-old woman underwent bilateral adrenalectomy for uncontrolled hypercortisolism due to an inoperable recurrence of Cushing's disease, and she was subsequently maintained on replacement therapy with glucocorticoid. She was diagnosed as having T2DM at 71 years of age and was treated with sitagliptin and miglitol. Since she presented with weight gain of about 5 kg over 6 months and her HbAlc level increased over 12%, 5 mg/day DAPA was added to her daily regimen. After the start of DAPA treatment, she developed hyperkalemia (6.5 mEq/L) with increased plasma renin activity of 53.1 ng/mL/h. She was diagnosed with aldosterone deficiency and started on fludrocortisone 0.1 mg daily, after which the hyperkalemia improved immediately. In this case, DAPA treatment could potentially increase the requirement for mineralocorticoid replacement, directly suggesting that the SGLT2 inhibition-induced natriuretic effect is accompanied by compensatory activation of the RAAS axis, which is essential to keep the serum potassium level within the normal range. Therefore, physicians should be careful about the development of hyperkalemia in patients when SGLT2 and RAAS inhibitors are used in combination. PMID- 29134560 TI - Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice. AB - MDMA (3,4-methylenedioxymethamphetamine) is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA acts at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) and is known to induce damage of dopamine and serotonin neurons. MDMA is often ingested with caffeine. Caffeine as a non-selective adenosine A1/A2A receptor antagonist affects dopaminergic and serotonergic transmissions. The aim of the present study was to determine the changes in DA and 5-HT release in the mouse striatum induced by MDMA and caffeine after their chronic administration. To find out whether caffeine aggravates MDMA neurotoxicity, the content of DA and 5-HT, density of brain DAT and SERT, and oxidative damage of nuclear DNA were determined. Furthermore, the effect of caffeine on MDMA-induced changes in striatal dynorphin and enkephalin and on behavior was assessed. The DA and 5-HT release was determined with in vivo microdialysis, and the monoamine contents were measured by HPLC with electrochemical detection. DNA damage was assayed with the alkaline comet assay. DAT and SERT densities were determined by immunohistochemistry, while prodynorphin (PDYN) and proenkephalin were determined by quantitative PCR reactions. The behavioral changes were measured by the open field (OF) test and novel object recognition (NOR) test. Caffeine potentiated MDMA-induced DA release while inhibiting 5-HT release in the mouse striatum. Caffeine also exacerbated the oxidative damage of nuclear DNA induced by MDMA but diminished DAT decrease in the striatum and worsened a decrease in SERT density produced by MDMA in the frontal cortex. Neither the striatal PDYN expression, increased by MDMA, nor exploratory and locomotor activities of mice, decreased by MDMA, were affected by caffeine. The exploration of novel object in the NOR test was diminished by MDMA and caffeine. Our data provide evidence that long-term caffeine administration has a powerful influence on functions of dopaminergic and serotonergic neurons in the mouse brain and on neurotoxic effects evoked by MDMA. PMID- 29134561 TI - Cannabinoid Receptor Type 1 Agonist ACEA Protects Neurons from Death and Attenuates Endoplasmic Reticulum Stress-Related Apoptotic Pathway Signaling. AB - Neurodegeneration is the result of progressive destruction of neurons in the central nervous system, with unknown causes and pathological mechanisms not yet fully elucidated. Several factors contribute to neurodegenerative processes, including neuroinflammation, accumulation of neurotoxic factors, and misfolded proteins in the lumen of the endoplasmic reticulum (ER). Endocannabinoid signaling has been pointed out as an important modulatory system in several neurodegeneration-related processes, inhibiting the inflammatory response and increasing neuronal survival. Thus, we investigated the presumptive protective effect of the selective cannabinoid type 1 (CB1) receptor agonist arachidonyl-2' chloroethylamide (ACEA) against inflammatory (lipopolysaccharide, LPS) and ER stress (tunicamycin) stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells). Cell viability analysis revealed that ACEA was able to protect against cell death induced by LPS and tunicamycin. This neuroprotective effect occurs via the CB1 receptor in the inflammation process and via the transient receptor potential of vanilloid type-1 (TRPV1) channel in ER stress. Furthermore, the immunoblotting analyses indicated that the neuroprotective effect of ACEA seems to involve the modulation of eukaryotic initiation factor 2 (eIF2alpha), transcription factor C/EBP homologous protein (CHOP), and caspase 12, as well as the survival/death p44/42 MAPK, ERK1/2-related signaling pathways. Together, these data suggest that the endocannabinoid system is a potential therapeutic target in neurodegenerative processes, especially in ER-related neurodegenerative diseases. PMID- 29134562 TI - SEOM clinical guidelines for the treatment of metastatic prostate cancer (2017). AB - Androgen deprivation treatment was the only treatment available for metastatic prostate cancer until recently, with docetaxel as the only treatment with a proven survival benefit in castration-resistant prostate cancer (CRPC). Several drugs have been approved in the castration-resistant disease (sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, radium-223). More recently, docetaxel and abiraterone have been moved to the hormone-sensitive disease setting, achieving better patient survival. The purpose of this article is to define the state of the art in the treatment of prostate carcinoma. PMID- 29134563 TI - Preoperative plasma fibrinogen is associated with poor prognosis in esophageal carcinoma: a meta-analysis. AB - PURPOSE: The aim of this meta-analysis was to investigate preoperative plasma fibrinogen (PPF) as a prognostic marker in esophageal carcinoma (EC) by meta analysis. METHODS: Relevant studies were sought in the databases including Pubmed, Web of Science, Cochrane library, and Wanfang databases up to Oct 10th, 2017. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were used as effective value, and pooled HRs were synthesized by STATA 14.0 to assess the prognostic impact of PPF on EC patients. RESULTS: A total of 8 studies with 2827 patients were collected in this meta-analysis. Our results revealed that high PPF was significantly associated with poor OS (HR = 1.90, 95% CI 1.56-2.33, P = 0.000; HR = 1.76, 95% CI 1.28-2.42, P = 0.000) and poor DFS (HR = 1.91, 95% CI 1.50-2.43, P = 0.000; HR = 1.51, 95% CI 1.16-1.97, P = 0.000) in EC patients from univariate and multivariate analysis results, respectively, which suggested that EC patients with high PPF will suffer from high postoperative mortality and recurrence rate. CONCLUSION: High PPF was significantly associated with poor OS and DFS in EC patients. Fibrinogen can serve as a prognostic marker and even a future targeting molecule during the treatment of EC patients. PMID- 29134565 TI - Prognostic value of FDG-PET and DWI in breast cancer. AB - OBJECTIVE: To investigate the prognostic value of preoperative FDG-PET/CT and diffusion weighted imaging (DWI) in patients with breast cancer. METHODS: A total of 73 patients with newly diagnosed invasive breast cancer who had undergone preoperative whole-body FDG-PET/CT and 3-Tesla breast MRI including DWI followed by surgery were identified. Effects of primary tumor PET parameters [maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)] and DWI parameters [mean apparent diffusion coefficient (ADCmean) and minimum ADC (ADCmin)] including clinicopathologic factors on disease-free survival (DFS) were retrospectively evaluated using the log-rank and Cox methods. RESULTS: After a median overall follow-up of 32.3 months in all patients, 6 (8.2%) of the 73 patients had recurrence. Receiver operating characteristic curve analysis and log-rank tests showed that patients with a high primary tumor SUVmax (>= 3.60), MTV (>= 3.15), and TLG (>= 16.0) had a significantly lower DFS rate than those with a low SUVmax (< 3.60), MTV (< 3.15), and TLG (< 16.0), respectively (p = 0.0054, p = 0.0054, and p < 0.0001, respectively). SUVmean, ADCmean, and ADCmin were not significantly associated with recurrence. Univariate analysis showed that SUVmax (p = 0.0054), MTV (p = 0.0054), TLG (p < 0.0001), tumor size (p = 0.0083), estrogen receptor negativity (p = 0.046), progesterone receptor negativity (p = 0.0023), human epidermal growth factor receptor 2 positivity (p = 0.043), and the presence of axillary lymph node metastasis (p = 0.0037) were also significantly associated with recurrence. However, in multivariate analysis, none of them were an independent factor. CONCLUSIONS: The preoperative SUVmax, MTV, and TLG of primary breast cancer are prognostic factors for recurrence, whereas ADC values are not. PMID- 29134564 TI - SEOM clinical guideline for treatment of kidney cancer (2017). AB - The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge. PMID- 29134566 TI - Lisdexamfetamine: A Review in Binge Eating Disorder. AB - Oral lisdexamfetamine dimesylate (Vyvanse(r); lisdexamfetamine), a prodrug of dextroamfetamine, is currently the only drug to be approved in the USA for the treatment of moderate to severe binge eating disorder (BED) in adult patients. Its approval was based on the results of two pivotal short-term (12 weeks) phase III studies, which showed a significantly greater reduction in binge eating days/week at the end of the study with lisdexamfetamine 50-70 mg/day than with placebo. The findings of these studies have been supported and extended by the results of longer-term (<= 52 weeks) phase III studies, including one with a randomized 26-week withdrawal phase, which showed that lisdexamfetamine markedly reduced the risk of BED relapse relative to placebo. Lisdexamfetamine was generally well tolerated in clinical trials in patients with moderate to severe BED, with a tolerability profile similar to that observed in ADHD patients; most treatment-emergent adverse events (TEAEs) were of mild or moderate intensity. The most common TEAEs in phase III trials included dry mouth, headache and insomnia; TEAEs infrequently led to study drug discontinuation. In conclusion, lisdexamfetamine 50-70 mg/day is an effective and generally well tolerated option for treating moderate to severe BED in adults. PMID- 29134567 TI - Abdominal pain in patient with antiphospholipid syndrome-the role of MDCT angiography on visceral blood vessels. AB - Antiphospholipid syndrome (APS) is an autoimmune disease defined by accelerated atherosclerosis, arterial and venous thrombosis, fetal loss, and the presence of antiphospholipid antibodies (aPL) in the serum and which leads to the occurrence of various vascular events. Nonspecific abdominal pain can be one of the symptoms due to changes on visceral blood vessels. The goal of our work is to show the results we obtained in multidetector computed tomography (MDCT) angiography examination of visceral arteries, comparing patients with primary antiphospholipid syndrome (PAPS) and secondary antiphospholipid syndrome (SAPS) with control group. In this study, we analyzed 50 patients with primary PAPS and 50 patients, with secondary SAPS. The results were compared to 50 patients in the control group. The groups were compared in terms of age, gender, and the most common risk factors except for the lipid status, since controls had significantly higher levels of cholesterol and triglycerides. The study was conducted on 64 MDCT, on which we analyzed quantitative and morphological characteristics of the blood vessel lesions. Patients from the control group had statistically significant elevation of cholesterol and triglyceride levels compared to the patients with SAPS and PAPS (p < 0.001 and p < 0.05). The results showed that the frequency of changes is statistically (p < 0.05 and p < 0.001) more common in patients with PAPS and SAPS than in the control group. Statistically significant difference between the groups was found in superior and inferior mesentery arteries. Analyzing the number of lesions, there was statistically high difference between the patients with one and two lesions than in patients with four or more lesions (p < 0.001), lower difference compared to the patients with three lesions (p < 0.01), while there was low, but yet statistically important difference between the patients with three lesions and those with five or more blood vessel lesions (p < 0.05). Analyzing percentage of diameter stenosis, we established that the lesions in the groups of 0-30% diameter stenosis (DS) and 30 50% DS in patients with PAPS (n = 42) and SAPS (n = 44) are more common than in the control group (n = 18, p < 0.05). Analyzing the qualitative characteristics of plaques, we established significantly higher frequency of soft tissue and mixed lesions than calcified ones in patients with PAPS and SAPS (p < 0.001; p < 0.05). Our study showed that the subclinical manifestation of the changes on visceral arteries is more common in patients with APS. Patients with abdominal pain were those with two or more lesions, and according to our results, majority had PAPS. Because of its safety and accuracy, the method of choice is MDCT angiography in monitoring the progression of disease. PMID- 29134568 TI - beta2-adrenergic stimulation of dendritic cells favors IL-10 secretion by CD4+ T cells. AB - Adrenergic receptor agonists and antagonists are extensively used as drugs in medicine for a broad spectrum of indications. We examined the consequences of beta2-adrenergic stimulation of murine dendritic cells (DCs) on CD4+ T cell activation. We demonstrated in vitro that treatment of LPS-matured DCs with the beta2-agonist salbutamol reduced their ability to trigger OT-II T cell proliferation specific for ovalbumin antigen. Salbutamol also induced a decrease in MHC class II molecule expression by DC through Gi protein activation. Co culture of CD4+ T cells with salbutamol-conditioned mature DC impaired TNFalpha and IL-6 secretion while preserving IL-10 production by T cells. Using a vaccination protocol in mice, we showed that salbutamol favored IL-10-producing CD4+ T cells. None of these effects was observed when working with beta2 adrenoreceptor deficient mice. Finally, we suggest that beta2-adrenergic stimulation of DC could be an interesting way to shape CD4+ T cell responses for the purposes of immunotherapy. PMID- 29134570 TI - Evaluation of Tobramycin Exposure Predictions in Three Bayesian Forecasting Programmes Compared with Current Clinical Practice in Children and Adults with Cystic Fibrosis. AB - BACKGROUND AND OBJECTIVES: Bayesian forecasting (BF) methods for tobramycin dose individualisation has not seen widespread clinical adoption, despite being endorsed by clinical practice guidelines. Several freeware and commercial programmes using BF methods are available to support personalised dosing. This study evaluated exposure estimates, dose recommendations, and predictive performance compared with current clinical practice. METHODS: Data from 105 patients (50 adults and 55 children) with cystic fibrosis who received intravenous tobramycin treatment and had paired concentration-time measurements were analysed using (1) log-linear regression analysis, and (2) three BF programmes: TDMx, InsightRX, and DoseMe. Exposure estimates and dose recommendations were compared using the Wilcoxon signed-rank test and Bland Altman analysis. Predictive performance of BF programmes was compared based on bias and imprecision. RESULTS: Median estimated tobramycin exposure with current clinical practice was significantly lower (87.8 vs. 92.5, 94.0 and 90.3 mg h l-1; p <= 0.01), hence median subsequent dose recommendations were significantly higher (10.1 vs. 9.4, 9.4 and 9.2 mg kg-1; p <= 0.01) compared with BF programmes. Furthermore, median relative dose-adjustment differences were higher in adults (> 10%) compared with children (4.4-7.8%), and differences in individual dose recommendations were > 20% on 19.1-27.4% of occasions. BF programmes showed low bias (< 7%) and imprecision (< 20%), and none of the programmes made consistently significantly different recommendations compared with each other. CONCLUSIONS: On average, the predictions made by the BF programmes were similar, however substantial individual differences were observed for some patients. This suggests the need for detailed investigations of true tobramycin exposure. PMID- 29134571 TI - Optimizing Residents' Performance of Lumbar Puncture: An RCT Comparing the Effect of Preparatory Interventions on Performance and Self-Confidence. AB - BACKGROUND: Lumbar puncture is often associated with uncertainty and limited experience on the part of residents; therefore, preparatory interventions can be essential. There is growing interest in the potential benefit of videos over written text. However, little attention has been given to whether the design of the videos impacts on subsequent performance. OBJECTIVE: To investigate the effect of different preparatory interventions on learner performance and self confidence regarding lumbar puncture (LP). DESIGN: Randomized controlled trial in which participants were randomly assigned to one of three interventions as preparation for performing lumbar puncture: 1) goal- and learner-centered video (GLV) presenting procedure-specific process goals and learner-centered information; 2) traditional video (TV) providing expert-driven content, but no process goals; and 3) written text (WT) with illustrations. PARTICIPANTS AND MAIN MEASURES: Participants were PGY-1 doctors without LP experience. After the preparatory intervention, participants performed an LP in a simulated setting with a standardized patient and an assistant. Two content experts, blinded to participant group allocation, assessed video recordings of the performance using the Lumbar Puncture Assessment Tool (LumPAT) and an overall global rating. Participants rated their self-confidence immediately prior to performing the procedure. The primary outcome was the difference in LumPAT scores among groups. KEY RESULTS: A total of 110 PGY-1 doctors were included. Results demonstrated significant differences in LumPAT mean scores among the three groups: GLV, 42.8; TV, 40.6; WT, 38.1 (p = 0.01). The global rating scores were highest in the GLV group (p = 0.026). Self-confidence scores differed significantly among the three groups (p = 0.003), with the TV group scoring the highest. There were no significant correlations between self-confidence scores and performance scores in any of the groups. CONCLUSION: A video designed with procedure-specific process goals and learner-centered information resulted in better subsequent LP performance than a traditionally designed video or written text. Participants' self-confidence was not predictive of their actual performance. PMID- 29134572 TI - Doc, I Just Ate: Interpreting Random Blood Glucose Values in Patients with Unknown Glycemic Status. PMID- 29134573 TI - Capsule Commentary on Ganguli et al., What Do High-Risk Patients Value? Perspectives on a Care Management Program. PMID- 29134574 TI - Correction to: Potential signaling pathways of acute endurance exercise-induced cardiac autophagy and mitophagy and its possible role in cardioprotection. AB - The article Potential signaling pathways of acute endurance exercise-induced cardiac autophagy and mitophagy and its possible role in cardioprotection, written by Youngil Lee. PMID- 29134575 TI - Impact of intramuscular administration of lipid-soluble and water-soluble vehicles into regenerating muscle at the distinct phases of skeletal muscle regeneration. AB - Interpretation on the effectiveness of potential substances to enhance skeletal muscle regeneration is difficult if an inappropriate vehicle is administered, since vehicle administration can directly enhance or suppress regenerative capacity. In the current study, intramuscular administration of lipid-soluble and water-soluble vehicles into regenerating muscle at the distinct phases of skeletal muscle regeneration (regenerative vs. remodeling) were investigated. Tested vehicles included lipid-soluble [olive oil, (0.1, 1, 5, and 40%) dimethyl sulfoxide (DMSO), and 40% propylene glycol (PG)] and water-soluble [0.9% NaCl, PBS, 0.1% ethanol, and distilled water]. Skeletal muscle regeneration was induced by 1.2% BaCl2 injection to the tibialis anterior muscle of 10-week-old C57BL/6 male mice. Histological features, skeletal muscle stem cell activity, regenerating muscle fiber formation, angiogenesis, extracellular matrix remodeling, and macrophage infiltration were examined. The results revealed repeated administration of 40% DMSO and 40% PG causes significant recurrent muscle injury, which is pronounced during the remodeling phase compared to the regenerative phase. These findings were supported by (1) massive infiltration of F4/80+ macrophages; (2) significant increase of skeletal muscle stem cell re activation and nascent regenerating muscle fiber formation; (3) excess fibrous formation; and (4) decreased regenerating muscle fiber cross-sectional area. These deleterious effects were comparable to 2% trypsin (degenerative substance) administration and less pronounced with a single administration. Nevertheless, recurrent muscle injury was still presented with 5% DMSO administration but it can be alleviated when 0.1% DMSO was administered during the remodeling phase. In contrast, none of the tested vehicles enhanced regenerative capacity compared with IGF-1 administration. Altogether, intramuscular administration of vehicle containing high concentration of DMSO or PG could impair skeletal muscle regenerative capacity and potentially affect validation of the investigational substance. PMID- 29134576 TI - Comparing speech and nonspeech context effects across timescales in coarticulatory contexts. AB - Context effects are ubiquitous in speech perception and reflect the ability of human listeners to successfully perceive highly variable speech signals. In the study of how listeners compensate for coarticulatory variability, past studies have used similar effects speech and tone analogues of speech as strong support for speech-neutral, general auditory mechanisms for compensation for coarticulation. In this manuscript, we revisit compensation for coarticulation by replacing standard button-press responses with mouse-tracking responses and examining both standard geometric measures of uncertainty as well as newer information-theoretic measures that separate fast from slow mouse movements. We found that when our analyses were restricted to end-state responses, tones and speech contexts appeared to produce similar effects. However, a more detailed time-course analysis revealed systematic differences between speech and tone contexts such that listeners' responses to speech contexts, but not to tone contexts, changed across the experimental session. Analyses of the time course of effects within trials using mouse tracking indicated that speech contexts elicited fewer x-position flips but more area under the curve (AUC) and maximum deviation (MD), and they did so in the slower portions of mouse-tracking movements. Our results indicate critical differences between the time course of speech and nonspeech context effects and that general auditory explanations, motivated by their apparent similarity, be reexamined. PMID- 29134577 TI - Perspective taking and theory of mind in hide and seek. AB - Does theory of mind play a significant role in where people choose to hide an item or where they search for an item that has been hidden? Adapting Anderson's "Hide-Find Paradigm" Anderson et al. (Action, Perception and Performance, 76, 907 913, 2014) participants viewed homogenous or popout visual arrays on a touchscreen table. Their task was to indicate where in the array they would hide an item, or to search for an item that had been hidden, by either a friend or a foe. Critically, participants believed that their sitting location at the touchtable was the same as-or opposite to-their partner's location. Replicating Anderson et al., participants tended to (1) select items nearer to themselves on homogenous displays, and this bias was stronger for a friend than foe; and (2) select popout items, and again, more for a friend than foe. These biases were observed only when participants believed that they shared the same physical perspective as their partner. Collectively, the data indicate that theory of mind plays a significant role in hiding and finding, and demonstrate that the hide find paradigm is a powerful tool for investigating theory of mind in adults. PMID- 29134578 TI - Experimental and Computational Comparative Study of the Supercritical Fluid Technology (SFT) and Kneading Method in Preparing beta-Cyclodextrin Complexes with Two Essential Oils (Linalool and Carvacrol). AB - Supercritical fluid technology (SFT) offers many advantages as a potential complexation method compared to the conventional kneading technique. Its applicability to processess in which solvents are not required is a significant benefit. The main aim of this study was to evaluate, experimentally and computationally, the applicability of SFT in the preparation of beta-cyclodextrin complexes with two selected essential oils, namely, carvacrol and linalool. Preparation of the complexes was performed using kneading and SFT method. Several methods were used in the solid-state characterization. These include thermal analysis, powder X-ray diffraction, Fourier transform infrared spectroscopy, and solid-state nuclear magnetic resonance. Besides, molecular dynamics simulations of all studied systems were conducted in order to have a deeper and a detailed insight, at the atomic level, of the nature of the two used techniques. Despite all the advantages of SFT, better results of guest molecule entrapment inside beta-cyclodextrin were obtained with the kneading method. The percentages of oil content for linalool samples were 70 +/- 14 and 84 +/- 9% for SFT and kneading method, respectively, while the drug content values for carvacrol samples were 67 +/- 15 and 81 +/- 13% for SFT and kneading method, respectively. Interestingly, simulation results were in perfect agreement with the experimental ones and, moreover, they provided a plausible explanation for the obtained results. In conclusion, our results showed that the SFT was unsuccessful in enhancing the stability of the studied complexes contrary to that of the conventational kneading method, and in both cases, molecular dynamics simulations correctly predicted the expected outcomes. PMID- 29134579 TI - Investigation on Secondary Structure Perturbations of Proteins Embedded in Solid Lipid Matrices as a Novel Indicator of their Biological Activity upon In Vitro Release. AB - Protein biologics are prone to conformational changes during formulation development. Limited methods are available for conformational analysis of proteins in solid state and in the presences of formulation excipients. The aim of this study was to investigate the secondary structures of proteins encased in solid lipid matrices as a novel indicator of their stability upon in vitro release. Model proteins namely catalase and lysozyme were incorporated into lipid namely Precirol(r) AT05 (glycerol palmitostearate, melting point 58 degrees C) at 30% w/w loading using melting and mixing and wet granulation methods. Attenuated total reflectance (ATR-FTIR) spectroscopy, size-exclusion chromatography (SEC) and biological activity analyses were performed. The information about secondary structure was acquired using second derivative analysis of amide-I band (1600 1700 cm-1). ATR analysis demonstrated interference of lipid spectrum with protein amide-I band which was subsequently subtracted to allow the analysis of the secondary structure. ATR spectra amide-I bands showed shifts peak band positions compared to native protein for matrices prepared using wet granulation. SEC analysis gave evidence of protein aggregation for catalase which was increased using wet granulation. The biological activity of catalase was statistically different from that of control and was affected by the incorporation method and was found to be in alignment with ATR spectral changes and extent of aggregation. In conclusion, ATR spectroscopy could analyze protein secondary structure in lipid matrices provided lipid interference was minimized. The ATR spectral changes and formation of aggregates can indicate the loss in biological activity of protein released from solid lipid matrices. PMID- 29134580 TI - Acute hemorrhagic leukoencephalitis after seasonal influenza vaccination. PMID- 29134581 TI - The Pain of Ambivalence over Emotional Expression. AB - PURPOSE: Ambivalence over emotional expression (AEE) is defined as the desire to express emotion but failing to do so. Recent studies have revealed that AEE is associated with more pain. Pain is common among cancer survivors. This cross sectional study investigated the association between AEE and pain, its underlying mechanism, and cultural relevance among cancer survivors. METHODS: Ninety-six Chinese American breast cancer survivors completed a questionnaire package assessing AEE and pain. RESULTS: AEE was positively associated with pain severity and pain interference. The association between AEE and pain interference was mediated by intrusive thoughts. CONCLUSION: Cancer survivors who are ambivalent over emotional expression may experience high levels of intrusive thoughts, which results in high levels of symptom reports in their pain. The study confirmed the association between AEE and pain and its underlying mechanism among a group whose culture generally encourages emotional suppression. Findings suggest interventions focusing on reducing intrusive thoughts may be effective at reducing pain. PMID- 29134583 TI - Basic Phage Mathematics. AB - Basic mathematical descriptions are useful in phage ecology, applied phage ecology such as in the course of phage therapy, and also toward keeping track of expected phage-bacterial interactions as seen during laboratory manipulation of phages. The most basic mathematical descriptor of phages is their titer, that is, their concentration within stocks, experimental vessels, or other environments. Various phenomena can serve to modify phage titers, and indeed phage titers can vary as a function of how they are measured. An important aspect of how changes in titers can occur results from phage interactions with bacteria. These changes tend to vary in degree as a function of bacterial densities within environments, and particularly densities of those bacteria that are susceptible to or at least adsorbable by a given phage type. Using simple mathematical models one can describe phage-bacterial interactions that give rise particularly to phage adsorption events. With elaboration one can consider changes in both phage and bacterial densities as a function of both time and these interactions. In addition, phages along with their impact on bacteria can be considered as spatially constrained processes. In this chapter we consider the simpler of these concepts, providing in particular detailed verbal explanations toward facile mathematical insight. The primary goal is to stimulate a more informed use and manipulation of phages and phage populations within the laboratory as well as toward more effective phage application outside of the laboratory, such as during phage therapy. More generally, numerous issues and approaches to the quantification of phages are considered along with the quantification of individual, ecological, and applied properties of phages. PMID- 29134582 TI - Long-term efficacy of comprehensive multidisciplinary antibiotic stewardship programs centered on weekly prospective audit and feedback. AB - OBJECTIVE: To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes. DESIGN: Before-after study. SETTING: National university hospital with 934 beds. INTERVENTION: Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration. METHODS: The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia. RESULTS: The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend). CONCLUSION: The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome. PMID- 29134584 TI - Analysis of Host-Takeover During SPO1 Infection of Bacillus subtilis. AB - When Bacillus subtilis is infected by bacteriophage SPO1, the phage directs the remodeling of the host cell, converting it into a factory for phage reproduction. Much synthesis of host DNA, RNA, and protein is shut off, and cell division is prevented. Here I describe the protocols by which we have demonstrated those processes, and identified the roles played by specific SPO1 gene products in causing those processes. PMID- 29134585 TI - Practical Advice on the One-Step Growth Curve. AB - The one-step growth experiment is fundamental to the description of a new bacteriophage. The following protocol is optimized for those working with rapidly growing bacterial cultures. PMID- 29134586 TI - Iron Chloride Flocculation of Bacteriophages from Seawater. AB - Viruses influence ecosystem dynamics by modulating microbial host population dynamics, evolutionary trajectories and metabolic outputs. While they are ecologically important across diverse ecosystems, viruses are challenging to study due to minimal biomass often obtained when sampling natural communities. Here we describe a technique using chemical flocculation, filtration and resuspension to recover bacteriophages from seawater and other natural waters. The method uses iron to precipitate viruses which are recovered by filtration onto large-pore size membranes and then resuspended using a buffer containing magnesium and a reductant (ascorbic acid or oxalic acid) at slightly acid pH (6 6.5). The recovery of bacteriophages using iron flocculation is efficient (>90%), inexpensive and reliable, resulting in preparations that are amenable to downstream analysis by next generation DNA sequencing, proteomics and, in some cases, can be used to study virus-host interactions. PMID- 29134587 TI - Purification of Bacteriophages Using Anion-Exchange Chromatography. AB - In bacteriophage research and therapy, most applications ask for highly purified phage suspensions. The standard technique for this is ultracentrifugation using cesium chloride gradients. This technique is cumbersome, elaborate and expensive. Moreover, it is unsuitable for the purification of large quantities of phage suspensions.The protocol described here, uses anion-exchange chromatography to bind phages to a stationary phase. This is done using an FLPC system, combined with Convective Interaction Media (CIM(r)) monoliths. Afterward, the column is washed to remove impurities from the CIM(r) disk. By using a buffer solution with a high ionic strength, the phages are subsequently eluted from the column and collected. In this way phages can be efficiently purified and concentrated.This protocol can be used to determine the optimal buffers, stationary phase chemistry and elution conditions, as well as the maximal capacity and recovery of the columns. PMID- 29134588 TI - Encapsulation Strategies of Bacteriophage (Felix O1) for Oral Therapeutic Application. AB - Due to emerging antibiotic-resistant strains among the pathogens, a variety of strategies, including therapeutic application of bacteriophages, have been suggested as a possible alternative to antibiotics in food animal production. As pathogen-specific biocontrol agents, bacteriophages are being studied intensively. Primarily their applications in the food industry and animal production have been recognized in the USA and Europe, for pathogens including Salmonella, Campylobacter, Escherichia coli, and Listeria. However, the viability of orally administered phage may rapidly reduce under the harsh acidic conditions of the stomach, presence of enzymes and bile. It is evident that bacteriophages, intended for phage therapy by oral administration, require efficient protection from the acidic environment of the stomach and should remain active in the animal's gastrointestinal tract where pathogen colonizes. Encapsulation of phages by spray drying or extrusion methods can protect phages from the simulated hostile gut conditions and help controlled release of phages to the digestive system when appropriate formulation strategy is implemented. PMID- 29134589 TI - Encapsulation of Listeria Phage A511 by Alginate to Improve Its Thermal Stability. AB - Microencapsulation is a versatile method for enhancing the stability of bacteriophages under harsh conditions, such as those which occur during thermal processing. For food applications, encapsulation in food-grade polymer matrices is desirable owing to their nontoxicity and low cost. Here, we describe the encapsulation of Listeria phage A511 using sodium alginate, gum arabic, and gelatin to maximize its viability during thermal processing. PMID- 29134590 TI - Application of a Virucidal Agent to Avoid Overestimation of Phage Kill During Phage Decontamination Assays on Ready-to-Eat Meats. AB - We describe a method for assessing the effectiveness of tea extract based virucide (TeaF) application to remove phage LISTEXTM P100 not bound to Listeria monocytogenes from stomached rinses prior to direct plating and bacterial enumeration, where the phage is being used as a decontaminant to reduce L. monocytogenes levels on ready-to-eat meat. PMID- 29134591 TI - Sequencing, Assembling, and Finishing Complete Bacteriophage Genomes. AB - Next-generation DNA sequencing (NGS) technologies have made generating genomic sequence for organisms of interest affordable and commonplace. However, NGS platforms and analysis software are generally tuned to be used on large and complex genomes or metagenomic samples. Determining the complete genome sequence of a single bacteriophage requires a somewhat different perspective, workflow, and sensitivity to the nature of phages. Because phage genomes consist of mostly coding regions (see Pope/Jacobs-Sera chapter), a very high standard should be adopted when completing these genomes so that the subsequent steps of annotation and analysis are not sabotaged by sequencing errors. While read quality and assembly algorithms have continued to improve, achieving this standard still requires a significant amount of human oversight and expertise. This chapter describes our workflow for sequencing, assembling, and finishing phage genomes to a high standard by the NGS platforms Illumina, Ion Torrent, and 454. PMID- 29134592 TI - Identification of DNA Base Modifications by Means of Pacific Biosciences RS Sequencing Technology. AB - Whole phage genomes can be sequenced readily using one or a combination of next generation sequencing (NGS) technologies. One of the most recently developed NGS platforms, the so-called Single-Molecule Real-Time (SMRT) sequencing approach provided by the PacBio RS platform, is particularly useful in providing complete (i.e., un-gapped) genome sequences, but differs from other technologies in that the platform also allows for downstream analysis to identify nucleotides that have been modified by DNA methylation. Here, we describe the methodological approach for the detection of genomic methylation motifs by means of SMRT sequencing. PMID- 29134593 TI - Analyzing Genome Termini of Bacteriophage Through High-Throughput Sequencing. AB - High-throughput sequencing (HTS) is an effective tool for bacteriophage genome and its termini analysis. HTS technology parallelizes the sequencing process, producing thousands to millions of reads concurrently. Terminal information of a bacteriophage genome is important and basic knowledge for understanding the biology of the bacteriophage. We have created a high-occurrence reads as termini theory and developed practical methods to determine the bacteriophage genome termini, which is based on the large data of HTS. With this method, the termini of the bacteriophage genome can be efficiently and reliably identified as a by product of bacteriophage genome sequencing, by solely analyzing the sequence statistics of the raw sequencing data (reads), without any further lab experiments. PMID- 29134594 TI - Amplification for Whole Genome Sequencing of Bacteriophages from Single Isolated Plaques Using SISPA. AB - Genomics has greatly transformed our understanding of phage biology; however, traditional methods of DNA isolation for whole genome sequencing have required phages to be grown to high titers in large-scale preparations, potentially selecting for only those phages that can grow efficiently under laboratory conditions. This may also select for mutations or deletions that enable more efficient growth in culture. The ability to sequence a bacteriophage genome from a single isolated plaque reduces these risks while decreasing the time and complexity of bacteriophage genome sequencing. A method of amplification and library preparation is described, utilizing Sequence Independent Single Primer Amplification (SISPA), that can be used for whole genome shotgun sequencing of bacteriophages from a single isolated plaque. PMID- 29134595 TI - Genome Sequencing of dsDNA-Containing Bacteriophages Directly from a Single Plaque. AB - The sequencing of phage genomes has become a routine procedure for phage characterization. The protocol presented here allows rapid isolation of DNA from a single phage plaque followed by building ready-to-sequence Illumina-compatible library. PMID- 29134596 TI - Preparing cDNA Libraries from Lytic Phage-Infected Cells for Whole Transcriptome Analysis by RNA-Seq. AB - Whole genome wide analysis of transcription using RNA-Seq methods is a powerful way to elucidate differential expression of gene features in bacteria across different conditions as well as for discovering previously exotic RNA species. Indeed, RNA sequencing has revolutionized the study of bacterial transcription with the diversity and quantity of small noncoding RNA elements that have been found and its ability to clearly define operons, promoters , and terminators . We discuss our experience with applying RNA sequencing technology to analyzing the lytic cycle, including extraction, processing, and a guide to the customized statistical analysis necessary for analyzing differential host and phage transcription. PMID- 29134597 TI - Essential Steps in Characterizing Bacteriophages: Biology, Taxonomy, and Genome Analysis. AB - Because of the rise in antimicrobial resistance there has been a significant increase in interest in phages for therapeutic use. Furthermore, the cost of sequencing phage genomes has decreased to the point where it is being used as a teaching tool for genomics. Unfortunately, the quality of the descriptions of the phage and its annotation frequently are substandard. The following chapter is designed to help people working on phages, particularly those new to the field, to accurately describe their newly isolated viruses. PMID- 29134598 TI - Annotation of Bacteriophage Genome Sequences Using DNA Master: An Overview. AB - Current sequencing technologies allow for the rapid and inexpensive sequencing of complete bacteriophage genomes, using small quantities of nucleic acid as starting material. Determination of the location and function of the gene features within the genome sequence, or annotation, is a necessary next step prior to submission to a public database, publication in a scientific journal, or advanced comparative genomic and proteomic studies. Gene prediction can be largely accomplished through the use of several freely available programs. However, manual inspection and refinement is essential to the production of the most accurate genome annotations. Here, we describe an overview of the annotation of a bacteriophage genome sequence using the freely available program DNA Master. PMID- 29134599 TI - Phage Genome Annotation Using the RAST Pipeline. AB - Phages are complex biomolecular machineries that have to survive in a bacterial world. Phage genomes show many adaptations to their lifestyle such as shorter genes, reduced capacity for redundant DNA sequences, and the inclusion of tRNAs in their genomes. In addition, phages are not free-living, they require a host for replication and survival. These unique adaptations provide challenges for the bioinformatics analysis of phage genomes. In particular, ORF calling, genome annotation, noncoding RNA (ncRNA) identification, and the identification of transposons and insertions are all complicated in phage genome analysis. We provide a road map through the phage genome annotation pipeline, and discuss the challenges and solutions for phage genome annotation as we have implemented in the rapid annotation using subsystems (RAST) pipeline. PMID- 29134600 TI - Visualization of Phage Genomic Data: Comparative Genomics and Publication-Quality Diagrams. AB - The presentation of bacteriophage genomes as diagrams allows the location and organization of features to be communicated in a clear and effective manner. A wide range of software applications are available for the clear and accurate visualization of genomic data. Several of these applications incorporate comparative analysis tools, allowing for insertions, deletions, rearrangements and variations in syntenic regions to be visualized. In this chapter, freely available software and resources for the generation of high-quality graphical maps of bacteriophage genomes are listed and discussed. PMID- 29134601 TI - Transposable Bacteriophages as Genetic Tools. AB - Phage Mu is the paradigm of a growing family of bacteriophages that infect a wide range of bacterial species and replicate their genome by replicative transposition. This molecular process, which is used by other mobile genetic elements to move within genomes, involves the profound rearrangement of the host genome [chromosome(s) and plasmid(s)] and can be exploited for the genetic analysis of the host bacteria and the in vivo cloning of host genes. In this chapter we review Mu-derived constructs that optimize the phage as a series of genetic tools that could inspire the development of similarly efficient tools from other transposable phages for a large spectrum of bacteria. PMID- 29134602 TI - Applications of the Bacteriophage Mu In Vitro Transposition Reaction and Genome Manipulation via Electroporation of DNA Transposition Complexes. AB - The capacity of transposable elements to insert into the genomes has been harnessed during the past decades to various in vitro and in vivo applications. This chapter describes in detail the general protocols and principles applicable for the Mu in vitro transposition reaction as well as the assembly of DNA transposition complexes that can be electroporated into bacterial cells to accomplish efficient gene delivery. These techniques with their modifications potentiate various gene and genome modification applications, which are discussed briefly here, and the reader is referred to the original publications for further details. PMID- 29134603 TI - Use of RP4::Mini-Mu for Gene Transfer. AB - Gene cloning is an invaluable technique in genetic analysis and exploitation of genetic properties of a broad range of bacteria. Numerous in vitro molecular cloning protocols have been devised but the efficiency of these techniques relies on the frequency with which the recombinant DNA can be introduced in the recipient strain. Here, we describe an in vivo gene transfer and cloning technique based on transposable bacteriophage Mu property to rearrange its host genome. This technique uses the broad host range plasmid RP4 carrying a transposable mini-MuA+ derivative and was successfully used as well in enteric as in environmental nonenteric bacteria. PMID- 29134604 TI - Muprints and Whole Genome Insertion Scans: Methods for Investigating Chromosome Accessibility and DNA Dynamics using Bacteriophage Mu. AB - Bacteriophage Mu infects a broad range of gram-negative bacteria. After infection, Mu amplifies its DNA through a coupled transposition/replication cycle that inserts copies of Mu throughout all domains of the folded chromosome. Mu has the most relaxed target specificity of the known transposons (Manna et al., J Bacteriol 187: 3586-3588, 2005) and the Mu DNA packaging process, called "headful packaging", incorporates 50-150 bp of host sequences covalently bound to its left end and 2 kb of host DNA linked to its right end into a viral capsid. The combination of broad insertion coverage and easy phage purification makes Mu ideal for analyzing chromosome dynamics and DNA structure inside living cells. "Mu printing" (Wang and Higgins, Mol Microbiol 12: 665-677, 1994; Manna et al., J Bacteriol 183: 3328-3335, 2001) uses the polymerase chain reaction (PCR) to generate a quantitative fine structure map of Mu insertion sites within specific regions of a bacterial chromosome or plasmid. A complementary technique uses microarray platforms to provide quantitative insertion patterns covering a whole bacterial genome (Manna et al., J Bacteriol 187: 3586-3588, 2005; Manna et al., Proc Natl Acad Sci U S A 101: 9780-9785, 2004). These two methods provide a powerful complementary system to investigate chromosome structure inside living cells. PMID- 29134605 TI - P2Y11 Receptors: Properties, Distribution and Functions. AB - The P2Y11 receptor is a G protein-coupled receptor that is stimulated by endogenous purine nucleotides, particularly ATP. Amongst P2Y receptors it has several unique properties; (1) it is the only human P2Y receptor gene that contains an intron in the coding sequence; (2) the gene does not appear to be present in the rodent genome; (3) it couples to stimulation of both phospholipase C and adenylyl cyclase. Its absence in mice and rats, along with a limited range of selective pharmacological tools, has hampered the development of our knowledge and understanding of its properties and functions. Nonetheless, through a combination of careful use of the available tools, suppression of receptor expression using siRNA and genetic screening for SNPs, possible functions of native P2Y11 receptors have been identified in a variety of human cells and tissues. Many are in blood cells involved in inflammatory responses, consistent with extracellular ATP being a damage-associated signalling molecule in the immune system. Thus proposed potential therapeutic applications relate, in the main, to modulation of acute and chronic inflammatory responses. PMID- 29134606 TI - Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol. AB - INTRODUCTION: HbA1c is the gold standard for glycemic control in pre-diabetes and diabetes. However, its validity has been questioned, especially in the presence of imbalanced iron homeostasis. The CLEVER trial aims to evaluate the relationship between iron deficiency and HbA1c (a biomarker for the diagnosis and therapeutic monitoring of type 2 diabetes) in a randomized, placebo-controlled, multicenter clinical trial. METHODS: The CLEVER (intravenous ferric CarboxymaLtosE for improVement of mEtabolic parameters in type 2 diabetes patients with iRon deficiency) trial is a randomized, single-blind, proof-of concept study with two treatment arms. 140 men and women diagnosed with type 2 diabetes and iron deficiency will receive either placebo or ferric carboxymaltose (500 or 1000 mg) as intravenous infusions. The primary outcome measure is the change in HbA1c level between baseline and after 12 weeks of treatment. Secondary endpoints include change of iron status and metabolic markers as well as treatment safety and tolerability. Furthermore, the potential clinical improvement in quality of life and the reliability of HbA1c measurement in patients with type 2 diabetes and iron deficiency will be investigated. RESULTS: Both excessive iron and iron deficiency are associated with metabolic disorders; excessive iron is a risk factor for the development of diabetes, whereas iron deficiency is associated with obesity and insulin resistance. It has been suggested that iron increases insulin secretion in pancreatic beta-cells. CLEVER is the first study to investigate the hypothesis that intravenous substitution with ferric carboxymaltose reduces HbA1c levels in patients with type 2 diabetes and iron deficiency, thereby improving metabolic status and quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01513369). FUNDING: GWT-TUD GmbH acts as sponsor of the clinical trial. Financial support is provided by Vifor Pharma. PMID- 29134607 TI - The Cost-effectiveness of Dulaglutide 1.5mg versus Exenatide QW for the Treatment of Patients with Type 2 Diabetes Mellitus in France. AB - INTRODUCTION: Dulaglutide is a novel onceweekly administered glucagon-like peptide 1 receptor agonist (GLP-1 RA) for the management of type 2 diabetes mellitus (T2DM). The objective of this analysis was to estimate the cost effectiveness of dulaglutide 1.5 mg versus exenatide QW for the management of T2DM in France. METHODS: The QuintilesIMS CORE Diabetes Model was used to estimate the expected lifetime direct medical costs and outcomes of T2DM from the perspective of the French National Health Service. In the absence of head-to-head data, relative efficacy was derived from a network meta-analysis. Patient cohort characteristics were derived from the AWARD-2 trial. All patients were assumed to remain on treatment for 2 years before escalating to insulin therapy. Costs included treatment costs and costs associated with long-term complications of T2DM. Utilities were estimated based on a recent systematic review. One-way sensitivity analyses (OWSA) and probabilistic sensitivity analysis (PSA) were conducted. Cost-effectiveness acceptability curves (CEACs) were generated. RESULTS: Dulaglutide 1.5 mg was associated with lower costs (lifetime costs ?41,562 vs ?43,021) and increased health benefits (lifetime quality-adjusted life years: QALYs 9.804 vs 9.757) versus exenatide QW for the treatment of T2DM in France. OWSA and PSA indicated that results were robust across a range of plausible input parameters. The CEAC indicated a 99.5% probability that dulaglutide would be considered cost-effective at a willingness to pay of ?30,000. CONCLUSION: Dulaglutide 1.5 mg reduced expected costs and increased expected QALYs when compared against exenatide QW for the treatment of T2DM in France. Compared with exenatide QW, dulaglutide 1.5 mg can provide additional health benefits for patients with T2DM and may result in cost savings for payers. FUNDING: Eli Lilly. PMID- 29134608 TI - Factors that may Account for Cardiovascular Risk Reduction with a Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, in Young Patients with Type 2 Diabetes Mellitus. AB - INTRODUCTION: In a meta-analysis, we observed a significant 37% relative risk reduction in prospectively adjudicated major adverse cardiac events [MACEs, comprising of non-fatal myocardial infarction, non-fatal stroke, cardiovascular (CV) death] with vildagliptin vs. comparators in younger (< 65 years) patients with type 2 diabetes mellitus (T2DM), while the risk was similar in older patients (>= 65 years). We carried out an exploratory analysis to identify the patient characteristics and on-treatment effects that may have contributed to the different outcomes in the two age groups. METHODS: On-treatment differences (vildagliptin vs. comparators) for the change from baseline in CV risk factors were analyzed using an analysis of covariance model with the baseline value for each variable of interest, treatment and study as covariates. Additional adjustments for background antihypertensive and statin use were performed when analyzing changes in blood pressure and lipids, respectively. Baseline characteristics and patient demographics were analyzed using descriptive statistics. RESULTS: Patients aged < 65 years had shorter diabetes duration (4.4 vs. 8.2 years) and slightly higher glycated hemoglobin (HbA1c) at baseline (8.3% vs. 8.0%) than patients aged >= 65 years. More patients in the >= 65 year age group had hypertension (73.1% vs. 51.3%), dyslipidemia (53.3% vs. 43.9%) and a history of CV events (32.2% vs. 12.9%). There were small, but statistically significant differences in the change in HbA1c and total cholesterol in favor of vildagliptin relative to comparators, which were similar in both age groups. Significant differences were observed in the reduction in systolic blood pressure (SBP) (- 0.52 mmHg; 95% CI - 0.97, - 0.07; p = 0.023), low-density lipoprotein (LDL cholesterol) (- 0.12 mmol/l; 95% CI - 0.19, - 0.04; p = 0.002) and weight (- 0.48 kg; 95% CI - 0.95, - 0.01; p < 0.047) in patients < 65 years, but not in patients >= 65 years. The incidence of hypoglycemic events was lower in patients treated with vildagliptin [2.1 and 3.5 per 100 subject years exposure (SYEs) in < 65 and >= 65 years, respectively] than with comparators (5.8 and 7.5 per 100 SYEs, respectively). CONCLUSION: Based on our findings, it can be hypothesized that the positive effects of vildagliptin on SBP, LDL cholesterol, hypoglycemia and weight observed in younger, but not in older patients could be associated with the lower risk of MACE in younger patients with T2DM. FUNDING: Novartis. PMID- 29134610 TI - Authors' Reply to Mona Kargar and Colleagues' Comment on "Adverse Drug Reaction Related Hospitalizations in Elderly Australians: A Prospective Cross-Sectional Study in Two Tasmanian Hospitals". PMID- 29134609 TI - Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1 related pancreatic neuroendocrine tumors. AB - PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1 related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs. PMID- 29134611 TI - Exploring white matter microstructure and olfaction dysfunction in early parkinson disease: diffusion MRI reveals new insight. AB - Olfaction dysfunction is considered as a robust marker of prodromal Parkinson disease (PD). Measurement of olfaction function as a screening test is unsatisfactory due to long lead time interval and low specificity for detection of PD. Use of imaging markers might yield more accurate predictive values and provide bases for combined use of imaging and clinical markers for early PD. Diffusion MRI connectometry was conducted on 85 de novo PD patients in and 36 healthy controls to find: first, white matter tracts with significant difference in quantitative anisotropy between PD groups with various degrees of olfaction dysfunction and second, second fibers with correlation with University of Pennsylvania Smell Identification Test (UPSIT) score in each group using a multiple regression analysis considering age, sex, GDS and MoCA score. Local connectomes were determined in seven of all the possible comparisons, correcting for false discovery rate (FDR). PD patients with anosmia and normal olfaction had the highest number of fibers with decreased connectivity in left inferior longitudinal fasciculus, bilateral fornix, bilateral middle cerebellar peduncle (MCP), bilateral cingulum, bilateral corticospinal tract (CST) and body, genu and splenium of corpus callosum (CC) (FDR = 0.0013). In multiple regression analysis, connectivity in the body, genu and splenium of CC and bilateral fornix had significant negative correlation (FDR between 0.019 and 0.083), and bilateral cingulum and MCP had significant positive correlation (FDR between 0.022 and 0.092) with UPSIT score. White matter connectivity in healthy controls could not be predicted by UPSIT score using the same model. The results of this study provide compelling evidence that microstructural degenerative changes in these areas underlie the clinical phenotype of prodromal olfaction dysfunction in PD and that diffusion parameters of these areas might be able to serve as signature markers for early detection of PD. This is the first report that confirms a discriminative role for UPSIT score in identifying PD specific changes in white matter microstructure. Our results open a window to identify microstructural signatures of prodromal PD in white matter. PMID- 29134612 TI - Altered connectivity patterns among resting state networks in patients with ischemic white matter lesions. AB - White matter lesions (WMLs) have been associated with cognitive and motor decline. Resting state networks (RSNs) are spatially coherent patterns in the human brain and their interactions sustain our daily function. Therefore, investigating the altered intra- and inter-network connectivity among the RSNs may help to understand the association of WMLs with impaired cognitive and motor function. Here, we assessed alterations in functional connectivity patterns based on six well-defined RSNs-the default mode network (DMN), dorsal attention network (DAN), frontal-parietal control network (FPCN), auditory network (AN), sensory motor network (SMN) and visual network (VN)-in 15 patients with ischemic WMLs and 15 controls. In the patients, Spearman's correlation analysis was further performed between these alterations and cognitive test scores, including Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. Our results showed wide alterations of inter-network connectivity mainly involving the SMN, DMN, FPCN and DAN, and some alterations correlated with cognitive test scores in the patients. The reduced functional connectivities in the SMN-AN, SMN-VN, FPCN-AN, DAN-VN pairs may account for the cognitive and motor decline in patients with ischemic WMLs, while the increased functional connectivities in the DMN-AN, DMN-FPCN and DAN-FPCN pairs may reflect a functional network reorganization after damage to white matter. It is unexpected that altered intra-network connectivities were found within the AN and VN, which may explain the impairments in verbal fluency and information retrieval associated with WMLs. This study highlights the importance of functional connectivity in understanding how WMLs influence cognitive and behavior dysfunction. PMID- 29134613 TI - DFD-01 Reduces Transepidermal Water Loss and Improves Skin Hydration and Flexibility. AB - INTRODUCTION: In plaque psoriasis, the benefit of topical steroids is well established. The vehicle formulation of topical steroids may also provide benefit in addition to the effects of the steroid itself. DFD-01 (betamethasone dipropionate spray, 0.05%) is a formulation composed of a topical steroid in an emollient-like vehicle that enhances penetration to the target site of inflammation in the skin. The aim of this study was to assess the effect of DFD 01 and its vehicle on skin hydration and barrier function in compromised skin and to evaluate its effect on flexibility in healthy skin. METHODS: Eighteen healthy white volunteers were enrolled in each of two studies. In Study 1, dry shaving of volar forearms created a compromised skin barrier, through which transepidermal water loss (TEWL) was measured using an evaporimeter. Capacitance, a measure of epidermal hydration, was also measured at baseline and at 1, 2 and 4 h after application of DFD-01 or its vehicle formulation. In Study 2, intact skin flexibility was tested with a cutometer before and at 1, 2 and 4 h after application of DFD-01 or vehicle. RESULTS: In Study 1, both DFD-01 and its vehicle were effective at reducing TEWL through the compromised stratum corneum. Capacitance measurements confirmed this finding; razor-chafed skin treated with either DFD-01 or vehicle exhibited levels of skin hydration similar to unshaved control skin. Study 2 found softening and greater flexibility of normal skin treated with either DFD-01 or vehicle compared with nontreated control skin samples. CONCLUSIONS: These tests suggest that the DFD-01 formulation and its vehicle are each effective at retaining moisture within a damaged skin barrier and for softening and increasing the flexibility of intact skin. FUNDING: Dr. Reddy's Laboratories. PMID- 29134615 TI - What is the place of POEMS syndrome in the current classification of monoclonal gammopathies of renal significance? PMID- 29134614 TI - Acute exercise during hemodialysis prevents the decrease in natural killer cells in patients with chronic kidney disease: a pilot study. AB - PURPOSE: To evaluate the acute response of natural killer (NK) cell subsets of chronic kidney disease patients submitted to intradialytic exercise in a randomized crossover study. METHODS: Nine patients were submitted to a single bout of 20-min intradialytic exercise and a control hemodialysis (HD) session with an interval of 7 days between them. Peripheral blood sample was collected at baseline, during HD and immediately after HD in each trial to evaluate the peripheral frequency of NK cells and their subsets (CD3-CD56bright and CD3 CD56dim), systemic cortisol concentrations, C-reactive protein (CRP), creatine kinase activity (CK), and urea and creatinine levels. RESULTS: HD therapy induced a significant decrease in NK cells frequency (p = 0.039), NK CD3-CD56bright cells (p = 0.04), and CD3-CD56dim cells (p = 0.036). On the other hand, no significant alterations were observed in NK cells and NK subsets during and after intradialytic exercise trial (p > 0.05). Neither trial altered CRP levels or serum CK activity during and after HD therapy (p > 0.05). However, HD therapy increased cortisol concentrations after HD therapy (p = 0.034). CONCLUSIONS: This study suggests the potential role of intradialytic exercise to prevent the decrease in peripheral frequency of NK cell subsets during HD therapy. Moreover, moderate intensity intradialytic exercise did not exacerbate the systemic inflammation or induce muscle damage during HD therapy. PMID- 29134616 TI - Zonulin, inflammation and iron status in patients with early stages of chronic kidney disease. AB - BACKGROUND/AIMS: Zonulin is the only known regulator of intestinal permeability. It is also considered as a potential inflammatory marker in several conditions such as diabetes and inflammatory bowel syndrome. The aim of the study was to investigate zonulin levels in patients with early stages of CKD and its possible correlation with inflammation, anemia and iron status parameters. METHODS: Eighty eight patients with early stages of CKD and 23 healthy volunteers were enrolled in the study. Zonulin, hepcidin-25, soluble transferrin receptor, interleukin-6 and high-sensitivity C-reactive protein were measured using commercially available assays. RESULTS: Zonulin was significantly lower among patients with CKD in comparison with healthy volunteers. There were no statistically significant differences in zonulin concentration between patients with and without inflammation. Zonulin was significantly correlated with hepcidin only in patients with inflammation. Zonulin was neither related to iron nor related to ferritin. CONCLUSIONS: Zonulin cannot be considered as an inflammatory marker in CKD. It does not play a role in the disturbances of iron metabolism in CKD. Its physiological role remains to be elucidated. PMID- 29134617 TI - Vascular calcification is not related to serum fetuin-A and osteopontin levels in hemodialysis patients. AB - INTRODUCTION: Vascular calcification (VC) in hemodialysis (HD) patients is a sign of severe cardiovascular disease and can predict cardiovascular outcomes. Fetuin A and osteopontin (OPN) inhibit VC. Serum fetuin-A levels are lower in patients with end-stage kidney disease (ESKD) and in those who are on chronic HD therapy. However, there are limited data concerning OPN in patients who are on dialysis. The aim of our study was to determine VC in HD patients, the relationship between VC and 25-OH-vitamin D, fetuin-A, and OPN levels, and independent predictors of VC. MATERIALS AND METHODS: Ninety-three patients with ESKD on HD therapy were recruited. Among these patients, 44 were male and 49 were female. The patient group was compared with a group of 20 healthy controls of similar age and sex. A plain radiograph of the hand was taken using a mammography machine for the evaluation of VC. Serum fetuin-A, OPN, and 25-OH-vitamin D levels of both patients and controls were measured. RESULTS: VC was detected in 45 (48.4%) HD patients. When patients were compared with healthy controls, fetuin-A levels (p < 0.029) were significantly lower in patients, whereas OPN (p < 0.000) and VC (p < 0.002) were significantly higher in the patient group. Age [odds ratio (OR) 1.036], the presence of diabetes mellitus (DM) (OR 17.527), and high parathyroid hormone (PTH) levels (OR 1.002) were independent predictors of VC in a logistic regression model including the following factors: age, the presence of DM, HD duration, and serum albumin, phosphate, PTH, 25-OH-vitamin D, fetuin-A, OPN, and calcium levels. No significant correlation was found between patients with VC and patients without VC in terms of fetuin-A, OPN, and 25-OH-vitamin D levels. CONCLUSIONS: VC is a frequent sign in patients undergoing HD and is not related to serum fetuin-A and osteopontin levels. Age, the presence of DM, and high PTH levels were independent predictors of VC in patients undergoing HD. Further studies are warranted to understand the mechanism underlying and the factors contributing to VC. PMID- 29134619 TI - Complete Acid-Based Hydrolysis Assay for Carbohydrate Quantification in Seaweed: A Species-Specific Optimized Approach. AB - Accurate quantification of the carbohydrate content of biomass is crucial for many bio-refining processes. The most commonly followed protocol is typically a modification of the NREL-based assay (specifically designed for carbohydrate analysis from lignocellulosic biomass). However, this NREL protocol was revealed to be excessively thermochemically harsh for seaweed biomass. This can result in erroneously low total sugar quantification as the reaction severity can degrade a proportion of the liberated sugars to decomposition products such as furans. Here we describe an optimization of the total acid hydrolysis protocol for accurate quantification of the carbohydrate content of seaweeds. Different species of seaweed can be accurately evaluated for their carbohydrate contents by following this optimized method. PMID- 29134620 TI - Pre-residency publication and its association with paediatric residency match outcome-a retrospective analysis of a national database. AB - INTRODUCTION: Scholarly activity is considered valuable in the resident selection process by candidates and program directors alike, despite existing literature suggesting applicants with scholarly work do not perform better in the match. These studies, however, are limited in that they have only measured whether candidates have successfully matched or not. To try and reconcile the existing disconnect in the value of pre-residency scholarly activity, we sought to deepen the understanding by investigating whether pre-residency publication is associated with a higher rank-order list match achievement. METHODS: Anonymized data were collected from the Canadian Residency Matching Service for individuals matched to paediatric programs from 2007-2012. The primary analysis was to identify whether documentation of >=1 pre-residency publication was associated with achieving a first-choice match. Secondary analyses included evaluating for an association between multiple pre-residency publications, academic presentations or a graduate degree and match outcome. RESULTS: Of a total of 843 matched individuals, 406 (48.2%) listed >=1 pre-residency publication and 494 (58.6%) matched to their first-choice program. The possession of >=1 pre residency publications was not associated with matching to a candidate's first choice program (odds ratio = 0.94 [95% confidence interval = 0.71-1.24], p = 0.66). Similarly, listing >=2 publications, >=3 publications, a graduate degree, or an academic presentation was not associated with achieving a first-choice match. CONCLUSIONS: The results provide increased support for the notion that in aggregate, candidate scholarly activity does not influence match outcome. Accordingly, it is recommended that medical student research activities are fostered with the goal to improve their skills as scientists, and not simply to achieve a better residency match outcome. PMID- 29134621 TI - Replication of Mini-Sentinel Study Assessing Mirabegron and Cardiovascular Risk in Non-Mini-Sentinel Databases. AB - BACKGROUND: In 2014, the US Food and Drug Administration (FDA) initiated a prospective routine surveillance using the Mini-Sentinel (M-S) program to assess potential signals of acute myocardial infarction (AMI) and stroke with use of mirabegron, indicated for the treatment of overactive bladder (OAB), compared with oxybutynin. PURPOSE: To replicate the FDA M-S analysis of mirabegron using datasets that did not contribute to the M-S program. METHODS: IMS PharMetrics Plus and Truven MarketScan claims data from 2012-2015 were converted to the M-S Common Data Model. New and non-new users of mirabegron and oxybutynin were analyzed per the publicly available M-S protocol, and propensity score-matched 1:1 using the M-S PROMPT 2 module. Incidence rates (IR) were calculated per 1000 person-years (PY). Adjusted hazard ratios (aHRs) for mirabegron versus oxybutynin were calculated using Cox regression models. RESULTS: In PharMetrics, 12,429 new mirabegron users and 61,548 new oxybutynin users were identified. The aHR was 0.67 (95% confidence interval (CI)] 0.33-1.37) for AMI (mirabegron IR 4.4/1000 PY), and 0.62 (95% CI 0.34-1.13) for stroke (mirabegron IR 6.3/1000 PY). In MarketScan, 17,182 new mirabegron users and 63,962 new oxybutynin users were identified. The aHR was 0.57 (95% CI 0.17-1.95) for AMI, and 0.69 (95% CI 0.30 1.62) for stroke; IRs were similar to those from PharMetrics. Neither dataset suggested an increased risk of AMI or stroke associated with mirabegron in non new users. CONCLUSIONS: Using the publicly-available M-S protocol and analysis programs with alternative (non M-S) data sources, no statistically significant increased risk of AMI or stroke was found among new or non-new users of mirabegron compared with oxybutynin. These findings were consistent with the FDA M-S mirabegron study. PMID- 29134622 TI - Development of Gender Typicality and Felt Pressure in European French and North African French Adolescents. AB - Trajectories of gender identity were examined from Grade 6 (Mage = 11.9 years) to Grade 9 in European French (n = 570) and North African French (n = 534) adolescents, and gender and ethnic group differences were assessed in these trajectories. In Grade 6, boys of both ethnic groups reported higher levels of gender typicality and felt pressure for gender conformity than girls. European French girls and boys and North African French girls reported decreasing gender typicality from Grade 6 to Grade 9, whereas North African French boys did not change. Felt pressure decreased among girls, did not change in European French boys, and increased in North African French boys. Ethnic and gender differences in gender identity development are discussed. PMID- 29134618 TI - The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis. AB - Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important. PMID- 29134624 TI - Challenges for Training Translational Researchers in the Era of Ubiquitous Data. AB - Our ability to collect data at every stage of the translational pipeline creates great opportunities for formulating hypotheses both "upstream" (towards clinical implementation) and "downstream" (back to basic discovery). Translational researchers therefore must integrate information at multiple scales to both generate and test hypotheses-to some extent they must all be comfortable with the basics of "big data" analyses. This increased focus on data-driven science requires an understanding of basic experimental and clinical data collection understanding that likely cannot efficiently be gathered through traditional apprenticeship models. Thus, new curricula are required to ensure that next generation scientists have a new combination of skills required for integrating data to catalyze discovery. PMID- 29134623 TI - Repeated evolution and reversibility of self-fertilization in the volvocine green algae. AB - Outcrossing and self-fertilization are fundamental strategies of sexual reproduction, each with different evolutionary costs and benefits. Self fertilization is thought to be an evolutionary "dead-end" strategy, beneficial in the short term but costly in the long term, resulting in self-fertilizing species that occupy only the tips of phylogenetic trees. Here, we use volvocine green algae to investigate the evolution of self-fertilization. We use ancestral-state reconstructions to show that self-fertilization has repeatedly evolved from outcrossing ancestors and that multiple reversals from selfing to outcrossing have occurred. We use three phylogenetic metrics to show that self-fertilization is not restricted to the tips of the phylogenetic tree, a finding inconsistent with the view of self-fertilization as a dead-end strategy. We also find no evidence for higher extinction rates or lower speciation rates in selfing lineages. We find that self-fertilizing species have significantly larger colonies than outcrossing species, suggesting the benefits of selfing may counteract the costs of increased size. We speculate that our macroevolutionary results on self-fertilization (i.e., non-tippy distribution, no decreased diversification rates) may be explained by the haploid-dominant life cycle that occurs in volvocine algae, which may alter the costs and benefits of selfing. PMID- 29134625 TI - The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. AB - The Human Cytochrome P450 (CYP) Allele Nomenclature Database, a critical resource for the pharmacogenetics and genomics communities, has transitioned to the Pharmacogene Variation (PharmVar) Consortium. In this report we provide a summary of the current database, provide an overview of the PharmVar consortium, and highlight the PharmVar database which will serve as the new home for pharmacogene nomenclature. PMID- 29134626 TI - Proton Pump Inhibitor Therapy and Dementia: What Is the Evidence? PMID- 29134627 TI - The evolution of genital shape variation in female cetaceans. AB - Male genital diversification is likely the result of sexual selection. Female genital diversification may also result from sexual selection, although it is less well studied and understood. Female genitalia are complex among whales, dolphins, and porpoises, especially compared to other vertebrates. The evolutionary factors affecting the diversity of vaginal complexity could include ontogeny, allometry, phylogeny, sexual selection, and natural selection. We quantified shape variation in female genitalia using 2D geometric morphometric analysis, and validated the application of this method to study soft tissues. We explored patterns of variation in the shape of the cervix and vagina of 24 cetacean species (n = 61 specimens), and found that genital shape varies primarily in the relative vaginal length and overall aspect ratio of the reproductive tract. Extensive genital shape variation was partly explained by ontogenetic changes and evolutionary allometry among sexually mature cetaceans, whereas phylogenetic signal, relative testis size, and neonate size were not significantly associated with genital shape. Female genital shape is diverse and evolves rapidly even among closely related species, consistent with predictions of sexual selection models and with findings in invertebrate and vertebrate taxa. Future research exploring genital shape variation in 3D will offer new insights into evolutionary mechanisms because internal vaginal structures are variable and can form complex spirals. PMID- 29134628 TI - Considerations About the Use of Biomarkers in Cancer Clinical Trials. AB - The rapid evolution of our understanding of cancer biology has affected every phase of patient management, from early detection to drug development and clinical management. Central to this issue is the challenge of using biomarkers to identify the driving mutations present and identifiable by current assays in many tumors. These biomarkers are integral to the process of selecting patients for the testing of new drugs, many of which are specifically designed to inhibit oncogenic pathways. PMID- 29134629 TI - Proton Pump Inhibitor Use and Dementia Risk: Prospective Population-Based Study. AB - OBJECTIVES: To determine whether higher cumulative proton pump inhibitor (PPI) exposure is associated with greater dementia risk. DESIGN: Prospective population based cohort study. SETTING: Kaiser Permanente Washington, an integrated healthcare delivery system in Seattle, Washington. PARTICIPANTS: Individuals aged 65 and older without dementia at study entry (N = 3,484). MEASUREMENTS: Participants were screened for dementia every 2 years, and those who screened positive underwent extensive evaluation. Dementia outcomes were determined using standard diagnostic criteria. Time-varying PPI exposure was determined from computerized pharmacy data and consisted of total standardized daily doses (TSDDs) dispensed to an individual in the prior 10 years. We also assessed duration of use. Multivariable Cox regression was used to estimate the association between PPI exposure and time to dementia or Alzheimer's disease (AD). RESULTS: Over a mean follow-up of 7.5 years, 827 participants (23.7%) developed dementia (670 with possible or probable AD). PPI exposure was not associated with risk of dementia (P = .66) or AD (P = .77). For dementia, the risk for specific levels of cumulative exposure compared to no use was: 365 TSDDs (HR 0.87, 95% CI 0.65-1.18), 1,095 TSDDs (HR 0.99, CI 0.75-1.30) and 1,825 TSDDs (HR 1.13, CI 0.82-1.56). These TSDD levels represent approximately 1, 3 and 5 years of daily use respectively. Duration of PPI use was not associated with dementia outcomes either. CONCLUSION: Proton pump inhibitor use was not associated with dementia risk, even for people with high cumulative exposure. Although there are other safety concerns with long-term PPI use, results from our study do not support that these medications should be avoided out of concern about dementia risk. PMID- 29134630 TI - Successful Community Discharge Following Postacute Rehabilitation for Medicare Beneficiaries: Analysis of a Patient-Centered Quality Measure. AB - OBJECTIVE: To determine the sociodemographic and clinical characteristics as well as health services use associated with successful community discharge. DATA SOURCE: Inpatient Rehabilitation Facility-Patient Assessment Instrument and Medicare Provider Analysis and Review files. STUDY DESIGN: We retrospectively examined 167,664 Medicare beneficiaries discharged from inpatient rehabilitation facilities (IRFs) in 2013 to determine the sociodemographic and clinical characteristics as well as health services use associated with successful community discharge. PRINCIPAL FINDINGS: In the multivariable model, sociodemographic (younger age, no disability, social support), clinical (higher motor and cognitive functional status at admission), and health services use (fewer acute care days and longer IRF days) variables were associated with successful community discharge. CONCLUSIONS: Remaining in the community is an important patient-centered outcome that could complement other postacute rehabilitation quality measures. PMID- 29134631 TI - Microbial expansion-collision dynamics promote cooperation and coexistence on surfaces. AB - Microbes colonizing a surface often experience colony growth dynamics characterized by an initial phase of spatial clonal expansion followed by collision between neighboring colonies to form potentially genetically heterogeneous boundaries. For species with life cycles consisting of repeated surface colonization and dispersal, these spatially explicit "expansion-collision dynamics" generate periodic transitions between two distinct selective regimes, "expansion competition" and "boundary competition," each one favoring a different growth strategy. We hypothesized that this dynamic could promote stable coexistence of expansion- and boundary-competition specialists by generating time varying, negative frequency-dependent selection that insulates both types from extinction. We tested this experimentally in budding yeast by competing an exoenzyme secreting "cooperator" strain (expansion-competition specialists) against nonsecreting "defectors" (boundary-competition specialists). As predicted, we observed cooperator-defector coexistence or cooperator dominance with expansion-collision dynamics, but only defector dominance otherwise. Also as predicted, the steady-state frequency of cooperators was determined by colonization density (the average initial cell-cell distance) and cost of cooperation. Lattice-based spatial simulations give good qualitative agreement with experiments, supporting our hypothesis that expansion-collision dynamics with costly public goods production is sufficient to generate stable cooperator defector coexistence. This mechanism may be important for maintaining public goods cooperation and conflict in microbial pioneer species living on surfaces. PMID- 29134632 TI - Heterogeneous Relationships between Labor Income and Health by Race/Ethnicity. AB - OBJECTIVE: To examine the race-stratified relationships between labor income and health among working-age adults in the United States. DATA SOURCES: Data from eight waves of the Panel Study of Income Dynamics from 1999 through 2013 were used for this study. STUDY DESIGN: The study utilized a retrospective observational longitudinal design with repeated measures of labor income and health measures. System-generalized method of moment and heteroscedasticity-based instrument regressions were used to examine the relationships between labor income and physical and mental health measures, respectively. Dynamic panel models were used to examine the effect of loss in income on health measures. DATA COLLECTION/EXTRACTION METHODS: We performed secondary data analysis. PRINCIPAL FINDINGS: Adults in higher labor income quartiles had better self-rated health than those in the lowest quartile regardless of racial group. The relationship between labor income and psychological distress varied by race groups. Reductions in labor income were associated with increases in psychological distress among whites only. CONCLUSION: These findings suggest heterogeneous relationships between labor income and overall health across racial groups. Our results highlight the need to provide safety nets for adults who experience a decline in income to prevent deterioration in health. PMID- 29134633 TI - First-in-Human Study With the Inhaled TLR9 Oligonucleotide Agonist AZD1419 Results in Interferon Responses in the Lung, and Is Safe and Well-Tolerated. AB - Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll-like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long-term disease modification. We present the nonclinical data and phase I clinical profile of an inhaled TLR9 agonist, AZD1419, a C-type CpG designed to induce interferon in the lung. In healthy volunteers, AZD1419 was found to be safe and well-tolerated. Target engagement in the lung was demonstrated at all dose levels tested. No evidence of tolerization or amplification of responses was evident on repeated dosing and 15.4 mg was defined as the maximum tolerated dose. AZD1419 clinical data supports its continued development as a potentially disease modifying therapeutic in asthma. PMID- 29134634 TI - Commentary on "The Universally Unrecognized Assumption in Predicting Drug Clearance and Organ Extraction Ratio". AB - Among pharmacokinetic concepts, clearance has been the most widely applied in clinical pharmacology and drug development. With so much written on the subject it might be thought that there is nothing more to say. So it is noteworthy that some basic aspects related to hepatic clearance, and specifically the most popular model, the well-stirred model, have been challenged by Benet et al. This commentary examines the challenge and provides our views. PMID- 29134635 TI - Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations. AB - Ribociclib (KISQALI), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2- advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) of clinical trial data, and 4) population PK (PopPK) analysis. This multipronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH-altering agents on the absorption of ribociclib, without a dedicated drug-drug interaction trial. The bioequivalence of ribociclib exposure with or without a high-fat meal was demonstrated in a clinical trial. Lack of restrictions on ribociclib dosing may facilitate better patient compliance and therefore clinical benefit. PMID- 29134636 TI - Expanding Role of Data Science and Bioinformatics in Drug Discovery and Development. AB - Numerous barriers have been identified which detract from successful applications of clinical trial data and platforms. Despite the challenges, opportunities are growing to advance compliance, quality, and practical applications through top down establishment of guiding principles, coupled with bottom-up approaches to promote data science competencies among data producers. Recent examples of successful applications include modern treatments for hematologic malignancies, developed with support from public-private partnerships, guiding principles for data-sharing, standards for protocol designs and data management, digital technologies, and quality analytics. PMID- 29134637 TI - An ERCC4 regulatory variant predicts grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy. AB - Platinum-based chemotherapy (PBC) in combination with the 3rd generation drugs is the first-line treatment for patients with advanced non-small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3-4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum-induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two-phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR)adj =1.61 and 2.35, 95% confidence interval (CI)=1.11-2.33 and 1.25-4.41, and Padj =0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57-0.65 vs. 0.55-0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment. PMID- 29134639 TI - Methods for second primary cancer evaluation have to be standardized. PMID- 29134638 TI - Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain. AB - BACKGROUND AND PURPOSE: Acid-sensing ion channels (ASICs) are primary acid sensors in mammals, with the ASIC1b and ASIC3 subtypes being involved in peripheral nociception. The antiprotozoal drug diminazene is a moderately potent ASIC inhibitor, but its analgesic activity has not been assessed. EXPERIMENTAL APPROACH: We determined the ASIC subtype selectivity of diminazene and the mechanism by which it inhibits ASICs using voltage-clamp electrophysiology of Xenopus oocytes expressing ASICs 1-3. Its peripheral analgesic activity was then assessed relative to APETx2, an ASIC3 inhibitor, and morphine, in a Freund's complete adjuvant (FCA)-induced rat model of inflammatory pain. KEY RESULTS: Diminazene inhibited homomeric rat ASICs with IC50 values of ~200-800 nM, via an open channel and subtype-dependent mechanism. In rats with FCA-induced inflammatory pain in one hindpaw, diminazene and APETx2 evoked more potent peripheral antihyperalgesia than morphine, but the effect was partial for APETx2. APETx2 potentiated rat ASIC1b at concentrations 30-fold to 100-fold higher than the concentration inhibiting ASIC3, which may have implications for its use in in vivo experiments. CONCLUSIONS AND IMPLICATIONS: Diminazene and APETx2 are moderately potent ASIC inhibitors, both inducing peripheral antihyperalgesia in a rat model of chronic inflammatory pain. APETx2 has a more complex ASIC pharmacology, which must be considered when it is used as a supposedly selective ASIC3 inhibitor in vivo. Our use of outbred rats revealed responders and non responders when ASIC inhibition was used to alleviate inflammatory pain, which is aligned with the concept of number-needed-to-treat in human clinical studies. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 29134641 TI - Molecular Tumor Boards: Realizing Precision Oncology Therapy. AB - Technological advances in high-throughput next-generation sequencing (NGS) along with advances in computational processes have brought about the dawn of the genomic medicine era. NGS has enabled molecular characterization of malignancies, and facilitated the development and approval of gene- and immune-targeted therapies, both of which impact the mutanome. Clinical implementation of this technology, approval of novel targeted agents, and establishment of molecular tumor boards has enabled precision oncology to become a reality. PMID- 29134640 TI - Reduced IL-6 levels and tumor-associated phospho-STAT3 are associated with reduced tumor development in a mouse model of lung cancer chemoprevention with myo-inositol. AB - Several promising chemopreventive agents have for lung cancer emerged in preclinical models and in retrospective trials. These agents have been shown to modulate pathways altered in carcinogenesis and reduce markers of carcinogenesis in animal and cell culture models. Cancer-prone transgenic mice with oncogenic Kras expressed in the airway epithelium (CcspCre/+ ; KrasLSL-G12D/+ ) were raised on diets compounded with myo-inositol. These animals form lung premalignant lesions in a stereotypical fashion over the ten weeks following weaning. Mice raised on myo-inositol containing diets showed potent reduction in the number, size, and stage of lesions as compared to those raised on control diets. myo inositol has previously been reported to inhibit phosphoinositide 3-kinase (PI3K) signaling. However, in mice raised on myo-inositol, total PI3K signaling was largely unaffected. Proteomic and cytokine analyses revealed large reduction in IL-6 related pathways, including STAT3 phosphorylation. This effect was not due to direct inhibition of IL-6 production and autocrine signaling within the tumor cell, but rather through alteration in macrophage recruitment and in phenotype switching, with an increase in antitumoral M1 macrophages. PMID- 29134643 TI - Corrigendum. PMID- 29134644 TI - DMCN 2017 highlights: advances in cerebral palsy, encephalitis, paediatric stroke, and more. PMID- 29134645 TI - The yin and yang of clinical research. PMID- 29134647 TI - Serial profiling of circulating tumor DNA for optimization of anti-VEGF chemotherapy in metastatic colorectal cancer patients. AB - Understanding the molecular changes in tumors in response to anti-VEGF chemotherapy is crucial for optimization of the treatment strategy for metastatic colorectal cancer. We prospectively investigated changes in the amount and constitution of circulating tumor DNA (ctDNA) in serial peripheral blood samples during chemotherapy. Sixty-one plasma samples taken at different time points (baseline, remission, and post-progression) and pre-treatment tumor samples were collected from 21 patients who received bevacizumab-containing first-line chemotherapy. Extracted DNA was sequenced by next-generation sequencing using a panel of 90 oncogenes. Candidate ctDNAs in plasma were validated using mutational data from matching tumors. ctDNAs encoding one to six trunk mutations were found in all 21 cases, and the mutant allele frequency (MAF) was distributed over a wide range (1-89%). Significant decreases in the MAF at remission and increases in the MAF after progression were observed (p < 0.001). Reduction in the MAF to below 2% in the remission period was strongly associated with better survival (16.6 vs. 32.5 months, p < 0.001). In two cases, mutations (in CREBBP and FBXW7 genes) were newly detected in ctDNA at a low frequency of around 1% in the post progression period. The use of ctDNA allows elucidation of the tumor clonal repertoire and tumor evolution during anti-VEGF chemotherapy. Changes in ctDNA levels could be useful as predictive biomarkers for survival. Mutations newly detected in ctDNA in the late treatment period might reveal the rise of a minor tumor clone that may show resistance to anti-VEGF therapy. PMID- 29134648 TI - Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients. AB - Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the concentration-vs.-time curve was 2,388 nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies. PMID- 29134649 TI - Response: Methods for second primary cancers evaluation have to be standardized. PMID- 29134650 TI - Thyroid-associated genetic polymorphisms in relation to breast cancer risk in the Malmo Diet and Cancer Study. AB - Previous studies have suggested that thyroid function is associated with breast cancer risk, which could have an important clinical impact, as one in eight women will develop a thyroid disorder during her lifetime. However, the underlying pathomechanism behind the association is still unknown. We used the Malmo Diet and Cancer Study (a population-based prospective study consisting of 17,035 women) to examine 17 single nucleotide polymorphisms (SNPs) previously related to levels of free thyroxine (free T4) and thyroid peroxidase antibodies (TPO-Ab) as potential genetic risk factors for breast cancer. A baseline examination including free T4 and TPO-Ab levels was conducted at the time of inclusion. Genotyping was performed on 901 breast cancer patients and 3335 controls. Odds ratios (95% confidence intervals) for high free T4, TPO-Ab positivity, and breast cancer were calculated by logistic regression and adjusted for confounders. We identified one free T4-related SNP (rs2235544, D101 gene) that was significantly associated with both free T4 level and breast cancer risk. There was a suggested association between rs11675434 (TPO gene) and TPO-Ab level, and TPO-Ab-related rs11675434 (TPO), rs3094228 (HCP5), rs1033662 (no registered gene), and rs301806 (RERE) were associated with breast cancer risk. There was an indicated interaction between rs6485050 (no registered gene) and free T4 level in regards to breast cancer risk. This is the first study to suggest an association between thyroid-related SNPs and breast cancer risk. All SNPs have a biological plausibility of being associated with breast cancer risk, and may contribute to the genetic predisposition to breast cancer. PMID- 29134651 TI - Heavy metal contamination, microbiological spoilage and biogenic amine content in sushi available on the Polish market. AB - BACKGROUND: The present study determined the heavy metal contamination (mercury, cadmium, lead, arsenic and nickel) of nori, restaurant-served sushi and ready-to eat sushi meals available via retail chains. Moreover, both microbiological load and biogenic amine content in ready-to-eat sushi meals were analysed. RESULTS: All of the nori samples contained high levels of Cd (2.122 mg kg-1 ), Ni (0.715 mg kg-1 ), As (34.56 mg kg-1 ) and Pb (0.659 mg kg-1 ). The studied sushi samples contained high levels of Ni and Pb, reaching 0.194 and 0.142 mg kg-1 wet weight, respectively, being potentially hazardous to women during pregnancy and lactation and small children. None of the studied samples contained high levels of Hg. Overall, 37% of ready-to-eat sushi meals exceeded a microbiological load of 106 cfu g-1 . However, biogenic amine content in all of the samples was low, with a highest histamine content of 2.05 mg kg-1 . CONCLUSION: Sushi is not the source of high levels of biogenic amines even with high microbiological loads. Nevertheless, the high microbiological loads at the end of the shelf-life indicate that some processors might have problems with the distribution chain or implement a poor hygienic regime. Moreover as a result of possible risk associated with heavy metal contamination, the present study highlights the need to establish new regulations regarding the contamination of nori and sushi. (c) 2017 Society of Chemical Industry. PMID- 29134652 TI - An overview of polyamine metabolism in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest major cancers, with a five year survival rate of less than 8%. With current therapies only giving rise to modest life extension, new approaches are desperately needed. Even though targeting polyamine metabolism is a proven anticancer strategy, there are no reports, which thoroughly survey the literature describing the role of polyamine biosynthesis and transport in PDAC. This review seeks to fill this void by describing what is currently known about polyamine metabolism in PDAC and identifies new targets and opportunities to treat this disease. Due to the pleiotropic effects that polyamines play in cells, this review covers diverse areas ranging from polyamine metabolism (biosynthesis, catabolism and transport), as well as the potential role of polyamines in desmoplasia, autophagy and immune privilege. Understanding these diverse roles provides the opportunity to design new therapies to treat this deadly cancer via polyamine depletion. PMID- 29134653 TI - Association between environmental factors including second-hand smoke and primary lung cancer in dogs. AB - OBJECTIVES: To estimate prevalence of exposure to environmental tobacco smoke and other environmental toxins in dogs with primary lung tumours and to analyse association between exposure and lung tumour development. MATERIALS AND METHODS: In this case-control study, an owner survey was developed to collect data on patient characteristics, general health care and environmental exposures. Dogs diagnosed with primary lung carcinomas formed the Case group. Dogs diagnosed with mast cell tumours served as Control Group 1 and dogs diagnosed with neurologic disease served as Control Group 2. Associations between diagnosis of primary lung tumour and patient and environmental exposure variables were analysed using bivariate and multivariate statistical methods. RESULTS: A total of 1178 owner surveys were mailed and 470 surveys were returned and included in statistical analysis, including 135 Cases, 169 dogs in Control Group 1 and 166 dogs in Control Group 2. An association between exposure to second-hand smoke and prevalence of primary lung cancer was not identified in this study. CLINICAL SIGNIFICANCE: Second-hand smoke is associated with primary lung cancer in people but a definitive association has not been found in dogs. The results of this study suggest that tobacco smoke exposure may not be associated with primary lung cancer development in dogs but study limitations may have precluded detection of an association. PMID- 29134655 TI - Protein components of post-synaptic density lattice, a backbone structure for type I excitatory synapses. AB - It is essential to study the molecular architecture of post-synaptic density (PSD) to understand the molecular mechanism underlying the dynamic nature of PSD, one of the bases of synaptic plasticity. A well-known model for the architecture of PSD of type I excitatory synapses basically comprises of several scaffolding proteins (scaffold protein model). On the contrary, 'PSD lattice' observed through electron microscopy has been considered a basic backbone of type I PSDs. However, major constituents of the PSD lattice and the relationship between the PSD lattice and the scaffold protein model, remain unknown. We purified a PSD lattice fraction from the synaptic plasma membrane of rat forebrain. Protein components of the PSD lattice were examined through immuno-gold negative staining electron microscopy. The results indicated that tubulin, actin, alpha-internexin, and Ca2+ /calmodulin-dependent kinase II are major constituents of the PSD lattice, whereas scaffold proteins such as PSD-95, SAP102, GKAP, Shank1, and Homer, were rather minor components. A similar structure was also purified from the synaptic plasma membrane of forebrains from 7-day-old rats. On the basis of this study, we propose a 'PSD lattice-based dynamic nanocolumn' model for PSD molecular architecture, in which the scaffold protein model and the PSD lattice model are combined and an idea of dynamic nanocolumn PSD subdomain is also included. In the model, cytoskeletal proteins, in particular, tubulin, actin, and alpha-internexin, may play major roles in the construction of the PSD backbone and provide linker sites for various PSD scaffold protein complexes/subdomains. PMID- 29134654 TI - PTEN loss and activation of K-RAS and beta-catenin cooperate to accelerate prostate tumourigenesis. AB - Aberrant phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and WNT signalling are emerging as key events in the multistep nature of prostate tumourigenesis and progression. Here, we report a compound prostate cancer murine model in which these signalling pathways cooperate to produce a more aggressive prostate cancer phenotype. Using Cre-LoxP technology and the probasin promoter, we combined the loss of Pten (Ptenfl/fl ), to activate the PI3K signalling pathway, with either dominant stabilized beta-catenin [Catnb+/lox(ex3) ] or activated K-RAS (K-Ras+/V12 ) to aberrantly activate WNT and MAPK signalling, respectively. Synchronous activation of all three pathways (triple mutants) significantly reduced survival (median 96 days) as compared with double mutants [median: 140 days for Catnb+/lox(ex3) Ptenfl/fl ; 182 days for Catnb+/lox(ex3) K-Ras+/V12 ; 238 days for Ptenfl/fl K-Ras+/V12 ], and single mutants [median: 383 days for Catnb+/lox(ex3) ; 407 days for Ptenfl/fl ], reflecting the accelerated tumourigenesis. Tumours followed a stepwise progression from mouse prostate intraepithelial neoplasia to invasive adenocarcinoma, similar to that seen in human disease. There was significantly elevated cellular proliferation, tumour growth and percentage of invasive adenocarcinoma in triple mutants as compared with double mutants and single mutants. Triple mutants showed not only activated AKT, extracellular-signal regulated kinase 1/2, and nuclear beta-catenin, but also significantly elevated signalling through mechanistic target of rapamycin complex 1 (mTORC1). In summary, we show that combined deregulation of the PI3K, MAPK and WNT signalling pathways drives rapid progression of prostate tumourigenesis, and that deregulation of all three pathways results in tumours showing aberrant mTORC1 signalling. As mTORC1 signalling is emerging as a key driver of androgen deprivation therapy resistance, our findings are important for understanding the biology of therapy-resistant prostate cancer and identifying potential approaches to overcome this. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29134656 TI - Long-term, dynamic synaptic reorganization after GABAergic precursor cell transplantation into adult mouse spinal cord. AB - Transplanting embryonic precursors of GABAergic neurons from the medial ganglionic eminence (MGE) into adult mouse spinal cord ameliorates mechanical and thermal hypersensitivity in peripheral nerve injury models of neuropathic pain. Although Fos and transneuronal tracing studies strongly suggest that integration of MGE-derived neurons into host spinal cord circuits underlies recovery of function, the extent to which there is synaptic integration of the transplanted cells has not been established. Here, we used electron microscopic immunocytochemistry to assess directly integration of GFP-expressing MGE-derived neuronal precursors into dorsal horn circuitry in intact, adult mice with short- (5-6 weeks) or long-term (4-6 months) transplants. We detected GFP with pre embedding avidin-biotin-peroxidase and GABA with post-embedding immunogold labeling. At short and long times post-transplant, we found host-derived synapses on GFP-immunoreactive MGE cells bodies and dendrites. The proportion of dendrites with synaptic input increased from 50% to 80% by 6 months. In all mice, MGE derived terminals formed synapses with GFP-negative (host) cell bodies and dendrites and, unexpectedly, with some GFP-positive (i.e., MGE-derived) dendrites, possibly reflecting autoapses or cross talk among transplanted neurons. We also observed axoaxonic appositions between MGE and host terminals. Immunogold labeling for GABA confirmed that the transplanted cells were GABAergic and that some transplanted cells received an inhibitory GABAergic input. We conclude that transplanted MGE neurons retain their GABAergic phenotype and integrate dynamically into host-transplant synaptic circuits. Taken together with our previous electrophysiological analyses, we conclude that MGE cells are not GABA pumps, but alleviate pain and itch through synaptic release of GABA. PMID- 29134657 TI - Mechanisms involved in hemoglobin-mediated oxidation of lipids in washed fish muscle and inhibitory effects of phospholipase A2. AB - BACKGROUND: Hemoglobin (Hb) is a lipid oxidation promoter in fish muscle. Phospholipase A2 (PLA2; EC 3.1.1.4) is linked to an increased resistance to lipid oxidation of frozen-thawed cod fillets via an unknown mechanism. The present study aimed to investigate the mechanism of Hb-mediated lipid oxidation with a focus on ferryl Hb and methemoglobin (metHb), the pro-oxidative Hb species, and to examine how porcine pancreatic PLA2 inhibits Hb-mediated lipid oxidation in washed cod muscle (WCM). Lipid hydroperoxides (LOOHs) and thiobarbituric acid reactive substances (TBARS) were measured as primary and secondary lipid oxidation products, respectively. The formation of metHb and ferryl Hb was also monitored. RESULTS: Ferryl Hb and metHb formed during the Hb-mediated lipid oxidation. PLA2 inhibited the formation of LOOHs and TBARS and suppressed the formation of metHb and ferryl Hb. WCM was pre-oxidized by hemin to increase the amount of LOOHs. PLA2 promoted the depletion of LOOHs in the pre-oxidized WCM with limited TBARS formation at the expense of the heme moiety of Hb. CONCLUSION: The results of the present study suggest that ferryl Hb may play a role in Hb mediated lipid oxidation and that PLA2 from pig pancreas may work together with Hb as a novel antioxidant with an ability to remove pre-formed LOOHs from a lipid substrate. (c) 2017 Society of Chemical Industry. PMID- 29134658 TI - "Best practice" for extracorporeal photopheresis in acute and chronic graft versus-host disease by Societa' Italiana di Emaferesi and Manipolazione Cellulare and Gruppo Italiano Trapianto Midollo Osseo: a national survey to ascertain its degree of application in Italian transplant centers. AB - BACKGROUND: A recent "best practice" promoted and published by Gruppo Italiano Trapianto Midollo Osseo (GITMO) and Societa' Italiana di Emaferesi and Manipolazione Cellulare (SIDEM) on the use of extracorporeal photopheresis (ECP) in acute and chronic graft-versus-host disease (GVHD) has been tested for the degree of agreement and application among Italian transplant centers. STUDY DESIGN AND METHODS: Twenty-four Italian centers coordinating a pair number of transplant programs completed the Web-based survey within the fixed deadline, representing approximately 52% of those centers that have a GITMO-accredited allogeneic transplant program that routinely uses ECP in GVHD. RESULTS: The level of full agreement was more than 85% for most of the answers given by the best practice (14 of 16) to the various issues. For the answers of two questions dealing with indications of ECP in acute GVHD and with safety and quality measures we observed a full agreement of 62 and 50%, respectively. CONCLUSION: This report shows a very good success of best practice among Italian centers, indicating that, after 3 years, it seems to be still updated and useful. More discussion has been observed for safety and quality measures and, likely, this issue deserves a dedicated focus on a future consensus report. PMID- 29134659 TI - Annual Research Review: The persistent and pervasive impact of being bullied in childhood and adolescence: implications for policy and practice. AB - BACKGROUND: We have known for some time that being bullied was associated with children's and adolescents' adjustment difficulties and well-being. In recent years, we have come to recognise that the impact of childhood bullying victimisation on the development of mental health problems is more complex. This paper aims to review the evidence for an independent contribution of childhood bullying victimisation to the development of poor outcomes throughout the life span, including mental, physical and socioeconomic outcomes, and discuss the implications for policy and practice. FINDINGS: Existing research indicates that (a) being bullied in childhood is associated with distress and symptoms of mental health problems. This large body of evidence supports actions aimed at reducing the occurrence of bullying behaviours; (b) the consequences of childhood bullying victimisation can persist up to midlife and, in addition to mental health, can impact physical and socioeconomic outcomes. These new findings indicate that interventions should also focus on supporting victims of bullying and helping them build resilience; (c) research has identified some factors that predispose children to be targeted by bullying behaviours. These studies suggest that public health interventions could aim at preventing children from becoming the target of bullying behaviours from an early age. CONCLUSIONS: It is a truism to emphasise that further work is needed to understand why and how young people's aspirations are often cut short by this all too common adverse social experience. In parallel, we must develop effective strategies to tackle this form of abuse and its consequences for the victims. Addressing bullying in childhood could not only reduce children's and adolescents' mental health symptoms but also prevent psychiatric and socioeconomic difficulties up to adulthood and reduce considerable costs for society. PMID- 29134660 TI - Reliability of CT measurement of induced radioulnar step in dogs using a circle superimposition technique. AB - OBJECTIVES: To evaluate the reliability of CT measurement of canine elbow axial radioulnar congruence using a duplicated circle superimposition technique. MATERIALS AND METHODS: CT of six cadaveric canine elbows was performed following either: (1) placement of an external fixator on the radius with ostectomy and radial shortening of 1 to 5 mm; (2) radial lengthening of 1 to 5 mm using a radial lengthening system; or, (3) no axial length adjustment. Four observers, on two occasions, blinded to the amount of radial adjustment, placed a circle of best fit of the ulnar trochlear notch on a sagittal image that was duplicated and transposed to the articular contour of the radial head; then the axial distance between circles relative to the dorsal radius was measured. Statistical analysis assessed differences between actual and observer-assessed radial length adjustment; inter-/intra-observer interclass correlation coefficients and sensitivity/specificity were calculated to evaluate measurement reliability. RESULTS: There was not a significant difference between actual and observer measures of radioulnar congruence. Inter- (intraclass correlation coefficient=0.98) and intra-observer reliability (intraclass correlation coefficient=0.94 to 0.99) were almost perfect for measurement of radioulnar incongruence when compared to the actual radial adjustment. A Bland-Altman plot revealed a 95% confidence interval range of -1.31 to 1.16 mm. Sensitivity and specificity were high for correct identification of congruent elbows and elbows with 1 or 2 mm incongruency. CLINICAL SIGNIFICANCE: The duplicated circle superimposition technique provides a simple and accurate means of assessing radioulnar axial incongruence. PMID- 29134662 TI - Dose capping of plerixafor in patients weighing more than 100 kg at one vial led to successful mobilization outcomes and significant cost savings. AB - BACKGROUND: Plerixafor is frequently used as an adjunct agent to improve mobilization of peripheral blood stem cells in many clinical settings. However, its high cost (>$8000 per single-use 24-mg vial) is a significant concern. The manufacturer-recommended dose is 0.24 mg/kg. Therefore, patients weighing more than 100 kg would require a second vial, thus doubling the drug cost per dose. We implemented a policy of capping the dose of plerixafor at 24 mg, or one vial, for patients weighing more than 100 kg. This retrospective study compares the mobilization of patients more than 100 kg who received capped doses, with historical control patients who received full, uncapped doses. STUDY DESIGN AND METHODS: Consecutive, eligible patients weighing more than 100 kg who received capped (n = 47) and full doses of plerixafor (n = 40) were identified. Plerixafor was given up-front, as a rescue agent due to suboptimal mobilization, or during remobilization. Baseline characteristics and mobilization data were collected and compared. RESULTS: Patients in the two groups showed comparable baseline characteristics. They collected similar total numbers of CD34+ cells/kg (median, 4.08 * 106 vs. 3.36 * 106 CD34+ cells/kg; p = 0.86) and achieved comparable collection success rates as defined by collecting more than 2.0 * 106 CD34+ cells/kg (98% vs. 90%, p = 0.21). However, patients who received capped doses required only half of the number of vials of plerixafor (median, 3 vials vs. 6 vials; p < 0.0001). CONCLUSION: Dose capping plerixafor at 24 mg for patients more than 100 kg is a cost-effective strategy, which achieved comparable mobilization outcomes and reduced the total number of vials of plerixafor used by half. PMID- 29134661 TI - Regulation of TMEM16A/ANO1 and TMEM16F/ANO6 ion currents and phospholipid scrambling by Ca2+ and plasma membrane lipid. AB - KEY POINTS: TMEM16 proteins can operate as Ca2+ -activated Cl- channels or scramble membrane phospholipids, which are both highly relevant mechanisms during disease. Overexpression of TMEM16A and TMEM16F were found to be partially active at 37 degrees C and at resting intracellular Ca2+ concentrations. We show that TMEM16 Cl- currents and phospholipid scrambling can be activated by modification of plasma membrane phospholipids, through reactive oxygen species and phospholipase A2. While phospholipids and Cl- ions are likely to use the same pore within TMEM16F, TMEM16A only conducts Cl- ions. Lipid regulation of TMEM16 proteins is highly relevant during inflammation and regulated cell death such as apoptosis and ferroptosis. ABSTRACT: TMEM16/anoctamin (ANO) proteins form Ca2+ activated ion channels or phospholipid scramblases. We found that both TMEM16A/ANO1 and TMEM16F/ANO6 produced Cl- currents when activated by intracellular Ca2+ , but only TMEM16F was able to expose phosphatidylserine to the outer leaflet of the plasma membrane. Mutations within TMEM16F or TMEM16A/F chimeras similarly changed Cl- currents and phospholipid scrambling, suggesting the same intramolecular pathway for Cl- and phospholipids. When overexpressed, TMEM16A and TMEM16F produced spontaneous Cl- currents at 37 degrees C even at resting intracellular Ca2+ levels, which was abolished by inhibition of phospholipase A2 (PLA2 ). Connversely, activation of PLA2 or application of active PLA2 , as well as lipid peroxidation induced by reactive oxygen species (ROS) using staurosporine or tert-butyl hydroperoxide, enhanced ion currents by TMEM16A/F and in addition activated phospholipid scrambling by TMEM16F. Thus, TMEM16 proteins are activated by an increase in intracellular Ca2+ , or independent of intracellular Ca2+ , by modifications occurring in plasma and intracellular membrane phospholipids. These results may help to explain why regions distant to the TMEM16 pore and the Ca2+ binding sites control Cl- currents and phospholipid scrambling. Regulation of TMEM16 proteins through modification of membrane phospholipids occurs during regulated cell death such as apoptosis and ferroptosis. It contributes to inflammatory and nerve injury induced hypersensitivity and generation of pain and therefore provides a regulatory mechanism that is particularly relevant during disease. PMID- 29134663 TI - Multiple plasmid-borne virulence genes of Clavibacter michiganensis ssp. capsici critical for disease development in pepper. AB - Clavibacter michiganensis ssp. capsici is a Gram-positive plant-pathogenic bacterium causing bacterial canker disease in pepper. Virulence genes and mechanisms of C. michiganensis ssp. capsici in pepper have not yet been studied. To identify virulence genes of C. michiganensis ssp. capsici, comparative genome analyses with C. michiganensis ssp. capsici and its related C. michiganensis subspecies, and functional analysis of its putative virulence genes during infection were performed. The C. michiganensis ssp. capsici type strain PF008 carries one chromosome (3.056 Mb) and two plasmids (39 kb pCM1Cmc and 145 kb pCM2Cmc ). The genome analyses showed that this bacterium lacks a chromosomal pathogenicity island and celA gene that are important for disease development by C. michiganensis ssp. michiganensis in tomato, but carries most putative virulence genes in both plasmids. Virulence of pCM1Cmc -cured C. michiganensis ssp. capsici was greatly reduced compared with the wild-type strain in pepper. The complementation analysis with pCM1Cmc -located putative virulence genes showed that at least five genes, chpE, chpG, ppaA1, ppaB1 and pelA1, encoding serine proteases or pectate lyase contribute to disease development in pepper. In conclusion, C. michiganensis ssp. capsici has a unique genome structure, and its multiple plasmid-borne genes play critical roles in virulence in pepper, either separately or together. PMID- 29134665 TI - Mechanistic contributions of FBXO7 to Parkinson disease. AB - Parkinson disease (PD) is, without doubt, a burden on modern society as the prevalence increases significantly with age. Owing to this growing number of PD cases, it is more critical than ever to understand the pathogenic mechanisms underlying PD to identify therapeutic targets. The discovery of genetic mutations associated with PD and parkinsonism paves the way toward this goal. Even though, familial forms of the disease represent the minority of PD cases and some forms are so rare that there are only a few affected families, the research on the associated genes is invaluable. Recent additions to PARK mutations are those in PARK15 that encodes the F-box protein O-type 7 (FBXO7). In this review, we highlight the recent research on FBXO7, which advances our knowledge of the etiopathological pathways and fills unexpected gaps therein, justifying the dedicated study of rare variants of PD. PMID- 29134664 TI - A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. AB - Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28-day cycles for the first 3 cycles. Azacytidine 25 mg/m2 (Day 1 5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m2 (Days 1-5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts. Thirty five patients were treated (MDS/MPN-U, n =14; CMML, n =17; aCML, n =4), with a median follow-up of 15.2 months (range, 1.0-41.5). All patients were evaluable by the 2015 international consortium proposal of response criteria for MDS/MPNs (ICP MDS/MPN) and 20 (57%) responded. Nine patients (45%) responded after the addition of azacytidine. A greater than 50% reduction in palpable splenomegaly at 24 weeks was noted in 9/14 (64%) patients. Responders more frequently were JAK2-mutated (P = .02) and had splenomegaly (P = .03) compared to nonresponders. New onset grade 3/4 anemia and thrombocytopenia occurred in 18 (51%) and 19 (54%) patients, respectively, but required therapy discontinuation in only 1 (3%) patient. Patients with MDS/MPN-U had better median survival compared to CMML and aCML (26.5 vs 15.1 vs 8 months; P = .034). The combination of ruxolitinib and azacytidine was well-tolerated with an ICP MDS/MPN-response rate of 57% in patients with MDS/MPNs. The survival benefit was most prominent in patients with MDS/MPN-U. PMID- 29134666 TI - Children's understanding of multiplication and division: Insights from a pooled analysis of seven studies conducted across 7 years. AB - Research suggests that children's conceptual understanding of multiplication and division is weak and that it remains poor well into the later elementary school years. Further, children's understanding of fundamental concepts such as inversion and associativity does not improve as they progress from grades 6 to 8. Instead, some children simply possess strong understanding while others do not. Other studies have identified an increase across these grades. The present investigation analyses data from seven studies of Grade 6 (n = 226), Grade 7 (n = 221), and Grade 8 (n = 216) children's three-term problem-solving (e.g., 3 * 24 / 24 and 3 * 24 / 6) and provides a unified account of multiplication and division understanding, one in which grade differences and individual variability coexist and are moderated by sex. Statement of contribution What is already known on this subject? Children's conceptual understanding of multiplication and division is weak and it is unclear whether it increases across the key grades of 6-8. Understanding of the inversion and associativity concepts is characterized by high individual variability, but grade and sex have never been found to be a contributing factor. What does this study add? A meta-analysis of seven data sets (n = 643) indicates that grade differences and individual variability coexist and are moderated by sex. Understanding increases across grade only for boys, but an equal number of boys and girls are in the top 10% of conceptual problem-solvers. PMID- 29134667 TI - Synthesis and Carbonic Anhydrase Inhibition of Tetrabromo Chalcone Derivatives. AB - In the present study, human carbonic anhydrase (hCA) enzyme was purified and characterized from fresh blood human red cells by Sepharose-4B-l-tyrosine sulfanilamide affinity gel chromatography. Secondly, a series of new tetrabromo chalcone derivatives containing 4,7-methanoisoindol-1,3-dione (2a-i) were synthesized from the addition of Br2 to related chalcone derivatives (1a-i). The structures of the new molecules (2a-i) were confirmed by means of 1 H NMR, 13 C NMR and elemental analysis. Finally, the inhibitory effects of 2a-i on CA activities were investigated using the esterase method under in vitro conditions. The compounds 2a-i exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 11.30-21.22 nM against hCA I and in the range of 8.21-12.86 nM against hCA II. Our findings suggest that the new compounds 2a-i have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor, with obtained Ki values of 34.50 and 28.93 nM against the hCA I and II isozymes, respectively. In addition to the inhibition assays, molecular modeling approaches were implemented for prediction of the binding affinities of compounds 2a and 2c, which had the highest inhibition effects, against the hCA I and II isozymes. PMID- 29134668 TI - Factors affecting patient-reported outcomes after red blood cell transfusion in medical patients. AB - BACKGROUND: Physical variables like mortality or cardiac events were used to evaluate the requirement of red blood cell (RBC) transfusion. However, patient reported outcomes (PROs) of blood transfusion recipients were seldom assessed. The health-related quality of life (HRQoL) of patients before and after RBC transfusion was compared in this study. STUDY DESIGN AND METHODS: The study period was February to June 2016. Standardized generic and anemia symptom specific HRQoL instruments were administered to patients receiving RBC transfusion in the medical unit of a single center. The primary outcome was the change in HRQoL scores on Days 1 and 7 posttransfusion from baseline values on the day of transfusion (Day 0). Multiple linear regression analysis was performed to study the effect of transfusion strategy and other factors on PRO. RESULTS: The analysis included 99 general medical patients. The median (interquartile range) pretransfusion hemoglobin level was 72 (66-78) g/L. Two or more units of RBCs were prescribed to 45 patients (45%) on Day 0. Functional Assessment of Cancer Therapy-Anemia Subscale improved significantly on Days 1 and 7 by effect sizes of 0.41 and 0.38, respectively (p < 0.001). Regression analysis showed that lower baseline HRQoL scores were associated with better PRO on both Day 1 and Day 7 (p < 0.001). Transfusion trigger and number of RBC units transfused did not affect the change in HRQoL. CONCLUSION: Worse pretransfusion HRQoL is a predictor of improvement in PRO after blood transfusion. There is no evidence that a restrictive transfusion or single-unit policy jeopardizes PRO. PMID- 29134669 TI - Unique contribution of Ecuadorian kindergartners' spontaneous focusing on numerosity to their early numerical abilities. AB - Recent evidence indicates that young children's spontaneous focusing on numerosity (SFON) uniquely contributes to their early numerical abilities. This study complements previous findings by validating the relation between young children's SFON and their early numerical abilities in a developing country, namely Ecuador. We analysed 355 Ecuadorian 5- to 6-year-olds' SFON in relation to their early numerical abilities at the start of kindergarten, controlling for children's socio-demographic (socio-economic status, age) and general cognitive (working memory, intelligence) characteristics. Our results evidence the unique contribution of Ecuadorian kindergartners' SFON to their early numerical abilities, controlling for children's working memory, intelligence, socio economic status, and age. Our findings support the validity of previous findings on the unique contribution of SFON to young children's early numerical abilities in developed countries for developing countries. Additionally, they raise timely questions for further theoretical and methodological studies on young children's numerical development worldwide, in developing and developed countries. Statement of contribution What is already known? SFON uniquely contributes to early numerical abilities. However, this is only documented in Finnish samples. Previously only limited control for domain-general cognitive and socio demographic characteristics. What does the study add? SFON uniquely contributes to early numerical abilities in Ecuadorian 5- to 6-year-olds. This unique contribution remains after controlling for WM, IQ, SES, and age. Evidence for the universal nature of the association between SFON and early numerical ability. PMID- 29134670 TI - Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer. AB - BACKGROUND: Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. METHODS: Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. RESULTS: We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). CONCLUSIONS: Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis. PMID- 29134672 TI - Quantitative aspects of the ruminating process in giraffes (Giraffa camelopardalis) fed with different diets. AB - Giraffes are ruminants feeding on fresh browse and twigs in the wild, but in zoos, their diet is mainly based on alfalfa hay, grains, and pellets occasionally supplemented by twigs and foliage. These diets, which differ in composition and digestibility, affect the behavior of the animals, tooth wear patterns, and chewing efficiency. We quantified several parameters of the rumination process in ten zoo housed giraffes of different sexes and ages fed either with alfalfa hay, fresh browse, or a combination of both. Chewing during rumination was highly ritualized and specimens showed an even distribution of chewing directions during this process, which prevents uneven tooth wear and use of chewing muscles. During rumination of alfalfa hay, chewing cycles of the giraffes took on average 49 s and included 54 jaw movements compared to 37 s and 42 jaw movements during rumination of browse, respectively. Single jaw movements (measured as basic chewing rates) were on average significantly slower during rumination of alfalfa hay (alfalfa: 1.10 chews per second, browse: 1.17 chews per second) and intercycle times between two chewing cycles took significantly longer (alfalfa: 7.77 s, browse: 7.46 s). Our results clearly indicate that several rumination parameters are influenced by the type of diet. PMID- 29134671 TI - Macrophage roles in the clearance of apoptotic cells and control of inflammation in the prostate gland after castration. AB - BACKGROUND: Androgen deprivation results in massive apoptosis in the prostate gland. Macrophages are actively engaged in phagocytosing epithelial cell corpses. However, it is unknown whether microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis (LAP) is involved and contribute to prevent inflammation. METHODS: Flow cytometry, RT-PCR and immunohistochemistry were used to characterize the macrophage subpopulation residing in the epithelial layer of the rat ventral prostate (VP) after castration. Stereology was employed to determine variations in the number of ED1 and ED2. Mice were treated with either chloroquine or L-asparagine to block autophagy. RESULTS: M1 (iNOS-positive) and M2 macrophages (MRC1+ and ARG1+) were not found in the epithelium at day 5 after castration. The percentage of CD68+ (ED1) and CD163+ (ED2) phenotypes increased after castration but only CD68+ cells were present in the epithelium. RT-PCR showed increased content of the autophagy markers Bcl1 and LC3 after castration. In addition, immunohistochemistry showed the presence of LC3+ and ATG5+ cells in the epithelium. Double immunohistochemistry showed these cells to be CD68+ /LC3+ , compatible with the LAP phenotype. LC3+ cells accumulate significantly after castration. Chloroquine and L-asparagine administration caused inflammation of the glands at day 5 after castration. CONCLUSIONS: CD68+ macrophages phagocytose apoptotic cell corpses and activate the LAP pathway, thereby contributing to the preservation of a non-inflammed microenvironment. Marked inflammation was detected when autophagy blockers were administered to castrated animals. PMID- 29134673 TI - Modified dixon-based renal dynamic contrast-enhanced MRI facilitates automated registration and perfusion analysis. AB - PURPOSE: Renal dynamic contrast-enhanced (DCE) MRI provides information on renal perfusion and filtration. However, clinical implementation is hampered by challenges in postprocessing as a result of misalignment of the kidneys due to respiration. We propose to perform automated image registration using the fat only images derived from a modified Dixon reconstruction of a dual-echo acquisition because these provide consistent contrast over the dynamic series. METHODS: DCE data of 10 hypertensive patients was used. Dual-echo images were acquired at 1.5 T with temporal resolution of 3.9 s during contrast agent injection. Dixon fat, water, and in-phase and opposed-phase (OP) images were reconstructed. Postprocessing was automated. Registration was performed both to fat images and OP images for comparison. Perfusion and filtration values were extracted from a two-compartment model fit. RESULTS: Automatic registration to fat images performed better than automatic registration to OP images with visible contrast enhancement. Median vertical misalignment of the kidneys was 14 mm prior to registration, compared to 3 mm and 5 mm with registration to fat images and OP images, respectively (P = 0.03). Mean perfusion values and MR-based glomerular filtration rates (GFR) were 233 +/- 64 mL/100 mL/min and 60 +/- 36 mL/minute, respectively, based on fat-registered images. MR-based GFR correlated with creatinine-based GFR (P = 0.04) for fat-registered images. For unregistered and OP-registered images, this correlation was not significant. CONCLUSION: Absence of contrast changes on Dixon fat images improves registration in renal DCE MRI and enables automated postprocessing, resulting in a more accurate estimation of GFR. Magn Reson Med 80:66-76, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 29134674 TI - Experimental validation of two dual-energy CT methods for proton therapy using heterogeneous tissue samples. AB - PURPOSE: The purpose of this work is to evaluate the performance of dual-energy CT (DECT) for determining proton stopping power ratios (SPRs) in an experimental environment and to demonstrate its potential advantages over conventional single energy CT (SECT) in clinical conditions. METHODS: Water equivalent range (WER) measurements of 12 tissue-equivalent plastic materials and 12 fresh animal tissue samples are performed in a 195 MeV broad proton beam using the dose extinction method. SECT and DECT scans of the samples are performed with a dual-source CT scanner (Siemens SOMATOM Definition Flash). The methods of Schneider et al. (1996), Bourque et al. (2014), and Lalonde et al. (2017) are used to predict proton SPR on SECT and DECT images. From predicted SPR values, the WER of the proton beam through the sample is predicted for SECT and DECT using Monte Carlo simulations and compared to the measured WER. RESULTS: For homogeneous tissue equivalent plastic materials, results with DECT are consistent with experimental measurements and show a systematic reduction of SPR uncertainty compared to SECT, with root-mean-square errors of 1.59% versus 0.61% for SECT and DECT, respectively. Measurements with heterogeneous animal samples show a clear reduction of the bias on range predictions in the presence of bones, with -0.88% for SECT versus -0.58% and -0.14% for both DECT methods. An uncertainty budget allows isolating the effect of CT number conversion to SPR and predicts improvements by DECT over SECT consistently with theoretical predictions, with 0.34% and 0.31% for soft tissues and bones in the experimental setup compared to 0.34% and 1.14% with the theoretical method. CONCLUSIONS: The present work uses experimental measurements in a realistic clinical environment to show potential benefits of DECT for proton therapy treatment planning. Our results show clear improvements over SECT in tissue-equivalent plastic materials and animal tissues. Further work towards using Monte Carlo simulations for treatment planning with DECT data and a more detailed investigation of the uncertainties on I-value and limitations on the Bragg additivity rule could potentially further enhance the benefits of this imaging technology for proton therapy. PMID- 29134676 TI - A safety and immunogenicity study of a novel subunit plague vaccine in cynomolgus macaques. AB - Plague has led to millions of deaths in history and outbreaks continue to the present day. The efficacy limitations and safety concerns of the existing killed whole cell and live-attenuated vaccines call for the development of new vaccines. In this study, we evaluated the immunogenicity and safety of a novel subunit plague vaccine, comprising native F1 antigen and recombinant V antigen. The cynomolgus macaques in low- and high-dose vaccine groups were vaccinated at weeks 0, 2, 4 and 6, at dose levels of 15 MUg F1 + 15 MUg rV and 30 MUg F1 + 30 MUg rV respectively. Specific antibodies and interferon-gamma and interleukin-2 expression in lymphocytes were measured. For safety, except for the general toxicity and local irritation, we made a systematic immunotoxicity study on the vaccine including immunostimulation, autoimmunity and anaphylactic reaction. The vaccine induced high levels of serum anti-F1 and anti-rV antibodies, and caused small increases of interferon-gamma and interleukin-2 in monkeys. The vaccination led to a reversible increase in the number of peripheral blood eosinophils, the increases in serum IgE level in a few animals and histopathological change of granulomas at injection sites. The vaccine had no impact on general conditions, most clinical pathology parameters, percentages of T-cell subsets, organ weights and gross pathology of treated monkeys and had passable local tolerance. The F1 + rV subunit plague vaccine can induce very strong humoral immunity and low level of cellular immunity in cynomolgus macaques and has a good safety profile. PMID- 29134675 TI - Analytical approach, dissipation pattern and risk assessment of pesticide residue in green leafy vegetables: A comprehensive review. AB - The category of 'leafy vegetables' comprises a wide range of plants, including cabbage, lettuce, leeks, spinach, Swiss chard and kale, and it forms a significant component of the human diet. Typically, leafy vegetables are low in calories and fat, are great sources of vitamins, protein, dietary fibre and minerals (including iron, calcium, and nitrates), and are rich in phytochemicals. To counter the impact of pests on vegetables, a broad variety of pesticides are used. Because of their large surface areas, leafy vegetables are expected to have high residual pesticide levels. As such, a sound analytical approach is needed to detect and quantify residue levels that are equal to or lower than the maximum residue limits, thus rendering the products safe for consumption. Overall, leafy vegetables consumed raw (after a tap water wash only), boiled or steamed contribute 2% of total vegetable consumption globally, and they might have a comparatively greater influence on health than cereal ingestion. Consequently, in this review paper, we highlight the importance of leafy vegetables, the pesticides that are commonly used on them and various analytical techniques, including sample preparation, extraction, clean-up and final detection. The effects on dissipation patterns, pre-harvest residue limits and safety/risks imposed by various pesticides are also reviewed and discussed. In conclusion, environmentally friendly extraction methods coupled with high-throughput techniques with greater reproducibility and lower uncertainty are needed for quantifying residues in leafy vegetables at very low concentrations. Commercial and household food preparation, such as washing, peeling, blanching and cooking are effective in removing most of the pesticide residues that are loosely attached on vegetables. PMID- 29134677 TI - Hybridization of MOFs and COFs: A New Strategy for Construction of MOF@COF Core Shell Hybrid Materials. AB - The exploration of new porous hybrid materials is of great importance because of their unique properties and promising applications in separation of materials, catalysis, etc. Herein, for the first time, by integration of metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), a new type of MOF@COF core-shell hybrid material, i.e., NH2 -MIL-68@TPA-COF, with high crystallinity and hierarchical pore structure, is synthesized. As a proof-of-concept application, the obtained NH2 -MIL-68@TPA-COF hybrid material is used as an effective visible-light-driven photocatalyst for the degradation of rhodamine B. The synthetic strategy in this study opens up a new avenue for the construction of other MOF-COF hybrid materials, which could have various promising applications. PMID- 29134679 TI - Prediction of protein structure with the coarse-grained UNRES force field assisted by small X-ray scattering data and knowledge-based information. AB - A new approach to assisted protein-structure prediction has been proposed, which is based on running multiplexed replica exchange molecular dynamics simulations with the coarse-grained UNRES force field with restraints derived from knowledge based models and distance distribution from small angle X-ray scattering (SAXS) measurements. The latter restraints are incorporated into the target function as a maximum-likelihood term that guides the shape of the simulated structures towards that defined by SAXS. The approach was first verified with the 1KOY protein, for which the distance distribution was calculated from the experimental structure, and subsequently used to predict the structures of 11 data-assisted targets in the CASP12 experiment. Major improvement of the GDT_TS was obtained for 2 targets, minor improvement for other 2 while, for 6 target GDT_TS deteriorated compared with that calculated for predictions without the SAXS data, partly because of assuming a wrong multimeric state (for Ts866) or because the crystal conformation was more compact than the solution conformation (for Ts942). Particularly good results were obtained for Ts909, in which use of SAXS data resulted in the selection of a correctly packed trimer and, subsequently, increased the GDT_TS of monomer prediction. It was found that running simulations with correct oligomeric state is essential for the success in SAXS-data-assisted prediction. PMID- 29134678 TI - Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-beta burden in several amyloid transgenic mouse models. AB - Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-gamma dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135 137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid-beta pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti-PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte-derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., (): Nature Medicine, 22:135-137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease. PMID- 29134680 TI - Vocal activities reflect the temporal distribution of bottlenose dolphin social and non-social activity in a zoological park. AB - Under natural conditions bottlenose dolphins (Tursiops truncatus) spend their time mostly feeding and then travelling, socializing, or resting. These activities are not randomly distributed, with feeding being higher in early morning and late afternoon. Social activities and vocal behavior seem to be very important in dolphin daily activity. This study aimed to describe the activity time-budget and its relation to vocal behavior for dolphins in a zoological park. We recorded behaviors and vocalizations of six dolphins over 2 months. All subjects performed more non-agonistic social interactions and play in the morning than in the afternoon. The different categories of vocalizations were distributed non-randomly throughout the day, with more chirps in the afternoon, when the animals were "less social." The most striking result was the strong correlation between activities and the categories of vocalizations produced. The results confirm the association between burst pulses and whistles with social activities, but also reveal that both are also associated with solitary play. More chirps were produced when dolphins were engaged in socio-sexual behaviors, emphasizing the need for further questioning about the function of this vocal category. This study reveals that: (i) in a group kept in zoological management, social activities are mostly present in the morning; and (ii) the acoustic signals produced by dolphins may give a reliable representation of their current activities. While more studies on the context of signal production are needed, our findings provide a useful tool for understanding free ranging dolphin behavior when they are not visible. PMID- 29134681 TI - Gravity Constraints Drive Biological Systems Toward Specific Organization Patterns: Commitment of cell specification is constrained by physical cues. AB - Different cell lineages growing in microgravity undergo a spontaneous transition leading to the emergence of two distinct phenotypes. By returning these populations in a normal gravitational field, the two phenotypes collapse, recovering their original configuration. In this review, we hypothesize that, once the gravitational constraint is removed, the system freely explores its phenotypic space, while, when in a gravitational field, cells are "constrained" to adopt only one favored configuration. We suggest that the genome allows for a wide range of "possibilities" but it is unable per se to choose among them: the emergence of a specific phenotype is enabled by physical constraints that drive the system toward a preferred solution. These findings may help in understanding how cells and tissues behave in both development and cancer. PMID- 29134682 TI - Differential effects of follistatin on porcine oocyte competence and cumulus cell gene expression in vitro. AB - Several oocyte-derived genes/proteins are essential to early embryonic development. The expression and stability of these proteins are influenced by the autocrine/paracrine activity of factors released by oocytes and cumulus cells. This study investigated the paracrine and autocrine activity of follistatin (FS), which is secreted by oocytes and cumulus cells as part of porcine embryogenesis. Immunohistochemical (IHC) localization of follistatin was conducted on 100 randomly selected early- and late-cleaving two-cell embryos. Dissociated cumulus cells were treated with various doses of follistatin for determination of the follistatin gene (FST) mRNA expression levels by quantitative real-time PCR analysis. Microinjection of siRNA induced a downregulation of FST mRNA during embryonic development, thereby decreasing the proportion embryos developing to the blastocyst stage (19.33%). Immunolocalization analysis showed enhanced staining for follistatin in early-cleavage stage embryos. Quantitative real-time PCR indicated a significantly lower FST transcript level in cumulus cells after application of the highest dose of follistatin (100 ng/ml). Exogenous follistatin treatment of in vitro maturation embryos resulted in statistically significant dose-dependent changes during development. Application of the highest concentration (100 ng/ml) of follistatin decreased the maturation rate of the oocytes. On the other hand, the application of 10 ng/ml follistatin resulted in an increase in the number of embryos. The observed differential effect of exogenous follistatin might be due to maternal FST and autocrine/paracrine factors secreted by cumulus cells. PMID- 29134683 TI - Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A single patient experience. PMID- 29134684 TI - Enhanced radiosensitization of enzalutamide via schedule dependent administration to androgen-sensitive prostate cancer cells. AB - BACKGROUND: Prostate cancer (PCa) is a progressive disease and the most diagnosed cancer in men. The current standard of care for high-risk localized PCa is a combination of androgen deprivation therapy (ADT) and radiation (XRT). The majority of these patients however become resistant due to incomplete responses to ADT as a result of selective cells maintaining androgen receptor (AR) activity. Improvement can be made if increasing radiosensitivity is realized. Therefore, the aim of this study is to investigate the efficacy of the next generation PCa drug Enzalutamide (ENZA), as a radiosensitizer in XRT therapy. METHODS: Using a number of androgen-dependent (LNCaP, PC3-T877A) and androgen independent (C4-2, 22RV1, PC3, PC3-AR V7) cell lines, the effect of ENZA as a radiosensitizer was studied alone or in combination with ADT and/or XRT. Cell viability and cell survival were assessed, along with determination of cell cycle arrest, DNA damage response and repair, apoptosis and senescence. RESULTS: Our results indicated that either ENZA alone (in AR positive, androgen-dependent PCa cells) or in combination with ADT (in AR positive, hormone-insensitive PCa cells) potentiates radiation response [Dose enhancement factor (DEF) of 1.75 in LNCAP and 1.35 in C4-2] stronger than ADT + XRT conditions. Additionally, ENZA sensitized androgen dependent PCa cells to XRT in a schedule-dependent manner, where concurrent administration of ENZA and radiation lead to a maximal radiosensitization when compared to either drug administration prior or after XRT. In LNCaP cells, ENZA treatment significantly prolonged the presence of XRT induced phospho-gammaH2AX up to 24 h after treatment; suggesting enhanced DNA damage. It also significantly increased XRT-induced apoptosis and senescence. CONCLUSIONS: Our data indicates that ENZA acts as a much stronger radiosensitizer compared to ADT. We have also observed that its efficacy is schedule dependent and related to increased levels of DNA damage and a delay of DNA repair processes. Finally, the initial abrogation of DNA-PKcs activity by AR inhibition and its subsequent recovery might represent an important mechanism by which PCa cells acquire resistance to combined anti-androgen and XRT treatment. This work suggests a new use of ENZA in combination with XRT that could be applicable in clinical trial settings for patients with early and intermediate hormone responsive disease. PMID- 29134685 TI - In ovo feeding of nutrients and its impact on post-hatching water and feed deprivation up to 48 hr, energy status and jejunal morphology of chicks using response surface models. AB - A Box-Behnken design (BBD) in a response surface methodology (RSM) was used to investigate the response of broiler chicks to in ovo feeding (IOF) of beta hydroxy beta-methylbutyrate (HMB), dextrin and the timing of the first water and feed deprivation. On day 18th of incubation, 1,500 eggs were randomly assigned to 15 experimental runs of BBD, each with 4 replicates, as 3 levels IOF of HMB (0%, 0.5% and 1%) and dextrin (0%, 20% and 40%), and 3 levels of the first water and feed deprivation (6, 27 and 48 hr). Day-old chicks from each replicate were then used to assess the effect of IOF and time first water and feed access on chick's responses. The IOF of dextrin leads to respectively 9.7%-15.5% lower hatchability for 20% and 40% inclusion (p < .05), whereas HMB inclusion appeared with no effect on hatchability (p > .05). Administration of dextrin or HMB into the amnion of embryos elevated length, width and surface area of villus, and increased glycogen content of liver and breast (p < .05). In all parameter models, the linear terms showed highest contribution (R2 = 0.81-0.97) to explain existing variation in chick's responses. The first water and feed deprivation had largest effect on BW2 and glycogen content of liver and breast. It is concluded that if possible, place chicks before 7 hr of hatch to preserve BW loss and have maximum response from IOF. If not possible, use IOF with 40% dextrin + 0.5% HMB to preserve gut integrity and energy status up to 48 hr. This should give advantage to chicks to recover fast after feeding, but that would have to be confirmed by trials growing birds to slaughter age. PMID- 29134687 TI - Bone reconstruction: A history of vascularized bone transfer. PMID- 29134686 TI - Selective proton-observed, carbon-edited (selPOCE) MRS method for measurement of glutamate and glutamine 13 C-labeling in the human frontal cortex. AB - PURPOSE: 13 C magnetic resonance spectroscopy (MRS) in combination with infusion of 13 C-labeled substrates has led to unique insights into human brain metabolism and neurotransmitter cycling. However, the low sensitivity of direct 13 C MRS and high radiofrequency power requirements has limited 13 C MRS studies to predominantly data acquisition in large volumes of the occipital cortex. The purpose of this study is to develop an MRS technique for localized detection of 13 C-labeling of glutamate and glutamine in the human frontal lobe. METHODS: We used an indirect (1 H-[13 C]), proton-observed, carbon-edited MRS sequence (selPOCE) for detection of 13 C-labeled metabolites in relatively small volumes located in the frontal lobe at 4 T. The SelPOCE method allows for selective and separate detection of glutamate and glutamine resonances, which significantly overlap at magnetic field strengths used for clinical MRI. RESULTS: Phantom data illustrate how selPOCE can be tuned to selectively detect 13 C labeling in different metabolites. Three-dimensional specific absorption rate simulations of radiofrequency power deposition show that the selPOCE method operates comfortably within the global and local Food and Drug Administration specific absorption rate guidelines. In vivo selPOCE data are presented, which were acquired from a 45-mL volume in the frontal lobe of healthy subjects. The in vivo data show the time dependent 13 C-labeling of glutamate and glutamine during intravenous infusion of [1-13 C]-glucose. Metrics describing spectral fitting quality of the glutamate and glutamine resonances are reported. CONCLUSIONS: The SelPOCE sequence allows the detection of 13 C-labeling in glutamate and glutamine from a relatively small volume in the human frontal lobe at low radiofrequency power requirements. Magn Reson Med 80:11-20, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29134688 TI - Neutropenic fever during peripheral blood progenitor cell mobilization is associated with decreased CD34+ cell collection and increased apheresis collection days. AB - BACKGROUND: Peripheral blood progenitor cell (PBPC) mobilization with chemotherapy in addition to Granulocyte-Colony Stimulating Factor (G-CSF) improves cell collection compared to G-CSF alone; however, it is associated with increased risk of neutropenic fever (NF). METHODS: We analyzed risk factors for post-priming NF and NF association with autologous stem cell transplant outcomes. Between 1998 and 2008, 593 adult patients with lymphoma underwent PBPC mobilization with etoposide and G-CSF. RESULTS: Median age was 51 years (range 18 77) and 372 (63%) were male. Diagnoses were 457 (77%) non-Hodgkin lymphoma and 136 (23%) Hodgkin lymphoma. Of 554 (93%) transplanted patients, majority were in complete or partial remission at time of transplant (88%). Overall, 141 (24%) patients were hospitalized for NF. Nine patients (6%) had bacteremia, 4 (3%) had pneumonia, 2 (<1%) had herpes simplex viral infections, and the remaining 126 (90%) had no identified infection source. NF patients had lower likelihood of proceeding to transplant (86% vs. 96%, P < .001), lower CD34+ cell dose collection (median 7.23 * 106 CD34+ cells/kg vs. 8.98 * 106 CD34+ cells/kg, P = .002), and were more likely to require > 4 days of apheresis (48% vs. 37%, P < .001). NF was associated with a higher 30-day readmission rate following transplant hospitalization (17% vs. 9%, P = .012). CONCLUSION: NF during etoposide priming is associated with lower likelihood of proceeding to transplant, lower CD34+ cell dose collection, more apheresis days required for collection and a higher 30-day readmission rate following transplant discharge. PMID- 29134689 TI - Effectiveness of controlled internal drug release device treatment to alleviate reproductive seasonality in anestrus lactating or dry Barki and Rahmani ewes during non-breeding season. AB - This study aimed to evaluate the effectiveness of hormonal treatments on ovarian activity and reproductive performance in Barki and Rahmani ewes during non breeding season. Forty-eight multiparous ewes, 24 Barki and 24 Rahmani ewes were divided into two groups, 12 lactating and 12 dry ewes for each breed. Controlled internal drug release (CIDR) device was inserted in all ewes for 14 days in conjunction with intramuscular 500 IU equine chronic gonadotrophin (eCG) at day of CIDR removal. Data were analysed using PROC MIXED of SAS for repeated measures. Breed, physiological status and days were used as fixed effects and individual ewes as random effects. Barki ewes recorded higher (p < .05) total number of follicles, number of large follicles, serum estradiol concentration and estradiol: progesterone (E2 :P4 ) ratio compared to Rahmani ewes. Lactating ewes recorded higher (p < .05) number of small follicles and lower concentration of total antioxidant capacity (TAC) compared to dry ewes. Number and diameter of large follicles recorded the highest (p < .05) values accompanied with disappearance of corpora lutea at day of mating. Serum progesterone concentration recorded lower (p < .05) value at day of mating and the highest (p < .05) value at day 35 after mating. CIDR-eCG protocol induced 100% oestrous behaviour in both breeds, but Rahmani ewes recorded longer (p < .05) oestrous duration compared to Barki. Conception failure was higher (p < .05) in Barki compared to Rahmani ewes. In conclusion, CIDR-eCG protocol was more potent in improving ovarian activity in Barki compared to Rahmani ewes, but this protocol seems to induce hormonal imbalance in Barki ewes that resulted in increasing conception failure compared to Rahmani ewes. PMID- 29134690 TI - Faecal calcium excretion does not decrease during long-term feeding of a low calcium diet in adult dogs. AB - According to a previous meta-analysis, adult dogs do not notably increase calcium absorption from the gastrointestinal tract when calcium intake is decreased. This results in a negative calcium balance even with a moderate calcium reduction. In this study we wanted to verify (i) whether a negative calcium balance occurs at a calcium intake equivalent to NRC (2006) (Nutrient requirements of dogs and cats, 2006, The National Academies Press, Washington, DC) minimal requirements, and if so (ii) whether the negative calcium balance will persist for up to 6 months on a low-calcium diet. After a pre-feeding period of at least 18 weeks with calcium intake slightly exceeding maintenance requirements (200 mg/kg body weight0.75 ), 12 dogs (6 Beagles, 6 Foxhound crossbreds) were fed a low-calcium diet for 28 weeks. One dog was removed from the trial for reasons unrelated to the study at week 23. Calcium intake amounted to 60 mg/kg body weight0.75 corresponding to the minimal requirement for maintenance in dogs (NRC, 2006 (Nutrient requirements of dogs and cats, 2006, The National Academies Press, Washington, DC)). Digestion trials were carried out at week 7, 14, 21 and 28 of the low calcium feeding period. At these time points, and at week 18 of the pre-trial, blood samples were taken and analysed for calcium, ionised calcium, phosphorus, parathyroid hormone, vitamin D, serum crosslaps and bone alkaline phosphatase. Apparent calcium digestibility was negative throughout the study, suggesting a negative calcium balance. There was no systematic decrease in faecal calcium excretion. Serum calcium, ionised calcium and phosphorus remained within the reference range. Serum crosslaps increased continuously from baseline to week 28 of trial, with averages increasing from 0.102 ng/ml to 0.279 ng/ml, suggesting osteoclastic activity, indicative of calcium mobilisation from the skeleton. The study supports the theory of a lack of adaptation of intestinal calcium absorption from diets with relatively low calcium content in dogs. This agrees with clinical findings in dogs eating low-calcium diet. PMID- 29134691 TI - Direct Probing of Polarization Charge at Nanoscale Level. AB - Ferroelectric materials possess spontaneous polarization that can be used for multiple applications. Owing to a long-term development of reducing the sizes of devices, the preparation of ferroelectric materials and devices is entering the nanometer-scale regime. Accordingly, to evaluate the ferroelectricity, there is a need to investigate the polarization charge at the nanoscale. Nonetheless, it is generally accepted that the detection of polarization charges using a conventional conductive atomic force microscopy (CAFM) without a top electrode is not feasible because the nanometer-scale radius of an atomic force microscopy (AFM) tip yields a very low signal-to-noise ratio. However, the detection is unrelated to the radius of an AFM tip and, in fact, a matter of the switched area. In this work, the direct probing of the polarization charge at the nanoscale is demonstrated using the positive-up-negative-down method based on the conventional CAFM approach without additional corrections or circuits to reduce the parasitic capacitance. The polarization charge densities of 73.7 and 119.0 uC cm-2 are successfully probed in ferroelectric nanocapacitors and thin films, respectively. The obtained results show the feasibility of the evaluation of polarization charge at the nanoscale and provide a new guideline for evaluating the ferroelectricity at the nanoscale. PMID- 29134692 TI - Water-Rich Biomimetic Composites with Abiotic Self-Organizing Nanofiber Network. AB - Load-bearing soft tissues, e.g., cartilage, ligaments, and blood vessels, are made predominantly from water (65-90%) which is essential for nutrient transport to cells. Yet, they display amazing stiffness, toughness, strength, and deformability attributed to the reconfigurable 3D network from stiff collagen nanofibers and flexible proteoglycans. Existing hydrogels and composites partially achieve some of the mechanical properties of natural soft tissues, but at the expense of water content. Concurrently, water-rich biomedical polymers are elastic but weak. Here, biomimetic composites from aramid nanofibers interlaced with poly(vinyl alcohol), with water contents of as high as 70-92%, are reported. With tensile moduli of ~9.1 MPa, ultimate tensile strains of ~325%, compressive strengths of ~26 MPa, and fracture toughness of as high as ~9200 J m-2 , their mechanical properties match or exceed those of prototype tissues, e.g., cartilage. Furthermore, with reconfigurable, noncovalent interactions at nanomaterial interfaces, the composite nanofiber network can adapt itself under stress, enabling abiotic soft tissue with multiscale self-organization for effective load bearing and energy dissipation. PMID- 29134694 TI - Intracorneal haemorrhage after intravitreal injections. PMID- 29134695 TI - Acute stimulation of a smooth muscle constrictor by oestradiol-17beta via GPER1 in bovine oviducts. AB - Oviducts play roles in reproductive processes, including gametes transport, fertilization and early embryo development. Oviductal transport is controlled by various factors such as endothelins (EDNs) and nitric oxide (NO), smooth muscle contracting and relaxing factor, respectively. EDNs and NO production depend on an ovarian steroid hormone, oestradiol-17beta (E2) and E2 quickly exerts their biological functions through G protein-coupled oestrogen receptor 1 (GPER1), which mediates rapid intracellular signalling. Because follicular fluid which contains a high concentration of E2 enters the oviduct, we hypothesized that E2 in the follicular fluid participates via GPER1 in producing EDNs and NO. To test this hypothesis, we investigated 1) the expression and localization of GPER1 in bovine oviductal tissues and 2) rapid effects of E2 via GPER1 on EDN1, EDN2 and inducible NO synthase (iNOS) expression in cultured bovine oviductal isthmic epithelial cells. GPER1 was observed in the oviductal epithelium, stroma and smooth muscle, and its expression was highest in the isthmus. Short-term treatments (<=1 hr) of E2 increased EDN2 mRNA expression in the isthmic epithelial cells, although E2 did not affect EDN1 and iNOS mRNA expressions. Results of GPER1-selective agonist G-1 and GPER1-selective antagonist G-15 treatments revealed acute stimulation by E2, which is mediated via GPER1. The overall findings suggested that E2 in follicular fluid rapidly stimulates EDN2 expression via GPER1 in the isthmic epithelial cells. Follicular fluid may play a role in retention of the ovulated oocyte in the end of ampulla by contracting the isthmus for successful fertilization. PMID- 29134693 TI - Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism. AB - Dysregulation in immune responses during pregnancy increases the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive, and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD. PMID- 29134696 TI - Refractive changes after intravitreal ranibizumab injections for diabetic macular oedema. AB - PURPOSE: The purpose of this study was to evaluate refractive changes after intravitreal ranibizumab injections for the treatment of diabetic macular oedema. METHODS: Participants in this retrospective study were 35 patients (35 eyes) with diabetic macular oedema, who received intravitreal ranibizumab injections. Spherical equivalent refractive power was evaluated before treatment and at least one month after the last injection where no fluid existed. Demographic characteristics, visual acuity, central retinal thickness and the number of injections were recorded and analysed. RESULTS: The spherical equivalent refractive power did not differ significantly pre- or post-injections. Changes in visual acuity and central retinal thickness were statistically significant before and after injections. CONCLUSIONS: Intravitreal ranibizumab injections did not seem to affect the refractive power of patients with diabetic macular oedema. Therefore, appropriate spectacle correction can be prescribed any time during ongoing treatment with ranibizumab injections. PMID- 29134697 TI - Cytological endometritis diagnosed at artificial insemination in repeat breeder dairy cows. AB - This study aimed to (i) assess the prevalence of cytological endometritis (CYTO) diagnosed at artificial insemination (AI); (ii) evaluate the effect of CYTO on the pregnancy outcome of the same AI sample; and (iii) determine the risk factors associated with CYTO diagnosed at AI in repeat breeder (RB) dairy cows. We analysed the productive and reproductive performances of 146 RB Holstein-Friesian cows. To obtain a CYTO sample at AI, we used the cytotape technique. Generalized mixed effect models were computed to find the risk factors associated with the pregnancy and CYTO outcome. Based on >=1% PMN cut-off point, the CYTO prevalence at AI in RB cows was 25.3%. The overall pregnancy at AI was 44.2%. The conception rate in CYTO-positive (n = 37) RB cows was 29.7% versus 49.5% for CYTO-negative (n = 109) cows. A RB cow diagnosed CYTO positive at AI had 0.47 [odds ratio (OR)] odds to become pregnant in comparison with a CYTO-negative cow. Cows that produced more milk than their counterparts in this study had increased odds (OR = 1.01) to be CYTO positive at AI. A novel risk factor positively associated with CYTO diagnosed at AI in RB cows was the level of daily milk urea (OR = 1.11). To conclude, CYTO at the moment of AI had a significantly negative effect on the pregnancy outcome in RB dairy cows. However, as only one of fourth of RB cows is affected with CYTO at AI, it may not be considered a key element associated with the RB syndrome. PMID- 29134698 TI - Central serous chorioretinopathy mimicking as choroiditis. PMID- 29134699 TI - Synthesis and Properties of a Photopatternable Lithium-Ion Conducting Solid Electrolyte. AB - One of the important considerations for the development of on-chip batteries is the need to photopattern the solid electrolyte directly on electrodes. Herein, the photopatterning of a lithium-ion conducting solid electrolyte is demonstrated by modifying a well-known negative photoresist, SU-8, with LiClO4 . The resulting material exhibits a room temperature ionic conductivity of 52 uS cm-1 with a wide electrochemical window (>5 V). Half-cell galvanostatic testing of 3 um thin films spin-coated on amorphous silicon validates its use for on-chip energy-storage applications. The modified SU-8 possesses excellent mechanical integrity, is thermally stable up to 250 degrees C, and can be photopatterned with micrometer scale resolution. These results present a promising direction for the integration of electrochemical energy storage in microelectronics. PMID- 29134700 TI - Comparative analysis of ovarian transcriptomes between prolific and non-prolific goat breeds via high-throughput sequencing. AB - To increase the current understanding of the gene expression in the pre-ovulatory ovary and identify the key genes involved in the regulation of ovulation rate, we compared the transcriptomes of ovaries from the prolific Jintang black goat (JTG) and the non-prolific Tibetan goat (TBG) during the follicular phase using the Illumina RNA-Seq method. Three ovarian libraries were constructed for each breed. On average, we obtained approximately 49.2 and 45.9 million reads for each individual ovary of TBGs and JTGs, respectively, of which 79.76% and 78.67% reads were covered in the genome database. A total of 407 differentially expressed genes (DEG) were detected between these two breeds, in which 316 were upregulated, and 91 were downregulated in the ovaries of JTGs versus TBGs. Based on the results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, some of these DEGs potentially play an important role in controlling the development of ovarian follicles. SRD5A2, MSMB, STAR and 3BHSD, etc. were the most significantly differentially expressed between these two distinct breeds. In addition, each ovary expressed 1,066 versus 989 novel transcripts, and 171,829 versus 140,529 putative SNPs in TBGs versus JTBs, respectively. All data sets (GEO and dbSNP) were available via public repositories. Our study provides insight into the transcriptional regulation of the ovaries of two distinct breeds of goats that might serve as a key resource for understanding goat fecundity. SRD5A2, MSMB, STAR and 3BHSD may be associated with the high fecundity of JTGs. PMID- 29134701 TI - Overexpression of a newly identified d-amino acid transaminase in Mycobacterium smegmatis complements glutamate racemase deletion. AB - Glutamate racemase (MurI) has been proposed as a target for anti-tuberculosis drug development based on the inability of DeltamurI mutants of Mycobacterium smegmatis to grow in the absence of d-glutamate. In this communication, we identify DeltamurI suppressor mutants that are detected during prolonged incubation. Whole genome sequencing of these DeltamurI suppressor mutants identified the presence of a SNP, located in the promoter region of MSMEG_5795. RT-qPCR and transcriptional fusion analyses revealed that the DeltamurI suppressor mutant overexpressed MSMEG_5795 14-fold compared to the isogenic wild type. MSMEG_5795, which is annotated as 4-amino-4-deoxychorismate lyase (ADCL) but which also has homology to d-amino acid transaminase (d-AAT), was expressed, purified and found to have d-AAT activity and to be capable of producing d glutamate from d-alanine. Consistent with its d-amino acid transaminase function, overexpressed MSMEG_5795 is able to complement both DeltamurI deletion mutants and alanine racemase (Deltaalr) deletion mutants, thus confirming a multifunctional role for this enzyme in M. smegmatis. PMID- 29134702 TI - Editable Supercapacitors with Customizable Stretchability Based on Mechanically Strengthened Ultralong MnO2 Nanowire Composite. AB - Although some progress has been made on stretchable supercapacitors, traditional stretchable supercapacitors fabricated by predesigning structured electrodes for device assembling still lack the device-level editability and programmability. To adapt to wearable electronics with arbitrary configurations, it is highly desirable to develop editable supercapacitors that can be directly transferred into desirable shapes and stretchability. In this work, editable supercapacitors for customizable shapes and stretchability using electrodes based on mechanically strengthened ultralong MnO2 nanowire composites are developed. A supercapacitor edited with honeycomb-like structure shows a specific capacitance of 227.2 mF cm 2 and can be stretched up to 500% without degradation of electrochemical performance, which is superior to most of the state-of-the-art stretchable supercapacitors. In addition, it maintains nearly 98% of the initial capacitance after 10 000 stretch-and-release cycles under 400% tensile strain. As a representative of concept for system integration, the editable supercapacitors are integrated with a strain sensor, and the system exhibits a stable sensing performance even under arm swing. Being highly stretchable, easily programmable, as well as connectable in series and parallel, an editable supercapacitor with customizable stretchability is promising to produce stylish energy storage devices to power various portable, stretchable, and wearable devices. PMID- 29134704 TI - Diastereomeric Right- and Left-Handed Helical Structures with Fourteen (R)-Chiral Centers. AB - The relationship between chiral centers and the helical-screw control of their peptides has already been reported, but it has yet to be elucidated in detail. A chiral four-membered ring alpha,alpha-disubstituted alpha-amino acid with a (R,R) butane-2,3-diol acetal moiety at the gamma-position, but no alpha-chiral carbon, was synthesized. X-ray crystallographic analysis unambiguously revealed that its homo-chiral heptapeptide formed right-handed (P) and left-handed (M) 310 -helical structures at a ratio of 1:1. They appeared to be enantiomeric at the peptide backbone, but diastereomeric with fourteen (R)-configuration chiral centers. Conformational analyses of homopeptides in solution also indicated that diastereomeric (P) and (M) helices existed at approximately equal amounts, with a slight preference toward right-handedness, and they quickly interchanged at room temperature. The circumstances of chiral centers are important for the control of their helical-screw direction. PMID- 29134705 TI - A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein. AB - Dystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated alpha-DG and the transmembrane beta-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of alpha-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of alpha-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the alpha-DG core protein influencing its binding to modifying enzymes. Recently, a homozygous mutation (p.Cys699Phe) hitting the beta-DG ectodomain has been identified in a patient affected by muscle-eye-brain disease with multicystic leucodystrophy, suggesting that other mechanisms than hypoglycosylation of alpha-DG could be implicated in dystroglycanopathies. Herein, we have characterized the DG murine mutant counterpart by transfection in cellular systems and high-resolution microscopy. We observed that the mutation alters the DG processing leading to retention of its uncleaved precursor in the endoplasmic reticulum. Accordingly, small-angle X-ray scattering data, corroborated by biochemical and biophysical experiments, revealed that the mutation provokes an alteration in the beta-DG ectodomain overall folding, resulting in disulfide-associated oligomerization. Our data provide the first evidence of a novel intracellular mechanism, featuring an anomalous endoplasmic reticulum-retention, underlying dystroglycanopathy. PMID- 29134706 TI - Effectiveness of different pre-treatments in recovering pre-burial isotopic ratios of charred plants. AB - RATIONALE: Isotopic analysis of archaeological charred plant remains offers useful archaeological information. However, adequate sample pre-treatment protocols may be necessary to provide a contamination-free isotopic signal while limiting sample loss and achieving a high throughput. Under these constraints, research was undertaken to compare the performance of different pre-treatment protocols. METHODS: Charred archaeological plant material was selected for isotopic analysis (delta13 C and delta15 N values) by isotope ratio mass spectrometry from a variety of plant species, time periods and soil conditions. Preservation conditions and the effectiveness of cleaning protocols were assessed through Fourier transform infrared spectroscopy and X-ray fluorescence (XRF) spectrometry. An acid-base-acid protocol, successfully employed in radiocarbon dating, was used to define a contamination-free isotopic reference. Acid-base acid isotopic measurements were compared with those obtained from untreated material and an acid-only protocol. RESULTS: The isotopic signals of untreated material and the acid-only protocol typically did not differ more than 10/00 from those of the acid-base-acid reference. There were no significant isotopic offsets between acid-base-acid and acid-only or untreated samples. Sample losses in the acid-base-acid protocol were on average 50 +/- 17% (maximum = 98.4%). Elemental XRF measurements showed promising results in the detection of more contaminated samples albeit with a high rate of false positives. CONCLUSIONS: For the large range of preservation conditions described in the study, untreated charred plant samples, water cleaned of sediments, provide reliable stable isotope ratios of carbon and nitrogen. The use of pre-treatments may be necessary under different preservation conditions or more conservative measurement uncertainties should be reported. PMID- 29134707 TI - Reproducibility of diagnostic criteria associated with atypical breast cytology. AB - OBJECTIVE: The aim of this project was to assess the interobserver and intraobserver variability when identifying cytological criteria, which were found to have a statistically significant association with C3 within a workplace environment. METHODS: Sixty C3 cases with known endpoints of malignant, benign proliferative or benign non-proliferative diagnoses were blindly and independently screened by seven experienced cytologists to identify previously reported statistically significant criteria associated with the C3 category. The criteria included the presence of myoepithelial cells or bare bipolar nuclei, cohesiveness, cystic background, papillary fragments with fibrovascular cores and tubular structures. Kappa statistics were used to measure interobserver variability. Two cytologists repeated the process 6 months later to obtain intraobserver data. RESULTS: The interobserver agreement was poor for all criteria except tubules which performed badly. The intraobserver variability for the two cytologists showed that one cytologist achieved moderate intraobserver agreement for all the criteria except cohesion which was poor, whilst the second cytologist showed poor agreement for all criteria. The reasons for the variability are multifactorial and include threshold effects where criteria lack good definition or error in identifying the criteria. CONCLUSION: Interobserver and intraobserver variability remains a significant challenge for cytologists. Despite attempts to define significant criteria associated with C3, good reproducibility could not be achieved. The C3 category is imprecise and highlights the inadequacy of the current classification reporting categories for breast FNA. The impending review of reporting breast cytology by the International Academy of Cytology is timely and appropriate. PMID- 29134703 TI - Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury. AB - Infants born prematurely are at high risk to develop white matter injury (WMI), due to exposure to hypoxic and/or inflammatory insults. Such perinatal insults negatively impact the maturation of oligodendrocytes (OLs), thereby causing deficits in myelination. To elucidate the precise pathophysiology underlying perinatal WMI, it is essential to fully understand the cellular mechanisms contributing to healthy/normal white matter development. OLs are responsible for myelination of axons. During brain development, OLs are generally derived from neuroepithelial zones, where neural stem cells committed to the OL lineage differentiate into OL precursor cells (OPCs). OPCs, in turn, develop into premyelinating OLs and finally mature into myelinating OLs. Recent studies revealed that OPCs develop in multiple waves and form potentially heterogeneous populations. Furthermore, it has been shown that myelination is a dynamic and plastic process with an excess of OPCs being generated and then abolished if not integrated into neural circuits. Myelination patterns between rodents and humans show high spatial and temporal similarity. Therefore, experimental studies on OL biology may provide novel insights into the pathophysiology of WMI in the preterm infant and offers new perspectives on potential treatments for these patients. PMID- 29134708 TI - Arsenic methylation by a novel ArsM As(III) S-adenosylmethionine methyltransferase that requires only two conserved cysteine residues. AB - Arsenic (As) biomethylation is an important component of the As biogeochemical cycle that can influence As toxicity and mobility in the environment. Biomethylation of As is catalyzed by the enzyme arsenite (As[III]) S adenosylmethionine methyltransferase (ArsM). To date, all identified ArsM orthologs with As(III) methylation activities have four conserved cysteine residues, which are thought to be essential for As(III) methylation. Here, we isolated an As(III)-methylating bacterium, Bacillus sp. CX-1, and identified a gene encoding a S-adenosylmethionine methyltranserase termed BlArsM with low sequence similarities (<= 39%) to other ArsMs. BlArsM has six cysteine residues (Cys10, Cys11, Cys145, Cys193, Cys195 and Cys268), three of which (Cys10, Cys145 and Cys195) align with conserved cysteine residues found in most ArsMs. BlarsM is constitutively expressed in Bacillus sp. CX-1. Heterologous expression of BlarsM conferred As(III) resistance. Purified BlArsM methylated both As(III) and methylarsenite (MAs[III]), with a final product of dimethylarsenate (DMAs[V]). When all six cysteines were individually altered to serine residues, only C145S and C195S derivatives lost the ability to methylate As(III) and MAs(III). The derivative C10S/C11S/C193S/C268S was still active. These results suggest that BlArsM is a novel As(III) S-adenosylmethionine methyltransferase requiring only two conserved cysteine residues. A model of As(III) methylation by BlArsM is proposed. PMID- 29134710 TI - Isolation by distance, not incipient ecological speciation, explains genetic differentiation in an Andean songbird (Aves: Furnariidae: Cranioleuca antisiensis, Line-cheeked Spinetail) despite near threefold body size change across an environmental gradient. AB - During the process of ecological speciation, reproductive isolation results from divergent natural selection and leads to a positive correlation between genetic divergence and adaptive phenotypic divergence, that is, isolation by adaptation (IBA). In natural populations, phenotypic differentiation is often autocorrelated with geographic distance, making IBA difficult to distinguish from the neutral expectation of isolation by distance (IBD). We examined these two alternatives in a dramatic case of clinal phenotypic variation in an Andean songbird, the Line cheeked Spinetail (Cranioleuca antisiensis). At its geographic extremes, this species shows a near threefold difference in body mass (11.5 to 31.0 g) with marked plumage differences. We analysed phenotypic, environmental and genetic data (5,154 SNPs) from 172 individuals and 19 populations sampled along its linear distribution in the Andes. We found that body mass was tightly correlated with environmental temperature, consistent with local adaptation as per Bergmann's rule. Using a PST -FST analysis, we found additional support for natural selection driving body mass differentiation, but these results could also be explained by environment-mediated phenotypic plasticity. When we assessed the relative support for patterns of IBA and IBD using variance partitioning, we found that IBD was the best explanation for genetic differentiation along the cline. Adaptive phenotypic or environmental divergence can reduce gene flow, a pattern interpreted as evidence of ecological speciation's role in diversification. Our results provide a counterexample to this interpretation. Despite conditions conducive to ecological speciation, our results suggest that dramatic size and environmental differentiation within C. antisiensis are not limiting gene flow. PMID- 29134711 TI - X exceptionalism in Caenorhabditis speciation. AB - Speciation genetics research in diverse organisms shows the X-chromosome to be exceptional in how it contributes to "rules" of speciation. Until recently, however, the nematode phylum has been nearly silent on this issue, despite the model organism Caenorhabditis elegans having touched most other topics in biology. Studies of speciation with Caenorhabditis accelerated with the recent discovery of species pairs showing partial interfertility. The resulting genetic analyses of reproductive isolation in nematodes demonstrate key roles for the X chromosome in hybrid male sterility and inviability, opening up new understanding of the genetic causes of Haldane's rule, Darwin's corollary to Haldane's rule, and enabling tests of the large-X effect hypothesis. Studies to date implicate improper chromatin regulation of the X-chromosome by small RNA pathways as integral to hybrid male dysfunction. Sexual transitions in reproductive mode to self-fertilizing hermaphroditism inject distinctive molecular evolutionary features into the speciation process for some species. Caenorhabditis also provides unique opportunities for analysis in a system with XO sex determination that lacks a Y-chromosome, sex chromosome-dependent sperm competition differences and mechanisms of gametic isolation, exceptional accessibility to the development process and rapid experimental evolution. As genetic analysis of reproductive isolation matures with investigation of multiple pairs of Caenorhabditis species and new species discovery, nematodes will provide a powerful complement to more established study organisms for deciphering the genetic basis of and rules to speciation. PMID- 29134709 TI - Light sensing by opsins and fungal ecology: NOP-1 modulates entry into sexual reproduction in response to environmental cues. AB - Understanding the genetic basis of the switch from asexual to sexual lifestyles in response to sometimes rapid environmental changes is one of the major challenges in fungal ecology. Light appears to play a critical role in the asexual-sexual switch-but fungal genomes harbour diverse light sensors. Fungal opsins are homologous to bacterial green-light-sensory rhodopsins, and their organismal functions in fungi have not been well understood. Three of these opsin like proteins were widely distributed across fungal genomes, but homologs of the Fusarium opsin-like protein CarO were present only in plant-associated fungi. Key amino acids, including potential retinal binding sites, functionally diverged on the phylogeny of opsins. This diversification of opsin-like proteins could be correlated with life history-associated differences among fungi in their expression and function during morphological development. In Neurospora crassa and related species, knockout of the opsin NOP-1 led to a phenotype in the regulation of the asexual-sexual switch, modulating response to both light and oxygen conditions. Sexual development commenced early in ?nop-1 strains cultured in unsealed plates under constant blue and white light. Furthermore, comparative transcriptomics showed that the expression of nop-1 is light-dependent and that the ?nop-1 strain abundantly expresses genes involved in oxidative stress response, genes enriched in NAD/NADP binding sites, genes with functions in proton transmembrane movement and catalase activity, and genes involved in the homeostasis of protons. Based on these observations, we contend that light and oxidative stress regulate the switch via light-responsive and ROS pathways in model fungus N. crassa and other fungi. PMID- 29134712 TI - Characterization of forced degradation products of canagliflozine by liquid chromatography/quadrupole time-of-flight tandem mass spectrometry and in silico toxicity predictions. AB - RATIONALE: Forced degradation studies are useful for better understanding of the stability of active pharmaceutical ingredients and drugs and to generate information about drug degradation pathways and formation of degradation products (DPs). Identification of DPs plays a vital role in establishing the safety and therapeutic benefit of a drug. METHODS: Canagliflozin (CAN) was subjected to different stress conditions as per International Conference on Harmonization guidelines (Q1A R2). All the DPs and the drug were well separated on an Aquity CSH C18 (100 * 2.1 mm, 1.7 MUm) column using acetonitrile-methanol (70:30, v/v) and formic acid in gradient mode. The same UPLC method was employed for LC/HRMS for the characterization of DPs. In addition, in silico toxicity was predicted for all the DPs by using TOPKAT and DEREK software tools. RESULTS: CAN was found to degrade under oxidative stress condition and formed DP1 and DP2. This is a typical case of degradation where co-solvents acetonitrile-water (50:50, v/v) and methanol-water (50:50, v/v) react with CAN under acid hydrolytic conditions leading to the formation of pseudo-DPs, DP3 and DP4, respectively. Among these, DP2 and DP3 showed ocular irritancy whereas DP1 showed skin sensitization. CONCLUSIONS: The drug was labile under oxidative stress condition. CAN reacted with co-solvent under acid hydrolytic conditions and gave pseudo-DPs. All the DPs were separated using UPLC and characterized by LC/QTOF/MS/MS. Toxicity of DPs was evaluated using TOPKAT and DEREK software tools. PMID- 29134713 TI - Comparative ecological transcriptomics and the contribution of gene expression to the evolutionary potential of a threatened fish. AB - Understanding whether small populations with low genetic diversity can respond to rapid environmental change via phenotypic plasticity is an outstanding research question in biology. RNA sequencing (RNA-seq) has recently provided the opportunity to examine variation in gene expression, a surrogate for phenotypic variation, in nonmodel species. We used a comparative RNA-seq approach to assess expression variation within and among adaptively divergent populations of a threatened freshwater fish, Nannoperca australis, found across a steep hydroclimatic gradient in the Murray-Darling Basin, Australia. These populations evolved under contrasting selective environments (e.g., dry/hot lowland; wet/cold upland) and represent opposite ends of the species' spectrum of genetic diversity and population size. We tested the hypothesis that environmental variation among isolated populations has driven the evolution of divergent expression at ecologically important genes using differential expression (DE) analysis and an anova-based comparative phylogenetic expression variance and evolution model framework based on 27,425 de novo assembled transcripts. Additionally, we tested whether gene expression variance within populations was correlated with levels of standing genetic diversity. We identified 290 DE candidate transcripts, 33 transcripts with evidence for high expression plasticity, and 50 candidates for divergent selection on gene expression after accounting for phylogenetic structure. Variance in gene expression appeared unrelated to levels of genetic diversity. Functional annotation of the candidate transcripts revealed that variation in water quality is an important factor influencing expression variation for N. australis. Our findings suggest that gene expression variation can contribute to the evolutionary potential of small populations. PMID- 29134714 TI - Identification of perivascular and stromal mesenchymal stem/progenitor cells in porcine endometrium. AB - Mammalian uterus contains a population of mesenchymal stem/progenitor cells that likely contribute to endometrial regeneration during each reproductive cycle. In human and mouse, they reside in perivascular, epithelial and stromal compartments of the endometrial functionalis and basalis. Here, we aimed to identify tissue resident cells expressing mesenchymal stem cell markers CD29, CD44, CD90, CD105, CD140b and CD146 in the porcine endometrium. We used single immunofluorescence and Western blotting. Each of these markers was detected in small cells surrounding endometrial blood vessels. CD105 and CD146 were also expressed in single stromal cells. A few stromal and perivascular cells showed the presence of pluripotency marker Oct4 in the cytoplasm, but not in the nucleus, which may imply they are not truly pluripotent. Endometrial cell cultures were examined for the expression of CD29, CD44, CD90, CD105 and CD140b proteins and tested in wound healing assay and culture model of chemotaxis. In conclusion, our results demonstrate perivascular location of prospective mesenchymal stem/progenitor cells in the porcine endometrium and may suggest that stromal CD105+ and CD146+ cells represent more mature precursors originating from their perivascular ancestors. PMID- 29134715 TI - Relationship between follicular volume and oocyte competence, blastocyst development and live-birth rate: optimal follicle size for oocyte retrieval. AB - OBJECTIVE: To analyze oocyte competence in gonadotropin-releasing hormone agonist (GnRHa) stimulation cycles with regard to maturity, fertilization and blastocyst rate, as well as clinical outcome (pregnancy and live-birth rate), in relation to follicular volume, measured by three-dimensional transvaginal sonography (3D TVS), and follicular fluid composition. METHODS: This was a prospective single center study conducted between June 2012 and June 2014, including 118 ovum pick ups with subsequent embryo transfer. Ovarian stimulation was performed using the GnRHa long protocol. Of 1493 follicles aspirated individually, follicular volume was evaluated successfully in 1236 using automated 3D-TVS during oocyte retrieval. Oocyte maturity and blastocyst development were tracked according to follicular volume. Intrafollicular concentrations of estradiol, testosterone, progesterone, luteinizing hormone, follicle-stimulating hormone and granulocyte colony stimulating factor were quantified by immunoassay. Clinical outcome, in terms of implantation rate, (clinical) pregnancy rate, miscarriage and live-birth rate (LBR), was evaluated. RESULTS: Follicles were categorized, according to their volume, into three arbitrary groups, which included 196 small (8-12 mm/0.3 0.9 mL), 772 medium (13-23 mm/1-6 mL) and 268 large (>= 24 mm/> 6 mL) follicles. Although oocyte recovery rate was significantly lower in small follicles compared with medium and large ones (63.8% vs 76.6% and 81.3%, respectively; P < 0.001), similar fertilization rates (85.1% vs 75.3% and 81.4%, respectively) and blastocyst rates (40.5% vs 40.6% and 37.2%, respectively) per mature metaphase II oocyte were observed. A trend towards higher LBR after transfer of blastocysts derived from small (< 1 mL) follicles compared with medium (1-6 mL) or large (> 6 mL) follicles (54.5% vs 42.0%, and 41.7%, respectively) was observed. No predictive value of follicular fluid biomarkers was identified. CONCLUSIONS: Our data indicate that the optimal follicular volume for a high yield of good quality blastocysts with good potential to lead to a live birth is 13-23 mm/1-6 mL. However, oocytes derived from small follicles (8-12 mm/0.3-0.9 mL) still have the capacity for normal development and subsequent delivery of healthy children, suggesting that aspiration of these follicles should be encouraged as this would increase the total number of blastocysts retrieved per stimulation. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29134717 TI - Superior colliculus resting state networks in post-traumatic stress disorder and its dissociative subtype. AB - OBJECTIVES: The innate alarm system (IAS) models the neurocircuitry involved in threat processing in posttraumatic stress disorder (PTSD). Here, we investigate a primary subcortical structure of the IAS model, the superior colliculus (SC), where the SC is thought to contribute to the mechanisms underlying threat detection in PTSD. Critically, the functional connectivity between the SC and other nodes of the IAS remains unexplored. EXPERIMENTAL DESIGN: We conducted a resting-state fMRI study to investigate the functional architecture of the IAS, focusing on connectivity of the SC in PTSD (n = 67), its dissociative subtype (n = 41), and healthy controls (n = 50) using region-of-interest seed-based analysis. PRINCIPAL OBSERVATIONS: We observed group-specific resting state functional connectivity between the SC for both PTSD and its dissociative subtype, indicative of dedicated IAS collicular pathways in each group of patients. When comparing PTSD to its dissociative subtype, we observed increased resting state functional connectivity between the left SC and the right dorsolateral prefrontal cortex (DLPFC) in PTSD. The DLPFC is involved in modulation of emotional processes associated with active defensive responses characterising PTSD. Moreover, when comparing PTSD to its dissociative subtype, increased resting state functional connectivity was observed between the right SC and the right temporoparietal junction in the dissociative subtype. The temporoparietal junction is involved in depersonalization responses associated with passive defensive responses typical of the dissociative subtype. CONCLUSIONS: Our findings suggest that unique resting state functional connectivity of the SC parallels the unique symptom profile and defensive responses observed in PTSD and its dissociative subtype. Hum Brain Mapp 39:563 574, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29134716 TI - Advances in computational and statistical diffusion MRI. AB - Computational methods are crucial for the analysis of diffusion magnetic resonance imaging (MRI) of the brain. Computational diffusion MRI can provide rich information at many size scales, including local microstructure measures such as diffusion anisotropies or apparent axon diameters, whole-brain connectivity information that describes the brain's wiring diagram and population based studies in health and disease. Many of the diffusion MRI analyses performed today were not possible five, ten or twenty years ago, due to the requirements for large amounts of computer memory or processor time. In addition, mathematical frameworks had to be developed or adapted from other fields to create new ways to analyze diffusion MRI data. The purpose of this review is to highlight recent computational and statistical advances in diffusion MRI and to put these advances into context by comparison with the more traditional computational methods that are in popular clinical and scientific use. We aim to provide a high-level overview of interest to diffusion MRI researchers, with a more in-depth treatment to illustrate selected computational advances. PMID- 29134718 TI - SIRT1 exhibits antioxidative effects in HT22 cells induced by tert-butyl alcohol. AB - Tertiary butyl alcohol (TBA) is a principal metabolite of methyl tertiary-butyl ether (MTBE), a common pollutant worldwide in the ground or underground water, which is found to produce nervous system damage. Nevertheless, few data regarding the effects of TBA has been reported. Studies indicated that oxidative stress plays a pivotal role in MTBE neurotoxic mechanism. Sirtuin 1 (SIRT1) has been reported to exert a neuroprotective effect on various neurologic diseases via resistance to oxidative stress by deacetylating its substrates. In this study, we examined levels of oxidative stress after exposure to TBA for 6 h in HT22 cells and HT22 cells with SIRT1 silencing (transfected with SIRT1 siRNA) or high expression (preconditioned with agonists SRT1720). We found that TBA activated oxidative stress by increasing generation of intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and Oxidized glutathione (GSSG), and decreasing contents of superoxide dismutase (SOD) and glutathione reductase (GSH). In additional, levels of TBA-induced oxidative stress were aggravated when SIRT1 silenced but alleviated when SIRT1 enhanced. Our study indicated that SIRT1 mitigated oxidative stress induced by TBA. PMID- 29134719 TI - Temporal genetic patterns of diversity and structure evidence chaotic genetic patchiness in a spiny lobster. AB - Population structure of many marine organisms is spatially patchy and varies within and between years, a phenomenon defined as chaotic genetic patchiness. This results from the combination of planktonic larval dispersal and environmental stochasticity. Additionally, in species with bi-partite life, postsettlement selection can magnify these genetic differences. The high fecundity (up to 500,000 eggs annually) and protracted larval duration (12-24 months) and dispersal of the southern rock lobster, Jasus edwardsii, make it a good test species for chaotic genetic patchiness and selection during early benthic life. Here, we used double digest restriction site-associated DNA sequencing (ddRADseq) to investigate chaotic genetic patchiness and postsettlement selection in this species. We assessed differences in genetic structure and diversity of recently settled pueruli across four settlement years and between two sites in southeast Australia separated by approximately 1,000 km. Postsettlement selection was investigated by identifying loci under putative positive selection between recently settled pueruli and postpueruli and quantifying differences in the magnitude and strength of the selection at each year and site. Genetic differences within and among sites through time in neutral SNP markers indicated chaotic genetic patchiness. Recently settled puerulus at the southernmost site exhibited lower genetic diversity during years of low puerulus catches, further supporting this hypothesis. Finally, analyses of outlier SNPs detected fluctuations in the magnitude and strength of the markers putatively under positive selection over space and time. One locus under putative positive selection was consistent at both locations during the same years, suggesting the existence of weak postsettlement selection. PMID- 29134720 TI - Investigation of sarin(Se) reactivity against human plasma proteins using liquid chromatography-tandem mass spectrometry. AB - Electron ionization mass spectrum of sarin(Se) was interpreted in compare of sarin MS spectrum. Inhibition of butyrylcholinesterase of human plasma by sarin and sarin(Se) was determined spectrophotometrically using modified Ellman method. It appeared that after incubation with sarin and sarin(Se), cholinesterase inhibition were 93% and 83%, respectively. Sarin, sarin(Se), and sarin(Se)-d7 were spiked into a vial containing human plasma, and albumin adduct metabolites were identified using liquid chromatography-tandem mass spectrometry. The experiments show that these agents are attached to tyrosine on albumin in human blood. Corresponding deuterated adducts were used to confirm the proposed mechanisms for the formation of the fragments in mass spectrometry experiments. PMID- 29134721 TI - ATR-FTIR spectroscopy and MU-EDXRF spectrometry monitoring of enamel erosion caused by medicaments used in the treatment of respiratory diseases. AB - Medicaments essential for alleviation of diseases may sometime adversely affect dental health by eroding the enamel, owing to their acidic nature. It is therefore highly desirable to be able to detect these effects quickly and reliably. In this study, we evaluated the erosive capacity of four most commonly prescribed respiratory disease syrup medicaments on enamel using micro-energy dispersive X-ray fluorescence spectrometry (u-EDXRF) and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). Fifty-five enamel fragments obtained from 30 bovine teeth were treated with artificial saliva (S), acebrofilin hydrochloride (AC), ambroxol hydrochloride (AM), bromhexine hydrochloride (BR), and salbutamol sulfate (SS); by immersing in 3 mL of respective solutions for 1 min, three times a day at intervals of 1 hr, for 5 days. u-EDXRF analysis of enamel surface did not reveal significant erosion caused by the medications. However, ATR-FTIR showed a detectable shift in the phosphate (PO4 ) antisymmetric stretching mode (nu3 ) at ~985 cm-1 for AM, BR, and SS, indicating erosion. Multivariate statistical analysis showed that AC, AM, SS, and BR could be classified with 70%, 80%, 100%, and 100% efficiency from S (control), further highlighting the ability of ATR-FTIR to identify degree of erosion. This suggests ATR-FTIR may be used to rapidly and nondestructively investigate erosive effects of medicaments. PMID- 29134722 TI - School Climate and College Attendance for Black Adolescents: Moving Beyond College-Going Culture. AB - Understanding how contexts promote positive educational outcomes is a critical objective of adolescent research. This study provides support for the established link between school climate and educational outcomes and expands our understanding of this association by examining multiple aspects of school climate in a sample of Black adolescents in the United States (N = 1,740). Data were drawn from the Education Longitudinal Study of 2002, and multinomial logistic regression and multiple group modeling in a structural equation modeling framework revealed that Black high school students' perceptions of school safety, school liking, and academic press were associated with enrollment in higher education. Null moderation results suggest that these facets of school climate operate similarly for all students regardless of their gender or socioeconomic status. PMID- 29134723 TI - The CT-Defined Hyperdense Arterial Sign as a Marker for Acute Intracerebral Large Vessel Occlusion. AB - BACKGROUND AND PURPOSE: To determine the sensitivity and specificity of the hyperdense artery sign (HAS) on thin-slice non-contrast computed tomography (NCCT), combined with brief clinical history, as an indicator for large vessel occlusion (LVO) in the setting of acute ischemic stroke. METHODS: Ninety-nine LVO and 102 non-LVO acute ischemic stroke patients were retrospectively identified from a prospective database at a single institution. After reviewing each patient's neurologic presentation based on his or her initial National Institute of Health Stroke Scale (NIHSS) and neurologic evaluation, all thin (1 mm) and thick (5 mm) NCCT scans were reviewed for the HAS. Analysis of sensitivity and specificity was conducted to determine the utility of the HAS sign as a reliable marker for LVO in acute ischemic stroke patients. RESULTS: Of the 99 LVO stroke patients, 66 HASs were identified on NCCT. Of the 102 non-LVO patients, 18 false positive HASs were identified. The sensitivity and specificity of the HAS, respectively, was 67% and 82%. By anatomic distribution, the sensitivity of identifying basilar artery occlusions was 75%, and the sensitivity of identifying middle cerebral artery (MCA) M1 branch occlusions was 76%. Among patients with an NIHSS > 10, the sensitivity was 79%; whereas sensitivity was 50% if NIHSS was <= 10. CONCLUSIONS: The HAS on thin-slice NCCT has a reasonably high sensitivity and specificity for identifying LVO in acute ischemic stroke patients presenting with an NIHSS > 10 and suspected MCA M1 or basilar artery occlusion. PMID- 29134725 TI - Reproducibility of Brain MRI Segmentation Algorithms: Empirical Comparison of Local MAP PSTAPLE, FreeSurfer, and FSL-FIRST. AB - BACKGROUND AND PURPOSE: Segmentation of human brain structures is crucial for the volumetric quantification of brain disease. Advances in algorithmic approaches have led to automated techniques that save time compared to interactive methods. Recently, the utility and accuracy of template library fusion algorithms, such as Local MAP PSTAPLE (PSTAPLE), have been demonstrated but there is little guidance regarding its reproducibility compared to single template-based algorithms such as FreeSurfer and FSL-FIRST. METHODS: Eight repeated magnetic resonance imagings of 20 subjects were segmented using FreeSurfer, FSL-FIRST, and PSTAPLE. We reported the reproducibility of segmentation-derived volume measurements for brain structures and calculated sample size estimates for detecting hypothetical rates of tissue atrophy given the observed variances. RESULTS: PSTAPLE had the most reproducible volume measurements for hippocampus, putamen, thalamus, caudate, pallidum, amygdala, Accumbens area, and cortical regions. FreeSurfer was most reproducible for brainstem. PSTAPLE was the most accurate algorithm in terms of several metrics include Dice's coefficient. The sample size estimates showed that a study utilizing PSTAPLE would require tens to hundreds less subjects than the other algorithms for detecting atrophy rates typically observed in brain disease. CONCLUSIONS: PSTAPLE is a useful tool for automatic human brain segmentation due to its precision and accuracy, which enable the detection of the size of the effect typically reported for neurological disorders with a substantially reduced sample size, in comparison to the other tools we assessed. This enables randomized controlled trials to be executed with reduced cost and duration, in turn, facilitating the assessment of new therapeutic interventions. PMID- 29134724 TI - Biogeography of mutualistic fungi cultivated by leafcutter ants. AB - Leafcutter ants propagate co-evolving fungi for food. The nearly 50 species of leafcutter ants (Atta, Acromyrmex) range from Argentina to the United States, with the greatest species diversity in southern South America. We elucidate the biogeography of fungi cultivated by leafcutter ants using DNA sequence and microsatellite-marker analyses of 474 cultivars collected across the leafcutter range. Fungal cultivars belong to two clades (Clade-A and Clade-B). The dominant and widespread Clade-A cultivars form three genotype clusters, with their relative prevalence corresponding to southern South America, northern South America, Central and North America. Admixture between Clade-A populations supports genetic exchange within a single species, Leucocoprinus gongylophorus. Some leafcutter species that cut grass as fungicultural substrate are specialized to cultivate Clade-B fungi, whereas leafcutters preferring dicot plants appear specialized on Clade-A fungi. Cultivar sharing between sympatric leafcutter species occurs frequently such that cultivars of Atta are not distinct from those of Acromyrmex. Leafcutters specialized on Clade-B fungi occur only in South America. Diversity of Clade-A fungi is greatest in South America, but minimal in Central and North America. Maximum cultivar diversity in South America is predicted by the Kusnezov-Fowler hypothesis that leafcutter ants originated in subtropical South America and only dicot-specialized leafcutter ants migrated out of South America, but the cultivar diversity becomes also compatible with a recently proposed hypothesis of a Central American origin by postulating that leafcutter ants acquired novel cultivars many times from other nonleafcutter fungus-growing ants during their migrations from Central America across South America. We evaluate these biogeographic hypotheses in the light of estimated dates for the origins of leafcutter ants and their cultivars. PMID- 29134726 TI - The divergence history of the perennial plant Linaria cavanillesii confirms a recent loss of self-incompatibility. AB - Many angiosperms prevent inbreeding through a self-incompatibility (SI) system, but the loss of SI has been frequent in their evolutionary history. The loss of SI may often lead to an increase in the selfing rate, with the purging of inbreeding depression and the ultimate evolution of a selfing syndrome, where plants have smaller flowers with reduced pollen and nectar production. In this study, we used approximate Bayesian computation (ABC) to estimate the timing of divergence between populations of the plant Linaria cavanillesii that differ in SI status and in which SI is associated with low inbreeding depression but not with a transition to full selfing or a selfing syndrome. Our analysis suggests that the mixed-mating self-compatible (SC) population may have begun to diverge from the SI populations around 2810 generation ago, a period perhaps too short for the evolution of a selfing syndrome. We conjecture that the SC population of L. cavanillesii is at an intermediate stage of transition between outcrossing and selfing. PMID- 29134727 TI - A sRNA in a reduced mutualistic symbiont genome regulates its own gene expression. AB - Similar to other nutritional endosymbionts that are obligate for host survival, the mutualistic aphid endosymbiont, Buchnera, has a highly reduced genome with few regulatory elements. Until recently, it was thought that aphid hosts were primarily responsible for regulating their symbiotic relationship. However, we recently revealed that Buchnera displays differential protein regulation, but not mRNA expression. We also identified a number of conserved small RNAs (sRNAs) that are expressed among Buchnera taxa. In this study, we investigate whether differential protein regulation in Buchnera is the result of post-transcriptional gene regulation via sRNAs. We characterize the sRNA profile of two Buchnera life stages: (i) when Buchnera is transitioning from an extracellular proliferating state in aphid embryos and (ii) when Buchnera is in an intracellular nonproliferating state in aphid bacteriocytes (specialized symbiont cells). Overall, we identified 90 differentially expressed sRNAs, 97% of which were upregulated in aphid embryos. Of these sRNAs, the majority were predicted to be involved in the regulation of various metabolic processes, including arginine biosynthesis. Using a heterologous dual expression vector, we reveal for the first time that a Buchnera antisense sRNA can post-transcriptionally interact with its cognate Buchnera coding sequence, carB, a gene involved in arginine biosynthesis. These results corroborate our in vivo RNAseq and proteomic data, where the candidate antisense sRNA carB and the protein CarB are significantly upregulated in aphid embryos. Overall, we demonstrate that Buchnera may regulate gene expression independently from its host by utilizing sRNAs. PMID- 29134728 TI - Recent advances in veterinary radiation oncology. PMID- 29134730 TI - Role of central versus peripheral opioid system in antinociceptive and anti inflammatory effect of botulinum toxin type A in trigeminal region. AB - BACKGROUND: Although botulinum toxin type A (BT-A) is approved for chronic migraine treatment, its site and mechanism of action are still elusive. Recently our group discovered that suppression of CGRP release from dural nerve endings might account for antimigraine action of pericranially injected BT-A. We demonstrated that central antinociceptive effect of BT-A in sciatic region involves endogenous opioid system as well. Here we investigated possible interaction of BT-A with endogenous opioid system within the trigeminal region. METHODS: In orofacial formalin test we investigated the influence of centrally acting opioid antagonist naltrexone (2 mg/kg, s.c.) versus peripherally acting methylnaltrexone (2 mg/kg, s.c.) on BT-A's (5 U/kg, s.c. into whisker pad) or morphine's (6 mg/kg, s.c.) antinociceptive effect and the effect on dural neurogenic inflammation (DNI). DNI was assessed by Evans blue-plasma protein extravasation. RESULTS: Naltrexone abolished the effect of BT-A on pain and dural plasma protein extravasation, whereas peripherally acting methylnaltrexone did not change either BT-A's effect on pain or its effect on dural extravasation. Naltrexone abolished the antinociceptive and anti-inflammatory effects of morphine, as well. However, methylnaltrexone decreased the antinociceptive effect of morphine only partially in the second phase of the test and had no significant effect on morphine-mediated reduction in DNI. CONCLUSIONS: Morphine acts on pain in trigeminal region both peripherally and centrally, whereas the effect on dural plasma protein extravasation seems to be only centrally mediated. However, the interaction of BT-A with endogenous opioid system, with consequent inhibition of nociceptive transmission as well as the DNI, occurs primarily centrally. SIGNIFICANCE: Botulinum toxin type A (BT-A)'s axonal transport and potential transcytosis suggest that its antinociceptive effect might involve diverse neurotransmitters at different sites of trigeminal system. Here we discovered that the reduction in pain and accompanying DNI involves the interaction of BT-A with central endogenous opioid system (probably at the level of trigeminal nucleus caudalis). PMID- 29134729 TI - Maintaining their genetic distance: Little evidence for introgression between widely hybridizing species of Geum with contrasting mating systems. AB - Within the plant kingdom, many genera contain sister lineages with contrasting outcrossing and inbreeding mating systems that are known to hybridize. The evolutionary fate of these sister lineages is likely to be influenced by the extent to which they exchange genes. We measured gene flow between outcrossing Geum rivale and selfing Geum urbanum, sister species that hybridize in contemporary populations. We generated and used a draft genome of G. urbanum to develop dd-RAD data scorable in both species. Coalescent analysis of RAD data from allopatric populations indicated that the species diverged 2-3 Mya, and that historical gene flow between them was extremely low (1 migrant every 25 generations). Comparison of genetic divergence between species in sympatry and allopatry, together with an analysis of allele frequencies in potential parental and hybrid populations, provided no evidence of contemporary introgression in sympatric populations. Cluster- and species-specific marker analyses revealed that, apart from four early-generation hybrids, individuals in sympatric populations fell into two genetically distinct groups that corresponded exactly to their morphological species classification with maximum individual admixture estimates of only 1-3%. However, we did observe joint segregation of four putatively introgressed SNPs across two scaffolds in the G. urbanum population that was associated with significant morphological variation, interpreted as tentative evidence for rare, recent interspecific gene flow. Overall, our results indicate that despite the presence of hybrids in contemporary populations, genetic exchange between G. rivale and G. urbanum has been extremely limited throughout their evolutionary history. PMID- 29134731 TI - Enigma portal case: Pleural effusion. PMID- 29134732 TI - Management Errors and System Reliability: A Probabilistic Approach and Application to Offshore Platforms. AB - Probabilistic risk analysis, based on the identification of failure modes, points to technical malfunctions and operator errors that can be direct causes of system failure. Yet component failures and operator errors are often rooted in management decisions and organizational factors. Extending the analysis to identify these factors allows more effective risk management strategies. It also permits a more realistic assessment of the overall failure probability. An implicit assumption that is often made in PRA is that, on the whole, the system has been designed according to specified norms and constructed as designed. Such an analysis tends to overemphasize scenarios in which the system fails because it is subjected to a much higher load than those for which it was designed. In this article, we find that, for the case of jacket-type offshore platforms, this class of scenarios contributes only about 5% of the failure probability. We link the PRA inputs to decisions and errors during the three phases of design, construction, and operation of platforms, and we assess the contribution of different types of error scenarios to the overall probability of platform failure. We compute the benefits of improving the design review, and we find that, given the costs involved, improving the review process is a more efficient way to increase system safety than reinforcing the structure. PMID- 29134733 TI - Risk Management as a Postnormal Science2. PMID- 29134734 TI - Distribution and Expected Time of Residence for U.S. Households. AB - For risk assessments, the average current residence time (time since moving into current residence) has often been used as a surrogate for the average total residence time (time between moving into and out of a residence). Since the distributions of the two quantities are not necessarily the same, neither are their averages. Housing surveys provide current residence time data; total residence times must, therefore, be inferred. By modeling the moving process, the total residence time distribution can be estimated from current residence time data. Using 1985 and 1987 U.S. housing survey data, distributions and averages for both current and total residence times were calculated for several housing categories. The average total residence time calculated for all U.S. households, 4.6 (se= 0.6) years, is less than half the average current residence time, 10.6 (se= 0.1) years. PMID- 29134735 TI - Software Listings. PMID- 29134736 TI - The Market Response to the Sioux City DC-10 Crash. AB - The 1989 DC-10 crash at Sioux City, Iowa presented a rare instance in which a potential threat to safety was both (i) intensely publicized over a short period and (ii) also amenable to the unobtrusive measurement of the market reaction it evoked. As such, it allowed a useful case study of the extent and duration of behavior change caused by a frightening event. Using reservations data from travel agencies in five states, this paper estimates the short-term effects of the Sioux City crash on passenger willingness to fly the DC-10. The data suggest that, in the first few weeks after the crash, more than one third of travelers who would normally have booked DC-10 flights chose instead to fly other aircraft. Within 2 months of the disaster, however, DC-10 bookings rebounded to within 10% of the level that would have been expected had the Sioux City crash not occurred. At no time, apparently, did the airlines that operate DC-10s use their "yield management" computer pricing systems unofficially to lower DC-10 fares relative to those on other types of plane. PMID- 29134737 TI - A Review of RISKPRO Version 2.1. PMID- 29134738 TI - Fungal community reveals less dispersal limitation and potentially more connected network than that of bacteria in bamboo forest soils. AB - A central aim of this microbial ecology research was to investigate the mechanisms shaping the assembly of soil microbial communities. Despite the importance of bacterial and fungal mediation of carbon cycling in forest ecosystems, knowledge concerning their distribution patterns and underlying mechanisms remains insufficient. Here, soils were sampled from six bamboo forests across the main planting area of Moso bamboo in southern China. The bacterial and fungal diversities were assessed by sequencing 16S rRNA and ITS gene amplicons, respectively, with an Illumina MiSeq. Based on structural equation modelling, dispersal limitation had strongest impact on bacterial beta diversity, while the mean annual precipitation had a smaller impact by directly or indirectly mediating the soil organic carbon density. However, only the mean annual temperature and precipitation played direct roles in fungal beta diversity. Moreover, the co-occurrence network analyses revealed a possibly much higher network connectivity in the fungal network than in the bacteria. With less dispersal limitation, stronger environmental selection and a potentially more connected network, the fungal community had more important roles in the soil carbon metabolisms in bamboo forests. Fungal beta diversity and the clustering coefficient explained approximately 14.4% and 6.1% of the variation in the carbon metabolic profiles among sites, respectively, but that of bacteria only explained approximately 1.7% and 1.8%, respectively. This study explored soil microbial spatial patterns along with the underlying mechanisms of dispersal limitation, selection and connectivity of ecological networks, thus providing novel insights into the study of the distinct functional traits of different microbial taxa. PMID- 29134739 TI - Phenotypic plasticity in response to environmental heterogeneity contributes to fluctuating asymmetry in plants: first empirical evidence. AB - Fluctuating asymmetry (FA) is widely used to quantify developmental instability (DI) in ecological and evolutionary studies. It has long been recognized that FA may not exclusively originate from DI for sessile organisms such as plants, because phenotypic plasticity in response to heterogeneities in the environment might also produce FA. This study provides the first empirical evidence for this hypothesis. We reasoned that solar irradiance, which is greater on the southern side than on the northern side of plants growing in the temperate zone of the Northern Hemisphere, would cause systematic morphological differences and asymmetry associated with the orientation of plant parts. We used geometric morphometrics to characterize the size and shape of flower parts in Iris pumila grown in a common garden. The size of floral organs was not significantly affected by orientation. Shape and particularly its asymmetric component differed significantly according to orientation for three different floral parts. Orientation accounted for 10.4% of the total shape asymmetry within flowers in the falls, for 11.4% in the standards and for 2.2% in the style branches. This indicates that phenotypic plasticity in response to a directed environmental factor, most likely solar irradiance, contributes to FA of flowers under natural conditions. That FA partly results from phenotypic plasticity and not just from DI needs to be considered by studies of FA in plants and other sessile organisms. PMID- 29134740 TI - Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: A potential biomarker for predicting inferior survival. AB - BACKGROUND: Studies on mitochondrial DNA copy number reveal an increase or decrease in copy number that appears to be cancer specific, but data on acute lymphoblastic leukemia have been inconsistent regarding the significance of changes in mitochondrial DNA copies. The purpose of this pilot study was to analyze mitochondrial DNA copy number and mitochondrial DNA integrity. PROCEDURE: Copy number and mitochondrial deletion ratios were estimated in the bone marrow of 51 patients and peripheral blood of 30 healthy controls using quantitative real-time PCR. The copy number values were correlated with prognostic markers in patients. RESULTS: Significantly increased mitochondrial DNA copy number (P-value < 0.0001) and increased mitochondrial deletion ratios (P-value = 0.0018) were observed in patients compared with controls. The copy numbers were significantly decreased in patients after chemotherapy (P-value = 0.0232). Patients with higher copy numbers exhibited significantly inferior survival than patients with lower copy numbers (for event-free survival, P-value = 0.04 and overall survival, P value = 0.1175). CONCLUSIONS: Significant decreases in mitochondrial DNA copy number with therapy indicates that copy number could be evaluated as a potential marker for therapeutic efficacy and a higher mitochondrial DNA copy number could be a poor prognostic marker. PMID- 29134741 TI - Contemporary evolution of a Lepidopteran species, Heliothis virescens, in response to modern agricultural practices. AB - Adaptation to human-induced environmental change has the potential to profoundly influence the genomic architecture of affected species. This is particularly true in agricultural ecosystems, where anthropogenic selection pressure is strong. Heliothis virescens primarily feeds on cotton in its larval stages, and US populations have been declining since the widespread planting of transgenic cotton, which endogenously expresses proteins derived from Bacillus thuringiensis (Bt). No physiological adaptation to Bt toxin has been found in the field, so adaptation in this altered environment could involve (i) shifts in host plant selection mechanisms to avoid cotton, (ii) changes in detoxification mechanisms required for cotton-feeding vs. feeding on other hosts or (iii) loss of resistance to previously used management practices including insecticides. Here, we begin to address whether such changes occurred in H. virescens populations between 1997 and 2012, as Bt-cotton cultivation spread through the agricultural landscape. For our study, we produced an H. virescens genome assembly and used this in concert with a ddRAD-seq-enabled genome scan to identify loci with significant allele frequency changes over the 15-year period. Genetic changes at a previously described H. virescens insecticide target of selection were detectable in our genome scan and increased our confidence in this methodology. Additional loci were also detected as being under selection, and we quantified the selection strength required to elicit observed allele frequency changes at each locus. Potential contributions of genes near loci under selection to adaptive phenotypes in the H. virescens cotton system are discussed. PMID- 29134742 TI - Innovative technologies for point-of-care testing of viral hepatitis in low resource and decentralized settings. AB - According to the Global Burden of Diseases, chronic viral hepatitis B and C are one of the most challenging global health conditions that rank among the first causes of morbidity and mortality worldwide. Low- and middle-income countries are particularly affected by the health burden associated with HBV or HCV infection. One major gap in efficiently addressing the issue of viral hepatitis is universal screening. However, the costs and chronic lack of human resources for using traditional screening strategies based on serology and molecular biology preclude any scaling-up. Point-of-care tests have been deemed a powerful potential solution to fill the current diagnostics gap in low-resource and decentralized settings. Despite high interest resulting from their development in recent years, very few point-of-care devices have reached the market. Scaling down and automating all testing steps in 1 single device (eg, sample preparation, detection and readout) is indeed challenging. But innovations in multiple disciplines such as nanotechnologies, microfluidics, biosensors and synthetic biology have led to the creation of chip-sized laboratory systems called "lab-on a-chip" devices. This review aims to explain how these innovations can overcome technological barriers that usually arise for each testing step while developing integrated point-of-care tests. Point-of-care test prototypes rarely meet the requirements for mass production, which also hinders their large-scale production. In addition to logistical hurdles, legal and economic constraints specific to the commercialization of in vitro diagnostics, which have also participated in the low transfer of innovative point-of-care tests to the field, are discussed. PMID- 29134743 TI - Rapid determination of ginkgolic acids in Ginkgo biloba kernels and leaves by direct analysis in real time-mass spectrometry. AB - A novel method based on direct analysis in real time integrated with mass spectrometry was established and applied into rapid determination of ginkgolic acids in Ginkgo biloba kernels and leaves. Instrument parameter settings were optimized to obtain the sensitive and accurate determination of ginkgolic acids. At the sample introduction speed of 0.2 mm/s, high intensity of [M-H]- ions for ginkgolic acids were observed in the negative ion mode by utilization of high purity helium gas at 450 degrees C. Two microliters of methanol extract of G. biloba kernels or leaves dropped on the surface of Quick-Strip module was analyzed after solvent evaporated to dryness. A series of standard solutions of ginkgolic acid 13:0 in the range of 2-50 mg/L were analyzed with a correlation coefficient r = 0.9981 and relative standard deviation (n = 5) from 12.5 to 13.7%. The limit of detection was 0.5 mg/L. The results of direct analysis in real time-mass spectrometry were in agreement with those observed by thermochemolysis gas chromatography. The proposed method demonstrated significant potential in the application of the high-throughput screening and rapid analysis for ginkgolic acids in dietary supplements. PMID- 29134744 TI - Acute oral sodium propionate supplementation raises resting energy expenditure and lipid oxidation in fasted humans. AB - Short-chain fatty acids (SCFAs), produced from fermentation of dietary fibre by the gut microbiota, have been suggested to modulate energy metabolism. Previous work using rodent models has demonstrated that oral supplementation of the SCFA propionate raises resting energy expenditure (REE) by promoting lipid oxidation. The objective of the present study was to investigate the effects of oral sodium propionate on REE and substrate metabolism in humans. Eighteen healthy volunteers (9 women and 9 men; age 25 +/- 1 years; body mass index 24.1 +/- 1.2 kg/m2 ) completed 2 study visits following an overnight fast. Tablets containing a total of 6845 mg sodium propionate or 4164 mg sodium chloride were provided over the 180-minute study period in random order. REE and substrate oxidation were assessed by indirect calorimetry. Oral sodium propionate administration increased REE (0.045 +/- 0.020 kcal/min; P = .036); this was accompanied by elevated rates of whole-body lipid oxidation (0.012 +/- 0.006 g/min; P = .048) and was independent of changes in glucose and insulin concentrations. Future studies are warranted to determine whether the acute effects of oral sodium propionate on REE translate into positive improvements in long-term energy balance in humans. PMID- 29134745 TI - Mechanosignalling in tumour progression. PMID- 29134747 TI - No sex difference in digit ratios (2D:4D) in the traditional Yali of Papua and its meaning for the previous hypotheses on the inter-populational variability in 2D:4D. AB - OBJECTIVES: The ratio between the 2nd and 4th digit (2D:4D) is considered to be a sexually dimorphic trait in humans, with males having on average lower 2D:4D values than females. However, significant inter- and intra-sexual differences in digit ratios across populations have been reported. In order to further explore factors influencing the variability of 2D:4D, we performed a study among the Yali, a traditional population from Papua. METHODS: We measured digit ratios of 79 adults (47 males) from the traditional Yali society, a polygamous group who inhabit a harsh high-mountain environment almost directly on the equator. RESULTS: Statistical analysis of the data show no significant inter-sexual difference in digit ratios in our sample. CONCLUSIONS: We discuss the results in light of various factors that putatively shape the differences in digit ratios. We conclude that the results of our study contribute to the existing evidence suggesting that digit ratio might not be universally sexually dimorphic in humans. PMID- 29134746 TI - Fenofibrate induced PPAR alpha expression was attenuated by oestrogen receptor alpha overexpression in Hep3B cells. AB - The physiological regulation of Oestrogen receptor alpha (ERalpha) and peroxisome proliferator-activated receptor alpha (PPARalpha) in Hepatocellular carcinoma (HCC) remains unknown. The present study we first treat the cells with fenofibrate and further investigated the possible mechanisms of 17beta-estradiol (E2 ) and/or ERalpha on regulating PPARalpha expression. We also found higher PPARalpha expression in the tumor area than adjacent areas and subsequently compared PPARalpha expression in four different hepatic cancer cell lines. Hep3B cells were found to express more PPARalpha than the other cell lines. Using the PPARalpha agonist fenofibrate, we found that fenofibrate increased Hep3B cell proliferation efficiency by increasing cell cycle proteins, such as cyclin D1 and PCNA, and inhibiting p27 and caspase 3 expressions. Next, we performed transient transfections and immuno-precipitation studies using the pTRE2/ERalpha plasmid to evaluate the interaction between ERalpha and PPARalpha. ERalpha interacted directly with PPARalpha and negatively regulated its function. Moreover, in Tet on ERalpha over-expressed Hep3B cells, E2 treatment inhibited PPARalpha, its downstream gene acyl-CoA oxidase (ACO), cyclin D1 and PCNA expression and further increased p27 and caspase 3 expressions. However, over-expressed ERalpha plus 17 beta-estradiol (10-8 M) reversed the fenofibrate effect and induced apoptosis, which was blocked in ICI/melatonin/fenofibrate-treated cells. This study illustrates that PPARalpha expression and function were negatively regulated by ERalpha expression in Hep3B cells. PMID- 29134748 TI - Novel topical agent containing superoxide dismutase 100 000 IU and 4% of plant extracts as a mono-therapy for atopic dermatitis. AB - INTRODUCTION: Corticosteroids are the mainstay of treatment for the acute phase of atopic dermatitis (AD), whereas topical emollients are mainly used for maintenance of remission. A topical agent that combines emollient and anti inflammatory properties would achieve control of all phases of AD, without the need for chronic corticosteroid use. AIM: To assess the efficacy of a novel topical agent containing superoxide dismutase (SOD) 100 000 IU and 4% of a combination of plant extracts (blackcurrant seed oil, sunflower oil concentrate, balloon vine extract). METHODS: Twenty patients (age range from 8 months to 72 years old) with mild-to-moderate atopic dermatitis were assessed. The product was used as mono-therapy, applied to the affected skin areas twice daily. Patients were evaluated before and after a 30-day course using the SCORAD and the Visual Analog Scale for assessment of pruritus intensity. Primary endpoint was improvement of AD according to SCORAD and clinical assessment. Secondary endpoint was patient satisfaction and improvement of pruritus. RESULTS: Mean SCORAD on day 0 was 32.61(range = 16.0-46.9) and decreased to 10.55 (range = 0-17.0) on day 30, reflecting a reduction of 67.6%. On day 30, all patients described significant improvement in pruritus and quality of sleep. CONCLUSION: The application of the study product cream resulted in significant improvement of AD, as reflected by the objective SCORAD measurement, and the subjective assessment of pruritus and quality of life. This novel anti-inflammatory emollient product may emerge as a safe and effective therapeutic tool for all phases of AD without the adverse effects of chronic use of corticosteroids. PMID- 29134749 TI - Transition-Metal pi-Ligation of a Tetrahalodiborane. AB - The reaction of tetraiododiborane (B2 I4 ) with trans-[Pt(BI2 )I(PCy3 )2 ] gives rise to the diplatinum(II) complex [{(Cy3 P)(I2 B)Pt}2 (MU2 :eta3 :eta3 -B2 I4 )], which is supported by a bridging diboranyl dianion ligand [B2 I4 ]2- . This complex is the first transition-metal complex of a diboranyl dianion, as well as the first example of intact coordination of a B2 X4 (X=halide) unit of any type to a metal center. PMID- 29134750 TI - Tumor predisposition syndromes: The challenge of de novo mutations. PMID- 29134751 TI - Cortical hemispheric asymmetries are present at young ages and further develop into adolescence. AB - Specialization of the auditory cortices for pure tone listening may develop with age. In adults, the right hemisphere dominates when listening to pure tones and music; we thus hypothesized that (a) asymmetric function between auditory cortices increases with age and (b) this development is specific to tonal rather than broadband/non-tonal stimuli. Cortical responses to tone-bursts and broadband click-trains were recorded by multichannel electroencephalography in young children (5.1 +/- 0.8 years old) and adolescents (15.2 +/- 1.7 years old) with normal hearing. Peak dipole moments indicating activity strength in right and left auditory cortices were calculated using the Time Restricted, Artefact and Coherence source Suppression (TRACS) beamformer. Monaural click-trains and tone bursts in young children evoked a dominant response in the contralateral right cortex by left ear stimulation and, similarly, a contralateral left cortex response to click-trains in the right ear. Responses to tone-bursts in the right ear were more bilateral. In adolescents, peak activity dominated in the right cortex in most conditions (tone-bursts from either ear and to clicks from the left ear). Bilateral activity was evoked by right ear click stimulation. Thus, right hemispheric specialization for monaural tonal stimuli begins in children as young as 5 years of age and becomes more prominent by adolescence. These changes were marked by consistent dipole moments in the right auditory cortex with age in contrast to decreases in dipole activity in all other stimulus conditions. Together, the findings reveal increasingly asymmetric function for the two auditory cortices, potentially to support greater cortical specialization with development into adolescence. PMID- 29134752 TI - Ideal Bandgap Organic-Inorganic Hybrid Perovskite Solar Cells. AB - Extremely high power conversion efficiencies (PCEs) of ~20-22% are realized through intensive research and development of 1.5-1.6 eV bandgap perovskite absorbers. However, development of ideal bandgap (1.3-1.4 eV) absorbers is pivotal to further improve PCE of single junction perovskite solar cells (PVSCs) because of a better balance between absorption loss of sub-bandgap photons and thermalization loss of above-bandgap photons as demonstrated by the Shockley Queisser detailed balanced calculation. Ideal bandgap PVSCs are currently hindered by the poor optoelectronic quality of perovskite absorbers and their PCEs have stagnated at <15%. In this work, through systematic photoluminescence and photovoltaic analysis, a new ideal bandgap (1.35 eV) absorber composition (MAPb0.5 Sn0.5 (I0.8 Br0.2 )3 ) is rationally designed and developed, which possesses lower nonradiative recombination states, band edge disorder, and Urbach energy coupled with a higher absorption coefficient, which yields a reduced Voc,loss (0.45 V) and improved PCE (as high as 17.63%) for the derived PVSCs. This work provides a promising platform for unleashing the complete potential of ideal bandgap PVSCs and prospects for further improvement. PMID- 29134753 TI - Freestanding NiFe Oxyfluoride Holey Film with Ultrahigh Volumetric Capacitance for Flexible Asymmetric Supercapacitors. AB - In this work, a freestanding NiFe oxyfluoride (NiFeOF) holey film is prepared by electrochemical deposition and anodic treatments. With the combination of good electrical conductivity and holey structure, the NiFeOF holey film offers superior electrochemical performance with maximum specific capacitance of 670 F cm-3 (134 mF cm-2 ), due to the following reasons: (i) The residual metal alloy framework can be used as the current collector to improve electrode conductivity. Moreover, the as-prepared freestanding NiFeOF holey film can be used as a supercapacitor electrode without reliance on binders and other additives. The residual metal alloy framework and binder-free electrode effectively reduce electrode resistance, thus improving electron transport. (ii) The highly interconnected holey structure and hierarchical pore distribution provide a high specific surface area to improve electron transport, enhancing rapid ion transport, and mitigating diffusion limitations throughout the holey film. (iii) The excellent mechanical characteristics facilitate flexibility and cyclability related performance. Additionally, the NiFeOF holey film presents exceptional electrochemical performance, showing that it is a promising alternative for small/microsize electronic devices. PMID- 29134754 TI - A decrease in the abundance and strategic sophistication of cleaner fish after environmental perturbations. AB - Coral reef ecosystems are declining worldwide and under foreseeable threat due to climate change, resulting in significant changes in reef communities. It is unknown, however, how such community changes impact interspecific interactions. Recent extreme weather events affecting the Great Barrier Reef, that is, consecutive cyclones and the 2016 El Nino event, allowed us to explore potential consequences in the mutualistic interactions involving cleaner fish Labroides dimidiatus (hereafter "cleaner"). After the perturbations, cleaner densities were reduced by 80%, disproportionally compared to the variety of reef fish clients from which cleaners remove ectoparasites. Consequently, shifts in supply and demand yielded an increase in the clients' demand for cleaning. Therefore, clients became less selective toward cleaners, whereas cleaners were able to choose from a multitude of partners. In parallel, we found a significant decline in the ability of cleaners to manage their reputation and to learn to prioritize ephemeral food sources to maximize food intake in laboratory experiments. In other words, cleaners failed to display the previously documented strategic sophistication that made this species a prime example for fish intelligence. In conclusion, low population densities may cause various effects on individual behavior, and as a consequence, interspecific interactions. At the same time, our data suggest that a recovery of population densities would cause a recovery of previously described interaction patterns and cleaner strategic sophistication within the lifetime of individuals. PMID- 29134755 TI - Analysis of the influence of collagen fibres in the dermis on skin optical reflectance by Monte Carlo simulation in a nine-layered skin model. AB - BACKGROUND: Collagen fibres in the dermis play an important structural role in the skin. Age-related changes to these fibres cause wrinkles and slackness of facial skin. However, it is not clear how dermal collagen fibres affect skin colour. The purpose of this study was to clarify the influence of altered collagen fibres on skin colour, using both experimental measurement of fibre density and Monte Carlo simulations in an optical model of skin. METHODS: Reflection spectra were measured from the cheeks of 12 Japanese women (22-65 years old) by spectral colorimeter. Two-dimensional autocorrelation functions were calculated from second harmonics generation (SHG) images acquired from the same locations and used to calculate collagen density indices. Monte Carlo simulations of light reflectance by skin were performed using a nine-layered model that precisely imitates skin structure. The relationship between dermal collagen fibre density and skin reflection spectra was analysed. RESULTS: A positive correlation was found between collagen density and skin brightness, as measured by the colour value, L* (using the L*a*b* colour space). In addition, collagen density showed a strong inverse correlation with age and with the optical absorption of dermis. The Monte Carlo simulations showed that the reflection spectrum of skin changes when the scattering coefficient of the dermis is altered. These changes were the same for simulated and experimentally measured reflection spectra. CONCLUSION: When collagen fibre density in the upper dermis is decreased with age, skin colour becomes less bright because light scattering in the skin is decreased. PMID- 29134756 TI - Development of Predictive QSAR Models of 4-Thiazolidinones Antitrypanosomal Activity Using Modern Machine Learning Algorithms. AB - This paper presents novel QSAR models for the prediction of antitrypanosomal activity among thiazolidines and related heterocycles. The performance of four machine learning algorithms: Random Forest regression, Stochastic gradient boosting, Multivariate adaptive regression splines and Gaussian processes regression have been studied in order to reach better levels of predictivity. The results for Random Forest and Gaussian processes regression are comparable and outperform other studied methods. The preliminary descriptor selection with Boruta method improved the outcome of machine learning methods. The two novel QSAR-models developed with Random Forest and Gaussian processes regression algorithms have good predictive ability, which was proved by the external evaluation of the test set with corresponding Q2ext =0.812 and Q2ext =0.830. The obtained models can be used further for in silico screening of virtual libraries in the same chemical domain in order to find new antitrypanosomal agents. Thorough analysis of descriptors influence in the QSAR models and interpretation of their chemical meaning allows to highlight a number of structure-activity relationships. The presence of phenyl rings with electron-withdrawing atoms or groups in para-position, increased number of aromatic rings, high branching but short chains, high HOMO energy, and the introduction of 1-substituted 2-indolyl fragment into the molecular structure have been recognized as trypanocidal activity prerequisites. PMID- 29134757 TI - Asymmetric Fullerene Nanosurfactant: Interface Engineering for Automatic Molecular Alignments. AB - Since the molecular self-assembly of nanomaterials is sensitive to their surface properties, the molecular packing structure on the surface is essential to build the desired chemical and physical properties of nanomaterials. Here, a new nanosurfactant is proposed for the automatic construction of macroscopic surface alignment layer for liquid crystal (LC) molecules. An asymmetric nanosurfactant (C60 NS) consisted of mesogenic cyanobiphenyl moieties with flexible alkyl chains and a [60]fullerene nanoatom is newly designed and precisely synthesized. The C60 NS directly introduced in the anisotropic LC medium is self-assembled into the monolayered protrusions on the surface because of its amphiphilic nature originated by asymmetrically programmed structural motif of LC-favoring moieties and LC-repelling groups. The monolayered protrusions constructed by the phase separation and self-assembly of asymmetric C60 NS nanosurfactant in the anisotropic LC media amplify and transfer the molecular orientational order from surface to bulk, and finally create the automatic vertical molecular alignment on the macroscopic length scale. The asymmetric C60 NS nanosurfactant and its self assembly described herein can offer the direct guideline of interface engineering for the automatic molecular alignments. PMID- 29134758 TI - Who is responsible for delivering palliative care to children with cancer? PMID- 29134759 TI - Ni-Nanocluster Modified Black TiO2 with Dual Active Sites for Selective Photocatalytic CO2 Reduction. AB - One of the key challenges in artificial photosynthesis is to design a photocatalyst that can bind and activate the CO2 molecule with the smallest possible activation energy and produce selective hydrocarbon products. In this contribution, a combined experimental and computational study on Ni-nanocluster loaded black TiO2 (Ni/TiO2[Vo] ) with built-in dual active sites for selective photocatalytic CO2 conversion is reported. The findings reveal that the synergistic effects of deliberately induced Ni nanoclusters and oxygen vacancies provide (1) energetically stable CO2 binding sites with the lowest activation energy (0.08 eV), (2) highly reactive sites, (3) a fast electron transfer pathway, and (4) enhanced light harvesting by lowering the bandgap. The Ni/TiO2[Vo] photocatalyst has demonstrated highly selective and enhanced photocatalytic activity of more than 18 times higher solar fuel production than the commercial TiO2 (P-25). An insight into the mechanisms of interfacial charge transfer and product formation is explored. PMID- 29134760 TI - JAK2 haplotype 46/1 and JAK2 V617F allele burden in MPN: New evidence against the "hypermutability" hypothesis? PMID- 29134761 TI - One-Pot Synthesis of Contracted and Expanded Porphyrins with meso-CF3 Groups. AB - Corrole and sapphyrin with the smallest meso-substituents reported so far were prepared in a one-pot synthesis that relies on a non-aldehydic precursor for introducing CF3 groups. The substantial amounts of products obtained by this facile pathway allowed for the full characterization of 5,10,15 tris(trifluoromethyl)corrole, the access to a variety of stable chelates thereof and investigations that disclose the unique structural and chemical properties induced by the CF3 substituents. The novel 5,10,15,20 tetra(trifluoromethyl)sapphyrin undergoes only single protonation, which according to its crystal structure is stabilized by favorable non-bonding F/H interaction between the meso-CF3 and the inverted pyrrolic NH. PMID- 29134762 TI - Introduction of Asian canine parvovirus in Europe through dog importation. AB - Canine parvovirus (CPV) is an important infectious agent of domestic and wild carnivores, responsible for severe and often fatal haemorrhagic gastroenteritis and leukopenia. This paper reports the genomic characterization of a CPV strain collected from a dog recently imported to Italy from Thailand. The virus was detected in all tissue samples collected. The whole genome encompassing the two open reading frames encoding for non-structural (NS1/NS2) and structural (VP1/VP2) proteins was amplified and sequenced. On the basis of genetic analysis of the VP2 gene, the isolate was characterized as CPV-2c, but it presented genetic signatures typical of Asian strains. Sequence analysis revealed the presence of amino acid changes never observed in European CPV-2c strains (NS1: Ile60Val, Tyr544Phe, Glu545Val, Leu630Pro; VP2: Ala5Gly, Phe267Tyr, Tyr324Ile, Gln370Arg). By phylogenetic analysis of full-length VP2 gene, the analysed strain clustered together with Asian viruses. Therefore, a possible introduction of the virus from Asia through the imported dog was suggested, thus confirming the important role of movement of dogs in the global spread of viruses. In addition, full-length genome analysis could help better trace the spread of canine viruses through different continents. PMID- 29134763 TI - Trends in Beverage Consumption Among Children and Adults, 2003-2014. AB - OBJECTIVE: This study aimed to provide the most recent national estimates for beverage consumption among children and adults in the United States. METHODS: Dietary data were collected from 18,600 children aged 2 to 19 years and from 27,652 adults aged >= 20 years in the 2003 to 2014 National Health and Nutrition Examination Survey. Total beverage and sugar-sweetened beverage (SSB) consumption was measured by 24-hour dietary recall. RESULTS: From 2003 to 2014, per capita consumption of all beverages declined significantly among children (473.8-312.6 calories; P < 0.001) and adults (425.0-341.1 calories; P < 0.001). In the 2013 2014 survey, 60.7% of children and 50.0% of adults drank SSBs on a given day, which is significantly lower than 2003-2004, when 79.7% of children and 61.5% of adults reported drinking SSBs. From 2003 to 2014, per capita consumption of SSBs declined from 224.6 calories to 132.5 calories (P < 0.001) for children and from 190.4 calories to 137.6 calories (P < 0.001) for adults. The absolute levels for the percentage of SSB drinkers and per capita consumption of SSBs were highest among black, Mexican American, and non-Mexican Hispanic children, adolescents, and young adults for all years of the study. CONCLUSIONS: Overall, beverage and SSB consumption declined for children and adults from 2003 to 2014. The levels of consumption are highest among black, Mexican American, and non-Mexican Hispanic participants. PMID- 29134764 TI - Peptides derived from histidine and methionine-rich regions of copper transporter 1 exhibit anti-angiogenic property by chelating extracellular Cu. AB - Angiogenesis is a process of synthesis of new blood vessels from preexisting vasculature. Copper (Cu) as a micronutrient is important to many proteins for their physiological roles. Cu is transported by ceruloplasmin from liver to other parts of the body. Copper transporter 1 (CTR1) is a transmembrane protein which participate in Cu transport across the cell. It is also known to be involved in angiogenesis. In this study, we have designed three peptides from copper-binding regions of CTR1 which are rich in histidine and methionine. These peptides were screened for their inhibitory effect on angiogenesis in the HUVEC model. Mass spectroscopy studies revealed that all the three peptides derived from CTR 1 (Pep 1, 2, and 3) bound to Cu. The intracellular Cu levels estimated by atomic absorption spectroscopy showed decreased levels of copper in peptide-treated cells as compared to control. These peptides inhibited proliferation, migration, and tube formation in HUVEC by sequestering copper, preventing its entry into the cell and thereby inhibiting angiogenesis. PMID- 29134765 TI - Developmental retinal ganglion cell death and retinotopicity of the murine retinocollicular projection. AB - During mammalian visual system development, retinal ganglion cells (RGCs) undergo extensive apoptotic death. In mouse retina, approximately 50% of RGCs present at birth (postnatal day 0; P0) die by P5, at a time when axons innervate central targets such as the superior colliculus (SC). We examined whether RGCs that make short-range axonal targeting errors within the contralateral SC are more likely to be eliminated during the peak period of RGC death (P1-P5), compared with RGCs initially making more accurate retinotopic connections. A small volume (2.3 nL) of the retrograde nucleophilic dye Hoechst 33342 was injected into the superficial left SC of anesthetized neonatal C57Bl/6J mice at P1 (n = 5) or P4 (n = 8), and the contralateral retina wholemounted 12 hr later. Retrogradely labelled healthy and dying (pyknotic) RGCs were identified by morphological criteria and counted. The percentage of pyknotic RGCs was analyzed in relation to distance from the area of highest density RGC labelling, presumed to represent the most topographically accurate population. As expected, pyknotic RGC density at P1 was significantly greater than P4 (p < 0.05). At P4, the density of healthy RGCs 500-750 um away from the central region was significantly less, although this was not reflected in altered pyknotic rates. However, at P1 there was a trend (p = 0.08) for an increased proportion of pyknotic RGCs, specifically in temporal parts of the retina outside the densely labelled center. Overall, the lack of consistent association between short-range targeting errors and cell death suggests that most postnatal RGC loss is not directly related to topographic accuracy. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 51 60, 2018. PMID- 29134766 TI - Comparative Analyses of Data Independent Acquisition Mass Spectrometric Approaches: DIA, WiSIM-DIA, and Untargeted DIA. AB - Data-independent acquisition (DIA) is an emerging technology for quantitative proteomics. Current DIA focusses on the identification and quantitation of fragment ions that are generated from multiple peptides contained in the same selection window of several to tens of m/z. An alternative approach is WiSIM-DIA, which combines conventional DIA with wide-SIM (wide selected-ion monitoring) windows to partition the precursor m/z space to produce high-quality precursor ion chromatograms. However, WiSIM-DIA has been underexplored; it remains unclear if it is a viable alternative to DIA. We demonstrate that WiSIM-DIA quantified more than 24 000 unique peptides over five orders of magnitude in a single 2 h analysis of a neuronal synapse-enriched fraction, compared to 31 000 in DIA. There is a strong correlation between abundance values of peptides quantified in both the DIA and WiSIM-DIA datasets. Interestingly, the S/N ratio of these peptides is not correlated. We further show that peptide identification directly from DIA spectra identified >2000 proteins, which included unique peptides not found in spectral libraries generated by DDA. PMID- 29134767 TI - Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation. AB - BACKGROUND: There is considerable public and political interest in the use of cannabis products for medical purposes. METHODS: The task force of the European Pain Federation (EFIC) conducted a survey with its national chapters representatives on the status of approval of all types of cannabis-based medicines, the covering of costs and the availability of a position paper of a national medical association on the use of medical cannabis for chronic pain and for symptom control in palliative/supportive care. RESULTS: Thirty-one out of 37 contacted councillors responded. Plant-derived tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray is approved for spasticity in multiple sclerosis refractory to conventional treatment in 21 EFIC chapters. Plant-derived THC (dronabinol) is approved for some palliative care conditions in four EFIC chapters. Synthetic THC analogue (nabilone) is approved for chemotherapy associated nausea and vomiting refractory to conventional treatment in four EFIC chapters'. Eight EFIC chapters' countries have an exceptional and six chapters an expanded access programme for medical cannabis. German and Israeli pain societies recommend the use of cannabis-based medicines as third-line drug therapies for chronic pain within a multicomponent approach. Conversely, the German medical association and a team of finish experts and officials do not recommend the prescription of medical cannabis due to the lack of high-quality evidence of efficacy and the potential harms. CONCLUSIONS: There are marked differences between the countries represented in EFIC in the approval and availability of cannabis-based products for medical use. EFIC countries are encouraged to collaborate with the European Medicines Agency to publish a common document on cannabis-based medicines. SIGNIFICANCE: There are striking differences between European countries in the availability of plant-derived and synthetic cannabinoids and of medical cannabis for pain management and for symptom control in palliative care and in the covering of costs by health insurance companies or state social security systems. PMID- 29134768 TI - Determination of multiple antibiotics in leafy vegetables using QuEChERS-UHPLC MS/MS. AB - A modified quick, easy, cheap, effective, rugged, and safe method was established for simultaneous extraction and cleanup of multiple antibiotics in leafy vegetables, and ultra-high performance liquid chromatography with tandem mass spectrometry was used for analysis. Antibiotics in leafy vegetables were extracted with citric acid/sodium citrate in mixed solvents consisting of acetonitrile/methanol (85:15, v/v) from 10 g of vegetables. Octadecylsilyl and graphitized carbon black were used as dispersant adsorbents. This method was able to effectively extract all of the target antibiotics from leafy vegetables. The average recoveries of 20 antibiotics ranged from 57 to 91%. The limits of detection were 0.33-2.92 MUg/kg. The developed method subsequently demonstrated its selectivity, sensitivity, and reliability for detecting multiple antibiotics in 15 samples. Antibiotic residues in vegetables have attracted great concern with respect to human health. It is recommended that standards should be established for antibiotic residues in vegetables to ensure food safety. PMID- 29134769 TI - Study of the Air-Tolerant 1,3-Diphosphacyclobutane-2,4-diyl through the Direct Arylation. AB - Installing pi-functional substituents on the skeletal phosphorus atoms of the air tolerant 1,3-diphosphacyclobutane-2,4-diyl unit are promising for tuning the open shell singlet P-heterocyclic chromophore. The sterically encumbered 1,3 diphosphaCycloButen-4-yl Anion (CBA), generated from the phosphorus-carbon triple bond, was available for the regioselective arylation via nucleophilic aromatic substitution (SN Ar) reaction, addition to arynes, and single-electron transfer (SET) process affording the corresponding P-arylated 1,3-diphosphacyclobutane-2,4 diyls. The photo-absorption and redox properties correlated with the effects of the aryl substituents on the 1,3-diphosphacyclobutane-2,4-diyl unit. The X-ray analyses enabled not only to discuss the metric parameters but also to visualize the radicalic electrons via the electron-density distribution analysis. The electron-donating character of the P-heterocyclic chromophores induced the p-type semiconductor behavior. Detection of hydrogen fluoride via formation of the 1lambda5 ,3lambda5 -diphosphete derivative was also developed. PMID- 29134770 TI - Directed RhI -Catalyzed Asymmetric Hydroboration of Prochiral 1-Arylcycloprop-2 Ene-1-Carboxylic Acid Derivatives. AB - A full account on rhodium-catalyzed asymmetric, directed hydroboration of functionalized prochiral cyclopropenes affording enantiomerically enriched cyclopropylboronates is reported. The scope and limitations of two alternate directing groups, ester and carboxamide, are evaluated. It was found that hydroboration of esters appeared to be more sensitive to substitution in the aromatic ring of the substrates. Specifically, ortho-halogens were detrimental for diastereo- and enantioselectivity, possibly because of additional coordination with rhodium. In contrast, more Lewis-basic amide directing groups allowed for stronger chelation to the transition metal, leading to consistently high diastereo- and enantioselectivity in hydroboration across a broader range of substrates. PMID- 29134772 TI - Micrometer to 15 nm Printing of Metallic Inks with Fountain Pen Nanolithography. AB - The field of printed electronics is continually trying to reduce the dimensions of the electrical components. Here, a method of printing metallic lines with widths as small as 15 nm and up to a few micrometers using fountain pen nanolithography (FPN) is shown. The FPN technique is based on a bent nanopipette with atomic force feedback that acts similar to a nanopen. The geometry of the nanopen allows for rapid placement accuracy of the printing tip, on any desired location, with the highest of optical sub-micrometer resolution. Using this nanopen, investigations of various inks are undertaken together with instrumental and script-tool development that allows accurate printing of multiple layers. This has led to the printing of conductive lines using inks composed of silver nanoparticles and salt solutions of silver and copper. In addition, it is shown that the method can be applied to substrates of various materials with minimal effect on the dimension of the line. The line widths are varied by using nanopens with different orifices or by tailoring the wetting properties of the ink on the substrate. Metallic interconnections of conducting lines are reported. PMID- 29134771 TI - Detection of beta-Amyloid by Sialic Acid Coated Bovine Serum Albumin Magnetic Nanoparticles in a Mouse Model of Alzheimer's Disease. AB - The accumulation and formation of beta-amyloid (Abeta) plaques in the brain are distinctive pathological hallmarks of Alzheimer's disease (AD). Designing nanoparticle (NP) contrast agents capable of binding with Abeta highly selectively can potentially facilitate early detection of AD. However, a significant obstacle is the blood brain barrier (BBB), which can preclude the entrance of NPs into the brain for Abeta binding. In this work, bovine serum albumin (BSA) coated NPs are decorated with sialic acid (NP-BSAx -Sia) to overcome the challenges in Abeta imaging in vivo. The NP-BSAx -Sia is biocompatible with high magnetic relaxivities, suggesting that they are suitable contrast agents for magnetic resonance imaging (MRI). The NP-BSAx -Sia binds with Abeta in a sialic acid dependent manner with high selectivities toward Abeta deposited on brains and cross the BBB in an in vitro model. The abilities of these NPs to detect Abeta in vivo in human AD transgenic mice by MRI are evaluated without the need to coinject mannitol to increase BBB permeability. T2 *-weighted MRI shows that Abeta plaques in mouse brains can be detected as aided by NP-BSAx -Sia, which is confirmed by histological analysis. Thus, NP-BSAx -Sia is a promising new tool for noninvasive in vivo detection of Abeta plaques. PMID- 29134773 TI - Design and biological functionality of a novel hybrid Ti-6Al-4V/hydrogel system for reconstruction of bone defects. AB - We have designed a unique injectable bioactive hydrogel comprising of alginate, gelatin, and nanocrystalline hydroxyapatite and loaded with osteoblasts, with the ability to infiltrate into three-dimensional Ti-6Al-4V scaffolds with interconnected porous architecture, fabricated by electron beam melting. A two step crosslinking process using the EDC/NHS and CaCl2 was adopted and found to be effective in the fabrication of cell-loaded hydrogel/Ti-6Al-4V scaffold system. This hybrid Ti-6Al-4V scaffold/hydrogel system was designed for the reconstruction of bone defects, which are difficult to heal in the absence of suitable support materials. The hybrid Ti-6Al-4V/hydrogel system favourably modulated the biological functions, namely, adhesion, proliferation, cell-to cell, and cell-material communication because of the presence of extracellular matrix-like hydrogel in the interconnected porous structure of 3D printed Ti-6Al 4V scaffold. The hydrogel was cytocompatible, which was proven through live/dead assay, the expression level of prominent proteins for cell adhesion and cytoskeleton, including 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. Furthermore, the high bone formation ability of the hydrogel was confirmed using alkaline phosphatase assay. A high equilibrium water content (~97%) in the hydrogel enables the delivery of cells and bioactive molecules, necessary for bone tissue growth. Although not studied, the presence of hydrogel in the pores of the scaffold can provide the space for the cell migration as well as vascularization through it, required for the effective exchange of nutrients. In conclusion, we underscore that the 3D-printed Ti-6Al-4V scaffold-loaded with bioactive hydrogel to treat the bone defects significantly impacted cellular functions and cell-material interaction. PMID- 29134774 TI - Identifying suitable reference genes for developing and injured mouse CNS tissues. AB - Accurate quantification of gene expression is fundamental for understanding the molecular, genetic and functional bases of tissue development and diseases. Quantitative real-time PCR (qPCR) is now the most widely used method of quantifying gene expression due to its simplicity, specificity, sensitivity, and wide quantification range. The use of appropriate reference genes to ensure accurate normalization is crucial for the correct quantification of gene expression from the early development, maturation, aging to injury processes in the central nervous system (CNS). In this study, we have determined the expression profiles of 12 candidate housekeeping genes (ACTB, CYC1, HMBS, GAPDH, HPRT1, RPL13A, YWHAZ, PPIA, RPLP0, TFRC, GUS, and 18S rRNA) in developing mouse brain and spinal cord. Throughout development, there was a significant degree of fluctuations in their expression levels, indicating the importance and complexity of finding appropriate reference genes. Three software including BestKeeper, geNorm and NormFinder were used to evaluate the stability of potential reference genes. GUS was the most stable gene and GUS/YWHAZ were the most stable reference gene pair across different developmental stages in different CNS regions, whereas HPRT1 and GAPDH were the most variable genes and thus inappropriate to use as reference genes. Therefore, our results identified GUS and YWHAZ as the best combination of two reference genes for expression data normalization in CNS developmental studies. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 39 50, 2018. PMID- 29134776 TI - Acute chest syndrome among children hospitalized with vaso-occlusive crisis: A nationwide study in the United States. AB - PURPOSE: Acute chest syndrome (ACS) is a common complication among pediatric inpatients with sickle cell disease and vaso-occlusive crisis (VOC). However, little is known about the factors associated with ACS complication. The present study assessed the epidemiological features of children hospitalized with VOC and ascertained factors associated with ACS complication. METHODS: Hospital discharge records of patients with VOC aged <20 years were obtained for the years 2003, 2006, 2009, and 2012 from the Kids' Inpatient Database. Data were weighted to estimate the annual hospitalization rates with respect to gender and race/ethnicity in the United States. Multivariable logistic regression was conducted to ascertain factors associated with ACS complication after adjusting for patient and hospital characteristics. RESULTS: The total annual hospitalizations for VOC increased from 22,511 in 2003 to 24,292 in 2012. Multivariable logistic regression analysis showed that children aged 5-9 years had 2.59 times higher odds of ACS than children aged 15-19 years (95% confidence interval [CI], 2.32-2.88). Comorbidity of asthma (odds ratio [OR], 1.42; 95% CI, 1.31-1.54) and obstructive sleep apnea (OR, 1.70; 95% CI, 1.31-2.20) were associated with ACS development. ACS was also associated with male gender and the summer and fall seasons. CONCLUSION: We reported nationwide estimates of the annual hospitalization rate for childhood VOC in the United States and demonstrated the major risk factors associated with ACS complication. Vigilance is needed for ACS complications in high-risk VOC admissions. PMID- 29134775 TI - Changes in Sensitivity to the Effects of Atrazine on the Luteinizing Hormone Surge in Female Sprague-Dawley Rats after Repeated Daily Doses: Correlation with Liver Enzyme Expression. AB - BACKGROUND: Atrazine suppression of the LH surge slowly develops over time and peaks after 4 days; sensitivity to atrazine decreases after 8 or 14 days of dosing. Adaptation of the LH response was correlated with increased phase I and phase II liver enzyme activity/expression. METHODS: The effect of atrazine on the LH surge was evaluated in female Sprague-Dawley rats administered 100 mg/kg/day atrazine by gavage for 1, 2, 3, or 4 consecutive days or 6.5, 50, or 100 mg/kg/day atrazine for 4, 8, or 14 days. RESULTS: No statistically significant effects of atrazine were seen on peak plasma LH or LH area under the curve (AUC) after one, two, or three doses of 100 mg/kg/day. Four daily doses of 50 or 100 mg/kg atrazine significantly reduced peak LH and LH AUCs, whereas 6.5 mg/kg/day had no effect. After 8 or 14 days of treatment, statistically significantly reduced peak LH and LH AUC were observed in the 100 mg/kg/day dose group, but not in the 6.5 or 50 mg/kg/day dose groups, although significantly reduced LH was observed in one sample 9 hr after lights-on in the 50 mg/kg/day dose group on day 14. The number of days of treatment required to achieve a significant suppression of the LH surge is consistent with the repeat-dose pharmacokinetics of the chlorotriazines. CONCLUSION: The apparent adaptation to the effect of atrazine on the LH surge after 8 or 14 days may be related to the induction of phase I or, more likely, phase II metabolism observed in this study after 8 days, or to a decreased sensitivity of the hypothalamic-pituitary-adrenal axis or an homeostatic adaption of the effect of atrazine on the LH surge mechanism. Birth Defects Research 110:246-258, 2018. (c) 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc. PMID- 29134777 TI - Epidemiological investigation of H9 avian influenza virus, Newcastle disease virus, Tembusu virus, goose parvovirus and goose circovirus infection of geese in China. AB - To deepen the knowledge about epidemic prevalence in the goose breeding field, a triplex PCR assay was established, and 478 samples were collected from scaled goose farms in 11 provinces in China. The results of this epidemiological investigation showed that incidence rates of H9 avian influenza and goose circovirus were the highest among five infectious diseases that were evaluated. In addition, the triplex PCR assay established remarkable sensitivity, rapidity and versatility compared to other diagnostic methods. Dual infection comprised a large proportion of the co-infections in the field, of which the combinations of H9/Tembusu, H9/goose circovirus and goose circovirus/Tembusu co-infected cases were more common. Epidemics were more severe in winter and spring. Additionally, significant differences in the prevalence of these infectious diseases were observed in association with different age groups. In addition, phylogenetic analysis, determined by the neighbour-joining method, was carried out to investigate the evolution of these viruses during the study period. For the most part, virus strains isolated during the study were consistent with most goose origin strains isolated from the Chinese mainland over the past few years. However, mutations were observed between isolated H9 avian influenza virus strains and sequences available from GenBank, which should draw much attention. PMID- 29134778 TI - The axonal endoplasmic reticulum: One organelle-many functions in development, maintenance, and plasticity. AB - The endoplasmic reticulum (ER) is highly conserved in eukaryotes and neurons. Indeed, the localization of the organelle in axons has been known for nearly half a century. However, the relevance of the axonal ER is only beginning to emerge. In this review, we discuss the structure of the ER in axons, examining the role of ER-shaping proteins and highlighting reticulons. We analyze the multiple functions of the ER and their potential contribution to axonal physiology. First, we examine the emerging roles of the axonal ER in lipid synthesis, protein translation, processing, quality control, and secretory trafficking of transmembrane proteins. We also review the impact of the ER on calcium dynamics, focusing on intracellular mechanisms and functions. We describe the interactions between the ER and endosomes, mitochondria, and synaptic vesicles. Finally, we analyze available proteomic data of axonal preparations to reveal the dynamic functionality of the ER in axons during development. We suggest that the dynamic proteome and a validated axonal interactome, together with state-of-the-art methodologies, may provide interesting research avenues in axon physiology that may extend to pathology and regeneration. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 181-208, 2018. PMID- 29134779 TI - Crochelins: Siderophores with an Unprecedented Iron-Chelating Moiety from the Nitrogen-Fixing Bacterium Azotobacter chroococcum. AB - Microbes use siderophores to access essential iron resources in the environment. Over 500 siderophores are known, but they utilize a small set of common moieties to bind iron. Azotobacter chroococcum expresses iron-rich nitrogenases, with which it reduces N2 . Though an important agricultural inoculant, the structures of its iron-binding molecules remain unknown. Here, the "chelome" of A. chroococcum is examined using small molecule discovery and bioinformatics. The bacterium produces vibrioferrin and amphibactins as well as a novel family of siderophores, the crochelins. Detailed characterization shows that the most abundant member, crochelin A, binds iron in a hexadentate fashion using a new iron-chelating gamma-amino acid. Insights into the biosynthesis of crochelins and the mechanism by which iron may be removed upon import of the holo-siderophore are presented. This work expands the repertoire of iron-chelating moieties in microbial siderophores. PMID- 29134781 TI - Clinical and molecular genetic characterization of a male patient with Sensenbrenner syndrome (cranioectodermal dysplasia) and biallelic WDR35 mutations. AB - BACKGROUND: Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease. Mutations in six genes: IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140 have been associated with this disorder. All known CED genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. CASE: We report a on 2-year-old male patient affected by Sensenbrenner syndrome. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, narrow chest, high forehead, epicanthal folds, telecanthus, broad nasal bridge, low-set ears, sparse hair, and widely space teeth. Craniosynostosis was surgically corrected at the age of 4 months. The patient presented chronic renal disease. Nephrologic picture showed early stages of nephronophthisis. Psychomotor development was apparently normal. Molecular analysis of the affected individual revealed compound heterozygosity for a novel nonsense p.(Arg113*) and a missense p.(Asp841Val) variant in the WDR35 gene. CONCLUSIONS: The observations of the CED patient in this study provide additional clinical data and expand the molecular spectrum of Sensenbrenner syndrome. Moreover, the two variants identified in the proband provide further evidence for the WDR35 mutations as the most common cause of this rare syndrome. PMID- 29134782 TI - Determination of the clean-up efficiency of the solid-phase extraction of rosemary extracts: Application of full-factorial design in hyphenation with Gaussian peak fit function. AB - We present a novel method for the quantitative determination of the clean-up efficiency to provide a calculated parameter for peak purity through iterative fitting in conjunction with design of experiments. Rosemary extracts were used and analyzed before and after solid-phase extraction using a self-fabricated mixed-mode sorbent based on poly(N-vinylimidazole/ethylene glycol dimethacrylate). Optimization was performed by variation of washing steps using a full three-level factorial design and response surface methodology. Separation efficiency of rosmarinic acid from interfering compounds was calculated using an iterative fit of Gaussian-like signals and quantifications were performed by the separate integration of the two interfering peak areas. Results and recoveries were analyzed using Design-Expert(r) software and revealed significant differences between the washing steps. Optimized parameters were considered and used for all further experiments. Furthermore, the solid-phase extraction procedure was tested and compared with commercial available sorbents. In contrast to generic protocols of the manufacturers, the optimized procedure showed excellent recoveries and clean-up rates for the polymer with ion exchange properties. Finally, rosemary extracts from different manufacturing areas and application types were studied to verify the developed method for its applicability. The cleaned-up extracts were analyzed by liquid chromatography with tandem mass spectrometry for detailed compound evaluation to exclude any interference from coeluting molecules. PMID- 29134783 TI - Electrospun titania fiber mats spin coated with thin polymer films as nanofibrous scaffolds for enhanced cell proliferation. AB - The incorporation of inorganic materials into electrospun nanofibres has recently gained considerable attention for the development of extracellular matrix-like scaffolds with improved mechanical properties and enhanced biological functions for tissue engineering applications. In this study, polymer-inorganic composite fibres consisting of poly(2-ethyl-2-oxazoline) (PEOXA) and tetrabutyl titanate as the titanium precursor were successfully fabricated through a combined sol gel/electrospinning approach. PEOXA/Ti(OR)n composite fibres were obtained with varying amounts of polymer and titanium precursors. Calcinations of the composite fibres were performed at varying temperatures to produce TiO2 fibres (TiO2 -T-60) with anatase, anatase/rutile mixed phase, and rutile crystal structures. Thin polymer films (i.e., poly(2-ethyl-2-oxazoline) (PEOXA), polycaprolactone (PCL), and poly(methyl methacrylate) (PMMA)) were subsequently deposited onto TiO2 -T-60 fibre mats by spin coating to facilitate handling of the electrospun substrates after calcination, which are rather brittle and disintegrate easily, and to probe cell-materials interactions. The cellular behaviour of mouse L929 fibroblasts after culture periods of 1-5 days was compared on the following fibre scaffolds: PEOXA/Ti(OR)n , TiO2 -T-60 (T = 600, 650, and 700 degrees C), TiO2 -T-60 spin coated with thin PCL film (PCL/TiO2 -T-60), and pure PCL. The results obtained from in vitro cell culture studies for the lactate dehydrogenase release assay and confocal microscopic visualization pointed out the synergistic interplay between the TiO2 crystal structure and spin-coated PCL film in facilitating cell interactions with the scaffold surface. The L929 cells were observed to adhere and proliferate better on the surface of TiO2 -700-60 having the rutile structure than on the surfaces of TiO2 -600-60 and TiO2 -650-60 fibre scaffolds with anatase and anatase/rutile mixed phase structures, respectively. PMID- 29134784 TI - A General Strategy for Development of Near-Infrared Fluorescent Probes for Bioimaging. AB - Near-infrared (NIR) fluorescent dyes with favorable photophysical properties are highly useful for bioimaging, but such dyes are still rare. The development of a unique class of NIR dyes via modifying the rhodol scaffold with fused tetrahydroquinoxaline rings is described. These new dyes showed large Stokes shifts (>110 nm). Among them, WR3, WR4, WR5, and WR6 displayed high fluorescence quantum yields and excellent photostability in aqueous solutions. Moreover, their fluorescence properties were tunable by easy modifications on the phenolic hydroxy group. Based on WR6, two NIR fluorescent turn-on probes, WSP-NIR and SeSP NIR, were devised for the detection of H2 S. The probe SeSP-NIR was applied in visualizing intracellular H2 S. These dyes are expected to be useful fluorophore scaffolds in the development of new NIR probes for bioimaging. PMID- 29134785 TI - Maintenance of Cartilaginous Gene Expression of Serially Subcultured Chondrocytes on Poly(2-Methoxyethyl Acrylate) Analogous Polymers. AB - Chondrocytes are important for cartilage tissue engineering. However, dedifferentiation during chondrocyte subculture prevents the application of cartilage tissue engineering. Therefore, prevention of this dedifferentiation is required. Here, the possibility of poly(2-methoxyethyl acrylate) (PMEA) and its analogous polymers, poly(tetrahydrofurfuryl acrylate) (PTHFA) and poly(2-(2 methoxyethoxy) ethyl acrylate-co-butyl acrylate) (PMe2A), for chondrocyte subculture without dedifferentiation is examined. Chondrocytes spread on PTHFA and polyethylene terephthalate (PET), whereas their spreading is delayed on PMEA and PMe2A. When primary chondrocytes are subcultured on these polymers, the expression levels of cartilaginous genes are higher on PMEA and PMe2A than on PET and PTHFA. Integrin contribution to the initial cell adhesion is lower on PMEA and PMe2A than on PTHFA and PET. This low level of integrin contribution to cell adhesion may cause a delay in cell spreading and the maintenance of cartilaginous gene expression. These results indicate that PMEA and PMe2A may be favorable substrates for chondrocyte subculture and cartilage tissue engineering. PMID- 29134787 TI - ERRATUM. PMID- 29134788 TI - Thermal acclimation in Arabidopsis lyrata: genotypic costs and transcriptional changes. AB - Frost and heat events can be challenging for sessile organisms that cannot escape thermal extremes. However, adverse effects of thermal stress on fitness may be reduced by pre-exposure to cold or heat, a process known as acclimation. To understand the ecological and evolutionary implications of acclimation, we investigated (1) the reduction in performance due to stress pre-exposure, (2) the magnitude of increased leaf resistance to subsequent stress, (3) the costs of acclimation and (4) the genes differing in expression due to stress pre-exposure. Plants of Arabidopsis lyrata were raised under three treatments of pre-exposure: bouts of frost, bouts of heat or constant temperature. Resistance of leaves to subsequent frost and heat stress was then measured by electrolyte leakage. RNA seq analysis was performed to examine the genes differentially expressed between stress-pre-exposed and control plants. Pre-exposure to stress during growth decreased plant size and increased leaf resistance to subsequent stress independent of whether pre-exposure was to frost or heat. But the highest increase in leaf resistance to frost was found after pre-exposure to frost (as a trend) and in leaf resistance to heat after pre-exposure to heat. No evidence for costs of acclimation was detected. RNA-sequencing suggested that acclimation by frost and heat pre-exposure was caused by distinct mechanisms: modification of the chloroplast membrane and modification of the cell wall and membrane, respectively. Our results suggest that thermal resistance is a labile complex of traits, strongly affected by the previously experienced stress environment, with undetermined costs. PMID- 29134786 TI - Investigation of dominant and recessive inheritance models in genome-wide association studies data of nonsyndromic cleft lip with or without cleft palate. AB - Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformation worldwide, and its etiology involves both genetic and environmental factors. Recent genome-wide and targeted genetic studies of nsCL/P have identified numerous genetic risk loci, under the hypothesis of a multiplicative mode of inheritance. The present study investigated whether novel nsCL/P risk loci could be identified by analyzing dominant/recessive genetic effects in single nucleotide polymorphism (SNP) data from genome-wide association studies. For this purpose, a genome-wide investigation of dominant/recessive common SNP effects was performed in our previously published meta-analysis data set. Twenty-four loci were identified as candidate regions. In a subsequent association analysis in an independent study cohort of 224 nsCL/P patients and 986 controls of European descent, none of the loci could be replicated. Therefore, our strategy of identifying novel loci by applying different genetic models did not yield any novel findings, suggesting that recessive/dominant common variation only make a limited contribution to nsCL/P in Europeans. However, we cannot rule out that such effects are present at some of the loci that have previously been identified, or are present in different populations. PMID- 29134789 TI - Either at left or right, both high and low frequency rTMS of dorsolateral prefrontal cortex decreases cue induced craving for methamphetamine. AB - BACKGROUND AND OBJECTIVES: The study is to investigate if left or right dorsolateral prefrontal cortex is important in modulating the craving to drug related cues. METHODS: The present investigation examined different combinations between left/right and high/low frequency rTMS on cue induced craving to methamphetamine, with active sham rTMS on P3 region on a total of 50 subjects. RESULTS: The results showed that either at left or right side, both high and low frequency rTMS are effective in decreasing the cue induced craving to methamphetamine. DISCUSSION AND CONCLUSIONS: In conclusion, bilateral frontal hemispheres are effective in modulating the cue induced craving to methamphetamine with rTMS. SCIENTIFIC SIGNIFICANCE: TMS targeting prefrontal cortex is effective for craving modulation; however the mechanism is more than potentiation or depression of single brain region. (Am J Addict 2017;26:776-779). PMID- 29134790 TI - Soybean mosaic virus: a successful potyvirus with a wide distribution but restricted natural host range. AB - TAXONOMY: Soybean mosaic virus (SMV) is a species within the genus Potyvirus, family Potyviridae, which includes almost one-quarter of all known plant RNA viruses affecting agriculturally important plants. The Potyvirus genus is the largest of all genera of plant RNA viruses with 160 species. PARTICLE: The filamentous particles of SMV, typical of potyviruses, are about 7500 A long and 120 A in diameter with a central hole of about 15 A in diameter. Coat protein residues are arranged in helices of about 34 A pitch having slightly less than nine subunits per turn. GENOME: The SMV genome consists of a single-stranded, positive-sense, polyadenylated RNA of approximately 9.6 kb with a virus-encoded protein (VPg) linked at the 5' terminus. The genomic RNA contains a single large open reading frame (ORF). The polypeptide produced from the large ORF is processed proteolytically by three viral-encoded proteinases to yield about 10 functional proteins. A small ORF, partially overlapping the P3 cistron, pipo, is encoded as a fusion protein in the N-terminus of P3 (P3N + PIPO). BIOLOGICAL PROPERTIES: SMV's host range is restricted mostly to two plant species of a single genus: Glycine max (cultivated soybean) and G. soja (wild soybean). SMV is transmitted by aphids non-persistently and by seeds. The variability of SMV is recognized by reactions on cultivars with dominant resistance (R) genes. Recessive resistance genes are not known. GEOGRAPHICAL DISTRIBUTION AND ECONOMIC IMPORTANCE: As a consequence of its seed transmissibility, SMV is present in all soybean-growing areas of the world. SMV infections can reduce significantly seed quantity and quality (e.g. mottled seed coats, reduced seed size and viability, and altered chemical composition). CONTROL: The most effective means of managing losses from SMV are the planting of virus-free seeds and cultivars containing single or multiple R genes. KEY ATTRACTIONS: The interactions of SMV with soybean genotypes containing different dominant R genes and an understanding of the functional role(s) of SMV-encoded proteins in virulence, transmission and pathogenicity have been investigated intensively. The SMV-soybean pathosystem has become an excellent model for the examination of the genetics and genomics of a uniquely complex gene-for-gene resistance model in a crop of worldwide importance. PMID- 29134791 TI - Qualitative analysis of flavors and fragrances added to tea by using GC-MS. AB - A precise identification method was developed to identify the flavors and fragrances added to tea matrix artificially using gas chromatography with mass spectrometry and gas chromatography with quadrupole time-of-flight mass spectrometry. The proposed method was based on the corresponding "three-column retention indices, two exact mass numbers, one mass spectrum matching degree" database of 40 kinds of common flavors and fragrances. The intraday and the interday relative standard deviation of the retention indices were less than 0.048 and 0.093%, respectively. The accuracy of exact mass was between 0.15 and 6.22 ppm. And the validation of the created database was performed by analyzing the tea samples. Thus, the proposed method is suitable for the precise identification of the flavors and fragrances added to tea matrix artificially without standard substances as a reference. PMID- 29134792 TI - Time and treatments: It is what you make of it that counts. PMID- 29134793 TI - The Role of Oxaliplatin in Chemoradiotherapy for Rectal Cancer. PMID- 29134794 TI - Recent Trends in Kidney Transplant in the United States . AB - The number of new wait list registrants has increased in the last decade but not to the same magnitude as the increase in the number of end stage renal disease patients in the United States. The number of wait list patients has increased at a much higher pace due to the lack of kidney supply. The overall number of kidney transplants only increased slightly. Paired exchange kidney transplant is a viable source of increasing the availability of kidney transplant and also offers access to transplant to patients with immunologic barriers to their intended donors. Paired donor exchange results in similar outcomes despite recipients' having a higher immunologic risk profile. The kidney allocation system (KAS) was recently implemented and so far has resulted in more access for patients with very high immunologic risk and allocation of lower kidney donor profile index organs to younger recipients. Longer follow up is needed to determine the net benefit of the KAS. PMID- 29134795 TI - Robust and Recyclable Substrate Template with an Ultrathin Nanoporous Counter Electrode for Organic-Hole-Conductor-Free Monolithic Perovskite Solar Cells. AB - A robust and recyclable monolithic substrate applying all-inorganic metal-oxide selective contact with a nanoporous (np) Au:NiOx counter electrode is successfully demonstrated for efficient perovskite solar cells, of which the perovskite active layer is deposited in the final step for device fabrication. Through annealing of the Ni/Au bilayer, the nanoporous NiO/Au electrode is formed in virtue of interconnected Au network embedded in oxidized Ni. By optimizing the annealing parameters and tuning the mesoscopic layer thickness (mp-TiO2 and mp Al2O3), a decent power conversion efficiency (PCE) of 10.25% is delivered. With mp-TiO2/mp-Al2O3/np-Au:NiOx as a template, the original perovskite solar cell with 8.52% PCE can be rejuvenated by rinsing off the perovskite material with dimethylformamide and refilling with newly deposited perovskite. A renewed device using the recycled substrate once and twice, respectively, achieved a PCE of 8.17 and 7.72% that are comparable to original performance. This demonstrates that the novel device architecture is possible to recycle the expensive transparent conducting glass substrates together with all the electrode constituents. Deposition of stable multicomponent perovskite materials in the template also achieves an efficiency of 8.54%, which shows its versatility for various perovskite materials. The application of such a novel NiO/Au nanoporous electrode has promising potential for commercializing cost-effective, large scale, and robust perovskite solar cells. PMID- 29134796 TI - Enhanced Electrical and Optoelectronic Characteristics of Few-Layer Type-II SnSe/MoS2 van der Waals Heterojunctions. AB - van der Waals heterojunctions formed by stacking various two-dimensional (2D) materials have a series of attractive physical properties, thus offering an ideal platform for versatile electronic and optoelectronic applications. Here, we report few-layer SnSe/MoS2 van der Waals heterojunctions and study their electrical and optoelectronic characteristics. The new heterojunctions present excellent electrical transport characteristics with a distinct rectification effect and a high current on/off ratio (~1 * 105). Such type-II heterostructures also generate a self-powered photocurrent with a fast response time (<10 ms) and exhibit high photoresponsivity of 100 A W-1, together with high external quantum efficiency of 23.3 * 103% under illumination by 532 nm light. Photoswitching characteristics of the heterojunctions can be modulated by bias voltage, light wavelength, and power density. The designed novel type-II van der Waals heterojunctions are formed from a combination of a transition-metal dichalcogenide and a group IV-VI layered 2D material, thereby expanding the library of ultrathin flexible 2D semiconducting devices. PMID- 29134797 TI - The Importance of Collaboration between Industry, Academics, and Nonprofits in Tropical Disease Drug Discovery. AB - Collaborations between academic, industrial, and nonprofit companies can provide sufficient impetus to propel projects that have little economic return; such projects are prevalent in tropical disease drug discovery. In these collaborations, each partner contributes a unique set of skills and technical expertise which is advantageous to the project as a whole. Highly product-focused processes and specialized expertise sets dominate industry groups. When coupled with the strategic guidance from public-private partnerships and the academic tendency to work on high-risk projects with low financial rewards, a powerful combination results. There are numerous examples throughout the literature about these collaborative efforts to combat a variety of tropical diseases (including leishmaniasis, Chagas disease, African sleeping sickness, and malaria), from all stages of the drug discovery process to the advancement of new drugs into the clinic. However, there is still uncertainty from many academic institutions as to how to establish and engage in these research consortiums. This Viewpoint highlights opportunities, benefits, and suggestions for productive collaborations in this disease space. PMID- 29134798 TI - Hierarchical Self-Assembly of a Copolymer-Stabilized Coacervate Protocell. AB - Complex coacervate microdroplets are finding increased utility in synthetic cell applications due to their cytomimetic properties. However, their intrinsic membrane-free nature results in instability that limits their application in protocell research. Herein, we present the development of a new protocell model through the spontaneous interfacial self-assembly of copolymer molecules on biopolymer coacervate microdroplets. This hierarchical protocell model not only incorporates the favorable properties of coacervates (such as spontaneous assembly and macromolecular condensation) but also assimilates the essential features of a semipermeable copolymeric membrane (such as discretization and stabilization). This was accomplished by engineering an asymmetric, biodegradable triblock copolymer molecule comprising hydrophilic, hydrophobic, and polyanionic components capable of direct coacervate membranization via electrostatic surface anchoring and chain self-association. The resulting hierarchical protocell demonstrated striking integrity as a result of membrane formation, successfully stabilizing enzymatic cargo against coalescence and fusion in discrete protocellular populations. The semipermeable nature of the copolymeric membrane enabled the incorporation of a simple enzymatic cascade, demonstrating chemical communication between discrete populations of neighboring protocells. In this way, we pave the way for the development of new synthetic cell constructs. PMID- 29134799 TI - E-Waste Driven Pollution in Pakistan: The First Evidence of Environmental and Human Exposure to Flame Retardants (FRs) in Karachi City. AB - Informal e-waste recycling activities have been shown to be a major emitter of organic flame retardants (FRs), contributing to both environmental and human exposure to laborers at e-waste recycling sites in some West African countries, as well as in China and India. The main objective of this study was to determine the levels of selected organic FRs in both air and soil samples collected from areas with intensive informal e-waste recycling activities in Karachi, Pakistan. Dechlorane Plus (DP) and "novel" brominated flame retardants (NBFRs) were often detected in high concentrations in soils, while phosphorus-based FRs (OPFRs) dominated atmospheric samples. Among individual substances and substance groups, decabromodiphenyl ether (BDE-209) (726 ng/g), decabromodiphenyl ethane (DBDPE) (551 ng/g), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE) (362 ng/g), and triphenyl-phosphate (?TPP) (296 ng/g) were found to be prevalent in soils, while OPFR congeners (5903-24986 ng/m3) were prevalent in air. The two major e-waste recycling areas (Shershah and Lyari) were highly contaminated with FRs, suggesting informal e-waste recycling activities as a major emission source of FRs in the environment in Karachi City. However, the hazards associated with exposure to PM2.5 appear to exceed those attributed to exposure to selected FRs via inhalation and soil ingestion. PMID- 29134801 TI - Adsorbed Polyzwitterion Copolymer Layers Designed for Protein Repellency and Interfacial Retention. AB - Poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC), when end-tethered to surfaces by the adsorption of copolymeric cationic segments, forms adsorbed layers that substantially reduce protein adsorption. This study examined variations in the molecular architecture of copolymers containing cationic poly(trimethylammonium ethyl methacrylate (pTMAEMA) anchor blocks that adsorbed strongly to negative surfaces. With appropriate copolymer design, the pTMAEMA blocks were shielded, by pMPC tethers, from solution-phase proteins. The most protein-resistant copolymer layers, eliminating fibrinogen and lysozyme adsorption within detectible limits of 0.01 mg/m2, had metrics (the amount of pMPC at the surface and the reduced tether footprint) consistent with the formation of an interfacial polymer brush. The p(TMAEMA-b-MPC) copolymer layers substantially outperformed the protein resistance of surface-polymerized pMPC layers when compared on a per-polyzwitterion-mass basis or on the basis of the scaled tether area. Additionally, p(TMAEMA-b-MPC) copolymer layers offered advantages over the much-studied cationically anchored poly(ethylene glycol) (PEG) graft copolymer system, which forms PEG brushes by the adsorption of a poly l-lysine (PLL) backbone. Although the optimized p(TMAEMA-b-MPC) and PLL-PEG copolymers were similarly fibrinogen-resistant, the cationic protein lysozyme was repelled by pMPC but adhered to the PEG brush via PEG-lysozyme attractions. Additionally, the adsorbed p(TMAEMA-b-MPC) copolymers were not displaced by poly l-lysine homopolymers, which completely displaced the PLL-PEG copolymer to expose a protein-adhesive surface. Thus, the p(TMAEMA-b-MPC) copolymer system comprises a scalable means to produce protein-repellent surfaces, free of the complexities of surface-initiated polymerization and with the advantages of polyzwitterions. PMID- 29134800 TI - High-Performance Solid-State PbS Quantum Dot-Sensitized Solar Cells Prepared by Introduction of Hybrid Perovskite Interlayer. AB - High-performance solid-state PbS quantum dot-sensitized solar cells (QD-SSCs) with stable 9.2% power conversion efficiency at 1 Sun condition are demonstrated by introduction of hybrid perovskite interlayer. The PbS QDs formed on mesoscopic TiO2 (mp-TiO2) by spin-assisted successive precipitation and anionic exchange reaction method do not exhibit PbSO4 but have PbSO3 oxidation species. By introducing perovskite interlayer in between mp-TiO2/PbS QDs and poly-3 hexylthiophene, the PbSO3 oxidation species are fully removed in the PbS QDs and thereby the efficiency of PbS QD-SSCs is enhanced over 90% compared to the pristine PbS QD-SSCs. PMID- 29134802 TI - Ab Initio Study of Interfacial Structure Transformation of Amorphous Carbon Catalyzed by Ti, Cr, and W Transition Layers. AB - Amorphous carbon (a-C) films composited with transition layers exhibit the desirable improvement of adhesion strength between films and substrate, but the further understanding on the interfacial structure transformation of a-C structure induced by transition layers is still lacked. In this paper, using ab initio calculations, we comparatively studied the interfacial structure between Ti, Cr, or W transition layers and a-C film from the atomic scale, and demonstrated that the addition of Ti, Cr, or W catalyzed the graphitic transformation of a-C structure at different levels, which provided the theoretical guidance for designing a multilayer nanocomposite film for renewed application. PMID- 29134803 TI - Fluorescent Binary Ensemble Based on Pyrene Derivative and Sodium Dodecyl Sulfate Assemblies as a Chemical Tongue for Discriminating Metal Ions and Brand Water. AB - Enormous effort has been put to the detection and recognition of various heavy metal ions due to their involvement in serious environmental pollution and many major diseases. The present work has developed a single fluorescent sensor ensemble that can distinguish and identify a variety of heavy metal ions. A pyrene-based fluorophore (PB) containing a metal ion receptor group was specially designed and synthesized. Anionic surfactant sodium dodecyl sulfate (SDS) assemblies can effectively adjust its fluorescence behavior. The selected binary ensemble based on PB/SDS assemblies can exhibit multiple emission bands and provide wavelength-based cross-reactive responses to a series of metal ions to realize pattern recognition ability. The combination of surfactant assembly modulation and the receptor for metal ions empowers the present sensor ensemble with strong discrimination power, which could well differentiate 13 metal ions, including Cu2+, Co2+, Ni2+, Cr3+, Hg2+, Fe3+, Zn2+, Cd2+, Al3+, Pb2+, Ca2+, Mg2+, and Ba2+. Moreover, this single sensing ensemble could be further applied for identifying different brands of drinking water. PMID- 29134804 TI - Concurrent La and A-Site Vacancy Doping Modulates the Thermoelectric Response of SrTiO3: Experimental and Computational Evidence. AB - To help understand the factors controlling the performance of one of the most promising n-type oxide thermoelectric SrTiO3, we need to explore structural control at the atomic level. In Sr1-xLa2x/3TiO3 ceramics (0.0 <= x <= 0.9), we determined that the thermal conductivity can be reduced and controlled through an interplay of La-substitution and A-site vacancies and the formation of a layered structure. The decrease in thermal conductivity with La and A-site vacancy substitution dominates the trend in the overall thermoelectric response. The maximum dimensionless figure of merit is 0.27 at 1070 K for composition x = 0.50 where half of the A-sites are occupied with La and vacancies. Atomic resolution Z contrast imaging and atomic scale chemical analysis show that as the La content increases, A-site vacancies initially distribute randomly (x < 0.3), then cluster (x ~ 0.5), and finally form layers (x = 0.9). The layering is accompanied by a structural phase transformation from cubic to orthorhombic and the formation of 90 degrees rotational twins and antiphase boundaries, leading to the formation of localized supercells. The distribution of La and A-site vacancies contributes to a nonuniform distribution of atomic scale features. This combination induces temperature stable behavior in the material and reduces thermal conductivity, an important route to enhancement of the thermoelectric performance. A computational study confirmed that the thermal conductivity of SrTiO3 is lowered by the introduction of La and A-site vacancies as shown by the experiments. The modeling supports that a critical mass of A-site vacancies is needed to reduce thermal conductivity and that the arrangement of La, Sr, and A-site vacancies has a significant impact on thermal conductivity only at high La concentration. PMID- 29134805 TI - Ion Pairing and Diffusion in Magnesium Electrolytes Based on Magnesium Borohydride. AB - One obstacle to realizing a practical, rechargeable magnesium-ion battery is the development of efficient Mg electrolytes. Electrolytes based on simple Mg(BH4)2 salts suffer from poor salt solubility and/or low conductivity, presumably due to strong ion pairing. Understanding the molecular-scale processes occurring in these electrolytes would aid in overcoming these performance limitations. Toward this goal, the present study examines the solvation, agglomeration, and transport properties of a family of Mg electrolytes based on the Mg(BH4)2 salt using classical molecular dynamics. These properties were examined across five different solvents (tetrahydrofuran and the glymes G1-G4) and at four salt concentrations ranging from the dilute limit up to 0.4 M. Significant and irreversible salt agglomeration was observed in all solvents at all nondilute Mg(BH4)2 concentrations. The degree of clustering observed in these divalent Mg systems is much larger than that reported for electrolytes containing monovalent cations, such as Li. The salt agglomeration rate and diffusivity of Mg2+ were both observed to correlate with solvent self-diffusivity: electrolytes using longer- (shorter-) chain solvents had the lowest (highest) Mg2+ diffusivity and agglomeration rates. Incorporation of Mg2+ into Mg2+-BH4- clusters significantly reduces the diffusivity of Mg2+ by restricting displacements to localized motion within largely immobile agglomerates. Consequently, diffusion is increasingly impeded with increasing Mg(BH4)2 concentration. These data are consistent with the solubility limitations observed experimentally for Mg(BH4)2-based electrolytes and highlight the need for strategies that minimize salt agglomeration in electrolytes containing divalent cations. PMID- 29134806 TI - Acid-Catalyzed Skeletal Rearrangements in Arenes: Aryl versus Alkyl Ring Pirouettes in Anthracene and Phenanthrene. AB - In 1 M triflic acid/dichloroethane, anthracene is protonated at C9, and the resulting 9-anthracenium ion is easily observed by NMR at ambient temperature. When heated as a dilute solution in triflic acid/dichloroethane, anthracene undergoes conversion to phenanthrene as the major volatile product. Minor dihydro and tetrahydro products are also observed. MALDI analysis supports the simultaneous formation of oligomers, which represent 10-60% of the product. Phenanthrene is nearly inert to the same superacid conditions. DFT and CCSD(T)//DFT computational models were constructed for isomerization and automerization mechanisms. These reactions are believed to occur by cationic ring pirouettes which pass through spirocyclic intermediates. The direct aryl pirouette mechanism for anthracene has a predicted DFT barrier of 33.6 kcal/mol; this is too high to be consistent with experiment. The ensemble of experimental and computational models supports a multistep isomerization process, which proceeds by reduction to 1,2,3,4-tetrahydroanthracene, acid-catalyzed isomerization to 1,2,3,4-tetrahydrophenanthrene with a predicted DFT barrier of 19.7 kcal/mol, and then reoxidation to phenanthrene. By contrast, DFT computations support a direct pirouette mechanism for automerization of outer ring carbons in phenanthrene, a reaction demonstrated previously by Balaban through isotopic labeling. PMID- 29134807 TI - High Time-Resolution Optical Sensor for Monitoring Atmospheric Nitrogen Dioxide. AB - High time-resolution monitoring of nitrogen dioxide (NO2) is of great importance for studying the formation mechanism of aerosols and improving air quality. Based on the Griess-Saltzman (GS) reaction, a portable NO2 optical sensor was developed by employing a porous polypropylene membrane tube (PPMT) integrated gas permeation collector and detector. The PPMT was filled with GS reagents and covered with a coaxial jacket tube for gas collection. Its two ends were respectively fixed with a yellowish-green light-emitting diode and a photodiode for optic signal reception. NO2 was automatically introduced through the collector by two air pumps cooperating with a homemade gas injector. Under the optimized conditions, the device presented good performance for monitoring NO2, such as a limit of detection of 5.1 ppbv (parts per billion by volume), an intraday precision of 4.1% (RSD, relative standard deviation, n = 11, c = 100 ppbv), an interday precision of 5.7% (RSD, n = 2-3 per day for 5 days, c = 100 ppbv), an analysis time of 4.0 min, and a linearity range extended to 700 ppbv. The developed device was successfully applied to analyzing outdoor air with a comparable precision to that of the standard method of China. The high time resolution characteristic that includes sampling 15 times per hour and a good stability for 10 days of urban air analysis had also been evaluated. PMID- 29134808 TI - Atom-Based Strong Correlation Method: An Orbital Selection Algorithm. AB - The present study proposes a methodology that advances the selection of initial orbitals for subsequent use in correlation calculations. The initial orbital sets used herein are split-localized orbitals that span a full-valence orbital space and were developed in a previous study ( J. Chem. Phys. 2013 , 139 , 234107 ) in order to reveal the bonding patterns of molecules in a specific, quantitative manner. On the basis of the quantitative chemical features of these localized orbitals, this new method systematically extracts orbital sets and assigns excitation levels that systematically recover strong correlation with smaller numbers of configurations than can be achieved with traditional as well as nontraditional correlation methods. Moreover, this method not only provides organized initial orbitals for correlation calculations but also results in compact configuration interaction expansions via the use of the split-localized orbitals. PMID- 29134809 TI - Ru(II)-Catalyzed C-H Amidation of Indoline at the C7-Position Using Dioxazolone as an Amidating Agent: Synthesis of 7-Amino Indoline Scaffold. AB - The Ru(II)-catalyzed C-H amidation of indoline at the C7-position en route for synthesizing the 7-amino indole scaffold has been achieved by using dioxazolone, which is an environmentally benign amidating reagent. This protocol paves the way for synthesizing a variety of 7-amino indole derivatives in excellent yields at ambient reaction conditions. The readily cleavable amide group has been utilized as a directing group for the amidation. The derivatives of 7-amino indole are synthetically useful for accessing a variety of natural products, drug molecules, and biologically active compounds. PMID- 29134810 TI - C-H Bond Functionalization of Tetrahydropyridopyrimidines and Other Related Hetereocycles. AB - A novel and efficient 2-step method for the functionalization of the C-H bond adjacent to the amino group of tetrahydropyridopyrimidine (THPP) is reported herein. The reaction features mild conditions and excellent tolerance of a wide range of functional groups. Moreover, this method is applicable to tetrahydroisoquinolone (THIQ), which provides a useful supplement to literature method. This method gives chemists a new tool to functionalize a C-H bond at late stage and may find applications in both synthetic organic and medicinal chemistry. PMID- 29134811 TI - Synthetic Utility of Arylmethylsulfones: Annulative pi-Extension of Aromatics and Hetero-aromatics Involving Pd(0)-Catalyzed Heck Coupling Reactions. AB - A straightforward and general method for the synthesis of annulated thiophene, dibenzothiophene, and carbazoles analogues has been achieved involving alkylation of 2-bromo-1-(phenylsulfonylmethyl)arene/heteroarene with arylmethyl bromides/heteroarylmethyl bromides using t-BuOK as a base in DMF, followed by Pd(0)-mediated intramolecular Heck coupling in the presence of K2CO3 in DMF at 80 140 degrees C. The attractive feature of this protocol is that a wide variety of pi-conjugated heterocycles could be readily accessed by an appropriate choice of arylmethylsulfones and benzylic bromides. PMID- 29134813 TI - Do We No Longer Need To Worry about Dietary Cholesterol? PMID- 29134812 TI - Deoxycholate-Enhanced Shigella Virulence Is Regulated by a Rare pi-Helix in the Type Three Secretion System Tip Protein IpaD. AB - Type three secretion systems (T3SS) are specialized nanomachines that support infection by injecting bacterial proteins directly into host cells. The Shigella T3SS has uniquely evolved to sense environmental levels of the bile salt deoxycholate (DOC) and upregulate virulence in response to DOC. In this study, we describe a rare i + 5 hydrogen bonding secondary structure element (pi-helix) within the type three secretion system tip protein IpaD that plays a critical role in DOC-enhanced virulence. Specifically, engineered mutations within the pi helix altered the pathogen's response to DOC, with one mutant construct in particular exhibiting an unprecedented reduction in virulence following DOC exposure. Fluorescence polarization binding assays showed that these altered DOC responses are not the result of differences in affinity between IpaD and DOC, but rather differences in the DOC-dependent T3SS tip maturation resulting from binding of IpaD to translocator/effector protein IpaB. Together, these findings begin to uncover the complex mechanism of DOC-enhanced Shigella virulence while identifying an uncommon structural element that may provide a much needed target for non-antibiotic treatment of Shigella infection. PMID- 29134814 TI - Direct UV-Triggered Thiol-ene Cross-Linking of Electrospun Polyester Fibers from Unsaturated Poly(macrolactone)s and Their Drug Loading by Solvent Swelling. AB - Electrospinning is considered a relatively simple and versatile technique to form high porosity porous scaffolds with micron to nanoscale fibers for biomedical applications. Here, electrospinning of unsaturated aliphatic polyglobalide (PGl) into well-defined fibers with an average diameter of 9 MUm is demonstrated. Addition of a dithiol cross-linker and a photoinitiator to the polymer solution enabled the UV-triggered intracross-linking of the fibers during the spinning process. The in situ cross-linking of the fibers resulted in amorphous material able to swell up to 14% in tetrahydrofurane (THF) without losing the fiber morphology. Seeding mesenchymal stem cells (MSCs) onto both cross-linked and non cross-linked PGl fibers proved their compatibility with MSCs and suitability as scaffolds for cell growth and proliferation of MSCs. Moreover, the ability to directly load cross-linked PGl with hydrophobic molecules by soaking the fiber mesh in solution is shown with Rhodamine B and Indomethacin, a hydrophobic anti inflammatory drug. This marks an advantage over conventional aliphatic polyesters and opens opportunities for the design of drug loaded polyester scaffolds for biomedical applications or tissue engineering. PMID- 29134815 TI - People diagnosed with HIV and in care in Italy in 2014: results from the second national survey. AB - We conducted a second National survey in all Italian Infectious Disease clinics to assess the number of people diagnosed and linked to care and, among these, the number of people on antiretroviral therapy and viral load suppressed. In 2014, 100,049 (0.16 per 100 residents) people diagnosed and linked to care were estimated, corresponding to an increase of 6.3% compared to the survey conducted in 2012. Among people diagnosed and linked to care, 91.9% were on antiretroviral therapy (increase of 11.4% compared to 2012), and among these, 87.7% were viral load suppressed. Overall, the majority were males (72.1%), Italians (82.7%), aged 25-49 years (45.6%); the most common HIV mode of transmission was reported to be in heterosexual contact (37.9%) and men who had sex with men (31.3%); 8.8% had less than 350 CD4 cells/MUL, 82.4% had VL <50 copies and 22.9% had a CDC stage C. In conclusion, the number of people diagnosed and linked to care was increasing. The vast majority of them was receiving ART but the percentage of people still with a detectable viral load was lower than the 90-90-90 WHO target. PMID- 29134816 TI - Liquifying PLDLLA Anchor Fixation in Achilles Reconstruction for Insertional Tendinopathy. AB - : Insertional Achilles tendinopathy (IAT) is a frequent cause of posterior heel pain and is often associated with Haglund's deformity. Surgical correction for refractory cases of IAT has been well studied; however, the method of tendon fixation to bone in these procedures remains controversial, and to date, no standard technique has been identified for tendon fixation in these surgeries. Often, after Haglund's resection, there is large exposed cancellous surface for Achilles reattachment, which may require unique fixation to optimize outcomes. Previous studies have consistently demonstrated improved patient outcomes after Achilles tendon reconstruction with early rehabilitation with protected weight bearing, evidencing the need for a strong and stable anchoring of the Achilles tendon that allows early weight bearing without tendon morbidity. In this report, we highlight the design, biomechanics, and surgical technique of Achilles tendon reconstruction with Haglund's deformity using a novel technique that utilizes ultrasonic energy to liquefy the suture anchor, allowing it to incorporate into surrounding bone. Biomechanical studies have demonstrated superior strength of the suture anchor utilizing this novel technique as compared with prior techniques. However, future research is needed to ensure that outcomes of this technique are favorable when compared with outcomes using traditional suture anchoring methods. LEVELS OF EVIDENCE: Level V: Operative technique. PMID- 29134818 TI - The Effect of Chain Length on Mid-Infrared and Near-Infrared Spectra of Aliphatic 1-Alcohols. AB - Effect of the chain length on mid-infrared (MIR) and near-infrared (NIR) spectra of aliphatic 1-alcohols from methanol to 1-decanol was examined in detail. Of particular interest were the spectra-structure correlations in the NIR region and the correlation between MIR and NIR spectra of 1-alcohols. An application of two dimensional correlation analysis (2D-COS) and chemometric methods provided comprehensive information on spectral changes in the data set. Principal component analysis (PCA) and cluster analysis evidenced that the spectra of methanol, ethanol, and 1-propanol are noticeably different from the spectra of higher 1-alcohols. The similarity between the spectra increases with an increase in the chain length. Hence, the most similar are the spectra of 1-nonanol and 1 decanol. Two-dimensional hetero-correlation analysis is very helpful for identification of the origin of bands and may guide selection of the best spectral ranges for the chemometric analysis. As shown, normalization of the spectra pronounces the intensity changes in various spectral regions and provides information not accessible from the raw data. The spectra of alcohols cannot be represented as a sum of the CH3, CH2, and OH group spectra since the OH group is involved in the hydrogen bonding. As a result, the spectral changes of this group are nonlinear and its spectral profile cannot be properly resolved. Finally, this work provides a lot of evidence that the degree of self-association of 1-alcohols decreases with the increase in chain length because of the growing meaning of the hydrophobic interactions. For butyl alcohol and higher 1-alcohols the hydrophobic interactions are more important than the OH OH interactions. Therefore, methanol, ethanol, and 1-propanol have unlimited miscibility with water, whereas 1-butanol and higher 1-alcohols have limited miscibility with water. PMID- 29134817 TI - The BCR-ABL1-negative myeloproliferative neoplasms: a review of JAK inhibitors in the therapeutic armamentarium. AB - INTRODUCTION: The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). They are characterized by stem cell-derived clonal proliferation, harbor Janus kinase 2 (JAK2), or calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) driver mutations and exert an over activated JAK-signal transducer and activator of transcription (STAT) pathway. Therefore JAK inhibiting strategies have been successfully investigated in MPN clinical trials. Areas covered: The present review aims to provide a concise overview of the current and future role of JAK inhibitors in the therapeutic armamentarium of MPN. Expert opinion: The JAK1/JAK2 inhibitor ruxolitinib has clearly enriched the therapeutic armamentarium of MPN and is now licenced for more than five years in MF and over three years as second line in PV. Momelotinib, although of limited activity in MPN trials, demonstrated unique property of improving MF associated anemia. Less myelosuppressive or more selective JAK inhibitors like pacritinib, NS-01872 or Itacitinib are new promising agents tested in MF. JAK inhibition has become a cornerstone of MPN therapy and future efforts focus on ruxolitinib-based combinations and new JAK inhibitors. PMID- 29134819 TI - Web-Based Intervention to Improve Implantable Cardioverter Defibrillator Patients' Shock-Related Anxiety and Quality of Life: A Randomized Controlled Trial. AB - In spite of its effectiveness, implantable cardioverter defibrillator (ICD) patients face psychological problems such as shock-related anxiety due to device shocks. The aim of this study was to evaluate whether a web-based intervention program for ICD patients would reduce shock-related anxiety and improve quality of life compared with usual care. This was a randomized controlled trial study including a total of 76 patients. Data were collected using Turkish versions of the Florida Shock Anxiety Scale and Short Form Health Survey (SF-36) at 0 (baseline), 3, and 6 months. Following intervention, there was a significant decrease in shock anxiety levels of patients and a statistically significant increase in social functioning, role-physical, mental health, vitality, and bodily pain subdimensions of SF-36. While no statistically significant difference was found between groups in terms of summary scores of SF-36, our results suggest that web-based interventions can be useful for ICD patients. PMID- 29134820 TI - Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized versus non vitrectomized eyes. AB - INTRODUCTION: The review aims to discuss effects of vitrectomy on pharmacokinetics of anti-vascular endothelial growth factor (anti-VEGF) agents, and attempt to provide treatment guidance. Areas covered: An Embase search was conducted using the terms 'anti-VEGF', 'pegaptanib', 'ranibizumab', 'bevacizumab', 'aflibercept', 'pharmacokinetics', 'half-life', 'clearance', 'metabolism', 'vitrectomy', 'vitrectomized'. Published data regarding the pharmacokinetic properties of the above drugs and the effect of vitrectomy in animal and human eyes was reviewed. Expert opinion: There are limited studies on the effect of vitrectomy on pharmacokinetic properties of anti-VEGF drugs in human eyes. Most animal models indicate that intravitreal drugs have reduced half lives and increased clearance in vitrectomized eyes. More studies, with carefully selected design, are required to explore this further. However, considering existing evidence, it is important to consider vitreous and lens status when monitoring and treating patients. Authors recommend fixed monthly dosing, with low threshold for increasing frequency of injection even to 2-weekly if required, as well as close monitoring of patients to establish individual response. There may be an increased role for slow-release steroid implants in vitrectomized eyes with DME or RVO. Longer acting substances currently under development such as brolucizumab or abicipar pegol, may become the treatment of choice in the future. PMID- 29134821 TI - Navigating unintelligibility: Queer Australian young women's negotiations of safe sex and risk. AB - Australian public health promotion positions safe sex as a biomedical, heteronormative concept. Consequently, there is a dearth of scholarly research examining queer young women's sexual health. To fill this knowledge gap, this article considers how Australian bisexual and queer young women understand 'safe sex' and conceptualise 'good' sexual citizenship. Drawing on qualitative interviews with 15 participants in Tasmania, findings reveal that although queer women understand heterosexual safe sex, there is little awareness of safer sexual practices with female partners. We argue that gendered sexual scripts shape perceptions of sexual health risk whereby queer women adopt multiple situation dependent approaches to safer sex. PMID- 29134822 TI - Treating Moderate-to-Severe Plaque Psoriasis With Guselkumab: A Review of Phase II and Phase III Trials. AB - OBJECTIVE: Guselkumab, an anti-interleukin-23 monoclonal antibody was recently approved for the treatment of patients with moderate-to-severe plaque psoriasis. This article will review the available phase II and phase III guselkumab clinical trial data. DATA SOURCES: A PubMed search was conducted using the terms guselkumab, interleukin-23, psoriasis, adalimumab, and ustekinumab (January 2014 to August 2017). STUDY SELECTION AND DATA EXTRACTION: Articles detailing the results of phase II and phase III clinical trials were selected for review. DATA SYNTHESIS: In 1 phase II and 2 phase III clinical trials, guselkumab was more effective than adalimumab and placebo in reducing Physician's Global Assessment and Investigator Global Assessment (IGA) scores in those with moderate-to-severe plaque psoriasis. In a separate phase III trial, transitioning to guselkumab treatment was more effective than continued ustekinumab use in reducing IGA scores in those who were minimally responsive to ustekinumab ( P = 0.001). Trial results did not reveal specific patterns in adverse event (AE) incidence; the most commonly reported AEs were nasopharyngitis, headache, and upper-respiratory tract infections. No increased incidence of malignancy, tuberculosis, or serious infections were observed with the use of guselkumab. CONCLUSIONS: Guselkumab appears to be a safe and effective option for the treatment of moderate-to-severe plaque psoriasis in patients who have been screened for susceptibility to infection and are candidates for systemic treatment or phototherapy. However, long-term safety data are lacking. PMID- 29134823 TI - Does Self-Efficacy Mediate the Relationships Between Social-Cognitive Factors and Intentions to Receive HPV Vaccination Among Young Women? AB - Drawing upon health behavior change theories, the current study examined whether self-efficacy mediated relationships between social-cognitive factors (i.e., perceived risk, perceived benefits, perceived barriers, perceived severity, and cue to action) and human papillomavirus (HPV) vaccination intentions among college women. Unvaccinated women ( N = 115) aged 18 to 25 years attending a Midwestern university completed an anonymous web-based survey assessing study variables. Correlational analyses and mediation analyses were conducted. Self efficacy mediated relationships between two social-cognitive factors (i.e., perceived barriers to HPV vaccination-indirect effect = -.16, SE = .06, 95% confidence interval [CI] = [-.31, -.06]-and perceived risk of HPV-related conditions-indirect effect = .16, SE = .09, 95% CI = [.01, .37]) and HPV vaccination intentions but was unrelated to the other three social-cognitive factors. Based on these findings, future research should test whether increasing self-efficacy through education on risk of HPV-related conditions and reducing barriers to HPV vaccination improves vaccine uptake in college women. PMID- 29134825 TI - Assessing the Need for a Comprehensive Acne Quality-of-Life Scale for Face and Torso Acne. AB - PURPOSE: While acne, a common condition, largely involves the face, chest, and back, current acne quality-of-life measures focus primarily on facial acne. The purpose of this study was to assess the need for a comprehensive quality-of-life measure intended for use with patients who have facial and/or torso acne. METHODS: We evaluated the need for a comprehensive quality-of-life scale for facial and torso acne based on data from an epidemiological survey (N = 690) in which participants were grouped according to the location of their acne (face, torso, or both) and where quality of life was assessed. RESULTS: Analysis of variance results revealed that participants with acne on their torso reported the highest levels of quality of life while participants with acne on their face reported the lowest levels. CONCLUSIONS: There is a need for a quality-of-life instrument that assesses the impact of acne on the face and torso separately. This unmet need can be addressed with a comprehensive acne quality-of-life measure that is inclusive of torso acne. PMID- 29134824 TI - An overview of the role of carfilzomib in the treatment of multiple myeloma. AB - INTRODUCTION: Carfilzomib is a second-generation proteasome inhibitor that binds selectively and irreversibly with the chymotrypsin-like site of the proteolytic core. Its initial approval by the Food and Drug Administration, as monotherapy for relapsed/refractory multiple myeloma (RR-MM), followed soon by a global authorization of its combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of RR-MM after 1-3 prior lines. In order to optimize its administration, carfilzomib is currently examined in different doses and regimens in relapsed/refractory as well as in newly diagnosed myeloma. Areas covered: This review will focus on the introduction of carfilzomib as an effective anti-myeloma treatment, describing the evolution of the drug from its pre-clinical development to its established use by phase III clinical trials. Based on the latest evidence, we will present its mechanism of action, its efficacy and its toxicity profile on treated myeloma patients and we will try to reply to all raised concerns about its current use. Expert opinion: Either alone or in combination with other agents, carfilzomib seems to be an effective and safe therapeutic option for MM management. Results of ongoing trials are expected to update its application, even at an earlier level of the disease course. PMID- 29134826 TI - Cancer Patients' Recommendations for Nature-Based Design and Engagement in Oncology Contexts: Qualitative Research. AB - OBJECTIVES: To explore cancer patients' recommendations for nature engagement based on their subjective nature experiences and observations in the cancer setting. The rationale was to gain practical insight for delineating relevant and translatable nature-based care and design opportunities in oncology contexts. BACKGROUND: Innovative cancer care services are needed to respond to growing demand and shifting healthcare needs. Engagement with nature has shown multiple health benefits and presents a promising opportunity for application in healthcare to improve outcomes. METHOD: Qualitative research design using content analysis was used. Eligible adults with any cancer diagnosis participated in semistructured and audio-recorded interviews. Transcribed textual data included responses to two open-ended questions querying about participants' recommendations related to nature-based opportunities in the cancer setting. Deductive analysis used three predetermined categories: "recommendation: features," "recommendation: functions," and "cautions." RESULTS: Twenty patients with cancer (nine female) participated. Broad recommendations incorporated (1) using nature for vital sensory stimulation and engagement, (2) using nature for personal space and freedom to enable private and social exploration, (3) using views to nature for distraction and comfort, and (4) accessing nature for physical activity and movement. Three critical factors were determined for avoiding adverse experiences: determining appropriate expenditure and resourcing, selection of appropriate nature-based design materials, and exercising caution around demanding nature engagement and harsh weather conditions. CONCLUSIONS: Cancer patients' recommendations reveal the importance of engaging with nature in their experiences of health and recovery. The findings can inform planning appropriate and safe integration of beneficial nature engagement in cancer settings and support services. PMID- 29134827 TI - Serum, plasma and saliva biomarkers for head and neck cancer. AB - INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) encompasses tumors arising from several locations (oral and nasal cavities, paranasal sinuses, salivary glands, pharynx, and larynx) and currently stands as the sixth most common cancer worldwide. The most important risk factors identified so far are tobacco and alcohol consumption, and, for a subgroup of HNSCCs, infection with high-risk types of human papillomavirus (HPV). Despite several improvements in the treatment of these tumors in the last decades, overall survival rates have only improved marginally, mainly due to the advanced clinical stage at diagnosis and the high rates of treatment failure associated with this late diagnosis. Areas covered: This review will focus on the feasibility of evaluating molecular based biomarkers (mRNA, microRNA, lncRNA, DNA methylation and protein expression) in body fluids (serum, plasma, and saliva) as markers for diagnosis, prognosis, and surveillance. Expert commentary: The potential use of those markers in the clinical setting would allow for early diagnosis, prediction of treatment response, improvement in treatment selection and provide disease monitoring for early detection of tumor recurrence. It can ultimately be translated into better survival rates and improved quality of life for HNSCC patients. PMID- 29134830 TI - Erratum. AB - Brown, G.R. (2017). On Psychic Determinism. Journal of the American Psychoanalytic Association 65:423-446. (Original DOI: 10.1177/0003065117712519) On page 442 (lines 6-7) of Robin Gordon Brown's "On Psychic Determinism" (JAPA 65/3, pp. 423-446), "In his review of Dale Boesky's Do You Hear What I Hear? A Review of Psychoanalytic Disagreements in Context (2008), Abramis (2010) writes" should read "In her review of Dale Boesky's Psychoanalytic Disagreements in Context (2008), Abramis (2010) writes." On page 445, the Abramis and Boesky references should read as follows: Abramis, M. (2010). Do you hear what I hear? A review of Psychoanalytic Disagreements in Context, by Dale Boesky. Contemporary Psychoanalysis 46:289-294. Boesky, D. (2008). Psychoanalytic Disagreements in Context. Lanham, MD: Aronson. PMID- 29134833 TI - Introduction. PMID- 29134831 TI - From "Either/or" to "and": The Analyst's Use of Multiple Models in Clinical Work. AB - In our "post-pluralistic era" (Cooper 2015), analysts, perhaps particularly in North America, are exposed to a multiplicity of formal theories in their training and their reading; their clinical work often reflects ideas drawn from more than one of them. An aspect of this development is the analyst's mental process as she draws on heterogeneous models when with the patient and when processing the events of the session afterward. A number of questions arise here: How does a new piece of clinical understanding, representing an alternative theoretical perspective-one that is not usually at the center of that analyst's thinking enter the mind of the working analyst? How can the analyst assess whether this is a useful piece of understanding? How can the new piece become assimilated in the analyst's broader thinking? That is, how can the analyst's practice influence her theory? (Canestri 2006). PMID- 29134838 TI - The Analyst's "Use" of Theory or Theories: The Play of Theory. AB - Two clinical vignettes demonstrate a methodological approach that guides the analyst's attention to metaphors and surfaces that are the focus of different theories. Clinically, the use of different theories expands the metaphorical language with which the analyst tries to make contact with the patient's unconscious life. Metaphorical expressions may be said to relate to each other as the syntax of unconscious fantasy (Arlow 1979). The unconscious fantasy itself represents a metaphorical construction of childhood experience that has persisted, dynamically expressive and emergent into adult life. This persistence is evident in how, in some instances, long periods of an analysis focus on translating one or a few metaphors, chiefly because the manifest metaphorical expressions of a central theme regularly lead to better understanding of an unconscious fantasy. At times employing another model or theory assists in a level of self-reflection about clinical understanding and clinical decisions. The analyst's choice of theory or theories is unique to the analyst and is not prescriptive, except as illustrating a way to think about these issues. The use of multiple models in no way suggests or implies that theories may be integrated. PMID- 29134839 TI - Committed to a Single Model and Open to Reality. AB - A view prevails that holding multiple models enhances analytic work, enriches our understanding of pathology, offers different methods of working to meet the needs of a range of patients, and reflects openness to other approaches and the complexity of reality. Against this view it is argued, based on an examination of the nature of analytic models, that because they present comprehensive, divergent conceptions of the person and of analysis, their integration in the context of clinical work, or any shifting between them, is impossible. Although under certain circumstances multiple models seem to be held, in fact this is not so. Adherence to one's commitment to a single model facilitates, rather than constricts, openness to reality and awareness of its complexity. PMID- 29134840 TI - The Ongoing Rediscovery of Apres-Coup as a Central Freudian Concept. AB - Apres-coup, Freud's Nachtraglichkeit, is an essential psychoanalytic concept structuring each of four concepts, four mental processes that lie at the foundation of Freud's thinking: psychic trauma, repression, the creation of the unconscious, and the creation of infantile sexuality. It is argued here that infantile sexual drives, in contrast to the self-preservative instincts, arise from a two-step process of translation and repression in which the residues of failed translation become source-objects of the drives. These residues of failed translation have an associative resonance with adult sexuality, and the child is driven to ongoing attempts to translate them, to make them meaningful apres coup. Thus, apres-coup is at the heart of the human subject as a sexual creature who requires, desires, and creates meaning. PMID- 29134841 TI - The Googled and Googling Analyst. AB - Kierkegaard's concept of leveling is applied to the dynamics of envy, particularly as they come into play among psychoanalysts doing clinical analytic work. This is illustrated in two clinical vignettes. The technocultural surround of the digital age impinges on analytic identity in ways that can evoke fantasied retreats into sameness and erasure of distinction. The "digital reality principle" is introduced as a way of conceptualizing an aspect of the hatred of thinking and certain envious responses to distinction. Charisma is considered as a possible release from sameness and the prevalent homogenization of experience. Among analysts, an internalized leveling process can sometimes function as a bulwark of homogenization. PMID- 29134844 TI - Exemplars. PMID- 29134845 TI - Soapbox. PMID- 29134847 TI - Letters to the Editor. PMID- 29134848 TI - Editorial. PMID- 29134849 TI - Guest Editorial. PMID- 29134850 TI - Readers' Choice. PMID- 29134851 TI - Perceptions and Uses of Public and Private Health Care in a Brazilian Favela. AB - Since 1988, Brazil has reorganized and expanded its public health care system, defining access to health care as a right of every citizen. In parallel, the private health care sector grew rapidly to become one of the largest in the world. We explore the use of public and private health care by a low-income population living in a favela, Rio das Pedras, in Rio de Janeiro. At the time of data collection, only part of the community was covered by the primary health care program. We conducted semistructured interviews with 14 adults, both with and without access to the public primary care program. Regardless of program coverage, participants noted barriers and negative experiences while accessing public health care. The perceived inability of health professionals to deal compassionately with a low-income population was prominent in their narratives, and in the expressed motivation for pursuing private sector health care alternatives. We explore the tension arising from the more recent rights-based health care provision and historic social control and assistentialist framing of state intervention in Brazilian favelas. PMID- 29134852 TI - Psychosis and Sexual Offending: A Review of Current Literature. AB - Sexual offending is a public health concern and societal risk requiring a multi disciplinary approach. While current data give an indication of the frequency of sexual victimization, these figures likely underestimate the severity of the concern as many of these incidents go unreported. And while sex offender research has increased over the past several decades, particular attention to those offenders with severe mental illness remains limited. In this descriptive review, literature describing sex offenders with psychotic disorders is explored with a focus on recent research. Important considerations are described, including theories surrounding psychosis and sexual offending, hospitalization rates, recidivism, not guilty by reason of insanity (NGRI), female offenders, and treatment considerations. By exploring these important aspects of sex offenders with psychosis, conclusions are drawn and future directions are proposed, with a particular emphasis on clinical application for the mental health treatment provider. PMID- 29134854 TI - Prediction of Recidivism With the Youth Level of Service/Case Management Inventory (Reduced Version) in a Sample of Young Spanish Offenders. AB - Intervention in youth recidivism is critical in helping prevent young people from continuing their criminal career into adulthood, on a life-course-persistent trajectory. Andrews and Bonta attempt to provide an explanation of risk and protective factors using a conversion of the Youth Level of Service/Case Management Inventory (YLS/CMI), which predicts recidivism. In this study, scores have been obtained from 382 adolescents ( M age = 16.33 years) from the juvenile court, to check the ability of a reduced version of the YLS/CMI, to predict recidivism. The outcome variables for recidivism were examined in the 2-year follow-up period, after their first assessment in the court. The risk factors showed good levels of recidivism prediction. Recidivists obtained significant higher mean total risk scores than nonrecidivists in the reduced ( M = 6.54, SD = 2.44; M = 3.66, SD = 2.85), with areas under the curve (AUCs) ranging from .601 to .857. The factors that emerged as the most discriminative were education/employment, criminal friends, and personality. All the protective factors differentiated between recidivists and nonrecidivists. The results, therefore, showed that this reduced version would be capable of predicting youth recidivism in a reliable way. PMID- 29134853 TI - Real-world clopidogrel utilization in acute coronary syndromes: patients selection and outcomes in a single-center experience. AB - BACKGROUND: With this study, we sought to identify patient characteristics associated with clopidogrel prescription and its relationship with in-hospital adverse events in an unselected cohort of ACSs patients. MATERIALS AND METHODS: We studied all consecutive patients admitted at our institution for ACSs from 2012 to 2014. Patients were divided into two groups based on clopidogrel or novel P2Y12 inhibitors (prasugrel or ticagrelor) prescription and the relationship between clopidogrel use and patient clinical characteristics and in-hospital adverse events was evaluated using logistic regression analysis. RESULTS: The population median age was 68 years (57-77 year) and clopidogrel was prescribed in 230 patients (46%). Patients characteristics associated with clopidogrel prescription were older age, female sex, non-ST-elevation ACS diagnosis, the presence of diabetes mellitus and anemia, worse renal and left ventricular functions and a higher Killip class. Patients on clopidogrel demonstrated a significantly higher incidence of in-hospital mortality (4.8%) than prasugrel and ticagrelor-treated patients (0.4%), while a nonstatistically significant trend emerged considering bleeding events. However, on multivariable logistic regression analysis female sex, the presence of anemia and Killip class were the only variables independently associated with in-hospital death. CONCLUSION: Patients treated with clopidogrel showed a higher in-hospital mortality. However, clinical variables associated with its use identify a population at high risk for adverse events and this seems to play a major role for the higher in-hospital mortality observed in clopidogrel-treated patients. PMID- 29134855 TI - Model-based sensitivity analysis for outcome reporting bias in the meta analysis of benefit and harm outcomes. AB - Outcome reporting bias occurs when outcomes in research studies are selectively reported, the selection being influenced by the study results. For benefit outcomes, we have shown how risk assessments using the Outcome Reporting Bias in Trials risk classification scale can be used to calculate bias-adjusted treatment effect estimates. This paper presents a new and simpler version of the benefits method, and shows how it can be extended to cover the partial reporting and non reporting of harm outcomes. Our motivating example is a Cochrane systematic review of 12 studies of Topiramate add-on therapy for drug-resistant partial epilepsy. Bias adjustments for partially reported or unreported outcomes suggest that the review has overestimated the benefits and underestimated the harms of the test treatment. PMID- 29134856 TI - Boston Offender Needs Delivery Project. AB - To bridge a gap in access to community services for releasing state inmates, the Boston Offender Needs Delivery (BOND) project was developed as a longitudinal study (2014-2016) of adult inmates with a history of substance use and co occurring mental health disorders returning to the community following detention in one of Massachusetts' State correctional facilities. Pre-release inmates who were wrapping up their sentence (i.e., no community supervision) and presented with mental illness and/or substance use disorder were recruited. Participants were provided substance abuse treatment immediately post-release, as well as a variety of recovery supports for a follow-up period of 6 months. This first manuscript is intended to describe the rationale behind the BOND project, as well as the methods and procedure used to collect the data. PMID- 29134858 TI - Ancel Benjamin Keys (1904-2004): His early works and the legacy of the modern Mediterranean diet. AB - Culturally congruent dietary patterns have evolved with geographic and societal traditions and can be traced as far back as pre-Hellenistic Greece. Today, the modern Mediterranean diet (MDiet) is recognized internationally as an anti obesogenic cardioprotective dietary model consisting of plant-based foods native to the Mediterranean basin, fish, olive oil, and an active lifestyle. With the assumption that obesity and heart disease rates adversely affected life expectancy, the MDiet was identified by Dr Ancel Keys as a primary characteristic among people-groups largely immune to these trends. Following extensive research on how food quality affected human performance, Keys engineered the largest ecologic investigation of dietary habits and their effects on heart disease and longevity known as the Seven Countries Study. A new understanding of how regionally and culturally specific diets affected entire populations led to the introduction of the MDiet to the global public health community. This historiographic portrait of Dr Keys describes his humble beginnings, highlights critical points in his career, discusses his seminal research into diet and culture as protective agents, and details his legacy as the pioneer of the modern MDiet. PMID- 29134857 TI - The association between physical activity and chronic diseases in European adults. AB - Chronic diseases are the leading cause of morbidity and mortality and are considered to be at epidemic levels worldwide. This is a cross-sectional multi country study based on data from the European Social Survey round 7, 2014, comprising 30,826 participants (14,813 men) with mean age 50.4 +/- 18.0. Physical activity and chronic diseases were self-reported. Men and women who practiced physical activity more often had lower odds of having heart problems, breathing problems, type 2 diabetes, and obesity. Engaged in physical activity 2-4 times/week and >=5 times/week decrease the odds of having heart problems, high blood pressure, breathing problems, type 2 diabetes, and obesity, compared with men and women who engaged in physical activity 1 or less times per week. For the women, the practice of physical activity >=5 times/week was significantly and negatively associated with having cancer, when compared with women who engaged in physical activity 1 or less times per week. Physical activity is associated with a lower risk of chronic diseases, in particular: heart problems, high blood pressure, breathing problems, allergies, type 2 diabetes, and obesity. Furthermore, even small amounts of weekly physical activity seem to decrease the risk of chronic diseases. PMID- 29134859 TI - An injectable and self-healing hydrogel for spatiotemporal protein release via fragmentation after passing through needles. AB - A dynamic hydrogel formulated by mixing a glycol chitosan (GC) and an oxidized dextran (Odex) were studied for protein-controlled release in conjunction with the hydrogel fragmentation. A series of injectable dynamic hydrogels were derived from GC and Odex upon simple mixing without the addition of chemical crosslinking agents. The gelation readily took place at physiological pH and temperature. The influence of the concentration of GC and Odex on the gelation time, mechanical properties, water content, in vitro degradation were investigated. The Odex/GC hydrogels showed good self-healing ability under physiological conditions and kept the dynamic Schiff-base linkage at over 2 wt %. The release kinetics of a model protein (bovine serum albumin) was found to be controlled by changing the needle size upon injection, attributed to modulation of apparent size and shape of the fragmented hydrogels even in the self-healed state. Therefore, the GC based injectable and dynamic hydrogels are expected to be a promising platform for protein delivery system and various biomedical applications. PMID- 29134860 TI - Exemplars. PMID- 29134861 TI - Eminent Editor. PMID- 29134862 TI - Soap Box. PMID- 29134864 TI - Guest Editorial. PMID- 29134863 TI - Response. PMID- 29134866 TI - Student Corner. AB - In the development of nursing as a profession there is a need for nurses to discuss the strategies they use to meet the emotional demands of the nurse patient relationship. These demands have changed over time. Hochschild's definition of emotional labour is used as a means to understand the content of nurses' emotional work. It is important that positive and supportive ward atmospheres are experienced by beginning nurse practitioners while they learn to cope with the emotional work involved in nursing. Emotional labour continues to be a very challenging aspect of nursing practice. PMID- 29134867 TI - The best of leaders at the worst of times: medical scientist and war premier. AB - Professor Juan Negrin Lopez was Prime Minister of the democratically elected left wing government of Spain for the latter two-and-a-half years of the three-year Civil War which ravaged the country between 1936 and 1939. The side loyal to the government lost, partly because of the generous aid received by their opponents from Germany and Italy, partly because of the Anglo-French agreement, observed by most countries but ignored by Germany and Italy, to outlaw arms supplies to either side, partly because of internal dissent, and partly because of the greater military capability of the enemy. Negrin led the country with tenacity and wisdom, but is remembered with ambivalence in Spain, and hardly at all elsewhere, although he spent the years of his post-war exile in the UK and France. This paper draws attention to a member of the medical profession who achieved both academic and political distinction, but whose career ended in a disaster which he was powerless to prevent. Among his admirable qualities, he should be remembered for his courage. Like most wars, the Spanish Civil War had its share of psychopaths and villains - but also its share of heroes, and Juan Negrin belongs among their number. PMID- 29134869 TI - Guest Editorial. PMID- 29134868 TI - "You've Changed": Low Self-Concept Clarity Predicts Lack of Support for Partner Change. AB - People often pursue self-change, and having a romantic partner who supports these changes increases relationship satisfaction. However, most existing research focuses only on the experience of the person who is changing. What predicts whether people support their partner's change? People with low self-concept clarity resist self-change, so we hypothesized that they would be unsupportive of their partner's changes. People with low self-concept clarity did not support their partner's change (Study 1a), because they thought they would have to change, too (Study 1b). Low self-concept clarity predicted failing to support a partner's change, but not vice versa (Studies 2 and 3), and only for larger changes (Study 3). Not supporting a partner's change predicted decreases in relationship quality for both members of the couple (Studies 2 and 3). This research underscores the role of partners in self-change, suggesting that failing to support a partner's change may stem from self-concept confusion. PMID- 29134870 TI - Student Corner. AB - The nursing process provides a framework for nursing practice. Nursing literature however, highlights that both nurses and patients may experience problems associated with its use. The nursing process may not be the best method of delivering holistic nursing care. PMID- 29134871 TI - Exemplars. PMID- 29134873 TI - Soapbox. PMID- 29134874 TI - Perceptions of performance and satisfaction after relocation to an activity-based office. AB - Many companies move from open-plan offices (OPO) to activity-based workplaces (ABWs). However, few studies examine the benefits and drawbacks following such a change. The aim of this study was to explore how physical conditions, office use, communication, privacy, territoriality, satisfaction and perceived performance change following a company's relocation from an OPO to an ABW. A mixed methods approach included pre- and post-relocation questionnaires and post-relocation focus groups, individual interviews and observations. The questionnaires enabled comparisons over time (n = 34) and broader analyses based on retrospective ratings of perceived change (n = 66). Results showed that satisfaction with auditory privacy, background noise, air quality, outdoor view and aesthetics increased significantly after relocation. Negative outcomes, such as lack of communication within teams, were perceived as being due to the high people-to workstation ratio and lack of rules. Overall satisfaction with the physical work environment increased in the ABW compared to the OPO. Perceived performance did not change significantly. Practitioner Summary: Activity-based workplaces (ABWs) are commonly implemented although their effects on performance and well-being are unclear. This case study gives advice to stakeholders involved in office planning. Despite shortcomings with the people-to-workstation ratio and rules, employees showed improved satisfaction with auditory privacy and aesthetics in the ABW compared with the previous open-plan office. PMID- 29134875 TI - Editorial. PMID- 29134877 TI - Updates From the Committee on Publication Ethics (COPE). PMID- 29134876 TI - Effects of accessible website design on nondisabled users: age and device as moderating factors. AB - This study examined how implementing recommendations from Web accessibility guidelines affects nondisabled people in different age groups using different technical devices. While recent research showed positive effects of implementing such recommendations for nondisabled users, it remains unclear whether such effects would apply to different age groups and kind of devices. A 2 * 2 * 2 design was employed with website accessibility (high accessibility vs. very low accessibility), age (younger adults vs. older adults) and type of device (laptop vs. tablet) as independent variables. 110 nondisabled participants took part in a usability test, in which performance and satisfaction were measured as dependent variables. The results showed that higher accessibility increased task completion rate, task completion time and satisfaction ratings of nondisabled users. While user age did not have any effects, users showed faster task completion time under high accessibility when using a tablet rather than a laptop. The findings confirmed previous findings, which showed benefits of accessible websites for nondisabled users. These beneficial effects may now be generalised to a wide age range and across different devices. Practitioner Summary: This work is relevant to the design of websites since it emphasises the need to consider the characteristics of different user groups. Accessible website design (aimed at users with disabilities) leads to benefits for nondisabled users across different ages. These findings provide further encouragement for practitioners to apply WCAG 2.0. PMID- 29134878 TI - Message From the APNA President. PMID- 29134880 TI - Guest Editorial. PMID- 29134879 TI - Corrigendum. AB - Evans, E.C., Deutsch, N.L., Drake, E., and Bullock, L. (2017). Nurse-Patient Interaction as a Treatment for Antepartum Depression: A Mixed-Methods Analysis. Journal of the American Psychiatric Nurses Association, 23, 347-359. (Original doi: 10.1177/1078390317705449) In the September/October issue of JAPNA the reference for Peplau (1997) was incorrectly listed and cited throughout the paper. This has been updated in the online version. The correct reference should have been: Peplau, H. E. (1952). Interpersonal relations in nursing: A conceptual frame of reference for psychodynamic nursing. New York: Putnam. PMID- 29134881 TI - Student Corner. AB - Oral history values the life experience of others. It provides insight into past events, offering a colourful historical perspective which is alive with emotion and rich in character. This account presents recollections of health care training from a markedly different social, economic, cultural and political environment. Reflecting on the oral history allows exploration of aspects of the interview. Confidentiality, respect, familiarity, bias, language and the generation gap impacted on the process. The potential of older members of the community to contribute to the compilation of historical accounts is recognised and their active role valued. PMID- 29134883 TI - Exemplars. PMID- 29134884 TI - Soap Box. PMID- 29134886 TI - Exemplars. PMID- 29134885 TI - Student Corner. AB - Improving the health of Australian Aborigines remains a challenge for health care professionals. Understanding the meaning of the term health is central to this issue. There are cultural differences that must be considered, and here the traditional Aboriginal view of health is compared with that of the World Health Organization. PMID- 29134888 TI - Editorial. PMID- 29134889 TI - Soap Box. PMID- 29134890 TI - Guest Editorial. PMID- 29134892 TI - On the Shoulders of Giants. PMID- 29134894 TI - Response. PMID- 29134891 TI - Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analyses of four multinational phase 3 randomized trials. AB - OBJECTIVES: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations. METHODS: Subgroup analyses (394 patients) of four phase 3 randomized controlled trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD [IR to conventional synthetic DMARDs (csDMARDs)], and RA BEACON (IR to tumor necrosis factor inhibitors receiving csDMARDs). RESULTS: For American College of Rheumatology 20% improvement (ACR20) response rate, Japanese patients receiving baricitinib 4-mg showed similar improvement compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese patients receiving baricitinib 4-mg also showed greater improvement compared with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies, baricitinib was well tolerated, with no deaths and one malignancy. In RA-BEGIN and RA-BEAM, herpes zoster rates were higher for Japanese patients than for overall populations; all events were mild/moderate. CONCLUSION: Data for baricitinib, with/without methotrexate, in Japanese subpopulations across all stages of the RA treatment continuum accord with the efficacy/safety profile in overall study populations. Baricitinib appears to be similarly effective in Japanese patients. PMID- 29134895 TI - Student Corner. AB - Prostatic cancer is a leading cause of mortality in Australian males and yet screening programs are accorded a low priority by the health professions. Literature to date suggests that there are strong cultural taboos to the effective implementation of a national screening program. Comparisons are made with screening programs for breast and cervical cancer, currently available to Australian women. PMID- 29134896 TI - Soapbox. PMID- 29134898 TI - Soap-Box. PMID- 29134897 TI - Exemplars. PMID- 29134899 TI - Exemplars. PMID- 29134901 TI - Response. PMID- 29134902 TI - Guest Editorial. PMID- 29134904 TI - Letters to the Editor. PMID- 29134906 TI - Editorial. PMID- 29134905 TI - Student Corner. AB - The struggle that nursing has experienced to gain just status and financial reward can be explained, at least in part, by examining dominant ideologies in Australian society today. For example, such ideologies devalue caring in various ways, and since caring is a basic tenet of nursing, these ideologies ultimately devalue nursing itself. This paper explores the way in which the image and role of nursing has been socially constructed in light of such hegemonic assumptions. PMID- 29134908 TI - Readers' Choice. PMID- 29134907 TI - Exemplars. PMID- 29134909 TI - Soapbox. PMID- 29134911 TI - Soap Box. PMID- 29134912 TI - Guest Editorial. PMID- 29134913 TI - Student Corner. AB - The purpose of this discussion is to provide the reader with a dual opportunity. It encompasses various ethical paradigms and concepts, thus broadening the horizons of those interested in the ethical processes. Furthermore, it deals with issues pertaining to AIDS/Human Immunodeficiency Virus (HIV) in an ethical framework. The discussion is designed not to provide answers, but rather to create a foundation for future postulation and discussion based on ethical issues arising from the complexities of AIDS/HIV. AIDS/HIV is discussed in three ways. The first perspective deals with the client's right to treatment, and the quality of treatment each should be able to expect. The second is the nurse's role in the care of clients with AIDS/HIV. It encompasses the right of refusal of a nurse to care for an HIV positive client if directed to do so. These arguments culminate in a final discussion which deals with discrimination; however, discrimination is presented in a predominantly ethical context. PMID- 29134914 TI - Exemplars. PMID- 29134915 TI - Editorial. PMID- 29134918 TI - Response. PMID- 29134919 TI - Guest Editorial. PMID- 29134921 TI - Soapbox. PMID- 29134920 TI - Exemplars. PMID- 29134922 TI - Exploring the relationship between postmigratory stressors and mental health for asylum seekers and refused asylum seekers in the UK. AB - Numerous studies have linked the high rates of traumatic events experienced by refugees to the elevated rate of mental health problems in these populations. A growing body of evidence has also highlighted the importance of considering postmigratory stressors when making sense of displaced person distress. This study explored the relationship between mental health and postmigratory stress for asylum seekers and refused asylum seekers in Britain. The study further examined if those refused asylum experienced elevated distress and postmigratory stress compared to those awaiting the outcome of asylum applications. Results indicated that participants ( N = 97) had endured a range of pre- and postmigratory stressors and had high scores on measures of anxiety, depression, and PTSD. A postmigratory factor comprising items associated with isolation, restrictive policies, and stressors associated with having an insecure immigration status, was significantly associated with PTSD scores. This relationship remained when controlling for the variance accounted for by premigratory trauma predictors. Being refused asylum was the strongest predictor of depression and anxiety. Those refused asylum scored higher on a factor associated with barriers to accessing services. Social materialist theories of distress are drawn upon to contextualise the heightened vulnerability of those refused asylum. The paper concludes by emphasising the problems associated with taking an exclusively trauma-focussed approach when working with asylum seekers and argues for community orientated interventions to support displaced people to cope with the various stressors endured in exile. PMID- 29134923 TI - Coefficient of friction, walking speed and cadence on slippery and dry surfaces: shoes with different groove depths. AB - OBJECTIVE: The present study aimed to determine the coefficient of friction (COF), walking speed (WS) and cadence while walking on slippery and dry surfaces using shoes with different sole groove depths to predict likelihood of fall. BACKGROUND: Design of shoe sole groove is crucial to prevent slipping during walking. METHODS: 22 healthy young men (mean age 24.5, body mass index 22.5) volunteered for this semi-experimental study. Six different conditions of the test (combination of three shoes and two surfaces) were defined and the condition was repeated three times. In total, 396 trials (22 subjects * 3 groove depths * 2 surfaces * 3 times) were obtained for data analysis. COF was recorded by force platform at 1000 Hz and walking parameters recorded using 3D motion analysis with six infrared cameras at 200 Hz. RESULTS: The highest COF was obtained from the deepest groove depth (5.0 mm) on both dry and slippery surfaces. The COF on slippery surfaces was significantly lower in comparison with dry surfaces. WS and cadence were not significantly different on dry and slippery surfaces. CONCLUSION: The deeper groove is better to prevent slipping because the COF increases by increasing the shoe sole groove depth. WS did not change on dry and slippery surfaces. PMID- 29134924 TI - Treatment evaluation of acute stroke for using in regenerative cell elements (TREASURE) trial: Rationale and design. AB - Rationale MultiStem(r) (HLM051) is one of the promising allogenic cell products for acute ischemic stroke with strong evidence. A previous phase 2 randomized, double-blind, placebo-controlled, multicenter dose-escalation trial showed the safety of MultiStem(r) for acute ischemic stroke, with a time window beyond that of rt-PA and endovascular thrombectomy. We aim to obtain stronger evidence and to show the efficacy of the MultiStem(r) for treatment of ischemic stroke. Sample size Estimated sample size is 220 (110 patients per group), which has 90% power at 5% significance level. Methods and design TREASURE is a randomized, double blind, placebo-controlled, multicenter phase 2/3 trial. The trial will be done at 31 medical centers in Japan. Patients with acute ischemic stroke including motor or speech deficit defined by a National Institution of Health Stroke Scale (NIHSS) score of 8-20 at baseline will be randomized 1:1 to receive a single intravenous infusion of MultiStem(r) or placebo within 18-36 h of stroke onset. Study outcomes Primary outcome in this study is the proportion of patients with an excellent outcome at day 90 defined by the functional assessment. Trial registration ClinicalTrials.gov (NCT02961504). Conclusion The TREASURE trial will provide a novel treatment option and expand the therapeutic window for patients with stroke if the results are positive. PMID- 29134925 TI - Effects of SSRI exposure on hemorrhagic complications and outcome following thrombolysis in ischemic stroke. AB - Background Selective serotonin reuptake inhibitors (SSRI) may interfere with platelet function, and pre-stroke SSRI treatment has been associated with increased hematoma volumes and mortality in hemorrhagic stroke patients. The effects of SSRI on the risk of hemorrhagic complications after thrombolysis in ischemic stroke patients are unclear. Aims To examine the effects of pre-stroke SSRI exposure on bleeding complications, functional outcome, and mortality following thrombolysis in ischemic stroke. Methods Data including standard demographic and clinical variables as well as baseline and follow-up stroke severity (measured by National Institutes of Health Stroke Score), functional outcome (measured by modified Rankin Scale) at 3 months, and mortality at 7 and 90 days were extracted from the Virtual International Stroke Trials Archive. Multivariable binary logistic regression was used for statistical analyses. Results Out of 1114 ischemic stroke patients treated with recombinant tissue-type plasminogen activator, 135 (12.1%) had previous SSRI exposure. Symptomatic intracranial hemorrhage occurred in 30 (2.7%) patients. Of those, 2 (1.5%, n = 135) were in the SSRI pretreatment group and 28 (2.9%, n = 979) were SSRI naive patients. Pre-stroke SSRI exposure in thrombolysed patients showed association with neither bleeding complications ( P = .58) nor functional outcome ( P = .38) nor mortality ( P = .65). Conclusions Results from this large retrospective ad hoc database cohort study indicate that pre-stroke SSRI exposure in ischemic stroke patients who receive thrombolytic treatment is not associated with bleeding complications, functional outcome, or mortality. PMID- 29134926 TI - Influence of stroke coordinators on delivery of acute stroke care and hospital outcomes: An observational study. AB - Background Stroke coordinators have been inconsistently used in various countries to support stroke care in hospital. Aim To investigate the association between stroke coordinators and the provision of evidence-based care and patient outcomes in hospitals with acute stroke units. Methods Observational study using cross sectional data from the 2015 National Acute Services Audit Program (Australia): including a retrospective medical record audit (40 records from each hospital) and a self-reported survey of organizational resources for stroke. Multilevel random effects logistic regression for patient outcomes including complications, independence on discharge, and death. Median regression for length of stay comparisons. Results A total of 109 hospitals submitted 4060 cases; 59 (54%) had a stroke coordinator. Compared with patients from stroke unit hospitals with no stroke coordinator ( N = 33, 1333 cases), patients in stroke unit hospitals with a stroke coordinator ( N = 53, 2072 cases) were more likely to receive clinical practices including rehabilitation therapy within 48 hours of initial assessment (88 vs. 82%, p < 0.001), risk factor modification advice (62 vs. 55%, p = 0.003) and receive a discharge care plan (65 vs. 48%, p < 0.001). No differences in complications, independence on discharge, or deaths were evident. Patients from hospitals with a stroke coordinator were more likely to access inpatient rehabilitation (adjusted odds ratio 1.8, 95% confidence interval 1.1-2.8) and have a reduced length of acute stay if discharged (median 14 h, p = 0.03). Conclusion Presence of stroke coordinators was associated with reduced length of stay and improved delivery of evidence-based care in hospitals with a stroke unit. PMID- 29134927 TI - Cerebral amyloid angiopathy associated with inflammation: A systematic review of clinical and imaging features and outcome. AB - Background Cerebral amyloid angiopathy associated with inflammation is an increasingly recognized condition, characterized by an inflammatory response to the vascular deposits of beta-amyloid within the brain that are the hallmark of cerebral amyloid angiopathy. Two main patterns of this inflammatory response have been identified to date: one involving a perivascular inflammatory cell infiltrate (cerebral amyloid angiopathy-related inflammation); the other a transmural vasculitic process (A-beta related angiitis). Unlike cerebral amyloid angiopathy itself, which predisposes to intracerebral hemorrhage and has no known treatment, cerebral amyloid angiopathy associated with inflammation typically presents in diverse ways and diagnosis may be challenging and delayed. Aims We sought to summarize the clinical features, imaging appearances and available data on outcome and treatment responses, using information derived from a systematic review of pathologically proven cases of cerebral amyloid angiopathy associated with inflammation. Summary of review We identified 213 distinct pathologically proven cases of cerebral amyloid angiopathy-related inflammation/A-beta related angiitis, from 104 publications. The clinical presentation, imaging features, pathology, treatment, and outcomes of cerebral amyloid angiopathy associated with inflammation are described. Conclusions Cerebral amyloid angiopathy associated with inflammation is an important and increasingly recognized clinical condition, which affects the older patient population and presents most commonly with cognitive decline, seizures, and headaches. Future research is required to develop and validate diagnostic criteria and determine optimum treatment strategies. PMID- 29134929 TI - Mucilaginibacter panaciglaebae sp. nov., isolated from soil of a ginseng field. AB - A Gram-reaction-negative, strictly aerobic, non-motile and rod-shaped bacterium, designated strain BXN5-31T, was isolated from soil of a ginseng field, and its taxonomic position was investigated using a polyphasic approach. Strain BXN5-31T grew at 18-37 degrees C and at pH 6.0-8.0 on R2A medium. Based on 16S rRNA gene sequence similarity, strain BXN5-31T was shown to belong to the genus Mucilaginibacter and was closely related to Mucilaginibactersoyangensis HME6664T, Mucilaginibacterximonensis XM-003T and Mucilaginibacterpuniceus WS71T. The DNA G+C content was 43.6 %. The predominant respiratory quinone was menaquinone 7 (MK 7) and the major fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c). The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. The DNA-DNA hybridization values between strain BXN5 31T and three reference strains (M. soyangensis HME6664T, M. ximonensis XM-003T and M. puniceus WS71T) were 9.4+/-1.9, 8.2+/-1.3 and 5.7+/-0.7 %, respectively. The DNA G+C content and chemotaxonomic data supported the affiliation of strain BXN5-31T to the genus Mucilaginibacter. Moreover, the physiological and biochemical results and low level of DNA-DNA relatedness allowed the phenotypic and genotypic differentiation of strain BXN5-31T from recognized species of the genus Mucilaginibacter. The isolate therefore represents a novel species, for which the name Mucilaginibacter panaciglaebae sp. nov. is proposed. The type strain is BXN5-31T (=KACC 14957T=JCM 17085T). PMID- 29134930 TI - Involvement of many chemotaxis sensors in negative chemotaxis to ethanol in Ralstonia pseudosolanacearum Ps29. AB - Ralstonia pseudosolanacearum Ps29 showed repellent responses to alcohols including methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1,3 propanediol and prenol. R. pseudosolanacearum Ps29 possesses 22 putative chemoreceptors known as methyl-accepting chemotaxis proteins (MCPs). To identify a MCP involved in negative chemotaxis to ethanol, we measured ethanol chemotaxis of a complete collection of single mcp gene deletion mutants of R. pseudosolanacearum Ps29. However, all the mutants showed repellent responses to ethanol comparable to that of the wild-type strain. We constructed a stepwise- and multiple-mcp gene deletion mutant collection of R. pseudosolanacearum Ps29. Analysis of the collection found that an 18-mcp-knockout mutant (strain POC18) failed to respond to ethanol. Complementation analysis using POC18 as the host strain found that introduction of mcpA, mcpT, mcp09, mcpM, mcp15 and mcp19 restored the ability of POC18 to respond to ethanol. However, unexpectedly, strain POC10II, harbouring unmarked deletions in 10 mcp genes including mcpA, mcpT, mcp09, mcpM, mcp15 and mcp19 showed repellent responses to ethanol comparable to that of wild-type Ps29. We hypothesised that multiple mcp mutations in POC18 led to a shortage of MCPs required for formation of functional chemoreceptor arrays. When pPS16 (encoding McpP involved in phosphate chemotaxis) was introduced into POC18, POC18(pPS16) did not respond to phosphate. This result supports the hypothesis. But, genetic analysis revealed that MCPs (Mcp07, Mcp13, Mcp20 and Mcp21) are not essential for ethanol chemotaxis. Thus, we conclude that many and unspecified MCPs are involved in negative chemotaxis to ethanol in R. pseudosolanacearum Ps29. PMID- 29134928 TI - Potential link between post-acute ischemic stroke exposure to hypoglycemia and hemorrhagic transformation. AB - Hemorrhagic transformation is a severe complication of acute ischemic stroke owing to its limited treatment options and poor prognosis. In the last decade, the rates of hemorrhagic transformation incidence have been associated with blood glucose levels. In particular, hyperglycemia at the time of admission has been associated with increased rates of hemorrhagic transformation in acute ischemic stroke patients. Recent pilot clinical trials have attempted to use intensive insulin therapy during stroke treatment to reduce the severity of cerebral infarction and possibly alleviate the risk of hemorrhagic transformation. However, the results of these studies have shown no clear clinical benefit. In addition, intensive insulin therapy has increased rates of hypoglycemia which may be associated with larger infarct growth. We hypothesize that hypoglycemia, similarly to hyperglycemia, is a risk factor for worse outcomes in acute ischemic stroke by promoting hemorrhagic transformation. This review serves to call attention to patterns present within intensive insulin therapy trials and shed light into the pathophysiological effects of hypoglycemia. It is critical that efforts be directed toward the prevention of hemorrhagic transformation by optimizing insulin therapy during the treatment of acute ischemic stroke. PMID- 29134931 TI - Glycomyces rhizosphaerae sp. nov., isolated from the root and rhizosphere soil of wheat (Triticum aestivum L.). AB - Two actinomycete strains, NEAU-C11T and NEAU-C8, isolated from rhizosphere soil and wheat root, respectively, collected from Langfang, Hebei Province, China. A polyphasic study was carried out to establish the taxonomic position of the two strains. Morphological and chemotaxonomic characteristics of the isolates coincided with the genus Glycomyces. Sequences analysis of the 16S rRNA gene also showed that the organisms belong to the genus Glycomyces and Glycomyces algeriensis is the highest sequence match for both strains. Furthermore, a combination of DNA-DNA hybridization results and some differential physiological and biochemical properties indicated that they were distinguishable from the phylogenetically closest relatives. Therefore, the two strains represent a novel species, for which the name Glycomycesrhizosphaerae sp. nov. is proposed. The type strain is NEAU-C11T (=CGMCC 4.7396T=DSM 104646T). PMID- 29134932 TI - Outbreak of Pichia kudriavzevii fungaemia in a neonatal intensive care unit. AB - PURPOSE: Fungaemia is associated with substantial morbidity and mortality in neonates admitted to neonatal intensive care units (NICUs). We report an outbreak of fungaemia in a NICU due to rare yeast, Pichia kudriavzevii (a teleomorph of Candida krusei). To the best of our knowledge, this is the first report of neonatal sepsis due to P. kudriavzevii. METHODOLOGY: Between August and September 2014, blood cultures from nine neonates diagnosed with late-onset sepsis in the NICU yielded yeast-like organisms. The molecular identification and typing of these isolates was performed by sequencing the D1/D2 region of 26S rDNA and fluorescent amplified fragment length polymorphism (FAFLP) respectively. Antifungal susceptibility was tested by broth microdilution as per the Clinical Laboratory Standards Institute (CLSI) guidelines. Sampling from environmental sources and the hands of healthcare workers (HCWs) in the NICU was performed. RESULTS: Of the nine neonates, eight were preterm and six had very low birth weight (VLBW). Thrombocytopenia was present in two neonates. Sequencing identified all the isolates as P. kudriavzevii and FAFLP showed their clonal origin. Antifungal susceptibility testing revealed the susceptibility of all isolates to the antifungals tested. Treatment with voriconazole was advised. However, only seven neonates were treated successfully and discharged after improvement, whereas two were lost for follow-up. Cultures from the environment and the hands of HCWs were negative. The outbreak was controlled by the strict implementation of infection control practices. CONCLUSION: This study emphasizes the importance of accurate identification of the aetiological agent of sepsis and vigilant monitoring for the possibility of an outbreak in NICUs. PMID- 29134933 TI - Baculoviruses require an intact ODV entry-complex to resist proteolytic degradation of per os infectivity factors by co-occluded proteases from the larval host. AB - Baculoviruses orally infect caterpillars in the form of occlusion-derived viruses (ODVs). The ODV-envelope contains a number of proteins which are essential for oral infectivity, called per os infectivity factors (PIFs). Most of these PIFs are involved in the formation of an ODV-entry complex that consists of a stable core, formed by PIF1, PIF2, PIF3 and PIF4, and the more loosely associated PIFs P74 (PIF0) and P95 (PIF8). PIF1, PIF2 and PIF3 are essential for formation of the stable core, whereas deletion of the pif4 gene results in the formation of a smaller complex. P74 is not needed for formation of the stable core. We show here in larva-derived ODVs of the Autographa californica multicapsid nucleopolyhedrovirus that PIF-proteins are degraded by host-derived proteases after deletion of a single pif-gene. Constituents of the stable core-complex appeared to be more resistant to proteases as part of the complex than as monomer, as in ODVs of a p74 deletion mutant only the stable core was found but no PIF monomers. When the stable core lacks PIF4, it lost its proteolytic resistance as the resulting smaller core complex was degraded in a pif4 deletion mutant. We also identified PIF6 as a loosely associated component of the entry complex that appeared nevertheless important for the proteolytic resistance of the stable core, which was degraded after deletion of pif6. We conclude from these results that an intact entry-complex in the ODV-envelope is prerequisite for proteolytic resistance of PIF-proteins under the alkaline conditions of the larval midgut. PMID- 29134934 TI - Paenibacillus shunpengii sp. nov., isolated from farmland soil. AB - A bacterial strain designated YYJ7-1T was isolated from farmland soil in China and characterized using a polyphasic taxonomic approach. Cells of strain YYJ7-1T were Gram-staining-positive, aerobic or facultatively anaerobic, rod-shaped, motile and endospore-forming. Growth occurred at 18-42 degrees C (optimum at 35 degrees C), at pH 6.0-8.0 (optimum at pH 7.5) and with 0.0-4.0 % NaCl (optimum with 0.5 %). Phylogenetic analysis based on 16S rRNA gene sequences showed that the strain belonged to the genus Paenibacillus and showed high levels of sequence similarity with respect to Paenibacillus provencensis 4401170T (98.6 %) and Paenibacillus urinalis 5402403T (98.4 %), while lower 16S rRNA gene sequence similarities were observed with all other type strains (97.0 %). However, strain YYJ7-1T showed low DNA-DNA relatedness with P. provencensis 4401170T 48.7+/-4.5 % (43.6+/-7.1 % in a reciprocal experiment), and P. urinalis 5402403T 38.9+/-5.7 % (35.6+/-6.8 %). The major cellular fatty acids (>10.0 %) of strain YYJ7-1T were anteiso-C15 : 0, iso-C16 : 0 and anteiso-C17 : 0. The polar lipid profile consisted of phospholipids, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The major isoprenoid quinone was MK-7. The DNA G+C content was 39.4 mol%. Based on these results, it is concluded that strain YYJ7 1T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus shunpengii sp. nov. is proposed, with YYJ7-1T (=ACCC 19965T=KCTC 33849T) as the type strain. PMID- 29134935 TI - Susceptibility of vancomycin-resistant and -sensitive Enterococcus faecium obtained from Danish hospitals to benzalkonium chloride, chlorhexidine and hydrogen peroxide biocides. AB - PURPOSE: In Danish hospitals, the number of infections caused by vancomycin resistant Enterococcus faecium (VRE faecium) has dramatically increased in recent years. Hospital disinfectants are essential in eliminating pathogenic microorganisms, and reduced susceptibility may contribute to hospital-associated infections. We have addressed whether clinical VRE faecium display decreased biocide susceptibility when compared to vancomycin-sensitive Enterococcus faecium (VSE faecium) isolates. METHODOLOGY: In total 12 VSE faecium and 37 VRE faecium isolates obtained from Danish hospitals over an extended time period were tested for susceptibility towards three commonly applied biocides, namely benzalkonium chloride, chlorhexidine and hydrogen peroxide. RESULTS: For benzalkonium chloride, 89 % of VRE faecium strains had a minimal inhibitory concentration (MIC) of 8 mg l-1, whereas for VSE faecium, only 25 % of the strains had an MIC of 8 mg l-1. For chlorhexidine, the MIC of 95 % of VRE faecium strains was 4 mg l 1 or higher, while only 33 % of VSE faecium strains displayed MIC values at the same level. In contrast, both VRE and VSE faecium displayed equal susceptibility to hydrogen peroxide, but a higher minimal bactericidal concentration (MBC) was found for the former. The efflux activity was also assessed, and this was generally higher for the VRE faecium strains compared to VSE faecium. CONCLUSION: VRE faecium from Danish hospitals demonstrated decreased susceptibility towards benzalkonium chloride and chlorhexidine compared to VSE faecium, where the use of chlorhexidine is particularly heavy in the hospital environment. These findings suggest that biocide tolerance may characterize VRE faecium isolated in Danish hospitals. PMID- 29134936 TI - Paenibacillus xanthanilyticus sp. nov., a xanthan-degrading bacterium isolated from soil. AB - A xanthan-degrading bacterium, strain AS7T, was isolated from soil and its taxonomic position was determined using a polyphasic approach. Strain AS7T was a Gram-stain-variable, spore-forming, motile, aerobic, rod-shaped bacterium. Phylogenetic analysis based on 16S rRNA gene sequence analysis revealed that strain AS7T belongs to the genus Paenibacillus, sharing the highest level of sequence similarity with Paenibacillus phyllosphaerae PALXIL04T (98.0 %). The cell-wall peptidoglycan contained meso-diaminopimelic acid. MK-7 was the dominant isoprenoid quinone and the major fatty acid was anteiso-C15 : 0. Polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and two unknown phospholipids. These chemotaxonomic characteristics were consistent with the isolate belonging to the genus Paenibacillus. The G+C content of the genomic DNA was 51.0 mol% and the DNA-DNA hybridization value between strain AS7T and P. phyllosphaerae PALXIL04T was only 14.4+/-2.5 %. On the basis of phylogenetic analyses, phenotypic and chemotaxonomic characteristics, and DNA-DNA relatedness value, strain AS7T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus xanthanilyticus sp. nov. is proposed. The type strain is AS7T (=IBRC M 10987T=LMG 29451T). PMID- 29134937 TI - 'Candidatus Phytoplasma noviguineense', a novel taxon associated with Bogia coconut syndrome and banana wilt disease on the island of New Guinea. AB - Bogia coconut syndrome (BCS) is one of the lethal yellowing (LY)-type diseases associated with phytoplasma presence that are seriously threatening coconut cultivation worldwide. It has recently emerged, and is rapidly spreading in northern parts of the island of New Guinea. BCS-associated phytoplasmas collected in different regions were compared in terms of 16S rRNA gene sequences, revealing high identity among them represented by strain BCS-BoR. Comparative analysis of the 16S rRNA gene sequences revealed that BCS-BoR shared less than a 97.5 % similarity with other species of 'Candidatus Phytoplasma', with a maximum value of 96.08 % (with strain LY; GenBank accession no. U18747). This result indicates the necessity and propriety of a novel taxon for BCS phytoplasmas according to the recommendations of the IRPCM. Phylogenetic analysis was also conducted on 16S rRNA gene sequences, resulting in a monophyletic cluster composed of BCS-BoR and other LY-associated phytoplasmas. Other phytoplasmas on the island of New Guinea associated with banana wilt and arecanut yellow leaf diseases showed high similarities to BCS-BoR and were closely related to BCS phytoplasmas. Based on the uniqueness of their 16S rRNA gene sequences, a novel taxon 'Ca.Phytoplasma noviguineense' is proposed for these phytoplasmas found on the island of New Guinea, with strain BCS-BoR (GenBank accession no. LC228755) as the reference strain. The novel taxon is described in detail, including information on the symptoms of associated diseases and additional genetic features of the secY gene and rp operon. PMID- 29134938 TI - Short-term incubation of positive blood cultures in brain-heart infusion broth accelerates identification of bacteria by matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry. AB - PURPOSE: Fast identification of bacteria directly from positive blood cultures (BCs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) can be achieved either using the MALDI Sepsityper kit (protein extraction method) or after a short-term pre-cultivation step on solid medium. We developed a new method that involves short-term enrichment of positive BCs in brain-heart infusion broth (BHI) prior to MALDI-TOF MS analysis. METHODOLOGY: Eighty-four BCs flagged as positive were included in this study; these were processed in parallel either directly using the MALDI Sepsityper kit or following a short-term culture either in BHI or on Columbia blood agar with 5 % sheep blood (CBA). RESULTS: Bacterial species were successfully identified in 91.6, 89.2 and 65.4 % of cases after pre-cultivation for 4 h in BHI, on CBA, or by using the MALDI Sepsityper kit, respectively. Overall, the mean incubation time to correct identification was shorter when pre-cultures were performed in BHI; the mean time for Gram-negative rods was 78.2 min in BHI and 108.2 min on CBA (P=0.045), and the mean time for Gram-positive cocci was 128.5 min in BHI and 169.6 min on CBA (P=0.013). CONCLUSION: Short-term enrichment of BCs in BHI accelerates identification of a number of bacterial species by MALDI-TOF MS. Further prospective studies are needed to validate our method and gauge its potential clinical impact on the management of bloodstream bacterial infections. PMID- 29134940 TI - Fasting alters aphid probing behaviour but does not universally increase the transmission rate of non-circulative viruses. AB - A fasting period prior to non-circulative virus acquisition has been shown to increase the rate of transmission by aphids. However, this effect has only been studied for a few virus-vector combinations, and there are contradictory results in the literature as to the role of fasting on virus acquisition. We analysed the influence of fasting on the transmission of three non-circulative viruses, Cucumber mosaic virus, Zucchini yellow mosaic virus and Cauliflower mosaic virus, by two aphid vector species: Myzus persicae Sulzer (Hemiptera: Aphididae) and Aphis gossypii Glover (Hemiptera: Aphididae). All variables tested, including the virus species and isolate, and the species of aphid, influenced the effect of a fasting period on virus transmission efficiency. Furthermore, when aphids were subjected to an overnight feeding period on a sucrose solution, the fasting effect disappeared and the probing behaviour of these aphids was markedly different to plant-reared aphids. The electrical penetration graph (EPG) technique revealed that fasting altered the probing behaviour of M. persicae and A. gossypii, with fasted aphids beginning to feed sooner and having a significantly longer first intracellular puncture, measured as a potential drop. Significantly longer sub-phase II-3 of the potential drop and more archlets during this sub-phase were also observed for fasted aphids of both species. However, these behavioural changes were not predictive of increasing virus transmission following a fasting period. The impacts of pre-acquisition fasting on aphid probing behaviour and on the mechanisms of non-circulative virus transmission are discussed. PMID- 29134939 TI - The nursing home elder microbiome stability and associations with age, frailty, nutrition and physical location. AB - PURPOSE: The microbiome from nursing home (NH) residents is marked by a loss in diversity that is associated with increased frailty. Our objective was to explore the associations of NH environment, frailty, nutritional status and residents' age to microbiome composition and potential metabolic function. METHODOLOGY: We conducted a prospective longitudinal cohort study of 23 residents, 65 years or older, from one NH that had four floors: two separate medical intensive floors and two floors with active elders. Residents were assessed using the mini nutritional assessment tool and clinical frailty scale. Bacterial composition and metabolic potential of residents' stool samples was determined by metagenomic sequencing. We performed traditional unsupervised correspondence analysis and linear mixed effect modelling regression to assess the bacteria and functional pathways significantly affected by these covariates.Results/Key findings. NH resident microbiomes demonstrated temporal stability (PERMANOVA P=0.001) and differing dysbiotic associations with increasing age, frailty and malnutrition scores. As residents aged, the abundance of microbiota-encoded genes and pathways related to essential amino acid, nitrogenous base and vitamin B production declined. With increasing frailty, residents had lower abundances of butyrate producing organisms, which are associated with increased health and higher abundances of known dysbiotic species. As residents became malnourished, butyrate producing organisms declined and dysbiotic bacterial species increased. Finally, the microbiome of residents living in proximity shared similar species and, as demonstrated for Escherichia coli, similar strains. CONCLUSION: These findings support the conclusion that a signature 'NH' microbiota may exist that is affected by the residents' age, frailty, nutritional status and physical location. PMID- 29134941 TI - Bacillus marinisedimentorum sp. nov., isolated from marine sediment. AB - A novel Gram-stain-positive, motile and facultatively anaerobic strain, designated NC2-31T, was isolated from sediment from the coast of Weihai, PR China. Optimal growth occurred at 37 degrees C, pH 7.5 and with 2.0-3.0 % (w/v) NaCl. MK-7 was the major respiratory quinone. Meso-diaminopimelic acid was a diagnostic diamino acid in the peptidoglycan. The major polar lipids of NC2-31T were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG) and phosphatidylethanolamine (PE). The genomic DNA G+C content of the strain was 46.3 mol%. The predominant cellular fatty acids (>10.0 %) of NC2-31T were iso-C15 : 0 (18.9 %), anteiso-C15 : 0 (15.8 %), summed feature 3 (C16 : 1omega7c and/or iso C15 : 0 2-OH) (15.3 %) and iso-C16 : 0 (10.3 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that NC2-31T should be classified as representing a member of the genus Bacillus. Based on data from the current polyphasic study, NC2-31T represents a novel species within the genus Bacillus, for which the name Bacillusmarinisedimentorum sp. nov. is proposed with type strain NC2-31T (=KCTC 33721T=MCCC 1K01239T). PMID- 29134942 TI - Intramammary infusion of a live culture of Lactococcus lactis in ewes to treat staphylococcal mastitis. AB - PURPOSE: Alternatives to antibiotic therapy for mastitis in ruminants are needed. We present an evaluation, in two trials, of the efficacy of an intramammary infusion of a live culture of Lactococcus lactis for the treatment of subclinical and clinical mastitis in ewes. METHODOLOGY: In total, 67 animals were enrolled: 19 lactating ewes (study 1), including healthy (N=6) and coagulase-negative staphylococci (CNS)-infected ewes (N=13); and 48 lactating ewes (study 2) with either CNS mastitis (N=32), or Staphylococcus aureus mastitis (N=16), for a total of 123 mammary glands. Intramammary infusions were performed with either L. lactis or PBS for 3 (study 1) or 7 (study 2) consecutive days. Antibiotic-treated and untreated control glands were included. Milk samples for microbiology, somatic cell analysis and milk production were collected before and after treatment.Results/Key findings.L. lactis rapidly activated the mammary glands' innate immune response and initiated an inflammatory response as evidenced by the recruitment of polymorphonuclear neutrophils and increased somatic cell counts. But while leading to a transient clearance of CNS in the gland, this response caused mild to moderate clinical cases of mastitis characterized by abnormal milk secretions and udder inflammation. Moreover, S. aureus infections did not improve, and CNS infections tended to relapse. CONCLUSION: Under our experimental conditions, the L. lactis treatment led to a transient clearance of the pathogen in the gland, but also caused mild to moderate clinical cases of mastitis. We believe it is still early to implement bacterial formulations as alternatives in treating mastitis in ruminants and further experimentation is needed. PMID- 29134943 TI - Phylogenomic analysis of Balantidium ctenopharyngodoni (Ciliophora, Litostomatea) based on single-cell transcriptome sequencing. AB - In this paper, we present transcriptome data for Balantidium ctenopharyngodoni Chen, 1955 collected from the hindgut of grass carp (Ctenopharyngodon idella). We evaluated sequence quality and de novo assembled a preliminary transcriptome, including 43.3 megabits and 119,141 transcripts. Then we obtained a final transcriptome, including 17.7 megabits and 35,560 transcripts, by removing contaminative and redundant sequences. Phylogenomic analysis based on a supermatrix with 132 genes comprising 53,873 amino acid residues and phylogenetic analysis based on SSU rDNA of 27 species were carried out herein to reveal the evolutionary relationships among six ciliate groups: Colpodea, Oligohymenophorea, Litostomatea, Spirotrichea, Heterotrichea and Protocruziida. The topologies of both phylogenomic and phylogenetic trees are discussed in this paper. In addition, our results suggest that single-cell sequencing is a sound method of obtaining sufficient omics data for phylogenomic analysis, which is a good choice for uncultivable ciliates. The transcriptome data for Balantidium ctenopharyngodoni are the first omics data within the subclass Trichostomatia, and provide a good basis for ciliate phylogenomic analysis, as well as related omics analysis. PMID- 29134945 TI - Drug-drug interaction potential of the HBV and HDV entry inhibitor myrcludex B assessed in vitro. AB - BACKGROUND: Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be coadministered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro. METHODS: Inhibition of P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates. Inhibition of cytochrome P450 enzymes (CYPs) was assessed with commercially available kits. mRNA induction of drug transporting and metabolizing enzymes was measured in LS180 cells after 4 days of treatment by quantitative real-time PCR. Pregnane X receptor (PXR) activation was assessed using a reporter-gene assay. RESULTS: Whereas activities of P-gp and BCRP were not influenced by myrcludex B, OATP1B1 and OATP1B3 were specifically inhibited with a 50% inhibitory concentration (IC50) of 0.5 and 8.7 uM, respectively. Myrcludex B weakly inhibited all CYPs tested at concentrations >=10 uM except CYP2D6, which was not inhibited at concentrations up to 2 uM. Myrcludex B had no influence on mRNA expression of CYP1A1, CYP3A4, UGT1A3, ABCB1, ABCC2 and ABCG2, and on PXR activity. CONCLUSIONS: Our in vitro study suggests that myrcludex B is not at major risk of acting as a perpetrator drug. A potential inhibition of the uptake transporters OATP1B1 and OATP1B3 and a previous clinical finding of potential CYP3A inhibition, requires further evaluation and should be carefully addressed in future trials. PMID- 29134944 TI - Distinct spatial coordinate of visual and vestibular heading signals in macaque FEFsem and MSTd. AB - Precise heading estimate requires integration of visual optic flow and vestibular inertial motion originating from distinct spatial coordinates (eye- and head centered, respectively). To explore whether the two heading signals may share a common reference frame along the hierarchy of cortical stages, we explored two multisensory areas in macaques: the smooth pursuit area of the frontal eye field (FEFsem) closer to the motor side, and the dorsal portion of medial superior temporal area (MSTd) closer to the sensory side. In both areas, vestibular signals are head-centered, whereas visual signals are mainly eye-centered. However, visual signals in FEFsem are more shifted towards the head coordinate compared to MSTd. These results are robust being largely independent on: (1) smooth pursuit eye movement, (2) motion parallax cue, and (3) behavioral context for active heading estimation, indicating that the visual and vestibular heading signals may be represented in distinct spatial coordinate in sensory cortices. PMID- 29134946 TI - Prediction of phonon-mediated superconductivity in hole-doped black phosphorus. AB - We study the conventional electron-phonon mediated superconducting properties of hole-doped black phosphorus by density functional calculations and get quite a large electron-phonon coupling (EPC) constant lambda ~ 1.0 with transition temperature T C ~ 10 K, which is comparable to MgB2 when holes are doped into the degenerate and nearly flat energy bands around the Fermi level. We predict that the softening of low-frequency [Formula: see text] optical mode and its phonon displacement, which breaks the lattice nonsymmorphic symmetry of gliding plane and lifts the band double degeneracy, lead to a large EPC. These factors are favorable for BCS superconductivity. PMID- 29134947 TI - Effects of Si/SiO2 interface stress on the performance of ultra-thin-body field effect transistors: a first-principles study. AB - First-principles density functional theory (DFT) based device simulations are performed for Si ultra-thin-body (UTB) field effect transistors with the explicit SiO2 atoms in the gate dielectric. In order to evaluate the Si/SiO2 interface stress effects on the UTB device performance, the interface stress tensor is extracted from the Si/SiO2 atomic structure by DFT calculations. The influence of the interface stress on the transport properties is examined through full quantum mechanical non-equilibrium Green's function calculations. Based on the analysis of the band structure and transfer characteristics, we demonstrate that the interface stress can characterize the overall effects of the SiO2 gate dielectric on the device performance in the nanoscale regime. PMID- 29134949 TI - PLA short sub-micron fiber reinforcement of 3D bioprinted alginate constructs for cartilage regeneration. AB - In this study, we present an innovative strategy to reinforce 3D-printed hydrogel constructs for cartilage tissue engineering by formulating composite bioinks containing alginate and short sub-micron polylactide (PLA) fibers. We demonstrate that Young's modulus obtained for pristine alginate constructs (6.9 +/- 1.7 kPa) can be increased threefold (up to 25.1 +/- 3.8 kPa) with the addition of PLA short fibers. Furthermore, to assess the performance of such materials in cartilage tissue engineering, we loaded the bioinks with human chondrocytes and cultured in vitro the bioprinted constructs for up to 14 days. Live/dead assays at day 0, 3, 7 and 14 of in vitro culture showed that human chondrocytes were retained and highly viable (~80%) within the 3D deposited hydrogel filaments, thus confirming that the fabricated composites materials represent a valid solution for tissue engineering applications. Finally, we show that the embedded chondrocytes during all the in vitro culture maintain a round morphology, a key parameter for a proper deposition of neocartilage extracellular matrix. PMID- 29134948 TI - Effect of scaffold morphology and cell co-culture on tenogenic differentiation of HADMSC on centrifugal melt electrospun poly (L-lactic acid) fibrous meshes. AB - Engineered tendon grafts offer a promising alternative for grafting during the reconstruction of complex tendon tears. The tissue-engineered tendon substitutes have the advantage of increased biosafety and the option to customize their biochemical and biophysical properties to promote tendon regeneration. In this study, we developed a novel centrifugal melt electrospinning (CME) technique, with the goal of optimizing the fabrication parameters to generate fibrous scaffolds for tendon tissue engineering. The effects of CME processing parameters, including rotational speed, voltage, and temperature, on fiber properties (i.e. orientation, mean diameter, and productivity) were systematically investigated. By using this solvent-free and environmentally friendly method, we fabricated both random and aligned poly (L-lactic acid) (PLLA) fibrous scaffolds with controllable mesh thickness. We also investigated and compared their morphology, surface hydrophilicity, and mechanical properties. We seeded human adipose derived mesenchymal stem cells (HADMSC) on various PLLA fibrous scaffolds and conditioned the constructs in tenogenic differentiation medium for up to 21 days, to investigate the effects of fiber alignment and scaffold thickness on cell behavior. Aligned fibrous scaffolds induced cell elongation and orientation through a contact guidance phenomenon and promoted HADMSC proliferation and differentiation towards tenocytes. At the early stage, thinner scaffolds were beneficial for HADMSC proliferation, but the scaffold thickness had no significant effects on cell proliferation for longer-term cell culture. We further co-seeded HADMSC and human umbilical vein endothelial cells (HUVEC) on aligned PLLA fibrous mats and determined how the vascularization affected HADMSC tenogenesis. We found that co-cultured HADMSC-HUVEC expressed more tendon-related markers on the aligned fibrous scaffold. The co-culture systems promoted in vitro HADMSC differentiation towards tenocytes. These aligned fibrous scaffolds fabricated by CME technique could potentially be utilized to repair and regenerate tendon defects and injuries with cell co-culture and controlled vascularization. PMID- 29134950 TI - Structural, magnetic and electronic properties of pulsed-laser-deposition grown SrFeO3-delta thin films and SrFeO3-delta /La2/3Ca1/3MnO3 multilayers. AB - We studied the structural, magnetic and electronic properties of [Formula: see text] (SFO) thin films and [Formula: see text]/[Formula: see text] [Formula: see text]MnO3 (LCMO) superlattices that have been grown with pulsed laser deposition (PLD) on [Formula: see text] [Formula: see text] [Formula: see text] [Formula: see text] [Formula: see text] (LSAT) substrates. X-ray reflectometry and scanning transmission electron microscopy (STEM) confirm the high structural quality of the films and flat and atomically sharp interfaces of the superlattices. The STEM data also reveal a difference in the interfacial layer stacking with a SrO layer at the LCMO/SFO and a LaO layer at the SFO/LCMO interfaces along the PLD growth direction. The x-ray diffraction (XRD) data suggest that the as grown SFO films and SFO/LCMO superlattices have an oxygen-deficient [Formula: see text] structure with I4/ mmm space group symmetry ([Formula: see text]). Subsequent ozone annealed SFO films are consistent with an almost oxygen stoichiometric structure ([Formula: see text]). The electronic and magnetic properties of these SFO films are similar to the ones of corresponding single crystals. In particular, the as grown [Formula: see text] films are insulating whereas the ozone annealed films are metallic. The magneto-resistance effects of the as grown SFO films have a similar magnitude as in the single crystals, but extend over a much wider temperature range. Last but not least, for the SFO/LCMO superlattices we observe a rather large exchange bias effect that varies as a function of the cooling field. PMID- 29134951 TI - Iron-based radiochromic systems for UV dosimetry applications. AB - Phototherapy treatment using ultraviolet (UV) A and B light sources has long existed as a treatment option for various skin conditions. Quality control for phototherapy treatment recommended by the British Association of Dermatologists and British Photodermatology Group generally focused on instrumentation-based dosimetry measurements. The purpose of this study was to present an alternative, easily prepared dosimeter system for the measurement of UV dose and as a simple quality assurance technique for phototherapy treatments. Five different UVA sensitive radiochromic dosimeter formulations were investigated and responded with a measurable and visible optical change both in solution and in gel form. Iron(III) reduction reaction formulations were found to be more sensitive to UVA compared to iron(II) oxidation formulations. One iron(III) reduction formulation was found to be especially promising due to its sensitivity to UVA dose, ease of production, and linear response up to a saturation point. PMID- 29134952 TI - Epigastrium: unusual site of incisional hernia from a 5 mm trocar. AB - : The observation of an unusual case of incisional hernia, found in the epigastric zone at the site of a 5 mm trocar incision for a cholecystectomy, has caused us to describe it and to review the literature. C.A. is a male aged 59 and He came to our attention in 2014, complaining about the presence, for about three months, a swelling in the epigastric area, without occlusive symptoms. An objective examination showed an epigastric mass at the scar of the insertion site of a 5mm trocar during the cholecystectomy operation. The patient was hospitalized and underwent traditional surgery: incision at the scar; isolation of the extruded fatty tissue, which had no sac, identified as part of the round ligament, herniated through the residual incision of the previous operation. Based on experience acquired it is useful to make careful sutures of 5 mm incisions repairing peritoneal laceration. KEY WORDS: Epigastrium, General surgery, Incisional hernia, Laparoscopy, Trocar. PMID- 29134954 TI - Completion axillary lymph node dissection can be avoid in patients with invasive breast cancer and sentinel lymph node micrometastases. AB - BACKGROUND: The prognostic value of sentinel lymph node (SLN) micrometastases in invasive breast cancer patients is still widely debated. Even if, in the absence of unequivocal guidelines, the axillary lynphadenectomy is not still performed in the routine clinical care of these patients. MATERIALS AND METHOD: We have retrospectively analyzed 897 patients with operable invasive breast cancer and clinically negative axillary lymph nodes underwent conservative surgery or total mastectomy with SLN biopsy. Two groups of patients with SLN micrometastases and isolated tumor cells (ITC) were considered, the first one treated with completion axillary dissection, the second one not followed by further surgical axillary procedure. The incidence of axillary recurrences has BEEN evaluated in both groups and only in the first group of patients the involvement of the remaining lymph nodes was analyzed. RESULTS: Micrometastases were found in 67 (7.4%) patients and ITC in 8 (0,9%) patients. 14 (20.9%) patients with micrometastases and 1 (12.5%) patient with ITC underwent completion axillary dissection. 53 (79.1%) patients with micrometastases and 7 (87.5%) with ITC didn't receive further surgical axillary procedure. No axillary recurrences were found during a median follow up of 65.7+/-8.69 months in both groups of patients. CONCLUSIONS: Based on the results and according to some recent randomized trials we can say that completion axillary dissection can be safely avoided when micrometastases are found in sentinel lymph nodes. It should be performed anyway, depending on the analysis of the biomedical profile of the tumor. KEY WORDS: Breast Carcinoma, Micrometastases Axillary Lymphonode Dissection, Sentinel Lymphonode. PMID- 29134953 TI - Incidental finding of upper lip Warthin tumor. AB - AIM: This report shows an incidental finding of Warthin tumor in upper lip mucosa during hospitalization for a biting lesion of cheek mucosa MATERIALS AND METHODS: A 32-year-old male affected by a biting lesion of cheek mucosa was presented at Maxillo- Facial Unit of Federico II University. Clinical examination showed as an incidental finding a solid mass in the superficial layer of upper lip mucosa. We performed mini-invasive surgical treatment to obtain a radical excision of the cheek lesion at the same time as excision of Warthin tumor. RESULTS: a follow up of 12 months was performed. The complete healing of the two wounds was achieved, with no recurrence of any of the pathologies. DISCUSSION: The location of this Warthin tumor of minor salivary glands is very unusual. The role of imaging in diagnosis of Warthin tumor of minor salivary glands is to define localization, shape and dimension, contour, malignant features, nodal involvement. The role of fine needle aspiration cytology (FNAC) is critical in the diagnosis and therapy of minor salivary gland tumors. The surgical treatment in patients affected by Warthin tumour of minor salivary glands is local excision with a wide tumor free margin to prevent potential recurrence. CONCLUSIONS: Warthin tumor of minor salivary glands is a rare disease. We report a singular case of Warthin tumor localized in the upper lip mucosa, found as an incidental finding during a recovery for a biting lesion of cheek mucosa. KEY WORDS: Incidental finding, Minor salivary glands, Warthin tumor. PMID- 29134956 TI - The 11th C2H2 zinc finger and an adjacent C-terminal arm are responsible for TZAP recognition of telomeric DNA. PMID- 29134957 TI - Hunting for the mutant without the MAP(K). AB - In a paper recently published in Cell Research, Yu et al. identify two MAPK related kinases, MAPK11 and HIPK3, as positive regulators of levels of mutant huntingtin protein, a toxic species highly involved in Huntington's disease (HD) pathology. The identification and validation of these kinases as therapeutic targets for knockdown in multiple relevant experimental model systems reveal novel potential approaches for treatment of HD. PMID- 29134958 TI - Immunotherapy: Nice to see you - evolving MHC I-peptide presentation. PMID- 29134961 TI - The Impact of Combinations of Alcohol, Nicotine, and Cannabis on Dynamic Brain Connectivity. AB - Alcohol, nicotine, and cannabis are among the most commonly used drugs. A prolonged and combined use of these substances can alter normal brain wiring in different ways depending on the consumed cocktail mixture. Brain connectivity alterations and their change with time can be assessed using functional magnetic resonance imaging (fMRI) because of its spatial and temporal content. Here, we estimated dynamic functional network connectivity (dFNC) as derived from fMRI data to investigate the effects of single or combined use of alcohol, nicotine, and cannabis. Data from 534 samples were grouped according to their substance use combination as controls (CTR), smokers (SMK), drinkers (DRN), smoking-and drinking subjects (SAD), marijuana users (MAR), smoking-and-marijuana users (SAM), marijuana-and-drinking users (MAD), and users of all three substances (ALL). The DRN group tends to exhibit decreased connectivity mainly in areas of sensorial and motor control, a result supported by the dFNC outcome and the alcohol use disorder identification test. This trend dominated the SAD group and in a weaker manner MAD and ALL. Nicotine consumers were characterized by an increment of connectivity between dorsal striatum and sensorimotor areas. Where possible, common and separate effects were identified and characterized by the analysis of dFNC data. Results also suggest that a combination of cannabis and nicotine have more contrasting effects on the brain than a single use of any of these substances. On the other hand, marijuana and alcohol might follow an additive effect trend. We concluded that all of the substances have an impact on brain connectivity, but the effect differs depending on the dFNC state analyzed. PMID- 29134962 TI - Role of Glutamatergic Projections from the Ventral CA1 to Infralimbic Cortex in Context-Induced Reinstatement of Heroin Seeking. AB - The prelimbic cortex (PL) and infralimbic cortex (IL) play a role in context induced reinstatement of heroin seeking in an animal model of drug relapse. Both the PL and IL receive direct glutamatergic projections from the ventral CA1 (vCA1), which is also involved in context-induced reinstatement of cocaine and heroin seeking. Here we studied the role of vCA1-PL and vCA1-IL projections in context-induced reinstatement of heroin seeking by using electrophysiological, neuropharmacological, chemogenetic, and molecular methods. We showed that context induced reinstatement of heroin seeking caused selective activation of the vCA1 IL but not vCA1-PL glutamatergic projections, decreased synaptosomal GluA2 expression in the IL, impaired basal synaptic transmission, and facilitation of long-term depression (LTD) in the vCA1-IL pathway. Additionally, chemogenetic inactivation of the vCA1-IL but not vCA1-PL pathway decreased context-induced reinstatement of heroin seeking. Inactivation of the vCA1-IL pathway also reversed synaptosomal GluA2 downregulation and basal transmission reduction, and blocked LTD induction. Taken together, our results demonstrate a critical role of the vCA1-IL glutamatergic projection in context-induced reinstatement of heroin seeking in a rat model of drug relapse. PMID- 29134963 TI - The Cochrane Review Conclusion for Hepatitis C DAA Therapies is Wrong. PMID- 29134959 TI - Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. AB - The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAFV600E mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly defined populations of patients with RET-mutant or RET-rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target or to the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies. PMID- 29134964 TI - A Randomized Trial Comparing High Definition Colonoscopy Alone With High Definition Dye Spraying and Electronic Virtual Chromoendoscopy for Detection of Colonic Neoplastic Lesions During IBD Surveillance Colonoscopy. AB - OBJECTIVES: Dye spraying chromoendoscopy (DCE) is recommended for the detection of colonic neoplastic lesions in inflammatory bowel disease (IBD). The majority of neoplastic lesions are visible endoscopically and therefore targeted biopsies are appropriate for surveillance colonoscopy. To compare three different techniques for surveillance colonoscopy to detect colonic neoplastic lesions in IBD patients: high definition (HD), (DCE), or virtual chromoendoscopy (VCE) using iSCAN image enhanced colonoscopy. METHODS: A randomized non-inferiority trial was conducted to determine the detection rates of neoplastic lesions in IBD patients with longstanding colitis. Patients with inactive disease were enrolled into three arms of the study. Endoscopic neoplastic lesions were classified by the Paris classification and Kudo pit pattern, then histologically classified by the Vienna classification. RESULTS: A total of 270 patients (55% men; age range 20-77 years, median age 49 years) were assessed by HD (n=90), VCE (n=90), or DCE (n=90). Neoplastic lesion detection rates in the VCE arm was non-inferior to the DCE arm. HD was non-inferior to either DCE or VCE for detection of all neoplastic lesions. In the lesions detected, location at right colon and the Kudo pit pattern were predictive of neoplastic lesions (OR 6.52 (1.98-22.5 and OR 21.50 (8.65-60.10), respectively). CONCLUSIONS: In this randomized trial, VCE or HD-WLE is not inferior to dye spraying colonoscopy for detection of colonic neoplastic lesions during surveillance colonoscopy. In fact, in this study HD-WLE alone was sufficient for detection of dysplasia, adenocarcinoma or all neoplastic lesions. PMID- 29134966 TI - Total Pancreatectomy and Islet Autotransplant in the Treatment of Chronic Pancreatitis: Tread Very, Very Carefully. PMID- 29134965 TI - Depression Is Associated With More Aggressive Inflammatory Bowel Disease. AB - OBJECTIVES: Depression is prevalent in inflammatory bowel disease (IBD) patients. The impact of depression on IBD is not well-studied. It is unknown how providers should assess depression. METHODS: We used data from the Sinai-Helmsley Alliance for Research Excellence cohort, to assess methods of diagnosing depression and effects of baseline depression on disease activity at follow-up. A patient health questionnaire (PHQ-8) score >=5 was consistent with mild depression. Relapse was defined as a modified Harvey-Bradshaw Index >=5 or Simple Clinical Colitis Activity Index >2. We performed binomial regression to calculate adjusted risk ratios (RRs). RESULTS: We included 2,798 Crohn's disease (CD) patients with 22 month mean follow-up and 1,516 ulcerative colitis (UC) patients with 24-month mean follow-up. A total of 64% of CD patients and 45% of UC patients were in remission at baseline. By self-report, 20% of CD and 14% of UC patients were depressed. By PHQ-8, 38% of CD and 32% of UC patients were depressed (P<0.01). Adjusted for sex, remission, and disease activity, CD patients with baseline depression were at an increased risk for relapse (RR: 2.3; 95% confidence interval (CI): 1.9-2.8), surgery, or hospitalization (RR: 1.3 95% CI: 1.1-1.6) at follow-up. UC patients with baseline depression were also at increased risk for relapse (RR: 1.3; 95% CI: 0.9-1.7), surgery, or hospitalization (RR: 1.3; 95% CI: 1.1-1.5) at follow-up. CONCLUSIONS: Baseline depression is associated with a higher risk for aggressive IBD at follow-up. A single question is not a sensitive method of assessing depression. Providers should consider administering the PHQ-8 to capture those at greater risk for aggressive disease. PMID- 29134967 TI - Irritable Bowel Syndrome: Pain in Spain. PMID- 29134968 TI - "Weekend Effect" in Patients With Upper Gastrointestinal Hemorrhage: A Systematic Review and Meta-analysis. AB - OBJECTIVES: "Weekend effect" refers to worse outcomes among patients presenting to the hospital on weekends or holidays. We performed a systematic review and meta-analysis of observational studies assessing the impact of the "weekend effect" in patients with upper gastrointestinal hemorrhage (UGIH). METHODS: We searched key bibliographic databases using keywords and MeSH terms related to gastrointestinal hemorrhage and "weekend effect". Our primary analysis evaluated mortality in patients with UGIH who were hospitalized on the weekend or after hours compared with a weekday. Secondary outcomes included need for definitive therapy and length of hospital stay. Relevant data were extracted and meta analyses were performed using random effects model. Subgroup sensitivity analyses were also performed to assess the effects of key variables. RESULTS: A total of 21 of 224 identified studies met inclusion criteria. Overall, there was no association between weekend admission and mortality among patients with UGIH (Odds Ratio (OR): 1.06; 95% confidence interval (CI): 0.99-1.14). However, meta analysis using only the nine studies that did not report having a weekend rounder showed a significant increase in mortality (OR: 1.12; 95% CI: 1.07-1.17). There was no effect of weekend admission on any of our secondary outcomes. CONCLUSIONS: Current evidence suggests that weekend admission is associated with significant increase in mortality in patients with non-variceal UGIH but no difference in mortality was noted in patients with variceal UGIH. Our findings are relevant to policymakers, practitioners and providers who should ensure the creation of consistent quality and access to care throughout the week. PMID- 29134970 TI - Circadian Potassium Excretion is Unaffected Following Furosemide Induced Increase in Sodium Delivery to the Distal Nephron. AB - The mineralocorticoid aldosterone is widely accepted as a key regulator of K+ balance as well as urinary K+excretion. However, recent evidence suggests that the circadian control of K+ excretion is independent of aldosterone. Thedelivery of Na+ to the distal nephron is known to be an important determinant of aldosterone mediated secretion of K+ in thissegment of the nephron. Examining the link between distal Na+ delivery and K+ excretion; and how this link affect circadianK+ excretion will advance what is currently known about the maintenance of K+ homeostasis. In the current study, weinvestigated the effect of furosemide induced increase in distal tubular Na+ on K+ excretion. Na+, K+ and aldosterone levelswere measured in 12-hour day time and 12-hour night time urine samples following furosemide administration, andcompared with controls in 10 apparently healthy male subjects. To confirm the increased delivery of Na+ to the distal nephronby furosemide, increased Na+ excretion and aldosterone activity was observed in subjects administered furosemide.Consistent with previous reports, night time K+ excretion was significantly lower than day time, and this observation wasunchanged even with increased Na+ delivery to the distal tubules. In healthy individuals, aldosterone increases K+ secretionand this is known to further increase with increased Na+ delivery to the potassium secreting segment of the nephron. Eventhough the administration of furosemide increased aldosterone activity and the delivery of Na+ to the distal tubules, the dipin night time K+ excretion was unchanged. Our findings suggest that the circadian control of K+ excretion is not linked toNa+ levels and thus independent of aldosterone. PMID- 29134969 TI - The Prevalence and Impact of Overlapping Rome IV-Diagnosed Functional Gastrointestinal Disorders on Somatization, Quality of Life, and Healthcare Utilization: A Cross-Sectional General Population Study in Three Countries. AB - OBJECTIVES: The population prevalence of Rome IV-diagnosed functional gastrointestinal disorders (FGIDs) and their cumulative effect on health impairment is unknown. METHODS: An internet-based cross-sectional health survey was completed by 5,931 of 6,300 general population adults from three English speaking countries (2100 each from USA, Canada, and UK). Quota-based sampling was used to generate demographically balanced and population representative samples with regards to age, sex, and education level. The survey enquired for demographics, medication, surgical history, somatization, quality of life (QOL), doctor-diagnosed organic GI disease, and criteria for the Rome IV FGIDs. Comparisons were made between those with Rome IV-diagnosed FGIDs against non-GI (healthy) and organic GI disease controls. RESULTS: The number of subjects having symptoms compatible with a FGID was 2,083 (35%) compared with 3,421 (57.7%) non GI and 427 (7.2%) organic GI disease controls. The most frequently met diagnostic criteria for FGIDs was bowel disorders (n=1,665, 28.1%), followed by gastroduodenal (n=627, 10.6%), anorectal (n=440, 7.4%), esophageal (n=414, 7%), and gallbladder disorders (n=10, 0.2%). On average, the 2,083 individuals who met FGID criteria qualified for 1.5 FGID diagnoses, and 742 of them (36%) qualified for FGID diagnoses in more than one anatomic region. The presence of FGIDs in multiple regions was associated with increasing somatization, worse mental/physical QOL, more medical therapies, and a higher prevalence of abdominal surgeries; all P<0.001. Notably, individuals with FGIDs in multiple regions had greater somatization and worse QOL than organic GI disease controls. CONCLUSIONS: Roughly a third of the general adult population fulfils diagnostic criteria for a Rome IV FGID. In a third of this subset multiple GI regions are involved and this overlap is associated with increased health impairment. PMID- 29134971 TI - Detection of DNA Fragmentation in Liver of Goats Exposed to Lead Poisoning in Bagega District of Zamfara State, Nigeria. AB - The ubiquitous presence of lead (Pb) and its release by anthropogenic activities has remained a majorenvironmental pollution risk to both humans and animals. Lead toxicity has been associated with different systemic toxicitiesand biochemical impacts (such as oxidative stress and DNA damaging effects) with dire health consequences. In Nigeria,the health problem associated with lead toxicity has been overwhelming in the Bagega District of Zamfara State whereartisanal gold mining has resulted in widespread environmental lead contamination. For this study, 24 goats were selectedfrom two communities, 12 goats (exposed groups) selected from Bagega District, Zamfara (a community with widespreadmining and lead contamination), while 12 goats (control) were selected from Apete, Ibadan with no previous mining history.The liver lead levels in the two groups were evaluated using the using Atomic Absorption Spectrophotometry and the leadlevel in the exposed group was categorized into 3 exposure categories (viz mild, moderate and severe). Representative liversamples from the 3 tissue lead exposure categories were analyzed using agarose gel electrophoresis for the detection ofapoptotic oligonucleosomal DNA fragmentation. The tissue lead level in the goats from the exposed group (32.42+/-13.85mg/kg) was significantly higher than the control group (0.36+/-0.12 mg/kg). DNA ladder was detected in the 3 exposure categories with a dose-related degree of DNA fragmentation. This study highlights the role of oligonucleosomal DNAfragmentation and apoptosis in the pathogenicity of lead in lead exposed goats and the associated the dose-gradient impactof tissue lead level on the degree of DNA fragmentation. PMID- 29134972 TI - Oestrual Phase at first exposure to Predator-induced Stress Determines Pattern of Alterations in Oestrous Cycle and Endocrine Response in the Rat. AB - Stress has been acknowledged as one of the aetiologies of female reproductive dysfunction, yet the mechanismsinvolved are not totally elucidated. Based on the paucity of information on how predator-induced stress (PS) affects oestrouscycle in rats, this study was designed to investigate the effect of PS on the oestrous cycle in rats. Forty-eight (48) SpragueDawley rats were used for this study. They were randomly divided into Control and PS group. Each group was divided intofour subgroups (n=6/group) according to the phases of oestrous cycle. Stress was induced by exposing rats to cat (predator)for 60 minutes/day for 14 consecutive days. PS caused significant disruption of the oestrous cycle. In animals subjected toPS at proestrus (PS-proestrus) and oestrus (PS-oestrus), percentage occurrence of proestrus, oestrus and metestrus phaseswere significantly reduced compared with control. In animals subjected to PS at metestrus (PS-metestrus) and diestrus (PSdiestrus), percentage occurrence of oestrus phase was not significantly affected. In all animals exposed to PS, percentageoccurrence of diestrus was significantly increased regardless of the phase of first exposure compared with control.Corticosterone and prolactin levels were significantly elevated in PS groups compared with control. Progesterone wassignificantly increased in animals at diestrus phase compared with oestrus phase and respective phases in control. Oestradiolwas significantly reduced in PS group compared with control at oestrus phase but not significantly different at diestrus phase.Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were significantly lower in PS groups at oestrusphase compared with diestrus phase. This study shows that PS disrupts the oestrous cycle secondary to perturbation ofhormonal control of female reproduction and is influenced by the phase at first exposure to stress. PMID- 29134973 TI - Effect of Cortisol on Plasma Lactate Levels following Cortisolinduced Hyperglycaemia in Common African Toad, Bufo regularis. AB - Previous studies in man have shown that cortisol induces hyperglycemia through gluconeogenesis. However,the metabolic substrates involved in cortisol-induced hyperglycemia and the role of adrenergic receptors in lactate productionin toads have not been well studied. This study investigated the effects of adrenergic receptor blockers in cortisol-inducedhyperglycemia and blood lactate levels in the common African toad (Bufo regularis). Each toad was fasted and anaesthetizedwith sodium thiopentone given intraperitoneally (50mg/kg/i.p). The animals (control) received 0.7% amphibian saline whileanimals (untreated) received cortisol intravenously (50ug/kg/i.v). In pre-treatment groups, animals received propanolol (0.5mg/kg/i.v), prazosin (0.2 mg/kg/i.v) and combination of propanolol (0.5mg/kg/i.v) and prazosin (0.2 mg/kg/i.v) respectivelyfollowed by administration of cortisol 50ug/kg/i.v. Thereafter, blood samples were collected for estimation of glucose andlactate using the modified glucose oxidase method and colorimetric method respectively. Cortisol caused significant increase in blood glucose level ((p<0.05) and reduction in blood lactate levels. Pre treatment with Prazosin (0.2 mg/kg/i.v) causedsignificant (p<0.05) increase in blood glucose level and significant reduction in blood lactate levels while pre treatment withPropanolol (0.5mg/kg/i.v) abolished cortisol-induced hyperglycemia and caused increase in blood lactate levels comparedwith the untreated group. The combination of both blockers abolished the hyperglycemic effect of cortisol and causedincrease in the blood lactate levels. The results of this study show that cortisol-induced hyperglycemia is a consequent ofgluconeogenesis and mediated through the beta-adrenergic receptors. The results also show that lactate is produced andused as a gluconeogenic substrate to induce cortisol hyperglycemia in the Common African toad bufo regularis. The betaadrenergic receptors are involved in the use of lactate to induce cortisol hyperglycemia in the Common African toad Buforegularis. PMID- 29134974 TI - Differences in Physical, Physiological and Motor Performance Traits between Volleyball and Basketball Athletes in a University in Ghana. AB - Physical, physiological and motor performance traits play substantial role in both volleyball (VB) and basketball(BB) competitions. The differences in these traits among University athletes in Ghana have not been reported. Hence, thisstudy documents and compares the physical, physiological and motor performance traits of VB and BB university athletes.Purposive sampling technique involving thirty-five university athletes (24 males and 11 females) with mean age of 21.77 +/-2.03years was used. Height, weightn, waist and hip circumferences, waist to hip ratio (WHR), body mass index (BMI), heartrate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), shoulder muscular endurance (SME), abdominal muscular endurance (AME), left and right Arm Strength, Leg Power, Reaction time, Agility and Speed traits were measured.Descriptive statistics was used while analysis of variable was by paired t-test and significance was at p<0.05. Volleyballplayers significantly have better WHR, AMS and agility while Basketball athletes possess better SBP, SME and reactiontime. Gender influence was significant in height, WHR, HR, SBP, SME, AME, LAS, RAS, speed, reaction time, power andagility. Athletes in both games do not have similar physical, physiological and motor performance traits. Volley Ball playershad better abdominal muscular endurance, right-hand muscular strength, speed, power and agility while BB players hadbetter shoulder muscular endurance and reaction time traits. These differences in traits should inform volleyball andbasketball coaches in their selection. PMID- 29134975 TI - Plasma Interleukin-1beta (IL-1beta) Concentrations at the Different Phases of the Oestrus Cycle in Clomiphene Treated Female Rats. AB - Interleukin - 1beta (IL-1beta) is a signal molecule known for its role in inflammation and immune response. However,there are reports on the possible effects of IL-1beta in ovulation and various aspects on female reproduction. It was thereforenecessary to determine plasma IL-1beta levels in female rats administered ovulation inducing agent clomiphene citrate. In thiswork, a total of forty (40) female wistar rats weighing between 150g and 225g were used. Twenty of the rats wereadministered 0.14mg/kg clomiphene citrate orally daily for five days while the other twenty which served as control, receivednormal saline. The phases of the oestrus cycle (proestrus, estrus, metestrus and diestrus) were determined between the hoursof 8.30am and 10.00am on the sixth day prior to collection of blood sample by cardiac puncture. The plasma IL-1betaconcentrations were determined using rat IL-1beta ELISA kits. From the experiment, 41.2% of the control rats were in thediestrus phase while 42.1% of the clomiphene citrate treated rats were in the estrus phase. The IL-1beta plasma concentrationswere higher in clomiphene treated rats at all the phases of the oestrus cycle of experimental rats when compared with thecontrol. The increase in plasma IL-1beta was significant (p?0.05) in the estrus phase of the clomiphene citrate treated rats(550.53pg/ml) when compared with the control (304.42pg/ml). The high plasma concentration of IL-1beta at the estrus phaseof clomiphene citrate treated rats suggests its possible involvement in oocyte maturation and ovulation which characterizesthe phase. PMID- 29134976 TI - Uptake of zinc by Pteridium aquilinum (bracken fern) and response of Clarias gariepinus juveniles during chronic and sub lethal exposure. AB - Zinc is an essential trace element but can be toxic to fish at elevated concentrations. This study was carried out to assess the uptake of zinc by Clarias gariepinus juveniles and Pteridium aquilinum during chronic exposure to sub lethal concentrations. Two experiments were undertaken simultaneously in static renewal bioassays for 28 days.Haematology, histology, zinc accumulation in tissues of C.gariepinus and P. aquilinum were recorded fortnightly. Packed Cell Volume, haemoglobin concentration, Red Blood Cells, White blood cells, Lymphocytes, Neutrophils, Mean Corpuscular Volume, Mean Corpuscular Haemoglobin Concentration and Mean Corpuscular Haemoglobin of C. gariepinus varied with increasing exposure period. RBC, WBC, LYM, and NEUT differed significantly among treatments. PMID- 29134977 TI - Metformin Effects are Augmented by Chronic Intermittent Cold Stress in High Fat Diet Fed Male Wistar Rats. AB - This study investigated the effects of metformin on some glucose regulatory indices in high fat diet (HFD) fedmale Wistar rats exposed to room temperature and chronic intermittent cold stress (CICS). Thirty rats were randomly dividedinto 5 groups. Group 1(control) was maintained on standard rat chow while groups 2-5 were maintained on HFD for 8weeksrespectively prior to experimental procedures. Control, group 2(HFD untreated) and group 3(HFD+metformin (250mg/kg)were exposed to room temperature while groups 4(HFD untreated+CICS) and 5(HFD+CICS+metformin) were exposed toCICS for 21days. Blood glucose was monitored before initial exposure to HFD and on days 1,7,14 and 21 respectively.Blood samples (5mls) were thereafter collected by cardiac puncture following light ether anaesthesia, serum was obtainedand analysed for insulin, cortisol, and lipid profile using laboratory kits. Pancreatic beta-cell function and insulin resistancewere estimated using the Homeostasis Model Assessment equations. It was observed that blood glucose reduced significantlyin groups 2-4 on day21 compared to day1 values. At day 21 post-treatment, insulin level and insulin resistance were increasedwhile cholesterol levels were reduced in all HFD groups compared to control. Cortisol was increased in group 2 but reducedin groups 3-4 compared to control. HDL was reduced in groups 2-3 while liver glycogen was increased in groups 2, 3 and 5compared to control. Beta cell function and muscle glycogen were increased while LDL and triglyceride were reduced ingroups 2-4 compared to control. In conclusion, metformin ameliorates high-fat diet (HFD) induced impairment of glucoseand lipid regulatory indices by facilitating an increase in the storage of glycogen in the liver and muscle. Chronic intermittentcold stress exposure in HFD rats does not ameliorate insulin resistance but reduces impaired glucose and lipid regulatoryindices likely through an increase in adaptive thermo genic mechanisms. The actions of metformin in reducing stressfulstimulus and preventing pre-diabetes syndrome in HFD fed rats are augmented by exposure to chronic intermittent coldstress. PMID- 29134978 TI - Testicular and Epididymal Histology of Rats Chronically Administered High Doses of Phosphodiesterase-5 Inhibitors and Tramadol. AB - Testicular oxidative stress, endocrine disruption and abnormal spermatogenesis in rats exposed to high doses ofphosphodiesterase-5 inhibitors (PDE5i) and opioids, with poor reversibility following withdrawal of treatment had beenreported. In this study, we examined the histopathological effects of high doses of sildenafil, tadalafil, tramadol andsildenafil+tramadol on the testes and epididymis of rats. Seventy male rats (180 - 200 g b.w) were assigned to one of fivegroups (n = 14), namely; A: control (0.2 mL normal saline), B: sildenafil (1 mg/100g b.w), C: tadalafil (1 mg/100g b.w), D:tramadol (2 mg/100g b.w) and E: sildenafil+tramadol group (dose as in groups B and D). The drugs were administered orallyfor 8 weeks. Seven rats were sacrificed per group while the remaining 7/group continued for 8 weeks without treatment.Histopathological examination was carried out at the end of both phases. After 8 weeks of treatment, mean Johnsen'stesticular biopsy score (MJTBS) and Leydig cell count decreased significantly (p=0.001) in all treated groups compared withthe control. The MJTBS and Leydig cell count decreased significantly in tramadol (p = 0.05) and sildenafil+tramadol (p<0.01)groups compared with tadalafil group. After recovery, MJTBS and Leydig cell count were significantly (p<0.05) lower in all the groups compared with the control. Histology of the testes of rats in groups B - E showed reduced germ cell andspermatozoa population in the seminiferous tubules after 8 weeks treatment. Additionally, their epididymis showed decreasedspermatozoa density. There was no complete reversibility of histopathological alterations following withdrawal of treatment.High doses of sildenafil, tadalafil, tramadol or sildenafil+tramadol impact negatively on testicular histology with poorreversal following withdrawal of treatment. PMID- 29134979 TI - Amlodipine Corrects Changes in Blood Pressure and Baroreceptor Reflex Sensitivity in Sprague Dawley Rats Fed a High Salt Diet. AB - High dietary salt ingestion causes elevated blood pressure both in humans and in experimental animals.Following reports that Calcium Channel Blockers may exhibit differences in the response of blood vessels to pressor agents,this study sought to test the effects of amlodipine on blood pressure (BP) and baroreceptor reflex sensitivity (BRS) responsesto high salt ingestion. Three groups of weanling Sprague-Dawley rats i.e. control rats (CR), salt loaded rats (SR) and saltloaded rats concomitantly administered orally with amlodipine (SR+Am) were used. At the end of 6-week experimentalperiod, terminal arterial BP was determined from one femoral artery. BRS was calculated from the change in heart rate perchange in mean arterial BP following bilateral carotid artery occlusion. Plasma sodium and potassium ion concentrationswere also determined. Results show that dietary salt loading in SR significantly increased systolic and diastolic BP and Na+concentration but decreased BRS and K+ concentrations significantly. These changes were abolished in the (SR+Am) rats indicating the ability of amlodipine to ameliorate the increase in blood pressure, reduction in baroreceptor reflex sensitivityand alterations in plasma Na+ and K+ levels that were observed in SD rats fed a high salt diet. PMID- 29134980 TI - Association between Adiponectin, Serum Lipids and Obesity in a University Setting in Nigeria. AB - Obesity is an energy imbalance condition, which is accompanied by metabolic and cardiovascular complications.Adiponectin, produced by adipocytes, is an important adipokine involved in carbohydrate and lipid metabolism. Adiponectinlevel is altered in obesity in various populations. In Nigeria, very few studies regarding adiponectin exist, and none, to thebest of our knowledge, investigated the relationship between adiponectin and lipid profile and obesity. Therefore, this studyaims to evaluate changes in adiponectin level and serum lipids with body mass index, and investigate the relationship betweenadiponectin, serum lipids and obesity in Nigerian adults. Anthropometric parameters and blood pressure were measured, and blood samples were collected for biochemical assessment after 12 hours fasting, in a total of 280 subjects, comprising of 186males and 94 females. Serum adiponectin level was evaluated by ELISA, while serum lipid profile was determined byenzymatic endpoint method. Quantitative data were analyzed for significant difference using ANOVA, and Pearson'scorrelation was used to evaluate relationships. Serum adiponectin level was significantly (P ? 0.05) highest within overweightmale subjects (1.6 +/- 0.06 ug/ml), and lowest within normal male subjects (1.4 +/- 0.03 ug/ml). The values for adiponectin concentrations were not significantly different in the female subjects. There was no association in serum lipids andadiponectin in both male (r = -0.035, P >0.05; r = -0.011, P >0.05; r = -0.053, P >0.05; r = -0.084, P >0.05) and female (r=0.061, P >0.05; r = 0.018, P>0.05; r = 0.057, P>0.05; r = -0.021, P >0.05) for LDL, HDL, TC and TRIG respectively. Lipidprofile was not different across BMI classes. There was no relationship between adiponectin and serum lipids in individualsin the study population of adult Nigerians. PMID- 29134981 TI - Biochemical, Hormonal and Histological Changes in Prostate of Wistar Rats Following Long Term Streptozotocin-induced Diabetes Mellitus. AB - Diabetes mellitus (DM) is characterized by hyperglycemia and endocrine disorder. Diabetes mellitus is knownto promote male infertility by affecting sperm quality through altered steroidogenesis. The role of prostatic fluid in maintenance of sperm quality have been established. However, the effect of DM on prostate health is poorly understood.This study was designed to investigate the biochemical, hormonal and histological changes in prostate of male Wistar ratsafter 3- and 5 months DM. Twenty-six adult male Wistar rats were assigned into three groups. Group I (non-diabetic rats)served as control (n=10), out of which five rats (n=5) were sacrificed as control for 3-month study and the remaining animals(n=5) as control for 5-month study. Group II served as 3-month DM (n=8) and group III served as 5-month DM (n=8).Diabetes mellitus was induced by administration of a single dose of streptozotocin (STZ) (35 mg/kg i.p.). Rats were sacrificedat 3- and 5- months after DM. Biochemical indices in serum and prostate, histological and immunohistochemical studies ofthe prostate were evaluated. Results indicated that the weight of prostate of 3- and 5-months DM rats significantly (p<0.05)decreased by 33% and 59%, respectively. Fasting blood glucose, plasma glycated haemoglobin and number ofmicronucleated polychromatic erythrocytes in the bone marrow significantly (p<0.05) increased in 3- and 5-months DM.Activities of serum alanine and aspartate aminotransferases significantly (p<0.05) increased in 3 months DM withconcomitant increase in serum total bilirubin and urea in both models. The activities of total acid phosphatase in 3- and 5-months DM decreased by 34% and 76%, respectively while prostatic acid phosphatase decreased by 48% in 5-months DM.Prostatic zinc and bicarbonate increased in 3-months DM by 1.7 and 1.9 folds, and in 5-months DM by 5.8 and 1.7 folds,respectively. The levels of serum luteinizing and follicle stimulating hormones and testosterone decreased in both models.Prostatic lipid peroxidation increased while activities of antioxidative enzymes decreased in both models. Histology revealedhyperplasia, intra-luminal budding of epithelia, mild expressions of Bcl2 and Ki67 in 3- and 5 months DM. Overall, prostate health was compromised and may increase infertility in diabetic animals. PMID- 29134982 TI - Electrocardiographic and Blood Pressure Measurements in Captive African Lions (Panthera leo) Immobilized with Xylazine-Ketamine Combination. AB - Electrocardiographic and blood pressure measurements are extremely valuable diagnostic tools in the evaluationof the cardiovascular system of living animals. In this study, 6-lead electrocardiograms were recorded from five male captiveAfrican lions (Panthera leo). Also, blood pressure measurements were recorded and compared from three different sites;fore limb, hind limb and the tail, were recorded. Immobilization was done with a combination of Ketamine Hydrochloride(10mg/kg) and Xylazine (3mg/kg). Measurements were recorded as mean +/- standard deviation. ECG readings were analysedusing descriptive statistics while blood pressure readings were compared using ANOVA at a 5% level of significance. Heartrate was 66+/-11.6 beats per minute. The heart rhythm was sinus in all the animals. Mean Electrical Axis (MEA) was between+810 and +930 degrees (Mean +89+/-5). Three animals had their MEA between +810 and +890 while two had MEA between+910 and +930. Fore limb measurements for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DAP) and MeanArterial Pressure (MAP) were 177.6+/-6.8 mmHg, 157.2+/-5.9 mmHg and 168.6+/-5.2 mmHg respectively. Hind limbmeasurements for the SBP, DBP and MAP were 135.4+/-9.5 mmHg, 120.6+/-5.9 mmHg and 123.0+/-6.8 mmHg respectivelywhile the tail measurements for the SBP, DBP and MAP were 149.6+/-8.3 mmHg, 132.8+/-5.9 mmHg and 137.2+/-5.8 mmHgrespectively. There was weak correlation between forelimb vs hindlimb and forelimb vs tail comparisons of SBP, DBP andMAP. However, a strong positive correlation was found between hindlimb and tail comparisons of those parameters. Resultsfrom this study should serve as a guide in the cardiovascular monitoring of captive African Lions immobilized with axylazine-ketamine combination. PMID- 29134983 TI - Anti-hyperglycaemic Effects of Rutin on Blood Glucose, Oxidative Stress Biomarkers and Lipid Peroxidation in Alloxan-induced Hyperglycaemic Wistar Rats. AB - The present study investigated the anti-hyperglycaemic effect of rutin on blood glucose, oxidative stressbiomarkers and lipid peroxidation in alloxan induced hyperglycaemic wistar rats. Diabetes was induced in rats by anintraperitoneal (i.p) injection of alloxan monohydrate 150 mg/kg body weight. Twenty five wistar rats were divided asfollows; Group1 served as diabetic control received distilled water 2 mg/kg, Group served as positive control received 2mg/kg glibenclamide, 3, 4 and 5 received rutin at 50, 100 and 200 mg/kg body weight for 28 days respectively. At the end of the treatment, rats were sacrificed and the blood and serum were used for the analysis of blood glucose and oxidativestress biomarkers respectively. The determinations of blood glucose levels were carried out at intervals of 7, 14, 21 and 28days respectively Serum oxidative stress biomarkers lipid peroxidation, were done on the 28 days. Administrations of rutinat the three different doses 50,100 and 200 mg/kg to diabetic rats significantly (p<0.05) decreased the blood glucose levelsas compared to diabetic control. The dose of 200 mg/kg exhibited a maximum glucose lowering effect with blood glucoseof 102.8+/- 0.06 as compared to diabetic control 346.2+/-0.16. Furthermore, in relation to the oxidative stress biomarkers therewas a significant (p<0.05) increased in the levels of gluthathione peroxidase, superoxide dismutase and catalase as comparedto control. However, there was also a significant decreased in the malondialdehyde levels as compared to control. It may beconcluded that oral administration of Rutin for 28 days decreases blood glucose levels and prevented oxidative stress andantioxidant status in hyperglycaemic rats. PMID- 29134984 TI - Evaluation of Neuroprotective Effect of Hibiscus sabdariffa Linn. Aqueous Extract Against Ischaemic-Reperfusion Insult by Bilateral Common Carotid Artery Occlusion in Adult Male Rats. AB - Ischaemic brain injury continues to be devastating, causing social, medical and relationship disruption. Oxidativedamage has been reported to be one of the mechanisms for brain damage following ischaemic stroke. The antioxidant activityof Hibiscus sabdariffa L. was investigated for a possible protective effect against ischaemia-induced brain damage in rats.Adult male Wistar rats (n=35) were divided into five groups of 7 rats per group. Group 1 served as control was given tapwater; Group 2: 500 mg/kg daily of Hibiscus sabdariffa L. extract (HSE); Group 3: bilateral common carotid artery occlusion(BCCAO) for 30 minutes followed by reperfusion for 24 hours; Group 4: 500 mg/kg (HSE) before BCCAO; Group 5: 500mg/kg vitamin E before BCCAO. All administrations were oral and lasted 3 weeks. Behavioural studies namely: transitions,rearings, groomings and forelimb grip strength were carried out. Rats were thereafter euthanized and biochemical[malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)], histological andmorphological investigations were carried out on rat whole brain. Animals pretreated with HSE showed a significant (p<0.05)reduction in their body weight compared to the control group. BCCAO produced a significant (p<0.05) reduction in GSH,SOD and CAT while elevating MDA non-significantly. The HSE and Vitamin E pretreatment ameliorated these biochemicalalterations and also attenuated reactive changes in cortical neurons. BCCAO treatment increased grooming and forelimbstrength which both HSE and vitamin E pretreatment reversed. The results suggest that H. sabdariffa L and vitamin E were protective in acute cerebral ischaemia induced by bilateral common carotid artery occlusion in adult male rats. PMID- 29134985 TI - Effects of Unripe Musa Paradisiaca on the Histochemistry of the Testis and Testosterone Levels in Adult Albino Rats. AB - This study was aimed at determining the effects of the unripe fruit of Musa paradisiaca on the testis andtestosterone levels in male Wistar rats. The animals were grouped into three, comprising a control, and 2 treatment groupsadministered with different doses (500 mg/kg and 1000 mg/kg) daily of the fruit flour over 28 days. Histochemical evaluationof the testes was done using Haematoxylin and Eosin, Periodic acid Schiff's (PAS) and Feulgen staining techniques, whilethe serum and homogenised testicular tissue were evaluated for testosterone levels using Accu-Bind ELISA Kit. The testisof the treated groups showed more rapidly dividing cells and more population of sperm cells compared to the control group,and also showed more positivity for Feulgen staining and PAS reaction. Both serum and testicular testosterone levels werehowever reduced. Serum testosterone was significantly lowered in the animals given the low dose (0.67 +/- 0.03 ng/ml),compared to those given high dose (0.85 +/- 0.02 ng/ml) and the control animals (1.88 +/- 0.15 ng/ml) (p < 0.05). Changes intesticular testosterone were not statistically significant. The study suggests that M. paradisiaca fruit has reproductiveenhancing potential when consumed moderately, but this benefit may not be related to testosterone levels. PMID- 29134986 TI - Phase separation in organic aerosol. AB - Organic aerosol is ubiquitous in the atmosphere, and impacts climate through the scattering and absorption of light and through the formation of nuclei for cloud droplets. These aerosol particles, which are composed of organic compounds and salts, are of great recent interest due to the complex chemistry that occurs within the particles as well as at the air-aerosol interface. Historically, organic aerosol was thought to undergo two phase transitions as the relative humidity around the particles is varied: efflorescence (crystallization) and deliquescence (water uptake). Recently, however, it was proposed that organic aerosol can undergo a phase transition in which liquid-liquid phase separation results in the formation of a particle with two liquid phases. This phenomenon has been recognized in the biophysical chemistry community for over a century, but atmospheric systems differ in several key aspects. Over the past 15 years, characterisation of the systems that undergo phase separation, the mechanisms by which this phase transition occurs, and the resultant morphologies have been investigated, sometimes with lingering questions. In addition, theory has been developed to model liquid-liquid phase separation in bulk systems. This review will cover these studies, focusing on experimental results, as well as covering recent results on the inhibition of liquid-liquid phase separation in nanoscale particles and studies that address the implications of this phase transition on climate-related properties of aerosol particles. PMID- 29134987 TI - Graphene quantum dots based fluorescence turn-on nanoprobe for highly sensitive and selective imaging of hydrogen sulfide in living cells. AB - Hydrogen sulfide (H2S), being an important gaseous signaling molecule, has been gaining increasing attention for its involvement in a wide range of physiological processes. Herein, we developed a novel fluorescence turn-on nanoprobe for selective and sensitive detection of H2S based on graphene quantum dots (GQDs) conjugated with (2,4-dinitrophenoxy)tyrosine (DNPTYR). Taking advantage of its high fluorescence quantum yield, biocompatibility, photostability, and ease to be uptaken by cells, the GQD-based fluorescence probe was further employed for real time monitoring of the triggered dynamic change of the intracellular H2S level in live cells. PMID- 29134988 TI - Prebiotic RNA polymerisation: energetics of nucleotide adsorption and polymerisation on clay mineral surfaces. AB - We measured the binding energy and bonding parameters between model nucleotide functional groups and model clay mineral surfaces in solutions of acidic pH. We demonstrate that basal surfaces of clay minerals interact most strongly with nucleobases and show that the adsorption of the phosphate group to clay edges could facilitate polymerisation. Our results suggest that Al- and Fe-rich edge sites behave similarly in nucleotide polymerisation through change of the phosphodiester bond strength. We present an internally consistent set of thermodynamic parameters that represent the nucleotide-clay mineral system. PMID- 29134989 TI - First principles prediction of CH4 reactivities with Co3O4 nanocatalysts of different morphologies. AB - Co3O4 nanocatalysts have been experimentally shown to have excellent performance in catalyzing CH4 combustion. These nanocatalysts of different morphologies, such as nanoparticle/nanocube, nanorod/nanobelt, and nanoplate/nanosheet, were previously synthesized and characterized to mainly expose the (001), (011), and (112) surfaces, respectively, with distinct reactivities. In this study, rigorous first principles calculations were performed to investigate CH4 reactivities of the above Co3O4 surfaces of different terminations. CH4 dissociation was predicted to occur at the Co-O pair site on these surfaces. For each surface, the most reactive Co-O pair site was identified based on calculated energy barriers of the different active sites, which should contribute most significantly to the reactivity of that surface. The lowest energy barriers for the (001), (011), and (112) surfaces were predicted to be 0.96, 0.90, and 0.79 eV, respectively, suggesting CH4 reactivity to increase in that order for the different Co3O4 surfaces, consistent with the trend found experimentally for Co3O4 nanocatalysts of different morphologies. Direct comparison between the estimated and experimental CH4 reaction rates per gram of the nanocatalysts at 325 degrees C further indicate that their relative ratios were well reproduced by considering three main factors: the effective energy barrier for CH4 dissociation, the surface area of the nanocatalyst, and the number of independent active sites per unit surface area. The important influence of surface area on CH4 reactivity is also demonstrated by the significant difference in the reactivities of the nanocatalysts when exposing the same facet but with distinct surface areas. PMID- 29134990 TI - DFT coupled with NEGF study of ultra-sensitive HCN and HNC gases detection and distinct I-V response based on phosphorene. AB - The sensing performances of pristine and X-doped phosphorene substrates (X = Al, Si, and S atoms) toward the adsorption of the toxic gases HCN and HNC were systematically investigated by first-principles simulations. The numerical results show that the pristine phosphorene is sensitive to HCN and HNC molecules with moderate adsorption energy, excellent charge transfer, high sensitivity and selectivity, implying its potential applications as excellent HCN and HNC sensors. In addition, the Al-doped phosphorene exhibits extremely high reactive activity toward HCN and HNC gases; thus, it has potential for use as a metal-free catalyst for activating or catalyzing HCN or HNC adsorbates. Moreover, the transport properties, i.e., current-voltage (I-V) characteristics, were calculated by the non-equilibrium Green's function (NEGF) method within the framework of the density functional theory (DFT). The obtained results reveal that the adsorbed HCN or HNC gas molecules have a remarkable impact on the electronic conductivity of phosphorene, and the zigzag direction of phosphorene is more sensitive to gas molecules than the armchair direction. The combination of the high sensitivity, superior selectivity, and moderate adsorption energy of pristine phosphorene toward HCN or HNC gas molecules adsorption, makes phosphorene an excellent candidate for HCN and HNC sensors. PMID- 29134991 TI - Exploration of VPO4 as a new anode material for sodium-ion batteries. AB - Carbon-coated VPO4 nanoparticles embedded into a porous carbon matrix were synthesized via a facile sol-gel approach and investigated as a novel polyanion anode material for sodium-ion batteries. The VPO4@carbon anode demonstrates excellent rate capability and superior cyclic stability (245.3 mA h g-1 at 1000 mA g-1 after 200 cycles). PMID- 29134992 TI - Formation of C2 oxygenates and ethanol from syngas on an Fe-decorated Cu-based catalyst: insight into the role of Fe as a promoter. AB - In this study, the formation mechanism of C2 oxygenates and ethanol from syngas on Fe-decorated Cu bimetallic catalyst was investigated using density functional theory (DFT) calculations together with microkinetic modeling. The results showed that CH2 was the most favored monomer among all the CHx (x = 1-3) species over the FeCu bimetallic catalyst, which was more favorable than CH3OH formation. Namely, the FeCu catalyst exhibited a good selectivity toward CH2 formation instead of CH3OH formation in syngas conversion. Starting from the CH2 monomer, CH2CO and CH3CO via CO insertion into CH2 and CH2CO hydrogenation were the major products instead of C2 hydrocarbons or methane, CH3CO was successively hydrogenated to ethanol via CH3CHO and CH3CH2O intermediates. Moreover, the microkinetic modeling showed that the FeCu bimetallic catalyst had a high selectivity toward ethanol rather than methanol and methane. Further, the addition of Fe into the Cu catalyst promoted CHx formation by accelerating C-O bond cleavage, suppressed methanol formation, and facilitated C2 oxygenate formation rather than methane formation, suggesting that the synergetic effect between Fe and Cu played an important role in the formation of C2 oxygenates and ethanol. In addition, it is believed that the insights derived from this study can provide clues for the catalyst design of oxygenate synthesis and other bimetallic catalytic systems. PMID- 29134993 TI - The promoting effect of tetravalent cerium on the oxygen evolution activity of copper oxide catalysts. AB - A new catalyst is presented for the oxygen evolution reaction (OER) based on cerium-modified copper oxide (CuOx) prepared using a facile electrodeposition procedure. Incorporation of Ce into CuOx leads to greatly improved OER activity, which reached an optimal value at a surface concentration of 6.9 at% Ce. Specifically, the OER current density at 400 mV overpotential for the most active Ce-modified CuOx catalyst (6.9 at% Ce) was 3.3 times greater compared to the pure CuOx. Coincident with the improved OER activity, Ce incorporation also leads to significant structural changes that manifested in increasing degrees of disorder. A further increase in the Ce concentration led to a decrease in the OER performance which can be attributed to the formation of a segregated CeO2 phase. A strong correlation was observed between the OER performance and tetravalent Ce (Ce4+) ion concentration, up to a concentration corresponding to CeO2 phase segregation. No particular trend was observed for the OER activity of these Ce modified CuOx catalysts with respect to the surface concentration of Cu ions, surface oxygen species or catalyst structure. The stability of these CuOx catalysts at 5 mA cm-2 was also improved with Ce incorporation, and the overpotential required to sustain this current density is much lower than that of pure CuOx. Overall, this study provides new insights regarding the promoting effect of tetravalent Ce ions on the OER activity of CuOx-based OER catalysts in alkaline electrolytes. PMID- 29134994 TI - Gas adsorption efficacy of graphene sheets functionalised with carboxyl, hydroxyl and epoxy groups in conjunction with Stone-Thrower-Wales (STW) and inverse Stone Thrower-Wales (ISTW) defects. AB - The complete reduction of graphene oxide is difficult to achieve, and hence oxygen-containing functional groups do exist in graphene, along with structural defects. On the other hand, efficient gas sensor materials have been a subject of relentless interest. This instigates the need to explore the gas adsorption on STW and ISTW defective graphene sheets functionalised by -COOH, -OH and C-O-C groups, using density functional theory calculations. Both defects are experimentally feasible as evident through their formation energies. Furthermore mono-functionalisation induces significant buckling of the sheet; in contrast, bi functionalisation of the sheet restores the planarity of the sheet. We found that the ISTW defective sheet is more reactive than the STW defective sheet to all the functional groups considered, and in particular -COOH is the most adsorptive group to both the defects, while epoxy has consistent adsorptivity towards the defects. Gas molecules such as CO2, H2, N2, CH4 and O2 are physisorbed, whereas HF and H2O are chemisorbed on the functionalised sheets. The sensitivity of the gas molecules towards the functionalised sheets is obtained by DeltaEg, which is pronounced for pristine + OH and STW + epoxy and bare ISTW defective sheets. However, the functionalised sheets exhibit improved sensing properties for O2; specifically, mono-epoxy functionalised and bi-carboxylated defective sheets show high sensitivity towards O2. Furthermore, the surface functionalisation enhances the selectivity of the sensor. From the TDOS plot, the functionalised sheet exhibits p-type behaviour. Thus, the results of this study reveal that the functionalised defective sheets can be utilized as O2 sensors. PMID- 29134995 TI - Rate constant for the H + H2O -> OH + H2 reaction at elevated temperatures measured by pulse radiolysis. AB - Maintaining the structural integrity of materials in nuclear power plants is an essential issue associated with safe operation. Hydrogen (H2) addition or injection to coolants is a powerful technique that has been widely applied such that the reducing conditions in the coolant water avoid corrosion and stress corrosion cracking (SCC). Because the radiation-induced reaction of OH + H2 -> H + H2O plays a crucial role in these systems, the rate constant has been measured at operation temperatures of the reactors (285-300 degrees C) by pulse radiolysis, generating sufficient data for analysis. The reverse reaction H + H2O -> OH + H2 is negligibly slow at ambient temperature; however, it accelerates considerably quickly at elevated temperatures. Although the reverse reaction reduces the effectiveness of H2 addition, reliable rate constants have not yet been measured. In this study, the rate constants have been determined in a temperature range of 250-350 degrees C by pulse radiolysis in an aqueous I- solution. PMID- 29134996 TI - Photo-cross-linked perylene diimide derivative materials as efficient electron transporting layers in inverted polymer solar cells. AB - We present an efficient and stable interfacial material based on a water-soluble perylene diimide derivative functionalized with ionic and methacrylate groups (abbreviated as PDIM), which can be stabilized by the photo-polymerization of diacrylate groups at both ends of the side chain in the PDIM. The characteristics of the photo-cross-linked PDIM films were examined using absorption spectra, cyclic voltammetry, work function, and surface morphology. The feasibility of the photo-cross-linked PDIM films as a novel electron transporting layer (ETL) in polymer solar cells (PSCs) was also investigated. The PTB7-Th:PC71BM-based PSC using the PDIM as the ETL achieved the excellent power conversion efficiency of 9.44% similar to the conventional polyethylenimine ethoxylated (PEIE) and better than ZnO. Furthermore, the PSC with the PDIM films exhibited a similar lifetime to that of the PEIE-based device. This approach suggests that the photo-cross linked PDIM film could be regarded as a promising interfacial material for fabricating highly efficient PSCs. PMID- 29134997 TI - Photoinduced dynamics in cycloparaphenylenes: planarization, electron-phonon coupling, localization and intra-ring migration of the electronic excitation. AB - Cycloparaphenylenes represent the smallest possible fragments of armchair carbon nanotubes. Due to their cyclic and curved conjugation, these nanohoops own unique photophysical properties. Herein, the internal conversion processes of cycloparaphenylenes of sizes 9 through 16 are simulated using Non-Adiabatic Excited States Molecular Dynamics. In order to analyze effects of increased conformational disorder, simulations are done at both low temperature (10 K) and room temperature (300 K). We found the photoexcitation and subsequent electronic energy relaxation and redistribution lead to different structural and electronic signatures such as planarization of the chain, electron-phonon couplings, wavefunction localization, and intra-ring migration of excitons. During excited state dynamics on a picosecond time-scale, an electronic excitation becomes partially localized on a portion of the ring (about 3-5 phenyl rings), which is not a mere static contraction of the wavefunction. In a process of non-radiative relaxation involving non-adiabatic transitions, the latter exhibits significant dynamical mobility by sampling uniformly the entire molecular structure. Such randomized migration involving all phenyl rings, occurs in a wave-like fashion coupled to vibrational degrees of freedom. These results can be connected to unpolarized emission observed in single-molecule fluorescence experiments. Observed intra-ring energy transfer is subdued for lower temperatures and adiabatic dynamics involving low-energy photoexcitation to the first excited state. Overall our analysis provides a detailed description of photo excited dynamics in molecular systems with circular geometry, outlines size-dependent trends and connotes specific spectroscopic signatures appearing in time-resolved experimental probes. PMID- 29134998 TI - 2D molybdenum and vanadium nitrides synthesized by ammoniation of 2D transition metal carbides (MXenes). AB - MXenes are a rapidly growing class of 2D transition metal carbides and nitrides, finding applications in fields ranging from energy storage to electromagnetic interference shielding and transparent conductive coatings. However, while more than 20 carbide MXenes have already been synthesized, Ti4N3 and Ti2N are the only nitride MXenes reported so far. Here by ammoniation of Mo2CTx and V2CTx MXenes at 600 degrees C, we report on their transformation to 2D metal nitrides. Carbon atoms in the precursor MXenes are replaced with N atoms, resulting from the decomposition of ammonia molecules. The crystal structures of the resulting Mo2N and V2N were determined with transmission electron microscopy and X-ray pair distribution function analysis. Our results indicate that Mo2N retains the MXene structure and V2C transforms to a mixed layered structure of trigonal V2N and cubic VN. Temperature-dependent resistivity measurements of the nitrides reveal that they exhibit metallic conductivity, as opposed to semiconductor-like behavior of their parent carbides. As important, room-temperature electrical conductivity values of Mo2N and V2N are three and one order of magnitude larger than those of the Mo2CTx and V2CTx precursors, respectively. This study shows how gas treatment synthesis such as ammoniation can transform carbide MXenes into 2D nitrides with higher electrical conductivities and metallic behavior, opening a new avenue in 2D materials synthesis. PMID- 29134999 TI - Micelle-assisted electrodeposition of highly mesoporous Fe-Pt nodular films with soft magnetic and electrocatalytic properties. AB - Mesoporous Fe-Pt nodular films (with a regular spatial arrangement of sub-15 nm pores) are grown onto evaporated Au, Cu and Al conductive layers by micelle assisted electrodeposition from metal chloride salts in the presence of Pluronic P123 tri-block copolymer dissolved in the aqueous electrolytic bath. This synthetic approach constitutes a simple, one-step, versatile procedure to grow multifunctional mesoporous layers appealing for diverse applications that take advantage of materials with an ultra-high surface area-to-volume ratio. The films exhibit tuneable composition with relative Fe/Pt weight ratios, disregarding oxygen, varying from 4/96 to 52/48. All the mesoporous alloys show a soft magnetic behaviour with tuneable saturation magnetization and coercivity values (the latter ranging from ca. 5 Oe to 40 Oe). In addition, the Au/Fe-Pt deposits (even the ones with higher Fe content) exhibit good performance towards hydrogen evolution reaction in both alkaline and acidic media due to the inherent mesoporosity, with excellent stability after running 50 cycles. The interest of alloying Fe with Pt is thus two-fold: (i) to confer magnetic properties to the mesoporous alloys and (ii) to reduce the amount of the costly noble metal in the electrocatalyst in an environmentally sustainable manner. PMID- 29135000 TI - Bioconjugated fluorescent organic nanoparticles targeting EGFR-overexpressing cancer cells. AB - The field of optical bioimaging has considerably flourished with the advent of sophisticated microscopy techniques and ultra-bright fluorescent tools. Fluorescent organic nanoparticles (FONs) have thus recently appeared as very attractive labels for their high payload, absence of cytotoxicity and eventual biodegradation. Nevertheless, their bioconjugation to target specific receptors with high imaging contrast is scarcely performed. Moreover, assessing the reality of bioconjugation represents high challenges given the sub-nanomolar concentrations resulting from the commonly adopted nanoprecipitation fabrication process. Here, we describe how the combination of a magnetic shell allows us to easily generate red-emitting FONs conjugated with the epidermal growth factor ligand (EGF), a small protein promoting cancer cell proliferation by activating the EGF receptor (EGFR) pathway. Dual color fluorescence correlation spectroscopy combined with immunofluorescence is originally harnessed in its time trace mode to unambiguously demonstrate covalent attachment between the FON and EGF at sub nanomolar concentrations. Strong asymmetric clustering of EGF-conjugated FONs is observed at the membrane of MDA-MB-468 human breast cancer cells overexpressing EGF receptors using super-resolution fluorescence microscopy. Such high recruitment of EGF-conjugated FONs is attributed to their EGF multivalency (4.7 EGF per FON) which enables efficient EGFR activation and subsequent phosphorylation. The large hydrodynamic diameter (DH ~ 301 nm) of EGF-conjugated FONs prevents immediate engulfment of the sequestered receptors, which provides very bright and localized spots in less than 30 minutes. The reported bioconjugated nanoassemblies could thus serve as ultra-bright probes of breast cancer cells with EGFR-overexpression that is often associated with poor prognosis. PMID- 29135001 TI - Nanomaterials for the optical detection of fluoride. AB - Overexposure to fluoride ions (F-) causes serious diseases in human beings. Extensive efforts have been made to develop sensitive and selective approaches for F- detection and a variety of F- sensors have been constructed recently. The burgeoning nanotechnology has provided novel materials for F- analysis due to the extraordinary properties of nanomaterials. In this review, we present the recent advances in different nanomaterials-based approaches for the optical F- detection via colorimetric, fluorescent and chemiluminescent responses. The materials include gold nanomaterials, CeO2 nanoparticles, semiconductor quantum dots, carbon quantum dots, metal-organic frameworks, upconversion nanoparticles, micellar nanoparticles, polymer dots, SiO2 nanoparticles and graphene oxide. The recent trends and challenges in the optical detection of F- with various nanomaterials are also discussed. PMID- 29135002 TI - The chemistry and chemical ecology of nudibranchs. AB - Covering: up to the end of February 2017Nudibranchs have attracted the attention of natural product researchers due to the potential for discovery of bioactive metabolites, in conjunction with the interesting predator-prey chemical ecological interactions that are present. This review covers the literature published on natural products isolated from nudibranchs up to February 2017 with species arranged taxonomically. Selected examples of metabolites obtained from nudibranchs across the full range of taxa are discussed, including their origins (dietary or biosynthetic) if known and biological activity. PMID- 29135003 TI - Elucidating electrolyte decomposition under electron-rich environments at the lithium-metal anode. AB - The lithium metal anode is one of the key components of the lithium-sulfur (Li-S) batteries, which are considered one of the most promising candidates for the next generation of battery systems. However, one of the main challenges that have prevented Li-metal anodes from becoming feasible to be used in commercial batteries is the continuous decomposition of the electrolyte due to its high reactivity, which leads to the formation of solid-electrolyte interphase (SEI) layers. The properties of the SEI can dramatically affect the performance of the batteries. Thus, a rigorous understanding of the electrolyte decomposition is crucial to elucidate improvements in performance of the Li-S technology. In this work, using density functional theory (DFT) and ab initio molecular dynamics simulations (AIMD), we investigate the effect of electron-rich environments on the decomposition mechanism of electrolyte species in pure 1,2-dimethoxyethane (DME) solvent and 1 M lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and lithium bis(fluorosulfonyl)imide (LiFSI) salt solutions. It is found that systems with pure DME require an average environment of at least ~0.9 |e| per molecule for a DME to decompose into CH3O- and C2H42-via a 4-electron transfer. In the case of mixtures, the salts are very prone to react with any excess of electrons. In addition, DME dehydrogenation due to reactions with fragments coming from the salt decompositions was detected. Formation of oligomer anionic species from DME and salt fragments were also identified from the AIMD simulations. Finally, the thermodynamics and kinetics of the most relevant electrolyte decomposition reactions were characterized. DME decomposition reactions predicted from the AIMD simulations were found to be thermodynamically favorable under exposure to Li atoms and/or by reactions with salt fragments. In most cases, these reactions were shown to have low to moderate activation barriers. PMID- 29135004 TI - Floppy molecules as candidates for achieving optoelectronic molecular devices without skeletal rearrangement or bond breaking. AB - Molecular species investigated as possible candidates for molecular photoswitches often toggle between two (low and high conductance) conformations implying skeletal rearrangement, bond breaking, and substantial changes of molecular length. All these represent shortcomings that impede the switching speed and straightforward incorporation in nanodevices. In the present paper we propose a mechanism wherein the photoinduced switching is from a nonplanar conformation to a planar conformation, and involves neither skeletal rearrangement nor bond breaking or significant molecular length changes. Specifically, by choosing typical floppy molecules consisting of two benzene or benzene-like rings that can easily rotate relative to each other, we present results of both ab initio and DFT quantum chemical calculations demonstrating that the lowest electronic excitation corresponds to a planar molecular conformation (phi = 0), in contrast to the nonplanar ground state characterized by phi ? 0. Because the low bias conductance scales as G ? cos2 phi, the planar conformation has a higher conductance than the non-planar conformation, acting therefore as ON and OFF states of the molecular switch, respectively. We analyze recent experimental data on illuminated single-molecule junctions (E.-D. Fung et al., Nano Lett., 2017, 17, 1255) and show that the measured photoinduced conductance enhancement is consistent with the presently proposed mechanism. Furthermore, based on recent results demonstrating the substantial impact of the SAM coverage on the twisting angle (I. Baldea, Faraday Discuss., 2017, 204, 35) we show that a photoinduced conductance enhancement can be much stronger than the rather modest enhancement obtained in the aforementioned experiment. PMID- 29135005 TI - Hydration of iron-porphyrins: ab initio quantum mechanical charge field molecular dynamics simulation study. AB - The ab initio quantum mechanical charge field molecular dynamics (QMCF-MD) simulation approach was successfully applied to Fe2+-P and Fe3+-P in water to evaluate their structural, dynamical and energetic properties. Based on the structural data, it was found that Fe2+-P accommodates one water molecule in the first coordination sphere of the Fe2+ ion including the four nitrogen atoms of the porphyrin system coordinating with central metal species. On the other hand, two water molecules were coordinated to Fe3+-P, thus forming a hexa-coordinated species. Comparison of dynamical properties such as the vibrational power spectrum and ligand mean residence times to other metal-free porphyrin systems demonstrate the ions' influence on the hydration structure, enabling a characterisation of the strong interaction of the ions which greatly reduces the hydrogen bonding potential of the complex. The association of water molecules with the metal ions in both solutes was quantified by computing the free energy of binding obtained via the potential of mean force. This further confirmed the strong association of water to the metal ions which was conversely weak as inferred from the energetic data for the Fe2+-P system. PMID- 29135006 TI - Effects of A-site non-stoichiometry in YxInO3+delta on the catalytic performance during methane combustion. AB - A novel non-stoichiometric YxInO3+delta (YIO-x, 0.8 <= x <= 1.04) perovskite catalyst with a large number of oxygen vacancies and high specific surface area was synthesized using glycine self-propagating gel combustion. It was found that low levels of non-stoichiometry in the A site of YxInO3+delta effectively increased the amount of oxygen desorption by 39-42% when compared to the original (YIO-1) due to Y-deficiency and oxygen vacancies. Further investigations showed that the non-stoichiometry also brings a significant change to the Lewis acid sites on the surface of the sample, which confirmed to be a great promoter for the catalytic combustion of methane. In addition, the catalytic performance increased with the increasing intensity of acid sites. After 50 h of the stability test, the catalysts maintained high activity, indicating their good catalytic stability. PMID- 29135007 TI - Nanoscale imaging and force probing of biomolecular systems using atomic force microscopy: from single molecules to living cells. AB - Due to the lack of adequate tools for observation, native molecular behaviors at the nanoscale have been poorly understood. The advent of atomic force microscopy (AFM) provides an exciting instrument for investigating physiological processes on individual living cells with molecular resolution, which attracts the attention of worldwide researchers. In the past few decades, AFM has been widely utilized to investigate molecular activities on diverse biological interfaces, and the performances and functions of AFM have also been continuously improved, greatly improving our understanding of the behaviors of single molecules in action and demonstrating the important role of AFM in addressing biological issues with unprecedented spatiotemporal resolution. In this article, we review the related techniques and recent progress about applying AFM to characterize biomolecular systems in situ from single molecules to living cells. The challenges and future directions are also discussed. PMID- 29135008 TI - Growth and relaxation of a ridge on a soft poroelastic substrate. AB - Elastocapillarity describes the deformations of soft materials by surface tensions and is involved in a broad range of applications, from microelectromechanical devices to cell patterning on soft surfaces. Although the vast majority of elastocapillarity experiments are performed on soft gels, because of their tunable mechanical properties, the theoretical interpretation of these data has been so far undertaken solely within the framework of linear elasticity, neglecting the porous nature of gels. We investigate in this work the deformation of a thick poroelastic layer with surface tension subjected to an arbitrary distribution of time-dependent axisymmetric surface forces. Following the derivation of a general analytical solution, we then focus on the specific problem of a liquid drop sitting on a soft poroelastic substrate. We investigate how the deformation and the solvent concentration field evolve in time for various droplet sizes. In particular, we show that the ridge height beneath the triple line grows logarithmically in time as the liquid migrates toward the ridge. We then study the relaxation of the ridge following the removal of the drop and show that the drop leaves long-lived footprints after removal which may affect surface and wetting properties of gel layers and also the motion of living cells on soft materials. Preliminary experiments performed with water droplets on soft PDMS gel layers are in excellent agreement with the theoretical predictions. PMID- 29135009 TI - Bacterial species-identifiable magnetic nanosystems for early sepsis diagnosis and extracorporeal photodynamic blood disinfection. AB - Despite the numerous bacteria detection and elimination techniques available nowadays, sensitive diagnosis and treatment of sepsis (caused by the presence of bacteria in the bloodstream), especially at the early stage, remain big challenges. Here we report a nanosystem for early sepsis diagnosis and complete extracorporeal blood disinfection, based on iron oxide magnetic nanoparticles functionalized with chlorin e6 molecules and bacterial species-identifiable aptamers (Fe3O4-Ce6-Apt). We demonstrate that the Fe3O4-Ce6-Apt nanosystem can achieve simultaneous blood bacterial species identification and enrichment in a single step, and the enriched bacteria can be easily detected with the assistance of fluorescence microscopic determination. Based on this Fe3O4-Ce6-Apt nanosystem, successful diagnosis of sepsis caused by a single (Staphylococcus aureus) or multiple species (Staphylococcus aureus and Escherichia coli) of bacteria in mice has been realized. Compared to the gold standard blood culture method, this Fe3O4-Ce6-Apt nanosystem-based strategy has a comparable detection sensitivity (around 10 colony-forming units) but a significantly shortened diagnosis turnaround time (within 1.5 h), revealing its great potential for early sepsis diagnosis in clinical settings. Moreover, benefitting from the strong photodynamic effect of the Fe3O4-Ce6-Apt nanosystem, complete extracorporeal blood disinfection has been achieved. Remarkably, we also demonstrate that the disinfected blood can be reused for mice transfusion application without inducing adverse reactions, indicating the fruitful potential of the Fe3O4-Ce6-Apt nanosystem for sepsis treatment. Apart from the sepsis-associated applications, we believe that the Fe3O4-Ce6-Apt nanosystem could find wide applications in the fields of health and environmental sciences that require bacteria monitoring and sterilization. PMID- 29135010 TI - Metal-free oxidative para-acylation of unprotected anilines with N heteroarylmethanes. AB - A selective oxidative para-acylation of unprotected anilines with methyl groups in N-heteroarylmethanes was achieved. This transformation proceeds under mild metal-free reaction conditions to produce the corresponding valuable diarylmethanones in good to high yields, featuring high site-selectivity, high functional-group-tolerance, gram-scale synthesis and easy product-derivation. Preliminary mechanistic studies revealed that the present oxidative para acylation would take place via a Friedel-Crafts-type process of in situ imines and the steric hindrance might be the key issue for the high regio-selectivity. PMID- 29135011 TI - Hierarchical self-assembly of enantiopure and racemic helicenes at the liquid/solid interface: from 2D to 3D. AB - The performance of organic nanostructures is closely related to the organization of the functional molecules. Frequently, molecular chirality plays a central role in the way molecules assemble at the supramolecular level. Herein we report the hierarchical self-assembly of benzo-fused tetrathia[7]helicenes on solid surfaces, from a single surface-bound molecule to well-defined microstructures, using a combination of various characterization techniques assisted by molecular modeling simulations. Similarities as well as discrepancies are revealed between homochiral and heterochiral aggregations by monitoring the hierarchical nucleation of helicenes on surfaces, where the impact of enantiopurity, concentration and adsorbate-substrate interaction on molecular organization are disclosed. PMID- 29135012 TI - Shrinking microbubbles with microfluidics: mathematical modelling to control microbubble sizes. AB - Microbubbles have applications in industry and life-sciences. In medicine, small encapsulated bubbles (<10 MUm) are desirable because of their utility in drug/oxygen delivery, sonoporation, and ultrasound diagnostics. While there are various techniques for generating microbubbles, microfluidic methods are distinguished due to their precise control and ease-of-fabrication. Nevertheless, sub-10 MUm diameter bubble generation using microfluidics remains challenging, and typically requires expensive equipment and cumbersome setups. Recently, our group reported a microfluidic platform that shrinks microbubbles to sub-10 MUm diameters. The microfluidic platform utilizes a simple microbubble-generating flow-focusing geometry, integrated with a vacuum shrinkage system, to achieve microbubble sizes that are desirable in medicine, and pave the way to eventual clinical uptake of microfluidically generated microbubbles. A theoretical framework is now needed to relate the size of the microbubbles produced and the system's input parameters. In this manuscript, we characterize microbubbles made with various lipid concentrations flowing in solutions that have different interfacial tensions, and monitor the changes in bubble size along the microfluidic channel under various vacuum pressures. We use the physics governing the shrinkage mechanism to develop a mathematical model that predicts the resulting bubble sizes and elucidates the dominant parameters controlling bubble sizes. The model shows a good agreement with the experimental data, predicting the resulting microbubble sizes under different experimental input conditions. We anticipate that the model will find utility in enabling users of the microfluidic platform to engineer bubbles of specific sizes. PMID- 29135013 TI - Synthesis of 2,2-bis(pyridin-2-yl amino)cyclobutanols and their conversion into 5 (pyridin-2-ylamino)dihydrofuran-2(3H)-ones. AB - A two-step protocol is presented for the preparation of 5-(pyridin-2 ylamino)dihydrofuran-2(3H)-ones from 2-hydroxycyclobutanone and some 2 aminopyridines via a catalyst-free synthesis of 2,2-bis(pyridin-2 ylamino)cyclobutanols followed by Dess-Martin periodinane mediated ring expansion. PMID- 29135015 TI - Bowen's Disease: Long-term Results of Treatment with 5-Fluorouracil Cream, Photodynamic Therapy or Surgical Excision. PMID- 29135014 TI - 25 years and still going strong: 2'-O-(pyren-1-yl)methylribonucleotides - versatile building blocks for applications in molecular biology, diagnostics and materials science. AB - Oligonucleotides (ONs) modified with 2'-O-(pyren-1-yl)methylribonucleotides have been explored for a range of applications in molecular biology, nucleic acid diagnostics, and materials science for more than 25 years. The first part of this review provides an overview of synthetic strategies toward 2'-O-(pyren-1 yl)methylribonucleotides and is followed by a summary of biophysical properties of nucleic acid duplexes modified with these building blocks. Insights from structural studies are then presented to rationalize the reported properties. In the second part, applications of ONs modified with 2'-O-(pyren-1-yl)methyl-RNA monomers are reviewed, which include detection of RNA targets, discrimination of single nucleotide polymorphisms, formation of self-assembled pyrene arrays on nucleic acid scaffolds, the study of charge transfer phenomena in nucleic acid duplexes, and sequence-unrestricted recognition of double-stranded DNA. The predictable binding mode of the pyrene moiety, coupled with the microenvironment dependent properties and synthetic feasibility, render 2'-O-(pyren-1-yl)methyl RNA monomers as a promising class of pyrene-functionalized nucleotide building blocks for new applications in molecular biology, nucleic acid diagnostics, and materials science. PMID- 29135016 TI - Light Chain Deposition Disease with Bullous Skin Lesions Mimicking Atypical Bullous Pemphigoid. PMID- 29135017 TI - Ichthyosis with Confetti Inherited from a Mosaic Father. PMID- 29135018 TI - Chronic Prurigo of Nodular Type: A Review. AB - Prurigo nodularis (PN) is a subtype of chronic prurigo presenting single to multiple symmetrically distributed, hyperkeratotic and intensively itching papules and nodules. PN evolves along with chronic pruritus in the context of diverse dermatological, systemic, neurological or psychiatric conditions. Permanent scratching is possibly a major trigger of PN, although its exact pathophysiology remains unclear. Current state-of-the-art therapy for PN consists of topical steroids, capsaicin, calcineurin inhibitors, ultraviolet (UV) therapy, systemic administration of gabapentinoids, MU-opioid receptor antagonists, antidepressants or immunosuppressants. Novel treatment concepts, such as inhibitors of neurokinin-1, opioid and interleukin-31 receptors, have been developed and are currently being clinically tested. PMID- 29135019 TI - MiRNAs participate in the diagnosis, pathogenesis and therapy of Parkinson's disease. AB - MicroRNAs (miRNAs), one kind of post-transcriptional modification, mediate transcriptional silencing of various metabolic enzymes that are involved in various life processes, including Parkinson's disease. At present, the pathogenesis of Parkinson's disease is not clear, although many studies suggest that miRNAs play a very important role in the progress of Parkinsonism. This paper reviews the biological characteristics of miRNAs and summarizes the progress of miRNAs in reference to the diagnosis and pathogenesis of Parkinson's disease. It even considers miRNAs as a potential target for Parkinson's disease therapy. PMID- 29135020 TI - Clinical application of biological variation data to facilitate interpretation of canine and feline laboratory results. AB - Interpretation of laboratory results is based on comparison of the patient's own results against established decision thresholds or reference intervals in the context of the clinical presentation and history. Blood measurand analysis has pre-analytical, analytical and physiological sources of variation, which may complicate interpretation of results. Biological variation describes the physiological random fluctuation of blood measurands around a homeostatic set point, which varies within and between individuals. This article reviews the practical applications of biological variation in the everyday clinical setting. Examples are offered to highlight how biological variation can be used to: (1) assess the usefulness of subject-based reference intervals, (2) determine measurand homeostatic set points, (3) interpret single or serial results for diagnosis of disease and (4) evaluate changes in serial results during monitoring. PMID- 29135021 TI - Diagnostic Accuracy of the Chinese Version of the Trail-Making Test for Screening Cognitive Impairment. AB - BACKGROUND/OBJECTIVES: The Trail-Making Test (TMT), which is commonly used to measure executive function, consists of two components (TMT-A and TMTB). There is a lack of normative TMT data for Chinese elderly adults. This study aimed to evaluate the validity of the TMT in screening for cognitive impairment. DESIGN: 2,294 Chinese-speaking adults aged 50 to 85: 1,026 with normal cognition (NC), 462 with mild cognitive impairment (MCI), 108 with Alzheimer's disease (AD), 113 with vascular mild cognitive impairment (VaMCI), 121 with vascular dementia (VaD), 282 with uncertain types of dementia, and 15 with mixed dementia. Receiver operating characteristic curve analysis was performed to test the ability of TMT scores to differentiate between NC and cognitive impairment. RESULTS: Age, education, and sex were significantly associated with TMT completion time. The TMT-A exhibited sensitivity of 77.8% and specificity of 92.0% with cut-off value of 98.5 seconds for discriminating AD from NC. The TMT-B had sensitivity of 83.3% and specificity of 91.8% with a cut-off value of 188.5 seconds for discriminating AD from NC. The TMT-A had sensitivity of 85.7% and specificity of 81.6% for discriminating NC from VaD with a cut-off value of 77.5 seconds, and the TMT-s had sensitivity of 81.6% and specificity of 83.9% with a cut-off value of 147.5 seconds. The TMT had less sensitivity distinguishing MCI from NC. CONCLUSION: The Chinese version of the TMT is reliable for detecting AD or VaD but poor at distinguishing MCI from NC. PMID- 29135022 TI - A fast and simple method to estimate relative, hyphal tensile-strength of filamentous fungi used to assess the effect of autophagy. AB - Fungal hyphal strength is an important phenotype which can have a profound impact on bioprocess behavior. Until now, there is not an efficient method which allows its characterization. Currently available methods are very time consuming, thus, compromising their applicability in strain selection and process development. To overcome this issue, a method for fast and easy, statistically verified quantification of relative hyphal tensile strength was developed. It involves off line fragmentation in a high shear mixer followed by quantification of fragment size using laser diffraction. Particle size distribution (PSD) is determined, with analysis time on the order of minutes. Plots of PSD 90th percentile versus time allow estimation of the specific fragmentation rate. This novel method is demonstrated by estimating relative hyphal strength during growth in control conditions and rapamycin-induced autophagy for Aspergillus nidulans (parental strain) and a mutant strain (DeltaAnatg8) lacking an important autophagy gene. Both strains were grown in shake flasks and relative hyphal tensile strength was compared. The mutant strain grown in control conditions appears to be weaker than the parental strain, suggesting that Anatg8 may play a role in other processes involving cell wall biosynthesis. Furthermore, rapamycin-induced autophagy resulted in apparently weaker cells even for the mutant strain. These findings confirm the utility of the developed method in strain selection and process development. PMID- 29135023 TI - Effects of Different Pretreatments to Fresh Fruit on Chemical and Thermal Characteristics of Crude Palm Oil. AB - This study selected 5 methods, including boiling, hot air drying, high pressurized steam, freezing, and microwave radiation to pretreat fresh oil palm fruit before solvent extraction of the oil. Using fresh fruit as a control, the pretreatment methods were compared for the effects on the activity of the 2 main enzymes in the fruit and some physicochemical properties of the crude palm oil. The results indicated, although all the 5 pretreatments could inactivate lipase and peroxidase in the treated flesh significantly (P < 0.05), the high pressurized steam was the most effective. There were also differences in the unsaturated fatty acid contents of the 6 oils. The crude oil from frozen fruit contained significantly more vitamin E (37829.33 ppm) than previously reported. Microwave radiation was shown to significantly decrease the free fatty acid content and the peroxide value, while increasing the oxidative stability index. Thermal behaviors of the oils were significantly different to each other with the exception a few parameters (P < 0.05). PMID- 29135024 TI - Reverse Stability Kinetics of Meat Pigment Oxidation in Aqueous Extract from Fresh Beef. AB - : The use of kinetic models is an evolving approach to describing quality changes in foods during processes, including storage. Previous studies indicate that the oxidation rate of myoglobin is accelerated under frozen storage conditions, a phenomenon termed reverse stability. The goal of this study was to develop a model for meat pigment oxidation to incorporate the phenomenon of reverse stability. In this investigation, the model system was an aqueous extract from beef which was stored under a range of temperatures, both unfrozen and frozen. The kinetic analysis showed that in unfrozen solutions, the temperature dependence of oxidation rate followed Arrhenius kinetics. However, under in frozen solutions the rate of oxidation increased with decreasing temperature until reaching a local maximum around -20 degrees C. The addition of NaCl to the model system increased oxidation rates at all temperatures, even above the initial freezing temperature. This observation suggests that this reaction is dependent on the ionic strength of the solution as well as temperature. The mechanism of this deviant kinetic behavior is not fully understood, but this study shows that the interplay of temperature and composition on the rate of oxidation of meat pigments is complicated and may involve multiple mechanisms. PRACTICAL APPLICATION: A better understanding of the kinetics of quality loss in a meat system allows for a re-examination of the current recommendations for frozen storage. The deviant kinetic behavior observed in this study indicates that the relationship between quality loss and temperature in a frozen food is not as simple as once thought. Product-specific recommendations could be implemented in the future that would allow for a decrease in energy consumption without a significant loss of quality. PMID- 29135025 TI - Focal cortical dysplasia in genetic epilepsy: new insights from PCDH19-related epilepsy. PMID- 29135026 TI - Sensory and Flavor Characteristics of Tomato Juice from Garden Gem and Roma Tomatoes with Comparison to Commercial Tomato Juice. AB - : The objective of this study was to characterize the flavor of a premium Florida tomato variety that has significant potential for producing a high quality processed juice product. A high-quality Florida plum tomato variety (Garden Gem), and a typical grocery-store plum tomato variety (Roma) were thermally processed into tomato juices without any additives. The 2 pilot products and a popular commercially available tomato juice (low sodium with sugar and flavor added) were compared using sensory evaluation and instrumental analysis. Flavor compounds in these products were identified using dynamic headspace purge and trap-gas chromatography-mass spectrometry (PT-GC-MS) by MS library match and retention index and were semi-quantitated using internal standards. Color, uniformity, overall liking, tomato flavor, sweetness and texture were rated using a hedonic scale. Analysis of variance, correlation and principal component analysis were used to analyze both sensory and flavor data. Among the 3 products, Garden Gem juice was rated significantly (P < 0.05) higher for overall liking, tomato flavor, and sweetness by the 119 consumer panelists in both seasons. Garden Gem juice was found to contain higher levels of 3 sweet/fruity related aroma compounds: 6-methyl-5-hepten-2-one, linalool, and beta-ionone. The commercial tomato juice contained a high level of the Maillard reaction-related notes furfural, dimethyl sulfide, and the least amount of green-related notes (hexanal, E-2-hexenal and Z-2-heptenal). The flavor profile of the Roma tomato juice was similar to Garden Gem juice except it contained substantially lower amounts of hexanal and 2-isobutylthiazole. The compound beta-ionone (fruity note) was not detected in either the commercial or Roma juice. PRACTICAL APPLICATION: This proof of concept study demonstrates that high flavor quality tomatoes can be used to create better tasting processed tomato products. The study also demonstrates how sensory preference can confer a potential market advantage over existing commercial products. The Garden Gem variety has potential to add desirable flavor attributes to processed tomato products. This research may also provide insights for product developers to which flavor volatiles best reflect sensory observations for different aspects of tomato flavor. PMID- 29135027 TI - Acrosomal alkalization triggers Ca2+ release and acrosome reaction in mammalian spermatozoa. AB - The sperm acrosome reaction (AR), an essential event for mammalian fertilization, involves Ca2+ permeability changes leading to exocytosis of the acrosomal vesicle. The acrosome, an intracellular Ca2+ store whose luminal pH is acidic, contains hydrolytic enzymes. It is known that acrosomal pH (pHacr ) increases during capacitation and this correlates with spontaneous AR. Some AR inducers increase intracellular Ca2+ concentration ([Ca2+ ]i ) through Ca2+ release from internal stores, mainly the acrosome. Catsper, a sperm specific Ca2+ channel, has been suggested to participate in the AR. Curiously, Mibefradil and NNC55-0396, two CatSper blockers, themselves elevate [Ca2+ ]i by unknown mechanisms. Here we show that these compounds, as other weak bases, can elevate pHacr , trigger Ca2+ release from the acrosome, and induce the AR in both mouse and human sperm. To our surprise, MUM concentrations of NNC55-0396 induced AR even in nominally Ca2+ free media. Our findings suggest that alkalization of the acrosome is critical step for Ca2+ release from the acrosome that leads to the acrosome reaction. PMID- 29135029 TI - Quantum crystallography: A perspective. AB - Extraction of the complete quantum mechanics from X-ray scattering data is the ultimate goal of quantum crystallography. This article delivers a perspective for that possibility. It is desirable to have a method for the conversion of X-ray diffraction data into an electron density that reflects the antisymmetry of an N electron wave function. A formalism for this was developed early on for the determination of a constrained idempotent one-body density matrix. The formalism ensures pure-state N-representability in the single determinant sense. Applications to crystals show that quantum mechanical density matrices of large molecules can be extracted from X-ray scattering data by implementing a fragmentation method termed the kernel energy method (KEM). It is shown how KEM can be used within the context of quantum crystallography to derive quantum mechanical properties of biological molecules (with low data-to-parameters ratio). (c) 2017 Wiley Periodicals, Inc. PMID- 29135028 TI - Effects of Hydrolyzed Rapeseed Cake Extract on the Quality Characteristics of Mayonnaise Dressing. AB - : Combined fractions (H2 O and 30% and 50% ethanol) of crude rapeseed cake extracts with 80% ethanol were hydrolyzed with NaOH solution. The hydrolyzed extract showed significantly higher contents of total phenolics (41.8 mg SAE/g) and sinapic acid (425.8 mg/g), as well as higher 1,1-diphenyl-2-picryl-hydrazyl radical-scavenging capacity (91.98 RSC%) than the crude extract (P < 0.05). Antimicrobial activity of the hydrolyzed extract was remarkably higher than that of the crude extract against selected Gram-positive and Gram-negative bacteria as well as yeast, as determined by the minimum inhibitory concentration method. Hydrolyzed extract (100, 250, or 500 ppm) was added to mayonnaise dressing, and several quality characteristics of the dressing were investigated by assessments of microbial, physical, and oxidative stabilities during 8 wk of storage. Microbial stability was higher in the dressing with hydrolyzed extract added (4.3 to 4.6 Log CFU/g) than the control (4.9 Log CFU/g). Physical characteristics of the dressing with hydrolyzed extract added were better than those of the control, based on increased viscosity and reduced emulsion separation. Hydrolyzed extract increased oxidative stability in a concentration-dependent manner, and the dressing with added 500 ppm of hydrolyzed extract resulted in a lower free fatty acid content (4.8% at week 8), peroxide value (13.5 meq/kg at week 6), and 2 thiobarbituric acid-reactive substances value (66.2 MUg/100 g at week 8) than the control. Therefore, it is expected that hydrolyzed rapeseed cake extract containing high sinapic acid content can be used in emulsion system as a value added ingredient. PRACTICAL APPLICATION: Crude extract of rapeseed cake was fractionated and alkaline-hydrolyzed to convert sinapine into sinapic acid, and the produced hydrolyzed extract showed higher antimicrobial and antioxidative activities than the crude extract. When the hydrolyzed extract was added to mayonnaise dressing, microbial stability increased along with physical characteristics and oxidative stability, thereby supporting the potential of hydrolyzed rapeseed extract as a food additive for quality management of mayonnaise dressing during storage. PMID- 29135030 TI - Hepatitis C Virus Clearance in Older Adults. AB - OBJECTIVES: To determine whether older adults with the hepatitis C virus (HCV) achieve a sustained viral response (SVR) after treatment with direct-acting antiviral therapy. PARTICIPANTS: Individuals aged 80 and older with chronic HCV infection (N = 253; n = 213 with cirrhosis, n = 40 with advanced fibrosis). MEASUREMENTS: We investigated the efficacy, safety, and global clinical effect of treatment with different combinations of direct antiviral agents (DAAs). Participants with cirrhosis were staged according to Child-Pugh-Turcotte class, Model for End-Stage Liver Disease score, and the D'Amico staging system. The type and number of comorbidities at baseline and hepatic and nonhepatic events during follow-up were registered. RESULTS: Ninety-five percent of participants with cirrhosis and 95% of those with advanced fibrosis attained SVR. The rate was independent of sex, HCV genotype, and treatment schedule. During a mean follow-up of 14 +/- 4 months (range 5-23 months), 34 events occurred in 27 participants: 10 hepatocellular carcinomas, 12 hepatic decompensations, 9 nonhepatic events, 3 deaths. Multivariate analysis of risk factors for experiencing adverse events during follow up showed that participants in D'Amico Stages 4 and 5, with a baseline serum albumin level of 3.5 mg/dL or less, and 3 or more comorbidities were the most at risk. CONCLUSION: In a real-world setting, DAAs are safe and effective in older adults with HCV-related advanced fibrosis or cirrhosis. Individuals with preserved albumin synthesis and fewer than 3 comorbidities at baseline have the most to gain from long-term DAA therapy. PMID- 29135031 TI - Comparative proteomics illustrates the molecular mechanism of potato (Solanum tuberosum L.) tuberization inhibited by exogenous gibberellins in vitro. AB - Among the multiple environmental signals and hormonal factors regulating potato tuberization, gibberellins (GAs) are important components of the signaling pathways in these processes. To understand the GAs-signaling response mechanism of potato tuberization, a comparative proteomics approach was applied to analyze proteome change of potato tuberization in vitro subjected to a range of exogenous GA3 treatments (0, 0.01, 0.1 and 1.0 MUM) using two-dimensional gel electrophoresis. Quantitative image analyses showed that a total of 37 protein spots have their abundance significantly altered more than 2-fold. Among these proteins, 13 proteins were up-regulated, 13 proteins were down-regulated, one protein was absent and 10 proteins were induced after treatment by exogenous GA3 . The MALDI-TOF/TOF MS analyses led to the identification of differentially abundant proteins that are mainly involved in bioenergy and metabolism, storage, signaling, cell defense and rescue, transcription, chaperones, transport. Furthermore, the comparative analysis of GA3 -responsive proteome allowed for general elucidation of underlying molecular mechanisms of potato tuberization inhibited by exogenous GA3 . Most of these cellular processes were not conducive to the transition from stolon elongation to tuber formation, including a blockage of starch and storage protein accumulation, the accelerated carbohydrate catabolism, a blockage of JA biosynthesis but an elevated endogenous GAs level, the amplification of GA3 signal transduction by other signaling pathways, and the regulation of cellular RNA metabolism for controlling tuberization. Our results firstly integrated physiology and proteome data to provide new insights into GA3 signaling response mechanisms of potato tuberization in vitro. PMID- 29135032 TI - Estimating muscle volume from two-dimensional measurements: a promising method for assessment. PMID- 29135033 TI - Primary and salvage laser surgery of 341 glottic cancers-Comparison of treatment outcomes between University Head Neck Tertiary Referral Center and Local Head Neck Department. AB - OBJECTIVE: The main goal was to compare the clinical data of patients with T1 and T2 glottic cancer treated with CO2 transoral laser microlaryngoscopy (TLM) in the Tertiary Referral University Department of Otolaryngology, Head Neck Surgery, Poznan and the local Department of Otolaryngology, Oncology and Maxillofacial Surgery, Bydgoszcz. MATERIAL AND METHODS: Unified databases for the 7-year period January 2005-December 2011 were created to compare these two cohorts. The database contained 341 patients: 231 from the tertiary center and 110 from the local department, of which 298 (87%) were men, and 43 (13%) were women. RESULTS: Cordectomy type I-IV was performed in 250 (73%) patients, cordectomy type V-VI in 84 (25%) patients, and cordectomy enlarged to epiglottic petiole in 7 (2%) patients. Local recurrence was observed in 96 (28%) cases. Among these cases, 81 (87.5%) patients had salvage surgery: 43 re-cordectomy, 10 open partial laryngectomy, and 28 total laryngectomy. The outcomes for the whole cohort, Tertiary Referral Center and Local Department respectively were as follows: larynx preservation rate was 91.8%, 93.6%, and 88%; 3-year disease specific survival was 97.4%, 97.9%, and 93.3%; 3-year overall survival was 93.5%, 96.6%, and 85.5%; 5-year disease specific survival was 95.2%, 95.2%, and 96.3%; and 5 year overall survival was 84.5%, 88.7%, and 76%, respectively. CONCLUSION: Comparison of the cohorts showed that outcomes of primary treatment were similar but there were noticeable differences in salvage treatment efficacy, favoring patients from the Tertiary Referral Center. Lasers Surg. Med. 50:311-318, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29135034 TI - Implementation and performance of the artificial force induced reaction method in the GRRM17 program. AB - This article reports implementation and performance of the artificial force induced reaction (AFIR) method in the upcoming 2017 version of GRRM program (GRRM17). The AFIR method, which is one of automated reaction path search methods, induces geometrical deformations in a system by pushing or pulling fragments defined in the system by an artificial force. In GRRM17, three different algorithms, that is, multicomponent algorithm (MC-AFIR), single component algorithm (SC-AFIR), and double-sphere algorithm (DS-AFIR), are available, where the MC-AFIR was the only algorithm which has been available in the previous 2014 version. The MC-AFIR does automated sampling of reaction pathways between two or more reactant molecules. The SC-AFIR performs automated generation of global or semiglobal reaction path network. The DS-AFIR finds a single path between given two structures. Exploration of minimum energy structures within the hypersurface in which two different electronic states degenerate, and an interface with the quantum mechanics/molecular mechanics method, are also described. A code termed SAFIRE will also be available, as a visualization software for complicated reaction path networks. (c) 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 29135035 TI - Analysis and measurement of serotonin. AB - Serotonin, also known as 5-hydroxytryptamine, is an important signaling molecule in the central and peripheral nervous systems of humans. Acting through several receptor types, it helps regulate the normal functioning of the gastrointestinal tract, cardiovascular system and brain. Serotonin signaling has also been implicated in the etiology of several diseases, including depression, anxiety disorders, hypertension and irritable bowel syndrome. The present review focuses on the chemical analysis of serotonin in biological fluids and biomatrices and traces the development and application of early methods based on UV absorbance or fluorescence to more widely used current methods such as high-performance liquid chromatography coupled to mass spectrometry. A brief summary of the biochemistry, metabolism and physiological roles of serotonin is also presented. PMID- 29135036 TI - Prospective studies of the efficacy and safety of the picosecond 755, 1,064, and 532 nm lasers for the treatment of infraorbital dark circles. AB - BACKGROUND: Infraorbital dark circles result from a combination of factors. The fractionated picosecond 755 nm alexandrite laser and dual wavelength picosecond Nd:YAG laser have not been examined as a method of addressing infraorbital hyperpigmentation. OBJECTIVE: To determine the efficacy and safety of treatment of infraorbital dark circles using fractionated picosecond 755 nm and dual wavelength picosecond Nd:YAG laser. METHODS AND MATERIALS: These trials did not utilize a comparative design; rather, these were separate, prospective, open label, evaluator-blinded trials utilizing two treatment regimens: (i) 19 adult subjects were treated in a single session with the dual wavelengths of 532 nm and 1,064 nm in consecutive passes using the fractionated lens; (ii) 10 adult subjects were treated using the picosecond 755 nm laser via the fractionated lens in three treatment sessions at 3 week intervals. Subjects in both studies were followed-up for blinded-investigator assessment of infraorbital hyperpigmentation, adverse events, and improvement compared to baseline. RESULTS: The dual wavelength picosecond Nd:YAG laser, blinded-investigator assessment did not demonstrate a significant improvement in infraorbital hyperpigmentation at day 60 (P = 0.16). The picosecond 755 nm alexandrite laser significantly improved infraorbital hyperpigmentation by day 42, with improvement maintained through day 132 (P = 0.07 and 0.00001, respectively). Adverse events were mild and temporary. CONCLUSION: A single treatment with the fractionated picosecond 1,064/532 nm lasers did not produce a significant improvement in infraorbital hyperpigmentation. A series of three treatments with the fractionated picosecond 755 nm laser resulted in significant improvement in hyperpigmentation. Lasers Surg. Med. 50:45-50, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29135037 TI - Analytical hessian fitting schemes for efficient determination of force-constant parameters in molecular mechanics. AB - Building upon our recently developed partial Hessian fitting (PHF) method (Wang et al., J. Comput. Chem. 2016, 37, 2349), we formulated and implemented two other rapid force-field parameterization schemes called full Hessian fitting (FHF) and internal Hessian fitting (IHF), and comparisons were made among these three parameterization schemes to assess their performance. FHF minimizes deviation between the Hessian matrices in Cartesian coordinates computed by quantum mechanics (QM) and molecular mechanics (MM), to determine the best possible MM force-constant parameters. While PHF requires step-by-step fittings of 3 * 3 partial Hessian matrices, FHF compares the lower triangular part of the QM and MM Hessian matrices, which allows simultaneous determination of all force-constant parameters. In addition to this simple FHF scheme, IHF was developed such that it considers the Hessian matrices in redundant internal coordinates, where all possible internal coordinates that arise from the user-defined interatomic connectivity are utilized. The results show that IHF performs best overall, followed by PHF and then FHF. Python-based programing codes were developed to automate various tedious steps involved in the parameterization processes. (c) 2017 Wiley Periodicals, Inc. PMID- 29135038 TI - Comparison of iatrogenic articular cartilage injury in canine stifle arthroscopy versus medial parapatellar mini-arthrotomy in a cadaveric model. AB - OBJECTIVE: To assess iatrogenic articular cartilage injury (IACI) resulting from arthroscopy versus medial parapatellar mini-arthrotomy of the stifle. STUDY DESIGN: Paired comparison of canine cadaver stifles treated with arthroscopy or mini-arthrotomy ANIMALS: Paired canine stifles from 14 cadavers (>=20 kg). METHODS: Stifles (N = 28) were assigned to arthroscopy or arthrotomy. Full stifle joint exploration and meniscal probing were performed. Joints were disarticulated and India ink assay performed. IACI was defined as sharply delineated lesions with India ink uptake. Incidence, number, and lesion area in defects articular cartilage, incision length, surgery duration, and joint structures visualized were recorded. RESULTS: Arthroscopy resulted in greater IACI than mini arthrotomy, including incidence of IACI (arthroscopy: 13 stifles, mini arthrotomy: 4 stifles; P = .009), number of IACI per stifle (arthroscopy: 3.4 +/- 2.90, mini-arthrotomy: 0.9 +/- 1.96; P = .04), and IACI area (arthroscopy: 5.9 +/ 7.58 mm2 , mini-arthrotomy: 1.7 +/- 4.50 mm2 ; P = .003). Incision length was shorter with arthroscopy (1.0 +/- 0.38 cm) versus mini-arthrotomy (5.3 +/- 0.61 cm; P < .0001). Surgical duration was not significantly different between groups (arthroscopy: 12.5 +/- 3.49 minutes, mini-arthrotomy: 11.05 +/- 1.60 minutes; P = .21). Visualization of articular structures was incomplete in 14/14 mini arthrotomy stifles and 1/14 arthroscopy stifles (P < .001). CONCLUSION: Incidence, number, and area of IACI were greater in the arthroscopy group versus the mini-arthrotomy group. Mini-arthrotomy resulted in a longer incision and incomplete joint visualization. Methods of preventing IACI and clinical significance of IACI warrant further investigation. PMID- 29135039 TI - A novel fast method for aqueous derivatization of THC, OH-THC and THC-COOH in human whole blood and urine samples for routine forensic analyses. AB - A novel aqueous in situ derivatization procedure with propyl chloroformate (PCF) for the simultaneous, quantitative analysis of Delta9 -tetrahydrocannabinol (THC), 11-hydroxy-Delta9 -tetrahydrocannabinol (OH-THC) and 11-nor-Delta9 tetrahydrocannabinol-carboxylic acid (THC-COOH) in human blood and urine is proposed. Unlike current methods based on the silylating agent [N,O bis(trimethylsilyl)trifluoroacetamide] added in an anhydrous environment, this new proposed method allows the addition of the derivatizing agent (propyl chloroformate, PCF) directly to the deproteinized blood and recovery of the derivatives by liquid-liquid extraction. This novel method can be also used for hydrolyzed urine samples. It is faster than the traditional method involving a derivatization with trimethyloxonium tetrafluoroborate. The analytes are separated, detected and quantified by gas chromatography-mass spectrometry in selected ion monitoring mode (SIM). The method was validated in terms of selectivity, capacity of identification, limits of detection (LOD) and quantification (LOQ), carryover, linearity, intra-assay precision, inter-assay precision and accuracy. The LOD and LOQ in hydrolyzed urine were 0.5 and 1.3 ng/mL for THC and 1.2 and 2.6 ng/mL for THC-COOH, respectively. In blood, the LOD and LOQ were 0.2 and 0.5 ng/mL for THC, 0.2 and 0.6 ng/mL for OH-THC, and 0.9 and 2.4 ng/mL for THC-COOH, respectively. This method was applied to 35 urine samples and 50 blood samples resulting to be equivalent to the previously used ones with the advantage of a simpler method and faster sample processing time. We believe that this method will be a more convenient option for the routine analysis of cannabinoids in toxicological and forensic laboratories. PMID- 29135040 TI - The Suppressive Effects of Geniposide and Genipin on Helicobacter pylori Infections In Vitro and In Vivo. AB - : Geniposide and genipin have been found in Gardenia jasminoides Ellis, a traditional Chinese medicine that exhibits multiple biological functions. However, no report showing the effects of geniposide and genipin on gastric protection in Helicobacter pylori infections in vitro and in vivo has been done. In this study, we clarified how geniposide and genipin suppress H. pylori mediated inflammation in gastric AGS cells and C57BL/6 mice. Our results demonstrated that genipin shows a strong ability to inhibit H. pylori growth and is able to reduce vacA and cagA gene expression of H. pylori in infected AGS cells. Genipin also attenuates the abilities of adhesion and invasion of H. pylori to AGS cells. An attenuation of interleukin (IL)-8 and IFN-gamma production caused by genipin was observed to inhibit cell inflammatory responses. In the in vivo experiments, geniposide and genipin both showed suppressive effects on the vacA gene expression in mice after H. pylori infection. The serum levels of IFN-gamma, IL-1beta, immunoglobulin A, and Immunoglobulin M were decreased by geniposide and genipin in infected mice. The inflammatory maker COX2 was downregulated in H. pylori-infected mice after exposure to geniposide and genipin. Together, geniposide and genipin effectively exert a healthy promotion to reduce H. pylori infections in vivo by interfering with the growth and virulence of H. pylori as well as attenuating the gastric inflammation caused by an H. pylori infection. PRACTICAL APPLICATION: Geniposide and genipin have a healthy promotion to eradicate H. pylori infections by interfering with the growth and virulence of H. pylori and to attenuate the gastric inflammation caused by an H. pylori infection. PMID- 29135041 TI - Risk factors for tibial damage associated with the modified Maquet technique in 174 stifles. AB - OBJECTIVE: To identify risk factors for tibial damage associated with the modified Maquet technique (MMT) in dogs with cranial cruciate ligament (CCL) disease. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: One hundred and seventy-four stifles from 147 client-owned dogs. METHODS: Medical records of dogs diagnosed with CCL disease and treated with the current version of MMT were reviewed. Dogs were included if immediate postoperative radiographs were available. Cortical hinge fracture or fissure, tibial tuberosity fracture, and diaphyseal fractures of the tibia were recorded. Age, body weight (BW), thickness of the tibial cortical hinge, and angle of opening of the osteotomy were tested as potential risk factors for tibial damage by univariate logistic regression analysis. RESULTS: Tibial damage included intraoperative tibial fissures in 37% of MMTs, intraoperative fractures of the cortical hinge in 3.4% of MMTs, postoperative tibial fractures in 14% of MMTs. Risk factors for intraoperative fissure included BW (P = .0153) and thickness of cortical hinge (P = .0006). The angle of opening of the osteotomy was identified as a risk factor for intraoperative cortical hinge fracture (P = .0034), angles below 11 degrees being preventive. No risk factor was identified for postoperative fracture. CONCLUSION: Based on these results, preventive measures against tibial damage associated with MMT should include: a thickness of cortical hinge based on the equation related to the BW; a length of osteotomy adjusted to the amount of TTA with an osteotomy angle below 10 degrees ; and slow advancement of the tibial tuberosity. PMID- 29135043 TI - A framework for ecological risk assessment of metal mixtures in aquatic systems. AB - Although metal mixture toxicity has been studied relatively intensely, there is no general consensus yet on how to incorporate metal mixture toxicity into aquatic risk assessment. We combined existing data on chronic metal mixture toxicity at the species level with species sensitivity distribution (SSD)-based in silico metal mixture risk predictions at the community level for mixtures of Ni, Zn, Cu, Cd, and Pb, to develop a tiered risk assessment scheme for metal mixtures in freshwater. Generally, independent action (IA) predicts chronic metal mixture toxicity at the species level most accurately, whereas concentration addition (CA) is the most conservative model. Mixture effects are noninteractive in 69% (IA) and 44% (CA) and antagonistic in 15% (IA) and 51% (CA) of the experiments, whereas synergisms are only observed in 15% (IA) and 5% (CA) of the experiments. At low effect sizes (~ 10% mixture effect), CA overestimates metal mixture toxicity at the species level by 1.2-fold (i.e., the mixture interaction factor [MIF]; median). Species, metal presence, or number of metals does not significantly affect the MIF. To predict metal mixture risk at the community level, bioavailability-normalization procedures were combined with CA or IA using SSD techniques in 4 different methods, which were compared using environmental monitoring data of a European river basin (the Dommel, The Netherlands). We found that the simplest method, in which CA is directly applied to the SSD (CASSD ), is also the most conservative method. The CASSD has median margins of safety (MoS) of 1.1 and 1.2 respectively for binary mixtures compared with the theoretically more consistent methods of applying CA or IA to the dose-response curve of each species individually prior to estimating the fraction of affected species (CADRC or IADRC ). The MoS increases linearly with an increasing number of metals, up to 1.4 and 1.7 for quinary mixtures (median) compared with CADRC and IADRC , respectively. When our methods were applied to a geochemical baseline database (Forum of European Geological Surveys [FOREGS]), we found that CASSD yielded a considerable number of mixture risk predictions, even when metals were at background levels (8% of the water samples). In contrast, metal mixture risks predicted with the theoretically more consistent methods (e.g., IADRC ) were very limited under natural background metal concentrations (<1% of the water samples). Based on the combined evidence of chronic mixture toxicity predictions at the species level and evidence of in silico risk predictions at the community level, a tiered risk assessment scheme for evaluating metal mixture risks is presented, with CASSD functioning as a first, simple conservative tier. The more complex, but theoretically more consistent and most accurate method, IADRC , can be used in higher tier assessments. Alternatively, the conservatism of CASSD can be accounted for deterministically by incorporating the MoS and MIF in the scheme. Finally, specific guidance is also given related to specific issues, such as how to deal with nondetect data and complex mixtures that include so-called data-poor metals. Environ Toxicol Chem 2018;37:623-642. (c) 2017 SETAC. PMID- 29135044 TI - Occurrence and distribution of organophosphorus flame retardants/plasticizers and synthetic musks in sediments from source water in the Pearl River Delta, China. AB - The Pearl River (China) and its tributaries receive discharges of treated/untreated domestic sewage and industrial wastewater throughout the entire drainage basin. The river provides source water for many local inhabitants, and there is great concern over its pollution status. Fifteen sediment samples were collected from source water areas in the Pearl River Delta, and analyzed for the occurrence and distribution of 2 classes of emerging pollutants, organophosphorus flame retardants (OPs) and synthetic musks. In most sediments, 5 polycyclic musks and 2 nitro musks were detected, and galaxolide (1,3,4,6,7,8-hexahydro 4,6,6,7,8,8-hexamethylcyclopenta (g)-2-benzopyran [HHCB]) and tonalide (7-acetyl 1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene [AHTN]) were the predominant components, with concentrations of 0.030 to 547 and 4.31 to 439 ng/g, respectively. Seven widely used OPs were found in most sediments, at varying total concentrations from 1.79 to 143 ng/g, with tris(2-butoxyethyl) phosphate (TBEOP), tris(2-chloro-isopropyl) phosphate (TCIPP), and triphenyl phosphate (TPHP) being the main components. The results indicated that industrial discharge and domestic sewage played important roles for synthetic musk and OP distribution in sediments in the study area. In general, higher levels of OPs and synthetic musks were found in Guangzhou, Foshan, and Dongguan, suggesting a significant impact from industrial discharges and the dense population of these regions. Environ Toxicol Chem 2018;37:975-982. (c) 2017 SETAC. PMID- 29135045 TI - An Alkynyl-Stabilized Pt5 Ag22 Cluster Featuring a Two-Dimensional Alkynyl Platinum "Crucifix Motif". AB - The "staple motif" has been widely applied to depict and predict the structures of thiolate or alkynyl-protected gold nanoclusters. By contrast, the composition, dimensions, configuration, and functionality of the platinum-ligand motif has remained completely unknown. Herein, we report the synthesis and crystal structure of a novel luminescent Pt5 Ag22 (C=CPh)32 (1) cluster, in which two dimensional and two-functional alkynyl-platinum "crucifix motif" was observed. Such a crucifix motif with one Pt center and four alkynyl groups in the same plane acts as a two-dimensional unit in the cluster and functions as both a protective cover and an intermediate joint. PMID- 29135046 TI - Quimp (quality of life impairment): an addition to the quality of life lexicon. PMID- 29135047 TI - Effects of voltage strength during electroporation on the development and quality of in vitro-produced porcine embryos. AB - This study was conducted to determine suitable conditions for an experimental method in which the CRISPR/Cas9 system is introduced into in vitro-produced porcine zygotes by electroporation. In the first experiment, when putative zygotes derived from in vitro fertilization (IVF) were electroporated by either unipolar or bipolar pulses, keeping the voltage, pulse duration and pulse number fixed at 30 V/mm, 1 msec and five repeats, respectively, the rate of blastocyst formation from zygotes electroporated by bipolar pulses decreased compared to zygotes electroporated by unipolar pulses. In the second experiment, the putative zygotes were electroporated by electroporation voltages ranging from 20 V/mm-40 V/mm with five 1-msec unipolar pulses. The rate of cleavage and blastocyst formation of zygotes electroporated at 40 V/mm was significantly lower (p < .05) than that of zygotes electroporated at less than 30 V/mm. Moreover, the apoptotic nuclei indices of blastocysts derived from zygotes electroporated by voltages greater than 30 V/mm significantly increased compared with those from zygotes electroporated by voltages less than 25 V/mm (p < .05). When zygotes were electroporated with Cas9 mRNA and single-guide RNA (sgRNA) targeting site in the FGF10 exon 3, the proportions of blastocysts with targeted genomic sequences were 7.7% (2/26) and 3.6% (1/28) in the embryos derived from zygotes electroporated at 25 V/mm and 30 V/mm, respectively. Our results indicate that electroporation at 25 V/mm may be an acceptable condition for introducing Cas9 mRNA and sgRNA into pig IVF zygotes under which the viability of the embryos is not significantly affected. PMID- 29135048 TI - The biomechanical construction of the horse's body and activity patterns of three important muscles of the trunk in the walk, trot and canter. AB - The activity patterns of trunk muscles are commonly neglected, in spite of their importance for maintaining body shape. Analysis of the biomechanics of the trunk under static conditions has led to predictions of the activity patterns. These hypotheses are tested experimentally by surface electromyography (EMG). Five horses, with and without a rider, were examined in the walk, trot and canter. Footfall was synchronised with EMG by an accelerometer. Averages of ten consecutive cycles were calculated and compared by statistical methods. The start and stop times of the muscle activities of 5-10 undisturbed EMG plots were determined and the averages and standard deviations calculated. In walking, muscle activities are minor. Electromyography (EMG) activity was increased in the m. rectus during the three-limb support. When the bending moments assume their greatest values, for example while the horses' mass is accelerated upward (two times earth acceleration) in the diagonal support phases in trot and canter the m. rectus, connecting the sternum with the pubic bone is most active. The m. obl. externus is most active when the torsional and bending moments are greatest during the same support phases, but not bilaterally, because the forces exerted on one side by the (recorded) m. obl. externus are transmitted on the other side by the (not recorded) m. obl. internus. While the hindlegs touch the ground in the trot and canter, ground reaction forces tend to flex the hip joint and the lumbar spine. Therefore, the vertebral column needs to be stabilised by the ipsilateral m. longissimus dorsi, which in fact can be observed. As a whole, our EMG data confirm exactly what has been predicted by theoretical analysis. PMID- 29135049 TI - Functional characterization of E2F3b in human HepG2 liver cancer cell line. AB - E2F3 is a transcription factor that has been shown to be overexpressed in hepatocellular carcinoma (HCC). It is well-known that the E2F3 gene encodes two proteins E2F3a and E2F3b. Therefore, the functions of the two distinct isoforms need to be clarified separately. To characterize the function of E2F3b in HCC, the effects of ectopic expression of E2F3b on cell proliferation, cell cycle, apoptosis and gene expression were investigated. E2F3b promoted G1/S phase transition and markedly increased cell proliferation, but had minor effect on apoptosis. Microarray analyses identified 366 differentially expressed genes (171 upregulated and 195 downregulated) in E2F3b- overexpressing cells. Differential expression of 16 genes relevant to cell cycle and cell proliferation were further verified by real-time PCR. Six genes, including CDC2, CCNE1, ARF, MAP4K2, MUSK, and PAX2 were confirmed to be upregulated by more than twofold; one gene, CCNA2 was validated to be downregulated by more than twofold. We also confirmed that E2F3b increased the protein levels of both cyclin E and Arf but did not affect cyclin D1 protein. These results suggest that E2F3b functions as an important promoter for cell proliferation and plays important roles in transcriptional regulation in HepG2 liver cancer cells. PMID- 29135050 TI - Belief About Mandatory School Vaccinations and Vaccination Refusal Among Ohio Appalachian Parents: Do Demographic and Religious Factors, General Health, and Political Affiliation Play a Role? AB - PURPOSE: To examine how demographic, general health, religious, and political characteristics influenced beliefs about mandatory school vaccinations and history of vaccination refusal for children among Ohio Appalachian parents. METHODS: In 2013 and 2014, baseline data were obtained from parents (n = 337) of girls aged 9-17 from 12 counties in rural Ohio Appalachia enrolled in the Community Awareness, Resources and Education (CARE II) Project. Multivariate logistic regression models were used to identify correlates of parental beliefs about mandatory school vaccinations and history of refusing a doctor-recommended vaccine for their child(ren). RESULTS: About 47% of parents agreed that parents should have the right to refuse mandatory school vaccinations for their child(ren). Participants who reported their political affiliation as Republican (OR = 2.45, 95% CI: 1.28-4.66) or Independent (OR = 3.31, 95% CI: 1.70-6.44) were more likely to agree that parents should have the right to refuse school-mandated vaccinations than parents who reported their political affiliation as Democrat. Approximately 39% of parents reported ever refusing a vaccine for their child(ren). Participants who were female (OR = 3.90, 95% CI: 1.04-14.58) and believed that parents should have the right to refuse mandatory school vaccinations (OR = 3.27, 95% CI: 1.90-5.62) were more likely to report ever refusing a vaccine for their child(ren). CONCLUSION: The study findings provide information to better understand factors related to vaccination refusal among parents in Appalachia Ohio that can be used to design interventions to improve vaccination uptake. PMID- 29135052 TI - Enhanced effect of human mesenchymal stem cells expressing human TNF-alphaR-Fc and HO-1 gene on porcine islet xenotransplantation in humanized mice. AB - BACKGROUND: Porcine islet xenotransplantation is considered an attractive alternative treatment for type 1 diabetes mellitus. However, it is largely limited because of initial rejection due to Instant Blood-Mediated Inflammatory Reaction (IBMIR), oxidative stress, and inflammatory responses. Recently, soluble tumor necrosis factor-alpha receptor type I (sTNF-alphaR) and heme oxygenase (HO) 1 genes (HO-1/sTNF-alphaR) have been shown to improve the viability and functionality of porcine islets after transplantation. METHODS: In this study, genetically modified mesenchymal stem cells (MSCs) expressing the HO-1/sTNF alphaR genes (HO-1/sTNF-alphaR-MSC) were developed using an adenoviral system, and porcine islet viability and function were confirmed by in vitro tests such as GSIS, AO/PI, and the ADP/ATP ratio after coculturing with HO-1/sTNF-alphaR-MSCs. Subsequently, isolated porcine islets were transplanted underneath the kidney capsule of diabetic humanized mice without MSCs, with MSCs or with HO-1/sTNF alphaR-MSCs. RESULTS: According to the results, the HO-1/sTNF-alphaR-MSC-treated group exhibited improved survival of porcine islets and could reverse hyperglycemia more than porcine islets not treated with MSCs or islets cotransplanted with MSCs. Moreover, the HO-1/sTNF-alphaR-MSC group maintained its morphological characteristics and the insulin secretion pattern of transplanted porcine islets similar to endogenous islets in immunocompetent humanized mice. CONCLUSIONS: Our results suggest that HO-1/sTNF-alphaR-MSCs are efficient tools for porcine islet xenotransplantation, and this study may provide basic information for pre-clinical animal models and future clinical trials of porcine islet xenotransplantation. PMID- 29135051 TI - Low molecular weight heparin and aspirin exacerbate human endometrial endothelial cell responses to antiphospholipid antibodies. AB - PROBLEM: Women with antiphospholipid antibodies (aPL) are at risk for pregnancy complications despite treatment with low molecular weight heparin (LMWH) or aspirin (ASA). aPL recognizing beta2 glycoprotein I can target the uterine endothelium, however, little is known about its response to aPL. This study characterized the effect of aPL on human endometrial endothelial cells (HEECs), and the influence of LMWH and ASA. METHOD OF STUDY: HEECs were exposed to aPL or control IgG, with or without low-dose LMWH and ASA, alone or in combination. Chemokine and angiogenic factor secretion were measured by ELISA. A tube formation assay was used to measure angiogenesis. RESULTS: aPL increased HEEC secretion of pro-angiogenic VEGF and PlGF; increased anti-angiogenic sFlt-1; inhibited basal secretion of the chemokines MCP-1, G-CSF, and GRO-alpha; and impaired angiogenesis. LMWH and ASA, alone and in combination, exacerbated the aPL-induced changes in the HEEC angiogenic factor and chemokine profile. There was no reversal of the aPL inhibition of HEEC angiogenesis by either single or combination therapy. CONCLUSION: By aPL inhibiting HEEC chemokine secretion and promoting sFlt-1 release, the uterine endothelium may contribute to impaired placentation and vascular transformation. LMWH and ASA may further contribute to endothelium dysfunction in women with obstetric APS. PMID- 29135054 TI - Association of Helicobacter pylori infection with Toll-like receptor-4 Thr399Ile polymorphism increased the risk of peptic ulcer development in North of Iran. AB - Toll-like receptor-4 (TLR4) polymorphisms may influence host immune response against Helicobacter pylori (H. pylori). This study aimed to investigate whether TLR4 polymorphisms are associated with H. pylori susceptibility and risk of peptic ulcer development or not. The TLR4 + 3725 G/C polymorphism was studied using polymerase chain reaction with confronting two-pair primers (PCR-CTPP). In addition, TLR4 Asp299Gly and Thr399Ile polymorphisms were evaluated by PCR restriction fragment length polymorphism (RFLP). There was no significant difference in TLR4 + 3725 G/C and Asp299Gly genotype frequencies between non peptic ulcer (NPUD) and peptic ulcer (PUD) individuals in the context of peptic ulcer development and susceptibility to infection with H. pylori. Nevertheless, a significant association with increased risk for PUD development was observed for polymorphism TLR4 Thr399Ile [odds ratio (OR) = 4.2; 95% confidence interval (CI) = 1.35-13.26; p = 0.01]. Correspondingly, TLR4 Thr399Ile polymorphism was associated with H. pylori susceptibility (OR = 0.27; 95% CI = 0.08-0.88; p = 0.04). In addition, TLR4 Thr399Ile polymorphism increased 4.2-fold, the risk of peptic ulcer development in individuals infected by H. pylori carrying CT + TT genotype. Our results showed that TLR4 Thr399Ile polymorphism along with H. pylori infection may play critical roles in peptic ulcer development in North of Iran. PMID- 29135053 TI - Chronic endometritis in patients with unexplained infertility: Prevalence and effects of antibiotic treatment on spontaneous conception. AB - PROBLEM: The correlations between chronic endometritis and unexplained infertility are unexplored. METHOD OF STUDY: We performed a retrospective study on consecutive patients referred to our hysteroscopy service due to unexplained infertility. All women underwent endometrial sampling with histological and cultural examinations. If chronic endometritis was diagnosed, patients received antibiotic therapy, and chronic endometritis resolution was subsequently ascertained by histological examination. We aimed to estimate chronic endometritis prevalence and the effects of antibiotic therapy on spontaneous conception during the year following hysteroscopy. RESULTS: A total number of 95 women were included. Pooled prevalence of chronic endometritis was 56.8%. Antibiotic therapy resulted in chronic endometritis resolution in 82.3% of patients, while in 17.6% disease was persistent. Women with cured chronic endometritis showed higher pregnancy rate and live birth rate in comparison with both women with persistent disease and women without chronic endometritis diagnosis (pregnancy rate = 76.3% vs 20% vs 9.5%, P < .0001; live birth rate = 65.8% vs 6.6% vs 4.8%, P < .0001). CONCLUSION: Chronic endometritis is highly prevalent in patients with unexplained infertility. Diagnosis and treatment of chronic endometritis improve spontaneous pregnancy rate and live birth rate in such patients. PMID- 29135055 TI - The modulatory role of cytokines IL-4 and IL-17 in the functional activity of phagocytes in diabetic pregnant women. AB - The study investigated the role of cytokines IL-4 and IL-17 in the modulation of the functional activity of mononuclear phagocytes in diabetic pregnant women with hyperglycemia. Sixty pregnant women were assigned to the following groups: nondiabetic (ND), mild gestational hyperglycemia (MGH), gestational diabetes mellitus (GDM), or type 2 diabetes mellitus (DM2). The functional activity of phagocytes from maternal blood, cord blood, and colostrum was assessed by determining their superoxide release, phagocytosis, microbicidal activity, and intracellular Ca2+ release. Irrespective of glycemic status, colostrum and blood cells treated with IL-4 and IL-17 increased superoxide release in the presence of enteropathogenic Escherichia coli (EPEC). The highest phagocytosis rate was observed in cells from the DM2 group treated with IL-4. In all the groups, phagocytes from colostrum, maternal blood, and cord blood exhibited higher microbicidal activity against EPEC when treated with cytokines. IL-17 increased intracellular Ca2+ release by colostrum phagocytes in diabetic groups. The results indicate that the IL-4 and IL-17 modulate the functional activity of phagocytes in the maternal blood, cord blood, and colostrum of diabetic mother. The natural immunity resulting from the interaction between the cells and cytokines tested may be an alternative procedure to improve the prognosis of maternal and newborn infections. PMID- 29135057 TI - Oxime Ether Radical Cations Stabilized by N-Heterocyclic Carbenes. AB - N-heterocyclic carbene (NHC) nitric oxide (NHCNO) radicals, which can be regarded as iminoxyl radicals stabilized by NHCs, were found to react with a series of silyl and alkyl triflates to generate the corresponding oxime ether radical cations. The structures of the resulting oxime ether radical cations were determined by X-ray crystallography, along with EPR and computational analysis. In contrast, lutidinium triflate produced a 1:1 mixture of [NHCNO+ ][OTf- ] and [NHCNHOH+ ][OTf- ] upon the reaction with NHCNO. This study adds an important example of stable singlet carbenes for stabilizing main-group radicals because of their pi-conjugating effect, the synthesis and structures of which have not been reported previously. PMID- 29135056 TI - A systematic review of the associations between HIV/HCV coinfection and biomarkers of cardiovascular disease. AB - The incidence of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection has been increasing with over 10 million people affected globally. The role biomarkers play as predictors of cardiovascular disease (CVD) risk among coinfected individuals is not well defined. We aimed to systematically review current evidence describing CVD biomarkers among individuals with HIV/HCV coinfection. We searched EMBASE, CINAHL, Google Scholar, PubMed, and Web of Science from inception to June 2017. MeSH terms and keywords were used to identify studies with information on HIV/HCV coinfection and CVD biomarkers (structural, functional, and serological) such as carotid intima-media thickness (CIMT), endothelial markers, C-reactive protein (CRP), homocysteine, and lipids. Among 332 articles screened, 28 were included (39,498 participants). Study designs varied: 18 cross-sectional, 9 cohort, and 1 clinical trial. Compared with healthy controls and people with HIV or HCV monoinfection, individuals with HIV/HCV coinfection had statistically significant lower levels of lipids and CRP and higher levels of endothelial markers (sICAM-1 and sVCAM-1), CIMT, homocysteine, and IL-6. One study found the odds of carotid plaque in coinfected individuals was 1.64 (0.91-2.94) compared with healthy controls, and another study showed the prevalence of vascular plaques (carotid and femoral) in coinfected individuals was higher compared with HIV monoinfected individuals (44% vs 14%, P = 0.04). Biomarkers of CVD have different patterns of association with HIV/HCV coinfection compared with monoinfection and healthy controls. Prospective studies are needed to confirm the predictive value of these biomarkers for clinical CVD risk among coinfected individuals. PMID- 29135058 TI - Distinct features of multivesicular body-lysosome fusion revealed by a new cell free content-mixing assay. AB - When marked for degradation, surface receptor and transporter proteins are internalized and delivered to endosomes where they are packaged into intralumenal vesicles (ILVs). Many rounds of ILV formation create multivesicular bodies (MVBs) that fuse with lysosomes exposing ILVs to hydrolases for catabolism. Despite being critical for protein degradation, the molecular underpinnings of MVB lysosome fusion remain unclear, although machinery underlying other lysosome fusion events is implicated. But how then is specificity conferred? And how is MVB maturation and fusion coordinated for efficient protein degradation? To address these questions, we developed a cell-free MVB-lysosome fusion assay using Saccharomyces cerevisiae as a model. After confirming that the Rab7 ortholog Ypt7 and the multisubunit tethering complex HOPS (homotypic fusion and vacuole protein sorting complex) are required, we found that the Qa-SNARE Pep12 distinguishes this event from homotypic lysosome fusion. Mutations that impair MVB maturation block fusion by preventing Ypt7 activation, confirming that a Rab-cascade mechanism harmonizes MVB maturation with lysosome fusion. PMID- 29135060 TI - A Study to Determine the Prevalence of Temporomandibular Disorders in a Young Adult Population and its Association with Psychological and Functional Occlusal Parameters. AB - PURPOSE: To determine the prevalence of temporomandibular disorders (TMD) in medical university students and to analyze the relationship of TMD with psychological and functional occlusal parameters. MATERIALS AND METHODS: 200 students (mean age 21.81 +/- 1.99) were screened for TMD with the TMD Pain Screener. Clinical examinations identified the participants with TMD. Based on their diagnostic criteria for TMD (DC/TMD) axis I diagnosis, participants were divided into three groups: group 1- non-TMD, group 2- pain related TMD and headaches, and group 3- intra-articular joint disorders. Further study was continued involving patients diagnosed with TMD as the study group, and an equal number of age- and sex-matched participants were selected in control group. Among these, emotional distress was evaluated using the "hospital anxiety and depression scale" (HADS). Occlusal evaluations were done by using the T-Scan computerized occlusal analysis system. Occlusion time, left lateral disclusion time, right lateral disclusion time, and protrusion disclusion time were measured with T-Scan III. These parameters were compared among the groups with ANOVA test at a significance level of 0.05. RESULTS: 17% of the population were affected by TMD. The mean HADSd (depression) and HADSa (anxiety) scores were significantly higher (p < 0.05) in group 2 (7.67 +/- 3.68; 10.60 +/- 3.33) and group 3 (6.89 +/ 3.23; 9.26 +/- 4.05) as compared to group 1 (3.18 +/- 2.33; 5.29 +/- 3.21). The mean values of occlusion time, left lateral disclusion time, right lateral disclusion time, and protrusion-disclusion time were also higher for group 2 and group 3 as compared to group 1. CONCLUSIONS: This study found that the prevalence of TMD in this university student population was 17%. There were significant associations of TMD with psychological parameters and functional occlusal parameters. PMID- 29135059 TI - Effect of Incorporation of Antifungal Agents on the Ultimate Tensile Strength of Temporary Soft Denture Liners. AB - PURPOSE: To investigate the ultimate tensile strength of temporary soft denture liners modified by minimum inhibitory concentrations (MICs) of antifungal agents for Candida albicans biofilm (SC5314) determined in previous microbiological research. MATERIALS AND METHODS: Dumbbell-shaped specimens (n = 7) with a central cross-sectional area of 6 * 3 * 33 mm were produced by Softone and Trusoft, without (control) or with incorporation of drugs in powder form at MICs for C. albicans biofilm (per g of material powder): nystatin (0.032 g), chlorhexidine diacetate (0.064 g), ketoconazole (0.128 g), miconazole (0.256 g), and itraconazole (0.256 g). After plasticization, specimens were immersed in distilled water at 37 degrees C for 24 hours, 7 or 14 days, and then tested in tension in a universal testing machine at 40 mm/min. Data of tensile strength (MPa) and elongation percentage (%) were submitted to 3-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: At the end of 14 days, the tensile strength for both materials was significantly lower in the groups modified by miconazole and itraconazole compared to the other groups (p < 0.0001), which showed no significant difference between them (p > 0.05). After 7 and 14 days in water, miconazole and itraconazole added into both materials resulted in significantly lower elongation percentages compared to the other antifungal agents and control (p < 0.0001), which were similar to each other (p > 0.05). CONCLUSIONS: The addition of the nystatin, chlorhexidine, and ketoconazole at MICs for C. albicans biofilm resulted in no harmful effects on the tensile strength and elongation percentage of the temporary soft denture liner materials up to 14 days. PMID- 29135061 TI - Transmembrane Signaling with Lipid-Bilayer Assemblies as a Platform for Channel Based Biosensing. AB - Artificial and natural lipid membranes that elicit transmembrane signaling is are useful as a platform for channel-based biosensing. In this account we summarize our research on the design of transmembrane signaling associated with lipid bilayer membranes containing nanopore-forming compounds. Channel-forming compounds, such as receptor ion-channels, channel-forming peptides and synthetic channels, are embedded in planar and spherical bilayer lipid membranes to develop highly sensitive and selective biosensing methods for a variety of analytes. The membrane-bound receptor approach is useful for introducing receptor sites on both planar and spherical bilayer lipid membranes. Natural receptors in biomembranes are also used for designing of biosensing methods. PMID- 29135062 TI - Organocatalyzed Photocontrolled Radical Polymerization of Semifluorinated (Meth)acrylates Driven by Visible Light. AB - Fluorinated polymers are important materials that are widely used in many areas. Herein, we report the development of a metal-free photocontrolled radical polymerization of semifluorinated (meth)acrylates with a new visible-light absorbing organocatalyst. This method enabled the production of a variety of semifluorinated polymers with narrow molar-weight distributions from semifluorinated trithiocarbonates or perfluoroalkyl iodides. The high performance of "ON/OFF" control and chain-extension experiments further demonstrate the utility and reliability of this method. Furthermore, to streamline the preparation of semifluorinated polymers, a scalable continuous-flow approach has been developed. Given the broad interest in fluorinated materials and photopolymerization, we expect that this method will facilitate the development of advanced materials with unique properties. PMID- 29135063 TI - Conductive Microporous Covalent Triazine-Based Framework for High-Performance Electrochemical Capacitive Energy Storage. AB - Nitrogen-enriched porous nanocarbon, graphene, and conductive polymers attract increasing attention for application in supercapacitors. However, electrode materials with a large specific surface area (SSA) and a high nitrogen doping concentration, which is needed for excellent supercapacitors, has not been achieved thus far. Herein, we developed a class of tetracyanoquinodimethane derived conductive microporous covalent triazine-based frameworks (TCNQ-CTFs) with both high nitrogen content (>8 %) and large SSA (>3600 m2 g-1 ). These CTFs exhibited excellent specific capacitances with the highest value exceeding 380 F g-1 , considerable energy density of 42.8 Wh kg-1 , and remarkable cycling stability without any capacitance degradation after 10 000 cycles. This class of CTFs should hold a great potential as high-performance electrode material for electrochemical energy-storage systems. PMID- 29135064 TI - Internal Peptide Late-Stage Diversification: Peptide-Isosteric Triazoles for Primary and Secondary C(sp3 )-H Activation. AB - Secondary C(sp3 )-H arylations were accomplished by palladium catalysis with triazoles as peptide bond isosteres. The unique power of this approach is highlighted by the possibility of achieving secondary C(sp3 )-H functionalizations on terminal peptides as well as the unprecedented positional selective C(sp3 )-H functionalization of internal peptide positions, setting the stage for modular peptide late-stage diversification. PMID- 29135065 TI - A Simple Prelithiation Strategy To Build a High-Rate and Long-Life Lithium-Ion Battery with Improved Low-Temperature Performance. AB - Lithium-ion batteries (LIBs) are being used to power the commercial electric vehicles (EVs). However, the charge/discharge rate and life of current LIBs still cannot satisfy the further development of EVs. Furthermore, the poor low temperature performance of LIBs limits their application in cold climates and high altitude areas. Herein, a simple prelithiation method is developed to fabricate a new LIB. In this strategy, a Li3 V2 (PO4 )3 cathode and a pristine hard carbon anode are used to form a primary cell, and the initial Li+ extraction from Li3 V2 (PO4 )3 is used to prelithiate the hard carbon. Then, the self-formed Li2 V2 (PO4 )3 cathode and prelithiated hard carbon anode are used to form a 4 V LIB. The LIB exhibits a maximum energy density of 208.3 Wh kg-1 , a maximum power density of 8291 W kg-1 and a long life of 2000 cycles. When operated at -40 degrees C, the LIB can keep 67 % capacity of room temperature, which is much better than conventional LIBs. PMID- 29135066 TI - Developing and Sustaining a Career as a Transdisciplinary Nurse Scientist. AB - PURPOSE: The purpose of this article is to provide an overview of strategies to build and sustain a career as a nurse scientist. This article examines how to integrate technologies and precision approaches into clinical practice, research, and education of the next generation of nursing scholars. DESIGN: This article presents information for shaping a sustainable transdisciplinary career. Programs of research that utilize self-management to improve quality of life are discussed throughout the article. The ongoing National Institute of Nursing Research-funded (R01 grant) iPhone Helping Evaluate Atrial Fibrillation Rhythm through Technology (iHEART) study is the first prospective, randomized controlled trial to evaluate whether electrocardiographic monitoring with the AliveCorTM device in the real world setting will improve the time to detection and treatment of recurrent atrial fibrillation over a 6-month period as compared to usual cardiac care. METHODS: Opportunities to sustain a career as a nurse scientist and build programs of transdisciplinary research are identified. These opportunities are focused within the area of research and precision medicine. FINDINGS: Nurse scientists have the potential and ability to shape their careers and become essential members of transdisciplinary partnerships. Exposure to clinical research, expert mentorship, and diverse training opportunities in different areas are essential to ensure that contributions to nursing science are visible through publications and presentations as well as through securing grant funding to develop and maintain programs of research. CONCLUSIONS: Transcending boundaries and different disciplines, nurses are essential members of many diverse teams. CLINICAL RELEVANCE: Nurse scientists are strengthening research approaches, clinical care, and communication and improving health outcomes while also building and shaping the next generation of nurse scientists. PMID- 29135067 TI - Selection for life-history traits to maximize population growth in an invasive marine species. AB - Species establishing outside their natural range, negatively impacting local ecosystems, are of increasing global concern. They often display life-history features characteristic for r-selected populations with fast growth and high reproduction rates to achieve positive population growth rates (r) in invaded habitats. Here, we demonstrate substantially earlier maturation at a 2 orders of magnitude lower body mass at first reproduction in invasive compared to native populations of the comb jelly Mnemiopsis leidyi. Empirical results are corroborated by a theoretical model for competing life-history traits that predicts maturation at the smallest possible size to optimize r, while individual lifetime reproductive success (R0 ), optimized in native populations, is near constant over a large range of intermediate maturation sizes. We suggest that high variability in reproductive tactics in native populations is an underappreciated determinant of invasiveness, acting as substrate upon which selection can act during the invasion process. PMID- 29135068 TI - Contribution of genes in the GABAergic pathway to bipolar disorder and its executive function deficit in the Chinese Han population. AB - In this study, we investigated the association between bipolar I disorder (BDI) and between cognitive deficits therein and SNPs in GABAergic receptor genes. The sample comprised 477 patients with BDI and 438 healthy controls, with three neurocognitive tests being administered in 123 patients and 164 controls. For three SNPs, rs505474, rs1398175, and rs4868029 in the GABRA2, GABRA4, and GABRP genes, respectively, their allele frequencies were significantly different between patients and controls (Bonferroni-adjusted p = values 3.84 * 10-4 , 9.92 * 10-3 , and 1.22 * 10-2 , respectively). Four haplotypes were significantly associated with BDI (TA and AG for rs3815762 and rs4868029 in GABRP, GG for rs11636988 and rs8024256 in GABRB3 and GAGG for rs2197414, rs4921195, rs13188991, and rs11956731 in GABRA6, with p values of 0.0038, 0.044, 0.0176, and 0.0267, respectively, on 10,000 permutations). Furthermore, the SNP (rs2912585) within 250 kb upstream of the GABRB3 gene displayed a strong association with the Tower of Hanoi (TOH) executive time in the patient group (p = 2.844 * 10-6 ). One other SNP (rs754661), which is located at the intronic region of the same gene, was associated with the global trait of the executive function and post hoc analysis showed significant SNP by group effect (p = 0.0094). Our study supports previous findings that GABAA receptor genes are associated with bipolar disorder; it also suggests that the GABAA genes, especially the GABRB3 gene, might play a role in the executive function deficit in bipolar disorder, although future replication with a larger sample size is needed. PMID- 29135070 TI - Prevalence of anti-retinal antibodies in epiretinal membranes and macular holes. PMID- 29135069 TI - Impaired secretion of active GLP-1 in patients with hypertriglyceridaemia: A novel lipotoxicity paradigm? AB - BACKGROUND: Lipotoxicity plays an important role in the pathogenesis of beta-cell dysfunction. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that exerts beneficial effects on the number and function of islet beta cells. However, the effect of lipotoxicity on GLP-1 secretion is still unknown. METHODS: Twenty-five patients who were newly diagnosed with diabetes were recruited from 400 subjects based on 75-g Oral Glucose Tolerance Test. Patients were divided into diabetes (DM) and DM combined with hypertriglyceridaemia (DM + HTG) groups according to their serum triglyceride (TG) levels. Seventy-one normal controls and 17 patients with isolated hypertriglyceridaemia were matched by age and gender. RESULTS: Total and active fasting GLP-1 and 2-hour GLP-1 levels were not significantly altered among the 4 groups. However, total and active DeltaGLP-1 levels (the difference between 2-hour GLP-1 and fasting GLP-1 levels) were significantly reduced in the isolated HTG, DM, and DM + HTG groups, particularly the DM + HTG group. The ratio of serum active GLP-1 (AGLP-1) to total GLP-1 (TGLP-1) levels was also decreased in patients with isolated HTG, suggesting that active GLP-1 secretion may be more seriously impaired. Both DeltaTGLP-1 and DeltaAGLP-1 levels were negatively correlated with serum TG levels, body mass index and fasting plasma glucose (FPG) levels and positively correlated with HDL-C levels. According to the multivariate linear regression analysis, only TG and FPG levels were independently associated with DeltaTGLP-1 and DeltaAGLP-1 levels. CONCLUSION: Impaired GLP-1 secretion was associated with hypertriglyceridaemia and diabetes, and a more obvious association was noted in hypertriglyceridaemic patients with diabetes. PMID- 29135071 TI - Cobalt-Catalyzed Suzuki Biaryl Coupling of Aryl Halides. AB - Readily accessed cobalt pre-catalysts with N-heterocyclic carbene ligands catalyze the Suzuki cross-coupling of aryl chlorides and bromides with alkyllithium-activated arylboronic pinacolate esters. Preliminary mechanistic studies indicate that the cobalt species is reduced to Co0 during the reaction. PMID- 29135072 TI - Measuring human placental blood flow with multidelay 3D GRASE pseudocontinuous arterial spin labeling at 3T. AB - BACKGROUND: Placenta influences the health of both a woman and her fetus during pregnancy. Maternal blood supply to placenta can be measured noninvasively using arterial spin labeling (ASL). PURPOSE: To present a multidelay pseudocontinuous arterial spin labeling (pCASL) combined with a fast 3D inner-volume gradient- and spin-echo (GRASE) imaging technique to simultaneously measure placental blood flow (PBF) and arterial transit time (ATT), and to study PBF and ATT evolution with gestational age during the second trimester. The PBF values were compared with uterine arterial Doppler ultrasound to assess its potential clinical utility. STUDY TYPE: This was a prospective study. SUBJECTS: Thirty-four pregnant women. FIELD STRENGTH/SEQUENCE: Multidelay 3D inner-volume GRASE pCASL sequence on 3T MR scanners. ASSESSMENT: Subjects underwent two longitudinal MRI scans within the second trimester, conducted between 14-16 and 19-22 weeks of gestational age, respectively. Placental perfusion was measured using the free breathing pCASL sequence at three postlabeling delays (PLDs), followed by offline motion correction and model fitting for estimation of PBF and ATT. STATISTICAL TESTS: A paired t-test was conducted to evaluate the significance of PBF/ATT variations with placental development. A two-sample t-test was conducted to evaluate the significance of PBF difference in subjects with and without early diastolic notch. RESULTS: The mean PBF and ATT for the second trimester were 111.4 +/- 26.7 ml/100g/min and 1387.5 +/- 88.0 msec, respectively. The average PBF increased by 10.4% (P < 0.05), while no significant change in ATT (P = 0.72) was found along gestational ages during the second trimester. PBF decreased 20.3% (P < 0.01) in subjects with early diastolic notches in ultrasound flow waveform patterns. DATA CONCLUSION: Multidelay pCASL with inner-volume 3D GRASE is promising for noninvasive assessment of PBF during pregnancy. Its clinical use for the detection of aberrations in placental function and prediction of fetal developmental disorders awaits evaluation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1667-1676. PMID- 29135073 TI - Prostate cancer detection using quantitative T2 and T2 -weighted imaging: The effects of 5-alpha-reductase inhibitors in men on active surveillance. AB - BACKGROUND: T2 -weighted imaging (T2 -WI) information has been used in a qualitative manner in the assessment of prostate cancer. Quantitative derivatives (T2 relaxation time) can be generated from T2 -WI. These outputs may be useful in helping to discriminate clinically significant prostate cancer from background signal. PURPOSE/HYPOTHESIS: To investigate changes in quantitative T2 parameters in lesions and noncancerous tissue of men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo daily for 6 months. STUDY TYPE: Retrospective. POPULATION/SUBJECTS: Forty men randomized to 6 months of daily dutasteride (n = 20) or placebo (n = 20). FIELD STRENGTH/SEQUENCE: Multiparametric 3T MRI at baseline and 6 months. This included a multiecho MR sequence for quantification of the T2 relaxation times, in three regions of interest (index lesion, noncancerous peripheral [PZ] and transitional [TZ] zones). A synthetic signal contrast (T2 Q contrast) between lesion and noncancerous tissue was assessed using quantitative T2 values. Signal contrast was calculated using the T2 -weighted sequence (T2 W contrast). ASSESSMENT: Two radiologists reviewed the scans in consensus according to Prostate Imaging Reporting and Data System (PI-RADS v. 2) guidelines. STATISTICAL TESTS: Wilcoxon and Mann-Whitney U-tests, Spearman's correlation. RESULTS: When compared to noncancerous tissue, shorter T2 values were observed within lesions at baseline (83.5 and 80.5 msec) and 6 months (81.5 and 81.9 msec) in the placebo and dutasteride arm, respectively. No significant differences for T2 W contrast at baseline and after 6 months were observed, both in the placebo (0.40 [0.29-0.49] vs. 0.43 [0.25-0.49]; P = 0.881) and dutasteride arm (0.35 [0.24-0.47] vs. 0.37 [0.22-0.44]; P = 0.668). There was a significant, positive correlation between the T2 Q contrast and the T2 W contrast values (r = 0.786; P < 0.001). DATA CONCLUSION: The exposure to antiandrogen therapy did not significantly influence the T2 contrast or the T2 relaxation values in men on active surveillance for prostate cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1646-1653. PMID- 29135074 TI - Effects of alcohol on plasma glucose and prevention of alcohol-induced hypoglycemia in type 1 diabetes-A systematic review with GRADE. AB - Because ethanol is thought to be a risk factor for severe hypoglycemia, patients with type 1 diabetes (T1D) are recommended to limit ethanol intake. However, little is known on how ethanol affects plasma glucose and how ethanol-induced hypoglycemia can be prevented. In this study, we systematically reviewed the literature for ethanol effects on plasma glucose and for prevention strategies on ethanol-induced hypoglycemia. Electronic searches on PubMed and Google were conducted in February 2017. Randomized clinical trials and observational studies were included. Studies involved patients with T1D with no history of ethanol abuse. The primary aims were changes in plasma glucose after ethanol intake and prevention strategies for ethanol-induced hypoglycemia. Quality of the studies was assessed by GRADE. Additionally, we searched for guidelines from diabetes associations on their suggested prevention strategies. We included 13 studies. Eight studies reported that ethanol, regardless of administration intravenously or orally, were associated with an increased risk of hypoglycemia due to decrease in plasma glucose, impaired counter-regulatory response, awareness of hypoglycemia, and cognitive function. Five studies did not report an increased risk of hypoglycemia. None of the studies investigated prevention strategies for ethanol-induced hypoglycemia. Recommendations from 13 diabetes associations were included. All associations recommend that ethanol should only be consumed with food intake. The majority of included studies showed that ethanol intake increased the risk of hypoglycemia in patients with T1D. However, the evidence for how to prevent ethanol-induced hypoglycemia is sparse, and further investigations are needed to establish evidence-based recommendations. PMID- 29135075 TI - The Role of Body, Mind, and Environment in Preterm Birth: Mind the Gap. AB - Preterm birth continues to be a problem affecting low-, middle-, and high-income countries, with rates increasing in some areas despite ongoing efforts to reduce the incidence. This emphasizes the need for more effective interventions, particularly if we aim to achieve the broad health targets of the Sustainable Development Goals (SDGs) by 2030. The current focus on medically-oriented interventions such as reducing nonmedically-indicated induction of labor, cesarean birth, and multiple embryo transfers associated with assisted reproductive technologies, as well as the application of cervical cerclage and use of progesterone therapy, though important, are likely only partial solutions to the complex phenomenon of preterm birth. Preterm birth has multiple etiologies. The biologic mechanisms involved in preterm labor and how it may be triggered are not well understood. There is growing evidence to suggest some of these triggers may also be related to stress and environmental conditions. In this review, we focus on evidence concerning psychosocial (mind) and environmental factors (environment) as well as briefly review the evidence related to maternal and fetal factors (body) associated with the risk of preterm birth, with reference to some of the SDGs. We also assess emerging evidence regarding the interaction of the body, mind, and environment in relation to preterm birth, currently a gap in our knowledge, and how these interactions could impact clinical practice. Findings suggest that multidisciplinary expertise and approaches will be needed to develop effective interventions to address the complex etiologies of preterm birth, as opposed to single-risk-factor mitigation. Clinicians and researchers will play key roles in identifying many of these risk factors and shaping interventions that address this complex issue. Addressing the interlinkages between body, mind, and environment through the integration of research and clinical practice is critical to reducing the risk of preterm birth and contributing to the achievement of the SDGs. PMID- 29135076 TI - A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX). AB - Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR. PMID- 29135077 TI - Anaesthetic perspective to 10 cases of paracentral acute middle maculopathy following cataract surgery. PMID- 29135078 TI - Molecular phylogeny of Entomobrya (Collembola: Entomobryidae) from China: Color pattern groups and multiple origins. AB - Highly diversified colorations among springtails (Collembola) have been widely used for species diagnosis, but their phylogenetic significance is poorly known. We addressed this issue in the largest Entomobryinae genus Entomobrya, which possesses variable color patterns among species. The relationships within the genus and to other genera have also rarely been studied. Based on material mainly from China, we have conducted a multilocus phylogeny and topology tests with likelihood and Bayesian algorithms, and accordingly demonstrated the non monophyly of Chinese Entomobrya. The division of five clades, including Entomobrya and several related genera, coincided well with five types of colorations, respectively. Further analyses of divergence time and historical biogeography revealed that Chinese Entomobrya originated mainly from Palearctic (northern and western) China in the Paleocene and Eocene. This study highlights the great phylogenetic values as well as taxonomic uses of coloration in Chinese Entomobrya. Multiple phylogenetic and biogeographic origins of Entomobrya imply its complicated relationships with both scaled and unscaled genera of Entomobryinae. PMID- 29135079 TI - Cigarette smoke extract and isoprene resulted in the induction of apoptosis and autophagy in human placenta choriocarcinoma JEG-3 cells. AB - In this study, the effects of cigarette smoke (CS) on the induction of apoptosis via reactive oxygen species (ROS) production and endoplasmic reticulum stress (ER stress) of JEG-3 human choriocarcinoma cells were examined to confirm the relationship between CS and placenta development. Upon TUNEL assay, CS extract (3R4F; 0.3 and 2.1 MUM) increased JEG-3 apoptosis. Western blot assay revealed that the protein expressions of p53, Bax, and CCAAT-enhancer-binding protein homologous protein (CHOP) increased, while the levels of Bcl-2 were reduced following CS extract treatment. Moreover, 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay revealed increased ROS production. Upon 3-(4-5-dimethylthiazol-2 yl)-2.5-dyhphenyltetrazolium bromide (MTT) assay, isoprene (IP), one of ingredients of CS, deceased JEG-3 cell viability (10-11 to 10-6 M). After based on the MTT assay, two IP concentrations of 10-11 and 10-8 M were selected and the protein expressions of cyclin D1, cyclin E1, p21, and p27 decreased in response to IP. Furthermore, IP showed the greatest increase in autophagy at 24 hours and further induction of cell death at 72 hours upon monodansylacadaverine and TUNEL assay. Western blot analysis confirmed the increase in autophagy markers, LC3beta and p62, as well as the increase or decrease of apoptosis markers p53, Bax, CHOP, and Bcl-2 in response to its treatments. In addition to confirming increases in ROS through DCFH-DA, we also confirmed the expression of Nrf2, an antioxidant marker, and the expression of Kelch-like ECH-associated protein 1 (KEAP1), which specifically degrades Nrf2, by Western blot. Taken together, these results indicate that CS and IP may inhibit the development of placenta via activation of ROS by inducing apoptosis and autophagy by affecting the expression of KEAP1, which regulates Nrf2 expression. PMID- 29135080 TI - Comparison of medication adherence and persistence in type 2 diabetes: A systematic review and meta-analysis. AB - Limited medication adherence and persistence with treatment are barriers to successful management of type 2 diabetes (T2D). We searched MEDLINE, EMBASE, the Cochrane Library, the Register of Controlled Trials, PsychINFO and CINAHL for observational and interventional studies that compared the adherence or persistence associated with 2 or more glucose-lowering medications in people with T2D. Where 5 or more studies provided the same comparison, a random-effects meta analysis was performed, reporting mean difference (MD) or odds ratio (OR) for adherence or persistence, depending on the pooled study outcomes. We included a total of 48 studies. Compared with metformin, adherence (%) was better for sulphonylureas (5 studies; MD 10.6%, 95% confidence interval [CI] 6.5-14.7) and thiazolidinediones (TZDs; 6 studies; MD 11.3%, 95% CI 2.7%-20.0%). Adherence to TZDs was marginally better than adherence to sulphonylureas (5 studies; MD 1.5%, 95% CI 0.1-2.9). Dipeptidyl peptidase-4 inhibitors had better adherence than sulphonylureas and TZDs. Glucagon-like peptide-1 receptor agonists had higher rates of discontinuation than long-acting analogue insulins (6 studies; OR 1.95; 95% CI 1.17-3.27). Long-acting insulin analogues had better persistence than human insulins (5 studies; MD 43.1 days; 95% CI 22.0-64.2). The methods used to define adherence and persistence were highly variable. PMID- 29135082 TI - HLA-DQB1*02:102, a novel allele identified by next-generation sequencing in a Spanish individual. AB - HLA-DQB1*02:102 differs from DQB1*02:01:01 by a single-nucleotide substitution resulting in an amino acid change. PMID- 29135081 TI - Adverse Childhood Experiences (ACEs) and Adiposity in Adolescents: A Cross-Cohort Comparison. AB - OBJECTIVE: This study aimed to assess the association between adverse childhood experiences (ACEs) and adiposity in adolescents from two cohorts in different socioeconomic contexts. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC, United Kingdom) and the 1993 Pelotas Cohort (Brazil) were used. Six ACEs were assessed in both cohorts up to age 15. At 15 years, body mass index (BMI) and waist circumference (WC) were measured, and at 18 years, BMI, fat mass index, and android fat percentage were assessed. RESULTS: Few associations were observed between ACEs and adiposity at 15 years, and they were not consistent across cohorts. For adiposity at age 15 in ALSPAC, physical abuse had a positive association with WC, and domestic violence had a positive association with both WC and BMI. A dose-response relationship between the ACE score and both WC and BMI at 15 years was observed in ALSPAC. In the 1993 Pelotas Cohort, the associations found in crude analysis were no longer evident after adjustment. CONCLUSIONS: This study found some evidence of an association between an ACE score and adiposity in adolescence in a United Kingdom cohort but no evidence of association in a Brazilian cohort. Residual confounding or context-specific relationships could explain the different pattern of associations. PMID- 29135083 TI - Comparison of the anticancer properties of a novel valproic acid prodrug to leading histone deacetylase inhibitors. AB - The HDAC inhibitory activity of valproic acid (VPA) has led to on-going evaluation of it as an anticancer agent. The histone deacetylase (HDAC) inhibitor AN446, a prodrug of VPA, releases the acid upon metabolic degradation. AN446 is >60-fold more potent than VPA in killing cancer cells in vitro. Herein, we compare the activities of AN446, as an anticancer agent, to those of representative types from each of the four major classes of HDAC inhibitors (HDACIs): vorinostat, romidepsin, entinostat, and VPA. AN446 exhibited the greatest selectivity and HDAC inhibitory activity against cancer cells. In glioblastoma cells only AN446, and in MDA-MB-231 cells only AN446 and VPA interacted in synergy with doxorubicin (Dox). AN446 was superior to the studied HDACIs in inducing DNA-damage in cancer cells, while in normal astrocytes and cardiomyoblasts AN446 was the least toxic. AN446 was the only HDACI tested that exhibited selective HDAC inhibitory activity that was high in cancer cells and low in noncancerous cells. This discriminating inhibition correlated with the toxicity of the HDACIs, suggesting that their effects could be attributed to HDAC inhibition. In cardiomyoblasts, the HDACIs tested, except for AN446, hampered DNA repair by reducing the level of Rad 51. VPA and AN446 were the most effective HDACIs in inhibiting in vitro migration and invasion. The advantages of AN446 shown here, position it as a potentially improved HDACI for treatment of glioblastoma and triple negative breast cancer. PMID- 29135084 TI - Identification of Bioactive Scaffolds Based on QSAR Models. AB - In medicinal chemistry, the molecular scaffolds commonly found in compounds with preferable biological activities are called bioactive scaffolds. They are important because if present in a structure, it is more likely that the compound will be bioactive. Traditionally, medicinal chemists use their knowledge to identify bioactive scaffolds from a given data set after systematic extraction of all candidate scaffolds. However, manually sorting all the scaffolds is not practical as the number of compounds in a data set is often very large. Herein, we propose a method to systematically identify bioactive scaffolds based on a structure generator and a QSAR model. Two proof-of-concept studies showed that known bioactive scaffolds as well as scaffolds containing important substructures were extracted. The proposed method does not depend on scaffold frequencies in a data set, which is different from currently used methods for bioactive scaffold identification. PMID- 29135085 TI - Retromer and the cation-independent mannose 6-phosphate receptor-Time for a trial separation? AB - The retromer cargo-selective complex (CSC) comprising Vps35, Vps29 and Vps26 mediates the endosome-to-Golgi retrieval of the cation-independent mannose 6 phosphate receptor (CIMPR). Or does it? Recently published data have questioned the validity of this long-established theory. Here, the evidence for and against a role for the retromer CSC in CIMPR endosome-to-Golgi retrieval is examined in the light of the new data that the SNX-BAR dimer is actually responsible for CIMPR retrieval. PMID- 29135087 TI - Screening Women for At-Risk Alcohol Use: An Introduction to Screening, Brief Intervention, and Referral to Treatment (SBIRT) in Women's Health. AB - A significant number of women engage in at-risk drinking behavior, or heavy alcohol use. Women are especially at risk for the negative impact of excessive alcohol consumption secondary to gender differences in body structure, chemistry, and alcohol absorption. In addition, women who drink alcohol during pregnancy risk fetotoxic effects. Screening for at-risk alcohol use is considered best practice during primary care and prenatal care visits and is an integral component of preventive care services for women. The purpose of this brief report is to introduce the Screening, Brief Intervention, and Referral to Treatment (SBIRT) model as it applies to alcohol use and its importance in women's health care services. SBIRT resources are evidence based, allowing the clinician to screen for use of alcohol, implement a brief intervention, and conduct referral to treatment, if necessary. Implementing SBIRT improves recognition of at-risk alcohol use or alcohol use disorder, facilitates awareness and education about use, enhances the referral-to-treatment process, and decreases overall health care costs. PMID- 29135086 TI - Can MR enterography screen for perianal disease in pediatric inflammatory bowel disease? AB - BACKGROUND: Pediatric Crohn's disease is associated with perianal disease (PAD). Magnetic resonance enterography (MRE) assesses small bowel involvement in pediatric inflammatory bowel disease (PIBD). Pelvic MRI (P-MRI) is the gold standard for assessing PAD. PURPOSE: To determine if MRE can accurately detect PAD in PIBD, distinguishing perianal fistulae (PAF) from perianal abscesses (PAA), referenced against P-MRI. STUDY TYPE: Retrospective. POPULATION: Seventy seven PIBD patients, 27 females (mean age 14.1 years), with P-MRI and MRE within 6 months. FIELD STRENGTH/SEQUENCE: 1.5T and 3T; P-MRI: sagittal fat suppressed (FS) T2 fast spin-echo (FSE), coronal short tau inversion recovery, axial T1 FSE, coronal and axial postcontrast FS T1 FSE; MRE: coronal balanced steady-state free precession (SSFP), coronal cine SSFP, coronal and axial single-shot T2 FS, axial SSFP, coronal ultrafast 3D T1 -weighted gradient echo FS (3D T1 GE), axial diffusion-weighted imaging, coronal and axial postcontrast 3D T1 GE FS. ASSESSMENT: Two radiologists independently, then by consensus, assessed randomized MRI exams, recording PAF number, location, and length; and PAA number, location, length, and volume. Sensitivity analysis used clinical disease as the gold standard, calculated separately for P-MRI and MRE. STATISTICAL TESTS: Comparing MRE and P-MRI consensus data, sensitivity, specificity, positive, and negative predictive values (P/NPV) were calculated. Inter- and intrareader reliability were assessed using kappa statistics. RESULTS: P-MRI and MRE were paired, detecting PAD in 73 patients, PAF in 63, and PAA in 31 P-MRI. MRE sensitivities, specificities, PPV, and NPV were: PAD 82%, 100%, 100%, 23%; PAF 74%, 71%, 92%, 38%; PAA 51%, 85%, 69%, 72%; clinical 82%, 22%, 37%, 69%; clinical P-MRI 96%, 8%, 37%, 80%. MRE interreader agreement for PAD was moderate (kappa = 0.51 [0.29-0.73]), fair for PAF and PAA. DATA CONCLUSION: Using a standard technique, MRE can detect PAD with high specificity and moderate sensitivity in PIBD, missing some PAF and small PAA. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1638-1645. PMID- 29135088 TI - The role of Toll-like receptors in ovarian cancer. AB - Ovarian cancer (OC) is the leading cause of death in gynecological malignancies in western countries. Chemoresistance represents a major issue and a better understanding of the interactions that take place within the tumor microenvironment is needed, such as the connection between inflammation and cancer. Toll like receptors (TLRs) are part of the basic mechanisms that are involved in the activation of the innate immune system, with extensive activation of various transcription factors, that subsequently lead to an adaptive immune response, making them key players that modulate the inflammatory response and tumor dynamics. In the same time, activation of TLRs on OC cells can lead to a different type of response that favors an aggressive phenotype and tumor progression. Herein, we review the recent evidence towards the role of TLRs in OC and the therapeutic strategies that have already commenced. PMID- 29135089 TI - FAK, Src and p-Paxillin expression is decreased in liver metastasis of colorectal carcinoma patients. AB - PURPOSE: The FAK/Src/Paxillin (PXN) axis has been implicated in malignant transformation, tumor growth, progression and metastasis. The present study aimed to assess FAK/Src/PXN protein expression in both primary and liver metastatic sites of colorectal adenocarcinoma (CRC). METHODS: FAK, Src and p-PXN expression was assessed immunohistochemically on 32 primary CRCs and their corresponding liver metastases, being also analyzed in relation with clinicopathological characteristics and patient survival. RESULTS: FAK, Src and p-PXN expression was significantly decreased in liver metastasis compared to matched paired primary CRCs (p<0.01). Increased FAK expression in primary CRCs was significantly associated with poor histological grade and advanced disease stage (p=0.0330 and p=0.0204, respectively). Increased Src expression in primary colorectal tumors was significantly associated with the presence of lymph node metastasis (p=0.0325), while elevated p-PXN expression with poor histological grade (p=0.0284). CONCLUSIONS: FAK, Src and p-PXN appear to play a role in the pathophysiological aspects of CRC. The lower expression of these proteins in liver metastasis compared to the primary CRC could significantly impact the choice of a novel therapeutic agent according to the disease stage. PMID- 29135090 TI - Gene expression profiling demonstrates WNT/beta-catenin pathway genes alteration in Mexican patients with colorectal cancer and diabetes mellitus. AB - PURPOSE: Several studies have shown a strong association between diabetes mellitus (DM) and increased risk of colorectal cancer (CRC). The fundamental mechanisms that support this association are not entirely understood; however, it is believed that hyperinsulinemia and hyperglycemia may be involved. Some proposed mechanisms include upregulation of mitogenic signaling pathways like MAPK, PI3K, mTOR, and WNT, which are involved in cell proliferation, growth, and cancer cell survival. The purpose of this study was to evaluate the gene expression profile and identify differently expressed genes involved in mitogenic pathways in CRC patients with and without DM. METHODS: In this study, microarray analysis of gene expression followed by quantitative PCR (qPCR) was performed in cancer tissue from CRC patients with and without DM to identify the gene expression profiles and validate the differently expressed genes. RESULTS: Among the study groups, some differently expressed genes were identified. However, when bioinformatics clustering tools were used, a significant modulation of genes involved in the WNT pathway was evident. Therefore, we focused on genes participating in this pathway, such as WNT3A, LRP6, TCF7L2, and FRA-1. Validation of the expression levels of those genes by qPCR showed that CRC patients without type 2 diabetes mellitus (T2DM) expressed significantly more WNT3Ay LRP6, but less TCF7L2 and FRA-1 compared to controls, while in CRC patients with DM the expression levels of WNT3A, LRP6, TCF7L2, and FRA-1 were significantly higher compared to controls. CONCLUSIONS: Our results suggest that WNT/beta-catenin pathway is upregulated in patients with CRC and DM, demonstrating its importance and involvement in both pathologies. PMID- 29135091 TI - Remarkably higher efficacy and a wider safety window for nonfrontline over first line drug combinations in the adenocarcinoma Colo 320DM cell line. AB - PURPOSE: To determine in vitro, the efficacy and safety window of not-front-line and first-line anti-colorectal (CRC) drug combinations. METHODS: The adenocarcinoma cell line Colo 320DM and normal human mesenchymal stem cells derived from adipose tissue were used respectively to determine the anti-CRC efficacy (% of Colo 320DM cell death [CD]) and safety window [SW] - % Colo 320DM percent cancer death (PCD)/% of mesenchymal stem cell's death) of drug combinations, using the adenosine triphosphate-based chemotherapy response assay (ATP-CRA). RESULTS: First-line anti-CRC drug combinations (5-fluorouracil [5FU]/oxaliplatin [oxa] and 5-FU/Oxa /leucovorin [Leuco]) produced 57.7% and 52.4% CD, and 1.38 and 2.44 SW, respectively. Combinations of 5-FU/Oxa and 1 to 3 non-front line drugs led to 56.3-99.8% CD and to 0.96-2.2 SW. The highest safety window corresponded to 5FU/Oxa/ carboplatin [Carbo] (93% CD and 1.4 SW) and to 5 FU/ Oxa/cisplatin [Cispl] (93.5% CD and 1.4 SW). In contrast, non-front line drugs led to 89.8-97.4% CD and to 1.1-78.2 SW. Outstandingly, those combinations containing Carbo/ Cispl/3,3'-diindolylmethane (DIM), aspirin (Asp), or 3,3'- DIM/ Asp showed a very high CD (91.9-96.9% [39.2-39.5 times higher than first-line combined drugs]) and very wide SW (57.8-81.56 [66.6-40 times higher than the first-line drug combinations]). CONCLUSIONS: Human mesenchymal stem cells could be an excellent alternative to laboratory animals, when testing the safety profiles of drugs. The most promising combinations of non-frontline drugs to treat CRC are Carbo/Cispl/ Asp and Carbo/Cispl/DIM. PMID- 29135092 TI - The prognostic role of Skp2 and the tumor suppressor protein p27 in colorectal cancer. AB - PURPOSE: This study aimed at exploring the role of Skp2, p27 and Cks1 expression as prognostic factors for colorectal cancer (CRC) patients, and to identify a correlation between their expression and the cell proliferation marker Ki67. METHODS: We conducted a retrospective study on 130 patients with CRC treated with surgery and adjuvant treatment at the Oncology Institute Cluj-Napoca between 2006 2010. The Skp2, p27, Cks1 and Ki67 immunoexpression was grouped from 1 to 4, according to percents of tumor cells with nuclear reactivity. Their correlation with overall survival (OS), recurrence free survival (RFS) and with the classical histopathological prognostic factors were analyzed. All patients had 5-year follow-up. RESULTS: The majority of patients had locally advanced TNM stages II and III. More than a half of the tumors had low immunoexpression of Skp2 and Cks1, and high and moderate p27 and Ki67 expression. Skp2 overexpression negatively influenced the p27 (p=0.002). Both OS and RFS were significantly higher in patients with moderate and high expression of p27 (p=0.005). Skp2 and Cks1 overexpression negatively influenced OS and RFS. Skp2 overexpression positively correlated with TNM stage (p<0.001), node capsular invasion (p=0.002) and lymphovascular invasion (p=0.042). Ki67 expression did not correlate with Skp2 (p=0.88), Cks1 (p=0.67) and p27 (p=0.40), neither with OS (p=0.841) and RFS (p=0.84). CONCLUSIONS: The most important prognostic factor was the Skp2 overexpression. It was the only protein we studied that correlated with the other well-known prognostic factors in CRC. The expression of Ki67 did not bring any novel prognostic information regarding CRC. PMID- 29135093 TI - Evaluation of safety of bevacizumab as second-line treatment of patients with metastatic colorectal cancer. AB - PURPOSE: Bevacizumab is a relatively new monoclonal antibody introduced in the treatment of metastatic colorectal cancer (CRC). Since varied efficiency and adverse events of this drug were reported, the purpose of this study was to assess the safety of bevacizumab as second-line treatment of patients with metastatic CRC. METHODS: This observational, non-interventional study involved 35 patients with metastatic CRC treated with bevacizumab. Patients were from the Oncology Clinic, Clinical Centre of Montenegro. Monitoring of patients was done according to the study protocol. RESULTS: The number of subjects with abnormal values of tumor marker CEA has decreased from 56.8% (enrollment visit) to 50% in the sixth visit (p<0.01). The number of subjects with abnormal values for tumor marker Ca19-9 ranged from initial 45% (enrollment visit) to 50% on the sixth visit (p>0.05). No significant differences in the average values of hematological and biochemical parameters and the average values of the CEA and Ca19-9 were noticed. In 26 (46.2%) patients, adverse events were recorded. Of 72 adverse events, 31 (43.05%) were related to bevacizumab. Regarding adverse events intensity, 68.1% were moderate. The most common adverse event was hypertension, which was recorded in 12 patients. There was no life-threatening adverse event connected with the drug use. CONCLUSION: Use of bevacizumab caused moderate adverse effects, none of which was life-threatening. PMID- 29135094 TI - Towards a tailored lymphadenectomy for gastric cancer based on the correlation between the primary tumor location and the first lymphatic drain basin: Preliminary data. AB - PURPOSE: The contradictory long-term results following D2 lymphadenectomy have revealed the necessity for a more tailored lymphadenectomy in cases of gastric cancer. Among the patients who had undergone a modified D2 lymphadenectomy for gastric cancer, we further analyzed the subgroup in which histologically and immunohistochemically solitary lymph node metastases were detected. Classifying the primary tumors as towards to the lesser and towards to the grater curvature, we propose possible routes of lymphatic spread and possible clinical implications. METHOD: Between January 2007 and December 2016, 212 patients suffering from gastric adenocarcinoma underwent a modified D2 lymphadenectomy. Solitary lymph node metastases were detected by histology in 14 patients (7 skip metastases) and by immunohistochemistry in an additional 10 patients (5 skip micrometastases). RESULTS: The incidence of the histologically detected solitary lymph node metastases was 6.6% for the whole cohort, increasing to 11.3% with the use of immunohistochemistry. The incidence of the histologically detected skip solitary lymph node metastases was 3.3% for the whole cohort, increasing to 5.7% with the use of immunohistochemistry. Tumors of the lower and middle third of the stomach were equally drained both to the level I and II lymph node stations. However, tumors towards the lesser curvature were mainly drained in the level II lymph node stations (12 out of 19; 63%), while tumors towards the greater curvature were all drained in the level I lymph node stations (5 out of 5; 100%). CONCLUSION: Primary gastric tumors towards the lesser curvature should be treated by a modified D2 lymphadenctomy. However, for tumors towards the greater curvature, a D1(+) lymphadenectomy always including the no. 7 & 9 lymph node stations complex, might be enough. PMID- 29135095 TI - Does upfront therapy with cytoreductive surgery and HIPEC confer a survival benefit in patients with synchronous gastric peritoneal carcinomatosis when compared with patients with metachronous gastric peritoneal carcinomatosis? AB - Gastric cancer (GC) remains the second leading cause of cancer death worldwide, accounting for 8% of the total cases and 10% of total deaths in 2008. Surgery remains the curative treatment option for GC and the main reason for treatment failure is peritoneal recurrence which, according to the literature, occurs in 40 60% of the cases, despite extensive surgery including D2 lymph node dissection. The hyperthermic intraperitoneal chemotherapy (HIPEC) technique is increasingly used in the treatment of primary and digestive peritoneal carcinomatosis (PC), in association with cytoreductive surgery (CRS). We retrospectively analyzed 14 patients with gastric peritoneal carcinomatosis (GPC) undergoing CRS/HIPEC in the last 10 years. Six patients already had GPC at the time of diagnosis (group A) and 8 developed metachronous GPC (group B). Treatment with CRS and HIPEC didn't seem to confer a survival benefit to patients with synchronous PC from gastric cancer. PMID- 29135096 TI - Silibinin promotes the apoptosis of gastric cancer BGC823 cells through caspase pathway. AB - PURPOSE: To investigate the effects of silibinin, a natural compound, on the proliferation and apoptosis of BGC-823 gastric cancer cell line and to figure out the relevant pathways. METHODS: BGC-823 gastric cancer cells were treated with silibinin at various concentrations (0,25,50,100,150 and 200MUM). Zero MUM was the control group and the other concentrations were defined as the experimental groups. The effects of silibinin on the proliferation of BGC-823 gastric cancer cells were explored through methylthiazolyldiphenyltetrazolium bromide (MTT). Silibinin's toxic effects were detected through determination of the concentration of lactic dehydrogenase (LDH). Flow cytometry was performed to explore the effects of silibinin on apoptosis of these cells. Western blotting was conducted to study the relevant pathways acting on the BGC-823 cells. RESULTS: MTT assay showed that with the increase in silibinin concentration and extension of exposure time, the inhibitory effect silibinin on cell proliferation was enhanced in an obvious time-dosage pattern. The results of LDH detection showed that the toxicity of silibinin to cells was enhanced in an obvious time dosage pattern with the increase in drug concentration and extension of exposure time. Flow cytometry revealed that with the increase in drug concentration, gradual increase in the proportion of early and late of apoptotic cells took place, and the comparison between the experimental and the control group showed that the difference had statistical significance. Western blotting indicated that silibinin could upregulate the expression of mitochondrial apoptosis-associated proteins, and the difference in comparison with the control group had statistical significance. CONCLUSION: Silibinin can inhibit the proliferation of BGC- 823 gastric cancer cells, and such an inhibitory effect is time- and concentration dependent. Additionally, silibinin can promote the apoptosis of BGC-823 gastric cancer cells, which may be realized through mitochondrial apoptosis. PMID- 29135097 TI - Analysis of expression profile of miRNA in stomach adenocarcinoma. AB - PURPOSE: Stomach adenocarcinoma (STAD) has become the second main cause of cancer death around the world, and accumulated evidence has suggested that micro-RNAs (miRNAs) are likely to be served as indicator for diagnosis and prognosis in a variety of tumors. The purpose of this study was to discover the miRNAs acting as independent prognostic factors of STAD and to provide reference for the STAD diagnosis and prognosis. METHODS: In this study, we analyzed the clinical data collected from 393 STAD cases of the Cancer Genome Atlas (TCGA;USA) and the expression data of 1881 miRNAs to screen miRNAs that were associated with STAD via Cox regression univariate analysis and those miRNAs with independent effect on the prognosis of STAD via Cox regression multivariate analysis. RESULTS: We found differential expressions of 218 miRNAs in STAD tumors and normal tissues, and a key role of miR- 7 in STAD. In Cox regression multivariate analysis, miR- 378i (p=0.0010), miR-7-3 (p=0.01), miR-137 (p=0.03) and miR-372 (p=0.04) were independent prognostic factors, for which we performed Kaplan-Meier analysis, and the results showed that there was a statistically significant difference in comparison of the survival duration between the highexpression and low-expression of miR-7-3 groups, but no differences were identified between the groups of miR 378i (p=0.7), miR-137 (p=0.11) and miR-372 (p=0.13). CONCLUSION: miR-7-3 is proved to be an independent prognostic indicator for STAD and this study confirmed that tumor-specific miRNA can predict the progression and prognosis of STAD. PMID- 29135098 TI - Meta-analysis of laparoscopic vs open liver resection for hepatocellular carcinoma: The European experience. AB - PURPOSE: The aim of this meta-analysis of studies conducted in Europe was to evaluate the effect of laparoscopic liver resection (LLR) on short- and long-term outcomes compared to open liver resection (OLR) in patients operated for hepatocellular carcinoma (HCC). METHODS: An electronic literature search was conducted in order to identify studies comparing LLR and OLR. Short-term outcomes evaluated included operative time, blood loss, need for transfusion, R0 resection, resection margin width, length of hospital stay, morbidity and 30-day postoperative mortality. Long-term outcomes included 1-year, 3-year, 5-year overall (OS) and disease-free survival (DFS) as well as tumor recurrence rate. RevMan 5.1 software was utilized for statistical meta-analysis. RESULTS: A total of 851 patients from 10 European studies were included in the present meta analysis reporting for short- and long-term results for LLR and ORL for HCC. Among them 321 (37.7%) underwent laparoscopic hepatectomy and the remaining 530 (62.3%) were operated through open approach. LLR were found to be strongly associated with lower blood loss as well as need for blood transfusion, shorter hospital stay, lower 30-day mortality and morbidity and finally improved 1-year OS and 5-year DFS. Operative time, R0 resection, resection margin width, tumor size, 3- and 5-year OS as well as 1- and 3-year DFS were not found significantly different among the two groups. CONCLUSION: The present meta-analysis demonstrates the superiority of laparoscopic over open approach for same sized tumors. Cirrhotic patients benefit from laparoscopy in terms of shorter hospital stay, complication rate and long-term oncologic outcomes. PMID- 29135099 TI - Tissue injury of the remnant liver following radiofrequency-assisted partial hepatectomy. AB - PURPOSE: To evaluate remnant liver tissue damage in a pig model of radiofrequency (RF)-assisted liver resection employing either the sequential coagulate cut (SCC) Belgrade technique using a monopolar RF electrode or the one using the bipolar Habib-4x device. METHODS: Sixteen pigs underwent either a) resection of part of the left lateral and left median hepatic lobes employing the SCC (SCC group), the Habib-4X (H group) or the "crushclamp" technique (CC group) or b) sham operation (Sham group). Forty-eight hours later, tissue specimens were excised from the right lateral hepatic lobe for histopathological examination and immunohistochemical assessment of tissue injury, mitosis and inflammation. RESULTS: Histopathologic lesions, apoptotic activity, HSP 40 and TNFalpha expression were more intense, while mitotic activity was less prominent in the SCC group technique compared to H group. Comparison between CC and H groups suggested the pivotal role of partial hepatectomy (PH) per se in the changes noted in H group. CONCLUSION: The Habib-4X liver resection technique proved to be less injurious in the remnant liver tissue after PH compared to the SCC technique. PMID- 29135100 TI - Safety and efficacy of liver resections in elderly patients. AB - PURPOSE: Elderly patients constitute a special group of surgical candidates due to the frequent coexistence of major comorbidities. We report our experience in performing liver resections in patients aged 75 years or older. METHODS: During a period of 62 months, 154 patients underwent liver resections, out of which 20 were 75 years old or older. Our prospectively maintained database was reviewed regarding patient and tumor characteristics, intraoperative and postoperative data. RESULTS: Out of the 20 patients aged 75 years or older, 15 were men and 5 women, with a mean age of 79.3 years. Sixteen patients (80%) had at least one major comorbidity. Indications for surgery was hepatocellular carcinoma (n=5), intrahepatic cholangiocarcinoma (n=7), liver metastases (n=5), liver abscess (n=2) and liver cyst with hemorrhage (n=1). Liver resections included 3 left hepatectomies, 1 left lateral hepatectomy combined with segmentectomy and wedge resection, 2 right hepatectomies, 1 central hepatectomy, 4 bisegmentectomies, 3 segmentectomies, 4 wedge resections and 2 unroofings of giant liver cysts. In 10 out of the 20 operations, patients underwent further procedures apart from the liver resection. Six patients were postoperatively admitted to intensive care unit for 1 or 2 days. Postoperative bile leak was documented in 2 patients and postoperative hemorrhage in 1 patient, for which no reoperation was needed. No postoperative death was recorded during the hospitalization of the patients. The mean length of hospital stay was 12.9 days. CONCLUSIONS: Liver resections, even major ones, can be tolerated by elderly patients with good postoperative outcomes under the presupposition of careful patient selection. PMID- 29135101 TI - NOR1 expression and its relationship with prognosis in patients with hepatocellular carcinoma. AB - PURPOSE: This study aimed to investigate the expression of NOR1 in hepatocellular carcinoma (HCC) tissue and its relationship with prognosis. METHODS: A sample of 60 specimens including HCC and adjacent normal tissues were collected from postoperative HCC patients from February to September 2011. Immunohistochemistry was used to detect the positive expression of the oxidored-nitro domain containing protein 1 (NOR1), the postoperative disease-free survival (DFS) rate and then the overall survival (OS) was analyzed by the Kaplan-Meier method. RESULTS: The results showed significantly lower expression of NOR1 in HCC tissue than that in adjacent normal tissue. Moreover, the OS and DFS rate of NOR1 (++) patients were significantly higher than those of other groups. CONCLUSION: Consequently, NOR1 is a protective protein in HCC, and the increase of its expression is favorable for the prognosis of patients. PMID- 29135102 TI - Changes in 18F-FDG-PET/CT tumor metabolism are not consistent with pathologic complete response in hormone-positive breast cancer. AB - PURPOSE: Current evaluation of response to neoadjuvant chemotherapy (NAC) shows that it could achieve pathological complete response (pCR). The purpose of this study was to assess the consistency of maximum uptake values (SUVmax) changes and pCR in hormone-positive locally advanced breast cancer (LABC). METHODS: Ninety hormone-positive LABC patients treated at Marmara University Medical Oncology Clinic, Istanbul, Turkey, between 2009 and 2015 were retrospectively studied. All eligible patients (n=5) received NAC (4-8 cycles) and were evaluated for pCR. 18F fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG- PET/CT) scan was performed before and after the completion of NAC. The relative changes of SUVmax both in the primary tumor and the axilla were assessed for consistency with pCR. RESULTS: The patient median age was 46 years (range 26- 76). The patients 13.7% achieved pCR. Values of >50% (n=40) and <50% (n=11) SUVmax changes were not associated with pCR (15% and 18% respectively) (p=1.00). Patients with >75% SUVmax changes could achieve pCR of 20%. Interestingly, most patients with complete metabolic response did not achieve pCR (81%). The difference of the Ki67 levels before and after NAC, tumor localization, HER- 2 positivity, menopausal status, grade of differentiation, lymphovascular and perineural invasion were not associated with pCR. CONCLUSION: SUVmax changes in later cycles of NAC as commonly practised in oncology clinics were not consistent with pCR (p=1.0). Complete metabolic response may not be associated with pCR in hormone-positive LABC. However, almost 80% of patients had >50% decrease in SUVmax and may still have a chance for conservative surgery and less postoperative morbidity. Therefore, 18F-FDG-PET/CT may still have a role to evaluate the tumor response with a need of larger studies and analysis for cost effectiveness. PMID- 29135103 TI - Impact of Oncotype DX on chemotherapy assignment: a retrospective single-center study on female breast cancer patients. AB - PURPOSE: This study was designed to determine the Recurrence Score (RS) distribution and its associated risk assessments based on traditional clinicopathologic characteristics in a single-center breast cancer (BC) deriving cohort in Greece, and to evaluate the impact of the RS results on adjuvant treatment decisions applied in this cohort. METHODS: This was a retrospective, single-center study regarding Greek female patients with early-stage breast cancer (ESBC). From 2009 to 2015, 114 cases lacking unanimity in the multidisciplinary breast meeting (MDM) fulfilled the inclusion criteria. The RS of the Oncotype DX (ODX) assay was the main outcome. RESULTS: The mean RS in the sample was 16.38 (SD=6.87). RS was positively correlated with Ki-67 (p=0.008). A negative progesterone receptor (PR) was associated with a higher RS (p<0.05). RS was higher for cases of chemotherapy assignment (p<0.001). According to the oncologists' pre-DX assay recommendations, 62.8% of the patients would have been 'wrongly' assigned to chemotherapy, while 14.3% of patients would have not been recommended this treatment even though they should have. The overall chemotherapy recommendation was significantly altered after the ODX RS assay was carried out (p=0.008) and, in the sample, it diminished by 39.5%. CONCLUSIONS: The distribution of the ODX RS in the specific cohort of Greek women is similar to that reported in other geographic regions of the world. Knowledge of the RS resulted in a shift in treatment recommendations towards lower-intensity regimens and in a greatly reduced proportion of chemotherapy recommendations. PMID- 29135104 TI - Clinicopathological and prognostic significance of cyclin D1 amplification in patients with breast cancer: a meta-analysis. AB - PURPOSE: Cyclin D1 plays a critical role in tumorigenesis and the regulation of the G1/S transition in the cell cycle. The relationship between cyclin D1 amplification and clinicopathological parameters in patients with breast cancer remains controversial and its impact on survival outcome is not completely clear. We conducted a meta-analysis to investigate the associations between cyclin D1 gene amplification and certain clinicopathological characteristics and the prognosis in breast cancer. METHODS: Literature search of PubMed (up to August 3, 2016) was performed. We used Stata 12.0 (Stata Corporation, Texas, US) to analyze the correlations between cyclin D1 amplification and clinicopathological features and the prognostic indicator relapse free survival (RFS) and overall survival (OS) in patients with breast cancer. Publication bias analysis and sensitivity analysis were performed. RESULTS: A total of 9,238 breast cancer patients from 21 studies were included. The pooled odds ratios (ORs) indicated that cyclin D1 amplification was significantly associated with estrogen receptor (ER), progesterone receptor (PR), histological grade and lymph node status, but not associated with human epidermal growth factor receptor-2 (HER2) and tumor size. The combined hazard ratios (HRs) for RFS and OS showed that patients with cyclin D1 amplification displayed a 1.31-fold higher risk of recurrence (HR =1.31, 95% confidence interval (95% CI):1.02-1.60, p<0.01), and a risk of mortality 1.22 fold higher times greater than those without cyclin D1 amplification (HR=1.22, 95% CI:0.99- 1.44, p<0.01), respectively. CONCLUSION: Our meta-analysis indicated that cyclin D1 amplification is significantly associated with established clinicopathological variables and can be used as a poor prognostic indicator for patients with breast cancer. PMID- 29135105 TI - Impact of ABCB1 and CYP2D6 polymorphisms on tamoxifen treatment outcomes and adverse events in breast cancer patients. AB - PURPOSE: This study was designed to evaluate the effect of CYP2D6 and ABCB1 polymorphisms and co-medication on the outcomes and adverse events (AEs) of tamoxifen therapy. METHODS: In total, 258 women (187 postmenopausal and 71 premenopausal) with hormone positive breast carcinoma were retrospectively evaluated. CYP2D6 polymorphisms were evaluated with AmpliChip (Roche), and polymorphisms of ATP-binding cassettes B1 (P-glycoprotein) (ABCB1) rs2032582 and rs1045642 with restriction fragment length polymorphisms polymerase chain reaction (RFLP-PCR). RESULTS: CYP2D6 polymorphisms or co-medication affecting CYP2D6 activity demonstrated no statistically significant effect on the efficacy of tamoxifen therapy or AE incidence. There was only a trend towards shortening the time to event (TTE) in CYP2D6-poor metabolisers. ABCB1 polymorphism rs2032582 was not associated with clinical outcomes, while a trend towards an increase in TTE, in variant allele carriers, was noted. The ABCB1 polymorphism rs1045642 demonstrated statistical significance, albeit only in premenopausal patients, i.e. the effect of two variant alleles on the TTE extension was demonstrated only in the premenopausal group (p=0.0012, HR 0.69; 95% CI 0.21-2.31), and statistical significance (p=0.0106) only for gynaecological/vasomotor AEs (p=0.0221, HR=1.0588), with no evidence of any influence on the incidence and onset of venous complications (i.e. deep venous thrombosis or pulmonary embolism). CONCLUSIONS: Although no conclusive statistical association between the examined polymorphisms and the outcome or incidence of AEs in tamoxifen therapy was found, the impact of ABCB1 polymorphisms warrants further research. The importance of finding predictive pharmacogenomic biomarkers is a major challenge for individualization and pharmaco-economic rationalization of therapy. The latest international guidelines support this notion. PMID- 29135106 TI - Evidence for the efficacy of disulfiram and copper combination in glioblastoma multiforme - A propos of a case. AB - Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately this condition is incurable. Besides the dismal prognosis of GBM, financial factors have also presented challenges for advancing treatments. Taking into consideration the high cost of developing new anticancer drugs as well as the fact that GBM is a rare disease, thus further limiting financial incentive for drug development, it becomes obvious that there has been growing interest for repurposing candidates. One of the most promising drugs to repurpose for treating GBM is disulfiram (DSF). DSF is a relatively nontoxic drug used for more than sixty years in the treatment of chronic alcoholism with the ability to readily cross the blood-brain barrier. Repurposing DSF for use as an anticancer drug in general has recently become of interest because of its preclinically described anticancer effects against various human cancers. Interestingly, a number of these effects were shown to be copper (Cu)-dependent. The purpose of this paper was to review the existing literature surrounding preclinical and clinical data on the effects of DSF -alone or in combination with Cu- in GBM. In addition, we present the first case of a GBM patient safely treated with DSF/Cu combination along with standard therapy exhibiting remarkably increased progression-free (PFS) and overall survival (OS). PMID- 29135107 TI - Benefit and outcome of using temozolomide-based chemoradiotherapy followed by temozolomide alone for glioblastoma in clinical practice. AB - PURPOSE: Temozolomide (TEM), an oral alkylating agent, has shown promising activity in the last 10 years in the treatment of glioblastoma multiforme (GBM). Our goal was to show the benefit of concomitant therapy involving 3D conformal radiotherapy and temozolomide in clinical practice. METHODS: This was a retrospective/prospective study and included a total of 113 patients with GBM diagnosis. Forty- seven patients received postoperative radiotherapy and 66 received concomitant temozolomide plus 3D conformal radiotherapy. RESULTS: The mean overall survival of patients who received postoperative radiotherapy alone was 9.93+/-6.475 months, compared to statistically longer overall survival in the group of patients who received radiotherapy plus temozolomide (13.89+/-8.049 months) (p=0.006). The latter group was divided into two subgroups, one consisting of patients who received 6 complete cycles of temozolomide, and a second with patients who received incomplete treatment. Statistically significant longer overall survival was registered in the first subgroup compared to the second (p=0.006). CONCLUSION: The concomitant usage of temozolomide and radiotherapy was beneficial, and statistically significant difference among groups and subgroups was observed regarding overall survival. PMID- 29135108 TI - Addressing the post-irradiation hypothalamic-pituitary endocrine abnormalities of brain tumors in pediatric patients. AB - PURPOSE: Hypothalamic-pituitary axis is susceptible to radiotherapy, causing endocrine disorders to childhood cancer survivors. We conducted a systematic review in order to assess the radiation-induced toxicity that leads to hormone secretion abnormalities and their severity in children with brain tumors. METHODS: The data were collected by relevant studies on PubMed and EMBASE. Articles up to December 2016 were included. We selected studies which focused on children patients (<18 yr old) with brain tumors treated with radiotherapy and the consequences for their endocrine system. RESULTS: Growth hormone (GH) deficiency was the most common post-irradiation abnormality among children cancer survivors, followed by gonadotrophin (GT), thyroid stimulating hormone (TSH), corticotropin (ACTH) and prolactin (PRL) disorders. CONCLUSIONS: The age of the patient, total radiotherapy dose, number of fractions, fraction size and the duration of treatment seem to determine the severity of these disturbances. PMID- 29135109 TI - 18F-FDG-PET/CT versus 99Tcm-MIBI-SPECT: which is better for detection of solitary pulmonary nodules ? AB - PURPOSE: To compare the diagnostic value of 99Tcm-MIBI- SPECT and 18F-FDG-PET/CT in differentiating benign from malignant solitary pulmonary nodules (SPNs). METHODS: 170 SPNs were involved in this study (78 with 99Tcm-MIBI-SPECT and 92 with 18F-FDG-PET/CT). Definite diagnosis of SPNs was determined by biopsy. The diagnostic efficiency of 99Tcm-MIBI-SPECT and 18F-FDGPET/ CT in differentiating benign from malignant SPNs was analyzed and compared. RESULTS: Seventy-eight patients with SPNs were examined with 99Tcm-MIBI-SPECT (26 with malignant SPNs and 52 with benign SPNs). The sensitivity, specificity and accuracy of 99Tcm-MIBI SPECT were 92.31, 88.46 and 89.74%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 80 and 95.83%, respectively. Ninety-two individuals with SPNs were examined using 18F-FDG-PET/CT (58 with malignant SPNs and 34 with benign SPNs). The sensitivity, specificity and accuracy of 18F-FDG-PET/CT were 96.55, 76.47 and 89.13%, respectively. The PPV and NPV were 87.50 and 92.86%, respectively. Statistical significance was not detected in sensitivity, specificity, accuracy, PPV and NPV between these two methods. CONCLUSION: 99Tcm-MIBI-SPECT has comparable diagnostic value with 18F FDG-PET/CT in differentiating benign from malignant SPNs. Considering its easy availability and low-cost, 99Tcm-MIBI-SPECT could be an alternative imaging modality in differentiating benign from malignant SPNs in areas with a backward economy. PMID- 29135110 TI - Pathway cross-talk network strategy reveals key pathways in non-small cell lung cancer. AB - PURPOSE: The purpose of this study was to explore the pathway cross-talks and key pathways in non-small cell lung cancer (NSCLC) to better understand the underlying pathological mechanism. METHODS: Integrated gene expression data, pathway data and protein-protein interaction (PPI) data were assessed to identify the pathway regulatory interactions in NSCLC, and constructed the background and disease pathway crosstalk networks, respectively. In this work, the attractor method was implemented to identified the differential pathways, and the rank product (RP) algorithm was used to determine the importance of pathways. RESULTS: Based on 787,896 PPI interactions from STRING database and 300 human pathways from KEGG, we constructed the back pathway cross-talk network with 300 nodes and 42239 edges. Integrating with expression data of NSCLC, each pathway cross-talk endowed with a weight value, and disease pathway cross-talks were identified. By RP algorithm and topology analysis of network, we selected 5 key pathways, including Alanine, DNA replication, Fanconi anemia pathway, Cell cycle and MicroRNAs in cancer under the pre-set thresholds. CONCLUSION: We successfully revealed the disease pathway cross-talks and explored 5 key pathways in NSCLC, which may be the underlying therapeutic targets for lung cancer. PMID- 29135111 TI - Curative intent for unresectable advanced squamous cell esophageal cancer: Overall survival after chemoradiation. AB - PURPOSE: To analyse the overall survival (OS) of patients with locally advanced, unresectable esophageal cancer treated with chemoradiation (CRT) with or without surgery. METHODS: CRT was administered to 63 patients with locally advanced (T3 4, N0-1), initially unresectable squamous cell esophageal cancer. After the assessment of tumor response to treatment, medically fit patients converted to operable stage were subjected to surgery. Regular follow-up was performed every 3 months during first 2 years, and then every 6 months. RESULTS: All 63 patients completed the whole radiotherapy course. Forty patients (63%) received complete 4 cycles of chemotherapy. In the remaining 23 patients (37%) chemotherapy was interrupted due to toxicity. Clinical response to CRT was: complete response (CR) in 4 patients (6%), partial response (PR in 27 (43%), stable disease (SD) in 22 (35%) patients, and 10 patients (16%) had disease progression (PD). After reevaluation, 23 patients (15 PR and 8 SD after CRT) underwent surgery (37%), all with R0 resection. OS in the whole group was 53% at one year, and 36% at two years. OS was significantly better in the operated group of patients than in the non-operated group. No statistically significant difference in OS was observed comparing operated to CR patients with no surgery (70 vs 50%). In the non operated group of patients there was no difference in OS between CR, PR, and SD patients. CONCLUSIONS: With appropriate selection, patients with advanced squamous cell esophageal cancer should be considered for potentially effective treatment. PMID- 29135112 TI - Symptom-triggered alcohol vapor inhalation for postoperative alcohol withdrawal syndrome in patients with gastroesophageal carcinoma. AB - PURPOSE: The purpose of this study was to investigate the feasibility and efficacy of alcohol vapor inhalation during fasting time for cancer patients with alcohol withdrawal symptoms (AWS) after surgery. METHODS: The data of 51 patients after esophagectomy or gastrectomy for gastroesophageal carcinoma in two hospitals from January 2011 to December 2016 was retrospectively analyzed. These patients were diagnosed with AWS with Clinic Institute Alcohol Withdrawal Syndrome Scale (CIWA-Ar) score >= 9 in two hospitals during fasting time from January 2011 to December 2016, and they were accordingly divided into alcohol vapor group (n=25) and diazepam group (n=26). As oral intake of wine was forbidden in the first 7 postoperative days, these patients received either alcohol vapor inhalation or intravenous administration of diazepam every 12 hrs. The difference in scores of CIWA-Ar, Riker Sedation-Agitation Scale (SAS), side effects and complications were registered and analyzed. RESULTS: The patients in both groups gained satisfactory efficacy which was indicated by CIWA-Ar scores after therapy, without obvious difference in terms of surgery-related complications, chest and abdominal drainage, serum biomarkers of hepatic function or postoperative hospital stay. However, the patients treated with alcohol vapor inhalation displayed lower alcohol craving and sleepiness, more significant decreased CIWA-Ar scores, as well as encouragingly higher degree of satisfaction, comparing with the diazepam group. CONCLUSION: Alcohol vapor inhalation is feasible and effective to alleviate AWS timely, which is reliable for patients to get through the fasting time after surgery. PMID- 29135113 TI - Minichromosome maintenance (MCM) protein 4 overexpression is a potential prognostic marker for laryngeal squamous cell carcinoma. AB - PURPOSE: The minichromosomal maintenance (MCM) proteins are involved in the initiation and DNA replication. The role of MCM4 remains to be elucidated. The purpose of this study was to investigate the effects of MCM4 in laryngeal squamous cell carcinoma (LSCC) cell growth and apoptosis. METHODS: LSCC cell line UMSCC 5 was used in this study. The small interfering RNA (siRNA) of MCM 4 gene was used to identify the effects of MCM4 on the proliferation and apoptosis using methylimidazole tetrazolium (MTT) assay and flow-cytometry, respectively. Confirmed LSCC and adjacent non-tumor tissues were collected from 34 patients who were willing to participate in the study, from 2010 through 2015, from 163 patients undergoing treatment in the Department of Otorhinolaryngology/Head and Neck Surgery of Beijing Tongren Hospital in Capital Medical University of P.R. China. Immunohistochemical staining of MCM4 expression in the resected tissues was performed to analyze the correlation between its expression and the clinicopathological characteristics. RESULTS: The results showed that siRNA of MCM4 could significantly inhibit LSCC cell line UMSCC 5 proliferation and induce apoptosis. MCM4 mRNA was higher expressed in carcinoma tissues than in adjacent normal tissues. MCM4 expression was correlated with male gender, smoking history and poor differentiation. CONCLUSIONS: We noticed a significant role for MCM4 overexpression in human LSCC tissues and their corresponding adjacent non neoplastic tissues and found that siRNA of MCM4 can significantly decrease the proliferation of cancer cells. It is suggested that MCM4 profiling could potentially be used to predict response to treatment and prognosis in LSCC. PMID- 29135114 TI - Expression and role of p53 in oral lichen planus patients. AB - PURPOSE: Oral lichen planus (OLP) is an autoimmune skin and mucosal disorder. The range of malignant transformation in OLP varies between 0.1-3%. p53 is a tumor suppressor protein. Defective p53 could allow abnormal cells to proliferate, resulting in cancer. p53 plays an important role in cell cycle control and apoptosis and loss of p53 function has been demonstrated in about half of all human cancers. The purpose of the study was to investigate the malignant potential of OLP on the basis of p53 expression and to correlate p53 expression with clinical and histopathological features of OLP. METHODS: 40 patients with OLP underwent biopsy. All tissue samples were treated immunohistochemicaly using avidin-biotin peroxidase complex method. RESULTS: In 80% of OLP specimens the nuclei of basal and parabasal keratinocytes were p53-positive, but in low numbers. Low percentage of p53-positive cells in older and medium percentage of p53-positive cells in younger group of OLP patients were noted. Higher intensity of p53 stained keratinocytes, no matter their low number, could represent mutant and more stable form of p53 protein, and at the same time signal for monitoring of disease due to potential malignant transformation. Low percentage and weak intensity of p53-positive cells was detected mostly in OLP specimens with highly expressed civatte bodies (CB). Upregulation of apoptosis didn't correspond with the expression of CB. CONCLUSION: We believe that low percentage of p53-positive and well-marked keratinocytes in OLP represent the influence of mutant p53 protein, and that increasing expression of this protein could serve as a valuable diagnostic sign of early carcinogenesis. According to our results intensity of p53 coloration of keratinocytes could help assessing the malignant potential of OLP. PMID- 29135115 TI - Effectiveness and safety profile of ipilimumab therapy in previously treated patients with unresectable or metastatic melanoma - the Romanian Patient Access Program. AB - PURPOSE: The Romanian Patient Access Program (Ro-PAP, CA 184-427), part of the European Expanded Access Program (EAP), was developed to evaluate the effectiveness and safety profile ipilimumab in previously treated patients with advanced melanoma (unresectable or metastatic melanoma). The objective of our retrospective observational study of patients included in this program was to provide data recorded in real-life settings. METHODS: We analysed 89 patients enrolled in Ro-PAP, CA 184-427 (54 men and 35 women) aged between 29 and 89 years. The patients received ipilimumab 3mg/kg, administered with short 30-min i.v. infusion every 3 weeks, having a total of 4 doses. Patients were assessed for tumor response, overall survival (OS) and progression-free survival (PFS), and were monitored for adverse events (AE). RESULTS: At 12 weeks after the completion of therapy, the complete and partial response rates were 6.74% each, stable disease 15.73%, with the best overall response rate 13.48% and disease control rate 29.21%. Median OS was 189.00 days (95% CI 69.50-308.49) and median PFS 124.00 days (95% CI 85.05-162.94). The level of patient functionality at the beginning of ipilimumab treatment showed to be an important predictor of outcome, as patients with ECOG performance status (PS) (0) before therapy with ipilimumab had a higher OS compared with those with impaired functionality. CONCLUSIONS: The use of ipilimumab in daily clinical practice demonstrated to be effective and safe, consistent with data coming from randomized clinical trials or other observational studies. PMID- 29135116 TI - Serum S100B levels correlate with stage, N status, mitotic rate and disease outcome in melanoma patients independent to LDH. AB - PURPOSE: S100B protein is currently used as an immunohistochemistry marker to confirm melanoma diagnosis in biopsy specimens. Moreover, accumulating evidence supports its potential use as a tumor biomarker in blood. This study aimed to explore the potential uses of serum S100B protein as a biomarker in melanoma patients. METHODS: From 2012 to 2015, 107 sequential patients were diagnosed and treated for melanoma. All patients were tested for serum S100B and lactate dehydrogenase (LDH) at diagnosis and during their regular follow-up. Potential correlations between S100B serum levels and baseline characteristics and its impact on survival were assessed. RESULTS: S100B serum levels were within normal limits in patients with stages I and II, elevated in stage III, and very high in stage IV. In bivariate analysis, serum S100B levels >0.11MUg/l and stage IV were the only independent prognostic factors associated with poor survival. Furthermore, S100B >0.5MUg/l was associated with stage IV and poor survival. However, there was no significant association with LDH. S100B serum levels were positively correlated with mitotic rate (p=0.003), but only in stage IV patients (p=0.015). In stage III, a statistically significant difference in S100B serum levels were observed between N3, N2 and N1 stages, with higher levels for N2 (p=0.012) and N3 (p=0.009) compared to N1, and no difference between stages N2 and N3 (p=1.000). Also, no correlation was found between the number of primary melanoma lesions and S100B. CONCLUSIONS: S100B serum levels reflect tumor load, correlate with response to treatment, might identify patients who are at increased risk of disease relapse, may predict prognosis independent to LDH, and could be used as early biomarkers of tumor recurrence. PMID- 29135117 TI - What is the connection between serum phosphorus, cancer and heroin? A medical hypothesis based on observational studies. AB - Considering the results of a previous study in which 2321 regular heroin addicts who died without having stopped taking the drug since they had started - from various causes but none from cancer, may mean something. Our first thought was: Can't we hypothesize, reinforcing our previous view that heroin is a "barrier" against cancer and as the user gets in the methadone program he/she lacks the "barrier" and therefore is liable to develop cancer? We have already reported that the amount of blood phosphorus in heroin addicted is significantly lower than in healthy ones. Additionally we have introduced the potential clinical impact of serum phosphorus as a screening test for cancer. Phosphorus regulated by heroin might be the key for preventing the development of cancer in human organism, in terms of keeping the phosphorus in normal levels in the blood. Cases of cancer patients after methadone detox treatment are reported. In the present study, in 200 cancer patients who underwent radical radiotherapy (RT), the phosphorus level is generally returning to normal levels three months postirradiation. Phosphorus and cancer seem to be significantly associated, with heroin adapting phosphorus in normal values. The pharmaceutical companies should look deep inside the molecule of heroin, by means of an analogue with the potential impact against cancer but without the addictive effect to humans. It's obvious that further research is needed to obtain reliable statistical data. PMID- 29135118 TI - The impact of dose matrix and voxel dimensions to dose calculation for stereotactic radiosurgery. AB - PURPOSE: The purpose of the present study was the optimization of dose calculation for intracranial stereotactic radiosurgery. METHODS: We evaluated the Singular Value Decomposition (SVD) analysis as a novel optimization technique. Our approach to dose distribution optimization was to recover estimates of minibeams weights from well-defined provisional dose matrices. The dose delivered by a set of minibeams is formulated as a matrix equation. We studied the influence of dose matrix and voxel dimensions on the conditioning of stereotactic radiotherapy inverse problem. Dose matrix dimensions varied from 16 to 96 mm3, while voxel dimension was kept constant at 2 mm3. In the assessment of voxel dimension, matrix dimension was kept constant at 80 mm3 while voxel dimensions varied from 1 to 8 mm3. The reconstruction of dose distributions was studied using a truncated SVD expansion in the calculation of approximation to the generalised matrix inverse. RESULTS: The conditioning was deteriorated by either the decreasing of dose matrix dimensions or by the increasing of voxel size. The condition number was equal to 89*103 and 7*103 for the 16 mm3 and 96 mm3 dose matrix dimensions, respectively. The condition number was equal to 9.9*103 and to 2.7*106 for 1 mm3 and 8 mm3 voxel size, respectively. The reconstruction of dose distributions revealed that an ill-conditioned problem yields poor quality reconstruction. CONCLUSION: We considered that a good compromise between quality of dose distribution, time calculation and hard disk memory would be the use of a 64 mm3 matrix dimension with a 2 mm3 voxel size. PMID- 29135120 TI - Immunohistochemical study of cyclin A and p16 expression in patients with renal cell carcinoma. AB - PURPOSE: Renal cell carcinoma (RCC) is the most common malignant kidney tumor in adults. Dysregulation of the cell cycle can lead to cancer development. In this study, the mitosis-associated cyclin A and p16, a negative controller, were investigated as potential key points in the RCC development. METHODS: This retrospective study included 74 patients with RCC. The expression of cyclin A and p16 and their correlation to histopathological parameters (TNM stage, histological subtype, nuclear grade, tumor size), gender, age, and clinical outcome were studied and analyzed. RESULTS: The highest median value for cyclin A (40%; range 0-70)) and for p16 (57.5%); range 35-80) were found in the papillary histological subtype. Survival analysis showed that in the group of patients that had died before September 2015, the median value for cyclin A was 20% (range 0 60), which was significantly higher than 5% (range 0-70), found in the group of patients that survived (p=0.019). CONCLUSIONS: In relation to the histological subtype, the papillary type of RCC was associated with a significantly higher expression of cyclin A and p16 compared to other subtypes of RCC. High expression of cyclin A indicated worse prognosis, therefore cyclin A could be considered to be a significant prognostic marker. PMID- 29135119 TI - Expression and significance of ARID1A mRNA in endometriosis- associated ovarian cancer. AB - PURPOSE: To investigate the expression and relevant clinical and pathological significance of AT-rich interactive domaincontaining protein 1A (ARID1A) mRNA in endometriosis-associated ovarian cancer. METHODS: The clinical and pathological data of 63 patients with ovarian clear cell carcinoma (OCCC) and of 43 patients with ovarian endometrioid adenocarcinoma (OEAC) were collected. The expression of ARID1A-encoded protein, baf250a, in ovarian cancer tissues was detected using immunohistochemistry. The ARID1A mRNA expression was detected via RNAscope hybridization in situ, and its correlation with the clinical and pathological features of patients was analyzed. RESULTS: The age at the onset of OEAC patients accompanied with endometriosis (CM-EAC) was lower than that of those not accompanied with endometriosis (NCM-EAC) (p<0.001). For patients with OCCC, the lymph node metastasis (LNM) rate of CM-CCC patients was significantly lower compared to NCM-CCC (p=0.02) and FIGO stage was earlier (stage I and II) (p=0.013). The expression of baf250a in OCCC group was significantly lower than that in the EAC group (p=0.033). In the OCCC group, baf250a was significantly related to early FIGO staging (stage I and II) (p=0.026), while its expression was not significantly associated with FIGO staging of EAC, age, tumor size, occurrence site and LND. The mRNA expression of ARID1A was positively correlated with the expression of baf250a (in OCCC group, rp=0.936, p<0.01; in OEAC group, rp=0.325, p=0.035). Analysis of prognosis showed that baf250a was an important prognostic factor rather than an independent prognostic factor, affecting the overall survival (OS) of patients with OCCC, while patients with low ARID1A mRNA expression had a longer-term OS. CONCLUSION: The decreased gene and protein expression levels of ARID1A are related to the occurrence and development of endometriosis-associated ovarian cancer, especially OCCC. The detection of ARID1A mRNA expression may be used to predict the OS of OCCC. PMID- 29135121 TI - Hepcidin and iron metabolism in the pathogenesis of prostate cancer. AB - PURPOSE: To investigate the relationship between Hepcidin and iron metabolism, and cell proliferation, migration, and apoptosis in prostate cancer cells. METHODS: PC3 prostate cancer cells were cultured in vitro and divided into the control group, Hepcidin overexpression group, and Hepcidin low expression group. Prostate specific antigen (PSA) and soluble transferrin receptor (sTfR) levels were measured by ELISA. The levels of the Hepcidin receptor membrane transporter, Ferroportin, were determined by Western blot. The intracellular iron distribution was determined by immunofluorescence assay. The cell proliferation rate was determined by MTT assay. Cell migration was measured by wound healing assay. Apoptosis was measured by flow cytometry. RESULTS: Compared with the control group, higher PSA level (p<0.05), lower sTfR level (p<0.05), lower Ferroportin level (p<0.05), lower intracellular iron level (p<0.05), higher cell proliferation and migration rate, and lower apoptotic rate (p<0.05) were found in the Hepcidin overexpression group. The opposite results were found in the Hepcidin low expression group. CONCLUSIONS: Hepcidin is highly expressed in prostate cancer cells, and can regulate cell proliferation, migration, and apoptosis by increasing intracellular iron transportation. PMID- 29135122 TI - The role of the multidisciplinary team in the decision making process in stage one testicular cancer - retrospective cohort analysis. AB - PURPOSE: To analyze the role of a multidisciplinary team (MDT) in the decision making process in clinical stage one (CS I) testicular cancer (TC). METHODS: We retrospectively evaluated data on 115 consecutive patients with CS I TC (excluding stage IS) who were referred to the Department of Oncology, University Hospital of Split, Croatia, from 2003 to 2012. Fifty-six patients (48.7%) were referred between 2003 and 2007, before the introduction of the MDT and 59 patients (51.3%) between 2008 and 2012, after the introduction of the MDT. We evaluated the overall treatment outcome (cure rate) and the total number of patients with CS I TC who were treated or monitored: in seminoma (SA) group adjuvant radiotherapy (ART) vs adjuvant chemotherapy (ACT) or active surveillance (AS) and in non-seminoma (NSA) group retroperitoneal lymphadenectomy (RPLND) vs ACT or AS. RESULTS: After the introduction of the MDT we stopped using ART for CS I SA, and significantly increased the usage of ACT and AS (p<0.001). RPLND in CS I NSA was used significantly less often after the introduction of the MDT while the usage of ACT and AS increased (p=0.047). CONCLUSION: With the MDT introduction we significantly changed the approach to patients with CS I TC. More aggressive and more toxic forms of the postoperative treatment were replaced by AS or less toxic ACT. Despite less aggressive adjuvant treatment approach, significant changes in the cure rate between two time periods were not noticed. PMID- 29135123 TI - Hepatobiliary and pancreatic procedures during cytoreductive surgery and HIPEC. AB - PURPOSE: The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been used as locoregional treatment in selected patients with peritoneal malignancy. The purpose of this study was to report on the outcomes of patients undergoing hepatobiliary and pancreatic procedures during CRS and HIPEC. METHODS: A prospectively maintained database was used to identify patients that underwent hepatobilliary and/or pancreatic procedures during CRS and HIPEC. Outcome variables included morbidity, 30-day or in-hospital mortality, return to operating theatre, and complications. RESULTS: Sixty eight patients were included in the study, in whom 67 hepatobiliary and 15 pancreatic procedures were performed. Complete cytoreduction (CC-0/1) was achieved in 64 patients (94.8%). Twelve patients underwent liver resections, 50 underwent resection of Glisson's capsule, 5 underwent procedures of the biliary tree and 15 patients underwent pancreatic procedures. Major complications were encountered in 30/68 patients (44.1%). Pancreatic fistulas (PFs) were observed in 42.8% of the patients that underwent distal pancreatectomy. Reoperation rate was 8.8%, while 2.9% of the patients died during their hospital stay. CONCLUSION: The need for hepatobiliary procedures bears a significant - but acceptable - rate of morbidity. However, it should not represent a definitive contraindication for CRS and HIPEC. PMID- 29135124 TI - Are male cancer patients more affected by losing their jobs than female patients? Gender as a moderator of the relationship between losing the job and well-being in a sample of Romanian cancer patients. AB - PURPOSE: Research indicates the heightened need of cancer patients to return to work, which would be beneficial for their emotional/mental health and well-being. The major aim of this study was to identify the overall effect of losing the job upon different dimensions of well-being, and possible gender differences related to this influence. METHODS: A sample of 800 Romanian cancer patients was screened in 2014 (461 female and 338 male). RESULTS: Our results indicate that losing one's job after being diagnosed with cancer affects male more than female patients on the physical, emotional, and functional dimensions of well-being. Furthermore, male patients perceive a higher level of interference between illness/treatment and paid work than female patients, and perceive themselves less able to work than female cancer patients. Also the fulfillment derived from work perceived by male patients is lower than that of female cancer patients. CONCLUSION: Counselors and therapists should focus on enlarging the patients' pool of alternative sources of meaning, thus enhancing their well-being and implicitly their clinical recovery. PMID- 29135125 TI - Follicle-stimulating hormone receptors: a new immunohistochemical marker in cancers? AB - PURPOSE: Follicle-stimulating hormone receptors (FSHR) have been reported in ovarian cancer and prostate cancer cells, but recent studies have highlighted their presence in the endothelium of blood vessels belonging to multiple neoplasias. Current research attempts to determine the role of FSHR in neoplastic proliferation and possible therapeutic or diagnostic implications. This paper aimed to analyze articles that have revealed the presence and/or role of FSHR in various neoplasms in humans. METHODS: After performing an extensive search of MEDLINE/ PubMed using MeSH terms "follicle-stimulating hormone receptors" and "cancer", 22 original articles were found relevant for the subject proposed for analysis. RESULTS: FSHR were found in all neoplasms studied, being present in both tumor cells and endothelial cells of intraand perineoplasic blood vessels. Although, the presence of these receptors seemed to be ubiquitary, conclusion and the exact role of these receptors could not be stated due to heterogeneous nature of the existing studies. CONCLUSIONS: Although extensive research studies are needed in order to elucidate the exact role of FSHRs and their utility in clinical practice, joint efforts in studying their implication in neoplastic processes can lead to the use of new diagnostic and therapeutic strategies for cancer patients. PMID- 29135127 TI - Is switching to tamoxifen the only choice of treatment for improving aromatase inhibitor toxicity? PMID- 29135126 TI - Unusual clinical features of cutaneous tuberculosis in a patient with myelodyplastic syndrome: Late complication of intravesical instillation of Bacillus Calmette- Guerin vaccine. PMID- 29135128 TI - IGF/IGFR and diabetes mellitus in head and neck squamous cell carcinoma patients. PMID- 29135129 TI - Do systemic recurrences increase after the use of scalp cooling in patients treated for breast cancer with chemotherapy? PMID- 29135131 TI - Risk factors for development of breast cancer in premenopausal women with atypical ductal hyperplasia are more complicated. PMID- 29135130 TI - The struggle for intensive care coverage of patients with hepatobiliary malignancies in Greece: Patients are not numbers. PMID- 29135132 TI - "The moon on the water": a characteristic ultrasonographic appearance of testicular lymphoma. PMID- 29135133 TI - The link between obesity and triple negative breast cancer. PMID- 29135134 TI - Treating the incurables: Cancer asylums in 18th and 19th century. AB - For centuries several hypotheses were formulated on cancer's pathogenesis such as contagiousness, melancholy, heredity and sexuality. In the 18th and 19th century, despite the advent of medical thought and practice, cancer was considered an incurable and contagious disease. Hospitals were refusing to treat cancer patients while the social stigma which followed the disease made primordial the need for the establishment of special institutions. In our article we will present the cancer asylums which counterbalanced the prejudices of the time and contributed to the establishment of modern cancer hospitals. PMID- 29135135 TI - [Ultrasound indicators of the prostate, urinary bladder and uroflowmetry parameters in the diagnosis of infravesical obstruction in men with benign prostatic hyperplasia]. AB - RELEVANCE: Benign prostatic hyperplasia (BPH) is one of the most common urologic diseases of males. In patients who failed drug therapy of lower urinary tract symptoms (LUTS) caused by BPH, the most important indication for surgery is the presence of infravesical obstruction (IVO). IVO is detected by pressure-flow studies and is characterized by high detrusor pressure with decreased urinary flow rate. The invasiveness and high cost of this investigation has stimulated a search for non-invasive techniques that could reliably characterize the presence of IVO secondary to BPH. AIM: To determine the value of ultrasound indicators of the prostate, urinary bladder and uroflowmetry parameters in the diagnosis of IVO in men with BPH. MATERIALS AND METHODS: Seventy-six men with moderate and severe LUTS secondary to BPH underwent a comprehensive urological examination, including a clinical history, digital rectal examination, International Prostate Symptom Score (I-PSS), serum prostate-specific antigen (PSA), various ultrasound indicators of the prostate and urinary bladder, uroflowmetry and a pressure/flow study. RESULTS: Infravesical obstruction (IVO) was detected in 73.1% of men with BPH. IVO was found to have the strongest correlation with ultrasound signs of the intravesical prostatic protrusion (IPP, r = 0,667, p <0,05) compared with the prostate volume, prostate transition zone volume, prostate transition zone index, prostatic urethral angle, urethral length of the transition zone, estimated prostate circumference, prostate peripheral zone thickness, residual urine volume, weight of urinary bladder, the thickness of the detrusor, maximum and average urine flow rates and I-PSS score. The incidence of IVO increased in parallel with the increase of IPP. We established a cut-off value for IPP of 10 mm for the diagnosis of IVO with a sensitivity of 68.2%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 53.3%. CONCLUSION: The ultrasound findings of IPP measuring more than 10 mm strongly correlates with the IVO in men with LUTS and BPH as compared with other ultrasound parameters of the prostate, urinary bladder and urinary flow rates. The IPP is anatomical parameter that do not require urination, and is easily detected by both transabdominal and transrectal ultrasound. However, at the PPI values less than 10 mm, the main method for detecting IVO remains the pressure/ flow study. PMID- 29135136 TI - [Structural-morphological changes of the connective tissue of the vaginal mucosa and perineal skin in women with stress urinary incontinence]. AB - AIM: To investigate the morphological and structural changes in the connective tissue of the vaginal mucosa and perineal skin in women with stress urinary incontinence. MATERIALS AND METHODS: From 2010 to 2013, 71 patients of reproductive age with stress incontinence were observed. The control group comprised 80 women, who also underwent biopsy of the vaginal mucosa and perineal skin. The sections of specimens were stained by Van Gieson, Mallory and Weigert. In immunohistochemical studies, rabbit antibodies specific for collagen types I, III, and IV were placed on each section. RESULTS: Morphological picture of the perineal skin the study group patients completely confirms the clinical manifestations and results of immunohistochemical test, broadens the notion of structural changes in tissues. According to immunohistochemical and histological examination of the vaginal mucosa, some fibrous elements in the lamina were weakly stained. Due to the decrease in the number of vessels and the destruction of their basal membranes and the basal membrane of the epithelial layer, the amount of type IV collagen was markedly reduced. DISCUSSION: Elastic fibers in the vaginal mucosa and skin of the perineum together with the collagen fibers are the supporting framework of the skin, and together with the interstitial substance of the above authorities lend elasticity in tension. Studies have shown that stress urinary incontinence may be the result of dysregulation of processes. For this pathology in the lamina propria of the vaginal mucosa and dermal lamina of the skin of the perineum destroyed elastic fibers and changes the ratio of collagen of various types. That is, the predominant type III collagen is type I collagen, as well as in the basal membranes, reduced the number of specific collagen type IV. CONCLUSION: Mucous membrane of the vagina and perineal skin in women with a stress urinary incontinence is found to exhibit marked pathomorphological changes due to inflammatory, destructive and compensatory adaptive processes leading to scarring of the connective tissue and alteration in the ratio of collagen content in various tissues. PMID- 29135137 TI - [Renal function after laparoscopic partial nephrectomy with superselective balloon embolization of renal artery]. AB - AIM: To evaluate the functional state of the renal parenchyma after partial nephrectomy, depending on surgical technique. MATERIALS AND METHODS: The study comprised 21 patients with kidney neoplasms of stage T1-2N0M0. The patients underwent either laparoscopic partial nephrectomy with superselective balloon embolization of the renal artery (study group, n=11), or partial nephrectomy with vascular clamping (control group, n=10). The mean age of the patients in the study group (3 men and 8 women) was 56.8 years. The tumor was located in the right kidney in 5 patients and in the left kidney in 6 patients. The size of the neoplasm ranged from 0.9 to 3.8 cm, averaging 1.9 cm. The complexity of the surgery was evaluated using R.E.N.A.L. Nephrometry Scoring System based on MSCT findings. The mean nephrometry score was 5.1, which corresponds to low complexity of the intervention. Patients of the control group underwent partial nephrectomy with vascular clamping and renal ischemia time of no more than 20 minutes. The mean age of the control group patients was 57.3 years. The tumor was located in the right kidney in 4 patients and in the left kidney in 6 patients. The tumor size ranged from 1 to 4.1 cm, averaging 2.2 cm. The mean nephrometry score based on MSCT findings was 6.1. In both groups, the difference in creatinine clearance between the operated and intact kidney was estimated before the operation and in the early postoperative period to assess the changes in glomerular filtration. RESULTS AND DISCUSSION: The level of serum creatinine remained within the normal range throughout the study period in both groups. In the postoperative period, the creatinine clearance of the operated kidneys showed 1.02-fold decrease after super selective embolization and 1.92-fold decrease after vascular clamping. The 1-minute diuresis of the operated kidney decreased by 83.21% and 43.53% after vascular clamping and embolization, respectively. CONCLUSION: The studys findings show there was no significant dysfunction of operated kidneys after superselective balloon embolization of the renal artery. PMID- 29135138 TI - [Laparoscopic radical cystectomy: innovations and classics]. AB - INTRODUCTION: Radical cystectomy remains the gold-standard treatment for muscle invasive bladder cancer. To combine the advantages of minimally invasive interventions and the well-established open surgery, we attempted to reproduce as accurately as possible the technique of open radical cystectomy using a laparoscopic procedure. MATERIALS AND METHODS: The study comprised 35 patients (27 men and 8 women) with invasive bladder cancer who underwent laparoscopic radical cystectomy (LRC) between April 2013 and March 2016. The study included only patients with fully intra-corporal ileum conduits. RESULTS: The operating time averaged 378 min., the mean blood loss was 285 ml, the mean postoperative hospital stay was 12.4 days. Only 20% of patients needed postoperative opioid analgesia. Postoperative complications occurred in 11.4% of patients. The vast majority of them were successfully managed by minimally invasive methods. CONCLUSION: Laparoscopic radical cystectomy is a safe and effective treatment modality for invasive bladder cancer. However, more patients and a longer observation period are needed to recommend the method as a standard of care. PMID- 29135139 TI - [Laparoscopic transperitoneal adrenalectomy]. AB - AIM: To analyze the results of laparoscopic adrenalectomy (LAE) in patients with adrenal gland tumors. MATERIALS AND METHODS: From 2011 to 2016, 24 patients (15 men, 9 women), mean age 49.6 +/- 8.2 years, underwent LAE. The right, left and bilateral LAE was performed in 12, 10 and 2 patients, respectively. Indications for surgery were mainly primary and metastatic adrenal tumors. The operations were performed using a transperitoneal 4-port approach. RESULTS: Twenty six LAE were successfully performed in 24 patients. There were no conversions. Blood transfusion was used only in 1 patient, who had a history of the laparoscopic left nephrectomy for the renal cell carcinoma 2 years earlier. She had bleeding due to a spleen injury during the left LAE. She also developed acute postoperative pancreatitis, resolved by conservative therapy. The mean intra- and postoperative blood loss was 160 (120-750) ml, the operative time was 135 (100 205) min, and the length of hospital stay was 4 (3-5) days. Histological examination revealed adenocarcinoma and adenoma in 20 (73.1%) and 6 (26.9%) removed adrenal glands, respectively. CONCLUSION: Laparoscopic adrenalectomy is an effective and safe surgical modality to treat patients with adrenal tumors. PMID- 29135140 TI - [General clinical and laboratory and instrumental characteristics of the chronic nonbapterial prostatite with the inflammatory component in men of the first period of mature age]. AB - AIM: To investigate the course of CNPIC in young men treated with general and local ozone therapy. MATERIALS AND METHODS: 306 patients underwent standard treatment concurrently with local and systemic ozone therapy. Clinical-laboratory and instrumental parameters were evaluated before and after treatment. In addition, the blood flow of the prostate, prostatic urethra and skin at the projection point of the prostate was studied. RESULTS: Standard treatment of CNPIC with the concurrent use of general and local ozone therapy resulted in a reduction of pain intensity and severity of dysuria, improvement of the sexual function and quality of life of men. There was an increase in blood flow in the arteries and veins of the prostate, a decrease in the prostate size and volume. The study findings showed an almost twofold decrease of the mean values of the CNPIC clinical index during treatment. In the prostate secretion, the leukocyte count decreased from 29.29+/-0.67 to 4.75+/-0.15. A statistically significant (p<0.001) decrease in all sizes of the prostate was observed: height (upper) from 40.99+/-0.22 to 39.13+/-0.21 mm, width (transverse dimension) from 41.94+/-0.21 to 39.94+/-0.22 mm, and thickness (anteroposterior size) from 30.52+/-0.20 to 29.15+/-0.18 mm. Prostate volume also decreased from 27.78+/-0.42 to 24.10+/-0.36 cm (p<0.001). PMID- 29135141 TI - [Effectiveness of Omnic and Omnic Ocas in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia (multi-center observing program)]. AB - AIM: To investigate the effectiveness and safety of six-month treatment course of Omnic and Omnic Ocas in patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) in a routine urology practice in Kazakhstan. DESIGN: This was a multicenter prospective observational program involving the collection of data from patients with LUTS caused by BPH, who received Omnic Ocas or Omnic as the first line treatment. MATERIALS AND METHODS: The program comprised 1513 patients with a verified diagnosis of LUTS/BPH, who received Omnic Ocas or Omnic (tamsulosin) administered by urologists at hospitals in the Republic of Kazakhstan. According to the program protocol, 1381 patients completed the study. The mean age of the patients was 63 years. The study program involved three follow-up visits: Visit 1 (baseline), during which the patient completed the IPSS questionnaire concerning urinary symptoms and quality of life. After that they underwent a baseline examination including maximum urinary flow rate (Qmax) measured by uroflowmetry, prostate volume determined by digital rectal examination and the serum PSA level. Visit 2 and Visits 3 were scheduled on average at three and six months after Visit 1, respectively, and aimed at assessing the treatment outcomes during the follow-up. RESULTS: During the 6 month treatment, patients of different age groups reported an improvement in the prostate symptom score (IPSS). The drug therapy was more effective in patients with a flow rate of <10 ml/s. There was a gradual decrease in the mean scores of both the storage and voiding I-PSS subscales. Uroflowmetry at six months showed a clinically significant increase in the urinary flow rate. Adverse events were reported by1.9% of patients. DISCUSSION: The study findings suggesting a significantly improved voiding function in all study participants with LUTS and BPH who received Omnic Ocas or Omnic (tamsulosin) (n=1381) indicate that: the groups "<55 years", "55-65 years" and ">65 years" showed a decrease in symptoms (the total IPSS score after 6-month treatment decreased by 41.6%), in feeling of incomplete emptying and the need to urinate more often than 2 hours after urination; there was less terminal dribbling. Therapy was well tolerated: adverse events were noted in 1.6% of patients. Thus, it can be concluded that Omnic and Omnic Ocas are effective in all age groups of patients with LUTS/BPH and have a favorable safety profile. CONCLUSION: The findings of this study suggest that Omnic and Omnic Ocas are highly effective in patients with LUTS/BPH of all age groups and have a favorable safety profile. PMID- 29135142 TI - [Investigation of serum cysteine concentration to monitor glomerular filtration rate for early diagnosis of acute kidney injury in patients with combined trauma]. AB - AIM: / To determine the early diagnostic criteria for acute kidney injury in patients with combined trauma using serum cystatin C as a biomarker in the diagnostic work-up of the affected patients. MATERIALS AND METHODS: / The study comprised 42 patients who suffered combined trauma from 2015 to 2016. Cystatin C level was measured in serum. Blood sampling was done on the 1st, 3rd, 7th, 14th day of the injury. The patients were predominantly men (80%). Renal function was tested by measuring the rate of filtration and reabsorption using the Reberg Tareev test. All patients were tested for the following parameters: serum and urine creatinine, 1-minute, 1-hour and 24-hour urine output, the rate of glomerular filtration and tubular reabsorption. RESULTS AND DISCUSSION: / Forty (95.3%) patients had normal Reberg-Tareev test values. In 2 (4.7%) patients Reberg-Tareev test results were below normal values, which was associated with the development of acute renal failure on the sixth or seventh day after trauma. The overwhelming majority of patients with combined trauma had a normal serum creatinine level (n=38). In 33 (78.6%) patients serum cystatin C level was more than 30 percent above normal values. Moreover, an increase in the cystatin C level was observed in the first 3 days, with a gradual decrease thereafter. The glomerular filtration rate, according to the Reberg-Tareev test was reduced only in 4 patients, but when the Hawk formula was used to calculate GFR, it was reduced in 33 patients. On the 3rd day after trauma, based on the increase in the serum cystatin level, 12 patients were found to have subclinical acute renal damage. At the same time, this group of patients had normal azotemia parameters. These findings suggest that measuring glomerular filtration rate using serum cystatin C has a greater accuracy in detecting latent renal dysfunction. PMID- 29135143 TI - [The effectiveness of Uroprofit in women with chronic cystitis]. AB - AIM: To evaluate the effectiveness of the biologically active dietary supplement Uroprofit in the comprehensive management of exacerbations of chronic recurrent cystitis in women. MATERIALS AND METHODS: We examined 40 women with chronic cystitis aged 20-68 years. All patients were allocated to receive either monotherapy with fosfomycin (Monural) (control group, n=20) or combination therapy with fosfomycin and biologically active dietary supplement Uroprofit (study group, n=20). The results were evaluated at 1 and 2 months after treatment initiation. All patients before and after treatment underwent diagnostic work-up including standard laboratory tests, uroflowmetry, cystometry, cystoscopy, and laser Doppler flowmetry to assess microcirculation. RESULTS: The patients of the study group showed faster improvement in clinical manifestations of the disease, laboratory indicators, the dynamics of the endoscopic pattern and had positive changes in the bladder mucosa microcirculation. DISCUSSION: Uroprofit produces an antimicrobial and anti-inflammatory effect, helps normalize urodynamics of the lower urinary tract, improves microcirculation in the bladder wall and reduces the risk of repeated relapses of chronic cystitis. CONCLUSION: Uroprofit could be recommended as a component of the comprehensive management of exacerbations of chronic recurrent cystitis in women and as the means of preventing relapses in disease-free periods. PMID- 29135145 TI - [Aesthetic criteria in surgical treatment of hypospadias in children]. AB - : Aesthetically acceptable cosmetic results of surgical correction of external genital organ defects are important for treatment evaluation along with well known criteria of good functional outcomes.The purpose of this study was to improve the results of treating children with hypospadias by improving the assessment of results and introducing multi-step correction modalities. MATERIALS AND METHODS: From 2013 to 2015, 476 patients with various forms of hypospadias were treated at the Department of Uroandrology of RCCH. The patients age ranged from 1 year to 17 years (mean age 3 years). All patients were divided into 3 groups depending on the form of hypospadias and type of treatment. They included patients with distal forms of hypospadias (group1, n=270), proximal forms (group 2, n=112) and patients with stem and penoscrotal hypospadias who underwent 3-6 operations before admission (group 3, n=94). RESULTS: The study evaluated both functional and cosmetic results. Cosmetic appearance was assessed using the HOPE scoring system [2]. Despite the difference in surgical methods used for all types of hypospadias, good cosmetic results have been achieved in the majority of patients (65%). Functional outcomes differed depending on the form of hypospadias. In primary patients with distal and proximal forms of hypospadias, good results were achieved in 96% and 77% of patients, respectively. At the same time, 72% of patients who underwent repeat interventions had good results, which is comparable to the group of primary patients with proximal forms. CONCLUSION: The results of treating patients after repeat/failed surgery confirm the high effectiveness of our surgical methods (the Bracka two-stage graft repair, buccal mucosa hypospadias repair, reconstruction with scrotal skin flaps, correction of scrotal transposition). Using the HOPE scoring system to assess cosmetic results helps motivate surgeons to achieve the best treatment results. PMID- 29135144 TI - [The use of ProstaDoz in patients with benign prostatic hyperplasia and coexistent high-grade prostatic intraepithelial neoplasia]. AB - INTRODUCTION: In recent years there has been an increasing interest in the drug treatment of benign prostatic hyperplasia (BPH) to improve the patients quality of life without surgical treatment. In this connection, phytotherapeutic drugs and biologically active dietary supplements (BADS), consisting of a combination of microelements, vitamins and plant extracts, have been increasingly used in addition to synthetic preparations. OBJECTIVE: To investigate the clinical effectiveness of dietary supplement ProstaDoz in the treatment of BPH with coexistent high-grade prostatic intraepithelial neoplasia (PIN). MATERIALS AND METHODS: The study group comprised 30 men with BPH and high-grade PIN who were diagnosed with primary biopsy and received ProstaDoz for three months. The control group included 18 patients with the same diagnosis who were treated with Tamsulosin. RESULTS: After a 3-month intake of the ProstaDoz, a statistically significant reduction was observed in symptom scores for BPH and the quality of life index by 18% (p<0.001) and 16.7% (p<0.001), respectively. The residual urine volume and total serum PSA decreased by 28.3% (p<0.001) and 46.8% (p<0.001), respectively. Unlike the control group, the rate of prostate cancer detection was 6.25 times lower in patients taking ProstaDoz, and 16% of them had lower grade PIN compared with baseline or no PIN at all. CONCLUSION: The findings suggest that using ProstaDoz in patients with BPH and high-grade PIN contributes to improving the quality of life (QoL) of patients and the regression of dysplasia. PMID- 29135147 TI - [Biomarkers of renal injury in contact ureteral lithotripsy]. AB - AIM: To optimize the transurethral endoscopic management of patients with ureterolithiasis by measuring biomarkers of renal parenchymal damage. MATERIALS AND METHODS: One hundred fifty-one patients with solitary ureteral stones were tested for levels of cystatin C, neutrophil gelatinase-associated lipocalin, 2 microglobulin and interleukin 18. RESULTS: An increase in the levels of markers of renal injury was observed both in the preoperative period and after CULT. Differences in the values of these indices depended on the timing of the CULT, the size and location of the stone and the type of lithotripter. CONCLUSIONS: All patients were found to have damage to the renal tubular system. The established critical values of the markers of renal injury in ureterolithiasis may be used as diagnostic criteria for renal injury. PMID- 29135148 TI - [Hemorrhagic complications of percutaneous interventions for nephrolithiasis]. AB - : Hemorrhagic complications are one of the major problems of percutaneous urolithiasis interventions. AIM: To investigate the incidence of hemorrhagic complications after percutaneous nephrolithotripsy. MATERIAL AND METHODS: This was a comparative analysis of 146 percutaneous nephrolithotripsies. The study group comprised 81 patients with stag horn nephrolithiasis; the rest of the patients were assigned to the control group. RESULTS: Both groups were comparable in age and sex (p>0.05). The body weight of the patients in the study group was statistically significantly higher than in the control group, amounting to 94.1+/ 15.4 and 68.3+/-9.6 kg, respectively (p<0.05), the body mass index in the study group averaged 45.9+/-7.6 kg/m2 versus 28.5+/-9.4 kg/m2 in the control group (p<0.05). 50.6% of the study group patients had urate urolithiasis. The blood loss depended on operative time and the number of accesses to the kidney. The incidence of hemorrhagic complications did not differ in both groups and was in the range of 16 to 16.9% (p> 0.05). Early hemorrhagic complications did not exceed Grade II, according to Clavien-Dindo classification. Anticoagulant and antiplatelet therapy did not increase the number of hemorrhagic complications. Arterial hypertension was the main risk factor for hemorrhagic complications. CONCLUSION: Arterial hypertension in patients scheduled for percutaneous nephrolithotripsy should be corrected. To stop ongoing renal bleeding, image guided endovascular interventions should be used. PMID- 29135149 TI - [Arterial priapism as a complication of a stab wound in the perianal area]. AB - The article describes a case of successful managenent of arterial priapism in a patient with a stab wound in the perianal area. Timely performed angiography revealed a pathological connection between a. Uretralis sinistra and spongy body. Disruption of the abnormal shunt resulted in immediate relief of erection with further preservation of erectile function. At the 3 and 6 months follow-up visits there were no signs of cavernous fibrosis or erectile dysfunction. The authors analyze the entire sequence of events in the management of the case, identify shortcomings, determine their significance and consider their prevention. The article is supplemented with a brief review of the literature on differential diagnosis of haemodynamic forms of priapism. PMID- 29135146 TI - [Laparoscopic heminephrureterectomy for duplex kidney in children]. AB - INTRODUCTION: Duplication of the upper urinary tract is one of the most common congenital urological anomalies. In patients with critically decreased or lost function of one of the renal segments, heminephrureterectomy is usually the treatment of choice. Until recently, this was an open surgery; in cases of complete removal of the ureter, an additional incision in the iliac region was required. Currently, heminephrureterectomy is increasingly performed laparoscopically. We report the experience in laparoscopic heminephrureterectomy (LHNUE) in 10 clinics in Russia and Belarus. Some of them have already used this technique for 10 years. AIM: The study aimed to to improve the treatment results in children with urodynamic dysfunction due to duplicated upper urinary tract. MATERIALS AND METHODS: We retrospectively analyzed medical records of 111 children treated from 2007 to 2016. There were 26 (23.4%) boys and 85 (76.6%) girls with mean age 44.6 months (from 2 to 170) at the time of surgery. All children included in the study had complete duplex kidneys, including 51 (45.9%) right-sided and 60 (54.1%) left-sided. All the children underwent LHNUE for a critical decrease or absence of function of the upper or lower segment of the duplex kidney caused by the following pathology: obstruction of the ureterovesical junction with the development of the megaureter of the upper ureteral segment in 57 (51.4%) patients; ureterocele in 28 (25.2%); extra-vesical ectopic ureter with urinary incontinence in 10 (9.0%) girls; high-grade UVR in 16 (14.4%) patients. RESULTS: There were no conversions in this series of patients. The mean operative time was 135 minutes (60-240 min.). All children included in the study were followed for 1 to 9 years after surgery. Complications occurred in 17 (15.3%) patients, of whom 12 (10.8%) required repeat surgery. In one patient with the loss of lower pole function, the treatment result was considered unsatisfactory. CONCLUSION: LHNUE for duplex kidney is performed by a few clinics and is still at the stage of development and accumulation of experience. Nevertheless, LHNUE, though an effective treatment modality, carries the risk of reducing or losing the function of the retained segment. PMID- 29135150 TI - [Chronic course of latent urogenital tuberculosis]. AB - This is a case report of an elderly patient with urogenital tuberculosis and concurrent tuberculosis of peripheral inguinal lymph nodes. The disease manifested by a fistulous form of inguinal lymphadenitis for 10 years and spread to the kidneys and genitals, but the patient did not seek medical attention. Changes on the glans penis prompted him to consult dermatovenereologist. Due to ineffective treatment and uncovering the scar in the inguinal area the patient was send to an anti-tuberculosis institution, where he was diagnosed with tuberculosis involving the kidneys, prostate, epididymis, penis, inguinal lymph nodes. The patient had a history of a contact with the patient with respiratory tuberculosis. Treatment with antituberculosis drugs produced a positive effect. PMID- 29135151 TI - [Case report of rare co-occurrence of renal cell carcinoma and crossed renal dystopia (L-shaped kidney)]. AB - L-shaped kidney refers to a rare anomaly of the relative kidney positioning. Due to low prevalence, the literature on the co-occurrence of this anomaly with malignancy is lacking. And, if the diagnosis of a renal anomaly does not present difficulties, if a tumor is detected in such a kidney, even MSCT does not always help differentiate a pelvic tumor from a tumor of the renal parenchyma spreading to the pelvicalyceal system. This has important implications for choosing an appropriate surgical strategy. A feature of the presented clinical observation is the co-occurrence of the rare anomaly of kidney position and locally advanced renal cell carcinoma spreading to the renal pelvis. Due to the massive spread of the tumor, an organ-sparing surgery was not feasible. Due to the suspicion of tumor spread to the renal pelvis, the patient underwent nephrureterectomy of the L-shaped kidney. Introduction to renoprival state with transfer to chronic hemodialysis became the only option to maintain homeostasis and extend the patients life. Histological examination revealed clear cell renal cell carcinoma with invasion of the pelvis and renal capsule, with no clear demarcation between the fused kidneys. PMID- 29135153 TI - [The evidence for the efficiency and safety of dapoxetine in treating premature ejaculation]. AB - The aim of the study is to assess the evidence on the efficacy and safety of dapoxetine in premature ejaculation (PE). The analysis includes results of randomized placebo-controlled trials, integrative reviews and one meta-analysis on the clinical efficacy and safety of dapoxetine. All studies have shown higher efficacy of dapoxetine in patients with PE compared with placebo. Its administration at a dosage of 30 and 60 mg results in an increase in the coitus duration up to approximately 3 and 3.5 minutes, respectively. The safety profile of dapoxetine allows using it in clinical practice. Dapoxetine is a novel and effective PE drug on the Russian market. PMID- 29135152 TI - [Masks of urogenital tuberculosis as the cause of diagnostic errors]. AB - Urogenital tuberculosis does not have pathognomonic symptoms, so diagnostic errors are quite common. This systematic review of literature was conducted to identify the causes and estimate the incidence of erroneous diagnoses. We critically evaluated some articles in which the authors describe observations of urogenital tuberculosis as rare and unusual because they never encountered this disease, but in fact that were typical manifestations of genitourinary tuberculosis. The authors analyzed and illustrated the features of urinary tuberculosis in patients with pulmonary tuberculosis, differential diagnosis of urogenital tuberculosis and kidney cancer and male genitourinary organs, described errors in the diagnosis of urethral, testicular, penile, prostatic and epididymal tuberculosis. Urolithiasis was described as a mask and concomitant disease of urogenital tuberculosis. Really rare forms of bladder tuberculosis as the cause of diagnostic errors are described. Examples of fatal outcomes of urogenital tuberculosis are given. The authors analyzed cases of granulomatous interstitial nephritis due to tuberculosis infection and tuberculosis of the renal artery as the cause of renovascular hypertension. The most common causes of late diagnosis of urogenital tuberculosis are the absence of a typical pattern and the tendency to manifest under the guise of other diseases. PMID- 29135154 TI - [Age-related androgen deficiency. The current state of the problem]. AB - This paper reviews the modern concept of age-related androgen deficiency. The authors discuss the prevalence of androgen deficiency and its relationship with age, concomitant diseases, pharmacotherapy and other factors. PMID- 29135155 TI - [Laser therapy for male infertility. Part 1. Etiology and pathogenesis. experimental studies]. AB - Male infertility is associated with a wide range of pathological conditions affecting both the sexual and other body systems: endocrine, nervous, blood, and immune. Laser therapy is a form of modern physiotherapy that applies low intensity laser radiation in various parts of the body. It is widely used in all areas of modern medicine due to its high efficiency, ease of use, the absence of contraindications and side effects. The authors reviewed the results of 171 studies investigating laser therapy, of which 93 were experimental (20 in Russian and 73 international publications), 4 clinical and experimental (all in Russian), 74 clinical (73 in Russian and 1in English). Along with domestic literature, publications in Russian from Belarus, Georgia, Kyrgyzstan, Uzbekistan and Ukraine were studied. The article analyzes the experimental studies, somehow related to the problem of infertility and its treatment using low-intensity lasers. The analysis findings suggest that there are all prerequisites to develop a laser therapy as an effective modality for treating infertile men. PMID- 29135156 TI - [Isolated teratozoospermia: is there a role for antioxidant therapy?] AB - Recently, literature has emerged that offers contradictory findings of idiopathic forms of isolated teratozoospermia that may confuse clinicians. Some researchers argue that at 0-1% of normal forms of spermatozoa, morphology itself cannot be a prognostic indicator of fertility, either in the planning of natural pregnancy, or when used in assisted reproduction. In this connection, the possible causes of teratozoospermia and alternative therapies are being actively sought, in addition to known invasive and costly procedures. There is convincing evidence that reactive oxygen species overproduction is associated with the occurrence of abnormal spermatozoa in the ejaculate. An abnormal morphology can be accompanied by damage to the sperm DNA, impaired chromatin condensation, and associated unsuccessful pregnancy outcomes. Most of the studies show that using antioxidants results in positive changes. This literature review highlights the role of oxidative stress and DNA fragmentation in the formation of morphologically abnormal spermatozoa. The authors discuss drug interventions to treat teratozoospermia and present their own recommendations for antioxidant therapy in the clinical management of idiopathic forms of male infertility. PMID- 29135157 TI - [Calciuria as a metabolic marker for various conditions and diseases]. AB - The article analyzes the literature on the features of human calcium homeostasis. The authors describe the etiopathogenetic role of calcitropic hormones, the plasma and urine acid-base status, various ions, lifestyle and nutrition and other factors contributing to hypercalciuria due to increased intestinal absorption, bone resorption, impairment of tubular calcium reabsorption, etc. They discuss the role of calciuria as a factor in forming urinary calculi and present their own observations. PMID- 29135159 TI - [The role of the Randalls plaques in the pathogenesis of recurrent urolitasis]. AB - The aim of the work was to present current concept of the pathogenesis of urolithiasis. Treatment and prevention of this disease a challenging issue. The article presents basic information about Randalls plaques that are described as calcium salt deposits on the surface of the transitional cell epithelium. The cause of Randalls plaques was the subject of many studies and is still not completely clear. To date, we can state that the deposit formation starts in the pelvicalyceal system and is directly linked to recurrent urolithiasis. The discovery of Randall plaques in the 1940s transformed the conception of stone formation, but there are even more questions about the pathogenesis of urolithiasis. In that respect, we consider it important to analyze the studies on Randalls plaques. PMID- 29135158 TI - [The role of pharmacological preconditioning in renal ischemic and reperfusion injury]. AB - Renal ischemic and reperfusion injury resulting in acute renal failure is a multidisciplinary problem at the junction of pathophysiology, transplantology, urology, nephrology, cardiac surgery and pharmacology. One of renal protection strategies is using the phenomenon of preconditioning. Preconditioning is one of the ways to adopt a tissue to repeated short-term effects of damaging factors to induce an enhanced tolerance to the long period of hypoxia and/or ischemia. There are multiple cellular and molecular mechanisms of the renal protective effects of preconditioning stimuli, but the key effectors and signaling molecules are ATP dependent potassium channels, nitric oxide synthase, nitric oxide, and mitochondrial pore. Contradictory data on the protective effect of ischemic preconditioning allow searching for approaches to pharmacological correction of ischemic and reperfusion injuries. The article provides data on possible ways of using erythropoietin, darbepoetin and phosphodiesterase 5 inhibitors. PMID- 29135160 TI - [The role of urinary tract infection in the development of recurrent nephrolithiasis]. AB - This is a literature review on the role of microbial flora in the development of recurrent urolithiasis. The authors outline pathogenetic aspects of recurrent stone formation associated bacterial flora. A number of studies reported that standard urine culture has limited sensitivity in detecting urinary tract infection. PMID- 29135161 TI - Dr Dreier's method. PMID- 29135162 TI - ? PMID- 29135163 TI - Exercise-induced rhabdomyolysis - a patient series. AB - BACKGROUND: No guidelines are available for the treatment and follow up of exercise-induced rhabdomyolysis. The purpose of this study was to describe the treatment, complications and follow-up of patients with exercise-induced rhabdomyolysis at Diakonhjemmet Hospital. MATERIAL AND METHOD: A retrospective observational study from 2011 up to and including 2015 of patients with exercise induced rhabdomyolysis >= 18 years and with creatine kinase > 5 000 IU/l. RESULTS: We registered a total of 42 patients and obtained informed consent from 31. Twenty were treated as inpatients with a median hospitalisation time of 2.5 (1-6) days. Median creatine kinase was 36 797 (17 172-53 548) IU/l upon admission and 16 051 (11 845-26 505) IU/l at discharge. Median intravenous fluid volume was 6 000 (1 000-27 700) ml. Eleven patients underwent urinary alkalinisation. None developed severe kidney injury or other serious complications such as electrolyte imbalance, compartment syndrome or disseminated intravascular coagulation, either during hospitalisation or in the course of the study period. INTERPRETATION: Healthy persons with exercise-induced rhabdomyolysis have a very low risk of complications. Our patients are treated as outpatients or considered for discharge with creatine kinase < 40 000 IU/l measured at least three days after their workout, and if they have no risk factors or other complications. PMID- 29135165 TI - ? PMID- 29135164 TI - ? PMID- 29135166 TI - ? PMID- 29135167 TI - A young man with respiratory infection and facial rash. PMID- 29135168 TI - [New classification of epileptic seizures]. PMID- 29135169 TI - [MRI examination of patients with pacemakers or implanted defibrillators]. PMID- 29135170 TI - Chronically suicidal? PMID- 29135171 TI - Can we predict suicide? PMID- 29135172 TI - [Antibiotic resistance must be fought globally]. PMID- 29135173 TI - ? PMID- 29135174 TI - ? PMID- 29135175 TI - Chronic fatigue in adult cancer survivors. AB - Pronounced fatigue including tiredness and lack of energy are common both during and after cancer treatment. Between 15-35 % of adult cancer survivors experience chronic fatigue. Chronic fatigue has a negative impact on affected individuals' social, occupational and general functioning, and may lead to a considerably reduced quality of life. PMID- 29135176 TI - [Prescribe Dostoyevsky. Against guilt]. PMID- 29135177 TI - ? PMID- 29135178 TI - ? PMID- 29135179 TI - [The purpose of the trial lecture is still undermined]. PMID- 29135181 TI - ? PMID- 29135180 TI - [Diet and public health in a generational perspective]. PMID- 29135182 TI - ? PMID- 29135183 TI - ? PMID- 29135184 TI - ? PMID- 29135185 TI - ? PMID- 29135186 TI - ? PMID- 29135187 TI - [Ring sideroblasts]. PMID- 29135188 TI - ? PMID- 29135189 TI - ? PMID- 29135190 TI - ? PMID- 29135191 TI - [Real world data]. PMID- 29135192 TI - [How big is the effect?]. PMID- 29135193 TI - [Donders or Donders' method?]. PMID- 29135194 TI - ? PMID- 29135195 TI - ? PMID- 29135197 TI - Erratum PMID- 29135196 TI - Trans people are being let down by the Health Service. PMID- 29135198 TI - Lung Cancer Worry and Home Screening for Radon and Secondhand Smoke in Renters. AB - Lung cancer is largely preventable by eliminating tobacco smoke and radon exposure. This exploratory study assessed the relationships of demographic factors, including having one or more smokers living in the household, and a) lung cancer worry and b) completion of home screening for radon and secondhand smoke (SHS) among renters. A convenience sample of renters (N = 47) received free test kits for radon and SHS as part of a larger study. Demographic factors, lung cancer worry, and completion of home testing were assessed at baseline. The sample was mostly Caucasian (68%), female (62%), and educated beyond high school (70%). The average age was 43 years (SD = 15), and roughly half lived with at least one smoker (49%). Gender, race/ethnicity, education, and whether they had smokers in the home accounted for 35% of the variability in lung cancer worry, F(4, 42) = 5.6, p = .001. Lung cancer worry was associated with lower level of education, b = 0.77; SE(b) = 0.32, and having at least one smoker living in the home, b = 0.71; SE(b) = 0.31. Renters tested their homes for radon and SHS whether they had smokers in the home or not. Constructing and delivering educational messages that target low-educated populations may promote radon testing and smoke-free homes. PMID- 29135199 TI - The Effect of Inspection Announcement on the Outcome of Food Science Establishment Sanitary Health Evaluations. AB - This study evaluated whether a difference existed between one-hour and one-day notice on inspection announcements versus unannounced inspections on health inspection ratings of food establishments. Three hundred food establishments were randomly assigned into three sections of no announcement, one-hour announcement, or one-day announcement. Certified food inspectors performed routine inspections of these establishments for foodborne illness risk factors. Inspection results were analyzed using chi-square analysis. A significant interaction was found: those who had no notice were more likely to have an unsatisfactory outcome (4%) than establishments that had either one-hour or one-day notice (0%). One-hour notice did not result in a significant difference in outcome when compared with no notification. One-day notice did result in a significant difference in outcome when compared with no notification. This result suggests that one-hour notification is not a significant amount of time to impact the outcome of an inspection, but is sufficient to allow management to logistically prepare for an inspection and still maintain the objective of the inspection process. PMID- 29135200 TI - Overview of Silica-Related Clusters in the United States: Will Fracking Operations Become the Next Cluster? AB - Silicosis is the oldest know occupational pulmonary disease. It is a progressive disease and any level of exposure to respirable crystalline silica particles or dust has the potential to develop into silicosis. Silicosis is caused by silica particles or dust entering the lungs and damaging healthy lung tissue. The damage restricts the ability to breathe. Exposure to silica increases a worker's risk of developing cancer or tuberculosis. This special report will provide background history of silicosis in the U.S., including the number of workers affected and their common industries. Over the years, these industries have impeded government oversight, resulting in silicosis exposure clusters. The risk of acquiring silicosis is diminished when industry implements safety measures with oversight by governmental agencies. Reputable authorities believe that the current innovative drilling techniques such as fracking will generate future cases of silicosis in the U.S. if safety measures to protect workers are ignored. PMID- 29135201 TI - Building Capacity Through Public Health Headlines. PMID- 29135202 TI - Direct From CDC/EHSB: CDC Takes Action to Improve the Reporting of Environmental Assessment Data During Foodborne Illness Outbreak Investigations. PMID- 29135203 TI - JEH Quiz #4: Lung Cancer Worry and Home Screening for Radon and Secondhand Smoke in Renters. PMID- 29135204 TI - DirecTalk: Musings From the 10th Floor: Size Does Not Make a Profession. PMID- 29135205 TI - Multiple Dimensions of Private Information: Evidence from the Long-Term Care Insurance Market. AB - We demonstrate the existence of multiple dimensions of private information in the long-term care insurance market. Two types of people purchase insurance: individuals with private information that they are high risk and individuals with private information that they have strong taste for insurance. Ex post, the former are higher risk than insurance companies expect, while the latter are lower risk. In aggregate, those with more insurance are not higher risk. Our results demonstrate that insurance markets may suffer from asymmetric information even absent a positive correlation between insurance coverage and risk occurrence. The results also suggest a general test for asymmetric information. PMID- 29135206 TI - Taxes, Cigarette Consumption, and Smoking Intensity. AB - This paper analyses the compensatory behavior of smokers. Exploiting data on cotinine concentration--a metabolite of nicotine--measured in a large population of smokers over time, we show that smokers compensate for tax hikes by extracting more nicotine per cigarette. Our study makes two important contributions. First, as smoking a given cigarette more intensively is detrimental to health, our results question the usefulness of tax increases. Second, we develop a model of rational addiction where agents can also adjust their intensity of smoking, and we show that the previous empirical results suffer from estimation biases. PMID- 29135207 TI - Assessing the Impact of a School Subsidy Program in Mexico: Using a Social Experiment to Validate a Dynamic Behavioral Model of Child Schooling and Fertility. AB - This paper uses data from a randomized social experiment in Mexico to estimate and validate a dynamic behavioral model of parental decisions about fertility and child schooling, to evaluate the effects of the PROGRESA school subsidy program, and to perform a variety of counterfactual experiments of policy alternatives. Our method of validation estimates the model without using post-program data and then compares the model's predictions about program impacts to the experimental impact estimates. The results show that the model's predicted program impacts track the experimental results. Our analysis of counterfactual policies reveals an alternative subsidy schedule that would induce a greater impact on average school attainment at similar cost to the existing program. PMID- 29135208 TI - A Dual-Self Model of Impulse Control. AB - We propose that a simple "dual-self" model gives a unified explanation for several empirical regularities, including the apparent time inconsistency that has motivated models of quasi-hyperbolic discounting and Rabin's paradox of risk aversion in the large and small. The model also implies that self-control costs imply excess delay, as in the O'Donoghue and Rabin models of quasi-hyperbolic utility, and it explains experimental evidence that increased cognitive load makes temptations harder to resist. The base version of our model is consistent with the Gul-Pesendorfer axioms, but we argue that these axioms must be relaxed to account for the effect of cognitive load. PMID- 29135209 TI - Estimating the Effects of Global Patent Protection in Pharmaceuticals: A Case Study of Quinolones in India. AB - Under the Agreement on Trade-Related Intellectual Property Rights, the World Trade Organization members are required to enforce product patents for pharmaceuticals. In this paper we empirically investigate the welfare effects of this requirement on developing countries using data for the fluoroquinolones subsegment of the systemic anti-bacterials segment of the Indian pharmaceuticals market. Our results suggest that concerns about the potential adverse welfare effects of TRIPS may have some basis. We estimate that the withdrawal of all domestic products in this subsegment is associated with substantial welfare losses to the Indian economy, even in the presence of price regulation. The overwhelming portion of this welfare loss derives from the loss of consumer welfare. PMID- 29135210 TI - Why Do Poor Children Lose Health Insurance in the SCHIP Era? The Role of Family Health. PMID- 29135211 TI - Efficient Kidney Exchange: Coincidence of Wants in Markets with Compatibility Based Preferences. AB - Patients needing kidney transplants may have donors who cannot donate to them because of blood or tissue incompatibility. Incompatible patient-donor pairs can exchange donor kidneys with other pairs only when there is a "double coincidence of wants." Developing infrastructure to perform three-way as well as two-way exchanges will have a substantial effect on the number of transplants that can be arranged. Larger than three-way exchanges have less impact on efficiency. In a general model of type-compatible exchanges, the size of the largest exchanges required to achieve efficiency equals the number of types. PMID- 29135212 TI - Child Protection and Child Outcomes: Measuring the Effects of Foster Care. AB - Little is known about the effects of placing children who are abused or neglected into foster care. This paper uses the placement tendency of child protection investigators as an instrumental variable to identify causal effects of foster care on long-term outcomes--including juvenile delinquency, teen motherhood, and employment--among children in Illinois where a rotational assignment process effectively randomizes families to investigators. Large marginal treatment effect estimates suggest caution in the interpretation, but the results suggest that children on the margin of placement tend to have better outcomes when they remain at home, especially older children. PMID- 29135213 TI - Stress and Birth Weight: Evidence from Terrorist Attacks. PMID- 29135214 TI - The Relationship between Economic Status and Child Health: Evidence from the United States. PMID- 29135215 TI - Can Hepatitis B Mothers Account for the Number of Missing Women? Evidence from Three Million Newborns in Taiwan. PMID- 29135216 TI - Interfacial Molecular Packing Determines Exciton Dynamics in Molecular Heterostructures: The Case of Pentacene-Perfluoropentacene. AB - The great majority of electronic and optoelectronic devices depend on interfaces between p-type and n-type semiconductors. Finding matching donor-acceptor systems in molecular semiconductors remains a challenging endeavor because structurally compatible molecules may not necessarily be suitable with respect to their optical and electronic properties, and the large exciton binding energy in these materials may favor bound electron-hole pairs rather than free carriers or charge transfer at an interface. Regardless, interfacial charge-transfer exciton states are commonly considered as an intermediate step to achieve exciton dissociation. The formation efficiency and decay dynamics of such states will strongly depend on the molecular makeup of the interface, especially the relative alignment of donor and acceptor molecules. Structurally well-defined pentacene perfluoropentacene heterostructures of different molecular orientations are virtually ideal model systems to study the interrelation between molecular packing motifs at the interface and their electronic properties. Comparing the emission dynamics of the heterosystems and the corresponding unitary films enables accurate assignment of every observable emission signal in the heterosystems. These heterosystems feature two characteristic interface-specific luminescence channels at around 1.4 and 1.5 eV that are not observed in the unitary samples. Their emission strength strongly depends on the molecular alignment of the respective donor and acceptor molecules, emphasizing the importance of structural control for device construction. PMID- 29135217 TI - Vitamin C-Conjugated Nanoparticle Protects Cells from Oxidative Stress at Low Doses but Induces Oxidative Stress and Cell Death at High Doses. AB - Although the antioxidant property of vitamin C is well-known for protecting cells from oxidative stress, a recent study shows that it can also generate oxidative stress under a high intracellular concentration and induce cell death. However, poor chemical stability and low biological concentration (micromolar) of vitamin C restrict its function primarily as an antioxidant. Here, we report two different nanoparticle forms of vitamin C with its intact chemical stability, glucose-responsive release from nanoparticle, and efficient cell delivery in micro to millimolar concentrations. Nanoparticles are composed of silica-coated Au nanoparticles or lipophilic polyaspartic acid-based polymer micelles which are conjugated with vitamin C via phenylboronic acid. Surface chemistry of nanoparticles is optimized for an efficient cellular interaction/uptake and for cell delivery of vitamin C. We found that vitamin C protects cells from oxidative stress at micromolar concentrations, but at millimolar concentrations, it induces cell death by generating oxidative stress. In particular, high-dose vitamin C produces H2O2, disrupts the cellular redox balance, and induces cell death. This study highlights the concentration-dependent biological performance of vitamin C and the requirement of a high-dose cell delivery approach for enhanced therapeutic benefit. PMID- 29135218 TI - Enhanced Photocatalytic and Fenton-like Performance of CuOx-Decorated ZnFe2O4. AB - A series of CuOx-decorated ZnFe2O4 samples were prepared by a hydrothermal method and investigated as a catalyst for the photocatalytic and Fenton-like degradation of Orange II. The active species and catalyst active sites in the two processes were also studied. It was found that the introduced CuOx significantly enhanced the photocatalytic and Fenton-like performance of ZnFe2O4. Especially, ZnFe2O4 Cu3 prepared with the Cu/Zn ratio of 3:7 exhibited a very high Fenton-like activity in the pH range 5-9. The enhanced photocatalytic activity of ZnFe2O4-Cu3 could be because the formed ZnFe2O4/Cu2O heterojunction improved the separation efficiency of the photogenerated carriers. The photogenerated hole was responsible for Orange II degradation. As for the Fenton-like reaction, *O2- was the active species, and the surface =Cu2+ with a higher redox ability should be the active site for H2O2 activation despite its lower surface content than that of =Cu+, =Fe2+, and =Fe3+. Finally, a possible pathway for Orange II degradation was proposed according to the liquid chromatography-mass spectrometry result. PMID- 29135219 TI - Room-Temperature and Solution-Processable Cu-Doped Nickel Oxide Nanoparticles for Efficient Hole-Transport Layers of Flexible Large-Area Perovskite Solar Cells. AB - Flexible perovskite solar cells (PSCs) using plastic substrates have become one of the most attractive points in the field of thin-film solar cells. Low temperature and solution-processable nanoparticles (NPs) enable the fabrication of semiconductor thin films in a simple and low-cost approach to function as charge-selective layers in flexible PSCs. Here, we synthesized phase-pure p-type Cu-doped NiOx NPs with good electrical properties, which can be processed to smooth, pinhole-free, and efficient hole transport layers (HTLs) with large-area uniformity over a wide range of film thickness using a room-temperature solution processing technique. Such a high-quality inorganic HTL allows for the fabrication of flexible PSCs with an active area >1 cm2, which have a power conversion efficiency over 15.01% without hysteresis. Moreover, the Cu/NiOx NP based flexible devices also demonstrate excellent air stability and mechanical stability compared to their counterpart fabricated on the pristine NiOx films. This work will contribute to the evolution of upscaling flexible PSCs with a simple fabrication process and high device performances. PMID- 29135220 TI - Strong Influence of Ti Adhesion Layer on Electron-Phonon Relaxation in Thin Gold Films: Ab Initio Nonadiabatic Molecular Dynamics. AB - Electron-phonon relaxation in thin metal films is an important consideration for many ultrasmall devices and ultrafast applications. Recent time-resolved experiments demonstrate a significant, more than a factor of five, increase in the electron-phonon coupling and acceleration in the electron-phonon relaxation rate when a narrow Ti adhesion layer is introduced between an Au film and a nonmetal substrate. Using nonadiabatic molecular dynamics combined with real-time time-dependent density functional theory, we identify the reasons that give rise to this strong effect. First, the Ti layer greatly enhances the density of states (DOS) in the energy region starting at 1 eV below the Fermi level and extending several electronvolts above it. Second, Ti atoms are four times lighter than Au atoms and therefore generate larger nonadiabatic (NA) electron-phonon coupling. Because the transition rates depend on coupling and DOS, both the factors accelerate the dynamics. Showing good agreement with the experiments, the time domain atomistic simulations provide a detailed mechanistic understanding of the electron-phonon relaxation dynamics in thin gold films and related nanomaterials. PMID- 29135221 TI - Superhydrophobic, Low-Hysteresis Patterning Chemistry for Water-Drop Manipulation. AB - A method for preparing superhydrophobic surfaces containing guiding lines that control water motion is described. The background surfaces exhibit contact angles of thetaA/thetaR = 173 degrees /171 degrees , and the guiding lines are also hydrophobic (thetaA/thetaR = 104 degrees /102 degrees ). The low-contact-angle hysteresis allows facile water motion. The sequence of steps used to prepare these surfaces is central to their success, is designed to minimize defects, and involves only two inexpensive and fluorine-free reagents: methyltrichlorosilane and dimethyldichlorosilane. Examples of patterned surfaces that direct water motion are described. The disparity in receding contact angles is identified as the key parameter for guided motion. PMID- 29135222 TI - Engineering the Mechanical Properties of Polymer Networks with Precise Doping of Primary Defects. AB - Polymer networks are extensively utilized across numerous applications ranging from commodity superabsorbent polymers and coatings to high-performance microelectronics and biomaterials. For many applications, desirable properties are known; however, achieving them has been challenging. Additionally, the accurate prediction of elastic modulus has been a long-standing difficulty owing to the presence of loops. By tuning the prepolymer formulation through precise doping of monomers, specific primary network defects can be programmed into an elastomeric scaffold, without alteration of their resulting chemistry. The addition of these monomers that respond mechanically as primary defects is used both to understand their impact on the resulting mechanical properties of the materials and as a method to engineer the mechanical properties. Indeed, these materials exhibit identical bulk and surface chemistry, yet vastly different mechanical properties. Further, we have adapted the real elastic network theory (RENT) to the case of primary defects in the absence of loops, thus providing new insights into the mechanism for material strength and failure in polymer networks arising from primary network defects, and to accurately predict the elastic modulus of the polymer system. The versatility of the approach we describe and the fundamental knowledge gained from this study can lead to new advancements in the development of novel materials with precisely defined and predictable chemical, physical, and mechanical properties. PMID- 29135223 TI - Room-Temperature Synthesis of GaN Driven by Kinetic Energy beyond the Limit of Thermodynamics. AB - The nitridation reaction is significantly important to utilize the unique properties of nitrides and nitrogen-doped materials. However, nitridation generally requires a high temperature or highly reactive reagents (often explosive) because the energies of N-N bond cleavage and nitrogen anion formation (N3-) are very high. We demonstrate the first room-temperature synthesis of GaN directly from GaCl3 by nanoscale atom exchange reaction. Nonequilibrium nitrogen molecules with very high translational energy were used as a chemically stable and safe nitrogen source. The irradiation of molecular nitrogen to the desired reaction area successfully provided a gallium nitride (GaN) nanosheet that exhibited a typical photoluminescence spectrum. Because this process retains the target substrate room temperature and does not involve any photon nor charged ion, it allows damage-less synthesis of the semiconducting metal nitrides, even directly on plastic substrates such as polyethylene terephthalate (PET). PMID- 29135224 TI - Radiation-Responsive Esculin-Derived Molecular Gels as Signal Enhancers for Optical Imaging. AB - Recent interest in detecting visible photons that emanate from interactions of ionizing radiation (IR) with matter has spurred the development of multifunctional materials that amplify the optical signal from radiotracers. Tailored stimuli-responsive systems may be paired with diagnostic radionuclides to improve surgical guidance and aid in detecting therapeutic radionuclides otherwise difficult to image with conventional nuclear medicine approaches. Because light emanating from these interactions is typically low in intensity and blue-weighted (i.e., greatly scattered and absorbed in vivo), it is imperative to increase or shift the photon flux for improved detection. To address this challenge, a gel that is both scintillating and fluorescent is used to enhance the optical photon output in image mapping for cancer imaging. Tailoring biobased materials to synthesize thixotropic thermoreversible hydrogels (a minimum gelation concentration of 0.12 wt %) offers image-aiding systems which are not only functional but also potentially economical, safe, and environmentally friendly. These robust gels (0.66 wt %, ~900 Pa) respond predictably to different types of IRs including beta- and gamma-emitters, resulting in a doubling of the detectable photon flux from these emitters. The synthesis and formulation of such a gel are explored with a focus on its physicochemical and mechanical properties, before being utilized to enhance the visible photon flux from a panel of radionuclides as detected. The possibility of developing a topical cream of this gel makes this system an attractive potential alternative to current techniques, and the multifunctionality of the gelator may serve to inspire future next generation materials. PMID- 29135226 TI - Raman Deuterium Isotope Probing Reveals Microbial Metabolism at the Single-Cell Level. AB - We illustrate that single-cell Raman microspectroscopy, coupled with deuterium isotope probing (Raman-DIP), provides a culture-independent and nondestructive approach to probe metabolic pathways of carbon substrates at the single-cell level. We found a distinguishable C-D vibration band at 2070-2300 cm-1 in single cell Raman spectra (SCRS) when Escherichia coli used deuterated glucose and Pseudomonas sp. used deuterated naphthalene as sole carbon sources. The intensity of the C-D band is proportional to the extent of deuteration in the carbon source, and as little as 5% deuteration can be distinguished by analysis of SCRS. It suggests that Raman-DIP could be used to semiquantitatively and sensitively indicate the metabolism of deuterated carbon source in microbes. A lower lipid conversion rate of deuterated naphthalene compared to that of deuterated glucose was observed, presumably owing to different anabolic pathways and membrane alteration. Apart from the C-D band shift from C-H, SCRS also reveal several isotopic shifts of the phenylalanine band, of which the positions correlate well with a computational model. A reduction in phenylalanine deuteration in Pseudomonas sp. compared to that in E. coli is due to the dilution effect of different pathways of phenylalanine biosynthesis in Pseudomonas sp. Collectively, we demonstrate that Raman-DIP can not only indicate metabolic activity using deuterated carbon sources but also reveal different metabolic pathways by analyzing SCRS. By harnessing such low-cost and versatile deuterated substrates, Raman-DIP has the potential to probe a wide range of metabolic pathways and functions at the single-cell level. PMID- 29135225 TI - Regional Variations of Spontaneous, Transient Adenosine Release in Brain Slices. AB - Transient adenosine signaling has been recently discovered in vivo, where the concentration is on average 180 nM and the duration only 3-4 s. In order to rapidly screen different brain regions and mechanisms of formation and regulation, here we develop a rat brain slice model to study adenosine transients. The frequency, concentration, and duration of transient adenosine events were compared in the prefrontal cortex (PFC), hippocampus (CA1), and thalamus. Adenosine transients in the PFC were similar to those in vivo, with a concentration of 160 +/- 10 nM, and occurred frequently, averaging one every 50 +/- 5 s. In the thalamus, transients were infrequent, occurring every 280 +/- 40 s, and lower concentration (110 +/- 10 nM), but lasted twice as long as in the PFC. In the hippocampus, adenosine transients were less frequent than those in the PFC, occurring every 79 +/- 7 s, but the average concentration (240 +/- 20 nM) was significantly higher. Adenosine transients are largely maintained after applying 200 nM tetrodotoxin, implying they are not activity dependent. The response to adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) differed by region; DPCPX had no significant effects in the PFC, but increased the average transient concentration in the thalamus and both the transient frequency and concentration in the hippocampus. Thus, the amount of adenosine available to activate receptors, and the ability to upregulate adenosine signaling with DPCPX, varies by brain region. This is an important consideration for designing treatments that modulate adenosine in order to cause neuroprotective effects. PMID- 29135227 TI - Peptide Arrays: Development and Application. PMID- 29135228 TI - Influence of Relativistic Effects on Bonding Modes in M(II) Dinuclear Complexes (M = Au, Ag, and Cu). AB - The stability and bonding in dinuclear group 11 metal complexes (M = Au, Ag, and Cu) in their +2 oxidation state has been investigated by quantum chemical methods. Two model complexes were selected as representatives of different bonding situations in the dinuclear M(II) complexes, a direct metal-metal bond between two ligand stabilized monomers and ligand-mediated bridged dimer system, making them interesting for a direct comparison and to study the influence of relativistic effects. Relativity substantially stabilizes the direct metal-metal bonded system obtaining the sequence in M-M bond stability Au > Ag > Cu. In the ligand-bridged structure, an asymmetric bonding situation is obtained for gold, resulting in two stronger/covalent and two weaker/ionic bonds per gold atom. Here we observe the opposite trend in stability Cu > Ag > Au. Our analysis nicely corroborates with what is known from experimental observation. PMID- 29135229 TI - Effects of NH4+, K+, Mg2+, and Ca2+ on the Cesium Adsorption/Desorption in Binding Sites of Vermiculitized Biotite. AB - The reversibility of cesium adsorption in contaminated soil is largely dependent on its interaction with micaceous minerals, which may be greatly influenced by various cations. Herein, we systematically investigated the effects of NH4+, K+, Mg2+, and Ca2+ on the adsorption/desorption of Cs+ into different binding sites of vermiculitized biotite (VB). Original VB was initially saturated by NH4+, K+, or Mg2+; we then evaluated the adsorption of Cs+ on three treated VBs, and the desorption by extraction with NH4+, K+, Mg2+, or Ca2+ was further evaluated. Our structural analysis and Cs+ extractability determinations showed that NH4+ and K+ both collapsed the interlayers of VB, resulting in the dominant adsorption of Cs+ to external surface sites on which Cs+ was readily extracted by NH4+, K+, Mg2+, or Ca2+ irrespective of their species, whereas Mg2+ maintained the VB with expanded interlayers, leading to the overwhelming adsorption of Cs+ in collapsed interlayer sites on which the Cs+ desorption was difficult and varied significantly by the cations used in extraction. The order of Cs+ extraction ability from the collapsed interlayers was K+ ? Mg2+ ~ Ca2+ ? NH4+. These results could provide important insights into Cs migration in soil and its decontamination for soil remediation. PMID- 29135230 TI - Multidimensional Spectral Fingerprints of a New Family of Coherent Analytical Spectroscopies. AB - Triply resonant sum frequency (TRSF) and doubly vibrationally enhanced (DOVE) spectroscopies are examples of a recently developed family of coherent multidimensional spectroscopies (CMDS) that are analogous to multidimensional NMR and current analytical spectroscopies. CMDS methods are particularly promising for analytical applications because their inherent selectivity makes them applicable to complex samples. Like NMR, they are based on creating quantum mechanical superposition states that are fully coherent and lack intermediate quantum state populations that cause quenching or other relaxation effects. Instead of the nuclear spin states of NMR, their multidimensional spectral fingerprints result from creating quantum mechanical mixtures of vibrational and electronic states. Vibrational states provide spectral selectivity, and electronic states provide large signal enhancements. This paper presents the first electronically resonant DOVE spectra and demonstrates the capabilities for analytical chemistry applications by comparing electronically resonant TRSF and DOVE spectra with each other and with infrared absorption and resonance Raman spectra using a Styryl 9 M dye as a model system. The methods each use two infrared absorption transitions and a resonant Raman transition to create a coherent output beam, but they differ in how they access the vibrational and electronic states and the frequency of their output signal. Just as FTIR, UV-vis, Raman, and resonance Raman are complementary methods, TRSF and DOVE methods are complementary to coherent Raman methods such as coherent anti-Stokes Raman spectroscopy (CARS). PMID- 29135231 TI - Solid, Semisolid, and Liquid Phase States of Individual Submicrometer Particles Directly Probed Using Atomic Force Microscopy. AB - Currently, the impact of various phase states of aerosols on the climate is not well understood, especially for submicrometer sized aerosol particles that typically have extended lifetime in the atmosphere. This is largely due to the inherent size limitations present in current experimental techniques that aim to directly assess the phase states of fine aerosol particles. Herein we present a technique that uses atomic force microscopy to probe directly for the phase states of individual, submicrometer particles by using nanoindentation and nano Wilhelmy methodologies as a function of relative humidity (RH) and ambient temperature conditions. When using these methodologies for substrate deposited individual sucrose particles, Young's modulus and surface tension can be quantified as a function of RH. We show that the force profiles collected to measure Young's modulus and surface tension can also provide both qualitative and quantitative assessments of phase states that accompany solid, semisolid, and liquid particle phases. Specifically, we introduce direct measurements of relative indentation depth and viscoelastic response distance on a single particle basis at a given applied force to quantitatively probe for the phase state as a function of RH and corresponding viscosity. Thus, we show that the three phase states and phase state transitions of sucrose can be identified and ultimately propose that this technique may also be used to study other atmospherically relevant systems. PMID- 29135232 TI - Confocal Raman Microscopy for the Determination of Protein and Quaternary Ammonium Ion Loadings in Biocatalytic Membranes for Electrochemical Energy Conversion and Storage. AB - The need to immobilize active enzyme, while ensuring high rates of substrate turnover and electronic charge transfer with an electrode, is a centrally important challenge in the field of bioelectrocatalysis. In this work, we demonstrate the use of confocal Raman microscopy as a tool for quantitation and molecular-scale structural characterization of ionomers and proteins within biocatalytic membranes to aid in the development of energy efficient biofuel cells. A set of recently available short side chain Aquivion ionomers spanning a range of equivalent weight (EW) suitable for enzyme immobilization was investigated. Aquivion ionomers (790 EW, 830 EW and 980 EW) received in the proton-exchanged (SO3H) form were treated with tetra-n-butylammonium bromide (TBAB) to neutralize the ionomer and expand the size of ionic domains for enzyme incorporation. Through the use of confocal Raman microscopy, membrane TBA+ ion content was predicted in calibration studies to within a few percent of the conventional titrimetric method across the full range of TBA+: SO3- ratios of practical interest (0.1 to 1.7). Protein incorporation into membranes was quantified at the levels expected in biofuel cell electrodes. Furthermore, features associated with the catalytically active, enzyme-coordinated copper center were evident between 400 and 500 cm-1 in spectra of laccase catalytic membranes, demonstrating the potential to interrogate mechanistic chemistry at the enzyme active site of biocathodes under fuel cell reaction conditions. When benchmarked against the 1100 EW Nafion ionomer in glucose/air enzymatic fuel cells (EFCs), EFCs with laccase air-breathing cathodes prepared from TBA+ modified Aquivion ionomers were able to reach maximum power densities (Pmax) up to 1.5 times higher than EFCs constructed with cathodes prepared from TBA+ modified Nafion. The improved performance of EFCs containing the short side chain Aquivion ionomers relative to Nafion is traced to effects of ionomer ion-exchange capacity (IEC, where IEC = EW-1), where the greater density of SO3- moieties in the Aquivion materials produces an environment more favorable to mass transport and higher TBA+ concentrations. PMID- 29135233 TI - Time-Dependent Determination of Unbiased Selectivity Coefficients of Ion Selective Electrodes for Multivalent Ions. AB - A new method for the determination of unbiased low selectivity coefficients for two of the most prevalent cases of multivalent ions (zi = 2, zj = 1 and zi = 1, zj = 2) was theoretically and experimentally substantiated. The method is based on eliminating the primary ion concentration near the membrane by extrapolating the linearized time dependencies of selectivity coefficients determined by the separate solutions method (KijPot(SSM) as a function of t-1/3 or t-1/6, depending on the charge combination of the two ions, to infinite time. The applicability of the method is demonstrated for ionophore-based Mg2+-, Ca2+-, and Na+-selective electrodes. It is shown that the high level of primary ion impurities in the salts of interfering ions can significantly limit the efficiency of the technique, as demonstrated with salts of different purity levels. PMID- 29135234 TI - Evaluating the Effect of Phosphorylation on the Structure and Dynamics of Hsp27 Dimers by Means of Ion Mobility Mass Spectrometry. AB - The quaternary structure and dynamics of the human small heat-shock protein Hsp27 are linked to its molecular chaperone function and influenced by post translational modifications, including phosphorylation. Phosphorylation of Hsp27 promotes oligomer dissociation and can enhance chaperone activity. This study explored the impact of phosphorylation on the quaternary structure and dynamics of Hsp27. Using mutations that mimic phosphorylation, and ion mobility mass spectrometry, we show that successive substitutions result in an increase in the conformational heterogeneity of Hsp27 dimers. In contrast, we did not detect any changes in the structure of an Hsp27 12-mer, representative of larger Hsp27 oligomers. Our data suggest that oligomer dissociation and increased flexibility of the dimer contribute to the enhanced chaperone activity of phosphorylated Hsp27. Thus, post-translational modifications such as phosphorylation play a crucial role in modulating both the tertiary and quaternary structure of Hsp27, which is pivotal to its function as a key component of the proteostasis network in cells. Our data demonstrate the utility of ion mobility mass spectrometry for probing the structure and dynamics of heterogeneous proteins. PMID- 29135235 TI - Estimating the Strength of Single Chitin Nanofibrils via Sonication-Induced Fragmentation. AB - We report the mechanical strength of native chitin nanofibrils. Highly crystalline alpha-chitin nanofibrils were purified from filaments produced by a microalgae Phaeocystis globosa, and two types of beta-chitin nanofibrils were purified from pens of a squid Loligo bleekeri and tubes of a tubeworm Lamellibrachia satsuma, with relatively low and high crystallinity, respectively. These chitin nanofibrils were fully dispersed in water. The strength of individualized nanofibrils was estimated using cavitation-induced tensile fracture of nanoscale filaments in a liquid medium. Both types of beta-chitin nanofibrils exhibited similar strength values of approximately 3 GP; in contrast, the alpha-chitin nanofibrils exhibited a much lower strength value of 1.6 GPa. These strength estimates suggest that the tensile strength of chitin nanofibrils is governed by the molecular packing modes of chitin rather than their crystallinity. PMID- 29135236 TI - Photoelectrochemical Immunoassays. PMID- 29135237 TI - Unveiling the Susceptibility of Functional Groups of Poly(ether sulfone)/Polyvinylpyrrolidone Membranes to NaOCl: A Two-Dimensional Correlation Spectroscopic Study. AB - A clear understanding of membrane aging process is essential for the optimization of chemical cleaning in membrane-based facilities. In this study, two-dimensional (2D) Fourier transformation infrared (FTIR) correlation spectroscopy (CoS) analysis was first used to decipher the sequential order of functional group changes of NaOCl-aged poly(ether sulfone)/polyvinylpyrrolidone (PES/PVP) membranes. The synchronous maps showed 12 major autopeaks in total. Based on the asynchronous maps, a similar aging sequence of membrane groups was clearly identified at three pHs (i.e., 6, 8, and 10): 1463, 1440, and 1410 (cyclic C-H structures) > 1662 (amide groups) > 1700 (succinimide groups) > 1320, 1292 (S?O asymmetric) > 1486, 1580 (aromatic structures) > 1241 (aromatic ether bands) > 1105, 1150 cm-1 (O?S?O symmetric). Among them, membrane chlorination occurred at 1241, 1410, and 1440 cm-1. Moreover, the initial degradation of PVP and the subsequent transformation of PES could be highly responsible for the increased water permeability and the enlargement of membrane pores, respectively, both leading to serious fouling with humic acid filtration. In summary, the 2D-FTIR CoS analysis is a powerful approach to reveal the interaction mechanisms of NaOCl membrane and could be also useful to probe the process of membrane fouling and chemical cleaning. PMID- 29135238 TI - Elucidating Protein/Ligand Recognition with Combined Surface Plasmon Resonance and Surface Enhanced Raman Spectroscopy. AB - The ability to distinguish between specific and nonspecific binding is important for assessing the interactions between protein receptors and ligands. Surface plasmon resonance (SPR) spectroscopy is an advanced tool to measure binding events, yet the ability to distinguish between specific and nonspecific binding remains a limitation. To address this problem, we use SPR spectroscopy correlated with surface enhanced Raman scattering (SERS). The chemical information present in SERS spectra provides insight into the molecular interactions between functionalized nanoparticles and proteins, which are not detectable by SPR alone. Using a custom instrument with the Kretschmann configuration, we successfully demonstrate simultaneous affinity and the chemical characterization of streptavidin-functionalized gold nanoparticles (STV-NPs) binding to biotin immobilized on a gold film in both air and flowing phosphate buffered saline (PBS). The SPR performance is consistent with that of previous reports. The association constant (KA) for streptavidin/biotin and STV-NPs/biotin interactions observed (2 +/- 1 * 107 M-1 and 2.4 +/- 0.3 * 1010 M-1, respectively) agree with literature values and show a strong avidity effect associated with the STV-NPs. The SERS scattering from STV-NPs is excited by the surface plasmon polariton and collected from an objective lens mounted over the fluidic channel. The SERS spectra are recorded simultaneously with the SPR sensorgram, and the detected Raman bands provide chemical insight into the binding event. Multivariate curve resolution analysis of the spectra can differentiate specific from nonspecific binding. This label-free, real time, and surface sensitive detection method provides chemical information to protein/ligand binding affinity measurements. PMID- 29135239 TI - Advances in Sulfidation of Zerovalent Iron for Water Decontamination. AB - Sulfidation has gained increasing interest in recent years for improving the sequestration of contaminants by zerovalent iron (ZVI). In view of the bright prospects of the sulfidated ZVI (S-ZVI), this review comprehensively summarized the latest developments in sulfidation of ZVI, particularly that of nanoscale ZVI (S-nZVI). The milestones in development of S-ZVI technology including its background, enlightenment, synthesis, characterization, water remediation and treatment, etc., are summarized. Under most circumstances, sulfidation can enhance the sequestration of various organic compounds and metal(loid)s by ZVI to various extents. In particular, the reactivity of S-ZVI toward contaminants is strongly dependent on S/Fe molar ratio, sulfidation method, and solution chemistry. Additionally, sulfidation can improve the selectivity of ZVI toward targeted contaminant over water under anaerobic conditions. The mechanisms of sulfidation-induced improvement in contaminants sequestration by ZVI are also summarized. Finally, this review identifies the current knowledge gaps and future research needs of S-ZVI for environmental application. PMID- 29135240 TI - An Osmotic Membrane Bioreactor-Membrane Distillation System for Simultaneous Wastewater Reuse and Seawater Desalination: Performance and Implications. AB - In this study, we demonstrate the potential of an osmotic membrane bioreactor (OMBR)-membrane distillation (MD) hybrid system for simultaneous wastewater reuse and seawater desalination. A stable OMBR water flux of approximately 6 L m-2 h-1 was achieved when using MD to regenerate the seawater draw solution. Water production by the MD process was higher than that from OMBR to desalinate additional seawater and thus account for draw solute loss due to the reverse salt flux. Amplicon sequencing on the Miseq Illumina platform evidenced bacterial acclimatization to salinity build-up in the bioreactor, though there was a reduction in the bacterial community diversity. In particular, 18 halophilic and halotolerant bacterial genera were identified with notable abundance in the bioreactor. Thus, the effective biological treatment was maintained during OMBR MD operation. By coupling biological treatment and two high rejection membrane processes, the OMBR-MD hybrid system could effectively remove (>90%) all 30 trace organic contaminants of significant concern investigated here and produce high quality water. Nevertheless, further study is necessary to address MD membrane fouling due to the accumulation of organic matter, particularly protein- and humic-like substances, in seawater draw solution. PMID- 29135242 TI - Computational Study on gamma-C-H Functionalization of alpha,beta-Unsaturated Ester Catalyzed by N-Heterocyclic Carbene: Mechanisms, Origin of Stereoselectivity, and Role of Catalyst. AB - The N-heterocyclic carbene (NHC)-catalyzed gamma-C-H deprotonation/functionalization of alpha,beta-unsaturated esters with hydrazones leading to the delta-lactams has been theoretically investigated by using density functional theory. Three possible reaction mechanisms including Mechanism A, for which the NHC catalyst serves as a nucleophilic catalyst to attack on the carbonyl carbon atom to initiate the reaction, Mechanism B, in which NHC triggers the reaction through the hydrogen bond, and Mechanism C, which is the direct deprotonation/functionalization process without the presence of NHC, have been suggested and studied in detail. The most favorable Mechanism A was identified to proceed through the following processes: nucleophilic attack on the carbonyl carbon of the ester by NHC, gamma-deprotonation, formal [4 + 2] cycloaddition of dienolate with hydrazone, and regeneration of NHC. Multiple possible deprotonation pathways were explored, and the additive base such as K2CO3 would significantly lower the energy barrier. The formal [4 + 2] cycloaddition step is the stereoselectivity-determining step, and R-configured rather than S-configured product was preferentially generated. In addition, the C-H...O, C-H...N, LP...pi, and C-H...pi interactions have been identified in the most energetically favorable transition state involved in the stereoselectivity-determining step. The additional analysis indicates that NHC strengthens the acidity and electrophilicity to promote the deprotonation, indicating this is not a simple NHC-catalyzed umpolung carbonyl reaction. The mechanistic insights and the significant role of NHC obtained in this study should provide valuable insights for understanding the organocatalytic gamma-C(sp3)-H bond functionalization reaction. PMID- 29135241 TI - The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport. AB - Novobiocin is an orally active antibiotic that inhibits DNA gyrase by binding the ATP-binding site in the ATPase subunit. Although effective against Gram-positive pathogens, novobiocin has limited activity against Gram-negative organisms due to the presence of the lipopolysaccharide-containing outer membrane, which acts as a permeability barrier. Using a novobiocin-sensitive Escherichia coli strain with a leaky outer membrane, we identified a mutant with increased resistance to novobiocin. Unexpectedly, the mutation that increases novobiocin resistance was not found to alter gyrase, but the ATPase that powers lipopolysaccharide (LPS) transport. Co-crystal structures, biochemical, and genetic evidence show novobiocin directly binds this ATPase. Novobiocin does not bind the ATP binding site but rather the interface between the ATPase subunits and the transmembrane subunits of the LPS transporter. This interaction increases the activity of the LPS transporter, which in turn alters the permeability of the outer membrane. We propose that novobiocin will be a useful tool for understanding how ATP hydrolysis is coupled to LPS transport. PMID- 29135243 TI - Foams Stabilized by beta-Lactoglobulin Amyloid Fibrils: Effect of pH. AB - beta-Lactoglobulin fibrils could serve as a surface-active component and form adsorption layers at the air/water interface. In this study, the physical parameters related to the surface adsorption, foaming, and surface properties of beta-lactoglobulin fibrils as a function of pH (2-8) were investigated. Results showed that an increase of pH from 2 to 5 led to a rise of the viscoelastic modulus of the surface adsorption layer and half-life time (t1/2) of foams, but it decreased foamability. When the pH was close to its isoelectric point (5.2), fibrils had the lowest electrostatic repulsion and entangled at the air/water interface resulting in a tightly packaged adsorption layer around bubbles to prevent coalescence and coarsening. When the pH (7-8) was higher than the pI of fibrils, the negatively charged beta-lactoglobulin fibrils possessed good foamability (~80%) and high foam stability (t1/2 ~ 8 h) simultaneously even at low concentration (1 mg/mL). It demonstrated that beta-lactoglobulin fibrils with negative charges presented a good foaming behavior and could be a potential new foaming agent in the food industry. PMID- 29135244 TI - Natural Products with Heteroatom-Rich Ring Systems. AB - This review focuses on all known natural products that contain a "heteroatom rich" ring system, specifically a five-, six- or seven-membered ring that contains three or more heteroatoms. The isolation and biological activity of these natural products is discussed, along with the biosynthetic processes that Nature employs to assemble these rare heterocyclic frameworks. PMID- 29135245 TI - Unique Transformation from Graphene to Carbide on Re(0001) Induced by Strong Carbon-Metal Interaction. AB - During graphene growth on various transition metals in the periodic table, metal carbides always emerge to behave as complex intermediates. On VIII metals, metastable carbides usually evolve and then transform into graphene along the phase interfaces, and even no metal carbides can form on IB-IIB metals. In contrast, during graphene growth on group IVB-VIB metals, carbides are usually generated even before the evolution of graphene and stably exist throughout the whole growth process. However, for the remaining transition metals, e.g., group VIIB, located in between IVB-VIB and VIII, the interplay between graphene and carbide is still vague. Herein, on Re(0001) (VIIB), we have revealed a novel transition from graphene to metal carbide (reverse to that on VIII metals) for the first time. This transition experienced graphene decomposition, dissolution, and carbon segregation processes, as evidenced by scanning tunneling microscopy (STM) and on-site, variable-temperature low electron energy diffraction (LEED) characterizations. This work thus completes the picture about the interplay between graphene and carbide on/in transition metals in the periodic table, as well as discloses a new territory for the growth of carbon-related materials, especially the metal carbide. PMID- 29135246 TI - Design of N-Coordinated Dual-Metal Sites: A Stable and Active Pt-Free Catalyst for Acidic Oxygen Reduction Reaction. AB - We develop a host-guest strategy to construct an electrocatalyst with Fe-Co dual sites embedded on N-doped porous carbon and demonstrate its activity for oxygen reduction reaction in acidic electrolyte. Our catalyst exhibits superior oxygen reduction reaction performance, with comparable onset potential (Eonset, 1.06 vs 1.03 V) and half-wave potential (E1/2, 0.863 vs 0.858 V) than commercial Pt/C. The fuel cell test reveals (Fe,Co)/N-C outperforms most reported Pt-free catalysts in H2/O2 and H2/air. In addition, this cathode catalyst with dual metal sites is stable in a long-term operation with 50 000 cycles for electrode measurement and 100 h for H2/air single cell operation. Density functional theory calculations reveal the dual sites is favored for activation of O-O, crucial for four-electron oxygen reduction. PMID- 29135247 TI - Divergent Synthesis of Porous Tetraphenylmethane Dendrimers. AB - Tetraphenylmethane-ethynylene-based shape-persistent dendrimers are a new class of nanoobjects with an intriguing 3D architecture. We report an efficient divergent strategy for their synthesis based on the Sonogashira Pd-catalyzed coupling of terminal alkynes with aryl iodides. As repeat unit, we prepared a tetraphenylmethane derivative bearing a terminal alkyne and three triazene moieties. Coupling of this building block to tetrakis(p-iodophenyl)methane afforded, after triazene activation, a dodecaiodo-terminated first generation dendrimer, which was transformed by another Sonogashira coupling into a methoxy terminated second generation dendrimer with persistent globular shape and well defined cavities. This work also unveils new aspects of triazene chemistry, i.e., the unprecedented efficient generation of an azo compound by mixing of a triazene with phenol. PMID- 29135248 TI - Biomimetics of [NiFe]-Hydrogenase: Nickel- or Iron-Centered Proton Reduction Catalysis? AB - The [NiFe] hydrogenase (H2ase) has been characterized in the Ni-R state with a hydride bridging between Fe and Ni but displaced toward the Ni. In nearly all of the synthetic Ni-R models reported so far, the hydride ligand is either displaced toward Fe, or terminally bound to Fe. Recently, a structural and functional [NiFe]-H2ase mimic ( Nat. Chem. 2016 , 8 , 1054 - 1060 ) was reported to produce H2 catalytically via EECC mechanism through a Ni-centered hydride intermediate like the enzyme. Here, a comprehensive DFT study shows a much lower energy route via an E[ECEC] mechanism through an Fe-centered hydride intermediate. Although catalytic H2 production occurs at the potential corresponding to the complex's second reduction, a third electron is needed to induce the second proton addition from the weak acid. The first two-electron reductions and a proton addition produce a semibridging hydride with a short Fe-H bond like other structured [NiFe]-biomimetics, but this species is not basic enough to add another proton from the weak acid without the third electron. The calculated mechanism provides insight into the origin of this structure in the enzyme. PMID- 29135249 TI - Photoreductive Removal of O-Benzyl Groups from Oxyarene N-Heterocycles Assisted by O-Pyridine-pyridone Tautomerism. AB - Facile photoreductive protocols have been developed to remove benzyl O-protective groups from oxyarene N-heterocycles at positions capable for 2-/4-O-pyridine-2-/4 pyridone tautomerism. Blue light irradiation, a [Ru] or [Ir] photocatalyst, and ascorbic acid in a water-acetonitrile solution debenzylates a variety of aryl N heterocycles cleanly and selectively. Ascorbic acid has two functions in the reaction. On the one hand, it protonates the N-heterocycles that reduces their reduction potentials notably and on the other hand it acts as a sacrificial reductant. Reduction potentials and free energy barriers calculated at the CPCM B3LYP/6-31+G** level can predict the reactivities of the studied substrates. PMID- 29135250 TI - Structure-Activity Relationships of 6- and 8-Gingerol Analogs as Anti-Biofilm Agents. AB - Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8 gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections. PMID- 29135251 TI - Micellar Thrombin-Binding Aptamers: Reversible Nanoscale Anticoagulants. AB - Aptamers are nucleic acid-based ligands that exhibit promising features including specific and reversible target binding and inhibition. Aptamers can function as anticoagulants if they are directed against enzymes of the coagulation cascade. However, they typically suffer from nucleolytic digestion and fast clearance from the bloodstream. We present thrombin-binding aptamer amphiphiles that self assemble into nanoscale polymeric micelles with a densely functionalized aptamer displaying corona. We show that these micellar aptamers retain their native secondary structure in a crowded environment and are stabilized against degradation by nucleases in human serum. Moreover, they are effective inhibitors of human plasma clotting in vitro. The inhibitory effect can be rapidly reversed by complementary nucleic acids that break the aptamers' secondary structure upon hybridization. Compared to free aptamers, the increased molecular weight and size of the overall assembly promotes extended blood circulation times in vivo. PMID- 29135252 TI - neo-Clerodane Diterpenoids from Salvia polystachya Stimulate the Expression of Extracellular Matrix Components in Human Dermal Fibroblasts. AB - Eleven neo-clerodane diterpenoids (1-11) including the new analogues 1, 2, and 10, and 3',5,6,7-tetrahydroxy-4'-methoxyflavone (12) were isolated from the aerial parts of Salvia polystachya. Polystachyne G (1) and 15-epi-polystachyne G (2) were isolated as an epimeric mixture, containing a 5-hydroxyfuran-2(5H)-one unit in the side chain at C-12 of the neo-clerodane framework. Polystachyne H (10) contains a 1(10),2-diene moiety and a tertiary C-4 hydroxy group. The structures of these compounds were established by analysis of their NMR spectroscopic and MS spectrometric data. The absolute configurations of compounds 3, 4, and 10 were determined through single-crystal X-ray diffraction analysis. The antibacterial, antifungal, and phytotoxic activities of the diterpenoids were determined. In addition, the stimulatory effect of the expression of extracellular matrix components of nine of the isolates (1-8 and 11) was assayed. Compounds 1-4, 8, and 11 increased the expression of the genes codifying for type I, type III, and type V collagens and for elastin. PMID- 29135253 TI - Correction to "Investigating Substrate Scope and Enantioselectivity of a Defluorinase by a Stereochemical Probe". PMID- 29135255 TI - Identification and Characterization of Molecular Bonding Structures by ab initio Quasi-Atomic Orbital Analyses. AB - The quasi-atomic analysis of ab initio electronic wave functions in full valence spaces, which was developed in preceding papers, yields oriented quasi-atomic orbitals in terms of which the ab initio molecular wave function and energy can be expressed. These oriented quasi-atomic orbitals are the rigorous ab initio counterparts to the conceptual bond forming atomic hybrid orbitals of qualitative chemical reasoning. In the present work, the quasi-atomic orbitals are identified as bonding orbitals, lone pair orbitals, radical orbitals, vacant orbitals and orbitals with intermediate character. A program determines the bonding characteristics of all quasi-atomic orbitals in a molecule on the basis of their occupations, bond orders, kinetic bond orders, hybridizations and local symmetries. These data are collected in a record and provide the information for a comprehensive understanding of the synergism that generates the bonding structure that holds the molecule together. Applications to a series of molecules exhibit the complete bonding structures that are embedded in their ab initio wave functions. For the strong bonds in a molecule, the quasi-atomic orbitals provide quantitative ab initio amplifications of the Lewis dot symbols. Beyond characterizing strong bonds, the quasi-atomic analysis also yields an understanding of the weak interactions, such as vicinal, hyperconjugative and radical stabilizations, which can make substantial contributions to the molecular bonding structure. PMID- 29135254 TI - Local Structure of Li+ in Concentrated Ethylene Carbonate Solutions Studied by Low-Frequency Raman Scattering and Neutron Diffraction with 6Li/7Li Isotopic Substitution Methods. AB - Isotropic Raman scattering and time-of-flight neutron diffraction measurements were carried out for concentrated LiTFSA-EC solutions to obtain structural insight on solvated Li+ as well as the structure of contact ion pair, Li+...TFSA , formed in highly concentrated EC solutions. Symmetrical stretching vibrational mode of solvated Li+ and solvated Li+...TFSA- ion pair were observed at nu = 168 177 and 202-224 cm-1, respectively. Detailed structural properties of solvated Li+ and Li+...TFSA- contact ion pair were derived from the least-squares fitting analysis of first-order difference function, DeltaLi(Q), between neutron scattering cross sections observed for 6Li/7Li isotopically substituted 10 and 25 mol % *LiTFSA-ECd4 solutions. It has been revealed that Li+ in the 10 mol % LiTFSA solution is fully solvated by ca. 4 EC molecules. The nearest neighbor Li+...O(EC) distance and Li+...O(EC)?C(EC) bond angle are determined to be 1.90 +/- 0.01 A and 141 +/- 1 degrees , respectively. In highly concentrated 25 mol % LiTFSA-EC solution, the average solvation number of Li+ decreases to ca. 3 and ca. 1.5. TFSA- are directly contacted to Li+. These results agree well with the results of band decomposition analyses of isotropic Raman spectra for intramolecular vibrational modes of both EC and TFSA-. PMID- 29135256 TI - Improved Solution-State Properties of Monoclonal Antibodies by Targeted Mutations. AB - Monoclonal antibody (mAb)-based therapeutics often require high-concentration formulations. Unfortunately, highly concentrated antibody solutions often have biophysical properties that are disadvantageous for therapeutic development, such as high viscosity, solubility limitations, precipitation issues, or liquid-liquid phase separation. In this work, we present a computational rational design principle for improving the thermodynamic stability of mAb solutions through targeted point mutations. Two publicly available IgG1 monoclonal antibodies that exhibit high viscosity at high concentrations were used as model systems. Guided by a computationally efficient approach that combines molecular dynamics simulations with three-dimensional reference interaction site model theory, point mutations of charged residues were introduced in the variable Fv regions in such a manner that the hydration free energy was optimized. Two selected point mutants were then produced by transient expression and characterized experimentally. Both engineered mAbs have reduced viscosity at high concentration, less negative second virial coefficient, and improved solubility compared to the respective wild-types. The results obtained with the suggested straightforward design principle underline the relevance of solvation effects for understanding, and ultimately optimizing, the properties of highly concentrated mAb solutions, with possible implications also for other biomolecular systems. PMID- 29135257 TI - Field-Theoretic Simulations of the Distribution of Nanorods in Diblock Copolymer Thin Films. AB - Using block copolymer microphases to guide the self-assembly of nanorods in thin films can give rise to polymeric materials with unique optical, thermal, and mechanical properties beyond those found in neat block copolymers. Often the design and manufacture of these materials require exquisite control of the nanorod distribution, which is experimentally challenging due to the large parameter space spanned by this class of materials. Simulation approaches, on the other hand, can access the thermodynamics that contribute to the nanorod distribution and hence offer valuable guidance toward the design and manufacture of the materials. In this work, we employ complex Langevin field-theoretic simulations to examine the thermodynamic forces that govern the assembly of nanorods in thin films of block copolymers with a particular focus on vertically oriented cylindrical and lamellar domains. Our simulations show that the nanorod geometry, the substrate selectivity for the distinct blocks of the copolymer, and the film thickness all play important roles in engineering both the nanorod orientation and spatial distribution in diblock copolymer thin films. In addition, we employ thermodynamic integration to examine how the nanorods alter the stability of vertical and horizontal domains in thin films, where we find that the tendency of the nanorods to stabilize a vertical orientation depends on both the film thickness and the nanorod concentration. PMID- 29135258 TI - Effect of Substrate Temperature on Pattern Formation of Bidispersed Particles from Volatile Drops. AB - In this study, pattern formation during evaporation of bidispersed drops (containing 1 and 3.2 MUm particles) placed on a smooth substrate at different temperatures is investigated. Five distinctive deposition patterns are observed depending on the substrate temperature: a relatively uniform pattern enclosed by a disk-shaped ring, a nearly nonuniform pattern inside a thick outer ring, a "dual-ring" pattern, a "rose-like" pattern, and a set of concentric rings corresponding to the "stick-slip" pattern. At drops edge, the particle size effect leads to the formation of three rings: an outermost ring formed by the nonvolatile additives smaller than 1 MUm, a middle ring built by particles with size of 1 MUm, and an innermost ring formed by the mixture of 1 and 3.2 MUm. For temperatures between 64 and 99 degrees C, the depinning of the contact line causes the same particle sorting at the other deposition lines in the interior of the drop. However, the width of the zone between the outermost ring and the middle ring at the initial edge of the drop is found to be smaller than that at the other deposition lines. The size of the width is found to be dependent on the contact angle. Particle velocity is measured by tracking particles during the evaporation. It is shown that particle velocity slightly increases with time, but it rapidly increases at the last stage of the drying process, known as "rush hour" behavior. The sudden change in the increase of the velocity occurs between the normalized time of 0.7 and 0.8 for temperatures from 22 to 81 degrees C. The increasing trend of velocity with time matches well with the theoretical model. The tracer particles are also used to measure the distance between the contact line and the nearest turning point of those particles return back toward the top of the drop due to the inward Marangoni flow. It is found that this distance decreases with increasing the substrate temperature. PMID- 29135259 TI - Thiadiazoloquinoxaline-Fused Naphthalenediimides for n-Type Organic Field-Effect Transistors (OFETs). AB - Thiadiazoloquinoxaline-fused naphthalenediimides (TQ-f-NDIs) are designed and synthesized. They show high electron affinities (EAs) of ~4.5 eV. Organic field effect transistor (OFET) devices, fabricated by dip-coating, provided maximum high electron mobilities of 0.03 cm2/(V.s) with an on/off ratio of 2 * 105. PMID- 29135260 TI - Copper-Catalyzed Alkenylation of Cyanamides. AB - An efficient procedure for the copper-catalyzed cross-coupling between a broad range of cyanamides and iodoalkenes is reported. Upon reaction with catalytic amounts of copper(I) iodide and 2,2'-bisimidazole in the presence of cesium carbonate in DMF at 80 degrees C, a fast, regioselective, and stereoretentive cross-coupling occurs. This reaction, which was found to have a broad substrate scope, provides the first general entry to N-alkenylcyanamides, building blocks that hold great synthetic potential. PMID- 29135261 TI - Nickel-Catalyzed Hydrogenolysis and Conjugate Addition of 2 (Hydroxymethyl)pyridines via Organozinc Intermediates. AB - 2-Hydroxymethylpyridines undergo nickel-catalyzed hydrogenolysis upon activation with a chlorophosphate. Reactions employ diethylzinc and are proposed to proceed through secondary benzylzinc reagents. Quenching with deuteromethanol provides straightforward incorporation of a deuterium label in the benzylic position. Intramolecular conjugate additions with alpha,beta-unsaturated esters are also demonstrated and support the intermediacy of a benzylzinc complex. PMID- 29135262 TI - A Low-Molecular-Weight Gelator Composed of Pyrene and Fluorene Moieties for Effective Charge Transfer in Supramolecular Ambidextrous Gel. AB - Charge-transfer (CT) gel materials obtained from low-molecular-weight (LMW) compounds through a supramolecular self-assembly approach have received fascinating attention by many researchers because of their interesting material property and potential applications. However, most of the CT gel materials constructed were of organogels while the construction of CT gels in the form of a hydrogel is a challenge because of the solubility issue in water, which considerably limits the use of CT hydrogels. Herein, for the first time, we report a new LMW gelator [Nalpha-(fluorenylmethoxycarbonyl)-Nepsilon-(delta butyric-1-pyrenyl)-l-lysine, (FmKPy)], composed of two functional moieties such as fluorenylmethoxycarbonyl and pyrene, which not only parade both hydro and organo (ambidextrous) supramolecular gel formation but also exhibit CT ambidextrous gels when mixed with an electron acceptor such as 2,4,7-trinitro-9 fluorenone (TNF). This finding is significant as the established CT organogelator in the literature did not form an organogel in the absence of an electron acceptor or lose their gelation property upon the addition of the acceptor. CT between pyrene and TNF was confirmed by the color change as well as the appearance of the CT band in the visible region of the absorption spectrum. CT between FmKPy and TNF was supported by the solvent dilution method using tetrahydrofuran as the gel breaker and pyrene fluorescence quenching in the case compound containing pyrene and TNF. The morphology of FmKPy ambidextrous gels indicates the fibrous nature while the self-assembled structure is primarily stabilized by pi-pi stacking among fluorenyl and pyrenyl moieties and hydrogen bonding between amide groups. The FmKPy-TNF CT ambidextrous gel retains the fibrous nature; however, the size of the fibers changed. In FmKPy-TNF CT gels, TNF is intercalated between pyrene moieties in the self-assembled structure as confirmed by fluorescence quenching and powder X-ray diffraction. The FmKPy ambidextrous gel exhibits significant properties such as low minimum gelation concentration (MGC), thixotropic nature, pH stimuli response, and high thermal stability. Upon the addition of TNF, the FmKPy-TNF CT ambidextrous gel maintains all these properties except MGC which increased for FmKPy-TNF. Because pyrene based LMW organogels have been developed widely for many applications while their hydrogels were limited, the current finding of the pyrene-based ambidextrous fluorescent gel with the CT property provides a wide opportunity to use FmKPy as a soft material maker and also for potential applications in fields like surface coating, three-dimensional printing, and so forth. PMID- 29135263 TI - Photoredox Divergent 1,2-Difunctionalization of Alkenes with gem-Dibromides. AB - The redox neutral photocatalytic divergent radical 1,2-difunctionalization of a wide array of structurally varied alkenes with gem-dibromides is presented. On the basis of the electronic effect of alkenes, predictable 1,2-carboxygenation and 1,2-carbohalogenation of alkenes are readily available regardless of steric effect. This protocol affords a practical approach to the biologically important furan skeleton. It is distinguished by good regioselectivity, good functional group compatibility, and late-stage modification and thus signifies an important step forward to divergent radical difunctionalization of alkenes. PMID- 29135264 TI - Peptide-Based Polymer-Polyoxometalate Supramolecular Structure with a Differed Antimicrobial Mechanism. AB - Because of the increasing prevalence of multidrug resistance feature, several investigations have been so far reported regarding the antibiotic alternative supramolecular bioactive agents made of hybrid assemblies. In this regard, it is well-established that combinational therapy inherited by assembled supramolecular structures can improve the bioactivity to some extent, but their mode of action has not been studied in detail. We provide first direct evidence that the improved mechanism of action of antimicrobial supra-amphiphilic nanocomposites differs largely from their parent antimicrobial peptide-based polymers. For the construction of a hybrid combinational system, we have synthesized side-chain peptide-based antimicrobial polymers via RAFT polymerization and exploited their cationic nature to decorate supra-amphiphilic nanocomposites via interaction with anionic polyoxometalates. Because of cooperative antimicrobial properties of both the polymer and polyoxometalate, the nanocomposites show an enhanced antimicrobial activity with a different antimicrobial mechanism. The cationic stimuli-responsive peptide-based polymers attack bacteria via membrane disruption mechanism, whereas free radical-mediated cell damage is the likely mechanism of polymer-polyoxometalate-based supra-amphiphilic nanocomposites. Thus, our study highlights the different antimicrobial mechanism of combinational systems in detail, which improves our understanding of enhanced antimicrobial efficacy. PMID- 29135265 TI - Evaluation of Early Therapeutic Effects after Near-Infrared Photoimmunotherapy (NIR-PIT) Using Luciferase-Luciferin Photon-Counting and Fluorescence Imaging. AB - Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that induces highly selective immunogenic cell death. It is based on an antibody photoabsorber conjugate (APC) that is activated by NIR light. The purpose of this study was to investigate the effects of NIR-PIT as measured by luciferase luciferin photon-counting and fluorescence imaging. Six days after subcutaneous injection of A431-luc-GFP cells tumors formed in a xenograft mouse model. The EGFR-targeting antibody, panitumumab, was conjugated to the photoabsorber, IRDye 700DX (pan-IR700), and was intravenously administered to tumor-bearing mice. Serial luciferase-luciferin photon-counting images and both green fluorescent protein (GFP) and IR700 fluorescence images were obtained from the same mice before and after NIR-PIT treatment (0, 10, 20, 30 min (early phase), and 24, 48 h (late phase) after NIR light exposure). Optical signal intensities were compared for each modality. IR700 fluorescence and luciferase-luciferin photon-counting images showed decreased intensities in both the early and late phases after NIR PIT (p < 0.01). On the other hand, GFP fluorescence images showed decreased intensities only in the late phase (p < 0.01). In the early phase, GFP fluorescence images showed smaller intensity reductions compared to IR700 fluorescence and luciferase-luciferin photon-counting (p < 0.01), while in the late phase, IR700 fluorescence showed smaller intensity reductions than luciferase-luciferin photon-counting and GFP fluorescence (p < 0.05), due to redistribution of pan-IR700 within the tumor bed. In conclusion, luciferase luciferin photon-counting imaging is suitable to evaluate early phase NIR-PIT effects, while both luciferase-luciferin photon-counting and GFP reflected later phase effects. PMID- 29135266 TI - Fast Metabolite Identification in Nuclear Magnetic Resonance Metabolomic Studies: Statistical Peak Sorting and Peak Overlap Detection for More Reliable Database Queries. AB - A lot of time is spent by researchers in the identification of metabolites in NMR based metabolomic studies. The usual metabolite identification starts employing public or commercial databases to match chemical shifts thought to belong to a given compound. Statistical total correlation spectroscopy (STOCSY), in use for more than a decade, speeds the process by finding statistical correlations among peaks, being able to create a better peak list as input for the database query. However, the (normally not automated) analysis becomes challenging due to the intrinsic issue of peak overlap, where correlations of more than one compound appear in the STOCSY trace. Here we present a fully automated methodology that analyzes all STOCSY traces at once (every peak is chosen as driver peak) and overcomes the peak overlap obstacle. Peak overlap detection by clustering analysis and sorting of traces (POD-CAST) first creates an overlap matrix from the STOCSY traces, then clusters the overlap traces based on their similarity and finally calculates a cumulative overlap index (COI) to account for both strong and intermediate correlations. This information is gathered in one plot to help the user identify the groups of peaks that would belong to a single molecule and perform a more reliable database query. The simultaneous examination of all traces reduces the time of analysis, compared to viewing STOCSY traces by pairs or small groups, and condenses the redundant information in the 2D STOCSY matrix into bands containing similar traces. The COI helps in the detection of overlapping peaks, which can be added to the peak list from another cross correlated band. POD-CAST overcomes the generally overlooked and underestimated presence of overlapping peaks and it detects them to include them in the search of all compounds contributing to the peak overlap, enabling the user to accelerate the metabolite identification process with more successful database queries and searching all tentative compounds in the sample set. PMID- 29135267 TI - Radical-Mediated Dearomatization of Indoles with Sulfinate Reagents for the Synthesis of Fluorinated Spirocyclic Indolines. AB - The dearomative introduction of trifluoromethyl and 1,1-difluoroethyl radicals, generated from their corresponding sulfinate salts, into the C2 position of indole derivatives allows the diastereoselective synthesis of three-dimensional 3,3-spirocyclic indolines over C-H functionalized indoles. PMID- 29135268 TI - Chemoselective One-Pot Synthesis of Functionalized Amino-azaheterocycles Enabled by COware. AB - Functionalized bicyclic amino-azaheterocycles are rapidly accessed in a one-pot cross-coupling/reduction sequence enabled by the use of COware. Incompatible reagents are physically separated in a single reaction vessel to effect two chemoselective transformations-Suzuki-Miyaura cross-coupling and heteroarene reduction. The developed method allows access to novel heterocyclic templates, including semisaturated Hedgehog and dual PI3K/mTOR inhibitors, which show enhanced physicochemical properties compared to their unsaturated counterparts. PMID- 29135269 TI - Return to Play After Hip Arthroscopic Surgery for Femoroacetabular Impingement in Professional Soccer Players. AB - BACKGROUND: Arthroscopic hip surgery has been shown to be effective in returning professional athletes back to play at a high level of performance in different sports. Limited information exists regarding professional soccer players and their return to play. PURPOSE: To determine the rate and time to return to sport for professional soccer players after hip arthroscopic surgery for the treatment of femoroacetabular impingement (FAI) and to identify possible risk factors associated with a delay in returning to play. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Professional soccer players who underwent hip arthroscopic surgery for FAI by a single surgeon between 2005 and 2015 were evaluated. Data retrieved from www.mlssoccer.com , www.fifa.com , www.transfermarkt.co.uk , and www.wikipedia.org included information on each player's professional career, participation on the national team, length of professional career before surgery, number of appearances (games) before surgery, time between surgery and first appearance in a professional game, and number of appearances after surgery. Other data were obtained from the patient's medical records. RESULTS: Twenty-four professional soccer players (26 hips) were included. The mean age at surgery was 25.0 +/- 4.0 years (range, 19-32 years). A total of 96% of patients were able to return to play at the professional level. The mean time between surgery and the first professional game played was 9.2 months (range, 1.9-24.0 months). On average, players played in 70 games after surgery (range, 0-224). National team players were able to return to play significantly earlier than the rest of the players (median, 5.7 months vs 11.6 months, respectively; P = .018). Severe chondral damage and microfracture did not interfere with return to play. CONCLUSION: The arthroscopic management of FAI in symptomatic professional soccer players allowed 96% of them to return to play. Players with national team experience were able to return to play earlier than those without it. Severe chondral damage and microfracture did not interfere with return to play. PMID- 29135270 TI - [Effectiveness of prenatal ultrasound in fetal and neonatal malformations and examination of difficulty and uncertainty factors]. AB - INTRODUCTION AND AIM: The birth prevalence of congenital malformations is around 2-3%. The aim of this study was to examine the efficacy of ultrasound diagnostics in detecting congenital malformations. METHOD: We have processed the prenatal sonographic and postnatal clinical details of 1867 inborn abnormalities in 1200 fetuses over a 7-year period. RESULTS: The mean maternal age upon delivery/abortion was 29.96 +/- 5.88 years. In 671 cases, the pregnancy concluded in delivery with a mean gestational age of 35.26 +/- 4.2 weeks and mean weight of 2408.67 +/- 944.41g. In case of the 529 abortions the mean gestational age was 19.88 +/- 2.53 weeks. Seventy-three fetuses were chromosomally abnormal, while 211 had multiple malformations. Prenatal ultrasound was highly sensitive in the detection of central nervous system and thoracic anomalies in utero (72.65% vs. 67.7% sensitivity). The detection rate was high in case of abdominal (59.58%), urogenital (54.55%), and limb/skeletal (50%) malformations as well. However, the diagnosis of face/neck anomalies was somewhat less efficient (31.85%). CONCLUSIONS: In approximately half of the cases, postnatally diagnosed abnormalities coincided with the prenatally discovered congenital malformations. The results have confirmed that ultrasonography plays an important role in diagnosing malformations prenatally but it fails to detect all of the developmental abnormalities. Orv Hetil. 2017; 158(45): 1794-1801. PMID- 29135271 TI - [Removal of giant adrenal tumors using the laparoscopic transperitoneal technique. A report of three successful cases]. AB - With the development of laparoscopic adrenalectomy, indications for resection gradually span from small and benign to bigger and even malignant lesions. We studied the results of laparoscopic adrenalectomy for giant (>10 cm) adrenal tumors in three cases. Three patients (2 female, 1 male, mean age 49.33 years, BMI 31) underwent laparoscopic transperitoneal adrenalectomy due to giant (>10 cm) adrenal lesions with a limited size Pfannenstiel incision. Mean operative time was 126.66 minutes, with a mean intraoperative blood loss of 150 ml. Final histology confirmed adrenocortical carcinoma in two cases, and neurofibroma in one case. Mean hospital stay was 4 days, without perioperative complications. R0 resection was carried out in all cases. During a mean follow-up period of 24 months no local or distant metastasis occurred. Under appropriate conditions adrenalectomy performed by the laparoscopic transperitoneal technique for giant malignant tumors proved to be a safe method fulfilling oncological requirements. Orv Hetil. 2017; 158(45): 1802-1807. PMID- 29135272 TI - [Protecting the inferior alveolar nerve: coronectomy of lower third molars. Review]. AB - Coronectomy of lower impacted wisdom teeth is the partial removal of third molars, aiming to avoid inferior alveolar nerve injuries. The coronectomy procedure has several crucial points, such as the pulpal, periapical preoperative conditions of the tooth, the way of crown sectioning and decoronation, the wound closure and the length of patients' follow up. In addition it is important to identify and manage possible intraoperative or postoperative complications correctly. According to the literature, the complication rate of coronectomy is usually lower, than that of total teeth removal, furthermore considering inferior alveolar nerve injuries, coronectomy is significantly the safer procedure. The aim of the authors was to review the relevant literature, defining the indications, contraindications and the correct implementation of the coronectomy and to demonstrate the causes and incidences of failures and complications. Further aim was to promote the domestic acceptance of this procedure. Orv Hetil. 2017; 158(45): 1787-1793. PMID- 29135273 TI - [Neuroscience of mental flexibility]. AB - Mental flexibility enabling shifts from the usual prepotent behaviour to new strategies and solutions is a significant factor in the successful adaptation to the changing environment. Components of mental flexibility comprise attention, salience detection, inhibition, working memory and switch processes which can be measured by neurocognitive tests. Data derived from examinations by the methods of cognitive neuroscience can be compared to the features, observed under resting state and during task performance, of brain structures and functions. Studying central nervous system correlates of mental flexibility by imaging, neurobiological, and pharmacological techniques revealed that certain cerebral regions (prefrontal cortex, anterior cingulate and insula, striatum, inferior parietal lobule) with their network connectivities, and some neurotransmitters (e.g. dopamine) have profound roles in this respect. Flexibility shares some similarities with artistic/scientific/everyday creativity and openness as a personality trait and this is also reflected in neurobiological parameters. According to precedents in art history, the public reception and acceptance of nonconform avant-garde artistic products are also dependent on flexibility and openness. Alterations of mental flexibility have been found in diseases (psychiatric and others), and in stress situations. Although flexible switch is generally considered as positive and beneficial, under certain conditions advantages might arise from keeping stability maintaining customs, conventions, and traditions. Orv Hetil. 2017; 158(45): 1771-1786. PMID- 29135274 TI - [Miscellaneous]. PMID- 29135275 TI - The Effects of Playing Multiple High School Sports on National Basketball Association Players' Propensity for Injury and Athletic Performance. AB - BACKGROUND: Athletes who specialize in their sport at an early age may be at risk for burnout, overuse injury, and reduced attainment of elite status. Timing of sport specialization has not been studied in elite basketball athletes. HYPOTHESIS: National Basketball Association (NBA) players who played multiple sports during adolescence would be less likely to experience injury and would have higher participation rates in terms of games played and career length compared with single-sport athletes. STUDY DESIGN: Descriptive epidemiology study. METHODS: First-round draft picks from 2008 to 2015 in the NBA were included in the study. From publically available records from the internet, the following data were collected for each athlete: participation in high school sports, major injuries sustained in the NBA, percentage of games played in the NBA, and whether the athlete was still active in the NBA. Athletes who participated in sports in addition to basketball during high school were defined as multisport athletes and were compared with athletes who participated only in basketball in high school. RESULTS: Two hundred thirty-seven athletes were included in the study, of which 36 (15%) were multisport athletes and 201 (85%) were single-sport athletes in high school. The multisport cohort played in a statistically significantly greater percentage of total games (78.4% vs 72.8%; P < .001). Participants in the multisport cohort were less likely to sustain a major injury during their career (25% vs 43%, P = .03). Finally, a greater percentage of the multisport athletes were active in the league at time of data acquisition, indicating increased longevity in the NBA (94% vs 81.1%; P = .03). CONCLUSION: While a minority of professional basketball athletes participated in multiple sports in high school, those who were multisport athletes participated in more games, experienced fewer major injuries, and had longer careers than those who participated in a single sport. Further research is needed to determine the reasons behind these differences. PMID- 29135276 TI - Effects of the New York State Concussion Management and Awareness Act ("Lystedt Law") on Concussion-Related Emergency Health Care Utilization Among Adolescents, 2005-2015. AB - BACKGROUND: All states have enacted legislation addressing the management of sports-related concussions (SRCs) in adolescent athletes. The effect of these laws on health care utilization is uncertain. Hypothesis/Purpose: The purpose was to evaluate the effects of New York's 2011 Concussion Management and Awareness Act ("Lystedt Law") on emergency department (ED) concussion health care visits (EDCHVs) and brain imaging utilization. It was hypothesized that New York concussion legislation would have a significant temporal effect on EDCHVs. STUDY DESIGN: Descriptive epidemiology study. METHODS: Using the New York State Department of Health Statewide Planning and Research Cooperative System (SPARCS) database, trends in EDCHVs from 2005 to 2015 were identified among 12- to 18-year old patients, comprising 5,740,403 total ED visits. RESULTS: Overall, 208,024 EDCHVs, including 54,669 for an SRC, occurred during the study period. EDCHVs increased from 13,664 (2.74% of all ED visits) in 2005 to a peak of 21,374 (4.26%) in 2013, with greatest relative increases from 2008 to 2013. SRCs followed a similar trend: 3213 (0.64%) in 2005 to a peak of 6197 (1.24%) in 2013. Brain imaging utilization decreased by 5.3% for EDCHVs and 15.4% for SRCs (all comparisons year-by-year and for trends; P < .001). CONCLUSION: The period of greatest increases in EDCHVs and decreases in brain imaging utilization for SRCs preceded New York concussion legislation by several years, suggesting a minimal direct effect on emergency care-seeking behavior for concussions. Instead, increased public awareness of SRCs and imaging guidelines may have driven EDCHV trends and imaging practices. PMID- 29135277 TI - Somato-Visceral Effects in the Treatment of Dysmenorrhea: Neuromuscular Manual Therapy and Standard Pharmacological Treatment. AB - OBJECTIVES: This study aims to verify whether neuromuscular therapy (NMT) or pharmacology therapy (PT) is more effective for reducing symptoms in women affected by primary dysmenorrhea and the effects associated with each treatment. DESIGN: A controlled, randomized, single-blind clinical trial within the framework of the chair of physical medicine and rehabilitation of the University "G. d'Annunzio" of Chieti-Pescara. The study was conducted on a sample of 60 women suffering from primary dysmenorrhea. Subjects were randomly divided in two groups (A and B). Group A was treated with NMT and group B with PT. Group B was given ibuprofen or naproxen because they are considered the best painkillers for this condition. Group A was treated with 8 neuromuscular manual lumbosacral and abdominal therapy sessions twice per week for 4 weeks. Results were analyzed at the beginning (T0) and end (T1) of the study with a menstrual distress questionnaire, brief pain inventory, and visual analogue scale. Twenty patients from Group A were selected for evaluation of their maintenance of the eventual improvement that was detected in T1 at follow-up (T2). RESULTS: Both therapies had significant short-term effects in reducing the perception and duration of pain. However, NMT appears to give more improvements in the duration of pain. NMT had a long-term effect on perception of pain because patients conserved the positive effects of treatment after 4 weeks. NMT also had a long-term effect on duration of pain because patients conserved benefits of treatment, but this improvement started to decrease after 4 weeks. CONCLUSIONS: In the treatment of primary dysmenorrhea, NMT represents a valid therapeutic alternative method to PT. NMT is free from potential adverse effects of analgesics, is noninvasive, and is easy to perform. PMID- 29135278 TI - Acral Fibrokeratoma A Rare Pedal Soft-Tissue Mass. AB - Acral fibrokeratoma is a rare soft-tissue mass, more commonly found on the hands and rarely on the feet. This case report of a 40-year-old Hispanic man highlights an unusually located acral fibrokeratoma on the second toe, describes the clinical presentation and microscopic and pathologic findings, discusses differential diagnoses, and presents treatment options. PMID- 29135279 TI - Cognitive Testing of the Brief Breastfeeding and Milk Expression Recall Survey. AB - BACKGROUND: Major U.S. federal maternal and child health surveys collect an infant feeding history for children under 6 years of age using survey questions that have changed little over decades. Yet, infant feeding and lactation practices have changed with the increasing popularity of milk expression (pumping). SUBJECTS AND METHODS: Cognitive interviews were conducted to test the 9-item Brief Breastfeeding and Milk Expression Recall Survey (BaByMERS) with a diverse sample of 15 U.S. mothers of children 1-5 years of age. A 42-item coding scheme was applied to identify interviewer and respondent problems in fielding and answering the questions. Problems were examined in relation to demographics and infant feeding and lactation history. RESULTS: The extent of problems was modest. Of 42 possible problem codes, only 9 were identified as actual problems for one or more respondents on one or more questions. The most common problems involved uncertainty about the timing of when one started expressing milk, making a mental shift to realize that maternal milk expression and the child's consumption of that milk could be distinct concepts, and difficulty with certain terms or phrases. Problems tended to arise among mothers with more complex infant feeding or lactation histories, who also tended to be those with higher levels of education. CONCLUSIONS: BaByMERS is a promising, brief tool for collecting a recalled infant feeding or lactation history among mothers with young children. Future research can evaluate additional characteristics of the tool to further confirm its utility for large epidemiological studies of maternal and child health. PMID- 29135280 TI - Factors Affecting Mouse Somatic Cell Nuclear Reprogramming by Rabbit Ooplasms. AB - Successful development of interspecies somatic cell nuclear transfer (iSCNT) embryos depends on compatibilities between ooplasmic and nuclear components. However, the mechanisms by which the compatibilities are regulated are still unknown. In this study, using mouse Oct4-green fluorescent protein (GFP) cells as donors and rabbit oocytes as recipients, we show that Oct4 and other pluripotency related genes were reactivated in some of mouse-rabbit iSCNT embryos, which could also activate Oct4 promoter-driven GFP reporter gene expression. Series nuclear transfer improved the efficiency of Oct4 reactivation. DNA demethylation of Oct4 promoter was detected in GFP positive iSCNT blastocysts, whereas GFP negative iSCNT embryos showed a low efficiency. Our results demonstrate that Oct4-GFP can well label the embryos with epigenetic remodeling and reactivation of pluripotent gene expression. Abundant rabbit mitochondria specific DNAs were identified in reconstructed mouse-rabbit embryos throughout preimplantation stages. Our data demonstrate that epigenetic remodeling and the complete mitochondrial match are not necessary for successful iSCNT embryo development before implantation. PMID- 29135282 TI - Genome-wide DNA methylation drives human embryonic stem cell erythropoiesis by remodeling gene expression dynamics. AB - AIM: To investigate the role of DNA methylation during erythrocyte production by human embryonic stem cells (hESCs). METHODS: We employed an erythroid differentiation model from hESCs, and then tracked the genome-wide DNA methylation maps and gene expression patterns through an Infinium HumanMethylation450K BeadChip and an Ilumina Human HT-12 v4 Expression Beadchip, respectively. RESULTS: A negative correlation between DNA methylation and gene expression was substantially enriched during the later differentiation stage and was present in both the promoter and the gene body. Moreover, erythropoietic genes with differentially methylated CpG sites that were primarily enriched in nonisland regions were upregulated, and demethylation of their gene bodies was associated with the presence of enhancers and DNase I hypersensitive sites. Finally, the components of JAK-STAT-NF-kappaB signaling were DNA hypomethylated and upregulated, which targets the key genes for erythropoiesis. CONCLUSION: Erythroid lineage commitment by hESCs requires genome-wide DNA methylation modifications to remodel gene expression dynamics. PMID- 29135281 TI - Ceritinib compassionate use for patients with crizotinib-refractory, anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer. AB - AIM: Ceritinib was evaluated within a compassionate use program of Italian patients. PATIENTS & METHODS: 70 patients with anaplastic lymphoma kinase positive crizotinib-refractory advanced non-small-cell lung cancer received ceritinib. RESULTS: Overall response was 40.6%, median progression-free survival was 8.2 months and median survival was 15.5 months. Dose reduction due to treatment-related adverse events occurred in 50.8% of patients starting at 750 mg/day. No significantly different progression-free survival was observed between patients who underwent any time dose reduction (n = 38) versus those who remained on the recommended dose of 750 mg/day (n = 32; p = 0.07). CONCLUSION: The efficacy of ceritinib compassionate use program resembled that of clinical trials. Dose reductions and adjustments did not appear to negatively affect clinical outcome. PMID- 29135283 TI - 10th Annual Symposium on Self-Monitoring of Blood Glucose, April 27-29, 2017, Warsaw, Poland. AB - International experts in the field of diabetes and diabetes technology met in Warsaw, Poland, for the 10th Annual Symposium on Self-Monitoring of Blood Glucose. The goal of these meetings is to establish a global network of experts to facilitate new collaborations and research projects that can improve the lives of people with diabetes. The 2017 meeting comprised a comprehensive scientific program, parallel interactive workshops, and four keynote lectures. PMID- 29135284 TI - Atezolizumab in urothelial bladder carcinoma. AB - Metastatic bladder cancer is an aggressive malignancy with a poor prognosis when presenting with advanced stage. Cisplatin-based therapy has been the mainstay of first-line treatment but therapy in second-line setting has been an unmet medical need for decades. Moreover, many patients are unable to receive cisplatin-based therapy. Recently, immune-checkpoint inhibitors transformed the management and prognosis of many malignancies and will certainly redefine the standard of care for bladder cancer. Atezolizumab, an anti-PD-L1 antibody, was the first immune checkpoint inhibitor to be approved by the US FDA in May 2016 for patients with urothelial carcinoma. In this review, we discuss the evidence behind this promising drug. PMID- 29135285 TI - Factors associated with confidence in decision making and satisfaction with risk communication among patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation is a prevalent cardiac arrhythmia. Effective communication of risks (e.g. stroke risk) and benefits of treatment (e.g. oral anticoagulants) is crucial for the process of shared decision making. AIM: The aim of this study was to explore factors associated with confidence in decision making and satisfaction with risk communication after a follow-up visit among patients who three months earlier had visited an emergency room for atrial fibrillation related symptoms. METHODS: A cross-sectional design was used and 322 patients (34% women), mean age 66.1 years (SD 10.5 years) with atrial fibrillation were included in the south of Sweden. Clinical examinations were done post an atrial fibrillation episode. Self-rating scales for communication (Combined Outcome Measure for Risk Communication and Treatment Decision Making Effectiveness), uncertainty in illness (Mishel Uncertainty in Illness Scale Community), mastery of daily life (Mastery Scale), depressive symptoms (Hospital Anxiety and Depression Scale) and vitality, physical health and mental health (36 item Short Form Health Survey) were used to collect data. RESULTS: Decreased vitality and mastery of daily life, as well as increased uncertainty in illness, were independently associated with lower confidence in decision making. Absence of hypertension and increased uncertainty in illness were independently associated with lower satisfaction with risk communication. Clinical atrial fibrillation variables or depressive symptoms were not associated with satisfaction with confidence in decision making or satisfaction with risk communication. The final models explained 29.1% and 29.5% of the variance in confidence in decision making and satisfaction with risk communication. CONCLUSION: Confidence in decision making is associated with decreased vitality and mastery of daily life, as well as increased uncertainty in illness, while absence of hypertension and increased uncertainty in illness are associated with risk communication satisfaction. PMID- 29135286 TI - Vitamin B12 supplementation influences methylation of genes associated with Type 2 diabetes and its intermediate traits. AB - AIM: To investigate the effect of B12 and/or folic acid supplementation on genome wide DNA methylation. METHODS: We performed Infinium HumanMethylation450 BeadChip (Zymo Research, CA, USA) assay in children supplemented with B12 and/or folic acid (n = 12 in each group) and investigated the functional mechanism of selected differentially methylated loci. RESULTS: We noted significant methylation changes postsupplementation in B12 (589 differentially methylated CpGs and 2892 regions) and B12 + folic acid (169 differentially methylated CpGs and 3241 regions) groups. Type 2 diabetes-associated genes TCF7L2 and FTO; and a miRNA, miR21 were further investigated in another B12-supplementation cohort. We also demonstrate that methylation influences miR21 expression and FTO, TCF7L2, CREBBP/CBP and SIRT1 are direct targets of miR21-3p. CONCLUSION: B12 supplementation influences regulation of several metabolically important Type 2 diabetes-associated genes through methylation of miR21. Hence, our study provides novel epigenetic explanation for the association between disordered one carbon metabolism and risk of adiposity, insulin resistance and diabetes and has translational potential. PMID- 29135287 TI - Molecular modelling studies in explaining the higher GPVI antagonistic activity of the racemic 2-(4-methoxyphenylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4 b]indole-3-carboxamide than its enantiomers. AB - The GPVI receptor on the platelets plays a major role in inhibiting arterial thrombosis with limited risk of bleeding and is considered a potential anti thrombotic target for arterial thrombosis. In the reported anti-thrombotics, tetrahydropyridoindoles, the title compound was the best inhibitor of the collagen mediated platelet aggregation by antagonizing the platelet receptor GPVI. Interestingly, the racemic title compound showed better antagonism (IC50 racemate = 6.7 MUM) than either of its enantiomers (IC50 S enantiomer = 25.3 MUM; IC50 R enantiomer = 126.3 MUM). In order to explain this, the molecular modelling approaches viz. site map analysis, protein-protein docking and molecular dynamics simulation were carried out, which led to the identification of a second binding site located near the primary antagonist binding site known to bind losartan. The induced fit docking studies for both the enantiomers at the primary and secondary binding sites showed that the S-enantiomer has better interactions at the primary binding site than the R-enantiomer, while the R-enantiomer has better interactions at the secondary site than the S-enantiomer. Hence, the overall interactions of the racemic compound containing equimolar mixture may be higher than any one of the enantiomers and may explain the higher activity than its enantiomers of the racemic compound. PMID- 29135288 TI - Selective Debridement With Labral Preservation Using Narrow Indications in the Hip: Minimum 5-Year Outcomes With a Matched-Pair Labral Repair Control Group. AB - BACKGROUND: Arthroscopic labral debridement in the hip can be an effective treatment for labral tears but has demonstrated inferior outcomes compared with labral repair. Thus, the role for labral debridement has become unclear. Hypothesis/Purpose: The purpose was to evaluate the outcomes of a selective debridement with labral preservation (SDLP) group with a minimum 5-year follow up. It was hypothesized that, with narrow indications, SDLP would produce statistically improved patient-reported outcome (PRO) scores, comparable with those of a matched-pair labral repair control group. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were collected on all patients undergoing primary hip arthroscopic surgery between February 2008 and September 2011. Exclusion criteria were acetabular or femoral head Outerbridge grade 4 chondral damage, preoperative Tnnis grade >=2, workers' compensation claims, previous hip conditions, severe dysplasia (lateral center-edge angle <18 degrees ), or previous ipsilateral hip surgery. Patients who underwent arthroscopic labral debridement and had preoperative and minimum 5-year PRO scores, including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), and Hip Outcome Score-Sports-Specific Subscale (HOS-SSS) as well as the visual analog scale (VAS) for pain, were included. In a nested matched-pair comparison, the SDLP group was matched 1:1 to an arthroscopic labral repair control group based on age +/-5 years, body mass index +/-5 kg/m2, sex, and Seldes tear type. RESULTS: One hundred twenty-five hips were eligible for inclusion, of which 101 (80.8%) hips had a minimum 5-year follow-up. All PRO scores were significantly improved ( P < .001) at latest follow-up (mHHS, 63.4 to 82.4; NAHS, 57.4 to 83.6; HOS-SSS, 44.2 to 74.5). The mean VAS score decreased from 5.8 to 2.3 ( P < .001). The mean patient satisfaction score was 8.1. Four (4.0%) patients underwent second-look arthroscopic surgery (mean, 18.5 months), and 14 (13.9%) patients converted to total hip arthroplasty (mean, 46.9 months). In the matched-pair comparison, 69 in the SDLP group were matched 1:1 with those undergoing labral repair. Outcomes at latest follow-up of the SDLP group were comparable with those of the control group, respectively: mHHS, 83.0 vs 86.1 ( P = .084); NAHS, 85.0 vs 85.4 ( P = .415); HOS-SSS, 74.8 vs 76.8 ( P = .219); VAS, 2.3 vs 2.0 ( P = .277); international Hip Outcome Tool-12 (iHOT-12), 73.8 vs 76.4 ( P = .136); Short Form Health Survey-12 (SF-12) mental, 57.4 vs 55.1 ( P = .031); SF-12 physical, 48.7 vs 48.9 ( P = .357); Veterans RAND Health Survey-12 (VR-12) mental, 61.6 vs 59.8 ( P = .160); VR-12 physical, 50.1 vs 50.2 ( P = .340); and patient satisfaction, 8.0 vs 8.3 ( P = .211). CONCLUSION: In select cases of stable labral tears, SDLP may allow the preservation of a functional labrum. At a minimum 5-year follow-up, SDLP using narrow indications produced favorable outcomes comparable with a matched-pair labral repair group. PMID- 29135289 TI - [What should we know about cardiac amyloidosis? From clinical signs to treatment]. AB - Systemic amyloidosis is a rare disease, in which the heart involvement is rather frequent and determines survival remarkably. Regarding the disease and organ involvement, new diagnostic procedures help to establish the diagnosis and to start the adequate treatment as soon as possible. Cardiac involvement is more likely to be characterised by monoclonal immunglobulin free light chain (AL amyloidosis) type and transthyretin type. In case of AL amyloidosis, heart involvement can lead to serious consequences. Biomarker assessments for cardiac function are important to determine disease severity at the beginning and to measure response to the treatment. In case of amyloidosis, the incidence of the heart involvement grows with age. The prevalence is not known exactly, but probably there are more cases than recognised. The authors present the clinical signs and diagnostic methods, emphasizing the importance of the cardiac examination methods. Orv Hetil. 2017; 158(46): 1811-1818. PMID- 29135291 TI - [Miscellaneous]. PMID- 29135290 TI - [Study of the canalis mandibulae morphology in different vertical facial types]. AB - INTRODUCTION: The precise knowledge of the position of canalis mandibulae and foramen mandibulae is important for surgical and endodontic interventions on the mandible. AIM: The aim of the study is to examine the position of these anatomical landmarks in different vertical facial types. METHOD: In the panorama radiograph of 26 normodivergent, 26 hypodivergent and 28 hyperdivergent arthritis (total of 1360 measurements) we measured the distance between the canalis mandibulae and interdental septums, the apex of the lateral teeth, the mandibular base, the goniac angle, and the steepness of the canal and the distance the foramen mandibulae to the anterior and posterior margin of the ramus. RESULTS: ANOVA and t-test statistical analysis showed that the foramen mandibulae is farer from the posterior margin of the ramus in hipodivergent facial types, in hyperdivergent facial types the canalis mandibulae was closer to the root apex of posterior teeth and in hypodivergent types to the base of the mandible. In normal and hyperdivergent individuals, the canalis mandibulae runs steeper and in the course of running it is increasingly distanced from the tangent to the base of the mandible. CONCLUSION: The position of the canalis mandibulae and the foramen mandibulae showed significant differences in the different vertical facial types. Orv Hetil. 2017; 158(46): 1841-1847. PMID- 29135292 TI - [Male hormonal contraception: past, present, future]. AB - In certain regions of the world the enormous rate of population growth raises economic and public health concerns and widely accessible contraceptive methods would be desired. In contrast, in other countries the use of effective contraception is a question of individual preferences. Today, most of the reliable contraceptive methods are applied by women, while the options for male methods are quite limited. It is well known that significant portion of pregnancies are still unplanned and several data revealed men's willingness to take part in family planning. Based on these needs, remarkable efforts have been made to develop a suitable hormonal contraceptive agent for men. With the exogenous suppression of follicle stimulating hormone and luteinizing hormone secretion, the inhibition of the testicular testosterone production and the spermatogenesis can be achieved. In the beginning, testosterone-derivatives, or testosterone-progestin combinations were administered, later synthetic androgen agents were developed. Despite of these efforts, unfortunately, there is no safe, widely feasible male hormonal contraception to date, but in the future this goal can be achieved by solving the key hurdles. Orv Hetil. 2017; 158(46): 1819-1830. PMID- 29135293 TI - [From the Hallervorden-Spatz eponym to the molecular terminology]. AB - INTRODUCTION AND AIM: A combination of Niemann-Pick- and Hallervorden-Spatz diseases led to the death of a 17-year-old boy in 1994. Genetic counseling necessitated further investigations in 2017. Meanwhile, the nomenclature of Hallervorden-Spatz disease has been abandoned. The author analyze the reasons for this change. METHOD: Professional activities of Hallervorden and Spatz during and after the Nazi euthanasia program are presented. Also, the scientific efforts that led to the discovery of the genetic background of the disease and ultimately to its new name are highlighted. RESULTS: In nazi Germany, a large number of mentally disabled were killed. The majority of pediatric-brains were transferred to the "Kaiser Wilhelm Institut fur Hirnforschung", led by Hugo Spatz, and was included in the "Hallervorden collection". Investigations exploring the connections between eponyms and nazi-activites started in the mid-1980s. This process was accelerated by the discovery of genetic alterations underlying disease entities, including neurodegeneration with brain iron accumulation (NBIA). NBIA has several subtypes, with the first being the disease described by Hallervorden and Spatz, and recently renamed to pantothenate kinase-associated neurodegeneration (PKAN). The case examined by the authors belongs to the third subtype, to the mitochondrial protein-associated neurodegeneration (MPAN). CONCLUSION: The works of the two noted neuropathologists strongly conflict with current ethical principles of human research studies. The buried "Hallervorden collection" in the Munich Waldfriedhof cemetery, and the memorial column erected there will remain a sad reminder of a time when a political system profoundly distorted the judgement of even academic physicians. Orv Hetil. 2017; 158(43): 1723-1727. PMID- 29135294 TI - [Study of socio-demographic factors in the treatment of unipolar major depression in a follow-up clinical trial]. AB - INTRODUCTION: Depression is one of the most widespread illnesses of our time, currently affecting more than 300 million people worldwide. Literature identifies several socio-demographic risk factors in the development of the depression. AIM: We aim to examine the socio-demographic factors involved in the remission of clinically diagnosed unipolar major depression. METHOD: Data collection was performed during 2016, at the 1st Psychiatric Clinic from Tirgu Mures. Participants were patients reporting no other physical or psychiatric disorder. Self-reporting questionnaire assessed socio-demographic factors, such as gender, age, neighborhood, education, marital status, employment, and unemployed period. DSM-5 criteria were used in diagnosis, and the severity and status tracking was assessed with the 17-item version of the Hamilton Depression Scale. The age distribution of the sample was between 18-65 years of age, 44 male (28.9%) and 108 female (71.1%), 66 inpatients and 86 outpatients. Patients received medication for 12 weeks, and were involved in HAM-D 17 testing when hospitalized, at 8 and 12 weeks. RESULTS: Scores of depression decreased significantly after 8 and 12 weeks of the treatment. Gender, age, and neighborhood did not influence the treatment, but patients with high education manifested less depressive symptoms at the end of treatment. Among married patients depression score was lower than among unmarried, and employees showed lower depression scores comparing to long-term unemployed patients. CONCLUSION: Marital status and employment were relevant predictors of remission, proving a significant effect on the treatment outcomes. Thus, psychotherapeutic intervention is recommendable in the case of single and unemployed patients. Orv Hetil. 2017; 158(43): 1715-1722. PMID- 29135295 TI - [Re-engineering of glucose exposure in peritoneal dialysis]. AB - The significance of peritoneal dialysis in kidney replacement therapy is expected to increase, so it is important to reconsider glucose exposure to minimize the adverse effects. The first step was to develop biocompatible modern PD solutions to reduce the local and systemic adverse effects of current conventional glucose based ones. According to the limited clinical experience, there are no clear data on better clinical outcome. Besides this there is a suspected theoretical correlation between development of encapsulating peritoneal sclerosis and chronic local irritation of peritoneal surface by glucose. The degree of actual systemic glycemic load can be evaluated by continuous tissue glucose monitoring, and cumulative damage can be measured by skin autofluorescence, however none of the methods have been extensively used in clinical practice. The early diagnosis of cardiovascular diseases is therefore of also paramount importance. Selecting the therapeutic steps including diabetological aspects, we must constantly strive to improve the life quality. Orv Hetil. 2017; 158(43): 1708-1714. PMID- 29135296 TI - [Ischaemic heart disease in cancer patients. Questions and problems]. AB - Cardiovascular and oncologic diseases are the causes of more than 50 percent of mortality in Europe. In 2015 oncologic and cardiovascular mortality reached 70 percent in Hungary. Patients who receive anticancer therapies are at a 2- to 7 fold greater long-term risk of acute coronary syndrome; also concomittant oncologic diseases further increase the mortality of myocardial infarction. Unfortunately there is not enough data concerning cardiovascular treatment of oncologic patients because they were excluded from most of the studies and registries. Because there is no clear protocol to treat such patients, only small studies and personal experiences could guide our medical therapies. The role of cardio-oncology is even more important, because due to the new treatments the number of tumor survivors rapidly increases. In the US more than 20 millions survivals are expected by 2025 who were treated by any kind of malignant tumors. It is not surprising that in 2014 the American Society of Cardiology declared cardio-oncology as a special and important field in cardiology, and in 2016 European Society of Cardiology released the first cardio-oncologic guideline. In this review we summarize questions and problems concerning the treatment of oncologic patient with ischaemic heart disease based on resent guidelines, published studies and local protocols. Orv Hetil. 2017; 158(43): 1691-1697. PMID- 29135298 TI - [Miscellaneous]. PMID- 29135297 TI - [Vitamin D and calcium supplementation in elderly patients with hip fracture]. AB - Vitamin D plays an important role in maintaining calcium and bone metabolism, a risk factor of osteoporosis, fall and fracture in old age. Reduction in D-vitamin levels associated with compensatory increased level of parathyroid hormone causes significant loss of bone matrix, so substitutions of vitamin D and calcium are very important. Many authors publish their recommended doses used for prevention of hip fracture during the last years. Some authors are satisfied only with vitamin D supplementation while others have better experiences with vitamin D and calcium substitution. On the other hand, some metaanalyses give contradictory results and propose further investigations. It is important to consider the patients' eating habits and lifestyle as well as the risk of cardiovascular and other chronic diseases. Further trials should be done in different age groups in order to examine the effects of different doses of vitamin D without and with calcium to make a final decision. Orv Hetil. 2017; 158(43): 1699-1707. PMID- 29135299 TI - Oxygen-Free Biochemistry: The Putative CHN Foundation for Exotic Life in a Hydrocarbon World? AB - Since Earth's biochemistry is carbon-based and water-borne, the main strategies for searching for life elsewhere are "follow the carbon" and "follow the water." Recently, however, there is a growing focus on the prospect that putative exotic life on other planets could rely on unearthly biochemistries. Here, we hypothesize a novel oxygen-free organic chemistry for supporting potential exotic biosystems, which is named CHN biochemistry. This oxygen-free CHN biochemistry starts from simple oxygen-free species (including hydrocarbons, hydrogen cyanide, and nitriles) and produces a range of functional macromolecules that may function in similar ways to terran macromolecules, such as sugars (cyanosugars), acids (cyanoacids), amino acids (amino cyanoacids), and nucleobases (cyanonucleobases). These CHN macromolecules could further interact with each other to generate higher "cyanoester" and "cyanoprotein" systems. In addition, theoretical calculations indicate that the energy changes of some reactions are consistent with their counterparts in Earth's biochemistry. The CHN biochemistry-based life would be applicable in habitats with a low bioavailability of oxygen, such as the alkane lakes of Titan and non-aquatic liquids on extrasolar bodies. Key Words: Oxygen-free biochemistry-Titan-Hydrocarbons-Hydrogen cyanide-Nitriles. Astrobiology 17, 1173-1181. PMID- 29135300 TI - Something New: Astrobiology in the Real World. PMID- 29135301 TI - Microbialite Biosignature Analysis by Mesoscale X-ray Fluorescence (MUXRF) Mapping. AB - As part of its biosignature detection package, the Mars 2020 rover will carry PIXL, the Planetary Instrument for X-ray Lithochemistry, a spatially resolved X ray fluorescence (MUXRF) spectrometer. Understanding the types of biosignatures detectable by MUXRF and the rock types MUXRF is most effective at analyzing is therefore an important goal in preparation for in situ Mars 2020 science and sample selection. We tested mesoscale chemical mapping for biosignature interpretation in microbialites. In particular, we used MUXRF to identify spatial distributions and associations between various elements ("fluorescence microfacies") to infer the physical, biological, and chemical processes that produced the observed compositional distributions. As a test case, elemental distributions from MUXRF scans of stromatolites from the Mesoarchean Nsuze Group (2.98 Ga) were analyzed. We included five fluorescence microfacies: laminated dolostone, laminated chert, clotted dolostone and chert, stromatolite clast breccia, and cavity fill. Laminated dolostone was formed primarily by microbial mats that trapped and bound loose sediment and likely precipitated carbonate mud at a shallow depth below the mat surface. Laminated chert was produced by the secondary silicification of microbial mats. Clotted dolostone and chert grew as cauliform, cryptically laminated mounds similar to younger thrombolites and was likely formed by a combination of mat growth and patchy precipitation of early formed carbonate. Stromatolite clast breccias formed as lag deposits filling erosional scours and interstromatolite spaces. Cavities were filled by microquartz, Mn-rich dolomite, and partially dolomitized calcite. Overall, we concluded that MUXRF is effective for inferring genetic processes and identifying biosignatures in compositionally heterogeneous rocks. Key Words: Stromatolites Biosignatures-Spectroscopy-Archean. Astrobiology 17, 1161-1172. PMID- 29135302 TI - In Memory: Clint Thompson, MS, ATC. PMID- 29135305 TI - Choroidal Thickness of Helicobacter-Positive Patients without Central Serous Chorioretinopathy. AB - PURPOSE: To evaluate the effect of Helicobacter pylori (H. pylori) infection on subfoveal choroidal thickness (SFCT) in patients without clinical central serous chorioretinopathy (CSC). MATERIALS AND METHODS: This prospective study included 50 patients with pathologically proven H. pylori infection (H. pylori (+)) and 50 patients without H. pylori infection (H. pylori (-)). All of the recruited patients were previously admitted to the Gastroenterology Department of the Namik Kemal University School of Medicine over the period of July 2014 to September 2015. All patients had 20/20 vision and underwent complete ophthalmological examination, macular optical coherence tomography (OCT), and enhanced depth imaging OCT. RESULTS: All patients had 20/20 vision and similar macular thicknesses. The mean SFCT of patients in the H. pylori (+) group was 309 +/- 41.1 um and 315 +/- 18.2 um in the H. pylori (-) group (p = 0.174). The right and left eyes of patients in the H. pylori (+) and (-) groups were not statistically significantly different (p = 0.852, p = 0.937). The age, sex, and choroidal thicknesses of patients in the H. pylori (+) and (-) groups were not correlated. CONCLUSION: H. pylori infection does not have an effect on choroidal thickness in patients without any ocular pathology. PMID- 29135306 TI - A Calculation Tool and Process to Pre-Position Pharmaceuticals for Anthrax Post Exposure Prophylaxis. AB - Anthrax, caused by Bacillus anthracis, is considered a severe bioterrorism threat because of its high mortality rate. The Chicago Healthcare System Coalition for Preparedness and Response (CHSCPR) aims to pre-position antibiotic medical countermeasures (MCMs) at healthcare facilities in order to provide on-site anthrax post-exposure prophylaxis. Pharmacists proposed moving toward a new process that involved the development of a standardized calculation methodology for acquiring supply drugs. This was an interventional quality improvement project aimed at optimizing inventory, acquisition, and distribution of antibiotic MCMs for anthrax post-exposure prophylaxis at Chicago hospitals for hospital personnel, associated first responders, and their families. The primary goal of the project was to pre-position a sufficient quantity of pharmaceuticals to allow Chicago hospitals to function as closed points of dispensing (PODs) for 72 hours; a secondary goal was to provide a 96-hour supply of anthrax post exposure prophylaxis. A total of 35 Chicago hospitals were invited to participate in this intervention study, and 30 hospitals agreed to participate. Based on our calculation tool, we initially identified 6 (20%) hospitals with adequate oral doxycycline and ciprofloxacin inventory to last 72 hours and 3 (10%) hospitals with inventory to last 96 hours as a closed POD for anthrax post-exposure prophylaxis. The necessary quantities of medication needed to establish 72 and 96 hours of anthrax post-exposure prophylaxis were calculated by the CHSCPR and negotiated with a drug wholesaler to obtain product with maximum shelf-life and discounted pricing. Acting as a group purchaser, the CHSCPR organized drop shipment of medication directly to facilities from a wholesaler. This systematically calculated, pre-deployed pharmaceutical cache enhanced availability of antibiotic MCMs for anthrax post-exposure prophylaxis in 30 Chicago hospitals, allowing them to function as closed PODs for 96 hours during an incident. PMID- 29135307 TI - Correlation between Flicker-Induced Retinal Vessel Vasodilatation and Plasma Biomarkers of Endothelial Dysfunction in Hypertensive Patients. AB - PURPOSE: Hypertension (HT) strongly affects the vascular endothelium, resulting in chronic inflammatory disease. Dynamic vessel analysis (DVA) is a modern methodological approach to analyze vascular function in the retinal microcirculation. The aim of this study was to examine whether a defective retinal vessels response is associated with HT-induced endothelial dysfunction. MATERIALS AND METHODS: Retinal vessel reactions to flicker stimulation were examined by DVA in both eyes of 37 hypertensive and 41 healthy control subjects. Plasma concentrations of C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha (TNFalpha) were measured using the enzyme-linked immunosorbent assay. RESULTS: Both arterial and vein responses to flicker stimulation were significantly decreased in patients with HT compared with the healthy controls (dilatation of the arteries was lower in the HT group by, on average, 1.31, p = 0.001 and dilatation of the veins was lower in the HT group by, on average, 1.32, p = 0.002) after independent adjustment for age, sex, body mass index, and pressure values. In the hypertensive group, there was a negative correlation between the arterial response to flicker stimulation and the plasma CRP concentration (Spearman's Rank-order Coefficient (Rs) = -0.29, p = 0.07). Similarly, the plasma TNFalpha concentrations negatively correlated with the arterial response to flicker stimulation (Rs = -0.39, p = 0.02). CONCLUSIONS: Our results indicate that DVA directly reflects the actual metabolic status of the retinal endothelium. DVA might be used as an early noninvasive screening tool to detect vascular dysregulation and pan-endothelial dysfunction in patients with HT. PMID- 29135308 TI - Anomalous Lateral Rectus Muscle Band in a Case of Duane Retraction Syndrome. AB - Anomalous orbital structures are suspected in restrictive strabismus with features of severe globe retractions, overshoots, or synergistic movements. We report a case of suspected Duane syndrome that was found to have an anomalous band beneath the lateral rectus muscle. Such abnormal structures are rare, but it is important to identify and manage them to optimize outcomes. PMID- 29135309 TI - Screening for platelet function disorders with Multiplate and platelet function analyzer. AB - Light transmission aggregation (LTA) is the gold standard for the diagnosis of platelet function disorders (PFDs), but it is time-consuming and limited to specialized laboratories. Whole-blood impedance aggregometry (Multiplate) and platelet function analyzer (PFA) may be used as rapid screening tools to exclude PFDs. The aim of this study is to assess the diagnostic performance of Multiplate and PFA for PFDs, as detected by LTA.Data from preoperative patients, patients referred to the hematologist for bleeding evaluation, and patients with a diagnosed bleeding disorder were used. PFDs were defined as >=2 abnormal LTA curves. Diagnostic performance of Multiplate and PFA for detecting PFDs was expressed as sensitivity and specificity. The ability of Multiplate agonists and PFA kits to detect corresponding LTA curve abnormalities was expressed as area under the receiver operating characteristic curve. Prevalence of PFDs was 16/335 (4.8%) in preoperative patients, 10/54 (18.5%) in referred patients, and 3/25 (12%) in patients with a diagnosed bleeding disorder. In preoperative and referred patients, the sensitivity of Multiplate and PFA for detecting mild PFDs varied between 0% and 40% and AUCs for detecting corresponding LTA curve abnormalities were close to 0.50. In patients with a diagnosed bleeding disorder, both assays could detect Glanzmann thrombasthenia (GT) with sensitivity of 100% and AUCs of 0.70-1.00. Multiplate and PFA cannot discriminate between preoperative and referred patients with and without mild PFDs, meaning that they cannot be used as screening tests to rule out mild PFDs in these populations. Both Multiplate and PFA can detect GT in previously diagnosed patients. PMID- 29135310 TI - ADAMTS 1, 4, 12, and 13 levels in maternal blood, cord blood, and placenta in preeclampsia. AB - The aim of this study is to compare ADAMTS (A Disintegrin and Metalloprotease Domains with Thrombospondins motifs) 1, 4, 12, and 13 levels in maternal and cord blood and placental tissue between preeclampsia and uncomplicated pregnancies. The enzyme-linked immunosorbent assay (ELISA) results showed that ADAMTS 1, 4, 12, and 13 levels in the maternal and cord blood were lower in the preeclampsia group than in the control group. Based on the immunohistochemistry (IHC) results, ADAMTS 1, 4, and 12 levels in placental tissues were higher in the preeclampsia group. According to the polymerase chain reaction (PCR) results, ADAMTS 1, 4, and 12 were higher, whereas ADAMTS 13 was lower in the preeclampsia group than in the control group. PMID- 29135311 TI - ATM, BCL2, and TGFbeta Gene Polymorphisms as Radiotherapy Outcome Biomarkers in Head and Neck Squamous Cell Carcinoma Patients. AB - AIMS: Polymorphisms in cell cycle genes are considered prognostic as radiosensitivity markers in patients with head and neck squamous cell carcinoma. Therefore, we aimed to investigate the relationship of ATM 5557G>A, ATM IVS62 + 60G>A, TP53 215G>C, BCL2-938C>A, TGFbeta-509C>T, and TGFbeta 29C>T with radiotherapy response. MATERIALS AND METHODS: Genotyping was performed by polymerase chain reaction followed by restriction fragment length polymorphism in 210 patients with oral cavity/oropharyngeal carcinoma and 101 patients with laryngeal tumors. RESULTS: In irradiated oral cavity/oropharyngeal tumors, the ATM IVS62 + 60G>A AA genotype significantly increased local recurrence risk (odds ratio [OR] = 4.43; confidence interval [CI] = 1.22-16.13) and the BCL2-938C>A C allele and the TGFbeta-509C>T T allele were associated with worse disease specific survival (hazard ratio [HR] = 0.46; CI = 0.24-0.90 and HR = 2.20; CI = 1.12-4.29, respectively). In irradiated laryngeal carcinoma, the TGFbeta 29C>T C allele was associated with increased local recurrence risk (OR = 0.09; CI = 0.02 0.53), death rate (OR = 0.18; CI = 0.04-0.86), and worse local disease-free and disease-specific survival rates (HR = 0.13; CI = 0.03-0.59 and HR = 0.21; CI = 0.07-0.60, respectively), while the BCL2-938C>A C allele was related to a worse disease-specific survival (HR = 0.32; CI = 0.12-0.83). DISCUSSION: These results can help individualize treatment according to a patient's genetic markers. We demonstrated that ATM IVS62 + 60G>A, TGFbeta 29C>T, TGFbeta-509C>T, and BCL2 938C>A can function as biomarkers of tumor radiosensitivity, being candidates for a predictive genetic profile of radiotherapy response. PMID- 29135312 TI - Rethinking the Biological and Toxin Weapons Convention? PMID- 29135314 TI - Correction to: Lind, Simonsen, Bjonness Ribu, Svendsen, Svennevig, and de Bot, Lexical access in a bilingual speaker with dementia: Changes over time. PMID- 29135313 TI - Third Cranial Nerve Palsy after a Chikungunya Virus Infection. AB - Chikungunya fever is a disease caused by a virus from the same family as dengue and Zika. It is endemic in several parts of the world and has recently spread to Latin America. We report the case of a patient, aged 58 years, from Rio de Janeiro, Brazil, who in 2013 developed an acute bilateral third cranial nerve palsy sparing the pupil. After extensive investigation, it was diagnosed as caused by chikungunya infection. The patient was treated with pulse therapy and after 5 months of the onset of the condition, the patient showed improvement. PMID- 29135315 TI - Risk allele of the FZD4 gene for familial exudative vitreoretinopathy. PMID- 29135317 TI - Erratum. PMID- 29135316 TI - Final Visual Outcomes and Treatment Received for Children Referred from a UK Primary School Visual Screening Program: A Comparison of An Orthoptic-led Program with Orthoptic-delivered Services. AB - : There is little published evidence relating to the final visual acuity of children who are identified as having reduced vision at a school screening program. The school vision screening program in Leeds (led by an orthoptist but delivered by health care support workers within the school nursing team) is examined. RESULTS: 7807 children were screened in school between November 1, 2013, and September 1, 2014. Of these, 319 (4%) failed the screen and were referred to the general optometry service and 547 (7%) were referred to the Children's Community Eye Service (CCES). Of the children who were referred to the CCES, 79.4% attended their first appointment and 86.4% were positive referrals. Of the children with reduced vision, 31 (8.3%) were found to have a manifest strabismus or eye movement disorder; 75 (20% of the positive referrals) required occlusion therapy for amblyopia; 52.6% of those with initially reduced vision obtained good visual acuity following spectacle correction alone within an 18- to 24-week refractive adaptation period. Of those who completed their treatment, 92.9% had vision within normal limits for their age in both eyes at discharge. Of children referred from vision screening who were found to have a defect, 64.6% had that treatment completed within three visits. CONCLUSION: Vision screening identifies individuals with treatable vision defects who have a greater than 90% chance of achieving normal visual acuity with good compliance to treatment. Vision screening programs led by an orthoptist but delivered by well-trained and monitored screeners can be of as good quality as a screening program delivered by orthoptists. PMID- 29135318 TI - The effect and safety of anacetrapib in the treatment of dyslipidemia: a systematic review and meta-analysis. AB - BACKGROUND: Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide. Anacetrapib may be a new treatment option that has a cardiovascular benefit for the management of dyslipidemia. OBJECTIVE: The aim of our current study was to perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) assessing the effect and safety of anacetrapib in the treatment of dyslipidemia. METHODS: We systematically searched PubMed, Embase, and Cochrane Library database from their inception to 5 October 2017, with the terms: 'anacetrapib' and 'placebo'. From 287 initial citations, 10 studies including 34781 patients with dyslipidemia were included in the final systematic review and meta-analysis. RESULTS: Pooled results showed that anacetrapib significantly increased high density lipoprotein cholesterol (HDL-C) [weighted mean differences (WMD) 53.07, 95% confidence interval (95% CI) 46.79 to 59.36] and apolipoprotein AI (ApoAI) (WMD 53.44, 95% CI 45.72 to 61.16). Our study also showed that anacetrapib significantly reduced low density lipoprotein cholesterol (LDL-C) (WMD -32.99; 95% CI -37.13 to -28.86), Non-HDL-C (WMD -39.19; 95% CI -52.22 to -26.16), triglycerides (TG) (WMD -9.97; 95% CI -10.54 to -9.41), apolipoprotein B (ApoB) (WMD -22.55; 95% CI -28.56 to -16.54) and lipoprotein a [LP(a)] (WMD -13.35; 95% CI -18.31 to -8.39). Our results demonstrated that there was no significant difference in all the following adverse events between the anacetrapib group and placebo group: [hepato-toxicity (OR 0.90, 95% CI: 0.75 to 1.07); musculoskeletal injury (OR 1.01, 95% CI: 0.88 to 1.15); drug-related adverse event (OR 1.00, 95% CI: 0.96 to 1.05); drug-related withdrawn (OR 1.01, 95% CI: 0.95 to 1.08)]. CONCLUSIONS: Although further studies are needed, our findings clearly offer support to the use of anacetrapib in the clinical management of patients with dyslipidemia. PMID- 29135320 TI - The Cultural Competence of Health Journalists: Obesity Coverage in Four Urban News Organizations. AB - This study sought to identify indicators of cultural competence in 670 news stories covering obesity by four urban news organizations: two mainstream newspapers and two ethnic newspapers serving the African-American and Hispanic communities. Through semantic network analysis, the research found that the news organizations converged on five themes: unhealthy lifestyle, food access and education, healthy lifestyle, public policy, and research. Public policy solutions were favored by the mainstream newspapers, while self-efficacy was emphasized in the ethnic papers. In all four newspapers, indicators of cultural competence were mixed. Ethnic newspapers showed particular competence in certain areas, such as community-based sourcing, direct mention of groups at risk for obesity, and lack of medical jargon. Chi-square tests showed, however, that the African-American newspaper discussed obesity less than expected, while the metropolitan daily directly mentioned ethnic groups at risk for obesity less than expected. PMID- 29135319 TI - Crosslinking Enzyme Lysyl Oxidase Modulates Scleral Remodeling in Form Deprivation Myopia. AB - PURPOSE: Scleral remodeling causes the excessive ocular elongation that underlies myopia. Lysyl oxidase (LOX), a copper-containing amine oxidase, can catalyze collagen and elastin crosslinking. The purpose of this study was to investigate the role of LOX in scleral remodeling in form-deprivation myopia (FDM). METHODS: Seventy-five guinea pigs were randomly divided into five groups as follows: a normal control group, an FDM group, an FDM plus beta-aminopropionitrile (BAPN) group, an FDM plus TGF-beta1 (TGF-beta1) group, and an FDM plus vehicle group. A translucent diffuser was used to induce FDM, and intravitreal injection was used to administer BAPN, TGF-beta1 or vehicle. The scleral LOX and collagen gene and protein levels and the posterior scleral ultrastructure and biomechanics were measured. RESULTS: In the FDM group, both the scleral LOX and collagen gene and protein levels were significantly lower than those in the control eyes. The collagen fibril diameters were significantly decreased in the FDM group compared with the diameters in the control group. A significant decrease in LOX gene and protein expression was observed after BAPN injection, and an increase was observed after TGF-beta1 treatment compared with the levels in the FDM group. Additionally, the scleral collagen fibrils were significantly decreased in the BAPN-treated eyes but increased in the TGF-beta1-treated eyes compared with the FDM eyes. The ultimate stress and Young's modulus of the sclera were lowest in the BAPN group, followed by the FDM group and the TGF-beta1 group. The ultimate strain (%) of the sclera was lowest in the TGF-beta1 group, followed by the FDM group and the BAPN group. CONCLUSION: LOX expression was significantly lowered in myopic sclera. Modulating LOX expression induced a change in both the scleral collagen fibril diameter and the scleral biomechanics. Therefore, LOX may play a key role in the myopia scleral remodeling procedure. PMID- 29135321 TI - Interactivity, Presence, and Targeted Patient Care: Mapping e-Health Intervention Effects Over Time for Cancer Patients with Depression. AB - This study examined the interplay of depression and different types of e-health interventions on breast cancer patients' perceived healthcare competence, emotional processing, and social well-being over time. The three e-health interventions--Internet Only as a control condition, CHESS (Comprehensive Health Enhancement Support System) Only, and CHESS with a Human Mentor, a cancer information specialist--provided varying degrees of interactivity and presence. A total of 328 women with breast cancer participated in one of the three interventions for a 6-month period. Women were further split into two groups based on reported levels of depression. For perceived healthcare competence and social well-being, results revealed significant interaction effects for intervention type by depression over time, such that breast cancer patients with higher levels of depression benefited most from the CHESS with Mentor intervention over the 6-month study period. For emotional processing, depressed cancer patients benefited more from the CHESS with Mentor than the other two interventions, regardless of time. These findings have (a) theoretical implications on how mental health factors can intersect with interactivity and presence to influence psychosocial outcomes, (b) conceptual implications for the role of human interaction within e-health systems, and PMID- 29135322 TI - Retinal Structure in Pre-Clinical Age-Related Macular Degeneration. AB - PURPOSE: To determine, if there are identifiable retinal structural changes associated with genetic risk for age-related macular degeneration (AMD). MATERIALS AND METHODS: Seventy-three subjects (range 51.5 to 68.9 years) participated in this prospective study. Subjects were recruited based on the presence of a family history of AMD in one or both parents. All participants underwent a complete ophthalmic exam and imagery for staging of disease severity and genetic testing to assess genetic risk for AMD development. Optical coherence tomography (OCT) imaging was performed on all participants. Semi-automated retinal layer segmentation was performed to assess retinal structural changes. RESULTS: Of 73 subjects, 47 subjects had normal appearing retina with no evidence of drusen or other changes consistent with AMD, 16 subjects were classified as early AMD, and 13 were designated as intermediate AMD. Retinal volume measures of total retina, outer retina, outer nuclear layer and the retinal pigment epithelium, were not related to AMD classification, genetic risk scores, or age. The thickness of the outer retina showed statistically significant thickening in the foveal region in only the intermediate AMD group and a statistically significant thickening of the RPE in early and intermediate AMD groups in the central retina. CONCLUSION: No consistent changes were observed in retinal structure at multiple locations that are associated with pre-clinical AMD, based on AMD genetic risk or with aging within the age range of our cohort. PMID- 29135323 TI - Impact assessment of the rational selection of training and test sets on the predictive ability of QSAR models. AB - This study performed an analysis of the influence of the training and test set rational selection on the quality and predictively of the quantitative structure activity relationship (QSAR) model. The study was carried out on three different datasets of Influenza Neuraminidase (H1N1) inhibitors. The three datasets were divided into training and test sets using three rational selection methods: based on k-means, Kennard-Stone algorithm and Activity and the results were compared with Random selection. Then, a total of 31,490 mathematical models were developed and those models that presented a determination coefficient higher than: r2train > 0.8, r2loo > 0.7, r2test > 0.5 and minimum standard deviation (SD) and minimum root-mean square error (RMS) were selected. The selected models were validated using the internal leave-one-out method and the predictive capacity was evaluated by the external test set. The results indicate that random selection could lead to erroneous results. In return, a rational selection allows for obtaining more reliable conclusions. The QSAR models with major predictive power were found using the k-means algorithm and selection by activity. PMID- 29135324 TI - Imaging the Tear Film: A Comparison Between the Subjective Keeler Tearscope PlusTM and the Objective Oculus(r) Keratograph 5M and LipiView(r) Interferometer. AB - PURPOSE: To compare non-invasive break-up time (NIBUT) when measured with the Tearscope-PlusTM and the Oculus(r) Keratograph 5M, and to compare lipid layer thicknesses (LLT) when measured with the Tearscope-PlusTM and the LipiView(r). This study also set out to establish the repeatability of these methods. METHODS: The following measurements were taken from both eyes of 24 participants on two occasions: non-invasive keratograph break-up time using the Oculus(r) (NIKBUT-1 and NIKBUT-average), NIBUT using the Tearscope-PlusTM, and LLT using the LipiView(r) (minimum, maximum, and average) and Tearscope-PlusTM. The Tearscope PlusTM grades were converted to nanometers. RESULTS: There were no significant differences between eyes (Tearscope-PlusTM NIBUT: p = 0.52; NIKBUT-1: p = 0.052; NIKBUT-average: p = 0.73; Tearscope-PlusTM LLT: p = 0.13; LipiView(r) average, maximum, or minimum: p = 0.68, 0.39 and 0.50, respectively) or days (Tearscope PlusTM NIBUT: p = 0.32; NIKBUT-1: p = 0.65; NIKBUT-average: p = 0.54; Tearscope PlusTM LLT: p = 0.26; LipiView(r) average, maximum, or minimum: p = 0.20, 0.09, and 0.10, respectively). LLT was significantly greater with the Tearscope-PlusTM (80.4 +/- 34.0 nm) compared with the LipiView(r) average (56.3 +/- 16.1 nm, p = 0.007), minimum (50.1 +/- 15.8 nm, p < 0.001) but not maximum (67.2 +/- 19.6 nm, p = 0.55). NIBUT was significantly greater with the Tearscope-PlusTM (15.9 +/- 10.7 seconds) compared to the NIKBUT-1 (8.2 +/- 3.5 seconds, p = 0.006) but not NIKBUT-average (10.9 +/- 3.9 seconds, p = 0.08). CONCLUSIONS: The Tearscope PlusTM is not interchangeable with either the Oculus(r) K5M measurement of tear stability (NIKBUT-1) or the LipiView(r) maximum and minimum lipid thickness. PMID- 29135325 TI - Facile development of nanocomplex-in-nanoparticles for enhanced loading and selective delivery of doxorubicin to brain. AB - AIM: Facile development of polysaccharides-based carrier system for efficient delivery of doxorubicin (DOX) to the brain. METHODS: DOX was nanocomplexed with alginate (Alg) followed by incorporation into chitosan (Cs) nanomatrices. The resulting carriers were optimized to have a net positive charge improving their delivery across the blood-brain barrier. The optimum DOX-loaded nanosystem was targeted to brain tissue via loading into various nasal dosage forms. RESULTS: The pH-dependent ionization of both DOX and Alg was found to have a significant effect on DOX entrapment efficiency which was improved from 4% at slightly acidic media to 85% using different pHs. The nasal dosage forms, especially the insert, delivered the loaded DOX mostly to the brain tissue with targeting efficiency reaching 480%. CONCLUSION: New intranasal carrier system was developed with efficient targeting of DOX to the brain. The carrier has potential to be used for delivery of other drugs acting on CNS. Graphical abstract: [Formula: see text]. PMID- 29135326 TI - Hydrogen/deuterium exchange mass spectrometry and computational modeling reveal a discontinuous epitope of an antibody/TL1A Interaction. AB - TL1A, a tumor necrosis factor-like cytokine, is a ligand for the death domain receptor DR3. TL1A, upon binding to DR3, can stimulate lymphocytes and trigger secretion of proinflammatory cytokines. Therefore, blockade of TL1A/DR3 interaction may be a potential therapeutic strategy for autoimmune and inflammatory diseases. Recently, the anti-TL1A monoclonal antibody 1 (mAb1) with a strong potency in blocking the TL1A/DR3 interaction was identified. Here, we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to obtain molecular-level details of mAb1's binding epitope on TL1A. HDX coupled with electron-transfer dissociation MS provided residue-level epitope information. The HDX dataset, in combination with solvent accessible surface area (SASA) analysis and computational modeling, revealed a discontinuous epitope within the predicted interaction interface of TL1A and DR3. The epitope regions span a distance within the approximate size of the variable domains of mAb1's heavy and light chains, indicating it uses a unique mechanism of action to block the TL1A/DR3 interaction. PMID- 29135327 TI - Coil Localization-Guided Video-Assisted Thoracoscopic Surgery for Lung Nodules. AB - PURPOSE: To determine the clinical efficacy of preoperative coil localization guided video-assisted thoracoscopic surgery (VATS) for lung nodules. MATERIALS AND METHODS: Between November 2015 and July 2017, 56 patients with lung nodules underwent coil localization-guided VATS procedure. The coil implantation was performed under the guidance of computed tomography (CT). The end tail of the coil remained above the visceral pleura. The target lung nodules were removed by VATS wedge resection. Data on the technical success of coil localization and wedge resection, procedure-related complications, and pathological results were collected and analyzed. RESULTS: Sixty-seven lung nodules in 56 patients (1.2 nodules/case) were localized. The technical success rate of coil localization was 89.6% (60/67). Sixty-three nodules were localized with one coil and four nodules with two coils. The mean time taken to perform CT-guided coil implantation was 15.7 +/- 5.3 (range: 8-40) minutes. Six patients (9.0%) experienced pneumothorax after coil implantation. The technical success rate of wedge resection was 97.0% (65/67). Two nodules were removed directly by video-assisted lobectomy. Nine patients with multiple target lung nodules underwent single-stage resection. The mean total operating time was 147.2 +/- 79.1 (range: 50-360) minutes. The mean volume of blood loss was 113.2 +/- 113.0 (range: 10-700) mL. Postoperative complications included prolonged air leak (n = 2) and pleural effusion (n = 5). CONCLUSIONS: Preoperative coil localization is a safe and effective method to facilitate a high successful rate of VATS wedge-resection for lung nodules. PMID- 29135328 TI - When the Solution Becomes A Problem: An Educational Discussion. PMID- 29135329 TI - YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. AB - Recent studies show that YTH domain family 2 (YTHDF2) preferentially binds to m6A containing mRNA regulates localization and stability of the bound mRNA. However, the role of YTHDF2 in pancreatic cancers remains to be elucidated. Here, we find that YTHDF2 expression is up-regulated in pancreatic cancer tissues compared with normal tissues at both mRNA and protein levels, and is higher in clinical patients with later stages of pancreatic cancer, indicating that YTHDF2 possesses potential clinical significance for diagnosis and prognosis of pancreatic cancers. Furthermore, we find that YTHDF2 orchestrates two cellular processes: promotes proliferation and inhibits migration and invasion in pancreatic cancer cells, a phenomenon called "migration-proliferation dichotomy", as well as epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. Furthermore, YTHDF2 knockdown significantly increases the total YAP expression, but inhibits TGF-beta/Smad signaling, indicating that YTHDF2 regulates EMT probably via YAP signaling. In summary, all these findings suggest that YTHDF2 may be a new predictive biomarker of development of pancreatic cancer, but a serious consideration is needed to treat YTHDF2 as a target for pancreatic cancer. PMID- 29135330 TI - Suffering in Advanced Cancer: A Randomized Control Trial of a Narrative Intervention. AB - BACKGROUND: Advanced cancer can erode patients' wellbeing. Narrative interventions have improved patients' wellbeing, but might not be feasible for widespread implementation. OBJECTIVES: (1) Test the effects of miLivingStory, a telephone-based life review and illness narrative intervention with online resources and social networking, on community-dwelling advanced cancer patients' wellbeing. (2) Explore intervention use and satisfaction. PATIENTS AND SETTING: Stage III or IV cancer patients having completed initial therapy were randomized to miLivingStory or to an active control group, miOwnResources. Data and Analysis: Primary outcomes measured at baseline, two and four months included subscales for the FACIT-Sp peace and meaning and the POMS-SF depressed, anxious, and angry mood, scored on 0-4-point Likert scales. Linear mixed modeling, controlling for baseline primary outcome scores, tested for group comparisons of repeated outcome measures. Pairwise comparisons tested for within- and between group differences. Intervention use and satisfaction data were collected automatically and by survey. RESULTS: Eighty-six primarily white, female patients with high baseline wellbeing completed the study. There were no between-group differences at baseline or at two months. At four months, miLivingStory had a direct and positive effect for peace (2.86 vs. 2.57, p = 0.029), a trend effect for lower depressed mood (0.55 vs. 0.77, p = 0.097), and appeared to protect against the control group's declining wellbeing between two and four months. miLivingStory use was low and assessed as helpful to quite helpful. CONCLUSIONS: Telephone-based narrative interventions hold promise in improving advanced cancer patients' wellbeing. Further testing of delivery and implementation strategies is warranted. PMID- 29135331 TI - Imaging microglial activation and amyloid burden in amnestic mild cognitive impairment. AB - Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer's disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Abeta) burden in-vivo . Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [18F]-FEPPA and [11C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high affinity binders were included. Dynamic [18F]-FEPPA PET images were analyzed using the 2-tissue compartment model with arterial plasma input function. Additionally, a supplementary method, the standardized uptake value ratio (SUVR), was explored. [11C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [11C]-PIB binding in the cortical regions. No significant differences in [18F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [18F]-FEPPA and [11C]-PIB bindings were correlated in the hippocampus. There were no correlations between our PET measures and cognition. Our findings demonstrate that while Abeta burden is evident in the aMCI stage, microglial activation may not be present. PMID- 29135332 TI - Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism. AB - Currently marketed Streptococcus pneumoniae (Spn) vaccines, which contain polysaccharide capsular antigens from the most common Spn serotypes, have substantially reduced pneumococcal disease rates but have limited coverage. A trivalent pneumococcal protein vaccine containing pneumococcal choline-binding protein A (PcpA), pneumococcal histidine triad protein D (PhtD), and detoxified pneumolysin is being developed to provide broader, cross-serotype protection. Antibodies against detoxified pneumolysin protect against bacterial pneumonia by neutralizing Spn-produced pneumolysin, but how anti-PhtD and anti-PcpA antibodies protect against Spn has not been established. Here, we used a murine passive protection sepsis model to investigate the mechanism of protection by anti-PhtD and anti-PcpA antibodies. Depleting complement using cobra venom factor eliminated protection by anti-PhtD and anti-PcpA monoclonal antibodies (mAbs). Consistent with a requirement for complement, complement C3 deposition on Spn in vitro was enhanced by anti-PhtD and anti-PcpA mAbs and by sera from PhtD- and PcpA-immunized rabbits and humans. Moreover, in the presence of complement, anti PhtD and anti-PcpA mAbs increased uptake of Spn by human granulocytes. Depleting neutrophils using anti-Ly6G mAbs, splenectomy, or a combination of both did not affect passive protection against Spn, whereas depleting macrophages using clodronate liposomes eliminated protection. These results suggest anti-PhtD and anti-PcpA antibodies induced by pneumococcal protein vaccines protect against Spn by a complement- and macrophage-dependent opsonophagocytosis. PMID- 29135335 TI - Retrospective Study of Tapered One-Piece Implants Placed Over a Ten-Year Period in a Single Private Practice. AB - Today, clinicians have a variety of treatment modalities available to address the increasing number of implant procedures performed each year. Single-stage implant surgery is now commonly used in implant dentistry. With patients' demands for immediate restoration, the utilization of 1-piece implants is gaining acceptance. This article reports the results of tapered 1-piece implants (Zimmer Biomet) placed in a single practice over a 10-year period. A total of 33 1-piece dental implants were placed in 24 patients and provisionally restored out of occlusion at the time of surgery. All 33 implants were definitively restored with ceramometal crowns after 3 months of provisionalization. Implant survival and success rates were 100% after 2.6-10 years of follow-up. Only 1 minor complication of crestal bone remodeling occurred among the 33 implants placed. Adequately stabilized tapered 1-piece implants can be successfully restored out of occlusion at the time of implant placement and definitively loaded in occlusion 3 months without adversely affecting function or esthetics. Additional long-term controlled studies are recommended to further understand these findings. PMID- 29135334 TI - Maternal high fat diet and its consequence on the gut microbiome: A rat model. AB - The biological changes that occur during pregnancy in the female mammal include shifts in hormonal regulation in preparation for parturition and lactation, and changes in energy metabolism. In women, studies have also shown that during pregnancy there is a reduction in bacterial species richness in the gut. In the current experiment rats were used to model the interaction of diet, reproductive status, and intestinal bacterial microbiota during pregnancy and lactation. In Experiment 1 rats were exposed to either standard chow or high-fat chow (60%) and were divided into two groups: unmated (NULL) or mated (RE). In Experiment 2, both NULL and RE rats were exposed to high-fat chow for a 30-day period. High throughput sequencing of the 16S rRNA gene revealed that pregnancy impacted the gut microbiota in a similar manner to humans. The impact of reproductive status on microbiota composition, however, was stronger in rats fed a high-fat (HF) diet. Diet-induced changes replicated some of the changes observed in humans, such as increasing the Firmicutes/Bacteroidetes ratio. However, in contrast to humans, pregnancy in rats did not increase beta-diversity between microbiota from different animals. These results indicate that during pregnancy in rats, the gut microbiota is altered in a similar manner to that which occurs in women, and that these changes are further exaggerated by exposure to a HF diet. Thus, the rat may allow modelling the effects of consumption of HF food during pregnancy and enable future studies to determine the risks of HF diets during pregnancy and its consequences on the offspring. PMID- 29135333 TI - Challenges of ligand identification for the second wave of orphan riboswitch candidates. AB - Orphan riboswitch candidates are noncoding RNA motifs whose representatives are believed to function as genetic regulatory elements, but whose target ligands have yet to be identified. The study of certain orphans, particularly classes that have resisted experimental validation for many years, has led to the discovery of important biological pathways and processes once their ligands were identified. Previously, we highlighted details for four of the most common and intriguing orphan riboswitch candidates. This facilitated the validation of riboswitches for the signaling molecules c-di-AMP, ZTP, and ppGpp, the metal ion Mn2+, and the metabolites guanidine and PRPP. Such studies also yield useful linkages between the ligands sensed by the riboswitches and numerous biochemical pathways. In the current report, we describe the known characteristics of 30 distinct classes of orphan riboswitch candidates - some of which have remained unsolved for over a decade. We also discuss the prospects for uncovering novel biological insights via focused studies on these RNAs. Lastly, we make recommendations for experimental objectives along the path to finding ligands for these mysterious RNAs. PMID- 29135336 TI - A retrospective observational analysis of post-pandemic influenza-related outcomes in the United Kingdom, 2010-2014. AB - This study set out to evaluate influenza- and respiratory-related illnesses recorded during primary care physician consultations in England following the H1N1 pandemic in 2009 and to enable the development of a dynamic disease model. Data were obtained from the Clinical Practice Research Datalink of primary care records over four influenza seasons (2010-2014). The primary outcome of the study was incidence of influenza- and respiratory-related diagnoses, calculated per practice and by season and age group. Upper respiratory tract infection diagnoses were most frequently recorded (mean seasonal practice level incidence; 3,762 consultations per 100,000 [SD = 1,989]), and influenza-related diagnoses were least frequently recorded across all seasons, except one. Incidence rates for the under 18 population were higher than those for the general population, in particular for upper respiratory tract infection (range of 8,024-9,950 versus 3,228-4,120, respectively) and otitis media diagnoses (2,668-3,652 versus 782 1,057, respectively). For influenza-related diagnoses, the 65+ age group, the 0 to <2 and 2 to <4 groups had a higher risk (risk ratio = 1.33, 1.12 and 1.16, respectively) than other age groups. This study provides valuable insight into the incidence of influenza- and respiratory-related diagnoses in the primary care setting in England, and suggests a higher burden of disease in young children and the elderly. The study also indicates that some influenza illness is likely to be reported under respiratory-related diagnoses, given the low incidence of influenza-related diagnoses in the study. PMID- 29135337 TI - DNA vaccines elicit durable protective immunity against individual or simultaneous infections with Lassa and Ebola viruses in guinea pigs. AB - We previously developed optimized DNA vaccines against both Lassa fever and Ebola hemorrhagic fever viruses and demonstrated that they were protective individually in guinea pig and nonhuman primate models. In this study, we vaccinated groups of strain 13 guinea pigs two times, four weeks apart with 50 ug of each DNA vaccine or a mock vaccine at discrete sites by intradermal electroporation. Five weeks following the second vaccinations, guinea pigs were exposed to lethal doses of Lassa virus, Ebola virus, or a combination of both viruses simultaneously. None of the vaccinated guinea pigs, regardless of challenge virus and including the coinfected group, displayed weight loss, fever or other disease signs, and all survived to the study endpoint. All of the mock-vaccinated guinea pigs that were infected with Lassa virus, and all but one of the EBOV-infected mock-vaccinated guinea pigs succumbed. In order to determine if the dual-agent vaccination strategy could protect against both viruses if exposures were temporally separated, we held the surviving vaccinates in BSL-4 for approximately 120 days to perform a cross-challenge experiment in which guinea pigs originally infected with Lassa virus received a lethal dose of Ebola virus and those originally infected with Ebola virus were infected with a lethal dose of Lassa virus. All guinea pigs remained healthy and survived to the study endpoint. This study clearly demonstrates that DNA vaccines against Lassa and Ebola viruses can elicit protective immunity against both individual virus exposures as well as in a mixed infection environment. PMID- 29135338 TI - Convergent and Divergent Signaling in PAMP-Triggered Immunity and Effector Triggered Immunity. AB - Plants use diverse immune receptors to sense pathogen attacks. Recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors localized on the plasma membrane leads to PAMP-triggered immunity (PTI). Detection of pathogen effectors by intracellular or plasma membrane-localized immune receptors results in effector-triggered immunity (ETI). Despite the large variations in the magnitude and duration of immune responses triggered by different PAMPs or pathogen effectors during PTI and ETI, plasma membrane localized immune receptors activate similar downstream molecular events such as mitogen-activated protein kinase activation, oxidative burst, ion influx, and increased biosynthesis of plant defense hormones, indicating that defense signals initiated at the plasma membrane converge at later points. On the other hand, activation of ETI by immune receptors localized to the nucleus appears to be more directly associated with transcriptional regulation of defense gene expression. Here, we review recent progress in signal transductions downstream of different groups of plant immune receptors, highlighting the converging and diverging molecular events. PMID- 29135339 TI - Improving rotavirus vaccine coverage: Can newer-generation and locally produced vaccines help? AB - There are two internationally available WHO-prequalified oral rotavirus vaccines (Rotarix and RotaTeq), two rotavirus vaccines licensed in India (Rotavac and Rotasiil), one in China (Lanzhou lamb rotavirus vaccine) and one in Vietnam (Rotavin-M1), and several candidates in development. Rotavirus vaccination has been rolled out in Latin American countries and is beginning to be deployed in sub-Saharan African countries but middle- and low-income Asian countries have lagged behind in rotavirus vaccine introduction. We provide a mini-review of the leading newer-generation rotavirus vaccines and compare them with Rotarix and RotaTeq. We discuss how the development and future availability of newer generation rotavirus vaccines that address the programmatic needs of poorer countries may help scale-up rotavirus vaccination where it is needed. PMID- 29135341 TI - In this issue: Fine tuners of immunity and their role in infectious and non infectious diseases. PMID- 29135340 TI - Generation and testing anti-influenza human monoclonal antibodies in a new humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO. IL-2Rgammac KO. NOD). AB - Pandemic outbreaks of influenza type A viruses have resulted in numerous fatalities around the globe. Since the conventional influenza vaccines (CIV) provide less than 20% protection for individuals with weak immune system, it has been considered that broadly cross-neutralizing antibodies may provide a better protection. Herein, we showed that a recently generated humanized mouse (DRAGA mouse; HLA-A2. HLA-DR4. Rag1KO. IL-2Rgc KO. NOD) that lacks the murine immune system and expresses a functional human immune system can be used to generate cross-reactive, human anti-influenza monoclonal antibodies (hu-mAb). DRAGA mouse was also found to be suitable for influenza virus infection, as it can clear a sub-lethal infection and sustain a lethal infection with PR8/A/34 influenza virus. The hu-mAbs were designed for targeting a human B-cell epitope (180WGIHHPPNSKEQ QNLY195) of hemagglutinin (HA) envelope protein of PR8/A/34 (H1N1) virus with high homology among seven influenza type A viruses. A single administration of HA180-195 specific hu-mAb in PR8-infected DRAGA mice significantly delayed the lethality by reducing the lung damage. The results demonstrated that DRAGA mouse is a suitable tool to (i) generate heterotype cross reactive, anti-influenza human monoclonal antibodies, (ii) serve as a humanized mouse model for influenza infection, and (iii) assess the efficacy of anti influenza antibody-based therapeutics for human use. PMID- 29135342 TI - Invisible Parasites and Their Implications for Coexisting Water Fleas. AB - The top-down effects of consumers, such as predators, are known to affect abundances, size structure, and species composition in aquatic ecosystems. Parasites are also important in shaping the ecology of free-living species; however, their effects are often overlooked because parasites can be difficult to detect. Parasites can be particularly challenging to observe in zooplankton hosts because of their small size and ephemeral infection periods. To overcome these challenges, we used a quarantine approach combined with high-magnification microscopy to increase detection of parasites of the tropical Cladoceran, Ceriodaphnia cornuta, in Lake Gatun, Panama. Using this approach, we were able to demonstrate that competing morphs of Ceriodaphnia experience differential rates of infection, where the subordinate competitor suffered higher parasite prevalence than did the dominant morph. Predation by fishes on the dominant morph is considered the principal mechanism for their coexistence, but we hypothesize that parasites may also play a role in maintaining morphotype diversity of Ceriodaphnia. PMID- 29135344 TI - Matrivax profile. PMID- 29135343 TI - Effects of influenza immunization on pneumonia in the elderly. AB - Influenza virus is a common pathogen implicated in respiratory tract infections, annually affecting up to 20% of the general population, and pneumonia is a leading cause of death after influenza infection. Post-influenza pneumonia is especially common in the elderly and chronically ill patients. The risk of post influenza pneumonia is significantly increased according to the number of concurrent comorbidities. Vaccination is the primary measure used to abate influenza epidemics and associated complications. In meta-analyses, influenza vaccine significantly reduces pneumonia- and influenza-related hospitalizations, with a vaccine effectiveness of 25-53%. However, considering the poor effectiveness of conventional influenza vaccines in the elderly, several highly immunogenic influenza vaccines have been developed. Further evaluations of the comparative effectiveness of diverse vaccine formulations are warranted to assess their utility for preventing influenza infection, post-influenza pneumonia, and related hospitalization/mortality. Based on cost-effectiveness and budget impact analysis, influenza vaccination strategies should be tailored in the elderly. PMID- 29135345 TI - Localized drug release and effective chemotherapy by hyperthermia-governed bubble generating hybrid nanocapsule system. AB - AIM: To build up a remote triggering drug delivery system with hyperthermia responsive ammonium bicarbonate salt and investigate its effects on tumor therapy. MATERIALS & METHODS: This hybrid nanocapsule system was prepared by a different strategy, doxorubicin (DOX) was encapsulated in the heparin shell first and then ammonium bicarbonate was diffused into the nanocapsules to generate DOX bicarbonate salt, its characterizations and effects on tumor therapy were investigated. RESULTS: Upon exposure to mild external thermal treatment (42 degrees C), DOX-bicarbonate salt began to decompose with the recovery of DOX fluorescence, carbon dioxide generation and rapid DOX release out of the nanocapsules, exhibiting great abilities to accumulate at tumor site rapidly and inhibit tumor cell growth. CONCLUSION: These hybrid nanocapsules demonstrate great potential in clinical applications triggering by external thermal treatment. PMID- 29135347 TI - Relative cerebral blood volume is associated with collateral status and infarct growth in stroke patients in SWIFT PRIME. AB - : We aimed to evaluate how predefined candidate cerebral perfusion parameters correlate with collateral circulation status and to assess their capacity to predict infarct growth in patients with acute ischemic stroke (AIS) eligible for endovascular therapy. Patients enrolled in the SWIFT PRIME trial with baseline computed tomography perfusion (CTP) scans were included. RAPID software was used to calculate mean relative cerebral blood volume (rCBV) in hypoperfused regions, and hypoperfusion index ratio (HIR). Blind assessments of collaterals were performed using CT angiography in the whole sample and cerebral angiogram in the endovascular group. Reperfusion was assessed on 27-h CTP; infarct volume was assessed on 27-h magnetic resonance imaging/CT scans. Logistic and rank linear regression models were conducted. We included 158 patients. High rCBV ( p = 0.03) and low HIR ( p = 0.03) were associated with good collaterals. A positive association was found between rCBV and better collateral grades on cerebral angiography ( p = 0.01). Baseline and 27-h follow-up CTP were available for 115 patients, of whom 74 (64%) achieved successful reperfusion. Lower rCBV predicted a higher infarct growth in successfully reperfused patients ( p = 0.038) and in the endovascular treatment group ( p = 0.049). Finally, rCBV and HIR may serve as markers of collateral circulation in AIS patients prior to endovascular therapy. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT0165746. PMID- 29135349 TI - Highlights from the Current Issue: August 2015. PMID- 29135348 TI - Development of a Surgical Infection Surveillance Program at a Tertiary Hospital in Ethiopia: Lessons Learned from Two Surveillance Strategies. AB - BACKGROUND: Surgical site infections (SSIs) are a leading cause of post-operative morbidity and mortality. We developed Clean Cut, a surgical infection prevention program, with two goals: (1) Increase adherence to evidence-based peri-operative infection prevention standards and (2) establish sustainable surgical infection surveillance. Here we describe our infection surveillance strategy. PATIENTS AND METHODS: Clean Cut was piloted and evaluated at a 523 bed tertiary hospital in Ethiopia. Infection prevention standards included: (1) Hand and surgical site decontamination; (2) integrity of gowns, drapes, and gloves; (3) instrument sterility; (4) prophylactic antibiotic administration; (5) surgical gauze tracking; and (6) checklist compliance. Primary outcome measure was SSI, with secondary outcomes including other infection, re-operation, and length of stay. We prospectively observed all post-surgical wounds in obstetrics over a 12 day period and separately recorded post-operative complications using chart review. Simultaneously, we reviewed the written hospital charts after patient discharge for all patients whose peri-operative adherence to infection prevention standards was captured. RESULTS: Fifty obstetric patients were followed prospectively with recorded rates of SSI 14%, re-operation 6%, and death 2%. Compared with direct observation, chart review alone had a high loss to follow-up (28%) and decreased capture of infectious complications (SSI [n = 2], endometritis [n = 3], re operations [n = 2], death [n = 1]); further, documentation inconsistencies failed to capture two complications (SSI [n = 1], mastitis [n = 1]). Concurrently, 137 patients were observed for peri-operative infection prevention standard adherence. Of these, we were able to successfully review 95 (69%) patient charts with recorded rates of SSI 5%, re-operation 1%, and death 1%. CONCLUSION: Patient loss to follow-up and poor documentation of infections underestimated overall infectious complications. Direct, prospective follow-up is possible but requires increased time, clinical skill, and training. For accurate surgical infection surveillance, direct follow-up of patients during hospitalization is essential, because chart review does not accurately reflect post-operative complications. PMID- 29135350 TI - Highlights from the Current Issue: November 2015. PMID- 29135351 TI - Human Studies of Vertical and Horizontal Alveolar Ridge Augmentation Comparing Different Types of Bone Graft Materials: A Systematic Review. AB - Alveolar ridge augmentation can be completed with various types of bone augmentation materials (autogenous, allograft, xenograft, and alloplast). Currently, autogenous bone is labeled as the "gold standard" because of faster healing times and integration between native and foreign bone. No systematic review has currently determined whether there is a difference in implant success between various bone augmentation materials. The purpose of this article was to systematically review comparative human studies of vertical and horizontal alveolar ridge augmentation comparing different types of bone graft materials (autogenous, allograft, xenograft, and alloplast). A MEDLINE search was conducted under the 3 search concepts of bone augmentation, dental implants, and alveolar ridge augmentation. Studies pertaining to socket grafts or sinus lifts were excluded. Case reports, small case series, and review papers were excluded. A bias assessment tool was applied to the final articles. Overall, 219 articles resulted from the initial search, and 9 articles were included for final analysis. There were no discernible differences in implant success between bone augmentation materials. Generally, patients preferred nonautogenous bone sources as there were fewer hospital days, less pain, and better recovery time. Two articles had industrial support; however, conclusions of whether that support influenced the outcomes could not be determined. Future comparative studies should compare nonautogenous bone sources and have longer follow-up times. PMID- 29135346 TI - Cerebral artery myogenic reactivity: The next frontier in developing effective interventions for subarachnoid hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (SAH) is a devastating cerebral event that kills or debilitates the majority of those afflicted. The blood that spills into the subarachnoid space stimulates profound cerebral artery vasoconstriction and consequently, cerebral ischemia. Thus, once the initial bleeding in SAH is appropriately managed, the clinical focus shifts to maintaining/improving cerebral perfusion. However, current therapeutic interventions largely fail to improve clinical outcome, because they do not effectively restore normal cerebral artery function. This review discusses emerging evidence that perturbed cerebrovascular "myogenic reactivity," a crucial microvascular process that potently dictates cerebral perfusion, is the critical element underlying cerebral ischemia in SAH. In fact, the myogenic mechanism could be the reason why many therapeutic interventions, including "Triple H" therapy, fail to deliver benefit to patients. Understanding the molecular basis for myogenic reactivity changes in SAH holds the key to develop more effective therapeutic interventions; indeed, promising recent advancements fuel optimism that vascular dysfunction in SAH can be corrected to improve outcome. PMID- 29135354 TI - Depression following traumatic brain injury in mice is associated with down regulation of hippocampal astrocyte glutamate transporters by thrombin. AB - Depression after traumatic brain injury (TBI) is common but the mechanisms by which TBI causes depression are unknown. TBI decreases glutamate transporters GLT 1 and GLAST and allows extravasation of thrombin. We examined the effects of thrombin on transporter expression in primary hippocampal astrocytes. Application of a PAR-1 agonist caused down-regulation of GLT-1, which was prevented by inhibition of Rho kinase (ROCK). To confirm these mechanisms in vivo, we subjected mice to closed-skull TBI. Thrombin activity in the hippocampus increased one day following TBI. Seven days following TBI, expression of GLT-1 and GLAST was reduced in the hippocampus, and this was prevented by administration of the PAR-1 antagonist SCH79797. Inhibition of ROCK attenuated the decrease in GLT-1, but not GLAST, after TBI. We measured changes in glutamate levels in the hippocampus seven days after TBI using an implanted biosensor. Stress-induced glutamate levels were significantly increased following TBI and this was attenuated by treatment with the ROCK inhibitor fasudil. We quantified depressive behavior following TBI and found that inhibition of PAR-1 or ROCK decreased these behaviors. These results identify a novel mechanism by which TBI results in down-regulation of astrocyte glutamate transporters and implicate astrocyte and glutamate transporter dysfunction in depression following TBI. PMID- 29135353 TI - Erratum. PMID- 29135352 TI - The Effectiveness of Daily Behavior Report Cards for Children With ADHD: A Meta Analysis. AB - OBJECTIVE: This meta-analysis examined group-design studies investigating the effectiveness of Daily Behavior Report Cards (DBRC) as a school-based intervention to manage the classroom behavior of students with ADHD. METHODS: A search of three article databases (PsycINFO, ERIC and Medline) identified seven group design evaluations of DBRC interventions. This meta-analysis included a total of 272 participants, with an average age of 7.9 years old. Three of the studies compared a control group to a treatment group with randomized group assignment, one study compared a control group to three treatment groups, two studies compared pre-and post-treatment scores in the same group, and one study compared pre-and post-treatment results of two intervention groups without random assignment. Dependent measures for these studies were teacher ratings (n = 5) and systematic direct observation of student academic and social behaviour (n = 2). Standardized mean differences ( Hedge's g) were calculated to obtain a pooled effect size using fixed effects. RESULTS: DBRCs were associated with reductions teacher-rated ADHD symptoms, with a Hedge's g of 0.36 (95% CI: 0.12-0.60, z=2.93, p <= .005) with low heterogeneity (Q-value: 2.40, I2 = 0.00). This result excluded two studies that used observational coding instead of standardized tests to evaluate the effects of the intervention. A moderator analysis indicated that the effect size for systematic direct observation was large ( Hedge's G = 1.05[95% CI: 0.66-1.44, z=5.25, p <= .00]), with very high heterogeneity (Q value: 46.34, I2: 93.53). A second moderator analysis found differences in the effects of DBRCs for comorbid externalizing symptoms with an overall effect size of 0.34 (95%CI: -0.04-0.72, z=1.76 p =0.08) with high heterogeneity (Q-value: 3.98, I2: 74.85). CONCLUSIONS: DBRCs effectively reduce the frequency and severity of ADHD symptoms in classroom settings. Additionally, they have a significant effect on co-occuring externalizing behaviors. It appears that systematic direct observation may be a more sensitive measure of treatment effects compared to teacher ratings of ADHD symptoms. PMID- 29135355 TI - Changes in Ocular Hemodynamics after Carotid Artery Angioplasty and Stenting (CAAS) in Patients with Different Severity of Ocular Ischemic Syndrome. AB - PURPOSE: To evaluate the effects of carotid artery angioplasty and stenting (CAAS) on patients who were diagnosed with ocular ischemic syndrome (OIS). METHODS: Sixty-four eyes of 64 OIS patients with ipsilateral internal carotid artery stenosis >=70% were included in the study. The study eyes were divided into two groups according to the presence of iris neovascularization: NVI-absent group and NVI-present group, with 32 eyes, respectively. All patients received ocular treatment modality according to the presence of non-perfusion area (pan retinal photocoagulation) and intraocular pressure (medical treatment included timolol maleate eye drops combined with brinzolamide eye drop; trabeculectomy and cyclophotocoagulation). All patients went through CAAS surgery for treatment of internal carotid artery stenosis. Best-corrected visual acuity (BCVA); intraocular pressure (IOP), slit lamp examination, iris fluorescence angiography, fundus fluorescein angiography and color Doppler ultrasound of the internal carotid artery (ICA), ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (PCA) were performed pre-operatively and 1 month, 3 months, 6 months, and 12 months post-operatively. RESULTS: There was no significant BCVA change postoperatively in the NVI-absent group, while postoperative BCVA in the INV-present group decreased significantly. There was no significant BCVA difference at pre-operative and 1month post-operative follow-up between the two groups. However, post-operative BCVA of NVI-present group starting from 3-months follow-up was significantly worse than NVI-absent group. Arm-retinal artery circulation time and arteriovenous circulation time decreased significantly in NVI-absent group, while showed no statistical difference in NVI present group during the 12-months follow-up. Postoperative peak systolic velocity (PSV) of the ophthalmic artery, the central retinal artery, and short posterior ciliary artery showed significant increases at 1 month, 3 months, 6 months and 12 months follow-up in both groups. CONCLUSION: CAAS can greatly improve ocular blood in OIS patients with and without iris neovascularization. However, CAAS improved BCVA only in patients without iris neovascularization. PMID- 29135356 TI - Antibody Prevalence to Influenza Type A in Wild Boar of Northern Ukraine. AB - A preliminary serological survey was carried out to assess the likelihood of influenza A (IA) infection in wild boar and begin to characterize the role of wild boar in the epidemiology of the IA virus (IAV). Sera collected from 120 wild boar that were hunted in 2014 were tested. To detect antibodies to IA, a blocking the enzyme-linked immunosorbent assay (ELISA) was used. Thirty boar were collected from each of four oblasts in the north central and northwestern regions of Ukraine. Antibodies against IAV were detected in 27 samples (22.5%; 95% confidence interval 16.0-30.8) and in at least some of the wild boar from all of the four oblasts. This preliminary survey of IA antibodies in wild boar populations of northern Ukraine indicates a substantial frequency of exposure to IAV throughout the region. Infection of wild boar populations could provide an alternative or additional route for spillover from wild populations to domestic animals and humans. PMID- 29135357 TI - Short-term Refractive Effects of Propranolol Hydrochloride Prophylaxis on Retinopathy of Prematurity in Very Preterm Newborns. AB - PURPOSE: Retinopathy of prematurity (ROP) is one of the major problems of surviving premature infants with several ophthalmic morbidities such as increased risk of refractive errors, strabismus, and cortical visual impairment. Use of propranolol hydrochloride (PH) for the prevention of ROP is a new promising treatment modality. However, long-term effects are still to be defined. In our study, we aimed to investigate the short-term refractive effects of PH used for ROP prophylaxis in very preterm newborns. METHODS: This is a prospective, randomized, double-blind, placebo-controlled study. Very preterm newborns with a birthweight less than or equal to 1500 g and/or born prior to 32 gestational weeks were included in the study. The subjects were randomly divided into two groups: control group (CG, n = 37) given placebo and PH group (PHG, n = 34) given PH starting from 4 weeks after birth (27.1 +/- 2.1 day). PHG patients received PH therapy for about 1 month (25.7 +/- 7.8 day). Anthropometric measurements including weight, length, and head circumference were recorded before PH treatment (at birth) and during eye control (at corrected age). Cycloplegic refraction values were measured by retinoscopy at corrected age (CG: 10.3 +/- 4.3 months, PHG: 11.4 +/- 4.8 months). RESULTS: Anthropometric measurements including gestational age, weight, length, and head circumference were similar at birth and corrected age in both groups. The mean level of spherical refraction was significantly less hyperopic in the PHG than in the CG (CG: 1.37 +/- 1.40 D, PHG: 0.37 +/- 1.44 D) (p = 0.005). CONCLUSION: PH may lead to myopic shift by affecting the beta-adrenergic receptors in the choroid or ciliary body of the developing eye. Long-term refractive follow-up is required in order to elucidate the effects of PH on emmetropization process of these very preterm infants. PMID- 29135358 TI - Training Area Agencies on Aging Case Managers to Improve Physical Function, Mood, and Behavior in Persons With Dementia and Caregivers: Examples from the RDAD Northwest Study. AB - The Reducing Disability in Alzheimer's Disease (RDAD) program has been shown to be an effective tool for teaching caregivers strategies to improve mood, behavior, and physical function in persons with dementia. This paper describes how RDAD has been translated and implemented for use by Area Agencies on Aging (AAA) case managers across Washington and Oregon. Modifications to the original RDAD program as part of its community translation included decreasing the number of in-person sessions while preserving all educational content; involving caregivers in exercise activities for themselves as well as acting as exercise coaches for care-receivers; and enrolling persons with cognitive impairment due to mixed etiologies. This paper describes these changes and their rationale, the challenges faced by community agencies recruiting for and delivering evidence based programs, and illustrates the actual RDAD implementation process through several brief case examples. Case examples also illustrate how RDAD-Northwest can be useful with care-receivers with a range of cognitive impairment severity, family caregiving situations, and levels of mood and behavioral challenges. PMID- 29135359 TI - Fitness, Competitive Ability, and Mutation Stability of Isolates of Colletotrichum acutatum from Strawberry Resistant to QoI Fungicides. AB - Quinone-outside inhibitor (QoI) fungicides are used to manage anthracnose of strawberry, caused by Colletotrichum acutatum. However, selection for resistance to QoI fungicides was first reported in 2013 in Florida and, subsequently, in strawberry nurseries and production areas across the United States and Canada. C. acutatum resistance to QoIs is associated with the G143A point mutation in the cytochrome b gene. This mutation is known to be associated with field resistance even at high rates of QoI. In this study, we investigated the relative fitness and competitive ability of QoI-resistant and -sensitive C. acutatum isolates. A fitness comparison did not indicate any difference between resistant and sensitive isolates in aggressiveness, spore production, and mycelial growth at different temperatures. Additionally, in the absence of selection pressure, resistant and sensitive isolates were equally competitive. Cultivation of QoI resistant and QoI-sensitive isolates for four culture cycles in vitro in the absence of azoxystrobin showed that QoI resistance was stable. The observed lack of fitness penalties and stability of the G143A mutation in QoI-resistant C. acutatum populations suggest that the interruption and further reintroduction of QoI fungicides might not be an option for strawberry nurseries and fruit production areas. Further investigation of alternative chemical and nonchemical C. acutatum control practices, in addition to the integration of multisite fungicides, is needed to reduce the occurrence and distribution of QoI-resistant populations in strawberry fields. PMID- 29135360 TI - Transcriptome Profiling of Melaleuca quinquenervia Challenged by Myrtle Rust Reveals Differences in Defense Responses Among Resistant Individuals. AB - Plants have developed complex defense mechanisms to protect themselves against pathogens. A wide-host-range fungus, Austropuccinia psidii, which has caused severe damage to ecosystems and plantations worldwide, is a major threat to Australian ecosystems dominated by members of the family Myrtaceae. In particular, the east coast wetland foundation tree species Melaleuca quinquenervia, appears to be variably susceptible to this pathogen. Understanding the molecular basis of host resistance would enable better management of this rust disease. We identified resistant and susceptible individuals of M. quinquenervia and explored their differential gene expression in order to discover the molecular basis of resistance against A. psidii. Rust screening of germplasm showed a varying degree of response, with fully resistant to highly susceptible individuals. We used transcriptome profiling in samples collected before and at 5 days postinoculation (dpi). Differential gene expression analysis showed that numerous defense-related genes were induced in susceptible plants at 5 dpi. Mapping reads against the A. psidii genome showed that only susceptible plants contained fungal-derived transcripts. Resistant plants exhibited an overexpression of candidate A. psidii resistance-related genes such as receptor like kinases, nucleotide-binding site leucine-rich repeat proteins, glutathione S transferases, WRKY transcriptional regulators, and pathogenesis-related proteins. We identified large differences in the expression of defense-related genes among resistant individuals. PMID- 29135361 TI - Molecular characteristics of new clonal complexes of Staphylococcus pseudintermedius from clinically normal dogs. AB - BACKGROUND: High prevalence of methicillin resistance among clinical isolates of Staphylococcus pseudintermedius obtained from dogs was reported in Seoul metropolitan area, South Korea. However, no information on genetic lineage and clonal spread is currently available. OBJECTIVE: The aim is to identify the genetic diversity of methicillin-resistant or -susceptible S. pseudintermedius (MRSP and MSSP, respectively) from healthy dogs. ANIMALS AND METHODS: From 119 healthy dogs, 29 isolates consisting of 20 MRSP and 9 MSSP were collected from June 2013 to February 2014. Phenotypic features, antibiogram, multilocus sequence type (MLST), Staphylococcal cassette chromosome mec (SCCmec) type and spa gene type were analyzed. RESULTS: MLST showed 24 sequence types (STs), including 20 new STs that were genetically distinct from the previous STs in other geographic areas. SCCmec typing revealed that all isolates had SCCmec type V, a predominant type in North America. spa gene typing was successful in only 13 isolates (10 MRSP and 3 MSSP) and revealed two known types (t02 and t06), as well as one novel type (t73). CONCLUSION: Our cumulative data indicate the presence of various populations of S. pseudintermedius in clinically normal dogs in Seoul metropolitan area. PMID- 29135363 TI - Total and Subtotal Laparoscopic Gastrectomy for the Treatment of Advanced Gastric Cancer: Morbidity and Oncological Outcomes. AB - BACKGROUND: A debate is still surrounding the use of laparoscopic surgery for advanced gastric cancer (AGC) related to doubts about the requirements to satisfy oncologic criteria. The aim of this study is to analyze the oncological results, the intraoperative complications, and the short- and medium-term morbidity and mortality in patients with AGC who underwent subtotal laparoscopic gastrectomy (SLG) or total laparoscopic gastrectomy (TLG) with extended lymphadenectomy. MATERIALS AND METHODS: We reviewed medical records of patients who underwent radical gastrectomy for AGC started laparoscopically with the intent of curative surgery, between July 2007 and October 2015. We recruited 74 patients and studied demographics, American Society of Anesthesiologists (ASA) score, pTNM stage, histologic pattern of the tumor, duration of surgery, conversion rate, estimated blood loss, number of resected lymph nodes, type of gastrointestinal reconstruction, postoperative complication, mortality rate, length of stay, time to canalization and resumption of food intake, and overall and disease-free survival rate. RESULTS: We performed 74 interventions, with a conversion rate of 14.9% (11/74). Sixty-three were performed totally as laparoscopic: 43 (68.25%) SLGs and 20 (31.75%) TLGs, all with an extended lymphadenectomy (D2 or more). Operative time was 150 +/- 34 minutes (range 75-225 minutes), the mean number of resected lymph nodes 21.4 +/- 6.2, global morbidity rate 25.39%, rate of reoperation 9.52%, and perioperative mortality at 30 days 0%. We performed an average follow-up of 48.7 months (range 18-60), and we observed 5-year overall and disease-free survival, respectively, of 48.6% and 42.7%. CONCLUSIONS: LG with extended lymphadenectomy for AGC is a feasible procedure with good results in terms of postoperative course, complications, and mortality. Thanks to the use of extremely precise and safe technologies the extended lymphadenectomy can be performed laparoscopically. The laparoscopic approach, when performed by experienced surgeons, ensures a correct oncological treatment in combination with the benefits of the laparoscopic technique. PMID- 29135364 TI - Mothers' Neural and Behavioral Responses to Their Infants' Distress Cues: The Role of Secure Base Script Knowledge. AB - This research examined mothers' secure base script knowledge-reflected in the ability to generate narratives in which attachment-relevant problems are recognized, competent help is offered, and problems are resolved-and its significance for early-stage processing of infants' distress cues, using event related potentials in an emotion oddball task. Mothers with lower secure base script knowledge exhibited (a) a heightened P3b response-reflective of greater allocation of cognitive resources-to their infants' distressed (but not happy) target facial expressions; (b) a larger P3b response to their infants' distressed (compared with happy) target facial expressions, which is indicative of allocating disproportional attentional resources to processing their infants' distress; and (c) poorer accuracy in identifying their infants' distressed target facial expressions. Findings suggest that mothers' attachment-relevant biases in processing their infants' emotion cues are especially tied to infant distress and shed light on underlying mechanisms linking mothers' attachment representations with sensitive responding to infant distress. PMID- 29135365 TI - Deep Learning to Classify Radiology Free-Text Reports. AB - Purpose To evaluate the performance of a deep learning convolutional neural network (CNN) model compared with a traditional natural language processing (NLP) model in extracting pulmonary embolism (PE) findings from thoracic computed tomography (CT) reports from two institutions. Materials and Methods Contrast material-enhanced CT examinations of the chest performed between January 1, 1998, and January 1, 2016, were selected. Annotations by two human radiologists were made for three categories: the presence, chronicity, and location of PE. Classification of performance of a CNN model with an unsupervised learning algorithm for obtaining vector representations of words was compared with the open-source application PeFinder. Sensitivity, specificity, accuracy, and F1 scores for both the CNN model and PeFinder in the internal and external validation sets were determined. Results The CNN model demonstrated an accuracy of 99% and an area under the curve value of 0.97. For internal validation report data, the CNN model had a statistically significant larger F1 score (0.938) than did PeFinder (0.867) when classifying findings as either PE positive or PE negative, but no significant difference in sensitivity, specificity, or accuracy was found. For external validation report data, no statistical difference between the performance of the CNN model and PeFinder was found. Conclusion A deep learning CNN model can classify radiology free-text reports with accuracy equivalent to or beyond that of an existing traditional NLP model. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29135366 TI - Radiofrequency Ablation versus Hepatic Resection for Small Hepatocellular Carcinoma: Systematic Review of Randomized Controlled Trials with Meta-Analysis and Trial Sequential Analysis. AB - Purpose To compare the benefits and harms of radiofrequency ablation (RFA) and hepatic resection (HR) and to test the consistency of currently available evidence. Materials and Methods PubMed, Embase, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) that compared the effects of HR and RFA for Barcelona Clinic Liver Cancer very early or early stage hepatocellular carcinoma (HCC). The primary outcome was overall survival, and secondary outcomes were recurrence rate, complication rate, and hospitalization duration. A random- or fixed-effects model according to the level of heterogeneity was applied. The meta-analysis was performed by using software, and trial sequential analysis (TSA) was performed. Results Five trials examining 742 patients were included in this study (sizes of trials: 161, 230, 168, 120, and 63 patients). The meta-analysis showed that RFA and HR had similar overall survival at 1 year (relative risk [RR], 1.39; 95% confidence interval [CI]: 0.36, 5.33; P = .63) and 3 years (RR, 1.40; 95% CI: 0.75, 2.62; P = .29), whereas RFA resulted in decreased overall survival compared with HR at 5 years (RR: 1.91; 95% CI: 1.32, 2.79; P = .001). The TSA showed that more trials were needed to control random errors. The incidence of overall recurrence was markedly higher and the hospitalization duration was significantly shorter in the RFA group than in the HR group, which was confirmed by TSA. Complications may have been less frequent in the RFA group, but TSA showed that additional trials were necessary to confirm this conclusion. Conclusion The indication for RFA as a primary treatment for patients who are eligible for HR with early stage HCC is unclear, and additional well-designed RCTs are needed. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29135367 TI - Trends in US Hospital Provision of Health Promotion Services, 1996-2014. AB - Hospitals have long played important roles in the provision of health promotion services (HPS) in local communities, defined as activities that enable people to increase control over and improve their health, including programs such as disease prevention and wellness. Nearly 2 decades ago, researchers cross sectionally documented the provision of HPS by hospitals, but little research has been done to update this work or document how HPS have changed over time. This study assessed changes in the provision of HPS among US hospitals between 1996 and 2014. Relationships were assessed using random effects Poisson regression models. The overall number of HPS reported by hospitals was relatively modest (approximately half of all possible services, on average). The number of services increased modestly over time, although the rate of increase became less positive over time. The findings highlight a number of opportunities to improve hospital provision of HPS. PMID- 29135368 TI - An Analysis of a Biometric Screening and Premium Incentive-Based Employee Wellness Program: Enrollment Patterns, Cost, and Outcome. AB - Since 2012, a large health care system has offered an employee wellness program providing premium discounts for those who voluntarily undergo biometric screenings and meet goals. This study evaluates the program impact on care utilization and total cost of care, taking into account employee self-selection into the program. A retrospective claims data analysis of 6453 employees between 2011 and 2015 was conducted, categorizing the sample into 3 mutually exclusive subgroups: Subgroup 1 enrolled and met goals in all years, Subgroup 2 enrolled or met goals in some years but not all, and Subgroup 3 never enrolled. Each subgroup was compared to a cohort of employees in other employer groups (N = 24,061). Using a difference-in-difference method, significant reductions in total medical cost (14.2%; P = 0.014) and emergency department (ED) visits (11.2%; P = 0.058) were observed only among Subgroup 2 in 2015. No significant impact was detected among those in Subgroup 1. Those in Subgroup 1 were less likely to have chronic conditions at baseline. The results indicate that the wellness program enrollment was characterized by self-selection of healthier employees, among whom the program appeared to have no significant impact. Yet, cost savings and reductions in ED visits were observed among the subset of employees who enrolled or met goal in some years but not all, suggesting a potential link between the wellness program and positive behavior changes among certain subsets of the employee population. PMID- 29135369 TI - T Cell Immunity to Zika and Dengue Viral Infections. AB - The 2015-2016 Zika virus (ZIKV) outbreak in the Americas has brought this relatively unknown flavivirus into the spotlight as the etiologic agent of congenital Zika syndrome in newborns and, potentially, of Guillain-Barre syndrome in adults. ZIKV shares a high degree of amino acid sequence homology with the closely related flavivirus Dengue virus (DENV). Due to the paucity of research investigating T cell-mediated immune responses to ZIKV, the precise roles of T cells in protection against and pathogenesis of ZIKV infection are unclear. Nevertheless, knowledge gained from studies of T cell responses to other flaviviruses, such as the four DENV serotypes, provides a framework for investigating and understanding anti-ZIKV T cell responses. In this review, we summarize our current understanding of how T cells respond to primary and secondary infections with DENV and ZIKV. A thorough understanding of the role of ZIKV-specific and DENV cross-reactive T cells in controlling infection is essential for developing ZIKV- and DENV-specific vaccines with maximal safety and efficacy. PMID- 29135370 TI - Pharmacokinetics-Based Adjusted Versus Standard Dose of Ribavirin Does Not Improve Virologic Response Rates in Chronic Hepatitis C Genotype 4 Patients: A Randomized Controlled Trial. AB - Optimal doses of Ribavirin (RBV) for hepatitis C virus (HCV) treatment are not known. To assess the safety and efficacy of PegIFNalfa-2a in combination with an adjusted (ADJ) RBV dose based on early pharmacokinetics versus a fixed standard (STD) dose of RBV in chronic HCV genotype (GT) 4-naive patients in a randomized trial. One hundred eighty-one patients were randomized. The baseline variables were similar in both arms and females were 50.3% of the patients, 76.5% had minimal-moderate fibrosis (F0-2). Sustained virologic response (SVR) was achieved in 99 (54.7%) subjects. SVR was seen in 50/90 (55.6%) of ADJ dose of RBV and 49/91 (53.9%) of STD dose subjects. Prematurely withdrawal or discontinuation of treatment prematurely in the ADJ RBV arm occurred in 11/90 patients (12.2%) compared with 6/91 subjects (6.6%) in the STD arm (P = 0.214). Similarly, virologic relapse was seen in 14/90 (15.6%) patients of the ADJ arm and 12/91 (13.2%) of the STD arm. Anemia grade 3-4 was seen in 36.7% in ADJ versus 17.6% in STD arm (P = 0.003). Occurrence of rapid virologic response and absences of F4 fibrosis predicted SVR in a univariate analysis. However, age, gender, weight, presence of diabetes, baseline alanine aminotransferase, and vitamin D levels were not significantly different in patients achieving SVR. ADJ higher doses of RBV based on its early pharmacokinetics-based RBV do not improve SVR rates in HCV GT4 treated in combination with peg-IFN alpha-2-a versus STD therapy. Patients on ADJ higher doses of RBV experienced higher rates of anemia and require more erythropoietin without increasing SVR. PMID- 29135371 TI - Follistatin-Like Protein-1 Upregulates Dendritic Cell-Based Immunity in Patients with Nasopharyngeal Carcinoma. AB - Follistatin-like protein-1 (FSTL1) is an inflammatory factor that can induce an inflammatory response and is expressed in cancers. However, little is known about its content and function in nasopharyngeal carcinoma (NPC). Interleukin (IL)-12 and IL-4 are primarily secreted by dendritic cells (DCs) and activated T lymphocytes, respectively; these factors can induce Th cell differentiation and cytotoxic lymphocyte production, both of which facilitate tumors through the STAT4 and STAT6 pathways, respectively. In this study, the relationship between FSTL1 and both IL-12 and IL-4 as well as the functional mechanism of these cytokines was explored. Enzyme-linked immunosorbent assay, flow cytometry, and Western blotting were used to assess the levels of key inflammatory factors and DC markers as well as elucidate the mechanism by which FSTL-1 mediates and exerts it antitumor effects. The results revealed that serum FSTL1 and IL-12 levels were significantly decreased in NPC patients compared with those in the control group (P < 0.05); conversely, IL-4 levels were increased (P < 0.05). Supernatants from the experimental groups (EGs) contained higher IL-4 and IL-12 levels than those from the control groups (P < 0.05). Additionally, phosphorylated-STAT6 and phosphorylated-STAT4 were increased in the EGs (P < 0.05). These results suggest that DC-mediated immunity was activated by FSTL1, which leads to an increase of IL-12 and IL-4 production and consequently activates the STAT4 and STAT6 pathways through upregulation of STAT4 and STAT6 phosphorylation, respectively. PMID- 29135372 TI - First Study on Interferon Regulatory Factor in Sturgeon: Expression Pattern of Interferon Regulatory Factor in Dabry's Sturgeon Acipenser dabryanus. AB - Interferon regulatory factors (IRFs) are crucial regulators in initiating the host innate immune response against pathogen invasions. Dabry's sturgeon (Acipenser dabryanus) is particularly a valuable fish species found in the Yangtze River, China for which there is scarce immunological data. In the present study, we investigated the expression profile of sturgeon IRF genes. All adIRFs were composed of 8 exons and 7 introns, except adIRF1, which possessed 9 exons interrupted by 8 introns. Moreover, the predicted protein sequence has a DNA binding domain (DBD) sharing high identity with spotted gar (Lepisosteus oculatus). Regarding the expression patterns, 5 adIRF genes were found to be constitutively expressed in all tissues examined, and were significantly higher in lymphoid organs (eg, blood, kidney, intestine, and spleen). Following Aeromonas hydrophila infection, the expression of adIRF1 and adIRF3 were upregulated in the spleen and caudal kidney, while both the adIRF5 and adIRF8 genes were downregulated in caudal kidney. In addition, adIRF4 was significantly upregulated at 3 h postinfection by A. hydrophila in the spleen and caudal kidney. These results suggest that adIRFs are related to the immune response to bacterial infection, which will help clarify the function of these IRFs and provide a fundamental basis for protecting the Dabry's sturgeon. PMID- 29135374 TI - Corrections. PMID- 29135375 TI - Corrections. PMID- 29135373 TI - High Dose of Silymarin in Patients with Decompensated Liver Disease: A Randomized Controlled Trial. AB - Hepatitis C virus (HCV) is a major public health problem being the most common cause of chronic liver disease in Egypt. HCV-induced decompensated liver cirrhosis patients have a median survival of 2 years even with currently used new treatments. Silymarin is the most commonly used herbal product in chronic liver disease for its anti-inflammatory, antiviral, antioxidant, and antifibrotic effects. The aim of this study was to assess the effects of silymarin in high dose on the clinical and biochemical status of chronic HCV-associated decompensated liver cirrhosis. The study was conducted on 62 chronic HCV decompensated cirrhotic patients. Patients were randomized according to treatment plans: group A, included 31 patients who received silymarin in dose of 1,050 mg/day, and group B, included 31 patients who received silymarin in dose of 420 mg/day. Patients were subjected to baseline history taking, laboratory evaluation, abdominal ultrasound, Child scoring, and quality-of-life (QoL) questionnaire. Follow-up was done every 2 weeks for 12 weeks. Silymarin in high dose had an effect on reducing alanine transaminase, aspartate aminotransferase levels (P <= 0.01), as well as improving albumin (P = 0.04), bilirubin (P = 0.02), and international normalized ratio (P = 0.03), thus resulted in improvement in Child score (P = 0.048), however, regular silymarin regimen (420 mg/day) failed to achieve the previous biochemical changes. High-dose regimen of silymarin also had a positive impact on improving QoL. No serious adverse events were reported. Silymarin in high dose is a good choice for improvement of liver biochemical profile and QoL in chronic HCV cirrhotic patients. PMID- 29135376 TI - Response to "Comorbidities in head and neck cancer: Agreement between self-report and chart review" by Vinidh Paleri. PMID- 29135377 TI - Response to the letter to the editor from Dr Peter Belafsky. PMID- 29135378 TI - Same-Sex Parenting: Identification of Social Representations in a Sample of Portuguese Professionals. AB - Although international scientific research and the position of professional associations reiterate that the parents' sexual orientation is not a criterion of parenting quality, the social recognition of same-sex parenting remains difficult in Portugal. Given the importance of forensic issues in this field, this study aims to identify the representations of psychologists, social workers, lawyers/attorneys, and judges regarding same-sex parenting. The study involves five homogeneous focus groups with a total of 19 professionals. Content analysis reveals reservations regarding same-sex couples' access to parenting, in particular among lawyers/attorneys. There also emerged narratives that highlight specific competencies in these families and that argue that sexual orientation does not define the quality of parenting. Social narratives are more expressive than scientific knowledge in support of professional representations. These findings have critical implications for professional practice and formation. PMID- 29135379 TI - Corrigendum. AB - Lim HJ, Kim YT, Choi SJ, et al. Efficacy of 3 different steroid treatments for sudden sensorineural hearing loss: a prospective, randomized trial. Otolaryngol Head Neck Surg. 2013;148:121-127. (original doi: 10.1177/0194599812464475 ). PMID- 29135380 TI - Antibiotics for Otitis Media with Effusion in Children. AB - The "Cochrane Corner" is a quarterly section in the journal that highlights systematic reviews relevant to otolaryngology-head and neck surgery, with invited commentary to aid clinical decision making. This installment features a Cochrane Review, "Antibiotics for Otitis Media with Effusion in Children," that does not support the routine use of antibiotics for treating otitis media with effusion in children. Although children treated with antibiotics had higher rates of effusion resolution, there was no impact on hearing levels or the need for tympanostomy tubes. PMID- 29135381 TI - Experimental Analysis of Temperature Differences During Implant Site Preparation: Continuous Drilling Technique Versus Intermittent Drilling Technique. AB - Implant site preparation through drilling procedures may cause bone thermonecrosis. The aim of this in vitro study was to evaluate, using a thermal probe, overheating at implant sites during osteotomies through 2 different drilling methods (continuous drilling technique versus intermittent drilling technique) using irrigation at different temperatures. Five implant sites 13 mm in length were performed on 16 blocks (fresh bovine ribs), for a total of 80 implant sites. The PT-100 thermal probe was positioned 5 mm from each site. Two physiological refrigerant solutions were used: one at 23.7 degrees C and one at 6.0 degrees C. Four experimental groups were considered: group A (continuous drilling with physiological solution at 23.7 degrees C), group B (intermittent drilling with physiological solution at 23.7 degrees C), group C (continuous drilling with physiological solution at 6.0 degrees C), and group D (intermittent drilling with physiological solution at 6.0 degrees C). The Wilcoxon rank-sum test (2-tailed) was used to compare groups. While there was no difference between group A and group B (W = 86; P = .45), statistically significant differences were observed between experimental groups A and C (W = 0; P =.0001), B and D (W = 45; P =.0005), and C and D (W = 41; P = .003). Implant site preparation did not affect the overheating of the bone. Statistically significant differences were found with the refrigerant solutions. Using both irrigating solutions, bone temperature did not exceed 47 degrees C. PMID- 29135383 TI - Response to "External auditory exostoses: Evaluation and treatment". PMID- 29135382 TI - Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities. AB - The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [11C]PBR28, [18F]DPA714 and [11C]-R PK11195. It is still unclear, however, whether the vascular signal is tracer dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [11C]-R-PK11195 data from six healthy subjects. Then, we compared the [11C]-R PK11195 vascular binding estimates with previously published values for [18F]DPA714 and [11C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [11C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering. PMID- 29135384 TI - Response to "Evaluation of submucosal minimally invasive lingual excision technique for treatment of obstructive sleep apnea/hypopnea syndrome". PMID- 29135385 TI - Redo Laparoscopic Heller's Cardiomyotomy for Recurrent Achalasia: Is Laparoscopic Surgery Feasible? AB - BACKGROUND: Achalasia cardia is an esophageal motor disorder with raised lower esophageal sphincter (LES) pressure. Minimally invasive procedures have become the procedure of choice compared with conventional open surgery. After the primary surgery, recurrence or persistent symptoms have been noted in almost 10% 20% of cases. MATERIALS AND METHODS: In this case series, we share our experience with a series of 7 patients who presented to us from January 2010 to January 2017 for recurrent symptoms, following Heller's myotomy for achalasia cardia. RESULTS: Commonest symptom of recurrence was dysphagia with mean duration of recurrence of 17.9 months between primary and redo surgery. Revisional Heller's myotomy with Dor's fundoplication was performed in all patients laparoscopically. Mean duration of surgery was 150 minutes. Incomplete gastric myotomy and fibrosis at previous myotomy scar were the main causes of recurrence. Mean duration of hospital stay was 3.5 days. Mean follow-up period was 23.5 months. All the patients were symptomatically better following the redo surgery. Subsequent manometry was performed at the end of 3 months with mean reduction in LES pressure of 7.5 + 1.2 mmHg. CONCLUSION: Laparoscopic redo Heller's cardiomyotomy is a possibly reasonable option with good long-term results and minimal postoperative complications in expert hands. PMID- 29135386 TI - Timing of Diagnosis: Understanding Resilience Narratives of HIV Positive Older Adults Diagnosed Pre- and Post-HAART. AB - BACKGROUND: Despite the growing population of older adults living with human immunodeficiency virus/ acquired immune deficiency syndrome (HIV/AIDS), few studies have examined this population in terms of timing of HIV diagnosis. This study explores resilience and protective factors among HIV-positive older adults, 17 of whom were diagnosed prior to the development of highly active antiretroviral therapy (HAART), and 13 of whom were diagnosed after the development of HAART. METHODS: We explored the concepts of resilience and protective factors in 30 older adults living with HIV in Ontario, Canada. A qualitative approach was used to conduct in-depth interviews and grounded theory techniques were used to analyze the interview transcripts. RESULTS: Having lived with HIV for nearly 30 years, the pre-HAART group had developed more personal strategies for enhancing resilience, including self-care behaviors. They were more regimented and dedicated to their daily health, and were more engaged in their medical care as opposed to the post-HAART group who viewed self-care as staying adherent and refraining from risky health behaviors. IMPLICATIONS: Although HAART has radically changed the prognosis of HIV, we have limited information about the differences between those who were diagnosed before and after the development of HAART. We will present recommendations for addressing previous trauma and improving self-care. PMID- 29135388 TI - Erratum. AB - Rudmik L, Smith TL. Economic evaluation of a steroid-eluting sinus implant following endoscopic sinus surgery for chronic rhinosinusitis. Otolaryngol Head Neck Surg. 2014;151:359-366. (Original DOI: 10.1177/0194599814533779 ) In the above-mentioned article, a grant from the National Institutes of Health/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) was incorrectly listed as a funding source for the study. The grant support from NIH/NIDCD should have been listed as a potential competing interest for Timothy L. Smith. This study was not NIH-funded. PMID- 29135387 TI - Effect on Bone Architecture of Marginal Grooves in Dental Implants Under Occlusal Loaded Conditions in Beagle Dogs. AB - The aim of this study was to clarify whether marginal grooves on dental implants affect osseointegration, bone structure, and the alignment of collagen fibers to determine bone quality under loaded conditions. Anodized Ti-6Al-4V alloy dental implants, with and without marginal grooves (test and control implants, respectively), were used (3.7 * 8.0 mm). Fourth premolars and first molars of 6 beagle mandibles were extracted. Two control and test implants were placed in randomly selected healed sites at 12 weeks after tooth extraction. Screw-retained single crowns for first molars were fabricated. Euthanasia was performed at 8 weeks after the application of occlusal forces. Implant marginal bone level, bone to implant contact (BIC), bone structure around dental implants, and the alignment of collagen fibers determining bone quality were analyzed. The marginal bone level in test implants was significantly higher than that in control implants. Occlusal forces significantly increased BIC in test implants ( P = .007), whereas BIC did not change in control implants, irrespective of occlusal forces ( P = .303). Moreover, occlusal forces significantly increased BIC in test implants compared with control implants ( P = .032). Additionally, occlusal forces preferentially aligned collagen fibers in test implants, but not control implants. Hence, marginal grooves on dental implants have positive effects on increased osseointegration and adapted bone quality based on the preferential alignment of collagen fibers around dental implants under loaded conditions. PMID- 29135389 TI - Cooling Thoughts Over the Holiday Season. PMID- 29135390 TI - Highlights from the Current Issue: December 2015. PMID- 29135391 TI - Gongylonema Parasites of Rodents: A Key to Species and New Data on Gongylonema neoplasticum. AB - Specimens of the genus Gongylonema were collected from the gastric mucosa of rodents of Rattus rattus Linnaeus, 1758, and Rattus norvegicus Berkenhout, 1769, collected in urban areas in Belem, Para, in the eastern Brazilian Amazon. The helminths were processed for analysis using light microscopy and scanning electron microscopy (SEM) techniques and presented taxonomic characteristics of the species Gongylonema neoplasticum. The SEM analyses revealed the presence of 2 developed buccal plates (1 dorsal, 1 ventral), also called interlabia, with a prominent and bifurcated ventral plaque. The occurrence of the bifurcated ventral interlabium had not yet been identified by any other author from G. neoplasticum. As a result of our extensive research on published data on Gongylonema spp., we propose a taxonomic key for species of this genus that parasitize rodents. This is the first record of G. neoplasticum in urban areas of the Brazilian Amazon. PMID- 29135393 TI - Assessing psychological distress in cancer patients: The use of distress thermometer in an outpatient cancer/hematology treatment center. AB - The purpose of this study is to assess the feasibility of the distress thermometer (DT) and the accompanying problem checklist (PC) as a screening tool for psychological distress and the sources of those distress at an outpatient cancer treatment center in Central California. Forty-three patients completed the DT and the PC. Based on a recommended DT cutoff score of 4, patients were classified as "distressed" (>4) and "not-distressed" (<4). Respondents ranged in age from 34 to 87 years (mean = 60.44, SD = 12.05), the majority of whom were female (55.8%). The most common types of cancer diagnosis were breast cancer, followed by blood abnormality (i.e., blood disorders), lung, and bladder cancer. Based on the recommended DT cutoff score, 51% of patients were identified as significantly distressed. Results showed significant difference on DT score between the distressed and not-distressed groups, t(41) = -4.25, p < .001. The most commonly reported sources of distress were in the practical, emotional, and physical domains of the PC list. Routine distress screening can significantly help improve identification of distress and the sources of the distress in cancer patients and enable healthcare professionals to facilitate appropriate psychosocial support and referrals. Implications for practice and research are discussed. PMID- 29135394 TI - Real life profile of asthma and chronic obstructive pulmonary disease patients in Turkey. AB - Introduction: Despite the presentation of similar symptoms, the airway diseases have different underlying pathophysiological processes and must be distinguished to enable the administration of appropriate treatment. In several studies the clinician- and patient-related causes of poor compliance to treatment in asthma/chronic obstructive pulmonary disease (COPD) patients have been evaluated. This study aimed to determine the clinical and sociodemographic characteristics of newly diagnosed treatment-naive asthma and COPD patients in Turkey. Materials and Methods: This national, multicentre, prospective, observational study was conducted in 122 centres. A questionnaire including items related to demographic, clinical, laboratory parameters was applied. All patients were intended to be followed-up for 12 months. Result: 1892 adult patients (1116 asthma and 776 COPD) from 122 centres were enrolled. Overall 95%, 86% and 65% of intermittent, mild persistent and moderate persistent asthma patients were over-treated. Among COPD patients, the percentages of over-treated patients were 66%, 79% and 82% for those with GOLD stage A, B and C. Physicians' adherence to guidelines was appropriate in 93% of severe persistent asthma patients and 89% of GOLD stage D COPD patients. Among patients with high compliance to treatment, proportion of asthma patients with total control was 44% and that of COPD patients at GOLD stage A was 41%. In consecutive two visits, this figure increased to 52% and 63% in asthma patients and 54% and 50% in COPD patients. Conclusions: The main findings are: (a) patients are frequently over-treated and (b) patients do not adhere to visits as expected, in both asthma and COPD. PMID- 29135395 TI - Pattern and predictors of paradoxical response in patients with peripheral lymph node tuberculosis. AB - Introduction: Many of the patients with lymph node tuberculosis show 'Paradoxical Response" in the form of appearance of new lymph node (LN) or increase in the size of existing LN, development of new disease in other organ and worsening of the disease while on treatment. Reason behind such response in only selective patients is not clearly understood. We evaluated the pattern and predictors for paradoxical response(s) (PR) in patients with peripheral lymph node tuberculosis (TB). Materials and Methods: Study included patients aged > 6 years with peripheral lymphadenopathy of tubercular etiology attending a tertiary care hospital from Jan 2010 to Dec 2010. PR in our study was defined as worsening of pre-existing disease or development of new lesions in a patient who has been on anti-TB therapy for at least 2 weeks. Result: One hundred ten patients with peripheral lymph node TB were included. Their mean age was 27.5 +/- 5 years and 68 (62%) were females. PR occurred in 28 (25%) patients, at a mean onset time of 6 weeks (range 2-12 weeks) after starting anti-TB medication. Four of these 28 patients experienced PR on two occasions. Of these, 22 (79%) patients presented with enlarged lymph nodes only, 8 (29%) with new nodes at same or different site and 2 (7%) with discharging sinus. PR was observed more in younger age group (p> 0.05), female gender (p> 0.05), unilateral lymphadenopathy (p> 0.05) and those with positive AFB on initial examination (p< 0.01). Conclusions: Paradoxical response in peripheral lymph node TB is associated with younger age, female gender, unilateral lymphadenopathy and those with positive AFB on initial examination. PMID- 29135396 TI - Serum telomerase levels in smokers and smokeless tobacco users as Maras powder. AB - Introduction: To the best of our knowledge, no previous study regarding the serum telomerase levels in Maras powder users (MPUs) has been founded. The aim of the current study was to investigate serum telomerase levels in smokers and MPUs. Materials and Methods: The study was carried out with 98 patients (36 MPUs, 32 smokers and 30 non-smokers). Blood samples were collected, and after having measured the serum telomerase and malondialdehyde (MDA) levels of the patients, comparison were made between the groups. Result: It has been observed that the serum telomerase and MDA levels of smokers (p< 0.001) and MPUs (p< 0.001) were significantly higher compared to those of the non-smoker control subjects. In addition, the levels of serum telomerase and MDA were observed to be higher in the MPU group compared to those of the smoker group (p< 0.001). Conclusions: The levels of serum telomerase and MDA were observed to be higher among MPUs and smokers. In this context, it may be useful to further measure and assess telomerase activity in such patients in order to better determine the harmful effects associated with these habits. PMID- 29135397 TI - Electrolytes imbalance caused by amikacin in patients receiving multi drug resistance- tuberculosis treatment at Hazara region Kpk, Pakistan. AB - Introduction: Multi drug resistance-tuberculosis (MDR-TB) is considered amongst one of the fatal medical and public health issue. Greater frequency of adverse reactions has been observed using 2nd line antituberculosis drugs, which rises the rate of morbidity. Hypokalemia and hyponatremia are common in patients receiving MDR-TB treatment. Materials and Methods: This study was aimed to assess the effect of amikacin as multidrug resistance tuberculosis treatment on serum sodium and potassium level. A total 179 subjects (82 males and 97 females) were screened within the period of one year for their serum electrolyte levels before and during the treatment. Their body weight and sociodemographic characteristics were also taken into considerations. Data were expressed in the form of mean +/- standard error using One-way analysis of variance (ANOVA), followed by Dunnett's test. All the statistical analyses were performed using GraphPad Prism v. 6. Result: The results showed that amikacin caused a significant (p< 0.05) hypokalemia when used in combination with other drugs having no known effect on serum potassium level which proved to be the side effect of amikacin. The average serum potassium level in both intensive and continuation phase was significantly lower (p< 0.05) than the baseline (3.73 mmol/L), however, in the continuation phase the potassium level (3.58 mmol/L) was slightly higher than that of intensive phase (3.54 mmol/L). The average serum sodium level in both phases; intensive and continuation, remained in steady state (137.25 mmol/L and 137.87 mmol/L respectively) throughout the study period as compared to the base line (135.5 mmol/L). The amikacin drug lowered serum potassium level but had no effect on sodium level. Conclusions: It is concluded that the serum electrolytes should be monitored during the course of treatment and corrected accordingly. PMID- 29135398 TI - The effect of obesity on dyspnea, exercise capacity, walk work and workload in patients with COPD. AB - Introduction: COPD and obesity are major public health problems that cause mortality and morbidity all over the world. The combined of COPD and obesity is predicted to increase further in the coming years. Obesity primarily affects the pulmonary system by altering respiratory functions, exercise capacity, pulmonary gas exchange, and endurance and power of respiratory muscles. In this study, we aimed to compare the dyspnea sensation, exercise capacity, walk work and workload in obese COPD patients compared to preobese and normal overweight COPD patients. Materials and Methods: 218 patients with COPD were included in the study. According to the WHO criteria for body mass index (BMI), the patients were classified as normal-weight (BMI=18.5-24.9 kg/m2), pre-obese (BMI= 25-29.9 kg/m2) and obese (BMI= 30-39.9 kg/m2). All patient respiratory function tests and arterial blood gas analysis were performed. The mMRC dyspnea scale was used to assess the dyspnoea of the patients. The exercise capacities of the patients were determined by the 6-min walking test. Walk work and workload were calculated based on 6 minutes walking distance. The obtained values were compared between the three groups. Result: The FEV1/FVC ratio and TLCO value in pulmonary function tests are significantly higher in obese COPD patients than in other patients, while the VC value is significantly lower in patients with COPD (p= 0.001, p< 0.001, p= 0.01). Partial carbon dioxidewas significantly higher in obese COPD patients compared to other patients (p= 0.001). Dyspnea perceptions and walking distances did not differ significantly between groups. Walkwork and workload were significantly higher in obese COPD patients (p< 0.001, p= 0.005). Conclusions: Obesity causes partial changes in blood gas and pulmonary function tests of patients with COPD. At the same time, it increases walkwork and workload. Despite all these changes, it has no negative effect on dyspnea perception and exercise capacity. PMID- 29135399 TI - [Investigation of parameters related to prognosis in diffuse parenchymal lung diseases prognosis in interstitial lung diseases]. AB - Introduction: Parameters related to prognosis in diffuse parenchymal lung disease (DPLD) have a decisive influence on treatment and follow-up processes. We aimed to define baseline characteristics and factors that effect the mortality of the group of patients with DPLD and to determine distinctions between subgroups. Materials and Methods: Demographic characteristics, complaints, comorbidity, treatment, pulmonary function tests, echocardiographic findings, six minute walking test (6MWT), arterial blood gases analysis, radiological findings and survival time were collected from outpatient clinics database. Patients' survival time and mortality-related parameters were evaluated. Result: This study consisted of 104 patients. Forty-four of them idiopathic pulmonary fibrosis (IPF), 34 scleroderma and 26 rheumatoid arthiritis (RA) with lung involvement. Mortality rates were similar for the groups but median survival was shorter in patients with IPF than scleroderma and RA (IPF: 35.1 +/- 22.4 months, scleroderma: 61.1 +/- 27.9 months, RA: 60.0 +/- 52.1 months; p= 0.001, p= 0.016 respectively). Mortality was higher in patients who are > 60 years old (24/64 vs. 5/40, p= 0.007), had chronic obstructive pulmonary disease (COPD) (5/7 vs. 24/97, p= 0.017), gastroesophageal reflux (7/13 vs. 22/91 p= 0.043) and usual interstitial pattern (11/48 vs. 18/56, p= 0.054), low PaO2 (< 60 mmHg) at admission (6/8 vs. 8/32, p= 0.014), desaturation on 6MWT (13/28 vs. 1/18, p= 0.003), high reduction of DLCO/year (6/10 vs. 4/33, p= 0.023). COPD and 6 minute walking distance (6MWD) were found as independently related factors for mortality (p= 0.013, p= 0.02) for whole group. Conclusions: As a result, 6MWD and COPD were found as independently related factors for mortality for all patients. In subgroup analysis for IPF, scleroderma, and RA; 6MWD is only independent factor for mortality. PMID- 29135400 TI - [The comparison of microscopy and real time polymerase chain reaction methods for the diagnosis of Pneumocystis Jirovecii pneumonia: evaluation of clinical parameters]. AB - Introduction: Pneumocystis jirovecii pneumonia (PCP) causes serious infections, especially in patients with immunosuppressive diseases. In this study, it was aimed to evaluate the results of samples obtained from PCP suspected patients using two different methods together with clinical data. Materials and Methods: Microscopy and real time polymerase chain reaction (real time PCR) methods were performed with bronchoalveolar lavage (BAL) samples sended to Ege University Medical Faculty Direct Parasitology Diagnostic Laboratory between March 2009 and June 2010. Demographic characteristics, clinical and laboratory data were also recorded retrospectively. The data were evaluated using the SPSS 16.0 program. Result: A total of 42 BAL samples collected from patients (24 males, mean age: 31.49 +/- 26.14) were included. There were totally 16 P. jirovecii positives either one of the tests. Sixteen and three samples were detected positive by real time PCR and microscopy, respectively. Trimethoprim-sulfamethoxazole was prescribed in 11 PCP diagnosed cases and 6 of them died. Conclusions: Today, despite the growing opportunities in diagnosis and treatment, PCP pneumonia is associated with high mortality. Careful examination of clinical data and immune status of the patients are important. Multidisciplinary approach is required for early PCP diagnosis. PMID- 29135401 TI - [Approach to chronic cough]. AB - Chronic cough, that 10-38% outpatients have, is an important cause of morbidity and mortality. This symptom can be seen 3-40% of adult patients and reduces quality of life. 95% patients that cough chronically have one of these three diseases: upper airway cough syndrome, gastroesophageal reflux or asthma. In this review these three diseases and rare causes of chronic cough will be discussed and diagnostic steps will be explained. PMID- 29135402 TI - [Schistosomiasis and pulmonary hypertension]. AB - Schistosomiasis is one of the most prevelant parazitic diseases in the world. It is endemic in more than 70 countries, and more than 200 million people worldwide are infected with Schistosoma. Pulmonary hypertension (PHT) is one of the chronic complications of schistosomiasis. The exact pathogenesis of schistosomiasis associated pulmonary hypertension (S-PHT) remains unclear, although several mechanisms such as parazitic arterial embolisation, pulmonary arteriopathy, and portopulmonary hypertension have been suggested. Pathological pulmonary vascular changes in S-PHT were found similar to those in idiopathic pulmonary arterial hypertension (IPAH). The fact that schistosomiasis is one of the most common causes of pulmonary arterial hypertension (PAH), particularly in the developing countries, underlines the importance of enhancing our knowledge on this disease. Developments in the treatment of PAH have resulted in improved prognosis and significant increase in life expectancy and quality of life in the last two decades, which has enhanced the importance of S-PHT. Schistosomiasis is treated with praziquantel. Nevertheless, there is limited evidence that this treatment is effective for PHT. Although antihelmintic medications do not lead to significant improvement, they have beneficial effects and may slow down disease progression. Using PAH-specific treatments in the patients with schistosomiasis-associated PAH (S-PAH) can improve prognosis. However, inadequate clinical studies and limited sources in the endemic regions restrict extensive usage of these expensive medications. Further studies are required to determine the efficacy of these treatment modalities. PMID- 29135403 TI - A case of relapsing polychondritis mimicking lung cancer. AB - Relapsing polychondritis (RP) is a rare autoimmune disease, characterized by episodic inflammatory attacks on cartilaginous tissue. Elastic cartilage of the ears and nose, hyaline cartilage of the peripheral joints, vertebral fibrocartilage, tracheobronchial cartilage, and tissues rich in proteoglycan such as those in the eyes, heart, blood vessels, and inner ear are more likely to be affected. A 35-year-old male presented with complaints of hoarseness, tinnitus and dyspnea for 19 years, with a history of several diagnostic and therapeutic interventions for laryngeal and respiratory tract. He was diagnosed to have inflammation of the tracheobronchial cartilage, cardiac valvulopathy and conductive hearing loss after intensive diagnostic studies. He responded well to low-dose steroids in combination with methotrexate. RP is a diagnostically challenging condition and may cause significant morbidities during diagnosis. RP should be considered in differential diagnosis of airway obstruction as a rare condition. PMID- 29135404 TI - [Bilateral total lung lavage in a patient with pulmonary alveolar proteinosis]. AB - Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterised by alveolar accumulation of surfactant composed of proteins and lipids. Three main categories of PAP have been defined depending on the aetiology: primer/idiopathic, neonatal/congenital, secondary and exogenous/environmental exposure. Radiologically diffuse ground glass opacities, interlobular and intralobular septal thickening is seen. Although open lung biopsy is accepted as the gold standard in diagnosis, it can be diagnosed by showing bronchoalveolar lavage (BAL) fluid with a milky appearance and periodic acid-schiff (PAS) positive globules in biopsy with clinical and radiological findings. Theraphy for PAP are supportive care (oxygen), total lung lavage, inhale/subcutaneous granulocyte macrophage colony stimulating factor (GM-CSF), rituximab, plasmapheresis, lung transplantation. We report a case of PAP presented with cough and shortness of breath, diagnosed with BAL and transbronchial lung biopsy, treated by total lung lavage by reviewing literature. PMID- 29135405 TI - Successfully chest irradiation for an advanced squamous cell lung cancer patient with predialysis renal insufficiency. PMID- 29135406 TI - Three-dimensional CT scan for Swyer-James syndrome. PMID- 29135407 TI - A long-term survival with cardiac tamponade due to small cell lung cancer. PMID- 29135408 TI - Hemoptysis due to bronchiectasis in a nonagenarian. PMID- 29135409 TI - Double inlay plus ventral onlay buccal mucosa graft for simultaneous penile and bulbar urethral stricture. AB - OBJECTIVES: Buccal mucosa grafts and fascio-cutaneous flaps are frequently used in long anterior urethral strictures (1). The inlay and onlay buccal mucosa grafts are easier to perform, do not need urethral mobilization and generally have good long-term results (2-4). In the present video, we present a case where we used a double buccal mucosa graft technique in a simultaneous penile and bulbar urethral stricture. MATERIALS AND METHODS: A 54 year-old male patient was submitted to appendectomy where a urethral catheter was used for two days in May 2015. Three months after surgery, the patient complained of acute urinary retention and a supra-pubic tube was indicated. Urethrocystography was performed two weeks later and showed strictures in penile and bulbar urethra with 3.5 cm and 3 cm in length respectively. Urethroplasty was proposed for the surgical treatment in this case. We used a perineal approach with a ventral sagittal urethrotomy in both strictures. Penile urethra stricture measuring 3.5 cm in length was observed and a free graft from the buccal mucosa was harvested and placed into the longitudinal incision in the dorsal urethra and fixed with interrupted suture as dorsal inlay. Bulbar urethra stricture measuring 3 cm was observed and a free graft from the buccal mucosa was harvested and placed into the longitudinal incision in the ventral urethra and fixed with interrupted suture as ventral onlay. The ventral urethrotomy was closed over a 16Fr Foley catheter and the skin incision was then closed in layers. RESULTS: No intraoperative or postoperative complications occurred. The patient could achieve satisfactory voiding and no complication was seen during the six-month follow-up. Postoperative imaging demonstrated a widely patent urethra, and the mean peak flow was 12 mL/s. CONCLUSION: The BMG placement can be ventral, dorsal, lateral or combined dorsal and ventral BMG in the meeting of stricture but the first two are most common (5, 6). Ventral location provides the advantages of ease of exposure and good vascular supply by avoiding circumferential rotation of the urethra (7). Early success rates of dorsal and ventral onlay with BMG were 96 and 85%, respectively. However, long-term follow-up revealed essentially no difference in success rates (8-11). Anterior urethral stricture treatments are various, and comprehensive consideration should be given in selecting individualized treatment programs, which must be combined with the patient's stricture, length, complexity, and other factors. Traditionally, anastomotic procedures with transection and urethral excision are suggested for short bulbar strictures, while longer strictures are treated by patch graft urethroplasty preferably using the buccal mucosa as gold-standard material due to its histological characteristics. The current management for complex urethral strictures commonly uses open reconstruction with buccal mucosa urethroplasty. However, there are multiple situations whereby buccal mucosa is inadequate (pan urethral stricture or prior buccal harvest) or inappropriate for utilization (heavy tobacco use or oral radiation). Multiple options exist for use as alternatives or adjuncts to buccal mucosa in complex urethral strictures (injectable antifibrotic agents, augmentation urethroplasty with skin flaps, lingual mucosa, colonic mucosa, and new developments in tissue engineering for urethral graft material). In the present case, our patient had two strictures and we chose to correct the first stricture with a dorsal graft and the bulbar stricture with a ventral graft because of our personal expertise. We can conclude that the double buccal mucosa graft is easier to perform and can be an option to repair multiple urethral strictures. PMID- 29135411 TI - Costs analysis of surgical treatment of stress urinary incontinence in a brazilian public hospital, comparing burch and synthetic sling techniques. AB - INTRODUCTION: Surgical treatment of urinary incontinence progressed significantly with the introduction of synthetic slings. However, in some public Brazilian hospitals, the costs of these materials prevent their routine use. OBJECTIVE: To compare the costs of ambulatory synthetic sling surgery with an historical series of patients submitted to Burch surgery in a Brazilian public hospital. MATERIALS AND METHODS: Twenty nine incontinent patients were selected to synthetic sling surgery. Demographic data were prospectively collected and also the costs of the procedure, including drugs and materials, use of surgical and recovery wards, medical staff and hospitalization. These data were compared to the costs of 29 Burch surgeries performed before the introduction of synthetic slings. RESULTS: Demographic data were similar, although median age was lower in the group submitted to Burch surgery (46.3+/-8.6 versus 56.2+/-11.3 (p<0.001)). Cost was significantly lower in patients submitted to sling in all items, except for time spent in recovery ward. Total value of 29 Burch surgeries was R$ 217.766.12, and of R$ 68.049.92 of 29 patients submitted to sling surgery (p<0.001). CONCLUSION: Burch surgery was more expensive than ambulatory synthetic transobturator sling surgery, even when the cost of the synthetic sling was considered. PMID- 29135412 TI - Surgical repair in case of covered exstrophy of bladder with complete duplication of lower genitourinary tract and visceral sequestration. PMID- 29135410 TI - Tissue-based molecular markers in upper tract urothelial carcinoma and their prognostic implications. AB - Upper tract urothelial carcinoma (UTUC) is a rare and aggressive disease that is associated with high rates of recurrence and death. Radical nephroureterectomy (RNU) with excision of the bladder cuff is considered the standard of care for high-risk UTUC, whereas kidney-sparing techniques can be indicated for select patients with low-risk disease. There is a significant lack of clinical and pathological prognostic factors for stratifying patients with regard to making treatment decisions. Incorporation of tissue-based molecular markers into prognostic tools could help accurately stratify patients for clinical decision making in this heterogeneous disease. Although the number of studies on tissue based markers in UTUC has risen dramatically in the past several years-many of which are based on single centers and small cohorts, with a low level of evidence many discrepancies remain between their results. Nevertheless, certain biomarkers are promising tools, necessitating prospective multi-institution studies to validate their function. PMID- 29135413 TI - Laparoscopic transperitoneal repair of retrocaval (circumcaval) ureter. PMID- 29135414 TI - Retroperitoneoscopic nephrectomy for huge autosomal-dominant polycystic kidney disease using morcellator. PMID- 29135415 TI - Re: Simplified Fournier's gangrene severe index score (SFGSI). PMID- 29135416 TI - Re: Serum tissue factor as biomarker for renal clear cell carcinoma: a comment. PMID- 29135417 TI - Retzius-sparing robot-assisted radical prostatectomy is safe for patients with prior transurethral prostate surgery. PMID- 29135418 TI - Dusting utilizing suction technique (DUST) for percutaneous nephrolithotomy: use of a dedicated laser handpiece to treat a staghorn stone. PMID- 29135419 TI - The Risk of Cancer Might be Lower Than We Think. Alternatives to Lifetime Risk Estimates. AB - BACKGROUND: Estimates of lifetime cancer risk are commonly used in the clinical setting and in health-care evaluations. These measures are based on lifetime cancer risk estimates and may create an unrealistically frightening perception of cancer risk for an individual. We suggest using two new measures of cancer risk to complement the cancer lifetime risk measure, namely estimates of cancer risk from birth to a specific age or from a specific age to life expectancy. METHODS: We calculated risks using incidence density data from the Israel National Cancer Registry of 2013, applying a well-known formula for calculating risk, for a follow-up time. The joint disease-free survival probability is calculated for several age intervals, and hence the risk (i.e. 1-survival) for the intervals. RESULTS: The risk of cancer to age 80 in Jewish men and women, respectively, ranged from about 0.336 and 0.329 at age 0, to 0.279 and 0.237 at age 60. The risk of cancer from birth up to an age in Jewish men and women, respectively, ranged from 0 and 0 at birth to 0.088 and 0.129 at age 60. The risk of cancer to age 80 in Arab men and women, respectively, ranged from 0.298 and 0.235 at age 0 to 0.249 and 0.161 at age 60. The risk of cancer from birth up to an age in Arab men and women, respectively, ranged from 0 and 0 at age 0 to 0.074 and 0.095 at age 60. In Jewish and Arab women, breast cancer risk to age 80 decreased from about 0.127 in Jewish women at age 40 to 0.079 at age 60 and from 0.080 to 0.043 in Arab women; the risk from birth up to a specific age ranged between 0 and 0.056, and 0 and 0.040, respectively. CONCLUSION: The two proposed new estimates convey important additional information to patients and physicians. These estimates are considerably lower than the frequently quoted 33% lifetime cancer risk and are more relevant to patients and physicians. Similarly, breast cancer risk estimates up to or from a specific age differ considerably from the frequently quoted lifetime risk estimates of 1 in 8 women. PMID- 29135420 TI - Clear Skies Ahead. PMID- 29135421 TI - State of the Journal, 2017. AB - The American Journal of Occupational Therapy (AJOT) has had another successful year, with increases in its journal impact factor and its ranking among rehabilitation journals indexed by Journal Citation Reports. The number of submissions has increased, with manuscripts received from 28 countries. Readership has also increased. AJOT remains the top-ranked occupational therapy journal in the world. In addition to its usual focus on publishing research broadly related to occupational therapy, AJOT created a Centennial section in each issue to celebrate the Centennial of the American Occupational Therapy Association. Centennial section topics were determined on the basis of their relevance to occupational therapy history and to future or emerging or increasing practice areas in occupational therapy. In her presidential address at the American Occupational Therapy Association's 2017 Annual Conference & Centennial Celebration, Amy Lamb honored occupational therapy's past and embraced its future. Occupational therapy practitioners have the power to serve as change agents, demonstrating their value during everyday opportunities as they design the future of occupational therapy. PMID- 29135422 TI - Unlocking the Potential of Everyday Opportunities. AB - In her presidential address at the American Occupational Therapy Association's 2017 Annual Conference & Centennial Celebration, Amy Lamb honored occupational therapy's past and embraced its future. Occupational therapy practitioners have the power to serve as change agents, demonstrating their value during everyday opportunities as they design the future of occupational therapy. PMID- 29135424 TI - AOTA Official Documents in the AJOT Online Supplement. PMID- 29135423 TI - Technology and Occupation: Past, Present, and the Next 100 Years of Theory and Practice. AB - During the first 100 years of occupational therapy, the profession developed a remarkable practice and theory base. All along, technology was an active and core component of practice, but often technology was mentioned only as an adjunct component of therapy and as if it was a specialty. This lecture proposes a new foundational theory that places technology at the heart of occupational therapy as a fundamental part of human occupation and the human experience. Moreover, this new Metaphysical Physical-Emotive Theory of Occupation pushes the occupational therapy profession and the occupational science discipline to overtly consider occupation on the level of a metaphysical-level reality. The presentation of this theory at the Centennial of the profession charges the field to test and further define the theory over the next 100 years and to leverage technology and its role in optimizing occupational performance into the future. PMID- 29135425 TI - Internationalization in an Occupational Therapy Curriculum: A Philippine-American Pilot Collaboration. AB - OBJECTIVE: This study is a pilot implementation of an Internationalization at Home (IaH) teaching and learning collaboration to enhance intercultural learning and understanding of concepts of occupation in two cohorts of occupational science and occupational therapy students from the Philippines and the United States. METHOD: In this collective case study, 149 students (Cohort 1, n = 65; Cohort 2, n = 84) participated. The collaboration included virtual conversations among students, faculty presentations, reflective assignments, and completion of an anonymous online survey. RESULTS: Analysis yielded three essential themes: (1) perception of increased knowledge about human occupation and the influence of culture, (2) identification of teaching-learning aspects that facilitated intercultural learning outcomes, and (3) identification of factors that were enablers of and barriers to learning. CONCLUSION: This study provides insights on how intercultural learning experiences can be integrated into occupational science and occupational therapy curricula and can increase understanding of concepts related to human occupation. PMID- 29135426 TI - Integrated Supported Employment for People With Schizophrenia in Mainland China: A Randomized Controlled Trial. AB - OBJECTIVE: In this randomized controlled trial, we investigated the effectiveness of integrated supported employment (ISE) compared with individual placement and support (IPS) and traditional vocational rehabilitation (TVR) for people with schizophrenia in mainland China. METHOD: One hundred and sixty-two participants with schizophrenia were randomly assigned to ISE (n = 54), IPS (n = 54), or TVR (n = 54). Blinded assessments of employment status, job tenure, and psychological outcomes were conducted at admission; completion of the 3-mo program; and follow up at 7, 11, and 15 mo. RESULTS: Significantly higher employment rate and longer job tenure were found in the ISE group (63.0%, 29.56 wk) compared with the IPS group (50.0%, 25.47 wk) and TVR group (33.3%, 9.91 wk). The ISE group also attained the most positive psychological outcomes. CONCLUSION: Work-related social skills training embedded in ISE with generalization strategies can enhance vocational and nonvocational outcomes for people with schizophrenia in mainland China. PMID- 29135427 TI - Effect of Bathroom Aids and Age on Balance Control During Bathing Transfers. AB - Bathroom assistive devices are used to improve safety during bathing transfers, but biomechanical evidence to support clinical recommendations is lacking. This study evaluated the effectiveness of common bathroom aids in promoting balance control during bathing transfers. Twenty-six healthy adults (12 young, 14 older) stepped into and out of a slippery bathtub while using a vertical grab bar on the side wall, a horizontal grab bar on the back wall, a bath mat, a side wall touch, or no assistance. Balance control was characterized using center of pressure measures and showed greater instability for older adults. The vertical grab bar and wall touch resulted in the safest (best controlled) transfers. The bath mat provided improved balance control in the axis parallel to the bathtub rim but was equivalent to no assistance perpendicular to the rim, in the direction of obstacle crossing. These results can support clinical recommendations for safe bathing transfers. PMID- 29135428 TI - Handwriting and Common Core State Standards: Teacher, Occupational Therapist, and Administrator Perceptions From New York State Public Schools. AB - Handwriting is the cornerstone of written performance and communication for school-age children. This mixed-methods study explored the impact of Common Core State Standards on handwriting instruction and its effects on perceptions regarding children's written responses in elementary school. Using surveys and interviews of elementary teachers, occupational therapists, and administrators in New York State public schools, we sought to understand current trends in handwriting instruction, changes in time spent on handwriting instruction in the classroom, supports offered to students who did not meet expectations for handwriting, and the impact of Common Core on children's written expression. Themes emerged revealing decreased handwriting instruction time and inconsistent use of handwriting instructional programs in the classroom after implementation of Common Core. Handwriting should be considered as a greater component in the foundational standards in Common Core. Occupational therapy services can support handwriting instruction implementation. PMID- 29135429 TI - Laboratory Food Acceptance in Children With Autism Spectrum Disorder Compared With Children With Typical Development. AB - Studies using parent-report measures have described the high prevalence of food selectivity in children with autism spectrum disorder (ASD). However, few studies have documented food acceptance in a controlled laboratory environment. The objective of this study was to compare laboratory food acceptance in children with ASD with that of children with typical development (TD). In addition, the relationships between food acceptance and the child's age, sensory processing pattern, and autism severity were explored. Results indicate that children with autism (n = 31) accepted fewer foods in the laboratory environment than the children with TD (n = 21) and that food acceptance was related to age but not to ASD severity. In addition, sensory processing scores were associated with food acceptance for the combined ASD and TD groups. Results are discussed in the context of the literature. This information has the potential to support evaluation and treatment of food selectivity. PMID- 29135430 TI - Impact of a Fieldwork Experience on Attitudes Toward People With Intellectual Disabilities. AB - OBJECTIVE: The objective of this study was to describe the effects of curriculum activities on changing attitudes of health professional students toward people with intellectual disabilities (IDs). METHOD: A nonrandomized, pretest-posttest design was used. Participants were college students assigned to one of three groups: two groups of students from different years in the occupational therapy program and one group of public health students. Each group completed the Attitudes Toward Intellectual Disabilities Questionnaire before and after each intervention. RESULTS: No significant differences were found in change of attitude after a lecture on the effects of stigma on people with disabilities. Length of time in program, age, and amount of experience with people with IDs affected changes in attitude for occupational therapy students after a fieldwork intervention. CONCLUSION: Level I fieldwork significantly improved the attitudes of occupational therapy students toward people with IDs, whereas a lecture did not. PMID- 29135431 TI - Intervention to Improve Medication Management: Qualitative Outcomes From a Phase I Randomized Controlled Trial. AB - OBJECTIVES: We sought to define an occupational therapy intervention to promote medication management and to evaluate the acceptability and effectiveness of the intervention. METHOD: Nineteen adults with chronic health conditions and poor medication adherence participated in a two-group, blinded, randomized study. They received either an occupational therapy or a standard care intervention. We used a qualitative method to measure participants' changes in medication management through an interview regarding participants' perceptions and behaviors. RESULTS: The occupational therapy intervention group reported greater improvements in medication management and implemented twice as many new adaptive strategies as the standard care group. Participants indicated that interventions related to advocacy, education, assistive technology, environmental modifications, self monitoring, and good rapport were the active ingredients of the intervention. CONCLUSIONS: Occupational therapy is an acceptable intervention for medication management, and it can lead to self-perceived improvements and the adoption of new medication management behaviors. Further research is warranted. PMID- 29135432 TI - Canadian Occupational Performance Measure (COPM) in Primary Care: A Profile of Practice. AB - OBJECTIVE: This study aimed to understand how the Canadian Occupational Performance Measure (COPM) can be used as an outcome measure in primary care and to identify the occupational performance profiles in this setting. METHOD: First, the COPM was administered to all eligible clients at two sites. Second, a focus group with participating occupational therapists explored the feasibility of using the COPM in primary care. RESULTS: A total of 161 COPMs were initially administered. Self-care goals were identified most frequently (n = 248), followed by productivity (n = 229) and leisure (n = 179) goals (total goals = 656). Mean initial performance and satisfactions scores were 3.2 and 2.8, respectively. The average change (n = 22) scores were 2.1 and 2.6, respectively. CONCLUSION: The COPM is an invaluable tool to guide initial assessments and offer an occupation focused lens. Given the lifespan approach and an emphasis on screening and assessment, the challenge was finding the opportunity for readministration. PMID- 29135433 TI - Highly Cited Occupational Therapy Articles in the Science Citation Index Expanded and Social Sciences Citation Index: A Bibliometric Analysis. AB - OBJECTIVE: A bibliometric analysis was completed of highly cited occupational therapy literature and authors published from 1991 to 2014 and accessible in the Science Citation Index Expanded (SCI-Expanded) and Social Sciences Citation Index (SSCI) databases. METHOD: Data were obtained from the SCI-Expanded and SSCI. Articles referenced >100 times were categorized as highly cited articles (HCA). RESULTS: Of 6,486 articles found, 31 were categorized as HCA. The American Journal of Occupational Therapy published the largest number of HCA (n = 8; 26%). The 31 HCA were distributed across seven countries: United States (20 articles), Canada (3), United Kingdom (3), Australia (2), the Netherlands (1), New Zealand (1), and Sweden (1). The three authors with the highest Y-index were S. J. Page, F. Clark, and W. Dunn. CONCLUSION: A latency period of 4 to 5 yr post-publication appears to be needed for a journal article to gain citations. PMID- 29135434 TI - Work Disability Prevention: A Primer for Occupational Therapists. AB - An estimated 313 million workplace accidents resulting in injury occur worldwide every year. Therefore, the burden of workplace injury and disability is present at the individual and the societal level and involves several stakeholders. There has been a shift in paradigm from workplace disability and injury treatment to workplace disability prevention. Occupational therapy practitioners are well positioned to address this multifaceted societal issue. Opening communication lines among stakeholders allows for a more holistic, collaborative, and comprehensive approach to disability, injury, and pain management. The positive results researchers have found at the individual level when using a holistic approach translate to benefits for all of the stakeholders involved. Occupational therapy practitioners may espouse a work disability prevention approach to reduce work disability rates and provide timely return-to-work outcomes for clients. The transition to the preventative model requires collaboration among stakeholders but would be beneficial to all stakeholders involved in the workplace. PMID- 29135437 TI - An adaptation of astronomical image processing enables characterization and functional 3D mapping of individual sites of excitation-contraction coupling in rat cardiac muscle. AB - In beating cardiomyocytes, synchronized localized Ca2+ transients from thousands of active excitation-contraction coupling sites (ECC couplons) comprising plasma and sarcoplasmic reticulum membrane calcium channels are important determinants of the heart's performance. Nevertheless, our knowledge about the properties of ECC couplons is limited by the lack of appropriate experimental and analysis strategies. We designed CaCLEAN to untangle the fundamental characteristics of ECC couplons by combining the astronomer's CLEAN algorithm with known properties of calcium diffusion. CaCLEAN empowers the investigation of fundamental properties of ECC couplons in beating cardiomyocytes without pharmacological interventions. Upon examining individual ECC couplons at the nanoscopic level, we reveal their roles in the negative amplitude-frequency relationship and in beta adrenergic stimulation, including decreasing and increasing firing reliability, respectively. CaCLEAN combined with 3D confocal imaging of beating cardiomyocytes provides a functional 3D map of active ECC couplons (on average, 17,000 per myocyte). CaCLEAN will further enlighten the ECC-couplon-remodelling processes that underlie cardiac diseases. PMID- 29135436 TI - Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis. AB - Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Deltaex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65 positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition. PMID- 29135440 TI - [Peter Fonagy on epistemic trust]. AB - No abstract available. PMID- 29135438 TI - Exposure to Perfluoroalkyl Substances and Metabolic Outcomes in Pregnant Women: Evidence from the Spanish INMA Birth Cohorts. AB - BACKGROUND: Exposure to perfluoroalkyl substances (PFASs) may increase risk for metabolic diseases; however, epidemiologic evidence is lacking at the present time. Pregnancy is a period of enhanced tissue plasticity for the fetus and the mother and may be a critical window of PFAS exposure susceptibility. OBJECTIVE: We evaluated the associations between PFAS exposures and metabolic outcomes in pregnant women. METHODS: We analyzed 1,240 pregnant women from the Spanish INMA [Environment and Childhood Project (INfancia y Medio Ambiente)] birth cohort study (recruitment period: 2003-2008) with measured first pregnancy trimester plasma concentrations of four PFASs (in nanograms/milliliter). We used logistic regression models to estimate associations of PFASs (log10-transformed and categorized into quartiles) with impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM), and we used linear regression models to estimate associations with first-trimester serum levels of triglycerides, total cholesterol, and C-reactive protein (CRP). RESULTS: Perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were positively associated with IGT (137 cases) [OR per log10-unit increase=1.99 (95% CI: 1.06, 3.78) and OR=1.65 ( 95% CI: 0.99, 2.76), respectively]. PFOS and PFHxS associations with GDM (53 cases) were in a similar direction, but less precise. PFOS and perfluorononanoate (PFNA) were negatively associated with triglyceride levels [percent median change per log10-unit increase=-5.86% (95% CI: -9.91%, -1.63%) and percent median change per log10-unit increase=-4.75% (95% CI: -8.16%, -0.61%, respectively], whereas perfluorooctanoate (PFOA) was positively associated with total cholesterol [percent median change per log10-unit increase=1.26% (95% CI: 0.01%, 2.54%)]. PFASs were not associated with CRP in the subset of the population with available data (n=640). CONCLUSIONS: Although further confirmation is required, the findings from this study suggest that PFAS exposures during pregnancy may influence lipid metabolism and glucose tolerance and thus may impact the health of the mother and her child. https://doi.org/10.1289/EHP1062. PMID- 29135441 TI - Mentalizing, attachment and epistemic trust: how psychotherapy can promote resilience. AB - No abstract available. PMID- 29135439 TI - Biological Cleavage of the C-P Bond in Perfluoroalkyl Phosphinic Acids in Male Sprague-Dawley Rats and the Formation of Persistent and Reactive Metabolites. AB - BACKGROUND: Perfluoroalkyl phosphinic acids (PFPiAs) have been detected in humans, wildlife, and various environmental matrices. These compounds have been used with perfluoroalkyl phosphonic acids (PFPAs) as surfactants in consumer products and as nonfoaming additives in pesticide formulations. Unlike the structurally related perfluoroalkyl sulfonic and carboxylic acids, little is known about the biological fate of PFPiAs. OBJECTIVES: We determined the biotransformation products of PFPiAs and some pharmacokinetic parameters in a rat model. METHODS: Male Sprague-Dawley rats received an oral gavage dose of either C6/C8PFPiA, C8/C8PFPiA, or C8PFPA. Blood was sampled over time, and livers were harvested upon sacrifice. Analytes were quantified using ultra-high-performance liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry. RESULTS: PFPiAs were metabolized to the corresponding PFPAs and 1H perfluoroalkanes (1H-PFAs), with 70% and 75% biotransformation 2 wk after a single bolus dose for C6/C8PFPiA and C8/C8PFPiA, respectively. This is the first reported cleavage of a C-P bond in mammals, and the first attempt, with a single dose exposure, to characterize the degradation of any perfluoroalkyl acid. Elimination half-lives were 1.9+/-0.5 and 2.8+/-0.8 days for C6/C8PFPiA and C8/C8PFPiA, respectively, and 0.95+/-0.17 days for C8PFPA. Although elimination half-lives were not determined for 1H-PFAs, concentrations were higher than the corresponding PFPAs 48 h after rats were dosed with PFPiAs, suggestive of slower elimination. CONCLUSIONS: PFPiAs were metabolized in Sprague-Dawley rats to form persistent PFPAs as well as 1H-PFAs, which contain a labile hydrogen that may undergo further metabolism. These results in rats produced preliminary findings of the pharmacokinetics and metabolism of PFPiAs, which should be further investigated in humans. If there is a parallel between the disposition of these chemicals in humans and rats, then humans with detectable amounts of PFPiAs in their blood may be undergoing continuous exposure. https://doi.org/10.1289/EHP1841. PMID- 29135442 TI - [Lottery and suicide - the effect of number of lottery tickets on Hungarian suicide rates]. AB - AIM: The relationship of suicide and gambling is a neglected field in the study of suicidology. In Hungary, no statistical studies have been published to date with regard to the whole of the population. Our study investigates the relationship between a very popular high prize game, lottery, and suicide rates. METHOD: The relationship between daily rates of suicide by gender and age and the number of winning tickets has been analysed over the periods between 1991 and 1997 and from 1997 to 2013. During the first period of time examined, the lottery draws took place on Fridays, while they were held on Saturdays in the second. Time series covariance analysis based on ARIMA modelling on detrended data was used to test the relationship of gambling and self-destruction. RESULTS: Out of the 27 models tested, the only significant models, which are also in line with what can be expected based on the literature, could be found during the period when the draws took place on Fridays. Corresponding to the increase in the number of lottery tickets, there was also an increase in the number of suicides somewhat delayed in time. The relationship only held true for males with one exception. CONCLUSIONS: In our study, we found a weak positive relationship between rates of suicide and the spread of the lottery game. The significance of our study is well reflected by the fact that - to the best of our knowledge - this effect has never been investigated on such a large sample before. Our results point to the significance of cultural and social factors, to differences in gender roles, and to the accentuated role of the factor of hopelessness in shaping the suicide scene in Hungary. In order to clarify the role of different factors in more detail, there seems to be a need for further studies on suicide conducted on large samples. PMID- 29135443 TI - Continuous maintenance antipsychotic treatment in schizophrenia. AB - During recent years concerns have been raised about the long-term cumulative and potentially negative impact of continuous maintenance antipsychotic treatment of schizophrenia on the human body, especially on the central nervous system. This paper aims at providing a summary of literature data on continuous maintenance treatment for practicing physicians. The results show that continuous maintenance antipsychotic treatment can significantly decrease the risk of relapses and improve the long-term outcome in schizophrenia. Regarding the long-term effects of antipsychotic treatment on the central nervous system, however, further research is needed to answer the question: are brain morphological and functional changes associated with the disease or the treatment or both? 'Based on the data available, low antipsychotic doses are effective and safe while high doses of antipsychotics should be avoided. This review concludes that the minimum effective doses of antipsychotics should be administered for continuous maintenance treatment. PMID- 29135444 TI - [Validation of Hungarian Smartphone Deprivation Inventory (HSDI) with school children]. AB - : The widespread use of smartphones generates new habits and behaviors among the users, including schoolchildren. Advance technology-based applications, capturing interest and attention, influence cognitive focus and time spent with the device. Examination of these factors points toward the risk of addiction, as well as the deprivations sensations associated with the latter, that call for scholastic attention. AIM: The aim of this study was to validate a Hungarian Smartphone Deprivation Inventory (HSDI), to gauge the deprivation feelings and their severity in schoolchildren when they cannot access their device. METHOD: A 9 item, 7-point, agree-disagree inventory was developed on the basis of an earlier exercise deprivation scale (Robbins and Joseph, 1985). The inventory was completed by 258 Hungarian schoolchildren (mean age=12.4 +/- SD = 1.71 years). RESULTS: The participants also completed the Hungarian version of the Brief Addiction to Smartphone Scale (BASS). An exploratory factor analysis of the HSDI yielded a single factor that accounted for 55.84 % of the variance. The internal consistency of the inventory was excellent (Cronbach's alpha = 0.90). Content validity of the HSDI was checked by comparing the scores of those scoring above and below the median on the BASS that yielded statistically significant differences (p < .001). The HSDI correlated statistically significantly with the BASS (r = .62, p < .001) as well as with the deprivation subscale of the BASS (r = .63, p < .001), which demonstrated the inventory's congruent validity. CONCLUSION: These findings show that the HSDI is a sensitive tool for measuring deprivation feelings related prevented smartphone access in schoolchildren. PMID- 29135445 TI - [A new method for the measurement of social cognition in schizophrenia]. AB - : Impairments in social cognitive functions and their long-term effects are well known in schizophrenia. However, so far no computer application has been available to assess these functions of patients. Our study is about introducing a new computer application measuring social cognitive abilities. The program (SCAN) is available on the following link and can be downloaded for anyone: psychiatry.pote.hu > Research > Workgroups > Schizophrenia. The hypothesis of our present study was that SCAN is able to assess the social cognitive ability of patients with schizophrenia in a rapid, complex and objective way. METHOD: 86 schizophrenia patients and 101 healthy controls were examined. SCAN was used to present verbal and nonverbal tasks to measure four different domains of social cognition. SCAN registered the responses and the reaction times as well. Furthermore, an additional application was developed (called Scanalizer) to evaluate the results of a person being tested. RESULTS: The results were evaluated by a two-dimensional analysis. This means that both task performance and the reaction time were taken into consideration while evaluating the results. As for the results, we found that the patients showed significantly worse functioning than the healthy subjects in the four domains of social cognition. CONCLUSION: Based on our results, SCAN is effective enough to detect the atypical social processing of schizophrenia patients. Moreover, Scanalizer is capable of evaluating the social cognitive abilities of schizophrenia patients in a complex, relatively fast and objective way. PMID- 29135446 TI - [Cross-Informant Agreement Between Parent-Reported and Adolescent Self-Reported Quality of Life in children with externalising symptoms]. AB - BACKGROUND: It is well-known phenomena both in clinical practice and research, that there is a discrepancy between the parents' and children's report about children's Quality of Life (QoL). The purpose of our research was to examine the differences in self and caregiver's proxy report of child's QoL. We also compared mothers', fathers' and other caregivers' reports of children's QoL. METHODS: Patients with externalizing symptoms in their history, aged 13-18 years were selected from the Vadaskert Child and Adolescent Psychiatry Hospital and Outpatient Clinic. We used the Inventory of Quality of Life in Children and Adolescents (QL), parent and children version to measure the children's QoL. We used F-factor analysis (Principal Component Analysis and direct oblimin rotation) and t-tests for data analysis. RESULTS: Altogether 138 caregiver-child dyads filled the QL. The adolescents mean age was 14.47 years (SD=.40). Seventy-four mothers, 37 fathers and 27 other caregivers were included into our study. The caregivers' ratings were settled sorted into three factors, the adolescents' ratings were settled sorted into two factors. We found significant differences between mothers, fathers and other caregivers' ratings in the following domains of QoL: school, loneliness, peer relations, physical health, mental health and problem/illness. The caregivers evaluated adolescents' QoL more positively then the adolescents did (t=761, df=139, p<0,0001). CONCLUSIONS: The caregivers and their children's reported different domains of QoL as problematic. Therefore, it is important to gain information from several sources about the adolescent's QoL. PMID- 29135447 TI - [Two contrasting emotional states immediately before suicide: anger or fear]. AB - No abstract available. PMID- 29135448 TI - [The psychotherapy of male patient with sex addiction]. AB - No abstract available. PMID- 29135449 TI - [A short note to the last two sentences of "Entirely And For Nothing"]. AB - No abstract available. PMID- 29135450 TI - Influence of acquisition frame-rate and video compression techniques on pulse rate variability estimation from vPPG signal. AB - In this paper, common time- and frequency-domain variability indexes obtained by pulse rate variability (PRV) series extracted from video-photoplethysmographic signal (vPPG) were compared with heart rate variability (HRV) parameters calculated from synchronized ECG signals. The dual focus of this study was to analyze the effect of different video acquisition frame-rates starting from 60 frames-per-second (fps) down to 7.5 fps and different video compression techniques using both lossless and lossy codecs on PRV parameters estimation. Video recordings were acquired through an off-the-shelf GigE Sony XCG-C30C camera on 60 young, healthy subjects (age 23+/-4 years) in the supine position. A fully automated, signal extraction method based on the Kanade-Lucas-Tomasi (KLT) algorithm for regions of interest (ROI) detection and tracking, in combination with a zero-phase principal component analysis (ZCA) signal separation technique was employed to convert the video frames sequence to a pulsatile signal. The frame-rate degradation was simulated on video recordings by directly sub-sampling the ROI tracking and signal extraction modules, to correctly mimic videos recorded at a lower speed. The compression of the videos was configured to avoid any frame rejection caused by codec quality leveling, FFV1 codec was used for lossless compression and H.264 with variable quality parameter as lossy codec. The results showed that a reduced frame-rate leads to inaccurate tracking of ROIs, increased time-jitter in the signals dynamics and local peak displacements, which degrades the performances in all the PRV parameters. The root mean square of successive differences (RMSSD) and the proportion of successive differences greater than 50 ms (PNN50) indexes in time-domain and the low frequency (LF) and high frequency (HF) power in frequency domain were the parameters which highly degraded with frame-rate reduction. Such a degradation can be partially mitigated by up-sampling the measured signal at a higher frequency (namely 60 Hz). Concerning the video compression, the results showed that compression techniques are suitable for the storage of vPPG recordings, although lossless or intra-frame compression are to be preferred over inter-frame compression methods. FFV1 performances are very close to the uncompressed (UNC) version with less than 45% disk size. H.264 showed a degradation of the PRV estimation directly correlated with the increase of the compression ratio. PMID- 29135451 TI - Software design and implementation concepts for an interoperable medical communication framework. AB - The new IEEE 11073 service-oriented device connectivity (SDC) standard proposals for networked point-of-care and surgical devices constitutes the basis for improved interoperability due to its independence of vendors. To accelerate the distribution of the standard a reference implementation is indispensable. However, the implementation of such a framework has to overcome several non trivial challenges. First, the high level of complexity of the underlying standard must be reflected in the software design. An efficient implementation has to consider the limited resources of the underlying hardware. Moreover, the frameworks purpose of realizing a distributed system demands a high degree of reliability of the framework itself and its internal mechanisms. Additionally, a framework must provide an easy-to-use and fail-safe application programming interface (API). In this work, we address these challenges by discussing suitable software engineering principles and practical coding guidelines. A descriptive model is developed that identifies key strategies. General feasibility is shown by outlining environments in which our implementation has been utilized. PMID- 29135452 TI - Drug-drug interactions in cancer chemotherapy: an observational study in a tertiary health care centre. AB - BACKGROUND: The objective of this study was to evaluate the occurrence of drug drug interactions (DDIs) in patients on cancer chemotherapy, with the identification of risk factors for these DDIs. METHODS: This was a cross sectional, descriptive study carried out at the Department of Onco-Radiation at Guru Gobind Singh Medical College, Faridkot, Punjab. The DDIs were recorded with the help of a drug interaction/interplay information software. RESULTS: In total, 354 interactions were identified from 283 patient records. The mean age of the patients in the study was 49.05+/-14.35 years. According to the mechanism of interaction, 306 (86.44%) drug interactions were classified as pharmacokinetic and 48 (13.56%) as pharmacodynamic in nature. CONCLUSIONS: Sensitization of the treating oncologist and the establishment of alerts, such as electronic alerts or a novel fully digital computerized technology that gives a warning when a health expert enters a patient's prescription orders into the electronic medical documentation, can be helpful in controlling DDIs. PMID- 29135453 TI - Analysis of subcellular structural tension in axonal growth of neurons. AB - The growth and regeneration of axons are the core processes of nervous system development and functional recovery. They are also related to certain physiological and pathological conditions. For decades, it has been the consensus that a new axon is formed by adding new material at the growth cone. However, using the existing technology, we have studied the structural tension of the nerve cell, which led us to hypothesize that some subcellular structural tensions contribute synergistically to axonal growth and regeneration. In this review, we classified the subcellular structural tension, osmotic pressure, microfilament and microtubule-dependent tension involved controllably in promoting axonal growth. A squeezing model was built to analyze the mechanical mechanism underlying axonal elongation, which may provide a new view of axonal growth and inspire further research. PMID- 29135456 TI - Probiotics and Their Use in Inflammatory Bowel Disease. AB - Context * Crohn's disease and ulcerative colitis result in similar gastrointestinal (GI) symptoms, including pain, diarrhea, stools with mucus or blood, and ulceration or tissue damage within the alimentary canal. Gut microbiota play a crucial role in triggering, maintaining, and exacerbating inflammatory bowel disease (IBD). Probiotics might help to rebalance the gut flora in a positive way, shifting from pro- to anti-inflammatory. Objectives * The study intended to investigate the safety and use of probiotics and the biological effects of probiotic bacteria on IBD. Design * The research team performed a literature review. The team conducted a database search in April 2015 using Google Scholar and PubMed to find studies relevant to probiotics and their use in IBD. Only papers that were published in English were considered, and all available years in each database were searched. The initial search identified 38 published articles, for which the research team obtained full texts and independently read them in full to identify those papers suitable for inclusion in the review. Setting * The study took place in the main library of the University of Lahore (Islamabad, Pakistan). Results * Many strains of probiotics exist, but the most common strains available today are (1) the Bifidobacterium species, (2) Enterococcus faecium, (4) the Lactobacillus strains, (4) Saccharomyces boulardii, (5) the Bacillus species, and (6) Pediococcus, all used to produce beneficial health effects. These species showed their beneficial effects on the host using different mechanisms involving (1) production of proteins, quorum sensing signaling inhibitors, butyrate, immunoglobulin A, and short-chain fatty acids; (2) decreased production of tumor necrosis factor alpha and interleukin 8; (3) increased expression of mucin 2; and (4) increased upregulation of defensin. Conclusions * Studies on probiotics in animal models of IBD are promising, and clinical results in IBD patients are encouraging; however, the data are limited, and few studies are placebo controlled. Additional placebo controlled, double-blind studies in IBD are required before recommendations can be offered for routine use of probiotics in IBD. Additional organisms may eventually be developed through genetic engineering. The current evidence also indicates that probiotic effects are strain specific; they do not act through the same mechanisms nor are all probiotics indicated for the same health conditions. More research is needed to determine what strains and at what dose probiotics become more useful as part of a clinical intervention. PMID- 29135455 TI - Transcriptome-wide association study of inflammatory biologic age. AB - Chronic low grade inflammation is a fundamental mechanism of aging. We estimated biologic age using nine biomarkers from diverse inflammatory pathways and we hypothesized that genes associated with inflammatory biological age would provide insights into human aging. In Framingham Offspring Study participants at examination 8 (2005 to 2008), we used the Klemera-Doubal method to estimate inflammatory biologic age and we computed the difference (?Age) between biologic age and chronologic age. Gene expression in whole blood was measured using the Affymetrix Human Exon 1.0 ST Array. We used linear mixed effect models to test associations between inflammatory ?Age and gene expression (dependent variable) adjusting for age, sex, imputed cell counts, and technical covariates. Our study sample included 2386 participants (mean age 67A+/-9 years, 55% women). There were 448 genes significantly were associated with inflammatory ?Age (P<2.8x10-6), 302 genes were positively associated and 146 genes were negatively associated. Pathway analysis among the identified genes highlighted the NOD-like receptor signaling and ubiquitin mediated proteolysis pathways. In summary, we identified 448 genes that were significantly associated with inflammatory biologic age. Future functional characterization may identify molecular interventions to delay aging and prolong healthspan in older adults. PMID- 29135457 TI - Toward an Explanatory Framework for Yoga Therapy Informed by Philosophical and Ethical Perspectives. AB - Context * Yoga Therapy is an emerging complementary and integrative health practice for which there is increasing interest from both clinical and research perspectives. Currently missing, however, is an explanatory framework for the profession that provides practitioners, clients, and the public with an understanding of how various yogic traditions and principles can be understood in modern health care contexts. Objective * This study proposes an explanatory framework for yoga therapy, informed by phenomenology, eudaimonia, virtue ethics, and first-person ethical inquiry. Conclusions * These 4 philosophical perspectives-phenomenology, eudaimonia, virtue ethics, and first-person ethical inquiry-provide a lens through which to understand how yogic practices support the individual's transformation in the experience of illness, pain, or disability. We propose that this transformation occurs through facilitating a reharmonization of body, mind, and environment toward the experience of eudaimonic well-being. PMID- 29135454 TI - Expression of a novel CNPY2 isoform in colorectal cancer and its association with oncologic prognosis. AB - Colorectal cancer (CRC) is a leading cause of cancer-related mortality. Recently, we identified a novel biomarker, canopy fibroblast growth factor signaling regulator 2 (CNPY2) isoform2, and subsequently investigated its expression and prognostic value in CRC patients. We initially generated CNPY2 isoform2 monoclonal antibodies and examined CNPY2 isoform2 expression in CRC cell lines and tissues using quantitative real-time polymerase chain reaction, western blot and immunohistochemistry analyses. We found that CNPY2 isoform2 expression significantly increased in tumor cell lines and tissues compared with that in normal colon epithelial cells and tumor-adjacent normal tissues. Survival analysis indicated that patients with low CNPY2 isoform2 expression had poorer 5 year overall survival (OS) in both the training cohort (41.7% vs. 77.7%, P = 0.007) and validation cohort (47.1% vs. 78.8%, P = 0.002). In multivariable analysis, CNPY2 isoform2 was identified as a predictor of 5-year OS in both the training cohort [hazard ratio (HR) = 5.001; 95% confidence interval (CI) 2.156 11.598, P < 0.001) and validation cohort (HR= 2.443; 95% CI 1.197- 4.983, P = 0.014). In conclusion, CNPY2 isoform2 represents as a novel and valuable prognostic indicator for CRC patients, while the oncologic function of CNPY2 requires further study. PMID- 29135458 TI - Immediate Effects of Osteopathic Treatment Versus Therapeutic Exercise on Patients With Chronic Cervical Pain. AB - Context * Alternatives to medication for immediate pain relief are needed because long-term use of pain medication has been associated with adverse effects. High velocity, low-amplitude (HVLA) manipulation techniques (MTs) and craniocervical flexion (CCF) exercises have been frequently used in the management of chronic cervical pain. Objective * The study intended to compare the immediate effects on pain of a treatment using HVLA manipulation versus one using a CCF exercise protocol. Design * The research team designed a single-blinded, randomized clinical trial. Setting * The study was conducted at osteopathic clinics. Participants * Participants were 25 volunteer patients with chronic neck pain. Intervention * Participants were randomly enrolled in one of 2 groups: the HVLA manipulation group (MT group), n = 12, or the CCF exercise protocol group (CCF group), n = 13. Participants in the CCF group performed the exercise for 10 repetitions of a 10-s duration, with a 10-s rest interval between each contraction, for a total contraction time of 100 s and a total time of the session of 190 s. Outcome Measures * The outcomes were measured at baseline and at 60 s postintervention. The measures included (1) a visual analogue scale (VAS) completed during range of motion (ROM) measurement, (2) an evaluation of the ROM of the cervical spine, (3) a test of pressure pain thresholds (PPTs), and (4) electromyographic (EMG) activation of sternocleidomastoid muscle during a craniocervical flexion test. Results * Following both interventions, significant changes were found between baseline and immediately postintervention in the VAS score during ROM measurement for both groups, with P = .004 and P = .015, respectively. In the MT group, the measures for flexion (P = .001), right-side bending (P = .002), and left rotation (P = .005) changed significantly between baseline and postintervention; however, only flexion (P = .026) and extension (P = .040) ROM changed significantly between baseline and postintervention in the CCF group. Significant changes were observed in upper trapezius PPT following both interventions-MT group, P = .043, and CCF group, P = .005. In addition, significant changes in C5 PPT had occurred in the CCR group (P = .020). Between group differences were significant for extension and right-side-bending ROM, with P = .019 and P = .012, respectively, and the changes between baseline and postintervention were greater in the MT group. None of the interventions led to changes in EMG. Conclusions * Although both interventions were associated with immediately improved ROM and pain after treatment, HVLA manipulation was more effective than CCF exercise in improving ROM and VAS during ROM. None of the interventions led to changes in EMG. PMID- 29135459 TI - Tailoring two-dimensional nanoparticle arrays into various patterns. AB - A simple and effective technique has been developed to fabricate patterns of nanoparticle arrays. Lithographically fabricated structures in resists serve as scissors to tailor two-dimensional nanoparticle arrays on a flat poly(dimethylsiloxane) (PDMS) stamp. The desired patterns of nanoparticle arrays remaining on the PDMS stamp after tailoring can be printed onto solid substrates. Various regular nanoparticle patterns, such as squares, triangles, disks, and pentagons, can be easily prepared using this technique. Arbitrary nanoparticle patterns as complex as Chinese characters have been successfully demonstrated. Moreover, nanoparticle stripes with width ranging from micrometers to quasi single nanoparticle diameter have also been achieved. Nanoparticle stripes have been integrated into electronic devices for transport measurements. PMID- 29135460 TI - Evaluation of the antimicrobial activity and cytotoxic effect of hydroxyapatite containing Brazilian propolis. AB - The aim of this work was to produce hydroxyapatite powder (HA) containing the dry extract of green and red propolis, and to evaluate the possible bactericidal activity of these materials over a short period of time through a fast release system. The ethanolic extracts of green and red propolis (EEP) were incorporated into the material by spray drying. After release tests, powders containing dry EEP were characterized regarding the content of total phenolics and flavonoids. Material characterization was undertaken by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). The antimicrobial activity was evaluated by plate colony counting, minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against Staphylococcus aureus (S. aureus). The cytotoxicity of the materials was determined by the neutral red incorporation method. The materials showed apparently spherical morphology, indicating a decrease in the degree of agglomeration with the addition of propolis. Characteristic HA and propolis functional groups were observed in the FTIR. The materials showed a higher release of phenolics and lower amounts of flavonoids when compared to the EEP, with the higher amounts of flavonoids observed for HA with red propolis. A bactericidal effect was observed for all materials within the interval of 0.5 and 1 h, showing lower inhibitory activity (MIC) and higher bactericidal activity (MBC) when compared to the EEP, with the best results attributed to HA with red propolis. The IC50 values (which is the concentration needed to inhibit cell growth by 50%) obtained from the cytotoxicity assay for HA with the green and red propolis lay between MIC and MCB. Considering these results, it is suggested that HA and propolis may be used as a possible antimicrobial agent, inhibiting the growth of S. aureus, although further in vivo biocompatibility should be investigated before using this material as a medical device with bactericidal potential. PMID- 29135461 TI - Site occupancy, composition and magnetic structure dependencies of martensitic transformation in Mn2Ni1+xSn1-x. AB - A delicate balance between various factors such as site occupancy, composition and magnetic ordering seems to affect the stability of the martensitic phase in Mn2Ni1+xSn1-x. Using first-principles DFT calculations, we explore the impacts of each one of these factors on the martensitic stability of this system. Our results on total energies, magnetic moments and electronic structures upon changes in the composition, the magnetic configurations and the site occupancies show that the occupancies at the 4d sites in the Inverse Heusler crystal structure play the most crucial role. The presence of Mn at the 4d sites originally occupied by Sn and its interaction with the Mn atoms at other sites decide the stability of the martensitic phases. This explains the discrepancy between the experiments and earlier DFT calculations regarding phase stability in Mn2NiSn. Our results qualitatively explain the trends observed experimentally with regard to martensitic phase stability and the magnetisations in Ni-excess, Sn-deficient Mn2NiSn system. PMID- 29135462 TI - Silver nanowires as the current collector for a flexible in-plane micro supercapacitor via a one-step, mask-free patterning strategy. AB - The fabrication of a current collector-contained in-plane micro-supercapacitor (MSC) usually requires the patterning of the current collector first and then subsequent patterning of the active material with the assistance of a photoresist and mask. However, this two-step patterning process is too complicated and the photoresist used is harmful to the properties of nanomaterials. Here, we demonstrate a one-step, mask-free strategy to pattern the current collector and the active material at the same time, for the fabrication of an all-solid-state flexible in-plane MSC. Silver nanowires (AgNWs) are used as the current collector. An atmospheric pressure pulsed cold micro-plasma-jet is used to realize the one-step, mask-free production of interdigitated multi-walled carbon nanotube (MWCNT)/AgNW electrodes. Remarkably, the fabricated MWCNT/AgNW-based MSC shows good flexibility and excellent rate capability. Moreover, the performance of properties including cyclic stability, equivalent series resistance, relaxation time and energy/power densities of the MWCNT/AgNW-based MSC are significantly enhanced by the presence of the AgNW current collector. PMID- 29135463 TI - New method for MBE growth of GaAs nanowires on silicon using colloidal Au nanoparticles. AB - We present a new method for the deposition of colloidal Au nanoparticles on the surface of silicon substrates based on short-time Ar plasma treatment without the use of any polymeric layers. The elaborated method is compatible with molecular beam epitaxy, which allowed us to carry out the detailed study of GaAs nanowire synthesis on Si(111) substrates using colloidal Au nanoparticles as seeds for their growth. The results obtained elucidated the causes of the difference between the initial nanoparticle sizes and the diameters of the grown nanowires. PMID- 29135464 TI - Polybenzimidazole/Mxene composite membranes for intermediate temperature polymer electrolyte membrane fuel cells. AB - This report demonstrated the first study on the use of a new 2D nanomaterial (Mxene) for enhancing membrane performance of intermediate temperature (>100 degrees C) polymer electrolyte membrane fuel cells (ITPEMFCs). In this study, a typical Ti3C2T x -MXene was synthesized and incorporated into polybenzimidazole (PBI)-based membranes by using a solution blending method. The composite membrane with 3 wt% Ti3C2T x -MXene showed the proton conductivity more than 2 times higher than that of pristine PBI membrane at the temperature range of 100 degrees C-170 degrees C, and led to substantial increase in maximum power density of fuel cells by ~30% tested at 150 degrees C. The addition of Ti3C2T x MXene also improved the mechanical properties and thermal stability of PBI membranes. At 3 wt% Ti3C2T x -MXene, the elongation at break of phosphoric acid doped PBI remained unaffected at 150 degrees C, and the tensile strength and Young's modulus was increased by ~150% and ~160%, respectively. This study pointed out promising application of MXene in ITPEMFCs. PMID- 29135465 TI - Thermally activated TRP channels: molecular sensors for temperature detection. AB - Temperature sensing is one of the oldest capabilities of living organisms, and is essential for sustaining life, because failure to avoid extreme noxious temperatures can result in tissue damage or death. A subset of members of the transient receptor potential (TRP) ion channel family is finely tuned to detect temperatures ranging from extreme cold to noxious heat, giving rise to thermoTRP channels. Structural and functional experiments have shown that thermoTRP channels are allosteric proteins, containing different domains that sense changes in temperature, among other stimuli, triggering pore opening. Although temperature-dependence is well characterized in thermoTRP channels, the molecular nature of temperature-sensing elements remains unknown. Importantly, thermoTRP channels are involved in pain sensation, related to pathological conditions. Here, we provide an overview of thermoTRP channel activation. We also discuss the structural and functional evidence supporting the existence of an intrinsic temperature sensor in this class of channels, and we explore the basic thermodynamic principles for channel activation. Finally, we give a view of their role in painful pathophysiological conditions. PMID- 29135466 TI - All-spinel oxide Josephson junctions for high-efficiency spin filtering. AB - Obtaining high efficiency spin filtering at room temperature using spinel ferromagnetic tunnel barriers has been hampered by the formation of antiphase boundaries due to their difference in lattice parameters between barrier and electrodes. In this work we demonstrate the use of LiTi2O4 thin films as electrodes in an all-spinel oxide CoFe2O4-based spin filter devices. These structures show nearly perfect epitaxy maintained throughout the structure and so minimise the potential for APBs formation. The LiTi2O4 in these devices is superconducting and so measurements at low temperature have been used to explore details of the tunnelling and Josephson junction behaviour. PMID- 29135467 TI - Univariate and multivariate conditional entropy measures for the characterization of short-term cardiovascular complexity under physiological stress. AB - OBJECTIVE: A defining feature of physiological systems under the neuroautonomic regulation is their dynamical complexity. The most common approach to assess physiological complexity from short-term recordings, i.e. to compute the rate of entropy generation of an individual system by means of measures of conditional entropy (CE), does not consider that complexity may change when the investigated system is part of a network of physiological interactions. This study aims at extending the concept of short-term complexity towards the perspective of network physiology, defining multivariate CE measures whereby multiple physiological processes are accounted for in the computation of entropy rates. APPROACH: Univariate and multivariate CE measures are computed using state-of-the-art methods for entropy estimation and applied to time series of heart period (H), systolic (S) and diastolic (D) arterial pressure, and respiration (R) variability measured in healthy subjects monitored in a resting state and during conditions of postural and mental stress. MAIN RESULTS: Compared with the traditional univariate metric of short-term complexity, multivariate measures provide additional information with plausible physiological interpretation, such as (i) the dampening of respiratory sinus arrhythmia and activation of the baroreflex control during postural stress; (ii) the increased complexity of heart period and blood pressure variability during mental stress, reflecting the effect of respiratory influences and upper cortical centers; (iii) the strong influence of D on S, mediated by left ventricular ejection fraction and vascular properties; (iv) the role of H in reducing the complexity of D, related to cardiac run-off effects; and (v) the unidirectional role of R in influencing cardiovascular variability. SIGNIFICANCE: Our results document the importance of employing a network perspective in the evaluation of the short-term complexity of cardiovascular and respiratory dynamics across different physiological states. PMID- 29135468 TI - Thermal effect of Zn quantum dots grown on Si(111): competition between relaxation and reconstraint. AB - Zn dots are potential solutions for metal contacts in future nanodevices. The metastable states that exist at the interface between Zn quantum dots and oxide free Si(111) surfaces can suppress the development of the complete relaxation and increase the size of Zn dots. In this work, the actual heat consumption of the structural evolution of Zn dots resulting from extrinsic thermal effect was analyzed. Zn dots were coherently grown on oxide-free Si(111) through magnetron RF sputtering. A compensative optical method combined with reflective second harmonic generation and synchrotron x-ray diffraction (XRD) was developed to statistically analyze the thermal effect on the Zn dot system. Pattern matching (3 m) between the Zn and oxide-free Si(111) surface enabled Si(111) to constrain Zn dots from a liquid to solid phase. Annealing under vacuum induced smaller, loose Zn dots to be reconstrained by Si(111). When the size of the Zn dots was in the margin of complete relaxation, the Zn dot was partially constrained by potential barriers (metastable states) between Zn(111) and one of the six in planes of Si<110>. The thermal disturbance exerted by annealing would enable partially constrained ZnO/Zn dots to overcome the potential barrier and be completely relaxed, which is obvious on the transition between Zn(111) and Zn(002) peak in synchrotron XRD. Considering the actual irradiated surface area of dots array in a wide-size distribution, the competition between reconstrained and relaxed Zn dots on Si(111) during annealing was statistically analyzed. PMID- 29135469 TI - Exploiting both optical and electrical anisotropy in nanowire electrodes for higher transparency. AB - Transparent electrodes such as indium tin oxide and random meshes of silver nanowires (AgNWs) have isotropic in-plane properties. However, we show that imparting some alignment to AgNWs can create anisotropic transparency and electrical conductivity characteristics that may benefit many applications. For example, liquid crystal displays and the touch sensors on top of them often only need to be transparent to one type of polarized light as well as predominantly conductive in only one direction. Herein, AgNWs are slightly preferentially aligned during their deposition by rod coating. Compared to randomly oriented AgNW films, the alignment boosts the transparency to perpendicularly polarized light, as well as achieves a higher transparency for a given sheet resistance in one direction compared to randomly oriented AgNWs films. These factors together increase the transparency of a 16 Omega/sq electrode by 7.3 percentage points. The alignment technique is cheap and scalable, compatible with roll-to-roll processes, and most importantly does not require extra processing steps, as rod coating is already a standard process for AgNW electrode fabrication. PMID- 29135470 TI - Planar screening by charge polydisperse counterions. AB - We study how a neutralising cloud of counterions screens the electric field of a uniformly charged planar membrane (plate), when the counterions are characterised by a distribution of charges (or valence), [Formula: see text]. We work out analytically the one-plate and two-plate cases, at the level of non-linear Poisson-Boltzmann theory. The (essentially asymptotic) predictions are successfully compared to numerical solutions of the full Poisson-Boltzmann theory, but also to Monte Carlo simulations. The counterions with smallest valence control the long-distance features of interactions, and may qualitatively change the results pertaining to the classic monodisperse case where all counterions have the same charge. Emphasis is put on continuous distributions [Formula: see text], for which new power-laws can be evidenced, be it for the ionic density or the pressure, in the one- and two-plates situations respectively. We show that for discrete distributions, more relevant for experiments, these scaling laws persist in an intermediate but yet observable range. Furthermore, it appears that from a practical point of view, hallmarks of the continuous [Formula: see text] behaviour are already featured by discrete mixtures with a relatively small number of constituents. PMID- 29135471 TI - First patients treated with a 1.5 T MRI-Linac: clinical proof of concept of a high-precision, high-field MRI guided radiotherapy treatment. AB - The integration of 1.5 T MRI functionality with a radiotherapy linear accelerator (linac) has been pursued since 1999 by the UMC Utrecht in close collaboration with Elekta and Philips. The idea behind this integrated device is to offer unrivalled, online and real-time, soft-tissue visualization of the tumour and the surroundings for more precise radiation delivery. The proof of concept of this device was given in 2009 by demonstrating simultaneous irradiation and MR imaging on phantoms, since then the device has been further developed and commercialized by Elekta. The aim of this work is to demonstrate the clinical feasibility of online, high-precision, high-field MRI guidance of radiotherapy using the first clinical prototype MRI-Linac. Four patients with lumbar spine bone metastases were treated with a 3 or 5 beam step-and-shoot IMRT plan. The IMRT plan was created while the patient was on the treatment table and based on the online 1.5 T MR images; pre-treatment CT was deformably registered to the online MRI to obtain Hounsfield values. Bone metastases were chosen as the first site as these tumors can be clearly visualized on MRI and the surrounding spine bone can be detected on the integrated portal imager. This way the portal images served as an independent verification of the MRI based guidance to quantify the geometric precision of radiation delivery. Dosimetric accuracy was assessed post-treatment from phantom measurements with an ionization chamber and film. Absolute doses were found to be highly accurate, with deviations ranging from 0.0% to 1.7% in the isocenter. The geometrical, MRI based targeting as confirmed using portal images was better than 0.5 mm, ranging from 0.2 mm to 0.4 mm. In conclusion, high precision, high-field, 1.5 T MRI guided radiotherapy is clinically feasible. PMID- 29135472 TI - Crystal growth and transport properties of Weyl semimetal TaAs. AB - We report the single crystal growth and transport properties of a Weyl semimetal TaAs. Unsaturated large magnetoresistance of about 22 100% at 2 K and 9 T is observed. From the Hall measurement, carrier concentrations n = 4.608 * 1024 m-3 and p = 3.099 * 1024 m-3, and mobilities u p = 2.502 m2 V-1 s-1 and u n = 16.785 m2 V-1 s-1 at 2 K are extracted. The de Haas-van Alphen oscillations at 2 K and 9 T suggest the presence of a Fermi surface, and the quantum electronic parameters such as effective cyclotron mass and Dingle temperature were obtained using Lifshitz-Kosevich fitting. Temperature dependent resistivity measurements at different static magnetic fields suggest the formation of an insulating gap in the Weyl semimetal TaAs. An angle-resolved photoemission spectroscopy study reveals Fermi arc surface states with different shaped features such as a long elliptical contour around each [Formula: see text] point, a bowtie-shaped contour around each [Formula: see text] point, and a crescent-shaped feature near the midpoint of each [Formula: see text] line. PMID- 29135473 TI - Controllable Nanoscale Inverted Pyramids for High-Efficient Quasi-Omnidirectional Crystalline Silicon Solar Cells. AB - Nanoscale inverted pyramid structures (NIPs) have always been regarded as one of the most paramount light management schemes to achieve the extraordinary performance in various devices, especially in solar cells, due to their outstanding antireflection ability with relative lower surface enhancement ratio. However, the current approaches to fabricating the NIPs are complicated and not cost-effective for the massive cell production in the photovoltaic industry. Here, controllable NIPs are fabricated on crystalline silicon (c-Si) wafers by Ag catalyzed chemical etching and alkaline modification, which is a preferable all solution-processed method. Through applying the NIPs to c-Si solar cells and optimizing the cell design, we have successfully achieved highly efficient NIPs textured solar cells with the champion efficiency of 20.5%. Importantly, the NIPs textured solar cells are further demonstrated to possess the quasi omnidirectional property over the broad sunlight incident angles of approximately 0 degrees -60 degrees . Moreover, the NIPs are theoretically revealed to offer light trapping advantage for ultrathin c-Si solar cells. Hence, the NIPs formed by the controllable method exhibit a great potential to be used in the future photovoltaic industry as surface texture. PMID- 29135474 TI - Inside Baseball-leveling the Playing Field in the Surgical Residency Selection Process. PMID- 29135475 TI - Using Activity Trackers to Quantify Postpartum Ambulation: A Prospective Observational Study of Ambulation after Regional Anesthesia and Analgesia Interventions. AB - BACKGROUND: Early postoperative ambulation is associated with enhanced functional recovery, particularly in the postpartum population, but ambulation questionnaires are limited by recall bias. This observational study aims to objectively quantify ambulation after neuraxial anesthesia and analgesia for cesarean delivery and vaginal delivery, respectively, by using activity tracker technology. The hypothesis was that vaginal delivery is associated with greater ambulation during the first 24 h postdelivery, compared to cesarean delivery. METHODS: Parturients having first/second cesarean delivery under spinal anesthesia or first/second vaginal delivery under epidural analgesia between July 2015 and December 2016 were recruited. Patients with significant comorbidities or postpartum complications were excluded, and participants received standard multimodal analgesia. Mothers were fitted with wrist-worn activity trackers immediately postdelivery, and the trackers were recollected 24 h later. Rest and dynamic postpartum pain scores at 2, 6, 12, 18, and 24 h and quality of recovery (QoR-15) at 12 and 24 h were assessed. RESULTS: The study analyzed 173 patients (cesarean delivery: 76; vaginal delivery: 97). Vaginal delivery was associated with greater postpartum ambulation (44%) compared to cesarean delivery, with means +/- SD of 1,205 +/- 422 and 835 +/- 381 steps, respectively, and mean difference (95% CI) of 370 steps (250, 490; P < 0.0001). Although both groups had similar pain scores and opioid consumption (less than 1.0 mg of morphine), vaginal delivery was associated with superior QoR-15 scores, with 9.2 (0.6, 17.8; P = 0.02) and 8.2 (0.1, 16.3; P = 0.045) differences at 12 and 24 h, respectively. CONCLUSIONS: This study objectively demonstrates that vaginal delivery is associated with greater early ambulation and functional recovery compared to cesarean delivery. It also establishes the feasibility of using activity trackers to evaluate early postoperative ambulation after neuraxial anesthesia and analgesia. PMID- 29135476 TI - Thrombogenicity evaluation in 221 patients with haemophilia B treated with nonacog alfa. AB - : Risk for thrombotic events with factor IX replacement therapy in patients with haemophilia B remains a concern for patients, those who treat them, and regulatory agencies, based on experience with early use of prothrombin complex concentrates. The current post hoc analysis assessed the incidence of thrombotic events and changes in prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer in 221 patients with haemophilia B who received nonacog alfa in clinical studies. Thrombotic event and coagulation marker data were collected from 8 interventional studies utilizing on-demand, prophylactic, and preventive regimens in patients with haemophilia B. Mean age was 25 years (min-max, 0-69), with 51 (23%) patients aged less than 12 years and 15 (7%) aged less than 2 years. None tested positive for inhibitors. Mean time on study was 60.9 +/- 32 weeks and mean number of exposure days was 69.3 (min-max, 1-496). Sixty-nine (31%) patients regularly received infusions that were approximately 100 IU/kg as part of a routine prophylaxis regimen, and 29 (13%) patients underwent surgical procedures. No clinical thrombotic events were reported, and no patient experienced clinically significant changes in coagulation markers between baseline and end-of-study testing. These collective data support the low thrombotic risk associated with nonacog alfa in paediatric, adult, and surgical patients with haemophilia B receiving different treatment regimens, including doses of approximately 100 IU/kg. Although careful thrombotic clinical evaluation is important, regular coagulation marker monitoring does not appear to be warranted in patients with haemophilia B. PMID- 29135477 TI - Thrombin potential and traditional coagulation assay: are they useful in exploring recurrent pregnancy loss risk? AB - : An adequate hemostatic balance is mandatory to get successful pregnancy. Obstetric complications, such as recurrent pregnancy loss (RPL), might be due to an impairment of placental perfusion possibly related to an underlying prothrombotic status. In this study, we used the global coagulation assay, calibrated automated thrombography and traditional coagulation assay to search for a possible underlying hypercoagulable status in women with history of RPL compared with uneventful pregnancy women. Thrombin generation, Fibrinogen, factor VIII (FVIII), Plasminogen Activator Inhibitor-1 (PAI-1) and von Willebrand factor levels were analyzed in 92 not pregnant unexplained RPL and 64 uneventful pregnancy women. In RPL women, significantly higher fibrinogen, FVIII and PAI-1 levels, and thrombin generation with respect to those observed in uneventful pregnancy women were found. By dividing the study population into quartiles of endogenous thrombin potential (ETP), a lower percentage of RPL women than uneventful pregnancy women in the second quartile was observed, whereas a higher percentage of RPL in comparison with uneventful pregnancy women in the third and fourth quartile was found (P = 0.009). Accordingly, the cut-off ETP of 1222.1 nmol/l was chosen; ETP above cut-off concentration was associated with more than two-fold increased risk of RPL (P = 0.008), also after adjustment for traditional risk factors (P = 0.009). We provided evidence of an underlying alteration of vascular network related to increased coagulation components, and fibrinolysis inhibitor levels in healthy women with history RPL; therefore, calibrated automated thrombography global assay and testing for FVIII and PAI-1 would be advisable in clinical practice to evaluate the hypercoagulable status in RPL women planning future pregnancy. PMID- 29135478 TI - Contralateral Involvement of Congenital Muscular Torticollis and Clavicular Fracture. AB - Congenital muscular torticollis (CMT) is known to concur with some conditions such as developmental dysplasia of the hip or brachial plexus injury, which gives us some insights for pathogenesis of CMT. Although clavicular fracture is the most common fracture in newborns, little is known about concurrence of CMT and clavicular fracture. Our clinical experience led us to realize that concurrence of CMT and clavicular fracture tended to occur on the contralateral side for each other rather than the ipsilateral side. This study aimed to verify contralateral concurrence of CMT and clavicular fracture. This is a retrospective cohort study in a tertiary hospital, including 996 subjects with CMT. Concurrent clavicular fracture was found in 20 of 996 subjects with CMT, with the concurrence rate being 2.01%. Concurrent clavicular fracture and clavicular fracture occurred on the contralateral side for each other in 18 subjects (90%) rather than the ipsilateral side. This contralateral concurrence between side of CMT and clavicular fracture was significant (P = 0.001), with an odds ratio of 81 (P = 0.0032). Concurrent clavicular fracture and clavicular fracture seem to occur significantly more on the contralateral side for each other. Underlying mechanism for consistent contralateral concurrence needs to be verified in the near future. PMID- 29135479 TI - Use of Remote Pulmonary Artery Pressure Monitoring (CardioMEMS System) in Total Artificial Heart to Assess Pulmonary Hemodynamics for Heart Transplantation. AB - The temporary total artificial heart (TAH-t) has been valuable as a bridge to transplantation in patients with biventricular failure. However, the challenges of accurately assessing pulmonary vascular resistance after TAH-t implantation can preclude these patients from heart transplantation, especially those with pre existing pulmonary hypertension. The CardioMEMS Heart Failure System (St. Jude's Medical, Little Canada, MN) comprises a wireless pressure sensor that is implanted percutaneously in the pulmonary artery and transmits real-time measurements of pulmonary artery pressures. Systolic and diastolic pulmonary artery (PA) pressures measurements have been well correlated between the CardioMEMS PA Sensor and traditional Swan-Ganz catheter and between the CardioMEMS PA Sensor and standard echocardiography. Here, we report the use of the CardioMEMS device in a patient with severe pulmonary hypertension supported with a SynCardia TAH-t (Tucson, AZ) during assessment for candidacy for transplantation. PMID- 29135480 TI - Mechanical Surface Area of Prosthetic Heart Valve: Adverse Clinical Impact of Large Mechanical Valve in Mitral Position. AB - Although thromboembolic accidents are serious adverse events associated with mechanical mitral valves, there have been no studies on the clinical impact of the large mechanical surface areas (MSAs) of mechanical mitral prostheses. Between 1995 and 2010, 488 consecutive adult patients underwent isolated mechanical mitral valve replacement. We measured the MSA via three-dimensional computed tomography for each prosthesis. Mean patient age was 50.6 +/- 11.1 years. The mean body surface area (BSA) and MSA index (MSAI, MSA/BSA) were 1.6 +/ 0.17 m and 12.9 +/- 1.7 cm/m, respectively. The patients were divided into two groups according to the median MSAI. Patients in the high MSAI group had higher indexed left ventricular end-diastolic dimensions and smaller BSAs. The multivariate analysis demonstrated that old age, New York Heart Association class III or IV, and high MSAI were independent predictors of death. With respect to thromboembolic complications, New York Heart Association class III or IV and high MSAI were identified as independent risk factors. There were 11 patients (3%) with mean pressure gradients across the mitral valve greater than 6 mm Hg 1 year after operation. A large MSA relative to patient size was identified as a predictor of poor clinical outcome after mechanical mitral valve replacement. PMID- 29135481 TI - Role and Limitations of Transcranial Doppler and Brain Death of Patients on Veno Arterial Extracorporeal Membrane Oxygenation. PMID- 29135483 TI - Coronary periarteritis associated with multivessel coronary artery disease. PMID- 29135482 TI - Long-term darapladib use does not affect coronary plaque composition assessed using multimodality intravascular imaging modalities: a randomized-controlled study. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) may play a role in plaque progression and vulnerability. We aimed to define plaque characteristics on multimodality intravascular imaging in patients with coronary endothelial dysfunction in response to long-term inhibition of Lp-PLA2 by darapladib. PATIENTS AND METHODS: This is a double-blinded, randomized study screening 70 patients, and enrolling 54 patients with suspected ischemia, without obstructive disease on angiography and with coronary endothelial dysfunction by invasive assessment. Patients were randomized to receive darapladib or placebo for 6 months. Forty patients underwent multimodality intravascular imaging at baseline and after 6 months of therapy. Several parameters of plaque vulnerability were measured, including maximum value of lipid core burden index for any of the 4-mm segment (maxLCBI4 mm) by near-infrared spectroscopy. Microchannels and macrophages were assessed using optical coherence tomography and necrotic core volume by virtual histology intravascular ultrasound. RESULTS: There was no significant difference in maxLCBI4 mm [64.56 (7.74, 128.56) vs. 22.43 (0, 75.63), P=0.522] or in macrophage images angle [-9.5 degrees (-25.53 degrees , 12.68 degrees ) vs. -16.7 degrees (-28.6 degrees , -4.8 degrees ), P=0.489] between groups. There was a trend toward shorter microchannel length in the darapladib arm [0, (-4.4, 0.2) mm vs. 0.8 (-0.15, 1.9) mm, P=0.08]. Percentage of necrotic core volume was not significantly different. CONCLUSION: Thus, long-term inhibition of endogenous Lp-PLA2 activity with darapladib was not associated with a change in plaque progression and vulnerability indices after 6 months of therapy, and the endogenous Lp-PLA2 pathway may not play a direct role in the progression of early atherosclerosis in humans. PMID- 29135484 TI - Update on revascularization in patients with heart failure and coronary artery disease. AB - PURPOSE OF REVIEW: The review explores the recent findings surrounding the evaluation and the treatment of patients with heart failure and coronary artery disease. It also shed the light on the gaps in this area. RECENT FINDINGS: Surgical revascularization in patients with ischemic cardiomyopathy has the potential to offer symptomatic and survival benefits. SUMMARY: Patients with heart failure and coronary artery disease should be considered candidates for revascularization on the basis of their symptoms, extent of the disease, and comorbidities. Surgical revascularization in these patients provides a symptomatic relief, and a survival benefit. PMID- 29135485 TI - Update on questionnaires for assessing adherence to inhaler devices in respiratory patients. AB - PURPOSE OF REVIEW: It has been estimated that adherence to inhaled medications in patients with asthma and chronic obstructive pulmonary disease (COPD) is around 50%. This low adherence rate increases morbidity and mortality of these disorders. The objective of this review was to update information on main questionnaires used in daily for assessing adherence to inhalers of patients with chronic respiratory diseases. RECENT FINDINGS: The test of the adherence to inhalers (TAI) is a recently developed and validated 12-item questionnaire to assess adherence to inhalers of aerosolized drugs in patients with asthma or COPD. The instrument can easily identify nonadherence, classify the level of adherence into good, intermediate and poor, and establish three nonadherence behaviour patterns of erratic, deliberate, and unwitting, which are useful for tailoring corrective measures. SUMMARY: Adherence to inhaler devices may be underestimated with the use of validated self-report questionnaires as compared with other more sensitive methods. However, validated self-report questionnaires are more advantageous from a cost-effective perspective in clinical practice. The recently validated TAI is a reliable and homogeneous instrument to identify easily nonadherence and behavioural barriers to the use of inhalers in patients with asthma or COPD. PMID- 29135486 TI - Drug-induced anaphylaxis: is it an epidemic? AB - PURPOSE OF REVIEW: The present review addresses the epidemiology, analyzes the current data and promotes global awareness of drug-induced anaphylaxis. RECENT FINDINGS: Anaphylaxis is a medical emergency that may cause death! In the last decade, studies have shown an increasing incidence and prevalence of anaphylaxis. SUMMARY: Drug-induced anaphylaxis fatalities have increased, and this syndrome remains underdiagnosed and undertreated. PMID- 29135487 TI - Update on endocrine aspects of childhood obesity. AB - PURPOSE OF REVIEW: Although childhood obesity has leveled off in the last decade, 'severe obesity' continues to be on the rise. Various genetic, environmental and hormonal factors contribute to obesity. This article reviews the most current understanding of obesity's multifactorial origin and recent recommendations for its management in childhood and adolescence. RECENT FINDINGS: Epigenetics plays a key role in transmitting obesity risk to offspring. Single-nucleotide polymorphisms at genetic loci for adipokines and their receptors are associated with obesity. Gut microbiota is an important regulator of weight status, and Bifidobacterium species improves metabolic status. The incidence of comorbidities including prediabetes and type 2 diabetes has increased. Novel biomarkers such as alpha-hydroxybutyrate and branched-chain amino acids correlate with insulin sensitivity and predict glycemic control in adolescents. Lifestyle modifications and pharmacotherapy can produce small BMI changes. Bariatric surgery induces substantial weight loss and remission of comorbidities. SUMMARY: Alterations in genetics, epigenetics and microbiota influence childhood obesity. Lifestyle modification remains the mainstay of management and pharmacotherapy with Food and Drug Administration approved medications is recommended only for patients resistant to lifestyle changes and for comorbidities. Bariatric surgery produces sustained weight loss and cardiovascular benefits and is an effective option for adolescents with severe obesity. PMID- 29135488 TI - Endocrine manifestations of Down syndrome. AB - PURPOSE OF REVIEW: To summarize the recent developments in endocrine disorders associated with Down syndrome. RECENT FINDINGS: Current research regarding bone health and Down syndrome continues to show an increased prevalence of low bone mass and highlights the importance of considering short stature when interpreting dual energy x-ray absorptiometry. The underlying cause of low bone density is an area of active research and will shape treatment and preventive measures. Risk of thyroid disease is present throughout the life course in individuals with Down syndrome. New approaches and understanding of the pathophysiology and management of subclinical hypothyroidism continue to be explored. Individuals with Down syndrome are also at risk for other autoimmune conditions, with recent research revealing the role of the increased expression of the Autoimmune Regulatory gene on 21st chromosome. Lastly, Down-syndrome-specific growth charts were recently published and provide a better assessment of growth. SUMMARY: Recent research confirms and expands on the previously known endocrinopathies in Down syndrome and provides more insight into potential underlying mechanisms. PMID- 29135489 TI - Endocrine disrupters and pubertal timing. AB - PURPOSE OF REVIEW: The current review summarizes recent epidemiologic data demonstrating the effects of endocrine disrupting compounds (EDCs) on the timing of puberty and highlights the complexity of understanding the interplay of environmental and genetic factors on pubertal timing. RECENT FINDINGS: In girls, there have been mixed results, with some exposures being associated with earlier timing of puberty, and some with later puberty. In boys, prepubertal exposures to nondioxin-like polychlorinated biphenyls accelerate puberty, whereas levels of insecticides, dioxin-like compounds, organochlorine pesticides, and lead delay puberty. SUMMARY: The effects of EDCs on pubertal timing are sexually dimorphic, compound specific, and varies according to the window of exposure. These studies confirm that low-level exposures to a mix of environmental compounds may mask the effects of individual compounds and complicate our ability to translate data from animal studies to human health and to fully understand the clinical implications of environmental epidemiology studies. PMID- 29135491 TI - Agreement analysis of oscillometric devices in the measure of resting heart rate in breast cancer survivors. AB - OBJECTIVE: The aim of this study was to verify the reproducibility of an oscillometric device in the measurement of resting heart rate (RHR) in breast cancer survivors. METHODS: This study included 85 breast cancer survivors with a mean age of 58.87+/-10.03 years. For the RHR evaluation, the equipment used was the Omron HEM 742, electronic and digital arm device, for measurement of blood pressure and heart rate (HR), with automatic cuff inflation and deflation. At the same time as the oscillometric measurement, HR was measured by the HR monitor Polar RS800 CX, which has been validated previously for HR uptake. The HR value obtained by the cardiofrequency meter was registered at the same time that the Omron device measured blood pressure and HR values. RESULTS: It was observed that the RHR values were very close in both devices and that the correlation values and intraclass correlation coefficient were high. These results were replicated when the female breast cancer survivors were stratified by age group. The agreement values presented by the Bland-Altman analysis showed good values; both for the entire sample and stratified by age, few cases were outside beyond 95% confidence interval range. CONCLUSION: The present study showed that the oscillometric device used presented good values of reproducibility in the detection of RHR values in breast cancer survivors compared with a cardiac monitor. PMID- 29135490 TI - The microbiome and HIV persistence: implications for viral remission and cure. AB - PURPOSE OF REVIEW: This article discusses the interaction between HIV infection, the gut microbiome, inflammation and immune activation, and HIV reservoirs, along with interventions to target the microbiome and their implications for HIV remission and cure. RECENT FINDINGS: Most studies show that HIV-infected adults have a gut microbiome associated with decreased bacterial richness and diversity, and associated systemic inflammation and immune activation. A unique set of individuals, elite controllers, who spontaneously control HIV replication, have a similar microbiome to HIV-uninfected individuals. Conversely, exposure to maternal HIV in infants was shown to alter the gut microbiome, even in infants who escaped perinatal infection. Emerging research highlights the importance of the metabolomics and metaproteomics of the gut microbiome, which may have relevance for HIV remission and cure. Together, these studies illustrate the complexity of the relationship between HIV infection, the gut microbiome, and its systemic effects. SUMMARY: Understanding the association of HIV with the microbiome, metabolome, and metaproteome may lead to novel therapies to decrease inflammation and immune activation, and impact HIV reservoir size and vaccine responses. Further research in this area is important to inform HIV remission and cure treatments. PMID- 29135492 TI - Decline in 2 Serial Postmortem Tryptase Measurements Beyond 72 Hours After Death in an Antibiotic-Related Anaphylactic Death. AB - Anaphylaxis can be difficult to diagnose in the postmortem setting. Postmortem tryptase is a widely used ancillary test in aiding the diagnosis in which an elevation supports a death from anaphylaxis. Postmortem tryptase can be difficult to interpret, and the effects of postmortem kinetics are not fully understood. Clinically, mast cell tryptase returns to baseline 24 to 72 hours after an anaphylactic stimulus. We report another anaphylactic death from antibiotic administration in which 2 serial postmortem total tryptase measurements at 3 days (72 hours) and 6 days (144 hours) after death declined from 522 MUg/L to 300 MUg/L (baseline, 5.6 MUg/L). The declination appears to be slower than what is expected in the clinical setting. This case highlights yet another example of the difficult and complex interaction of postmortem interval on postmortem tryptase, especially in an anaphylactic death. We suggest that early blood sampling and serial tests be performed if possible in suspected anaphylactic death. PMID- 29135494 TI - Enhanced Recovery Protocols (ERP): Need for Action. PMID- 29135493 TI - Relationship Between Postoperative Pain and Overall 30-Day Complications in a Broad Surgical Population: An Observational Study. AB - OBJECTIVE: The aim of this study was to establish the relationship between postoperative pain and 30-day postoperative complications. BACKGROUND: Only scarce data are available on the association between postoperative pain and a broad range of postoperative complications in a large heterogeneous surgical population. METHODS: Having postoperative pain was assessed in 2 ways: the movement-evoked pain score on the Numerical Rating Scale (NRS-MEP) and the patients' opinion whether the pain was acceptable or not. Outcome was the presence of a complication within 30 days after surgery. We used binary logistic regression for the total population and homogeneous subgroups to control for case complexity. Results for homogeneous subgroups were summarized in a meta-analysis using inverse variance weighting. RESULTS: In 1014 patients, 55% experienced moderate-to-severe pain on the first postoperative day. The overall complication rate was 34%. The proportion of patients experiencing postoperative complications increased from 0.25 [95% confidence interval (CI) = 0.21-0.31] for NRS-MEP = 0 to 0.45 (95% CI = 0.36-0.55) for NRS-MEP = 10. Patients who found their pain unacceptable had more complications (adjusted odds ratio = 2.17 (95% CI = 1.51 3.10; P < 0.001)). Summary effect sizes obtained with homogeneous groups were similar to those obtained from the total population who underwent very different types of surgery. CONCLUSIONS: Higher actual postoperative pain scores and unacceptable pain, even on the first postoperative day, are associated with more postoperative complications. Our findings provide important support for the centrality of personalized analgesia in modern perioperative care. PMID- 29135495 TI - Prenatal microRNA miR-200b Therapy Improves Nitrofen-induced Pulmonary Hypoplasia Associated With Congenital Diaphragmatic Hernia. AB - OBJECTIVE: We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH). BACKGROUND: Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR 200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy. METHODS: We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model. RESULTS: We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR 200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-beta signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH. CONCLUSIONS: Our data indicate that miR 200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH. PMID- 29135496 TI - Omission of Regional Nodal Irradiation in Patients With Sentinel Lymph Node Positive Patients: "The Believer is Happy while the Doubter is Wise". PMID- 29135497 TI - Pancreatic Chymotrypsin Activity Rather Than Amylase Level Better Predicts Postoperative Pancreatic Fistula. AB - OBJECTIVE: To assess the predictive value of chymotrypsin activity in pancreatic juice on clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatic resection, since pancreatic peptidases rather than glycolytic enzymes play a pivotal role in causing tissue damage due to pancreatic leakage. BACKGROUND: The risk of CR-POPF has been estimated based on amylase level in abdominal drainage fluid. METHODS: Eighty-one consecutive patients underwent pancreatoduodenectomy, and postoperative pancreatic juice and drainage fluids were collected for 14 days. The chymotrypsin activity and fluid amylase level in these fluids were measured, and their susceptibility to the elapsed postoperative time and circadian rhythm were evaluated. The predictive value for the development of CR-POPF was compared between assessment of pancreatic chymotrypsin activity versus fluid amylase level. RESULTS: No significant differences in the daily pancreatic chymotrypsin activity were observed, whereas the amylase level in pancreatic juice was susceptible to the postoperative interval and circadian rhythm. CR-POPF developed in 19 patients (23%). Assessment of pancreatic chymotrypsin activity on the first postoperative day predicted CR-POPF with a sensitivity/specificity of 84/87% (area under the curve, 0.855; cut-off value, 0.5 arbitrary units), which was better than measurement of fluid amylase level. Independent predictors of CR-POPF were the day-1 pancreatic chymotrypsin activity (>=0.5 arbitrary units, P < 0.001) and the main pancreatic duct index (<0.25, P = 0.039). CONCLUSIONS: Assessment of pancreatic chymotrypsin activity may allow for more rapid and accurate prediction of CR-POPF than use of conventional diagnostic criteria based on fluid amylase level, enabling individualized surgical procedures and postoperative drain management. PMID- 29135498 TI - State of the John L. Cameron, MD Division of Hepatobiliary and Pancreatic Surgery "The Program That John Cameron Built". AB - : The pancreatic surgery program at Johns Hopkins is recognized as being among the top programs in the field. It is part of the newly formed John L. Cameron Division of HPB surgery. This division of surgery is a highly productive group of academic surgeons in terms of clinical volume, research endeavors, and education. The division functions as part of a large multidisciplinary group at Johns Hopkins. The program has an interesting history and can trace its roots back to the actions of a single individual-John L. Cameron. The John L. Cameron Division of HPB surgery and the Johns Hopkins Pancreas Disease program would not exist without him. It is the program that Dr Cameron built. PMID- 29135499 TI - 'PREVENT' and 'STOMAMESH' Trials in Preventing Parastomal Herniation. PMID- 29135500 TI - Association of Driving Pressure With Mortality Among Ventilated Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: A recent post hoc analysis suggested that driving pressure may be more important than traditional ventilatory variables in determining outcome in mechanically ventilated patients with acute respiratory distress syndrome. We conducted a systematic review and meta-analysis to summarize the risk of mortality for higher versus lower driving pressure. DATA SOURCES: MEDLINE, EMBASE, PubMed, CINAHL, and Cochrane CENTRAL from inception to February 10, 2017. STUDY SELECTION: Studies including mechanically ventilated adult patients with acute respiratory distress syndrome, reporting driving pressure and mortality. DATA EXTRACTION: Seven studies including five secondary analysis of previous randomized controlled trials and two observational studies (6,062 patients) were eligible for study. All studies were judged as having a low risk of bias. Median (interquartile range) driving pressure between higher and lower driving pressure groups was 15 cm H2O (14-16 cm H2O). Median (interquartile range) mortality of all included studies was 34% (32-38%). DATA SYNTHESIS: In the meta-analyses of four studies (3,252 patients), higher driving pressure was associated with a significantly higher mortality (pooled risk ratio, 1.44; 95% [CI], 1.11-1.88; I = 85%). A sensitivity analysis restricted to the three studies with similar driving pressure cutoffs (13-15 cm H2O) demonstrated similar results (pooled risk ratio, 1.28; 95% CI, 1.14-1.43; I = 0%). CONCLUSIONS: Our study confirmed an association between higher driving pressure and higher mortality in mechanically ventilated patients with acute respiratory distress syndrome. These findings suggest a possible range of driving pressure to be evaluated in clinical trials. Future research is needed to ascertain the benefit of ventilatory strategies targeting driving pressure in patients with acute respiratory distress syndrome. PMID- 29135501 TI - Temperature Variability in a Modern Targeted Temperature Management Trial. AB - OBJECTIVES: The Eurotherm3235 trial showed that therapeutic hypothermia was deleterious in patients with raised intracranial pressure following traumatic brain injury. We sought to ascertain if increased temperature variability within the first 48 hours, or for 7 days post randomization, were modifiable risk factors associated with poorer outcome. DESIGN: Eurotherm3235 was a multicenter randomized controlled trial. Patients were randomized to receive either therapeutic hypothermia in addition to standard care or the later only. Mean moving range (mr) was used to stratify subjects into tertiles by the variability present in their core temperature within the first 48 hours post randomization and within 7 days post randomization. The primary outcome measure was a collapsed Glasgow Outcome Scale-Extended at 6 months post randomization. The temperature variability effect was estimated with ordinal logistic regression adjusted for baseline covariates and treatment effect. SETTING: Forty-seven critical care units in 18 countries. PATIENTS: Patients enrolled in the Eurotherm3235 trial to either therapeutic hypothermia or control treatments only. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-six patients were included in our study. High level of temperature variability during the first 48 hours was associated with poorer collapsed Glasgow Outcome Scale-Extended. This effect remained statistically significant when only the control arm of the study was analyzed. No statistically significant effect was seen within the first 48 hours in the hypothermia group or within 7 days in either group. CONCLUSIONS: When targeting normothermia, temperature variability may be a statistically significant variable in an ordinal analysis adjusted for baseline covariates. PMID- 29135502 TI - The Crown Jewel, an Enigmatic Solitary Mass of Follicular Origin: Challenge. PMID- 29135503 TI - Slowly Enlarging Nodule on the Chest. PMID- 29135504 TI - Cutaneous Collagenous Vasculopathy: A Unique Case With Positive Direct Immunofluorescence Findings. PMID- 29135505 TI - Unusual Case of Combined Gliomeningeal Heterotopia on the Nose of an Infant. AB - Nasal glial heterotopia ("nasal glioma") and cutaneous heterotopic meningeal nodules ("primary cutaneous meningioma") are rare congenital lesions characterized by the presence of heterotopic mature cerebral tissues. Nasal glial heterotopia occurs predominantly in the nasal area and typically does not contain meningothelial elements, whereas heterotopic meningeal nodules occur predominantly on the scalp and do not contain glial elements. In this article, we report an unusual case of cutaneous heterotopia on the nose of an infant composed of both glial and meningothelial elements. The glial component was characterized by irregular islands of predominantly astrocytic cells, on a fibrillary background. The meningothelial component was characterized by bland ovoid cells with focal intranuclear inclusions forming whorled arrangements, with associated psammomatous calcification. To our knowledge, this is the first time such a lesion has been documented. It has also provided us with an opportunity to review the literature regarding heterotopic deposits of both glial and meningothelial tissues. PMID- 29135506 TI - Digital Apocrine Hidrocystoma: The Exception Confirms the Rule. PMID- 29135507 TI - Immunohistochemical and Fluorescence In Situ Hybridization Analysis of MYC in a Series of 17 Cutaneous Angiosarcomas: A Single-Center Study. AB - Cutaneous angiosarcoma (AS) is an uncommon, aggressive sarcoma whose incidence is rising because of the increasing use of radiation therapy, especially in breast cancer. The few studies on the relevance of prognostic factors, such as MYC status in cutaneous AS, have reported inconclusive findings, with some authors reporting MYC amplification only in postirradiation and lymphedema-associated AS and others reporting evidence of MYC amplification in idiopathic AS. We analyzed 17 cases of cutaneous AS (6 idiopathic AS, 10 postirradiation AS, and 1 lymphedema-associated AS) treated at our institute between 2000 and 2015. Follow up data were available in all cases. We compared the presence/absence of MYC amplification by fluorescence in situ hybridization (FISH) and immunohistochemical (IHC) MYC overexpression in the different AS subtypes. We also investigated potential associations between MYC amplification and prognosis. MYC amplification was observed by FISH in 6 of 14 informative cases. The positive cases were all secondary AS (5 postirradiation AS and 1 lymphedema-associated AS). IHC detected MYC overexpression in 8 of 15 informative cases (7 secondary AS and 1 idiopathic AS). In conclusion, MYC amplification and MYC overexpression were detected almost exclusively in secondary AS. No associations were found between MYC amplification/overexpression and prognosis. We found MYC amplification or overexpression in a similar proportion of the patients who died and who were still alive at the end of the study. In the group of 9 patients who died, MYC was detected by FISH in 4 cases and by IHC in 5. The corresponding figures in the group of 6 patients still alive were 2 by FISH and 3 by IHC. PMID- 29135508 TI - New Histologic Finding of Amyloid Insulin Bodies at an Insulin Injection Site in a Patient With Diabetes. AB - Amyloidosis is a heterogeneous group of protein deposition diseases with more than 40 known clinical presentations. Localized amyloidosis occurs when the protein deposits exist in a singular location. Patients with diabetes mellitus who inject insulin at the same site can develop localized insulin-derived amyloidosis (AIns) at the injection site, which can be confused clinically with lipoma, lipohyperplasia, lipoatrophy, and fat necrosis. Histologic examination is performed to confirm localized AIns. We report a case of a patient with a long history of type 2 diabetes who presented with a subcutaneous mass in the abdomen at a preferred insulin injection site. Examination by light microscopy revealed diffuse deposition of eosinophilic material. Two of the tissue fragments contained numerous 30-40 MUm spherical bodies within the eosinophilic material. The bodies had dark centers with peripheral eosinophilic material. Polarized sections stained with Congo red showed apple green birefringence, a characteristic of amyloid. Immunohistochemistry was positive for insulin antibodies in the dark spherules and the surrounding matrix. Proteomic analysis by mass spectrometry showed that the Congo red-positive material was insulin. Electron microscopy showed a background matrix consisting of nonbranching protein fibrils measuring 8.8-16.1 nm, consistent with amyloid; the spherules contained dark globular proteins in the center surrounded by nonbranching fibrillary proteins. Because these spherules were positive for insulin by immunohistochemistry and showed amyloid ultrastructurally, we refer to them as amyloid insulin bodies. The identification of AIns, specifically with amyloid insulin bodies, is important for diagnosis and treatment and may further our understanding of amyloidogenesis. PMID- 29135509 TI - Unilesional Follicular Mycosis Fungoides: Report of 6 Cases and Review of the Literature. AB - Unilesional follicular mycosis fungoides (MF) is a rare variant of cutaneous T cell lymphoma characterized by selective involvement of the hair follicles by neoplastic T lymphocytes presenting initially as a solitary lesion occupying less than 5% of the body surface; there are 22 previous reported cases. We describe 6 patients with this rare variant of MF, all males (age range 6-64 years; mean age: 28 years) presenting with a solitary lesion primarily on the face and scalp except 1 patient who presented with a truncal lesion. All the patients had the lesions for at least a few months. The lesions were associated with follicular prominence and hair loss. In each, the biopsies showed an atypical folliculotropic lymphocytic infiltrate accompanied by follicular mucinosis in certain cases. The infiltrate involved the lower isthmic part of the follicle, and in 1 case, there was an alopecia areata-like neoplastic lymphomatoid bulbitis. There was no evidence of large cell transformation nor was there a significant degree of infiltration of the interfollicular dermis or epidermis. Higher magnification disclosed marked cerebriform atypia amidst the lymphocytes. Phenotypic studies demonstrated a high CD4 to CD8 ratio in excess of 5 with a significant loss of CD7. One patient developed additional similar lesions involving the thigh and buttock after a period of at least 3-4 years of untreated unilesional MF. Unilesional follicular MF is a potentially curable form of MF with a young male predilection. Early diagnosis and treatment intervention likely define a cornerstone for ensuring the best patient outcome and preventing clinical evolution to either tumor stage MF and or multilesional MF. PMID- 29135510 TI - Mycosis Fungoides Manifesting as Giant Cell Lichenoid Dermatitis. AB - Mycosis fungoides (MF) is the most common form of primary cutaneous lymphoma with a broad clinicopathological spectrum. Unusual histopathologic patterns of MF include lichenoid, interstitial, folliculotropic, spongiotic, granulomatous, and many others. Several cases of unusual lichenoid reaction characterized by a mixed lichenoid inflammatory infiltrate with prominent infiltration of the papillary dermis and epidermis by multinucleated giant cells were described under the name of "giant cell lichenoid dermatitis," most of them were considered to represent a drug eruption. Herein, we describe a 77-year-old woman with a 5-year history of MF displaying microscopic features of giant cell lichenoid dermatitis. Histology revealed a dense band-like lichenoid epidermotropic infiltrate composed of CD4 small to medium-sized lymphocytes with cerebriform nuclei with the presence of multinucleated giant cells in the papillary dermis, within the epidermis, and some hair follicles. Monoclonal TCR gene rearrangement was detected using PCR. To the best of our knowledge, this pattern was never described in MF. PMID- 29135511 TI - Violaceous Pink Axillary and Intertriginous Patches: Challenge. PMID- 29135512 TI - Cytokeratin Profile of Basal Cell Carcinomas According to the Degree of Sun Exposure and to the Anatomical Localization. AB - Basal cell carcinoma (BCC) seems to originate from ultraviolet light-induced mutations involving the bulge or the outer sheath of the hair follicle cells. However, the etiopathogenic mechanisms involved in the development of these tumors in nonphotoexposed and in hairless areas remain unclear. The cytokeratin (CK) profile (including CK5/6, CK7, CK14, CK15, CK17, and CK19) from a series of different BCC subtypes developing in sun-exposed and non-sun-exposed areas, including hairless regions, was evaluated. The authors have observed that CK7 expression in BCC is associated with the anatomical localization of the tumor and its sun-exposition, but not with other factors such as histological subtype. The expression of this CK is higher in BCCs located in non-sun-exposed and nonhairy areas, such as the vulvar semimucosa and the nipple. Because CK7 is a marker of simple glandular epithelia, the authors suggest a glandular origin for BCCs located in hairless and nonphotoexposed areas. PMID- 29135513 TI - Collection of nasal secretions and tears and their use in allergology. AB - PURPOSE OF REVIEW: The identification of immunological markers in nasal secretions and tears is becoming essential in the study of allergic diseases. The collection procedure of nasal and ocular secretions directly influences the results, thus it is of paramount importance to validate and standardize the sampling process. RECENT FINDINGS: Current techniques for nasal secretions sampling are mainly based on three principles: collection of spontaneous secretions, nasal washings, and absorption. Collection of spontaneous secretions is appropriate in subjects with nasal hypersecretion, whereas in healthy individuals the collected volume is frequently insufficient. Nasal washings are associated with an unpredictable, high dilution and concentrations of markers often fall below detection limits of immunological assays. Absorption seem to provide the best compromise between sufficient sample amounts and detectability of inflammatory mediators and immunoglobulin E. Tear samples can be obtained by glass capillary tubes, filter paper strips and ophthalmic sponges. Volumes are however small or highly diluted through reflex tearing. SUMMARY: Secretions reflect the local inflammatory activity and provide valuable information about the immunological reaction to allergens at the target organ. There is increasing evidence of the potential clinical role of their analysis, for diagnosis, and monitoring of allergic rhino-conjunctivitis. Appropriate collection and processing is very important and requires special attention. PMID- 29135514 TI - Prevalence and clinical characteristics of local allergic rhinitis to house dust mites. AB - PURPOSE OF REVIEW: Local allergic rhinitis (LAR) is a recently classified subtype of rhinitis defined by a nasal allergic response in patients without systemic evidence of atopy. Recent studies have reported the prevalence, clinical course, culprit allergens, diagnostic methods and treatment outcomes of LAR. The purpose of this review is to summarize the most relevant and updated scientific evidence for LAR, especially focusing on its prevalence and clinical characteristics. RECENT FINDINGS: LAR is found in a significant proportion (3.7-61.9%) of patients previously diagnosed with nonallergic rhinitis, but the prevalence may differ among ethnic groups and countries. Common allergens of LAR are similar to those of allergic rhinitis, in which house dust mites are the most common cause, followed by grass pollen, tree pollen, weed pollen and animal dander confirmed by provocation tests. Although the nasal provocation test to a single allergen is considered the gold standard method, the detection of allergen-specific IgE and other inflammatory mediators from nasal secretions and the basophil activation test can assist in the diagnosis of LAR. Conjunctivitis and asthma are the most common comorbid conditions, and the occurrence rate of asthma increases over period. However, the conversion rate to allergic rhinitis was not significantly different between LAR and healthy controls. SUMMARY: LAR is a well-differentiated entity of rhinitis, which should be considered in patients with persistent and severe symptoms without any systemic evidence of atopy. Further research is needed to investigate the long-term outcome, and geographic and ethnic differences of LAR. PMID- 29135515 TI - Association between allergic and nonallergic rhinitis and obstructive sleep apnea. AB - PURPOSE OF REVIEW: Allergic rhinitis and nonallergic rhinitis (NAR) are common disorders, which have been considered as potential risk factors for obstructive sleep apnea (OSA). This review summarizes the proposed underlying pathophysiological mechanisms to provide a better understanding of the relationship between these conditions. RECENT FINDINGS: In adults, allergic rhinitis and NAR may be considered as symptoms potentiating, rather than risk potentiating factors in the pathophysiology of OSA, whereas in children, these are considered to be independent predictors for sleep-disordered breathing (SDB) and failure of adeno-tonsillectomy, the recommended first-line therapy for children with OSA. Current advances suggest IL-6 may be important in regulating the sleep-wake cycle, and serum soluble IL-6 receptor (sIL-6R) levels may reflect the severity of OSA. Elevated Th17/Treg ratio correlates positively with apnea hypopnea index of OSA patients, and Th17 and Treg imbalances caused by allergic rhinitis and OSA, respectively, may possibly promote each other, leading to further imbalance. Moreover, obesity is a strong risk factor for OSA, and leptin plays an important role in ventilatory function and upper airway obstruction. The variant trigeminocardiac reflex and nasotrigeminal reflex may also be involved in the association between rhinitis and OSA. SUMMARY: Allergic rhinitis/NAR and OSA are closely associated, and each condition can be detrimental to the other. Thus, clinicians should pay attention to the potential presence of allergic rhinitis/NAR in OSA patients and vice versa. PMID- 29135516 TI - International Endocervical Adenocarcinoma Criteria and Classification (IECC): A New Pathogenetic Classification for Invasive Adenocarcinomas of the Endocervix. AB - We sought to classify endocervical adenocarcinomas (ECAs) based on morphologic features linked to etiology (ie, human papillomavirus [HPV] infection), unlike the World Health Organization 2014 classification. The International Endocervical Adenocarcinoma Criteria and Classification (IECC criteria), described herein, distinguishes between human papillomavirus-associated adenocarcinoma (HPVA), recognized by the presence of luminal mitoses and apoptosis seen at scanning magnification, and no or limited HPVA features (nonhuman papillomavirus associated adenocarcinoma [NHPVA]). HPVAs were then subcategorized based on cytoplasmic features (mostly to provide continuity with preexisting classification schemes), whereas NHPVAs were subclassified based on established criteria (ie, gastric-type, clear cell, etc.). Complete slide sets from 409 cases were collected from 7 institutions worldwide. Tissue microarrays representing 297 cases were constructed; immunohistochemistry (p16, p53, vimentin, progesterone receptor) and chromogenic in situ hybridization using an RNA-based probe set that recognizes 18 varieties of high-risk HPV were performed to validate IECC diagnoses. The 5 most common IECC diagnoses were usual-type (HPVA) (73% of cohort), gastric-type (NHPVA) (10%), mucinous adenocarcinoma of HPVA type, including intestinal, mucinous not otherwise specified, signet-ring, and invasive stratified mucin-producing carcinoma categories (9%), clear cell carcinoma (NHPVA) (3%) and adenocarcinoma, not otherwise specified (2%). Only 3 endometrioid carcinomas were recognized and all were NHPVA. When excluding cases thought to have suboptimal tissue processing, 90% and 95% of usual-type IECC cases overexpressed p16 and were HPV, whereas 37% and 3% of NHPVAs were p16 and HPV, respectively. The 1 HPV gastric-type carcinoma was found to have hybrid HPVA/NHPVA features on secondary review. NHPVA tumors were larger and occurred in significantly older patients, compared with HPVA tumors (P<0.001). The high-risk HPV chromogenic in situ hybridization probe set had superior sensitivity, specificity, and positive and negative predictive values (0.955, 0.968, 0.992, 0.833, respectively) compared with p16 immunohistochemistry (0.872, 0.632, 0.907, 0.545, respectively) to identify HPV-related usual carcinoma and mucinous carcinoma. IECC reliably segregates ECAs into HPVA and NHPVA types using morphology alone. This study confirms that usual-type ECAs are the most common type worldwide and that mucinous carcinomas comprise a mixture of HPVA and NHPVA, with gastric-type carcinoma being the major NHPVA type. Endometrioid and serous carcinomas of the endocervix are extraordinarily rare. Should clinical outcomes and genomic studies continue to support these findings, we recommend replacement of the World Health Organization 2014 criteria with the IECC 2017. PMID- 29135517 TI - MYB Translocation Status in Salivary Gland Epithelial-Myoepithelial Carcinoma: Evaluation of Classic, Variant, and Hybrid Forms. AB - Epithelial-myoepithelial carcinoma (EMC) is a malignant salivary gland neoplasm comprised of a biphasic arrangement of inner luminal ductal cells and outer myoepithelial cells. Adenoid cystic carcinoma (AdCC) is also a biphasic tumor comprised of ductal and myoepithelial cells, but these components tend to be arranged in a more cribriform pattern. The occurrence of "hybrid carcinomas" that show mixed patterns of EMC and AdCC raises questions about the relationship of these morphologically overlapping but clinically distinct tumors. AdCCs frequently harbor MYB-NFIB gene fusions. Mapping of EMCs (including hybrid forms with an AdCC component) for this fusion could help clarify the true nature of EMC as a distinct entity or simply as some variant form of AdCC. Twenty-nine cases of EMC were evaluated including 15 classic low-grade EMCs, 7 intermediate-grade EMCs, 2 EMCs with myoepithelial anaplasia, 1 EMC with high-grade transformation, and 4 hybrid EMCs with an AdCC component. Break apart fluorescence in situ hybridization for MYB was performed, as was MYB immunohistochemistry. For the hybrid carcinomas and those with high-grade transformation, the divergent tumor components were separately analyzed. A MYB translocation was identified in 5 of 28 (18%) tumors including 3 of 4 (75%) hybrid carcinomas and 2 of 7 (29%) intermediate-grade EMCs. For the positive hybrid carcinomas, the fusion was detected in both the EMC and AdCC components. The MYB fusion was not detected in any of the classic EMCs (0/15) or in any of the EMCs with myoepithelial anaplasia (0/2) or high-grade transformation (0/1). The fluorescence in situ hybridization assay was unsuccessful in 1 case. MYB immunostaining was seen in 5 of 5 fusion positive cases, and also 9 of 23 fusion-negative tumors. Classic low-grade EMCs are genetically distinct from AdCCs in that they do not harbor MYB fusions. The presence of a MYB fusion in EMCs showing hybrid features of AdCC or exhibiting highly infiltrative growth points to a subset of these tumors that may well be true AdCCs masquerading as EMCs. PMID- 29135518 TI - Substantial Interobserver Agreement in the Diagnosis of Dysplasia in Barrett Esophagus Upon Review of a Patient's Entire Set of Biopsies. AB - The pathologic diagnosis of dysplasia in Barrett esophagus (BE) suffers from interobserver disagreement. Many of the studies demonstrating disagreement in the diagnosis of dysplasia have pathologists review individual biopsy slides in isolation. To more closely mimic daily practice, 3 pathologists reviewed hematoxylin and eosin slides made from 549 individual biopsy jars obtained from 129 unique patients with a diagnosis of BE. Each pathologist reviewed the entirety of a given patient's biopsy material. The grade of dysplasia present in each biopsy jar was given as well as an overall highest grade of dysplasia from the patient's entire set of biopsies. The interobserver agreement in the diagnosis of dysplasia per biopsy jar and per patient's set of biopsies was measured by Fleiss kappa statistic for multiple raters. The kappa values for each diagnosis was higher in the per patient analysis compared with the per biopsy jar analysis indicating that pathologists are more likely to agree on the overall grade of dysplasia compared with the grade in an individual biopsy jar. In the per patient analysis, the interobserver agreement in the diagnosis of nondysplastic BE and high-grade dysplasia were substantial (kappa=0.66; 95% confidence interval [CI], 0.56-0.76 and kappa=0.76; 95% CI, 0.66-0.86, respectively). The interobserver agreement in the diagnosis of low-grade dysplasia (LGD) was fair (kappa=0.31; 95% CI, 0.21-0.42). When LGD and high-grade dysplasia were collapsed into 1 category of positive for dysplasia, the interobserver agreement in the per patient analysis remained substantial (kappa=0.70; 95% CI, 0.60-0.80), suggesting that much of the disagreement in LGD is not due to lack of recognition of dysplastic Barrett's mucosa, but rather the degree of dysplasia. These results indicate that pathologists can reliably distinguish between nondysplastic BE and dysplastic BE when a patient's entire set of biopsies is reviewed as a group. When second opinions are obtained, all available slides from that endoscopic procedure should be sent for review. PMID- 29135519 TI - Syphilis of the Aerodigestive Tract. AB - Syphilis, a sexually transmitted infection caused by the Gram-negative bacterium Treponema pallidum, is increasing in prevalence in the United States. It has been our experience that primary and secondary syphilis of the aerodigestive tract can afflict a large age spectrum with varied clinical and histopathologic findings, which can lead to diagnostic problems and frequent misdiagnosis. In this study, we describe the histopathologic patterns of syphilis of the aerodigestive tract to expand awareness of its varied appearance. We identify 3 patterns of inflammatory response to syphilis: plasma cell-rich, lymphohistiocytic, and lymphoma-like. We also report the presence of immunoglobulin G4-predominant plasma cells in the inflammatory response as a potential mimicker of immunoglobulin G4-related disease. Lastly, we found that use of T. pallidum immunohistochemical stain is more reliable than Steiner silver stain at the identification of spirochetes. Our study highlights that despite convention, plasma cells are not always abundant in syphilis. Awareness of the histopathologic range of syphilis in the aerodigestive tract by the surgical pathologist can lead to the correct diagnosis and guide appropriate treatment. PMID- 29135520 TI - Epithelial-Myoepithelial Carcinoma: Frequent Morphologic and Molecular Evidence of Preexisting Pleomorphic Adenoma, Common HRAS Mutations in PLAG1-intact and HMGA2-intact Cases, and Occasional TP53, FBXW7, and SMARCB1 Alterations in High grade Cases. AB - We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion. PMID- 29135521 TI - The Effect of ICU Out-of-Hours Admission on Mortality: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Organizational factors are associated with outcome of critically ill patients and may vary by time of day and day of week. We aimed to identify the association between out-of-hours admission to critical care and mortality. DATA SOURCES: MEDLINE (via Ovid) and EMBASE (via Ovid). STUDY SELECTION: We performed a systematic search of the literature for studies on out-of-hours adult general ICU admission on patient mortality. DATA EXTRACTION: Meta-analyses were performed and Forest plots drawn using RevMan software. Data are presented as odds ratios ([95% CIs], p values). DATA SYNTHESIS: A total of 16 studies with 902,551 patients were included in the analysis with a crude mortality of 18.2%. Fourteen studies with 717,331 patients reported mortality rates by time of admission and 11 studies with 835,032 patients by day of admission. Admission to ICU at night was not associated with an increased odds of mortality compared with admissions during the day (odds ratio, 1.04 [0.98-1.11]; p = 0.18). However, admissions during the weekend were associated with an increased odds of death compared with ICU admissions during weekdays (1.05 [1.01-1.09]; p = 0.006). Increased mortality associated with weekend ICU admissions compared with weekday ICU admissions was limited to North American countries (1.08 [1.03-1.12]; p = 0.0004). The absence of a routine overnight on-site intensivist was associated with increased mortality among weekend ICU admissions compared with weekday ICU admissions (1.11 [1.00-1.22]; p = 0.04) and nighttime admissions compared with daytime ICU admissions (1.11 [1.00-1.23]; p = 0.05). CONCLUSIONS: Adjusted risk of death for ICU admission was greater over the weekends compared with weekdays. The absence of a dedicated intensivist on-site overnight may be associated with increased mortality for acute admissions. These results need to be interpreted in context of the organization of local healthcare resources before changes to healthcare policy are implemented. PMID- 29135522 TI - Determinants of Long-Term Neurological Recovery Patterns Relative to Hospital Discharge Among Cardiac Arrest Survivors. AB - OBJECTIVE: To explore factors associated with neurological recovery at 1 year relative to hospital discharge after cardiac arrest. DESIGN: Observational, retrospective review of a prospectively collected cohort. SETTING: Medical or surgical ICUs in a single tertiary care center. PATIENTS: Older than 18 years, resuscitated following either in-hospital or out-of-hospital cardiac arrest and considered for targeted temperature management between 2007 and 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Logistic regressions to determine factors associated with a poor recovery pattern after 1 year, defined as persistent Cerebral Performance Category Score 3-4 or any worsening of Cerebral Performance Category Score relative to discharge status. In total, 30% (117/385) of patients survived to hospital discharge; among those discharged with Cerebral Performance Category Score 1, 2, 3, and 4, good recovery pattern was seen in 54.5%, 48.4%, 39.5%, and 0%, respectively. Significant variables showing trends in associations with a poor recovery pattern (62.5%) in a multivariate model were age more than 70 years (odds ratio, 4; 95% CIs, 1.1-15; p = 0.04), Hispanic ethnicity (odds ratio, 4; CI, 1.2-13; p = 0.02), and discharge disposition (home needing out-patient services (odds ratio, 1), home requiring no additional services (odds ratio, 0.15; CI, 0.03-0.8; p = 0.02), acute rehabilitation (odds ratio, 0.23; CI, 0.06-0.9; p = 0.04). CONCLUSIONS: Patients discharged with mild or moderate cerebral dysfunction sustained their risk of neurological worsening within 1 year of cardiac arrest. Old age, Hispanic ethnicity, and discharge disposition of home with out-patient services may be associated with a poor 1 year neurological recovery pattern after hospital discharge from cardiac arrest. PMID- 29135523 TI - Targeting nonpulmonary vein triggers during atrial fibrillation ablation: is the game worth the candle? AB - PURPOSE OF REVIEW: Triggers for atrial fibrillation are found outside the pulmonary veins in 12-20% of cases. The role of addressing these triggers during catheter ablations has not been well defined. Therefore, the aim of this review is to summarize the effect of ablation of nonpulmonary vein triggers in addition to pulmonary vein isolation across the spectrum of atrial fibrillation in patients receiving catheter ablation. RECENT FINDINGS: In paroxysmal atrial fibrillation, an inducible nonpulmonary vein trigger is an independent predictor of recurrence. These triggers are inducible by adenosine and isoproterenol infusion. Nonpulmonary vein triggers cause a significant proportion of atrial fibrillation recurrence seen during repeat procedure and addressing them decreases such recurrence. Targeting inducible nonpulmonary vein triggers also decreases recurrence in persistent atrial fibrillation and was associated with a 25-30% relative reduction in arrhythmia recurrence compared with pulmonary vein isolation alone. In persistent atrial fibrillation, the addition of left atrial appendage isolation was associated with 55% reduction in arrhythmia recurrence. There was no benefit to the empirical ablation of the superior vena cava and the addition of extensive linear lines. There was insufficient evidence to assess the effects of empirical ablation of the coronary sinus, crista terminalis, left atrial posterior wall and the vein of Marshall on arrhythmia recurrence. SUMMARY: Evidence suggests that the presence of an inducible nonpulmonary vein trigger is a strong predictor of arrhythmia recurrence. Efforts to detect and ablate nonpulmonary vein triggers are warranted. Further studies are required to fully identify the role nonpulmonary vein trigger ablation. PMID- 29135524 TI - A palliative approach for heart failure end-of-life care. AB - PURPOSE OF REVIEW: The current review discusses the integration of guideline and evidence-based palliative care into heart failure end-of-life (EOL) care. RECENT FINDINGS: North American and European heart failure societies recommend the integration of palliative care into heart failure programs. Advance care planning, shared decision-making, routine measurement of symptoms and quality of life and specialist palliative care at heart failure EOL are identified as key components to an effective heart failure palliative care program. There is limited evidence to support the effectiveness of the individual elements. However, results from the palliative care in heart failure trial suggest an integrated heart failure palliative care program can significantly improve quality of life for heart failure patients at EOL. SUMMARY: Integration of a palliative approach to heart failure EOL care helps to ensure patients receive the care that is congruent with their values, wishes and preferences. Specialist palliative care referrals are limited to those who are truly at heart failure EOL. PMID- 29135531 TI - Recurrent Subanesthetic Ketamine Infusions for Complex Regional Pain Syndrome Leading to Biliary Dilation, Jaundice, and Cholangitis: A Case Report. AB - Complex regional pain syndrome is a chronic pain condition that may be resistant to many treatment modalities. Ketamine infusions have demonstrated some promising results, though their use may be associated with a number of adverse effects limiting their widespread applicability. Hepatotoxicity and cholangiopathy have been described in chronic ketamine abuse, though rarely in therapeutic use. We report the impact of recurrent short subanesthetic ketamine infusions for the treatment of complex regional pain syndrome resulting in biliary dilation, jaundice, and cholangitis. We recommend that prescribing physicians consider this and monitor liver function tests throughout the treatment period to minimize morbidity. PMID- 29135532 TI - Meta-analysis in evidence-based healthcare: a paradigm shift away from random effects is overdue. AB - Each year up to 20 000 systematic reviews and meta-analyses are published whose results influence healthcare decisions, thus making the robustness and reliability of meta-analytic methods one of the world's top clinical and public health priorities. The evidence synthesis makes use of either fixed-effect or random-effects statistical methods. The fixed-effect method has largely been replaced by the random-effects method as heterogeneity of study effects led to poor error estimation. However, despite the widespread use and acceptance of the random-effects method to correct this, it too remains unsatisfactory and continues to suffer from defective error estimation, posing a serious threat to decision-making in evidence-based clinical and public health practice. We discuss here the problem with the random-effects approach and demonstrate that there exist better estimators under the fixed-effect model framework that can achieve optimal error estimation. We argue for an urgent return to the earlier framework with updates that address these problems and conclude that doing so can markedly improve the reliability of meta-analytical findings and thus decision-making in healthcare. PMID- 29135533 TI - Understanding propensity scores. PMID- 29135534 TI - The Multiple Faces of Programmed Cell Death Ligand 1 Expression in Malignant and Nonmalignant Cells. AB - Preliminary data suggest that tumor expression of programmed cell death ligand 1 (PD-L1) protein in human cancers, as determined by immunohistochemistry in formalin-fixed, paraffin-embedded tissue samples, may predict clinical response to anti-PD-1/PD-L1 therapy. PD-L1 is not a specific tumor marker and its expression is also observed in various nonmalignant cells, such as macrophages and lymphocytes, causing confusion in immunohistochemistry analysis when these inflammatory cells are overlapping with tumors cells. The aim of the current study was to examine PD-L1 expression in formalin-fixed, paraffin-embedded malignant and nonmalignant cells from human tumors to establish potential characteristic patterns of PD-L1 expression in tumor tissues. We used a commercial PD-L1 clone (E1L3N) previously validated in our laboratory to characterize PD-L1 expression in surgically resected lung adenocarcinomas, lung squamous cell carcinomas, malignant melanomas, renal cell carcinomas, hepatocellular carcinomas, and ductal breast carcinomas. We observed different patterns of PD-L1 expression by malignant cells and nonmalignant cells as membrane, cytoplasmic, and nuclear expression. The distribution of expression was variable including the entire malignant cells population, heterogonous with random distribution, peripheral distribution, minimal expression by few cells and negative expression. Similar, nonmalignant cells showed randomly and peripherally distribution through the tumors. We concluded that the PD-L1 cell protein expression patterns and distributions are variable and differ between resected tumor specimens. The expression and distribution pattern described here provide a useful knowledgment of PD-L1 expression in tumor samples.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 29135535 TI - Blood glucose concentrations in prehospital trauma patients with traumatic shock: A retrospective analysis. AB - BACKGROUND: Deranged glucose metabolism after moderate to severe trauma with either high or low concentrations of blood glucose is associated with poorer outcome. Data on prehospital blood glucose concentrations and trauma are scarce. OBJECTIVES: The primary aim was to describe the relationship between traumatic shock and prehospital blood glucose concentrations. The secondary aim was to determine the additional predictive value of prehospital blood glucose concentration for traumatic shock when compared with vital parameters alone. DESIGN: Retrospective analysis of the predefined, observational database of a nationwide Helicopter Emergency Medical Service (34 bases). SETTING: Emergency trauma patients treated by Helicopter Emergency Medical Service between 2005 and 2013 were investigated. PATIENTS: All adult trauma patients (>=18 years) with recorded blood glucose concentrations were enrolled. OUTCOMES: Primary outcome: upper and lower thresholds of blood glucose concentration more commonly associated with traumatic shock. Secondary outcome: additional predictive value of prehospital blood glucose concentrations when compared with vital parameters alone. RESULTS: Of 51 936 trauma patients, 20 177 were included. In total, 220 (1.1%) patients died on scene. Hypoglycaemia (blood glucose concentration 2.8 mmol l or less) was observed in 132 (0.7%) patients, hyperglycaemia (blood glucose concentration exceeding 15 mmol l) was observed in 265 patients (1.3%). Blood glucose concentrations more than 10 mmol l (n = 1308 (6.5%)) and 2.8 mmol l or less were more common in patients with traumatic shock (P < 0.0001). The Youden index for traumatic shock ((sensitivity + specificity) - 1) was highest when blood glucose concentration was 3.35 mmol l (P < 0.001) for patients with low blood glucose concentrations and 7.75 mmol l (P < 0.001) for those with high blood glucose concentrations. In logistic regression analysis of patients with spontaneous circulation on scene, prehospital blood glucose concentrations (together with common vital parameters: Glasgow Coma Scale, heart rate, blood pressure, breathing frequency) significantly improved the prediction of traumatic shock in comparison with prediction by common vital parameters alone (P < 0.0001). CONCLUSION: In adult trauma patients, low and high blood glucose concentrations were more common in patients with traumatic shock. Prehospital blood glucose concentration measurements in addition to common vital parameters may help identify patients at risk of traumatic shock. PMID- 29135536 TI - Investigating Uranium Isotopic Ratios and Activity Ratios in Groundwaters in the State of Idaho. AB - Analyzing uranium isotopic and activity ratios can give valuable information for hydrologic and environmental studies such as insights to weathering processes, estimating water mixing ratios, and identifying water sources. The authors employed an inductively coupled plasma mass spectrometer (ICP-MS) to perform environmental level concentration measurements of isotopic uranium on 380 groundwater samples from various locations within the state of Idaho. The U:U uranium activity ratios (UAR) for these samples range between 0.91 and 6.21, which suggests that the parent U is not in equilibrium with its decay product U. The U:U isotopic ratio was also measured for each sample to confirm that there was no depleted or enriched uranium present. All 380 samples exhibited the natural isotopic ratios of U and U isotopes. Therefore, it was concluded that the U:U UARs reflect natural variations in the Idaho groundwater systems. PMID- 29135537 TI - Status and Perception of Risk Management in Radiation Therapy: Survey Among Korean Medical Physicists. AB - This study was conducted as part of an endeavor to improve the risk management system of radiation therapy departments in the Republic of Korea. An online survey on the status and perception of Korea's medical physicists on risk management in radiation therapy was carried out. A total of 40 domestic radiation oncology departments participated. This survey is divided into three categories: (1) work environment; (2) risk management status; and (3) opinions on how to improve risk management. Based on the results of the survey, the conclusions that can be derived are (1) the majority of respondents have a high interest in the risk management of radiation therapy; (2) the lack of staffing is one cause of risk management difficulties; (3) a risk-related terminology and classification system at the national or professional association level are required; (4) each hospital should create a voluntary reporting system for the handling of incidents; (5) medical physicists should establish incident reporting, analysis and countermeasures; and (6) government should develop education and training programs. It was confirmed that the current risk management system should be changed by education in the hospital and at the national level in order to improve risk management related to radiation therapy. In addition, it was recognized that a dedicated staff and a risk management certification system and organization for patient safety in radiotherapy are needed. PMID- 29135538 TI - Cervical morbidity in Alsace, France: results from a regional organized cervical cancer screening program. AB - In 1994, a pilot program of cervical cancer screening was introduced in the Alsace region, France. Women aged 25-65 years were proposed to have one Pap smear every 3 years. The objective was to assess cervical morbidity in Alsace before the human papillomavirus vaccinated population reaches the age of screening. Data on cervical lesions and cancers were collected by EVE for the period September 2008 to August 2011 from existing medical services and cytopathology laboratories in Alsace. Cytological and histological data were completed with data from the two cancer registries covering the region (Bas-Rhin and Haut-Rhin). Cancer incidence rates were computed for the target population (truncated to 25-64 years) and were age standardized according to the world reference population. World standardized incidence rates for the whole female population were obtained from the two cancer registries. During 2008-2011, 565 153 smears were performed in 498 913 women aged 25-64 years, representing an average of 1.13 smears/woman and 1.62 smears/screened woman. The overall screening coverage was 70.1% over the 3-year period. Histologically confirmed high-grade lesions were found in 2303 women (0.5%). Moreover, 215 cervical cancers were reported among women aged 25-64 years (crude and standardized truncated incidence rate of 10.6 and 10.0/100 000 women-years, respectively). The overall screening coverage of 70% at 3 years is higher than the national rate (57%), and the overall cancer incidence of 5.5/100 000 is below the national French level. The EVE database will be useful to assess trends in cervical morbidity over time and to further assess the effect of screening as well as of human papillomavirus vaccination. PMID- 29135550 TI - Transfusion-associated Circulatory Overload or Degassing? PMID- 29135551 TI - In Reply. PMID- 29135552 TI - Situations Where Intravenous Lidocaine Should Not Be Used as an Analgesic Adjunct? PMID- 29135553 TI - In Reply. PMID- 29135554 TI - Pain as a Predictor of Disability in Elderly Population. PMID- 29135555 TI - In Reply. PMID- 29135556 TI - Can Remote Ischemic Preconditioning Really Improve Long-term Kidney Outcomes after Cardiac Surgery? PMID- 29135557 TI - In Reply. PMID- 29135558 TI - What Is the Role of Cytokines during Ventilator-induced Lung Injury? PMID- 29135559 TI - In Reply. PMID- 29135560 TI - Anesthesia, Consciousness, and Language. PMID- 29135561 TI - Ideal Body Weight Is Not Really Ideal. PMID- 29135562 TI - Advances in cataract surgery in patients with multiple ocular diagnoses. PMID- 29135563 TI - The prevalence and sociodemographic determinants of uninvestigated dyspepsia in the Czech Republic: a multicentre prospective study accomplished 10 years after the first study from the same geographical areas. AB - OBJECTIVE: The epidemiology of uninvestigated dyspepsia was studied in the Czech Republic for the first time in 2001. The aim of the current multicenter prospective study was to evaluate dyspepsia using the same methods in a representative sample of general unselected population from the same geographical areas 10 years later. PARTICIPANTS AND METHODS: A total of 38 147 individuals comprised the general population for a random two-step selection process. A total of 1836 participants (863 males and 973 females; aged 5-98 years) took part in the questionnaire-based study. Helicobacter pylori status was investigated in all participants by means of C-urea breath test. RESULTS: The overall prevalence of dyspepsia was 2.6% among children and adolescents aged 5-17 years and 16.0% among adults aged 18-98 years. We did not detect any statistically significant sex differences in the prevalence of total dyspepsia or its subtypes. Overall, 2.4% of H. pylori-negative children and adolescents aged less than 18 years reported dyspepsia, and 16.8% of H. pylori-negative adults reported it. Among H. pylori positive children and adolescents and adults, dyspepsia was present in 8.3 and 15.8%, respectively. Type A dyspepsia (as the only long-lasting symptom) was statistically significantly associated with H. pylori status among children and adolescents. Among adults aged 18 years or older, we noted a lower prevalence of dyspepsia in adults with elementary education compared with university education. Current use of antibiotics was associated with an increased prevalence of dyspepsia in adults. CONCLUSION: Despite the substantial decrease of H. pylori infection in the Czech Republic over the past 10 years, the prevalence and sociodemographic determinants of uninvestigated dyspepsia did not change significantly. PMID- 29135564 TI - Bacterial vaginosis: A practical review. AB - Bacterial vaginosis is a common vaginal infection that causes discharge, odor, and irritation. It can predispose women to sexually transmitted infections (STIs) including HIV. Recurrent bacterial vaginosis may require prolonged treatment to return the vaginal flora to a normal predominately lactobacilli-dominated environment. PMID- 29135565 TI - Pediatric and adolescent anterior shoulder instability: clinical management of first-time dislocators. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss the epidemiology, pathoanatomy, diagnosis, and clinical management of pediatric and adolescent patients following a first-time shoulder dislocation. RECENT FINDINGS: Shoulder instability is becoming increasingly common as pediatric and adolescent patients engage in earlier organized sports competition. Recommended treatment following a first-time glenohumeral dislocation event in adolescents depends on several factors, but surgical stabilization is becoming more frequently performed. Surgical indications include bony Bankart lesion, ALPSA lesion, bipolar injury (e.g. Hill-Sachs humeral head depression fracture) or off-season injury in an overhead or throwing athlete. Complications following surgical treatment are rare but most commonly are associated with recurrent instability. Young children (eg. open proximal humerus growth plate), individuals averse to surgery, or in-season athletes who accept the risk of redislocation may complete an accelerated rehabilitation program for expedited return to play in the absence of the structural abnormalities listed above. SUMMARY: Following a first-time dislocation event in pediatric and adolescent patients, a detailed discussion of the risks and benefits of nonoperative versus operative management is critical to match the recommended treatment with the patient's injury pattern, risk factors, and activity goals. PMID- 29135566 TI - Management of hypertonia in cerebral palsy. AB - PURPOSE OF REVIEW: The review provides an update on the treatment of hypertonia in cerebral palsy, including physical management, pharmacotherapy, neurosurgical, and orthopedic procedures. RECENT FINDINGS: Serial casting potentiates the effect of Botulinum neurotoxin A injections for spasticity. Deep brain stimulation, intraventricular baclofen, and ventral and dorsal rhizotomy are emerging tools for the treatment of dystonia and/or mixed tone. The long-term results of selective dorsal rhizotomy and the timing of orthopedic surgery represent recent advances in the surgical management of hypertonia. SUMMARY: Management of hypertonia in cerebral palsy targets the functional goals of the patient and caregiver. Treatment options are conceptualized as surgical or nonsurgical, focal or generalized, and reversible or irreversible. The role of pharmacologic therapies is to improve function and mitigate adverse effects. Further investigation, including clinical trials, is required to determine the role of deep brain stimulation, intraventricular baclofen, orthopedic procedures for dystonia, and rhizotomy. PMID- 29135567 TI - Benign Reactive Lymphoid Hyperplasia of the Conjunctiva Treated With Cyclosporine. AB - PURPOSE: To describe a case of reactive lymphoid hyperplasia (RLH) of the conjunctiva responding to cyclosporine immunosuppressant monotherapy. METHODS: A 66-year-old man with a 2-year history of biopsy-proven bilateral RLH presented for dry eye evaluation with chief complaints of burning, stinging, and irritation in both eyes. After slit-lamp examination and positive findings of matrix metalloproteinase 9 in the patient's tear film, he was diagnosed with meibomian gland dysfunction and tear-insufficiency dry eye disease. The patient was subsequently treated with topical cyclosporine (ophthalmic emulsion 0.5 mg/mL two times per day) in both eyes. RESULTS: Examination at the 3-month follow-up visit revealed significant reduction of the RLH lesions bilaterally. CONCLUSIONS: This report represents the first case of benign ocular RLH responsive to topical cyclosporine therapy. We believe that cyclosporine could play a role in treating patients with benign ocular RLH and warrants further investigation to evaluate its full efficacy. PMID- 29135568 TI - Dynamic Prediction of Outcome for Patients With Ovarian Cancer: Application of a Joint Model for Longitudinal Cancer Antigen 125 Values. AB - OBJECTIVE: In clinical practice, gynecologic oncologists are interested in predicting the prognosis of patients through information from different sources. Recently, the overall survival (OS) of ovarian cancer patients has been widely and intensively researched, and a large number of risk factors have been determined, including the biomarker of cancer antigen 125 (CA-125). For newly diagnosed patients, it is critical to construct effective prognostic models to predict prognosis dynamically by combining their CA-125 values with adjusted clinical factors. METHODS/MATERIALS: A total of 227 ovarian cancer participants entered this study. A 4-step method was used to construct a joint model to examine the association between longitudinal CA-125 measurements and OS time, to explore time-independent predictive factors influencing OS, and to obtain an accurate and credible dynamic prediction of OS for specific subjects. RESULTS: We found that CA-125 values were greatly affected by observation time, menarche, Federation International of Gynecology and Obstetrics stage, and ascites at baseline. Similarly, CA-125 values, menopause, Federation International of Gynecology and Obstetrics stage, and surgery state at baseline were selected from the best Cox proportion hazard model and showed a strong correlation with OS. In addition, the analyses presented by the joint model depict that, as time goes by, increasing CA-125 was deemed to be a significant predictor of death. CONCLUSIONS: Together, our results show that a joint model could be highly efficient in clinical consultation and diagnosis for patients newly diagnosed as having ovarian cancer. Longitudinal CA-125 values, which are measured over time, can be used to credibly predict OS after taking all adjusted covariates into account. PMID- 29135569 TI - Exposure to Passive Smoking and Impairment in Physical Function in Older People. PMID- 29135570 TI - The Spillover Influence of Partner's Education on Myocardial Infarction Incidence and Survival. AB - BACKGROUND: Education is believed to have positive spillover effects across network connections. Partner's education may be an important resource preventing the incidence of disease and helping patients cope with illness. We examined how partner's education predicted myocardial infarction (MI) incidence and survival net of own education and other socioeconomic resources in Finland. METHODS: A sample of adults aged 40-69 years at baseline in Finland in 1990 was followed up for MI incidence and mortality during the period 1991-2007 (n = 354,100). RESULTS: Lower own and spousal education both contributed independently to a higher risk of MI incidence and fatality when mutually adjusted. Having a partner with basic education was particularly strongly associated with long-term fatality in women with a hazard ratio of 1.53 (95% confidence interval, 1.22-1.92) compared with women with tertiary level educated partners. There was some evidence that the incidence risk associated with basic spousal education was weaker in those with own basic education. The highest risks of MI incidence and fatality were consistently found in those without a partner, whereas the most favorable outcomes were in households where both partners had a tertiary level of education. CONCLUSIONS: Accounting for spousal education demonstrates how health enhancing resources accumulate to some households. Marriage between people of similar educational levels may therefore contribute to the widening of educational differences in MI incidence and survival. PMID- 29135571 TI - Validation of Cancer Cases Using Primary Care, Cancer Registry, and Hospitalization Data in the United Kingdom. AB - BACKGROUND: In the United Kingdom, hospital or cancer registry data can be linked to electronic medical records for a subset of general practices and years. METHODS: We used Clinical Practice Research Datalink data (2004-2012) from patients treated for overactive bladder. We electronically identified provisional cases of 10 common cancers in General Practitioner Online Database data and validated them by medical profile review. In practices with linkage to Hospital Episodes Statistics and National Cancer Data Repository (2004-2010), we validated provisional cancer cases against these data sources. This linkage also let us identify additional cancer diagnoses in individuals without cancer diagnosis records in the General Practitioner Online Database. RESULTS: Among 50,840 patients, 1,486 provisional cancer cases were identified in the General Practitioner Online Database for 2004-2012. Medical profile review confirmed 93% of 661 cases in nonlinked practices (range, 100% of non-Hodgkin lymphomas and uterine cancer to 77% of skin melanomas) and 96% of 825 cases in linked practices (100% of kidney and uterine cancers to 92% of melanomas). In the subset of linked practices, for 2004-2010, 720 cases were confirmed, of which 68% were identifiable in the General Practitioner Online Database (range, 90% of breast to 36% of kidney cancers). CONCLUSIONS: Most cases of cancer identified electronically in the General Practitioner Online Database were confirmed. A substantial proportion of cases, especially of cancer types not typically managed by general practitioners, would be missed without Hospital Episodes Statistics and National Cancer Data Repository data (and are likely missed in nonlinked practices). See video abstract at, http://links.lww.com/EDE/B315. REGISTRATION (BEFORE STUDY CONDUCT): European Union electronic Register of Post-Authorisation Studies (EU PAS Registry) number EUPAS5529, http://www.encepp.eu/encepp/viewResource.htm?id=11107. PMID- 29135572 TI - Long-term observational studies of chronic granulomatous disease. AB - PURPOSE OF REVIEW: Chronic granulomatous disease (CGD) is a primary immunodeficiency, with a defect of phagocytes in killing specific pathogens. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory response. Since its first description as fatal disease about 60 years ago, a significant improvement in outcome has been achieved in the last 20 years. The purpose of this review is to framework recent advances in CGD immunopathogenesis, management of disease manifestation and cure of CGD patients. RECENT FINDINGS: For years, CGD is a known cause of life-threatening infections and excessive inflammation. The cause and the management of inflammatory reactions, however, have not been clarified, and the range of clinical presentation is growing with corresponding novel therapeutic interventions. Recent work focuses on the best outcome of hematopoietic stem cell transplantation (HSCT) and gene therapy for the cure of CGD patients, more specifically, those with X-linked and p47 mutations. SUMMARY: The genetics and phenotype of CGD is well characterized; however, the underlying mechanisms, the treatment of its inflammatory manifestations and the cure of CGD is under further investigation. PMID- 29135573 TI - Evidence of inflammasome activation and formation of monocyte-derived ASC specks in HIV-1 positive patients. AB - OBJECTIVE: The formation of large intracellular protein aggregates of the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain; also know as PYCARD) is a hallmark of inflammasome activation. ASC speck-forming cells release the highly proinflammatory cytokine IL-1beta in addition to ASC specks into the extracellular space during pyroptotic cell death. There ASC specks can propagate inflammation to other nonactivated cells or tissues. HIV-1 retroviral infection triggers inflammasome activation of abortively infected CD4+ T cells in secondary lymphatic tissues. However, if pyroptosis occurs in other peripheral blood mononuclear cells (PBMCs) of HIV-1-infected patients is currently unknown. We investigated if ASC speck positive cells are present in the circulation of HIV-1 infected patients. DESIGN AND METHODS: PBMCs or plasma of HIV-1 infected, antiretroviral therapy-naive patients were analyzed for the presence of ASC speck+ cells or extracellular ASC and compared with healthy controls. Intracellular staining for ASC was employed to detect ASC speck+ cells within PBMCs by flow cytometry, and ELISA to detect free ASC in the plasma. ASC multimerization was confirmed by immunoblot. RESULTS: Peripheral blood CD14++CD16 monocytes were ASC speck+ in HIV patients, but not in healthy controls. In the subgroup analysis, HIV patients with lower CD4+ T-cell counts and higher viral load had significantly more ASC speck+ monocytes. ASC speck formation did not correlate with Gag expression, coinfection, lactate dehydrogenase or C-reactive protein. CONCLUSION: Our findings suggest that pyroptotic CD14++CD16- classical monocytes of HIV-1-infected patients release ASC specks into the blood stream, a phenomenon that may contribute to HIV-1 induced inflammation and immune activation. PMID- 29135575 TI - Chronic kidney disease incidence and survival of Thai HIV-infected patients. AB - OBJECTIVES: As data on chronic kidney disease (CKD) incidence among Asian HIV patients has been limited, the present study aimed to estimate the CKD incidence in HIV-infected patients who received standard antiretroviral therapy in Thailand and to compare baseline demographics and clinical characteristics of the patients who developed CKD with those who do not. DESIGN: A multicenter, observational prospective cohort of HIV patients with normal kidney functions who received standard antiretroviral therapy. METHODS: CKD was diagnosed based on the KDIGO 2012 criteria, using Chronic Kidney Disease Epidemiology Collaboration based estimated glomerular filtration rate with and without urine protein. The cumulative probability of CKD incidence was analyzed using Kaplan-Meier estimation. RESULTS: Of 5552 patients, 96 patients with pre-existing CKD and 26 patients with incomplete data were excluded, and 5430 patients were analyzed. Their mean age was 39.87 years, 41.52% were women, and 49.45% were homosexual. They were followed up for 49.41 months on average, with 229 incident cases (4.22%) being identified during 22 035 person-years at risk. Overall CKD incidence rate was 10.39 per 1000 person-years. Average time to CKD was 26.4 months (95% confidence interval: 24.44-28.83). The adjusted relative hazard significantly increased by 8.6% and 10.3% for each additional year of patient age and each additional log10 copies/ml of HIV viral load, respectively. Patients with diabetes mellitus and hypercholesterolemia had significantly higher adjusted relative hazard (3.37 and 1.41; P < 0.001 and P = 0.014), respectively. CONCLUSION: CKD incidence among the Thai HIV-infected patients was lower than in white and non-Southeast Asian populations. Diabetes, hypercholesterolemia, age, and HIV viral load were the significant risk factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01328275. PMID- 29135577 TI - Protease inhibitors and preterm delivery: another piece in the puzzle. AB - BACKGROUND: Questions remain regarding preterm delivery (PTD) risk in HIV infected women on antiretroviral therapy (ART), including the role of ritonavir (RTV)-boosted protease inhibitors, timing of ART initiation and immune status. METHODS: We examined data from the UK/Ireland National Study of HIV in Pregnancy and Childhood on women with HIV delivering a singleton live infant in 2007-2015, including those pregnancies receiving RTV-boosted protease inhibitor-based (n = 4184) or nonnucleoside reverse transcriptase inhibitors-based regimens (n = 1889). We conducted logistic regression analysis adjusted for risk factors associated with PTD and stratified by ART at conception and CD4 cell count to minimize bias by indication for treatment and to assess whether PTD risk differs by ART class and specific drug combinations. RESULTS: Among women conceiving on ART, lopinavir/RTV was associated with increased PTD risk in those with CD4 cell count 350 cells/MUl or less [odds ratio 1.99 (1.02, 3.85)] and with CD4 cell count more than 350 cells/MUl [odds ratio 1.61 (1.07, 2.43)] vs. women on nonnucleoside reverse transcriptase inhibitors-based (mainly efavirenz and nevirapine) regimens in the same CD4 subgroup. Associations between other protease inhibitor-based regimens (mainly atazanavir and darunavir) and PTD risk were complex. Overall, PTD risk was higher in women who conceived on ART, had low CD4 cell count and were older. No trend of association of PTD with tenofovir or any specific drug combinations was observed. CONCLUSION: Our data support a link between the initiation of RTV-boosted/lopinavir-based ART preconception and PTD in subsequent pregnancies, with implications for treatment guidelines. Continued monitoring of PTD risk is needed as increasing numbers of pregnancies are conceived on new drugs. PMID- 29135576 TI - Assisted partner notification services are cost-effective for decreasing HIV burden in western Kenya. AB - BACKGROUND: Assisted partner services (aPS) or provider notification for sexual partners of persons diagnosed HIV positive can increase HIV testing and linkage in Sub-Saharan Africa and is a high yield strategy to identify HIV-positive persons. However, its cost-effectiveness is not well evaluated. METHODS: Using effectiveness and cost data from an aPS trial in Kenya, we parameterized an individual-based, dynamic HIV transmission model. We estimated costs for both a program scenario and a task-shifting scenario using community health workers to conduct the intervention. We simulated 200 cohorts of 500 000 individuals and projected the health and economic effects of scaling up aPS in a region of western Kenya (formerly Nyanza Province). FINDINGS: Over a 10-year time horizon with universal antiretroviral therapy (ART) initiation, implementing aPS in western Kenya was projected to reach 12.5% of the population and reduce incident HIV infections by 3.7%. In sexual partners receiving aPS, HIV-related deaths were reduced by 13.7%. The incremental cost-effectiveness ratio of aPS was $1094 (US dollars) (90% model variability $823-1619) and $833 (90% model variability $628 1224) per disability-adjusted life year averted under the program and task shifting scenario, respectively. The incremental cost-effectiveness ratios for both scenarios fall below Kenya's gross domestic product per capita ($1358) and are therefore considered very cost-effective. Results were robust to varying healthcare costs, linkage to care rates, partner concurrency rates, and ART eligibility thresholds (<=350 cells/MUl, <=500 cells/MUl, and universal ART). INTERPRETATION: APS is cost-effective for reducing HIV-related morbidity and mortality in western Kenya and similar settings. Task shifting can increase program affordability. PMID- 29135578 TI - When prevention of mother-to-child HIV transmission fails: preventing pretreatment drug resistance in African children. PMID- 29135579 TI - Markers of chronic obstructive pulmonary disease are associated with mortality in people living with HIV. AB - OBJECTIVE: Aging people living with HIV (PLWH) face an increased burden of comorbidities, including chronic obstructive pulmonary disease (COPD). The impact of COPD on mortality in HIV remains unclear. We examined associations between markers of COPD and mortality among PLWH and uninfected study participants. DESIGN: Longitudinal analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study. METHODS: EXHALE includes 196 PLWH and 165 uninfected smoking-matched study participants who underwent pulmonary function testing and computed tomography (CT) to define COPD and were followed. We determined associations between markers of COPD with mortality using multivariable Cox regression models, adjusted for smoking and the Veterans Aging Cohort Study (VACS) Index, a validated predictor of mortality in HIV. RESULTS: Median follow-up time was 6.9 years; the mortality rate was 2.7/100 person-years among PLWH and 1.7/100 person-years among uninfected study participants (P = 0.11). The VACS Index was associated with mortality in both PLWH and uninfected study participants. In multivariable models, pulmonary function and CT characteristics defining COPD were associated with mortality in PLWH: those with airflow obstruction (forced expiratory volume in 1 s/ forced vital capacity <0.7) had 3.1 times the risk of death [hazard ratio 3.1 (95% confidence interval 1.4 7.1)], compared with those without; those with emphysema (>10% burden) had 2.4 times the risk of death [hazard ratio 2.4 (95% confidence interval 1.1-5.5)] compared with those with <= 10% emphysema. In uninfected subjects, pulmonary variables were not significantly associated with mortality, which may reflect fewer deaths limiting power. CONCLUSION: Markers of COPD were associated with greater mortality in PWLH, independent of the VACS Index. COPD is likely an important contributor to mortality in contemporary PLWH. PMID- 29135580 TI - Wake me up before you go: a strategy to reduce the latent HIV reservoir. PMID- 29135581 TI - High rates of hypertension, diabetes, elevated low-density lipoprotein cholesterol, and cardiovascular disease risk factors in HIV-infected patients in Malawi. AB - OBJECTIVES: Data on cardiovascular disease risks among HIV-infected patients taking antiretroviral therapy (ART) over long periods of time are lacking in Sub Saharan Africa. METHODS: A cross-sectional study was conducted in Chiradzulu, Malawi from December 2015 to June 2016. HIV-infected persons on ART for more than 10 years (patients) and HIV-negative individuals (controls) from selected clinics participated. Following informed consent, a standardized questionnaire, clinical and laboratory examinations were performed. The prevalence of cardiovascular disease risk factors was calculated and stratified by age group. RESULTS: Overall, 379 HIV-infected patients and 356 controls participated. Median time on ART among patients was 11.6 years (interquartile range 10.6-12.4).Within the 30 44, 45-59, and at least 60-year age groups, respectively, the prevalence of hypertension was 10.8, 20.4, and 44.7% among patients and 6.1, 25.8, and 42.9% among controls. Hypertension was previously undiagnosed in 60.3% patients and 37.0% controls with elevated blood pressure. The prevalence of diabetes within the respective age groups was 5.0, 6.4, and 13.2% among patients, and 3.4, 4.2, and 1.7% among controls. HIV-infected patients were more likely to have an glycated hemoglobin at least 6.0% (adjusted odds ratio 1.9; 95% confidence interval 1.1-3.2, P = 0.02). Prevalence of low-density lipoprotein cholesterol more than 130 mg/dl within the respective age groups was 8.0, 15.4, and 23.7% among patients and 1.8, 12.5, and 11.8% among controls. CONCLUSION: Noncommunicable diseases were a significant burden in Malawi, with high prevalence of hypercholesterolemia in all survey participants and an especially acute diabetes burden among older HIV infected. Hypertension screening and treatment services are needed among identified high-risk groups to cover unmet needs. PMID- 29135582 TI - HIV is associated with airway obstruction: a matched controlled study. AB - OBJECTIVE: To explore whether airway obstruction is associated with HIV in a cohort of HIV-infected and uninfected smokers. METHODS: People living with HIV (PLWHIV) participated in the ANRS EP48 HIV CHEST study, an early lung cancer diagnosis study with low-dose chest tomography. HIV-uninfected study participants were from the CONSTANCES cohort. Inclusion criteria were an age greater than 40 years, a smoking history of at least 20 pack-years, and for PLWHIV, a CD4 T lymphocyte nadir less than 350/MUl and last CD4 cell count more than 100 cells/MUl. Two randomly selected HIV-uninfected study participants were matched by age and sex with one PLWHIV. Prebronchodilatator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio was the primary outcome, and association of FEV1/FVC ratio less than 0.70 and FEV1 less than 80% of the theoretical value, as a proxy of chronic obstructive pulmonary disease, the secondary outcome. RESULTS: In total, 351 PLWHIV and 702 HIV-uninfected study participants were included. Median age was 50 years, and 17% of study participants were women. Plasma HIV RNA was less than 50 copies/ml in 89% of PLWHIV, with a median CD4 cell count of 573 cells/MUl. HIV (beta -2.19), age (per 10 years increase; beta -2.81), tobacco use (per 5 pack-years increase; beta 0.34), and hepatitis C virus serology (beta-2.50) were negatively associated with FEV1/FVC. HIV [odds ratio (OR: 1.72)], age (per 10 years increase; OR 1.77), and tobacco use (per 5 pack-years increase; OR 1.11) were significantly associated with the secondary outcome. CONCLUSION: Our study found a significant association of airway obstruction with HIV status in smokers aged more than 40 years with previous immunodeficiency. PMID- 29135583 TI - Effect of immediate initiation of antiretroviral treatment on the risk of acquired HIV drug resistance. AB - OBJECTIVE: We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/MUl and initiation with CD4 cell count less than 350 cells/MUl. DESIGN: Cohort study based on routinely collected data from the HIV CAUSAL collaboration. METHODS: For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics. RESULTS: In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/MUl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/MUl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/MUl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2). CONCLUSION: Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation. PMID- 29135584 TI - Concomitant medication polypharmacy, interactions and imperfect adherence are common in Australian adults on suppressive antiretroviral therapy. AB - OBJECTIVES: We quantified concomitant medication polypharmacy, pharmacokinetic and pharmacodynamic interactions, adverse effects and adherence in Australian adults on effective antiretroviral therapy. DESIGN: Cross-sectional. METHODS: Patients recruited into a nationwide cohort and assessed for prevalence and type of concomitant medication (including polypharmacy, defined as >=5 concomitant medications), pharmacokinetic or pharmacodynamic interactions, potential concomitant medication adverse effects and concomitant medication adherence. Factors associated with concomitant medication polypharmacy and with imperfect adherence were identified using multivariable logistic regression. RESULTS: Of 522 participants, 392 (75%) took a concomitant medication (mostly cardiovascular, nonprescription or antidepressant). Overall, 280 participants (54%) had polypharmacy of concomitant medications and/or a drug interaction or contraindication. Polypharmacy was present in 122 (23%) and independently associated with clinical trial participation, renal impairment, major comorbidity, hospital/general practice-based HIV care (versus sexual health clinic) and benzodiazepine use. Seventeen participants (3%) took at least one concomitant medication contraindicated with their antiretroviral therapy, and 237 (45%) had at least one pharmacokinetic/pharmacodynamic interaction. Concomitant medication use was significantly associated with sleep disturbance and myalgia, and polypharmacy of concomitant medications with diarrhoea, fatigue, myalgia and peripheral neuropathy. Sixty participants (12%) reported imperfect concomitant medication adherence, independently associated with requiring financial support, foregoing necessities for financial reasons, good/very good self-reported general health and at least 1 bed day for illness in the previous 12 months. CONCLUSION: In a resource-rich setting with universal healthcare access, the majority of this sample took a concomitant medication. Over half had at least one of concomitant medication polypharmacy, pharmacokinetic or pharmacodynamic interaction. Concomitant medication use was associated with several adverse clinical outcomes. PMID- 29135585 TI - The regulation of aldosterone secretion by leptin: implications in obesity related cardiovascular disease. AB - PURPOSE OF REVIEW: Although it has been known for some time that increases in body mass enhance aldosterone secretion, particularly in women, the origin of this elevation in aldosterone production is not well defined. Adipocyte-derived factors have emerged as potential candidates to increase aldosterone production in obesity. RECENT FINDINGS: Emerging evidence suggests the presence of a mechanistic link in which the adipocyte-derived hormone leptin stimulates aldosterone production in obesity, thereby creating a positive feedback loop for obesity-associated cardiovascular disease. In addition, recent reports give credence to the concept that this leptin-aldosterone stimulation pathway in obesity is an underlying mechanism for sex-discrepancies in obesity-associated cardiovascular disease. SUMMARY: Leptin appears as a new direct regulator of adrenal aldosterone production and leptin-mediated aldosterone production is a novel candidate mechanism underlying obesity-associated hypertension, particularly in females. PMID- 29135588 TI - In Response. PMID- 29135586 TI - Increased Hyperalgesia and Proinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion After Surgery and/or Fentanyl Administration in Rats. AB - BACKGROUND: Perioperative fentanyl has been reported to induce hyperalgesia and increase postoperative pain. In this study, we tried to investigate behavioral hyperalgesia, the expression of proinflammatory cytokines, such as interleukin 1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha), and the activation of microglia in the spinal cord and dorsal root ganglion (DRG) in a rat model of surgical plantar incision with or without perioperative fentanyl. METHODS: Four groups of rats (n = 32 for each group) were subcutaneously injected with fentanyl at 60 MUg/kg or normal saline for 4 times with 15-minute intervals. Plantar incisions were made to rats in 2 groups after the second drug injection. Mechanical and thermal nociceptive thresholds were assessed by the tail pressure test and paw withdrawal test on the day before, at 1, 2, 3, 4 hours, and on the days 1-7 after drug injection. The lumbar spinal cord, bilateral DRG, and cerebrospinal fluid of 4 rats in each group were collected to measure IL-1beta, IL-6, and TNF-alpha on the day before, at the fourth hour, and on the days 1, 3, 5, and 7 after drug injection. The lumbar spinal cord and bilateral DRG were removed to detect the ionized calcium-binding adapter molecule 1 on the day before and on the days 1 and 7 after drug injection. RESULTS: Rats injected with normal saline only demonstrated no significant mechanical or thermal hyperalgesia or any increases of IL-1beta, IL 6, and TNF-alpha in the spinal cord or DRG. However, injection of fentanyl induced analgesia within as early as 4 hours and a significant delayed tail mechanical and bilateral plantar thermal hyperalgesia after injections lasting for 2 days, while surgical plantar incision induced a significant mechanical and thermal hyperalgesia lasting for 1-4 days. The combination of fentanyl and incision further aggravated the hyperalgesia and prolonged the duration of hyperalgesia. The fentanyl or surgical incision upregulated the expression of IL 1beta, IL-6, and TNF-alpha in the spinal cord and bilateral DRG for more than 7 days and increase of ionized calcium-binding adapter molecule 1 in the spinal cord. The combination of fentanyl and incision resulted in higher increase of IL 1beta, IL-6, and TNF-alpha in the spinal cord and bilateral DRG. CONCLUSIONS: The surgical plantar incision with or without perioperative fentanyl induced significant mechanical and thermal hyperalgesia, an increased expression of IL 1beta, IL-6, TNF-alpha in the spinal cord and DRG, and activation of microglia in the spinal cord. PMID- 29135589 TI - Safety and Effectiveness of a Novel Facemask for Positive Pressure Ventilation. AB - BACKGROUND: Manual positive pressure ventilation is an essential skill in a variety of clinical situations. The C&E technique is commonly used with standard facemasks to provide effective ventilation. The Tao mask is a novel design that allows a more ergonomic grip. A seal between the mask and face is made with downward pressure of the palm, centered on the mask, and jaw lift is achieved with 4 fingers centered under the mandible. The purpose of this study was to evaluate the safety and effectiveness of the Tao mask compared to a standard mask before and after the administration of neuromuscular blockade (NMB) using 2 previously established ventilation scales. METHODS: One hundred fifty-two patients >18 years of age who were scheduled for general anesthesia were recruited. All care team members were shown a brief instructional video on the use of the Tao mask. After induction of general anesthesia with a standardized protocol, each patient was ventilated with both the standard (Vital Signs #082510) and Tao masks and effectiveness was measured using the Han and Warters scales. This process was repeated after NMB. The sequence of masks was determined with a random-number generator. RESULTS: Tao mask ventilation scores were significantly better than standard mask scores on both the Han scale and the Warters scale before the administration of NMB (P < .001 for both). Tao mask scores were also significantly better than standard mask scores on the Warters scale after the administration of NMB (P < .001). However, there was no significant difference on the Han scale between the 2 mask types after NMB (P = .180). On the Warters scale, there were significantly fewer patients who were difficult to ventilate with the Tao mask than the standard mask before NMB (18 vs 40; P < .001) and after NMB (8 vs 17; P = .005). No adverse events were reported with either mask. CONCLUSIONS: Our results indicate that the Tao mask demonstrated equivalent safety and superior effectiveness compared to a standard mask. The study design favored the standard mask because all participating practitioners had multiple years of experience with the standard mask and no prior experience with the Tao mask. Since the incidence of inadequate mask ventilation goes up significantly with inexperienced operators, the improved effectiveness of the Tao mask could be even more profound with novice operators. PMID- 29135590 TI - The Analgesic Effect of Ultrasound-Guided Quadratus Lumborum Block After Cesarean Delivery: A Randomized Clinical Trial. AB - BACKGROUND: Landmark and ultrasound-guided transversus abdominis plane blocks have demonstrated an opioid-sparing effect postoperatively after cesarean delivery. The more posterior quadratus lumborum (QL) might provide superior local anesthetic spread to the thoracolumbar fascia and paravertebral space. The aim of our study was to evaluate the efficacy of the QL block after cesarean delivery. METHODS: A randomized, double-blind, controlled trial was performed. Forty parturients undergoing cesarean delivery received bilateral ultrasound-guided QL blocks with either 2 mg/mL ropivacaine or saline postoperatively. All patients received spinal anesthesia with bupivacaine and sufentanil and a postoperative analgesic regimen of paracetamol, ibuprofen, and ketobemidone administered by a patient-controlled analgesic pump. The ketobemidone consumption and time of each dose administered were recorded. The primary outcome was ketobemidone consumption during the first 24 hours postoperatively. Secondary and exploratory analyses compared repeated measures of pain scores, nausea, and fatigue, and total differences in time until patients were able to stand and able to walk 5 m, and the interaction between the effective analgesic score and time. RESULTS: All 40 patients completed the trial, 20 in each group. The cumulative ketobemidone consumption in 24 hours was reduced in the active group compared with the control group (P = .04; ratio of means = 0.60; 95% confidence interval, 0.37-0.97). The effective analgesic scores were significantly better in the treatment group compared with the placebo group both at rest (P < .01) and during coughing (P < .01). CONCLUSIONS: QL block with ropivacaine reduces the postoperative ketobemidone consumption and pain intensity as a part of a multimodal analgesic regimen that excludes neuraxial morphine. PMID- 29135591 TI - In Response. PMID- 29135592 TI - Hypoxia and Postoperative Stroke: The Picture Is Still Not Clear. PMID- 29135593 TI - Ultrasound-Guided Dynamic Needle Tip Positioning Technique Versus Palpation Technique for Radial Arterial Cannulation in Adult Surgical Patients: A Randomized Controlled Trial. AB - BACKGROUND: Radial arterial cannulation is most commonly done using palpation, but the use of ultrasound has increased the cannulation success rate. This improvement, albeit significant, has not led to a very high success rate especially in trainees. A modified ultrasound technique for vascular cannulation (dynamic needle tip positioning) has been described for peripheral venous cannulation. We therefore assessed the success rate of this technique compared to the palpation technique for radial artery cannulation in adult surgical patients. METHODS: We enrolled patients who were having nonemergent operations that required a radial arterial catheter for intraoperative monitoring. Patients were randomized to either palpation or dynamic needle tip positioning technique. Arterial cannulation was performed by anesthesia residents or faculty members. The primary end point was successful cannulation on the first pass. Secondary end points were overall 5-minute success rate and number of attempts within 5 minutes. RESULTS: Two hundred sixty patients were evaluated. The first-pass success rate was 83% in the dynamic needle tip positioning technique group (n = 132) and 48% in the palpation group (n = 128; P < .001); relative risk was 2.5; 95% confidence interval, 1.7-3.6. The overall 5-minute success rate was 89% in the dynamic needle tip positioning technique group compared to 65% in the palpation group (P < .001), relative risk was 2.4; 95% confidence interval, 1.2 1.6. The number of skin puncture attempts was significantly more in the palpation group (P < .001). The median cannulation times and interquartile ranges were 81.5 (61-122) seconds in the dynamic needle tip positioning and 76 (48-175) seconds (P = .7) in the palpation group. CONCLUSIONS: The use of the ultrasound-guided dynamic needle tip positioning technique increased the first and overall success rates compared to palpation in anesthesia residents and faculty members. PMID- 29135594 TI - In Response. PMID- 29135595 TI - Least Injurious Mechanical Ventilation in Pulmonary Resection Surgery. PMID- 29135596 TI - General Anesthetics to Treat Major Depressive Disorder: Clinical Relevance and Underlying Mechanisms. AB - Major depressive disorder is a frequent and devastating psychological condition with tremendous public health impact. The underlying pathophysiological mechanisms involve abnormal neurotransmission and a relatedly impaired synaptic plasticity. Since general anesthetics are potent modulators of neuronal activity and, thereby, can exert long-term context-dependent impact on neural networks, an intriguing hypothesis is that these drugs could enhance impaired neural plasticity associated with certain psychiatric diseases. Clinical observations over the past few decades appear to confirm this possibility. Indeed, equipotency of general anesthesia alone in comparison with electroconvulsive therapy under general anesthesia has been demonstrated in several clinical trials. Importantly, in the past 15 years, intravenous administration of subanesthetic doses of ketamine have also been demonstrated to have rapid antidepressant effects. The molecular, cellular, and network mechanisms underlying these therapeutic effects have been partially identified. Although several important questions remain to be addressed, the ensemble of these experimental and clinical observations opens new therapeutic possibilities in the treatment of depressive disorders. Importantly, they also suggest a new therapeutic role for anesthetics that goes beyond their principal use in the perioperative period to facilitate surgery. PMID- 29135597 TI - Society for Obstetric Anesthesia and Perinatology 2017 Meeting Report. PMID- 29135598 TI - Cardiac Arrest in the Operating Room: Resuscitation and Management for the Anesthesiologist: Part 1. AB - Cardiac arrest in the operating room and procedural areas has a different spectrum of causes (ie, hypovolemia, gas embolism, and hyperkalemia), and rapid and appropriate evaluation and management of these causes require modification of traditional cardiac arrest algorithms. There is a small but growing body of literature describing the incidence, causes, treatments, and outcomes of circulatory crisis and perioperative cardiac arrest. These events are almost always witnessed, frequently known, and involve rescuer providers with knowledge of the patient and their procedure. In this setting, there can be formulation of a differential diagnosis and a directed intervention that treats the likely underlying cause(s) of the crisis while concurrently managing the crisis itself. Management of cardiac arrest of the perioperative patient is predicated on expert opinion, physiologic rationale, and an understanding of the context in which these events occur. Resuscitation algorithms should consider the evaluation and management of these causes of crisis in the perioperative setting. PMID- 29135599 TI - Neuroplasty Is a Safe, Effective Procedure. PMID- 29135600 TI - Balance and Functional Outcomes for Older Community-Dwelling Adults Who Practice Tai Chi and Those Who Do Not: A Comparative Study. AB - BACKGROUND AND PURPOSE: A growing body of literature substantiates that Tai Chi is a form of exercise that may help older adults increase strength, improve balance, lower fall rates, and experience less fear of falling. Few studies, however, offer controlled experimental design and simultaneously investigate multiple factors known to contribute to fall risk. The purpose of this study was to compare performance on measures relating to fall risk (strength, balance, functional mobility, and fear of falling) in older community-dwelling adults who participated in a community-based Tai Chi program with a control group of their peers who had no Tai Chi training over the same time period. METHODS: A quasi experimental comparative pre- and posttest design was used to compare an experimental group of 16 community-dwelling older adults, mean (SD) age = 80.4 (6.8) years, participating in a 16-week Tai Chi training program with a group of 13 adults, mean (SD) age = 71.2 (6.1) years, who had no Tai Chi experience in the areas of knee extension strength (measured by handheld dynamometry), functional strength (by five-time sit to stand), mobility (by Timed Up and Go [TUG] test and Fifty-Foot Walk Test), balance (by Functional Reach and Berg Balance Scale), and fear of falling (by Activity-specific Balance Confidence scale). Within-group and between-groups comparisons were made using 2*2 mixed analysis of variance. RESULTS: Tai Chi participants improved in nearly all measures, whereas controls did not. Tai Chi participants experienced significant improvement in the TUG test during the training period (P = .003), with significant difference when compared with controls (P = .049) and moderate effect size and observed power (etap = 0.165; observed power = 0.512). Significant knee extension strength improvement occurred (P = .042) with moderate effect size and observed power (etap = 0.183; observed power = 0.543). While the total balance confidence scale score did not change significantly, responses on many individual items did reach a level of significant change for persons participating in the Tai Chi training. CONCLUSION: Older adults' participation in a community-based Tai Chi program may lead to improvement in strength, mobility, and confidence in performing functional tasks. Incorporation of elements of Tai Chi into therapy programs for older adults at risk for fall and referral to community-based Tai Chi programs may be viable options in the continuum of health-related care for older adults. PMID- 29135601 TI - Sex Differences in Cardiac Baroreflex Sensitivity after Isometric Handgrip Exercise. AB - PURPOSE: This study aimed to investigate potential sex-related differences on spontaneous cardiac baroreflex sensitivity (cBRS) after acute isometric handgrip (IHG) exercise. METHODS: Twenty men (age, 23 +/- 3 yr) and 20 women (age, 24 +/- 4 yr) randomly performed four sets of 2-min IHG exercise (two sets for each limb) at 30% maximal voluntary contraction (experimental) or 3% maximal voluntary contraction (sham). Beat-to-beat heart rate (HR) and arterial blood pressure (BP) were monitored using finger photoplethysmography before and 10, 20, and 30 min after IHG. Spontaneous cBRS was assessed via the sequence technique and cardiac autonomic modulation via time- and frequency-domain HR variability. RESULTS: After IHG, spontaneous cBRS increased during 10 min of recovery in men (Delta13% +/- 5%, P = 0.03 vs rest) and increased further in women (Delta23% +/- 4%, P < 0.01 vs rest; P = 0.04 vs men). During 20 and 30 min of recovery, cBRS returned to baseline in men but remained elevated in women. HR decreased 10 min after IHG in men (10 min: Delta-2 +/- 1 bpm, P < 0.01 vs rest; 20 min: Delta-1 +/- 1 bpm, P = 0.39 vs rest; 30 min: Delta1 +/- 1 bpm, P = 0.31 vs rest) and throughout recovery in women (10 min: Delta-5 +/- 1 bpm, P < 0.01 vs rest; 20 min: Delta-3 +/- 1 bpm, P < 0.01 vs rest; 30 min: Delta-2 +/- 1 bpm, P < 0.01 vs rest). Systolic BP increased 10 min after IHG and remained elevated during 20 min and 30 min in men (P < 0.05). In women, systolic BP increased during 10 min (P < 0.01) and returned to baseline during 20 and 30 min of recovery. Time-domain HR variability (root mean square of successive differences) was increased during recovery in men and women (P < 0.05). Sham had no effect on any variables. CONCLUSIONS: Acute IHG exercise increases cBRS and cardiac vagal activity in healthy young subjects, but the magnitude and the time course of changes in cBRS differ between men and women. PMID- 29135602 TI - Ocular Surface Alterations in the Context of Corneal In Vivo Confocal Microscopic Characteristics in Patients With Fibromyalgia. AB - PURPOSE: To quantify the morphology of corneal basal epithelium and subbasal nerves and to evaluate the ocular surface alterations in patients with fibromyalgia (FM). METHODS: Patients with FM (n = 34) and healthy controls (n = 42) were enrolled. All participants underwent ocular surface tests in the following order: corneal sensitivity, tear film breakup time, lissamine green staining, Schirmer test, and the Ocular Surface Disease Index questionnaire. Basal epithelial cells and subbasal nerves were evaluated using in vivo confocal microscopy (IVCM). Demographic characteristics, Visual Analog Scale for Pain (VAS), American College of Rheumatology 1990, the Widespread Pain Index (WPI), and the Symptom Impact Questionnaire (SIQR) scores of patients with FM were obtained. RESULTS: Corneal sensitivity was 0.4 g/mm (fiber length: 6.0 cm) in all eyes. Patients with FM had a higher Ocular Surface Disease Index (42.2 +/- 18.9 vs. 1.2 +/- 1.7, P < 0.001), higher lissamine green staining scores (0.5 +/- 0.5 vs. 0.05 +/- 0.2, P < 0.001), and lower tear breakup time scores (9.0 +/- 3.6 vs. 10.3 +/- 1.5, P = 0.003) than the controls. Basal epithelial cell density (2709 +/- 494 vs. 4491 +/- 724), total nerve density (1563 +/- 620 vs. 2545 +/- 973), long nerve fibers (3.4 +/- 1.3 vs. 4.5 +/- 1.0), and the number of nerves (5.0 +/ 1.8 vs. 10.3 +/- 2.1) were all lower in patients with FM compared with those of the controls (P < 0.001 for all). There was a statistically significant negative correlation between the WPI score and Schirmer test results (rho = -0.374, P = 0.03) and between WPI and total nerve density (rho = -0.334, P = 0.054). CONCLUSIONS: To the best of our knowledge, this is the first study that evaluated ocular surface alterations in the context of corneal IVCM characteristics. Patients with FM should be evaluated in terms of ocular surface diseases. IVCM may be used in FM to assess small fiber neuropathy. PMID- 29135603 TI - Role of Hemidivisional Corneal Topographic Astigmatisms (CorTs) in the Regularization and Reduction of Irregular Astigmatism. AB - PURPOSE: To demonstrate how the concept of hemidivisional corneal topographic astigmatism (hemiCorT) enables the planning of hemidivisional corneal treatments to reduce irregularity and overall astigmatism. METHODS: Whole-of-cornea corneal topographic astigmatism (CorT) is calculated from topography data derived from a corneal topographer or tomographer. The cornea is conceptually divided into 2 hemidivisions along the flat meridian of the CorT. For each hemidivision, hemiCorTs are calculated. The regularization treatment for each hemidivision is the treatment required to target the whole-of-cornea CorT, which is a symmetrical orthogonal corneal astigmatism. The regularization is then combined with astigmatism reduction treatment, which could be a conventional refractive treatment or a vector-planned treatment. For each hemidivision, the combined astigmatic effect of the regularization treatment and reduction treatment can be determined through double-angle vector summation. The 2 hemidivisional treatments together regularize and reduce corneal astigmatism. RESULTS: A theoretical pair of hemidivisional treatments is derived from an actual example of a cornea displaying idiopathic asymmetric nonorthogonal astigmatism. CONCLUSIONS: HemiCorTs allow for the design of hemidivisional corneal treatments of asymmetric nonorthogonal astigmatism. Such treatments should be suitable in the routine treatment of commonly occurring irregular astigmatism, while also allowing the spherical refractive error to be treated concurrently. PMID- 29135604 TI - Chemical Burns of the Eye: The Role of Retinal Injury and New Therapeutic Possibilities. AB - PURPOSE: To propose a new treatment paradigm for chemical burns to the eye - in the acute and chronic phases. METHODS: Recent laboratory and clinical data on the biology and treatment of chemical burns are analyzed. RESULTS: Corneal blindness from chemical burns can now be successfully treated with a keratoprosthesis, on immediate and intermediate bases. Long term outcomes, however, are hampered by early retinal damage causing glaucoma. New data suggest that rapid diffusion of inflammatory cytokines posteriorly (TNF-alpha, etc) can severely damage the ganglion cells. Prompt anti-TNF-alpha treatment is markedly neuroprotective. Long term profound reduction of the intraocular pressure is also vital. CONCLUSION: A new regimen, in addition to standard treatment, for severe chemical burns is proposed. This involves tumor necrosis factor alpha (TNF-alpha) inhibition promptly after the accident (primarily for retinal neuroprotection), prophylactic maximal lowering of the intraocular pressure (starting immediately), and keratoprosthesis implantation in a later quiet state. PMID- 29135605 TI - Novel Method to Detect Corneal Lymphatic Vessels In Vivo by Intrastromal Injection of Fluorescein. AB - PURPOSE: Corneal lymphatic vessels are clinically invisible because of their thin walls and clear lymph fluid. There is no easy and established method for in vivo imaging of corneal lymphatic vessels so far. In this study, we present a novel approach to visualize corneal lymphatic vessels in vivo by injecting intrastromal fluorescein sodium. METHODS: Six- to eight-week-old female BALB/c mice were used in the mouse model of suture-induced corneal neovascularization. Two weeks after the suture placement, fluorescein sodium was injected intrastromally. The fluorescein, taken up by the presumed lymphatic vessels, was then tracked using a clinically used Spectralis HRA + OCT device. Immunohistochemistry staining with specific lymphatic marker LYVE-1 and pan-endothelial marker CD31 was used to confirm the indirect lymphangiography findings. RESULTS: By injecting fluorescein intrastromally, both corneal blood and lymphatic vessels were detected. While the lymphatic vessels were visible as bright vessel-like structures using HRA, the blood vessels appeared as dark networks. Fluorescein-labeled lymphatic vessels were colocalized with LYVE-1 in immunohistochemically stained sections of the same specimen. CONCLUSIONS: Corneal lymphatic vessels can be easily imaged in vivo in the murine model using intrastromal fluorescein injection. PMID- 29135606 TI - Reply. PMID- 29135607 TI - Targeting the perivascular niche in brain tumors. AB - PURPOSE OF REVIEW: Brain tumors are composed of primary tumors of the central nervous system, such us glioblastoma (GBM), and secondary metastatic tumors, such as melanoma, non-Hodgkin lymphoma as well as lung and breast cancers. Brain tumors are highly deadly, and unfortunately not many improvements have been achieved to improve the survival of patients with brain tumors. Chemoradiation resistance is one of the most clinically relevant challenges faced in patients with brain tumors. The perivascular niche is one of the most relevant microenvironment hubs in brain tumors. The understanding of the cellular crosstalk established within the brain tumor perivascular niche might provide us with key discoveries of new brain tumor vulnerabilities. RECENT FINDINGS: Radio and chemoresistance in GBM and brain metastases is attributed to cancer stem cells (CSCs), which intrinsically modulate several pathways that make them resistant to therapy. Growing evidence, however, highlights the perivascular space as a niche for CSC survival, resistance to therapy, progression and dissemination. Here, I review the latest discoveries on the components and features of brain tumor vascular niches and the possible therapeutic strategies aimed at targeting its vulnerabilities, thus preventing GBM and metastasis chemoradiation resistance and recurrence. SUMMARY: Recent discoveries suggest that targeting the brain perivascular niche has the potential of sensitizing brain tumors to therapies and reducing the occurrence of metastases. PMID- 29135609 TI - Is Minimally Invasive Transforaminal Interbody Fusion Superior to Traditional Open Technique? PMID- 29135608 TI - The Epidemiology of Vertebral Osteomyelitis in the United States From 1998 to 2013. AB - STUDY DESIGN: This is a epidemiological database analysis. OBJECTIVES: The objectives of this article are to assess the following characteristics of vertebral osteomyelitis (VO): (1) incidence and patient demographics, (2) mortality rate, (3) length-of-stay (LOS), and (4) admission costs. SUMMARY OF BACKGROUND: VO is a serious disease with potentially devastating clinical consequences. At present, there is limited data on the epidemiology of VO in the United States as previous reports are based on older studies with small sample sizes. METHODS: We used the Nationwide Inpatient Sample database and estimated that 228,044 patients were admitted for VO in the United States between 1998 and 2013. Data were extracted on patient demographics, comorbidities, inpatient mortality, LOS, and inflation-adjusted hospitalization charges. Multivariable regression analyses were performed. RESULTS: The incidence of VO admission was 4.8 per 100,000, increasing from 8021 cases (2.9/ 100,000) in 1998 to 16,917 cases (5.4/100,000) in 2013. Majority of patients were white (74%), male (51%), younger than 59 years of age (49.5%), and carried Medicare insurance (50%). The increase in incidence for male and females was similar. The mortality rate during hospital stay was 2.1%, decreasing from 2% in 1998 to 1.7% in 2006 and increasing to 2.2% in 2013. Risk factors for mortality included increased age, male sex, and higher comorbidity score. History of congestive heart failure [odds ratio (OR)=2.45], cerebrovascular disease (OR=1.92), liver disease (OR=2.33), hepatitis C (OR=2.36), and renal disease (OR=1.88) was associated with higher mortality rate. Mean LOS was 9.2 days, decreasing from 9.1 days in 1998 to 8.8 days in 2013. The mean estimated hospital charges for admission were $54,599, however, this increased from $24,102 in 1998 (total of $188.8 millions) to $80,786 in 2013 (total of $1.3 billions). CONCLUSION: This condition is associated with lengthy and expensive hospital stays resulting in a significant burden to patients and the health care system. PMID- 29135610 TI - Meralgia Paresthetica After Spine Surgery on the Jackson Table. AB - Meralgia paresthetica is a non-life-threatening neurological disorder characterized by numbness, tingling, and burning pain over the anterolateral thigh due to impingement of the lateral femoral cutaneous nerve. This disorder has been seen in patients with diabetes mellitus and obesity, but has also been observed in patients after procedures such as posterior spine surgery, iliac crest bone grafts, lumbar disk surgery, hernia repair, appendectomies, and pelvic osteotomies that ultimately lead to compression or damage to the lateral femoral cutaneous nerve. Overall, permanent sequelae of meralgia paresthetica are rare, however, some cases do require intervention. PMID- 29135611 TI - 18F-FDG PET/CT of Generalized Arteritis. AB - A 75-year-old man presented with significant weight loss, persistent cough, single episode of frontotemporal pulsatile headache, and leg weakness. A paraneoplastic syndrome was suspected, and F-FDG PET/CT was performed. Diffuse, moderate-to-intense tracer symmetrical uptake of many large and medium arteries was unexpectedly noted. The peculiarity of this case is the extensive involvement of both large and medium head and neck and extremity vessels, whereas the aorta was relatively spared. PMID- 29135612 TI - Solitary Orbital Metastasis in Carcinoma Esophagus: Findings on Serial 18F-FDG PET/CT Scans. AB - Orbital metastasis is an uncommon and atypical presentation of recurrent esophageal cancer that has been only seldom reported in literature. F-FDG PET/CT is routinely performed for staging and response assessment in patients with esophageal carcinoma. This case demonstrates use of follow-up FDG PET/CT scans in characterizing solitary metastatic disease in orbit and in evaluating response to therapy. It also highlights a key teaching point that postradiation-related inflammatory/infective changes may interfere in accurate assessment of PET/CT scan; however, frequently used clinical and radiological correlation may not be entirely sufficient to rule out pathological involvement. PMID- 29135613 TI - 68Ga-DOTATATE Uptake in Ischemic Stroke. AB - A 76-year-old man known to have a pancreatic neuroendocrine tumor with hepatic and lymph nodes metastasis had a follow-up Ga-DOTATATE PET/CT before Lu-DOTATATE therapy. A new cerebral lesion expressing somatostatin receptors was discovered in the right temporal lobe, suggestive of an ischemic stroke territory. This was later confirmed from the hospital chart where an ischemic stroke was described a month ago. PMID- 29135614 TI - Improving the Work Life of Health Care Workers: Building on Nursing's Experience. PMID- 29135616 TI - Intermittent extracorporeal CO2 removal in chronic obstructive pulmonary disease patients: a fiction or an option. AB - PURPOSE OF REVIEW: Aim of this article is to review evidence recently generated on the application of extracorporeal carbon dioxide removal (ECCO2R) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation (invasive and non invasive) for hypercapnic respiratory failure. RECENT FINDINGS: To date, the paucity of evidences on ECCO2R to decrease the rate of noninvasive ventilation (NIV) failure and to wean hypercapnic patients from invasive mechanical ventilation (IMV) precludes to systematically apply this technology to COPD patients. SUMMARY: Although several efforts have been made to reduce invasiveness and to improve the efficiency of extracorporeal systems, further randomized studies are needed to assess the effects of this technique on both short-term and long-term clinical outcomes. PMID- 29135615 TI - Diffusion of Bevacizumab Across Oncology Practices: An Observational Study. AB - BACKGROUND: Technological advances can improve care and outcomes but are a primary driver of health care spending growth. Understanding diffusion and use of new oncology therapies is important, given substantial increases in prices and spending on such treatments. OBJECTIVES: Examine diffusion of bevacizumab, a novel (in 2004) and high-priced biologic cancer therapy, among US oncology practices during 2005-2012 and assess variation in use across practices. RESEARCH DESIGN: Population-based observational study. SETTING: A total of 2329 US practices providing cancer chemotherapy. PARTICIPANTS: Random 20% sample of 236,304 Medicare fee-for-service beneficiaries aged above 65 years in 2004-2012 undergoing infused chemotherapy for cancer. MEASURES: Diffusion of bevacizumab (cumulative time to first use and 10% use) in practices, variation in use across practices overall and by higher versus lower-value use. We used hierarchical models with practice random effects to estimate the between-practice variation in the probability of receiving bevacizumab and to identify factors associated with use. RESULTS: We observed relatively rapid diffusion of bevacizumab, particularly in independent practices and larger versus smaller practices. We observed substantial variation in use; the adjusted odds ratio (95% confidence interval) of bevacizumab use was 2.90 higher (2.73-3.08) for practices 1 SD above versus one standard deviation below the mean. Variation was less for higher-value [odds ratio=2.72 (2.56-2.89)] than lower-value uses [odds ratio=3.61 (3.21-4.06)]. CONCLUSIONS: Use of bevacizumab varied widely across oncology practices, particularly for lower-value indications. These findings suggest that interventions targeted to practices have potential for decreasing low-value use of high-cost cancer therapies. PMID- 29135617 TI - Lessons to learn from epidemiologic studies in ARDS. AB - PURPOSE OF REVIEW: Recent advances in our understanding of the epidemiology of ARDS has generated key insights into the incidence, risk factors, demographics, management and outcomes from this devastating clinical syndrome. RECENT FINDINGS: ARDS occurs in 10% of all ICU patients, in 23% of all mechanically ventilated patients, with 5.5 cases per ICU bed each year. Although some regional variation exists regarding ARDS incidence, this may be less than previously thought. Subphenotypes are increasingly identified within the ARDS cohort, with studies identifying a 'hyperinflammatory' or 'reactive' subgroup that has a higher mortality, and may respond differently to therapeutic interventions. Demographic factors, such as race, may also affect the therapeutic response. Although mortality in ARDS is decreasing in clinical trials, it remains unchanged at approximately 40% in major observational studies. Modifiable ventilatory management factors, including PEEP, airway pressures, and respiratory rate are associated with mortality in ARDS. Hospital and ICU organizational factors play a role in outcome, whereas socioeconomic status is independently associated with survival in patients with ARDS. The Kigali adaptation of the Berlin ARDS definition may provide useful insights into the burden of ARDS in the developing world. SUMMARY: ARDS exerts a substantial disease burden, with 40% of patients dying in hospital. Diverse factors, including patient-related factors such as age and illness severity, country level socioeconomic status, and ventilator management and ICU organizational factors each contribute to outcome from ARDS. Addressing these issues provides opportunities to improve outcome in patients with ARDS. PMID- 29135618 TI - Pathway for the Management of Hyperglycemia in the Cardiac Care Unit. AB - Inpatient hyperglycemia has been associated with increased morbidity and mortality in critically ill patients. Optimal control of blood glucose (BG) levels using insulin infusion protocols has been shown to improve clinical outcomes. Protocols have been developed to prescribe a safe and effective rate of insulin infusion for optimal control of BG levels; however, a major obstacle in their implementation is their complexity. We have revised and updated our previously published pathway for the management of hyperglycemia, which introduces the "wheel" concept for insulin dosing. The "wheel" serves as a treatment guide. It is made up of 6 concentric circles. The core circle represents the goal of BG in critically ill patients, with inner circle showing the actual BG range of the patient. The 4 outer circles correspond to increasing rates of insulin infusion from tier 1 to tier 4. Simple guidelines are provided to facilitate conversion from insulin infusion to a subcutaneous insulin-delivery regimen in preparation for transfer from the cardiac care unit (CCU) setting. Our protocols also provide guidelines for management of diabetic ketoacidosis and hyperosmolar hyperglycemic states while at the same time creates a flowchart for activation of diabetes care team and their involvement in the multidisciplinary care of a patient in CCU with hyperglycemia and/or diabetes mellitus. This pathway provides a comprehensive and detailed, yet simple and practical algorithm for management of hyperglycemia in the CCU. PMID- 29135619 TI - The HEART Pathway and Hospital Cost Savings. AB - Chest pain is a common complaint in emergency departments. Several guidelines and tools exist to help the clinician determine need for hospitalization. For low risk patients, clinical judgment can underestimate a patient's risk of major adverse cardiac event. Implementation of an advanced diagnostic protocol with the HEART Pathway can reduce hospital cost. For our academic institution, we saw an approximate $1 million in total savings during the initial implementation year along with increased outpatient visits. In addition, an increase in outpatient visits confirmed previous estimates that implementation of the HEART Pathway results in >20% reduction of hospital costs. We also identify challenges and considerations for facilities looking to repeat our successes. PMID- 29135620 TI - Safety of a 1-hour Rule-out High-sensitive Troponin T Protocol in Patients With Chest Pain at the Emergency Department. AB - BACKGROUND: The 1-hour rule-out high-sensitive cardiac troponin T protocol (hs cTnT), in which a serial troponin measurement is performed 1 hour after the first to assess the possibility of acute coronary syndrome (ACS), has been implemented in the European guidelines in 2015. Our aim was to assess the safety of this protocol in low-risk patients in the Emergency Department (ED) when implemented in daily practice. METHODS: Patients with acute chest pain presenting to the ED of our hospital and younger than 75 years were included (May 2013 to October 2014, The Netherlands). Hs-cTnT was measured at presentation (T0) and 1-1.5 hours after T0 (T1). Patients with a first troponin (T0) >= 0.012 ug/l were excluded. Primary endpoint was the 6-week occurrence of major adverse cardiac events (MACEs), defined as unstable angina, acute myocardial infarction (AMI), percutaneous coronary intervention, significant stenosis managed conservatively, coronary artery bypass grafting, and death. RESULTS: Of the 374 analyzed patients, 16 patients (4.3%) developed 35 MACE. Of these 16 patients with endpoints, 3 were primarily discharged with noncardiac chest pain but returned within 6 weeks with unstable angina. Importantly, no patients experienced an AMI or died during follow-up. CONCLUSION: No AMIs or deaths occurred after introducing the 1-hour hs-cTnT protocol to rule-out ACS in chest pain patients, but other MACE such as unstable angina occurred. Our results suggest the protocol is safe to implement in the ED in The Netherlands. PMID- 29135621 TI - Efficacy of Implementation of a Chest Pain Center at a Community Hospital. AB - INTRODUCTION: Chest pain is the second leading cause for emergency department (ED) visits in the United States; however, <20% of the patients have acute coronary syndrome that require immediate attention. The HEART score is designed for rapid risk stratification of ED chest pain patients using the following criteria: history, electrocardiogram, age, risk factors, and troponin. It has been shown to be superior in identifying patients with low (HEART score 0-3) and high (7-10) risk of major adverse cardiac events, who can then be rapidly discharged or admitted for intervention. OBJECTIVE: This retrospective review and assessment sought to evaluate the efficacy of implementation of a Chest Pain Center (CPC) at a predominantly Asian-based community hospital in the United States. Additionally, this assessment sought to evaluate the effectiveness and safety of a HEART protocol in the first 4 months after its adoption. MATERIALS AND METHODS: The facility implemented the CPC, an observation unit, in October 2016. ED physicians risk stratified patients using the HEART score. The guidelines allow ED physicians to stratify patients into 3 categories: to discharge low-risk patients, observe moderate-risk patients in the CPC, and admit high-risk patients. Patients in the CPC received additional diagnostic work-up under the care of ED physicians and cardiologists for less than 24 hours. In addition, CPC patients were followed-up 2 and 30 days after discharge. RESULTS: A total of 172 patients presented at the ED with a chief complaint of chest pain. The majority of the patients were classified into the moderate-risk group (n = 101). Low-risk patients spent significantly less hours in the hospital than the moderate- and high-risk groups, and the high-risk group spent more time in the hospital than the moderate-risk group. The staff followed-up with 74 CPC patients through telephone calls to assess if patients were still experiencing chest pain and if they had followed-up with a cardiologist or primary care physician. The 2- and 30-day survival rates were 100% and 97%, respectively. DISCUSSION: The data showed a significant reduction in total length of stay for all chest pain patients. This retrospective program evaluation demonstrated some evidence in using HEART score to safely risk stratify chest pain patients to the appropriate level of care. As healthcare moves from a fee-for-service environment to value based purchasing, hospitals need to devise and implement innovative strategies to provide efficient, beneficial, and safe care for the patients. PMID- 29135622 TI - Troponin Limit of Detection Plus Cardiac Risk Stratification Scores to Rule Out Acute Myocardial Infarction and 30-Day Major Adverse Cardiac Events in ED Patients. AB - When screening for acute myocardial infarction (AMI), troponin levels below the 99th percentile, including those below the limit of detection (LOD), are considered normal. We hypothesized that a low-risk HEART score (0-3) or ACS Pretest Probability Assessment <2% plus a single troponin below the LOD would rule out both AMI and 30-day major adverse cardiac events (MACE). We studied all patients who presented to a single academic emergency department and received a troponin I (Siemens Ultra Troponin I) from September 1, 2013, to November 13, 2013 (n=888). Demographic and clinical data were abstracted from the electronic medical record. Primary outcome was a final encounter diagnosis of myocardial infarction. Secondary outcome was 30-day MACE, defined as composite of myocardial infarction, revascularization, or death from a cardiac or uncertain etiology. Sensitivities of low-risk HEART score and ACS Pretest Probability <2% alone were 98% (95% confidence interval [CI], 89%-100%) and 96% (95% CI, 86%-100%) for AMI and 94% (95% CI, 86%-98%) and 95% (95% CI, 88%-99%), respectively, for 30-day MACE. When combined with troponin below the LOD, sensitivity for AMI was 100% (95% CI, 93%-100%; difference 2%; 95% CI, -2% to 6%) for low-risk HEART Score and 100% (95% CI, 93%-100%; difference 4%; 95% CI, -1.5% to 10%) for ACS Pretest Probability <2%. When combined with troponin below the LOD, sensitivity for 30 day MACE was 100% (95% CI, 95%-100%; difference 6%; 95% CI, 1%-12%) for low-risk HEART Score and 100% (95% CI, 95%-100%; difference 5%; 95% CI, 0.2%-10%) for ACS Pretest Probability <2%. Addition of a single troponin below the LOD to these scores improves sensitivity for 30-day MACE. PMID- 29135623 TI - Patient Ethnicity Predicts Poor Health Access and Gaps in Perception of Personal Cardiovascular Risk Factors. AB - BACKGROUND: Focus of health literacy campaigns has centered around raising awareness. It is unknown whether awareness of coronary artery disease risk factors accurately reflects personalization of one's own cardiovascular risk. METHODS: A cross-sectional survey was performed in consecutive patients presenting with chest pain admitted to an observation unit of a tertiary care hospital. A 32-item questionnaire in English or Spanish examined knowledge of coronary artery disease risk factors. Separately, the personalization of coronary risk factors was determined by having patients list their individual risk factors for having a heart attack. Primary outcome was the evaluation of ethnic disparities in awareness of cardiovascular risk factors and the patient's misperceptions on personal risk factors. Secondary outcome was the assessment of access to information in the same population by gender and ethnicity. RESULTS: Between October 2006 and April 2008, 1584 consecutive patients were screened, and 1051 patients were enrolled. Participants were 57.5% female and 62.8% self identified White, 22.5% Black, and 11.5% Hispanic. Misperception about personal risk was significantly higher in non-White compared with the White participants for diabetes (in Blacks [odds ratio (OR), 2.22; 95% confidence interval (CI), 1.08-5.57] and Hispanics [OR, 3.50; 95% CI, 1.49-8.20]) and for hyperlipidemia (in Hispanics [OR, 2.21; 95% CI, 1.19-4.10]). Although the majority (85%) had a primary care physician, Blacks and Hispanics were less likely to have access to information (OR, 0.25; 95% CI, 0.10-0.49; and OR, 0.71; 95% CI, 0.37-1.04, respectively). CONCLUSIONS: There are major gaps between awareness and personalization of risk in major modifiable coronary artery disease risk factors in different ethnic groups. PMID- 29135624 TI - Potassium Chloride Sustained Release Dosing Pathway in an Academic Medical Center. AB - Potassium supplementation can be administered intravenously or orally with either immediate release or sustained release formulations. Sustained release potassium chloride allows for delayed absorption and peak effects. In the inpatient setting, it is important to monitor and prevent both hypokalemia and hyperkalemia. Our tertiary-care academic hospital created a clinical pathway for sustained release potassium chloride supplementation in the inpatient population. Our clinical pathway for sustained release potassium chloride creates dosing restrictions designed to prevent hyperkalemia, while allowing exceptions for patients with high requirements. PMID- 29135625 TI - Impact of Sex on Long-term Clinical Outcomes After Percutaneous Coronary Intervention. AB - AIMS: To evaluate the impact of sex on long-term clinical outcomes after percutaneous coronary intervention (PCI). METHODS: In a large prospective cohort, 5664 patients (1716 women and 3948 men) who underwent PCI in a tertiary cardiac center between March 2007 and March 2010 were enrolled. Patients were followed up for median of 74.3 months. We compared the occurrence of long-term mortality, myocardial infarction (MI), and repeated revascularization between 2 sexes. Major adverse cardiac events were defined as a composite end point consisting of occurrence of all-cause mortality, nonfatal MI, or target vessel revascularization during follow-up period. RESULTS: Women were older and had more conventional coronary artery disease risk factors, had smaller vessel diameter, and received drug-eluting stents more frequently than men. On the contrary, men were much more smokers and had higher frequency of acute coronary syndrome, multivessel disease, total coronary occlusion, and lower ejection fraction. After >6 years of follow-up, the all-cause mortality, nonfatal MI, target vessel revascularization, major adverse cardiac events, patient-oriented composite end point, and total repeat PCI were similar between 2 sexes. After adjusting for potential confounders, the total repeat PCI was the only observed difference that was significantly lower in women [11.2% in women vs. 12.4% in men, adjusted subdistributional hazard ratio=0.73 (95% confidence interval, 0.6-0.88); P = 0.001). CONCLUSIONS: During >6 years of follow-up, no significant difference was observed in major clinical outcomes between 2 sexes. PMID- 29135626 TI - Community Outreach in Terms of Early Heart Attack Care as a New Way of Thinking in Chest Pain Center/Unit Care Giving-Commentary on the German Chest Pain Unit Network. PMID- 29135627 TI - Quantitative Computed Tomography Metrics From the Transplanted Lung can Predict Forced Expiratory Volume in the First Second After Lung Transplantation. AB - PURPOSE: Bronchiolitis obliterans syndrome after lung transplantation (LTx) manifests as a sustained decline in forced expiratory volume in the first second (FEV1). Quantitative computed tomography (QCT) metrics may predict FEV1 better than semiquantitative scores (SQSs), and the transplanted lung may provide better information than the native lung in unilateral LTx. MATERIALS AND METHODS: Paired inspiratory-expiratory CT scans and pulmonary function testing of 178 LTx patients were analyzed retrospectively. SQS were graded (absent, mild, moderate, severe) for features including mosaic attenuation and bronchiectasis. QCT included lung volumes and air-trapping volumes, by lobe. Multivariate Pearson correlation and multivariate linear least squares regression analyses were performed. RESULTS: Multivariate linear least squares regression models using FEV1 as the outcome variable and SQS or QCT metrics as predictor variables demonstrated SQS to be a weak predictor of FEV1 (adjusted R, 0.114). QCT metrics were much stronger predictors of FEV1 (adjusted R, 0.654). QCT metrics demonstrated stronger correlation (r) with FEV1 than SQS. In bilateral LTx, whole lung volume difference (r=0.69), left lung volume difference (r=0.69), and right lung volume difference (r=0.65) were better than the sum of SQS (r=-0.54). Interestingly, in left LTx we obtained r=0.81, 0.86, 0.25, and -0.39, respectively. In right LTx, we obtained r=0.69, 0.49, 0.68, and -0.31, respectively. CONCLUSIONS: QCT metrics demonstrate stronger correlations with FEV1 and are better predictors of pulmonary function than SQS. SQS performs moderately well in bilateral LTx, but poorly on unilateral LTx. In unilateral LTx, QCT metrics from the transplanted lung are better predictors of FEV1 than QCT metrics from the nontransplanted lung. PMID- 29135629 TI - The use of pulsed CO2 lasers for the treatment of vulvovaginal atrophy: Erratum. PMID- 29135628 TI - Endothelial factors in the pathogenesis and treatment of chronic kidney disease Part II: Role in disease conditions: a joint consensus statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors and the Japanese Society of Hypertension. AB - : After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes. PMID- 29135630 TI - News and Views on Caffeine, Creatine Kinase Levels, and Sickle Cell Trait. PMID- 29135632 TI - Cervical Spine Injuries. PMID- 29135633 TI - Manipulating Cadence for Gait Re-training in Runners. PMID- 29135634 TI - Clearance and Return to Play for the Female Athlete Triad: Clinical Guidelines, Clinical Judgment, and Evolving Evidence. PMID- 29135635 TI - Acute Occlusion of Brachial Artery Caused by Blunt Trauma in Football Player: Case Report and Review of the Literature. PMID- 29135636 TI - Track and Field Throwing Sports: Injuries and Prevention. AB - Throwing events in track and field are among the oldest sporting events in recorded history and include shot put, discus, hammer, and javelin. All throwing athletes use the kinetic chain to transfer energy from the lower extremities, through the pelvis, trunk, shoulder, arm, wrist, hand, and finally into the implement to generate maximum force. Throughout this sequential activation, mobilization, and stabilization of body segments, there is opportunity for breakdown in the chain, which can lead to injury. This review describes the biomechanics and kinetic chain components of each event and highlights injuries common among all throwers as well as injuries unique to each event. The cornerstone of prevention is practicing and competing with proper technique. It is important to understand the breadth of injuries that can affect these athletes to develop evidence based diagnosis, treatment, and prevention strategies. PMID- 29135637 TI - Triathlon Injuries: Transitioning from Prevalence to Prediction and Prevention. AB - The Ironman triathlon began in Hawaii in 1978 with 50 participants. Since then, the race has continued to grow in popularity. Injuries are very common among triathletes. Studies have looked at the relationship between injuries and many different factors. Sex, age, and morphological characteristics, such as height, weight, and body mass index, have not been shown to correlate with injury. The association between training volume and injury has shown inconsistent results. This could be due to multiple factors in study design including definitions and evaluation of training volume. Recent literature highlights the complex relationship between risk factors and injury occurrence. This article reviews the epidemiology and risk factors for musculoskeletal injuries in Ironman distance triathletes as well as general research and theories on training volume assessment and injury risk to provide recommendations for future studies and strategies for injury prevention. PMID- 29135638 TI - Mountain Biking Injuries. AB - With the increasing popularity of mountain biking, also known as off-road cycling, and the riders pushing the sport into extremes, there has been a corresponding increase in injury. Almost two thirds of acute injuries involve the upper extremities, and a similar proportion of overuse injuries affect the lower extremities. Mountain biking appears to be a high-risk sport for severe spine injuries. New trends of injury patterns are observed with popularity of mountain bike trail parks and freeride cycling. Using protective gear, improving technical proficiency, and physical fitness may somewhat decrease the risk of injuries. Simple modifications in bicycle-rider interface areas and with the bicycle (bike fit) also may decrease some overuse injuries. Bike fit provides the clinician with postural correction during the sport. In this review, we also discuss the importance of race-day management strategies and monitoring the injury trends. PMID- 29135639 TI - Sleep and Athletic Performance. AB - Sleep is an essential component of health and well-being, with significant impacts on physical development, emotional regulation, cognitive performance, and quality of life. Along with being an integral part of the recovery and adaptive process between bouts of exercise, accumulating evidence suggests that increased sleep duration and improved sleep quality in athletes are associated with improved performance and competitive success. In addition, better sleep may reduce the risk of both injury and illness in athletes, not only optimizing health but also potentially enhancing performance through increased participation in training. Despite this, most studies have found that athletes fail to obtain the recommended amount of sleep, threatening both performance and health. Athletes face a number of obstacles that can reduce the likelihood of obtaining proper sleep, such as training and competition schedules, travel, stress, academic demands, and overtraining. In addition, athletes have been found to demonstrate poor self-assessment of their sleep duration and quality. In light of this, athletes may require more careful monitoring and intervention to identify individuals at risk and promote proper sleep to improve both performance and overall health. This review attempts to highlight the recent literature regarding sleep issues in athletes, the effects of sleep on athletic performance, and interventions to enhance proper sleep in athletes. PMID- 29135640 TI - Neuromechanical Considerations for Postconcussion Musculoskeletal Injury Risk Management. AB - Recent epidemiological studies have documented increased susceptibility to musculoskeletal injury after sport-related concussion, which raises questions about the adequacy of current clinical practices to ensure safe return to sport. A growing body of evidence derived from advanced neuroimaging and neurological assessment methods strongly suggests that mild traumatic brain injury has long lasting adverse effects that persist beyond resolution of clinical symptoms. Plausible interrelationships among postconcussion changes in brain structure and function support the rationale for specific methods of clinical assessment and training to target the interaction of cognitive and motor function for reduction of musculoskeletal injury risk after concussion. The findings of preliminary clinical studies are presented to support suggested strategies for reduction of postconcussion musculoskeletal injury risk, and to identify novel approaches that we consider worthy areas for further research. PMID- 29135641 TI - The Pediatric Endurance Athlete. AB - Youth sports participation numbers continue to grow in the United States. A shift toward sport specialization has caused an increase in sport training frequency and intensity that places the growing athlete at risk for overtraining, nutritional deficits, and injuries. Individuals who participate in endurance sports are at especially high risk. Youth runners and swimmers are high-risk populations that require special attention to their training schedules, nutritional intake, and injuries. Appropriate scheduling of training, dedicating time to rest, and nutrition education can help prevent problems in the endurance athlete. PMID- 29135642 TI - Introduction to the Special Issue: Pertinent Topics in Sports Medicine. PMID- 29135643 TI - Featuring Martin Schwellnus, MBBCh, MSc (Med), MD, FACSM, FFIMS. PMID- 29135644 TI - Early Sports Specialization: An International Perspective. PMID- 29135645 TI - Phosphodiesterase Type 5 Inhibitors, Sport and Doping. AB - Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors. PMID- 29135646 TI - Foot Structure and Function in Habitually Barefoot and Shod Adolescents in Kenya. AB - : Habitually barefoot (HB) children from the Kalenjin tribe of Kenya are known for their high physical activity levels. To date, there has been no comprehensive assessment of foot structure and function in these highly active and HB children/adolescents and link with overuse injuries. PURPOSE: The aim of this research is to assess foot structure, foot function, injury and physical activity levels in Kenyan children and adolescents who are HB compared with those who were habitually shod (HS). METHODS: Foot structure, function, injury prevalence, and physical activity levels were studied using two studies with equal numbers of HS and HB. HS and HB children and adolescents were matched for age, sex, and body mass. Foot arch characteristics, foot strength, and lower-limb injury prevalence were investigated in Study 1 (n = 76). Heel bone stiffness, Achilles tendon moment arm length and physical activity levels in Study 2 (n=62). Foot muscle strength was measured using a strength device TKK 3360 and heel bone stiffness by bone ultrasonometry. The moment arm length of the Achilles tendon was estimated from photographs and physical activity was assessed using questionnaires and accelerometers. RESULTS: Foot shortening strength was greater in HB (4.8 +/- 1.9 kg vs 3.5 +/- 1.8 kg, P < 0.01). Navicular drop was greater in HB (0.53 +/- 0.32 cm vs 0.39 +/- 0.19 cm, P < 0.05). Calcaneus stiffness index was greater (right 113.5 +/- 17.1 vs 100.5 +/- 116.8, P < 0.01 left 109.8 +/- 15.7 vs 101.7 +/- 18.7, P < 0.05) and Achilles tendon moment arm shorter in HB (right, 3.4 +/- 0.4 vs 3.6 +/- 0.4 cm, P < 0.05; left, 3.4 +/- 0.5 vs 3.7 +/- 0.4 cm, P < 0.01). Lower-limb injury prevalence was 8% in HB and 61% in HS. HB subjects spent more time engaged in moderate to vigorous physical activity (60 +/- 26 min.d vs 31 +/- 13 min.d; P < 0.001). CONCLUSIONS: Significant differences observed in foot parameters, injury prevalence and general foot health between HB and HS suggest that footwear conditions may impact on foot structure and function and general foot health. HB children and adolescents spent more time engaged in moderate to vigorous physical activity and less time sedentary than HS children and adolescents. PMID- 29135647 TI - The Role of Platelet-Rich Plasma in Muscle Healing. AB - The healing of a muscle injury is a complex and dynamic process characterized by different overlapping phases resulting in the restoration of the anatomic continuity and function. This process, triggered by the tissue injury itself, is modulated by different growth factors capable of directing the recruitment, duplication, activation, and differentiation of different cell types. This key role played by different growth factors is the basis of the use of platelet-rich plasma in several circumstances, all of them characterized by the need of activating or ameliorating the process of tissue repair. There is an extensive documentation of in vitro and in vivo studies demonstrating the safety and efficacy of growth factors in the muscle healing process. Unfortunately, for many different reasons, experimental results are usually difficult to interpret, clinical results are controversial, and the relevance of use is still debatable. The present article aims to review the available scientific literature with particular focus on actual clinical applications. PMID- 29135648 TI - The Presented Evidence to Support Symptomatic Hypovolemic-Associated EAH Is Not Convincing. PMID- 29135649 TI - Response to Letter-to-the-Editor "The Presented Evidence to Support Symptomatic Hypovolemic-Associated EAH Is Not Convincing". PMID- 29135651 TI - Comparison of the Pharmacokinetics and Pharmacodynamics of Single-Dose Tenofovir Vaginal Film and Gel Formulation (FAME 05). AB - OBJECTIVE: Although preexposure prophylaxis with oral tenofovir (TFV) disoproxil fumarate/emtricitabine reduces HIV acquisition rates, poor adherence to and acceptability of daily vaginal gels have led to development of vaginal film formulations to improve adherence and, potentially, to enable episodic use. STUDY DESIGN: In this 2-arm, cross-over study of a fast-dissolving tenofovir film (40 mg) compared with a previously studied semisolid tenofovir 1% gel (40 mg), 10 healthy women received a single vaginal dose of each study product. Clinical, pharmacokinetic, and antiviral assessments were performed over 1 week after dose. RESULTS: Nine of 10 participants experienced mild to moderate adverse effects, similar between products, with no severe adverse events or events attributed to study products. TFV concentrations after film dosing exceeded concentrations after gel dosing in plasma between 8 and 24 hours (P <= 0.02). TFV concentrations in cervicovaginal fluid and both TFV and TFV diphosphate concentrations in cervical tissue homogenates were higher after film dosing (all P values < 0.04). The differences ranged from median (interquartile range) 2.9-fold (1.1, 9.0; midvaginal cervicovaginal fluid) to 4.4-fold (2.9, 7.7; plasma). Neither film nor gel demonstrated reduced cervical tissue biopsy infectivity after ex vivo HIV challenge. CONCLUSION: Single-dose tenofovir film demonstrated consistently higher concentrations in plasma and cervicovaginal samples when compared with gel during the first day after dosing. Single-dose cervical tissue TFV-diphosphate concentrations at 5 hours exceeded steady-state concentrations previously reported with daily oral Truvada dosing. Tenofovir film may provide an alternative to tenofovir oral and gel formulations. Clinical efficacy remains to be tested. PMID- 29135652 TI - Are HIV Seroconversions Among Young Men Who Have Sex With Men Associated With Social Network Proximity to Recently or Long-Term HIV-Infected Individuals? AB - Debate remains as to the relative HIV transmission contributions from individuals who are recently HIV-infected and individuals who have long-term infections. In this study, we examine the relationship between new HIV seroconversions occurring among young black men who have sex with men and network proximity to recently or long-term HIV-infected individuals. A cohort of young black men who have sex with men (N = 618) was generated through respondent-driven sampling across 3 waves. A recent HIV infection was defined as either: (1) a confirmed seroconversion <=9 months before interview date or (2) a laboratory confirmed acute infection; long term HIV-infected individuals were defined as a diagnosis date >=9 months before interview date. Respondent-driven sampling-weighted logistic regression was used to examine network proximity of HIV transmission events to HIV-infected individuals in the network. Within the cohort, 343 (55.5%) participants were identified as HIV seronegative at baseline. Of these, 33 (9.6%) seroconverted during the study period. The odds of seroconversion increased significantly with each additional recent HIV-infected individual in one's network [adjusted odds ratio = 12.96; 95% confidence interval: 5.69 to 29.50], but were not significantly altered by the number of long-term infected individuals in one's network. In addition, for each member of one's network who used pre-exposure prophylaxis, the odds of seroconversion decreased significantly (adjusted odds ratio = 0.44; 95% confidence interval: 0.20 to 0.96). Early diagnosis and treatment is a critical first step in the HIV care continuum and together with pre-exposure prophylaxis awareness and use are critical targets for disrupting the transmission of HIV through most at-risk networks. PMID- 29135653 TI - People Born in Non-Main English Speaking Countries Are Less Likely to Start HIV Treatment Early in Australia: A National Cohort Analysis, 2014-15. PMID- 29135650 TI - Pathways From HIV-Related Stigma to Antiretroviral Therapy Measures in the HIV Care Cascade for Women Living With HIV in Canada. AB - BACKGROUND: Associations between HIV-related stigma and reduced antiretroviral therapy (ART) adherence are widely established, yet the mechanisms accounting for this relationship are underexplored. There has been less attention to HIV-related stigma and its associations with ART initiation and current ART use. We examined pathways from HIV-related stigma to ART initiation, current ART use, and ART adherence among women living with HIV in Canada. METHODS: We used baseline survey data from a national cohort of women living with HIV in Canada (n = 1425). Structural equation modeling using weighted least squares estimation methods was conducted to test the direct effects of HIV-related stigma dimensions (personalized, negative self-image, and public attitudes) on ART initiation, current ART use, and 90% ART adherence, and indirect effects through depression and HIV disclosure concerns, adjusting for sociodemographic factors. RESULTS: In the final model, the direct paths from personalized stigma to ART initiation (beta = -0.104, P < 0.05) and current ART use (beta = -0.142, P < 0.01), and negative self-image to ART initiation (beta = -0.113, P < 0.01) were significant, accounting for the mediation effects of depression and HIV disclosure concerns. Depression mediated the pathways from personalized stigma to ART adherence, and negative self-image to current ART use and ART adherence. Final model fit indices suggest that the model fit the data well [chi(25) = 90.251, P < 0.001; comparative fit index = 0.945; root-mean-square error of approximation = 0.044]. CONCLUSIONS: HIV-related stigma is associated with reduced likelihood of ART initiation and current ART use, and suboptimal ART adherence. To optimize the benefit of ART among women living with HIV, interventions should reduce HIV related stigma and address depression. PMID- 29135654 TI - Cost-Effectiveness of Peer- Versus Venue-Based Approaches for Detecting Undiagnosed HIV Among Heterosexuals in High-Risk New York City Neighborhoods. AB - INTRODUCTION: We used a computer simulation of HIV progression and transmission to evaluate the cost-effectiveness of a scale-up of 3 strategies to seek out and test individuals with undiagnosed HIV in New York City (NYC). SETTING: Hypothetical NYC population. METHODS: We incorporated the observed effects and costs of the 3 "seek and test" strategies in a computer simulation of HIV in NYC, comparing a scenario in which the strategies were scaled up with a 1-year implementation or a long-term implementation with a counterfactual scenario with no scale-up. The simulation combined a deterministic compartmental model of HIV transmission with a stochastic microsimulation of HIV progression, calibrated to NYC epidemiological data from 2003 to 2015. The 3 approaches were respondent driven sampling (RDS) with anonymous HIV testing ("RDS-A"), RDS with a 2-session confidential HIV testing approach ("RDS-C"), and venue-based sampling ("VBS"). RESULTS: RDS-A was the most cost-effective strategy tested. When implemented for only 1 year and then stopped thereafter, using a societal perspective, the cost per quality-adjusted life-year (QALY) gained versus no intervention was $812/QALY, $18,110/QALY, and $20,362/QALY for RDS-A, RDS-C, and VBS, respectively. When interventions were implemented long term, the cost per QALY gained versus no intervention was cost-saving, $31,773/QALY, and $35,148/QALY for RDS-A, RDS-C, and VBS, respectively. When compared with RDS-A, the incremental cost-effectiveness ratios for both VBS and RDS-C were dominated. CONCLUSIONS: The expansion of the RDS-A strategy would substantially reduce HIV-related deaths and new HIV infections in NYC, and would be either cost-saving or have favorable cost effectiveness. PMID- 29135655 TI - Neutrophil Activation and Enhanced Release of Granule Products in HIV-TB Immune Reconstitution Inflammatory Syndrome. AB - BACKGROUND: Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) remains incompletely understood. Neutrophils are implicated in tuberculosis pathology but detailed investigations in TB-IRIS are lacking. We sought to further explore the biology of TB-IRIS and, in particular, the role of neutrophils. SETTING: Two observational, prospective cohort studies in HIV/TB coinfected patients starting antiretroviral therapy (ART), 1 to analyze gene expression and subsequently 1 to explore neutrophil biology. METHODS: nCounter gene expression analysis was performed in patients with TB-IRIS (n = 17) versus antiretroviral-treated HIV/TB coinfected controls without IRIS (n = 17) in Kampala, Uganda. Flow cytometry was performed in patients with TB-IRIS (n = 18) and controls (n = 11) in Cape Town, South Africa to determine expression of neutrophil surface activation markers, intracellular cytokines, and human neutrophil peptides (HNPs). Plasma neutrophil elastase and HNP1-3 were quantified using enzyme-linked immunosorbent assay. Lymph node immunohistochemistry was performed on 3 further patients with TB-IRIS. RESULTS: There was a significant increase in gene expression of S100A9 (P = 0.002), NLRP12 (P = 0.018), COX-1 (P = 0.025), and IL-10 (P = 0.045) 2 weeks after ART initiation in Ugandan patients with TB-IRIS versus controls, implicating neutrophil recruitment. Patients with IRIS in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week 2. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls whereas patients with IRIS demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of the lymph nodes of the patients with TB-IRIS. CONCLUSIONS: Neutrophils in TB-IRIS are activated, recruited to sites of disease, and release granule contents, contributing to pathology. PMID- 29135656 TI - Brief Report: Frequency of Monitoring Kidney Function in HIV-Uninfected Persons Using Daily Oral Tenofovir Disoproxil Fumarate Pre-exposure Prophylaxis. AB - BACKGROUND: Wide-scale implementation of oral tenofovir-based pre-exposure prophylaxis (PrEP) for HIV prevention is now policy in many settings. However, the optimal frequency for monitoring kidney function remains uncertain. We investigated the impact of 6-monthly compared with 3-monthly creatinine clearance (CrCl) monitoring on the identification of moderate kidney dysfunction, defined as CrCl <60 mL/min. METHODS: Data were from 2 prospective daily oral PrEP studies in Kenya and Uganda: the Partners PrEP Study, a randomized safety, and efficacy trial of PrEP that conducted 3-monthly CrCl monitoring (n = 4404) and the Partners Demonstration Project (n = 954), an open-label delivery study of PrEP that used 6-monthly monitoring. CrCl >=60 mL/min was required for enrollment in both studies. Abnormal results were followed with confirmatory testing within approximately 1 week. Follow-up was for up to 24 months. RESULTS: Of 5358 participants included in the analysis, 87% were younger than 45 years, a third were female, and 21% had a baseline CrCl between 60 and 90 mL/min. Confirmed CrCl <60 mL/min events were rare, occurring in 52 individuals (<1%) in 24 months. The 12-month cumulative proportion of persons with CrCl <60 mL/min was 0.2% with 3 monthly screening and 0.5% with 6-monthly screening. Older age (>45 years), lower weight (<55 kg), elevated blood pressure (>140 mm Hg), and baseline CrCl between 60 and 90 mL/min were independently associated with CrCl decline <60 mL/min during follow-up. CONCLUSIONS: In these 2 PrEP studies, with generally young participants, the occurrence and pattern of clinically relevant decline in CrCl were not qualitatively different based on 3- or 6-monthly CrCl monitoring schedule. These data suggest that for most persons receiving PrEP for up to 24 months, less frequent CrCl monitoring would be safe and reduce required expenditures for repeat confirmatory testing. PMID- 29135657 TI - Adapted Sojourn Models to Estimate Activity Intensity in Youth: A Suite of Tools. AB - : The challenges of using physical activity data from accelerometers have been compounded with the recent focus on wrist-worn monitors and raw acceleration (as opposed to activity counts). PURPOSE: This study developed and systematically evaluated a suite of new accelerometer processing models for youth. METHODS: Four adaptations of the Sojourn method were developed using data from a laboratory based experiment in which youth (N = 54) performed structured activity routines. The adaptations corresponded to all possible pairings of hip or wrist attachment with activity counts (AC) or raw acceleration (RA), and they estimated time in sedentary behavior, light activity, and moderate-to-vigorous physical activity. Criterion validity was assessed using direct observation in an independent free living sample (N = 27). Monitors were worn on both wrists to evaluate the effect of handedness on accuracy, and status quo methods for each configuration were also evaluated as benchmarks for comparison. Tests of classification accuracy (percent accuracy, kappa statistics, and sensitivity and specificity) were used to summarize utility. RESULTS: In the development sample, percent accuracy ranged from 68.5% (wrist-worn AC, kappa = 0.42) to 71.6% (hip-worn RA, kappa = 0.50). Accuracy was lower in the free-living evaluation, with values ranging from 49.3% (hip-worn RA, kappa = 0.25) to 56.7% (hip-worn AC, kappa = 0.36). Collectively, the suite predicted moderate-to-vigorous physical activity well, with the models averaging 96.5% sensitivity and 67.5% specificity. However, in terms of overall accuracy, the new models performed similarly to the status quo methods. There were no meaningful differences in performance at either wrist. CONCLUSIONS: The new models offered minimal improvements over existing methods, but a major advantage is that further tuning of the models is possible with continued research. PMID- 29135658 TI - Muscle Strength Influences Pressor Responses to Static Handgrip in Men and Women. AB - PURPOSE: Whether differences in absolute muscle strength affect blood pressure (BP) responses to relative intensity static exercise remains controversial but could contribute to known sex-based differences and influence the interpretation of cross-sectional data. METHODS: One hundred thirty-two healthy participants (66 men and 66 women; age, 22 +/- 3 yr) underwent continuous seated measurements of BP (Finometer) and heart rate (electrocardiography) during baseline rest and 2 min of static handgrip (30% maximal voluntary contraction (MVC)). BP and heart rate responses were quantified in 30-s epochs during exercise and compared between men and women with and without statistical adjustment (ANCOVA) for differences in baseline BP (or heart rate), forearm girth, and handgrip MVC. Within each sex, BP and heart rate responses were compared also between tertiles of handgrip MVC (n = 22 per group). RESULTS: Men had larger systolic, diastolic, and mean arterial pressure responses during static handgrip than did women (interaction term, all P < 0.0005), although heart rates responses were similar (interaction term, P = 0.25). These sex-based BP differences persisted after statistical adjustment for differences in baseline BP or forearm girth; however, controlling for handgrip MVC abolished differences in BP responses during static handgrip exercise between men and women (interaction term, all P > 0.35). In men, BP responses were smaller within the lowest tertile of handgrip MVC (interaction term, all P < 0.006), whereas in women, BP responses were larger within the highest tertile of handgrip MVC (interaction term, all P < 0.04). CONCLUSIONS: Our findings suggest an important between- and within-sex role of absolute handgrip strength in mediating the BP response to static handgrip exercise and highlight the importance of controlling for interindividual differences in future work. PMID- 29135659 TI - Opioids and Orthopaedics in North America: Addressing a Growing Concern. PMID- 29135660 TI - Preferably Not My Surgery: A Survey of Patient and Family Member Comfort with Concurrent and Overlapping Surgeries. AB - BACKGROUND: Concurrent and overlapping surgical procedures are a timely topic. The 2 largest publications on the topic were limited to a journalistic overview and a government committee report. Since then, a recent survey of paid individuals found that they disapprove of overlapping surgical procedures in many cases. Still, we are aware of no work that specifically polled patients and their family members about their beliefs on concurrent and overlapping surgical procedures. We hypothesized that patients and family members will be uncomfortable with 1 surgeon performing overlapping or concurrent surgical procedures. METHODS: A survey about concurrent and overlapping surgical procedures was given to 200 patients and their family members at a single, urban academic medical center. Participants were asked to respond to questions about their knowledge of concurrent and overlapping surgical procedures, their comfort with different surgical scenarios, and their beliefs on possible reasons for such surgical scenarios. Individuals were approached about the survey until 200 patients and family members responded. RESULTS: On average, respondents were neutral with surgical procedures involving overlap of 2 noncritical portions and were not comfortable with overlap involving a critical portion of 1 or both surgical procedures. They agreed that hospitals allow overlapping surgical procedures to increase revenue. CONCLUSIONS: Patients undergoing a surgical procedure at an academic medical center and their family members were neutral or uncomfortable with concurrent or overlapping surgical procedures, affirming the hypothesis. Knowing these preferences is relevant to surgeons' practices and to informed consent discussions. It appears beneficial for surgeons to address the advantages and disadvantages of overlapping surgical procedures with their patients if applicable. PMID- 29135661 TI - Reconsidering the Affordable Care Act's Restrictions on Physician-Owned Hospitals: Analysis of CMS Data on Total Hip and Knee Arthroplasty. AB - BACKGROUND: Concerns about financial incentives and increased costs prompted legislation limiting the expansion of physician-owned hospitals in 2010. Supporters of physician-owned hospitals argue that they improve the value of care by improving quality and reducing costs. The purpose of the present study was to determine whether physician-owned and non-physician-owned hospitals differ in terms of costs, outcomes, and patient satisfaction in the setting of total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: With use of the U.S. Centers for Medicare & Medicaid Services (CMS) Inpatient Charge Data, we identified 45 physician-owned and 2,657 non-physician-owned hospitals that performed >=11 primary TKA and THA procedures in 2014. Cost data, patient satisfaction scores, and risk-adjusted complication and 30-day readmission scores for knee and hip arthroplasty patients were obtained from the multiyear CMS Hospital Compare database. RESULTS: Physician-owned hospitals received lower mean Medicare payments than did non-physician-owned hospitals for THA and TKA procedures ($11,106 compared with $12,699; p = 0.002). While the 30-day readmission score did not differ significantly between the 2 types of hospitals (4.48 compared with 4.62 for physician-owned and non-physician-owned, respectively; p = 0.104), physician-owned hospitals had a lower risk-adjusted complication score (2.83 compared with 3.04; p = 0.015). Physician-owned hospitals outperformed non-physician-owned hospitals in all patient-satisfaction categories, including mean linear scores for recommending the hospital (93.9 compared with 87.9; p < 0.001) and overall hospital rating (93.4 compared with 88.4; p < 0.001). When controlling for hospital demographic variables, status as a non-physician-owned hospital was an independent risk factor for being in the upper quartile of all inpatient payments for Medicare Severity-Diagnosis Related Group (MS-DRG) 470 (odds ratio, 3.317; 95% confidence interval, 1.174 to 9.371; p = 0.024), which may be because of a difference in CMS payment methodology. CONCLUSIONS: Our findings suggest that physician-owned hospitals are associated with lower mean Medicare costs, fewer complications, and higher patient satisfaction following THA and TKA than non-physician-owned hospitals. Policymakers should consider these data when debating the current moratorium on physician-owned hospital expansion. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135662 TI - Reverse Shoulder Arthroplasty for the Treatment of Rotator Cuff Deficiency: A Concise Follow-up, at a Minimum of 10 Years, of Previous Reports. AB - : We previously evaluated 94 patients (96 shoulders) who underwent reverse shoulder arthroplasty using a central compressive screw with 5.0-mm peripheral locking screws for baseplate fixation and a center of rotation lateral to the glenoid as treatment for end-stage rotator cuff deficiency. The purpose of this study was to report updated results at a minimum follow-up of 10 years. Forty patients (42 shoulders) were available for clinical follow-up. In the patients available for study, implant survivorship, with the end point being revision for any reason, was 90.7%. Since our 5-year report, 2 patients underwent revision surgery; 1 patient sustained a periprosthetic fracture 7 years postoperatively and 1 patient had a dislocation because of chronic shoulder instability at 8 years postoperatively. At a minimum follow-up of 10 years, the patients continued to maintain their improved outcome scores and range of motion, which were comparable with earlier follow-up evaluations. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135663 TI - Serum Fructosamine: A Simple and Inexpensive Test for Assessing Preoperative Glycemic Control. AB - BACKGROUND: Although the medical community acknowledges the importance of preoperative glycemic control, the literature is inconclusive and the proper metric for assessment of glycemic control remains unclear. Serum fructosamine reflects the mean glycemic control in a shorter time period compared with glycated hemoglobin (HbA1c). Our aim was to examine its role in predicting adverse outcomes following total joint arthroplasty. METHODS: Between 2012 and 2013, we screened all patients undergoing total joint arthroplasty preoperatively using serum HbA1c, fructosamine, and blood glucose levels. On the basis of the recommendations of the American Diabetes Association, 7% was chosen as the cutoff for HbA1c being indicative of poor glycemic control. This threshold correlated with a fructosamine level of 292 MUmol/L. All patients were followed and total joint arthroplasty complications were evaluated. We were particularly interested in retrieving details on surgical-site infection (superficial and deep). Patients with fructosamine levels of >=292 MUmol/L were compared with those with fructosamine levels of <292 MUmol/L. Complications were evaluated in a univariate analysis followed by a stepwise logistic regression analysis. RESULTS: A total of 829 patients undergoing primary total joint arthroplasty were included in the present study. There were 119 patients (14.4%) with a history of diabetes and 308 patients (37.2%) with HbA1c levels in the prediabetic range. Overall, 51 patients had fructosamine levels of >=292 MUmol/L. Twenty patients (39.2%) had a fructosamine level of >=292 MUmol/L but did not have an HbA1c level of >=7%. Patients with fructosamine levels of >=292 MUmol/L had a significantly higher risk for deep infection (adjusted odds ratio [OR], 6.2 [95% confidence interval (CI), 1.6 to 24.0]; p = 0.009), readmission (adjusted OR, 3.0 [95% CI, 1.1 to 8.1]; p = 0.03), and reoperation (adjusted OR, 3.4 [95% CI, 1.2 to 9.2]; p = 0.02). In the current study with the given sample size, HbA1c levels of >=7% failed to show any significant correlation with deep infection (p = 0.14), readmission (p = 1.0), or reoperation (p = 0.7). CONCLUSIONS: Serum fructosamine is a simple and inexpensive test that appears to be a good predictor of adverse outcome in patients with known diabetes and those with unrecognized diabetes or hyperglycemia. Our findings suggest that fructosamine can serve as an alternative to HbA1c in the setting of preoperative glycemic assessment. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135664 TI - Pain Relief After Operative Treatment of an Extremity Fracture: A Noninferiority Randomized Controlled Trial. AB - BACKGROUND: Opioid pain medication is frequently given to patients recovering from a surgical procedure for an extremity fracture in spite of evidence that acetaminophen may be adequate. The aim of this study was to determine whether prescription of step 1 pain medication (acetaminophen) is noninferior to step 2 pain medication (acetaminophen and tramadol) after operative treatment of an extremity fracture. METHODS: Fifty-two patients with a single extremity fracture were randomized from July 2012 to March 2015 in this 2-week follow-up, noninferiority trial in a level-I trauma center in the Netherlands. Patients were randomly assigned to receive step 1 (acetaminophen) or step 2 (acetaminophen and tramadol) medication in standard doses on an as-needed basis on discharge. Intention-to-treat and per-protocol analyses were conducted. The primary outcome was self-reported satisfaction with pain relief measured on an 11-point ordinal scale. The hypothesis being tested was formulated before the collection of data. The mean differences between the groups were reported for intention-to-treat and per-protocol analyses. RESULTS: A total of 52 patients, with equal baseline characteristics, were analyzed in this study; the step 1 group consisted of 27 subjects and the step 2 group consisted of 25 subjects. The mean satisfaction with pain management was 8.3 for step 1 and 8.5 for step 2 medications. This mean difference of 0.2 point (95% confidence interval [CI], -0.78 to 1.30 points) did not exceed the noninferiority margin of 2.0 points, indicating that step 1 was noninferior to step 2. A similar result was found in the per-protocol analysis (mean difference, 0.2 point [95% CI, -1.03 to 1.57 points]). CONCLUSIONS: This study offers evidence to suggest that prescription of acetaminophen is not inferior compared with acetaminophen and tramadol in patients who underwent operative treatment for an extremity fracture. Given that tramadol has more side effects and is potentially habit-forming, acetaminophen should be considered the mainstay for pain relief in patients recovering from extremity fracture surgical procedures. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135665 TI - Cryoablation of Bone Metastases from Renal Cell Carcinoma for Local Tumor Control. AB - BACKGROUND: Patients with bone metastases from renal cell carcinoma often are not surgical candidates and have a poor prognosis. There are limited data on the use of cryoablation as a locoregional therapy for bone metastases. Our objective was to assess the local tumor-control rate following cryoablation of bone metastases in the setting of renal cell carcinoma. METHODS: We retrospectively reviewed the medical records of patients with metastatic renal cell carcinoma who underwent cryoablation for bone metastases between 2007 and 2014. We excluded patients if the intent of treatment was for pain palliation only, if cryoablation was performed without an attempt for complete tumor control (cytoreduction), or if the patient had no further follow-up beyond the cryoablation procedure. We recorded patient demographics, procedural variables, and complications. Cross sectional imaging and clinical follow-up were reviewed to determine disease recurrence. The median overall survival and recurrence-free survival were determined using the Kaplan-Meier method. RESULTS: Forty patients (30 male and 10 female) with 50 bone metastases were included for analysis. The mean patient age was 62 years (range, 47 to 82 years). The median follow-up was 35 months (95% confidence interval [CI], 22.7 to 74.4 months). Twenty-five (62.5%) of the 40 patients had oligometastatic disease, defined as <=5 metastases at the time of ablation. The mean tumor size was 3.4 +/- 1.5 cm. Metastases in the pelvic region represented 68% of the treated tumors (34 of 50). The overall local tumor-control rate per lesion was 82% (41 of 50). Patients with oligometastatic disease experienced better local tumor control (96% [24 of 25]) compared with patients who had >5 metastases (53.3% [8 of 15]) (p = 0.001). The local tumor-control rate was better for lesions for which a larger mean difference between maximum ice ball diameter and maximum lesion diameter was achieved (2.2 +/- 0.9 cm for those without recurrence versus 1.35 +/- 1.2 cm for those with recurrence; p = 0.005). There were 3 grade-3 complications and 1 grade-4 complication. CONCLUSIONS: Cryoablation can be effective for achieving local oncologic control in bone metastases from renal cell carcinoma and may represent a valuable alternative to surgical metastasectomy in select patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135666 TI - Total Hip Arthroplasty with Use of the Cementless Zweymuller Alloclassic System: A Concise Follow-up, at a Minimum of 25 Years, of a Previous Report. AB - : We previously reported the 10 to 13-year follow-up results for 104 total hip replacements with the Zweymuller Alloclassic stem and a threaded cup in 94 patients. The present study is a clinical and radiographic outcome update after a minimum follow-up of 25 years. Four patients (4 hips) were lost and 46 patients (50 hips) died, leaving 44 patients (50 hips) available for follow-up. Since our previous report, 7 cups and 2 stems were revised. At 20 years, the probability of survival of any component was 84.1% (95% confidence interval [CI], 73.91% to 94.29%) and the cumulative probability of not having stem loosening was 95.9% (95% CI, 95.51% to 96.29%). We observed proximal femoral osteolysis in 15 hips (30%), cortical hypertrophy in 21 hips (42%), and proximal femoral osteopenia in 30 hips (60%). The Zweymuller Alloclassic stem continues to provide excellent results after extended follow-up. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135667 TI - Nationwide Analysis of Femoral Neck Fractures in Elderly Patients: A Receding Tide. AB - BACKGROUND: Geriatric femoral neck fractures are associated with substantial morbidity and medical cost. We evaluated the incidence and management trends of femoral neck fractures in recent years in the U.S. METHODS: Patient data from 2003 through 2013 were obtained from the Nationwide Inpatient Sample database. Femoral neck fractures in patients >=65 years old were identified and grouped using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes for internal fixation, hemiarthroplasty, or total hip arthroplasty (THA). The nationwide incidence of femoral neck fractures was calculated and presented as an age-adjusted population rate. Univariable methods were used for trend analysis and comparisons between groups. Logistic regression modeling was used to analyze complications. RESULTS: From 2003 to 2013, we identified 808,940 femoral neck fractures in patients >=65 years old. The national age-adjusted incidence of femoral neck fractures decreased from 242 per 100,000 U.S. adults in 2003 to 146 in 2013. The proportion of fractures managed operatively with THA increased over time (5.9% in 2003 versus 7.4% in 2013; p < 0.001). Concurrently, the use of hemiarthroplasty declined (65.1% versus 63.6%; p < 0.001). In 2013, the median age of the patients treated with THA was significantly younger (77.3 years) compared with that in the hemiarthroplasty and internal fixation groups (83.2 and 82.0 years). The THA group had significantly higher median initial hospital costs ($17,097) compared with the hemiarthroplasty and internal fixation groups ($14,776 and $10,462). CONCLUSIONS: In the last decade, the total number and population rate of femoral neck fractures in the elderly declined significantly. There was a modest but significant increase in the utilization of THA. CLINICAL RELEVANCE: This report identifies the changing trends in clinical practice in the treatment of geriatric femoral neck fractures in the U.S. Treating physicians should be aware of these trends, which include a decreasing national incidence of geriatric femoral neck fractures as well as an increase in the use of THA. PMID- 29135668 TI - Hemiarthroplasty and Total Hip Replacement for Displaced Intracapsular Fracture in Active Elderly Patients Did Not Differ for Function at 12 Years After Surgery. PMID- 29135669 TI - Arthroscopic Transosseous Suture Repair and Single-Row Anchor Fixation for Rotator Cuff Lesions Did Not Differ for Pain, Function, or Rotator-Cuff Integrity at 15 Months. PMID- 29135670 TI - In Early Bilateral Medial Compartment Arthritis, Unicondylar and Total Knee Arthroplasty Resulted in Similar Improvements in Patient-Reported Outcomes at 2 Years. PMID- 29135671 TI - Support for Safer Opioid Prescribing Practices: A Catalog of Published Use After Orthopaedic Surgery. PMID- 29135672 TI - What's New in Orthopaedic Rehabilitation. PMID- 29135673 TI - Myocardial Cobalt Levels Are Elevated in the Setting of Total Hip Arthroplasty. AB - BACKGROUND: Arthroplasty implants commonly contain elemental metal that may undergo wear-related release. Recently, cases of hip implant-associated myocardial injury have been reported. However, we are not aware of any previous study that has systematically measured myocardial metal levels or examined the relationship with total hip arthroplasty (THA). METHODS: Archives of our institution were queried for autopsies of individuals who had undergone THA between 1990 and 2013. Myocardial tissue samples were analyzed for cobalt (Co) and chromium (Cr) levels with inductively coupled plasma mass spectroscopy. Seventy-five Co/Cr-on-polyethylene THA cases were included (mean age at time of death = 77.4 years; 49% women) as were 73 non-arthroplasty controls matched for age, sex, and history of hypertension and diabetes mellitus. RESULTS: Significantly higher median myocardial concentrations of Co were observed in individuals with THA compared with controls (0.12 versus 0.06 MUg/g, p < 0.0001). The median Co concentration was 69% higher in patients who had undergone THA revision (0.169 MUg/g) than in those who underwent primary THA (0.100 MUg/g; p = 0.004). In general, higher Co levels were observed in those with multiple replaced joints, although this finding only trended toward significance. Cardiomegaly, interstitial fibrosis, and decreased ejection fraction were observed more frequently in the postmortem samples of patients with implants than in those of controls (p = 0.0002, 0.044, and 0.0039, respectively). CONCLUSIONS: We believe this to be the first study to quantify metal levels in cardiac tissue in patients with and without joint replacement. The elevated Co levels, in concert with cardiomegaly and increased interstitial fibrosis found during autopsy, in the arthroplasty cohort are novel, important findings. Although Co levels were significantly elevated above those in controls, the majority were below those seen in clinical case reports of death from Co cardiotoxicity associated with metal-on-metal prostheses. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135674 TI - The Pursuit of Scholarship: Why We Should Care About Resident Research. AB - Research is a foundational component of an orthopaedic residency. It fosters intellectual curiosity and pursuit of excellence, while teaching discipline and the scientific method. These are the key principles for careers in both community based practice and academia. Currently, no consensus exists on how to best engage residents and support their research endeavors. In 2014, the American Academy of Orthopaedic Surgeons Board of Specialty Societies Research and Quality Committee convened a Clinician-Scientist Collaboration Workgroup. The workgroup's task was to identify barriers to clinical and basic science research, and to propose feasible recommendations to overcome these barriers. Herein, we have compiled the opinions of various stakeholder constituencies on how to foster scholarly pursuits during an orthopaedic residency. These opinions reflect the workgroup's conclusions that research is directly and indirectly influenced by funding, departmental support, and mentorship, and that early exposure and dedicated time to pursue scholarly activities may have a positive impact on lifelong research interests. PMID- 29135675 TI - Novel Strategies to Improve Resident Selection by Improving Cultural Fit: AOA Critical Issues. AB - Residency selection is a perennial multifactorial process that differs considerably from the recruitment processes that other professional occupations enjoy. The 2016 meeting of the American Orthopaedic Association's Council of Orthopaedic Residency Directors highlighted a series of symposia that sought to present a novel manner of resident selection. Specifically, the presenters for each symposium were asked to do the following: present some general recruitment best practices in industries outside of medicine, present how branding of a program may translate into a better interview season, investigate evidence that the applicant pool to orthopaedic surgery may have changed and that residency program brands may have to reflect this, and assess our current evaluation techniques for talent identification and resident selection with respect to a specific department's appearance or brand. The meeting concluded with an understanding of the level to which programs can successfully create or adopt a brand and how this may go a long way in focusing the entire match process and allow emphasis to be placed on applicants who possess desired traits. The goal for this meeting was that attendees would leave with tangible practices and techniques that could be adopted at their home institutions. PMID- 29135676 TI - Physician-Owned Hospitals: Down but Not Out? The Evidence Versus the Hype: Commentary on an article by P. Maxwell Courtney, MD, et al.: "Reconsidering the Affordable Care Act's Restrictions on Physician-Owned Hospitals. Analysis of CMS Data for Total Hip and Knee Arthroplasty". PMID- 29135677 TI - A Cheap, Simple Test That Predicts Complications: What's Not to Like?: Commentary on an article by Noam Shohat, MD, et al.: "Serum Fructosamine: A Simple and Inexpensive Test for Assessing Preoperative Glycemic Control". PMID- 29135678 TI - Can It Be Done-Opioid-Free Recovery?: Commentary on an article by Gijs T.T. Helmerhorst, MD, et al.: "Pain Relief After Operative Treatment of an Extremity Fracture: A Noninferiority Randomized Controlled Trial". PMID- 29135679 TI - Characterization of the Human Pancreas Side Population as a Potential Reservoir of Adult Stem Cells. AB - OBJECTIVES: The side population (SP) contains cells with stem cell/progenitor properties. Previously, we observed that the mouse pancreas SP expanded after pancreatic injury. We aimed to characterize the SP in human pancreas as a potential source of stem cells. METHODS: Human organ donor pancreata were fractionated into islets and exocrine tissue, enriched by tissue culture and dispersed into single cells. Cells were phenotyped by flow cytometry, and the SP was defined by efflux of fluorescent dye Hoechst 33342 visualized by ultraviolet excitation. Cells were flow sorted, and their colony-forming potential measured on feeder cells in culture. RESULTS: An SP was identified in islet and exocrine cells from human organ donors: 2 with type 1 diabetes, 3 with type 2 diabetes, and 28 without diabetes. Phenotyping revealed that exocrine SP cells had an epithelial origin, were enriched for carbohydrate antigen 19-9 ductal cells expressing stem cell markers CD133 and CD26, and had greater colony-forming potential than non-SP cells. The exocrine SP was increased in a young adult with type 1 diabetes and ongoing islet autoimmunity. CONCLUSIONS: The pancreatic exocrine SP is a potential reservoir of adult stem/progenitor cells, consistent with previous evidence that such cells are duct-derived and express CD133. PMID- 29135681 TI - Piercing and Metal Sensitivity: Extended Analysis of the North American Contact Dermatitis Group Data, 2007-2014. AB - BACKGROUND: Body piercing provides a unique route of metal exposure. OBJECTIVE: The aim of this study was to update previous analyses using the North American Contact Dermatitis Group data comparing pierced and unpierced individuals. METHODS: This was a retrospective cross-sectional analysis of 17,912 patients patch tested by the North American Contact Dermatitis Group from 2007 to 2014 for demographics, positive reactions to metals (nickel, cobalt, chromium), and detailed analysis of nickel reactions by age, sex, and source of exposure. RESULTS: Piercing was significantly associated with female sex, being older than 18 years, and atopy (P < 0.003). Nickel sensitivity was associated with 1 or more piercing for men and women combined (P < 0.0001; relative risk [RR], 2.54; 95% confidence interval [CI], 2.35-2.75), although this association was stronger for men (RR, 2.21; 95% CI, 1.77-2.76) than women (RR, 1.47; 95% CI, 1.31-1.65). The frequency of positivity to nickel increased with number of piercings (14.3% for 1 piercing to 34.0% with >=5 piercings). Piercing was not significantly associated with cobalt sensitivity alone (P = 0.8992) and was negatively associated with chromium sensitivity (P < 0.0001). Jewelry was the most common source of allergic reactions to nickel irrespective of sex or pierced status. CONCLUSIONS: Nickel sensitivity was significantly associated with piercing in both men and women. Jewelry was the most common source. PMID- 29135682 TI - Occupationally Induced Allergic Contact Dermatitis to Aerosolized Quaternary Ammonium Compounds. PMID- 29135683 TI - Sigfrid Fregert. PMID- 29135684 TI - Defining Gaps in Dermatitis Care. PMID- 29135685 TI - Olivocochlear Efferent Activity Is Associated With the Slope of the Psychometric Function of Speech Recognition in Noise. AB - OBJECTIVES: The medial olivocochlear (MOC) efferent system can modify cochlear function to improve sound detection in noise, but its role in speech perception in noise is unclear. The purpose of this study was to determine the association between MOC efferent activity and performance on two speech-in-noise tasks at two signal-to-noise ratios (SNRs). It was hypothesized that efferent activity would be more strongly correlated with performance at the more challenging SNR, relative to performance at the less challenging SNR. DESIGN: Sixteen adults aged 35 to 73 years participated. Subjects had pure-tone averages <=25 dB HL and normal middle ear function. High-frequency pure-tone averages were computed across 3000 to 8000 Hz and ranged from 6.3 to 48.8 dB HL. Efferent activity was assessed using contralateral suppression of transient-evoked otoacoustic emissions (TEOAEs) measured in right ears, and MOC activation was achieved by presenting broadband noise to left ears. Contralateral suppression was expressed as the decibel change in TEOAE magnitude obtained with versus without the presence of the broadband noise. TEOAE responses were also examined for middle ear muscle reflex activation and synchronous spontaneous otoacoustic emissions (SSOAEs). Speech-in-noise perception was assessed using the closed-set coordinate response measure word recognition task and the open-set Institute of Electrical and Electronics Engineers sentence task. Speech and noise were presented to right ears at two SNRs. Performance on each task was scored as percent correct. Associations between contralateral suppression and speech-in-noise performance were quantified using partial rank correlational analyses, controlling for the variables age and high-frequency pure-tone average. RESULTS: One subject was excluded due to probable middle ear muscle reflex activation. Subjects showed a wide range of contralateral suppression values, consistent with previous reports. Three subjects with SSOAEs had similar contralateral suppression results as subjects without SSOAEs. The magnitude of contralateral suppression was not significantly correlated with speech-in-noise performance on either task at a single SNR (p > 0.05), contrary to hypothesis. However, contralateral suppression was significantly correlated with the slope of the psychometric function, computed as the difference between performance levels at the two SNRs divided by 3 (decibel difference between the 2 SNRs) for the coordinate response measure task (partial rs = 0.59; p = 0.04) and for the Institute of Electrical and Electronics Engineers task (partial rs = 0.60; p = 0.03). CONCLUSIONS: In a group of primarily older adults with normal hearing or mild hearing loss, olivocochlear efferent activity assessed using contralateral suppression of TEOAEs was not associated with speech-in-noise performance at a single SNR. However, auditory efferent activity appears to be associated with the slope of the psychometric function for both a word and sentence recognition task in noise. Results suggest that individuals with stronger MOC efferent activity tend to be more responsive to changes in SNR, where small increases in SNR result in better speech-in-noise performance relative to individuals with weaker MOC efferent activity. Additionally, the results suggest that the slope of the psychometric function may be a more useful metric than performance at a single SNR when examining the relationship between speech recognition in noise and MOC efferent activity. PMID- 29135687 TI - Environmental and epigenetic regulation of postprandial lipemia. AB - PURPOSE OF REVIEW: Postprandial lipemia (PPL), the prolonged increase in plasma triglyceride-rich lipoproteins following food consumption, is an independent risk factor for cardiovascular disease. Genetic variation, environment and the interplay between these direct an individual's postprandial lipid response. From such interplay, inducible and reversible epigenetic changes arise. Increasing evidence suggests epigenetic variation contributes to postprandial response in lipids and risk. RECENT FINDINGS: Diet and exercise are central agents affecting postprandial lipemia - triglyceride, but heterogeneity of the findings warrant more and larger studies. Several epigenetic loci identified from a human intervention study account for a substantial proportion of PPL phenotype variation, but the burden to conduct an intervention study of postprandial responses likely limits translation to personalized nutrition. SUMMARY: The impact of both DNA methylation patterns and environmental factors such as diet, exercise, sleep and medication on PPL is multifaceted. Discovery of interactions that modify the association between CpG (oligodeoxydinucleotide) methylation and postprandial phenotypes is unfolding. PMID- 29135686 TI - Cortical Correlates of Binaural Temporal Processing Deficits in Older Adults. AB - OBJECTIVES: This study was designed to evaluate binaural temporal processing in young and older adults using a binaural masking level difference (BMLD) paradigm. Using behavioral and electrophysiological measures within the same listeners, a series of stimulus manipulations was used to evaluate the relative contribution of binaural temporal fine-structure and temporal envelope cues. We evaluated the hypotheses that age-related declines in the BMLD task would be more strongly associated with temporal fine-structure than envelope cues and that age-related declines in behavioral measures would be correlated with cortical auditory evoked potential (CAEP) measures. DESIGN: Thirty adults participated in the study, including 10 young normal-hearing, 10 older normal-hearing, and 10 older hearing impaired adults with bilaterally symmetric, mild-to-moderate sensorineural hearing loss. Behavioral and CAEP thresholds were measured for diotic (So) and dichotic (Spi) tonal signals presented in continuous diotic (No) narrowband noise (50-Hz wide) maskers. Temporal envelope cues were manipulated by using two different narrowband maskers; Gaussian noise (GN) with robust envelope fluctuations and low-noise noise (LNN) with minimal envelope fluctuations. The potential to use temporal fine-structure cues was controlled by varying the signal frequency (500 or 4000 Hz), thereby relying on the natural decline in phase-locking with increasing frequency. RESULTS: Behavioral and CAEP thresholds were similar across groups for diotic conditions, while the masking release in dichotic conditions was larger for younger than for older participants. Across all participants, BMLDs were larger for GN than LNN and for 500-Hz than for 4000 Hz conditions, where envelope and fine-structure cues were most salient, respectively. Specific age-related differences were demonstrated for 500-Hz dichotic conditions in GN and LNN, reflecting reduced binaural temporal fine structure coding. No significant age effects were observed for 4000-Hz dichotic conditions, consistent with similar use of binaural temporal envelope cues across age in these conditions. For all groups, thresholds and derived BMLD values obtained using the behavioral and CAEP methods were strongly correlated, supporting the notion that CAEP measures may be useful as an objective index of age-related changes in binaural temporal processing. CONCLUSIONS: These results demonstrate an age-related decline in the processing of binaural temporal fine structure cues with preserved temporal envelope coding that was similar with and without mild-to-moderate peripheral hearing loss. Such age-related changes can be reliably indexed by both behavioral and CAEP measures in young and older adults. PMID- 29135688 TI - Membrane microdomains and the regulation of HDL biogenesis. AB - PURPOSE OF REVIEW: The major cardio-protective function of HDL is to remove excess cellular cholesterol in the process of HDL particle formation and maturation. The HDL biogenic procedure requiring protein-lipid interactions has been incompletely understood, and here we discuss recent progress and insights into the mechanism of HDL biogenesis. RECENT FINDINGS: The initial and rate limiting step of HDL biogenesis is the interaction between apoA-I and plasma membrane microdomains created by ATP-binding cassette transporter A1 (ABCA1) transporter. Computer simulation of molecular dynamics suggests that ABCA1 translocates phospholipids from the inner to the outer leaflet of the plasma membrane to create a transbilayer density gradient leading to the formation of an exovesiculated plasma membrane microdomain. The cryo-electron microscopy structure of ABCA1 suggests that an elongated hydrophobic tunnel formed by the extracellular domain of ABCA1 may function as a passageway to deliver lipids to apoA-I. In contrast to ABCA1-created plasma membrane microdomains, desmocollin 1 (DSC1) contained in a cholesterol-rich plasma membrane microdomain binds apoA-I to prevent HDL biogenesis. The identification of DSC1-containing plasma membrane microdomains as a negative regulator of HDL biogenesis may offer potential therapeutic avenues. SUMMARY: Isolation and characterization of plasma membrane microdomains involved in HDL biogenesis may lead to a better understanding of the molecular mechanism of HDL biogenesis. PMID- 29135689 TI - VLDL triglyceride accumulation in skeletal muscle and adipose tissue in type 2 diabetes. AB - PURPOSE OF REVIEW: Insulin resistance is closely linked to accumulation of lipid outside adipose tissue (ectopic fat storage). VLDL particles transport lipids from the liver to peripheral tissues. However, whether abnormalities in VLDL triglyceride storage in muscle and adipose tissue exist in type 2 diabetes has previously been unknown, primarily because of methodological difficulties. Here, we review recent research on VLDL-triglyceride storage. RECENT FINDINGS: In a recent study, men with type 2 diabetes had increased skeletal muscle VLDL triglyceride storage compared to weight-matched nondiabetic men, potentially leading to intramyocellular triglyceride accumulation. In contrast, studies of adipose tissue VLDL-triglyceride storage have shown similar storage capacity in men with and without diabetes, both in the postabsorptive and the postprandial period. In the initial submission, studies have failed to show associations between lipoprotein lipase activity, considered the rate-limiting step in storage of lipids from lipoproteins, and VLDL-TG storage in both muscle and adipose tissue. SUMMARY: Differences in muscle VLDL-triglyceride storage may lead to ectopic fat storage and contribute to the development of type 2 diabetes, whereas the ability to store VLDL-triglyceride in adipose tissue is preserved in type 2 diabetes. PMID- 29135690 TI - Microbiota and HDL metabolism. AB - PURPOSE OF REVIEW: Accumulating evidence has provided new insights regarding potentially effective therapeutic options targeting modulation of HDL metabolism, resulting in the prevention of cardiovascular diseases. The gut microbiota has now been convincingly linked to host health, but its impact on host lipid metabolism, especially HDL metabolism, remains poorly understood. This review focuses on the recent progress in establishing associations between gut microbiota and host HDL metabolism. It also discusses causality and mechanisms, and how to translate the findings into clinical use. RECENT FINDINGS: Recent human and animal studies have demonstrated that the gut microbiota composition can explain a substantial proportion of the individual variation in host blood lipid profiles. In addition, signaling molecules produced by gut microbiota have been shown to have potent effects on reverse cholesterol transport, a crucial atheroprotective function of HDL, which could subsequently influence the development of atherosclerosis. Ultimately, selective manipulation of gut microbiota may serve as an ideal therapeutic approach for improving HDL function and cardiovascular risk, although further studies are needed for a better understanding of which specific bacteria, or alternatively, which bacterial metabolites, are appropriate targets. SUMMARY: We are just beginning to understand how the gut microbiota, a newly recognized endocrine organ system, influences HDL metabolism and atherosclerotic diseases. From recent experimental and clinical perspectives, it can be targeted for therapeutic benefit with respect to HDL function and cardiovascular diseases. PMID- 29135691 TI - Control of intestinal lipoprotein secretion by dietary carbohydrates. AB - PURPOSE OF REVIEW: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (CVD). Lipoproteins secreted by the intestine can contribute to dyslipidemia and may increase risk for CVD. This review focuses on how dietary carbohydrates can impact the production of chylomicrons, thereby influencing plasma concentrations of triglycerides and lipoproteins. RECENT FINDINGS: Hypercaloric diets high in monosaccharides can exacerbate postprandial triglyceride concentration. In contrast, isocaloric substitution of monosaccharides into mixed meals has no clear stimulatory or inhibitory effect on postprandial triglycerides. Mechanistic studies with oral ingestion of carbohydrates or elevation of plasma glucose have demonstrated enhanced secretion of chylomicrons. The mechanisms underlying this modulation remain largely unknown but may include enhanced intestinal de novo lipogenesis and mobilization of intestinally stored lipids. SUMMARY: The studies reviewed here have implications for dietary recommendations regarding refined carbohydrate intake and prevention of CVD. PMID- 29135692 TI - Ultrasound with neurostimulation compared with ultrasound guidance alone for lumbar plexus block: A randomised single blinded equivalence trial. AB - BACKGROUND: Ultrasound-guided lumbar plexus blocks usually require confirmatory neurostimulation. A simpler alternative is to inject local anaesthetic inside the posteromedial quadrant of the psoas muscle under ultrasound guidance. OBJECTIVE: We hypothesised that both techniques would result in similar total anaesthesia time, defined as the sum of performance and onset time. DESIGN: A randomised, observer-blinded, equivalence trial. SETTING: Ramathibodi Hospital and Maharaj Nakorn Chiang Mai Hospital (Thailand) from 12 May 2016 to 10 January 2017. PATIENTS: A total of 110 patients undergoing total hip or knee arthroplasty, who required lumbar plexus block for postoperative analgesia. INTERVENTION: In the combined ultrasonography-neurostimulation group, quadriceps-evoked motor response was sought at a current between 0.2 and 0.8 mA prior to local anaesthetic injection (30 ml of lidocaine 1% and levobupivacaine 0.25% with epinephrine 5 MUg ml and 5 mg of dexamethasone). In the ultrasound guidance alone group, local anaesthetic was simply injected inside the posteromedial quadrant of the psoas muscle. MAIN OUTCOMES MEASURES: We measured the total anaesthesia time, the success rate (at 30 min), the number of needle passes, block-related pain, cumulative opioid consumption (at 24 h) and adverse events (vascular puncture, paraesthesia, local anaesthetic spread to the epidural space). The equivalence margin was 7.4 min. RESULTS: Compared with ultrasound guidance alone, combined ultrasonography-neurostimulation resulted in decreased mean (+/-SD) total anaesthesia time [15.3 (+/-6.5) vs. 20.1 (+/-9.0) min; mean difference, -4.8; 95% confidence interval, -8.1 to -1.9; P = 0.005] and mean (+/-SD) onset time [10.2 (+/-5.6) vs. 15.5 (+/-9.0) min; P = 0.004). No inter-group differences were observed in terms of success rate, performance time, number of needle passes, block-related pain, opioid consumption or adverse events. CONCLUSION: Although the ultrasonography-neurostimulation technique results in a shorter total anaesthesia time compared with ultrasound guidance alone, this difference falls within our accepted equivalence margin (+/-7.4 min). TRIAL REGISTRATION: www.clinicaltrials in the (Study ID: TCTR20160427003). PMID- 29135693 TI - Improving the Reproducibility and Quality of Reporting for Animal Studies in Inflammatory Bowel Disease. PMID- 29135694 TI - Impact of Prostate Cancer and Its Treatment on the Outcomes of Ileal Pouch-Anal Anastomosis. AB - BACKGROUND: There are scant published data in the impact of prostate cancer and its treatment on functional outcomes and quality of life (QOL) in patients with ileal pouch-anal anastomosis (IPAA). The aim of the study was to evaluate the influence of prostate cancer and its treatment on functional outcomes and QOL in patients with IPAA. METHODS: Patients with IPAA with prostate cancer were compared to age and pouch duration-matched controls without prostate cancer in a 1:2 ratio. Pouch function and QOL were compared between pretreatment and posttreatment for prostate cancer as well as between subjects and controls. RESULTS: A total of 30 patients with IPAA with prostate cancer and 60 matched controls were included. Treatment modalities of prostate cancer included prostatectomy (n = 22), brachytherapy (n = 5), watchful waiting (n = 2), and hormonal therapy (n = 1). The median length of follow-up was 6 (interquartile range, 2.7-8) years. Permanent fecal diversion was required in 5 (16.7%) patients with prostate cancer who developed pouch failure, as compared with 2 patients in the control group (P = 0.04). In patients who retained their pouches, the pouch functional outcomes at the latest follow-up were similar to that before prostate cancer treatment and to that of the matched controls, in terms of bowel movements, daytime seepage, nighttime bowel movements, nighttime seepage, and QOL score. CONCLUSIONS: The risk of pouch failure may be increased after the diagnosis of prostate cancer with or without treatment. However, for those with retained pouches, their pouch function and QOL did not seem to be adversely affected. PMID- 29135695 TI - Short-term Impact of Assisted Deliveries: Evaluation Based on Behavioral Pain Scoring and Heart Rate Variability. AB - OBJECTIVES: Assisted deliveries (ADs) are used in current practice by obstetrical teams during labor when the fetus is likely to face difficulties. In this study, we hypothesized that pain related to instrumental delivery could impair autonomic nervous system (ANS) activity. MATERIALS AND METHODS: We investigated infants born by spontaneous delivery (SD group, n=35) and those whose deliveries were assisted by vacuum, forceps, or both (AD group, n=35) between the second and fourth hours of life. Pain was evaluated using the Echelle de Douleur et d'Inconfort du Nouveau-Ne/Neonatal Pain and Discomfort Scale (EDIN) behavioral pain scale. ANS activity was analyzed using the newborn infant parasympathetic evaluation (NIPE) index, a heart rate variability based index which is related to the autonomic activity mediated by the parasympathetic nervous system. RESULTS: Neonates in the AD group presented higher EDIN scores than neonates born by spontaneous vaginal deliveries (SD group) (P<0.0001). In contrast, the NIPE index was significantly reduced in the AD group compared with the SD group (P=0.005). A significant inverse correlation was found between the NIPE index and the EDIN score (r=-0.287, P=0.016). DISCUSSION: ADs (vacuum, forceps, or both) are associated with persistent pain after birth, unlike normal vaginal deliveries. Moreover ADs are associated with reduced NIPE. Taken together, our results suggest that pain related to instrumental delivery impairs the ANS activity. PMID- 29135697 TI - Does Working Memory Moderate the Within-Person Associations Between Pain Intensity and Negative Affect and Pain's Interference With Work Goal Pursuit? AB - OBJECTIVES: Chronic pain exerts a pervasive negative influence on workers' productivity. However, a paucity of research has addressed the mechanisms underlying the pain -> productivity relation. In the present study using intensive daily diary data, we examined whether working memory (WM) moderates the positive within-person associations between (1) morning pain intensity and (2) morning negative affect (NA) and later day pain's interference of work-goal (WG) pursuit. METHODS: A community sample of 131 adults with chronic pain completed a battery of questionnaires, laboratory-measured WM, and a 21-day daily diary. RESULTS: WM did not moderate the positive within-person association between morning pain intensity and afternoon/evening ratings of pain's interference with work goal pursuit. However, individuals with higher WM showed significantly attenuated positive within-person association between morning negative affect and pain's interference with afternoon/evening work goal pursuit. DISCUSSION: WM appears to protect goal-relevant information from distractions due to negative affective arousal. The continued use of ecologically valid observational and intervention studies would shed further light on the influence of WM on the pursuit of valued work goals in the face of pain and negative affect. PMID- 29135696 TI - Effect of a Scenario-tailored Opioid Messaging Program on Parents' Risk Perceptions and Opioid Decision-making. AB - OBJECTIVES: Poor parental understanding of prescription opioid risks is associated with potentially dangerous decisions that can contribute to adverse drug events (ADE) in children and adolescents. This study examined whether an interactive Scenario-tailored Opioid Messaging Program (STOMP) would (1) enhance opioid risk perceptions and (2) improve the safety of parents' decision-making. MATERIALS AND METHODS: In total, 546 parents were randomized to receive the STOMP versus control information and 516 completed the program. A baseline survey assessed parents' opioid risk knowledge, perceptions, and preferences for pain relief versus risk avoidance (Pain Relief Preference). Parents then made hypothetical decisions to give or withhold a prescribed opioid for high-risk (excessive sedation) and low-risk (no ADE) scenarios. The STOMP provided immediate feedback with specific risk and guidance information; the control condition provided general information. We reassessed knowledge, perceptions, and decision-making up to 3 days thereafter. RESULTS: Following the intervention, the STOMP group became more risk avoidant (Pain Relief Preference, mean difference 1.27 [95% confidence interval, -0.8 to -1.75]; P<0.001) and gained higher perceptions of the critical risk, excessive sedation (+0.56 [0.27 to 0.85]; P<0.001). STOMP parents were less likely than controls to give a prescribed opioid in the high-risk situation (odds ratio, -0.14 [-0.24 to -0.05]; P=0.006) but similarly likely to give an opioid for the no ADE situation (P=0.192). DISCUSSION: The STOMP intervention enhanced risk perceptions, shifted preferences toward opioid risk avoidance, and led to better decisions regarding when to give or withhold an opioid for pain management. Scenario-tailored feedback may be an effective method to improve pain management while minimizing opioid risks. PMID- 29135698 TI - Associations Between Early Care Decisions and the Risk for Long-term Opioid Use for Patients With Low Back Pain With a New Physician Consultation and Initiation of Opioid Therapy. AB - OBJECTIVE: The aim of this study was to identify associations between early care decisions and long-term opioid (LTO) use in opioid-naive patients with a new physician consultation for low back pain (LBP) at which an opioid was prescribed. METHODS: A retrospective study of claims data was used to identify opioid-naive LBP patients who were prescribed opioids at the index physician visit. Early care variables captured included additional nonopioid medications prescribed within 14 days and provider visits or diagnostic imaging within 30 days of the index visit. A multivariate logistic model was used to identify early care variables associated with the outcome of (LTO) use in the year following the index visit controlling for patient factors. RESULTS: A total of 707 patients were included in this study. The mean age was 38.1 (+/-11.6), and 67.8% were female individuals and 76.9% were Medicaid beneficiaries. Early care medications were muscle relaxants (32.2%), nonsteroidal anti-inflammatories (29.3%), oral steroids (11.7%), and benzodiazepines (8.3%). The most common early care provider visits were with primary care (31.0%) and physical therapy (13.0%). A total of 172 patients (24.3%) progressed to LTO use. Controlling for patient factors, early care variables increasing risk for LTO use were an early benzodiazepine prescription and primary care visit. An early physical therapy visit was associated with reduced risk for LTO use. DISCUSSION: Early care decisions were predictive of LTO use following a new LBP consultation at which opioids were prescribed. Our results support recommendations to avoid concurrent benzodiazepine prescribing and to consider other evidence-based pain treatments such as physical therapy early, particularly for patients at high risk for LTO use or misuse. PMID- 29135699 TI - Phenytoin-induced Excessive Sedation During Awake Craniotomy: An Unusual Observation. PMID- 29135700 TI - Safety Outcomes Following Spine and Cranial Neurosurgery: Evidence From the National Surgical Quality Improvement Program. AB - BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) was used to establish predictors for 30-day postoperative complications following spine and cranial neurosurgery. MATERIALS AND METHODS: The ACS-NSQIP participant use files were queried for neurosurgical cases between 2005 and 2015. Prevalence of postoperative complications following neurosurgery was determined. Nested multivariable logistic regression analysis was used to identify demographic, comorbidity, and perioperative characteristics associated with any complication and mortality for spine and cranial surgery. RESULTS: There were 175,313 neurosurgical cases (137,029 spine, 38,284 cranial) identified. A total of 23,723 (13.5%) patients developed a complication and 2588 (1.5%) patients died. Compared with spine surgery, cranial surgery had higher likelihood of any complication (22.2% vs. 11.1%; P<0.001) and mortality (4.8% vs. 0.5%; P<0.001). In multivariable analysis, cranial surgery had 2.73 times higher likelihood for mortality compared with spine surgery (95% confidence interval, 2.46-3.03; P<0.001), but demonstrated lower odds of any complication (odds ratio, 0.93; 95% confidence interval, 0.90-0.97; P<0.001). There were 6 predictors (race, tobacco use, dyspnea, chronic obstructive pulmonary disease, chronic heart failure, and wound classification) significantly associated with any complication, but not mortality. Paradoxically, tobacco use had an unexplained protective effect on at least one complication or any complication. Similarly, increasing body mass index was protective for any complication and mortality, which suggests there may be a newly observed "obesity paradox" in neurosurgery. CONCLUSIONS: After controlling for demographic characteristics, preoperative comorbidities, and perioperative factors, cranial surgery had higher risk for mortality compared with spine surgery despite lower risk for other complications. These findings highlight a discrepancy in the risk for postoperative complications following neurosurgical procedures that requires emphasis within quality improvement initiatives. PMID- 29135701 TI - Verification of the Optimal Chest Compression Depth for Children in the 2015 American Heart Association Guidelines: Computed Tomography Study. AB - OBJECTIVE: The 2015 American Heart Association guidelines recommended pediatric rescue chest compressions of at least one-third the anteroposterior diameter of the chest, which equates to approximately 5 cm. This study evaluated the appropriateness of these two types by comparing their safeties in chest compression depth simulated by CT. DESIGN: Retrospective study with data analysis conducted from January 2005 to June 2015 SETTING:: Regional emergency center in South Korea. PATIENTS: Three hundred forty-nine pediatric patients 1-9 years old who had a chest CT scan. INTERVENTIONS: Simulation of chest compression depths by CT. MEASUREMENTS AND MAIN RESULTS: Internal and external anteroposterior diameter of the chest and residual internal anteroposterior diameter after simulation were measured from CT scans. The safe cutoff levels were differently applied according to age. One-third external anteroposterior diameters were compared with an upper limit of chest compression depth recommended for adults. Primary outcomes were the rates of overcompression to evaluate safety. Overcompression was defined as a negative value of residual internal anteroposterior diameter-age-specific cutoff level. Using a compression of 5-cm depth simulated by chest CT, 16% of all children (55/349) were affected by overcompression. Those 1-3 years old were affected more than those 4-9 years old (p < 0.001). Upon one-third compression of chest anteroposterior depth, only one subject (0.3%) was affected by overcompression. Rate of one-third external anteroposterior diameter greater than 6 cm in children 8 and 9 years old was 16.1% and 33.3%, respectively. CONCLUSIONS: A chest compression depth of one-third anteroposterior might be more appropriate than the 5-cm depth chest compression for younger Korean children. But, one-third anteroposterior depth chest compression might induce deep compressions greater than an upper limit of compression depth for adults in older Korean children. PMID- 29135702 TI - Relationship Between Sensory Dysfunction and Walking Speed in Patients With Clinically Isolated Syndrome. AB - PURPOSE: The aim of this study was to investigate a relationship between sensory dysfunction examined with somatosensory-evoked potentials of the posterior tibial nerve (tSSEP) and walking speed in patients with clinically isolated syndrome. METHODS: In 120 patients (mean age 32.2 +/- 8.7 years, 84 females), Expanded Disability Status Scale (EDSS), timed 25-foot walk test (T25FW), brain and spinal cord MRI, and tSSEP were performed. P40 latencies and N22a-P40 interlatencies were analyzed, and the z-score for each latency was calculated and combined into total tSSEP z-score. RESULTS: T25FW significantly correlated with total tSSEP z score (rs = 0.211; P = 0.021). When looking at each component of the tSSEP separately, T25FW significantly correlated with z-scores of P40 wave latencies (rs = 0.223; P = 0.014) and N22a-P40 interlatencies (rs = 0.241; P = 0.008) of the left side. There were no significant correlations with N22a wave latencies. Patients who presented with transverse myelitis (N = 41) and patients who had spinal cord lesions on MRI (N = 53) had significantly higher total tSSEP z-score compared with other patients (0.07 vs. -0.28, P = 0.019 and -0.02 vs. -0.38 P = 0.023; respectively). Somatosensory-evoked potentials of the posterior tibial nerve z-score corrected for age, sex, cervical spinal cord MRI lesions, and total number of supratentorial T2 lesions was a statistically significant predictor for T25FW (B = 0.267, P = 0.023). CONCLUSIONS: Spinal somatosensory dysfunction is one of the factors associated with reduction in walking speed in early patients with multiple sclerosis. Somatosensory-evoked potentials of the posterior tibial nerve may potentially be useful in identifying patients at higher risk for the development of walking impairment in the future. PMID- 29135703 TI - A CASE OF RELAPSING RETINAL PIGMENT EPITHELIAL DETACHMENT IN PERIPAPILLARY PACHYCHOROID PIGMENT EPITHELIOPATHY. AB - PURPOSE: To report the findings in a patient with peripapillary pachychoroid pigment epitheliopathy who demonstrated a retinal pigment epithelial detachment (PED) that was present at some times but not other times. METHODS: A review of 24 months of the clinical course and findings on multimodal imaging, including color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, and enhanced depth imaging optical coherence tomography. Choroidal thickness was measured by exporting the optical coherence tomography images to ImageJ (National Institutes of Health) for analysis. RESULTS: A 75-year-old Asian woman complaining of metamorphopsia had a relapsing PED but no intraretinal or subretinal fluid. Multimodal imaging demonstrated an orange-reddish appearance and hyperautofluorescence/hypoautofluorescence in the nasal macula, chronically thickened choroid located beneath the PED and peripapillary region, and variability in the presence of Sattler layer of the choroid, with its disappearance in the foveal region during exacerbation of the condition, and its emergence when the PED resolved. CONCLUSION: In pachychoroid pigment epitheliopathy, PED can develop and spontaneously resolve, and variations in choroidal thickness and the presence of Sattler layer may be an indicator of changes in disease activity. PMID- 29135704 TI - POPPER MACULOPATHY: LONG-TERM FOLLOW-UP AND CASE SERIES. AB - PURPOSE: To report a case series of popper maculopathy. METHODS: Clinical history, examination findings, retinal imaging, and progress of the disease are described. RESULTS: Four male patients with a mean age of 37 years (range 25-48) and different duration of popper use (ranging from first time user to chronic user) presented with central scotomata, phosphenes, or photophobia. Optical coherence tomography in all cases demonstrated subfoveal disruption of the ellipsoid zone. Three cases also showed hyperreflectivity of the ellipsoid zone, and one case had a foveal detachment. Chronic user of poppers was associated with more severe macular changes. One patient had a 3-year follow-up and demonstrated complete resolution of signs on retinal imaging after ceasing popper use. CONCLUSION: Popper maculopathy may show complete resolution of signs on long-term follow-up, even after chronic popper ingestion. PMID- 29135705 TI - Effect of Simplifying Drilling Technique on Heat Generation During Osteotomy Preparation for Dental Implant. AB - OBJECTIVES: To test the hypothesis that there would be no difference in heat production by reducing the number of drills during the implant site preparation relative to conventional drilling sequence. METHODS: A total of 120 implant site preparations with 3 different diameters (3.6, 4.3, and 4.6 mm) were performed on bovine ribs. Within the same diameter group, half of the preparations were performed by a simplified drilling procedure (pilot drill + final diameter drill) and other half using the conventional drilling protocol (pilot drill followed by graduated series of drills to widen the site). Heat production by different drilling techniques was evaluated by measuring the bone temperature using k-type thermocouple and a sensitive thermometer before and after each drill. RESULTS: Mean for maximum temperature increase during site preparation of the 3.6, 4.3, and 4.6-mm implants was 2.45, 2.60, and 2.95 degrees when the site was prepared by the simplified procedure, whereas it was 2.85, 3.10, and 3.60 degrees for the sites prepared by the conventional technique, respectively. No significant difference in temperature increase was found when implants of the 3 different diameters were prepared either by the conventional or simplified drilling procedure. CONCLUSIONS: The simplified drilling technique produced similar amount of heat comparable to the conventional technique that proved the initial hypothesis. PMID- 29135706 TI - Magnetic Resonance Imaging of a Urethral Caruncle and the Pathologic Correlation: A Report of 3 Cases. AB - A urethral caruncle is the most common disease of the urethra in postmenopausal women. A definitive diagnosis can usually be reached based on physical examination. Cross-sectional imaging is performed when malignant urethral tumor is suspected, such as a urethral carcinoma. No articles have discussed the detailed imaging of urethral caruncles. We present 3 patients with symptomatic urethral caruncles who underwent magnetic resonance imaging preoperatively. PMID- 29135707 TI - Outcome of Therapeutic Keratoplasty in Hopeless Microbial Keratitis Cases Otherwise Advised Evisceration. AB - PURPOSE: To study the outcome of therapeutic keratoplasty in severe microbial keratitis cases otherwise advised evisceration. METHODS: A retrospective, single center clinical audit included 28 patients with severe microbial keratitis presenting from April 2014 to April 2016. Patients with microbial keratitis either affecting more than 2 quadrants of the limbus and/or cases with infections involving more than 180 mm of the cornea who were advised evisceration by more than one ophthalmologist were included. Cases with endophthalmitis were excluded. At 3 months, the outcome was "success" if resolution of infection occurred without recurrence and evisceration was not required. Success was termed "complete" if best vision was 6/24 or better and "partial" otherwise. The outcome was termed a "failure" if infection recurred in the graft or the eye was eviscerated. RESULTS: Mean age of the patients (male:female, 17:11) was 49.5 years, and the mean duration of symptoms before surgery was 28.6 days. Evisceration was required in 2/28 cases. The outcome was "success" in 22/28 cases (78.6%)-complete (10/22); partial (12/22)-and "failure" in 6/28 cases. The outcome was poorer in general in fungal keratitis (n = 16) than bacterial keratitis (n = 7). CONCLUSIONS: Primary evisceration is best avoided in infections limited to the anterior segment. Even in hopeless cases, every eye deserves a fair chance. PMID- 29135708 TI - High Permeability and Intercellular Space Widening With Brimonidine Tartrate Eye Drops in Cultured Stratified Human Corneal Epithelial Sheets. AB - PURPOSE: To investigate the toxicity of topical glaucoma medications using cultured stratified human corneal epithelial sheets (HCES). METHODS: HCES were exposed for 30 minutes to the following glaucoma medications: 0.1% brimonidine with sodium chlorite as the preservative, 0.005% latanoprost with 0.02% benzalkonium chloride (BAC) as the preservative, and 0.5% timolol with 0.005% BAC as the preservative. Then, cell viability and barrier function were tested by the WST-1 assay and carboxyfluorescein permeability assay, respectively. After exposure to glaucoma medications, HCES were evaluated by hematoxylin and eosin staining, periodic acid-Schiff staining, scanning electron microscopy, and transmission electron microscopy. RESULTS: HCES exposed to brimonidine showed higher viability and better preservation of cell morphology and microvilli compared with cell sheets exposed to latanoprost or timolol. The carboxyfluorescein permeability assay demonstrated that the barrier function was preserved after HCES were exposed to timolol, but not after exposure to brimonidine or latanoprost. Transmission electron microscopy revealed widening of intercellular junctions with prominent deposits of glycogen or mucopolysaccharide (periodic acid-Schiff positive) after exposure of HCES to brimonidine. CONCLUSIONS: The toxicity of 0.1% brimonidine containing sodium chlorite for HCES was lower than that of ophthalmic preparations containing BAC. Reduction of the barrier function occurred after HCES were exposed to brimonidine because of widening of intercellular junctions. PMID- 29135709 TI - Pilot Study Comparing Topical Anesthetic Agents in Pterygium Surgery: Subconjunctival Injection Versus 2% Lidocaine Gel Versus 5% Lidocaine Gel. AB - PURPOSE: To compare the efficacy of different concentrations of topical lidocaine gel with standard subconjunctival anesthesia. METHODS: This was a prospective randomized controlled pilot study with 3 different groups. Group SC received subconjunctival lidocaine and proparacaine drops as needed during surgery. Group L2 received 2% lidocaine gel and group L5 received 5% lidocaine gel. Both lidocaine gel groups could receive another gel dose as needed during the procedure. The primary outcome was pain, which was experienced during and after surgery. The assessment was done using a 10-point linear analog scale at predetermined stages of surgery (1-first incision, 2-pterygium body excision, 3 conjunctival suturing, 4-immediate postoperative period after patching, and 5 assessment by a trained nurse in the absence of a surgeon after operation). RESULTS: We enrolled 45 consecutive patients who underwent primary pterygium surgery. Statistical significance between groups was found in mean pain at administration (2.2 vs. 0.4 vs. 0.0 in SC, L2, and L5 groups, respectively, with P < 0.05). The number of reapplications of anesthetic drops did not differ between the groups. We found a correlation between reapplication of the anesthetic and pain at administration and duration of the procedure. CONCLUSIONS: We demonstrated that the use of lidocaine gel at concentrations of 2% and 5% in pterygium surgery was as effective as subconjunctival injection of lidocaine in reducing intraoperative and postoperative pain, producing significantly less pain during initial administration of the anesthetic. PMID- 29135710 TI - Adjustment of Intrastromal Corneal Ring Segments After Unsuccessful Implantation in Keratoconic Eyes. AB - PURPOSE: To evaluate visual, refractive, and corneal topography outcomes in eyes with keratoconus that have undergone exchange/adjustment surgery with a new intrastromal corneal ring segment (ICRS) combination after unsuccessful visual and/or refractive outcomes after primary ICRS surgery. METHODS: A retrospective nonrandomized case series was conducted including consecutive eyes of patients with keratoconus that underwent ICRS adjustment after an unsuccessful visual outcome. Patients were divided into 2 groups: group 1 was made up of patients with Intacs ICRSs that were exchanged for the Ferrara ICRS type, and group 2 consisted of patients who maintained the same ICRS type after undergoing ICRS adjustment surgery (change of the arc length or thickness). Uncorrected distance visual acuity, best-corrected distance visual acuity (CDVA), keratometry, asphericity, higher-order aberrations, and corneal regularity indexes (ISV and IHD) (Pentacam HR; OCULUS) were assessed preoperatively and 12 months after each procedure. RESULTS: Twenty-six eyes from 26 patients were included, 8 eyes in group 1 and 18 eyes in group 2. The eyes in both groups improved their CDVA values after ICRS exchange, in group 1 from 0.27 +/- 0.11 preoperatively to 0.54 +/- 0.17 postoperatively (P = 0.001), and in group 2 from 0.34 +/- 0.22 to 0.61 +/- 0.15 (P < 0.0001). In both groups, there was also a significant improvement in the refractive cylinder, topographic cylinder, and coma after ICRS adjustment (P < 0.05). CONCLUSIONS: ICRS implantation has been shown to be a reversible and adjustable surgical procedure for keratoconus treatment. Good outcomes can be obtained after ICRSs are exchanged. PMID- 29135711 TI - Artificial Anterior Chamber Pressure and Corneal Thinning Rate in UT-DSAEK. PMID- 29135712 TI - Limbal Stem Cell Preservation During Proton Beam Irradiation for Diffuse Iris Melanoma. PMID- 29135713 TI - Reply. PMID- 29135714 TI - Ritanserin, a serotonin-2 receptor antagonist, inhibits functional recovery after cerebral infarction. AB - It has been suggested that serotonin (5-HT) may be implicated in functional recovery after stroke; however, the underlying molecular mechanisms remain unknown. Here, the role of 5-HT was verified using ritanserin, a potent 5-HT2A receptor antagonist, and protein expression and modification were analyzed to further understand the association between paralysis recovery and molecular mechanisms in the brain. Experimental cerebral cortex infarctions were induced by photothrombosis in rats. Voluntary exercise was initiated 2 days after surgery. Motor performance was then measured using the rotarod test. Differences in protein expression and phosphorylation in the perilesional cortex were analyzed using western blot. In behavioral evaluations, performance in the rotarod test was significantly increased by exercise. However, there was a significantly lower value in time until falling after combined exercise and ritanserin administration compared with that of exercise alone. Protein expression analysis revealed that phosphorylation of protein kinase C (PKC) alpha, PKCepsilon, and growth associated protein 43 (GAP43) was significantly upregulated by exercise. These effects were attenuated by ritanserin administration. These data suggest that 5 HT may be related to the underlying mechanisms of exercise-dependent paralysis recovery, that is, exercise-dependent plasticity through the phosphorylation of PKC and GAP43. PMID- 29135715 TI - DNP Project Timeline Template: A Guide for Successful Completion. PMID- 29135716 TI - High-Stakes Testing in Nursing Education: A Review of the Literature. AB - In an aim to improve first-time NCLEX-RN pass rates, some nursing programs have instituted high-stakes testing. This literature review investigated nursing faculty understanding of and student experiences with high-stakes testing. High stakes testing is an assessment used to make decisions about student progression or completion of a nursing program. The literature revealed both negative and positive consequences associated with high-stakes testing. Literature from state boards of nursing and professional nursing organizations was also reviewed for recommendations. PMID- 29135717 TI - Traditional Versus Hybrid Outpatient Cardiac Rehabilitation: A COMPARISON OF PATIENT OUTCOMES. AB - PURPOSE: Due to the suboptimal uptake of cardiac rehabilitation (CR), alternative models have been proposed. This study compared the effectiveness of a traditional supervised program in a medical setting versus a hybrid CR model, where patients transition to unsupervised programming. METHODS: This was a prospective, 2-arm, nonrandomized study. Health-related quality of life (HRQoL), functional capacity, physical activity, diet, smoking, blood pressure, lipids, blood glucose, anthropometrics, and depressive symptoms were assessed before and after the 8 week program models. Program adherence and completion were also recorded. Both models offered outpatient supervised exercise sessions, group health education classes, and a resource manual. The hybrid model involved a blend of supervised and unsupervised, independent home-based exercise, and followup phone calls. RESULTS: One hundred twenty-five cardiac patients consented to the study, of whom 72 (57.6%) and 53 chose the traditional and hybrid programs, respectively. One hundred ten (traditional: n = 62, 86.1%; hybrid: n = 48, 92.3%; P > .05) participants completed their program. Significant improvements were observed for both models over time in HRQoL (P < .001), physical activity (P < .001), and diet (P < .001). Significant reductions in smoking (P = .043), systolic blood pressure (P < .001), total cholesterol (P < .001), low-density lipoprotein (P < .001), waist circumference (P < .001), and depressive symptoms (P < .001) were also observed. There were no significant differences pre- and postprograms between models for any outcome. CONCLUSIONS: Hybrid CR was not significantly different from the traditional model in terms of HRQoL, functional capacity, heart health behaviors, and risk factors, with no differences in completion rates. PMID- 29135718 TI - Case Report: Adenocarcinoma of the Lacrimal Gland Presenting as an Abduction Deficit. AB - SIGNIFICANCE: It is imperative to follow the clinical guidelines for abduction deficits to ensure prompt diagnosis of potentially serious etiologies and monitor only those in which a microvascular etiology is most likely. This case reports highlights a rare diagnosis of a malignant tumor of the lacrimal gland presenting as an abduction deficit. PURPOSE: Tumors of the lacrimal gland can cause abduction deficits, which may mimic an abducens nerve palsy. Abducens nerve palsies are often encountered by optometrists. This case report highlights the appropriate workup of an abduction deficit and reviews the literature of adenocarcinoma not otherwise specified. CASE REPORT: A 67-year-old white man was transferred to the optometry clinic with a presumed ischemic abducens palsy. He was found to have an isolated left abduction deficit without vascular risk factors that prompted neuroimaging revealing a mass of the lacrimal gland. After an en bloc resection, a diagnosis of adenocarcinoma not otherwise specified was made. The patient underwent aggressive surgical exenteration followed by radiation. CONCLUSIONS: Using the guidelines for evaluation of an abduction deficit, this serious malignancy was diagnosed. An adenocarcinoma not otherwise specified of the lacrimal gland is rare, and there are limited data on its clinical course, prognosis, and treatment. Recurrence and metastases occur at high rates; therefore, prompt diagnosis and aggressive intervention are crucial. PMID- 29135719 TI - Corneal Biomechanical Properties in High Myopia Measured by Dynamic Scheimpflug Imaging Technology. AB - SIGNIFICANCE: The cornea is a viscoelastic tissue with viscous and elastic properties. The information of corneal biomechanical changes in high myopia has implications for understanding the pathogenesis of high myopia and primary open angle glaucoma. However, the knowledge of corneal biomechanics in high myopia is limited. PURPOSE: To compare the corneal biomechanical properties in high-myopia subjects and emmetropia subjects. METHODS: Dynamic Scheimpflug imaging technology was used to measure intraocular pressure, central corneal thickness, and corneal biomechanical parameters, including time at the first applanation, velocity at the first applanation, length at the first applanation, deformation amplitude at the first applanation, time at the second applanation, A2V (velocity at the second applanation), length at the second applanation (A2L), deformation amplitude at the second applanation, time at the highest concavity, radius curvature at the highest concavity (HCR), maximal deformation amplitude (MDA), and peak distance. RESULTS: This study included 40 subjects with high myopia and 61 emmetropia subjects. The high-myopia demonstrated greater MDA compared with the emmetropia (1.07 +/- 0.01 vs. 1.02 +/- 0.01 mm; P < .001) after adjusting for age and intraocular pressure. Pooling analysis found that the high myopia exhibited a smaller HCR, greater MDA, faster A2V and shorter A2L, with a pooled mean difference of -0.21 mm (95% confidential interval [95% CI], -0.30 to -0.13; P < .001) for HCR, 0.05 mm (95% CI, 0.04 to 0.06; P < .001) for MDA, -0.03 m/s (95% CI, -0.06 to -0.002; P = .034) for A2V, and -0.05 mm (95% CI, -0.08 to 0.02; P = .001) for A2L. CONCLUSIONS: Eyes with high myopia showed a significantly smaller HCR, greater MDA, faster A2V, and shorter A2L than did those with emmetropia, which indicated that the cornea in an eye with high myopia becomes weaker and more deformable. PMID- 29135720 TI - Clinical Outcome Following Total Joint Replacement and Arthrodesis for Hallux Rigidus: A Systematic Review. AB - BACKGROUND: Hallux rigidus is a common cause of foot pain in the elderly and has a negative impact on quality of life. Several operative treatment options are available for feet that are refractory to conservative treatment. Of these, total joint replacement and arthrodesis of the first metatarsophalangeal joint are the most commonly performed interventions. Nevertheless, it is still not known which intervention results in the best clinical outcome and the fewest complications. METHODS: PubMed/MEDLINE, Embase, and the Cochrane Library were systematically searched for studies assessing outcome with the American Orthopaedic Foot & Ankle Society-Hallux Metatarsophalangeal Interphalangeal (AOFAS-HMI) score, Foot Function Index (FFI), visual analog scale (VAS) for pain, or Short Form-36 (SF 36) in patients who underwent an arthrodesis or total joint replacement for the treatment of symptomatic hallux rigidus. Secondary outcomes were complications and revision rates. The screening of titles and abstracts, data collection, data extraction, and study quality assessment were performed independently by 2 reviewers. Study quality was determined with use of risk-of-bias tools. Results of included studies were presented in a qualitative manner, and the results of high-quality studies were pooled. RESULTS: Thirty-three studies, describing a total of 741 arthrodeses and 555 total joint replacements, were included in the qualitative analysis. Six different prostheses were used for total joint replacement, and various fixation techniques were used for arthrodesis. The results of 6 arthrodesis studies and 7 total joint replacement studies were pooled in the quantitative analysis. Pooled results showed superiority of arthrodesis compared with total joint replacement for improving clinical outcome (by 43.8 versus 37.7 points on the AOFAS-HMI score) and reducing pain (a decrease of 6.56 versus 4.65 points on the VAS pain score). Because of the rare reporting of the FFI and SF-36, no comparison could be made for these outcomes. Fewer intervention-related complications (23.1% versus 26.3%) and revisions (3.9% versus 11%) were reported after arthrodesis as compared with total joint replacement, with pain and nonunion and prosthetic loosening being the most commonly reported complications after arthrodesis and total joint replacement, respectively. CONCLUSIONS: The present systematic review of the literature indicated that arthrodesis is superior for improving clinical outcome and reducing pain, and is less often accompanied by intervention-related complications and revisions, compared with total joint replacement in patients with symptomatic hallux rigidus. Prospective, randomized controlled trials will need to be conducted to verify this conclusion. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29135721 TI - Clinical outcomes and prognostic factors of radioiodine ablation therapy for lymph node metastases from papillary thyroid carcinoma. AB - OBJECTIVE: A total of 118 patients with papillary thyroid carcinoma treated with radioactive iodine for lymph node metastases were analyzed retrospectively between August 2008 and June 2014. We describe the clinical course of these patients and focus on factors associated with lymph node metastases response to iodine-131 (I) treatment. PATIENTS AND METHODS: A total of 118 postoperative papillary thyroid carcinoma patients who underwent I treatment with lymph nodes as the only site of metastasis on whole-body scan (I Rx-WBS) and single-photon emission computed tomography-computed tomography (SPECT-CT) were enrolled. Clinical and laboratory evaluations including I Rx-WBS, serum thyroglobulin level, and radiographic findings were carried out during follow-up. RESULTS: At the end of follow-up, the rates of complete remission and partial response were 28.0% (33/118) and 52.5% (62/118), respectively. An overall effective rate of 80.5% (95/118) was obtained after three times radioiodine therapy and administration of 3.7-16.7 GBq I. CONCLUSION: Our data indicate that I therapy is highly effective in the treatment of lymph node metastases from papillary thyroid carcinoma; patients with a small size of metastatic lymph node, younger patients, those with lower thyroglobulin levels, and patients with lymph node metastases detectable on the first postablative I Rx-WBS and single-photon emission computed tomography-computed tomography showed a good response to radioiodine ablation therapy. PMID- 29135722 TI - Assessment of biological and clinical aggressiveness of invasive ductal breast cancer using baseline 18F-FDG PET/CT-derived volumetric parameters. AB - OBJECTIVE: The aim of this study was to evaluate the relationship of baseline fluorine-18-fluorodeoxyglucose PET/computed tomography (CT)-derived volumetric parameters for the primary tumor with clinicopathological risk factors and molecular subtypes in patients with invasive ductal breast carcinoma (IDBC). PATIENTS AND METHODS: We evaluated 65 patients who underwent fluorine-18 fluorodeoxyglucose PET/CT for initial breast cancer staging. The association of maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume, and total lesion glycolysis (TLG) with clinicopathological risk factors and molecular subtypes was investigated and the discriminative power of significant features was assessed. RESULTS: All volumetric parameters were significantly higher for tumors measuring more than 2 cm and with a Ki-67 index of at least 20. Estrogen receptor (ER) and progesterone receptor (PR)-negative (ER-/PR-), human epidermal growth factor receptor 2 positive (HER2+), and triple-negative tumors showed increased SUVmax. SUVmax and SUVmean were higher for triple-negative and HER2+ IDBC than for ER+/HER2- IDBC. Metabolic tumor volume and TLG showed no differences among subtypes. All volumetric parameters correlated with the clinical tumor size and the Ki-67 index; these correlations differed among the different subtypes. Patients with systemic metastases showed significantly higher TLG. Receiver operating characteristic analysis showed that SUVmax had the highest discriminative power for the different subtypes, whereas TLG had a statistically significant discriminative power for systemic metastasis. CONCLUSION: SUVmax may appropriately reflect the immunohistochemical characteristics of IDBC, whereas TLG is associated with clinical risk factors and systemic metastasis. Our preliminary findings suggesting different relationships between volumetric parameters and the clinical tumor size and the Ki-67 index for different subtypes require further evaluation. PMID- 29135723 TI - Oral-Health-Related Quality of Life After Surgical Treatment of Osteonecrosis of the Jaws. AB - The aim of this study is to analyze the clinical outcome and the change in oral health-related quality of life (QoL) of osteoporotic patients affected by medication-related osteonecrosis of the jaws (MRONJ). Forty-one patients, consecutively treated for a 10-year period, were retrospectively analyzed. All the patients underwent a marginal osseous resective jaw surgery. A clinical 12 months postoperative evaluation has been performed and the complete mucosal healing, the absence of swelling and suppuration, and no signs of disease recurrence were defined like success parameters. Quality-of-life surveys tests like EORTC QQ-C30 and QLQ-HN35 appendices in conjunction with a perceived oral health visual analog scale (VAS) were administered before (time of diagnosis of MRONJ) and after surgery (at least 6 months) in order to record the different oral health status of the treated patients. The majority of MRONJ-diagnosed patients complained symptoms like pain, eating discomfort, and sense problems, with occasional involvement of the social dimension. There was a prevalence of troubles with social eating and social contact.The complete mucosal healing was achieved in 100% of the patients and the administered survey tests reported a significant improvement in all the investigated spheres. Similarly, an increased mean score of perceived oral health VAS was reported.Marginal-resective surgery of the necrotic jaw bone can be an effective treatment of osteoporotic patients affected by localized MRONJ. Quality-of-life parameters are demonstrated to be useful for recording the patient-centered outcome of MRONJ treatment. PMID- 29135724 TI - Alignment Strategy for Constricted Maxillary Dental Arch in Patients With Unilateral Cleft Lip and Palate Using Fixed Orthodontic Appliance. AB - The purpose of this study was to compare the alignment pattern of the constricted maxillary dental arch by fixed orthodontic treatment (FOT) in the well-aligned and constricted arches of unilateral cleft lip and palate (UCLP) patients. 19 UCLP patients were divided into Group 1 (well-aligned arch, n = 9) and Group 2 (constricted arch, n = 10). After the cephalometric and maxillary dental arch variables before (T1) and after FOT (T2) were measured, statistical analysis was performed. There were no significant differences in the surgical timing of cheiloplasty, palatoplasty, and secondary alveolar bone grafting and in the surgical method of cheiloplasty between the 2 groups. However, Group 2 had a higher percentage of palatoplasty method, which could leave the denuded bone for secondary healing than Group 1 (P < 0.05). Although Group 2 showed more constriction and asymmetry in the maxillary dental arch compared to Group 1 at the T1 stage (inter-second premolar width, greater segment angle [GSA], and lesser segment angle [LSA], all P < 0.05), these problems could be effectively resolved by FOT. As a result, at the stage T2, there was no significant difference in all the variables between the 2 groups. During T1-T2, there was a different pattern in change of variables between Groups 1 and 2 (anterior segment angle in the greater segment [P < 0.05] in Group 1 and U1-SN [P < 0.01], inter molar width [P < 0.05], GSA [P < 0.05[, and LSA [P < 0.01] in Group 2). Therefore, according to the maxillary dental arch shape, different strategy is necessary to obtain proper alignment by FOT. PMID- 29135725 TI - Firm Elevation of Reconstructed Auricle Using Polydactyly Digit in Microtia. AB - Total ear reconstruction for microtia is usually accomplished in 2 stages which is known as Nagata technique. After framework fabrication and implantation, the elevation procedure is required as a second step surgery. The authors are introducing a novel material for augmenting projection of rib cartilage framework in microtia treatment. PMID- 29135726 TI - Valgus Hindfoot Deformity Secondary to Neonatal Intravenous Infiltration. AB - Orthopedic complications of intravenous (IV) infiltration are rare, with only a handful of cases reported in the literature. Because of the relatively high rate of IV infiltration in neonates, however, such complications do occur and can include growth arrest, limb length discrepancy, and joint deformities that require surgical intervention. The risk of these complications is highest in preterm neonates. A 7-year-old girl presented to our institution with a severe valgus hindfoot deformity that developed secondary to a neonatal IV infiltration injury. Management consisted of a medial displacement calcaneal osteotomy followed 5 years later by a triple arthrodesis, Strayer procedure, and free flap transfer. PMID- 29135727 TI - Comparative Cost Analysis of Single and Mutli-Stage Temporal Deformity Correction Following Neurosurgical Procedures. AB - PURPOSE: Temporal hollowing deformity (THD) is a visible concavity/convexity in the temporal fossa; a complication often seen following neurosurgical/craniofacial procedures. Although numerous techniques have been described, no study to date has shown the healthcare costs associated with temporal hollowing correction surgery. Thus, the purpose here is to compare and contrast the direct costs related to temporal cranioplasty using various methods including: liquid poly-methyl-methacrylate (PMMA) implants with screw fixation, prebent, modified titanium mesh implants, and customized cranial implants (CCIs) with dual-purpose design. Understanding the financial implications related to this frequently encountered complication will help to motivate surgeons/healthcare facilities to better prevent and manage THD. METHODS: This is a single-surgeon, single-institution retrospective review of 23 THD patients randomly selected from between 2008 and 2015. Cost analysis variables include length of hospital stay, facility/professional fees, implant material fees, payer information, reimbursement rate, and net revenue. RESULTS: Of the 23 patients, ages ranged from 23 to 68 years with a mean of 48.3 years (SD 11.6). Within this cohort, 39.1% received dual-purpose PMMA CCIs (CCI PLUS), 17.4% received modified titanium mesh implants, and 43.5% received hand-molded, liquid PMMA implants with screw fixation. Total facility and/or professional charges ranged from $1978.00 to $126478.00. Average total facility charges per patient with dual-purpose CCIs were $34775.89 (SD +/- $22205.09) versus $35826.00 (SD +/- $23509.93) for modified titanium mesh implants and $46547.90 (SD +/- 81061.70) for liquid PMMA implants with screws. Mean length of inpatient stay was 5.7 days (SD = 8.1), and did not differ between implant types (P = 0.387). CONCLUSION: Temporal hollowing deformity is an expensive complication post-neurosurgery, and in the most severe form, requires a revision surgery for definitive correction. Therefore, surgeons should take further initiatives to employ reconstructive methods capable of minimizing risk for costly revision surgery, reducing morbidity related to visible deformity and accompanying social stigmata, and improving overall patient satisfaction. PMID- 29135728 TI - Internal Distraction Resulted in Improved Patient-Reported Outcomes for Midface Hypoplasia. AB - BACKGROUND: Both internal and external distraction devices have been used successfully in correcting midface hypoplasia. Although the indication for surgery and the osteotomy techniques may be similar, deciding when to use internal versus external devices has not been studied. The authors studied patient-reported outcomes with FACE-Q and functional surveys for internal and external devices for midface distraction patients. METHODS: Patients who underwent distraction advancement after Le Fort I and Le Fort III were surveyed using the FACE-Q survey and a functional survey. Equal groups of internal and external device patients were compared (n = 64). Data recorded included: sex, age, follow-up, diagnosis, operating room time, expected blood loss, length of stay, distraction length, consolidation time, and complications. RESULTS: Internal and external device groups were similar with regards to patient diagnosis, operative time, expected blood loss, distraction length but consolidation times differed (internal = 3.6 versus external = 1.1 months). For FACE-Q appearance appraisal, there were similarities in domain and scale. For the functional survey (airway/breathing, ocular/vision, occlusion/eating, speech/articulation), there was also similar scoring. However, internal device patients had superior FACE-Q scores for Quality of Life: Social Function (80.9 versus 68.9), Early Life Impact (92.9 versus 62.4), Dental Anxiety (70.2 versus 48.3), Psychological Well-being (87.8 versus 68.6); and Decision Satisfaction (81.2 versus 56.9) and Outcome Satisfaction (91.0 versus 84.7). CONCLUSIONS: Internal and external midface distraction patients had similar patient-reported outcomes for appearance and functional improvement; however, internal device patients were more satisfied with their quality of life and their decision to undergo the procedure. PMID- 29135729 TI - Strengthening Evidence in Cleft and Craniofacial Surgery. PMID- 29135730 TI - A Novel Secretome Biotherapeutic Influences Regeneration in Critical Size Bone Defects. AB - Severe traumatic injuries often result in critical size bone defects, which are unable to heal without treatment. Autologous grafting is the standard of care but requires additional surgeries for graft procurement. Amnion-derived multipotent progenitor cells release a secretome of biomolecules identified as integral to the process of bone regeneration and angiogenesis. This secretome is currently under development as a biotherapeutic. The efficacy of this secretome biotherapeutic was evaluated in vitro on the proliferation and migration of mesenchymal stem cells and osteoprogenitor cells as well as in vivo using a critical size rat calvarial defect model. The secretome biotherapeutic was loaded onto a collagen scaffold and placed into the defect, which was allowed to heal for 4 and 12 weeks. The secretome biotherapeutic enhanced the proliferation and migration of mesenchymal stem cells and proliferation of osteoprogenitor cells. Further, the secretome biotherapeutic improved new bone volume and connectivity by 12 weeks and significantly improved angiogenesis at 4 weeks and bone density at 4 and 12 weeks with no deleterious effects. The improvement in new bone volume, connectivity, and angiogenesis suggests that the secretome biotherapeutic has beneficial effects for bone healing and a higher dose of the secretome biotherapeutic may further improve regeneration. PMID- 29135731 TI - Drug Release: Proper Control to Help Clinical Application. PMID- 29135733 TI - Treatment of Maxillary Hypoplasia in Cleft Lip and Palate: Segmental Distraction Osteogenesis With Hyrax Device. AB - The objective of this work is to describe a segmental maxillary distraction osteogenesis (SDO) with segmental Lefort I with an inexpensive device.Four patients who presented severe class III and maxillary hypoplasia due to cleft lip and palate sequel were treated. A SDO was performed using a dental-anchored Hyrax device, achieving enlargement of the upper jaw without altering speech, with adequate and stable occlusion. Dental implants in a new formed bone were installed.The authors can conclude that SDO is a good treatment alternative for patients with maxillary hypoplasia. It preserves velopharyngeal function and is a stable treatment, maintaining the overjet achieved with distraction osteogenesis, without changes in posterior occlusion. The open bite generated with tooth-borne devices can be solved with temporary anchorage devices and intermaxillary elastics during consolidation phase. Modified Hyrax device allows expanding and moving forward the maxillary arch, with a low cost. PMID- 29135734 TI - Cone Beam Computed Tomography Assessment of Accessory Infraorbital Foramen and Determination of Infraorbital Foramen Position. AB - There is no evidence about evaluating accessory infraorbital foramen by 3 dimensional analysis like multi slice computed tomography or cone beam computed tomography (CBCT) in human subjects. To authors' best knowledge this is a first study to assess the accessory infraorbital foramen and position of infraorbital foramen in relation to crown of maxillary teeth using CBCT. This study primarily aimed to assess the location and number of accessory infraorbital foramen (AIOF), to measure the distance between main infraorbital foramen and AIOF and secondarily to determine the position of infraorbital foramen in relation to crowns of maxillary second premolar, first molar, and second molar. Cone beam computed tomography volumes of 200 patients were retrieved from the digital imaging and communications in medicine archive folder. Accessory infraorbital foramen was recognized in 29% of the patients among whom 46.6% were present on the right side, 31% on the left side, and 22.4% located bilaterally. The most frequent position of infraorbital foramen was found to be in line with crown of second premolar. The presence of AIOF and inability to recognize it in preoperative evaluation could be considered among the other reasons of failure or incomplete anesthesia. PMID- 29135735 TI - A Personal Approach to Bilateral Cleft Lip Repair. AB - Dr Michael B. Lewis has been using his personal approach to bilateral cleft lip (BCL) repair for 30 years to achieve a loose, pouting upper lip, a 90-degree columellar-labial angle, and a projecting nasal tip. This article describes technique and results. PMID- 29135736 TI - Use of Acellular Dermal Matrix in Craniosynostosis. AB - In craniofacial surgery, a wide spectrum of pathological conditions are usually treated. The aetiology of these could be congenital, traumatic, infective, post tumor resection, postradiation, autoimmune, iatrogenic, or other miscellaneous conditions. The surgical approach for the procedures is usually via a coronal incision. In a large proportion of the patients, the frontal bone is removed to obtain intracranial access. The frontal bone is then replaced either in its original form or in a remodeled state. In congenital conditions the supraorbital bar and frontal bone is often also removed, remodeled, and replaced. One of the common late sequelae following craniofacial surgery is contour irregularities of the frontal region. These irregularities can vary in their extent. They are invariably palpable and often visible. Surgeons have attempted various methods to improve the contour irregularities. Despite these measures contour irregularities can still ensue. In the authors' unit, the authors have been using acellular dermal matrix in an attempt to diminish the contour irregularities in the frontal region following craniofacial reconstruction for craniosynostosis. This has been used in 35 patients undergoing craniosynostosis correction. Of the 35 patients, 12 were for plagiocephaly, 7 for brachycephaly, 10 for scaphocephaly, 4 for trigonocephaly, and 2 for combined coronal and metopic synostosis. The age of the patients ranged from 5 months to 12 years (mean 20.5 months). There were 21 males and 14 females. The follow-up ranged from 10 to 48 months (mean 23 months). PMID- 29135737 TI - Effect of Long-Term Use of Facemask With Miniplate on Maxillary Protraction in Patients With Cleft Lip and Palate. AB - The purpose of this retrospective study was to investigate the effect of a long term use of facemask with miniplate (FM-MP) on maxillary protraction in cleft lip and palate (CLP) patients. The subjects were 21 CLP patients (16 unilateral CLP and 5 bilateral CLP patients), who were treated with identical lip and palate surgical method and FM-MP therapy performed by single surgeon and single orthodontist. Lateral cephalogram was taken before (T1; mean age, 11.1 years) and after maxillary protraction (T2; mean age, 16.9 years). The mean duration of FM MP was 68.0 months. After 17 cephalometric variables were measured, statistical analysis was performed. During T1-T2, the maxilla showed significant forward movement (DeltaA-vertical reference plane, 4.8 mm, P < 0.001; DeltaSNA, 1.9 degree, P < 0.001; DeltaA-N perp, 1.9 mm, P < 0.05), although the mandible exhibited a forward growth (DeltaSNB, 1.2 degree, P < 0.05). Despite downward movement of the posterior maxilla with counterclockwise rotation (Deltapalatal plane angle, -1.5 degree, P < 0.05), the mandible did not exhibit clockwise rotation but counterclockwise rotation (DeltaSN to mandibular plane angle, -1.4 degree, DeltaBjork sum, -1.4 degree, Deltaocclusal plane to SN plane angle, -1.5 degree, DeltaFMA, -1.0 degree, all P < 0.05) and showed decrease in Gonial angle (-1.2 degree, P < 0.01). Although there was labioversion of the maxillary incisor (DeltaU1 to SN, 4.1 degree, P < 0.05), the mandibular incisor did not exhibit significant linguoversion (DeltaIMPA, -1.3 degree, P > 0.05). Long-term use of FM MP is effective on maxillary protraction in adolescent CLP patients without clockwise rotation of the mandible, the main drawback of conventional facemask with tooth-borne anchorage. PMID- 29135739 TI - Opportunities and challenges in a world of data abundance. PMID- 29135738 TI - Efficacy of Rebamipide Instillation for Contact Lens Discomfort With Dry Eye. AB - OBJECTIVE: To examine the effects of rebamipide ophthalmic solution on the symptoms, signs, and cytokine concentrations in tear fluid among soft contact lens (SCL) wearers with Dry eye disease (DED). METHODS: From November 2015 to June 2017, this open-label, single-arm study examined 40 eyes of 20 SCL wearers with DED who had been using daily disposable SCLs for >3 months (mean age, 30.0+/ 8.33 years; range, 20-47 years). Signs, symptoms, and cytokine concentrations were assessed before and 4 weeks after starting 2% rebamipide ophthalmic solution 4 times/day. Dry eye disease was diagnosed according to: compromised tear dynamics (Schirmer test <=5 mm or tear break-up time (TBUT) <=5 sec); ocular surface abnormalities (positive vital staining with fluorescein or lissamine green); and presence of symptoms. Touch thresholds using a Cochet-Bonnet anesthesiometer were also determined for the cornea and conjunctivae. Symptoms were assessed using the 12-item Ocular Surface Disease Index questionnaire. Concentrations of cytokines in tear fluid were measured. RESULTS: Significant improvements in signs were seen for TBUT, surface abnormalities, and touch thresholds. Ocular Surface Disease Index scores likewise improved significantly in all the 12 items. Of the cytokines measured, only interleukin-1beta, interleukin-8, and monocyte chemotactic protein-1 were found in >=60% of tear samples, with no significant differences in concentrations before and after rebamipide use. CONCLUSIONS: Rebamipide significantly improved all signs and symptoms in patients with DED who wore daily disposable SCLs. Rebamipide is effective for DED treatment with SCL wear. PMID- 29135740 TI - Experiences of women discharged less than 24 hours post vaginal birth: a systematic review protocol. AB - REVIEW QUESTION: The objective of this qualitative review is to synthesize the best available evidence on the meaning of early hospital discharge for women following a normal vaginal birth. PMID- 29135741 TI - The association between anti-thyroid antibodies and quality of life in patients with thyroid disorders: a systematic review protocol. AB - REVIEW QUESTION: The objective of this systematic literature review is to identify the association between anti-thyroid antibodies and quality of life in patients with thyroid disorders. PMID- 29135742 TI - The effect of high fidelity simulated learning methods on physiotherapy pre registration education: a systematic review protocol. AB - REVIEW OBJECTIVE: The objective of this review is to identify if high fidelity simulated learning methods are effective in enhancing clinical/practical skills compared to usual, low fidelity simulated learning methods in pre-registration physiotherapy education. PMID- 29135743 TI - Experiences of people with Parkinson's disease and their views of physical activity interventions: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVES:: This review aims to explore the experiences of people with Parkinson's disease (pwPD) participation in physical activity and their views of interventions designed to engage and sustain engagement. Synthesis of the best available evidence will be used to determine any gaps in the research literature and make recommendations on approaches to increase and maintain engagement in physical activity in pwPD living in a community setting. The specific objectives are to. PMID- 29135744 TI - Digital technologies in occupational therapy and physiotherapy undergraduate and postgraduate education: a scoping review protocol. AB - REVIEW QUESTION AND OBJECTIVE: How have digital technologies been used in occupational therapy and physiotherapy undergraduate and postgraduate education?Specifically, the objective of this scoping review is to present an overview of research on the use of digital technologies in terms of type of digital technology used, pedagogy associated with the use of digital technology, subject/topic/area of application, experiences/perception of digital technology used, outcomes of the digital technology used and challenges to the use of digital technologies in occupational therapy and physiotherapy undergraduate and postgraduate education. PMID- 29135745 TI - Factors influencing self-management in adults with diabetes: an umbrella review protocol. AB - REVIEW OBJECTIVES: The aim of this umbrella review is to identify and describe factors influencing diabetes self-management (DSM) in adults with diabetes. More specifically, we will address DSM-related factors and their relationships, considering both qualitative and quantitative components of available literature.The review question for the qualitative component of the umbrella review is:The review questions for the quantitative component of the umbrella review are:An additional question will be applied to both the qualitative and quantitative components of the overview. PMID- 29135746 TI - Computerized clinical decision support system utilization in nursing: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this scoping review is to comprehensively identify and examine the available literature on computerized clinical decision support systems utilized in nursing. The following focus questions will be used as an initial starting point in order to map and discuss important characteristics of the work done in this field. PMID- 29135747 TI - Experiences of HIV-infected adults and healthcare providers with healthcare delivery practices influencing engagement in primary healthcare settings: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this qualitative systematic review is to examine the experience and impact of health care delivery on health care engagement for adults infected with the human immunodeficiency virus receiving primary care. This review will identify and synthesize the best available evidence on health care structures, processes and practices that promote patient engagement in primary health care.The review question to be addressed is: What are the experiences of people living with human immunodeficiency virus (PLWH) and their health care providers with health care delivery processes and practices that impact engagement in primary health care settings (clinics, physician offices, and other community-based health care settings)? Specifically this review will compile evidence to illuminate health care system structures, provider practices, care delivery and programmatic processes that impact engagement in primary health care, as perceived by PLWH and their providers. PMID- 29135748 TI - Emotional intelligence in nurse management and nurse job satisfaction and retention: a scoping review protocol. AB - OBJECTIVE: The objective of this review is to map what is known about emotional intelligence (EI) in relation to staff job satisfaction and retention in nursing, and the tools that are used to measure EI in this context. REVIEW QUESTIONS: The primary question of this review is: What is known about nurse managers' EI as it relates to staff job satisfaction and retention in nursing?Sub-question 1: What tools are being used to measure nurse managers' EI and what theoretical frameworks are they based on?Sub-question 2: What gaps exist in the research related to nurse managers' EI as it relates to staff job satisfaction and retention in nursing? PMID- 29135749 TI - Recurrence rates of hyperemesis gravidarum in pregnancy: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The quantitative objective of this review is to identify the recurrence rate of hyperemesis gravidarum (HG) in subsequent pregnancies. PMID- 29135750 TI - Student and educator experiences of maternal-child simulation-based learning: a systematic review of qualitative evidence. AB - BACKGROUND: Although maternal-child care is a pillar of primary health care, there is a global shortage of maternal-child health care providers. Nurse educators experience difficulties providing undergraduate students with maternal child learning experiences for a number of reasons. Simulation has the potential to complement learning in clinical and classroom settings. Although systematic reviews of simulation are available, no systematic reviews of qualitative evidence related to maternal-child simulation-based learning (SBL) for undergraduate nursing students and/or educators have been located. OBJECTIVES: The aim of this systematic review was to identify the appropriateness and meaningfulness of maternal-child simulation-based learning for undergraduate nursing students and nursing educators in educational settings to inform curriculum decision-making. The review questions are: INCLUSION CRITERIA TYPES OF PARTICIPANTS: Pre-registration or pre-licensure or undergraduate nursing or health professional students and educators. PHENOMENA OF INTEREST: Experiences of simulation in an educational setting with a focus relevant to maternal child nursing. TYPES OF STUDIES: Qualitative research and educational evaluation using qualitative methods. CONTEXT: North America, Europe, Australia and New Zealand. SEARCH STRATEGY: A three-step search strategy identified published studies in the English language from 2000 until April 2016. METHODOLOGICAL QUALITY: Identified studies that met the inclusion criteria were retrieved and critically appraised using the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) by at least two independent reviewers. Overall the methodological quality of the included studies was low. DATA EXTRACTION: Qualitative findings were extracted by two independent reviewers using JBI-QARI data extraction tools. DATA SYNTHESIS: Findings were aggregated and categorized on the basis of similarity in meaning. Categories were subjected to a meta-synthesis to produce a single comprehensive set of synthesized findings. RESULTS: Twenty-two articles from 19 studies were included in the review. A total of 112 findings were extracted from the included articles. Findings were grouped into 15 categories created on the basis of similarity of meaning. Meta-synthesis of these categories generated three synthesized findings.Synthesized finding 1 Students experienced simulated learning experiences (SLE) as preparation that enhanced their confidence in practice. When simulation was being used for evaluation purposes many students experienced anxiety about the SLE.Synthesized finding 2 Pedagogical practices thought to be appropriate and meaningful included: realistic, relevant and engaging scenarios, a safe non-threatening learning environment, supportive guidance throughout the process, and integration with curriculum.Synthesized finding 3 Barriers and enablers to incorporating SLEs into maternal child education were identified including adequate resources, technological support and faculty development. Students and educators recognized that some things, such as relationship building, could not be simulated. CONCLUSIONS: Students felt that simulation prepared them for practice through building their self-confidence related to frequently and infrequently seen maternal-child scenarios. Specific pedagogical elements support the meaningfulness of the simulation for student learning. The presence or absence of resources impacts the capacity of educators to integrate simulation activities throughout curricula. PMID- 29135751 TI - Perceptions, experiences and preferences of patients receiving a clinician's touch during intimate care and procedures: a qualitative systematic review. AB - BACKGROUND: Clinical practice frequently involves the practitioner touching patients' bodies in areas that are highly personal. If inappropriately performed, such intimate touch may result in much anxiety, confusion and misinterpretation. Examination of evidence is necessary to guide practice in this area to mitigate risks and foster optimal clinician-patient relations and care. OBJECTIVES: The objective of this qualitative systematic review was to identify and synthesize findings on the perceptions, experiences and preferences of patients receiving a clinician's touch during intimate care and procedures INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review considered studies that included patients who had received a clinician's touch during intimate care and procedures. PHENOMENA OF INTEREST: The current review considered qualitative studies that evaluated patients' perceptions, experiences and preferences of a clinician's touch during intimate care and procedures. TYPES OF STUDIES: The current review considered studies that collected qualitative data and included studies using designs such as phenomenology, grounded theory, ethnography, action research, qualitative description, focus group methodology and feminist research. In the absence of research studies, other text such as opinion papers and reports were considered. CONTEXT: The current review considered studies that included patients' perceptions, experiences and preferences of a clinician's touch during intimate care and procedures. Intimate care is likely to occur in any clinical setting where patients need assistance with personal care, where physical examinations occur, or in settings were gynecologic, genitourinary, lower intestinal, dermatologic, cardiac or other procedures involving highly personal areas of the body are performed. SEARCH STRATEGY: A three-step search strategy was used to find published and unpublished studies in English from 1970 to 2016, searching various databases which included searches of reference lists of studies selected for appraisal. METHODOLOGICAL QUALITY: Included studies were assessed for methodological quality independently by two reviewers using the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) prior to inclusion. Of the two studies included in the review, one did not discuss ontological and epistemological assumptions, and the other did not include the personal assumptions and role of the researcher. DATA EXTRACTION: Data were extracted using the data extraction tool from the JBI-QARI. The data extracted included details about the phenomenon of interest, populations and study methods. DATA SYNTHESIS: Qualitative findings were synthesized using JBI-QARI. RESULTS: Two studies were included in this review. Seven findings were organized into three categories and one synthesized finding, "clinician respect". The finding suggests that clients prefer engaged and meaningful communication prior to and during an intimate touch encounter, expect autonomy over their bodies and desire shared decision making relative to how and by whom intimate touch is provided. CONCLUSION: The synthesized finding from this review suggests that:More research is needed to explore the perceptions and preferences for intimate touch among diverse populations, generations, cultures and contexts. Particular exploration is needed for populations with additional vulnerabilities to misunderstandings, anxiety and abuse, such as pediatric and geriatric patients, and patients with physical, mental and cognitive impairments. PMID- 29135752 TI - Experiences and shared meaning of teamwork and interprofessional collaboration among health care professionals in primary health care settings: a systematic review. AB - BACKGROUND: During the last decade, teamwork has been addressed under the rationale of interprofessional practice or collaboration, highlighted by the attributes of this practice such as: interdependence of professional actions, focus on user needs, negotiation between professionals, shared decision making, mutual respect and trust among professionals, and acknowledgment of the role and work of the different professional groups. Teamwork and interprofessional collaboration have been pointed out as astrategy for effective organization of health care services as the complexity of healthcare requires integration of knowledge and practices from differente professional groups. This integration has a qualitative dimension that can be identified through the experiences of health professionals and to the meaning they give to teamwork. OBJECTIVE: The objective of this systematic review was to synthesize the best available evidence on the experiences of health professionals regarding teamwork and interprofessional collaboration in primary health care settings. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The populations included were all officially regulated health professionals that work in primary health settings: dentistry, medicine, midwifery, nursing, nutrition, occupational therapy, pharmacy, physical education, physiotherapy, psychology, social work and speech therapy. In addition to these professionals, community health workers, nursing assistants, licensed practical nurses and other allied health workers were also included. PHENOMENA OF INTEREST: The phenomena of interest were experiences of health professionals regarding teamwork and interprofessional collaboration in primary health care settings. CONTEXT: The context was primary health care settings that included health care centers, health maintenance organizations, integrative medicine practices, integrative health care, family practices, primary care organizations and family medical clinics. National health surgery as a setting was excluded. TYPES OF STUDIES: The qualitative component of the review considered studies that focused on qualitative data including designs such as phenomenology, grounded theory, ethnography, action research and feminist research. SEARCH STRATEGY: A three-step search strategy was utilized. Ten databases were searched for papers published from 1980 to June 2015. Studies published in English, Portuguese and Spanish were considered. METHODOLOGICAL QUALITY: Methodological quality was assessed using the Qualitative Assessment and Review Instrument developed by the Joanna Briggs Institute. All included studies received a score of at least 70% the questions in the instrument, 11 studies did not address the influence of the researcher on the research or vice-versa, and six studies did not present a statement locating the researcher culturally or theoretically. DATA EXTRACTION: Qualitative findings were extracted using the Joanna Briggs Institute Qualitative Assessment and Review Instrument. DATA SYNTHESIS: Qualitative research findings were pooled using a pragmatic meta-aggregative approach and the Joanna Briggs Institute Qualitative Assessment and Review Instrument software. RESULTS: This review included 21 research studies, representing various countries and healthcare settings. There were 223 findings, which were aggregated into 15 categories, and three synthesized findings: CONCLUSIONS: This review shows that health professionals experience teamwork and interprofessional collaboration as a process in primary health care settings; its conditions, consequences (benefits and barriers), and finally shows its determinants. Health providers face enormous ideological, organizational, structural and relational challenges while promoting teamwork and interprofessional collaboration in primary health care settings. This review has identified possible actions that could improve implementation of teamwork and interprofessional collaboration in primary health care. PMID- 29135753 TI - Prevention of neonatal unplanned extubations in the neonatal intensive care unit: a best practice implementation project. AB - BACKGROUND: Adverse events of mechanically ventilated neonates such as unplanned extubations may be associated with serious negative outcomes. Unplanned extubation rates have been monitored by many neonatal intensive care units as a quality of care metric. OBJECTIVES: The objective was to implement evidence-based best practice and assess the effects of these strategies on minimizing unplanned extubation in the neonatal intensive care unit in a large tertiary children's hospital. METHODS: Evidence-based audit criteria were used to conduct an audit in the neonatal intensive care unit, Children's Hospital of Fudan University, Shanghai. The program included three phases and was conducted from May 2016 to October 2016. The Joanna Briggs Institute Practical Application of Clinical Evidence System and Getting Research into Practice audit tools for promoting change in health practice were used to ascertain compliance with the criteria before and after the implementation of best practice. RESULTS: Compared with the baseline audit, the follow-up audit results demonstrated increased compliance rates for securement procedures, documentation of position and security of the endotracheal tube. Compliance for standardized care practice documentation increased from 0% to 100%; compliance for standard care practice implementation increased from 0% to 54.9%; and compliance for staff education increased from 66.7% to 100%. The neonatal intensive care unit also achieved the benchmark of less than one UE per 100 intubation days. CONCLUSIONS: This implementation project achieved a significant improvement in establishing evidence-based prevention of unplanned extubations in the neonatal intensive care unit of Children's Hospital of Fudan University, China. Standardizing the procedures represented an important step toward refining the quality improvement process. PMID- 29135754 TI - Implementation of a pediatric behavioral staffing algorithm in an acute hospital: a best practice implementation project. AB - BACKGROUND: A progressive decline in acute psychiatric facility beds has led to a steadily increasing number of pediatric psychiatric patients hospitalized on acute care medical-surgical units. Clinical nurses in this environment feel ill equipped to provide quality behavioral health care. AIMS/OBJECTIVES: This project aimed to improve continuity of care as well as staff and patient safety in pediatric acute and transitional care units. The specific objectives related to implementation of a resource allocation algorithm for staffing behavioral health admissions and consistent use of an interdisciplinary psychiatric huddle. METHODS: This project used the Joanna Briggs Institute's Practical Application of Clinical Evidence System (PACES) and Getting Research into Practice (GRiP) audit tool for promoting health practice change. A baseline medical record audit was conducted which was followed by charge nurse education on the resource allocation algorithm and huddle initiation. Three follow-up audits measured compliance with best practice criteria for assessing and managing care of behavioral pediatric patients. RESULTS: Compliance with comprehensively assessing children with challenging behaviors who were hospitalized in acute care units achieved 100% for the first three months following algorithm implementation. Nurses reached 100% compliance with initiating psychiatric huddles. All audits for individualized care plans, which included family or carer involvement, were fully compliant. CONCLUSIONS: Use of a resource allocation algorithm for individualizing care of pediatric behavioral patients enhanced quality of care through a standardized process which enabled acute care nurses to better meet the safety needs of this patient population. Early signs of sustaining improvements were promising for hard-wiring workflows. Future plans include adoption of the algorithm and huddle by all in-patient areas in the children's hospital. PMID- 29135755 TI - Management of skin toxicity caused by epidermal growth factor receptor inhibitors: an evidence-based implementation project. AB - BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) bind to and inhibit epidermal growth factor receptors (EGFRs) in cancer cells, slowing/preventing tumor growth. As a type of "targeted therapy", they have demonstrated therapeutic effects on solid tumors including colorectal, lung, and head and neck cancers. While effective, various skin reactions are associated with EGFRI therapy which can lead to dose modification or discontinuation as well as discomfort, pain and reduced quality of life. With adequate knowledge and skills, EGFRI-induced skin toxicity can be effectively managed collaboratively by clinicians and people affected by cancer. OBJECTIVES: This project aimed to improve management of skin toxicity caused by EGFRIs by implementing evidence informed practice within a chemotherapy department. METHODS: Evidence-informed recommendations for practice and corresponding audit criteria were developed based on a series of literature reviews. Current practice was reviewed against these criteria with 19 nurses and 21 patients within a chemotherapy department. Barriers to adherence to evidence-informed practice were identified and strategies to improve compliance were implemented with clinicians and patients. A follow-up audit against the criteria was used to measure changes in clinical practice. RESULTS: Multiple strategies for getting research into practice appear to have been successful. The follow-up audit demonstrated large improvements in compliance across all audit criteria in comparison with baseline results with all but one criterion achieving 100% compliance. Low rates of suspected infection meant that clinical practice could not be measured for criterion 7. CONCLUSIONS: Auditing current practice and implementation of strategies to improve compliance with evidence-informed practice were effective. Sustaining these improvements is vital to ensure clinical practice continues to support better patient outcomes. PMID- 29135756 TI - Letter From the President. PMID- 29135757 TI - Editorial. PMID- 29135758 TI - Interview With Rulon F. Stacey, PhD, FACHE, Managing Director, Healthcare, Navigant Consulting. PMID- 29135759 TI - Sustaining and Growing a Winning Culture. PMID- 29135760 TI - Creating a System of Consistent Safety in the Froedtert & Medical College of Wisconsin Health Network. PMID- 29135761 TI - Ten CEO Imperatives for Healthcare Transformation: Lessons From Top-Performing Academic Medical Centers. AB - EXECUTIVE SUMMARY: The transition from a delivery model based on volume to a model based on value is underpinning an unprecedented rate of change in healthcare. Our research identifies academic medical centers that have successfully moved their organizations from a volume-based care delivery model to a model that is based on value, achieving top decile performance in the transition. We asked senior leaders about their key imperatives in achieving system-wide healthcare transformations.Major teaching hospitals were sampled using data envelopment analysis to identify hospitals that produced the best value-based purchasing process of care, Hospital Consumer Assessment of Healthcare Providers and Systems scores, and mortality scores with the most efficient utilization of human and financial organizational resources. On-site interviews were conducted with the CEOs of the top-performing hospitals. Content analysis of the transcribed interviews revealed 10 clear imperatives that our sample of CEOs said were essential. PMID- 29135762 TI - Practitioner Application: Ten CEO Imperatives for Healthcare Transformation: Lessons From Top-Performing Academic Medical Centers. PMID- 29135763 TI - Health System Creation and Integration at a Health Sciences University: A Five Year Follow-up. AB - EXECUTIVE SUMMARY: Shifting healthcare market forces and regulation have exerted near-constant pressure on U.S. academic health centers (AHCs) attempting to successfully execute their traditional tripartite mission. A governance structure and organizational alignment that works well under one set of conditions is rarely optimal when conditions change. Thus, the degree and type of alignment of an AHC's clinical, educational, and faculty practice organizations have changed regularly within the sector, typically landing near one end or the other on a continuum from fully aligned with centralized governance to largely independent with separate governance. The authors examine the case of Georgia Regents University and Health System in this context. In step with industry trends, the institution's governance structure swung from fully aligned/centralized governance in the early 1990s to essentially separate and decentralized by 2000. In 2010, the Georgia Regents University organizations achieved rapid realignment by creating a governance structure of sufficient strength and flexibility to absorb and adjust to continuing external upheaval. The hospitals, clinics, and physician-faculty practice group were combined into one integrated health system, then aligned with the university to form the state's only public AHC under aligned, but distinct, corporate and management structures. The years since reorganization have seen significant growth in patient volumes and complexity, improved service quality, and enhanced faculty physician satisfaction, while also significantly increasing economic contributions from the health system to the academic mission. This case study offers observations and lessons learned that may be useful to other higher education institutions considering reorganization. PMID- 29135764 TI - Practitioner Application: Health System Creation and Integration at a Health Sciences University: A Five-Year Follow-up. PMID- 29135765 TI - The Effects of Price and Health Consciousness and Satisfaction on the Medical Tourism Experience. AB - EXECUTIVE SUMMARY: The objective of this study was to analyze the effects of price and health consciousness on medical tourism. Accordingly, we explore the utility of the theory of planned behavior for assessing the relationships between several variables and explain consumers' intentions to be repeat medical tourists. A 26-item questionnaire was developed, and data were collected from 407 patients who visited South Korea for medical purposes. Structural equation modeling was used to analyze the data. The results indicate that medical tourists' price consciousness was significant with respect to their satisfaction with medical and travel services. However, health consciousness also influenced their decision-making process. The study results reveal that health consciousness did not have a significant effect on tourists' satisfaction with medical travel services. Although this study was conducted in South Korea, the findings may be relevant elsewhere. When developing products and services for the medical tourism industry, policymakers and service providers should focus on the importance of cost-effectiveness. PMID- 29135766 TI - Practitioner Application: The Effects of Price and Health Consciousness and Satisfaction on the Medical Tourism Experience. PMID- 29135767 TI - Implementing Accountable Care Organizations: Lessons From a Qualitative Analysis of Four Private Sector Organizations. AB - EXECUTIVE SUMMARY: Accountable care organizations (ACOs) are emerging across the healthcare marketplace and now include Medicare, Medicaid, and private sector payers covering more than 24 million lives. However, little is known about the process of organizational change required to achieve cost savings and quality improvements from the ACO model. This study applies the complex innovation implementation framework to understand the challenges and facilitators associated with the ACO implementation process. We conducted four case studies of private sector ACOs, selected to achieve variation in terms of geography and organizational maturity. Across sites, we used semistructured interviews with 68 key informants to elicit information regarding ACO implementation. Our analysis found challenges and facilitators across all domains in the conceptual framework. Notably, our findings deviated from the framework in two ways. First, findings from the financial resource availability domain revealed both financial and nonfinancial (i.e., labor) resources that contributed to implementation effectiveness. Second, a new domain, patient engagement, emerged as an important factor in implementation effectiveness. We present these deviations in an adapted framework. As the ACO model proliferates, these findings can support implementation efforts, and they highlight the importance of focusing on patients throughout the process. Importantly, this study extends the complex innovation implementation framework to incorporate consumers into the implementation framework, making it more patient centered and aiding future efforts. PMID- 29135768 TI - Practitioner Application: Implementing Accountable Health Organizations: Lessons From a Qualitative Analysis of Four Private Sector Organizations. PMID- 29135769 TI - Medicaid Coverage of Methadone Maintenance and the Use of Opioid Agonist Therapy Among Pregnant Women in Specialty Treatment. AB - BACKGROUND: Opioid agonist therapy (OAT) is the standard of care for pregnant women with opioid use disorder (OUD). Medicaid coverage policies may strongly influence OAT use in this group. OBJECTIVE: To examine the association between Medicaid coverage of methadone maintenance and planned use of OAT in the publicly funded treatment system. RESEARCH DESIGN: Retrospective cross-sectional analysis of treatment admissions in 30 states extracted from the Treatment Episode Data Set (2013 and 2014). SUBJECTS: Medicaid-insured pregnant women with OUD (n=3354 treatment admissions). MEASURES: The main outcome measure was planned use of OAT on admission. The main exposure was state Medicaid coverage of methadone maintenance. Using multivariable logistic regression models adjusting for sociodemographic, substance use, and treatment characteristics, we compared the probability of planned OAT use in states with Medicaid coverage of methadone maintenance versus states without coverage. RESULTS: A total of 71% of pregnant women admitted to OUD treatment were 18-29 years old, 85% were white non Hispanic, and 56% used heroin. Overall, 74% of admissions occurred in the 18 states with Medicaid coverage of methadone maintenance and 53% of admissions involved planned use of OAT. Compared with states without Medicaid coverage of methadone maintenance, admissions in states with coverage were significantly more likely to involve planned OAT use (adjusted difference: 32.9 percentage points, 95% confidence interval, 19.2-46.7). CONCLUSIONS: Including methadone maintenance in the Medicaid benefit is essential to increasing OAT among pregnant women with OUD and should be considered a key policy strategy to enhance outcomes for mothers and newborns. PMID- 29135770 TI - An Electronic Health Record-based Algorithm to Ascertain the Date of Second Breast Cancer Events. AB - OBJECTIVES: Studies of cancer recurrences and second primary tumors require information on outcome dates. Little is known about how well electronic health record-based algorithms can identify dates or how errors in dates can bias analyses. RESEARCH DESIGN: We assessed rule-based and model-fitting approaches to assign event dates using a previously published electronic health record-based algorithm for second breast cancer events (SBCE). We conducted a simulation study to assess bias due to date assignment errors in time-to-event analyses. SUBJECTS: From a cohort of 3152 early-stage breast cancer patients, 358 women accurately identified as having had an SBCE served as the basis for this analysis. MEASURES: Percent of predicted SBCE dates identified within +/-60 days of the true date was the primary measure of accuracy. In the simulation study, bias in hazard ratios (HRs) was estimated by averaging the difference between HRs based on algorithm assigned dates and the true HR across 1000 simulations each with simulated N=4000. RESULTS: The most accurate date algorithm had a median difference between the true and predicted dates of 0 days with 82% of predicted dates falling within 60 days of the true date. Bias resulted when algorithm sensitivity and specificity varied by exposure status, but was minimal when date assignment errors were of the magnitude observed for our date assignment method. CONCLUSIONS: SBCE date can be relatively accurately assigned based on a previous algorithm. While acceptable in many scenarios, algorithm-assigned dates are not appropriate to use when operating characteristics are likely to vary by the study exposure. PMID- 29135771 TI - Detecting Lung and Colorectal Cancer Recurrence Using Structured Clinical/Administrative Data to Enable Outcomes Research and Population Health Management. AB - INTRODUCTION: Recurrent cancer is common, costly, and lethal, yet we know little about it in community-based populations. Electronic health records and tumor registries contain vast amounts of data regarding community-based patients, but usually lack recurrence status. Existing algorithms that use structured data to detect recurrence have limitations. METHODS: We developed algorithms to detect the presence and timing of recurrence after definitive therapy for stages I-III lung and colorectal cancer using 2 data sources that contain a widely available type of structured data (claims or electronic health record encounters) linked to gold-standard recurrence status: Medicare claims linked to the Cancer Care Outcomes Research and Surveillance study, and the Cancer Research Network Virtual Data Warehouse linked to registry data. Twelve potential indicators of recurrence were used to develop separate models for each cancer in each data source. Detection models maximized area under the ROC curve (AUC); timing models minimized average absolute error. Algorithms were compared by cancer type/data source, and contrasted with an existing binary detection rule. RESULTS: Detection model AUCs (>0.92) exceeded existing prediction rules. Timing models yielded absolute prediction errors that were small relative to follow-up time (<15%). Similar covariates were included in all detection and timing algorithms, though differences by cancer type and dataset challenged efforts to create 1 common algorithm for all scenarios. CONCLUSIONS: Valid and reliable detection of recurrence using big data is feasible. These tools will enable extensive, novel research on quality, effectiveness, and outcomes for lung and colorectal cancer patients and those who develop recurrence. PMID- 29135772 TI - Can Composite Measures Provide a Different Perspective on Provider Performance Than Individual Measures? AB - BACKGROUND: Composite measures, which aggregate performance on individual measures into a summary score, are increasingly being used to evaluate facility performance. There is little understanding of the unique perspective that composite measures provide. OBJECTIVE: To examine whether high/low (ie, high or low) performers on a composite measures are also high/low performers on most of the individual measures that comprise the composite. METHODS: We used data from 2 previous studies, one involving 5 measures from 632 hospitals and one involving 28 measures from 112 Veterans Health Administration (VA) nursing homes; and new data on hospital readmissions for 3 conditions from 131 VA hospitals. To compare high/low performers on a composite to high/low performers on the component measures, we used 2-dimensional tables to categorize facilities into high/low performance on the composite and on the individual component measures. RESULTS: In the first study, over a third of the 162 hospitals in the top quintile based on the composite were in the top quintile on at most 1 of the 5 individual measures. In the second study, over 40% of the 27 high-performing nursing homes on the composite were high performers on 8 or fewer of the 28 individual measures. In the third study, 20% of the 61 low performers on the composite were low performers on only 1 of the 3 individual measures. CONCLUSIONS: Composite measures can identify as high/low performers facilities that perform "pretty well" (or "pretty poorly") across many individual measures but may not be high/low performers on most of them. PMID- 29135773 TI - Tree-based Claims Algorithm for Measuring Pretreatment Quality of Care in Medicare Disabled Hepatitis C Patients. AB - BACKGROUND: To help broaden the use of machine-learning approaches in health services research, we provide an easy-to-follow framework on the implementation of random forests and apply it to identify quality of care (QC) patterns correlated with treatment receipt among Medicare disabled patients with hepatitis C virus (HCV). METHODS: Using Medicare claims 2006-2009, we identified 1936 patients with 6 months continuous enrollment before HCV diagnosis. We ran a random forest on 14 pretreatment QC indicators, extracted the forest's representative tree, and aggregated its terminal nodes into 4 QC groups predictive of treatment. To explore determinants of differential QC receipt, we compared patient-level and county-level (linked AHRF data) characteristics across QC groups. RESULTS: The strongest predictors of treatment included "liver biopsy," "HCV genotype testing," "specialist visit," "HCV viremia confirmation," and "iron overload testing." High QC [n=360, proportion treated (pt)=33.3%] was defined for patients with at least 2 from the above-mentioned metrics. Good QC patients (n=302, pt=12.3%) had either "HCV genotype testing" or "specialist visit," whereas fair QC (n=282, pt=7.1%) only had "HCV viremia confirmation." Low QC patients (n=992, pt=2.5%) had none of the selected metrics. The algorithm accuracy of predicting treatment was 70% sensitivity and 78% specificity. HIV coinfection, drug abuse, and residence in counties with higher supply of hospitals with immunization and AIDS services correlated with lower QC. CONCLUSIONS: Machine-learning techniques could be useful in exploring patterns of care. Among Medicare disabled HCV patients, the receipt of more QC indicators was associated with higher treatment rates. Future research is needed to assess determinants of differential QC receipt. PMID- 29135774 TI - Creating a National Provider Identifier (NPI) to Unique Physician Identification Number (UPIN) Crosswalk for Medicare Data. AB - INTRODUCTION: Many health services researchers are interested in assessing long term, individual physician treatment patterns, particularly for cancer care. In 2007, Medicare changed the physician identifier used on billed services from the Unique Physician Identification Number (UPIN) to the National Provider Identifier (NPI), precluding the ability to use Medicare claims data to evaluate individual physician treatment patterns across this transition period. METHODS: Using the 2007-2008 carrier (physician) claims from the linked Surveillance, Epidemiology and End Results (SEER) cancer registry-Medicare data and Medicare's NPI and UPIN Directories, we created a crosswalk that paired physician NPIs included in SEER Medicare data with UPINs. We evaluated the ability to identify an NPI-UPIN match by physician sex and specialty. RESULTS: We identified 470,313 unique NPIs in the 2007-2008 SEER-Medicare carrier claims and found a UPIN match for 90.1% of these NPIs (n=423,842) based on 3 approaches: (1) NPI and UPIN coreported on the SEER Medicare claims; (2) UPINs reported on the NPI Directory; or (3) a name match between the NPI and UPIN Directories. A total of 46.6% (n=219,315) of NPIs matched to the same UPIN across all 3 approaches, 34.1% (n=160,277) agreed across 2 approaches, and 9.4% (n=44,250) had a match identified by 1 approach only. NPIs were paired to UPINs less frequently for women and primary care physicians compared with other specialists. DISCUSSION: National Cancer Institute has created a crosswalk resource available to researchers that links NPIs and UPINs based on the SEER-Medicare data. In addition, the documented process could be used to create other NPI-UPIN crosswalks using data beyond SEER-Medicare. PMID- 29135775 TI - Adjustment for Variable Adherence Under Hierarchical Structure: Instrumental Variable Modeling Through Compound Residual Inclusion. AB - BACKGROUND: Variable adherence to assigned conditions is common in randomized clinical trials. OBJECTIVES: A generalized modeling framework under longitudinal data structures is proposed for regression estimation of the causal effect of variable adherence on outcome, with emphasis upon adjustment for unobserved confounders. RESEARCH DESIGN: A nonlinear, nonparametric random-coefficients modeling approach is described. Estimates of local average treatment effects among compliers can be obtained simultaneously for all assigned conditions to which participants are randomly assigned within the trial. Two techniques are combined to address time-varying and time-invariant unobserved confounding residual inclusion and nonparametric random-coefficients modeling. Together these yield a compound, 2-stage residual inclusion, instrumental variables model. SUBJECTS: The proposed method is illustrated through a set of simulation studies to examine small-sample bias and in application to neurocognitive outcome data from a large, multicenter, randomized clinical trial in sleep medicine for continuous positive airway pressure treatment of obstructive sleep apnea. RESULTS: Results of simulation studies indicate that, relative to a standard comparator, the proposed estimator reduces bias in estimates of the causal effect of variable adherence. Bias reductions were greatest at higher levels of residual variance and when confounders were time varying. CONCLUSIONS: The proposed modeling framework is flexible in the distributions of outcomes that can be modeled, applicable to repeated measures longitudinal structures, and provides effective reduction of bias due to unobserved confounders. PMID- 29135776 TI - Validation of Molecular Pathology Codes for the Identification of Mutational Testing in Lung and Colon Cancer. AB - BACKGROUND: Targeted therapy for patients with lung and colon cancer based on tumor molecular profiles is an important cancer treatment strategy, but the impact of gene mutation tests on cancer treatment and outcomes in large populations is not clear. In this study, we assessed the accuracy of an algorithm to identify tumor mutation testing in administrative claims data during a period before test-specific Current Procedural Terminology codes were available. MATERIALS AND METHODS: We used Pennsylvania Cancer Registry data to select patients with lung or colon cancer diagnosed between 2007 and 2011 who were treated at the University of Pennsylvania Health System, and we obtained their administrative claims. A combination of Current Procedural Terminology laboratory codes (stacking codes) was used to identify potential tumor mutation testing in the claims data. Patients' electronic medical records were then searched to determine whether tumor mutation testing actually had been performed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: An algorithm using stacking codes had moderate sensitivity (86% for lung cancer and 81% for colon cancer) and high specificity (98% for lung cancer and 96% for colon cancer). Sensitivity and specificity did not vary significantly during 2007-2011. In patients with lung cancer, PPV was 98% and NPV was 92%. In patients with colon cancer, PPV was 96% and NPV was 83%. CONCLUSIONS: An algorithm using stacking codes can identify tumor mutation testing in administrative claims data among patients with lung and colon cancer with a high degree of accuracy. PMID- 29135777 TI - Validity of Using Inpatient and Outpatient Administrative Codes to Identify Acute Venous Thromboembolism: The CVRN VTE Study. AB - BACKGROUND: Administrative data are frequently used to identify venous thromboembolism (VTE) for research and quality reporting. However, the validity of these codes, particularly in outpatients, has not been well-established. OBJECTIVE: To determine how well International Classification of Diseases, Ninth Revision (ICD-9) codes for VTE predict chart-confirmed acute VTE in inpatient and outpatients. PATIENTS AND METHODS: We selected 4642 adults with an incident ICD-9 diagnosis of VTE between years 2004 and 2010 from the Cardiovascular Research Network Venous Thromboembolism cohort study. Medical charts were reviewed to determine validity of events. Positive predictive values (PPVs) of ICD-9 codes were calculated as the number of chart-validated VTE events divided by the number with specific VTE codes. Analyses were stratified by VTE type [pulmonary embolism (PE), deep venous thrombosis (DVT)], code position (primary, secondary), and setting [hospital/emergency department (ED), outpatient]. RESULTS: The PPV for any diagnosis of VTE was 64.6% for hospital/ED patients and 30.9% for outpatients. Primary diagnosis codes from hospital/ED patients were more likely to represent acute VTE than secondary diagnosis codes (78.9% vs. 44.4%, P<0.001). Primary hospital/ED codes for PE and lower extremity DVT had higher PPV than for upper extremity DVT (89.1%, 74.9%, and 58.1%, respectively). Outpatient codes were poorly predictive of acute VTE: 28.0% for PE and 53.6% for lower extremity DVT. CONCLUSIONS: ICD-9 codes for VTE obtained from outpatient encounters or from secondary diagnosis codes do not reliably reflect acute VTE. More accurate ways of identifying VTE in outpatients are needed before these codes can be adopted for research or policy purposes. PMID- 29135778 TI - Accuracy of Medicare Claim-based Algorithm to Detect Breast, Prostate, or Lung Cancer Bone Metastases. AB - BACKGROUND: We had previously developed an algorithm for Medicare claims data to detect bone metastases associated with breast, prostate, or lung cancer. This study was conducted to examine whether this algorithm accurately documents bone metastases on the basis of diagnosis codes in Medicare claims data. METHODS: We obtained data from Medicare claims and electronic medical records of patients 65 years or older with a breast, prostate, or lung cancer diagnosis at a teaching hospital and/or affiliated clinics during 2005 or 2006. We calculated the sensitivity and positive predictive value (PPV) of our algorithm using medical records as the "gold standard." The kappa statistic was used to measure agreement between claims and medical record data. RESULTS: The agreement between claims and medical record data for bone metastases among breast, prostate, and lung cancer patients was 0.93, 0.90, and 0.69, respectively. The sensitivities of our algorithm for bone metastasis in patients with breast, prostate, and lung were 96.8% [95% confidence interval (CI)=83.8% to 99.4%], 91.7% (95% CI=78.2% to 97.1%), and 74.1% (95% CI=55.3% to 86.8%), respectively; and the PPVs were 90.9% (95% CI=76.4% to 96.9%), 91.7% (95% CI=78.2% to 97.1%), and 71.4% (95% CI=52.9% to 84.8%), respectively. CONCLUSIONS: The algorithm for detecting bone metastases in claims data had high sensitivity and PPV for breast and prostate cancer patients. Sensitivity and PPV were lower but still moderate for lung cancer patients. PMID- 29135779 TI - Impact of Cross-level Measurement Noninvariance on Hospital Rankings Based on Patient Experiences With Care in 7 European Countries. AB - BACKGROUND: Hospital-level findings on patient experiences with care are increasingly reported publicly. A critical aspect left unexamined is the commonality of composite measures of patient experiences across different groups of patients, nursing units, hospitals, and countries. Absence of commonality is termed measurement noninvariance and is hypothesized to have a strong impact on performance assessment. AIM: The aim of this study is to examine measurement invariance across groups and levels under study (patients, nursing units, hospitals, and countries) and illustrate the degree to which this method of analysis impacts hospital rankings. RESEARCH DESIGN: Data were collected from 11,289 patients in 7 European countries, 186 hospitals, and 824 nursing units. Multilevel factor analytic models were applied to evaluate measurement invariance across the hierarchical levels of the study and across groups at specific levels (self-perceived health at patient level; unit speciality at nursing unit level). Hospital rankings for the final multilevel model were compared with those from a single-level factor model that is unsuspecting of measurement invariance. RESULTS: Cross-group invariance was shown for levels of self-perceived health and to a large degree also for nursing unit speciality. Patient experience composite measures were, however, not invariant across patient, unit, and hospital levels. Hospital rankings were largely impacted when accounted for this cross-level invariance. The percentage of hospitals with discordant ranks by >10 percentile points varied from 26.7% in Spain to 70% in Poland. CONCLUSIONS: Leaving unexamined possible noninvariance across groups and hierarchical levels may have far reaching consequences for how the public perceives hospitals' position relative to other hospitals. PMID- 29135780 TI - Examining Measures of Income and Poverty in Medicare Administrative Data. AB - Disparities by economic status are observed in the health status and health outcomes of Medicare beneficiaries. For health services and health policy researchers, one barrier to addressing these disparities is the ability to use Medicare data to ascertain information about an individual's income level or poverty, because Medicare administrative data contains limited information about individual economic status. Information gleaned from other sources-such as the Medicaid and Supplemental Security Income programs-can be used in some cases to approximate the income of Medicare beneficiaries. However, such information is limited in its availability and applicability to all beneficiaries. Neighborhood level measures of income can be used to infer individual-level income, but level of neighborhood aggregation impacts accuracy and usability of the data. Community level composite measures of economic status have been shown to be associated with health and health outcomes of Medicare beneficiaries and may capture neighborhood effects that are separate from individual effects, but are not readily available in Medicare data and do not serve to replace information about individual economic status. There is no single best method of obtaining income data from Medicare files, but understanding strengths and limitations of different approaches to identifying economic status will help researchers choose the best method for their particular purpose, and help policymakers interpret studies using measures of income. PMID- 29135781 TI - Defining Rurality in Medicare Administrative Data. AB - Rural beneficiaries make up nearly one quarter of the Medicare population, yet rural providers and patients face specific challenges with health and health care delivery that remain inadequately understood. Health disparities between rural and urban residents are widespread, barriers to health care in rural communities persist, and the rural health care workforce is limited. To better understand and track the relationship between rurality and performance under Medicare's payment programs, researchers must be able to identify rural beneficiaries, providers, and hospitals. Although numerous definitions of rurality are applied across the Medicare program, empirical research is lacking comparing the different definitions of rurality and the impact of their application to quality, outcome, or costs. Definitions that recognize rurality as a graded concept, rather than a dichotomous one, hold promise. Understanding the strengths and limitations of different approaches to identifying rurality will help researchers choose the best method for their particular purpose, and help policymakers interpret studies using these approaches. PMID- 29135782 TI - Examining Race and Ethnicity Information in Medicare Administrative Data. AB - Racial and ethnic disparities are observed in the health status and health outcomes of Medicare beneficiaries. Reducing these disparities is a national priority, and having high-quality data on individuals' race and ethnicity is critical for researchers working to do so. However, using Medicare data to identify race and ethnicity is not straightforward. Currently, Medicare largely relies on Social Security Administration data for information about Medicare beneficiary race and ethnicity. Directly self-reported race and ethnicity information is collected for subsets of Medicare beneficiaries but is not explicitly collected for the purpose of populating race/ethnicity information in the Medicare administrative record. As a consequence of historical data collection practices, the quality of Medicare's administrative data on race and ethnicity varies substantially by racial/ethnic group; the data are generally much more accurate for whites and blacks than for other racial/ethnic groups. Identification of Hispanic and Asian/Pacific Islander beneficiaries has improved through use of an imputation algorithm recently applied to the Medicare administrative database. To improve the accuracy of race/ethnicity data for Medicare beneficiaries, researchers have developed techniques such as geocoding and surname analysis that indirectly assign Medicare beneficiary race and ethnicity. However, these techniques are relatively new and data may not be widely available. Understanding the strengths and limitations of different approaches to identifying race and ethnicity will help researchers choose the best method for their particular purpose, and help policymakers interpret studies using these measures. PMID- 29135783 TI - Beyond the Bottom of the Foot: Topographic Organization of the Foot Dorsum in Walking. AB - INTRODUCTION: Sensory feedback from the foot dorsum during walking has only been studied globally by whole nerve stimulation. Stimulating the main nerve innervating the dorsal surface produces a functional stumble corrective response that is phase-dependently modulated. We speculated that effects evoked by activation of discrete skin regions on the foot dorsum would be topographically organized, as with the foot sole. METHODS: Nonnoxious electrical stimulation was delivered to five discrete locations on the dorsal surface of the foot during treadmill walking. Muscle activity from muscles acting at the ankle, knee, hip, and shoulder were recorded along with ankle, knee, and hip kinematics and kinetic information from forces under the foot. All data were sorted on the basis of stimulus occurrence in 12 step cycle phases, before being averaged together within a phase for subsequent analysis. RESULTS: Results reveal dynamic changes in reflex amplitudes and kinematics that are site specific and phase dependent. Most responses from discrete sites on the foot dorsum were seen in the swing phase suggesting function to conform foot trajectory to maintain stability of the moving limb. In general, responses from lateral stimulation differed from medial stimulation, and effects were largest from stimulation at the distal end of the foot at the metatarsals; that is, in anatomical locations where actual impact with an object in the environment is most likely during swing. Responses to stimulation extend to include muscles at the hip and shoulder. CONCLUSIONS: We reveal that afferent feedback from specific cutaneous locations on the foot dorsum influences stance and swing phase corrective responses. This emphasizes the critical importance of feedback from the entire foot surface in locomotor control and has application for rehabilitation after neurological injury and in footwear development. PMID- 29135784 TI - Fitness, Fatness, Physical Activity, and Autonomic Function in Midlife. AB - PURPOSE: Although low cardiorespiratory fitness (CRF), physical inactivity, and obesity are associated with impaired autonomic function, they are also extensively interrelated. The present study aimed to assess the extent to which they contribute to autonomic function independently of each other. METHODS: At the age of 46 yr, 1383 men and 1761 women without cardiorespiratory diseases and diabetes underwent assessments of vagally mediated heart rate (HR) variability (root mean square of successive differences in R-R interval (rMMSD)), peak HR during a submaximal step test (CRF), and 60-s HR recovery (HRR). Moderate-to vigorous physical activity (MVPA; >=3.5 METs, 2 wk) was measured by wrist-worn accelerometer and body fat percentage (Fat%) by bioimpedance. RESULTS: In men, CRF and Fat% were significantly associated with higher rMSSD (standardized beta = 0.31 and -0.16) and HRR (beta = 0.19 and -0.18), whereas higher MVPA was linked with higher HRR (beta = 0.13) when including CRF, MVPA, and Fat% in the initial regression. After adjustments for other lifestyle and cardiometabolic factors, CRF remained significantly associated with rMMSD (beta = 0.24) and HRR (beta = 0.14), as did MVPA with HRR (beta = 0.11). In women, CRF was associated with rMSSD (beta = 0.23) and HRR (beta = 0.15), and MVPA (beta = 0.17) and Fat% (beta = -0.07) with HRR, when CRF, MVPA, and Fat% were adjusted for each other. After further adjustments, CRF remained a significant determinant of rMSSD (beta = 0.20) and HRR (beta = 0.13), as did MVPA with HRR (beta = 0.15). The final models explained 23% and 21% of variation in rMSSD and HRR in men, and 10% and 12% in women, respectively. CONCLUSIONS: CRF was a more important determinant of cardiac autonomic function than MVPA and body fat. Furthermore, MVPA but not body fat was independently associated with cardiac autonomic function in both men and women. PMID- 29135785 TI - Comparison of Polar M600 Optical Heart Rate and ECG Heart Rate during Exercise. AB - PURPOSE: The purpose of this study was to evaluate the accuracy of the Polar M600 optical heart rate (OHR) sensor compared with ECG heart rate (HR) measurement during various physical activities. METHODS: Thirty-six subjects participated in a continuous 76-min testing session, which included rest, cycling warm-up, cycling intervals, circuit weight training, treadmill intervals, and recovery. HR was measured using a three-lead ECG configuration and a Polar M600 Sport Watch on the left wrist. Statistical analyses included OHR percent accuracy, mean difference, mean absolute error, Bland-Altman plots, and a repeated-measures generalized estimating equation design. OHR percent accuracy was calculated as the percentage of occurrences where OHR measurement was within and including +/-5 bpm from the ECG HR value. RESULTS: Of the four exercise phases performed, the highest OHR percent accuracy was found during cycle intervals (91.8%), and the lowest OHR percent accuracy occurred during circuit weight training (34.5%). OHR percent accuracy improved steadily within exercise transitions during cycle intervals to a maximum of 98.5% and during treadmill intervals to a maximum of 89.0%. Lags in HR calculated by the Polar M600 OHR sensor existed in comparison to ECG HR, when exercise intensity changed until steady state occurred. There was a tendency for OHR underestimation during intensity increases and overestimation during intensity decreases. No statistically significant interaction effect with device was found in this sample on the basis of sex, body mass index, VO2max, skin type, or wrist size. CONCLUSIONS: The Polar M600 was accurate during periods of steady-state cycling, walking, jogging, and running, but less accurate during some exercise intensity changes, which may be attributed to factors related to total peripheral resistance changes and pulse pressure. PMID- 29135786 TI - Are RCP and Critical Power Equivalent? The Issue of Mean Response Time. PMID- 29135787 TI - Response. PMID- 29135788 TI - Foreword. PMID- 29135789 TI - Demographic Predictors of Family Functioning and Its Change Over the First 5 Years Postpartum: Findings From the Healthy Beginnings Trial. AB - There are very few longitudinal studies examining family functioning in early childhood. This was a prospective cohort study to identify maternal sociodemographic factors associated with family functioning over the first 5 years postpartum, using data from the Healthy Beginnings Trial. Family functioning was measured using the General Functioning Subscale of the McMaster Family Assessment Device. A total of 667 first-time mothers participated, of which 369 remained at 5 years. Family functioning did not change significantly over the 5 years. Mothers being Australian born, being employed, and having a partner were predictors for healthy family functioning. Targeting support for immigrants, low-income and single-mother families may therefore improve family functioning. PMID- 29135790 TI - Using a Cultural Framework to Assess Motivation for Physical Activity Among Older Hispanic Women: Application of the PEN-3 Model. AB - Culturally relevant strategies for intervention design and implementation, emphasizing strengths and resources, are essential to address cardiovascular health disparities among older Hispanic women. The purpose of this article is to present the process and results of focus group discussions conducted to understand the meaning of cultural, social, and contextual strengths to promote motivation for physical activity and cardiovascular health in this population. The PEN-3 model guided analysis of focus group data. Fifteen older Hispanic women (mean = 61, SD = 6) participated in 3 focus groups. Three interrelated domains were evaluated: (a) cultural identity, (b) relationships and expectations, and PMID- 29135791 TI - An Ecological Approach to Understanding Preventive Service Utilization Among the Underserved. AB - Preventive services have the potential to reduce health disparities; however, these services are underutilized, particularly among the underserved. Patients with low socioeconomic status and racial and ethnic minorities experience significant health disparities related to cancer and infectious and chronic diseases but face multilevel challenges accessing preventive care. The purpose of this article is to enhance understanding of preventive service utilization among underserved patients by providing an ecological framework that addresses factors at multiple levels that influence patient care. In addition to factors that directly impact the patient, the framework incorporates influences on the patient's experience of the health system. PMID- 29135792 TI - The Use of Family Rituals in Eating Behaviors in Hispanic Mothers. AB - Food rituals often abruptly change when Hispanic families migrate to the United States. This report describes changes in rituals of food procurement, preparation, and presentation (food-PPP) in Hispanic women following migration to the United States. Focus groups and face-to-face interviews were conducted with 13 low-income, overweight/obese Hispanic women 27 to 40 years of age. Content analysis was used to analyze cultural and contextual sources for food-PPP. Changes in rituals and traditions in food-PPP occurred, including materials and ingredients for traditional meals. Food rituals may play a role in healthful eating and could, therefore, serve as leverage points for interventions designed to promote healthy eating behaviors. PMID- 29135793 TI - An Ecological Model of Well-being After Sexual Assault: The Voices of Victims and Survivors. AB - In this article, the authors describe factors that enhance or detract from well being after adult sexual assault from the perspective of sexual assault victims and survivors. The authors present a holistic view of the complex ways in which women respond to and cope with the impact of adult sexual assault while trying to create a sense of well-being. The forces that facilitate or detract from well being are organized into an ecological model. The data originate from a grounded theory study in 2015, with 22 adult female adult sexual assault victims/survivors. PMID- 29135794 TI - Fostering Oral Hygiene Habits and Self-Regulation Skills: An Intervention With Preschool Children. AB - The purpose of this study was to evaluate a program to promote self-regulation for self-care skills in preschool-aged children focused on oral habits and good oral health. Participants were 210 Mexican children aged 4 to 5 years who attended the Children's Assistance Community Centers (CAIC in Spanish). Findings showed that children who participated in the program, compared with those who did not, decreased significantly the teeth-bacteria plaque. The former also improved their self-regulation skills and dental hygiene habits. Data highlighted the key role of close adults in promoting young children's self-regulation for self-care focusing on dental hygiene habits. PMID- 29135795 TI - Families and the Juvenile Justice System: Considerations for Family-Based Interventions. AB - We conducted focus groups with defense lawyers, clinicians, and education advocates to gather their perspectives on families' experiences with the juvenile justice system. Our quantitative descriptive analysis identified a range of themes such as discussions about the poor treatment of families as well as recommendations for a shifting of power to families. These perspectives may provide insights about the context in which families are expected to participate in interventions, meet probationary demands, and provide for their youth's well being. The results support evidence gathered from families about the impact of youth incarceration on their lives and has implications for practitioners and researchers working with families whose youth have been incarcerated. PMID- 29135796 TI - Voices of the Filipino Community Describing the Importance of Family in Understanding Adolescent Behavioral Health Needs. AB - Filipinos are a large, yet invisible, minority at high risk for adolescent behavioral health problems. Limited research describes the family as offering a source of positive support for some Filipino youths and yet for some it is also a source of stress and isolation, leading to struggles with adolescent depression and suicidal behavior. This article describes a qualitative study that investigates the role of family when understanding behavioral health needs among Filipino adolescents. Findings highlight the importance of addressing family cohesion when designing interventions aimed at improving the well-being of Filipino youth. PMID- 29135797 TI - USE OF A THRESHOLD OF INTERLEUKIN-10 AND IL-10/IL-6 RATIO IN OCULAR SAMPLES FOR THE SCREENING OF VITREORETINAL LYMPHOMA. AB - PURPOSE: To determine a threshold for interleukin (IL)-10 and IL-10/IL-6 ratio in the aqueous humor (AH) and the vitreous for the screening of vitreoretinal lymphoma (VRL). METHODS: One hundred nineteen patients for whom IL-10 and IL-6 in the AH and/or vitreous had been measured were included: 16 patients with a final diagnosis of VRL and 103 patients with final diagnosis of uveitis. Groups were compared according to IL-10 and IL-6 levels and demographic data. RESULTS: In patients with VRL (Group 1), mean IL-10 values were 5,636 pg/mL, and in patients with uveitis (Group 2), 6.7 pg/mL in the vitreous and 190 pg/mL in Group 1 and 8.6 pg/mL in the AH. In Group 1, the mean IL-10/IL-6 ratio was 29.02 in the vitreous and 10.9 in the AH; in Group 2, ratio was 0.1 in both humors. These values were significantly different between patients with VRL and with uveitis (P < 0.001). A cutoff of 65 pg/mL and 30 pg/mL IL-10 in the vitreous and AH, respectively, was associated with sensitivity of 93% and 78%, respectively, and specificity of 100% and 97%, respectively. A ratio higher than 1 in the vitreous had sensitivity of 93% and specificity of 100%. CONCLUSION: Vitreoretinal lymphoma diagnosis is difficult, and tools like interleukin measurements in AH and vitreous can make it easier. The use of a cutoff for IL-10 and IL-10/IL-6 ratio could allow for an earlier diagnosis that may improve prognosis. PMID- 29135798 TI - VITRECTOMY WITH SUBRETINAL TISSUE PLASMINOGEN ACTIVATOR AND GAS TAMPONADE FOR SUBFOVEAL HEMORRHAGE: Prognostic Factors and Clinical Outcomes. AB - PURPOSE: To study the prognostic factors and clinical outcomes of patients who underwent pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and gas tamponade for the treatment of subfoveal hemorrhage (SFH). METHODS: A retrospective noncomparative interventional case series. RESULTS: Seventy-eight eyes from 77 patients were included. A total of 84.6% of eyes developed SFH from age-related macular degeneration. Partial or complete displacement of the SFH was achieved in 91.5% of eyes within 2 months of surgery. Visual acuity improved from 20/1,449 preoperatively to 20/390 after a mean follow up time of 6.3 months, corresponding to approximately 5 lines of Snellen acuity improvement (P < 0.001). Better visual acuity was associated with the absence of age-related macular degeneration (P = 0.02) and less hemorrhage superior to the fovea (P < 0.001). Final visual acuity was not associated with the area of SFH (P = 0.17), use of anticoagulants (P = 0.14), or visibility of the ellipsoid layer by optical coherence tomography (P = 0.64). Nine patients (11.5%) developed a recurrence of SFH within the follow-up period. Recurrence of SFH was not associated with concurrent anticoagulant therapy (P = 0.52). CONCLUSION: An etiology other than age-related macular degeneration with less hemorrhage superior to the fovea predicts a better outcome in patients with SFH treated with pars plana vitrectomy, subretinal tissue plasminogen activator, and gas tamponade. PMID- 29135800 TI - OUTCOMES OF PNEUMATIC RETINOPEXY PERFORMED BY VITREORETINAL FELLOWS. AB - PURPOSE: To evaluate the anatomical and visual outcomes of patients who underwent pneumatic retinopexy by vitreoretinal fellows. METHODS: We included 198 eyes (198 patients) that underwent pneumatic retinopexy by vitreoretinal fellows at a single academic institution between November 2002 and June 2016. Main outcomes were single-operation success and final anatomical success in retinal reattachment, as well as visual acuity at 3 months and 6 months after treatment. RESULTS: Single-operation success rate was 63.6% at 3 months and 59.5% at 6 months. Final anatomical reattachment was achieved in 92.9% (n = 184) and 96.6% (n = 143) at 3 months and 6 months, respectively. Logarithm of the minimum angle of resolution visual acuity improved from 0.72 +/- 0.1 (~20/100 Snellen) at baseline to 0.36 +/- 0.06 (~20/40 Snellen) at 6 months (P < 0.001). There was no statistical difference in anatomical success rates or visual outcomes between cases performed by first- or second-year fellows (P > 0.50). Single-operation success was associated only with size of detachment (P = 0.01). Visual outcome was associated with macula status at baseline (P = 0.032) and number of reoperations (P < 0.001). CONCLUSION: Anatomical and visual outcomes of fellow performed pneumatic retinopexy are comparable with those reported in the previous literature. PMID- 29135799 TI - PERIPAPILLARY PACHYCHOROID SYNDROME. AB - PURPOSE: To describe the features of peripapillary pachychoroid syndrome (PPS), a novel pachychoroid disease spectrum (PDS) entity. METHODS: Medical records of 31 eyes (16 patients) with choroidal thickening associated with intraretinal and/or subretinal fluid in the nasal macula extending from the disk were reviewed (patients with PPS). Choroidal thickness was compared with 2 age-matched cohorts: typical PDS (17 eyes with central serous chorioretinopathy or pachychoroid neovasculopathy) and 19 normal eyes. RESULTS: The patients with PPS were 81% men aged 71 +/- 7 years. Peripapillary pachychoroid syndrome eyes displayed thicker nasal versus temporal macular choroids, unlike PDS eyes with thicker temporal macular choroids (P < 0.0001). Peripapillary intraretinal and/or subretinal fluid was often overlying dilated Haller layer vessels (pachyvessels). Fundus autofluorescence and fluorescein angiography illustrated peripapillary pigmentary mottling without focal leakage. Most PPS eyes (70%) exhibited other PDS findings including serous pigment epithelial detachment or gravitational tracks. Indocyanine green angiography illustrated dilated peripapillary pachyvessels and choroidal hyperpermeability. The disk was usually crowded, with edema noted in 4/31 (13%) eyes and mild late fluorescein disk leakage identified in half of the cases. Choroidal folds (77%), short axial lengths (39% less than 23 mm), and hyperopia (86%) were common. CONCLUSION: Peripapillary pachychoroid syndrome is a distinct PDS variant, in which peripapillary choroidal thickening is associated with nasal macular intraretinal and/or subretinal fluid and occasional disk edema. Recognition of PPS is important to distinguish it from disorders with overlapping features such as posterior uveitis and neuro-ophthalmologic conditions. PMID- 29135801 TI - TIMING AND OUTCOME OF SURGERY FOR PERSISTENT MACULAR HOLE. AB - PURPOSE: To evaluate the efficacy and optimum timing for resurgery in case of persistent macular hole (MH). METHODS: Twenty-five eyes of 25 patients who underwent fluid-air exchange with intravitreal C3F8 for persistent MH after vitrectomy + internal limiting membrane peeling + SF6 were included in the study. Best-corrected visual acuity, optical coherence tomography features including base diameter and configuration of MH, and time duration between the two surgeries were noted. RESULTS: Patients who underwent resurgery within 3 months of the first surgery had better anatomical closure rate compared with those who underwent resurgery after 3 months (P < 0.05). Significant improvement was seen in best-corrected visual acuity in eyes with closed MH. Eyes having MH with irregular edges on optical coherence tomography had better anatomical closure rates compared with the eyes having MH with round edges. CONCLUSION: Patients undergoing repeat gas injection within 3 months of the primary surgery for persistent MH have better anatomical closure rates compared with late intervention. PMID- 29135802 TI - PANRETINAL PHOTOCOAGULATION VERSUS RANIBIZUMAB FOR PROLIFERATIVE DIABETIC RETINOPATHY: COMPARISON OF PERIPAPILLARY RETINAL NERVE FIBER LAYER THICKNESS IN A RANDOMIZED CLINICAL TRIAL. AB - PURPOSE: Compare changes in retinal nerve fiber layer (RNFL) thickness between eyes assigned to intravitreous ranibizumab or panretinal photocoagulation and assess correlations between changes in RNFL and visual field sensitivity and central subfield thickness. METHODS: Eyes with proliferative diabetic retinopathy were randomly assigned to ranibizumab or panretinal photocoagulation. Baseline and annual follow-up spectral domain optical coherence tomography RNFL imaging, optical coherence tomography macular imaging, and automated static perimetry (Humphrey visual field 60-4 algorithm) were performed. RESULTS: One hundred forty six eyes from 120 participants were analyzed. At 2 years, for the ranibizumab (N = 74) and panretinal photocoagulation (N = 66) groups, respectively, mean change in average RNFL thickness was -10.9 +/- 11.7 MUm and -4.3 +/- 11.6 MUm (difference, -4.9 MUm; 95% confidence interval [-7.2 MUm to -2.6 MUm]; P < 0.001); the correlation between change in RNFL thickness and 60-4 Humphrey visual field mean deviation was -0.27 (P = 0.07) and +0.33 (P = 0.035); the correlation between change in RNFL thickness and central subfield thickness was +0.63 (P < 0.001) and +0.34 (P = 0.005), respectively. CONCLUSION: At 2 years, eyes treated with ranibizumab had greater RNFL thinning than eyes treated with panretinal photocoagulation. Correlations between changes in RNFL thickness, visual field, and central subfield thickness suggest that the decrease in RNFL thickness with ranibizumab is likely due to decreased edema rather than loss of axons. PMID- 29135803 TI - VASCULAR ABNORMALITIES IN DIABETIC RETINOPATHY ASSESSED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY WIDEFIELD IMAGING. AB - PURPOSE: To detect vascular abnormalities in diabetic retinopathy using swept source optical coherence tomography angiography (SS-OCTA) widefield images, and to compare the findings with color fundus photographs (CFPs) using Early Treatment Diabetic Retinopathy Study severity grading. METHODS: 3 mm * 3 mm and 12 mm * 12 mm scans were acquired to cover 70 degrees to 80 degrees of the posterior pole using a 100-kHz SS-OCTA instrument. Two masked graders assessed the presence of vascular abnormalities on SS-OCTA and the Early Treatment Diabetic Retinopathy Study level on CFP. The grading results were then compared. RESULTS: A total of 120 diabetic eyes (60 patients) were imaged with the SS-OCTA instrument. Cohort 1 (91 eyes; SS-OCTA grading only) showed microaneurysms in 91% (n = 83), intraretinal microvascular abnormalities in 79% (n = 72), and neovascularization in 21% (n = 19) of cases. Cohort 2 (52 eyes; CFP grading compared with SS-OCTA) showed microaneurysms on CFP in 90% (n = 47) and on SS OCTA in 96% (n = 50) of cases. Agreement in intraretinal microvascular abnormality detection was fair (k = 0.2). Swept-source optical coherence tomography angiography detected 50% of intraretinal microvascular abnormality cases (n = 26), which were missed on CFP. Agreement in detecting neovascularization was moderate (k = 0.5). CONCLUSION: Agreement in detection of diabetic retinopathy features on CFP and SS-OCTA varies depending on the vascular changes examined. Swept-source optical coherence tomography angiography shows a higher detection rate of intraretinal microvascular abnormalities (P = 0.039), compared with Early Treatment Diabetic Retinopathy Study grading. PMID- 29135804 TI - Surgical Management of Tumors Involving Meckel's Cave and Cavernous Sinus: Role of an Extended Middle Fossa and Lateral Sphenoidectomy Approach. AB - OBJECTIVE: To study the indications and outcomes of lateral sphenoidectomy as part of a combined skull base approach in the treatment of tumors involving Meckel's cave (MC) and cavernous sinus (CS). STUDY DESIGN: Retrospective patient series. SETTING: Tertiary referral center. PATIENTS: Twenty-two consecutive patients (mean age: 45 yr, range: 16-76) who underwent transzygomatic, extended middle fossa approaches for tumors involving MC and CS. INTERVENTIONS: Surgical access to MC and CS was achieved via extended middle fossa, trans-clinoid approach. Lateral sphenoidectomy was defined as drill-out of the greater sphenoid wing lateral to foramen rotundum and ovale, decompression of superior orbital fissure, and removal of anterior clinoid process. Reconstruction was achieved using combination of autologous and synthetic materials. Eleven patients (50%) received adjuvant radiation. MAIN OUTCOME MEASURES AND RESULTS: Tumor pathologies included meningioma (16 patients), epidermoid cyst (2), trigeminal schwannoma (2), invasive pituitary adenoma (1), and chondrosarcoma (1). Mean (range) preoperative tumor size was 4.0 cm (1.3-9). Mean (range) length of follow-up was 4 years (range 0.1-10). Overall tumor control and gross total resection were achieved in 95 and 23% of patients, respectively. Lateral sphenoidectomy was performed in 16 patients (73%) for enhanced surgical access and/or tumor extension to the infratemporal fossa (6 patients). Postoperatively, cranial nerve deficits occurred in 12 (55%) patients (V-9 patients; III, IV, or VI-4; VII-2; VIII-2). Cerebrospinal fluid leak and hydrocephalus occurred in two and four patients, respectively. CONCLUSION: In combination with middle fossa-based approaches to tumors involving MC and CS, lateral sphenoidectomy may play a viable role in tumor access and control. PMID- 29135805 TI - Failure of Invasive Airway Placement on the First Attempt Is Associated With Progression to Cardiac Arrest in Pediatric Acute Respiratory Compromise. AB - OBJECTIVES: The aim of this study was to describe the proportion of acute respiratory compromise events in hospitalized pediatric patients progressing to cardiopulmonary arrest, and the clinical factors associated with progression of acute respiratory compromise to cardiopulmonary arrest. We hypothesized that failure of invasive airway placement on the first attempt (defined as multiple attempts at tracheal intubation, and/or laryngeal mask airway placement, and/or the creation of a new tracheostomy or cricothyrotomy) is independently associated with progression of acute respiratory compromise to cardiopulmonary arrest. DESIGN: Multicenter, international registry of pediatric in-hospital acute respiratory compromise. SETTING: American Heart Association's Get with the Guidelines-Resuscitation registry (2000-2014). PATIENTS: Children younger than 18 years with an index (first) acute respiratory compromise event. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 2,210 index acute respiratory compromise events, 64% required controlled ventilation, 26% had return of spontaneous ventilation, and 10% progressed to cardiopulmonary arrest. There were 762 acute respiratory compromise events (34%) that did not require an invasive airway, 1,185 acute respiratory compromise events (54%) with successful invasive airway placement on the first attempt, and 263 acute respiratory compromise events (12%) with failure of invasive airway placement on the first attempt. After adjusting for confounding variables, failure of invasive airway placement on the first attempt was independently associated with progression of acute respiratory compromise to cardiopulmonary arrest (adjusted odds ratio 1.8 [95% CIs, 1.2-2.6]). CONCLUSIONS: More than 1 in 10 hospitalized pediatric patients who experienced an acute respiratory compromise event progressed to cardiopulmonary arrest. Failure of invasive airway placement on the first attempt is independently associated with progression of acute respiratory compromise to cardiopulmonary arrest. PMID- 29135806 TI - Fluid intelligence relates to the resting state amplitude of low-frequency fluctuation and functional connectivity: a multivariate pattern analysis. AB - The goal of this study was to investigate the relationship between fluid intelligence (gF) and the pattern of the functional characteristics in the resting state in adults using multivariate pattern analysis. Resting-state functional images from 100 participants in the Human Connectome Project data set were analyzed. The amplitude of low-frequency fluctuation (ALFF) was first calculated, and a support vector regression approach was used to identify the association with gF. To discover whether the connectivity of the gF-associated areas was also related to gF, we further checked the seed-based functional connectivity using the seeds from the ALFF. The ALFF showed that gF was correlated with the left anterior cingulate cortex, which is involved in high cognitive control processes. The functional connectivity showed that the connection between the right prefrontal cortex (Brodmann area 8) and the left anterior cingulate cortex could predict gF. The multivariate pattern analysis result indicated that the brain functional activity and functional integrity that we identified have the potential to become an objective biomarker for evaluating individual differences in gF. PMID- 29135809 TI - Definition of Recurrent Urinary Tract Infections in Women: Which One to Adopt? AB - OBJECTIVES: The aim of this study was to systematically review the various definitions of recurrent urinary tract infection (RUTI) recommended by experts and specialty societies cited in biomedical literature. METHODS: A systematic review of RUTI in women was conducted using MEDLINE, EMBASE, and PubMed between 1966 and 2016 according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Statement. Twenty-five publications were selected for inclusion in this analysis. RESULTS: From review of included publications, 14 definitions of RUTI were obtained. Each source was searched for a textual definition of RUTI as well as presence or absence of specific key elements including urinary symptoms, colony forming unit count, bacterial species, number of UTIs per year, interval time between infections and a negative intervening culture. All data were reviewed by 2 separate investigators. The definition of RUTI was found highly variable in the literature. The tallying of key elements in included definitions suggests that a minimum RUTI definition should include urinary symptoms, urine culture colony forming unit/mL threshold, differentiation of bacterial persistence versus reinfection by bacterial species, and number of UTIs per year. CONCLUSIONS: This review of major RUTI definition recommendations by expert individuals and specialty societies underlines the lack of uniformity and the need for a more robust and generally agreeable RUTI definition for use in clinical and academic practice. PMID- 29135807 TI - Effects of stressor controllability on transcriptional levels of c-fos, Arc, and brain-derived neurotrophic factor in mouse amygdala and medial prefrontal cortex. AB - Controllability is an important factor in determining stress outcomes. Uncontrollable stress is associated with the development of psychopathology such as post-traumatic stress disorder, whereas controllable stress is associated with adaptive stress responses and positive outcomes. In this study, we investigated how controllability affects poststress neurobiology by assessing transcriptional levels of activity-dependent genes in medial prefrontal cortex (mPFC) and amygdala, regions important in mediating stress outcomes. Mice were subjected to either escapable shock (ES) or yoked inescapable shock (IS) as models of controllable and uncontrollable stress, respectively. Immediately (0 h) or at 2 h after shock training (20 trials; 0.5 mA, 5.0 s maximum duration; 1.0 min interstimulus interval), mice were killed, and we interrogated expression levels of the immediate-early genes, c-fos and Arc, and a delayed primary response gene, brain-derived neurotrophic factor, in mPFC, amygdala, and somatosensory cortex (a control region), using real-time reverse transcription quantitative PCR (RT qPCR). We found ES-associated up-regulation of brain-derived neurotrophic factor in amygdala as well as in mPFC. IS suppressed c-fos in mPFC (0 h) but induced more Arc in amygdala (2 h) in comparison with ES. Freezing, an index of fear memory, and serum level corticosterone, an index of the stress response, did not differ between mice trained with ES or IS. The data are discussed with respect to the potential functional involvements of the amygdala and mPFC in mediating differential outcomes of controllable and uncontrollable stress. PMID- 29135810 TI - Can Urodynamic Parameters Predict Sling Revision for Voiding Dysfunction in Women Undergoing Synthetic Midurethral Sling Placement? AB - OBJECTIVE: The objective of the study was to evaluate the utility of urodynamic studies performed before primary midurethral sling placement for stress urinary incontinence in predicting the need for subsequent sling release for voiding dysfunction. METHODS: The health records of women managed with primary synthetic midurethral sling placement at Mayo Clinic (Rochester, MN) from January 1, 2002, to December 31, 2012, were reviewed. The primary outcome was surgical sling release for postoperative voiding dysfunction (ie, prolonged retention, elevated postvoid residual volumes with new voiding symptoms, or de novo onset or worsening of overactive bladder symptoms). Logistic regression models were used to evaluate associations between potential clinical risk factors and the primary outcome. RESULTS: Overall, 1629 women underwent primary synthetic midurethral sling placement during the study time frame, including 1081 patients (66%) who underwent a preoperative multichannel urodynamic evaluation. A sling release for voiding dysfunction was performed for 51 patients (3.1%) at a median of 1.9 months postoperatively (interquartile range, 1.3-9.3 months). Patients undergoing sling release were significantly more likely to have had retropubic sling placement (P = 0.003) and concomitant prolapse surgery (P = 0.005). On univariate analysis, no urodynamic parameters were associated with the risk of sling release; evaluated parameters included peak flow rate (P = 0.20), postvoid residual volume (P = 0.37), voiding without detrusor contraction (P = 0.96), and detrusor pressure at maximal flow (P = 0.23). CONCLUSIONS: Sling release for voiding dysfunction was rare in our cohort. No urodynamic parameters were associated with the risk of sling release. PMID- 29135811 TI - The Relationship Between Intra-Abdominal Pressure and Body Acceleration During Exercise. AB - OBJECTIVES: High intra-abdominal pressure (IAP) may influence the development of pelvic floor disorders. We and others have used intravaginal pressure transducers to measure IAP in women during exercise and daily activities, but utilizing the transducer for long-term measurements creates compliance issues. Waist-worn accelerometers are prominent in research and may be a reliable alternative for approximating IAP. We hypothesized that there are pair-wise positive correlations between the mean maximal accelerometer vector magnitude and 2 IAP measurements: mean maximal IAP and area under the curve (AUC). METHODS: Twenty-five women who regularly participated in exercise performed 13 activities. Intra-abdominal pressure was measured with an intravaginal transducer and acceleration with a waist-worn accelerometer. We determined the mean maximal IAP, AUC for IAP, and mean maximal accelerometer vector magnitude for each activity and participant. The relationship between IAP and acceleration was determined by computing the Pearson correlation coefficient (R) and the 95% confidence interval for mean maximal accelerometer vector magnitude versus mean maximal IAP and mean maximal accelerometer vector magnitude versus AUC for IAP. RESULTS: The R values were 0.7353 for mean maximal accelerometer vector magnitude versus mean maximal IAP (including walking) and 0.5059 for mean maximal accelerometer vector magnitude versus AUC for IAP (excluding walking). Walking at 3 speeds, analyzed separately, presented R values of 0.72208 for mean maximal IAP and 0.21678 for AUC. CONCLUSION: Waist-worn accelerometers may provide a viable method for approximating mean maximal IAP in a population of women during most activities. PMID- 29135812 TI - Optic Nerve Head Drusen: The Relationship Between Intraocular Pressure and Optic Nerve Structure and Function. AB - OBJECTIVE: To determine whether at the time of diagnosis, the intraocular pressure (IOP) in patients with optic nerve head drusen (ONHD) correlates with the perimetric mean deviation (PMD) and the mean retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT). METHODS: This retrospective chart review included adults with ONHD from 2 academic medical centers. Inclusion criteria were age older than 18 years, definitive diagnosis of ONHD, measurement of IOP, and an automated visual field (VF) within 3 months of diagnosis. Exclusion criteria were unreliable VFs, use of IOP-lowering therapy, and visually significant ocular comorbidities. Data were collected from the initial visit. Age, IOP, method of diagnosis of ONHD, mean RNFL thickness, and PMD were recorded. Multiple and logistic regression models were used to control for potential confounders in statistical analyses. RESULTS: Chart review identified 623 patients, of which 146 patients met inclusion criteria. Mean age was 44.2 years (range: 19-82 years). Average PMD of 236 eyes was -5.22 dB (range, -31.2 to +1.21 dB). Mean IOP was 15.7 mm Hg (range: 6-24 mm Hg). Forty eyes (16.9%) underwent RNFL measurement using OCT; mean RNFL thickness was 79.9 MUm (range: 43 117 MUm). There was no statistically significant association between IOP and PMD (P = 0.13) or RNFL thickness (P = 0.65). Eyes with ocular hypertension tended to have less depressed PMD than those without (P= 0.031). Stratified analyses of visible and buried subgroups yielded similar results. CONCLUSIONS: Lowering IOP in patients with ONHD has been proposed as a means to prevent progression of optic neuropathy. Our study demonstrated that among predominately normotensive eyes, higher IOP was not associated with greater VF loss or thinner RNFL at the time of presentation. This suggests that lowering IOP may not be beneficial in preventing visual loss in normotensive eyes with ONHD. PMID- 29135813 TI - Pendular Seesaw Nystagmus in a Patient With a Giant Pituitary Macroadenoma: Pathophysiology and the Role of the Accessory Optic System. AB - Seesaw nystagmus is characterized by cyclic eye movements with a conjugate torsional component and a dissociated vertical component. In the first half of the cycle, one eye elevates and intorts, whereas the other eye depresses and extorts. The pattern is reversed in the remaining half of the cycle. We describe a patient with a giant pituitary adenoma who developed pendular seesaw nystagmus. Disturbance in the visuovestibular system is postulated to contribute to this form of seesaw nystagmus. Lesions compressing the optic chiasm and the accessory optic system could interrupt the transmission of retinal error signals to the inferior olivary nucleus and the interstitial nucleus of Cajal, thus interfering with the adaptive mechanism of the vestibulo-ocular reflex and leading to pendular seesaw nystagmus. PMID- 29135814 TI - Neuro-Ophthalmology at a Tertiary Eye Care Centre in India. AB - BACKGROUND: Neuro-ophthalmology as a specialty is underdeveloped in India. The aim of our study was to determine the spectrum and profile of patients presenting to a tertiary eye care center with neuro-ophthalmic disorders. METHODS: A retrospective hospital-based study was conducted, and records of all patients seen at the neuro-ophthalmology clinic of Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India, over a 1-year period were retrieved and evaluated. RESULTS: Of a total of 30,111 patients referred to various specialty clinics in a span of 1 year, 1597 (5%) were referred for neuro-ophthalmology evaluation. The mean patient age was 30.8 +/- 19.5 years, with a male dominance (M:F = 2.02:1). Among these patients, optic nerve disorders were noted in 63.8% (n = 1,020), cranial nerve palsy in 7% (n = 114), cortical visual impairment in 6.5% (n = 105), and others (eye/optic nerve hypophasia, blepharospasm, and optic disc drusen) in 6% (n = 95). Among the patients with optic nerve disorders, optic neuropathy without disc edema/(traumatic optic neuropathy, hereditary, tumor-related, retrobulbar neuritis, toxic, and idiopathic) was noted in 42.8% (n = 685) and optic neuropathy with disc edema (ischemic optic neuropathy, papilledema, post papilledema optic atrophy, papillitis, neuroretinitis, and inflammatory optic neuropathy) in 20.9% (n = 335). Sixteen percent of patients (n = 263) were incorrect referrals. CONCLUSION: The neuro-ophthalmic clinic constitutes a significant referral unit in a tertiary eye care center in India. Traumatic and ischemic optic neuropathies are the most common diagnoses. Neuro-ophthalmology requires further development as a subspecialty in India to better serve the nation's population. PMID- 29135815 TI - Weighing the Risks and Benefits of Antidepressants in Idiopathic Intracranial Hypertension. PMID- 29135817 TI - A Primer on the Use of Equivalence Testing for Evaluating Measurement Agreement. AB - PURPOSE: Statistical equivalence testing is more appropriate than conventional tests of difference to assess the validity of physical activity (PA) measures. This article presents the underlying principles of equivalence testing and gives three examples from PA and fitness assessment research. METHODS: The three examples illustrate different uses of equivalence tests. Example 1 uses PA data to evaluate an activity monitor's equivalence to a known criterion. Example 2 illustrates the equivalence of two field-based measures of physical fitness with no known reference method. Example 3 uses regression to evaluate an activity monitor's equivalence across a suite of 23 activities. RESULTS: The examples illustrate the appropriate reporting and interpretation of results from equivalence tests. In the first example, the mean criterion measure is significantly within +/-15% of the mean PA monitor. The mean difference is 0.18 METs and the 90% confidence interval of -0.15 to 0.52 is inside the equivalence region of -0.65 to 0.65. In the second example, we chose to define equivalence for these two measures as a ratio of mean values between 0.98 and 1.02. The estimated ratio of mean VO2 values is 0.99, which is significantly (P = 0.007) inside the equivalence region. In the third example, the PA monitor is not equivalent to the criterion across the suite of activities. The estimated regression intercept and slope are -1.23 and 1.06. Neither confidence interval is within the suggested regression equivalence regions. CONCLUSIONS: When the study goal is to show similarity between methods, equivalence testing is more appropriate than traditional statistical tests of differences (e.g., ANOVA and t tests). PMID- 29135816 TI - Dopaminergic Genetic Variants and Voluntary Externally Paced Exercise Behavior. AB - PURPOSE: Most candidate gene studies on the neurobiology of voluntary exercise behavior have focused on the dopaminergic signaling pathway and its role in the mesolimbic reward system. We hypothesized that dopaminergic candidate genes may influence exercise behavior through additional effects on executive functioning and that these effects are only detected when the types of exercise activity are taken into account. METHODS: Data on voluntary exercise behavior and at least one single-nucleotide polymorphism/variable number of tandem repeat (VNTR) were available for 12,929 participants of the Netherlands Twin Registry. Exercise activity was classified as externally paced if a high level of executive function skill was required. The total volume of voluntary exercise (minutes per week) as well as the volume specifically spent on externally paced activities were tested for association with nine functional dopaminergic polymorphisms (DRD1: rs265981, DRD2/ANKK1: rs1800497, DRD3: rs6280, DRD4: VNTR 48 bp, DRD5: VNTR 130-166 bp, DBH: rs2519152, DAT1: VNTR 40 bp, COMT: rs4680, MAOA: VNTR 30 bp), a polygenic score (PGS) based on nine alleles leading to lower dopamine responsiveness, and a PGS based on three alleles associated with both higher reward sensitivity and better executive functioning (DRD2/ANKK1: "G" allele, COMT: Met allele, DAT1: 440 bp allele). RESULTS: No association with total exercise volume or externally paced exercise volume was found for individual alleles or the nine-allele PGS. The volume of externally paced exercise behavior was significantly associated with the reward and executive function congruent PGS. This association was driven by the DAT1 440-bp and COMT Met allele, which acted as increaser alleles for externally paced exercise behavior. CONCLUSIONS: Taking into account the types of exercise activity may increase the success of identifying genetic variants and unraveling the neurobiology of voluntary exercise behavior. PMID- 29135818 TI - Trends of Magnet Ingestion in Children, an Ironic Attraction. AB - BACKGROUND AND OBJECTIVES: Ingestion of rare earth magnets is a serious ongoing hazard for pediatric patients. Our study aims to investigate whether 2012 Consumer Product Safety Commission (CPSC) policy action, in coordination with efforts from consumer and physician advocacy groups, decreased the incidence of magnet ingestions in children in the United States since 2012. METHODS: Data from the National Electronic Injury Surveillance System (NEISS) was used to evaluate trends in emergency department (ED) encounters with pediatric patients (<18 years) who presented with suspected magnet ingestions (SMI) from 2010 to 2015. National estimates of SMI were made using the NEISS-supplied weights and variance variables. RESULTS: An estimated 14,586 children (59% male, 50% age <5 years) presented to the ED for SMI from 2010 to 2015. A significant upward trend in magnet-related ED visits preceded the CPSC action, with the peak ingestions of 3167 (95% confidence interval, 1612-4723) recorded in 2012. This was followed by a steady decrease in the rate of SMI to 1907 (95% confidence interval, 1062-2752) in 2015, an average annual decrease of 13.3%. Most importantly, post-federal action estimates demonstrated a downward trend in overall SMI ED visits (P = 0.03). CONCLUSIONS: The frequency of magnet ingestions continued to rise from 2010 and then peak in 2012, followed by a decline in magnet ingestion ED visits during the post-federal action years. This down trend emphasizes the importance of advocacy on decreasing magnet ingestions in children. Further study will be required to determine the impact of the court decision to lift the magnet ban in 2016. PMID- 29135819 TI - Prophylactic rtPA in the Prevention of Line-associated Thrombosis and Infection in Short Bowel Syndrome. AB - BACKGROUND: Central venous access devices (CVADs) are essential for total parenteral nutrition administration in patients with short bowel syndrome (SBS). They are, however, fraught with complications including infection and venous thromboembolism (VTE), which increases associated morbidity and mortality in this population. There is evidence linking the development of CVAD-associated thrombosis and line-related infection. Thus, it has been postulated that prevention of catheter-related clot formation could minimize the risk of infection originating from the catheter. Recombinant tissue plasminogen activator (rtPA, alteplase), lyses clots by binding plasmin-bound fibrin in a clot and cleaving plasminogen to plasmin; moreover, it is widely used to clear occluded CVADs. METHODS: Prophylactic rtPA lock therapy in children with SBS was evaluated as a single site pilot study to minimize line-associated VTE, infection, need for line replacement, and hospitalization at the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center. rtPA lock therapy was administered by parents/caregivers on a weekly basis over a 6-month time period in place of heparin lock therapy. Comparisons were made between line-associated complications in the cohort in the 6 months before study versus during the study period. RESULTS: Six out of 8 subjects completed the study over a 1-year time period. As a group, subjects experienced a significant decrease in the number of line associated bloodstream infections from a mean of 1.9 infections in the 6 months before the study to a mean of 0.5 infections (P = 0.025). There was no change in the need for line replacement amongst subjects while on study. The primary outcome of VTE was not found in the cohort, and it is unclear whether rtPA lock therapy contributed to the lack of thrombosis development. Given the success of rtPA in this pilot study in reducing bloodstream infections, further investigation or rtPA lock therapy in patients with SBS is warranted. PMID- 29135820 TI - Avoiding Small Intestinal Biopsies for Diagnosis of Celiac Disease in Children: A Reliable Strategy for All Patients? AB - BACKGROUND: Current reports applying ESPGHAN exception criteria (EEC) to diagnose celiac disease (CD) without duodenal biopsies indicate that a high percentage of patients with CD may be identified when applied correctly in specialized settings. Application of the EEC, however, in "daily life conditions" at the different levels of medical services is not clear. METHODS: EEC was applied to 130 pediatric patients evaluated for CD at 5 public hospitals in Santiago, Chile, during 2010 to 2015. Clinical presentation, serum anti-tissue transglutaminase 2 and anti-endomysium antibodies (EMA), genotyping, and small intestinal histology were obtained from clinical charts. RESULTS: A total of 78 of 130 patients reviewed had some of the data required for analysis, but EMA was determined in 54% and genotyping in 2.3% of patients, limiting the study. After offering free genotyping, only 12 of 78 (15%) had all data required for EEC application. In this small group, 10 of 12 (83.3%) patients could avoid duodenal biopsies and 2 (16.7%) with potential CD were misdiagnosed. Main reasons for not doing EMA and genotyping were that they are expensive, unavailable in the local health care center, and considered "not necessary" for diagnosis. CONCLUSION: Limited resources in clinical settings reduce availability of EMA and genotyping, making application of EEC criteria difficult and only possible only in 15% of our patients. Within this subgroup, biopsies could be avoided in 83.3%, and 16.7% of patients with potential CD were misdiagnosed. Insufficient studies and incorrect interpretation of EEC contributed to incomplete assessment in 52 of 130 (40%) patients. The Chilean public health system is likely representative of several others present in developing and developed countries. PMID- 29135821 TI - Compliance With Fecal Calprotectin Testing in Pediatric Patients With Inflammatory Bowel Disease. AB - Fecal calprotectin (FC) is a highly sensitive biomarker for inflammatory bowel diseases (IBDs). Utilization of this assay has been steadily increasing. Adherence levels for FC have, however, yet to be examined in the pediatric IBD setting. We analyzed 100 consecutive patients diagnosed with IBD between 2014 and 2015 at Texas Children's Hospital. Fifty-six percent of patients were men and median age at diagnosis was 13.7 years. Following diagnosis of IBD, 84 patients had a minimum of 1 FC requested, and 95.2% of these patients completed the test at least once. An average of 2 FCs per patient was ordered each year, and the overall compliance was 76.6%. Patients who completed the initial testing with a minimum of 3 consecutive tests were more likely to remain compliant than those who failed to perform the first lab (P < 0.001). Our findings indicate good compliance with FC testing in pediatric patients with IBD. PMID- 29135822 TI - Premature Infants have Lower Gastric Digestion Capacity for Human Milk Proteins than Term Infants. AB - OBJECTIVES: Whether premature infants have lower gastric protein digestive capacity than term infants and the extent to which human milk proteases contribute to overall gastric digestion are unknown and were investigated in this study. METHODS: Human milk and infant gastric samples were collected from 16 preterm (24-32 wk gestational age) and 6 term (38-40 wk gestational age) mother infant pairs within a range of 5 to 42 days postnatal age. For each pair, an aliquot of human milk was adjusted to pH 4.5 and incubated for 2 hours at 37 degrees C to simulate the gastric conditions without pepsin (milkinc). Their gastric protein digestion capacity was measured as proteolysis (free N-terminals) and protease activities. Two-way analysis of variance followed by Tukey post hoc test was applied to compare measurements between preterm and term infants as well as among human milk, milkinc, and gastric samples. RESULTS: Measurements of gastric protein digestion were significantly lower in preterm infants than term infants. Overall milk protease activity did not differ between human milk samples from term- and preterm-delivering mothers. As protease activity did not increase with simulated gastric incubation, milk proteases likely contributed minimally to gastric digestion. CONCLUSIONS: Preterm infants have lower gastric protein digestion capacity than term infants, which could impair nutrient acquisition. Human milk proteases contribute minimally to overall gastric digestion. The limited activity of milk proteases suggests that these enzymes cannot compensate for the premature infant's overall lower gastric protein digestion. PMID- 29135823 TI - The Changing Face of Pediatric Ulcerative Colitis: A Population-based Cohort Study. AB - OBJECTIVES: The aims of this retrospective study were to describe ulcerative colitis (UC) phenotype at diagnosis and follow-up and to identify possible predictors of severe disease course. METHODS: This was a retrospective, single center study. We reviewed the charts of patients with UC diagnosed between 2 and 18 years at our referral center from January 2007 to January 2016. Laboratory and clinical features at diagnosis, such as disease extent, atypical phenotypes, extraintestinal manifestations, and therapies, and pattern changes during the follow-up, including relapse rate, disease extension, and the cumulative risk for colectomy were collected. RESULTS: One hundred eleven patients were enrolled. Atypical phenotypes were identified at diagnosis in 55 out of 111 patients (49.5%). Extraintestinal manifestations were detected in 16 out of 111 (14.4%) at the diagnosis. During the follow-up 60 out of 111 (54%) patients needed to start azathioprine, 9 out of 111 (8.1%) patients started biologic therapy and 10 out of 111 (patients underwent surgery, resulting in a cumulative risk of 8% at 5 years and 16% at 10 years. Steroid refractoriness (hazard ratio: 13.9) and starting of biologic therapy (hazard ratio: 25.3) represented the best predictors for surgery. The cumulative probability of first relapse was 47% at 6 months and 63% at 1 year. Disease extension was reported in 21 out of 70 patients (30%). CONCLUSION: Pediatric UC is associated with a severe phenotype and a high percentage of atypical features. Surgery rate seems to be decreased from early reports. PMID- 29135824 TI - Shortened 8 Weeks Course of Dual Sofosbuvir/Daclatasvir Therapy in Adolescent Patients, With Chronic Hepatitis C Infection. AB - Recently, sofosbuvir and the fixed-dose combination of sofosbuvir/ledipasvir were approved for the treatment of chronic hepatitis C virus infection in adolescents, criteria being 12 years old and above or weighing at least 35 kg. Here we present the results of a pilot single cohort of 10 consecutive adolescent patients with chronic hepatitis C virus and treated with dual sofosbuvir/daclatasvir therapy for a response-tailored duration of 8 weeks for those who achieved very rapid virologic response (vRVR) and 12 weeks for those who did not. All patients achieved vRVR at week 2 and completed the shortened 8 weeks course. All patients (10/10) (100% [confidence interval 72.25-100%]) achieved sustained vRVR at week 12 post-treatment with good tolerability and no serious adverse events. These data could provide support to our suggested response-tailored protocol of dual therapy with sofosbuvir/daclatasvir in adolescents particularly for shortened duration in those who achieved vRVR. Further larger randomized controlled studies are recommended. PMID- 29135825 TI - Rational Diagnostics and Therapies in Child Refugees. PMID- 29135826 TI - Vaccination in Pregnancy-Recent Developments. PMID- 29135827 TI - Norovirus and Rotavirus Disease Severity in Children: Systematic Review and Meta analysis. AB - BACKGROUND: Rotaviruses (RVs) and noroviruses (NoVs) are the most common causes of severe acute gastroenteritis in children. It is generally accepted that RVs cause severe acute gastroenteritis in a higher proportion of cases compared with NoVs. To our knowledge, there are no systematic reviews and meta-analyses comparing the severity of NoV and RV disease. METHODS: We searched MEDLINE for studies reporting data for NoV and RV medically attended disease severity in children. We included studies where all children had been tested for both NoV (reverse transcription polymerase chain reaction) and RV (enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction) and that reported disease severity using the Vesikari or modified Vesikari score, or provided clinical information on severity. We generated pooled estimates of the mean with 95% confidence intervals using random effects meta-analysis. RESULTS: We identified 266 publications, of which 31 were retained for qualitative analysis and 26 for quantitative analysis. Fourteen studies provided data on severity score for the meta-analysis. The pooled mean severity scores (95% confidence interval) among outpatients were 10 (8-12) and 11 (8-14) for NoV and RV, respectively. Among inpatients, they were 11 (9-13) for NoV and 12 (10-14) for RV. The difference was statistically significant among inpatients, but relatively small (1 point in a 20-point scale). About 20% more children with RV required rehydration when compared with children with NoV. CONCLUSIONS: NoV causes moderate to severe disease similar to RV in young children. This information should be useful for future evaluations of an eventual introduction of NoV vaccines in national immunization programs. PMID- 29135828 TI - Improved Diagnostic Performance of an Immunofluorescence-based Rapid Antigen Detection Test for Group A Streptococci in Children With Pharyngitis. AB - BACKGROUND: Accurate diagnosis and appropriate treatment of group A streptococcal (GAS) pharyngitis are important to prevent complications. Most available rapid antigen detection tests (RADTs) have shown excellent specificity but often lack sensitivity. Our objective was to compare the diagnostic performances of a new fluorescence-based immunoassay and a classic immunochromatographic RADT using standard throat culture or polymerase chain reaction as references. METHODS: Prospective observational study in 2 pediatric emergency departments in children 3-15 years of age presenting with pharyngitis and a McIsaac score >=2. Three throat swabs were obtained simultaneously: one for culture and one for each of both RADTs. Polymerase chain reaction assay of the DNaseB sequence was performed in case of discordant results (culture negative and either RADTs positive). RESULTS: A total of 1002 patients were analyzed, with an overall 37.1% prevalence of GAS pharyngitis. Sensitivity, specificity, positive and negative predictive values were, respectively, 84.9%*, 96.8%, 94.0% and 91.6% for the new fluorescence-based immunoassay, and 75.3%*, 98.1%, 95.9% and 87.0% for the immunochromatographic test (*P < 0.05). CONCLUSIONS: The immunofluorescence-based assay demonstrated improved diagnostic performances over the standard immunochromatographic RADT. Similarly specific for GAS detection, it demonstrates significantly higher sensitivity in children with McIsaac scores 2 or more. A negative result rules out a risk of GAS pharyngitis in 91.6% of children, making it an appropriate tool in pediatric emergency settings. Combined to the low incidence of rheumatic strains, critical appraisal of current practice to routinely perform a backup throat culture from children with pharyngitis and with negative GAS RADT could be reconsidered. PMID- 29135829 TI - Chikungunya Virus Infections Among Infants-Who Classification Not Applicable. AB - Chikungunya virus caused an epidemic on Curacao in 2014-2015. Infants are highly at risk for clinical syndromes as sepsis-like illness and central nervous system disease. Clinical recognition is important if laboratory test, polymerase chain reaction and enzyme-linked immunosorbent assay are not available. The World Health Organization created criteria for identification of probable Chikungunya virus. None of the studied infants met these criteria. We believe the criteria suggested by World Health Organization should be modified for infants. PMID- 29135830 TI - Tissue-Resident Lymphocytes in Solid Organ Transplantation: Innocent Passengers or the Key to Organ Transplant Survival? AB - Short-term outcomes of solid organ transplantation have improved dramatically over the past several decades; however, long-term survival has remained static over the same period, and chronic rejection remains a major cause of graft failure. The importance of donor, or "passenger," lymphocytes to the induction of tolerance to allografts was recognized in the 1990s, but their precise contribution to graft acceptance or rejection has not been elucidated. Recently, specialized populations of tissue-resident lymphocytes in nonlymphoid organs have been described. These lymphocytes include tissue-resident memory T cells, regulatory T cells, gammadelta T cells, invariant natural killer T cells, and innate lymphoid cells. These cells reside in commonly transplanted solid organs, including the liver, kidneys, heart, and lung; however, their contribution to graft acceptance or rejection has not been examined in detail. Similarly, it is unclear whether tissue-resident cells derived from the pool of recipient-derived lymphocytes play a specific role in transplantation biology. This review summarizes the evidence for the roles of tissue-resident lymphocytes in transplant immunology, focussing on their features, functions, and relevance for solid organ transplantation, with specific reference to liver, kidney, heart, and lung transplantation. PMID- 29135831 TI - LivSim: An Open-Source Simulation Software Platform for Community Research and Development for Liver Allocation Policies. PMID- 29135833 TI - Occupational Noise Exposure, Bilateral High-Frequency Hearing Loss, and Blood Pressure. AB - OBJECTIVE: The aim of this study was to investigate the relationships between occupational noise exposure and blood pressure using self-reported occupational exposure and bilateral high-frequency hearing loss. METHODS: This study included 4548 participants aged 20 to 69 years from the National Health and Nutrition Examination Survey 1999 to 2004. On the basis of self-reported exposure status, participants were divided into the current, former, or never exposed groups. Bilateral high-frequency hearing loss was defined as the average high-frequency hearing threshold at least 25 dB in both ears. RESULTS: The currently exposed participants had slightly increased diastolic blood pressure compared with those never exposed. Among previously exposed participants, those with bilateral high frequency hearing loss had increased systolic blood pressure, heart rate, and the prevalence of hypertension compared with those with normal high-frequency hearing. CONCLUSION: Although there were some significant results, the evidence was not consistent to support the associations between occupational noise exposure and blood pressure. PMID- 29135832 TI - Prognostic Value of the Persistence of C1q-Binding Anti-HLA Antibodies in Acute Antibody-Mediated Rejection in Kidney Transplantation. AB - BACKGROUND: The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown. METHODS: We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q binding capacity assessment. RESULTS: Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q binding DSAs in 4 patients had low MFI values without a prozone effect. CONCLUSION: The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification. PMID- 29135834 TI - Associations Between Fixed-Term Employment and Health and Behaviors: What are the Mechanisms? AB - OBJECTIVE: To analyze the associations between fixed-term employment and health (work ability and mental health) and behaviors (engagement and performance). Psychological contract fulfilment (PCF) and breach (PCB) are investigated as potential mediators of these associations. METHODS: Seven hundred workers employed on fixed-term contracts from a broad range of organizations participated in the study. The Structural Equation Model was performed to analyze the data. RESULTS: Mediation analyses revealed that good physical and mental health and productivity are more likely to be achieved by those workers who perform non manual work and (to some extent) accept their contracts because they experience high levels of PCF and low levels of PCB. CONCLUSIONS: Apart from the lack of physical workload, psychological contract fulfilment has been revealed as yet another significant mediator between a higher socioeconomic position and good health and productivity of fixed-term workers. PMID- 29135835 TI - Cardiovascular Disease and Type 2 Diabetes Risk Across Occupational Groups and Industry in a Statewide Study of an Australian Working Population. AB - OBJECTIVE: The aim of this study was to investigate prevalence of type 2 diabetes (diabetes) and cardiovascular disease (CVD) risk in occupational and industry groups in a large, diverse working population. METHODS: Five hundred thousand Victorian workers undertook health checks, including lifestyle, anthropometric, and biomedical cardiovascular risk factor assessment. Five-year diabetes (AUSDRISK) and absolute CVD risk were estimated. RESULTS: High diabetes and CVD risk was increased in many occupational groups and industries relative to managers and Professional/Scientific/Technical Services, respectively. Significantly more blue-collar workers had high diabetes risk [males prevalence ratio (PR) 1.19 (95% confidence interval, 95% CI 1.17 to 1.20); females 1.34 (95% CI 1.30 to 1.38)], high CVD risk [males 1.45 (95% CI 1.37 to 1.53); females 1.48 (95% CI 1.17 to 1.88], and risk factors including smoking [males 2.26 (95% CI 2.22 to 2.30); females 2.20 (95% CI 2.13 to 2.27)], compared with white-collar workers. CONCLUSION: Targeting occupational and industry groups within sustainable workplace programs could assist in reducing chronic diseases, lowering sickness absence, and improving productivity. PMID- 29135836 TI - Psychosocial Work Hazards, Self-Rated Health and Burnout: A Comparison Study of Public and Private Sector Employees. AB - OBJECTIVES: To compare psychosocial work conditions and health status between public and private sector employees and to examine if psychosocial work conditions explained the health differences. METHODS: Two thousand four hundred fourty one public and 15,589 private sector employees participated in a cross sectional survey. Psychosocial work hazards, self-rated health (SRH), and burnout status were assessed by questionnaire. RESULTS: As compared with private sector employees, public sector employees reported better psychosocial work conditions and better SRH, but higher risk of workplace violence (WPV) and higher levels of client-related burnout. Regression analyses indicated that higher psychosocial job demands, lower workplace justice, and WPV experience were associated with poor SRH and higher burnout. The public-private difference in client-related burnout remained even with adjustment of psychosocial work factors. CONCLUSION: Greater risks of WPV and client-related burnout observed in public sector employees warrant further investigation. PMID- 29135837 TI - Evaluation of the Work Loss Data Institute's Official Disability Guidelines. AB - OBJECTIVE: The widely used Official Disability Guidelines (ODG), a utilization review guideline for occupational conditions, has not been independently evaluated recently. METHODS: We applied the appraisal of guidelines for research and evaluation (AGREE II) and modified a measurement tool to assess systematic reviews (AMSTAR) instruments to assess guideline development methods and the quality of supporting systematic reviews. Multidisciplinary experts rated the validity of clinical content for 47 topics. RESULTS: The overall AGREE II score was 58% due to a combination of favorable attributes (breadth, clear recommendations, frequent updating, and application tools) and unfavorable attributes (scant input from workers and uncertainty about editorial independence). The modified AMSTAR rating was fair/good due to limited information on methods. Panelists rated clinical content as valid for 41 topics. CONCLUSIONS: ODG appears to be acceptable to clinicians, but ODG requires greater rigor to keep pace with methodological advances in the field of guideline development. PMID- 29135838 TI - Characteristics of Compensation Claimants Reporting an Occupational Injury Associated With Disability Benefits in the Subsequent Year: A Follow-Up Study. AB - OBJECTIVE: To describe characteristics of claimants reporting an occupational injury associated with disability benefits for income independently granted by the municipality the subsequent year. METHOD: Multivariate logistic regression was used on self-reported data and register data. Primary outcome was long-term disability benefits. RESULTS: We found that perceived low work ability, high emotional stress, perceived low health, and expected recognition increased the risk of disability benefits. Work ability was the most influential factor. Work ability of responders on benefits was 2.40 [2.23 to 2.58] (scale 1 to 10-low to high). Responders with recognized claims differed only little in characteristics regarding benefits. Responders with ongoing claims had highest risk (18.48%) of benefits despite few health differences. CONCLUSIONS: Low perceived work ability was characteristic; health and social issues explained only little of the differences in long-term benefits according to decision of workers' compensation system. PMID- 29135839 TI - Patterns of Opioid Prescribing and Predictors of Chronic Opioid Use in an Industrial Cohort, 2003 to 2013. AB - OBJECTIVE: To appreciate the impact of the opioid epidemic in workers, we described opioid prescription patterns in a US industrial cohort over a 10-year period and assessed predictors of chronic prescription. METHODS: A multiyear (2003 to 2013) cross-sectional analysis of employer-sponsored health care claims for enrolled workers (N: 21,357 to 44,769) was performed. RESULTS: The proportion of workers prescribed opioids nearly doubled in the 10-year period. The strongest predictor of chronic opioid prescribing was year, with an increase in prescriptions each year from 2003 to 2013 (odds ratio = 2.90, 95% confidence interval: 2.41 to 3.48). Additional predictors included older age, white race, hourly wage, low back pain, and osteoarthritis. CONCLUSIONS: Opioid prescribing for industrial workers substantially increased from 2003 to 2013. Occupational health professionals should be aware of the potential for chronic opioid use among workers to assess job safety and appropriate treatment of work-related injuries. PMID- 29135840 TI - Costs and Burden Associated With Loss of Labor Productivity in Informal Caregivers of People With Dementia: Results From Spain. AB - AIMS: We analyzed indirect costs related to loss of labor productivity (LLP) in informal caregivers (ICs) of people with dementia (PwD) and the associated caregiver burden and patients' clinical variables. METHODS: Multicenter cohort study of PwD and their ICs (n = 287) focused on two groups: (1) home care and (2) institutional long-term care. The costs of LLP were assessed using the Resource Utilization Dementia instrument and a human capital approach. RESULTS: The cost for LLP was 378&OV0556;/month or 4.536&OV0556;/year. Greater disease severity increased the likelihood of reducing working hours and missing a working day. There was a significant association between partial absenteeism and burden in employed informal caregiver in both the home and institutional setting. CONCLUSION: Cognitive impairment contributes to the cost of LLP in IC especially in home-care. LLP has a negative impact on IC burden. PMID- 29135841 TI - Severe Warm Autoimmune Hemolytic Anemia in a 7-Month-Old Infant Associated With a Mycoplasma Pneumoniae Infection. AB - A 7-month-old female infant had clinical and laboratory evidence of severe warm autoimmune hemolytic anemia. She also had clinical evidence of an upper respiratory tract infection with molecular detection of Mycoplasma pneumoniae. Although reticulocytopenic initially, she responded to red blood cell transfusion, steroids, and intravenous immunoglobulin and remains well today. With the increasing use of multiplex respiratory viral and bacterial pathogen detection systems, the rare association described in this report may prove to be more common than previously thought and may provide insight into the pathogenesis and clinical consequences of red blood cell autoantibodies. PMID- 29135842 TI - Genomic Profiles of Neuroblastoma Associated With Opsoclonus Myoclonus Syndrome. AB - Opsoclonus myoclonus syndrome (OMS), often called "dancing eyed syndrome," is a rare neurological condition associated with neuroblastoma in the majority of all childhood cases. Genomic copy number profiles have shown to be of prognostic significance for neuroblastoma patients. The aim of this retrospective multicenter study was to analyze the genomic copy number profiles of tumors from children with neuroblastoma presenting with OMS at diagnosis. In 44 cases of neuroblastoma associated with OMS, overall genomic profiling by either array comparative genomic hybridization or single nucleotide polymorphism array proved successful in 91% of the cases, distinguishing tumors harboring segmental chromosome alterations from those with numerical chromosome alterations only. A total of 23/44 (52%) tumors showed an segmental chromosome alterations genomic profile, 16/44 (36%) an numerical chromosome alterations genomic profile, and 1 case displayed an atypical profile (12q amplicon). No recurrently small interstitial copy number alterations were identified. With no tumor relapse nor disease-related deaths, the overall genomic profile was not of prognostic impact with regard to the oncological outcome in this series of patients. Thus, the observation of an excellent oncological outcome, even for those with an unfavorable genomic profile of neuroblastoma, supports the hypothesis that an immune response might be involved in tumor control in these patients with OMS. PMID- 29135843 TI - Abscessing Infection by Streptococcus mitis Mimicking Metastatic Lesions in a 5 Year-Old Girl With Nephroblastoma: A Case Report. AB - Streptococcus mitis is a common pathogen causing infections in oncological patients. However, cases of abscesses caused by Streptococcus mitis in oncological patients have not been reported so far. We report on 5-year-old child with nephroblastoma and pulmonary and hepatic metastases at diagnosis who went into complete remission undergoing chemotherapy and nephrectomy, and who developed new round lesions in liver and lungs under continuous chemotherapy suggestive of new metastases. Biopsy of the lesions revealed abscesses with detection of Streptococcus mitis. The child was successfully treated with antibiotics, finished chemotherapy per protocol and has been in complete remission for 14 months. Infectious lesions involving organs of typical metastatic dissemination can easily be misdiagnosed as metastases, especially in the absence of symptoms. Histologic proof of lesions suspicious of metastases is mandatory if it leads to a change of prognosis and therapy. Streptococcus mitis can be a causative organism of pulmonary and hepatic abscesses in oncological patients. PMID- 29135844 TI - Magnet(r) Enculturation. AB - In this column, the senior manager for the Magnet Appraiser Program(r) relates the importance of the components of the journey to Magnet with developing and sustaining a culture of excellence through the appraisal period and beyond. Sustainment of excellence includes regular critical assessments and support in nursing practice, governance models, and resources throughout organizational settings where nursing is practiced. PMID- 29135845 TI - Registered Nurse and Nursing Assistant Perceptions of Limited English-Proficient Patient-Clinician Communication. AB - In this article, the authors discuss implications for nurse administrators from a recent qualitative study regarding nursing personnel perceptions of limited English proficient (LEP) patient-clinician communication. Few studies have examined nursing personnel's use and perceptions of communication resources when caring for LEP patients. PMID- 29135846 TI - Bringing the OhioHealth Nursing Strategic Plan to Life With the AONE Care Innovation and Transformation Program. AB - Contemporary CNOs are committed to developing the next generation of nurse leaders. At OhioHealth, the nursing strategic vision includes the belief that every nurse will be a leader in improving health across the care continuum. In 2016, the OhioHealth System partnered with AONE to participate in the Care Innovation and Transformation program resulting in bedside nurses living this strategic vision and creating positive changes in quality, safety, and satisfaction for patients and families. PMID- 29135847 TI - A Two-Pronged Approach to Retaining Millennial Nurses. AB - Despite increased staff engagement and improved new hire on-boarding, organizations struggle to retain millennial nurses. One dominant trait is shared by organizations that have successfully reduced turnover for this group: investment in select strategies that cement loyalty to the organization. In this article, the authors describe 2 strategies for retaining early-tenure millennial nurses. In the 1st article of this series, the authors described why nursing leaders must supplement their organization's current investments in engagement with strategies targeted at millennials in their 1st 3 years. This 2nd part of the series will outline these strategies. PMID- 29135848 TI - Using Simulation to Hardwire Bedside Shift Report. AB - Numerous attempts to move nursing handoff to the bedside failed within our organization. Upon retrospect, previous attempts lacked standardization, coordination, and clear expectations. With emphasis on implementing patient- and family-centered care to increase patient experience scores, we developed a standardized staff training methodology using didactic and simulation to address staff barriers to adoption, a standardized implementation process, and a process to hardwire the practice. PMID- 29135849 TI - December 2017 Editorial Thank You. PMID- 29135850 TI - Incorporating Nurse Input and Evidence Into a Newly Designed Unit to Improve Patient and Nursing Outcomes. AB - OBJECTIVE: The aim of this study was to identify processes, outcomes, and lessons learned from designing a new evidence-based unit. A research study was conducted simultaneously to rigorously measure changes in patient and staff outcomes. BACKGROUND: Nursing leadership and frontline nursing engagement are critical in evidence-based design to promote positive outcomes and workflow. METHODS: Quality indicators were tracked premove and postmove. Nursing workflow was tracked, and teamwork was examined. RESULTS: The incidence of falls and methicillin-resistant Staphylococcus aureus decreased on the new unit. Patient satisfaction improved; the greatest improvement was noise reduction. Teamwork remained stable. Nurses spent significantly more time in the patient rooms on the new unit. CONCLUSIONS: This hospital found nursing engagement in the unit design process to be imperative to promote positive patient outcomes and stable or improved teamwork. Nursing leaders should be involved at the onset of the design process to facilitate optimal outcomes. PMID- 29135851 TI - The Impact of an Electronic Medication Administration Record (eMAR) and Computerized Physician Order Entry (CPOE) on Nurse Extender and Unit Clerk Staffing. AB - OBJECTIVE: The aim of this study is to describe the impact of the introduction of health information technology (HIT) on the utilization and payroll costs of nurse extenders and unit clerks in medicine and surgery units in a large regional health system. BACKGROUND: Long-term policy goals of HIT implementation are reported to include system-level reductions in labor costs, achieved through improved efficiency. METHODS: Using a retrospective cohort model, we analyzed how hours worked per patient day and staffing costs per patient day varied with the implementation of HIT over time at 2 different hospitals within a health system. RESULTS: Implementation of electronic medication administration records was not associated with significant changes in staffing or labor costs. Both labor hours and costs associated with nurse extenders and unit clerks were significantly reduced after the subsequent addition of computerized provider order entry. Simultaneously, units that did not implement any HIT experienced a significant increase in both labor hours and costs. CONCLUSION: Health information technology implementation in the inpatient setting is associated with significant savings in labor hours and costs in non-registered nursing roles. PMID- 29135852 TI - Quantifying Missed Nursing Care Using the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) Survey. AB - OBJECTIVE: The aim of this article is to describe the use of Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) data to measure missed nursing care and construct a missed nursing care metric. BACKGROUND: Missed nursing care varies widely within and between US hospitals. Missed nursing care can be measured utilizing the HCAHPS data. METHODS: This cross-sectional study used HCAHPS data to measure missed care. RESULTS: This analysis includes HCAHPS data from 1125 acute care patients discharged between January 2014 and December 2014. A missed care index was computed by dividing the total number of missed care occurrences as reported by the patient into the total number of survey responses that did not indicate missed care. The computed missed care index for the organization was 0.6 with individual unit indices ranging from 0.2 to 1.4. CONCLUSIONS: Our methods utilize existing data to quantify missed nursing care. Based on the assessment, nursing leaders can develop interventions to decrease the incidence of missed care. Further data should be gathered to validate the incidence of missed care from HCAHPS reports. PMID- 29135853 TI - Social Return on Investment: A New Approach to Understanding and Advocating for Value in Healthcare. AB - OBJECTIVE: To determine whether the methodology of social return on investment (SROI) could be a way in which the value of a healthcare-related program (children's cancer camp) could be captured, evaluated, and communicated. BACKGROUND: The value of healthcare goes beyond what can be captured in financial terms; however, this is the most common type of value that is measured. The SROI methodology accounts for a broader concept of value by measuring social, environmental, and economic outcomes and uses monetary values to represent them. METHODS: The steps/stages of an SROI analysis were applied to the context of a children's camp for this article. RESULTS: Applying the SROI methodology to this healthcare-related program was feasible and provided insight and understanding related to the impacts of this program. CONCLUSIONS: Because of SROI's flexibility, it is a tool that has great potential in a healthcare environment and for leaders to evaluate programmatic return on investment. PMID- 29135854 TI - An Academic-Practice Partnership Model to Grow and Sustain Advanced Practice Nursing. AB - OBJECTIVE: The aims of this article were to describe the implementation of an academic-practice partnership for healthcare system workforce development and provide preliminary outcomes of the associated pilot study. BACKGROUND: The demand for cross-continuum healthcare delivery models necessitates creation of workforce development structures for advanced practice nursing. METHODS: An academic-practice partnership specified enrollment of 5 cohorts of BSN staff nurses in a 3-year DNP program. Qualitative methods were used to explore pilot data at midpoint of cohort 1 student progression to determine learning outcomes and DNP projects with potential for impact on organization goals. RESULTS: Partnership implementation experiences indicate that contractual agreements and an established evaluation plan are keys to academic-practice partnership success. Pilot study findings suggest that curriculum core courses provide a foundation for designing DNP projects congruent with acute and primary care health system goals. Implementing an academic-practice partnership is a strategy for workforce development to increase retention of advanced practice nurses. CONCLUSION: Academic-practice partnerships can serve as a catalyst for a paradigm shift for changing models of care, thus enhancing workforce development succession planning for sustainable growth in healthcare systems. PMID- 29135855 TI - Factors Associated With the Implementation of a Nurse Staffing Directive. AB - BACKGROUND: In 2010, the Veterans Health Administration issued a Staffing Methodology (SM) Directive to provide a standardized, data-driven method for determining appropriate inpatient nurse staffing. OBJECTIVE: We aimed to describe experiences and factors related to SM implementation. METHODS: We administered a Web-based survey to chief nurse executives to obtain their implementation experiences. Structural, process, and outcome factors and barriers associated with self-reported implementation success were identified. RESULTS: Respondents representing 104 of 117 facilities participated. Almost all facilities (96%) had completed at least 1 cycle of SM, yet only half (52%) rated their implementation highly successful. Early implementation date, higher levels of leadership confidence in SM, and higher frequency in which nursing staff think in terms of hours per patient day were associated with higher SM implementation success. Time, staff training and educational needs, and engagement were common barriers. DISCUSSION: Understanding factors that influence successful implementation of staffing policies is important to ensuring safe staffing. PMID- 29135856 TI - The Authors' Reply. PMID- 29135857 TI - The Authors' Reply. PMID- 29135858 TI - Should Persistent Hepatitis E Virus Replication in Transplant Patients Be Tolerated? PMID- 29135859 TI - Developing a Risk Score to Predict Long-term Adverse Outcomes After Kidney Transplantation. PMID- 29135860 TI - Chronic Airway Fibrosis in Orthotopic Mouse Lung Transplantation Models-An Experimental Reappraisal? PMID- 29135861 TI - In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid. AB - Melanoma, an aggressive skin tumor with high metastatic potential, is associated with high mortality and increasing morbidity. Multiple available chemotherapeutic and immunotherapeutic modalities failed to improve survival in advanced disease, and the search for new agents is ongoing. The aim of this study was to investigate antimelanoma effects of O,O-diethyl-(S,S)-ethylenediamine-N,N'di-2-(3 cyclohexyl) propanoate dihydrochloride (EE), a previously synthesized and characterized organic compound. Mouse melanoma B16 cell viability was assessed using acid phosphatase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, sulforhodamine B, and lactate dehydrogenase assays. Apoptosis and autophagy were investigated using flow cytometry, fluorescence and electron microscopy, and western blotting. In vivo antitumor potential was assessed in subcutaneous mouse melanoma model after 14 days of treatment with EE. Tumor mass and volume were measured, and RT-PCR was used for investigating the expression of autophagy-related, proapoptotic, and antiapoptotic molecules in tumor tissue. Investigated organic compound exerts significant cytotoxic effect against B16 cells. EE induced apoptosis, as confirmed by phosphatidyl serine externalisation, caspase activation, and ultrastructural features typical for apoptosis seen on fluorescence and electron microscopes. The apoptotic mechanism included prompt disruption of mitochondrial membrane potential and oxidative stress. No autophagy was observed. Antimelanoma action and apoptosis induction were confirmed in vivo, as EE decreased mass and volume of tumors, and increased expression of several proapoptotic genes. EE possesses significant antimelanoma action and causes caspase-dependent apoptosis mediated by mitochondrial damage and reactive oxygen species production. Decrease in tumor growth and increase in expression of proapoptotic genes in tumor tissue suggest that EE warrants further investigation as a candidate agent in treating melanoma. PMID- 29135862 TI - Management of Sigmoid Sinus Associated Pulsatile Tinnitus: A Systematic Review of the Literature. AB - OBJECTIVES: Although studies demonstrate 4 to 20% of patients with pulsatile tinnitus (PT) have associated sigmoid sinus anomalies, no consensus exists regarding optimal management. Our objective was to perform a systematic review exploring surgical and endovascular intervention of PT caused by sigmoid sinus anomalies. DATA SOURCES/EXTRACTION: A systematic review was performed using the Preferred Reporting Systems for Systematic Reviews and Meta-Analysis guidelines for reporting of results, with a target population encompassing patients with PT and either sigmoid sinus diverticulum or sigmoid wall dehiscence. From an initial search yielding 74 articles, 21 manuscripts met inclusion criteria. DATA SYNTHESIS: Of 139 patients, 90.4% were female. Mean age was 39.0 years. Diagnosis was sigmoid sinus diverticulum/aneurysm in 47.5% of patients, sigmoid sinus dehiscence in 35.3% of patients, and both in 17.3%. Sigmoid sinus wall reconstruction/resurfacing (SSW R/R) was used in 91.4% and endovascular procedures in 7.9% of patients. Postoperative recurrence was 3.5% (mean follow-up 21.1 m). Although there was no association between resolution rate and age or sex, right-sided PT resolved at a higher rate. For every increase in body mass index by 1 kg/m, the odds of PT resolution increased 9.2%. CONCLUSION: PT as a result of sigmoid sinus diverticula, aneurysms, and dehiscence is a rare, but largely treatable condition. Available interventions include SSW R/R, endovascular intervention, and cardiac U-clip techniques. In SSW R/R, bone pate, unspecified soft-tissue graft, and bone cement had the highest rates of PT resolution. While temporalis fascia and autologous bone chips were the materials most commonly used, they had significantly lower rates of PT resolution compared with the other materials, with the exception of auricular cartilage and bone cement. Most episodes of recurrence are resolved with medical management or a revision procedure. This study serves to summarize the current state of knowledge on the treatment of pulsatile tinnitus across disciplines. PMID- 29135864 TI - Patterns of Extended High-frequency Hearing Loss Following Stapes Surgery. AB - OBJECTIVE: Thresholds in the extended high-frequency (EHF) range (> 8 kHz) often worsen after otherwise successful stapedectomy. The aims of this study were to document the prevalence of hearing loss from 0.25 to 16 kHz after stapedectomy and the relative rates of transient and permanent EHF hearing loss. STUDY DESIGN: Prospective, observational, longitudinal. SETTING: Tertiary referral center. PATIENTS: Thirty-nine patients who underwent 44 primary or revision stapes surgeries. INTERVENTION: Hearing thresholds were measured at 0.25 to 16 kHz preoperatively, and at approximately 1 week, 1, 3, 6, and 12 months postoperatively. MAIN OUTCOME MEASURES: Average threshold changes in bands of frequencies (0.25-1, 2-8, 9-11.2, 12.5-16 kHz) and the percentage of patients with a change in the highest frequency at which a hearing threshold could be measured were evaluated at each assessment. RESULTS: A mean hearing loss was documented in the EHF range at all postoperative assessments. There was a decrease in the highest frequency at which a hearing threshold was measureable in 77% of patients at the first postoperative assessment, and despite some improvement over time, in 50% of patients 12 months postoperatively. CONCLUSION: There is a significant incidence of EHF loss after stapedectomy. Although partial recovery often occurs, more than half of patients retain an EHF hearing loss 12 months postoperatively. As hearing loss in the EHF range is more common than loss at 4 kHz, EHF measurements may be a more sensitive model to compare surgical factors and evaluate pharmacologic interventions. PMID- 29135863 TI - Effectiveness in Rehabilitation of Current Wireless CROS Technology in Experienced Bone-Anchored Implant Users. AB - OBJECTIVE: To compare the effectiveness of current contralateral routing of signal technology (CROS) to bone-anchored implants in experienced bone-anchored implant users with unilateral severe-profound sensorineural hearing loss. DESIGN: Prospective, within-subject repeated-measures comparison study. SETTING: Tertiary referral center. PATIENTS: Adult, English-speaking patients (n = 12) with severe profound unilateral sensorineural hearing loss implanted with a bone-anchored implant for the indication of single-sided deafness. INTERVENTION: Subjects were fitted with contralateral routing of signal amplification and tested for speech in noise performance and localization error. OUTCOME MEASURES: Speech perception in noise was assessed using the BKB-SIN test materials. Localization was assessed using narrow band noises centered at 500 and 4000 Hz, as well as a broadband speech stimulus presented at random to the front hemifield by 19 speakers spatially separated by 10 degrees. RESULTS: There was no improvement in localization ability in the aided condition and no significant difference in performance with CROS versus bone-anchored implants (BAI). There was a significant improvement in speech in noise performance for monaural listeners in the aided condition for speech poorer ear/noise better ear, speech front/noise front, and speech front/noise back. No significant difference was observed on performance with CROS versus BAI subjects. CONCLUSION: Contrary to earlier studies suggesting improved performance of BAIs over CROS, the current study found no difference in performance in BAI over CROS devices. Both CROS and BAI provide significant benefit for monaural listeners. The results suggest that noninvasive CROS solutions can successfully rehabilitate certain monaural listening deficits, provide improved hearing outcomes, and expand the reach of treatment in this population. PMID- 29135865 TI - Electrode Impedance Fluctuations as a Biomarker for Inner Ear Pathology After Cochlear Implantation. AB - OBJECTIVES/HYPOTHESIS: Cochlear implant surgery now aims to preserve residual low frequency hearing. The current research explores whether fluctuations in the electrical impedance of cochlear implant electrodes may act as a biomarker for pathological changes that lead to the delayed loss of residual hearing. STUDY DESIGN: Secondary analysis of a double-blinded randomized trial, where methylprednisolone was administered intravenously before cochlear implantation with a view to preserving residual hearing. METHODS: Seventy-four patients with residual hearing after cochlear implant surgery were investigated for an impedance "spike," defined as a median rise of >=4 kOmega across all electrodes from the baseline measurements. Spikes were related to objective and subjective hearing loss, dizziness, and tinnitus. RESULTS: An impedance spike occurred in 14% (10/74) of enrolled patients. Three months after surgery, five patients exhibited spikes and three of these patients had a total loss of their residual hearing. 4.3% of the 69 patients without spikes lost residual hearing. At 1 year, 9 of 10 patients who exhibited spikes had lost all their residual hearing. 8.1% of the 37 patients who did not experience a spike lost their residual hearing. Seventy percent of patients exhibiting a spike also experienced vertigo. The administration of steroids at the time of surgery did not influence the occurrence of spikes. CONCLUSION: Our results suggest that there is a relationship between a spike and the loss of residual hearing. It seems that rises in impedance can reflect pathology within the inner ear and predict the future loss of residual hearing. PMID- 29135866 TI - Importance of Perimodiolar Electrode Position for Psychoacoustic Discrimination in Cochlear Implantation. AB - HYPOTHESIS: Modiolar proximity of the cochlear implant electrodes and low impedance values have a positive effect on electrical pitch discrimination. BACKGROUND: The proximity of the cochlear electrode to the modiolar wall can determine changes in tissue and fluid environment. With the onset of soft-surgery techniques, the trauma caused during surgery has been reduced, minimizing fibrous growth. METHODS: Computed tomography-scan measurements of electrode-inner wall distance and psychoacoustic electrode discrimination tests were done. Neural Response Telemery and impedance data were used in the study. RESULTS: It was found that patients fitted with perimodiolar arrays have lower impedance values and smaller electrode-inner wall distances than those fitted with straight arrays. These variables were significantly correlated to electrode discrimination. It was found that a closer distance to the modiolus also results in better electrode discrimination. CONCLUSION: Perimodiolar electrodes could be a better solution in terms of pitch discrimination both because they are closer to the modiolus and because their impedance is lower. PMID- 29135867 TI - Analysis of Otologic Features of Patients With Primary Ciliary Dyskinesia. AB - OBJECTIVE: To evaluate otologic features of primary ciliary dyskinesia (PCD), especially eardrum features, audiometric findings, and clinical course. STUDY DESIGN: Retrospective patient review. SETTING: Tertiary referral center. PATIENTS: Fifteen patients (mean age, 16.9 years [range, 1-32 yr]; 8 males and 7 females) diagnosed with PCD at our university hospital in the last 12 years. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Electron microscopy of nasal cilia, gene mutation analysis, endoscopy of 30 eardrums, pure-tone audiometry, and tympanometry. RESULTS: All 15 patients showed ciliary ultrastructural abnormalities on electron microscopy and/or biallelic mutations in genes associated with ciliary function or structure. All 30 eardrums examined showed certain abnormalities. Fourteen patients had otitis media with effusion or its sequelae. The remaining patient had chronic otitis media. Pure-tone audiometry revealed the mean air conduction thresholds to be 25.0 and 26.4 dB in the right and left ears, respectively. In the ears with better hearing and worse hearing, the mean air conduction thresholds were 22.3 and 29.0 dB respectively. CONCLUSION: Otologic disease among patients with PCD essentially comprised otitis media with effusion, and the patients' eardrums showed a variety of findings. Knowledge of these otologic features may lead to the early detection of PCD. PMID- 29135868 TI - Endoscopic Transcanal Transpromontorial Approach for Vestibular Schwannoma Resection: A Case Series. AB - OBJECTIVE: To demonstrate successful surgical management of vestibular schwannomas via an exclusively endoscopic transcanal transpromontorial approach (EETTA). PATIENTS: Four patients with vestibular schwannomas. INTERVENTIONS: Surgical excision via EETTA. MAIN OUTCOMES: Technique refinements, tumor access, complete tumor removal, and patient morbidity. RESULTS: Three tumors were Koos grade I and one tumor was Koos grade II. All ears had non-serviceable hearing prior to surgery. The EETTA enabled access to the internal auditory canal and porus acousticus as well as limited access to the cerebellopontine angle. Gross total tumor resection was achieved in all cases. There were no intraoperative or postoperative complications and the mean hospital duration was 2.8 days. After a mean follow-up of 5.0 months, all cases had a good facial nerve outcome. CONCLUSIONS: The EETTA can be successfully used for the management of small vestibular schwannomas in ears without serviceable hearing. Additional studies are needed to fully elucidate the risk-benefit profile of this minimally invasive approach. PMID- 29135869 TI - Usefulness of High-Resolution 3D Multi-Sequences for Peripheral Facial Palsy: Differentiation Between Bell's Palsy and Ramsay Hunt Syndrome. AB - OBJECTIVE: To investigate the usefulness of magnetic resonance imaging (MRI) including three-dimensional (3D) sequences in the differentiation between Bell's palsy (BP) and Ramsay Hunt syndrome (RHS). STUDY DESIGN: A prospective study. SETTING: Tertiary care center. PATIENTS: Twenty patients: 15 patients with BP and five patients with RHS. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: Clinical diagnosis (BP or RHS). RESULTS: The presence of hyperintensity on 3D-fluid attenuated inversion recovery sequence (3D-FLAIR) and enhancement on gadolinium enhanced (CE)-3D-FLAIR and CE-3D-T1-weighted image (3D-T1WI) along the internal auditory canal (IAC) wall were significantly associated with RHS (p < 0.05). Hyperintensity in the inner ear was observed on pre- and postcontrast 3D-FLAIR, and enhancement of the cranial nerve (CN)-VIII was observed only on CE-3D-FLAIR. The presence of these findings also showed significant relationships with RHS (p < 0.05). Moreover, thickening of the CN-VII in the fundus of the IAC in 3D constructive interference on steady state sequence (3D-CISS) also showed a significant association with RHS (p < 0.05). In contrast, the presence of hyperintensity of the CN-VII in the fundus of the IAC on 3D-FLAIR did not demonstrate a significant relationship (p = 0.95), and enhancement in this region was observed in all cases on CE-3D-FLAIR and gadolinium-enhanced-three dimensional-T1-weighted gradient echo sequence (CE-3D-T1WI). CONCLUSIONS: 3D MRI sequences are useful for differentiating RHS from BP. In particular, the enhancement in the CN-VIII and/or along the IAC wall are valuable findings, and CE-3D-FLAIR is the most useful sequence to evaluate these findings. Thickening of the CN-VII on 3D-CISS is also an important finding. PMID- 29135870 TI - The Importance of Using the Modified Fisch Classification and the Determination of the Natural Rate of Growth of Tumor by Wait-and-Scan Approach Before Offering Radiosurgery for Tympanojugular Paragangliomas. PMID- 29135871 TI - Ocular Vestibular Evoked Myogenic Potentials: Where Are We Now? AB - OBJECTIVE: Over the last decade, ocular vestibular evoked myogenic potentials (oVEMPs) have evolved as a new clinical test for dynamic otolith (predominantly utricular) function. The aim of this review is to give an update on the neurophysiological foundations of oVEMPs and their implications for recording and interpreting oVEMP responses in clinical practice. CONCLUSION: Different lines of anatomical, neurophysiological, and clinical evidence support the notion that oVEMPs measure predominantly contralateral utricular function, while cervical cVEMPs are an indicator of ipsilateral saccular function. Bone-conducted vibration (BCV) in the midline of the forehead at the hairline (Fz) or unilateral air-conducted sound (ACS) are commonly used as stimuli for oVEMPs. It is recommended to apply short stimuli with short rise times for obtaining optimal oVEMP responses. Finally, this review summarizes the clinical application and interpretation of oVEMPs, particularly for vestibular neuritis, Meniere's disease, superior canal dehiscence and "challenging" patients. PMID- 29135872 TI - The Role of Auditory Evoked Potentials in the Context of Cochlear Implant Provision. AB - : Auditory evoked potentials (AEP) are highly demanded during the whole process of equipping patients with cochlear implants (CI). They play an essential role in preoperative diagnostics, intraoperative testing, and postoperative monitoring of auditory performance and success. The versatility of AEP's is essentially enhanced by their property to be evokable by acoustic as well as electric stimuli. Thus, the electric responses of the auditory system following acoustic stimulation and recorded by the conventional surface technique as well as by transtympanic derivation from the promontory (Electrocochleography [ECochG]) are used for the quantitative determination of hearing loss and, additionally, electrically evoked compound actions potentials (ECAP) can be recorded with the intracochlear electrodes of the implant just adjacent to the stimulation electrode to check the functional integrity of the device and its coupling to the auditory system. The profile of ECAP thresholds is used as basis for speech processor fitting, the spread of excitation (SOE) allows the identification of electrode mislocations such as array foldover, and recovery functions may serve to optimize stimulus pulse rate. These techniques as well as those relying on scalp surface activity originating in the brainstem or the auditory cortex accompany the CI recipient during its whole life span and they offer valuable insights into functioning and possible adverse effects of the CI for clinical and scientific purposes. PMID- 29135873 TI - The Effect of Peripheral Vestibular Recovery on Improvements in Vestibulo-ocular Reflexes and Balance Control After Acute Unilateral Peripheral Vestibular Loss. AB - BACKGROUND: Patients with an acute unilateral peripheral vestibular deficit (aUPVD), presumed to be caused by vestibular neuritis, show asymmetrical vestibular ocular reflexes (VORs) that improve over time. Questions arise regarding how much of the VOR improvement is due to peripheral recovery or central compensation, and whether differences in peripheral recovery influence balance control outcomes. METHODS: Thirty patients were examined at aUPVD onset and 3, 6, and 13 weeks later with four different VOR tests: caloric tests; rotating (ROT) chair tests performed in yaw with angular accelerations of 5 and 20 degrees/s; and video head impulse tests (vHIT) in the yaw plane. ROT and vHIT responses and balance control of 11 patients who had a caloric canal paresis (CP) more than 90% at aUPVD onset and no CP recovery (no-CPR) at 13 weeks in caloric tests were compared with those of 19 patients with CP recovery (CPR) to less than 30%, on average. Balance control was measured with a gyroscope system (SwayStar) recording trunk sway during stance and gait tasks. RESULTS: ROT and vHIT asymmetries of no-CPR and CPR patients reduced over time. The reduction was less at 13 weeks (36.2% vs. 83.5% on average) for the no-CPR patients. The no-CPR group asymmetries at 13 weeks were greater than those of CPR patients who had normal asymmetries. The greater asymmetries were caused by weaker deficit side responses which remained deficient in no-CPR patients at 13 weeks. Contra-deficit side vHIT and ROT responses remained normal. For all balance tests, sway was slightly greater for no-CPR compared with CPR patients at aUPVD onset and 3 weeks later. At 13 weeks, only sway during walking eyes closed was greater for the no CPR group. A combination of 5 degrees/s ROT and balance tests could predict at onset (90% accuracy) which patients would have no-CPR at 13 weeks. CONCLUSIONS: These results indicate that for ROT and vHIT tests, central compensation is observed in CPR and no-CPR patients. It acts primarily by increasing deficit side responses. Central compensation provides approximately 60% of the VOR improvement for CPR patients. The rest of the improvement is due to peripheral recovery which appears necessary to reduce VOR asymmetry to normal at 13 weeks on average. Balance control improvement is more rapid than that of the VOR and marginally affected by the lack of peripheral recovery. Both VOR and balance control measures at onset provide indicators of future peripheral recovery. For these reasons VOR and balance control needs to be tested at aUPVD onset and at 13 weeks. PMID- 29135874 TI - Meniere and Friends: Imaging and Classification of Hydropic Ear Disease. AB - BACKGROUND: Over 75 years ago, endolymphatic hydrops was discovered as the pathologic correlate of Meniere's disease. However, this pathologic finding could be ascertained only in postmortem histologic studies. Due to this diagnostic dilemma and the variable manifestation of the various audiovestibular symptoms, diagnostic classification systems based on clinical findings have been used hitherto. METHODS: A review of the literature of magnetic resonance (MR) imaging of hydropic ear disease. RESULTS: Recent developments of high resolution MR imaging of the inner ear have now enabled us to visualize in vivo endolymphatic hydrops in patients with suspected Meniere's disease. The existing knowledge from temporal bone histologic studies and from the emerging evidence on imaging based evaluation of patients with suspected Meniere's disease indicate that endolymphatic hydrops not only is responsible for the full-blown clinical triad of simultaneous attacks of auditory and vestibular dysfunction, but also for other clinical presentations such as "vestibular" and "cochlear Meniere's disease." CONCLUSION: As a consequence, we propose the term "Hydropic Ear Disease" as a new terminology which is based on symptomatic and imaging characteristics of these clinical entities to clarify and simplify their diagnostic classification. PMID- 29135875 TI - Cochlear Pericytes Are Capable of Reversibly Decreasing Capillary Diameter In Vivo After Tumor Necrosis Factor Exposure. AB - OBJECTIVE: The aim of this work was to evaluate the effect of tumor necrosis factor (TNF) and its neutralization with etanercept on the capability of cochlear pericytes to alter capillary diameter in the stria vascularis. METHODS: Twelve Dunkin-Hartley guinea pigs were randomly assigned to one of three groups. Each group was treated either with placebo and then placebo, TNF and then placebo, or TNF and then etanercept. Cochlear pericytes were visualized using diaminofluorescein-2-diacetate and intravasal blood flow by fluorescein-dextrane. Vessel diameter at sites of pericyte somas and downstream controls were quantified by specialized software. Values were obtained before treatment, after first treatment with tumor necrosis factor or placebo and after second treatment with etanercept or placebo. RESULTS: Overall, 199 pericytes in 12 animals were visualized. After initial treatment with TNF, a significant decrease in vessel diameter at sites of pericyte somas (3.6 +/-4.3%, n = 141) compared with placebo and downstream controls was observed. After initial treatment with TNF, the application of etanercept caused a significant increase (3.3 +/-5.5%, n = 59) in vessel diameter at the sites of pericyte somata compared with placebo and downstream controls. CONCLUSION: We have been able to show that cochlear pericytes are capable of reducing capillary diameter after exposition to TNF. Moreover, the reduction in capillary diameter observed after the application of TNF is revertible after neutralization of tumor necrosis factor by the application of etanercept. It seems that contraction of cochlear pericytes contributes to the regulation of cochlear blood flow. PMID- 29135876 TI - Effectiveness of Directional Microphones in Bilateral/Bimodal Cochlear Implant Users-Impact of Spatial and Temporal Noise Characteristics. AB - OBJECTIVE: To measure speech reception thresholds (SRTs) in co-located (S0N0) and diffuse noise conditions (multi-source noise field, MSNF) and to assess the impact of beamforming algorithms in MSNF in cochlear implant (CI) users. STUDY DESIGN: Non-randomized, open, prospective study. SETTING: Tertiary referral cochlear implantation center. PATIENTS: Participants included 14 CI users (7 bimodal, 7 bilateral) and 14 normal hearing young adults. INTERVENTIONS: Cochlear implantation. MAIN OUTCOME MEASURES: SRTs were assessed by means of a German matrix sentence test in either continuous or modulated noise. Loudspeakers were configured in two different conditions: S0N0 and MSNF (speech source in front, four speakers distributed at +/-28.6 and +/-151.4 degrees). In MSNF, the CI speech processor microphone was set in different directional sensitivity settings: standard (sub-cardioid), fixed (super-cardioid), and adaptive. RESULTS: In continuous noise, SRTs of both CI groups were comparable. In modulated noise, bimodal CI users showed lower SRTs than bilateral CI group, but significant benefit from glimpsing was only demonstrated in normal hearing participants. All subject groups showed significant spatial release from masking (i.e., SRT improvement in MSNF compared with S0N0 condition) in continuous noise. A tendency of improved SRT (1 dB bimodal, 2 dB bilateral) with fixed and adaptive directional sensitivity was found which could not be statistically confirmed due to large between-subject variations. CONCLUSIONS: The absence of the glimpsing effect in CI users was reaffirmed in the present study. Although very effective in single noise source conditions, the beneficial impact of beamforming algorithms in multiple noise source conditions is poor. PMID- 29135877 TI - Evaluation of Cochlear Implant Receiver Position and Its Temporal Changes. AB - HYPOTHESIS: It was the aim of this study to establish normative data regarding intended changes in cochlear implants (CI) receiver positioning by one surgeon over time. BACKGROUND: With the increasing number of CI patients, the probability of needing magnetic resonance imaging (MRI) increases. The accessibility of cerebral structures is limited by MRI artifacts caused by CI. New studies show a dependence of the visibility of intracranial structures by the MRI sequences and the position of the CI receiver itself. METHODS: Retrospective and interindividual investigation of topograms with regard to the nasion-external auditory canal-internal magnet angle and the distance between the internal magnet and the external auditory canal. We evaluated scans of 150 CI recipients implanted from 2008 until 2015. RESULTS: The most common implant position in the years 2008 to 2015 was a nasion-external auditory canal-internal magnet angle between 121 and 140 degrees (mean, 127 degrees) and an internal magnet-external auditory canal distance between 61 and 80 mm (mean, 70 mm). Over time the nasion external auditory canal-internal magnet angle increased and the internal magnet external auditory canal distance decreased, both to a statistically significant degree. A difference between the manufacturers was not observed. CONCLUSION: The CI receiver position is important for an artifact-free examination of the internal auditory canal and the cochlea. The realization of the position over a time course supports awareness of artifact-related visibility limitations. PMID- 29135878 TI - Single-Sided Deafness: Impact of Cochlear Implantation on Speech Perception in Complex Noise and on Auditory Localization Accuracy. AB - OBJECTIVE: To assess auditory localization accuracy and speech reception threshold (SRT) in complex noise conditions in adult patients with acquired single-sided deafness, after intervention with a cochlear implant (CI) in the deaf ear. STUDY DESIGN: Nonrandomized, open, prospective patient series. SETTING: Tertiary referral university hospital. PATIENTS: Eleven patients with late-onset single-sided deafness (SSD) and normal hearing in the unaffected ear, who received a CI. All patients were experienced CI users. INTERVENTION: Unilateral cochlear implantation. MAIN OUTCOME MEASURES: Speech perception was tested in a complex multitalker equivalent noise field consisting of multiple sound sources. Speech reception thresholds in noise were determined in aided (with CI) and unaided conditions. Localization accuracy was assessed in complete darkness. Acoustic stimuli were radiated by multiple loudspeakers distributed in the frontal horizontal plane between -60 and +60 degrees. RESULTS: In the aided condition, results show slightly improved speech reception scores compared with the unaided condition in most of the patients. For 8 of the 11 subjects, SRT was improved between 0.37 and 1.70 dB. Three of the 11 subjects showed deteriorations between 1.22 and 3.24 dB SRT. Median localization error decreased significantly by 12.9 degrees compared with the unaided condition. CONCLUSION: CI in single sided deafness is an effective treatment to improve the auditory localization accuracy. Speech reception in complex noise conditions is improved to a lesser extent in 73% of the participating CI SSD patients. However, the absence of true binaural interaction effects (summation, squelch) impedes further improvements. The development of speech processing strategies that respect binaural interaction seems to be mandatory to advance speech perception in demanding listening situations in SSD patients. PMID- 29135879 TI - Cochlear Implantation in Children With Congenital Unilateral Deafness: A Case Series. AB - OBJECTIVES: Cochlear implant is regarded as a treatment option for hearing rehabilitation of adults with unilateral sensorineural hearing loss. A clear benefit has been experienced in regard to speech comprehension in noise, localization, and quality of life. The aim of this study was to investigate the benefit of cochlear implantation for children with congenital unilateral hearing loss. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center; cochlear implant program. PATIENTS: Ten children with congenital unilateral hearing loss. INTERVENTION: After extensive consultation with the families and intensive counseling, the children received a cochlear implant. MAIN OUTCOME MEASURES: Categories of auditory performance, speech discrimination in open set, subjective assessment by Speech, Spatial and Qualities scale questionnaire. CONCLUSION: Eight of ten children use their cochlear implant consistently on a daily basis. Two children who were equipped with an implanted device at a later age tend to nonuse of the device. The evaluation of binaural hearing in small children is still difficult and methods have to be developed to allow objective assessment. PMID- 29135880 TI - Histological Osteoarthritic Changes in the Human Cervical Spine Facet Joints Related to Age and Sex. AB - STUDY DESIGN: Cross-sectional autopsy study. OBJECTIVE: Quantify histological changes in the lower cervical spine facet joints with regard to age and sex using systematic random sampling of entire joints. SUMMARY OF BACKGROUND DATA: Neck pain is a common debilitating musculoskeletal condition and one of the highest ranked causes of years lived with disability. The cause of neck pain is multifactorial and osteoarthritis is one potential cause. The cervical spine facet joints have been implicated in the etiology of chronic neck pain. Hence, a detailed description of their anatomy and age- and sex-related changes is needed. METHODS: The lower four cervical spine segments (C4-C7 included) were obtained from 72 subjects during autopsy; 29 women (median age 53 years [22-77]) and 43 men (median age 38 years [20-78]). A total of 1132 articular facets were embedded in toto in hard plastic and sliced into 3-mm thick sections from where 10 MUm thick histological sections were produced. Morphological variables were evaluated microscopically and histomorphometric variables were retrieved using random sampling methods. Data were analyzed with a linear regression model. RESULTS: Significant associations were found between increasing age and in particular splitting, fissures, osteophytes, thickness of the calcified cartilage, and subchondral bone plate. The thickness of the calcified cartilage and subchondral bone plate increased with increasing age, whereas the hyaline cartilage thickness decreased. Males had more extensive degenerative changes in the cartilage. CONCLUSION: Using semiquantitative histological methods, degenerative findings were observed at all spinal levels involving the articular cartilage and the osseous structures of the cervical spine facet joints similar to those observed in larger weight-bearing joints. In particular, the thickening of the calcified cartilage and the subchondral bone identified the osteocartilaginous junction as an important area in osteoarthritis. These findings may be relevant for the pathogenesis of osteoarthritis. LEVEL OF EVIDENCE: 3. PMID- 29135881 TI - Maturity Indicators and Adolescent Idiopathic Scoliosis: Evaluation of the Sanders Maturity Scale. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To determine the correlation between the Sanders Maturity Scale (SMS) and Risser stages, between both systems and menarche, and whether Risser can be used to predict SMS. SUMMARY OF BACKGROUND DATA: Predicting curve progression is critical to understanding adolescent idiopathic scoliosis and making treatment recommendations. The SMS is a better predictor of the curve acceleration phase of growth than the Risser stage. However, Scoliosis Research Society bracing criteria utilize the Risser stage and menarche. METHODS: Consecutive female patients, 8 to 16 years old, evaluated for idiopathic scoliosis or spinal asymmetry over a 31-month period were included. Main curve size, Risser stage, menarchal status, and SMS stage were recorded for each encounter, and analyzed using Spearman rank correlation and regression models. RESULTS: Six hundred fifty-six encounters (452 patients) were included with SMS staging, including 402 encounters that included menarchal data. The correlation between the Risser stage and the SMS stage was 0.9031 (P < 0.0001). However, ranges for the SMS at each Risser stage were large. Correlation between Risser stage and menarche was 0.7327 (P < 0.0001), and between SMS and menarche was 0.8355 (P < 0.0001). Eighty-five percent of SMS 3 patients were Risser 0, with or without open triradiate cartilages. Eighty-one percent of Risser 1 patients were SMS 4 or greater. CONCLUSION: When assessing maturity in idiopathic scoliosis, SMS correlates strongly with Risser stages, and both SMS and Risser correlate with menarche. However, Risser stage is a poor predictor of the exact SMS stage for individual patients due to the large ranges. The majority of patients who are >=Risser 1 have passed the curve acceleration phase of growth. Developing brace criteria based upon the SMS stage may allow more accurate predictions regarding which patients will benefit from bracing. LEVEL OF EVIDENCE: 2. PMID- 29135882 TI - Point of View: Early Effects of Medicare's Bundled Payment for Care Improvement Program for Lumbar Fusion. PMID- 29135883 TI - An Analysis of the Incidence and Outcomes of Major vs. Minor Neurological Decline after Complex Adult Spinal Deformity Surgery: A Sub-analysis of Scoli-RISK-1 Study. AB - STUDY DESIGN: A sub-analysis from a prospective, multicenter, international cohort study in 15 sites (Scoli-RISK-1). OBJECTIVE: To report detailed information regarding the severity of neurological decline related to complex adult spine deformity (ASD) surgery and to examine outcomes based on severity. SUMMARY OF BACKGROUND DATA: The basis of post-operative neurological decline after ASD surgeries can occur due to nerve root(s) or spinal cord dysfunction. The impact of decline and the pattern of recovery may be related to the anatomic location and the severity of the injury. METHODS: An investigation of 272 prospectively enrolled complex ASD surgical patients with neurological status measured by American Spinal Injury Association Lower Extremity Motor Scores (LEMS) was undertaken. Post-operative neurological decline was categorized into "major" (>=5 points loss) vs. "minor" (<5 points loss) deficits. Timing and extent of recovery in LEMS were investigated for each group. RESULTS: Among the 265 patients with LEMS available at discharge, 61 patients (23%) had neurological decline, with 20 (33%) experiencing major decline. Of note, 90% of the patients with major decline had deficits in 3 or more myotomes. Full recovery was seen in 24% at 6 weeks and increased to 65% at 6 months. However, 34% continued to experience some neurological decline at 24 months, with 6% demonstrating no improvement. Of 41 patients (67%) with minor decline, 73% had deficits in 1 or 2 myotomes. Full recovery was seen in 49% at 6 weeks and increased to 70% at 6 months. Of note, 26% had persistence of some neurological deficit at 24 months, with 18% demonstrating no recovery. CONCLUSION: In patients undergoing complex ASD correction, a rate of post-operative neurological decline of 23% was noted with 33% of these being "major". While most patients showed substantial recovery by 6 months, approximately one-third continued to experience neurological dysfunction. LEVEL OF EVIDENCE: 2. PMID- 29135885 TI - What's New in Shock, December 2017? PMID- 29135886 TI - Interpreting the MINT Randomized Trials Evaluating Radiofrequency Ablation for Lumbar Facet and Sacroiliac Joint Pain: A Call From ASRA for Better Education, Study Design, and Performance. PMID- 29135884 TI - Prognostic Factors and Treatment of Spinal Astrocytomas: A Multi-institutional Cohort Analysis. AB - STUDY DESIGN: Retrospective cohort analysis of patients with spinal astrocytoma from multi-institutional data and the literature. OBJECTIVE: To determine the prognostic factors, treatment, and survival of patients. SUMMARY OF BACKGROUND DATA: Our current understanding of the epidemiology, prognosis, and optimal treatment of spinal astrocytoma is limited. The literature is confined to case reports or small institutional case series. METHOD: Patient demographics, tumor characteristics, treatments, and outcomes were extracted. Univariate Kaplan-Meier survival analysis was performed to identify prognostic factors followed by multivariate Cox proportional hazard analysis. Wilcoxon signed-rank test was performed on pre- and postoperational functional status as measured by McCormick score. RESULTS: Ninety-four patients from four institutions and 339 patients from the literature were included. For the multi-institutional cohort, WHO grade IV tumors had shorter progression-free survival (PFS) than those of lower grades, whereas gross total resection (GTR) (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.14-1.27, P = 0.124) trended toward longer PFS when compared to subtotal resection (STR). Age 18 years or older, paresthesia as a presenting symptom, and higher WHO grade were associated with shorter overall survival (OS), whereas thoracic tumor location when compared to cervical tumor location, biopsy when compared to STR, and radiotherapy (HR: 0.42, 95% CI: 0.20-0.88, P = 0.022) were associated with longer OS. For the literature cohort, GTR (HR 0.43, 95% CI: 0.24-0.77, P = 0.005) was associated with longer PFS when compared to STR, whereas higher WHO grade was associated with shorter PFS. Higher WHO grade and recurrence/progression were associated with shorter OS. Postoperative McCormick score was significantly higher than preoperative score (P < 0.001), but subgroup analysis of the change in McCormick score by extent of resection revealed no differences among groups (P = 0.551). CONCLUSION: In patients with spinal astrocytomas, GTR likely resulted in longer PFS when compared to STR. Adjuvant radiotherapy appears to be effective in improving survival outcomes for high grade tumors. LEVEL OF EVIDENCE: 4. PMID- 29135887 TI - Ischemia-Reperfusion Injury in Aged Livers-The Energy Metabolism, Inflammatory Response, and Autophagy. AB - Because of the lack of adequate organs, the number of patients with end-stage liver diseases, acute liver failure or hepatic malignancies waiting for liver transplantation is constantly increasing. Accepting aged liver grafts is one of the strategies expanding the donor pool to ease the discrepancy between the growing demand and the limited supply of donor organs. However, recipients of organs from old donors may show an increased posttransplantation morbidity and mortality due to enhanced ischemia-reperfusion injury. Energy metabolism, inflammatory response, and autophagy are 3 critical processes which are involved in the aging progress as well as in hepatic ischemia-reperfusion injury. Compared with young liver grafts, impairment of energy metabolism in aged liver grafts leads to lower adenosine triphosphate production and an enhanced generation of free radicals, both aggravating the inflammatory response. The aggravated inflammatory response determines the extent of hepatic ischemia-reperfusion injury and augments the liver damage. Autophagy protects cells by removal of damaged organelles, including dysfunctional mitochondria, a process impaired in aging and involved in ischemia-reperfusion-related apoptotic cell death. Furthermore, autophagic degradation of cellular compounds relieves intracellular adenosine triphosphate level for the energy depressed cells. Strategies targeting the mechanisms involved in energy metabolism, inflammatory response, and autophagy might be especially useful to prevent the increased risk for ischemia reperfusion injury in aged livers after major hepatic surgery. PMID- 29135888 TI - EXIT STRATEGY IN A TREAT-AND-EXTEND REGIMEN FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To evaluate the outcome of an exit strategy in a treat-and-extend regimen for neovascular age-related macular degeneration. METHODS: Five hundred and ninety-eight eyes of 488 patients with neovascular age-related macular degeneration receiving intravitreal anti-vascular endothelial growth factor injections according to a treat-and-extend regimen were included in this retrospective study. A treat-and-extend regimen with either interval extension by 2 weeks or shortening by 1 week was used. "Exit criteria" were defined as 3 consecutive injections 16 weeks apart with stable findings after which the patient was exited from treatment and followed up at 3 to 4 monthly intervals without therapy. Best-corrected visual acuity, central retinal thickness at treatment initiation and termination, incidence of recurrence after treatment termination, presence of characteristics in the optical coherence tomography, duration of therapy, number and intervals of injections were analyzed. RESULTS: Seventeen percent of all included eyes met the exit criteria. The mean number of anti-vascular endothelial growth factor injections was 23.7 +/- 14.7 with a mean treatment duration of 4.5 +/- 2.5 years. Twelve percent reached exit with the minimal number of injections. Thirteen percent had recurrent disease after a mean of 37 +/- 16 weeks. In the subgroup with recurrent disease, rate of pigment epithelial detachment at treatment termination was significantly higher than without recurrence (77% vs. 30%, P = 0.0018) with a significant higher proportion of serous pigment epithelial detachment (31% vs. 7%, P = 0.0247). CONCLUSION: The high percentage of patients meeting the exit criteria and the relatively low incidence of recurrences underline the usefulness of a predefined exit strategy. However, in a subgroup of patients, continuation of therapy may be advisable.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29135889 TI - COMPARISON OF RESOLUTION OF VITREOMACULAR TRACTION AFTER OCRIPLASMIN TREATMENT OR VITRECTOMY. AB - PURPOSE: To compare the functional and morphologic outcome of patients with vitreomacular traction (VMT) treated with either ocriplasmin treatment or vitrectomy. METHODS: Retrospective case series of patients treated with ocriplasmin or vitrectomy for VMT. OUTCOME MEASURES: resolution of VMT, change in outer retinal thickness, integrity of ellipsoid zone, subretinal fluid formation, and best-corrected visual acuity 2 weeks and 4 months after treatment. RESULTS: Fourteen eyes received ocriplasmin (Group 1). Vitreomacular traction resolved in 50% (Group 1a), and in 50%, it did not (Group 1b). Ten eyes underwent vitrectomy (Group 2). Vitreomacular traction resolved in 100%. Outer retinal thickness decreased significantly 2 weeks after treatment in Group 1 (P = 0.003) and in 1a (P = 0.018). Two weeks after treatment, Group 1a showed a disruption of the ellipsoid zone (P = 0.001) and subretinal fluid formation (P = 0.01) more often than 1b. Neither was observed 4 months after treatment. Best-corrected visual acuity decreased significantly in Groups 1 (P = 0.034) and 1a (P = 0.026). CONCLUSION: Most patients treated with ocriplasmin for VMT showed a transient reduction of best-corrected visual acuity, accumulation of subretinal fluid, and a loss of the ellipsoid zone after the resolution of VMT. Patients with surgical resolution of VMT did not show these findings. The advantage of a less-invasive intravitreal injection of ocriplasmin must be weighed against the lower success rate, the (transient) morphologic changes, and the uncertain visual benefit. PMID- 29135890 TI - Intrascleral Fixation of Implantable Polypropylene Capsular Hook(s): A New Sutureless Technique to Reposition Dislocated Intraocular Lens-Capsular Bag Complex. PMID- 29135891 TI - Evaluation of Preoperative and Postoperative Patient Satisfaction and Quality of Life in Patients Undergoing Rhinoplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Improvement of nasal aesthetics by means of rhinoplasty is a highly sought-after procedure and leads to increased patient confidence. The aim of the study was to provide a quantitative synthesis of existing data regarding the ability of cosmetofunctional rhinoplasty to improve patient satisfaction and quality of life measured by the Rhinoplasty Outcomes Evaluation scale. METHODS: Electronic databases were searched for studies evaluating quality of life following aesthetic rhinoplasty. Study results were pooled and analyzed using a random effects model. Effect size was estimated using standardized mean difference at a 95 percent confidence interval. Heterogeneity and benefit were assessed and reported using the I and standard mean difference. Subgroup analyses were performed based on follow-up period and age group segregation. RESULTS: A total of 377 articles were retrieved, of which eight studies were included in the final analysis. Overall, patient satisfaction analyzed by pooling eight observational studies improved following cosmetofunctional rhinoplasty (standard mean difference, 5.87; 95 percent CI, 3.55 to 8.19; I = 100 percent). In addition, further subgroup analyses revealed that maximum benefit was derived by younger patients (standard mean difference, 6.69; 95 percent CI, 3.65 to 9.74; I = 99 percent) compared with older patients (standard mean difference, 3.48; 95 percent CI, 3.01 to 3.96; I = 0 percent). Postoperative patient satisfaction levels showed maximum improvement during a follow-up period of 6 to 12 months (standard mean difference, 11.07; 95 percent CI, -8.79 to 32.12; I = 100 percent). CONCLUSION: Cosmetofunctional rhinoplasty improves patients' quality of life as evidenced by an improvement in Rhinoplasty Outcomes Evaluation scores. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29135892 TI - Lower Body Lift in the Massive Weight Loss Patient: A New Classification and Algorithm for Gluteal Augmentation. AB - BACKGROUND: An often-neglected part of the lower body lift procedure is the gluteal region. The objective of this study was to classify massive weight loss patients undergoing a body lift procedure and provide a safe, standardized approach for gluteal augmentation. METHODS: A retrospective review of all body lift procedures performed between January of 2012 and January of 2017 was conducted. Patients undergoing a lower body lift with or without gluteal augmentation were included for analysis. Patients were classified as follows: type I, minimal lower and upper back fat and deflated buttock; type II, substantial lower back fat, minimal upper back fat, and deflated buttock; type III, substantial lower and upper back fat and deflated buttock; and type IV, good buttock projection. Type I patients had gluteal implants, type II patients had autologous flap augmentation, type III patients had gluteal lipofilling, and type IV patients did not have any gluteal augmentation. RESULTS: Two hundred eighty patients were included for analysis. Two hundred thirty-eight underwent concomitant gluteal augmentation (85 percent): 213 had autologous flaps (76 percent), 13 had gluteal implants (5 percent), and 12 had large-volume lipofilling (4 percent). Forty-two patients underwent a body lift with no gluteal augmentation (15 percent). Gluteal augmentation did not increase the rate of complications. In both groups, no skin necrosis, venous thrombosis, or pulmonary embolism was reported. Patients who had a sleeve gastrectomy had significantly lower odds of complications compared with gastric bypass (OR, 0.45; p = 0.017). CONCLUSION: A standardized algorithmic approach for gluteal augmentation may optimize the result without increasing the complication rate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29135893 TI - Inhibition of Skin Wound Contraction by Nanofibrillar Cellulose Hydrogel. AB - BACKGROUND: Although wound contraction is an essential part of healing, excessive contraction can compromise healing through induction of scarring and fibrosis. This in turn leads to development of wound contractures that limit elasticity and function. Major research efforts have focused on development of novel therapeutic approaches to gain inhibitory control over wound contraction. Despite these efforts, the need for cost-effective, clinically feasible, and effective agents to inhibit wound contraction remains. METHODS: In this study, the authors investigated the effect of nanofibrillar cellulose hydrogel on wound contraction both in vitro and in vivo. Two different porcine full-thickness wounds (8-mm punch-biopsy wounds and 4 * 4-cm wounds covered with a 1:3-meshed split-thickness skin graft) were treated with or without nanofibrillar cellulose or carboxymethylcellulose (Purilon hydrogel), which was used as a reference treatment. Wound contraction was observed macroscopically, and histologic sections were taken at 14-day follow-up. RESULTS: Nanofibrillar cellulose hydrogel inhibited 70 percent of punch-biopsy wound contraction, whereas the carboxymethylcellulose hydrogel was ineffective. Importantly, application of nanofibrillar cellulose on split-thickness skin grafts did not inhibit epithelialization of the interstices or cell migration from the graft. CONCLUSION: The authors' results, although preliminary, indicate a potential for nanofibrillar cellulose hydrogel as a novel material for controlling excessive wound contraction. PMID- 29135895 TI - Comparing Efficacy and Costs of Four Facial Fillers in Human Immunodeficiency Virus-Associated Lipodystrophy: A Clinical Trial. AB - BACKGROUND: The objective of this study was to evaluate and compare the safety and effectiveness of four different dermal fillers in the treatment of facial lipoatrophy secondary to human immunodeficiency virus. METHODS: The authors conducted a clinical trial including 147 patients suffering from human immunodeficiency virus-induced lipoatrophy treated with Sculptra (poly-L-lactic acid), Radiesse (calcium hydroxylapatite), Aquamid (polyacrylamide), or autologous fat. Objective and subjective changes were evaluated during a 24-month follow-up. Number of sessions, total volume injected, and overall costs of treatment were also analyzed. A comparative cost-effectiveness analysis of the treatment options was performed. RESULTS: Objective improvement in facial lipoatrophy, assessed by the surgeon in terms of changes from baseline using the published classification of Fontdevila, was reported in 53 percent of the cases. Patient self-evaluation showed a general improvement after the use of facial fillers. Patients reported being satisfied with the treatment and with the reduced impact of lipodystrophy on their quality of life. Despite the nonsignificant differences observed in the number of sessions and volume, autologous fat showed significantly lower costs than all synthetic fillers (p < 0.05). CONCLUSIONS: Surgical treatment of human immunodeficiency virus-associated facial lipoatrophy using dermal fillers is a safe and effective procedure that improves the aesthetic appearance and the quality of life of patients. Permanent fillers and autologous fat achieve the most consistent results over time, with lipofilling being the most cost-effective procedure. PMID- 29135894 TI - Deferoxamine Preconditioning of Irradiated Tissue Improves Perfusion and Fat Graft Retention. AB - BACKGROUND: Radiation therapy is a mainstay in the treatment of many malignancies, but collateral damage to surrounding tissue, with resultant hypovascularity, fibrosis, and atrophy, can be difficult to reconstruct. Fat grafting has been shown to improve the quality of irradiated skin, but volume retention of the graft is significantly decreased. Deferoxamine is a U.S. Food and Drug Administration-approved iron-chelating medication for acute iron intoxication and chronic iron overload that has also been shown to increase angiogenesis. The present study evaluates the effects of deferoxamine treatment on irradiated skin and subsequent fat graft volume retention. METHODS: Mice underwent irradiation to the scalp followed by treatment with deferoxamine or saline and perfusion and were analyzed using laser Doppler analysis. Human fat grafts were then placed beneath the scalp and retention was also followed up to 8 weeks radiographically. Finally, histologic evaluation of overlying skin was performed to evaluate the effects of deferoxamine preconditioning. RESULTS: Treatment with deferoxamine resulted in significantly increased perfusion, as demonstrated by laser Doppler analysis and CD31 immunofluorescent staining (p < 0.05). Increased dermal thickness and collagen content secondary to irradiation, however, were not affected by deferoxamine (p > 0.05). Importantly, fat graft volume retention was significantly increased when the irradiated recipient site was preconditioned with deferoxamine (p < 0.05). CONCLUSIONS: The authors' results demonstrated increased perfusion with deferoxamine treatment, which was also associated with improved fat graft volume retention. Preconditioning with deferoxamine may thus enhance fat graft outcomes for soft-tissue reconstruction following radiation therapy. PMID- 29135896 TI - Vertical Skin Paddle Orientation for the Latissimus Dorsi Flap in Breast Reconstruction: A Modification to Simultaneously Correct Inferior Pole Constriction and Improve Projection. AB - : The latissimus dorsi myocutaneous flap is a reliable and frequently used option to bring vascularized skin and soft tissue to improve the stability and aesthetic result in breast reconstruction. Standard techniques with skin paddle inset in a horizontal or oblique fashion preferentially improve anterior projection (when inset at the mastectomy scar) or lower pole and inframammary fold constriction (when inset into the inframammary fold). Here, the authors describe a modification for inset of the latissimus dorsi myocutaneous flap that improves both anterior projection and lower pole/inframammary fold constriction, and also allows the latissimus muscle to fan out and provide complete implant coverage. The vertical inset modification brings new skin and soft tissue into both the inferior pole and the central mastectomy scar, allowing simultaneous improvement in both areas and full use of the latissimus muscle to cover the implant or expander. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29135898 TI - Acute Illness Protocol for Urea Cycle Disorders. AB - Inborn errors of metabolism (IEMs) are genetic disorders that disrupt enzyme activity, cellular transport, or energy production. They are individually rare but collectively have an incidence of 1:1000. Most patients with IEMs are followed up by a physician with expertise in biochemical genetics (metabolism), but may present outside this setting. Because IEMs can present acutely with life threatening crises that require specific interventions, it is critical for the emergency physician, internist, and critical care physician as well as the biochemical geneticist to have information on the initial assessment and management of patients with these disorders. Appropriate early care can be lifesaving. This protocol is not designed to replace the expert consultation of a biochemical geneticist, but rather to improve early care and increase the level of comfort of the acute care physician with initial management of urea cycle disorders until specialty consultation is obtained. PMID- 29135897 TI - Is BMI a valid measure of obesity in postmenopausal women? AB - OBJECTIVE: Body mass index (BMI) is a widely used indicator of obesity status in clinical settings and population health research. However, there are concerns about the validity of BMI as a measure of obesity in postmenopausal women. Unlike BMI, which is an indirect measure of obesity and does not distinguish lean from fat mass, dual-energy x-ray absorptiometry (DXA) provides a direct measure of body fat and is considered a gold standard of adiposity measurement. The goal of this study is to examine the validity of using BMI to identify obesity in postmenopausal women relative to total body fat percent measured by DXA scan. METHODS: Data from 1,329 postmenopausal women participating in the Buffalo OsteoPerio Study were used in this analysis. At baseline, women ranged in age from 53 to 85 years. Obesity was defined as BMI >= 30 kg/m and body fat percent (BF%) greater than 35%, 38%, or 40%. We calculated sensitivity, specificity, positive predictive value, and negative predictive value to evaluate the validity of BMI-defined obesity relative BF%. We further explored the validity of BMI relative to BF% using graphical tools, such as scatterplots and receiver operating characteristic curves. Youden's J index was used to determine the empirical optimal BMI cut-point for each level of BF% defined obesity. RESULTS: The sensitivity of BMI-defined obesity was 32.4% for 35% body fat, 44.6% for 38% body fat, and 55.2% for 40% body fat. Corresponding specificity values were 99.3%, 97.1%, and 94.6%, respectively. The empirical optimal BMI cut-point to define obesity is 24.9 kg/m for 35% BF, 26.49 kg/m for 38% BF, and 27.05 kg/m for 40% BF according to the Youden's index. CONCLUSIONS: Results demonstrate that a BMI cut-point of 30 kg/m does not appear to be an appropriate indicator of true obesity status in postmenopausal women. Empirical estimates of the validity of BMI from this study may be used by other investigators to account for BMI-related misclassification in older women. PMID- 29135899 TI - New Oxidative Stress Markers Useful in the Diagnosis of Acute Appendicitis in Children: Thiol/Disulfide Homeostasis and the Asymmetric Dimethylarginine Level. AB - OBJECTIVES: The aim of this study was to evaluate 2 new oxidative stress markers, thiol/disulfide homeostasis status and the asymmetric dimethylarginine (ADMA) level, in children with acute appendicitis (AA) and to evaluate their diagnostic utility. METHODS: This case-control study included 45 patients with AA and 35 healthy children. Age, sex, white blood cell count, neutrophil-to-lymphocyte ratio, high-sensitivity C-reactive protein (hs-CRP) level, ultrasonographic findings, thiol/disulfide homeostasis parameters (native and total thiol levels, native thiol/total thiol ratios [antioxidant parameters], and disulfide, disulfide/native thiol, and disulfide/total thiol ratios [oxidant parameters]), and the ADMA level were compared between the 2 groups. RESULTS: The native and total thiol levels, and the native thiol/total thiol ratio, were significantly lower, and the disulfide level and disulfide/native thiol and disulfide/total thiol ratios significantly higher, in the AA compared with the control group (all P < 0.001). The ADMA level was significantly higher in a perforated versus nonperforated subgroup of AA patients, but the thiol/disulfide homeostasis parameters did not differ significantly between the two subgroups. In addition, the hs-CRP level and appendiceal wall thickness were higher in the perforated subgroup. The thiol/disulfide antioxidant parameters and ADMA level correlated negatively with the white blood cell count, the neutrophil-to-lymphocyte ratio, and the hs-CRP level, in the AA group, but correlated positively with oxidant parameters. The sensitivity and specificity of the disulfide/native thiol and disulfide/total thiol ratios were high when used to diagnose AA, whereas the sensitivity of the ADMA level was high when used to diagnose perforated appendicitis. CONCLUSIONS: Thiol/disulfide homeostasis and the ADMA level, together with certain other parameters, may be useful biomarkers of AA in children. PMID- 29135900 TI - Ondansetron Prescription for Home Use in a Pediatric Emergency Department. AB - OBJECTIVES: Ondansetron has been shown to decrease admission rates and the need for intravenous fluids among pediatric emergency department (ED) patients with acute gastroenteritis, but there is limited evidence regarding its use after ED discharge. This study describes prescribing patterns for ondansetron and assesses the effects of ondansetron home prescription on rate of return. METHODS: Data were gathered from the electronic health record on 2 separate but overlapping groups of patients seen in a pediatric ED from 2012 to 2014. The Gastroenteritis Group included all patients with a discharge diagnosis of gastroenteritis by International Classification of Diseases, Ninth Revision, code. The All Ondansetron Group included any child prescribed ondansetron at discharge. Patterns of ondansetron use and 3- and 7-day ED return rate were assessed for both groups. Discharge diagnosis was evaluated for the any Ondansetron Group. RESULTS: A total of 996 patients with acute gastroenteritis were identified during the study period. Of these, 76% received ondansetron in the ED, and 71% were discharged with prescriptions for ondansetron. Seven-day ED return rates were similar between groups (6% with prescription, 5% without, P = 0.66). A total of 2287 patients received home prescriptions for ondansetron. Fifty-four percent of these patients' discharge diagnoses were classed as gastrointestinal complaints, 14% other infectious conditions, 9% respiratory, and 4% injuries. Their return rate was 6%. There was wide variation in the number of doses prescribed. CONCLUSIONS: Home-use ondansetron is widely prescribed in this urban academic pediatric ED for a variety of indications, without effect on 3- or 7-day ED return. Further prospective studies are necessary to determine the efficacy of this practice. PMID- 29135901 TI - Clinical Factors Associated With Pediatric Brain Neoplasms Versus Primary Headache: A Case-Control Analysis. AB - OBJECTIVE: Pediatric headaches are a common presentation to emergency departments accounting for almost half a million annual visits. Providers are left with the difficult task of deciding who has a secondary headache etiology that warrants neuroimaging. METHODS: We conducted a retrospective case-control study. Patients from a pediatric neuro-oncology clinic database with brain cancer and a headache at presentation were identified as cases. Controls were patients from 2 local pediatric tertiary care emergency departments with a final diagnosis of headache after negative neuroimaging. Clinical factors were decided a priori, and logistic regression was used to determine which clinical factors were related to case/control status. RESULTS: A total of 334 patients (203 controls and 131 cases) were included. Patients with a history of headaches had 0.5 (95% confidence interval [CI]: 0.3-0.9; P = 0.03) times the odds of being a case. Patients with vomiting had increased odds of being a case compared with controls regardless of the time of day (early morning 1.8 [95% CI: 1.0-3.2; P = 0.04] and non-early morning 6.6 [95% CI: 2.0-21.7; P < 0.01]). Patients with neurological signs had 10.3 (95% CI: 5.4-19.4; P < 0.01) times the odds of being a case, and patients with an associated seizure had 10.9 (95% CI: 3.8-30.7; P < 0.01) times the odds of being a case. CONCLUSIONS: This study identified clinical factors associated with pediatric brain neoplasms that may guide acute neuroimaging decisions. This study also provides insight into potential clinical factors to be studied prospectively to derive a clinical decision rule. PMID- 29135902 TI - Should the Absence of Urinary Nitrite Influence Empiric Antibiotics for Urinary Tract Infection in Young Children? AB - OBJECTIVES: Screening for urinary tract infection (UTI) includes urinary nitrite testing by dipstick urinalysis. Gram-negative enteric organisms produce urinary nitrite and represent the most common uropathogens. Enterococcus, a less common uropathogen, does not produce nitrite and has a unique antibiotic resistance pattern. Whether to adjust empiric antibiotics in the absence of urinary nitrite has not been established. Our primary objective was to determine prevalence of enterococcal UTI among young children with a nitrite negative urinalysis. METHODS: A retrospective study of children aged less than 2 years evaluated in the emergency department for possible UTI and had a paired urinalysis and urine culture was performed. Urinary tract infection was defined by catheterized culture yielding greater than or equal to 50,000 colony-forming units per milliliter of a single uropathogen. Prevalence of uropathogens among nitrite negative samples was studied. RESULTS: A total of 7599 children were studied. Median (interquartile range) age was 5.6 (2.3-11.2) months, and 57% were female. Prevalence of UTI was 8.1%. Enterococcus was the uropathogen in 2.1% of UTIs, and all cases had negative dipstick nitrite. Among nitrite negative UTIs, 95.6% of uropathogens were gram-negative and only 3.2% (confidence interval, 1.8%-5.3%) were enterococcus. None of the 200 UTIs with positive nitrite yielded enterococcus (upper confidence interval, 1.4%). Among children with positive leukocyte esterase and negative nitrite, only 0.7% of cases had enterococcal UTI. CONCLUSIONS: Only 3% of nitrite negative UTIs were caused by enterococcus. Given the low prevalence of enterococcal UTI, the absence of dipstick nitrite should not affect routine empiric antibiotic choice for presumptive UTI in young children. PMID- 29135903 TI - Micturition Syncope in Childhood: How to Recognize and Manage It. AB - Frequently, general pediatricians could face a patient with syncope, which represents approximately 1% to 3% of emergency visits. Micturition syncope is a transient loss of consciousness with onset immediately before, during, or after micturition. Literature evidence indicates that healthy young men are a population with major risk for presenting micturition syncope, with a peak of incidence around 40 to 50 years of age. Usually, this syncope occurs in the morning, after wake-up, or, more generally, when the male patients assume the orthostatic position after a period of supine position in a warm bed. No information on micturition syncope clinical presentation and prevalence in childhood is available in the literature, and probably, this kind of syncope is unrecognized in childhood. We describe 4 unreported pediatric patients with a diagnosis of micturition syncope and well-defined clinical presentation. In all patients, the syncope has been presented in the same conditions: in the morning; after wake-up; in an orthostatic position; just before, after, or during urinary bladder voiding; and with spontaneous recovery in few minutes. Interestingly, 1 patient presented with the syncope during urinary bladder voiding by autocatheterization. In our patients, all investigations made as the first approach in the pediatric emergency department did not show any abnormal results, possibly underlying the syncope episodes. By describing our experience, we want to underline the clinical presentation of micturition syncope and give to the clinicians the elements to recognize and manage it easily in children. PMID- 29135904 TI - Patient Factors Associated With the Decision to Transfer Adult Patients From a Pediatric Emergency Department For Definitive Care. AB - OBJECTIVE: Adults presenting to pediatric emergency departments are transferred to general emergency departments in proportions between 20% and 60%. How illness severity is related to the decision to transfer is poorly understood. We compared the proportion of adults with emergent and nonemergent conditions with respect to their final disposition. We also determined characteristics associated with transfer. METHODS: We conducted a retrospective review of the electronic medical record and identified all patients 25 years and older presenting to a large urban freestanding pediatric emergency department from 2008 to 2013. We collected demographic and clinical information and used a preexisting algorithm to classify visits as emergent or nonemergent. We created a multivariate logistical regression model to determine independent variables associated with transfer. RESULTS: Among 246,694 encounters, 1182 (0.5%) patients were older than 25 years. We excluded 402 (34%) because they were not categorized. Of the 780 categorized, 32% had an emergent and 68% had a nonemergent condition. Only 22% were transferred. Compared with nonurgent patients, the proportion transferred was twice as high for emergent patients (36% vs 15%), but even for emergent patients, most (63%) were retained for definitive care and/or disposition. Emergent diagnosis, age 45 to 64 years, and higher triage acuity were independently associated with the decision to transfer. CONCLUSION: Regardless of illness severity, a minority of adult patients were transferred away for definitive care. Factors independently associated with transfer were emergent condition, higher triage acuity, and older age. PMID- 29135905 TI - Unsuccessful Suicide Attempt With Tiapride. AB - To the best of our knowledge, no case has been published in the literature that reports an overdose of tiapride, either alone or in combination with other drugs. We report a self-poisoning case in an 18-year-old girl, with approximately 10 times the usual daily dose (ie, 2.5 g). Although the blood concentration was 20/30-fold higher than usually observed after therapeutic drug intakes (17,300 mcg/L), the patient remained almost asymptomatic. PMID- 29135906 TI - Effect of Age and Allele Variants of CYP3A5, CYP3A4, and POR Genes on the Pharmacokinetics of Cyclosporin A in Pediatric Renal Transplant Recipients From Serbia. AB - BACKGROUND: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR*28). The aim of this study was to assess the impact of age, CYP3A5*3, CYP3A4*22, and POR*28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. METHODS: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5*3, CYP3A4*22, and POR*28. RESULTS: CYP3A5 nonexpressers had higher overall dose adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 +/- 12.75 versus 22.44 +/- 7.12, P = 0.01). CYP3A5 nonexpressers carrying POR*28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with POR*1/*1 genotype (165.54 +/- 70.40 versus 210.55 +/- 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 +/- 4.72 versus 34.19 +/- 11.89, P = 0.001) and C2/dose (106.75 +/- 26.99 versus 209.20 +/- 71.57, P < 0.001) compared with older children. Carriers of CYP3A5*3 allele aged <=6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of POR*28 allele aged <=6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and CYP3A5 variation (P < 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and POR variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both CYP3A5 and POR variations (P < 0.016). CONCLUSIONS: Younger age, POR*28 allele, and CYP3A5*3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy. PMID- 29135907 TI - Efavirenz Therapeutic Range in HIV-1 Treatment-Naive Participants. AB - BACKGROUND: Efavirenz is currently suggested as an alternative to recommended antiretroviral (ARV) regimens by the Department of Health and Human Services for the treatment of HIV-1 in ARV-naive patients. A mid-dosing interval therapeutic range between 1000 and 4000 ng/mL for efavirenz has been proposed in the literature, with patients more likely to experience virologic failure below this range and adverse effects above. The current study reports an analysis of virologic outcome between those above, below, or within the reported efavirenz therapeutic range (1000-4000 ng/mL) and within subgroups. METHODS: This analysis examined efavirenz plasma concentrations obtained from participants enrolled in AIDS Clinical Trials Group Study A5202. This investigation divided subjects into those who experienced virologic failure and those who did not. These subjects were further separated to investigate those who had "high," "within," or "low" plasma concentrations, based on the therapeutic range. The association between virologic failure and plasma concentration was statistically examined in addition to the variables: race/ethnicity, sex, assigned nucleos(t)ide reverse transcriptase inhibitor backbone, age at study entry, history of intravenous drug use, weight, and screening HIV-1 RNA stratification level. RESULTS: In univariate analyses, a statistically significant difference was found when comparing the efavirenz concentration groups, (22 failures among the "low" concentration group [19%], 65 failures among the "within" concentration group [12%], and 11 failures among the "high" concentration group [9%]) when evaluating virologic failure as an outcome (P = 0.04). In addition, the proportion of participants with virologic failure differed across race/ethnicity groups (P = 0.03) with black non-Hispanic participants observed to have the highest rate (17%). Efavirenz concentration group, race/ethnicity, age, weight, and the interaction between efavirenz concentration group and weight were found to be significantly associated with virologic failure in multivariable logistic regression analysis. CONCLUSIONS: The proposed efavirenz therapeutic range, combined with the impact of a patient's weight, is associated with virologic failure in HIV-infected ARV-naive individuals in the United States. Additional analysis is recommended to determine the most appropriate concentration value that defines the lower limit of the efavirenz therapeutic range. PMID- 29135908 TI - Evaluation of a Novel Immunoassay for Lacosamide Therapeutic Drug Monitoring: Comparison With a Liquid Chromatography-Mass Spectrometry Assay. AB - BACKGROUND: Monitoring serum levels of lacosamide, other than to establish individualized reference ranges may be helpful in several settings, including patients with liver and/or kidney failure or settings that may result in altered pharmacokinetic characteristics and to assess patients' compliance with therapy. In this study, the EurekaOne liquid chromatography-mass spectrometry (LC-MS/MS) method (in use method) and the ARK immunoassay method (new method) for lacosamide monitoring were compared. METHODS: Lacosamide concentrations were determined in 39 patient samples using (1) antiepileptic drug LC-MS/MS kit by EurekaOne on a Thermo Fisher Scientific TSQuantum Access Max system and (2) the lacosamide immunoassay by ARK Diagnostic Inc. (research use only kit), on a Abbott Architect System. RESULTS: Measured total imprecision of the new method is 6.29% at 6.59 MUmol/L, 8.82% at 30.20 MUmol/L, and 6.45% at 64.51 MUmol/L. Passing-Bablok regression analysis showed a nonsignificant intercept of -0.03015 [95% confidence interval (CI), -1.2243 to 0.8593] and a slope of 1.05 (95% CI, 0.9973-1.1166), showing that the method does not deviate from linearity and absence of proportional systematic error. Bland-Altman analysis showed a systematic bias of 3.296% (95% CI, -5.81 to -0.78) with 95% of the LC-MS/MS-ARK mean % of differences ranging from -18.5 to 11.9. Despite this bias, data of the combined imprecision of the 2 methods show that the new method is still acceptable within the maximum allowable error of 15%. CONCLUSIONS: The performance of the new ARK method on the Architect system is acceptable and may be used routinely to measure serum lacosamide concentration in the clinic although the nature of the bias has to be carefully addressed. PMID- 29135909 TI - Food Swamps Predict Obesity Rates Better Than Food Deserts in the United States. AB - This paper investigates the effect of food environments, characterized as food swamps, on adult obesity rates. Food swamps have been described as areas with a high-density of establishments selling high-calorie fast food and junk food, relative to healthier food options. This study examines multiple ways of categorizing food environments as food swamps and food deserts, including alternate versions of the Retail Food Environment Index. We merged food outlet, sociodemographic and obesity data from the United States Department of Agriculture (USDA) Food Environment Atlas, the American Community Survey, and a commercial street reference dataset. We employed an instrumental variables (IV) strategy to correct for the endogeneity of food environments (i.e., that individuals self-select into neighborhoods and may consider food availability in their decision). Our results suggest that the presence of a food swamp is a stronger predictor of obesity rates than the absence of full-service grocery stores. We found, even after controlling for food desert effects, food swamps have a positive, statistically significant effect on adult obesity rates. All three food swamp measures indicated the same positive association, but reflected different magnitudes of the food swamp effect on rates of adult obesity (p values ranged from 0.00 to 0.16). Our adjustment for reverse causality, using an IV approach, revealed a stronger effect of food swamps than would have been obtained by naive ordinary least squares (OLS) estimates. The food swamp effect was stronger in counties with greater income inequality (p < 0.05) and where residents are less mobile (p < 0.01). Based on these findings, local government policies such as zoning laws simultaneously restricting access to unhealthy food outlets and incentivizing healthy food retailers to locate in underserved neighborhoods warrant consideration as strategies to increase health equity. PMID- 29135910 TI - Sleep-Disordered Breathing in Children with Recurrent Wheeze/Asthma: A Single Centre Study. AB - The relationship between asthma and sleep-disordered breathing is bidirectional due to common risk factors that promote airway inflammation. Obstructive sleep disordered breathing and recurrent wheeze/asthma are conditions that involve the upper and the lower respiratory system, respectively. The aim of the present study was to investigate the sleep disordered breathing in children with recurrent wheeze/asthma. This was a retrospective study concerning children older than 2 years who underwent-between January 2014 and November 2016-an in laboratory overnight polygraphic study. We match the children between those who do or do not have recurrent wheeze/asthma disease. We examined the clinical records of 137 children. We excluded eight patients because of neurological and genetic conditions. Children with recurrent wheeze/asthma (N = 28) were younger (p = 0.002) and leaner (p = 0.013) compared to non-affected children (N = 98). Children with wheeze/asthma and unaffected ones had a similar obstructive apnea hypopnea index (p = 0.733) and oxygen desaturation index (p = 0.535). The logistic regression analysis, in which the condition of wheeze/asthma (yes/no) was a dependent variable, while demographic (age, sex, body mass index (BMI) Z score) and polygraphic results during sleep (obstructive apnea-hypopnea index, central apnea index, peripheral oxygen saturation (SpO2), and snoring) were covariates, showed that children with wheeze/asthma had higher central apnea index (Exp(B) = 2.212; Wald 6.845; p = 0.009). In conclusion, children with recurrent wheeze/asthma showed an increased number of central sleep apneas than unaffected children. This finding may suggest a dysfunction of the breathing control in the central nervous system during sleep. Systemic or central inflammation could be the cause. PMID- 29135911 TI - The Apoptogenic Toxin AIP56 Is Secreted by the Type II Secretion System of Photobacterium damselae subsp. piscicida. AB - AIP56 (apoptosis-inducing protein of 56 kDa) is a key virulence factor of Photobacterium damselae subsp. piscicida (Phdp), the causative agent of a septicaemia affecting warm water marine fish species. Phdp-associated pathology is triggered by AIP56, a short trip AB toxin with a metalloprotease A domain that cleaves the p65 subunit of NF-kappaB, an evolutionarily conserved transcription factor that regulates the expression of inflammatory and anti-apoptotic genes and plays a central role in host responses to infection. During infection by Phdp, AIP56 is systemically disseminated and induces apoptosis of macrophages and neutrophils, compromising the host phagocytic defence and contributing to the genesis of pathology. Although it is well established that the secretion of AIP56 is crucial for Phdp pathogenicity, the protein secretion systems operating in Phdp and the mechanism responsible for the extracellular release of the toxin remain unknown. Here, we report that Phdp encodes a type II secretion system (T2SS) and show that mutation of the EpsL component of this system impairs AIP56 secretion. This work demonstrates that Phdp has a functional T2SS that mediates secretion of its key virulence factor AIP56. PMID- 29135912 TI - A Statistical Study on the Effect of Hydrostatic Pressure on Metastable Pitting Corrosion of X70 Pipeline Steel. AB - Hydrostatic pressure effects on pitting initiation and propagation in X70 steel are investigated by evaluating metastable pitting probability using electrochemical methods and immersion corrosion tests in containing chlorine ion solution. Potentiodynamic tests indicated that hydrostatic pressure can decrease the breakdown potential and lead to a reduced transpassivity region. Metastable test results revealed that hydrostatic pressure can increase metastable pitting formation frequency and promote stabilization of metastable pitting growth. Electrochemical impedance spectroscopy (EIS) results indicate that Hydrostatic pressure decreases the charge transfer resistance and increases the dissolution rate within the cavities. Corrosion test results also indicated that pitting initiation and propagation are accelerated by hydrostatic pressure. Result validity was verified by evaluating metastable pitting to predict pitting corrosion resistance. PMID- 29135913 TI - Management of Ciguatoxin Risk in Eastern Australia. AB - Between 2014 and 2016, five cases of ciguatera fish poisoning (CFP), involving twenty four individuals, were linked to Spanish Mackerel (Scomberomorus commerson) caught in the coastal waters of the state of New South Wales (NSW) on the east coast of Australia. Previously, documented cases of CFP in NSW were few, and primarily linked to fish imported from other regions. Since 2015, thirteen individuals were affected across four additional CFP cases in NSW, linked to fish imported from tropical locations. The apparent increase in CFP in NSW from locally sourced catch, combined with the risk of CFP from imported fish, has highlighted several considerations that should be incorporated into risk management strategies to minimize CFP exposure for seafood consumers. PMID- 29135914 TI - Cross-Cultural Adaptation of the Social Vulnerability Index for Use in the Dutch Context. AB - Being able to identify socially frail older adults is essential for designing interventions and policy and for the prediction of health outcomes, both on the level of individual older adults and of the population. The aim of the present study was to adapt the Social Vulnerability Index (SVI) to the Dutch language and culture for those purposes. A systematic cross-cultural adaptation of the initial Social Vulnerability Index was performed following five steps: initial translation, synthesis of translations, back translation, a Delphi procedure, and a test for face validity and feasibility. The main result of this study is a face valid 32 item Dutch version of the Social Vulnerability Index (SVI-D) that is feasible in health care and social care settings. The SVI-D is a useful index to measure social frailty in Dutch-language countries and offers a broad, holistic quantification of older people's social circumstances related to the risk of adverse health outcomes. PMID- 29135915 TI - Evaluation of Polyamine Transport Inhibitors in a Drosophila Epithelial Model Suggests the Existence of Multiple Transport Systems. AB - Increased polyamine biosynthesis activity and an active polyamine transport system are characteristics of many cancer cell lines and polyamine depletion has been shown to be a viable anticancer strategy. Polyamine levels can be depleted by difluoromethylornithine (DFMO), an inhibitor of the key polyamine biosynthesis enzyme ornithine decarboxylase (ODC). However, malignant cells frequently circumvent DFMO therapy by up-regulating polyamine import. Therefore, there is a need to develop compounds that inhibit polyamine transport. Collectively, DFMO and a polyamine transport inhibitor (PTI) provide the basis for a combination therapy leading to effective intracellular polyamine depletion. We have previously shown that the pattern of uptake of a series of polyamine analogues in a Drosophila model epithelium shares many characteristics with mammalian cells, indicating a high degree of similarity between the mammalian and Drosophila polyamine transport systems. In this report, we focused on the utility of the Drosophila epithelial model to identify and characterize polyamine transport inhibitors. We show that a previously identified inhibitor of transport in mammalian cells has a similar activity profile in Drosophila. The Drosophila model was also used to evaluate two additional transport inhibitors. We further demonstrate that a cocktail of polyamine transport inhibitors is more effective than individual inhibitors, suggesting the existence of multiple transport systems in Drosophila. Our findings reinforce the similarity between the Drosophila and mammalian transport systems and the value of the Drosophila model to provide inexpensive early screening of molecules targeting the transport system. PMID- 29135916 TI - Lactones from the Sponge-Derived Fungus Talaromyces rugulosus. AB - The marine-derived fungus Talaromyces rugulosus isolated from the Mediterranean sponge Axinella cannabina and cultured on solid rice medium yielded seventeen lactone derivatives including five butenolides (1-5), seven (3S)-resorcylide derivatives (6-12), two butenolide-resorcylide dimers (13 and 14), and three dihydroisocoumarins (15-17). Among them, fourteen compounds (1-3, 6-16) are new natural products. The structures of the isolated compounds were elucidated by 1D and 2D NMR (Nuclear Magnetic Resonance) spectroscopy as well as by ESI-HRMS (ElectroSpray Ionization-High Resolution Mass Spectrometry). TDDFT-ECD (Time Dependent Density Functional Theory-Electronic Circular Dichroism) calculations were performed to determine the absolute configurations of chiral compounds. The butenolide-resorcylide dimers talarodilactones A and B (13 and 14) exhibited potent cytotoxicity against the L5178Y murine lymphoma cell line with IC50 values of 3.9 and 1.3 uM, respectively. PMID- 29135917 TI - Asperlin Inhibits LPS-Evoked Foam Cell Formation and Prevents Atherosclerosis in ApoE-/- Mice. AB - Asperlin is a marine-derived natural product with antifungal and anti inflammatory activities in vitro. In the present study, we isolated asperlin from a marine Aspergillus versicolor LZD4403 fungus and investigated its anti atherosclerotic effects in vitro and in vivo. Asperlin significantly inhibited lipopolysaccharides (LPS)- but not oxidated low-density lipoprotein (oxLDL) evoked foam cell formation and promoted cholesterol efflux in RAW264.7 macrophages. Supplementation with asperlin also suppressed LPS-elicited production of pro-inflammatory factors in RAW264.7 macrophages, decreased the expression levels of iNOS, IL-1beta and TNFalpha, and increased the expression of IL-10 and IL-4, indicating a remarkable shift in M1/M2 macrophages polarization. In vivo experiments in high-fat diet (HFD)-fed ApoE-/- mice showed that oral administration of asperlin for 12 weeks remarkably suppressed atherosclerotic plaque formation in the aorta, as revealed by the reduced aortic dilatation and decreased atherosclerotic lesion area. Asperlin also decreased serum levels of pro-inflammatory factors but showed little impact on blood lipids in ApoE-/- atherosclerotic mice. These results suggested that asperlin is adequate to prevent atherosclerosis in vivo. It may exert atheroprotective function through suppressing inflammation rather than ameliorating dyslipidemia. PMID- 29135919 TI - Acoustic Sensors Based on Amino-Functionalized Nanoparticles to Detect Volatile Organic Solvents. AB - Love-wave gas sensors based on surface functionalized iron oxide nanoparticles has been developed in this research. Amino-terminated iron oxide nanoparticles were deposited, by a spin coating technique, onto the surface of Love-wave sensors, as a very reproducible gas-sensing layer. The gases tested were organic solvents, such as butanol, isopropanol, toluene and xylene, for a wide and low concentration range, obtaining great responses, fast response times of a few minutes (the time at which the device produced a signal change equal to 90%), good reproducibilities, and different responses for each detected solvent. The estimated limits of detection obtained have been very low for each detected compound, about 1 ppm for butanol, 12 ppm for isopropanol, 3 ppm for toluene and 0.5 ppm for xylene. Therefore, it is demonstrated that this type of acoustic wave sensor, with surface amino-functionalized nanoparticles, is a good alternative to those ones functionalized with metal nanoparticles, which result very expensive sensors to achieve worse results. PMID- 29135918 TI - Phospholipids of Animal and Marine Origin: Structure, Function, and Anti Inflammatory Properties. AB - In this review paper, the latest literature on the functional properties of phospholipids in relation to inflammation and inflammation-related disorders has been critically appraised and evaluated. The paper is divided into three sections: Section 1 presents an overview of the relationship between structures and biological activities (pro-inflammatory or anti-inflammatory) of several phospholipids with respect to inflammation. Section 2 and Section 3 are dedicated to the structures, functions, compositions and anti-inflammatory properties of dietary phospholipids from animal and marine sources. Most of the dietary phospholipids of animal origin come from meat, egg and dairy products. To date, there is very limited work published on meat phospholipids, undoubtedly due to the negative perception that meat consumption is an unhealthy option because of its putative associations with several chronic diseases. These assumptions are addressed with respect to the phospholipid composition of meat products. Recent research trends indicate that dairy phospholipids possess anti-inflammatory properties, which has led to an increased interest into their molecular structures and reputed health benefits. Finally, the structural composition of phospholipids of marine origin is discussed. Extensive research has been published in relation to omega-3 polyunsaturated fatty acids (PUFAs) and inflammation, however this research has recently come under scrutiny and has proved to be unreliable and controversial in terms of the therapeutic effects of omega-3 PUFA, which are generally in the form of triglycerides and esters. Therefore, this review focuses on recent publications concerning marine phospholipids and their structural composition and related health benefits. Finally, the strong nutritional value of dietary phospholipids are highlighted with respect to marine and animal origin and avenues for future research are discussed. PMID- 29135920 TI - Environmental Burkholderia cenocepacia Strain Enhances Fitness by Serial Passages during Long-Term Chronic Airways Infection in Mice. AB - Burkholderia cenocepacia is an important opportunistic pathogen in cystic fibrosis (CF) patients, and has also been isolated from natural environments. In previous work, we explored the virulence and pathogenic potential of environmental B. cenocepacia strains and demonstrated that they do not differ from clinical strains in some pathogenic traits. Here, we investigated the ability of the environmental B. cenocepacia Mex1 strain, isolated from the maize rhizosphere, to persist and increase its virulence after serial passages in a mouse model of chronic infection. B. cenocepacia Mex1 strain, belonging to the recA lineage IIIA, was embedded in agar beads and challenged into the lung of C57Bl/6 mice. The mice were sacrificed after 28 days from infection and their lungs were tested for bacterial loads. Agar beads containing the pool of B. cenocepacia colonies from the four sequential passages were used to infect the mice. The environmental B. cenocepacia strain showed a low incidence of chronic infection after the first passage; after the second, third and fourth passages in mice, its ability to establish chronic infection increased significantly and progressively up to 100%. Colonial morphology analysis and genetic profiling of the Mex1-derived clones recovered after the fourth passage from infected mice revealed that they were indistinguishable from the challenged strain both at phenotypic and genetic level. By testing the virulence of single clones in the Galleria mellonella infection model, we found that two Mex1-derived clones significantly increased their pathogenicity compared to the parental Mex1 strain and behaved similarly to the clinical and epidemic B. cenocepacia LMG16656T. Our findings suggest that serial passages of the environmental B. cenocepacia Mex1 strain in mice resulted in an increased ability to determine chronic lung infection and the appearance of clonal variants with increased virulence in non vertebrate hosts. PMID- 29135921 TI - Nox, Reactive Oxygen Species and Regulation of Vascular Cell Fate. AB - The generation of reactive oxygen species (ROS) and an imbalance of antioxidant defence mechanisms can result in oxidative stress. Several pro-atherogenic stimuli that promote intimal-medial thickening (IMT) and early arteriosclerotic disease progression share oxidative stress as a common regulatory pathway dictating vascular cell fate. The major source of ROS generated within the vascular system is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (Nox), of which seven members have been characterized. The Nox family are critical determinants of the redox state within the vessel wall that dictate, in part the pathophysiology of several vascular phenotypes. This review highlights the putative role of ROS in controlling vascular fate by promoting endothelial dysfunction, altering vascular smooth muscle phenotype and dictating resident vascular stem cell fate, all of which contribute to intimal medial thickening and vascular disease progression. PMID- 29135922 TI - Targeting Immune Cell Checkpoints during Sepsis. AB - Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence of secondary opportunistic infections. Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis. Engagement of these inhibitory molecules on various immune cells has been consistently shown to inhibit innate immune cell functions (e.g., phagocytosis, cytokine production and pathogen clearance) and also lead to impaired T cell competence. In numerous pre-clinical models of sepsis, therapeutic agents aimed at blocking engagement of inhibitory immune checkpoints on immune cells have been shown to improve innate and adaptive immune cell functions, increase host resistance to infection and significantly improve survival. Therefore, immunotherapy with immune cell checkpoint inhibitors holds significant potential for the future of sepsis therapy and merits further investigation. PMID- 29135923 TI - The Association between Serum 25(OH)D Status and Blood Pressure in Participants of a Community-Based Program Taking Vitamin D Supplements. AB - BACKGROUND: Vitamin D deficiency is a risk factor for hypertension. METHODS: We assessed 8155 participants in a community-based program to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) status and blood pressure (BP) and the influence of vitamin D supplementation on hypertension. Participants were provided vitamin D supplements to reach a target serum 25(OH)D > 100 nmol/L. A nested case-control study was conducted to examine the effect of achieving physiological vitamin D status in those who were hypertensive and not taking BP lowering medication, and hypertensive participants that initiated BP-lowering medication after program entry. RESULTS: At baseline, 592 participants (7.3%) were hypertensive; of those, 71% were no longer hypertensive at follow-up (12 +/- 3 months later). There was a significant negative association between BP and serum 25(OH)D level (systolic BP: coefficient = -0.07, p < 0.001; diastolic BP: coefficient = -0.1, p < 0.001). Reduced mean systolic (-18 vs. -14 mmHg) and diastolic (-12 vs. -12 mmHg) BP, pulse pressure (-5 vs. -1 mmHg) and mean arterial pressure (-14 vs. -13 mmHg) were not significantly different between hypertensive participants who did and did not take BP-lowering medication. CONCLUSION: Improved serum 25(OH)D concentrations in hypertensive individuals who were vitamin D insufficient were associated with improved control of systolic and diastolic BP. PMID- 29135924 TI - The Impact of Synaptic Zn2+ Dynamics on Cognition and Its Decline. AB - The basal levels of extracellular Zn2+ are in the range of low nanomolar concentrations and less attention has been paid to Zn2+, compared to Ca2+, for synaptic activity. However, extracellular Zn2+ is necessary for synaptic activity. The basal levels of extracellular zinc are age-dependently increased in the rat hippocampus, implying that the basal levels of extracellular Zn2+ are also increased age-dependently and that extracellular Zn2+ dynamics are linked with age-related cognitive function and dysfunction. In the hippocampus, the influx of extracellular Zn2+ into postsynaptic neurons, which is often linked with Zn2+ release from neuron terminals, is critical for cognitive activity via long-term potentiation (LTP). In contrast, the excess influx of extracellular Zn2+ into postsynaptic neurons induces cognitive decline. Interestingly, the excess influx of extracellular Zn2+ more readily occurs in aged dentate granule cells and intracellular Zn2+-buffering, which is assessed with ZnAF-2DA, is weakened in the aged dentate granule cells. Characteristics (easiness) of extracellular Zn2+ influx seem to be linked with the weakened intracellular Zn2+ buffering in the aged dentate gyrus. This paper deals with the impact of synaptic Zn2+ signaling on cognition and its decline in comparison with synaptic Ca2+ signaling. PMID- 29135925 TI - Membrane-Active Properties of an Amphitropic Peptide from the CyaA Toxin Translocation Region. AB - The adenylate cyclase toxin CyaA is involved in the early stages of infection by Bordetella pertussis, the causative agent of whooping cough. CyaA intoxicates target cells by a direct translocation of its catalytic domain (AC) across the plasma membrane and produces supraphysiological levels of cAMP, leading to cell death. The molecular process of AC translocation remains largely unknown, however. We have previously shown that deletion of residues 375-485 of CyaA selectively abrogates AC translocation into eukaryotic cells. We further identified within this "translocation region" (TR), P454 (residues 454-484), a peptide that exhibits membrane-active properties, i.e., is able to bind and permeabilize lipid vesicles. Here, we analyze various sequences from CyaA predicted to be amphipatic and show that although several of these peptides can bind membranes and adopt a helical conformation, only the P454 peptide is able to permeabilize membranes. We further characterize the contributions of the two arginine residues of P454 to membrane partitioning and permeabilization by analyzing the peptide variants in which these residues are substituted by different amino acids (e.g., A, K, Q, and E). Our data shows that both arginine residues significantly contribute, although diversely, to the membrane-active properties of P454, i.e., interactions with both neutral and anionic lipids, helix formation in membranes, and disruption of lipid bilayer integrity. These results are discussed in the context of the translocation process of the full length CyaA toxin. PMID- 29135927 TI - Design and Calibration of a Novel Bio-Inspired Pixelated Polarized Light Compass. AB - Animals, such as Savannah sparrows and North American monarch butterflies, are able to obtain compass information from skylight polarization patterns to help them navigate effectively and robustly. Inspired by excellent navigation ability of animals, this paper proposes a novel image-based polarized light compass, which has the advantages of having a small size and being light weight. Firstly, the polarized light compass, which is composed of a Charge Coupled Device (CCD) camera, a pixelated polarizer array and a wide-angle lens, is introduced. Secondly, the measurement method of a skylight polarization pattern and the orientation method based on a single scattering Rayleigh model are presented. Thirdly, the error model of the sensor, mainly including the response error of CCD pixels and the installation error of the pixelated polarizer, is established. A calibration method based on iterative least squares estimation is proposed. In the outdoor environment, the skylight polarization pattern can be measured in real time by our sensor. The orientation accuracy of the sensor increases with the decrease of the solar elevation angle, and the standard deviation of orientation error is 0 . 15 ? at sunset. Results of outdoor experiments show that the proposed polarization navigation sensor can be used for outdoor autonomous navigation. PMID- 29135926 TI - Proline-Based Carbamates as Cholinesterase Inhibitors. AB - Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1 carboxylate (IC50 = 46.35 MUM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2 bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 MUM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2 hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure-inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3'-/4'-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE. PMID- 29135928 TI - Wearable Wide-Range Strain Sensors Based on Ionic Liquids and Monitoring of Human Activities. AB - Wearable sensors for detection of human activities have encouraged the development of highly elastic sensors. In particular, to capture subtle and large scale body motion, stretchable and wide-range strain sensors are highly desired, but still a challenge. Herein, a highly stretchable and transparent stain sensor based on ionic liquids and elastic polymer has been developed. The as-obtained sensor exhibits impressive stretchability with wide-range strain (from 0.1% to 400%), good bending properties and high sensitivity, whose gauge factor can reach 7.9. Importantly, the sensors show excellent biological compatibility and succeed in monitoring the diverse human activities ranging from the complex large-scale multidimensional motions to subtle signals, including wrist, finger and elbow joint bending, finger touch, breath, speech, swallow behavior and pulse wave. PMID- 29135929 TI - Potential of Sentinel-1 Radar Data for the Assessment of Soil and Cereal Cover Parameters. AB - The main objective of this study is to analyze the potential use of Sentinel-1 (S1) radar data for the estimation of soil characteristics (roughness and water content) and cereal vegetation parameters (leaf area index (LAI), and vegetation height (H)) in agricultural areas. Simultaneously to several radar acquisitions made between 2015 and 2017, using S1 sensors over the Kairouan Plain (Tunisia, North Africa), ground measurements of soil roughness, soil water content, LAI and H were recorded. The NDVI (normalized difference vegetation index) index computed from Landsat optical images revealed a strong correlation with in situ measurements of LAI. The sensitivity of the S1 measurements to variations in soil moisture, which has been reported in several scientific publications, is confirmed in this study. This sensitivity decreases with increasing vegetation cover growth (NDVI), and is stronger in the VV (vertical) polarization than in the VH cross-polarization. The results also reveal a similar increase in the dynamic range of radar signals observed in the VV and VH polarizations as a function of soil roughness. The sensitivity of S1 measurements to vegetation parameters (LAI and H) in the VV polarization is also determined, showing that the radar signal strength decreases when the vegetation parameters increase. No vegetation parameter sensitivity is observed in the VH polarization, probably as a consequence of volume scattering effects. PMID- 29135930 TI - Regulation of Chemokine-Receptor Interactions and Functions. AB - Inflammation is the body's response to injury or infection. As early as 2000 years ago, the Roman encyclopaedist Aulus Cornelius Celsus recognised four cardinal signs of this response-redness, heat, swelling and pain; a fifth sign is loss of function.[...]. PMID- 29135931 TI - Analytical Parameters of an Amperometric Glucose Biosensor for Fast Analysis in Food Samples. AB - Amperometric biosensors based on the use of glucose oxidase (GOx) are able to combine the robustness of electrochemical techniques with the specificity of biological recognition processes. However, very little information can be found in literature about the fundamental analytical parameters of these sensors. In this work, the analytical behavior of an amperometric biosensor based on the immobilization of GOx using a hydrogel (Chitosan) onto highly ordered titanium dioxide nanotube arrays (TiO2NTAs) has been evaluated. The GOx-Chitosan/TiO2NTAs biosensor showed a sensitivity of 5.46 MUA.mM-1 with a linear range from 0.3 to 1.5 mM; its fundamental analytical parameters were studied using a commercial soft drink. The obtained results proved sufficient repeatability (RSD = 1.9%), reproducibility (RSD = 2.5%), accuracy (95-105% recovery), and robustness (RSD = 3.3%). Furthermore, no significant interferences from fructose, ascorbic acid and citric acid were obtained. In addition, the storage stability was further examined, after 30 days, the GOx-Chitosan/TiO2NTAs biosensor retained 85% of its initial current response. Finally, the glucose content of different food samples was measured using the biosensor and compared with the respective HPLC value. In the worst scenario, a deviation smaller than 10% was obtained among the 20 samples evaluated. PMID- 29135932 TI - Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents. AB - Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha (Co) and Rosmarinus officinalis (Ro) extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); (c) Ro extract-treated myocardial infarction (MI-Ro); (d) Co extract-treated myocardial infarction (MI-Co); or (e) Ro+Co-treated myocardial infarction (MI-Ro+Co). Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD)-Cu2+/Zn2+, SOD-Mn2+, and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2'-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1), increased vasodilators agents (angiotensin 1-7 and bradikinin) and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators. PMID- 29135933 TI - Adolescent Alcohol Drinking Renders Adult Drinking BLA-Dependent: BLA Hyper Activity as Contributor to Comorbid Alcohol Use Disorder and Anxiety Disorders. AB - Adolescent alcohol drinking increases the risk for alcohol-use disorder in adulthood. Yet, the changes in adult neural function resulting from adolescent alcohol drinking remain poorly understood. We hypothesized that adolescent alcohol drinking alters basolateral amygdala (BLA) function, making alcohol drinking BLA-dependent in adulthood. Male, Long Evans rats were given voluntary, intermittent access to alcohol (20% ethanol) or a bitter, isocaloric control solution, across adolescence. Half of the rats in each group received neurotoxic BLA lesions. In adulthood, all rats were given voluntary, intermittent access to alcohol. BLA lesions reduced adult alcohol drinking in rats receiving adolescent access to alcohol, but not in rats receiving adolescent access to the control solution. The effect of the BLA lesion was most apparent in high alcohol drinking adolescent rats. The BLA is essential for fear learning and is hyper-active in anxiety disorders. The results are consistent with adolescent heavy alcohol drinking inducing BLA hyper-activity, providing a neural mechanism for comorbid alcohol use disorder and anxiety disorders. PMID- 29135934 TI - UltraPse: A Universal and Extensible Software Platform for Representing Biological Sequences. AB - With the avalanche of biological sequences in public databases, one of the most challenging problems in computational biology is to predict their biological functions and cellular attributes. Most of the existing prediction algorithms can only handle fixed-length numerical vectors. Therefore, it is important to be able to represent biological sequences with various lengths using fixed-length numerical vectors. Although several algorithms, as well as software implementations, have been developed to address this problem, these existing programs can only provide a fixed number of representation modes. Every time a new sequence representation mode is developed, a new program will be needed. In this paper, we propose the UltraPse as a universal software platform for this problem. The function of the UltraPse is not only to generate various existing sequence representation modes, but also to simplify all future programming works in developing novel representation modes. The extensibility of UltraPse is particularly enhanced. It allows the users to define their own representation mode, their own physicochemical properties, or even their own types of biological sequences. Moreover, UltraPse is also the fastest software of its kind. The source code package, as well as the executables for both Linux and Windows platforms, can be downloaded from the GitHub repository. PMID- 29135935 TI - Tucum-do-Cerrado (Bactris setosa Mart.) May Promote Anti-Aging Effect by Upregulating SIRT1-Nrf2 Pathway and Attenuating Oxidative Stress and Inflammation. AB - Aging may be related to oxidative damage accumulation and a low-grade inflammation, both responses are modulated by iron and phytochemicals. This study investigated the effect of tucum-do-cerrado (Bactris setosa Mart.) consumption on the expression of sirtuins (SIRT 1 and 3) and senescence marker protein-30 (SMP30), and on the redox and inflammatory responses, in adult rats supplemented or not with dietary iron. Male Wistar rats were treated for 12 weeks with: control diet (CT); iron enriched-diet (+Fe); control diet + 15% tucum-do-cerrado (Tuc); or iron enriched-diet + 15% tucum-do-cerrado (Tuc + Fe). Iron supplementation (+Fe) increased liver, spleen and intestine iron levels, transferrin saturation, serum iron, serum TNF-alpha and IL-6 levels, hepatic carbonyl content and and superoxide dismutase (SOD) activity, hepatic Nrf2 protein and Nqo1 mRNA levels and decreased the renal Sirt1 mRNA levels in relation to CT group. Tucum-do-cerrado consumption (Tuc) increased hepatic SOD activity, Nrf2 and SIRT1 mRNA and protein contents, and Nqo1 mRNA levels, while it decreased the renal SOD activity compared with the CT diet. The consumption of tucum-do-cerrado associated with the iron-enriched diet (Tuc + Fe) increased the iron levels in tissues and serum transferrin saturation, compared to the CT diet, while promoting a decrease in hepatic carbonyl and renal malondialdehyde levels, marginally reducing serum IL-6 levels, and increasing hepatic SIRT1 protein content, renal Sirt1 and hepatic Nrf2 mRNA levels, compared to the +Fe group. None of the treatments altered Smp30 mRNA levels. The results suggest that tucum do-cerrado consumption might promote an anti-aging effect by increasing SIRT1 expression, which may enhance Nrf2 mRNA and protein levels and its downstream pathway, which in turn decrease oxidative damage to proteins and the levels of inflammatory cytokines (IL-6 and TNF-alpha), induced by iron excess. PMID- 29135936 TI - A Role of Sp1 Binding Motifs in Basal and Large T-Antigen-Induced Promoter Activities of Human Polyomavirus HPyV9 and Its Variant UF-1. AB - Human polyomavirus 9 (HPyV9) was originally detected in the serum of a renal transplant patient. Seroepidemiological studies showed that ~20-50% of the human population have antibodies against this virus. HPyV9 has not yet been associated with any disease and little is known about the route of infection, transmission, host cell tropism, and genomic variability in circulating strains. Recently, the HPyV9 variant UF-1 with an eight base-pair deletion, a thirteen base-pair insertion and with point mutations, creating three putative Sp1 binding sites in the late promoter was isolated from an AIDS patient. Transient transfection studies with a luciferase reporter plasmid driven by HPyV9 or UF1 promoter demonstrated that UF1 early and late promoters were stronger than HPyV9 promoters in most cell lines, and that the UF1 late promoter was more potently activated by HPyV9 large T-antigen (LTAg). Mutation of two Sp1 motifs strongly reduced trans activation of the late UF1 promoter by HPyV9 LTAg in HeLa cells. In conclusion, the mutations in the UF1 late promoter seem to strengthen its activity and its response to stimulation by HPyV9 LTAg in certain cells. It remains to be investigated whether these promoter changes have an influence on virus replication and affect the possible pathogenic properties of the virus. PMID- 29135938 TI - Effects of a Lutein and Zeaxanthin Intervention on Cognitive Function: A Randomized, Double-Masked, Placebo-Controlled Trial of Younger Healthy Adults. AB - Background: Past studies have suggested that higher lutein (L) and zeaxanthin (Z) levels in serum and in the central nervous system (as quantified by measuring macular pigment optical density, MPOD) are related to improved cognitive function in older adults. Very few studies have addressed the issue of xanthophylls and cognitive function in younger adults, and no controlled trials have been conducted to date to determine whether or not supplementation with L + Z can change cognitive function in this population. Objective: The purpose of this study was to determine whether or not supplementation with L + Z could improve cognitive function in young (age 18-30), healthy adults. Design: A randomized, double-masked, placebo-controlled trial design was used. Fifty-one young, healthy subjects were recruited as part of a larger study on xanthophylls and cognitive function. Subjects were randomized into active supplement (n = 37) and placebo groups (n = 14). MPOD was measured psychophysically using customized heterochromatic flicker photometry. Cognitive function was measured using the CNS Vital Signs testing platform. MPOD and cognitive function were measured every four months for a full year of supplementation. Results: Supplementation increased MPOD significantly over the course of the year, vs. placebo (p < 0.001). Daily supplementation with L + Z and increases in MPOD resulted in significant improvements in spatial memory (p < 0.04), reasoning ability (p < 0.05) and complex attention (p < 0.04), above and beyond improvements due to practice effects. Conclusions: Supplementation with L + Z improves CNS xanthophyll levels and cognitive function in young, healthy adults. Magnitudes of effects are similar to previous work reporting correlations between MPOD and cognition in other populations. PMID- 29135937 TI - Relax, Cool Down and Scaffold: How to Restore Surface Expression of Folding Deficient Mutant GPCRs and SLC6 Transporters. AB - Many diseases arise from mutations, which impair protein folding. The study of folding-deficient variants of G protein-coupled receptors and solute carrier 6 (SLC6) transporters has shed light on the folding trajectory, how it is monitored and how misfolding can be remedied. Reducing the temperature lowers the energy barrier between folding intermediates and thereby eliminates stalling along the folding trajectory. For obvious reasons, cooling down is not a therapeutic option. One approach to rescue misfolded variants is to use membrane-permeable orthosteric ligands. Antagonists of GPCRs are-in many instances-effective pharmacochaperones: they restore cell surface expression provided that they enter cells and bind to folding intermediates. Pharmacochaperoning of SLC6 transporters is less readily achieved because the ionic conditions in the endoplasmic reticulum (ER) are not conducive to binding of typical inhibitors. The second approach is to target the heat-shock protein (HSP) relay, which monitors the folding trajectory on the cytosolic side. Importantly, orthosteric ligands and HSP-inhibitors are not mutually exclusive. In fact, pharmacochaperones and HSP inhibitors can act in an additive or synergistic manner. This was exemplified by rescuing disease-causing, folding-deficient variants of the human dopamine transporters with the HSP70 inhibitor pifithrin-MU and the pharmacochaperone noribogaine in Drosophila melanogaster. PMID- 29135939 TI - Bioactive Molecules Release and Cellular Responses of Alginate-Tricalcium Phosphate Particles Hybrid Gel. AB - In this article, a hybrid gel has been developed using sodium alginate (Alg) and alpha-tricalcium phosphate (alpha-TCP) particles through ionic crosslinking process for the application in bone tissue engineering. The effects of pH and composition of the gel on osteoblast cells (MC3T3) response and bioactive molecules release have been evaluated. At first, a slurry of Alg and alpha-TCP has been prepared using an ultrasonicator for the homogeneous distribution of alpha-TCP particles in the Alg network and to achieve adequate interfacial interaction between them. After that, CaCl2 solution has been added to the slurry so that ionic crosslinked gel (Alg-alpha-TCP) is formed. The developed hybrid gel has been physico-chemically characterized using Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and a swelling study. The SEM analysis depicted the presence of alpha-TCP micro-particles on the surface of the hybrid gel, while cross-section images signified that the alpha-TCP particles are fully embedded in the porous gel network. Different % swelling ratio at pH 4, 7 and 7.4 confirmed the pH responsiveness of the Alg-alpha-TCP gel. The hybrid gel having lower % alpha-TCP particles showed higher % swelling at pH 7.4. The hybrid gel demonstrated a faster release rate of bovine serum albumin (BSA), tetracycline (TCN) and dimethyloxalylglycine (DMOG) at pH 7.4 and for the grade having lower % alpha-TCP particles. The MC3T3 cells are viable inside the hybrid gel, while the rate of cell proliferation is higher at pH 7.4 compared to pH 7. The in vitro cytotoxicity analysis using thiazolyl blue tetrazolium bromide (MTT), bromodeoxyuridine (BrdU) and neutral red assays ascertained that the hybrid gel is non-toxic for MC3T3 cells. The experimental results implied that the non-toxic and biocompatible Alg-alpha-TCP hybrid gel could be used as scaffold in bone tissue engineering. PMID- 29135940 TI - Comparative Proteomic Analysis of Lysine Acetylation in Fish CIK Cells Infected with Aquareovirus. AB - Grass carp (Ctenopharyngodon idellus) is an important worldwide commercial freshwater culture species. However, grass carp reovirus (GCRV) causes serious hemorrhagic disease in fingerlings and yearlings of fishes. To understand the molecular pathogenesis of host cells during GCRV infection, intensive proteomic quantification analysis of lysine acetylation in Ctenopharyngodon idella kidney (CIK) cells was performed. Using dimethylation labeling-based quantitative proteomics, 832 acetylated proteins with 1391 lysine acetylation sites were identified in response to GCRV infection, among which 792 proteins with 1323 sites were quantifiable. Bioinformatics analysis showed that differentially expressed lysine acetylated proteins are involved in diverse cellular processes and associated with multifarious functions, suggesting that extensive intracellular activities were changed upon viral infection. In addition, extensive alterations on host-protein interactions at the lysine acetylation level were also detected. Further biological experiments showed that the histone deacetylases (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) could significantly suppress the GCRV replication. To our knowledge, this is the first to reveal the proteome-wide changes in host cell acetylome with aquatic virus infection. The results provided in this study laid a basis for further understanding the host response to aquareovirus infection in the post translational modification aspect by regulating cell lysine acetylation conducive to viral replication. PMID- 29135942 TI - Morphological Transition in Diamond Thin-Films Induced by Boron in a Microwave Plasma Deposition Process. AB - The purpose of this study is to understand the basic mechanisms responsible for the synthesis of nanostructured diamond films in a microwave plasma chemical vapor deposition (MPCVD) process and to identify plasma chemistry suitable for controlling the morphology and electrical properties of deposited films. The nanostructured diamond films were synthesized by MPCVD on Ti-6Al-4V alloy substrates using H2/CH4/N2 precursor gases and the plasma chemistry was monitored by the optical emission spectroscopy (OES). The synthesized thin-films were characterized by x-ray diffraction and scanning electron microscopy. The addition of B2H6 to the feedgas during MPCVD of diamond thin-films changes the crystal grain size from nanometer to micron scale. Nanostructured diamond films grown with H2/CH4/N2 gases demonstrate a broad (111) Bragg x-ray diffraction peak (Full Width at Half-Maximum (FWHM) = 0.93 degrees 2theta), indicating a small grain size, whereas scans show a definite sharpening of the diamond (111) peak (FWHM = 0.30 degrees 2theta) with the addition of boron. OES showed a decrease in CN (carbon-nitrogen) radical in the plasma with B2H6 addition to the gas mixture. Our study indicates that CN radical plays a critical role in the synthesis of nanostructured diamond films and suppression of CN radical by boron-addition in the plasma causes a morphological transition to microcrystalline diamond. PMID- 29135941 TI - The Small Heat Shock Protein alpha-Crystallin B Shows Neuroprotective Properties in a Glaucoma Animal Model. AB - Glaucoma is a neurodegenerative disease that leads to irreversible retinal ganglion cell (RGC) loss and is one of the main causes of blindness worldwide. The pathogenesis of glaucoma remains unclear, and novel approaches for neuroprotective treatments are urgently needed. Previous studies have revealed significant down-regulation of alpha-crystallin B as an initial reaction to elevated intraocular pressure (IOP), followed by a clear but delayed up regulation, suggesting that this small heat-shock protein plays a pathophysiological role in the disease. This study analyzed the neuroprotective effect of alpha-crystallin B in an experimental animal model of glaucoma. Significant IOP elevation induced by episcleral vein cauterization resulted in a considerable impairment of the RGCs and the retinal nerve fiber layer. An intravitreal injection of alpha-crystallin B at the time of the IOP increase was able to rescue the RGCs, as measured in a functional photopic electroretinogram, retinal nerve fiber layer thickness, and RGC counts. Mass-spectrometry-based proteomics and antibody-microarray measurements indicated that a alpha-crystallin injection distinctly up-regulated all of the subclasses (alpha, beta, and gamma) of the crystallin protein family. The creation of an interactive protein network revealed clear correlations between individual proteins, which showed a regulatory shift resulting from the crystallin injection. The neuroprotective properties of alpha-crystallin B further demonstrate the potential importance of crystallin proteins in developing therapeutic options for glaucoma. PMID- 29135943 TI - The Effects of 4'-Esterified Resveratrol Derivatives on Calcium Dynamics in Breast Cancer Cells. AB - Triple-negative breast cancer is a highly aggressive subtype of breast cancer. Frequently, breast cancer cells modulate their calcium signaling pathways to optimize growth. Unique calcium pathways in breast cancer cells could serve as a way to target tumorigenic cells without affecting normal tissue. Resveratrol has previously been shown to activate calcium signaling pathways. We use cell viability, single-cell calcium microscopy, and RT-PCR assays to determine the activity and mechanism of three different 4'-esterified resveratrol derivatives. We demonstrate that two of the derivatives reduce cell viability more effectively than resveratrol in MDA-MB-231 human breast cancer cells. The derivatives also activate similar pro-apoptotic calcium signaling pathways. In particular, the pivalated and butyrated resveratrol derivatives are intriguing putative chemotherapeutics because they are more effective at decreasing cell viability in vitro and inhibiting the plasma membrane Ca2+-ATPase, a protein that is often modulated in breast cancer. PMID- 29135944 TI - Design, Synthesis, and Use of Peptides Derived from Human Papillomavirus L1 Protein for the Modification of Gold Electrode Surfaces by Self-Assembled Monolayers. AB - In order to obtain gold electrode surfaces modified with Human Papillomavirus L1 protein (HPV L1)-derived peptides, two sequences, SPINNTKPHEAR and YIK, were chosen. Both have been recognized by means of sera from patients infected with HPV. The molecules, Fc-Ahx-SPINNTKPHEAR, Ac-C-Ahx-(Fc)KSPINNTKPHEAR, Ac-C-Ahx SPINNTKPHEAR(Fc)K, C-Ahx-SPINNTKPHEAR, and (YIK)2-Ahx-C, were designed, synthesized, and characterized. Our results suggest that peptides derived from the SPINNTKPHEAR sequence, containing ferrocene and cysteine residues, are not stable and not adequate for electrode surface modification. The surface of polycrystalline gold electrodes was modified with the peptides C-Ahx-SPINNTKPHEAR or (YIK)2-Ahx-C through self-assembly. The modified polycrystalline gold electrodes were characterized via infrared spectroscopy and electrochemical measurements. The thermodynamic parameters, surface coverage factor, and medium pH effect were determined for these surfaces. The results indicate that surface modification depends on the peptide sequence (length, amino acid composition, polyvalence, etc.). The influence of antipeptide antibodies on the voltammetric response of the modified electrode was evaluated by comparing results obtained with pre-immune and post-immune serum samples. PMID- 29135945 TI - Nutritional Profile and Dietary Patterns of Lebanese Non-Alcoholic Fatty Liver Disease Patients: A Case-Control Study. AB - Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disease in the world. Dietary habits have a significant impact on the biological and physical profile of patients and increase the risk of NAFLD. The overall pattern of diet intake is more associated with health outcomes than nutrients. The aim of this study was to evaluate the nutritional profile and the dietary patterns of Lebanese NAFLD patients and compare it with controls. During this study; 112 NAFLD Lebanese adult patients (55 men and 57 women); and 110 controls (44 men and 66 women) were recruited. Dietary intake was evaluated by two 24-h recalls and a semi-quantitative 90-item food frequency questionnaire. Dietary patterns were determined by factor analysis. Results from the study demonstrated that 40% of cases belonged to the high fruit group as compared to 30% following a high meat; fast food dietary pattern. Both groups increased the odds of NAFLD by four-fold (p < 0.05). The traditional diet decreases the odds by 33% after adjustment with the covariables. The high fruit diet group was, as with the high meat, fast food dietary pattern, the main potential risk factor for NAFLD in Lebanese patients. PMID- 29135946 TI - Sensitivity to Heavy-Metal Ions of Unfolded Fullerene Quantum Dots. AB - A novel type of graphene-like quantum dots, synthesized by oxidation and cage opening of C60 buckminsterfullerene, has been studied as a fluorescent and absorptive probe for heavy-metal ions. The lattice structure of such unfolded fullerene quantum dots (UFQDs) is distinct from that of graphene since it includes both carbon hexagons and pentagons. The basic optical properties, however, are similar to those of regular graphene oxide quantum dots. On the other hand, UFQDs behave quite differently in the presence of heavy-metal ions, in that multiple sensitivity to Cu2+, Pb2+ and As(III) was observed through comparable quenching of the fluorescent emission and different variations of the transmittance spectrum. By dynamic light scattering measurements and transmission electron microscope (TEM) images we confirmed, for the first time in metal sensing, that this response is due to multiple complexation and subsequent aggregation of UFQDs. Nonetheless, the explanation of the distinct behaviour of transmittance in the presence of As(III) and the formation of precipitate with Pb2+ require further studies. These differences, however, also make it possible to discriminate between the three metal ions in view of the implementation of a selective multiple sensor. PMID- 29135947 TI - Computational Experiments on the Step and Frequency Responses of a Three-Axis Thermal Accelerometer. AB - The sensor response has been reported to become highly nonlinear when the acceleration added to a thermal accelerator is very large, so the same response can be observed for two accelerations with different magnitudes and opposite signs. Some papers have reported the frequency response for the horizontal acceleration to be a first-order system, while others have reported it to be a second-order system. The response for the vertical acceleration has not been studied. In this study, computational experiments were performed to examine the step and frequency responses of a three-axis thermal accelerometer. The results showed that monitoring the temperatures at two positions and making use of cross axis sensitivity allow a unique acceleration to be determined even when the range of the vertical acceleration is very large (e.g., -10,000-10,000 g). The frequency response was proven to be a second-order system for horizontal acceleration and a third-order system for vertical acceleration. PMID- 29135948 TI - Effect of a Lactobacillus Salivarius Probiotic on a Double-Species Streptococcus Mutans and Candida Albicans Caries Biofilm. AB - The aim of the study was to evaluate the anti-cariogenic effects of Lactobacillus salivarius by reducing pathogenic species and biofilm mass in a double-species biofilm model. Coexistence of S. mutans with C. albicans can cause dental caries progression or recurrence of the disease in the future. Fifty-nine children with diagnosed early childhood caries (ECC) were recruited onto the study. The condition of the children's dentition was defined according to the World Health Organization guidelines. The participants were divided into children with initial enamel demineralization and children showing dentin damage. The study was performed on the S. mutans and C. albicans clinical strains, isolated from dental plaque of patients with ECC. The effect of a probiotic containing Lactobacillus salivarius on the ability of S. mutans and C. albicans to produce a double species biofilm was investigated in an in vitro model. The biomass of the formed/non-degraded biofilm was analyzed on the basis of its crystal violet staining. The number of colonies of S. mutans and C. albicans (CFU/mL, colony forming units/mL) forming the biofilm was determined. Microorganism morphology in the biofilm was evaluated using a scanning electron microscope (SEM). In vitro analysis demonstrated that the presence of S. mutans increased the number of C. albicans colonies (CFU/mL); the double-species biofilm mass and hyphal forms produced in it by the yeast. L. salivarius inhibited the cariogenic biofilm formation of C. albicans and S. mutans. Under the influence of the probiotic; the biofilm mass and the number of S. mutans; C. albicans and S. mutans with C. albicans colonies in the biofilm was decreased. Moreover; it can be noted that after the addition of the probiotic; fungi did not form hyphae or germ tubes of pathogenic potential. These results suggest that L. salivarius can secrete intermediates capable of inhibiting the formation of cariogenic S. mutans and C. albicans biofilm; and may inhibit fungal morphological transformation and thereby reduce the pathogenicity of C. albicans; weakening its pathogenic potential. Further research is required to prove or disprove the long-term effects of the preparation and to achieve preventive methods. PMID- 29135949 TI - Prevalence of Mental Health Problems and Associated Risk Factors among Rural-to Urban Migrant Children in Guangzhou, China. AB - Rural-to-urban migration, which has achieved a huge scale during China's economic reform, is a potential risk factor for the mental health of migrant children. To test this hypothesis, this study assessed the mental health status of rural-to urban migrant children. Guided by Andersen's behavioral model, the study explored the risk factors associated with mental health. The study recruited 1182 fifth/sixth-grade children from four private and four public primary schools in Guangzhou in 2014 in a descriptive cross-sectional design. Mental health status was measured by the strengths and difficulties questionnaire. Predisposing characteristics including demographics (e.g., age, gender), social structure (e.g., education, occupation) and health beliefs (health attitude) were recorded. Enabling characteristics including family and community resources and the need for health services were analyzed to explore the risk factors. The results indicate that more rural-to-urban migrant children were classified in the abnormal (21.0%) or borderline (18.8%) categories based on the total difficulties scores, the proportions of which were much higher than those of local children (9.8% abnormal, 13.8% borderline). Factors associated with a greater likelihood of mental health problems included single-parent families, seeking health information actively, family income cannot meet basic needs and poor perceived health status. Compared with the local children, the rural-to-urban migrant children had relatively poor mental health, hence monitoring and supporting mental health for rural-urban migrant children is critical. PMID- 29135950 TI - Establishing Smoke-Free Homes in the Indigenous Populations of Australia, New Zealand, Canada and the United States: A Systematic Literature Review. AB - A smoke-free home can have multiple benefits by reducing exposure to secondhand smoke (SHS), supporting quit attempts among active smokers, and discouraging adolescents from taking up smoking. The aim of this review was to summarize the literature on the establishment of smoke-free homes in Indigenous populations and identify the supporting influences and barriers, using the Social Cognitive Theory lens. A search of the Medline, CINAHL, Cochrane Collaboration and PyscINFO databases and manual searches of relevant peer-reviewed literature was completed, focusing on Indigenous populations in developed economies of North America and Oceania. Of 2567 articles identified, 15 studies were included. Ten studies included Indigenous participants only, and of these just three focused entirely on SHS in the home. Knowledge of the harms associated with SHS was the most common theme represented in all the studies. This knowledge fueled parents' motivation to protect their children from SHS by establishing smoke-free homes. Individuals who approached implementation with confidence, coupled with clear communication about smoke-free home rules were more successful. Barriers included challenges for families with multiple smokers living in the same dwelling. There is limited research regarding managing smoking behaviors in the home among Indigenous populations, even though this approach is a successful catalyst for smoking prevention and cessation. Research to understand the influences that support the establishment of smoke-free homes is required for better-informed intervention studies. PMID- 29135951 TI - Circular Regression in a Dual-Phase Lock-In Amplifier for Coherent Detection of Weak Signal. AB - Lock-in amplification (LIA) is an effective approach for recovery of weak signal buried in noise. Determination of the input signal amplitude in a classical dual phase LIA is based on incoherent detection which leads to a biased estimation at low signal-to-noise ratio. This article presents, for the first time to our knowledge, a new architecture of LIA involving phase estimation with a linear circular regression for coherent detection. The proposed phase delay estimate, between the input signal and a reference, is defined as the maximum-likelihood of a set of observations distributed according to a von Mises distribution. In our implementation this maximum is obtained with a Newton Raphson algorithm. We show that the proposed LIA architecture provides an unbiased estimate of the input signal amplitude. Theoretical simulations with synthetic data demonstrate that the classical LIA estimates are biased for SNR of the input signal lower than -20 dB, while the proposed LIA is able to accurately recover the weak signal amplitude. The novel approach is applied to an optical sensor for accurate measurement of NO 2 concentrations at the sub-ppbv level in the atmosphere. Side by-side intercomparison measurements with a commercial LIA (SR830, Stanford Research Inc., Sunnyvale, CA, USA ) demonstrate that the proposed LIA has an identical performance in terms of measurement accuracy and precision but with simplified hardware architecture. PMID- 29135952 TI - Integrated Pest Management of Coffee Berry Borer in Hawaii and Puerto Rico: Current Status and Prospects. AB - The coffee berry borer (CBB), Hypothenemus hampei, is the most significant insect pest of coffee worldwide. Since CBB was detected in Puerto Rico in 2007 and Hawaii in 2010, coffee growers from these islands are facing increased costs, reduced coffee quality, and increased pest management challenges. Here, we outline the CBB situation, and summarize the findings of growers, researchers, and extension professionals working with CBB in Hawaii. Recommendations for the Integrated Pest Management (IPM) program for CBB in Hawaiian Islands and Puerto Rico include: (1) establish a CBB monitoring program, (2) synchronize applications of insecticides with peak flight activity of CBB especially during the early coffee season, (3) conduct efficient strip-picking as soon as possible after harvest and perform pre-harvest sanitation picks in CBB hotspots if needed, (4) establish protocols to prevent the escape of CBB from processing areas and when transporting berries during harvest, and (5) stump prune by blocks. Progress achieved includes the introduction of the mycoinsecticide Beauveria bassiana to coffee plantations, the coordination of area-wide CBB surveys, the establishment and augmentation of native beetle predators, and an observed reduction of CBB populations and increased coffee quality where IPM programs were established. However, CBB remains a challenge for coffee growers due to regional variability in CBB pressures, high costs, and labor issues, including a lack of training and awareness of CBB management practices among growers. PMID- 29135953 TI - Spatial-Temporal Dynamics of Cropping Frequency in Hubei Province over 2001-2015. AB - Mapping crop patterns with remote sensing data is of great importance for agricultural production, food security and agricultural sustainability. In this paper, a hierarchical clustering method was proposed to map cropping frequency from time-series Moderate Resolution Imaging Spectroradiometer (MODIS) Enhanced Vegetation Indices (EVI) data and the spatial and temporal patterns of cropping frequency from 2001 to 2015 in Hubei Province of China were analyzed. The results are as follows: (1) The total double crop areas decreased slightly, while total single crop areas decreased significantly during 2001 and 2015; (2) The transfer between double crop and single crop was frequent in Hubei with about 11~15% croplands changed their cropping frequency every 5 years; (3) The crop system has obvious regional differentiation for their change trend at the county level. PMID- 29135954 TI - Effect of Structure on Charge Distribution in the Isatin Anions in Aprotic Environment: Spectral Study. AB - Five isatin anions were prepared by deprotonation of initial isatins in aprotic solvents using basic fluoride and acetate anions (F- and CH3COO-). The F- basicity is sufficient to deprotonate isatin NH hydrogen from all the studied compounds. This process is reversible. In the presence of proton donor solvents, the anions form the corresponding isatins. The isatin hydrogen acidity depends on the overall structure of the isatin derivatives. The anions were characterized by ultraviolet-visible (UV-Vis), Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. Interestingly, the anions form aggregates at concentrations above 10-3 mol.dm-3. Further, the effect of cations on the UV Vis spectra of the studied anions was studied. Charge transfer and its distribution in the anion depends on the radius and the cation electron configuration. The alkali metal cations, tetrabutylammonium (TBA+), Mg2+ and Ag+, interact with the C-2 carbonyl oxygen of the isatin anion. The interaction has a coulombic character. On the other hand, Cd2+, Zn2+, Hg2+, Co2+, and Cu+ cations form a coordinate bond with the isatin nitrogen. PMID- 29135956 TI - An Improved Aerial Target Localization Method with a Single Vector Sensor. AB - This paper focuses on the problems encountered in the actual data processing with the use of the existing aerial target localization methods, analyzes the causes of the problems, and proposes an improved algorithm. Through the processing of the sea experiment data, it is found that the existing algorithms have higher requirements for the accuracy of the angle estimation. The improved algorithm reduces the requirements of the angle estimation accuracy and obtains the robust estimation results. The closest distance matching estimation algorithm and the horizontal distance estimation compensation algorithm are proposed. The smoothing effect of the data after being post-processed by using the forward and backward two-direction double-filtering method has been improved, thus the initial stage data can be filtered, so that the filtering results retain more useful information. In this paper, the aerial target height measurement methods are studied, the estimation results of the aerial target are given, so as to realize the three-dimensional localization of the aerial target and increase the understanding of the underwater platform to the aerial target, so that the underwater platform has better mobility and concealment. PMID- 29135955 TI - Humidity May Modify the Relationship between Temperature and Cardiovascular Mortality in Zhejiang Province, China. AB - Background: The evidence of increased mortality attributable to extreme temperatures is widely characterized in climate-health studies. However, few of these studies have examined the role of humidity on temperature-mortality association. We investigated the joint effect between temperature and humidity on cardiovascular disease (CVD) mortality in Zhejiang Province, China. Methods: We collected data on daily meteorological and CVD mortality from 11 cities in Zhejiang Province during 2010-2013. We first applied time-series Poisson regression analysis within the framework of distributed lag non-linear models to estimate the city-specific effect of temperature and humidity on CVD mortality, after controlling for temporal trends and potential confounding variables. We then applied a multivariate meta-analytical model to pool the effect estimates in the 11 cities to generate an overall provincial estimate. The joint effects between them were calculated by the attributable fraction (AF). The analyses were further stratified by gender, age group, education level, and location of cities. Results: In total, 120,544 CVD deaths were recorded in this study. The mean values of temperature and humidity were 17.6 degrees C and 72.3%. The joint effect between low temperature and high humidity had the greatest impact on the CVD death burden over a lag of 0-21 days with a significant AF of 31.36% (95% eCI: 14.79-38.41%), while in a condition of low temperature and low humidity with a significant AF of 16.74% (95% eCI: 0.89, 24.44). The AFs were higher at low temperature and high humidity in different subgroups. When considering the levels of humidity, the AFs were significant at low temperature and high humidity for males, youth, those with a low level of education, and coastal area people. Conclusions: The combination of low temperature and high humidity had the greatest impact on the CVD death burden in Zhejiang Province. This evidence has important implications for developing CVD interventions. PMID- 29135957 TI - Dietary Supplement Use among Australian Adults: Findings from the 2011-2012 National Nutrition and Physical Activity Survey. AB - (1) Background: Supplement use is prevalent worldwide; however, there are limited studies examining the characteristics of people who take supplements in Australia. This study aimed to investigate the demographics, lifestyle habits and health status of supplement users; (2) Methods: Adults aged >19 years (n = 4895) were included from the 2011-2012 National Nutrition and Physical Activity Survey (NNPAS). A supplement user was defined as anyone who took one or more supplements on either of two 24-h dietary recalls. Poisson regression was used to estimate the prevalence ratio (PR) of supplement use, according to demographics, lifestyle characteristics and health status of participants; (3) Results: Supplement use was reported by 47% of women and 34% of men, and supplement use was higher among older age groups, among those with higher education levels and from areas reflecting the least socioeconomic disadvantaged. An association was found between blood pressure and supplement use; (4) Conclusions: A substantial proportion of Australians take supplements. Further investigation into the social, psychological and economic determinants that motivate the use of supplements is required, to ensure appropriate use of supplements among Australian adults. PMID- 29135958 TI - Novel alpha, beta-Unsaturated Sophoridinic Derivatives: Design, Synthesis, Molecular Docking and Anti-Cancer Activities. AB - Using sophoridine 1 and chalcone 3 as the lead compounds, a series of novel alpha, beta-unsaturated sophoridinic derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity. Structure-activity relationship (SAR) analysis indicated that introduction of alpha, beta-unsaturated ketone moiety and heterocyclic group might significantly enhance anticancer activity. Among the compounds, 2f and 2m exhibited potential effects against HepG-2 and CNE-2 human cancer cell lines. Furthermore, molecular docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound. PMID- 29135959 TI - Intratumoral Delivery of Doxorubicin on Folate-Conjugated Graphene Oxide by In Situ Forming Thermo-Sensitive Hydrogel for Breast Cancer Therapy. AB - By taking advantage of the pH-sensitive drug release property of graphene oxide (GO) after intracellular uptake, we prepared folic acid (FA)-conjugated GO (GOFA) for targeted delivery of the chemotherapeutic drug doxorubicin (DOX). GOFA-DOX was further encapsulated in an injectable in-situ forming thermo-sensitive hyaluronic acid-chitosan-g-poly(N-isopropylacrylamide) (HACPN) hydrogel for intratumoral delivery of DOX. As the degradation time of HACPN could be extended up to 3 weeks, intratumoral delivery of GOFA-DOX/HACPN could provide controlled and targeted delivery of DOX through slow degradation HACPN and subsequent cellular uptake of released GOFA-DOX by tumor cells through interactions of GOFA with folate receptors on the tumor cell's surface. GOFA nano-carrier and HACPN hydrogel were first characterized for the physico-chemical properties. The drug loading experiments indicated the best preparation condition of GOFA-DOX was by reacting 0.1 mg GOFA with 2 mg DOX. GOFA-DOX showed pH-responsive drug release with ~5 times more DOX released at pH 5.5 than at pH 7.4 while only limited DOX was released from GOFA-DOX/HACPN at pH 7.4. Intracellular uptake of GOFA by endocytosis and release of DOX from GOFA-DOX in vitro could be confirmed from transmission electron microscopic and confocal laser scanning microscopic analysis with MCF-7 breast cancer cells. The targeting effect of FA was revealed when intracellular uptake of GOFA was blocked by excess FA. This resulted in enhanced in vitro cytotoxicity as revealed from the lower half maximal inhibitory concentration (IC50) value of GOFA-DOX (7.3 MUg/mL) compared with that of DOX (32.5 MUg/mL) and GO-DOX (10 MUg/mL). The flow cytometry analysis indicated higher apoptosis rates for cells treated with GOFA-DOX (30%) compared with DOX (8%) and GO-DOX (11%). Animal studies were carried out with subcutaneously implanted MCF-7 cells in BALB/c nude mice and subject to intratumoral administration of drugs. The relative tumor volumes of control (saline) and GOFA DOX/HACPN groups at day 21 were 2.17 and 1.79 times that at day 0 with no significant difference. In comparison, the relative tumor volumes of treatment groups at the same time were significantly different at 1.02, 0.67 and 0.48 times for DOX, GOFA-DOX and GOFA-DOX/HACPN groups, respectively. The anti-tumor efficacy was also supported by images from an in vivo imaging system (IVIS) using MCF-7 cells transfected with luciferase (MCF-7/Luc). Furthermore, tissue biopsy examination and blood analysis indicated that intratumoral delivery of DOX using GOFA-DOX/HACPN did not elicit acute toxicity. Taken together, GOFA-DOX/HACPN could be deemed as a safe and efficient intratumoral drug delivery system for breast cancer therapy. PMID- 29135960 TI - The Impact of Salts on Single Chain Amphiphile Membranes and Implications for the Location of the Origin of Life. AB - One of the key steps in the origins of life was the formation of a membrane to separate protocells from their environment. These membranes are proposed to have been formed out of single chain amphiphiles, which are less stable than the dialkyl lipids used to form modern membranes. This lack of stability, specifically for decanoate, is often used to refute ocean locations for the origins of life. This review addresses the formation of membranes in hydrothermal vent like conditions, as well as other environmental constraints. Specifically, single chain amphiphiles can form membranes at high sea salt concentrations (150 g/L), high temperatures (65 degrees C), and a wide pH range (2 to 10). It additionally discusses the major challenges and advantages of membrane formation in both ocean and fresh water locations. PMID- 29135962 TI - Design, Recombinant Fusion Expression and Biological Evaluation of Vasoactive Intestinal Peptide Analogue as Novel Antimicrobial Agent. AB - Antimicrobial peptides represent an emerging category of therapeutic agents with remarkable structural and functional diversity. Modified vasoactive intestinal peptide (VIP) (VIP analogue 8 with amino acid sequence "FTANYTRLRRQLAVRRYLAAILGRR") without haemolytic activity and cytotoxicity displayed enhanced antimicrobial activities against Staphylococcus aureus (S. aureus) ATCC 25923 and Escherichia coli (E. coli) ATCC 25922 than parent VIP even in the presence of 180 mM NaCl or 50 mM MgCl2, or in the range of pH 4-10. VIP analogue 8 was expressed as fusion protein thioredoxin (Trx)-VIP8 in E. coli BL21(DE) at a yield of 45.67 mg/L. The minimum inhibitory concentration (MIC) of the recombinant VIP analogue 8 against S. aureus ATCC 25923 and E. coli ATCC 25922 were 2 MUM. These findings suggest that VIP analogue 8 is a promising candidate for application as a new and safe antimicrobial agent. PMID- 29135961 TI - Probiotic, Prebiotic, and Brain Development. AB - Recently, a number of studies have demonstrated the existence of a link between the emotional and cognitive centres of the brain and peripheral functions through the bi-directional interaction between the central nervous system and the enteric nervous system. Therefore, the use of bacteria as therapeutics has attracted much interest. Recent research has found that there are a variety of mechanisms by which bacteria can signal to the brain and influence several processes in relation to neurotransmission, neurogenesis, and behaviour. Data derived from both in vitro experiments and in vivo clinical trials have supported some of these new health implications. While recent molecular advancement has provided strong indications to support and justify the role of the gut microbiota on the gut-brain axis, it is still not clear whether manipulations through probiotics and prebiotics administration could be beneficial in the treatment of neurological problems. The understanding of the gut microbiota and its activities is essential for the generation of future personalized healthcare strategies. Here, we explore and summarize the potential beneficial effects of probiotics and prebiotics in the neurodevelopmental process and in the prevention and treatment of certain neurological human diseases, highlighting current and future perspectives in this topic. PMID- 29135963 TI - Comprehensive Survey on Improved Focality and Penetration Depth of Transcranial Magnetic Stimulation Employing Multi-Coil Arrays. AB - Multi-coil arrays applied in transcranial magnetic stimulation (TMS) are proposed to accurately stimulate brain tissues and modulate neural activities by an induced electric field (EF). Composed of numerous independently driven coils, a multi-coil array has alternative energizing strategies to evoke EFs targeting at different cerebral regions. To improve the locating resolution and the stimulating focality, we need to fully understand the variation properties of induced EFs and the quantitative control method of the spatial arrangement of activating coils, both of which unfortunately are still unclear. In this paper, a comprehensive analysis of EF properties was performed based on multi-coil arrays. Four types of planar multi-coil arrays were used to study the relationship between the spatial distribution of EFs and the structure of stimuli coils. By changing coil-driven strategies in a basic 16-coil array, we find that an EF induced by compactly distributed coils decays faster than that induced by dispersedly distributed coils, but the former has an advantage over the latter in terms of the activated brain volume. Simulation results also indicate that the attenuation rate of an EF induced by the 36-coil dense array is 3 times and 1.5 times greater than those induced by the 9-coil array and the 16-coil array, respectively. The EF evoked by the 36-coil dispense array has the slowest decay rate. This result demonstrates that larger multi-coil arrays, compared to smaller ones, activate deeper brain tissues at the expense of decreased focality. A further study on activating a specific field of a prescribed shape and size was conducted based on EF variation. Accurate target location was achieved with a 64 coil array 18 mm in diameter. A comparison between the figure-8 coil, the planar array, and the cap-formed array was made and demonstrates an improvement of multi coil configurations in the penetration depth and the focality. These findings suggest that there is a tradeoff between attenuation rate and focality in the application of multi-coil arrays. Coil-energizing strategies and array dimensions should be based on an adequate evaluation of these two important demands and the topological structure of target tissues. PMID- 29135965 TI - Comparison of Ground-Based and Satellite-Derived Solar UV Index Levels at Six South African Sites. AB - South Africa has been measuring the ground-based solar UV index for more than two decades at six sites to raise awareness about the impacts of the solar UV index on human health. This paper is an exploratory study based on comparison with satellite UV index measurements from the OMI/AURA experiment. Relative UV index differences between ground-based and satellite-derived data ranged from 0 to 45% depending on the site and year. Most of time, these differences appear in winter. Some ground-based stations' data had closer agreement with satellite-derived data. While the ground-based instruments are not intended for long-term trend analysis, they provide UV index information for public awareness instead, with some weak signs suggesting such long-term trends may exist in the ground-based data. The annual cycle, altitude, and latitude effects clearly appear in the UV index data measured in South Africa. This variability must be taken into account for the development of an excess solar UV exposure prevention strategy. PMID- 29135964 TI - The killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom. AB - Coniine, a polyketide-derived alkaloid, is poisonous to humans and animals. It is a nicotinic acetylcholine receptor antagonist, which leads to inhibition of the nervous system, eventually causing death by suffocation in mammals. Coniine's most famous victim is Socrates who was sentenced to death by poison chalice containing poison hemlock in 399 BC. In chemistry, coniine holds two historical records: It is the first alkaloid the chemical structure of which was established (in 1881), and that was chemically synthesized (in 1886). In plants, coniine and twelve closely related alkaloids are known from poison hemlock (Conium maculatum L.), and several Sarracenia and Aloe species. Recent work confirmed its biosynthetic polyketide origin. Biosynthesis commences by carbon backbone formation from butyryl-CoA and two malonyl-CoA building blocks catalyzed by polyketide synthase. A transamination reaction incorporates nitrogen from l alanine and non-enzymatic cyclization leads to gamma-coniceine, the first hemlock alkaloid in the pathway. Ultimately, reduction of gamma-coniceine to coniine is facilitated by NADPH-dependent gamma-coniceine reductase. Although coniine is notorious for its toxicity, there is no consensus on its ecological roles, especially in the carnivorous pitcher plants where it occurs. Lately there has been renewed interest in coniine's medical uses particularly for pain relief without an addictive side effect. PMID- 29135966 TI - Monocular Visual-Inertial SLAM:Continuous Preintegration and Reliable Initialization. AB - In this paper, we propose a new visual-inertial Simultaneous Localization and Mapping (SLAM) algorithm. With the tightly coupled sensor fusion of a global shutter monocular camera and a low-cost Inertial Measurement Unit (IMU), this algorithm is able to achieve robust and real-time estimates of the sensor poses in unknown environment. To address the real-time visual-inertial fusion problem, we present a parallel framework with a novel IMU initialization method. Our algorithm also benefits from the novel IMU factor, the continuous preintegration method, the vision factor of directional error, the separability trick and the robust initialization criterion which can efficiently output reliable estimates in real-time on modern Central Processing Unit (CPU). Tremendous experiments also validate the proposed algorithm and prove it is comparable to the state-of-art method. PMID- 29135967 TI - Modifying the Morphology of Silicon Surfaces by Laser Induced Liquid Assisted Colloidal Lithography. AB - Single, or isolated small arrays of, spherical silica colloidal particles (with refractive index ncolloid = 1.47 and radius R = 350 nm or 1.5 MUm) were placed on a silicon substrate and immersed in carbon tetrachloride (nliquid = 1.48) or toluene (nliquid = 1.52). Areas of the sample were then exposed to a single laser pulse (8 ps duration, wavelength lambda = 355 nm), and the spatial intensity modulation of the near field in the vicinity of the particles revealed via the resulting patterning of the substrate surface. In this regime, ncolloid < nliquid and the near-field optical intensification is concentrated at and beyond the edge of the particle. Detailed experimental characterization of the irradiated Si surface using atomic force microscopy reveals contrasting topographies. The same optical behavior is observed with both liquids, i.e., the incident laser light diverges on interaction with the colloidal particle, but the resulting interaction with the substrate is liquid dependent. Topographic analysis indicates localized ablation and patterning of the Si substrate when using toluene, whereas the patterning induced under carbon tetrachloride is on a larger scale and extends well below the original substrate surface-hinting at a laser induced photochemical contribution to the surface patterning. PMID- 29135968 TI - Body Burden of Dichlorodiphenyl Dichloroethene (DDE) and Childhood Pulmonary Function. AB - Longitudinal studies have shown that early life exposure to dichlorodiphenyl dichloroethene (DDE) can lead to growth reduction during childhood and adolescence. In addition, DDE exposure has been linked to respiratory tract infections and an increased risk of asthma in children. Our aim was to understand the relationships between DDE exposure and pulmonary function in children, and, particularly, whether associations are mediated by the height of the children. We used data from an environmental epidemiologic study conducted in central Germany in children aged 8-10 years. The pulmonary function (forced vital capacity, FVC, and forced expiratory volume in one second, FEV1) were measured in three consecutive years. Blood DDE levels were measured at 8 and 10 years. We used linear mixed models for repeated measurements and path analyses to assess the association between blood levels of DDE and pulmonary function measurements. All models were adjusted for confounders. Linear mixed approaches and modelling concurrent effects showed no significant associations. The path analytical models demonstrated that DDE measured at eight years had significant, inverse, indirect, and total effects on FVC at ten years (n = 328; -0.18 L per MUg/L of DDE) and FEV1 (n = 328; -0.17 L per MUg/L of DDE), mediated through effects of DDE on height and weight. The DDE burden reduces pulmonary function through its diminishing effects on height and weight in children. Further studies are required to test these associations in other samples, preferably from a region with ongoing, high DDT application. PMID- 29135969 TI - HLA-B27 Correlates with the Intracellular Elimination, Replication, and Trafficking of Salmonella Enteritidis Collected from Reactive Arthritis Patients. AB - BACKGROUND The aim of this study was to explore the correlation between HLA-B27 and the intracellular elimination, replication, and trafficking of Salmonella enteritidis (S. enteritidis) collected from patients with reactive arthritis. MATERIAL AND METHODS Confocal microscopy, flow cytometry, and sandwich enzyme linked immunosorbent assay (ELISA) were employed in this study to evaluate the localization of proteins of interest, to assess the intracellular trafficking of S. enteritidis, and to measure the production of cytokines of interest. RESULTS HLA-B27 was negatively associated with intracellular S. enteritidis elimination in healthy human monocytes/macrophages. In S. enteritidis infected monocytes/macrophages, HLA-27B was also negatively correlated with bacteria elimination but positively related to bacteria replication. S. enteritidis did not co-localize with NRAMP1 and LAMP1/2 in HLA-B27 cells. S. enteritidis did not co-exist with transferrin or dextran within HLA-B27 and A2 cells. CONCLUSIONS HLA B27 is closely associated with the intracellular elimination and replication of S. enteritidis. Replicated bacteria in HLA-B27 monocytic cells were located within unique vacuoles rather than disturbing host endocytosis. PMID- 29135971 TI - Build your own soil: exploring microfluidics to create microbial habitat structures. AB - Soil is likely the most complex ecosystem on earth. Despite the global importance and extraordinary diversity of soils, they have been notoriously challenging to study. We show how pioneering microfluidic techniques provide new ways of studying soil microbial ecology by allowing simulation and manipulation of chemical conditions and physical structures at the microscale in soil model habitats. PMID- 29135970 TI - Metabolic shift at the class level sheds light on adaptation of methanogens to oxidative environments. AB - Methanogens have long been considered strictly anaerobic and oxygen-sensitive microorganisms, but their ability to survive oxygen stress has also been documented. Indeed, methanogens have been found in oxidative environments, and antioxidant genes have been detected in their genomes. How methanogens adapt to oxidative environments, however, remain poorly understood. Here, we systematically predicted and annotated antioxidant features from representative genomes across six well-established methanogen orders. Based on functional gene content involved in production of reactive oxygen species, Hierarchical Clustering analyses grouped methanogens into two distinct clusters, corresponding to the Class I and II methanogens, respectively. Comparative genomics suggested a systematic shift in metabolisms across the two classes, resulting in an enrichment of antioxidant features in the Class II. Moreover, meta-analysis of 16 S rRNA gene sequences obtained from EnvDB indicated that members of Class II were more frequently recovered from microaerophilic and even oxic environments than the Class I members. Phylogenomic analysis suggested that the Class I and II methanogens might have evolved before and around the Great Oxygenation Event, respectively. The enrichment of antioxidant features in the Class II methanogens may have played a key role in the adaption of this group to oxidative environments today and historically. PMID- 29135972 TI - Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption. AB - OBJECTIVE: Bariatric surgery appears as the most efficient therapeutic alternative in morbidly obese patients. In addition to its efficiency to decrease body weight, it also improves metabolic complications associated to morbid obesity, including dyslipidemia. Although the cholesterol-lowering effect varies with the bariatric procedures, the underlying molecular mechanisms remain poorly defined. This study aims to assess the consequence of both restrictive (sleeve gastrectomy; SG) and malabsorptive (Roux-en-Y gastric bypass; RYGB) procedures on cholesterol metabolism in mice. SUBJECTS: Ten-week-old C57BL6/J males were fed with a high-fat diet for 8-14 weeks before sleeve or RYGB surgery. RESULTS: SG has a modest and transient effect on plasma cholesterol levels, linked to a reduction in food intake. In contrast, modified RYGB led to a sustained ~35% reduction in plasma cholesterol concentrations with a drastic increase in fecal cholesterol output. Mechanistically, RYGB exerts a synergystic effect on cholesterol metabolism by inducing the trans-intestinal cholesterol efflux and reducing the intestinal cholesterol absorption. CONCLUSIONS: In mice, RYGB, but not sleeve, strongly favors plasma cholesterol elimination by concomitantly increasing trans-intestinal cholesterol excretion and by decreasing intestinal cholesterol absorption. Our models open new perspective for deciphering the hypocholesterolemic effects of bariatric procedures. PMID- 29135973 TI - HDAC6 regulates microRNA-27b that suppresses proliferation, promotes apoptosis and target MET in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Histone deacetylase 6 (HDAC6) is frequently altered in DLBCL and inhibition of HDAC6 has potent anti-tumor effects in vitro and in vivo. We profiled miRNAs that altered in the HDAC6 knockdown DLBCL cells with NanoString nCounter assay and identified microRNA-27b (miR-27b) as the most significantly increased miRNA. We validated decreased expression of miR-27b in DLBCL tissues, and we found that low expression of miR-27b was associated with poor overall survival of patients with DLBCL. In addition, forced expression of miR-27b suppressed DLBCL cell viability and proliferation in vitro, and inhibited tumor growth in vivo. Mechanistically, Rel A/p65 is found to negatively regulate miR 27b expression, and its acetylation and block of nuclear translocalization caused by HDAC6 inhibition significantly elevates miR-27b expression. Furthermore, miR 27b targets MET and thus represses the MET/PI3K/AKT pathway. These findings highlight an important role of miR-27b in the development of DLBCL and uncover a HDAC6-Rel A/p65-miR-27b-MET signaling pathway. Elevating miR-27b through HDAC6 inhibition would be a promising strategy for DLBCL treatment. PMID- 29135974 TI - Early meteorological records from Latin-America and the Caribbean during the 18th and 19th centuries. AB - This paper provides early instrumental data recovered for 20 countries of Latin America and the Caribbean (Argentina, Bahamas, Belize, Brazil, British Guiana, Chile, Colombia, Costa Rica, Cuba, Ecuador, France (Martinique and Guadalupe), Guatemala, Jamaica, Mexico, Nicaragua, Panama, Peru, Puerto Rico, El Salvador and Suriname) during the 18th and 19th centuries. The main meteorological variables retrieved were air temperature, atmospheric pressure, and precipitation, but other variables, such as humidity, wind direction, and state of the sky were retrieved when possible. In total, more than 300,000 early instrumental data were rescued (96% with daily resolution). Especial effort was made to document all the available metadata in order to allow further post-processing. The compilation is far from being exhaustive, but the dataset will contribute to a better understanding of climate variability in the region, and to enlarging the period of overlap between instrumental data and natural/documentary proxies. PMID- 29135975 TI - Transcriptomic profiling of human breast and melanoma cells selected by migration through narrow constraints. AB - The metastatic spread of cancer cells is a step-wise process that starts with dissociation from primary tumours and local invasion of adjacent tissues. The ability to invade local tissues is the product of several processes, including degradation of extracellular matrices (ECM) and movement of tumour cells through physically-restricting gaps. To identify properties contributing to tumour cells squeezing through narrow gaps, invasive MDA-MB-231 human breast cancer and MDA-MB 435 human melanoma cells were subjected to three successive rounds of selection using cell culture inserts with highly constraining 3 MUm pores. For comparison purposes, flow cytometry was also employed to enrich for small diameter MDA-MB 231 cells. RNA-Sequencing (RNA-seq) using the Illumina NextSeq 500 platform was undertaken to characterize how gene expression differed between parental, invasive pore selected or small diameter cells. Gene expression results obtained by RNA-seq were validated by comparing with RT-qPCR. Transcriptomic data generated could be used to determine how alterations that enable cell passage through narrow spaces contribute to local invasion and metastasis. PMID- 29135976 TI - Loss of peri-Wolffian duct stromal Frs2alpha expression in mice leads to abnormal ureteric bud induction and vesicoureteral reflux. AB - : BackgroundFibroblast growth factor receptor 2 (Fgfr2) deletion from murine peri Wolffian duct stroma (ST) results in aberrant ureteric bud induction, abnormal ureteral insertion into the bladder, and high rates of vesicoureteral reflux (VUR). It is unclear which receptor docking protein(s) is/are responsible for Fgfr2 actions in these tissues. We investigated whether the docking protein, fibroblast receptor substrate 2alpha (Frs2alpha), had a role in peri-Wolffian duct ST similar to Fgfr2.MethodsWe conditionally deleted Frs2alpha in peri Wolffian duct ST with a Tbx18cre mouse line (Frs2alphaST-/-). We assessed for ureteric induction defects and alterations in downstream targets mediating defects. We performed euthanized cystograms and assessed ureter-bladder junctions by three-dimensional (3D) reconstructions.ResultsEmbryonic day (E) 11.5 Frs2alphaST-/- embryos had many displaced ureteric bud induction sites when compared with controls. E11.0 Frs2alphaST-/- embryos had decreased Bmp4 expression and signaling, which can cause abnormal ureteric bud induction. Postnatal day 1 (P1) and P30 Frs2alphaST-/- mice had higher VUR rates and grades vs. CONTROLS: Mutant refluxing ureters that inserted improperly into the bladder had shortened intravesicular tunnels (IVTs) when compared with controlsConclusionFrs2alphaST-/- embryos have aberrant ureteric induction sites, improper ureteral insertion, shortened intravesicular lengths, and VUR. Induction site defects appear secondary to reduced Bmp4 expression, similar to Fgfr2 mutants. PMID- 29135978 TI - Association between the 2012 Health and Social Care Act and specialist visits and hospitalisations in England: A controlled interrupted time series analysis. AB - BACKGROUND: The 2012 Health and Social Care Act (HSCA) in England led to among the largest healthcare reforms in the history of the National Health Service (NHS). It gave control of L67 billion of the NHS budget for secondary care to general practitioner (GP) led Clinical Commissioning Groups (CCGs). An expected outcome was that patient care would shift away from expensive hospital and specialist settings, towards less expensive community-based models. However, there is little evidence for the effectiveness of this approach. In this study, we aimed to assess the association between the NHS reforms and hospital admissions and outpatient specialist visits. METHODS AND FINDINGS: We conducted a controlled interrupted time series analysis to examine rates of outpatient specialist visits and inpatient hospitalisations before and after the implementation of the HSCA. We used national routine hospital administrative data (Hospital Episode Statistics) on all NHS outpatient specialist visits and inpatient hospital admissions in England between 2007 and 2015 (with a mean of 26.8 million new outpatient visits and 14.9 million inpatient admissions per year). As a control series, we used equivalent data on hospital attendances in Scotland. Primary outcomes were: total, elective, and emergency hospitalisations, and total and GP-referred specialist visits. Both countries had stable trends in all outcomes at baseline. In England, after the policy, there was a 1.1% (95% CI 0.7%-1.5%; p < 0.001) increase in total specialist visits per quarter and a 1.6% increase in GP-referred specialist visits (95% CI 1.2%-2.0%; p < 0.001) per quarter, equivalent to 12.7% (647,000 over the 5,105,000 expected) and 19.1% (507,000 over the 2,658,000 expected) more visits per quarter by the end of 2015, respectively. In Scotland, there was no change in specialist visits. Neither country experienced a change in trends in hospitalisations: change in slope for total, elective, and emergency hospitalisations were -0.2% (95% CI -0.6%-0.2%; p = 0.257), -0.2% (95% CI -0.6%-0.1%; p = 0.235), and 0.0% (95% CI -0.5%-0.4%; p = 0.866) per quarter in England. We are unable to exclude confounding due to other events occurring around the time of the policy. However, we limited the likelihood of such confounding by including relevant control series, in which no changes were seen. CONCLUSIONS: Our findings suggest that giving control of healthcare budgets to GP-led CCGs was not associated with a reduction in overall hospitalisations and was associated with an increase in specialist visits. PMID- 29135980 TI - Bioequivalence of twice-daily oral tacrolimus in transplant recipients: More evidence for consensus? AB - In this Perspective on the clinical trial by Rita Alloway and colleagues, Simon Ball explains the benefits to healthcare systems and individual patients of the bioequivalence established between generic and brand-name formulations of an immunosuppressive drug in transplant recipients. PMID- 29135979 TI - A systematic review of grandparents' influence on grandchildren's cancer risk factors. AB - Many lifestyle patterns are established when children are young. Research has focused on the potential role of parents as a risk factor for non communicable disease in children, but there is limited investigation of the role of other caregivers, such as grandparents. The aim of this review was to identify and synthesise evidence for any influence grandparents' care practices may have on their grandchildren's long term cancer risk factors. A systematic review was carried out with searches across four databases (MEDLINE, Embase, Web of Science, PsycINFO) as well as searches of reference lists and citing articles, and Google Scholar. Search terms were based on six areas of risk that family care could potentially influence-weight, diet, physical activity, tobacco, alcohol and sun exposure. All study designs were included, as were studies that provided an indication of the interaction of grandparents with their grandchildren. Studies were excluded if grandparents were primary caregivers and if children had serious health conditions. Study quality was assessed using National Institute for Health and Care Excellence checklists. Grandparent impact was categorised as beneficial, adverse, mixed or as having no impact. Due to study heterogeneity a meta-analysis was not possible. Qualitative studies underwent a thematic synthesis of their results. Results from all included studies indicated that there was a sufficient evidence base for weight, diet, physical activity and tobacco studies to draw conclusions about grandparents' influence. One study examined alcohol and no studies examined sun exposure. Evidence indicated that, overall, grandparents had an adverse impact on their grandchildren's cancer risk factors. The theoretical work in the included studies was limited. Theoretically underpinned interventions designed to reduce these risk factors must consider grandparents' role, as well as parents', and be evaluated robustly to inform the evidence base further. PMID- 29135981 TI - Pioneer cells established by the [SWI+] prion can promote dispersal and out crossing in yeast. AB - To thrive in an ever-changing environment, microbes must widely distribute their progeny to colonize new territory. Simultaneously, they must evolve and adapt to the stresses of unpredictable surroundings. In both of these regards, diversity is key-if an entire population moved together or responded to the environment in the same way, it could easily go extinct. Here, we show that the epigenetic prion switch [SWI+] establishes a specialized subpopulation with a "pioneer" phenotypic program in Saccharomyces cerevisiae. Cells in the pioneer state readily disperse in water, enabling them to migrate and colonize new territory. Pioneers are also more likely to find and mate with genetically diverse partners, as inhibited mating-type switching causes mother cells to shun their own daughters. In the nonprion [swi-] state, cells instead have a "settler" phenotype, forming protective flocs and tending to remain in their current position. Settler cells are better able to withstand harsh conditions like drought and alkaline pH. We propose that these laboratory observations reveal a strategy employed in the wild to rapidly diversify and grant distinct, useful roles to cellular subpopulations that benefit the population as a whole. PMID- 29135982 TI - STING expression and response to treatment with STING ligands in premalignant and malignant disease. AB - Human papilloma virus positive (HPV+) tumors represent a large proportion of anal, vulvar, vaginal, cervical and head and neck squamous carcinomas (HNSCC) and late stage invasive disease is thought to originate from a premalignant state. Cyclic dinucleotides that activate STimulator of INterferon Genes (STING) have been shown to cause rapid regression of a range of advanced tumors. We aimed to investigate STING ligands as a novel treatment for papilloma. We tested therapies in a spontaneous mouse model of papilloma of the face and anogenital region that histologically resembles human HPV-associated papilloma. We demonstrate that STING ligands cause rapid regression of papilloma, associated with T cell infiltration, and are significantly more effective than Imiquimod, a current immunotherapy for papilloma. In humans, we show that STING is expressed in the basal layer of normal skin and lost during keratinocyte differentiation. We found STING was expressed in all HPV-associated cervical and anal dysplasia and was strongly expressed in the cancer cells of HPV+ HNSCC but not in HPV-unrelated HNSCC. We found no strong association between STING expression and progressive disease in non-HPV oral dysplasia and oral pre-malignancies that are not HPV related. These data demonstrate that STING is expressed in basal cells of the skin and is retained in HPV+ pre-malignancies and advanced cancers, but not in HPV-unrelated HNSCC. However, using a murine HNSCC model that does not express STING, we demonstrate that STING ligands are an effective therapy regardless of expression of STING by the cancer cells. PMID- 29135984 TI - A video-based real-time adaptive vehicle-counting system for urban roads. AB - In developing nations, many expanding cities are facing challenges that result from the overwhelming numbers of people and vehicles. Collecting real-time, reliable and precise traffic flow information is crucial for urban traffic management. The main purpose of this paper is to develop an adaptive model that can assess the real-time vehicle counts on urban roads using computer vision technologies. This paper proposes an automatic real-time background update algorithm for vehicle detection and an adaptive pattern for vehicle counting based on the virtual loop and detection line methods. In addition, a new robust detection method is introduced to monitor the real-time traffic congestion state of road section. A prototype system has been developed and installed on an urban road for testing. The results show that the system is robust, with a real-time counting accuracy exceeding 99% in most field scenarios. PMID- 29135985 TI - Evidence-based restructuring of health and social care. AB - In this Perspective, Aziz Sheikh discusses research to evaluate health policy changes in the provision of care, commenting on a study by James Lopez Bernal and colleagues that examined specialist-dominated hospital care versus community based care in the United Kingdom. PMID- 29135983 TI - Arginase expression modulates nitric oxide production in Leishmania (Leishmania) amazonensis. AB - BACKGROUND: Arginase is an enzyme that converts L-arginine to urea and L ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L arginine is also the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite. This competition can define the fate of Leishmania infection. METHODOLOGY/PRINCIPAL FINDINGS: The transcriptomic profiling identified a family of oxidoreductases in L. (L.) amazonensis wild-type (La-WT) and L. (L.) amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. We highlighted the identification of an oxidoreductase that could act as nitric oxide synthase-like (NOS-like), due to the following evidences: conserved domain composition, the participation of NO production during the time course of promastigotes growth and during the axenic amastigotes differentiation, regulation dependence on arginase activity, as well as reduction of NO amount through the NOS activity inhibition. NO quantification was measured by DAF-FM labeling analysis in a flow cytometry. CONCLUSIONS/SIGNIFICANCE: We described an arginase-dependent NOS-like activity in L. (L.) amazonensis and its role in the parasite growth. The increased detection of NO production in the mid-stationary and late-stationary growth phases of La-WT promastigotes could suggest that this production is an important factor to metacyclogenesis triggering. On the other hand, La-arg- showed an earlier increase in NO production compared to La-WT, suggesting that NO production can be arginase-dependent. Interestingly, La-WT and La-arg- axenic amastigotes produced higher levels of NO than those observed in promastigotes. As a conclusion, our work suggested that NOS-like is expressed in Leishmania in the stationary growth phase promastigotes and amastigotes, and could be correlated to metacyclogenesis and amastigotes growth in a dependent way to the internal pool of L-arginine and arginase activity. PMID- 29135986 TI - Splenomegaly - Diagnostic validity, work-up, and underlying causes. AB - PURPOSE: Our aim was to assess the validity of the ICD-10 code for splenomegaly in the Danish National Registry of Patients (DNRP), as well as to investigate which underlying diseases explained the observed splenomegaly. BACKGROUND: Splenomegaly is a common finding in patients referred to an internal medical department and can be caused by a large spectrum of diseases, including haematological diseases and liver cirrhosis. However, some patients remain without a causal diagnosis, despite extensive medical work-up. PATIENTS AND METHODS: We identified 129 patients through the DNRP, that had been given the ICD 10 splenomegaly diagnosis code in 1994-2013 at Odense University Hospital, Denmark, excluding patients with prior splenomegaly, malignant haematological neoplasia or liver cirrhosis. Medical records were reviewed for validity of the splenomegaly diagnosis, diagnostic work-up, and the underlying disease was determined. The positive predictive value (PPV) with 95% confidence interval (CI) was calculated for the splenomegaly diagnosis code. Patients with idiopathic splenomegaly in on-going follow-up were also invited to be investigated for Gaucher disease. RESULTS: The overall PPV was 92% (95% CI: 85, 96). Haematological diseases were the underlying causal diagnosis in 39%; hepatic diseases in 18%, infectious disease in 10% and other diseases in 8%. 25% of patients with splenomegaly remained without a causal diagnosis. Lymphoma was the most common haematological causal diagnosis and liver cirrhosis the most common hepatic causal diagnosis. None of the investigated patients with idiopathic splenomegaly had Gaucher disease. CONCLUSION: Our findings show that the splenomegaly diagnosis in the DNRP is valid and can be used in registry-based studies. However, because of suspected significant under-coding, it should be considered if supplementary data sources should be used in addition, in order to attain a more representative population. Haematological diseases were the most common cause, however in a large fraction of patients no causal diagnosis was found. PMID- 29135987 TI - Determining the optimal screening interval for type 2 diabetes mellitus using a risk prediction model. AB - BACKGROUND: Progression to diabetes mellitus (DM) is variable and the screening time interval not well defined. The American Diabetes Association and US Preventive Services Task Force suggest screening every 3 years, but evidence is limited. The objective of the study was to develop a model to predict the probability of developing DM and suggest a risk-based screening interval. METHODS: We included non-diabetic adult patients screened for DM in the Cleveland Clinic Health System if they had at least two measurements of glycated hemoglobin (HbA1c), an initial one less than 6.5% (48 mmol/mol) in 2008, and another between January, 2009 and December, 2013. Cox proportional hazards models were created. The primary outcome was DM defined as HbA1C greater than 6.4% (46 mmol/mol). The optimal rescreening interval was chosen based on the predicted probability of developing DM. RESULTS: Of 5084 participants, 100 (4.4%) of the 2281 patients with normal HbA1c and 772 (27.5%) of the 2803 patients with prediabetes developed DM within 5 years. Factors associated with developing DM included HbA1c (HR per 0.1 units increase 1.20; 95%CI, 1.13-1.27), family history (HR 1.31; 95%CI, 1.13 1.51), smoking (HR 1.18; 95%CI, 1.03-1.35), triglycerides (HR 1.01; 95%CI, 1.00 1.03), alanine aminotransferase (HR 1.07; 95%CI, 1.03-1.11), body mass index (HR 1.06; 95%CI, 1.01-1.11), age (HR 0.95; 95%CI, 0.91-0.99) and high-density lipoproteins (HR 0.93; 95% CI, 0.90-0.95). Five percent of patients in the highest risk tertile developed DM within 8 months, while it took 35 months for 5% of the middle tertile to develop DM. Only 2.4% percent of the patients in the lowest tertile developed DM within 5 years. CONCLUSION: A risk prediction model employing commonly available data can be used to guide screening intervals. Based on equal intervals for equal risk, patients in the highest risk category could be rescreened after 8 months, while those in the intermediate and lowest risk categories could be rescreened after 3 and 5 years respectively. PMID- 29135988 TI - Evolution of acute hepatitis C virus infection in a large European city: Trends and new patterns. AB - The aims of this study were to describe the evolution of acute hepatitis C virus (HCV) infections since 2004 and to determine its associated factors. Acute HCV infections diagnosed in Barcelona from 2004 to 2015 were included. Incidence ratios (IR) were then estimated for sex and age groups. Cases were grouped between 2004-2005, 2006-2011 and 2012-2015, and their incidence rate ratios (IRR) were calculated. In addition, risk factors for acute HCV infection were identified using multinomial logistic regression for complete, available and multiple imputed data. 204 new HCV cases were identified. Two peaks of higher IR of acute HCV infection in 2005 and 2013 were observed. Men and those aged 35-54 had higher IR. IRR for men was 2.9 times greater than in women (95% confidence intervals (CI): 1.8 - 4.7). Factors related to the period 2012-2015 (versus 2006 2011) were: a) sexual risk factor for transmission versus nosocomial (relative risk ratio (RRR): 13.0; 95% CI: 2.3 - 72.1), b) higher educated versus lower (RRR: 5.4; 95% CI: 1.6 - 18.7), and c) HIV co-infected versus not HIV-infected (RRR: 53.1; 95% CI: 5.7 - 492.6). This is one of the few studies showing IR and RRRs of acute HCV infections and the first focused on a large city in Spain. Sexual risk for transmission between men, higher educational level and HIV co infection are important factors for understanding current HCV epidemic. There has been a partial shift in the pattern of the risk factor for transmission from nosocomial to sexual. PMID- 29135989 TI - High stress, lack of sleep, low school performance, and suicide attempts are associated with high energy drink intake in adolescents. AB - OBJECTIVE: Although an association between energy drinks and suicide has been suggested, few prior studies have considered the role of emotional factors including stress, sleep, and school performance in adolescents. This study aimed to evaluate the association of energy drinks with suicide, independent of possible confounders including stress, sleep, and school performance. METHODS: In total, 121,106 adolescents with 13-18 years olds from the 2014 and 2015 Korea Youth Risk Behavior Web-based Survey were surveyed for age, sex, region of residence, economic level, paternal and maternal education level, sleep time, stress level, school performance, frequency of energy drink intake, and suicide attempts. Subjective stress levels were classified into severe, moderate, mild, a little, and no stress. Sleep time was divided into 6 groups: < 6 h; 6 <= h < 7; 7 <= h < 8; 8 <= h < 9; and >= 9 h. School performance was classified into 5 levels: A (highest), B (middle, high), C (middle), D (middle, low), and E (lowest). Frequency of energy drink consumption was divided into 3 groups: >= 3, 1-2, and 0 times a week. The associations of sleep time, stress level, and school performance with suicide attempts and the frequency of energy drink intake were analyzed using multiple and ordinal logistic regression analysis, respectively, with complex sampling. The relationship between frequency of energy drink intake and suicide attempts was analyzed using multiple logistic regression analysis with complex sampling. RESULTS: Higher stress levels, lack of sleep, and low school performance were significantly associated with suicide attempts (each P < 0.001). These variables of high stress level, abnormal sleep time, and low school performance were also proportionally related with higher energy drink intake (P < 0.001). Frequent energy drink intake was significantly associated with suicide attempts in multiple logistic regression analyses (AOR for frequency of energy intake >= 3 times a week = 3.03, 95% CI = 2.64-3.49, P < 0.001). CONCLUSION: Severe stress, inadequate sleep, and low school performance were related with more energy drink intake and suicide attempts in Korean adolescents. Frequent energy drink intake was positively related with suicide attempts, even after adjusting for stress, sleep time, and school performance. PMID- 29135991 TI - Building a profile of subjective well-being for social media users. AB - Subjective well-being includes 'affect' and 'satisfaction with life' (SWL). This study proposes a unified approach to construct a profile of subjective well-being based on social media language in Facebook status updates. We apply sentiment analysis to generate users' affect scores, and train a random forest model to predict SWL using affect scores and other language features of the status updates. Results show that: the computer-selected features resemble the key predictors of SWL as identified in early studies; the machine-predicted SWL is moderately correlated with the self-reported SWL (r = 0.36, p < 0.01), indicating that language-based assessment can constitute valid SWL measures; the machine assessed affect scores resemble those reported in a previous experimental study; and the machine-predicted subjective well-being profile can also reflect other psychological traits like depression (r = 0.24, p < 0.01). This study provides important insights for psychological prediction using multiple, machine-assessed components and longitudinal or dense psychological assessment using social media language. PMID- 29135990 TI - Curcumin affects gene expression and reactive oxygen species via a PKA dependent mechanism in Dictyostelium discoideum. AB - Botanicals are widely used as dietary supplements and for the prevention and treatment of disease. Despite a long history of use, there is generally little evidence supporting the efficacy and safety of these preparations. Curcumin has been used to treat a myriad of human diseases and is widely advertised and marketed for its ability to improve health, but there is no clear understanding how curcumin interacts with cells and affects cell physiology. D. discoideum is a simple eukaryotic lead system that allows both tractable genetic and biochemical studies. The studies reported here show novel effects of curcumin on cell proliferation and physiology, and a pleiotropic effect on gene transcription. Transcriptome analysis showed that the effect is two-phased with an early transient effect on the transcription of approximately 5% of the genome, and demonstrates that cells respond to curcumin through a variety of previously unknown molecular pathways. This is followed by later unique transcriptional changes and a protein kinase A dependent decrease in catalase A and three superoxide dismutase enzymes. Although this results in an increase in reactive oxygen species (ROS; superoxide and H2O2), the effects of curcumin on transcription do not appear to be the direct result of oxidation. This study opens the door to future explorations of the effect of curcumin on cell physiology. PMID- 29135992 TI - Internal quality assurance in diagnostic microbiology: A simple approach for insightful data. AB - Given the importance of microbiology results on patient care, high quality standards are expected. Internal quality assurance (IQA) could mitigate the limitations of internal quality control, competency assessment and external quality assurance, adding a longitudinal insight, including pre- and post analytical steps. Here, we implemented an IQA program in our clinical microbiology facilities with blind resubmission of routine samples during 22 months. One-hundred-and-twenty-one out of 123 (98.4%) serological analyses and 112 out of 122 (91.8%) molecular analyses were concordant. Among the discordances in molecular biology analyses, 6 results were low positive samples that turned out negative, likely due to stochastic repartition of nucleic acids. Moreover, one identified retranscription error led us to implement automated results transmission from the Applied Biosystems instruments to the laboratory information system (LIS). Regarding Gram stain microscopy, 560 out of 745 (75.2%) of compared parameters were concordant. As many as 67 out of 84 (79.8%) pairs of culture results were similar, including 16 sterile pairs, 27 having identical identification or description and semi-quantification and 24 only showing variations in semi-quantification with identical description or identification of colonies. Seventeen pairs had diverging identification or description of colonies. Culture was twice only done for one member of the pairs. Regarding antibiotic susceptibility testing, a major discrepancy was observed in 5 out of 48 results (10.4%). In conclusion, serological tests were highly reproducible. Molecular diagnosis also revealed to be robust except when the amounts of nucleic acids present in the sample were close to the limits of detection. Conventional microbiology was less robust with major discrepancies reaching 39.5% of the samples for microscopy. Similarly, culture and antibiotic susceptibility testing were prone to discrepancies. This work was ground for reconsidering multiples aspects of our practices and demonstrates the importance of IQA to complete the other quality management procedures. PMID- 29135993 TI - Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial. AB - BACKGROUND: Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, "brand") product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant. METHODS AND FINDINGS: From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11-15.81) and the concentration maximum (Cmax) (range 17.96 24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%-118.13% and 80.00%-125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study. CONCLUSIONS: Using an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other. TRIAL REGISTRATION: ClinicalTrials.gov NCT01889758. PMID- 29135994 TI - Perioperative risk factors for postoperative pneumonia after major oral cancer surgery: A retrospective analysis of 331 cases. AB - OBJECTIVE: Postoperative pneumonia (POP) is common and results in prolonged hospital stays, higher costs, increased morbidity and mortality. However, data on the incidence and risk factors of POP after oral and maxillofacial surgery are rare. This study aims to identify perioperative risk factors for POP after major oral cancer (OC) surgery. METHODS: Perioperative data and patient records of 331 consecutive subjects were analyzed in the period of April 2014 to March 2016. We individually traced each OC patient for a period to discharge from the hospital or 45 days after surgery, whichever occur later. RESULTS: The incidence of POP after major OC surgery with free flap construction or major OC surgery was 11.6% or 4.5%, respectively. Patient-related risk factors for POP were male sex, T stage, N stage, clinical stage and preoperative serum albumin level. Among the investigated procedure-related variables, incision grade, mandibulectomy, free flap reconstruction, tracheotomy, intraoperative blood loss, and the length of the operation were shown to be associated with the development of POP. Postoperative hospital stay was also significantly related to increased incidence of POP. Using a multivariable logistic regression model, we identified male sex, preoperative serum albumin level, operation time and postoperative hospital stay as independent risk factors for POP. CONCLUSION: Several perioperative risk factors can be identified that are associated with POP. At-risk oral cancer patients should be subjected to intensified postoperative pulmonary care. PMID- 29135995 TI - Efficacy of a new rapid diagnostic test kit to diagnose Sri Lankan cutaneous leishmaniasis caused by Leishmania donovani. AB - BACKGROUND: Cutaneous leishmaniasis (CL) in Sri Lanka is caused by Leishmania donovani. This study assessed the diagnostic value of a new rapid diagnostic immunochromatographic strip (CL-DetectTM IC-RDT), that captures the peroxidoxin antigen of Leishmania amastigotes. METHODOLOGY/PRINCIPAL FINDINGS: We sampled 74 clinically suspected CL lesions, of which 59 (79.7%) were positive by PCR, 43 (58.1%) by Giemsa stained slit skin smear (SSS) and 21 (28.4%) by the new IC-RDT. All samples which were positive either by SSS or IC-RDT or both were positive by PCR. The sensitivities of the IC-RDT and SSS compared to PCR were 36% and 73%, respectively. Fifteen patients from this endemic region were negative by all three tests. Twenty two clinically non-CL skin lesions from a CL non-endemic region were also negative by all three methods. Specificity and PPV of both IC RDT and SSS compared to PCR were 100%; the NPVs of IC-RDT and SSS were 37% and 58%, respectively. The median parasite grading of the 59 PCR positive samples was 2+ (1-10 parasites/100 HPFs) and IC-RDT positive lesions was 3+ (1-10 parasites /10HPFs). The duration of the lesion was not associated with IC-RDT positivity. CONCLUSIONS/SIGNIFICANCE: The median parasite grade of Sri Lankan CL lesions is low. The low sensitivities of SSS and CL DetectTM IC-RDT may be due to low parasite counts or low expression of peroxidoxin antigen in amastigotes of the Sri Lankan L. donovani strain. Our results indicate that negative SSS has to be combined with PCR for confirmation of CL in Sri Lanka. The current commercially available IC-RDT is not suitable to diagnose CL in Sri Lanka; an IC-RDT with improved sensitivity to detect L. donovani would be a valuable addition in the diagnostic tool kit for Sri Lanka. PMID- 29135996 TI - Clinicopathological and prognostic value of transforming acidic coiled-coil containing protein 3 (TACC3) expression in soft tissue sarcomas. AB - Transforming acidic coiled-coil-containing protein 3 (TACC3), a microtubule regulator, is associated with various cancers. However, the relationship between TACC3 and soft tissue sarcomas (STS) remains unclear. We investigated the expression of TACC3 in 136 STS patient samples using immunohistochemical (IHC) staining, and the statistical associations between TACC3 expression and clinicopathological characteristics were evaluated. Additionally, the expression levels of the tumor suppressor p53 and of the cell proliferation marker Ki-67 were also assessed by IHC. High TACC3 expression was detected in 94/136 of STS cases (69.1%), and significantly correlated with higher grade according to the French Federation Nationale des Centres de Lutte Contre le Cancer system (P<0.0001), poorer tumor differentiation (P<0.0001), increased mitotic counts (P<0.0001), advanced stage per American Joint Committee on Cancer guidelines (P<0.0001), higher p53 expression (P = 0.0487), higher Ki-67 expression (P<0.0001), and undergoing postoperative therapy (P = 0.0001). Disease-free survival (DFS) and overall survival (OS) of patients with high TACC3 expression were significantly shorter (P<0.0001 and P<0.0001, respectively). On multivariate analyses, high TACC3 expression was an independent negative prognostic factor for both DFS and OS (hazard ratio [HR]: 3.074; P = 0.0235 and HR: 8.521; P = 0.0415, respectively). Our results suggest that TACC3 is an independent prognostic factor and may be a novel therapeutic target for the treatment of STS. PMID- 29135997 TI - Performances of the PIPER scalable child human body model in accident reconstruction. AB - Human body models (HBMs) have the potential to provide significant insights into the pediatric response to impact. This study describes a scalable/posable approach to perform child accident reconstructions using the Position and Personalize Advanced Human Body Models for Injury Prediction (PIPER) scalable child HBM of different ages and in different positions obtained by the PIPER tool. Overall, the PIPER scalable child HBM managed reasonably well to predict the injury severity and location of the children involved in real-life crash scenarios documented in the medical records. The developed methodology and workflow is essential for future work to determine child injury tolerances based on the full Child Advanced Safety Project for European Roads (CASPER) accident reconstruction database. With the workflow presented in this study, the open source PIPER scalable HBM combined with the PIPER tool is also foreseen to have implications for improved safety designs for a better protection of children in traffic accidents. PMID- 29135999 TI - "Life-like" assessment of antimicrobial surfaces by a new touch transfer assay displays strong superiority of a copper alloy compared to silver containing surfaces. AB - Transmission of bacteria from inanimate surfaces in healthcare associated environments is an important source of hospital acquired infections. A number of commercially available medical devices promise to fulfill antibacterial activity to reduce environmental contamination. In this study we developed a touch transfer assay modeling fingerprint transmission to investigate the antibacterial activity of surfaces, with confirmed antibacterial activity by a modified ISO 22196 (JIS Z 2801) assay to test such surfaces under more realistic conditions. Bacteria were taken up from a dry standardized primary contaminated surface (PCS) with disinfected fingers or fingers covered with sterile and moistened cotton gloves. Subsequently, bacteria were transferred by pressing on secondary contaminated surfaces (SCS) with or without potential antibacterial activity and the relative reduction rate was determined after 24 h. A stable transmission rate between PCS and SCS was observed using moistened sterile gloves. A copper containing alloy displayed at least a tenfold reduction of the bacterial load consistently reaching less than 2.5 cfu/cm2. In contrast, no significant reduction of bacterial contamination by silver containing surfaces and matured pure silver was observed in the touch transfer assay. With the touch transfer assay we successfully established a new reproducible method modeling cross contamination. Using the new method we were able to demonstrate that several surfaces with confirmed antimicrobial activity in a modified ISO 22196 (JIS Z 2801) assay lacked effectiveness under defined ambient conditions. This data indicate that liquid based assays like the ISO 22196 should be critically reviewed before claiming antibacterial activity for surfaces in the setting of contamination of dry surfaces by contact to the human skin. We suggest the newly developed touch transfer assay as a new additional tool for the assessment of potential antimicrobial surfaces prior utilization in hospital environments. PMID- 29136000 TI - Point cloud registration from local feature correspondences-Evaluation on challenging datasets. AB - Registration of laser scans, or point clouds in general, is a crucial step of localization and mapping with mobile robots or in object modeling pipelines. A coarse alignment of the point clouds is generally needed before applying local methods such as the Iterative Closest Point (ICP) algorithm. We propose a feature based approach to point cloud registration and evaluate the proposed method and its individual components on challenging real-world datasets. For a moderate overlap between the laser scans, the method provides a superior registration accuracy compared to state-of-the-art methods including Generalized ICP, 3D Normal-Distribution Transform, Fast Point-Feature Histograms, and 4-Points Congruent Sets. Compared to the surface normals, the points as the underlying features yield higher performance in both keypoint detection and establishing local reference frames. Moreover, sign disambiguation of the basis vectors proves to be an important aspect in creating repeatable local reference frames. A novel method for sign disambiguation is proposed which yields highly repeatable reference frames. PMID- 29135998 TI - Multivariate regression analysis of structural MRI connectivity matrices in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia among older people and increasing longevity ensures its prevalence will rise even further. Whether AD originates by disconnecting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. An important related challenge is to predict whether a given subject, with a mild cognitive impairment (MCI), will convert or not to AD. Here, our aim is to characterize the structural connectivity pattern of MCI and AD subjects using the multivariate distance matrix regression (MDMR) analysis, and to compare it to those of healthy subjects. MDMR is a technique developed in genomics that has been recently applied to functional brain network data, and here applied to identify brain nodes with different connectivity patterns, in controls and patients, because of brain atrophy. We address this issue at the macroscale by looking to differences in individual structural MRI brain networks, obtained from MR images according to a recently proposed definition of connectivity which measures the image similarity between patches at different locations in the brain. In particular, using data from ADNI, we selected four groups of subjects (all of them matched by age and sex): HC (healthy control participants), ncMCI (mild cognitive impairment not converting to AD), cMCI (mild cognitive impairment converting to AD) and AD. Next, we built structural MRI brain networks and performed group comparison for all the pairs of groups. Our results were three fold: (i) considering the comparison of HC with the three other groups, the number of significant brain regions was 4 for ncMCI, 290 for cMCI and 74 for AD, out of a total of 549 regions; hence, in terms of the structural MRI connectivity here adopted, cMCI subjects have the maximal altered pattern w.r.t. healthy conditions. (ii) Eight and seven nodes were significant for the comparisons AD ncMCI and AD-cMCI, respectively; six nodes, among them, were significant in both comparisons and these nodes form a connected brain region (corresponding to hippocampus, amygdala, Parahippocampal Gyrus, Planum Polare, Frontal Orbital Cortex, Temporal Pole and subcallosal cortex) showing reduced strength of connectivity in the MCI stages; (iii) The connectivity maps of cMCI and ncMCI subjects significantly differ from the connectome of healthy subjects in three regions all corresponding to Frontal Orbital Cortex. PMID- 29136001 TI - A combination intervention strategy to improve linkage to and retention in HIV care following diagnosis in Mozambique: A cluster-randomized study. AB - BACKGROUND: Concerning gaps in the HIV care continuum compromise individual and population health. We evaluated a combination intervention strategy (CIS) targeting prevalent barriers to timely linkage and sustained retention in HIV care in Mozambique. METHODS AND FINDINGS: In this cluster-randomized trial, 10 primary health facilities in the city of Maputo and Inhambane Province were randomly assigned to provide the CIS or the standard of care (SOC). The CIS included point-of-care CD4 testing at the time of diagnosis, accelerated ART initiation, and short message service (SMS) health messages and appointment reminders. A pre-post intervention 2-sample design was nested within the CIS arm to assess the effectiveness of CIS+, an enhanced version of the CIS that additionally included conditional non-cash financial incentives for linkage and retention. The primary outcome was a combined outcome of linkage to care within 1 month and retention at 12 months after diagnosis. From April 22, 2013, to June 30, 2015, we enrolled 2,004 out of 5,327 adults >=18 years of age diagnosed with HIV in the voluntary counseling and testing clinics of participating health facilities: 744 (37%) in the CIS group, 493 (25%) in the CIS+ group, and 767 (38%) in the SOC group. Fifty-seven percent of the CIS group achieved the primary outcome versus 35% in the SOC group (relative risk [RR]CIS vs SOC = 1.58, 95% CI 1.05-2.39). Eighty-nine percent of the CIS group linked to care on the day of diagnosis versus 16% of the SOC group (RRCIS vs SOC = 9.13, 95% CI 1.65-50.40). There was no significant benefit of adding financial incentives to the CIS in terms of the combined outcome (55% of the CIS+ group achieved the primary outcome, RRCIS+ vs CIS = 0.96, 95% CI 0.81-1.16). Key limitations include the use of existing medical records to assess outcomes, the inability to isolate the effect of each component of the CIS, non-concurrent enrollment of the CIS+ group, and exclusion of many patients newly diagnosed with HIV. CONCLUSIONS: The CIS showed promise for making much needed gains in the HIV care continuum in our study, particularly in the critical first step of timely linkage to care following diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT01930084. PMID- 29136002 TI - The role of character positional frequency on Chinese word learning during natural reading. AB - Readers' eye movements were recorded to examine the role of character positional frequency on Chinese lexical acquisition during reading and its possible modulation by word spacing. In Experiment 1, three types of pseudowords were constructed based on each character's positional frequency, providing congruent, incongruent, and no positional word segmentation information. Each pseudoword was embedded into two sets of sentences, for the learning and the test phases. In the learning phase, half the participants read sentences in word-spaced format, and half in unspaced format. In the test phase, all participants read sentences in unspaced format. The results showed an inhibitory effect of character positional frequency upon the efficiency of word learning when processing incongruent pseudowords both in the learning and test phase, and also showed facilitatory effect of word spacing in the learning phase, but not at test. Most importantly, these two characteristics exerted independent influences on word segmentation. In Experiment 2, three analogous types of pseudowords were created whilst controlling for orthographic neighborhood size. The results of the two experiments were consistent, except that the effect of character positional frequency was absent in the test phase in Experiment 2. We argue that the positional frequency of a word's constituent characters may influence the character-to-word assignment in a process that likely incorporates both lexical segmentation and identification. PMID- 29136003 TI - Longitudinal acquisition of endotracheal intubation skills in novice physicians. AB - Little is known about the acquisition of intubation skills among novice physicians during their one-year clinical training. Our primary objective was to determine the changes in the intubation skills of novice physicians between prior to the clinical training and after completion of the clinical training. We used data of a prospective longitudinal multicenter data registry developed to investigate factors associated with the improvement of intubation skills among novice physicians. The study participants included 90 postgraduate year 1 physicians in 2015-2016. We used 4 simulation scenarios based on the devices used (direct laryngoscope [DL] and Airway scope [AWS]) and difficulty of intubation (normal and difficult scenarios). As a marker of the intubation skills, we used the force applied on the maxillary incisors and the tongue with each intubation. We compared the data obtained prior to clinical training with those obtained after completion of one-year clinical training. When using DL, compared to prior, significantly less force were applied on the maxillary incisors and the tongue after clinical training in the normal scenario (28.0 N vs 19.5 N, p < 0.001, and 11.1 N vs 8.4 N, p = 0.004). Likewise, when using AWS, compared to prior, significantly less force were applied on the tongue after clinical training in the normal scenario (22.0 N vs 0 N, p < 0.001). The force on the tongue decreased after clinical training but not significant. These associations persisted in the difficult airway scenario. These findings suggest that force applied on oral structures can be quantified as a marker of intubation skills by using high fidelity simulators, and the assessment of procedural competency is recommended for all novice physicians prior to performing intubation in the clinical setting to improve the quality of emergency care. PMID- 29136004 TI - Predictability of machine learning techniques to forecast the trends of market index prices: Hypothesis testing for the Korean stock markets. AB - The prediction of the trends of stocks and index prices is one of the important issues to market participants. Investors have set trading or fiscal strategies based on the trends, and considerable research in various academic fields has been studied to forecast financial markets. This study predicts the trends of the Korea Composite Stock Price Index 200 (KOSPI 200) prices using nonparametric machine learning models: artificial neural network, support vector machines with polynomial and radial basis function kernels. In addition, this study states controversial issues and tests hypotheses about the issues. Accordingly, our results are inconsistent with those of the precedent research, which are generally considered to have high prediction performance. Moreover, Google Trends proved that they are not effective factors in predicting the KOSPI 200 index prices in our frameworks. Furthermore, the ensemble methods did not improve the accuracy of the prediction. PMID- 29136005 TI - A 17-molecule set as a predictor of complete response to neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer. AB - BACKGROUND: Recently, neoadjuvant chemotherapy with docetaxel/cisplatin/5 fluorouracil (NAC-DCF) was identified as a novel strong regimen with a high rate of pathological complete response (pCR) in advanced esophageal cancer in Japan. Predicting pCR will contribute to the therapeutic strategy and the prevention of surgical invasion. However, a predictor of pCR after NAC-DCF has not yet been developed. The aim of this study was to identify a novel predictor of pCR in locally advanced esophageal cancer treated with NAC-DCF. PATIENTS AND METHODS: A total of 32 patients who received NAC-DCF followed by esophagectomy between June 2013 and March 2016 were enrolled in this study. We divided the patients into the following 2 groups: pCR group (9 cases) and non-pCR group (23 cases), and compared gene expressions between these groups using DNA microarray data and KeyMolnet. Subsequently, a validation study of candidate molecular expression was performed in 7 additional cases. RESULTS: Seventeen molecules, including transcription factor E2F, T-cell-specific transcription factor, Src (known as "proto-oncogene tyrosine-protein kinase of sarcoma"), interferon regulatory factor 1, thymidylate synthase, cyclin B, cyclin-dependent kinase (CDK) 4, CDK, caspase-1, vitamin D receptor, histone deacetylase, MAPK/ERK kinase, bcl-2 associated X protein, runt-related transcription factor 1, PR domain zinc finger protein 1, platelet-derived growth factor receptor, and interleukin 1, were identified as candidate molecules. The molecules were mainly associated with pathways, such as transcriptional regulation by SMAD, RB/E2F, and STAT. The validation study indicated that 12 of the 17 molecules (71%) matched the trends of molecular expression. CONCLUSIONS: A 17-molecule set that predicts pCR after NAC-DCF for locally advanced esophageal cancer was identified. PMID- 29136006 TI - Lipopolysaccharide potentiates platelet responses via toll-like receptor 4 stimulated Akt-Erk-PLA2 signalling. AB - Lipopolysaccharide (LPS) from the cell envelope of Gram-negative bacteria is a principal cause of the symptoms of sepsis. LPS has been reported to modulate the function of platelets although the underlying mechanisms of LPS action in these cells remain unclear. Platelets express the Toll-like receptor 4 (TLR4) which serves as a receptor for LPS, although the potential role of TLR4 and associated cell signalling in controlling platelet responses to LPS has not been extensively explored. In this study, we therefore investigated the actions of LPS prepared from different strains of Escherichia coli on platelet function, the underlying signalling mechanisms, and the potential role of TLR4 in orchestrating these. We report that LPS increased the aggregation of washed platelets stimulated by thromboxane (U46619) or GPVI collagen receptor agonists, effects that were prevented by a TLR4 antagonist. Associated with this, LPS enhanced fibrinogen binding, P-selectin exposure and reactive oxygen species (ROS) release. Increase of ROS was found to be important for the actions of LPS on platelets, since these were inhibited in the presence of superoxide dismutase or catalase. The effects of LPS were associated with phosphorylation of Akt, ERK1/2 and PLA2 in stimulated platelets, and inhibitors of PI3-kinase, Akt and ERK1/2 reduced significantly LPS enhanced platelet function and associated ROS production. Furthermore, inhibition of platelet cyclooxygenase or the thromboxane receptor, revealed an important role for thromboxane A2. We therefore conclude that LPS increases human platelet activation through a TLR4-PI3K-Akt-ERK1/2-PLA2 -dependent pathway that is dependent on ROS and TXA2 formation. PMID- 29136007 TI - Perinatal mortality associated with induction of labour versus expectant management in nulliparous women aged 35 years or over: An English national cohort study. AB - BACKGROUND: A recent randomised controlled trial (RCT) demonstrated that induction of labour at 39 weeks of gestational age has no short-term adverse effect on the mother or infant among nulliparous women aged >=35 years. However, the trial was underpowered to address the effect of routine induction of labour on the risk of perinatal death. We aimed to determine the association between induction of labour at >=39 weeks and the risk of perinatal mortality among nulliparous women aged >=35 years. METHODS AND FINDINGS: We used English Hospital Episode Statistics (HES) data collected between April 2009 and March 2014 to compare perinatal mortality between induction of labour at 39, 40, and 41 weeks of gestation and expectant management (continuation of pregnancy to either spontaneous labour, induction of labour, or caesarean section at a later gestation). Analysis was by multivariable Poisson regression with adjustment for maternal characteristics and pregnancy-related conditions. Among the cohort of 77,327 nulliparous women aged 35 to 50 years delivering a singleton infant, 33.1% had labour induced: these women tended to be older and more likely to have medical complications of pregnancy, and the infants were more likely to be small for gestational age. Induction of labour at 40 weeks (compared with expectant management) was associated with a lower risk of in-hospital perinatal death (0.08% versus 0.26%; adjusted risk ratio [adjRR] 0.33; 95% CI 0.13-0.80, P = 0.015) and meconium aspiration syndrome (0.44% versus 0.86%; adjRR 0.52; 95% CI 0.35-0.78, P = 0.002). Induction at 40 weeks was also associated with a slightly increased risk of instrumental vaginal delivery (adjRR 1.06; 95% CI 1.01-1.11, P = 0.020) and emergency caesarean section (adjRR 1.05; 95% CI 1.01-1.09, P = 0.019). The number needed to treat (NNT) analysis indicated that 562 (95% CI 366 1,210) inductions of labour at 40 weeks would be required to prevent 1 perinatal death. Limitations of the study include the reliance on observational data in which gestational age is recorded in weeks rather than days. There is also the potential for unmeasured confounders and under-recording of induction of labour or perinatal death in the dataset. CONCLUSIONS: Bringing forward the routine offer of induction of labour from the current recommendation of 41-42 weeks to 40 weeks of gestation in nulliparous women aged >=35 years may reduce overall rates of perinatal death. PMID- 29136008 TI - Automated tracking and quantification of angiogenic vessel formation in 3D microfluidic devices. AB - Angiogenesis, the growth of new blood vessels from pre-existing vessels, is a critical step in cancer invasion. Better understanding of the angiogenic mechanisms is required to develop effective antiangiogenic therapies for cancer treatment. We culture angiogenic vessels in 3D microfluidic devices under different Sphingosin-1-phosphate (S1P) conditions and develop an automated vessel formation tracking system (AVFTS) to track the angiogenic vessel formation and extract quantitative vessel information from the experimental time-lapse phase contrast images. The proposed AVFTS first preprocesses the experimental images, then applies a distance transform and an augmented fast marching method in skeletonization, and finally implements the Hungarian method in branch tracking. When applying the AVFTS to our experimental data, we achieve 97.3% precision and 93.9% recall by comparing with the ground truth obtained from manual tracking by visual inspection. This system enables biologists to quantitatively compare the influence of different growth factors. Specifically, we conclude that the positive S1P gradient increases cell migration and vessel elongation, leading to a higher probability for branching to occur. The AVFTS is also applicable to distinguish tip and stalk cells by considering the relative cell locations in a branch. Moreover, we generate a novel type of cell lineage plot, which not only provides cell migration and proliferation histories but also demonstrates cell phenotypic changes and branch information. PMID- 29136009 TI - Early resumption of sexual activity following voluntary medical male circumcision in Botswana: A qualitative study. AB - Unprotected sexual intercourse after undergoing voluntary medical male circumcision but prior to complete wound healing can lead to major adverse events including HIV acquisition. To better understand perceptions related to early resumption of sex prior to wound healing, 27 focus group discussions were conducted among 238 adult men, women, and community leaders in Botswana. Median age among all participants was 31 years of whom 60% were male and 51% were either employed and receiving salary or self-employed. Only 12% reported being currently married. Pain, not risk of HIV acquisition, was perceived as the main adverse consequence of early resumption of sex. In fact, no participant mentioned that early resumption of sex could lead to an increase in HIV risk. Demonstrating masculinity and virility, fear of losing female partners, and misperception about post-operative wound healing also played key roles in the decision to resume sex prior to complete wound healing. Findings from this study highlight a potentially widespread lack of awareness of the increased risk of HIV acquisition during the wound healing period. Strengthening post-operative counseling and identifying strategies to discourage the early resumption of sex will be increasingly important as older men and HIV-positive men seek voluntary medical male circumcision services. PMID- 29136010 TI - Association between birth season and physical development in children under 3 years old residing in low-income counties in western China. AB - OBJECTIVE: To explore the association between birth season and physical development and provide a necessary reference value to inform the implementation of public health services. DESIGN: Cross-sectional study. SETTING: Forty-five counties in ten provinces in western China in 2005. SUBJECTS: A sample of 13,387 children under 3 years old and their mothers were recruited using a stratified, multistage, cluster random sampling method. RESULTS: The results of the circular distribution analysis suggested that stunting and underweight exhibited time aggregation (Z = 32.57, P<0.05; Z = 10.42, P<0.05) among children under 3 years old. The Z - value for wasting, however, was not statistically significant (P>0.05). The generalized linear mixed models showed that children born in the summer were less likely to exhibit stunting (OR: 0.74~0.97) than were children born in the winter after adjusting for confounders, but no significant differences were identified for the other seasons. In addition, among children aged 25 to 36 months, those born in the summer and autumn were less likely to exhibit stunting after adjusting for confounders than were children born in the winter, but the association between birth in spring and stunting was not statistically significant. CONCLUSIONS: Stunting was associated with season of birth among children under 3 years old in low-income counties in western China, especially children aged 25 to 36 months, and children born in the summer and autumn were less likely to exhibit stunting than were children born in the winter. PMID- 29136011 TI - Ten year experience with antiretroviral treatment in Cambodia: Trends in patient characteristics and treatment outcomes. AB - BACKGROUND: Although HIV disease stage at ART initiation critically determines ART outcomes, few reports have longitudinally monitored this within Asia. Using prospectively collected data from a large ART program at Sihanouk Hospital Center of Hope in Cambodia, we report on the change in patient characteristics and outcomes over a ten-year period. METHODS: We conducted a retrospective analysis including all adults (>= 18 years old) starting ART from March 2003-March 2013 in a non-governmental hospital in Phnom Penh, Cambodia. The cumulative incidence of death, lost to follow-up (LTFU), attrition (death or LTFU) and first line treatment failure were calculated using Kaplan-Meier methods. Independent risk factors for these outcomes were determined using Cox regression modeling. RESULTS: Over the ten-year period, 3581 patients initiated ART with a median follow-up time of 4.8 years (IQR 2.8-7.2). The median age was 35 years (IQR 30 41), 54% were female. The median CD4 count at ART initiation increased from 22 cells/MUL (IQR 4-129) in 2003 to 218 (IQR 57-302) in 2013. Over the 10 year period, a total of 282 (7.9%) individuals died and 433 (12.1%) were defined LTFU. Program attrition (died or LTFU) was 11.1% (95% CI: 10.1%- 12.4%) at one year, 16.3% (95% CI: 15.1%-17.6%) at three years, 19.8% (95% CI: 18.5%-21.2%) at five years and 23.3% (95% CI: 21.6-25.1) at ten years. Male sex and low baseline body mass index (BMI) were associated with increased attrition. Factors independently associated with mortality included a low baseline CD4 count, older age, male sex, low baseline BMI and hepatitis B co-infection. Individuals aged above 40 years old had an increased risk of mortality but were less likely to LTFU. There were a total of 137 individuals with first line ART failure starting second line treatment. The probability of first line failure was estimated at 2.8% (95% CI: 2.3%-3.4%) at 3 years, 4.6% (95% CI: 3.9%-5.5%) at 5 years and 7.8% (95% CI 4.8% 12.5%) at ten years of ART. The probability was particularly high in the first few program years. A lower risk was observed among individuals starting ART during the 2006-2008 period. Factors independently associated with an increased risk of treatment failure included ART-experience, NVP-based ART and a baseline CD4 count below 200 cells/MUL. CONCLUSIONS: Overall program outcomes were fair, and generally compare well to other reports from the region. Despite gradually earlier initiation of ART over the ten year period, ART is still initiated at too low CD4 count levels, warranting increased efforts for early HIV diagnosis and enrolment/retention into HIV care. Tailored strategies for poor prognostic groups (older age, male, low BMI) should be designed and evaluated. PMID- 29136012 TI - Regional knockdown of NDUFS4 implicates a thalamocortical circuit mediating anesthetic sensitivity. AB - Knockout of the mitochondrial complex I protein, NDUFS4, profoundly increases sensitivity of mice to volatile anesthetics. In mice carrying an Ndufs4lox/lox gene, adeno-associated virus expressing Cre recombinase was injected into regions of the brain postulated to affect sensitivity to volatile anesthetics. These injections generated otherwise phenotypically wild type mice with region specific, postnatal inactivation of Ndufs4, minimizing developmental effects of gene loss. Sensitivities to the volatile anesthetics isoflurane and halothane were measured using loss of righting reflex (LORR) and movement in response to tail clamp (TC) as endpoints. Knockdown (KD) of Ndufs4 in the vestibular nucleus produced resistance to both anesthetics for movement in response to TC. Ndufs4 loss in the central and dorsal medial thalami and in the parietal association cortex increased anesthetic sensitivity to both TC and LORR. Knockdown of Ndufs4 only in the parietal association cortex produced striking hypersensitivity for both endpoints, and accounted for half the total change seen in the global KO (Ndufs4(KO)). Excitatory synaptic transmission in the parietal association cortex in slices from Ndufs4(KO) animals was hypersensitive to isoflurane compared to control slices. We identified a direct neural circuit between the parietal association cortex and the central thalamus, consistent with a model in which isoflurane sensitivity is mediated by a thalamic signal relayed through excitatory synapses to the parietal association cortex. We postulate that the thalamocortical circuit is crucial for maintenance of consciousness and is disrupted by the inhibitory effects of isoflurane/halothane on mitochondria. PMID- 29136013 TI - Monomer conversion, dimensional stability, strength, modulus, surface apatite precipitation and wear of novel, reactive calcium phosphate and polylysine containing dental composites. AB - PURPOSE: The aim was to assess monomer conversion, dimensional stability, flexural strength / modulus, surface apatite precipitation and wear of mono / tri calcium phosphate (CaP) and polylysine (PLS)-containing dental composites. These were formulated using a new, high molecular weight, fluid monomer phase that requires no polymerisation activator. MATERIALS AND METHODS: Urethane and Polypropylene Glycol Dimethacrylates were combined with low levels of an adhesion promoting monomer and a light activated initiator. This liquid was mixed with a hybrid glass containing either 10 wt% CaP and 1 wt% PLS (F1) or 20 wt% CaP and 2 wt% PLS (F2). Powder to liquid mass ratio was 5:1. Commercial controls included Gradia Direct Posterior (GD) and Filtek Z250 (FZ). Monomer conversion and polymerisation shrinkage were calculated using Fourier Transform Infrared (FTIR). Subsequent volume increases in water over 7 weeks were determined using gravimetric studies. Biaxial flexural strength (BFS) / modulus (BFM) reduction and surface apatite precipitation upon 1 and 4 weeks immersion in water versus simulated body fluid (SBF) were assessed using a mechanical testing frame and scanning electron microscope (SEM). Mass / volume loss and surface roughness (Ra) following 7 weeks water immersion and subsequent accelerated tooth-brush abrasion were examined using gravimetric studies and profilometer. RESULTS: F1 and F2 exhibited much higher monomer conversion (72%) than FZ (54%) and low calculated polymerization shrinkage (2.2 vol%). Final hygroscopic expansions decreased in the order; F2 (3.5 vol%) > F1 (1.8 vol%) ~ Z250 (1.6 vol%) > Gradia (1.0 vol%). BFS and BFM were unaffected by storage medium type. Average BFS / BFM upon 4 weeks immersion reduced from 144 MPa / 8 GPa to 107 MPa / 5 GPa for F1 and 105 MPa / 6 GPa to 82 MPa / 4 GPa for F2. Much of this change was observed in the first week of immersion when water sorption rate was high. Surface apatite layers were incomplete at 1 week, but around 2 and 15 micron thick for F1 and F2 respectively following 4 weeks in SBF. Mass and volume loss following wear were equal. Average results for F1 (0.5%), F2 (0.7%), and FZ (0.5%) were comparable but lower than that of GD (1%). Ra, however, decreased in the order; F1 (15 MUm) > F2 (11 MUm) > GD (9 MUm) > FZ (5 MUm). CONCLUSIONS: High monomer conversion in combination with large monomer size and lack of amine activator should improve cytocompatibility of the new composites. High monomer molecular weight and powder content enables low polymerisation shrinkage despite high conversion. Increasing active filler provides enhanced swelling to balance shrinkage, which, in combination with greater surface apatite precipitation, may help seal gaps and reduce bacterial microleakage. High monomer conversion also ensures competitive mechanical / wear characteristics despite enhanced water sorption. Furthermore, increased active filler could help reduce surface roughness upon wear. PMID- 29136014 TI - Treatment guidelines and early loss from care for people living with HIV in Cape Town, South Africa: A retrospective cohort study. AB - BACKGROUND: South Africa has undergone multiple expansions in antiretroviral therapy (ART) eligibility from an initial CD4+ threshold of <=200 cells/MUl to providing ART for all people living with HIV (PLWH) as of September 2016. We evaluated the association of programmatic changes in ART eligibility with loss from care, both prior to ART initiation and within the first 16 weeks of starting treatment, during a period of programmatic expansion to ART treatment at CD4+ <= 350 cells/MUl. METHODS AND FINDINGS: We performed a retrospective cohort study of 4,025 treatment-eligible, non-pregnant PLWH accessing care in a community health center in Gugulethu Township affiliated with the Desmond Tutu HIV Centre in Cape Town. The median age of participants was 34 years (IQR 28-41 years), almost 62% were female, and the median CD4+ count was 173 cells/MUl (IQR 92-254 cells/MUl). Participants were stratified into 2 cohorts: an early cohort, enrolled into care at the health center from 1 January 2009 to 31 August 2011, when guidelines mandated that ART initiation required CD4+ <= 200 cells/MUl, pregnancy, advanced clinical symptoms (World Health Organization [WHO] stage 4), or comorbidity (active tuberculosis); and a later cohort, enrolled into care from 1 September 2011 to 31 December 2013, when the treatment threshold had been expanded to CD4+ <= 350 cells/MUl. Demographic and clinical factors were compared before and after the policy change using chi-squared tests to identify potentially confounding covariates, and logistic regression models were used to estimate the risk of pre treatment (pre-ART) loss from care and early loss within the first 16 weeks on treatment, adjusting for age, baseline CD4+, and WHO stage. Compared with participants in the later cohort, participants in the earlier cohort had significantly more advanced disease: median CD4+ 146 cells/MUl versus 214 cells/MUl (p < 0.001), 61.1% WHO stage 3/4 disease versus 42.8% (p < 0.001), and pre-ART mortality of 34.2% versus 16.7% (p < 0.001). In total, 385 ART-eligible PLWH (9.6%) failed to initiate ART, of whom 25.7% died before ever starting treatment. Of the 3,640 people who started treatment, 58 (1.6%) died within the first 16 weeks in care, and an additional 644 (17.7%) were lost from care within 16 weeks of starting ART. PLWH who did start treatment in the later cohort were significantly more likely to discontinue care in <16 weeks (19.8% versus 15.8%, p = 0.002). After controlling for baseline CD4+, WHO stage, and age, this effect remained significant (adjusted odds ratio [aOR] = 1.30, 95% CI 1.09-1.55). As such, it remains unclear if early attrition from care was due to a "healthy cohort" effect or to overcrowding as programs expanded to accommodate the broader guidelines for treatment. Our findings were limited by a lack of generalizability (given that these data were from a single high-volume site where testing and treatment were available) and an inability to formally investigate the effect of crowding on the main outcome. CONCLUSIONS: Over one-quarter of this ART-eligible cohort did not achieve the long-term benefits of treatment due to early mortality, ART non-initiation, or early ART discontinuation. Those who started treatment in the later cohort appeared to be more likely to discontinue care early, and this outcome appeared to be independent of CD4+ count or WHO stage. Future interventions should focus on those most at risk for early loss from care as programs continue to expand in South Africa. PMID- 29136015 TI - The influences of walking, running and stair activity on knee articular cartilage: Quantitative MRI using T1 rho and T2 mapping. AB - OBJECTIVE: To explore the different influences of walking, running and stair activity on knee articular cartilage with T1 rho and T2 mapping sequences. MATERIALS AND METHODS: MRI (3.0-T) scans of the right knee were performed in twenty-three young healthy adults immediately after 30 minutes of rest, walking, running and stair activity respectively. Articular cartilage was quantitatively assessed based on T1 rho and T2 relaxation times. Analysis of variance for random block design data, bonferroni test and paired samples t tests were performed to estimate the different influences of physiological activities on articular cartilage. RESULTS: T1 rho and T2 values had reductions after physiological activities in all regions of articular cartilage. T1 rho and T2 values were decreased more after running than walking. T1 rho and T2 values were decreased more after stair activity than running, except for femoral cartilage. The superficial layer of patella cartilage had higher reduction rates than the deep layer. The T1 rho and T2 values of articular cartilage were reduced in the following order: patellofemoral cartilage> medial tibiofemoral cartilage> lateral tibiofemoral cartilage. Patellofemoral cartilage experienced reductions in the following order: lateral part> middle part> medial part. Tibiofemoral cartilage had reductions in the following order: posterior part> middle part> anterior part. CONCLUSIONS: T1 rho and T2 mapping sequences can quantitatively reflect the different influences of physiological activities on knee articular cartilage. Fluid shifts, collagen fiber deformation, spatial heterogeneity, inherent differences in material properties and tissue stiffness have close relationship with cartilage loading characteristics. PMID- 29136016 TI - Monitoring the effects of land cover change on the supply of ecosystem services in an urban region: A study of Santiago-Valparaiso, Chile. AB - Mankind's quest for well-being results in continuous pressure to transform landscapes, with said transformation driven by land use changes, urbanization, production activity, and protective measures in addition to climate variability and other environmental drivers. The relationship between anthropogenic landscape changes and the provision of ecosystem services (ES) is a topic of increasing interest in Latin America. In Chile, land cover changes due to increased urbanization and forestry, and expansion of agricultural land, in addition to conservation initiatives as a part of land planning, have been intensive in the last few decades. In this study, the effects of anthropogenic landscape changes on the supply of ES were analyzed for the urban region of Santiago-Valparaiso (Chile) using a method based on expert consultation and land cover change assessment. A pool of experts scored the potential of specific land covers to provide certain ES. The results enabled calculation and mapping of changes in the potential of the landscape to supply ES. The aforementioned changes over a period of 15 years were evaluated. The results indicate a tenuous balance between positive and negative changes to the supply of ES derived from land cover changes. Understanding and reporting how these processes occur in urban regions contributes to the conservation of valuable landscapes through spatial planning tools, especially in areas close to housing developments and sensitive ecosystems. PMID- 29136017 TI - Practices in security and confidentiality of HIV/AIDS patients' information: A national survey among staff at HIV outpatient clinics in Vietnam. AB - INTRODUCTION: Breach of confidentiality or invasion of privacy from the collection and use of medical records, particularly those of patients with HIV/AIDS or other diseases sensitive to stigmatization, should be prevented by all related stakeholders in healthcare settings. The main focus of this study was to assess practices regarding security and confidentiality of HIV-related information among staff at HIV outpatient clinics (HIV-OPCs) in Vietnam. METHODS: A descriptive cross-sectional study was conducted at all 312 HIV-OPCs across the country using an online survey technique. RESULTS: In general, the staff practices for securing and protecting patient information were at acceptable levels. Most staff had proper measures and practices for maintaining data security; however, the protection of patient confidentiality, particularly for data access, sharing, and transfer still required improvement. Most HIV-OPC staff had good or moderate knowledge and positive perceptions towards security and confidentiality issues. Staff who were not trained in the practice of security measures differed significantly from those who were trained (OR: 3.74; 95%CI: 1.44-9.67); staff needing improved knowledge levels differed significantly from those with good (OR: 5.20; 95%CI: 2.39-11.32) and moderate knowledge levels (OR: 5.10; 95%CI: 2.36-11.00); and staff needing improved perception levels differed significantly from those with good (i.e., with 100% proper practices) and moderate perception levels (OR: 5.67; 95%CI: 2.93-10.95). Staff who were not trained in the protection of data confidentiality differed significantly from those who were trained (OR: 2.18; 95%CI: 1.29-3.65). CONCLUSIONS: Training is an important factor to help raise the levels of proper practices regarding confidentiality and security, to improve knowledge and raise awareness about change among staff. The operation and management of HIV treatment and care in Vietnam are currently transitioning from separate healthcare clinics (HIV-OPC) into units integrated into general hospitals/healthcare facilities. The findings of this study highlight topics that could be used for improving management and operation of information system and revising guidelines and regulations on protection measures/strategies for data security and confidentiality of HIV/AIDS patients by Vietnam health authorities or other countries facing similar situations. Secure infrastructure and secure measures for data access and use are very important, worthwhile investments. The provision of continuous training and active enforcement and monitoring of the practices of healthcare personnel might lead to an improved understanding and acknowledegement of the importance of national policies/guidelines regarding HIV-related patient information. PMID- 29136018 TI - Adverse obstetric outcomes in pregnant women with uterine fibroids in China: A multicenter survey involving 112,403 deliveries. AB - OBJECTIVE: To estimate the association between uterine fibroids and adverse obstetric outcomes. METHODS: This was a retrospective cross-sectional study of 112,403 deliveries from 14 provinces and 39 different hospitals in 2011 in mainland China. We compared pregnancy outcomes in women with and without uterine fibroids who underwent detailed second trimester obstetric ultrasonography during 18 to 22 weeks. Obstetric outcomes include cesarean delivery, breech presentation, preterm delivery, placenta previa, placental abruption, premature rupture of membranes and neonatal birthweight. Univariate analyses and multivariate logistic regression analyses were performed. RESULTS: Of 112,403 women who underwent routine obstetric survey, 3,012 (2.68%) women were identified with at least 1 fibroid. By univariate and multivariate analyses, the presence of uterine fibroids was significantly associated with cesarean delivery (Adjusted odds radio [AOR] 1.8, 95% confidence interval [CI] 1.7-2.0), breech presentation (AOR 1.3, 95% CI 1.2-1.5) and postpartum hemorrhage (AOR 1.2, 95% CI 1.1-1.4). The size of uterine fibroids and location in uterus had important effect on the mode of delivery. The rates of PPH were significantly higher with increasing size of the uterine fibroid (P<0.001). And the location of fibroid (intramural, submucosal or subserosal) also have a statistically significant impact on the risk of PPH (5.6% [subserosal] vs 4.7% [submucosal] vs 8.6% [intramural]). CONCLUSION: Pregnant women with uterine fibroids are at increased risk for cesarean delivery, breech presentation and postpartum hemorrhage. And different characteristics of uterine fibroids affect obstetric outcomes through different ways. Such detailed information may be useful in risk-stratifying pregnant women with fibroids. PMID- 29136019 TI - Comparative rates of upstaging and upgrading in Caucasian and Korean prostate cancer patients eligible for active surveillance. AB - PURPOSE: To investigate the impact of race on the risk of pathological upgrading and upstaging at radical prostatectomy (RP) in an Asian (Korean) and Western (Caucasian) cohort eligible for active surveillance (AS). MATERIALS AND METHODS: We performed a retrospective cohort study of 854 patients eligible for AS who underwent RP in United States (n = 261) and Korea (n = 593) between 2006 and 2015. After adjusting for age, PSA level, and prostate volume, we utilized multivariate logistic regression analysis to assess the effect of race on upgrading or upstaging. RESULTS: There were significant differences between Caucasian and Korean patients in terms of age at surgery (60.2 yr. vs. 64.1 yr.), PSA density (0.115 ng/mL/mL vs. 0.165 ng/mL/mL) and mean number of positive cores (3.5 vs. 2.4), but not in preoperative PSA values (5.11 ng/mL vs. 5.05 ng/mL). The rate of upstaging from cT1 or cT2 to pT3 or higher was not significantly different between the two cohorts (8.8% vs. 11.0%, P = 0.341). However, there were higher rates of upgrading to high-grade cancer (Gleason 4+3 or higher) in Korean patients (9.1%) when compared to Caucasian counterparts (2.7%) (P = 0.003). Multivariate logistic regression analysis showed that age (OR 1.07, P < 0.001) and smaller prostate volume (OR 0.97, P < 0.001), but not race, were significantly associated with upstaging or upgrading. CONCLUSIONS: There were no differences in rates of upgrading or upstaging between Caucasian and Korean men eligible for active surveillance. PMID- 29136020 TI - Evolutionary dynamics of group formation. AB - Group formation is a quite ubiquitous phenomenon across different animal species, whose individuals cluster together forming communities of diverse size. Previous investigations suggest that, in general, this phenomenon might have similar underlying reasons across the interested species, despite genetic and behavioral differences. For instance improving the individual safety (e.g. from predators), and increasing the probability to get food resources. Remarkably, the group size might strongly vary from species to species, e.g. shoals of fishes and herds of lions, and sometimes even within the same species, e.g. tribes and families in human societies. Here we build on previous theories stating that the dynamics of group formation may have evolutionary roots, and we explore this fascinating hypothesis from a purely theoretical perspective, with a model using the framework of Evolutionary Game Theory. In our model we hypothesize that homogeneity constitutes a fundamental ingredient in these dynamics. Accordingly, we study a population that tries to form homogeneous groups, i.e. composed of similar agents. The formation of a group can be interpreted as a strategy. Notably, agents can form a group (receiving a 'group payoff'), or can act individually (receiving an 'individual payoff'). The phase diagram of the modeled population shows a sharp transition between the 'group phase' and the 'individual phase', characterized by a critical 'individual payoff'. Our results then support the hypothesis that the phenomenon of group formation has evolutionary roots. PMID- 29136021 TI - Saturation effects and the concurrency hypothesis: Insights from an analytic model. AB - Sexual partnerships that overlap in time (concurrent relationships) may play a significant role in the HIV epidemic, but the precise effect is unclear. We derive edge-based compartmental models of disease spread in idealized dynamic populations with and without concurrency to allow for an investigation of its effects. Our models assume that partnerships change in time and individuals enter and leave the at-risk population. Infected individuals transmit at a constant per partnership rate to their susceptible partners. In our idealized populations we find regions of parameter space where the existence of concurrent partnerships leads to substantially faster growth and higher equilibrium levels, but also regions in which the existence of concurrent partnerships has very little impact on the growth or the equilibrium. Additionally we find mixed regimes in which concurrency significantly increases the early growth, but has little effect on the ultimate equilibrium level. Guided by model predictions, we discuss general conditions under which concurrent relationships would be expected to have large or small effects in real-world settings. Our observation that the impact of concurrency saturates suggests that concurrency-reducing interventions may be most effective in populations with low to moderate concurrency. PMID- 29136022 TI - Prognostic significance of cytokeratin 19 expression in pancreatic neuroendocrine tumor: A meta-analysis. AB - BACKGROUND: Pancreatic neuroendocrine tumor (PNET) comprises 1-2% of all pancreatic tumors, but its incidence is increasing. Although many studies have investigated the correlation between cytokeratin 19 (CK-19) and PNET, the prognostic significance of CK-19 expression in PNET is inconclusive. METHODS: Eligible studies were retrieved from Pubmed, Elsevier, Embase, Cochrane Library and Web of Science databases. All relevant data were extracted to analyze the relationship between CK-19 and PNET. We utilized a fixed or random effects model to calculate the pooled odds ratio (OR) with 95% confidence intervals (CI). RESULTS: Pooled data indicated CK-19 expression was significantly associated with poor 3- and 5-year overall survival (OS) for PNET, but not for 1-year overall survival. Additionally, positive CK-19 expression was correlated with large tumor size, advanced differentiation grade in World Health Organization-2010 (WHO-2010) and WHO-2004, vascular invasion, lymph node metastasis and liver metastasis. CONCLUSIONS: Positive CK-19 expression can be used as a predictor of poor prognosis of PNET. PMID- 29136023 TI - Modifications of hemoglobin and myoglobin by Maillard reaction products (MRPs). AB - High performance liquid chromatography (HPLC) coupled with a Fraction Collector was employed to isolate Maillard reaction products (MRPs) formed in model systems comprising of asparagine and monosaccharides in the 60-180 degrees C range. The primary MRP which is detected at 60 degrees C is important for Acrylamide content and color/aroma development in foods and also in the field of food biotechnology for controlling the extent of the Maillard reaction with temperature. The discrete fractions of the reaction products were reacted with Hemoglobin (Hb) and Myoglobin (Mb) at physiological conditions and the reaction adducts were monitored by UV-vis and Attenuated Total Reflection-Fourier transform infrared (FTIR) spectrophotometry. The UV-vis kinetic profiles revealed the formation of a Soret transition characteristic of a low-spin six-coordinated species and the ATR FTIR spectrum of the Hb-MRP and Mb-MRP fractions showed modifications in the protein Amide I and II vibrations. The UV-vis and the FTIR spectra of the Hb-MRPs indicate that the six-coordinated species is a hemichrome in which the distal E7 Histidine is coordinated to the heme Fe and blocks irreversibly the ligand binding site. Although the Mb-MRPs complex is a six-coordinated species, the 1608 cm-1 FTIR band characteristic of a hemichrome was not observed. PMID- 29136024 TI - Severe oxidative stress in an acute inflammatory demyelinating model in the rhesus monkey. AB - Oxidative stress is increasingly implicated as a co-factor of tissue injury in inflammatory/demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While rodent experimental autoimmune encephalomyelitis (EAE) models diverge from human demyelinating disorders with respect to limited oxidative injury, we observed that in a non-human primate (NHP) model for MS, namely EAE in the common marmoset, key pathological features of the disease were recapitulated, including oxidative tissue injury. Here, we investigated the presence of oxidative injury in another NHP EAE model, i.e. in rhesus macaques, which yields an acute demyelinating disease, which may more closely resemble acute disseminated encephalomyelitis (ADEM) than MS. Rhesus monkey EAE diverges from marmoset EAE by abundant neutrophil recruitment into the CNS and destructive injury to white matter. This difference prompted us to investigate to which extent the oxidative pathway features elicited in MS and marmoset EAE are reflected in the acute rhesus monkey EAE model. The rhesus EAE brain was characterized by widespread demyelination and active lesions containing numerous phagocytic cells and to a lesser extent T cells. We observed induction of the oxidative stress pathway, including injury, with a predilection of p22phox expression in neutrophils and macrophages/microglia. In addition, changes in iron were observed. These results indicate that pathogenic mechanisms in the rhesus EAE model may differ from the marmoset EAE and MS brain due to the neutrophil involvement, but may in the end lead to similar induction of oxidative stress and injury. PMID- 29136025 TI - Effects of RTV coating on the electrical performance of polymer insulator under lightning impulse voltage condition. AB - Located near the equator, Malaysia is a country with one of the highest lightning densities in the world. Lightning contributes to 70% of the power outages in Malaysia and affects power equipment, automated network systems, causes data losses and monetary losses in the nation. Therefore, consideration of insulator evaluation under lightning impulses can be crucial to evaluate and attempt to overcome this issue. This paper presents a new approach to increase the electrical performance of polymer insulators using a Room Temperature Vulcanisation (RTV) coating. The evaluation involves three different settings of polymer insulator, namely uncoated, RTV type 1, and RTV type 2 upper surface coatings. All the insulators were tested under three different conditions as dry, clean wet and salty under different impulse polarities using the even-rising test method. The voltage breakdown for each test was recorded. From the experiment, it was found that the effectiveness of the RTV coating application became apparent when tested under salty or polluted conditions. It increased the voltage withstand capabilities of the polymer insulator up to 50% from the basic uncoated insulator. Under dry and clean conditions, the RTV coating provided just a slight increase of the breakdown voltage. The increase in voltage breakdown capability decreased the probability of surface discharge and dry band arcing that could cause degradation of the polymeric material housing. The RTV type 1 coating was found to be more effective when performing under a lightning impulse. The findings might help the utility companies improve the performance of their insulators in order to increase power system reliability. PMID- 29136026 TI - Operative technique at caesarean delivery and risk of complete uterine rupture in a subsequent trial of labour at term. A registry case-control study. AB - OBJECTIVE: To estimate the relation of single-layer closure at previous caesarean delivery, and other pre-labour and intra-partum risk factors for complete uterine rupture in trial of vaginal birth after a caesarean (TOLAC) at term. STUDY DESIGN: Population-based case-control study. We identified all women (n = 39 742) recorded in the Danish Medical Birth Registry (DMBR) during a 12-year period (1997-2008) with a singleton pregnancy at term and TOLAC. Among these, all women with a complete uterine rupture were identified (cases). Information from the registry was validated against medical records. Controls were selected in the DMBR as the following two births with TOLAC at term and no uterine rupture. Detailed information from cases and controls was collected from manual review of medical records. Main outcome measure was complete uterine rupture during TOLAC at term. RESULTS: Upon validation, 175 cases and 272 controls met the above criteria. After adjustment for possible confounding factors there was no association between single layer closure and uterine rupture (aOR 1.38, CI: 0.88 2.17). Significant risk factors were: Induction with an unfavourable cervix (aOR 2.10 CI: 1.19-3.71), epidural (aOR 2.17 CI 1.31-3.57), augmentation by oxytocin for more than one hour (aOR 2.03 CI: 1.20-3.44), and birth weight >= 4000g (aOR 2.65 CI 1.05-6.64). Previous vaginal delivery (aOR 0.41 CI: 0.25-0.68) and inter delivery interval of more than 24 months (aOR 0.38 CI: 0.18-0.78) reduced the risk of uterine rupture. CONCLUSION: Single-layer uterine closure did not remain significantly associated to uterine rupture during TOLAC at term after adjustment for confounding factors. Induction of labour with an unfavourable cervix, birth weight >= 4000g and indicators of prolonged labour were all major risk factors for uterine rupture. PMID- 29136027 TI - Expression of Toll-like receptors (TLRs) in the lungs of an experimental sepsis mouse model. AB - BACKGROUND: Sepsis is a condition characterized by high mortality rates and often accompanied by multiple-organ dysfunction. During sepsis, respiratory system may be affected and possibly result in acute respiratory distress syndrome (ARDS). Toll-like receptors (TLRs), as a first line defense against invading pathogens, seem to be highly expressed in septic states. Therefore, expression of TLRs in the lungs of a sepsis animal model could indicate the involvement of the respiratory system and appear as a severity index of the clinical course. MATERIALS AND METHODS: A total of 72 C57BL/6J mice, aged 12-14 weeks, were studied. The animals were divided into 3 sepsis (S) groups (24h, 48h and 72h) and 3 control (C) groups (24h, 48h and 72h), each consisting of 12 mice. The S-groups were subjected to cecal ligation and puncture (CLP) while the C-groups had a sham operation performed. Blood samples were drawn from all groups. Total blood count analysis was performed along with the measurement of certain biochemical markers. Additionally, lung tissues were harvested and the expression of TLRs, namely TLR 2, TLR 3, TLR 4 and TLR 7 were evaluated by means of immunofluorescence (IF) and qRT-PCR (quantitative-Polymerase Chain Reaction). Statistical analysis was performed by using one-way ANOVA followed by student t-test. Results were considered statistically significant when p<0.05. RESULTS: WBCs and lymphocytes were decreased in all S-groups compared to the corresponding C-groups (p<0.05), while RBCs showed a gradual decline in S-groups with the lowest levels appearing in the S72 group. Only, monocytes were higher in S-groups, especially between S48 C48 (p<0.05) and S72-C72 (p<0.05). Creatinine, IL-10 and IL-6 levels were significantly increased in the S-groups compared to the corresponding C-groups (S24 vs C24, S48 vs C48 and S72 vs C72, p<0.05). IF showed that expression of TLRs 2, 3, 4 and 7 was increased in all S-groups compared to the time-adjusted C groups (p<0.05). Similarly, qRT-PCR revealed that expression of all TLRs was higher in all S-groups compared to their respective C-groups in both lungs and intestine (p<0.05). Comparing lung and intestinal tissues from S-groups, TLRs 2 and 4 were found increased in the lung at 24, 48 and 72 hours (p<0.05), whereas TLR 3 was higher in the intestine at all time points examined (p<0.05). Finally, TLR 7 levels were significantly higher in the intestinal tissues at 24 hours (p<0.0001), while lungs predominated at 48 hours (p<0.0001). CONCLUSION: TLRs seem to be highly expressed in the lungs of septic mice, therefore suggesting a potential role in the pathogenesis of ARDS during sepsis. While more studies need to be conducted in order to completely understand the underlying mechanisms, TLRs may represent a promising target for establishing novel therapeutic strategies in the treatment of sepsis. PMID- 29136028 TI - Path-oriented test cases generation based adaptive genetic algorithm. AB - The automatic generation of test cases oriented paths in an effective manner is a challenging problem for structural testing of software. The use of search-based optimization methods, such as genetic algorithms (GAs), has been proposed to handle this problem. This paper proposes an improved adaptive genetic algorithm (IAGA) for test cases generation by maintaining population diversity. It uses adaptive crossover rate and mutation rate in dynamic adjustment according to the differences between individual similarity and fitness values, which enhances the exploitation of searching global optimum. This novel approach is experimented and tested on a benchmark and six industrial programs. The experimental results confirm that the proposed method is efficient in generating test cases for path coverage. PMID- 29136029 TI - A structural review of foliar glands in Passiflora L. (Passifloraceae). AB - Extrafloral glands in Passifloraceae species have aroused the interest of many researchers because of their wide morphological diversity. The present work analyzed the foliar glands on 34 species of Passiflora from samples containing glands in the petiole and foliar blade fixed in 50% solution of formaldehyde ethanol-acetic acid and stored in a 70% ethanol solution. For anatomical analyses, part of the material was embedded in Paraplast, longitudinally sectioned and double stained with safranin and astra blue. Scanning electron microscopy analysis was also carried out. To analyze the presence of sugars in the secretion of foliar glands, a glucose strip test was used. Based on the results of morphological, anatomical and glucose strip tests, the foliar secretory glands in Passiflora can be grouped into two categories: Type I glands, defined as nectaries, can be elevated or flattened, and can have a sugar content high enough to be detected by the glucose strip test analysis. Type II glands are elevated and did not show a positive reaction to the glucose strip test. From an anatomical viewpoint, glands characterized as extrafloral nectaries show a multistratified secretory epidermis, typically followed by two flat layers of nectariferous parenchyma with dense content. Internal to these layers, vascular bundles are immersed in the subsecretory parenchyma and terminate in phloem cells. On the other hand, type II glands show a single layer of elongated secretory epidermal cells. Internal to this single layer, parenchyma and vascular tissue with both phloem and xylem elements can be observed. The analyzed species show a wide diversity of gland shape and distribution, and the combined analysis of morphology, anatomy and preliminary tests for the presence of glucose in the exudate in different Passiflora subgenera suggests the occurrence of two categories of glands: nectaries and resin glands. PMID- 29136030 TI - Prospects for passive immunity to prevent HIV infection. AB - In a Perspective, Lynn Morris and Nonhlanhla Mkhize discuss the prospects for broadly neutralizing antibodies to be used in preventing HIV infection. PMID- 29136031 TI - Quantification of the sit-to-stand movement for monitoring age-related motor deterioration using the Nintendo Wii Balance Board. AB - Simple methods for quantitative evaluations of individual motor performance are crucial for the early detection of motor deterioration. Sit-to-stand movement from a chair is a mechanically demanding component of activities of daily living. Here, we developed a novel method using the ground reaction force and center of pressure measured from the Nintendo Wii Balance Board to quantify sit-to-stand movement (sit-to-stand score) and investigated the age-related change in the sit to-stand score as a method to evaluate reduction in motor performance. The study enrolled 503 participants (mean age +/- standard deviation, 51.0 +/- 19.7 years; range, 20-88 years; male/female ratio, 226/277) without any known musculoskeletal conditions that limit sit-to-stand movement, which were divided into seven 10 year age groups. The participants were instructed to stand up as quickly as possible, and the sit-to-stand score was calculated as the combination of the speed and balance indices, which have a tradeoff relationship. We also performed the timed up and go test, a well-known clinical test used to evaluate an individual's mobility. There were significant differences in the sit-to-stand score and timed up and go time among age groups. The mean sit-to-stand score for 60s, 70s, and 80s were 77%, 68%, and 53% of that for the 20s, respectively. The timed up and go test confirmed the age-related decrease in mobility of the participants. In addition, the sit-to-stand score measured using the Wii Balance Board was compared with that from a laboratory-graded force plate using the Bland Altman plot (bias = -3.1 [ms]-1, 95% limit of agreement: -11.0 to 3.9 [ms]-1). The sit-to-stand score has good inter-device reliability (intraclass correlation coefficient = 0.87). Furthermore, the test-retest reliability is substantial (intraclass correlation coefficient = 0.64). Thus, the proposed STS score will be useful to detect the early deterioration of motor performance. PMID- 29136032 TI - Virological response and resistance among HIV-infected children receiving long term antiretroviral therapy without virological monitoring in Uganda and Zimbabwe: Observational analyses within the randomised ARROW trial. AB - BACKGROUND: Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring. METHODS AND FINDINGS: In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART. All children had VL assayed retrospectively after a median of 4 years on ART; those with >1,000 copies/ml were genotyped. Three hundred and sixteen children had VL and genotypes assayed longitudinally (at least every 24 weeks). Overall, 67 (6%) switched to second-line ART and 54 (4%) died. In children randomised to WHO-recommended 2NRTI+NNRTI long-term ART, 308/378 (81%) monitored with CD4 counts versus 297/375 (79%) without had VL <1,000 copies/ml at 4 years (difference = +2.3% [95% CI -3.4% to +8.0%]; P = 0.43), with no evidence of differences in intermediate/high-level resistance to 11 drugs. Among children with longitudinal VLs, only 5% of child-time post-week 24 was spent with persistent low-level viraemia (80-5,000 copies/ml) and 10% with VL rebound >=5,000 copies/ml. No child resuppressed <80 copies/ml after confirmed VL rebound >=5,000 copies/ml. A median of 1.0 (IQR 0.0,1.5) additional NRTI mutation accumulated over 2 years' rebound. Nineteen out of 48 (40%) VLs 1,000 5,000 copies/ml were immediately followed by resuppression <1,000 copies/ml, but only 17/155 (11%) VLs >=5,000 copies/ml resuppressed (P < 0.0001). Main study limitations are that analyses were exploratory and treatment initiation used 2006 criteria, without pre-ART genotypes. CONCLUSIONS: In this study, children receiving first-line ART in sub-Saharan Africa without real-time VL monitoring had good virological and resistance outcomes over 4 years, regardless of CD4 monitoring strategy. Many children with detectable low-level viraemia spontaneously resuppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound >=5,000 copies/ml were much less likely to resuppress, but NRTI resistance increased only slowly. These results are relevant to the increasing numbers of HIV-infected children receiving first-line ART in sub-Saharan Africa with limited access to virological monitoring. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN24791884. PMID- 29136033 TI - Sun exposure in pigs increases the vitamin D nutritional quality of pork. AB - There is a high prevalence of vitamin D insufficiency and deficiency worldwide likely because of both limited sun-exposure and inadequate dietary intake. Meat, including pork, is not typically considered a dietary source of vitamin D, possibly because of management practices that raise pigs in confinement. This experiment determined the vitamin D content of loin and subcutaneous adipose tissue in sun-exposed finisher pigs. Two separate groups of pigs were used. The first group (28 white Landrace-Duroc) was assigned at random to either sunlight exposure (SUN) in spring and summer or confinement per standard practice (Control). The second (24 Yorkshire-Duroc-Landrace) underwent the same exposure protocol but was exposed in summer and fall or assigned to control (Control). A subsample of five SUN and four Control pigs, matched for weight and body condition score, was selected for slaughter from each group. Pigs (n = 10 SUN, n = 8 Control) had blood drawn for analysis of 25(OH)D3 concentration before/after sun exposure or control, and tissue samples were taken at slaughter for analysis of tissue vitamin D3 and 25(OH)D3 concentration. Three random samples from a single loin chop and surrounding adipose were collected and analyzed. Serum concentrations of 25(OH)D3 did not differ (P>=0.376) between treatments prior to sun exposure in either group, but was increased (time*treatment interaction, P<0.001) with SUN exposure. Total vitamin D content (D3 plus 25(OH)D3) of loin tissue was increased (P < 0.001) with sun exposure and averaged 0.997+/-0.094 MUg/100g and 0.348+/-0.027 MUg/100g for sun and control pigs, respectively. While exposure to sunlight increased (P = 0.003) tissue content of 25(OH) D in subcutaneous adipose tissue, vitamin D3 content was similar between treatments (P = 0.56). Sunlight exposure in pigs increased the vitamin D content of loin, and may provide an additional source of dietary vitamin D. PMID- 29136034 TI - A fast stochastic framework for automatic MR brain images segmentation. AB - This paper introduces a new framework for the segmentation of different brain structures (white matter, gray matter, and cerebrospinal fluid) from 3D MR brain images at different life stages. The proposed segmentation framework is based on a shape prior built using a subset of co-aligned training images that is adapted during the segmentation process based on first- and second-order visual appearance characteristics of MR images. These characteristics are described using voxel-wise image intensities and their spatial interaction features. To more accurately model the empirical grey level distribution of the brain signals, we use a linear combination of discrete Gaussians (LCDG) model having positive and negative components. To accurately account for the large inhomogeneity in infant MRIs, a higher-order Markov-Gibbs Random Field (MGRF) spatial interaction model that integrates third- and fourth- order families with a traditional second order model is proposed. The proposed approach was tested and evaluated on 102 3D MR brain scans using three metrics: the Dice coefficient, the 95-percentile modified Hausdorff distance, and the absolute brain volume difference. Experimental results show better segmentation of MR brain images compared to current open source segmentation tools. PMID- 29136036 TI - Correction: Occurrence of Leishmania infantum in the central nervous system of naturally infected dogs: Parasite load, viability, co-infections and histological alterations. AB - [This corrects the article DOI: 10.1371/journal.pone.0175588.]. PMID- 29136035 TI - Comparative efficacy and safety of antibiotics used to treat acute bacterial skin and skin structure infections: Results of a network meta-analysis. AB - OBJECTIVE: This NMA compared the efficacy and safety between IV antibiotics that are used in the current standard of care for managing adult patients (>=18 years of age) with ABSSSI. METHODS: Comparators were chosen on the basis that both direct and indirect comparisons between the interventions of interest could be performed. Outcomes of the analysis were selected on the basis that they are frequently measured and reported in trials involving ABSSSI patients, and only published randomised control trials of any size and duration and with any blinding status were eligible for inclusion in the analysis. The NMA was performed using both a fixed-effect and random-effect model. Efficacy-related endpoints were (1) clinical treatment success and (2) microbiological success at TOC visit. Safety-related endpoints were (1) number of discontinuations due to AEs/SAEs, (2) patients experiencing AEs, (3) patients experiencing SAEs and (4) all-cause mortality. RESULTS: Study interventions included daptomycin, dalbavancin, linezolid and tigecycline. Vancomycin was the comparator in all studies, except in two where it was linezolid and teicoplanin. The NMA showed that irrespective of patient subgroup, the likelihood of clinical and microbiological success with dalbavancin was statistically similar to the comparators studied. No statistically significant differences were observed between dalbavancin and any of the comparators in the discontinuation rate due to AEs/SAEs. In contrast, dalbavancin was associated with a significantly lower likelihood of experiencing an AE than linezolid, a significantly lower likelihood of experiencing a SAE than vancomycin and daptomycin, and a significantly lower risk of all-cause mortality than vancomycin, linezolid and tigecycline. CONCLUSION: Dalbavancin affords a promising, new alternative IV antimicrobial agent which is as effective as traditional therapies, but with the added benefit of enabling clinicians to treat patients with ABSSSI in different organisational settings. Notwithstanding, any introduction of an effective treatment with a differential mode of administration into healthcare systems must be followed by a change in clinical practice and patient management in order to fully achieve desirable economic outcomes. PMID- 29136038 TI - Midterm outcomes of single port thoracoscopic surgery for major pulmonary resection. AB - INTRODUCTION: Single-port thoracoscopic surgery has widened the current minimally invasive surgical techniques toward more less invasive procedures in terms of reducing the number of incisions. However, the current status of oncologic outcome with this technique is not well known for lung cancer surgery. The purpose of this study is to evaluate the oncologic outcomes in early stage lung cancer for impact of the survival outcomes with our experience of conversion to a single-port approach from the conventional three-port approach. MATERIALS AND METHODS: Retrospective data of patients who underwent thoracoscopic major lung resection for non-small cell lung cancer between January 2006 and June 2015 were analyzed. Patients' characteristics, perioperative outcomes, pathologic result, and postoperative follow-up data of thoracoscopic surgery were reviewed and surgical outcomes were compared between conventional three-port (n = 168), two port (n = 68), and single-port thoracoscopic surgery (n = 203). RESULTS: Of the 203 single-port thoracoscopic surgeries, we performed 167 single-port thoracoscopic lobectomy and mediastinal lymph node dissections. During the learning period of each thoracoscopic approach, the mean operation time for single-port thoracoscopic surgery (189+/-62 min) was not significantly different from those of two-port (175+/-46 min) and three-port (195+/-75 min) thoracoscopic lobectomy (p = 0.165). Perioperative outcomes including drain indwelling time (p <0.001), complication (p = 0.185) and conversion event (p = 0.911) were not worsened during learning period with two-port. Midterm survival (p = 0.753) and recurrence free survival (p = 0.656) of single port thoracoscopic lobectomy showed acceptable results compared with two- and three-port approach. CONCLUSIONS: Single-port thoracoscopic surgery is safe and a feasible option for major lung resection in lung malignancy and this approach following experiences of two-port approach may yield similar oncologic results to those of conventional multi-port approach during thoracoscopic lobectomy. PMID- 29136037 TI - Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV uninfected adults: Results of a phase 1 randomized trial. AB - BACKGROUND: VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. METHODS AND FINDINGS: HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18 50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 MUg/ml (95% CI: 1,033, 1,340) and 420 MUg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 MUg/ml (95% CI: 10, 27) and 6 MUg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 MUg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits. CONCLUSIONS: VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials. TRIAL REGISTRATION: Clinical Trials Registration: NCT02165267. PMID- 29136039 TI - Exposure time, running and skill-related performance in international u20 rugby union players during an intensified tournament. AB - PURPOSE: This study investigated exposure time, running and skill-related performance in two international u20 rugby union teams during an intensified tournament: the 2015 Junior World Rugby Championship. METHOD: Both teams played 5 matches in 19 days. Analyses were conducted using global positioning system (GPS) tracking (Viper 2TM, Statsports Technologies Ltd) and event coding (Opta Pro(r)). RESULTS: Of the 62 players monitored, 36 (57.1%) participated in 4 matches and 23 (36.5%) in all 5 matches while player availability for selection was 88%. Analyses of team running output (all players completing >60-min play) showed that the total and peak 5-minute high metabolic load distances covered were likely-to very likely moderately higher in the final match compared to matches 1 and 2 in back and forward players. In individual players with the highest match-play exposure (participation in >75% of total competition playing time and >75-min in each of the final 3 matches), comparisons of performance in matches 4 and 5 versus match 3 (three most important matches) reported moderate-to-large decreases in total and high metabolic load distance in backs while similar magnitude reductions occurred in high-speed distance in forwards. In contrast, skill-related performance was unchanged, albeit with trivial and unclear changes, while there were no alterations in either total or high-speed running distance covered at the end of matches. CONCLUSIONS: These findings suggest that despite high availability for selection, players were not over-exposed to match-play during an intensified u20 international tournament. They also imply that the teams coped with the running and skill-related demands. Similarly, individual players with the highest exposure to match-play were also able to maintain skill related performance and end-match running output (despite an overall reduction in the latter). These results support the need for player rotation and monitoring of performance, recovery and intervention strategies during intensified tournaments. PMID- 29136040 TI - Morphological adaptations in breast cancer cells as a function of prolonged passaging on compliant substrates. AB - Standard tissue culture practices involve propagating cells on tissue culture polystyrene (TCP) dishes, which are flat, 2-dimensional (2D) and orders of magnitude stiffer than most tissues in the body. Such simplified conditions lead to phenotypical cell changes and altered cell behaviors. Hence, much research has been focused on developing novel biomaterials and culture conditions that more closely emulate in vivo cell microenvironments. In particular, biomaterial stiffness has emerged as a key property that greatly affects cell behaviors such as adhesion, morphology, proliferation and motility among others. Here we ask whether cells that have been conditioned to TCP, would still show significant dependence on substrate stiffness if they are first pre-adapted to a more physiologically relevant environment. We used two commonly utilized breast cancer cell lines, namely MDA-MB-231 and MCF-7, and examined the effect of prolonged cell culturing on polyacrylamide substrates of varying compliance. We followed changes in cell adhesion, proliferation, shape factor, spreading area and spreading rate. After pre-adaptation, we noted diminished differences in cell behaviors when comparing between soft (1 kPa) and stiff (103 kPa) gels as well as rigid TCP control. Prolonged culturing of cells on complaint substrates further influenced responses of pre-adapted cells when transferred back to TCP. Our results have implications for the study of stiffness-dependent cell behaviors and indicate that cell pre-adaptation to the substrate needs consideration. PMID- 29136042 TI - Effects of small-scale clustering of flowers on pollinator foraging behaviour and flower visitation rate. AB - Plants often grow in clusters of various sizes and have a variable number of flowers per inflorescence. This small-scale spatial clustering affects insect foraging strategies and plant reproductive success. In our study, we aimed to determine how visitation rate and foraging behaviour of pollinators depend on the number of flowers per plant and on the size of clusters of multiple plants using Dracocephalum moldavica (Lamiaceae) as a target species. We measured flower visitation rate by observations of insects visiting single plants and clusters of plants with different numbers of flowers. Detailed data on foraging behaviour within clusters of different sizes were gathered for honeybees, Apis mellifera, the most abundant visitor of Dracocephalum in the experiments. We found that the total number of flower visitors increased with the increasing number of flowers on individual plants and in larger clusters, but less then proportionally. Although individual honeybees visited more flowers in larger clusters, they visited a smaller proportion of flowers, as has been previously observed. Consequently, visitation rate per flower and unit time peaked in clusters with an intermediate number of flowers. These patterns do not conform to expectations based on optimal foraging theory and the ideal free distribution model. We attribute this discrepancy to incomplete information about the distribution of resources. Detailed observations and video recordings of individual honeybees also showed that the number of flowers had no effect on handling time of flowers by honeybees. We evaluated the implications of these patterns for insect foraging biology and plant reproduction. PMID- 29136041 TI - Profiling analysis of circulating microRNA in peripheral blood of patients with class IV lupus nephritis. AB - Renal involvement in Systemic Lupus Erythematous (SLE) patients is one of the leading causes of morbidity and a significant contributor to mortality. It's estimated that nearly 50% of SLE individuals develop kidney disease in the first year of the diagnosis. Class IV lupus nephritis (LN-IV) is the class of lupus nephritis most common in Colombian patients with SLE. Altered miRNAs expression levels have been reported in human autoimmune diseases including lupus. Variations in the expression pattern of peripheral blood circulating miRNAs specific for this class of lupus nephritis could be correlated with the pathophysiological status of this group of individuals. The aim of this study was to evaluate the relative abundance of circulating microRNAs in peripheral blood from Colombian patients with LN-IV. Circulating miRNAs in plasma of patients with diagnosis of LN-IV were compared with individuals without renal involvement (LNN group) and healthy individuals (CTL group). Total RNA was extracted from 10 ml of venous blood and subsequently sequenced using Illumina. The sequences were processed and these were analyzed using miRBase and Ensembl databases. Differential gene expression analysis was carried out with edgeR and functional analysis were done with DIANA-miRPath. Analysis was carried out using as variables of selection fold change (>=2 o <=-2) and false discovery rate (0.05). We identified 24 circulating microRNAs with differential abundance between LN-IV and CTL groups, fourteen of these microRNAs are described for the first time to lupus nephritis (hsa-miR-589-3p, hsa-miR-1260b, hsa-miR-4511, hsa-miR-485-5p, hsa miR-584-5p, hsa-miR-543, hsa-miR-153-3p, hsa-miR-6087, hsa-miR-3942-5p, hsa-miR 7977, hsa-miR-323b-3p, hsa-miR-4732-3p and hsa-miR-6741-3p). These changes in the abundance of miRNAs could be interpreted as alterations in the miRNAs-mRNA regulatory network in the pathogenesis of LN, preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of LN. PMID- 29136043 TI - [First woman lecturer in prosthetic dentistry: Miss J.G. Schuiringa (1887-1975)]. AB - As the first woman lecturer in prosthetic dentistry at the Dental Institute of the University of Utrecht, Jans Gretha Schuiringa (1887-1975) had to win a position in a rapidly developing field. She undeniably made a significant contribution to the development of dental education and more specifically to the field of dental surgical prosthetics. Her dedication to her patients led her to strive continuously for better methods of treatment. From time to time, however, her militant character provoked resistance from her colleagues, curators of the medical faculty and students. After dentistry had obtained the ius promovendi in 1947, she was passed over for a professorship and felt, as a result, that she was not properly acknowledged. Archival research shows that her personality played a major role in her rejection. PMID- 29136044 TI - [Women and work, with a specific focus on doctors and dentists]. AB - The differences between men and women in their participation in the labour force and education are diminishing: in 2015, 71% of all women between the ages of 20 and 65 had a paid job (in comparison with 82% of men) and the Emancipation monitor 2016 reveals that women more often receive higher education than men. In the study of medicine, this expresses itself in the fact that 68% of new students in 2015 were women. As a consequence the number of women doctors is increasing. The numbers for 2013 show that 65% of active dentists are men and 35% women. They, too, indicate an obvious increase of women. Statements that medicine, including dentistry, is feminising are incorrect because there are still more male doctors than female. The male-female ratio among medical specialists is 60:40 at the moment. It can be concluded that the medical and dental professions serve a well-educated and diverse public. It is precisely for this reason, that the medical and dental professions should offer positions to men and women and to people (m/f) with a Dutch and an immigrant background. PMID- 29136045 TI - [Dental care by women: how does that work in (the) practice?] AB - With a growing number of female dentists, changes in the collaboration between dentists and dental hygienists are possible. To assess the possible consequences of these changes in dentistry for cooperation with dental hygienists, two important aspects are discussed: differences in vision with respect to treatment and the profession and differences in communication styles. Female dentists seem to be more prevention-orientated and people-orientated and are therefore more like the group of female dental hygienists. The communication style of female dentists is also consistent with the style of their female colleague hygienists; wishes and expectations are more aligned with each other, which makes optimal cooperation more likely. This focus on prevention and the consistency in communication styles offer opportunities for inter-professional collaboration between dentists and dental hygienists. Does this actually mean better collaboration, however, and what about the cooperation between male dentists and female dental hygienists? PMID- 29136046 TI - [A woman at the chair is nothing out of the ordinary. Dental practice by female dentists in the Netherlands.] AB - Women currently make up 40% of the dentist population in the Netherlands. On the basis of enrolment in educational programmes their share can be expected to grow to more than half. The literature shows gender differences in preferences regarding work setting and duration of the working week. Men and women also differ from each other with respect to the way dental care is provided. The presented data demonstrate an increase in the number of women working in dentistry and research data have confirmed the presumed differences between male and female dentists. Women are less likely to be the owner of a practice, women who do own a practice are more likely to collaborate with colleagues and have a shorter working week. With regard to providing dental care, women seem to be slightly more orientated to the individual patient and are more likely to pay attention to the patient's general health. Theories about work values provide explanations for these gender differences. Women's preference for collaboration accords with the general development in dental care to work in teams. PMID- 29136047 TI - [Feminisation: does it make a difference?] AB - In a digital orientating survey of gender differences among 156 male and 98 female dentists in the Netherlands, many similarities were found between the two groups. Men and women generally report that they are in good health, experience comparable levels of burnout (about 10%) and are equally satisfied with their choice of profession. To a large extent, they perceive the same aspects of their work as attractive, with 'patient care' as by far the most attractive feature. According to the dentists as well as 122 assistants and dental hygienists (who were also questioned in this survey), they have comparable leadership styles, while the dentists, on average, rate their leadership behaviour more highly than the assistants and dental hygienists do. In addition, a limited number of significant gender differences were found in the sample. Women feel less competent in conducting complex interventions than men, and they find surgical interventions and complex restorative treatments less attractive aspects of their work. Women consult colleagues more often and their preference for working in a team is greater. PMID- 29136048 TI - [Musculoskeletal disorders among dentists and dental students in the Netherlands]. AB - In this study, the prevalence of musculoskeletal symptoms among dentists and dental students in the Netherlands was inventoried by means of 2 corresponding web surveys. 196 (25% response) dentists and 359 (40% response) dental students participated. 80% of the dentists and 95% of the dental students reported to have suffered from pain in muscles and joints in the last 12 months. In particular, they mentioned complaints of the neck, the shoulders and the lower back. Dental students also frequently reported complaints of the upper back. Many physical complaints were more common among females than male students. In contrast, no gender difference was observed for dentists, but regarding this group stress proved to be an important risk factor for developing musculoskeletal complaints. Given the negative impact on the profession, further research into the prevention of musculoskeletal disorders is urgently needed, in particular about the efficiency of (postgraduate) education and occupational briefing in that domain. PMID- 29136049 TI - [A PhD completed. Oral health care and oral health-related quality of life of frail and care-dependent older people]. AB - When older people become frail, they often give up making dental visits, while their oral health care and oral health deteriorate. Open interviews and questionnaires were used to explore why frail older people change their oral health care behaviour and which (frailty-related) factors contribute to this change. These are mainly motivation-related factors. There seems to be a turning point where frail older people discontinue their oral health care routines and stop caring whether or not they loose teeth, because the perceived efforts no longer outweigh the perceived benefits of making dental visits and upkeep of oral hygiene. The use of standard questionnaires such as the validated Geriatric Oral Health Assessment Index-NL to measure oral health-related quality of life is limited, because they do not provide personal context required to interpret the outcomes. From a pre-frail stage (oral) care providers should monitor specific factors that might negatively affect oral health and oral health care behaviour, like chronic pain or diminished mobility, dexterity, cognition, will to live, energy and social support. PMID- 29136050 TI - Granulomatous pigmented purpuric dermatosis. AB - Granulomatous pigmented purpuric dermatosis (GPPD) is a rare histologic variant of pigmented purpuric dermatosis (PPD). It includes classic histology changes of PPD with superimposed granulomas. This variant is thought to be associated with hyperlipidemia and is found predominantly in individuals in the Far East; however, a review of the literature that included 26 documented cases of GPPD revealed these associations might be becoming less clear. We report a case of GPPD in an elderly white man who had an eruption involving the majority of the lower legs. PMID- 29136052 TI - Major changes in the American Board of Dermatology's certification examination. PMID- 29136051 TI - Melanotrichoblastoma: a rare pigmented variant of trichoblastoma. AB - Trichoblastomas are rare cutaneous tumors arising from the hair bulb and mesenchyme. Although they are benign, they can pose a diagnostic dilemma for the clinician and pathologist because they clinically and histologically mimic more common lesions such as basal cell carcinomas (BCCs) and trichoepitheliomas. It is important for the clinician and pathologist to be aware of such tumors and their variants. We present a case of a melanotrichoblastoma, an exceedingly rare variant of trichoblastoma, as well as review the current literature on the clinical presentation and histologic differentiation of these unique tumors with their more commonly seen mimics. PMID- 29136053 TI - Cyanosis of the foot. PMID- 29136054 TI - Verrucoid lesion on the eyelid. PMID- 29136055 TI - Skin cancer in military pilots: a special population with special risk factors. AB - Military pilots may be at greater risk for skin cancer, particularly melanoma. Military-specific studies are limited, but skin cancer rates in civilian pilots and aircrews have previously been examined. Risk factors for all pilots may include exposure to UV radiation (UVR) at higher altitudes, cosmic radiation, and electromagnetic energy from cockpit instruments, as well as altered sleep-wake cycles. The study of aviation-specific risk factors for skin cancer is relevant to all pilots and dermatologists who care for them. PMID- 29136056 TI - Ideals of facial beauty. AB - Facial aesthetic procedures are central to cosmetic dermatology. Success depends not only on improving individual structures but also on establishing facial harmony. Several canons of aesthetic dimensions have been described, and these concepts can provide a useful basis for procedural planning. Here, we review aesthetic facial measurements and proportions as well as the variations that may occur in different ethnic groups and the changes that develop with age. PMID- 29136057 TI - Assessing the effectiveness of knowledge-based interventions in increasing skin cancer awareness, knowledge, and protective behaviors in skin of color populations. AB - Skin of color (SOC) populations (ie, blacks, Hispanics, Asians) are at a notably higher risk for mortality from skin cancers such as melanoma than white individuals. In this article, we seek to answer the following question: Do knowledge-based interventions increase skin cancer awareness among SOC patients? Following an extensive literature search, a total of 4 articles were analyzed and discussed in this review. PMID- 29136058 TI - Do infants fed rice and rice products have an increased risk for skin cancer? PMID- 29136059 TI - Concurrent Sturge-Weber syndrome, facial infantile hemangioma, and cutis marmorata telangiectatica congenita. AB - We present a unique case of 3 vascular malformations-Sturge-Weber syndrome (SWS), facial infantile hemangioma (IH), and cutis marmorata telangiectatica congenita (CMTC)-with dermatologic manifestations presenting in the same patient. This case highlights the possibility of occurrence of multiple vascular malformations in the same patient; the potential role of epigenetic factors; and the importance of a multidisciplinary approach to diagnose, treat, and manage this complicated interplay of vascular abnormalities to achieve the best outcome. PMID- 29136060 TI - Clinical trial designs for topical antifungal treatments of onychomycosis and implications on clinical practice. AB - There currently are 3 topical agents approved by the US Food and Drug Administration (FDA) to treat onychomycosis: tavaborole, efinaconazole, and ciclopirox. The phase 3 clinical trial designs for these treatments and their notable differences make it difficult for clinicians to interpret the data into clinical practice. For example, the primary end point predominantly used to assess efficacy in all the trials is complete cure, defined as no involvement of the nail plus mycologic cure; also, a notable number of patients fail to achieve a complete cure despite clear improvement in the nail. Despite close similarities in the end points and overall design of the clinical trials used for these agents, differences in design are notable, including the age range of participants, the range of mycotic nail involvement, the presence/absence of tinea pedis, and the nail trimming/debridement protocols used. The differences in clinical trial designs for the 3 FDA-approved topical agents and the lack of head to-head studies makes efficacy interpretation and comparison inappropriate. This article reviews the phase 3 clinical trials that led to FDA approval of these agents, focusing on their similarities and differences. PMID- 29136061 TI - Painless telangiectatic lesion on the wrist. PMID- 29136062 TI - Irregular erythematous patch on the face of an infant. PMID- 29136063 TI - Levofloxacin-induced purpura annularis telangiectodes of Majocchi. PMID- 29136064 TI - Chromoblastomycosis infection from a house plant. PMID- 29136065 TI - Sunburn purpura. PMID- 29136066 TI - Unsuspected lymphomatoid granulomatosis in a patient with antisynthetase syndrome. AB - Clinical diagnosis of lymphomatoid granulomatosis (LYG) often is difficult, especially in patients with multiple comorbidities. We present a 60-year-old woman with worsening fatigue, night sweats, unintentional weight loss, and dyspnea of 2 weeks' duration. Her medical history was remarkable for recent radiation therapy for recurrent breast cancer and antisynthetase syndrome complicated by interstitial lung disease and controlled with azathioprine. Computed tomography showed ground-glass opacities and nodular infiltrates in all lung lobes, raising concern for radiation pneumonitis and drug toxicity. Skin examination revealed erythematous and hemorrhagic papules, macules, and blisters on the lower leg. A diagnosis of LYG was made on a skin biopsy showing large angiocentric Epstein-Barr virus (EBV)-positive B cells. The patient soon progressed to develop nodal large B-cell lymphoma and died 6 weeks later. This rare report of LYG in a patient with antisynthetase syndrome highlights the diagnostic difficulty and aggressive course of LYG as well as the important role of skin biopsy in establishing the diagnosis. PMID- 29136067 TI - Vesiculobullous and pustular diseases in newborns. AB - This article exhibits the most common presentations of vesiculobullous diseases in newborns and reviews the clinical characteristics unique to each diagnosis. Furthermore, a schematic for the workup of neonatal vesicular disorders is presented to empower dermatology residents to execute accurate diagnoses and maximize patient care. PMID- 29136069 TI - Ionization and separation as a strategy for significantly enhancing the thermal stability of an instable system: a case for hydroxylamine-based salts relative to that for pure hydroxylamine. AB - Energetic ionic salts (EISs) are attracting extensive attention because of their ready preparation and some excellent properties and performances that are comparable to those of common explosives with neutral molecules. Hydroxylamine (HA) is protonated or ionized as H-HA+ and preferred to be introduced into EISs to form HA-based EISs with almost all kinds of anions since these EISs possess higher packing densities and thus more excellent detonation performances than others with the same anions. Moreover, relative to that of pure HA, the thermal stability of HA-based EISs is significantly enhanced. This significantly enhanced thermal stability can extend the application of HA via deprotonation of H-HA+ back to HA; however, the mechanism for stabilization of HA by salification remains unclear. Herein, we employed thermodynamic and kinetic calculations and molecular dynamics simulations to reveal the thermal stability mechanisms of many currently synthesized HA-based EISs and some previously reported EISs with inorganic anions as well as those of pure HA and its aqueous solution. As a result, we have found that the enhanced stability of HA-based EISs is mainly due to the ionization and separation of HA molecules themselves. That is, H-HA+, as an ionized product, is more molecularly stable than HA, with significantly strengthened covalent bonds. The separation of H-HA+ ions or HA molecules makes decomposition more difficult as decomposition initiation varies from bimolecular to unimolecular reactions of HA, with a significant increase in the energy barrier. We have, therefore, proposed a strategy for the stabilization of unstable systems, such as neutral N-rich energetic compounds, by ionization and separation to strengthen these systems and change the decomposition mechanism by increasing the energy barriers of trigger steps such that these barriers become more difficult to overcome, respectively. PMID- 29136068 TI - Electrokinetically operated microfluidic devices for integrated immunoaffinity monolith extraction and electrophoretic separation of preterm birth biomarkers. AB - Biomarkers are often present in complex biological fluids like blood, requiring multiple, slow sample preparation steps that pose limitations in simplifying analysis. Here we report integrated immunoaffinity extraction and separation devices for analysis of preterm birth biomarkers in a human blood serum matrix. A reactive polymer monolith was used for immobilization of antibodies for selective extraction of target preterm birth biomarkers. Microfluidic immunoaffinity extraction protocols were optimized and then integrated with microchip electrophoresis for separation. Using these integrated devices, a ~30 min analysis was carried out on low nanomolar concentrations of two preterm birth biomarkers spiked in a human serum matrix. This work is a promising step towards the development of an automated, integrated platform for determination of preterm birth risk. PMID- 29136070 TI - Atomistic potential for graphene and other sp2 carbon systems. AB - We introduce a torsional force field for sp2 carbon to augment an in-plane atomistic potential of a previous work [G. Kalosakas et al., J. Appl. Phys., 2013, 113, 134307] so that it is applicable to out-of-plane deformations of graphene and related carbon materials. The introduced force field is fit to reproduce density-functional-theory calculation data of appropriately chosen structures. The aim is to create a force field that is as simple as possible so it can be efficient for large scale atomistic simulations of various sp2 carbon structures without significant loss of accuracy. We show that the complete proposed potential reproduces characteristic properties of fullerenes and carbon nanotubes. In addition, it reproduces very accurately the out-of-plane acoustic and optical modes of graphene's phonon dispersion as well as all phonons with frequencies up to 1000 cm-1. PMID- 29136071 TI - Gold nanoclusters with a wide range of fluorescence characteristics generated in situ in polymer thin films: potential gas sensing application. AB - Fabrication of gold nanoclusters (GNCs) with tunable fluorescence characteristics inside polymer thin films is attractive from the device application perspective. In this study, GNCs are generated in situ in poly(methyl methacrylate) films exploiting their weak reducing capability with no additional reducing agent, and by short and mild thermal annealing; the chemistry involved is probed through control experiments. The nanoclusters formed with ~0.5 weight percent of gold are very stable and show appreciable fluorescence emission with a small Stokes shift (~40 nm); interestingly, blending polystyrene enhances the fluorescence. The Au10 clusters formed in situ are characterized by using mass spectrometry, microscopy and computational modeling. Composite thin films fabricated with a gold content of ~9 weight percent showed an unusually distinct absorption peak and enhanced fluorescence emission. Gradual coalescence of the nanoclusters in these films could be arrested by incorporating thiourea; the mechanistic aspects of the thiourea interaction are probed. The resulting films showed strong, stable and visible red emission, with very large Stokes shift (~320 nm) and quantum yield (~30%), attributable to ligand effects and nanocluster aggregation in the film. The study presents a novel and facile route to the in situ generation of GNCs in polymer thin films, exhibiting fluorescence emission with variable energy, intensity and Stokes shift. Preliminary experiments show that Au10 cluster embedded thin films can be used for the detection of POCl3, an important precursor for nerve agents. PMID- 29136072 TI - Structural basis for the selective incorporation of an artificial nucleotide opposite a DNA adduct by a DNA polymerase. AB - The possibility to sequence cytotoxic O6-alkylG DNA adducts would greatly benefit research. Recently we reported a benzimidazole-derived nucleotide that is selectively incorporated opposite the damaged site by a mutated DNA polymerase. Here we provide the structural basis for this reaction which may spur future developments in DNA damage sequencing. PMID- 29136073 TI - Engineering transition metal phosphide nanomaterials as highly active electrocatalysts for water splitting. AB - Transition metal phosphide (TMP) nanomaterials are recently considered to be versatile electrocatalysts with excellent activity and stability towards water splitting. This Frontier article will highlight recent advances in engineering the composition and structure of TMPs for higher electrochemical performances. PMID- 29136074 TI - Crystal structure and chemical bonding in the mixed anion compound BaSF. AB - BaSF was synthesised by a solid state reaction at high temperature and its crystal structure was determined thanks to X-ray diffraction on a single crystal. This transparent yellow fluorochalcogenide has an intergrowth structure built from the stacking of fluorite type layers and sulfur layers. In BaSF sulfur atoms form dimers with interatomic distances as short as 2.1074(10) A. DFT calculations confirm that this compound is a band insulator with the Fermi level lying in between the antibonding pi* and sigma* molecular orbitals of the sulfur dimers. Reflectance measurements show that the optical band gap of BaSF is about 2.7 eV in good agreement with the value found from DFT calculations. PMID- 29136075 TI - Coordinatively- and electronically-unsaturated square planar cobalt(iii) complexes of a pyridine dianionic pincer ligand. AB - A series of low-valent Co(iii) square planar complexes supported by a dianionic pincer ligand bis(arylamido)pyridine ([NNN]2-) was synthesized, including the first structurally characterized square planar hydroxide complex ([NNN]Co(OH), 4) of a 3d transition metal in the +3 oxidation state. The magnetic properties of the Co(iii) complexes were highly dependent on the charge of the complex and on the coordination environment of the metal. The diamagnetic cationic complex {[NNN]Co(py)}BF4 (2) can be converted to neutral paramagnetic complexes [NNN]Co(OR) (R = Ph 3a, iPr 3b, and H 4) by a simple substitution of the ancillary pyridine ligand in 2. The double bond character between the metal and the anilido nitrogen was evident from short Co-N2,3 bond lengths in the solid state structures, and further supported by density functional theory calculations. Complex 2 showed well-behaved redox processes at -0.93 and +0.70 V assigned to CoII/III and [NNN]2-/1- redox couples, respectively. In contrast, both complexes 3a and 4 showed some irreversibility in redox processes on either cobalt or ligands. PMID- 29136076 TI - Enhancing the photostability of poly(phenylene ethynylene) for single particle studies. AB - Single molecule fluorescence (SMF) studies on conjugated polymers yield enhanced information on exciton dynamics and on the interplay between polymer conformation/morphology and photophysical behavior. SMF studies, however, demand good signal stability, excellent photostability, and high photon yields (a measure of both photostability and brightness) and thus the development of strategies to help conjugated polymers (CPs) meet these requirements is a topic of great interest. Here, we evaluate the effect of a number of triplet quencher additives on the photostability of a 49-mer long poly(phenylene-ethynylene) conjugated polymer bearing carboxylate side groups (PPE-CO2-49) that is deposited onto 100 nm diameter SiO2 nanoparticles (NPs). The additives tested include ascorbic acid (AA), beta-mercaptoethanol (BME), Ni2+, trolox (TX), and a trolox/trolox quinone mixture (TX/TQ), used either with or without an enzymatic oxygen scavenging system (glucose oxidase/catalase, GODCAT). Total internal reflection fluorescence microscopy (TIRFM) studies enabled the determination of the effect of the additives on the rates of photobleaching, the initial intensity, and the total photon output for hundreds of conjugated polymer coated SiO2 nanoparticles monitored in parallel. Addition of the antioxidant/triplet quenchers AA and TX led to a 3-8-fold increase in the number of photons collected as well as an enhancement of the initial emission intensity, consistent with an increase in the duty cycle attributed to the quenching of triplet states. Removal of oxygen led to an impressive 10-15-fold increase in the photostability relative to buffer, implicating reactive oxygen species (ROS) as an important agent in the photodegradation of PPE-CO2-49. Combining AA and TX with GODCAT had a deleterious rather than an additive effect, suggesting that an oxidizing agent is in fact necessary to rescue the polymer from reactive intermediates formed via reaction with AA/TX. beta-Mercaptoethanol and Ni2+ were not found to have useful properties toward the photostabilization of PPE-CO2-49. The results of this study provide suitable imaging conditions to conduct single molecule imaging experiments on conjugated polyelectrolytes. PMID- 29136080 TI - Ultraviolet radiation-induced immunosuppression and its relevance for skin carcinogenesis. AB - The realisation that UV radiation (UVR) exposure could induce a suppressed immune environment for the initiation of carcinogenesis in the skin was first described more than 40 years ago. Van der Leun and his colleagues contributed to this area in the 1980s and 90s by experiments in mice involving UV wavelength and dose dependency in the formation of such tumours, in addition to illustrating both the local and systemic effect of the UVR on the immune system. Since these early days, many aspects of the complex pathways of UV-induced immunosuppression have been studied and are outlined in this review. Although most experimental work has involved mice, it is clear that UVR also causes reduced immune responses in humans. Evidence showing the importance of the immune system in determining the risk of human skin cancers is explained, and details of how UVR exposure can down regulate immunity in the formation and progression of such tumours reviewed. With increasing knowledge of these links and the mechanisms of UVR-induced immunosuppression, novel approaches to enhance immunity to skin tumour antigens in humans are becoming apparent which, hopefully, will reduce the burden of UVR induced skin cancers in the future. PMID- 29136081 TI - Imaging the dynamics of ion-molecule reactions. AB - A range of ion-molecule reactions have been studied in the last years using the crossed-beam ion imaging technique, from charge transfer and proton transfer to nucleophilic substitution and elimination. This review presents the detailed insights that have been gained with respect to the dynamics of both cation molecule and anion-molecule reactions studied with this method. In particular, we show the recent progress that has been achieved to understand the atomistic energetics and dynamics of ion-molecule reactions, such as the effects of vibrational quantum states, the formation of carbon-carbon bonds, and the competition between nucleophilic substitution and elimination. PMID- 29136083 TI - Differentiation of enantiomeric anions by NMR spectroscopy with chiral bisurea receptors. AB - Chiral anionic species are ubiquitous and play important roles in biological systems. Despite the recent advancements in synthetic anion receptors bearing urea functionalities, urea-based chiral solvating agents (CSAs) that can separate the NMR signals of racemic anions remain limited. Herein, three dibenzofuran based C2-symmetric chiral bisureas were synthesized from the reaction of (R,R) 4,6-bis(1-aminopropyl)dibenzo[b,d]furan with phenyl isocyanate, phenyl thioisocyanate, or tosyl isocyanate. The chiral anion recognition properties of these bisureas were examined by 1H NMR spectroscopy using dl-tetrabutylammonium mandelate (TBAM) as a model substrate. A clear baseline separation of the enantiomeric signals of the benzylic proton of TBAM was achieved upon mixing with 0.5 equivalents of bis(phenylurea). In contrast to previous urea-based chiral anion receptors that differentiate the enantiomers of chiral anions by forming 1 : 1 host-guest complexes, a high chiral recognition ability of chiral bis(phenylurea) was achieved owing to the generation of an equilibrium between free guests, 1 : 1 host-guest complexes, and 1 : 2 host-guest complexes. Chiral bis(phenylurea) was also successfully employed in the separation of the enantiomeric 1H NMR signals of various racemic anions. PMID- 29136084 TI - Predicting loop conformational ensembles. AB - Motivation: Protein function is often facilitated by the existence of multiple stable conformations. Structure prediction algorithms need to be able to model these different conformations accurately and produce an ensemble of structures that represent a target's conformational diversity rather than just a single state. Here, we investigate whether current loop prediction algorithms are capable of this. We use the algorithms to predict the structures of loops with multiple experimentally determined conformations, and the structures of loops with only one conformation, and assess their ability to generate and select decoys that are close to any, or all, of the observed structures. Results: We find that while loops with only one known conformation are predicted well, conformationally diverse loops are modelled poorly, and in most cases the predictions returned by the methods do not resemble any of the known conformers. Our results contradict the often-held assumption that multiple native conformations will be present in the decoy set, making the production of accurate conformational ensembles impossible, and hence indicating that current methodologies are not well suited to prediction of conformationally diverse, often functionally important protein regions. Contact: marks@stats.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29136085 TI - Transforming growth factor beta1 from endometriomas promotes fibrosis in surrounding ovarian tissues via Smad2/3 signaling. AB - To elucidate whether the endometriotic cells of endometriomas synthesize transforming growth factor beta1 (TGF-beta1) and understand how it affects surrounding ovarian tissue. We collected biopsies of the cystic walls from 42 endometriomas and 29 mature teratomas and compared mRNA and protein expression of fibrosis-related factors between the cystic walls. Then we detected TGFB1 mRNA synthesis in endometriomas, and tested TGF-beta1 fibrotic effect in vitro. Moreover, we verified the expression of Smad2/3 signaling components in the endometriotic cystic wall in order to understand whether TGF-beta1/Smad signaling is involved in fibrosis formation of the tissue surrounding endometriomas. The cystic walls from endometriomas demonstrated severe adhesion to ovarian tissue and obvious fibrosis compared with the mature teratomas, which was proven by the increased mRNA expression of fibrotic markers. Additionally, TGFB1 was obviously expressed in the endometriotic cystic wall, and total TGFB1 protein was significantly higher in the cystic walls of endometriomas than mature teratomas. Interestingly, TGFB1 mRNA was confirmed to be specifically synthesized in the endometriotic loci through fluorescence in situ hybridization. Cultured endometriomas derived stromal cells showed obvious fibrosis after exposed to TGF beta1. Furthermore, components of the TGF-beta1/Smad pathway such as Smad2, Smad3, Smad4, and their phosphorylated forms were also expressed in the same location as TGF-beta1, TGF-beta receptor1, and fibrotic factors expressed in the endometriotic cystic walls. In summary, endometriotic cells of endometriomas synthesize TGF-beta1 leading to fibrosis and adhesion to ovarian tissues, and TGF beta1/Smad signaling pathway is involved in this pathological process. PMID- 29136086 TI - Intraoperative oliguria predicts acute kidney injury after major abdominal surgery. AB - Background: The threshold of intraoperative urine output below which the risk of acute kidney injury (AKI) increases is unclear. The aim of this retrospective cohort study was to investigate the relationship between intraoperative urine output during major abdominal surgery and the development of postoperative AKI and to identify an optimal threshold for predicting the differential risk of AKI. Methods: Perioperative data were collected retrospectively on 3560 patients undergoing major abdominal surgery (liver, colorectal, gastric, pancreatic, or oesophageal resection) at Kyoto University Hospital. We evaluated the relationship between intraoperative urine output and the development of postoperative AKI as defined by recent guidelines. Logistic regression analysis was performed to adjust for patient and operative variables, and the minimum P value approach was used to determine the threshold of intraoperative urine output that independently altered the risk of AKI. Results: The overall incidence of AKI in the study population was 6.3%. Using the minimum P -value approach, a threshold of 0.3 ml kg -1 h -1 was identified, below which there was an increased risk of AKI (adjusted odds ratio, 2.65; 95% confidence interval, 1.77-3.97; P <0.001). The addition of oliguria <0.3 ml kg -1 h -1 to a model with conventional risk factors significantly improved risk stratification for AKI (net reclassification improvement, 0.159; 95% confidence interval, 0.049-0.270; P =0.005). Conclusions: Among patients undergoing major abdominal surgery, intraoperative oliguria <0.3 ml kg -1 h -1 was significantly associated with increased risk of postoperative AKI. PMID- 29136087 TI - The utility and perspectives of NGS-based methods in BSL-3 and BSL-4 laboratory - sequencing and analysis strategies. AB - Modern diagnostics is in general based on molecular biology methods. Nowadays sequencing-based methods, especially whole genome sequencing, are becoming increasingly important. Implementation of such methods into routine diagnostic of highly dangerous pathogens, like Bacillus anthracis, Francisella tularensis, Yersinia pestis, Ebola virus, MERS, Lassa virus etc. would be very helpful. The best diagnostic strategy would be the metagenomic sequencing directly from the clinical sample. Implementation of majority of currently available WGS platforms inside the BSL-3 or 4 laboratory is impractical because of the size of the equipment and time consuming wet lab part (e.g. library preparation). Nowadays there is a possibility to implement pocket size MinION - real time whole genome sequencer into BSL-3 and 4 laboratory for rapid and precise diagnostic purposes. PMID- 29136089 TI - Nutritional Status During Inpatient Alcohol Detoxification. AB - Aims: As low rates of thiamine are thought to be implicated in alcohol-related cognitive disorders, we wanted to assess patients with alcohol use disorders (AUD) during detoxification for their nutritional status and test if vitamins blood levels were associated with a surrogate of cognitive impairment. Methods: We performed a retrospective chart review of medical records of 94 consecutive patients hospitalized for alcohol detoxification in a specialized addiction medicine department. Nutritional status was assessed with Body Mass Index (BMI). Vitamins blood levels were available for 80 patients, but thiamine only for 52 patients. The Montreal Cognitive Assessment (MoCA) score was used to screen for cognitive impairment at Day 10 of entry and was available in 59 patients. A binary logistic regression was performed to identify factors associated with MoCA scores below the threshold (26 points). Results: The mean BMI was 23.28 +/- 3.78 kg/m2 and 8.79% of weighted patients qualified for malnutrition. The mean MoCA score was 22.75 +/- 4.88 points, and 66% of tested patients were below the threshold of suspected cognitive impairment. No low blood thiamine level was found. In multivariate analysis, BMI, but not vitamins blood rates, was significantly associated with a pathological MoCA screening test. Conclusion: Clinical examination is more sensitive than biomarkers to determine malnourished AUD patients who are at-risk for cognitive impairment. Malnourished patients with AUD should receive a full neuropsychological testing. Summary: This retrospective chart review study screened for cognitive disorders during alcohol inpatient detoxification with the MoCA test. Body mass index, but not vitamins blood rates, was associated with a pathological MoCA. Clinical examination is more sensitive than biomarkers to determine malnourished AUD patients who are at-risk for cognitive impairment. PMID- 29136090 TI - Perfect for a Gin and Tonic: How Context Drives Consumption Within a Modified Bogus Taste Test. AB - Aim: To implement a modified bogus taste test (BTT) and to examine the interactive effects of environmental and social contexts on levels of 'alcohol' consumption. Method: University students (Study 1 n = 38, Study 2 n = 80), recruited via opportunity sampling, completed a modified BTT under the pretence of assessing garnish preference for gin and tonic. All participants were tested alone or as part of an existing friendship group. In Study 1 participants were in a laboratory setting but were exposed to different contextual cues (alcohol related or neutral) by way of posters displayed on the walls. In Study 2, participants assessed the drinks in either a pub or a library setting. Results: In Study 1 participants tested in a group consumed significantly more when exposed to pub-related stimuli in contrast to those who were exposed to library related stimuli. Participants who were alone and exposed to library-related cues consumed significantly more than those in a group and exposed to these cues. In Study 2, as in Study 1, participants tested in a group condition consumed significantly more of what they believed to be alcohol when in the pub compared to those who were tested in the library. Higher group consumption was also evident in the library condition, although the size of this difference was not as large as in the pub testing condition. Conclusion: In the absence of any pharmacological effects of alcohol, social and environmental context have an interactive impact on shaping consumption. PMID- 29136088 TI - ABCD1 dysfunction alters white matter microvascular perfusion. AB - Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood-brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment. PMID- 29136091 TI - Clinical presentation and prognosis in MOG-antibody disease: a UK study. PMID- 29136092 TI - microRPM: a microRNA prediction model based only on plant small RNA sequencing data. AB - Motivation: MicroRNAs (miRNAs) are endogenous non-coding small RNAs (of about 22 nucleotides), which play an important role in the post-transcriptional regulation of gene expression via either mRNA cleavage or translation inhibition. Several machine learning-based approaches have been developed to identify novel miRNAs from next generation sequencing (NGS) data. Typically, precursor/genomic sequences are required as references for most methods. However, the non availability of genomic sequences is often a limitation in miRNA discovery in non model plants. A systematic approach to determine novel miRNAs without reference sequences is thus necessary. Results: In this study, an effective method was developed to identify miRNAs from non-model plants based only on NGS datasets. The miRNA prediction model was trained with several duplex structure-related features of mature miRNAs and their passenger strands using a support vector machine algorithm. The accuracy of the independent test reached 96.61% and 93.04% for dicots (Arabidopsis) and monocots (rice), respectively. Furthermore, true small RNA sequencing data from orchids was tested in this study. Twenty-one predicted orchid miRNAs were selected and experimentally validated. Significantly, 18 of them were confirmed in the qRT-PCR experiment. This novel approach was also compiled as a user-friendly program called microRPM (miRNA Prediction Model). Availability and implementation: This resource is freely available at http://microRPM.itps.ncku.edu.tw. Contact: nslin@sinica.edu.tw or sarah321@mail.ncku.edu.tw. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29136093 TI - Overuse of preoperative laboratory coagulation testing and ABO blood typing: a French national study. AB - Background: Following publication of guidelines on routine preoperative tests, the French Society of Anaesthesiology and Intensive Care (SFAR), in association with French national public health insurance, conducted a survey to evaluate adherence to guidelines and the economic consequences. Methods: Using the French Hospital Discharge Database and National Health Insurance Information system, tests performed during the 30 days before surgery were analysed for two situations: (1) standard laboratory coagulation tests and ABO blood typing in children able to walk and scheduled for tonsillectomy/adenoidectomy; and (2) ABO blood typing in adults before laparoscopic cholecystectomy, thyroidectomy, lumbar discectomy or breast surgery. Guidelines do not recommend any preoperative tests in these settings. Results: Between 2013 and 2015, a coagulation test was performed in 49% of the 241 017 children who underwent tonsillectomy and 39% of the 133 790 children who underwent adenoidectomy. A similar pattern was observed for ABO blood typing although re-operation rates for bleeding on the first postoperative day were very low (0.12-0.31% for tonsillectomy and 0.01-0.02% for adenoidectomy). Between 2012 and 2015, ABO blood typing was performed in 32-45% of the 1 114 082 patients who underwent one of the four selected procedures. The transfusion rate was very low (0.02-0.31%). The mean cost for the four procedures over the 4 yr period was ?5 310 000 (sd ?325 000). Conclusions: Standard laboratory coagulation tests and ABO blood typing are still routinely prescribed before surgery and anaesthesia despite current guidelines. This over-prescription represents a high and unnecessary cost, and should therefore be addressed. PMID- 29136094 TI - Effects of multidomain lifestyle intervention, omega-3 supplementation or their combination on physical activity levels in older adults: secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) randomised controlled trial. AB - Background/objectives: to investigate the effects of a 3-year multidomain lifestyle intervention, omega-3 supplementation or both on physical activity (PA) in older adults with subjective memory complaints. Design/settings/subjects: the Multidomain Alzheimer Preventive Trial was a 3-year randomised controlled trial that enroled 1,680 community-dwelling adults aged 70 years or over, with subjective memory complaints. Participants were randomised to omega-3 supplementation (total daily dose of 800 mg docosahexanoic acid and up to 225 mg eicosapentanoic acid), multidomain intervention (nutritional and exercise counselling and cognitive training), omega-3 plus multidomain intervention or placebo with usual care. Methods: PA was assessed using a self-reported questionnaire. From this, global moderate-to-vigorous PA, leisure-time PA, non leisure-time PA and light PA were measured in metabolic equivalent tasks-minutes per week (MET-min/week). Results: in the multidomain groups, participants significantly increased their moderate-to-vigorous and leisure-time PA at 6 months (>=300 MET-min/week for both in the multidomain groups; P <= 0.002) before returning to baseline by the end of the trial. Activity in the placebo/usual care and omega-3/usual care groups declined overtime. Between-group differences remained significant for both multidomain groups for leisure-time physical activity at 2- and 3-year follow-ups. Compared to placebo/usual care, interventions had no significant effects on non-leisure-time PA and light PA. Omega-3 supplementation alone had no effects on PA. Conclusions: a multidomain intervention focused on cognitive training, and nutritional and PA counselling increased PA in the short-term and limited its decline in the long-term among older adults with memory complaints. ClinicalTrials.gov-Registration number: NCT0067268. PMID- 29136095 TI - Left Ventricular Hypertrophy and Coronary Artery Calcifications: A Dangerous Duet? PMID- 29136096 TI - Alcohol Warning Label Awareness and Attention: A Multi-method Study. AB - Aims: Evaluation of alcohol warning labels requires careful consideration ensuring that research captures more than awareness given that labels may not be prominent enough to attract attention. This study investigates attention of current in market alcohol warning labels and examines whether attention can be enhanced through theoretically informed design. Attention scores obtained through self-report methods are compared to objective measures (eye-tracking). Methods: A multi-method experimental design was used delivering four conditions, namely control, colour, size and colour and size. The first study (n = 559) involved a self-report survey to measure attention. The second study (n = 87) utilized eye tracking to measure fixation count and duration and time to first fixation. Analysis of Variance (ANOVA) was utilized. Results: Eye-tracking identified that 60% of participants looked at the current in market alcohol warning label while 81% looked at the optimized design (larger and red). In line with observed attention self-reported attention increased for the optimized design. Conclusions: The current study casts doubt on dominant practices (largely self report), which have been used to evaluate alcohol warning labels. Awareness cannot be used to assess warning label effectiveness in isolation in cases where attention does not occur 100% of the time. Mixed methods permit objective data collection methodologies to be triangulated with surveys to assess warning label effectiveness. Short summary: Attention should be incorporated as a measure in warning label effectiveness evaluations. Colour and size changes to the existing Australian warning labels aided by theoretically informed design increased attention. PMID- 29136097 TI - Nonrandom contribution of left and right testes to germline transmission from mouse spermatogonial stem cells. AB - Vast amounts of sperm are produced from spermatogonial stem cells (SSCs), which continuously undergo self-renewal. We examined the possible effect of laterality in male germline transmission efficiency of SSCs using a spermatogonial transplantation technique. We transplanted the same number of wild-type and Egfp transgenic SSCs in the same or different testes of individual recipient mice and compared the fertility of each type of recipient by natural mating. Transgenic mice were born within 3 months after transplantation regardless of the transplantation pattern. However, transgenic offspring were born at a significantly increased frequency when wild-type and transgenic SSCs were transplanted separately. In addition, this type of recipient sired significantly more litters that consisted exclusively of transgenic mice, which suggested that left and right testes have different time windows for fertilization. Thus, laterality plays an important role in germline transmission patterns from SSCs.